PMID- 8671893 TI - Glomerulosclerosis: intrinsic and extrinsic pathways. PMID- 8671894 TI - Effects of lipoprotein(a) on mesangial cell proliferation and viability. AB - BACKGROUND: Lipoprotein abnormalities are considered to accelerate glomerular injury in various forms of renal disease, probably affecting mesangial proliferation. Serum levels of the atherogenic Lipoprotein(a) (Lp(a)) are elevated in patients with nephrotic syndrome and Lp(a) deposits have been identified in diseased glomeruli. So far, the influence of Lp(a) on mesangial cell function has not been defined. METHODS: The influence of Lp(a) on mesangial cell proliferation was assessed in a rat mesangial cell culture model by direct measurement of cell growth as well as analysis of DNA-synthesis and mRNA levels of c-fos and c-myc, two growth-associated 'immediate early response genes'. Results. Lp(a) triggered a biphasic response on DNA synthesis: 3H-thymidine uptake was increased when cells were incubated with Lp(a) (2.5-10 microg/ml) for 24 h. The response was dose dependent, a maximal effect was seen for Lp(a) 5 microg/ml. The stimulatory properties of Lp(a) were comparable to 10% fetal calf serum (FCS). No additive effect of 10% FCS and Lp(a) on DNA synthesis was observed. Cell proliferation was moderately stimulated (120+/-9% of control) by low levels of Lp(a) in the presence of small amounts of FCS. Messenger RNA levels for c-fos and c-myc were upregulated as early as 15 min after incubation with Lp(a) 5 microg/ml, a maximum response was observed after 20 and 240 min respectively. Stimulation of DNA synthesis was partly blunted when cells were incubated with Lp(a) in the presence of catalase 100 U/ml and superoxide dismutase 10(-7)M (SOD) but not in the presence of SOD alone. Lp(a) in concentrations above 10 microg/ml depressed DNA-synthesis and elicited signs of cytotoxicity. The cytotoxic effects of Lp(a) were not blunted by oxygen radical scavengers. The stimulatory and cytotoxic effects of Lp(a) were not restricted to specific isoform. CONCLUSION: Low concentrations of Lp(a) stimulated growth of mesangial cells, whereas higher concentrations had antiproliferative or toxic effects. The stimulation on mesangial cell proliferation as well as the cytotoxic effects caused by Lp(a) are both likely to have a negative impact on the course of renal disease. PMID- 8671895 TI - Receptors for advance glycation end-products (AGE) - expression by endothelial cells in non-diabetic uraemic patients. AB - BACKGROUND: Cellular actions of advanced glycation end-products (AGE) are mediated by a receptor for AGE (RAGE), a novel integral membrane protein. Immunohistochemical studies show only low-level RAGE antigen expression in endothelial cells. Design. It was the purposes of the study to compare expression of RAGE antigen by endothelial cells in non-diabetic uraemic patients (n=8) with non-uraemic controls (n=11). Samples of arterial tissue were obtained at the time of renal transplantation (in uraemic patients) and abdominal surgery (in controls). RAGE antigen was visualized using guinea-pig anti-RAGE IgG and PAP technique. RESULTS: Marked staining for RAGE was noted in endothelial cells, both arterial endothelium and endothelium of vasa vasorum of normoglycaemic uraemic patients, but was not demonstrable in endothelial cells of large arteries and only faintly expressed in vasa vasorum of non-uraemic individuals. CONCLUSION: Normal endothelial cells do not constitually express RAGE antigen; in contrast it is expressed by arterial and capillary endothelial cells of uraemic patients. The observation is of note in view of the putative role of AGE of causing atherosclerotic and non-atherosclerotic vascular lesions. PMID- 8671896 TI - Clinical features in two patients with IgA glomerulonephritis and thin-basement membrane disease. AB - BACKGROUND: Both IgA glomerulonephritis (IgA gn) and thin basement membrane disease (TBMD) are common forms of glomerulonephritis. Patients with these conditions may present with identical clinical features, but higher urinary RBC counts, heavier proteinuria, and impaired renal function are more common in patients with IgA gn. Because IgA gn and TBMD are common, some patients will have both diseases. SUBJECTS: We describe the clinical features of two individuals with both Iga gn and TBMD, and compare them with the clinical and laboratory characteristics in patients with TBMD (n=15) or IgA gn (n=32) alone. RESULTS: IgA gn was found in two individuals of the 110 with TBMD who were studied. They both had haematuria with >/100 000 RBC/ml and proteinuria >0.2/day (one had more than 1 g/day). These features were more consistent with Iga gn than TBMD alone. However, both individuals had normal serum creatinine and creatinine clearance at presentation. Additional clinical features were macroscopic haematuria in one and hypertension in both. CONCLUSIONS: IgA deposits are not uncommon in patients with TBMD, and these patients have clinical features that resemble those seen in IgA gn rather than TBMD. Patients with both IgA gn and TBMD do not necessarily have the worse prognosis noted in some patients with Iga gn. PMID- 8671897 TI - The renal response to exogenous insulin in non-insulin-dependent diabetes mellitus in relation to blood pressure and cardiovascular hormonal status. AB - BACKGROUND: Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by insulin resistance hyperinsulinaemia and a high frequency of hypertension. It has recently been shown that insulin exerts a sodium-retaining effect, which is preserved in NIDDM: We sought to determine whether insulin affected renal sodium handling differently in hypertensive and normotensive NIDDM patients. METHODS: After a baseline period of 2 h, eight normotensive (N-) NIDDM patients and eight NIDDM patients with hypertension (H-) underwent a euglycaemic clamp with infusion of two sequential doses of insulin (50 and 500 mU/kg/h) or vehicle (time control) during 2-h periods each. Fractional clearances of sodium and lithium were determined according to standard methods. Fractional lithium clearance was used to assess segmental tubular sodium handling. RESULTS: Insulin induced similar decrements in fractional sodium excretion (N-NIDDM: 43+/-5.9 and 57+/-9.1%,H-N IDDM: 48+/-16.4 and 62+/-12.5%, low and high insulin dose respectively). Distal tubular sodium absorption increased simultaneously. A fall in fractional proximal sodium reabsorption was observed in N-NIDDM (4.4+/-2.7 and 29.8+/-5.1%, low and high insulin dose respectively), which was attenuated in H-NIDDM (-5.0+/-7.3 and 2.1+/-13.9% respectively). The latter appeared to be related to a defective atrial natriuretic factor (ANF) and renal cyclic GMP response. A modest decrease in blood pressure occurred during insulin infusion that was not related to changes in ANF or FeLi. CONCLUSIONS: The findings suggest that insulin-induced sodium retention may contribute to hypertension in NIDDM if the homeostatic response to offset this effect fails. PMID- 8671898 TI - Retention of an albumin-bound furan dicarboxylic acid in patients with chronic renal failure or after a kidney transplant. AB - BACKGROUND: 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid (5-propyl FPA) is a furan dicarboxylic acid which accumulates in the plasma of patients with renal impairment. 5-Propyl FPA is an inhibitor of the binding of drugs to albumin and is also implicated in other aspects of the uraemic syndrome. METHODS: Plasma concentrations of propyl FPA have been measured in non-dialysis-dependent, chronic renal failure patients and in renal transplant patients by high performance liquid chromatography. Concentrations of haemoglobin, albumin and creatinine were also determined. RESULTS: There was a positive correlation between serum creatinine and 5-propyl FPA and a negative correlation between haemoglobin concentration and 5-propyl FPA in chronic renal failure patients. There was a negative correlation between 5-propyl FPA and duration of transplant only when the serum creatinine was >200 microM. The mean plasma concentration of 5-propyl FPA in chronic renal failure patients with plasma creatinine CONCLUSIONS: This retention of 5-propyl FPA may therefore reflect a specific tubular defect in renal transplant patients treated with cyclosporin and points to the possibility that 5-propyl FPA may serve as a marker of tubular dysfunction. PMID- 8671899 TI - Cross-linked iron dextran is an efficient oral phosphate binder in the rat. AB - BACKGROUND: There is a need for alternative oral phosphate binders. In-vitro studies showed that iron(III)oxide-hydroxide-modified cross-linked dextran is a promising, insoluble phosphate-binding agent. The present study was designed to assess its in-vivo efficacy and safety in the rat. STUDY, DESIGN AND METHODS: Iron(III)oxide-hydroxide modified dextran beads were mixed with normal rat feed in a proportion of 8% by weight. With this formula rats were fed for 4 weeks. A control group received the same diet without added phosphate binder. Samples of blood, urine, and faeces were taken from each animal before the phosphate binder was administered, 2 weeks later, and at the end of the examination period (day 29). Phosphate, calcium, iron were analysed in the blood samples. Calcium and phosphate concentrations were determined in the urine, phosphate, calcium, and iron concentrations in the excrements. Stability of the material in the duodenum was also simulated. RESULTS AND CONCLUSIONS: The results demonstrate an excellent phosphate-binding capacity of the material and a good tolerance during the intestinal passage. No significant chemical or enzymatic degradation, histological alterations, or other treatment-related macroscopic findings were recorded. The present efficacy and toxicity study has shown effective phosphate binding with no toxicity and no iron release after ingestion of this novel phosphate binding agent. We propose clinical evaluation studies to assess whether similar efficacy and safety can be shown in humans. PMID- 8671900 TI - Renal bone disease in 76 patients with varying degrees of predialysis chronic renal failure: a cross-sectional study. AB - BACKGROUND: Renal osteodystrophy has been studied less extensively in predialysis than in dialysis patients. Different types or histological patterns in their natural evolution from moderate to advanced severity of renal insufficiency are only partially known, with special regard to adynamic bone disease and its relationship with osteomalacia. METHODS: We conducted a cross-sectional retrospective study on 76 unselected patients with chronic renal failure undergoing conservative treatment, with a wide range of severity of renal insufficiency. All the patients were subjected to bone biopsy for histological and histomorphometric evaluation. The patients, 44 males and 32 females ranging in age from 18 to 72 years and with serum creatinine 1.2-11.4 mg/dl, had not been exposed to aluminium-containing drugs and had never been treated with vitamin D or calcitriol. RESULTS: Ten patients had normal bone, nine were diagnosed with adynamic bone disease, 26 with mild mixed osteodystrophy, seven with predominant osteomalacia, 22 with advance mixed osteodystrophy, and two with predominant hyperparathyroidism. Patients with adynamic bone disease had less severe chronic renal failure than the other pathological subgroups, intact PTH above the upper limit of normal, normocalcaemia, and reduced serum osteocalcin in line with a significantly lower ObS/BS. Osteomalacia was found in a more advanced stage of chronic renal failure with relative hypocalcaemia and more severe metabolic acidosis. A creatinine clearance of 20 ml/min served as a clear demarcation between this histological group and adynamic bone disease. CONCLUSIONS: It is postulated that adynamic bone disease is a form of renal osteodystrophy, separate from osteomalacia, appearing when bone resistance to PTH develops, probably a transient stage to more hyperparathyroid histological classes with increasing severity of chronic renal failure. PMID- 8671901 TI - 'Oversaturation' of transferrin after intravenous ferric gluconate (Ferrlecit(R)) in haemodialysis patients. AB - BACKGROUND: Chronic haemodialysis causes blood loss and iron-deficiency. This can be corrected with intravenous preparations, e.g. sodium ferric-gluconate (FeGl). In two patents complaints of hypotension and malaise during FeGl infusion coincided with high levels of serum iron and a calculated transferrin iron saturation above 100%. Iron toxicity could be the cause of these complaints. Free iron is known to aggravate the toxicity of free radicals and other reactive oxygen products that are constantly formed in the body. We compared four rates of FeGl infusion with regard to iron parameters. METHODS: 20 dialysis patients received a total of 26 infusions of FeGl. A rapid infusion of 135 mg (Protocol A (n=10)) or 62.5 mg (Protocol B (n=7)) of FeGl was given during the last 30 min of dialysis. A slow infusion of 125 mg (Protocol C (n=9)) or 62.5 mg (Protocol D (n=10)) was given during 4 or 4.5 h of dialysis. Blood was taken at regular intervals, before, during, and after dialysis for determination of serum iron, transferrin, ferritin, haematocrit, total protein, albumin, and lactate dehydrogenase (LDH). Transferrin saturation was calculated from transferrin and serum iron. RESULTS: With rapid infusion A (125 mg) the highest levels of serum iron (median 120 (range 40-159) micromol/l) and transferrin saturation (207 (84 331)%) were seen at the end of the infusion. These were significantly higher than the peak levels with B, C, and D (P30 nm) or arrangement (FG, random; ITG, focally organized). RESULTS: Proteinuria (FG approximately 100%, ITG approximately 100%), nephrotic syndrome (FG approximately 71%, ITG approximately 82%), haematuria (FG approximately 71%, ITG approximately 64%), hypertension (FG approximately 67%, ITG approximately 45%), and renal insufficiency (FG approximately 54%, ITG approximately 42%) were frequent clinical correlates of both FG and ITG, irrespective of the ultrastructural criteria for diagnosis. Twenty-five patients presenting to our institutions (24 FG, 1 ITG) were divided into three groups based on rate of decline of GFR (mean slope of 1/serum creatinine versus time: group 1 -0. 103+/-0.238; group 2 0.121+/ 0.040; group 3 0.466+/-0.318) in an attempt to identify clinical predictors of progression at presentation. Rapid progressors (Group 3) had an increased incidence of nephrotic syndrome and tended to have higher blood pressure than patients with milder disease, but did not differ from other groups in age, prevalence of haematuria or degree of renal insufficiency. The number of patients requiring dialysis was 0/10 in group 1, 2/6 in group 2, and 2/4 in group 3 over a follw-up period 47+/-46, 55+/-32, and 19+/-19 months respectively; two predialysis deaths being recorded in group 3. Four patients received five renal allografts (one patient being transplanted twice) and were followed for 4-11 years. Whereas recurrence of FG was documented in three allografts undergoing post-transplant biopsy, the rate of deterioration of GFR was invariably slower in allografts than native kidneys (mean slope of 1/Cr versus time: 0.036+/-0.01 versus 0. 0301+/-0.18 respectively). The strength of association between FG-ITG and lymphoproliferative malignancy varied depending on whether patients with monoclonal-gammopathy-associated fibrillary deposits were included or excluded from the analysis. CONCLUSIONS: We contend that patients presenting with Congo red-negative fibrillary deposits on renal biopsy should be evaluated carefully for monoclonal-gammopathy and cryoglobulins, but there is insufficient published data, as yet, to justify subclassification of FG and ITG as distinct clinical entities. Indeed, we argue that it remains to be determined if FG-ITG represents a unique condition or a forme fruste of cryoglobulin- or gammopathy-associated renal disease. Although the optimal treatment for FG-ITG has not been determined, renal transplantation appears an attractive option in patients with end-stage renal failure. PMID- 8671906 TI - Cyst sclerotherapy with minocycline hydrochloride in patients with autosomal dominant polycystic kidney disease. AB - BACKGROUND: The enlarged cysts in autosomal dominant polycystic kidney disease (ADPKD) frequently cause abdominal discomfort. Cyst sclerotherapy with minocycline hydrochloride was performed to relieve this symptom. METHODS: Ten symptomatic ADPKD cases were recruited. As a sclerosant, minocycline hydrochloride solution (10 mg/dl) was used. This solution was instilled into the cysts under ultrasonographic control. Renal volume was calculated before therapy and at 6-month intervals thereafter. Renal function and blood pressure were regularly monitored. The effect of sclerotherapy on symptoms was also assessed at 6-month intervals. RESULTS: At 6 months, renal volume was statistically lower than the presclerotherapy, and was associated with improvement in chronic symptoms. However, such ameliorating effects were blunted at 12 months. Renal volume reduction at 6 and 12 months showed a significant positive correlation with the dose of minocycline injected. No significant influence in renal function and blood pressure was observed. CONCLUSIONS: These results suggest that cyst sclerotherapy with minocycline hydrochloride is a valid treatment regime for the relief of chronic symptoms in ADPKD cases, although repeated application of this approach may be required to obtain a more long-term effect. PMID- 8671907 TI - Brief report: evaluation of the upper gastrointestinal tract in uraemic patients undergoing haemodialysis. AB - PURPOSE OF THE STUDY: This study was performed to determine the gastrointestinal symptoms, and endoscopic and histopathological findings in patients on maintenance haemodialysis. STUDY DESIGN: Nintey-two patients on haemodialysis were enrolled in this study and 100 consecutive dyspeptic patients referred for endoscopy served as controls. They were interviewed to obtain information regarding GI symptoms and endoscopy was performed and biopsies were taken from antral mucosa for histopathological evaluation and helicobacter identification. RESULTS: Prevalence of GI symptoms in the dialysis group was extremely common (77%); with more cases in those with periods of dialysis longer than 6 months. Endoscopically observed of hiatus hernia was present in 27 patients in the dialysis group versus 14 in the control group (P<0.02). Duodenal ulcers were present in three patients of the dialysis group compared with 16 in the control group (P<0.01). Histologically, chronic superficial gastritis and mucosal atrophy tended to be more common in the dialysed patients, but this difference was not statistically significant. Helicobacter pylori were present in 45 patients in the dialysis group versus 73 in the control group (P<0.01). PMID- 8671908 TI - Ranitidine reduces phosphate binding in dialysis patients receiving calcium carbonate. AB - BACKGROUND: In a previous controlled study we showed that ranitidine significantly reduced the phosphate binding of aluminium hydroxide in patients with renal failure, probably increasing intragastric pH. METHODS: In this study we have investigated the effect of ranitidine on the phosphate binding of calcium carbonate in fifteen dialysis patients. Ranitidine 300 mg or a placebo tablet was taken before breakfast for two 4-week periods in a double-blind crossover trial with no washout period. The mean daily dose of calcium carbonate was 2 g and neither the dose nor the patient's diet was changed during the study period. Blood was taken at 2-weekly intervals for serum phosphate, calcium, albumin, and alkaline phosphatase measurements, and at the end of each treatment period for parathyroid hormone (PTH) level. RESULTS: Serum phosphate concentrations were significantly higher during the ranitidine than the placebo phase, 1. 78 (+/-0.43 SD) versus 1.59 (+/-0.49 SD) mmol/l (P<0.001). Serum calcium, albumin, PTH, and alkaline phosphatase concentrations did not differ between the two treatment periods. CONCLUSION: This study shows that ranitidine has a significant adverse effect on the phosphate binding of calcium carbonate in patients with renal failure. PMID- 8671909 TI - Non-Hodgkin lymphoma and glomerulonephritis. What kind of relation? PMID- 8671910 TI - Immunoactoid glomerulopathy in a HIV-infected patient: a novel association. PMID- 8671911 TI - Graves' disease and sarcoidosis in a patient with minimal-change glomerulonephritis. PMID- 8671912 TI - Coexistent membranous nephropathy and ANCA-positive crescentic glomerulonephritis in association with penicillamine. PMID- 8671913 TI - Multiple tubular dysfunction induced by mixed Chinese herbal medicines containing cadmium. PMID- 8671914 TI - Watermelon stomach. An unusual cause of recurrent upper GI tract bleeding in the uraemic patient: efficient treatment with oestrogen-progesterone therapy. PMID- 8671915 TI - Systemic amyloidosis secondary to pyonephrosis. Resolution after nephrectomy. PMID- 8671916 TI - Deep venous thrombosis in haemodialysis patients - a pointer to the presence of malignancy? PMID- 8671917 TI - Relative efficacy of haemoperfusion, haemodialysis and CAPD in the removal of procainamide and NAPA in a patient with severe procainamide toxicity. PMID- 8671918 TI - Acute renal failure in the setting of the neuroleptic malignant syndrome. PMID- 8671919 TI - Self-expanding metallic stent in the treatment of ureteral obstruction after renal transplantation. PMID- 8671920 TI - Nephrectomy and solitary kidney biopsy in a patient with Munchausen's syndrome. PMID- 8671921 TI - Factitious hypertensive crisis (Munchausen syndrome). PMID- 8671922 TI - Coma in a haemodialysed patient. PMID- 8671923 TI - Schizophrenic mood pervasive in American nephrologists. PMID- 8671924 TI - Atrial natriuretic peptide in childhood nephrotic syndrome. PMID- 8671925 TI - High titres of circulating 29-kDa ANCAs in two patients with Wegener's granulomatosis in long-term clinical remission. PMID- 8671926 TI - HIV and IgA nephropathy. PMID- 8671927 TI - Anti-HCV prevalence, viraemic status and genotype distribution in an Italian haemodialysis population. PMID- 8671928 TI - Lp(a) concentration and serum albumin in haemodialysis patients. PMID- 8671929 TI - Can hypertension during erythropoietin be prevented by antiplatelet therapy? PMID- 8671931 TI - Oral vitamin D3 pulse therapy for overt secondary hyperparathyroidism at pre dialysis stage. PMID- 8671932 TI - Placement of central venous catheters by overinsertion of guide wires: low complication rate in 1527 central venous access devices. PMID- 8671933 TI - Interferon-alpha treatment of haemodialysis patients with chronic viral hepatitis and its impact on kidney transplantation. PMID- 8671934 TI - Prospective study of percutaneous jugular vein catheters for long term haemodialysis catheters. PMID- 8671935 TI - Comparison between straight single-cuff and curled double-cuff catheters in patients on continuous ambulatory peritoneal dialysis. PMID- 8671937 TI - Salt sensitivity as a phenotype for genetic studies of human hypertension. PMID- 8671938 TI - Are low osmolality contrast media less nephrotoxic? PMID- 8671939 TI - Ace inhibition in chronic renal failure: a step forward. PMID- 8671940 TI - Advanced glycation end products and beta2-microglobulin. The story unfolds. PMID- 8671941 TI - Glomerular involvement in type II diabetes - is it all diabetic glomerulosclerosis? PMID- 8671942 TI - De novo diabetes in dialysis patients: when diabetes is not diabetic nephropathy. PMID- 8671943 TI - Are cardiac troponins reliable serodiagnositic markers of cardiac ischaemia in end-stage renal disease? PMID- 8671944 TI - Torsade de pointes in haemodialysis patients. PMID- 8671945 TI - Quality of water and dialysate in haemodialysis. PMID- 8671946 TI - Adhesion molecules and the mechanisms of kidney rejection. PMID- 8671947 TI - Immunomodulation by proteolytic enzymes. PMID- 8671948 TI - The management of the failed renal allograft. PMID- 8671949 TI - Cytotoxicity of peritoneal dialysis fluid - is it related to glucose breakdown products? PMID- 8671950 TI - Minisymposium. Ethical issues in nephrology - Jewish perspectives. PMID- 8671951 TI - Minisymposium. Definition of death, organ donation and interruption of treatment of Islam. PMID- 8671952 TI - Minisymposium. Bioethical issues from a Roman Catholic perspective. PMID- 8671953 TI - The history of salt - aspects of interest to the nephrologist. PMID- 8671954 TI - Genetics of human kidney malformations. PMID- 8671955 TI - Nephrology and renal replacement therapy in South Korea: a brief report on the Korean Society of Nephrology and Korean Society of Transplantation. PMID- 8671956 TI - Acceptance for chronic dialysis treatment: insufficient and unequal. AB - BACKGROUND: Evidence suggests that a number of end-stage renal disease (ESRD) patients die without receiving dialysis. We investigated and compared ESRD patients who died without receiving treatment and those who were accepted for dialysis. METHODS: All patients starting chronic dialysis in 1991 in the city of Sao Paulo and prospectively registered in the Health Secretariat files were studied. From death certificates we obtained data from all patients dying with an underlying cause associated with chronic renal failure. Medical records from a sample of patients who died without receiving dialysis were reviewed. RESULTS: Of 2127 patients, 1582 (74.7%) received dialysis and 545 (25.6%) did not. The best chance of being dialysed occurred in the 20-29 age group. The age groups with the least chance of receiving dialysis were 0-9 years and over 79 years old. The odds ratio (95% Cl) of not receiving dialysis was 12.42 (6.63-23.82) times greater for patients over 60 years old compared to those aged 10-19 years. Patients with renal failure due to congenital diseases, chronic pyelonephritis, unknown cause, and hypertension were less likely to receive dialysis than those with glomerulonephritis or diabetes. CONCLUSIONS: Our results suggest that many ESRD patients die without receiving dialysis. Age and cause of renal disease influence the chance of being accepted for treatment. Restrictions of treatment need to be corrected to guarantee that maintenance dialysis will be accessible to ESRD patients. PMID- 8671957 TI - Beneficial effect of proteases on allograft arteriosclerosis in a rat aortic model. AB - Recently it has been shown that protease therapy ameliorates certain immune mediated diseases. Thus we studied the effect of administration of a protease mixture on aortic transplant arteriosclerosis in rats. Segments of abdominal aorta from SHR strain were transplanted orthotopically into WKY recipients. Two groups of allografted rats were used. One group (n = 8) was treated with daily intraperitoneal injections of 12 mg of a protease formulation containing trypsin, bromelain and rutosid, and another group (n = 8) with placebo. Eight WKY rats were transplanted with syngenic aortas and treated with placebo. After 8 weeks, structural changes of the grafted segment were evaluated by morphometric analysis of formalin-fixed sections with specific stains. In untreated allografts there was a marked intimal thickening, medial necrosis with disruption of elastic fibres, and inflammatory infiltrates in the adventitia. Administration of proteases inhibited formation of neointima by 59.0% when cross-sectional areas were compared (80+/-11 versus 195+/-11 microm2, P<0.01; protease-versus placebo treated allograft recipients respectively) and decreased medial injury as estimated by the integrity of elastic fibres and smooth-muscle cell density. Thus, in an experimental model of rat aortic allograft, protease administration ameliorates rejection-induced arterial wall remodelling. PMID- 8671958 TI - Lovastatin inhibits lipopolysaccharide-induced NF-kappaB activation in human mesangial cells. AB - BACKGROUND: HMG-CoA reductase inhibitors have been shown to reduce glomerular injury in different models of progressive renal damage. The transcription factor NF-kappaB plays a major role in the induced expression of genes involved in cellular proliferation and inflammatory responses that could be important in the pathogenesis of glomerular injury. We therefore examined the effects of the HMG CoA reductase inhibitor lovastatin on NFkappaB activation in human mesangial cells. METHODS: Cultured human mesangial cells were stimulated with bacterial lipopolysaccharide (LPS) in the presence or absence of lovastatin. NF-kappaB activity was measured by electrophoretic mobility shift assay (EMSA). RESULTS: LPS-stimulated mesangial cells exhibited an NF-kappaB-like activity as assessed by EMSA competition assays, and supershift assays with antibodies against the p50 and p65 subunits of NF-kappaB. Treatment of mesangial cells with lovstatin in the presence of exogenous cholesterol resulted in a significant reduction of the LPS induced NF-kappaB activity. In the presence of either mevalonate or the mevalonate metabolite farnesyl pyrophosphate, the lovastatin inhibition of NF kappaB activation was substantially reversed, supporting a role for mevalonate metabolites in LPS-induced mesangial cell NF-kappaB activation. CONCLUSIONS: These data suggest an additional mechanism by which HMG-CoA reductase inhibitors may reduce glomerular injury, namely, by inhibiting NF-kappaB activation and the subsequent proliferative and inflammatory responses. PMID- 8671959 TI - Expression of bcl-2 oncoprotein in various types of glomerulonephritis and renal allografts. AB - BACKGROUND: Bcl-2 oncogene was identified as a transcript associated with the t (14;18) and exhibits the unique functional role of blocking apoptosis. Apoptosis as a remodelling mechanism has been reported to embryonic and adult kidney. The aim of this study was to investigate the expression of bcl-2 protein in normal and diseased renal tissue and to define any correlation with the type of renal injury. MATERIALS AND METHODS: Our material comprised of 10 normal adult kidneys, 31 renal allografts with acute (22) and chronic (9) rejection, and 70 renal biopsies with various types of primary (49) (31 proliferative and 18 non proliferative) and secondary (21) glomerulonephritis. The immunohistochemical strept.ABC method was performed on paraffin sections for the detection of bcl-2 protein with a monoclonal antibody after microwave pretreatment. RESULTS: Bcl-2 protein was detected in all the cases of normal and diseased renal tissue, showing an analogous expression. The antigen was expressed in a few parietal epithelial cells, and in the majority of distal and collecting tubular epithelial cells, but not in the glomerular capillary tuft. No difference was found in bcl-2 expression between cases of proliferative and non-proliferative glomerulonephritis as a whole, or between primary and secondary glomerulonephritis. Bcl-2 expression in acute and chronic rejection demonstrated a similar cytoarchitectural expression to the one observed in normal kidneys and glomerulonephritis. Bcl-2 was detected in podocytes near intraglomerular fibrotic lesions and in epithelial cells of early adhesions and cellular crescents, wherever observed in cases of glomerulonephritis. However, bcl-2 expression in proximal tubular epithelial cells was significantly higher in cases of proliferative glomerulonephritis than in non-proliferative glomerulonephritis (P<0.01), while bcl-2 expression in parietal epithelial cells in cases of chronic rejection was higher than in cases of acute rejection (P<0.08). CONCLUSIONS: The absence of bcl-2 expression in normal and diseased glomeruli suggests and supports the reported notion that the mechanism of apoptosis may be available in the injured glomerulus. Moreover, bcl-2 expression in podocytes near intraglomerular fibrotic lesions and in epithelial cells of early adhesions and cellular crescents indicates the deregulation of apoptosis and its possible role in the progression of glomerular scarring. Key words: apoptosis; bcl-2 oncoprotein; glomerulonephritis; immunohistochemical; renal rejection. PMID- 8671960 TI - Effect of ramipril, nifedipine, and moxonidine on glomerular morphology and podocyte structure in experimental renal failure. AB - BACKGROUND: Experimental renal failure causes structural alterations of the kidney. It is still unresolved how these changes are modified by antihypertensive treatment. Purpose of the study. To examine the effects of different antihypertensive agents (ramipril, nifedipine, moxonidine) mainly on glomerular geometry, cell number, cell morphology, and capillarization, in a subtotal nephrectomy model of renal failure. MATERIAL AND METHODS: Sham-operated male SD rats and subtotally nephrectomized (SNX) ad libitum-fed rats were examined. Groups of 8-10 SNX rats were left untreated or were treated with ramipril (0.5 mg/kg b.w. per day), nifedipine (20 mg/kg b.w. per day) or moxonidine (10 mg/kg b.w.per day) respectively. After perfusion fixation the kidneys were examined using stereological techniques. RESULTS: Systolic blood pressure (by tail plethysmography) was 110+/-13 mm Hg in sham-op and 119+/-9 in SNX. It was effectively and comparably reduced below normal values by ramipril (89+/-11 mmHg), nifedipine (98+/-23 mmHg) and moxonidine (92+/-11 mmHg). The glomerulosclerosis index (SI) was significantly increased in SNX versus sham-op; it was similarly decreased by ramipril and moxonidine but less so by nifedipine. Vascular damage (preglomerular vessels) was reduced by all treatments whereas tubulointerstitial damage was signficantly reduced only by ramipril and moxonidine. Mean glomerular tuft volume was increased in SNX compared to sham-op. controls and was normalized only by ramipril treatment. Glomerular cells were differentially affected the three antihypertensive agents. After subtotal nephrectomy an increase in podocyte volume and mesangial cell number per glomerulus was noted. Nifedipine, and to a lesser extent ramipril, prevented mesangial cell hyperplasia. In contrast, only the ACE inhibitor ramipril, but not nifedipine or moxonidine prevented podocyte abnormalities, particularly podocyte hypertrophy. CONCLUSIONS: (i) Despite comparable reduction in systolic blood pressure, different classes of antihypertensive agents had diverse effects on renal damage in subtotally nephrectomized rat. This observation is consistent with specific, non-hemodynamic actions of anti-hypertensives. (ii) Glomerular and tubulointerstitial damage are prevented by treatment with ACE inhibitors and antisympathotonic agents, but not with the calcium antagonist nifedipine. In contrast, renal vascular changes were also prevented by nifedipine. (iii) Only ACE inhibitors effectively inhibited podocyte hypertrophy and mesangial cell hyperplasia. Whether the superior effect of ACE inhibitors on glomerulosclerosis is related to inhibition of glomerular growth and podocyte hypertrophy as well as preservation of podocyte structure, or whether these findings are merely a passive reflection of greater efficacy, remains unresolved. PMID- 8671961 TI - Adriamycin-induced proteinuria in nude mice: an immune-system-mediated toxic effect. AB - BACKGROUND: The renal minimal lesion disease induced in rats by adriamycin (ADR) is generally thought to be consequent to a direct cytotoxic effect of this drug on glomerular epithelial cells. Only recently an altered synthesis of mediators, including reactive oxygen species and monocyte-macrophage cytokines, has been hypothesized. METHODS: A mouse strain (nude) bearing a congenital thymic aplasia is a suitable experimental animal to evaluate the role of immune reactions in the development of the ADR nephropathy, provided mouse susceptibility to its toxic effect. Therefore, experimental mice were divided into three groups (G) each receiving adriamycin 7.5 mg/kg b.w.: GA (15 heterozygous nu/O mice with normal immune system); GB (15 homozygous nu/nu athymic mice); GC (15 homozygous nu/nu mice which were also splenectomized, irradiated, and treated with anti-asialo Gm1 antibody to abolish NK and decrease macrophage activity). All animals were maintained under pathogen-free conditions. Urinary proteins, albumin and TNF alpha excretion were measured. RESULTS: After 14 days the proteinuria was 43.8+/ 1.7 microg/min in GA, 30.2+/-2.9 microg/min in GB (P<0.05) and 12.2+/-2.8 microg/min in GC (GA vs GC, P<0.0001; GB vs GC, P<0.05). Albuminuria gave a similar profile. TNG-alpha urinary excretion was significantly higher in GA (17.3+/-3.2 mU/min) than in GB (5+/-0.6 mU/min, P<0.001) and GC (3.2+/-0.9 mU/min, P<0.001). A significant correlation was found in GA between urinary TNF alpha and protein losses (r2=0.63 P<0.0001). Kidney tissue homogenates failed to show in each experimental group any evidence of mRNA encoding for TNF-alpha, which was detectable in peripheral mononuclear cells from GA and GB, but undetectable in GC mice. Segmental effacements of glomerular epithelial cell foot process were observed by electron-microscopy in GA only, while they were minimal in GB and absent in GC. Iron colloidal staining for anionic sites on frozen sections always showed a normal pattern. CONCLUSIONS: Nude mice bearing cellular immunity deficiency are protected from proteinuria following ADR toxicity. An impaired synthesis and release of lymphomonocyte mediators including TNF-alpha could be envisaged. PMID- 8671962 TI - Angiotensin-II type 1 receptor gene polymorphism and diabetic microangiopathy. AB - BACKGROUND: Genotypic abnormalities of the renin-angiotensin system have been suggested as risk factors for the development of hypertension, diabetic nephropathy and proliferative retinopathy. Most of the known actions of angiotensin-II are exerted through the angiotensin-II type 1 receptor, which is present particularly in vascular smooth muscle cells, myocardium and the kidney. A transversion of adenine to cytosine at nucleotide position 1166 in the gene coding for the angiotensin-II type 1 receptor has been associated with hypertension in the non-diabetic population. METHODS: We studied the relationship between the A1166-->C polymorphism in the angiotensin-II type 1 receptor gene in patients with insulin dependent diabetes mellitus (IDDM) and diabetic nephropathy (121 men, 77 women, age 41 +/- 10 years, diabetes duration 27 +/- 8 years) and in IDDM patients with normoalbuminuria (116 men, 74 women, age 43 +/- 10 years, diabetes duration 27 +/- 8 years). 156 patients (40%) had proliferative retinopathy, 67 patients (17%) had no diabetic retinopathy. RESULTS: There was no difference in genotype distribution between IDDM patients with diabetic nephropathy and normoalbuminuria 103 (52%) / 81 (41%) / 14 (7%) vs. 97 (51%) / 80 (42%) / 13 (7%) had AA/AC/CC genotypes, respectively. The allele frequencies (A/C) in patients with nephropathy (0.73/0.27) and patients with normoalbuminuria (0.72/0.28) were also similar. No difference in genotype distribution between IDDM patients with proliferative retinopathy and without diabetic retinopathy was found either: 77 (50%) / 66 (42%) / 13 (8%) vs. 42 (63%) / 22 (33%) / 3 (4%) had AA/AC/CC genotypes, respectively. CONCLUSIONS: The A1166-->C polymorphism in the angiotensin-II type 1 receptor gene does not contribute to the genetic susceptibility to diabetic nephropathy or proliferative retinopathy in caucasian IDDM patients. PMID- 8671963 TI - Glomerular deposition of the complement C4 isotypes C4A and C4B in glomeruonephritis. AB - BACKGROUND: Complement C4 is a component of the classical complement pathway, which is a major mediator of inflammation in many forms of glomerulonephritis. The two isoforms of C4-C4A and C4B-differ in their physicochemical and functional properties. METHODS: The glomerular deposition of C4A and C4B was investigated in 39 cases of glomerulonephritis with classical pathway activation using isotype specific monoclonal antibodies 99H7 (C4A) and 1288 (C4B) and indirect immunofluorescence. Complement C4 phenotypes of all patients were determined by agarose gel electrophoresis and immunoprecipitation. RESULTS: Three biopsies contained only the isotype C4B. C4 phenotyping revealed complete C4A deficiency in these three patients. Both isotypes C4A and C4B were detected in 36 biopsies. In 19 (53%) thereof staining for both isotypes was identical. In the remaining 17 (47%), staining intensity of C4A predominated over C4B. The distribution of these two staining patterns did not differ between membranous glomerulonephritis and lupus nephritis. They were also independent of C4A and C4B allotypes including the presence or absence of null alleles at either gene locus. In no case was C4B staining stronger than C4A staining. Serum creatinine and proteinuria did not differ between patients with identical and C4A-dominant C4 deposition. CONCLUSIONS: The most likely but still hypothetical explanation for predominance in glomerular deposition of C4A over C4B in many cases of immune complex-mediated glomerulonephritis is the greater affinity of C4A to protein-containing immune complexes as compared to C4B. PMID- 8671964 TI - Glomerular ultrastructure in kidneys transplanted simultaneously with a segmental pancreas to patients with type 1 diabetes. AB - BACKGROUND: Pancreas transplantation has been reported to prevent development and progression of diabetic glomerulopathy. STUDY DESIGN: Kidneys transplanted to type 1 diabetic patients were investigated for signs of diabetic glomerulopathy. Biopsies were obtained from 11 patients 2-4 years after simultaneous pancreas and kidney transplantation and from six patients 2-6 years after kidney transplantation alone. During follow-up, glycaemic control was monitored as glycated haemoglobin and, in the pancreas transplant patients, as i.v. glucose tolerance. RESULTS: Measures of glycaemic control were consistently normal in only two pancreas transplant patients. Four had mean k values <1.0. In kidney biopsies from the pancreas transplant patients, thickness of the glomerular basement membrane was 395 (0.13) nm (mean, coefficient of variation), which is higher than normal (324 (0.13) nm, P=0.01) and not different from diabetic patients with kidney transplants alone, 418 (0.15) nm. The mean calculated annual increase in thickness did not differ between patients with and without a pancreas transplant, 26 (0.77) versus 29 (0.54) nm/year. Estimates of the mesangium and mesangial matrix were in the normal range in both groups while the interstitial volume fraction was increased and to a similar extent. CONCLUSION: The increase in thickness of the glomerular basement membrane in kidneys transplanted simultaneously with a segmental pancreas is probably an expression of diabetic glomerulopathy caused by the modest impairment in glucose metabolism present in most patients. PMID- 8671965 TI - Atrial natriuretic peptide, sodium retention, and proteinuria in nephrotic syndrome. AB - BACKGROUND: Oedema formation in the nephrotic syndrome is primarily due to tubular sodium retention. The pathogenetic role of alpha atrial natriuretic peptide (ANP), a hormonal promoter of natriuresis is unknown. METHODS: In 31 patients (aged 35+/-11 years) with nephrotic syndrome and histopathological evidence of primary glomerulonephritis, we investigated plasma ANP concentration and its influence on renal haemodynamics, natriuresis, and proteinuria (total protein, albumin, IgG excretion). Patients with a compensated treated form of nephrotic syndrome due to primary glomerulonephritis were included in the study. Serum creatinine levels were <=1.4 mg/dl. Diuretic medication was discontinued at least 24 h before the investigation was started. Patients were randomly assigned to ANP infusion (0.005 microg/kg*min; group II, n=15) or received placebo (group III, n=16). Ten healthy subjects (group I) served as normal controls. RESULTS: In normal subjects (group I), ANP caused an increase in natriuresis from 14.5+/-4.2 mmol/h to 26.4+/-11.1 mmol/h (P<0.01). In patients with nephrotic syndrome (group II), baseline sodium excretion of 10.5+/-6.0 mmol/h was increased to 19.6+/-14.8 mmol/h with ANP infusion (P<0.01). No changes were seen in the placebo group III. The absolute increase in ANP induced natriuresis was not significantly different between group I and II. However, plasma ANP levels were significantly higher in patients with nephrotic syndrome (166+/-87 pg/ml vs. 74+/-21 pg/ml, P<0.05) and also reached higher levels after ANP infusion (P<0.01). Therefore, natriuresis was significantly reduced when circulating ANP levels were taken into account (P<0.05). ANP administration resulted in an increase of total protein excretion in patients with the nephrotic syndrome (group II, from 219+/-277 mg/h to 264+/ 268 mg/h). Albumin elimination rose from 128+/-151 mg/h to 167+/-170 mg/h (P<0.05) and IgG excretion from 4.91+/-6.67 mg/h to 9.27+/-10.78 mg/h (P<0.05). Healthy subjects also showed a small but significant increase in albuminuria (48+/-38%, P<0.05). Low-dose ANP infusion did not, however, induce any significant alteration in GFR, ERPF and blood pressure. CONCLUSION: ANP plasma concentrations in the steady state are elevated in patients with the nephrotic syndrome. The natriuretic effect of ANP is reduced when referring to circulating ANP plasma levels. Elevated ANP levels enhance urinary protein excretion in the nephrotic syndrome. This is not due to modulation of GFR or FF, but is most probably attributable to increased glomerular permeability. PMID- 8671966 TI - IgA nephropathy in patients over 50 years of age: a multicentre, prospective study. AB - BACKGROUND: IgA nephropathy (IgAN) is considered as a disease of young men under 30 years of age. Findings on clinical and histological presentation and outcome in older patients have rarely been published. METHODS: In a prospective cohort of IgAN patients, recruited over 3 years, 33 patients over age 50 were compared to 96 patients under age 50, according to clinical and histological findings. Actuarial renal survival rate was studied after a mean post-biopsy follow-up of 41 months. RESULTS: Both groups of patients were comparable at baseline for frequency of proteinuria, microscopic haematuria and gross haematuria, but older patients had a significantly higher incidence of hypertension (65 vs 24%, P<0.01). Time between onset and diagnosis of IgAN was similar in both groups. Proteinuria/day, systolic blood pressure, and serum IgA levels were significantly higher, and Ccr was significantly lower in older patients at the time renal biopsy was performed, but serum creatinine and albumin were not. No difference was observed between the two groups for the presence of glomerular or tubulointerstitial lesions. Only endarteritis was significantly more common in older patients (75 vs 34%, P<0.01). End-stage renal failure (ESRF) was confirmed in five patients over 50 and 17 under 50. Renal actuarial survival curves did not show any significant difference between the two groups, even though the six patients who died were classified as ESRF. CONCLUSIONS: When the histological diagnosis of IgAN was established, factors that carry a poor prognosis, i.e. proteinuria, high blood pressure, and decreased Ccr were more commonly present in patients over 50 than under 50. However, after the completion of a relatively short follow-up period, renal survival was identical in the two study groups. Prolonged follow-up is necessary to confirm this trend. PMID- 8671967 TI - Incidence of analgesic nephropathy among patients undergoing renal replacement therapy in Czech Republic and Slovak Republic. The Group of Czech and Slovak Nephrologists. AB - BACKGROUND: The occurrence of analgesic nephropathy (AN) among renal replacement therapy patients in former Czechoslovakia is not known. Previous surveys were not based on representative samples and lacked uniform criteria for diagnosing the disease. METHODS: Incidence of AN in former Czechoslovakia was investigated in patients commencing renal replacement therapy in 24 (1/3 of all) dialysis centres from 1 January to 31 December 1992. Patients showing an unclear renal diagnosis (n = 149) were investigated with an interview and renal imaging techniques. The diagnosis of AN was withheld or rejected on the base of recently published diagnostic criteria demonstrating that a decreased renal mass of both kidneys combined with bumpy contours and/or papillary calcifications had a high performance for diagnosing AN (Nephrol Dial Transplant 1992; 7: 479-486). RESULTS: Based on the renal imaging criteria, AN was diagnosed in 30 of 328 registered patients, resulting in an AN incidence of 9.1% while the EDTA data only mentioned an incidence of 4.8% (period 1986-1989). The products most commonly abused were analgesic mixtures containing two analgesic substances combined with caffeine and/or codeine. CONCLUSIONS: AN was found to be a common disease in the Czech and Slovak Republics. The disease was diagnosed using reliable renal imaging criteria. PMID- 8671968 TI - Prognostic markers in older patients starting renal replacement therapy. AB - AIMS: We assessed all patients starting renal replacement therapy during a 1-year period to identify factors influencing 1-year survival in older and younger dialysis patients. METHODS: Data was collected from 113 patients. Twenty-four possible prognostic factors were introduced into a multivariate, time-based analysis. RESULTS: Hazard ratios, and hence risk of mortality, were increased with increasing alcohol consumption, cardiac dyskinesis, age at onset of dialysis, serum phosphate, number of comorbid illnesses, and Karnofsky score (listed in decreasing order of risk). Risk of death within 1 year was reduced in patients with normal serum albumin and higher Barthel scores at the time of commencing dialysis. No age interactions were found. In the elderly age group the risk of death was also increased if left ventricular dilatation was present. Comorbidity and the age of onset were not independent risk factors in patients aged over 65 years at the time of starting dialysis. CONCLUSIONS: All factors listed above increase the 1-year mortality of elderly patients. Factors known to increase medium-term morbidity in dialysis patients including diabetes mellitus, ischaemic heart disease, and hypertension do not appear to be important in the short-term survival of older patient on dialysis. PMID- 8671969 TI - Hydrodynamic thrombectomy of haemodialysis grafts and fistulae: results of 51 procedures. AB - PURPOSE: To describe efficacy of hydrodynamic thrombectomy for occluded dialysis native and graft fistulae in 51 instances. MATERIALS AND METHODS: Fifty-one hydrodynamic thrombectomies of 34 native and graft a-v fistulae were performed. There were 32 thrombectomies in PTFE grafts and 19 procedures in native Brescia Cimino fistulae. Multiple thrombectomies were performed in 11 of 34 fistulae. The estimated occlusion time was 36.4+/-22 h. The length of the occluded segment ranged from 2 to 50 cm (mean 28.8 cm). In all cases, a 7 F hydrodynamic thrombectomy catheter was used. Double-cannulation technique was used for graft fistulae, single-cannulation for native fistulae. Additionally, balloon dilatation was performed in all 51 cases, stenting in six, and aspiration thrombectomy in two cases. RESULTS: Arterialized flow was re-established by hydrodynamic thrombectomy and PTA in 43 of 51 cases (84%). By additional use of other techniques, technical success improved to 46 of 51 procedures (90%). Early re-thrombosis occurred in six cases within 24 h of thrombectomy (11%). Clinical success was achieved in 39 of 46 technically successful cases (85%). Cumulative patency was calculated at 63% after 1 week, 57% after 1 month, 48% after 3 months, 37% after 6 months, and 32% after 12 months. Patency of native fistulae after thrombectomy was better than patency of grafts. CONCLUSIONS: Hydrodynamic thrombectomy is an effective percutaneous technique for declotting haemodialysis fistulae and grafts recently thrombosed. PMID- 8671970 TI - Low serum levels of alkaline phosphatase of bone origin: a good marker of adynamic bone disease in haemodialysis patients. AB - BACKGROUND: Adynamic bone disease was recently described to be increasingly prevalent in the dialysis population. At present the diagnosis of this type of renal osteodystrophy can only be made by bone histomorphometry. We assessed the value of different biochemical serum markers in the diagnosis of adynamic bone disease. METHODS: In 103 haemodialysis patients a bone biopsy was performed after double tetracycline labelling, and the serum levels of intact PTH, osteocalcin, and the bone isoenzyme of alkaline phosphatase were determined. Bone alkaline phosphatase was measured by an optimized agarose gel electrophoretic method, recently shown to have a high accuracy, precision and reproducibility, also in the lower range. RESULTS: In 38 (37%) of the patients the diagnosis of adynamic bone disease was histologically established. Constructing receiver operator curves optimal cut-off levels for the diagnosis of adynamic bone disease were determined, being <=27 U/litre for the bone isoenzyme of alkaline phosphatase, <=14 microg/litre for osteocalcin and <=150 pg/ml for intact PTH. Concentrations of bone alkaline phosphatase or intact PTH below these cut-off levels, were shown to be the best performing tests in the detection of adynamic bone disease as indicated by a sensitivity of 78.1 and 80.6% and a specificity of 86.4 and 76.2% respectively. Applying Bayes' theorema, it was calculated that in the current haemodialysis population in which a prevalence of adynamic bone disease up to 35% has been described, the positive predictive values for the proposed cut-off values are 75% for bone alkaline phosphatase, 65% for intact PTH and 55% for osteocalcin. Moreover, in this population, levels of bone alkaline phosphatase and intact PTH below the optimal cut-off excluded hyperparathyroid bone disease. CONCLUSION: In view of the relative easy and accurate methodology for bone alkaline phosphatase determination, the closer physiological link with osteoblast function and the lesser expense for its determination we suggest that this marker is a useful tool in the non-invasive diagnosis of the adynamic type of bone disease in the individual patient. PMID- 8671971 TI - Lymphocyte subsets in dialyser eluates: a new parameter of bioincompatibility? AB - INTRODUCTION: During haemodialysis (HD), several adverse reactions in peripheral blood can occur, which have been attributed to the bioincompatibility of the dialyser membrane. Utilizing a dialyser elution technique, we have demonstrated that polymorphonuclear cells (PMN) manifested non-membrane dependent signs of activation during HD with cellulose triacetate (CTA), cuprammonium (CU) and polysulphone (PS) membranes. In the present study, we employed this elution technique to investigate the influence of HD with these membranes on lymphocytes. METHODS: Eight patients were studied during HD with CTA, CU, and PS dialysers in a randomized crossover design. Dialyser elution was performed after 3 h of HD. Besides total leukocyte count and differentiation, lymphocyte subpopulations and activation status in peripheral blood and dialyser eluates were analysed by flow cytometry. RESULTS: Only with CU was a significant leukocyte decrease observed in peripheral blood at 30 min (P<0.001). Neither the total number of lymphocytes nor the proportion of T(CD3+) and B(CD19+) cells had markedly changed after HD with either membrane. Meanwhile, all membranes induced a relative decline in natural killer cells -NK(CD3-/CD16+/56+)- at the end of dialysis, although this was only significant for CTA (P=0.04). As for the T-lymphocyte subsets, the proportion of CD4+ cells had markedly increased after three hours of HD with all three dialysers, CTA and PS being significant (P<0.05). Dialyser eluates contained 33.8 82.2 x 10(6) cells, CTA yielding the highest cell counts. The majority (81-91%) of the eluted cells consisted of PMN dialyser eluates versus peripheral blood: P<0.05), whereas only few lymphocytes were found (4-13%, absolute 2.6 x 10(6)). Lymphocyte subpopulations in dialyser eluates were comparable to peripheral blood at t 180 in case of CTA and CU. In contrast PS eluates contained significantly fewer T-cells (37%), but more B-cells (22%) and NK-cells (30%) in comparison with peripheral blood at 180 min (peripheral blood: 79, 6 and 16% respectively; P<0.05). The expression of activation markers on T-cells (HLA-DR, CD25) in dialyser eluates was comparable with peripheral blood. Conclusions. The absolute number of lymphocytes in dialyser eluates of CTA, CU, and PS dialysers was low (mean 2.6 x 10(6)) in comparison with peripheral blood (mean 1.4 x 10(9)/l). Whereas non-selective adhesion occurred in CU and CTA dialysers, a selective adhesion pattern of lymphocyte subpopulations was observed in case of PS, suggesting a difference in bioincompatibility. Apparent T-cell activation was not noted, either in peripheral blood or in dialyser eluates. Because PMN in the dialyser eluates of three different membranes showed similar activation patterns in a previous study, we hypothesize that eluted lymphocyte, rather than PMN, represent a preferable parameter of bioincompatibility. PMID- 8671972 TI - Regular low-dose intravenous iron therapy improves response to erythropoietin in haemodialysis patients. AB - BACKGROUND: Erythropoietin (Epo) is an effective but expensive treatment for anaemia in patients with chronic renal failure. Hyporesponsiveness to Epo, particularly in haemodialysis patients, is most commonly due to a functional iron deficiency, which is difficult to monitor reliably. METHODS: Forty-six stable haemodialysis patients, receiving Epo therapy, were commenced on regular low-dose intravenous iron (sodium ferric gluconate complex) at a dose of 62.5 mg/5 ml given as a slow injection post-dialysis twice weekly, weekly, or fortnightly, according to their serum ferritin levels. Haemoglobin, serum ferritin, Epo dose, and iron dose were measured at 6-weekly intervals over a 6-month period. RESULTS: At the beginning of the study, 12 patients in the group had ferritin levels of less than 100 microg/l, and were thus considered to potentially have an absolute iron deficiency. The study group was therefore split into two subgroups for the purpose of analysis, i.e. the 12 patients with ferritin levels of less than 100 microg/l at the start of the study or 'low ferritin group', and the remaining 34 patients with ferritin levels of greater than 100 microg/l at the start of the study or 'normal ferritin group'. In the low ferritin group (n=12), intravenous iron therapy increased serum ferritin levels, and produced a significant rise in haemoglobin, and a significant reduction in Epo dose. (Ferritin pre-iron, median (range) 68 (20-96) microg/l; post-iron, 210.5 (91-447) microg/l, P<0. 003, Wilcoxon. Haemoglobin pre-iron, 10.05 (8.2-11.9) g/dl; post-iron, 11.0 (9.9-11.9) g/dl, P<0.03. Epo dose pre-iron, 9000 (4000-30 000)-i.u./week, P<0.05). Similar results were obtained in the normal ferritin group (n=34) following intravenous iron therapy, with significant increases in serum ferritin levels and haemoglobin concentrations, and a significant reduction in Epo dose. (Ferritin pre-iron, 176 (103-519) microg/l; post-iron, 304.5 (121-792) microg/l, P<0.0001. Haemoglobin pre-iron, 9.85 (6.5-12.8) g/dl; post-iron: 11.25 (9.9-13.3) g/dl, P<0.0001. Epo dose pre-iron, 6000 (2000-15 000) i.u./week; post-iron, 4000 (0-15 000) i.u./week, P<0. 005). CONCLUSION: Regular intravenous iron supplementation in haemodialysis patients improves the response to Epo therapy. PMID- 8671973 TI - On-line urea kinetics in haemodiafiltration. AB - BACKGROUND: Calculation of Kt/V and assessment of nutrition have so far been dependent upon off-line urea measurements of blood or dialysate samples. Here we describe a biosensor for on-line urea measurement during haemodiafiltration. Methods. The biosensor consisted of a cartridge containing covalently linked urease placed between two conductivity cells. The biosensor was placed on the outlet line of a haemofilter in series with a dialyser in order to obtain an aliquot of plasma ultrafiltrate for on-line measurement of urea. RESULTS: Urea nitrogen concentrations were highly correlated to the difference (Delta) in conductivity measured by the two conductivity cells both in aqueous solutions (in vitro studies, y=-6. 676+32.12x, R2=0.998, P<0.0001) and in ultrafiltrates (ex vivo studies, y=-637+32.01x, R2=0.98, P<0.00001). Delta conductivity was highly reproducible (% variation: ).8-5.3%) and stable (maximal % variation at 150 mg/dl after 100 min. 0.9+/-0.3 vs initial values). The intradialytic plasma water urea profile was obtained in 10 haemodialysis patients. To study recirculation, the plasma water urea profile was analysed before and 3 min after stopping the dialysate flow. The pre- and post-stopped flow ratio (1.21+/-0.1, mean+/-1 SD) was superimposable to conventional blood sampling data (opposite arm venous arterial: 1.22+/-0.11) and allowed correction for recirculation. A novel approach to urea kinetic modelling was described and used to reliably project end-dialysis and post-dialysis rebound urea concentration as early as 90 min. Projected (29.2+/-10.4 g) or measured (29.8+/-10.5 g) net urea removal was highly correlated with the amount of urea collected in the total spent dialysate (29.7+/ 10.6 g) (R2=0.99, R2=0.97 respectively). CONCLUSIONS: These results indicate that on-line, real-time analysis of urea kinetics may provide information on delivery of adequate dialysis in high-efficiency techniques. PMID- 8671974 TI - Hepatitis E virus (HEV) infection in haemodialysis patients. The Multicentre Haemodialysis Cohort Study on Viral Hepatitis. AB - BACKGROUND: The aim of this study was to determine the prevalence of hepatitis E virus (HEV) infection among patients undergoing haemodialysis (HD) and to evaluate whether chronic haemodialysis is associated with an increased risk of HEV infection. METHODS: Serum samples from 420 HD patients and 316 healthy volunteers were tested for IgG and IgM antibodies to HEV (anti-HEV). Anti-HEV IgG positive sera were confirmed using synthetic peptides. RESULTS: Anti-HEV IgG was confirmed in 27/420 (6.4%) of the HD patients and in 7/316 (2. 2%) of the reference group (P=0.07). However, multiple logistic regression analysis showed that the prevalence of anti-HEV IgG was not significantly higher in HD patients compared with the reference group, after controlling for age and sex. No patient was found positive for anti-HEV IgM. The presence of anti-HEV was associated with sex in HD patients (P=0.04). No significant association was found between anti HEV and underlying renal disease, anti-HCV, anti-HBc, blood transfusions, history of elevated transaminases, history of clinical hepatitis and renal transplantation. A marginal association, which was observed with the duration of haemodialysis in univariate analysis (P=0.07), was not confirmed in multivariate analysis. CONCLUSIONS: Chronic haemodialysis is not associated with an increased risk of exposure to HEV, and the high prevalence of anti-HEV IgG in HD patients reported in uncontrolled studies is possibly due to the confounding effect of age and sex. PMID- 8671975 TI - Increased urinary excretion of monocyte chemoattractant protein-1 during acute renal allograft rejection. AB - BACKGROUND: Acute rejection is characterized histologically by infiltration of the interstitium by mononuclear cells. Monocyte chemoattractant protein 1 (MCP-1) has recently been identified as a monocyte chemotactic factor. This study examined the possible role of MCP-1 in renal transplantation. METHODS: The concentration of MCP-1 in urine and serum of 19 renal transplant patients was investigated using an inhibition radioimmunoassay. The patients were divided into a non-rejection (NRj) and a rejection (Rj) group. Normal healthy volunteers were included as controls. Immunoperoxidase staining for MCP-1 and CD14, as a marker for macrophages, was performed in renal biopsies of transplant patients with rejection and six biopsies from histologically normal kidneys, as controls. The size of urinary MCP-1 was determined by gel filtration chromatography and in a number of fractions assessed for monocyte chemotactic activity using a modified Boyden chamber assay. RESULTS: Urinary excretion of MCP-1 in the Rj group ranged between 250 ng/mmol Cr and 3148 ng/mmol Cr with a median of 612 ng/mmol Cr. This is significantly higher than the results in the NRj group, ranging between 47 ng/mmol Cr and 288 ng/mmol Cr with a median of 229 ng/mmol Cr. In the normal control group, urinary MCP-1 levels ranged between 38 ng/mmol Cr and 74 ng/mmol Cr with a median of 50 ng/mmol Cr. The fractional excretion of MCP-1, calculated on the basis of MCP-1 and creatinine clearances, was found also to be significantly higher in the Rj group as compared to the NRj group. However, there was no significant difference in the serum levels of MCP-1 between the Rj, NRj, and normal control group. The intensity of MCP-1 staining in tubular epithelial cells and the degree of CD14+ cells in the interstitium was significantly higher in renal allograft biopsies than in the normal kidneys. In addition, MCP-1 isolated from urine of renal transplant patients with rejection was filtered with apparent molecular weight of 13 kDa and 11 kDa. Both sizes are chemotactically active for monocytes. CONCLUSIONS: These data suggest that urinary excretion of MCP-1 can be used as a marker for the episodes of acute rejection. The increase of urinary excretion of MCP-1 most likely is the result of local production by tubular epithelia cells. MCP-1 produced locally may, at least in part, be responsible for the influx of macrophages into the interstitium during rejection. PMID- 8671976 TI - Impaired outcome of continuous ambulatory peritoneal dialysis in immunosuppressed patients. AB - BACKGROUND: Although immunodeficiency predisposes to CAPD peritonitis with fungal or unusual organisms, the role of immunosuppression as a predisposing factor for CAPD peritonitis, as well as the outcome of such episodes, remains uncertain. METHODS: The incidence, spectrum of infectious organisms, and outcome of CAPD peritonitis was retrospectively reviewed in 39 immunosuppressed and 146 non immunosuppressed patients treated with CAPD over the calendar year 1993. RESULTS: Immunosuppressed patients were younger (mean 44 vs 57 years, P<0.001) and had an increased incidence of previous transplantation, glomerulonephritis, systemic lupus erythematosus, and vasculitis. Immunosuppressed patients had more episodes of peritonitis (69/29 patients vs 99/147, P<0.001), required more frequent hospital admission (25/39 vs 33/146, P<0.001), had more days off CAPD (331 vs 242, P<0.001), and required more laparotomies to remove infected CAPD catheters (11/39 vs 14/146, P<0. 01). Immunosuppression was associated with increased infection due to S.aureus and fungi, which may have contributed towards increased morbidity in this group. Current immunosuppression or a recent history of immunosuppression appeared to be equally potent risk factors for infection. There was a trend for the incidence of infection to parallel the aggressiveness of immunosuppression. CONCLUSIONS: Immunosuppression is an important risk factor for CAPD peritonitis. A high index of suspicion for infection and aggressive chemotherapy are mandatory. CAPD may not be the initial therapy of choice in this high-risk group. PMID- 8671977 TI - Prevalence and risk factors for hepatitis C virus infection in continuous ambulatory peritoneal dialysis patients. AB - BACKGROUND: Studies on hepatitis C virus antibodies (Anti-HCV) in CAPD patients are scarce and include a small number of patients. Nevertheless, risk factors related to Anti-HCV in these patients are still subject to controversy. Purpose of the study. To analyse the incidence and risk factors associated with the presence of Anti-HCV in CAPD patients. METHODS: We studied 255 patients from five different treatment centres of our region. The analysis was repeated after excluding 161 patients who had previously received haemodialysis treatment at least once. Anti-HCV testing was made by the 2nd-generation ELISA: As a supplementary test we used RIBA-4 in three centers and INNOLIA in the other two. Risk factors were analysed using logistic regression model for multivariate analysis. RESULTS: In the whole group, 29 patients (11.4%) were anti-HCV positive. Logistic regression analysis determined the following variables as independent risk factors: hepatitis previous to CAPD (P<0.001, odds ratio (OR):44.9), Anti HBc positivity (P=0.019, OR:9. 24), blood transfusions previous to CAPD (P=0.015, OR:1.05) and CAPD duration were excluded, the prevalence of HCV antibodies was 8.5% (8/94). In this group multivariate analysis showed that Anti HCV positivity correlated with hepatitis previous to CAPD (P<0.0003, OR: 126) and Anti HBc positivity (P=0.002, OR:41.9). CONCLUSIONS: Our prevalence of hepatitis C virus (HCV) infection in CAPD patients was lower than other renal replacement therapy modalities, and correlated to events occurring mainly before starting CAPD treatment. This technique could be considered as low risk for HCV infection. PMID- 8671978 TI - Effect of electric charge on the transperitoneal transport of plasma proteins during CAPD. AB - BACKGROUND: Controversy exists as to whether electric charges of plasma proteins influence their transport across the peritoneal membrane during CAPD. Fixed negative charges in the peritoneal membrane are diminished during peritonitis in rats. METHODS: Peritoneal clearances of 10 proteins and their isoforms were used to establish the relationship between peritoneal clearance and molecular weight. The observed protein clearances were compared with the predicted clearances based on molecular weight. Clearances of proteins with different charge but identical size were compared. Stable patients and peritonitis patients were compared. Results. Only the peritoneal clearance of lipase, LDH 4/5 and IgG3 were significantly different from the predicted values (P<=0.05). The peritoneal clearance of slightly anionic beta2 microglobulin (1072 microl/min) and cationic lysozyme (572 microl/min) showed no evidence for charge selectivity; neither did the peritoneal clearance of slightly anionic transferrin (86 microl/min) and highly anionic albumin (99 microl/min). The peritoneal clearance of IgG1, IgG2 and IgG4 were identical (32, 31 and 31 microl/min), despite their different charge. The peritoneal clearance of cationic LDH 4/5 was 137 microl/min and higher than the peritoneal clearance of neutral LDH 3 (97 microl/min, P=0.01) and LDH 1 (59 microl/min, P=0. 02). These results suggested charge selectivity; however in five additional patients during peritonitis the peritoneal clearance of LDH 4/5 increased to 10 times the peritoneal clearance of LDH 1. Local LDH isoenzyme release from the cells present in the dialysate was shown to be responsible in stable and peritonitis patients. Likewise, the higher peritoneal clearance of neutral pancreatic amylase (234 microl/min) compared to anionic salivary amylase (142 microl/min, P=0.03) could probably be attributed to local release of the former from the pancreas, as the peritoneal clearance of lipase (highly anionic) was higher than predicted and the difference remained during peritonitis. CONCLUSIONS: The peritoneal membrane constitutes a size- but probably not a charge-selective barrier for the transport of macromolecules between blood and dialysate during stable CAPD. PMID- 8671979 TI - Etoposide: more effective and less bone-marrow toxic than standard immunosuppressive therapy in systemic vasculitis? AB - In two patients suffering from ANCA-positive systemic vasculitis (one from Wegener's granulomatosis, the other from microscopic polyangiitis), who were both resistant to or could not tolerate standard immunosuppressive therapy, complete clinical and biochemical remission was obtained within few months, treating with cyclic etoposide. Etoposide therapy was found to be significantly less bone marrow toxic than standard immunosuppressive therapy. PMID- 8671980 TI - The impact of diabetes on patients' survival in dialysis patients with non diabetic renal disease and in patients who develop diabetes during chronic dialysis. AB - BACKGROUND: It is well known that dialysis patients with diabetic nephropathy have a poor prognosis, but data concerning the survival of dialysis patients with diabetes plus a non-diabetic primary nephropathy or the survival of patients who develop diabetes after the start of regular dialysis are scarce. AIM AND METHODS: We reviewed the survival of two cohorts of dialysis patients in whom diabetes mellitus was associated with non-diabetic primary nephropathy. In the first cohort (18 patients with a primary diagnosis of APKD) diabetes mellitus precede hyperazotaemia, whilst the second cohort of 34 patients developed diabetes after the start of regular dialysis. We compared the survival of each group of patients to the survival of a group of dialysis patients with a primary diagnosis of diabetic nephropathy, and to the survival of each control group of non-diabetic dialysis patients. Within each case series, groups were similar according to age at start of RRT, and place of treatment. All patients were selected among those alive in treatment at 31 December 1986 and were followed up to 31 December 1991. RESULTS: In both case series the survival of patients with diabetes was similar irrespective of the primary diagnosis (Lee-Desu statistics: first cohort P=0.43; second cohort, P=0.08). Moreover, the survival of patients either with diabetic nephropathy or with diabetes in association with non-diabetic primary nephropathy was significantly worse compared to the survival of the non-diabetic patients (Lee-Desu statistics: first case series P=0.02 and P<0.01; second case series P<0.05 and P<0.01). Logistic regression showed that survival was negatively associated to diabetes and age but not to sex, duration of diabetes and diagnosis of diabetic nephropathy. CONCLUSIONS: Our limited data show that the survival of diabetic patients on regular dialysis is poor, irrespective of the primary cause of renal failure and of the duration of diabetes. These data need confirmation and further study. PMID- 8671981 TI - Membranous nephropathy: recurrence after kidney transplantation. AB - BACKGROUND: It is supposed that about 5% of dialysis patients had membranous nephropathy as a cause for their renal failure. Despite of this prevalence, only 33 cases of recurrent membranous nephropathy after kidney transplantation have been reported in the English literature. METHODS: Among 509 recipients of renal allografts, membranous glomerulonephritis was the cause of renal failure in five patients, who received six transplants. RESULTS: Recurrence of the disease was observed in three allografts (50%) in three patients, all of them were on treatment with cyclosporin and low-dose prednisone. Proteinuria appeared at 2, 5 and 19 months after grafting. One patient experienced a spontaneous remission after 12 months and he is free from proteinuria and with good renal function after 5 years. The remaining two patients presented progressive renal function deterioration and returned to haemodialysis 24 and 17 months after th appearance of proteinuria. In these patients increasing the immunosuppression did not produce any beneficial effect. One of those patients underwent a second transplant; recurrence of the membranous nephropathy has not been observed after 3 years of follow-up. CONCLUSIONS: In this study three new cases of recurrence of membranous nephropathy are reported. One patient experienced a spontaneous remission of proteinuria. Recurrence of membranous nephropathy in renal allograft was very high in our series. Its appearance was associated with poor prognosis of the graft in most patients, although spontaneous remission of proteinuria is possible. PMID- 8671982 TI - Nocardiosis in renal transplant recipients in Kuwait. AB - BACKGROUND: Nocardiosis has emerged as an important bacterial disease among renal transplant recipients, leading to considerable morbidity and mortality. Apart from the increasing problem of resistance in pathogenic nocardiae, the spectrum of species causing disease has enlarged in recent years. There are no published reports on nocardiosis from Middle-East countries. METHODS: A retrospective review of case records of 513 renal transplant recipients between January 1989 and January 1995 was done in the transplant unit of our hospital. Information was collected on clinical details, type of donor, immunosuppressive therapy, prophylaxis, and outcome. Isolation of Nocardia species from appropriate clinical specimens was the sole criterion for diagnosis. RESULTS: Nocardiosis was diagnosed in six recipients with a disease incidence of 1.2%. Four patients had received unrelated kidneys. Co-morbid conditions were diabetes mellitus (3), viral hepatitis (2) and neutropenia (1). Clinical manifestations included deep seated skin abscesses and pulmonary disease in three each. Cerebral abscess and meningitis were found in two patients with pulmonary disease. Pathogens were Nocardia asteroides in four and N. otiti discaviarum and N. farcinica in one each. In contrast to in vitro susceptibility results, clinical response was different in that five patients who received trimethoprim-sulphamethoxazole (TMP SMX) alone (2) or in combination with cefuroxime (3) responded well. CONCLUSIONS: The study stresses a high index of suspicion for nocardiosis in susceptible hosts who present with cutaneous abscess, pulmonary infiltrative lesions, and cerebral manifestations. TMP-SMX in combination with cefuroxime seems to be a highly effective therapy. It does not appear mandatory to reduce or discontinue immunosuppressive therapy during treatment of nocardiosis. PMID- 8671983 TI - Acute renal failure in the neonate induced by the administration of indomethacin as a tocolytic agent. PMID- 8671984 TI - Caroli's syndrome associated with medullary sponge kidney and nephrocalcinosis. PMID- 8671985 TI - Distal renal tubular acidosis associated with non-autoimmune hypothyroidism. PMID- 8671986 TI - Pulmonary haemorrhage in association with IgA nephropathy. PMID- 8671987 TI - Ear buzzing and lumbar pain revealing a late arteriovenous fistula of the kidney. PMID- 8671988 TI - Torsades de pointes during low-dosage sotalol therapy in haemodialysis patients. PMID- 8671989 TI - Peritoneal leak and chronic pericardial effusion in a CAPD patient. PMID- 8671990 TI - Cyclosporin-induced trichomegaly of accessory lashes as a cause of ocular irritation. PMID- 8671991 TI - Kaposi sarcoma in a paediatric renal transplant recipient. PMID- 8671992 TI - Epstein-Barr-virus-associated post-transplant B-cell lymphoma presenting as allograft artery stenosis. PMID- 8671993 TI - HCV-associated cryoglobulinaemia presenting with vasculitis, hepatitis, and glomerulonephritis - a therapeutic dilemma. PMID- 8671994 TI - Renal involvement in ankylosing spondylitis (Bechterew's disease) PMID- 8671995 TI - Therapeutic approach to organ transplantation. PMID- 8671996 TI - Hypocitraturia and Ureaplasma urealyticum urinary tract infection in patients with idiopathic calcium nephrolithiasis. PMID- 8671997 TI - DFO low-dose therapy. PMID- 8671999 TI - Beta-microglobulin modified with advanced glycation end-products induces monocyte chemotaxis in vivo. PMID- 8672000 TI - Is treatment with interferon-alpha in renal transplant recipients still justified? PMID- 8672003 TI - Kidney graft dysfunction after drug interaction between clarithromycin and cyclosporin. PMID- 8672004 TI - Procollagen type I (PICP) in CAPD patients. PMID- 8672006 TI - Effects of agmatine, an active metabolite of arginine metabolism, on the kidney. PMID- 8672007 TI - Central role for nucleosomes in lupus. PMID- 8672008 TI - Urinary kidney stone inhibitors. Where are we? PMID- 8672009 TI - Does it make sense to administer albumin to the patient with nephrotic oedema? PMID- 8672010 TI - Spiral CT angiography--can we forget about arteriography to diagnose renal artery stenosis? PMID- 8672011 TI - Trace elements in renal failure: are they clinically important? PMID- 8672012 TI - Subarachnoid haemorrhage in ADPKD patients: how to recognize and how to manage? PMID- 8672013 TI - Reduced cardiac ischaemia tolerance in uraemia - what is the role of structural abnormalities of the heart? PMID- 8672014 TI - How 'dry' must the septic patient be kept - potentially conflicting interests of lung and peripheral circulation? PMID- 8672015 TI - Bacterial infections during immunosuppression - immunosuppressive agents interfere not only with immune response, but also with polymorphonuclear cell function. PMID- 8672016 TI - Reverse transcription polymerase chain reaction for cytokines in the mixed lymphocyte culture. Is there a role in renal transplantation? PMID- 8672017 TI - Is there a link between erythropoietin therapy and adynamic bone disease? PMID- 8672018 TI - Does continuous renal replacement therapy favourably influence the outcome of the patients? AB - Continuous haemodialysis and continuous haemofiltration are efficient and safe techniques for the treatment of acute renal failure. Theoretical advantages are improved haemodynamic stability and easier fluid removal. All 15 available studies comparing intermittent (522 patients) with continuous (651 patients) renal replacement therapy have been reviewed. From these studies it cannot be established, whether the use of a continuous instead of an intermittent treatment modality improves the outcome in patients with acute renal failure. Reviewing all 67 published studies dealing with continuous renal replacement therapy revealed a trend to a decreasing mortality rate (P<0.08) over the last 11 years, whereas the mean age and the severity of illness of the patients, measured by the APACHE II score, did not change, In order to establish whether the quality of treatment has improved as a function of time, two quality factors (QF) were created, i.e. QF for age (mean age/mean mortality rate of the patients treated) and QF for severity of diseases (mean APACHE II/mean mortality rate). Both QF improved from 1984 until 1994, when analyzed for continuous (P<0.001) or intermittent (P<0.001) treatment modality. Thus the quality of treatment of patients with acute renal failure improved during the last decade. However, there is no evidence with respect to survival rate that a continuous renal replacement therapy is superior to an intermittent one. PMID- 8672019 TI - Glomerular basement membrane thickness - a comparison of two methods of measurement in patients with unexplained haematuria. AB - BACKGROUND: Thin glomerular basement membranes may be an important cause of microscopic haematuria. Unfortunately measurements are often not made because of the complicated methods currently employed. METHODS: A simplified method of measurement of glomerular basement membrane thickness, involving only 16 selected measurements on a single glomerulus, was compared with the accepted, but time consuming, orthogonal intercept technique. Thirty-one needle biopsies from patients with renal haematuria unexplained by conventional histology and immunofluorescence were studied. Measurements were made on the same ultrathin sections. RESULTS: The new method was found to give much lower values (mean (SD) 202+/-51 versus 282+/-52 nm) with limits of agreement of -131 to -30 nm compared with the orthogonal intercept method. The coefficient of repeatability was 39 nm for the orthogonal intercept method and 56 nm for the new method. However, using two glomeruli the new method had limits of agreement of -120 to -41 nm with a coefficient of repeatability of 38 nm. CONCLUSIONS: Provided two glomeruli are measured the new technique is sufficiently accurate for the diagnosis of thin membrane nephrology, in appropriate cases, and is much simpler and cheaper than the orthogonal intercept method. PMID- 8672020 TI - Malignant hypertension in children in India. AB - BACKGROUND: Malignant hypertension is now an uncommon entity in the western world but still remains a significant problem in India. Therefore we studied the aetiological spectrum, management, and outcome of these patients. METHODS: Forty consecutive children (<16 years) with malignant hypertension were admitted and investigated to exclude or confirm the secondary causes of hypertension. For acute control of blood pressure sublingual nifedipine was used in dosage of 0.3 0.6 mg/kg, failing which intravenous nitroglycerin was used. In patients with aortoarteritis with active disease, steroids were used. Angioplasty was carried out for renal artery stenosis whenever possible. RESULTS: Renoparenchymal disease was the commonest cause of malignant hypertension, and was seen in 25 cases, renovascular hypertension in 13 cases (11 aortoarteritis and two fibromuscular dysplasia) and two had essential hypertension. For acute control of severe hypertension, sublingual nifedipine was effective in 92.5% of patients. Of the patients with renoparenchymal disease five became normotensive with treatment of the underlying disease, four received renal allograft, seven died, and nine are stable on antihypertensive drugs. Renal angioplasty was carried out in seven patients with renovascular hypertension (4 cured, 3 improved) and six are controlled on drugs. CONCLUSIONS: We conclude that apart from renoparenchymal disease, aortoarteritis is a common cause of malignant hypertension in children. Sublingual nifedipine is effective for the rapid control of severe hypertension, and angioplasty is effective in aortoarteritis for short-term preservation of renal function and control of hypertension. PMID- 8672021 TI - Increased serum concentrations of pro-gastrin-releasing peptide in patients with renal dysfunction. AB - BACKGROUND: Gastrin-releasing peptide has a prominent role as a tumour marker in the diagnosis of small-cell lung carcinoma. This study was designed to assess the validity of a newly developed enzyme-linked immunosorbent assay (ELISA) for pro gastrin-releasing peptide in patients with renal and systemic diseases. METHODS: Pro-gastrin-releasing peptide concentrations in sera from normal subjects and patients with small-cell lung carcinoma, diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, chronic glomerulonephritis, or undialysed or dialysed chronic renal failure were measured with the TND-4 Kit, a newly developed ELISA for pro-gastrin-releasing peptide. RESULTS: All of the patients with normal renal function, whether they had diabetes mellitus (n=16), rheumatoid arthritis (n=10), systemic lupus erythematosus (n=12) or chronic glomerulonephritis (n=14), had serum pro-gastrin-releasing peptide concentrations less than 46 ng/l, the upper limit in normal subjects. In contrast, 14 or 16 patients (88%) with small-cell lung carcinoma, who had normal renal function, and 25 of 26 (96%) patients with chronic renal failure on haemodialysis had serum pro gastrin-releasing peptide concentrations greater than 46 ng/l. The highest serum pro-gastrin-releasing peptide levels in patients with chronic renal failure, before and after initiating haemodialysis were 183 and 290 ng/l respectively. Ten of 16 (63%) small-cell lung carcinoma patients had serum pro-gastrin-releasing peptide concentrations greater than 290 ng/l, the highest level in haemodialysed patients. Serum pro-gastrin-releasing peptide concentrations were also elevated in patients with chronic glomerulonephritis or diabetes mellitus when their serum creatinine concentrations were greater than 120 micromol/l. And, there was a significant correlation, y=23.5+0.15x(n=22, r=0.82, P<0.001),between serum pro gastrin-releasing peptide (y, in ng/l) and serum creatine (x in micromol/l) concentrations in those patients with renal dysfunction. The correlation between serum pro-gastrin-releasing peptide and serum urea nitrogen concentrations was likewise significant. CONCLUSIONS: The evaluation of patients as to their renal functional state may be mandatory when serum pro-gastrin-releasing peptide levels are to be applied as one of the diagnostic tools for small-cell lung carcinoma or as a marker monitoring their clinical course. PMID- 8672022 TI - Complications of autosomal dominant polycystic kidney disease in 50 haemodialysed patients. A case-control study. The U.C.L. Collaborative Group. AB - BACKGROUND: The impact of renal and extrarenal manifestations of autosomal dominant polycystic kidney disease (ADPKD) during chronic haemodialysis (HD) has never been assessed in a paired case-control study. METHODS: Comparison of the course of 50 ADPKD patients with 50 matched control (C) patients who started chronic HD at the same time. RESULTS: Follow-up averaged 48 and 39 months in the ADPKD and C groups respectively. Actuarial survival was similar in both groups. Prevalence of renal pain (36 vs 2%, P=0.0001), haematuria (36 vs 16%, P<0.03) and renal infection (16 vs 2%, P<0.04) was higher in the ADPKD than in the C group. Nephrectomy during HD was performed in six ADPKD (in 4 cases in preparation for transplantation) and in one control patient. Number of patients with coronary and heart valve complications was similar in both groups. Stroke occurred in three patients from both groups. Only two ADPKD patients experienced a single episode of pain related to liver cyst. Prevalence of severe infection was similar in the ADPKD group (36%) and the C group (28%). Number and duration of hospitalizations were similar in both groups. CONCLUSIONS: The overall outcome of ADPKD patients on maintenance HD is similar to that of HD patients with other primary renal diseases. Complications related to cystic kidneys are frequent but rarely severe. Extrarenal manifestations of ADPKD have a limited clinical impact in this short term study. PMID- 8672023 TI - Outcome and risk factors for left ventricular disorders in chronic uraemia. AB - BACKGROUND: Left ventricular disease occurs frequently in dialysis patients. It may be manifest as concentric LV hypertrophy, LV dilatation with or without LV hypertrophy, or systolic dysfunction. Little is known concerning the clinical outcome and risk factors for these disorders. METHODS: A cohort of 432 end-stage renal disease patients who survived at least 6 months had an echocardiogram on initiation of dialysis therapy. Clinical, laboratory and echocardiographic data was obtained annually during follow-up. RESULTS: On initiation of ESRD therapy 16% of patients had systolic dysfunction, 41% concentric LV hypertrophy, 28% LV dilatation, and only 16% had normal echocardiograms. Median time to development of heart failure was 19 months in patients with systolic dysfunction, 38 months in concentric LV hypertrophy and 38 months in LV dilatation. The relative risks of heart failure in the three groups were significantly worse than in the normal group, after adjusting for age, diabetes and ischaemic heart disease. Median survival was 38 months in systolic dysfunction, 48 months in concentric hypertrophy, 56 months in LV dilatation, and >66 months in the normal group. Two hundred and seventy-five patients had a follow-up echocardiogram 17 months after starting dialysis therapy together with serial measurement of potential risk factors prior to the echocardiogram. On follow-up echocardiogram the degree of concentric LV hypertrophy was independently related to hypertension while on dialysis, older age, and anaemia while on dialysis; the degree of LV dilatation was related to ischaemic heart disease, anaemia, hypertension and hypoalbuminemia while on dialysis; the degree of systolic dysfunction was associated with ischaemic heart disease and anaemia during follow-up. CONCLUSIONS: Manifestations of left ventricular disease are frequent and persistent in chronic uraemia, and are associated with high risks of heart failure and death. Potentially reversible risk factors include anaemia, hypertension, hypoalbuminaemia and ischaemic heart disease. PMID- 8672024 TI - A computer model for predicting the demand for end-stage renal failure (ESRF) treatment, contract setting and monitoring. AB - BACKGROUND: The high cost of end-stage renal failure (ESRF) treatment, and the anticipated need for expansion of the service at a time of limited resources for health care expenditure, means that careful planning of such an expansion is necessary. This needs to inform the setting and monitoring of contracts between commissioning organizations and providers of treatment. A spreadsheet based computer model is described which fulfils both of these needs. METHODS: A computer programme was written to run on a commonly available spreadsheet in order to predict the demand for ESRF treatment, set contracts, and monitor in year performance. RESULTS: The model described has facilitated contracting for ESRF services. Purchasers have used it to examine various planning scenarios, while the provider unit has used it to support a business case for further development. Using this model, the predictions for the Sheffield resident population are that the total number of patients on the ESRF treatment programme will increase from a mid-year average of 204 patients in the year 1994-95 to 266 patients in the year 1999-2000, while costs increased over the same time period from 2.37 million pounds to 2.78 million pounds. CONCLUSIONS: A computer spreadsheet based model described is a useful tool for predicting demand, and setting and monitoring contracts, for treatment for ESRF. Problems with the model and potential further developments are discussed. PMID- 8672025 TI - Abnormal calcaemic response to PTH in the uraemic rat without secondary hyperparathyroidism. AB - BACKGROUND: Skeletal resistance to the calcaemic action of parathyroid hormone (PTH) is an important pathogenic factor in the development of secondary hyperparathyroidism. Since parathyroidectomy normalizes the calcaemic response to PTH in uraemic animals, the increase in PTH levels has been advanced as a cause of skeletal resistance to the calcaemic action of PTH. This study was designed to evaluate in uraemic rats the effect of normal PTH levels on the calcaemic response to PTH. METHODS: To maintain normal PTH levels, rats were parathyroidectomized (PTX) and rat 1-34 PTH was infused at a rate of 0.022 microg/100 g per hour via a subcutaneously implanted miniosmotic pump; this rate of infusion was considered to be the normal PTH replacement dose since it normalized serum calcium and phosphorus in PTX rats with normal renal function. Two separate studies were performed. In the first study, rats were maintained on a moderate-phosphorus (0.6%) diet and rats were divided into four groups: (I) normal; (II) uraemic; (III) PTX with normal PTH replacement; and (IV) uraemic with PTX and normal PTH replacement. In a second study, the groups were the same except that a high-phosphorus (1.2%) diet was given to increase the magnitude of hyperparathyroidism in rats with intact parathyroid glands; an additional group (V) identical to group IV except that rats received daily calcitriol was included. After 14 days, rats received a 48-h infusion of high-dose rat 1-34 PTH (0.11 microg/100 g per hour) to evaluate the calcaemic response to PTH. Results. The calcaemic response to PTH was similar in normal rats and PTX rats replacement on both a moderate and high-phosphorus diet. In uraemic rats, the calcaemic response to PTH was decreased and the maintenance of normal PTH levels by PTH replacement did not correct the decreased calcaemic response to PTH; moreover, calcitriol supplementation did not improve the calcaemic response to PTH. Finally, hypocalcaemia was observed in uraemic rats with PTH replacement and was more profound than in rats on a high-phosphorus diet. CONCLUSIONS: This study demonstrates that the maintenance of a normal PTH level in uraemic rats did not correct the impaired calcaemic response to PTH, suggesting that factors intrinsic to uraemia, independent of phosphorus, calcitriol, and PTH participate in the decreased calcaemic response to PTH in uraemia. PMID- 8672026 TI - Coagulation, fibrinolysis and fibrinolysis inhibitors in haemodialysis patients: contribution of arteriovenous fistula. AB - BACKGROUND: End-stage renal disease (ESRD) patients, not uncommonly, might exhibit thrombotic complications, as well as they may present with a bleeding diathesis. Changes in vessel wall and/or blood flow in native arteriovenous fistula (AVF) might also augment these disarrangements, as vascular endothelium is predominantly involved in the regulation of haemostatic pathways. OBJECTIVE: This study was designed to evaluate the state of coagulation and fibrinolysis and the role of AVF on haemostatic defects, in ESRD patients on maintenance haemodialysis. METHODS: Plasma samples for prothrombin fragment 1+2, thrombin antithrombin III complex, plasmin-alpha2 antiplasmin complex, tissue type plasminogen activator antigen, urokinase type plasminogen activator antigen, u-PA activity, plasminogen activity, alpha2-antiplasmin and alpha2-macroglobulin assays were obtained from AVF and contralateral large veins of ESRD patients and from peripheral veins of the control group. RESULTS: Our results indicate a predominant thrombotic state as evidenced by activated coagulation markers and enhanced fibrinolysis in systemic circulation of ESRD patients. However the most novel finding is the probable contribution of AVF on haemostatic activation, as proven by the statistically different and positively correlated concentrations of both coagulation, fibrinolysis, and fibrinolysis inhibitors in AVF when compared to the levels in peripheral venous circulation. CONCLUSION: In addition to systemic derangements of haemostasis in ESRD patients, AVF individually might have a substantial role in the modulation of coagulation and fibrinolytic cascade. PMID- 8672027 TI - Delayed function reduces renal allograft survival independent of acute rejection. AB - BACKGROUND: Mechanisms by which delayed allograft function reduces renal allograft survival are poorly understood. This study evaluated the relationship of delayed allograft function to acute rejection and long-term survival of cadaveric allografts. METHODS: 338 recipients of cadaveric allografts were followed until death, resumption of dialysis, retransplantation, loss to follow up, or the study's end, which ever came first. Delayed allograft function was defined by dialysis during the first week following transplantation. Multivariate Cox proportional hazards survival analysis was used to assess the relationship of delayed allograft function to rejection and allograft survival. RESULTS: Delayed allograft function, recipient age, preformed reactive antibody levels, prior kidney transplantation, recipient race, rejection during the first 30 days and rejection subsequent to 30 days following transplantation were predictive of allograft survival in multivariate survival models. Delayed allograft function was associated with shorter allograft survival after adjustment for acute rejection and other covariates (relative rate of failure [RR]+1.72 [95% CI, 1.07, 2.76]). The adjusted RR of allograft failure associated with any rejection during the first 30 days was 1.99 (1.23, 3.21), and for rejection subsequent to the first 30 days was 3.53 (2.9 08, 6.00). The impact of delayed allograft function did not change substantially (RR=1.84 [1.15, 2.95]) in models not controlling for acute rejection. These results were stable among several subgroups of patients and using alternative definitions of allograft survival and delayed allograft function. CONCLUSIONS: This study demonstrates that delayed allograft function and acute allograft rejection have important independent and deleterious effects on cadaveric allograft survival. These results suggest that the effect of delayed allograft function is mediated, in part, through mechanisms not involving acute clinical rejection. PMID- 8672028 TI - Repeated successful pregnancies after kidney transplantation in 102 women (Report by the EDTA Registry). AB - BACKGROUND: Between 1967 and 1990, 820 successful pregnancies in 718 women on renal replacement therapy (RRT) were reported to the EDTA Registry. METHODS: This study analyses data on repeated successful pregnancies in 102 of these women, of whom 99 had two and three had three pregnancies. RESULTS: Primary renal diseases were mainly glomerulonephritis (41%), pyelonephritis (32%), and congenital malformations such as cystic diseases and hypoplasia or dysplasia (3%). Mean age at start of RRT was 21 years +/-5 SD. Ninety-four per cent of the women had the same transplant during the first and second pregnancies; 85% of these were alive with their first graft and 9% with a second graft; 4% were retransplanted after the first pregnancy and 2% were back on dialysis during the second pregnancy. Of the mothers with two successful pregnancies, two-thirds had a serum creatinine below 121 micromol/l after the first or after the second pregnancy. Six mothers lost their first graft after the first pregnancy. None of the mothers had died after delivery of the second or third baby. Several features of the first and the second pregnancy in these mothers were quite similar. Mean gestational age was 36 weeks+/-3SD during first and second pregnancy. Mean birth weight (height) of the first child was 2490 g+/-660 SD (48 cm+/-4 SD) and 2587 g+/-639 SD (50 cm+/-3 SD) of the second child (NS). Neonatal mortality was 4% after the first and second delivery; congenital abnormalities were found in five and three children respectively. CONCLUSIONS: Fourteen per cent of mothers who had a successful pregnancy on RRT subsequently had a second baby. Repeated pregnancies should not adversely affect graft function and/or fetal development provided that graft function was well preserved at the time of conception. PMID- 8672029 TI - Reduced speed of sound in tibial bone of haemodialysed patients: association with serum PTH level. AB - BACKGROUND: In end-stage renal disease, average bone mineral density has been reported to be normal or only modestly reduced, more so in the cortical bone. The purpose of the present study was to explore the potential use of quantitative ultrasound, a method reflecting both quantitative and qualitative properties of bone, in assessing bone status in patients on maintenance haemodialysis. METHODS: We studied 71 patients (age 17-81 years, time on dialysis 0-18 years). The speed of sound waves (tSOS; m/s) propagating along the cortical bone has been determined at the tibial shaft. tSOS results were expressed as Z scores, i.e. units of standard deviations from age- and sex-matched normal mean values, and correlated with relevant clinical and biochemical variables. RESULTS: SOS Z score averaged -2. 0 (range -6.8 to 0.6; P<0.001) and was negative in 93% of the patients. Significant inverse correlations were found between SOS Z score and both time on dialysis (r=-0.52; P<0.0001) and serum PTH (r=-0.39; P=0.0002). Markedly reduced SOS Z score, below -2, was found in 80% of the patients whose PTH levels exceeded 34 pmol/l (five times the upper normal limit), compared with 43% of the patients whose PTH levels were below 34 pmol/l(P=0.04). Compared to patients without bone pain (n=51), subjects with bone pain (n=20) had somewhat lower SOS Z scores -2.5+/-2.0 versus -1.8+/-1.4; P=0. 08), but this could be accounted for by longer time on dialysis. CONCLUSIONS: tSOS is substantially reduced in the majority of haemodialysed patients and is related to time on dialysis and serum PTH level. The clinical value of this novel method needs further exploration. PMID- 8672031 TI - Is cholesterol embolic disease an unrecognized cause of renal graft dysfunction? PMID- 8672030 TI - Nosocomial outbreak of Aspergillus fumigatus infection among patients in a renal unit? AB - Aspergillus fumigatus is present in the environment worldwide and it is only able to infect debilitated or immunodepressed subjects. Nosocomial outbreaks of A. fumigatus infection have been associated with hospital reconstruction. Spores are released into the environment and are inhaled by immunodepressed patients housed in nearby Medical Units. Specific clinical syndromes are allergic bronchopulmonary aspergillosis and invasive pulmonary aspergillosis with characteristic radiological features. Invasive A. fumigatus infection is commonly fatal, even if promptly diagnosed and treated. Three consecutive cases of A. fumigatus infection occurred in debilitated patients housed in our Renal Unit while building renovation near the Unit was being performed. Two of these patients died and pulmonary and diffuse aspergillosis was found on postmortem examination. The third patient, highly suspected to be infected with Aspergillus, was aggressively and successfully treated with liposomal amphotericin B. Our experience suggests that fungal infections have gained increasing prominence in clinical medicine and they must be considered in chronic debilitated patients including dialysis patients, and that liposomal amphotericin B represents an important advance in the treatment of aspergillosis. PMID- 8672032 TI - Images in nephrology. Left ventricular disorders detected by M-mode echocardiography in chronic uraemia. PMID- 8672033 TI - Haemolytic uraemic syndrome following bone marrow transplantation. Case report and review of the literature. AB - Thrombotic microangiopathy (TMA) can be a late complication of bone marrow transplantation (BMT). A patient is described in whom the haemolytic uraemic syndrome developed 10 months after BMT and who died of E. coli sepsis while on maintenance haemodialysis. The literature is reviewed, regarding clinical presentation, incidence, pathogenesis and therapy. TMA can be observed, after an interval of 3-12 months, in about 6-26% of patients following BMT. Reported cases vary considerably in clinical severity, from mild presentations to severe TMA with high mortality rates despite intensive therapy. Important pathogenetic roles are ascribed to the conditioning total body irradiation and the use of cyclosporin A, but other factors may be involved as well. Next to supportive therapy, plasma exchange and the use of ACE inhibitors may be of value in treating BMT-associated TMA. PMID- 8672034 TI - Rheumatoid arthritis associated with membranous nephropathy and IgA nephritis with necrotizing lesions. PMID- 8672035 TI - Hepatitis C virus infection complicating lupus nephritis. PMID- 8672036 TI - Symptomatic intrarenal arteriovenous fistula detected 25 years after percutaneous renal biopsy. PMID- 8672037 TI - Kimura's disease and minimal-change nephrotic syndrome. PMID- 8672038 TI - Fibrillar glomerulopathy associated with chronic lymphocytic leukaemia. PMID- 8672039 TI - Systemic fibromuscular dysplasia masquerading as polyarteritis nodosa. PMID- 8672040 TI - Rapidly progressive interstitial renal fibrosis due to a chronic intake of a herb (Aristolochia pistolochia) infusion. PMID- 8672041 TI - Subclavian artery to right atrium haemodialysis bridge graft for superior vena caval occlusion. PMID- 8672042 TI - Tesio catheters: findings in post-mortem examination. PMID- 8672043 TI - Severe hypophosphataemia due to intraperitoneal nutrition in a CAPD patient. PMID- 8672044 TI - Chronic parvovirus B19 infection-associated pure red cell anaemia in a kidney transplant recipient. PMID- 8672045 TI - Azathioprine-induced pure red-cell aplasia. PMID- 8672046 TI - Cyclosporin-induced cerebellar syndrome in a pancreatico-renal transplant recipient. PMID- 8672048 TI - Apparent neoplasm of the clavicle of a dialysis patient, ultimately revealed as tuberculosis. PMID- 8672047 TI - Pneumonia due to blastomyces dermatitidis in a European renal transplant recipient. PMID- 8672049 TI - Renovascular hypertension after renal transplantation - don't look only after the graft artery. PMID- 8672050 TI - A case of a lethal febrile illness in a renal transplant patient presenting after a dental visit. PMID- 8672051 TI - Historical note. On the contributions of Paracelsus to nephrology. PMID- 8672056 TI - MPGN and HCV infection in Istanbul, Turkey. PMID- 8672057 TI - Analysis and prediction of structure-reactive toxicity relationships of substituted aromatic compounds. PMID- 8672058 TI - Relationships between molecular structure and chromosomal aberrations in in vitro human lymphocytes induced by substituted nitrobenzenes. PMID- 8672059 TI - Developmental toxic effects of fusaric acid in CD1 mice. PMID- 8672060 TI - Gaseous aliphatic aldehydes in smoke from burning raw materials of Chinese joss sticks. PMID- 8672061 TI - Cross-reactivity analysis using a four-parameter model applied to environmental immunoassays. PMID- 8672062 TI - Distribution of low organochlorine residues in a woodland ecosystem. PMID- 8672063 TI - Accumulation and effect of cadmium in the wood-rotting basidiomycete Daedalea quercina. PMID- 8672064 TI - Fate of vinclozolin in creeping bentgrass turf under two application frequencies. PMID- 8672065 TI - Soil dissipation of the post-emergence herbicide sulcotrione in maize crops treated with organic fertilizers. PMID- 8672066 TI - Acclimation and selection for methanesulfonic acid (MSA) degrading microbial population using continuous culture techniques. PMID- 8672067 TI - Determination of triazine residues in water: comparison between a gas chromatographic method and an enzyme-linked immunosorbent assay (ELISA). PMID- 8672068 TI - In vivo estrogenic action of nonylphenol in immature female rats. PMID- 8672069 TI - Irgarol 1051, an antifouling compound in freshwater, sediment, and biota of Lake Geneva. PMID- 8672070 TI - Pulp mill sourced organic compounds and sodium levels in water and sediments from the Tarawera River, New Zealand. PMID- 8672071 TI - Pesticides in water and fish from rivers flowing into Lake Biwa. PMID- 8672072 TI - Sulfide tolerance of four marine species used to evaluate sediment and pore-water toxicity. PMID- 8672073 TI - Histopathological effects of phenol on the digestive gland of Amphimelania holandri Fer. (Gastropoda, prosobranchia). PMID- 8672074 TI - Non-, mono-, and di-o-chlorobiphenyl concentrations and their toxic equivalents to 2,3,7,8-tetrachlorodibenzo[p]dioxin in Aroclors(R) and digestive glands from American lobster (Homarus americanus) captured in Atlantic Canada. PMID- 8672075 TI - Growth rate of Ankistrodesmus falcatus and Scenedesmus bijuga in mixed culture exposed to monocrotophos. PMID- 8672076 TI - Effect of carbaryl on tissue composition, maturation, and breeding potential of Cirrhina mrigala (Ham.). PMID- 8672077 TI - Effects of sublethal doses of fenvalerate (a synthetic pyrethroid) administered continuously for four weeks on the blood, liver, and muscles of a freshwater fish, Ctenopharyngodon idella. PMID- 8672078 TI - Effects of naled, synergized, and non-synergized resmethrin on the swimming performance of young trout. PMID- 8672079 TI - Comparative studies on the effects of herbicide atrazine on freshwater fish Oreochromis niloticus and Chrysichthyes auratus at Assiut, Egypt. PMID- 8672080 TI - Ion channel permeable for divalent and monovalent cations in native spinach thylakoid membranes. AB - A cation-selective channel was characterized in isolated patches from osmotically swollen thylakoids of spinach (Spinacea oleracea). This channel was permeable for K+ as well as for Mg2+ and Ca2+ but not for Cl-. When K+ was the main permeant ion (symmetrical 105 mM KCl) the conductance of the channel was about 60 pS. The single channel conductance for different cations followed a sequence K+ > Mg2+ >/= Ca2+. The permeabilities determined by reversal potential measurements were comparable for K+, Ca2+, and Mg2+. The cation channel displayed bursting behavior. The total open probability of the channel increased at more positive membrane potentials. Kinetic analysis demonstrated that voltage dependence of the total open probability was determined by the probability of bursts formation while the probability to find the channel in open state within a burst of activity was hardly voltage-dependent. The cation permeability of intact spinach thylakoids can be explained on the single channel level by the data presented here. PMID- 8672081 TI - Evidence for involvement of a zymogen granule Na+/H+ exchanger in enzyme secretion from rat pancreatic acinar cells. AB - We have characterized a Na+/H+ exchanger in the membrane of isolated zymogen granules (ZG) from rat exocrine pancreas and investigated its role in secretagogue-induced enzyme secretion. ZG Na+/H+ exchanger activity was estimated by measuring Na+ or Li+ influx and consequent osmotic swelling and lysis of ZG incubated in Na- or Li-acetate. Alternatively, intragranule pH was investigated by measuring absorbance changes in ZG which had been preloaded with the weak base acridine orange. Na+- or Li+-dependent ZG lysis was enhanced by increasing inward to outward directed H+ gradients. Na+-dependent ZG lysis was not prevented by an inside-positive K+ diffusion potential generated by valinomycin which argues against parallel operation of separate electrogenic Na+ and H+ permeabilities and for coupled Na+/H+ exchange through an electroneutral carrier. Na+- and Li+ dependent ZG lysis was inhibited by EIPA (EC50 approximately 25 microM) and benzamil (EC50 approximately 100 microM), but only weakly by amiloride. Similarly, absorbance changes due to release of acridine orange from acidic granules into the medium were obtained with Na+ and Li+ salts only, and were inhibited by EIPA, suggesting the presence of a Na+/H+ exchanger in the membrane. Na+ dependent lysis of ZG was inhibited by 0.5 mm MgATP and MgATP-gamma-S by about 60% and 35%, respectively. Inhibition by MgATP was prevented by incubation of ZG with alkaline phosphatase (100 U/ml), or by the calmodulin antagonists calmidazolium (0.75 microM), trifluoperazine (100 microM) and W-7 (500 microM), suggesting that the ZG Na+/H+ exchanger is regulated by a ZG membrane-bound calmodulin-dependent protein kinase. Na+ dependence of secretagogue (CCK-OP) stimulated amylase secretion was investigated in digitonin permeabilized rat pancreatic acini and was higher in acini incubated in Na+ containing buffer (30 mm NaCl/105 mm KCl buffer; 6.4 +/- 0.4% of total amylase above basal) compared to buffer without Na+ (0 mm NaCl/135 mm KCl buffer; 4.7 +/- 0.4% of total amylase above basal, P < 0.03). EIPA (50 microM) reduced CCK-OP-induced amylase secretion in Na+ containing buffer from 7.5 +/- 0.6% to 4.1 +/- 0.8% (P < 0.02). In the absence of Na+ in the buffer, CCK-OP-stimulated amylase release was not inhibited by 50 microM EIPA. The data suggest that an amiloride insensitive, EIPA inhibitable Na+/H+ exchanger is present in ZG membranes, which is stimulated by calmodulin antagonists and could be involved in secretagogue-induced enzyme secretion from rat pancreatic acini. PMID- 8672082 TI - Regulation of epithelial Na+ permeability by protein kinase C is tissue specific. AB - Protein kinase C (PKC) is a major regulator of a broad range of cellular functions. Activation of PKC has been reported to stimulate Na+ transport across frog skin epithelium by increasing the apical Na+ permeability. This positive natriferic response has not been observed with other epithelial preparations, and could reflect the specific experimental conditions of different laboratories, or species or organ specificity of the response to PKC. In the present study, measurements were conducted with skins and urinary bladders from the same animals of two different species. The PKC activator TPA uniformly increased the transepithelial Na+ transport (measured as amiloride-sensitive short-circuit current, ISC, across skins from Rana temporaria and Bufo marinus, and inhibited ISC across bladders from the same animals. Inhibitors of PKC (staurosporine, H-7 and chelerythrine) partially blocked the TPA-induced stimulation of ISC across frog skin. The specificity of the PKC response by amphibian skin could have reflected an induction of moulting, similar to that observed with aldosterone. However, light micrographs of paired areas of frog skin revealed no evidence of the putative moulting. Separation of stratum corneum from the underlying stratum granulosum could be detected following application of aldosterone. We conclude that the effect of PKC on epithelial Na+ channels is organ, and not species specific. The stimulation of Na+ permeability in amphibian skin does not arise from sloughing of the stratum corneum. These observations are consistent with the hypothesis that the natriferic action arises from the calcium-independent isozyme of PKC previously detected in frog skin. PMID- 8672083 TI - Effects of hyperthermia on intracellular chloride. AB - Hyperthermia induces transient changes in [Na+]i and [K+]i in mammalian cells. Since Cl- flux is coupled with Na+ and K+ in several processes, including cell volume control, we have measured the effects of heat on [Cl-]i using the chloride indicator, MQAE, with flow cytometry. The mean basal level of [Cl-]i in Chinese hamster ovary cells was 12 mM. Cells heated at 42.0 degrees or 45.0 degrees C for 30 min had about a 2.5-fold increase in [Cl-]i above unheated control values when measured immediately after heating. There was about a 3-fold decrease in [Na+]i under the same conditions, as measured by Sodium Green. The magnitude of the increase in [Cl-]i depended upon time and temperature. The [Cl-]i recovered in a time-dependent fashion to control values by 30 min after heating. When cells were heated at 45.0 degrees C for 30 min in the presence of 1.5 mM furosemide, the heat-induced [Cl-]i increase was completely blocked. Since furosemide inhibits the Na+/K+/2Cl- cotransporter, Cl- channels, and even Cl-HCO3 exchange, these ion transporters may be involved in the heat-induced increase in [Cl-]i. PMID- 8672084 TI - L-lysine transport in chicken jejunal brush border membrane vesicles. AB - The properties of l-lysine transport in chicken jejunum have been studied in brush border membrane vesicles isolated from 6-wk-old birds. l-lysine uptake was found to occur within an osmotically active space with significant binding to the membrane. The vesicles can accumulate l-lysine against a concentration gradient, by a membrane potential-sensitive mechanism. The kinetics of l-lysine transport were described by two saturable processes: first, a high affinity-transport system (KmA = 2.4 +/- 0.7 micromol/L) which recognizes cationic and also neutral amino acids with similar affinity in the presence or absence of Na+ (l-methionine inhibition constant KiA, NaSCN = 21.0 +/- 8.7 micromol/L and KSCN = 55.0 +/- 8. 4 micromol/L); second, a low-affinity transport mechanism (KmB = 164. 0 +/- 13.0 micromol/L) which also recognizes neutral amino acids. This latter system shows a higher affinity in the presence of Na+ (KiB for L-methionine, NaSCN = 1.7 +/- 0.3 and KSCN = 3.4 +/- 0.9 mmol/L). L-lysine influx was significantly reduced with N ethylmaleimide (0.5 mmol/L) treatment. Accelerative exchange of extravesicular labeled l-lysine was demonstrated in vesicles preloaded with 1 mmol/L l-lysine, l arginine or l-methionine. Results support the view that l-lysine is transported in the chicken jejunum by two transport systems, A and B, with properties similar to those described for systems b0,+ and y+, respectively. PMID- 8672085 TI - Regulation of Na-K-ATPase activity in the proximal tubule: role of the protein kinase C pathway and of eicosanoids. AB - To evaluate further the signal transduction mechanisms involved in the short-term modulation of Na-K-ATPase activity in the mammalian kidney, we examined the role of phospholipase C-protein kinase C (PLC-PKC) pathway and of various eicosanoids in this process, using microdissected rat proximal convoluted tubules. Dopamine (DA) and parathyroid hormone (either synthetic PTH1-34 or PTH3-34) inhibited Na-K ATPase activity in dose-dependent manner; this effect was reproduced by PKC530 558 fragment and blocked by the specific PKC inhibitor calphostin C, as well as by the PLC inhibitors neomycin and U-73122. Pump inhibition by DA, PTH, or arachidonic acid, and by PKC activators phorbol dibutyrate (PDBu) or dioctanoyl glycerol (DiC8) was abolished by ethoxyresorufin, an inhibitor of the cytochrome P450-dependent monooxygenase pathway, but was unaffected by indomethacin or nordihydroguaiaretic acid, inhibitors of the cyclooxygenase and lipoxygenase pathways of the arachidonic acid cascade, respectively. Furthermore, each of the three monooxygenase products tested (20-HETE, 12(R)-HETE, or 11,12-DHT) caused a dose-dependent inhibition of the pump. The effect of DA, PTH, PDBu or DiC8, as well as that of 20-HETE was not altered when sodium entry was blocked with the amiloride analog ethylisopropyl amiloride or increased with nystatin. We conclude that short-term regulation of proximal tubule Na-K-ATPase activity by dopamine and parathyroid hormone occurs via the PLC-PKC signal transduction pathway and is mediated by cytochrome P450-dependent monooxygenase products of arachidonic acid metabolism, which may interact with the pump rather than alter sodium access to it. PMID- 8672086 TI - Activity and stoichiometry of Na+:HCO3- cotransport in immortalized renal proximal tubule cells. AB - The proximal tubule Na+-HCO3- cotransporter is located in the basolateral plasma membrane and moves Na+, HCO3-, and net negative charge together out of the cell. The presence of charge transport implies that at least two HCO-3 anions are transported for each Na+ cation. The actual ratio is of physiological interest because it determines direction of net transport at a given membrane potential. To determine this ratio, a thermodynamic approach was employed that depends on measuring charge flux through the cotransporter under defined ion and electrical gradients across the basolateral plasma membrane. Cells from an immortalized rat proximal tubule line were grown as confluent monolayer on porous substrate and their luminal plasma membrane was permeabilized with amphotericin B. The electrical properties of these monolayers were measured in a Ussing chamber, and ion flux through the cotransporter was achieved by applying Na+ or HCO3- concentration gradients across the basolateral plasma membrane. Charge flux through the cotransporter was identified as difference current due to the reversible inhibitor dinitro-stilbene disulfonate. The cotransporter activity was Cl- independent; its conductance ranged between 0.12 and 0.23 mS/cm2 and was voltage independent between -60 and +40 mV. Reversal potentials obtained from current-voltage relations in the presence of Na+ gradients were fitted to the thermodynamic equivalent of the Nernst equation for coupled ion transport. The fit yielded a cotransport ratio of 3HCO3-:1Na+. PMID- 8672088 TI - Bifidobacteria strain behavior toward cholesterol: coprecipitation with bile salts and assimilation. AB - Resting cells and growing cells of bifidobacteria strains exhibited an ability to remove cholesterol in the presence of bile salts. In resting cell assays, the removed cholesterol was precipitated in the presence of cholic acid at pH values lower than 5.4. However, this precipitated cholesterol was redissolved when the pellets were washed with phosphate buffer, pH 7, and no cholesterol was found in the cells. It appears that this precipitation is a transient phenomenon. In the case of growing cells, the removed cholesterol was partially recovered when cells were washed with phosphate buffer, pH 7, while the remaining cholesterol was extracted from the cells. Cultured in the presence of radiolabeled free or esterified cholesterol, bifidobacteria strains were able to assimilate esterified cholesterol. It is concluded that the removal of cholesterol from the growth medium by bifidobacteria strains is due to both bacterial assimilation and precipitation of cholesterol. PMID- 8672087 TI - The ACh-evoked, Ca2+-activated whole-cell K+ current in mouse mandibular secretory cells. Whole-cell and fluorescence studies. AB - In our previous studies on sheep parotid secretory cells, we showed that the K+ current evoked by acetylcholine (ACh) was not carried by the high-conductance voltage- and Ca2+-activated K+ (BK) channel which is so conspicuous in unstimulated cells, notwithstanding that the BK channel is activated by ACh. Since several studies from other laboratories had suggested that the BK channel did carry the ACh-evoked K+ current in the secretory cells of the mouse mandibular gland, and that the current could be blocked with tetraethylammonium (TEA), a known blocker of BK channels, we decided to investigate the ACh-evoked K+ current in mouse cells more closely. We studied whether the ACh-evoked K+ current in the mouse is inhibited by TEA and quinine. Using the whole-cell patch clamp technique and microspectrofluorimetric measurement of intracellular Ca2+, we found that TEA and quinine do inhibit the ACh-evoked K+ current but that the effect is due to inhibition of the increase in intracellular Ca2+ evoked by ACh, not to blockade of a K+ conductance. Furthermore, we found that the K+ conductance activated when ionomycin is used to increase intracellular free Ca2+ was inhibited only by quinine and not by TEA. We conclude that the ACh-evoked K+ current in mouse mandibular cells does not have the blocker sensitivity pattern that would be expected if it were being carried by the high-conductance, voltage- and Ca2+-activated K+ (BK) channel. The properties of this current are, however, consistent with those of a 40 pS K+ channel that we have reported to be activated by ACh in these cells [16]. PMID- 8672089 TI - Isolation and characterization of a species-specific DNA probe for the detection of Candida krusei. AB - In an attempt to design species-specific primers for the detection of Candida krusei by polymerase chain reaction, a partial genomic DNA library from Candida krusei was screened for hybridization with radiolabeled genomic probes from a broad variety of fungal and bacterial species and from human. Species-specific candidate DNA inserts were then tested for hybridization with dot blots of DNA from various organisms. One 570-basepair insert from Candida krusei DNA that hybridized under stringent conditions only with DNA from Candida krusei and human was sequenced. It revealed considerable homology with the gene for the mitochondrial inner membrane protease I of Saccharomyces cerevisiae, and the 147 amino acid residues deduced from an open reading frame showed considerable homology with the N-terminal portion of the enzyme from Saccharomyces cerevisiae. From the sequence of the Candida krusei DNA fragment, a pair of 21-base oligonucleotide primers enclosing a 501-basepair sequence was designed for polymerase chain reaction. When these primers were tested with a broad range of genomic DNAs, the expected amplification was obtained only with Candida krusei DNA and not with DNA from any other source, including human. Experiments with DNA from mixed cultures of Candida krusei and other yeasts and bacteria showed that the polymerase chain reaction was specific for Candida krusei and that as few as ten cells could be detected. PMID- 8672090 TI - Extracellular alpha-Glucosidase with Dextran-Hydrolyzing Activity from the Thermophilic Fungus, Thermomyces lanuginosus AB - The thermophilic fungus Thermomyces lanuginosus, which is able to use dextran as primary carbon source for growth, excreted during the early phases of growth an enzyme activity capable of degrading dextran. The activity peaked at 22 h and decreased rapidly after the culture entered the stationary phase, probably caused by protease activity. Results from growth on a number of different carbon sources showed that polymer carbohydrates yielded the highest dextranase activities. On the basis of the substrate specificity and the release of glucose in the alpha anomeric form from the hydrolysis of maltose, it is proposed that the enzyme responsible for the necessary degradation of dextran to smaller saccharides is an alpha-glucosidase. PMID- 8672091 TI - Octopine- and Nopaline-Inducible Proteins in Agrobacterium tumefaciens Are Also Induced by Arginine AB - Octopine induced the synthesis of 83, 76, 62, 58, 44, 42, 31, and 22 kDa proteins in Agrobacterium tumefaciens strains harboring the tumor-inducing (Ti) plasmids pTiA6 and pTiAch5. Nopaline induced the synthesis of 83, 76, 62, 58, 56, 44, 42, 31, and 22 kDa proteins in A. tumefaciens strains harboring the Ti plasmids pTiC58 and pTiT37. The molecular masses of proteins induced by octopine and nopaline were very similar. In accordance with the 'opine concept', octopine and nopaline were found to induce protein synthesis only in strains harboring the respective Ti plasmids. Arginine, a common catabolic product of octopine and nopaline, induced the synthesis of most of the proteins induced by the two opines. Our results show that only the initial step(s) of octopine and nopaline catabolism are induced by specific opines in the respective strains. The subsequent steps are likely to be regulated by arginine in both strains. PMID- 8672092 TI - Copper Resistance and Accumulation in the Zygomycete Mucor rouxii AB - Two copper-resistant (Copr) mutants, strains P1 and P3, were obtained from the dimorphic fungus Mucor rouxii. They were characterized as to their ability to take up copper in a growth medium supplemented with this metal ion. Detection of copper by linear sweep striping voltammetry in cell walls and in the cell wall free fraction of disrupted cells revealed a higher content of the metal in both mutant fractions, as compared with those of the copper-sensitive (Cops) parental strain. Copper binding by M. rouxii growing cells was also studied through the use of a cytochemical method based on the compounds neocuproine (NCP) and sodium diethyldithiocarbamate (DTC). This method indicated that the P1 Copr strain accumulated more metal than the parental Cops strain, both on the cellular surface and in the intracellular milieu. PMID- 8672094 TI - Regulation of the Expression of the Photosynthetic Apparatus of Rhodobacter capsulatus Grown in Nitrogen-Limited Chemostat Cultures AB - Rhodobacter capsulatus was grown in chemostat cultures under different dilution rates and with ammonium ions as the limiting nutrient. The maximal growth rate (MUmax) and the Monod cell growth saturation coefficient (Ks), were calculated from batch cultures grown at different concentrations of NH4+. The experiments in chemostat were carried out at 0.25 mM (NH4)2SO4, and the dilution rates were varied between 38% and 75% of MUmax. The results indicated that under continuous culture conditions the cell yield coefficient (Y) (mg dry weight x MUmol consumed ammonium sulfate-1) decreased with increasing dilution rate (D). On the contrary, the cell yield was constant when expressed as mg cellular protein x MUmol consumed ammonium sulfate-1. This occurred as a consequence of both an increase in the consumed ammonium sulfate and a simultaneous decrease in the cell biomass production at increasing growth rates. The cells produced at higher growth rates had a higher protein content per cell. The specific content of bacteriochlorophyll (Bchl) decreased (between 3 and 4 times) with increasing growth rates measured in either cells or chromatophores. However, the absorption spectra of the cells indicated that the ratio LHI (light-harvesting complex I) to LHII (light-harvesting complex II) Bchl complexes did not change. The reaction center (RC) complex content varied in parallel with the total Bchl content, yielding a constant photosynthetic unit of 65 mol Bchl x mol RC-1 at different Ds. On the other hand, the uncoupled ATPase-specific activity measured in chromatophores was usually between 30% and 40% higher at the highest growth rates reached in these experiments. PMID- 8672093 TI - In vitro activities of fourteen antimicrobial agents against drug susceptible and resistant clinical isolates of Mycobacterium tuberculosis and comparative intracellular activities against the virulent H37Rv strain in human macrophages. AB - Minimal inhibitory concentrations (MICs) of 14 first and second-line antituberculous drugs against drug-susceptible and drug-resistant clinical isolates of Mycobacterium tuberculosis (including the multiple drug-resistant or MDR-TB isolates), as well as the type strain H37Rv, were determined radiometrically by the Bactec 460-TB methodols. MICs (microg/ml) of all the fourteen drugs were within an extremely narrow range in case of susceptible strains; isoniazid (0. 02-0.04), rifampin (0.2-0.4), ethambutol and streptomycin (0.5-2.0), ethionamide (0.25-0.5), D-cycloserine (25-75), capreomycin (1-2), kanamycin (2-4), amikacin (0.5-1.0), clofazimine (0.1-0.4), ofloxacin (0.5-1.0), ciprofloxacin (0.25-1.0), and sparfloxacin (0.1-0.4). The activity of second-line drugs remained unaltered against MDR-TB isolates resistant to routine first-line drugs. With peak serum level concentrations (Cmax), the intracellular killing of the virulent H37Rv strain was studied in detail in cultured human macrophages. Based on an decreasing order of bactericidal activity, our results showed the following spectrum of intracellular drug action: among the first-line drugs, rifampin > ethionamide = isoniazid > ethambutol > streptomycin > D-cycloserine; among second-line drugs, clofazimine = amikacin > kanamycin = capreomycin; among fluoroquinolones, sparfloxacin > ofloxacin > ciprofloxacin. On the other hand, contrary to atypical mycobacteria, the macrolide drug clarithromycin was inactive against both extracellular and intracellular M. tuberculosis. PMID- 8672095 TI - Purification and Characterization of Glutamine Synthetase from the Basidiomycete Pleurotus ostreatus AB - The purification and some properties of glutamine synthetase (GS) from the mycelium of the basidiomycete Pleurotus ostreatus are described. The enzyme was purified to apparent homogeneity with ion exchange chromatography and a Dyematrex Green A column as the major purification steps. The GS has a molecular weight of 470 kDa and is composed of eight subunits with a molecular weight of 58 kDa. A tetrameric form of the enzyme may also be active. The apparent Km values for the biosynthetic reaction varied in different mycelial extracts from 2.5 to 3.5 mM and from 0.02 to 0.06 for glutamate and ammonium respectively. In the transferase reaction, Km values of 48 mM and 6.2 mM were found for L-glutamine and hydroxylamine, respectively. From the divalent cations tested, Mn2+ showed the strongest stimulatory effect both on the transferase and the biosynthetic reaction. ADP was the only nucleotide having an activating effect on the transferase reaction. The biosynthetic reaction was strongly inhibited by AMP and the transferase reaction by carbamoylphosphate. L-Alanine and glycine inhibited both reactions. PMID- 8672096 TI - Ultraviolet-B lethal damage on Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa has shown an increased sensitivity compared with that of Escherichia coli and Enterobacter cloacae, when they were exposed to 0.4 kJ/m2 of ultraviolet-B radiation. The rapid decay in cell viability observed in Pseudomonas aeruginosa after the irradiation was influenced by factors such as culture media and the presence of pyocyanine during the irradiation. The radioinduced lethal damage could be prevented by photoreactivating treatment, indicating that pyrimidine dimer formation was the mechanism causing bacterial death. The results indicate that several environmental conditions may act as protective agents against ultraviolet-B-induced damage. PMID- 8672097 TI - The Lactic Acid Stress Response of Lactococcus lactis subsp. lactis AB - The lactic acid tolerance response (LATR) of the lactic acid bacterium Lactococcus lactis subsp. lactis has been studied. A dramatic increase in survival to a severe acid stress (pH 3.9) was obtained by preexposing the cells for 30 min to a mildly acid shock at pH 5.5. Whole-cell protein extract analysis revealed that during the acid tolerance response 33 polypeptides are induced over the level of naive cells. Among these are the major heat shock proteins DnaK and GroEL. In conjunction with a previous report (Hartke et al. 1994), the results establish that L. lactis can adapt to lactic acid exposure in two different ways: a logarithmic phase LATR, which may be activated by protons, and a stationary phase LATR, which needs no activation by protons. Both systems are independent of de novo protein synthesis. PMID- 8672098 TI - Role of type 1 fimbriae in the adhesion of Escherichia coli to salivary mucin and secretory immunoglobulin A. AB - Saliva is known to modulate the adhesion of bacteria in the oral cavity. The present work was performed to assess the effect of salivary components on the adhesion of Escherichia coli to a model oral surface. Several genetically engineered E. coli strains were used to examine the role of type 1 fimbriation in the interaction of these strains with salivary components in solution or adsorbed to hydroxyapatite. High (MG1) and low (MG2) molecular weight salivary mucins, and secretory immunoglobulin A (sIgA), were found to interact with the surface of E. coli, and these interactions were independent of the expression of fimbriae or capsule. In contrast, fimbriated strains of E. coli adhered to a greater extent to saliva-coated synthetic hydroxyapatite (HAP) than did nonfimbriated strains. Testing of salivary components separated by gel filtration chromatography revealed that only high-molecular-weight components promoted adhesion of E. coli to HAP. Additional studies found that purified MG2 and sIgA promoted the adhesion of E. coli to HAP. Expression of type 1 fimbriae enhanced adhesion, while mannose inhibited adhesion of fimbriated strains, to saliva-coated HAP and to HAP coated with MG2 and sIgA. We conclude that salivary MG2 and sIgA may provide receptors for the adhesion of type 1 fimbriated E. coli to oral surfaces. PMID- 8672123 TI - High sequence identity between the SRY HMG box from humans and insectivores. PMID- 8672124 TI - The use of compound heterozygotes and Hprt selection to analyze X-linked mottled alleles associated with prenatal lethality. AB - X-linked mutant alleles associated with prenatal male lethality are difficult to analyze because only heterozygous females are readily available for study. Genomic analysis of the mutant allele is facilitated by the construction of somatic cell hybrids because this enables the segregation of the X Chromosomes (Chrs) that carry the mutant and wild-type alleles. We describe here a method that ensures that the X Chr carrying the mutant allele is retained in somatic cell hybrids in an active selectable state. This is achieved by mating heterozygous females to males that carry a mutation at the hypoxanthine phosphoribosyl transferase (Hprt) locus. The resultant F1 females are compound heterozygotes, and when cells from these females are fused to HPRT- Chinese hamster cells and subjected to selection in HAT medium, the only survivors are those hybrid cells that retain an active X Chr carrying the mutant allele together with the wild-type Hprt allele. We use hybrids constructed by this method to demonstrate that there are no gross deletions or genomic rearrangements present in three mottled alleles associated with prenatal male lethality. PMID- 8672125 TI - Molecular analysis of a recombinational hotspot adjacent to Lmp2 gene in the mouse MHC: fine location and chromatin structure. AB - Meiotic recombinations in the proximal region of the mouse major histocompatibility complex (MHC) are clustered within certain segments of chromosome, known as hotspots. In this study, we found that one of such hotspots, previously mapped between the Pb and Ob genes, is located very close to the 3' end of the Lmp2 gene, which encodes a subunit of a proteolytic proteasome. To analyze the molecular basis of the site specificity of hotspots, we examined the structure of the chromatin around this Lmp2 hotspot and another one located in the MHC class II Eb gene, by monitoring DNase I-hypersensitive sites (DHSSs) of the chromatin. DHSSs were detected at the both hotspots in the somatic cells. In the meiotic cells, DHSS was detected within the Eb hotspot, as previously reported, but not in the Lmp2 hotspot. Thus, open structure of chromatin during meiosis, as monitored by hypersensitivity to DNase I, is not a general feature of mouse recombinational hotspots, contrasting the case of the lower eukaryote, S. cerevisiae, in which hotspots are always associated with DHSSs. PMID- 8672126 TI - Effect of the mouse scid mutation on meiotic recombination. AB - The goal of this study was to determine the effect of the mouse severe combined immunodeficiency (scid) mutation on the rate of meiotic recombination, by standard backcross linkage analysis. For this purpose, we examined four crosses that involved F1 hybrid animals heterozygous for the strain C57BL/6 and BALB/c genomes. In one set of reciprocal crosses, F1 animals were homozygous scid/scid, and in a second set of reciprocal crosses, F1 mice were homozygous wild-type (+/+) at the scid locus. Backcross progeny were typed for recombination between selected genetic markers on mouse Chromosomes (Chrs) 1, 4, 6, 7, 9, 15, and 17. Although some differences in recombination were observed over some intervals, the expression of the SCID phenotype did not appear to have a major or consistent effect on meiotic recombination. PMID- 8672127 TI - Genetic mapping of the human and mouse phospholipase C genes. AB - To determine chromosome positions for 10 mouse phospholipase C (PLC) genes, we typed the progeny of two sets of genetic crosses for inheritance of restriction enzyme polymorphisms of each PLC. Four mouse chromosomes, Chr 1, 11, 12, and 19, contained single PLC genes. Four PLC loci, Plcb1, Plcb2, Plcb4, and Plcg1, mapped to three sites on distal mouse Chr 2. Two PLC genes, Plcd1 and Plcg2, mapped to distinct sites on Chr 8. We mapped the human homologs of eight of these genes to six chromosomes by analysis of human x rodent somatic cell hybrids. The map locations of seven of these genes were consistent with previously defined regions of conserved synteny; Plcd1 defines a new region of homology between human Chr 3 and mouse Chr 8. PMID- 8672128 TI - Mapping of two genetic loci, Ten-1 and Ten-2, associated with thymus enlargement in BUF/Mna rats. AB - The thymoma-prone BUF/Mna rat is a useful model for human thymoma. Thymoma develops spontaneously in these rats at an incidence of nearly 100%. At pre thymoma age, BUF/Mna rats have extremely large thymuses when compared with those of rats of the other strains, suggesting the presence of genes that regulate the thymus enlargement. We performed linkage study to identify the genetic loci associated with thymus enlargement in {(WKY/NCrj x BUF/Mna) F1 x BUF/Mna} backcross rats. Linkage study showed the significant associations between thymus size and markers on Chromosomes (Chrs) 1 and 13, suggesting the presence of two genes, Ten-1 and Ten-2, which regulate the thymus enlargement. Ten-1 was located between myosin light chain, muscle 2 (MYL2) and D1Mgh11 loci on Chr 1, and Ten-2 was located between synaptotagmin II (SYT2) and D13N2 loci on Chr 13. PMID- 8672129 TI - Evaluation and characterization of a porcine small intestine cDNA library: analysis of 839 clones. AB - A porcine small intestine directionally cloned cDNA library was constructed in the vector lambda Zap II. Clones were hybridized with total labeled cDNA such that putative high-copy number transcripts could be differentiated from middle- and low-copy number transcripts prior to selection and characterization by DNA sequencing. More than 2000 non-hybridizing and 242 hybridizing clones were collected. In total, 839 clones were sequenced from the 3' end of the cDNA, and after inter-clone comparison, the unique clones were sequenced from the 5' end of the cDNA. The 5' data were used to query the sequence in databases and resulted in the identification of 630 different gene transcripts, of which 604 are new porcine genes. The identity of 361 transcripts could be identified from sequence comparison studies. The validity of this semi-random selection approach was verified by the identification of a large number of unique transcripts. PMID- 8672130 TI - Syntenic assignment of human serotonin receptor subtype 2 (HTR2), esterase D (ESD), and fms-related tyrosine kinase (FLT) homologs to bovine chromosome 12. AB - Bovine x rodent somatic hybrid cells have been used to syntenically map three bovine genes homologous to loci on human Chromosome (Chr) 13. These three loci, fms-related tyrosine kinase gene (FLT), esterase D (ESD), and 5-hydroxytryptamine receptor 2 (HTR2; serotonin receptor subtype 2), were assigned to bovine Chr 12 (BTA12) with 91-95% concordance to the coagulation factor 10 (F10) locus. Along with a previously mapped BTA12 gene, retinoblastoma-1 (RB1), this conserved synteny group spans 178 cM on human Chr 13 (HSA13). Previous reports suggested homology between HSA13 and both BTA2 and BTA12. Results reported here extend the boundary of the HSA13-BTA12 comparative map, contradict the previous preliminary assignment of ESD to BTA2, and suggest instead that the q arm of HSA13 may be entirely conserved in BTA12. PMID- 8672131 TI - Characterization of a human ubiquitin-conjugating enzyme gene UBE2L3. AB - Ubiquitin-conjugating enzymes (E2s) are essential components of the post translational protein ubiquitination pathway, mediating the transfer of activated ubiquitin to substrate proteins. We have identified a human gene, UBE2L3, localized on Chromosome (Chr) 22q11. 2-13.1, encoding an E2 almost identical to that encoded by the recently described human L-UBC (UBE2L1) gene present on Chr 14q24.3. Using chromosome-specific vectorette PCR, we have determined the intron/exon structure of UBE2L3. In contrast to the intronless UBE2L1 gene, the coding sequence of UBE2L3 is interrupted by three large introns. UBE2L3-derived mRNA appears to be the predominant species in most tissues rather than the transcript from UBE2L1 or another homologous gene UBE2L2, which maps to Chr 12q12. We also present additional evidence that these genes are members of a larger multigene family. The primary sequence of the protein encoded by UBE2L3 is identical to partial peptide sequence derived from the rabbit E2 'E2-F1,' suggesting that we have identified the human homolog of this protein. This latter E2 has been demonstrated to participate in transcription factor NF-kappaB maturation, c-fos degradation, and human papilloma virus-mediated p53 degradation in vitro. PMID- 8672132 TI - Strain distribution pattern for SSLP markers in the SWXJ recombinant inbred strain set: chromosomes 7 to X. AB - The SWXJ recombinant inbred (RI) set was developed for genetic analysis of heritable ovarian tumors. In this report we present data for 223 simple sequence length polymorphisms spanning Chromosomes (Chrs) 7-X to complete the genetic marking of this RI set. The strain distribution patterns (SDP) for these loci were combined with data from 19 other polymorphic genes, resulting in densely marked maps for Chrs 7-X. Combined with the 165 loci for Chr 1-6 reported previously (Svenson et al., Mamm. Genome 6, 867, 1995), the SWXJ RI set represents a powerful tool for mapping genes in neoplastic as well as other heritable disorders. PMID- 8672133 TI - Isolation, physical mapping, and northern analysis of the X-linked human gene encoding methyl CpG-binding protein, MECP2. PMID- 8672135 TI - Cloning of a polymorphic sequence from the nontranscribed spacer of horse rDNA. PMID- 8672134 TI - Exclusion of Sox9 as a candidate for the mouse mutant tail-short. AB - The Sry-related gene Sox9 has been proposed as the gene responsible for the mouse skeletal mutant Tail-short (Ts), on the basis of its expression in skeletogenic mesenchymal condensations in the mouse embryo and its chromosomal location in the region of Ts on distal Chromosome (Chr) 11. We present here detailed mapping of Ts locus relative to the Sox9, using an intersubspecific cross. Among 521 backcross progeny, 16 recombinants were detected between Sox9 and Ts, suggesting a separation of 3.5 +/- 0.01 cM, and excluding Sox9 as a candidate for Ts. A further nine recombinants were detected between Ts and the polycomb-like gene M33, suggesting that these loci are separated by 1.8 +/- 0.011 cM. Six microsatellite markers were co-localized to the Ts locus, providing reagents for positional cloning of Ts. PMID- 8672136 TI - Restriction map of two yeast artificial chromosomes spanning the murine casein locus. PMID- 8672137 TI - Genomic characterization of two introgression strains (B6.Cb4i5) for the analysis of QTLs. PMID- 8672138 TI - Mapping new murine polymorphisms detected by random amplified polymorphic DNA (RAPD) PCR. PMID- 8672139 TI - The ets-related mouse Pea3 gene maps to distal chromosome 11. PMID- 8672140 TI - A polymorphic trinucleotide repeat sequence mapping to distal mouse chromosome 4. PMID- 8672141 TI - Assignment of the mouse ataxia-telangiectasia gene (Atm) to mouse chromosome 9. PMID- 8672142 TI - The fld mutation maps near to but distinct from the Apob locus on mouse chromosome 12. PMID- 8672143 TI - Localization of mouse peroxisome proliferator-activated receptor delta (Ppard) on chromosome 17 near colipase (Clps). PMID- 8672144 TI - Genes for the neuronal immunoglobulin domain cell adhesion molecules neurofascin and Nr-CAM map to mouse chromosomes 1 and 12 and homologous human chromosomes. PMID- 8672145 TI - Genetic mapping of the endothelin receptor type A gene on sheep chromosome 17. PMID- 8672146 TI - Linkage mapping of the apolipoprotein A-I gene to bovine chromosome 15. PMID- 8672147 TI - Smcx lies distal to DXHX674 and DXHX679 on the mouse X chromosome. PMID- 8672148 TI - Localization of the Pfkfb 2 gene on rat chromosome 13. PMID- 8672149 TI - High-resolution mapping of the genes Kcnb3 and Ly63 on distal mouse chromosome 4. PMID- 8672150 TI - Linkage mapping of the carboxyl ester lipase gene (Cel) to rat chromosome 3. PMID- 8672151 TI - A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. AB - BACKGROUND: Uncontrolled studies suggest that a combination of chemotherapy and radiotherapy improves the survival of patients with esophageal adenocarcinoma. We conducted a prospective, randomized trial comparing surgery alone with combined chemotherapy, radiotherapy, and surgery. METHODS: Patients assigned to multimodal therapy received two courses of chemotherapy in weeks 1 and 6 (fluorouracil, 15 mg per kilogram of body weight daily for five days, and cisplatin, 75 mg per square meter of body-surface area on day 7) and a course of radiotherapy (40 Gy, administered in 15 fractions over a three-week period, beginning concurrently with the first course of chemotherapy), followed by surgery. The patients assigned to surgery had no preoperative therapy. RESULTS: Of the 58 patients assigned to multimodal therapy and the 55 assigned to surgery, 10 and 1, respectively, were withdrawn for protocol violations. At the time of surgery, 23 of 55 patients (42 percent) treated with preoperative multimodal therapy who could be evaluated had positive nodes or metastases, as compared with 45 of the 55 patients (82 percent) who underwent surgery alone (P<0.001). Thirteen of the 52 patients (25 percent) who underwent surgery after multimodal therapy had complete responses as determined pathologically. The median survival of patients assigned to multimodal therapy was 16 months, as compared with 11 months for those assigned to surgery alone (P=0.01). At one, two, and three years, 52, 37, and 32 percent, respectively, of patients assigned to multimodal therapy were alive, as compared with 44, 26, and 6 percent of those assigned to surgery, with the survival advantage favoring multimodal therapy reaching significance at three years (P=0.01). CONCLUSIONS: Multimodal treatment is superior to surgery alone for patients with resectable adenocarcinoma of the esophagus. PMID- 8672152 TI - A prospective study of risk factors for symptomatic urinary tract infection in young women. AB - BACKGROUND: Although acute urinary tract infections are common in young women, the associated risk factors have not been defined prospectively. METHODS: We recruited sexually active young women who were starting a new method of contraception at a university health center or a health maintenance organization (HMO) and monitored them for six months for symptomatic urinary tract infections. Daily diaries and serial interviews were used to collect data on potential risk factors. RESULTS: Among 796 women, the incidence of urinary tract infections per person-year was 0.7 in the university cohort (mean age, 23 years; n = 348) and 0.5 in the HMO cohort (mean age, 29; n = 448). In both cohorts, there were strong dose-response relations between the risk of infection and both recent use of a diaphragm with spermicide (respective relative risks for one, three, and five days of use in the past week, 1.42, 2.83, and 5.68 in the university cohort, P<0.001; and 1.29, 2.14, and 3.54 in the HMO cohort, P=0.04) and recent sexual intercourse (respective relative risks for one, three, and five days with intercourse in the past week, 1.37, 2.56, and 4.81 in the university cohort, P<0.001; and 1.24, 1.91, and 2.96 in the HMO cohort, P=0.002). The risk of acute infection was also associated with a history of recurrent infection (relative risk, 5.58 in the university group and 2.10 in the HMO group) but not with cervical-cap use, ABO-blood-group nonsecretor phenotype, or delayed postcoital voiding. CONCLUSIONS: Among sexually active young women the incidence of symptomatic urinary tract infection is high, and the risk is strongly and independently associated with recent sexual intercourse, recent use of a diaphragm with spermicide, and a history of recurrent urinary tract infections. PMID- 8672153 TI - Costs and charges associated with three alternative techniques of hysterectomy. AB - BACKGROUND: Many hysterectomies are now performed by a laparoscopically assisted vaginal technique. This procedure is controversial, partly because of concern about cost. We studied hospital charges and costs for the procedure as compared with those for total abdominal hysterectomy and total vaginal hysterectomy in clinically similar groups of patients. METHODS: From hospital-discharge data and patients' charts, we identified hysterectomies performed in 1993 and 1994 by 96 surgeons at a community teaching hospital to treat benign conditions. The patients were grouped according to the surgical procedures performed in conjunction with the hysterectomy. Data on hospital charges and cost-to-charge ratios for 64 hospital cost centers were used to assess charges and costs for specific resources, as well as for the hospitalization overall. RESULTS: Of 1049 patients studied, 26 percent underwent laparoscopically assisted vaginal hysterectomy, 54 percent underwent abdominal hysterectomy, and 20 percent underwent vaginal hysterectomy. The average hospital stays were 2.6, 3.9, and 2.9 days, respectively, and the mean total charges (facility charges plus professional fees) for the hospitalizations were $6,116, $5,084, and $4,221 (P<0.001 for the comparison of the laparoscopic technique with both other techniques). The mean facility costs were $4,914, $3,954, and $3,116, respectively (P<0.001 for the same comparison), with similar findings in all subgroups. The higher charges and costs for laparoscopically assisted vaginal hysterectomy were due to higher supply costs, particularly when disposable supplies were used, and to longer operating-room time. CONCLUSIONS: Despite shorter hospital stays, in-hospital charges and costs for laparoscopically assisted vaginal hysterectomy are higher than for either alternative procedure, because of the disposable supplies that are typically used and the longer operating-room time. PMID- 8672154 TI - Use of alternative techniques of hysterectomy in Ohio, 1988-1994. AB - BACKGROUND: Laparoscopically assisted vaginal hysterectomy has been promoted as a substitute for both abdominal and vaginal hysterectomy, with claimed benefits of lower costs, shorter hospital stays, and quicker postoperative recovery. METHODS: Using computerized hospital-discharge data for 1988-1994 from 180 hospitals in Ohio, we analyzed rates of abdominal, vaginal, and laparoscopically assisted vaginal hysterectomy and their association with characteristics of patients, complications, in-hospital mortality, and hospital charges. RESULTS: The annual age-adjusted rate of hysterectomy fell 10 percent, from 4.53 per 1000 female state residents in 1988 to 4.07 per 1000 in 1994 (P<0.001). In 1988, 1.1. percent of all hysterectomies were performed by the laparoscopically assisted vaginal technique; this proportion increased to 9.2 percent in 1993 and declined to 7.5 percent in 1994. For gynecologic conditions other than cancer or pregnancy, women undergoing laparoscopically assisted vaginal hysterectomy as compared with one of the other techniques were more likely to have commercial insurance and to have their surgery at an urban hospital for diagnoses related to pain, endometriosis, or pelvic inflammatory disease. With abdominal and laparoscopically assisted vaginal hysterectomy, the complication rates were similar and were higher than those with vaginal hysterectomy. In-hospital mortality was similar for vaginal and laparoscopically assisted vaginal hysterectomy and was lower than for abdominal hysterectomy. Median hospital charges were $8,108 for laparoscopically assisted vaginal hysterectomy, $5,723 for abdominal hysterectomy, and $5,049 for vaginal hysterectomy. CONCLUSIONS: The rate of hysterectomy in Ohio decreased from 1988 to 1994, as laparoscopically assisted vaginal hysterectomy became more common. Laparoscopically assisted vaginal hysterectomy was associated with higher hospital charges than the other techniques. PMID- 8672155 TI - The management of chronic heart failure. PMID- 8672157 TI - Multimodal therapy for adenocarcinoma of the esophagus and esophagogastric junction. PMID- 8672158 TI - Sex and urinary tract infections. PMID- 8672159 TI - Laparoscopic hysterectomy--is there a benefit? PMID- 8672160 TI - The emerging role of "hospitalists" in the American health care system. PMID- 8672166 TI - Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. AB - BACKGROUND: Estrogen therapy in postmenopausal women has been associated with a decreased risk of heart disease. There is little information, however, about the effect of combined estrogen and progestin therapy on the risk of cardiovascular disease. METHODS: We examined the relation between cardiovascular disease and postmenopausal hormone therapy during up to 16 years of follow-up in 59,337 women from the Nurses' Health Study, who were 30 to 55 years of age at base line. Information on hormone use was ascertained with biennial questionnaires. From 1976 to 1992, we documented 770 cases of myocardial infarction or death from coronary disease in this group and 572 strokes. Proportional-hazards models were used to calculate relative risks and 95 percent confidence intervals, adjusted for confounding variables. RESULTS: We observed a marked decrease in the risk of major coronary heart disease among women who took estrogen with progestin (multivariate adjusted relative risk, 0.39; 95 percent confidence interval, 0.19 to 0.78) or estrogen alone (relative risk, 0.60; 95 percent confidence interval, 0.43 to 0.83), as compared with women who did not use hormones [corrected]. However, there was no significant association between stroke and use of combined hormones (multivariate adjusted relative risk, 1.09; 95 percent confidence interval, 0.66 to 1.80) or estrogen alone (relative risk, 1.27; 95 percent confidence interval, 0.95 to 1.69). CONCLUSIONS: The addition of progestin does not appear to attenuate the cardioprotective effects of postmenopausal estrogen therapy. PMID- 8672167 TI - Redesigning graduate medical education -- location and content. PMID- 8672168 TI - Longitudinal comparison of carbohydrate-deficient transferrin and gamma-glutamyl transferase: complementary markers of excessive alcohol consumption. AB - The utility of carbohydrate-deficient transferrin (CDT) and gamma-glutamyl transferase (GGT) as biochemical markers of excessive alcohol consumption was studied in alcohol-dependent subjects. Serum samples were collected once weekly from 10 male out-patients undergoing a 6-month alcohol treatment programme. Frequency of relapse into drinking (defined as any intake of alcoholic beverage) was assessed by self-reports during patient interviews three times per week and by daily determination of the 5-hydroxytryptophol level in urine. A marked decrease in mean CDT and GGT values was observed during the initial month. Only one patient remained totally abstinent throughout the observation period, while four had sporadic relapses (2-5 days with alcohol consumption). Both CDT and GGT remained below the respective reference limits in those patients. The other five patients drank more frequently (range 22-57 days) and increased their mean levels of CDT and GGT after the initial decrease. As determined from the values at admission and during the course of the study, CDT appeared to be the most sensitive marker in six out of the 10 patients. In one patient, both markers were affected in a parallel way, whereas two of those with frequent relapses responded to alcohol consumption with a marked increase in GGT, but with no or only a slight increase in CDT. One patient did not show any abnormal CDT or GGT values. In 54 female and 60 male serum samples collected at random from patients during admission at an alcohol detoxification unit, 35% and 58% of the CDT values exceeded the reference limits for females and males, respectively. For GGT, 59% of the female and 67% of the male values were above cut-off. Carbohydrate deficient transferrin and GGT were not significantly correlated. Taken together, the present results indicate that measurement of both CDT and GGT will increase the possibility of identifying excessive alcohol consumption. By following changes in CDT and GGT values during a period of alcohol withdrawal, the most sensitive individual marker can be determined. This in turn allows for improved detection of relapse into heavy drinking during long-term monitoring of out patients. PMID- 8672169 TI - The irreversible gamma-aminobutyrate transaminase inhibitor vigabatrin in the treatment of the alcohol withdrawal syndrome. PMID- 8672170 TI - Some thoughts and reflections on authorship. PMID- 8672171 TI - Ethics, funding and alcohol research. AB - The field of alcohol research is a multidisciplinary area of inquiry. Moreover the debate about alcohol issues is highly politicized, involving not only researchers but also 'advocates' and those with strong ideological orientations or who represent powerful vested interests. Researchers may easily be caught in the crossfire in polemics involving such people. From time to time ethical malpractice is evident, yet there are often neither clear guidelines to delineate which behaviours are unacceptable nor how ethical violations are to be handled. This paper considers a number of key issues currently topical in the field. These are specifically concerned with the relationships between funders or sponsors and policy makers and researchers. Such issues include the ownership of data, sponsor control and the divergent cultures and outlooks of researchers and sponsors/funders. It is concluded that the field of alcohol research requires a code of ethics to regulate the relationship between researchers and funders. This should provide protection for subjects, patients, clients, researchers and those who pay for research. Some tentative suggestions are put forward for discussion. PMID- 8672172 TI - Thiamine administration during chronic alcohol intake in pregnant and lactating rats: effects on the offspring neurobehavioural development. AB - A number of mechanisms may be involved in the pathogenesis of thiamine deficiency in the alcoholic. Among these mechanisms are inadequate dietary intake of thiamine, impaired intestinal transport of the vitamin and decreased conversion of thiamine to the active coenzyme. The present study was undertaken to further investigate the mechanism by which alcohol can interfere with thiamine deficiency in the brain. Thus, the neurobehavioural development of rat pups (E) nursed by 12% ethanol/water-drinking mothers, or pups (E-T) nursed by mothers drinking 12% ethanol/water + thiamine hydrochloride mixture, was monitored from the 1st to 45th postnatal days. Appropriate pair-fed saccharose (S) and ad libitum controls (C) were assessed. Histological studies were performed at the age of 45 days on the hippocampal CA3 pyramidal neurons of the offspring from each treatment. Exposing rat pups to ethanol during pregnancy and lactation showed a significant impairment of neurobehavioural development, more cornered pyramidal cells in the hippocampal field CA3, reduced cell number and cell size. The results point out long-lasting effects of maternal alcohol exposure in the offspring. Both functional and structural studies showed that neurotoxic effects of developmental alcohol exposure were not reversed by thiamine administration. However, adverse effects of undernutrition following developmental alcohol exposure were suppressed by thiamine administration. From this work, we suggest that inadequate dietary intake of thiamine and impaired intestinal transport of the vitamin are not critical mechanisms leading to thiamine deficiency in chronic alcoholism. The most prevalent mechanism contributing to ethanol-induced thiamine deficiency in chronic alcoholics would be the alteration of thiamine metabolism, and particularly the reduction of the vitamin conversion to its metabolically active form TPP (thiamine pyrophosphate). PMID- 8672173 TI - Increased female drinking in accordance with post-industrial urbanization in Japan. AB - We studied the relationship between living in an urban area and the alcohol consumption habits of young mothers in light of the recent increase of the female drinking population in Japan, particularly among those from 20 to 39 years of age. We conducted a survey in four areas in and around Tokyo, each area representing a different level of urbanization. The study population consisted of 6418 mothers of 3-year-old children; an 84.9% response rate was obtained. Thirty eight per cent of the respondents had drunk at least four units of alcohol (about 44 g of pure ethanol) during the most recent month. The proportion of current drinkers in a more-urbanized area was greater than that in a less-urbanized area, and this tendency was significant (P < 0.001). Current workforce participation was significantly positively associated with current drinking (P < 0.01). Younger age significantly increased chances of current drinking (P < 0.05). Effects of living in a more-urbanized area on current drinking of mothers of 3-year-old children after excluding the effects of workforce participation and age was significantly positive (P < 0.001). An increase in female drinking in Japan was considered to be due to acculturation associated with urbanization in a post industrial society. PMID- 8672174 TI - Effect of chronic ethanol consumption on glycosylation processes in rat liver microsomes and Golgi apparatus. AB - Previous studies have demonstrated that acute ethanol intoxication affects various steps of protein glycosylation at the level of rat liver endoplasmic reticulum and Golgi apparatus. The aim of this investigation was to demonstrate whether chronic ethanol intake can induce definitive changes of liver glycoprotein processing. Rats were given ethanol by liquid diet for 8 weeks. At the end of this period the triglyceride levels in liver homogenate and microsomes were significantly higher than in controls. Isolated hepatocytes prelabelled with [3H]Na palmitate and [14C]glucosamine showed a significant storage of the lipid and carbohydrate radioactivity in microsomes and Golgi apparatus and a significant impairment of labelled glycolipoprotein secretion. Changes of the glycosylation steps were observed both in endoplasmic reticulum and in Golgi apparatus: in the former the levels of dolichyl phosphate, which is rate-limiting for the synthesis of glycoprotein, showed a significant reduction; in the latter the activity of the main enzymes responsible for the terminal glycosylation process was significantly decreased. These data suggest that an impairment of glycoprotein maturation may be involved in the pathogenesis of liver injury induced by chronic ethanol intake. PMID- 8672175 TI - Simple versus sophisticated models of breath alcohol exhalation profiles. AB - For medicolegal purposes, breath alcohol content is typically determined from an end-expiratory sample. Measurements obtained by this method necessarily underestimate the alveolar breath alcohol content, and therefore underestimate the blood alcohol content. We suggest and analyse an improved paradigm which uses the entire time-series of breath alcohol measurements during exhalation, not simply the last recorded value. We present two mathematical models for the exhaling lung, and discuss the implications of each for more accurate and therefore more reliable breath alcohol measurement. PMID- 8672176 TI - Changes in the ileal disaccharidase activities in rats after long-term ethanol feeding. AB - Brush border enzymatic activities (maltase, lactase and sucrase) have been determined in the ileal mucosa of rats subjected to a 30% ethanol ingestion for 3 and 5 months. The data were compared with the results obtained with control rats. Mucosal protein content after 3 months of ethanol treatment was similar to that of control rats. Maltase, lactase and sucrase specific activities in ileal mucosa were significantly decreased in ethanol-fed animals as compared to control rats. After 5 months of ethanol consumption, the protein content was decreased in ethanol-fed rats. However, no differences were found between specific activities of maltase, lactase and sucrase of ethanol-fed with respect to control rats. It is suggested that prolonged exposure of rats to ethanol results in adaptive responses to the effects of shorter periods of exposure on intestinal mucosal function. PMID- 8672177 TI - Ethics in alcohol research and publishing. PMID- 8672178 TI - The effects of disulfiram on equine hepatic alcohol dehydrogenase and its efficiency against alcoholism: vinegar effect. AB - The effects of disulfiram, its metabolite diethyldithiocarbamate and dithiodipyridine on alcohol metabolism of equine hepatic alcohol dehydrogenase (EC.1.1.1.1.) have been investigated. They were found to form enzyme-NAD(+) inhibitor complexes which were competitive inhibitors of alcohol metabolism with dissociation constants (KEO,I) at pH 7.0 of 50 microM, 1.3 mM, and 260 microM, respectively. Acetate and vinegar behaved similarly in forming an inhibitory enzyme-NAD(+)-acetate ternary complex competitive with ethanol, with at pH 7.0 essentially identical dissociation constants of 4.0 mM and 3.8 mM, respectively. Disulfiram, diethyldithiocarbamate and dithiodipyridine were also found to exhibit affinity-labelling kinetics with liver alcohol dehydrogenase. The liver enzyme is chemically modified and inactivated in a similar manner by all three reagents via binary enzyme complexes with dissociation constants of 30 microM, 200 microM and 50 microM, respectively. Used as a protector against enzyme inactivation by DL-alpha-bromo-beta-(5-imidazolyl)-propionic acid, disulfiram, diethyl-dithiocarbamate and dithiodipyridine were found to form competitive binary enzyme complexes by binding to the active zinc site with KE,I values of 30 microM, 170 microM and 50 microM, respectively. The disulfiram and acetate binding to zinc results in the formation of binary and ternary complexes which inhibit alcohol metabolism at the enzyme level. Due to many unwanted side effect), and the easy removal of its anti-drinking effects by drinking vinegar (vinegar effect), disulfiram may still be questioned as an effective drug against alcoholism. PMID- 8672179 TI - Effects of alcohol on blastocyst implantation site blood flow in the rat. AB - The effect of alcohol on blood flow at sites of blastocyst implantation versus adjacent intersites was measured in conscious unrestrained rats on day 5 of pregnancy. Alcohol (0.75 ml of 100% ethanol diluted 1:2, v/v) was injected into the femoral vein (1 g/kg body wt); controls received an equivalent volume of vehicle (physiological saline). Implantation sites were rendered visible by intravenous injection of Evans Blue dye. Blood flow was measured at 15 min after alcohol injection by the 86Rb fractionation method. In controls, blood flow was significantly greater (P < 0.05) at implantation sites (0.77 +/- 0.04 ml/min/g) than at intersites (0.43 +/- 0.03 ml/min/g). Alcohol markedly increased (P < 0.05) perfusion at both sites (2.17 +/- 0.22 ml/min/g) and intersites (1.74 +/- 0.15 ml/min/g) vs respective controls. Blood alcohol levels exceeded 100 mg/dl at 10 min post-injection. Mean cardiac output and haematocrit values did not differ significantly between control and treated rats. The data indicate that alcohol enhances uterine vascular perfusion and that the vascular bed of implantation sites is susceptible to the haemodynamic effects of alcohol. Enhanced uterine blood flow may contribute to the alcohol-induced changes in embryo development, blastocyst implantation and endometrial decidualization observed in the rat. PMID- 8672180 TI - Chronic ethanol consumption ameliorates the maturity-onset diabetes-obesity syndrome in CBA mice. AB - The effects of a chronic ethanol drinking schedule (20% solution for 6 weeks) on energy balance and carbohydrate and lipid metabolism have been investigated in lean (32-36 g) and obese-diabetic (40-44 g) CBA/Ca mice. The untreated obese diabetic mice exhibited hyperglycaemia, hypertriglyceridaemia, hyper-insulinaemia and insulin resistance. The chronic ethanol treatment, which yielded plasma ethanol levels of between 1 and 11 mM, lowered the blood glucose, plasma insulin and triacylglycerol levels towards normal in the obese mice, but did not affect these parameters in the lean mice. The body weight of the obese mice tended to return to normal during the 6-week drinking period, although their total energy intake (9.2-10.0 kJ/g/week, food plus ethanol-derived calories) was almost double that of the lean mice (4.8-5.4 kJ/g/week). The blood glucose response to acute insulin injection, which was significantly reduced in the obese mice, became indistinguishable from the response of normal mice after chronic ethanol treatment. Soleus muscle glycogen synthesis in both lean and obese mice was not significantly altered by ethanol drinking, but brown adipose tissue lipogenesis was significantly increased (by 50%) in the obese mice. It is proposed that ethanol is acting chronically to restore insulin sensitivity in the obese diabetic mice at doses which have little or no effect in normal lean animals. This action is exerted, at least in part, at the level of brown adipose tissue lipogenesis. PMID- 8672181 TI - The impact of a preconceptional health promotion program on intendedness of pregnancy. AB - The objective for this study was to determine whether a brief preconceptional health promotion program for low-income women attending family planning clinics impacts on intendedness of pregnancy. In this prospective study, we examined data on 1378 women presenting for prenatal care at three local health departments. Each of the departments offers a standardized preconceptional health promotion program in its family planning clinics. Comparisons were undertaken for 456 women who had been exposed to the family planning preconception program, 309 women who had attended the family planning clinics but had not been exposed to the program, and 613 women who were unknown to the health department before beginning prenatal care. Women exposed to information on preconceptional health during routine family planning visits, the experimental group, had a 51.8% (p = 0.064) greater likelihood of identifying their pregnancies at intended than a group known to the local health departments' family planning programs but unexposed to the intervention. Furthermore, the experimental group had a 64.2% (p = 0.0009) greater likelihood of intendedness than a comparison group not known to the health departments before the initiation of prenatal care. Our study indicates that an introductory program of preconceptional health promotion which is targeted to women not planning a pregnancy in the immediate future is associated with a higher rate of intendedness in subsequent pregnancies. Expansion of similar preconceptional programs in family planning clinics may prove a useful approach for promoting intendedness of pregnancy in low-income women. PMID- 8672182 TI - The relation of maternal complications to outcomes in very low birthweight infants in an era of changing neonatal care. AB - We examine the relation of key neonatal outcomes to pregnancy complications and to the use of antenatal steroids and investigate whether there is evidence of recent change in this relation. Complete information on pregnancy and neonatal course was available for 749 out of 949 singleton births without major congenital anomalies below 1501 g admitted to seven regional neonatal intensive care units between August 1, 1988 and June 30, 1991. Mortality was highest in infants born after labor with spontaneous rupture of fetal membranes of less than 24 hours duration (odds ratio [OR] = 1.6, 95% confidence interval [1.0, 2.6]). Spontaneous rupture of membranes of over 24 hours duration was associated with decreased risk of respiratory distress syndrome (OR = 0.42, [0.28, 0.64]) and decreased risk of patent ductus arteriosus (OR = 43, [0.28, 0.66]). Pregnancy induced hypertension was associated with increased risk of respiratory distress syndrome in those born at less than 20 weeks' gestation (OR = 6.0, [2.0, 17]). Labor with or without rupture of membranes of short duration was associated with increased risk of intraventricular hemorrhage (OR = 1.9, [1.2, 2.5]). These associations were not different in early versus late time periods of the study. Antenatal steroids were associated with dramatically reduced risk of mortality (OR = 0.20, [0.09, 0.50] ), respiratory distress syndrome (OR = 0.52, [0.32, 0.85]), and intraventricular hemorrhage (OR = 0.37, [0.21-0.65]). PMID- 8672183 TI - Bilateral fetal chylothorax: results of unilateral in utero therapy. AB - The optimal method for antenatal treatment of pleural effusions from congenital chylothorax unknown. A fetus with bilateral congenital chylothorax and hydrops had a pleural catheter placed in utero on only one side of the fetal chest for 14 days prior to delivery. The fetal hydrops partially resolved. After birth there was significantly less drainage from the pleural space that had been antenatally drained. This case demonstrates potential neonatal advantages of pleuro-amniotic shunt placement. PMID- 8672184 TI - Effect measures for behavioral factors adversely affecting fetal growth. AB - The purpose of this study was to estimate the proportion of ultrasonically diagnosed fetal growth retardation that may be attributable to potentially remediable factors (for example, cigarette smoking, alcohol use, and drug addition). We computed multivariate odds ratios for fetal growth retardation associated with cigarette smoking and alcohol and illicit drug consumption in 350 singleton pregnancies complicated by fetal growth retardation and 700 controls. The odds ratio of fetal growth retardation among women who smoked throughout pregnancy was 2.61 (95% confidence interval, 1.38 to 4.93) compared to women who claimed to have stopped smoking by the 18th week of gestation. The summary attributable risk of fetal growth retardation associated with behavioral variables measured during the first trimester and thereafter ranged from 18 to 21%. By implication, the maximum proportion of fetal growth retardation that could theoretically be prevented by eliminating these risk factors accounts for about 1% of all births. However, allowance for the limited modifiability of preventable factors and the consistent overlap between them would probably reduce such estimate to less than 1%. We conclude that only interventions to reduce the prevalence of strong risk factors (for example, preeclampsia, sociodemographic variables) may have a substantial effect on the incidence of impaired fetal growth and subsequent infant morbidity. PMID- 8672185 TI - Predicting neonatal outcomes. PMID- 8672186 TI - Transition from housestaff in the neonatal intensive care unit: a time to review, revise, and reconfirm. PMID- 8672187 TI - Clinical commentary: the bromocriptine (Parlodel) controversy and recommendations for lactation suppression. AB - Mounting concerns about bromocriptine (Parlodel) and rare cardiovascular and cerebrovascular accidents have prompted the manufacturer to remove the drug from the market for use in postpartum lactation suppression. No drug is available now or will be in the forseeable future for the indication. This change in prescribing practice should alert the physician to counseling the expectant mother about the merits of breast feeding and about simple, non-pharmacologic methods of suppressing milk production. PMID- 8672189 TI - Pregnancy in a patient with Goodpasture syndrome and renal transplantation. AB - Patients with Goodpasture syndrome have classically had decreased fertility and associated pregnancy wastage. Renal transplantation can increase the likelihood of successful pregnancy. We describe a patient who carried a pregnancy into the third trimester and had a good neonatal outcome. However, she developed superimposed preeclampsia with subsequent graft rejection. PMID- 8672188 TI - Effects of obesity on pregnant women: maternal hemodynamic change. AB - The purpose of this study is to clarify the effects of obesity on hemodynamic change in pregnant women. From 1322 primiparous women and 1027 multiparous women who delivered singleton babies with no life-threatening anomalies, 110 primiparous obese women, 1050 primiparous normal-weight women, 139 multiparous obese women, and 816 multiparous normal-weight women were selected according to body mass index at the first visit prior to the 10th gestational week. Women exhibiting chronic hypertension, over diabetes mellitus, and extreme skinniness were excluded. All of the women had been under the same management at Osaka City University Hospital. Their medical records were analyzed retrospectively. The study determined the arterial blood pressure of obese women to be significantly higher than that of normal-weight women throughout pregnancy in both primipara and multipara. The incidence of pregnancy-induced hypertension in obese women was significantly higher in primipara (22.7% versus 8.2%) and multipara (15.8% versus 5.0%). The incidence of intrapartum hypertension was also higher in the obese group. Hematocrit count at 3 gestational months (37.7 +/- 3.1 in primipara, and 37.6 +/- 2.7 in multipara) and 8 gestational months (34.4 +/- 2.7 in primipara, and 33.7 +/- 2.7 in multipara) were significantly higher than those in normal weight women. Exercise tests using impedance cardiographs showed poor cardiac function in 5 of 17 obese women. These findings led us to conclude that obesity during pregnancy is clearly accompanied by hypertension, hemoconcentration, and poor cardiac function. PMID- 8672190 TI - Effect of vibroacoustic stimulation on fetal meconium passage in labor. AB - It has been suggested that vibroacoustic stimulation might be stressful to the fetus. The present study was designed to evaluate whether the stimulus induces passage of meconium in labor. Patients in labor at term with healthy fetuses and intact membranes were randomized to a vibroacoustic stimulation or sham test. The incidence of meconium was the same in both groups. Pregnancy outcome variables were also similar in both groups. In conclusion, vibroacoustic stimulation does not increase the incidence of meconium passage of labor of healthy fetuses. PMID- 8672191 TI - Elevated umbilical erythropoietin levels during labor in newborns of smoking mothers. AB - Umbilical cord blood erythropoietin levels and hematocrit are significantly higher in smoking mothers than those nonsmoking ones. In addition, the incidence of newborns with low birthweight is higher in women who smoke. We conclude that in addition to other parameters, cord blood erythropoietin might be used as a valuable indicator of fetal distress in smokers. PMID- 8672192 TI - First trimester biological markers for the prediction of pregnancy-induced hypertension. AB - The purpose of this study is to predict pregnancy-induced hypertension (PIH) by standard methods at the first antenatal visit prior to the 12th gestational week (GW). This is a retrospective study of 1189 primipara and 957 multipara who delivered singleton babies having no major malformations after the 32nd GW. Multiple regression analysis for the development of PIH was performed using the mean arterial blood pressure (MBP), body mass index (BMI), hematocrit count at the first visit prior to the 12th GW, a family history of hypertension number of pregnancies, number of deliveries, past history of hypertension and evidence of threatened abortion as explanatory variables in primipara and multipara, respectively. We obtained a significant regression equation in both primipara and multipara. Multiple correlation coefficient for primipara was 0.40223 (p < 0.01) and for multipara was 0.50764 (p < 0.01). When MBP was over 80 mm Hg, BMI was over 23.6, a family history of hypertension was present, or a past history of hypertension was present, these variables were significantly correlated with the development of PIH both in primipara and multipara. By combining these variables, we obtained 32.7% positive predictive value, 93.5% negative predictive value, 31.7% sensitivity, and 93.7% specificity in primipara and 24.6%, 96.7%, 52.6%, and 89.8% in multipara, respectively. As the incidence of PIH was 8.7% in primipara and 5.9% in multipara, we could predict 3.7 and 4.1 times higher than the true incidence. PIH can therefore be predicted by the simple combination of MBP, BMI, a family history of hypertension, and a past history of hypertension prior to the 12th GW. It can also be predicted by the multiple-regression equation with the use of nine explanatory variables. PMID- 8672193 TI - Hyperreactio luteinalis associated with pregnancy: a case report and review of the literature. AB - Hyperreactio luteinalis is a condition associated with bilateral and, in rare cases, unilateral ovarian enlargement due to theca lutein cysts. Hyperreactio luteinalis is a benign condition, usually found incidentally at cesarean section, which can appear anaplastic and lead to unnecessary ovarian resection. A 21-year old Hispanic woman, G2P1, presented at 19 weeks with a singleton pregnancy, bilaterally enlarged ovaries, and a normal beta hCG. Over the next four months, her ovaries increased 75% in size with the right ovary becoming entrapped in the pelvis. The patient underwent a primary low transverse cesarean section. The ovaries had an anaplastic appearance and on frozen section revealed multiple benign theca lutein cysts. There are 51 reported cases of hyperreactio luteinalis associated with a normal pregnancy in the literature. It is estimated that approximately 60% of the cases of hyperreactio luteinalis unassociated with trophoblastic disease occur with normal singleton pregnancy. There are multiple benign ovarian lesions including hyperreactio luteinalis that can mimic ovarian neoplasms. Accordingly, it is important to exclude these from the differential diagnosis via a wedge biopsy and frozen section to avoid unnecessary surgical excision. PMID- 8672194 TI - An outbreak of antibiotic multiresistant Klebsiella at the Neonatal Intensive Care Unit, Kaplan Hospital, Rehovot, Israel, November 1991 to April 1992. AB - From November 1991 through April 1992, 8 infants developed systemic infections due to antibiotic multiple resistant Klebsiellaa (MRK). All were premature and 6 of the 8 weighed less than 1100 g; 7 of the 8 had received previous antibiotic therapy. Five infections occurred during the first week of life. MRK were isolated from blood (8 cases), tracheal secretions (TS-6), stool (3), and CSF (1). All Klebsiella blood isolates were resistant to ampicillin, mezlocillin, and cefotaxime, 7 of 8 to ceftazidime and amikacin, and 4 of 7 to aztreonam; all isolates were sensitive to quinolones and imipenem. Four infants died. In all 4 of the isolates, they were sensitive only to quinolones and imipenem, and the empiric therapy used for suspected sepsis proved to be inappropriate. The outbreak was terminated by temporary closure of NICU in May 1992. Strict hand washing practices were reemphasized, and the previous empiric antibiotic protocol used for suspected sepsis (mezlocillin plus amikacin, and lately ceftazidime plus amikacin) was changed to imipenem and amikacin in the risk population. At closure, 5 additional infants had MRK in stools and/or tracheal suction specimens. Development of MRK organisms should dictate a rational use of empiric antibiotics for neonatal infections in NICU. PMID- 8672195 TI - [Manual medicine in otorhinolaryngology. Theoretical principles-- clinical practice--principles of therapy and prevention]. AB - Manual medicine or ?chirotherapy? has become a recognized part of medical training in Germany. In the last few decades, research in various fields has shed light on the pathoanatomic and pathophysiologic causes of functional disorders of the cervical vertebral column whose previous management was characterized by treatment of symptoms. The Arthron system provides a cybernetic model in the form of a closed-loop feedback system for visualization and training purposes. A momentary isolated disorder or recurrent exogenous disorders can be represented as reversible processes; the phases of reflex buildup, development of a vicious circle, and/or exhaustion of compensatory processes can be identified and modeled. The Arthron system focuses on neuromuscular dysfunction as the cause of reversible disturbance (and not on joint dysfunction as the did earlier theoretical models). By focussing on the ?on-target? manoevre, chirotherapy aims at resolving joint dysfunction (blocks) and achieve manual and reflex mobilization. Therapy includes medical relaxation of tense musculature and transient interruption of the nerve pathway. PMID- 8672196 TI - [Self assessment and actual intelligibility of speech audiometry test material]. AB - Self-estimated and measured intelligibility were compared using different instructions in speech audiometric tests. The results of 69 tested persons reveal that there exist speech levels in both test procedures where the intelligibility reaches 0% or 100%, respectively. In general, self-estimated intelligibility was significantly higher than real identification. Therefore, the self-estimation of intelligibility does not appear as an appropriate procedure to automated speech audiometry. The results are a speech audiometric equivalent of the subject's to have correctly understood speech in daily life in which in fact was misunderstood. Connections to central speech processing seem to be possible. Audiologists might be influenced by the effect of overestimation of speech intelligibility as well. However, preliminary investigations concerning pseudohypacusis show different results. PMID- 8672197 TI - [Clinical aspects of coping with tinnitus]. AB - Forty-two patients suffering form chronic tinnitus participated in our psychologically oriented treatment last year. The following study presents the results of the psychological management of chronic tinnitus combining counselling with relaxation training. Furthermore individual therapy is compared with group therapy. The therapeutical efficiency can be tested using visual analog scales. The individual estimated loudness and annoyance of tinnitus are registered. A quantitative assessment of complaints is made via questionnaires (adapted to Back Depression Inventory). In most cases a reduction of tinnitus loudness and annoyance after individual and group therapy is seen directly. But a constant therapeutical effect is only found is individual therapy. In group therapy, many of our patients reported an increase in the pretherapeutical estimation of tinnitus loudness and annoyance. We believe that permanent confrontation with the tinnitus problem may advance the psychological conflict in many cases. Therefore, psychological management of tinnitus should be concentrated on temporary limited support aimed at overcoming tinnitus sensation. PMID- 8672198 TI - [Anxiety syndrome in vertigo patients. A comparison of neuro-otologic findings in patients with and without anxiety]. AB - Anxiety is a common symptom is vertigo patients. ACute anxiety is known in neurology and psychiatry as panic disorder. The cardiovascular and the gastrointestinal subtypes have been used in the classification of panic disorders up to now. Frommberger and co-workers (1993) have also defined a vestibular subtype. In this study, we have compared the neurotologic test results of 53 patients with vertigo in combination with panic disorder and of 53 patients with balance disorders without anxiety to clarify, whether disturbances in the vestibular systems can be objectivated or not. Differences of both groups were found in history data, especially in the vertigo characteristics, the accompanying vegetative symptoms, the releasing mechanisms, the duration of the attacks, and the total time of the dizziness complaints. The mean age was less significant in the patients with panic disorder than in the control group. The test results of the anxiety group showed a higher rate of right-directed spontaneous nystagmus and less pathological vestibular findings in the caloric and rotating test as well as in the Unterberger stepping test when compared to the control group. Some of the patients with panic disorder developed acute anxiety during the examination. PMID- 8672199 TI - [Dimorphism of cerumen, facts and theory]. AB - ?Dimorphism? means the existence of two phenotypic different types of the human cerumen and morphology of the cerumen glands. In this paper, the morphological, biochemical, and functional differences are reviewed. The wet cerumen is better adapted to a hot and humid climate where infections of the outer ear are very frequent and sometimes severe. In a cold and dry climate, the dry cerumen is advantageous. In the moderate climates, both types are equivalent (balanced dimorphism). PMID- 8672200 TI - [Current immunohistochemical results of localization of vasoactive intestinal polypeptide (VIP) in nasal mucosa of the human]. AB - Besides classic neurotransmitters, neuropeptides seem to participate in the control of human nasal physiology. In this region vasoactive intestinal peptide (VIP) is found in higher concentration than other neuropeptides. The aim of this study was to localize VIP in neuronal and non-neuronal structures of the human nasal mucosa using immunocytochemical techniques. Paraffin and frozen serial sections of the inferior turbinate were incubated with antibodies against neuronspecific enolase (NSE) to demonstrate neuronal structures or against VIP. The immunocomplexes were visualized by the Avidin-Biotin-Complex (ABC)-method. VIP-positive nerve fibers were found around the acinus cells and the ducts of the seromucous glands. These results emphasize the influence of VIP on nasal gland secretion. Few immunoreactions to the VIP were demonstrated in the nerves of the adventitia of veins and arteries. Additionally, by comparing NSE nad VIP localization, strong extranerval immunoreactions in the tunica medica of the arterioles were demonstrated, as were lesser but still visible immunoreactions in the muscular layer of thick veins. These morphological findings in vessels and the well known vasodilatory effect of VIP underline the functions of this neuropeptide on the nasal mucosa in man. Thus, by increasing the blood flow and volume, VIP, in conjunction with other control factors, seems to participate in the physiological processes of the swelling mechanism of nasal turbinates and influence nasal congestion. PMID- 8672201 TI - [Rhinomanometric analysis of vestibular stenoses of the nose]. AB - The distinction of the resistance in the nasal vestibule (valve area) and cavity (turbinates, septum deviations, crest, spine) is important for the settlement of the operative course in nasally impaired patients. Collapsed valves, free floating polyps, spines, and other turbulence producing factors in the nose are characterized in active anterior rhinomanometry (AAR) as decreased ?percentage of flow increase? (deltaV150-300). This parameter allows no distinction between underlying anatomical factors. Other patients have increased resistance in the vestibule area that is static; rhinomanometry is unable to document these instances. The aim of this study was to investigate the influence of the vestibule dilator on nasal flow, and to determine if the diagnostic findings of AAR could be improved by the data obtained from the measurement with the dilator. METHODS: To prove the influence of the vestibule dilator on the nasal airflow, we determined typical rhinomanometric parameters in 20 nasally healthy and 40 nasally impaired persons with and without the dilator. For the measurements, we used a computer-aided rhinomanometer (Rhinodat K, Heinemann Medizintechnik, D Hamburg). Tubular vestibule dilators were produced from silicon guide rails of tracheal tubes (Ruschelit, Fa. Rusch, D-Kernen) and individually adapted to the patient's vestibule, ensuring dilation between the external ostium and the nasal isthmus. RESULTS: Active interior rhinomanometry revealed a significant effect of the vestibule dilator in repeated application (mean variation 3%). Total nasal flow showed a mean increase of about 48% with the dilator. In AAR, we found 5 patients with decreased deltaV150-300 below 25%. To demonstrate the presence of vestibule stenosis, we compared the changes of deltaV150-300 is AAR with and without dilator. In rhinomanometry with the dilator, deltaV150-300 of patients with vestibule stenosis showed physiological values. In these patients, mean difference of deltaV150-300 between conventional rhinomanometry and rhinomanometry with a vestibule dilator was significantly higher (47,2%) than observed in all other persons (3,8%). The static vestibule resistance in the total nasal resistance was obtained by calculating the difference between nasal flows with and without the dilator. CONCLUSIONS; Stenosis in the nasal vestibule could be proved and measured via active anterior rhinomanometry using a vestibule dilator. Data obtained from this method are helpful in functional assessment of nasally impaired patients, particularly to answer the question of whether the vestibule requires surgical treatment. PMID- 8672202 TI - [The lymph vessel system of the mouth cavity and pharynx]. AB - BACKGROUND: The understanding of pathological processes involving the lymphatic system of the upper digestive tract requires a detailed knowledge of the lymphovascular architecture of this region. METHODS: The lymphatic system of the upper digestive tract was examined in 390 patients by different methods such as light microscopy, electron microscopy, histochemistry, and indirect lymphography. RESULTS: The mucous membrane of the upper digestive tract is permeated by two communicating lymphatic networks with regionally varying density. There are no areas without lymphatics. The lymphatic fluid of the nasopharynx flows from the posterior wall mainly towards the retropharyngeal and accessory lymph nodes (level II). The lymphatic flow from the buccal mucous membrane, the anterior floor of the mouth, the oral tongue, and the hard palate mostly drains toward the submandibular and craniojugular areas. Lymphatic fluid from the tonsils, the soft palate, and the hypopharynx flows primarily to the deep cervical lymph nodes (level II and III). CONCLUSION: These results are a basis for the understanding of a) secondary lymphatic edemas and b) frequency and direction of lymphogenous metastasis of carcinomas in this region. The direction of metastasis usually follows the physiologic lymphatic drainage. Metastasis towards untypical areas can in most cases be explained by an alteration of the lymphatic flow secondary to inflammation, radiotherapy, previous surgery, and subsequent scar formation or tumor growth. PMID- 8672203 TI - [Systematic analysis of local growth behavior and cervical lymph node metastasis of nasopharyngeal carcinoma--a clinical and computerized tomography examination]. AB - BACKGROUND: Assessment of the incidence and patterns of cervical lymph node involvement according to the location, extension, and histological subtype of nasopharyngeal carcinoma. PATIENTS AND METHODS: The findings of the clinical and CT examinations of 80 patients with histological evidence of nasopharyngeal carcinoma (9T1-, 20 T2-, 17 T3-, 34 T4-carcinomas, lymph node involvement in 59 cases) were evaluated retrospectively. The histological subtype, local tumor spread, relation of the primary to the parapharyngeal fascias, compartments, and skull base structures were analysed and related to the cervical lymph node involvement. RESULTS: Two main types of nasopharyngeal carcinomas with different patterns of cervical lymph node involvement were identified: the posterior wall type, which spreads into the retropharyngeal and spinal accessorial neck node chains and the ventral type, which is located which is located at the roof, anterior, and lateral walls of the nasopharynx and spreads into the jugular neck node chains, preferring the neck side in which the main part of the primary is located. The border of lymph drainage via retropharyngeal-spinal accessorial or via jugular neck node chains is localised ventral of the origin of the m. capitus longus at the skull base. If the primary involves the prestyloidal compartment, the tumor may spread into the ipsilateral submaxillary lymph nodes. Combinations of the different types are frequently found with the neck node spread following the described directions. CONCLUSIONS: Knowledge of the regular patterns of spread of nasopharyngeal carcinoma is important for treatment procedures, especially for planning 3-dimensional radiotherapy. PMID- 8672204 TI - [Treatment of vascular malformations and pigment disorders of the face and neck by pulsed dye laser, Photoderm VL and Q-switched ruby laser]. AB - BACKGROUND: Two new types of lasers, the pulsed dye laser and the Q-switched ruby laser, have shown good to excellent results in the treatment of vascular malformations and benign pigmented lesions of the skin. A new and very effective alternative to pulsed dye laser is the recently introduced Photoderm VL. This device is based on the use of a wide-band non-coherent intense pulsed light source which emits a continuous spectrum in the range of 515 nm to 1200 nm. PATIENTS AND METHODS: More than a 1000 patients with a variety of lesions of the skin were treated by these new laser systems and the Photoderm VL. The Q-switched ruby laser (wavelength 694 nm, pulse duration 25 ns) is suitable for the treatment of benign lentigines, cafe-au-lait macules, seborrhoic ceratosis, tattoos, and traumatic tattoos. The pulsed dye laser (585 nm, 0,3-0,45 ms) treats nevi flammei, capillary hemangiomas, telangiectasias, xanthelasma, hypertrophic scarring, and adenoma sebaceum. In addition we present the facilities of the new Photoderm VL (515 nm-1200 nm, 0,5-20 ms) for the treatment of nevi flammei, benign hemangiomatous malformations, telangiectasias, erythrosis interfollicularis colli, hypertrophic scarring, and hypertrichosis. RESULTS AND CONCLUSIONS: the Q-switched ruby laser, the pulsed dye laser, and the Photoderm VL show excellent results in the treatment of lesions of the skin, which otherwise would have been difficult to treat of untreatable. The efficiency of the laser types presented is based on the theory of selective photothermolysis. Scarring is almost never seen and hypo- or hyperpigmentation is in most cases transient. PMID- 8672206 TI - [A clinic in rapidly changing times. Recollections of the Cologne University Otorhinolaryngologic Clinic 1933-1953]. PMID- 8672205 TI - [Unusual metastatic site of a kidney carcinoma. A case report with review of the literature]. AB - BACKGROUND: An isolated intralaryngeal metastasis developed six years after removal of the right kidney because of hypernephroma. PATIENTS: We report this rare case of laryngeal metastasis of hypernephroma in a 42-year-old female. A round intralaryngeal tumor inserting at the anterior commissure was found and removed. RESULTS AND CONCLUSIONS: Knowledge of the history of the malignoma of the kidney led us to correct diagnosis. The clinical and histological findings are presented. Neoplasms of the kidney can metastasize years after removal of the primary tumor. The cause of this behavior of the tumor cells is still unknown. In patients with a history of hypernephroma, every polypus of the mucous membrane of the upper aerodigestive tract has to be considered suspect. Histological examination should always include immunohistological examination of the tissue. At least in the case of isolated laryngeal metastasis, a laryngectomy should be considered. PMID- 8672207 TI - [Detection of hearing loss in patrons of a discoteque using TEOAE and DPOAE]. AB - BACKGROUND: The aim of the study was to investigate the potential and difference of pure tone audiogram, TEOAE and DPOAE in the detection of temporary threshold shift. METHODS: 46 disco visitors who were exposed to disco music at an average intensity of 105 dB (A) for 1, 1 1/2 and 2 hours respectively underwent audiological examination before and after noise exposure. Audiological measurements performed were an audiogram and measurements of the TEOAE and DPOAE using the system ILO 92 (Otodynamics). RESULTS: The frequency range where the threshold shift occurred was around 4000 Hz in the 1 hour group and spread over all frequencies when the exposure time increased. The average threshold shift over all frequencies and probands was 6.2 dB for the 1 hour group, 7.1 dB for the 1 1/2 hour group and 10.1 dB after 2 hours of noise exposure. TEOAE amplitudes showed significant reduction only at 2000 and 3000 Hz. Even at threshold shifts exceeding 15 dB, however not in all cases, a reduction of TEOAE amplitudes occurred. Similar results were obtained regarding the DPOAE measurements. CONCLUSIONS: We conclude that TEOAE and DPOAE are not ideal instruments in the detection of temporary threshold shift after noise exposure. PMID- 8672208 TI - [Amplitude changes in distortion products of otoacoustic emissions after acute noise exposure]. AB - BACKGROUND: The inner ear responds to acute impact of high-intensity noise with a temporary threshold shift (TTS), which represents a reaction of the outer hair cells. That is why TTS should be detectable as changes of distortion-product otoacoustic emissions (DPOAE). METHODS: DPOAE were measured in 102 ears in 59 test subjects with normal hearing before and after definitive noise exposure (20 min of "white noise" at 90 dB HL). We also registrated the TTS (4kHz) immediately after noise and measured DP changes during a 30-min recovery period. RESULTS: Typically we found a reduction of DP amplitude. It averaged between 2.0 and 2.5 dB HL in the frequency range from 2 to 5 kHz. There was no correlation between TTS and DP amplitude reduction at 4kHz. During the recovery period, individual ears showed an erratic pattern of DP amplitudes. However, a tendency toward incremental DP amplitude regeneration appeared after averaging. As many as 10% of the measured ears showed an atypical reaction with an increase of DP amplitudes. Whether the latter is due to errors in the test procedure or is evidence of a particularly stable inner ear remains to be discussed. CONCLUSIONS: The results are further proof for the reaction of the outer hair cells on acute noise impact, which apparently leads to an increase of the stiffness of basilary membrane due to contraction processes. It may be possible to differentiate vulnerable inner ears from stable ones. PMID- 8672209 TI - [Postmortem changes in ear canal resonance and tympanic membrane impedance in the human ear]. AB - BACKGROUND: The human temporal bone preparation is a common model for research of physical processes of the ear canal and middle ear. In the past decade only a few reports were published discussing changes of the vibration behaviour of the tympanic membrane, as well as the ear canal resonance, during the time between death and preparation of the temporal bone. The aim of our study is to verify whether measurements at the temporal bone of dead humans can be really applied to the in vivo situation. METHODS: We investigated whether changes of the ear canal resonance and the vibration of the tympanic membrane depend on temperature and time after death. In a female human body we defined the resonance of the outer ear and the impedance of the tympanic membrane using a tympanometer and a real ear measurement system during nine hours post mortem. RESULTS: We were able to prove that before the preparation of the temporal bone none of the parameters changed significantly. CONCLUSIONS: In conclusion, the method of preserving the bone after its preparation is decisive for the validity of measurements at the isolated (post mortem) human temporal bone. PMID- 8672210 TI - [Dura-plasty in the area lf the sphenoid sinus]. AB - BACKGROUND: Surgical treatment of CSF leakage in the sphenoid sinus is difficult for several reasons: 1. the close neighbourhood between the sphenoid sinus and the internal carotid artery, the cavernous sinus and cranial nerves (II, III, IV, VI), 2. a strong liquorrhoea caused by basal cisterns surrounding the sphenoid sinus, 3. it can be difficult to visualise completely the sphenoid sinus depending on the extent of pneumatisation. MATERIALS AND METHODS: In this retrospective study 20 cases of duraplasty around the sphenoid sinus were evaluated. The approach, materials, operative techniques and results are described. RESULTS: 90% of the dura lesions were closed successfully by one operation (average follow-up time 5 years). Including our two revisions all defects have been sealed effectively. CONCLUSIONS: Currently, the endonasal approach using microscope and endoscope is the technique of choice for dura repair in the sphenoid sinus. The different techniques and materials vary in order of size, location and etiology of the dura lesion. PMID- 8672211 TI - [What becomes of free septum cartilage transplants? Experimental studies of orthotopic cartilage transplantation]. AB - BACKGROUND. Orthotopic septal cartilage transplants are grafted in numerous rhinosurgical operations. To ensure long-lasting success of surgery, preservation of the vitality of the grafted cartilage is imperative. Although many studies have been conducted on heterotopic cartilage transplants, no studies have been published on a follow-up of the course of orthotopic grafts. METHODS. We performed submucous septal resection in 33 rabbits and then regrafted the cartilage between the laminae of the mucous membrane. Microangiography was performed one, two, six and twelve weeks later and the cartilage was then examined histologically. Cartilage biopsies were performed on humans and compared with the experimental results. RESULTS. Integration of the cartilage presented a characteristic pattern: In the rabbit, the grafted cartilage had healed completely and had been stably integrated in three months' time. Reintegration with the orthotopic cartilage occurred by means of appositional reorganisation of cartilage originating from the inner perichondrium. Microangiography revealed that reintegration took place the faster, the shorter the distance between the cartilage cells and the vessels. We confirmed these experimental results also clinically by means of the cartilage biopsies in man. PMID- 8672212 TI - [Endonasal endoscopic ethmoidectomy in acute therapy refractory sinusitis]. AB - BACKGROUND: Acute sinusitis usually requires conservative treatment with antibiotics and decongestion nose drops. However, a certain number of cases do not respond to that treatment. Because functional endoscopic endonasal sinus surgery (FESS) has been proven to be a valuable tool in treatment of all kind of chronic sinus diseases, it was adopted for acute complicated sinusitis. METHODS: Between 1990 and 1993, ethmoidectomy was performed in 43 patients with acute inflammatory sinus disease in whom conservative treatment had failed (frontal sinusitis n = 11, max. sinusitis n = 10, isolated ethmoiditis n = 5, orbital complications of sinusitis n = 10, sphenoidsinusitis n = 2, acute pyomucocele n = 5). Coronal CT scan revealed mucosal pathology of the ethmoid region in 41 cases. None of the patients had intranasal polyposis. Complete ethmoidectomy was performed under general anesthesia using an endoscope and the transnasal route. RESULTS: All patients had relief of their symptoms within the first two postoperative days. One patient with a mucocele and two patients with orbital complications following osteoplastic procedures required revision surgery for removal of screws and plates from previous surgery. None of the patients developed recurrent symptoms of acute complicated sinusitis within the mean postoperative observation period of nine months. CONCLUSION: FESS should early be considered as a possible treatment of acute sinusitis and its complications if conservative treatment fails. PMID- 8672213 TI - [Early indications for surgical vocal cord medial relocation in unilateral recurrent nerve paralysis in advanced age]. AB - BACKGROUND: Unilateral vocal cord paralysis is usually treated conservatively. Phonosurgery is not indicated before 1 year after the onset of the palsy as during this period spontaneous recovery can be expected. In the elderly patient conservative voice rehabilitation is often limited by a restricted general condition. In these cases a severe communication disorder may result unless vocal cord function recovers spontaneously. PATIENTS AND METHODS: In 4 patients aged 68 to 79 years who had suffered from latrogenic unilateral vocal cord paralysis for 6 to 9 months, surgical medialisation of the paralysed vocal cord was carried out in local anaesthesia as an Isshiki-Type-I-operation after unsuccessful conservative treatment prior to surgery. RESULTS: In all cases a definite amelioration of voice function could be reached. There were no local or general complications. No spontaneous recovery of nerve function could be detected by electromyography between 6 to 9 months after the operation. Voice function remained stable during this period. CONCLUSIONS: We conclude that in elderly patients with unilateral vocal cord paralysis with no signs of spontaneous recovery and unsuccessful conservative treatment, surgical voice rehabilitation may be indicated before 1 year after the onset of the palsy. PMID- 8672214 TI - [Interdisciplinary therapeutic concept in severe bacterial infections of the central respiratory tract in childhood]. AB - BACKGROUND: Apart from all advances made in the management of central airway infections, Acute Epiglottitis (AE) and Bacterial Tracheitis (BT) continue to be causes of life-threatening airway obstruction in children. The aim of this retrospective study was to evaluate deficiencies in the diagnostical protocol, to clarify the role of airway endoscopy in acute childhood stridor, and to identify current reasons for fatalities in these diseases. MATERIAL: In the observation period between 1980-92, we found 12 patients suffering from BT and 21 from AE managed in close cooperation of the involved disciplines at the pediatric intensive care unit of the University of Cologne. RESULTS: Laryngoscopy with fiberoptic or small rigid endoscopes allowed in awake cooperative children accurate diagnose of AE, and the exclusion of supraglottic inflammation in BT without complications. Furthermore, additional endoscopic information of the degree of inflammation was helpful in the next critical decision, whether artificial airway or rigid tracheobronchoscopy was required. Nasotracheal intubation was necessary in 76% of our patients, in one child tracheostomy was performed (5%). Premature extubation necessitating reintubation occurred in 33% of the children suffering from BT. In these patients, our method of advancing a flexible endoscope for tracheoscopy through the respiration tube failed because of a low tube diameter. Another remarkable finding was the high mortality in AE (14%). Affected children were admitted in poor post-hypoxia conditions following outdoor cardiorespiratory arrest. CONCLUSION: In the analysis of the clinical course we found three decisive turning points in managing the disorder; First, the confirmation of the correct admission diagnosis; second, the decision, as to whether an artificial airway should be established; and third, the proper time of extubation. The most decisive factor in decreasing mortality seems to be timely, appropriate presentation at referral centers if AE or BT is suspected. Clinically, progressive management of childhood stridor requires close cooperation between the Pediatric, Anesthesiologic, and ENT Departments. Fiberoptic endoscopy as a guide to current airway management is a major step forward and should be a part of every established protocol. PMID- 8672215 TI - [Immune response to p53 protein in patients with squamous epithelial carcinoma of the upper aerodigestive tract is independent of p53 point mutation]. AB - OBJECTIVE: Mutations of the p53 gene are the most prevalent genomic changes in human malignancies. The detection of these mutations is usually carried out by gene sequencing or with immunohistochemical methods. A new approach is to search for p53 antibodies in serum of cancer patients. The cause for the production of antibodies against p53 is unclear. The aim of this study was to show the correlation between p53 pointmutations and p53 antibodies in patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS: A semiquantitative ELISA was employed to screen the serum of 117 patients with SCCHN for p53 antibodies. Sixty-one tumor samples were evaluated with SSCP-analysis for point mutations in exons 4 to 9. RESULTS: Twenty-three (19.7%) of the cancer patients had antibodies to p53. There was no significant difference in the frequency of p53 point mutations in exon 4 to 9 between the whole cancer patient group and the p53 antibody positive group. CONCLUSIONS: The accumulation of p53 in the tumor cell is one hypothesis as to how p53 becomes immunogenic. This leads to a decrease in tolerance after a certain amount of time. In contrast to this it is assumed that after a p53 point mutation, important protein determinants are changed and p53 becomes antigenic. The results of this study indicate that p53 point mutations in SCCHN seem to have no influence on the development of p53 antibodies. Therefore this study supports the theory that the loss of tolerance and subsequently the antibody production is induced by an accumulation of p53. The type of p53 point mutations on exon 4-9 seems to have no influence that p53 gains immunogenic potential in SCCHN: PMID- 8672216 TI - [Aneurysmal bone cyst of the mandible]. AB - BACKGROUND: Aneurysmal bone cysts are benign lesions of bone consisting of a septated, cystic cavity filled with non-endothelium-lined, blood-filled spaces. Aneurysmal bone cysts mainly occur in children and adolescents. Only a few occur in the jaws. PATIENT: This is the report of a 9-year-old girl with an aneurysmal bone cyst in the condyle of the mandible who was admitted to the hospital with swelling in front of her right ear. Because of the location and to eliminate recurrence, complete surgical excision of the condyle was performed. DISCUSSION: Fifty-seven cases of aneurysmal bone cyst of the mandible have been reported to date. Aneurysmal bone cyst is treated by surgical excision, which ranges from enucleation and curettage to conservative resection. CONCLUSION: Simple curettage for aneurysmal bone cyst is reported to be associated with a high recurrence rate, a result of the difficulty of completely excising such a vascular lesion. We recommend complete surgical excision as the best treatment. PMID- 8672217 TI - [Diaphanoscopic localization of tear ducts in endonasal dacryocystorhinostomy]. AB - BACKGROUND: Endonasal dacryocystorhinostomy is a well established technique in the surgical treatment of stenosis of the lacrimal system. Due to individual anatomic variations it can be difficult and time consuming to localize the stenosis of the lacrimal system intraoperatively. METHODS AND PATIENTS: To simplify the localization of the lacrimal system, a diaphanoscopic technique that has been used in oral surgery was modified for endonasal dacryocystorhinostomy. A sterile optical fiber is passed through the lacrimal canal from the eye into the lacrimal sac or down to the stenosis. Its light can be detected in the nose and marks the sac or the stenosis. To date we have performed twelve operations with this technique. RESULTS: In our experience, endonasal dacryocystorhinostomy is simplified and accelerated by localizing the lacrimal system with diaphanoscopy. CONCLUSIONS: The diaphanoscopic localization of the lacrimal system during endonasal dacryocystorhinostomy is a slight technical modification that is simple and helpful and could therefore be incorporated into the surgical routine. PMID- 8672218 TI - [History of the ear speculum. Images from the history of otorhinolaryngology, highlighted by instruments from the collection of the German Medical History Museum in Ingolstadt]. AB - BACKGROUND. Inspection of or interventions in the external ear canal and the nostrils pose similar technical problems. This is the reason why early instruments devised for otoscopy and rhinoscopy were based on an identical principle. They were shaped like a pair of tongs, comparable to nasal specula of today. A similar type of instrument had been developed earlier by barber surgeons for inspecting narrow wound cavities. TONG-SHAPED SPECULA. The first description and illustration of an aural and nasal speculum was provided by Guy de Chauliac in Montpellier, France in 1363. Sophisticated models were presented by Fabricius Hildanus in Germany in 1646 and J.J. Perret in Paris in 1772, who offered them in his illustrated catalogue of surgical instruments at fixed prices. W. Kramer (1836) in Berlin improved this tong-shaped instrument and devised the ear speculum named after him that was generally favored during the first half of the 19th century. Further variations of this type were presented by Lincke and Schmalz (1846) in Germany. FUNNEL-SHAPED SPECULA. Ignaz Gruber in Vienna in 1838 devised the first tunnel-shaped ear specula made of metal. They had a simple conical shape, were not divided into separate jaws, and could not be spread. Gruber himself did not publish his invention, but he demonstrated his ear specula to W. R. Wilde from Dublin, who had paid a visit to his office in Vienna. Wilde reported on this in 1844, and subsequently systematically refined Gruber's specula. A. v. Troltsch from Wurzburg (Germany) had seen these instruments at Wilde's office and it was Wilde himself and v. Troltsch who helped this type of ear speculum to gain acceptance on an international scale. A different type of bottle-shaped ear speculum was first used by Schmalz (1846) and Erhard (1859) in Germany, but it was only developed into a commercially available instrument by Josef Gruber in Vienna in 1870. The ear specula most in use today were first presented by A. Hartmann in Berlin in 1881. SUPPLEMENTARY INVENTIONS. An important supplementary invention was the pneumatic ear speculum by E. Siegle in Stuttgart (Germany) in 1864. It permitted not only inspecting the tympanic membrane but also examining its compliance and response to variations in air pressure in the ear canal. The importance of this instrument was recognized at once and has remained undisputed to this day. J. Bruton, an English military surgeon, presented his otoscope in 1862. It was the first device to incorporate interchangeable ear specula, illumination by a perforated mirror, and a magnifying lens into one handy instrument. It is the precursor of the modern diagnostic sets comprised of a battery-handle, various specula, and accessories for otoscopy, rhinoscopy, and ophthalmoscopy which started to come into use in the late twenties of this century. This historical development of the ear specula is described and illustrated in detail. PMID- 8672219 TI - [Duplicate study on the dietary intake of some metals/metalloids by children in Germany. I. Arsenic and mercury]. AB - The dietary intake of arsenic and mercury by 47 children (aged 5-8 years) living in West-Germany (Duisburg) is reported. Duplicate portions of all food and beverages were obtained on 2 days. Arsenic and mercury were measured by atomic absorption spectrometry under careful quality control. Results of are shown in the following table. [table: see text] Fish was consumed at 3 of 94 sampling days only. The arsenic and mercury intake on days with fish consumption was much higher compared with the other days (median, range): arsenic 8821; 4431-11954; mercury 123.7; 80, 0-167.5 ng/kg b.w. and day. The dietary arsenic and mercury intake was much lower than the FAO/WHO PTWI. For mercury the median intake amounted to 1.7% on days without and to 16.6% on days with fish consumption, for arsenic on days without fish consumption to 5.2% PTWI (only for inorganic arsenic compounds established) and on days with fish consumption (in fish mainly organic arsenic occur) 411% of PTWI. Based on the PTWI our data indicate no health risks for German 5-8-year-old children due to arsenic and mercury dietary intake. PMID- 8672220 TI - [Duplicate study on the dietary intake of some metals/metalloids by children in Germany. part II. Aluminum, cadmium and lead]. AB - The dietary intake of aluminium, cadmium and lead by 47 children (aged 5-8 years) living in West-Germany (Duisburg) is reported. Duplicate portions of all food and beverages were obtained on 2 days. Aluminium, cadmium and lead were measured by atomic absorption spectrometry under careful quality control. Results are shown in the following table. [table: see text] The dietary intake of aluminium was low. The median amounted to 2.9% and the maximum value to 11.2% of the FAO/WHO PTWI. The correspondent data for cadmium were 30.2 and 98.7% and for lead 22.2% and 72.1% respectively. PMID- 8672221 TI - Polymerase chain reaction assay for detection of Campylobacter coli and Campylobacter jejuni in poultry meat. AB - Primers of 16S rRNA and flaA genes were used to optimise a PCR technique for detecting thermotolerant campylobacters in poultry meat. Different methods for crude DNA extraction were also evaluated. The use of flaA primers and extraction of nucleic acid by boiling and proteinase K gave good results in the detection of Campylobacter either in artificially or naturally contaminated foodstuffs. The lowest sensitivity limit for the PCR reaction was 10(1)-10(2) thermophilic Campylobacter cells either in pure cultures or in artificially and naturally contaminated poultry skins, corresponding to a concentration of 10(2)-10(3) Campylobacter/ml or g product. The PCR method we devised had a high sensitivity and specificity. It appears to give better results than conventional methods and is very easy and fast, requiring only eight hours to detect thermotolerant Campylobacter from poultry meat. In contrast, conventional methods require almost 4 days. PMID- 8672222 TI - Survival of E. coli and Salmonella populations in aerobic thermophilic composts as measured with DNA gene probes. AB - Aerobic, thermophilic composting is a widely practiced method for disposal of organic wastes. The wastes which are composted include biosolids from waste water treatment plants (WWTP), and biowastes (food scraps and yardwaste). Important hygiene issues are involved in composting since many potential pathogens may be present in the fresh wastes. In this study, the survival of Salmonella and Escherichia coli is examined during aerobic composting of municipal solid wastes, municipal wastewater sludge and biowastes. A laboratory compost was prepared by inoculating with 10(7) Salmonella typhimurium Q and Escherichia coli B. In both industrial and laboratory trials, gene probes were used to determine at what time during the composting and at what temperature these bacteria became undetectable. It was observed that Salmonella and E. coli survived for 59 days at about 60 degrees C in an industrial compost. The bacteria became undetectable after the temperature decreased from 62 degrees C to about 40 degrees C in the compost curing. The bench scale trials showed that E. coli B survived for at least 9 days at 60-70 degrees C in a biowaste (food waste) compost or a waste water sludge compost. Salmonella typhimurium Q survived for at least 9 days over 60 degrees C in the food biowaste compost and at least 5 days in the waste water sludge compost. Data collected show that the temperature or the time of high temperature is difficult to correlate to the destruction of the pathogen, Salmonella, or the pathogen indicator, E. coli. These results suggest that the mechanism for removal of these microorganisms during aerobic composting is complex and not simply the result of a thermal physical environment. PMID- 8672223 TI - [Air microbial burden at garbage sorting facilities]. AB - At two german garbage sorting facilities, germ concentrations in the air were analyzed at different working environments (waste reception, manual sorting). At plant A, maximum concentrations of total bacteria (14700 CFU/m3), gram-negative bacteria (7279 CFU/m3) and moulds (> 84806 CFU/m3) occurred in the air at the final manual sorting belts. Referring to concentrations of total bacteria and moulds, concentrations in the air at the final sorting belts were significantly higher (p < 0.001) than at the other working environments. At plant B, the counts of total bacteria reached 7173 CFU/m3 in the air at the waste reception site and 5512 CFU/m3 at the manual sorting belt. Maximum concentrations for gram-negative bacteria were 247 resp. 206 CFU/m3 and 70919 resp. 60848 CFU/m3 for moulds. At the waste reception site, the aerial concentrations of total bacteria lay highly significantly (p < 0.001) and of moulds significantly (p < 0.05) above aerial concentrations at the manual sorting belt. As causes, an intensive mechanical pretreatment of recycle material at plant A and whirling up of sedimentary dust of the floor during manual sweeping of the material on to the transportation at plant B are discussed. PMID- 8672224 TI - [Risk for the Rostock water supply from the Warnov river by an old deposit at Schwann?]. AB - Accidents of the city gasworks in the end of the fifties at Schwaan, a small town south of Rostock, resulted in an emission of tar and waste water into the river Warnow, from which the city of Rostock is supplied with drinking water about 20 km downstream. The tar contaminated river sediment (old deposit) covering an area of about 200 m2 has a high pollutant inventory: Steam-distillable phenolic compounds 407 mg/kg in the fresh sediment, polycyclic aromatic hydrocarbons (PAH) 400 to 1100 micrograms/l in the aqueous eluate. The mutagenic potential was detected by the AMES-test. As shown by PAH determinations there were no other pollutant sources in the catchment area, in the tributaries or on other places of the river. The mean PAH concentrations of the river Warnow and his tributaries during 1991 to 1994 were found to be in the range lower than 10 ng/l. Further investigations showed a continuous emission of PAH from the tar laugh in small amounts. An additional emission of pollutants (PAH) and their transportation in the river is expected in the case of sediment disturbances. This emission and their possible consequences are difficult to estimate, even though the seston and the humic substances content of the river seems to reduce the PAH risk. Concluding from our results the probability is very low that pollutants were transported downstream to Rostock and pass the water works but may not totally be excluded. Nevertheless from the viewpoint of care a removal of the old deposit is necessary. PMID- 8672225 TI - [Composition and ways of reusing activated carbon sludge from surface water treatment plants]. AB - By using activated carbon (PAC) or by other water treatment procedures remarkable amounts of sludges are produced that have normally to be discharged as wastes outside the plant site. The research objective of this study is to get basic information about the quality of PAC sludges to characterise these materials in order to decide between depositing or re-use/recycling. On four water works with artificial ground water recharge and PAC treatment plants to eliminate pesticides from surface waters detailed analyses and experiments were carried out. The determination of carbon, nitrogen, other nutrient elements, heavy-metals and organic pollutants reveal greatly differing amounts within the water works and during the year. The treatment techniques had an important influence on the chemical composition of the sludges. Mixing of PAC sludges with other sludges strongly reduced the amount of carbon. Heavy metals were present only in small quantities. Sludge from one plant, however, contained elevated concentrations of arsenic. PAC sludges from plants treating river water had considerably high amounts of adsorbable organohalogen. Leaching experiments performed with the sludges demonstrated that only small quantities of pollutants are extractable. For most sludges a deposition on domestic refuse dumps is possible. An alternative way is to discharge the liquid sludges into municipal sewage treatment plants. Addition to the biological treatment tank significantly reduced the concentration of AOX in the sewage effluent. Laboratory experiments and field studies on heavily polluted dump leachates showed a remarkable remaining adsorption capacity of the PAC. As a consequence, PAC sludges have to be considered not exclusively as wastes, but rather as valuable materials for purification processes treating waste waters with high loads of organic, especially organohalogen, substances. PMID- 8672226 TI - [Eradication of Legionella from warm water systems--documentation of our own experiences with thermal disinfection]. AB - A nosocomial case of Legionellosis in a recently built hospital was the reason for an investigation and thermal disinfection of the complete warm water distribution system. Furthermore weak points in the tubing of the warm water system, which promoted the contamination of potable water, were eliminated as far as technically possible. A lasting reduction of the numbers of Legionella spp. isolated could be measured (factor 10-1000), but a complete decontamination of the warm water distribution system was not possible. As Legionella spp. may cause serious infections in immunodeficient patients, additional measures for the disinfection of the hospital water distribution system must be taken into consideration. PMID- 8672227 TI - [Input of DDT into the environment by forest pest control in 1983/84 in Brandenburg--assessment of the contamination level]. AB - In 1983/84 pesticides including DDT were applied in aviochemical forest pest control in Brandenburg. Our investigations determined loading sites on airfields formerly used for the delivery of pesticides to forest target areas to be the focal points of environmental contamination with DDT. The matrices food, forage, drinking water and soil were analysed in detail with regard to the level of burden. Following from the analytical results the agricultural exploitation of the areas in question is not restricted. An impairment of the quality of drinking water cannot be detected at present. Soil analyses were assessed according to toxicologically derived standard values. An amount of 0.4 mg/kg was accepted as a tolerable burden whilst values exceeding 2.7 mg/kg suggest that remediation will be necessary. The DDT burden level in the upper soil does not restrict utilization. PMID- 8672228 TI - Pancreastatin: further evidence for its consideration as a regulatory peptide. AB - Pancreastatin is a 49 amino acid peptide first isolated, purified and characterized from the porcine pancreas, and whose biological activity in different tissues can be assigned to the C-terminal part of the molecule. Pancreastatin has a prohormonal precursor, chromogranin A (CGA), which is a glycoprotein present in neuroendocrine cells, including the endocrine pancreas. Both intracellular and extracellular processing of CGA can yield pancreastatin. This processing is tissue-specific, with the pancreatic islet and antral gastric endocrine cells being the major source of fully processed pancreastatin. Most of the circulating CGA is secreted by chromaffin tissue. Therefore, peripheral processing of CGA is probably the major indirect source of pancreastatin. Pancreastatin seems to have a general modulatory control on endocrine (insulin, glucagon, parathormone) and exocrine (pancreatic, gastric) secretion from tissues close to the source of production. This has led to the assumption that pancreastatin may be a peptide with an autocrine and paracrine function. It has recently been revealed to be a peptide with a metabolic function counter regulatory to insulin action. This effect, in conjunction with the inhibitory effect on insulin and pancreatic exocrine secretion, points to a role in the physiology of stress. The molecular mechanism of the glycogenolytic effect of pancreastatin is better known, although further work is still needed. In general, more studies should be carried out at the molecular level to investigate the mechanism of action of pancreastatin and thus to clarify its physiological role in the neuroendocrine system. PMID- 8672229 TI - Peptide and immunochemical mapping of the ectodomain of the porcine LH receptor. AB - The LH/hCG receptor is a G protein-coupled receptor with an N-terminal extracellular domain involved in hormone-receptor interaction. The recombinant porcine receptor, stably expressed in Chinese hamster ovary (CHO) cells, has the same characteristics (Kd and cAMP production) as in Leydig cells. Six synthetic peptides derived from the receptor ectodomain and two polyclonal anti-peptide sera were tested in the homologous system porcine LH and porcine LH receptor. Their ability to inhibit hormone binding and signal transduction on CHO cells expressing the recombinant receptor was evaluated. Peptides 25-40 and 107-121 exhibited a high transduction inhibition as compared with hormone binding, peptides 21-36, 102-111, and 102-121 inhibited hormone binding more efficiently than signal transduction, and peptide 7-24 exhibited inhibition of both hormone binding and hormone-induced cAMP production. Immunoglobulins against peptides 21 36 and 102-111 inhibited both hormone binding and receptor activation suggesting that these sequences are located on the receptor surface. The data suggest that multiple, discontinuous regions of the extracellular domain of porcine LH receptor are involved in hormone binding and signal transduction. Two minimum critical sequences, 21-24 and 102-107, are involved in hormone binding and vicinal segments may be implicated in signal transduction. PMID- 8672230 TI - Cloning of rabbit prolactin cDNA and prolactin gene expression in the rabbit mammary gland. AB - cDNA clones coding for rabbit prolactin were isolated from a pituitary library using a rat prolactin RNA probe. One cDNA contained 873 bases including the entire coding sequence of rabbit prolactin, its signal peptide and the 5' and 3' untranslated regions of 44 and 145 nucleotides respectively. The deduced amino acid sequence of the cloned prolactin cDNA presented a 93-78% identity with mink, porcine and human prolactins. The prolactin gene transcription was investigated by RT-PCR analysis in several organs of midlactating New Zealand White rabbits. The ectopic transcription of the prolactin gene was examined in more detail in the mammary gland. A strong PCR signal was detected in the mammary gland of virgin does and was also observed during pregnancy and at the beginning of lactation. This PCR signal was very weak in mid-lactating and absent in post weaning mammary gland. PMID- 8672231 TI - Nature of ligand affinity and dimerization of corticotrophin-releasing factor binding protein may be detected by circular dichroism. AB - As the association of corticotrophin-releasing factor (CRF) with its binding protein (BP) to form a dimer complex (CRF2/BP2) appears to be dependent on the nature of the ligand we have compared the circular dichroism difference spectra after association of the BP with ovine (o) CRF, human (h) CRF and the alpha helical CRF (9-41) antagonist. All three ligands caused a negative change in molar ellipticity above 210 nm, with oCRF having the least and hCRF the greatest effect. Below 210 nm there was a marked divergence of difference spectra, with the reaction with the natural peptides, hCRF and oCRF, resulting in a positive change in ellipticity, whilst that with the antagonist produced a negative change. In view of the BP spectrum indicating predominantly beta-sheet and the peptides showing mainly alpha-helix these results were interpreted as the changes above 210 nm being due to dimerization and below 210 nm to a change in the conformation of ligand on binding. The opposite change in alpha-helicity of the antagonist observed on binding compared with the two natural CRF peptides could have fundamental pharmacological implications. PMID- 8672232 TI - A monoclonal antibody to mammalian angiotensin II AT1 receptor recognizes one of the angiotensin II receptor isoforms expressed by the eel (Anguilla anguilla). AB - Using labelled ligand-binding methods, previous studies have identified specific angiotensin II receptors (Ang II-Rs) in eel liver, kidney and intestine membranes. Isoelectric focusing on polyacrylamide gels also showed that there are two Ang II-R isoforms in eel liver, focusing at isoelectric points (pI) 6.5 and 6.7. These may have different functions. In contrast, eel enterocyte plasma membrane and renal brush border membranes contain only the pI 6.5 form. To characterize the eel receptors more fully, a newly developed monoclonal antibody (6313/G2) which selectively recognizes the AT1 subtype of mammalian Ang II-R was used. In ligand-binding experiments, the preincubation of eel liver membranes with 6313/G2 antibody eliminated the specific [3,5-3H]Tyr4-Ile5-Ang II binding. Moreover, Ang II-receptor complexes from solubilized liver membranes, which were immunoprecipitated by 6313/G2-coated beads, had a pI of 6.5. In immunoblotting experiments, the antibody recognized the isoform focusing at pI 6.5 in eel intestine and liver preparations, but not the liver pI 6.7 isoform. Immunoblotting of SDS gels showed that the antibody bound to a single protein of molecular mass of 75 kDa in eel liver, gill and kidney and to a doublet of molecular mass of about 74 and 75 kDa in intestinal membrane preparations. Immunocytochemistry of paraffin-embedded and cryostat sections of eel liver, kidney, intestine and gill showed that antibody 6313/G2 bound to uniformly distributed intracellular sites and cell surface membranes in proximal tubular cells, absorptive intestinal cells, hepatocytes and chloride cells. It also stained endothelium and both the longitudinal and circular layers of smooth muscle cells in the intestine. The data suggest that the previously described Ang II-R from eel liver, kidney and intestine may be similar to the mammalian AT1 subtype. PMID- 8672233 TI - Angiotensin II stimulation of the basolateral located Na+/H+ antiporter in eel (Anguilla anguilla) enterocytes. AB - The pH-sensitive fluorescent dye, 2',7'-bis-carboxyethyl-5, 6-carboxyfluorescein acetoxymethyl ester, was used to examine the effects of fish or human angiotensin II (Ang II) on the activity of the basolateral located Na+/H+ antiporter in eel intestinal cell suspensions. Exposure of eel enterocytes to either hormone led to an increased activity of the antiporter. This time- and dose-dependent stimulatory effect was inhibited by the specific antiporter inhibitor dimethylamiloride (DMA). Preincubation with a monoclonal antibody (6313/ G2), directed against the N-terminal extracellular domain of the mammalian AT1 Ang II receptor, prevented the stimulatory effect of the hormone and inhibited the binding of [3,5-3H] Tyr4-Ile5-Ang II to intestinal cell suspensions, suggesting specific binding of the antibody to the eel Ang II receptor. The results indicate that both fish and human Ang II stimulate the DMA-sensitive Na+/H+ antiporter present in eel intestinal cells by means of a mammalian AT1-like receptor. PMID- 8672234 TI - Molecular cloning and characterization of the yellowtail GH gene and its promoter: a consensus sequence for teleost and avian Pit-1/GHF-1 binding sites. AB - The gene and 5' flanking promoter region for yellowtail (Seriola quinqueradiata) GH (yGH) have been cloned, sequenced and characterized. The yGH gene spans approximately 4.6 kb and consists of six exons and five introns, as has been observed with rainbow trout, Atlantic salmon and tilapia GH genes. This result suggests that the structure of six exons and five introns is a dominant form in fish GH genes. A typical TATA box exists 26 bp upstream from the transcription start site, and Pit-1/GHF-1 (Pit-1) binding site-homologous regions were found in the promoter region of the yGH gene. In a gel shift assay, however, a single shifted band was detected with the fragments containing a region from -128 to -90 of the yGH 5' flanking region when they were incubated with yellowtail pituitary nuclear extracts. The bound fragments contained an octamer base sequence similar, but not identical, to mammalian consensus Pit-1 binding element. A consensus octamer sequence is also proposed in this report for the binding of teleost and avian Pit-1 transcription factors. PMID- 8672235 TI - Cloning of a gar (Lepisosteus osseus) GH cDNA: trends in actinopterygian GH structure. AB - A cDNA containing the sequence of GH was cloned and sequenced from a pituitary cDNA library for the holostean fish Lepisosteus osseus (common name: gar). The gar GH cDNA contained an open reading frame of 633 nucleotides and a 3' untranslated region (including the terminal codon TAG) of 1058 nucleotides. The overall length of the gar GH cDNA including leader sequence, signal sequence, hormone sequence and 3' untranslated region was 1713 nucleotides. Thus, the gar GH cDNA is the largest vertebrate GH cDNA yet cloned. A comparison of GH sequences from ancient (holostean fishes-gar and bowfin; one chondrostean fish the Russian sturgeon) and more modern (27 species of teleosts) members of class Actinopterygii indicate that members of this class have maintained many of the invariant residues deemed necessary for GH folding motifs (intramolecular relationships) observed in mammals. PMID- 8672236 TI - In vitro pituitary GH secretion after GHRH, forskolin, dibutyryl cyclic-adenosine 3',5'-monophosphate and phorbol 12-myristate 13-acetate stimulation in long-term orchidectomized rats. AB - In the present work in vitro GH pituitary responsiveness to GHRH in short-term (STO) and long-term orchidectomized (LTO) male rats was compared. In agreement with previous data obtained in vivo, pituitaries from STO rats showed reduced GH release after GHRH stimulation while LTO male pituitaries presented responses similar to those from control animals after maximal GHRH (10(-6)M) stimulation. This suggests that compensatory mechanisms have taken place, probably at the pituitary level, in order to restore GH pituitary responsiveness to high doses of GHRH. However, LTO male rats showed a reduced sensitivity to GHRH relative to intact males, as indicated by a higher EC50 vs controls (40.82 +/- 12.03 nM vs 0.35 +/- 0.09 nM in intact males). We aimed to investigate further the events involved in the compensatory mechanisms that take place in LTO rats. For this purpose, we compared in vitro GH secretion by pituitaries from intact and LTO male rats after stimulation with specific activators of the signal transduction pathways related to GH release. Forskolin and dibutyryl cyclic-adenosine 3',5' monophosphate were more effective in eliciting GH secretion (expressed in terms of percent increment over basal GH release) in LTO males, whereas phorbol 12 myristate 13-acetate was completely ineffective in stimulating GH release in this group. Thus, our results clearly showed that long-term orchidectomy enhances the effectiveness of the cAMP pathway in inducing GH release while it completely blunts that of the protein kinase C pathway. In conclusion, orchidectomy decreased the effectiveness of GHRH in eliciting GH release in vitro. However, long-term orchidectomy activated compensatory mechanisms that restored complete GH pituitary responsiveness to maximal GHRH stimulation. These mechanisms seem not to operate in STO rats. An increased effectiveness of the cAMP pathway in eliciting GH release in LTO rats is probably involved in the aforementioned compensatory mechanisms. PMID- 8672237 TI - Production of a human epidermal growth factor fusion protein and its degradation in rat gastrointestinal flushings. AB - This study describes the biosynthesis of a human epidermal growth factor fusion protein, Long EGF, that has a 53 amino acid extension peptide derived from the 46 N-terminal amino acids of porcine GH. The approach allowed the production of Long EGF at high efficiency due to the expression of the fusion protein in high yield as inclusion bodies in Escherichia coli. Long EGF had a slightly lower potency compared with native EGF in a range of assays, including binding to anti-EGF antibodies or the EGF receptor, stimulation of Balb/3T3 fibroblast and rat intestinal epithelial cell growth, as well as counteracting the inhibition of mink lung epithelial cell proliferation by transforming growth factor-beta 1. Degradation of Long EGF and native EGF was compared in gastrointestinal flushings as an indication of whether the EGF domain of the fusion protein would be protected from proteolytic cleavage and be useful as a trophic agent in the gut. Incubation with flushings from the stomach or jejunum of rats caused rapid cleavage of the extension peptide, releasing native EGF. A C-terminal truncation of Arg53 in the stomach and a removal of the C-terminal pentapeptide (49 Trp-Trp Glu-Leu-Arg53) in the small bowel was demonstrated by N-terminal sequencing and mass spectrometry. The degradation patterns were reflected by changes in migration of products on SDS-PAGE and in subsequent binding activities to the EGF receptor and anti-EGF antibodies. The data show that a human EGF fusion protein can be produced efficiently in a bacterial expression system and that it retains biological activity in vitro. Although the extension peptide was rapidly cleaved from Long EGF in both stomach and small bowel producing similar biological activity to native EGF, it could not prevent subsequent degradation of the EGF domain. Other strategies are being investigated to develop an effective oral form of EGF that resists digestion by proteases in the gastrointestinal tract. PMID- 8672238 TI - Cloning and analysis of the cDNA for the common alpha-subunit of the donkey pituitary glycoprotein hormones. AB - Reverse transcription-PCR was used to clone the coding region of the donkey (Equus asinus) glycoprotein hormone alpha-subunit transcript from pituitary gland RNA. The donkey alpha-subunit sequence demonstrated considerable identity with the horse (97% at the nucleotide level), confirming the very close evolutionary linkage between these two species. The predicted amino acid sequence revealed that the donkey alpha-subunit has the same unusual C-terminus as the horse alpha subunit, when compared with all other mammalian alpha-subunits, including a Tyr His transposition between positions 87 and 93 and Ile instead of Ser as the C terminal residue. Since recent evidence indicates important involvement of this region of the alpha-subunit in receptor binding, these findings provide a possible partial explanation for the unique biological properties of the equine gonadotrophins. PMID- 8672239 TI - Characterization of a helicase-like transcription factor involved in the expression of the human plasminogen activator inhibitor-1 gene. AB - A 5.4-kb cDNA encoding the protein that binds to the B Box of the plasminogen activator inhibitor-1 (PAI-1) gene was isolated and sequenced. The protein, named helicase-like transcription factor (HLTF), contains a DNA-binding domain, a RING finger domain, and seven helicase domains and is homologous to SWI/SNF proteins. Two HLTF mRNAs of 5.5 and 4.5 kb were detected in most human tissues, a single gene was located on chromosome 3q24-25, and the protein was located in the nucleoplasm. Two HLTF proteins differing in translation start site (Met-1 or Met 123) were obtained by in vitro translation in reticulocyte lysate or by immunoprecipitation from HeLa cell nuclear extracts. In vitro transcription from the PAI-1 promoter in HeLa cell extracts was inhibited by HLTF antibodies and by the HLTF DNA binding domain. Over-expression of HLTF or HLTFMet123 produced a three-fold induction of PAI-1-LUC transient expression in HeLa cells. Mutation of the PAI-1 B Box led to an eight-fold reduction of basal PAI-1-LUC expression in these cell lines, but did not affect the four- to six-fold induction by phorbol esters. PMID- 8672240 TI - Ras is involved in gap junction closure in proliferating fibroblasts or preadipocytes but not in differentiated adipocytes. AB - A decrease in gap junctional, intercellular communication (GJIC) has been associated with cells neoplastically transformed by a variety of factors. To investigate the role of the Ras oncogene product in gap junction function, a panel of murine C3H10T1/2 (10T1/2) fibroblasts was constructed in which the levels of ras gene expression could be effectively up- or down-regulated. Intercellular communication was measured using a novel technique of in situ electroporation of adherent cells on a partly conductive slide. The introduction of increasing amounts of activated Ras(leu61) in mouse 10T1/2 fibroblasts proportionally reduced GJIC, while the downregulation of endogenous c-ras gene expression increased junctional permeability. These results indicate that Ras plays an important role in the junction closure pathway leading to the proliferation of normal cells. However, differentiation of c-Ras-deficient preadipocytes entirely abolished their initially extensive GJIC, indicating that junction closure in response to adipocytic differentiation is independent of Ras. PMID- 8672241 TI - Cloning and chromosomal mapping of bovine interleukin-2 receptor gamma gene. AB - Interleukin-2 receptor (IL-2R) gamma chain, a member of the cytokine receptor superfamily, forms a high-affinity receptor with IL-2R alpha and beta chains that plays an important role in interleukin-2 (IL-2) signal transduction. We have cloned and characterized the bovine IL-2Rgamma gene and corresponding cDNA. Bovine IL-2Rgamma is a single-copy gene that contains 8 exons and spans approximately 3.8 kb. The promoter region lacks conventional TATA and CCAAT consensus sites, but contains several regulatory elements that are recognition sites for the GATA binding proteins, AP-1 and AP-2. Physical assignment by fluorescence in situ hybridization (FISH) placed the bovine IL-2Rgamma gene on chromosome Xq23. PMID- 8672242 TI - Characterization of the rat catechol-O-methyltransferase gene proximal promoter: identification of a nuclear protein-DNA interaction that contributes to the tissue-specific regulation. AB - The methylating enzyme catechol-O-methyltransferase (COMT) is an important inactivator of substrates containing catechol-structure, such as catechol neurotransmitters and hormones. In previous studies, the rat COMT gene has been cloned and characterized, and it has been shown that the two COMT polypeptides, S and MB-COMT, are expressed from one gene by cooperation of two separate promoters. One promoter, P2, functions constitutively, whereas the other, the proximal P1 promoter, is regulated in a tissue-specific manner. In this report, a more detailed analysis of the rat P1 promoter is presented. By using reporter gene constructs, it is shown that upstream sequences of the P1 promoter contain several regions that modulate the expression either positively or negatively. These experiments also show that the region between the MB- and S-ATG translation initiation codons is indispensable for the activity of this promoter. Analysis of this region by DNase I footprinting and gel retardation assays identified the presence of several DNA elements with SP1 and NF1 recognition site homologies that bound both liver and brain nuclear proteins. However, one 11-nucleotide-long DNA region containing an overlapping consensus binding sequence for CREB and C/EBP-like factors reacted only with the liver nuclear lysate. Supershift experiments suggest that the transcription factor C/EBPalpha mediates the tissue specific expression of the rat COMT P1 promoter. PMID- 8672244 TI - Isolation and characterization of a stereospecific 3beta-hydroxysteriod sulfotransferase (pregnenolone sulfotransferase) cDNA. AB - In contrast to humans, who possess a hydroxysteroid sulfotransferase (HSST), namely, DHEA sulfotransferase (DHEA-ST), that displays broad substrate specificities, HSSTs of the guinea pig show a high substrate stereoselectivity, as shown by the recent cloning of a chiral-specific 3alpha-hydroxysteroid sulfotransferase. Herein, we report the cloning and expression of the substrate and chiral-specific pregnenolone sulfotransferase (PREG-ST). Transfection of the pCMV expression vector containing PREG-ST cDNA in transformed human embryonal kidney (293) cells showed that the expressed enzyme selectively catalyzes the 3beta-hydroxysteroid substrate. It converts pregnenolone to pregnenolone sulfate most efficiently, whereas dehydroepiandrosterone and epiandrosterone were transformed at a much lower rate, and androsterone, a 3alpha-hydroxysteroid, was not significantly metabolized (30-fold lower). Thus, the enzyme was identified as pregnenolone sulfotransferase. DNA analysis predicts a protein of 287 amino acids with a calculated molecular mass of 34,199 daltons. Alignment of the amino acid sequence with other sulfotransferases indicated that guinea pig pregnenolone sulfotransferase shares 75 and 80% homology with human DHEA sulfotransferase and rat hydroxysteroid dehydrogenase, respectively. RNA blot analysis using guinea pig liver, intestine, adrenal, kidney, epididymis, testis, and lung showed a single RNA species at 1.3 kb is expressed in liver, intestine, and kidney. Guinea pig 3beta-hydroxysteroid sulfotransferase is thus different from that in humans, who possess two mRNA species of 1.3 and 1.8 kb. PMID- 8672243 TI - Quantitative analysis of aquaporin mRNA expression in rat tissues by RNase protection assay. AB - The RNase protection assay was applied to quantify mRNA expression of five principal mammalian water channels in 18 different rat tissues, and to determine the influence of dehydration on renal water channel expression. Probes consisted of labeled cRNAs transcribed from cDNA fragments of rat CHIP28 (AQP-1, bp 238-575 of coding sequence), AQP-CD (AQP2, bp 53-606), MIWC (AQP4, bp 235-572), GLIP (AQP3, bp 219-604), and AQP5 (bp 56-612). Results were normalized to expression of rat beta-actin by quantitative densitometry of autoradiograms. CHIP28 mRNA was expressed strongly in heart, kidney > placenta, skeletal muscle, and urinary bladder and detected weakly in eye, lung, trachea, spleen, liver, colon, prostate, and skin. AQP-CD was detected only in kidney. MIWC mRNA expression was highest in brain, followed by eye, trachea, lung, stomach, kidney, and skeletal muscle. GLIP was found in eye, trachea, kidney, urinary bladder, skin, prostate, placenta, and skeletal muscle. AQP5 was detected in salivary gland, eye, lung, and trachea. An alternatively spliced form of MIWC (sMIWC) was also identified in lung and kidney by RNase protection assay, corresponding to deletion of exon 2 of MIWC. In response to dehydration (3 days, -15 % body weight), renal expression of CHIP28 and MIWC were unchanged, whereas expression of AQP-CD and GLIP were increased significantly by 2.18 +/- 0.04 and 1.36 +/- 0.11 fold (SE, n = 5), respectively. These results establish quantitative values for aquaporin transcript expression in multiple mammalian tissues. The sensitive RNase protection assay revealed the expression of water channels in several tissues not studied previously or in which mRNA levels were too low to detect by Northern blot analysis. The observation of GLIP up-regulation in kidney by dehydration suggests a role in the urinary concentrating mechanism. PMID- 8672245 TI - Mutational analysis of the carboxy-terminal region of UDP-glucuronosyltransferase 2B1. AB - UDP-glucuronosyltransferases (UGTs) are membrane-bound glycoproteins that are resident in the endoplasmic reticulum with a type I topology. The roles of the membrane-spanning and membrane-proximal cytoplasmic domains in UGT activity were investigated. Site-directed and deletional mutagenesis techniques were used to generate truncated forms of the enzyme, forms with altered residues, or forms with heterologous tails appended to the carboxyl terminus. The presence of the transmembrane domain was a critical requirement for UGT activity whereas the cytoplasmic domain seemed to be a modulator of activity but was not essential. Truncation of the protein did not appear to lead to scavenging and degradation, although appending long heterologous tails to the cytoplasmic domain did seem to trigger proteolysis. Analysis of enzyme kinetic parameters and enzyme latency allowed us to discount substrate binding or substrate transport defects as the cause of ameliorated UGT activity in the mutants. PMID- 8672246 TI - Molecular cloning of mouse somatic and testis-specific H2B histone genes containing a methylated CpG island. AB - We have isolated a mouse testis-specific H2B histone gene based on the unusual methylation of the CpG island of rat testis-specific H2B gene in somatic tissues. After digestion of genomic DNA with the methylation-sensitive restriction enzyme Hha I, we found that, among 10-20 copies of mouse H2B histone genes, at least three copies are methylated in somatic tissues, but not in testis. Cloning and sequence analysis of two methylated H2B genes revealed that one gene, MTH2B, is strikingly similar to the testis-specific histone H2B (TH2B) gene of rat and the other, psH2B, is a pseudogene of the somatic-type H2B gene. Northern blot analysis revealed that the expression of the MTH2B gene is testis-specific. During spermatogenesis, the MTH2B gene is expressed predominantly in pachytene spermatocytes, as observed in the expression of rat TH2B gene. Interestingly, the MTH2B gene is largely unmethylated in embryonic stem cells, but methylated in F9 embryonal carcinoma cells. The psH2B pseudogene is methylated in somatic tissues and F9 cells, but only partially methylated in embryonic stem cells. Methylation of the psH2B pseudogene seems to be attributed to its location within the context of repetitive sequences including the B1 element. The unmethylation of both H2B histone genes in the testis explains how CpG islands of those histone genes can be maintained during evolution despite heavy methylation in somatic tissues. PMID- 8672247 TI - Molecular characterization of the Drosophila Mo25 gene, which is conserved among Drosophila, mouse, and yeast. AB - To study the general physiological role of the Mo25 gene, which has been cloned from mouse cleavage-stage embryos, we isolated a Drosophila equivalent, dMo25, cDNA from an embryo cDNA library. The 2,222 nucleotides contained a single open reading frame encoding a polypeptide of 339 amino acid residues with a calculated molecular mass of 39,278 daltons. The deduced amino acid sequence of the dMo25 cDNA had 69.3% identity with mouse Mo25. A homology search revealed that these were similar to a protein encoded in an open reading frame near the calcineurin B subunit gene on chromosome XI in Saccharomyces cerevisiae. In particular, the carboxy-terminal region was highly conserved in Drosophila, mouse, and yeast. The dMo25 gene was mapped to the left arm of the third chromosome at 73AB, and 2.3- and 1.8-kb mRNA bands were detected during development and in adult Drosophila. Conservation of the gene structure and the wide expression profile indicated that the function of the gene is likely to be fundamental in many cell types as well as during development. PMID- 8672248 TI - A tissue-specific repressor in the sea urchin embryo of Lytechinus pictus binds the distal G-string element in the LpS1-beta promoter. AB - LpS1 RNA transcripts and proteins are expressed exclusively in the aboral ectoderm of the embryo in the sea urchin Lytechinus pictus. We have characterized the LpS1-beta promoter to identify the cis-acting elements that may be involved in the aboral ectoderm-specific expression of the LpS1-beta gene. The distal G string site, composed of six contiguous guanine deoxynucleotides located at -721 to -726, was analyzed. A mutation at the distal G-string caused over a two-fold increase in reporter chloramphenicol acetyltransferase gene activity and inappropriate expression of reporter green fluorescent protein in nonaboral ectoderm cells in L. pictus embryos. These results suggest that the proteins that bind the distal G-string act as a spatial repressor in the nonaboral ectoderm cells of the developing embryo. PMID- 8672249 TI - [Epidemiological surveillance of homicides and suicides. A report on the Cali workshop]. AB - Underregistration of homicides and suicides is a problem that exists in most of the countries of the region, owing to the variety of ways these causes are coded and analyzed, insufficient funding for information management, and lack of trained personnel, of coordinated data collection, and of a non-centralized system for issuing reports. The health sector plays an important role in recording information about violent acts, but the information collected and evaluated by the health services is usually limited to the sex and age of the victim, the nature of the injuries, and, occasionally, the type of weapon or means of aggression. The morbidity and mortality statistics compiled by the services do not reflect the true magnitude of the epidemiologic problem of violence because of, among other reasons, underreporting in emergency rooms and outpatient clinics. In addition, victims--for example, those who experience violence within their families--often do not seek services at health institutions. PMID- 8672250 TI - Disorders of platelet function. AB - Qualitative platelet disorders are described and reviewed above. The acquired platelet function defects are very common, and sometimes result in hemorrhage, especially in association with trauma or surgery. However, the specific biochemical defect is absent, and no characterized platelet abnormalities have been recognized. On the other hand, the hereditary qualitative platelet defects are rare, but the platelet abnormalities are characteristic. The study of these patients had led to an increased understanding of the normal primary hemostatic mechanism. Recently, the molecular basis analysis of the platelet defects has been developed. This will help us understand the molecular events involved in platelet adhesion and aggregation. PMID- 8672252 TI - Difficulties in the antemortem diagnosis of gliomatosis cerebri: report of a case with diffuse increase of gemistocyte-like cells, mimicking reactive gliosis. AB - A 46-year-old woman presented with a 2-month history of right hemiparesis and disorientation. CT showed only slightly abnormal findings, while the T2-weighted MRI findings disclosed high intensity in both hemispheres. Two weeks before her death, a biopsy specimen showed monotonous increase of gemistocyte-like cells, mimicking reactive gliosis. However, autopsy revealed some different cytological features; i.e. nuclear atypia and higher cellularity, and the diagnosis of gliomatosis cerebri was made. It is suggested that establishing an antemortem diagnosis of gliomatosis cerebri remains difficult in some cases, even with MRI and biopsy. Careful examination of autopsy material may be necessary for a definitive diagnosis. PMID- 8672251 TI - Small cell lung cancer: biological and therapeutic aspects. PMID- 8672253 TI - Adult onset of the Dandy-Walker syndrome. AB - We describe a case of adult onset Dandy-Walker syndrome. A 35-year-old woman presented with symptoms of increased intracranial pressure and cerebellar signs. After excision of the cyst wall of the posterior fossa. The patient recovered completely. The role of magnetic resonance imaging in establishing the diagnosis and following the course of operation are emphasized. Possible pathophysiological mechanisms involved in the late appearance of the clinical symptoms and the treatment of this anomaly are discussed. PMID- 8672254 TI - Is transcranial Doppler sonography useful in detecting late cerebral ischaemia after aneurysmal subarachnoid haemorrhage? AB - Transcranial Doppler (TCD) examination was performed in 109 patients with aneurysmal subarachnoid haemorrhage. Fifty-seven demonstrated flow velocities exceeding 120 cm/s in the middle cerebral artery. Of these, 23 developed delayed ischaemic deficit (DID). Mean flow velocity in this group was 170, SD 12.8 cm/s, in comparison with 155, SD 11.2 cm/s in the 34 patients without late signs of cerebral ischaemia. This difference is significant (p = 0.0269). In the 34 patients without DID, but TCD > 120 cm/s, 17 received anti-ischaemic therapy based on TCD values only, while 17 were given no additional treatment. The mean TCD values and the neurological outcome in the two groups were similar. A rapid increase in flow velocities of 50 cm/s or more during a 24-h period seemed to be a strong predictor of symptomatic vasospasm as seven out of 12 patients developed DID, five with permanent neurological sequelae. The study confirms results from other centres, that a strict correlation between high TCD flow velocities and occurrence of DID does not exist. PMID- 8672255 TI - The role of emergency surgery in malignant spinal extradural compression: assessment of functional outcome. AB - The role of emergency surgery for spinal cord or cauda equina compression secondary to extradural metastases is assessed in terms of functional outcome in 84 cases. The records of patients with proven malignant extradural spinal compression were reviewed retrospectively to determine the influence of emergency versus elective decompressive surgery on functional outcome. A greater proportion undergoing emergency surgery, rather than electively (within 24 h) on the next list showed functional improvement, with recovered mobility (61.5% vs 25%). Overall, 70% of patients were mobile postoperatively. The findings suggest that despite initial delays in referral, and even if the patient is incontinent and immobile, emergency spinal decompression is justified. PMID- 8672256 TI - Outcome of chronic subdural haematoma: analysis of prognostic factors. AB - Prognostic factors for the outcome of patients with a chronic subdural haematoma were analysed in a consecutive study of 260 patients, regardless of the method of neurosurgical treatment. CT findings such as haematoma volume, midline shift and residual subdural collections had no influence on the outcome. The only statistically significant factor of importance for the outcome of patients with chronic subdural haematoma was the neurological condition at the time of treatment. Early diagnosis is therefore of major importance. PMID- 8672257 TI - Early postoperative gadolinium-DTPA-enhanced MR imaging after successful lumbar discectomy. AB - A prospective study was undertaken to establish the normal spectrum of early gadolinium-enhanced magnetic resonance (MR) imaging findings in patients who had resolution of symptoms after lumbar discectomy. Thirty-four patients underwent MR examinations 6 weeks and 6 months after lumbar discectomy on a 1.5 T superconducting unit, including sagittal and axial spin-echo (SE) T1-weighted images before and after intravenous administration of gadolinium-DTPA, as well as sagittal turbo (or fast-) SE T2-weighted images. All patients showed soft tissue enhancement along the surgical track in the subcutaneous soft tissue lateral to the spinous process and in the epidural space. There was only minimal (45%) or no (55%) mass effect on the dural sac associated with epidural scar formation 6 months after surgery, but often the nerve root at the operative level was surrounded by this enhancing tissue. Facet joint enhancement was seen in most patients 6 weeks (63%) and 6 months (53%) after surgery. Intrathecal nerve root enhancement was observed in six patients, 6 weeks after surgery. Nine patients (20%) had residual mass effect on the neural elements with an enhancement pattern suggestive of a disc fragment. Enhancement of the intervertebral space was seen in 67% of patients 6 weeks after surgery and in 86% of patients after 6 months. It may be concluded that, despite the use of gadolinium-DTPA, MR studies obtained in the initial postoperative period are difficult to interpret, because of the normal sequence of changes. Consequently, the clinical picture still remains the major indicator for recurrent surgery. PMID- 8672258 TI - Paediatric brain tumour therapy. PMID- 8672259 TI - Subcellular distribution and photocytotoxicity of aluminium phthalocyanines and haematoporphyrin derivative in cultured human meningioma cells. AB - The photocytotoxicity characteristics of aluminium phthalocyanine chloride (AIPc), aluminium phthalocyanine disulphonate (AlS2Pc), aluminium phthalocyanine tetrasulphonate (AlS4PC) and haematoporphyrin derivative (HpD) were compared using primary cultures of human meningioma cells. Cells were preincubated with the photosensitising agent for 16 h, then illuminated for 15 min with broad band red light (5 OW/cm2). The resultant cytotoxicity was assessed by tetrazolium (MTT) reduction 24 h later. AlPc was found to be 400, 10,000 and 250 times more potent that AlS2Pc, AlS4Pc and HpD, respectively, as an in vitro photosensitizing agent for meningioma cells. The subcellular localisation of AlPc, AlS2Pc, AlS4Pc and HpD in meningioma cells was determined by confocal laser scanning microscopy. None of the agents localized to the nucleus. The distribution of ALPc was quite diffuse through the cytoplasm. In contrast, AlS2Pc and AlS4Pc were localized vesicles suggestive of lysosomes, and HpD in membranous organelles distinct from mitochondria. AlPc and HpD were tested with five different meningioma samples and provided a range of IC50 values from 0.009 to 0.022 OM and from 3.5 to 6.5 OM, respectively. When the MTT assay with AlPc was performed 0, 24, 48 and 72 h after illumination, the mean IC50 values were 0.25, 0.037, 0.019 and 0.012 OM, respectively, indicating that the cytotoxic effect continued to increase up to 72 h. Cells were incubated with AlPc and HpD for different times up to 24 h before exposure to light. AlPc cytotoxicity was half-maximal with an incubation time of 8 h, whereas HpD cytotoxicity was half-maximal with an incubation time of 2 h, implying slower uptake kinetics for AlPc than for HpD. These data indicate unique features of AlPc which suggests its application as a potent, non-toxic photosensitizer in the photodynamic therapy of human meningiomas. PMID- 8672260 TI - Meningiomas of the cerebellopontine angle. A report of 41 cases. AB - A retrospective study of the surgical management of 41 cerebellopontine angle (CPA) meningiomas was performed. All patients were treated by a single surgeon (TTK) over a 25 year period (1967-1992). There were 13 males, 28 females with a median age of 53.5 years. The median follow-up after surgery was 9 years (range 2 20.4 years). Tumours were classified anatomically into six groups (lateral, midpetrosal, petroclival, internal auditory meatal, Meckel's cave and inferior). Only the petroclival tumours posed difficulties with complete resection (achieved in 7 out of 16) and for most of them a transtentorial transpetrous approach was used. In other groups, complete resection was achieved in all patients. There were four recurrences (two mid-petrosal, one petroclival, one internal auditory meatal), three of which had complete macroscopic resection at the initial operation. PMID- 8672261 TI - "Subdural' pressure measurement during craniotomy. Correlation with tactile estimation of dural tension and brain herniation after opening of dura. AB - In 30 patients subjected to craniotomy, subdural pressure was measured with a 22G/0.8 mm Venflon cannula connected to a pressure transducer system. The measurements were performed after removal of the bone flap and just before opening of the dura. The subdural pressure was correlated with the tactile estimation of dural tension and the tendency to brain herniation after opening the dura. The results indicate that generally there is a poor agreement between the tactile feeling of dural tension and subdural pressure. Thus, in some patients with a relatively high dural pressure the dural tension was evaluated as relaxed. At subdural pressure below 6 mmHg brain herniation never occurred. On the other hand, at tensions over 7 mmHg some brain herniation occurred in all patients, and at tension over 11 mmHg pronounced brain herniation occurred. The method of subdural pressure used in this study is simple, the duration of the measurement is less than 1 min. It is concluded that measurement of subdural pressure before opening of the dura gives important information. PMID- 8672262 TI - Does the child with shunted hydrocephalus require long-term neurosurgical follow up? AB - A prospective study was initiated to investigate parents' and doctors' attitudes towards how the follow-up of children treated with shunts for hydrocephalus should be undertaken. Twenty-three out of 85 (27%) of families whose children had been treated more than 6 months previously failed to attend for their clinic appointment compared with 15% of those attending for other (non-hydrocephalus related) problems. The possible reasons for this discrepancy have been analysed together with the results of a questionnaire filled in by both the parents and the clinic doctors at the time of the appointment. Although both parties felt that there was a sizeable group of patients for whom continuing neurosurgical follow-up was no longer required there was little concordance in identifying who these patients actually were. Also taken into account were the economic factors which influence both parental and medical decision-making. In the light of our study, new ways of managing the follow-up of these children have been formulated. PMID- 8672263 TI - Cystic craniopharyngioma: a simple technique to aid the stereotactic insertion of an Ommaya reservoir drainage system. AB - Percutaneous aspiration of a cystic craniopharyngioma is a recognised technique. We report a simple method using X-ray screening to aid the stereotactic insertion of an Ommaya reservoir drainage system into a cystic craniopharyngioma which ensures optimal catheter placement. PMID- 8672264 TI - Trigeminal neuralgia due to vascular compression in multiple sclerosis--post mortem findings. AB - A 71-year-old male with multiple sclerosis and trigeminal neuralgia due to vascular compression underwent multiple radio-frequency nerve lesioning bilaterally. He was anaesthetic on the left side and required right microvascular decompression. He died after this procedure. The pathology of the pons and the effects of treatment are described. PMID- 8672265 TI - Cerebrospinal fluid and blood lymphocyte subpopulations following subarachnoid haemorrhage. AB - Lymphocyte subpopulations from 10 patients who had had a subarachnoid haemorrhage were analysed. In CSF, an increase of CD3 cells was found in two of ten, CD4 in one of ten, CD8 in three of ten, and CD19 in three of ten patients. Three patients with delayed ischaemic deficit (DID) showed a statistically significant increase of intrathecal suppressor/cytotoxic/NK-cells. The cellular inflammation had been modulated within the CNS indicating a pathogenic role in the biochemical cascades following SAH. PMID- 8672266 TI - Wylie McKissock--reminiscences of a commanding figure in British neurosurgery. AB - Wylie McKissock founded the neurosurgical unit at Atkinson Morley's Hospital which has grown to become the largest neurosurgical unit serving London. He trained a large number of British and overseas neurosurgeons, six of whom achieved presidency of the Society of British Neurological Surgeons. McKissock made a great contribution to the development of British neurosurgery, and reminiscences from some of his trainees and colleagues are collected together in this article. PMID- 8672267 TI - Intradural, extramedullary spinal cord compression from tuberculous granuloma. AB - A 19-year-old girl presented with acute cord compression following treatment for tuberculous meningitis. Magnetic resonance imaging showed a posterior compressive lesion between T1 and T4. At laminectomy, an intradural extramedullary tuberculous granuloma was excised. To our knowledge, this is the first report of spinal cord compression occurring from a subdural tuberculous mass. PMID- 8672268 TI - Extra-axial clival blastomycosis granuloma: a case report. AB - A case of extra-axial fungal (Blastomyces dermatitidis) granuloma in the region of the lower clivus is presented. The lesion simulated a meningioma both on radiological examination and on the macroscopic appearance at operation. PMID- 8672269 TI - Malignant occipital astrocytoma in a patient with Lhermitte-Duclos disease (cerebellar dysplastic gangliocytoma). AB - A case of Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum) is described. Seventeen years after the diagnosis was made, the patient developed a malignant astrocytoma of the cerebrum, an association only once previously reported. The clinical presentation and radiological features are presented. PMID- 8672270 TI - Alan McEwan Paton. 30 April 1922-3 August 1994. PMID- 8672271 TI - Direct identification of the common cheese contaminant Penicillium commune in factory air samples as an aid to factory hygiene. AB - Creatine sucrose dichloran agar (CREAD) was used as a selective medium for Penicillium commune and related species found in air samples in a cheese factory. Using growth and simple colony characters on CREAD together with detection of indole metabolites with a filter paper method, it was possible to identify all 22 P. commune isolates from a total of 43 Penicillium isolates. Penicillium commune numbers on CREAD were compared with those found on a general isolation medium, dichloran 18% glycerol agar. PMID- 8672272 TI - The opportunistic pathogen Nocardia farcinica is a foam-producing bacterium in activated sludge plants. AB - A Gram-positive unicellular coccal-diphtheroid rod causing foam in an activated sludge plant was successfully isolated by micromanipulation. Phenotypic characterization and 16S rDNA sequencing identified it as Nocardia farcinica. This is the first report that this opportunistic pathogen is a foam-causing bacterium in activated sludge, and the clinical implications of these observations are discussed. PMID- 8672273 TI - Development of a polymerase chain reaction assay for the detection of Listeria monocytogenes in foods. AB - Species-specific oligonucleotide primers were selected from the coding region of the listeriolysin O gene of Listeria monocytogenes and were used in conjunction with genus-specific primers and an internal control fragment for polymerase chain reaction amplification. The specificity of the primers was confirmed by testing 40 isolates of L. monocytogenes, other Listeria species and other micro-organisms which are ubiquitous in the environment. The reliability of these primers was further tested in parallel with standard cultural methods. In a preliminary study, over 250 different food samples were examined and PCR results were in complete agreement with those obtained from standard cultural procedures. PMID- 8672274 TI - Behaviour of Listeria monocytogenes during the traditional manufacture of water buffalo Mozzarella cheese. AB - The behaviour of a four-strains mixture of Listeria monocytogenes (strains Scott A, V7, OH and Cal) during the traditional manufacture of water-buffalo Mozzarella cheese was investigated at two levels of inoculation: ca 10(5) and 10(3) cfu ml-1 of vat milk. No significant change in Listeria counts was observed during the curd ripening (4.0-4.5 h), at the end of which the pH ranged between 4.83 and 4.91. A decrease of about 2 log was observed after stretching of the curd in hot water (95 degrees C), followed by complete elimination of Listeria after 48 and 24 h of storage of the final cheese in the conditioning liquid (skim water resulting from the stretching, pH ca 4.0) with initial high and low contamination of the cheese milk respectively. Results also indicated that a 1.7 log reduction of L. monocytogenes could be achieved during the preparation of the natural whey culture utilized as starter in cheesemaking. PMID- 8672275 TI - Detection of Bacteroides fragilis by PCR assay targeting the neuraminidase encoding gene. AB - Oligonucleotide primers were designed on the basis of the sequence of the neuraminidase-encoding gene (nanH) of Bacteroides fragilis and used for the specific detection of this anaerobe by the nested PCR assay. Fifty-nine of 60 representative strains of Bact. fragilis were detected, while none of 45 strains of other species generated visible PCR products. The detection limits of Bact. fragilis cells and DNA by the nested PCR were 10 colony-forming units and 10 fg of chromosomal DNA, respectively. The PCR assay targeting the nanH gene has the potential for the detection of Bact. fragilis. PMID- 8672276 TI - Growth and viability of Alcaligenes eutrophus JMP134 in seawater as affected by substrate and nutrient amendment. AB - Growth and viability of Alcaligenes eutrophus JMP134 was studied in laboratory microcosms with 0.2 microns-filtered seawater prior to release in field-based mesocosms. In unamended systems JMP134 did not grow and viability, measured as direct viable counts combined with immunofluorescence microscopy, was 40-50%. Addition of a nitrogen + phosphorus nutrient mixture caused a greater growth response than amendment with a carbon substrate. Amendment with substrate and/or nutrients caused an increase in viability to ca 100% but only for a brief period coinciding with cell proliferation. Hence, Alc. eutrophus JMP134 has a limited survival potential in seawater unless it is supplied with additional nutrients. PMID- 8672277 TI - A method for evaluating the cariogenicity of oral bacteria using radio-labelled synthetic hydroxyapatite. AB - Radioactive hydroxyapatite was synthesized using 45Ca to evaluate the cariogenicity of oral streptococci. Discs prepared from it were suspended in media containing sucrose, then inoculated with Streptococcus mutans or Streptococcus sanguis. The radioactivity in the supernatant fluid was measured at specified time intervals. Released 45Ca in the supernatant fluids markedly increased in both species during the experimental period, while Strep. mutans showed much higher decalcification than Strep. sanguis. The present method would be useful for semi-quantitative evaluation of bacterial decalcification ability. PMID- 8672278 TI - The use of a rapid Salmonella latex serogrouping test (Spectate) to assist in the confirmation of ELISA-based rapid Salmonella screening tests. AB - Spectate, a 10 min, simple, latex-based agglutination test for serogrouping of salmonellae, has been investigated as a tool to assist in the confirmation of ELISA presumptive positive broth samples when screening for salmonellae in foods. When obtaining a combined ELISA and Spectate positive result, there was a 90% (27/30) confidence limit of a genuine positive result, some one or two working days quicker than the traditional methods. Of the 10% (3/30) that were not confirmed as salmonellas, two gave a Spectate result which is advised as being a possible Citrobacter spp. and one sample gave a positive confirmation by Spectate only, which suggested a failure of the traditional confirmation process, a finding confirmed at other sites. Extensive studies performed at several food company microbiology laboratories showed Spectate to be a useful additional tool in the confirmation process of ELISA screening techniques for salmonellae in food. Additionally the concept of a "false positive' may need to be refined to that of a "not culturally' positive, given the apparent possible failure of the traditional confirmation methods. PMID- 8672279 TI - The clones of Listeria monocytogenes detected in food depend on the method used. AB - Restriction enzyme analysis (REA) with pulsed-field gel electrophoresis (PFGE) has been used to characterize and compare Listeria monocytogenes strains isolated from foods by two methods, an enrichment procedure and a direct plating procedure. In total 151 isolates from nine foods were investigated. In six of the foods (101 strains investigated) only one clone of L. monocytogenes was found irrespective of the method used. In three foods (50 strains investigated) the direct plating procedure yielded more clones than the enrichment procedure. At the most, five clones were detected in the same food. The results presented here indicate that direct plating from the food reveals more L. monocytogenes clones than revealed by an enrichment procedure. PMID- 8672280 TI - A new esterase for the cleavage of pivalic acid-containing prodrug esters of cephalosporins. AB - An extracellular esterase from the actinomycetes Amycolatopsis orientalis was found by screening. It is capable of splitting the isomeric mixture (K/J) of (I, Scheme 1) into 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid, pivalic acid, and acetaldehyde with a high yield. The purified enzyme of 55.4 Kd by SDS-PAGE shows an N-terminal sequence of VRTCADLVRTYDLPGAVTH. The isoelectric point is 8.9 +/- 0.1. It can be immobilized with good yield to VA-Epoxy Biosynth. Besides the above-mentioned reaction, the esterase cleaves many other esters such as methyl-2 chloropropionic acid. PMID- 8672281 TI - Heterologous expression of full-length and truncated forms of the recombinant guluronate-specific alginate lyase of Klebsiella pneumoniae. AB - The alyA gene, which encodes a guluronate-specific alginate lyase from Klebsiella pneumoniae, was cloned into the plasmid pCT54 to facilitate heterologous expression of the enzyme in Escherichia coli. The greatest enzyme specific activity was observed when the complete gene and flanking regions of DNA (contained within a 1.95 kb HindIII fragment) were cloned in the correct orientation relative to the vector-encoded trp promoter. Heterologous expression of the intact gene complete with flanking regions resulted in a 20-fold increase in enzyme yield compared to the original construct, pRC5. PCR mutagenesis and/or restriction endonuclease digestion was used to generate a series of fragments containing either the whole or truncated versions of the gene. Active enzyme was produced from constructs in which the region encoding the signal peptide had been deleted, although the recombinant protein was retained within the bacterial cells. An internal methionine (position 74) could be used as a start site for translation but resulted in the accumulation of inactive protein within inclusion bodies. PMID- 8672282 TI - In vitro glycosylation of proteins: an enzymatic approach. AB - The glycosylation pathway is the most important post-translational modification of a protein and is moreover a highly specific process. The majority of proteins of pharmaceutical interest are glycoproteins. Therefore, it is necessary to identify the composition, the structure, the function and the biosynthesis of the glycoproteins. The present knowledge is described here. In addition, the performed studies about structure-function relationship of the glycoproteins have shown that the oligosaccharide part of a glycoprotein confers important and specific biological roles. Thus, the modification of the structure of the glycan chains can lead to a modification of the activity of the glycoprotein. This phenomenon is encountered at the time of the production of recombinant glycoprotein in a heterologous system. Indeed, the glycosylation profile of a protein is specific to both the host cell and the culture conditions of this cell. Thus, the advantages and the drawbacks of the different host cells used for the glycosylation engineering are presented. In this way, the identification of the different specific enzymes glycosyltransferases and glycosidases involved in the glycosylation pathway is now necessary to improve the production of recombinant glycoprotein. The structure and the characteristics of these enzymes, and more particularly the oligosaccharyltransferase and the galactosyltransferase, are also described. PMID- 8672283 TI - Dynamics of ammonia uptake in nitrogen limited anaerobic cultures of Saccharomyces cerevisiae. AB - Dynamics of the ammonia uptake by Saccharomyces cerevisiae under anaerobic conditions was studied in ammonia limited continuous cultures. A large number of pulse additions of ammonia (25-100 mg 1(-1)) were made at different dilution rates (0.05-0.20 h-1). The response was followed by on-line monitoring of the carbon dioxide evolution rate (CER), optical density, and by frequent analysis of extra- and intracellular metabolites. The uptake of a pulse of ammonia proceeded in a qualitatively highly reproducible pattern. Initially, a rapid and growth rate dependent uptake of ammonia was observed (lasting for about 10-15 min). Next followed a phase with little uptake (approx. 5 min). Finally, the rest of the ammonia pulse was taken up at a somewhat smaller rate which also depended on the growth rate. The first phase coincided with an increase in CER caused by mobilization of the intracellular carbohydrate trehalose and subsequently of glycogen. Regardless of dilution rate and the amount of ammonia added, the initial high uptake rate of ammonia was maintained until approximately the same amount of ammonia had been taken up. Transition from the first to the second uptake phase was associated with an increased glycerol production, indicating an elevated anabolic activity. PMID- 8672284 TI - Expression of the major bean proteins from Theobroma cacao (cocoa) in the yeasts Hansenula polymorpha and Saccharomyces cerevisiae. AB - The production in two yeast expression systems of recombinant forms of the major proteins from the cocoa bean is described. Three major protein species are found in the cocoa bean: an albumin of molecular mass 21 kDa (p21) and two insoluble vicilin-like proteins of molecular mass 31 kDa and 47 kDa (p31 and p47, respectively). The p31 and p47 species are known to be derived from a common 67 kDa precursor (p67) by post-translational processing that includes the deletion of a hydrophilic domain located immediately after an N-terminal signal sequence. All three proteins appear to be targeted to membrane-bound storage organelles by N-terminal signal sequences. The p21 and p67 coding sequences were expressed in Hansenula polymorpha using the powerful methanol oxidase (MOX) promoter and in Saccharomyces cerevisiae using the promoter of the pyruvate kinase (PYK) gene. The expression constructs contained the native plant signal sequence, or various yeast signals. The p21 protein was successfully expressed and secreted from both yeasts. The insoluble p67 protein proved more difficult. Species of the correct molecular mass were recovered internally and small amounts of a p47 species were secreted using a yeast leader sequence. However, proteolytic cleavage, probably due to Kex2p-like processing, led to the appearance of other protein species. PMID- 8672285 TI - Purification and properties of levanase from Rhodotorula sp. AB - Levanase, a slime dissolving enzyme of Rhodotorula sp., was purified to approx. 26-fold by ammonium sulphate precipitation, DEAE and gel filtration (Sephacryl S 200) chromatography. The molecular mass of the enzyme was 39 kDa. The purified levanase showed maximum activity at pH 6.0 and 40 degrees C. Enzyme was quite stable at 4 degrees C and at pH 5.5 to 6.5. Hg2+ at a level of 10 mM completely inhibited the levanase activity, while 2-mercaptoethanol at the same concentration showed a 2.93-times increase in activity. In addition to levan, the enzyme also showed substrate specificity towards inulin. PMID- 8672286 TI - Recombinant interferon gamma for the therapy of immunological and oncological diseases. PMID- 8672287 TI - Eradication of rabies, using a rec-DNA vaccine. PMID- 8672288 TI - Efficient production from Aspergillus niger of a heterologous protein and an individual protein domain, heavy isotope-labelled, for structure-function analysis. AB - Aspergillus niger has been used successfully to secrete proteins labelled with 13C and/or 15N to a specific activity of > 99% for high resolution NMR analysis. In the case of a heterologous protein, hen egg-white lysozyme, 15N single labelled and 13C, 15N double-labelled forms were secreted at yields of 100-200 mg l-1 by optimising the type of carbon source used and the ratio of carbon to nitrogen. Another protein, the glucoamylase starch-binding domain from A. niger, was also produced as the 15N single-labelled form at 20-40 mg l-1. PMID- 8672289 TI - The importance of ammonia in mammalian cell culture. AB - Ammonia has been reported to be toxic and inhibitory for mammalian cell cultures for many years. Reduction of growth rates and maximal cell densities in batch cultures, changes in metabolic rates, perturbation of protein processing and virus replication have been reported. However, cellular mechanisms of ammonia toxicity are still the subject of controversy and are presented here. The physical and chemical characteristics of ammonia and ammonium are important, with the former capable of readily diffusing across cellular membranes and the latter competing with other cations for active transport by means of carrier proteins. The main source of the ammonia which accumulates in cell cultures is glutamine, which plays an important role in the metabolism of rapidly growing cells. Strategies to overcome toxic ammonia accumulation include substitution of glutamine by glutamate or other amino acids, nutrient control, i.e., controlled addition of glutamine at low concentrations, or removal of ammonia or ammonium from the culture medium by means of ion-exchange resins, ion-exchange membranes, gas-permeable membranes or electrodialysis. PMID- 8672290 TI - Measurement of intracellular pH in cultured cells by flow cytometry with BCECF AM. AB - This study evaluates the suitability of flow cytometry with the fluorochrome BCECF for measuring the intracellular pH (pHi) of cultured cells, and monitors the changes in pHi in murine hybridoma in batch culture and chick embryo fibroblast in monolayer culture (5th passage). The technique produced highly reproducible, repeatable results. The theoretical sensitivity from the calibration curve was 0.0004 pH units. But analysis of the standard deviation of the histogram of the green/red fluorescence ratios indicated a mean sensitivity of 0.08 (0.07-0.09) pH units. Interference due to cell size, fluorochrome incorporation and esterases were minimized by establishing a calibration curve with the cells whose pHi was to be measured using the 525/610 nm fluorescence ratio after excitation at 488 nm. The pHi of exponentially growing, batch cultured hybridomas was 7.50 at the start of culture. pHi increased during the exponential growth phase and dropped towards cell death. The pHi of the chick fibroblasts in monolayer culture was 7.30. PMID- 8672292 TI - Impact of plasmid presence and induction on cellular responses in fed batch cultures of Escherichia coli. AB - Fed batch cultivations of plasmid-free and recombinant Escherichia coli were employed in order to determine cellular responses and effects of plasmid presence and induction on the host cell physiology. While plasmid presence was shown to have minor influence on overall biomass yield, induction with 0.1 mM IPTG led to a marked reduction. The number of dividing cells, measured as colony forming ability, was influenced by plasmid presence and to a larger extent by induction. The latter caused a decline in the number of dividing cells to less than 10% of the population within 10 h. However, this cell segregation did not affect the specific rate of product formation, which was approximately constant throughout the cultivations. Analysis of the in vivo degradation rate of the product indicated that it was proteolytically stable. The cellular content of the stringent response signal substance, ppGpp, peaked immediately after transition from batch to fed batch mode to stabilise at a higher value than in the batch phase. When the specific growth rate declined below 0.06 h-1 an additional rise in ppGpp concentration was observed. PMID- 8672291 TI - Expression and purification of human matrilysin produced in baculovirus-infected insect cells. AB - The baculovirus expression system was used to produce recombinant human matrilysin. Expression of promatrilysin reached a peak at 72 h post-infection. Most of the recombinant protein remained in the intracellular fraction in an insoluble form, which after renaturation was purified by S-Sepharose and Green A Dyematrex chromatography in order to remove host proteases. Active recombinant matrilysin degraded casein, type I and type IV collagens and fibronectin. Expression of recombinant human matrilysin using the baculovirus system represents a useful tool for obtaining large amounts of this metalloproteinase in order to carry out further biochemical studies and to screen for inhibitors. PMID- 8672293 TI - Survival of luxAB-marked Alcaligenes eutrophus H850 in PCB-contaminated soil and sediment. AB - A rifampicin-resistant PCB-degrading Alcaligenes eutrophus H850 strain was marked with luxAB reporter genes and designated H850Lr. This strain was enumerated in soil by viable plating and counting of light-emitting colonies. The marked strain was also inoculated into soil and sediment microcosms contaminated with PCBs and treated with rhamnolipid biosurfactants produced by Pseudomonas aeruginosa UG2Lr or inoculated with the P. aeruginosa UG2Lr strain. A. eutrophus H850Lr exhibited similar survival in sandy loam soil in the absence or presence of PCBs over 56 days. Survival of A. eutrophus H850Lr in PCB-contaminated sediment was less than in sandy soil under the same incubation conditions. Addition of P. aeruginosa UG2 rhamnolipids to soil increased the culturable indigenous heterotrophic population, and numbers of A. eutrophus H850Lr cells. P. aeruginosa UG2Lr cells did not affect survival of A. eutrophus H850, as cell enumerations after 2 months were the same as in microcosms containing only A. eutrophus H850 inoculum. P. aeruginosa UG2Lr survived in soils as demonstrated by the slight decrease in CFU from 1 x 10(8) to 2 x 10(6) CFU cm-3 after 2 months. Direct extraction of DNA from soil and purification for use in PCR amplification using primers specific for the bphC gene detected 8 x 10(2) A. eutrophus H850Lr CFU g-1 soil in PCB contaminated soils. Colony lifts of bacteria isolated from microcosms containing PCB-contaminated soil did not hybridize with LB400 bphC probe. However, enrichment of PCB-contaminated soil with biphenyl, followed by DNA extraction and probing with bphC gene probe detected indigenous PCB-degrading bacteria containing a similar gene sequence in PCB-contaminated sediment. This study demonstrates the usefulness of using the lux reporter system in monitoring bacterial survival in PCB-contaminated soils and sediments. PMID- 8672294 TI - Apparent heterogeneity of recombinant interferon gamma receptors produced in prokaryotic and eukaryotic expression systems. AB - Recombinant proteins show several types of heterogeneity and post-translational modifications which are usually related to their production system. The apparent heterogeneity of recombinant interferon gamma receptors and interferon gamma receptor-immunoglobulin G fusion proteins expressed in Escherichia coli, baculovirus-infected insect cells and Chinese hamster ovary cells have been studied. In general, all proteins tested showed some type of heterogeneity which was detectable by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The E. coli-derived receptor included non-native conformations involving mis-paired or non-formed disulfides. This type of heterogeneity affected the biological activity of the protein. In addition, the prokaryotic protein had trapped phosphoric acid during downstream processing. The phosphoric acid entrapment did not affect ligand binding capacity. The eukaryotic proteins showed heterogeneity because of the unequal cleavage of the signal peptide and because of differences in glycosylation. The latter types of heterogeneity did not affect activity. Glycosylation-related heterogeneity was partially derived from the unequal utilization of the potential N-glycosylation sites and differently affected the apparent molecular masses and migrations of the proteins on polyacrylamide gels. The results may be useful in characterization studies of recombinant proteins. PMID- 8672295 TI - Tungsten in biological systems. AB - Tungsten (atomic number 74) and the chemically analogous and very similar metal molybdenum (atomic number 42) are minor yet equally abundant elements on this planet. The essential role of molybdenum in biology has been known for decades and molybdoenzymes are ubiquitous. Yet, it is only recently that a biological role for tungsten has been established in prokaryotes, although not as yet in eukaryotes. The best characterized organisms with regard to their metabolism of tungsten are certain species of hyperthermophilic archaea (Pyrococcus furiosus and Thermococcus litoralis), methanogens (Methanobacterium thermoautotrophicum and Mb. wolfei), Gram-positive bacteria (Clostridium thermoaceticum, C. formicoaceticum and Eubacterium acidaminophilum), Gram-negative anaerobes (Desulfovibrio gigas and Pelobacter acetylenicus) and Gram-negative aerobes (Methylobacterium sp. RXM). Of these, only the hyperthermophilic archaea appear to be obligately tungsten-dependent. Four different types of tungstoenzyme have been purified: formate dehydrogenase, formyl methanufuran dehydrogenase, acetylene hydratase, and a class of phylogenetically related oxidoreductases that catalyze the reversible oxidation of aldehydes. These are carboxylic reductase, and three ferredoxin-dependent oxidoreductases which oxidize various aldehydes, formaldehyde and glyceraldehyde 3-phosphate. All tungstoenzymes catalyze redox tungsten in these enzymes is bound by a pterin moiety similar to that found in molybdoenzymes. The first crystal structure of a tungsten- or pterin-containing enzyme, that of aldehyde ferredoxin oxidoreductase from P. furiosus, has revealed a catalytic site with one W atom coordinated to two pterin molecules which are themselves bridged by a magnesium ion. The geochemical, ecological, biochemical and phylogenetic basis for W- vs. Mo-dependent organisms is discussed. PMID- 8672296 TI - Tetrapolar fungal mating types: sexes by the thousands. AB - In order to achieve genetic rearrangement in a sexual cycle, eukaryotes go through the processes of meiosis and mating. Different mating types assure that mating is only possible between two genetically diverse individuals. Basidiomycetous fungi display thousands of different mating types that are determined by two genetically unlinked loci. One locus is multiallelic and contains genes for homeodomain transcription factors which are able to form heterodimers. The activation of target genes is dependent on heterodimers formed from the monomeric transcription factor proteins originating from different alleles of this genetic locus. The interactions between the two monomeric transcription factors and the activation of target genes by the heterodimeric proteins make this regulatory system both complex and interesting. The second locus contains a pheromone receptor system: the pheromone receptor is similar to the G protein-linked serpentine receptors in Saccharomyces cerevisiae that activate the pheromone response via a phosphorylation signal transduction cascade in S. cerevisiae. This pheromone perception is a trigger of sexual development and not, as with yeast, itself under control of mating type genes. Rather it directly senses diversity at the mating type loci. Whereas heterobasidiomycetes display a bi-allelic structure for this locus with recognition between one receptor and the opposite pheromone, homobasidiomycetes contain multiple specificities for pheromone receptors and pheromones. PMID- 8672297 TI - [Malignant brain tumor]. PMID- 8672298 TI - [To disclose to the patients the diagnosis and information about the likely course of amyotrophic lateral sclerosis]. PMID- 8672299 TI - [Information giving in Parkinson's disease]. PMID- 8672300 TI - [Epilepsy]. PMID- 8672301 TI - [Some problems in giving notice of the name of a disease: with special reference to Alzheimer's disease and vascular dementia]. PMID- 8672302 TI - [Informed consent to the patient with hereditary ataxia]. PMID- 8672303 TI - [Prolonged QTc intervals in Parkinson's disease--relation to sudden death and autonomic dysfunction]. AB - Sudden death has been reported in Parkinson's disease (PD), but the cause of death has not been fully clarified. A prolonged QT interval on the electrocardiogram (ECG) of patients without cardiac dysfunction is an independent risk factor for sudden death regardless of etiology. QT prolongation is believed to be related to cardiac autonomic dysfunction. We suspected that QTc intervals, as well as QT intervals, might be related to the clinical characteristics of PD and to the function of the autonomic nervous system in PD and also postulated a relationship between QTc prolongation and sudden death in PD. We investigated the QTc intervals on the ECGs of 48 PD patients (20 males 28 females) aged 64.5 +/- 9.4 years and 44 controls aged 60.0 +/- 8.2 years, and excluded patients with heart disease. QTc intervals were determined by using ECG-8210, ECAPS12 (Nihon Kohden). The autonomic nervous system was evaluated by measuring CVR-R and performing orthostatic tests. Since the autonomic nervous system is considered to play an important role in the mechanism of diurnal blood pressure variation (DBPV), we assessed DBPV in 19 PD patients by determining blood pressure automatically every 30 minutes for 24 hours with an ambulatory blood pressure monitor (90202, Space Lab). QTc intervals were significantly longer in the PD patients (412 +/- 26 msec) than in the controls (401 +/- 14 msec) (p < 0.02, t test). QTc prolongation was significantly correlated with severity according to Hoehn and Yahr stage (r = 0.509, p < 0.001), orthostatic hypotension, and decreased CVR-R ratio but not with duration of PD or treatment. The incidence of QTc prolongation was higher in the PD patients with non-dipper type DBPV than in those with the dipper type. Two of the PD patients died suddenly. Their QTc intervals a year before their death were 451 msec and 470 msec, respectively, suggesting that cardiac dysautonomia may have been involved in the cause of their death. These findings suggest that cardiac autonomic dysfunction is related to the severity of PD, and that it may predispose such patients to cardiac disorders including sudden cardiac death. PMID- 8672304 TI - [Sequential analysis of the integrated images of PET, CT and MR in malignant brain tumors before and after radiotherapy]. AB - 11C-methyl-L-methionine (C-11 Met)PET, CT and MR imaging were performed in eleven patients with malignant brain tumors before and after RT to evaluate the usefulness of positron emission tomography (PET) in monitoring tumor response to radiotherapy (RT). The subjects included five cases of intracranial malignant lymphoma (ICML) and six cases of glioma. C-11 Met uptake by the tumor (T) and the contralateral gray matter (NT) was calculated on the PET images. The mean T/NT ratio of the ICMLs and gliomas changed from 2.33 and 1.87, respectively, before RT to 1.31 and 1.58, respectively, after RT.No significant difference was found between the T/NT ratios before and after RT in either the ICMLs or the gliomas (t test). We tentatively defined the minimum T/NT ratio, 1.2, as the threshold between tumor and nontumor regions. Tumors with a ratio of 1.2 or more were imaged as "hot" (MET) and coincided with CT or MR image lesions which were visualized as contrast-enhancing (CE) and low-density (LD) or high-intensity (HI). The relationships between PET, CT and MRI lesions were classified as follows: Type I (MET < or = CE), Type II [CE < MET < LD (HI)], Type III [LD(HI) < or = MET]. MET lesions extending regionally ( > 1 cm) beyond the respective CT or MR image lesions were designated "MET-extension" and LD (HI) lesions protruding ( > 1 cm) beyond the MET lesions were recorded as "LD (HI)-extension" on the integrated images. The type II pattern of the MET areas in all five cases of ICML before RT had changed to Type I in one case, Type III in one case and Type II in three cases, after RT, while the two Type II patterns and four Type III patterns of the gliomas had converted to four Type II and two Type III patterns. These findings indicate that gliomas tend to invade into areas of peritumoral edema more than ICMLs. There were two ICML MET-extension sites in the cortex before RT, as opposed to two in the cortex, one in the basal ganglia, one in the thalamus, and one in the corpus callosum among the gliomas. On follow-up CT or MR images MET-extension (75%) had converted to a CE or LD (HI) region. Four ICML LD (HI) extension sites before RT were found in periventricular white matter, versus one in the cortex and three in the white matter among the gliomas. LD (HI)-extension appeared to represent vascular edema because it decreased or diminished after completion of therapy. Sequential analysis of integrated C-11 Met PET, CT and MR images is useful in detecting the extent of tumor infiltration by ICMLs and gliomas, particularly at an early stage, and for evaluating the effect of RT in the treatment of both. PMID- 8672305 TI - [Cerebral atrophy and ventricular enlargement in physiological ageing--a morphometrical study in 28 autopsy brain of normal old people]. AB - It is generally agreed that the adult human brain shows atrophy with advance of ageing. Although this phenomenon has been confirmed, mainly by measurement on CT images, there were only a few studies on brains over the age of 70 years. We measured the cranial cavity volume brain volume and ventricular volume in 28 normal autopsy brains of from 63 to 96 years of age (mean 81.4 years). We found that the ratio between the brain volume and the cranial cavity volume (B/C ratio), and the ratio between the ventricular volume and the brain volume (V/B ratio), had no significant correlation to age (B/C ratio: r = 0.22, p = 0.28, V/B ratio; r = 0.13, p = 0.50). Although our results are compatible with the previous studies on very old people, they are different from those on middle aged and presenile people. We considered that the cerebral atrophy become far less marked after 70 years of age. PMID- 8672306 TI - [A long-term clinical effect of selegiline hydrochloride on Parkinson's disease]. AB - A long-term follow-up evaluation on the clinical usefulness of selegiline hydrochloride (selegiline) was performed in 13 patients with Parkinson's disease. All patients, except one case, subjected to the study were symptomatically improved by combination therapy of selegiline with L-DOPA in the preceding short term evaluation. One patient continued the therapy after an evaluation of no symptomatic improvement in the short-term study, because this patient strongly requested continuation of medication, expecting to stop the progression of the disease. The average daily dose of selegiline at the last evaluation was 7.0 +/- 2.8 mg. The average daily dose of L-DOPA at each evaluation point in the patients who continued the therapy for 12 months remained low compared to that prior to the therapy (before: 450 +/- 138 mg, at the 12th month: 383 +/- 98 mg). In the analysis of individual parkinsonian symptoms, the improvement in the mean score for most of the symptoms, especially the wearing-off phenomenon and frozen gait, persisted for the entire period of study. Global improvement rates (moderately improved) at the 6th and 12th month, and the last evaluation were 60.0%, 50.0% and 50.0%, respectively. Among 10 patients, therapy was discontinued only in one case due to hallucination. Although the global improvement rate declined in the course of the therapy, selegiline seems to be useful for improving L-DOPA responsive symptoms in long-term therapy for Parkinson's disease. PMID- 8672307 TI - [A case of cranial hypertrophic pachymeningitis with intracranial hemorrhage]. AB - A case of cranial hypertrophic pachymeningitis of unknown etiology in a patient with 15-year history of headaches, cranial nerve palsies, and gait disturbance is reported. A 77-year-old woman was brought to our institute in a coma. CT revealed intracerebral hemorrhage in the right temporal lobe and thickening of the falx and tentorium. Fifteen years previously the patient had undergone CT scanning because of headaches, cranial nerve palsies, and progressive gait disturbance and a thickened tentorium, mild hydrocephalus and edematous change in the right temporal lobe had been reported. Since the etiology of her symptoms was unclear at the time, she did not receive adequate treatment. Her symptoms gradually progressed thereafter, and her visual acuity and hearing deteriorated. MR imaging in 1994 showed the thickened tentorium as a hypointense area with hyperintense edges on Gd-DTPA enhanced images. Angiography revealed narrowing of posterior portion of the superior sagittal sinus. The patient's condition rapidly deteriorated due to the intracranial hypertension and she subsequently died. Autopsy revealed a thickened tentorium with xanthochromic surface. This hypertrophic change was also seen in the dura mater of the posterior and middle cranial fossa. Microscopic examination of the thickened tentorium revealed extensive fibrous tissue with a chronic inflammatory infiltrate, predominantly of lymphocytes. No specific lesions were revealed by staining with hematoxylin eosin, PAS, Gram's or Ziehl-Neelsen stains. The patient had no inflammatory or infectious diseases of other organs, and a diagnosis of idiopathic cranial hypertrophic pachymeningitis of unknown etiology was made. Considering the above findings, the thickened tentorium depicted as a hypointense area on the T1- and T2-weighted images and the Gd-enhanced edges of the tentorium are thought to be represent fibrous tissue and inflammatory regions, respectively. PMID- 8672308 TI - [A case of Rathke's cleft cyst in association with anterior communicating artery aneurysm presenting a rare visual field defect]. AB - We report a case of Rathke's cleft cyst associated with anterior communicating artery aneurysm. The patient was 60-year-old woman who developed visual disturbance two months before admission to our hospital. Visual acuity on the right was 0.06 and on the left was 0.08. The visual fields showed a complete temporal hemianopsia on the left eye and an incomplete temporal hemianopsia of the right eye with a central defect of the temporal visual field. CT and MR imagings showed an intra- and suprasellar mass lesion with no enhancement. Angiography showed bilateral A1 elevations and anterior communicating artery aneurysm. The operation was performed through interhemispheric approach. Suprasellar cystic mass compressed upward the optic nerves and chiasm, and aneurysmal dome stuck in the central region of chiasm. This anatomical disorders affected to the optic chiasm resulted in a rare visual field defect. Neck clipping of aneurysm and opening of the cyst were performed. A diagnosis of Rathke's cleft cyst was made. Following surgery, her visual fields resolved but she suffered from diabetes insipidus. PMID- 8672310 TI - Measurement of competence. PMID- 8672309 TI - [A 78-year-old man with young onset parkinsonism and sudden death]. AB - We report a right-handed 78-year-old man with early onset parkinsonism. The patient had an onset of micrographia at 23 years of the age in 1939. Seven years later he started to drag his right foot, and at 38 years of age, he walked with small steps with festination. Tremor was also present in his right hand. His daily life was independent as a otorhinolaryngologist. He visited our clinic on March 24, 1977 when he was mentally sound and showed mild parkinsonism consisting of masked face, stooped posture, small step gait, bradykinesia, and right side dominant rigidity and tremor. He showed good response to trihexyphenidyl and amantadine HCl. Two month later, he developed dyskinesia and some worsening of parkinsonism, and was admitted to our hospital for the first time. He was treated with 400 to 600 mg/day of levodopa/ carbidopa. He showed marked improvement, however, dyskinesia remained in his mouth. He was doing well until 77 years of age (June of 1993) when he developed hallucination and motor fluctuations. He was admitted again to our hospital on June 22, 1993. On admission, he was alert and appeared mentally sound. However, Hasegawa dementia scale was 18/30. Upward gaze was slightly restricted (3/5). Voice was somewhat small but no masking was noted. His posture was stooped and the gait was of small step. Dyskinesia was noted during walk. No rigidity nor tremor was noted. Deep tendon reflexes were lost but no sensory loss or motor weakness was noted. Routine laboratory studies were unremarkable. A cranial CT scan revealed only mild to moderate cortical atrophy. Motor and sensory conduction velocities were within normal limits, however, motor action potentials could not be obtained with stimulation to the right common peroneal nerve. He was treated with 600 mg/day of levodopa with carbidopa, 100 mg of amantadine HCl, 300 mg of Dops, and 25 mg of tiapride. He continued to show motor fluctuations, and was discharged on July 23, 1993. Since then his motor functions had become progressively worse with frequent falls, but he was still able to walk without support. On October 3 of 1994, he went to bed as usual. On the next morning, he was found dead in his bed at 9: 30. The patient was discussed in neurological CPC, and the chief discussant arrived at the conclusion that the patient had young-onset Parkinson's disease with Lewy bodies in the substantia nigra. Opinions were divided between Parkinson's disease and Lewy body negative young onset parkinsonism. Postmortem examination revealed obstruction of the trachea by aspirated foods, and the cause of death appeared to have been suffocation by the foods. Macroscopically, the external appearance of the brain was unremarkable except for slight frontal atrophy. The substantia nigra showed depigmentation in the lateral part, but the pigmentation of the medial part was well preserved. Upon histologic examination, the number of pigmented neurons in the dorsomedial part was well preserved. In the lateral part, pigmented neurons were well preserved in the dorsal area, however, in the ventral area, only non pigmented neurons were seen; they appeared to be neurons in the pars reticulata. No gliosis was seen in any of the nigral areas. No Lewy bodies were seen in the remaining neurons. So-called immature neurons with rounded shape without neuromelanin could not be detected. The locus coeruleus neurons were well preserved. The putamen and the other basal ganglia structures were also intact. Slight myelin pallor was noted in the subcortical white matter, however, otherwise cerebral cortices were normal. The histology of this patient is unique in that only the ventrolateral part of the substantia nigra showed abnormal finding consisting of lack of pigmented neurons without gliosis. It is not clear whether the nigral change represents degeneration or a congenital "hypoplasia'. To our knowledge, such a unique pathology of the substantia nigra has not been reported in the literature. Our patient ma PMID- 8672311 TI - Use of suxamethonium in children. PMID- 8672312 TI - Nocturnal hypoxaemia in late pregnancy. AB - We have measured arterial oxygen saturation (SpO2) continuously overnight in 13 non-pregnant (NP), 13 pregnant normotensive (NPIH) and 15 pregnant patients with a diagnosis of pregnancy-induced hypertension (PIH). The two pregnant groups did not differ in duration of pregnancy (> 35 weeks) and none was in labour. There was no significant difference in age between these three groups. Mean SpO2 in group NP was 98.5% (range 97-99%). This was significantly higher than that in group NPIH (95.2 (91-98) %) and group PIH (94.9 (89-99) %). In seven pregnant patients, more than 20% of the recording was spent with an SpO2 < 90%. We conclude that a significant number of pregnant women (> 35 weeks' gestation) suffer from prolonged nocturnal hypoxaemia. PMID- 8672313 TI - Cerebrospinal fluid progesterone in pregnant women. AB - To assess the possible relationship between an increase in progesterone concentration in cerebrospinal fluid (CSF) and enhancement of spread of spinal anaesthesia, we have measured CSF progesterone concentrations in 134 patients undergoing spinal anaesthesia with hyperbaric amethocaine 8 mg. Patients were allocated to one of five groups according to the gestational period: non-pregnant group (n = 13), first trimester group (8-12 weeks, n = 16), second trimester group (13-24 weeks, n = 18), third trimester group (25-36 weeks, n = 38) and term group (37-41 weeks, n = 49). Progesterone concentration in CSF was higher in the third trimester and term groups than in the non-pregnant, first trimester and second trimester groups. Maximum cephalad spread of analgesia was higher in the second trimester, third trimester and term groups than in the non-pregnant and first trimester groups. Although an increase in CSF progesterone concentration in the second trimester group was similar in magnitude to that observed in the first trimester group, enhanced spread of spinal anaesthesia, comparable in magnitude with that observed in the term group, occurred in the second trimester group. There was no significant correlation between CSF progesterone concentration and spread of spinal anaesthesia in any of the groups. These data suggest that not only a minimum level of progesterone in CSF but also a certain duration of exposure to elevated CSF progesterone concentrations may be necessary for enhancement of spread of spinal anaesthesia, and that values of CSF progesterone concentration do not correlate directly with enhancement of spread of spinal anaesthesia. PMID- 8672314 TI - Extensive extradural spread in the elderly may not relate to decreased leakage through intervertebral foramina. AB - It has been suggested that the extensive longitudinal extradural spread of local anaesthetics in the elderly is attributed to decreased leakage through the intervertebral foramina. We have examined radiologically, in 53 patients, the relationship between leakage of iohexol through the thoracic intervertebral foramina and age. Iohexol was injected through an extradural catheter advanced 5 cm cephalad from one of the interspaces between T6 and T12. A significant correlation was observed between longitudinal spread of iohexol and age, but there was no correlation between leakage of iohexol through the intervertebral foramina and age. Our data suggest that longitudinal extradural spread of local anaesthetics in the elderly may not be attributed to decreased leakage through the intervertebral foramina. PMID- 8672315 TI - Effects of adrenaline and hyaluronidase on plasma concentrations of lignocaine and bupivacaine after peribulbar anaesthesia. AB - We have measured peak plasma concentrations of lignocaine and bupivacaine after dual injection peribulbar block and investigated the influence of adrenaline and hyaluronidase. Twenty-four patients were allocated randomly to one of four groups: (I) local anaesthetic alone (lignocaine 10 mg ml-1-bupivacaine 3.75 mg ml 1); (II) local anaesthetic with adrenaline (5 micrograms ml-1); (III) local anaesthetic with hyaluronidase (75 iu ml-1); or (IV) local anaesthetic with adrenaline and hyaluronidase. Venous plasma concentrations of lignocaine and bupivacaine were measured in 24 patients using gas liquid chromatography before and at 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 180, 300 and 540 min after completion of the peribulbar injections. Main outcome measures were analysed using two-way analysis of variance. All patients, with one exception, received 10 ml of the local anaesthetic mixture. Overall peak plasma concentrations varied from 230 to 1910 micrograms ml-1 for lignocaine and from 160 to 1090 micrograms ml-1 for bupivacaine. Adrenaline significantly reduced peak plasma concentrations of lignocaine to 57% (P = 0.001) and bupivacaine to 61% (P = 0.004) compared with the nonadrenaline groups. Hyaluronidase had no significant effect on peak plasma concentrations of lignocaine and bupivacaine, which were 90% (P = 0.34) and 100% (P = 0.84) of the non-hyaluronidase groups. The area under the plasma concentration-time curves to 300 min (AUC300) behaved similarly. There was a reduction in AUC300 for lignocaine (P = 0.005) and bupivacaine (P = 0.011) in the adrenaline groups compared with the non-adrenaline groups, in contrast with no significant effects of hyaluronidase on AUC300 for lignocaine (P = 0.14) or bupivacaine (P = 0.53) compared with the non-hyaluronidase groups. PMID- 8672316 TI - Comparison of the effects of adrenaline, clonidine and ketamine on the duration of caudal analgesia produced by bupivacaine in children. AB - Sixty boys, aged 1-10 yr, undergoing orchidopexy were allocated randomly to receive one of three solutions for caudal extradural injection. Group A received 0.25% bupivacaine 1 ml kg-1 with adrenaline 5 micrograms ml-1 (1/200,000), group C received 0.25% bupivacaine 1 ml kg-1 with clonidine 2 micrograms kg-1 and group K received 0.25% bupivacaine 1 ml kg-1 with ketamine 0.5 mg kg-1. Postoperative pain was assessed using a modified objective pain score and analgesia was administered if this score exceeded 4. The median duration of caudal analgesia was 12.5 h in group K compared with 5.8 h in group C (P < 0.05) and 3.2 h in group A (P < 0.01). There were no differences between the groups in the incidence of motor block, urinary retention or postoperative sedation. PMID- 8672317 TI - Effect of digital pressure on the neurovascular sheath during perivascular axillary block. AB - We have assessed prospectively the influence of digital pressure on the effectiveness of perivascular axillary block using a catheter technique in two groups of patients. Ninety-eight patients received axillary injections of 2% mepivacaine with adrenaline 20 ml mixed with contrast agent 20 ml. During injection firm digital pressure was applied either on the neurovascular sheath (group 1) or 6-8 cm below it (group 2). The patient's arm was then adducted. Axillary radiographs were obtained in 90 patients after 30 min. In the last eight patients radiographs were obtained after injecting 2, 20 and 40 ml of the mixture to study the dynamics of spread. There were no statistically significant differences in proximal flow of mepivacaine or in the success rate of the block between the groups. Signs of flow obstruction by the head of the humerus were seen in only eight patients. In the majority of patients local anaesthetic spread above the coracoid process, which increased the success rate of the block, but did not guarantee an effective block. PMID- 8672318 TI - Changes in blood volume distribution between legs and trunk during halothane anaesthesia. AB - To assess the influence of halothane anaesthesia on the distribution of blood volume in supine humans, we used albumin labelled with 99mTc to measure blood volume distribution along the craniocaudal axis. We studied 6 volunteers in the supine position before, during and after anaesthesia with 1% halothane and 66% nitrous oxide. Using collimated detectors above and below the subject, counts were obtained from the legs, pelvis, abdomen, rib cage and head, with the arms excluded. During anaesthesia, the proportion of counts detected in the legs increased, but failed to achieve significance (P = 0.059). On recovery from anaesthesia, leg counts decreased significantly. Counts in the abdomen and rib cage decreased significantly during anaesthesia and the abdomen counts increased again on recovery (P = 0.036 for all changes). These results confirm other studies of the vascular effects of halothane, and do not support the hypothesis that blood volume redistributes from the legs to within the chest wall during anaesthesia. PMID- 8672319 TI - Comparison of the effects of sub-hypnotic concentrations of propofol and halothane on the acute ventilatory response to hypoxia. AB - To compare the effects of sub-anaesthetic concentrations of propofol and halothane on the respiratory control system, we have studied the acute ventilatory response to isocapnic hypoxia (AHVR) in 12 adults with and without three different concentrations of propofol and halothane. Target doses for propofol were 0, 0.05, 0.1 and 0.2 of the effective plasma concentration (EC50 = 8.1 micrograms ml-1). Target doses for halothane were 0, 0.05, 0.1 and 0.2 minimum alveolar concentration (MAC = 0.77%). The doses achieved experimentally were 0.01, 0.06, 0.13 and 0.26 of the EC50 for propofol and 0, 0.05, 0.11 and 0.20 MAC for halothane. During the experiment subjects breathed via a mouthpiece from an end-tidal forcing system. End-tidal PO2 (PE'O2) was held at 13.3 kPa for 5 min, and then at 6.7 kPa for 5 min. End-tidal PCO2 (PE'CO2) was held constant at 0.13-0.27 kPa greater than the subject's natural level throughout. The mean values for AHVR with propofol were: 12.8 (SEM 2.4) litre min-1 (0.01 EC50), 10.0 (1.9) litre min-1 (0.06 EC50), 9.8 (2.3) litre min-1 (0.13 EC50) and 4.9 (1.2) litre min-1 (0.26 EC50). The values for AHVR with halothane were: 11.9 (2.4) litre min-1 (0 MAC), 7.8 (1.6) litre min-1 (0.05 MAC), 5.9 (1.2) litre min-1 (0.11 MAC) and 3.2 (1.6) litre min-1 (0.2 MAC). The decline in AHVR with increasing dose for both drugs was statistically significant (ANOVA, P < 0.001); there was no significant difference between the two drugs with respect to this decline. Normoxic ventilation with propofol declined from 13.2 (1.6) litre min-1 (0.01 EC50) to 8.3 (0.9 litre min-1 (0.26 EC50), and with halothane declined from 13.5 (2.0) litre min-1 (0 MAC) to 11.8 (1.6) litre min-1 (0.2 MAC). This was significant for both drugs (ANOVA, P < 0.001). PMID- 8672320 TI - Comparison between oxygen consumption calculated by Fick's principle using a continuous thermodilution technique and measured by indirect calorimetry. AB - We calculated oxygen consumption by the reverse Fick principle (cVO2) using cardiac output measured with a new technique of continuous thermal dilution and compared these values with measurements made at the same time using a gas exchange method (mVO2). We studied nine patients in a stable condition after cardiac surgery. In each patient six successive measurements of continuous cardiac output and mVO2 were made over 5 min at 10-min intervals. The mean difference between the estimates (mVO2-cVO2) was 15 ml min-1 m2 (95% confidence limits, -3 to 33 ml min-1 m2). The relative error of each method was 5% and 4% (continuous cardiac output and gas exchange methods, respectively). Calculation of VO2 using the new cardiac output technology had good repeatability compared with direct measurement, probably because of the high precision of measurement of cardiac output. PMID- 8672321 TI - Cytokine balance and immunosuppressive changes at cardiac surgery: contrasting response between patients and isolated CPB circuits. AB - In vitro work suggests that IL-10 plays a pivotal role in controlling the balance of pro- and anti-inflammatory cytokines and monocyte HLA-DR expression. In 20 patients undergoing cardiac surgery, we investigated elaboration of interleukin 10 (IL-10) and its relationship to pro- and anti-inflammatory cytokines and leucocyte expression of HLA-DR and adhesion molecules. There were small increases in pro-inflammatory cytokines (IL-1, IL-8 and tumour necrosis factor (TNF) after induction, returning to baseline on induction of cardiopulmonary bypass (CPB). After CPB another transient increase in IL-8 occurred (P < 0.05). The anti inflammatory response began with elevated IL-10 during CPB (P < 0.001), which peaked early in recovery (P < 0.001), by which time IL-1 receptor antagonist (IL 1ra) and the TNF soluble receptors (TNFsr) had also increased (P < 0.01). The next day IL-10 and IL-1ra were decreasing but TNFsr continued to increase. Induction of anaesthesia caused HLA-DR downregulation. The IL-10 peak was associated with further monocyte HLA-DR downregulation (P < 0.001) and return towards baseline of granulocyte adhesion molecule expression which transiently increased during CPB (P < 0.001). To determine which aspects of the immune response arose from the interaction of blood with the CPB apparatus, the above variables were studied within an isolated CPB circuit and the influence of fentanyl on the magnitude of any such changes determined. Five healthy volunteers donated two, 250-ml samples of blood to which was added either fentanyl 175 micrograms with heparin 1050 u. or heparin alone 1050 u. These were used to prime two identical isolated CPB circuits and circulation was conducted under identical conditions for 90 min. Of the pro-inflammatory cytokines, only IL-8 was elevated at 90 min CPB (P < 0.05). There was no increase in anti-inflammatory cytokines and TNFsr decreased (P < 0.001). Granulocyte adhesion molecules were increased during CPB. In the fentanyl group, the CD11b increase was greater and preceded CPB. The reduction in lymphocyte HLA-DR expression, observed throughout the study period (P < 0.01), was greater with fentanyl (P < 0.05). Monocyte HLA-DR expression increased (P < 0.05), but to a lesser extent with fentanyl (P > 0.05). In contrast with the in vivo response where there was a phased anti-inflammatory response beginning with IL-10, in the isolated CPB model no anti-inflammatory cytokine response occurred. PMID- 8672322 TI - Prophylaxis of alcohol withdrawal syndrome in alcohol-dependent patients admitted to the intensive care unit after tumour resection. AB - Prophylaxis of alcohol withdrawal syndrome (AWS) in alcohol-dependent patients shortens the duration of stay in the intensive care unit (ICU). The objective of this study was to assess the effect of four different prophylactic regimens on the duration of ICU stay, prevention of AWS and rate of major intercurrent complications in alcohol-dependent patients admitted to the ICU after tumour resection. A total of 197 alcohol-dependent patients, diagnosed by the Diagnostic and Statistical Manual of Mental Disorders (third revised edition) with a daily ethanol intake of 60 g, were allocated randomly to one of the following regimens which were commenced on admission to the ICU: flunitrazepam-clonidine, chlormethiazole-haloperidol, flunitrazepam-haloperidol or ethanol. The duration of ICU stay, prevention of AWS, incidence of tracheobronchitis and major intercurrent complications such as pneumonia, sepsis, cardiac disorders, bleeding disorders and death were documented. On admission, patients did not differ significantly in age, APACHE II and multiple organ failure scores. ICU stay, incidence of AWS, severity of AWS (revised clinical institute withdrawal assessment for alcohol scale > 20) and major intercurrent complication rate did not differ significantly between groups. Although there was no advantage in any of the four regimens with respect to the primary outcome measures, pulmonary and cardiac patients were not included in the study. Patients in the chlormethiazole haloperidol group had a significantly increased incidence of tracheobronchitis (P = 0.0023), probably because of an increased incidence of hypersecretion. PMID- 8672323 TI - Does the type of volume therapy influence endothelial-related coagulation in the critically ill? AB - The endothelium plays an important role in the regulation of haemostasis by producing substances such as thrombomodulin (TM). The influence of long-term volume replacement with different types of fluid on the TM-protein C-protein S system was investigated in a prospective, randomized study. Thirty trauma patients and 30 patients suffering from sepsis after major surgery received either 10% low-molecular weight (LMW) hydroxyethylstarch solution (HES-trauma, n = 15; HES-sepsis, n = 15) or 20% human albumin (HA-trauma, n = 15; HA-sepsis, n = 15) for 5 days to maintain central venous pressure (CVP) between 12 and 16 mm Hg. Plasma concentrations of TM, protein C, (free) protein S and thrombin antithrombin (TAT) were measured in arterial blood samples obtained on the day of admission to the intensive care unit or on the day of diagnosis of sepsis and over the next 5 days. There were no differences between HA- and HES-treated trauma patients. Protein C and protein S also did not differ between HA- and HES treatments. At baseline, TM plasma concentrations were increased to > 40 micrograms litre-1 in both sepsis groups only. In the HA-sepsis group, TM increased significantly (from 48.1 (SD 13.9) to 68.4 (13.0) micrograms litre-1), whereas it remained almost unchanged in the HES-sepsis group. In HES-sepsis patients, protein C (from 51.0 (10.1) to 71.9 (8.9)%) and protein S (from 19.0 (6.0) to 40.8 (11.4)%) increased significantly during the study, whereas both remained reduced in HA-patients. TAT (indicating intravascular coagulation) did not differ between the two fluid groups. We conclude that in trauma patients, the type of volume therapy had no influence on the TM-protein C-protein S system. In sepsis patients, volume therapy with HES was beneficial, whereas infusion of HA had no substantial positive effect on endothelial-associated coagulation. PMID- 8672324 TI - Improved haemodynamic stability with administration of aprotinin during orthotopic liver transplantation. AB - In a placebo-controlled, double-blind study, we have investigated the hypothesis that patients for orthotopic liver transplantation (OLT) treated with high-dose aprotinin (serum concentrations > or = 200 kiu ml-1) show greater haemodynamic stability on graft reperfusion. We studied 55 adult patients presenting for OLT, and 52 were included in the analysis. The treatment and placebo groups were similar in patient characteristics. The anaesthetic regimen used was standardized, and veno-venous bypass were used in all patients. Cardiac output measurements and haemodynamic profiles were recorded at intervals throughout anaesthesia and surgery. Arterial and mixed venous oxygen saturations were measured by co-oximetry. Derived variables were measured using standard formulae. Aprotinin treated patients had greater values for systemic vascular resistance on reperfusion, with a lesser cardiac index and calculated oxygen delivery. Oxygen consumption, however, was significantly greater, despite reduced delivery. PMID- 8672325 TI - Do nitrous oxide and halothane influence opioid receptor binding in SH-SY5Y human neuroblastoma cells? AB - The site of interaction of opioids and inhalation anaesthetic agents is unknown, but may be at the level of the opioid receptor. In this study we have used SH SY5Y human neuroblastoma cells, which express both mu and delta receptors, to examine the effects of halothane on the receptor binding profiles of [3H]diprenorphine (DPN), an opioid receptor antagonist, and [3H] [D-Ala2,MePhe4, Gly(ol)5]enkephalin (DAMGO), a mu receptor selective agonist. Binding of [3H]DPN and [3H]DAMGO was performed at 37 degrees C for 60 min in the presence of air, nitrous oxide (75%) or air containing halothane (0.5-5.0% v/v). Compared with air controls, neither 75% nitrous oxide nor 0.5, 1.0, 2.0 and 5.0% halothane influenced DPN binding variables. Binding of [3H]DAMGO was unaffected by 1.0% halothane, but 5.0% halothane reduced the affinity, with a modest increase in Kd (1.15 (0.16) to 1.7 (0.2) nmol litre-1) without effect on Bmax. Our data suggest that the site of opioid and volatile anaesthetic interaction is not at the opioid receptor. PMID- 8672326 TI - Sevoflurane improves neurological outcome after incomplete cerebral ischaemia in rats. AB - We have studied the effects of sevoflurane on neurological outcome in a rat model of incomplete cerebral ischaemia. After institutional approval, 30 non-fasted male Sprague-Dawley rats (455-555 g) were anaesthetized, the trachea intubated and the lungs ventilated mechanically with isoflurane and 30% oxygen in air. Catheters were inserted into the right femoral artery, both femoral veins and into the right jugular vein for measurement of arterial pressure, drug administration and blood sampling. At completion of surgery, isoflurane was discontinued and the rats were allowed an equilibration period of 30 min according to the following regimens: group 1 (n = 10) received 70% nitrous oxide in oxygen and fentanyl (bolus 10 micrograms kg-1 i.v.; infusion 25 micrograms kg 1 h-1); group 2 (n = 10) received 1.98 vol% sevoflurane in oxygen and air (FIO2 0.3); group 3 (n = 10) received 1.98 vol% sevoflurane in oxygen and air (FIO2 0.3) and 40% glucose (6 ml kg-1 i.p.) 30 min before ischaemia. Ischaemia was produced by combined unilateral common carotid artery ligation and haemorrhagic hypotension to 35 mm Hg for 30 min. Temperature, arterial blood-gas variables and arterial pH were maintained within the physiological range. Plasma glucose concentration was measured before, during and after ischaemia. Neurological deficit was evaluated for 3 days after ischaemia. Neurological outcome was better in sevoflurane anaesthetized animals, regardless of the plasma glucose concentration, compared with nitrous oxide-fentanyl controls. This indicates that differences in plasma glucose concentrations do not account for the cerebral protection seen with sevoflurane. PMID- 8672327 TI - Effects of halothane, enflurane and isoflurane on contraction of rat aorta induced by endothelin-1. AB - Volatile anaesthetics induce hypotension by both indirect and direct effects; they have been reported to inhibit vasoconstriction produced by a variety of agonists. These studies were performed to see if halothane, enflurane and isoflurane attenuate endothelin-1-evoked contraction and if they interact with endothelium-dependent or -independent vasoactive substances. Rat aortic rings were suspended in aerated Krebs' solution (37 degrees C) and contracted by incremental doses of endothelin-1 5 x 10(-10) to 5 x 10(-8) mol litre-1. Volatile anaesthetics at 1 and 2 MAC were tested on endothelium intact and denuded rings. They were tested also on L-NAME incubated endothelium intact and indomethacin incubated endothelium intact and denuded rings. Responses to endothelin-1 were compared in the presence and absence of volatile anaesthetics. Isoflurane at 1 and 2 MAC concentration, and enflurane at 2 MAC, induced a rightward shift of the dose-response curve obtained with endothelin-1 in both endothelium denuded and intact rings, associated with a decrease in maximal tension generated in the latter rings. In L-NAME-incubated endothelium intact rings and in indomethacin endothelium denuded rings, the anaesthetics induced a rightward shift of the dose response curve without modification of maximal tension. In indomethacin-incubated endothelium intact rings there was significant attenuation of endothelin-1 contraction in control rings which was not enhanced by volatile anaesthetics in treated rings. The present study indicates that isoflurane at 1 and 2 MAC, and enflurane at 2 MAC, significantly decreased endothelin-1-induced contraction of isolated rat aorta. This inhibition was observed in both intact and denuded rings and probably involves mechanisms within the smooth muscle. Nevertheless, our results suggest that part of the anaesthetic-induced inhibition of endothelin-1 evoked vasocontraction involves an "indomethacin-like" effect on an endothelial derived vasoconstricting cyclo-oxygenase product. PMID- 8672328 TI - Starch, gloves and extradural catheters. AB - We have investigated contamination of extradural catheters during normal handling with starch powdered gloves. In the laboratory, extradural catheters were handled in sterile fields with both powdered and non-powdered gloves, simulating preparation for patient insertion. The catheters together with glove samples were then examined using a Zeiss 940 scanning electron microscope. Microscopy of samples revealed starch contamination of the catheters handled with powdered gloves, especially in the side hole areas. We conclude that extradural catheters may be contaminated easily by starch powder from surgical gloves. This powder may then be deposited into the extradural space. The effect of starch in the extradural space is not known but starch is known to cause inflammatory and granulomatous reactions in other parts of the body as well as being directly allergenic. Powder contamination of catheters may be avoided easily by the use of powder-free gloves and we feel that these should be used whenever possible. PMID- 8672329 TI - Sonoclot analysis. AB - Assessment of perioperative bleeding disorders, especially those related to platelet dysfunction, remains a clinical challenge. The management of the bleeding patient in the operating theatre or on the postoperative ward is often empirical with little scientific basis. Much of the reason for this is that conventional clotting studies are not immediately available and there is a perceived urgency, particularly among trainee doctors, to treat bleeding disorders without first establishing the exact nature of the coagulopathy. SCT provides useful information on platelet function, particularly in patients after cardiopulmonary bypass, and has enabled practitioners to rationalize the management of bleeding disorders and not expose their patients to the risks of unnecessary transfusion of blood products. Undoubtedly further studies are required before this instrument can be used reliably in the clinical setting but it may prove to be a useful addition to the available techniques for monitoring perioperative bleeding disorders. PMID- 8672330 TI - Preoxygenation--the importance of a good face mask seal. AB - We have studied 16 healthy volunteers whose lungs were preoxygenated six times each in order to assess the amount of room air entrained during tidal volume preoxygenation if a good seal is not maintained between the face mask and the face. With a fresh gas flow of 10 litre min-1, we found that using gravity alone to hold the face mask in position, more than 20% room air was entrained; if the face mask was held adjacent to the face, more than 40% room air was entrained. PMID- 8672331 TI - Anaesthetic implications of aortic stent surgery. AB - We present a case of abdominal aortic aneurysm repair using a new technique of aortic stenting and discuss the anaesthetic technique used and the perioperative advantages of the technique. PMID- 8672332 TI - Cardiovascular collapse after laparoscopic liver biopsy. AB - We describe a unique complication of laparoscopic liver biopsy. The increased intra-abdominal pressure associated with carbon dioxide pneumoperitoneum produced haemodynamic stability by tamponading a trochar-induced retroperitoneal haemorrhage. After deflation of the abdomen, release of the tamponade resulted in acute cardiovascular collapse. Other complications associated with laparoscopic surgery are also discussed. PMID- 8672333 TI - Emergency use of the laryngeal mask airway in severe upper airway obstruction caused by supraglottic oedema. AB - We report two cases of severe upper airway obstruction caused by supraglottic oedema which developed rapidly at the time of anaesthesia. Conventional methods to relieve the obstruction failed and it was only overcome when a laryngeal mask airway (LMA) was inserted and positive pressure applied manually during inspiration. In one case a fibrescope was passed via the LMA and this revealed two cushions of oedematous false vocal cords protruding into the bowel of the LMA which were pushed out of the way when positive pressure was applied during inspiration. We believe that the LMA should be considered in the emergency management of severe upper airway obstruction even when this involves supraglottic oedema. PMID- 8672334 TI - Ventilatory arrest after a fluid challenge in a neonate receiving s.c. morphine. AB - S.c. infusions of morphine have been advocated for postoperative analgesia in children, but experience with this technique is limited. We report a case in which an s.c. infusion of morphine given after operation to a neonate failed to provide acceptable analgesia until the child had been adequately rehydrated. However, restoration of peripheral perfusion with a fluid challenge was followed by sudden ventilatory arrest which required resuscitation and naloxone infusion. This report emphasizes the dangers of giving morphine by a peripheral route in the dehydrated or hypovolaemic infant. PMID- 8672335 TI - Inadvertent extradural insertion of an internal jugular catheter in an infant. AB - We present an unusual complication of left internal jugular vein catheterization in an 11-week-old infant which we believe has not been described previously. After failed subclavian catheterization, a left internal jugular catheter was placed without apparent difficulty. Confirmatory chest x-ray revealed that the tip of the catheter was in the extradural space. PMID- 8672336 TI - Intraoperative transoesophageal echocardiography for implantation of a pulsatile left ventricular assist device. AB - We describe the insertion of a permanent implantable left ventricular assist device and intraoperative transoesophageal echocardiography in this instance. We also review the literature on the use of intraoperative transoesophageal echocardiography. PMID- 8672337 TI - Nitric oxide improves hypoxaemia following reperfusion oedema after pulmonary thromboendarterectomy. AB - A patient underwent pulmonary thromboendoarterectomy for chronic, major-vessel thromboembolic pulmonary hypertension. After operation the patient developed reperfusion oedema and hypoxaemia which was treated successfully with inhalation of nitric oxide. Before operation, the response to inhaled nitric oxide was characterized by a slight reduction in pulmonary vascular resistance but without improvement in gas exchange. The postoperative improvement in oxygenation after inhalation of nitric oxide contrasted sharply with the preoperative reaction. PMID- 8672338 TI - Use of esmolol in a parturient with hypertrophic obstructive cardiomyopathy. AB - The physiological changes occurring during pregnancy and labour may reveal or exacerbate the symptoms of hypertrophic obstructive cardiomyopathy (HOCM). We describe the management of labour in a patient with severe HOCM during which esmolol, a short-acting beta adrenergic antagonist, was used together with extradural analgesia and invasive cardiovascular monitoring to achieve an assisted vaginal delivery with minimal haemodynamic disturbance. The effects on the infant are described and the literature on the use of esmolol in pregnancy is reviewed. PMID- 8672339 TI - A statistical approach to measuring the competence of anaesthetic trainees at practical procedures. AB - Cusum analysis is a statistical technique to distinguish deviations from an acceptable failure rate. The progress of anaesthetic trainees learning four practical procedures (obstetric extradural anaesthesia, spinal anaesthesia, central venous cannulation and arterial cannulation) was monitored from their first attempt using cusum analysis. Suitable acceptable and unacceptable failure rates for each procedure were chosen by consultant anaesthetists. For obstetric extradural anaesthesia, four trainees eventually achieved acceptable failure rates (5%) and the number of attempts required to demonstrate this statistically ranged from 29 to 185; three trainees had an unacceptable failure rate (10%) and five trainees had inconclusive records. For spinal anaesthesia, two trainees achieved an acceptable failure rate (10%) and the number of attempts required to demonstrate this statistically ranged from 39 to 67; two trainees had an unacceptable failure rate (20%) and four trainees had inconclusive records. One trainee demonstrated statistically an acceptable failure rate in arterial cannulation (20%) after 14 attempts and four trainees had inconclusive records. Two records of central venous cannulation were inconclusive. Some records showed variable failure rates which were sometimes associated with lack of practice or a change in technique. Cusum analysis can be used to monitor training in practical procedures and as a continuous audit of quality of clinical practice. PMID- 8672340 TI - The role of an anaesthetist in a field hospital during the cholera epidemic among Rwandan refugees in Goma. AB - In 1849 John Snow, already the leading anaesthetic practitioner and innovator of his day, made a historic contribution to the epidemiology of infectious disease by his famous study of the distribution of cholera around the area of Broad Street in London. We report on our experience as anaesthetists in a field hospital, dispatched as part of the international rescue effort to Goma, Zaire, to help combat the effects of cholera among the Rwandan refugees. PMID- 8672341 TI - Intraoperative awareness and the isolated forearm technique. PMID- 8672342 TI - Comparison between two methods of measuring cardiac output: misleading analyses? PMID- 8672343 TI - Fires and explosions with anaesthetics. PMID- 8672344 TI - Increase in Mallampati score during pregnancy. PMID- 8672345 TI - Peripheral analgesic effect of morphine. PMID- 8672346 TI - Mivacurium and prolonged neuromuscular block. PMID- 8672347 TI - Thiopentone anaesthesia at Pearl Harbor. PMID- 8672348 TI - Maximum dose of lignocaine for brachial plexus block. PMID- 8672349 TI - Remembrance of times past: the significance of c-fos in pain. PMID- 8672350 TI - Effects of morphine on atrial preparations obtained from nonfailing and failing human hearts. AB - We have examined the effects of morphine in auricular myocardium from non-failing and failing human hearts. In both preparations morphine induced inhibition. These responses were not antagonized by naloxone. Comparison of mean IC30 values obtained in non-failing (3.9 (SEM 0.2) x 10(-8) mol litre-1) and failing (5010 (200) x 10(-8) mol litre-1) hearts indicated that the morphine concentration response curves were significantly (P < 0.001) shifted to the right in preparations from failing hearts. In addition, a decrease in the maximal response was observed. These data indicate that opioid receptors are not involved in the cardiac effects induced by morphine and that there is a decrease in responses to morphine in the failing heart. PMID- 8672351 TI - A perfusion system for in vitro measurement of human cilia beat frequency. AB - We have designed and built a perfusion system and perfusion chamber to allow investigation of the effects of anaesthetic agents on human cilia in vitro. Using this system, samples of human respiratory cilia can be maintained in a stable and controlled environment for several hours. We measured cilia beat frequency of nasal respiratory epithelium from 10 healthy volunteers; cilia beat frequency was constant over a 4-h period, and measurements were found to be in good agreement with previously published work [1]. In a separate study we investigated the effect of a sleep dose of propofol on cilia beat frequency in samples from six patients undergoing minor surgery; samples were obtained before and immediately after induction of anaesthesia with propofol 2-3 mg kg-1. There was no statistically significant difference in cilia beat frequency between data obtained before and after induction with propofol. PMID- 8672352 TI - Effects of 3 MAC of halothane, enflurane and isoflurane on cilia beat frequency of human nasal epithelium in vitro. AB - We have measured the effects of three times the minimum alveolar concentration (MAC) of halothane, enflurane and isoflurane on cilia beat frequency of human nasal epithelial brushings from 18 healthy adult patients. Using the transmitted light technique and paired perfusion chambers, the cilia were exposed to 2.25% halothane, 5% enflurane or 3.6% isoflurane in air, or air alone, in a controlled and blinded manner. Over a 4-h observation period, cilia beat frequency of the samples exposed to inhalation anaesthetic agents demonstrated a significant reduction in frequency compared with controls exposed to air alone. Mean cilia beat frequency for the samples exposed to halothane was 9.3 (SEM 1.3) compared with its controls of 11.4 (1.0); for the samples exposed to enflurane, 10.9 (1.3) compared with its controls of 11.6 (1.2); and for the samples exposed to isoflurane, 10.8 (1.1) compared with its controls of 11.6 (1.2). There was a statistically significant difference between the samples exposed to all three volatile agents and their associated controls (halothane, P = 0.01; enflurane, P = 0.03; isoflurane, P = 0.01; nested repeated measures analysis of variance utilizing polynomial contrasts). PMID- 8672353 TI - Effect of phosphodiesterase inhibitors on human arteries in vitro. AB - In the present study, we investigated if the relaxant effects of phosphodiesterase (PDE) III inhibitors on human vessels could be inhibited by a nitric oxide synthase blocker, L-NAME, or by a blocker of ATP-sensitive potassium channels (KATP), glibenclamide. The experiments were performed using an isometric myograph in isolated human s.c. small arteries obtained from healthy donors. After a priming procedure consisting of exposure to high potassium (120 mmol litre-1) solutions, phenylephrine 10 mumol litre-1 and an equilibrium period of 30 min, the preparations were contracted with a thromboxane A2 mimetic agent, U46619 1 mumol litre-1. Subsequently, cumulative concentration-response curves were constructed for the selective PDE III inhibitors amrinone, milrinone and enoximone, and for theophylline and dipyridamole, with and without the addition of L-NAME 100 mumol litre-1 or glibenclamide 1 mumol litre-1. Addition of L-NAME to the organ bath resulted in significantly higher pEC50 values (-log of the concentration required for 50% relaxation) for milrinone compared with the control: 2.77 (SEM 0.24) mol litre-1 (n = 5) vs 3.49 (0.17) mol litre-1 (n = 7) (P < 0.05). There was no significant difference between any other group. From our data we conclude that the relaxant properties of amrinone, enoximone, theophylline and dipyridamole are not dependent on nitric oxide release or on interaction with KATP channels. However, the effect of milrinone may be partly endothelium-dependent in human vessels in vitro. PMID- 8672354 TI - Cardiopulmonary bypass with modified fluid gelatin and heparin-coated circuits. AB - We have assessed the efficacy of cardiopulmonary bypass (CPB) using normal colloid oncotic pressure (COP) in a randomized, controlled study of 20 patients undergoing elective coronary artery surgery using heparin-coated circuits. For CPB, we used either crystalloid priming 1650 ml (n = 10) or colloid priming 1650 ml (2.4% modified fluid gelatin, n = 10). While COP did not change during bypass in the colloid group, a decline was observed in the crystalloid group (P = 0.005). By the end of bypass, the decrease in COP compared with baseline (delta COP) was 8.5 (S.D. 1.1) mm Hg in the crystalloid group compared with 1.5 (2.1) mm Hg in the colloid group (P = 0.0001). delta COP correlated positively with fluid balance during bypass (r2 = 0.41, P = 0.002). Similar increments in complement factors C3b/c and C4b/c, tumour necrosis factor-alpha and neutrophil elastase, but not endotoxins, were found in both groups as indicators of a systemic inflammatory response. A clinical performance score composed of fluid balance, postoperative duration of intubation and the difference between rectal temperature and skin temperature was more favourable in patients treated with colloid priming (P = 0.03). Median postoperative hospital stay was 7 (range 5-16) days in the crystalloid group compared with 5 (4-8) days in the colloid group (P = 0.016). Regression analysis indicated that CPB time, fluid balance during operation and postoperative PO2/FlO2 ratio were independent factors that predicted postoperative hospital stay. From these preliminary results we conclude that in the absence of endotoxaemia, use of a normal COP during CPB with modified fluid gelatin in heparin-coated circuits resulted in an improved postoperative course an a reduction in hospital stay. PMID- 8672355 TI - Effect of pneumoperitoneum and Trendelenburg position on gastro-oesophageal reflux and lower oesophageal sphincter pressure. AB - We have measured the effect of pneumoperitoneum and the Trendelenburg position on lower oesophageal sphincter (LOSP) and barrier pressures (BrP) in 11 anaesthetized pigs while measuring the incidence of gastro-oesophageal reflux with a pH electrode. Propofol in combination with sufentanil had no effect on LOSP or BrP. Adoption of the Trendelenburg position with a pneumoperitoneum of 15 mm Hg resulted in a significant increase in LOSP (P < 0.002) and BrP (P < 0.001). However, in two of 11 pigs who had the lowest LOSP before induction, there was regurgitation. PMID- 8672356 TI - Recent developments in the pathophysiology and management of pre-eclampsia. PMID- 8672357 TI - Extradural and subarachnoid catheterization using the Seldinger technique. AB - The Seldinger technique was developed using a plastic introducer through which introduction and manipulations of a silicone spinal catheter, an extradural stimulation lead or a small diameter fibreoptic scope are possible without the risk of damage to the vulnerable devices. It is not intended as a replacement of the standard technique of introducing a spinal catheter through a Tuohy needle in general anaesthetic practice. Silicone spinal catheters and stimulation leads are used for long-term therapy in intractable chronic pain and spasticity. A fibreoptic scope is used for endoscopic examination of the subarachnoid or extradural space. Using a standard Tuohy needle the soft silicone extradural lead can be damaged easily by manipulations during insertion. For this reason the manufacturer modified the Tuohy needle for extradural silicone lead introduction. The disadvantages of this modified Tuohy needle are: first, difficulty in localization of the extradural space, second, the needle is unsuitable for a subarachnoid catheter or introduction of a fibreoptic scope. The Seldinger technique was performed 25 times in 18 patients, introducing a spinal silicone catheter (n = 14), an extradural silicone stimulation lead (n = 2) or a small diameter fibreoptic endoscope (n = 9). Paraesthesiae caused by neural irritation occurred in awake patients. This did not differ from the technique using a Tuohy needle only. Neural damage or trauma did not occur with the Seldinger technique. The incidence of post-spinal headache was the same for both techniques. No further complications were noted. PMID- 8672358 TI - Regional anaesthesia for outpatient nasal surgery. AB - Regional anaesthesia is not used widely for outpatient nasal surgery. The aim of this study was to determine the role of nasociliary and infraorbital nerve block in 24 patients undergoing nasal surgery comprising: cosmetic or reconstructive surgery of the nose and surrounding soft tissue, polypal removal, turbinectomy, reduction of fractured nasal bones, small tumour resection or emergency surgery on isolated facial lacerations. Mild sedation with midazolam 0.03 mg kg-1 was used before anaesthesia. Nasociliary and infraorbital blocks were technically easy to perform, safe and provided good intraoperative conditions. Only minor complications were observed, including local bruising in eight patients and transient diplopia in one patient. No patient received general anaesthesia, but infiltration of local anaesthetic was necessary in four patients because of incomplete anaesthesia in the surgical area. Operative conditions were judged as good or excellent by surgeons in 20 of 24 patients. Twenty of 24 patients were very satisfied or satisfied with anaesthesia. Duration of surgery exceeding 60 min and excessive bleeding in the nasopharynx were the main limiting factors for the use of facial regional anaesthesia. PMID- 8672359 TI - Effect of smoking on dose requirements for vecuronium. AB - We have compared the potency of vecuronium given to 12 smokers and 12 non-smokers during propofol-alfentanil-nitrous oxide anaesthesia. After obtaining individual dose-response curves, bolus doses of vecuronium were given to maintain neuromuscular block at 90-98% for 60 min. Adductor pollicis EMG was used to monitor neuromuscular block. Mean ED95 values were 61.38 micrograms kg-1 and 47.49 micrograms kg-1 for smokers and non-smokers, respectively (P < 0.01). The dose of vecuronium to maintain 90-98% neuromuscular block was 25% higher in smokers than in non-smokers (96.80 vs 72.11 micrograms kg-1 h-1; P < 0.01). These data reflect the effects of smoking on neuromuscular block induced by vecuronium. The effect may be at the receptor level, although possible increased metabolism of vecuronium in smokers cannot be excluded. PMID- 8672360 TI - Airway problems after carotid endarterectomy. AB - Respiratory obstruction has been reported as a complication of carotid endarterectomy; the causes include traumatic mucosal oedema, direct tracheal compression by haematoma and oedema secondary to lymphatic and venous congestion. We report four cases of acute respiratory obstruction complicating carotid endarterectomy. Two of these cases suffered respiratory arrest in the postoperative ward and required emergency tracheal intubation in difficult circumstances. All of these patients had developed wound haematomas and all required surgical intervention. PMID- 8672361 TI - Mivacurium chloride and late onset congenital myopathy. AB - We describe the successful use of the short-acting, non-depolarizing neuromuscular blocking agent, mivacurium, in a 53-yr-old female patient with late onset congenital myopathy, undergoing elective submucous resection of the inferior turbinates. She was unable to climb stairs and walking was limited to periods of 15 min because of generalized weakness, fatigue and shortness of breath. A Datex Relaxograph was used to monitor the train-of-four count. No increase in sensitivity to mivacurium was demonstrated. A dose of 12 mg (three times the recommended ED95) resulted in 88% reduction of the first of the train of-four count (T1) compared with control (TC). Spontaneous recovery of T1/TC to 100% took 11 min 20 s from the time maximum block was first achieved. The recovery index (25-75% T1/TC) was 4 min 40 s. PMID- 8672362 TI - Anaesthesia and juvenile hyaline fibromatosis. AB - Juvenile hyaline fibromatosis is a rare autosomal recessive disease characterized by large cutaneous nodules, especially around the head and neck and often involving the lips. The effects become increasingly severe with age and also include joint contractures, gingival hypertrophy and osteolytic lesions. We describe the anaesthetic management of two sisters with this disease. Safe maintenance of a patent airway is the principal anaesthetic challenge. PMID- 8672363 TI - Cannabis as a medicine. PMID- 8672364 TI - Visceral pain during caesarean section. PMID- 8672365 TI - Naproxen after day-case laparoscopic sterilization. PMID- 8672366 TI - Systolic pressure variation--a way to recognize dynamic hyperinflation. PMID- 8672367 TI - Intrathecal insertion of an extradural catheter during combined spinal-extradural anaesthesia. PMID- 8672368 TI - Intrathecal insertion of an extradural catheter during combined spinal-extradural anaesthesia. PMID- 8672369 TI - RAE tube obstruction during tonsil dissection. PMID- 8672370 TI - Extradural clonidine for postoperative pain relief. PMID- 8672371 TI - Porphyria, propofol and rats. PMID- 8672372 TI - Porphyria, propofol and rats. PMID- 8672373 TI - Pupil changes during cardiopulmonary bypass. AB - Pupil diameter is used during anaesthesia to assess depth of anaesthesia and indicate cerebral hypoxia. This is especially so during cardiac bypass when other autonomic signs cannot be monitored. We have used a pupillometer to determine the effect of cardiopulmonary bypass on the pupil. We have also investigated if any effect was caused by washout of opioid from the central nervous system by allocating patients to one of two groups: in one the bypass pump was preloaded with fentanyl, in the other with 0.9% saline. Cardiopulmonary bypass caused pupil dilatation of between 17% and 53%, which was unaffected by preloading the bypass pump with fentanyl. This effect lasted for the duration of the study, which ended 30 min after the start of cardiopulmonary bypass. Sympathetic nervous system reflexes and hypothermia may account for this observation, but further research is necessary to exclude other contributory factors. PMID- 8672374 TI - Vecuronium infusion requirements in paediatric patients in intensive care units: the use of acceleromyography. AB - Neuromuscular blocking drugs in intensive care units (ICU) may cause complications, including prolonged neuromuscular block as a result of overdosage and post-ventilation muscle weakness. These may be increased by using inappropriately high infusion rates for infants, in whom published studies are scarce, and by failure to monitor neuromuscular block. There is little ICU experience of acceleromyography, which may permit more reliable monitoring. To determine appropriate vecuronium infusion rates, 12 neonates/infants (median age 4 (interquartile range (IQR) 2-5) months) and 18 children (median age 3.07 (2-10 yr) were studied. The vecuronium infusion rate was adjusted to maintain train-of four (TOF) at 1 response using the TOF guard accelerometer. Recovery time was measured from cessation of infusion until spontaneous TOF ratio recovery of 0.7. Neonates and infants required 45% less vecuronium (mean infusion rate 54.7 (SEM 4.23) micrograms kg-1 h-1) than older children (98.7 (7.07) micrograms kg-1 h-1) and had faster recovery to 70% T4/T1 (45 (IQR 20-51) min vs 65 (55-103) min), with no evidence of prolonged weakness. Routine monitoring of neuromuscular block in ICU is essential; acceleromyography is convenient and reliable. PMID- 8672375 TI - Pharmacokinetics of rocuronium after bolus and continuous infusion during halothane anaesthesia. AB - We have studied the pharmacokinetics of a single bolus of rocuronium (Org 9426), followed by an infusion, in eight patients during anaesthesia with halothane and nitrous oxide in oxygen. Neuromuscular block was monitored using train-of-four (TOF) stimulation and recording the force of contraction of the adductor pollicis muscle. Rocuronium was administered as an initial bolus dose of 0.45 mg kg-1 followed by an infusion adjusted manually to maintain T1 (first response in the TOF) at 10% of control. Mean onset time and time to recovery of T1 to 10% were 72 (SD 19.6) s and 27 (9.6) min, respectively. The infusion rates were stable in 19.8 (6.5) min. The mean requirement for rocuronium for steady state 90% block of T1 was 528 (163.3) micrograms kg-1 h-1. After cessation of surgery the infusion was stopped and patients were allowed to recover spontaneously. The times to attain a T1 of 90% and a TOF ratio of 0.7 were 31 (11.7) min and 36 (7.3) min, respectively. Blood samples were collected for 390 min after cessation of infusion and concentrations of rocuronium and its putative metabolites measured using HPLC. A two-exponential equation was used to describe the pharmacokinetic data. The rate of clearance, mean residence time and volume of distribution at steady state were 3.3 (0.77) ml kg-1 min-1, 67.2 (18.8) min and 212.5 (40.1) ml kg-1, respectively. The distribution (T1/2 alpha) and elimination (T1/2 beta) half-lives were 7.5 (3.33) min and 85.6 (18.4) min, respectively. These values were not significantly different from previously published data for a single bolus dose of rocuronium. PMID- 8672376 TI - Effect of suxamethonium on the auditory evoked response in humans. AB - We have studied the arousal effect of suxamethonium on the auditory evoked response (AER) of the electroencephalogram (EEG) in 40 ASA I and II patients during isoflurane anaesthesia. After induction of anaesthesia, the patient's lungs were ventilated for 20 min with 0.6 MAC end-expiratory isoflurane (0.59 0.77% depending on the age of the patient), and 50% nitrous oxide in oxygen. The patients were then allocated randomly to one of two groups: 21 received suxamethonium 1 mg kg-1, while 19 were given saline. The AER before and after administration of suxamethonium or saline was compared to determine the changes in Pa and Nb amplitudes and latencies. Pa amplitude after suxamethonium increased by 53% (95% confidence interval (CI) 15, 104%) compared with a reduction in Pa amplitude in the saline group of 19% (95% CI, -41, 12%) (P = 0.004) suggesting an arousal effect. Similarly, Nb amplitude increased in the suxamethonium group by 47% (95% CI, 3, 110%) and decreased in the saline group by 11% (95% CI, -33, 19%) (P = 0.03). We conclude that suxamethonium caused arousal according to the AER and postulate that this may have been caused by increased muscle afferent activity after stimulation of muscle spindles, although further studies are required to confirm this. PMID- 8672377 TI - Analgesic effect in humans of subanaesthetic isoflurane concentrations evaluated by evoked potentials. AB - The aim of this study was to see if an analgesic effect of subanaesthetic concentrations of isoflurane could be detected with evoked potentials elicited by nociceptive stimuli. We studied 10 healthy volunteers breathing three steady state subanaesthetic concentrations of isoflurane (0.08, 0.16 and 0.24 vol% end tidal). Reaction time, subjective pain intensities and evoked vertex potentials to laser (LEP) and electrical (SEP) stimuli were recorded and compared with auditory evoked potentials (AEP). Compared with baseline, the subanaesthetic concentrations of isoflurane did not change the latencies of the evoked potentials, but caused a significant reduction in the amplitudes of the LEP and SEP at 0.16 and 0.24 vol% and of the AEP at all three concentrations. There were no changes in perceived pain intensity, and isoflurane produced similar reductions in evoked potentials elicited by both nociceptive and non-nociceptive stimuli. The reaction time was increased significantly at 0.24 vol% isoflurane. The results demonstrated that subanaesthetic isoflurane concentrations caused similar changes in evoked potentials with both painful and non-painful stimuli, with no effect on perceived pain intensity. PMID- 8672378 TI - Use of near infrared spectroscopy to estimate cerebral blood flow in conscious and anaesthetized adult subjects. AB - Near infrared spectroscopy (NIRS) can be used to quantify cerebral haemodynamic states non-invasively and to estimate cerebral blood flow (CBF). In the first part of this study we have compared CBF measurements in conscious and anaesthetized subjects. In the second part we have compared paired measurements made during anaesthesia, first on the scalp and then the dura after craniotomy. Mean CBF was 17 (SD 7) ml 100 g-1 min-1 in the conscious subjects compared with 21 (8) ml 100 g-1 min-1 on the scalp during anaesthesia (P > 0.1). Mean CBF on the dura was 68 (21) ml 100 g-1 min-1 (P < 0.0001). Computer modelling suggests that the difference in magnitude between scalp and dura measurements of CBF is likely to be caused by the optical effect of extracerebral tissue which powerfully scatters light passing through it but does not contribute significantly to the measured CBF because it has only a small blood content itself. The results lend support to this method of estimating CBF although formal validation by comparison with an established technique is needed. PMID- 8672379 TI - Effect of transdermal hyoscine on nausea and vomiting during and after middle ear surgery under local anaesthesia. AB - The efficacy of transdermal hyoscine in the reduction of nausea, retching and vomiting was compared with placebo during and after stapedo- and tympanoplasty under local anaesthesia in a double-blind, prospective and randomized study. In the placebo group (n = 29), 69% of the patients were free from emetic symptoms during and 41% after the operation. The corresponding figures were 93% (P < 0.05) and 74% (P < 0.05) in the hyoscine group (n = 27). The patients in the placebo group needed more droperidol during and after operation (P < 0.05). The frequency of side effects was similar in both groups. In posturography the patients with emetic sequelae in the placebo group had a markedly deteriorated upkeep of posture (P < 0.05) measured as body sway velocities. A strong correlation was found between motion sickness and emetic sequelae after surgery, and patients with a history of motion sickness benefited most from hyoscine. PMID- 8672380 TI - Dobutamine increases oxygen consumption during constant flow cardiopulmonary bypass. AB - We have studied the effects of flow and dobutamine on systemic haemodynamic variables, oxygen delivery (DO2) and oxygen consumption (VO2) in 20 patients during cardiopulmonary bypass (CPB) with mild hypothermia (34 degrees C). In a subgroup of seven patients, we also studied the effects on gastric microcirculatory blood flow (MCF) using laser Doppler flowmetry. During CPB, measurements were made before and after two interventions: the first consisted of increasing flow from 2.4 to 3.0 litre min-1 m-2 for 10 min; the second consisted of an infusion of dobutamine at a rate of 6 micrograms kg-1 min-1 for 10 min during constant flow CPB. There were no significant differences in DO2, VO2 or haemodynamic variables between the two baseline measurements. The increase in flow raised DO2 (27%, P < 0.001), mean arterial pressure (P < 0.01) and MCF (P < 0.01), but failed to increase VO2. In contrast, dobutamine infusion increased VO2 (11%, P < 0.001) during constant flow CPB without significant changes in DO2, systemic haemodynamic variables or MCF. These results indicate that increases in VO2 during dobutamine may be flow-independent. PMID- 8672381 TI - Single dose i.v. tropisetron in the prevention of postoperative nausea and vomiting after gynaecological surgery. AB - In a prospective, randomized, multicentre, double-blind, placebo-controlled study, we have compared the efficacy of a single i.v. dose of tropisetron 0.5 mg, 2 mg and 5 mg in the prevention of postoperative nausea and vomiting (PONV). We studied 385 ASA class I and II female patients undergoing abdominal or vaginal gynaecological surgery, including laparoscopy. Tropisetron or placebo were administered before a standardized general anaesthetic. The frequency of vomiting in the 24-h period after entry into the recovery room was reduced from 44% after placebo to 31%, 26% and 30% after tropisetron 0.5 mg, 2 mg and 5 mg, respectively (P = 0.06, P = 0.009 and P = 0.043; unadjusted). Compared with placebo, nausea was reduced from 55% to 46%, 34% and 46% (P = 0.25, P = 0.003, P = 0.22), and need for rescue treatment from 39% to 29%, 23% and 35% (P = 0.13, P = 0.017 and P = 0.59) for the same groups. Tropisetron 2 mg appeared to be the optimal dose for prophylaxis against PONV with a side-effect profile similar to that of placebo. PMID- 8672382 TI - Randomized trial of bolus phenylephrine or ephedrine for maintenance of arterial pressure during spinal anaesthesia for Caesarean section. AB - Thirty-eight healthy women undergoing elective Caesarean section under spinal anaesthesia at term were allocated randomly to receive boluses of either phenylephrine 100 micrograms or ephedrine 5 mg for maintenance of maternal arterial pressure. The indication for administration of vasopressor was a reduction in systolic pressure to < or = 90% of baseline values. Maternal arterial pressure (BP) and heart rate (HR) were measured every minute by automated oscillometry. Cardiac output (CO) was measured by cross-sectional and Doppler echocardiography before and after preloading with 1500 ml Ringer lactate solution and then every 2 min after administration of bupivacaine. Umbilical artery pulsatility index (PI) was measured using Doppler before and after spinal anaesthesia. The median (range) number of boluses of phenylephrine and ephedrine was similar; 6 (1-10) vs 4 (1-8) respectively. Maternal systolic BP and CO changes were similar in both groups, but the mean [95% CI] maximum percentage change in maternal HR was larger in the phenylephrine group (-28.5 [-24.2, 32.9]%) than in the ephedrine group (-14.4 [-10.6, -18.2]%). As a consequence atropine was required in 11/19 women in the phenylephrine group compared with 2/19 in the ephedrine group (P < 0.01). Mean umbilical artery pH [95% CI] was higher in the phenylephrine group (7.29 [7.28-7.30]) than in the ephedrine group (7.27 [7.25-7.28]). The results of the present study support the use of phenylephrine for maintenance of maternal arterial pressure during spinal anaesthesia for elective Caesarean section. PMID- 8672383 TI - A double-blind comparison of 0.25% ropivacaine and 0.25% bupivacaine for extradural analgesia in labour. AB - Ropivacaine is a new aminoamide local anaesthetic. Compared with bupivacaine, ropivacaine possesses a higher threshold for systemic toxicity and a high selectivity for sensory fibres. We have compared prospectively these two agents in a concentration of 0.25% for extradural analgesia in labour. A total of 104 parturients requesting extradural analgesia were randomized to receive either ropivacaine or bupivacaine. The women in the bupivacaine group required more top up doses to maintain analgesia (median 3.0 vs 2.0) (P < 0.05). The onset of sensory block, quality of analgesia, ultimate level of maximum sensory block and maternal satisfaction were similar in both groups. The incidence, intensity and duration of motor block were slightly but not significantly less in the ropivacaine group. The ropivacaine group had a higher incidence of spontaneous vaginal delivery (70.59% vs 52.00%). There was no significant difference in neonatal outcome as assessed by Apgar scores, umbilical acid-base status and neurological and adaptive capacity score at 2 and 24 h after delivery. We conclude that ropivacaine and bupivacaine in a concentration of 0.25% produced comparable analgesia for pain relief of labour with no detectable adverse effect on the neonate. PMID- 8672384 TI - Absence of an early pre-emptive effect after thoracic extradural bupivacaine in thoracic surgery. AB - We have determined if thoracic extradural block before surgical incision for thoracotomy produces pre-emptive analgesia. Using a double-blind, placebo controlled, crossover design, 45 patients (ASA II-III) undergoing posterolateral thoracotomy for lung resection were randomized to one of three groups: group 1 received 0.5% bupivacaine and adrenaline 1/200,000 (B+E) 8 ml through a thoracic extradural catheter (tip T3-T5) 30 min before skin incision and saline 8 ml 15 min after skin incision; group 2 received saline 8 ml extradurally before incision and B+E 8 ml after incision; group 3 received saline 8 ml extradurally before and after incision. General anaesthesia was induced and maintained with propofol, alfentanil and atracurium. The alfentanil infusion was stopped before chest closure and fentanyl 50 micrograms in saline 10 ml was given extradurally. Patient-controlled extradural analgesia (PCEA) was commenced with 0.125% bupivacaine, adrenaline 1/400,000 and fentanyl 6 micrograms ml-1 (continuous rate of 2 ml h-1 and supplementary doses of 0.5 ml per 6 min). Visual analogue scale (VAS) scores (recorded at rest, on mobilization and after cough), verbal rating scale (VRS) (recorded at rest), number of successful PCEA demands and complications were measured during the first 48 h after operation. There was no significant difference between groups, either in PCEA requirements (P > 0.21) or in VAS scores (either at rest, during mobilization of the ipsilateral arm of surgery or after cough). No significant differences between groups were found in the VRS. Thoracic extradural block with bupivacaine did not produce an early preemptive effect after thoracotomy. PMID- 8672385 TI - Prilocaine 3% is superior to a mixture of bupivacaine and lignocaine for peribulbar anaesthesia. AB - We have compared motor block of the extraocular muscles produced by injections of 3% prilocaine and a mixture of equal parts of 2% lignocaine and 0.75% bupivacaine into the medial compartment of the orbit. A volume of 8 ml was used initially, and a vasoconstrictor and hyaluronidase were added to both solutions. Ninety patients undergoing cataract surgery were allocated randomly to one of two groups in double-blind study. Eight minutes after block insertion, the median ocular movement score in the prilocaine group was 1 and in the lignocaine-bupivacaine group 3. This difference was statistically significant (P = 0.016). Twenty of the patients who received prilocaine and 29 of the patients who received the lignocaine-bupivacaine mixture required an additional inferotemporal injection. This difference was not statistically significant (P = 0.094). PMID- 8672386 TI - Haemodynamic effects of moderate normovolaemic haemodilution in conscious and anaesthetized patients. AB - We have assessed the haemodynamic effects of moderate normovolaemic haemodilution in ASA I patients, either conscious or during enflurane-fentanyl anaesthesia (10 patients in each group). Cardiac index (CI), stroke index (SI) and ejection fraction (EF) were measured by transthoracic electrical bioimpedance and, in the anaesthesia group, arterial and central venous blood samples were obtained to assess oxygen delivery (DO2), oxygen consumption (VO2) and oxygen extraction ratio (O2ER). In conscious patients, heart rate (HR) remained unchanged as SI, EF and CI increased. When haemodilution was performed during anaesthesia, CI remained stable in spite of a slight increase in SI, as HR decreased. This produced a reduction in DO2 which was compensated for by an increase in O2ER, allowing maintenance of VO2 without alteration in blood lactate concentration. PMID- 8672387 TI - Analysis of ethanol in expired air during low-flow isoflurane anaesthesia. AB - Monitoring of ethanol concentration in expired air is a method for assessing fluid absorption during transurethral prostatic surgery and endometrial resection, but the validity of this technique has not been studied in low-flow ventilation systems. For this purpose, we have compared the concentration-time profiles of ethanol in expired gas and in venous blood during an i.v. infusion of 0.4 g kg-1 of ethanol over 30 min in 10 women during isoflurane anaesthesia and in the awake state. Anaesthesia increased the ethanol concentration in expired gas by 13% and in venous blood by 34%. The expired gas-blood difference during infusion was abolished, and the central volume of distribution for ethanol was reduced from 20.9 to 8.6 litre, on average. We conclude that breath sampling during low-flow isoflurane anaesthesia reflects an alcohol load well, but that a change in ethanol disposition makes the values slightly higher than in the awake state. PMID- 8672388 TI - Effects of sevoflurane and isoflurane on systemic vascular resistance: use of cardiopulmonary bypass as a study model. AB - We have examined the dose-related effects of sevoflurane and isoflurane on systemic vascular resistance (SVR) during cardiopulmonary bypass (CPB) in patients undergoing elective coronary artery surgery. Fifty-two patients were allocated randomly to one of six groups to receive 1.0, 2.0 or 3.0 vol% (inspiratory) sevoflurane or 0.6, 1.2 or 1.8 vol% isoflurane, or to a control group. During hypothermic (32-33 degrees C) non-pulsatile CPB, systemic vascular resistance index (SVRI) was recorded before administration of volatile anaesthetics and every 5 min for 20 min. Sevoflurane and isoflurane concentrations were measured next to the gas inlet port and at the gas outlet port of the oxygenator. Wash-in of sevoflurane occurred more rapidly than that of isoflurane, reaching a relatively steady state for both agents from the 10th to the 20th min. There was no significant change in SVRI in patients receiving 1.0 and 2.0 vol% sevoflurane, and 0.6 and 1.2 vol% isoflurane, compared with baseline values. However, 3 vol% sevoflurane decreased SVRI at 10, 15 and 20 min, and 1.8 vol% isoflurane decreased SVRI significantly at 15 and 20 min, whereas SVRI increased at 15 and 20 min in the control group. Thus during CPB, sevoflurane had similar vasodilator effects on SVRI as isoflurane. PMID- 8672389 TI - Perioperative mucosal pH and splanchnic endotoxin concentration in orthotopic liver transplantation. AB - Although impairment of splanchnic perfusion may induce mucosal hypoxia and endotoxaemia during orthotopic liver transplantation (OLT), little is known about the changes in mucosal oxygenation during and after the procedure. To study the effects of liver surgery itself on mucosal pH (pHi) and the response of pHi to acute changes in portal flow, we measured gastric pHi during six liver resections using tonometry: in two patients, after clamping of the hepatoduodenal ligament, pHi decreased within 30 min and recovered promptly after reperfusion. We then investigated gastric and sigmoid pHi (pHig, pHis) during the perioperative phase in 18 OLT. Median pHi values were low before surgery (pHig 7.28 (first/third quartiles 7.22/7.34); pHis 7.27 (7.12/7.36)). Although global oxygen delivery and haemodynamic variables remained constant and veno-venous bypass (VVB) was used to maintain portal flow, pHi declined during the anhepatic phase (pHig 7.19 (7.13/7.23), P < 0.01; pHis 7.13 (7.06/7.24), P < 0.05). After reperfusion of the graft, pHi recovered and did not differ from baseline values by the end of OLT. After operation pHig increased further, reaching the highest values 30 h after ICU admission (7.34 (7.26/7.38)). In the intraoperative period, no significant endotoxaemia was observed either in portal or systemic blood. The maximum reduction in pHi was related neither to the duration of VVB and OLT nor to the number of red cell units transfused. pHi after reperfusion did not correlate with graft viability or dysfunction of the lung or kidney. We conclude that pHi indicates mucosal ischaemia during OLT which is not necessarily associated with endotoxaemia, and intraoperative pHi monitoring does not appear to be a valuable predictor of postoperative graft failure and organ dysfunction. PMID- 8672390 TI - Nitrous oxide or halothane, or both, fail to suppress c-fos expression in rat spinal cord dorsal horn neurones after subcutaneous formalin. AB - In rats injected s.c. with formalin, behavioural correlates of the amount and pattern of Fos-like immunoreactivity (Fos-Ll) (molecular responses to pain) were studied to test if early phase treatment with 75% nitrous oxide or 2% halothane, or both, suppressed subsequent spinal sensitization. Rats were allocated to four treatment groups: (1) 100% oxygen (control, n = 15), (2) 75% nitrous oxide (0.5 MAC, n = 12), (3) 2% halothane (1 MAC, n = 12), and (4) 75% nitrous oxide with 2% halothane (1.5 MAC, n = 18) for 20 min. Each rat then received a s.c. injection of 1% formalin 50 microliters into the left hindpaw and anaesthesia was maintained for another 5 min (early phase). A fifth group of rats receiving fentanyl 100 micrograms kg-1 (n = 12) 10 min before formalin injection were studied simultaneously as a positive control. Rats in all groups were killed 60 min after formalin injection and maximal counts of Fos-Ll labelled neurones in the dorsal horn of the rat spinal cord were compared according to laminar distribution. Formalin-induced behavioural hyperalgesia during the early phase was suppressed completely by fentanyl, 75% nitrous oxide, or 2% halothane, or both. The late phase response was attenuated by all four anaesthetic regimens within 20 min after injection, whereas behavioural scores for the nitrous oxide, halothane, or both, groups were nearly identical to the control 20 min later. Fentanyl suppressed the late phase response until 30 min after formalin injection but failed to reduce it thereafter. The numbers of Fos-Ll labelled neurones for groups given nitrous oxide, or halothane, or both, were identical to the control, whereas numbers for fentanyl were 47.2% less (P < 0.01). The decrease occurred predominantly in the neck of the dorsal horn (44.9% of control, P < 0.01) and also in the nucleus proprius and superficial laminae (54.4% and 56.2% of control, P < 0.05). In summary, we found that nitrous oxide, or halothane, or both, did not suppress subsequent spinal sensitization to noxious stimulation. This result supports the previous hypothesis that inhalation anaesthesia lacks pre-emptive analgesic action. Inhalation anaesthetic agents, unlike fentanyl, suppress the early and late phase response because of anaesthetic but not analgesic effects. Thus, we suggest that measuring the genetic product of c-fos proto-oncogene is a useful adjunct to pharmacological tests whenever behavioural hyperalgesia is questionable or unobtainable. PMID- 8672391 TI - Outcomes of a risk-reduction intervention with high-risk populations: the Harlem AIDS project. AB - Many studies of interventions with high-risk populations have reported reductions in risk behaviors. To assess effectiveness of interventions, data are also needed on the characteristics of subjects lost to follow-up, and on follow-up risk behaviors for subjects who were not participants in the intervention. This paper reports on a study conducted in Harlem, New York, recruiting 1,770 injection drug users (IDUs) and sex partners of IDUs, randomly assigned to two interventions. Repeated-measures analyses for the two intervention groups and those who participated in no intervention indicated that all groups reported significant reductions in risk behaviors, with no group effect. Comparisons of those followed up and not followed-up indicate that those followed-up were less likely to: be homeless, be Latinos, and to use "shooting galleries." The discussion focuses on the need to assess outcomes for all types of participants, and to distinguish the impact of interventions from other explanations for behavior changes. PMID- 8672392 TI - Quasi-experimental evaluation of three AIDS prevention activities for maintaining knowledge, improving attitudes, and changing risk behaviors of high school seniors. AB - Twelfth graders in a small southern city participated in one of three interventions: a question and answer (QA) session, a presentation by a person with AIDS (PWA), or a role-play activity (RP). A pre-intervention questionnaire assessed AIDS-related knowledge and attitudes. Immediate post-intervention questionnaires assessed knowledge and the intervention itself, and, five weeks later, a questionnaire reassessed knowledge and attitudes in addition to changes in risk behaviors. Knowledge gains were similar in the three groups; forgetting was greatest among PWA students. The attitudes of the RP group toward persons with AIDS tended to be the most positive, but differences among the groups were not statistically significant. The pro- portion of RP students (65.9% ) who reported changing their sexual activities after the intervention was significantly greater than that proportion of the other groups. These findings suggest that role-play activities can be more effective in achieving HIV/AIDS related attitudinal and behavioral change than question-and-answer discussions or presentations by PWAs. PMID- 8672393 TI - Condom awareness and use in the Arusha and Kilimanjaro regions, Tanzania: a population-based study. AB - A cross-sectional study of condom awareness, perceived availability, and use was conducted using a questionnaire in the Arusha and Kilimanjaro regions in northern Tanzania. The questionnaire was administered to a random sample (n = 1,081) of males and females (15-54 years of age) from four localities in the Arusha, Babati, Moshi, and Same districts. Of the 1,081 respondents, 69.9% knew what condoms are and, of these, 31.7% reported having ever used a condom, while 20.7% stated that they used condoms regularly. Furthermore, of the 756 respondents who knew what condoms are, 62.2% stated that condoms were available in their localities and, of these, 44.1% reported having used condoms regularly. The results suggested that, while the majority of the respondents knew about condoms and stated that condoms were available in their localities, reported regular condom use was low. Age, gender, marital status, occupation, and place of residence appeared to be significant determinants of condom awareness and use, while educational status was not. Although barmaids and professional drivers have been shown to practice high-risk sexual behavior, reported condom use among them was low. PMID- 8672394 TI - Perception of AIDS risk and high-risk behaviors in African-American methadone dependent women. AB - AIDS poses a particularly serious threat to African-American women who are or have been intravenous drug users. This study evaluated relationships among AIDS knowledge, perceptions of chances of contracting AIDS, and high-risk AIDS behaviors in 102 low-income African-American women from four methadone maintenance clinics in Baltimore, who volunteered to answer questions about AIDS and their sexual and drug-use behaviors. The participants demonstrated a high level of AIDS knowledge, which was significantly correlated with their perception of likelihood of having the AIDS virus (r = .49, p < .05). However, there was little evidence of avoidance of high-risk sexual behaviors. Despite this knowledge, these data indicate that understanding how the virus is transmitted does not assure a change in behavior. The issue is complicated by the question of how knowledge possessed by individuals relates to their sense of powerlessness or empowerment and the risks and benefits associated with using that knowledge. PMID- 8672395 TI - Stress, coping, and attitudes toward HIV treatment in injecting drug users: a qualitative study. AB - An exploratory study was conducted with 27 injecting drug users (IDUs) on psychosocial factors (stress, coping reactions, and attitudes toward HIV illness and treatment) which are relevant to treatment acceptance and adherence. A semi structured interview was used to collect qualitative data in a sample of 13 seropositive and 14 seronegative subjects. The results indicated a range of HIV specific stressors such as social stigma, uncertainty about the future, disclosure of seropositive status, and monitoring of HIV illness. Seeking of social support, relapse to substance abuse, and mental disengagement were the most common coping reactions reported by the sample; there was a lack of behavioral, problem-focused responses. The study also provided descriptive information on attitudes toward HIV treatment, including fatalism, optimism (hope and control), and ambivalence regarding treatment efficacy. Clinical implications and suggestions for future research are discussed. PMID- 8672396 TI - The Nurses' Attitudes About AIDS Scale (NAAS): development and psychometric analysis. AB - This article describes the development and psychometric evaluation of the Nurses' Attitudes About AIDS Scale (NAAS). Based on a review of the literature on attitude theory and measurement and on HIV/AIDS, 273 items were developed for inclusion in the scale. Content validity was established by a panel of ten nurses in current practice, six experts in AIDS education and adult health nursing, and one expert in attitude and scaling theory and measurement. On this basis, 60 items were selected and pilot tested for face validity on 33 practicing nurses. Responses from a purposive sample of 731 working RNs were evaluated. A factor analysis yielded a single homosexuality factor explaining 53% of the variance in the 2 1 -item measure. This subscale was labeled attitudes about people with AIDS. Alpha reliability coefficient was .96. Two subscales were identified in the AIDS dimension: attitudes about nursing care concerns (12 items; alpha = .83) and attitudes about social-professional concerns (8 items; alpha = .72). These subscales explained 38.5% of the variance. Additional evidence of construct validity as well as predictive validity were established. PMID- 8672397 TI - Pharmacists as HIV/AIDS information resources: survey of Alabama pharmacists. AB - Alabama pharmacists were surveyed by researchers from the University of Alabama at Birmingham's School of Public Health in collaboration with investigators at the Schools of Pharmacy at Auburn University and Stamford University as part of a statewide pharmacists' demonstration project to mobilize pharmacists and pharmacy locations as information resources for HIV/AIDS education and prevention. The objectives of the survey were to: (1) establish a baseline of knowledge and attitudes among Alabama pharmacists about HIV/AIDS; (2) to assess Alabama pharmacists' willingness to assume the role of HIV/AIDS information resources in their communities; and (3) to identify perceived barriers to assuming the role of information resources. The results of the survey were used in the development of an educational intervention program and will be used subsequently to assess the impact of the implementation of the Alabama demonstration project. Findings from this project will serve as a basis for development of a nationwide project as part of a collaborative agreement between the Centers for Disease Control and Prevention's National Partnership Program and the Foundation of Pharmacists and Corporate America for AIDS Education. PMID- 8672398 TI - Aldolase C/zebrin II and the regionalization of the cerebellum. AB - The cerebellum is comprised of multiple bands of cells, each with characteristic afferent and efferent projections, and patterns of gene expression. The most studied example of a striped pattern of expression is the antigen recognized by monoclonal antibody antizebrin II. Zebrin II is expressed by subsets of Purkinje cells that form an array of parasagittal bands that extend rostrocaudally throughout the cerebellar cortex, separated by similar bands of Purkinje cells that do not express zebrin II. Recent cloning studies have revealed that the zebrin II antigen is the respiratory isoenzyme aldolase C. This article reviews the cellular and molecular compartmentation of the cerebellum together with the molecular biology of the aldolase C gene, and speculates on possible reasons for a striped pattern of expression. PMID- 8672399 TI - Direct evidence that the POU family transcription factor Oct-2 represses the cellular tyrosine hydroxylase gene in neuronal cells. AB - The POU family transcription factor Oct-2 was originally identified in B lymphocytes but has been shown to be expressed in neuronal cells, although it is absent in most other cell types. Cotransfection of Oct-2 expression vectors into nonneuronal cells with a tyrosine hydroxylase promoter/reporter plasmid suggests that Oct-2 can repress this promoter in this artificial situation. Here we report that reduction of endogenous Oct-2 levels in a neuronal cell line by an antisense approach results in an increase in endogenous tyrosine hydroxylase levels. In contrast, the level of the neuronal marker protein PGP9.5 remains unchanged in the antisense lines whereas that of the neuronal nitric oxide synthase decreases. Hence, the tyrosine hydroxylase gene is a natural target for repression by Oct-2 in neuronal cells. The significance of this effect is discussed in terms of the processes that regulate tyrosine hydroxylase gene expression and the role of Oct 2 in neuronal cells. PMID- 8672400 TI - A transcriptional enhancer of the glutamine synthetase gene that is selective for retinal Muller glial cells. AB - This article demonstrates that the chicken glutamine synthetase (GS) promoter contains cis-acting elements that direct transcription to retinal Muller glial cells. The transient assay system developed to identify these elements involved electroporation of intact retinal tissue with GS-beta-galactosidase fusion genes followed by preparation of primary cultures and histochemical assay of cells expressing beta-galactosidase. Plasmids containing beta-galactosidase under transcriptional control by two different viral promoters are expressed primarily in neuronal cells after transfection of intact embryonic d 12 retina. In sharp contrast, expression is primarily in Muller glia after transfection with a GS beta-galactosidase fusion gene. Although GS is glucocorticoid inducible, steroid hormone is not required to achieve Muller cell-selective expression of the GS beta-galactosidase fusion gene. Deletion studies indicate that multiple cis acting elements located between nucleotides-436 and -61 relative to the GS transcription start site contribute to produce Muller cell selectivity. Moreover, these upstream elements enhance expression of a heterologous promoter in Muller cells not neurons. These results indicate that an enhancer located between 61 and 436 nucleotides upstream of the transcription start site contributes to Muller cell-selective expression of the GS gene in the retina. PMID- 8672401 TI - Expression levels of B-50/GAP-43 in PC12 cells are decisive for the complexity of their neurites and growth cones. AB - To study the role of the protein B-50/GAP-43 in NGF-induced neurite outgrowth, a number of stable PC12 subclones with either very low or considerably enhanced expression levels of the protein were selected. Cell bodies of subclones with suppressed B-50 expression (-B2, -B5, or -B12) possessed a relative small spherical shape and, on NGF-treatment for 7 d, developed processes that were virtually devoid of branches and that mostly bore short or blunt-ended growth cones. Cells of subclones with overexpression of B-50 (+B3, +B4, or +B11), on NGF treatment, acquired a flattened, spiky appearance with highly branched neurites possessing extended and complex growth cones. Confocal microscopy with immunofluorescence for B-50 and F-actin revealed that in neurites and growth cones of the B-50-deficient subclone -B2, no detectable B-50 and reduced amounts of filamentous F-actin were present, whereas in overexpressing +B3 cells, cell membranes, neurites, and complex growth cones were intensively stained for B-50 and exhibited numerous spikes, in which B-50 was strikingly colocalized with F actin. These data suggest that, under normal conditions of neuritogenesis, the expression level of B-50 in PC12 cells is decisive for the complexity of neurites and growth cones. PMID- 8672404 TI - Honey revisited: a reappraisal of honey in pre-industrial diets. AB - In pre-industrial times, honey was the main source of concentrated sweetness in the diets of many peoples. There are no precise figures for per capita consumption during most periods in history because honey was part of either a hunter-gatherer or subsistence economy. Until now, historians and food writers have proposed that it was a scarce commodity available only to a wealthy few. We do know, however, that in a cash economy honey was sold in large units (gallons and even barrels) and it was present in such abundance that mead, made from honey, was a common alcoholic drink. A reappraisal of the evidence from the Stone Age, Antiquity, the Middle Ages and early Modern times suggests that ordinary people ate much larger quantities of honey than has previously been acknowledged. Intakes at various times during history may well have rivalled our current consumption of refined sugar. There are implications therefore for the role of sugar in modern diets. Refined sugar may not have displaced more nutrient-rich items from our present-day diets but only the nutritionally comparable food, honey. PMID- 8672402 TI - Immediate upstream promoter regions required for neurospecific expression of SNAP 25. AB - The promoter structure and regulation of Snap, a gene encoding the presynaptic t SNARE SNAP-25 implicated in synaptic vesicle docking and fusion, was studied. Transcription start-site analysis revealed two major start sites located 42 nucleotides apart. Nucleotide sequence of a promoter region 2073 nucleotides upstream of the first transcription site contains three AP-1, one CRE sequence, and three Sp1-like sites close to the TATA box. Further upstream of these sites two TG repeats were found. The ability of regions within the 5' upstream sequence to promote basal neural-specific expression in tissue culture cells was evaluated using a series of constructs containing both Snap gene start sites with progressively restricted 5' sequence linked to the chloramphenicol acetyl transferase (CAT) reporter gene. CAT expression was maximal in neuron-like undifferentiated ND7 and PC12 cells transfected with constructs containing Snap sequences up to 127 bp from the start site. In contrast, nonneuronal fibroblast cell lines did not express significant amounts of CAT, suggesting that this short 127-bp sequence is sufficient to drive neural specific expression of SNAP-25. Band shift analysis of oligonucleotides spanning from -127 to -41 bp of the Snap promoter revealed three distinct DNA-protein complexes generated by brain nuclear extracts and one by liver nuclear extracts, indicating that transcription factors that bind to this 86-bp sequence located just upstream of the TATA box are involved in regulation of basal neurospecific expression of this gene. PMID- 8672403 TI - The bovine rod outer segment guanylate cyclase, ROS-GC, is present in both outer segment and synaptic layers of the retina. AB - Cyclic-GMP, which plays a pivotal role in visual transduction in the vertebrate retina, is synthesized by guanylate cyclase. The purpose of this study was to localize a rod outer segment-derived particulate guanylate cyclase (ROS-GC) to the retina of several species that have different populations of rods and cones. A rabbit antibody was raised against a synthetic peptide, corresponding to the sequence A107-L125 of bovine ROS-GC. Western blot analysis showed a single immunoreactive band at about 115 kDa with bovine rod outer segments but not with human rod outer segments. Light microscopic immunocytochemistry of tissue sections revealed immunoreactivity in the outer segment layer and in the outer and inner plexiform layers. The rod-rich rat retina showed uniform immunolabeling of outer segments; the cone-containing cat retina showed heavily labeled cone outer segments and lighter labeling of rod outer segments; the cone-rich chicken retina showed a uniformly and intensely labeled outer segment layer. Preincubation of the primary antibody with the peptide completely blocked antibody binding. Electron microscopic immunocytochemistry of the cat retina confirmed the presence of guanylate cyclase in photoreceptor outer segments and demonstrated its association with disk and plasma membranes. These data support a concept in which guanylate cyclase is much more concentrated in the outer segments of cones than rods. The immunolabeling of the plexiform layers suggests that the particulate guanylate cyclase is not unique to the photoreceptor outer segments, and may also play a role in transduction processes of retinal synapses. PMID- 8672405 TI - Ability of mathematical models to predict faecal output with a pulse dose of indigestible marker. AB - The aim of the work was to compare the faecal output and digestibility estimated by two mathematical approaches with the actual amount of faeces excreted or feed digested by Simmental cows. Experimental data (intakes and digestibility measured over 5 d) and faecal Cr concentrations (measured at 0, 4, 8, 12, 16, 24, 32, 48, 56, 72, 96, 120 and 144 h after a pulse dose of Cr-mordanted forage) were collected from published experiments and fitted to a multicompartmental (MC) model and a gamma age-dependent (AD) model. From a statistical point of view, the MC model was very satisfactory while the AD model produced lower r2 and higher SE values and reached satisfactory statistical values only for higher DM intakes (lactating animals). The MC model produced higher correlations with the digestibility values while the AD model generated better correlations with the intake data; DM intake and digestibilities were more highly correlated with the model's parameters than neutral-detergent fibre terms. The regression between the estimated faecal outputs obtained with the two models showed an intercept close to 0 (P > 0.05) and angular coefficients near 1; there was a good correspondence of the estimates especially for the lowest values of output. The r2 values of the regressions were 0.800 and 0.829 for the MC and AD models respectively and their SE were 2.93 and 2.63. The ability of the two models to predict faecal output and digestibility was very similar, independent of the statistical accuracy of fitting the Cr-concentration data. The results indicate that variation of Cr concentration is the result of the entire digestive process, i.e. dilution and passage, which interact in a competitive or associative way. PMID- 8672406 TI - The dietary intake of a group of vegetarian children aged 7-11 years compared with matched omnivores. AB - There is a lack of information concerning the diet of vegetarian children. The present study compared the dietary intake of fifty vegetarian children, aged 7-11 years, with fifty matched omnivores. Three 3 d food records were completed by each child at intervals of 6 months. The day after completing the record each child was interviewed to clarify food items and assess portion sizes. Food records were analysed using Microdiet (University of Salford). Finger-prick cholesterol and haemoglobin measurements were taken from a subsample of the group. Only one child's family was a member of the Vegetarian Society and almost one-third of vegetarian children had omnivorous parents (seventeen of fifty subjects). The energy intake (MJ) of the vegetarians was significantly lower than that of the omnivores, 7.6 (SD 1.05) and 8.0 (SD 1.36) respectively; there were no significant differences in Fe or fat intakes. For the vegetarians polyunsaturated:saturated fat ratio (P:S 0.7 (SD 0.04)) and NSP intake (13.8 (SD 0.7) g/d) were significantly higher than those of the omnivores (P:S 0.5 (SD 0.02), NSP 10.3 (SD 0.4) g/d). There was no significant difference in cholesterol measurements (mmol/l) between the two groups: vegetarian 3.5 (SD 0.12), omnivores 3.7 (SD 0.15). The haemoglobin level (g/l) of the vegetarians (11.8 (SD 0.2)) was significantly below that of the omnivores (12.4 (SD 0.2)); 47.5% of the vegetarian children fell below the third percentile of the Dallman reference curves (Dallman & Siimes, 1979). The intake of the vegetarians more closely resembled current recommendations (Department of Health, 1991), although they need to be as aware as omnivores of the need to reduce fat intake. The haemoglobin levels of vegetarian children suggest that they need dietary advice to ensure optimal absorption of Fe. PMID- 8672407 TI - Fat substitution and food intake: effect of replacing fat with sucrose polyester at lunch or evening meals. AB - The objective of the present study was to determine the effect of replacement of fat by sucrose polyester (SPE) within a lunch or evening meal on subsequent energy intake and appetite control. The 2 x 2 design was intended to examine the effect on appetite of reducing the total energy and fat content of a meal (lunch or dinner) by replacement of natural fat with 55 g SPE. The effects were monitored by measuring motivation to eat or actual food consumption during the remainder of the test day (day 1) and throughout the following day (day 2). The 2 x 2 design yielded four conditions which were a control meal (5192 kJ, 73.2 g fat) and a fat-replaced meal (3305 kJ, 54.6 g SPE, 24 g fat) at midday (lunch) or in the early evening (dinner). No significant differences were seen in ad lib. energy intake after the test meals on day 1 or day 2. Certain differences were detected in fat intake on day 2 but these did not suggest nutrient compensation in response to the fat replacement. Subjective assessment of motivation to eat did not indicate that the fat-reduced meal had a weaker satiating efficiency than the control meal. A reduction in fat content, using fat replacement, did not reduce the satiating efficiency of a test meal given at lunch or dinner. No energy or macronutrient compensation occurred following the reduction in energy or fat intake during the rest of the test day or during the whole of the next day. PMID- 8672408 TI - Comparative effects on blood lipids and faecal steroids of five legume species incorporated into a semi-purified, hypercholesterolaemic rat diet. AB - The cholesterolaemic effects in rats of a diet (VS) containing Bambara groundnuts (Vigna subterranea), a popular legume eaten in Nigeria, were compared with diets PV, PS, LC and PL, containing baked beans (Phaseolus vulgaris), marrowfat peas (Pisum sativum), lentils (Lens culinaris Medik.) and butter beans (Phaseolus lunatus) respectively. Sixty Sprague-Dawley rats were fed on hypercholesterolaemic semi-purified diets supplemented with 10 g cholesterol and 5 g cholic acid/kg and formulated to provide 40% of energy from fat, as in a typical Western-type human diet. Legumes were substituted for 330 g/kg of the semi-purified diet on a dry-matter basis, which was modified to maintain the same contribution of energy sources as the control diet C3. Another ten rats were fed on control diet C2, which was similar to diet C3 but with no added cholesterol. The rats were fed for 8 weeks and plasma cholesterol levels were measured at weeks 4 and 8. The diets incorporating the five different legume species produced very different cholesterolaemic effects. Diets PV and PL were more potent at lowering raised plasma cholesterol levels than diets PS and LC. Inclusion of the Bambara groundnut into the semi-purified diet resulted in an exaggeration of hypercholesterolaemia. Differences in cholesterol-lowering capacity of the various legume diets in this experiment could not be related to concentrations of faecal bile acids or neutral sterols. However, there was evidence that the inclusion of legumes in the diets reduced the faecal excretion of secondary bile acids. PMID- 8672409 TI - Carry-over effects of dietary crude protein and triiodothyronine (T3) in broiler chickens. AB - Indian River male broiler chickens growing from 7 to 30 d of age were fed on diets containing crude protein levels ranging from 120 to 300 g/kg plus 0 or 1 mg triiodothyronine (T3)/kg diet. The purpose of this study was to examine the effects of these treatments on lipogenesis after a common diet was fed (180 g crude protein/kg diet from 30 to 56 d of age). Dietary treatment groups were sampled at 30 and 56 d. In vitro lipogenesis was determined by incubating liver explants for 2 h at 37 degrees in Hanks' salts containing 25 mM-HEPES and 10 mM [2-14C]acetate and then measuring acetate incorporation into total lipid. Growth and feed consumption from 7 to 30 d increased (P < 0.01) as dietary protein increased from 120 to 210 g/kg diet. Both measurements decreased as crude protein increased from 210 to 300 g/kg diet. T3 decreased (P < 0.01) growth and feed intake during this period. Low-protein (< 180 g/kg) diets increased (P < 0.05) and T3 decreased lipogenesis in 30-d-old chickens. Although birds given T3 from 7 to 30 d grew at the greatest rate from 30 to 56 d of age, the final body weight was still less than controls. In vitro lipogenesis at 56 d of age was not affected by either of the two dietary treatments. In contrast, the relative size of the abdominal fat pad (g/kg body weight) at 56 d was decreased by feeding T3 from 7 to 30 d. Any changes in metabolism elicited by either dietary protein levels or hormone treatments may be specific to the particular dosing interval and are not sustained when a common diet is fed during a repletion period. PMID- 8672410 TI - Accumulation of polyunsaturates is decreased by weight-cycling: whole-body analysis in young, growing rats. AB - Whole-body fatty acid analysis in rats has previously shown that 50-70% of dietary linoleate and alpha-linolenate is beta-oxidized to CO2 and that this value increases with refeeding after a single episode of fasting. Our hypothesis was that repeated fasting-refeeding or weight-cycling would increase the beta oxidation of linoleate and alpha-linolenate thereby depleting their whole-body levels. In rats consuming 3% energy as linoleate and 0.15% energy as alpha linolenate during a 16 d balance period, 19% of the linoleate consumed accumulated in weight-cycled rats compared with 34% in the free-fed controls (P < 0.01). Similarly, 11% of the alpha-linolenate consumed accumulated in the weight cycled rats compared with 22% in the controls (P < 0.01). Arachidonate and docosahexaenoate also accumulated to lower extents in the weight-cycled rats than in the controls. In contrast, whole-body accumulation of palmitate, stearate and oleate was not different between the weight-cycled group and the controls when measured as a proportion of intake or relative to weight gain. Thus, whole-body depletion of linoleate and alpha-linolenate did not occur per se but the partitioning of linoleate and alpha-linolenate was significantly altered by weight-cycling resulting in lower whole-body accumulation and higher apparent oxidation of all polyunsaturates especially linoleate and alpha-linolenate. PMID- 8672411 TI - Maternal undernutrition during late pregnancy in sheep. Its relationship to maternal condition, gestation length, hepatic physiology and glucose metabolism. AB - There is a paucity of information on the metabolic effects of undernutrition of the ewe carrying multiple fetuses in late pregnancy. In the present study the effects of induction of ketosis from 132 d gestation in ewes carrying twin fetuses were compared with a control group. The ewes were well fed up to 132 d. Ketotic ewes showed a loss of condition score from 3.7 (SE 0.11) at 130 d gestation to 3.0 (SE 0.15) 10 d later after clinical recovery, compared with control twin-pregnant ewes (P < 0.01). The weight loss during the same time period was from 70.6 (SE 2.7) kg at 130 d to 64.2 (SE 2.7) kg at 140.d gestation. As expected, both groups lost weight and condition score in the first 28 d of lactation. Induction of ketosis caused a significant shortening of the gestation period to 142.8 (SE 0.7) d compared with 150 (SE 0.4) d in normal twin-pregnant ewes (P < 0.001). Ewes with induced ketosis recovered clinically and showed a normal feed intake by 3.4 (SE 0.07) d; three required treatment. Induction of ketosis resulted in reduction of hepatic uptake of bromosulphthalein (P < 0.01) and its biliary excretion (P < 0.05), metabolic clearance rate (P < 0.001), fractional clearance (P < 0.001) and 15 and 30 min retention compared with control twin-pregnant ewes. Most values had returned to normal by the first week of lactation. It is thought that in human pregnancy similar changes in bromosulphthalein clearance may be related to reduced binding sites for bromosulphthalein in the liver caused by increased circulating oestrogens. Induction of ketosis resulted in a significant hypoglycaemic (P < 0.01), ketotic (P < 0.001) state compared with well-fed twin-pregnant ewes. These changes could be correlated with the severity of the clinical signs, together with a significant rise in plasma urea (P < 0.001) and NH3 (P < 0.05) concentrations. Again, the return of most of these values to normal by the first week of lactation lends support to the reversibility of hepatic lesions caused by fatty infiltration of the liver. The severity of this condition in naturally occurring cases suggests that factors other than undernutrition may be contributory, such as the general body condition of the ewe and glucose metabolism by the liver, including the conversion of propionate to glucose. PMID- 8672413 TI - Streptozotocin-induced diabetes in rats is associated with impaired metabolic availability of vitamin A (retinol). AB - Using streptozotocin-induced diabetic Wistar rats, studies were carried out to examine the metabolic availability of vitamin A in the plasma, liver and the retina of the eye. Control and diabetic rats were fed ad lib. on a semi-purified diet either with or without (basal) vitamin A supplementation, or pair-fed on the basal diet for 4 weeks. Despite the fact that diabetic rats consumed 48% more feed, they had lower plasma concentrations of retinol (P < 0.003). The decrease in plasma retinol concentration was a response to diabetes (or diabetes-induced trauma), since neither pair-feeding (P < 0.01) nor vitamin A supplementation altered this effect (P < 0.05). Furthermore, the hepatic concentrations of the vitamin in these animals remained elevated and this increase was greater in the supplemented diabetic group (P < 0.001). Decreases in 11-cis retinal (a component of rhodopsin) concentrations in the retina were also observed in diabetic animals. The increased hepatic and the decreased plasma and retina vitamin A levels suggest a defect in the transport of the vitamin from the liver. PMID- 8672412 TI - Zinc absorption in adult humans: the effect of protein sources added to liquid test meals. AB - The influence of different protein sources on Zn absorption was evaluated in healthy adults by radioisotopic labelling of single meals, followed by whole-body retention measurements 14 d after intake. Semi-synthetic liquid diets were used for the evaluation of different animal-protein sources and dephytinized soyabean protein isolate (< 0.01 g phytic acid/kg). Zn absorption was measured in the same subjects from identical test meals containing no added protein. No statistically significant differences were found in the Zn absorption from test meals containing bovine whey, casein or egg albumen when compared with test meals without added protein. Bovine serum albumin (BSA) and soyabean-protein isolate (< 0.01 g phytic acid/kg) significantly reduced the mean absorption of Zn from 45 49% (no added protein) to 38.0 (SD 10.9) (BSA, P < 0.05) and 33.9 (SD 12.6)% (soyabean-protein isolate < 0.01 g phytic acid/kg, P < 0.01). These results demonstrate that Zn absorption is inhibited by certain protein sources, such as BSA and dephytinized soyabean-protein isolate, while other proteins have little or no effect. PMID- 8672414 TI - Supplemental vitamin A enhances the recovery from iron deficiency in rats with chronic vitamin A deficiency. AB - Studies with anaemic children and pregnant women from areas where vitamin A deficiency is endemic have shown a beneficial effect on Fe status of supplemental vitamin A in addition to Fe supplementation. This suggests a relationship between vitamin A and Fe status, which we attempted to mimic in rats with anaemia and chronic vitamin A deficiency. Male rats were fed on Fe-adequate diets (35 mg Fe/kg) containing different levels of vitamin A (1200, 450, 150, 75 and 0 retinol equivalent (RE)/kg feed) until they were 5 weeks old. These diets were identical to the diets fed to their mothers. Then the young male rats were transferred to diets containing the same levels of vitamin A but no added Fe. After another 2 weeks the rats were repleted with Fe (35 mg/kg feed) without or with vitamin A to a level of 1200 RE/kg feed. Increased vitamin A intake by the groups previously fed on diets with either 0 or 75 RE/kg produced a reduction in blood haemoglobin concentration, packed cell volume and erythrocyte count. In the group which had been fed on the diet without vitamin A, supplemental vitamin A raised mean cell volume, plasma Fe concentration and total Fe-binding capacity. Vitamin A supplementation during the period of Fe repletion produced a decrease in splenic and tibia Fe concentration, the effect being greater with increasing severity of previous vitamin A deficiency. The paradoxical effect of supplemental vitamin A on haemoglobin, packed cell volume and erythrocyte count can be explained by a decrease in the degree of haemoconcentration. Thus, the positive effect of supplemental vitamin A seen in humans is also observed with rats under controlled experimental conditions. We speculate that supplemental vitamin A during Fe repletion contributes to optimum erythropoiesis and Fe mobilization when baseline vitamin A status is impaired. PMID- 8672415 TI - Changes in vitamin-D metabolites and parathyroid hormone in plasma following cholecalciferol administration to pre- and postmenopausal women in the Netherlands in early spring and to postmenopausal women in Curacao. AB - To study the effect on plasma 25-hydroxycholecalciferol (25(OH)D), 1,25 dihydroxycholecalciferol (1,25(OH)2D) and parathyroid hormone (PTH) we supplemented premenopausal (aged 30 (SD 7) years) and postmenopausal (aged 61 (SD 2) years) white women living in The Netherlands in late winter/early spring, and elderly black and white women (aged 75 (SD 6) years) living in Curacao (Dutch Antilles) with either 10 or 20 micrograms cholecalciferol/d for 4, 5 and 9 weeks respectively. Baseline plasma 25(OH)D concentration of Dutch women was lower than that of Curacao women. Postmenopausal Dutch women had a higher PTH concentration in plasma than premenopausal Dutch and postmenopausal Curacao women. There were no differences in plasma 1,25(OH)2D. Cholecalciferol administration increased 25(OH)D in all groups, 1,25(OH)2D in postmenopausal Curacao women and PTH in postmenopausal Curacao women and premenopausal Dutch women. Serum and urinary Ca and phosphate concentrations did not change. There were no response differences between 10 and 20 microgram doses. Oral cholecalciferol administration (either 10 or 20 micrograms/d) to women living at northern latitudes in late winter/early spring increased 25(OH)D levels to the baseline levels of elderly people living in the tropics. PMID- 8672416 TI - Differentiation of catalytic sites on Escherichia coli F1ATPase by laser photoactivated labeling with [3H]-2-Azido-ATP using the mutant beta Glu381Cys:epsilonSer108Cys to identify different beta subunits by their interactions with gamma and epsilon subunits. AB - The ATP binding affinities of the catalytic sites in the three beta subunits of the Escherichia coli F1 ATPase (ECF1) have been explored in relation to the interaction of these subunits with the small subunits gamma and epsilon. ECF1 from the mutant beta E381C:epsilonS108C was reacted with different concentrations of [3H]-2-azido-ATP and covalent insertion of the nucleotide analogue induced by photoactivation of the azide group to a nitrene with single-pulse UV laser excitation. The enzyme showed cooperative binding of [3H]-2-azido-ATP in the presence of Mg2+. The highest affinity site was located at betafree, the one of the three beta subunits in the mutant that does not form disulfide bonds with either the gamma or the epsilon subunit. This beta subunit is, therefore, the site of unisite catalysis in the enzyme. The second mole of [3H]-2-azido-ATP to bind was located in the beta subunit that links to epsilon (betaepsilon), while the lowest affinity binding of the substrate analogue was with the beta subunit that links to gamma (betagamma). In the absence of Mg2+, all three beta subunits bound [3H]-2-azido-ATP with a similar, low affinity. The results show that binding of MgATP is determined by, and/or must determine, the interactions of the different alpha-beta subunit pairs with the single-copy subunits gamma, delta, and epsilon of the enzyme. PMID- 8672417 TI - Effects of protein RNase inhibitor and substrate on the quaternary structures of bovine seminal RNase. AB - The effect of the protein RNase inhibitor (PRI) on the activity of bovine seminal RNase (BS-RNase) was investigated using the isolated quaternary forms, MxM and M=M, of the enzyme reported earlier [Piccoli, R., et al., (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1870-1874]. We found that the inhibitor does not interact with the intact isolated forms but has dramatic, differential effects on the two forms when the assays are performed under reducing conditions. These conditions, which are essential for full activity of the inhibitor, and are typical of its cytosolic localization, also promote monomerization of the M=M form, while under identical conditions the MxM form becomes a noncovalent dimer (NCD). The sensitivity of BS-RNase or that of the isolated quaternary forms under reducing conditions thus appears to be related to differential monomerization of the two forms of the enzyme; monomer being sensitive to PRI. The present study also shows that the interconversion between the two forms in equilibrium occurs at much higher rates in a reducing environment and that PRI further affects the interconversion and alters the equilibrium favoring monomerization of the protein. An opposite effect on the equilibrium between the forms is played by the substrate, which is found to stabilize the NCD form of the protein with a shift in the equilibrium between the two forms towards the dimer. These results are analyzed in the light of the antitumor action of the enzyme which is exerted in the cytosol, i.e., in the compartment housing the PRI and the ribosomal RNA, the molecular target of the enzyme. PMID- 8672418 TI - Two simultaneous binding sites for nucleotide analogs are kinetically distinguishable on the sarcoplasmic reticulum Ca(2+)-ATPase. AB - Erythrosin B and eosin Y stimulate p-nitrophenyl phosphate hydrolysis by purified sarcoplasmic reticulum Ca(2+)-ATPase by nearly 2-3 fold in the presence of Ca(2+). This stimulation is not due to the change on the apparent affinity for substrate but is indeed due to acceleration of the turnover rate of the enzyme. Stimulation reaches a maximum at approximately 5 microM erythrosin or 20 microM eosin and is strictly dependent on the presence of Ca(2+) in reaction media, while higher concentrations of dye progressively inhibit phosphatase activity. Labeling with fluorescein isothiocyanate (FITC) largely shifts the Km for p nitrophenyl phosphate (pNPP) and completely abolishes the stimulation of phosphatase activity induced by erythrosin in the presence of Ca(2+), apparently by FITC impairing dye binding to an activator site and allowing only manifestation of an inhibitory binding site. In the absence of Ca(2+), both erythrosin and eosin inhibit pNPP hyrolysis with Ic50 values 3-4 fold higher than the maximally stimulatory enzyme with FITC, which by its turn does not affect pNPPase activity in absence of Ca(2+). It is suggested that stimulation and inhibition of phosphatase activity are related to two simultaneous and physically different nucleotide analog binding sites. PMID- 8672419 TI - Structural requirements for the association of native and partially folded conformations of alpha-lactalbumin with model membranes. AB - The effect of the structure and stability of several conformers of alpha lactalbumin in aqueous solution on their association to negatively charged large unilamellar vesicles has been studied by circular dichroism, infrared spectroscopy, differential scanning calorimetry, and by content leakage experiments. Our results indicate that the affinity of alphaLA for negatively charged vesicles strongly depends on its conformational properties in solution. Analysis of the pH dependence of the interaction for the different conformers reveals that native-like, calcium-bound, ordered conformations become bilayer associated through electrostatic forces. However, partially folded conformers are able to interact with negatively charged membranes at pHs higher than the protein isoelectric point, suggesting that hydrophobic interactions brought about by the exposure of hydorphobic residues at the protein surface are able to overcome the unfavorable electrostatic repulsion. Calorimetric and spectroscopic data in solution also indicate that substantial protein destabilization facilitates its subsequent membrane binding, and that the association process is favored for a set of conformers having significant secondary structure, but lacking native like, stable tertiary structure. Aggregation of the unfolded alpha-lactalbumin molecules and burial of hydrophobic surfaces upon formation of ordered tertiary structure significantly reduce their membrane perturbing activity. These observations suggest that formation of a flexible strucutral intermediate of alpha-lactalbumin in solution is a prerequisite for its association with membranes. PMID- 8672420 TI - Kinetic characterization of the chymotryptic activity of the 20S proteasome. AB - In this paper, we report kinetic studies for the chymotryptic activity of the 20S proteasome. Major observations include the following: (1) Reaction progress curves that are recorded at concentrations of Suc-Leu-Leu-Val-Tyr-AMC greater than about 40 microM are biphasic and characterized by initial velocities that decay by a first-order process to final, steady-state velocities. (2) Also at [Suc-Leu-Leu-Val-Tyr-AMC] > 40 microM, initial and steady-state velocities are smaller than predicted from simple, Michaelis-Menten kinetics. (3) The first order rate constant for the approach to steady-state has a complex dependence on substrate concentration and decreases sigmoidally as substrate concentration increases. These results indicate that the 20S proteasome is a hysteretic enzyme and is subject to substrate inhibition. To explain these observations we propose a minimal kinetic model with two critical mechanistic features: (1) the 20S proteasome has two cooperative active sites for Suc-Leu-Leu-Val-Tyr-AMC and (2) there are two interconvertible conformers of active 20S proteasome. To probe this mechanism in greater detail, we explored the kinetic mechanism of inhibition of the 20S proteasome-catalyzed hydrolysis of Suc-Leu-Leu-Val-Tyr-AMC by the peptide aldehyde, Ac-Leu-Leu-Nle-H. Our studies reveal a nonlinear dependence of reciprocal steady-state velocity on inhibitor concentration (i.e., parabolic inhibition) as well as a nonlinear dependence of the apparent inhibitor dissociation constant on substrate concentration. Both of these observations are explained by binding of inhibitor at multiple sites on the enzyme. Taken together, the results of this study indicate that the 20S proteasome is a conformationally flexible protein that can adjust to the binding of ligands and that has multiple and cooperative active sites. These results support a view of the proteasome's substrate specificity in which (1) substrates are recognized and hydrolyzed by more than one active site; (2) each active site can bind substrates that possess a variety of P1 residues; and (3) the P1 residue plays a relatively minor role as a specificity determinant. Finally, we interpret the results of this study to suggest that, in vivo, the 20S proteasome requires conformational plasticity for its interactions with regulatory complexes and, after it has combined with appropriate regulatory complexes, to catalyze hydrolysis of proteins. PMID- 8672421 TI - Limited proteolysis of Salmonella typhimurium nicotinic acid phosphoribosyltransferase reveals ATP-linked conformational change. AB - Nicotinic acid phosphoribosyltransferase (NAPRTase;EC 2.4.2.11) couples stoichiometric ATP hydrolysis with formation of nicotinate mononucleotide (NAMN) from nicotinic acid and alpha-D-5-phosphoribosyl 1-pyrophosphate (PRPP). Trypsin rapidly inactivated the ATPase and NAMN synthesis activities of NAPRTase in parallel, with cleavages at Arg-384 and Lys-374 of the 399-residue protein. ATP and PRPP each provided protection against tryptic cleavage. Limited chymotryptic proteolysis of NAPRTase exhibited very similar behavior, with specific cleavage at Phe-382 and protection by substrates. Results suggest that a solvent-exposed loop encompassing Lys-374, Phe-382, and Arg-384 is protected by ATP- or PRPP induced conformational changes. The ability of ATP to protect even under conditions in which enzyme phosphorylation was prevented by EDTA provides evidence for a distinct ATP-induced protein conformation that acts as an intermediate in energy coupling. PMID- 8672422 TI - Energy coupling in Salmonella typhimurium nicotinic acid phosphoribosyltransferase: identification of His-219 as site of phosphorylation. AB - Energy coupling between ATP hydrolysis and other enzyme reactions requires the phosphorylation of substrate-derived intermediates, or the existence of enzyme derived intermediates capable of storage and transfer of energy. Salmonella typhimurium nicotinic acid phosphoribosyltransferase (NAPRTase, EC 2.4.2.11) couples net ATP hydrolysis to formation of NAMN and PPi from alpha-PRPP and nicotinic acid [Vinitsky, A., & Grubmeyer, C (1993) J. Biol. Chem. 268, 26004 26010]. In the current work, we have determined that the enzyme reacts with ATP to produce a covalently phosphorylated form of the enzyme (E-P), which is common to both the ATPase and NAMN synthesis functions of NAPRTase. We have isolated E-P and verified its catalytic competence. E-P showed acid lability and base stability, diagnostic of a phosphoramidate linkage. Pyridine and hydroxylamine catalyzed hydrolysis of E-P gave second-order rate constants consistent with published values for phosphohistidine. Two-dimensional thin-layer chromatography of alkaline-hydrolyzed E-32P showed that the phosphorylated residue co-migrated with authentic 1-phosphohistidine. Chymotrypsin and trypsin proteolysis followed by HPLC and peptide sequencing localized the phosphopeptide to Ala-210 to Phe-222 of the 399-residue protein. This peptide contains a single histidine residue, His 219. NAPRTase phosphorylated at His-219 is an intermediate in the energy transduction mechanism of NAPRTase. PMID- 8672423 TI - Modulation of protein function by exogenous ligands in protein cavities: CO binding to a myoglobin cavity mutant containing unnatural proximal ligands. AB - A variety of heterocyclic ligands can be exchanged into the proximal cavity of sperm whale myoglobin mutant H93G, providing a simple method for introduction of the equivalent of unnatural amino acid side chains into a functionally critical location in this protein. These modified proteins bind CO on the distal side. 1H NMR data on H93G(Im)CO, where Im is imidazole, demonstrate that the structure of the distal heme pocket in H93G(Im)CO is very similar to that of wild type; thus, the effects of the proximal ligand's properties on CO binding can be studied with minimal perturbation of distal pocket structure. The exogenous proximal ligands used in this study include imidazole (Im), 4-methylimidazole (4-MeIm), 4 bromoimidazole (4-BrIm), N-methylimidazole (N-MeIm), pyridine (Pyr), and 3 fluoropyridine (3-FPyr). Substitution of the proximal ligand is found to produce substantial changes in the CO on and off rates, the equilibrium binding constant, and the vibrational stretch frequency of CO. Many of the changes are as large as those reported for distal pocket mutants prepared by site-directed mutagenesis. The ability to systematically vary the nature of the proximal ligand is exploited to test the effects of particular properties of the proximal ligand on CO binding. For example, 4-MeIm and 4-BrIm are similar in size and shape but differ significantly in pKa. The same relationship is true for Pyr and 3-FPyr. By comparison of the IR spectra and CO recombination kinetics of these complexes, the effects of proximal ligand pKa on the CO binding are assessed. Likewise, N MeIm and 4-MeIm are similar in size and pKa but differ in their ability to hydrogen bond to amino acid residues in the proximal cavity. Comparisons of IR spectra and CO binding kinetics in these complexes reveal that proximal ligand conformation and hydrogen bonding affect the kinetics of CO binding. The mechanism of proximal ligand exchange between solution and the proximal cavity in CO complexes was investigated by obtaining the 19F NMR spectrum of H93G(3 FPyr)CO, whose 19F signal can be observed without interference from resonances of the protein. The proximal ligand is found to exchange within a few seconds by saturation transfer. This exchange rate is about 2 orders of magniture faster than what is observed for the isoelectronic metcyano complex [Decatur, S. M., & Boxer, S. G. (1995) Biochemistry 34, 2122-2129]; in both the ferrous CO and ferric cyano complexes, the proximal ligand exchange rate is independent of ligand concentration. These results suggest that the rate-limiting step in proximal ligand exchange is breakage of the iron-ligand bond, followed by rapid diffusion of the ligand through the protein to bulk solution. PMID- 8672424 TI - Partitioning of HIV-1 Gag and Gag-related proteins to membranes. AB - The binding of HIV-1 Gag and Gag-related proteins to model membranes was examined using three experimental systems: (i) large unilamellar phospholipid vesicles (LUVs) and recombinant Gag purified from Escherichia coli; (ii) LUVs added to a mammalian cell extract in which Gag proteins were expressed by a coupled transcription/translation system; and (iii) inside-out plasma membrane vesicles purified from human red blood cells (RBC) and recombinant, purified Gag from E. coli. Several novel aspects of HIV-1 Gag membrane interactions were observed: (i) Gag proteins bound with high affinity to both model membranes with a negatively charged surface and to RBC membranes. (ii) Binding of the Gag precursor and mature Gag proteins exhibited different sensitivities to ionic strength indicating that the precursor directed membrane binding through interactions that were qualitatively and quantitatively distinct from those of any of its individual domains. Studies using energy transfer between tryptophan residues in the proteins and anthroyloxy-containing probes inserted in the LUVs indicated that the orientation of the precursor and of the mature proteins on the membrane surface were distinct; (iii) Gag oligomers appear to have facilitated high affinity binding under high salt conditions, suggesting that protein-protein interactions led to formation of stronger electrostatic or new hydrophobic membrane binding determinants. Since binding studies with model membranes permit quantitative analysis, these experimental approaches may permit identification of interactions that drive Gag assembly on the membrane. PMID- 8672425 TI - Asparagine 229 mutants of thymidylate synthase catalyze the methylation of 3 methyl-2'-deoxyuridine 5'-monophosphate. AB - The conserved Asn 229 of thymidylate synthase (TS) forms a cyclic hydrogen bond network with the 3-NH and 4-O of the nucleotide substrate 2'-deoxyuridine 5' monophosphate (dUMP). Asn 229 is not essential for substrate binding or catalysis [Liu, l., & Santi, D. B. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 8604-8608] but is a major determinant in substrate specificity [Liu, l., & Santi, D. V. (1993) Biochemistry 32, 9263-9267]. 3-Methyl-dUMP (3-MedUMP) is neither a substrate nor an inhibitor of wild type TS but is converted to 3-methyl 2'-deoxythymidine 5' monophosphate by many TS Asn 229 mutants. Some of the Asn 229 mutants (N229C, -I, -M, -A, and -V) have kcat values for 3-MedUMP methylation which are up to about 20% of that for wild type TS-catalyzed methylation of dUMP, and some mutants (N229C and -A) catalyze methylation of 3-MedUMP more efficiently than that of dUMP. Mutants with hydrophobic side chains tended to be more active in catalysis of methylation of 3-MedUMP than those with hydrophilic side chains. The ability of 3-MedUMP to serve as a substrate for Asn 229 mutants shows that the active form of dUMP involves the neutral pyrimidine base and that ionization of the 3-NH group does not occur in the course of catalysis. In contrast to the negligible binding of 3-MedUMP to wild type TS, both 3-MedUMP and dUMP showed similar Km values with the Asn 229 mutants, suggesting similar binding affinities to the mutants. The X-ray crystal structure of the TS N229C--3-MedUMP complex showed that the side chain of Cys 229 was rotated away from the pyrimidine ring to allow placement of a water molecule and the 3-methyl group of 3-MedUMP in the active site. Our results suggest that the inability of 3-MedUMP to undergo methylation by wild type TS is due to its inability to bind to the enzyme, which in turn is simply a result of steric interference of the 3-methyl group with the side chain of Asn 229. PMID- 8672426 TI - Probing the conformation of the lactose permease of Escherichia coli by in situ site-directed sulfhydryl modification. AB - By using site-directed chemical labeling of lactose permease, conformational changes induced by ligand binding are observed in the native membrane of Escherichia coli. Membranes containing permease mutants with a single-Cys residue and a biotin-acceptor domain were labeled with radioactive N-ethylmaleimide (NEM) in the presence or absence of beta-D-galactopyranosyl 1-thio-beta-D galactopyranoside (TDG) or a proton electrochemical gradient, followed by solubilization in n-dodecyl beta-D-maltopyranoside and adsorption to avidin. TDG induced enhancement of the reactivity of membrane-embedded Val315-->Cys (helix X) permease is observed, while the reactivity of Val331-->Cys (helix X) permease is inhibited by ligand binding or imposition of a proton electrochemical gradient. In contrast, the reactivity of permease with a single native Cys residue at position 148 (helix V) is blocked by TDG, but unaffected by the proton electrochemical gradient. Furthermore, as shown with right-side-out and inside out membrane vesicles, the accessibility of Cys148 to either NEM or impermeant methanethiosulfonate derivatives is comparable from both sides of the membrane. On the other hand, TDG protects Cys148 from alkylation more effectively in right side-out vesicles (apparent KD = 20-50 microM) than inside-out vesicles (apparent KD ca. 1.0 microM). The findings provide strong support for the conclusion that the permease retains close to native conformation in n-dodecyl-beta-D maltopyranoside. In addition, the results are consistent with the idea that lactose permease has two binding sites: one with higher affinity on the periplasmic surface of the membrane and another with lower affinity on the cytoplasmic surface. PMID- 8672427 TI - Site-directed mutagenesis of residues in a conserved region of bovine aspartyl (asparaginyl) beta-hydroxylase: evidence that histidine 675 has a role in binding Fe2+. AB - The roles in catalysis of several residues in bovine aspartyl (asparaginyl) beta hydroxylase that are located in a region of homology among alpha-ketoglutarate dependent dioxygenases were investigated using site-directed mutagenesis. Previous studies have shown that when histidine 675, an invariant residue located in this highly conserved region, was mutated to an alanine residue, no enzymatic activity was detected. A more extensive site-directed mutagenesis study at position 675 has been undertaken to define the catalytic role of this essential residue. The partial hydroxylase activity observed with some amino acid replacements for histidine 675 correlates with the potential to coordinate metals and not with size, charge, or hydrophobic character. Furthermore, the increase in Km for Fe2+ observed with the H675D and H675E mutant enzymes can account for their partial activities relative to wild type. No significant changes in the Km for alpha-ketoglutarate (at saturating Fe2+) or Vmax were observed for these mutants. These results support the conclusion that histidine 675 is specifically involved in Fe2+ coordination. Further site-directed mutagenesis of other highly conserved residues in the vicinity of position 675 demonstrates the importance of this region of homology in catalysis for Asp (Asn) beta-hydroxylase and, by analogy, other alpha-ketoglutarate-dependent dioxygenases. PMID- 8672428 TI - Direct determination of the substrate specificity of the alpha-active site in heterodimeric beta-hexosaminidase A. AB - The beta-hexosaminidase isozymes are produced through the combination of alpha and beta subunits to form any one of three active dimers (monomeric subunits are not functional). Heterodimeric hexosaminidase A (alpha beta) is the only isozyme that can hydrolyze GM2 ganglioside in vivo, requiring the presence of the GM2 activator protein. Hexosaminidase S (alpha alpha) exists but is not considered a physiological isozyme. Although hexosaminidase B (beta beta) is present in normal human tissues, it has no known unique function in vivo. However, a unique function for the beta-active site present in both hexosaminidase A and B has been indicated in a previous study of the various substrate specificities of the homodimeric forms of hexosaminidase (S and B). It was concluded that the alpha active site is only able to efficiently hydrolyze negatively charged substrates, and the beta-active site is only able to hydrolyze neutral substrates. When this model of nonoverlapping alpha- and beta-substrates is extrapolated to heterodimeric hexosaminidase A, it has a major effect on the interpretation of recent results relating to the mode of action of the GM2 activator protein. In this report, we directly examine these substrate specificities using a novel form of hexosaminidase A containing an inactive beta subunit, produced in permanently transfected CHO cells. We demonstrate that, whereas the beta-active site has the same substrate specificities in either its A-heterodimeric or B-homodimeric forms, the alpha-active site in the A-heterodimer has different kinetic parameters than the alpha-active site in the S-homodimer. We conclude that the alpha and beta subunits in hexosaminidase A participate equally in the hydrolysis of neutral substrates. PMID- 8672429 TI - Contribution to activity of histidine-aromatic, amide-aromatic, and aromatic aromatic interactions in the extended catalytic site of cysteine proteinases. AB - Within the papain family of cysteine proteinases few other residues in addition to the catalytic triad, Cys25-His159-Asn175 (papain numbering) are completely conserved [Berti & Storer (1995) J. Mol. Biol. 246, 273-283]. One such residue is tryptophan 177 which participates in a Trp-His-type interaction with the catalytic His159. In all enzymes of this class for which a three-dimensional structure has been reported, an additional highly conserved tryptophan, Trp181, also interacts with Trp177 via an aromatic-aromatic interaction in which the planes of the indole rings are essentially perpendicular. Also, both indole rings participate as pseudo-hydrogen bond acceptors in interactions with the two side chain amide protons of Asn175. Clearly, the proximity of Trp177 and Trp181 to the catalytic triad residues His159 and Asn175 and their network of interactions points to potential contributions of these aromatic residues to catalysis. In this paper, using cathepsin S, a naturally occurring variant that has a phenylalanine residue at position 181, we report the kinetic characterization of mutants of residues 175, 177, and 181. The results are interpreted in terms of the side chain contributions to catalytic activity and thiolate-imidazolium ion pair stability. For example, the side chain of Asn175 has a major influence on the ion-pair stability presumably through its hydrogen bond to His159. The magnitude of this effect is modulated by Trp177, which shields the His159-Asn175 hydrogen bond from solvent. The His159-Trp177 interaction also contributes significantly to ion-pair stability; however, Trp181 and its interactions with Asn175 and Trp177 do not influence ion-pair stability to a significant degree. The observation that certain mutations at positions 177 and 181 result in a reduction of kcat/Km but do not appear to influence ion-pair stability probably reflects the contributions of these residues to substrate binding. PMID- 8672430 TI - Characterization of mouse ZP3-derived glycopeptide, gp55, that exhibits sperm receptor and acrosome reaction-inducing activity in vitro. AB - During fertilization, free-swimming mouse sperm bind to mZP3 (approximately 83 000 Mr), one of three zona pellucida glycoproteins, and once bound undergo the acrosome reaction, a type of cellular exocytosis [Wassarman, P. M., & Litscher, E. S. (1995) Curr. Top. Dev. Biol. 30, 1-19]. Sperm recognize and bind to specific serine/threonine-linked oligosaccharides located at the mZP3 combining site for sperm. Here, we examined certain characteristics of gp55, a approximately 55 000 Mr glycopeptide derived from the carboxy-terminal half of mZP3 polypeptide to which sperm bind [Rosiere, T. K., & Wassarman, P. M. (1992) Dev. Biol. 154, 309-317]. gp55 is heterogeneous with respect to Mr (approximately 47 000-62 000 Mr) and has a relatively low pI (approximately 4.3-4.5) compared to the polypeptide portion of the glycopeptide (pI approximately 6.5). gp55 inhibits binding of sperm to eggs (i.e., exhibits sperm receptor activity) and induces sperm to undergo the acrosome reaction in vitro at about the same concentrations required for intact mZP3 (approximately 50-200 nM). Each of three different size fractions of gp55, separated by SDS-PAGE, also exhibits bioactivity in vitro. Removal of asparagine-linked (N-linked) oligosaccharides from gp55, by extensive digestion with N-glycanase, reduces its Mr to approximately 21 000 and increases it pI to approximately 5.3, but does not significantly affect its ability to inhibit binding of sperm to eggs or to induce sperm to undergo the acrosome reaction. Similarly, digestion of gp55 with either endo-beta-galactosidase or neuraminidase alters its Mr and/or pI, but does not significantly affect either of its bioactivities. These observations are consistent with the proposal that neither N-linked oligosaccharides nor sialic acid is an essential element of the mZP3 combining site for sperm. They also indicate that a relatively small mZP3 glycopeptide is able to induce sperm to undergo the acrosome reaction (i.e., cellular exocytosis) in vitro. PMID- 8672431 TI - Identification of amino acid residues in transmembrane helices VI and VII of the lutropin/choriogonadotropin receptor involved in signaling. AB - The lutropin/chroriogonadotropin receptor (LH/CG-R) is a member of the G protein coupled receptor superfamily containing a relatively large extracellular domain responsible for high affinity ligand binding. There is a paucity of information on the mechanism of ligand-mediated transmembrane signaling via the seven transmembrane helices (TMH) of these receptors. In the present study we have used site-directed mutagenesis to replace each of nine conserved amino acid residues in the TMHs of rat LH/CG-R. COS-7 cells were transiently transfected with the eukaryotic expression vector pSVL-LH/CG-R, wild-type and mutants, followed by measurements of human CG binding and human CG-mediated cAMP production. Three point mutants of LH/CG-R were prepared that diminished signaling but not binding: Pro-562-Leu (TMH VI), Pro-591-Leu(TMH VII), and Tyr-601-Ala (TMH VII). Two point mutants of LH/CG-R, Pro-479-Leu(TMH IV) and Pro-598-Leu(TMH VII), resulted in impaired localization, and four receptor mutants, Thr-424-Ala (TMH III), Ser-562 Ala (TMH VI), Met-560-Leu (TMH VI), and Tyr-590-Ala (TMH VII), were similar to wild-type LH/CG-R. In summary, these findings indicate a critical role of Tyr-601 in transmembrane signaling of LH/CG-R since an Ala replacement results in almost total abolition of cAMP production in response to human CG; prolines 562 and 591 also appear to be important for full signaling. PMID- 8672432 TI - Altered ligand specificity by protonation in the ligand binding domain of cyclic nucleotide-gated channels. AB - Cyclic nucleotide-gated (CNG) ion channels are the critical mediators between the second messengers of sensory transduction and the cell's membrane potential. The photoreceptor CNG channels are activated by the direct binding of cGMP but can also be activated to a much lesser extent by cAMP. In rod CNG channels expressed in Xenopus oocytes, we demonstrate two types of potentiation by protons. One type potentiated cGMP-bound and cAMP-bound channels to the same extent, while another potentiated only cAMP-bound channels. Both types of potentiation could be described by a mechanism in which protons bound primarily to the channel open configuration. The potentiation specific to cAMP-bound channels could be accounted for by protonation of aspartic acid 604 (D604). It is the unfavorable electrostatic interaction between the carboxylate of D604 and the purine ring of cAMP that accounts for the normally poor activation of the channels by cAMP. Protonation at this site removed the unfavorable interaction and allowed cAMP to act as nearly a full agonist. Protonation of a second amino acid, H468, contributed to the nucleotide-nonspecific potentiation and is likely to be an element of the channel gating assembly. Protons potentiate native rod channels less than channels formed from subunit 1. In heteromultimeric channels formed by coexpressing subunit 1 with subunit 2, we found a similar attenuation of potentiation. The absence of protonatable amino acids in subunit 2 at positions corresponding to H468 and D604 can explain the reduced effects of pH on native channels. PMID- 8672433 TI - Physical determinants of intermembrane protein transfer. AB - Intermembrane protein transfer between erythrocytes and phospholipid vesicles was examined under a variety of conditions to investigate physical factors governing this process. Human erythrocytes were incubated with sonicated dimyristoylphosphatidylcholine vesicles containing trace [14C]dipalmitoylphosphatidylcholine. Protein-vesicle complexes were separated from cells and from membrane fragments by density gradient centrifugation. The yield of isolated protein vesicles was determined from the 14C-vesicle marker; protein compositions were analyzed by SDS-polyacrylamide gel electrophoresis. Enzymatic removal of portions of the cytoplasmic or exoplasmic domains of cell membrane proteins had little effect on the extent of protein transfer. Membrane additives such as cholate produced a 2-fold increase in protein-vesicle yield. The selectivity of protein transfer from erythrocytes was influenced by the lipid composition of recipient vesicles: inclusion of cholesterol increased band 3 content while the presence of anionic phospholipids reduced transfer. Proteins transferred from 32P-labeled cells differed in specific radioactivity from bulk cell proteins: glycophorin, highly phosphorylated in the cell membrane, showed no detectable labeling in the corresponding protein-vesicle band. These observations suggest that cell-to-vesicle protein transfer is insensitive to bulk steric and electrostatic properties of cell membranes, but enhanced by membrane defects. Recipient membrane composition influences the selectivity of transferred proteins and may reveal subtle differences in the membrane association of protein subpopulations. PMID- 8672434 TI - Reversible oligonucleosome self-association: dependence on divalent cations and core histone tail domains. AB - Regularly spaced nucleosomal arrays equilibrate between unfolded and highly folded conformations in <2 mM MgCl2, and self-associate above 2 mM MgCl2 [Schwarz, P. M., & Hansen, J. C. (1994) J. Biol. Chem. 269, 16284-16289]. Here we use analytical and differential sedimentation techniques to characterize the molecular mechanism and determinants of oligonucleosome self-association. Divalent cations induce self-association of intact nucleosomal arrays by binding to oligonucleosomal DNA and neutralizing its negative charge. Neither linker histones nor H2A/H2B dimers are required for Mg2+ - dependent self-association. However, divalent cations are unable to induce self-association of trypsinized nucleosomal arrays lacking their N- and C-terminal core histone tail domains. This suggests that the H3/H4 tail domains directly mediate oligonucleosome self association through a non-Coulombic-based mechanism. Self-association occurs independently of whether the oligonucleosome monomers are folded or unfolded. The first step in the self-association pathway is strongly cooperative and produces a soluble association intermediate that sediments approximately 10 times faster than the oligonucleosome monomers. The size of the oligonucleosome polymers increases rapidly as a consequence of small increases in the divalent cation concentration, eventually producing polymeric species that sediment at >> 10 000 S. Importantly, all steps in the self-association pathway are freely reversible upon removal of the divalent cations. Taken together, these data indicate that short oligonucleosome fragments composed of only core histone octamers and DNA possess all of the structural features required to achieve chromosome-level DNA compaction. These findings provide a molecular basis for explaining many of the recently uncovered structural features of interphase and metaphase chromosomal fibers. PMID- 8672435 TI - Solution Strucutres of DNA duplexes containing a DNA x RNA hybrid region, d(GG)r(AGAU)d(GAC) x d(GTCATCTCC) and d(GGAGA)r(UGAC) x d(GTCATCTCC). AB - The solution structures of two DNA duplexes containing a DNA*RNA hybrid region at different sites, d(GG)r(AGAU)d(GAC) x d(GTCATCTCC) (DHD, where D and H represent the DNA and DNA x RNA hybrid segments, respectively) and d(GGAGA)r(UGAC) x d(GTCATCTCC) (DDH), were determined by nuclear magnetic resonance spectroscopy to clarify the structural features of the D-H and H-D junctions. All proton-proton distances were derived from the NOESY spectra, with mixing times of 45 ms, and the restrained molecular dynamics were carried out starting from the typical A- and B-form conformations. Both duplexes were converged from the respective initial structures into structures with RMSD values of less than 1.0 angstrom. These structures were subjected to full relaxation matrix refinement to produce the final structures. In the case of the D-H junction, where the ribonucleotide was linked to the 3'-end of the DNA, the H2' and H2" signals of the deoxynucleotide overlapped completely, and the ribonucleotide had a H1'-H2' coupling constant larger than that of the normal C3'-endo sugar pucker. The dihedral angles, the pseudorotation phase angles, and the helical parameters changed at the H-D junction, but not at the D-H junction. A detailed comparison of the two duplexes revealed the structural heterogeneity between the DNA segment and the DNA x RNA hybrid region and the transitions at the junctions. PMID- 8672436 TI - NMR study of the conformation of the 2-aminopurine:cytosine mismatch in DNA. AB - DNA polymerase makes errors by misincorporating natural DNA bases and base analogs. Because of the wide variety of possible mismatches and the varying efficiency with which they are repaired, structural studies are necessary to understand in detail how these mispairs differ and can be distinguished from standard Watson-Crick base pairs. 2-Aminopurine (AP) is a highly mutagenic base analog. The objective of this study was to determine the geometry of the AP x C mispair in DNA at neutral pH. Although several studies have focused on the AP x C mispair in DNA, there is not as of yet consensus on its structure. At least four models have been proposed for this mispair. Through the use of NMR spectroscopy with selective 15N-labeling of exocyclic amino nitrogens on bases of interest, we are able to resolve ambiguities in previous studies. We find here that, in two different DNA sequences, the AP x C mispair at neutral and high pH is in a wobble geometry. The structure and stability of this base mispair is dependent upon the local base sequence. PMID- 8672437 TI - Equilibrium DNA binding of Sac7d protein from the hyperthermophile Sulfolobus acidocaldarius: fluorescence and circular dichroism studies. AB - The thermodynamics of the binding of the Sac7d protein of Sulfolobus acidocaldarius to double-stranded DNA has been characterized using spectroscopic signals arising from both the protein and the DNA. Ligand binding density function analysis has been used to demonstrate that the fractional change in protein intrinsic tryptophan fluorescence quenching that occurs upon DNA binding is equal to the fraction of protein bound. Reverse titration data have been fit directly to the McGhee-von Hippel model [McGhee, J., & von Hippel, P. (1974) J. Mol. Biol. 86, 469-489] using nonlinear regression. Sac7d binds noncooperatively to poly(dGdC) x poly(dGdC) with an intrinsic affinity of 6.5 x 10(6) M(-1) and a site size of 4 base pairs in 1 mM KH2PO4 and 50 mM KC1 (pH 6.8). Some binding sequence preference is noted, with the binding to poly(dIdC) x poly(dIdC) over 10 fold stronger than to poly(DAdT) x poly(dAdT). The binding is largely driven by the polyelectrolyte effect and is consistent with a release of 4.4 monovalent cations from DNA upon complex formation or the formation of 5 ion pairs at the protein-DNA interface. Extrapolation of salt back-titration data to 1 M KC1 indicates a -2.2 kcal/mol nonelectrostatic contribution to the binding free energy. A van't Hoff analysis of poly(dGdC) x poly(dGdC) binding shows that the binding enthalpy is approximately zero and the process is entropically driven. The affinity decreases slightly between pH 5.4 and 8.0. There is no significant difference between the binding parameters of recombinant Sac7d and native Sac7 proteins, indicating that methylation of the native protein has no effect on the DNA binding function. The binding of Sac7d to various DNAs leads to a significant increase in the DNA long-wavelength circular dichroism (CD) band, the intensity of which shows a sigmoidal dependence on Sac7d concentration. The sigmoidal CD binding isotherm can be quantitatively modeled by a conformational transition in the DNA that is cooperatively induced when protein monomers are bound within a given number of base pairs, ranging from zero for poly(dIdC) x poly(dIdC) to 8 or less for poly(dAdG) x poly(dCdT). PMID- 8672438 TI - Site-directed mutagenesis of the CP 47 protein of photosystem II: alteration of conserved charged residues in the domain 364E-444R. AB - The intrinsic chlorophyll-protein CP 47 is a component of photosystem II in higher plants, green algae and cyanobacteria. We had shown previously by biochemical methods that the domain 364E-440D of CP 47 interacts with the 33 kDa extrinsic protein of photosystem II [Odom, W. R., & Bricker, T. M. (1992) Biochemistry 31, 5616-5620]. In this study, using oligonucleotide-directed mutagenesis in the cyanobacterium Synechocystis 6803, mutations at 17 conserved charged residues were introduced into the domain 364E-444R of the CP 47 protein. Only mutations introduced at positions 384R and 385R led to a modified PS II phenotype. We previously described a mutation at (RR384385GG) which resulted in a mutant with a defective oxygen-evolving complex [Putnam-Evans, C., & Bricker, T. M. (1992) Biochemistry 31, 11482-11488]. An additional set of mutations, 384R to 384G, 385R to 385G, and 384,385RR to 384,385EE has now been introduced at this site yielding the mutants R384G, R385G, and RR384385EE, respectively. Steady state oxygen evolution measurements and quantum yield measurements demonstrated that these mutants exhibited significant alterations in their ability to evolve oxygen. Total fluorescence yield measurements indicated that all of these mutants contained about 85%-90% of the PS II reaction centers found in the control strain. This decrease was insufficient to explain the oxygen evolution results. Analysis of oxygen flash yield parameters indicated that there was little change in the S-state parameters alpha, beta, gamma, or delta. Measurement of the S2 lifetime, however, demonstrated that the S2 lifetime of the mutants was 2-3 times longer than that of the control. Additionally, examination of the risetime of the oxygen signal indicated that there was a significant retardation (6-7-fold) in the rate of oxygen release, suggesting a retarded S3-[S4]-S0 transition. These data reinforce our hypothesis that the positive charge density at positions 384R and 385R in the large extrinsic loop of CP 47 is necessary for its function in water oxidation. We speculate that this positive charge density may be an important factor in establishing the proper interaction between CP 47 and the 33kDa extrinsic protein. PMID- 8672439 TI - A linkage of the pKa's of asp-85 and glu-204 forms part of the reprotonation switch of bacteriorhodopsin. AB - Because asp-85 is the acceptor of the retinal Schiff base proton during light driven proton transport by bacteriorhodopsin, modulation of its pKa in the photocycle is to be expected. The complex titration of asp-85 in the unphotolyzed protein was suggested [Balashov, S. P., Govindjee, R., Imasheva, E. S., Misra, S., Ebrey, T. G., Feng, Y., Crouch, R. K., & Menick, D. R (1995) Biochemistry 34, 8820-8834] to reflect the dependence of this residue on the protonation state of another, unidentified group. From the pH dependencies of the rate constant for the thermal equilibration of retinal isomeric states (dark adaptation) and the deprotonation kinetics of the Schiff base during the photocycle in the E204Q and E204D mutants, we identify the residue as glu-204. The nature of its interaction with asp-85 is that at neutral pH either residue can be anionic but not both. This is consistent with our recent finding that glu-204 is the origin of the proton released to the extracellular surface upon protonation of asp-85 during the transport. We propose, therefore, that the following series of events occur in the photocycle. Protonation of asp-85 in the proton equilibrium with the Schiff base of the photoisomerized retinal results in the dissociation of glu-204 and proton release to the extracellular surface. The deprotonation of glu-204, in turn, raises the pK(a) of asp-85, and the equilibrium with the Schiff base shifts toward complete proton transfer. This constitutes the first phase of the reprotonation switch because it excludes asp-85 as a donor in the reprotonation of the Schiff base that follows. The sequential structural changes of the protein that ensue, detected earlier by diffraction, are suggested to facilitate the change of the access of the Schiff base toward the cytoplasmic side as the second phase of the switch, and the lowering the pKa of asp-96, so as to make it a proton donor, as the third phase. PMID- 8672440 TI - Hydrogen bonds of water and C==O groups coordinate long-range structural changes in the L photointermediate of bacteriorhodopsin. AB - Fourier transform infrared spectra of light-adapted bacteriorhodopsin exhibit a band at 1618 cm(-1) that shifts to 1625 cm(-1) upon formation of the L intermediate. It is assigned to the peptide C==O of Val49 from the fact that it shifts in [1-(13)C]valine-labeled bacteriorhodopsin and appears perturbed in the Val49-->Met mutant. The intensity of the BR-->L difference band is reduced in the Thr46-->Val mutant but restored by the additional mutation of Asp96-->Asn. These intensity changes are closely correlated with the H-bonding change of water olecules, suggesting that the peptide C==O of Val49 is hydrated. This could arise in the Thr46-->Val mutant because of perturbation of the C==O of Val46, which points toward Val49. The Val49-->Ala mutation influences a peptide N-H, presumably of Val49, and the carboxylic C==O of Asp96, as well as water molecules proximal to Asp85. Conversely, the water molecule assumed to be in the cavity that arises from the missing two methyl groups in V49A could be affected in the mutant of Asp96-->Asn. We propose that the perturbation exerted on Asp85 by the Schiff base in the L intermediate is transmitted to Asp96 through H-bonding of water molecules in the Asp85-Val49 region, the C==O of Val49, H-bonding between Val49 and Thr46, and H-bonding between Thr46 and Asp96. PMID- 8672441 TI - Conformational heterogeneity of stability of apomyoglobin studied by hydrogen/deuterium exchange and electrospray ionization mass spectrometry. AB - The solution conformations and stability of apomyoglobin (apo-Mb), at both neutral and acidic pH, have been investigated by analyzing charge state distributions observed in the mass spectra, and by on-line monitoring of the hydrogen/deuterium (H/D) exchange using electrospray ionization mass spectrometry (ESI-MS) in combination with circular dichroism (CD). The results demonstrate that the conformation of apo-Mb, which lacks the heme group, is considerably less stable than that of holomyoglobin in identical solution conditions at neutral pH. ESI-MS shows that apo-Mb in the buffered solution at pH 7 (native state) and at pH 4.3 (intermediate state) yields two distinct charge state distributions that presumably correspond to different protein conformations. Both conformations have the same H/D exchange rate. This provides strong evidence that both the native and the intermediate state of apo-Mb have highly dynamic structures, consisting of two or more rapidly interconverting conformations rather than single fixed conformations. However, the H/D exchange rate of the acid-induced compact state of apo-Mb at pH approximately 2 [Goto, Y., Calciano, L. J., & Fink, A. L. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 573-577] indicates that it has a stable, partially folded conformation. Although CD data suggest that apo-Mb in H20 at pH 6 and in the buffered solution at pH 7 has a native-like secondary structure, the charge state distribution and the H/D exchange rate measurements indicate that a large portion of the apo-Mb molecules are unfolded or partially unfolded under these conditions. Thus, conformational information obtained from ESI-MS measurements of the charge state distributions and H/D exchange rates is complementary to that obtained from CD measurements. The combination of these three measurements can be used to assess the conformational stability and conformational heterogeneity of a protein. PMID- 8672442 TI - Reversible oligomerization and denaturation of the chaperonin GroES. AB - The chaperonin GroEL can assist protein folding and normally acts with the co chaperonin GroES. These Escherichia coli proteins are encoded on the same operon, with GroES positioned first. In this report, we have investigated the reversible folding of GroES. Using fluorescence anisotropy of dansyl-labeled GroES, intrinsic fluorescence, bis-ANS binding, sedimentation velocity, and limited proteolysis, we show that GroES unfolds in a single, two-state transition. Importantly, intrinsic fluorescence and sedimentation velocity analyses show that GroES is capable of refolding and reassembling from a urea denatured state. The refolded GroES is fully active as shown by its ability to assist GroEL in the refolding of rhodanese. These results indicate that chaperonins may not require other chaperonins for successful folding/assembly. We also show that GroES is capable of assisting in the refolding/reassembly of fully denatured GroEL. The reversible folding of GroES coupled with the ability of GroES to assist the refolding/reassembly of GroEL suggest that the groE operon may be organized in a manner that provides a structural role in GroES/GroEL assembly as well as a functional role. PMID- 8672443 TI - Folding, unfolding, and refolding of the vesicular stomatitis virus glycoprotein. AB - Folding and refolding of the vesicular stomatitis virus (VSV) glycoprotein (G protein), New Jersey serotype, were studied both in infected cells and after urea denaturation and reduction of isolated protein in vitro. To assess the contribution of disulfide bonds to the conformation of this type I membrane glycoprotein, reduced and alkylated forms were compared with unreduced G proteins by their mobility on SDS-polyacrylamide gels and by their reactivity with conformation-dependent monoclonal antibodies (MAbs). Pulse-chase experiments showed that G protein folding in the endoplasmic reticulum (ER) of infected cells occurred rapidly (estimated half-time of 1-2 min) and involved transient association with the ER chaperone calnexin. Inhibition of glycosylation by tunicamycin slowed the folding process and emergence from the ER but did not prevent the appearance of a conformationally mature transport-competent G protein. For in vitro refolding studies, native G protein isolated from virus particles was denatured and reduced with urea and beta-mercaptoethanol. When rapidly diluted into a denaturant-free buffer containing oxidized glutathione and the nonionic detergent octyl glucoside, the G protein regained considerable native structure, as determined by reactivity with five monoclonal antibodies specific for different conformation-dependent epitopes. Whereas the refolding process was slow and inefficient in vitro relative to folding in the cell, this observation nonetheless demonstrated that an integral fully glycosylated membrane protein can be refolded to form a structure similar to that of the original protein processed during in vivo synthesis. If, however, unfolded nonglycosylated G protein was the starting material, refolding in vitro failed. In summary, we have shown that VSV G protein folding can be analyzed both in vivo and in vitro and that folding in the cell involves at least one chaperone and can occur in vivo even if not glycosylated. PMID- 8672444 TI - Reversible thermal unfolding of ribonuclease T1 in reverse micelles. AB - The reverse micellar system formed by the negatively charged surfactant AOT and the organic solvent isooctane is used to solubilize the protein RNase T1. The physicochemical properties of the entrapped protein have been studied using intrinsic tryptophan fluorescence and far-and near-UV CD. These studies indicate a similar structure for the protein in reverse micelles and in pH 7.0 buffer. Thermal unfolding has been studied as a function of W0, the molar ratio of water to AOT, in the solution. Measuring the change in fluorescence intensity as a function of temperature, we observe a reversible transition for W0 in the range 5 12. Heating rate dependencies carried out on these transitions (0.6-3.0 degrees C/min) indicate that the transition temperature and the apparent van't Hoff enthalpy change depend on the scanning rate as well as on W0. The values of the transition temperature, T(m) and the enthalpy change, delta H degrees(un), extrapolated to an infinitely slow scanning rate, are analyzed considering the electrostatic interaction of the charged residues of the protein with the charges of the surfactant molecules forming reverse micelles, the variation of the size of the reverse micelles, and the relative rates of unfolding, refolding, and irreversible denaturation. PMID- 8672445 TI - Assembly of the tetra-Mn site of photosynthetic water oxidation by photoactivation: Mn stoichiometry and detection of a new intermediate. AB - The process of photoactivation, the assembly of the water-oxidizing complex (WOC) of photosystem II (PSII) membranes, has been examined using two major improvements in methodology. First a new lipophilic chelator, N,N,N',N' tetrapropionate-1,3-bis(aminomethyl)benzene (TPDBA), has been used that permits complete extraction of both manganese and calcium and the three extrinsic WOC polypeptides while minimizing damage to the apo-PSII protein and, importantly, eliminating the need to use reductants. Second, an ultrasensitive, fast-response, polarographic cell and detection system were built. The apparatus features (a) an ultrabright red light-emitted diode (LED) for controlling the light intensity, pulse duration, and dark intervals, features critical for minimization of photoinhibition; (b) a microvolume (5 microL) O2 polarographic cell (Clark type) fitted with a thin silicone membrane for rapid response (100 ms); and (c) DC/AC preamplifier integrated into the microcell and interfaced to a bandpass AC amplifier. The sensitivity enables detection of approximately 5 x 10(-14) mol of O2 per flash at a signal to noise = 5/1. These improvements permit 100-fold lower Mn concentrations to be explored. Under optimum conditions, complete recovery of O2-evolving activity could be restored compared to that of PSII membranes depleted of the three extrinsic polypeptides (35% Vmax vs intact PSII). Titration of the photoactivation steady-state O2 yield, Yss, and the half-time for recovery, t1/2, vs Mn concentration demonstrate that 4.0 Mn/P680 are cooperatively taken up at 95% restoration of Yss and that 1.1-1.2 Mn atoms are involved in the rate-limiting photolytic step under steady-state conditions. Due to minimization of photoihibition, this intermediate exhibits a single exponential recovery kinetic over the entire population of PSII centers. Mn atoms in excess of 4 Mn/P680 accelerate the rate of photoactivation but decrease the yield above 8-10 Mn/P680. Maxima in both Yss and t1/2 are observed at similar electrochemical potentials of the medium, 380 and 340 mV, respectively. We attribute this maximum to either elimination of a recombination reaction between the redox-active tyrosine-161 of the D1 polypeptide (Y(Z)+) and an electron acceptor, possibly cytochrome b559, or stabilization of an intermediate in photoactivation. At low Mn2+ concentrations, a new pre-steady-state kinetic intermediate which binds fewer than 4 Mn atoms can be directly observed. This early kinetic phase has a rate that depends on Mn concentration and is independent of the electron acceptor identity and concentration. PMID- 8672446 TI - Stabilization of human triosephosphate isomerase by improvement of the stability of individual alpha-helices in dimeric as well as monomeric forms of the protein. AB - Human triosephosphate isomerase (hTIM) is a dimeric enzyme of identical subunits, adopting the alpha/beta-barrel fold. In a previous work, a monomeric mutant of hTIM was engineered in which Met14 and Arg98, two interface residues, were changed to glutamine. Analysis of equilibrium denaturation of this monomeric mutant, named M14Q/R98Q, revealed that its conformational stability, 2.5kcal/mol, is low as compared to the stability of dimeric hTIM (19.3 kcal/mol). The fact that this value is also lower than the conformational stabilities usually found for monomeric proteins suggests that the hTIM monomers are thermodynamically unstable. In the present work, we attempted to stabilize the M14Q/R98Q mutant by introducing stabilizing mutations in alpha-helices of the protein. Five mutations were proposed, designed to increase alpha-helix propensity by introducing alanines at solvent-exposed sites (Q179A, K193A), to introduce favorable interactions with helix dipoles (Q179D, S105D), or to reduce the conformational entropy of unfolding by introducing proline residues at the "N-cap" position of alpha-helices (A215P). Three replacements (Q179D, K193A, and A215P) were found to increase the stability of the native dimeric hTIM and the monomeric M14Q/R98Q. These results suggest that the monomeric hTIM mutant can be stabilized to a considerable extent by following well-established rules for protein stabilization. A comparison of the stabilizing effect performed by the mutations on the dimeric hTIM and the monomeric M14Q/R98Q allowed us to reinforce a model of equilibrium denaturation proposed for both proteins. PMID- 8672447 TI - Structure of the R65Q mutant of yeast 3-phosphoglycerate kinase complexed with Mg AMP-PNP and 3-phospho-D-glycerate. AB - The structure of a ternary complex of the R65Q mutant of yeast 3-phosphoglycerate kinase (PGK) with magnesium 5'-adenylylimidodiphosphate (Mg-AMP-PNP) and 3 phospho-D-glycerate (3-PG) has been determined by X-ray crystallography to 2.4 angstrom resolution. The structure was solved by single isomorphous replacement, anamalous scattering, and solvent flattening and has been refined to an R-factor of 0.185, with rms deviations from ideal bond distance and angles of 0.009 angstrom and 1.78 degrees, respectively. PGK consists of two domains, with the 3 PG bound to a "basic patch" of residues from the N-terminal domain and the Mg-AMP PNP interacting with residues from the C-terminal domain. The two ligands are separated by approximately 11 angstrom across the interdomain cleft. The model of the R65Q mutant of yeast PGK is very similar to the structures of PGK isolated from horse, pig, and Bacillus stearothermophilus (rms deviations between equivalent alpha-carbons in the individual domains < 1.0 angstrom) but exhibits substantial variations with a previously reported yeast structure (rms deviations between equivalent alpha-carbons in the individual domains of 2.9-3.2 angstrom). The most significant tertiary structural differences among the yeast R65Q, equine, porcine, and B. stearothermophilus PGK structures occur in the relative orientations of the two domains. However, the relationships between the observed conformations of PGK are inconsistent with a "hinge-bending" behavior that would close the interdomain cleft. It is proposed that the available structural and biochemical data on PGK may indicate that the basic patch primarily represents the site of anion activation and not the catalytically active binding site for 3 PG. PMID- 8672448 TI - Targeted A --> T and G --> T mutations induced by site-specific deoxyadenosine and deoxyguanosine adducts, respectively, from the (+)-anti-diol epoxide of dibenz[a,j]anthracene in M13mp7L2. AB - The studies described in this report directly examined the mutagenicity in Escherichia coli of both a deoxyadenosine (dAdo) and a deoxyguanosine (dGuo) adduct derived from (+)-anti-dibenz[a,j]-anthracene-3,4-diol 1,2-epoxide [(+)anti DB[a,j]A-DE] that were site-specifically placed in a single-stranded M13mp7L2 replication vector. An 11-base oligonucleotide (5'-CTC ACG CTT CT-3') containing either a single (+)anti-DB[a,j]A-DE--trans-N2-dGuo or (+)anti-DB[a,j]A-DE--trans N6dAdo adduct was successfully incorporated into single-stranded M13mp7L2 plasmid via ligation. In vitro studies using E. coli DNA polymerase I (Klenow fragment)indicated that both adducts were effective blocks for polymerase action. E. coli strains JM103 and JM103 uvrA6 were subsequently transformed with control (unadducted) and adduct-containing M13mp7L2 constructs followed by analysis of progeny DNA. In both JM103 and JM103 uvrA6 cells, plaque yields were markedly reduced with adduct containing vectors compared to control vectors. Activation of the inducible bacterial DNA repair system (SOS) by UV light only slightly increased the number of plaques recovered from either bacterial strain transformed with adduct-containing vectors. Targeted mutations were obtained with both adduct-containing vectors in both bacterial strains, whereas no mutations were detected in plaques recovered from control M13mp7L2 vectors. In JM103 cells, (+)anti-DB[a,j]A-DE--N6-dAdo induced exclusively A --> t transversions and (+)anti-DB[a,j]A-DE--N2-dGuo induced exclusively G --> T transversions. In JM103 uvrA6 cells, similar targeted transversion mutations were also obtained except that a few C deletions (i.e., aprroximately 10% of the mutations) were detected immediately 3' to the dAdo adduct. While mutagenesis was SOS dependent in JM103 cells [<0.15% (-SOS) vs approximately 1.3% (+SOS)], it appeared to be SOS independent in JM103 uvrA6 cells (approximately 1-2% in the presence or absence of SOS induction). It is argued that adduct-induced G --> T mutations can be rationalized by either misinformational or noninformational mechanisms. In contrast, A --> T mutations are unlikely to arise via a misinformational pathway, which provides the strongest support to date that bulky DNA adducts can induce mutations via a noninformational pathway. PMID- 8672449 TI - C-terminal zinc-containing peptide required for RNA recognition by a class I tRNA synthetase. AB - Escherichia coli isoleucyl-tRNA synthetase is one of five closely related class I tRNA synthetases. The active site of the 939 amino acid polypeptide is in an N terminal domain which contains an insertion believed essential for interactions with the tRNA acceptor helix. The enzyme was shown previously to contain an essential (for function in vivo) zinc bound to a Cys4 cluster at the C-terminal end of the polypeptide. The specific function of this zinc has been unknown. We show here that aminoacylation activity can be reconstituted in vitro by combining a 53 amino acid zinc-containing C-terminal peptide with a protein consisting of the remaining 886 amino acids. Reconstitution of aminoacylation is zinc dependent. In contrast, the zinc-containing peptide is dispensable for synthesis of isoleucyl adenylate. Affinity coelectrophoresis showed that the 53 amino acid C-terminal peptide is required specifically for tRNA binding. We propose that the zinc-containing peptide curls back to the active site to make contact with the acceptor helix of bound tRNA, but not with isoleucine or ATP. It is the first example of a zinc-containing peptide in a class I tRNA synthetase that is essential for tRNA binding interactions. The design of this enzyme may be part of a more general scheme for class I tRNA synthetases to acquire acceptor helix binding elements during the development of the genetic code. PMID- 8672450 TI - Mutation spectra of M13 vectors containing site-specific Cis-Syn, Trans-Syn-I, (6 4), and Dewar pyrimidone photoproducts of thymidylyl-(3'-->5')-thymidine in Escherichia coli under SOS conditions. AB - The mutations spectra of cis-syn, trans-syn-I, (6-4), and Dewar pyrimidone photoproducts of the TT site of AATTAA and TATTAT in the (-) strand of a heteroduplex M13 vector were obtained in an excision and photoreversal repair deficient Escherichia coli host under SOS conditions. Oligonucleotides containing site-specific photoproducts were annealed to a complementary uracil-containing (+) strand that contained one or more unique pairs of nucleotide mismatches and used to prime (-) strand synthesis with a DNA polymerase and dNTPs. Following DNA synthesis, the reaction mixtures were incubated with T4 DNA ligase and ATP and then used to transfect SOS-induced competent CSRO6F' cells (uvrA6 and phr-1). The transfectants were plated, gridded, and probed by oligonucleotides specific for progeny of the (-) and (+) strands. Individual progeny of the photoproduct containing (-) strands were plaque purified and sequenced by the dideoxy method. The cis-syn and trans-syn-I dimers were found not to be very mutagenic (<9%), the Dewar product more so (<33%), and the (6-4) product the most mutagenic (<73%). The mutation spectra were similar to those previously reported for the same photoproducts of the TT site of AGTTGG in the (+) strand of an M13 vector [Lawrence, C. W., et al. (1990) Mol. Gen Genet. 222, 166-168; LeClerc, J. E., et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 9685-9689] except that -1 deletion mutations were not observed for the trans-syn-I photoproducts, and a lower frequency of 3'-T-->C mutations was observed for the (6-4) photoproduct. Evidence that a small percentage of (+) strand repair of a double mismatch to the 3'-side of the photoproduct. Evidence that a small percentage of (+) strand repair of a double mismatch to the 3'-side was obtained from transfection experiments in which a second double mismatch was introduced opposite or flanking the photoproduct. Analysis of the minor tandem mutations induced by the (6-4) and Dewar products suggests that the SOS polymerase complex is able to elongate what amounts to double mismatches opposite these photoproducts and is consistent with the action of a highly processive polymerase that lacks proofreading ability. PMID- 8672451 TI - Members of the G protein-coupled receptor kinase family that phosphorylate the beta2-adrenergic receptor facilitate sequestration. AB - We recently reported that a beta2-adrenergic receptor (beta2AR) mutant, Y326A, defective in its ability to sequester in response to agonist stimulation was a poor substrate for G protein-coupled receptor kinase (GRK)-mediated phosphorylation; however, its ability to be phosphorylated and sequestered could be restored by overexpressing GRK2 [Ferguson et al. (1995) J. Biol. Chem. 270, 24782]. In the present report, we tested the ability of each of the known GRKs (GRK1-6) to phosphorylate and rescue the sequestration of the Y326A mutant in HEK 293 cells. We demonstrate that in addition to GRK2, GRK3-6 can phosphorylate the Y326A mutant and rescue its sequestration; however, GRK1 was totally ineffective in rescuing either the phosphorylation or the sequestration of the mutant receptor. We found that the agonist-dependent rescue of Y326A mutant phosphorylation by GRK2, -3, and -5 was associated with the agonist-dependent rescue of sequestration. In contrast, overexpression of GRK4 and -6 led mainly to agonist-independent phosphorylation of the Y326A mutant accompanied by increased basal receptor sequestration. Our results demonstrate that phosphorylation per se, but not the interaction with a specific GRK, is required to facilitate beta2AR sequestration. PMID- 8672452 TI - Membrane topology of the melibiose permease of Escherichia coli studied by melB phoA fusion analysis. AB - In order to study the secondary structure of the melibiose permease of Escherichia coli, 57 melB-phoA gene fusions were constructed and assayed for alkaline phosphatase activity. In general agreement with a previously suggested secondary structure model of melibiose permease [Botfield, M. C., Naguchi, K., Tsuchiya, T., & Wilson, T.H. (1992) J. Biol. Chem. 267, 1818], clusters of fusions exhibiting low and high phosphatase activity fusions alternate along the primary sequence. Fusions with high activity generally cluster at residues predicted to be in the periplasmic half of transmembrane domains or in periplasmic loops, while fusions with low activity cluster at residues predicted to be in the cytoplasmic half of transmembrane domains or in cytoplasmic loops. Taken together, the findings strongly support the contention that melibiose permease contains 12 transmembrane domains that traverse the membrane in zigzag fashion connected by hydrophilic loops that are exposed alternatively on the periplasmic or cytoplasmic surfaces of the membrane with the N and C termini on the cytoplasmic face of the membrane. Moreover, on the basis of the finding that the cytoplasmic half of an out-going segment is sufficient for alkaline phosphatase export to the periplasm while the periplasmic half of an in-going segment prevents it [Calamia, T., & Manoil, C. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 4937], the activity profile of the melibiose permease-alkaline phosphatase fusions is consistent with the predicted topology of seven of 12 transmembrane segments. However, five transmembrane domains require adjustment, and as a consequence, the size of the central cytoplasmic loop is reduced and a significant number of charged residues are shifted from a hydrophilic to a hydrophobic domain in this region of the transporter. PMID- 8672453 TI - Alternative adhesion sites in human fibrinogen for vascular endothelial cells. AB - Fibrinogen mediates endothelial cell adhesion, spreading, and angiogenesis through integrin alphavbeta3. Previous studies by several investigators have suggested that the Arg-Gly-Asp (RGD) site at position 572-574 on the alpha chain of human fibrinogen can bind to alphavbeta3. However, this RGD sequence is absent in fibrinogen from most other species, including bovine, hamster, monkey, mouse, pig, and rat fibrinogen. In these species, an RGD site exists at the equivalent of position alpha252-254, which has the sequence RGG in humans. In addition, the role of an integrin binding site on the gamma chain at position 400-411 has been an issue of controversy. In the present studies, recombinant fibrinogen molecules with mutations in the potential endothelial cell binding sites have been used to test the role of these sites directly. The results show that the RGD at alpha572 574 is the primary adhesion site, and that the gamma chain site plays no significant role. Human and bovine plasma fibrinogens were also assayed for their ability to support adhesion of human and bovine vascular endothelial cells. The results show that although the two types of fibrinogen have RGD sequences at widely divergent sites, there is no significant difference in their ability to support endothelial cell adhesion. Furthermore, a chimeric human fibrinogen molecule with an RGD sequence at the bovine site, position alpha252-254, also supported adhesion. These results indicate that an RGD site in human fibrinogen at either position alpha252-254 or position alpha572-574 can mediate endothelial cell adhesion. PMID- 8672454 TI - Thermodynamics of folding of the RNA pseudoknot of the T4 gene 32 autoregulatory messenger RNA. AB - Nucleotides U(-67) to C(-40) at the extreme 5' end of the gene 32 mRNA in bacteriophage T4 have been shown to fold into an RNA pseudoknot proposed to be important for translational autoregulation. The thermal denaturation of three in vitro transcribed RNAs corresponding to the pseudoknot region has been investigated as a function of Mg2+ concentration to begin to elucidate the determinants of the structure and stability of this conformation. T4-35 is a 35 nucleotide RNA containing a 5' G followed by the natural T4 sequence starting with the mature 5' end of the mRNA, nucleotides A(-71) to C(-38). A 32-nucleotide RNA, termed T4-32, contains the native sequence form U(-67) to C(40) with 5'GC and 5'CA single-stranded regions appended to the 5' and 3' ends of the core sequence, respectively. T4-28 contains only the 28 core nucleotides, and the predicted closing U(-67)-A(-52) base pair in stem 1 has been replaced with a phylogenetically allowed G(-67)-C(-52) base pair. Ribonuclease mapping of T4-32 and imino proton NMR experiments of T4-35 show that both sequences adopt a pseudoknotted conformation. At pH 6.9 and 50 mM NaCl, T4-35 and T4-32 RNAs are characterized by a single major melting transition over a wide range of [Mg2+] (0 6 mM). The delta H degree of unfolding for T4-35 and T4-32 shows a large dependence on Mg2+ concentration; the maximum delta H degree occurs at about 2.0 mM Mg2+ with further addition of Mg2+ simply increasing the tm. Investigation of the [Mg2+] dependence of the tm suggests that a net of one Mg2+ ion is released upon denaturation of T4-35 and T4-32 RNAs. Over the entire [Mg2+] range, the delta G degree (37 degrees C) for the folding of T4-35 is consistently 1-1.5 kcal mol(-1) more negative than T4-32 due to a higher stabilization enthalpy for the natural sequence molecule. In contrast to this behavior, T4-28 gives consistently higher tm's but less negative enthalpies and is destabilized (at 37 degrees C) by about 0.5-1.5 kcal mol(-1) relative to T4-32 and by about 2-3 kcal mol(-1) relative to T4-35, depending upon cation concentration. (1)H NMR experiments suggest that, even in the presence of 4.0 mM Mg2+, T4-28 RNA does not adopt a stable pseudoknotted conformation. These data show that the stability of the pseudoknot in the gene 32 mRNA encoded by the 28-nucleotide core sequence is significantly influenced by the number and nature of the immediately adjacent "single-stranded" 5' and/or 3' nucleotides appended to the core structure. These findings are discussed within the context of the structural model for the evolutionarily related phage T2 and T6 gene 32 mRNA pseudoknots presented in the following paper [Du, Z., Giedroc, D. P., & Hoffman, D. W. (1996) Biochemistry 35, 4187-4198]. PMID- 8672455 TI - Structure of the autoregulatory pseudoknot within the gene 32 messenger RNA of bacteriophages T2 and T6: a model for a possible family of structurally related RNA pseudoknots. AB - A 36-nucleotide RNA with a sequence corresponding to the 5' end region of the gene 32 mRNA of bacteriophages T2 and T6 was analyzed by one- and two-dimensional NMR methods. NMR results provide clear evidence that the RNA is folded into a pseudoknot structure with two coaxial stems connected by two loops, in a classic pseudoknot topology. The pseudoknot is unusual in that one of the loops consists of only one nucleotide, which spans the major groove of a seven base pair helical stem. Imino proton resonances indicate the hydrogen bonding pattern within the pseudoknot, and two-dimensional NOE spectra provide information that describes many of the structural features. The temperature dependence of the UV absorption and imino proton exchange rates provides insight into the stability of the pseudoknot. A three-dimensional model of the pseudoknot that is consistent with our NMR data is presented, and features that may be important for stabilizing the pseudoknot structure are discussed. A substantial number of other putative RNA pseudoknots described in the literature have sequences and topologies that appear to be related to the T2 and T6 pseudoknots. We propose that these RNAs may be members of a family of pseudoknots related by a similar structural motif, which we refer to as "common pseudoknot motif 1" or CPK1. The bacteriophage T2/T6 pseudoknot can be considered a structural model for the CPK1 family. The common features of the CPK1 pseudoknots are a stem 2 with six or seven base pairs, a loop 1 consisting of a single adenosine, and a variable length stem 1 and loop 2. The first "dangling" nucleotide at the 3' end of the molecule probably stabilizes stem 2. The CPK1 family includes several of the retroviral pseudoknots associated with mRNA frameshifting and readthrough. The work presented here describes the first detailed NMR analysis of an RNA pseudoknot with an entirely natural nucleotide sequence. PMID- 8672456 TI - An EPSP synthase inhibitor joining shikimate 3-phosphate with glyphosate: synthesis and ligand binding studies. AB - A novel EPSP synthase inhibitor 4 has been designed and synthesized to probe the configurational details of glyphosate recognition in its herbicidal ternary complex with enzyme and shikimate 3-phosphate (S3P). A kinetic evaluation of the new 3-dephospho analog 12, as well as calorimetric and (31)P NMR spectroscopic studies of enzyme-bound 4, now provides a more precise quantitative definition for the molecular interactions of 4 with this enzyme. The very poor binding, relative to 4, displayed by the 3-dephospho analog 12 is indicative that 4 has a specific interaction with the S3P site. A comparison of Ki(calc) for 12 versus the Ki(app) for 4 indicates that the 3-phosphate group in 4 contributes about 4.8 kcal/mol to binding. This compares well with the 5.2 kcal/mol which the 3 phosphate group in S3P contributes to binding. Isothermal titration calorimetry demonstrates that 4 binds to free enzyme with an observed Kd of 0.53 +/- 0.04 microM. As such, 4 binds only 3-fold weaker than glyphosate and about 150-fold better than N-methylglyphosate. Consequently, 4 represents the most potent N alkylglyphosate derivative identified to date. However, the resulting thermodynamic binding parameters clearly demonstrate that the formation of EPSPS x 4 is entropy driven like S3P. The binding characteristics of 4 are fully consistent with a primary interaction localized at the S3P subsite. Furthermore, (31)P NMR studies of enzyme-bound 4 confirm the expected interaction at the shikimate 3-phosphate site. However, the chemical shift observed for the phosphonate signal of EPSPS x 4 is in the opposite direction than that observed previously when glyphosate binds with enzyme and S3P. Therefore, when 4 occupies the S3P binding site, there is incomplete overlap at the glyphosate phosphonate subsite. As a glyphosate analog inhibitor, the potency of 4 most likely arises from predominant interactions which occur outside the normal glyphosate binding site. Consequently, 4 is best described as an S3P-based substrate-analog inhibitor. These combined results corroborate the previous kinetic model [Gruys, K. J., Marzabadi, M. R., Pansegrau, P. D., & Sikorski, J. A. (1993) Arch. Biochem. Biophys. 304, 345-351], which suggested that 4 interacts well with the S3P subsite but has little, if any, interaction at the expected glyphosate phosphonate or phosphoenolpyruvate-Pi subsites. PMID- 8672457 TI - Exchange of K+ or Cs+ for Na+ induces local and long-range changes in the three dimensional structure of the tryptophan synthase alpha2beta2 complex. AB - Monovalent cations activate the pyridoxal phosphate-dependent reactions of tryptophan synthase and affect intersubunit communication in the alpha2beta2 complex. We report refined crystal structures of the tryptophan synthase alpha2beta2 complex from Salmonella typhimurium in the presence of K+ at 2.0 angstrom and of Cs+ at 2.3 angstrom. Comparison of these structures with the recently refined structure in the presence of Na+ shows that each monovalent cation binds at approximately the same position about 8 angstrom from the phosphate of pyridoxal phosphate. Na+ and K+ are coordinated to the carbonyl oxygens of beta Phe-306, beta Ser-308, and beta Gly-232 and to two or one water molecule, respectively. Cs+ is coordinated to the carbonyl oxygens of beta Phe 306, beta Ser-308, beta Gly-232, beta Val-231, beta Gly-268 and beta Leu-304. A second binding site for Cs+ is located in the beta/beta interface on the 2-fold axis with four carbonyl oxygens in the coordination sphere. In addition to local changes in structure close to the cation binding site, a number of long-range changes are observed. The K+ and Cs+ structures differ from the Na+ structure with respect to the positions of beta Asp-305, beta Lys-167, and alpha Asp-56. One unexpected result of this investigation is the movement of the side chains of beta Phe-280 and beta Tyr-279 from a position partially blocking the tunnel in the Na+ structure to a position lining the surface of the tunnel in the K+ and Cs+ structures. The results provide a structural basis for understanding the effects of cations on activity and intersubunit communication. PMID- 8672458 TI - Evidence for the existence of a pseudoknot structure at the 3' terminus of the flavivirus genomic RNA. AB - The 3'-terminal nucleotides of the flavivirus genomic RNA form conserved secondary structures that may function as cis-acting signals for RNA replication. Here we provide evidence for the existence of a conserved pseudoknot structure at the 3' terminus of the flavivirus genomic RNA. A truncated version of the West Nile virus (WNV) 3'-terminal RNA sequence was used as the model for these studies. Circular dichroism spectra indicated the presence of a highly structured RNA conformation with a significant amount of A-form helix. Ribonuclease probing not only confirmed the presence of the predicted secondary structure, which consists of a long stem-loop (SL1) and a shorter stem-loop (SL2), but also suggested that base pairing occurs between nucleotides in the loop of SL2 and those in an internal loop strand located on the 5' side of SL1. Analysis of three mutant RNAs further supported the existence of pseudoknot interactions. UV melting analysis of the WNV 3' model RNA showed three transitions with significant hyperchromicity at approximately 46, 62, and 79 degrees C. UV-melting analysis with either SL1 or SL2 RNA alone suggested that the 62 and 79 degree C transitions represent the unfolding of SL2 and SL1, respectively. The 46 degree C transition is most likely due to the opening of the proposed tertiary structure. A similar melting curve was obtained for another flavivirus (dengue-3 virus) 3' terminal RNA, providing further support for the conservation of the structure among flaviviruses. Molecular modeling of the RNA indicated that a pseudoknot structure is a stereochemically and energetically reasonable model for the 3' terminus of flavivirus genomic RNA. PMID- 8672459 TI - Roles of surface hydrophobic residues in the interfacial catalysis of bovine pancreatic phospholipase A2. AB - The interfacial binding is a unique and important step in the phospholipase A2 (PLA2) catalyzed hydrolysis of phospholipids which is distinct from the binding of a substrate to the active site. To assess the roles of surface hydrophobic residues of PLA2 in these processes, we selectively mutated Leu-19 and Leu-20 of bovine pancreatic PLA2 to charged (L19K and L20K), uncharged polar (L19S and L20S), and amphiphilic (L19W and L20W) groups and measured their kinetic and binding properties using various phospholipid aggregates, including micelles, monolayers, and polymerized mixed liposomes. The mutations of Leu-19 and Leu-20 did not significantly change either the tertiary structure or the thermodynamic stability of bovine pancreatic PLA2. Toward monomeric 1,2-dihexanoyl-sn-glycero-3 phosphocholine, all Leu-20 mutants (L20S, L20W, and L20K) showed activities comparable to that of wild type whereas the substitution of Leu-19 with less hydrophobic side chains (L19S and L19K) reduced the activity to 70% and 50%. Toward zwitterionic 1,2-dioctanoyl-sn-glycero-3-phosphocholine (diC8PC) micelles, L20S and L20K mutants showed only 30% and 35% of the wild-type activity, respectively, whereas L20W was about twice as active as wild type. Also, L19S and L19K showed 75% and 15% of the wild-type activity, respectively. Toward anionic Trition X-100/sodium deoxycholate/diC8PC (4:2:1) mixed micelles, L20W and L20K were 2.6 times and twice more active than wild type. To determine the sn-2 acyl group selectivity of wild type and mutants, polymerized mixed liposomes were used which contained 1,2-bis[12-(lipoyloxy)-dodecanoyl]-sn-glycero-3-phosphoglycerol and 1 mol % of either 1-2[12-(1-pyrenebutanoyloxy)dodecanoyl]-2-hexanoyl-sn glycero-3-++ +phosphocholine or 1-[12-(1-pyrenebutanoyloxy)dodecanoyl]-2 dodecanoyl-sn-glycero-3-+ ++phosphocholine. These measurements showed that Leu-19 was involved in the substrate binding and the sn-2 acyl group selectivity of bovine pancreatic PLA2 and that Leu-20 made a direct contact with the surface of phospholipid aggregates. The binding affinities of mutants to micelles, polymerized liposomes, and monolayers were well consistent with their kinetic behaviors, supporting the notion that the altered activities of Leu-19 mutants and Leu-20 mutants were due to the change in their substrate binding and interfacial binding, respectively. Finally, the L20W mutant represents the first example of protein engineering of PLA2 which results in a significant increase in interfacial binding to densely packed neutral monolayers and bilayers. PMID- 8672460 TI - Structure of cyclodextrin glycosyltransferase complexed with a maltononaose inhibitor at 2.6 angstrom resolution. Implications for product specificity. AB - Crystals of the Y195F mutant of cyclodextrin glycosyltransferase from Bacillus circulans strain 251 were subjected to a double soaking procedure, in which they were first soaked in a solution containing the inhibitor acarbose and subsequently in a solution containing maltohexaose. The refined structure of the resulting protein-carbohydrate complex has final crystallographic and free R factors for data in the 8-2.6 angstrom resolution range of 15.0% and 21.5%, respectively, and reveals that a new inhibitor, composed of nine saccharide residues, is bound in the active site. The first four residues correspond to acarbose and occupy the same subsites near the catalytic residues as observed in the previously reported acarbose-enzyme complex [Strokopytov et al. (1995) Biochemistry 34, 2234-2240]. An oliogosaccharide consisting of five glucose residues has been coupled to the nonreducing end of acarbose. At the fifth residue the polysaccharide chain makes a sharp turn, allowing it to interact with residues Tyr89, Phe195, and Asn193 and a flexible loop formed by residues 145 148. On the basis of the refined model of the complex an explanation is given for the product specificity of CGTases. PMID- 8672461 TI - Protein stabilization by removal of unsatisfied polar groups: computational approaches and experimental tests. AB - The role of polar and charged side chains in partially buried protein environments has been probed in a variant of Arc repressor (MYL) in which hydrophobic interactions between Met31, Tyr36, and Leu40 replace the wild-type salt-bridge interactions between Arg31, Glu36, and Arg40. In the absence of this salt-bridge triad, three additional side chains were identified by continuum electrostatic calculations as incurring larger desolvation penalties during folding than were recovered in favorable electrostatic interactions in the folded state. These side chains (Asn29, Ser44, and Glu48) were mutated singly and collectively to alanine in the MYL background, and the thermodynamic stabilities of the resulting mutant proteins were found to be increased by 0.1 to 1.3 kcal/mol of dimer. All of the mutants displayed cooperative thermal melts and appeared to have well-packed hydrophobic cores by near-UV circular dichroism spectroscopy, indicating that conformational specificity is maintained. The Arc variant (MYL-NA29/SA44/EA48) in which the entire six-residue polar network is replaced by nonpolar groups is 5.1 kcal/mol of dimer more stable than wild type, indicating that the strategy of replacing buried or partially buried charged and polar side chains with hydrophobic residues can lead to substantial stabilization. PMID- 8672462 TI - Electron paramagnetic resonance spectroscopy of the heme domain of inducible nitric oxide synthase: binding of ligands at the arginine site induces changes in the heme ligation geometry. AB - The electron paramagnetic resonance spectra of the heme domain of inducible nitric oxide synthase (iNOS) demonstrate a close relationship to the corresponding spectra of the neuronal isoform (nNOS). The binding of ligands to the iNOS arginine site perturbs the environment of the high-spin ferriheme in a highly ligand-specific manner. The iNOS forms five-coordinate, high-spin complexes with arginine analogs which are clearly related to the corresponding complexes of nNOS. Studies indicate that the binding of L-arginine, N(omega) hydroxy-L-arginine (NHA), and N(omega)-methyl-L-arginine (NMA) produces various spectroscopic species closely corresponding to the equivalent complexes of nNOS, while N(omega)-nitro-L-arginine (NNA) binding produces a state which appears intermediate in character between the nNOS NNA and arginine complexes. These spectroscopic studies have permitted the determination of ligand-specific high spin states which reveal similarities and differences between iNOS and nNOS. PMID- 8672463 TI - Reconstitution of phospholipid scramblase activity from human blood platelets. AB - Cellular activation, accompanied by elevation of cytoplasmic Ca2+ levels, can induce a progressive loss of plasma membrane phospholipid asymmetry, resulting from increased transbilayer movement (flip-flop) of phospholipids. While this process has been demonstrated in a variety of different cells, it is most active in blood platelets. In order to test whether this lipid scrambling process is mediated by a membrane protein, platelet membranes were solubilized in cholate and fractionated by anion exchange chromatography, and fractions were reconstituted into phospholipid vesicles by detergent dialysis in the presence of small amounts of fluorescent (NBD) phospholipids. Using dithionite reduction to monitor the transbilayer location of NBD phospholipids, it was shown that addition of Ca2+ and ionomycin to vesicles reconstituted with a particular fraction results in transbilayer movement of the fluorescent phospholipid analogs from the vesicle's inner to outer leaflet. Lipid vesicles reconstituted in the absence of membrane protein, or reconstituted with another platelet membrane protein fraction, were devoid of this activity. Heating the active fraction or incubating it with pronase or the SH reagent pyridyldithioethylamine markedly diminished the ability of the vesicles to translocate fluorescent phospholipid analogs across the bilayer in response to Ca2+ and ionophore. These results argue that a membrane protein (or proteins) from blood platelets is required to catalyze Ca2+-induced transbilayer movement of phospholipids, suggesting its (or their) involvement in the loss of lipid asymmetry that can occur during cellular activation. PMID- 8672465 TI - A refined model of the thyrotropin-releasing hormone (TRH) receptor binding pocket. Experimental analysis and energy minimization of the complex between TRH and TRH receptor. AB - Seven transmembrane (TM) spanning, G protein-coupled receptors (GPCRs) appear to bind large glycoprotein hormones predominantly within their extracellular domains, small nonpeptidic ligands within the TM helical bundle, and peptide ligands within the extracellular domains and TM bundle. The tripeptide thyrotropin-releasing hormone (TRH, pyroGlu-His-ProNH2) may bind entirely within the TM bundle of the TRH receptor (TRH-R). We have previously demonstrated direct binding contacts between the pyroGlu of TRH and two residues in TM helix 3 (TM-3) of TRH-R and proposed a model of the binding pocket of TRH-R [Perlman, J. H., Laakkonen, L., Osman, R., & Gershengorn, M. C. (1994) J. Biol. Chem. 269, 23383 23386]. Here, we provide evidence for two additional direct interactions between TRH and TRH-R. One interaction is between the aromatic ring of Tyr 282 of TM-6 and His of TRH. This is based on a large increase in the half-maximally effective concentration (EC50) of TRH for stimulation of inositol phosphate formation by Y282A TRH-R and a loss of selectivity of this mutant receptor for TRH analogs substituted at His. We provide evidence for another interaction between Arg 306 of TM-7 and the terminal carboxamide of TRH. Using four direct interactions as anchors, a refined model of the TRH-R binding pocket was constructed using geometry optimization through energy minimization. A novel method for modeling GPCRs based on Monte Carlo and stochastic dynamics simulations is presented in the accompanying paper [Laakkonen, L. J., Guarnieri, F., Perlman, J. H., Gershengorn, M. C., & Osman, R. (1996) Biochemistry 35, 7651-7663]. PMID- 8672464 TI - Interlobe communication in 13C-methionine-labeled human transferrin. AB - [1H, 13C] NMR investigations of metal-induced conformational changes in the blood serum protein transferrin (80 kDa) are reported. These are thought to play an important role in the recognition of this protein by its cellular receptors. [1H, 13C] NMR resonance assignments are presented for all nine methionine 13CH3 groups of recombinant deglycosylated human transferrin on the basis of studies of recombinant N-lobe (40 kDa, five Met residues), NOESY-relayed [1H, 13C] HMQC spectra, and structural considerations. The first specific assignments for C-lobe resonances of transferrin are presented. Using methionine 13CH3 resonances as probes, it is shown that, with oxalate as the synergistic anion, Ga3+ binds preferentially to the C-lobe and subsequently to the N-lobe. The NMR shifts of Met464, which is in the Trp460-centered hydrophobic patch of helix 5 in the C lobe in contact with the anion and metal binding site, show that Ga3+ binding causes movement of side chains within this helix, as is also the case in the N lobe. The C-lobe residue Met382, which contacts the N-lobe hinge region, is perturbed when Ga3+ binds to the N-lobe, indicative of interlobe communication, a feature which may control the recognition of fully-metallated transferrin by its receptor. These results demonstrate that selective 13C labeling is a powerful method for probing the structure and dynamics of high-molecular-mass proteins. PMID- 8672466 TI - A refined model of the thyrotropin-releasing hormone (TRH) receptor binding pocket. Novel mixed mode Monte Carlo/stochastic dynamics simulations of the complex between TRH and TRH receptor. AB - Previous mutational and computational studies of the thyrotropin-releasing hormone (TRH) receptor identified several residues in its binding pocket [see accompanying paper, Perlman et al. (1996) Biochemistry 35, 7643-7650]. On the basis of the initial model constructed with standard energy minimization techniques, we have conducted 15 mixed mode Monte Carlo/stochastic dynamics (MC SD) simulations to allow for extended sampling of the conformational states of the ligand and the receptor in the complex. A simulated annealing protocol was adopted in which the complex was cooled from 600 to 310 K in segments of 30 ps of the MC-SD simulations for each change of 100 K. Analysis of the simulation results demonstrated that the mixed mode MC-SD protocol maintained the desired temperature in the constant temperature simulation segments. The elevated temperature and the repeating simulations allowed for adequate sampling of the torsional space of the complex with successful conservation of the general structure and good helicity of the receptor. For the analysis of the interaction between TRH and the binding pocket, TRH was divided into four groups consisting of pyroGlu, His, ProNH2, and the backbone. The pairwise interaction energies of the four separate portions of TRH with the corresponding residues in the receptor provide a physicochemical basis for the understanding of ligand-receptor complexes. The interaction of pyroGlu with Tyr106 shows a bimodal distribution that represents two populations: one with a H-bond and another without it. Asp195 was shown to compete with pyroGlu for the H-bond to Tyr106. Simulations in which Asp195 was interacting with Arg283, thus removing it from the vicinity of Tyr106, resulted in a stable H-bond to pyroGlu. In all simulations His showed a van der Waals attraction to Tyr282 and a weak electrostatic repulsion from Arg 306. The ProNH2 had a strong and frequent H-bonding interaction with Arg306. The backbone carbonyls show a frequent H-bonding interaction with the OH group of Tyr282 and strong, often multiple, interactions with Arg306. Three structures, which maintained these interactions simultaneously, were selected as candidates for ligand-receptor complexes. These show persistent interactions of TRH with Ile 109 and Ile 116 in HX 3 and with Tyr310 and Ser313 in HX 7, which will be tested to refine the structure of the ligand-receptor complex. The superposition of the three structures shows the extent of structural flexibility of the receptor and the ligand in the complex. The backbone of TRH inside the receptor is in an alpha helical conformation, suggesting that the receptor, through its interaction with the ligand, provides the energy required for the conformational change in the ligand from an extended to the folded form. PMID- 8672467 TI - NMR structure of a bacteriophage T4 RNA hairpin involved in translational repression. AB - A high-resolution structure of a 16-nucleotide bacteriophage T4 RNA hairpin, 5' GCCU[AAUAACUC]GGGC (loop bases in square brackets), has been determined in solution by proton, phosphorus, and carbon (natural abundance) NMR spectroscopy. This RNA hairpin is known to play a crucial role in the translational repression of bacteriophage T4 DNA polymerase. Ultraviolet absorbance melting curves indicate that the structure formed is unimolecular. The NMR spectra indicate that a single conformation consistent with a hairpin structure is formed. Strong imino imino NOEs confirm the formation of the G.U base pair at the stem-loop junction. There is no evidence that A5 is protonated (at pH 6.0) and involved in an A+.C pair. However, the NMR data indicate that the stem is extended beyond the G.U pair and that A-form stacking continues for three nucleotides on the 5' side and one nucleotide on the 3' side. Structure calculations using restraints obtained from NMR data give a precisely defined structure with an average root mean square deviation (RMSD) of approximately 1.2 A for the entire molecule. The assignment of all the protons and most of the 31P resonances in the loop yielded a large number of distance and torsion angle restraints for these nucleotides. These helped obtain a well-defined loop with an average RMSD of 1.1 A for the loop nucleotides of 11 converged structures. PMID- 8672468 TI - A quadruple mutant T4 RNA hairpin with the same structure as the wild-type translational repressor. AB - The solution structure of a 16-nucleotide RNA hairpin, 5'-GCCUAG[CAAC]CUGGGC (loop bases in square brackets), has been determined by proton, phosphorus, and carbon (natural abundance) nuclear magnetic resonance (NMR) spectroscopy. This RNA tetraloop hairpin varies in four loop nucleotides from the wild-type T4 RNA hairpin (with eight loop nucleotides) involved in the translational repression of bacteriophage T4 DNA polymerase. Despite the differences in their sequence and proposed secondary structures, these two hairpins bind T4 DNA polymerase with equal affinity. The NMR spectra of the mutant hairpin indicate that its stem is extended in comparison to that of the wild-type hairpin by the formation of two additional Watson-Crick base pairs. The NMR data provide a precisely defined structure for the mutant hairpin with an average root mean square deviation of approximately 0.7 A for all 16 residues in the molecule. The structure of the mutant loop is very similar to that determined previously for the wild-type hairpin. The three loop bases that are conserved between the mutant and wild-type hairpins point out in solution with the groups capable of hydrogen bond formation exposed to the solution. This is exactly what was seen for the wild-type hairpin. Also, unusual, long-range NOEs, loop hydrogen bonds, and even the position at which the loop bends are common features between the two loops. This explains how two different hairpins, by adopting similar three-dimensional structures, have the same affinity for the DNA polymerase. PMID- 8672469 TI - Structure determination of the N-terminal thioredoxin-like domain of protein disulfide isomerase using multidimensional heteronuclear 13C/15N NMR spectroscopy. AB - As a first step in dissecting the structure of human protein disulfide isomerase (PDI), the structure of a fragment corresponding to the first 120 residues of its sequence has been determined using heteronuclear multidimensional NMR techniques. As expected from its primary structure homology, the fragment has the thioredoxin fold. Similarities and differences in their structures help to explain why thioredoxins are reductants, whereas PDI is an oxidant of protein thiol groups. The results confirm that PDI has a modular, multidomain structure, which will facilitate its structural and functional characterization. PMID- 8672470 TI - Motion of spin-labeled side chains in T4 lysozyme. Correlation with protein structure and dynamics. AB - Thirty single cysteine substitution mutants of T4 lysozyme have been prepared and spin-labeled with a sulfhydryl-specific nitroxide reagent in order to systematically investigate the relationship between nitroxide side-chain mobility and protein structure. The perturbation caused by replacement of a native residue with a nitroxide amino acid was assessed from the resulting changes in biological activity, circular dichroism, and free energy of folding. The nitroxide produced context-dependent changes in stability and activity similar to those observed for substitution with natural amino acids at the same site but had little effect on the circular dichroism spectra. At solvent-exposed sites, the structural perturbation appears to be small at the level of the backbone fold. Nitroxide side-chain mobility faithfully reflects the protein tertiary fold at all sites investigated. The primary determinants of nitroxide side-chain mobility are tertiary interactions and backbone dynamics. Tertiary interactions constrain the side-chain mobility to an extent closely correlated with the degree of interaction. At interhelical loop sites, the side chains have a high mobility, consistent with high crystallographic thermal factors. On the exposed surfaces of alpha-helices, the side-chain mobility is not restricted by interactions with nearest neighbor side chains but appears to be determined by backbone dynamics. An unexpected result is a striking difference between the mobility of residues near the C- and N-termini of helices. These results provide the foundation for another dimension of information in site-directed spin-labeling experiments that can be interpreted in terms of the protein tertiary fold, its equilibrium dynamics and time-dependent conformational changes. PMID- 8672471 TI - Modulation of cyclobutane pyrimidine dimer formation in a positioned nucleosome containing poly(dA.dT) tracts. AB - We have used a defined-sequence nucleosome to concomitantly investigate the generation and location of DNA lesions in nucleosomes and their influence on nucleosome positioning (translational and rotational setting). A 134 bp HISAT sequence from the yeast DED1 promoter, containing a polypyrimidine region (40 bp) with a T6-tract, two T5-tracts, and a T9-tract, was reconstituted in nucleosomes with a defined rotational setting. T-tracts adopt unusually rigid DNA structures in solution ("T-tract structure") and are hot spots of cyclobutane pyrimidine dimer (CPD) formation by UV light (254 nm). DNA was irradiated with UV light before or after reconstitution. The CPD yields and distribution were analyzed by cleavage with T4 endonuclease V. The rotational setting of nucleosomal DNA was characterized by DNase I digestion. With the exception of one T5-tract (1T5), the T6-, the 2T5-, and the T9-tracts formed T-tract structure in solution. T-tract structure was lost upon folding in nucleosomes, demonstrating a dominant constraint of DNA folding in nucleosomes over that of T-tract structure. CPD formation was strongly modulated by the nucleosome structure, but the CPD distribution differed from that reported for mixed-sequence DNA. CPD formation in the nucleosome had no effect on the rotational setting of nucleosomal DNA, but the rotational setting was affected when nucleosomes were assembled on damaged DNA. The toleration of DNA distortions imposed by CPDs in nucleosomes may have important implications for the recognition and repair of these damages in chromatin. PMID- 8672472 TI - Crystal structures of the binary and ternary complexes of 7 alpha-hydroxysteroid dehydrogenase from Escherichia coli. AB - 7 alpha-Hydroxysteroid dehydrogenase (7 alpha-HSDH;1 EC 1.1.1.159) is an NAD+ dependent oxidoreductase belonging to the short-chain dehydrogenase/reductase (SDR) 1 family. It catalyzes the dehydrogenation of a hydroxyl group at position 7 of the steroid skeleton of bile acids. The crystal structure of the binary (complexed with NAD+) complex of 7 alpha-HSDH has been solved at 2.3 A resolution by the multiple isomorphous replacement method. The structure of the ternary complex [the enzyme complexed with NADH, 7-oxoglycochenodeoxycholic acid (as a reaction product), and possibly partially glycochenodeoxycholic acid (as a substrate)] has been determined by a difference Fourier method at 1.8 A resolution. The enzyme 7 alpha-HSDH is an alpha/beta doubly wound protein having a Rossmann-fold domain for NAD (H) binding. Upon substrate binding, large conformation changes occur at the substrate binding loop (between the beta F strand and alpha G helix) and the C-terminal segment (residues 250-255). The variable amino acid sequences of the substrate-binding loop appear to be responsible for the wide variety of substrate specificities observed among the enzymes of the SDR family. The crystal structure of the ternary complex of 7 alpha-HSDH, which is the only structure available as the ternary complex among the enzymes of the SDR family, indicates that the highly conserved Tyr159 and Ser146 residues most probably directly interact with the hydroxyl group of the substrates although this observation cannot be definite due to an insufficiently characterized nature of the ternary complex. The strictly conserved Lys163 is hydrogen-bonded to both the 2'- and 3'-hydroxyl groups of the nicotinamide ribose of NAD(H). We propose a new catalytic mechanism possibly common to all the enzymes belonging to the SDR family in which a tyrosine residue (Tyr159) acts as a catalytic base and a serine residue (Ser146) plays a subsidiary role of stabilizing substrate binding. PMID- 8672473 TI - Involvement of the carboxyl groups of glutathione in the catalytic mechanism of human glutathione transferase A1-1. AB - The present study proposes the participation of both carboxylate groups of the glutathione molecule as functional entities in the catalytic apparatus of human glutathione transferase (GST) A1-1. Functional studies in combination with structural data provide evidence for the alpha-carboxylate of the Glu residue of glutathione acting as a proton acceptor in the catalytic mechanism. The Glu carboxylate is hydrogen-bonded to a protein hydroxyl group and a main-chain NH, as well as to a water molecule of low mobility in the active site region. The Glu alpha-carboxylate of glutathione is bound in a similar manner to the active sites of mammalian glutathione transferases of classes Alpha, Mu, and Pi, for which three-dimensional structures are known. Mutation of the hydroxyl group that is hydrogen-bonded to the alpha-carboxylate of the Glu residue of glutathione (Thr68 >Val) caused a shift of the pH dependence of the enzyme-catalyzed reaction, suggesting that the acidic limb of the pH-activity profile reflects the ionization of the carboxylate of the Glu residue of glutathione. The second carboxylate group of glutathione, which is part of its Gly residue, interacts with two Arg side chains in GST A1-1. One of these residues (Arg45) may influence an ionic interaction (Arg221/Asp42), which appears to contribute to binding of the second substrate by fixing the C-terminal alpha-helix as a lid over the active site. Removal of the Gly residue from the glutathione molecule caused a 13 fold increase in the KM value for the electrophilic substrate. Thus, the Gly carboxylate of glutathione, by way of influencing the topology of the active site, contributes to the binding of the second substrate of the enzyme. Consequently, the glutathione molecule has several functions in the glutathione transferase catalyzed reactions, not only as a substrate providing the thiol group for different types of chemical reactions but also as a substrate contributing a carboxylate that acts as a proton acceptor in the catalytic mechanism and a carboxylate that modulates binding of the second substrate to the enzyme. PMID- 8672474 TI - Deterministic pressure dissociation and unfolding of triose phosphate isomerase: persistent heterogeneity of a protein dimer. AB - Subunit dissociation and unfolding of dimeric rabbit muscle triose phosphate isomerase (TIM) induced by hydrostatic pressure were investigated. Changes in fluorescence emission of TIM (both intrinsic and of covalently attached probes) indicated that pressure ranging from 1 bar to 3.5 kbar promoted subunit dissociation and unfolding. Instrinsic fluorescence changes upon unfolding by pressure included a 27 nm red-shift of the emission, a decrease in fluorescence anisotropy from 0.14 to about 0.01, and a 1.5-fold increase in fluorescence quantum yield, similar to that observed in the presence of guanidine hydrochloride. Kinetics of pressure-induced fluorescence changes were slow (t 1/2 approximately 15 min) and little dependent on pressure. In order to selectively monitor subunit dissociation, fluorescence resonance energy transfer (FRET) measurements were carried out with TIM that was separately labeled with 5-((((2 iodoacetyl)-amino)ethyl)amino)naphthalene-1-sulfonic acid (1,5-IAEDANS) or fluorescein-5-isothiocyanate (FITC). FRET measurements indicated that subunit dissociation and unfolding took place concomitantly, both under equilibrium conditions and in kinetic experiments in which dissociation/unfolding was triggered by a sudden increase in pressure. Release of pressure caused monomer refolding and dimerization. Contrary to what would be expected for a process involving subunit dissociation, pressure effects on TIM were not dependent on protein concentration. Experiments involving a series of pressure jumps demonstrated persistent heterogeneity in sensitivity toward pressure in the ensemble of TIM dimers. This kind of deterministic behavior is similar to that exhibited by higher order protein aggregates and indicates that not all individual dimers are energetically identical in solution. The heterogeneity of native TIM revealed by sensitivity to pressure could not be detected by traditional means of protein separation, such as polyacrylamide gel electrophoresis (under both native and denaturing conditions) and size exclusion gel chromatography. This suggests that energetic heterogeneity originates from conformational heterogeneity of the protein. The possible biological relevance of the deterministic character of stability of TIM is discussed. PMID- 8672475 TI - Kinetics of the reductive half-reaction of the iron-sulfur flavoenzyme CDP-6 deoxy-L-threo-D-glycero-4-hexulose-3-dehydrase reductase. AB - The conversion of CDP-4-keto-6-deoxy-D-glucose to CDP-4-keto-3,6-dideoxy-D glucose is a key step in biosynthesis of ascarylose, the terminal dideoxyhexose of the O-antigen tetrasaccharide of the lipopolysaccharide from Yersinia pseudotuberculosis V. This transformation is catalyzed by two enzymes: CDP-6 deoxy-L-threo-D-glycero-4-hexulose-3-dehydrase (E1), which contains a pyridoxamine and a [2Fe-2S] center, and an NADH-dependent CDP-6-deoxy-L-threo-D glycero-4-hexulose-3-dehydrase reductase (E3), which contains both an FAD and a [2Fe-2S] center. E1 reacts to form a Schiff base with CDP-4-keto-6-deoxy-D glucose and catalyzes the elimination of the hydroxyl at position 3 of the glucose moiety, resulting in the formation of a covalently bound CDP-6-deoxy delta(3,4)-glucoseen intermediate. E3 transfers electrons from NADH to E1, which uses these to reduce the delta(3,4)-glucoseen bond to produce CDP-4-keto-3,6 dideoxy-D-glucose. In this work, we have investigated the reductive half-reaction of E3 using both single wavelength and diode array stopped flow absorbance spectroscopy. We find that NADH binds to both oxidized (Kd = 52.5 +/- 2 microM) and two-electron-reduced (Kd = 12.1 +/- 1 microM) forms of E3. Hydride transfer from NADH to the FAD moiety occurs at 107.5 +/- 3 s-1 and exhibits a 10-fold deuterium isotope effect when (4R)-[2H]NADH is substituted for NADH. Following the hydride transfer reaction, NAD+ is released at 42.5 +/- 1 s-1 and electron transfer from the reduced FAD to the [2Fe-2S] center occurs rapidly. The extent of the intramolecular electron transfer reaction is pH-dependent with a pKa of 7.3 +/- 0.1, which may represent the ionization state of the N-1 position of the FAD hydroquinone of E3. Finally, E3 is converted to the three-electron-reduced state in a slow disproportionation reaction that consumes NADH: The [2Fe-2S] center of E3 was selectively disassembled by titration with mersalyl to give E3(apoFeS). The properties of this form of the enzyme are compared to those of the holoenzyme. Similarities and differences of the reductive half-reactions of E3 and related iron-sulfur flavoenzymes are discussed. PMID- 8672476 TI - Caged compounds of hydrolysis-resistant analogues of cAMP and cGMP: synthesis and application to cyclic nucleotide-gated channels. AB - Photolabile compounds which rapidly release cAMP or cGMP after photolysis are widely used for in situ studies of signaling pathways inside cells. We synthesized two novel caged compounds, 4,5-dimethoxy-2-nitrobenzyl 8-Br-cAMP (caged 8-Br-cAMP) and 4,5-dimethoxy-2-nitrobenzyl 8-Br-cGMP caged 8-BR-cGMP), which respectively release the hydrolysis-resistant analogues 8-Br-cAMP and 8-Br cGMP. Their usefulness for physiological studies was examined in a mammalian cell line expressing the cyclic nucleotide-gated (CNG) ion channel of bovine olfactory sensory neurons. The synthesis procedure resulted in diastereomeric mixtures which were chromatographically separated into the axial and equatorial isomers of caged 8-BR-cAMP and of caged 8-BR-cGMP. The axial isomers which have a higher solubility and better solvolytic stability than the equatorial forms were used for experiments with CNG channels. Flashes of UV light produced steps in the concentration of 8-Br-cGMP which activated currents through CNG channels. Concentration steps inside the cell could be calibrated precisely using the relation between the ligand concentration and the normalized current. Similar results were obtained with caged 8-Br-cAMP. Control experiments with caged cGMP showed that flash-induced currents decayed within a few minutes because photoreleased cGMP was degraded by endogenous phosphodiesterase activity. The rise time of the 8-Br-cGMP-activated whole-cell current was consistent with a bimolecular reaction between channel and ligand. PMID- 8672477 TI - Characterization of C415 mutants of neuronal nitric oxide synthase. AB - Nitric oxide synthase (NOS) catalyzes the oxidation of L-arginine to citrulline and nitric oxide. C415H and C415A mutants of the neuronal isoform of NOS (nNOS) were expressed in a baculovirus system and purified to homogeneity for spectral analysis and activity measurements. UV-visible spectra of each mutant lacked an observable Soret peak, suggesting that neither mutant contained heme. When reduced in the presence of CO, however, a small Soret centered at 417 nm could be detected for the C415H mutant, further supporting the assignment of C415 as the axial ligand to the heme. In addition to a deficiency in bound heme, neither mutant had any detectable bound tetrahydrobiopterin, as compared to wild-type enzyme, which had a ratio of 0.84 mol of bound pteridine:1 mol of nNOS 160 kDa subunit. The C415H mutant contained bound FAD and FMN at levels of 1.0 +/- 0.1 and 0.9 +/- 0.1 mol/mol of nNOS subunit, respectively. UV-visible spectra of both nNOS mutants retained the distinctive absorbance due to tightly associated oxidized flavin prosthetic groups. Further, the spectra suggested the presence of a neutral flavin semiquinone. Ferricyanide oxidation of the C415A mutant yielded a spectrum that was essentially that of oxidized flavin. Ferricyanide titration showed that the C415A mutant contained approximately 1 reducing equiv. Circular dichroism spectra suggested that each mutant was folded properly, in that both spectra were found to be essentially identical to the spectrum of wild-type nNOS. Neither mutant could synthesize nitric oxide, and neither mutant had the ability to oxidize NADPH unless an exogenous electron acceptor was added. The rate of cytochrome c reduction by each mutant was found to be slightly less, but very similar to the rate (approximately 20 mumol mg-1 min-1) observed with wild-type nNOS. In all cases, the rate of cytochrome c reduction increased approximately 15 fold with the addition of calmodulin. Overall, these spectral and activity data suggest that C415 is the axial heme ligand and that a point mutation at C415 prevents binding of heme and tetrahydrobiopterin without interfering with the global folding or the reductase function of nNOS. PMID- 8672478 TI - Identification of S-(2,3-dihydroxypropyl)cystein in a macrophage-activating lipopeptide from Mycoplasma fermentans. AB - Mycoplasmas are capable of stimulating monocytes and macrophages to release cytokines, prostaglandins, and nitric oxide. The aim of this study was to characterize the chemical nature of the previously isolated [Muhlradt, P. F., & Frisch, M. (1994) Infect. Immun. 62, 3801-3807] macrophage-stimulating material "MDHM" from Mycoplasma fermentans. Mycoplasmas were delipidated, and MDHM activity was extracted with octyl glucoside and further purified by reversed phase HPLC. Macrophage-stimulating activity was monitored by nitric oxide release from peritoneal macrophages from C3H/HeJ endotoxin low responder mice. HPLC purified MDHM was rechromatographed on an analytic scale RP 18 column before and after proteinase K treatment. Proteinase treatment did not diminish biological activity but shifted MDHM elution toward higher lipophilicity, suggesting that the macrophage-stimulating activity might reside in the lipopeptide moiety of a lipoprotein. Proteinase K-treated MDHM was hydrolyzed, amino groups were dansylated, and the dansylated material was isolated by HPLC. Dansylated S-(2,3 dihydroxypropyl)cystein (glycerylcystein thioether), typical for Braun's murein lipoprotein, and Dns-Gly and Dns-Thr were identified by tandem mass spectrometry. These amino acids were isolated from biologically active but not from the neighboring inactive HPLC fractions. IR spectra from proteinase K-treated, HPLC purified MDHM and those from the synthetic lipopeptide [2,3-bis(palmitoyloxy)-(2 RS)-propyl]-N-palmitoyl-(R)-CysSerSer AsnAla were very similar. The data, taken together, indicate that lipoproteins of a nature previously detected in eubacteria are expressed in M. fermentans and that at least one of these lipoproteins and a lipopeptide derived from it constitute the macrophage activating principle MDHM from these mycoplasmas. PMID- 8672479 TI - Escherichia coli outer membrane phospholipase A: role of two serines in enzymatic activity. AB - In the outer membrane phospholipase A (OMPLA) of Escherichia coli, Ser144 has previously been identified by chemical modification as the active site serine residue. In a specific OMPLA-negative mutant strain, the pldA gene coding for OMPLA was shown to differ from the wild-type gene by a single point mutation, resulting in the substitution of Ser152 by phenylalanine. The role in catalysis of these two serine residues in OMPLA was investigated by site-directed mutagenesis. Ser144 and Ser152 were replaced one at the time by either alanine, valine, phenylalanine, threonine, or cysteine. Ser152 was furthermore replaced by asparagine. Replacement of Ser144 by cysteine resulted in 1% residual activity, whereas the other substitutions at this position yielded virtually inactive enzymes. Substitution of Ser 152 by threonine or asparagine resulted in 40% and 2% residual activity respectively, whereas all other substitutions at this position resulted in the loss of enzymatic activity. We propose that Ser144 is the nucleophile in catalysis, and that Ser152 is involved in hydrogen bonding either to the catalytic triad or in the oxyanion hole. PMID- 8672480 TI - Spectroscopic characterization of intermediate steps involved in donor-side induced photoinhibition of photosystem II. AB - The reaction center protein D1 in photosystem II shows a high turnover during illumination. The degradation of the D1 protein is preceded by photoinhibition of the electron transport in photosystem II. There are two distinct mechanisms for this: acceptor-side- and donor-side-induced photoinhibition. Here, donor-side induced photoinhibition was studied in photosystem II membranes after Cl- depletion or washing with tris(hydroxymethyl)aminomethane (Tris) which destroys water oxidation, reversibly or irreversibly, respectively. Photoinhibition after these treatments leads to fast degradation of the D1 protein, and the mechanism behind this was investigated. Illumination of Cl- depleted photosystem II membranes resulted in a rapid and simultaneous inhibition of Cl(-) reconstitutable oxygen evolution, loss of 2 Mn ions per photosystem II center, increase in the electron transfer between the electron donor diphenylcarbazide and electron acceptor 2,6-dichlorophenolindophenol, and an increase in the EPR signal IIfast from tyrosine-Zox. The destruction of the Mn cluster leads to the loss of oxygen evolution and to an increased accessibility for diphenylcarbazide to donate electrons to Tyr-Zox. The increase in the EPR signal from Tyr-Zox can be explained by slower reduction kinetics of Tyr-Zox due to the Mn release. On a longer photoinhibition time scale, a decrease in the amplitude of Tyr-Zox and inhibition of the electron transport from diphenylcarbazide to 2,6 dichlorophenolindophenol occurred simultaneously in both Cl(-)-depleted and Tris washed photosystem II membranes. These slower photoinhibition reactions were then studied in detail in Tris-washed photosystem II membranes. Compared to photoinhibition of Tyr-Zox, the EPR signal from tyrosine-Dox decreased much slower. Tyr-Dox was photoinhibited in parallel with the EPRsignals from reduced QA, reduced pheophytin, and an oxidized chlorophyll radical (chlorophyllz). This shows that the acceptor side components and the primary charge separation reaction (P680+ pheophytin-) were operational although Tyr-Z was inactivated. The amount of the D1 protein also declined in parallel with Tyr-Dox, which shows that the D1 protein is not damaged until long after the Mn complex and Tyr-Z have become inactivated. Instead, it is likely that the strongly oxidizing P680+ is responsible for the damage to the D1 protein. PMID- 8672481 TI - Pigment quantitation and analysis by HPLC reverse phase chromatography: a characterization of antenna size in oxygen-evolving photosystem II preparations from cyanobacteria and plants. AB - Photosystem II, the photosynthetic water-oxidizing complex, can be isolated from both plants and cyanobacteria. A variety of methods have been developed for purification of this enzyme, which can be isolated in several functional and structural forms. Knowledge of the pigment content of photosystem II preparations is important for precise spectroscopic, biochemical, and functional analysis. We have determined pigment stoichiometries in oxygen-evolving photosystem II preparations from plants and cyanobacteria. We have employed a solvent system for the isocratic elution of a reverse phase HPLC column in which we have determined the extinction coefficients of the relevant pigments. Pigments were extracted from four photosystem II preparations. These preparations included spinach photosystem II membranes [Berthold, D. A., Babcock, G. T., & Yocum, C. F. (1981) FEBS Lett. 134, 231-234], spinach photosystem II reaction center complexes [Ghanotakis, D. F., & Yocum, C. F. (1986) FEBS Lett. 197, 244-248], spinach photosystem II complexes [MacDonald, G. M., & Barry, B. A. (1992) Biochemistry 31, 9848-9856], and photosystem II particles isolated from the cyanobacterium, Synechocystis sp. PCC 6803 [Noren, G. H., Boerner, R. J., & Barry, B. A. (1991) Biochemistry 30, 3943-3950]. Pigment stoichiometries were determined using two different methods of data analysis and were based on the assumption that there are two pheophytin a molecules per photosystem II reaction center. The pigment stoichiometries obtained were comparable for the two methods of data analysis and agreed with previous biophysical and biochemical characterizations of the preparations. The average pigment stoichiometries (chlorophyll:plastoquinone-9 per 2 pheophytin a) determined using the two data analysis methods were as follows: photosystem II membranes, 274:3.2; photosystem II reaction center complexes, 78:2.5; Synechocystis PS II particles, 55:2.4; photosystem II complexes, 121:2.0. PMID- 8672482 TI - Isolation and characterization of soluble electron transfer proteins from Chromatium purpuratum. AB - Several soluble electron transfer proteins were isolated and characterized from the marine purple-sulfur bacterium Chromatium purpuratum. The C. purpuratum flavocytochrome c is similar in molecular mass (68 kDa) and isoelectric point (6.5) to flavocytochromes isolated from other phototrophs. Redox titrations of the flavocytochrome c hemes show two components with midpoint potential values of +15 and -120 mV, behavior similar to that observed with the flavocytochrome isolated from the thermophilic Chromatium tepidum. Moreover, N-terminal amino acid sequence analysis of both the flavin and the cytochrome subunit indicates substantial homology to the primary structure of the flavocytochrome c of Chromatium vinosum. In contrast, the C. purpuratum high-potential iron-sulfur protein (HiPIP) differs from those isolated from other photosynthetic bacteria in its relatively high midpoint potential (+390 mV) and the possibility that it exists as a dimer in solution. Two low molecular mass c-type cytochromes were also characterized. One appears to be a high-potential (+310 mV) c8-type cytochrome. Amino acid sequencing suggests that the second cytochrome may be a homologue of the low-potential cytochrome c-551, previously described in two species of Ectothiorhodospirillaceae. PMID- 8672483 TI - The determinants of pKas in proteins. AB - Although validation studies show that theoretical models for predicting the pKas of ionizable groups in proteins are increasingly accurate, a number of important questions remain: (1) What factors limit the accuracy of current models? (2) How can conformational flexibility of proteins best be accounted for? (3) Will use of solution structures in the calculations, rather than crystal structures, improve the accuracy of the computed pKas? and (4) Why does accurate prediction of protein pKas seem to require that a high dielectric constant be assigned to the protein interior? This paper addresses these and related issues. Among the conclusions are the following: (1) computed pKas averaged over NMR structure sets are more accurate than those based upon single crystal structures; (2) use of atomic parameters optimized to reproduce hydration energies of small molecules improves agreement with experiment when a low protein dielectric constant is assumed; (3) despite use of NMR structures and optimized atomic parameters, pKas computed with a protein dielectric constant of 20 are more accurate than those computed with a low protein dielectric constant; (4) the pKa shifts in ribonuclease A that result from phosphate binding are reproduced reasonably well by calculations; (5) the substantial pKa shifts observed in turkey ovomucoid third domain result largely from interactions among ionized groups; and (6) both experimental data and calculations indicate that proteins tend to lower the pKas of Asp side chains but have little overall effect upon the pKas of other ionizable groups. PMID- 8672484 TI - Active site structure of Rieske-type proteins: electron nuclear double resonance studies of isotopically labeled phthalate dioxygenase from Pseudomonas cepacia and Rieske protein from Rhodobacter capsulatus and molecular modeling studies of a Rieske center. AB - Continuous wave electron nuclear double resonance (CW ENDOR) spectra of [delta 15N,epsilon(-14)N]histidine-labeled phthalate dioxygenase (PDO) from Pseudomonas cepacia were recorded and found to be virtually identical to those previously recorded from [delta,epsilon-15N2]histidine-labeled protein [Gurbiel, R. J., Batie, C. J., Sivaraja, M., True, A. E., Fee, J. A., Hoffman, B. M., & Ballou, D. P. (1989) Biochemistry 28, 4861-4871]. Thus, the two histidine residues, previously shown to ligate one of the irons in the cluster [cf. Gurbiel et al. 1989)], both coordinate the metal at the N(delta) position of their imidazole rings. Pulsed ENDOR studies showed that the "remote", noncoordinating nitrogen of the histidine imidazole ring could be observed from the Rieske protein in a sample of Rhodobacter capsulatus cytochrome bc1 complex uniformly labeled with 15N but not in a sample of PDO labeled with [delta-15N,epsilon-14N]histidine, but this atom was easily observed with a sample of Rh. capsulatus cytochrome bc1 complex that had been uniformly labeled with 15N; this confirmed the conclusion from the CW ENDOR studies that ligation is exclusively via N(delta) for both ligands in the PDO center. Modifications in the algorithms previously used to simulate 14N ENDOR spectra permitted us to compute spectra without any constraints on the relative orientation of hyperfine and quadrupole tensors. This new algorithm was used to analyze current and previously published spectra, and slightly different values for the N-Fe-N angle and imidazole ring rotation angles are presented [cf. Gurbiel et al. (1989) Gurbiel, R. J., Ohnishi, T., Robertson, D. E., Daldal, F., and Hoffman, B. M. (1991) Biochemistry 30, 11579-11584]. This analysis has permitted us to refine the proposed structure of the [2Fe-2S] Rieske type cluster and rationalize some of the properties of these novel centers. Although the spectra of cytochrome bc1 complex from Rh. capsulatus are of somewhat lower resolution than those obtained with samples of PDO, our analysis nevertheless permits the conclusion that the geometry of the cluster is essentially the same for all Rieske and Rieske-type proteins. Structural constraints inferred from the spectroscopic results permitted us to apply the principles of distance geometry to arrive at possible three-dimensional models of the active site structure of Rieske protein from Rh. capsulatus. Results from this test case indicate that similar procedures should be generally useful in metalloprotein systems. We also recorded the pulsed and CW ENDOR spectra of 57Fe labeled PDO, and the resulting data were used to derive the full hyperfine tensors for both Fe(III) and Fe(II) ions, including their orientations relative to the g tensor. The A tensor of the ferric ion is nominally isotropic, while the A tensor of the ferrous ion is axial, having A(parallel) > A(perpendicular); both tensors are coincident with the observed g tensor, with A(parallel) of the ferrous ion lying along the maximum g-value, g1. These results were examined using refinements of existing theories of spin-coupling in [2Fe-2S]+ clusters, and it is concluded that current theories are not adequate to fully describe the experimental results. PMID- 8672485 TI - Two-stage nucleotide binding mechanism and its implications to H+ transport inhibition of the uncoupling protein from brown adipose tissue mitochondria. AB - The uncoupling protein (UCP) from brown adipose tissue mitochondria is the simplest H+ translocator known. H+ transport is regulated by fatty acids as activators and by pruine nucleotides as inhibitors. Nucleotide binding again is strongly influenced by the pH [Klingenberg, M. (1988) Biochemistry 27, 781-791]. Previously, by using fluorescent 2'-O-dansyl (DANS) derivatives of purine nucleotides, a two-stage binding mechanism was unraveled with a slow transition from a loose into a tight conformational state in the isolated UCP [Huang, S.-G., & Klingenberg, M. (1995) Biochemistry 34, 349-360]. Whereas with the unsubstituted nucleotides the transition to the tight state is nearly complete, various DANS and DAN (dimethylaminonaphthoyl) nucleotides bind more to the loose state. Here we investigated the relationships between the two-stage nucleotide binding and the inhibition of the H+ transport activity in reconstituted proteoliposomes. Further, limited tryptic digestion was used as an indicator of conformational change induced by the nucleotide binding in the isolated protein. The inhibition of H+ transport activity in reconstituted UCP proteoliposomes correlated only with the fraction of tight state of nucleotide binding. Unsubstituted nucleotides (ATP, GTP, and ADP) as well as DANSGTP inhibit fully the H+ transport, whereas DANSATP and DANSADP inhibit only to about 50%, and DANSAMP is nearly ineffective. Even for the loose conformational state the nucleotide derivatives exhibit considerable affinity. This allows DANSAMP to replace prebound ATP from UCP and relieve the inhibition of H+ transport by reversing the distribution of UCP from the tight into the loose conformational state. The pH dependence of the fraction of nucleotide binding in the tight state correlates closely with the pH dependence of the degree of H+ transport inhibition. Titration with DANS nucleotides of UCP incorporated into phospholipid vesicles revealed that over 70% of binding sites had an affinity comparable with that for the isolated UCP while the remaining sites displayed substantially lower affinity, due to nonhomogeneity of the reconstituted system. The sensitivity against trypsin digestion is inversely correlated with the fraction of nucleotide binding in the tight state. Whereas unsubstituted nucleotides and DANSGTP protect strongly against trypsinolysis, DANSATP and DANSADP do only partially, and DANSAMP does not at all. The counteracting influences of the DANS substitution are shown with DANSAMP, which has an affinity comparable to that of DANSATP or DANSADP but cannot form the tight inhibited complex. These data show that nucleotide binding only in the tight state is associated with a strong conformational change, which further causes an inhibition of H+ transport. In conclusion, UCP can exist in a loose noninhibited and a tight inhibited conformational state. The equilibrium between these two conformations is shifted to the tight state with unsubstituted nucleotides but remains to variable degrees in the loose state with DANS and DAN derivatives. The DANS group hinders progressively the transition to the tight state as the binding affinity of the underlying nucleotide decreases. PMID- 8672486 TI - Mechanism of carbon dioxide-catalyzed oxidation of tyrosine by peroxynitrite. AB - Peroxynitrite ion (ONO2-) reacted rapidly with CO2 to form a short-lived intermediate provisionally identified as the ONO2CO2- adduct. This adduct was more reactive in tyrosine oxidation than ONO2- itself and produced 3 nitrotyrosine and 3,3'-dityrosine as the major oxidation products. With tyrosine in excess, the rate of 3-nitrotyrosine formation was independent of the tyrosine concentration and was determined by the rate of formation of the ONO2CO2- adduct. The overall yield of oxidation products was also independent of the concentration of tyrosine and medium acidity; approximately 19% of the added ONO2- was converted to products under all reaction conditions. However, the 3 nitrotyrosine/3,3'-dityrosine product ratio depended upon the pH, tyrosine concentration, and absolute reaction rate. These data are in quantitative agreement with a reaction mechanism in which the one-electron oxidation of tyrosine by ONO2CO2- generates tyrosyl and NO2 radicals as intermediary species, but are inconsistent with mechanisms that invoke direct electrophilic attack on the tyrosine aromatic ring by the adduct. Based upon its reactivity characteristics, ONO2CO2- has a lifetime shorter than 3 ms and a redox potential in excess of 1 V, and oxidizes tyrosine with a bimolecular rate constant greater than 2 x 10(5) M-1 s-1. In comparison, in CO2-free solutions, oxidation of tyrosine by peroxynitrite was much slower and gave significantly lower yields (approximately 8%) of the same products. When tyrosine was the limiting reactant, 3,5-dinitrotyrosine was found among the reaction products of the CO2-catalyzed reaction, but this compound was not detected in the uncatalyzed reaction. PMID- 8672487 TI - Probing the functional role of two conserved active site aspartates in mouse adenosine deaminase. AB - Two adjacent aspartates, Asp 295 and Asp 296, playing major roles in the reaction catalyzed by mouse adenosine deaminase (mADA) were altered using site-directed mutagenesis. These mutants were expressed and purified from an ADA-deficient bacterial strain and characterized. Circular dichroism spectroscopy shows the mutants to have unperturbed secondary structure. Their zinc content compares well to that of wild-type enzyme. Changing Asp 295 to a glutamate decreases the kcat but does not alter the Km for adenosine, confirming the importance of this residue in the catalytic process and its minimal role in substrate binding. The crystal structure of the D295E mutant reveals a displacement of the catalytic water from the active site due to the longer glutamate side chain, resulting in the mutant's inability to turn over the substrate. In contrast, Asp 296 mutants exhibit markedly increased Km values, establishing this residue's critical role in substrate binding. The Asp 296->Ala mutation causes a 70-fold increase in the Km for adenosine and retains 0.001% of the wild-type kcat/Km value, whereas the ASP 296->Asn mutant has a 10-fold higher Km and retains 1% of the wild-type kcat/Km value. The structure of the D296A mutant shows that the impaired binding of substrate is caused by the loss of a single hydrogen bond between a carboxylate oxygen and N7 of the purine ring. These results and others discussed below are in agreement with the postulated role of the adjacent aspartates in the catalytic mechanism for mADA. PMID- 8672488 TI - Expression and gene disruption analysis of the isocitrate dehydrogenase family in yeast. AB - Mammalian and yeast cells contain three isozymes of isocitrate dehydrogenase: mitochondrial NAD- and NADP-specific enzymes and a cytosolic NADP-specific enzyme. Independent metabolic functions of these enzymes in Saccharomyces cerevisiae were examined by analyses of expression and of phenotypes displayed by mutants containing all possible combinations of isozyme gene disruptions. All three isocitrate dehydrogenases are expressed at high levels with growth on nonfermentable carbon sources, whereas the mitochondrial NADP-specific enzyme constitutes the major cellular activity with growth on glucose. Distinct growth phenotypes are observed for mutants expressing a single isozyme, and expression of at least one isozyme is necessary for glutamate-independent growth. The NADP specific tricarboxylic acid cycle isocitrate dehydrogenase from Escherichia coli was expressed in mitochondrial and cytosolic compartments of the yeast disruption mutants using plasmids carrying gene fusions of yeast promoters and a mitochondrial targeting presequence with the bacterial coding sequence. The bacterial enzyme is competent for restoration of NADP-specific functions in either compartment but does not compensate for function of the yeast NAD-specific tricarboxylic acid cycle enzyme. PMID- 8672489 TI - Studies of the redox properties of CDP-6-deoxy-L-threo-D-glycero-4-hexulose-3 dehydrase (E1) and CDP-6-deoxy-L-threo-D-glycero-4-hexulose-3-dehydrase reductase (E3): two important enzymes involved in the biosynthesis of ascarylose. AB - Studies of the biosynthesis of ascarylose, a 3,6-dideoxyhexose found in the lipopolysaccharide of Yersinia pseudotuberculosis V, have shown that the C-3 deoxygenation is a process consisting of two enzymatic steps. The first enzyme involved in this transformation is CDP-6-deoxy-L-threo-D-glycero-4-hexulose-3 dehydrase (E1), which is a pyridoxamine 5'-phosphate dependent iron-sulfur protein. The second catalyst, CDP-6-deoxy-L-threo-D-glycero-4-hexulose-3 dehydrase reductase, formally called CDP-6-deoxy-delta(3,4)-glucoseen reductase (E3), is an NADH dependent plant type [2Fe-2S] containing flavoenzyme. To better understand the electron transfer carried out by these two enzymes, the potentials of the E1 and E3 redox cofactors were determined spectroelectrochemically. At pH 7.5, the midpoint potential of the E3 FAD was found to be -212 mV, with the FADox/FADsq couple (E1o') and the FADsq/FADhq couple (E2o') calculated to be -231 and -192 mV, respectively. However, the E1o' and E2o' of the FAD in E3(apoFeS) at pH 7.5 were estimated to be -215 and -240 mV, respectively, which are quite different from those of the holo-E3, suggesting a significant effect of the iron sulfur center on the redox properties of the flavin coenzyme. Our data also showed that the midpoint potential of the E3 iron-sulfur is -257 mV and that of the E1 [2Fe-2S] center is -209 mV. These values indicated a thermodynamic barrier to the proposed electron transfer of NADH->FAD=>E3[2Fe-2S]->E1[2Fe-2S] at pH 7.5. Regulation of electron transfer by several mechanisms is possible and experiments were performed to examine ways of overcoming the unfavorable electron transfer energetics in the E1/E3 system. It was found that both binding of E3 with NAD+ and complex formation between E3 and E1 showed no effect on the midpoint potentials of the E3 FAD and iron-sulfur center. Interestingly, the midpoint potential of the E3 FAD shifts dramatically to -273 mV (E1o' approximately -345 mV and E2o' approximately -200 mV) at pH 8.4, with very little semiquinone stabilization (< 5%). The potential of the E3 [2Fe-2S] center at pH 8.4 was also found to undergo a negative shift to -279 mV, and that of the E1 iron sulfur center remained essentially the same at -206 mV. These data indicated that the redox properties of this system may be regulated by pH and the electron transfer between the E3 redox centers may be prototropically controlled. These results also demonstrated that E3 is unique among this class of enzymes. PMID- 8672490 TI - Mutation of the conserved domains of two inositol polyphosphate 5-phosphatases. AB - Two short amino acid motifs, WXGDXNXR and PXWCDRXL, define a large family of inositol polyphosphate 5-phosphatases. We tested the importance of seven of these conserved amino acids to substrate binding and catalysis by mutating each to alanine in the platelet 75 kDa inositol polyphosphate 5-phosphatase II (5 phosphatase II). Native and mutant forms of 5-phosphatase II were expressed in baculovirus-infected Sf9 cells, and the recombinant proteins were purified by Mono Q chromatography and studied for enzyme activity. Mutants D476A, N478A, D553A, and R554A had no detectable activity using all four known substrates for this enzyme. Mutants R480A, W551A, and I555A showed greatly reduced hydrolysis of Ins(1,4,5)P3 when compared to native enzyme [Km = 75 microM, Vm = 8300 nmol of Ins(1,4,5)P3 hydrolyzed min-1 (mg of protein)-1]. Mutants W551A and I555A had a Km for Ins(1,4,5)P3 hydrolysis similar to that of the native enzyme (35 microM and 81 microM, respectively), suggesting that these amino acids do not play a role in binding substrate. By contrast, mutant R480A had both increased Km (634 microM) and decreased Vm [855 nmol of Ins(1,4,5)P3 hydrolyzed min-1 (mg of protein)-1]. As judged by measurement of Km, mutant R480A retained normal binding of Ins(1,3,4,5)P4, suggesting that the arginine in motif 2 has a greater role in Ins(1,4,5)P3 binding than in Ins(1,3,4,5)P4 binding. Mutant I555A bound Ins(1,3,4,5)P4 with 8-fold reduced affinity. These mutations markedly reduced 5 phosphatase II hydrolysis of the three other substrates, Ins(1,3,4,5)P4, PtdIns(4,5)P2, and PtdIns(3,4,5)P3. We also tested a mutation comparable to D553A, D460A, in the 110 kDa form of the signaling inositol polyphosphate 5 phosphatase (5SIP110). 5SIP110 D460A had no detectable enzyme activity but retained the ability to bind GRB2. These results are consistent with a role for these conserved amino acids in substrate binding and catalysis. PMID- 8672491 TI - Rabbit muscle creatine kinase: consequences of the mutagenesis of conserved histidine residues. AB - Creatine kinase (CK; EC 2.7.3.2) catalyzes the reversible conversion of creatine and MgATP to phosphocreatine and MgADP. In the absence of an X-ray crystal structure, we have used the sequence homology of creatine kinases and other guanidino kinases from a variety of sources to identify the conserved histidine residues in rabbit muscle CK, as well as to try to pinpoint a reactive histidine that has been implicated in the active site. This residue has been proposed to act as a general acid/base catalyst assisting in the phosphoryl transfer mechanism [Cook et al. (1981) Biochemistry 20, 1204-1210]. There are 17 histidine residues in rabbit muscle CK, and of these, only five have been conserved in all guanidino kinase sequences published to date [Muhlebach et al. (1994) Mol. Cell. Biochem. 133, 245-62]. In rabbit muscle CK, these residues are H96, H105, H190, H233, and H295. We have carried out site-specific mutagenesis of these five histidine residues, replacing each with an asparagine. Each of these mutants exhibited enzymatic activity but to varying degrees. The H105N, H190N, and H233N mutants displayed specific activities similar to that of the wild-type enzyme. H96N has high activity, but appears to be quite unstable, losing catalytic activity upon cell lysis by sonication and/or chromatographic steps involved in purification. H295N shows a significantly reduced catalytic activity relative to the native enzyme, due to marked decreases in kcat and the affinities for both substrates. Each of the five mutants is inactivated by diethyl pyrocarbonate (DEP), and inactivation is reversible upon incubation with hydroxylamine. However, only H295N shows a dramatically reduced rate of inactivation relative to native CK, consistent with H295 being the residue modified by DEP in the native enzyme. These intriguing results indicate that four of the conserved histidines (H96, H105, H295, and H233) are not essential for activity, and while H295 may be at the active site of CK, it is unlikely to play the role of a general acid/base catalyst. PMID- 8672492 TI - Accumulation of unsaturated acylcarnitine molecular species during acute myocardial ischemia: metabolic compartmentalization of products of fatty acyl chain elongation in the acylcarnitine pool. AB - Long-chain acylcarnitines accumulate during myocardial ischemia and contribute to membrane dysfunction in ischemic zones. On the basis of the 3-fold selectivity for saturated fatty acid accumulation during myocardial ischemia, it was implicitly assumed that saturated long chain acylcarnitine molecular species predominantly accumulated in ischemic myocardium. By exploiting the analytical power of electrospray ionization mass spectroscopy, we now report that unsaturated acylcarnitines are the predominant molecular species of acylcarnitine which accumulate during myocardial ischemia (rank order: octadecadienoyl carnitine > octadecanoyl carnitine > hexadecanoyl carnitine > octadecanoyl carnitine). The aliphatic chain distribution of myocardial acylcarnitine molecular species identified by electrospray ionization mass spectroscopy was independently substantiated by sequential HPLC purification and capillary gas chromatography. Detailed analysis of the individual molecular species of long chain acylcarnitine demonstrated that fatty acyl chain elongation was prominent in ischemic myocardium (e.g., following 20 min of ischemia, greater than 15% of the accumulated acylcarnitines consisted of 20-carbon unsaturated molecular species). Chain-elongated lipids were essentially confined to the long chain acylcarnitine pool since [9,10-3H]octadec-9'-enoic acid was converted to [3H]eicosenoyl carnitine (12% of the radiolabeled acylcarnitine pool) in ischemic hearts without substantive amounts of [3H]eicosenoyl residues in the fatty acid, triglyceride, and phospholipid pools. Collectively, these results demonstrate the preponderance of unsaturated acylcarnitines in ischemic myocardium and document the metabolic compartmentation of downstream products of fatty acyl chain elongation in the acylcarnitine pool during ischemia. PMID- 8672493 TI - Two novel alpha-neurotoxins isolated from the taipan snake, Oxyuranus scutellatus, exhibit reduced affinity for nicotinic acetylcholine receptors in brain and skeletal muscle. AB - Three novel toxic peptides were purified to homogeneity from the venom of the Australian taipan snake, Oxyuranus scutellatus scutellatus. On the basis of complete amino acid sequence analyses, two of these toxins belong to the family of short-chain alpha-neurotoxins found in elapid and hydrophid snake venoms and are the first postsynaptic neurotoxins identified in taipan venom. Radioligand binding studies confirm that taipan toxins 1 and 2 inhibit the binding of [125I] alpha-bungarotoxin to nicotinic acetylcholine receptors in skeletal muscle with IC50 values of 2.4-2.5 nM but are 5-fold less potent in this assay than alpha bungarotoxin or the two short-chain alpha-neurotoxins erabutoxin a and erabutoxin b. Taipan toxins 1 and 2 do not antagonize [125I]-alpha-bungarotoxin binding to central neuronal nicotinic receptors at concentrations up to 3 microM. We find that erabutoxin a and erabutoxin b do inhibit the binding of [125I]-alpha bungarotoxin to central neuronal nicotinic receptors but are over 350-fold less potent than long-chain alpha-neurotoxins at these receptors. The novel alpha neurotoxins from taipan venom do not inhibit the binding of [3H]nicotine to high affinity nicotine receptors in brain, a property they share with alpha bungarotoxin and the erabutoxins. The results demonstrate that at least two neuromuscular junction-blocking peptides are present in taipan venom. Nonconservative substitutions at position 32 in both taipan toxin 1 and 2 may be responsible for the observed decreases in affinities of the toxins of 5-fold for muscle receptors (compared to alpha-bungarotoxin) and over 10-fold for alpha bungarotoxin-sensitive nicotinic receptors in brain (compared to the structurally similar short-chain alpha-neurotoxins erabutoxin a and erabutoxin b). PMID- 8672494 TI - Photolabile derivatives of 125I-apamin: defining the structural criteria required for labeling high and low molecular mass polypeptides associated with small conductance Ca(2+)-activated K+ channels. AB - The structure of apamin-sensitive Ca(2+)-activated K+ channels has been investigated using high-affinity, photolabile azidoaryl derivatives of 125I [alpha-formyl-Cys1]apamin and 125I-[epsilon-formyl-Lys4]-apamin. Labeling patterns suggest that similar structural constraints are required for labeling analogous polypeptides associated with distinct channel subtypes. When photoprobes are coupled at the epsilon-amino-Lys4 position of apamin, comparable low molecular mass (approximately 30 kDa) polypeptides are efficiently labeled on either brain or liver plasma membranes, irrespective of the structure of the photoprobe. However, when photoprobes are coupled at the alpha-amino-Cys1 position of apamin, the pattern of labeling on both brain and liver plasma membranes varies, depending upon the length of the spacer arm incorporated into the photoprobe. Spacer arms of approximately 8-9 A efficiently label only high molecular mass polypeptides (86, 59 kDa), accompanied by weak, variable labeling of a 44-kDa component. A shorter spacer arm (5.7 A) results in feeble labeling of 86- and 59-kDa polypeptides and barely detectable labeling of 44- and approximately 30-kDa polypeptides. In contrast, a long spacer arm (12.8 A) efficiently labels only approximately 30-kDa polypeptides. These findings point to close similarities in the topography of the 125I-apamin binding site present on pharmacologically distinct subtypes of apamin-sensitive Ca2+-activated K+ channels and indicates that heterooligomeric association of high and low molecular mass polypeptide subunits may be a general structural feature of members belonging to this family of K+ channels. PMID- 8672495 TI - Follitropin conformational stability mediated by loop 2 beta effects follitropin receptor interaction. AB - Follicle-stimulating hormone (FSH) is in the family of pituitary/placental glycoprotein hormones which also includes luteinizing hormone (LH), chorionic gonadotropin (hCG), and thyroid-stimulating hormone. These hormones are heterodimers composed of common alpha- and similar but unique beta-subunits. The 21 amino acid loop between Y33 and F53 of the FSH beta-subunit (L2 beta) can be switched into L2 beta of hCG beta without a loss of receptor binding, yet mutation of hFSH beta 37LVY39 to 37AAA39 was antecendent to a 20-fold reduction in receptor binding (based on ID50). A mutation in the LH beta gene, which causes Q54 to be R, causes hypogonadism. This residue is conserved in the glycoprotein hormones and corresponds to Q48 in hFSH beta. Mutation of hFSH beta 48QKTCT52 to 48AAACA52 resulted in a failure of heterodimer formation. In the current study single mutations were made to pinpoint which of the seven hFSH beta residues in the 37LVY39 to 37AAA39 and the 48QKTCT52 to 48AAACA52 mutants were responsible for the observed phenotypes. A single mutation of T52 to alanine was sufficient to cause a reduction in expression of heterodimeric hormone. Single mutants Q48A, T50A, V38A, Y39A, and, to a lesser extent, T52A formed heterodimer. However, these hFSH mutants were markedly unstable at pH 2.0. Thus, acid dissociation can be used to reveal metastable forms of this protein. Mutant hFSH beta Q48A was also 8-fold less active than wild-type hFSH when assayed for binding to hFSH receptors. hFSH beta V38A and Y39A mutants affected receptor binding; however, neither mutation alone caused greater than a 2-fold decrease in receptor binding activity. In summary, these results identify single important residues in the long loop (between Y33 and F53) of the hFSH beta-subunit which are required for proper subunit interactions that provide conformational stability which in turn is necessary for FSH-receptor interaction. PMID- 8672497 TI - Expression and functional characterization of isoforms 4 of the plasma membrane calcium pump. AB - PMCA isoforms 4CII (generated by splicing at the C-terminus) and 4BICI (a pump version lacking the 10th transmembrane domain) were expressed in Sf9 cells using the baculovirus system. The purified PMCA4CII had a 20-fold lower affinity for calmodulin than the PMCA4CI, the PMCA4 isoform of the erythrocytes' membranes, but had a higher activity in the absence of calmodulin. The amount of phosphoenzyme intermediate formed by PMCA4CII in the presence of Ca2+ alone was almost 3 times higher than in PMCA4CI and was increased by La3+ less than in the PMCA4CI. The isoform lacking the 10th transmembrane domain (PMCA4BICI) had no Ca2+-dependent ATPase activity, but was still able to form the phosphoenzyme intermediate starting from phosphate. When expressed in COS cells, this isoform was retained in the endoplasmic reticulum; changes in membrane architecture apparently occurred during its expression; the C-terminal portion of the isoform was located in the cytosol, indicating that the deletion of the 10th transmembrane domain resulted in the loss of at least another transmembrane domain. PMID- 8672496 TI - Effects of submicellar bile salt concentrations on biological membrane permeability to low molecular weight non-ionic solutes. AB - Bile salts have been hypothesized to mediate cytotoxicity by increasing membrane permeability to aqueous solutes. We examined whether submicellar bile salt concentrations affect model and native membrane permeability to small uncharged molecules such as water, urea, and ammonia. Osmotic water permeability (Pf) and urea permeability were measured in large unilamellar vesicles composed with egg yolk phosphatidylcholine (EYPC) +/- cholesterol (Ch) or rat liver microsomal membranes by monitoring self-quenching of entrapped carboxyfluorescein (CF). Ammonia permeability was determined utilizing the pH dependence of CF fluorescence. Submicellar bile salt concentrations did not significantly alter Pf of EYPC +/- Ch or rat liver microsomal membranes. At taurodeoxycholate (TDC) or tauroursodeoxycholate concentrations approaching those that solubilized membrane lipids, CF leakage occurred from vesicles, but Pf remained unchanged. Higher bile salt concentrations (0.5-2 mM TDC) did not alter Pf of equimolar EYPC/Ch membranes. The activation energy for transmembrane water flux was unchanged (12.1 +/- 1.2 kcal/mol for EYPC) despite the presence of bile salts in one or both membrane hemileaflets, suggesting strongly that bile salts do not form transmembrane pores that facilitate water flux. Furthermore, submicellar bile salt concentrations did not increase membrane permeability to urea or ammonia. We conclude that at submicellar concentrations, bile salts do not form nonselective convective channels that facilitate transmembrane transport of small uncharged molecules. These results suggest that bile salt-mediated transport of specific substrates, rather than nonselective enhancement of membrane permeability, underlies bile salt cytotoxicity for enterocytes and hepatocytes. PMID- 8672498 TI - Preferential binding of the archaebacterial histone-like MC1 protein to negatively supercoiled DNA minicircles. AB - The interaction of the archaebacterial MC1 protein with 207 bp negatively supercoiled DNA minicircles has been examined by gel retardation assays and compared to that observed with the relaxed DNA minicircle. MC1 binding induces a drastic DNA conformational change of each minicircle, leading to an increase of the electrophoretic mobility of the DNA. A slight increase in salt concentration enhances the amount of bound MC1, and high NaCl concentrations are required to dissociate the complexes. Furthermore, the salt effect on binding depends on the supercoiling state of the DNA. The dissociation rates decrease with increasing linking difference of the minicircles relative to their relaxed configuration to reach a maximum at -2 turns. In addition, differences between the topoisomers are also observed in terms of stoichiometry of the strongest complexes. So with the 2 topoisomer the complex with two MC1 molecules is the most stable, while with the -1 and -3 topoisomers, the strongest ones are those with one MC1 molecule per DNA ring. PMID- 8672499 TI - Conformational flexibility of three-way DNA junctions containing unpaired nucleotides. AB - Time-resolved fluorescence resonance energy transfer has been used to examine the global structure and conformational flexibility of three-way DNA junctions containing unpaired bases at the branch point. Three-way junctions were prepared with donor (fluorescein) and acceptor (tetramethyl-rhodamine) dyes attached to the ends of different helical arms in various pairwise combinations. The time resolved fluorescence decay of the donor in each labeled junction was measured by time-correlated single photon counting. The distributions of donor-acceptor (D-A) distances present between each pair of labeled helices were recovered from analysis of the donor decay profiles using a Gaussian distribution model. The recovered D-A distance distributions reveal the mean distance between each pair of helices, as well as the range of distances that exists between each pair. For the junction lacking unpaired bases, the three mean interarm distances are similar, indicating an extended structure. In addition, a relatively broad range of distances is present between each pair of helices, showing that the structure is flexible. The addition of unpaired bases causes the junction to fold into a different structure, with one interarm distance being shorter than the other two. The change in overall geometry of the junction appears to be primarily due to the repositioning of one of the helices flanking the bulge. In bulged junctions containing unpaired thymine, cytosine, or adenine bases, the helix containing the 3' portion of the bulged strand appears to undergo the greatest change in its mean position relative to the other helices. In contrast, in the bulged junction containing unpaired guanine bases, the helix containing the 5' portion of the bulged strand is displaced. In all bulged junctions, there is a wide range of distances between the perturbed helix and the other two helices, indicating high mobility for the perturbed arm. These results indicate that the overall structure and conformational flexibility of three-way DNA junctions are sensitive to the presence of unpaired bases at the branch point of the junction and that the precise effect of a bulge depends on the nature of the unpaired bases. PMID- 8672500 TI - An unnatural folate stereoisomer is catalytically competent in DNA photolyase. AB - The folate chromophore in native Escherichia coli DNA photolyase ([6R]-5,10-CH+ H4Pte(Glu)n=3-6) serves as an antenna, transferring light energy to the fully reduced flavin (FADH2) reaction center at high efficiency (EET = 0.92). Apophotolyase reconstituted after an overnight incubation with [6R,S]-5,10-CH+ H4folate (a monoglutamate analogue of the native cofactor) contains equimolar amounts of the [6R]- and [6S]-isomers, suggesting similar binding affinities. A rapid, biphasic increase in fluorescence (approximately 100-fold) is observed upon binding of 5,10-CH+-H4folate to apophotolyase at 5 degrees C; the [6S] isomer binds about 25-fold faster than the [6R]-isomer. Although identical absorption and fluorescence emission maxima are observed for enzyme reconstituted with [6S]-, [6R]-, or [6R,S]-5,10-CH+-H4folate, folate fluorescence quantum yield values vary depending on the stereochemical configuration at the 6 position (theta = 0.18, 0.82, or 0.46, respectively, at 5 degrees C), a feature not seen with free folate. The fluorescence of enzyme-bound folate is quenched upon flavin binding; the efficiency of quenching by flavin radical (EQ = 0.96) or FADH2 (EQ = 0.89) is the same for both folate isomers. In contrast, energy transfer from folate to FADH2 is sensitive to the stereochemical configuration at the 6 position. The efficiency of energy transfer observed for enzyme containing FADH2 and [6S]-, [6R]-, or [6R,S]-5,10-CH+-H4folate (theta = 0.26, 0.66, or 0.44, respectively) is directly proportional to the fluorescence quantum yield observed for folate in the absence of FADH2, as expected for Forster-type energy transfer. Although less efficient, the unnatural [6S]-isomer is catalytically functional, a feature not previously observed with other folate-dependent enzymes. Fluorescence quantum yield studies at 77 K with free (theta = 0.67) and enzyme-bound (theta = 1.0) folate suggest that differences in solvent exposure may contribute to the fluorescence efficiency differences observed with the enzyme-bound folate isomers at 5 degrees C. PMID- 8672501 TI - Enzymatic and chemical footprinting of anthracycline antitumor antibiotics and related saccharide side chains. AB - DNase I and three DNA chemical footprinting agents were used to compare the DNA binding properties of the anthracycline antitumor antibiotics daunomycin, aclacinomycin A, and ditrisarubicin B. These anthracyclines contain a tetracyclic chromophore which intercalates into DNA and a monosaccharide, trisaccharide, and two trisaccharide side chains, respectively. These side chains consist of between one and three 2,6-dideoxy, 1,4-diaxially linked sugars. Three chemical probes, fotemustine, dimethyl sulfate, 4-(2'-bromoethyl)phenol, and the enzymic probe DNase I were used in the footprinting experiments. The chemical probes provided a clear picture of the binding pattern at 37 degrees C and more detailed information than that obtained using the standard DNase I footprinting assay. All three anthracyclines showed preferred binding to 5'-GT-3' sequences in both the chemical and enzymatic footprinting. DNase I footprinting showed that the number of base pairs of DNA protected from cleavage increased with the number of saccharide groups present at particular sites and is consistent with DNA binding of the saccharide side chains. Alkylation of runs of guanine by fotemustine was inhibited by all three anthracyclines, while alkylation by dimethyl sulfate was enhanced for most guanines. The probe 4-(2'-bromoethyl)phenol showed that all three anthracyclines completely protected all of the adenines in the minor groove from alkylation, and enhanced major groove guanine alkylation was observed with aclacinomycin A, daunomycin, and, to a much lesser extent, ditrisarubicin B. These results are consistent with intercalation of the aglycone ring and binding of the rigid, hydrophobic saccharide side chains in the minor groove. Footprinting of four methyl glycosides related to the anthracyclines showed no evidence of DNA binding with any of the agents studied. PMID- 8672502 TI - Fluorescence studies on the molecular action of amphotericin B on susceptible and resistant fungal cells. AB - The molecular action of amphotericin B (AmB) on the cell membranes of both AmB susceptible and AmB-resistant fungal cells was investigated through the use of the fluorescent membrane probe trimethylammonium diphenylhexatriene (TMA-DPH). AmB, the most effective drug for the treatment of systemic fungal infections, is known to interact specifically with membrane sterols, especially ergosterol (the major sterol in fungal cells). Treatment of AmB-susceptible Candida albicans and Cryptococcus neoformans cells with AmB induced a novel biphasic change in TMA-DPH fluorescence intensity over time. The initial decrease in fluorescence intensity results from energy transfer between AmB and TMA-DPH when AmB binds to the fungal cell membrane. The second phase of increasing fluorescence intensity is interpreted in terms of a combination of probe repartitioning and probe segregation as a result of the formation of membrane pores via the aggregation of AmB-ergosterol complexes. An AmB-resistant strain of C. neoformans, containing 94% of aberrant delta-8 double-bonded ergosterol precursors and only 4% of ergosterol (74% ergosterol in wild-type cells), exhibited the first phase of AmB binding but not the second phase of increasing fluorescence intensity. This result suggests that AmB's antifungal activity lies in its ability to form membrane pores due to aggregation of AmB-ergosterol complexes. The AmB-Induced biphasic fluorescence intensity profile may lead to further elucidation of the molecular action of AmB on fungal cells and may provide a sensitive method for screening the development of drug resistance in fungal cells. PMID- 8672503 TI - A model for the T-antigen-induced structural alteration of the SV40 replication origin based upon experiments with specific probes for bent, straight, and unwound DNA. AB - The T-antigen-induced structural changes of the SV40 replication origin were probed with three DNA-reactive antitumor agents: (+)-CC-1065, bizelesin, and pluramycin. (+)-CC-1065 is an N3 adenine minor groove alkylating agent that selectively reacts with AT-rich DNA sequences with a bent conformation; bizelesin also reacts with the minor groove of AT-rich sequences but is selective for a conformation; bizelesin also reacts with the minor groove of AT-rich sequences but is selective for a straight DNA conformation. Pluramycin is an intercalative guanine alkylator whose reactivity is increased by unwinding and decreased by compression of the minor and/or major grooves of DNA. We show that while binding of T-antigen reduced the ability of (+)-CC-1065 to alkylate the AT tract in the SV40 replication origin, it did not interfere with bizelesin modification of the same sequence. These unexpected results suggest that when T-antigen binds to the SV40 origin the AT tract is in a straight DNA conformation. High-resolution DNase I footprinting experiments indicate that at least three helically in-phase T antigen binding sites exist in the GC box region located immediately downstream of the AT tract. The binding of T-antigen enhances the reactivity of (+)-CC-1065 to the two 5'-AGTTA(asterisk) (the asterisk indicates the covalent bonding site) drug modification sites in the GC box region, demonstrating that these sites are in a bent conformation. In contrast, T-antigen inhibited the reactivity of pluramycin at sequences within the GC box region that are known not to bind T antigen. These data, in combination with the DNase I footprinting results, suggest that T-antigen binding induces a conformational change in the DNA that no longer favors pluramycin intercalation. Based on our results, we propose that T antigen binds tightly to the upstream region of the AT tract of SV40 replication origin forming double hexamers. In the downstream region, binding of T-antigen to the helically in-phase sites in the GC box region induces DNA bending in the opposite direction of the natural AT tract bending, while simultaneously transforming the naturally bent AT tract DNA into a straight conformation. PMID- 8672504 TI - Kinetics of G-quartet-mediated tetramer formation. AB - The phosphorothioate and phosphodiester oligodeoxynucleotides d(TTGGGGTT) form parallel-stranded tetramer structures stabilized by guanosine quartets. The phosphorothioate tetramer has been shown to inhibit human immunodeficiency virus (HIV) in vitro. The kinetics of association and dissociation of both tetramers have been determined as a function of temperature using size exclusion chromatography to measure the ratio of single strand to tetramer. In phosphate buffered saline (pH 7.2) at 37 degrees C, the fourth-order association rate of the phosphorothioate tetramer was 6.1 (+/- 0.5) x 10(4) M-3 s-1; the dissociation rate was 8.2 (+/- 0.2) x 10(-6) min-1, resulting in a t(1/2) of about 60 days. The association rate of the phosphodiester was about one order of magnitude faster and the dissociation rate about one order of magnitude slower than that of the phosphorothioate tetramer. The association reaction had a negative energy of activation for both compounds. Despite thermodynamic instability of the tetramer at low concentrations, the extremely slow dissociation rate may allow use of the phosphorothioate tetramer for AIDS chemotherapy. PMID- 8672505 TI - Electrogenic K+ transport by the Kdp-ATPase of Escherichia coli. AB - Charge translocation by the Kdp-ATPase of Escherichia coli was measured by adsorption of proteoliposomes to a planar lipid membrane. The proteoliposomes were prepared by reconstitution of purified Kdp-ATPase into liposomes prepared from E. coli lipids. The protein was activated by a ATP concentration jump produced by photolysis of a protected derivative of ATP, caged ATP. Charge translocation was measured with a time resolution of 15-40 ms. Stationary currents demonstrated the continuous pumping activity of the enzyme. Control measurements with the potential-sensitive dye DiSC3(5) showed a negative potential inside the proteoliposomes after activation with ATP. The measured electrical signals as well as the dye measurements correspond to the transport of positive charge to the intracellular face of the protein. The electrical signal was increased when K+ was inside the proteoliposomes (K0.5 approximately 50 microM) and was inhibited by vanadate. These experiments demonstrate the electrogeneity of the Kdp-ATPase in a purified reconstituted system. PMID- 8672506 TI - Cyclodextrin-mediated removal of sterols from monolayers: effects of sterol structure and phospholipids on desorption rate. AB - In this study, we have examined a number of parameters which affect the rate of sterol desorption from a model membrane surface (a monolayer at the air/water interface) to cyclodextrins (CD) in the aqueous subphase. The desorption experiments were carried out at a constant lateral surface pressure with a zero order trough, which allowed for a determination of desorption rates which were unaffected by monolayer substrate concentration. At a surface pressure of 20 mN/m (30 degrees C), 0.9 mM beta-CD caused a desorption of about 13 pmol of cholesterol per minute and square centimeter of monolayer area. The desorption of cholesterol proceeded linearly as a time function and was sensitive to the concentration of beta-CD in the subphase. The rate of cholesterol desorption increased as the monolayer surface pressure increased (3->35 mN/m) but decreased slightly with increasing temperature (15->30 degrees C). The rate of sterol desorption appeared to be influenced by the relative polarity of the sterols. Oxidized sterols desorbed significantly faster than cholesterol (e.g., 4 cholesten-3-one desorbed 8.4-fold faster than cholesterol), whereas less polar sterols desorbed at slower rates [e.g., 20(R)-isoheptyl-5-pregnen-3 beta-ol, a cholesterol analogue with a ten-carbon branched side chain, desorbed at 1/10 of the rate of cholesterol]. Cholesterol desorption from a monolayer membrane containing both cholesterol and a phospholipid was much slower than from a pure cholesterol monolayer. When the effect of dipalmitoylphosphatidylcholine and N palmitoylsphingomyelin on cholesterol desorption rate was compared, it was found that cholesterol desorption was much more retarded from sphingomyelin monolayers as compared to that from phosphatidylcholine monolayers. Taken together, the results of this study show that the beta-CD-enhanced desorption of cholesterol (and other sterols) from monolayer membranes is influenced by the polarity of the desorbing molecules, as well as by lipid/lipid interactions in the membranes. Since beta-CD has no surface activity of its own, it appears to be a useful, nonintrusive catalyzer of cholesterol desorption and is expected to become a valuable probe in membrane and cell research. PMID- 8672507 TI - N-palmitoyl sphingomyelin bilayers: structure and interactions with cholesterol and dipalmitoylphosphatidylcholine. AB - The structure and thermotropic properties of N-palmitoyl sphingomyelin (C16:0-SM) and its interaction with cholesterol and dipalmitoylphosphatidylcholine (DPPC) have been studied by differential scanning calorimetry (DSC) and X-ray diffraction methods. DSC of hydrated multi-bilayers of C16:0-SM shows reversible chain-melting transitions. On heating, anhydrous C16:0-SM exhibits an endothermic transition at 75 degrees C (delta H = 4.0 kcal/mol). Increasing hydration progressively lowers the transition temperature (TM) and increases the transition enthalpy (delta H), until limiting values (TM = 41 degrees C, delta H = 7.5 kcal/mol) are observed for hydration values > 25 wt % H2O. X-ray diffraction at temperatures below (29 degrees C) TM show a bilayer gel structure (d = 73.5 A, sharp 4.2 A reflection) for C16:0-SM at full hydration; above TM, at 55 degrees C, a bilayer liquid-crystal phase is present (d = 66.6 A, diffuse 4.6 A reflection). Addition of cholesterol to C16:0-SM bilayers results in a progressive decrease in the enthalpy of the transition at 41 degrees C, and no cooperative transition is detected at > 50 mol % cholesterol. X-ray diffraction shows no difference in the bilayer periodicity, position/width of the wide-angle reflections, or electron density profiles at 29 and 55 degrees C when 50 mol % cholesterol is present. Thus, cholesterol inserts into C16:0-SM bilayers progressively removing the chain-melting transition and changing the structural characteristics of the bilayer. DSC and X-ray diffraction data show that DPPC is completely miscible with C16:0-SM bilayers in both the gel and liquid-crystalline phases; however, 30 mol % C16:0-SM removes the pre-transition exhibited by DPPC. PMID- 8672508 TI - Cell cycle-dependent phosphorylation of nucleoporins and nuclear pore membrane protein Gp210. AB - During mitosis in higher eukaryotic cells, the nuclear envelope membranes break down into distinct populations of vesicles and the proteins of the nuclear lamina and the nuclear pore complexes disperse in the cytoplasm. Since phosphorylation can alter protein-protein interactions and membrane traffic, we have examined the cell cycle-dependent phosphorylation of nuclear pore complex proteins. Nonmembrane nucleoporins Nup153, Nup214, and Nup358 that are modified by O-linked N-acetylglucosamine and recognized by a monoclonal antibody were phosphorylated throughout the cell cycle and hyperphosphorylated during M phase. Pore membrane glycoprotein gp210, that has a cytoplasmic, carboxyl-terminal domain facing the pore, was not phosphorylated in interphase but specifically phosphorylated in mitosis. Mutant and wild-type fusion proteins containing the cytoplasmic domain of gp210 were phosphorylated in vitro and their phosphopeptide maps compared to that of mitotic gp210. This analysis showed that Ser1880 of gp210 was phosphorylated in mitosis, possibly by cyclin B-p34cdc2 or a related kinase. Several nuclear pore complex proteins are therefore differentially phosphorylated during mitosis when pore complexes disassemble and reassemble. PMID- 8672509 TI - Iterative optimization of high-affinity proteases inhibitors using phage display. 1. Plasmin. AB - We generated a series of libraries having variants of the first Kunitz domain of human lipoprotein-associated coagulation inhibitor (LACI-D1, also known as tissue factor pathway inhibitor-I) displayed on bacteriophage M13 as pIII-fusions. We varied LACI-DI iteratively in two regions: the P1 region (positions 10-21) and the "second loop", (positions 31-39), which together form one end of the domain. Display-phage library Lib#1 allows 31 200 amino-acid sequences in P1 region (residues 13, 16-19). Preliminary, we screened Lib#1 against human plasmin (PLA, EC 3.4.21.7) immobolized on agarose to enrich for phage displaying variants with PLA affinity. We introduced a 1600-fold increase in second-loop diversity (residues 31, 32, 34, 39) into the population of selectants from Lib#1, yielding Lib#2. Lib#2 (allowing approximately 50 million amino-acid sequences) was screened against PLA-agarose to isolate highest affinity binders. Protein EPI P211, derived from the best isolate of Lib#2, inhibits PLA with Ki = 2 nM (at least 500-fold better than LACI-D1) and with high specificity. We used amino-acid sequences of PLA-binding selectants to design a PLA-biased library (Lib#3) which we screened against PLA. The protein EPI-P302 (derived from the best binder obtained from Lib#3) has Ki for PLA inhibition of 87 pM, which is 25-fold better than the first-round best binder and > or = 12 500-fold better than LACI-D1. EPI P302 also shows very high specificity for PLA vs other human proteases and is resistant to inactivation by oxidants and extremes of temperature or pH. Thus, one can use selectants from one library to design target-tailored combinatorial libraries and obtain quite stable, highly specific, very high-affinity binding molecules while maintaining an essentially human framework. PMID- 8672510 TI - Iterative optimization of high-affinity protease inhibitors using phage display. 2. Plasma kallikrein and thrombin. AB - As discussed in the accompanying paper [Markland, W., Ley, A. C., & Ladner, R. C. (1996) Biochemistry 35, 8045-8057], we generated libraries from the first Kunitz domain of human lipoprotein-associated coagulation inhibitor (LACI-D1) using multivalent M13 III display and derived potent inhibitors of human plasmin (PLA) by iterative variegation and selection. Here, we show that high-affinity, high specificity binders to human plasma kallikrein (pKAL) and human thrombin (THBN) can be obtained starting from the identical library and employing the same iterative variegation procedures used to obtain PLA inhibitors. Lib#1 (allowing 31 200 variants involving five positions near the P1 residue of LACI-D1) and its pKAL-biased derivative, Lib#4 (allowing an additional 1600 variants at residues 31, 32, 34, and 39), were screened against pKAL, yielding potent inhibitors. One of these, EPI-K401, has Ki = 284 pM, very high specificity, and excellent stability. We used information from Lib#4 selectants to design Lib#5 (allowing 1.5 x 10(6) amino-acid sequences involving nine varied positions) from which we obtained an inhibitor (EPI-K503) having high affinity for pKAL (Ki = 40 pM) and retaining the high specificity of EPI-K401. When we screened Lib#1 and its THBN tailored derivative, Lib#6, against THBN, we obtained a different and very homogeneous population of selected molecules. The purified proteins derived from Lib#6 selectants bound to THBN-agarose beads but did not inhibit proteolytic activity of THBN, suggesting that these selectants bind to a site on THBN other than the catalytic site. Thus, a single large combinatorial library can serve as a source to obtain highly specific, high-affinity binding molecules for each of several targets. Furthermore, the results with THBN show that the binding of Kunitz domains to other proteins is not limited to the catalytic sites of trypsin homologous proteases. PMID- 8672511 TI - Unusual affinity of cyanide for ferrous and ferric Scapharca inaequivalvis homodimeric hemoglobin. Equilibria and kinetics of the reaction. AB - The homodimeric hemoglobin from the mollusk Scapharca inaequivalvis (HbI) yields very stable ferrous and ferric cyanide adducts. The stability of the ferrous complex is particularly unusual such that it enabled determination of the spectroscopic properties of the complex and the characterization of the cyanide binding reaction to deoxygenated HbI at equilibrium and kinetically. The absorption spectrum of the ferrous cyanide complex is typical of a low-spin derivative; in the near-infrared region, it displays two bands at 695 and 840 nm attributable to charge transfer transitions. At pH 9.2, cyanide binds to deoxy HbI with no cooperativity and an apparent affinity constant of 17 M-1, which is about 10-fold higher than that for deoxy horse heart myoglobin. The rate of cyanide dissociation from both the ferrous and the ferric HbI adducts is slow relative to those of the other hemoproteins investigated to date and provides the major contribution to the unusual affinity for the ligand. The rate of cyanide binding to the ferric protein, in which the pentacoordinate derivative is the dominant species, is about 100-fold faster relative to that of the ferrous protein. In structural terms, the high affinity for cyanide of Scapharca hemoglobin has been ascribed to the decreased overall polarity of the heme pocket which is related to the localization of the heme groups at the subunit interface. PMID- 8672512 TI - N (epsilon)-(carboxymethyl)lysine protein adduct is a major immunological epitope in proteins modified with advanced glycation end products of the Maillard reaction. AB - Long-term incubation of proteins with glucose leads to the formation of advanced glycation end products (AGE). Recent immunological studies have suggested the potential role of AGE in atherosclerosis, aging, and diabetic complications. We previously prepared a monoclonal (6D12) as well as a polyclonal anti-AGE antibody and proposed the presence of a common AGE structure(s) that may act as a major immunochemical epitope [Horiuchi, S., Araki, N., & Morino, Y. (1991) J. Biol. Chem. 266, 7329-7332]. The purpose of the present study was to determine the major epitope. Amino acid analysis of AGE-proteins indicated that N(epsilon) (carboxymethyl)lysine (CML) was a major modified lysine residue. Immunologic studies demonstrated the positive reaction of 6D12 not only to all CML-modified proteins tested, but also to BSA modified with several aldehydes known to generate a CML-protein adduct, and a linear correlation between the CML contents of CML-BSA and their immunoreactivity to 6D12 up to approximately 8 mol/mol of protein. Further experiments with CML analogs revealed that the epitope of 6D12 is a CML-protein adduct with an important carbonyl group. In contrast to 6D12, our polyclonal anti-AGE antibody showed a significant but much weaker immunoreactivity to CML-BSA, suggesting that the polyclonal antibody contains two populations, one reactive to CML (CML-PA) and the other unreactive to CML (Non CML-PA). Non-CML-PA separated from CML-PA by CML-BSA affinity chromatography did not react with all CML-modified preparations, but retained its property to react commonly with AGE preparations obtained from proteins, lysine derivatives, and monoaminocarboxylic acids. Therefore, it is clear that a CML-protein adduct is a major immunological epitope in AGE structures, but there still exist other major epitope(s) expressed commonly in AGE-proteins. PMID- 8672513 TI - Thermodynamics of the unfolding and spectroscopic properties of the V66W mutant of Staphylococcal nuclease and its 1-136 fragment. AB - Spectroscopic studies have been performed to characterize the solution structure of the V66W mutant of Staphylococcal nuclease and the corresponding 1-136 fragment, referred to as V66W'. Whereas wild-type nuclease has a single tryptophan residue at position 140, the V66W mutant has a second tryptophan residue at position 66, which is the only such residue in V66W'. Steady-state and time-resolved fluorescence studies show Trp-66 in V66W' to have a blue emission, a relatively large fluorescence quantum yield, a long lifetime, a significant degree of protection from solute quenchers, and to depolarize with a relatively long rotational correlation time. These results characterize Trp-66 in V66W' as being a buried residue, which indicates that this fragment retains some global structure. Circular dichroism (CD) data are consistent with the fragment having lost most of the alpha-helical content of the wild type, while retaining beta sheet structure. The CD spectrum in the aromatic region also suggests that Trp-66 in the fragment experiences an asymmetric environment, which is not identical to that in the full length mutant, V66W. In addition, optical detection of triplet state magnetic resonance (ODMR) spectroscopy can clearly resolve the tryptophan residues and demonstrates differences between the local environment of Trp-66 in V66W and in V66W', as well as small differences in the Trp-140 environment in wild type and in V66W. Guanidine-HCl induced and thermally induced unfolding studies were performed by simultaneously acquiring CD and fluorescence data as a function of the perturbation and then performing a global analysis of such multiple data sets in terms of two-state and three-state unfolding models. Whereas data for wild-type nuclease and the V66W' fragment are well characterized by a two-state unfolding model, data for the V66W mutant are better characterized by a three-state process. That is, both the denaturant- and temperature-induced unfolding of V66W involves the significant population of an equilibrium unfolding intermediate. Our global analyses yield thermodynamic parameters for the unfolding transitions, and we show that the data for V66W can be described by a constrained three-state model in which the transition of the intermediate to the fully unfolded state is fixed to have the same thermodynamic parameters that describe the unfolding of the V66W' fragment. PMID- 8672514 TI - Diagnosis, surveillance, and epidemiologic evaluation of viral infections in pediatric cardiac transplant recipients with the use of the polymerase chain reaction. AB - BACKGROUND: Viral infections, particularly those caused by cytomegalovirus, are a major cause of postoperative morbidity and mortality in heart transplant recipients. These infections have classically been diagnosed by history, physical examination, peripheral viral cultures, and serologic studies. These methods are often time-consuming and lack sensitivity. Positive viral cultures from the heart are rarely obtained, and viral myocarditis and acute cellular rejection are unable to be differentiated histologically. We have therefore used the polymerse chain reaction to diagnose possible viral infection in pediatric heart transplant recipients with findings consistent with acute unexplained rejection. METHODS: Polymerase chain reaction was used as an aid to diagnose cytomegalovirus infection of cardiac tissue obtained by right ventricular endomyocardial biopsy and follow its long-term course. In addition, polymerase chain reaction was used to diagnose infection of the heart by other viruses in patients with clinical and histologic evidence of rejection, especially those with unexplained late rejection or chronic rejection. Polymerase chain reaction primers were designed to amplify nucleic acid sequences from cytomegalovirus, parvovirus, adenovirus, herpes simplex virus, Epstein-Barr virus, and the RNA viruses of the Enterovirus family. RESULTS: Forty patients underwent serial right ventricular endomyocardial biopsy (129 samples) for rejection surveillance with positive results obtained in 41 samples (32%) from 21 patients. Viral genome amplified included cytomegalovirus in 16 samples, adenovirus in 14, enterovirus in 6, parvovirus in 3, and herpes simplex virus in 2. In 13 of the 21 patients positive for viral genome (62%), endomyocardial biopsy histologic scores were consistent with multifocal moderate to severe rejection (Internal Society for Heart and Lung Transplantation scores of 3A or greater). CONCLUSIONS: Polymerase chain reactions may be used as a rapid and sensitive method to evaluate postoperative viral infections in heart transplant recipients, especially in those with late-onset rejection or chronic rejection. Polymerase chain reaction may also be useful in the serial analysis of cytomegalovirus status in transplant recipients. The use of multiple viral primers improves the diagnostic evaluation of these patients and may lead to a better understanding of the epidemiologic characteristics of posttransplantation viral infections and the cause of late or chronic rejection. PMID- 8672515 TI - Prognostic determinants of six-month morbidity and mortality in heart transplant recipients. The Italian Study Group on Infection in Heart Transplantation. AB - BACKGROUND: Knowledge of time course and risk factors for morbidity and mortality may allow better cardiac graft allocation, surveillance timing, and planning of immunosuppressive strategies. METHODS: Six-month morbidity and mortality were retrospectively analyzed in a multiinstitutional series of 645 heart transplant recipients. RESULTS: During a 3432 patient-months follow-up, 87 patients died of infection (n = 11), rejection (n = 11), multiorgan failure (n = 9) and other transplant-related causes (n = 56); six-month survival rate was 86%. Three hundred thirty-seven recipients had 967 treated rejection episodes (2.87 episodes/patient with rejection, lethality 3.2%); 223 major infectious episodes occurred in 162 patients (1.38 episodes/infected patient, lethality 7%). Six month rejection and infection-free survival rates were 44% and 73%. Total mortality and cause-specific morbidity sharply declined after the first month; 160 patients (25%) had no events during follow-up. At multivariable analysis, significant risk factors for mortality were postoperative acute kidney failure, prolonged cardiopulmonary bypass time, and previous cardiac surgery. Rejection was associated with steroid-free and globulin-free immunosuppression and infection was associated with steroid immunosuppression, cytolytic treatment, venous lines placement greater than 7 days, and mechanical ventilation time. No single or combination of variables was able to discriminate patients with an event-free course. CONCLUSIONS: Morbidity and mortality have the highest incidence during the early posttransplantation phase. Preoperative variables are of limited value with respect to immunosuppressive treatment in predicting outcome. Infection is far less frequent than rejection but, in view of the higher lethality rate, deserves a vigorous effort for prevention, which is best addressed by appropriate modulation of immunosuppressive strategies. PMID- 8672516 TI - Electric myocardial impedance registration in humoral rejection after heart transplantation. AB - BACKGROUND: Because of the absent lymphocyte infiltrate, humoral-mediated rejection after heart transplantation is not diagnosed by the usual staining technique (hematoxylin-eosin method) of the endomyocardial biopsy specimen. However, humoral rejection is characterized by a distinct myocardial edema caused by capillary leakage. Because tissue edema increases the electric myocardial impedance of the corresponding tissue compartment the electric myocardial impedance method should be able to detect these episodes more reliably than biopsy. METHODS: To evaluate this hypothesis eight DLA-matched beagle dogs were subjected to heterotopic neck heart transplantation after multiple sensitization by skin grafts of the heart donor. For electric myocardial impedance registrations rectangular impulses (wide 1 msec) were applied over two intramyocardial electrodes and the impulse response was registered. Day-to-day comparisons were made and an increase of electric myocardial impedance of 10% or more was used as an indicator of rejection. To assess the influence of edema caused by electrode implantation, cortisone administration, narcosis, ischemia, or reperfusion on the electric myocardial impedance, identical electrodes were implanted in the native hearts of five additional dogs via lateral thoracotomy. These animals each received 100 mg methylprednisolone between postoperative days 20 and 22 and underwent heterotopic neck heart transplantation on postoperative day 28 without previous sensitization (protocol 2). Electric myocardial impedance electrodes were also implanted in these allografts (protocol 3). After transplantation myocardial biopsies were done every 2 days and the samples graded according to the International Society for Heart and Lung Transplantation classification in all dogs. RESULTS: Despite triple-drug immunosuppression (cyclosporine A, prednisolone, azathioprine) humoral rejection developed in all sensitized dogs as established by immunofluorescent staining of myocardial biopsy samples and functional deterioration. All episodes were diagnosed by electric myocardial impedance (sensitivity 100%), whereas only in one case the biopsy specimen was positive (International Society for Heart and Lung Transplantation grade > 1) (sensitivity 12.5%). All eight episodes could be treated successfully, that is, myocardial performance and electric myocardial impedance showed an immediate and full recovery. During the first 12 days none of the nonsensitized dogs exhibited rejection. Protocol 2 indicated that narcosis and the administration of cortisone did not per se have an influence on electric myocardial impedance and the influence of electrode implantation was negligible. Contrarily, edema caused by ischemia and reperfusion during transplantation (protocols 1 and 3) led to a significant increase in electric myocardial impedance. However, after 2 days this edema had faded away such that it no longer disturbed rejection diagnosis. CONCLUSION: We conclude that the registration of the electric myocardial impedance diagnoses humoral rejection episodes after heart transplantation not only reliably but also early, that is, before the onset of irreversible graft damage. PMID- 8672517 TI - Lung Transplantation in patients with systemic diseases: an eleven-year experience at Papworth Hospital. AB - BACKGROUND: The presence of a systemic disease has traditionally been considered a contraindication to lung transplantation. METHODS: We present a retrospective review of 19 patients undergoing lung transplantation for end-stage pulmonary disease associated with a systemic illness since 1984. There were 11 male and 8 female patients, aged from 23 to 59 years (median 43 years) with end-stage pulmonary involvement by sarcoidosis (11 patients), Langerhan's cell histiocytosis (three patients), systemic vasculitis (four patients: three with systemic lupus erythrematosis, one with Churg-Strauss), and common variable immunodeficiency (one patient). Ten patients received a heart-lung transplant, and eight patients received a single lung transplant. One patient underwent single lung transplantation after an earlier heart-lung transplant. RESULTS: The 30-day mortality was 5.3%. Nine patients died overall. Two of these had systemic lupus erythrematosis with anticardiolipin antibodies and died from complications of their underlying vasculitis. The mean 1- and 2-year actuarial survivals for all patients were 71% (standard error +/- 10.8%) and 64% (standard error +/- 11.9%), respectively. All patients surviving longer than 3 months achieved an improvement in functional status to New York Heart Association class I or II, and a significant increase occurred in mean forced expiratory volume in 1 second and forced vital capacity. Disease recurrence without clinical significance occurred in two patients with sarcoidosis. Of the nine patients who died, seven had autopsies and none showed evidence of disease recurrence in the lungs. CONCLUSIONS: Patients with systemic diseases can be considered for lung transplantation and each case should be judged on its individual merits. However, patients with systemic lupus erythrematosis (particularly when associated with anticardiolipin antibodies) should probably not be offered lung transplantation because they are likely to develop further complications of their underlying vasculitis. PMID- 8672518 TI - Hearts from donors with chronic alcohol use: a possible risk factor for death after heart transplantation. AB - BACKGROUND: Careful donor and recipient selection are important factors for the success of heart transplantation. Currently, donors with a history of alcohol use are routinely accepted despite the potential deleterious effects of alcohol on the heart. METHODS: We examined the frequency of chronic alcohol use (> 2 ounces of pure alcohol daily for > or = 3 months) among organ donors and the outcome of the receipients after heart transplantation. Of 99 consecutive patients who underwent transplantation between December 1988 and August 1993 with an adequate donor history, 17 (17%) had a history of chronic alcohol use (alcohol group), and 82 (83%) did not (nonalcohol group). All recipients received triple-drug immunosuppression, and 10 to 14 days of OKT3. RESULTS: Survival rates at 1 and 2 years were significantly lower in the alcohol group (61% +/- 13% and 61$ +/- 13%) than in the nonalcohol group (95% +/- 3% and 91% +/-4%, p = 0.0001). Most deaths in the alcohol group occurred within 3 months after transplantation. The incidence of rejection episodes did not differ significantly. Fatal rejection occurred more frequently in the alcohol group and was associated with severe ventricular dysfunction before death. Cox multiple regression analysis identified donor alcohol use as an independent risk factor for death after heart transplantation. CONCLUSIONS: A substantial proportion (17%) of heart donors have a history of chronic alcohol use. The unfavorable early outcome of patients receiving hearts from alcoholic donors suggests the presence of a subclinical alcoholic cardiomyopathy before transplantation and poor tolerance of rejection episodes after transplantation. Larger prospective studies are needed to determine the mechanism of fatal rejection and whether such hearts can be used safely for transplantation. PMID- 8672519 TI - Pulmonary allograft ischemic time: an important predictor of survival after lung transplantation. AB - BACKGROUND: Traditionally organ availability in human lung transplantation has been limited by aiming to keep the graft ischemic time under 6 hours. To maximize organ supply in a country with a widely spread population, we have routinely procured organs beyond this time. Our experience outlines the clinical consequences of a prolonged allograft ischemic time. METHODS: Between 1990 and 1994 we performed 106 lung or heart-lung transplantations. The average graft ischemic time was 323 +/- 93 minutes. Lung preservation included a prostacyclin infusion (40 to 80 ng/kg/min for 10 minutes) and cold modified Euro-Collins solution flush. Organs were stored and transported on ice at 6 degrees to 10 degrees C. Graft ischemic time, transplant type, age, gender, cytomegalovirus status, and anesthetic time were subject to multivariate Cox regression analysis. RESULTS: Survival and graft ischemic times for heart-lung (n = 38), single lung (n = 33), and bilateral lung transplantation (n = 35) were not significantly different. Graft ischemic time was an independent predictor of survival (p < 0.01). Subgroup analysis notes the effect to be most pronounced beyond 5 hours (p = 0.02, hazard ratio 3.44, confidence interval 1.12 to 9.8). CONCLUSIONS: Pulmonary allograft ischemic time beyond 5 hours does not result in acceptable outcomes although survival is reduced. Attempts should be made to minimize graft ischemic times with careful coordination of transport and personnel. PMID- 8672520 TI - Does donor organ ischemia over four hours affect long-term survival after lung transplantation? AB - BACKGROUND: Lung transplantation is currently limited by a donor shortage and the need for a short organ ischemic time. The purpose of this analysis was to evaluate prolonged donor organ ischemia and its effect on overall survival. METHODS: We conducted a retrospective analysis of 83 patients undergoing single (n = 62) or bilateral sequential lung transplantation (n = 21) from June 1, 1989, through July 31, 1994. All allografts were flushed with modified EuroCollins solution at 4 degrees C and stored in cold saline solution. Ischemic time was measured from aortic crossclamping at organ procurement to reperfusion. Ischemic times were divided into three groups: group I < 240 minutes (n = 39), group II 240 to 360 minutes (n = 36), and group III > 360 minutes (n = 8). Ischemic times ranged from 97 to 708 minutes (median, 245 minutes; mean, 252 minutes). Bilateral sequential and single lung transplantations were considered together. RESULTS: Actuarial survival was not significantly different among groups (p = 0.09). We found no significant difference in time spent in the intensive care unit (p = 0.27) or in total hospital stay (p = 0.57) after transplantation, in forced expiratory volume in 1 second at 1 month after transplantation (p = 0.74), or in the number of acute rejection episodes (p = 0.65). In addition, length of follow up was similar among groups (p = 0.24). CONCLUSIONS: Prolonged donor allograft ischemic times were not associated with an adverse effect on survival. The use of allografts with ischemic times through 6 hours achieved acceptable 2-year survival rates after transplantation. The use of donor organs with prolonged ischemic times should prompt the United Network for Organ Sharing to move toward better allocation of donor organs. PMID- 8672521 TI - Physiologic definitions of obliterative bronchiolitis in heart-lung and double lung transplantation: a comparison of the forced expiratory flow between 25% and 75% of the forced vital capacity and forced expiratory volume in one second. AB - BACKGROUND AND METHODS: A comparison of the forced expiratory flow between 25% and 75% of the forced vital capacity (FEF25-75) and forced expiratory volume in 1 second (FEV1) was conducted for the detection of obstructive airway disease as an early manifestation of obliterative bronchiolitis. Pulmonary function tests performed on heart-lung and double lung transplant recipients between March 1981 and March 1983 were reviewed. Thirty patients were identified who showed progressive deterioration in pulmonary function after transplantation. Ratios determining proportionate decreases were calculated from measurements of absolute values for the FEF25-75 and FEV1 at the point when the FEF25-75 reached < 70% and < or = 30% of predicted, divided by baseline values obtained before the decline in function. Similar ratios were obtained for FEV1 and FEF25-75 at the point the FEV1 declined > or = 20% from its baseline value. RESULTS: Comparison of the ratios for the FEF25-75 and FEV1 at FEF25-75 values < 70% and < or = 30% of predicted and a similar comparison when the FEV1 declined > or = 20% from baseline showed a greater proportional decrease in FEF25-75 than FEV1 (p < 0.01). With the use of the FEF25-75, declines in airway function were detected earlier. After transplantation a decline in FEF25-75 to < 70% of predicted occurred approximately 112 days before a 20% decline a FEV1. CONCLUSION: The FEF25-75 is more sensitive than the FEV1 for the early detection of obliterative bronchiolitis. A presumptive diagnosis of obliterative bronchiolitis can be made with physiologic criteria, providing infection or acute rejection has been ruled out. When conducting epidemiologic studies or for vital statistics we propose that a decline in FEF25-75 to < 70% be used to define the onset of obliterative bronchiolitis. PMID- 8672522 TI - Lung retransplantation: institutional report on a series of twenty patients. AB - BACKGROUND AND METHODS: Between 1986 and 1995, 124 isolated lung and 29 combined heart-lung transplantations were performed at our institution. Twenty of these procedures were retransplantations. Four different types of reoperations were performed: ipsilateral single lung retransplantation (n = 3), single lung retransplantation after bilateral or heart-lung transplantation (n = 7), bilateral retransplantation after bilateral lung transplantation (n = 5), and bilateral retransplantation after single lung transplantation (n = 5). Nine patients underwent retransplantation while still in the intensive care unit after the primary transplantation. Indications for retransplantation in these patients were primary graft failure in seven and bronchial complications in two patients. In 11 patients a late retransplantation (3 to 30 months after the first transplantation) was performed. The indication was obliterative bronchiolitis in nine and late bronchial complications in two patients. Overall, 13 patients were ventilator-dependent before retransplantations. RESULTS: Overall survival was 52.8% and 36.2% at 1 and 12 months, respectively. For early retransplantation the survival rate at 1 month was only 22.2% with 2 patients alive 5 and 22 months after the retransplantation. For late retransplantation survival at 1 and 12 months was 70.7% and 50.5%, respectively (p = 0.07), and the longest surviving patient was at 47 months after retransplantation at the time this article was written. Patients who were ventilator-dependent before retransplantation had a significantly worse outcome (survival at 1 and 12 months: 33.8% and 25.4% versus 85.7% and 57.1% for all others, p = 0.055). Of those surviving to date, all were in New York Heart Association class I or II. CONCLUSIONS: We conclude that late and elective lung retransplantation achieves acceptable results when offered to patients with chronic pulmonary dysfunction but with otherwise stable conditions. In view of the poor results, early acute retransplantation should be performed much more restrictively. PMID- 8672524 TI - Diagnostic yield and therapeutic impact of flexible bronchoscopy in lung transplant recipients. AB - BACKGROUND: Bronchoalveolar lavage and transbronchial biopsy are often used for definitive diagnosis of lung rejection and infection in lung transplant recipients. Although protected specimen brushing is of value in nosocomial bacterial pneumonia, its role in lung transplant recipients had not been widely reported. The aim of the study is to review the diagnostic yield and therapeutic impact of flexible bronchoscopy with the use of a combination of bronchoalveolar lavage, protected specimen brushing, and transbronchial biopsy in lung transplant recipients. METHODS: We reviewed flexible bronchoscopy data in 83 transplant recipients between February 1990 and March 1995. Only those with bronchoalveolar lavage, protected specimen brushing, and transbronchial biopsy were included in the analysis. There were 282 bronchoscopies performed for clinically suspected lung rejection or infection (clinical bronchoscopy) and 38 bronchoscopies for follow-up of a previously detected histologic abnormality (follow-up bronchoscopy). RESULTS: The total yields for rejection and infection for clinical and follow-up bronchoscopies were 67.4% and 58.9%, respectively. Acute rejection was detected with transbronchial biopsy in 26.2% and 34.2% of clinical and follow up bronchoscopies, respectively. Cytomegalovirus pneumonitis was detected with transbronchial biopsy in 4.0% and 11.4% of clinical and follow-up bronchoscopies, respectively. Overall, bacteria was the most common cause of lower respiratory tract infection. When used together, protected specimen brushing and bronchoalveolar lavage were complementary techniques for detection of bacterial lower respiratory tract infection with a significantly higher proportion detected with protected specimen brushing ( > or = 10(3) colony forming units/ml) compared with bronchoalveolar lavage ( > or = 10(5) colony forming units/ml) (p < 0.001). Complications were hemorrhage (1.9%), pneumothorax (2.5%) and transient hypoxemia (10.5%). The results had an impact on management of rejection and infection in 57.8% of clinical and 39.5% of follow-up bronchoscopies. CONCLUSIONS: We conclude that bronchoscopy, with the use of a combination of bronchoalveolar lavage, protected specimen brushing, and transbronchial biopsy, is safe with a high diagnostic yield and therapeutic impact for treating lung transplant recipients. PMID- 8672523 TI - Donor-recipient size matching in pediatric heart transplantation: a word of caution about small grafts. AB - BACKGROUND: The increased shortage of donor organs led centers to extend the conventional donor criteria, particularly regarding donor-recipient size mismatching. Little information is available in the pediatric age group. METHODS: Between December 1987 and May 1994, 73 pediatric orthotopic heart transplantations were performed. Indications for heart transplantation included congenital heart defect (29 patients), cardiomyopathy (40 patients), valvular disease (1 patient), and retransplantation (3 patients). Patients ranged in age from 9 days to 18 years (mean: 5.7 +/- 5 years). The following factors were evaluated: cardiomyopathy, congenital heart disease, age, pretransplantation pulmonary hypertension, previous sternotomy, status at transplantation, donor to recipient weight ratio, graft ischemic time, degree of donor inotropic support, ABO compatibility, gender mismatch. RESULTS: The overall mortality rate before discharge (7 days to 4.5 months) was 27.4%. Donor heart failure occurred in 31.5%. Donor heart failure and early mortality were strongly correlated (p = 0.0002). Risk factors for donor heart failure were pretransplantation pulmonary hypertension (p = 0.024), donor/recipient ratio (p = 0.033), and major donor inotropic support (p = 0.034). Donor heart failure rate was 50% in donor/recipient ratio less than 1, 33% in donor/recipient ratio between 1 and 1.6, and 7% in donor/recipient ratio more than 1.6. Donor/recipient ratio less than 1 was the only significant risk of postoperative death by univariate (p = 0.0045) and multivariate (p < 0.01) analysis. CONCLUSIONS: Donor heart failure remains the main cause of early mortality in pediatric heart transplantation. The use of oversized donor may be beneficial, particularly in patients with pretransplantation pulmonary hypertension. The use of undersized donor grafts should be strongly discouraged. PMID- 8672525 TI - Semiquantitative measurement of cytokine messenger RNA in endomyocardium and peripheral blood mononuclear cells from human heart transplant recipients. AB - BACKGROUND: Cytokines play a central role in inflammatory responses and in specific immune responses directed toward alloantigens. The pattern and quantity of cytokines produced in graft rejection can yield valuable information regarding the cellular and molecular mechanisms of the antigraft response. METHODS: We used the polymerase chain reaction to semiquantitatively measure changes in the amount of messenger RNA from the interleukin-1 beta, interleukin-2, interleukin-4, interleukin-6, interleukin-10, tumor necrosis factor-alpha, interferon-gamma, interleukin-1 receptor antagonist, and the interleukin-2 receptor genes in the peripheral blood and endomyocardium of cardiac allograft recipients during the first 8 weeks after transplantation. A total of 328 samples of resting (n = 251) and stimulated (n = 77, stimulated with phytohemagglutinin and lipopolysaccharide for 18 hours) peripheral blood mononuclear cells collected from 16 patients were measured. To measure intragraft cytokine levels, we analyzed 150 endomyocardial biopsy specimens from 19 patients. RESULTS: No elevation in expression was seen before injection, but, after the onset of rejection and concomitant with treatment, there was a decrease in detectable mRNA (p < 0.05) for the pro inflammatory monokines interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha in resting peripheral blood mononuclear cells, and a decrease for the T-cell derived cytokines interleukin-4 and interleukin-10 in stimulated peripheral blood mononuclear cells. These changes in mRNA expression occurred coincidentally with decreases in the percentage of lymphocytes and monocytes in the peripheral blood after administration of rejection therapy. In endomyocardial biopsy specimens, there were no detectable changes in the quantities of cytokine mRNA specimens for the interferon-gamma, interleukin-6, interleukin-10, interleukin-1ra, and interleukin-1 beta genes before rejection. In general, the levels of these cytokines were near the lower limits of detection by our assay in endomyocardial biopsies, mRNA from the interleukin-2, interleukin-4, tumor necrosis factor-alpha, and interleukin-2R genes were undetectable. CONCLUSIONS: We conclude that changes in the expression of cytokine mRNA in both peripheral blood mononuclear cells and endomyocardial biopsy specimens as measured by the semiquantitative polymerase chain reaction method used in this study does not effectively predict rejection. The decline in peripheral blood mononuclear cell cytokine mRNA after rejection treatment is likely due to changes in the proportion of lymphocytes and monocytes in the peripheral blood in concert with a steroid-induced downregulation by cytokine gene transcription. PMID- 8672526 TI - Cell cycle regulation by the retinoblastoma family of growth inhibitory proteins. AB - The retinoblastoma family of growth-inhibitory proteins act by binding and inhibiting several proteins with growth-stimulatory activity, the most prominent of which is the cellular transcription factor E2F. In higher organisms, progression through the cell division cycle is accompanied by the cyclical activation of a number of protein kinases, the cyclin-dependent kinases. Phosphorylation of retinoblastoma family proteins by these cyclin-dependent kinases leads to release of the associated growth-stimulatory proteins which in turn mediate progression through the cell division cycle. PMID- 8672528 TI - Cyclin E: in mid-cycle. PMID- 8672527 TI - Regulation, substrates and functions of src. AB - Src is the best understood member of a family of 9 tyrosine kinases that regulates cellular responses to extracellular stimuli. Activated mutants of Src are oncogenic. Using Src as an example, and referring to other Src family members where appropriate, this review describes the structure of Src, the functions of the individual domains, the regulation of Src kinase activity in the cell, the selection of substrates, and the biological functions of Src. The review concentrates on developments in the last 6-7 years, and cites data resulting from the isolation and characterization of Src mutants, crystallographic studies of the structures of SH2, SH3 and tyrosine kinase domains, biochemical studies of Src kinase activity and binding properties, and the biology of transgenic and knockout mouse strains. PMID- 8672529 TI - Association of TM4SF proteins with integrins: relevance to cancer. PMID- 8672530 TI - Integrin-mediated signaling in normal and malignant cells: a role of protein tyrosine kinases. PMID- 8672531 TI - p53 in growth control and neoplasia. PMID- 8672532 TI - Gastric chief cells possess NK1 receptors which mediate pepsinogen secretion and are regulated by agents that increase cAMP and phospholipase C. AB - In order to determine whether tachykinins alter the function of chief cells and to characterize the receptors mediating the effect, we investigated the abilities of various substance P (SP)-related peptides to inhibit the binding of 125I Bolton-Hunter labeled substance P (125I-BH-SP) and their abilities to alter cell function in dispersed chief cells from guinea pig stomach. Binding of 125I-BH-SP was saturable, reversible, time- and temperature-dependent and was inhibited by several SP-related peptides with relative potencies of SP = physalaemin (IC50:0.19 nM) > SP methyl ester (SP-ME) (IC50:3.3 nM) > eledoisin (IC50:6.1 nM) > neurokinin A (NKA) (IC50: 65 nM) > neurokinin B (NKB) (IC50:80 nM). Analyses of these binding data demonstrated that chief cells possess a high and low affinity class of binding sites. Neither 125I-NKA nor [phenylalanyl-3,4,5-3H]senktide demonstrated saturable binding to chief cells. Acid stripping experiments demonstrated rapid ligand internalization with 55% of the bound radioligand internalized by 10 min. Phospholipase C activating agents (carbachol, CCK-8), adenylate cyclase activating agents (secretin, VIP), TPA and the calcium ionophore, A23187, all inhibited the binding of 125I-BH-SP and it was due to inhibition of ligand internalization with no change in surface bound parameters. SP (0.1 microM) stimulated pepsinogen secretion but was 4-times less efficacious than CCK-8 (10 nM) or carbachol (1 mM). 10 nM SP stimulated a rapid increase in cytoplasmic free calcium concentration ([Ca2+]i) followed by a sustained elevation lasting 2 min. Single cell spectroscopy demonstrated SP (10 pM to 1 microM) did not cause calcium oscillations. The NK1 receptor antagonist, CP96,345 specifically inhibited the SP-stimulated changes in [Ca2+]i and pepsinogen secretion. The relative potencies of SP-related peptides to stimulate pepsinogen secretion and [Ca2+]i demonstrated a close agreement with their abilities to inhibit the binding of 125I-BH-SP, and comparison of the dose-response curves suggests occupation of the low affinity sites mediate changes in biologic activity. In conclusion, the present study demonstrates that chief cells possess a NK1 subtype of tachykinin receptor, occupation of the low affinity sites of this receptor cause calcium mobilization and pepsinogen secretion, and that binding to this receptor is regulated by agents that activate phospholipase C, adenylate cyclase, protein kinase C and calcium mobilization. PMID- 8672533 TI - Type II transglutaminase expression in rabbit articular chondrocytes in culture: relation with cell differentiation, cell growth, cell adhesion and cell apoptosis. AB - Depending on the cell type studied, the involvement of type II transglutaminase (TGase) has been proposed in almost any event of the cell life such as differentiation, apoptosis, growth, aging, cell morphology and adhesion, metastatic capacity or extracellular matrix stabilization. In order to define the field(s) where this enzyme may be implicated in chondrocytes, type II TGase expression was studied in chondrocytes at different passages which differentiated state was modulated by retinoic acid, dihydrocytochalasin B or staurosporin. Results showed that (i) type II TGase expression is not incompatible with type II collagen expression, a main marker of chondrocyte differentiation (ii) type II TGase expression is higher when cells are in the exponential phase of growth than when growth arrested (iii) a high type II TGase expression does not imply that cells are apoptotic although cell apoptosis correlates with increased type II TGase expression (iv) non-adherent cells do not express type II TGase whereas adherent cells do whatever their differentiation state as assessed by type II collagen synthesis. These results suggest that, in articular chondrocytes, type II TGase is specifically implicated in the cell adhesion capacity. PMID- 8672534 TI - Alteration of glutathione transferase subunits composition in the liver of young and aged rats submitted to hypoxic and hyperoxic conditions. AB - In the present work, we have studied glutathione transferase (GST) activity and GST subunits distribution in the liver of young and aged rats kept under hypoxic or hyperoxic normobaric conditions as model of oxidative stress. A significant decrease of GST activity was detected in young hypoxic rat liver, whereas a significant increase occurred in aged hypoxic liver. No significant alteration of activity was obtained in both young and aged rat livers subjected to hyperoxic treatment. Substrate specificity measurements, SDS/PAGE analysis and reverse phase HPLC, of GSH-affinity purified fractions were used to study the changes in the GST subunits pattern occurring in the liver of rat as a consequence of hypoxic and hyperoxic treatment. The results demonstrate that young and aged rat liver has a different constitutive GST subunit pattern which are markedly and differentially altered in hypoxia or hyperoxia. The hyperoxic treatment caused an increase of GST subunit 3 in aged, but not in young liver. In aged liver, both the hypoxic and hyperoxic treatment produced a decrease of GST subunit 4. After hypoxic treatment GST subunit 3 significantly increased in both young and aged liver. GST subunit 1a increased in both young and adult liver after hyperoxia. Following hypoxia a decrease of subunit 1a was seen in both young and aged liver. After hypoxic treatment, subunit 6 doubled in young, but not in aged, livers. It was concluded that the alterations in GST subunit expression occurring in the liver as a consequence of hypoxic or hyperoxic treatment respond to the necessity of a better protection of liver against the products of oxidative metabolism. PMID- 8672535 TI - Glucagon-like peptide-1(7-36)amide enhances insulin-stimulated glucose uptake and decreases intracellular cAMP content in isolated rat adipocytes. AB - We investigated the effect of GLPs on glucose uptake in isolated rat adipocytes. GLP-1(7-36)amide significantly enhanced glucose uptake in the presence of 1 nM insulin. GLP-1(7-36)amide at 15 nM increased glucose uptake maximally by 56.4% as compared with 1 nM insulin alone (P < 0.01). In contrast, with less than 1 nM insulin or without insulin GLP-1(7-36)amide showed no effect on glucose uptake. Full-sequence GLP-1(1-37) at 15 nM in the presence of 1 nM insulin increased glucose uptake by 24.6% as compared with 1 nM insulin alone (P < 0.05). GLP-2 showed no effect on glucose uptake. Further, we examined the effect of GLP-1(7 36)amide on cAMP content in isolated rat adipocytes. Insulin at 1 nM caused a significant decrease of cAMP content. The combination of 15 nM GLP-1(7-36)amide and 1 nM insulin caused a further reduction of cAMP content. These data indicate that GLP-1(7-36)amide possesses augmentative effects on insulin action in isolated rat adipocytes. Furthermore, it is suggested that the stimulatory effect of GLP-1(7-36)amide occurs through the reduction of intracellular cAMP content. PMID- 8672536 TI - Biphasic modulation of cell growth by recombinant human galectin-1. AB - Human soluble galactose-binding lectin (galectin-1) has been expressed as an Escherichia coli fusion protein, following the amplification by polymerase chain reaction of cDNA prepared from a human osteosarcoma cell line. The fusion protein is a functional beta-galactoside-binding lectin, as is the recombinant galectin when purified from the cleaved fusion protein. The recombinant galectin has a biphasic effect on cell proliferation. Unlike the fusion protein, it functions as a human cell growth inhibitor, confirming earlier findings with natural human galectin-1, though it is less effective than the natural galectin. This reaction is not significantly inhibited by lactose, and is thus largely independent of the beta-galactoside-binding site. At lower concentrations, recombinant galectin-1 is mitogenic, this activity being susceptible to inhibition by lactose, and thus attributable to the beta-galactoside-binding ability of the protein. Some tumour cells are susceptible to the growth-inhibitory effect, and the galectin-1 gene is expressed in both normal and tumour cells. PMID- 8672537 TI - Diadenosine polyphosphates regulate cytosolic calcium in human fibroblast cells by interaction with P2x purinoceptors coupled to phospholipase C. AB - The effects of diadenosine pentaphosphate (AP5A), and diadenosine hexaphosphate (AP6A) on the cytosolic-free Ca2+ concentration ([Ca2+]i) were evaluated in cultured human fibroblast cells (HF cells) using the fluorescent dye technique. AP5A, and AP6A concentration-dependently increased [Ca2+]i in HF cells. The addition of 10 mumol/1 AP5A and AP6A significantly increased [Ca2+]i in HF cells from 71 +/- 3 nmol/1 (n = 184) to 241 +/- 39 nmol/1 (n = 11; P < 0.001 compared to resting value) and to 227 +/- 26 nmol/1 (n = 23; P < 0.001), respectively. The purinoceptor P2 blockers, suramin and pyridoxal-phosphate-6-azophenyl-2',4' disulphonic acid (PPADS), inhibited the diadenosine polyphophate-induced [Ca2+]i increase, whereas the P2y purinoceptor blocker, reactive blue, had no effect. Adenosinetriphosphate (ATP) and the P2x agonist, alpha 1 beta-methylene-ATP also significantly increased [Ca2+]i in HF cells, whereas the P2y agonist methylthio ATP showed only a small [Ca2+]i response. Diadenosine polyphosphates mainly induced transplasmamembrane Ca2+ influx as was confirmed by experiments in the absence of extracellular Ca2+ or by manganese quenching studies. Organic (verapamil) and inorganic Ca2+ channel blockers (NiCI2) significantly reduced the AP6A induced transplasmamembrane Ca2+ influx. The inhibitor of phosphatidylcholine-specific phospholipase C, D609, significantly reduced the effect of diadenosine polyphosphates on [Ca2+]i in HF cells. It is concluded that diadenosine polyphosphates regulate transplasmamembrane Ca2+ influx after occupation of P2x receptors via activation of phosphatidylcholine-specific phospholipase C and hence of voltage-operated Ca2+ channels. PMID- 8672538 TI - Potentiation of the intracellular Ca2+ response to arginine vasopressin by increased cytosolic-free Mg2+ in rat vascular smooth muscle cells. AB - Although the inhibitory effects of extracellular Mg2+ on Ca2+ influx are well established, little is known about the effects of intracellular Mg2+ on Ca2+ handling. In the present study, the effects of cytosolic-free Mg2+ concentration in the physiological (submillimolar) range on Ca2+ handling were investigated after stimulation of rat vascular smooth muscle cells with arginine vasopressin. Cytosolic Mg2+ was manipulated by culturing cells in medium containing different Mg2+ concentrations. Peak cytosolic-free Ca2+ concentration responses to arginine vasopressin (1 mumol/1) were measured in the presence and absence of external Ca2+. The results suggest that an increase in cytosolic-free Mg2+ concentration increases both Ca2+ discharge from intracellular stores and Ca2+ influx, whereas a decrease in intracellular Mg2+ attenuates Ca2+ influx. PMID- 8672539 TI - Localization of mRNA for the muscarinic M1 receptor in rat stomach. AB - Cholinergic stimulation of receptors in the oxyntic mucosa results in secretion of mucus, pepsinogen and hydrochloric acid. There has been speculation as to the cellular localization of these receptors in the mucosa and as to which subtype is present in the different cell types. In the present study, utilizing radioactive riboprobes for the M1 muscarinic receptor subtype, we carried out in situ hybridization to determine which cells of the gastric corpus transcribe mRNA for this receptor. The antisense M1 probe hybridized strongly on the zymogen cells and, to a lesser extent, on the surface mucous cells and the muscle layers. Control sections from brain also displayed specific hybridization. PMID- 8672540 TI - Alterations in macrophage G proteins are associated with endotoxin tolerance. AB - Previous studies have suggested that endotoxin tolerance induces macrophage desensitization to endotoxin through altered guanine nucleotide regulatory (G) protein function. In the present study the binding characteristics of the nonhydrolyzable GTP analogue GTP gamma [35S] to macrophage membranes from endotoxin tolerant and control rats were determined. Membranes were prepared from peritoneal macrophages harvested from rats 72 h after two sequential daily doses of vehicle or Salmonella enteritidis endotoxin (100 micrograms/kg on day 1 and 500 micrograms/kg on day 2). GTP gamma [35S] bound to a single class of sites that were saturable and displaceable in control and endotoxin tolerant macrophage membranes. The maximum specific binding of GTP gamma [35S] was significantly (P < 0.01) decreased in membranes from tolerant rats compared to control (Bmax = 39 +/ 7 pmol/mg protein in control vs. 11 +/- 2 pmol/mg protein in endotoxin tolerant; n = 5). There were no significant differences in the Kd values. To determine whether the reduced GTP gamma S binding was due to decreases in G proteins, macrophage membrane G protein content was determined by western blotting with specific antisera to Gi1,2 alpha, Gi3 alpha, Gs alpha, and the beta subunit of G. Scanning densitometric analysis demonstrated differential decreases in tolerant macrophage membrane G proteins. Gi3 alpha was reduced the most to 48 +/- 8% of controls (n = 3), and this reduction was significant compared to those of other G proteins. Gi1,2 alpha and G beta were reduced to 73 +/- 5% (n = 3) and 65 +/- 4% (n = 3) of control values, respectively. Gs alpha(L) and Gs alpha(H) were reduced to 61 +/- 5% (n = 3) and 68 +/- 3% (n = 3) of control, respectively. These results demonstrate that endotoxin tolerant macrophages exhibit decreased membrane GTP binding capacity and differential reductions in the content of specific G proteins. The cellular mechanisms leading to such alterations in G proteins and their functional significance in the acquisition of endotoxin tolerance merit further investigation. PMID- 8672541 TI - Phosphatase 2A regulates the responsiveness of olfactory cilia. AB - The odorant-induced second messenger response in olfactory cilia was monitored in the presence of phosphatase modulators. Okadaic acid, a phosphatase inhibitor, attenuated the odorant-induced cAMP-response in a dose-dependent manner, half maximal inhibition was obtained at 1.5 nM okadaic acid indicating that phosphatase 2A may be involved. Protamine, a selective activator of phosphatase 2A, led to significantly stronger cAMP-responses. Western blot and immunohistochemical analysis employing specific antibodies revealed that phosphatase 2A is present in olfactory tissues in particular in olfactory cilia. The results suggest that phosphatase 2A may play a regulatory role in governing the responsiveness of olfactory neurons. PMID- 8672542 TI - Calcium efflux mechanism in sperm mitochondria. AB - This paper reports an investigation on calcium efflux mechanism in ram sperm mitochondria. Energized sperm mitochondria take up Ca2+ via the ruthenium-red sensitive uniporter, and possess a ruthenium-red insensitive efflux mechanism. Extramitochondrial Na+ did not affect the rate of Ca2+ efflux indicating that Na+/Ca2+ exchange mechanism is not involved. Depolarization of inner mitochondrial membrane induced by the uncoupler carbonylcyanide-p trifluoromethoxyphenyl hydrazone (FCCP) or by the organomercurial SH-reagent mersalyl, causes high stimulation in Ca2+ efflux. This stimulated Ca2+ efflux determined in the presence of ruthenium-red and phosphate, is not inhibited by cyclosporin A (CSA), indicating that mitochondrial permeability transition pore (MTP) is not involved in this Ca2+ efflux mechanism. The stimulated Ca2+ efflux is inhibited by ADP or atractyloside suggesting that the Ca2+ transport mechanism might be intrinsic to the ADP/ATP carrier (AAC). Thus, the data indicate that sperm mitochondria contain a Ca2+ efflux mechanism operated via AAC and regulated by mitochondrial membrane potential and by ADP concentration. PMID- 8672543 TI - Identification of sites on epidermal growth factor receptors which are phosphorylated by pp60src in vitro. AB - The Epidermal Growth Factor Receptor (EGF-R) becomes constitutively tyrosine phosphorylated on two novel sites in v-Src transformed cells, and these phosphorylations are associated with enhanced signaling activity [1]. To determine whether Src could directly phosphorylate these sites, we have examined the ability of the Src kinase to phosphorylate both wild-type and kinase defective EGF-Rs in vitro. Although purified Src could phosphorylate EGF-Rs, the pattern of phosphorylation sites was not identical to what was previously found in vivo [1]: Src in vitro directly phosphorylated EGF-Rs on one autophosphorylation site (Tyr 1173) which was not a site of re-induced in vivo phosphorylation, suggesting the in vivo inaccessibility of this site. One Src specific in vitro phosphorylation site (Tyr 03) appeared to correspond to one of the in vivo Src-induced sites (sPY2), but the other Src-specific in vivo site (sPY1) was not significantly phosphorylated in vitro, raising the possibility of a Src-induced tyrosine kinase cascade. The ability of Src to phosphorylate the EGF-R is consistent with the suggestion that the receptor can function as a kinase substrate independent of its intrinsic enzymatic activity, as implied by recent studies on signaling by kinase-defective EGF-Rs. PMID- 8672544 TI - Highly-expressed S100A3, a calcium-binding protein, in human hair cuticle. AB - Analyses on sodium dodecyl sulfate-polyacrylamide gel electrophoreses showed that the human hair cuticle extracts mainly consist of a 7-kDa component and keratin proteins. The S-carboxymethylation of the cuticle extracts made the 7-kDa band shift to the 15-kDa position. After electroblotting of the S-carboxymethyl derivative, the membrane pieces carrying the 15-kDa band were treated with trypsin and the released peptides were separated by reverse-phased HPLC. Amino acid sequence analyses revealed that the peptides corresponded to the partial sequences deduced from human genome coding for S100A3, a cysteine-rich calcium binding protein. The anti S100A3 serum, prepared by immunizing a synthetic peptide antigen, reacted with the 7-kDa and 15-kDa bands in immunoblotting analyses. Immunofluorescence microscopy showed intense labeling to the cuticular layer with the anti S100A3 serum. These results indicated that S100A3 was highly expressed in the human hair cuticle. PMID- 8672545 TI - Expression of cytidine deaminase in human solid tumors and its regulation by 1 alpha,25-dihydroxyvitamin D3. AB - We found that vitamin D3 up-regulates the expression of cytidine deaminase (CDD) gene in some human solid tumor cell lines as well as the monocytic leukemia cell lines. Two kinds of full length CDD cDNA were identified from human placenta: one has glutamine and the other one has lysine at codon 27. The expression was tested in various normal tissues and the cancer cell lines. Northern blot analysis demonstrated high levels of CDD mRNA in leukocytes and moderate levels in liver, kidney, placenta, spleen and lung. Expression of CDD in 20 human cancer cell lines was highly variable and not related to its expression in normal tissues. Treatment of the cell lines with 1 alpha,25-dihydroxyvitamin D3 resulted in up regulation of CDD expression in some lines but not others. Three of five gastric carcinoma cell lines and five of eight colorectal cancer lines had increased levels of CDD mRNA following 24 h treatment with vitamin D3. Increased mRNA was detected in gastric cancer MKN 45 cells after 3 h of treatment with vitamin D3 and increased enzyme activity was measured after 24 to 48 h. But no combined effect of calcitriol with 9-cis retinoic acid was found. Our results demonstrate that CDD can be up-regulated by vitamin D3 in some solid tumor cell lines. PMID- 8672546 TI - Lactational changes in the rat exocrine pancreas somatostatin receptors and modulation of guanylate cyclase. AB - Hyperplasia of the pancreatic tissue during late lactation (third week) and lasting for at least the first two weeks after weaning has been observed by several authors. Since the tetradecapeptide somatostatin (SS) inhibits pancreatic growth and its plasma levels are elevated during these periods, the aim of the present study was to determine the possible implication of the somatostatinergic system in the pancreatic changes cited above. Thus, the present study investigated 125I-Tyr(11)-somatostatin (125I-Tyr(11)-SS) binding and the effects of SS on guanylate cyclase activity as well as pancreatic somatostatin-like immunoreactivity (SSLI) levels in pancreatic acinar membranes from control, lactating and weaning rats. SS receptors were identified using 125I-Tyr(11)-SS and isolated pancreatic acinar membranes in vitro. There was an increase in the number of SS receptors after the third week of lactation (244 +/- 6 vs. 155 +/- 12 fmol/mg protein, P < 0.01) and the first two weeks after weaning (327 +/- 8 vs. 164 +/-10 fmol/mg protein, P < 0.001). No change in the affinity of the receptor site was detected at either study time. In addition, SS-stimulated guanylate cyclase activity was markedly increased at the third week of lactation (119%) and at the second week after weaning (158%) when compared with the control group. In contrast, basal guanylate cyclase activity was not modified at either study period. Thus, SS-stimulated guanylate cyclase activity is increased in pancreatic acinar membranes at late lactation and at the second week after beginning weaning probably due to an increase in the number of SS receptors. Significant decreases in SSLI content were observed at the third week of lactation (69%) and the second week after weaning (37%) when compared with the respective controls. The present results suggest that pancreatic acinar cell growth observed at the third week of lactation and the second week after weaning is associated with up-regulation of SS receptors which would represent a mechanism promoted by the cell that would negatively regulate the mitogenic activity of the increased number of pancreatic growth factors observed during both periods. PMID- 8672547 TI - In vitro effect of adenosine agonist GR79236 on the insulin sensitivity of glucose utilisation in rat soleus and human rectus abdominus muscle. AB - The dose-response effects of a new adenosine agonist, GR79236, were examined in isolated rat soleus muscle strips and human rectus abdominus muscle strips. Effects on the insulin sensitivity of carbohydrate metabolism were examined, in particular upon insulin stimulated glycogen synthesis and glycolytic flux. In the presence of adenosine deaminase (ADA), GR79236 increased insulin sensitivity of pyruvate release from rat soleus muscle strips by 24% from 82.5 +/- 10.0 to 102.5 +/- 10.0 (P < 0.01), by 27% to 105.0 +/- 12.5 (P < 0.01) and by 24% to 102.5 +/- 10.0 (P < 0.01) nmol/25 mg per h at 0.1 and 10 microM GR79236, respectively. Rates of lactate release followed a similar but non-significant trend. Addition of GR79236 in the presence of ADA had no effect on rates of glycogen synthesis. Insulin stimulated rates of pyruvate or lactate release or of glycogen synthesis were unaffected by the addition of adenosine deaminase or GR79236 in human rectus abdominus muscle strips. Adenosine agonists may act indirectly to modulate insulin sensitivity of carbohydrate metabolism. PMID- 8672548 TI - Regulation of hepatic pyruvate dehydrogenase kinase by insulin and dietary manipulation in vivo. Studies with the euglycaemic-hyperinsulinaemic clamp. AB - The provision of a high-fat diet (47% of energy as fat) for 28 days led to a significant increase in hepatic pyruvate dehydrogenase kinase activity, together with significant suppression of hepatic pyruvate dehydrogenase (active form). An enhanced hepatic pyruvate dehydrogenase kinase activity continued to be observed at 6 h after the withdrawal of the high-fat diet. Significant suppression of hepatic pyruvate dehydrogenase kinase activity was observed in post-absorptive, high-fat-fed rats after a 2.5 h euglycaemic-hyperinsulinaemic clamp, such that differences in pyruvate dehydrogenase kinase activities between control and high fat-fed rats were no longer evident. Starvation for 24 h in rats previously maintained on standard diet also evoked a substantial increase in hepatic pyruvate dehydrogenase kinase activity. This latter response was only partially reversed by 2.5 h of euglycaemic hyperinsulinaemia. Suppression of pyruvate dehydrogenase kinase activity by 2.5 h euglycaemic hyperinsulinaemia in high-fat fed rats was associated with a substantial increase in hepatic pyruvate dehydrogenase activity (active form) whereas no significant increase in hepatic pyruvate dehydrogenase activity (active form) was observed after 2.5 h euglycaemic hyperinsulinaemia in 24 h-starved rats. The results are consistent with the proposition that hepatic pyruvate dehydrogenase kinase responds directly to an increase in lipid oxidation which is facilitated by insulin deficiency or an impaired action of insulin. PMID- 8672549 TI - Lung collagen cross-links in rats with experimentally induced pulmonary fibrosis. AB - Rats were intratracheally instilled with bleomycin or with silica (quartz) dust to induce lung fibrosis. Several weeks later, purified collagen chains (or collagen digests) were isolated from the lungs of these animals and from age matched controls instilled intratracheally with saline solution, and the ratios of hydroxylysine to lysine and of the dysfunctional cross-links DHLNL to HLNL were quantified. Collagen from fibrotic lungs had significantly higher ratios of DHLNL:HLNL than did control lungs, 15.5 +/- 4.8 and 17.1 +/- 4.8 vs. 2.3 +/- 0.5 for the silica-instilled and the bleomycin-instilled animals, respectively. The hydroxylysine:lysine ratio was significantly increased for the alpha 1(I) chain, to a value 170% of that of lung collagen from control animals, and for several of its constituent CNBr peptides. Lung tissue was exhaustively digested with collagenase and specific cross-linked peptides were isolated and characterized. The cross-linked alpha 1(I) x alpha 1(I) peptide linked by the residues 87 x 16C, with a ratio of DHLNL:HLNL of 17:1, demonstrated that the increased hydroxylation of the dysfunctional cross-links in fibrotic lung collagen could be accounted for in part by increased hydroxylation of the lysine residue at position 16C of the C terminal telopeptide of the collagen alpha 1(I) chain. It proved impossible to locate the corresponding N-terminal cross-linked fragment from alpha 1(I) x alpha 1(I) chains, 9N x 930, possibly due to further reactions of this material to form the material referred to as poly(CB6). Isolated poly (CB6) accounted for more than half of the total alpha 1(I)CB6 peptide expected in lung collagen, and had a hydroxylysine:lysine content 2.8 times greater in bleomycin-treated animals than in their age-matched controls. Evidence was also found for a cross-linked alpha 1(III) x alpha 1(I) peptide linking residue 87 from the alpha 1(III) chain with residue 16C from the alpha 1(I) chain; it also had an increased ratio of DHLNL:HLNL. We conclude that the increased hydroxylation of lysine observed in two different animal models of lung fibrosis occurs preferentially at the N- and C-terminal nonhelical extension peptides of the alpha 1(I) collagen chains, and that this apparent specificity of overhydroxylation of fibrotic collagen may have important structural and pathological consequences. PMID- 8672550 TI - Activation of transcription factor NF-kappa B in experimental glomerulonephritis in rats. AB - NF-kappa B plays a pivotal role in cells of the immune system as an inducible transcriptional activator. NF-kappa B regulates the transcription of many genes of pro-inflammatory cytokines and cell adhesion molecules, which could be involved in the pathogenesis of glomerulonephritis. Using a gel shift assay, we investigated NF-kappa B DNA-binding activity in glomeruli of WKY rats injected with nephrotoxic serum (NTS). Kinetic analysis indicated that the NF-kappa B DNA binding activity in glomeruli, composed of p50 subunit determined by a supershift assay, increased on day 1 after NTS injection and the maximal activation was observed on day 3 to 5. NF-kappa B activation persisted at least until day 14. Pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of NF-kappa B activation, inhibited the NTS-induced increase of glomerular NF-kappa B DNA-binding activity, followed by the inhibition of mRNA expression of IL-1 beta, MCP-1, ICAM-1 and iNOS, which are known to be regulated by NF-kappa B. PDTC also prevented urinary protein excretion which is a pathophysiological parameter for glomerulonephritis. These results suggest that NF-kappa B activation causes the induction of pro inflammatory factors in nephritic glomeruli, which may play significant roles in the pathogenesis of glomerulonephritis. PMID- 8672551 TI - Binding properties of a blood group Le(a+) active sialoglycoprotein, purified from human ovarian cyst, with applied lectins. AB - Studies on the structures and binding properties of the glycoproteins, purified from human ovarian cyst fluids, will aid the understanding of the carbohydrate alterations occurring during the biosynthesis of blood group antigens and neoplasm formation. These glycoproteins can also serve as important biological materials to study blood group A, B, H, Le(a), Le(b), Le(x), Le(y), T and Tn determinants, precursor type I and II sequences and cold agglutinin I and i epitopes. In this study, the binding property of a cyst glycoprotein from a human blood group Le(a+) nonsecretor individual, that contains an unusually high amount (18%) of sialic acid (HOC 350) was characterized by quantitative precipitin assay with a panel of lectins exhibiting a broad range of carbohydrate-binding specificities. Native HOC 350 reacted well only with three out of nineteen lectins tested. It precipitated about 80% of Ricinus communis (RCA1), 50% of Triticum vulgaris (WGA) and 37% of Bauhinia purpurea aba (BPA) agglutinins, respectively. However, its asialo product had dramatically enhanced reactivity and reacted well with many I/II (Gal beta1 --> 3/4GcNAc), T(Gal beta1 --> 3GalNAc) and Tn(GaNIAc alphaI --> Ser/Thr) active lectins. It bound best to Jacalin, BPA, and abrin-a and completely precipitated all the lectins added. Asialo-HOC 350 also reacted strongly with Wistaria floribunda, Abrus precatorius agglutinin, ricin and RCA1 and precipitated over 75% of the lectin nitrogen added, and moderately with Arachis hypogaea, Maclura pomifera, WGA, Vicia viosa B4, Codium fragile tomentosoides and Ulex europaeus-II. But native HOC 350 and its asialo product reacted not at all or poorly with Dolichos biflorus, Helix pomatia, Lotus tetra-gonolobus, Ulex europaeus-I, Lens culinaris lectins and Con A. The lectin-glycoform interactions through bioactive sugars were confirmed by precipitin inhibition assay. Mapping the precipitation profiles of the interactions have led to the conclusion that HOC 350 contains a large number of receptors for I/II, T, and Tn active lectins. But in the untreated (or native) substance, most of these determinants are masked by sialic acids. PMID- 8672552 TI - Variations of muscle mitochondrial creatine kinase activity in mitochondrial diseases. AB - Mitochondrial creatine kinase (mtCK) activity has been measured in the mitochondria isolated from the muscle of 69 patients suspected of mitochondrial diseases. The isolated mitochondria did not contain significant amounts of the muscle isoform of creatine kinase, as checked by an immunoassay performed after electrophoretic separation of the various isoforms. Hence, the enzyme assay reliably represented the mtCK activity. Therefore, a simple measurement of CK activity in isolated mitochondria permitted the measurement of mtCK activity. An absence of mtCK activity in muscle was never observed. The lowest activities were not associated to defined mitochondrial diseases linked to defects of respiratory chain complexes or to defects of citric cycle enzymes. On the contrary, mtCK activity was significantly increased in the muscle of patients exhibiting ragged red fibers. This increase was generally associated to an increase of citrate synthase activity. Since ragged-red fibers and elevated mtCK activities were generally not found in children younger than 3 years, even in cases of characteristic oxidative phosphorylation deficiency, it is suggested that the increase in mtCK activity as well as the appearance of ragged-red fibers are not the first events which occur during the evolution of mitochondrial diseases but would rather be long-term secondary processes which slowly develop in deficient mitochondria. PMID- 8672553 TI - Calcium stores in cultured fibroblasts and their changes with Alzheimer's disease. AB - The experiments in this paper identify multiple calcium compartments in cultured human fibroblasts and reveal abnormalities in one of these pools in cells from Alzheimer patients. In the presence of external calcium, bradykinin (BK) increased cytosolic free calcium ([Ca2+]i) about 3-fold and then [Ca2+]i rapidly declined. Omission of calcium from the media did not affect the BK-induced peak, which indicates that the peak reflects internal stores. Other compounds that also released calcium from internal stores included A23187 (a calcium ionophore), thapsigargin (Tg; an inhibitor of endoplasmic reticulum ATPase), and FCCP (an uncoupler of oxidative phosphorylation). The [Ca2+]i response to sequential addition of compounds in calcium-free media identified discrete internal calcium stores. BK depleted internal calcium pools such that subsequent stimulation with BK, FCCP or bombesin did not increase [Ca2+]i. However, A23187 or thapsigargin still elicited responses. A23187 depleted essentially all internal calcium pools. Either Tg or FCCP reduced the calcium stores that could be released by BK or A23187. Thus, cellular calcium compartments that respond to BK and A23187 partially overlap. The common pool includes Tg-and FCCP-sensitive compartments. Calcium stores were examined in cells from Alzheimer disease patients, because previous studies suggest that their calcium homeostasis is altered. A23187 addition to BK-treated cells produced a 95% greater response in cell lines from Alzheimer patients (n = 7) than in those from controls (n = 5). Thus, various calcium stores can be pharmacologically distinguished in fibroblasts and at least one of these compartments is abnormal in Alzheimer's disease. PMID- 8672554 TI - Troponin I phosphorylation in heart homogenate from diabetic rat. AB - Although cardiac myofibrillar ATPase activity has been shown to be depressed during the development of diabetic heart dysfunction, the mechanisms of this alteration are not fully understood. Since phosphorylation of troponin I (TnI) is known to decrease the myofibrillar ATPase activity, the present study was undertaken to examine the TnI phosphorylation capacity in the diabetic heart homogenate. For this purpose rats were made diabetic by injecting streptozotocin (65 mg/kg; i.v.) and the hearts were removed 8 wk later. Some 6 wk diabetic animals were injected with insulin (3 U/day) for 2 wk. TnI content in the heart homogenate was measured by immunoblot assay, the mRNA abundance for TnI gene was determined by Northern blot analysis and the in vitro phosphorylation level of TnI was estimated by the ratio of phosphorylated TnI and total (phosphorylated and unphosphorylated) TnI. No significant changes in TnI content and gene expression of TnI were observed in right and left ventricles from the diabetic rats. However, the phosphorylation of TnI was higher (approximately 40%) in the diabetic hearts; this change was reversible upon insulin treatment. These results regarding TnI phosphorylation measured under in vitro conditions suggest that increased phosphorylation of TnI may contribute toward the depression in cardiac myofibrillar ATPase activity in chronic diabetes. PMID- 8672555 TI - Natural ligand motifs of closely related HLA-DR4 molecules predict features of rheumatoid arthritis associated peptides. AB - Rheumatoid arthritis (RA), one of the most common autoimmune disorders, is believed to be mediated via. T lymphocytes and genetic studies have shown that it is strongly associated with HLA-DR4. The DR4 subtypes DR4Dw4, DR4Dw14 and DR4Dw15 represent increased risk factors for RA, whereas DR4Dw10 is not associated with the disorder. Our study determines and compares the natural ligand motifs of these MHC class II molecules and identifies 60 natural ligands. At relative position 4 (P4), only the RA-associated DR4 molecules allow, or even prefer, negatively charged amino acids, but do not allow those which are positively charged (Arg, Lys). In the case of DR4Dw10 the preference for these amino acids is reversed. The results predict features of the putative RA-inducing peptide(s). A remarkable specificity, almost exclusively for negative charges (Asp, Glu), is found at P9 of the DR4Dw15 motif. This specificity can be ascribed to amino acid beta57 of the DR beta chain, and gives an important insight into the beta57 association of another autoimmune disease, insulin-dependent diabetes mellitus type I. PMID- 8672556 TI - Coordination of side-to-side head movements and walking in amphetamine-treated rats: a stereotyped motor pattern as a stable equilibrium in a dynamical system. AB - Rats injected with 5.0 mg/kg (+)-amphetamine perform, at one stage of the drug's influence, rhythmic side-to-side head movements while walking. This makes them an interesting preparation for investigating how stereotyped motor patterns emerge from the coordination of periodic movements. We report here such a pattern we have isolated: the left foreleg and the right hindleg land on the ground as the head reaches the peak of its movement to the right, and vice versa (contra lateral pattern). We show that this pattern can be explained as a stable equilibrium in a simple, nonlinear dynamical model, similar to models developed for tapping with both hands in human subjects. The model also accounts for sequences of behavior that are not in the contra-lateral pattern, explaining them as a flow of the system back towards the stable equilibrium after a disturbance. Motor patterns that constitute the building blocks of unconstrained behavior are often defined as fixed phase relations between movements of the parts of the body. This study applies the paradigm of Dynamic Pattern Generation to free (unconstrained) behavior: motor patterns are defined as stable equilibria in dynamical systems, assembled by mutual influence of concurrent movements. Our findings suggest that this definition is more powerful for the description of free behavior. The amphetamine-treated rat is a useful preparation for investigating this notion in an unconstrained animal whose behavior is still not as complex and variable as that of the normal animal. PMID- 8672558 TI - A biologically inspired neural net for trajectory formation and obstacle avoidance. AB - In this paper we present a biologically inspired two-layered neural network for trajectory formation and obstacle avoidance. The two topographically ordered neural maps consist of analog neurons having continuous dynamics. The first layer, the sensory map, receives sensory information and builds up an activity pattern which contains the optimal solution (i.e. shortest path without collisions) for any given set of current position, target positions and obstacle positions. Targets and obstacles are allowed to move, in which case the activity pattern in the sensory map will change accordingly. The time evolution of the neural activity in the second layer, the motor map, results in a moving cluster of activity, which can be interpreted as a population vector. Through the feedforward connections between the two layers, input of the sensory map directs the movement of the cluster along the optimal path from the current position of the cluster to the target position. The smooth trajectory is the result of the intrinsic dynamics of the network only. No supervisor is required. The output of the motor map can be used for direct control of an autonomous system in a cluttered environment or for control of the actuators of a biological limb or robot manipulator. The system is able to reach a target even in the presence of an external perturbation. Computer simulations of a point robot and a multi-joint manipulator illustrate the theory. PMID- 8672557 TI - Temporal coding in vision: coding by the spike arrival times leads to oscillations in the case of moving targets. AB - The 'oscillations' which have been observed in the visual cortex of cats and monkeys in the case of moving targets are discussed in relation to a temporal coding based on the arrival times of spikes or bursts. A decoding process for this temporal coding is proposed in which neurons work in a correlator mode. In the case of motion analysis, periodic resetting is needed to avoid information jamming. This resetting is proposed to be responsible for the 'oscillations'. Good initial synchronization is required for the decoding process to be performed efficiently. A diffusive process based on interdendritic ionic currents is proposed and shown to operate efficiently, without any loss of spatial and temporal resolving powers. PMID- 8672559 TI - Recognition-by-parts: a computational approach to human learning and generalization of shapes. AB - In this paper human pattern recognition is modeled in terms of how human observers learn to describe patterns in terms of their perceived parts, their unary (part) and binary (relational) attributes and the way in which such attribute states "evidence' different classes of shapes. This approach, originally developed in the area of computer vision, is concerned with algorithms which enable the learning of shape descriptions from examples and the classification of new data (generalization) efficiently and accurately. An object in such an "evidence-based' system is represented by a set of rules, where each rule provides a certain amount of evidence for each object class in the database. The accumulated class evidence over all activated rules can then be used to determine the classification probability. We have examined how well this model reflects human perception by training observers to classify compound Gabor patterns and then testing them with versions of such patterns which were segmented (gray-level transformed) versions of the original training set. If the observers were to construct rules to define each pattern class in terms of perceived parts and their relations, then it should be expected that classification performance would generalize to these new patterns from the original set. Results confirm this hypothesis and the specific feature extraction, learning and rule generation model used to predict performance. PMID- 8672560 TI - Neuron as time coherence discriminator. AB - Neuronal excitability under stimuli with a complex time course is investigated on the basis of the numerical solution of the Hodgkin-Huxley equations. Each stimulus is composed of 100-1000 unitary excitatory postsynaptic potentials (uEPSP) that start randomly within a definite time window. Probability of initiating a spike [firing probability, FP(W)] as a function of the window width W is calculated by the Monte Carlo method. FP(W) has a step-like shape: it becomes equal to 1 for small W and almost vanishes as W exceeds some value Ws. The role of long-lasting somatic inhibition is analysed. Ws depends on the inhibition potential, but the step-like shape of FP is preserved. It is concluded that the capability of multisynaptic stimulation to cause a spike can be expressed in terms of temporal coherence between the synaptic inputs. Namely, the spike is initiated if the temporal coherence between active inputs is above a definite threshold. The threshold value can be effectively regulated by varying the inhibition potential. PMID- 8672561 TI - A distributed-parameter model of the myelinated human motor nerve fibre: temporal and spatial distributions of electrotonic potentials and ionic currents. AB - The double cable model is used to investigate the electrotonic responses of the myelinated human motor nerve fibre to 100 ms depolarizing and hyperpolarizing current pulses. The model calculations provide estimates of the spatial and temporal distributions of the transaxonal and transmyelin components of the electrotonic potentials, both in different segments of the fibre and at different moments during and after the pulses. The temporal distributions of the potentials exhibit fast (rise time < 1 ms) and slow (from 10 to 100 ms) components, while the discontinuous spatial distributions of the potentials reflect the heterogeneous structure of the fibre. The distributions of the transaxonal and transmyelin currents along the fibre, and their contributions from different ionic channels, are also explored. The different axolemmal channel types beneath the myelin sheath make an important contribution to the responses to the long lasting current pulses. PMID- 8672562 TI - Informational properties of neural nets performing algorithmic and logical tasks. AB - It is argued that the genetic information necessary to encode an algorithmic neural processor tutoring an otherwise randomly connected biological neural net is represented by the entropy of the analogous minimal Turing machine. Such a near-minimal machine is constructed performing the whole range of bivalent propositional logic in n variables. Neural nets computing the same task are presented; their informational entropy can be gauged with reference to the analogous Turing machine. It is also shown that nets with one hidden layer can be trained to perform algorithms solving propositional logic by error back propagation. PMID- 8672563 TI - Genetic redundancy caused by gene duplications and its evolution in networks of transcriptional regulators. AB - In various organisms loss-of-function mutations of individual genes with unexpectedly weak or no phenotypic effects in the homozygous state have been observed. In several of these case, independent evidence shows that the respective gene products do have essential biological functions. An explanation emerging from detailed biochemical and genetic studies on such genes is that two or more genetically redundant genes contribute to that function, i.e., a group of genes that is able to substitute partially for a loss of function in one member of that group. The often-observed sequence similarity among redundant genes suggests gene duplications as a frequent source of genetic redundancy. Aside from this observation, the evolution of genetic redundancy is poorly understood. Genetic redundancy is potentially of great relevance to organismal evolution, since it may (i) 'protect' organisms from potentially harmful mutations, and (ii) maintain pools of functionally similar, yet diverse gene products, and thus represent a source of evolutionary novelty at the biochemical level. The question of how genetic redundancy evolves should ideally be answered by experimentation. However, the large time scales involved and insufficient quantitative understanding of the underlying regulatory pathways are likely to preclude such an approach in the foreseeable future. Preliminary answers are sought here by using a biochemically motivated model of a small but central part of a developmental pathway. Sets of transcription regulators are modeled that mutually regulate each other's expression and thereby form stable gene expression patterns. It is then studied how genetic redundancy caused by gene duplications might evolve in such networks. The results obtained suggest that redundancy may, at least in some cases, be a global property of gene interactions within a regulatory pathway, rather than a local property of genes in that pathway. They also raise the possibility that duplications of a whole regulatory gene network, as may have taken place during the evolution of HOM/Hox genes in chordates, are less likely to be reversible (by gene deletions) than duplications of individual network genes. These findings are discussed with reference to experimental evidence on the evolution of HOM/Hox genes. PMID- 8672564 TI - Selection and treatment of candidates for heart transplantation. AB - Improved outcome of heart failure in response to medical therapy, coupled with a critical shortage of donor organs, make it imperative to confine heart transplantation to patients who are most disabled by heart failure and who are likely to derive the maximum benefit from heart transplantation. Hemodynamic and functional indices of prognosis (such as peak exercise oxygen consumption) has improved the ability to identify adult patients who should be selected for heart transplantation. These patients should have a poor prognosis despite optimization of medical and surgical therapy. When deciding the impact of individual comorbid conditions on a patient's candidacy for heart transplantation, the detrimental effects of each comorbid condition on post heart transplantation outcome should be weighed. Evaluation of patients with severe heart failure should be done by a multidisciplinary team expert in the management of heart failure, performance of cardiac surgery in patients with low left ventricular ejection fractions, and transplantation. Potential heart transplantation candidates should be reevaluated on a regular basis to assess the continued need for heart transplantation. PMID- 8672565 TI - Surgical techniques for cardiac transplantation. AB - The surgical technique for cardiac transplantation was introduced by Lower and Shumway more than 30 years ago. It is known as "biatrial technique for cardiac transplantation" and has been used in more than 20,000 patients. However, since the early days of cardiac transplantation, atrial arrhythmias and atrioventricular conduction disturbances were noted so frequently that Dr. Barnard suggested a modification of the original technique to the present biatrial technique, in which the inferior vena cava orifice is enlarged with an atriotomy incision curving toward the base of the right atrial appendage, away from the sinus node. Atrial arrhythmias and other conduction abnormalities have, however, persisted and have resulted in the need for pacemaker insertion in a significant number of patients. Over the past years, with the more frequent use of transthoracic and transesophageal echocardiography, other abnormalities have been noted on follow-up of transplanted patients. These include tricuspid and mitral regurgitation, enlarged left and right atria with thrombus formation in the atrial suture line, asynchronous contraction of donor and recipient's atria, and right ventricular dysfunction in the early postoperative period. In the last 5 years, a new surgical technique for cardiac transplantation has been used in a few centers. This technique requires total excision of the recipient's heart and individual's caval and pulmonary vein anastomosis, "bicaval technique for cardiac transplantation." This technique seems to avoid the problems encountered with the biatrial technique. A comparison of the two surgical techniques, based on recently published surgical series, is presented. PMID- 8672566 TI - The surgical management of allograft coronary disease: a paradigm shift. AB - The surgical options for heart transplant recipients who develop obstructive coronary artery disease in their allograft have historically been limited to retransplantation. Given the worse outcome in recipients of second grafts, often caused by recurrence of coronary disease, coupled with the significant increase in the number of patients on the transplantation waiting lists, has made retransplantation a limited option. However, as heart transplant recipients continue to live longer, there are an increasing number of patients who develop allograft coronary disease. Coronary bypass surgery has not been offered to these patients because of numerous pathology reports describing uniform involvement of the coronary vessel from its origin to the distal intramural branches, thereby eliminating any reasonable runoff vascular bed to handle increased flow that might be delivered with bypass conduits. However, new diagnostic techniques such as measurement of coronary flow reserve by Doppler flow wire can define the physiological vasodilating capacity or reserve which, if normal, should allow conventional bypass surgery if adequate target epicardial vessels are present. This approach would allow a more reasonable alternative to many patients who otherwise would die of this disease without any intervention. Other alternatives such as transmyocardial laser revascularization are discussed. PMID- 8672567 TI - Posttransplantation lymphoproliferative disorders (PTLD): current perspectives. AB - Posttransplant lymphoproliferative disorders (PTLDs) are a family of lymphoid hyperplasias and neoplasias that occur in the context of organ transplantation and immunosuppression. A strong association exists with Epstein-Barr virus (EBV) infection of the B lymphocyte. This review summarizes clinical and pathological aspects of these lesions and explains the terminology used to describe them. Clinical diagnosis and therapy, including experimental approaches, are outlined. Patient outcomes from published series are given. The clinical heterogeneity and the need to individualize therapy for these patients are stressed. PMID- 8672568 TI - Chimerism and thoracic organ transplantation. AB - Current nonspecific immunosuppression for thoracic organ transplantation is limited by infection, end-organ toxicity, malignancy, and failure to completely control rejection. Donor-specific transplantation tolerance after bone marrow transplantation and the creation of mixed chimerism is a promising means for achieving drug-free allograft acceptance. This review explores bone marrow transplantation as a method for tolerance induction, the superior clinical characteristics of mixed chimerism, and recent developments that enhance marrow engraftment, minimize graft-versus host disease, and avoid lethal conditioning of the recipient. The importance of microchimerism in clinical transplantation and clinical trials aimed at augmentation of this phenomenon are reviewed. PMID- 8672569 TI - Molecular strategies for clinical xenotransplantation in cardiothoracic surgery. AB - The current shortage of donors for allotransplantation has generated interest in the potential use of animal organs to meet increasing clinical transplant needs, ie, xenotransplantation. However, when phylogenetically distant species such as the pig are transplanted into unmodified primate hosts--discordant xenotransplantation--the grafts undergo a rapid rejection process characterized by edema, hemorrhage, and diffuse microvascular thrombosis. "Hyperacute rejection" as such is mediated by an IgM natural antibody directed against the galactose alpha(1,3) galactose epitope expressed on the endothelial cell surface of all mammals except old world monkeys, apes, and humans which collectively lack the galactosyltransferase enzyme necessary for antigen expression. Transplants between nonhuman primates and human recipients--concordant xenotransplantation- avoid hyperacute rejection, but nonetheless undergo "acute vascular rejection" and progressive microthrombotic injury. Acute vascular rejection is associated with endothelial cell "activation," loss of vascular integrity, and progressive thrombosis. Molecular strategies for avoiding xenograft rejection involve insertion of genes into the donor pig genome capable of modifying xenoreactive antigen expression and regulating antibody-mediated endothelial cell damage. PMID- 8672570 TI - Thoracic outlet syndrome: introduction. PMID- 8672571 TI - Thoracic outlet syndrome: a current overview. AB - Thoracic outlet syndrome and the surgery associated with this diagnosis have a controversial reputation. The majority of patients with thoracic outlet syndrome seen in the context of the work place will have a multiplicity of components to their symptomatology, including multilevel nerve compression and muscle imbalance of the neck, shoulder, and back. Identification and conservative management of these problems make the necessity for surgery for thoracic outlet syndrome a rare event. Decompression of the brachial plexus, with or without first rib resection, is a technically demanding surgical procedure requiring expertise in peripheral nerve, vascular and thoracic surgery. Evaluation of these patients requires an understanding of neuromuscular physiology and chronic pain syndromes. PMID- 8672572 TI - Historical perspectives and anatomic considerations. Thoracic outlet syndrome. AB - The major developments in the evolution of understanding the thoracic outlet syndromes is presented in a chronologically historical record beginning with the first mention of a cervical rib by Galen in the second century A.D. Appreciation of the vascular and neurologic types of TOS progressed slowly through the centuries until detailed clinical studies were presented in the early 1900s. Interest in these syndromes increased steadily since then with description of the effectiveness of first rib resection by Murphy in 1910, and scalenotomy without cervical rib resection favored by Adson in 1927. The term "thoracic outlet syndrome" was coined by Peete et al in 1956 to encompass all the forms and causes of neurovascular compression in the base of the neck. Although rib resection may be considered the oldest operation on mankind, its application to treatment for TOS became popular only after Clagett's description of the posterior periscapular approach in 1962 and the transaxillary approach in 1966. The techniques of arteriography and venography were introduced in the 1960s and remain the hallmark for evaluation of the arterial and venous types of TOS. The neuroelectric studies introduced by Jebsen in 1968 have become popular, but offer little definitive diagnostic information for the neurogenic form of this syndrome. Recent histochemical studies of scalene muscles have shown important changes at the cellular level of the scalene muscles with trauma leading to TOS. The basic cause of the various neurovascular symptoms relates to anatomic abnormalities, either congenital or developmental, that cause abnormal compression and irritation of the major nerves and vessels in the thoracic outlet, causing certain people to have anatomic susceptibility to develop symptoms under certain conditions. These anomalies are described in some detail to facilitate the understanding, diagnosis, and surgical treatment of these special patients. PMID- 8672573 TI - Evaluation of the patient with thoracic outlet syndrome. AB - Clinical evaluation is paramount in making the diagnosis of thoracic outlet syndrome. Complaints of paresthesia and numbness will relate to the nerve compression component of thoracic outlet syndrome, whereas the pain associated with this syndrome is largely caused by muscle imbalance in the neck, shoulders, and upper back. Utilization of a pain evaluation scale assists in assessing a functional overlay to the pain complaints. Detailed sensory testing at rest and after provocation of the patient's symptoms with overhead activity will assist in the diagnosis. Radiographic test results are frequently normal in this patient population. By contrast, vascular testing results are frequently abnormal in a normal patient population. Electrodiagnostic tests are useful in ruling out other, more distal nerve entrapments. PMID- 8672574 TI - Conservative management of thoracic outlet syndrome. AB - Conservative management of thoracic outlet syndrome requires accurate evaluation of the peripheral nervous system, posture, and the cervico-scapular muscles. Patients should be instructed in postural correction in sitting, standing and sleeping, stretching exercises (ie, upper trapezius, levator scapulae, suboccipitals, scalenes, sternocleidomastoid and pectoral muscles), and strengthening exercises of the lower scapular stabilizers beginning in gravity assisted positions to regain normal movement patterns in the cervico-scapular region. Patient education, compliance to an exercise program, and behavioral modification at home and work are critical to successful conservative management. PMID- 8672575 TI - Supraclavicular first rib resection. AB - A supraclavicular approach will facilitate brachial plexus decompression and first rib resection. It allows the surgeon a complete visualization of all the neurovascular elements and removal of the first rib. In particular, under direct vision, the most posterior aspects of the first rib can be easily visualized and removed. During this dissection, care is taken to preserve the supraclavicular nerves. The technique of opening the pleura to allow drainage into the pleural cavity rather than around the brachial plexus will decrease postoperative scarring around the neural elements. Similarly, gentle but early postoperative movement of the head, neck, and upper extremity is encouraged in order to minimize scar formation around the brachial plexus. PMID- 8672576 TI - The transaxillary approach for treatment of thoracic outlet syndromes. AB - The diagnosis and management of thoracic outlet syndromes is based on the surgical management of more than 3,000 patients, 800 of which have had recurrent thoracic outlet syndromes. Accurate diagnosis for peripheral nerve compression is based on measurement of the ulnar and median nerve conduction velocities across the thoracic outlet. For sympathetic maintained pain syndrome or causalgia, a stellate ganglion block is helpful. Arteriography and venography are critical to show vascular compression. Conservative management is successful in most cases (70%) initially. For arterial reconstruction, the supraclavicular-infraclavicular approach is recommended. For the Paget-Schroetter syndrome (effort thrombosis of the axillary subclavian vein), prompt thrombolysis followed by transaxillary first rib resection is mandatory. No long-term anticoagulants are necessary. For hyperhidrosis, causalgia, sympathetic maintained pain syndrome or reflex sympathetic dystrophy, transaxillary dorsal sympathectomy with first rib resection or thoracoscopy is the preferred management when conservative therapy fails. For recurrent thoracic outlet syndrome and sympathetic maintained pain syndrome, a high thoracoplasty posterior approach is preferable with neurolysis of the nerve roots and brachial plexus as well as a dorsal sympathectomy. The technique of transaxillary first rib resection with or without dorsal sympathectomy is presented. The use of the thoracoscope expedites the procedure and improves the teaching capability. PMID- 8672577 TI - Results of the surgical treatment for thoracic outlet syndrome. AB - Excellent and good results following different operations for TOS are close to 80%, using simple statistics, where results included many patients followed up for only a few months. Using life-table methods, the success rate is 6% to 9% less, close to 70%, at 5 years. The results were virtually identical for anterior and middle scalenectomy, transaxillary first rib resection, and combined supraclavicular scalenectomy and first rib resection. Secondary success, the results of reoperation on patients in whom the first operation failed, improved the results of the primary operation 15% and 17%, respectively, for transaxillary rib resection and anterior and middle scalenectomy. When the initial operation was combined rib resection and scalenectomy, fewer patients underwent reoperation, as only neurolysis could be performed, and the results improved only 3%. A significant variable in results was etiology: Work-related injuries versus non-work-related accidents, usually auto accidents. Results of three independent studies showed better success rates by 13% to 15%, in patients who had non-work related auto accidents, as compared with work-related injuries. PMID- 8672578 TI - Intestinal ciliates found in the feces of Japanese native Tokara pony, with the description of a new genus and a new species. AB - The composition of intestinal ciliates excreted in the feces of 20 Tokara native ponies kept in Iriki farm of Kagoshima University was surveyed. Eleven genera consisting of 18 species were identified based on the description of Strelkow. One new genus including a new species, Wolskana tokarensis n. gen., n. sp., of the family Buetschliidae was recognized and described. The average ciliate density of all horses was 13.8 x 10(3)/ml. Those of stallions (n = 5), mares (n = 11) and foals (n = 4) were 3.9, 16.1 and 43.3 x 10(3)/ml respectively. The value of stallions was significantly lower and that of foals higher than that of mares. Brillouin's diversity index of all horses was 1.554 on average. The index of stallions, 1.470, was significantly lower than those of mares, 1.539, and foals, 1.698. The average number of species per host was 11.7. PMID- 8672579 TI - Mycoplasma hyorhinis infection levels in lungs of piglets with porcine reproductive and respiratory syndrome (PRRS). AB - The infection levels of Mycoplasma hyorhinis, M. hyopneumoniae and M. hyosynoviae in the lung of piglets were examined in relation to porcine reproductive and respiratory syndrome (PRRS). These animals consisted of 43 PRRS piglets with PRRS, 2 piglets infected with PRRS virus but symptom-free, and 10 control piglets free of PRRS virus and its antibody. M. hyorhinis was isolated from 40 of the 43 PRRS piglets, from 1 of the 2 latent infected piglets and from 3 of the 10 control piglets. The number of M. hyorhinis isolated from the lungs of PRRS piglets was more than 10(5) CFU/g, but those isolated from the latent infected piglets and the control piglets were less than 10(3) CFU/g. In addition to this, Haemophilus parasuis and Pasteurella spp. were frequently isolated from the piglets with PRRS (51.2% and 25.6%, respectively). On the other hand, M. hyopneumoniae was isolated from only 4 of 55 piglets tested, and M. hyosynoviae was not isolated. M. hyorhinis was also detected directly in the lung emulsion samples from almost all the PRRS piglets using a polymerase chain reaction-based method. PMID- 8672580 TI - Characteristics of the anticoccidial activity of 6-azauracil. AB - The characteristics of anticoccidial activities of 6-azauracil (AzU) were investigated in the battery trials utilizing the White Leghorn cockerels, which were infected with Eimeria tenella, E. necatrix, E. acervulina, E. maxima and/or E. brunetti. AzU was mixed into the basal starter feed and fed ad libitum to the birds from 1 day before the inoculation of oocysts to the time of necropsy. AzU showed remarkable anticoccidial activity against E. tenella and E. necatrix infections at doses of 1,000 ppm in feed or more, and fairly good effect against E. acervulina infection at the dose of 4,000 ppm in feed. Inadequate effect against E. maxima infection and null in effect against E. brunetti at the dose of 4,000 ppm were resulted for this drug. The effect of 6-azauridine, ribonucleoside of AzU against E. tenella and E. necatrix infections at 1,000 ppm was tested and revealed negative results. In the test with AzU-resistant line of E. tenella, cross resistance was confirmed between AzU and emimycin riboside, a uridine analogue. Activity of AzU was studied in vitro against E. tenella in chick kidney cells. AzU inhibited the development of the first- and second-generation schizonts at 100-200 ppm in the medium. Degenerated parasites were observed. PMID- 8672581 TI - Antagonistic effect of nucleic acid precursors on the anticoccidial activity of 6 azauracil. AB - The antagonistic phenomena to anticoccidial activities of 6-azauracil (AzU) induced by certain nucleic acid precursors were examined in battery experiments. Each nucleic acid precursor, orotate, orotidine, uracil, uridine, adenine and adenosine was mixed in feed in combination with effective levels of AzU. The test feed was provided through the test term to White Leghorn cockerels which were infected with Eimeria tenella, E. necatrix or E. acervulina. In vitro tests were also conducted for antagonistic phenomena similarly to in vivo test using E. tenella cultured in chick kidney (CK) cells. Orotate and uridine reduced dose dependently the anticoccidial activity of AzU in E. tenella infection in chickens. Uracil and orotidine revealed similar effect. Adenine and adenosine did not show any antagonistic effect to AzU. In E. necatrix infection, orotate and uridine had a similar tendency to that of E. tenella, whereas uracil and orotidine was less pronounced. The activity of AzU against E. acervulina was also blocked by the treatment with uridine and orotate. AzU inhibited the schizont's development of E. tenella in the CK cells, and this effect was reduced by uridine, but not by orotate and orotidine. The antagonistic effect of the pyrimidine nucleic acid precursors on AzU activity suggested that the anticoccidial effect of AzU to E. tenella, E. necatrix and E. acervulina is derived from inhibition of the metabolism of pyrimidine nucleotide synthesis in these parasites. PMID- 8672582 TI - Investigation for the characteristic anticoccidial activity of diclazuril in battery trials. AB - To clarify the character of the anticoccidial activity of diclazuril a series of battery trials was conducted. Diclazuril showed excellent anticoccidial activity in the infection of chickens with Eimeria tenella, E. necatrix or E. acervulina at the feeding level of 0.1 ppm. When diclazuril was administered in combination with a nucleic acid precursor, uracil, uridine, orotate or orotidine, the reduction of the activity of diclazuril to the infections induced by above species was not observed. While, bloody droppings with severe cecal lesions were resulted, when diclazuril was administered in combination with uridine 5(1) diphosphoglucose (UDPG) or its N-acetyl amine (UDPGNAC) to chickens infected with E. tenella. While, body weight gain of the birds and oocyst output was not affected by these combination-treatment. Results demonstrated that the antagonistic effect of UDPG and UDPGNAC to diclazuril was partial. The possibility of the cross resistance between diclazuril and 6-azauracil (AzU) in E. tenella was investigated using two populations induced resistance to AzU or diclazuril. The results demonstrated that the cross resistance does not exist between AzU and diclazuril, indicating that the mode of action of each drug is different. PMID- 8672583 TI - Histopathological findings on ulcerative lesions of carpal and tarsal joints in Japanese black cattle. AB - In order to determine the pathogenesis of ulcerative lesions of the articular cartilages in Japanese Black cattle, tissue samples of the ulcerative lesion, marginal portion of the ulcer, macroscopically normal portions and synovial membranes were histopathologically examined by light microscopy, scanning electron microscopy and contact microradiography. The results are summarized as follows: (1) In the ulcerative lesions, degeneration and complete destruction of articular cartilage and its replacement with a proliferation of myelogenic connective tissue were observed. (2) In macroscopically normal portions, fissures of the articular surface and changes of the trabecular pattern in subchondral bone were present. (3) In the marginal portions of the ulcerative lesions, evidences of the repair process such as connective tissue growth from subchondral bones and articular cartilages were seen. (4) In synovial membranes, no pathological findings were observed. And (5) among the above mentioned changes, no inflammatory findings were seen. In conclusion, the ulcerative lesions of bovine articular cartilage may be regarded as the early stage of osteochondrosis to osteoarthrosis since the findings such as noninflammatory destruction or degeneration and remodeling of the joints are characteristics of the latter. PMID- 8672584 TI - Changes in plasma concentrations of gonadotropins and steroid hormones during the formation of bovine follicular cysts induced by the administration of ACTH. AB - Bovine follicular cysts were induced by treatments with ACTH (3 mg, im) daily for 14 days beginning in the late luteal phase. Cortisol concentrations in plasma significantly increased after ACTH treatments. During the formation of follicular cysts induced by the injections of ACTH, mean plasma concentrations of progesterone were significantly higher than those in the untreated preovulatory period, while mean plasma concentrations of estradiol-17 beta were significantly lower. During the treatment period, mean plasma concentrations of LH and FSH remained low, and the preovulatory surges of LH and FSH did not occur. Suppressed concentrations of LH and FSH might be caused by the increases in secretions of cortisol and progesterone, and by the decrease in secretion of estradiol-17 beta. PMID- 8672585 TI - Radiographical and histological evaluation of canine decidual reaction induced by intralumenal injection of bouillon solution mixed with or without barium sulfate. AB - Radiographical examination of the canine uterus intralumenally injected with barium solution revealed that barium was gradually condensed, segmented and distributed equally along the lumen like embryos in early pregnant uterus. Histological examination of the uterus intralumenally injected with bouillon solution alone showed a remarkable fish net- or tree branch-like growth of superficial glands towards the uterine lumen. The uterus injected with barium in bouillon solution induced two different histological changes: One consisted of cystic glandular hyperplasia in the whole endometrium, which was a so-called Swiss cheese endometrium, and the other was composed of a fish net- or tree branch-like growth in the superficial layer accompanied with cystic glandular hyperplasia in the basal layer. The latter represented endometrial differentiation into spongy layer, supraglandular layer and basal glandular layer, being similar to that during normal early placentation. These findings suggest that clotted barium in bouillon solution has stimulating effects on the uterus similar to those of embryos. PMID- 8672586 TI - Canine deciduoma induced by intralumenal insertion of uterine grafts. AB - This report deals with evaluation of histological characteristics of the canine deciduoma induced by insertion of the uterine grafts as a biological stimulus. Autografts induced severe uterine cystic endometrial hyperplasia, and the grafts were organized by maternal endometrium. On the other hand, allografts induced more severe hyperplasia of the uterine endometrium with stronger inflammation than autografts. Almost all allografts became necrotic and lytic in the uterine lumen. These results suggest that uterine grafts could induce deciduoma and that the maternal endometrium, though under the functional corpora lutea, recognized the uterine grafts to be a stimulant and showed severe cystic endometrial hyperplasia. PMID- 8672587 TI - A canine case of profound granulomatosis due to Paecillomyces fungus. AB - A 5-year-old dog showed remarkable edematous swelling of the left hock with lameness and local cellulitis, and paecillomyces fungus was isolated from ulcerative lesion of the hock joint and mediastinum. At autopsy severe effusive pleuritis was shown and numerous necrotizing and granulomatous lesions with fungal elements were seen in the liver, pancreas, kidney and mediastinal lymph nodes. PMID- 8672588 TI - Peripheral neuropathy of dietary riboflavin deficiency in racing pigeons. AB - An occurrence of peripheral neuropathy in nine 14- to 55-day-old racing pigeons was documented. The predominant clinical signs were diarrhea, and leg and wing paralysis. Grossly, there was discoloration and swelling of all the peripheral nerve trunks. Microscopic lesions comprising swelling, fragmentation and demyelination of myelin sheaths, and proliferation of Schwann cells, were seen in the peripheral nerves of all birds examined. These changes were associated with moderate to severe swelling, fragmentation, atrophy and loss of axons. The peripheral nerve lesions in these cases were similar to those of dietary riboflavin deficiency in chickens. An analysis of the diet given to the pigeons indicated that the riboflavin concentration was only 0.9 mg/kg feed. PMID- 8672589 TI - Analysis of neutral glycosphingolipids of Theileria sergenti piroplasms. AB - Neutral glycosphingolipids (GSLs) were isolated from a lipid extract of Theileria sergenti piroplasms and analyzed by thin-layer chromatography (TLC) and liposome immune lysis assay (LILA); two predominant GSLs, designated as N-1 and N-2 were separated on TLC. N-1 GSL showed the same mobility as lactosylceramide (LacCer) on the TLC plate. On the other hand, the mobility of N-2 GSL on the TLC plate was identical to that of galactosylparagloboside. In order to characterize the molecular species of neutral GSLs from T. sergenti, N-1 and N-2 GSLs were tested by LILA with antibodies against LacCer and galactosylparagloboside, respectively, N-1 GSL had reactivity to anti-LacCer antibody and N-2 reacted with the antibody to galactosylparagloboside. These results suggest that N-1 and N-2 GSLs are LacCer (Gal beta 1-4Glc beta 1-1Cer) and galactosylparagloboside (Gal alpha 1 3Gal beta 1-4GlcNAc beta 1-3Gal beta 1-4Glc beta 1-1Cer), respectively. PMID- 8672591 TI - A consideration on the relationship between worm age and mortality of Setaria marshalli recovered from the peritoneal cavity of calves born in Tottori prefecture, Japan. AB - Eight calves born in November-December of 1992 were necropsied at the age of 29 230 days in an attempt to estimate the life span of Setaria marshalli in Japan. Worm ages were estimated on the base of active season for mosquitoes. Thirty worms estimated 4-9 months old recovered from 4 calves were all alive in the peritoneal cavity. Thirty-five out of 50 worms estimated 7-13 months old were dead with being entrapped by fibrin on the peritoneum. It is speculated that this is a normal fate of this parasite at the end of its life, and therefore, the life span of S. marshalli would be approximately one year after prenatal infection. PMID- 8672590 TI - Medication of feedlot calves infected with Eimeria spp. by a combination of sulfamonomethoxine and ormetoprim. AB - Feedlot calves naturally infected with Eimeria spp. were medicated by a combination of sulfamonomethoxine and ormetoprim (Ektecin). Calves, less than one year old and positive for coccidiosis, were administered with Ektecin (5, 10 and 20 ml/100 kg of body weight/day) and Daimeton (100% sulfamonomethoxine: 5 g/100 kg of body weight/day) for five days. No diarrhea were found on and after 3 days of medication in all the groups, and no oocysts were detected on and after day 5, 2, 1 or 3 from calves of the respective medicated groups. In samples from a group of calves administered with lowest dose of Ektecin, eimerian oocysts of 4 species were detected on day 0, and additionally 3 species (totally 7 species) were found on day 3 of medication. PMID- 8672593 TI - A case of megakaryoblastic leukemia in a dog. AB - An 8-year-old intact female Maltese was presented with anorexia and weight loss. Severe anemia, leukocytosis, and marked thrombocytosis were noticed. Blast cells resembled to megakaryoblasts were observed in peripheral blood smear. Based on bone marrow biopsy and histopathological examination, it was diagnosed as megakaryoblastic leukemia. Canine megakaryoblastic leukemia is very rare, however this is the first case report in Japan. PMID- 8672592 TI - Purification and activity of recombinant chicken stem cell factor produced by using a baculovirus vector. AB - Stem cell factor is a pleiotropic cytokine that plays an essential role in the development of hematopoietic cells, germ cells, and melanocytes. To obtain recombinant soluble chicken stem cell factor (chSCF), a baculovirus containing the cDNA encoding chSCF polypeptide from amino acids -25 to 170 was constructed. The chSCF produced in insect cells infected with the virus was purified by ion exchange column chromatography. The ability of the purified protein to induce the outgrowth of neurites from chicken dorsal root ganglia cultured in vitro was demonstrated. PMID- 8672594 TI - Detection of serum-dependent cytotoxic activity of Campylobacter jejuni and its characteristics. AB - We previously set forth appropriate three assay systems using Chinese hamster ovary cells to detect the Campylobacter jejuni cytotoxin. Although we could not reach a conclusion because the cytotoxins shown in this study were not purified, at least three different cytotoxins were detected in these assay systems. The first cytotoxin in the presence of fetal calf serum (FCS) was heat-labile and the molecular weight (Mw) was estimated at 50-100 k by ultrafiltration. The second cytotoxin detected in the presence of newborn calf serum (NCS) was heat-stable and Mw was estimated at 0.5-3.0 k. The third cytotoxin detected in serum-free culture (SFC) assay was heat-labile and non dialyzable. However, Mw was not estimated since the low Mw and heat-stable cytotoxin was also detected in this assay. The cytotoxic activity detected in FCS and NCS assays, but not that detected in SFC assay, was completely abolished by treatment with a reducing agent. In contrast, the cytotoxicity detected in both FCS and NCS assays was not inactivated by such an enzyme as trypsin, lipase, neuraminidase, and beta galactosidase. When the filtrate was heated at 100 degrees C to inactivate the heat-labile cytotoxin, the cytotoxic activity was detected in the NCS assay but not in FCS assay. However, when NCS was added to this heated filtrate, the cytotoxicity was restored in FCS assay. Furthermore, when normal rabbit serum (NRS) was added, no cytotoxicity was restored. The cytotoxic activity in SFC assay was completely inactivated with FCS or NRS. These findings suggest that the cytotoxic activity is dependent on serum added to tissue culture medium and that the substance amplifying and/or inhibiting the cytotoxic activity may be present in serum. PMID- 8672595 TI - Lipid peroxide levels and superoxide-scavenging abilities of Sera obtained from hotbred (Thoroughbred) horses. AB - Hotbred (Thoroughbred) horses were grouped into three classes according to the levels of constant physical exercise (foals, 6 months old; racing horses, 5 years old; horses for breeding, 6-10 years old), and lipid peroxide levels in their sera were measured as thiobarbituric acid-reactive substances. No significant differences were observed among them. The superoxide-scavenging abilities of sera were measured next; to examine the antioxidative properties of hotbreds, and were found to be highest in the racing horses. The higher scavenging ability of the racing horses might contribute to keep their lipid peroxide levels as low as those of the other two groups. HPLC analysis of substances in sera suggested that the presence of albumin-bound bilirubin was one of the reasons for the high superoxide-scavenging ability of sera of the racing horses. When the hotbreds were compared with coldbred (crossbred) horses, the lipid peroxide levels of hotbreds was higher (7.0 +/- 1.2 nmol/ml) than that of coldbreds (2.6 +/- 0.7 nmol/ml). Comparison of the superoxide-scavenging abilities of sera between hotbreds and coldbreds showed that the hotbreds possessed higher scavenging ability than the coldbreds. These results indicated that the lipid peroxide level in sera of hotbreds was higher than that of coldbreds regardless of the higher superoxide-scavenging abilities of sera. PMID- 8672596 TI - Perinatal vitamin A (retinol) status of northern Canadian mothers and their infants. AB - Vitamin A (retinol) status was determined in two groups living in the northern part of Canada: native (Indian and Inuit) and non-native (Caucasian). The dietary intake of vitamin A and its plasma concentration were measured prenatally, at delivery and postnatally in mothers. Plasma concentrations were also measured at birth and postnatally in their infants. The mean vitamin A intake of native mothers was significantly lower than that of non-native mothers, 661 +/- 485 versus 1,377 +/- 1,418 retinol equivalents (p < 0.00005), with a higher risk of deficiency without supplementation, 35% versus 8%. Plasma retinol concentrations, although not in the deficient range, were significantly lower in native than non native mothers prenatally and postnatally. Infant mean plasma retinol concentrations at birth averaged only 52% of those of their mothers and were significantly lower among native than non-native infants although no clinical evidence of vitamin A deficiency was noted. We speculate that vitamin A supplementation in native Northern Canadian mothers during pregnancy and in their neonates during infancy may have a role to play in the prevention of vitamin A deficiency. We also postulate that plasma retinol concentrations of 50-60% of maternal levels and between 0.7 and 2.5 mumol/l represent a 'normal' range for newborn infants. PMID- 8672597 TI - In vitro analysis of the Na(+)-K+ ATPase activity in neonatal and adult red blood cells. AB - We studied the role of albuterol in inducing potassium flux mediated by Na(+)-K+ ATPase in neonatal cells under hyperkalemic conditions. Using rubidium as a tracer element, we determined net transmembrane potassium flux in neonatal and adult red blood cells (RBCs) maintained in a buffer solution containing 10 mM KCl. We demonstrated that under these hyperkalemic conditions, albuterol does not increase the net transmembrane potassium flux of the adult RBC. However, neonatal RBCs maintained in these same hyperkalemic conditions demonstrate a significant 50% increase in net transmembrane potassium flux when exposed to albuterol. We conclude the albuterol may be useful in lowering the serum potassium levels in neonates even with extreme hyperkalemia. PMID- 8672598 TI - Effects of chloral hydrate on the cardiorespiratory response to hypoxia in newborn piglets. AB - To assess the effects of chloral hydrate (CH) on the cardiorespiratory response to hypoxia in the neonate, 17 newborn piglets were chronically instrumented 48-72 h before study and randomly assigned to a CH group (100 mg/kg, i.p.) or saline group. The animals were intubated and studied under quiet sleep which was determined by behavioral states, and continuous electro-oculographic and electroencephalographic monitoring. Minute ventilation (VE), tidal volume, respiratory rate, arterial blood gases (ABG), oxygen consumption (VO2), arterial blood pressure (ABP) and heart rate (HR) were measured before and after CH or saline administration during room air and after 10 min of hypoxia (fraction of inspired oxygen concentration = 0.10). Cardiorespiratory response to hypoxia was similar before and after saline infusion. Basal VE and the ventilatory response to hypoxia were similar before and after CH administration. In contrast, the basal ABP decreased significantly (p < 0.05) after CH administration, but the ABP response to hypoxia was similar before and after CH. A significant increase in both basal HR and HR with hypoxia was observed after CH administration. In addition, VO2 and ABG were not modified by CH treatment during normoxia and hypoxia. These data demonstrate that a sedative dose of CH does not significantly modify the ventilatory response to hypoxia in newborn piglets. However, CH produced some changes in the cardiovascular system which should be considered when using it in infants with hemodynamic derangements. PMID- 8672600 TI - Recent Advances in Neonatal Medicine, International Symposium and 11th Workshop on Surfactant Replacement. Tubingen, April 26-28, 1996. Abstracts. PMID- 8672599 TI - Antenatal glucocorticoid treatment attenuates immediate postnatal prostacyclin and thromboxane levels in plasma of very preterm lambs. AB - The effect of antenatal glucocorticoid treatment on the production of cyclooxygenase metabolites was studied in very preterm lambs. Seven fetal lambs, 121 days of gestation, received a single dose of betamethasone, 0.5 mg/kg i.m., 48 h prior to delivery. Five age-matched controls received saline intramuscularly. Each fetus was delivered and ventilated for 3 h and sacrificed. Plasma was prepared from blood drawn from the umbilical cord of each fetus, and 60, 120 and 180 min after delivery. Mesenteric (MESA) and femoral (FEMA) arteries were isolated and incubated in Krebs' buffer for 10 min at 37 degrees C. Samples were extracted for prostacyclin (PGI2), and thromboxane (Tx)A2, purified by HPLC and measured by specific radioimmunoassay. Amounts of metabolites measured postnatally from betamethasone-treated preterm lambs were significantly lower (p < 0.05) than the amounts from saline lambs. Prostacyclin production by MESA and FEMA of betamethasone-treated lambs was lower than by vessels of saline-treated lambs. There was no difference in TxA2 production by vessels from the two groups of preterm lambs. Our data show that antenatal betamethasone treatment decreased systemic prostanoid production suggesting a decreased reactivity of the vascular membrane. PMID- 8672601 TI - Transcranial magnetic stimulation: a potential new frontier in psychiatry. PMID- 8672602 TI - Variability of brain lithium levels during maintenance treatment: a magnetic resonance spectroscopy study. AB - In vivo magnetic resonance spectroscopy (MRS) was used to determine the relationship between serum and brain lithium levels in bipolar patients (n=25). Over the broad range of serum lithium levels observed, the correlation (r=.68) with brain lithium levels was high. This correlation was much weaker (r=.39) when limited to only those patients with serum lithium levels in the range of 0.6-1.0 mmol/l. This variability may account for failure of lithium prophylaxis in some patients who have serum lithium levels in the therapeutic range. PMID- 8672603 TI - Regional 133xenon cerebral blood flow and cerebral 99mTc-HMPAO uptake in patients with obsessive-compulsive disorder before and during treatment. AB - We previously reported increased regional cerebral cortical uptake and decreased caudate nucleus uptake of 99mTc-HMPAO in patients with obsessive-compulsive disorder(OCD) before treatment compared to matched normal controls. In the present study, we determined whether or not these changes persisted during treatment. Single-photon emission computed tomography was used to measure regional cerebral blood flow (rCBF) by 133Xe inhalation and cerebral uptake of 99mTc-HMPAO in eight adult male OCD patients before and during treatment with chlomipramine, and in eight age-matched normal male controls. With 133Xe, there were no significant differences in rCBF between patients with OCD and their matched controls, and no significant differences in rCBF in the patients before and during treatment. Significantly increased HMPAO uptake in the orbital frontal cortex, posterofrontal cortex, and high dorsal parietal cortex bilaterally occurred in the OCD patients before treatment compared to their matched controls, and there were significant reductions of HMPAO uptake, into the normal range, in all these areas in the patients during treatment. Significantly reduced HMPAO uptake in the caudate nucleus bilaterally occurred in the patients before treatment compared to their matched controls, and these reductions persisted during treatment. This study provides additional support for the involvement of both the orbital frontal cortex and the caudate nuclei in the pathophysiology of OCD. PMID- 8672604 TI - Abnormal brain glucose metabolism in the delusional misidentification syndromes: a positron emission tomography study in Alzheimer disease. AB - Brain lesions have been reported with increasing frequency in the delusional misidentification syndromes (DMS). This is the first controlled study to describe DMS regional cerebral metabolic rates of glucose (rCMRglc). We compared rCMRglc (using positron emission tomography) and neuropsychological data in 9 patients with DMS and Alzheimer dementia (AD), 15 AD patients without DMS, and 17 healthy controls. The DMS group differed from the AD group without DMS in having significant hypometabolism in paralimbic (orbitofrontal and cingulate areas bilaterally) and left medial temporal areas, and significant bilateral normalized hypermetabolism in sensory association cortices (superior temporal and inferior parietal) without right left asymmetry. Compared to healthy controls, both AD groups had significant dorso lateral frontal hypometabolism bilaterally. No specific DMS neuropsychological profile was identified. Dysfunctional connections among multimodal association areas, paralimbic structures, and dorsolateral frontal cortex are proposed as the predisposing neural deficit underlying DMS, causing cognitive-perceptual-affective dissonance, which under specific conditions results in "positive" delusion formation. PMID- 8672605 TI - Effects of ipsapirone on plasma cortisol and body temperature in major depression. AB - Major depressed patients have been reported to exhibit significantly attenuated hypothermic responses to ipsapirone, a serotonin (5-HT)-1A partial agonist, compared to normal controls. This study further investigated the cortisol and temperature responses to ipsapirone (0.5 mg/kg orally) and placebo in 20 normal volunteers and 12 major depressed patients. Both plasma cortisol and temperature were measured every 30 min before ipsapirone or placebo administration until 180 min post administration. Ipsapirone administration produced a significant increase in plasma cortisol levels as well as hypothermia. Major depressed patients showed significantly blunted ipsapirone-induced cortisol responses compared to normal controls. No significant differences in ipsapirone-induced hypothermic responses were found between major depressed patients and normal controls. PMID- 8672607 TI - Changes in platelet 3-H-imipramine binding: influences of protein concentration of varying proportions of cytosol or intact platelets and displacing agents used. AB - Platelet 3-H-imipramine binding exhibits considerable variation, both interindividually and between several groups. The aim of this study was to measure 3-H-imipramine binding, simultaneously in platelet membranes vs. intact platelets vs. cytosol or intracytosolic protein in order to determine their effect on Bmax and Kd values. 3-H-imipramine binding was carried out at different protein concentrations. Our results indicate that the affinity constant is heavily influenced by the presence of cytosol and intact platelets in membrane preparations. Finally, we demonstrate a negative correlation between Bmax and protein concentration. Only perfect analytical conditions will allow platelet 3-H imipramine binding to be a biological marker for affective disorders. PMID- 8672606 TI - The role of pterins in depression and the effects of antidepressive therapy. AB - Urinary excretion of neopterins (N) and biopterins (B) was measured in 48 patients with depression before and after treatment with placebo, antidepressants, or electroconvulsive therapy (ECT), and in 26 healthy control subjects. Patients prior to and after treatment had a significantly greater neopterin/biopterin (N:B) ratio than control subjects. There was a significant correlation between N:B ratios and the severity of depression and plasma cortisol. As a raised N:B ratio implies failure to convert neopterin to biopterin, it is possible that reduced availability of tetrahydrobiopterin, the essential cofactor for the formation of noradrenaline, serotonin and dopamine, may exert rate-limiting control over the synthesis of monoamines implicated in the pathogenesis of depressive illness. PMID- 8672608 TI - Long-term decrease in the hippocampal [3H]inositoltriphosphate binding following repeated electroshock in the rat. AB - A quantitative autoradiographic study was made on the binding of the phosphatidylinositol system ligand [3H]inositol(1,4,5)-triphosphate (IP3) to forebrain sections from electroconvulsive shock (ECS)-treated rats. One group of rats was sacrificed 1 day and 1 month, respectively, after 12 ECSs administered three times weekly for 4 weeks. SHAM-stimulated rats served as controls. A single ECS did not change the [3H]IP3 binding in any of the brain regions examined. One day after the last of 12 ECSs, a decrease in [3H]IP3 binding (21%) was found within the CA1 region of the hippocampus and the piriform cortex (39%). In rats sacrificed 1 month after the last of 12 ECSs, the [3H]IP3 binding in piriform cortex had returned to control level. In the CA1 region of the hippocampus, the binding was still decreased (24%). It is possible that changes in the phosphatidylinositol system may play a part in the neurobiological events responsible for the therapeutic effect of electroconvulsive therapy. PMID- 8672609 TI - Attributes of heavy vs. occasional marijuana smokers in a college population. AB - We sought to assess whether college students who smoked marijuana heavily were distinguishable from students who had used the drug only occasionally. We compared 45 long-term heavy marijuana smokers (individuals who had smoked daily for at least 2 years) with 44 "occasional" smokers (individuals who had never smoked more than 10 times in a month at any time in their lives), drawn from the student populations at two Boston-area colleges. measures included a questionnaire covering a range of demographic, drug use, and subjective items; the Rand Mental Health Inventory; and both the Axis I and Axis II sections of the Structured Clinical Interview for DSM-III-R. Heavy smokers reported higher rates of use of other substances, especially hallucinogens and cocaine, and they described greater subjective impairment of memory and motivation than occasional smokers; however, on a wide range of demographic, family background, and mental health measures, the heavy smokers proved almost indistinguishable from occasional smokers. Even the heaviest college marijuana smokers exhibit few demographic or psychiatric features that distinguish them from students who smoke only occasionally. PMID- 8672610 TI - Diagnostic specificity of focal white matter abnormalities in bipolar and unipolar mood disorder. PMID- 8672611 TI - Abnormal saccadic eye movements associated with positive family history schizophrenics. PMID- 8672612 TI - [Education and research in emergency medicine. Responsibilities of the anesthesiology specialty]. PMID- 8672613 TI - [Circulating cerebral microembolisms. Detection with transcranial Doppler ultrasound]. AB - Ischaemic stroke is predominantly caused by cerebral emboli which may originate from cardiac sources or atherosclerotic lesions of the cerebral arteries. The diagnosis is primarily based on clinical symptoms and may be confirmed by typical patterns in cranial computed tomography. Echocardiography, ultrasonography of the supraaortic vessels, and angiography are additional diagnostic tools and helpful in clarifying the pathogenesis. Circulating cerebral emboli can be detected using transcranial Doppler sonography (TCD). Emboli are characterised by short-term, high-intensity ultrasonic signals with characteristic audible "chirps". Because of their acoustic impedance, gaseous emboli reflect the ultrasonic beam with a higher intensity than do formed particles. The differentiation between true embolic signals and artifacts (probe dislocation, electrocautery) requires an experienced observer. With recent developments in automatic detection systems, monitoring will become more feasible for clinical applications. During cardiovascular surgery, TCD signals implying cerebral emboli have been registered in various studies. The incidence of embolic signals during cardiopulmonary bypass varies with stage (before, after aortic declamping) and type of surgery (coronary, valve replacement) and the perfusion regime (bubble, membrane oxygenator). For carotid surgery, embolic signals are most likely to occur with carotid clamping, during shunt insertion, and after declamping. There are some studies suggesting a relation between intraoperative embolic signal count and post-operative neurologic state, but the prognostic significance of these signals is still under debate. Strictly controlled prospective studies including a large number of patients have to be conducted to answer the question whether embolic signal count indicates an increased stroke risk. The high number of patients after valve replacement showing up to 30 embolic signals per minute without suffering from neurologic symptoms raises the question whether continuous, predominantly gaseous microembolisation may cause cumulative brain damage. At present, the nature of emboli (gaseous vs. solid) cannot be easily identified by TCD in clinical settings. Future technical improvement of ultrasonic devices may solve this problem, since detection of solid rather than gaseous emboli seems more likely to be clinically relevant. PMID- 8672614 TI - [Is infection and septic shock caused by a global oxygen deficiency? An overview in 2 parts. 1: Infection and correlation between DO2 and VO2]. AB - A global hypoxia resulting in an oxygen debt is assumed to be present in patients who suffer from the different stages and degrees of sepsis including septic shock and ARDS. As a consequence, the therapeutic concept of optimal values for cardiac output and oxygen delivery for these patients was proposed. This article reviews the literature with the objective of determining whether investigations dealing with oxygen delivery and consumption and with the plasma lactate concentration support the idea of the global hypoxia in septic patients. The finding of a pathologic oxygen supply dependency and an increase in plasma lactate concentration were taken as evidence for a global hypoxia. Between 1983 and 1991, oxygen supply dependency in septic patients was reported in an increasing number of publications. The increase in plasma lactate concentration was interpreted as lactic acidosis without presentation of plasma pH values and taken as evidence of global hypoxia and oxygen debt. From 1989 on, the number of publications that failed to show oxygen supply dependency even in the presence of an increased plasma lactate concentration increased. The problem in the method of determination of oxygen supply dependency became evident. Deducing both oxygen consumption and oxygen delivery from cardiac output from a common shared variable subject to measurement error may produce errors in the calculation of the regression between oxygen delivery and consumption. Oxygen supply dependency was not demonstrated in most investigations in which oxygen delivery and consumption were measured independently of each other. No decrease in mortality could be shown in prospective randomized studies for patients with sepsis and septic shock who were treated according to the concept of the optimal values. The lactate plasma concentration was below 5 mmol/l in most studies, which represents the borderline value for a clinically significant lactic acidosis. The term acidosis is not justified without a decrease in plasma pH or a decrease in the bicarbonate plasma concentration. An increased lactate plasma concentration can be merely the result of a hypermetabolism which is often found in septic patients. There is no proven evidence for global tissue hypoxia in septic patients from the investigations of oxygen delivery and consumption. This is also true for patients in septic shock after plasma volume expansion. The dogmatic proposal to increase cardiac output and oxygen delivery to certain levels cannot be sustained. However, regional hypoperfusion (e.g., of the splanchnic vascular bed) cannot be excluded. New approaches like gastric mucosal tonometry, measurement of splanchnic blood flow, and determination of regional metabolism are currently under investigation. PMID- 8672616 TI - [Premedication of coronary risk patients--results of a survey]. AB - AIM: The perioperative risk in patients undergoing coronary artery bypass grafting (CABG) might be influenced by premedication procedures. This study was undertaken to evaluate present premedication regimens in CABG patients in Germany. METHODS: Using a detailed written questionnaire, each of the 58 German centres of cardioanaesthesia were asked to complete it. RESULTS: 37 (64%) of all questionnaires were returned and analysed. All centres used orally administered drugs for premedication in the evening before the operation. Flunitrazepam is the most often administered drug (54%), followed by dipotassium clorazepat (8%), and diazepam (8%). Premedication in the morning on the day of surgery is performed orally in 29 centres (78%), of which 18 centres (49%) prefer flunitrazepam and 6 centres (16%) midazolam as first choice. In contrast, 7 centres (19%) used intramuscularly administered regimens. 5 centres (14%) combined intramuscularly opioids with sedatives for that indication. If anaesthesia was induced late in the morning or in the afternoon, respectively, 11 centres (30%) administered additional benzodiazepines early in the morning. 68% of all centres maintained the administration of chronic treatment with ss-blockers until the morning of the operating day. Chronic treatment with nitrates is continued in 65%, treatment with calcium-channel blockers in 62%. Angiotensin converting enzyme inhibitors are continued in 30%, alpha 2-agonists in 27%, other antihypertensive drugs in 19%, and inotropic glycosids in 11%. 31 of 37 centres (84%) discontinued the administration of acetylsalicylic acid 5 or more days prior to surgery, but 68% tolerate individual exceptions from this principle. CONCLUSIONS: The results of our survey indicate that most of the German cardioanaesthesia centres use oral premedication regimens in patients undergoing coronary revascularisation. Anti anginal medications, with the exception of anti-platelet agents, were continued until the day of surgery in most of the centres. PMID- 8672615 TI - [Differential administration of non-opioids in postoperative analgesia, I. Quantification of the analgesic effect of metamizole using patient-controlled analgesia]. AB - OBJECTIVE: The aim of this study was to investigate: 1. Whether the perioperative administration of metamizol causes a significant reduction in postoperative opioid requirements within the first 24 h after surgery. 2. The opioid-sparing effect after different types of operations. 3. Whether preoperative application of metamizol causes a significant reduction of the pain-score immediately after operation. METHODS: In a double-blind, randomised, placebo-controlled study, 117 patients, scheduled for minor orthopaedic or laparoscopic surgery or other operations (mainly resection of the thyroid gland and inguinal herniotomies) received either metamizol (1 g/100 ml NaCl 0.9%) or placebo (100 ml NaCl 0.9%) intravenously over 15 min in three separate doses: the first dose was given just before induction and the others 6 h and 12 h later. After surgery all patients were allowed to self-administer buprenorphine from a PCA (patient-controlled analgesia) pump (Bolus: 30 microgram, lockout: 5 min in the recovery room, 30 min on the ward). Every hour for the first 6 h and after 24 h, cumulated doses of buprenorphine, pain scores (0-10), blood pressure, pulse and side effects were recorded. RESULTS: After minor orthopaedic and laparoscopic surgery, metamizol treated patients had significantly less pain immediately after surgery and used a significantly lower cumulated dose of opioid in the first 24 h after surgery ( 20% and -67% respectively) than patients receiving placebo. After the other types of surgery no analgesic effect could be established. CONCLUSIONS: Perioperative administration of metamizol results in better pain relief and significantly lower buprenorphine requirements particularly after laparoscopic operations. To achieve a significant pain reduction immediately after the operation, the first dose should be applied before induction. PMID- 8672617 TI - [Attempt at a definition of the individual anesthesia level by repetitive pain stimulation: correlation with EEG findings]. AB - AIM: Previous studies using EEG for assessment of depth of anaesthesia correlate anaesthetic concentration with the anaesthetic stage. This procedure neglects the well known effect of individual different susceptibility to anaesthetics. Thus, patients receiving similar concentrations of anaesthetics may not necessarily be at the same level of "anaesthetic depth". The aim of this study was to define an interindividual comparable level of anaesthesia by recording the autonomic cardiovascular reaction to a standardised painful stimulus (tetanic stimulus, 80 mA, 100 Hz). METHODS: In 61 patients undergoing orthopaedic surgery general anaesthesia was performed with isoflurane in 66% N2O. Starting from 0.4% isoflurane, endtidal isoflurane concentration was increased in a stepwise manner (0.1% isoflurane) until the patient did not show any relevant cardiovascular reaction (increase of heart rate and/or blood pressure < 10%) after tetanic stimulation of the ulnar nerve. If patients demonstrated no haemodynamic changes at 0.4% isoflurane, the concentration was decreased until a relevant cardiovascular reaction was registered. During each steady state period multichannel EEG was recorded and mean values of power density (median: microV2/Hz) were computed. RESULTS: Comparing EEG-results between both groups exhibiting a cardiovascular reaction (CVR+ , median endtidal Iso: 0.5%) and without reaction (CVR- , median endtidal Iso: 0.6%) an increase in low frequency bands and a significant decrease in high frequencies was found (Wilcoxon-test, p < 0.05). In contrast, comparing EEG-data only in relation to endtidal isoflurane concentration neglecting individual haemodynamic responses, no differences of power density in high frequency bands were detected. CONCLUSION: This method to define individual depth of anaesthesia as described, results in more consistent EEG patterns and may be useful in relating EEG to depth of anaesthesia. PMID- 8672618 TI - [Integrated concept for implementing clinical training in emergency medicine]. AB - Since 1993 special lectures in emergency medicine are part of curriculum in the study of medicine at German universities. To intensify practical teaching in this field an integrative concept was followed in performing emergency training, the experiences of which are described in this paper. Seminars dealing with the most important subjects of preclinical care were combined with practical training blocks such as attendance at operations of the preclinical emergency physician service, resuscitation training using computerised resuscitation models (Mega Code), and an anatomical training course for endotracheal intubation, coniotomy, thoracic drainage, or central venous catheterisation on a corpse. If supported by physicians, senior students may supervise groups of 4 to 5 students during the Mega Code training in a tutorial system, thus allowing to intensify practical education. Since the integrative concept is based on cooperation of different medical specialties, the students expect one or two physicians to be chiefly responsible for the entire course. Additional dates during the semester interfere with the students' leisure activities and require individual practical activity. This means giving up a passively receptive attitude. However, as reflected by the results of the exams and questionnaires, response to this step of improvement in Emergency Medical Education has been very positive. Future efforts are directed at including more physicians as practical supervisors, scattering of training dates, an increase in compulsory practical participation such as one-day attendance at an intensive care unit, and intensified exams on practical issues. However, the improvement of the quality of teaching is imperative in the job planning of the medical profession. PMID- 8672619 TI - [The Ulm emergency medicine training course. 1: Concept]. AB - The course in emergency medicine was introduced by the German Federal Government to meet the requirements of the curriculum of the 4th year of medical education in 1992. The Department of Anaesthesiology of the University Hospital Ulm drew up a course consisting of one week of practical instructions (Table 3) for groups of 24 students, case presentation and accompanying lectures that cover the topics of emergency medicine (Table 2). The course is part of continuous education in emergency medicine. It starts with courses in "first aid" and "first medical attendance to emergencies" followed by the "course"in emergency medicine" and further training weeks on the "mobile intensive care unit (MICU)" during the "internship" as well as a course on emergency medicine for ambulance doctors and the training on he job by an emergency physician during residency (Table 1). The aim of the course is training competence (psychomotoric skills and clinical competence) for the primary care of life-threatening emergencies. The following educational methods were included in the concept: problem oriented learning, situation-oriented learning, learning by doing (cognitive apprenticeship). PMID- 8672621 TI - [Alcohol as therapeutic drug in alcohol dependent intensive care patients: contra]. PMID- 8672622 TI - [Alcohol administration for prevention of withdrawal delirium in alcohol dependent surgical intensive care patients: pro]. PMID- 8672620 TI - [Comparative study of the cost-/effectiveness relationship of initial therapy with imipenem/cilastatin in nosocomial pneumonia. Group study]. AB - AIM OF THE STUDY: The present study assessed the total cost involved in the therapy of nosocomial pneumonia. Cost for patients receiving Imipenem as initial antibiotic therapy was compared with that for patients treated by selected alternative regimens. Secondary objectives included the evaluation of fever days, days of antibiotic therapy, days at ICU and days of overall hospitalisation required for the treatment of the nosocomial pneumonia for both methods of treatment. METHODS: A prospective randomised open study involving multiple study sites was conducted. Total cost, efficacy and safety of an initial therapy with Imipenem were compared to results achieved with selected other antibiotic regimens. Altogether 109 patients were enrolled into the study; 85 patients could be assessed. RESULTS: Both treatment methods showed equal clinical efficacy. Total cost of the therapy of nosocomial pneumonia for all patients was in the range between 1,616 DM and 82,141 DM, the arithmetic mean was calculated to be 11,307 DM and the median was found to be 6,507 DM. Imipenem-treated patients incurred lower cost (median 5,649 DM, mean 10,009 DM) than patients treated with other antibiotics (median 9,334 DM, mean 12,701 DM). CONCLUSION: The total cost of treatment of nosocomial pneumonia was lower for Imipenem-treated patients than for patients receiving initially other selected antibiotic regimens. The savings are apparently due to a faster recovery of the patients resulting in reduced duration of therapy. The study shows that assessment of cost of therapy per day might be misleading in the economic analysis of antimicrobial chemotherapy. PMID- 8672623 TI - [Carbon dioxide absorption]. PMID- 8672624 TI - [Resuscitation in multiple trauma]. AB - We report on a case of successful outpatient cardiopulmonary resuscitation of cardiac arrest after blunt multisystem injury. The literature is discussed and prognostic indicators are described. PMID- 8672625 TI - [Intubation with the Combitube-TM in massive hemorrhage from the locus Kieselbachii]. AB - Massive nasal haemorrhage occurred during an attempted nasal endotracheal intubation in a 52-year old patient, scheduled for bone grafting to the mandibula. Ventilation of the patient by face mask and conventional endotracheal intubation by laryngoscopy were not possible due to massive bleeding. This situation was successfully managed by the use of a Combitube. The role of the Combitube in difficult airway management as well as its extensive contraindications are discussed. Rare complications when using the Combitube, their diagnosis and treatment are mentioned. PMID- 8672626 TI - Characterization of hydrogels using luminescence spectroscopy. AB - In this contribution the literature relevant to characterization of polyelectrolytes, polyelectrolyte complexes and hydrogels using luminescence spectroscopy is reviewed. A brief introduction to the fundamentals of luminescence is followed by a description of the various types of spectroscopic studies which may be used to characterize hydrogels. In addition to experiments based upon the addition of a viscosity, temperature- or polarity-sensitive fluorescent probe to characterize the local environment, experiments and techniques based upon luminescence quenching, fluorescence polarization, phosphorescence depolarization and excimer fluorescence are discussed. This review succinctly describes the utility of luminescence spectroscopy in the characterization of hydrogel systems, with a focus on recent developments in the characterization of hydrogels and polyelectrolyte complexes. PMID- 8672627 TI - Release of foreign bodies (particles) by clinical use of intravenous infusion sets. AB - In clinical practice, stripping the plastic tubes of intravenous (i.v.) infusion sets with a scissor blade is a commonly used method for re-establishing flow in malfunctioning i.v. sets. The present investigation concludes that this procedure results in release of plastic particles from the luminal wall of the tube. Particles are subsequently flushed into the patient. The average amount of particles released exclusively from the i.v. infusion sets under these circumstances may exceed the standards for acceptable particle content per millilitre in large volume i.v. injectable fluids, according to the British Pharmacopoeia (1980) and the United States Pharmacopoeia (1990). PMID- 8672628 TI - Physical and biological effects of a surface coating procedure on polyurethane catheters. AB - Central venous catheters are widely used in clinical practice; however, complications such as venous thrombosis or infection are frequent. The physical and biological effects of a coating procedure designed to improve the blood contacting properties of polyurethane central venous catheters (CVCs) were studied. The surface atomic composition of poly(vinyl pyrrolidone) (PVP)-coated or uncoated Pellethane single lumen CVCs was characterized by electron spectroscopy for chemical analysis (ESCA), which confirmed the presence of an oxygen-rich PVP layer on the former material. Topological analysis of both single and triple lumen CVCs by scanning force microscopy (SFM) revealed a very smooth surface in PVP-coated catheters compared to the more frequent surface irregularities found either in uncoated Pellethane or in four additional randomly selected, commercially available triple lumen polyurethane CVCs. The PVP-coated Pellethane showed a strong reduction in either fibrinogen or fibronectin adsorption compared to all other PVP-free polyurethane CVCs. This decreased protein adsorption led to a proportional reduction in protein-mediated adhesion of either Staphylococcus aureus or Staphylococcus epidermidis and in the binding of a monoclonal antibody directed against the cell-binding domain of fibronectin. Increased surface smoothness and hydrophilic properties of polyurethane CVCs might decrease the risk of bacterial colonization and infection. PMID- 8672629 TI - In vitro degradation of dermal sheep collagen cross-linked using a water-soluble carbodiimide. AB - Bacterial collagenase was used to study the susceptibility of dermal sheep collagen (DSC) cross-linked with a mixture of the water-soluble carbodiimide 1 ethyl-3-(3-dimethyl aminopropyl)-carbodiimide hydrochloride and N hydroxysuccinimide (E/N-DSC) towards enzymatic degradation. Contrary to non-cross linked DSC (N-DSC), which had a rate of weight-loss of 18.1% per hour upon degradation, no weight loss was observed for E/N-DSC during a 24 h degradation period. The tensile strength of the E/N-DSC samples decreased during this time period, resulting in partially degraded samples having 80% of the initial tensile strength remaining. The susceptibility of E/N-DSC samples towards enzymatic degradation could be controlled by varying the degree of cross-linking of the samples. Ethylene oxide sterilization of E/N-DSC samples made the material more resistant against degradation compared with non-sterilized E/N-DSC samples. This may be explained by a decrease of the adsorption of bacterial collagenase onto the collagen owing to reaction of ethylene oxide with remaining free amine groups in the collagen matrix. PMID- 8672630 TI - Role of polymers in improving the results of stenting in coronary arteries. AB - This article is a review of recent developments of polymer-related stents mainly employed in the coronary arteries, including polymer-coated stents, biostable stents and biodegradable stents. Polymer paving is covered as well. The problems with the stents currently investigated and the development of new stents are discussed. PMID- 8672631 TI - Effects of different osteopromotive membrane porosities on experimental bone neogenesis in rats. AB - Biologically inert expanded polytetrafluorethylene (e-PTFE) membranes (GORE-TEX) have earlier been shown to improve healing of different types of bone defects, to be able to restore earlier existing bone, and to produce bone neogenesis. This study was performed to investigate the influence of membrane porosity on the osteopromotive efficacy and to determine bone neogenesis times in the rat. Three different e-PTFE membrane qualities with different porosities (internodal distances < 8, 20-25 and 100 microns) and four healing periods (6, 12, 18 weeks and 6 months) were studied. Dome-shaped e-PTFE membranes (5 mm inner diameter) were placed on denuded rat calvaria and covered with the periosteum and skin. After the respective time intervals, specimens were prepared for histology, and the bone obtained within the domes was quantified by an image analysis system. The results confirmed that it is possible to produce new bone by the use of the osteopromotion technique. The rate of bone neogenesis depended on the quality of membrane used; the membranes with the smallest internodal distance were less efficient than the others in that osteogenesis was somewhat delayed. The amount of new bone achievable was essentially already obtained after 6 weeks with the two most porous membranes, whereas the least porous one lagged behind. After 12 weeks there was no difference in the amount of newly formed bone. There was an obvious time sequence, in that the newly formed bone showed an increased maturity with longer observation periods. The material with the smallest internodal distance did not integrate well with the surrounding soft tissue, leading to a lack of stabilization of the membrane and more soft tissue ingrowth from the side. It is concluded that there is a porosity range within which osteogenesis beneath the membranes is optimal, tissue integration for stability is adequate enough, and soft connective tissue ingrowth is avoided. PMID- 8672633 TI - Histological evaluation of bone reactions to aluminium oxide dental implants in man: a case report. AB - Alumina implants have been shown to possess high biocompatibility. The authors present the case of an aluminium oxide ceramic implant removed because of fracture of the abutment after a 30-month loading period. It was possible to observe microscopically that the implant was covered by highly mineralized mature compact lamellar bone; no connective tissue or inflammatory cells were present at the interface. Osteocytes were observed very close to the bone-implant interface. These features indicate the good biocompatibility of the implant. PMID- 8672632 TI - Effect of controlled release of platelet-derived growth factor from a porous hydroxyapatite implant on bone ingrowth. AB - Platelet-derived growth factor (PDGF) is one of several osteogenic factors which affect bone growth and fracture healing. This study examined the potential of hydroxyapatite (HA) rods with interconnected pores of mean diameter 200 microns to be used as a matrix for the release of PDGF to enhance bone ingrowth into the implant. In the initial phase of the study the sustained release of PDGF from the HA rods was characterized in vitro for two different PDGF loadings, 10 and 100 micrograms per implant. The second phase of the study examined bone ingrowth in HA implants placed into the medullary canals of rabbit femora. The specimens were dumb-bell shaped, with a reduced central diameter so that bone growth across a gap could also be determined. Bone ingrowth into HA implants was compared with growth into HA implants loaded with 100 micrograms of PDGF. Pushout measurements were made of average shear strength across the bone-implant interface and backscatter scanning electron microscopy of thick sections was used to quantify the amount of bone ingrowth into the implant. Although greater interfacial shear strength and area of ingrowth were observed, especially across gap sites, in specimens loaded with PDGF, no difference was statistically significant. PMID- 8672634 TI - Degradation of poly(D,L-lactic acid) nanoparticles coated with albumin in model digestive fluids (USP XXII). AB - Entirely biodegradable poly(D, L-lactic acid) (PLA50) nanoparticles coated with albumin were prepared by the solvent evaporation technique. Their degradative properties were investigated in simulated gastric and intestinal fluids (USP XXII). The degradation of the albumin coating was monitored by HPLC, whereas PLA50 degradation was determined by size exclusion chromatography (SEC) as well as by the detection of lactate in bulk solution by enzymatic assay. As expected, the coating effect of albumin, a readily digestible protein, rapidly disappeared in both gastric and intestinal media, thus exposing albumin-free PLA50 cores to hydrolytic processes. In pepsin-rich simulated gastric fluid, no degradation of the PLA50 core was observed over 8 h incubation time. In contrast, in pancreatin rich simulated intestinal fluid, the PLA50 nanoparticles were rapidly converted into lactate. The results showed that the PLA50 degradation was mainly due to an enzymatic cleavage process. Further experiments showed the involvement of lipases in the degradation of the PLA50 core in simulated intestinal fluid. PMID- 8672635 TI - Analysis of osteoblast mineral deposits on orthopaedic/dental implant metals. AB - Neonatal rat calvarial osteoblasts were cultured on Ti-6Al-4V, Co-Cr-Mo alloy, 316L stainless steel and polystyrene (reference substrate) in the presence of ascorbic acid and 10 mM beta-glycerophosphate for 16, 17, 18, 19, 20, 21, 24 and 28 d. Scanning electron microscopy examination revealed that osteoblasts cultured on these orthopaedic/dental implant metals synthesized and deposited an extracellular matrix containing collagenous and non-collagenous components, as well as mineral nodules of various morphologies. Energy dispersive spectrometry revealed that the mineral deposits consisted of three distinct chemical compositions: calcium phosphate, calcium-sulphur-phosphorus, and calcium only. Backscattered electron imaging demonstrated that both the calcium phosphate and calcium-only deposits were electron dense, while the calcium-sulphur-phosphorus deposits were electron translucent. X-ray diffraction analysis indicated that the bulk of the osteoblast mineral deposits was amorphous hydroxyapatite; in addition, electron diffraction analysis revealed small regions of crystalline hydroxyapatite. PMID- 8672636 TI - Influence of filler parameters on the mechanical coherence of dental restorative resin composites. AB - Next to the presence of (chemical) coupling between filler and resin, filler particle size is important for the mechanical coherence of dental resin composites which are used for posterior restorations. In the range of the current composites a smaller particle size is desirable. The better mechanical coherence for composites with smaller particles found in an in vitro erosive wear test is probably related to the size of food fibres, which are part of the erosive medium. It appears that there is a critical value of the filler particle size (1.3-1.5 microns), under which the food fibres are not able to penetrate in the interparticle space, so the erosive capability of the erosive medium will be reduced. PMID- 8672637 TI - Effect of phagocytosis of pHEMA particles and of heat-killed Candida albicans on expression of carbohydrate-binding sites such as endogenous lectins in phagocytes. AB - Phagocytosis of particles is an integral part of the defence system. Besides clearing the environment of foreign material this mechanism may affect the expression of physiologically relevant epitopes such as carbohydrate-binding sites, e.g. lectins. To determine the effect of particle design on the expression of such determinants in human monocytes and peritoneal macrophages either in suspension or after adherence, the binding of labelled (neo)glycoproteins was comparatively studied after exposure to poly (2-hydroxyethyl methacrylate) particles and heat-inactivated Candida albicans cells. A stimulatory effect of phagocytosis on extent of expression of binding sites for (neo)glycoproteins in phagocytic cells was observed. The levels of responsiveness varied according to the type of particle, adherence of the cell adding a further regulatory parameter. These results support the notion of a potential influence of the chemical structure and/or the form of an engulfed particle on phagocyte differentiation. PMID- 8672638 TI - In vitro hydrodynamic characteristics of DE-T2 biological heart valve prosthesis. AB - Our goal was to evaluate the DE-T2 biological heart valve prosthesis in our own pulse duplicator system. Pressure drop measurements were made across DE-T2 biological aortic valve size 21. All the pulsatile flow experiments were conducted in the Marmara Research Center pulse duplicator system. The pulsatile flow pressures were measured with Motorola MPX5100DP 9306 transducers, interfaced to Vishay 4270A, 4280, 4290, bridge amplifiers and Motorola System 4000. The valve DE-T2 had a vitellium ring with a central bar. The sewing ring was covered with bovine pericardium that continued to form the leaflets. A special incision was made in the pericardium at a 90 degrees angle to the central bar for the formation of two non-anatomical leaflets. The biological aortic valve prosthesis DE-T2 is similar to the natural aortic valve in systolic function. The closing volume is a little higher than the natural valve. Studies are continuing with the aim of diminishing the closing volume and searching for the ideal preservation solution for the pericardium. PMID- 8672639 TI - [The quality of publications]. PMID- 8672640 TI - [Collection of data on primary care activities by sampling]. AB - OBJECTIVES: To choose, as part of a strategy of change in the records system, the best sampling design for obtaining data on primary care activity and to evaluate the appropriateness of introducing this design. DESIGN: An experimental study of the errors committed and the precision of four different sampling designs. A: 8 days a month at random. B: 8 consecutive days a month. C: one day in three systematically (7 days a month). D: one day in four systematically (5 days a month). MEASUREMENTS AND MAIN RESULTS: The calculations of activity indicators obtained monthly for each of the two health centres (31 doctors in general medicine and paediatrics) were compared with the real values, which we already knew from a prior exhaustive search. Type B samples gave the worst results while D contributed the best. In the variables referring to health programmes, unacceptable errors were obtained for all of them. CONCLUSIONS: Type D sampling was selected as the most appropriate. However, the positive and negative aspects to do with the necessity for, and use of, each piece of data, the required precision, the redistribution of tasks needed and the improvement in recording acceptability, must be assessed before it is put into practice. PMID- 8672641 TI - [Does the communication between primary and secondary levels function?]. AB - OBJECTIVE: To analyse the quality of information transmitted by the interclinical form (DI-1) between primary and secondary care levels; and the frequency and causes of the primary care doctor's not receiving a reply. DESIGN: Descriptive and blind for the doctors taking part. SETTING: Seven health centres and 12 specialist out-clinics in the Bizkaia Health region. PARTICIPANTS: The DIs issued by 43 general practitioners and answers from the specialists. INTERVENTIONS: We recorded all the referrals during a 7-day period (18-26 April 1994). After the normal waiting time we went to the centres to collect the returned DIs. Patients whose form was not found in the records were phoned. Five people (3 family doctors: one as Director and two specialists) evaluated the DI, in line with established criteria. RESULTS: Information was lost in 78% of the total number of referrals. The main cause was the specialist not replying (50.7%); the second, the route the form took and the patient (20.9%). The quality of information of the DI analysed was good/acceptable in 92.5% of those issued and in 90% of replies. CONCLUSIONS: The high percentage loss of information was mainly due to the specialist and, secondly, to the route taken and patient. We recommended the introduction of internal mail between both levels and a study of the attitudes and expectations of the professionals concerned in order to improve the interrelationship and quality of health provision. PMID- 8672642 TI - [Violence and sexism in television cartoons for children. Analysis of the contents]. AB - OBJECTIVE: To detect features of violence and sexism in cartoons in the children's programmes of Spanish television companies. DESIGN: Analysis of the content of cartoons broadcast by TV-1, TV-2, Canal Sur, Antena 3 and Tele 5 during one week. MEASUREMENTS AND MAIN RESULTS: The programmes recorded were viewed by two independent observers, first separately and then together. All those scenes with violent contents or sexist messages were noted. The main findings were: a) violent contents were very common; b) roles and jobs linked to gender were found; c) advertising accompanied and was inserted within children's programming. CONCLUSIONS: The points identified show the need for both school and family to encourage children to develop a critical attitude to the messages they receive. PMID- 8672643 TI - [Attitude to incurable disease]. AB - OBJECTIVE: To find the opinions and attitudes of our patients regarding questions of incurable disease and death. DESIGN: A crossover, descriptive study. SETTING: 2 medical clinics and 2 nursing stations at 2 health centres. PATIENTS: 720 patients between 14 and 90 seeking health-care. Sampling of their appropriateness was performed, with systematic daily questionnaires. Known carriers of cancer or AIDS were excluded, as were those with understanding, communication or hearing problems. MEASUREMENTS AND RESULTS: A survey was carried out after a pilot period, using a specially composed questionnaire with seven closed questions. The study period was three months. 60.8% of those questioned would be willing to tell a close family member if the latter had an incurable illness; 60.9% would allow a doctor to do so. 69% would want to be told the truth if they suffered an incurable illness, with 57.3% opting for a doctor as spokesperson. 58.6% would prefer to die at home and 31.3% in hospital. Preference for hospital was unconnected to age or fear of pain. 44% pointed to pain as their greatest fear in an incurable illness, followed by 25.7% whose greatest fear was disability. CONCLUSIONS: On the whole, our patients seemed favorable to telling the truth about a hypothetical incurable illness, whether their own or a family member's. The majority would prefer to die at home and mainly fear pain. PMID- 8672644 TI - [Evaluation of simple and complex carbohydrate intake by diabetics]. AB - OBJECTIVE: To determine the percentages of total, simple and complex carbohydrates (CH) in the diet of a group of type II diabetics and to compare them with the recommended standards. DESIGN: Crossover study. SETTING: Primary Care Centre at Ciutat Badia. PARTICIPANTS: TARGET POPULATION: 436. SAMPLE: 205. Exclusions and drop-outs: 63. MEASUREMENTS AND RESULTS: Habitual intake was calculated by means of three dietary recordings over 24 hours. Average daily kilocalories were 1,757 kcal. 86.3% of the sample consumed a percentage of total CH below that recommended. Only 3.1% of the sample consumed a percentage of complex CH above the recommended minimum, while 70.2% of the sample consumed a percentage of simple CH above the recommended. CONCLUSIONS: The diabetic patients attended at our centre do not follow present dietary recommendations regarding the distribution of CH. New educational strategies adapted to the characteristics of this population must be worked out. PMID- 8672645 TI - [The perceived quality of service at a family planning clinic: a marketing focus]. AB - OBJECTIVE: To measure the perceived quality of service at a Family Planning Clinic (FPC) in Burriana (Castellon), taking as reference the empirical studies developed in commercial marketing. DESIGN: A descriptive study based on a survey using a questionnaire adapted from the SERVQUAL and SERVPERF ones, then a multivariant analysis of the data. SETTING: Burriana Family Planning Clinic, Castellon. PARTICIPANTS: 183 women were interviewed after being attended, of whom 155 (85%) filled out the questionnaire correctly. MEASUREMENTS AND MAIN RESULTS: The overall quality of service is highly valued (6.1 out of 7 points). Six factors which explained 63.3% of the total variance were identified: high personal attention, little bureaucracy, modern installations and equipment, professionalism and competence of staff, accessibility, reputation and layout. It was also found that the Cronbach alpha coefficients were not acceptable in three factors. CONCLUSIONS: off Marketing proposes that the quality of health service provision must be measured from the user's point of view, i.e. the important question is the perceived quality. Research is still at an experimental stage and the two measuring tools (SERVQUAL and SERVPERF) are still under discussion. The conclusion is that marketing can be adapted perfectly to the needs of health provision, although a line of research to design the appropriate method for measuring the quality of any health service needs to be followed. PMID- 8672646 TI - [Drug advertising in medical journals]. AB - OBJECTIVE: To find the percentage of pages of advertising in 6 Spanish medical journals and compare their principal features with the criteria of the international committee of editors of medical journals. DESIGN: A descriptive crossover study. SETTING: The Spanish general medical journals with the highest circulation. PARTICIPANTS: All the issues of journals published between January and March 1993 (n = 56) were selected in order to calculate the average percentage of advertising. To analyse the adverts, all the adverts in 32 issues (n = 657) were selected by means of stratified random sampling of journals from the period July 1992 to June 1993. RESULTS: The average number of advertising pages was 39.16%. 7.8% were publicity articles with or without an advertisement. Adverts filled the best pages of the journals. In 11.7% of cases the adverts were connected with articles in the journal; in 23.9% they were inserted within article. 13.4% of the adverts analysed were for drug products with doubtful or nil intrinsic value; and 34.5% were pharmaceutical novelties (marketed after 1991). The therapeutic groups with most advertisements were ACE inhibitors (13.2%), analgesics (7.8%), calcium antagonists (7.2%) and AINE (7.2%). Paracetamol (6.1%) was the active principal advertised most often. CONCLUSION: The percentage of advertising seems excessive in all the journals except one and very much above the non-advertising informative material. There should be improvement by bringing journals into line with international editorial criteria. PMID- 8672647 TI - [Usefulness of prescription of generic drugs for cost containment in pharmaceutics. Analysis in the Community of Navarra]. AB - OBJECTIVE: To determine the effect of the use of generics drugs on the costs of pharmaceutical prescription, in order to help decide on their use. DESIGN: Descriptive study. SETTING: Prescriptions from all the doctors in the Health Service of Navarra-Osasunbidea. MEASUREMENTS AND MAIN RESULTS: Pharmaceutical products with over 5,000 containers consumed during 1994 in Navarra, and with a generic drug which had the same presentation, were selected. The cheapest generics drug was chosen and the hypothetical saving over the brand-name drug was calculated. None of the 285 products in most common use were generics. Use of generics instead of brand drugs would have saved 109,748,344 pesetas. Use of generics drugs instead of commercial products would reduce cost for the drugs studied by 21%. This saving would mean a 1.2% decrease in the overall cost of pharmaceutical prescription. CONCLUSIONS: Although generics drugs are not readily available, their use would decrease the cost of pharmaceutical prescription, with results comparable to those obtained from negotiation with the industry and pharmacists' representatives. The effect would be more long-lasting, as it would mean a change in doctors' prescription habits. PMID- 8672648 TI - [New trends in the design and production of teaching materials in continuing medical education]. PMID- 8672649 TI - [Side effects of antihypertensive drugs]. PMID- 8672650 TI - [Prescription of antibiotics in acute respiratory infections]. PMID- 8672651 TI - [Discrepancies in primary care text]. PMID- 8672653 TI - Technical papers composing the proceedings of the 33rd Annual Rocky Mountain Bioengineering Symposium and the 33rd International ISA Biomedical Sciences Instrumentation Symposium. Colorado Springs, Colorado, April 12-13, 1996. PMID- 8672652 TI - [Hyponatremia in the aged]. PMID- 8672654 TI - Long distance transmission of diagnostic cardiovascular information. AB - Availability of advanced cardiac diagnostic procedures has proven to decrease the morbidity and mortality associated with common cardiovascular diseases. It was requested that the University of Nebraska Medical Center (UNMC) provide a rural hospital with advanced cardiology services. The services included monitoring of inpatients and rapid interpretation of cardiac diagnostic tests. UNMC proposed to solve this problem by building a computer-based system to transmit diagnostic cardiac information from a rural hospital to UNMC for interpretation by a cardiologist. The information transmitted to UNMC was grouped into two categories: 1) cardiovascular ultrasound, 2) ambulatory and 12-lead electrocardiograms. The information consisted of digital and analog waveform information, static images, and 30 fps video. The system provided rapid data transmission to UNMC over a T-1 line. The system utilized a compression technology which did not degrade the interpretation quality of the data. This system has increased the availability of advanced cardiac diagnostic services to general medical practitioners in a rural hospital. In addition, the system has significantly reduced the time and cost to transmit vital cardiac diagnostic information, thus improving the quality of care received by rural patients. PMID- 8672655 TI - Vector expansion techniques for the inverse problem of electrocardiography: application to a realistic heart-torso geometry. AB - We have previously compared four numerical techniques utilizing both a homogeneous and inhomogeneous eccentric sphere model problem. In those studies we found that the Generalized Eigensystem approach generally gave superior performance over both truncated singular value decomposition and zero order Tikhonov regularization. In this paper we extend the comparison to the case of a realistic heart-torso geometry. With this model, the generalized eigensystem approach again provides superior performance as measured by both relative error and correlation coefficient. PMID- 8672656 TI - Neurons' and glia role in electrocephalogram--evoked potential (EEG-EP) dynamics. AB - These studies are concerned with the interactive mechanisms of the EEG-EP in the processing of sensory and cognitive information. The (EP) following auditory and visual stimulation are studied in unanesthesized free moving cats. Special attention is given to frequency and time domain studies of the (EEG) preceding stimulation and the changes in the EEG following auditory and visual stimuli. Special consideration is given to glial and neuronal interactive and their role in the electrogenesis of evoked potentials. Synchronous electrical activity of groups of neurons are likely to depolarize glial cells in distributed brain areas as in (EEG-EP) and sequences of (EP) in periodic flicker light stimulation. These may play a role in coupling processes in neuronal groups. Glial membranes share with neuronal membranes in the extracellular space which neuronal activities can enrich with potassium. PMID- 8672657 TI - Frequency and time domain studies of the micro-EEG from the brain extracellular space. AB - In these studies, recordings from the brain extracellular space of cats are considered. Macro and microelectrodes are utilized. Special studies using visual, auditory stimuli and certain drugs are done. Coherence, power phase and partial coherence spectra of wave field potentials and unit potentials are investigated. The electrographic profile of the micro electroencephalogram (EEG) and micro evoked response (ER) of the extracellular space is different than the macropotentials of the macro (EEG) and the macro (ER). The electrographic patterns of the micro (EEG) and the micro (ER) will vary with the microelectrode size, location and the variable microanatomy. There are many single neuron field potentials differentiated in space and time. In these unit fields there are varying electronic interactions varying in space and time. There are patterned inputs varying in space and time. There are fluctuating microfields distributed in overlapping layers, columns, slabs and patches and periaxonal extracellular spaces of the cerebral and cerebellar white matter. In these anatomical situations there are variable, degrees of local and general selective patterns of synchronization with variable direction, and selective spread. The extracellular space micro (EEG) shows complex and dynamic shifts of the micro (EEG) to the macro (EEG) frequencies and tuned macrofields. PMID- 8672658 TI - Analysis of capsular tissue from patients undergoing primary and revision total hip arthroplasty. AB - Late aseptic loosening of revision total hip replacements is a common cause of failure. At revision surgery, a foreign pseudo capsule membrane surrounding the implant develops. These tissues are thought to reflect a response due in part to an increase in particulate debris, generated by normal wear of the bearing surfaces. The foreign body membrane consists of macrophages and giant cells lying in between the bone and the implant. The cell types identified at the interface included lymphocytes, histiocytes, macrophages, and giant cells, and their contribution to implant loosening due to bone resorption is the focus of this investigation. Capsular tissues surrounding failed joint arthroplasties were characteristically different by gross morphological observations. The capsular tissue contained a region of tissue approximately 4-6 cell layers in depth lining the capsule, which resembled synovial like cells. This region of the capsular tissue consisted of loosely organized fibrous tissue containing numerous histiocytes and foreign body giant cells demonstrated by hematoxylin and eosin. Immunological staining of the capsular tissue for IL-1 activity showed the reactivity to be localized directly adjacent to the implant in well vascularized areas. Tissue farthest from the implant were less reactive and resembled tissue extracted from primary patients. Quantitative ELISA data for IL-1 activity from these areas reflect the observations observed by immunostaining. PMID- 8672659 TI - Evaluation of the biomaterial-interface of screw threads in patients having clinical pain. AB - Fixation devices are normally anchored and stabilized with the use of metallic screws. Under normal circumstances, the patient has no adverse response to the fixation device. However, there are some patients that experience a significant amount of pain and the hardware needs to removed. Removal of the hardware, alleviates the pain. The tissues adjacent to the implanted devices were harvested and analyzed histochemically for cellular detail and immunochemically for the presence of PGE2. These tissues were compared with tissues retrieved from nonpainful stable fixation devices that were removed when they no longer were needed for stabilization. The results showed radiographically the presence of osteolysis in the area of the screw thread in patients with clinical pain. Also, histologically there was a presence of synovial-like granuloma tissue possibly produced by the micromotion of the loosened screw. When the tissues were analysed qualitatively by ELISA for PGE2 they had a statistically significant amount in comparison with tissue retrieved from patients with no clinical pain. The presence of PGE2 in the tissues suggest that this inflammatory mediator is produced in tissues adjacent to unstable devices and may mediate the osteolysis associated with the late implant failure and clinical pain. PMID- 8672660 TI - Effects of cerebellar lesions on saccade simulations. AB - Experimental studies involving cerebellar lesions have been important tools for learning about the operation of the saccadic eye movement system. These studies have been used to further develop a neural network model for horizontal saccadic eye movement control. The neural control mechanism is first order time optimal, initiated by the deep layers of the superior colliculus and terminated by the cerebellar fastigial nucleus. The neural circuit consists of neurons in the paramedian pontine reticular formation (burst, tonic and pause cells), the vestibular nucleus, abducens nucleus, oculomotor nucleus, cerebellum, substantia nigra, nucleus reticularis tegmenti pontis, the thalamus, the deep layers of the superior colliculus and the oculomotor plant for each eye. Agonist burst cell activity is initiated with maximal firing due to an error between the target and eye position, and continues until the internal eye position in the cerebellar vermis reaches the desired position, then decays to zero. The cerebellar vermis is responsible for adapting the duration of maximal firing based on the initial position of the eye. There are two sets of neural integrators in the neural network. One operates within the cerebellar vermis to predict the width of the pulse, and the other within the paramedian pontine reticular formation to maintain the eyes at their destination. Antagonist neural activity is inhibited during the agonist burst activity. After the agonist burst, antagonist neural activity rises with a stochastic rebound burst and from input from the fastigial nucleus, then falls to a tonic firing level necessary to keep the eye at its destination. The onset of the antagonist tonic firing is stochastic, weakly coordinated with the end of the agonist burst, and under cerebellar control. A common mechanism of action is described, based on cerebellar gating, through the fastigial nucleus, that explains a number of different saccadic eye movement types, including dynamic overshoot, glissadic overshoot and undershoot, and undershoot. A linear homeomorphic oculomotor muscle model is used in the simulations of the operation of the neural network. Each of the neural sites in the model fire similar to experimental data, and simulate fast eye movements. PMID- 8672661 TI - Comparison of the in vivo wear rates of 43 surgically retrieved direct compression molded and ram extruded ultra high molecular weight polyethylene acetabular components. AB - The objective of this study was to investigate retrieved ultra high molecular weight polyethylene (UHMWPE) liners from Total HIp Arthroplasty (THA) revisions. The amount of in vivo wear on compression molded v. ram extruded and machined acetabular liners was the focus of comparison between 43 surgically retrieved samples. The principal experimental methods were scanning electron microscope (SEM) observations and a fluid displacement method to quantify volumetric wear. SEM observations revealed similar wear mechanisms between the compression molded and ram extruded and machined UHMWPE retrieved liners. More third body wear corresponded with more volumetric in vivo wear. This study found that the ram extruded and machined UHMWPE liners had a significantly larger average wear rate than the compression molded UHMWPE liners. In order to determine whether the observed difference in wear rates can be attributed to the different types of UHMWPE processing, a more controlled experiment would have to be performed. PMID- 8672662 TI - "In vivo" pose estimation of artificial knee implants using computer vision. AB - This paper describes an algorithm to estimate the position and orientation (pose) of artificial knee implants from fluoroscopy images using computer vision. The resulting information is used to determine contact position from " in vivo" bone motion in implanted knees. This determination can be used to support the development of improved prosthetic knee implants. Current generation implants have a limited life span due to premature wear of the polyethylene material at the joint surface. To get "in vivo" motion, fluoroscopy videos were taken of implant patients performing deep knee bends. Our algorithm determines the full 6 degree of freedom translation and rotation of knee components. This is necessary for artificial knees which have shown significant rotation out of the sagittal plane, in particular internal/external rotations. By creating a library of images at known orientation and performing a matching technique, the 3-D pose of the femoral and tibial components are determined. By transforming the coordinate systems into one common system contact positions can be determined. The entire process, when used at certain knee angles, will give a representation of the positions in contact during normal knee motion. PMID- 8672663 TI - Patellofemoral joint study via image processing. AB - Plain Merchant-view X-rays of patellofemoral joints are used to study the geometry and kinematics of the patellofemoral joint. A method for calculating the kinematic parameters: sulcus angle (SA), patellofemoral congruence angle (PFC), lateral patellar angle (LPA), patellar rotation angle (PR) and lateral patellar displacement (LPD) is presented. Using digitized X-ray images of patellofemoral joints, contours of the patella and the femur can be acquired by boundary detection and morphological thinning. A radiograph is converted to a line drawing and the data points required for calculation of the parameters are chosen automatically without human intervention. Parameter measurements were demonstrated for 5 X-rays of 3 patients. Comparisons between computer calculated and hand calculated parameters were made. This technique is inexpensive but will provide the necessary information, and is practical, especially during the evaluation of patients with patellofemoral abnormalities. PMID- 8672664 TI - Digital particle image velocimetry (DPIV) measurements of the velocity profiles through bileaflet mechanical valves: in vitro steady. AB - Although velocity profiles downstream of mechanical valves have been measured in vitro using Laser Doppler Anemometry (LDA), these studies have not measured velocities in the immediate proximity of the leaflets since the LDA technique prevents velocities from being measured in the immediate vicinity of any structure. Laser based Digital Particle Image Velocimetry (DPIV) is a new technique that allows for accurate measurement of an entire two-dimensional velocity field with no beam angulation. DPIV was used to measure two-component velocity vectors immediately proximal and distal to a 25 mm bileaflet mechanical valve (St. Jude) mounted in a transparent steady flow in-vitro model. Measurements of flow similar in Reynolds number (Re) to mitral inflow (Re = 2000 4000) showed clear hemi-elliptical isovelocity convergence zones proximal to each of the three orifices. DPIV measurements of flow distal to the orifice revealed clear vortex rollups generated from the internal ring of the valve with separate velocity profiles immediately distal to the leaflets. These studies prove the feasibility of the DPIV technique to provide accurate velocity measurements of flow profiles through mechanical valves. PMID- 8672665 TI - Review of non-invasive techniques of measuring aortic pressure through the use of ultrasound. AB - Aortic pressure is a hemodynamic property that is needed for analysis of the cardiovascular system. Current aortic pressure techniques involve the use of invasive methods and insertion of foreign objects into the body which may cause infections, diseases, and other clinical manifestations. Therefore, a non invasive method of measuring aortic pressure both clinically and experimentally is needed. Through the use of aortic wall motion it has experimentally been proven that aortic pressure may be found by the range of motion of the vessel wall. The wall motion may be found by the use of ultrasound and the properties of the vessel's wall elasticity. This paper reviews various ultrasonic methods for detecting wall motion such as pulsed Doppler, ultrasonic transit time and phased locked echo tracking, and moving target indicator ultrasound. PMID- 8672666 TI - Noninvasive aortic pressure and flow measurement. AB - The long-term aim of this project is to noninvasively measure aortic blood pressure and aortic blood flow using a portable ultrasonic device. It is envisioned that a small array of ultrasonic crystals will be placed on the suprasternal notch of the neck. The ultrasound beam will be continually positioned onto the aortic arch by a computer. Wall motion will be used as an index of pressure, and flow will be determined through Doppler techniques. The short-term aim is to adapt an ultrasonic hyperthermia array design and control system to produce a focused ultrasound beam from a linear array for aortic pressure and flow measurement. The linear array consists of eight transmitting/receiving crystals, whose focus is controlled by continually changing the time delays for the excitation of each crystal. The hardware and software necessary to produce the delayed excitation signals is discussed. PMID- 8672667 TI - Development of an in-vitro circulatory system with known resistance and capacitance. AB - An in-vitro (hydrodynamic) model of the circulatory system was developed. The model consisted of a pump, compliant tubing, and valves for resistance. The model is used to simulate aortic pressure and flow. These parameters were measured using a Konigsburg Pressure transducer and a Triton ART2 flow probe. In addition, venous pressure and flow were measured on the downstream side of the resistance. The system has a known compliance and resistance. Steady and pulsatile flow tests were conducted to determine the resistance of the model. A static compliance test was used to determine the compliance of the system. The aortic pressure and flow obtained from the hydrodynamic model will be used to test the accuracy of parameter estimation models such as the 2-element and 4-element Windkessel models and the 3-element Westkessel model. Verifying analytical models used in determining total peripheral resistance (TPR) and systemic arterial compliance (SAC) is important because it provides insight into hemodynamic parameters that indicate baroreceptor responsiveness to situations such as changes in gravitational acceleration. PMID- 8672668 TI - Comparison of rat aortic, carotid & femoral artery viscoelastic properties using harmonic analysis. AB - Viscoelastic properties of rat (Wistar Kyota) large (6 aorta), medium (12 carotid) and small (8 femoral) in vitro artery segments, were contrasted over a wide range of static and dynamic pressures. Relationship of change in static pressure (delta dyne/mm2) to diameter (delta mm) was used to estimate a segment's incremental elasticity (KD) at each pressure level. Dynamic intravascular pressure response (Po) was recorded during swept frequency pressure (2-200 Hz; +/ 10 mm Hg) inputs as superimposed on mean pressure steps of 40, 80, 120, 160 and 200 mm Hg (P(i)). Analysis of dynamic data included Fast Fouier Transform of Po/P(i) with FANSIM (TUTSIM Products) curve fit to Bode plots. Curve fit coefficients were used to estimate properties of natural frequency (omega n) damping, viscosity and inertia. Statistical analysis employed ANOVA and SNK multiple comparison procedures. Results indicated that as step-pressure was increased diameter, KD and omega n increased proportionately in all segments. Values of KD and omega n were always highest in femoral and lowest in aortic segments. In all segments damping decreased inversely with increasing pressure while, viscosity and inertia were lowest between 80 and 160 mm Hg. These results documented distinct viscoelastic properties for the three arteries as well as, differences in their response characteristics. PMID- 8672669 TI - Factors influencing electrovaporization in the treatment of benign prostatic hyperplasia. AB - Electrovaporization refers to the process of vaporizing tissue using electrical energy. Proposed as a new treatment method for benign prostatic hyperplasia (BPH), this technique allows removal of prostatic tissue with simultaneous coagulation, thereby minimizing blood loss. The recent increase in popularity of electrovaporization in the treatment of BPH warrants a quantitative assessment of the process, including an objective evaluation of its influencing factors. In this study, the effects of power, mechanical loading, and excursion rate on tissue removal by electrovaporization were examined in fresh skeletal muscle. A monopolar electrode was attached to the weighted arm of a linear motion system and rolled across the tissue surface while activated by a radio-frequency generator. The tissue samples were frozen and cut longitudinally to allow visualization and measurement of the vaporized groove using an optical imaging technique. The volume of tissue removed increased significantly when power was increased from 120 to 150 W (46 to 119 mm3, p = 0.006), when the load was increased from 20 to 50 gm (20 to 119 mm3, p = 0.002), and when the excursion rate was decreased from 25 to 15 mm/s (29 to 69 mm3, p < 0.05) and from 15 to 10 mm/s (69 to 137 mm3, p < 0.05). There was no significant gain in volume removed when power was increased to 180 W or when the load was increased to 70 gm, indicating that these factors are constrained with regard to optimal tissue removal. Using a novel method to quantitatively assess tissue removal by electrovaporization, this study has demonstrated that greater tissue removal can be achieved by increasing power, increasing the load, or decreasing the excursion rate, but only within limits. PMID- 8672670 TI - Tissue impedance as a function of temperature and time. AB - Tissue impedance dependence on temperature has been measured for six tissue types. The information was gathered using an automated laboratory under computer control. This information is needed to be able to input these values into a computer model that predicts temperature distribution produced by delivery of radio frequency energy. Due to the thermal dose of time and temperature, tissue properties change and no published data are available that document this. Since there are no theoretical predictions, empirical data were measured to supply this information. Using an aluminum cylindrical cavity of volume 1.69 cm3, muscle, liver, brain, and fat tissue impedance were measured at 500 kHz over a range of temperatures. All tests began at room temperature where baseline measurements were made. The cylinder was then placed in a constant temperature water bath at between 30 and 90 degrees C. The tests were run for a period of 10 to 30 minutes. Temperature homogeneity was carefully studied throughout the volume of the cylinder. It was found that thermal equilibrium occurred within four minutes. Special care was taken with the tissue sample in regard to optimize moisture and freshness, and minimize fat content. Grain orientation was also taken into consideration depending on the test. For all tissue types, resistivity decreased initially as the sample temperature equilibrated with the bath temperature. For temperatures less than 75 degrees C, resistivity values remained approximately constant over time. PMID- 8672671 TI - Development of an integrated automated retinal surgical laser system. AB - Researchers at the University of Texas and the USAF Academy have worked toward the development of a retinal robotic laser system. The overall goal of this ongoing project is to precisely place and control the depth of laser lesions for the treatment of various retinal diseases such as diabetic retinopathy and retinal tears. Separate low speed prototype subsystems have been developed to control lesion depth using lesion reflectance feedback parameters and lesion placement using retinal vessels as tracking landmarks. Both subsystems have been successfully demonstrated in vivo on pigmented rabbits using an argon continuous wave laser. Preliminary testing on rhesus primate subjects have been accomplished with the CW argon laser and also the ultrashort pulse laser. Recent efforts have concentrated on combining the two subsystems into a single prototype capable of simultaneously controlling both lesion depth and placement. We have designated this combined system CALOSOS for Computer Aided Laser Optics System for Ophthalmic Surgery. Several interesting areas of study have developed in integrating the two subsystems: 1) "doughnut" shaped lesions that occur under certain combinations of laser power, spot size, and irradiation time complicating measurements of central lesion reflectance, 2) the optimal retinal field of view (FOV) to achieve both tracking and lesion parameter control, and 3) development of a hybrid analog/digital tracker using confocal reflectometry to achieve retinal tracking speeds of up to 100 dgs. This presentation will discuss these design issues of this clinically significant prototype system. Details of the hybrid prototype system are provided in "Hybrid Eye Tracking for Computer-Aided Retinal Surgery" at this conference. The paper will close with remaining technical hurdles to clear prior to testing the full-up clinical prototype system. PMID- 8672672 TI - Hybrid eye tracking for computer-aided retinal surgery. AB - We describe initial results of a new hybrid digital and analog design for tracking the retina and controlling the laser beam. The results demonstrate tracking rates which exceed the equivalent of 50 degrees per second in the eye, with automatic lesion pattern creation and robust loss of lock detection. Robotically-assisted laser surgery to treat conditions such as diabetic retinopathy, macular degeneration, and retinal tears can now be realized under clinical conditions with requisite safety using standard video hardware and inexpensive optical components. PMID- 8672673 TI - A centromere attribute integration approach to centromere identification. AB - Automated and nonautomated approaches to chromosome classification involves assessing several chromosome attributes. The centromere is an important attribute which provides insight to other features such as chromosome orientation and the banding pattern sequence. Improving the ability to identify the centromere will enhance feature determination and analysis. Techniques to identify the centromere attempt to isolate specific centromere attributes. The centromere can be characterized as possessing the following properties: 1) usually the narrowest region in the chromosome image, 2) usually located in a region containing extreme concavities along the chromosome contour, and 3) usually located in a region of uniform dark grey-level. A centromere attribute integration approach for automated centromere identification has been developed which has a correct identification rate of 93.5% on a diversified data set. This approach determines and evaluates centromere candidates based on quantified centromere attributes. Centromere attribute integration incorporates other commonly used techniques for centromere identification. Some of the techniques integrated into the experimental algorithm include evaluating chromosome curvature, analyzing the shape profile, and inspecting the width profile. PMID- 8672674 TI - Cutting force measurements platform for quantitative assessment of surgical cutting instruments. AB - This paper describes the design and development of a Cutting Force Measurement Platform (CFMP) in the R&D department at Valleylab, Inc. for quantitative assessment of surgical instruments used for cutting tissue. This system controls various parameters including cutting speed, while measuring the force required as a function of time. The cutting force measurements are acquired and analyzed by a data acquisition program. The relevance of the cutting force measurements with regards to electrosurgery are discussed. PMID- 8672675 TI - Visual basic for biomedical applications: tissue impedance and power delivery in an ESU system. AB - The typical ESU found in most hospitals utilizes a microprocessor. This microprocessor supervises many tasks these include: time keeping, dosage monitoring, and display control. It must also perform complex tissue impedance measurement in real time as well as establishing a communication protocol to and from test hardware. This article will describe a means of displaying this information. PMID- 8672676 TI - Correlation of flexural structural properties with bone physical properties: a four species survey. AB - The present investigation explores the relationship between animal and bone physical traits and the mechanical properties of whole bone from four species. Mechanical testing was performed using three-point flexure on the femora and tibiae of mice, rats, rabbits and cats. Interspecies correlations of the physical traits to the mechanical properties were used to elucidate the most likely physical predictors of mechanical properties within a single species. Physical traits measured were total bone length (BL), mid-diaphyseal cortical area (CA), body mass (BM), body mass times bone length (BMBL) and bone dry mass (DM). Bone mechanical parameters determined by flexure testing to failure were the structural properties of stiffness (S), elastic strength (Pe), maximum strength (Pm), and the material properties of modulus of elasticity (E), elastic stress (sigma e), and elastic strain (epsilon e). Linear regressions were used to relate the physical trait to the mechanical properties. Interspecies regressions of physical traits to mechanical characteristics implied bone dry mass (DM) is a significant predictor of bone structural properties. Further evidence of this relationship was obtained by exploring the linear relationship for the femora of a single species (rabbit, N = 17) in which age and bone size were allowed to vary. Strength at the elastic limit (in N) within a single species was described by the equation, Pe = 42.9*DM + 42.9 +/- 42.0N, where DM is in grams. PMID- 8672677 TI - An apparatus for spine biomechanical testing. AB - A testing system that applies a pure bending moment will uniformly load a spinal construct and be capable of identifying its weakest point. This study describes an apparatus for use with a material testing machine that is simple, inexpensive, and reliably creates a pure bending moment along the whole spine. We tested the system using two strain gauges attached to an aluminum alloy beam. First we verified the reliability and accuracy of the strain gauges system by comparing experimental measurement strain to theoretical prediction of strain in a cantilever beam model. The second experiment assessed the moment and strain created at two locations on a beam which was fixed at one end. The mean strain recorded from the two gauges demonstrated that moment is not uniformly distributed along the length of beam that is fixed at one end. The third experiment was similar to the second except that the beam was attached to an X-Y table instead of being fixed. Results demonstrated that a pure bending moment status is achieved when the end of the beam is fixed to an X-Y table. PMID- 8672678 TI - Learning and generating human natural behaviours for design evaluation using artificial neural networks. AB - Biomechanical consideration is becoming very important when designing a product. Animation and strength prediction tools are available to perform the necessary analysis. However with most of these tools, animation is achieved via a sequence of key frames constructed by manipulating the human model to the desired position in each key frame. The resulting motion is therefore unnatural. Most strength predictions are based on static strength measurements of a selected population. Existing prediction tools are not flexible so as to allow data from other populations and/or additional parameters such as dynamic strength to be included in the prediction equations. In this paper we present an approach using neural networks that will allow learning and generation of natural human behaviours. We also propose using neural networks for strength prediction because of the flexibility in specifying inputs and outputs and the ability to map non-linear relationships. PMID- 8672679 TI - Evaluation of a neural net approach for assessing the rehabilitation status of ACL injuries. AB - The purpose of this investigation was to explore the potential for using a neural network approach in objectively determining the status of ACL (anterior cruciate ligament) rehabilitation. Nine male subjects (three each of non-injured, in rehab, post-rehab conditions) were matched for size and strength. The testing protocol was established by a physical therapist: each leg was tested at three different speeds on a Cybex machine with electromyography (EMG) and torque data collected concurrently. Neural net training and testing sets were created from the values of peak torque, time to peak torque, EMG mean power frequency, the EMG root mean square (RMS), and a value representing the ACL condition of the tested leg from each of 15 repetitions. The network was then run until reaching a pre set mean square error value of 0.05 during training. Subsequent test sets were correctly classified with 99% accuracy, demonstrating the potential of the method as a diagnostic aid for detecting and identifying changes over time in the rehabilitation patterns of individuals having ACL injuries. PMID- 8672680 TI - A versatile electronic drive for rehabilitation devices, vehicles for the disabled and senior citizens. AB - Electronic drives have various applications in rehabilitation devices, partly to strengthen muscles of specific parts of the body (e.g. legs), partly to support the mobility of the patient during the rehabilitation process. Physically disabled people with limited walking ability also benefit from support devices equipped with electrical drives, and senior citizens often appreciate easy-to handle, quiet and cost-effective individual transport means for local traffic. The paper describes a versatile, novel electronic drive, consisting of an electric motor and a control circuit. Explanations concentrate on the design goals and solutions that guarantee a smooth transition between muscle- and electric driving of the different devices or vehicles, and the benefits of the very high efficiency of the drive, like reduced weight or extended range. PMID- 8672681 TI - Effective written communication in biomedical sciences. AB - The written word is the biomedical scientist's most important and most enduring communication tool. Nevertheless, the development of writing skills receives little attention in most scientific disciplines and the ability to conduct research is often viewed as more important than the ability to communicate the results of that research. Consequently, many scientists lack the writing skills necessary to effectively convey essential aspects of their research. In this paper, we will discuss the importance of good writing skills, give examples of common mistakes that are made in biomedical science writing and offer suggestions on how to improve written communication. PMID- 8672683 TI - Hand-held instrument for evaluation of breast engorgement. AB - A second-generation instrumentation system is described for obtaining qualitative (and inferred quantitative) measurements of breast engorgement in postpartum nursing mothers. It also has application in evaluating the extent of edema in tissue. The system uses an LVDT and associated electronics. PMID- 8672682 TI - BreathSim, a mathematical model-based simulation of the anesthesia breathing circuit, may facilitate testing and evaluation of respiratory gas monitoring equipment. AB - BreathSim is a new computer simulation of the anesthesia breathing circuit, ventilator, and respiratory system. The system permits user-control over various respiratory parameters, ventilator functions, and the integrity and performance of the anesthesia machine and breathing circuit. Respiratory gas pressure, flow, and carbon dioxide (CO2) concentration data may be simultaneously displayed from several locations in the system. Pressure-volume and flow-volume tracings (spirometry) are displayed as well. In addition, an animation which is synchronized to the simulation displays the movement of oxygen and CO2 in the system. We propose the use of the simulator to test and evaluate the software algorithms utilized in respiratory gas monitoring equipment and anesthesia workstations. The output of the simulator can provide a "patient signal" input to the monitor and specific algorithms (e.g. breath detection, waveform recognition) could be evaluated. Rare but significant clinical states may be easily simulated, and the simulator may be driven by "scripts" to permit reproducibility. PMID- 8672684 TI - The use of a direct current electromagnetic tracking device in a metallic environment. AB - The use of a relatively new direct current (DC) electromagnetic tracking device in conjunction with a hostile metal environment of Material Testing Machine was studied. In this research, we first evaluated the reliability and performance of the DC tracking system operating in an ideal metal-free environment for both the translational and rotational error in static and dynamic conditions. When the tracking system with the same factory default configuration was moved into a heavy metal environment, serious translational and rotational distortion were observed. Through a series of evaluation of the physical environment and modification of the settings, the tracking system could perform satisfactorily and both the translational and angular error could be reduced in manufacturer's specifications. The safe working region for the DC tracking systems operating in a material testing machine environment was successfully mapped out. This study provides information for using the DC electromagnetic tracing device in the heavy metal environment exists in the material testing machine. PMID- 8672685 TI - Multiple neural network response variability as a predictor of neural network accuracy for chromosome recognition. AB - Human chromosome classification requires all chromosome appearing in a microphotograph of a dividing human cell to be classified within the known normal or abnormal 24 chromosome types. In recent years, research has focused on the use of neural networks for classification of normal chromosomes. Experimental work in this area led us to question whether learning variability, resulting when multiple neural networks are trained to solve the same problem, could be used as a predictor of classification performance. The Copenhagen chromosome data bank, consisting of 30-component feature vectors from 8106 chromosomes isolated from 180 cells, was divided into a training and a test subsets. Back propagation neural networks with 30 input nodes, 1 to 100 nodes in the hidden layer, and 24 output nodes were trained with the same learning parameters. After training, each neural network was tested. The neural network yielding the best classification was labeled as the optimal neural network. An error variability score was calculated for each test chromosome. This score was a function of all (100) neural network outputs obtained for that chromosome. The error variability scores ranged from 0.16 to 1.31 with a mean value of 0.41 and a SD of 0.12. There was significant difference (p < 0.0001) between the variability scores from chromosomes classified correctly (mean = 0.4, SD = 0.1, n = 3804) and incorrectly (mean = 0.62, SD = 0.19, n = 241) by the optimal neural network. When the variability score was used as a threshold to decide whether or not to accept the output of the optimal neural network, a peak classification rate of 98.93% was observed for chromosomes with an error variability score < 0.35. Results indicate that the error variability of multiple neural network responses can be used as a confidence indicator for a optimal neural network. PMID- 8672686 TI - Nanocontrollers for biomedical applications. AB - Several semiconductor companies now manufacture low cost single-chip microcontrollers in dual inline packages having twenty or fewer pins. The controllers are field programmable by means of inexpensive development boards linked to personal computers. These processors were designed with a minimalist philosophy which provide them with only a few dozen bytes of on-chip RAM, hundreds of bytes of PROM, a parallel port, a counter/timer, and reduced instruction sets. The better-equipped members of this class may have special on chip hardware, such as analog-to-digital input, pulse-width modulation output and a serial port. Most must be programmed in assembler, although some support BASIC, "C" or other languages. Their tiny size, design simplicity and operational single mindedness earn them the nickname "nanocontrollers". Despite meager resources, these controllers can be successfully employed in a variety of biomedical applications. Such uses include: consolidation of multi-chip "glue logic" circuitry; functioning as subsystem elements in complex designs; serving as device drivers or protocol converters; and forming the building blocks of hypercube processor arrays or artificial neural networks. This paper describes the general capabilities, special features, and some application examples of "nanocontroller" technology. PMID- 8672687 TI - Dynamic simulation using a graphical programming language. AB - A power oscillator, suitable for energizing an ultrasonic surgical cutter was simulated using a graphical programming language. The simulation included a model of the amplitude control system as well as the ultrasonic actuator. In addition, those elements which existed in a practical oscillator and were typically obscure to the design requirements were identified, simulated and discussed. PMID- 8672688 TI - A hybrid approach to clustering biomedical data. AB - Cluster analysis is often used in an attempt to determine the number and characteristics of patterns present in vectors of biomedical response parameters. An iterative clustering procedure based upon the combined supervised and unsupervised learning algorithm of Pao is described. The present paper illustrates this procedure using growth curves of indices of family functioning in adaptation to pediatric chronic illness. This clustering procedure is based upon neural network approaches to supervised (discriminant analysis) and unsupervised (cluster analysis) learning and is similar to fuzzy set algorithms developed to assess the degree of relatedness among a number of discrete units. PMID- 8672689 TI - Interrelationship between buffer systems and particle sizes of TCPL drug delivery system. AB - The specific objective of this investigation is to study the effect of tricalcium phosphate delivery system (TCPL) particle sizes on the final density as well as the delivery profiles of various organic compounds in three different buffer environments. Each TCPL matrices were fabricated using three different particle sizes ranges between 1-38, 45-63 and 63-75 microns. The sintered microcrystal material was impregnated with either progesterone (P, 100 mg each) or bovine serum albumin (BSA, 100 mg each). In phase I of the study, each device was suspended in a serum bottle containing 100 mls of ethanol solution (50% wt/vol.) for P release or 100 mls of PBS (pH 7.4) for BSA release. In phase II, similar capsules were suspended in human plasma instead of standard buffers. The vials were agitated at 100 cycle per minute in a water bath set at 37 degrees C. The amount of P or BSA released from the devices into the buffered medium was measured spectrophotometrically. The results of this investigation revealed that a significant difference in the densities of the devices made from the range of individual particle sizes. The rate of steroid hormone and protein released from the devices made from 1-38 micron particle sizes was slower (p < 0.05) than the rate of delivery of P and BSA released from devices fabricated from either 45-63 or 63-75 micron particles. Regardless of the particle sizes effect the results show that the delivery profiles of BSA was higher than the rate of P. This observation could be attributed to the molecular structure as well as the physiochemical characteristics of the drug. In conclusion the data obtained from this study suggest that: (1) Particle sizes variations influence the density of the TCPL delivery system, (2) the rate of release of organic compounds from the ceramic devices is considerably affected by the physiochemical characteristics of medium or buffer system, and (3) the delivery rate of drugs from TCPL devices is directly proportional to the size of the device initial particles and macropores, and inversely proportional to the number of micropores within each device. PMID- 8672690 TI - Immunochemical and histopathological evaluation associated with sustained delivery of 5-alpha androstanedione using adult rats as a model. AB - The specific objective of this study was to evaluate the effect of androstanedione (dihydrotestosterone (DHT)), delivered in a sustained manner by tricalcium phosphate lysine (TCPL) delivery devices, on the biochemical and cytological architecture of reproductive organs using adult rats as a model. A total of twenty four rats were distributed randomly into three equal groups. Rats in group II were implanted (S/C) with empty TCPL devices and served as sham controls. Group III rats were implanted with 1.51 (250 micrograms/day) g/cm3 CDD containing 300 mg DHT each. Group I animals served as unimplanted controls at time zero. Upon sacrifice (6 weeks), the prostatic tissue were collected, fixed, embedded, and sectioned (H&E) by using standard lab protocols. Data analysis of prostatic tissue obtained from rats implanted with such low density TCPL showed microscopic appearance varied somewhat from one area of the gland to another, but generally, there was considerable hyperplasia, as evidenced by accentuation of glandular folds and an increase in the number and size of the epithelial cells, with some areas of the gland showing more severe hyperplasia than others. Meanwhile, cross-sections of prostate obtained from rats implanted with empty CDD were characterized by an essentially normal histological appearance of the gland. These data exemplify the complex interactions which occur between prostate components and exogenous sustained delivery of DHT that are reflected in cell structure and function. Biochemical analysis of the serum revealed that there is remarkable reduction in HDL, and IL 1 (33%). In contrast the level of IL 6 increased (50%) in experimental animals compared to the sham operated animals. In conclusion, this experiment demonstrates that TCPL capsules are capable of delivering supraphysiological doses of DHT in a sustained manner for 6 weeks. The results also reveal that doses of DHT slightly above the physiological level can result in systemic toxicity. In addition, supraphysiological levels of DHT could cause severe BNH and regression to spermatogenesis after 6 weeks in rats, and an increase in the risk factors associated with CVD. PMID- 8672691 TI - Development of a ceramic device for the continuous local delivery of steroids. AB - Testosterone has been shown to stimulate bone healing. However, large doses of testosterone have been associated with liver damage and prostate enlargement. Sustained release of testosterone by a device placed next to a bone fracture could deliver effective amounts of the steroid necessary for bone healing without the adverse side effects associated with oral delivery or intramuscular injection. The release of 1 mg of testosterone into 1 ml of 50% ethanol from one hour calcined hydroxyapatite (HA) ceramics (n = 6) and twelve-hour calcined HA ceramics (n = 6) was measured over four days. The twelve-hour calcined HA ceramics exhibited a consistently slower testosterone release. A 200mg HA/0.1% PLA/gentamicin (1mg) ceramic cylinder containing 0, 0.5, 1.0, or 1.5 mg testosterone was placed adjacent to a 4 x 1 x 1 mm femoral defect created in four equal groups of twenty-seven castrated male Sprague Dawley rats. After four weeks, none of the ceramics contained any residual testosterone. Histological examination showed that the traumatized bone of the animals implanted with testosterone-containing ceramics healed faster for the first four weeks than the controls. This data suggests that the twelve-hour calcined HA should be used to extend the release of testosterone to enhance healing of traumatized bone. PMID- 8672692 TI - Application of robust data processing methods to the analysis of eye movements. AB - We have developed a robust, nonlinear differentiating digital filter for the estimation of eye velocity from an eye-position signal. This filter is equally applicable to a large variety of other biomedical signals. The filter is implemented by taking an odd number of two-point differences around the point of interest and then selecting the median difference. Dividing the median difference by the time interval yields the derivative of the input signal. The Robust Differentiator (RD) is a classic order-statistic filter consisting of a bank of linear filters (the two-point differences) followed by the median operation to select one difference for the derivative calculation. The RD has no impulse response function and eliminates the "ringing" that is typical of all linear filters. The RD not only performs better than the FIR differentiating filters for impulse noise but is equally effective for both broad-band and narrow-band Gaussian noise. The RD "bandwidth" is adjustable by selecting the interval for the two-point differences. PMID- 8672693 TI - The effect of HA, TCP and ALCAP bioceramic capsules on the viability of human monocyte and monocyte derived macrophages. AB - The relationship between various bioceramics used in surgical implantation and inflammatory cellular response has not been fully elucidated. The objective of this study was to investigate the effect of various biomedical ceramics such as tricalcium phosphate (TCP), hydroxyapatite (HA), and aluminum-calcium-phosphorous oxide (ALCAP) on the adherence and viability of human monocyte and monocyte derived macrophages in vitro. The monocytes were isolated from human peripheral blood and seeded at a density of 5 x 10(5) cells/well according to standard laboratory procedures. Cells were considered macrophages after remaining in culture for 24 hours. Cells were then plated in each microtiter well loaded with ceramic capsules (HA, TCP and ALCAP) and buffered control. At the end of 1, 2, 3, and 7 days the viability and cell number of monocyte or monocyte derived macrophages were determined using an established assay. Cell number was determined in control wells with known amounts of cell number, a standard curve was generated by plotting absorbance units versus cell number. Biochemical analysis was performed on the aliquots obtained from the experimental and control wells at the end of each phase of the investigation. The data from this experiment suggest that: (I) monocytes and macrophages are capable of adhering to the surface of HA, TCP and ALCAP in an in vitro environment for over a 7 day period. (II) Long term incubation of ceramic capsules with macrophages revealed that the cells experienced gradual disassociation phenomenon with a greater number of cell detachment seen in the ALCAP contained wells. (III) SEM analysis of representative capsules demonstrated that there is an increase in the number of micropores on the surface of the materials after contacting a cellular environment. This observation suggest that the material surface has been modified (TCP > HA = ALCAP). (IV) Biochemical analysis of aliquots at the end of each phase showed a significant change (P < 0.05) in the activity of catalase and superoxide dismutase (SOD). Information obtained from this study provided new insights on the interrelationship between bioceramics and the possible cell response during chronic inflammation at the site of implantation. PMID- 8672695 TI - Abdominal fetal EKG noise removal. AB - Accurate detection of the fetal heart signal (FEKG) early during pregnancy enhances the physician's ability to diagnose possible congenital cardiac defects. However, FEKG acquisition is hampered by excessive noise contamination from the maternal ekg (MEKG) and uterine muscular contraction. METHODS: A new computerized system was developed to record FEKG and MEKG signals from multiple leads. Removal of noise sources was performed using a blanking procedure, which selectively removes MEKG signal, and signal averaging procedure. RESULTS: 20 subjects showed 11 positive and 9 negative findings of FEKG. Blanking out the maternal QRS complex also removed part of the fetal signal making it unusable. The signal averaging procedure applied to 10-20 maternal QRS's still produced false positive fetal QRS signals. Two of the negative results were from biological noise with QRS type waveform and frequency of 8.75Hz. The depth of the fetus (5-10 cm) and period of gestation (17-40 weeks) had no bearing on finding FEKG. CONCLUSION: Blanking is not an optimal method for maternal noise removal because of removal of some fetal QRS complex. Averaging is a viable method except in cases where the peak fetal signals are less than 75 micro Volts. Preliminary studies using an adaptive algorithm with the maternal chest EKG as reference promises to be a better solution for maternal EKG removal. PMID- 8672694 TI - Cytological evaluation of capsular tissue surrounding TCPL implant in adult rats. AB - Inflammatory response and the subsequent fibrous capsule formation are often used as a screening method to determine biocompatibility of an implanted material. In this study, porous implants of tricalcium phosphate-lysine (TCPL) delivery devices were implanted intraperitoneally (i.p.) and subcutaneously (s.c.) using adult male rats as a model. The fibrous capsule surrounding the implant was studied histochemically to determine the resorbability rate of the devices. Fibrous capsular tissues were carefully dissected away from the capsule noting the tissue closest to the implanted material. Evaluation of the sections (5um, H&E) collected from various areas of the implants (n = 15 per group) revealed that: (1) regardless of the site of surgical implantation, all devices were encapsulated with fibrous tissue within three days post implantation and the thickness of the capsular tissue was found to be directly proportional to duration of implantation, (2) the thickness of fibrous tissues collected from i.p. site were significantly higher than those collected from s.c. site of implantation, (3) vascularity, macrophages, multinucleated giant cells and plasma cells at the TCPL implant-interface were evident after the first week, and the persistence of these cell types and progressive angiogenesis in subsequent weeks was apparent. The formation of distinct cell layers was remarkable in the fifth week phase, (4) SEM and radiographic analysis of retrieved devices showed a significant (P < 0.05) increase in the number of macropores (12 to 36 um2) in TCPL devices implanted s.c. than the number of macropores in TCPL devices implanted i.p. The mechanism of biodegradation process in an in vivo environment is not fully elucidated. This observation and previous observations led us to suggest that the site of surgical implantation is an instrumental key in designing TCPL delivery system. PMID- 8672696 TI - Estimation of respiratory frequency from autoregressive spectral analysis of heart period. AB - Variability in heart period is modulated by respiration. Using an autoregressive spectral analytic approach on the heart period time series produces a components analysis. The central frequency of the heart period spectral component in the frequency of respiration (HFFreq) has been suggested as an index of respiratory frequency. The present experiment measured heart period variability (HPV) using an autoregressive algorithm and respiratory frequency using a mercury strain gauge (SGResp) to assess the relationship between the respiratory frequency indexed by the two methods. Twenty human participants were studied during resting baseline, relaxation, and mental effort conditions. Within- and between-person Pearson correlations and t-tests were used to assess the concordance between HFFreq and SGResp. Both within-person and between-person correlations indicated good concordance among the two methods. Moreover, t-tests, corrected for Type I error, indicated no significant differences between the respiratory frequency estimates derived from the two methods. The resolution of the estimates was approximately 1 breath per minute. These results suggest that the HFFreq may be a useful index of respiratory frequency. PMID- 8672697 TI - Quasilikelihood estimation in measurement error models with correlated replicates. AB - We consider quasilikelihood models when some of the predictors are measured with error. In many cases, the true but fallible predictor is impossible to measure, and the best one can do is to obtain replicates of the fallible predictor. We consider the case that the replicates are not independent. If one assumes that replicates are independent and they are not, one typically underestimates the extent of the measurement error, leading to an inconsistent errors in variables correction. We devise techniques for estimating the measurement error covariance matrix. In addition, we discuss how one might perform a quasilikelihood analysis by computing the mean and variance functions of the observed data, both using approximations and also exactly through a Monte Carlo method. The methods are illustrated on a data set involving systolic blood pressure and urinary sodium chloride, where the measurement errors appear to be approximately normally distributed but highly correlated, and the distribution of the true predictor is reasonably modeled as a mixture of normals. PMID- 8672698 TI - Coupled error spending functions for parallel bivariate sequential tests. AB - Sequential procedures are developed to facilitate marginal monitoring of bivariate response vectors in clinical trials. The general approach is based on an extension of the error spending function methodology of Lan and DeMets (1983, Biometrika 70, 659-663) and is sufficiently flexible that one may elect to fix the experimental type I error rate (Cook, 1994, Controlled Clinical Trials 15(3), 187-200) or the marginal type I error rates. Sample size calculations are described to ensure power requirements are satisfied for marginal tests of significance. Reformulating the procedures in terms of repeated confidence intervals (Jennison and Turnbull, 1989, Journal of the Royal Statistical Society, Series B 51, 305-361) lends added flexibility to the monitoring process. The developments are discussed in the context of responses with a bivariate normal distribution. Data from an asthma intervention trial are used for illustrative purposes. PMID- 8672699 TI - A mixed effects model for multivariate ordinal response data including correlated discrete failure times with ordinal responses. AB - The mixed effects model for binary responses due to Conaway (1990, A Random Effects Model for Binary Data) is extended to accommodate ordinal responses in general and discrete time survival data with ordinal responses in particular. Given a multinomial likelihood, cumulative complementary log-log link function, and log-gamma random effects distribution, the resulting marginal likelihood has a closed form. As a result, a Newton-Raphson estimation procedure is feasible without resorting to numerical, approximation-based, or Monte Carlo integration techniques. The parameters in the model have a proportional hazards interpretation in terms of multivariate discrete time data with ordinal responses. Using data from a psychological example, the proposed method is compared with other mixed effects approaches as well as population-averaged models. PMID- 8672700 TI - Fitting a multiplicative incidence model to age- and time-specific prevalence data. AB - We discuss the assessment of age- and time-specific disease incidence using prevalence data. A method is described for conveniently fitting a discrete-time multiplicative model, subject to positivity constraints, using the EM-algorithm. Together with smoothing, it allows essentially nonparametric assessment of incidence trends. The method is illustrated using previously analyzed data on toxoplasmosis. PMID- 8672701 TI - A proportional hazards model for arbitrarily censored and truncated data. AB - Turnbull (1976, Journal of Royal Statistical Society, Series B 38, 290-295) proposed a method for nonparametric estimation of the distribution function when the data are incomplete because of censoring and truncation. However, as noted by Frydman (1994, Journal of Royal Statistical society, Series B 56, 71-74), Turnbull's method has to be modified to accommodate both truncation and censoring. This paper presents a detailed correction of Turnbull's method and an extension to the regression analysis: a method of fitting the proportional hazards model for arbitrarily censored and truncated data is developed. The method allows partial testing for zero regression coefficients. The test can be performed using the likelihood ratio test or the Wald test. The methodology is applied to estimate the distribution of the induction time of patients diagnosed with transfusion-associated AIDS and to estimate the distribution of time from diabetes onset to development of diabetic nephropathy for insulin-dependent diabetics. PMID- 8672702 TI - Meta-analysis of published data using a linear mixed-effects model. AB - This paper describes the use of a linear mixed-effects regression model as a framework for the meta-analysis of published data. It generalizes the random effects models used by DerSimonian and Laird (1986, Controlled Clinical Trials 7, 177-188) and Begg and Pilote (1991, Biometrics 47, 899-906), and describes the use of the model using examples from these papers and the data given by Tori et al. PMID- 8672703 TI - Robust tests for treatment comparisons based on recurrent event responses. AB - Robust nonparametric tests are considered for use in longitudinal studies in which the response of interest is a recurrent event. The tests are robust in the sense that they do not rely on distributional assumptions regarding the processes generating the events. The methods we describe are presented in the context of a clinical trial with attention initially directed at the two-sample problem in which a single experimental treatment is compared to a control. We investigate a family of generalized pseudo-score statistics (Lawless and Nadeau, 1995, Technometrics 37, 158-168) in which weight functions may be chosen to generate tests sensitive to various types of departure from the null hypothesis that the mean functions for the treatment and control groups are identical. All tests we consider are evaluated by simulation with respect to the type I error rate and power under a variety of practical scenarios. An application involving data from a kidney transplant study illustrates these procedures. For trials with multiple treatment arms, we generalize these approaches and indicate test statistics appropriate for unstructured alternatives and tests based on linear contrasts of the treatment-specific mean functions. Extensions of this methodology for stratified designs are also indicated. PMID- 8672704 TI - A flexible model for human circadian rhythms. AB - Many hormones and other physiological processes vary in a circadian pattern. Although a sine/cosine function can be used to model these patterns, this functional form is not appropriate when there is asymmetry between the peak and nadir phases. In this paper we describe a semiparametric periodic spline function that can be fit to circadian rhythms. The model includes both phase and amplitude so that the time and the magnitude of the peak or nadir can be estimated. We also describe tests of fit for components in the model. Data from an experiment to study immunological responses in humans are used to demonstrate the methods. PMID- 8672705 TI - Tests for the analysis of variance of crossover designs with correlated errors. AB - The usual analysis of variance based on ordinary least squares (OLS) may be inappropriate to analyze the crossover designs because of correlations within subjects arising from the repeated measurements. The tests used with OLS are compared with three alternative tests that take into account the structure of the covariance matrix for testing the treatment and carryover effects under the assumption of multivariate normality. A modified F-test approximation and a test derived from a Pearson curve fit are shown to give adequate control over Type I error compared to the OLS tests and to tests following an empirical generalized least squares analysis. PMID- 8672706 TI - Latent variable models with fixed effects. AB - We discuss latent variable models that allow for fixed effect covariates, as well as covariates affecting the latent variable directly. Restricted maximum likelihood and maximum likelihood are used to estimate model parameters. A generalized likelihood ratio test can be used to test significance of the covariates effecting the latent outcomes. Special cases of the proposed model correspond to factor analysis, mixed models, random effects models, and simultaneous equations. The model is applied to birth defects data, where continuous data on the size of infants who were exposed to anticonvulsant medications in utero are compared to controls. PMID- 8672707 TI - Continual reassessment method: a likelihood approach. AB - The continual reassessment method as described by O'Quigley, Pepe, and Fisher (1990, Biometrics 46, 33-48) leans to a large extent upon a Bayesian methodology. Initial experimentation and sequential updating are carried out in a natural way within the context of a Bayesian framework. In this paper we argue that such a framework is easily changed to a more classic one leaning upon likelihood theory. The essential features of the continual reassessment method remain unchanged. In particular, large sample properties are the same unless the prior is degenerate. For small samples and as far as the final recommended dose level is concerned, simulations indicate that there is not much to choose between a likelihood approach and a Bayesian one. However, for in-trial allocation of dose levels to patients, there are some differences and these are discussed. In contrast to the Bayesian approach, a likelihood one requires some extra effort to get off the ground. This is because the likelihood equation has no solution until we observe a toxicity. Initially then we suggest working with either a standard Up-and-Down scheme or standard continual reassessment method until toxicity is observed and then switching to the new scheme. PMID- 8672708 TI - Nonparametric tests of tumor prevalence data. AB - This note discusses the statistical analysis of tumor prevalence data arising from tumorgenicity experiments with focus on the comparison of different treatments. In this situation, the commonly used tests can be classified into two types: interval-based tests and model-based tests (Hoel, D. G. and Walburg, H. E., 1972, Journal of the National Cancer Institute 49, 361-372; Dinse, G. E. and Lagakos, S. W. 1983, Applied Statistics 32, 236-248). It is known that the results obtained from the interval-based tests may vary according to the choice of intervals and, for the model-based tests, it may be difficult to justify the assumed model. A computationally simple alternative to these tests is proposed; this alternative is not interval-based and makes no strong model assumption. The results of a simulation study comparing the proposed test with other tests are presented and suggest that the proposed approach is quite satisfactory. PMID- 8672709 TI - Design considerations in crossover trials with a single interim analysis and serial patient entry. AB - A two-stage sequential design is presented to facilitate a single interim analysis in crossover trials with serial patient entry. The interim analysis is based on a linear statistic that combines data from individuals observed for only one treatment period with data from those observed for both periods (Cook, R. J., 1995, Biometrics 51, 932-945). The final analysis is based on the usual test statistic used in crossover trials. The size of this procedure is controlled by partitioning the experimental type I error rate over the two analyses and deriving the appropriate critical values. We investigate the design implications of adopting this procedure over the usual analysis for crossover trials by examining the necessary sample size inflation factors to maintain power, and indicate the expected savings in terms of the number of responses required. Data from a study designed to compare two antiemetic therapies for previously untreated chemotherapy patients (Osaba, D., et al., 1986, Clinical and Investigative Medicine 9, 225-231) are used to illustrate the procedure. PMID- 8672710 TI - Analyzing bivariate repeated measures for discrete and continuous outcome variables. AB - A considerable body of literature has arisen over the past 15 years for analyzing univariate repeated measures data. However, it is rare in applied biomedical research for interest to be restricted to a single outcome measure. In this paper, we consider the case of bivariate repeated measures. We apply a generalized estimating equations (GEE) approach to relate each set of repeated measures to important explanatory variables. We then invoke the seemingly unrelated regression paradigm to combine these GEE models into an overall analysis framework. This approach provides a great deal of flexibility in modeling the relationships to fixed and time-dependent covariates for each set of outcome variables. Estimation and hypothesis testing issues are described and the methodology is illustrated with an example. PMID- 8672712 TI - Remembrances of Bill Harrington. PMID- 8672711 TI - The score test for independence in R x C contingency tables with missing data. AB - In this paper, the score test statistic for testing independence in R x C contingency tables with missing data is proposed. Under the null hypothesis of independence, the statistic has an approximate chi-squared distribution with (R - 1)(C - 1) degrees of freedom. The proposed test statistic is quite similar to the Pearson chi-squared statistic with complete data and, unlike the likelihood ratio statistic for testing independence, its computation is simple and noniterative. In addition, a score test statistic is proposed for testing independence when the rows and columns of the R x C table are ordinal. Finally, extensions of the score statistics to test for conditional independence in a set of (R x C) contingency tables with missing data are described. This yields score test statistics that are natural extensions of the Mantel-Haenszel statistic. An example, using a subset of data from the Six Cities Study, is presented to illustrate the methods. PMID- 8672713 TI - Measurement of protein structure change in active muscle by hydrogen-tritium exchange. AB - A hydrogen-tritium exchange method was developed to study protein structure changes at the molecular level in active muscle. Skinned rabbit psoas fibers mounted on a specially designed holder were selectively tritium labeled at peptide group NH sites that change from a highly protected form in rigor to an easily exchangeable, essentially random coil condition when muscle is activated. The number of sites found to show this behavior varies linearly with thick filament-thin filament overlap, and would correspond to 83 amino acids per myosin molecule in the muscle, although the experiments do not yet place these sites in any given protein. Half of the sensitive sites respond to relaxing conditions as well to activation. PMID- 8672714 TI - Specificity mechanisms in the control of transcription. AB - In this overview we analyze and illustrate the principles underlying some of the specificity mechanisms that control the initiation, elongation, and termination phases of transcription. Thermodynamic mechanisms dominate in the first steps of initiation, where promoters at various levels of activation can be considered to be in competition for a limiting supply of core RNA polymerase. In the later stages of initiation, as well as in elongation and termination, the regulatory mechanisms that control specificity are largely kinetic, involving rate competition between branching reaction pathways where the outcome depends on the rates (and equilibria) of reaction and interconversion of different forms of the transcription complex. Elongation complexes are very stable at most positions along the DNA template, meaning that only RNA chain elongation (and editing) can occur at these positions. However, the stability of transcription complexes decreases abruptly when termination sequences are encountered, and here the outcome can be easily switched between elongation and termination (RNA release) by minor changes in the relative rates of these competing processes. Cis effectors, defined as sites at which regulatory proteins bind to upstream activation loci on either the DNA or the nascent RNA, play important roles in the control of both initiation and of the elongation-termination decision. Examples, drawn from studies of phage lambda N-dependent antitermination and E. coli rho dependent termination processes, illustrate the flexibility and additivity of regulatory components within control mechanisms in transcription that involve multiple determinants. The generality of such regulatory principles are stressed. PMID- 8672715 TI - The enthalpy of transfer of unfolded proteins into solutions of urea and guanidinium chloride. AB - G. Makhatadze and P. Privalov [J. Mol. Biol., 226 (1995) 491] have recently measured the enthalpy of transfer of three proteins into urea and guanidinium chloride solutions as a function of concentration and temperature. The present paper applies the solvent-exchange model [J.A. Schellman, Biopolymers, (1994)] to the data and compares it with the binding model utilized in the original publication. Both calculations assume identical binding sites. It is found that the data may be fit tolerably well using either procedure, but that the parameters describing the binding vary considerably. Consideration of the transfer properties of amino acid moieties and small peptides leads to the conclusion that solvation sites are heterogeneous and that the quantities determined by both methods are statistical averages. The parameters describe an identical-site system that has (approximately) the same properties as the real heterogeneous system. The results have mainly heuristic and mechanistic value. One quantity determined with these simplified isotherms, sigma kj delta hj, is a property of the real system and can serve as a measure of a thermal binding capacity for a protein. The appendices contain a resume of the solution theory required for the exchange model of solvation as well as the development of a number of empirical equations for the thermodynamic properties of urea and guanidinium chloride solutions. PMID- 8672716 TI - A comparison of the properties of the binary and ternary complexes formed by calmodulin and troponin C with two regulatory peptides of phosphorylase kinase. AB - The regulatory peptides Phk13 (301-327) and a modified form of Phk5 (342-367) from the gamma-subunit of glycogen phosphorylase kinase form binary and ternary complexes with both calmodulin and the related muscle protein troponin C. Neither peptide appears to affect to a major extent a fluorescent probe linked to Cys-27 of wheat germ calmodulin. Phk13, but not Phk5, significantly modifies the properties of a probe joined to Cys-98 of troponin C. A comparison by means of radiationless energy transfer of the average separations of Trp-16 of Phk5 from specific groups in the N- and C-terminal halves of calmodulin and troponin C indicate significant changes upon going from the 1:1 binary complex to the 1:1:1 ternary complex with Phk13. A comparison of the effects of addition of Phk13 to calmodulin, troponin C, and their binary complexes with Phk5 suggests that the conformation of Phk13 is similar in the binary and ternary complexes. PMID- 8672717 TI - A bifunctional fusion protein containing the maltose-binding polypeptide and the catalytic chain of aspartate transcarbamoylase: assembly, oligomers, and domains. AB - The in vivo synthesis of many target proteins or polypeptides has been enhanced dramatically and their purification facilitated through the use of gene fusion techniques which lead to the expression of fusion proteins. This approach was used to characterize the product formed in Escherichia coli encoded by a DNA construct comprising malE, the gene encoding maltose binding protein, linked to a small 30 nucleotide region which, in turn, was linked to pyrB, the gene encoding the catalytic (c) chains of aspartate transcarbamoylase (ATCase). The resulting fusion protein, MBP-C, was produced in excellent yield and readily purified in two steps because of its binding to an amylose column and displacement by maltose. The complex was studied by both sedimentation velocity and sedimentation equilibrium and shown to be a trimer of c chains with one MBP linked covalently to each chain. Treatment of the fusion protein with factor Xa cleaved each chain at the tetrapeptide encoded by the linker region yielding purified MBP with a minor modification at the C-terminus and the catalytic (C) trimer of ATCase. The MBP-C complex was fully active as an enzyme and could be reversibly denatured in 6 M urea. Scanning calorimetry studies on the fusion protein demonstrated that the MBP domain melted at the same temperature as did the purified protein. Similarly, the Tm for the C trimer in the complex was identical to the value for C trimer isolated from ATCase. Moreover, the thermal stability of the C trimer in the MBP-C complex was greatly enhanced by the addition of the bisubstrate ligand, N-(phosphonacetyl)-L-aspartate (PALA), just as observed with purified C trimer. Analogous denaturation experiments with varying concentrations of guanidine-HCl indicated that the fusion protein was denatured at much lower concentration of denaturant than observed for C trimer. These experiments demonstrate that the linker between the two structural genes encodes a polypeptide of sufficient length to permit independent folding and assembly of each protein and permit the subsequent specific cleavage at the factor Xa recognition site, thereby yielding both active proteins. PMID- 8672718 TI - Investigation of electrostatic interactions in two-stranded coiled-coils through residue shuffling. AB - The effects of electrostatic interactions on the stability of coiled-coils were investigated using the strategy of shuffling the sequence without changing the overall content of amino acid residues in the peptides. Shuffling the sequence provides peptides with thermodynamically similar unfolded states. Therefore, the unfolded state can be used as a universal reference state in comparing the thermodynamic properties of the folded coiled-coil structure of the peptides, while varying the configuration of ionized groups, that is, changing the types and number of potential electrostatic interactions. The relative stabilities of these states were determined by monitoring the temperature-induced folding/unfolding of the peptides in solutions with different pH and ionic strength by circular dichroism spectroscopy and scanning microcalorimetry. It was found that, in solutions with low ionic strength, ionic pairs contribute significantly to the stability of the coiled-coil conformation. The stability increases with an increase in the number of ionized groups in the peptide upon changing pH from acidic to neutral. In contrast, in the solutions with high ionic strength, the coiled-coil becomes less stable at neutral pH than at acidic pH. Most surprisingly, the increase in Gibbs energy of stabilization of the coiled coil state with increasing pH at low ionic strength proceeds with a decrease in the enthalpy and entropy of unfolding. This observation can be explained only by hydration of ionized groups upon unfolding of coiled-coils which is associated with significant negative enthalpy and entropy effects. PMID- 8672719 TI - Phase transitions and the molecular mechanism of contraction. AB - In this paper, the rotating cross-bridge mechanism for muscle contraction is discussed and much contradictory evidence is put forward. As an alternative, a model is given in which the motor of muscle contraction is placed in the myosin rod hinge and/or in the actin filament. No definite choice for one of the proposed models can be made yet, although it is clear that some kind of phase transition plays an important role in the mechanism. PMID- 8672720 TI - Recent developments in the theory of protein folding: searching for the global energy minimum. AB - Statistical mechanical theories and computer simulation are being used to gain an understanding of the fundamental features of protein folding. A major obstacle in the computation of protein structures is the multiple-minima problem arising from the existence of many local minima in the multidimensional energy landscape of the protein. This problem has been surmounted for small open-chain and cyclic peptides, and for regular-repeating sequences of models of fibrous proteins. Progress is being made in resolving this problem for globular proteins. PMID- 8672721 TI - Complexes of myosin subfragment-1 with adenosine diphosphate and phosphate analogs: probes of active site and protein conformation. AB - Previous work has revealed phosphate-dependent differences in the complexes formed from myosin subfragment-1 with adenosine diphosphate (S1.ADP) and aluminum fluoride (AlF4-) or beryllium fluoride (BeFx) [Phan and Reisler, Biophys. J., 66 (1994) A78], with the former resembling more the S1**.ADP.Pi state while the latter resembles more the S1.ATP state. In this work, the conformations of the S1.epsilon ADP.AlF4- and S1.epsilon ADP.BeFx, complexes were examined by nucleotide chase and collisional quenching experiments. epsilon ADP release from S1.epsilon ADP.AlF4- was slower than that from S1.epsilon ADP.BeFx. However, acrylamide titrations of S1.epsilon ADP.AlF4- and S1.epsilon ADP.BeFx showed little difference in nucleotide protection from quenching between the two complexes. This contrasts with the earlier observation on phosphate analog dependent changes in the reactivity of the SH1 group on S1. To confirm phosphate related perturbation of the SH1-SH2 sequence, emission spectra of fluorescein (IAF)-labeled SH1 and IANBD-labeled SH2 were recorded for S1 complexes with nucleotides and phosphate analogs. Considerable differences were found between the BeFx and AlF4- complexes with S1.MgADP for both SH1- and SH2-labeled proteins. These results are consistent with a recent crystallographic study of S1 complexes with ADP and phosphate analogs [Fisher et al., Biophys. J., 68 (1995) 19S] and the idea that the opening of the nucleotide cleft on S1 does not change much during ATP hydrolysis [Franks-Skiba et al., Biochemistry, 33 (1994) 12720], while significant changes in the SH1-SH2 region accompany phosphate cleavage. PMID- 8672722 TI - Hydrogen exchange and the unfolding pathway of ribonuclease A. AB - Recently, when the kinetic unfolding process of ribonuclease A was monitored by hydrogen exchange (T. Kiefhaber and R.L. Baldwin, Proc. Natl. Acad. Sci. USA, 92 (1995) 2657-2661), all peptide hydrogen bonds were found to undergo rapid exchange in a single kinetic step under conditions where unfolding is slow and the intrinsic rate of hydrogen exchange is fast (pH 8.0, 10 degrees C, 4.5 M guanidinium chloride). Comparison with the unfolding rate measured by circular dichroism indicates that hydrogen exchange is caused by the rate-limiting step of unfolding. No evidence was found for partly unfolded intermediates that are formed slowly enough to be observed by EX1 (unfolding-limited) hydrogen exchange. Some peptide NH protons were found to show, in addition to EX1 exchange, faster EX2 exchange that is base-catalyzed. The EX2 exchange is caused by species that equilibrate rapidly with the native protein at the start of the unfolding process. These species might include rapidly formed unfolding intermediates. We show here that any such unfolding intermediates must have large protection factors because the EX2 reactions of ribonuclease A under these unfolding conditions have protection factors > or = 2500. PMID- 8672723 TI - Regulation of contraction by calcium binding myosins. AB - Contraction of molluscan muscles is triggered by binding of Ca2+ to myosin. Molluscan myosins are regulated molecules, their light chains serve as regulatory subunits. They differ from myosins of skeletal muscles in requiring Ca2+ for activity and having a specific high-affinity Ca2+ binding site. As all conventional myosins molluscan myosins also consist of two heavy chains, two regulatory and two essential light chains. Scallop myosin is particularly suitable for studying light chain function since its regulatory light chains readily dissociate in the absence of divalent cations and its essential light chains can be exchanged with foreign light chains. The structural, mutational and biochemical studies presented here are aimed to elucidate the role of the light chains in regulation, to describe the interactions between the myosin subunits and to locate the regions and the amino acids responsible for the differences between functional and non-functional light chains. PMID- 8672724 TI - Thermal unfolding of Acanthamoeba myosin II and skeletal muscle myosin. AB - Studies on the thermal unfolding of monomeric Acanthamoeba myosin II and other myosins, in particular skeletal muscle myosin, using differential scanning calorimetry (DSC) are reviewed. The unfolding transitions for intact myosin or its head fragment are irreversible, whereas those of the rod part and its fragments are completely reversible. Acanthamoeba myosin II unfolds with a high degree of cooperativity from ca. 40-45 degrees C at pH 7.5 in 0.6 M KCl, producing a single, sharp endotherm in DSC. In contrast, thermal transitions of rabbit skeletal muscle myosin occur over a broader temperature range (ca. 40-60 degrees C) under the same conditions. The DSC studies on the unfolding of the myosin rod and its fragments allow identification of cooperative domains, each of which unfolds according to a two-state mechanism. Also, DSC data show the effect of the nucleotide-induced conformational changes in the myosin head on the protein stability. PMID- 8672725 TI - Depression, stressful events and the risk of cancer. PMID- 8672726 TI - Repair of the in vitro HIV-1-induced immunosuppression and blockade of the generation of functional suppressive CD8 cells by anti-alpha interferon and anti Tat antibodies. AB - The acute human immunodeficiency virus type 1 (HIV-1) infection of activated peripheral blood mononuclear cells (PBMCs) from normal donors results in inhibition of cell proliferation and generation of functional suppressive T cells. Cultured HIV-1 infected PBMCs but not uninfected PBMCs, following irradiation, can inhibit the proliferation of antigen-activated autologous T cells in a dose-dependent way. CD8+ cell subpopulation is responsible for this inhibition. The presence of anti-alpha interferon (IFN alpha) and anti-Tat antibodies in the culture medium counteracts the HIV-1-induced immunosuppression and prevents the generation of suppressive T cells by these PBMCs. The reported data should have major implications for strategies of AIDS treatment which, in association with antiviral drugs, aim at targetting immune disorders. PMID- 8672727 TI - Cytoxicity of [(5,6-dichloro-9a-n-propyl-2,3,9,9a-tetrahydro-3-oxo-1H fluoren-7 yl)oxy]acetic acid, an agent known to reduce brain edema. AB - A known agent, [(5,6-dichloro-9a-n-propyl-2,3,9,9a-tetrahydro-3-oxo-1H fluoren-7 yl)oxy]acetic acid, which blocks brain edema, was also shown to be a potent cytotoxic agent in leukemia cells. The major site of action of the agents appears to be in the de novo purine synthetic pathway in L1210 leukemic cells. Both PRPP amido transferase and IMP dehydrogenase activities were suppressed by the agent. The inhibition of both regulatory enzymes of the pathway along with the reduction of dihydrofolate reductase activity would account for the observed suppression of DNA and RNA syntheses and subsequent cancer cell death. PMID- 8672728 TI - Oral administration of type II collagen suppresses non-specifically induced chronic arthritis in rats. AB - The present study was designed to investigate the efficacy of oral administration of type II collagen (CII) on non-specifically induced chronic arthritis in rats, induced by intra-articular injection of a mineral oil, squalene. When CII was fed before injection of squalene, no chronic arthritis developed. Feeding CII after the induction of arthritis was also effective in suppressing the progression of chronic joint inflammation. Lymph node cells from rats with squalene-induced arthritis failed to show proliferative responses to CII. In rats fed and primed with CII, there was a decrease in proliferative responses to CII. Arthritis induced by the mineral oil was markedly suppressed by the spleen cells from animals fed CII. These results indicate that non-specifically induced arthritis may be downregulated by the oral administration of CII and that the downregulation of joint inflammation may be due to the generation of CII-specific regulatory T cells that react to CII abundance in cartilage. PMID- 8672729 TI - Prognostic factors in multiple myeloma: selection using Cox's proportional hazard model. AB - The pretreatment characteristics of 210 patients with multiple myeloma, observed between 1980 and 1994, were evaluated as potential prognostic factors for survival. Multivariate analysis according to Cox's proportional hazard model identified in the 160 dead patients with myeloma, among 26 different single prognostic variables, the following factors in order of importance: beta 2 microglobulin; bone marrow plasma cell percentage, hemoglobinemia, degree of lytic bone lesions, serum creatinine, and serum albumin. By analysis of these variables a prognostic index (PI), that considers the regression coefficients derived by Cox's model of all significant factors, was obtained. Using this it was possible to separate the whole patient group into three stages: stage I (PI < 1.485, 67 patients), stage II (PI: 1.485-2.090, 76 patients), and stage III (PI > 2.090, 67 patients), with a median survivals of 68, 36 and 13 months (P < 0.0001), respectively. Also the responses to therapy (P < 0.0001) and the survival curves (P < 0.00001) presented significant differences among the three subgroups. Knowledge of these factors could be of value in predicting prognosis and in planning therapy in patients with multiple myeloma. PMID- 8672730 TI - Therapeutical management of depression during adolescence. AB - Our model of reference remains essentially the psychoanalytic theory of psychic functioning which has permitted us to have a general outlook on the individual: taking into account the genetic and biological aspects of mental functioning, cognitive capacities, requirements concerning learning, as well as the role of affectivity such as is organized through interactions with the environment throughout the patient's life. We suggest that the therapeutical management of depression in adolescence is related to the psychopathology of the patient, especially when there are narcissistic dimensions. PMID- 8672731 TI - A case of abdominal aortic aneurysm infected by Nocardia asteroides. PMID- 8672732 TI - Mud pack treatment increases serum antioxidant defenses in osteoarthrosic patients. PMID- 8672733 TI - Insulin therapy corrects NK cells abnormality in type I diabetes mellitus patients. PMID- 8672734 TI - The future of antidepressants. AB - A common action of many antidepressants is the inhibition of the reuptake of the biogenic amines norepinephrine, serotonin (5-HT) and/or dopamine into nerve terminals. Another postulated mechanism of action for many antidepressants is the downregulation of beta-adrenergic receptors postsynaptically after chronic administration. Many antidepressants have been reported to produce changes in the regulation of 5-HT1 and 5-HT2 receptors chronically. None of these mechanisms is completely satisfactory as a common antidepressant mechanism of action. Is it possible to unify these hypotheses of antidepressant action? A number of receptor changes have been recognized in depression. Usually, these implicated receptors are linked to a G protein. Thus, it could be hypothesized that depression may be the result of a disorder of the large family of receptor-linked G proteins. Depression, a disorder in which there seems to be an important genetic component, could be expressed in either the receptor or in the G proteins, leading to a defective linkage between the receptor and the G protein, resulting in abnormal transduction mechanisms. The concept of antidepressants is changing rapidly as these agents appear with new therapeutic indications other than depression, such as panic disorder, obsessive compulsive disorder, etc. It can be expected that the presently available antidepressants might eventually be considered anxiolytics or that benzodiazepines and 5-HT1A agonists could come to be viewed as disinhibiting substances. PMID- 8672735 TI - Dose-dependent effects of a nitric oxide biosynthesis inhibitor on hyperdynamic circulation in two models of portal hypertension in conscious rats. AB - The role of nitric oxide (NO) in the hyperkinetic circulation in portal hypertension has not been clearly elucidated. Different doses of NO inhibitors, haemodynamic values and experimental conditions might explain the discrepant results. The aim of the present study was to investigate the acute effects of a specific biosynthesis inhibitor of NO, Nomega-nitro-L-arginine (L-NNA), on the systemic and splanchnic circulation in normal conscious rats and rats with portal hypertension due to either partial portal vein stenosis or secondary biliary cirrhosis. The administration of L-NNA (15 to 960 micrograms.kg-1.min-1) induced a significant dose dependent increase in arterial pressure which was not different among the three groups of rats. Following an acute and maximal vasopressive dose of L-NNA (1 mg.kg-1.min-1) cardiac index decreased more in portal vein stenosed and cirrhotic rats (-45 +/- 3% and -45 +/- 2%, respectively) than in normal rats (-31 +/- 2%), and systemic vascular resistance increased more in the two groups of portal hypertensive rats than in normals (+ 161 +/- 13% and + 154 +/- 10% vs + 85 +/- 6%, respectively). L-NNA caused a greater decrease in portal tributary blood flow in portal vein stenosed and cirrhotic rats (-63 +/- 4% and -55 +/- 4%, respectively) than in normal rats (-45 +/- 6%). Similarly, the increase in portal territory vascular resistance was significantly more marked in portal vein stenosed and cirrhotic rats (+ 337 +/- 62% and + 214 +/- 24%, respectively) than in normal rats (+ 153 +/- 23%). Portal pressure did not change. Following the acute administration of L-NNA, no significant difference in splanchnic and systemic haemodynamics were noted between portal vein stenosed and normal rats, except for portal pressure. In cirrhotic rats, splanchnic and systemic values remained different from normal rats. This study confirms that NO plays a role in the haemodynamic changes in portal hypertension, and shows that NO inhibitors have a dose-dependent effect in conscious portal hypertensive rats. PMID- 8672736 TI - A comparison of Doppler flowmetry with conventional assessment of acute changes in hepatic blood flow. AB - The validity and clinical relevance of Doppler flowmetry in measuring changes in regional blood flow are uncertain. In the present study we compared changes induced ketanserin in regional splanchnic blood flow as measured by Doppler flowmetry with changes in conventionally measured systemic and in hepatic haemodynamic indices estimated pharmacokinetically using indocyanine green. Fourteen patients with alcoholic cirrhosis and portal hypertension were evaluated. On multivariate analyses, significant associations were noted for only three indices: changes in estimated hepatic blood flow were predicted jointly by changes in flow in the main and right portal veins and hepatic artery (R2 = 0.80); changes in intrahepatic shunting (indocyanine green extraction) were predicted by changes in flow in the main and right portal veins (R2 = 0.55); and changes in sinusoidal perfusion (indocyanine green clearance) were significantly predicted by changes in main portal vein flow alone (R2 = 0.76). These data support the validity of Doppler flowmetry in quantifying change in regional blood flow, but highlight the limitations in its clinical application and interpretation. The association of changes in main portal vein flow with changes in sinusoidal perfusion has clinical potential but requires confirmation using other modulating drugs. PMID- 8672737 TI - Biliary strictures after liver transplantation: clinical picture, correlates and outcomes. AB - We retrospectively examined 154 adults to ascertain the frequency, site of and pre-disposing factors for biliary strictures after liver transplantation, as well as their management and clinical outcome. Twenty patients (12.5%) were identified with biliary strictures; 16 were non-anastomotic and four were anastomotic strictures. The median time from transplantation to stricture diagnosis was 17 weeks (range 3-366). Of the 16 non-anastomotic strictures, six were intrahepatic, eight hilar and two extrahepatic (donor bile duct). A control group (n = 32) of patients transplanted immediately before and after index cases was used to examine for correlates in patients with non-anastomotic strictures. At the time of diagnosis in the non-anastomotic index cases, there was a higher incidence of: (i) biliary sludge (63 vs 0%; P < 0.001); and (ii) clinical cholangitis (75 vs 0%; P < 0.001) compared with controls. Primary sclerosing cholangitis was more often the diagnosis in index patients with non-anastomotic strictures compared with controls (31 vs 9%; P < 0.05). There were no differences between index patients and controls (non-anastomotic group) in ABO blood group non-identity, cold allograft ischaemia time, use of OKT3 (murine monoclonal antibody to CD3) and hepatic artery thrombosis. Of 15 patients treated with balloon dilatation, seven required stent insertion although none have required surgery. As determined by liver function tests, there was evidence of persisting graft dysfunction in index patients compared with controls (SAP 381 vs 112 U/L, P < 0.001; GGT 529 vs 80 U/L, P < 0.001), but there was no difference in survival during a median follow-up time of 16 months (range: 3-48 months) from stricture diagnosis. In conclusion, biliary strictures tend to occur within 6 months of transplantation and are an important cause of ongoing graft dysfunction. Non-anastomotic strictures were more common in patients requiring transplantation for primary sclerosing cholangitis. PMID- 8672738 TI - Characterization of an animal model of hepatic metastasis. AB - The experimental study of possible therapies for control of the growth of liver metastases requires the availability of a model which is technically feasible and appears to exhibit growth characteristics similar to human tumours. We report on the development of an intrasplenic injection model of liver metastases, and describe the histology, growth pattern and blood flow demonstrated by light microscopy, stereology and laser Doppler flowmetry. The hepatic metastases were induced in mice by intrasplenic injection of dimethylhydrazine (DMH) induced primary colonic carcinoma cells (10(6) cells in 1 mL). The growth and development of metastases was studied over a period of 3 weeks at predetermined time points. Tumour cells were visible in the hepatic sinusoids by day 7 by light microscopy. Macroscopically visible tumours with a diameter of 0.18 +/- 0.02 cm (mean +/- s.d.) were seen by day 10. By this time the tumours had derived a blood supply from the hepatic sinusoids adjacent to the tumour periphery. With further vascularization the tumours reached a diameter of 0.96 +/- 0.50 cm by day 22. Metastatic growth was quantitated by stereological analysis of tumour volume in relation to non-diseased hepatic tissue. Normal mouse liver had a mean volume of 1.13 +/- 0.14 cm3. Tumour growth occurred in three phases. During the initial slow phase the volume of metastases increased from 0.03 +/- 0.02 cm3 at day 10 to 0.22 +/- 0.24 cm3 by day 16. Rapid tumour growth, occurring over the next 3 days, constituted the intermediate phase with metastatic volume reaching 1.21 +/- 0.74 cm3 by day 19 (P = 0.0003 compared with day 16). This growth was followed by a plateau phase when the metastatic volume was 1.40 +/- 0.55 cm3 at day 22. The volume of total liver and of tumour necrosis followed a similar growth pattern. A necrotic tumour volume of 0.004 +/- 0.006 cm3 first seen on day 10 increased to 0.05 +/- 0.06 cm3 by day 16, and to 0.25 +/- 0.20 cm3 by day 22 (P = 0.0022 compared with day 16). The blood flow in metastases measured by laser Doppler flowmetry was lower compared to the non-diseased liver. Tumour blood flow, expressed as a percentage of normal liver blood flow, was 63.31 +/- 26.28% at day 10 and diminished to 27.91 +/- 8.99% by day 22, with an increase in tumour size and age. The decrease in flow was significant between days 13 and 16 (P = 0.0015). This intrasplenic mouse model of metastases is reproducible and should prove useful in the study of treatment of hepatic metastases. PMID- 8672739 TI - Influence of clinicopathological variables on CYP protein expression in human liver. AB - Drug metabolism is usually impaired in malnourished patients with decompensated cirrhosis, but the separate influence of clinicopathological variables, including nutritional status, on the expression of hepatic cytochrome P450 proteins has not been well characterized. We determined the hepatic content of CYP1A2, CYP2C8/10, CYP2E1 and CYP3A proteins in 71 subjects, 21 with histologically normal livers and 50 with chronic liver disease, and then tested for potential relationships between patient variables and individual CYP proteins by multivariate linear regression analysis. Variables analysed included nutritional status (determined by experienced clinicians), serum albumin and bilirubin concentrations, prothrombin time, the grade of ascites and hepatic encephalopathy, and the Child Pugh score. Impaired nutrition and cachexia were associated with reductions of CYP2C8/10 levels of approximately 19 and 39%, respectively, relative to cases in which nutrition was replete. Similarly, CYP2E1 protein was reduced by approximately 13 and 26%, according to the apparent severity of nutritional impairment. In contrast, nutritional status did not contribute to variability in expression of CYP1A2 or CYP3A proteins. Of the clinicopathological variables analysed, only serum bilirubin was shown to have an independent influence on CYP protein content. Thus, elevated serum bilirubin concentrations were associated with significant declines in the contents of CYP1A2 and CYP2C8/10 but not CYP3A or CYP2E1. The mechanisms for the effects of nutritional status and serum bilirubin concentration on the levels of CYP proteins are unclear, but could be mediated by factors such as cytokines, dietary composition and alterations in the level of serum bile acids. Knowledge of the influence of clinicopathological factors and nutritional status on CYP expression should lead to more rational drug prescribing in patients with hepatic disease. PMID- 8672740 TI - Echo-Doppler measurements of portal vein and superior mesenteric artery blood flow in humans: inter- and intra-observer short-term reproducibility. AB - The reproducibility of echo-Doppler measurements of portal vein and superior mesenteric artery blood flow has not been extensively studied. In the present study, two groups of subjects were examined to test inter- and intra-observer reproducibility. Each study population consisted of 15 nonportal hypertensive and 15 portal hypertensive subjects. With a standardized technique, the crosssectional area and velocity of blood flow in the portal vein and superior mesenteric artery were recorded in triplicate by skilled operators. The flow volume of each vessel was calculated by multiplying the cross-sectional area by the velocity of blood flow. The measurements were performed in a blind fashion over a 60 min period. The reproducibility of measurements was assessed by calculation of intraclass correlation coefficients and coefficients of variation. The intra-observer intraclass correlation coefficient was 0.77 for portal vein blood flow and 0.84 for superior mesenteric artery blood flow, suggesting good reproducibility. The intra-observer coefficient of variation was 11 and 9%, respectively. In contrast, the interobserver intraclass correlation coefficient was calculated to be 0.49 for portal blood vein blood flow and 0.57 for superior mesenteric artery blood flow, indicating fair reproducibility. In addition, the interobserver coefficients of variation were calculated to be 20 and 18%, respectively. These data suggest that intra-observer reproducibility in echo Doppler measurements of portal vein and superior mesenteric artery blood flow is acceptable but inter-observer reproducibility is not. Examination by a single operator, rather than multiple operators, is therefore advisable. Even when measurements are performed by a single investigator an approximate variance of 10% in the measurement in a single subject should be expected. PMID- 8672741 TI - Changes in the localization of colorectal cancer: implications for clinical practice. AB - A hospital-based study was performed in order to examine the subsite distribution of colorectal cancer diagnosed in 1992-93 in the Zaanstreek region. The localization was compared with tumours diagnosed in the years 1972-73 and 1982 83. The number of colorectal cancers has markedly increased, and a significant rise in localization of tumours proximal to the splenic flexure has occurred (32% in 1972-73 to 43% in 1992-93). There also appears to be greater incidence of colorectal cancer in women. A trend towards an increase of proximal localization of tumours in women was noted. Possible explanations for this phenomenon are discussed. The results of this study suggest the importance of improved diagnostic accuracy in colorectal cancer and, in addition, may have consequences for screening programmes. PMID- 8672742 TI - Treatment of gastric fundal varices by balloon-occluded retrograde transvenous obliteration. AB - Although less common than oesophageal varices in portal hypertension, gastric fundal varices carry a higher mortality rate when they rupture. They are less amenable to sclerotherapy. We have developed a minimally invasive balloon occluded retrograde transverse obliteration (B-RTO) procedure to treat gastric fundal varices. B-RTO involves inserting a balloon catheter into an outflow shunt (gastric-renal or gastric-vena caval inferior) via the femoral or internal jugular vein. Blood flow is then blocked by inflating the balloon, and 5% ethanolamine oleate iopamidol is injected in a retrograde manner. The embolized gastric varix subsequently disappears. B-RTO was performed in 32 patients with gastric varices. Follow-up endoscopies were performed at intervals of 2-4 months for an average observation period of 14 months. Eradication of the varices has been confirmed in 31 of 32 patients. No recurrence occurred in any patients in the follow-up period. There were no significant changes in liver function after the procedure. We conclude that B-RTO is a safe and effective procedure for the treatment of gastric fundal varices. PMID- 8672743 TI - Prevalence of gastric ulcer in cirrhotic patients and its relation to portal hypertension. AB - The prevalence of gastric ulcer and its relationship to the severity of cirrhosis and degree of portal hypertension was evaluated in 245 cirrhotic patients, and compared with 245 age- and sex-matched healthy subjects. Portal and systemic haemodynamic studies were performed in cirrhotic patients. The prevalence of gastric ulcer in cirrhotic patients was 20.8%, which was significantly higher than the 4.0% found in healthy controls. Using a multivariate logistic regression model, the hepatic venous pressure gradient was found to be the only predictor of the prevalence of gastric ulcer in cirrhotic patients to present with gastric ulcer. The hepatic venous pressure gradient was significantly higher in cirrhotic patients with gastric ulcer than in those without (17.3 +/- 4.4 vs 15.5 +/- 5.0 mmHg, P = 0.01). Other variables, including sex, smoking, cardiac output and severity or aetiology of cirrhosis did not show significant differences between the two patient groups. The prevalence of gastric ulcer in cirrhotic patients whose hepatic venous pressure gradient was below 12 mmHg (4.5%) was similar to that observed in the healthy controls (4.0%). However, when the hepatic venous pressure gradient was > 12 mmHg, the prevalence of gastric ulcer (24.4%) was significantly higher than that in control subjects. However, the incidence of gastric ulcer was not related to the degree of portal hypertension. In conclusion, the prevalence of gastric ulcer in cirrhotic patients was found to be significantly higher than in the age- and sex-matched healthy subjects. Portal hypertension with a hepatic venous pressure gradient > 12 mmHg may be an important factor contributing to the increased prevalence of gastric ulcer observed in patients with liver cirrhosis. PMID- 8672744 TI - The effect of minimum luminal nutrition on bacterial translocation and atrophy of the jejunum during parenteral nutrition. AB - In situations of catabolic stress, the gut becomes atrophic and may have diminished barrier function as evidenced by an increase in bacterial translocation. The aim of this study was to examine the effect of minimum luminal nutrition during parenteral nutrition on the extent of jejunal atrophy and rate of bacterial translocation. Central venous lines were inserted into 30 rats before they underwent randomization to receive nutritional support with: (a) conventional parenteral nutrition; (b) conventional parenteral nutrition with 3 g/day of rat food (i.e., minimum luminal nutrition); or (c) rat food ad libitum. The rats were assessed after 10 days for nutritional status, extent of jejunal atrophy, caecal flora, as well as the extent of bacterial translocation to the mesenteric lymph nodes, liver and spleen. Rats in the rat food ad libitum group lost the smallest amount of weight and had the least amount of jejunal atrophy, yet had a similar rate of bacterial translocation as the parenterally nourished groups. When compared with the conventional parenteral nutrition group, the minimum luminal nutrition group had better preservation of the weight of the small bowel and its isolated mucosa (P < 0.01), but had a similar rate of bacterial translocation. Minimum luminal nutrition reduced the extent of atrophy of the gut but did not affect the incidence of bacterial translocation. It is inferred that there is no direct relationship between the extent of mucosal atrophy and incidence of bacterial translocation. PMID- 8672745 TI - Plasma cytokine levels and monocyte activation in patients with obstructive jaundice. AB - Some monocytic cytokines are important immune regulators. We have investigated cytokine production by monocytes and the blood levels of IL-1 beta, IL-6, TNF alpha, and TGF beta, in patients with obstructive jaundice. The supernatant from LPS stimulated monocytes from jaundiced patients released significantly increased quantities of TNF alpha by both bioassay and radioimmunoassay (RIA) (12.4 +/- 2.5 fmol/mL and 32.6 +/- 8.3 fmol/mL, respectively, for jaundice, compared with 1.6 +/- 0.3 fmol/mL and 2.4 +/- 0.5 fmol/mL respectively for controls, and also of IL 6 (54.8 +/- 5.0 fmol/mL in jaundice compared with 35.6 +/- 5.0 fmol/mL for controls). The production of IL-1 beta and TGF beta by stimulated monocytes was unchanged. Jaundiced patients had significantly higher plasma TGF beta, but TNF alpha and IL-1 beta were below the limits of detection. The highest monocyte TNF alpha and IL-6 levels were seen in malignant disease patients, especially those with a poor immediate prognosis. We conclude that the production of some cytokines by monocytes is up-regulated in patients with obstructive jaundice. PMID- 8672746 TI - Patterns of methane production in a Burmese (Myanmar) population. AB - While up to 50% of Western populations produce methane, this is less than that of rural black Africans and there is no information on methane production in populations from Asian developing countries. Females consistently produce methane more commonly than males, and methane production in children under the age of five years, except in Nigeria, is unusual. Breath methane was sampled in 1426 subjects from Myanmar ranging in age from 1 month to 88 years, with a mean age of 26.2 years. Half (49.8%) of the Myanmar population produced methane, this figure comprising 53% of females and 46% of males sampled. Methane production increases with age and reaches adult levels after 10 years of age. A high prevalence of methane production was found in children under 3 years of age (15.8%). Methane production was absent in 13 solely breast-fed children and increased as other food was introduced into the diet. There was an association of methane production within families and with smoking. The prevalence of methane production increased in male and female smokers, with 75% of smokers producing methane. Methane production was not associated with occupation, education, income, water source, latrine type, previous diarrhoea, antibiotic usage or socio-economic status. PMID- 8672747 TI - Clinicopathological study of colorectal mucinous carcinoma in Taiwan: a multivariate analysis. AB - The clinicopathological significance of colorectal mucinous carcinoma is controversial, although some authors feel mucinous carcinoma has a worse prognosis than that of non-mucinous carcinoma. To clarify the significance of this type of carcinoma in Taiwan, a retrospective review of patients with colorectal carcinoma treated at Chang Gung Memorial Hospital between 1984 and 1988 was undertaken. During this period, 53 mucinous carcinomas and 401 non mucinous carcinomas fulfilling the inclusion criteria were analysed. Mucinous carcinomas were more common in patients 39 years of age or under (P < 0.005). Most mucinous carcinomas were located in the rectum/rectosigmoid, followed by the right colon; however, the right colon had a higher relative incidence (38 vs 8%, respectively; P < 0.005). Mucinous carcinomas presented at a significantly more advanced stage (23 vs 8%, respectively, stage D disease; P < 0.005) and had a markedly lower curative resection rate (68 vs 84%, respectively; P < 0.05). Following curative resection, mucinous carcinomas tended to have an increased incidence of subsequent distant metastasis (27.8 vs 18.8%, respectively; P < 0.005). The overall survival rate of patients with mucinous carcinoma was worse than that of non-mucinous carcinoma (P < 0.005). Multivariate analysis showed that clinically important predictive factors were stage of disease on diagnosis and subsequent distant metastasis. The mucinous histological type itself was not an independent prognostic factor in colorectal cancer. PMID- 8672748 TI - Some factors associated with mortality in perforated peptic ulcer: a case-control study. AB - This study examined the associations of individual coexisting illnesses, septicaemia, intra-abdominal abscess, marital status, smoking and alcohol use, with mortality following perforation of peptic ulcer without pre-operative evidence of haemorrhage. Patients who died in hospital following ulcer perforation (cases; n = 300) were compared with patients who survived following ulcer perforation (controls; n = 276). The controls were frequency-matched to the cases on age, sex and perforation site. Data were analysed by logistic regression. Cardiac, respiratory, cerebrovascular, renal, liver and malignant diseases, and septicaemia and intra-abdominal abscess were associated with mortality and the coexisting illnesses were significantly increased in cases compared to controls both on admission and at the end of hospital stay. During hospitalization, the odds of pneumonia decreased in cases, otherwise there was little change in strengths of associations over this period. Being widowed or never married was positively associated with mortality, and moderate alcohol use was negatively associated. In conclusion, this study identifies several coexisting illnesses, septicaemia and intra-abdominal abscess as risk factors for mortality following ulcer perforation. The results suggest that, with little exception, the same level of mortality risk is associated with coexisting illnesses whether the beginning or end of hospital stay is used as the index time point. PMID- 8672749 TI - Sulindac and indomethacin inhibit formation of aberrant crypt foci in the colons of dimethyl hydrazine treated rats. AB - Aberrant crypt foci are microscopic lesions found in the colons of rodents treated with carcinogens, and in patients with premalignant colorectal conditions. They consist of single or multiple abnormal crypts and show cellular changes ranging from dysplasia to microscopic adenomacarcinoma. It is thought that these lesions represent the initial stages of the adenomacarcinoma path that results in the development of colorectal neoplasia. We have examined the effect of sulindac and indomethacin on the formation of aberrant crypt foci in rats treated with dimethylhydrazine (DMH). Aberrant crypt foci were induced in male Sprague-Dawley rats with two oral doses of dimethyl hydrazine at 25 mg/kg per dose. Rats were randomized to receive sulindac at 3 mg/kg (n = 20) or 10 mg/kg (n = 18) b.d., indomethacin at 1 mg/kg per day (n = 18) or 2 mg/kg per day (n = 19) or control (n = 37). Drug treatment was started on the day following the first dose of carcinogen and continued for 3 weeks. Colons were fixed flat overnight in 10% formalin and stained with 0.2%. Methylene Blue solution before being studied. There was a significant reduction in the number of aberrant crypt foci in rats treated with 10 mg/kg b.d., sulindac (P = 0.001) and indomethacin at 2 mg/kg per day (P = 0.0002). Sulindac, at 3 mg/kg b.d., and indomethacin, at 1 mg/kg per day, did not have a statistically significant effect (P = 0.089 and P = 0.052, respectively). None of the drug treatments affected the relative frequency of single crypt vs multiple crypt foci. Previous studies have shown that sulindac and indomethacin will significantly inhibit the growth and development of tumours in DMH treated rats. The current data suggest that one of the pathways of action of NSAID is to inhibit the formation of early preneoplastic lesions. PMID- 8672750 TI - Risk factors, Helicobacter pylori and a role for laparoscopic treatment of perforated peptic ulcer? PMID- 8672751 TI - Pancreatic calculi superimposed upon slow growing pancreatic cancer. AB - We report on a 59 year old male patient with cancer of the head of the pancreas, upon which pancreatic calculi were superimposed during the 3 year clinical course. Pancreatic calculi were noted in the main pancreatic duct (MPD) on both computed tomographic scans and ultrasonographs of the abdomen approximately 10 months after the recognizable dilatation of the MPD. Existence of the calculi was confirmed by autopsy. Elemental analysis and infrared spectrophotometry of the calculi demonstrated that the main constituent of the calculi was calcium carbonate. Histopathological examination showed that the pancreatic cancer was moderately differentiated adenocarcinoma. Immunohistochemical studies revealed that pancreatic stone protein (lithostathine) was present in the cytoplasm of tumour cells. In this case, pancreatic cancer progressed to obstruct the MPD unusually slowly, resulting in stagnation of pancreatic secretion and subsequent formation of the calculi. PMID- 8672752 TI - Bowel preparation for colonoscopy: a randomized prospective trail comparing sodium phosphate and polyethylene glycol in a predominantly elderly population. AB - Many patients find polyethylene glycol-based preparations (PEG) difficult to take because of the large volume of fluid they are required to consume. One hundred and sixteen predominantly elderly patients were randomized to receive either sodium phosphate (n = 61) or PEG (n = 55) bowel preparations before colonoscopy. Patients with a history of symptomatic ischaemic heart disease or cerebrovascular disease in the preceding 6 months, severe liver disease or heart failure, or serum creatinine above 200 micrograms/L were excluded from the study. Each patient filled in a questionnaire about the bowel preparation prior to the procedure. The colonoscopists, who were not aware which preparation had been used, were asked to complete a questionnaire about the quality of the bowel preparation after the procedure. The patients found the sodium phosphate preparation slightly more tolerable than PEG. Side effects were slightly more common with sodium phosphate. Neither difference was statistically significant. However, 91% of patients who had previously had PEG found sodium phosphate easier to take. Approximately 25% of patients in each group experienced at least one episode of incontinence. The colonoscopists found no difference in the overall quality of the bowel preparation. The amount of fluid in the colon was greater in patients prepared with PEG. As expected, patients taking sodium phosphate developed hyperphosphataemia (mean phosphate level before colonoscopy 1.56 mmol/L, normal 0.8 -1.3). They also had a lower mean serum potassium level (3.8 mmol/L) than the PEG group (4.2 mmol/L). However, there were no clinically significant consequences. Sodium phosphate was a safe and effective bowel preparation for colonoscopy in this carefully selected group of patients. It was preferred by patients who had previously had PEG. Many elderly patients were found to develop faecal incontinence, irrespective of the type of bowel preparation used. PMID- 8672753 TI - Gastric metaplasia of regenerating duodenal mucosa and deformity of duodenal bulb: a correlative study. AB - The correlation between the presence and degree of gastric metaplasia of regenerating duodenal mucosa and the deformity of duodenal bulb was studied. Based on the endoscopically morphological patterns of bulb, the duodenal ulcers were divided into three types: type I, with a normal-shaped bulb; type II, with mildly deformed bulb; and type III, with a markedly deformed bulb. A total of 159 patients with active duodenal ulcers were scheduled to be treated with H2 receptor antagonists. Of these patients, 124 proved to have a healed duodenal ulcer 4 weeks after initial treatment upon follow-up endoscopic examinations. Two biopsies were taken from the centre of the ulcer scar when the ulcer was found to be healed for light microscopic study. Histologically, the degree of gastric metaplasia was divided into three grades: grades 0, 1 and 2. The results show that a healed duodenal ulcer with a normal-shaped bulb is not frequently accompanied by gastric metaplasia. However, a healed ulcer with a markedly deformed bulb has a high incidence and degree of gastric metaplasia, which may be easily colonized by Helicobacter pylori and thus develop an environment of easy recurrence. Therefore, a cycle of healing and recurrence may exist in patients with a duodenal ulcer and a markedly deformed bulb. Eradication of H. pylori may be the best way to break this cycle. PMID- 8672754 TI - A comparative study of the influence of differing barley brans on DMH-induced intestinal tumours in male Sprague-Dawley rats. AB - The influence of barley brans on the incidence and burden of intestinal tumours in rats induced by 1,2-dimethylhydrazine (DMH) was studied in a 7 month feeding experiment. The basic diet was American Institute of Nutrition (AIN) 76 modified by adjustment to 20% fat and 40% starch; brans were added so as to supply 5% dietary fibre. The barley brans studied were commercial barley bran (BB1; 13.0% dietary fibre) from the aleurone/subaleurone layer, outerlayer barley bran (BB2) including the germ (25.5% dietary fibre) and spent barley grain bran (SBG; a by product of the brewery and including the hull; 47.7% dietary fibre). They were compared with wheat bran (WB; 44% dietary fibre) and cellulose (or control; 98% dietary fibre). Commercial barley bran and wheat bran were most effective in reducing tumour incidence and burden. The incidence of tumours fell significantly from 70% (BB2) and 50% (SBG) to 10% (BB1) and 20% (WB) and tumour burden and tumour mass index (TMI) were also reduced by similar orders of magnitude. There were significantly higher short chain fatty acid (SCFA) concentrations in WB- and BB1-fed rat faecal pellets relative to cellulose- and BB2-fed rat faeces; butyrate, in particular, was affected. Regression analysis of butyrate against tumour incidence showed a trend (r = 0.898: P = 0.055), but the concentration of butyrate alone could not account for the reduction in tumour incidence observed. In a second experiment, when two brans (BBI and SBG) were introduced after DMH dosing, there were higher incidences and burdens of tumours, indicating that protection by such brans was not as effective under these circumstances. Commercially available barley bran and wheat bran appear to significantly reduce tumour incidence and burden in this model relative to other brans, influencing both the initiatory as well as promotional stages of chemically induced carcinogenesis. PMID- 8672755 TI - Duodenal mucosal histology and histochemistry in active, treated and healed duodenal ulcer: correlation with duodenal prostaglandin E2 production. AB - We investigated whether impaired duodenal mucosal prostaglandin E2 (PGE2) production previously observed in duodenal ulcer (DU) was a primary pathophysiological abnormality or secondary to mucosal architectural changes that accompany ulceration. One hundred patients were studied: at endoscopy, paired duodenal biopsies were taken in patients with normal endoscopies and from the ulcer edge or scar and background mucosa in active or healed DU. One of the pair of biopsies was used to estimate PGE2 synthesis ability, the other was processed for histology and histochemistry. The following features graded: goblet cell numbers and staining with Periodic acid-Schiff reagent (PAS), epithelial staining with PAS, villous atrophy, columnar cell height, inflammatory cell infiltrate and micro-erosions and gastric metaplasia taken as a whole. Patients were found to have normal endoscopy (n = 31), active untreated DU (n = 20) active DU on treatment with either cimetidine or ranitidine (n = 13), healed DU on maintenance treatment (n = 27) and healed DU off treatment (n = 9). Active duodenal ulceration was found to be associated with decreased numbers of goblet cells, loss and blunting of villi, increased columnar cell height, increased epithelial cell PAS staining and with gastric metaplasia. After healing, only villous blunting remained. These changes were present, but less marked, at sites removed from the ulcer and were not apparent in the patient groups with healed ulcers. A strong correlation between overall gastric metaplasia and epithelial cell PAS staining and the reduced ability to synthesize PGE2 (P < 0.001) was only apparent when biopsies from all patients were grouped together, but not within individual patient subgroups. There was no consistent correlation between PGE2 generation and individual parameters of pathological change in duodenum. We conclude that, although inflammatory and mucosal changes may contribute, the evidence suggests that the impaired PGE2 generation in DU disease is, to a large extent, independent of histological and histochemical features. PMID- 8672756 TI - Vagal hyperactivity in stress induced gastric ulceration in rats. AB - Indirect evidence suggests that stress ulceration is provoked by vagal hyperactivity. However, direct evidence of hypervagal activity during stress conditions is lacking. Experiments were designed to directly measure vagal activity under different stress conditions in rats. Starvation stress for 48 h did not change the mean amplitude of action potentials, but their frequency was significantly decreased. Restraint stress at 22 degrees C increased vagal activity, both amplitude and frequency, in the first 60 min; these responses were markedly enhanced by cold (4 degrees C) and persisted for at least 2 h. Starvation for 48 h did not induce any gastric mucosal lesions. Restraint alone produced petechiae in the gastric mucosa, but cold restraint induced severe haemorrhagic ulcers. It is concluded that cold restraint stress provokes a prolonged vagal hyperactivity, which is one of the causative factors for gastric ulceration. PMID- 8672757 TI - Effects of transforming growth factors on the wound repair of cultured rabbit gastric mucosal cells. AB - We have evaluated the role of two different transforming growth factors in the restoration of rabbit primary cultured gastric mucosal cells using a new wound repair model. After forming confluent monolayer cell sheets, a wound with a constant size (2 mm2) was made using a rotating silicon tip. Either TGF alpha (0.1 - 100 ng/mL or TGF beta 1 (0.1 - 10 ng/mL) was added to the medium and the process of wound repair was monitored and analysed quantitatively by an image analyser. Cell proliferation was examined by BrdU staining. After wounding, the cells fronting the wound formed lamellipodia and migrated towards the centre of the wound. In the control group, the wound healed completely 48 h after wounding. TGF alpha promoted wound healing and wound healed within 36 h in the presence of TGF alpha. TGF alpha increased the number of proliferative cells and they appeared in an earlier phase of healing than in controls. TGF beta did not have any effect on the wound repair process. In conclusion, TGF alpha promotes mucosal cell repair processes in the rabbit primary cultured gastric mucosal wound repair model in a dose-dependent manner by accelerating migration and proliferation. TGF alpha may modulate the healing process of a gastric ulcer or erosion in vivo. PMID- 8672758 TI - Herbal medicine 'Sho-saiko-to' induces tumour necrosis factor-alpha and granulocyte colony-stimulating factor in vitro in peripheral blood mononuclear cells of patients with hepatocellular carcinoma. AB - 'Sho-saiko-to' (TJ-9) is a Japanese herbal medicine that is commonly administered to patients with chronic viral liver disease in order to improve their overall physical condition and to prevent the development of liver cancer, The present in vitro study demonstrated that, by adding TJ-9 to cell cultures, there were dose dependent increases in production levels of tumour necrosis factor-alpha (TNF alpha) and granulocyte colony-stimulating factor (G-CSF) in peripheral mononuclear cells of patients with hepatocellular carcinoma accompanied by liver cirrhosis. Increases in the production of TNF-alpha and G-CSF in control cell cultures exposed to different herbal medicines were low, and this indicates the specificity of the response increases in production of these cytokines to TJ-9. TNF-alpha and G-CSF are known to play important roles in the biological defence mechanism. Administration of TJ-9 may, therefore, be beneficial for patients afflicted with intractable liver diseases because it could mildly induce these cytokines. PMID- 8672759 TI - Severe clinical rebound upon withdrawal of corticosteroid before interferon therapy: incidence and risk factors. AB - To analyse the incidence and risk factors of clinical rebound and hepatic decompensation during or upon withdrawal of prednisolone pretreatment before interferon (IFN) therapy, two series of Taiwanese patients with chronic viral hepatitis from two independent randomized controlled trails were compared. Group 1 included 41 patients with chronic hepatitis B who were pretreated with daily prednisolone (30 mg) for 3 weeks, 15 mg for 1 week and no prednisolone for 2 weeks prior to lymphoblastoid IFN therapy. Group 2 consisted of 59 patients with chronic hepatitis B who were pretreated with daily prednisolone (40 mg) for 2 weeks, 30 mg prednisolone for 2 weeks, 20 mg prednisolone for 2 weeks and no prednisolone for 2 weeks prior to INF alpha-2a therapy. Clinical rebound developed more frequently in group 2 (67.8%) than in group 1 patients (41.5%; P < 0.01). The peak serum transaminase levels of group 1 and 2 patients during clinical rebound were similar. Icteric and symptomatic clinical rebound occurred in four (one cirrhotic) group 2 patients. The incidence of hepatic decompensation was 3.4% in group 2 patients, or 5.0% in group 2 patients with clinical rebound. Patients pretreated with a higher dose (40 mg) of prednisolone (odds ratio 3.0; 95% CI 1.3-6.6; P < 0.01) and non-cirrhotic patients (odds ratio 6.2; 95% CI 1.2 32.1; P < 0.02) tended to suffer from clinical rebound more frequently. However, once clinical rebound develops in cirrhotic patients, the relative risk of decompensation is 16 times that of non-cirrhotic patients. These results suggest that clinicians should be cautious in prescribing a short course of corticosteroids for patients with chronic viral hepatitis, because hepatic decompensation might occur in Oriental people with or without cirrhosis. PMID- 8672760 TI - Endoscopic management of postoperative bile leak. AB - Significant bile leak is an uncommon but serious complication of biliary tract surgery. Of twenty-five patients presenting with postoperative bile leak, 11 had complete tie-off of common bile duct and required surgery, while the remaining 14 had injury without complete obstruction and could be managed by endoscopic methods. Of these 14 cases, bile leak occurred from the cystic duct in 11 patients and from the common hepatic duct, right hepatic duct and left hepatic duct in one patient each. Endoscopic procedures performed included sphincterotomy alone (four patients), sphincterotomy and stent placement (seven patients) and sphincterotomy followed by nasobiliary catheter drainage (three patients). There was no technical failure and bile leak was stopped in all patients. One patient died of haemobilia 5 days after stent placement. When technically feasible, postoperative bile leak can be managed safely and effectively by endoscopic methods, obviating the need for surgical reexploration. PMID- 8672761 TI - Role of endotoxaemia in hyperdynamic circulation in rats with extrahepatic or intrahepatic portal hypertension. AB - This study investigated the role of endotoxaemia in the development of hyperdynamic circulation observed in rats with extrahepatic (high collateralization) or intrahepatic (low collateralization) portal hypertension. Compared with sham-operated rats, decreased mean arterial pressure and systemic vascular resistance were detected on days 1, 4, and 14 following partial portal vein ligation. By day 1, the cardiac index of portal vein-ligated rats was similar to that of sham-operated rats and progressively increased, thereafter, reaching statistically higher values days 4 and 14. No differences in plasma endotoxin levels were found between portal vein-ligated and sham-operated rats throughout the observation period. Both carbon tetrachloride-induced cirrhotic rats with and without ascites had a higher cardiac index and lower systemic vascular resistance. Plasma endotoxin levels were higher in cirrhotic rats with ascites (8.6 +/- 2.0 pg/mL; P < 0.01) than those of control rats (2.2 +/- 0.3 pg/mL) and cirrhotic rats without ascites (2.4 +/- 0.6 pg/mL). These results suggest that factors other than endotoxaemia play a role in the development of hyperdynamic circulation observed in rats with extrahepatic portal hypertension and cirrhotic rats without ascites, but that endotoxaemia may contribute to the maintenance of hyperdynamic circulation found in cirrhotic rats with ascites. The severity of liver disease may be a more important factor than the presence of portosystemic shunting for the development of endotoxaemia in portal hypertensive states. PMID- 8672762 TI - Long-term administration of natural interferon-alpha in patients with chronic hepatitis C: relationship to serum RNA concentration, HCV-RNA genotypes, histological changes and hepatitis C virus. AB - To virologically assess the efficacy of interferon therapy in chronic hepatitis C, either 5 or 10 MU/day natural interferon-alpha (IFN alpha) was administered to 57 patients with chronic hepatitis C for 38 weeks. A complete and sustained response (CR-SR), as evidenced by the absence of serum hepatitis C virus (HCV) RNA during the administration period and at 6 months after the final administration of IFN alpha and normal GPT level at 6 months after final administration, occurred in 42.6% (23/54) of subjects. Liver tissue was histologically evaluated using the histological activity index (HAI) score before and after the administration period. In CR-SR cases, significant improvements (P < 0.01) occurred in periportal necrosis, intralobular necrosis, portal inflammation and total score. A comparison, by HCV genotypes, revealed that CR-SR occurred in 60% (9/15) of subjects with type 2a and 30.3% (10/33) of subjects with type 1b. A comparison by virus concentration revealed that CR-SR occurred in 71.4% (15/21) of those subjects having a virus concentration of < 10(5) copies/mL, but in only 24.2% (8/33) of those having a virus concentration of > 10(5) copies/mL. Analysis by a multiple logistic model revealed a strong correlation between the therapeutic effect of interferon therapy and the pre administration virus concentration (P = 0.0061) and genotype (P = 0.0015). These results suggest that the pre-administration virus concentration and genotype are both key factors affecting the therapeutic effect of interferon therapy in chronic hepatitis C and that the therapeutic effect of interferon is satisfactorily high, irrespective of virus concentration, in subjects with type 2a HCV, but varies depending on virus concentration in subjects with type 1b. PMID- 8672763 TI - Relationship between hepatocellular carcinoma and subtypes of hepatitis C virus: a nationwide analysis. AB - Although hepatitis C virus (HCV) has now been classified into several subtypes, the clinical significance of HCV subtypes is not well known. Typing of HCV is now routinely performed in Japan. In the present study, HCV subtypes in hepatocellular carcinoma (HCC) patients were analysed from nationwide data collected in Japan using a standard questionnaire. Answers to the questionnaire concerning HCV subtypes in patients with chronic hepatitis (CH), liver cirrhosis (LC) and HCC were obtained from 14 hospitals. The prevalence of the 1b-related subtype, which includes the mixed subtype of 1b and 2a or 2b, in patients with LC and HCC in each hospital was higher than in patients with CH, with few exceptions. However, the differences were not statistically significant because of the small number of patients in each hospital. In summarized data from all 14 hospitals, the 1b-related subtype was found in 1370 of 1922 patients with CH (71.2%). In 356 LC and 426 HCC patients, the prevalence of the 1b-related subtype was 79.8 and 80.5%, respectively. The prevalence of the 1b-related subtype in patients with LC and HCC was significantly higher than in patients with CH. There was no significant difference between the prevalence of the 1b-related subtype in patients with HCC and LC. These results indicate that the oncogenic activity of subtype 1b, although not yet clearly characterized, may be stronger than subtypes 2a and 2b. PMID- 8672764 TI - Endemicity and clinical picture of liver disease due to obstruction of the hepatic portion of the inferior vena cava in Nepal. AB - Obstructive lesion of the hepatic portion of the inferior vena cava is common in Nepal. The clinical data on 150 patients who were seen at the Liver Unit, Bir Hospital, Kathmandu, in three years from 1990 to 1992 were analysed. Although the majority of patients were over 20 years of age, 25 patients were below 10 years of age; there were more males than females in this study. This disease accounted for 17% of 866 patients with chronic liver disease and for nearly one quarter of 267 biopsies performed on this patient group during the same period. Obstructive lesions of the inferior vena cava seem to be more common among poor people with malnutrition. Clinically, our patient group could be divided into acute (n = 27), subacute (n = 43) and chronic (n = 80) cases. The important clinical features are hepatomegaly and/or ascites and, in chronic cases, prominent dilated superficial veins over the body trunk with cephalad flow. Ultrasound is the most helpful diagnostic procedure, especially in subacute and chronic cases, as it frequently demonstrates caval obstruction, thrombosis, dilated hepatic veins and intrahepatic collaterals. Diagnosis is confirmed by cavography, which shows a caval obstruction of varying lengths at the cavo-atrial junction or a marked narrowing of the hepatic portion of the vena cava. In subacute and chronic cases cavography also demonstrates collateral veins, such as the ascending lumbar, hemiazygos and azygos that drain into the superior vena cava. Chronic cases had periods of exacerbation often associated with bacterial infection. The aetiology of inferior vena cava obstruction at its hepatic portion is not known, but there seems to be a frequent association of bacterial infection with the disease. PMID- 8672765 TI - Acute pancreatitis associated with hypercalcaemia in adult T-cell leukaemia lymphoma. PMID- 8672766 TI - Does Crohn's disease need differentiation from tuberculosis? AB - Crohn's disease (CD) and tuberculosis (TB) of the gastrointestinal tract pose major diagnostic problems for clinicians where these conditions coexist. Clinically and radiologically, the diseases are similar. In the West, TB is considered in the differential diagnosis of all suspected cases of CD, particularly among Asian migrants. Earlier age of presentation, perianal disease and enteric fistulae favour a diagnosis of CD. Aphthoid ulceration, pseudopolyps and filiform mucosa at endoscopy are suggestive of CD and a negative tuberculin test us useful. The final diagnosis depends largely on histopathology and the presence or absence of acid fast bacilli. Tuberculosis is more common in developing countries and intestinal TB frequently coexists with pulmonary tuberculosis. TB is known to affect all age groups and fistulous communication, although uncommon, does occur. In addition to radiology and endoscopy, laparotomy may be required to establish the diagnosis. In developing countries, CD is uncommon and remains largely a diagnosis of exclusion. A trial of anti tuberculosis therapy may often be prescribed before definitely diagnosing CD. The development of molecular biology techniques had led to a revival of interest in mycobacteria as a possible aetiological agent in CD. DNA from Mycobacterium paratuberculosis and Mycobacterium kansaii have both been identified in CD cases but the significance of this finding has not been established. However, in the near future polymerase chain reaction will become increasingly useful in differentiating CD from intestinal TB because it allows the amplification and identification of very small quantities of mycobacterium DNA. PMID- 8672767 TI - Chronic liver disease: do alcohol and hepatitis C virus interact. AB - In chronic liver disease, alcoholism and hepatitis C virus (HCV) frequently coexist, and it is widely believed that they interact to result in more severe disease. However, the issue is far more complex and that view may be incorrect. Newer HCV assays cast doubt on the earlier results. Data acquired in one country are often at variance with those from other countries, suggesting that other factors may be involved in the variability of the disease. Further comparison of histologically different groups of individuals with excess alcohol intake is unlikely to shed further light on the issue unless information on the duration and quantity of alcohol consumption and the duration of HCV infection is available. The net evidence is that HCV and alcohol produce different histological appearances in the precirrhosis stage with the end result cirrhosis often being indistinguishable, regardless of aetiology. Nevertheless, even with both aetiologies, progression is slow and only a minority of people develop cirrhosis despite the combination of HCV and heavy alcoholism. As yet there is no definite evidence that cirrhosis develops more frequently or sooner if both HCV and alcohol are present . Although the majority of the evidence suggests that these insults are probably additive, there is a possibility that alcohol and HCV do interact in the pathogenesis of chronic liver disease. Further studies will be necessary, however, to clarify their relationship. PMID- 8672768 TI - Acute pancreatitis induced by hypercalcaemia associated with adult T-cell leukaemia: a case report. AB - A 44 year old Japanese woman with adult T-cell leukaemia (ATL) was admitted to Kyushu University hospital to receive a course of alpha-interferon treatment. She experienced a sudden onset of hypercalcaemia and epigastric pain associated with an increase in the level of pancreatic enzymes. Her serum parathyroid hormone related protein level was above normal although her high sensitive PTH level was within the normal range. Ultrasonography and computed tomography (CT) of the abdomen showed enlargement of the pancreas with indistinct margins and massive accumulation of extrapancreatic fluid. Cullen's sign was observed. A few days after the onset of acute pancreatitis, the serum amylase level increased to 3400 IU/L, and the serum calcium level fell to 4.2 mg/dL from 13.3 mg/dl. Her fasting blood glucose level increased to 242 mg/dL. Although the first episode of pancreatitis appeared to respond to treatment, she experienced a second episode of pancreatitis accompanied by an elevation of the serum calcium level. These findings suggest that acute pancreatitis was caused by hypercalcaemia associated with ATL. PMID- 8672769 TI - Hepatic angiomyelolipoma and tuberous sclerosis. AB - A patient with angiomyelolipoma of the liver, together with radiological evidence of pancreatic, renal and bony lesions characteristic of tuberous sclerosis, is described. Although the patient had no other clinical features of tuberous sclerosis, her daughter was found to suffer from the classical triad of this syndrome and also has had hepatic lipomatous lesions and bony involvement. This is the first histologically proven case of hepatic angiomyelolipoma associated with tuberous sclerosis. PMID- 8672770 TI - [The structural reform of a university clinic. The Mainz reform model]. PMID- 8672771 TI - [Spiral CT with reduced radiation dosage]. AB - PURPOSE: To examine the clinical use of a reduced dose in high-resolution spiral CT (HR-SCT) in combination with a multiplanar volume reconstruction technique (MPVR) to decrease image noise. MATERIAL AND METHODS: Facial bones, skull and extremities of 33 patients with different pathological findings were examined with spiral-CT using a slice thickness of 1 mm (pitch 1.7-2.0), a tube amperage of 40 mA and tube voltages of 80 or 120 kV. Additionally, 2-D, 3-D, and MPVR images reconstructions were performed. MPVR takes advantage of displaying planar volumes of variable thickness. RESULTS: Increased image noise was negligible if high contrast structures like bones were examined. However, very small bony structures like the stapes of the middle ear were not seen. Soft tissues could also be imaged by using the MPVR-technique. This technique did reduce image noise while at the same time partial volume averaging was increased. The skin entrance dose per investigation did not exceed 3 mGy, which is based on twelve dose measurements in two patients. CONCLUSION: It is feasible to perform HR-SCT with secondary reconstructions of facial bones, skull and extremities using reduced skin entrance doses by 10 to 20 fold to below 3 mGy. With the exception of imaging very small structures, sufficient image quality can be accomplished in routine examinations without relevant diagnostic compromise. PMID- 8672772 TI - [The CT of calcaneal fractures: 3-D reconstructions with electronic disarticulation]. AB - PURPOSE: To evaluate the clinical value of 3-D-reformations with and without electronic disarticulation of calcaneal fractures compared to axial CT and sagittal reformations. MATERIAL AND METHODS: 25 patients with intra-articular calcaneal fractures underwent diagnostic CT-examinations. Axial slices, sagittal and 3-D-reformations with and without electronic disarticulation were performed. The sagittal and both types of 3-D-reformations were compared to the axial slices with regard to the diagnostic criteria: involvement of articular facets, number of fragments, and traumatic changes of the hindfoot. RESULTS: The best proof of involvement of articular facets is found in axial slices and 3-D-reconstructions after disarticulation followed by sagittal reconstructions. Usually on 3-D reconstructions without disarticulation articular facets cannot be identified because of overlapping bones. The number of fragments is clearly demonstrated by axial slices and sagittal reconstructions followed by 3-D-reconstructions after disarticulation. Traumatic changes of the hindfoot can be diagnosed in all four forms of visualisation. CONCLUSION: The decisive diagnosis for treatment planning is made based on the axial slices supported by sagittal reformations. In unclarified cases 3-D-reformations after electronic disarticulation may provide further information. 3-D-reformations without disarticulation are useless. PMID- 8672774 TI - [MR angiography in fibromuscular dysplasia of the cervical arteries]. AB - PURPOSE: To determine 3-D time of flight MR angiography for evaluation of fibromuscular dysplasia in cervical vessels. MATERIAL AND METHODS: In 386 selective angiograms of cervical vessels fibromuscular dysplasia was revealed in 4 female patients in the age of 30-54 years. FMD was located in the carotid artery (n = 5) and in the vertebral artery (n = 2) with a total of 8 lesions. RESULTS: 6/8 of the lesions of the seven cervical vessels were located typically in the mid cervical portion of the vessels and 2/6 lesions were located in the atlas loop of the vertebral artery. 4 lesions showed moderate stenosis and 4 vessels showed only mild stenosis. These patterns which demonstrated the typical morphology of fibromuscular dysplasia with alternating irregular zones of widening and narrowing were evaluated well with MR angiography, the others were missed. CONCLUSION: MR angiography is suitable for detection of fibromuscular dysplasia when the characteristic pattern is combined with moderate stenosis of the vessel. Conventional angiography remains the standard of reference. PMID- 8672773 TI - [The accuracy of angiography and CT angiography of the carotid bifurcation compared to macro-morphological correlation]. AB - PURPOSE: To compare the degree of carotid artery stenosis in angiography and CT angiography with the degree of stenosis measured in an intact eversion endarterectomy specimen. METHODS: Preoperative angiograms (intraarterial DSA, 512 x 512 matrix) and CT-angiograms (24 sec spiral scan, slice thickness 2 mm, pitch 1.5) were taken in 12 patients with symptomatic carotid stenosis. Evaluation of the degree of stenosis was performed according to the NASCET ("distal" degree) and ECST ("local" degree) methods. These data were compared with measurements of the surgical specimens. RESULTS: The median "local" degree of stenosis in angiograms was 81.5% (range: 70-99%), in CT angiograms 83% (59-94%) and in specimens 85.5% (65-96%). The "distal" degree of stenosis was 79% (50-99%) in angiograms, 85.5% (55-99%) in CT angiograms and 81% (52-95%) in specimens. CT angiography slightly overestimated the degree of stenosis compared with the specimen, whereas angiography slightly underestimated the true degree of stenosis. However, these differences were not statistically significant. CONCLUSION: CT angiography is able to predict the degree of internal carotid stenosis when compared with an intact surgical specimen. It is as accurate as the "gold standard" of invasive angiography. PMID- 8672775 TI - [MRI tomographic blood volume measurements in the diagnosis of a stroke: the results of a clinical pilot study]. AB - PURPOSE: In this study the sensitivity of proving a stroke using regional cerebral blood volume (rCBV) maps were investigated. Another aim was to evaluate the strength of the ischaemia. METHODS: Seven patients were examined during the acute phase of a stroke, eight during the subacute or chronically stage. To calculate rCBV-maps of one slice low dosed Gd-DTPA was injected as a bolus. Using the relaxation-effect the obtained signal intensity-time curves were converted pixel-wise to rCBV images. For the region of the infarction rCBV ratios were calculated relative to the corresponding area in the contralateral hemisphere. RESULTS: Only 63% of the investigations carried out during the acute phase were utilizable. In all those cases a decrease of rCBV was found. The infarct area could only visually recognized if the rCBV ratio was lower than 0.7. The ratios of completely and partial necrotic areas of the infarctions were 0.481 and 1.028 respectively. With a p = 0.0015 these values are even statistically different. CONCLUSIONS: During the acute stage the sensitivity of the rCBV measurement was not as high as that of morphological MR imaging. However, rCBV maps make it possible to estimate the strength of the ischaemia even during the first hours. PMID- 8672776 TI - [Magnetic resonance tomography of the kidney: the testing of new pulse sequences and comparison with CT in the differential diagnosis of space-occupying lesions]. AB - PURPOSE: To evaluate new pulse sequences (turbo-spin-echo [TSE] and turbo-field echo [TFE] sequences) for study protocol optimisation and to assess the role of MRI in the differential diagnosis of renal tumours. METHODS: In six volunteers MRI of the kidney was performed at 0.5 T using a conventional T2 weighted spin echo (SE) sequence (TR/TE 1800/90 ms) and three different TSE sequences (TR 1800 5000 ms, TE 90-150 ms). Additionally CT and MRI was performed in 34 patients with 41 renal masses. Two readers evaluated both images regarding the differentiation between malignant and benign masses. RESULTS: The pilot study showed that the heavily T2-weighted TSE sequence (TR/TE 5500/150 ms) was superior to other sequences with regard to image quality and differentiation of the corticomedullary junction. In the clinical study malignant tumours were correctly classified with CT and MRI in 86.4% and 95.5% of the cases, whereas the accuracy in the diagnosis of benign lesions of CT and MRI was 73.7% and 89.5%, respectively. CONCLUSION: Using new puls sequences MRI is superior to CT in the differential diagnosis of renal tumours. MRI is superior to CT in the differentiation between complicated cysts and cystic or hypovascular renal cell carcinomas. PMID- 8672777 TI - [Preoperative staging of bladder carcinomas with Gd-DTPA-supported dynamic magnetic resonance tomography. Comparison with plain and Gd-DTPA-supported spin echo sequences]. AB - PURPOSE: Evaluation of dynamic Gd-DTPA enhanced MR imaging in the staging of bladder cancer. METHODS: We studied 40 patients with histologically proven bladder cancer. All patients were examined with routine T1- and T2-weighted MRI and late Gd-DTPA enhanced T1-weighted MRI. Additionally, a dynamic study was performed with 10 subsequent short FLASH-2-D gradient echo sequences without delay immediately after bolus injection of Gd-DTPA. Signal intensities of the tumour and of the surrounding tissue as well as image contrast parameters were quantified. RESULTS: The dynamic study showed a higher accuracy in the evaluation of stage pTa to pT2 cancer compared to spin echo MRI (63% and 46%, respectively) and no difference regarding the sensitivity (87.5%). However, overstaging was a problem with both modalities. The contrast-to-noise ratio of bladder tumour and muscle was equal or significant higher with the dynamic study compared to spin echo MRI. A higher signal-to-contrast ratio of bladder tumour and bladder muscle was calculated for the dynamic study compared with the spin-echo MRI (p < 0.01; Mann-Whitney U test). CONCLUSION: Dynamic Gd-DTPA enhanced MRI is recommended to be used additionally in the preoperative staging of bladder neoplasms. PMID- 8672778 TI - [Injuries to the lateral ligaments of the ankle joint: study technic and demonstration by means of MRI]. AB - PURPOSE: To evaluate the visualisation and extent of injury of lateral ankle ligaments using MRI. METHODS: 56 patients with the clinical diagnosis of sprained ankles were investigated. Evaluation of the anterior (AFTL) and posterior fibulotalar ligament (PFTL) was performed with the foot in dorsiflexion (20 degrees) and of the fibulo calcanear ligament (FCL) in plantarflexion (45 degrees). Axial T1w-SE and T2w-TSE images were obtained. Full-length visualisation of ligaments in one slice and the extent of injury were evaluated. 12 ankle injuries were confirmed by operation. RESULTS: With MRI full-length visualisation of lateral ankle ligaments was possible in 86%. A partial/complete rupture of the AFTL was noticed in 33/64% and of the FCI in 29/39%, and of the PFTL in 27/5%. Sensitivity/specificity of MRI when compared to surgery was 100/100% for injuries of the AFTL, 64/100% for the FCL, and 33/78% for the PFTL. CONCLUSION: Full-length visualisation of ligaments, achieved by appropriate combination of foot position and imaging plane is essential for evaluation of injured ankle ligaments on MRI. High assessment for ligamentous injuries on MRI in relation to surgery was found. PMID- 8672779 TI - [Percutaneous dynamic atherectomy with the aid of 12-F and 14-F transluminal atherectomy catheters (TEC): initial results]. AB - OBJECTIVE: The presented study reports on the first experience with the large diameter 12 F and 14 F TEC system for percutaneous dynamic atherectomy of peripheral vascular obstructions. METHODS AND PATIENTS: The 12 F and 14 F TEC extraction catheter was used to recanalize peripheral vascular obstructions in 4 patients. The extracted material was continuously aspirated during the procedure. Three patients with intermittent claudication suffered from chronic arterial occlusion (two cases) or from stenosis of an implanted stent (one case) in the region of the superficial femoral artery. In another patient with long-term dialysis history an insufficient collier shunt was treated by atherectomy. RESULTS: Complete vascular recanalisation was achieved in all cases. Supplementary intervention was not necessary. There were no complications. CONCLUSION: Atherectomy with the large diameter 12 F and 14 F TEC allows a safe and complete recanalisation of complex peripheral vascular occlusions. Further studies must show whether the enlarged vascular intrusion is justified by more favourable results. PMID- 8672780 TI - [Percutaneous transluminal angioplasty (PTA) of isolated crural arterial stenoses in critical arterial occlusive disease]. AB - PURPOSE: Retrospective analysis of the results after infrapopliteal PTA of isolated crural limb artery stenoses in patients with critical crural limb ischaemia. PATIENTS AND METHODS: Between 1989 and 1994 70 infrapopliteal dilatations of isolated crural limb artery stenoses in 44 patients (47 PTA procedures) were done with small diameter balloon catheters. 45 patients were stage IV according to Fontaine's classification, two patients were stage III. No patient had a relevant obstruction up to the popliteal artery. Follow up ranged from 1-50 months (mean 13.3 months). RESULTS: A technical success with a residual stenosis below 30% compared to the original vessel diameter was achieved in 80% of patients (n = 56). The cumulative limb-salvage rate was 76.6% after 6 to 36 months after PTA. RESULTS: In patients with chronical critical crural limb ischaemia PTA of isolated crural limb artery stenoses is an efficient therapy modality for limb-salvage. In many cases PTA is the last alternative method to amputation surgery if there is no sufficient distal vessel for a bypass. PMID- 8672781 TI - [The initial results of percutaneous therapy of popliteal aneurysms with stents]. AB - PURPOSE: Are percutaneous stents a therapeutic alternative to bypass surgery in the treatment of popliteal aneurysms? MATERIAL AND METHODS: Three patients with femoropopliteal occlusion related to popliteal aneurysms were treated percutaneously. In two cases coated stents were used. In the third patient who underwent prior bypass surgery due to local fibrinolysis a reperfusion of the aneurysm occurred. He was treated with a Wallstent. RESULTS: Primary stent treatment was successful in all cases. There were no complications. One patient was lost to follow-up. One of the two coated stents occluded after one month due to a poor run-off of only one lower limb artery. The other coated stent is still patent after 6 months proven by angiography. CONCLUSION: Percutaneous therapy with coated stents could be an alternative to surgical bypass therapy for popliteal aneurysms. Obviously long-time patency is related to sufficient run off. PMID- 8672782 TI - [Radiation exposure in interventional radiology as exemplified by the chemoembolization of hepatocellular carcinoma and laser angioplasty of the pelvic arteries]. AB - PURPOSE: Estimation of radiogenic risks for patient and radiologist in chemoembolisation of hepatocellular carcinoma (HCC) and laser angioplasty of the pelvic arteries. METHODS: In 5 chemoembolisations of HCC (4 males, one female) and 6 laser angioplasties of the pelvic arteries (5 males, one female) the surface doses received by patient and operator were measured using thermoluminescent dosimeters in standardised positions. The organ doses of the patient were derived by conversion factors employed on the measured surface doses. Effective dose was determined according to the recommendations of ICRP 60. RESULTS: The risk of lethal malignant disease and genetic disorder derived from the doses in the patient was found to be of the magnitude of 10(-4)-10(-5). The thresholds for transient erythema of the skin and depression of hematopoiesis can be reached after high expositions. A theoretical maximum of 700 laser angioplasties of the pelvic arteries allowable in one year was calculated based on the dose to the operator's left hand. For chemoembolisation of HCC, the dose to the left eye lens would reach the yearly maximum after approximately 1000 procedures. Remarkable risks for malignant disease of skin and thyroid as well as detectable opacities of the eye lens can occur after frequent interventions for many years. CONCLUSIONS: Because of the lower life expectancy the patient's risk for stochastic effect can be seen as minimal. No clinically relevant deterministic effects will occur. In the case of frequent interventions, the dose absorbed by the radiologist is likely to exceed the prescribed dose limit and to cause remarkable risk for stochastic and non-stochastic effects after many years. PMID- 8672783 TI - [Spiral CT angiography: computed improvement of the slice thickness profile]. AB - It is possible to improve on the low skirt selectivity of the slice sensitivity profile (SSP) in spiral CT by interpolation of the raw data or suitable image after-processing. We determined the SSP function of spiral CT by means of a plexiglas phantom which we subsequently modified empirically-mathematically by a correction function until we obtained maximum possible skirt selectivity and smallest possible FWHM (= full width at half maximum) of the corrected image data set. The corrected image data set was obtained by bilateral convolution of a real image data set with a correction function. This resulted in most cases in a more realistic imaging of the angiographic morphology when applied to SSD and MIP (3D) reconstructions of a. mesenterica sup. and tr. coeliacus from spiral CT data sets, compared with the original data sets. PMID- 8672784 TI - [Spinal chloroma as the initial manifestation of the transformation of essential thrombocythemia into acute myeloid leukemia]. PMID- 8672785 TI - Epiploic appendicitis: ultrasound and CT characteristics. PMID- 8672786 TI - [Pneumoperitoneum in asymptomatic pneumatosis intestinalis--much ado about nothing?]. PMID- 8672787 TI - Activities of an occupational health organization in Japan, in special reference to services for small- and medium-scale enterprises. AB - This paper reports the activities of occupational health organizations in Japan, taking Nishinihon Occupational Health Service Center, one of the largest scale occupational health service providers, as an example. The organizations, at the request of enterprises, provide occupational health services on a profit basis especially for small- and medium-scale enterprises which lack the human resources and/or facilities to meet legal requirements on occupational health. The main services include: (1) providing various types of medical examinations for workers, (2) measuring work environment, (3) occupational physicians and occupational health nurses providing a comprehensive service. Among these services, legally required health examinations and work environment measurements are well served even for small-scale enterprises. Less effective are the health promotion and occupational health service by the occupational health staffs. In the future, these service will be better provided by a newly developed network system to support occupational heath activities in small-scale enterprises. PMID- 8672788 TI - Estimated exposure to static magnetic fields for the staffs of NMR-units. AB - Exposure of the staffs to static magnetic fields of NMR-units, was investigated at two departments for chemical analysis (static field strength of the systems 11.7 and 4.7 Tesla) and two for clinical imaging (0.5 and 0.02 Tesla). The exposure time was estimated by personal interviews. The magnetic flux density was highly dependent on distance to the magnet, and the magnetic fields in normal work with the NMR-units were, during most working time, lower than 1 milliTesla (mT), which is far below the whole-body limit recommended by the American Conference of Governmental and Industrial Hygienists (60 mT), the British National Radiation Protection Board (200 mT), or the international Commission on Non-Ionizing Radiation Protection (200 mT). During short periods, when changing samples or assisting anxious patients, the fields may be strong (100-150 mT). The recommended ceiling values (2-5 Tesla) are, however, not exceeded. PMID- 8672789 TI - Quality improvement by means of "differential' occupational health care: an experiment in a regional occupational health centre. AB - From a general policy of quality improvement, the regional Occupational Health Centre Eastern Gelderland has developed a method of company health care based on the particular demands and needs of companies. A procedure of care "made to measure' based on company and work characteristics was designed. For one year, an experiment was carried out in seven companies, to investigate if this "differential care' is feasible, and if its quality is better than the traditional "standard' form. After the experiment, the companies' satisfaction proved to have increased. The influence of the Occupational Health Centre on working conditions was estimated more important than before. The increased satisfaction is considered to be an indication of better quality of care, compared with the traditional "standard' care. The differential approach appeared to be feasible. The method requires skills of professionals in the field of planning, cooperation, estimating costs and negotiating. PMID- 8672790 TI - Do attitudes and beliefs influence work loss due to low back trouble? AB - Recent evidence indicates that the influence of psychosocial factors on low back disability is as great as, if not greater than, ergonomic aspects; negative attitudes and beliefs are likely to be related to absenteeism. To measure workers attitudes and beliefs about low-back trouble, pain, work and activity five questionnaires were used. Two new instruments (Back Beliefs Questionnaire and Psychosocial Aspects of Work questionnaire) were developed and tested. The attitudes and beliefs were measured among workers in a biscuit manufacturing factory, and the responses related to absenteeism. Workers who had taken in excess of one week's absence due to low-back trouble had significantly more negative attitudes and beliefs when compared with workers who had taken shorter absence (or indeed those reporting no history of back trouble). A subset of the psychosocial parameters accounted for 32% of the variance in absence. Interventions designed to reduce negative attitudes and promote positive beliefs may help to reduce detrimental, inappropriate longer-term absenteeism due to low back trouble. PMID- 8672791 TI - Health surveillance for hospital employees exposed to respiratory sensitizers. AB - Seventy-eight National Health Service occupational health departments were invited to take part in an audit of health surveillance for employees exposed to respiratory sensitising agents. Most of the departments had responsibility for workers using glutaraldehyde, formaldehyde, methyl methacrylate and X-ray processing chemicals, but the extent to which health surveillance was provided for these employees varied. Many departments had no written policies for surveillance, and the methods used were often unnecessarily labour intensive. Only a minority of departments had made arrangements for communicating the collective results of screening to employees, failure to do so indicating a breach of statutory duty. There were major discrepancies between departments in criteria for excluding employees from work with respiratory sensitising agents. Occupational physicians caring for hospital staff should discuss and establish guidelines for effective surveillance of people working with the commonly encountered sensitisers. PMID- 8672792 TI - Work-related asthma in a population exposed to grain, flour and other ingredient dusts. AB - The purpose of the study was to determine the prevalence and causation of work related asthmatic symptoms in a population exposed to grain, flour and other ingredient dusts. Where workers complained of asthmatic symptoms which were the result of dust exposure, follow-up aimed to identify whether the symptoms were the result of sensitisation or of non-specific irritation. A questionnaire was presented to 3,450 workers who had exposure to dust during the course of flour milling (528), bread baking (1,756), cake baking (209) and other activities in food preparation (957). Those with positive responses were followed-up by taking a formal history, examination, skin prick testing and serial peak flow measurement. The overall prevalence of work-related asthmatic symptoms was 4.4% (153 out of 3,450). In the group who were followed-up (128 out of 153), non specific respiratory irritation was thought to be the cause in 90 (2.6%), whilst sensitisation was responsible for symptoms in 12 (0.3%). Of the 12 cases due to sensitisation, the agents responsible were: fungal amylase (10 cases, all associated with bread baking), flour (one case, associated with flour packing), and grain (one case, associated with flour milling). Non-specific irritation is considerably more common than sensitisation as the cause of work-related asthmatic symptoms in flour milling, baking and other flour-based industries. The prevalence of sensitisation to flour is very low (less than 1 in 1,000) in all these industries. The principal sensitiser encountered in modern plant bakeries appears to be fungal amylase. The most important source of exposure to fungal amylase is probably the debagging, sieving, weighing and mixing of bread improvers. PMID- 8672793 TI - The use of chelating agents in occupational lead poisoning. AB - Chelating agents have long been used in the pharmacological treatment of lead poisoning, whose management is still a problem, particularly in developing countries. This article reviews the pharmacological properties of dimercaprole, peniclliamine. CaNa2EDTA and dimercaprosuccinic acid, examines their indications, contraindications and side effects and discusses the possible use of each drug in occupational Pb poisoning. Proposals are also presented for the treatment and follow-up of subjects with signs and symptoms of poisoning and of subjects with low-moderate Pb absorption. CaNa2EDTA seems to be the most reliable and safer chelating agent nowadays available and with a wider spectrum of action. DMSA seems to be promising in the treatment of occupational Pb poisoning. Even though there is no doubt that chelation therapy has significantly contributed to reduce mortality and morbidity from occupational Pb poisoning, the efficacy of this treatment in subjects with subtle neurological or renal damage has not yet been studied properly. PMID- 8672794 TI - Compliance with the Control of Substances Hazardous to Health Regulations (COSHH) 1988 and health and safety awareness in hairdressing establishments. AB - Hairdressers are known commonly to suffer work-related skin problems. To explore the steps taken by employers and employees to prevent or control such problems, we visited 12 randomly selected high street hairdressing establishments in North Wiltshire and interviewed the proprietors and 43 of the employees by means of structured questionnaires. Relatively few of the establishments had taken any steps to comply with the statutory requirements of the Control of Substances Hazardous to Health (COSHH) Regulations 1988. Some premises lacked basic skin care facilities and employers often failed to provide hand care training and health monitoring. More than half of the employees had experienced work-related skin problems, typically dermatitis. Those with skin problems more commonly identified precautionary skin care measures; however, many employees could not identify desirable skin precautions when questioned. A fifth had never received skin care training. For the remainder the median elapsed interval since last trained exceeded 6 years. Only one establishment had a satisfactory skin care programme. Future efforts should be directed at training and influencing the attitudes of hairdressing employers. PMID- 8672795 TI - Problem-based learning as a training modality in the occupational medicine curriculum. AB - Problem-based learning has been used as a curricular modality in the academic year of the Occupational Medicine Residency Program. The method was applied to the resolution of problems presented by patients referred to a university clinic specifically for the determination of possible work-relatedness of the syndrome or symptoms presented. Following the usual development of the occupational and medical histories, physical examination, and determination of certain clinical laboratory values, the resident would then have to seek assistance through consultation with related specialists, a perusal of the pertinent toxicology, epidemiology, or other discipline literature, and ultimately prepare a university level report, following case conferences with fellow residents and faculty members. No formal direction was given the student, the problems of diagnosis, occupational etiology and medicolegal acceptance of the resulting report having to be resolved through self-perusal of informational sources. The knowledge gained from the exercise would be longer-lasting than that attained strictly from lecture attendance. PMID- 8672796 TI - A survey of hearing loss in Army aircrew. AB - Military aircrew are exposed to excessive noise at work, with the concurrent risks of acquiring Noise Induced Hearing Loss (NIHL). Past studies have related aircrew NIHL to a variety of factors; however, no clear causal relationship has been shown. The difficulty of establishing NIHL due to flying remains when many other confounders are present, especially age and exposure to firearms noise in the military environment. A cross sectional prevalence study of hearing loss in Army Air Corps aircrew has been undertaken. One hundred and twenty one aircrew who had more than ten years flying experience were studied and the results show that there appears to be a threshold shift in excess of that expected from the ISO levels for otologically normal males of the same age. The hearing threshold shift was found to correlate with the number of years flying and aircrew age, with the number of flying hours being less significant. PMID- 8672797 TI - Cumulative blood lead levels and nerve conduction parameters. AB - Most studies on the effects of lead on the peripheral nerves used "current' blood lead levels of the workers and infer the nerve conduction's findings to it. This practice is not ideal as the toxicity of lead on the peripheral nerves occurs over a period of time. Seventy-two workers in a lead battery manufacturing factory and 82 referents were studied with the aim of (1) correlating the nerve conduction parameters of the median and ulnar nerves of the dominant forearms with the blood cumulative lead-years (BPbCum) results; (2) determining a "noeffect' cumulative dose of lead on the peripheral nerves. The mean BPb for the exposed and referent were 36.9 micrograms/100ml and 10.5 micrograms/100ml, respectively. The mean BPbCum was 136.8 (range = 6.7-1087.0)micrograms year/100ml. Significant differences were found in the adjusted (for age, ethnical groups, smoking and drinking habits by ANCOVA) means median sensory conduction velocity, motor conduction veloclty, distal latency and amplitude between the exposed and referent groups. But for the ulnar nerve only, distal latency was significantly different. With the BPbCum groups, dose response relations are noted in both the nerve conduction parameters of the median and ulnar nerves. There were no significant differences for the ulnar and median nerves conduction parameters between BPbCum < 40 micrograms-year/100ml group and referent. Based on the study's findings, it would suggest that a maintained blood lead level of less than 40micrograms/100ml for one year may not have significant effects on the median and ulnar nerves. PMID- 8672799 TI - Mortality from scrotal cancer in metal machinists in England and Wales, 1979-80 and 1982-90. AB - The hazard of scrotal cancer from cutting oils was first recognized in the 1950s, and led to various control measures including the introduction of solvent refined oils, use of splash guards, provision of protective clothing and washing facilities and education of workers to encourage early detection and treatment of tumours. To assess how effective these controls have been, we have analyzed occupational mortality from scrotal cancer in England and Wales during 1979-80 and 1982-90. Over this 11-year period 85 deaths were attributed to the disease in man aged 20-74. This represents a reduction in mortality from the 1960s. Significantly elevated proportional mortality ratios (PMRs) were found in press and machine tool setters (PMR 1,678, five deaths), centre lathe turners (PMR 1,099, three deaths) and machine tool operators (PMR 303, eight deaths), but all of the metal machinists who died of scrotal cancer had been born before 1930, and could have worked with cutting oils before controls were introduced. These findings are reassuring, but continued monitoring of scrotal cancer incidence and mortality is required. PMID- 8672798 TI - Musculoskeletal symptoms among dentists in a dental school. AB - A cross-sectional study of symptoms from the musculoskeletal system among employees in a school of dentistry was performed. A questionnaire was answered by 139 dentists, dental auxiliaries and office workers, e.g. 68% of the employees. The answers from the dentists were compared to the answers from all the other employees. No significant differences in musculoskeletal symptoms between the dentists and the other employees were found. Female dentists reported more musculoskeletal symptoms than did male dentists. No difference was found comparing the occurrence of musculoskeletal symptoms among female dentists and females in the reference group. This indicates that the symptoms are not related to the work as a dentist, but to female working conditions in general or to factors outside work. PMID- 8672800 TI - Effects of vibration on the hand-arm system of miners in India. AB - Sixty-six Jackhammer drillers and 35 blasters from two mines were clinically screened for hand-arm vibration syndrome (HAVS). The screening consisted of questionnaire-based information, clinical examination including measurement of phalangeal circumferences of fingers (FCT) and motor nerve conduction (MCV) studies. In a warm environment, the prevalence of symptom complexes suggested the existence of peripheral neuropathy and musculoskeletal abnormalities rather than any peripheral circulatory disorders. Clinical examination revealed soft tissue wasting in the hands (26 cases), ulnar nerve impairment (23 cases), median nerve impairment (16 cases) and Dupuytren's contracture (4 cases). Mean motor nerve conduction velocities of 59 out of 66 drillers who volunteered for this assessment were not significantly different from those of the 35 blasters. The results of their correlation coefficients varied considerably for MCVs when age and years of vibration exposure underwent regression analysis. However, comparison of MCV and FCT of 30 drillers with 30 matched blasters revealed that the mean MCV of the right median nerve in the vibration exposed group was significantly decreased (p < 0.01) and for the mean FCT, the proximal phalanxes of the right index finger, left thumb and left ring fingers were thinner in the vibration exposed group (p < 0.05). PMID- 8672801 TI - Dental problems in the offshore oil and gas industry: a review. AB - The study of medical evacuation records from offshore installation workers indicates that dental pathology is a significant problem. Dental evacuations (dentivacs) account for the highest single category of medical evacuation (medivacs). Dentivacs result in human suffering and are the cause of many lost man hours for the major oil operators in the United Kingdom. This paper reviews the reporting of dentivacs at Shell Expro over a seven year period and makes some suggestions for the way forward in the handling of offshore dental problems. PMID- 8672802 TI - Hempson Industries UK Ltd. A case study in occupational health services. AB - Hempson Industries Inc. is a large (and fictitious), multi-national American owned corporation. Its wholly owned UK subsidiary, Hempson Industries UK Ltd., is a diversified organization with operations dispersed throughout the UK. The UK Chief Medical Officer, Dr. Stephen Saunders, has been with the company for nearly two years and has been proud of his achievements in establishing a professional and proactive in-house occupational health services department. His perceived success, however, has been questioned by some significant recent events. PMID- 8672803 TI - Occupational tuberculosis and a failed postgraduate medical examination. AB - A 40 year old pathologist presented with a tuberculous pleural effusion approximately one year after performing an autopsy as part of a postgraduate medical examination. She had made a diagnosis of disseminated tuberculosis but was told that this was incorrect and failed the examination. Bladder tissue from the cadaver was subsequently found to have grown M tuberculosis though none was cultured from lung tissue. No particular precautions against airborne infection were taken at the time of the autopsy and we speculate not only that the pathologist's original diagnosis was correct but that she became infected with M tuberculosis during the examination. PMID- 8672804 TI - Methyl bromide intoxication during grain store fumigation. AB - There have been over 300 cases of methyl bromide poisoning reported in the literature. The first objective of this case report was to bring out an experience with the false belief that work in a closed space is safe when accompanied by the use of a cartridge respirator with activated charcoal. The second objective of this article was to demonstrate the marked toxicity of methyl bromide with the potential to cause long-term neurological damage. Two experienced fumigation workers (equipped with rapidly saturable respiratory cartridges) entered a building where the concentration of methyl bromide was 17g x m-3 instead of the advised 20mg x m-3. They felt rapidly unwell and complained of nausea and shortness of breath, followed for one them by generalized convulsions. Five months later this last man was still bedridden. The other worker had almost no after-effects. The highest bromide level was found in the blood and also in the activated charcoal cartridge of the most injured worker. There was a relationship between methyl bromide level exposure and neurological damage importance. PMID- 8672805 TI - Dealing with spilt mercury. PMID- 8672806 TI - [International collaboration for health]. PMID- 8672807 TI - [Public health nurse staffing requirements for health examination of infants and children in municipalities of Japan]. AB - In accordance with the Maternal and Child Health Service Act, public health centers and municipalities offer health education, health counseling, health examinations, and home visits for children and their mothers in their jurisdiction. On the basis of the new Maternal and Child Health Service Act, municipalities will have the responsibility to effectively promote health examination for three-year-old children beginning in 1997. To provide health examinations to infants and children, establishing a health personnel system, especially the public health nurse program, is extremely important. The purpose of this study is to determine fundamental facts concerning health manpower development among public health nurses in the municipalities, by reviewing research on health examinations for both infants and children. To determine personnel staffing requirements necessary for health examinations of infants and children in the municipalities of Japan, pertinent references were systematically reviewed. The main results are as follows; 1) The correlation coefficients between the total working hours of the public health nurse for MCH and the population per area and number of birth per year were significantly positive. 2) Total working hours for health examination of three-year-old children per 100 births per year, by the public health nurse were 143 hours, of which 79% were spent just for performing the examination itself. 3) Due to the lack of health personnel, rural towns and villages with small populations required public health nurses to be assisted by other staff, most often public health nurses from prefectural Health Centers. For example, in those areas with a population of less than 3,000, 43% of the total volume of work performed by public health nurses during the health examinations of three-year-old children required the assistance of prefectural public health nurses. 4) On the other hand, in those areas with populations more than 10,000, 88% of the total volume of work required to be performed by public health nurses during the health examinations for three-year old children was covered by municipal public health nurses. 5) When the total number of working hours of the public health nurse for Maternal and Child Health was divided into the four parts of planning, implementation, evaluation and training, 86.7% of working hours were spent on implementation itself. 6) In those cities designated by the Government, the health personnel system was sufficient to carry out these health examinations. 7) It was found that in towns and villages with small populations, the health examinations for infants and children can be better carried out in combination with assistance by prefectural public health nurses. 8) The review of the findings suggests that it is important to clarify by further studies not only the relationship between the health manpower system and implementation of the health examination but also the relationship between this system and the effectiveness of the health examination in near future. PMID- 8672808 TI - [Questionnaire survey of AIDS examination recipients at government-run public health center regarding AIDS awareness promotion and HIV examinations]. AB - An anonymous questionnaire survey was conducted among persons who had undergone screening for AIDS at public health centers under the auspices of 7 local government bodies (Hokkaido, Metropolitan Tokyo, Aichi Prefecture, Osaka Prefecture, Kobe City, Saga Prefecture, Okinawa Prefecture). There were 1,230 replies, for a response rate of 46.8%. Questions in the survey pertained to general knowledge of AIDS, information desired by the recipients, desired ways to foster awareness, and a desirable examination system. A comparison was made in terms of gender, marriage status (married, single) and age (less than 40 years of age, more than 40 years of age), respectively. The survey results were as follows. 1. Concerning the infection route, accurate response rate was low with regard to the mother-child infection, mosquito transmission, and use of contaminated needles. 2. Desired methods to promote AIDS awareness expressed among replies were given in the following order or frequency: "information via radio and TV," "spread of knowledge through telephone consultation," and "holding an AIDS Week or similar kinds of campaigns." 3. Information sought by respondents frequently included AIDS treatment, pathology, and spread. This trend was most obvious among those under 40 years of age. 4. As for the AIDS examination system, replies most often reflected the hope that the examination site would be the Public Health Center, the charge would be gratis, and that one could be examined at night during the week, and on days off. 5. For those undergoing examination where there was no actual concern of possibility of HIV infection, single persons, accounted for around 80% of the overall. 6. More than half of those who had been examined mentioned having experienced concerns about maintaining confidentiality at the time they were examined. PMID- 8672809 TI - [Relationship between participation in annual health examinations and mortality rate over a 5-year period]. AB - A total of 34,000 adults in Fukui City who had participated in annual health examinations at least once between 1986 and 1988, were followed for a period of 5 years. The results were as follows; (1) The mortality rate during a 5 year period was significantly lower for participants in health examinations than in nonparticipants of the same age group. (2) Mortality was significantly related to obesity, systolic and diastolic blood pressure, glucosuria, proteinuria, occult blood in urine, GOT and cholesterol in man, in women obesity, systolic and diastolic blood pressure, glucosuria, proteinuria, GOT, GPT and cholesterol were related to mortality. (3) An increase in hazard ratio with increasing degree of thinness was suggested particularly in males. (4) Hazard ratios increased with decreasing cholesterol in both men and women combined. (5) Except for hypertension which increased risk for circulatory disease, none of the above data appeared to be related to specific causes of death. PMID- 8672810 TI - [Evaluative indicators for the pre-hospital care system]. AB - Survival factors for out-of-hospital cardiac arrest treated by 80 emergency/critical care centers in Japan were studied. As a result, the following three indicators to evaluate the prehospital care system are proposed. 1) Bystander initiated resuscitation at the scene of collapse 2) Defibrillation by emergency medical technicians 3) Referral system by regional hospitals to emergency/critical care centers These indicators are especially important now, when emergency medical technician services are being expanded in all areas. Also accurate diagnosis of death cause in DOA is important from the sudden death prevention standpoint. PMID- 8672811 TI - [Association of cytochrome P-450 1A1 (CYP1A1) gene polymorphism to smoking status and hematologic findings]. AB - Measures to control smoking are important in the field of preventive medicine. In order to clarify differences in susceptibility in individuals to lung cancer of genotypes of CYP1A1, which are considered to be related to lung carcinogenesis were evaluated in 391 healthy males to study relationship to smoking status and hematological findings. No correlation was observed between genotypes of CYP1A1 and smoking status. White blood cell counts in smokers with a Val allele were significantly higher than in those without a Val allele. Multiple regression analysis showed that the genotype of CYP1A1 and daily cigarette consumption had significant relationship with white blood cell count in smokers. However, red blood cell count, hemoglobin, hematocrit, MCV, MCH, or MCHC were not significantly associated with genotype of CYP1A1. There have been no previous reports on the relationship between the genotype of CYP1A1 and hematological findings. In consideration of the epidemiologic findings that many individuals with increased white blood cell counts have cancer or cardiac diseases, and reports that the increase in the white blood count was associated with poor respiratory function, white blood cell count may be candidate to for being a risk marker and thus contribute to prevention of these diseases. PMID- 8672812 TI - [Health and welfare of foreign children and pregnant women overstaying their visas in Japan]. AB - In recent years, the problems of foreign nationals who are working in Japan without proper visa status, or who are illegally staying in Japan (overstaying) have been actively discussed by the mass media as constituting a major social problem. The rapid increase in number of "stateless" children suggests that the issue of foreign mothers and children, in particular, can no longer be neglected. Obtaining accurate knowledge of the current state of this problem is, however, difficult as almost no nationwide surveys have been conducted. Our study was conducted among welfare centers throughout Japan for the purpose of determining the current state of overstaying foreign children and pregnant women, and to reveal problems in the health and welfare of these mothers and children. At the same time, future directions were examined. A questionnaire was mailed to welfare centers throughout Japan in August 1993, and 562 responses were received with the following information: 1) About 10% of the welfare centers investigated have been consulted by overstaying foreign children and pregnant women. 2) About 70% of the welfare centers consulted by overstaying foreigners have helped them as far as possible. 3) About 20% of the welfare centers have asked for the cooperation of individual volunteers and nongovernmental organizations to provide solutions in such cases. 4) Of the consultations related to children, infants of less than three years of age accounted for about 90%. 5) Common problems related to pregnant women were the cost of childbirth and guarantee of visa status. 6) Some of the problems in these cases were solved by application of the Livelihood Protection Law, the Child Welfare Law, and the Child and Maternal Health Law. 7) Individual cases were reported by welfare centers throughout Japan, and revealed the existence of various health and welfare problems. Mechanisms for welfare centers to handle these cases and provide assistance poses a significant challenge for the future. PMID- 8672813 TI - [Functions of a health center to support health services of a municipality--a questionnaire to municipalities in Shikoku]. PMID- 8672814 TI - Cloning and characterization of a melanin biosynthetic THR1 reductase gene essential for appressorial penetration of Colletotrichum lagenarium. AB - Melanin biosynthesis of Colletotrichum lagenarium is essential for appressorial penetration of the host plant. A melanin deficient mutant 9141 (Thr-) has a defect in the conversion of 1,3,8-trihydroxynaphthalene to vermelone in the melanin biosynthetic pathway. The mutant formed nonmelanized appressoria and had little infectivity on cucumber leaves. A cosmid clone pCR1 was selected from a cosmid library of wild-type C. lagenarium by means of a heterologous probe BRM2, one of the clustered genes involved in melanin biosynthesis of Alternaria alternata. pCR1 transformed the Thr- mutant 9141 to wild-type phenotype. A DNA fragment (THR1) homologous to BRM2 was subcloned from pCR1 and the nucleotide sequence determined. THR1 contains one open reading frame that encodes a protein of 282 amino acids. A transformant resulting from gene disruption showed a light brown phenotype different from the dark brown phenotype of the wild-type 104-T. The transformant formed nonmelanized appressoria and had little infectivity. The THR1 amino acid sequence contains a region highly similar to the Ver1 gene involved in the conversion of versicolorin A to sterigmatocystin in aflatoxin biosynthesis by Aspergillus parasiticus and to the T4HN reductase gene involved in the conversion of 1,3,6,8-tetrahydroxynaphthalene to scytalone and 1,3,8 trihydroxynaphthalene to vermelone in melanin biosynthesis by Magnaporthe grisea. Expression of the THR1 gene during spore germination of C. lagenarium was detected by RNA blotting. We propose that the C. lagenarium THR1 gene encodes a reductase involved in conversion of 1,3,8-trihydroxynaphthalene to vermelone. PMID- 8672815 TI - Biotin and other water-soluble vitamins are key growth factors for alfalfa root colonization by Rhizobium meliloti 1021. AB - Rhizosphere growth limitations imposed on Rhizobium meliloti by availability of biotin, thiamine, and riboflavin were overcome by adding nanomolar amounts of these vitamins. Studies done with R. meliloti 1021 showed that both synthesis and uptake of biotin promote colonization of alfalfa roots. Two lines of evidence indicated that plant-derived biotin normally promotes root colonization: (i) adding avidin significantly (P < or = 0.01) reduced rhizosphere growth of R meliloti 1021, and (ii) growth of Tn5-induced biotin auxotrophs still increased 10-fold in the rhizosphere. Synthesis, however, is the more important source of biotin for R. meliloti 1021 because in root colonization tests biotin auxotrophs competed very poorly with the parent strain. Mutations conferring biotin auxotrophy were closely linked on a single restriction fragment, and one was complemented with the Escherichia coli bio operon. Initial nucleotide sequencing and DNA-DNA hybridization tests showed the biotin synthesis genes in R. meliloti are quite different from those in E. coli. PMID- 8672816 TI - mucS, a gene involved in activation of galactoglucan (EPS II) synthesis gene expression in Rhizobium meliloti. AB - In addition to the exopolysaccharide succinoglycan, Rhizobium meliloti can produce a galactoglucan exopolysaccharide, EPS II. The production of EPS II occurs in certain mutant strains, in strains containing extra copies of EPS II synthesis genes, or in the wild-type strain under phosphate-limiting conditions. We have identified a gene, mucS, that is in a locus required for EPS II induction by extra gene copies and by phosphate limitation, and that activates the expression of at least one other EPS II synthesis gene. mucS lies within a cluster of EPS II synthesis genes and contains an open reading frame of 190 amino acids. MucS does not show any significant similarity to known genes and may represent a new type of regulatory protein. PMID- 8672817 TI - Characterization and distribution of tartrate utilization genes in the grapevine pathogen Agrobacterium vitis. AB - Agrobacterium vitis is a common pathogen of grapevine. Most strains utilize tartrate, an abundant compound in grapevine. Strain AB3 carries two tartrate utilization (or TAR) regions: TAR-I (on the large pTrAB3 plasmid) and TAR-II (on the AB3 Ti plasmid). TAR-I and TAR-II were structurally and functionally analyzed and are similar to the TAR-III region from the tartrate utilization plasmid pTrAB4 of the nopaline-type A. vitis strain AB4 (Crouzet and Otten, J. Bacteriol. 1995, 177:6518-6526). The minimal tartrate utilization region of TAR-I contains four genes (ttuA-ttuD). The ttuC gene is homologous to the tartrate dehydrogenase gene from Pseudomonas putida. Outside the minimal region a second ttuC-like gene is found (ttuC') which is transcribed and complements a ttuC mutant. Most grapevine isolates carry one or two of the three characterized TAR regions and show a considerable degree of polymorphism around these regions. PMID- 8672818 TI - Characterization of defense-related genes ectopically expressed in viroid infected tomato plants. AB - Differential hybridization was used to isolate genes induced by viroid infection in tomato plants. Four new cDNA clones encoding a peroxidase, a desaturase-like enzyme, a lipoxygenase, and a proteinase inhibitor, were selected and characterized. All of these genes display a characteristic expression pattern, showing constitutive expression in roots of healthy plants and being ectopically activated in aerial tissues upon viroid infection and ethephon treatment. Possible functions for these genes in the viroid-tomato interaction are proposed. The existence of an integrated program that compiles developmental and defense related responses is also suggested to explain the characteristic expression pattern detected for these genes as well as for other defense-related genes. PMID- 8672819 TI - Engineered RNA-mediated resistance to tomato spotted wilt virus is sequence specific. AB - Transgenic plants were produced that expressed a wide range of randomly chosen sequences of the tripartite tomato spotted wilt virus (TSWV) RNA genome or its complement. Testing the progenies of these plants revealed that only transgenic expression of N or NS(M) gene sequences resulted in resistance to TSWV. PMID- 8672821 TI - Dosing adjustment of 10 antimicrobials for patients with renal impairment. AB - OBJECTIVE: To describe a program of creatinine clearance-based dosage adjustment of 10 renally eliminated antimicrobial agents and to discuss the utility of such a program in a hospital as a method of quality assurance (by ensuring that patients with renal impairment receive generally accepted dosage adjustments), based on pharmacodynamic principles. METHODS: Consecutive patients prescribed any of 10 targeted renally eliminated antibiotics were included. Recommendations for dosage adjustment were made to the prescriber based on a calculated creatinine clearance. Additional adjustments in drug therapy were performed, including dosage recommendations of nontargeted drugs, simplification of antibiotic regimens, and conversion of intravenous to oral therapy. A cost analysis was performed. RESULTS: During a 6-month study period, 160 dosage changes (7.6% of total number screened) were recommended in 137 patients receiving the targeted antimicrobial agents. Prescribers accepted 147 recommendations (91.9%). A dosage change recommendation was necessary more than 12% of the time for acyclovir, ceftazidime, and imipenem/cilastatin. A cost avoidance of $11,702.08 was realized. Ancillary drug recommendations that were offered and accepted during the program realized a cost avoidance of $6613.75. CONCLUSIONS: This dosage adjustment program using pharmacodynamic principles was successful in optimization of dosing, potential minimization of morbidity caused by excessive dosing, and demonstration of direct and potentially indirect cost avoidance. A dosing program for patients with renal impairment would be of benefit to other clinicians and institutions seeking to optimize patient care. PMID- 8672820 TI - Administration of lipid-emulsion versus conventional amphotericin B in patients with neutropenia. AB - OBJECTIVE: To evaluate the usefulness of a 20% lipid emulsion as a delivery system for amphotericin B (1 mg/mL) administered over 1 hour to patients with neutropenia with hematologic malignancies compared with amphotericin B (0.1 mg/mL) administered in dextrose 5% solution over the same time. DESIGN: A prospective, comparative, randomized, labeled study. SETTING: Hematology unit, pharmacy service, university general hospital. PARTICIPANTS: Twenty patients with neutropenia with hematologic malignancies and proven or suspected fungal infections, 10 in the fat emulsion group (group 1) and 10 in the dextrose 5% group (group 2). MAIN OUTCOME MEASURES: Clinical tolerance (i.e., fever, shaking chills, nausea, blood pressure, pulse rate) and biologic tolerance (i.e., urea, creatinine, sodium, potassium). RESULTS: Clinical tolerance was comparable in both groups although amphotericin B in fat emulsion was better tolerated. Medication for symptoms related to the administration of amphotericin B was given in 6 cases in group 1 and in 8 cases in group 2. There was a statistically significant difference in the urea concentrations between the 2 groups (p = 0.023); there was an observed increase between the initial and the final serum urea (56.8 mg/d in group 1, 79.8 mg/dL in group 2). Statistically significant differences in creatinine serum concentrations (84.9 mumol/L in group 1, 123.8 mumol/L in group 2) (p = 0.047) were found. No differences were found in the antifungal efficacy of the treatment. However, as amphotericin B was started in the majority of cases (75%) as empiric treatment for fever unresponsive to antibiotic therapy, it is difficult to compare the efficacy of both preparations. CONCLUSIONS: The clinical tolerance of lipid-emulsion infusions is similar to that of conventionally administered amphotericin B therapy. Renal toxicity appears to be decreased when the drug is administered in a fat emulsion. This type of preparation permits the reduction of the volume and the time of administration for amphotericin B therapy. PMID- 8672822 TI - Experience in the development of a postmarketing surveillance network: the pharmacy medication monitoring program. AB - OBJECTIVE: To describe the pilot and early implementation phase of a system for assembling and recruiting cohorts of patients taking selected prescription medications and prospectively monitoring them for new health events. DESIGN: Prospective observational study, based on telephone interviews, of 1475 patients filling prescriptions for a nonsteroidal antiinflammatory drug (NSAID). Patients were interviewed by telephone using trained interviewers at a central site. Hospitalizations and deaths were followed up and reviewed by an independently physician. SETTING: Community setting in a region of Hamilton, Ontario, Canada. PARTICIPANTS: All consenting patients filling new or repeat prescriptions for NSAIDs at participating pharmacies. MAIN OUTCOME MEASURES: The authors report on the development and assessment of systems for: (1) ongoing recruitment of patients through community pharmacies; (2) data transfer from pharmacies to the coordinating center; (3) surveying patients; (4) classifying, coding, and evaluating new health events; and (5) following up on new serious adverse events. RESULTS: Fifty-one percent of patients approached were recruited, and 83% of these provided completed interviews. For patients picking up their own medications, pharmacy workload varied from 4 to 10 minutes per patient approached. Nineteen percent of patients reported having a new health problem or unusual symptom at the initial telephone interview. Reported health-related events were similar to those described in other studies of NSAIDs. CONCLUSIONS: Most aspects of the monitoring system performed well. One limitation was the low recruitment rate for patients who did not directly drop off or pick up their own prescriptions. Even so, this method of patient accrual may complement alternative monitoring programs. PMID- 8672823 TI - Self-initiated modification of hypertension treatment in response to perceived problems. AB - OBJECTIVE: To assess the prevalence of patient-initiated modification of drug instructions and the association between different classes of problems and the modification of hypertension therapy. DESIGN AND METHODS: In this cross-sectional study, all patients (n = 1215) who had been examined at a hypertension clinic during a 1-year period were surveyed. The response rate to the questionnaire was 85%. Of the 1035 respondents, 623 currently taking antihypertensive medication (self-report) were included in the study. RESULTS: Of the patients taking antihypertensive drugs, 36% admitted that they had tried to manage their condition with a lower dosage and/or fewer drugs than prescribed. The percentage of patients who modified their drug regimen decreased with increasing age. One or more problems with the treatment of hypertension were reported by 79% of the respondents. The odds ratio (95% confidence interval) for modification among patients who reported 1 or more problems compared with those not reporting any problem was 3.5 (2.12 to 5.67). The prevalence of modification increased with the number of problems; this was seen in all age groups and among men and women. CONCLUSIONS: Perceived problems in drug taking in the treatment of hypertension have an important impact on the prevalence of modifying drug instructions. PMID- 8672824 TI - HIV infection and AIDS: attitudes and knowledge of Arizona pharmacists. AB - OBJECTIVE: To assess Arizona pharmacists' attitudes and knowledge regarding HIV infection and AIDS. METHODS: Mailing of a 7-page survey, which included demographic and attitudinal items, as well as preparedness, comfort, and knowledge scales. SETTING: Randomly selected pharmacists registered and residing in Arizona. PARTICIPANTS: Of the 479 pharmacists surveyed, 41 were removed from the sample because they had moved with no forwarding address, were retired or not practicing, or had died. The response rate was 46% for the remaining 438 pharmacists. A final sample size of 199 was obtained. RESULTS: The respondents had a high level of preparedness and comfort in addition to positive attitudes. Overall, their knowledge level was low. Inpatient pharmacists had a higher level of therapeutic knowledge (p < 0.0001) and were more willing to work with a person infected with HIV than were outpatient pharmacists (p = 0.05). Pharmacists who had attended at least 1 HIV/AIDS-related continuing education (CE) program had higher levels of preparedness (p < 0.0001), comfort (p = 0.01), and knowledge (p < 0.0001) than those who had not. The majority of respondents believed that an HIV/AIDS CE program should be mandatory. CONCLUSIONS: Although Arizona pharmacists feel prepared, are comfortable, and have positive attitudes regarding patients with HIV/AIDS, their level of knowledge is low. The results of this study may be used by CE providers to design programs to meet the educational needs of pharmacists. PMID- 8672825 TI - Establishment of a drug information service on a public-access computer bulletin board. AB - OBJECTIVE: Computerized bulletin board services (BBSs) have existed for several decades; in recent years there has been increased use and acceptance. We have established a drug information service called The Pharmacy on a local public access BBS, the Cleveland FreeNet. The goal of this service is to provide drug information to the lay public as well as healthcare professionals. DESCRIPTION: The Pharmacy is divided into 4 areas: (1) About the Pharmacy, which provides instructions for use; (2) Drug Information, which contains postings on selected drug information topics that are prepared by the BBS staff; (3) Pharmacy Questions, the most popular feature, where FreeNet users are invited to post questions, the answers to which are provided by clinical, staff, and consultant pharmacists, as well as baccalaureate and graduate pharmacy students; and (4) Investigational Studies, where patient recruitment for investigational studies is done. RESULTS: A total of 259 questions have been posted in the first 3 years of operation. An average of 5.2, 7.78, and 8.7 questions/month have been posted in 1992, 1993, and 1994, respectively. Four drug information monographs have been prepared and posted, and approximately 5 investigational studies have been advertised. CONCLUSIONS: A computerized BBS is a new means of distributing drug information to the public and healthcare professionals. In addition to meeting a need for a public service of drug information in the community, it permits increased visibility for pharmacists and a unique learning experience for students. PMID- 8672826 TI - Oral vitamin K1: an option to reduce warfarin's activity. AB - OBJECTIVE: To report 6 patients taking oral vitamin K1 (phytonadione) to reduce warfarin's activity. CASE SUMMARY: Six patient cases are summarized in which oral vitamin K1 was used to reduce the international normalized ratio (INR) in patients at risk of bleeding. DISCUSSION: The use of oral vitamin K1 to antagonize warfarin's effects is discussed, as well as the benefits of oral vitamin K1 administration and the disadvantages of parenteral vitamin K1 administration. In addition, an extensive literature review of the discovery and clinical development of warfarin and vitamin K1 is described. CONCLUSIONS: In patients receiving warfarin therapy who have an increased INR and are at risk of bleeding, oral vitamin K1 therapy may be safer, less painful, and more cost effective than the traditional parenteral route of administration. PMID- 8672827 TI - Exacerbation of congestive heart failure after administration of polyethylene glycol-electrolyte lavage solution. AB - OBJECTIVE: To report a patient with exacerbation of congestive heart failure after administration of polyethylene glycol-electrolyte lavage solution (PEG ELS). METHODS: A MEDLINE search was performed, using the terms congestive heart failure (CHF), gastric lavage, colonoscopy, irrigation, and gastroparesis, of English-language articles published from January 1980 through January 1995, as well as review of pertinent articles' bibliographies. CASE SUMMARY: A 45-year-old white woman with left ventricular systolic dysfunction and diabetic gastroparesis received 4 L of a PEG-ELS as preparation for colonoscopy. Within 24 hours she presented to the emergency department with shortness of breath and increased bilateral lower extremity edema. She was admitted and treated with intravenous furosemide therapy. After aggressive diuresis her symptoms returned to baseline and she was discharged. DISCUSSION: The literature search revealed no report of a patient requiring hospitalization as a result of sodium and water retention after bowel preparation with PEG-ELS. CHF is not considered a contraindication to the use of this solution; however, most studies that included patients with heart failure did not describe the degree of left ventricular dysfunction. Our patient's severe CHF, in combination with chronic renal insufficiency, resulted in significant retention of sodium and water. CONCLUSIONS: Patients with severe left ventricular dysfunction and chronic renal insufficiency who are being considered for procedures that necessitate bowel cleansing with PEG-ELS may be at risk for sodium and water retention and exacerbation of CHF. PMID- 8672828 TI - Invasive aspergillosis: a life-threatening complication of short-term steroid treatment. AB - OBJECTIVE: To describe a patient with invasive pulmonary aspergillosis related to short-term steroid treatment. CASE SUMMARY: A 78-year-old man with chronic obstructive pulmonary disease (COPD) developed an invasive pulmonary aspergillosis after short-term (less than 1 week) intravenous steroid therapy. The diagnosis was established by recovering Aspergillus fumigatus from a bronchoalveolar lavage and was confirmed by autopsy, with the additional finding of an aspergilloma. DISCUSSION: This case is of interest for 3 reasons: (1) it illustrates that invasive aspergillosis may be followed by a rapidly progressive respiratory failure, even in the absence of a fever; (2) this patient had simultaneously an aspergilloma and an invasive aspergillosis; and (3) it confirms reports indicating that short-term steroid therapy for COPD represents a significant risk factor for opportunistic lung infections. CONCLUSIONS: In patients with COPD who receive even short-term steroid therapy and who have progressive respiratory failure caused by pneumonia, invasive aspergillosis should be suspected early and acted upon accordingly. PMID- 8672829 TI - Ifosfamide-induced nonconvulsive status epilepticus. AB - OBJECTIVE: To describe a patient with ifosfamide-induced nonconvulsive status epilepticus. CASE SUMMARY: A 71-year-old woman with a history of malignant mixed mesodermal tumor involving the uterus, cervix, and vagina was admitted because of local recurrence. After receiving 3 doses of ifosfamide/mesna, she was found to be unresponsive. Physical examination and laboratory data revealed no significant changes. An electroencephalogram was consistent with the diagnosis of nonconvulsive status epilepticus. The patient's mental status returned to baseline after treatment with intravenous phenytoin and discontinuation of ifosfamide therapy. DISCUSSION: Central nervous system (CNS) toxicity has been described with ifosfamide, with most cases reported in the pediatric population. Among CNS toxicities, generalized tonic-clonic seizures have been reported in both children and adults. This represents the first report of nonconvulsive status epilepticus induced by ifosfamide. CONCLUSIONS: There was a temporal relationship between the onset of nonconvulsive status epilepticus and initiation of ifosfamide infusion. No other identifiable factor contributed to the unresponsiveness. PMID- 8672830 TI - Granisetron: the second serotonin-receptor antagonist. AB - OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of granisetron, focusing on critical analysis of published clinical trials and comparison with other antiemetic agents, including ondansetron. DATA SOURCES: MEDLINE (1966-1995) and CANCERLIT (1991-1995) searches of English-language literature using the terms "granisetron" and "granisetron (rn)" were performed. STUDY SELECTION AND DATA EXTRACTION: All articles were considered for possible inclusion in this review. Abstracts of clinical trials were included only when they were judged to add critical information not otherwise available in the medical literature. For studies published more than once, the most recent publication was cited. DATA SYNTHESIS: Nausea and vomiting are rated by patients as the most distressing chemotherapy-related adverse effects and may produce potentially life-threatening complications. The discovery of the role of serotonin in nausea and vomiting and the development of selective serotonin3-receptor (5-HT3) antagonists has significantly diminished the incidence and consequences of chemotherapy-related nausea and vomiting. Granisetron is the second 5-HT3-receptor antagonist to be marketed in the US. Granisetron has been compared with other antiemetic agents, including ondansetron, against highly and moderately emetogenic chemotherapy. The results of these trials have shown granisetron to be superior to conventional antiemetics and as effective as ondansetron in the prevention of chemotherapy-induced nausea and vomiting. The optimal dose of granisetron has yet to be determined. Formulary decisions should be based on a cost comparison among the 5-HT3-receptor antagonists at individual institutions. CONCLUSIONS: Granisetron is a safe, effective antiemetic agent for the management of nausea and vomiting caused by cancer chemotherapy. PMID- 8672831 TI - Comparative role of omeprazole in the treatment of gastroesophageal reflux disease. AB - OBJECTIVE: To review gastroesophageal reflux disease (GERD) and its treatment, with emphasis on the use and place of omeprazole, a proton pump inhibitor. DATA SOURCES: A compilation prepared by the National Library of Medicine's Interactive Retrieval Services (Medlars II) for the period 1987 to 1994 was used as the data source. STUDY SELECTION: Focus was placed on human comparative clinical studies with well-accepted measures of esophageal healing (endoscopy) and symptom resolution. Safety data were compiled from the clinical trials literature and large postmarketing data studies. Pharmacoeconomic studies selected were judged to meet the criteria of good design, presence of sensitivity testing, and statement of perspective. DATA EXTRACTION: Data were obtained from double-blind, controlled clinical studies. Other data were extracted from pertinent literature of good design and significant results. DATA SYNTHESIS: Overall, the clinical trials of omeprazole for the treatment of patients with erosive GERD demonstrate that omeprazole provides superior therapy in terms of esophageal healing symptom resolution and patient compliance when compared with histamine2-receptor antagonists (H2RAs) and antacids. In addition, studies also indicate that omeprazole is the most effective agent for the treatment of patients with GERD refractory to other treatments. Dosage adjustment is not necessary in patients with impaired renal or hepatic function or in the elderly. Finally, although the acquisition drug cost for daily treatment of patients with GERD is highest with the use of omeprazole, pharmacoeconomic studies indicate that treatment is more cost-effective with the use of omeprazole than with H2RA or antacid treatment alone or combined with nonpharmacologic approaches. CONCLUSIONS: Based on efficacy, safety, and cost-effectiveness, omeprazole is the drug of choice for the treatment of patients with endoscopically confirmed erosive GERD. PMID- 8672832 TI - Glutathione in health and disease: pharmacotherapeutic issues. AB - OBJECTIVE: To review the current research and importance of glutathione (GSH) therapy in health and disease and to provide a basic overview of the widespread use and interest in this compound. DATA IDENTIFICATION: Articles were obtained via a MEDLINE search of the term glutathione in conjunction with specific disease states mentioned, and via extensive review of references found in articles identified by computer search. STUDY SELECTION: Emphasis was placed on the most recent research, human research, and in discussing multiple disease states. DATA EXTRACTION: The literature was reviewed for methodology, quality, and practical aspects of interest to clinical pharmacists. DATA SYNTHESIS: GSH is a tripeptide of extreme importance as a catalyst, reductant, and reactant. It continues to be investigated in diverse areas such as acute respiratory distress syndrome, toxicology, AIDS, aging, oncology, and liver disease. Despite the widespread clinical interest in GSH, we were not able to identify an in-depth review of this compound in the pharmacy literature. CONCLUSIONS: The list of potential indications for modulation of GSH is extensive and broad. This review introduces clinicians to what GSH is, its basic chemistry, and some areas of active research. PMID- 8672833 TI - Adverse interactions between warfarin and nonsteroidal antiinflammatory drugs: mechanisms, clinical significance, and avoidance. AB - OBJECTIVE: To review the mechanisms and clinical significance of adverse interactions between warfarin and nonsteroidal anti-inflammatory drugs (NSAIDs) and discuss how these interactions can be avoided. DATA SOURCES: Previous studies of interactions between warfarin and NSAIDs or reports of adverse interactions were identified from a MEDLINE search (1976 to present) and from the reference lists of pertinent articles. STUDY SELECTION AND DATA EXTRACTION: All articles were considered for inclusion in the review. Pertinent information was selected for discussion. DATA SYNTHESIS: All NSAIDs can prolong bleeding time by inhibiting platelet function. High-dose aspirin has a direct hypoprothrombinemic effect. Phenylbutazone and its analogs enhance the hypoprothrombinemic effect of warfarin through a pharmacokinetic interaction by inhibiting the hepatic metabolism of warfarin. Mefenamic acid also enhances the anticoagulant effect of warfarin, but the mechanism is not known. The clinical relevance of protein binding displacement in the interaction between warfarin and NSAIDs has been overstated, although a significant one may be more likely in the presence of high concentrations of NSAIDs in patients with slow elimination of warfarin (e.g., those with severe heart failure or impaired liver function). NSAIDs can induce gastrointestinal bleeding, which is likely to be more severe if warfarin is also given. CONCLUSIONS: The combined use of warfarin and NSAIDs is generally discouraged because of the increased risk of bleeding in these patients. In patients receiving warfarin who also require NSAIDs, phenylbutazone and its analogs, high-dose aspirin, mefenamic acid, excessive use of topical methyl salicylate, and NSAIDs that are associated with a higher risk of bleeding peptic ulcers should be avoided. Patients should be closely monitored for anticoagulant control and bleeding complications during the combined use of warfarin and NSAIDs. PMID- 8672834 TI - Potential withdrawal syndrome associated with SSRI discontinuation. PMID- 8672835 TI - Adenosine in acute theophylline intoxication. AB - Although it appears that adenosine would be theoretically useful in the emergent therapy of theophylline toxicity, published clinical data supporting the efficacy and safety of using adenosine for such a situation are currently lacking. The use of adenosine also is not without some risk. In addition, the use of adenosine infusions can be relatively expensive. Until more clinical evidence can be obtained, the routine use of adenosine in the treatment of acute theophylline ingestion cannot be recommended. PMID- 8672836 TI - Use of zidovudine to prevent maternal transmission of HIV. PMID- 8672837 TI - Warfarin and nonsteroidal antiinflammatory drugs: why not? PMID- 8672839 TI - Influencing the destiny of pharmacy. PMID- 8672838 TI - The future of pharmacy: Armageddon or Pollyanna? AB - OBJECTIVE: To review important events and predictions about pharmacy that have occurred in the practice since my career began and describe changes in opportunities that have developed over the past 35 years. DATA SOURCES: I used personal recollections and information from the State of Florida Pharmacy Association journal over a 35-year period. Other supporting data were used to describe current practice opportunities. DATA SYNTHESIS: Over the past 35 years many people have predicted the demise of the pharmacy profession. The reasons stated for this demise have varied over the years and include government interference, the expansion of chain and mail-order pharmacies, managed care, loss of the compounding function, Medicaid reimbursement, national health insurance, and pharmacy technicians. Despite these gloomy predictions, community and hospital pharmacies have flourished over the past 35 years and new roles for pharmacists have emerged in managed care, consultant pharmacy, academic pharmacy, and the pharmaceutical industry. With the enactment of the Omnibus Budget Reconciliation Act of 1990 requirements, it appears that the public has even greater expectations from community pharmacists as medication advisors. The pharmacy profession is changing more rapidly than ever and pharmacists must prepare for these rapid changes. Colleges of pharmacy should inculcate in their students the importance of lifelong learning to keep abreast with change. CONCLUSIONS: Society will always need experts on drugs. Pharmacists must rise to the challenge and accept new and changing roles in drug therapy management. If that occurs the future of pharmacy will be ensured. PMID- 8672840 TI - Death associated with inappropriate ketorolac dosing. PMID- 8672841 TI - Oral mucosal ulceration from disopyramide. PMID- 8672842 TI - Dosage regimens of trimethoprim/sulfamethoxazole (TPM/SMX) in patients with renal dysfunction. PMID- 8672843 TI - No interaction between dopamine and phenytoin. PMID- 8672844 TI - Inadequate warnings and misleading information in OTC package inserts for medicated oils containing methyl salicylate. PMID- 8672845 TI - Treatment of valproate-induced alopecia. PMID- 8672846 TI - Prescribing of analgesic agents in a south african patient population. PMID- 8672847 TI - Comment: leucovorin-phenytoin: a drug-drug interaction? PMID- 8672848 TI - Comment: comparison of HMG-CoA reductase inhibitors. PMID- 8672849 TI - Comment: effect of lithium in water handling. PMID- 8672850 TI - [A paradoxic tumor: retinoblastoma]. PMID- 8672852 TI - Imaging and biodistribution of 125I tyramine oligonucleotide in nude mice bearing human breast tumor. Preliminary report. AB - Although the range of applications for antisense oligonucleotides is vast, current research concentrates mainly on virology and oncology. We have conducted in vivo and in vitro investigations of radiolabelling and biodistribution of a 22 mer phosphodiester oligonucleotide injected in athymic mice bearing xenograft of human mammary tumor (coculture: MCF7 and fibroblasts strain AF-11). Tumor/healthy tissue ratio of the 22-mer phosphodiester oligonucleotide fixation is high during the 24 hours after injection instead of fast elimination. PMID- 8672851 TI - [Modulation of integrin alpha-v-beta-1 expression on human tumor cells by leukemia inhibitory factor (LIF) and oncostatin M (OSM)]. AB - Integrins belong to a large family of heterodimeric membrane glycoproteins which mediate cell-cell or cell-extracellular matrix interactions. These interactions could play a major role during the migration of tumor cells across the extracellular matrix and vascular endothelium and would thus appear to be a requisite for the metastatic process. Treatment of the Foss human melanoma cell line with LIF or OSM, two cytokines involved in acute-phase response, increased the expression of membrane alpha v beta 1 by 1.5-2 fold. The same phenomenon was observed on the SK-N-SH human neuroblastoma cell line. This modulation, which was inhibited by specific monoclonal antibodies against alpha v or beta 1 integrin subunits, was concomitant with improved tumor cell attachment to the fibronectin matrix. Similar results were obtained after TNF-alpha treatment. Our findings demonstrate the ability of LIF and OSM to modulate tumor cell capacity to adhere to the matrix component, suggesting a potential role for these cytokines in modulation of tumoral progression. PMID- 8672853 TI - Tumor-host interaction in non-random metastatic pattern distribution. AB - In the clinical evolution of malign tumors, prognosis depends on whether metastasis develops or not. Biologically speaking, the formation of metastasis implies the existence of tumor cells capable of successfully performing all the steps in the metastatic process: local invasion, lymphatic or hematogenous dissemination, arrest in the microvascular bed of an organ, extravasation and growth of a secondary colony. Clinical observations have demonstrated that for each primary tumor there is a colonization pattern determined by the characteristics of the microvascular endothelium and the functional environment of the target organ. Moreover, the formation of metastasis depends on at least two additional factors: a) tumor cell-tumor cell and tumor cell-host cell relations modulated by intercellular contact and/or soluble paracrine or autocrine growth factors; b) the antitumor efficiency of the immune system, mediated primarily by the action of NK/LAK cells, macrophages and cytolytic T lymphocytes, whose activity is in turn regulated by a complex of cytokines, including interferons, tumor necrosis factors and interleukins. In this work, we first review certain aspects of tumor biology that are specifically involved in tumor cell-host cell interactions determining non-random metastatic pattern distribution, and then review the implication of certain cytokines in the regulation of tumor proliferation. PMID- 8672854 TI - [Taxotere (docetaxel) and CPT 11 (irinotecan): phase I trials]. AB - Two new drugs from two new chemotherapy compound families were developed concomitantly: Taxoter (docetaxel), a taxane derivate and CPT 11 (irinotecan) a topoisomerase inhibitor. Six phase I trials of Taxoter were performed. The limiting toxicity is neutropenia. The recommended dosage for phase II trial is 100 mg/m2 administered in 1 hour perfusion, every 21 days. Neutropenic fever is unfrequent. Other toxicities are mucositis, skin toxicity, hypersensibility reaction, weight gain and oedema. None of these toxicities were limiting. Six phase I studies were conducted to determine the maximum tolerated dose of CPT 11 (irinotecan). Two different schedules were studied: the weekly 30-90 minutes infusion and an infusion administered every three weeks in one day or daily over three or five consecutive days. The limiting toxicity of the weekly schedule is diarrhea. Therefore the recommended dosage is 100-150 mg/m2/week. While dose limiting toxicities in the three week schedule are diarrhea as well as neutropenia. The recommended dose is 350 mg/m2. Since diarrhea appeared to be the major problem in achieving high dose intensity with CPT 11, a dose escalation trial with drug support against diarrhea was performed. A recommended dosage of 500 mg/m2 is therefore described. These two drugs are under evaluation in a large spectrum of tumors. Their original mechanism of action suggests interesting therapeutic properties. Clinical studies in combination with other drugs are in progress to define the role of topoisomerase I inhibitors and taxane in cancer therapy. PMID- 8672855 TI - [Expression of the MDR1 gene in five human cell lines of medullary thyroid cancer and reversion of the resistance to doxorubicine by ciclosporin A and verapamil]. AB - Medullary thyroid carcinoma (MTC) is frequently resistant to chemotherapy. Multidrug resistance (MDR) is one of the involved mechanisms. In this work we have studied the MDR1 gene expression in five MTC human cell lines that we have isolated and we have compared this expression to that of normal thyroid tissue. We have also tried to reverse the resistance to doxorubicin with verapamil (VRP) and ciclosporin A (CSA). MDR1 ARNm expression was studied and quantified by polymerase chain reaction (PCR) in normal and pathological thyroid tissues. The doxorubicin-induced cytotoxicity was evaluated with the 3,-4,5 dimethylthiazol 2,5 diphenyl tetrazolium bromide (MTT) test, the neutral red (NR) uptake and with total glutathione (GSH) or intracellular lactate dehydrogenase (LDH) measurements. We found an increase of MDR1 ARNm in MTC as compared with normal tissues. Doxorubicin was cytotoxic after a 48-h coincubation with the cells. Three microM CSA and 10 microM VRP reversed the doxorubicin resistance only after a 48-h coincubation, generally followed with a 24 h-post-incubation. In these conditions, the GSH levels were decreased only by VRP in all the five cell lines. In conclusion, a chemoresistance related to the MDR1 gene overexpression was found in the five human MTC lines tested. VRP and CSA reversed the resistance to doxorubicin in all the MTC cell lines tested. PMID- 8672856 TI - [Motivations for breast reconstruction after mastectomy. A comparative study]. AB - The aim of this study is to define the psychosocial profile and the motivations of women who seek post-mastectomy reconstruction. A questionnaire was administered to 45 women who had breast reconstruction several months after mastectomy and 51 who did not. Statistical analysis of data shows significant differences between the two groups regarding age, education, leisure activities, sexual intercourse and fear of recurrence. A qualitative analysis shows how women feel about reconstruction. The results suggest that information concerning reconstruction must be adapted to the psychosocial profile of women. Moreover, reconstruction must be considered by the surgeon as an essential stage of breast cancer treatment. In order to help women in their choice, they must give them appropriate information on the technique of breast reconstruction, on the risk of relapse and on the possibility of reimbursement of medical expenses. PMID- 8672857 TI - [Determining factors for adjuvant treatment of breast cancer in the Cote d'Or region 1982-1990. Registry of gynecologic cancers at the Cote d'Or]. AB - In the search for changing medical practices, this population-based study dealt with the breakdown of adjuvant systemic breast cancer treatments from 1982 to 1990. The 1,760 women recorded by the cancer registry of the French Cote d'Or region (241,020 women in 1990) during 1982-1990, who were found to have both a non metastatic breast invasive carcinoma and a no perceptible residual disease after locoregional treatment completion were the subjects of this analysis. Forty percent of the patients received adjuvant treatment: 17% only had chemotherapy, 7% had chemotherapy associated with hormonal therapy and 16% only had hormonal therapy. Chemotherapy was the only adjuvant treatment for the patients under 35 years of age. Hormonal therapy was the main treatment for the patients over 74. For patients from 35 to 74 with a non-inflammatory tumour, the determination of adjuvant treatment was multifactorial. For each modality of adjuvant treatment, the logistic regression model provided an assessment of the contribution of each independant variable to the risk of being treated. This method has focused on period effect after adjustment on the tumor and patient characteristics. Adjuvant treatments were more widely used in the late 1980s than in the early 1980s (OR = 1.9; p = 0.006). On the one hand, the use of chemotherapy-hormonal therapy association remained stable and the use of chemotherapy decreased with a boundary significance (OR = 0.6; p = 0.056); on the other hand, the use of hormonal therapy dramatically increased and was 3.5 times as high for the period 1988-1990 as for the period 1982-1984 (OR = 3.5, p < 0.0001). Comprehensive study of survival trends after breast cancer should take into account the adjuvant systemic treatments and the conditions of their indications to separate their potential beneficial effects from the effects of lead time bias. Necessity of treatment indicator quality control was emphasised. PMID- 8672858 TI - [Maintenance of the dose-intensity of chemotherapy combining carboplatin, cyclophosphamide, etoposide in women with ovarian cancer aged 70 and over]. AB - Elderly patients are often considered as subjects at risk for bad tolerance to chemotherapy. They are therefore treated in a less aggressive way compared with younger women. In a retrospective study, we evaluated the dose-intensity of a chemotherapy for 15 patients older than 70 years of age, presenting an ovarian carcinoma. Median age was 73 years. All but one were classified in stage III-IV and only four were presented with a complete surgery or with a pathological residue < 2 cm. Six patients were considered as non operable. Performance status (PS) was in 11 cases equal to 0 or 1. The treatment associated from D1 to D4: carboplatine 75 mg/sqm/day, cyclophosphamide 250 mg/sqm/day, etoposide 50 mg/sqm/day for six cycles each over four weeks. We compared for each drug the delivered dose-intensity (DID) all along the six cycles to the forecast dose intensity (FID). Except for the patients with a PS > or = 2, treated in first intention by a 2/3 dose, the DID/FID ratio was > 90%. It decreased between the 1st and 3rd cycles, then remained unchanged. Treatment was well tolerated by patients with a PS < 2 whose 4/11 have presented a grade III-IV hematologic toxicity. In return, despite the initial dose reduction, 3/4 patients with a PS > or = 2 had severe complications. There were no toxic deaths. Three patients only had a delay for reinduction. Three out of six non operables at first had a surgical second-look with possibility of residual masses cutting of (3 PRh). Four patients were alive in first CR at 18, 22, 23 and 28 months. Women older than 70 years with a good performance status presenting an ovarian carcinoma can be treated as younger women are. A chemotherapy using efficient drugs can be delivered with an acceptable toxicity and a high dose-intensity. PMID- 8672859 TI - [Optimal control by ondansetron of acute and prolonged emesis induced by chemotherapy without cisplatin]. AB - Chemotherapy-induced emesis is dependent not only on individual parameters but also on treatment parameters (type and dose of the cytotoxic drug, combination with other cytotoxic drugs). Cyclophosphamide-based chemotherapy is potentially emetogenic and the emtogenicity is proportionally dependent on the dose. Therefore, the preventive antiemetic treatment must be adapted to this emetogenic risk. A number of studies have assessed the efficacy of ondansetron, a highly selective 5-HT3 receptor antagonist, for the control of 'non cisplatin' chemotherapy. In mild emetogenic regimens, oral ondansetron is more effective than placebo and its efficacy is similar to the classic antiemetic regimen metoclopramide-dexamethasone. Concerning moderately emetogenic chemotherapies, iv ondansetron is highly effective and its effecicay is superior to that of metoclopramide and alizapride. Delayed nausea and vomiting can be controlled by an oral ondansetron treatment. This allows to maintain the good response obtained by the initial antiemetic regimen. With very high doses of cyclophosphamide, as in conditioning chemotherapy and total body irradiation prior to bone marrow transplantation, no optimal antiemetic treatment has still been defined; but the combination of ondansetron with dexamethasone should be used according to the poor control obtained with ondansetron alone. However, studies combining 5-HT3 receptor antagonists with dexamethasone are warranted in order to define the optimal treatment in this particularly emetogenic treatment setting. PMID- 8672860 TI - [Acute cerebellar syndrome after treatment with 5-fluorouracil]. AB - We report on a case of 5-fluorouracil induced neurotoxicity during 5-fluorouracil cisplatin combination chemotherapy for advanced head and neck squamous cell carcinoma. The initial manifestations included an acute cerebellar syndrome and peripheral neuropathy. Computed tomography of the brain was normal. The results of nerve-conduction studies were compatible with the diagnosis of distal sensory neuropathy. The patient experienced improvement, without treatment, four weeks after cessation of chemotherapy. The role of cisplatin and alcohol abuse in this neurotoxic episode, can not yet completely be excluded. PMID- 8672861 TI - [Atypical decubitus fibroplasia: a recent entity. Apropos of a case of an adolescent girl]. AB - Atypical decubital fibroplasia (FAD) occurs especially in elderly and physically debilited or immobilized patients. We report one observation which is peculiar due to the patient's young age and its circumstances. The painless mass is situated in hyperpressure areas (shoulder, posterior or lateral chest wall, sacrum). The lesion is situated in the deep subcutis and has ill defined limits; it is characterized by zones of fibrinoid necrosis and fibrosis and a prominent myxoid stroma. The differential diagnoses includes mesenchymatous malignant tumors and non neoplastic fibroblastic proliferations such as proliferative fasciitis and decubitus ulcer. The prominent underlying factor and the initial event contributing to its pathogenesis seems to be ischemia. Although some recurrent cases have been reported, FAD is a benign lesion whose treatment is surgical removal. PMID- 8672862 TI - [The annual meeting of the American Association for Cancer Research (AACR), Toronto (Ontario), 18-22 May 1995]. AB - The state of the art concerning major biological phenomenons of importance for current research on urological cancers is first briefly presented, followed by notes on the more outstanding presentations in this field. These notes are organized in a synthetic fashion, in order to point to the meaning of the hypotheses and findings presented, when taken together, as they pertain to the understanding of the mechanisms at play in urological cancers, as we see them in 1995. Some concepts seem to have now reached a point where we can expect to see some applications in a not so distant future: in prostate cancer, it is confirmed that the machinery of apoptosis is functional even in the hormone-insensitive cells, suggesting that its enhancement might be useful in these often difficult situations; techniques to detect circulating malignant cells, which have been greatly refined (RT-PCR of PSA and PSM), are now extremely sensitive and may prove unvaluable in providing intermediate end points to compare the relative efficacy of treatment regimens in clinical trials; the symposium on prostate cancer screening by PSA dosage was an excellent opportunity to review extensively the data available on this topic, but -as expected- it could not decide on some essential issues; in bladder tumors, data on the expression of adhesion molecules (CD44 variant) are still preliminary, but some provocative observations have been reported (presence on mature ARN, only in bladder cancer cells, of intronic sequences that have not been excised); in renal cell cancer, a considerable amount of knowledge has accumulated on the von Hippel-Lindau gene, a putative anti-oncogene, and work is in progress to define the function of its protein; finally, pathways essential to understanding and treating cancer have been dissected, particularly the apoptosis-proliferation network, and the involvement in it of p53, Waf-1 and the bcl-2 gene family cascade. PMID- 8672863 TI - Chemical carcinogen mechanisms of action and implications for testing methodology. AB - Chemical carcinogens are of two distinct types, DNA-reactive and epigenetic. Testing methodology can be directed toward detecting effects of both types of carcinogen. Carcinogens of the DNA-reactive type are defined by the formation of covalently bound DNA adducts. These chemicals have structures that yield electrophilic reactants either directly or after bioactivation. These agents cause genomic alteration in the structure or function of DNA in the target cell. In addition, these compounds can exert other cellular and tissue epigenetic effects, such as cell proliferation and growth promotion. Carcinogens of the epigenetic (paragenetic) type, in contrast, do not react with DNA, but rather display cellular effects such as neoplasm growth promotion, cytotoxicity, inhibition of tissue growth regulation, peroxisome proliferation, endocrine modification, immunosuppression and/or sustained tissue ischemia that can be the basis for increases in neoplasia. Their chemical structure is such that they do not give rise to a reactive electrophile. The testing methodologies to identify either type follow a Decision Point Approach designed to identify potential carcinogenicity and yield mechanistic information on the production of effects that underlie carcinogenicity. It has 5 stages focusing on the chemical structure, DNA-reactivity, epigenetic effects, limited bioassays and finally the application of the accelerated bioassay (ABA). ABA requires 40 weeks and applies the use of sensitive markers for induction of neoplasia in comparison to positive control compounds for important organs in human carcinogenesis. It enables data acquisition of the entire carcinogenic process directed toward developing mechanistic information. The ABA has the potential to replace the chronic bioassay in rodents in some circumstances and can serve as an alternative to a chronic bioassay in a second species. PMID- 8672864 TI - Medium-term liver and multi-organ carcinogenesis bioassays for carcinogens and chemopreventive agents. AB - To bridge the gap between long-term carcinogenicity tests and short-term screening assays such as the Ames test, several types of medium-term bioassay for rapid detection of carcinogenic agents have been developed using male F344 rats. The liver model, in which diethylnitrosamine initiation and acceleration of carcinogenesis by partial hepatectomy are essential components, requires only 8 weeks of animal experimentation and a few weeks for quantitative analysis of hepatic preneoplastic lesions. Using the model, a total of 250 chemicals have been analyzed and the efficacy of the system for hapatocarcinogens has thereby been well established. Other models are so-called multi-organ bioassays for detection of carcinogenic agents in multiple organs within relatively short periods. Among these, the DMBDD bioassay with 5 known carcinogens as initiators has been found to be most applicable and has now been introduced for practical use. Data from these bioassays and several single organ carcinogenesis systems have demonstrated that carcinogenic and modifying effects of individual exogenous agents may markedly differ from organ to organ. Therefore, research into chemoprevention should be based on a whole body level analysis. The present medium-term systems are very useful for this purpose. PMID- 8672865 TI - The effects of dietary restriction on drug testing and toxicity. PMID- 8672866 TI - The sensitivity of the NTP bioassay for carcinogen hazard evaluation can be modulated by dietary restriction. AB - Studies were undertaken to compare outcomes when four chemicals were evaluated under typical NTP bioassay conditions as well as by protocols employing dietary restriction. Four chemicals, using three different routes of exposure (in utero [accomplished by feeding the dam dosed feed], dosed feed, and gavage) were used to 1) evaluate the effect of diet restriction on the sensitivity of the bioassay toward chemically-induced chronic toxicity and carcinogenicity; and 2) evaluate the effect of weight-matched control groups on the sensitivity of the bioassays. Control and chemical exposed F344 rats and B6C3F1 mice (50-60/group) were fed NIH 07 diet either ad libitum or at restricted levels such that body weights were approximately 80% of ad libitum control weights. The dietary restricted groups were either sacrificed at the end of two or 3-years. Results consistently show that feed restriction decreased the incidence of neoplastic and non-neoplastic lesions at a variety of anatomic sites in both control and chemical exposed animals. Furthermore, the sensitivity of the bioassay to detect chemical carcinogenic response were altered by dietary restriction: three of the four chemicals were found to increase the incidence of neoplastic lesions at four sites when evaluated under standard ad libitum conditions for 104 weeks. When unexposed and exposed groups were both subjected to dietary restriction, none of these 4 sites were detected as a target for carcinogenesis after two or three years. Rather, two different sites of carcinogenesis were detected. When the top dosed ad libitum fed animals were compared against their weight-matched control groups, a total of 10 sites were identified as targets for carcinogenesis. These included all four sites identified under the ad libitum protocol, both sites identified under the feed restricted protocol, and an additional four sites that were not identified under the other two protocols. These studies show that dietary restriction of all animals can be expected of decrease the sensitivity of carcinogenesis bioassays. However, restricting only unexposed groups (weight matching) of control for non-specific weight loss in chemical exposed groups yielded the most sensitivity among our comparisons. PMID- 8672867 TI - The effects of overfeeding and moderate dietary restriction on Sprague-Dawley rat survival, pathology, carcinogenicity, and the toxicity of pharmaceutical agents. AB - Ad libitum (AL) overfeeding is the most significant uncontrolled variable effecting the rodent bioassay. There is a highly significant correlation between food consumption, the resultant body weight, and two-year survival in laboratory rats. We have studied the effects of AL overfeeding, moderate dietary restriction (DR) and several modified diets on Sprague-Dawley (SD) rat longevity, spontaneous disease, carcinogenesis and the toxicity of pharmaceuticals. AL feeding of diets varying in protein, fiber and metabolizable energy content did not significantly alter two-year rat survival. Moderate DR (within the range of reported AL food intake) of all diets tested significantly improved survival and delayed the onset of spontaneous degenerative disease and diet-related tumors compared to AL-fed rats. Moderate DR resulted in a similar incidence of spontaneous tumors by 2 years, however, the tumors were more likely to be incidental and not result in early mortality. There was a decreased, age-adjusted incidence of pituitary and mammary gland tumors, but tumor volume and growth time was similar between AL and DR groups indicating similar tumor progression with a delay in tumor onset. Moderate DR did not change Phase I and Phase II drug metabolizing enzyme levels and did not significantly alter the toxicological response to 5 pharmaceuticals tested at maximum tolerated doses (MTDs). Additional studies with 4 pharmaceutical candidates did demonstrate that moderate DR allowed higher doses of compounds to be given before classical MTDs were observed. However, toxicokinetic studies of two of these compounds demonstrated steady state systemic exposures that were either equal of higher in the moderate DR fed rats. These and other data indicate that the moderate DR fed SD rat is a more appropriately controlled rodent model for toxicity and carcinogenicity studies to assess human safety of candidate pharmaceuticals. PMID- 8672869 TI - Are lifespan rodent carcinogenicity studies defensible for pharmaceutical agents? AB - For most pharmaceuticals, the assessment of carcinogenic risk to humans can be made from information available from a) genotoxicity studies in vivo, b) 3-6 month toxicology studies in two or more animal species and c) clinical investigations in Phase I and II studies aimed at assessing the existence of risk factors (genotoxicity, immune suppression, hormonal activity and chronic irritation/inflammation) associated with cancer in humans caused by pharmaceuticals. The rodent carcinogenicity bioassay is redundant for compounds with such properties. In considering the utility of a bioassay, one must recognize that the outcome of the bioassay has been shown to be predictable for about half of a random selection of chemicals in the US National Toxicology Program (NTP). The predictability of bioassay outcomes for many pharmaceuticals should be even better, given the availability of extensive knowledge on genotoxic potential in vivo and of pharmacological mechanisms, this adding to the redundancy of the bioassay. Furthermore, the value of the bioassay is itself questionable. The inconsistencies in tumor responses between rodent species and strains, the simultaneous tumor increase and decreases within a study and the susceptibility to tumorigenicity from non-genotoxic chemicals by mechanisms now shown to be of no relevance to humans, together make the use of rodents highly misleading as predictors of human cancer risk. For pharmaceuticals with a novel or poorly-understood pharmacodynamic mechanism, useful information on long-term adverse effects that might presage a carcinogenic hazard to humans may be obtained from a 12 month study, usually in rats, conducted at clinically relevant dose levels. PMID- 8672868 TI - Oncogenes and growth factors as indicators of carcinogen exposure. AB - The occurrence of different components of the cell growth regulation pathway as expressed in experimental skin carcinogenesis in haired carcinogen-sensitive NMRI, in haired carcinogen resistant DBA/2 mice and in hairless SKH/1 mice was studied by morphological and immunohistochemical methods. The results were compared with respect to neoplastic response, number of tumors, tumor behaviour and to the inducing agent (UV irradiation or chemical carcinogen), in order to increase our understanding of specific alterations in neoplastic development caused by extraneous agents and to determine their possible usefulness as indicators of carcinogen exposure. The expression of growth factors (transforming growth factor alpha and epidermal growth factor), growth factor receptors (epidermal growth factor receptor/c-erbB-1 and c-erbB-2/neu), cell signalling component c-myc, the nuclear transcription factor Harvey-Ras and the tumor suppressor gene p53, were studied in carcinogen- and UV-induced tumor formation in mouse. The results showed increased oncogene expression as well as growth factor expression in the skin during tumor development appearing early in neoplastic and premalignant conditions and becoming more distinct during neoplastic progression. Efforts to delineate specifically initiated cells prior to the appearance of morphologically detectable alterations including dysplasia, papilloma formation and squamous cell carcinomas, were unsuccessful. Increased staining by antibodies to growth factors and oncogenes were also observed in DBA/2 animals resistant to tumor formation. It is concluded that oncogene expression and growth factor protein deposits are associated with carcinogenic effects, partly explaining the mechanism of action of these agents, but the applicability, as such, for the analysis of potential hazardous agents needs further studies. PMID- 8672870 TI - Cost-effective methods for identifying carcinogens. PMID- 8672871 TI - The evaluation of potential human carcinogens: a histopathologist's point of view. AB - Over 100 marketed drugs induce neoplasia when administered at high doses to rats and mice for periods of up to two years. Despite their diverse chemical structures and biological activities, these compounds produce a relatively limited range of tumour types in rodents, most commonly in the liver. Tumours usually develop only after long periods of time following high exposure to drug. The main exceptions are DNA-reactive anticancer drugs such as alkylating agents which produce tumours rapidly in rodents in several organs. In this laboratory, mouse carcinogenicity studies are performed using the C57BL/10J strain. This strain infrequently develops hepatic tumours spontaneously but it is sensitive to the effects of DNA-reactive carcinogens. Moreover, hepatic neoplasms regularly develop in male but not female C57BL/10J mice following long-term treatment with nongenotoxic drugs that produce hepatic enlargement associated with diverse hepatocellular effects. Studies in this strain with the tumorigenic liver enlarger, phenobarbitone, have shown that although such liver enlargement is characterised by a brief burst of hepatocyte replication, this is associated with persistent regional modulation of hepatic growth stimulatory and inhibitory factors and their associated receptors. These findings indicate that there is a sustained alteration to the internal hepatic environment characterised by regional alterations to the balance of hepatocyte mitogens and inhibitors of replication and their respective receptors. Thus, the development of hepatocellular tumours in C57BL/10J mice following two-year treatment with nongenotoxic drugs appears to be a regular response of an organ to an exaggerated and long-term disruption of its homeostasis. Agents that produce tumours in rodents in this way seem likely to pose little or no risk to humans if administered under appropriate clinical circumstances at doses which show no significant disruption of organ homeostasis. However, drugs that produce this type of response need to be distinguished from those that induce unusual and rapid patterns of tumour development because these agents may have high tumorigenic potency of potential hazard to humans. PMID- 8672872 TI - Proliferation markers. AB - Types of growth include embryonic, fetal, neonatal, juvenile and mature. Until full differentiation is achieved, cells grow through proliferation from progenitor cells. At maturity, the cellular genome is fixed with committed patterns of cell cycle duration and adaptation, ranging from static to renewing type 3. The static cell type cannot proliferate and adapts through hypertrophy. The renewing type continuously proliferates even without stimulus. In all cell types the processes of differentiation and proliferation are mutually exclusive. Cellular kinetics involve (a) the duration of the cell cycle, (b) the birth rate of cells, and (c) the growth rate fractions. The duration of the cell cycle is 2 4 days. All growth factors (GF) exert their influence during G1 phase. Release a GF by one cell type can influence the proliferation of another (= paracrine stimulation). At the end of G1 is the point of highest sensitivity to toxicity. Tumor suppressor genes act here through tyrosine phosphorylation. During S, the cell replicates its chromosomes. During G2 the immune surveillance and DNA damage repair mechanisms operate. Injured cells stay here longer enabling repair of their damaged DNA. Cell division involves both nuclear (mitosis) and cytoplasmic (cytokinesis) phases giving rise to 2 new cells. The cell cycle has 2 checkpoints. The first involves the G1-S transition and the second the G2-M transition. The types of cell cycle inhibition include (a) cycle- and phase specific inhibition; (b) cycle-and nonphase-specific inhibition; (c) noncycle-and nonphase-specific inhibition, and finally (d) noncycle, nonphase-, and nonorgan specific inhibition. Proliferation is a circadian process and it is stimulated by a variety of stimuli which include (1) interference with hormonal feedback pathways; (2) inhibition of the tissue trophic activity; (3) sustained presence of antigenic substances; (4) tissue ischemia; (5) changes of conditions luminally or on surfaces of tissues; (6) sustained cytotoxicity; (7) cell death; and (8) surgical resection. Proliferation can be arrested through senescence, apoptosis, injury or even during the development of immune cells. In the past, tissue/cell kinetics have been studied by tritiated thymidine histoautoradiography. Recently, monoclonal antibodies to proliferation-associated antigens, have been successfully employed. These antigens are cycle-associated proteins and include (1) PCNA; (2) p53; (3) Ki67; (4) AGNOR; (5) Statin; and (6) BrdU. Practical examples are given comparing PCNA and BrdU markers from 3 tissues, i.e. liver, glandular stomach, and uterus, across 2 or 3 strains of rats. Mean values of labeling indices are cited. Within the PCNA marker, 2 different clones are compared from the glandular stomach of SD rats of 2 different ages. Gender and across species comparisons are also made. All these comparisons denote that in every study where markers are used (a) there is a need for a concurrent study control group of the same age; (b) there is a need for in-house control data for this particular organ by species, strain, gender and age; (c) there is ancillary assessment of the trophic status of the target tissue; (d) there is a need for at least 2 different time points during assessment; (e) there is a need for such proliferation data prior to commencing the 2 year rodent bioassay; and (f) that PCNA is the most reliable and versatile of all markers used, capable of rendering good results even from archival specimens. PMID- 8672873 TI - The 37 year history of the Delaney Clause. AB - The Delaney Clause has been part of the US Food, Drug and Cosmetic laws since it was enacted by the Congress in 1958. It states that no cancer-causing agent, as demonstrated in humans or animals, shall be deliberately added to, or found as a contaminant in food. The FDA was charged with enforcing this Clause. Other agencies such as EPA used similar approaches with the avowed aim to prevent cancer. Legal cases have been brought against Agencies who failed to comply with this law to the letter. Since 1958, research has elucidated the main mechanisms whereby chemicals cause cancer. The leading causative factors of the major human cancers are basically known, and include smoking and tobacco use, excessive alcohol, and common dietary practices and nutritional traditions. The etiology of lymphomas, leukemias and cervical cancer may be viruses. The Delaney Clause was designed to protect against these many cancer types. It was based on the hypothesis held in the 1950s that human cancers are due to environmental chemicals. This is clearly not true for the great majority of cancers and therefore, the Delaney Clause as framed has not saved any lives, is obsolete, and should be eliminated. PMID- 8672874 TI - Epigenetic carcinogens: evaluation and risk assessment. AB - Regulatory policies in the U.S. have been developed based upon a single model of cancer causation, which assumes chemical-induced genetic alterations. Such a model predicts some degree of cancer risk even at extremely low exposure levels. Many chemicals that produce tumors in experimental animals have been shown to act by epigenetic mechanisms that do not involve an attack by the chemical on DNA leading to subsequent genetic alteration. Such indirect mechanisms require prolonged exposures to high levels of chemicals for the production of tumors. For chemicals that are carcinogenic in this manner, the cancer mechanism would not be operative at exposures below a threshold at which the relevant cellular effect does not occur. Also, in contrast to DNA-reactive mechanisms, epigenetic effects may be unique to the rodent species used for testing. Certain chemical tumorigens have been well studied and provide examples for the use of mechanistic information in risk assessment. Butylated hydroxyanisole and saccharin are nongenotoxic food additives for which no risk to humans is predicted based upon low exposure levels and the likelihood that humans are either insensitive or much less sensitive to the tumorigenic effects found in rodent test species. For another non-genotoxic food additive d-limonene, the mechanism that underlies kidney tumor development in male rats is not expected to be operative in humans at all. The pharmaceutical phenobarbital represents a large group of non genotoxic liver microsome enzyme inducers, which produce liver cancer in mice at levels that are near to therapeutic doses in humans. Epidemiology studies have not shown phenobarbital-related tumors in humans, indicating that humans may be less sensitive to the effects of phenobarbital. The mechanistic considerations involved in the risk assessment of these agents demonstrate that humans are not at risk from current exposure levels of many epigenetic carcinogens. PMID- 8672875 TI - Risk assessment of carcinogens in Japan. PMID- 8672876 TI - Impact of the Delaney Clause at the FDA. PMID- 8672877 TI - Impact of the Delaney Clause in the EPA. AB - The U.S. Environmental Protection Agency serves as the lead agency of the Federal government for the regulation of pesticide use in the United States. Regulatory responsibilities are mandated in the Federal Insecticide Fungicide and Rodenticide Act (FIFRA) and several sections of the Federal Food Drug and Cosmetic Act (FFDCA). In order for a pesticide to be used in the U.S., it must either be granted a full registration under Section 3, or offered special consideration under Section 18 or 24 of FIFRA. Tolerances (maximum allowable residue limits) for pesticides to be used on agricultural commodities meant for human consumption or animal feed are established under Sections 408 and/or 409 of FFDCA. This presentation will describe the underlying conflict between Section 409 of FFDCA and both Section 408 and FIFRA, the recommendations made by the National Academy of Sciences in its 1987 publication Regulating Pesticides in Food--The Delaney Paradox, EPA's attempts to implement these recommendations, the true impact of "Delaney" on the ability of EPA to grant tolerances on raw or processed foods for chemicals determined to meet the "induce cancer" criterion and the status of legislation designed to "fix" Delaney. PMID- 8672878 TI - Human protection against non-genotoxic carcinogens in the US without the Delaney Clause. AB - Cancers of many types are major chronic diseases with a high fatality rate and a high cost to society. In the USA, the Delaney Clause was implemented in 1958 because the public believed that many cancers stem from food additives and food contaminants. In the intervening years, research has provided key information about the mechanisms of carcinogenesis and demonstrated that there are two major classes of carcinogens, genotoxic and non-genotoxic. Two case reports are presented, of sodium saccharin and ethylenebisdithiocarbamates that were banned based on the Delaney Clause in an unjustified manner, based on the underlying mechanisms not relevant for non-genotoxic carcinogens. Also, the causes of major cancers have been discovered. Most cancers are associated with lifestyle, specifically tobacco and excessive alcohol use, inappropriate nutritional traditions, and lack of exercise. These lifestyle components involve now known genotoxic carcinogens and importantly, non-genotoxic carcinogens. The effect of non-genotoxic carcinogens is highly dose dependent and also reversible upon lowering the dose below a threshold. Thus, it is quite possible to lower human cancer risk, and also the risk of related chronic diseases such as coronary heart disease, hypertension and stroke, adult on-set diabetes, by proper lifestyle adjustments. Clearly, the Delaney Clause plays no role in disease prevention. PMID- 8672880 TI - 2nd Conference of the International Federation of Societies of Toxicologic Pathologists. Tours, France, April 23-26, 1995. Proceedings. PMID- 8672879 TI - Risk assessment of carcinogens in food with special consideration of non genotoxic carcinogens. Scientific arguments for use of risk assessment and for changing the Delaney Clause specifically. AB - The document "Risk Assessment of Carcinogens in Food with Special Consideration of Non-Genotoxic Carcinogens" was produced by the International Federation of Societies of Toxicologic Pathologists on the occasion of its triannual meeting in Tours, France, April 23-26, 1995. Subsequently, it was endorsed by the North American Society of Toxicologic Pathologists at its annual meeting in San Diego, CA, USA, June 11-15, 1995. This document was written to address up-to-date risk assessment of carcinogens and anachronisms in the Delaney Clause of the US Federal Food, Drug and Cosmetic Act which have become evident since its enactment in 1958. In the intervening years, major progress has been made in understanding mechanisms of cancer induction and in recognizing causes of human cancer. The Clause in conjunction with its present legal interpretation and implementation does not provide for rational, scientific evaluation of carcinogens. It ignores the fact that the diverse mechanisms now known to underlie cancer increases in rodents exposed to high doses of chemicals are often inapplicable to man. In this regard, current evaluation of chemicals based on the tenets of the Delaney Clause is irrational in many cases. The document presents several examples of chemicals to which humans may be exposed through food and which illustrate the need for science-based risk assessment. Appropriate risk assessment methods are available to provide assurance of negligible risk, and accordingly, it is recommended that the Delaney Clause be rescinded as it has outlived its usefulness. This will enable US governmental agencies to regulate the use of chemicals in foods by using appropriate current scientific methods on a case by case basis within the context of other relevant legislation. PMID- 8672881 TI - Etiology of cancer in humans and animals. AB - Cancer is a multistep disease with a multifactorial aetiology. Among the avoidable causes of human cancer are exposure to environmental carcinogens, ionizing and non-ionizing radiation, chronic inflammatory states (viruses and parasites) and life style factors, in particular diet. There is increasing evidence that these aetiologic factors may interact with each other resulting in a more than additive cancer risk. This has been demonstrated for example with hepatitis B virus and aflatoxins in hepatocellular carcinoma and alcohol and tobacco in cancer of the esophagus. The integration of molecular markers of exposure, biological effect and individual susceptibility into epidemiological studies can contribute to strengthening the causal link between exposure and disease and thus help assess the relative contribution of multiple risk factors to the aetiology of a specific cancer. For some genotoxic carcinogens the sequence of events leading to tumour formation is well understood from exposure, to metabolism and ultimately to specific mutations in transformation-associated genes. The mechanisms of action of carcinogens which do not interact directly with DNA but exert adverse effects through receptor-mediated modulation of intercellular signal pathways is far less well understood and an example of this is the interaction between diet and hormones. Furthermore, there is increasing awareness that individual response to environmental agents may depend to a significant extent on the genetic background of the individual or population. This has long been known from animal experiments but human cancer susceptibility is a complex genetic trait involving genes responsible for carcinogen metabolism, DNA repair and as yet unidentified cell specific susceptibility genes. Phenotypic changes observed during tumour progression reflect the sequential acquisition of genetic alterations. To assess the contribution of mutations in the various genes involved in the carcinogenic process may require their expression in transgenic animals or knock out mice. This has again placed animal experimentation into the forefront of mainstream cancer research. PMID- 8672882 TI - Origin of allelic diversity in antirrhinum S locus RNases. AB - In many plant species, self-incompatibility (SI) is genetically controlled by a single multiallelic S locus. Previous analysis of S alleles in the Solanaceae, in which S locus ribonucleases (S RNases) are responsible for stylar expression of SI, has demonstrated that allelic diversity predated speciation within this family. To understand how allelic diversity has evolved, we investigated the molecular basis of gametophytic SI in Antirrhinum, a member of the Scrophulariaceae, which is closely related to the Solanaceae. We have characterized three Antirrhinum cDNAs encoding polypeptides homologous to S RNases and shown that they are encoded by genes at the S locus. RNA in situ hybridization revealed that the Antirrhinum S RNase are primarily expressed in the stylar transmitting tissue. This expression is consistent with their proposed role in arresting the growth of self-pollen tubes. S alleles from the Scrophulariaceae form a separate group from those of the Solanaceae, indicating that new S alleles have been generated since these families separated (approximately 40 million years). We propose that the recruitment of an ancestral RNase gene into SI occurred during an early stage of angiosperm evolution and that, since that time, new alleles subsequently have arisen at a low rate. PMID- 8672884 TI - Transcription factor veracity: is GBF3 responsible for ABA-regulated expression of Arabidopsis Adh? AB - Assignment of particular transcription factors to specific roles in promoter elements can be problematic, especially in systems such as the G-box, where multiple factors of overlapping specificity exist. In the Arabidopsis alcohol dehydrogenase (Adh) promoter, the G-box regulates expression in response to cold and dehydration, presumably through the action of abscisic acid (ABA), and is bound by a nuclear protein complex in vivo during expression in cell cultures. In this report, we test the conventional wisdom of biochemical approaches used to identify DNA binding proteins and assess their specific interactions by using the G-box and a nearby half G-box element of the Arabidopsis Adh promoter as a model system. Typical in vitro assays demonstrated specific interaction of G-box factor 3 (GBF3) with both the G-box and the half G-box element. Dimethyl sulfate footprint analysis confirmed that the in vitro binding signature of GBF3 essentially matches the footprint signature detected in vivo at the G-box. Because RNA gel blot data indicated that GBF3 is itself induced by ABA, we might have concluded that GBF3 is indeed the GBF responsible in cell cultures for binding to the Adh G-box and is therefore responsible for ABA-regulated expression of Adh. Potential limitations of this conclusion are exposed by the fact that other GBFs bind the G-box with the same signature as GBF3, and subtle differences between in vivo and in vitro footprint signatures indicate that factors other than or in addition to GBF3 interact with the half G-box element. PMID- 8672883 TI - Functional domains of the floral regulator AGAMOUS: characterization of the DNA binding domain and analysis of dominant negative mutations. AB - The Arabidopsis MADS box gene AGAMOUS (AG) controls reproductive organ identity and floral meristem determinacy. The AG protein binds in vitro to DNA sequences similar to the targets of known MADS domain transcription factors. Whereas most plant MADS domain proteins begin with the MADS domain, AG and its orthologs contain a region N-terminal to the MADS domain. All plant MADS domain proteins share another region with moderate sequence similarity called the K domain. Neither the region (I region) that lies between the MADS and K domains nor the C terminal region is conserved. We show here that the AG MADS domain and the I region are necessary and sufficient for DNA binding in vitro and that AG binds to DNA as a dimer. To investigate the in vivo function of the regions of AG not required for in vitro DNA binding, we introduced several AG constructs into wild type plants and characterized their floral phenotypes. We show that transgenic Arabidopsis plants with a 35S-AG construct encoding an AG protein lacking the N terminal region produced apetala 2 (ap2)-like flowers similar to those ectopically expressing AG proteins retaining the N-terminal region. This result suggests that the N-terminal region is not required to produce the ap2-like phenotype. In addition, transformants with a 35S-AG construct encoding an AG protein lacking the C-terminal region produced ag-like flowers, indicating that this truncated AG protein inhibits normal AG function. Finally, transformants with a 35S-AG construct encoding an AG protein lacking both K and C regions produced flowers with more stamens and carpels. The phenotypes of the AG transformants demonstrate that both the K domain and the C-terminal region have important and distinct in vivo functions. We discuss possible mechanisms through which AG may regulate downstream genes. PMID- 8672886 TI - Chromosomal organization of TOX2, a complex locus controlling host-selective toxin biosynthesis in Cochliobolus carbonum. AB - Race 1 isolates of the filamentous fungus Cochliobolus carbonum are exceptionally virulent on certain genotypes of maize due to production of a cyclic tetrapeptide, HC-toxin. In crosses between toxin-producing (Tox2+) and toxin nonproducing (Tox2-) isolates, toxin production segregates in a simple 1:1 pattern, suggesting the involvement of a single genetic locus, which has been named TOX2. Earlier work had shown that in isolate SB111, TOX2 consists in part of two copies of a gene, HTS1, that encodes a 570-kD cyclic peptide synthetase and is lacking in Tox2- isolates. The genomic structure of TOX2 and the relationship between the two copies of HTS1 have now been clarified by using pulsedfield gel electrophoresis and physical mapping. In isolate SB111, both copies of HTS1 are on the largest chromosome (3.5 Mb), which is not present in the related Tox2- strain SB114. Two other genes known or thought to be important for HC-toxin biosynthesis, TOXA and TOXC, are also on the same chromosome in multiple copies. Other independent Tox2+ isolates also have two linked copies of HTS1, but in some isolates the size of the chromosome containing HTS1 is 2.2 Mb. Evidence obtained with Tox2+ -unique and with random probes is consistent with a reciprocal translocation as the cause of the difference in the size of the HTS1 containing chromosome among the Tox2+ isolates studied here. Physical mapping of the 3.5-Mb chromosome of SB111 that contains HTS1 using rare-cutting restriction enzymes and engineered restriction sites was used to map the chromosome location of the two copies of HTS1 and the three copies of TOXC. The results indicate that TOX2 is a complex locus that extends over more than 500 kb. The capacity to produce HC-toxin did not evolve by any single, simple mechanism. PMID- 8672885 TI - Early transcription of Agrobacterium T-DNA genes in tobacco and maize. AB - We developed a sensitive procedure to investigate the kinetics of transcription of an Agrobacterium tumefaciens transferred (T)-DNA-encoded beta-glucuronidase gusA (uidA) gene soon after infection of plant suspension culture cells. The procedure uses a reverse transcriptase-polymerase chain reaction and enables detection of gusA transcripts within 18 to 24 hr after cocultivation of the bacteria with either tobacco or maize cells. Detection of gusA transcripts depended absolutely on the intact virulence (vir) genes virB, virD1/virD2, and virD4 within the bacterium. Mutations in virC and virE resulted in delayed and highly attenuated expression of the gusA gene. A nonpolar transposon insertion into the C-terminal coding region of virD2 resulted in only slightly decreased production of gusA mRNA, although this insertion resulted in the loss of the nuclear localization sequence and the important omega region from VirD2 protein and rendered the bacterium avirulent. However, expression of gusA transcripts in tobacco infected by this virD2 mutant was more transient than in cells infected by a wild-type strain. Infection of tobacco cells with an Agrobacterium strain harboring a mutant virD2 allele from which the omega region had been deleted resulted in similar transient expression of gusA mRNA. These data indicate that the C-terminal nuclear localization signal of the VirD2 protein is not essential for nuclear uptake of T-DNA and further suggest that the omega domain of VirD2 may be required for efficient integration of T-DNA into the plant genome. The finding that the initial kinetics of gusA gene expression in maize cells are similar to those shown in infected tobacco cells but that the presence of gusA mRNA in maize is highly transient suggests that the block to maize transformation involves T-DNA integration and not T-DNA entry into the cell or nuclear targeting. PMID- 8672887 TI - High-level transgene expression in plant cells: effects of a strong scaffold attachment region from tobacco. AB - We have previously shown that yeast scaffold attachment regions (SARs) flanking a chimeric beta-glucuronidase (GUS) reporter gene increased per-copy expression levels by 24-fold in tobacco suspension cell lines stably transformed by microprojectile bombardment. In this study, we examined the effect of a DNA fragment originally identified in a tobacco genomic clone by its activity in an in vitro binding assay. The tobacco SAR has much greater scaffold binding affinity than does the yeast SAR, and tobacco cell lines stably transformed with constructs containing the tobacco SAR accumulated greater than fivefold more GUS enzyme activity than did lines transformed with the yeast SAR construct. Relative to the control construct, flanking the GUS gene with plant SARs increased overall expression per transgene copy by almost 140-fold. In transient expression assays, the same construct increased expression only approximately threefold relative to a control without SARs, indicating that the full SAR effect requires integration into chromosomal DNA. GUS activity in individual stable transformants was not simply proportional to transgene copy number, and the SAR effect was maximal in cell lines with fewer than approximately 10 transgene copies per tobacco genome. Lines with significantly higher copy numbers showed greatly greatly reduced expression relative to the low-copy-number lines. Our results indicate that strong SARs flanking a transgene greatly increases expression without eliminating variation between transformants. We propose that SARs dramatically reduce the severity or likelihood of homology-dependent gene silencing in cells with small numbers of transgenes but do not prevent silencing of transgenes present in many copies. PMID- 8672888 TI - A null mutation in the first enzyme of flavonoid biosynthesis does not affect male fertility in Arabidopsis. AB - Flavonoids are a major class of secondary metabolites that serves a multitude of functions in higher plants, including a recently discovered role in male fertility. Surprisingly, Arabidopsis plants deficient in flavonoid biosynthesis appear to be fully fertile. Using RNA gel blot analysis and polymerase chain reaction-based assays, we have shown that a mutation at the 3' splice acceptor site in the Arabidopsis chalcone synthase gene completely disrupts synthesis of the active form of the enzyme. We also confirmed that this enzyme, which catalyzes the first step of flavonoid biosynthesis, is encoded by a single-copy gene. HPLC analysis of whole flowers and stamens was used to show that plants homozygous for the splice site mutation are completely devoid of flavonoids. This work provides compelling evidence that despite the high levels of these compounds in the pollen of most plant species, flavonoids are not universally required for fertility. The role of flavonoids in plant reproduction may therefore offer an example of convergent functional evolution in secondary metabolism. PMID- 8672889 TI - The same Arabidopsis gene encodes both cytosolic and mitochondrial alanyl-tRNA synthetases. AB - In plants, all aminoacyl-tRNA synthetases are nuclearly encoded, despite the fact that their activities are required in the three protein-synthesizing cell compartments (cytosol, mitochondria, and chloroplasts). To investigate targeting of these enzymes, we cloned cDNAs encoding alanyl-tRNA synthetase (AlaRS) and the corresponding nuclear gene, ALATS, from Arabidopsis by using degenerate polymerase chain reaction primers based on highly conserved regions shared between known AlaRSs from other organisms. Analysis of the transcription of the gene showed the presence of two potential translation initiation codons in some ALATS mRNAs. Translation from the upstream AUG would generate an N-terminal extension with features characteristic of mitochondrial targeting peptides. A polyclonal antibody raised against part of the Arabidopsis AlaRS revealed that the Arabidopsis cytosolic and mitochondrial AlaRSs are immunologically similar, suggesting that both isoforms are encoded by the ALATS gene. In vitro experiments confirmed that two polypeptides can be translated from AlATS transcripts, with most ribosomes initiating on the downstream AUG to give the shorter polypeptide corresponding in size to the cytosolic enzyme. The ability of the presequence encoded between the two initiation codons to direct polypeptides to mitochondria was demonstrated by expression of fusion proteins in tobacco protoplasts and in yeast. We conclude that the ALATS gene encodes both the cytosolic and the mitochondrial forms of AlaRS, depending on which of the two AUG codons is used to initiate translation. PMID- 8672890 TI - GT-2: in vivo transcriptional activation activity and definition of novel twin DNA binding domains with reciprocal target sequence selectivity. AB - GT-2 is a novel DNA binding protein that interacts with a triplet functionally defined, positively acting GT-box motifs (GT1-bx, GT2-bx, and GT3-bx) in the rice phytochrome A gene (PHYA) promoter. Data from a transient transfection assay used here show that recombinant GT-2 enhanced transcription from both homologous and heterologous GT-box-containing promoters, thereby indicating that this protein can function as a transcriptional activator in vivo. Previously, we have shown that GT-2 contains separate DNA binding determinants in its N- and C-terminal halves, with binding site preferences for the GT3-bx and GT2-bx promoter motifs, respectively. Here, we demonstrate that the minimal DNA binding domains reside within dual 90-amino acid polypeptide segments encompassing duplicated sequences, termed trihelix regions, in each half of the molecule, plus 15 additional immediately adjacent amino acids downstream. These minimal binding domains retained considerable target sequence selectivity for the different GT-box motifs, but this selectivity was enhanced by a separate polypeptide segment farther downstream on the C-terminal side of each trihelix region. Therefore, the data indicate that the twin DNA binding domains of GT-2 each consist of a general GT-box recognition core with intrinsic differential binding activity toward closely related target motifs and a modified sequence conferring higher resolution reciprocal selectivity between these motifs. PMID- 8672891 TI - Calmodulin isoforms differentially enhance the binding of cauliflower nuclear proteins and recombinant TGA3 to a region derived from the Arabidopsis Cam-3 promoter. AB - Many stimuli increase cytoplasmic Ca2+ concentrations as an early signal transduction event and alter the patterns of nuclear gene transcription, but the mechanisms by which Ca2+ signals are transduced to the nucleus are not known. This article shows that at least four DNA binding proteins from cauliflower nuclear extracts are also calmodulin (CaM) binding proteins. CaM enhances the binding of these proteins to a C/G-box sequence element in the Arabidopsis Cam-3 promoter. Binding to the C/G-box is enhanced preferentially by the CaM isoform encoded by Cam-3. However, it is not clear whether the effect is mediated directly by CaM or indirectly through the activity of a CaM-regulated protein phosphatase. CaM also binds recombinant TGA3 and enhances its binding to the same Cam-3 promoter element. These results are consistent with the idea that a Ca(2+) mediated signalling pathway eliciting some changes in gene expression may consist of CaM, or a structurally related Ca2+ binding protein, and transcription factors. PMID- 8672892 TI - The tomato Dwarf gene isolated by heterologous transposon tagging encodes the first member of a new cytochrome P450 family. AB - To transposon tag the tomato Dwarf (D) gene, a tomato line that carries a T-DNA containing a maize Activator (Ac) transposable element closely linked to D was pollinated with a stock homozygous for the d mutation. Hybrid seedlings were screened for dwarf progeny, and three independent dwarf lines were obtained. Two of these lines showed inheritance of a recessive phenotype similar to that conferred by the extreme dwarf (dx) allele. Variegation for the dwarf phenotype in one of these lines suggested that D had been tagged by Ac. Genomic DNA adjacent to Ac in these two lines was isolated by use of the inverse polymerase chain reaction, and the two insertions mapped approximately 2 kb apart. Partial complementation of d was observed when the corresponding wild-type sequence was used in transformation experiments. A cDNA clone of D was sequenced, and the predicted amino acid sequence has homology to cytochrome P450 enzymes. PMID- 8672894 TI - Selected international perspectives on the regulation of assisted reproduction. The United Kingdom's experience with a regulatory body. PMID- 8672893 TI - Assisted reproduction: a process ripe for regulation? A conference of the National Advisory Board on Ethics in Reproduction. PMID- 8672895 TI - Selected international perspectives on the regulation of assisted reproduction. The recommendations of the Canadian Royal Commission on new reproductive technologies. PMID- 8672896 TI - Selected clinical perspectives in the United States. Collection of clinical data on assisted reproduction. PMID- 8672897 TI - Selected clinical perspectives in the United States. The laboratory as a partner in assisted reproduction. PMID- 8672898 TI - Legal and ethical issues in assisted reproduction. A view in favor of preserving procreative liberty. PMID- 8672899 TI - Legal and ethical issues in assisted reproduction. A call for ethical boundaries in assisted reproduction. PMID- 8672900 TI - U.S. regulatory issues. Federal oversight of assisted reproduction: Public Health, Consumer Protection, and Public resources. PMID- 8672901 TI - New reproductive technologies: the Canadian perspective. PMID- 8672902 TI - Regulating assisted reproductive technologies: an ethical framework. PMID- 8672904 TI - [XIV Academic meeting of German speaking professors of gynecology and obstetrics. Graz, Austria, 4-6 May 1995. Proceedings]. PMID- 8672903 TI - Regulating assisted reproductive technologies: public health, consumer protection, and public resources. PMID- 8672905 TI - [Clinical and endocrine effects of laparoscopic ovarian surgery in patients with polycystic ovary syndrome]. AB - OBJECTIVES: Is minimal invasive ovarian surgery an alternative infertility treatment for patients with polycystic ovary (PCO) syndrome? METHODOLOGY: 52 anovulatory patients with the clinical and endocrine characteristics of PCO syndrome were treated with laparoscopic Nd: YAK (n = 11) or CO2 (n = 41) laser surgery to drain atretic follicles and destroy the ovarian stroma. RESULTS: Following surgical reduction of serum androgen and estrogen levels (p < 0,01), 83% of the PCO patients ovulated spontaneously or following ovulation induction; pregnancies occurred in 38%. At re-laparoscopies, 86% of patients had no periovarian adhesions. CONCLUSIONS: Since laparoscopic laser surgery is capable of inducing profound clinical and endocrine effects, it may represents a feasible alternative for infertility treatment in PCO patients. PMID- 8672906 TI - [Is co-administration of ethanol to the distension medium in surgical hysteroscopy a screening method to prevent fluid overload? A prospective randomized comparative study of ablative versus non-ablative hysteroscopy and various ethanol concentrations]. AB - OBJECTIVE: Is it possible to diagnose early a beginning fluid absorption during operative hysteroscopy by adding ethanol to the distension medium? METHODS: A prospectively randomised comparative study of ablative versus non-ablative operative hysteroscopy with differing ethanol concentration was performed. Purisole (a mannitol/sorbitol solution) was used as distension medium. RESULTS: The results of the study show that at those hysteroscopical procedures at which the endometrium is not or only minimally injured (e.g. syneciolysis, hysteroscopic proximal tubal catheterisation) an intraoperative screening is not necessary due to the low absorbing amounts. At the hysteroscopical procedures as the resection of myoma, endometriumablation and septumresection, however, an addition of ethanol of 2% to the distension medium has proved to be useful, because with this method absorbing amounts from 400 mls can be established by positive values of breath alcohol. As the result of a further absorption of fluid, but delayed in time compared to the first positive value of breath alcohol, there is an increase of the central venous pressure and a hyponatraemia. CONCLUSION: The intraoperative ethanol-monitoring is a non-invasive procedure which can be performed at ablative-operative hysteroscopies and has no negative influence on the course of the intervention and the general condition of the patients. PMID- 8672907 TI - [Recent prognostic factors in vulvar carcinoma: histological, immunohistochemical and flow cytometry studies]. AB - OBJECTIVES: Are newer histologic investigations helpful in the evaluation of the prognosis of vulvar carcinoma? METHODS: 147 primary squamous cell carcinomas of the vulva were examined for overall- and disease-free survival (mean observation 59.6 months). RESULTS: A significance in prognosis was found for FIGO-stage, a new-created histologic grade, p53- and vimentin-expression and amount of T lymphocytes in tumoral stroma. Unfavourable prognosis was detected for tumors with elevated growth fraction, high proliferating cell-compartment (S + G2 + M) and increased cytokeratin-8-expression. CONCLUSIONS: These investigations are able to describe the malignant potential of a vulvar carcinoma and should therefore influence the decision for a modified radical therapy. PMID- 8672908 TI - [GnRH antagonists in gynecology: initial results within the scope of controlled ovarian hyperstimulation]. AB - OBJECTIVE: Applicability of the GnRH-antagonist Cetrorelix within controlled ovarian hyperstimulation (COH) to avoid the premature LH-surge should be examined. METHODS: 35 patients suffering from tubal infertility were stimulated for In Vitro Fertilization (IVF) by human menopausal gonadotrophins (HMG) and concomitant administration of Cetrorelix in different dosages (3 mg, 1 mg, 0,5 mg). RESULTS: No premature LH-surge could be observed. CONCLUSIONS: Short term administration of the GnGR-antagonists avoids the occurrence of a premature LH surge. PMID- 8672909 TI - [3-D ultrasound in prenatal diagnosis]. AB - OBJECTIVE: Within the past several years, 3-D ultrasonography has developed to a highly advanced diagnostic procedure. The aim of this study was to define the advantages of 3-D ultrasound in prenatal diagnosis in comparison to the conventional 2-D technique. METHODS: Since 1989 we have routinely examined a total of 458 fetuses (242 normal and 216 with anomalies) between 16 and 38 weeks of gestation, supplementing our conventional 2-D ultrasound scans with a 3-D examination using an abdominal volume transducer (Combison 330 and 530, 3.5/5 MHz, Kretztechnik Austria). With this system all 3 orthogonal planes can be displayed on the ultrasound monitor and high-quality 3-D surface or transparent images can be calculated and displayed on the ultrasound monitor as well without need for an external workstation. RESULTS: The comparison of the 2-D and 3-D techniques shows that 3-D provides a diagnostic gain in a large percentage of cases (64.2%). The simplest 3-D technique of the orthogonal image display provided a diagnostic gain in 46.2% (61/132) of the cases owing to the accurate topographic depiction of the desired image plane. The combined 3-D display (orthogonal format plus a 3-D surface or transparent view) provided a diagnostic gain in 71.5% (233/326) of the cases, due to the additional 3-D surface reconstruction and the ability to depict the skeletal anatomy in the transparent mode. Problems with 3-D imaging are encountered in patients with oligohydramnios, which prevents surface reconstruction, and in the examination of moving objects, which produce motion artifacts. CONCLUSION: Today 3-D ultrasonography offers both the patient and the examiner an entirely new visual experience in prenatal diagnosis. PMID- 8672910 TI - [Value of measuring fetal oxygen saturation for reducing the need for fetal blood analysis in abnormal cardiotocogram. Experiences with 2 sensor generations of fetal reflexion pulse oximetry]. AB - OBJECTIVES: Does the knowledge of fetal oxygen saturation allow to avoid fetal scalp blood sampling and to predict a pH < or = 7.25 of the fetal blood sample? STUDY DESIGN: Out of a group of 135 fetuses we determined the median, the 10th, 5th and 3rd percentile of oxygen saturation values by a blinded fetal pulse oximeter. Due to abnormal FHR-patterns, 110 fetal scalp blood samples (FBA) were assessed by the technique introduced by Saling. The pH of these FBA's ranged from 7,16-7,48 (median 7,28). We chose a 20 minute period before the FBA and calculated the individual median and percentiles. According to the pH of < or = 7,25 in FBA we calculated the chi-square test for significance. RESULTS: The median of <35% SpO2 has a sensitivity of 23%, specificity of 77%, positive predictive value of 27% and a negative predictive value of 73%. CONCLUSION: Fetal oxygen saturation alone shows a high specificity and a low sensitivity for pH < 7,25. In addition to FHR monitoring, pulse oximetry. PMID- 8672911 TI - [Measuring the concentration of various plasma and placenta extract proteolytic and vascular factors in pregnant patients with HELLP syndrome, pre-/eclampsia and highly pathologic Doppler flow values]. AB - OBJECTIVE: Impaired trophoblast invasion plays a major role in the development of preeclampsia. Therefore various factors that are involved in invasion were investigated in gestational disease. METHODS: In pregnant women with HELLP syndrome (n = 18), pre-/eclampsia (n = 21) and highly pathological Doppler flow measurements (hpD) (n = 13), plasma and placental tissue extract concentrations of uPA, uPA-receptor, tPA, PAI-1, MMP-8, MMP-9, TIMP-1, thrombomodulin, and angiogenin were measured using ELISA. RESULTS: In all three collectives, PAI-1 plasma concentrations were significantly higher (p < 0,05) than in normal pregnancies, in patients with HELLP-syndrome, tPA and TIMP-1 plasma levels were also elevated. MMP-9 concentrations in placental tissue extracts were lower in pre-/eclampsia than in normal pregnancies. CONCLUSIONS: Impaired placental implantation and remodelling in gestational disease is reflected by changes in plasma and placental tissue extract concentrations of various factors that are involved in these processes. PMID- 8672912 TI - [Morphology in intracytoplasmic sperm injection]. AB - OBJECTIVE: Was to determine if severe morphological defects of spermatozoa in Oligo-Astheno-Teratozoospermia (OAT) have any impact on the fertilization process in intracytoplasmic sperm injection (ICSI) and, if there are any specific morphological characteristics of unfertilized oocytes after the ICSI procedure. METHODS: Ejaculates of males with severe subfertility and unfertilized oocytes after the ICSI procedure were investigated by transmissionelectronmicroscopy. RESULTS: ICSI provided a fertilization rate of 66% in cases of severe defective spermatozoa. The ultrastructure revealed severe head and neck alterations in particular. The ultrastructure of the unfertilized oocyte displayed mostly no signs of activation and lack of decondensation of sperm chromatin. CONCLUSIONS: Our findings support the hypothesis that not severe sperm defects but the lack of intracytoplasmic sperm-oocyte interaction displays the most critical role in the fertilization process in intracytoplasmic sperm injection. PMID- 8672913 TI - [Manometric and clinical long-term outcome after grade III perineal rupture]. AB - OBJECTIVE: To investigate the manometrical and clinical long-term results following a tear III. PATIENTS: 27 Primiparae with a tear III following a spontaneous vaginal delivery were retrospectively compared with 22 Primiparae without sphincter injury (follow-up: 27 months). METHODS: Water-Perfusion Manometry and clinical assessment (modified Kelly-Score). Manometric parameter (at rest and during contraction): sphinctertone and - length, vectorvolume, radial asymmetry. Wilcoxon-Text (p < 0.05). RESULTS: Tear III patients showed a significant decrease in sphincter length and vector volume both at rest and during contraction. On clinical assessment there was no difference. CONCLUSION: A tear III weakens the anal sphincter by decreasing sphincter length and vector volume. This weakness can be demonstrated only manometrically but not clinically. PMID- 8672914 TI - [Prognostic significance of the S-phase and MIB1 (Ki-67) proliferation parameters in node-negative breast carcinoma]. AB - OBJECTIVE: In 90 patients with primary node-negative breast carcinomas we compared the prognostic impact of total S-phase fraction (SPF) and MIB1 proliferation rate (MIB1-PR) after a median follow-up of 34 months (9-72 months). METHODS: SPF was determined flow cytometrically and MIB1 (Ki-67) immunohistochemically in parallel-cut, paraffin-embedded tissue sections. RESULTS: SPF was significantly correlated to tumor size and steroid hormone receptor status, MIB1-PR to grading. In univariate analysis both SPF and MIB1-PR were significant prognostic factors for disease-free survival. In multivariate analysis however, S-phase fraction was the only significant prognostic factor when compared to MIB1-PR, tumor size, steroid hormone receptor status, menopausal status, grading, lymph vessel invasion, and tumor necrosis. CONCLUSIONS: In our study SPF was of higher prognostic strength and may therefore be better suited for clinical application than MIB1-PR in node-negative breast cancer. PMID- 8672915 TI - [Sequence analysis of PCR amplification products of old formalin fixed conisation tissue sections]. AB - OBJECTIVE: Standard analytical techniques (DNA hybridisation methods) require high-quality DNA. In very small samples and in processed tissue (e.g. analysis of DNA in paraffin-embedded archival tissues) these methods fail due to their restricted sensitivity. METHODS: In this study we used the considerably more sensitive PCR for analysis of HPV-16-e6/-e7 DNA in histologic cone biopsy sections. HPV-16-e6 and -e7 ORF were amplified, subcloned into M13mp18 and sequenced. RESULTS: The sequence is identical to the published e6/e7 sequence. CONCLUSIONS: Due to its high sensitivity the PCR is suitable to give answers to questions in cellular microbiology even in formalin-fixed paraffin-embedded tissues. PMID- 8672916 TI - [Do cell cycle changes of human ovarian carcinoma cells after exposure to cytostatic drugs in vitro correlate with cytotoxicity?]. AB - OBJECTIVES: Is there a correlation between cell cycle perturbations and cytotoxicity in ovarian cancer cells exposed to cytotoxic drugs in vitro? METHODS: We tested the association between cytotoxicity and in vitro cell cycle perturbations after exposure of human ovarian cancer cells to seven cytotoxic agents. RESULTS: Three principal patterns of cell cycle alterations were observed; a sequential S-G/M block after exposure to the non phase-specific agents cis-platinum, 4-hydroperoxy-eyclophosphamide, and mitomycin C (Group I); an isolated G2/M block after exposure to the G2/M phase-specific drugs etoposide and vincristine (Group II); and an isolated S block following exposure to the S phase-specific agents 5-fluorouracil and cytosine arabinoside (Group III). Overall, there was no direct correlation between the degree of cell cycle perturbations and cytotoxicity. However, when the three subgroups of phase non specific agents, S phase-specific agents, and G2/M specific agents were analyzed separately, positive correlations between the magnitude of cell kinetic alterations and cytotoxicity were observed. CONCLUSIONS: Cell kinetic alterations appeared to precede cytotoxicity. The experimental model may be particularly useful to study cell kinetic effects after high-dose chemotherapy since, in contrast to conventional chemotherapy, the magnitude of cell kinetic perturbations after this kind of treatment is significantly increased. PMID- 8672917 TI - [Estimating the peripheral vascular resistance of the aorta of fetal sheep by external Doppler ultrasound diagnosis]. AB - OBJECTIVE: Do external Doppler indices correlated sufficiently to the peripheral resistance? METHODS: The resistance of 7 fetal sheep was measured inductively and was correlated to external Doppler measurements. The correlation of different indices and methods was compared. RESULTS: Only bloodflow velocities and the harmonic component index (HCI) yield good correlations (r > or = 7) to the peripheral resistance. PI, RI, S/D-Ratio and Vpeak/Vmean showed r-values from .47 to .59. None of the Doppler parameters reached the values of indices derived from the inductive flow probe. CONCLUSIONS: The blood flow velocities and the HCI seem to be superior to the classical indices in estimation of blood flow in the fetal aorta. PMID- 8672918 TI - [Increased serum level of c-erbB-2-coded protein p105 in patients with pre eclampsia]. AB - OBJECTIVE: This study investigated p105 serum levels in normal pregnancies and in preeclamptic women. PATIENTS AND METHODS: The p105 serum level was determined in 65 women with normal pregnancy and 25 preeclamptic women. RESULTS: The mean p105 serum level for the control group was 102-333 fmol/ml (median 163 fmol/ml). Preeclamptic women had significant higher serum levels (97-368 fmol/ml, median 202 fmol/ml, p < 0,005). CONCLUSION: Elevated serum levels of the c-erbB-2 encoded protein p105 in preeclamptic women could be the result of endothelial dysfunction in preeclampsia. PMID- 8672919 TI - [Generation and activation of tumor-infiltrating lymphocytes (TIL) within the scope of lymphokine activated killer cell therapy (LAK-TIL therapy) in patients with advanced breast and ovarian carcinoma]. AB - In this study we examined a combined immunotherapy using lymphokine activated tumor infiltrating lymphocytes and active specific immunotherapy with virus modified tumor cells in disseminated breast and ovarian cancer patients. During the therapy a significant increase in cytotoxicity could be observed, which nevertheless could not be maintained after the end of therapy. In an ongoing prospective randomized study we are using antigen specific stimulated cytotoxic T lymphocytes to extend this effect. PMID- 8672920 TI - [Coping with illness/quality of life and immunologic parameters of patients with breast carcinoma and benign tumors]. AB - OBJECTIVE: Maladaptive coping of the cancer illness leads to considerable psychosocial burden which can-as a chronic stress factor-impair various immune functions, e.g. cellular immunity. PATIENTS AND METHODS: In a collective of 118 patients suffering from mammary carcinoma and 48 patients suffering from benign mammary tumors Coping was measured with the EORTC-MAC-scale and Quality of life with three questionnaires. Out of the immunologic variables the lymphocyte subpopulations were determined with flow cytometry. Immunglobulines, neopterin, C reactive protein, and herpes serology were determined using standard methods. RESULTS: At follow up a slight increase of the mean vales of sum-scores is observed for the adverse coping mechanisms, like helplessness/despair and fear. On the other hand, the values for the coping styles fatalism and denial decrease. Significant correlations are seen between anxious attitude and number of natural killer cells (CD16 and CD56). It must be pointed out that area of social contact show an inverse correlation in patients with mammary cancers: a strong improvement correlates with diminished natural killer cells as well as reduced activated killer cells. CONCLUSIONS: The aim of this study is to determine whether a high risk group can be defined using these parameters and if these parameter can be influenced by psychotherapeutic interventions such as establishing "Coping-support-groups". PMID- 8672921 TI - [Cerebral ischemia: ontogenetic differences in energy metabolism and protein biosynthesis]. AB - OBJECTIVE: Are ontogenetic differences in the resistance of the brain towards ischemia reflected by differences in the postischemic disturbance of cerebral protein synthesis (PS) independently from energy metabolism (EM)? METHODS: We studied hippocampal slices from immature (E60) and mature (E60) fetal guinea pigs as well as from adult guinea pigs. Cerebral EM and PS were measured during and up to 24 h after ischemia. RESULTS: After in vitro ischemia there was no inhibition in cerebral PS in immature fetuses, a transient inhibition in mature fetuses, and a permanent inhibition in adults. During and after in vitro ischemia cerebral EM was hardly disturbed in immature fetuses. No differences in cerebral EM could be observed between mature fetuses and adults. CONCLUSION: Ontogenetic differences in the resistance of the brain towards ischemia are reflected by differences in the postischemic disturbance of cerebral PS. The differences between mature fetuses and adults are independent from cerebral EM. PMID- 8672922 TI - [Specific serologic studies with a novel authentic HPV antigen (virus-like particles) for HPV-6 antibodies in gynecologic patient samples]. AB - OBJECTIVE: A serological assay for genital HPV infection would provide important additional information to HPV DNA diagnostic methods, since it would evaluate prior exposure to the viruses, detect significant systemic immunologic response to virus infection, and could be performed in most clinical laboratories. METHODS: Serum samples from three groups of patients attending a gynecology clinic were analysed by direct ELISA for specific IgG antibodies to baculovirus expressed HPV-6 and BPV-1-L1-VLPs. RESULTS: Positive IgG reactivity to HPV-6-L1 VLPs were 4/72 (6%) in a control group, 28/73 (38%) in a condyloma group and 17/62 (17%) in cervical intraepithelial neoplasia patients. Individual IgG ELISA values of condyloma and CIN patients for HPV-6-L1-VLPs demonstrated no correlation to results with BPV-1-L1-VLPs. CONCLUSIONS: These data show that HPV 6-L1-VLPs are effective antigens for serological studies and can detect species specific antibodies with important implications for diagnosis, epidemiology, insights to natural course of disease, prognosis and evaluation of vaccination. PMID- 8672923 TI - [Immunohistologic tumor cell detection in lymph nodes in node negative breast cancer: correlation with "established" and "recent" prognostic factors]. AB - OBJECTIVES: The prognostic value of immunohistochemically detected micrometastases in lymph nodes as well as its association with newer prognostic factors is discussed controversially. PATIENTS AND METHODS: Using a monoclonal pancytoceratine antibody 1807 axillary lymph nodes of 122 pT1-2N0M0-patients were examined. Histological findings, established and newer prognostic factors were investigated additionally. The mean follow up time was 50 months. RESULTS: The detection of micrometastases in 16 of 122 (13.1%) patients were related with a prognostic disadvantage for recurrence free survival (p = .03). Tumour size, grading, vessel invasion and S-phase, but not the detection of micrometastases, were confirmed as independent prognostic factors in nodal negative patients by Cox-regression. CONCLUSION: Immunohistochemically detected micrometastases in axillary lymph nodes are of prognostic and therapeutic value but they are not independent prognostic factors. PMID- 8672924 TI - [Complexity analysis and intrapartum CTG]. AB - OBJECTIVES: This study was performed to prove, if the use of methods, that are based on procedures for analysis of chaotic systems ("complexity analysis"), can give information on the fetal condition during birth and predict both the course of delivery and fetal outcome. PATIENTS AND METHODS: Fetal ECG was derived in 37 pregnancies (36-42 weeks of gestation) during birth for two to seven hours. In 12 cases delivery was uncomplicated, in 24 cases FHR tracings had been pathological. RESULTS: Complexity analysis of fetal ECG signals showed within short observation intervals criteria that may be a hint for imminent fetal distress and acidosis. CONCLUSIONS: Application of complexity analysis in the future may give additional information for evaluation of intrapartum CTG in cases of suspicious FHR patterns. PMID- 8672925 TI - [Secretion of endothelin-1 by trophoblast cells and binding of endothelin-1 to trophoblast membranes in healthy and pre-eclampsia pregnancies]. AB - OBJECTIVES: The hypothesis was tested that the synthesis or binding of endothelin 1 (ET-1) by the trophoblast are altered in preeclampsia. METHODS: Trophoblast cells (TC) were isolated from 15 normal (C) und 18 pre-eclamptic pregnancies (P). Binding of [125I]ET-1 to plasma membranes of TC was determined after 48 h in culture. Concentration of ET-1 in culture media were measured after each 24 h over 5 day culture period. RESULTS: Specific binding was 150% (week 37-40) - 400% (week 31-36) higher (P < 0.01) in P. In contrast, the release of ET-1 was 60% (week 31-36) - 71% (week 37-40) lower (P < 0.01) in P than in healthy controls. CONCLUSIONS: Pre-eclampsia is associated with a lower release and increased binding of ET-1 by trophoblast cells. PMID- 8672926 TI - [Animal experiment, pharmacokinetic and clinical studies of intraperitoneal therapy with interleukin-2 (n Il-2) in patients with ovarian carcinoma]. AB - OBJECTIVE: In an orthotopic transplantation model using human ovarian cancer xenografts we evaluated antitumor effects of nIL-2 as well as its side effects in a clinical phase I/II study. METHODS: In patients with advanced ovarian cancer nIL-2 was administered i.p. in escalating doses every two days by means of a Tenckhoff-catheter. RESULTS: Considerable stimulation of intraperitoneal immune cells was observed without severe toxic side effect WHO grade III/IV. CONCLUSIONS: Due to pharmacological-pharmacokinetic advantages using the i.p. route nIL-2 was very well tolerated and showed considerable stimulation of local immune cells. PMID- 8672927 TI - [Comparison of different methods for determination of proliferative activity of breast carcinomas]. AB - OBJECTIVES: Different methods for evaluation of nuclear atypia and proliferative activity were compared in fifty cases of breast cancer. METHODS: Beneath histopathologic grading, ploidy of the stem cell line and S-phasefraction were measured by flow cytometry. Ki67-index was determined immunohistochemically and by image cytometry on smears grade of malignancy and 2cDI were measured. RESULTS: Only Ki67-index was correlated with histopathological grading. The various proliferative indices (Ki67-index, S-phase-fraction, 2cDI) were not correlated. Between image- and flow-cytometric DNA-analysis significant differences were found. CONCLUSIONS: With the immunohistochemical determination of Ki67-index in conjunction with image-cytometry a morphologic control of the material investigated is possible. So in comparison with flow-cytometry a more differentiated analysis can be performed. PMID- 8672928 TI - [Spermatozoa antigen SAA-1 and co-precipitating molecules: regulation of human acrosome reaction]. AB - OBJECTIVES: Examination of the regulation of the human sperm acrosome reaction as an example of ligand-induced exocytosis. METHODS: Development of monoclonal antibodies (mab) against immunaffinity-purified sperm antigen SAA-1. Examination of cross-reactivity of the mabs to human tissues using immunohistochemistry. Examination of reactivity to endometrial carcinoma cell lines and to PC-12 cells by immunohistochemistry and by radioimmunoassay. RESULTS: Mabs to immunoaffinity purified SAA-1 recognize three coprecipitating molecules. Cross-reactivity was demonstrated to glandular epithelia exhibiting ligand-induced exocytosis, and to endometrial carcinoma and PC-12 cells. CONCLUSIONS: The proteins described could be components of the exocytosis-regulating machinery of human spermatozoa. PMID- 8672929 TI - [Detection of genetic alterations in sporadic breast tumors]. AB - OBJECTIVE: Loss of heterozygosity (LOH) indicates the existence of tumor suppressor genes (TSG) in the affected chromosomal loci. In order to uncover the involvement of such genes, we analyzed LOH in different chromosomal regions of sporadic breast carcinomas. MATERIAL AND METHOD: 47 breast cancer patients were screened for LOH with microsatellite markers on 18 different loci. DNA fragments were amplified by PCR from tumor and reference tissue. The PCR products were run on 8% denaturing polyacrylamide gels and visualized by silver straining. RESULTS: The following LOH-rates were found for the different loci: D6S497 (6p21, WAF Region): 0%, D7S495: 9%, D7S522: 13%, D7S523: 22%, D11S488 (11q24-25): 38%, D13s321 and D13s765 (13q13-14, Rb-Region): 30% and 17%, D13S260 and D13S267 (13q12.3, BRCA2-Region): 28% both, D16S539 (16q22-24, E-Cadherin-Region): 35%, D17S5 (17p13.3): 17%, TP53 (17p13.1): 32% D17S250 (17q11-12): 22%, D17S855 (17q21 within the BRCA1 gene): 25%, D17S579 (17q21 telomer from BRCA1): 13%, D17S846 (centromere from BRCA1): 17%, 17q24 (SSTR 2): 9%, D22S684 (22q12, NF2-Region): 20%. Overall 66% of the tumors exhibited LOH. Lymphnode positive tumors showed significantly higher LOH rates than lymphnode negative tumors. CONCLUSIONS: Highest LOH-rates were found on chromosomes 11, 13, 16 and 17 indicative of relevant TSG's in the examined loci. In addition the findings indicate prognostic relevance of multiple LOH's in breast cancer. PMID- 8672930 TI - [Angiogenesis of human breast cancers: neovascularization in xenotransplants and oxygenation in situ in patients]. AB - OBJECTIVE: Recent reports have shown that vascularization of breast cancers is an independent prognostic parameter. Tumor growth and neovascularization were investigated in xenotransplants of breast cancers and tissue oxygenation was measured in patients with breast tumors. METHODS: Tumor cells of the breast cancer MX-1 were implanted intradermally in 40 nude mice. Tumor growth and neovascularization were quantified microscopically. Tissue oxygenation was determined in 66 patients with breast tumors using the pO2-histography technique. RESULTS AND CONCLUSION: The angiogenesis begins prior to tumor growth, is insufficient and leads to chaotic blood flow. This results in a heterogeneity of tissue oxygenation in breast cancers. Oxygenation at the tumor periphery appears to be of prognostic importance for clinical outcome of breast cancer. PMID- 8672931 TI - [Comparative study of maternal side effects of various forms of intravenous therapy with fenoterol in premature labor]. AB - OBJECTIVE: The aim of the present study was to compare different regimes of intravenous fenoterol tocolysis concerning their side effects. METHODS: A total of 59 patients with intravenous tocolysis due to preterm labor has been studied. They were chronologically alternating and thus randomly stratified into three groups: (a) continuous i.v.-tocolysis and oral application of magnesium sulfate (b) continuous i.v-tocolysis and i.v.-application of magnesium sulfate (c) pulsatile i.v.-application of fenoterol (bolus tocolysis) and oral application of magnesium sulfate. For all groups, heart rate, systolic and diastolic blood pressure, need for beta-blockers, K+, water balance over 24 hours as well as different subjective side effects were quantified. RESULTS: The side effects were found to be significantly less among patients treated with bolus tocolysis and they were also found to be slightly less in continuous tocolysis with i.v.- application of magnesium compared to continuous tocolysis with oral Mg2+ substitution; however, the difference between the two groups treated with continuous tocolysis was not significant. CONCLUSION: The present results suggest that bolus tocolysis shows significantly less side effects compared to the continuous tocolysis and thus it should be favored in clinical practise. PMID- 8672932 TI - [Reaction of umbilical cord arteries to PGF2 alpha and glycerol trinitrate during the first days post partum]. AB - OBJECTIVE: Are there changes in the reactivity of umbilical cord arteries within the first day after parturition? METHODS: Groups of rings made from umbilical cord arteries were investigated by a force transducer for their reactions to PGF2 alpha and glycerol trinitrate after 1, 6, 12 and 24 hours after parturition. RESULTS: PGF2 alpha induces vasoconstriction, glycerol trinitrate vasodilatation of the umbilical cord arteries. The quantity of these reactions remains the same at each of the investigation times. But the standard deviation decreases 12 and 24 hours after parturition. CONCLUSIONS: There is an increase of the reproducibility of these investigations in the second half of the first day after parturition. The higher standard deviation in the first 6 hours after parturition may be caused by endogenous autacoids. PMID- 8672934 TI - [Functional significance of CD56 large granular lymphocytes in the decidua in early pregnancy in the human]. AB - OBJECTIVE: The study was undertaken to characterize the large granular lymphocytes (LGL) found in large numbers in the decidua of early pregnancy, in order to investigate their functional significance in placentation. METHODS: The LGL were investigated by immunohistochemical, flow cytometric and molecular biological techniques. RESULTS AND CONCLUSIONS: The LGL resemble a small subpopulation of Natural Killer cells (NK-cells) in the peripheral blood, express activation antigens and produce cytokines that may have a regulatory/modulatory influence on trophoblast growth. PMID- 8672933 TI - [Secretion of inflammatory cytokines and prostaglandins by fetal trophoblast cells induces uterine contraction and labor onset]. AB - OBJECTIVE: Induce infection-associated cytokines intrauterine secretion of prostaglandins and term labor? METHODS: Concentrations of Il-6, Il-1 beta, TNF alpha, PGF2 and PGF2 alpha were determined in cervical secretions and amniotic fluid during spontaneous term labor. The supernatant of amnion-, chorion-, decidua- and trophoblast cells, cultured after elective cesarean section or spontaneous delivery, was analysed for cytokine- and prostaglandin activity. RESULTS: Term labor always is associated with intrauterine cytokine- and prostaglandin release. Increased production of cytokines and prostaglandins in case of normal term labor only was found by fetal trophoblast cells. CONCLUSIONS: Signal for parturition is of trophoblast and therefore of fetal origin. PMID- 8672935 TI - [Modification of chorionic carcinoma cells by immunomodulators. Cytokines and chorionic carcinoma cells]. AB - OBJECTIVES: The role of inflammatory cytokines on regulation of hCG biosynthesis was studied. METHODS: JAR choriocarcinoma cells were cultured and treated with interleukin-1 (IL-1), IL-3. IL-4, stem cell factor (SCF), tumor necrosis factor (TNF), and granulocyte or granulocyte-macrophage-colony stimulating factor. hCG concentration was determined by immunoradiometric methods and cell number was enumerated by means of an electronic particle counter. RESULTS: Il-1 and TNF increased biosynthesis of holo-hCG as well as the free alpha- and free beta subunit and the beta-core protein. Proliferation was not affected by any cytokine tested. CONCLUSION: Inflammatory cytokines are able to increase the biosynthesis of hCG. PMID- 8672936 TI - [Overexpression of p53 protein in ovarian carcinomas: correlation with histopathologic data and clinical course]. AB - OBJECTIVES: The accumulation of p53 protein was analysed immunohistochemically in ovarian cancer and correlated with clinical data to further clarify the role of p53 mutations for prognosis in these patients. METHODS: Tumor tissues from 126 epithelial ovarian carcinomas were analysed immunohistochemically on paraffin embedded tissue and in 21 cases on frozen tissue with monoclonal antibodies PAb 1801, PAb 421 and PAb 240. RESULTS: Nuclear p53 staining was found in 31 ovarian carcinomas (25%) and correlated with advanced stage of the disease (p = 0,038) and poor differentiation (P = 0,032) of the tumor. Disease-free and overall survival time were slightly, but not significantly shortened for patients with p53 positive tumors. CONCLUSION: Immunohistochemically detectable p53 protein expression in ovarian carcinoma is associated with poor differentiation, advanced stage of the disease and a tendency for shortened disease-free and overall survival. PMID- 8672937 TI - [Ultrasound blood flow measurement in malignant tumors is a possible new prognostic factor]. AB - OBJECTIVE: The aim of the present study was to find a possible relationship between biological behavior of breast cancer and sonographically detectable blood flow. METHODS: 157 patients with ductal invasive breast cancer were examined by means of a new sonographic procedure, the MEM (Maximum Entropy Method), able to detect considerably lower blood flow velocities than doppler sonography. In the absence of objectifyable quantification methods, findings were allotted to 3 classes, depending on the visual color information obtained. Blood flow was correlated to tumor size, lymph node and receptor status, ploidy and S-phase fraction. RESULTS: Most patients with small tumors, no lymph node metatases, positive receptors, diploid genome and low S-phase found to have low blood flow. CONCLUSION: This close relation between established prognostic factors and results of sonographic blood flow examination with the MEM might indicate a new preoperative prognostic factor, which, however, will have to be proven by larger studies. PMID- 8672938 TI - [Community-based cervical cancer screening in seven townships in Taiwan]. AB - Cervical cancer is the leading malignant neoplasm in women in Taiwan. In order to compare the validity of various cervical neoplasia screening methods, estimate the prevalence of low- and high-grade squamous intraepithelial lesions (LSIL and HSIL), and identify risk factors for LSIL and HSIL, a community-based cervical neoplasia screening program was implemented in Sanchi, Chutung, Potzu, Kaohsu, Makung, Huhsi, and Paihsa townships, Taiwan. Both cervical smears and cervicograms were used for the screening of cervical neoplasia. Subjects who had positive cervical smears, cervicogram, or both, were further confirmed by colposcopy-guided biopsy. A total of 10,628 married women aged 30 to 64 years were recruited from seven study townships which gave a response rate of 25.2%. Among 667 subjects who screened positive, 555 (82%) underwent colposcopy-guided biopsy. The age-adjusted prevalence was 3.4% for LSIL and 1.7% for HSIL. The biopsy-confirmed rates for cervical smear-detected LSIL and HSIL were 62.8% and 80.6%, respectively; while 56.6% of minor lesions and 22.2% of major lesions identified by cervicogram were biopsy-confirmed as LSIL and HSIL, respectively. The sensitivity of detecting LSIL was higher for cervicograms (79.3%) than for cervical smears (16.7%), and cervicograms had a lower sensitivity in detecting HSIL (48.4%) than cervical smears (90.0%). Multiple logistic regression analysis showed a striking geographical variation in prevalence of LSIL and HSIL. The prevalence of LSIL decreased with the increase in age, and increased with the duration of taking oral contraceptives. The prevalence of HSIL increased with the parity and the duration of taking oral contraceptives and was also significantly associated with the history of cervical cancer among mother and sisters. It is suggested that improvements in the participation rate of cervical neoplasia screening would promote women's health in Taiwan. PMID- 8672939 TI - [Isolation of Rickettsia tsutsugamushi from the blood samples of patients in Taiwan]. AB - Scrub typhus, an acute febrile eruptive disease caused by Rickettsia tsutsugamushi, is one of the most commonly reported communicable diseases in Taiwan. However, information about the epidemic trends of scrub typhus in Taiwan is still very limited. Therefore, this study was performed to isolate the causative agent and determine the prevalence of three different serotypes. From June 1992 to December 1994, lymphocyte cell cultures were grown from different regions of Taiwan. Cell cultures were assayed for R. tsutsugamuhi via immuno fluorescence, using antisera against Gillian, Karp and Kato strains. Thirty-three of the specimens were positive for R. tsutsugamushi, including one from Keelung, 23 from Taitung, 2 from Kinmen and 7 from Lienjan. Of these, 15 were classified as Gillian-related types, 10 were Karp-related types and 8 were not positively classified. These results indicate Gilliam-and Karp-related serotype are more prevalent than the Kato-related serotype in Taiwan. PMID- 8672940 TI - [Outcome and cost of mechanical ventilation in patients with inoperable solid tumors and hematologic malignancies]. AB - The application of mechanical ventilation can be life-saving in patients with acute respiratory failure, but is frequently ineffective in terminally ill patients. To analyze the outcome and cost of mechanical ventilation for patients with malignancies, we retrospectively reviewed 115 patients with inoperable solid tumors or hematologic malignancies who received mechanical ventilation. Eighty eight of these 115 patients (77%) died while on mechanical ventilation; 18 patients (16%) were weaned from mechanical ventilation but still died during their hospitalization. Six patients (5%) were discharged but survived less than 3 months and only three patients (3%) survived for more than 3 months after discharge. The total time of mechanical ventilation was 772 person-days, which represented 5.5% (772/13974) of the total mechanical ventilator use in our hospital in 1993. The total hospital cost from initiation of mechanical ventilation to discharge or death of these 115 patients was NT $11,238,022 (US $432,200) and daily hospital cost per person during mechanical ventilation was approximately NT $10,845 (US $420). The "daily cost of discharge survival" (defined as total hospitalization cost from the initiation of mechanical ventilation to discharge or death divided by total discharge person-days) for patients with inoperable solid tumors was NT $73,421 (US $2,820)/per person-day. We concluded that mechanical ventilation should not be routinely used in patients with inoperable solid tumors and hematologic malignancies. Physicians should explain the poor outcome to these patients and their families in advance and inquire about their willingness to forego mechanical ventilation. PMID- 8672941 TI - [Influenza virus infections in Taiwan from 1979 to 1994]. AB - In order to understand the epidemic trends of influenza virus infection in Taiwan, 5,677 throat-swab specimens were collected from June 1979 to December 1994. The influenza virus was detected in 300 specimens including samples collected at Taichung and Tainan from 1981 to 1982. Among them, 209 isolates (67.9%) were identified as influenza virus type A and 99 isolates (32.1%) were type B influenza virus. Influenza virus infection can be identified, based on the frequency of detection of the virus, throughout the year in Taiwan. Some strains were referred to as intermediate strains due to antigenic drift. About 80% of the isolates identified in this laboratory were from the children under 12 years old. The rate of isolation of the virus was about 47% during the epidemic season. The influenza virus strain A/Taiwan/1/86(H1N1) used as the standard strain for the CDC reagent kit was first isolated by this laboratory in April 1986. We isolated a new strain of influenza virus on December 16, 1991 and later the virus was identified as A/Beijing/32/92-like, which was first isolated on January 31, 1992 at Beijing. Prior to the identification of B/Panama/45/90, we isolated a strain similar to B/Panama/45/90 on January 3, 1990. Owing to delays in shipping of the isolated viruses to the CDC for further confirmation, however, the two new isolates missed the chance to be named as Taiwan strains and otherwise would be listed as standard Strains by the CDC. PMID- 8672942 TI - [Diagnostic value of ultrasonically guided lung aspiration in pneumonia]. AB - To determine the diagnostic value of ultrasonic lung aspiration for patients with pneumonia, 60 patients with a tentative diagnosis of pneumonia were included in this study. After recording ultrasonographic findings, lung aspiration was done with a spinal needle and aspirated specimens were sent for Papanicolaou, May Giemsa, acid fast, and Gram stains. The remaining specimens were sent for bacterial, mycobacterial and fungal culture. Twelve patients were excluded from the study because of the final diagnosis of non-infectious pulmonary diseases. In 28 cases of bacterial pneumonia, the diagnostic sensitivity of smear was 50% and culture 61%. The overall sensitivity of needle aspiration and culture was 71%. In 11 cases of bacterial pneumonia with a negative bacterial culture result, 7 cases were afebrile at the time of examination. To increase the diagnostic yield, needle aspiration should be performed at the acute stage of bacterial pneumonia. In 15 cases of pulmonary tuberculosis, the diagnostic rate of acid-fast smear was 47% and mycobacterial culture was 46%. The overall sensitivity of smear and culture was 60%. The diagnostic rate of needle biopsy was 75% and cytologic examination was 77%. Needle biopsy and cytologic examination enhanced the diagnostic rate of sputum-negative pulmonary tuberculosis. Cryptococcosis was documented by smear and needle biopsy in all of the five cases of cryptococcosis. Cryptococcosis is not easily detected by routine cytologic examination, and clinical information is still necessary to enhance the diagnostic rate. Our results show that ultrasonically guided lung aspiration is a technique with a high diagnostic yield and a low complication rate for various types of pneumonia. It is especially useful for patients without satisfactory clinical responses or without accurate microbiologic diagnosis. PMID- 8672943 TI - [Operative laparoscopy in gynecology oncology]. AB - Because of the poor sensitivity and accuracy of noninvasive nonsurgical methods of detection of occult pelvic and para-aortic lymph nodes, as well as the cost and discomfort of surgical staging, Keelung Chang Gung Memorial Hospital introduced laparoscopic procedures in the staging of cervical cancer from May 1992. Since then, 112 such surgical procedures have been undertaken, including 36 pelvic lymphadenectomies, 20 para-aortic lymphadenectomies, 6 infrarenal paraaortic lymphadenectomies, 22 simple hysterectomies, 6 extended hysterectomies, 2 Schauta's radical hysterectomies, 4 omentectomies, 5 appendectomies, 3 ovarian transpositions, and 8 second look operations for ovarian cancer. All patients tolerated the procedures smoothly except for one who had hemostasis. There was also one complication of tumor seeding at the laparoscopic skin site. Our preliminary experience shows the feasibility and safety of laparoscopic procedures for gynecology and oncology patients. The potential application of laparoscopy in managing gynecologic malignancies is highly appreciated in our institute. The birth of operative laparoscopy in the subspecialty of gynecologic oncology has taken place. PMID- 8672944 TI - [A comparison of compression stockings of different pressures with lower leg edema in spinal cord injury or lesions patients]. AB - We tested 80 spinal cord injury or lesion patients admitted to Department of Rehabilitation Medicine of Chang Gung Memorial hospital from Jan, 1994 to Aug, 1994, in order to assess the effectiveness of compression stockings of different pressures. The study group consisted of patients who, after leaving bed for 4 hours, had a volume change in the lower extremities greater than 50 c.c., as measured by a specially designed water bucket. One of the lower limb was used as the control group and the other limb was used as the experimental group. Different stocking compression pressure, 12 mmHg 20 mmHg, and 30 mmHg, were used for the experimental limb. No placebo stocking was used in the control group. Change in the lower limb volume and degree of comfort after leaving bed for 4 hours were measured. The experimental results reveal that wearing stocking with compression pressure, 12 mmHg, 20 mmHg, 30 mmHg, had therapeutic effects (P < 0.01). The therapeutic effects of the 12 mmHg stocking was less than the 20 mmHg and 30 mmHg stocking. There was no significant difference between the therapeutic effects of the 20 mmHg and 30 mmHg stocking. As for the degree of comfort, 12 mmHg was better than 20 mmHg, and 20 mmHg better than 30 mmHg. When choosing the type of compression stocking to treat lower leg edema in spinal cord injury or lesion patients, we suggest starting with 20 mmHg compression pressure stockings would be a better choice, as they are cheaper, more comfortable to wear and can provide the same therapeutic effects as 30 mmHg compression stockings. PMID- 8672945 TI - [The first successful case or Norwood operation for hypoplastic left heart syndrome in Taiwan]. AB - Hypoplastic left heart syndrome is not infrequently seen in Taiwan, but all died previously. An 8 day-old-male baby suffering from hypoplastic left heart syndrome was transferred to our hospital after cardiopulmonary resuscitation. Oral prostaglandin E2 was used to maintain ductal patency and carbon dioxide was used through a respirator to control his pulmonary blood flow. He underwent Norwood operation at age 15 days under deep hypothermia and circulatory arrest. The postoperative course was smooth and occasional tachypnea was controlled by carbon dioxide inhalation through a mask. A follow up echocardiogram showed patent shunt and neoaortic pathway, good interatrial communication and mild tricuspid regurgitation. The baby survived and has fared well 2 years postoperatively. CONCLUSION: We recommend carbon dioxide manipulation before and after the Norwood operation for hypoplastic left heart syndrome with increased pulmonary blood flow uncontrollable by the respirator. PMID- 8672946 TI - [Disseminated Strongyloides stercoralis infection mimicking pneumonia]. AB - Strongyloides stercoralis is an intestinal nematode. In an immunocompetent host, Strongyloides infections usually produce only mild gastrointestinal symptoms. However, in an immunocompromised host, widespread dissemination of larvae to the extra-intestinal organs may occur. If unrecognized, the mortality rate is high. Here we report a case of disseminated strongyloidiasis in a chronic obstructive pulmonary disease (COPD) subject whose chest radiograph demonstrated multiple pneumonic patches and interstitial infiltrates. Strongyloides larvae were found in stool, sputum, and urine, and embryonated eggs were also found in sputum. The patient was treated successfully with mebendazole and alben albendazole. In conclusion, although high mortality rate is noted in disseminated strongyloidiasis, it is still a curable disease when early diagnosis and treatment could be made. PMID- 8672947 TI - [Intracranial aneurysm in Taiwan]. AB - We reviewed the epidemiologic and clinical features of ruptured intracranial aneurysms based on the available data in the literature reported in Taiwan. Among 28,763 stroke patients registered by members of the Neurological Society of Taiwan, 600 patients had verified intracranial aneurysms (2.1%), constituting only 34.7% of 1,730 patients with subarachnoid hemorrhage. The male to female ratio was 0.68.1. The mean age was 54.6 +/ 14.3 years in men, and 56.5 +/ 13.8 years in women. Among the 409 patients whose aneurysmal sites were recorded, the aneurysm occurred at the anterior communicating artery in 109 (26.7%), at the posterior communicating artery in 90 (22.0%), at the internal carotid artery in 82 (20.1%), at the middle cerebral artery in 80 (19.6%), at the anterior cerebral artery in 50 (12.2%), at the vertebral-basilar system in 13 (3.2%), and multiple sites in 33 (8.1%). Cerebral angiography was performed in 72.2% of patients and operation was undergone in 57.7%. A randomized follow-up study in 59 patients showed survival rates of 63% for 1 month, 53.3% for 6 months and 43.6% for 1 year. The reported surgical mortality rates ranged from 7.7% to 12.5%. Prognosis was related to the score on the World Federation of Neurological Societies Subarachnoid Hemorrhage Scale. In Taiwan, the number of patients with intracranial aneurysm has been underestimated among who have presented with subarachnoid hemorrhage. The high mortality and morbidity of aneurysm rupture justify an aggressive attempt to establish a prompt and accurate diagnosis. PMID- 8672948 TI - [Health behavior in Hualien city high school students]. AB - Chronic diseases and motor vehicle-related injuries are currently the major causes of death in Taiwan. Smoking, alcohol use and inappropriate driving behavior are important risk factors. Most health behavior develop during adolescence. Smoking and alcohol use always serve as "gateways" for other adverse health behavior. In this study, 1195 high school students from 27 classes were selected by a random systematic cluster sampling method, and a structured self administered questionnaire was used to investigate their prevalent health behavior. The prevalence of current smoking was 9.9%, alcohol 18.7% and betel-nut chewing 5.4% among the academic high school students, whereas the prevalence among vocational school students was smoking 20.5%, alcohol 26.6% and betel-nut chewing 13.9%. Seventeen percent of vocational students reported that they often rode motorcycles after alcohol consumption. An aggregation of adverse health behavior, such as smoking, alcohol consumption and chewing betel-nuts was commonly observed. Designing comprehensive intervention programs to prevent and modify high school students adverse health behavior is an important task for school health-officials. PMID- 8672949 TI - [Three years' experience of emergency medical services in Ilan County]. AB - The Emergency Medical Services (EMS) aims to improve the survival rate of patients who are dead on arrival (DOA) at hospital, particularly those whose coronary artery disease (CAD) has induced sudden death. Based on the low prevalence of CAD-induced sudden death in Taipei city, as well as the differences between urban and rural communities in Taiwan, an understanding of the characteristics of rural areas is necessary in order to establish a well organized and cost-effective EMS policy in this country. The data were drawn from a computer database which stored prehospitalization information from Ilan County from 1992 through 1994, including age, sex, response time, time spent on the scene, transportation time, service unit, reasons for emergency call and trauma mechanism. In 1096 study days, 20058 cases (18/day) were collected, of which 16560 (15/day; 83.6%) were transported to hospital. Trauma was responsible for the majority (77%) of these cases, followed by chronic diseases (4.0%), trivial matters (2.6%), drunkenness (2.3%), altered mental status (2.3%), suicide attempt (2.2%), and cardiac arrest (1.8%). Among the trauma cases, traffic accidents were the most common cause (84%); motorcycle accidents comprised 65% of trauma cases. The average response time was 6.6 minutes, time spent on the scene was 3.6 minutes, and transportation time was 17.7 minutes. Trauma and non-trauma accounted for half of the DOA cases, with each making up 0.9% of the total cases transported. In conclusion, it is important that the EMS needs of each community are known for a proper system appropriate to that particular area to be developed. PMID- 8672950 TI - [Community-based hepatocellular carcinoma screening in seven townships in Taiwan]. AB - The early detection and prompt treatment of hepatocellular carcinoma (HCC) may prolong life and improve the quality of life of affected patients. In order to compare sensitivity and specificity of various screening biomarkers, identify subjects with a high risk of developing HCC, and estimate prevalence and incidence of HCC among subjects, a community-based HCC screening program was implemented in Sanchi, Chutung, Potzu, and Kaohsu, Taiwan Island as well as Makung, Huhsi and Paihsa in Penghu Islets. First stage screening of HCC was based on serological markers including hepatitis B surface antigen (HBsAg), antibody against hepatitis C virus (anti-HCV), alpha-fetoprotein (AFP > or = 20 ng/mL), alanine transaminase (> or = 40 IU/L), and aspartate transaminase (> or = 45 IU/L); as well as history of liver cirrhosis or HCC among first-degree relatives. Subjects who were positive for at least one of above six first-stage criteria were referred for second-stage screening by abdominal ultrasonography. Confirmatory diagnosis of HCC was made in suspicious cases according to aspiration cytology surgical pathology, digital substracted angiogram and/or computed tomography. A total of 12,026 men in seven study townships and 1,800 women in two townships in Penghu were recruited for first-stage screening (response rate: men, 25.5%; women, 46.8%). The positive rates for first-stage screening were 30.9% men and 34.6% women. The response rates for second-stage screening were 91% men and 90.5% women. Age-standardized prevalence of HCC per 1,000 subjects was 5.2 for men and 0.8 for women in Penghu Islets and 1.2 for men on Taiwan island. Among five serological biomarkers, HBsAg carrier status had the highest sensitivity (88.2%) and AFP had the second highest sensitivity (43.1%). The specificity of these markers was highest for AFP (99.0%) and lowest for HBsAg carrier status (80.3%). There were 16 new HCC cases identified after an intensive follow-up of 137 cases affected with liver cirrhos is giving an annual HCC incidence rate of 5.3%, while the rate for non-cirrhotic subjects who were positive on first-stage screening was only 0.15%. The combination of HBsAg and AFP for the first-stage screening and abdominal ultrasonography for the second state screening seems valid for the early detection of HCC, but its cost effectiveness remains to be elucidated by a longer follow-up study. PMID- 8672951 TI - [Autofluorescence diagnosis of malignant tumors of the head and neck]. AB - A new method for diagnosing human malignant tumors is dealt with, which is based on fluorescence of malignant neoplasms and their adjacent normal tissue. To measure the fluorescence spectra, a fiber optic system and a multi-channel optic spectral analyser have been designed. While analysing the resultant spectra, a greater fluorescence excess was observed in the red wave band in the tumors than in normal tissue. Further investigations are required in order to use the method in question in clinical diagnosis. PMID- 8672952 TI - [Expression of epidermal growth factor receptors and their ligands in malignant tumors of the breast]. AB - Epidermal growth factor receptors (EGFR) have been investigated in the tumors of 166 breast cancer patients and concentrations of their ligands (alpha-TGF and EGF) were measured in 104 tumors by radioimmunoassay. EGFR and both growth factors were simultaneously detected in 18% and EGFR and one of the ligands were found in 11%. There were trends to higher frequency of EGFR expression in advanced tumors, in ductal and lobular infiltrative cancers with high grade of malignancy and in estrogen receptor negative breast cancers. A possible role of the parameters studied in the prediction of breast cancer and in the choice of therapy is discussed. PMID- 8672953 TI - [Occupation and breast cancer in women]. AB - Breast cancer mortality was studied in 35 occupational groups of female pensioners from 32 urban areas of the former Soviet Union. The 35 groups included nine predominantly professional or office-work groups and 26 groups of labour. Breast cancer mortality was significantly increased among the retired women who had been usually employed in white- collar jobs. Blue-collar jobs that also demonstrated excess breast cancer mortality included food industry workers, railroad workers, urban transport employees, sales women, and waitresses. The highest breast cancer mortality was observed among physicians who had 7-fold rates than among stokers who had the lowest breast cancer. The associations are thought to be due to their lifestyle and sexual and reproductive patterns connected with the socioeconomical status. PMID- 8672954 TI - [Possible use of parameters of tumor cell ploidies and carcinoembryonic antigen levels in the prognostication of epidermoid lung cancer]. AB - Whether the DNA index (DNAI) of tumor cells and serum carcinoembryonic antigen (CEA) may be used to make prognosis in 78 patients with epidermoid lung cancer at the stage of T1-3 N(o) Mo was studied. There was a direct correlation between tumor ploidy and CEA levels. The two-year relapse- free survival among the operated-on patients at the stage T1-2 N(o) Mo was not shown to be associated with DNAI. At the same time in the T1-3 M1-2 Mo patients radically operated on, the two-year survival correlates with DNAI: it is significantly (p < 0,05) higher in patients with diploid tumors (DNAI = 1.0) than in those with aneuploid cancer (DNAI > 1.05). The patients with low preoperative CEA levels ( < 10 micrograms/l) have a more favourable prognosis after radical surgical treatment. PMID- 8672955 TI - [Use of thermal radiochemotherapy in patients with anal epidermoid cancer]. AB - The authors have developed a new original procedure for combined and multimodal treatment of patients with anal dermoid cancer, which includes radiation therapy, polychemotherapy (platidiam and bleomycin) by using topical superhigh-frequency hyperthermia and antioxidants. The treatment regimen proposed has turned out to be highly effective. It allows sphincter-preserving therapy to be performed without rectal extirpation in most primary patients with anal dermoid cancer. PMID- 8672956 TI - [Urban air pollution by carcinogenic N-nitrosamines]. AB - Moscow is used as an example to discuss the problem of urban atmospheric pollution by carcinogenic N-nitrosamines. An analytical method is proposed, which is based on the use of a Russian gas chromatograph compatible with a chemiluminescence detector, that is a TEA thermal energy analyzer (USA) having some modifications to reduce the time of analysis and loss during sample pretreatment. The minimal detected concentration is 3 ng/m3 for 2-hour sampling. The method identifies and quantifies 7 volatile N-nitrosamines: N nitrosodimethylamine (NDMA), N-nitrosodiethylamine, N-nitrosodibutylamine, N nitrosodipropylamine, N-nitrosopiperidine, N-nitrosopyrrolidine, N nitrosomorpholine. The pollution of the Moscow air was evaluated in the center of Moscow (30-60 ng/m3 for NDMA), in the industrial emission area (as high as several hundred ng/m3, and in the heavy traffic area (100 ng/m3 or more). It is proposed to study the working area for rubber and tire industries, to establish nitrosamine tolerances for these industries and maximum allowable discharge concentrations in the urban air and to monitor these parameters. PMID- 8672957 TI - [Effects of interferon inducers on chemically-induced mutagenesis and carcinogenesis]. AB - The murine bone marrow cellular chromosomal aberration technique was used to reveal anticlastogenic effects of the natural interferon inductors ridostin and larifan, as well as the synthetic ones polyguacil and amyxin. The action of the interferon inductors was timed to the maximum production of interferon in the body. Anticarcinogenic, antitumor, and antimetastatic properties of the above interferon inductors were found by using classical experimental models of carcinogenesis. Some mechanisms of antimutagenic and coupled anticarcinogenic action of interferon inductors were considered. The natural interferon inductor larifan was found to have an antipromoter activity. The treatment regimen by using interferon inductors in combination with the immunomodulator thymosin, a thymic hormone, was under discussion. PMID- 8672958 TI - [Possibilities of adoptive immunochemotherapy in the treatment of non-small-cell lung cancer]. PMID- 8672959 TI - [Effects of the antioxidant ionol on humoral immune response in experimental influenza]. AB - The effect of the antioxidant ionol on a humoral immune response was studied in experimental influenza. With preventive introduction of ionol, the affinity of anti-influenza G antibodies circulating in the blood stream was shown to be decreased as compared to that in control animals. The changes in the affinity during influenza infection were cyclic and less marked in the group of animals receiving ionol. The administration of the antioxidant substantially reduced the detection rate of specific blood immune complexes and contributed to the production of antibody-forming cells. The findings suggest that ionol has a favourable effect on a humoral immune response in experimental influenza and alleviates the course of an infectious process. PMID- 8672960 TI - [Role of lipid peroxidation in the pathogenesis of influenza and search for antiviral protective agents]. AB - This study has provided evidence for a considerable role of lipid peroxidation in the pathogenesis of murine influenza infection. The virus-induced activation of lipid peroxidation was followed by the enhanced activity of endogenous enzymes of the antioxidative protection system. The preventive effect of an antioxidant and the therapeutical effect of an antihypoxant were recorded in the prevention of murine death due to influenza. The mechanisms of the protective effect of the antihypoxant is due both to its immediate antihypoxant function and its correcting influence on lipid peroxidation. PMID- 8672961 TI - [Clinical significance of specific features of HLA antigen incidence in patients with mucoviscidosis and in their relatives]. AB - The distribution of antigens in the HLA system was studied in 57 patients with mucoviscidosis and in their 43 relatives. The examinees were found to have increased incidence of the HLA antigens B40, CW2, CW3, CW4. The haplotype AIB40 was associated with the mutation carriage of the CF gene deletion F508 both in patients and their relations heterozygous for this mutation. The analysis of the level of HLA antigens in the tissue of CF patients may predict the development of particular clinical features of mucoviscidosis and the nature of the course of the disease. PMID- 8672962 TI - [Obtaining and properties of recombinant protein G]. AB - A gene for G protein from Streptococcus strain G148 was cloned in Escherichia coli, which gave rise to several plasmids. One plasmid containing a 1.5 kb insert coding for entire G protein with 63 kD. This protein had both an IgG binding capacity and albumin-binding activity. The second plasmid containing a 0.7 kD insert coded for protein with MM of 38 kD and had only an IgG-binding activity. The third coding for protein with 25 kD has only albumin-binding activity. After subcloning the 1.5-kb insert into the other vector pSP65 and analysing the nucleotide sequence of this insert both in pSP65 vector, the authors came to the conclusion that the proteins obtained are fusion protein of G protein and beta galactosidase. All the proteins were prepared by affinity chromatography on IgG sepharose or on HSA sepharose. The interaction between G protein and polyclonal and monoclonal IgG of the reactions between G protein and human IgG have determined. PMID- 8672963 TI - [Hepatitis B as nosocomial infection (aspects of epidemiology and prevention)]. AB - Hepatitis B (HB) was recorded in 1478 (32.3%) of 4577 patients with acute viral hepatitis in Moscow in 1992. Half (50.6%) the patients were infected with HB virus during therapeutical and diagnostic parenteral interventions in 66.1% of them at hospitals, in 7.5% during transfusions of blood and its components (at hospitals too) in the others via natural routes. The HB morbidity per 100,000 patients treated in some Moscow one-profile hospitals sharply differed (74.2 to 89.6 at one hospitals and 5.9 to 7.6% at others). The high HB morbidity at some Moscow hospitals, the group incidence of the disease were associated with the inadequate sterilization quality of medical and laboratory instruments, with the shortage of expendable instruments. The implementation of a complex of measures at individual hospitals, which were aimed at stopping the artificial HB virus transmission routes resulted in 8.2-11.7%-reductions in HB morbidity rates among the patients treated there. In 1990-1992 the HB morbidity among Moscow medical staff was 3.0-3.5-fold than among adults of the city. Surgeons, reanimatologists, and laboratory personnel more frequently fell ill. HB vaccination should be high priority among this contingent. PMID- 8672964 TI - [Morphophysiological analysis of the formation of mechanisms of the activity-rest cycle in human ontogenesis]. AB - The natural behavior of normal and anencephalic fetuses at 20 to 41 weeks of the development was studied by ultrasound monitoring and continuous recording of heart rate (HR) and motor activity (MA), followed by processing and presentation on [symbol: see text]CM computer. The statistical characteristics of HR and MA changes in the anencephalic fetuses were corrected by the degree of CNS deficiency. The comparative study of 20 normal and 34 anencephalic fetuses showed: 1) when the spinal cord was present, stable HR (about 150 bpm) seems to be due to cardiac automatism and sharp decelerations unaccompanied by MA were recorded; 2) in fetuses with the medulla oblongata present showed a decrease in baseline HR up to 140 bpm, repeated pronounced decelerations and spontaneous single motor acts dissociated with the latter; 3) when a rudiment of the midbrain was present, some reductions in the amplitude of decelerations and manifestation of weak accelerations, cluster motor acts, brief episodes of the active state were revealed; 4) the quiet state was observed in fetuses with the cerebral cortex; 5) the rest-activity cycle formed with further differentiation of the cerebral cortex. PMID- 8672965 TI - [Expression of primitive stem cell antigens on the blast cells of patients with chronic myeloid leukemia]. AB - The review presents the data available in the literature on an immunological phenotype of early precursors of human hemopoietic cells. Due to advances in hybrid technology, a great lot of monoclonal antibodies suitable for investigations of precursors of hemopoietic cells, including those of a stem cell have been designed. The review gives the basic characteristics of the antigens CD34, CD33, CD7, Thy-1, HLA-DR, and nonstrain-limited antigens expressed on the hemopoietic precursors and provides data on the expression of these antigens on the blast cells of patients with chronic myeloid leukemia (CML). It also discusses whether to identify immunological subvariants of the blast crisis of CML is expedient. PMID- 8672966 TI - Gastrointestinal tract sonography. PMID- 8672967 TI - Intraoperative ultrasonography. PMID- 8672968 TI - Arteriocholedochal fistula: an unusual cause of hemobilia. AB - We report an unusual cause of hemobilia in a patient with a transhepatic biliary catheter. Hemobilia was due to an extrahepatic fistula between the gastroduodenal artery and the common bile duct and was responsible for significant blood loss. The fistula was successfully treated with transarterial embolization that resulted in no further episodes of hemobilia during the following 12 months. PMID- 8672970 TI - Hepatocellular carcinoma with sarcomatous change: characteristic findings of two phased incremental CT. AB - BACKGROUND: Because of its poor prognosis, the diagnosis of hepatocellular carcinoma with sarcomatous change (HCCSC) is clinically important. The purpose of this study is to elucidate the characteristic CT findings of HCCSC. METHODS: Two phased dynamic incremental CT images of six histologically proven HCCSC were retrospectively reviewed. RESULTS: All tumors (100%) exhibited peripheral enhancement on delayed CT images. Lymphadenopathy was observed in 100% (six of six patients); intrahepatic metastases, in 83% (five of six). Both metastatic lesions showed findings similar to those of the primary hepatic tumors, such as peripheral enhancement. Histopathological delayed and/or prolonged peripherally enhanced areas consisted of viable cancer cells with sarcomatous changes. CONCLUSIONS: The appearance of HCCSC on CT is that of an irregularly demarcated intrahepatic mass with delayed or prolonged peripheral enhancement, frequently with intrahepatic metastases and lymphadenopathy. PMID- 8672969 TI - Focal hepatic nodules after transcatheter oily chemoembolization; detection with spiral CT versus conventional CT. AB - BACKGROUND: The objective of this study was to determine if spiral computed tomography (CT) results in increased rate of detection of focal hepatic nodules containing iodized oil after transcatheter oily chemoembolization when compared with conventional CT. METHODS: Spiral CT with single 24-s breath-hold technique was compared with conventional sequential CT in 42 patients with suspected hepatocellular carcinomas. Two sets of CT scans obtained after transcatheter oily chemoembolization were independently reviewed by two radiologists. The slice thickness was 10 mm for both data sets. The number and sizes of focal hepatic nodules containing iodized oil were documented. All 42 patients had at least hepatic nodule. The lesion size varied from 2 mm to 12 cm. RESULTS: In six of the 42 patients, more hepatic nodules could be identified on spiral CT compared with conventional CT. When scans with spiral CT were used, 107 nodules were detected, whereas 98 nodules were detected with conventional CT. Overall, nine (9%) more nodules were detected with spiral CT (p = .002). If lesions larger than 2 cm are excluded, nine (15%) more lesions were detected with spiral CT (p = .002). CONCLUSION: Spiral CT results in increased rate of detection of focal hepatic nodules after transcatheter oily chemoembolization, particularly in lesions smaller than 2 cm. PMID- 8672972 TI - Correlation of perfusion abnormalities on CTAP and immediate postintravenous gadolinium-enhanced gradient echo MRI. AB - BACKGROUND: The purpose of this study was to evaluate patients with wedge-shaped perfusion defects seen on spiral CT arterial portography for the presence of transient increased wedge-shaped enhancement on dynamic gadolinium-enhanced gradient echo MR images. METHODS: Nineteen patients underwent CTAP and MRI within a 2-week interval. All patients with wedge-shaped perfusion defects on CT arterial portography were evaluated in a separate review session for the presence of transient increased segmental hepatic enhancement on dynamic gadolinium enhanced spoiled gradient echo (SGE) MR images. RESULTS: Eight patients were identified to have subsegmental, segmental, or lobar wedge-shaped perfusion defects by CT arterial portography. In 8/8 patients, there was transient wedge shaped increased hepatic enhancement on MR images which corresponded to the perfusion defects identified on CT arterial portography. Transient increased enhancement on MR images was observed on immediate postgadolinium images as high signal intensity of the involved subsegment, segment, or lobe. This relatively high-signal area faded to near isointensity in all cases on images obtained at 45 s. CONCLUSION: Wedge-shaped perfusion defects demonstrated by CT arterial portography corresponded to wedge-shaped increased hepatic enhancement following gadolinium administration on SGE MR images. PMID- 8672971 TI - Small hepatocellular carcinoma: differentiation from adenomatous hyperplasia with color Doppler US and dynamic Gd-DTPA-enhanced MR imaging. AB - BACKGROUND: To investigate the usefulness of color Doppler ultrasound (US) and dynamic Gd-DTPA-enhanced magnetic resonance (MR) imaging in the differentiation of small hepatocellular carcinoma (HCC) and adenomatous hyperplasia (AH). METHODS: Thirty-eight small (3 cm or less) nodular lesions (in 38 cirrhotic patients) with US features consistent with HCC underwent evaluation with color Doppler US and MR imaging. Breath-hold T1-weighted rapid acquisition spin echo MR sequence after bolus injection of 0.1 mmol/kg gadopentetate dimeglumine was used to evaluate dynamic enhancement. US-guided tissue-core percutaneous biopsy established the diagnosis: HCC in 28 cases and AH in 10. RESULTS: Color signals with pulsatile or continuous Doppler spectrum were demonstrated in 19 of 28 HCCs (68%) but in none of the AHs. Although there was considerable overlap in signal intensity between HCC and AH on both unenhanced T1- and T2-weighted images, early enhancement on breath-hold T1-weighted images obtained 40 s after starting contrast administration was observed in 22 of 28 HCCs (79%) but in none of the AHs. In 26 of 28 HCCs (93%), pulsatile or continuous flow at color Doppler US, early enhancement at dynamic MR imaging, or both were observed. CONCLUSION: Findings with color Doppler US and dynamic Gd-DTPA-enhanced MR imaging enable a reliable distinction between small HCC and AH. PMID- 8672973 TI - The frequency, appearance, and significance of splenic perfusion defects in CT arterial portography. AB - BACKGROUND: The purpose of this study was to determine the frequency, appearance, and significance of splenic perfusion defects on computed tomographic arterial portography (CTAP). METHODS: CTAP was performed with dynamic scanning at 1-cm increments on 46 consecutive patients prior to laparotomy. Two readers retrospectively reviewed these studies in consensus and recorded the number, size, and shape of focal splenic perfusion defects. These defects were later correlated with surgical findings and at least one of the following imaging modalities: delayed CT 4-6 h after CTAP, intravenously enhanced CT, sonography, or magnetic resonance imaging (MRI). RESULTS: Splenic perfusion defects were present in 14 of 46 CTAP studies (30%), and in seven patients these defects were multiple. Most defects were wedge-shaped and peripherally located, although several round defects simulating metastases were also present. The spleen was normal at surgery in all patients, and comparison imaging revealed only a small splenic infarct in one patient on MRI. CONCLUSIONS: Splenic perfusion defects occur in about one-third of patients referred for CTAP, are usually wedge-shaped but may be round, and should not be interpreted as metastases without other evidence of a space-occupying mass. PMID- 8672974 TI - Spontaneous rectus sheath hematomas: clinical and radiological features. AB - We reviewed the clinical and radiological features in eight patients with spontaneous rectus sheath hematoma (RSH). The diagnosis was confirmed at surgery in four patients, and spontaneous resolution occurred in the other four. All patients were elderly adults. Acute abdominal pain and a palpable mass after muscular strain, such as coughing or twisting, were features highly suggestive of RSH. Sonographically, these hematomas may be confused with abdominal wall tumors. On CT scans, a hyperdense mass posterior to the rectus abdominis muscle with ipsilateral anterolateral muscular enlargement is considered characteristic of acute RSH, although chronic RSH may be isodense or hypodense relative to the surrounding muscle. MRI is very useful in the diagnosis of RSH, which is demonstrated as a high signal intensity area on both T1- and T2-weighted images, especially when the CT findings are not specific for RSH. PMID- 8672975 TI - Rectus sheath hematoma: diagnostic classification by CT. AB - A method of classification for hematomas of the rectus abdominis sheath (RSH) is proposed based on findings observed in CT in the 13 cases of RSH in the present study. Type I hematomas (five cases) are slight and do not require hospitalization. Type II (three cases) and type III (five cases) are moderate and severe hematomas, respectively, and do require hospitalization. The patients with type III hematomas were all undergoing anticoagulant therapy and presented with a picture of acute abdomen, and in all five cases blood transfusion was carried out. Ultrasonography and, in particular, CT permitted a correct diagnosis of RSH. RSH should be considered (anticoagulant therapy induced) in females with sudden abdominal pain to avoid unnecessary surgical intervention. PMID- 8672976 TI - Appendiceal stump abscess. AB - Recurrence of traditionally treated appendicitis is rarely reported but known to surgeons and is probably underestimated. We described a case, illustrated by CT, of stump abscess 2 years after laparoscopic appendectomy. Sonography and CT are helpful in detecting pericecal changes, but diagnosis is confirmed by laparotomy. PMID- 8672977 TI - Enhancing ascites: an aid to CT diagnosis. AB - Enhancement of ascitic fluid on delayed contrast-enhanced CT has been described as a potential pitfall in diagnosis. We present a case in which the phenomenon was beneficial to diagnosis. Enhancement of ascites was useful in delineating the entire extent of a cystic pelvic mass. We also discuss probable molecular and histologic mechanisms responsible for this unique type of enhancement. PMID- 8672978 TI - Peritoneopleural communication associated with cirrhotic ascites: scintigraphic demonstration. AB - Demonstration of peritoneopleural communication in patients with cirrhotic ascites has an important impact on treatment planning. We studied 12 such patients and found presence of peritoneopleural communication in five. Two had bilateral, one right-side and two left-side, pleural effusion. Pleural fluid protein content was less than 2 g/dL in all patients. PMID- 8672979 TI - Renal cell carcinoma arising from the free wall of a renal cyst. AB - We report an unusual case of a 1 cm papillary renal cell carcinoma arising from the outer surface of the free wall of a radiographically simple renal cyst. Most malignancies arising from the wall of a renal cyst are present along the inner surface, usually adjacent to underlying renal parenchyma. While this is a rare occurrence, it does reinforce the need to explore even small solid renal masses. PMID- 8672980 TI - Subcapsular renal spread of a pancreatic pseudocyst. AB - In pancreatitis, the fluid collection may extend to unusual sites and organs and form a pseudocyst. We present US and CT findings of a pancreatic tail pseudocyst extending into the subcapsular space of the left kidney. PMID- 8672982 TI - Occult bilateral ectopic vaginal ureters causing urinary incontinence: diagnosis by computed tomography. AB - Diagnosis of an ectopic, infrasphincteric ureter can be difficult because the renal moiety drained by the ectopic ureter is often small and functions poorly. We present a 6-year-old girl with urinary incontinence caused by bilateral vaginal ectopic ureters that were not seen on excretory urography or renal sonography and were diagnosed only by contrast-enhanced computerized tomography. PMID- 8672981 TI - Suprapubic versus transrectal ultrasonography in assessing the volume of the prostate and the transition zone in patients with benign prostatic hyperplasia. AB - The reliability of suprapubic ultrasonography (SU) in assessing the size of the prostate was examined in 95 patients with benign prostatic hyperplasia (BPH). Volumetric measurements of the prostate and the transition zone of the prostate (TZP) performed by SU were compared with corresponding measurements obtained by transrectal ultrasonography measurements obtained by transrectal ultrasonography (TU). A very strong correlation was found between suprapubically and transrectally performed measurements for both the total prostate gland (r = 0.948, p < 0.001) and the TZP volume (r = 0.953, p < 0.001). According to the results of this study, SU appears to be reliable as TU in assessing the size of the prostate and the TZP and may be used effectively in the evaluation of patients with BPH, as it is less cumbersome, better tolerated, and a widely available examination technique. PMID- 8672983 TI - Ultrasonography of the gastrointestinal tract in infants and children. PMID- 8672984 TI - Genetic and cellular changes in colorectal cancer: proposed targets of chemopreventive agents. AB - Progress in development of a genetic model for colorectal tumorigenesis and human chemoprevention research may allow the mechanism-based identification of targets and chemopreventive agents that will protect against colorectal cancer. For example, numerous mutagenic events can occur throughout colorectal carcinogenesis, including loss of heterozygosity in tumor suppressor genes such as APC, MCC, DCC, and p53, as well as in oncogenes such as K-ras. Chemopreventive agents that inhibit mutagenic activity such as N-acetyl-l-cysteine, oltipraz, and nonsteroidal anti-inflammatory drugs may protect against these mutations. Also, agents such as perillyl alcohol and lovastatin that interfere with protein isoprenylation and, hence, inhibit oncogene activation may protect against aberrant K-ras expression. Hyperproliferation in normal mucosa, leading to growth and progression of neoplasia, are also aspects of colorectal carcinogenesis that can be controlled by chemopreventive agents. Calcium is a chemopreventive agent for which there is both clinical and experimental evidence of inhibition of cell proliferation in colon mucosa. Other examples of antiproliferative agents with potential chemopreventive efficacy in colon are 2-difluoromethylornithine, dehydroepiandrosterone, and selenium. Differentiating agents such as retinoids and deltanoids also may slow proliferation and progression. Antioxidants have potential for interfering with both mutagenicity and proliferation (e.g., by preventing oxidative activation of carcinogens and scavenging activated oxygen species generated during inflammation). The same mechanistic principles apply to identification of dietary chemopreventive intervention for colorectal carcinogenesis. For example, lowering dietary fat and increasing dietary fiber lead to lower colorectal mucosal proliferation, and cruciferous vegetables contain agents such as indoles and dithiolthiones that have shown antimutagenic activity. PMID- 8672985 TI - Aspirin and other nonsteroidal anti-inflammatory drugs and risk of colorectal adenomatous polyps among endoscoped individuals. AB - Most epidemiological evidence supports the inverse association between use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) and colorectal cancer. Few studies have investigated the relation between use of aspirin and other NSAIDs and adenomatous polyps, which are recognized as precursors of colorectal cancer. We examined the association of adenomatous polyps and the dose and duration of use of aspirin and other NSAIDs in a case-control study of dietary risk factors for colorectal adenomatous polyps. The study population comprised 157 case and 480 control individuals who underwent an endoscopy at collaborating gastroenterology clinics in Houston, TX. Face-to-face interviews were conducted to obtain risk factor data that included information on frequency and duration of use of aspirin and other NSAIDs. Compared to the nonusers, the multivariate odds ratios for individuals who took aspirin and other NSAIDs on a weekly basis and for those who took these once/day or more were 0.77 (95% confidence interval, 0.39-1.55) and 0.36 (95% confidence interval, 0.20-0.63), respectively. Compared to the nonusers, the odds ratio for individuals who used aspirin and other NSAIDs for <5 years was 0.39 (95% confidence interval, 0.39 1.55) and 0.36 (95% confidence interval, 0.20-0.71), and for those who used these for 5 years or more, the odds ratio was 0.60 (95% confidence interval, 0.32 1.14). The results of this study suggest that aspirin and other NSAIDs are associated with a decreased risk for adenomatous polyps. Limited dose-response analyses found that the point estimate decreased with the frequency but not the duration of use of aspirin and other NSAIDs. PMID- 8672986 TI - Red cell and plasma folate, folate consumption, and the risk of colorectal adenomatous polyps. AB - Epidemiological and experimental evidence suggests that dietary folate may protect against colorectal carcinogenesis. The epidemiological relationship between a biochemical measure of folate status and colorectal neoplasia in a sizeable and generally healthy population does not yet appear to have been reported. We conducted a case-control study of the relationships among red cell folate, plasma folate, folate intake, and adenomatous polyps, intermediate markers for colorectal cancer. During 1991-1993, fasting blood samples were assayed and dietary and nondietary risk factor questionnaires were administered to men and women ages 50-75 years who had a free sigmoidoscopy at a health maintenance organization. We analyzed data from 682 subjects (332 cases and 350 controls), controlling for potential confounding by sex, age, sigmoidoscopy date, and clinic. For red cell folate levels 160 ng/ml (363 nmol/liter) or more, compared to lower levels, the odds ratio was 0.76 [95% confidence interval (CI) = 0.53-1.08]. For men, the corresponding odds ratio was 0.53 (CI = 0.32-0.87); for women, it was 1.16 (CI = 0.67-2.00). Results were essentially unchanged when adjusted for levels of blood nutrients and other potential confounding variables. Plasma folate and folate intake results were similar to red cell folate results, but the associations with polyps were weaker. Results are consistent with a protective effect of red cell folate concentration against the development of colorectal polyps, at least in men. A folate effect may depend on sex-specific interactions with other nutritional or physiological factors. PMID- 8672987 TI - Comparison of rectal mucosal proliferation measured by proliferating cell nuclear antigen (PCNA) immunohistochemistry and whole crypt dissection. AB - Rectal mucosal proliferation has been promoted as an intermediate marker for risk of colorectal neoplasia. Proliferating cell nuclear antigen (PCNA) immunohistochemistry has become a standard method to measure cell proliferation. Whole-crypt dissection may provide a technically simpler method for determining proliferation within an entire crypt. We conducted a study to assess the reliability (reproducibility) of whole-crypt dissection in 10 subjects. Reliability of whole-crypt dissection with the subject as the unit of observation was excellent. The intraclass correlation coefficient for subjects was 0.93. Biopsy-to-biopsy reliability was lower (r=0.86) and crypt-to-crypt reliability lower still (r = 0.35). There was poor correlation between measures of proliferation index using the two techniques (Kendall's tau = 0.13; P = 0.08). Compartment analysis based on the percentage of the total number of labeled cells appearing in each crypt quartile also did not demonstrate a significant correlation between the two measures. We conclude that PCNA labeling index and whole-crypt mitotic count are not comparable measures of rectal mucosal proliferation. PMID- 8672988 TI - Lifetime alcohol consumption and breast cancer risk among postmenopausal women in Los Angeles. AB - Although most data support an overall relation of alcohol consumption with risk of breast cancer, the timing of alcohol consumption as it relates to risk of breast cancer is still debatable. The authors examined this issue in a case control study conducted among non-Hispanic white and Hispanic women in Los Angeles. Cases aged 55-64 years at diagnosis in 1987-1989 were enrolled through the Cancer Surveillance Program of Los Angeles County (a Surveillance, Epidemiology, and End Results Program registry). Community controls were individually matched to cases by age (+/- 3 years), ethnicity, and neighborhood. In-person interviews were completed with 1510 matched pairs, of which 1431 met the inclusion criteria for the present analysis. In a multivariate conditional logistic regression model that simultaneously included terms for alcohol consumption at age 25 years, age 40 years, and in the recent past, clear differences among the age-specific associations were not observed, and the results suggested associations were not observed, and the results suggested that intake at each time independently contributed to risk. The odds ratios associated with estimated average lifetime intake were: for <6 g/day, 1.01; for 6-11 g/day, 1.21; for 12-18 g/day, 0.94; for 19-32 g/day, 1.63; for 33-45 g/day, 2.45 and for > or = 46 g/day, 0.94 compared with abstainers (P for trend = 0.01). Use of estrogen replacement therapy did not modify the risk associated with alcohol consumption, in contrast with the findings in two previous studies. This large study supports a relation between risk of breast cancer and alcohol consumption and suggests that lifetime intake may be the best indicator of alcohol-associated risk. PMID- 8672989 TI - Plasma lipids, lipoproteins, and mammographic densities. AB - There is strong evidence that the risk of breast cancer in populations is influenced by environmental factors. Plasma lipids and lipoproteins are known to be under environmental control and to have epidemiological and/or biological characteristics that suggest they may be relevant to breast cancer risk. The purpose of the study described here was to determine whether plasma lipids, lipoproteins, and the urinary excretion of the mutagen malondialdehyde (MDA) are associated with differences in breast cancer risk. We measured plasma lipids, lipoproteins, and urinary MDA in women without breast cancer but with different degrees of density of the breast parenchyma on mammography, a strong risk factor for breast cancer. Mammograms from 273 premenopausal women were digitized to high spatial resolution by a scanning densitometer, and images were analyzed to quantify the extent of density. The percentage of the breast occupied by mammographic densities was found, after controlling for the effects of age and the Quetelet index of obesity, to be significantly associated with plasma levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, apoprotein B, and urinary excretion of MDA. A multivariate model comprised of the Quetelet index of obesity, alcohol consumption, apoprotein B, parity, daily MDA excretion, and the skinfold thickness sum accounted for 36% of the variation in breast density. These results suggest that differences in lipid metabolism are associated with differences in breast cancer risk as defined by mammographic densities. These findings are consistent with several other observations that show a relationship between plasma lipids, lipoproteins, and risk factors for breast cancer. PMID- 8672990 TI - Serum androgens and sex hormone-binding globulins in relation to lifestyle factors in older African-American, white, and Asian men in the United States and Canada. AB - Differences in endogenous androgen levels have been hypothesized to explain ethnic differences in prostate cancer risk. To examine this hypothesis, we gathered data on serum concentrations of androgens and sex hormone-binding globulin (SHBG) in healthy older men from four ethnic groups at different levels of prostate cancer risk. As part of a population-based case-control study of prostate cancer we conducted in California, Hawaii, and Vancouver, Canada, 1127 African-American, white, Chinese-American, and Japanese-American control men, mostly ages 60 years or older (mean age, 69.9 years) provided information on various lifestyle factors and donated an early morning fasting blood sample between March 1990 and March 1992. We used these data to examine the distributions of serum androgens [testosterone (total, free, and bioavailable), dihydrotestosterone (DHT)], the ratio of DHT to total testosterone (DHT:testosterone ratio), and SHBG in these four ethnic groups. We also assessed correlations between concentrations of these measures with age, body size, physical activity, and other personal characteristics, and we evaluated ethnic differences in concentrations of androgens and SHBG after adjusting for these characteristics. In each of the four ethnic groups, concentrations of free and bioavailable testosterone declined with age, whereas SHBG concentrations increased with age. Age-adjusted concentrations of all androgen measures and SHBG decreased with increasing levels of Quetelet's index. After adjustment for age and Quetelet's index, androgens and SHBG showed no clear and consistent relationships to physical activity, alcohol consumption, or tobacco use. DHT:testosterone ratio was higher in men reporting a history of benign prostate disease than in men without such a history, and higher in vasectomized men than in nonvasectomized men. SHBG concentrations were higher in men reporting one or more first-degree relatives with prostate cancer than in men without such a family history. After adjustment for age and Quetelet's index, the levels of total and bioavailable testosterone were highest in Asian-Americans, intermediate in African-Americans, and lowest in whites. However, the DHT:testosterone ratio was highest in African-Americans, intermediate in whites, and lowest in Asian Americans, corresponding to the respective incidence rates in these groups and providing indirect evidence for ethnic differences in 5alpha-reductase enzyme activity. PMID- 8672991 TI - Genetic susceptibility to lung cancer as determined by lymphocytic chromosome analysis. AB - Chromosomal anomalies were analyzed in the lymphocyte cultures among 96 untreated lung cancer patients and 74 clinically normal comparison subjects. The analysis revealed that >15% of the lung cancer patients showed structural or numerical rearrangements in chromosomes 1,3,5,7,9,12,14, and 21. A case control comparison showed that these aberrations were significantly higher in chromosome 7 [odds ratio (OR) = 2.32; 95% confidence interval (CI), 1.14 and 4.82], chromosome 9 (OR = 2.61; 95% CI, 1.27 and 5.48), chromosome 12 (OR = 4.10; 95% CI, 1.40 and 14.54), and chromosome 21 (OR = 7.75; 95% CI, 1.73 and 70.80) of the patients than in the controls. However, only chromosome 9 (OR = 3.57; 95% CI, 1.33 and 9.46) and chromosome 21 (OR = 6.94; 95% CI, 3.15 and 9.98) retained significance after stratifying on smoking status. Among the lung cancer patients, the breakpoints cluster in specific regions of some of these chromosomes. These regions are 1p13-q21, 3q21-q13, 7p12-q12, 7q12-q12,7q22, 7q32, 9p13-q13, 12p13, 14q11, and 14q32. The distribution of lung cancer patients, according to histological types, showed that aberrations in chromosomes 1,7, and 9 dominated the scenario of chromosomal changes in non-small cell lung carcinomas. Thus, the data on lymphocytic chromosomal rearrangements in lung cancer patients not only indicate the importance of specific genetic changes in the etiology of lung cancer but also emphasizes the putative role of such analysis in determining primary genetic abnormalities in the large heterogeneous group of lung cancers. PMID- 8672992 TI - Cigarette smoking, intracellular vitamin deficiency, and occurrence of micronuclei in epithelial cells of the buccal mucosa. AB - The study focuses on the assessment of chromosomal damage associated with folate and vitamin B12 deficiency, and with cigarette smoking in a tissue directly exposed to cigarette smoke (buccal mucosa) while controlling for potential confounding factors. A cross-sectional study was carried out among 39 current smokers (CSs) and 60 noncurrent smokers (NCSs). Buccal mucosal cells, saliva, and blood samples were collected from each subject. The Health Habits and History Questionnaire (Block et al., 1986) was modified to obtain dietary and other relevant information. Methods used to measure folate, vitamin B12 levels, and the frequency of micronucleated cells in buccal mucosal cells gave reproducible results. The study results suggest that CSs have buccal mucosal folate and vitamin B12 levels that are lower than those among NCSs. CSs were three times more likely to have micronucleated buccal mucosal cells compared to NCSs. There appeared to be no association between low buccal folate and vitamin B12 levels chromosomal damage. The salivary vitamin B12 concentrations and plasma vitamin C and E concentrations, however, seem to be marginally protective against the occurrence of buccal mucosal micronuclei, whereas plasma beta-carotene seems to increase the occurrence of micronuclei. Overall, the results do not support the concept that localized folate and vitamin B12 deficiencies in the buccal mucosal cells of smokers are associated with chromosomal damage in those cells. The presence of vitamin B12 deficiencies in the buccal mucosal cells of smokers are associated with chromosomal damage in those cells. The presence of vitamin B12 in the immediate environment (saliva) and vitamin C and E in the plasma, however, appear to be marginally protective against chromosomal damage in buccal mucosal cells. PMID- 8672993 TI - Deletion of genetic material from a poly(ADP-ribose) polymerase-like gene on chromosome 13 occurs frequently in patients with monoclonal gammopathies. AB - Recently, by using a probe for the nuclear DNA repair enzyme poly(ADP-ribose) polymerase gene, a pseudogene was found on the long arm of chromosome 13. RFLP analysis demonstrates the presence of a common "A" allele and a rare "B" allele, which has a deletion of approximately 200 bp. This deletion occurs more frequently in blacks than in whites in the United States. In two B-cell malignancies, Burkitt's and follicular lymphomas, there is a marked increased frequency of the expression of the B allele. Thus, we have analyzed the frequency of this allele in another B-cell malignancy, multiple myeloma (MM), which is also more frequently observed in blacks. We studied 97 patients with MM (41 black and 56 white patients) and 30 patients with the related disorder monoclonal gammopathy of undetermined significance (MGUS; 13 black and 17 white patients). The results demonstrate that the overall frequency of B allele expression (37%) is higher than in a noncancer control population (23%; P < 0.01). This difference is mainly due to the much higher frequency of B expression in black patients (52 versus 35% in black controls; P < 0.01), whereas there is no significant difference in white patients (18 versus 14% in white controls). Overall, B allelic frequency is similar in patients with MM and MGUS. Matched germline and tumor DNA show identical patterns of expression of these alleles. These results suggest germline B allelic expression predisposes one to MM and MGUS. PMID- 8672994 TI - Mutations in the tumor suppressor gene p53 in human liver cancer induced by alpha particles. AB - The p53 tumor suppressor gene is mutated in varying fractions of almost all tumor types studied. The rate of mutations and the mutational spectrum in some tumors are specific for environmental mutagens assumed to be involved in the carcinogenic process. Thus, hepatocellular carcinomas supposedly induced by aflatoxin exposure often contain a specific point mutation in codon 249, and in lung cancers of miners with heavy radon exposure, another specific point mutation in codon 249 suggestive of an alpha-particle-specific mutation has been shown. The interpretation of studies linking the mutational spectrum with specific environmental exposures is complicated by the multifactorial or unknown genesis of most tumors. However, people given injections of the X-ray contrast medium Thorotrast (Th) in the past have experienced an enormous risk of liver tumors, and virtually all of these are supposedly induced by alpha-particles from the decay of 232Th. The examination of these tumors may provide evidence as to whether specific p53 point mutations are relevant in alpha-particle carcinogenesis. Therefore, we collected paraffin-embedded, formalin-fixed archival tissues from 18 hepatocellular carcinomas, 9 cholangiocarcinomas, and 9 hepatic angiosarcomas from Thorotrast-exposed patients. The tissues were analyzed for p53 protein expression by immunohistochemical staining by using the mAb DO-7 and for mutations of exons 5-8 by PCR and constant denaturant gel electrophoresis. G --> T transversions of the third base of codon 249 of the p53 gene were specifically screened for by restriction enzymes. No high score for p53 protein expression (i.e., positive staining of >20% of examined cells) was observed; lower scores were seen in 5 of 18 (28%) hepatocellular carcinomas, 1 of 9 (11%) cholangiocarcinomas, and 0 of 8 (0%) hepatic angiosarcomas. Only one p53 mutation, a heterozygous T --> G transversion of the first base codon 176, occurred in a hepatocellular carcinoma. The rate of p53 point mutations in alpha particle-induced liver tumors seems to be lower than in European hepatocellular carcinomas in general. The study does not exclude the possibility that alpha particle carcinogenesis may involve inactivation of p53 by gross deletions of the gene, but it speaks against the proposed specificity of point mutations of codon 249 in cancer supposedly induced by alpha-particles from radon progeny. PMID- 8672995 TI - Altered aromatic amine metabolism in epileptic patients treated with phenobarbital. AB - The fate of carcinogens differs among individuals who have different activities of drug-metabolizing enzymes that are important in activating and detoxifying carcinogens. A drug that profoundly alters the metabolism of the drugs and carcinogens is the anticonvulsive agent phenobarbital. To investigate why epileptic patients appear to have a low risk of cancer of the urinary bladder, and on the basis of the observation that levels of aromatic amine-hemoglobin adducts are strongly associated with various risk factors for cancer at that site, we determined aromatic amine-hemoglobin adducts in 62 epileptic patients as a surrogate measure of the reaction of carcinogenic metabolites with DNA in target tissue. Although adducts were detected in all subjects, the levels were proportional to daily tobacco consumption. When the subjects were stratified into groups smoking 20 g tobacco/day or more, smoking <20 g/day, and not smoking, an effect of medication was detected. Epileptic patients treated chronically with phenobarbital or primidone, which is effectively metabolized to phenobarbital, were found to have lower levels of 4-aminobiphenyl adducts than patients on the other treatment (P = 0.02; ANOVA). In nonsmokers, no effect of medication could be demonstrated above background variation; however, an increasing effect was seen with tobacco consumption with only one-half the increase in adducts per g of tobacco smoked as epileptic patients on other treatment. The difference in the increases (slopes of regression lines) was highly significant statistically. This reduction in the level of hemoglobin-aromatic amine adducts is probably due to induction of detoxification enzymes in the patients treated with phenobarbital. PMID- 8672997 TI - Community Clinical Oncology Program participation in the Breast Cancer Prevention Trial: factors affecting accrual. AB - Cancer prevention and control involves a diverse spectrum of activities that range from preventing the disease to providing rehabilitation to its survivors. The range of activities included within the definition of cancer prevention and control makes it difficult to determine factors that would predict accrual to specific cancer prevention and control trials. The participation of 36 CCOP organization in the National Cancer Institute-sponsored Breast Cancer PRevention TRial (BCPT) presented the opportunity to assess the ability of Community Clinical Oncology Program (CCOPs) to enroll subjects in one of the nation's first large-scale cancer prevention trials and to compare characteristics of CCOP accrual to the BCPT with factors associated with accrual by CCOPs to cancer treatment and other cancer prevention and control clinical trials. Although representing only 13% of participating health care organizations, CCOPs presently contribute nearly 30% of total BCPT accrual. Comparison of regression models representing accrual to treatment, cancer control, and chemoprevention (i.e., BCPT) protocols shows similar predictors between treatment and chemoprevention models. Cancer control models, however, did not share similar predictors. Thus, accrual to chemoprevention trials is associated, to a greater extent, with the characteristics that facilitate accrual to treatment trials rather than to cancer control trials. Results have implications for the planning and ongoing management of cancer treatment, control, and chemoprevention clinical trials. PMID- 8672996 TI - Dosing time with ascorbic acid and nitrate, gum and tobacco chewing, fasting, and other factors affecting N-nitrosoproline formation in healthy subjects taking proline with a standard meal. AB - The N-nitrosoproline (NPRO) test measures the potential for intragastric formation of carcinogenic nitrosamines in humans. Nitrate and L-proline are administered to volunteers. Noncarcinogenic NPRO is produced by an acid-catalyzed reaction of proline (a model for ingested amines) with nitrate-derived nitrite in the stomach. It is then absorbed and excreted in the urine, which is analyzed for NPRO. We studied the effect of certain dietary and other factors on the levels of urinary NPRO. For (generally) 5 days, healthy adult subjects (mostly men) followed a diet low in preformed NPRO, nitrate, proline, and (on days 4 and 5) ascorbic acid. The tests were conducted on days 4 and 5. In the standard test, the subjects took 400 mg nitrate at 11 a.m., and at noon they ate a standard 700 calorie meal containing 500 mg proline. (In previous tests, proline was given 1 h after or between meals.) Urines were collected for 24 h, and samples were analyzed for NPRO by published methods. This standard test yielded 26 +/- 2 (mean +/- SE) nmol NPRO compared with 5 +/- 1 nmol NPRO when proline alone was taken. In variations of the standard test, NPRO yield was not significantly affected by the subjects' gender, the time at which the standard meal was eaten, the size of the meal, or the drinking of extra water after the meal. Doses of 100 and 200 mg nitrate had lesser effects on NPRO yield than did the dose of 400 mg nitrate. Nitrate (400 mg) produced the most NPRO when it was given 1 h before the meal. Fasting increased NPRO yield by 3-4 times compared to giving proline with a meal. One g of ASC given 5 or 2 h before, with, or 1 or 2 h after the meal with proline inhibited NPRO formation by mean values of 0, 71, 71, 67, and 19%, respectively. Chewing gum or tobacco for 2-3 h after the test meal did not increase NPRO formation or salivary nitrate levels, but salivary nitrite was not taken, chewing tobacco appeared to increase salivary nitrite and nitrate levels. The weak carcinogen N-nitrososarcosine (NSAR) was also detected in some tests, and the standard group showed 21 +/- 3 nmol NSAR. A high NSAR result (44 +/- 7 nmol) for women undergoing the standard test should be reexamined. We discuss applying these results to the conduct of future NPRO tests, as well as their implications for reducing the potential production of carcinogenic nitrosamines in the stomach. PMID- 8672998 TI - p53 and K-ras in radon-associated lung adenocarcinoma. AB - Mutations in the p53 tumor suppressor gene and the K-ras proto-oncogene are common genetic defects in lung cancer. Analysis of the patterns of damage in these genes may provide important insights into the mechanisms by which environmental mutagens initiate cancer. Previously, our laboratory found that a rare p53 codon 249 mutation (AGG(ARG) to ATG(MET) transversion) was present in 31% of a series of 52 large and squamous cell lung cancers from uranium miners, suggesting that this mutation might be a marker for radon exposure. In the current study, we analyzed 23 lung adenocarcinomas from the same cohort of highly exposed uranium miners. These tumors failed to show the codon 249 transversion, but 9 (39%) of 23 contained 1 or more mutations within hotspots in the K-ras gene. The results suggest that there is a histological tissue-type specificity for the codon 249 mutation; although this mutation was common in squamous and large cell tumors from very highly exposed uranium miners, it is rare in adenocarcinomas from the same cohort of miners. PMID- 8672999 TI - Fecal diacylglycerol concentrations and calcium supplementation. AB - Growth factors are known to stimulate colonic proliferation via activation of protein kinase C by production of diacylglycerol (DAG) from membrane phosphatidyl inositol. Previous studies from our laboratories have shown that fecal bacteria can produce and metabolize DAG and that DAG can be absorbed by colonocytes, and thus might contribute to neoplasia. Calcium is a putative chemopreventive agent, and we have shown that calcium administration reduces fecal DAG concentrations, as well as rectal proliferation in patients after jejuno-ileal bypass surgery. The present study in normal volunteers eating self-selected diets demonstrates that fecal DAG concentrations are very constant with a coefficient of variation from 6.7 to 10.2%. Calcium administration showed a trend to reduce fecal DAG by 11% (P < 0.08). We conclude that fecal DAG levels can be determined in individuals on a self-selected diet from a single stool determination. If the trend to reduce fecal DAG by calcium is verified in more extensive studies, then the effects of calcium used in chemopreventive might, in part, reflect changes in the luminal lipid content. PMID- 8673000 TI - Rapid rise and subsequent decline in prostate cancer incidence rates for New Mexico, 1989-1993. AB - Beginning in the late 1980s, a large increase in incidence rates for prostate cancer occurred in association with increased prostate-specific antigen (PSA) screening. In New Mexico, the increased screening was associated with earlier detection of cancers and decreased prostate cancer mortality, suggesting that PSA screening may be effective. PSA screening has become a controversial topic of public debate, and anecdotal reports from physicians indicated that prostate cancer screening practice patterns were changing in New Mexico. To assess whether PSA-associated trends in prostate cancer incidence were continuing, we examined incidence rates from 1989 to 1993 among men in New Mexico. From 1989 to 1992, age adjusted rates increased substantially for non-Hispanic whites (77%), Hispanics (50%), and American Indians (27%). Although rates increased for all stages combined, incidence rates decreased for distant-stage disease, especially for non Hispanic whites, indicating a continuing trend toward earlier detection. In 1993, incidence rates unexpectedly decreased from 203 to 158/100,000 in non-Hispanic whites, largely as a result of changes in rates in men over age 65 years. Although incidence rates decreased, the trend toward earlier detection was maintained for non-Hispanic whites. In contrast, among Hispanic and American Indians, rates did not change substantially between 1992 and 1993. Because the epidemic in prostate cancer was associated with increased PSA screening, it is likely that the trends for non-Hispanic whites are also related to PSA screening. We suggest that the decrease in rates and the continued stage shift are consistent with repeated screening of men in the population at risk. PMID- 8673001 TI - Effect of beta-carotene supplementation on serum alpha-tocopherol concentration. AB - Conflicting reports of the effects of beta-carotene supplementation on serum alpha-tocopherol concentration led us to evaluated serum alpha-tocopherol in subjects with and without beta-carotene (30 mg/day) supplementation for up to 2 years duration in an ongoing chemoprevention trial. No adverse effect has been observed at any of the time periods examined. PMID- 8673002 TI - Highly conserved N-methyltransferases as an integral part of peptide synthetases. AB - The methyltransferase portion of the N-methyl-peptide-synthetase gene, synthesizing enniatin from Fusarium sambucinum, was amplified with the polymerase chain reaction (PCR) using primers derived from the highly conserved sequences of the flanking peptide synthetase domain. The deduced amino acid sequence of the product shares high similarity to the 430 amino acid methyltransferase portion of enniatin synthetase of Fusarium scirpi and the corresponding portions of another fungal peptide synthetase catalyzing the biosynthesis of the N-methylated cyclopeptide cyclosporin. As the methyltransferase portions show only local similarity to motifs apparently conserved within methyltransferases, the segments of peptide synthetases involved in the biosynthesis of bioactive peptides represent a new class of S-adenosyl-L-methionine dependent methyltransferases. PMID- 8673003 TI - Solubilization and characterization of an ATP diphosphohydrolase (EC 3.6.1.5) from rat brain synaptic plasma membranes. AB - The effect of different detergents on the ATPase and ADPase activities from synaptic plasma membrane were investigated. Triton X-100, deoxycholate, CHAPS, Nonidet, N-octylglucoside and C12E8, which is commonly used to solubilize plasma membrane proteins, easily inactivated the ATPase and ADPase activities, while digitonin was not harmful to the enzyme. Treatment of the synaptic plasma membrane from rat brain with 0.5% digitonin solubilizes 80% of the proteins and 50% and 60% of ATPase and ADPase, respectively, with the following characteristics: stimulation by Ca2+ in the millimolar range, insensitivity to ATPase inhibitors (ouabain, olygomicyn, orthovanadate), inhibition with sodium azide and NEM and broad substrate specificity for the hydrolysis of nucleoside di and triphosphate. To further characterize the enzyme solubilized, polyclonal antibodies specific for ATP diphosphohydrolase from potato tuber were tested. Western blot showed that two electrophoretic bands with a molecular mass close to 60-70 kDa had cross-immunoreactivity with antibodies against potato apyrase. The results presented here demonstrate for the first time the solubilization of ATPase and ADPase activities with characteristics of a true ATP diphosphohydrolase from synaptic plasma membrane from rat brain and with cross immunoreactivity with antibodies against potato apyrase. PMID- 8673004 TI - Fatty acids in plasma and red blood cell membranes in humans, rats, rabbits and dogs. AB - Fatty acids were estimated in plasma and red blood cell membrane in rats, rabbits, dogs and humans. The fatty acid pattern of plasma and red blood cell membrane was similar in all species and humans with little exceptions. C18:2 was higher in plasma than red blood cell membrane whereas C20:4 was higher in red blood cell membrane than plasma except rabbit. C18:2 was high in rabbit red blood cell membrane when compared to others. Dog was exceptionally very low in C18:2 and high in C20:4 in red blood cell membrane whereas rabbit was low in C20:4 and high in C18:2. 22-Carbon fatty acids showed some variation. Among 22-carbon fatty acids C22:6 was found highest in human red blood cell membrane, with quite high amounts in rat and rabbit but not in dog. Rats were closest to human in their fatty acid patterns. PMID- 8673005 TI - Activation of platelet heparitinase by vascular cell lysates. AB - Tumour cells have been reported to contain an activator of platelet heparitinase which is absent from normal cells. Using an assay which measures the degradation of radiolabelled heparin, we observed that lysates of metastatic melanoma cells did activate platelet radiolabelled heparin, we observed that lysates of metastatic melanoma cells did activate platelet heparitinase but that lysates of arterial endothelial and smooth muscle cells did likewise, with the latter being particularly effective. The activator largely survived a 10 min preincubation of the cell lysates at 70 degrees C, but not at 100 degrees C. Experimental results indicated that the contents of 10(5) vascular smooth muscle cells could increase platelet heparitinase activity in vitro to 6 times its initial value. We suggest such activation may have physiological relevance and may even assist the development of certain cardiovascular diseases in man. PMID- 8673006 TI - Inhibition of platelet heparitinase by phosphorothioate DNA oligonucleotides. AB - In view of the role that heparitinase and heparanase enzymes are thought to play in regulating the proliferation of smooth muscle cells, inhibitors of these enzymes may have therapeutic value in the treatment of vascular hyperplasia. Here we report that phosphorothioate oligodeoxynucleotides inhibit platelet heparitinase and related enzymes in vitro. The inhibition is greatly enhanced by the presence of a GGG motif in the oligonucleotide, and also increases with oligonucleotide for two phosphorothioate DNA 30-mers consisting solely of guanosine and thymidine nucleotides. Their inhibitory efficacy was greater when heparan sulphate was used as substrate. PMID- 8673007 TI - Inhibition of Helicobacter pylori urease activity by ebrotidine. AB - Helicobacter pylori is considered a primary factor in the pathogenesis of gastric disease, and the successful mucosal colonization is linked to its urease activity. In this study, we assessed the effect of antiulcer agent, ebrotidine, on the in vitro activity of H. pylori urease. The results of assays showed a dose dependent inhibition of the urease activity. A maximum inhibition (77%) in H. pylori urease activity occurred at 2.1 microM ebrotidine. A known H2-blocker, ranitidine, in a parallel experiment gave a maximal inhibition of 73% at a considerably higher concentration (6.4 microM). The results demonstrate that ebrotidine with its combined acid suppressant and anti-H. pylori activities offers an excellent choice in the treatment of H. pylori associated gastric disease. PMID- 8673008 TI - EPR studies of spin-trapped free radicals in paraquat-treated lung microsomes. AB - Electron Spin Resonance and Spin Trapping techniques were used to demonstrate the generation of free radicals during incubation of paraquat with lung microsomes. Aerobic incubation of paraquat resulted in the production of superoxide radical (.O2-) which was trapped by 5, 5-dimethyl-pyrroline-N-oxide or phenyl-tert-butyl nitrone. The formation of .O2- and hydroxyl radical (.OH) by paraquat during microsomal incubation was also confirmed by the inhibition of the EPR spectra of DMPO-O2- and DMPO-OH spin adducts by superoxide dismutase and dimethyl sulfoxide, respectively. Our results provide direct evidence for the generation of reactive oxygen species during redox cycling of paraquat in microsomes. The formation of DMPO-H spin adduct during incubation of paraquat in the microsomal system is a strong indication of the involvement of hydrogen atom transfer mechanisms in paraquat-induced generations of reactive oxygen species in the lung. PMID- 8673009 TI - Primary structure of bovine aorta biglycan core protein deduced from cloned CDNA. AB - Two overlapping cDNA clones for core protein of a biglycan of bovine aorta were isolated from a pSPORT bovine aorta tissue cDNA library. The 2043-bp cDNA contains a 114-bp 5' untranslated region, a 1224-bp cDNA open reading frame and a 705-bp 3' untranslated region. The encoded core preproprotein contains a prepeptide (residues no. -37 to -19) and a propeptide (residues no. -18 to -1), with 369 amino acid residues corresponding to a molecular mass of 41.6 kDa. The deduced amino acid sequence revealed a striking homology to rat vascular smooth muscle cell, human bone and bovine articular cartilage biglycans from cell culture. PMID- 8673010 TI - Oxidant-induced stress response in lymphoid cells. AB - The stress response to reactive oxygen species is an important defence system which can reduce their potential to induce biomolecule damage. In this investigation the effect of exposing Molt-3 lymphoblastoid cells or peripheral blood lymphocytes to a non-toxic dose of hydrogen peroxide (10 microM) was studied. Cellular response to a subsequent high dose of hydrogen peroxide (100 200 microM) was assessed by measurement of growth, viability, proliferation and DNA damage (lymphocytes only) and intracellular activities of the enzymes, superoxide dismutase, glutathione peroxidase and catalase (Molt-3 only). The results indicate that pretreatment of lymphocytes with 10 microM hydrogen peroxide can elicit a response which is protective against DNA damage normally inducible in these cells by subsequent exposure to toxic doses of hydrogen peroxide. It appears from the results with Molt-3 cells that altered activities of glutathione peroxidase may contribute to this enhanced resistance to hydrogen peroxide. PMID- 8673011 TI - The specificity and product of quenching singlet oxygen by 2,2,6,6 tetramethylpiperidine. AB - The specificity of 2,2,6,6-tetramethylpiperidine to singlet oxygen was shown using Rose Bengal as a singlet oxygen generator, and Xanthine-Xanthine Oxidase and KO2 as the sources for the superoxide radical. The highest concentration of produced-singlet oxygen occurred at 25% of O2 by Rose Bengal photosensitization. The linewidth of the EPR signal for photosensitized nitroxyl radical, increasing solvent polarity. Deuterated solvents enlarge the EPR signal intensity in a dose dependent manner. No EPR signal increase was observed in xanthine-xanthine oxidase reaction or KO2 systems, indicating that TEMP does not react with the superoxide anion. Thus, reaction of TEMP with 1O2 is highly specific. PMID- 8673012 TI - Purification and characterization of DNA-dependent RNA polymerase II from Candida utilis. AB - DNA-dependent RNA polymerase II from Candida utilis has been purified to near homogeneity. The purified enzyme resolved into three subforms, viz. IIO, IIA and IIB. On SDS-PAGE the enzyme showed ten polypeptides with molecular weights in the range of 205 kDa to 14 kDa. By two dimensional electrophoresis (IEF followed by SDS-PAGE) the presence of basic and acidic polypeptides has been demonstrated. The enzyme showed Km values of 5, 5.6 and 8 microM for GTP, CTP and ATP, respectively, and the activity was inhibited by low levels of alpha-amanitin and antibodies raised against bovine RNA polymerase II. By Western blot analysis the enzyme was found to cross-react with antibodies to bovine RNA polymerase II. RNA polymerase II from C. utilis is a phosphoprotein, the subunits RPB1 and RPB10 were found to be phosphorylated. Analysis of carboxy-terminal domain indicated that it was functionally redundant at least in case of non-specific transcription, implicating its role in other nuclear processes, such as promoter specific initiation or transcription activation or RNA processing. PMID- 8673013 TI - Antibodies raised against guanosine bind to double-stranded DNA. AB - Antibodies elicited against guanosine have been reported to bind to single stranded DNA. Using an avidin-biotin microELISA, we report that these antibodies also bind to double-stranded DNA. The binding is specific and is completely inhibited by the homologous hapten. The cross-reactivity of double-stranded DNA binding antibodies to single-stranded DNA is low. The antibodies are shown to bind to the topoisomers of plasmid DNA as assessed by a gel retardation assay. PMID- 8673014 TI - An investigation of the kinase activity of aurochs heart pyruvate dehydrogenase complex. AB - The purified aurochs heart pyruvate dehydrogenase complex (PDC) saturated to approximation 60% with endogenous thiamine pyrophosphate (TPP), was slowly and incompletely inactivated by its kinase in the presence of ATP. Exogenous TPP or ADP, but not pyruvate, strongly inhibited the kinase activity. The kinetic properties of the aurochs heart PDC kinase suggested the occurrence of two active sites each with different affinities for ATP (K'm - 1.7 microM, K''m = 48 microM). PMID- 8673015 TI - Effect of NAD(P)H:quinone oxidoreductase on tyrosinase-mediated oxidation of opioid neuropeptides Leu-enkephalin and Met-enkephalin. AB - In vitro experiments are reported showing that NAD(P)H:(quinone acceptor) oxidoreductase (QR), purified from Glycine max seedlings, reduces Leu- and Met enkephalin-tyrosinase oxidation products, in the presence of NADH or NADPH. QR was not capable to catalyze the reduction of N-acetyl-dopaquinone formed by the cation of mushroom tyrosinase on N-acetyl-L-tyrosine, while it was able to reduce dopachrome. The results support the hypothesis that QR can inhibit the formation of melanin-like compounds, as catalyzed by the action of tyrosinase on Leu enkephalin and Met-enkephalin. It is proposed that, in the presence of NAD(P)H as the electron donor, the inhibition occurs by the specific conversion of the dopachrome-derivative into the reduced precursor, leucodopachrome-derivative. PMID- 8673016 TI - Evidences for possible involvement of Rhp51 protein in mitotic events including chromosome segregation. AB - To understand the role of the Rhp51 protein in Schizosaccharomyces pombe, we examined the phenotypes of the null mutant for the rhp51+ gene. Unlike Saccharomyces cerevisiae rad51 mutants, S. pombe rhp51 mutants (rhp51delta cells) displayed slow growth and heterogeneity in cell size, indicating perturbation of the cell cycle. Furthermore, many aberrant nuclear structures found in 4',6' diamidino-2-phenylindole (DAPI)-stained rhp51delta cells and the caffeine hypersensitivity of the mutant cells suggested an involvement of the Rhp51 protein in normal chromosome segregation. These data suggested that the Rhp51 proteins were required for normal cell growth as well as a DNA repair pathway. Moreover, rhp51delta mutants showed a considerable sensitivity to ultraviolet (UV) light-irradiation as well as methyl methanesulfonate (MMS) treatment, indicating that the Rhp51 proteins are involved in both the active excision mechanism of UV-induced DNA damage and recombinational repair in S. pombe. Taken together, we suggest that the role(s) of the Rhp51 protein in S. pombe may be different from those of Rad51 in S. cerevisiae. PMID- 8673017 TI - A simple and efficient method for the isolation of total RNA from the fission yeast Schizosaccharomyces pombe. AB - A simple and efficient procedure was described for the isolation of total RNA from the fission yeast Schizosaccharomyces pombe. The present study demonstrated that the quality and the quantity of S. pombe RNA were increased by substituting phenol/chloroform mixture for phenol as a deproteinizing agent in the first vortexing step and using an ice bath instead of a dry ice-ethanol bath in the freezing step. Additionally, this protocol had the advantage of extracting total RNA without any degradation of S. pombe cells. Furthermore, the high amounts and quality of RNA extracted by this modified procedure enabled us to perform some experiments such as Northern blot, S1 mapping, primer extension, and reverse transcriptase reaction-polymerase chain reaction (RT-PCR) without further RNA purification. We suggest that this procedure is very useful to analyse primary structures and steady-state levels of RNA from S. pombe. PMID- 8673018 TI - Oxidative processes in red blood cells from normal and diabetic individuals. AB - The oxidation processes in normal and diabetic erythrocytes after cell exposure to H2O2 and t-butyl hydroperoxide, as well as the effect of malondialdehyde (a stable end product of lipid peroxidation) on erythrocyte membrane structure and stability were studied. The malondialdehyde level began to increase only after oxidation of most of the red blood cell glutathione by peroxides. The activation energy of malondialdehyde was 53 +/- 7 kj/mol. Sodium azide inhibited the oxidation processes induced by t-butyl hydroperoxide. The modification of erythrocytes by malondialdehyde decreased the fluidity of the membrane lipid bilayer measured by fluorescence anisotropy and increased the osmotic stability of the cells. The level of endogenous thiobarbituric acid-reactive species was higher and antioxidative activity was lower in diabetic cells. It seems likely that oxidation processes and accumulation of malondialdehyde can contribute directly to changes in the properties of ?diabetic? red blood cells and may cause the development of long-term complications. PMID- 8673019 TI - Evidence for superoxide radical production in peroxynitrite decomposition. AB - Peroxynitrite decomposition was investigated by ESR spin trapping. The spin trap used was 5,5-dimethyl-1-pyrroline N-oxide (DMPO). A mixture of peroxynitrite and DMPO generated predominantly DMPO-O2- adduct. A combination of SOD and catalase suppressed the formation of DMPO-O2-. The DMPO-O2- signal reached its maximum at pH lower than 7 and decreased as pH increased. The DMPO-O2- signal also depended on peroxynitrite concentration with maximum signal intensity appearing at 4.2 mM. The results demonstrate that peroxynitrite decomposition generates O2.-. Since reaction of H2O2 with NO2- generates peroxynitrite, the results point out a pathway for conversion of H2O2 to O2.- via peroxynitrite as an intermediate. PMID- 8673020 TI - Modelling cortical cataractogenesis 17: in vitro effect of a-lipoic acid on glucose-induced lens membrane damage, a model of diabetic cataractogenesis. AB - The effect of R, S, and racemic forms of a-lipoic acid was tested on the formation of opacity in normal rat lenses incubated with 55.6 mM glucose, as a model for in vivo diabetic cataractogenesis. Control lenses, incubated 8 days with 5.56 mM glucose, did not develop opacities. Formation of lens opacities in vitro was correlated with lactate dehydrogenase (LDH) leakage into the incubation medium. Opacity formation and LDH leakage, resulting from incubation in medium containing 55.6 mM glucose to model diabetes, were both suppressed by the addition of 1 mM R-lipoic acid. Addition of 1 mM racemic lipoic acid reduces these damaging effects to the lens by one-half, while S-lipoic acid potentiated LDH leakage, consistent with the hypothesis that R-lipoic acid is the active form. Although HPLC analysis demonstrated that both stereoisomers of lipoic acid were reduced to dihydrolipoate at comparable rates by the intact lens, the mitochondrial lipoamide dehydrogenase system is highly specific for reduction of exogenous R-lipoic to dihydrolipoic acid. Therefore, stereospecific protection against this opacity is consistent with specific reduction of R-lipoic acid in mitochondria of the vulnerable cells at the lens equator where the first globular degeneration is seen in glucose cataract. PMID- 8673021 TI - alpha-Guanidinoglutaric acid as a free radical generator. AB - alpha-Guanidinoglutaric acid (alpha-GGA) was first isolated from the cobalt induced epileptic focus of cat cerebral cortex by us in 1980. alpha-GGA could induce behavioral convulsion as well as electroencephalography-documented epileptic seizures, when it was administered into the brain. alpha-GGA was also found to be a potent nitric oxide synthase inhibitor, suggesting that suppression of this activity may result in epileptic seizures. It is now observed that alpha GGA generates reactive oxygen species as superoxide and hydroxyl radicals in aqueous solution. These findings suggest that reactive oxygen species may damage cell membranes, thus leading to neuronal depolarization, which is closely related to epileptogenesity. PMID- 8673022 TI - Elucidation of antioxidant activity of dihydrolipoic acid toward hydroxyl radical using a novel hydroxyl radical generator NP-III. AB - The photosensitive organic hydroperoxide, NP-III, which produces hydroxyl radicals on illumination by UVA light, was used to examine the antioxidant activity of dihydrolipoic acid toward hydroxyl radical. Apolipoprotein (apo-B) of human low density lipoprotein (LDL), and bovine serum albumin (BSA), were irradiated with UVA in the presence of NP-III and dihydrolipoic acid. The oxidation of BSA and apo-B of LDL by NP-III was completely inhibited by dihydrolipoic acid. ESR studies using dimethylpyrroline oxide (DMPO) as a spin trapping reagent also revealed that in the presence of dihydrolipoic acid, the DMPO-OH adduct produced from the irradiation of NP-III and DMPO completely disappeared. Hence, the scavenging activity of dihydrolipoic acid is not due to its chelating activity toward transition metals (ferrous ions). The results lead us to conclude that dihydrolipoic acid is an efficient hydroxyl radical scavenger through the direct reaction of dihydrolipoic acid with hydroxyl radical. PMID- 8673023 TI - Alpha-fetoprotein-mediated targeting of anti-cancer drugs to tumor cells in vitro. AB - An oncofetal protein, human alpha-fetoprotein, was selected as a vector molecule for targeted delivery of antitumor substances. Conjugates of alpha-fetoprotein with doxorubicin, daunomycin, calichemicin, carboxyphosphamide, bleomycetin, chlorbutin, cis-platinum, methotrexate were synthesized. All conjugates displayed a highly selective antitumor cytotoxic activity towards human cell cultures. The optimal alpha-fetoprotein:cytotoxic compound ratio was shown to be 1:3 - 1:5. The results obtained serve as a basis for creating antitumor preparations of a new generation, which are highly selective to tumor cells owing to receptor-mediated endocytosis. PMID- 8673024 TI - Synergistic gene expressions of cyclin E, cdk2, cdk5 and E2F-1 during the prolactin-induced G1/S transition in rat Nb2 pre-T lymphoma cells. AB - G1 cyclins and some cyclin-dependent kinases (cdks) have been implicated in the G1/S transition during the eukaryotic cell cycle initiation. The present study demonstrates that the genes of cyclin E, cdk2, cdk5 and the transcriptional factor E2F-1 are expressed during the prolactin (PRL)-induced G1/S transition in rat Nb2 pre-T lymphoma cells. The mRNAs for these four cell cycle regulators were synergistically synthesized and degraded after the stimulation by PRL. The maximal levels of these mRNAs were observed at 8 to 12 h after the PRL addition, while DNA replication reached to the maximum between 12 and 16 h. These results suggest that cyclin E, cdk2, cdk5 and E2F-1 play the roles in the G1/S transition being expressed by a common cellular mechanism(s) in the PRL-stimulated pre-T lymphoma cells. PMID- 8673025 TI - Individual response patterns and treatment matching in the phobic disorders: a review. AB - Studies using response profile treatment matching in the phobic disorders are reviewed. It is argued that the research effort to date is plagued by a multitude of methodological problems which bring into question the validity of the major findings. While there have clearly been some encouraging data, too many inconsistent results exist to offer unqualified endorsement of the procedure. At this point, the optimum strategy for clinicians would appear to involve the inclusion of a treatment component consistent with the dominant response system of the individual patient, but not at the expense of well-established procedures (e.g. graduated in vivo exposure). PMID- 8673026 TI - The factor structure of "schizotypal' traits: a large replication study. AB - The heterogeneity of schizotypal traits, suggested in previous research, was further investigated in a sample of subjects (N = 1095) administered a composite questionnaire consisting of a large number of published scales the majority of which were designed to measure psychotic characteristics. Factor analysis confirmed the four components previously indicated in our work with the same instrument; namely, "aberrant perceptions and beliefs', "cognitive disorganization', "introvertive anhedonia' and "asocial behaviour'. This structure was maintained regardless of whether or not the analysis included scales from the Eysenck Personality Questionnaire, which might otherwise have been held to explain the variance. "Aberrant perceptions and beliefs'-reminiscent of the positive symptoms of schizophrenia-was the strongest component; but, given the multidimensional nature of the data, together with the pattern of factor loadings and intercorrelations for the scales involved, it was concluded that the broader term "psychosis-proneness' or "psychoticism' (in a non-Eysenckian sense) might be a better descriptor of the clinical and personality domain sampled. PMID- 8673027 TI - Aversive stimulation by staff and violence by psychiatric patients. AB - This study investigated the frequency with which violence by psychiatric in patients was preceded by aversive interpersonal stimulation. The precursors of 63 assaults by psychiatric patients on nurses were studied using semi-structured interviews conducted within 72 hours of the assault. Reliability data were collected from staff witnesses and assaultive patients in a subgroup of assaults. Eighty-six per cent of the assaults were immediately preceded by the assaulted nurse having delivered an aversive stimulus to the patient, e.g. frustration, activity demand or physical contact. There were significant associations between diagnosis and the type of aversive stimulation which preceded assaults. Interpersonal factors and diagnosis therefore seem to play a significant role in most violence in psychiatric hospitals and only a minority of patients behave aggressively in the absence of aversive stimulation. An explanation of the link between psychosis and aggressive behaviour in terms of distorted social cognition is discussed. PMID- 8673028 TI - A test of the hopelessness theory of depression in unemployed young adults. AB - Recent research has failed to support the prediction based on hopelessness theory that hopelessness mediates the full relationship between attributional style for negative outcomes and depression. A re-examination of hopelessness theory, however, provides the hypothesis that a measure of hopelessness containing items directly relevant to an ongoing negative life-event will mediate the full relationship between attributional style for negative outcomes and depression. Hopelessness theory was extended with a second hypothesis that attributional style for positive outcomes is involved in the aetiology of depression and that hopelessness also mediates the full relationship between attributional style for positive outcomes and depression. The third hypothesis was that a series of "background variables' (e.g. age, sex) omitted in previous research would be implicated in the generation of depression. The three hypotheses were tested and supported with data collected from a sample of young unemployed adults. A further aspect of hopelessness theory overlooked in most research is an ability to account for reductions in depression associated with the cessation of a negative life-event and occurrence of a positive life-event. The hopelessness theory and the three hypotheses were again supported with data collected from individuals who were unemployed and others who had recently undergone the transition from unemployment to employment. PMID- 8673030 TI - Hunger, caloric preloading and the selective processing of food and body shape words. AB - Fifty-three female subjects performed a modified Stroop colour-naming task 30 minutes after consuming a high-calorie preload, a low-calorie preload or water. Half of the subjects were 18 hours food deprived prior to testing. Food restriction and the caloric density of the preload had no effect on the colour naming of food-related words. However, impairments in the colour-naming of food related words did vary according to the subjects' self-reported hunger level. This relationship between hunger and colour-naming impairment was not linear, with the most hungry subjects displaying the smallest impairment in the colour naming of food words. The results are interpreted in terms of recent thought on the relationship between attentional processing and fear arousal. PMID- 8673029 TI - The Short NART: utility in a memory disorders clinic. AB - Beardsall & Brayne (1990) have introduced a method for estimating full-length National Adult Reading Test (NART) scores using the scores on the first half of the test only. They suggest that this is appropriate for subjects who are of low reading ability and might otherwise find testing distressing. Crawford, Parker, Allan, Jack & Morrison (1991) have subsequently explored the accuracy with which Short NART predicted full NART scores and in addition WAIS IQ scores in a large cross-validation sample. They concluded that the Short NART could be used with modest confidence when estimating premorbid IQ. However, when applied to 202 consecutive referrals to this Memory Disorders Clinic, the accuracy with which the Short NART predicted full NART error scores was less satisfactory. Results indicated that discrepancies between Short NART and full NART error scores were outside the bounds of both clinical and statistical acceptability. Examination of these results revealed that one possible source of difficulty lay in variation in the accuracy with which words are pronounced. It is concluded that, despite the appeal of a shortened version of the NART to estimate premorbid IQ, without further modification its use in clinical practice cannot be recommended. PMID- 8673031 TI - Challenging behaviour and intellectual disability: assessment, analysis and treatment. PMID- 8673032 TI - Aphasia therapy. PMID- 8673033 TI - The IIP-32: a short version of the Inventory of Interpersonal Problems. AB - Three related studies are presented focusing on the development of a short 32 item version of the Inventory of Interpersonal Problems (IIP). Study 1 presents the procedures for item selection on the IIP short version; Study 2 presents a confirmatory analysis of the IIP short version on an independent sample; and Study 3 provides preliminary normative (general population and out-patient) data and additional evidence of the psychometric properties of the IIP short form. The results suggest that the short version sacrifices little compared to the original 127-item version in terms of its psychometric properties while being considerably more convenient for routine clinical practice. PMID- 8673034 TI - Why do patients turn to complementary medicine? An empirical study. AB - Over 250 patients from three complementary medicine practices-acupuncture, osteopathy and homoeopathy-completed a questionnaire rating 20 potential reasons for seeking complementary treatment. The reasons that were most strongly endorsed were "because I value the emphasis on treating the whole person'; "because I believe complementary therapy will be more effective for my problem than orthodox medicine'; "because I believe that complementary medicine will enable me to take a more active part in maintaining my health'; and "because orthodox treatment was not effective for my particular problem'. Five factors were identified, in order of importance: a positive valuation of complementary treatment, the ineffectiveness of orthodox treatment for their complaint, concern about the adverse effects of orthodox medicine, concerns about communication with doctors and, of less importance, the availability of complementary medicine. Groups were compared, using analysis of covariance to control for demographic differences between the three patient groups. Osteopathy patients' reasons indicated they were least concerned about the side effects of orthodox medicine and most influenced by the availability of osteopathy for their complaints. Homoeopathy patients were most strongly influenced by the ineffectiveness of orthodox medicine for their complaints, a fact which was largely accounted for by the chronicity of their complaints. Results are discussed in terms of the limited research in this area. Future studies should separate the reasons for beginning complementary treatment from the reasons for continuing it. It is possible, for instance, that the failure of orthodox medicine is the strongest motive for seeking complementary treatment but that, once treatment has been experienced, other more positive factors become more important. PMID- 8673035 TI - The health beliefs and behaviours of orthodox and complementary medicine clients. AB - This study examined different attitudes towards health and illness among an adult, working, German population. Two hundred and two subjects completed a questionnaire which assessed such beliefs as control over one's health; preventative and restorative measures in staying healthy; perceived efficacy of orthodox vs. complementary medical treatment; the underlying physiological or psychological bases of illnesses, and health consciousness. There was some evidence that females were more inclined to attend complementary forms of treatment, and that younger persons were more likely to consult an orthodox general practitioner, otherwise demographic variables were unrelated to preference for orthodox or complementary forms of treatment. Overall, the complementary medicine (CM) group compared to the general practitioner (GP) group were more critical and sceptical of the effectiveness of orthodox medicine; they felt their health could be improved; they were more loyal to their practitioner, and appeared to display more ecologically aware life-styles. Thus clients who select complementary forms of treatment may do so less from disenchantment with, and bad experience of, orthodox medical techniques rather than from a deep-seated belief in the effectiveness of complementary medicine. PMID- 8673036 TI - Causal attributions for criminal offending and sexual arousal: comparison of child sex offenders with other offenders. AB - Causal attributions for their offending, and for sexual arousal and sexual behaviour, were investigated for 50 males convicted of child sex offences. These attributions were compared with those obtained from 150 males convicted of one of three other criminal offences: rape, property offences and violent offences against persons. In semi-structured interviews, the Offence and Sexual Arousal and Behaviour Attribution Questionnaires were administered. Offenders offered causal attributions for their offending and for their sexual arousal, and they rated these causes on attribution dimensions. Results showed that child sex offenders attributed both their offending and their sexual arousal to internal, stable and uncontrollable causes. Rapists and property offenders attributed their offending behaviour to external, stable and uncontrollable causes; and violent offenders to internal, stable and uncontrollable causes. In contrast to child sex offenders, the other three groups all attributed their sexual arousal and sexual behaviour to external, unstable and controllable causes. The findings are discussed in terms of their implications for intervention programmes. PMID- 8673037 TI - Intellectual impairment among recently abstinent alcohol abusers. AB - Two samples of adequately detoxified hospital-treated alcohol abusers were neuropsychologically assessed for alcohol-related cognitive impairment. Both groups manifested the commonly found impairments on the Wechsler Adult Intelligence Scale (N = 50) and the Revised Wechsler Adult Intelligence Scale (N = 44). In addition, an almost identical pattern of substantial impairment was found when both groups were examined by Russell's (1975, 1988) version of the logical memory and visual reproduction subtests of the Wechsler Memory Scale. A clear pattern of memory impairment for both verbal and non-verbal memory was found. PMID- 8673038 TI - The Symptom Questionnaire: British standardization data. AB - The Symptom Questionnaire is a simple and quick measure of emotional state; previous work has indicated that the Questionnaire has good reliability and validity. However the original sample on which it was based was small, and exclusively North American. Data from a large sample (N = 707) of British psychiatric in-patients, out-patients, day hospital attenders, and a non-patient population sample are presented. Consistent differences between the patient and non-patient samples were obtained on the scales, with a few exceptions; there were no significant differences due to sex. PMID- 8673039 TI - The relations between sociotropy and autonomy, positive and negative affect and two proposed depression subtypes. AB - We examined relations between the cognitive/personality model of sociotropy (SOC) and autonomy (AUT; Beck, 1983) and the affect/personality model of positive affect (PA) and negative affect (NA; Tellegen, 1985; Watson & Clark, 1984, 1992), and their relations to two proposed depression subtypes (Beck, 1983) in 60 adult depressed out-patients. SOC and NA scores shared significant common variance while facets of AUT and low PA were moderately related. Autonomous depressive symptoms appeared more depression-specific than sociotropic depressive symptoms. Findings did not confirm the usefulness of sociotropy and autonomy in the prediction of the symptom clusters, possibly due to the measurement of the depressive symptom clusters. PMID- 8673040 TI - Autologous bone marrow and peripheral blood progenitor cell transplants in small cell lung cancer. PMID- 8673041 TI - Immunologic attributes of cytokine mobilized peripheral blood stem cells and recovery following transplantation. AB - The immunologic attributes of cytokine mobilized peripheral blood stem cell (PSC) products (n = 52) and the resulting reconstitution of the hematopoietic and immunologic system following autologous transplantation were examined in a consecutive population of non-Hodgkin lymphoma (NHL), or solid tumor patients at the University of Nebraska Medical Center. Granulocyte-monocyte colony stimulating factor (GM-CSF)-mobilized PSC products had a high frequency of monocytes (31%) and bands (15%) as compared to normal peripheral blood (PB) cells. The phenotypic analysis of the mobilized PSC product revealed that they had normal levels of CD4+ cells, an increased frequency of CD8+ cells and a corresponding decrease in the CD4+:CD8+ cell ratio as compared to the peripheral blood leukocytes (PBL) of normal individuals. PSC products also had an increase in CD34+ cells as compared to PB. Natural killer (NK) and T cell activity in the PSC products were also lower than that observed in PB. Post-transplantation there was an accelerated reconstitution of NK-cell function in the PB as compared to T cell function (PHA (phytohemagglutinin) mitogenesis) which did not return to normal by day 100 post-transplantation. We also report for the first time high levels of an irradiation resistant suppressor cell activity in the PSC product and in the PB post-transplantation. There was also a concomitant increase in CD4 , CD8-, TCR alpha/beta+ cells (phenotypic homolog of 'natural suppressor' (NS) cells) in the PB post-transplantation. The number of months of prior chemotherapy correlated with PHA response but the NS activity and frequency of CD4-, CD8- and TCR alpha/beta+ cells did not. Further, cytokine mobilization and apheresis appears to contribute to the loss of PHA responsiveness and the increased levels of suppressor cell activity. PMID- 8673042 TI - Cutaneous chronic graft-versus-host disease localized to the field of total lymphoid irradiation. AB - A 20-year-old woman with aplastic anemia underwent bone marrow transplantation from an HLA-identical sibling after total lymphoid irradiation (TLI) and cyclophosphamide (CY). The post-transplant course was uneventful. CYA was discontinued on day 221. Three weeks later, the patient developed cutaneous GVHD precisely localized to the field of TLI. No other organs were involved. Immunohistochemical staining of the affected skin was strongly positive for ICAM 1, PECAM-1 and ELAM-1; normal skin was only weakly positive for ICAM-1. CYA was restarted, and the skin lesions disappeared. TLI may contribute to an unusual presentation of cutaneous GVHD associated with specific expression of adhesion molecules. PMID- 8673043 TI - Refractory thrombocytopenia due to anti-PLA1 antibodies following autologous peripheral blood stem cell transplantation: case report and review of literature. AB - A 43-year-old woman developed life-threatening refractory thrombocytopenia following autologous peripheral blood stem cell transplantation for metastatic breast carcinoma. Anti-PLA1 antibodies were demonstrated in the patient's plasma. Treatment with intravenous immunoglobulin and transfusion of PLA1-negative blood products restored platelet responsiveness. PLA1 allo-antibodies should be considered as a possible cause of severe refractory thrombocytopenia in marrow transplant patients. It is important to make this diagnosis as the mainstay of treatment is the avoidance of blood products from PLA1-positive donors (98% of the population). PMID- 8673044 TI - Bone marrow transplantation in a thalassemia patient with congenital heart disease. AB - We report a thalassemia patient suffering from congenital transposition of the great arteries, surgically corrected according to Mustard technique at the age of 4 months, who underwent bone marrow transplantation. Despite a syncopal episode occurring during the first day after marrow infusion the transplant was successful. Thirty-two months later, normalization of hematologic parameters was observed together with a substantial improvement in cardiac function. PMID- 8673045 TI - Late diagnosis and correction of purine nucleoside phosphorylase deficiency with allogeneic bone marrow transplantation. AB - A 5-year-old boy with spastic quadriplegia, T cell immunodeficiency, hypouricemia and immune cytopenias from age 8 months, was found to have purine nucleoside phosphorylase (PNP) deficiency, and developed chronic lung disease. Successful matched sibling BMT for PNP deficiency has not previously been reported. BMT using marrow from an HLA-identical sibling donor was performed after conditioning with busulfan (16 mg/kg), cyclophosphamide (200 mg/kg), melphalan (90 mg/m2) and anti-thymocyte globulin (36 mg/kg). T lymphocyte numbers, PNP activity and uric acid levels rapidly improved and he remains well 12 months after transplant. PMID- 8673046 TI - Acute graft-versus-host disease in a recipient of a twin blood cell transplant. AB - There are reports of acute graft-versus-host disease (GVHD) after autologous and twin bone marrow transplants but they are controversial because of the difficulty of accurate diagnosis. We report a subject with Philadelphia chromosome-positive CML who received two syngeneic transplants of blood cells. In the first transplant of 2.6 x 10(8) mononuclear cells/kg, no pretransplant conditioning was given; in the second transplant of 4.9 x 10(8) mononuclear cells/kg, pretransplant conditioning therapy consisted of chemotherapy and TBI. Although no symptoms were seen after the first transplant, the second was followed by fever, diarrhea, rash and liver function test abnormalities coincident with engraftment. Symptoms resolved spontaneously. The patient was not on any medication and had not received any transfusions. Our observations suggest either that acute GVHD in a twin transplant is a direct consequence of conditioning or that pretransplant conditioning is a prerequisite for developing features resembling acute GVHD. PMID- 8673047 TI - Do not drink mate. An additional source of infection in South American neutropenic patients. PMID- 8673049 TI - A cell-saving non-radioactive limiting dilution analysis-assay for the combined determination of helper and cytotoxic T lymphocyte precursor frequencies. AB - We have developed a limiting dilution analysis-assay which makes the determination of both helper and cytotoxic T lymphocyte precursor frequencies possible. The way in which T helper precursor frequencies are determined in this combined assay is essentially the same as the method published previously. Experimental conditions for the combined assay have been optimized to obtain cytotoxic T lymphocyte precursor frequencies that are comparable to those determined in the assay routinely used in our laboratory. For all situations where the amount of available cell material is a limiting factor, it will be an advantage that with the same number of cells needed for a standard cytotoxic T lymphocyte precursor frequency determination, in the combined assay both helper and cytotoxic T lymphocyte precursor frequencies can be determined. This is especially convenient in the case of bone marrow transplantation, where evidence is accumulating that low or negative cytotoxic T lymphocyte and/or T helper precursor frequencies may be a prerequisite for a successful transplantation with a minimal risk of graft-versus-host disease. PMID- 8673048 TI - Results of allogeneic bone marrow transplantation for acute leukemia have improved in Europe with time--a report of the acute leukemia working party of the European group for blood and marrow transplantation (EBMT). AB - To evaluate whether the results of bone marrow transplantation have improved in Europe with time, we analyzed the outcome for 2195 patients with acute leukemia. 1405 had acute myeloid leukemia (AML) and 790 had acute lymphoblastic leukemia (ALL), and were allografted in first complete remission between September 1979 and December 1991 with marrow from an HLA-identical sibling donor. We found a continuing improvement more evident since 1987 for AML and since 1986 for ALL. A substantial reduction in the 3 years transplant related mortality (TRM): 26 vs 39% for AML (P = 10(-4)), and 25 vs 39% for ALL (P = 10(-4)), has resulted in an increase of the 5-year actuarial leukemia-free survival (LFS). 57 vs 45% for AML (P < 10(-4)) and 54 vs 45% (P = 10(-4)) for ALL. Four important changes have occurred. (1) Graft-versus-host disease (GVHD) prevention has involved an increased use of cyclosporin A (CsA) alone and subsequently its use in combination with methotrexate: this was associated with lower TRM both in AML and ALL; (2) Use of total body irradiation as pretransplant regimen has decreased; (3) a shorter interval from remission to BMT is more common; (4) an older population of patients has undergone BMT. Multivariate analyses were performed separately in AML and ALL. In AML four variables significantly influenced TRM favorably: year of BMT (P = 10(-4)), younger age at BMT (P = 10(-4)), prevention of GVHD including CsA (P = 0.008), sex match other than female donor to male recipient (P = 0.002). The relapse incidence (RI) was lower in patients with FAB M1-2-3 vs M4-5 (P = 0.0004). The LFS improved by year of BMT (P = 0.0004), younger age at BMT (P = 10(-4)), prevention of GVHD including CsA (P = 0.01), FAB M1-2-3 (P = 0.03). In ALL, three variables were associated with a lower TRM: year of BMT (P = 10(-4)), younger age at BMT (P = 10(-4)), sex combination other than female to male (P = 0.008). The LFS was better after 1986 (P = 0.0004) and in younger patients (P = 10(-4)). However a better outcome after 1986/87 was observed in patients receiving the same GVHD prophylaxis: therefore, other unidentified factors resulting in better patient care have also contributed to this. The improved results of allogeneic BMT are entirely related to a reduction in TRM without loss of the antileukemic effect since relapse incidence has not changed over the years. PMID- 8673050 TI - Myelosuppressive chemotherapy to mobilize normal stem cells in chronic myeloid leukemia. AB - Ten patients with Ph+ chronic myeloid leukemia (CML) were treated with idarubicin, cytarabine and etoposide followed by G-CSF to harvest Ph-negative progenitor cells. Six were in first chronic phase (CP1), and four beyond CP1. Between two and six aphereses (median 3, total 36) were performed starting 9-26 days (median 14.5) after chemotherapy when the leukocyte count was 0.6-4.7 x 10(9)/l (median 1.2). 1.3-3.6 x 10(8) mononuclear cells/kg (median 2.8), 0-128.4 x 10(4) CFU-GM/kg (median 1.2; seven patients) and 0.3-25.1 x 10(6) CD34+ cells/kg (median 9.8; seven patients) were collected. Seven of 27 harvests showing metaphases were 100% Ph-negative, 11 partially Ph-negative, and nine were 100% Ph+. All three patients with 100% Ph-negative collections were in CP1 and within 4-26 months of diagnosis. Four of six CP1 patients showed significant cytogenetic response compared with none of four beyond CP1 (P = 0.036). The absolute neutrophil count remained < 0.5 x 10(9)/l for 9-44 days (median 15.5) following chemotherapy. Four patients (three Ph-negative) were autografted after 16 mg/kg busulfan (n = 2) or 200 mg/m2 melphalan (n = 2). One of the three patients receiving Ph-negative cells died of graft failure, and two are alive with 15% and 50% Ph-negative cells at 15 and 11 months on interferon-alpha. We conclude that it is possible to harvest Ph-negative cells after myelosuppressive chemotherapy in some CML patients treated early in the course of CP1. However, in view of lack of consistent response, investigation of alternative approaches is necessary. PMID- 8673051 TI - Use of recombinant human granulocyte colony-stimulating factor in children given allogeneic bone marrow transplantation for acute or chronic leukemia. AB - The role of recombinant human granulocyte colony-stimulating factor (rHuG-CSF) in myeloid recovery of children given an allogeneic bone marrow transplant (BMT) from an HLA-identical sibling for acute leukemia was evaluated in a retrospectively historically controlled study, involving 20 consecutive treated patients and 30 historical controls. In order to investigate the efficacy of rHuG CSF in patients given a matched unrelated BMT with methotrexate as part of graft versus-host disease (GVHD) prophylaxis, we also analyzed the kinetics of engraftment in eight further children with acute or chronic leukemia, transplanted using a volunteer donor. Patients were treated with 5 micrograms/kg/day of rHuG-CSF by 1-h intravenous infusion from day +5 until the absolute neutrophil count (ANC) was > or = 2 x 10(9)/l. No adverse effect related to treatment was observed in any patients. Children transplanted from an HLA identical sibling and treated with rHuG-CSF reached an ANC count greater than 0.5 x 10(9)/l, 1 x 10(9)/l and of 2 x 10(9)/l in a significantly shorter time than the control group (day +9, +10 and +12, vs day +15, +22 and +29, respectively). An accelerated granulocyte production was also observed in patients receiving an unrelated transplant after a GVHD prophylaxis schedule including methotrexate, the median time to neutrophil recovery above 0.5 x 10(9)/l, 1 x 10(9)/l and 2 x 10(9)/l being +14, +15 and +17 days, respectively. In comparison to historical controls, all rHuG-CSF-treated patients had fewer days of fever, of antibiotic therapy and, only for children with HLA-compatible siblings, of hospitalization, whereas in the three groups the duration and severity of mucositis were comparable. No difference between the rHuG-CSF-treated patients and the historical controls given BMT from HLA-identical sibling was seen with regard to incidence of acute or chronic GVHD, relapse rate and actuarial event-free survival at day +100 and 1 year after transplantation. Our data suggest that in children given allogeneic BMT for acute or chronic leukemia, rHuG-CSF reduces duration of neutropenia, without increasing the rate of relapse or the incidence and severity of GVHD. PMID- 8673052 TI - Outcome of second bone marrow transplantation following a uniform conditioning regimen as therapy for malignant relapse. AB - Twenty-three second bone marrow transplants (BMT) were performed between October 1987 and January 1994 for patients with malignant relapse following initial BMT. For first BMT, twenty-one of 23 (91%) were conditioned with cyclophosphamide plus total body irradiation. For second BMT, a uniform conditioning regimen consisting of busulfan and cyclophosphamide was used. Eleven patients had chronic myelogenous leukemia, seven acute leukemia, four lymphoma, and one myelodysplastic syndrome. Median patient age at second BMT was 32 years, the median time between first BMT and relapse was 22 months, and the median time to second BMT after relapse was 5 months. The second BMT marrow source included: autologous marrow (1), unrelated donors (4), new matched sibling donors (5) and same matched sibling donors as the first BMT (13). The Kaplan-Meier disease-free survival and survival rates at 3 years were 38 and 43%, respectively (median follow-up of survivors was 45 and 48 months, respectively), and five patients survive disease-free at 4-6 years. Nine of the 13 deaths occurred within 100 days after second BMT; eight had relapsed within 1 year of the first BMT. We conclude that: (1) second BMT can offer durable long-term survival in certain patients, especially those who relapse late after first transplant; (2) busulfan and cyclophosphamide is a suitable conditioning regimen for second BMT. PMID- 8673053 TI - Unrelated donor bone marrow transplantation for Fanconi anemia. AB - Patients with Fanconi anemia (FA) commonly develop bone marrow failure, which may evolve to myelodysplasia or acute myeloid leukemia (AML). Treatment of these patients is complicated by their marked hypersensitivity to DNA cross-linking agents. In this report we describe the results of allogeneic unrelated donor bone marrow transplantation in seven FA patients, using a low-dose cyclophosphamide (40 mg/kg) and TBI (400-450 cGy) conditioning regimen. Two patients had bone marrow failure with normal chromosomes and no dysplasia prior to transplant. The remaining five had clonal chromosomal abnormalities. One patient had refractory anemia with excess blasts in transformation and two had early AML with 20 and 25% blasts, respectively. Two patients died early (before day 28) without hematological evidence of engraftment, one of veno-occlusive disease and one of infection (fungal). Four of the remaining five patients achieved sustained engraftment after the first marrow infusion; one patient had secondary graft failure requiring repeat marrow infusion but subsequently achieved engraftment. Of five evaluable patients, three had mild (grades I-II) acute GVHD and two had grade IV GVHD, which was fatal in both cases. Two of three evaluable surviving patients have chronic GVHD controlled with immunosuppression. Three patients survive 9 months to 3 years post-unrelated donor BMT: two who had early leukemia and one with severe aplasia at the time of transplant. These data indicate that unrelated donor BMT can be performed successfully in FA patients using cyclophosphamide 40 mg/kg and TBI 400 to 450 cGy, even after evolution to early leukemia. However, significant problems with both GVHD and engraftment remain. Future studies will evaluate the role of T cell depletion in improving the results of unrelated donor marrow transplantation in FA patients. PMID- 8673054 TI - Partially mismatched related donor transplants as salvage therapy for patients with refractory leukemia who relapse post-BMT. AB - Patients who relapse post-ABMT are usually resistant to conventional therapy, and a potentially curative therapy with allogeneic BMT is limited due to availability of a matched donor. To assess whether such patients can be salvaged using partially mismatched related donors (PMRD), eight patients age 6-50 years old underwent PMRD-BMT. All patients ALL (n = 3) and AML (n = 5) were in relapse 7-31 months after first BMT. Donors (1-3 Ag mismatch) were selected from family members. Conditioning included TBI, etoposide, Ara-C and cytoxan (n = 3), or busulfan, thiotepa, and etoposide (n = 5). GVHD prophylaxis consisted of partial T cell depletion followed by systemic immunosuppression. All evaluable patients established sustained engraftment by day 18. Severe regimen-related toxicity was evident in the gastrointestinal and hepatic systems (6/8 and 4/8, respectively), the latter associated with poor outcome (P < 0.014). Acute but not chronic GVHD, grade > or = II occurred in 3/7 patients. Four of eight patients are disease free, maintaining longer remission than following their first BMT (14 vs 9 months). In conclusion, our data shows that PMRD-BMT is a feasible option for patients who relapse post-BMT and use of such alloreactive grafts may be appropriate earlier in the disease course of high risk patients. PMID- 8673055 TI - Gonadal damage and effects on fertility in adult patients with haematological malignancy undergoing stem cell transplantation. AB - Gonadal damage, often associated with irreversible failure, is an invariable effect of high-dose myeloablative chemotherapy used for allogeneic or autologous bone marrow transplantation. Although not life threatening, the psychological consequences are significant. Therefore semen cryopreservation is advisable prior to initial therapy, but oocyte storage is not yet possible and embryo cryopreservation seldom feasible. Treatment protocols should be carefully selected to maximise cure rates whilst limiting injury to the reproductive system. Involvement of a reproductive endocrinologist is thus ideal from presentation, and certainly necessary pretransplant and for long-term follow-up in order to provide the endocrine assessment, counselling and fertility management which are essential for adequate transplant care. Improvement in bone marrow transplant technology and more rigorous patient selection have resulted in a higher proportion of long-term survivors. This has increased the awareness of long-term effects, such as gonadal failure, which may become apparent several months or years after transplantation. Premature ovarian and testicular failure may be overlooked by physicians managing the life-threatening disease, but for patients, the physical, emotional, psychological and social consequences of functional castration consequent on high-dose therapy can be devastating. The pathophysiology, diagnosis and management of gonadal failure are reviewed here. PMID- 8673056 TI - Unrelated donor marrow transplantation: initial experience of the Italian bone marrow transplant group (GITMO). AB - From 1 September 1988 to 30 September 1993, a search for an unrelated donor (URD) was started for 633 Italian patients. Eighty-five of them (13%) were transplanted. Despite the introduction of more strict criteria for the selection of compatible donors, the percentage of patients who reached transplant increased significantly after December 1992. For patients who started a search before and after January 1993, respectively the probability of transplant by 8 and 16 months from search activation was 4 and 10%, compared to 22 and 37% (P = 0.0001). The average intervals between search activation and graft were 15 and 8 months respectively, for the first and second group (P = 0.0001). Data of 75 consecutive transplants performed up to March 1994 were analyzed. Actuarial 2-year survival was 15% for patients grafted before 1992 and 40% for those grafted after January 1992. In this latter period, survival of patients with malignant and non malignant disorders was 32 and 67%, respectively. In univariate analysis, patients younger than 16 years (P = 0.01), patients grafted after 1992 (P = 0.01) and patients receiving the marrow from a 6-antigen matched donor (P = 0.01) showed a higher survival probability. Multivariate analysis did not show any difference, probably due to the low number of patients and to short follow-up. The adoption of stricter and more accurate HLA-matching criteria and the consequent reduction of deaths related to acute GVHD were the main reasons for the improvement of survival observed in patients grafted after 1992. PMID- 8673057 TI - Iron overload and liver dysfunction after allogeneic or autologous bone marrow transplantation. AB - Patients who require a bone marrow transplant (BMT) for leukaemia, lymphoma or other haematological disorders receive large quantities of blood products, including red cell concentrates, during the transplant period. Many receive red cell transfusions as part of treatment prior to BMT, adding to the potential iron load. However, organ dysfunction as a consequence of the transfused iron load would be surprising given the amounts of iron transfused. We studied 76 survivors of allogeneic and autologous BMT who were at least 1 year post-transplant and found that the majority (88%) had raised ferritins. Impaired liver function was common in these patients and in half was unexplained by viral hepatitis, veno occlusive disease or graft-versus-host disease (GVHD), suggesting that iron overload may be an important contributing factor to liver disease in the stable post-transplant setting. This view is supported by the observation of improving liver function tests in 10 patients after a trial of venesection therapy. PMID- 8673058 TI - Multi-organ dysfunction associated with high-dose carboplatin therapy prior to autologous transplantation. AB - The specific contribution of high-dose carboplatin to regimen-related toxicity after autologous transplantation has been difficult to determine, particularly in patients receiving cyclophosphamide or ifosfamide. We report five cases of severe multi-system failure in patients receiving high-dose carboplatin in addition to other cytotoxics prior to autologous transplantation. Two of these patients did not receive ifosfamide or cyclophosphamide as part of their chemotherapy. The clinical picture consisted of early onset acute renal failure, arrhythmias and/or myocardial hypokinesia, mental obtundation and other neurological deficits and, in two patients, an acute myopathy. In the two patients in whom serum platinum was measured, levels were very high at the time of marrow infusion. All patients had received prior cisplatin therapy but showed either normal or only modestly impaired creatinine clearance before the transplant. These observations are consistent with a specific clinical syndrome associated with carboplatin toxicity and suggest that creatinine clearance may be inadequate as an indicator of potential renal failure when high-dose carboplatin is used. PMID- 8673060 TI - Pilot study of combined cryosupernatant and protein A immunoadsorption exchange in the treatment of grade 3-4 bone marrow transplant-associated thrombotic microangiopathy. AB - Bone marrow transplant-associated thrombotic microangiopathy (BMT-TM) ranges in severity from a self-limiting to a fatal disorder. There is no specific therapy for this condition to date. We have previously described a simple clinical grading system (grade 0-4) for BMT-TM; patients with grade 3-4 BMT-TM do poorly. A previous study in our institution suggested that a combination of exchange with cryosupernatant replacement and protein-A immunoadsorption (PAI) might be of benefit. Therefore we performed a pilot study to evaluate the effectiveness of cryosupernatant alternating with PAI exchange for 2 weeks in a series of 13 patients with grade 3-4 BMT-TM. Twelve of 13 patients had undergone allogeneic BMT a median of 25 days (range of 5-458 days) prior to the onset of grade 3-4 BMT TM. The thirteenth patient had undergone autologous peripheral stem cell transplant 11 days prior to grade 4 BMT-TM. Pre-therapy, 10 patients had grade 4 BMT-TM and three had grade 3. Eight (62%) showed a response to treatment. Post therapy, four responders had grade 3, three had grade 2 and one had grade 0 BMT TM. The median follow-up of the responders is 90 days (range 21 to 464). Three responders have died at 21, 44, and 226 days following the development of BMT-TM of interstitial pneumonia in one, aspergillus in one, and multiorgan failure syndrome (MOFS) in one. The remaining responders are alive 66-465 days post-TM. All non-responders died of MOFS at 6-31 days post-TM. These results suggest that combined exchange with cryosupernatant alternating with PAI is effective therapy for some patients with moderate to severe BMT-TM and may improve survival. PMID- 8673061 TI - Non-tunneled catheters in children undergoing bone marrow transplantation. AB - We analyzed the use of non-tunneled (polyurethane double lumen) central venous catheters (CVCs) in 62 children undergoing bone marrow transplantation. The catheters were inserted in the Critical Care Unit without surgery or general anesthesia. The complications were pneumothorax in two patients and hemopneumothorax in two other patients (6.06%), entry site infection in six patients (9.6%), catheter-related infection in eight patients (12.9%) and catheter-related sepsis in nine patients (14.5%). The catheters were removed upon completion of therapy in 46 patients (74.1%), death in seven patients (11.3%) and in nine cases (14.5%) for infection. Despite the complications specific to non tunneled catheter insertion, we believe this is indicated for patients during conditioning, transplantation and immediate post-transplantation periods. PMID- 8673059 TI - Risk factors for hepatic veno-occlusive disease following HLA-identical sibling bone marrow transplants for leukemia. AB - The objective was to analyze risk factors for veno-occlusive disease of the liver (VOD) after allogeneic bone marrow transplantation. A cohort of 1717 recipients of HLA-identical sibling transplants for leukemia between 1988 and 1990, in 200 transplant teams worldwide, was studied. Patients were scored as having VOD if liver tissue showed typical histologic features or if they had all three of the following: (1) jaundice; (2) hepatomegaly and right upper quadrant abdominal pain; and (3) ascites and/or unexplained weight gain. Patients surviving more than 7 days post-transplant without histologic or any of these clinical features of VOD were classified as not having VOD. Patient-, disease- and transplant related characteristics of 95 patients with VOD were compared to those of 1514 without VOD. Variables correlated with an increased risk of VOD were: pretransplant conditioning with busulfan and cyclophosphamide compared to total body radiation (relative risk (RR) 2.8; P < 0.0001), pretransplant fungal infection (RR 4.1; P = 0.011), pretransplant Karnofsky performance score < 90% (RR 1.9; P = 0.012), prior liver disease (RR 1.9; P = 0.05) and age > 20 years (RR 1.8; P = 0.05). In patients receiving radiation for conditioning, intravenous immune globulin decreased VOD risk (RR 0.26; P = 0.003). This analysis identifies risk factors for VOD. The data suggest several strategies for modifying transplant regimens to reduce VOD risk and which patients might be suitable subjects for trials of strategies of VOD prevention. PMID- 8673062 TI - Criteria for marrow engraftment: comparison of reticulocyte maturity index with conventional parameters. AB - Reticulocyte maturity index (RMI) has recently been proposed as an early indicator of marrow engraftment. We compared the RMI with conventional bone marrow engraftment criteria including total leukocyte count (WBC), absolute neutrophil count (ANC), reticulocyte count (RC) and the day of last platelet transfusion required to maintain the platelet count (PC) > or = 20 x 10(9)/l in 37 patients undergoing allo- or autologous BMT. There was no discrepancy in predicting engraftment between RMI, ANC, WBC and RC. RMI indicated engraftment earlier (median day 17, range 10-63 days) than the ANC (median day 19, range 8-63 days), WBC (median day 19, 9-71), RC (median day 19, 11-125) or PC (median day 29, 11-237). RMI heralded engraftment preceded ANC, WBC, RC or PC in 22, 21, 34 and 32 patients, respectively. RMI signal occurred 6 days prior to the rise in ANC in patients who engrafted later than 25 days (n = 7). Trend analysis showed that ANC fluctuated more frequently (6/37 patients) than RMI (1/37). Combined use of ANC and RMI (whichever increased first) predicted engraftment earlier (median 15 days) and more confidently (no false starts) than either used alone. PMID- 8673063 TI - Delayed engraftment of 4-hydroperoxycyclophosphamide-purged autologous bone marrow after induction treatment containing mitoxantrone for acute myelogenous leukemia. AB - We have previously documented that adults with de novo acute myelogenous leukemia (AML) who are induced into first complete remission with mitoxantrone and high dose cytarabine are more likely than those induced with daunorubicin and high dose cytarabine to develop a bone marrow injury pattern with delayed cytopenias after achieving initial complete remission, a phenomenon we have termed post remission cytopenia syndrome. We therefore retrospectively compared the engraftment kinetics of mitoxantrone and daunorubicin patients following 4 hydroperoxycyclophosphamide (4HC) purged autologous bone marrow transplant (ABMT) with busulfan-etoposide conditioning. Despite equivalent graft colony forming units granulocyte macrophage (CFU-GM), mitoxantrone patients (n = 13) took a median 7 weeks longer to achieve 1.0 x 10(9)/l granulocytes, 5 weeks longer to achieve platelet transfusion independence, and 10 weeks longer to achieve red blood cell transfusion independence, and required more platelet transfusions (P = 0.008), than daunorubicin patients (n = 13). Patients experiencing the post remission cytopenia syndrome (n = 11) had significantly slower engraftment than those not experiencing the syndrome (n = 15; P < or = 0.04). Two mitoxantrone and five daunorubicin patients have relapsed after ABMT (P = 0.38). We conclude that the type of induction chemotherapy used in untreated adults with de novo AML can influence subsequent engraftment after 4HC-purged ABMT. We believe that mitoxantrone combined with high-dose cytarabine should be avoided as induction chemotherapy in patients for whom 4HC-purged ABMT is planned. PMID- 8673064 TI - The role of cdc2, cdc25 and cyclin A genes in the maintenance of immortalization and growth arrest in a rat embryonic fibroblast conditional cell line. AB - Immortalization of rodent cells by oncogenes is a complex biological process which involves the abnormal regulation of genes who control cellular proliferation. The role of the cell cycle control genes cdc2, cdc25 and cyclin A in the maintenance of immortalization and in growth arrest was examined in the tsa14, a SV40 T antigen rat embryonic fibroblast conditional for growth cell line. Analysis of RNA expression showed minimal levels of cdc2 mRNA in both proliferating and growth-arrested tsa14 cells. In contrast, cyclin A mRNA was found downregulated in growth-arrested tsa14 cells, as well as in senescent primary rat embryonic fibroblasts (REFS). The ability of cdc2, or cdc25, or cyclin A genes to maintain the tsa14 immortal phenotype was also examined by electroporations of these genes into the tsa14 cells. Clones over-expressing the electroporated cdc2, or cdc25, or cyclin A, or combinations of these genes growth arrested at the non-permissive conditions similar to controls, thereby suggesting that the expression of these genes alone is insufficient for tsa14 maintenance of immortalization. PMID- 8673065 TI - Ontogeny of angiotensin II receptors. AB - Aside from the well known role of angiotensin II (Ang II) in blood pressure regulation and fluid homeostasis, accumulating evidence suggests that the octapeptide hormone also plays a role in growth and development. There are two major classes of Ang II receptors (AT1 and AT2) which mediate Ang II action. Both classes are members of the large superfamily of seven transmembrane domain spanning receptors. Fetal tissue express high levels of AT receptors. Throughout fetal and postpartum life, the AT1 and AT2 tissue distribution changes dramatically. The evolution of each receptor type is distinct and varies according to the organ. Thus, the different patterns of temporal expression of each receptor class could be related to various roles that Ang II may play during development. PMID- 8673066 TI - Collagen synthesis and cell growth in chick embryo fibroblasts: influence of colchicine, cytochalasin B and concanavalin A. AB - Culturing of chick embryo fibroblasts in the presence of colchicine or cytochalasin B with and without concanavalin A (Con A) demonstrated that colchicine induces greater neosynthesis of endocellular type I collagen, whereas cytochalasin B boosts secretion. The effects are modified by the addition of Con A, which increases alpha 2 more than a1 chain production. 3H-thymidine incorporation is unaffected by cytochalasin B, but stimulated by colchicine. Con A neutralizes the stimulatory action of colchicine. It would therefore seem that Con A exerts transmembrane control of effects induced by colchicine and cytochalasin B by binding to cell surface receptors and so triggering rearrangement of the cytoskeleton. PMID- 8673067 TI - Muscarinic acetylcholine receptor subtype mRNAs in the human and rat vestibular periphery. AB - The expression of the five muscarinic acetylcholine receptor (mAChR) subtypes (m1 m5) in the vestibular end-organs and in the primary afferent vestibular ganglia of the human and rat was studied using RT-PCR from the two tissue populations from both species. In the human, although all five mAChR subtypes were expressed in brain, only the m1, m2, and m5 mAChR subtypes were amplified from both the vestibular ganglia and the vestibular end-organs, while in the rat, all five mAChR subtypes were expressed. These data suggest that the efferent cholinergic axo-dendritic and axo-somatic synapses have a muscarinic component and that there are pharmacologic implications for patients with vestibular dysfunction. PMID- 8673068 TI - Distribution of annexin I during non-pathogen or pathogen phagocytosis by confocal imaging and immunogold electron microscopy. AB - Annexin I is an abundant protein in U937 cells differentiated towards a macrophagic phenotype. These cells become able to kill Escherichia coli, however, the intracellular pathogen Brucella suis, known to interfere with phagosome maturation, multiply in these differentiated cells. We have analysed by confocal and electron microscopy the cellular localization of annexin I during phagocytosis of yeast, non-pathogenic E. coli and the intracellular pathogen B. suis. Using immunocytochemical detections annexin I was found mainly as patches in the cytoplasm of uninfected cells. Upon phagocytosis of yeast or E. coli organisms, annexin I rapidly translocated and concentrated around phagosomes. On the other hand, annexin I was never detected around live B. suis-containing phagosomes. However, when dead brucellae were used, annexin I did translocate to the periphagosomal region. Our results suggest that annexin I could play a role in the molecular mechanism of phagosome maturation, which is impaired by some intracellular pathogens. PMID- 8673069 TI - Antisense inhibition of the 27 kDa heat shock protein production affects growth rate and cytoskeletal organization in MCF-7 cells. AB - MCF-7 cells were co-transfected with the human HSP27 antisense cDNA and the neomycin resistance gene, included in the constitutive expression vector pSVL, and the phenotypical changes associated with decreased expression of the HSP27 protein were analysed. Three out of 10 neomycin-resistant clones obtained proliferated normally and showed a normal HSP27 content (Western blot). The seven other clones (designated as alpha HSP27 clones) were characterized by a dramatic growth inhibition associated with alterations in cellular morphology. Cells became progressively hypertrophied, exhibited lamellar protrusions and tended to lose contact with each other. They also acquired characteristics of secretory cells, namely the presence of numerous refractile granules and secretory canaliculi. Among the alpha HSP27 clones, two were immunocytochemically analysed for HSP27 content. Both clones were immunonegative for HSP27, contrary to parental cells and neo-transfectants. Actin immunostaining in one of these HSP27 negative clones revealed that microfilament organization changed from diffuse to punctate distribution. Our data support the current concept of a role for HSP27 in cell growth and differentiation and further suggests that this might occur through a control on actin polymerization-depolymerization. PMID- 8673070 TI - Digital image analysis of chromatin fibre phenotype after "in situ' digestion with restriction endonucleases. AB - Restriction Endonucleases (REs) may recognize, cleave and remove DNA from fixed chromatin producing specific chromosome banding patterns. However, the modifications produced in the chromatin fibre are not easy to evaluate and compare. The aim of the present investigation was to visualize differences resulting in the texture of the chromatin fibre from metaphase chromosomes after each digestion using digital image analysis (DIA) facilities. To this purpose, metaphase chromosomes derived from a L-929 mouse cell line were digested with different REs (AluI, HpaII and HaeIII). Since light microscopy does not permit the observation of the chromatin fibre, DIA was performed on digitalized images of metaphase chromosomes under electron microscopy. The application of a LUT (Look Up Table) within the DIA software assigns a colour to each grey level of a digital image. The results obtained using a particular LUT, which permits the discrimination of specific chromatin fibre phenotypes resulting from each digestion, are reported and compared with those obtained under the light microscope. PMID- 8673071 TI - Synthesis and biological evaluation of new diisocyanide- and triisocyanide-99mTc complexes. AB - This paper describes the synthesis of four new polyisocyanides (three diisocyanides and one triisocyanide). The complexation of 99mTc with these ligands is also studied through chromatography and revealed the formation of hexacoordinated 99mTc+1 complexes. Finally, biodistributions of these complexes in mice are given and compared. Heart captations are lower than the ones with [99mTc(MIBI)6]+ but remain constant and a satisfactory lungs clearance, probably due to the metabolization of the ligands, is observed. PMID- 8673072 TI - Synthesis and preliminary evaluation of [11C]KF17837, a selective adenosine A2A antagonist. AB - An 11C-labeled selective adenosine A2A antagonist, (E)-8-(3,4-dimethoxystyryl) 1,3-dipropyl-7-[11C]-methylxanthine ([11C]KF17837), was prepared by reaction of (E)-8-(3,4-dimethoxystyryl)-1,3-dipropylxanthine and [11C]methyl iodide with decay-corrected radiochemical yield of 19-50%, radiochemical purity of > 99%, sp. act. of 17-100 GBq/mumol and preparation time of 20-25 min. In mice, the myocardium showed the highest (13.4% ID/g) at 5 min after i.v. injection, which decreased gradually with time. The specific myocardial uptake was visualized by gamma-camera. In the brain region the radioactivity level was higher in the A2A receptors-rich striatum than in the cortex and cerebellum. The specific striatal uptake in rats was clearly demonstrated by PET. These results have shown that [11C]KF17837 is a potential PET radioligand for mapping the adenosine A2A receptors in the heart and brain. PMID- 8673073 TI - An evaluation of the environmental implications of petroleum refinery emissions by multielemental neutron activation analysis of rumen fluid ash of buffaloes. AB - In order to study environmental pollution in and around a petroleum refinery complex, a multielemental instrumental neutron activation analysis (INAA) method was used to assay concentrations of As, Ba, Br, Cl, Co, Cr, Cs, Cu, Fe, Hg, La, Mn, Mo, K, Na, P, Sc, Rb, Se, Sr, W and Zn in the rumen fluid ash samples of buffaloes from the vicinity of the refinery. Corresponding samples from a control area 300 km away from the refinery were analysed. Standard Reference Materials, Bovine liver (SRM 1577a), Oyster tissue (SRM 1566a) and Animal bone (CRM H-5) were also analysed for quality control. Samples were irradiated with thermal neutrons at 10(12)-10(13) n cm-2 s-1 and counted by high-resolution gamma spectrometry. Mean elemental concentrations of As, Ba, Br, Cr, Hg and Fe were found to be enhanced, whereas those of Na, K, Cl, Cu, Mn and P were depleted in samples from the vicinity of the refinery complex compared to controls. The environmental implications of anomalous elemental concentrations are discussed. PMID- 8673074 TI - Molecular cloning and function expression of a diuretic hormone receptor from the house cricket, Acheta domesticus. AB - Insect diuretic hormones regulate fluid and ion secretion and the receptors with which they interact are attractive targets for new insect control agents. Recently, a diuretic hormone receptor from the moth Manduca sexta was isolated by expression cloning and found to be a member of the calcitonin/secretin/corticotropin releasing factor family of G-protein coupled receptors [Reagan J. D. (1994) J. Biol. Chem. 269, 9-12]. Degenerate oligonucleotides were designed based upon conserved regions in this receptor family and used to isolate a diuretic hormone receptor from the house cricket, Acheta domesticus. The complementary DNA isolated encodes a protein consisting of 441 amino acids with seven putative membrane spanning regions. Interestingly, unlike the M. sexta diuretic hormone receptor, the cricket diuretic hormone receptor contains a putative signal sequence. The receptor shares 53% and 38% sequence identity with the M. sexta diuretic hormone and human corticotropin releasing factor receptors respectively. When expressed in COS-7 cells, the receptor binds A. domesticus diuretic hormone with high affinity and stimulates adenylate cyclase with high potency. Four other insect diuretic hormones are considerably less effective at stimulating adenylate cyclase in COS-7 cells transfected with the receptor. This is in contrast to the M. sexta diuretic hormone receptor which is stimulated by all five insect diuretic hormones with high potency. PMID- 8673075 TI - Catabolism of dopamine and 5-hydroxytryptamine by monoamine oxidase in the ixodid tick, Amblyomma hebraeum. AB - The purpose of this study was to assess biogenic amine catabolism in Amblyomma hebraeum Koch (an African cattle tick). We assayed haemolymph and saliva for a variety of biogenic amines (usually following injection of substrate into the haemolymph) in partially fed females using HPLC coupled to electrochemical detection. Dopamine (DA) and 5-hydroxytryptamine (5-HT) were rapidly converted to dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) respectively, indicating that monoamine oxidase (MAO) constitutes a major catabolic pathway for biogenic amines in this species. We could not detect N acetylated or gamma-glutamyl conjugated metabolites of these important neurotransmitters. [In a few samples we looked for but could not detect homovanillic acid or 3-methoxytyramine (O-methylated metabolites of DOPAC and DA respectively).] Deprenyl was about 44-72 times more potent an inhibitor of MAO than clorgyline when either DA or 5-HT was offered as substrate, suggesting that this MAO is of the MAOB type. Conversion of DA to DOPAC was also detected in several tissues incubated with DA in vitro; in descending order of MAO activity (pmol mg-1 h-1 at about 18 degrees C) tissues tested were: skeletal muscle (approximately 100), Malpighian tubule (approximately 50), ovary (approximately 45), salivary gland (approximately 30), midgut (approximately 20), and haemolymph (approximately 4-5). This study suggests that ticks differ considerably from insects in utilizing MAO as an important metabolic pathway for biogenic amines. PMID- 8673076 TI - Putative odorant-binding protein in antennae and legs of Carausius morosus (Insecta, Phasmatodea). AB - A 19 kDa protein has been purified by gel filtration and anion-exchange chromatography from the antennae of Carausius morosus. Its amino terminal amino acid sequence shows significant similarity (30% identity) with another putative odorant-binding protein, the so called OS-D protein isolated from the antennae of Drosophila melanogaster; only 20% of its amino acids are shared with some members of Lepidoptera pheromone-binding proteins. Polyclonal antibodies, raised against a synthetic amino terminal peptide cross-react with 19 kDa band in the legs extracts, but not with soluble proteins from other parts of the body. The amino terminal sequence of this protein, purified from the legs was identical with that of the antennal protein. PMID- 8673077 TI - Bombyxin-related peptides: cDNA structure and expression in the brain of the hornworm Agrius convolvuli [corrected]. AB - We have cloned three cDNAs from the sweet potato hornworm Agrius convolvuli that encode precursor molecules for peptides structurally related to bombyxin, an insulin-related brain secretory peptide in Bombyx mori. The Agrius bombyxin related peptide (ABRP) cDNAs are classified into type A and B according to their sequence similarity. The prepro-ABRPs deduced from the cDNA sequences have the insulin-like domain organization of signal peptide/B chain/C peptide/A chain. The ABRP transcripts in Agrius brain were shown to locate in four pairs of medial neurosecretory cells, the homologous group of neurosecretory cells that produce bombyxins in Bombyx brain. Genomic Southern analysis indicated the presence of multiple copies of ABRP gene in the Agrius genome. Results showed that the ABRP genes are remarkably different from the vertebrate insulin genes in the number of copy and spatial localization of the transcripts. PMID- 8673078 TI - Changes in the methylation of amplified esterase DNA during loss and reselection of insecticide resistance in peach-potato aphids, Myzus persicae. AB - Insecticide resistance in peach-potato aphids, Myzus persicae, results from the amplification of genes encoding an esterase that hydrolyses and sequesters insecticides. Resistance is normally stable, but highly resistant aphid clones sometimes lose resistance when insecticidal selection pressure is removed. This loss of resistance, termed reversion, arises from a loss of elevated esterase enzyme through transcriptional control, i.e. without loss of the amplified esterase DNA sequences. We have shown that loss of the elevated enzyme occurred simultaneously with loss of methylation at CCGG sites in the amplified DNA sequences. During reselection of resistance in these revertant clones, enzyme levels increased, but there was no corresponding return of methylation to DNA sequences. Thus, although DNA methylation is closely correlated with expression of the amplified esterase genes during reversion, it may not be a factor in the reverse process. PMID- 8673079 TI - Purification and characterization of multiple forms of odorant/pheromone binding proteins in the antennae of Mamestra brassicae (Noctuidae). AB - Proteins extracted form the antennae of Mamestra brassicae (L.) (Lepidoptera: Noctuidae) adults were biochemically characterized as pheromone-binding proteins (PBP) and general odorant-binding proteins (GOBP). PBP and GOBP were purified by two successive and different HPLC (high performance liquid chromatography) systems and native polyacrylamide gel electrophoresis (native-PAGE). Their N terminal sequence was determined by Edman microsequencing. The combined results showed evidence for three different PBPs in males, and two different PBPs in females. In addition, one GOBP was characterized in both males than in females antennae. In the males, two isoforms of PBP have the same N-terminal sequence, but different apparent mobilities and hydrophobicities: they could be separated by electrophoresis and reverse phase-HPLC (RP-HPLC). The other PBP sequence (SQEIM) showed particularly high homology (88%) with the PBP of Heliothis virescens, another noctuid moth. The existence of several forms of PBP in the same animal strongly supports the hypothesis of the specificity of binding between the proteins and their odorant ligands, the pheromonal compounds. The observed microdiversity at the soluble proteins level could provide a good model for studying their involvement in the initial stages of odor discrimination. PMID- 8673080 TI - Identification of a developmentally regulated gene, esr16, in the tracheal epithelium of Manduca sexta, with homology to a protein from human epididymis. AB - Events related to both ecdysis and metamorphosis require the expression of a new set of genes, the majority of which are regulated by the changes in ecdysteroid levels. We have initiated studies to identify genes whose expression is up regulated between 24 and 4 h before pupal ecdysis in Manduca sexta. In this paper we report the partial characterization of one such gene, esr16. The transcript of esr16 is detected by Northern blot analysis in nervous tissue, muscle and trachea isolated from animals 4 h before, but not 24 h before pupal ecdysis. In situ hybridization showed that the transcript was expressed in epithelial cells of the large tracheae surrounding the nervous system and muscle. Sequence analysis suggested that the gene encoded a secreted protein with 35% identity to HE1, a human epididymal-specific gene. PMID- 8673081 TI - Cyclic nucleotide-induced termination of vitellogenin uptake by Hyalophora cecropia follicles. AB - Endocytosis of vitellogenin by isolated follicles of Hyalophora cecropia terminated after membrane-permeable analogs of cAMP or cGMP were added to the culture medium. Depending on the concentration of the analog, a lag period of 30 min to 3 h preceded termination. Forskolin and IBMX both stimulated a rise in endogenous cAMP, and this also induced termination, as did pharmacological activation of the cyclic nucleotide-dependent protein kinases PKA and PKG. Inhibitors of PKA or PKG protected follicles from the corresponding cyclic nucleotide effect. When cAMP or cGMP was added to homogenates of vitellogenic follicles, a 32 kDa polypeptide was phosphorylated; inhibition of PKA, prevented phosphorylation of this protein. The rate of vitellogenin uptake did not accelerate significantly when PKA or PKG was inhibited in culture, which suggests that these kinases are normally inactive or operating below threshold during the several days of vitellogenesis. They seem thus not to be involved in the steady state modulation of protein uptake. A more likely function of this control pathway in follicle development would be to trigger the termination of vitellogenesis, which normally occurs spontaneously in follicles of this species as they reach a length of 2 mm. PMID- 8673082 TI - Purification and characterization of a digestive cathepsin D proteinase isolated from Tribolium castaneum larvae (Herbst). AB - A digestive proteinase was isolated from larval extracts of Tribolium castaneum. The enzyme was partially purified using gel-filtration and ion-exchange chromatography. It is an acidic proteinase with a maximal activity at pH 3. Considering its inhibition by Pepstatin A, plus its selectivity to hydrolyze hemoglobin but not bovine serum albumin, it was classified as Cathepsin D proteinase. Its relative molecular weight is 22 kDa and it shows a high sensitivity to temperature. Unlike other cathepsin D found in animals, this enzyme is free of carbohydrate, and its activity is not affected by the presence of different anions which are known to affect the activity of plant aspartic proteinases. PMID- 8673083 TI - Capitalizing on the genome. PMID- 8673084 TI - The gene for hereditary sensory neuropathy type I (HSN-I) maps to chromosome 9q22.1-q22.3. AB - Hereditary sensory neuropathy type I (HSN-I, also known as hereditary sensory and autonomic neuropathy type I (HSAN-I), or hereditary sensory radicular neuropathy) is an autosomal dominant disorder that is the most common of a group of degenerative disorders of sensory neurons. HSN-I was initially recognized as a disease that produced mutilating ulceration leading to amputation of digits (Fig. 1). It was given names such as familial ulcers with mutilating lesions of the extremities and perforating ulcers with osseous atrophy. The disease involves a progressive degeneration of dorsal root ganglion and motor neurons, leading to distal sensory loss and later distal muscle wasting and weakness and variable neural deafness. Sensory deficits include loss of all modalities, particularly loss of sensation to pain and temperature. Skin injuries may lead to chronic skin ulcers, osteomyelitis, and extrusion of bone fragments, especially the metatarsals. Onset of symptoms is in the second or later decades. We undertook a genome screen using linkage analysis in four Australian HSN-I kindreds. We now show that the HSN1 gene maps to an 8-centiMorgan (cM) region flanked by D9S318 and D9S176 on chromosome 9q22.1-q22.3. Multipoint linkage analysis suggests a most likely location at D9S287, within a 4.9-cM confidence interval. PMID- 8673085 TI - Identification of the gene FMR2, associated with FRAXE mental retardation. AB - Five folate-sensitive fragile sites have been characterized at the molecular level (FRAXA, FRAXE, FRAXF, FRA16A and FRA11B). Three of them (FRAXA, FRAXE and FRA11B) are associated with clinical problems, and two of the genes (FMR1 in FRAXA and CBL2 in FRA11B) have been identified. All of these fragile sites are associated with (CCG)n/(CGG)n triplet expansions which are hypermethylated beyond a critical size. FRAXE is a rare folate sensitive fragile site only recently recognized. Its cytogenetic expression was found to involve the amplification of a (CCG)n repeat adjacent to a CpG island. Normal alleles vary from 6 to 25 copies. Expansions of greater than 200 copies were found in FRAXE expressing males and their FRAXE associated CpG island was fully methylated. An association of FRAXE expression with concurrent methylation of the CpG island and mild non specific mental handicap in males has been reported by several groups. We now report the cloning and characterization of a gene (FMR2) adjacent to FRAXE. Elements of FMR2 were initially identified from sequences deleted from a developmentally delayed boy. We correlate loss of FMR2 expression with (CCG)n expansion at FRAXE, demonstrating that this is a gene associated with the CpG island adjacent to FRAXE and contributes for FRAXE-associated mild mental retardation. PMID- 8673086 TI - Identification of FMR2, a novel gene associated with the FRAXE CCG repeat and CpG island. AB - Five folate-sensitive fragile sites have been identified at the molecular level to date. Each is characterized by an expanded and methylated trinucleotide repeat CGG (CCG). Of the three X chromosome sites, FRAXA, FRAXE and FRAXF, the former two are associated with mental retardation in their expanded forms. FRAXA expansion results in fragile X syndrome due to down regulation of expression of the FMR1 gene, which carries the hypermutable CGG repeat in the 5' untranslated portion of its first exon. Mild mental retardation without consistent physical findings has been found associated with expanded CCG repeats at FRAXE. We have identified a large gene (FMR2) transcribed distally from the CpG island at FRAXE, and down-regulated by repeat expansion and methylation. The gene is novel, expressed in adult brain and placenta, and shows similarity with another human protein, MLLT2, expressed from a gene at chromosome 4q21 involved in translocations found in acute lymphoblastic leukaemia (ALL) cells. Identification of this gene will facilitate further studies to determine the role of its product in FRAXE associated mental deficiency. PMID- 8673087 TI - DNA helicases: the long unwinding road. PMID- 8673088 TI - Localization of the gene for Cowden disease to chromosome 10q22-23. AB - Cowden disease (CD) (MIM 158350), or multiple hamartoma syndrome, is a rare autosomal dominant familial cancer syndrome with a high risk of breast cancer. Its clinical features include a wide array of abnormalities but the main characteristics are hamartomas of the skin, breast, thyroid, oral mucosa and intestinal epithelium. The pathognomonic hamartomatous features of CD include multiple smooth facial papules, acral keratosis and multiple oral papillomas. The pathological hallmark of the facial papules are multiple trichilemmomas. Expression of the disease is variable and penetrance of the dermatological lesions is assumed to be virtually complete by the age of twenty. Central nervous system manifestations of CD were emphasized only recently and include megalencephaly, epilepsy and dysplastic gangliocytomas of the cerebellum (Lhermitte-Duclos disease, LDD). Early diagnosis is important since female patients with CD are at risk of developing breast cancer. Other lesions include benign and malignant disease of the thyroid, intestinal polyps and genitourinary abnormalities. To localize the gene for CD, an autosomal genome scan was performed. A total of 12 families were examined, resulting in a maximum lod score of 8.92 at theta = 0.02 with the marker D10S573 located on chromosome 10q22-23. PMID- 8673089 TI - A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. AB - The BRCA2 gene on chromosome 13 has been shown to be associated with familial male and female breast cancer. Here we describe a study on BRCA2 in 21 Icelandic families, including 9 with male breast cancer. We have previously reported linkage to the BRCA2 region in an Icelandic male breast cancer family and subsequently found a strong indication of linkage to BRCA2 and the same BRCA2 haplotype in breast cancer cases from 15 additional families, indicating a common origin. We describe a five base-pair deletion in exon 9 of BRCA2 in an affected male from the male breast cancer family. The same mutation occurs in all the families with the shared BRCA2 haplotype indicating a founder effect. Among mutation carriers there are 12 males with breast cancer, which accounts for 40% of all males diagnosed with breast cancer in Iceland over the past 40 years. Three of them have no family history of breast cancer indicating that this mutation may have variable penetrance. The same BRCA2 mutation appears to be associated with different cancer phenotypes in this population including male and female breast cancer, prostate cancer, pancreas cancer and ovarian cancer. PMID- 8673090 TI - Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. AB - The hereditary breast cancer gene BRCA2 was recently cloned and is believed to account for almost half of site-specific breast cancer families and the majority of male breast cancer families. We screened 49 site-specific breast cancer families for mutations in the BRCA2 gene using single strand conformation analysis (SSCA) followed by direct sequencing. We found mutations in eight families, including all four families with male breast cancer. The eight mutations were small deletions with the exception of a single nonsense mutation, an all were predicted to interrupt the BRCA2 coding sequence and to lead to a truncated protein product. Other factors which predicted the presence of a BRCA2 mutation included a case of breast cancer diagnosed at age 35 or below (P = 0.01) and a family history of pancreatic cancer (P = 0.03). Two mutations were seen twice, including a 8535delAG, which was detected in two French Canadian families. Our results suggest the possibility that the proportion of site-specific breast cancer families attributable to BRCA2 may be overestimated. PMID- 8673092 TI - Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. AB - The lifetime risk of breast cancer may approach 80-90% in women who have germline mutations of either of two genes, BRCA1 or BRCA2. A single BRCA1 mutation, 185delAG, has been noted in approximately 20% of Ashkenazi Jewish women with early onset breast cancer and in 0.9% of the Ashkenazi population. We recently detected a 6174delT frameshift mutation in BRCA2 in an hereditary breast cancer kindred of Ashkenazi Jewish ancestry. Here, we investigated the frequency of this mutation in 200 women with early-onset breast cancer. Six of 80 Ashkenazi Jewish women (8%) diagnosed with breast cancer before the age of 42, wer heterozygous for the 6174delT mutation, compared to none of 93 non-Jewish women diagnosed with breast cancer at the same age (P = .005). These cases were ascertained without regard to family history. Two of 27 (7%) additional Jewish families in which the proband was diagnosed with breast cancer at age 42 to 50 and had a family history of breast or ovarian cancer had germline 6174delT mutations. The results of this report suggest that a recurrent mutation of BRCA1 and a recurrent mutation BRCA2 together may account for over a quarter of all early-onset breast cancer in the setting of a personal or family history of ovarian cancer in Ashkenazi Jewish women. PMID- 8673091 TI - BRCA2 germline mutations in male breast cancer cases and breast cancer families. AB - The breast cancer susceptibility gene, BRCA2 on chromosome 13q12-13, was recently isolated. Mutations in BRCA2 are thought to account for as much as 35% of all inherited breast cancer as wall as a proportion of inherited ovarian cancer. Many BRCA2-linked families also contain cases of male breast cancer. We have analysed germline DNA from 50 males with breast cancer (unselected for family history) and 26 individuals from site-specific female breast and breast-ovarian cancer families for mutations in BRCA2. All 17 breast-ovarian cancer families have been screened for BRCA1 coding region mutations and none were detected. Conformation sensitive gel electrophoresis (CSGE) analysis of PCR-amplified DNA followed by direct sequencing was used to detect sequence variants. Three of eleven individuals carry the same mutation, all are of Ashkenazi Jewish descent, supporting the observation by Neuhausen et al. in this issue that there is a common mutation in this population. Eleven truncating mutations and nine polymorphisms were identified -- all were coding region variants. No loss-of transcript mutations were identified in the sixteen samples for which this analysis was possible. Seven of the nine disease-associated mutations were detected in the 50 men with breast cancers; for thus in our series, BRCA2 mutations account for 14% of male breast cancer, all but one of which had a family history of male and/or female breast cancer. PMID- 8673093 TI - Mutation of the gene in a family with optic nerve colobomas, renal anomolies and vesicoureteral reflux. PMID- 8673094 TI - A landmark for orphan genomes? PMID- 8673095 TI - Breast cancer susceptibility testing: realities in the post-genomic era. PMID- 8673096 TI - Leptin receptor missense mutation in the fatty Zucker rat. PMID- 8673097 TI - Chromosome-size dependent control of meiotic recombination in humans. PMID- 8673098 TI - Menkes disease mutations and response to early copper histidine treatment. PMID- 8673099 TI - Internal repeats in the BRCA2 protein sequence. PMID- 8673100 TI - Genetic analysis of ageing: role of oxidative damage and environmental stresses. AB - Evolutionary theory predicts substantial interspecific and intraspecific differences in the proximal mechanisms of ageing. Our goal here is to seek evidence for common ('public') mechanisms among diverse organisms amenable to genetic analysis. Oxidative damage is a candidate for such a public mechanism of ageing. Long-lived strains are relatively resistant to different environmental stresses. The extent to which these stresses produce oxidative damage remains to be established. PMID- 8673101 TI - A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3). AB - X-linked retinitis pigmentosa (xlRP) is a severe progressive retinal degeneration which affects about 1 in 25,000 of the population. The most common form of xlRP, RP3, has been localised to the interval between CYBB and OTC in Xp21.1 by linkage analysis and deletion mapping. Identification of microdeletions within this region has now led to the positional cloning of a gene, RPGR, that spans 60 kg of genomic DNA and is ubiquitously expressed. The predicted 90 kD protein contains in its N-terminal half a tandem repeat structure highly similar to RCC1 (regulator of chromosome condensation), suggesting an interaction with a small GTPase. The C-terminal half contains a domain, rich in acidic residues, and ends in a potential isoprenylation anchorage site. The two intragenic deletions, two nonsense and three missense mutations within conserved domains provide evidence that RPGR (retinitis pigmentosa GTPase regulator) is the RP3 gene. PMID- 8673102 TI - Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. AB - The discovery that some cases of familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) has focused much attention on the function of SOD1 as related to motor neuron survival. Here we describe the creation and characterization of mice completely deficient for this enzyme. These animals develop normally and show no overt motor deficits by 6 months in age. Histological examination of the spinal cord reveals no signs of pathology in animals 4 months in age. However Cu/Zn SOD deficient mice exhibit marked vulnerability to motor neuron loss after axonal injury. These results indicate that Cu/Zn SOD is not necessary for normal motor neuron development and function but is required under physiologically stressful conditions following injury. PMID- 8673104 TI - Effective treatment of familial hypercholesterolaemia in the mouse model using adenovirus-mediated transfer of the VLDL receptor gene. AB - Liver directed gene transfer with adenoviral vectors is being considered for the treatment of several metabolic diseases, including familial hypercholesterolaemia (FH). Gene replacement therapy of human low density lipoprotein (LDL) receptor gene into the murine model of FH transiently corrected the dyslipidaemia; however, humoral and cellular immune responses to LDL receptor developed- possibly contributing to the associated hepatitis and extinguishing of transgene expression. We evaluated an alternative strategy of ectopic expression in the liver of the very low density lipoprotein (VLDL) receptor, which is homologous to the LDL receptor but has a different pattern of expression. Infusion of recombinant adenoviruses containing the VLDL receptor gene corrected the dsylipidaemia in the FH mouse and circumvented immune responses to the transgene leading to a more prolonged metabolic correction. PMID- 8673103 TI - Exclusive paternal origin of new mutations in Apert syndrome. AB - Apert syndrome results from one or other of two specific nucleotide substitutions, both C-->G transversions, in the fibroblast growth factor receptor 2 (FGFR2) gene. The frequency of new mutations, estimated as 1 per 65,000 live births, implies germline transversion rates at these two positions are currently the highest known in the human genome. Using a novel application of the amplification refractory mutation system (ARMS), we have determined the parental origin of the new mutation in 57 Apert families: in every case, the mutation arose from the father. This identifies the biological basis of the paternal age effect for new mutations previously suggested for this disorder. PMID- 8673105 TI - Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. AB - The muscle myosins and hexomeric proteins consisting of two heavy chains and two pairs of light chains, the latter called essential (ELC) and regulatory (RLC). The light chains stabilize the long alpha helical neck of the myosin head. Their function in striated muscle, however, is only partially understood. We report here the identification of distinct missense mutations in a skeletal/ventricular ELC and RLC, each of which are associated with a rare variant of cardiac hypertrophy as well as abnormal skeletal muscle. We show that myosin containing the mutant ELC has abnormal function, map the mutant residues on the three dimensional structure of myosin and suggest that the mutations disrupt the stretch activation response of the cardiac papillary muscles. PMID- 8673106 TI - The South African malady. PMID- 8673107 TI - A molecular defect in loricrin, the major component of the cornified cell envelope, underlies Vohwinkel's syndrome. AB - Terminal keratinocyte differentiation involves coordinated expression of several functionally interdependent genes, many of which have been mapped to the epidermal differentiation complex (EDC) on chromosome 1q21. We have identified linkage of Vohwinkel's syndrome in an extended pedigree to markers flanking the EDC region with a maximum multipoint lod score of 14.3. Sequencing of the loricrin gene revealed an insertion that shifts the translation frame of the C terminal Gly- and Gln/Lys-rich domains, and is likely to impair cornification. Our findings provide the first evidence for a defect in an EDC gene in human disease, and disclose novel insights into perturbations of cornified cell envelope formation. PMID- 8673108 TI - High frequency de novo alterations in the long-range genomic structure of the mouse pseudoautosomal region. AB - The pseudoautosomal region (PAR) is a segment of shared homology between the X and Y chromosomes. Here we report physical linkage of three mouse PAR probes: DXYHgu1, DXYMov15 and (TTAGGG)n. Steroid sulphatase (Sts) maps distal to these probes, indicating that there is an internal array of the telomere sequence (TTAGGG)n in the PAR. Pseudoautosomal PacI restriction fragments, up to 2 Mb in size, are unstable in C57BL/6 x C57BL/6 crosses. New alleles, often several hundred kilobases different in size, occur at a sex-averaged rate of approximately 30% per allele. Such frequent large-scale germline genome arrangements are without precedent in mammals. PMID- 8673109 TI - Cloning and expression of the mouse pseudoautosomal steroid sulphatase gene (Sts). AB - Steroid sulphatase (STS) is an important enzyme in steroid metabolism. The human STS gene has been cloned and mapped to Xp22.3, proximal to the pseudoautosomal region (PAR). Using quantitative differences in STS activity among various mouse strains, a segregation pattern consistent with autosomal linkage was first reported, but more recent studies have linked Sts to the mouse PAR. Failed attempts to clone the mouse Sts gene using human reagants (STS cDNA and anti-STS antibodies) suggest a substantial divergence between these genes. However, partial amino-terminal sequence from purified rat liver Sts is very similar to its human counterpart, and several domains are conserved among all the sulphatases. We followed a degenerate-primer reverse transcriptase-PCR (RT-PCR) approach to amplify a conserved fragment of the rat Sts cDNA that was then used to clone the mouse Sts cDNA. This 2.3-kb cDNA revealed 75% similarity with rat Sts cDNA, while it was only 63% similar to human STS cDNA. Transfection of STS(-) A9 cells with the mouse Sts cDNA restored STS enzymatic activity. Sts was also mapped physically to the distal end of the mouse sex chromosomes, and our backcross studies placed Sts distal to the 'obligatory' cross-over in male meiosis. PMID- 8673111 TI - A paternal wash in Apert syndrome. PMID- 8673110 TI - A genetic linkage map of the Syrian hamster and localization of cardiomyopathy locus on chromosome 9qa2.1-b1 using RLGS spot-mapping. AB - The Syrian cardiomyopathic hamster (BIO14.6) has an inherited form of progressive myocardial necrosis and congestive heart failure. Although widely studied as an animal model for human hypertrophic cardiomyopathy, further genetic analysis has been limited by a scarcity of DNA markers. Until now, only six autosomal linkage groups have been described and the number of polymorphic loci was extremely limited. In this study, we applied the restriction landmark genome scanning (RLGS) spot-mapping method to construct a genetic map of the Syrian hamster (Mesocricetus auratus) using 72 back-cross progeny. Although the polymorphic rate is very low (3-7%) between the strains, 531 polymorphic spots/loci were mapped, showing the power of this approach and reasonable applicability to other organisms lacking a well-defined genetic map. Further, the spot markers which flank the cardiomyopathy (cm) locus were cloned to determine the chromosomal location of cm by fluorescent in situ hybridization (FISH) analysis, resulting in the assignment of the locus to the centromeric region of hamster chromosome 9qa2.1-b1. Several candidate genes responsible for hypertrophic cardiomyopathy in humans have been excluded. PMID- 8673112 TI - Epigenetic modifications during oocyte growth correlates with extended parthenogenetic development in the mouse. AB - In mammals, the maternal and paternal genomes are required for embryonic development. This is due to genomic imprinting which leads to the expression or repression of genes solely on the basis of the parent from which they were inherited. As a result, parthenogenetic embryos die before day 10 of gestation and show limited development of extra-embryonic membranes. Maternal imprinting is established during oogenesis and is associated with allele specific modifications in DNA methylation. We have investigated epigenetic modifications during oocyte growth using nuclear transfer techniques to produce mature oocytes with maternal chromatin derived from non-growing oocytes. Parthenogenetic activation of such oocytes leads to the development of normal size fetuses with a well developed placenta on day 13.5 of gestation; three days further than previously recorded for parthenogenetic development. In contrast, after fertilization, only one embryo was recovered on 9.5 days of gestation. Further, in these embryos we investigated the well characterized methylation pattern of the maternally expressed insulin-like growth factor II receptor gene (Igf2r) and found that the pattern of methylation was indeed different to that of fertilized control embryos. Thus, the embryonic phenotypes observed here correlate with changes in epigenetic events that normally occur during oocyte growth. PMID- 8673113 TI - A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria. AB - Variegate porphyria (VP), a low-penetrant autosomal dominant inherited disorder of haem metabolism, is characterised by photosensitivity (Fig. 1) and a propensity to develop acute neuropsychiatric attacks with abdominal pain, vomiting, constipation, tachycardia, hypertension, psychiatric symptoms and, in the worst cases, quadriplegia. Acute attacks, often precipitated by inappropriate drug therapy, are potentially fatal. While earlier workers thought the distal haem biosynthetic enzyme ferrochelatase may be involved in the genesis of VP, it was shown in the early 1980's, and is now accepted, that VP is associated with decreased protoporphyrinogen oxidase activity (PPO) (E.C.1.3.3.4). VP prevalence is much higher in South Africa than elsewhere; probably due to a founder effect with patients descending from a 17th century Dutch immigrant. PPO cDNAs from Bacillus subtilis, Myxococcus xanthus, human placenta and mouse liver have been cloned, sequenced and expressed. Human and mouse cDNAs consist of open reading frames 1431 nucleotides long, encoding a 477 amino acid protein. The human PPO gene contains thirteen exons, spanning approximately 4.5 kb. We have identified a C to T transition in codon 59 (in exon 3) resulting in an arginine to tryptophan substitution (R59W). A protein expressed from an in vitro-mutagenized PPO construct exhibits substantially less activity than the wild type. The R59W mutation was present in 43 of 45 patients with VP from 26 of 27 South African families investigated, but not in 34 unaffected relatives or 9 unrelated British patients with PPO deficiency. Since at least one of these families is descended from the founder of South African VP, this defect may represent the founder gene defect associated causally with VP in South Africa. PMID- 8673115 TI - The yeast genome--a common currency. PMID- 8673114 TI - Severe autosomal dominant hypertension and brachydactyly in a unique Turkish kindred maps to human chromosome 12. AB - Finding genes that cause human hypertension is not straightforward, since the determinants of blood pressure in primary hypertension are multifactorial. One approach to identifying relevant genes is to elucidate rare forms of monogenic hypertension. A relevant mutation may provide a rational starting point from which to analyse the pathophysiology of a condition affecting 20% of the world's population. In 1973 a family with autosomal dominantly inherited brachydactyly and severe hypertension, where the two traits cosegregated completely, was described. We have now re-examined this kindred, and localized the hypertension and brachydactyly locus to chromosome 12p in a region defined by markers D12S364 and D12S87. As the renin-angiotensin-system and sympathetic nervous system respond normally in this form of hypertension, the condition resembles essential hypertension. This feature distinguishes this form of hypertension from glucocorticoid remediable aldosteronism and Liddle's syndrome, which are salt sensitive forms of monogenic hypertension with very low plasma renin activity. We suggest that identification of the gene involved in hypertension and brachydactyly and its mutation will be of great relevance in elucidating new mechanisms leading to blood pressure elevation. PMID- 8673116 TI - Natural gene therapy and the Darwinian legacy. PMID- 8673117 TI - Hox mutations au naturel. PMID- 8673118 TI - Model mice and human disease. PMID- 8673119 TI - Mismatch repair goes meiotic. PMID- 8673120 TI - BRCA1 protein products: antibody specificity... PMID- 8673121 TI - BRCA1 protein products ... Functional motifs... PMID- 8673122 TI - . . . and secreted tumour suppressors. PMID- 8673123 TI - . . . and secreted tumour suppressors. PMID- 8673124 TI - LIM-kinase deleted in Williams syndrome. PMID- 8673125 TI - Prenatal folic acid treatment suppresses acrania and meroanencephaly in mice mutant for the Cart1 homeobox gene. AB - The paired-class homeobox-containing gene, Cart1, is expressed in forebrain mesenchyme, branchial arches, limb buds and cartilages during embryogenesis. Here, we show that Cart1-homozygous mutant mice are born alive with acrania and meroanencephaly but die soon after birth-a phenotype that strikingly resembles a corresponding human syndrome caused by a neural tube closure defect. Developmental studies suggest that Cart1 is required for forebrain mesenchyme survival and that its absence disrupts cranial neural tube morphogenesis by blocking the initiation of closure in the midbrain region that ultimately leads to the generation of lethal craniofacial defects. Prenatal treatment of Cart1 homozygous mutants with folic acid suppresses the development of the acrania/meroanencephaly phenotype. PMID- 8673126 TI - The molecular basis of hypodactyly (Hd): a deletion in Hoxa 13 leads to arrest of digital arch formation. AB - Hypodactyly (Hd) is a semidominant mutation in mice that maps in a genetic interval overlapping the Hoxa cluster. The profound deficiency of digital arch structures in Hd/Hd mice is consistent with a defect in a gene activated late in limb morphogenesis. We have determined the structure of the Hoxa13 gene and describe a 50-base pair deletion in the first exon of the Hd allele that probably arose from unequal recombination or misalignment between triplet repeats. It is predicted that no Hoxa13 protein is made from Hd mRNA. The hypodactyly limb phenotype is similar to that of Hoxd13-deficient mice in sharing defects along multiple axes and alterations in cartilage maturation; however, the overall effects on digital arch formation are more severe in Hd/Hd mice. Our results confirm the critical role of AbdB-like Hox genes in the development of the autopod, and add to the spectrum of mutations involving triplet repeats. PMID- 8673127 TI - Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency. AB - Somatic mosaicism in genetic disease generally results from a de novo deleterious mutation during embryogenesis. We now describe a somatic mosaicism due to the unusual mechanism of in vivo reversion to normal of an inherited mutation. The propositus was an adenosine deaminase-deficient (ADA-) child with progressive clinical improvement and unexpectedly mild biochemical and immunologic abnormalities. Mosaicism due to reversion was evidenced by absence of a maternally transmitted deleterious mutation in 13/15 authenticated B cell lines and in 17% of single alleles cloned from blood DNA, despite retention of a maternal 'private' ADA polymorphism linked to the mutation. Establishment of significant somatic mosaicism following reversion to normal could modify any disorder in which revertant cells have a selective advantage. PMID- 8673128 TI - A single mouse gene encodes the mitochondrial transcription factor A and a testis specific nuclear HMG-box protein. AB - Mitochondrial transcription factor A (mtTFA) is a key regulator of mammalian mitochondrial DNA transcription. We report here that a testis-specific isoform of mouse mtTFA lacks the mitochondrial targeting sequence and is present in the nucleus of spermatocytes and elongating spermatids, thus representing the first reported mammalian gene encoding protein isoforms targeted for the mitochondria or the nucleus. The presence of the mitochondrial transcriptional activator in the nucleus raises the possibility of a role for this protein in both genetic systems. Mutations in the nuclear mtTFA gene may therefore exhibit phenotypic consequences due to altered function in either or both genetic compartments. PMID- 8673129 TI - Identification of the murine beige gene by YAC complementation and positional cloning. AB - The beige mutation is a murine autosomal recessive disorder, resulting in hypopigmentation, bleeding and immune cell dysfunction. The gene defective in beige is thought to be a homologue of the gene for the human disorder Chediak Higashi syndrome. We have identified the murine beige gene by in vitro complementation and positional cloning, and confirmed its identification by defining mutations in two independent mutant alleles. The sequence of the beige gene message shows strong nucleotide homology to multiple human ESTs, one or more of which may be associated with the Chediak-Higashi syndrome gene. The amino acid sequence of the Beige protein revealed a novel protein with significant amino acid homology to orphan proteins identified in Saccharomyces cerevisiae, Caenorhabditis elegans and humans. PMID- 8673130 TI - Signalling by the W/Kit receptor tyrosine kinase is negatively regulated in vivo by the protein tyrosine phosphatase Shp1. AB - Protein tyrosine phosphorylation plays a key role in regulating eukaryotic cell proliferation and differentiation. Genetic analysis in invertebrates has been invaluable for dissecting the signalling events downstream of receptor tyrosine kinases (RTKs). We have used this approach in mammals to analyse the interactions between the Kit RTK encoded by the murine Dominant white spotting (W) locus and the Shp1 protein tyrosine phosphatase, the product of the murine motheaten (me) gene. Homozygosity for mutations in both W and me ameliorates aspects of both the me and W phenotypes, including the lethal lung disease associated with me and the embryonic lethality and mast cell deficiency associated with W, demonstrating that the Kit receptor plays a role in the pathology of the me phenotype and conversely that Shp1 negatively regulates Kit signalling in vivo. PMID- 8673131 TI - Abnormal myotonic dystrophy protein kinase levels produce only mild myopathy in mice. AB - Myotonic dystrophy (DM) is commonly associated with CTG repeat expansions within the gene for DM-protein kinase (DMPK). The effect of altered expression levels of DMPK, which is ubiquitously expressed in all muscle cell lineages during development, was examined by disrupting the endogenous Dmpk gene and overexpressing a normal human DMPK transgene in mice. Nullizygous (-/-) mice showed only inconsistent and minor size changes in head and neck muscle fibres at older age, animals with the highest DMPK transgene expression showed hypertrophic cardiomyopathy and enhanced neonatal mortality. However, both models lack other frequent DM symptoms including the fibre-type dependent atrophy, myotonia, cataract and male-infertility. These results strengthen the contention that simple loss- or gain-of-expression of DMPK is not the only crucial requirement for development of the disease. PMID- 8673132 TI - Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy. AB - Myotonic dystrophy (DM) is an autosomal dominant disorder resulting from the expansion of a CTG repeat in the 3' untranslated region of a putative protein kinase (DMPK). To elucidate the role of DMPK in DM pathogenesis we have developed Dmpk deficient (Dmpk-/-) mice. Dmpk-/-mice develop a late-onset, progressive skeletal myopathy that shares some pathological features with DM. Muscles from mature mice show variation in fibre size, increased fibre degeneration and fibrosis. Adult Dmpk-/-mice show ultrastructural changes in muscle and a 50% decrease in force generation compared to young mice. Our results indicate that DMPK may be necessary for the maintenance of skeletal muscle structure and function and suggest that a decrease in DMPK levels may contribute to DM pathology. PMID- 8673133 TI - Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over. AB - Mice that are deficient in either the Pms2 or Msh2 DNA mismatch repair genes have microsatellite instability and a predisposition to tumours. Interestingly, Pms2 deficient males display sterility associated with abnormal chromosome pairing in meiosis. Here mice deficient in another mismatch repair gene, Mlh1, possess not only microsatellite instability but are also infertile (both males and females). Mlh1-deficient spermatocytes exhibit high levels of prematurely separated chromosomes and arrest in first division meiosis. We also show that Mlh1 appears to localize to sites of crossing over on meiotic chromosomes. Together these findings suggest that Mlh1 is involved in DNA mismatch repair and meiotic crossing over. PMID- 8673134 TI - Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. AB - Chromosome deletions are the most common genetic events observed in cancer. These deletions are generally thought to reflect the existence of a tumour suppressor gene within the lost region. However, when the lost region does not precisely coincide with a hereditary cancer locus, identification of the putative tumour suppressor gene (target of the deletion) can be problematic. For example, previous studies have demonstrated that chromosome 18q is lost in over 60% of colorectal as well as in other cancers, but the lost region could not be precisely determined. Here we present a rigorous strategy for mapping and evaluating allelic deletions in sporadic tumours, and apply it to the evaluation of chromosome 18 in colorectal cancers. Using this approach, we define a minimally lost region (MLR) on chromosome 18q21, which contains at least two candidate tumour suppressor genes, DPC4 and DCC. The analysis further suggested genetic heterogeneity, with DPC4 the deletion target in up to a third of the cases and DCC or a neighbouring gene the target in the remaining tumours. PMID- 8673136 TI - Accelerated telomere shortening in ataxia telangiectasia. AB - Ataxia telangiectasia (AT) is characterized by neurological deterioration, immunodeficiency, spontaneous chromosomal instability, hypersensitivity to ionizing radiation, predisposition to cancer, particularly T cell leukaemia and lymphoma, and premature ageing. The most commonly observed defect affecting telomeres in humans is telomeric fusions, particularly in T lymphocytes in AT patients. Rarely, some tumour cells, like senescent cells, have dicentric chromosomes that may arise as a result of telomeric sequence loss. We show that the AT mutation in the homozygous state confers a predisposition to accelerated telomere shortening with increasing age in peripheral blood lymphocytes (PBLs), which may be linked to premature senescence. We also show that telomeric fusions are associated with large (> 90%) preleukaemic translocation clones in T cells. We propose that these fusions may result from a compound effect of accelerated telomere shortening, together with a growth advantage of cells in large clones which leads to further telomere loss. Fusions are not observed in leukaemic cells in these patients. There is no evidence that either accelerated telomere loss per se or telomeric fusions are important in tumourigenesis. Telomerase is present in both normal and AT lymphocytes and so neither telomere shortening nor telomeric fusions can be explained by the absence of telomerase. PMID- 8673135 TI - Mad-related genes in the human. AB - Resistance to the growth inhibitory effects of TGF-beta is common in human cancers. However, the mechanism(s) by which tumour cells become resistant to TGF beta are generally unknown. We have identified five novel human genes related to a Drosophila gene called Mad which is thought to transduce signals from TGF-beta family members. One of these genes was found to be somatically mutated in two of eighteen colorectal cancers, and three of the other genes were located at chromosomal positions previously suspected to harbor tumour suppressor genes. These data suggest that this gene family may prove to be important in the suppression of neoplasia, imparting the growth inhibitory effects of TGF-beta like ligands. PMID- 8673137 TI - Thyroid hormone receptor beta is essential for development of auditory function. AB - Congenital thyroid disorders are often associated with profound deafness, indicating a requirement for thyroid hormone (T3) and its receptors in the development of hearing. Two T3 receptor genes, Tr alpha and Tr beta are differentially expressed, although in overlapping patterns, during development. Thus, the extent to which they mediate unique or redundant functions is unclear. We demonstrate that Tr beta-deficient (Thrb-/-) mice exhibit a permanent deficit in auditory function across a wide range of frequencies, although they show no other overt neurological defects. The auditory-evoked brainstem response (ABR) in Thrb-/- mice, although greatly diminished, displayed normal waveforms, which suggested that the primary defect resides in the cochlea. Although hypothyroidism causes cochlear malformation, there was no evidence of this in Thrb-/- mice. These findings suggest that Tr beta controls the maturation of auditory function but not morphogenesis of the cochlea. Thrb-/- mice provide a model for the human endocrine disorder of resistance to thyroid hormone (RTH), which is typically associated with dominant mutations in Tr beta. However, deafness is generally absent in RTH, indicating that dominant and recessive mutations in Tr beta have different consequences on the auditory system. Our results identify Tr beta as an essential transcription factor for auditory development and indicate that distinct Tr genes serve certain unique functions. PMID- 8673138 TI - Missense mutation in the gene encoding the alpha subunit of rod transducin in the Nougaret form of congenital stationary night blindness. AB - Patients with congenital stationary night blindness enjoy normal daytime vision, which is mediated by cone photoreceptors, but are blind when ambient light is so dim that a normal individual would utilize only rod photoreceptors to see without colour discrimination. The disease is genetically heterogeneous. One form of dominantly inherited congenital night blindness is eponymously named "Nougaret' because pedigree analysis reveals that the disease originated in Jean Nougaret (1637-1719), a butcher who lived in Vendemian in southern France. Here we report that his affected descendants carry a missense mutation in the gene encoding the alpha subunit of rod transducin the G-protein that couples rhodopsin to cGMP phosphodiesterase in the phototransduction cascade. Based on these results, rod transducin joins rhodopsin and the beta subunit of rod cGMP-phosphodiesterase to become the third component of the rod phototransduction cascade where a defect is implicated as a cause of stationary night blindness. Interestingly, the amino acid residue in transducin affected by the Nougaret mutation is in the position homologous to that affected by the oncogenic mutation originally reported in p21ras, a distant relative in the G-protein superfamily. PMID- 8673139 TI - A translocation interrupts the COL5A1 gene in a patient with Ehlers-Danlos syndrome and hypomelanosis of Ito. AB - Ehlers-Danlos syndrome (EDS) is a genetically and pathogenetically heterogeneous group of disorders of which at least 11 types have been described. All are connective tissue disorders characterized by defects of the skin, ligaments and blood vessels with the clinical spectrum ranging from innocuous findings to lethality. Mutations in the genes encoding the major fibrillar collagen types I and III have been demonstrated in EDS types VII and IV, respectively, while mutations in the lysyl hydroxylase and ATP7A genes, with roles in collagen cross linking, are responsible for EDS types VI and IX. The biochemical and molecular bases for the most common forms of EDS (types I, II and III) are unknown. Here, we describe a balanced translocation between chromosome 9 and an X chromosome that disrupts the minor fibrillar collagen type V gene COL5A1 in a patient with both EDS type I and hypomelanosis of Ito. The breakpoint occurs at 9q34 within COL5A1 intron 24 and interestingly, within a LINE-1 (L1) element at Xp21.1. A fusion mRNA between COL5A1 and an Alu sequence is produced, but no aberrant protein is detectable. Rather, the amount of type V collagen is reduced in the patient's fibroblasts, suggesting haploinsufficiency as a cuase of the phenotype. This demonstrates that a mutation in a type V collagen gene, COL5A1, results in EDS type I, and shows the involvement of L1 sequences in a constitutional chromosomal translocation. Because collagen type V is a heteromorphic protein in which molecules may be composed of polypeptides encoded by three COL5A genes, this suggests all three genes as candidates for mutations in EDS. PMID- 8673140 TI - Epithelial detachment due to absence of hemidesmosomes in integrin beta 4 null mice. AB - Integrins are heterodimeric transmembrane glycoproteins which are engaged in a variety of cellular functions, such as adhesion, migration and differentiation1. The integrin alpha 6 beta 4 is expressed on squamous epithelia, on subsets of endothelial cells, immature thymocytes and on Schwann cells and fibroblasts in the peripheral nervous system. In stratified epithelia, alpha 6 beta 4 is concentrated in specialised adhesion structures, called hemidesmosomes, which are implicated in the stable attachment of the basal cells to the underlying basement membrane by connecting the intermediate filaments with the extracellular matrix. The nature of the interactions between the various hemidesmosomal proteins, that lead to the formation of hemidesmosome is poorly understood. To study the contribution of the integrin alpha 6 beta 4 in hemidesmosome formation and their anchoring properties, we inactivated the beta 4 gene in mice by targeted gene disruption. Homozygous beta 4 null mice died shortly after birth and displayed extensive detachment of the epidermis and other squamous epithelia. The dramatically reduced adhesive properties of the skin was accompanied by the absence of hemidesmosomes at the basal surface of keratinocytes. No evidence was found for impaired T-cell development, nor for defects in myelination in the peripheral nervous system. PMID- 8673141 TI - Absence of integrin alpha 6 leads to epidermolysis bullosa and neonatal death in mice. AB - Cell-extracellular matrix interactions have important roles in many biological processes, including embryonic development, growth control and differentiation. Integrins are the principal receptors for extracellular matrix. They are composed of non-covalently associated alpha and beta chains. Integrin alpha 6 can associate with either beta 1 or beta 4 (refs 2,3). Both integrin complexes are receptors for laminins, major components of basement membranes. The distribution of alpha 6 (refs 4-10) as well as studies using function-blocking antibodies have suggested an essential role for this laminin receptor during embryogenesis, in processes such as endoderm migration or kidney tubule formation9. Here we report that, surprisingly, mice lacking the alpha 6 integrin chain develop to birth. However, they die at birth with severe blistering of the skin and other epithelia, a phenotype reminiscent of the human disorder epidermolysis bullosa. Hemidesmosomes are absent in mutant tissue. This absence is likely to result from the lack of alpha 6/beta 4, the only integrin in hemidesmosomes of stratified squamous and transitional epithelia. Mutations in the genes encoding integrin beta 4 and chains of laminin-5 have been implicated in junctional epidermolysis bullosa. Our study provides evidence that some forms of epidermolysis bullosa may originate from defects of the alpha 6 gene. PMID- 8673143 TI - The moss, Physcomitrella patens, transformed with apoaequorin cDNA responds to cold shock, mechanical perturbation and pH with transient increases in cytoplasmic calcium. AB - The gene for apoaequorin has been used previously to indicate cytosolic calcium changes in higher plants. Here we report the transformation of the moss Physcomitrella patens with the cDNA for apoaequorin. Stable transformants were obtained in the wild type which reconstitute the calcium-sensitive luminescent protein aequorin in vivo after incubation in coelenterazine, and continue to grow normally. The wild type responds to cold-shock (0-10 degrees C) with increases in cytosolic calcium. Mechanical perturbation, in the form of touch, also induces transient increases in cytosolic calcium. A smaller response to pH, distinct from the touch response and exhibiting different kinetics, can also be detected. PMID- 8673142 TI - Regulation and expression of transgenes in fish -- a review. AB - Transgenic fish, owing to a number of advantages which they offer over other species, are proving to be valuable model systems for the study of gene regulation and development genetics in addition to being useful targets for the genetic manipulation of commercially important traits. Despite having begun only a decade ago, the production of transgenic fish has become commonplace in a number of laboratories world-wide and considerable progress has been made. In this review, we initially consider the various regulatory elements and coding genes which have been used in fish, and subsequently discuss and compare both the transient and long-term fate and expression patterns of injected DNA sequences in the context of the different factors which are likely to have an effect on the expression of transgenes. PMID- 8673145 TI - Accumulation of a sulphur-rich seed albumin from sunflower in the leaves of transgenic subterranean clover (Trifolium subterraneum L.). AB - A gene encoding a sulphur-rich, sunflower seed albumin (23% cysteine plus methionine) was modified to contain the promoter for the 35S RNA of cauliflower mosaic virus, in order to obtain leaf expression in transgenic plants. In addition, a sequence encoding an endoplasmic reticulum-retention signal was added to the 3' end of the coding region so as to stabilize the protein by diverting it away from the vacuole. The modified gene was introduced into subterranean clover (T. subterraneum L.) and its expression was detected by northern and western blots and by immunogold localization. The albumin was accumulated in the lumen of the endoplasmic reticulum, and, among six independent, transformed lines, it accumulated in the leaves of T0 transgenic plants at varying levels up to 0.3% of the total extractable protein. The level of accumulation of the sunflower albumin increased with increasing leaf age, and in the older leaves of the most highly expressing plants of the T1 generation it reached 1.3% of total extractable protein. Expression of the SSA gene was stable in the first and second generation progeny. These results indicate that there is potential for significantly improving the nutritional value of subterranean clover for ruminant animals such as sheep by expressing genes that code for sulphur-rich, rumen-stable proteins in leaves. PMID- 8673144 TI - A model for the mechanism of precise integration of a microinjected transgene. AB - A unique transgenic mouse line has undergone transgene integration in a very precise fashion. The phenotype displayed by mice of the line followed the predicted inheritance patterns for X-linked transgene insertion which has been confirmed. In order to investigate the mechanism of integration the DNA sequence of the transgene and cellular junctions have been determined. A comparison between wild type and transgenic mutant sequences at the site of insertion revealed that there was no loss or rearrangement of cellular DNA upon integration of the transgene. The cellular sequences at the transgene 5' and 3' joins are contiguous in the wild type. The integrant exists as a head to tail tandem dimer with minimal loss of sequence compared with the injected monomer. Analysis of the site of insertion has revealed a 5 bp homology between the 5' end of the transgene and the cellular sequences. In addition, adjacent to the site of insertion within the cellular sequences, there are several sequence motifs implicated in recombination events including a clustering of strong consensus sites of DNA topoisomerase type I and a region of homology to the human minisatellite consensus core sequence, the Escherichia coli Chi site and the meiotic recombination hotspot within the E beta gene of the murine major histocompatibility complex. This clustering of features is likely to have been factorial in the integrity of the insertion event. A model depicting the mechanism of this precise integration is proposed. PMID- 8673146 TI - Increased plasma corticosterone levels in bovine growth hormone (bGH) transgenic mice: effects of ACTH, GH and IGF-I on in vitro adrenal corticosterone production. AB - Previous work from our laboratory provided evidence for increased plasma corticosterone levels in mice transgenic for human and bovine growth hormone (GH). Corticosterone was elevated in both sexes, under both basal and ether induced stress conditions. The objectives of the present study were to investigate the in vitro adrenal sensitivity to ACTH, GH and/or IGF-I in normal and bGH transgenic mice, to examine plasma corticosterone levels at different times of the day, and to determine plasma levels of ACTH in these animals. For the measurement of plasma corticosterone and ACTH levels, transgenic and normal siblings were housed 2 per cage and decapitated simultaneously within 20 seconds of the first disturbance of the cage. The corticosterone production by in vitro adrenal incubations did not differ between adrenals from normal and transgenic mice at the basal level or in the presence of different doses of ACTH. Growth hormone or IGF-I did not have any effect on corticosterone production in vitro when given alone, and did not modify the effects of ACTH on the accumulation of corticosterone production in vitro when alone, and did not modify the effects of ACTH on the accumulation of corticosterone in the media. Plasma corticosterone concentrations were higher in transgenic than in normal animals in both morning and evening. Plasma concentrations of ACTH in animals killed in the morning were sharply increased in transgenic males as compared with their normal siblings. The results indicate that increased circulating levels of corticosterone in transgenic mice are not due to a potentiation of ACTH actions by GH or IGF-I, but rather to a chronic increase in plasma ACTH levels. The increase in ACTH is presumably a reflection of GH actions in the hypothalamic-pituitary system. PMID- 8673148 TI - Tracking H-2 alleles in transgenic mice by RFLP and heteroduplex analysis. AB - Transgenic mice provide valuable tools for biological research including many areas of immunology. In studies involving the major histocompatibility complex (MHC), it is often necessary to place the desired transgene in a specific H-2 (the murine MHC) environment. In this regard, the strains commonly used for the production of transgenic mice also carry well characterized H-2 alleles and provide an appropriate genetic background for MHC related experiments. In this study, a highly polymorphic microsatellite of tetranucleotide repeats from the second intron of the class II Eb gene within the H-2 complex was used in order to identify the corresponding alleles. The relevant H-2 allele(s) along with the transgene were then tracked throughout the production of a chicken ovalbumin specific transgenic strain. The technique involved PCR-amplification of a DNA sequence encompassing the H-2 specific microsatellite followed by RFLP and heteroduplex analyses. This approach is likely to find wide application in the background checking of transgenic mice, especially in immunological research requiring a defined H-2 background. PMID- 8673147 TI - Improved metabolic action of a bacterial lysine decarboxylase gene in tobacco hairy root cultures by its fusion to a rbcS transit peptide coding sequence. AB - The gene of a bacterial lysine decarboxylase (ldc) fused to a rbcS transit peptide coding sequence (tp), and under the control of the CaMV 35S promoter, was expressed in hairy root cultures of Nicotiana tabacum. The fusion of the ldc to the targeting signal sequence improved the performance of the bacterial gene in the plant cells in many respects. Nearly all transgenic hairy root cultures harbouring the 35S-tp-ldc gene contained distinctly higher lysine decarboxylase activity (from 1.5 to 30 pkat LDC per mg protein) than those which had been transformed with constructs in which the gene had been directly cloned behind the CaMV 35S promoter. The higher enzyme activity led to the accumulation of up to 0.7% cadaverine on a dry mass basis. In addition, part of the cadaverine pool was used for increased biosynthesis of anabasine, an alkaloid which was hardly detectable in control cultures. The best line contained anabasine levels of 0.5% dry mass, which could be further be enhanced by feeding of lysine. PMID- 8673149 TI - Genomic DNA analysis from mouse toe lysates. AB - The protocol described in this report provides a simple, accurate and efficient assay for detection of transgenes and mutations in large colonies of rodents, using crude lysates prepared from the digit cut from the animals for identification purposes. This can be done as early as 6 days of age, minimizing trauma to the mice and allowing assays to be completed long before weaning. PMID- 8673150 TI - Ubiquitin promoter-based vectors for high-level expression of selectable and/or screenable marker genes in monocotyledonous plants. AB - A set of plasmids has been constructed utilizing the promoter, 5' untranslated exon, and first intron of the maize ubiquitin (Ubi-1) gene to drive expression of protein coding sequences of choice. Plasmids containing chimaeric genes for ubiquitin-luciferase (Ubi-Luc), ubiquitin-beta-glucuronidase (Ubi-GUS), and ubiquitin-phosphinothricin acetyl transferase (Ubi-bar) have been generated, as well as a construct containing chimaeric genes for both Ubi-GUS and Ubi-bar in a single plasmid. Another construct was generated to allow cloning of protein coding sequences of choice on Bam HI and Bam HI-compatible restriction fragments downstream of the Ubi-1 gene fragment. Because the Ubi-1 promoter has been shown to be highly active in monocots, these constructs may be useful for generating high-level gene expression of selectable markers to facilitate efficient transformation of monocots, to drive expression of reference reporter genes in studies of gene expression, and to provide expression of biotechnologically important protein products in transgenic plants. PMID- 8673151 TI - Hormone replacement therapy: aspects of bleeding problems and compliance. AB - Mitigation of vasomotor symptoms and urogenital problems, along with reductions in osteoporosis and cardiovascular disease, provides the rationale for using hormone replacement therapy (HRT), and the duration of use. However, user surveys have indicated poor compliance with HRT, and that means user time may be less than 12 months, a period unlikely to influence metabolic disorders. The main reasons for discontinuing HRT are unacceptable bleeding pattern and fear of cancer. There is solid evidence that HRT does not increase gynecological, gastrointestinal, or other adenocarcinomas. In fact, the only remaining controversy relates to breast cancer. Since the media often underscore and strengthen "old wives' tales" about the menopause and HRT, access to correct, unbiased information is the key to combating the misconceptions about HRT. Information also helps women understand the nature of menstrual-like bleeding, and thus contributes to compliance. Unfortunately, existing formulations do not control the bleeding pattern in every women. Our understanding of spotting and breakthrough bleeding is still poor. Older data, which suggested routine endometrial histology to find the cause and select treatment of vaginal bleeds, have been contradicted, rendering endometrial biopsy less useful in decision making; endometrial ultrasonography seems to be of more value for endometrial surveillance in HRT. Recent advances in understanding the nature and function of growth factors in uterine tissues help to unravel an array of events of importance for explaining the bleeding sometimes encountered during continuous combined therapy. The pharmaceutical industry should be challenged to work closely with scientists and regulating agencies. Doing so will help to advance our knowledge and therapeutic modalities, which will help us to combat the chief cause of poor compliance to, and discontinuation of, a very important potential contributor to maintaining quality of life of elderly women. PMID- 8673152 TI - Regulation of estrogen/progestogen receptors in the endometrium. AB - Patient acceptance of standard cyclic hormonal replacement therapy (HRT) has been poor. One major cause of non-acceptance is thought to be the resumption of menses as a result of induced withdrawal bleeding. In order to prevent bleeding, continuous combined estrogen and progestin HRT has been utilized. However, most publications report irregular breakthrough bleeding in a majority of patients receiving the continuous HRT regimen. The cause of the irregular bleeding remains unclear at present. It is known that the continuous presence of progestin causes down-regulation of estrogen and progestin receptors and endometrial atrophy. Endometrial atrophy may result in withdrawal of stromal support for blood vessels leading to dilatation and extravasation of blood. In addition, progestin has been implicated in neovascularization, possibly by stimulation of vascular endothelial growth factor (VEGF). Finally, programmed cell death and apoptosis appear to occur in endometrial stroma after prolonged exposure to progesterone and may contribute to breakthrough bleeding. We have developed a novel interrupted progestin HRT regimen in which estrogen is given continuously, but with progestin administered in a 3-days-on and 3-days-off schedule. The rationale for this regimen is to prevent total receptor down-regulation by allowing estrogen to up regulate estrogen and progestin receptors during the progestin-free periods. Interrupting the progestin may also prove to be favorable in reducing neo angiogenesis. Clinically, we have demonstrated low bleeding rates in menopausal women, and in premenopausal women on long-term GnRH-agonist treatment for endometriosis or severe PMS, in whom the interrupted regimen has been used for addback HRT. Further basic and clinical studies, preferably in prospective randomized trials, are required to demonstrate reduced bleeding and improved patient acceptance compared to continuous combined HRT. PMID- 8673153 TI - Endometrial morphology and bleeding patterns as a function of progestogen supplementation. AB - Progestogens are added to estrogen replacement therapy for postmenopausal women to prevent endometrial hyperplasia and adenocarcinoma, and in sequential therapy to promote a regular and predictable bleed. This protective effect of progestogens is well recognized, but it is not due to endometrial shedding at a withdrawal bleed and cannot be predicted from the pattern or timing of the bleed. While irregular bleeding may be a reflection of endometrial abnormality and possibly insufficient progestogen, a regular controlled bleed may also occur in the presence of endometrial abnormality. A large multicenter study of postmenopausal women who were taking standard 28-day sequential regimens of estrogen and progestogen found a 2.7% prevalence of complex hyperplasia, and most of these women had a normal and regular bleeding pattern. Regular bleeding may also occur from an atrophic endometrium. Therapy employing a longer cycle with a course of progestogen given every 4 or 4 months may improve patient continuance for long-term therapy. During the estrogen-only phase, the endometrium becomes increasingly proliferative, and simple or cystic hyperplasia may develop only after about 12 weeks, and then can be corrected by progestogen. Women seem to prefer a less frequent withdrawal bleed despite the higher incidence of breakthrough bleeding compared to a monthly loss. Continuous combined therapy with estrogen and progestogen taken every day causes no withdrawal bleed, though some will have light breakthrough bleeding for the initial 2 or 3 months. The continuous progestogen keeps the endometrium atrophic and also converts preexisting complex endometrial hyperplasia occurring during sequential therapy to a normal state. As yet, there are no clinical guidelines that can give reassurance about the state of the endometrium in postmenopausal women who are taking hormone replacement therapy. PMID- 8673154 TI - The impact of different HRT regimens on compliance. AB - Epidemiological data strongly suggest a substantial improvement of quality of life for post-menopausal women using hormonal replacement therapy (HRT). Nevertheless, reluctance of women to choose HRT is high. Various attempts to develop regimens with substantially better acceptance are being investigated. Sequential and continuous combined regimens, oral and transdermal routes of administration are available; however, no regimen nor any mode of administration has proven superior with regard to patients' compliance. Research on the specific problems of compliance in HRT has not yet offered solutions to the medical community about optimal conditions concerning long-term hormonal therapy. Unless metabolic profiles of the various modes of treatment are defined in long-term trials, general recommendations are difficult to justify. As long as the occurrence of uterine bleeding is associated with any concept of HRT in non hysterectomized women, adherence has been reported to be very low. Persisting endometrial atrophy has not been achieved by any type of HRT. New regimens not stimulating endometrial growth are essential, since women in most cultures do not accept uterine bleeding after cessation of ovarian function. Educational programs should be developed to inform women about the physiology of menopause in general and the rationale of HRT. The occurrence of uterine bleeding due to the present types of HRT needs to be specifically addressed. Risk-benefit assessments are to be explained to patients to reach an informed decision on HRT, and fears of women about actual or alleged negative metabolic impacts of HRT need to be discussed. PMID- 8673155 TI - Laparoscopy in surgical treatment of vaginal aplasia: laparoscopy-assisted colpopoiesis and perineal hysterectomy with colpopoiesis. AB - OBJECTIVE: To optimize methods of surgery in patients with malformations of the genitalia. METHODS: Comparative evaluation of effectiveness of reconstructive plastic operations for malformations of uterus and vagina, performed by conventional methods or via laparoscopy. RESULTS: Laparoscopy permits identification of the pelvic peritoneum plus opening it and using the most mobile portion to create the vaginal fornix. In patients with vaginal and cervical aplasia and non-communicating functional rudimentary uterus, laparoscopy assists hysterectomy performed by the vaginal approach, as well as the last step of colpopoiesis. CONCLUSIONS: Laparoscopy significantly facilitates the procedure, reduces operating time and risks, and makes the operation available to the wide range of surgeons skilled in laparoscopy. PMID- 8673156 TI - The importance of computer-assisted semen analysis and sperm function testing in an IVF program. AB - OBJECTIVE: To study the relationship of sperm motion characteristics, sperm morphology, and hypo-osmotic swelling test with fertilization rates in vitro. DESIGN: Computer-assisted measures of fresh seminal and processed sperm preparations, sperm morphology, and hypo-osmotic swelling test results were assessed for predicting fertilization by step-wise regression analysis. SETTINGS: In vitro fertilization laboratory, department of infertility management, university affiliated-hospital. INTERVENTIONS: None. PATIENTS: One hundred and two couples who underwent IVF were studied. MAIN OUTCOME MEASURES: Computer assisted sperm motion variables in semen and following semen processing in capacitating media; hypo-osmotic swelling of sperm tails before and after semen processing; morphology of sperm before and after processing; fertilization of oocytes as evidenced by presence of two pronuclei as the end point. RESULTS: Various sperm motion parameters, hypo-osmotic swelling test results, and normal morphology of sperm were directly correlated to fertilization as judged by the Karl-Pearsons test. However, in step-wise regression analysis, normal morphology of sperm from seminal fraction exhibited 61% correlation with fertilization rates (P < .001). In step 2, normal morphology along with percent motility exhibited a 64% correlation with fertilization rates (P < .001). In step 3, normal morphology, percent motility, and linearity showed a 67% correlation with fertilization rates (P < .001). The hypo-osmotic swelling test did not predict fertilization rates (regression coefficient = 0.066, P = 0.474). In the processed sample preparations, normal sperm morphology showed a 72% correlation with fertilization rate (P < .001). In step 2, normal morphology along with curvilinear velocity exhibited a 77% correlation with fertilization rates (P < .001). In step 3, normal morphology, curvilinear velocity, and average path velocity showed a 79% correlation with fertilization rates (P < .001). The hypo osmotic swelling test did not predict fertilization rates (regression coefficient = 0.076, P = 0.512). CONCLUSIONS: Morphology of sperm and computer-assisted sperm motion variables, such as motility, linearity, curvilinear velocity, and average path velocity, may serve as prognostic indicators for fertilization potential of sperm. The hypo-osmotic swelling test may describe only physiological intactness, rather than the fertilization potential of sperm. The results suggest that objective analysis of sperm motion characteristics and precise sperm morphology may form a first, and obligatory, step for critical evaluation of patients before they start IVF treatment. PMID- 8673157 TI - Hemothorax after Lupron therapy of a patient with pleural endometriosis--a case report and literature review. AB - BACKGROUND: Pulmonary endometrial implants, although uncommon, have been well described in the literature. Symptoms occur with menses and may include recurrent pleuritic chest pain, pneumothorax, hemoptysis, or hemothorax. Exacerbation of pulmonary symptoms by Lupron therapy has not been previously described. CASE REPORT: A 38-year-old African-American female with known endometriosis but no history of pulmonary disease was evaluated for a 2-year history of severe dysmenorrhea. A trial of hormonal suppression was unsuccessful, and she was offered Lupron therapy. Three weeks after its initiation, and shortly after the onset of menses, she came to the emergency room with pleuritic chest pain and shortness of breath and was found to have a right-sided hemopneumothorax. Thoracentesis treatment was successful in eliminating this symptom. CONCLUSION: Although pulmonary endometriosis is rare, physicians should be aware that Lupron therapy can exacerbate pulmonary symptoms during the initial phase of therapy. PMID- 8673158 TI - Human factors and the FDA's goals: improved medical device design. AB - The Food and Drug Administration's new human factors design requirements for medical devices were previewed by the director of the FDA's Center for Devices and Radiological Health (CDRH) at AAMI/FDA's Human Factors in Medical Devices Conference held in September 1995. Director Bruce Burlington, MD, said the FDA plans to take a closer look at how new medical devices are designed to ensure proper attention has been paid to human error prevention. As a medical practitioner who has witnessed use-related deaths and injuries, Burlington stressed the importance of the medical community's reporting use errors as they occur and manufacturers' creating easy-to-use labeling and packaging. He also called for simplicity and quality of design in medical products, and asked for a consolidated effort of all professionals involved in human factors issues to help implement and further the FDA's new human factors program. An edited version of his presentation appears here. PMID- 8673159 TI - The IVAC infusion pump: user-centered design. PMID- 8673160 TI - Improving ease of use through automation and design. PMID- 8673161 TI - Designing user instructions. PMID- 8673162 TI - Total quality in biomedical technician training. University of Michigan Quality Improvement Teams. PMID- 8673163 TI - Safe, effective, and reliable software design and development. PMID- 8673164 TI - Software requirements: definition and specification. AB - The software requirements specification is the single most important document in the software development process. It provides the basis for development as well as for validation. The SRS needs to include adequate definition of all requirements without specifying implementation or project management issues. The SRS should be completed early in the development process. However, it is very likely that changes will occur during the development life cycle. This is not an excuse for approving and releasing the current version of the SRS. When changes occur, the SRS must be revised. In any case, the concept is to deal with the current, approved version of the SRS. Ultimately, the SRS should include all the information needed to proceed into the design phase of software development. PMID- 8673165 TI - Radiofrequency field surveys in hospitals. AB - The authors surveyed levels of radiofrequency (RF) fields in the frequency range 0.1-1,000 MHz in four hospitals in the Philadelphia area, to obtain background information related to the possible interference of radiofrequency fields with medical equipment. Two large center-city hospitals, a regional county hospital, and two suburban hospitals were surveyed. Measurements were made at six to 12 sites in each hospital, in each of the three frequency bands. More limited additional measurements were conducted in a fifth hospital as well. Sites were selected to include areas where strong RF signals from transmitting antennas might be expected to be present (e.g., locations close to windows in upper stories of buildings near paging antennas) as well as other representative sites in the hospital. The median RF field strengths were quite low (0.1-0.5 V/m), but at specific locations the RF signals from broadcast sources exceeded 1 V/m. Much stronger fields were recorded close to electrosurgical units and hand-held transmitters (cellular telephones and UHF transceivers). PMID- 8673166 TI - Evaluation of an instrument for noninvasive blood pressure monitoring in the forearm. AB - Attempts have been made to improve noninvasive clinical blood pressure (BP) monitoring by using monitoring sites more easily accessible than the traditional brachium. The purpose of the current study was to evaluate the performance of an automatic, noninvasive BP monitoring instrument that measures BP at the forearm. The only forearm BP monitoring instrument found on the market was the BP/Clinic (CardioAnalysis Systems). Blood pressure and heart rate (HR) measurements from the BP/Clinic were compared with sequentially recorded BPs determined by the auscultatory method and HRs determined by palpation of the radical artery. Accuracy, precision, and failure rates were determined for the BP/Clinic using linear regression, correlation coefficients, and standard error of the estimates. The accuracy and precision of the BP/Clinic approximated those of the standard methods. Systolic BP (r = 0.82) and HR (r = 0.85) correlated more closely with the standard than did diastolic BP (r = 0.75). It appears from this study that the forearm is an acceptable site for clinically useful systemic BP and HR measurements. In addition, the BP/Clinic performed sufficiently easily, accurately, and reliably to be useful for monitoring BP and HR. PMID- 8673167 TI - Central venous catheter placement using electromagnetic position sensing: a clinical evaluation. AB - A critical step in placing a central venous catheter (CVC) is positioning the catheter tip in a location just outside the heart in the lower superior vena cava. The authors report the clinical evaluation of a new commercially available system that uses electromagnetic technology to sense the position of a catheter tip during CVC insertion. Fifty catheters were implanted using fluoroscopy to monitor system accuracy. The catheters were accurately placed (within 2.5 cm of the desired optimal position) in 46 of the 50 cases (92%). In two patients with abnormal chest geometry (short, barrel chests), catheter tip location was difficult to determine. In two other cases, procedural difficulties unrelated to the system (difficulty in external landmark determination and unclear fluoroscopic view of the optimal position) resulted in catheter placement outside the targeted range. The electromagnetic system provides an opportunity to eliminate "blind" CVC placement procedures and to reduce or omit perioperative fluoroscopy of x-ray during CVC insertion. PMID- 8673168 TI - IEEE standards for physical and data communications. PMID- 8673169 TI - Engineers in clinical engineering: does the need remain? PMID- 8673170 TI - Should clinical engineering departments charge for their services? PMID- 8673171 TI - Should clinical engineering departments charge for their services? PMID- 8673173 TI - AIDS and HIV-1 infection in the United Kingdom: monthly report. PMID- 8673172 TI - New scheme for surveillance of hospital acquired infections. PMID- 8673174 TI - Bacterial meningitis in Europe: surveillance report for 1994. PMID- 8673175 TI - Cancer mortality among workers in the German rubber industry: 1981-91. AB - OBJECTIVES: To determine the cancer specific mortality of active and retired workers of the German rubber industry with emphasis on cancer sites which have been associated with the rubber industry in previous studies. METHODS: A cohort of 11,663 German men was followed up for mortality from 1 January 1981 to 31 December 1991. Cohort members were active (n = 7536) or retired (n = 4127) at the beginning of the study, and had been employed for at least one year in one of five study plants producing types or general rubber goods. Vital status was ascertained for 99.7% of the cohort members, and cause of death found for 96.8% of the 2719 decedents. Age and calendar year adjusted standardised mortality ratios (SMR) and 95% confidence intervals (95% CI) were calculated overall from national reference rates and stratified by year of hire and by years since hire. RESULTS: Mortalities from all causes (SMR 108; 95% CI 104-112) and all cancers (SMR 111; 95% CI 103-119) were significantly increased in the study cohort. Significant excesses in the mortalities from lung cancer (SMR 130; 95% CI 115 147) and pleural cancer (SMR 401; 95% CI 234-642) were identified. SMRs higher than 100 were found for cancers of the pharynx (SMR 144; 95% CI 76-246), oesophagus (SMR 120; 95% CI 74-183), stomach (SMR 110; 95% CI 86-139), rectum (SMR 123; 95% CI 86-170), larynx (SMR 129; 95% CI 69-221), prostate (SMR 108; 95% CI 84-136), and bladder (SMR 124; 95% CI 86-172), as well as for leukaemia (SMR 148; 95% CI 99-213). Mortalities from liver cancer, brain cancer, and lymphoma were lower than expected. CONCLUSIONS: Mortalities from cancer of several sites previously associated with the rubber industry were also increased among workers of the German rubber industry. Results of the stratified analyses are consistent with a role of occupational exposure in the aetiology of some of these cancers. PMID- 8673176 TI - Mortality study of employees with potential exposure to epichlorohydrin: a 10 year update. AB - OBJECTIVES: A 10 year extension of follow up (up to 1993) of 863 employees who had potential exposure to epichlorohydrin at two chemical plants between May 1948 and December 1965 was conducted to further evaluate the previously reported potential association between exposure to epichlorohydrin and heart disease. METHODS: The mortality observed was compared with that expected from the death rates from the local male population where these chemical plants are located. Workers were assigned to one of five exposure categories based on their job with the highest level of potential exposure. Vital status was ascertained to the end of 1993. RESULTS: Among diseases of particular interest, there were no excess deaths from heart disease (standardised mortality ratio (SMR) 63.3), lung cancer (SMR 63.8), or non-malignant respiratory disease (SMR 37.7) for employees with 20 or more years after first exposure. Based on the level of potential exposure to epichlorohydrin, mortality for heart disease was slightly higher (SMR 75.7, 95% confidence interval (95% CI) 51.8-106.7) in the moderate to heavy exposure group than in the none to light exposure group (SMR 59.5, 95% CI 37.7-89.3); this difference is well within the range of random variation. The SMR for heart disease was 90.4 among employees who had both probable exposure to allyl chloride and moderate to heavy exposure to epichlorohydrin, although it was 88.1 among employees who had moderate to heavy potential exposure to epichlorohydrin but no exposure to allyl chloride. CONCLUSIONS: This study does not support an association between exposure to epichlorohydrin and heart disease or lung cancer. There were no additional deaths from leukaemia in this update; the raised SMR for leukaemia noted in the previous study has substantially decreased from 500.0 to 161.3 (95% CI 33.2-471.0) and is not significant. The overall mortality and cancer mortality of employees potentially exposed to epichlorohydrin continued to be lower than that of the local population. PMID- 8673177 TI - Radium in drinking water and risk of bone cancer in Ontario youths: a second study and combined analysis. AB - OBJECTIVES: Radium induces bone sarcomas at high doses, but there is controversy about risk at low doses. A previous study in Ontario found an association between the presence of radium in birthplace water supplies and an increased risk of death from bone cancer in young people. An investigation was performed to test the findings of the previous study with an independent group of subjects for whom complete information on radium exposure would be obtained. METHODS: A population based case-control study (238 cases; 432 controls) was conducted with incident cases of bone sarcoma identified from the Ontario cancer registry. Residential histories were collected by questionnaire and water samples were obtained and analysed for radium content. RESULTS: There was an association between risk of osteosarcoma and birthplace exposures (odds ratios (ORs) and 90% confidence intervals (90% CIs) 1.77 (1.03-3.00) but not with lifetime measures of exposure. When lifetime exposure was dichotomised, the OR was 1.31 (0.76-2.24) for osteosarcoma. There was no trend with increasing exposure. Bootstrap resampling was used to simulate lifetime doses in a pooled analysis of 1293 subjects from the two Ontario studies. The ORs were 1.38 (1.08-1.73) for all sarcomas, and 1.44 (1.01-1.87) for osteosarcoma. Geometric mean doses in bone were about 26 mRad. CONCLUSIONS: An association was found between the presence of radium in birthplace water supplies and increased risk of bone sarcoma in two studies. Increased risk was present for lifetime measures of exposure, but the association was not significant, and there was no dose-response trend. Our findings are compatible with the absence of risk at low doses, but they might also reflect inadequate statistical power to measure a true risk at environmental exposure levels. If the increased risk at environmental doses is causal, risk of bone sarcoma is effectively linearly related to dose over five orders of magnitude. PMID- 8673178 TI - Dust exposure, respiratory symptoms, and longitudinal decline of lung function in young coal miners. AB - OBJECTIVES: To study the role of dust exposure on incidence of respiratory symptoms and decline of lung function in young coal miners. METHODS: The loss of lung function (forced vital capacity (FVC), forced expiratory volume in one second (FEV1), forced expiratory flow (MEF), carbon monoxide transfer factor (TLCO)) with time and the incidence of respiratory symptoms in 909 Sardinian coal miners (followed up between 1983 and 1993 with seven separate surveys) has been compared with the past and current individual exposures to respirable mixed coal dust. Multiple linear and logistic regression models were used simultaneously controlling for age, smoking, past occupational exposures, and other relevant covariates. RESULTS: According to the relatively low dust exposures experienced during the follow up few abnormal chest x ray films were detected. In the cross sectional analysis of initial data, significant associations between individual cumulative exposure to dust, decrements in FEV1 and MEFs, and increasing prevalence of respiratory symptoms were detected after allowing for the covariates included in the model. The yearly decline of FVC, FEV1, and single breath carbon monoxide transfer factor (TLCO/VA) was still significantly related to the individual exposure to dust experienced during the follow up, even after allowing for age, smoking, initial cumulative exposure to dust, and initial level of each functional variable. In logistic models, dust exposure was a significant predictor of the onset of respiratory symptoms besides age and smoking. CONCLUSIONS: The results show that even moderate exposures to mixed coal dust, as in our study, significantly affect lung function and incidence of symptoms of underground miners. Although the frequency of chest x ray examination might be fixed at every three or four years, yearly measurements of lung function (spirometry, MEFs, and TLCO) are recommended for evaluation of the respiratory risk from the coal mine environment to assess the need for further preventive interventions. PMID- 8673179 TI - Geographical and temporal differences in the urinary excretion of inorganic arsenic: a Belgian population study. AB - OBJECTIVE: This Belgian study assessed the geographical and temporal differences in the exposure of the population to inorganic arsenic, a known carcinogen. METHODS: In the CadmiBel study (1985-9) the 24 h urinary arsenic excretion was measured, as an index of recent exposure, in industrialised cities (Liege: n = 664, Charleroi: n = 291), in a rural control area (Hechtel-Eksel: n = 397), and in rural districts in which the population had possibly been exposed through the drinking water or the emissions of nonferrous smelters (Wezel: n = 93, Lommel: n = 111, and Pelt: n = 133). In the PheeCad study, in 1991-5, the rural areas (n = 609) were re-examined together with an urban control area (Leuven: n = 152). RESULTS: The CadmiBel results showed that after adjustment for sex, age, and body mass index, the 24 h arsenic excretion was on average low in Liege (91 nmol), Charleroi (155 nmol), Hechtel-Eksel (144 nmol), and Wezel (158 nmol), whereas the highest excretions were found in Lommel (570 nmol) and Pelt (373 nmol). During the PheeCad study, the mean 24 h arsenic excretion in the rural areas ranged from 81 to 111 nmol. This was lower than six years earlier and similar to the excretion in the control town (108 nmol). Longitudinal studies in 529 people living in the rural areas confirmed that their 24 h arsenic excretion had decreased (P < 0.001) from 222 to 100 nmol. As well as the drinking water, industry was likely to be a source of the increased exposure in Lommel and Pelt in 1985-9, because at that time the urinary arsenic excretion did not follow the regional differences in the arsenic content of the drinking water, because the fall in the arsenic excretion over time coincided with the implementation by industry of stricter environmental regulations, because in individual subjects the urinary arsenic excretion was inversely correlated with the distance to the nearest smelter, and because an increased arsenic excretion was only found downwind from the main smelter. The official network that monitors the arsenic concentration in airborne and fall out dust did not detect the high exposure in Lommel and Pelt between 1985 and 1989. CONCLUSION: This study highlights the necessity to validate environmental monitoring programmes by directly estimating the internal exposure of the population. PMID- 8673181 TI - Exposure to magnetic fields estimated from last job held in an electrical utility in Quebec, Canada: a validation study. AB - OBJECTIVES: To investigate how closely the variables of exposures to magnetic fields based on the last job held in an electrical utility in Quebec, Canada, compared with those based on the workers' entire employment history with the company. METHODS: In large cohort studies, the last job held is often used to assign exposure to the study subjects. Exposure was assigned in this way for a mortality study of a cohort of electrical utility workers in Quebec. For the present study, a sample of the cohort was used to compare the exposure estimates obtained from the last job with those obtained from full work histories. RESULTS: The correlations between indices based on the last job and on all jobs varied between 0.75 and 0.78. The mean was slightly lower when only the last job was used. The last job was particularly good in identifying the most highly exposed people (for the exposure cut off point of 90th percentile for the last job and for all jobs, sensitivity = 0.69, specificity = 0.97, kappa = 0.66). The results suggest that although not all workers starting in highly exposed jobs stayed in them, it seemed that the workers who ended their working life in highly exposed jobs had stayed in these jobs throughout their working life. CONCLUSION: The results indicated some (but not catastrophic) loss of information when estimates of exposure were based on the last job only. PMID- 8673180 TI - Biomarkers of exposure to low concentrations of benzene: a field assessment. AB - OBJECTIVE: To carry out a comprehensive field investigation to evaluate various conventional and recently developed biomarkers for exposure to low concentrations of benzene. METHODS: Analyses were carried out on environmental air, unmetabolised benzene in blood and urine, urinary trans, transmuconic acid, and three major phenolic metabolites of benzene: phenol, catechol, and hydroquinone. Validations of these biomarkers were performed on 131 never smokers occupationally exposed to the time weighed average benzene concentration of 0.25 ppm (range, 0.01 to 3.5 ppm). RESULTS: Among the six biomarkers studied, unmetabolised benzene in urine correlated best with environmental benzene concentration (correlation coefficient, r = 0.76), followed by benzene in blood (r = 0.64). When urinary metabolites were compared with environmental benzene, trans, trans-muconic acid showed a close correlation (r = 0.53) followed by hydroquinone (r = 0.44), and to a lesser extent with urinary phenol (r = 0.38). No correlation was found between catechol and environmental benzene concentrations. Although unmetabolised benzene in urine correlates best with benzene exposure, owing to serious technical drawbacks, its use is limited. Among the metabolites, trans, trans-muconic acid seems to be more reliable than other phenolic compounds. Nevertheless, detailed analyses failed to show that it is specific for monitoring benzene exposures below 0.25 ppm. CONCLUSION: The overall results suggest that most of the currently available biomarkers are unable to provide sufficient specificity for monitoring of low concentrations of benzene exposure. If a lower occupational exposure limit for benzene is to be considered, the reliability of the biomarker and the technical limitations of measurements have to be carefully validated. PMID- 8673182 TI - Retinal angiography in divers. AB - OBJECTIVE: In the light of previous reports, to examine the possibility that professional diving might cause abnormalities of the retina and choroid. METHODS: The retinal fluorescein angiograms of 55 Royal Naval divers and 24 non-diver servicemen were compared. RESULTS: No differences were found between divers and non-divers and the prevalence of abnormalities was not correlated with diving experience. CONCLUSION: In contrast to previous reports, there seem, at least in naval personnel, to be no ocular consequences of diving. PMID- 8673183 TI - Mortality from injuries and other causes in a cohort of 21,800 Brazilian steel workers. AB - OBJECTIVES: Injury is the leading cause of death in the male working population of Brazil. An important fraction of these deaths are work related. Very few cohort studies of steel workers, and none from developing countries, have reported on mortality from injuries. This paper analyses mortality from work and non-work related injuries among Brazilian steel workers. METHODS: Deaths during employment from 1 January 1977 to 30 November 1992 were analysed in a cohort of 21,816 male steel workers. Mortality rates specific for age and calendar year among the workers were compared with those of the male population of the state where the plant is located. Work related injuries were analysed by comparing the mortality rates for different subgroups of the cohort. RESULTS: The number of deaths (391) was less than half that expected based on death rates of the general population. Over 60% (242) of deaths were due to injuries. Mortality from most causes was substantially below that in the general population, but that from unintentional injury, was 50% above that of the general population. Standardised mortality ratios (SMRs) were highest for the youngest and the oldest employees and for labourers and clerical workers. Mortality from motor vehicle injury was twice that expected from population rates (SMR = 209, 95% confidence interval (95% CI) 176-244). There was a 67% fall in the age adjusted mortality from occupational injuries in the study period. CONCLUSION: The healthy worker effect in this cohort was greater than that commonly found in studies of occupational groups in developed countries, probably because of a greater socioeconomic gap between employed and unemployed populations in Brazil, and unequal distribution of health care resources. Mortality was especially high for motor vehicle injuries. The fall in mortality from occupational injuries during the study period was probably due to improvement in safety standards, increased automation, and better medical care. There is a need to investigate risk factors for unintentional injuries among steel workers, especially those due to motor vehicle injuries. Prevention of occupational and nonoccupational injuries should be a main priority in Brazil. PMID- 8673184 TI - Psychosocial and physical risk factors for musculoskeletal disorders of the neck, shoulders, and lower back in salespeople. AB - OBJECTIVES: To analyse the association between symptoms from the musculoskeletal system and many psychosocial and other physical stressors in the job demand control-support model. Also to analyse the influence of personality characteristics. METHODS: 1306 salespeople answered a self administered questionnaire on job characteristics, exposures, personality characteristics, social network, smoking and drinking habits, and symptoms of the neck, shoulders, and low back. RESULTS: In multivariate analyses, high job demands were related to neck and shoulder symptoms (ORs 1.43-1.47 in the highest exposure groups compared with the lowest), and tendency to become overworked and lack of social support from colleagues were related to back pain (OR 1.81-2.04 in the highest exposure groups compared with the lowest). Lack of variation in the job, low control over time, and high competition were related to neck symptoms, but there was an interaction so that both low control over time and high competition had to be present to increase the OR. Also, driving long distances and sedentary work were related to neck and low back pain, and time spent in the car to shoulder pain (ORs 1.64-2.80 in the three highest groups v the lowest exposure groups). CONCLUSION: Both psychosocial and physical factors were associated with musculoskeletal symptoms. Many dimensions of the demand-control-support model were associated with symptoms. Only one personality characteristic, tendency to feel overworked, significantly influenced the prevalence of musculoskeletal symptoms. PMID- 8673185 TI - Risk of myelogenous leukaemia and multiple myeloma in workers exposed to benzene. PMID- 8673186 TI - Comment on EQM testmate OP cholinesterase kit. PMID- 8673187 TI - The myth of conscious sedation. PMID- 8673188 TI - Levels of consciousness and ventilatory parameters in young children during sedation with oral midazolam and nitrous oxide. AB - OBJECTIVE: To determine the ventilatory effects and levels of consciousness achieved during sedation with the combination of oral midazolam and inhaled nitrous oxide. DESIGN: Case series. SETTING: Surgical suite. PATIENTS: Twenty-two consecutive children, aged 1 to 3 years, were seen for elective, ambulatory surgery. INTERVENTIONS: Patients were premedicated with oral midazolam hydrochloride, 0.5 mg/kg, and then breathed 4 concentrations of nitrous oxide (N2O) in oxygen (15%, 30%, 45%, and 60%) for 4 minutes at each concentration prior to induction of general anesthesia. MAIN OUTCOME MEASURES: Levels of consciousness (conscious vs deep sedation) and ventilatory parameters: respiratory rate, end-tidal carbon dioxide tension (PETCO2), and oxyhemoglobin saturation (SPO2). Upper airway obstruction was diagnosed by clinical assessment by an experienced pediatric anesthesiologist (R.S.L.) and respiratory impedance plethysmography. RESULTS: During inhalation of N2O, 12 of the 20 children demonstrated a mild degree of ventilatory depression; PETCO2 values were equal to or greater than 45 mm Hg during at least 2 concentrations of N2O studied. There were no significant changes in SPO2 or PETCO2 with increasing concentrations of N2O (P > .05). Respiratory rates tended to be lower during inhalation of 15% N2O than at higher concentrations (P = .05). No child developed upper airway obstruction or hypoxemia (SPO2 < 92%) at any level of N2O inhalation. Sedation scores were significantly higher at 60% N2O than at all other concentrations of N2O (P < .02) At 15% N2O, 12 children were not clinically sedated, 8 children met the American Academy of Pediatrics definition of conscious sedation, and no child met the definition of deep sedation. At 30% N2O, 10 children were not clinically sedated, 9 met the definition of conscious sedation, and 1 child met the definition of deep sedation. At 45% N2O, 9 children were not clinically sedated, 9 met the definition of conscious sedation, and 2 met the definition of deep sedation. At 60% N2O, 6 children were not clinically sedated, 6 met the definition of conscious sedation, 6 met the definition of deep sedation, and 1 child progressed to a deeper level of sedation in that there was no response to a painful stimulus. One child was withdrawn from the study during inhalation of 45% N2O because of emesis. CONCLUSIONS: The combination of oral midazolam, 0.5 mg/kg, and up to 60% inhaled N2O caused mild ventilatory depression in some children and resulted in a progression from conscious to deep sedation beginning at 30% N2O. When using this particular combination of sedatives, practitioners should monitor each child's mental status continuously and adhere to the appropriate published guidelines for the monitoring and management of such patients. PMID- 8673190 TI - Tuberculosis testing. Physician attitudes and practice. AB - OBJECTIVE: To assess physician agreement with and adoption of American Academy of Pediatrics' (AAP) recommendations on tuberculosis screening in children. DESIGN AND PARTICIPANTS: Survey of a random sample of 1272 community pediatricians and family physicians (excluding academic institutions) in 4 mid-Atlantic states and the District of Columbia. RESULTS: The response rate was 66%. Seventy-five percent of the respondents were aware of the 1994 AAP screening recommendations. Most (64%) test children at low risk periodically (at age 1 year, preschool age, and adolescent age), and 81% test children at high risk annually. Eighty-one percent of the respondents estimated that 10% or less of their patients were at high risk for tuberculosis. Most use patient-specific factors, geographic or community prevalence, or both as principal criteria to determine risk. Eighty seven percent used multiple-puncture tests in 1993; this declined to 55% in 1994. Multiple-puncture tests are still used exclusively by 29% of the respondents. Ninety-one percent of those using multiple-puncture tests and 19% of those using the Mantoux test allow parents to read the test reaction. Forty-six percent of the respondents believed that if a return visit was required for reading the test reaction, 50% or less of their patients would return. Only 22% of the respondents adhere to the 1994 AAP recommendations regarding frequency, testing method, and reading the test reaction. Factors associated with adherence to AAP recommendations included physician and practice characteristics and knowledge of AAP recommendations. CONCLUSIONS: Physician practice of tuberculosis testing varies widely; most do not adhere to the 1994 AAP recommendations. Most physicians vary the frequency and testing method based on a patient's risk status. The use of multiple-puncture tests has declined, although they are still widely used. Accurate reading of screening tests remains a major concern. PMID- 8673189 TI - Intramuscular ketamine is superior to meperidine, promethazine, and chlorpromazine for pediatric emergency department sedation. AB - OBJECTIVE: To compare ketamine hydrochloride (KET) with combined meperidine hydrochloride, promethazine hydrochloride, and chlorpromazine hydrochloride (MPC) for pediatric emergency department sedation with respect to onset, duration, and efficacy. DESIGN: Prospective, randomized, double-blind clinical trial. SETTING: Pediatric emergency department in an urban university hospital. PATIENTS: Convenience sample of 29 patients, 6 months to 6 years of age, requiring sedation for suturing, wound or burn debridement, or lumbar puncture. INTERVENTION: Children received intramuscular KET (4 mg/kg) with atropine sulfate (0.01 mg/kg) or MPC (meperidine hydrochloride 2 mg/kg, promethazine hydrochloride 1 mg/kg, chlorpromazine hydrochloride 1 mg/kg). Data collection included demographics, vital signs, and onset of sedation; procedural distress using the Observational Scale of Behavioral Distress; and time to recovery. The operator was questioned on satisfaction with the drug, and parents received follow-up to assess parental satisfaction. RESULTS: Of the 29 patients enrolled in the study, 2 were excluded for protocol violation, 15 received KET, and 12 received MPC. Demographics and baseline vital signs did not differ. Although patients in the 2 groups had a similar duration of sedation (KET, 82 min vs MPC, 97 min, P = .15), patients receiving KET had more rapid onset of sedation (3 min vs 18 min, P < .01) a shorter time to discharge (85 min vs 113 min, P 0 .01) and lower Observational Scale of Behavioral Distress scores (9.9 vs 19.2, P = .003). All 15 physicians using KET would request it again vs 5 of 12 (42%) of the physicians using MPC (P < .001). No serious adverse reactions occurred. There were no differences in parental satisfaction. CONCLUSION: Ketamine has a faster onset and results in more rapid discharge from the pediatric emergency department while providing for less patient distress during procedures. Ketamine is also associated with greater physician satisfaction than MPC. PMID- 8673191 TI - Effects of maternal hypertension in very-low-birth-weight infants. AB - OBJECTIVE: To determine the effects of mild vs severe maternal hypertension on the neonatal morbidity of very-low-birth-weight infants. DESIGN: Cohort case control study. SETTING: Tertiary care center neonatal intensive care unit. PATIENTS: Thirty-nine infants born to mothers with maternal hypertension (blood pressure > or = 140/90 mm Hg on 2 occasions during pregnancy) among 267 very-low birth-weight infants (< or = 1250 g) admitted to the special care nursery between January 1, 1991, and December 31, 1992. Each infant was matched for gestational age and survival to 2 control infants born to normotensive mothers. The cohort included 11 infants of mothers with mild hypertension, 28 with severe hypertension, and 78 controls. MAIN OUTCOME MEASURES: Late and variable decelerations, incidence of small size for gestational age, respiratory distress syndrome, intraventricular hemorrhage, patent ductus arteriosus, apnea, ventilator therapy, oxygen requirement, and bronchopulmonary dysplasia. RESULTS: The mild and severe maternal hypertension groups had significantly lower birth weights and more infants small for gestational age than did controls. The incidence of respiratory distress syndrome, however, was significantly lower in infants of mothers with mild hypertension than in those with mothers with severe hypertension. Those in the mild group had fever days of ventilatory therapy and lower oxygen requirements than both the infants in the severe group and control infants. The incidence of apnea in the mild hypertension group was significantly lower than that in the severe hypertension group. CONCLUSIONS: Although mothers with both mild and severe hypertension have an increased incidence of infants small for gestational age, the infants born to mothers with mild hypertension had less respiratory distress syndrome, apnea, ventilator therapy, oxygen requirements, and bronchopulmonary dysplasia when compared with very-low-birth weight infants born to mothers with severe hypertension. PMID- 8673192 TI - Risk and resilience among children and youth with disabilities. AB - OBJECTIVE: To review the literature on risk and protective factors as applied to children with chronic and disabling conditions so as to assist the health care professional in developing clinical strategies and interventions. DESIGN: Literature review. MAIN OUTCOME VARIABLES: Risk factors (eg, emotional problems, school failure) and protective variables (eg, family cohesion, school involvement). RESULTS: Both risk and protective factors can be identified at multiple levels: the condition, the child, the family, and the community. Conditions that are invisible have remitting-relenting courses, and where the prognosis is uncertain, these conditions are associated with the greatest emotional problems. Males with chronic conditions appear to have more emotional sequelae than do females. Likewise, personality characteristics of sociability and flexibility and physical characteristics of attractiveness are protective. Families with clear boundaries and a capacity to balance competing family needs, maintain flexibility, and ascribe positive meanings to life events all are protective. CONCLUSIONS: As increasing numbers of children with chronic conditions survive through adolescence to adulthood, the creation of environments where children can optimally develop becomes ever more pressing. It is evident that a range of factors, many amenable to interventions, can influence outcomes for these young people. PMID- 8673193 TI - Drinking on campus. Undergraduate intoxication requiring emergency care. AB - OBJECTIVES: To (1) determine the incidence of undergraduate graduate students with alcohol intoxication who presented to our emergency department (ED), (2) examine the demographic correlates of the students, and (3) look at associated injuries that were sustained by the students. DESIGN: Retrospective case series. SETTING: A tertiary care medical center that was located on the campus of a major university. PATIENTS: Undergraduate students with alcohol intoxication who presented to the ED. MAIN OUTCOME MEASURES: Demographic data and associated injuries of intoxicated students who presented to the ED during 2 academic years. RESULTS: Forty-four students presented with alcohol intoxication for a yearly incidence of 3.9 per 1000 students. Freshmen were overrepresented compared with students in other higher classes, with an incidence of 9.3 per 1000 per year (P < .001). Nine (20%) of the 44 students sustained an injury from a fall, and 1 required mechanical ventilation for treatment of apnea. CONCLUSIONS: Alcohol intoxication that requires emergency care is not uncommon among college students, and many students with alcohol intoxication present to the ED following a fall. Freshmen are particularly likely to present for care in an ED. PMID- 8673194 TI - Role of the primary care provider in expediting care of children with acute appendicitis. AB - OBJECTIVE: To assess the role of the primary care provider (PCP) in the diagnosis and treatment of acute appendicitis in children by determining whether there were differences in the treatment and outcome of children whose parents contacted the PCP before taking the child to the hospital compared with those who did not. DESIGN: Retrospective review of medical records of pediatric patients discharged from the hospital with the diagnosis of acute appendicitis. SETTING: An urban children's hospital. METHODS: The medical records of children treated for acute appendicitis from July 1, 1990, through June 30, 1994, were identified through review of hospital discharge data and divided into 2 groups based on whether the children's parents had contacted the PCP before their arrival at the hospital. Contact with the PCP was determined by record review or telephone interview with the parent. The 2 groups were then studied for differences in treatment and outcome. Statistical analysis was by the X2 test and the Student t test, as appropriate, with the level of significance determined at P < .05. RESULTS: During the 4-year period, 343 children underwent appendectomy. Medical records were available for review for 321 children (94%). After review, records of 38 children were excluded because the primary problem was not acute appendicitis. Of the 283 children whose records were included in the study, the parents of 160 had contacted the PCP before arrival at the hospital (group 1, those who called) and the parents of 99 had not called (group 2, those who did not call). It could not be determined whether a call had been made for 24 children. The mean age of the children in group 1 was 124 months and in group 2 was 126 months (P = .74). Of group 1, 24% arrived at the hospital on a Saturday or Sunday, compared with 40% of group 2 (P = .007). Children in group 1 who arrived at the hospital during the weekend were operated on a mean (SD) of 4.7 hours (3.7 hours) after arrival at the hospital, compared with 10.6 hours (17.1 hours) for children in group 2 (P = .04). The mean (SD) interval between arrival at the hospital and operation on weekdays (Monday through Friday) was similar in both groups: 12 hours (20.6 hours) in group 1 and 13.7 hours (25.6 hours) in group 2 (P = .63). Appendiceal perforation was less likely in children in group 1 (62/160 [39%]) than in those in group 2 (53/99 [54%]; P = .03). Parents of 50 (89%) of 56 children who belonged to a health maintenance organization called the PCP compared with 96 (62%) of the 156 with fee-for-service insurance and 10 (26%) of the 38 with Medicaid (P < .001). No difference was noted in the interval between arrival at the hospital and operation or incidence of appendiceal perforation according to type of insurance. CONCLUSIONS: Children with appendicitis whose parents contacted the PCP before arrival at the hospital were less likely to have appendiceal perforation than those whose parents did not call the PCP, irrespective of insurance status. Children whose parents called the PCP before arrival at the hospital during the weekend were operated on more promptly than were children whose parents did not call the PCP. Contact with the PCP was associated with more expeditious care of children with acute appendicitis. PMID- 8673195 TI - Effect of a state law on reported bicycle helmet ownership and use. AB - OBJECTIVE: To evaluate the effect of a state law on reported bicycle helmet ownership and use. DESIGN: Multistage cluster random-digit-dialing telephone survey. SETTING: Georgia, June through November 1993. PARTICIPANTS: Adults who reported the behavior of bicyclists 4 through 15 years old. INTERVENTION: State law mandating helmet use after July 1, 1993, for all bicyclists aged younger than 16 years. MAIN OUTCOME MEASURES: Bicycle helmet ownership and use. RESULTS: Reported helmet ownership increased from 39% before the law took effect to 57% afterward (+ 46%, P = .06). Reported use increased from 33% before to 52% afterward (+ 58%, P < .05). About 7% of riders changed from "never-wearing" to "always-wearing" behavior. After the law took effect, in those households in which the law was known, 69% of riders owned and 64% used a helmet. By comparison, in those households in which the law was not known, only 30% owned and 25% used a helmet (P < .01). Reported ownership and use were 93% concordant, inversely related to rider age, and directly related to household income. Multivariable analysis indicated that race was an effect modifier of reported helmet ownership and use. In black riders, knowledge of the law appeared to be highly associated with both reported helmet ownership and use but was not significant in white riders. In white riders, though age and income were significantly associated with reported helmet ownership and use. CONCLUSIONS: This law appeared important in increasing reported helmet ownership and use, particularly in black riders. Since knowledge of the law was associated with increased ownership and use, additional publicity about the law might further increase helmet use. Because most riders who owned helmets used them, give-away programs targeting areas of low ownership may also increase use. PMID- 8673196 TI - The Adolescents Training and Learning to Avoid Steroids (ATLAS) prevention program. Background and results of a model intervention. AB - OBJECTIVE: To develop and test a school-based intervention to prevent anabolic androgenic steroid use among high-risk adolescent athletes. DESIGN: Nonrandom controlled trial. SETTING: Two urban high schools. PARTICIPANTS: Fifty-six adolescent football players at the experimental school and 24 players at the control school. INTERVENTION: Eight weekly, 1-hour classroom sessions delivered by the coach and adolescent team leaders, and eight weight-room sessions delivered by research staff. The intervention addressed sports nutrition and strength training as alternatives to steroid use, drug refusal role play, and antisteroid media campaigns. OUTCOME MEASURES: A preintervention and postintervention questionnaire that assessed attitudes toward and intent to use steroids and other drugs; knowledge of drug effects; and diet, exercise, and related constructs. RESULTS: Compared with controls, experimental subjects were significantly less interested in trying steroids after the intervention, were less likely to want to use them even if their friends used them, were less likely to believe steroid use was a good idea, believed steroids were more dangerous, had better knowledge of alternatives to steroid use, had improved body image, increased their knowledge of diet supplements, and had less belief in these supplements as beneficial. CONCLUSIONS: Significant beneficial effects were found despite the sample size, suggesting that the effects of the intervention was large. This outcome trial demonstrates an effective anabolic androgenic steroid prevention program for adolescent athletes, and the potential of team-based interventions to enhance adolescents' health. PMID- 8673197 TI - Screening for tuberculosis infection in urban children. AB - OBJECTIVES: To determine the proportion of children who are at high risk for tuberculosis (TB) as defined by the American Academy of Pediatrics (AAP) criteria, the rate of compliance with visits for tuberculin skin test (TST) interpretation, and the prevalence of TB infection. DESIGN: A cross-sectional study of 401 children, 12 months to 18 years of age, who attended a hospital based, urban pediatric clinic for well-child visits was undertaken from April 13, 1994, through August 30, 1994. Respondents completed a self-administered questionnaire, an intradermal TST was applied, and an appointment was scheduled for skin test interpretation in 48 to 72 hours. SETTING: Hospital-based, pediatric primary care center in Rochester, NY, serving children of low to moderate income (67% were receiving Medicaid). RESULTS: Of the 401 children, 342 (85%) had at least 1 risk factor for TB identified: 96 (24%) reported contact with persons who were considered to be at high risk for TB; 170 (42%) had at least 1 parent who was born in a high prevalence country; and 269 (67%) reported a household income of less than $15,500. Of the 401 children, 300 returned for TST interpretation, 257 (64%) by 48 to 72 hours and an additional 43 (11%) by 96 hours. Four (1.3%) of the 300 children had a positive TST (ie, induration > or = 10 mm). All 4 of the children who were TST positive had at least 1 parent from a high-risk country and were identified using AAP-defined risk criteria. The mean age of children who were TST positive was 15.3 years (range 13-17 years) compared with 8.1 years for those who were TST negative (P < .01). The positive predictive value of the questionnaire, which included income as a risk factor for TB, was only 1.5 (95% confidence interval = 0.5-4.0); when household income was not considered a risk factor, the positive predictive value was 2.0 (95% confidence interval = 0.7, 5.5). The estimated cost per child who was TST positive ranged from $430 for those who had contact with an incarcerated adult to $855 per child who was TST positive identified by using AAP-defined criteria. CONCLUSIONS: The overall sensitivity of the AAP-defined criteria and having at least 1 parent from a TB-endemic country were high. However, because of the low prevalence of TB infection, the positive predictive value of these criteria was very low. These data support AAP recommendations only to skin test children who are at high risk for TB, but they also suggest that annual testing may not be cost-effective for many communities in the United States. PMID- 8673198 TI - Directly observed preventive therapy. Turning the tide against tuberculosis. AB - OBJECTIVE: To compare compliance between directly observed preventive therapy and daily treatment for students with inactive (class II) tuberculosis. DESIGN: Cohort analytic study and cost-effectiveness analysis. Students found to be positive for purified protein derivative and having no abnormal chest x-ray films on mandated screening were advised to have prophylactic treatment with isoniazid. Treatment was either directly observed in the school health clinic or provided as daily therapy by the Department of Health. Treatment completion, age, sex, ethnicity, and recent immigration were compared between the 2 treatment groups. SETTING: A school-based clinic at an inner-city New York, NY, high school. RESULTS: In 1993, 864 students were screened. The positive purified protein derivative rate was 19.3%. All 161 students had negative findings on chest x-ray films. Of the students, 105 (65.2%) were enrolled in the school-based clinic directly observed preventive therapy program, 22 were referred to the Department of Health for daily therapy, and 34 excluded from the study before treatment. The 2 treatment groups did not differ in composition. Completion of therapy in the directly observed preventive therapy group (87.6%) was significantly greater than that in the daily therapy group (50%) (P = 0.001, X2 = 11.8) and that reported in the literature for programs other than directly observed preventive therapy (30% 70%). Directly observed preventive therapy was administered by existing personnel without additional expenditure. CONCLUSION: Directly observed preventive therapy is an effective strategy that should be used in the school clinic setting to increase compliance with prophylactic treatment for tuberculosis. PMID- 8673199 TI - Pediatric trauma documentation. Adequacy for assessment of child abuse. AB - OBJECTIVE: To determine how frequently information considered necessary for identification of potential cases of child abuse or neglect was adequately documented in cases of pediatric trauma. DESIGN: Retrospective study; medical record review. SETTING: Tertiary care hospital. SUBJECTS: The study included 1018 children treated in the emergency department or admitted to the hospital for trauma during the first 6 months of 1992. MAIN OUTCOME MEASURE: Physicians' documentation of information pertinent to the identification of child abuse and neglect. RESULTS: Of the 642 medical records that met study criteria, 28 (4%) included no history of how the child's injury occurred. A complete examination was documented in only 209 (33%) of the cases. The presence of a witness at the time of injury and inquiries about any previous injury were inadequately documented. The color of the injury was noted in only 57 (9%) of the medical records reviewed. The injury was consistent with the history in 614 (96%) of the cases. In 41 (6%) of the cases, because of inadequate documentation, reviewers were uncertain whether child abuse or neglect had occurred. Only 23 cases (4%) were reported to child protective services at the time of the examination. CONCLUSIONS: Documentation of pediatric trauma remains inadequate to differentiate accidental trauma from abuse. Inadequately explained or repeated injuries in children must be reported as suspected child abuse and neglect, and those reports should include well-documented histories and physical examinations by the physician involved. PMID- 8673200 TI - A program to control an outbreak of hepatitis A in Alaska by using an inactivated hepatitis A vaccine. AB - OBJECTIVE: To stop an epidemic of hepatitis A in rural Alaska by mass immunization of susceptible persons with 1 dose of an inactivated hepatitis A vaccine. DESIGN: Nonrandomized, uncontrolled trial. Hepatitis A vaccine was offered to all persons in susceptible age groups in villages with documented cases of hepatitis A. Immune globulin was not offered at the time of vaccination. SETTING: Twenty-five rural communities located in interior Alaska and along the northwest coast of the Bering Sea and Arctic Ocean. PARTICIPANTS: Persons without a history of acute hepatitis A in age groups selected by applying results of a previous serosurvey conducted on serum collected before the epidemic. INTERVENTION: One dose of a formalin-inactivated hepatitis A vaccine was given to each participant. Adults 20 years of age and older received 1440 enzyme-linked immunosorbent assay units and persons younger than 20 years received 720 enzyme linked immunosorbent assay units. Prevaccination and postvaccination levels of antibody to hepatitis A IgG were obtained from 136 participants. MAIN OUTCOME MEASURES: An active surveillance system was established to detect persons with symptomatic illnesses compatible with hepatitis A; persons who met the illness criteria were tested for antibody to hepatitis A IgM. One area (the Kotzebue region), where all communities were offered vaccine, was selected for intensive surveillance and analysis. RESULTS: During the 12-month period before the vaccine trial, 529 cases of icteric hepatitis A were reported, and 443 were confirmed to be positive for antibody to hepatitis A IgM. Hepatitis A vaccine was administered to 4930 persons, 3517 of whom were younger than 20 years. After vaccination began, 237 persons positive for antibody to hepatitis A IgM were identified during a 60-week surveillance period; 46 were vaccines and 191 were unvaccinated susceptible persons. In the Kotzebue region, in communities in which more than 80% of persons considered susceptible were vaccinated, the outbreak ceased in 4 to 8 weeks, whereas in 1 large community in which less than 50% of susceptible persons were vaccinated, the outbreak continued for more than 50 weeks. More than 90% of seronegative persons developed antibody to hepatitis A IgG 3 to 4 weeks after vaccination. CONCLUSION: This trial suggested that by providing both short term and long-term protection, hepatitis A vaccine used without immune globulin halted an established epidemic of hepatitis A in rural Alaska. PMID- 8673201 TI - Musculoskeletal pain syndromes that affect adolescents. AB - Musculoskeletal pain is one of the most common pains of adolescence, along with headache and abdominal pain, and arthralgia is the single most common reason for referral to the pediatric rheumatologist. Not surprisingly, the pediatric rheumatologist is frequently called to distinguish organic from functional symptoms. During the past decade, the pediatric rheumatology community has been evaluating increasing numbers of adolescents and preadolescents who experience musculoskeletal symptoms presumably as a defense against emotional stress from achievement either in academic work or in sports. To complicate the challenge further, coexistent organic and psychologic disturbance is not rare. Clearly, organic illness does not protect a patient from emotional plan, and it may be most difficult to differentiate nonorganic pain in a patient with a known organic illness. Conversely, adolescents with organic illness may use their disease for secondary gain. Fear of misdiagnosis of physical illness as psychiatric and the notion that all of the patient's complaints should be explained by a unifying diagnosis cause diagnostic error in both psychogenic illness with physical manifestations and physical illness with psychogenic symptoms. PMID- 8673202 TI - Deficiencies in calculation and applied mathematics skills in pediatrics among primary care interns. AB - OBJECTIVE: To discover how well new house officers in primary care residency programs perform the mathematical calculations necessary to function effectively in pediatric and nursery settings. DESIGN: Criterion-referenced survey examination testing unit conversion, fluid and rehydration management, and drug dosing skills. SETTING: Five primary care residences in family practice and pediatrics at urban and community campus sites in Illinois. PARTICIPANTS: Twenty three family practice residents and 11 pediatric residents tested during residency orientations sessions or in conferences during the first 3 months of training. INTERVENTIONS: None. RESULTS: The mean score for all residents was 42%. Pediatric residents (mean score, 57.8%) performed significantly better than family medicine residents (mean score, 34.4%) (P = .002). Conversion from conventional to metric units was more difficult for family practice residents, but pediatric residents also made errors. Pediatric residents were significantly better than family medicine residents at calculation of fluid maintenance requirements (P < .05). Only 5 of 34 residents wrote acceptable fluid orders. Nutritional and drug therapy calculations showed fewer mathematical errors, but neither group routinely wrote medical orders that specified the drugs or formula, concentration, volume required per dose or feeding, route of administration, dosing interval, and duration of therapy. CONCLUSIONS: The potential for serious clinical errors caused by faculty calculation of dosage by house staff officers is high. New residents should have their orders for fluids and drugs double checked by senior personnel early in their training. Residency programs should provide remedial skills training for house officers with deficiencies in applied mathematics. The medical school faculty needs to assess students' competence in mathematics before allowing independent clinical responsibility. PMID- 8673203 TI - Munchausen syndrome by proxy. Child abuse in the medical system. AB - Munchausen syndrome by proxy often is managed differently from other forms of child maltreatment, although it is differentiated from them only by the active engagement with the medical profession in the production of morbidity. We suggest a more rigorous approach to Munchausen syndrome by proxy, with explicit acknowledgement that it is abuse and that the medical system is critical to its genesis. This leads us to question the broadness with which the label is applied (eg, in cases of imposed upper airway obstruction) and to argue for management strategies closer to those accepted for other forms of child maltreatment. PMID- 8673204 TI - Radiological case of the month. Penetrating chest trauma in children. PMID- 8673205 TI - Picture of the month. Femoral hypoplasia-unusual facies syndrome. PMID- 8673207 TI - US pediatric clerkship directors call for core curriculum. PMID- 8673206 TI - Pathological case of the month. Thrombocytosis in sickle cell anemia. PMID- 8673208 TI - Probable community acquisition of group B Streptococcus in an infant with late onset disease: demonstration using field inversion gel electrophoresis. PMID- 8673209 TI - Use of checklists in pediatric practice. PMID- 8673210 TI - Accessory auricles: unusual sites and the preferred treatment option. PMID- 8673211 TI - Neck symptoms with subtle causes. PMID- 8673212 TI - Infantile colic. PMID- 8673213 TI - Cardinal clinical signs in the differentiation of heart murmurs in children. PMID- 8673214 TI - Routine chest measurement in the newborn. PMID- 8673215 TI - [Estimation of absorbed doses by dominant species of the ecosystem in Polesski state radio-ecological reserve]. AB - The absorbed doses of radiation for dominant species of natural ecosystems of Polesski State radio-ecological reserve were calculated. The received values, absence of morphological anomalies in plants, and stability of their specific and numerical structure indicate high resistance of phytocenosis to the influence of radiation. PMID- 8673216 TI - [Studies of the radiation-protective effects of indralin on the hematopoietic system of different species of animals]. AB - The experiments were made on mice, guinea pigs and dogs. Radioprotector indraline increased radioresistant state of hematopoietic stem cells in vivo and in vitro, decreased the amount of post-radiation chromosome aberrations in marrow, induced more early and intensive post-radiation proliferative repair of marrow and spleen, faster regeneration of the initial amount of leukocytes, thrombocytes and erythrocytes in blood of mice, guinea pigs and dogs. Antiradiation efficiency of indraline in hematopoietic system is equal to 1.5-2 by FMD. Radioprotective mechanism of indraline effect on hematopoietic system is discussed. PMID- 8673217 TI - [Experience in the search of new prolonged-action radiation-protective agents]. AB - The cysteamine derivative-guanidinoethanesulfanylthiosulfuric acid was demonstrated to have radioprotective properties protecting mice against X-rays and fission neutron irradiation hazard. Radioprotective efficacy shows itself for 2 hours after i.p. and p.o. administration of the preparation. It was established an opportunity of the prolonged protective action of gammaphos as a result of its cross-linking to dextran. The preparation has a radioprotective action on X-ray and neutron irradiation. PMID- 8673218 TI - [Radiation-protective action of microbial substances]. AB - The referenced and our data on the radioprotective effect of microbial substances have been analysed. It was shown that Gram-negative microbe polysaccharides produce the maximum effect. The radioprotective mechanism of polysaccharides is considered in connection with their effect on the immune and hemopoietic systems. PMID- 8673219 TI - [Effects of chronic effects of lead nitrate and ionizing radiation on mutagenesis in Arabidopsis Thaliana (L.) Heynh]. AB - Plants of Arabidopsis thaliana were grown in a laboratory conditions on the soil (black earth, chemozem) which was polluted with a radioactive isotopes of caesium, 134 + 137 Cs. Increase in specific activity of samples from 217 to 1025 and 2529 Bq/kg resulted in increase of embryonic mutation rate in Arabidopsis from 8.2 to 20.2 and 51.6% respectively. Bringing Pb2+ in a dose of 16 mg into the soil resulted in statistically significant decrease in mutation rate. Further increase of lead concentration in radioactive soils to 32, 64, 96, 128, 160 and 320 mg/kg resulted in growth of the mutation rates in the plants which were grown on the soil with "low" and "'middle" specific activity of caesium, and in decrease of the mutation rates in the plants which were grown on the soil with "high" specific radioactivity. The last process apparently was connected with the intensive growth in the number of sterile seeds in the pods. PMID- 8673221 TI - [Radiosensitivity and postradiation kinetics of megakaryocyte release of the bone marrow (analysis based on data of the Chernobyl AES accident sequelae)]. AB - The radiosensitivity of cellular elements of megakaryocytic spring in accordance of their maturity has been evaluated on the basis of analysis of changes in thrombocyte level in peripheral blood of the Chernobyl disaster victims. The radiosensitivity of committed cellular elements of megakaryocytic spring by the criterion D0 is presumably 1.6-1.7 Gy(n = 1). More mature polyploid cells (megakaryoblasts, megakaryocytes) apparently are "absolutely" radioresistant and within the analysed range of doses (0.1-13.7 Gy) their function of thrombocyte producing remains intact. It has been proved that the rate of thrombocyte escape from peripheral blood rises with the acute radiation disease under going in the comparison with the norm that seriously affects the lifetime of thrombocytes. The transit time of megakaryocyte starting from primarily committed cell and ending with a cellular element, producing thrombocytes, is not a constant value. The normal transit time is approximately 28 days. PMID- 8673220 TI - [Effects of combined action of Cd and gamma radiation on DNA damage and repair in lymphoid tissues of mice]. AB - The effect of combined treatment of Cd and gamma-irradiation on DNA damage and repair was studied in lymphoid tissues of mice using single-cell gel assay. Single i.p. injection of CdCl2 (1 mg Cd/kg body wt), 2 h prior to irradiation resulted in increasing of DNA lesions in peripheral blood lymphocytes(PBL) when compared to non-injected animals. However, the same treatment, 48 h prior to irradiation is shown to decrease DNA damage in PBL and splenocytes in comparison with untreated mice. In thymocytes maximal protective effect of Cd was determined when mice were irradiated in 24 h after injection. The protective effect observed is due to decreasing of initial level of DNA damage in thymocytes as well as acceleration of DNA repair in PBL and splenocytes. PMID- 8673222 TI - [Effects of Co-60 gamma irradiation on sensitivity to UV light and photoreactivity of Escherichia coli Bs-1 bacteria]. AB - The reduction of photoreactivity and the change of UV-sensitivity of E. coli Bs-1 bacteria have been demonstrated after irradiation of cells with 60Co gamma-rays. The effect resulted from interaction of sub-damages induced by processes of ionization and excitation. The similar consequences can take place after irradiation of microorganisms with sparsely ionizing radiation of high energy. PMID- 8673223 TI - [Combined radiation injuries]. AB - The results of investigations of combined radiation damages caused by external gamma-irradiation and internal irradiation with nuclear fission products are presented. Experiments were carried out under laboratory conditions and field conditions of nuclear explosions. The radiation damages of animals of high, medium and small degrees were observed. The questions of pathogenesis and clinic of combined radiation damages are treated and relative contributions of external and internal irradiations to the damages are presented. PMID- 8673225 TI - [Native protein activated by low doses of gamma radiation as a source of secondary biogenic radiation]. AB - If is demonstrated that native protein of egg-white after being gamma-irradiated with law doses is able to stimulate transition of cells of remote biological detector from non-cycling state to proliferation even if irradiated protein is separated from detector by quartz-glass. Animal tissues which have a high protein content (freshly cut hair; insect bodies) reveal the same ability. The role of natural background radiation in the maintenance of energy excitation, state of living tissue proteins is discussed. PMID- 8673224 TI - [Several indicators of lipids, blood hormones and T-cell unit of the immune system in mice with increased body mass at distant periods after local irradiation of the thymus, hypothalamus-hypophysis and gonads]. AB - In hybrid mice it was shown that the local irradiation of zones of thymus, hypothalamus-hypophysis (0.5, 1 and 10 Gy in both cases) and gonads (10 Gy) resulted in significant increase in weight at long terms after irradiation. In animals with increased weight the amount of lipids raised, balance of hormones and state of thymus-dependent unit of immune system changed, and exterior symptoms of early aging were observed. After irradiation of spleen and thigh muscles (10 Gy in both cases) all indices at the same period corresponded to age control. PMID- 8673226 TI - [Effects of prolonged low-dose gamma irradiation on testes of rats]. AB - Dose-dependent characteristics of rat testicular cytosol androgen reception at varied terms after prolonged whole-body gamma-irradiation (0.1, 0.25 and 0.5 Gy at dose rate of 5.83 x 10(-7) Gy/s) coupled with an electron microscopy morphological characteristics of Sertoli cells. Leydig's cells and other populations of testicular cells, were examined. Analysis of the data obtained suggests the existence of gamma-sensor in brain of mammals, that involved on hypothalamic-pituitary-testicular levels in realisation of radiation stress suppression of Sertoli cell functions at a relatively "low" (0.1-0.5 Gy) doses by means of hypothalamic releasing factors and, therefore pituitary gonadotropins hypersecretion. PMID- 8673227 TI - [Natural ultraviolet radiation as a human risk factor (review)]. AB - Natural ultraviolet radiation spectral irradiance at the terrestrial zones of various latitudes and altitudes was measured. On this basis biologically effective intensities and times for induction of erythema, photo keratoconjunctivitis, cataract, immunosuppression and skin pigmentation after acute UV-irradiation were calculated. Skin cancer, cataract and vitamin D deficit risk values dependences on intensity and dose of prolonged UV-exposure were considered. PMID- 8673229 TI - Proceedings of the 19th International Symposium on Column Liquid Chromatography. Innsbruck, Austria, 28 May-2 June 1995. Part I. PMID- 8673228 TI - [Use of dose parameters of UHF irradiation in the interpretation of lethal effects in laboratory animals]. AB - Based on the devised calorimetric equipment the values of absorbed doses of UHF radiation were obtained for laboratory animals. The advantage of application of the specific absorption rate (SAR) and the absorbed dose in comparison with exposure dose and energy flux density was demonstrated. The influence of SAR on lethality in laboratory animals was investigated. It was shown that interspecific sensitivity of laboratory animals was dependent on SAR. PMID- 8673230 TI - Immobilized-artificial-membrane chromatography: measurements of membrane partition coefficient and predicting drug membrane permeability. AB - Immobilized artificial membranes (IAMs) are chromatographic surfaces prepared by covalently immobilizing cell membrane phospholipids to solid surfaces at monolayer densities. IAM surfaces mimic fluid cell membranes. For 23 structurally unrelated compounds, solute capacity factors [log (k'IAM)] measured on IAM columns correlate very well with the solute equilibrium partition coefficients [log (Km)] measured in fluid liposome systems (r = 0.907). This indicates that solute partitioning between the IAM bonded phase and the aqueous mobile phase is similar to the solute partitioning between liposomes and the aqueous phase. IAMs also predicted oral drug absorption in mice and drug permeability through Caco-2 cells. IAM chromatography is experimentally simple and large volume screening of experimental compounds for drug absorption is possible. Solute retention on IAMs was found to be dominated by a partitioning mechanism. The structural requirements for HPLC bonded phases to predict solute-membrane partitioning are briefly discussed. PMID- 8673231 TI - Reversed-phase liquid chromatography on a microspherical carbon column at high temperature. AB - The chromatographic conditions for the use of a spherical carbon column at high temperatures up to 160 degrees C are described. The column heating system and the eluate cooling system are also described. Under the conditions studied, it was found that the carbon column at elevated temperature was stable and could be applicable to any compounds that are durable under these conditions. The peptide bonds at this high temperature and at this acidity were still stable enough for analysis, but the indole residues showed poor stability. PMID- 8673232 TI - Effect of mobile phase additives on peptide retention in reversed-phase chromatography with pellicular and totally porous sorbents. AB - The effect of two mobile phase additives, trifluoroacetic acid and phosphoric acid, on the energetics of peptide retention in reversed-phase chromatography was investigated using Hy-Tach C18 micropellicular and Vydac C4 and C18 totally porous stationary phases. The effect of the relatively low phase ratio of columns packed with micropellicular sorbents was also examined. The logarithmic retention factors, of two model peptides, Ac-RGGGGLGLGK-amide and Ac-RGAGGLGLGK-amide, were evaluated with different columns and additives in a practical range of eluent strength. The dependence of the logarithmic retention factor on the concentration of acetonitrile in the mobile phase was linear in all cases. The higher sensitivity of the retention to the organic modifier concentration in the case of the Hy-Tach C18 column is attributed to the relatively low phase ratio of this column. Pairwise plots of the logarithmic retention factors were linear. The plots of data obtained with the two additives has unit slopes and thus reveal homoenergetic retention behavior. On the other hand data obtained on two different columns manifest homeoenergetic retention, the slopes of plots are different from unity. The analysis has yielded consistent results and validated the assumption that the retention free energy can be divided into two components arising from mobile phase and stationary phase contributions. The approach also allowed an estimation of the relative phase ratios of the columns and the Vydac C18 column was found to have an 3 and 8 times higher phase ratio than the Vydac C4 and the Hy-Tech C18 column, respectively. PMID- 8673233 TI - Stepwise binary gradient high-performance liquid chromatographic system for routine drug monitoring. AB - Drug therapy is usually optimized by concentration measurement in patient serum. High-performance liquid chromatography (HPLC) is one of the most important analytical techniques used for therapeutic drug monitoring (TDM) of drugs for which no immunoassay kits are available. HPLC has been frequently used for screening purposes in toxicology, too. The Merck Tox Screening System (MTSS) has been developed for the identification of substances by a combination of gradient HPLC with diode-array detection and identification with a database system. For routine TDM an isocratic HPLC system is more suitable because of shorter analysis time, better reproducibility of retention index and better precision of results. Therefore we defined a set of methods in steps of 10% of the two MTSS eluents. Three examples are shown: Amiodarone, Indometacine and Thiopental. New applications to test for other substances can be transferred to an isocratic system after a complete MTSS gradient run. PMID- 8673234 TI - Bonded cellulose-derived high-performance liquid chromatography chiral stationary phases. I. Influence of the degree of fixation on selectivity. AB - Four mixed 10-undecenoyl-3,5-dimethylphenylaminocarbonyl derivatives of cellulose, with an increasing proportion of alkenoyl groups, were synthesized and chemically bonded on allylsilica gel. The influence of the degree of fixation of the cellulose derivative on the matrix for the four resulting chiral stationary phases on their selectivity is discussed. PMID- 8673235 TI - Bonded cellulose-derived high-performance liquid chromatography chiral stationary phases. II. Influence of the porosity of the silica gel matrix on performance. AB - Two cellulose derivatives bearing simultaneously 10-undecenoyl and 3,5 dimethylphenylaminocarbonyl groups in different ratios were chemically bonded on allylsilica gels of different porosity. The systematic study of the effect of the silica gel pore size on the bonding of the polysaccharide derivative and on the performance of the resulting chiral supports is presented. PMID- 8673236 TI - Effect of the degree of substitution of cyclodextrin derivatives on chiral separations by high-performance liquid chromatography and capillary electrophoresis. AB - Optical isomers of some basic racemic drugs (oxprenolol, AMEBD, ephedrine) were separated by high-performance liquid chromatography (HPLC) and/or capillary electrophoresis (CE) using carboxymethyl-beta-cyclodextrin (CMBCD) with various degree of substitution (DS). The effects of the separation conditions (pH, concentration and DS of CMBCD) were studied and compared using CE and HPLC. The degree of substitution had a significant effect on the resolution of the optical isomers and the ionic strength of the separation media, hence the use of well characterized CD derivatives is crucial. Different optimum DS values for the same test samples were obtained when HPLC or CE was used. PMID- 8673237 TI - Separation of enantiomeric beta-methyl amino acids and of beta-methyl amino acid containing peptides. AB - Erythro-D,L- and threo-D,L-beta-methylphenylalanine, -beta-methyltyrosine and beta-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid were synthesized. High-performance liquid chromatographic methods were developed for the separation and identification of the enantiomers of the beta-methyl amino acids, with the application of 1-fluoro-2,4-dinitrophenyl-5-L-alanine amide and 2,3,4,6-tetra-O acetyl-beta-D-glucopyranosyl isothiocyanate as derivatizing reagents. These amino acids were incorporated into the mu-agonist/delta-antagonist opioid peptides H beta-MeTyr-Tic-Phe-Phe-NH2, H-Tyr-Tic-beta-MePhe-Phe-NH2 and H-Tyr-Tic-Phe-beta MePhe-NH2, and the delta-antagonist H-Tyr-beta-MeTic-Phe-Phe-OH, by solid-phase peptide synthesis. Each peptide has four stereoisomers. The peptide stereoisomers were separated on different columns and in different eluent systems and the elution order of the peptide epimers was determined. PMID- 8673238 TI - Neural networks in high-performance liquid chromatography optimization: response surface modeling. AB - The usefulness of artificial neural networks for response surface modeling in HPLC optimization is compared with (non-)linear regression methods. The number of hidden nodes is optimized by a lateral inhibition method. Overfitting is controlled by cross-validation using the leave one out method (LOOM). Data sets of linear and non-linear response surfaces (capacity factors) were taken from literature. The results show that neural networks offer promising possibilities in HPLC method development. The predictive results were better or comparable to those obtained with linear and non-linear regression models. PMID- 8673239 TI - Use of principal component analysis for the study of the retention behaviour of anticancer drugs on a beta-cyclodextrin polymer-coated silica column. AB - The retention parameters of eighteen commercial anticancer drugs were determined on a beta-cyclodextrin polymer-coated silica support (beta CDP) using methanol water mixtures as eluent and the relationship between the retention behaviour and physico-chemical parameters was elucidated by principal component analysis (PCA) followed by two-dimensional non-linear mapping. No significant linear correlation was found between the retention behaviour of drugs on octadecylsilica and beta CDP silica columns, indicating that the retention capacity and selectivity of the columns are considerably different. The results of PCA indicated that hydrophobic and electronic interactions and steric conditions govern the retention of anticancer drugs on beta CDP column, suggesting a mixed retention mechanism. PMID- 8673240 TI - Structure-retention relationships of steroid hormones in reversed-phase liquid chromatography and micellar electrokinetic capillary chromatography. AB - Quantitative structure-retention relationship (QSRR) studies are useful in retention prediction, finding the relevant structural descriptors for analytes and estimating the relative biological activities of a series of analytes. Most of the studies have been conducted by RP-HPLC and a few by micellar electrokinetic capillary chromatography (MECC). The aim of this work was to find structural parameters and characteristics related to the RP retention and electrophoretic migration of steroids in order to predict the retention/migration of steroid hormones on the basis of their molecular structure. Retention data were obtained with an ODS column using a mobile phases aqueous methanol acetonitrile (mobile phase A) and methanol-tetrahydrofuran (mobile phase B). MECC was conducted with a sodium dodecyl sulfate (SDS)-borate system and with a mixed micellar solution of SDS and sodium cholate. Several topological indices, such as the connectivity indices, chi, were used as structural parameters. Steric factors seem to have a great effect on the retention of steroid hormones, especially with the MeCN-containing mobile phase. Retention in mobile phase B could be predicted more accurately. Topological indices can be used in the modelling and prediction of the retention/migration of steroid hormones when the solutes form a congeneric series and stereochemical properties do not govern the separation process. PMID- 8673241 TI - Laboratory-scale purification of microcystins using flash chromatography and reversed-phase high-performance liquid chromatography. AB - Microcystins were extracted from 7 l (equivalent to 313 g dry weight) of cyanobacterial scum collected from Rutland Water in Leicestershire, UK in 1989. The resulting aqueous extract was rapidly concentrated on a C18 flash chromatography cartridge and microcystins were eluted using a step gradient. Fractions were collected manually and monitored by UV spectrophotometer and analytical HPLC. Fractions containing microcystins of similar polarity were pooled to give three fractions. Simple isocratic methods for separating each fraction were developed on an analytical column and scaled up to a 15 x 7.5 cm I.D. column. Closed-loop recycling was used to maximise yield and purity of two hydrophobic microcystins. PMID- 8673242 TI - Assessment of chromatographic peak purity by means of artificial neural networks. AB - An improved chemometric approach is proposed for assessing chromatographic peak purity by means of artificial neural networks. A non-linear transformation function with a back-propagation algorithm was used to describe and predict the chromatographic data. The Mann-Whitney U-test was used for the concluding the purity of the chromatographic peak. Simulation data and practical analytical data for both pure and mixture samples were analysed with satisfactory results. A prior knowledge of the impurity and the related compound is unnecessary when a slight difference between their chromatogram and spectrum exists. The performance on simulated data sets by this approach was compared with the results from principal component analysis. PMID- 8673243 TI - Determination of monocyclic aromatic hydrocarbons in fruit and vegetables by gas chromatography-mass spectrometry. AB - Monocylic aromatic hydrocarbons (MAHs: benzene, toluene, ehtylbenzene and xylenes) were isolated from fruit and vegetables using a solvent extraction technique. GC-MS (with selected-ion monitoring mode) was applied for determination of the isolated pollutants. It was observed that uptake of MAHs depends on the species and takes place in different morphological parts of the biological material. The highest concentrations of MAHs were found in parsley leaves (m- and p-xylene) and in orange peel (toluene). Estimation of the daily human exposure to MAHs through eating contaminated fruit and vegetables was performed. PMID- 8673244 TI - Potential of on-line isotachophoresis-capillary zone electrophoresis with hydrodynamic counterflow in the analysis of various basic proteins and recombinant human interleukin-3. AB - Isotachophoresis-capillary zone electrophoresis with hydrodynamic counterflow was applied to the analysis of various basic model proteins and recombinant human interleukin-3. The use of coated capillaries and simple modifications of a commercial capillary zone electrophoresis (CZE) system allowed the detection of concentrations in the 10(-8) M region. The limit of detection was decreased by a factor of 100 compared to conventional CZE. The separation efficiency was unaffected by the preceding isotachophoretic step. Our method is applicable to the analysis of proteins with an isoelectric point higher than 7.0. PMID- 8673245 TI - Determination of polar pesticides in ground water using liquid chromatography mass spectrometry with atmospheric pressure chemical ionization. AB - A method is described for determination of pesticides in ground water by liquid chromatography combined with mass spectrometry (LC-MS) using atmospheric pressure chemical ionization (APCI). The study demonstrates the sensitivity of the technique, with detection limits for water samples of about 0.001-0.005 microgram/l, corresponding to 50-300 pg injected. Performance data for the method such as recovery, precision and linearity are also reported. It is illustrated that the technique is applicable for many different types of pesticide structures, such as triazines, phenylurea herbicides, acetanilides, organophosphorus insecticides, etc. Twelve different pesticides and pesticide degradation products are included in the study. The optimization of inlet conditions with respect to sheath gas pressure, vaporizer temperature, capillary temperature and corona current is reported. Applicability of the method for analysis of "real-world" ground water samples is demonstrated. PMID- 8673246 TI - Isolation by gel-permeation chromatography of a non-covalent complex of Cibacron Blue F3G-A with human serum albumin. AB - The isolation by gel-permeation chromatography on Sephadex G-100 of a non covalent complex of Cibacron Blue F3G-A (CB) with human serum albumin (HSA) is described. The complex presents a molar ratio of 3:1 CB-HSA and can be re chromatographed under the same conditions without modification of its composition. However, complete dissociation occurs when the complex is chromatographed in the presence of denaturing agents. The effect of pH on the molar composition of the complex was also investigated by gel-permeation chromatography. Analogous complexes between CB and A and C cyanogen bromide fragments of unreduced HSA were also isolated by gel-permeation chromatography on Sephadex G-50. They present a molar ratio of 0.8:1 and 1.3:1 CB-protein for fragments A and C, respectively. These results suggest that two of the three molecules of CB bound to HSA may be located in the hydrophobic pocket corresponding to subdomain IIA, with the other molecule in the hydrophobic site corresponding to subdomain IIIA. The UV-Vis and dichroic circular spectra of the isolated complexes are reported. PMID- 8673247 TI - Isolation of cholesterol oxidation products from animal fat using aminopropyl solid-phase extraction. AB - Cholesterol oxidation products were separated from triglycerides and cholesterol in a single step on an aminopropyl solid-phase extraction column. The products were purified by subsequent transesterification and saponification, derivatized to trimethylsilyl ethers and analyzed by gas chromatography. Heated cholesterol containing fat samples were autoxidized by bubbling air through them. When the flow-rate of air was set at 100 ml/min, the concentration of cholesterol oxidation products in the fat increased to a maximum after 1-2 h and then decreased to almost a zero level after 8 h. The concentration of cholesterol oxidation products in the fat increased over a similar time period, without reaching a maximum, when the flow-rate of air was decreased to 5 ml/min. PMID- 8673248 TI - Electrochromatography in chemically modified etched fused-silica capillaries. AB - A new method of electrochromatography is described in which a 50-microns capillary is etched with ammonium hydrogen difluoride, followed by modification of the new surface via a silation reaction with triethoxysilane to produce a hydride intermediate, and then subsequently subjected to hydrosilation using 1 octadecene in the presence of a platinum complex catalyst. The C18 bonded phase is then compared with bare capillaries, etched bare capillaries and the hydride etched capillary to determine if any solute-bonded phase interactions are present. With bradykinin as a test solute, peak efficiencies are quite similar for all capillaries without C18 but become noticeably broader when the organic moiety is attached to the etched capillary wall. A test mixture of peptides and proteins displays shorter retention for some of the components when methanol is added to the mobile phase which is typical of reversed-phase behavior. The same result is also obtained when a mixture of tetracyclines is separated on the C18 capillary with and without methanol as part of the mobile phase. The reproducibility of retention times for two proteins is +/- 1.5%. A few results for several neutral compounds indicate small but measurable k' values. PMID- 8673249 TI - Large-scale amino-acid analysis for proteome studies. AB - Amino-acid analysis is a relatively new method for identification of proteins separated by two-dimensional gel electrophoresis and blotted onto polyvinylidene difluoride (PVDF) membranes. This article describes modified amino-acid analysis methods for this purpose. Streamlined sample handling is a key feature of the process. To minimise sample manipulation, a single vial is used for hydrolysis and the protein hydrolysate on PVDF membrane is extracted by a one-step procedure. The hydrolysate should not be stored for long periods before analysis. Applications of the technique are presented to demonstrate the identification procedure. This approach is the most cost-effective and time-effective first step in mass protein screening for a large-scale proteome project. PMID- 8673251 TI - Separation of tetracyclines by high-performance capillary electrophoresis and capillary electrochromatography. AB - Separations of various tetracycline mixtures by high-performance capillary electrophoresis (HPCE) and a new form of electrochromatography (CEC) are compared. The new CEC method involves etching the inner wall of the capillary surface with an appropriate reagent (ammonium dihydrogen fluoride) in order to produce a significant increase in surface area. The etched surface is then modified by a silation/hydrosilation reaction sequence to first produce a hydride intermediate which is then further reacted to attach a C18 moiety. The bare and hydride capillaries are tested under HPCE conditions while the C18 capillary functions in the CEC mode. The effects of pH and the presence of an organic modifier (methanol) are also studied. Detection limits ( < 10 micrograms/ml) are comparable to previous HPLC and HPCE results. Resolutions for mixtures which simulate real analytical problems are equal to or better than those reported for separations on polymeric and diol columns by HPLC and in earlier studies by HPCE and MECC. PMID- 8673250 TI - Investigation of enantioselective separation of quinolonecarboxylic acids by capillary zone electrophoresis using vancomycin as a chiral selector. AB - When a chiral selector that is a pharmaceutical compound is added to the separation buffer in capillary electrophoresis, the enantioselectivity and the mobility of analytes which interact with that chiral selector may be altered. The changes in enantioselectivity and mobility of the analyte are a function of the strength of the affinity interaction, which depends on the structure of each. The macrocyclic antibiotic vancomycin contains a variety of functionalities that are known to be useful for enantioselective interactions (e.g., hydrogen bonding groups, hydrophobic pockets, aromatic groups, amide linkages). Capillary electrophoresis with vancomycin as a buffer additive was used to separate the enantiomers of different compounds. In this study, the chiral separation of quinolonecarboxylic acids that exhibit marked antibacterial activity and of related compounds was achieved by capillary electrophoresis using vancomycin. The correlations between the separation parameters and analyte structures were investigated. The molecular interaction, which is based on the differences of structure, and the effect of experimental parameters on the enantioselective separation between the quinolonecarboxylic acids and vancomycin are discussed. PMID- 8673252 TI - Chromatographic resolution of partially perdeuterated diglucosyldiacylglycerols from Acholeplasma laidlawii. AB - Diglucosyldiacylglycerol from Acholeplasma laidlawii was isolated by adsorption chromatography and subsequently subjected to molecular species analysis by reversed-phase high-performance liquid chromatography. Twenty-three molecular species were resolved. The bacterium was grown in a medium supplemented with a mixture of oleic acid and perdeuterated palmitic acid, and incorporation of perdeuterated acyl moieties occurred in several molecular species. Short and odd numbered acyl chains were found in combinations with palmitic acid, perdeuterated palmitic acid and oleic acid. Also, molecular species differing only by perdeuterated and protonated acyl chain content were resolved chromatographically. Separation between diglucosyldiacylglycerol and digalactosyldiacylglycerol isolated from a plant source was achieved with adsorption chromatography. The polarity of diglucosyldiacylglycerol as compared to digalactosyldiacylglycerol is discussed. PMID- 8673253 TI - Precolumn fluorescence derivatization of the antagonist [Arg6,D-Trp7,9,MePhe8] substance P[6-11] with benzoin in high-performance liquid chromatography and selective detection of arginine-containing fragments in its degradation products. AB - Precolumn fluorescence derivatization for the determination of the antagonist [Arg6,D-Trp7,9,MePhe8]-Substance P?6-11? (antagonist G) using benzoin in HPLC was studied. Under the conditions chosen (0.067 M NaOH, heating at 100 degrees C for 10 s), a good yield of fluorescent derivatives was obtained and no methodology related degradation occurred. The detection limit of antagonist G was 0.21 nmol/ml. The method has been applied to the selective and sensitive detection of arginine-containing fragments in degradation products of antagonist G. PMID- 8673254 TI - Improved potency assay for recombinant bovine somatotropin by high-performance size-exclusion chromatography. AB - A high-performance size-exclusion chromatographic method was developed for the determination of potency of recombinant bovine somatotropin (rbST) monomer and the estimation of dimer and soluble aggregates in bulk drug substances. These proteins can be completely extracted from bulk drug substances with sodium borate ethylenediamine-tetraacetic acid disodium salt (EDTA) at pH 9.5 and separated on TSK G3000SW column with a mobile phase of pH 7.3 sodium borate-EDTA. The results demonstrated that this method was a non-denaturing assay for the determination of potency of rbST monomer and the data obtained in this study correlated well with data of the hypophysectomized rat body weight gain bioassay. The rbST monomer and dimer in the separation were verified by liquid chromatography-electrospray mass spectrometry. This method was optimized and validated. PMID- 8673255 TI - Development of protamine-bonded phase for separation of saccharides in liquid chromatography. AB - A protamine-bonded polymer gel was synthesized by passing this protein through an activated carbamate polyamine polymer gel layer. This new packing material was suitable for versatile separation of monosaccharides, oligosaccharides, sugar alcohols and uronic acids in liquid chromatography. The column packed with this gel could be operated at room temperature and gave excellent recovery for the reducing monosaccharides such as 2-deoxyribose, 2-deoxyglucose, ribose and mannose for which the conventional alkylamine-bonded phase column gave poor recovery. This column was used for the analysis of saccharides in urine using a post-column reaction detection system. PMID- 8673256 TI - Purification of hydrophobic integral membrane proteins from Mycoplasma hyopneumoniae by reversed-phase high-performance liquid chromatography. AB - A general and practical approach for isolating, fractionating and purifying large quantities of outer membrane hydrophobic proteins is described as applied to membrane proteins of Mycoplasma hyopneumoniae. Outer membrane proteins were extracted with Triton X-114 detergent and were precipitated from the detergent phase with 90% ethanol. Precipitated proteins were dissolved in 65% formic acid and separated by RP-HPLC using a formic acid-acetonitrile gradient. A M(r) 48 000 protein was obtained in high yield and at greater than 90% purity by optimisation of parameters for RP-HPLC. The combination of Triton X-114 extraction followed by high resolution RP-HPLC is a novel and rapid procedure for the isolation and purification of hydrophobic proteins. Proteins purified by this approach were suitable for subsequent characterisation by direct sequencing of the amino terminus as well as generation of peptides by digestion with cyanogen bromide. PMID- 8673257 TI - Non-native capillary isoelectric focusing for the analysis of the microheterogeneity of glycoproteins. AB - A simple capillary isoelectric focusing method in bare fused-silica capillaries under denaturing conditions was developed for the separation of the glyco isoforms of recombinant tissue plasminogen activator (rTPA) which have pI values ranging from pH 6 to 8. The glycoprotein was denatured in 8 M urea and separated in the presence of 0.75% carrier ampholytes, 0.4% hydroxypropylmethylcellulose and 4 M urea. Excellent separation of the glyco-isoforms of rTPA was achieved. Good reproducibilities for peak area and migration times were obtained using pressure mobilization of the focused protein zones. The method optimized for rTPA was also successfully applied to other glycoproteins (recombinant human erythropoietin and a monoclonal antibody) with different carbohydrate contents (3 55%). PMID- 8673258 TI - Determination of plasticisers in food by gas chromatography-mass spectrometry with ion-trap mass detection. AB - In this paper a method for the determination of plasticisers in food by gas chromatography-mass spectrometry with ion-trap mass detection is described. The plasticisers were quantified by an internal standard addition method using diisobutyl phthalate as the internal standard. Four selected food samples were spiked with nine different plasticisers at about 0.3 microgram/g. The recoveries of the plasticisers were in the range of 90 to 106%. The proposed method shows an improvement in precision and exhibits good linearity over a wide concentration range. The new method was applied to the analysis of real samples and the results were found to agree with those obtained using the well-established isotope dilution technique. PMID- 8673259 TI - High-performance thin-layer chromatographic method for the fluorescence detection of three nitroimidazole residues in pork and poultry tissue. AB - A high-performance thin-layer chromatographic method with fluorescence detection was developed for the qualitative determination of ronidazole, dimetridazole and their major metabolite, hydroxydimetridazole, in pork and poultry muscle. After extraction with dichloromethane and evaporation, the nitroimidazoles are redissolved in ammonium acetate buffer. The buffer phase is washed with hexane. The sample is cleaned-up by solid-phase extraction and the eluate evaporated. The final extract is resuspended in methanol and then spotted on an HPTLC plate. After multiple development with methanol and ethylacetate, the plate is dried, sprayed with pyridine and observed on an UV box (312 nm). The detection limits of this method are about 2 micrograms/kg for ronidazole, 5 micrograms/kg for dimetridazole and less than 5 micrograms/kg for hydroxydimetridazole. Validation was performed to levels of 10 micrograms/kg for dimetridazole, 5 micrograms/kg for ronidazole and 5 micrograms/kg for hydroxydimetridazole. PMID- 8673260 TI - Efficient capillary zone electrophoretic separation of wood-derived neutral and acidic mono- and oligosaccharides. AB - Neutral and acidic monosaccharides, commonly present as structural units in wood derived hemicelluloses, were derivatized by reductive amination using 6 aminoquinoline (6-AQ) and subsequently separated as their borate complexes by capillary zone electrophoresis. By using a quite concentrated (420 mmol 1(-1) alkaline borate buffer, a fused-silica capillary column with a small inner diameter (30 microns nominal I.D.) and a constant power of 1200 mW (corresponding to an applied voltage of approximately 21 kV), optimal separation was achieved. Under these conditions, the monosaccharides investigated were separated with a resolution, Rs, of 1.0-1.2 or greater. On-column UV detection at 245 nm was found to provide highly sensitive detection of the 6-AQ-derivatized monosaccharides. The minimum detectable concentrations were on the order of 10(-6) mol 1(-1) (corresponding to an estimated limit of detection of a few fmol). The linear calibration range of the method, including the 6-AQ derivatization step, was found to be about two orders of magnitude. Several neutral beta (1-4)-D xylooligomers and acidic oligosaccharides containing 4-O-methyl-D-glucuronic acid units, which are common structural elements in hemicelluloses such as birch and spruce xylan, were also efficiently separated as 6-AQ derivatives, using the same buffer system. Finally, the usefulness of this analytical method has been demonstrated using a spruce wood xylan sample subjected to chemical and enzymatic hydrolysis. PMID- 8673261 TI - The polyubiquitin gene of the mosquito Anopheles gambiae: structure and expression. AB - The polyubiquitin gene from the mosquito Anopheles gambiae has been cloned and sequenced, and its structure is reported along with sequence analysis results. The gene consists of approximately seven tandem head-to-tail repeat units of the seventy-six amino acid-coding ubiquitin monomer. It is expressed constitutively in larvae, pupae and adults of An. gambiae, as well as in a cell line derived from this mosquito species. A probe made from a DNA fragment containing the coding region of the gene recognizes transcripts of approximately 3.6 kb and 4.4 kb in RNA isolated from all mosquito developmental stages and a unique transcript of approximately 3.0 kb in RNA from the cell line. Single monomeric units of the An. gambiae polyubiquitin gene shared from 75.9% to 85.5% identity at the DNA level with homologous sequences from other organisms ranging from yeast to man. A comparison of individual repeat units of the An. gambiae gene revealed that, in general, the 5' ends of the individual monomers are more highly conserved than the 3' ends. The gene mapped by in situ hybridization on ovarian nurse cell polytene chromosomes to a primary site at division 12C on chromosome 2R and to a secondary site at division 9C on the same chromosome. PMID- 8673262 TI - Mosquito dopa decarboxylase cDNA characterization and blood-meal-induced ovarian expression. AB - Dopa decarboxylase (DDC) functions in insect catecholamine biochemistry to produce materials essential for cross-linking reactions that result in tanning and/or melanization, include tanning of the mosquito egg chorion and encapsulation of parasites. We have cloned Ddc from the mosquito, Aedes aegypti, and studied its expression in response to blood-feeding, which initiates events necessary for egg maturation in mosquitoes. The Ae. aegypti Ddc cDNA was isolated via heterologous screening using a clone from Drosophila melanogaster. A resulting 1.87 kilobase (kb) clone was sequenced to reveal an open reading frame of 1464 bp, as well as 5'- and 3'-untranslated segments. The inferred amino acid sequence of this clone shares 81% identity with the published Drosophila Ddc cDNA, including complete identity with twenty-four contiguous amino acids encompassing the pyridoxal-5-phosphate cofactor binding domain. Analysis of an F2 intercross population derived from a parental cross between two Ae. aegypti strains (Hamburg and Moyo-In-Dry) allowed us to map Ddc to a locus on linkage group 2. Expression studies demonstrated the presence of a 2.1 kb message, the majority of which occurs in the ovaries where Ddc-specific mRNA is up-regulated in response to ingestion of a blood meal. The potential for egg-tanning in anautogenous mosquitoes as a model for understanding specific genetic events in the regulation of catecholamine metabolism is addressed. PMID- 8673263 TI - The sequence and structure of the meadow grasshopper (Chorthippus parallelus) mitochondrial srRNA, ND2, COI, COII ATPase8 and 9 tRNA genes. AB - The nucleotide sequence of the mitochondrial ND2, COI, COII, ATPase8, srRNA and nine tRNA genes have been sequenced from two individual of the meadow grasshopper Chorthippus parallelus. Comparisons are made to other insects for which the same regions are completely sequenced. Percentage A + T is found to be relatively low in C. parallelus though consistent with that of the other Orthopteran, Locusta migratoria. The relative number of substitutions observed in the different protein-coding genes was analysed between pairs of insect species sharing different levels of relatedness. A clear change in this rate was observed between the within-genus and between-genera comparisons. This change is interpreted in terms of the functional constraints acting on these four different genes. The patterns seem to result from an early saturation of COI and COII genes with synonymous substitutions, and a tolerance of ND2 and ATPase8 function to high levels of amino acid replacements. This analysis highlights a need for further sequence studies and comparisons between taxa of different levels of divergence in order to understand the patterns of mtDNA evolution on which many evolutionary investigations are based. PMID- 8673264 TI - Precise excision of TTAA-specific lepidopteran transposons piggyBac (IFP2) and tagalong (TFP3) from the baculovirus genome in cell lines from two species of Lepidoptera. AB - Transposon mutagenesis of baculoviruses provides an ideal experimental system for analysis of the movement of a unique family of mobile element identified from lepidopteran genomes. Members of this family of short-inverted-repeat elements are characterized by their extreme specificity for TTAA target sites. This report describes the analysis of excision events for two representatives of this family, tagalong (formerly TFP3) and piggyBac (formerly IFP2). These elements were tagged with a polyhedrin/lacZ reporter gene and inserted back into the virus genome either by homologous recombination or by transposition. Revertants were selected based on a white plaque phenotype. Both elements excise in a precise fashion from their positions in the baculovirus genome in either TN-368 cells or IPLB-SF21 AE cells. The precise excision of these elements in infected IPLB-SF21 AE cells occurs in the absence of either tagalong or piggyBac element encoded functions. The common characteristics of both insertion and excision for these elements provides further validation for their inclusion in a single family of unique transposons. PMID- 8673265 TI - Identification and characterization of a RAPD-PCR marker for distinguishing Asian and North American gypsy moths. AB - The recent introduction of the Asian gypsy moth (Lymantria dispar L.) into North America has necessitated the development of genetic markers to distinguish Asian moths from the established North American population, which originated in Europe. We used RAPD-PCR to identify a DNA length polymorphism that is diagnostic for the two moth strains. The polymorphism maps to an autosomal locus with codominant Mendelian inheritance. DNA sequence analyses of the Asian and North American forms enabled development of locus-specific primers so that this marker, designated FS-1, will be useful for strain identification under varying conditions in different laboratories. PMID- 8673266 TI - Phylogeny of fourteen Culex mosquito species, including the Culex pipiens complex, inferred from the internal transcribed spacers of ribosomal DNA. AB - Ribosomal DNA sequence divergence in the internal transcribed spacer regions (ITS 1 and ITS-2) was examined for fourteen species and four subgenera (sixty-two clones) in the mosquito genus Culex (Diptera: Culicidae). A neighbour-joining tree produced with Kimura 2-parameter distances showed that each of the four subgenera was monophyletic at confidence probabilities of 70-99%. Culex (Lutzia) formed the sister group of Cx. (Culex). Two major clades, a Cx. pipiens complex Cx. torrentium assemblage and a Cx. restuans-Cx. salinarius-Cx. erythrothorax assemblage, formed monophyletic groups. Cx. torrentium was closely related to members of the Cx. pipiens complex. Phylogenetic analysis of ITS-1 and ITS-2 sequences from members of the Cx. pipiens complex separated populations from northern latitudes and southern latitudes, but did not support the traditional taxa as monophyletic units. PMID- 8673267 TI - A hierarchical analysis of population genetic structure in Rhizobium leguminosarum bv. trifolii. AB - Little is known about the population processes that shape the genetic diversity in natural populations of rhizobia. A sample of 912 Rhizobium leguminosarum biovar trifolii isolates were collected from naturalized red clover populations (Trifolium pratense) and analysed for 15 allozyme loci to determine the levels and distribution of genetic diversity. Hierarchical analyses compared different sampling levels, geographical separation, and temporal separation. Total genetic diversity across all isolates was H = 0.426, with 57.6% of the total diversity found among isolates obtained from individual red clover plants. Relatively low genetic differentiation among populations and high differentiation among plants within populations was observed; this suggests that gene flow and founder effect act differently at geographical and local scales. Significant differences were observed in (i) allele frequencies among populations and among plants within populations, and (ii) the frequency distribution of the most widespread and the most abundant strains. When multilocus linkage disequilibrium was calculated, significant levels of disequilibrium were observed in the total sample and in three of the eight populations. PMID- 8673268 TI - DNA fingerprinting data and the problem of non-independence among pairwise comparisons. AB - Multilocus DNA fingerprinting is commonly used to assess genetic similarity within and between geographically disjunct populations. Typically, the proportion of DNA fingerprinting bands shared between two individuals (SXY) is calculated for all possible pairwise comparisons and the resulting data analysed parametrically to test differences in mean band-sharing among groups. The degree to which covariation among interdependent SXY values (S(ab)-Sbc) biases the analyses is often unknown. Here, we assess the extent of covariation in four DNA fingerprinting studies and evaluate the effectiveness of two corrective procedures, a permutation test and a subsampling routine using only independent pairwise comparisons drawn without replacement from the overall data. Covariation among interdependent SXY values was significantly greater than zero in every data set examined, including those from a bee, a rodent, and two passerine birds. Permutation tests did not correct for interdependence and yielded significance values nearly identical to those derived from uncorrected parametric procedures. In contrast, the subsampling procedure yielded corrected estimates of the standard error that were two to four times larger than those derived parametrically. As a result, comparisons that were significant using parametric tests were either non-significant or only marginally significant with the subsampling routine. We conclude that interdependence among SXY values poses a substantial obstacle to hypothesis testing that must be addressed in future studies. PMID- 8673269 TI - Hierarchical genetic structure and gene flow in three sympatric species of Amazonian rodents. AB - The population genetic structure of three species of Amazonian rodents (Oligoryzomys microtis, Oryzomys capito, and Mesomys hispidus) is examined for mtDNA sequence haplotypes of the cytochrome b gene by hierarchical analysis of variance and gene flow estimates based on fixation indices (NST) and coalescence methods. Species samples are from the same localities along 1000 km of the Rio Jurua in western Amazonian Brazil, but each species differs in important life history traits such as population size and reproductive rate. Average haplotype differentiation, hierarchical haplotype apportionment, and gene flow estimates are contrasted in discussing the current and past population structure. Two species exhibit isolation by distance patterns wherein gene flow is largely limited to geographically adjacent localities. Mesomys exhibits this pattern throughout its range along the river. More than 75% of haplotype variation is apportioned among localities and regions, and estimates of Nm for pair-wise comparisons are nearly always less than 1. Oligoryzomys shows weak isolation by distance, but only over the largest geographical distances. Nm values for this species are nearly always above 1 and most (about 80%) of haplotype variation is contained within local populations. In contrast, Oryzomys exhibits no genetic structure throughout its entire distribution; Nm values average 17 and nearly 90% of the total haplotype variance is contained within local populations. Although gene flow estimates are high, the pattern of Nm as a function of geographical distance suggests that this species experienced a more recent invasion of the region and is still in genetic disequilibrium under its current demographic conditions. PMID- 8673270 TI - Distinguishing between primary and secondary intergradation among morphologically differentiated populations of Anolis marmoratus. AB - Distinguishing between primary and secondary intergradation among differentiated populations, and the relative importance of drift and selection, are persistent problems in evolutionary biology. An historical perspective on population interactions can provide insight into the nature of contacts, and thus help resolve these questions. Continuously distributed populations of Anolis marmoratus from the island of Basse Terre in the Guadeloupean archipelago of the Lesser Antilles show a striking degree of geographic variation in morphology. Initial surveys of mtDNA variation from throughout the Guadeloupean Archipelago revealed one case where levels of sequence difference and phylogenetic relationships of alleles from morphologically differentiated populations from the east coast of Basse Terre were consistent with primary intergradation. In this paper, I examine the genetic population structure of a series of populations spanning this north-south cline in morphological variation to test the hypothesis of primary intergradation. Sequences of the mitochondrial cytochrome-b gene from 50 individuals representing five populations spanning the cline were obtained and fourteen unique haplotypes (differing by 2% or less) were detected. Patterns of nucleotide substitution among haplotypes do not deviate from neutral expectation indicating no effect of selection at the level of mtDNA sequences. Estimates of population structure and gene flow were made using both summary statistics for nucleotide diversity (Nst) and cladistic methods. The results are sensitive to the choice of gene flow model, and this is discussed in detail. Mitochondrial variation in the northern populations may not be at equilibrium, and the phylogeny of alleles is consistent with a recent increase in effective population size. Estimates of nucleotide diversity, gene flow, and the phylogenetic relationships of haplotypes indicate that the southern-most population (representing the extreme of morphological variation along this cline) has been relatively isolated from populations to the north and has experienced a reduced effective population size. The apparent clinal variation between the southern population and the others may therefore reflect secondary contact and introgression rather than primary intergradation. PMID- 8673271 TI - Genotypic diversity revealed by allozymes and oligonucleotide DNA fingerprinting in French populations of the aquatic macrophyte Sparganium erectum. AB - The vast majority of perennial plants reproduce sexually and vegetatively at the same time. This may lead to important variation among clonal plant populations in their amount of genotypic diversity. In order to verify this assumption, we compare the clonal diversity of 10 natural populations of the aquatic clonal macrophyte Sparganium erectum in France. Diversity was quantified by DNA fingerprinting and allozyme electrophoresis for a sample of 10 shoots per population. Two DNA probes (CA)8 and (TAA)6TA, were selected among 10 synthetic oligonucleotide probes containing simple repeat motifs. Both allozymes and DNA fingerprints revealed different amounts of diversity among populations. Five populations consist of a single genotype, whereas two populations were genetically highly diverse. In four of the monomorphic populations, absence of fingerprints diversity was combined with uniformly heterozygous allozyme loci, suggesting that each population was composed of a single clone. In the highly diverse populations, the level of clonal diversity combined with the allele segregation of the two allozyme loci Lap and Est suggests frequent seedling recruitment. The origin of new genotypes remains unclear but the absence of widespread genotypes together with the discrete distribution of Sparganium erectum populations implies that new genotypes are locally produced through sexual reproduction. PMID- 8673272 TI - Low genetic variability of the koala Phascolarctos cinereus in south-eastern Australia following a severe population bottleneck. AB - Genotyping of koalas at CA-repeat microsatellite loci has revealed significant differences in the levels of allelic diversity (A) and expected heterozygosity (H(E)) between populations from north-eastern and south-eastern Australia. In the 10 populations studied, allelic diversity ranged from 8.0 in the Nowendoc population to 1.7 in the Kangaroo Is. population, and values of H(E) ranged from 0.831 in the Nowendoc population to 0.331 in the Kangaroo Is. population. Data from pooled populations revealed koalas from the north-eastern region had significantly higher levels of allelic diversity (A = 11.5 +/- 1.4) than those from south-eastern Australia (A = 5.3 +/- 1.0). Furthermore significantly higher heterozygosity levels were found in the north-eastern (H(E) = 0.851) vs. the south-eastern (H(E) = 0.436) regions of Australia. Following a near-extinction bottleneck in the 1920s, mainland Victorian and Kangaroo Is. koalas have been involved in an extensive program of relocations. The source populations of the relocated animals were islands in Westernport Bay, which were founded by very few individuals in the late 1800s and early 1900s. The significantly lower levels of variation between south-eastern Australian populations suggests that human intervention has had a severe effect on levels of genetic diversity in this region, and this may have long-term genetic consequences. PMID- 8673273 TI - Identification of sex in cetaceans by multiplexing with three ZFX and ZFY specific primers. AB - We sequenced 540 nucleotides of the last exon in the ZFY/ZFX gene in two males and two females for eight cetacean species; four odontocetes (toothed whales) and four mysticetes (baleen whales). Based upon the obtained nucleotide sequences, we designed two sets of oligonucleotide primers for specific amplification of the ZFX and the ZFY sequence in odontocetes and mysticetes, respectively. Each primer set consisted of three oligonucleotides; one forward-orientated primer, which anneals to the ZFY as well as the ZFX sequence, and two reverse-orientated primers that anneal to either the ZFX or or the ZFY sequence. The resulting two amplification products (specific for the ZFY and ZFX sequences) can be distinguished by gel-electrophoresis through 2% NuSieve(TM). The accuracy of the technique was tested by determination of gender in 214 individuals of known sex. Finally we applied the technique to determine the sex of 3570 cetacean specimens; 2284 humpback whales, 315 fin whales, 37 blue whales, 7 minke whales, as well as 592 belugas, 335 narwhals and 25 harbour porpoises. PMID- 8673274 TI - Molecular sexing of the communally breeding pukeko: an important ecological tool. AB - A central biological parameter in the study of any animal population is the accurate assignment of sex. Indeed any ecological study of a population requires information on sex composition in relation to such biological factors as behaviour, movement, mortality and birth rate. However, our ability to assign the sex of adults of many avian species is poor and the sexing of young is universally difficult. We report here the successful application of a molecular technique for the assignment of sex in the communally breeding pukeko or purple swamphen (Porphyrio porphyrio melanotus). W- and Z-linked chromosome fragments in digested genomic DNA of pukeko were detected with the DNA probe pMg1. We consequently show that this species breeds in polyandrous, polygynous and polygynandrous groups. Finally we discuss why recent molecular methods represent important new tools in ecology. PMID- 8673275 TI - Highly conserved nuclear copies of the mitochondrial control region in the desert locust Schistocerca gregaria: some implications for population studies. AB - Animal mitochondrial DNA has proved a valuable marker in intraspecific systematic studies. However, if nucleotide sequence heterogeneity exists at the individual level, its usefulness will be much reduced. The study demonstrates that the presence of highly conserved non-coding mitochondrial sequences in the nuclear genome of Schistocerca gregaria greatly impairs the use of mtDNA in population genetic studies. Caution is called for in other organisms; and it seems necessary to check for conserved nuclear copies of mitochondrial sequences before launching into a large scale analysis of populations using mtDNA as a genetic marker. Experimental procedures are suggested for this purpose. PMID- 8673277 TI - Highly polymorphic microsatellites in the house sparrow Passer domesticus. PMID- 8673276 TI - Owl pellets as a source of DNA for genetic studies of small mammals. AB - Owl pellets contain a good skeletal record of the small mammals consumed, and correspond to the undigested portions of prey which are regurgitated. These pellets are easy to find at the roosting site of owls. As it has been demonstrated that amplifiable DNA can be isolated from ancient bone remains, the possibility of using owl pellets as a source of DNA for small mammal genetics studies via the polymerase chain reaction has been investigated. The main uncertainties when isolating DNA from such a material are firstly the possibility that the extracted DNA would be too degraded during the digestion in the stomach of the owl, and secondly that extensive cross-contaminations could occur among the different prey consumed. The results obtained clearly demonstrate that cross contamination does not occur, and that mitochondrial and nuclear DNA can be amplified using skulls of small mammals found in owl pellets as a source of DNA. The relative efficiency of two methods of DNA extraction is estimated and discussed. Thus, owl pellets represent a non-invasive sampling technique which provides a valuable source of DNA for studying population genetics of small mammals. PMID- 8673278 TI - Development of PCR primers for nine polymorphic American mink Mustela vison microsatellite loci. PMID- 8673279 TI - Polymorphic microsatellites from sperm whales and their use in the genetic identification of individuals from naturally sloughed pieces of skin. PMID- 8673280 TI - Usefulness of heterologous microsatellites obtained from brook charr, Salvelinus fontinalis Mitchill, in other Salvelinus species. PMID- 8673281 TI - Primate phylogeny: morphological vs. molecular results. AB - Our comparative study of morphological (our data on selected living primates) and molecular characters (from the literature) confirms that, overall, phylogenetic reconstructions of Primates, and consequently their classifications, are more similar than dissimilar. When data from fossil Primates are incorporated, there may be several possible relationships among living Primates; the difference between most of them hinges mainly on the position of Tarsius. In one hypothesis, tarsiers are closely related to lemurs and lorises, and thus Primates is divided into Prosimii [lorises, lemurs, and tarsiers] and Anthropoidea [Platyrrhini and Catarrhini, i.e., monkeys, apes, and humans]. Two additional alternatives are that Tarsius is a sister group to the clade embracing lorises + lemurs and Anthropoidea and that in which all three lineages (Tarsius, lorises + lemurs, and Anthropoidea) form a polychotomy. In another hypothesis, tarsiers are closely related to anthropoids, giving these two branches: Strepsirhini [lemurs, lorises] and Haplorhini [tarsiers and Anthropoidea (Platyrrhini, the New World monkeys, and Catarrhini, Old World monkeys and Hominoidea)]. The first three alternatives gain some support from the fossil record, and the fourth from morphology of the living Tarsius and molecular data. It is emphasized that the morphological characters employed in this study for Tarsius are based on the only surviving genus of once-diverse tarsiiform primates known from the Eocene, and, although considered a "living fossil," it cannot represent all of them. Furthermore, Tarsius embodies derived features of its own which may affect its systematic position, but not necessarily the position of Tarsiiformes. Although the early Tertiary adapoids might have more nearly resembled anthropoids in their biochemistry and placental developments, this hypothesis is not testable from fossils, and any inferred relationships here must be based on characters of skeletal anatomy. Alternatively, anthropoids may be derived from certain omomyids or from some as yet undiscovered Eocene African taxon. Close relationships among Homo, Pan, and Gorilla have been confirmed during recent decades; Pongo is the sister group to this trichotomy. With increasing molecular data, Homo and Pan appear to be closer to each other than to any other living hominid taxon. Gorilla is a sister group to the Homo-Pan clade and Pongo is a sister group to all of them. Morphologists have given limited evidence for such a dichotomous grouping. In this study, we support the Homo-Pan clade, although with characters not as strong as for other clades. PMID- 8673282 TI - Cases of ancient mobile element DNA insertions that now affect gene regulation. AB - There is no doubt that mobile elements are a major source of mutation and that in many cases insertions cause changes in the expression of genes, but a question remains open. What has the long-term effect of these processes been? The data collected here show that in many eukaryotes, segments of repetitive DNA (mobile elements) that have been inserted in the past in regions of many eukaryote genes have been preserved by selection and now affect the transcriptional control of these specific genes. At least five of the examples are considered to be solid cases demonstrating this history. There are a number of significant but less compelling sets of evidence that support the concept that the insertion of mobile elements in gene regions could be a major source of regulatory variation in evolution. PMID- 8673283 TI - Genetic and morphological records of the Hominoidea and hominid origins: a synthesis. AB - Molecular genetics has had a major impact on phylogenetics, although many hominoid paleontologists and morphologists ignore or remain unaware of genetic data. However, substantial genetic evidence shows chimpanzees and humans as closest relatives. Living hominoids share many postcranial similarities, many of which are retained from the extant hominoid common ancestor. Miocene hominoid fossils consisted until recently mostly of teeth and jaw fragments which are relatively uninformative phylogenetically. As their postcrania have become better sampled, surprisingly few of these taxa share significant similarities with living apes, suggesting that few if any are related to specific extant lineages. Given the genetically inferred relationships of hominoids and the morphology of the earliest hominids, the common ancestor of humans and chimpanzees was probably chimp-like, a knuckle-walker with small thin-enameled cheek teeth. If correct, this scenario implies that known Miocene hominoids, most of which are postcranially archaic and have large, thickly enameled cheek teeth, throw little if any direct light on hominid origins. PMID- 8673284 TI - Hominoid phylogeny and taxonomy: a consideration of the molecular and fossil evidence in an historical perspective. PMID- 8673285 TI - Evolutionary strategies for the elucidation of cis and trans factors that regulate the developmental switching programs of the beta-like globin genes. AB - We describe three strategies for the identification of specific cis and trans factors that regulate globin gene expression, all three of which are based on the evolution of the globin genes and their expression patterns. The first approach, phylogenetic footprinting, relies on a search for sequence similarities and is designed to elucidate the factors that control those expression patterns which are shared by orthologous globin genes of all eutherian mammals (e.g., the expression of the epsilon globin genes in the embryonic yolk sac and its repression in fetal and adult hematopoietic tissues). The second approach, differential phylogenetic footprinting, relies on a search for sequence differences. This approach may be of value in identifying the mechanisms underlying the generation of novel expression patterns in specific lineages (e.g., the expression of gamma as a fetal gene in the simian primates in contrast with the embryonic expression of gamma in all other mammals). Finally, motif based phylogenetic analysis takes into consideration the fact that many transcription factors are quite flexible in the recognition of their cognate sites. The approach allows the detection of functionally conserved binding sites despite their sequence variation. PMID- 8673286 TI - Rates of nucleotide substitution in primates and rodents and the generation-time effect hypothesis. AB - DNA sequence data from introns, flanking regions, and the eta globin pseudogene region all show a significantly higher rate of nucleotide substitution in the Old World monkey lineage than in the human lineage after the separation of the two lineages, or, in other words, the data support the hominoid rate-slowdown hypothesis. Data from both protein sequences and DNA sequences show that the rate of evolution is significantly higher in the rodent lineage than in the primate lineage. Furthermore, DNA sequences from introns show that the rate of nucleotide substitution is at least two times higher in rodents than in higher primates. The male-to-female ratio of mutation rate is estimated to be between 3 and 6 in higher primates, whereas it is only 2 in mice and rats. These ratios are similar to the corresponding male-to-female ratios of germ cell divisions in higher primates and in rodents, suggesting that errors in DNA replication during germ cell division are the primary source of mutation, or, in other words, mutation is largely DNA replication-dependent. This conclusion provides further support for the generation-time effect hypothesis. PMID- 8673287 TI - The evolution of human populations: a molecular perspective. AB - Human evolution exhibits repeated speciations and conspicuous morphological change: from Australopithecus to Homo habilis, H. erectus, and H. sapiens; and from their hominoid ancestor to orangutans, gorillas, chimpanzees, and humans. Theories of founder-event speciation propose that speciation often occurs as a consequence of population bottlenecks, down to one or very few individual pairs. Proponents of punctuated equilibrium claim in addition that founder-event speciation results in rapid morphological change. The major histocompatibility complex (MHC) consists of several very polymorphic gene loci. The genealogy of 19 human alleles of the DQB1 locus coalesces more than 30 million years ago, before the divergence of apes and Old World monkeys. Many human alleles are more closely related to pongid and cercopithecoid alleles than to other human alleles. Using the theory of gene coalescence, we estimate that these polymorphisms require human populations of the order of N = 100,000 individuals for the last several million years. This conclusion is confirmed by computer simulations showing the rate of decay of the polymorphisms over time. Computer simulations indicate, in addition, that in human evolution no bottlenecks have occurred with fewer than several thousand individuals. We evaluate studies of mtDNA, Y-chromosome, and microsatellite autosomal polymorphisms and conclude that they are consistent with the MHC result that no narrow population bottlenecks have occurred in human evolution. The available molecular information favors a recent African origin of modern humans, who spread out of Africa approximately 100,000 to 200,000 years ago. PMID- 8673288 TI - Human coding and noncoding DNA: compositional correlations. AB - As the correlations between GC levels in third codon positions (GC3) and intergenic sequence GC levels can be used to assess the distribution of genes in the human genome, they were studied in detail. Previous work from our laboratory has demonstrated the existence of linear correlations between GC levels of exons, introns, third codon positions, 5' flanking regions of genes, and long genomic DNA sequences (> or = 10 kb) or DNA molecules (50-100 kb) in which the genes are embedded. The present study confirms and extends the previous results using a larger set of data. Furthermore, an analysis of 4270 human genomic DNA and cDNA sequences has allowed us to confirm a correlation of GC3 against GC1+2. Recent additions to the sequence database have also allowed separate analyses of the 5' flanking regions of CpG island and non-CpG island genes as well as analyses of 3' flanking regions, which suggest that the GC levels of 3' flanking regions are closer to those of intergenic DNA than are those of other regions of genes. PMID- 8673289 TI - A new approach to studying modern human origins: hypothesis testing with coalescence time distributions. AB - A new approach for testing hypotheses about modern human origins using molecular divergence dates is presented. Coalescence times from many unlinked loci are needed to test the alternative models. Hypotheses are evaluated on the basis of their differing predicted distribution patterns of coalescence times from multiple genes. No single coalescence time from one genetic system is sufficient to reject any of the three alternative models. Several nuclear datasets give recent dates for human genetic ancestors, at approximately the mitochondrial coalescence time, while some nuclear datasets support older dates. Given the overall distribution of available mitochondrial and nuclear coalescence times, the rapid replacement hypothesis is the likeliest model for modern human origins. The unusual nature of the human mitochondrial pattern is highlighted by comparative data from nonhuman hominoids. To understand the pattern of modern human genetic variability better, more nuclear data from all hominoid species are needed. PMID- 8673290 TI - Private polymorphisms: how many? How old? How useful for genetic taxonomies? AB - The data on the distribution and frequencies of private polymorphisms in the tribal populations of Central and South America are used to address the question of the extent to which such data can be used to address questions of phylogenetic history. It is shown that due to the great increases in population number that accompanied agricultural development, most private polymorphisms have arisen since population settlement and tribal differentiation. Conversely, the absence of Amerindian variants of wide distribution confirms the small size of the hemispheric population until relatively recent times. Patterns of recent population decline and recovery that accompanied European contact since 1492 have also had a strong impact on the age distribution of extant variants, eliminating many that were relatively young in 1492. The majority of surviving variants that have achieved polymorphic frequencies in a tribe or group of tribes are from 100 to 400 generations old (2500 to 10,000 years). Such genetic variants thus characterize tribes, or groups of closely related tribes, but do not provide a greater time depth of phylogenetic history. PMID- 8673291 TI - Behavioral influences on the evolution of human genetic diversity. AB - Unique aspects of human behavior account for special features of human evolution. For instance, the best data on the mating patterns of undisturbed hunting gathering populations are those of Norman Tinsdale for Australian Aborigines. Among some 574 linguistically distinct tribes, he collected information on 755 marriages from the period prior to significant contact with Europeans. One can extrapolate from these data on 1510 individuals. In an average tribe of some 500 individuals, 62-65 of them would have had one parent who was a member of a different tribe and 7 or 8 of them would have been offspring of a parent from a distant tribe, not an adjacent one. Such rates of intergroup marriage, generation after generation, would have produced considerable gene flow, a pattern that likely has occurred during most of human prehistory. The pattern of descent is trellis-like, not one of successive fissioning. Some genetic diversity between tribes must have existed, but most genetic variation would have been within rather than between tribal groups. One implication of this pattern is that ethnically defined groups are not a suitable basis for studying human genetic diversity. Geographically stratified random sampling of the species would be more likely to ensure an unbiased estimate of genome variability. PMID- 8673292 TI - The four founding lineage hypothesis for the New World: a critical reevaluation. AB - It has been proposed that all native American mitochondrial DNA variation in the New World can be attributed to divergence from four "founding lineages" which entered the New World in three waves of migration from across the Bering Strait (T.G. Schurr et al., 1990, Am. J. Hum. Genet. 46: 613-623; A. Torroni and D. C. Wallace, 1995, Am. J. Hum. Genet. 56: 1234-1236; A. Torroni et al., 1994, Am. J. Hum. Genet. 54: 303-318; A. Torroni et al., 1994, Proc. Natl. Acad. Sci. USA 91: 1158-1162; A. Torroni et al., 1994, Am. J. Phys. Anthropol. 93: 189-199; A. Torroni et al., 1993a, Am. J. Hum. Genet. 53: 563-590; A. Torroni et al., 1993b, Am. J. Hum. Genet. 53: 591-608; Wallace and A. Torroni, 1992, Hum. Biol. 64(3): 403-416). Torroni et al. (1993a) believe that only one haplotype from each of these four founding lineages arrived in the New World via migration, and all the additional variation arose in the New World. Any other types were attributed to Caucasian admixture. G. Bailliet et al. (1994, Am. J. Hum. Genet. 55: 27-33), N. O. Bianchi and F. Rothhammer (1995, Am. J. Hum. Genet. 56: 1236-1238), and D. A. Merriwether (1994, Experientia 50: 592-601; 1995, Am. J. Phys. Anthropol. 98(4): 411-430) suggest that multiple variants of each lineage entered the New World, and that additional unrelated lineages also entered. We present the distribution of multiple variants of the four founding lineages, plus two additional lineages which we call X6 and X7, throughout the New World, Siberia, and Asia. These distributions are strong evidence that at least nine different founding lineage haplotypes entered the New World. Further, we find these distributions among Native Americans best fit a single wave of migration into the New World. PMID- 8673294 TI - Is there a paradigm shift in genetics? Lessons from the study of human diseases. AB - The flood of genetic data made possible by recent technological advances has led to a number of important changes in our conceptual model, or working "paradigm," of genetics. Among these changes are recognition that (1) most mutations are unique; (2) there are many alleles at every locus, not just two; (3) these alleles have a hierarchical, or cladistic, history-dependent structure and geographic distribution; (3) the genotype-to-phenotype relationship is complex and quantitative, even for single-locus traits; (4) genotype-phenotype relationships often depend on the organization of the genome into linkage groups, gene families, and the like; and (5) genes affecting quantitative traits can be individually identified rather than solely being viewed as a polygenic aggregate, and these genes each have the same characteristics as genes for single-locus phenotypes. The latter provides a profound unifying impact on biology by reconciling long-standing conceptual differences on qualitative vis-a-vis quantitative phenotypes and their relative importance and evolution. Many of the data that have led to these advances have been generated in the study of genes associated with diseases in human populations. The conceptual changes affect all of biology, but are especially important in the human context, because the amount, complexity, and historical dependence of the variation in the human genome have serious societal implications regarding the epistemology of genetic causation and applications in public health. But whether these changes constitute a real "paradigm shift" in genetics, or are merely adjustments in the classical models developed early in this century, is unclear. PMID- 8673293 TI - The variety of human virus evolution. AB - There have been many wise suggestions of ways that evolution may occur but those ways seem often hard to support with good examples. Viruses have proven to be replete with some of these items. This paper reviews work that shows: (1) very fast rates of evolution; (2) positive Darwinian selection with the selective pressure specifically identified; (3) viral reassortment; (4) grossly unequal rates of evolution depending upon the host of the virus; (5) accurate dating of the cenancestor, the most recent common ancestor; (6) correspondence between the evolutionary tree and the geography of the place of isolation; (7) punctuated molecular evolution; and (8) network evolution. PMID- 8673295 TI - Overview of the symposium on molecular anthropology. Wayne State University, March 13-14, 1995. PMID- 8673296 TI - Epilogue: a personal account of the origins of a new paradigm. PMID- 8673297 TI - Analysis and comparison of the mouse and human immunoglobulin heavy chain JH-Cmu Cdelta locus. AB - We report here 23,686 bases of contiguous DNA sequences from the mouse germline immunoglobulin heavy chain (H) constant (C) mu delta region. The sequence spans the joining (JH) regions, the mu constant region (C mu), the delta constant region (C delta) coding regions, a domain relic, the mu switch region (S mu), seven blocks of simple sequence repeats, a large unique sequence inverted repeat, a large unique sequence forward repeat, and all of the intervening material. A comparison of this 23.7-kb region with the corresponding human C mu/C delta region reveals clear homology in the coding and introns of C mu but not in the 5' flanking J gene segments nor in the intergenic and C delta regions. This mixed pattern of similarity between the human and the mouse sequences contrasts with high levels of similarity found in the T-cell receptor C alpha/C delta region and alpha and beta myosin genes and the very low levels found in the gamma crystallin, XRCC1, and beta-globin gene clusters. The human and mouse comparison further suggests the incorporation of novel sequences into expressed genes of IgD. PMID- 8673298 TI - Functional diversity, conservation, and convergence in the evolution of the alpha , beta-, and gamma-carbonic anhydrase gene families. AB - The carbonic anhydrases (CA) catalyze with high efficiency the reversible hydration of carbon dioxide, a reaction underlying many diverse physiological processes in animals, plants, archaebacteria, and eubacteria. We examined the evolutionary history and functional convergence of the CAs encoded by members of three independent CA gene families (alpha-CA, beta-CA and gamma-CA). Surprisingly, the six mammalian alpha-CA isozymes of defined function and tissue expression are evolving more rapidly than four mammalian alpha-CA-related proteins of unknown function. We have identified and included several previously unrecognized CA homologues present in the sequence databases, many of which are the fruits of genome project sequencing and expressed cDNA studies. We examined alpha-CA active site evolution and the putative beta-CA and gamma-CA active sites. We found support for the "introns late" hypothesis by analysis of alpha-CA intron locations. The view that alpha-CAs would be restricted to the animal kingdom and plant green algae (Chlamydomonas), the beta-CAs to plants and eubacteria, and the gamma-CAs to archaebacteria and eubacteria is breaking down. The plant Arabidopsis has homologues of all three families. PMID- 8673299 TI - Support for interordinal eutherian relationships with an emphasis on primates and their archontan relatives. AB - Current knowledge about mammalian interordinal relationships is growing rapidly; thus this contribution is an attempt to summarize the past 5 years of this literature. We have focused on the recent controversies in mammalian phylogenetics including hypotheses concerning the monophyly of Archonta, the diphyly of Chiroptera, and the polyphyly of Rodentia. All of these issues have been proposed recently, challenging these phylogenetic hypotheses. We have attempted to include all of the comprehensive analyses of eutherian mammal systematics with an emphasis on morphological and molecular data sets where discrete characters are listed so they could be compiled and used in support of interordinal relationships. Particular attention is given to determining which of the living eutherian orders is the closest relative to primates. In reviewing relationships among the mammals, we have focused on collating all of the available evidence so that one could know where each of the specific data sets is in support of the various relationships. PMID- 8673300 TI - Evidence on mammalian phylogeny from sequences of exon 28 of the von Willebrand factor gene. AB - Phylogenetic relationships among 27 extant mammalian species (representing 15 placental orders) were studied using sequences of exon 28 of the gene encoding von Willebrand Factor (vWF), a glycoprotein which functions in blood clotting. Analysis of sequences coding for vWF revealed evidence for several subordinal and superordinal groupings, but the earliest branching sequence of placental mammals was left largely unresolved. Strong support was found for a monophyletic clade consisting of elephants, sea cows, hyraxes, aardvarks, and elephant shrews. This systematic placement of the elephant shrews agrees strongly with two other molecular data sets (interphotoreceptor retinoid binding protein and alpha-lens crystallins) and is consistent with analysis of fossil elephant shrews recently discovered in north Africa. Evidence from vWF sequences agrees with a number of previous molecular and morphological studies in providing strong support for the monophyly of both bats and rodents. The orders Primates, Proboscidea, Carnivora, Perissodactyla, and Artiodactyla were represented by more than one species which joined in each case to form a monophyletic order. PMID- 8673301 TI - Laparoscopic adrenalectomy compared to open adrenalectomy for benign adrenal neoplasms. AB - BACKGROUND: Laparoscopic adrenalectomy has recently been used for removing a variety of adrenal neoplasms. The purpose of the present study was to compare results and outcomes in patients who underwent either laparoscopic or open adrenalectomy at our institution from 1988 to the present. STUDY DESIGN: The records of 66 consecutive patients with benign adrenal neoplasms who underwent adrenalectomy from 1988 through 1995 were retrospectively reviewed. Patients were divided into three groups based on the operative approach: group I (n = 25), open anterior transabdominal approach; group II (n = 17), open posterior retroperitoneal approach; and group III (n = 24), laparoscopic transabdominal flank approach. Various parameters were compared and statistical analyses were performed. RESULTS: The three groups were similar in age, gender, American Society of Anesthesiologists class, and distribution of unilateral compared with bilateral adrenalectomy. Mean tumor size was slightly larger in group I (3.4 +/- 1.4 cm) than in group II (2.4 +/- 1.4 cm) or group III (2.7 +/- 1.4 cm) (p = NS). Mean operative times for unilateral adrenalectomy were 142 +/- 38 minutes in group I, 136 +/- 34 minutes in group II, and 183 +/- 35 minutes in group III (p < 0.001, groups I and II compared with group III). For bilateral adrenalectomy, mean operative times were 205 +/- 71 minutes (group I), 328 +/- 11 minutes (group II), and 422 +/- 77 minutes (group III). Patients who underwent laparoscopic adrenalectomy had significantly less operative blood loss (mean, 104 mL compared to 408 mL in group I and 366 mL in group II, p < 0.001) and a lower incidence of perioperative blood transfusion. Laparoscopic adrenalectomy was also associated with significantly reduced parenteral pain medication requirements (p < or = 0.001) and more rapid resumption of a regular diet (p < or = 0.01) compared to open adrenalectomy. Postoperative length of stay was significantly longer in group I (8.7 +/- 4.5 days) and in group II (6.2 +/- 3.9 days) after open adrenalectomy than after laparoscopic adrenalectomy (3.2 +/- 0.9 days) (p < 0.01). Total hospital charges were similar for groups II and III but somewhat higher for group I. Patients were able to resume 100 percent activity an average of 10.6 +/- 4.9 days after laparoscopic adrenalectomy and returned to work a mean of 16.0 +/- 6.1 days postoperatively. CONCLUSIONS: Laparoscopic adrenalectomy is a safe and effective procedure and has several advantages over open adrenalectomy. Laparoscopic adrenalectomy should become the preferred operative approach for the treatment of patients with small, benign adrenal neoplasms. PMID- 8673302 TI - Comparison of a new type of polytetrafluoroethylene patch (Mycro Mesh) and polypropylene prosthesis (Marlex) for repair of abdominal wall defects. AB - BACKGROUND: Two types of prosthetic material used for repairing hernial defects of the abdominal wall were compared: Mycro Mesh and Marlex. Mycro Mesh (MM) is a new polytetrafluoroethylene product of layered, microporous structure. Macroscopically, it presents regularly distributed, 2-mm orifices that perforate the biomaterial. Marlex (PL) is a well-known polypropylene mesh product with a macroporous structure. STUDY DESIGN: In 24 white New Zealand rabbits, a full thickness (except skin) 5 x 7-cm defect was created in the anterior wall of the abdomen. Defects were repaired with either MM (n = 12) or PL (n = 12) implants and studied at 14, 30, 60, and 90 days after implantation. Samples of the interfaces between prosthesis and subcutaneous tissue, visceral peritoneum, and receptor tissue, respectively, were studied. Samples were processed for optical microscopy and scanning electron microscopy (SEM). An immunohistochemical study was made using RAM-11, a monoclonal antibody specific for rabbit macrophages. The tensile strength of the repairs was made using an Instron tensiometer on 2-cm wide transversal strips that included the prosthesis and its anchor zones to the receptor tissue. RESULTS: The formation of adhesions between the prosthesis and intestine was important with the PL implants but not with the MM implants. Optical microscopy and SEM showed formation of an organized connective tissue surrounding the MM implants. At 90 days, compact bridges of connective tissue linked the tissue on the subcutaneous and peritoneal sides of the prosthesis. The PL implants became integrated into a disorganized, highly vascularized connective tissue. The intensity of the macrophage response was similar in both prostheses and decreased between days 14 and 90 (Student-Newman-Keuls test p = 0.01). The tensile strength of the PL implants was greater than that of the MM implants. At 90 days, the tensile strength of the PL implants was mean equals 33.11 N and of the MM implants, mean equals 22.65 N (Mann-Whitney test p < 0.001). CONCLUSIONS: The tissue integration of the PL and MM implants differed; fewer visceral adhesions formed on MM than on PL; the macrophage reaction was not determinant of the success of failure of either biomaterial; and the tensile strength of the prosthesis-receptor tissue interface was much greater in the PL implants than in the MM implants. PMID- 8673303 TI - Effect of Merocel vaginal sponge on growth of Staphylococcus aureus and production of toxic shock syndrome-associated toxins. AB - BACKGROUND: Staphylococcus aureus toxic shock syndrome toxin-1 and enterotoxin B are the major causes of toxic shock syndrome. These toxins are produced in sufficient concentrations to produce illness in the presence of certain tampons. This necessitates evaluating tampons, as well as wound dressings for their effects on S. aureus growth and toxin production. STUDY DESIGN: In this study, the Merocel vaginal sponge was evaluated both in vitro and in vivo in a rabbit model for effect on S. aureus. The Merocel sponge was tested in Erlenmeyer shake flasks containing growth media and in dialysis tubing immersed in agar growth media for both effect on S. aureus plate counts compared to media alone and effect on production of toxic shock syndrome toxins. The in vivo test included placement of Merocel sponges subcutaneously along the flanks of rabbits with subsequent inoculation with toxic shock syndrome bacteria and evaluation for development of illness and death. RESULTS: In the two standard in vitro tests, the shake flask and tampon sac, the Merocel sponge inhibited both growth of toxic shock syndrome S. aureus and production of toxic shock syndrome toxin-1 and enterotoxin B. The Merocel sponge also prevented development of toxic shock syndrome in a rabbit model. CONCLUSIONS: The data suggest the Merocel sponge may reduce the risk of development of toxic shock syndrome in association with its use. These studies may serve as models for evaluation of other products that are intended to be used on mucosal and skin surfaces, for their effect on toxic shock syndrome toxins. PMID- 8673304 TI - Parathyroid localization with technetium-99m-sestamibi: a prospective evaluation. AB - BACKGROUND: The purpose of this study was to prospectively evaluate parathyroid localization using technetium-99m-sestamibi (MIBI). STUDY DESIGN: Technetium-99m sestamibi scintigraphy was performed in 124 patients with hyperparathyroidism and the results were correlated with serum calcium and parathyroid hormone (PTH) levels, weight, location, and pathology of parathyroid tissue, and associated thyroid abnormalities. RESULTS: Hyperparathyroidism was primary in 118 patients, secondary in four patients, and tertiary in two patients. The parathyroid pathology was a solitary adenoma in 95 patients (77 percent), double adenoma in five (4 percent), hyperplasia in 14 (11 percent), carcinoma in one (1 percent), and unconfirmed in nine (7 percent) who underwent noncurative parathyroidectomy. Associated thyroid disease was present in 29 (23 percent) patients. Fourteen patients (11 percent) had undergone previous parathyroid exploration. The mean calcium level was 11.4 +/- 0.8 mg/dL (range, 8.3 to 13.7 mg/dL) and the mean adjusted PTH level was 395 +/- 702 (range, 70 to 4,331). The sensitivity and positive predictive value of MIBI scintigraphy were 81 and 89 percent, respectively, in patients with a solitary adenoma and 37 and 100 percent, respectively, in patients with multiglandular disease. The mean adjusted PTH level was higher in patients with true-positive scans compared with false negative scans (440 +/- 628 compared with 243 +/- 499, p > 0.05). The mean adenoma weight was 1,877 +/- 3,212 mg in patients with a true-positive scan compared with 485 +/- 296 mg with a false-negative scan (p > 0.05). CONCLUSIONS: The sensitivity and positive predictive value of MIBI scintigraphy is comparable to or better than the results reported for other localization procedures. Its lack of sensitivity for detection of multiglandular disease precludes its use in lieu of routine bilateral neck exploration in the management of patients with hyperparathyroidism. PMID- 8673305 TI - The impact of laparoscopic cholecystectomy on the management and outcome of biliary tract disease in North Carolina: a statewide, population-based, time series analysis. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) has had a major impact on the treatment of patients with biliary tract disease, but the magnitude and the details of its effects on biliary surgery remain incompletely described. The purpose of this study was to perform a statewide, population-based, time-series analysis of the effects of LC on biliary surgery. STUDY DESIGN: Patient data were obtained from the statewide hospital discharge database that collects data from all 157 hospitals in the state of North Carolina. All patients with hospital admissions for biliary tract disease from 1988 through 1993 were selected for analysis. RESULTS: The use of open cholecystectomy (OC) dropped from 100 percent of all cholecystectomies in 1988 to 32.3 percent in 1993, while LC increased from eight cases in 1988 to over 7,800 per year in 1993. The increase in the rate of LC was not associated with an increase in the overall rate of cholecystectomy. Bile duct (BD) repairs increased from 13 in 1988 to a high of 36 in 1992. There was a strong, statistically significant correlation between the rate of LCs and the rate of BD repairs (R = 0.89, p = 0.0001). Hospital charges and component charges were lower for patients having elective LC compared to those having elective OC (p = 0.001). This remained true after stratification by age and type of gallbladder disease. Hospital stays were shorter for patients having LC than for those having OC (p = 0.001 for all). Surgeons in smaller hospitals were slower at adopting LC. Younger and board certified surgeons adopted LC more rapidly than older and non-board certified surgeons. CONCLUSIONS: In North Carolina, LCs progressed from nonexistent to the dominant approach for managing patients with cholelithiasis in a matter of a few years. Associated with this change were shorter hospitalizations and lower charges. Contrary to other published reports, North Carolina did not experience an increase in the overall rate of cholecystectomy with the adoption of LC. There was a highly correlated increase in the rate of bile duct repairs in the first years of the study. PMID- 8673306 TI - Colorectal surgery in octogenarians. AB - BACKGROUND: Elderly patients are often viewed as high-risk surgical candidates. Recent reports, however, have recommended applying the standard surgical approach to this group. Many of these series report mortality rates that are substantially higher than those in the younger population. Therefore, the applicability of these procedures for the elderly may be questionable. STUDY DESIGN: We retrospectively studied 140 patients older than 80 years who underwent colorectal surgery at our institution between January 1990 and January 1995. Of these, 123 underwent colon or rectal resections and 17 had diverting colostomy only. Ninety seven (79 percent) of the colorectal resections were for carcinoma. In this study, perioperative care, operative results, and survival are analyzed. RESULTS: Elective and emergent colorectal resections totaled 80.5 and 19.5 percent, respectively. The mortality rate for elective resections was 3 percent and for emergency resections it was 21 percent. Postoperative morbidity was 27 percent and the average hospital stay was 13.1 days. Diverting colostomy was associated with a 24 percent mortality rate. The survival rate after colorectal resections for one, two, and five years was 85, 72, and 40 percent, respectively. CONCLUSIONS: The results support the view that elective colorectal resection in the elderly population is worthwhile and should be performed for the same indications as in younger patients. Although emergent operations were associated with a poor outcome, the majority of the patients survived and left the hospital. PMID- 8673307 TI - Elective bedside tracheostomy in the intensive care unit. AB - BACKGROUND: Tracheostomy is a frequently performed procedure, and historically has had a high reported complication rate. This has led some authors to suggest that a tracheostomy should be done only in the operating room (OR). Concerns regarding the hazards of transporting critically ill patients to the OR may inhibit the use of tracheostomy. Bedside tracheostomy in the Intensive Care Unit (ICU) has been shown to be safe, but this concept has not been widely accepted. STUDY DESIGN: We retrospectively reviewed consecutive patients undergoing tracheostomy over a four-year period and compared the safety of elective beside tracheostomy with OR tracheostomy. RESULTS: We studied 536 patients who underwent tracheostomy during the four years, in 470 of whom the procedures were elective. Of these, 66 percent were done at the bedside without an anesthesiologist present. For the 311 patients who underwent bedside tracheostomy, the complication rate was 8.7 percent compared to 9.4 percent of 159 patients undergoing OR tracheostomy (p values were not significant). No deaths were directly associated with tracheostomy procedures, although the overall hospital mortality rate for these patients was 59 percent. CONCLUSIONS: A tracheostomy can safely be performed in an ICU without requiring transport of the patient to the operating suite, thereby eliminating the hazards of transport. PMID- 8673308 TI - Intrahepatic bile duct stenosis causing intrahepatic calculi formation following excision of a choledochal cyst. AB - BACKGROUND: Formation of intrahepatic calculi is one of the major late complications after excision of a choledochal cyst. There are few studies, however, that have examined this complication. Generally, an anastomotic stricture is believed to be the main cause of intrahepatic calculi. We report our experience with eight patients who had intrahepatic calculi after excision of a choledochal cyst. STUDY DESIGN: To determine what caused the intrahepatic calculi to form, seven patients underwent cholangioscopy and direct visual inspection during the operation, and one patient underwent percutaneous transhepatic cholangioscopy. Intrahepatic bile was cultured, and calculi were analyzed. RESULTS: Two types of stenoses (membranous and septal) were demonstrated near the hepatic hilum in all patients. Calculi were always located on the hepatic side of the stenoses. No anastomotic strictures were found in the region of the hepaticojejunostomy. The calculi contained mainly calcium bilirubinate. Escherichia coli and Klebsiella pneumoniae were cultured from the bile in all patients. CONCLUSIONS: Stenoses of the intrahepatic bile ducts were demonstrated in all eight patients. The stenoses were considered to be the primary cause of intrahepatic calculi formation after excision of the choledochal cysts. PMID- 8673309 TI - Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. Diabetic Ulcer Study Group. AB - BACKGROUND: There has been a broad interest in the use of growth factors to treat patients with chronic nonischemic diabetic ulcers. STUDY DESIGN: One hundred eighteen patients were studied in a randomized, prospective, double-blind, multicenter trial comparing treatment with topically applied recombinant human platelet-derived growth factor (rhPDGF) or placebo (vehicle) and were treated until completely healed or to 20 weeks. All patients had aggressive sharp debridement of their ulcers before randomization and repeat debridement of callus and necrotic tissue as needed. The influence of debridement was evaluated by reviewing the records of the office visits where debridement was performed. RESULTS: Forty-eight percent of patients treated with rhPDGF healed compared with 25 percent of patients who received placebo (p = 0.01). The mean percentage of office visits where debridement was performed was comparable for the two treatment groups: 46.8 percent (rhPDGF) and 48.0 percent (placebo). In general, a lower rate of healing was observed in those centers that performed less frequent debridement. The improved response rate observed with more frequent debridement was independent of the treatment group. However, for any given center, the percentage of patients who healed was greater with rhPDGF than placebo. CONCLUSIONS: Wound debridement is a vital adjunct in the care of patients with chronic diabetic foot ulcers. PMID- 8673310 TI - Accessory duct sphincteroplasty is preferred for long-term prevention of recurrent acute pancreatitis in patients with pancreas divisum. AB - BACKGROUND: The putative relationship between pancreas divisum and clinical pancreatitis continues to be controversial. Indications for surgical or endoscopic manipulations of the accessory duct ampulla are unclear, and the relative merits of surgical sphincteroplasty, endoscopic sphincterotomy, and accessory duct stenting have not been established. STUDY DESIGN: Thirty-seven patients with documented pancreas divisum and acute pancreatitis identified by readily available clinical criteria were entered into a prospective five-year study of the value of surgical sphincteroplasty in preventing recurrent episodes of acute pancreatitis and eliminating "pancreatic pain." A broader therapeutic perspective was developed by means of an extensive analysis of existing surgical and endoscopic literature. RESULTS: Surgical accessory duct sphincteroplasty was successful in 83.8 percent of our patients in the long-term prevention of recurrent acute pancreatitis, but was significantly less successful in improving "pancreatic pain" (p < 0.001). Collected surgical results are superior to reported outcomes from endoscopic accessory papillotomy with regard to relief of "pancreatic pain," rate of restenosis, and generation of procedure-specific complications. Prolonged stenting of the accessory duct cannot be recommended. CONCLUSIONS: Patients with pancreas divisum and recurrent acute pancreatitis who will benefit from therapy can be identified by clinical means. Surgical sphincteroplasty provides superior long-term results compared to endoscopic sphincterotomy. PMID- 8673311 TI - Laparoscopic adrenalectomy. PMID- 8673312 TI - Temporary shunt between right portal vein and vena cava in living related liver transplantation. PMID- 8673313 TI - A practical method for quick assessment of bile duct patency during hepatic resection. PMID- 8673314 TI - Preoperative laboratory evaluation. PMID- 8673315 TI - A non-invasive continuous method of measuring blood volume during haemodialysis using optical techniques. AB - Hypotension during haemodialysis and fluid overload between treatments are major problems for haemodialysis patients. Clinical means of assessing hydration state can be relatively imprecise. We describe a non-invasive method of measuring absolute blood volume (BV) during a mock in vitro haemodialysis session which adds objective information to that assessment. As fluid is removed by ultrafiltration, haemoglobin concentration [Hb] rises proportionately with the fall in BV. An optical monitor clamped across the transparent dialysis tubing gives a continuous readout of near infra-red light transmitted through the blood, and this can be converted to [Hb] values. The net change in BV is the difference between the volume of fluid ultrafiltered and the volume which refills the vascular compartment from the extravascular space. By analysing the change in [Hb] and therefore the change in BV at two different rates of fluid removal, the absolute BV can be determined. The accuracy of this method was tested in vitro. This optical method accurately measures the change in BV over a range of [Hb] from 4 to 15 g/dl and blood circulation pump speeds of 150-300 ml/min. A series of 10 in vitro experiments was performed. The mean relative difference between the measured BV and the calculated BV, was 5.7 +/- 2.5%. This readily repeatable technique can accurately measure BV during a mock in vitro haemodialysis session, thus providing information for the clinical assessment of the hydration state. Information from these experiments will assist in future in vivo studies. PMID- 8673316 TI - Vaginal temperature sensing using UHF radio telemetry. AB - User-induced errors are common when women repetitively employ conventional probe type thermometers to chart their basal body temperatures in an effort to indicate ovulation. An alternative technique employing a two-part telemetric thermometer is proposed, with low-power, SAWR-controlled UHF radio as the transmission medium. Worn overnight in the vagina, the 1 microW erp telemetry transmitter sends pulse modulated data continuously to a microcontroller in a nearby receiver; a real time clock enables programmable sampling and storage of the subject's temperature to 0.1 degrees C resolution. Initial clinical results indicate an enhanced performance compared to oral and axillary temperature trends taken by a mercury-in-glass thermometer. Polar plots of both the isolated and body-worn telemetry transmitter are presented; body induced attenuations of up to 30 dB were measured. PMID- 8673317 TI - Fixation of femoral allograft/prosthesis composites after 25%, 50% and 75% resection. AB - The relative linear and angular displacements of proximal femoral reconstructions were compared within six different replacement techniques during ex vivo axial compression, mediolateral bending, and axial torsion in dogs. Each femur was osteotomized at 25%, 50%, or 75% of its length and the proximal portion subsequently replaced using one of six techniques. The reconstruction techniques included various combinations of proximal and distal fixation methods (graft fixation/distal fixation): (1) an allograft/prosthesis composite (APC) press-fit proximally and cemented distally (press-fit/cement); (2) APC cemented proximally and distally (cement/cement); (3) APC cemented proximally and the host bone/graft interface double plated (cement/plates); (4) APC cemented proximally and secured distally with bicortical screws (cement/screws); (5) APC secured proximally and distally with bicortical screws (screws/screws); (6) Segmental proximal femoral replacement cemented into the distal femur without an allograft (no graft/cement). For axial compression and mediolateral bending, the combined resection lengths revealed no differences in linear and angular displacements, respectively, between reconstruction methods. During axial torsion, the cement/cement technique allowed larger angular displacements than all but the press-fit/cement technique which had larger displacements than the cement/screws, screws/screws, and no graft/cement groups (p < 0.0001). Overall, the measured implant stability was solid and consistent as evidenced by small amounts of relative displacement and small error values. PMID- 8673319 TI - Computationally efficient sub-band coding of ECG signals. AB - A data compression technique is presented for the compression of discrete time electrocardiogram (ECG) signals. The compression system is based on sub-band coding, a technique traditionally used for compressing speech and images. The sub band coder employs quadrature mirror filter banks (QMF) with up to 32 critically sampled sub-bands. Both finite impulse response (FIR) and the more computationally efficient infinite impulse response (IIR) filter banks are considered as candidates in a complete ECG coding system. The sub-bands are threshold, quantized using uniform quantizers and run-length coded. The output of the run-length coder is further compressed by a Huffman coder. Extensive simulations indicate that 16 sub-bands are a suitable choice for this application. Furthermore, IIR filter banks are preferable due to their superiority in terms of computational efficiency. We conclude that the present scheme, which is suitable for real time implementation on a PC, can provide compression ratios between 5 and 15 without loss of clinical information. PMID- 8673318 TI - Stress and strain distribution within the intact femur: compression or bending? AB - The aim of this research was to test the hypothesis that the intact femur is loaded predominately in compression. The study was composed of two parts: a finite element analysis of the intact femur to assess if a compressive stress distribution could be achieved in the diaphyseal region of the femur using physiological muscle and joint contact forces; a simple radiological study to assess the in vivo deflections of the femur during one legged stance. The results of this investigation strongly support the hypothesis that the femur is loaded primarily in compression, and not bending as previously thought. The finite element analysis demonstrated that a compressive stress distribution in the diaphyseal femur can be achieved, producing a stress distribution which appears to be consistent with the femoral cross-sectional geometry. The finite element analysis also predicted that for a compressive load case there would be negligible deflections of the femoral head. The radiological study confirmed this, with no measurable in vivo deflection of the femur occurring during one legged stance. PMID- 8673320 TI - A method for the extraction of an object from a noisy background. AB - The removal of the background from a noisy image to leave the object of interest, with well defined edges, is a difficult task. Images obtained using radioisotopes have low signal-to-noise ratios due to scattered photons, as well as emitted radiation from the background. Moreover, noise is, also, a consequence of the low number of detected photons. A scan of a row or column of such an image demonstrates that the pixels do not change value rapidly near the edge of the object. In addition, clusters of pixels, which can be found outside the edges of the object and in the background, can have higher values than those in the object. This effect is worse in abnormal images, where the abnormal clusters may have values as low as those of the noisy clusters. An image processing technique has been developed to determine the object edges. It is part of a research project in the field of the computer aided diagnosis, which involves artificial neural networks. It makes use of the so-called 'moving window operations' which are very common in digital image processing. The technique was tested using male lung images that were taken by a gamma camera. PMID- 8673321 TI - Design of an FECG scalp electrode fetal heart rate monitor. AB - The design of a fetal heart rate (FHR) monitor using fetal electrocardiogram (FECG) scalp electrodes is described. It is shown that the design approach followed two stages: generation of FHR pulses at R-R intervals and FHR computation. The former uses a simple hardware approach for QRS detection and R wave enhancement, while the latter requires a software implementation in order to produce FHR traces on a beat to beat basis. The QRS detection is based on bandpass filtering using switched mode capacitor technique; the R-wave enhancement and amplitude information are achieved by differentiation followed by fullwave rectification and peak detection. An adaptive threshold together with a comparator circuit are used to generate FHR pulses at R-R intervals. Beat to beat variations of FHR traces are produced by hardware and software implementation on a Z80 microprocessor board. Results obtained by the FHR monitor are evaluated and contrasted to other commercial FHR monitors. PMID- 8673322 TI - A fluid dynamics study of the Trac catheter. AB - A fluid mechanics study of the Trac catheter was done using a 10 x scaled model. Wall pressure distributions and particle and dye flow visualization studies show that a primary vortex develops due to the spinning tip, and a secondary flow recirculates material along the chamber wall to the base of the chamber and back to the tip. Strong, nearly instantaneous mixing occurs throughout the vortex for speeds above 50,000 rpm scaled for the full-scale catheter. Close-contact pressure studies also show that wall pressures of the order of 0.4 MPa may be obtained for a full-scale catheter. PMID- 8673323 TI - Patient monitoring system for load measurement with spinal fixation devices. AB - Fractures of the spine can be stabilized by different implants. Their stiffness varies widely and only little is known about the loads acting on these devices. In order to measure the forces and moments in the implant, the internal fixator after Dick was modified. An inductively powered telemetry unit is placed inside the fixator and is hermetically sealed against body fluids. An integrated eight channel telemetry chip was developed to measure the signals of six strain gauge sensors, the implant temperature and the power supply. Because two fixators are implanted together, two telemetry transmitters run at the same time. This paper describes the function of the instrumented implant and the external system components. PMID- 8673324 TI - Application of finite elements to the stress analysis of articular cartilage. AB - A common effect of arthritic disease processes in synovial joints is deterioration of the articular cartilage. Therefore, an improved understanding of the relationships between the composition and structure of articular cartilage and the mechanical behaviour is a subject of considerable interest. The numerical modelling tool of finite element (FE) analysis has been widely applied to analyse the behaviour of articular cartilage under compressive stress. FE analysis enables parameters and boundary conditions to be investigated which are not accessible experimentally or analytically. The biphasic theory describes the constitutive behaviour of soft hydrated biological tissues, such as articular cartilage, and has been successfully implemented using FE analysis. The development of successively more comprehensive biphasic models is described here detailing the use of FE analysis in modelling experimental configurations such as indentation. Key work in the area is reviewed in this paper. PMID- 8673325 TI - Analysis of load-relaxation in compressed segments of lumbar spine. AB - Load-relaxation was measured in 12 segments of human cadaveric lumbar spine. Each segment consisted of an intact intervertebral disc attached to half of its adjacent vertebrae with the posterior elements removed. Six specimens were each compressed at six different strains (corresponding to initial loads of 0.5-2.5 kN) and, for each strain, the load-relaxation was measured for a period of 20 min at room temperature. These load-relaxation curves were used to plot three isochrones for each specimen. All isochrones were linear (r values in the range 0.95-0.99). This result indicated that a linear model could be used to represent load-relaxation. Four specimens were tested at a single strain (corresponding to an initial load of about 2 kN) at 37 degrees C for a period of 4-6 h. Load was plotted against the logarithm of time. The resulting plots did not show any peaks, indicating that relaxation effects did not predominate at any particular times during load-relaxation. However, it was possible to model the load relaxation as a simple linear system which can be represented as two Maxwell elements in parallel. These elements were characterized by relaxation times of 16 +/- 8 min and 4.6 +/- 0.8 h. Fourier transformation of the load-relaxation curves showed a gradual increase in the storage modulus and a gradual decrease in the loss modulus for frequencies of about 1 Hz and above. At these frequencies, the spine cannot function as a shock-absorber in pure compression. PMID- 8673326 TI - Algorithms for finding the axis of a helix: fast rotational and parametric least squares methods. AB - Several methods for finding the axis of a helix are presented and compared. The most accurate determines the helix axis as the axis of rotation necessary to map point i to point i + 1 of the helix. The fastest method calculates the helix axis as the best-fit line through the coordinates by a three-dimensional parametric linear least-squares algorithm, taking advantage of the sequential nature of the data. PMID- 8673327 TI - An ounce of prevention. Toward preventing gastrointestinal endoscopic complications. AB - This preventive or preemptive approach to endoscopic complications is based on the premise that the knowledgeable and prepared physician can ensure that the procedure is performed under optimal conditions and results in maximal patient safety. It is obvious that a directed patient history is one of the keys to this preventive approach. This information is only a primer and requires continuous updating to improve patient outcomes. PMID- 8673328 TI - Complications of conscious sedation. AB - Complications are a part of the practice of medicine. This is amply true for gastrointestinal endoscopy. The medications currently used in the practice of gastrointestinal endoscopy are essential to our ability to perform the wide array of diagnostic and therapeutic procedures that have become the hallmark of modern day gastroenterology. As in all of medicine, a decision is based on an assessment of risk versus benefit. Yes, these medications do carry risk with their use; however, with proper preparation and careful administration, the benefits derived far exceed the risks. We are able to perform a host of endoscopic surgical procedures precluding higher risk alternatives; patients are saved the anxiety and discomfort associated with the procedure and, in situations where follow-up procedures are necessary, they usually are more than willing to return. Maintaining these gains is the responsibility of the gastrointestinal endoscopist community and requires the recognition of the risks and a continuous effort to minimize them. PMID- 8673329 TI - Complications of upper gastrointestinal endoscopy. AB - Complications of upper gastrointestinal endoscopy are uncommon. Approximately one complication occurs with every 1000 procedures. The mortality rate is estimated to be between 0.5 and 3 per 10,000 cases. Cardiopulmonary events comprise 50% of all major complications, and most of these events result from the medications used for conscious sedation. Diagnosis, treatment, and prevention of common complications are discussed; rare complications are mentioned. PMID- 8673330 TI - Complications related to endoscopic hemostasis techniques. AB - Endoscopic therapy has had a significant impact on the management of bleeding peptic ulcers and varices. Therapy is effective at stopping immediate bleeding and has been shown to improve key patient outcomes. Ulcer therapy has few significant complications, whereas variceal therapy is fraught with serious complications, which are reviewed. PMID- 8673331 TI - Complications of endoscopic gastrointestinal dilation techniques. AB - Endoscopic dilations are infrequently attended by complications. Despite the acceleration in dilation rate for benign strictures that seems to have accompanied the introduction of balloon dilators, perforations in such situations remain uncommon. Perforation is more likely with malignant esophageal strictures and possibly with caustic strictures. The outcome of perforation, when it does occur, is more severe with malignant strictures and possibly with radiation related strictures. Bacteremia-related complications are important not because of their frequency but because of their potential severity and insidious presentation. The endoscopy-assisted dilation techniques when applied throughout the gastrointestinal tract compare favorably with other dilation methods from the standpoint of complications. The additional advantages of endoscopy rather than differences in complication rates factor into the overall efficacy of these dilation techniques. PMID- 8673332 TI - Complications of colonoscopy and flexible sigmoidoscopy. AB - Complications can occur during both diagnostic and therapeutic endoscopy. Most statistics concerning complications are based on reports generated when colonoscopy was in its infancy. This article examines the diagnosis and treatment of complications that arise during the course of both colonoscopy and polypectomy. Surgery may not be required in all cases. The criteria for operative or nonoperative treatment are presented. PMID- 8673333 TI - Complications related to diagnostic and therapeutic endoscopic retrograde cholangiopancreatography. AB - Endoscopic retrograde cholangiopancreatography (ERCP) is examined from a variety of viewpoints in this article, including physician experience with ERCP and the environment in which the procedure is performed, the initial intent to treat, and complications, including their severity. Specific complications discussed include pancreatic hemorrhage, perforation, septic complications, complications related to stents, rare complications, and late complications following sphincterotomy. PMID- 8673334 TI - Complications of percutaneous endoscopic gastrostomy. AB - Percutaneous endoscopic gastrostomy has become the procedure of choice for the establishment of enteral feedings in most clinical settings. Minor modifications in the technique and tools of PEG may have had some effect on the type of complications seen with this procedure. The major and minor complications of PEG are reviewed with a focus on those manipulations that may assist in reducing the incidence of common complications of this procedure. PMID- 8673335 TI - Complications of laparoscopic general surgery. AB - With the growth of laparoscopic general surgery, both minor and major complications are being encountered. This article discusses complications related to operative laparoscopy, including those associated with access techniques and the pneumoperitoneum. Complications specific to certain procedures, including laparoscopic cholecystectomy, appendectomy, colon resection, anti-reflux surgery, and herniorrhaphy, are also discussed in detail. PMID- 8673336 TI - Complications of pediatric endoscopy. AB - In pediatric patients, UGI endoscopy and colonoscopy may provide essential information for diagnosis and management. Diagnostic endoscopic procedures generally are safe with a rate of less than 1% of serious complications. Therapeutic procedures carry higher rates of complications, but usually are also accomplished without problems. The rarity of complications creates a unique situation: many endoscopists encounter problems infrequently. Their personal experience is limited. When evaluating a patient for a potentially serious complication, the endoscopist struggles with maintaining objectivity and clear judgment. The responsible physician re-examines and re-evaluates the preceding events: Were risks explained clearly? Were correct decisions made during the procedure? Were early problems overlooked? Simultaneously, the physician endeavors to discern the seriousness of the patient's apparent problem and to design appropriate intervention. Dealing with these multiple issues may impair decision-making. In these trying situations, experienced colleagues and consultants can provide invaluable advice and counsel. Each physician must recognize situations in which soliciting help represents a critical initial step in the process of correcting or treating the complication. Optimal patient care results from review of the procedural details, assessment of the patient's current status, discussion of potential interventions, and evaluation of the effectiveness of interventions with trusted and experienced colleagues. The knowledge of who and when to call for support and guidance provides a final measure of insurance for minimizing the risk of procedure-related complications. PMID- 8673337 TI - Negative outcomes related to gastrointestinal endoscopic procedures. Definitions, classification, and quality review process. AB - Endoscopic retrograde cholangiopancreatography (ERCP), together with its substantial therapeutic capabilities, carries a higher potential for complications compared with other endoscopic procedures. Complications of ERCP vary in severity from trivial to lethal, and their presentation has a variable timing. The incidence of ERCP complications correlates with physician experience and clinical environments and may be underestimated if routine follow-up is not provided. Physicians should be fully trained in therapeutic endoscopy, and their volume of procedure should be sufficient to maintain therapeutic skills. PMID- 8673338 TI - Ethylene-induced gene expression of osmotin-like protein, a neutral isoform of tobacco PR-5, is mediated by the AGCCGCC cis-sequence. AB - Osmotin-like protein (OLP) is a neutral isoform in the group 5 pathogenesis related (PR) tobacco proteins. The OLP gene, like the basic PR protein genes, is constitutively expressed in tobacco roots and cultured cells. OLP is not naturally present in intact healthy leaves, but ethylene treatment induces a high accumulation there. To study the mechanism of OLP gene expression as induced by ethylene, we cloned the gene from Nicotiana sylvestris, an ancestor of N. tabacum. Sequence analysis showed that it has no intron and that its promoter region contains two AGCCGCC sequences that are conserved in most basic PR-protein genes. The function of the AGCCGCC sequences in transgenic tobacco plants that harbor the wild and mutated OLP promoter::GUS fusion genes was analyzed. Mutation in the AGCCGCC sequences clearly inhibited the GUS expression induced by ethylene, indicative that the AGCCGCC sequence(s) is a DNA element(s) responsive to ethylene. An EREBP2 protein, isolated as one of the proteins binding to the AGCCGCC sequence of the tobacco beta-1,3-glucanase gene, also was found to bind to the AGCCGCC sequence(s) of OLP gene. These results suggest that the ethylene induced expression of OLP is regulated by a trans-acting factor(s) common to basic PR-proteins. PMID- 8673339 TI - Emergence of proteases in germinating cucumber cotyledons and their roles in the two-step degradation of storage protein. AB - The degradation of storage protein in germinating cucumber seeds was shown to proceed via two distinct steps. First, several proteases with acidic isoelectric points (pIs) were involved in solubilization and partial degradation of 11S globulin. Treatment of seedlings with cycloheximide inhibited this step and the expression of these proteases. Thus, the first step appeared to be governed by these proteases, which were synthesized de novo after imbibition. The first step was observed in dark-grown cotyledons, but the complete degradation of 11S globulin did not occur in the absence of illumination. An additional protease, with a pI of 4.5, was induced by illumination, and it was involved in the further cleavage of the partially degraded products of 11S globulin. Thus, the complete degradation of the storage protein proceeded via a two-step process in illuminated germinating seedlings. Light is needed to induce the second step in the degradation of 11S globulin that supplies the nitrogen required for development of the photosynthetic apparatus in the greening cotyledon. PMID- 8673340 TI - Identification of the product of ndhA gene as a thylakoid protein synthesized in response to photooxidative treatment. AB - A 76 amino acid sequence of NDH-A (the protein encoded by plastid ndhA gene) from barley (Hordeum vulgare L.) was expressed as a fusion protein with beta galactosidase in E. coli. The corresponding antibody generated in rabbits was used to investigate localization, expression and synthesis in vitro of NDH-A. NDH A was identified as a 35 kDa polypeptide localized in thylakoid membrane. Western blots shows a large increase in NDH-A levels when barley leaves were incubated under photooxidative conditions, which was more pronounced in mature-senescent leaves than in young leaves. Immunoprecipitation of the [35S]methionine labelled proteins, synthesized in vitro by isolated chloroplasts, demonstrated the synthesis in chloroplasts of the NDH-A 35 kDa polypeptide when barley leaves had been incubated under photooxidative conditions. The results indicate that ndh genes may be involved in the protection of chloroplasts against photooxidative stress, particularly in mature-senescent leaves. PMID- 8673341 TI - Identification of the chlB gene and the gene product essential for the light independent chlorophyll biosynthesis in the cyanobacterium Plectonema boryanum. AB - We cloned a 6.0-kb HindIII fragment from the cyanobacterium Plectonema boryanum using the chloroplast chlB (ORF513) gene of the liverwort (Marchantia polymorpha) as a probe. An open reading frame (ORF508) encoding a polypeptide of 508 amino acid residues was found within the nucleotide sequence of the 4,437-bp HindIII EcoRV subfragment. The deduced amino acid sequence of ORF508 shows very high similarity to that encoded by the liverwort chlB gene (72.7%). A mutant, YFB14, in which ORF508 was inactivated by the insertion of a kanamycin-resistance cartridge, was unable to synthesize chlorophyll, accumulating protochlorophyllide in darkness while synthesizing chlorophyll normally in the light. Thus, the chlB gene is the third gene that is essential for the light-independent reduction of protochlorophyllide. The other two genes are chlL and chlN, and the results suggest that the light-independent protochlorophyllide reductase consists of at least three subunits, which are encoded by chlL, chlN and chlB. Using an antiserum prepared against a ChlB-6xHis fusion protein expressed in Escherichia coli, we detected a protein with an apparent molecular weight of 58,000 in the membrane fraction of the cyanobacterium. These results indicate that either the cytoplasmic or thylakoid membranes could be the site of the light-independent reduction of protochlorophyllide. PMID- 8673342 TI - Resistance to cadmium ions and formation of a cadmium-binding complex in various wild-type yeasts. AB - The resistance to cadmium ions (Cd-resistance) and possible formation of cadmium binding complexes were examined in eight different wild-type yeasts. Saccharomyces exiguus, Pichia farinosa, Torulaspora delbrueckii and Schizosaccharomyces octosporus exhibited partial Cd-resistance, as compared to the Cd-resistant strain 301N and the Cu-resistant but Cd-sensitive strain X2180 1B of Saccharomyces cerevisiae. Saccharomyces carlsbergensis, Pichia mogii, Zygosaccharomyces rouxii and Kluyveromyces lactis were all Cd-sensitive. The partially Cd-sensitive species, with the exception of S. exiguus, accumulated Cd2+ ions in the cytoplasmic fraction to varying extents. This fraction from S. octosporus included a Cd-binding complex that contained (gamma EC)nG peptides known as cadystins or phytochelatins, while P. farinosa and T. delbrueckii synthesized Cd-binding proteins that were similar to the Cd-metallothionein produced by S. cerevisiae 301N in terms of molecular weight and amino acid composition. These results suggest that such cytoplasmic molecules play a role in the Cd-tolerance of the above three species of yeast. S. exiguus retained most cadmium in the cell wall fraction and no Cd-binding complex was found in the cytoplasm, an indication of the important role of the cell wall in its Cd tolerance. Different modes of binding of Cd2+ ions appear to be involved in the Cd-resistance of wild-type yeasts and fungi. PMID- 8673343 TI - A cytosolic phospholipase A2 from potato tissues appears to be patatin. AB - Phospholipase (PL) A2 is involved in signal transduction in the resistance reaction that is induced in potato by inoculation of an incompatible race of Phytophthora infestans, the late blight fungus, or by treatment with fungal elicitor hyphal wall components (Kawakita et al. 1993). In this study, PLA2 in the soluble fraction from potato tuber was purified. The following results suggested that the enzyme was, in fact, patatin: (1) the molecular mass of the purified enzyme was 40 kDa, the same as that of patatin; (2) the pI of the purified enzyme was approximately 4.75, which corresponds to that of patatin; and (3) the amino-terminal amino acid sequence of the purified enzyme showed a high degree of homology to that of patatin. Patatin is known as a storage protein of the potato tuber and it has been shown to have esterase activity. However, other enzymatic activities and the function(s) of patatin are unknown. We investigated the PLA activities of the purified patatin. The PLA2 activity of the patatin was much higher than the PLA1 activity, even though the protein exhibited both activities. The PLA2 activity of the enzyme was particularly apparent when phosphatidylcholine with linoleic acid at the sn-2 position was used as substrate. Lower activity was observed with phosphatidylcholine with palmitic acid, oleic acid and arachidonic acid at the sn-2 position. PMID- 8673344 TI - The seed-specific transcription factor VP1 (OSVP1) is expressed in rice suspension-cultured cells. AB - A seed-specific transcriptional regulator, VP1, is required for the induction of ABA-regulated genes that include Lea (late embryogenesis abundant protein) genes. Although the induction of one rice Lea gene, Osem, by ABA is normally restricted to seed tissues, we found that the expression was strongly induced by ABA in the Oc line of rice suspension-cultured cells. Since this observation suggested that rice VP1 (OSVP1) protein or a functionally similar protein might be expressed in the cultured cells, we analyzed the expression of Osvp1 in these cells at both the mRNA and the protein level, we detected Osvp1 mRNA and OSVP1 protein in the cultured cells at levels similar to or higher than those in developing embryos. In the cultured cells, neither the level of total cellular OSVP1 nor that of nuclear OSVP1 protein was affected by ABA. Based on the results, the mechanism for the transcriptional regulation of VP1-dependent ABA-inducible genes is discussed. PMID- 8673346 TI - cDNA cloning of thylakoid-bound ascorbate peroxidase in pumpkin and its characterization. AB - A cDNA for thylakoid-bound ascorbate peroxidase of pumpkin was cloned and characterized. Thylakoid-bound ascorbate peroxidase had a high similarity to cytosolic ascorbate peroxidases, and the precursor contained a transit peptide to chloroplasts at its amino-terminus and a putative membrane-spanning region at its carboxy-terminus. PMID- 8673345 TI - Molecular cloning and characterization of a cDNA clone that encodes a Cdc2 homolog from Nicotiana tabacum. AB - We have isolated a cDNA clone (cdc2Nt1) that encodes a homolog of p34(cdc2/CDC28) kinase from tobacco (Nicotiana tabacum). The cdc2Nt1 protein showed extensive similarity to other homologs of Cdc2 from plants. Complementation studies showed that the cdc2Nt1 gene was able to overcome cell cycle arrest at both the G1/S and the G2/M transitions of cdc28ts mutants of budding yeast, demonstrating that the cdc2Nt1 protein was able to replace the Cdc28 kinase at both the G1/S and the G2/M transitions. Analysis of gene expression demonstrated that the cdc2Nt1 gene was transcribed constitutively throughout the cell cycle but that it was preferentially expressed in activity dividing tobacco BY-2 cells. PMID- 8673347 TI - Educational group support for patients with gynaecological cancer and their families. AB - Prior to the start of a psychosocial project for patients with gynaecological cancer and their families, a questionnaire was mailed to evaluate their potential interest in an educational and supportive group. Another aim was to rank the most important issues. Group I consisted of patients with a newly diagnosed cancer and group II comprised patients who had been in clinical remission for 2-5 years; 173 questionnaires were sent. The response rate was 80%. The rates of interest in the proposed group sessions were 63% and 65% from patients and relatives in group I, and 52% and 36% from those in group II (P < 0.05). Younger individuals, couples and people with a higher formal education were generally more interested in participating (P < 0.05). The highest-ranked issues (mean 3.9-3.7 on a four-point scale) were cancer and cancer treatment, living with a cancer diagnosis, side effects of treatment, cancer pain and psychological reactions to cancer. Among patients in group I, the interest in questions related to sexual activity was moderate (mean 2.8); the corresponding figure was significantly higher in group II (P < 0.05). Interest in supportive and educational groups was significantly higher than in comparable studies. Since relaxation programmes and issues concerning problems with relationships have been generally regarded as the most crucial topics in supportive programmes, the preference for specifically cancer related issues was surprising. The study underlines the importance of specifically ascertaining which issues an intended group considers to be important. PMID- 8673348 TI - Patients' beliefs about cancer management. AB - The results of a questionnaire answered by 205 medical patients are reported (100 patients with cancer and 105 with other medical conditions). The questionnaire examined beliefs and preferences regarding various aspects of cancer, including expectations of medical management and treatment. The issues examined relate to beliefs and preferences about information giving, trust of doctors' control of decision making, expectations of help, expectations of treatment, the treatment of cancer pain including morphine use, and issues of terminal care. Some patients appear to hold the inconsistent beliefs that doctors should tell them all they want to know, but that doctors do not know a lot of what they would like to be told. They were also ambivalent about who should make decisions, patient or doctor, suggesting a preference for collaborative consensus decision making. It may be important to inform patients more clearly about what doctors can and cannot reasonably be expected to know and do. Some incorrect beliefs about management were related to fear about having cancer. The results suggest the need for better communication between patients and their professional carers and the need for accessible health information about cancer management to be available to the general public. PMID- 8673349 TI - Patients' and doctors' perception of long-term morbidity in patients with testicular cancer clinical stage I. A descriptive pilot study. AB - Patient-based questionnaires were designed with the aim to identify and rank long term somatic and psychosocial morbidity in patients with low-stage testicular cancer. A further intention was to compare patients' assessments with experienced doctors' general opinion on quality of life items in cured testicular cancer patients. In pilot study I, 103 tumour-free patients ranked items of physical and psychosocial morbidity after having had various kinds of treatment. Though the ranking procedure appeared to cause some difficulties amongst the patients and subsequently was abandoned, the results indicated considerable differences between the patients' and doctors' evaluations. In pilot study II patients were asked to score the different items. The questionnaire of pilot study II was completed by 107 patients from the Norwegian Radium Hospital (NRH) and 99 relapse free patients from the Royal Marsden Hospital (RMH) with testicular cancer stage I at least 1 year after infradiaphragmatic radiotherapy (n = 94) or adjuvant chemotherapy (2 cycles, n = 26), or patients who had been followed on the surveillance program (n = 86). A total of 93 doctors completed a similar questionnaire, thereby expressing their general opinion on long-term morbidity in comparable testicular cancer patients as seen during routine clinical follow-up. Both the irradiated patients and those on the surveillance program reported slight degrees of Raynaud-like phenomena, neurotoxicity and ototoxicity, most probably representing "background morbidity" in an age-matched general male population. Doctors tended to underestimate their patients' somatic morbidity, but often overestimated the degree of psychological distress, in particular in patients on the surveillance program. Significant differences between RMH and NRH patients with regard to sexual problems and to leisure time activity may be explained by cultural differences in the two countries. The items presented in the questionnaire used identify important issues for patients cured of testicular cancer which may be used in future multicentre trans-cultural studies assessing these patients' quality of life. This will provide sufficient data for psychometric testing and, together with the findings from patients' free comments, support the final design of a testicular cancer quality of life module. PMID- 8673350 TI - Evaluation by multidimensional instruments of health-related quality of life of elderly cancer patients undergoing three different "psychosocial" treatment approaches. A randomized clinical trial. AB - Our study belongs to the clinical trials in which the health-related quality of life (HQL) evaluation constitutes the primary endpoint. It was carried out with the aim of comparing the impact of three different types of psychological intervention, namely a psychopharmacological treatment alone, the same treatment plus social support carried out by volunteers (SSV) and a third treatment modality including "structured psychotherapy" (autogenous training), on improving the HQL of elderly cancer patients undergoing antineoplastic therapy with symptoms of anxiety and/or depression related to their disease. The eight questionnaires used for HQL evaluation were generally self-rated and multidimensional but unidimensional models were also employed. Seventy-four patients aged over 65 years with either solid tumors in different sites or hematological malignancies, generally in advanced stages (III-IV), were enrolled in the study. Of these patients, 72 (42 men and 30 women, mean age 70.68 years, range 66-85) were evaluable. Our study highlighted the usefulness of the pharmacological therapy (alprazolam + sulpiride) and of other specific ancillary treatments in reducing the incidence of the main HQL-related side-effects of antineoplastic therapy and the superiority of an "integrated" strategy, based both on psychopharmacology and psychosocial interventions, such as SSV with or without structured psychotherapy. The one-way analysis of variance carried out by us did not allow us to draw definitive conclusions about which of the two integrated treatments was to be considered the treatment of choice, as they proved to be almost equally effective. PMID- 8673351 TI - Dose-ranging evaluation of the antiemetic efficacy of intravenous dolasetron in patients receiving chemotherapy with doxorubicin or cyclophosphamide. AB - Selective 5-HT3 antagonists have proven to be safe and effective for the prevention of chemotherapy-induced nausea and vomiting. Dolasetron is a new highly selective addition to this class of antiemetics that has been shown to have significant antiemetic activity in patients receiving cisplatin-containing regimens. This pilot study was designed to evaluate the antiemetic efficacy of dolasetron in cancer patients receiving doxorubicin and/or cyclophosphamide. This study used an open-label, non-randomized design to evaluate the efficacy and safety of intravenous dolasetron in the prevention of emesis in patients receiving doxorubicin (25-75 mg/m2) and/or cyclophosphamide (400-1200 mg/m2). Sixty-nine patients received a single, intravenous dose of dolasetron over 15-20 min beginning 30 min prior to the start of chemotherapy. Dose levels of dolasetron studied were: 0.3, 0.6, 1.2, 1.8 and 2.4 mg/kg. Patients were monitored for emesis, nausea and adverse events for 24h after the start of chemotherapy. Overall, 61% of patients experienced complete control of emesis. No significant trend towards increased antiemetic efficacy (P = 0.076) or nausea control with increasing dolasetron dose was noted, although the power to detect significant differences was limited by the small number of patients on the 0.3 mg/kg and 2.4-mg/kg dose levels. Age, gender, and type of chemotherapy were significant predictors of complete antiemetic control. Adverse events were generally mild and included headache, chills, lightheadedness, fever, diarrhea, dizziness, and asymptomatic prolongation of ECG intervals. Intravenous dolasetron is safe and effective in the prevention of emesis induced by doxorubicin and/or cyclophosphamide. PMID- 8673352 TI - Volume of hydration in terminal cancer patients. AB - In this retrospective study we reviewed the volume and modality of hydration of consecutive series of terminal cancer patients in two different settings. In a palliative care unit 203/290 admitted patients received subcutaneous hydration for 12 +/- 8 days at a daily volume of 1015 +/- 135 ml/day. At the cancer center, 30 consecutive similar patients received intravenous hydration for 11.5 +/- 5 days (P > 0.2) but at a daily volume of 2080 +/- 720 ml/day (P < 0.001). None of the palliative care unit patients required discontinuation of hydration because of complications. Hypodermoclysis was administered mainly as a continuous infusion, an overnight infusion, or in one to three 1-h boluses in 62 (31%), 98 (48%) and 43 (21%) patients, respectively. Our findings suggest that, in some settings, patients may be receiving excessive volumes of hydration by less comfortable routes such as the intravenous route. Increased education and research in this area are badly needed. PMID- 8673353 TI - Communication in cancer care: is there enough to talk about? PMID- 8673354 TI - U.S.: marihuana for cancer-related symptoms. PMID- 8673355 TI - The development of a palliative care team at the Western General Hospital, Edinburgh. AB - The evolution of palliative medicine as a specialty in the UK has meant that specialist services for palliative care are now being integrated into the acute hospital setting. The developing multidisciplinary team at the Western General Hospital is the first in Scotland and is based in the Regional Cancer Unit but has a hospital-wide remit. Advice is given on complex aspects of advancing disease to patients (and their families) suffering from cancer as well as on non malignant disease. Evaluation of these teams and their effectiveness is discussed. PMID- 8673356 TI - A qualitative study to explore the concept of fatigue/tiredness in cancer patients and in healthy individuals. AB - Interest in fatigue research has grown since the finding that fatigue/tiredness is the most frequently reported symptom of cancer and its treatment. But even though several authors have tried to conceptualise fatigue, its mechanisms are still poorly understood. The aim of this study was twofold: (a) to explore fatigue in cancer patients inductively, and (b) to compare experiences of fatigue/tiredness of healthy individuals with those of cancer patients to identify cancer-specific fatigue/tiredness and related concepts. A qualitative research strategy was adopted using a grounded-theory approach. The prospective study took place in the oncology department of the Kantonsspital, St. Gallen, Switzerland, with samples of 20 cancer patients and 20 healthy individuals. Unstructured, tape-recorded interviews were conducted to collect data. The transcripts of the interviews were analysed using content analysis and constant comparison. Different themes emerged between the two groups although both fitted a classification system that categorised fatigue into physical, affective and cognitive expressions of fatigue/tiredness. Physical signs were more frequent than affective and cognitive signs in both groups. In the cancer patients, fatigue involved decreased physical performance, extreme, unusual tiredness, weakness and an unusual need for rest, which was distinctly different for healthy persons. Affective and cognitive distress was also more prominent in cancer patients. Interestingly, the concept of malaise was not identified by either sample and not understood as an expression of fatigue by this German-speaking population. Linguistic differences in the description of fatigue/tiredness between healthy and ill individuals revealed different perceptions of the phenomenon. A step-like theory, explaining the production of fatigue/tiredness was tentatively put forward involving nociception, perception and expression of tiredness. The emerging concepts break tiredness/fatigue into an expression of physical, affective and cognitive tiredness/fatigue. The experience is different between healthy individuals and cancer patients. Care must be taken when drawing generalised conclusions but the results of the study identify and clarify ideas that might form an important basis for further, controlled studies. PMID- 8673357 TI - Understanding patients: let's talk about it. A study of cancer communication. AB - As part of a project on quality of life in patients with lung cancer, an investigation was carried out to examine how patients reacted to the study. A group of 82 patients attending a chest clinic were interviewed by means of a short questionnaire. They were asked to indicate whether an interview was preferable to filling in a questionnaire and whether a home visit was preferable to a clinic interview, and their feelings about interviews. In addition, we documented our observations during the study period. All patients agreed to participate in the study, of whom, 56 patients (68%) preferred to be interviewed, 8 (10%) preferred to fill in a questionnaire by themselves, and the remaining 18 (22%) expressed no preference. Forty-one patients (50%) preferred to be interviewed at their homes, 13 (16%) in the clinic, and 28 (34%) expressed no preference. Nearly all patients (96%) indicated that they found being interviewed very or quite comfortable. Our observations indicated that patients were pleased to talk about and discuss their perceived cultural and social values or daily life experiences. The findings suggest that, despite the strenuous attempts by clinicians to deliver effective health care, proper communication with patients remains limited. The finding has some implications for community care. PMID- 8673358 TI - The relationship between articulation time and memory performance in verbal and visuospatial tasks. AB - The number of verbal items which can be recalled immediately is related to the rate at which an individual can speak. Subvocal rehearsal, or articulatory recoding in working memory, has been assumed to mediate this relation. For spatial items recalled in order there is also a relationship with articulation rate, which is not related to verbal rehearsal of the items. One reason for this might be that the relationship is mediated by speed of memory scanning for serial position tags in a memory set, which is related to processing speed. Subjects were asked to perform visuospatial memory tasks which involved serial position and visuospatial memory tasks in which serial position was not involved. They also performed a digit span task. The results indicated that the visuospatial memory tasks were highly related, that they were only weakly related to digit span, and that articulation rate was correlated with every measure of memory performance used, whether serial position was involved or not. There is no support for the hypothesis that speed of scanning for serial position information in immediate spatial memory leads to a relationship with articulation rate, nor is there any support for the view that memory span tasks in different domains share resources for dealing with serial order. The results are discussed in relation to Cowan, Keller, Hulme, Roodenrys, McDougall & Rack's (1994) suggestion that the relationship between articulation rate and memory span may be mediated by general processing speed. PMID- 8673359 TI - The measurement of hand preference: a validation study comparing three groups of right-handers. AB - Three groups of right-handers were identified using the Edinburgh Handedness Inventory. Exclusive strong right-handers (Rs: N = 18) reported that they always used the right hand for eight or more of the 10 activities, and usually used the right hand for the remainder. Exclusive weak right-handers (Rw: N = 15) usually used the right hand for three or more activities, and always used the right hand for the remainder. Predominant right-handers (Rp: N = 18) preferred the right hand for most items, but used the left hand for at least one activity. These groups did not differ on three measures of relative skill of the two hands: peg moving, tapping and dotting. Groups Rs and Rw were also indistinguishable in terms of the hand used for reaching for cards placed in different spatial positions. However, the reaching measure did discriminate group Rp, which included some individuals who reached predominantly with the left hand. It is concluded that preference batteries should quantify degree of hand preference in terms of the number of activities for which a preference is shown, ignoring the distinction between 'usually' and 'always'. The behavioural reaching measure shows promise as a method for providing a unitary scale of hand preference. PMID- 8673360 TI - Are visual search procedures adapted to the nature of the script? AB - Letters are processed differently from other shapes in a visual search task where subjects have to decide whether or not a predesignated target symbol is present in a subsequently presented string of five such symbols. If the M-shaped letter search function, which relates correct reaction time to target position, reflects an efficient strategy used in word recognition, it should be produced by skilled readers of English who also read a logographic script. A cross-linguistic study of biscriptal Mandarin/English and monoscriptal English readers (Expt 1) provided evidence of the generality of a basic search strategy for alphabetic targets. Hand-of-response affected the search function in an asymmetric fashion for both groups of readers, and although case differences between target and string increased reaction times overall, the classic M-shaped function remained. In Expt 2, we used a within-subjects design and examined the extent to which biscriptal Mandarin/English readers produced different search functions for letters and logographs. Consistent with expectation, these readers showed an M-shaped function for letters but a more U-shaped function for logographs. Hand-of response exerted a consistent effect for both types of material. Taken together, these experiments support the view that skilled readers develop script-specific procedures. PMID- 8673361 TI - Methodological issues in assessment of the perceptual component of body image disturbance. AB - An individual's body image consists of both a perceptual and an attitudinal (subjective) component. Methodological issues relative to the measurement of the perceptual component of body image are discussed. Traditionally, research in body image has employed psychophysical techniques and analyses which confound these two components. Psychophysical techniques which allow for a separate measurement of these two components are discussed, including method of constant stimuli, signal detection theory and adaptive probit estimation. The results of research utilizing these techniques are described and the importance of separately measuring perceptual and attitudinal components is discussed. PMID- 8673362 TI - Atypical Cogan's syndrome associated with antineutrophil cytoplasmic autoantibodies. PMID- 8673363 TI - Tenidap versus diclofenac in rheumatoid arthritis. PMID- 8673364 TI - Pregnancy, schizophrenia and rheumatoid arthritis. PMID- 8673365 TI - [Current problems of occupational medicine and industrial ecology]. PMID- 8673366 TI - [Current aspects of mechanisms underlying effects of multi-component natural gas, its toxicity and selectivity]. AB - Experiments on animals included acute, subacute and chronic inhalation of natural gas containing hydrogen sulfide. The multi-component natural gas was proved to induce more intensive toxic effects, than its components do. When inhaled in concentrations equal to the MACs for its components, the gas induces higher permeability of cellular membranes, compromised biocatalysis systems, 2 times increased lipid peroxidation, disturbed thiol disulfide balance. Mechanism underlying primary effect of the natural gas is associated mostly with activated free radicals, methylation and oxidation of sulfur compounds and their interaction with proteins containing sulfides and metals. PMID- 8673367 TI - [Dynamics of blood lipid levels in urban inhabitants]. AB - The screening covered serum levels of lipids and lipoproteins in 3 random selects of males aged 20 to 59. The examinees residing in major industrial city (Ufa) demonstrated reliably higher occurrence of dyslipoproteinemia in comparison with the rural inhabitants. Serum levels of triglycerides, cholesterol and lipoprotein bound cholesterol among the urban examinees vary (p < 0.05) in comparison with the rural ones. Age-related trends of lipid parameters are changed. Coefficient of atherogenicity tends to change more drastically among the workers, if compared to that among the rural examinees, so a conclusion on higher relative atherogenic risk could be made. PMID- 8673368 TI - [Prognostication in chronic pesticide poisoning in agricultural workers: state of lipid metabolism]. AB - The authors discuss a possibility to estimate risk of chronic intoxication by 2,4 D agricultural preparations and phosphorus organic pesticides among rural inhabitants having occupational contact with the chemicals. The estimation could be based on lipid metabolism parameters. PMID- 8673370 TI - [Concerning the article by A.I. Khalepo, A.I, Korbakova, I.V. Sanotskii, I.P. Ulanova, "Hygienic aspects of the regulation of occupational chemicals"]. AB - The authors suggest changing a definition "Maximal allowed concentration of chemical hazard in the air of workplace", that was previously included into the Russian State Standard. Moreover, they support to rename maximal single MACs into the average shift ones. For calculation of maximal single MACs, the authors suggest 3-5 times increase of the average shift ones. According to the authors, an idea is to legalize acceptable risk for the workers' health due to chemical hazards in concentrations equal to the MACs and, actually, to increase the former MACs 3-5 times. Those suggestions seem groundless and divergent with the principles of national hygiene, so are met with disagreement. Such radical changes in hygienic regulation should proceed after consultation with wide hygienic community, occupational pathologists and trade unions. PMID- 8673369 TI - [Hygienic aspects of the regulation of occupational chemicals]. AB - Hygienic regulation of chemical hazards in the air of workplace has a 70-year history in this country. Now a definition "maximal allowable concentration in the air of workplace" needs to be more precise, and a list of MACs should be modified. PMID- 8673371 TI - [Present-day health policy in the area of chemical safety]. AB - The article deals with priority spheres of anti-chemical protection of workers and general population in up-to-date conditions. The authors suggest and discuss new definition for a term "maximal allowable concentration". PMID- 8673372 TI - [Selection of diagnostically significant parameters in integral evaluation of the effects of occupational biologic and chemical hazards]. AB - Clinical and immunologic study including evaluation of immune state, allergic reactivity and adaptation covered 1174 workers engaged into microbiologic synthesis of proteins (production of proteovitamin concentrates and hydrolytic yeast) and 543 ones working at chemical enterprises in contact with gases irritating respiratory tract, with isocyanate and acryl compounds. Homeostasis of the examinees was assessed by means of an integral parameter, and the parameter's limits were defined for the diseases under study. The research determined diagnostically valuable parameters for some entities diagnosed in the examinees. The suggested approach could benefit early diagnosis and prophylaxis of diseases associated with occupational hazards. PMID- 8673373 TI - [Hygienic evaluation of work conditions in the production of liladox (starter of vinyl chloride polymerization)]. PMID- 8673374 TI - [Effects of chronic intoxication induced by components of high-temperature superconducting ceramics on respiration and oxidative phosphorylation in liver mitochondria (an experimental study)]. PMID- 8673375 TI - [Information and consultation toxicological center: results and prospects of activities]. PMID- 8673376 TI - [Several aspects of clinical signs and pathogenesis of pneumopathies in acute poisoning caused by sulfur-containing natural gas]. AB - The article summarizes and analyzes data on 32 cases of acute intoxication varying in severity and caused by inhalation of sulfur-containing natural gas of Astrakhan gas deposit (SCNGAGD). The data were obtained in experimental poisoning of 120 Wistar rats with the gas. Pneumopathies (toxic pulmonary edema, pneumonitis, asthmatic bronchitis, alveolitis) appeared to play the central role among other syndromes of the intoxication by SCNGAGD. Mechanisms of the pneumopathies were traced to morphologic disorders of blood-lung barrier, compromised functions of lung surfactant, disturbances in lipid peroxidation and anaerobic glycolysis. PMID- 8673377 TI - [40th anniversary of the Ufa Research Institute of Occupational Medicine and Human Ecology. Results of activities]. PMID- 8673378 TI - [Retired people and causes of their death in relation to residence and former place of employment]. AB - Elaboration of Act on Death helped to study death causes among retired people. Levels and causes of mortality among retired people could be traced to age, mortality levels among able-bodied population, influence of the former occupational hazards and ambient air pollution in the residence area. The authors discovered that the prevalent death causes among the retired people were cardiovascular diseases, malignancies, respiratory disorders. Share of the individual causes varied in accordance with the residence area and former occupation. PMID- 8673379 TI - [Possibilities of the use of oxymethacil as an antioxidant in the prevention of intoxication in industrial surroundings and ecologically unhealthy areas]. AB - Thorough clinical studies covering the workers engaged into chlorphenol production prove that prophylactic course of oxymethacyl results in long immune stimulation and antioxidant activity in the body. These properties make the medication essential for treatment and prophylaxis of intoxications of occupational and ecologic origin, as their underlying mechanisms are associated with prooxidant effects. PMID- 8673380 TI - [Evaluation of the health status of stonemasons]. AB - Thorough study of work conditions and health state of stone masons proved physical overload to be a principal factor in charge of the occupational diseases. The physical overload is associated with prevalent manual tasks, frequent monotonous movements, lifting and manual carriage of heavy net weight during the working shift, uncomfortable working postures, unfavorable climate conditions. Nearly half (55.9%) of the examinees were diagnosed as having peripheral neurologic disorders and locomotion diseases--autonomous and sensory polyneuropathy, "frozen shoulder" syndrome, shoulder epicondylitis. PMID- 8673382 TI - [Prospects of the use of a quantitative functional-morphological method in the evaluation of toxicity of chemical substances]. AB - The article describes possible application of quantitative functional and morphologic analysis to evaluation of chemical toxicity. Alteration caused by low doses of chemicals was proved to be mediated by neuroendocrine system. The regulatory disorders result from compromised interaction of cellular elements composing blood-tissue barriers in endocrine organs. The alteration caused by toxic chemicals could be lowered through the use of physiologic stabilization of endocrine system. Criteria to evaluate chemical toxicity are suggested. PMID- 8673381 TI - [Health status of female workers of oil-processing enterprises]. AB - Women working at oil-processing enterprises are exposed to a group of toxic chemicals and influenced by some social and everyday factors. The women demonstrate functional disorders of nervous, cardiovascular systems, disturbances in menstrual and child-bearing functions. Occupational factors influence course of pregnancy, delivery and state of newborn. PMID- 8673383 TI - [Again about occupational diseases]. AB - The article deals with a new physiologic and hygienic approach to evaluation of risk factors for occupational diseases and proves their occurrence even in individuals who have no exposure to critical and intensive work conditions causing occupational diseases. PMID- 8673384 TI - [Conditions of waste fluid accumulation at petrochemical and oil processing enterprises and prevention of their harm to water bodies]. AB - Waste waters released by oil-processing and petrochemical enterprises are characterized by high amounts of oil products, polycyclic and aromatic hydrocarbons, phenols, metal derivatives, surface-active substances, sulfides, naphthylenic acids and other chemicals. Due to ineffectiveness of purification systems, the waste waters grow into serious danger for water bodies. Control taking into account some priorities suggested should cover contents of the waste waters before the inflow into water bodies as well as quality of waters in the sources. PMID- 8673385 TI - [Functional leukocyte tests in the diagnosis of toxic leukopenia]. AB - Adrenalin test in 69% of examinees who had faced long exposure to oil products revealed redistribution leukopenia caused by compromised neurovascular regulation. Toxic origin of the leukopenia in 10.4% of workers was supported not only by the adrenalin test but also by pyrogenal one which proved exhaustion of granulocyte reserve in the bone marrow. PMID- 8673386 TI - [Protection of medical personnel hands with Steriprest preparation]. AB - A new ointment base "Amfilubre" is a chemically bound copolymer of hydrophobic silicone and hydrophylic polyethylene glycol. That provides tight adhesion of the composition to the skin and effective intramolecular incorporation of variable substances. When polyformaldehyde is dispersed in "Amfilubre", the obtained preparation "Steriprest" enables momentary sterilization of skin and instruments due to discharge of the disinfectant from the protective covering layer. The process lasts for several hours, leading to longer protection time. PMID- 8673387 TI - [Industrial hygiene of workers in diphenylolpropane production]. PMID- 8673388 TI - [Prevalence of occupational diseases among agricultural workers]. PMID- 8673389 TI - [Industrial hygiene in the Bashkortostan Republic]. AB - Bashkortostan National Council of Ministers adopted a resolution (No 136, April 12, 1995) "On formation of interdepartmental Committee for Industrial Hygiene in Bashkortostan Republic". The Committee puts into practice principles of the Governmental policy in industrial hygiene according to a law "On industrial hygiene in Bashkortostan Republic"; deals with problems and makes proposals in industrial hygiene; coordinates the specific activities of the Ministries, Departments and public organization of Bashkortostan Republic; cooperates with the competent professionals, organizations and researchers for progress in industrial hygiene. PMID- 8673390 TI - [Medical and biological aspects of the dioxin problem]. AB - The article deals with the problem of dioxidine and similar chemicals influencing unfavorable ecologic situation in the world. The authors briefly describe medical and biologic aspects of the problem, demonstrating the present data accumulated mostly by foreign authors and associated primarily with experiments on animals. The information connected with humans appears to be limited, and all researchers have no universal opinion on dioxidine's degree of jeopardy for humans. Scientists of Ufa Research Center for Human Ecology and Occupational Medicine collected unique material on changes in health state of workers after the exposure to 2,4,5-T and dioxidine-related disorder as chloracne. The authors define main spheres of research on the problem. PMID- 8673391 TI - [State of the care of occupational diseases in the Bashkortostan Republic and prospects of its development]. AB - The article describes activities of Bashkortostan Center for Occupational Diseases for 14 years since its foundation. The article analyses occupational morbidity in Bashkortostan in connection with the industries, according to various entities and defines some prospective goals for the Center's research. PMID- 8673392 TI - [Experimental studies evaluating oncogenic effects of copper-nickel sulfide ore dust]. AB - The experiments on animals studied mutagenic activity of copper-nickel sulfide ore dust. Micronucleus test proved mild mutagenic activity of the ore under study. Chronic inhalation of the dust induced malignancies (mostly lung tumors and leukoses) in 52% of the experimental Wistar rats, that could be caused by dissolution of the dust components in the body fluids. PMID- 8673393 TI - [Biological effects of chemicals used in oil and gas extraction and purification of water bodies polluted with oil]. AB - Hemopoietic system and liver are primary biologic targets damaged. That was proved by evaluation of biologic effects induced by preparations widely used in extraction of oil and gas, in purification of water from oil. Phosphorus organic compounds induce gonadotoxic effects. Surface-active chemicals and phosphorus organic compounds are similar in general toxic effects, but differ in specific influence. PMID- 8673394 TI - [Work conditions and health status of workers in present-day production of disperse azo dyes]. AB - The work conditions appeared to be unfavorable in modern production of dispersed nitro dyes, having up-to-date technologic equipment and automated control systems. The main occupational hazards are semiproducts (nitroaniline derivatives containing chlorine, bromine and cyanides) used as diazo components in dyes synthesis, dispersers based on sodium lignosulfonate, outlet forms of dispersed nitro dyes. Medical examination of the workers exposed to combination of chemicals amounting several times over the MACs proved frequent diseases of upper respiratory tract and cardiovascular system, functional disorders of liver and CNS, propensity for allergic conditions. Specific effects of dispersed nitro dyes and semiproducts of their synthesis on the red blood were methemoglobin formation, suppressed antioxidant activity of RBC (lower serum level of reduced glutathione and ascorbic acid) and stimulated erythropoiesis in bone marrow (increased serum Hb and RBC count, reticulocytosis). The studies helped to elaborate well-justified complex of sanitary, hygienic, therapeutic and prophylactic measures to better the work conditions and prevent the occupational diseases among the workers. PMID- 8673395 TI - [Need for universal scientific language (remarks concerning the article by V.O. Krasovskii and L.M. Karamova, "Again on occupationally related diseases)]. PMID- 8673396 TI - [Toxicity of chemicals produced by thermal destruction of synthetic materials based on polyvinyl chloride and used in coal mines]. AB - The experiments on mongrel white rats studied toxicity of the products appearing during thermal destruction of conveyer tape TK-200 based on polyvinyl chloride and used in coal mines. The studies helped to define parameters of acute toxicity and the MACs for products of the conveyer tape burning, considering the main contents and the exposure intensity for 30-120 minutes; to determine jeopardy class; to calculate specific volatilization; to design recommendations for prevention of poisoning during fire in the mines. PMID- 8673397 TI - [Concentration of imidazolines in the air]. AB - Using chamber for adjustable mode and dosing apparatus, the authors studied conditions of imidazolines' condensation from the air into 60% ethanol, to paper filters of "white tape" type, to analytic filters of AFA-HP type, into a shell with ultrathin layer of sorbent (2.7% sulfuric acid in 20% solution of glycerine in water). The best results were provided by experiments using the paper filter of "white tape" type and absorbing objects filled with 60% ethanol and containing spongy plate. Rate of the air pumping equalled 2-3 l/min and 0.5 l/min respectively. PMID- 8673398 TI - [Occupational brucellosis: epidemiology and clinico-immunological correlations]. PMID- 8673399 TI - [Risk factors of cardiovascular diseases among geological expedition members]. PMID- 8673400 TI - [Evaluation of present-day production of propylene oxide and prognostication of health status of the workers]. PMID- 8673401 TI - [Epidemiologic-hygienic aspects of the assessment of carcinogenic risk in methacrylate production]. AB - The authors studied oncologic mortality among the workers exposed to some acryl monomers. The oncologic risk was estimated for the individuals exposed to acrylonitrile, methyl methacrylate, methyl- and butyl acrylate, methacrylic acid. Occurrence of the malignancies appeared to depend on the dose of methyl methacrylate. PMID- 8673402 TI - [Experimental assessment of carcinogenic hazards of copper-nickel ore]. AB - The study proved that the dust extracted from "Oktjabrsky" mine and containing 83.25% of nickel have marked carcinogenic effects, induces lung tumors and leukosis, if administered intratracheally to Wistar rats. Diagnosed leukosis suggests that carcinogens of the ores dissolve in the tissue liquids and circulate in the body. PMID- 8673403 TI - Amygdaloid nuclei lesions differentially affect glucocorticoid-induced memory enhancement in an inhibitory avoidance task. AB - This study examined the involvement of the amygdala in the effects of glucocorticoids on the formation of memory for aversive training. Male Sprague Dawley rats with neurochemically induced lesions of either the basolateral (BLA), central (CEA), or medial amygdala (MEA) were trained in a one-trial inhibitory avoidance task. Systemic (sc) injections of either vehicle, corticosterone (0.3 mg/kg) or the more selective glucocorticoid receptor (GR) agonist dexamethasone (0.3 mg/kg) were administered immediately after training, and retention was tested 48 h later. Retention of animals with lesions of the CEA was impaired, but retention of animals with BLA or MEA lesions was unimpaired. CEA-lesioned animals had increased locomotor activity as indicated by the number of crossings between the starting and shock compartments. Dexamethasone enhanced retention in sham operated controls as well as in animals with lesions of the CEA, but did not enhance retention of animals with BLA or MEA lesions. Post-training corticosterone did not affect retention. Neither dexamethasone nor corticosterone altered the number of crossings between compartments. These findings are consistent with previous evidence suggesting that the effects of glucocorticoids on memory storage are mediated by an activation of GRs, and indicate that the BLA and MEA nuclei are critical areas involved in integrating these hormonal influences on learning and memory. PMID- 8673404 TI - Changes in rabbit cerebellar cortical and interpositus nucleus activity during acquisition, extinction, and backward classical eyelid conditioning. AB - Multiple- and single-unit neuronal activities were recorded from cerebellar cortex (Larsell's lobule HVI and adjacent ansiform cortex) and the cerebellar interpositus nucleus during forward (CS-US), backward (US-CS), and explicitly unpaired classical eyeblink conditioning in several rabbits. Whereas learning related activity was observed in the interpositus nucleus only during forward pairing of the conditioning stimuli, a variety of patterns of learning-related neuronal firings were observed in cerebellar cortex during forward, backward, and even unpaired presentations of the conditioning stimuli. These data suggest that the cerebellar cortex and the deep cerebellar nuclei play different roles during classical eyeblink conditioning. PMID- 8673405 TI - Reversal of beta-amyloid-induced retention deficit after exposure to training and state cues. AB - We explored amnesia induced by posttraining injection of beta-amyloid protein (beta A4) in four experiments. Previous reports showed that beta A4 impaired retention of learning maintained either by food reward or by shock relief. The experiments in this paper attempted to determine (1) if the amnesia is specific to the 1-40 beta A4 amino-acid sequence; and (2) if the amnesia can be attributed to a consolidation process. Subjects were 190 male Sprague-Dawley rats, 3 to 6 months old. Subjects were given five training trials on a left-right discrimination in a Y-maze with a food reward and injected immediately afterward with beta A4(1-40) or vehicle. One week later they were trained to criterion. Experiment 1 used a control group that was injected with the reverse-sequence peptide (40-1). The performance of the beta A4(40-1) group was unimpaired. Experiments 2 and 3 attempted to reverse the amnestic effects of beta A4 using noncontingent presentation of aspects of the training context during the retention interval. Experimental subjects in Experiment 2 were exposed to the Y maze in the absence of reinforcers, 24, 22, and 2 h before retention testing. In Experiment 3, subjects were given a 1-min exposure to the reinforcers, outside the Y-maze, 24 h before retention testing. Both manipulations reversed beta A4 induced amnesia. In Experiment 4, beta A4-induced impairments were reversed by reinjecting beta A4 immediately before retention testing. Results indicate that beta A4 injected after partial training does not interfere with a consolidation process. PMID- 8673406 TI - Ultrastructural evidence for increased contact between astrocytes and synapses in rats reared in a complex environment. AB - Rats raised from weaning in a complex environment have an increased number of synapses per neuron in the visual cortex in comparison to animals housed in standard laboratory cages. Previous research has suggested that experience dependent synaptic changes may be coordinated with changes in astrocytes. The present study used electron microscopy to examine astrocytic processes in the visual cortex of rats raised in a complex environment (EC) or in standard laboratory cages, either individually (IC) or in pairs (social condition, SC). Measurements of the surface density of astrocytic membrane in direct apposition to synaptic elements revealed that astrocytic processes have increased contact with synaptic elements within the visual cortex of EC rats in comparison to SC and IC animals. In contrast, other astrocytic size variables revealed no significant change in astrocytic processes per unit volume of tissue. Previous work has indicated no significant differences in synaptic density in these subjects. The specific increase in the contact between astrocytes and synapses suggests an experience-related enhancement of the astrocytic involvement in synaptic activity. PMID- 8673407 TI - Amygdala beta-noradrenergic influences on memory storage involve cholinergic activation. AB - These experiments examined the involvement of the amygdaloid complex as a site of interaction of adrenergic and muscarinic cholinergic influences on memory storage. Male Sprague-Dawley rats (60 days old; 250-300 g) were given a single training trial in an inhibitory avoidance task and a retention test trial 48 h later. Immediately after training buffer control or drug solutions (0.5 microliter) were infused into the amygdala and, in the first experiment only, other drugs were administered intraperitoneally (ip). The first experiment examined the effects of post-training systemic injections of the muscarinic agonist oxotremorine (100.0 micrograms/kg) administered alone or together with intraamygdala injections of either the muscarinic antagonist atropine (1.0 microgram) or the beta-noradrenergic antagonist propranolol (0.3 microgram). Oxotremorine enhanced retention and atropine, but not propranolol, attenuated the effects of oxotremorine. In the second experiment intraamygdala infusions of the beta-noradrenergic agonist clenbuterol (10.0 ng) were administered either alone or together with atropine (1.0 microgram). Clenbuterol enhanced retention and atropine blocked the effects of clenbuterol. In the third experiment intraamygdala infusions of oxotremorine (3, 10, 30, or 100 ng) were administered either alone or together with propranolol (0.3 microgram). Oxotremorine (3.0 and 10.0 ng) enhanced retention and propranolol did not block the effects of oxotremorine. These findings are consistent with the view that memory storage is regulated by an interaction of beta-noradrenergic and cholinergic influences and suggest that the noradrenergic influences are mediated by the release of acetylcholine and activation of muscarinic cholinergic receptors within the amygdala. PMID- 8673408 TI - Inactivation of hippocampus or caudate nucleus with lidocaine differentially affects expression of place and response learning. AB - Involvement of the hippocampus and caudate nucleus in place and response learning was examined by functionally inactivating these brain regions bilaterally with infusions of lidocaine. Rats were trained to approach a consistently baited arm in a cross-maze from the same start box (four trials/day/14 total days). On Days 8 and 16 a single probe trial was given, in which rats were placed in the start box opposite that used in training and allowed to approach a maze arm. Three minutes prior to the probe trial, rats received bilateral injections of either saline or a 2% lidocaine solution (in order to produce neural inactivation) into either the dorsal hippocampus or dorsolateral caudate nucleus. On the probe trials, rats which entered the baited maze arm (i.e., approached the place where food was located during training) were designated place learners, and rats which entered the unbaited maze arm (i.e., made the same turning response as during training) were designated response learners. Saline-treated rats displayed place learning on the Day 8 probe trial and response learning on the Day 16 probe trial, indicating that with extended training there is a shift in learning mechanisms controlling behavior. Rats given lidocaine injections into the hippocampus showed no preference for place or response learning on the Day 8 probe trial, but displayed response learning on the Day 16 probe trial, indicating a blockade of place learning following inactivation of the hippocampus. Rats given lidocaine injections into the caudate nucleus displayed place learning on both the Day 8 and the Day 16 probe trials, indicating a blockade of response learning following inactivation of the caudate nucleus. The findings indicate: (1) the hippocampus and caudate nucleus selectively mediate expression of place and response learning, respectively (2), in a visually cued extramaze environment, hippocampal-dependent place learning is acquired faster than caudate-dependent response learning, and (3) when animals shift to caudate dependent response learning with extended training, the hippocampal-based place representation remains intact. PMID- 8673409 TI - Scopolamine administered before and after training impairs both contextual and auditory-cue fear conditioning. AB - When administered before training to 23-day-old Long-Evans rats, scopolamine hydrobromide significantly impaired both contextual and auditory-cue fear conditioning in a dose-dependent manner. Methylscopolamine which does not cross the blood-brain barrier, however, had no effect on either form of conditioned fear. Scopolamine administered up to 3 h after training also impaired both forms of fear conditioning when administered following a single pairing of the auditory cue and shock. When rats received three pairings, however, a posttraining treatment with scopolamine only impaired contextual fear conditioning. These results suggest that central cholinergic systems are involved in the posttrial processes that establish the memory trace for the conditioning experience. PMID- 8673410 TI - Micro- and macrostructure of learning in active avoidance: a quantitative approach. AB - The dynamics of learning in the Active Avoidance test was analyzed at the trials level as well as at the level of daily sessions, each comprising numerous trials. The two scales (large scale for the sessions and small scale for the trials) were demonstrated to be mutually independent. The intermediate derived scales (blocks of trials) were found consistent among themselves and with small scale but independent of the large one. Moreover, the two extreme scales were kinetically discriminable. These results point to the existence of two independent mechanisms for large and small scale learning together with the need to postulate a consolidation process during the rest period. PMID- 8673411 TI - Reunion of separated sibling mice: neurobiological and behavioral aspects. AB - Outbred albino NMRI male mice encountering a brother in adulthood, after a long period of separation, show an opioid-dependent increase in pain threshold. Unrelated and unfamiliar males show no similar changes in pain sensitivity. This study investigates which kind of stimuli from the partner may be responsible for such a modification at the neural level. The tail-flick test is used as a measure of pain sensitivity. Exposure to the scent of the brother's home cage, as well as exposure to visual, olfactory and auditory stimuli and partial physical contact with the related male, are not sufficient to induce changes in nociception. Physical affiliative contact between males is higher in sib than in nonsib pairs, and a positive correlation exists in sib pairs between huddling behavior and pain sensitivity at the end of a 2-h social session. Siblings injected with naloxone, an opioid receptor blocker, show a decrease in social behaviors involving physical contact. These results suggest that physical affiliative contact between sibling mice may be responsible for the enhancement of nociceptive threshold. PMID- 8673412 TI - Blockade of NMDA receptors during song model exposure impairs song development in juvenile zebra finches. AB - Juvenile zebra finches (Poephila guttata) learn their courtship song by memorizing and then reproducing the song of an adult male. Several brain regions involved in song behavior contain N-methyl-D-aspartate (NMDA) receptors, and within one brain nucleus necessary for normal song development, the density of these receptors is twice as high in juveniles that are learning song then in adults that can no longer modify their songs. To determine whether NMDA receptor activation is necessary for normal song development, juvenile zebra finches were systemically injected with the NMDA receptor antagonist MK-801 (0.1 mg/kg) before exposure to an adult male tutor. One control group received the same number of MK 801 injections 24 h out of phase with tutoring, and another received saline before tutoring. In adulthood, birds given MK-801 before tutoring showed little evidence of learning from the tutor, and their songs contained abnormal syllables typical of untutored birds. In contrast, all control birds developed normal songs and copied an average of 72.5% of the tutor's syllables. Acute injections of MK 801 did not alter auditory brainstem evoked potentials in juveniles, indicating that the behavioral effects of MK-801 on song learning were not due to temporary hearing loss. Our results suggest that normal song development in juvenile zebra finches requires NMDA receptor activation during song model presentation. PMID- 8673413 TI - Repeated assessment of spatial discrimination performance of aged rats in the Morris water escape task. PMID- 8673414 TI - Blood-brain barrier after resuscitation from 10-min clinical death in rats. AB - In rats 10-min clinical death was induced by intrathoracic compression of the cardiac vessel bundle. The animals were sacrificed from 15 min to 7 days after resuscitation. They were decapitated 15 sec after intracarotid injection of mixture of L-[U-14C]glutamic acid and tritiated water. Using by the dual label method the brain uptake index (BUI) and percent of injected dose of amino acid in the cerebral hemisphere were calculated. In 45% of animals an increase of amino acid transfer and rise of BUI revealed the blood-brain barrier (BBB) alterations. The most pronounced changes developed after 120 min and 1 day after resuscitation. The impaired vs. normal BBB state depends probably on uneven recovery of cerebral circulation in individual animals after resuscitation. PMID- 8673415 TI - The features of peripheral nerve lesions in young and adult rabbits after vincristine administration. AB - The comparison of neuropathological picture of vincristine induced neuropathy immediately after the end of its administration and after three months of survival was performed. The adult rabbits and six litters of newborns received vincristine once a week in increasing doses 0.05-0.25 mg/kg of body weight. The early changes consisted in degeneration of axons and myelin sheaths and lesions of the Schwann cells. The features of changes allow to suspect that vincristine may induce, in addition to the well known primary axonal damage, a toxic effect on the Schwann cells with secondary damage of myelin sheaths. The changes were more severe in adults than in young animals. The observations after three months of survival allow to think that the administered doses of vincristine did not impede the improvement when treatment was interrupted. PMID- 8673416 TI - Morphological changes in the corpus callosum in chronic alcoholism. AB - In a group of 66 patients (age 24 to 78 years) with the clinical diagnosis of chronic alcoholism the changes in the corpus callosum were evaluated. The period of alcohol abuse varied from 3 to over 30 years. In 57 cases atrophy of the corpus callosum was noted. The trunk was involved most frequently. Myelin sheaths exhibited abnormalities from slight pallor to total destruction. In 19 cases the damage of myelin sheaths was restricted to disseminated, perivascular, spongy degenerations. The vessels were sclerotic, especially periventricular ones exhibited degenerative changes. Perivascular gliosis was also seen. Conclusions from the present study indicate that the structural changes observed in the corpus callosum during chronic alcohol abuse are connected with CNS involution and with degenerative changes within vessels walls. The damage of myelin sheaths localized in our material similarly as Marchiafava-Bignami disease, differs from the later by less advanced changes, perivascular spreading of demyelination, and frequent destruction of axons. PMID- 8673417 TI - Transformation of sterols pattern in course of late development of rat brain. AB - Free sterol content was determined in the late period of development of the rat brain using the method of gas chromatography-mass spectrometry. The results obtained have shown that the free sterol pattern is very unstable in course of late period of ontogenic development. In contrast to young adult rats, in which apart from cholesterol only trimethylcholestenon and trace amounts of desmosterol were visible, in the brain of 1 and 2 years old rats some new sterols are appearing. There are cholestadien, cholest-5-en-3-on, 4 methyl-cholesten, cholest 5-en-3-ethoxy and 4,4,14-trimethyl-5-alpha-cholest-24-en-3-en. There are also qualitative differences in the structure of some sterols (various isomers) between both groups of late development. These changes, indicating some transformation of cellular membranes seem to be the result of biologically programmed late ontogenic development. PMID- 8673418 TI - Primitive neuroectodermal tumor (PNET). A case report. AB - The authors present a case of relatively rare tumor of the central nervous system (CNS) in a 19-year-old female, who died 18 months after the first manifestation of meningismus, increased intracranial pressure and secondary hydrocephalus. Brain autopsy revealed abundant neoplastic infiltrations, which spread through the subarachnoid space. Neoplastic infiltrations were also present in the third ventricle and in a form of small subependymal nodules along the whole ventricular system. The microscopical examination showed that neoplasm consisted of small cells, which formed neuroblastic Homer Wright rosettes. Immunohistochemical studies (for synaptophysin, chromogranin A, GFAP, vimentin) together with morphology and localization of neoplasm suggested diagnosis of primitive neuroectodermal tumor (PNET) that spread mainly in the leptomeninges and caused obliteration of subarachnoid space. PMID- 8673419 TI - Immunohistochemical and ultrastructural studies of stromal cells in hemangioblastoma. AB - In order to shed more light on the controversial tissue histogenesis of the stromal cells (SC), light microscopic, immunohistochemical and electron microscopic studies were performed on surgical specimens of hemangioblastomas (36, 26 and 7 cases, respectively). SC were immunoreactive for vimentin, S-100 protein, and neuron specific enolase (NSE) in all cases. Occasional SC were also positive for desmin, smooth muscle actin, Factor VIII, Ulex europaeus lectin receptors, GFAP, and Factor XIIIa. However, majority of these cells were negative with all the endothelial and smooth muscle cell markers used. Electron microscopy demonstrated several different types of SC that were reminiscent of pericytes, smooth muscle cells and abnormal endothelium as well as the intermediate forms between all the above cell types. Few SC were found lining the vascular lumina. Some SC formed small cavities reminiscent of early capillaries. However, typical Weibel-Palade bodies were not found in these SC. It is concluded that SC represents a heterogeneous population of lipidized cells, derived predominantly from the vasogenic mesenchyme. Although immunohistochemistry failed to reveal any consistent antigenic property of SC, ultrastructural findings strongly support the hypothesis that these cells are modified or abnormally differentiated endothelial cells and pericytes. PMID- 8673420 TI - Immuno-electron microscopic demonstration of GABA and glutamate synapses in Mongolian gerbils hippocampus after ischemia. AB - The subcellular distribution of glutamate and GABA in synapses of Mongolian gerbils hippocampus was examined using post-embedding immunogold staining method for electron microscopy. Immunolabelling was performed with 10 nm gold-antibody complexes for glutamate and GABA. The gold particle densities gave reliable information about the relative concentrations of these amino acid neurotransmitters. Our results indicate that ischemia leads to the temporal decrease of GABA-like immunoreactivity in symmetric synapses and a slight enhancement of the level of glutamate-like reactivity in asymmetric ones. The striking finding was a redistribution of glutamate-like immunoreactivity from neurons to glia. This suggests the capacity of glia to metabolize the excess of glutamate after ischemia. The disturbances at the level of neurotransmitters and their possible role in hippocampal neuronal injury were stressed. PMID- 8673421 TI - Multiple cerebral cavernous angiomas. Case report. AB - This 26-year-old woman was admitted to Neurosurgery Department in 1972 for the first time due to increased intracranial pressure and since observed and treated by ventriculo-peritoneal shunt during next twenty years. First symptoms such as visual disturbances, hemiparesis and hemianesthesia appeared 8 years earlier followed 4 years later by epileptic fits. Ventriculography revealed hydrocephalus and the tumor in the region of the third ventricle. CT scan visualized multiple hyperdense foci. Ventriculo-peritoneal shunt provided good improvement. During the next twenty years condition of the patient gradually worsened. Diagnosis of multiple cavernous angiomas was established only at autopsy. PMID- 8673422 TI - A case of radionecrosis mimicking metastatic tumor of the cerebral hemisphere. AB - A case of delayed radiation necrosis of the cerebral hemisphere in a patient with irradiation after orbital adenocarcinoma surgery is presented in order to warn of a possible misdiagnosis with a metastatic CNS tumor. In the case surgical treatment of orbital adenocarcinoma was followed by X-ray therapy. Focal necrotic changes appearing two years later were the cause of neurological symptoms. PMID- 8673423 TI - Central nervous system leukostasis in patients with leukemias and lymphomas. AB - The clinical and neuropathological investigations have been done on 133 autopsied patients died of leukemia or non-Hodgkin's lymphoma of high malignancy. A study was performed to analyse the role of various factors particularly with respect to adhesion and aggregation in the CNS leukostasis development. The findings were also designated to evaluate the distribution of leukostasis in different CNS regions and to recognize its intensity in various CNS vessels. Basing on the studies the authors conclude that the risk of CNS leukostasis increases evidently when the leukocyte counts are elevated above 50 G/l. The adhesion and aggregation of leukemic and lymphomatous cells as well as local anatomical factors in the CNS vessels play and important role in the CNS leukostasis development, which is more intensive in the white matter and leptomeninges. The medium-sized vessels are much involved, whereas cortical capillaries are relatively less affected by leukostasis. The CNS leukostasis appears to be dynamic and reversible phenomenon, which undergoes fluctuations according to the leukocyte counts increase or decrease. PMID- 8673424 TI - Papers presented on neuropathological conference on pathology of the cerebral blood vessels. Warsaw, June 3, 1995. PMID- 8673425 TI - The vascularization of the developing human brain. AB - The principal rules of vascularization of developing central nervous system are presented. The angiogenesis as a mechanism of cerebral vessels formation was explained. The time of epiparenchymal plexus formation and penetration of endothelial channels into nervous tissue was reviewed evidentiating the correlation between the development of brain structures and their vascularization. Particular attention was devoted to the problem of formation and maturation of vessels within cerebral hemispheres, the rates of blood supply and drainage of their structures. PMID- 8673426 TI - Selected histochemical and immunocytochemical markers of biological activity of brain blood vessels. AB - In the review dyes, enzymes and molecules were described, which serve as markers of various functions of blood vessels or their structural elements. From among histochemically revealed enzymes those were described which are of significance in the characteristics of the blood-brain barrier function. Attention has been paid to dyes with which pathology in blood vessel wall can be visualized. Among molecules, mainly adhesion and markers of angiogenesis were described. Their discovery is possible with the use of antibodies in immunohistochemical methods taking into account the accessibility to antibodies and their usefulness in the recognition of pathophysiological processes in the central nervous system. PMID- 8673427 TI - Developmental failures of blood vessels within central nervous system. AB - Basing on the literature and her own material the author considers some of developmental vessel malformations: aneurysms, teleangiectases, angiomas and cavernous angiomas. The author pays attention to difficulties in classifying of developmental vascular malformations and choice of terminology. Presumable etiopathogenesis of some malformations with particular regard to role of viral oncogenes is taken into account. PMID- 8673428 TI - Pathology of the vessels in cerebral amyloid angiopathy. AB - We review here current data on congophilic amyloid angiopathy (congophilic angiopathy) or cerebral amyloid angiopathy in both transmissible and non transmissible cerebral amyloidoses. A beta peptide is the amyloid in congophilic angiopathy of Alzheimer's disease, and in majority of cases of Creutzfeld-Jakob disease and Gerstmann-Straussler-Scheinker disease. A variant of Cystatin C is the amyloid in hereditary cerebral hemorrhage with amyloidosis-Icelandic type. The only exception is a curious GSS-like family from Japan characterized by 145 stop codon at the PRNP gene. Both molecular pathology and neuropathology are covered by this review. PMID- 8673429 TI - Neoplastic vascular tumors of the central nervous system. AB - We report here neuropathology of vascular brain neoplastic tumors. These include haemangioblastoma, haemangiopericytoma, angiosarcoma. The most recent molecular data on the histogenesis of gliosarcoma are also discussed. PMID- 8673430 TI - Localization of endothelin in the blood-brain interphase in rat hippocampus after global cerebral ischemia. AB - Electron microscopic immunocytochemical evaluation of localization and distribution of endothelins 1, 2 and 3 in the CA1 hippocampal sector in rats submitted to 10 min global cerebral ischemia was performed. The studies were done in different postischemic periods (10 min, 3, 6, 12 and 24 h) with postembedding immuno-gold technique for electron microscopy. Endothelin-like immunoreactivity was found in endothelial cells of hippocampal microvessels and in astrocytes, microglia, macrophages and in some axonal endings. The most pronounced changes appeared 24 h after ischemia. At that period all structural elements of blood brain interphase: endothelium, basal membrane and perivascular astrocytic processes showed intensive endothelin-like immunoreactivity. Especially marked immunoreactivity was found in macrophages appearing in the proximity of microvessels. It has been stressed that ischemia-induced increased content of endothelin may play an important role in the pathogenesis of postischemic tissue abnormalities. PMID- 8673431 TI - Antiphospholipid syndrome in systemic lupus erythematosus--immunomorphological study of the central nervous system; case report. AB - We present a case of a 44-year-old female with systemic lupus erythematosus (SLE) with secondary antiphospholipid syndrome (APS). The patient died in the 15th year of the disease. The paraffin sections of the brain and spinal cord were examined using routine histological methods and immunohistochemistry with monoclonal antibodies against CD31, FVIIIAg and polyclonal antibodies IgG, fibrinogen and C3. Numerous thrombi-recent, organized and recanalized and focal vasculitis were seen. The immunopositive reaction in thickened vessel walls for CD31 and FVIIIAg indicated the process of the local incorporation of the thrombi. The immunoreactivity for fibrinogen, IgG and C3 suggests the immunological complexes formation in vessel walls, perivascular astrocytes and neurons. PMID- 8673432 TI - Rare vascular changes in the brain in a case of subacute cutaneous lupus erythematosus. AB - Histopathological changes in leptomeningeal and cerebral blood vessels in a case of subacute cutaneous lupus erythematosus (SCLE) with the involvement of the central nervous system are presented. A 46-year-old woman died because of cerebral stroke after a 19-year duration of the disease. The general autopsy showed changes in the kidneys, myocardium, spleen and pancreas, typical of systemic lupus erythematosus. The brain autopsy revealed large necrosis in the supply territory of the middle and posterior cerebral arteries in the left hemisphere. In addition, small focal necroses, partially hemorrhagic, were found in both cerebellar hemispheres. Small cortical necrosis was also visible in the right insular area. A diffuse damage of the blood vascular system in the form of fibrinoid necrosis of small sized cerebral blood vessels with inflammatory infiltrates of the vessel wall (necrotizing leukocytoclastic vasculitis) predominated in the microscopic examination of the brain. Vascular changes of vasculopathy type in the form of hyalinization of the vascular wall and fibrinoid necrosis with concomitant numerous, small necroses were observed. In the lumen of left internal carotid artery infiltrated by inflammatory cells, an organized thrombus was found. Giant cells were observed within vascular infiltration. PMID- 8673433 TI - Morphological study of endothelial cells in the human fetus during early period of gestation. AB - During the formation of blood vessels, proliferation and migration of endothelial cells (ECs) are one of the most important mechanisms. The development of the vessels involves two different mechanisms: vasculogenesis i.e. differentiation of ECs in situ from mesenchymal precursors, and angiogenesis i.e. sprouting of ECs from pre-existing vessels. The frontal lobes from 20 brains of human fetuses ranging from 8 to 17 weeks of gestation (GW) were subjected to correlative light and electron microscopic studies. Our observations demonstrate the sprouting of ECs from pre-existing vessels in leptomeninges (angiogenesis) during the formation of a capillary network of the fetal human brain. In addition, the study did not reveal after the 8th GW the mitotic proliferation of ECs in examined specimens which allows to underline the importance of sprouting and elongation of ECs channels for this phase of vascularization of cerebral hemispheres. PMID- 8673434 TI - Coexistence of various vascular malformations within the brain. AB - Authors present two cases of basilar artery aneurysm accompanied by different development failures of blood vessels. In both cases anomaly in formation of brain base vessels, angioma consisted of different size thin-walled vessels and arterio-venous angioma within brain stem were stated. Besides, conglomerates of abnormal vessels, angiosis within pia matter, diffused lacunar and fetal as well as thin-walled venous vessels were found. Pathological vessels, their conglomerates were present in brain stem, cerebellum and cerebral hemispheres. The variability of vascular malformations seems to point at long-lasting action pathogenic factor during ontogenesis. Authors try to refer particular developmental anomalies to proper stage of ontogenesis. PMID- 8673435 TI - Cavernous angioma of brain stem mimicking multiple sclerosis. AB - A 14-year-old boy was admitted to our Department due to peripheral palsy of right VII and bilateral of the VI cranial nerves, spasticity, cerebellar symptoms as well as to dysphagia and dysarthria. In general, he was hospitalized 13 times because of the disease of a relapsing-remitting and next progressive course. He died 31 years after onset of the disease. Multiple sclerosis was diagnosed. Brain autopsy revealed tumor involving almost all brain stem structures and a part of right cerebellar hemisphere. Histologically, cavernous angioma was diagnosed. PMID- 8673436 TI - Vascular malformations associated with other congenital anomalies of the central nervous system: coexistence and possible causal relations. AB - Two cases of vascular malformations coexisting with other congenital defects of the central nervous system (CNS) are presented here. The first patient was a 14 year-old girl mentally retarded who demonstrated seizures and balance disturbances with onset in early infancy. The neuropathological examination revealed vascular malformations in the pons, diastematomyelia (triple central canal) in the sacral spinal cord and palleocerebellar granular layer dysplasia. The second patient was a 10-year-old boy hospitalized because of purulent dermatitis who suddenly developed recurrent generalized and focal motor seizures. The neuropathological examination disclosed multiple capillary teleangiectases with focal anomalies within cerebral cortex of the frontal and parietal lobes. The relations between several developmental anomalies in the CNS and possible causal relation between such malformations are discussed. PMID- 8673437 TI - Ultrastructure of brain vessel in vincristine treated rabbits. AB - Ultrastructure of the brain blood vessels has been examined in rabbits treated with a single intraperitoneal injection of vincristine (VCR). The results provided evidence that some microvessels in these animals undergo vasoconstriction concomitant with projection of numerous endothelial microvilli into the vessel lumen. Vasoconstriction was followed by microvessel loss of regular shape and degeneration of some endothelial cells resulting in the digestion of apoptotic bodies by perivascular pericytes. Most of those changes (eg. vasoconstriction) appeared transient and were not observed seven days after treatment. PMID- 8673438 TI - Characteristics of periventricular matrix vascularization in image computer transformation system. AB - Observations of periventricular matrix vascularization were performed. Following technics were used: injection Pickword's method, infrared, image computer analysis. Various transformations were applied; linear and mathematical morphology. The examined material consisted of 200 fetuses aged 4-8 months of gestation. Subependymally localized and sinusoidally extended vessels were observed. Arteries reaching the ventricular lumen were seen as anatomically and functionally terminal, dendroidally ramificating only at the periphery. The connections between vessels of periventricular matrix and those of surrounding white matter were evidentiated. PMID- 8673439 TI - Programmed cell death and its clearance in the developing mammalian kidney. PMID- 8673441 TI - Cell proliferation and development of the Malpighian tubules in Drosophila melanogaster. PMID- 8673440 TI - Growth factor control of developing kidney endothelial cells. PMID- 8673442 TI - Genetics and molecular pathology of cystic renal disease. PMID- 8673443 TI - Does the kidney express redundant or important molecules during nephrogenesis? PMID- 8673444 TI - Inductive interactions between the mesenchyme and the ureteric bud. PMID- 8673445 TI - Roles of Paxgenes in nephrogenesis. PMID- 8673446 TI - Extracellular matrix and cell adhesion molecules in nephrogenesis. PMID- 8673447 TI - Growth factors and metanephrogenesis. PMID- 8673448 TI - Mapping vertebrate embryos. PMID- 8673449 TI - Axon guidance: following the Eph plan. AB - Recently discovered 'Eph' family receptors and their ligands appear likely to provide the 'cytochemical tags' that Sperry speculated enable axons projecting from the retina to find their correct targets in the brain. PMID- 8673450 TI - Bacterial differentiation: sizing up sporulation. AB - New results on Bacillus subtilis sporulation suggest that size differences between the post-septation compartments trigger differential gene expression, which is then coordinated by communication between the nascent mother cell and forespore compartments. PMID- 8673451 TI - Protein biogenesis: chaperones for nascent polypeptides. AB - A number of molecular chaperones have been found to interact with nascent polypeptides attached to ribosomes, allowing these protein-synthesis machines to play a key part in protein folding and targeting. PMID- 8673452 TI - Neural modulation: following your own rhythm. AB - Recent studies of an invertebrate neural circuit show how presynaptic inhibition can play a key role in the generation of oscillatory activity, and can allow the directly affected axon terminal to engage in rhythmic activity independently of the rest of the neuron. PMID- 8673453 TI - Plant genetics: fast flowering. PMID- 8673454 TI - SH2 domains: a question of independence. AB - The three-dimensional structures of parts of two enzymes that contain tandem Src homology 2 (SH2) domains have recently been determined. The structures suggest how the SH2 domains function in concert to regulate enzymatic activity and localization. PMID- 8673455 TI - Mitochondrial DNA: molecular fossils in the nucleus. AB - The nuclear genomes of many animals contain non-functional copies of mitochondrial genes that provide new opportunities for evolutionary analysis. PMID- 8673456 TI - Cortical development: with an eye on neurotrophins. AB - Recent observations suggest that neurotrophins are involved in activity-dependent plasticity of the developing cerebral cortex. What molecular mechanisms underlie activity-dependent competition between axons for trophic factors? PMID- 8673457 TI - Immunoglobulin diversity: rearranging by cutting and repairing. AB - The recombination process that assembles antigen-receptor genes is now understood in some biochemical detail. The initial steps reflect a common theme seen in retroviral integration and prokaryotic transposition, and the later steps involve the enzymatic machinery for double-strand break DNA repair. PMID- 8673458 TI - Protein translocation: nuclear export--out of the dark. PMID- 8673459 TI - Vision: filling in and pop out. AB - The 'pop out' of a distinctive element embedded in a regular pattern, and the 'filling in' of a blind spot, are dramatic manifestations of the way context affects visual perception. Recent studies shed light on the neurophysiological bases of these phenomena. PMID- 8673460 TI - Plant hormones: more than one way to detect ethylene. PMID- 8673461 TI - Neuroanatomy: mushrooming mushroom bodies. AB - A revolution is spreading in the study of mushroom bodies, structures within the insect brain that mediate learning and memory processes and pheromonal discrimination of the opposite sex. PMID- 8673462 TI - The evolution of chromosomal sex determination and dosage compensation. AB - In many species, sex is determined by a system based on X and Y chromosomes, the latter having lost much of their genetic activity. Y chromosomes have evolved independently many times, and the associated change in gene dosage in the heterogametic (XY) sex is often compensated for by regulatory mechanisms which ensure equal amounts of gene products of X-linked loci in males and females. There have recently been substantial advances in our knowledge of the molecular biology and genetics of sex chromosomes and dosage compensation, and in our understanding of the population genetic processes which are involved in their evolution. PMID- 8673463 TI - The Hin dimer interface is critical for Fis-mediated activation of the catalytic steps of site-specific DNA inversion. AB - BACKGROUND: Hin is a member of an extended family of site-specific recombinases- the DNA invertase/resolvase family--that catalyze inversion or deletion of DNA. DNA inversion by Hin occurs between two recombination sites and requires the regulatory protein Fis, which associates with a cis-acting recombinational enhancer sequence. Hin recombinase dimers bind to the two recombination sites and assemble onto the Fis-bound enhancer to generate an invertasome structure, at which time they become competent to catalyze DNA cleavage and strand exchange. In this report, we investigate the role of the Hin dimer interface in the activation of its catalytic functions. RESULTS: We show that the Hin dimer is formed at an interface that contains putative amphipathic alpha-helices in a manner that is very similar to gamma delta resolvase. Certain detergents weakened cooperative interactions between the subunits of the Hin dimer and dramatically increased the rate of the first chemical step of the reaction--double-strand cleavage events at the center of the recombination sites. Amino-acid substitutions within the dimer interface led to profound changes in the catalytic properties of the recombinase. Nearly all mutations strongly affected the ability of the dimer to cleave DNA and most abolished DNA strand exchange in vitro. Some amino-acid substitutions altered the concerted nature of the DNA cleavage events within both recombination sites, and two mutations resulted in cleavage activity that was independent of Fis activation in vitro. Disulfide-linked Hin dimers were catalytically inactive; however, subsequent to the addition of the Fis-bound enhancer sequence, catalytic activity was no longer affected by the presence of oxidizing agents. CONCLUSIONS: The combined results demonstrate that the Hin dimer interface is of critical importance for the activation of catalysis and imply that interactions with the Fis-bound enhancer may trigger a conformational adjustment within the region that is important for concerted DNA cleavage within both recombination sites, and possibly for the subsequent exchange of DNA strands. PMID- 8673464 TI - Engineering green fluorescent protein for improved brightness, longer wavelengths and fluorescence resonance energy transfer. AB - BACKGROUND: Variants of the green fluorescent protein (GFP) with different colors would be very useful for simultaneous comparisons of multiple protein fates, developmental lineages and gene expression levels. The simplest way to shift the emission color of GFP is to substitute histidine or tryptophan for the tyrosine in the chromophore, but such blue-shifted point mutants are only dimly fluorescent. The longest wavelengths previously reported for the excitation and emission peaks of GFP mutants are 488 and 511 nm, respectively. RESULTS: Additional substitutions, mainly in residues 145-163, have improved the brightness of the blue-shifted GFP mutants with histidine and tryptophan in place of tyrosine 66. Separate mutations have pushed the excitation and emission peaks of the most red-shifted mutant to 504 and 514 nm, respectively. At least three different colors of GFP mutants can now be cleanly distinguished from each other under the microscope, using appropriate filter sets. A fusion protein consisting of linked blue- and green-fluorescent proteins exhibits fluorescence resonance energy transfer, which is disrupted by proteolytic cleavage of the linker between the two domains. CONCLUSIONS: Our results demonstrate that the production of more and better GFP variants is possible and worthwhile. The production of such variants facilitates multicolor imaging of differential gene expression, protein localization or cell fate. Fusions between mutants of different colors may be useful substrates for the continuous in situ assay of proteases. Demonstration of energy transfer between GFP variants is an important step towards a general method for monitoring the mutual association of fusion proteins. PMID- 8673465 TI - Double labelling of subcellular structures with organelle-targeted GFP mutants in vivo. AB - BACKGROUND: The green fluorescent protein (GFP) of Aequorea victoria is emerging as a unique tool for monitoring complex phenomena such as gene expression and organelle structure and dynamics in living cells. The recent description of GFP mutants with modified spectral properties opens numerous new applications in cell biology. However, the expression and the characteristics of these GFP mutants in living eukaryotic cells have not been verified yet. RESULTS: Here, we demonstrate the usefulness of the GFP mutants for cell biology studies in vivo, by the use of wild-type GFP, a 'bright' GFP mutant (S65T) and a mutant with blue-shifted excitation and emission spectra (Y66H/Y145F). We have constructed two GFP chimeras targeted to mitochondria, mtGFP(S65T) and mtGFP(Y66H/Y145F), with the same strategy used previously for mtGFP. In addition, two GFP chimeras targeted to the nucleus, nuGFP and nuGFP(S65T), were constructed by fusing the wild-type GFP or the (S65T) mutant to the rat glucocorticoid receptor. By co-transfecting mtGFP(Y66H/Y145F) and nuGFP, the nucleus and the mitochondria were visualized simultaneously in living cells. Similarly, mtGFP and mtGFP(Y66H/Y145F) were transfected into different populations of cells, and the events of cellular fusion, and mitochondrial intermixing and/or fusion, were directly monitored. CONCLUSIONS: The successful expression of organelle-targeted GFP mutants in live eukaryotes expands the uses of this fluorescent protein in cell biology, allowing direct access to key biological issues, such as the study of the interactions of different organelles in vivo. These results also open the way to other exciting applications, such as the direct study of protein redistribution and protein protein interactions in living cells. PMID- 8673466 TI - Subcellular distribution of p21 and PCNA in normal and repair-deficient cells following DNA damage. AB - BACKGROUND: The p21 protein binds to both cyclin-dependent kinases (Cdks) and the proliferating cell nuclear antigen (PCNA). In mammalian cells, DNA damage results in an increase in the level of p53 protein, which stimulates expression of the gene encoding p21, which in turn leads to an inhibition of Cdk activity. Biochemical studies have shown that the direct interaction between p21 and PCNA blocks the latter's function in DNA replication but not in DNA repair. In addition to the p53-dependent damage response, the stimulation of quiescent cells with serum can also cause a p53-independent elevation in p21 gene expression. It is not clear, however, whether the induction of p21 protein under these two circumstances serves the same purpose. In this study, we have investigated the kinetics of p21 induction by DNA damage and serum stimulation and the consequent effects on cell-cycle progression. Using both normal and repair-deficient human cells, we have also analyzed the nuclear distribution of p21 in relation to that of PCNA. RESULTS: In vivo immunofluorescence staining experiments indicate that, following UV damage, DNA repair is not inhibited by the presence of a large amount of p21 protein in the nucleus; in contrast, cells undergoing DNA replication during S phase contain very low amounts of p21. The addition of serum induced a transitory elevation of p21 levels, whereas UV damage to cells resulted in a sustained, high level of p21 that was more tightly associated with the nuclear structure. Interestingly, cells deficient in global nucleotide excision repair displayed a distinct pattern of detergent-insoluble p21 that co-localized with PCNA. CONCLUSIONS: The in vivo studies presented here, which are consistent with our previous findings in vitro, indicate that p21 has a differential effect on DNA replication and DNA repair, and that the induction of p21 by serum and DNA damage may have different consequences. Furthermore, the co-localization of p21 and PCNA in the nucleus of normal and repair-deficient human cells indicates that p21 and PCNA interact during post-damage events. PMID- 8673467 TI - Human colour discrimination based on a non-parvocellular pathway. AB - BACKGROUND: Traditionally, colour information is assumed to be carried by neural channels in the parvocellular pathway and to be encoded in an opponent manner, while other, non-parvocellular, spectrally non-opponent channels are thought to play no part in colour vision. But is the parvocellular pathway the only way that colours can be discriminated in human vision? We studied two patients with cerebral achromatopsia, who lack conscious colour perception but are nevertheless able to make use of colour information. In particular, we investigated whether, in these patients, colour discrimination is mediated by the parvocellular pathway. RESULTS: The achromatopsic patients carried out a forced-choice colour- and luminance-discrimination task, and showed clear evidence of unconscious colour processing, consistent with previous studies. We added different types of luminance noise to see when this unconscious colour information could be masked. The results of the colour-discrimination-with-noise and the brightness-non additivity experiments showed a double-dissociation between patients. This indicates that, in one patient, unconscious colour discrimination may be subserved by a spectrally non-opponent mechanism, which does not have the characteristics of the parvocellular pathway and which is responsive to fast flicker. Spectral sensitivity, contrast sensitivity and motion perception experiments confirmed that this patient lacks a working opponent parvocellular system. The second achromatopsic patient showed evidence of a residual parvocellular system. CONCLUSIONS: Our results show that chromatic discrimination need not be mediated by neural mechanisms, the parvocellular system in particular, normally assumed to subserve conscious colour perception. Such discrimination may be mediated by a neural subsystem which responds to fast flicker, is spectrally non-opponent, and supports normal motion perception. PMID- 8673468 TI - A new family of regulators of G-protein-coupled receptors? AB - Organisms as diverse as fungi and humans use G-protein-coupled receptors to control signal transduction pathways responsive to various hormones, neuroregulatory molecules and other sensory stimuli. Continual stimulation of these receptors often leads to their desensitization, which is mediated in part by the consecutive actions of two families of proteins--the G-protein-coupled receptor kinases, which phosphorylate the agonist-occupied receptors, and the arrestin proteins, which subsequently bind to the receptors. We now present evidence that a group of proteins--the G0S8/Sst2p family--may be a third class of receptor-desensitizing factors. PMID- 8673469 TI - Molecular abnormality of a phosphoglycerate kinase variant (PGK-Alabama). AB - The molecular abnormality of a phosphoglycerate kinase variant associated with severe red cell enzyme deficiency ( about 4% of normal) and episodes of hemolysis with jaundice was examined. The Michaelis constants for the substrates and co enzymes (1.3-diphosphoglycerate, 3-phosphoglycerate, ATP and ADP) were not grossly different from that of normal. However that variant enzyme was very labile in vitro. Nucleotide sequence analysis of the variant cDNA revealed a deletion of codon AAG in exon 7. The codon deletion should result in the election of one of the tandem lysine residues existing at amino acid 190-191 of the enzyme protein. Based on the three dimensional structure of the protein, molecular instability could could be induced by the deletion of a lysine residue. PMID- 8673470 TI - Expression of the Fanconi anemia gene FAC in human cell lines: lack of effect of oxygen tension. AB - Fanconi anemia (FA) is a recessively inherited disease characterized by bone marrow failure, congenital anomalies, chromosomal instability and hypersensitivity to crosslinking agents. Some of the cellular defects of FA are known to be responsive to the ambient oxygen concentration. We examined the responsiveness of the FA complementation group C (FAC) gene to changes in oxygen concentration using two types of human cell lines, hypoxia-responsive Hep3B hepatoma cells and Epstein-Barr virus-immortalized lymphoblasts (normal and FA complementation groups B and C). Although the expression of erythropoietin in Hep3B cells was induced in response to the hypoxia-mimicking agent CoCl2, there was no concomitant induction in FAC expression as assessed by mRNA levels and immunoprecipitable protein, and no detectable change in the cytoplasmic location of the FAC polypeptide as determined by indirect immunofluorescence. In human lymphoblasts we examined the effect of oxygen (0.1% -95% O2) on cell proliferation and FAC expression. FA lymphoblasts had a normal sensitivity to the cytostatic effect of hyperoxia, while in both control and FA lymphoblasts FAC mRNA levels were unaffected by oxygen. Our results indicate that ambient oxygen is not a regulator of the FAC gene. PMID- 8673471 TI - Expression of granulocyte colony stimulating factor (G-CSF) and granulocyte/macrophage colony stimulating factor (GM-CSF) mRNA upon stimulation with phorbol ester. AB - Stimulated human peripheral blood mononuclear cells (MNC) have been shown to express both G-CSF and GM-CSF, Furthermore, G-CSF is expressed by monocytes but not lymphocytes, whereas GM-CSF is expressed largely by T lymphocytes and at low levels in monocytes/macrophages, Here we present the effect of TPA (120-O tetradecanoyl phorbol-13-acetate) on G-CSF and GM-CSF expression in stimulated human MNCs and T lymphocytes. We observed that TPA (30nM) decreased G-CSF mRNA levels in MNCs, while ionomycin increased G-CSF in a dose-dependent manner. TPA and ionomycin individually increased GM-CSF mRNA levels in T-lymphocytes and MNCs. Further, GM-CSF was induced synergistically by TPA plus ionomycin, whereas this combination markedly decreased G-CSF mRNA levels in MNCs. These data suggest at least two signaling pathway by which G-CSF and GM-CSF and GM-CSF mRNA levels are modulated in a mixed population of monocytes and T lymphocytes, namely protein kinase C (PKC) and calcium. These signals seems to act synergistically in lymphocytes to increase GM-CSF, and not G-CSF mRNA levels specifically. It would also appear these signals act on MNCs in an opposing manner to decrease G-CSF mRNA levels, indicating that activation of PKC and the calcium signaling pathway lead to a cell-type specific modulation of individual cytokines and precise regulation of granulocyte production. PMID- 8673472 TI - Cell-free activation of the respiratory burst oxidase by protein kinase C. AB - In intact neutrophils, phorbol ester treatment activates the respiratory burst oxidase, the enzyme responsible for O2-production by phagocytes. This effect is thought to be dependent on protein kinase C and on the phosphorylation of p47phox. In this paper, we report that protein kinase C activates the respiratory burst oxidase in a cell-free system consisting of isolated neutrophil cytosol and membrane. Oxidase activation required a highly active protein kinase C, recombinant p47phow and ATP, and was inhibited by the protein kinase C inhibitors H-7 and GF-109203X. PERIl depletion of cytosolic ATP by dialysis reduced oxidase activation by over 50% In contrast, neither protein kinase C inhibitors nor ATP depletion affected oxidase activation by SDS. These findings strongly suggest that in the cell-free system, the oxidase can be activated by the phosphorylation of p47phox. PMID- 8673474 TI - Platelet microparticles bind, activate and aggregate neutrophils in vitro. AB - The interaction of activated platelets with leukocytes are believed to play an important role in ischemic reperfusion injury and other thrombotic conditions. Upon activation, platelets shed platelet microparticles (PMP) and express activation markers CD62P expressed on activated platelets mediates adhesion of platelets to leukocytes, chiefly neutrophils, but little is known of the interaction of PMP isolated from stored platelets or thrombin activated platelets was incubated with leukocytes and binding assessed by flow cytometry. FITC labeled alpha-CD41 was used to assess platelet material associated with WBC. Like platelets PMP bound preferentially to neutrophils rather than lymphocytes, and exhibited an absolute dependence on the presence of Ca2+. Binding was time-and concentration-dependent, reaching a plateau at 10 min at a ratio of PMP to neutrophils of 150:1. Fluorescence microscopy showed that most of the neutrophils were aggregated into clusters of 5-20 cells. Clustering of neutrophils was not observed to result form interaction with platelets. In these clusters the adherent PMP appeared to serve as bridges between the neutrophil. Addition of EGTA after brief incubation (5-10 min) released most of the bound PMP but if added after > 10 min, only approximately 60% of bound PMP were released. In contrast, nearly all bound platelets were released by EGTA at the same time of incubation. Incubation of neutrophils with PMP gave significantly higher percentage of CD41a(+)neutrophils than did platelets incubated at the same numerical ratio. PMP association with neutrophils was less markedly inhibited by alpha-CD62P (AC1.2) than platelets, but binding of both PMP and activated platelets was inhibited approximately 90% by antisialyl Lewis X. PMP binding to neutrophils induced a significant increase in both CD11b expression and phagocytic activity in a concentration-dependent manner. These findings suggest a possible role for PMP in addition to providing platelet factor 3, specifically, as an activator and mediator of neutrophils in ischemic injury, thrombosis, and inflammation. PMID- 8673473 TI - A strategy for cloning the hereditary hemochromatosis gene. AB - Selective hybridization of small intestine and liver cDNA libraries was carried out using yeast artificial chromosomes (YACs) surrounding D6S105, the microsatellite that appears to be close to the gene for hereditary hemochromatosis (HFE). Of 14 candidate probes hybridizing with these YACs, only one, designated. LD5-1, detected abnormalities in southern blots of patients with hemochromatosis. Two different abnormalities. were detected in 3 of 55 patients with hemochromatosis with the LD5-1 probe, and one of these was detected in one of 44 normal subjects. The gene that hybridizes with this probe is located about 300-400 kb centromeric of D6S105. It is transcribed into mRNA that is about 8.5 kb in length in many tissues, including peripheral blood leukocytes. The available sequence indicates tha it codes for a zinc finger protein. We propose that there is a reasonable probability that LD5-1 hybridizes with the gene for hereditary hemochromatosis. PMID- 8673475 TI - A novel human catalase mutation (358 T-->del) causing Japanese-type acatalasemia. AB - Japanese-type acatalasemia is characterized by the almost total loss of catalase activity in red cells and is often associated with ulcerating oral lesions. A splicing mutation in intron 4 of catalase gene has so far been a sole disease causing mutation found in Japanese-type acatalasemic patients. We report here a novel single base deletion in the catalase gene causing Japanese-type acatalasemia. The patient was a 72 year-old Japanese male. His maternal grandmother and his father were first cousins. Molecular analysis using non-RI PCR-SSCP analysis combined with direct sequencing revealed a deletion of the 358th thymine in exon 4 of the patient's catalase gene. The proband was a homozygote and his mother and his three children were heterozygotes for this mutation. The frame shift caused by the nucleotide deletion should alter the downstream amino acid sequence and introduce a new termination codon TGA 43 bp 3' to the mutation. Although the truncated peptide chain consisted of 133 amino acid residues might be translated in the patient's tissue, such an aberrant protein is expected to be extremely unstable and have no catalytic function at all. Our results suggest that Japanese-type acatalasemia is heterogeneous. PMID- 8673476 TI - Relation between hematological recovery and number of transplanted mononuclear cells in patients after high dose chemotherapy with peripheral blood stem cell rescue. AB - The aim of the study is to investigate the relation between the hematological recovery in patients after high dose chemotherapy and peripheral blood stem cell (PBSC) rescue and the number of reinfused previously collected stem cells assessed by the number of mononuclear cells (MNCs), CFU-GMs and CD34(+) cells in th harvest. Forty nine patients mobilized with different techniques were transplanted. Our data indicate that the number of reinfused MNCs and CFU-GMS has a statistical significant relationship with the duration of leukopenia and thrombocytopenia following high dose chemotherapy and PBSC rescue in patients with various malignancies. PMID- 8673477 TI - Safety and effectiveness of long-term interferon gamma therapy in patients with chronic granulomatous disease. AB - In chronic granulomatous disease (CGD), diminished or absent neutrophil NADPH oxidase function leads to recurrent pyogenic infections and granuloma formation. In a recent randomized, placebo-controlled trail, short-term prophylactic use of recombinant human interferon gamma (rIFN-gamma 1b) reduced the risk of serious infection in CGD patients by 67%, The current study evaluated the safety and effectiveness of long-term rIFN-gamma therapy in CGD patients. Patients were treated three times weekly with rIFN-gamma and evaluated semiannually. Serious infections (requiring hospitalization and parenteral antibiotic therapy), adverse clinical events, and measures of growth and development were noted. Thirty patients were evaluated for 12 months. The total average duration of rIFN-gamma therapy was 2.5 years. Three patients developed a total of four serious infections (0.13 infections per patient year). This rate compare favorably with rates of 1.10 and 0.38 infections per patient year found in the placebo and rIFN gamma groups, respectively, during a previous study. Common adverse events were fever (23%), diarrhea (13%), and flu-like illness (13%). No serious adverse event was attributable to rIFN-gamma therapy and no obvious effects on growth and development were observed. rIFN-gamma is a safe and effective adjunctive therapy for reducing the frequency and severity of serious infections in CGD patients. PMID- 8673479 TI - Somatotopic motor representation in the human anterior cerebellum. A high resolution functional MRI study. AB - Though somatotopic encoding of function is a prominent feature in brain structures involved in sensori-motor processing, it has not been well established for the human cerebellum. We delineated the representation of hand, foot and tongue movements in the anterior cerebellar lobe of eight healthy subjects using dynamic high-resolution MRI sensitized to changes in cerebral blood oxygenation (CBO). Activation was determined by pixel-by-pixel correlation of signal intensity time courses with the performance protocol. All subjects showed task related signal increases in an ipsilateral region during distal limb movements. For the hand task, the centre of activation was located in the intermediate hemispheric portion of Larsell lobules H IV-V. Foot movements activated areas within the central lobule, Larsell lobules II-III, medial and anterior to the corresponding hand areas in all subjects. Responses for tongue movements were less consistent across subjects but found in areas posterior to the respective individual hand representation. PMID- 8673478 TI - Late-onset hereditary ataxia with global thermoanalgesia and absence of fungiform papillae on the tongue in a Japanese family. AB - Two Japanese male siblings, aged 68 and 59 years, affected by late-onset progressive ataxia distinguished by extensive sensory and mild autonomic disturbances are described. They had global thermoanalgesia, positive Romberg signs, sensorineural deafness, canal paresis and ageusia. Their autonomic disturbances consisted of absence of overflow tears with usual stimuli, dysphagia, blood pressure and vasomotor instability, diarrhoea/constipation, and urinary frequency. Sensory nerve action potentials were completely absent, whereas motor conduction velocity was slightly reduced only in the lower extremities. Sural nerve biopsy on the younger brother demonstrated a marked loss of myelinated fibres and a reduction in the number of unmyelinated axons. Tongue histology revealed absence of fungiform papillae and taste buds. Autonomic function tests showed widespread but mild sympathetic and parasympathetic failures. Neuro-imaging studies revealed atrophy of the spinal cord, cerebellum, brainstem and corpus callosum, and enlargement of the lateral, third and fourth ventricles. These siblings represent a previously unrecognized variant of late onset hereditary spinocerebellar degeneration with global thermoanalgesia and absence of fungiform papillae on the tongue. PMID- 8673480 TI - The course of cortico-hypoglossal projections in the human brainstem. Functional testing using transcranial magnetic stimulation. AB - Cortico-hypoglossal projections were investigated in 11 patients with unifocal ischaemic lesions of different brainstem levels using transcranial magnetic stimulation. Lesion topography was documented by MRI studies. In seven patients the projections to the ipsi- and contralateral hypoglossal nuclei were separately affected. Pontine lesions at the ventral paramedian base close to the midline affect the contralateral projections while lateral lesions at the pontine base affect the ipsilateral projections. Lesions of the paramedian dorsal pontine base do not involve the cortico-hypoglossal projections. Our findings indicate that the cortico-hypoglossal fibres branch off the main ventral pyramidal tract. Lesions of the dorso- and mediolateral medulla impair only the ipsilateral projections. We conclude that ipsilateral projections enter the hypoglossal nucleus from its lateral aspect and that the contralateral projections cross the midline at the pontomedullary junction. PMID- 8673481 TI - Brain metabolism is abnormal in the mdx model of Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder primarily affecting young boys, often causing mental retardation in addition to the well known progressive muscular weakness. Normal dystrophin expression is lacking in skeletal muscle and the CNS of both DMD children and the mdx mouse model. To date, 31P-magnetic resonance spectroscopy (MRS) has shown in vivo several abnormalities within skeletal muscle of mdx mice and DMD boys. In this study, we determined whether similar abnormalities occur in mdx brain in vivo by using 31P MRS in addition to metabolite and enzyme analysis to study cerebral metabolism. An increased inorganic phosphate (P(i))/phosphocreatine (PCr) and pH was found in vivo for mdx brain compared with controls, and biochemical analysis showed a reduction in total creatine, an increased extracellular and decreased intracellular volume in mdx brain. No differences were found in any glycolytic or mitochondrial maximal enzyme activities. These changes are discussed with respect to the biochemical changes found in muscle from DMD patients and mdx mice. It is proposed that these biochemical changes may be a factor in the reduced cognitive capacity of mdx mice and some DMD children. PMID- 8673482 TI - Self-initiated versus externally triggered movements. I. An investigation using measurement of regional cerebral blood flow with PET and movement-related potentials in normal and Parkinson's disease subjects. PMID- 8673483 TI - Spinal cord atrophy and disability in multiple sclerosis. A new reproducible and sensitive MRI method with potential to monitor disease progression. AB - Recent MRI studies in multiple sclerosis have highlighted the potential importance of spinal cord atrophy (implicating axonal loss) in the development of disability. However, the techniques applied in these initial studies have poor reproducibility which limits their application in the serial monitoring of patients. The aim of this study was to develop a highly reproducible and accurate method for the quantification of atrophy. The technique we describe demonstrates an intra-observer coefficient of variation (scan-rescan) of only 0.8%. When applied to 60 patients with clinically definite multiple sclerosis there was a strong correlation between spinal cord area and disability measured by Kurtzke's Expanded Disability Status Scale (EDSS) (r = -0.7, P < 0.001). The correlation was graded providing evidence for a causal connection. At levels 3 and 8 of the EDSS we observed a reduction in average cord area of 12 and 35%, respectively. Given its reproducibility, the magnitude of the change detected and the strong correlation with disability, this new technique should prove to be a sensitive measure of progressive neurological deterioration and could be readily incorporated into imaging protocols aimed at monitoring therapy. PMID- 8673484 TI - Spinal MRI in patients with suspected multiple sclerosis and negative brain MRI. AB - Although MRI detects the white matter lesions of multiple sclerosis within the brain with high sensitivity, a minority of patients have normal brain MRI. We describe 20 patients, selected from over 170 who had undergone brain imaging with minimal (n = 12) or no (n = 8) abnormalities (median number of lesions = I, range, 0-3) but in whom spinal MRI was abnormal. Twelve had clinically definite or laboratory supported definite multiple sclerosis according to the Poser criteria; one had clinically probable disease and seven, not fulfilling the Poser criteria, were classified as possible multiple sclerosis. All had presented with symptoms and signs referable to the spinal cord or optic nerves. Eleven had a primary progressive course, eight relapsing-remitting and only one secondary progressive. Moderate or severe disability was the rule in the primary progressive cases; all the relapsing-remitting patients had minimal disability. All had at least one lesion visible in the spinal cord (median 2; range 1-6). In patients in whom the diagnosis of multiple sclerosis is not supported by abnormalities on brain MRI, imaging of the spinal cord can be of considerable value. PMID- 8673485 TI - Assessment of lesion pathology in multiple sclerosis using quantitative MRI morphometry and magnetic resonance spectroscopy. AB - Quantitative measurement of MRI-defined brain lesions can provide an index of the extent and activity of disease in multiple sclerosis patients. However, the relationships between these indices and clinical features are not well understood. Heterogeneity of the pathological changes underlying MRI lesions may be an important factor determining the correlation between MRI lesion volumes and clinical measures. Recent studies have suggested that with magnetic resonance spectroscopy (MRS), it may be possible to define chemical changes that better reflect the pathological changes in multiple sclerosis. Here we report results of combined quantitative brain T2-weighted MRI lesion volume and proton MRS examinations that demonstrate heterogeneity of the chemical pathology underlying brain lesions in patients selected on the basis of similar clinical disability but differing with respect to the presence or absence of clinical relapses. We examined 29 patients with disease characterized by either clear relapses with at least partial remissions (RR) or secondary, chronic progression after an earlier history of a more relapsing and remitting course (SP). Total hemispheric lesion volume was greater (P < 0.04) in the RR (32.5 +/- 20.9 cm3) than in the SP (16.2 +/- 9.0 cm3) patients, despite the longer duration of disease in the latter group. Central brain N-acetyl aspartate: creatine (NAA:Cr) ratios were reduced relative to normal controls (4.0 +/- 0.3, n = 19) by similar amounts in the two patients groups (RR, 3.1 +/- 0.5; SP, 3.2 +/- 0.4; P < 0.0001). The ratio lesion volume:(NAA:Cr) was greater for the RR group (11.7 +/- 9.3 cm3) than for the SP group (5.4 +/- 3.3 cm3, P < 0.05), implying a greater average degree of axonal loss per unit lesion volume defined by MRI for subjects in the SP group or, alternatively, a greater proportion of lesions without axonal damage or loss in the RR group. Our results emphasize a limitation of using T2-weighted MRI lesion volume alone and suggest that combined analysis of MR-based chemical and imaging data might allow improved non-invasive assessment of lesion pathology in order to better understand its relationship to clinical features of multiple sclerosis. PMID- 8673486 TI - Retinal and cortical evoked responses to chromatic contrast stimuli. Specific losses in both eyes of patients with multiple sclerosis and unilateral optic neuritis. AB - It is known that colour vision may be altered in optic neuritis. Our aim was to establish whether chromatic and achromatic vision are differentially impaired using stimuli designed to favour the activity of either the magnocellular or the parvocellular stream of the visual pathway. Fourteen patients with a past history of unilateral optic neuritis in the course of multiple sclerosis and 10 age matched control subjects were included in the study. Patients had relatively good visual acuity in the affected eyes and no gross colour deficits (Ishihara). Stimuli were alternating gratings of low spatial frequency and of different chromaticity along the red-green axis. The psychophysical contrast sensitivity (CS) was measured at 5 Hz as a function of colour ratio [red/(red + green)] to evaluate both the equiluminant point (the colour ratio corresponding to the lowest CS) and the CS for isochromatic, luminance gratings (red-black and green black). Steady-state (2-24 Hz) and transient pattern electroretinograms (PERGs) and visually evoked potentials (VEPs) were recorded in response to high contrast (90%) stimuli of low spatial frequency (0.3 cycles deg-1) modulated in either pure chromatic contrast (equiluminant red-green) or pure luminance contrast (yellow-black). On average, CSs were reduced (10 dB) in optic neuritis eyes compared with controls for both luminance and chromatic gratings. In the VEPs (both transient and steady-state) amplitude losses and latency delays were far larger for the chromatic VEPs than for the luminance VEPs. Chromatic VEP latency delays were remarkable also in the fellow, clinically normal, eyes. Significant losses were apparent in both the luminance and chromatic PERG. However, the chromatic PERG was comparatively more altered. In agreement with previous reports, selective losses were not apparent at threshold. By contrast, suprathreshold electrophysiological responses displayed a clear dissociation between luminance and colour, suggesting that the parvocellular stream, compared with the magnocellular stream is more impaired in optic neuritis. PMID- 8673487 TI - Auditory neuropathy. AB - Ten patients presented as children or young adults with hearing impairments that, by behavioural and physiological testing, were compatible with a disorder of the auditory portion of the VIII cranial nerve. Evidence of normal cochlear outer hair cell function was provided by preservation of otoacoustic emissions and cochlear microphonics in all of the patients. Auditory brainstem potentials showed evidence of abnormal auditory pathway function beginning with the VIII nerve: the potentials were absent in nine patients and severely distorted in one patient. Auditory brainstem reflexes (middle ear muscles; crossed suppression of otoacoustic emissions) were absent in all of the tested patients. Behavioural audiometric testing showed a mild to moderate elevation of pure tone threshold in nine patients. The extent of the hearing loss, if due to cochlear receptor damage, should not have resulted in the loss of auditory brainstem potentials. The shape of the pure tone loss varied, being predominantly low frequency in five patients, flat across all frequencies in three patients and predominantly high frequency in two patients. Speech intelligibility was tested in eight patients, and in six was affected out of proportion to what would have been expected if the pure tone loss were of cochlear origin. The patients were otherwise neurologically normal when the hearing impairment was first manifest. Subsequently, eight of these patients developed evidence for a peripheral neuropathy. The neuropathy was hereditary in three and sporadic in five. We suggest that this type of hearing impairment is due to a disorder of auditory nerve function and may have, as one of its causes, a neuropathy of the auditory nerve, occurring either in isolation or as part of a generalized neuropathic process. PMID- 8673488 TI - Vestibular neuritis spares the inferior division of the vestibular nerve. AB - Acute unilateral vestibulopathy, or vestibular neuritis, is the second most common cause of vertigo. To quantify the involvement of the different semicircular canal (SCC) afferents in this disease, we studied the three dimensional (3D) properties of the vestibuloocular reflex (VOR) in 16 patients 3 10 days after onset of symptoms. Using 3D magnetic search coil eye movement recordings, we measured the speed and axis of eye rotation during spontaneous nystagmus and during rotation in the planes of the different SCCs. In all patients, spontaneous nystagmus axes clustered between the direction expected with involvement of just one horizontal SCC and the direction expected with combined involvement of the horizontal and anterior SCC on one side. Likewise, dynamic asymmetries were found only during rotations about axes which stimulated the ipsilesional horizontal or ipsilesional anterior SCCs. No asymmetry was found when the ipsilesional posterior SCC was stimulated. Thus, both measurements suggest that vestibular neuritis is a partial and not a complete unilateral vestibular lesion and that this partial lesion affects the superior division of the vestibular nerve which includes the afferents from the horizontal and anterior SCCs. PMID- 8673489 TI - Focal upper limb demyelinating neuropathy. AB - Observations are presented on nine selected patients with chronic upper limb demyelinating neuropathy to illustrate the range of manifestations that may be observed. In three, the involvement was purely motor, in five, mixed motor and sensory and, in one, virtually purely sensory; in seven the symptoms were unilateral and in two bilateral. The presence of reduced nerve conduction velocity and conduction block and the response to treatment in seven of the cases indicate that they represented examples of chronic inflammatory demyelinating polyneuropathy (CIDP) with focal involvement. This was confirmed by nerve biopsy in two cases. The presentation in one patient was accompanied by forearm swelling initially suspected of being a tumour but shown to be due to muscle hypertrophy. This was probably the consequence of recurrent muscle cramps and fasciculation and possibly neuromyotonia. The patient with predominant sensory involvement restricted to the upper limbs demonstrates that sensory CIDP can present focally. In one patient with monomelic motor and sensory involvement, nerve biopsy showed multifocal areas of hypertrophic demyelinating neuropathy distally in the ulnar nerve without inflammatory infiltration. This patient failed to respond to therapy. Response in the others was satisfactory, although one patient with a monomelic motor neuropathy showed a severe deterioration after being given corticosteroids; he subsequently improved with intravenous human immunoglobulin therapy. PMID- 8673490 TI - Selective loss of myelin-associated glycoprotein from myelin correlates with anti MAG antibody titre in demyelinating paraproteinaemic polyneuropathy. AB - The IgM monoclonal autoantibodies of patients with demyelinating paraproteinaemic polyneuropathy recognize a carbohydrate structure present on both myelin associated glycoprotein (MAG) and protein zero (P0). These autoantibodies are sufficient to cause the disease but the mechanism of demyelination remains unclear. We have analysed nerve biopsies from eight patients with polyneuropathy and anti-MAG antibodies by quantitative immunohistochemistry and find a concordant pattern of reduced expression of myelin markers with the loss of myelinated fibres. We report here novel features of this disease, in particular a selective lack of detectable MAG in a large proportion of myelinated-fibres containing P0, myelin basic protein (MBP) and periaxin. There is also an inverse correlation of the distribution of MAG in peripheral nerve myelin with the serum anti-MAG antibody titres but no correlation of these titres with the loss of myelinated fibres. Double immunofluorescence staining of paraproteinaemic polyneuropathy (PPN) nerves shows anti-MAG IgM deposited on the periphery of myelinated fibres associated with or lacking MAG staining. These data suggest that the binding of anti-MAG antibodies to MAG and/or other myelin component(s) results in MAG downregulation and may have an essential role in the molecular mechanisms leading to demyelination and partial regeneration in this disease. PMID- 8673491 TI - Tremor associated with benign IgM paraproteinaemic neuropathy. AB - The clinical and neurophysiological features of six patients with action tremor of the upper limbs associated with IgM paraproteinaemic neuropathy are described. Symptomatic tremor was confined to the upper limbs and was broadly symmetrical. The frequency of associated rhythmic muscle activity ranged from 2.8 to 5.5 Hz in abductor pollicis brevis and from 3.7 to 5.5 Hz in the forearm flexor muscles. Magnetic brain stimulation, somatosensory evoked potentials (SEPs) and stretch reflex studies did not provide evidence for delayed conduction within central pathways. There was marked slowing of the maximum motor conduction velocities in peripheral nerves. Forearm stretch reflexes were present but their latencies were prolonged. Somatosensory evoked potentials were obtained in the majority of patients, but were delayed. Wrist tremor could be modulated by mechanical perturbations or median nerve electrical shocks. Simple voluntary wrist movements were of normal duration and peak velocity, but the kinematic profile was asymmetric. Each movement was associated with a triphasic EMG pattern in agonist antagonist-agonist muscles but the durations of the bursts were prolonged and the onset of the second agonist was delayed. These results support the hypothesis that distorted, mistimed peripheral inputs reach a central processor (probably the cerebellum) which although intact is misled into producing tremor in certain parts of the body. PMID- 8673492 TI - Effects of levodopa and viscosity on the velocity and accuracy of visually guided tracking in Parkinson's disease. AB - Deficits in velocity generation and movement accuracy occur in Parkinson's disease and are postulated to contribute to the characteristic bradykinesia. In the present study, we attempted to clarify the relationship between the deficits in velocity generation and movement accuracy. Patients with Parkinson's disease and normal controls tracked visually displayed sinusoidal and step targets with the wrist. Performance was evaluated using measurements of velocity and error. Movement velocity was manipulated by two methods: (i) administration of levodopa; (ii) viscous loading. Dependencies of velocity and error on disease state, medication state and viscosity were examined. Visually guided pursuit tracking was characterized by intermittent and frequent velocity excursions in both the patients and controls. For sinusoidal tracking, levodopa significantly increased velocity in the severely affected parkinsonian patients. Prior to the administration of levodopa, step tracking velocity was significantly lower in all patients than in controls. The "on' state produced an increase in velocity to control levels. Error was significantly greater in the parkinsonian subjects than in controls, but was unchanged by levodopa for both tracking tasks. Manipulations of viscosity produced greater changes in velocity than did levodopa, yet a similar independence with respect to accuracy remained. Velocity significantly changed by 40-60% in the two tracking tasks from the viscous to antiviscous loads. Error did not change significantly in 12 out of 14 comparisons of subgroups based on disease and medication state. This contradicts the hypothesis that patients with Parkinson's disease primarily reduce velocity during tracking to maintain acceptable accuracy in the presence of a defective error correction system. Although parkinsonian subjects tracked with reduced accuracy, both normal and parkinsonian subjects were able to compensate for significant changes in velocity due to external loading. Thus a propulsion deficit exists in parkinsonism that may be alleviated with either antiviscosity or levodopa. An error correction deficit is also present in parkinsonism, but is not modified by antiviscosity or levodopa. PMID- 8673493 TI - Effects of magnetic stimulation over supplementary motor area on movement in Parkinson's disease. AB - Movement execution can be delayed by transcranial magnetic stimulation delivered over primary motor cortical areas, resulting in transient inhibition of cortico motor output. Inhibition or disruption of higher-order motor planning and preparatory processes, such as are thought to occur in the supplementary motor area (SMA), would allow an examination of processes at other stages of the motor control system. In this study, six subjects with Parkinson's disease and six healthy control subjects performed a non-cued sequential finger movement task. At various times relative to movement, high-intensity single-pulse magnetic stimulation was delivered over the region of the SMA, with minimal current spread to primary motor areas. When magnetic stimulation was given at early stages during the movement for parkinsonian subjects, movement times were significantly increased, indicating disrupted movements. Supplementary motor area stimulation had no effect when delivered during later stages of the movement or immediately prior to movement onset, and had no apparent effect on control subjects at any time. It is therefore suggested that the SMA is important in motor planning and preparatory processes, since SMA stimulation has no effect on movements in their later stages when planning may be complete, but may disrupt movements in their early stages, when preparation for later stages may still be in progress. Further, possible instability of motor planning/preparation processes in Parkinson's disease is suggested, since these processes appeared more susceptible to disruption by magnetic stimulation in parkinsonian subjects than controls. PMID- 8673494 TI - Alterations in peptide levels in Parkinson's disease and incidental Lewy body disease. AB - The levels of the neuropeptides Met- and Leu-enkephalin (MET-ENK, LEU-ENK), substance P and neurotensin were measured by a combined high performance liquid chromatography/radioimmunoassay (HPLC/RIA) method in postmortem samples of basal ganglia from Parkinson's disease patients, incidental Lewy body disease patients (pre-symptomatic Parkinson's disease) and matched controls. Dopamine (DA) levels were reduced in the caudate nucleus and putamen in Parkinson's disease, but unaltered in incidental Lewy body disease. The levels of MET-ENK were reduced in the caudate nucleus, putamen and substantia nigra in Parkinson's disease. Met enkephalin levels were reduced in the caudate nucleus and in the putamen in incidental Lewy body disease. Leu-enkephalin levels were decreased in the putamen and were undetectable in the substantia nigra in Parkinson's disease. Leu enkephalin levels were unchanged in incidental Lewy body disease, although there was a tendency to a reduction in putamen. Substance P levels were reduced in the putamen in Parkinson's disease. No significant changes in substance P content were observed in incidental Lewy body disease. Neurotensin levels were increased in the substantia nigra in Parkinson's disease. Neurotensin levels in incidental Lewy body disease were not altered significantly, but tended to parallel the changes in Parkinson's disease. The changes in basal ganglia peptide levels in incidental Lewy body disease generally followed a trend similar to those seen in Parkinson's disease, but were less marked. This suggests that they are an integral part of the pathology of the illness and not secondary to DA neuronal loss or a consequence of prolonged drug therapy. PMID- 8673495 TI - What can artificial neural networks teach us about neurodegenerative disorders with extrapyramidal features? AB - Artificial neural networks (ANNs), computer paradigms that can learn, excel in pattern recognition tasks such as disease diagnosis. Artificial neural networks operate in two different learning modes: supervised, in which a known diagnostic outcome is presented to the ANN, and unsupervised, in which the diagnostic outcome is not presented. A supervised learning ANN could emulate human expert diagnostic performance and identify relevant predictive markers in the diagnostic task, while an unsupervised learning ANN could suggest reasonable alternative diagnostic classification criteria. In the present study, we used ANN methodology to try to overcome the neuropathological difficulties in differentiating the subtypes of progressive supranuclear palsy (PSP), and in differentiating PSP from postencephalitic parkinsonism (PEP) and corticobasal degeneration, or Pick's disease from corticobasal degeneration. First, we applied supervised learning ANN to classify 62 cases of these disorders and to identify diagnostic markers that distinguish them. In a second experiment, we used unsupervised learning ANN to investigate possible alternative nosological classifications. Artificial neural networks input data for each case consisted of values representing histological features, including neurofibrillary tangles, neuronal loss and gliosis found in multiple brain sampling areas. The supervised learning ANN achieved excellent accuracy in classifying PSP but had difficulty classifying the other disorders. This method identified a few features that might help to differentiate PEP, supported currently proposed criteria for Pick's disease, corticobasal degeneration and typical PSP, but detected no features to characterize the atypical subtype of PSP. In general, unsupervised learning ANN supported the present nosological classification for PSP, PEP, Pick's disease and corticobasal degeneration, although it overlapped some groups. Artificial neural networks methodology appears promising for studying neurodegenerative disorders. PMID- 8673496 TI - A mathematical model of line bisection behaviour in neglect. AB - Subjects with left hemispatial neglect frequently demonstrate an array of abnormal behaviours on line bisection tasks. They misbisect long horizontal lines to the right of true midline. They bisect short lines to the left of true midline. They exaggerate the left-sided length of lines when placing the endpoints for 'invisible' lines, and they underestimate the length of the left side of long lines that are shown to them bisected accurately. No current theory of neglect explains all these features of line bisection behaviour. A mathematical model of line bisection behaviour in neglect is presented that proposes that subjects bisect lines at the point where they perceive the 'salience' of the two line segments created by their bisection mark to be equal. Salience is determined by the brain's attentional systems which map salience amplitude to spatial position following a bell shaped distribution. Right hemisphere strokes simulated by decreasing the 'height' and "breadth' of the right hemisphere salience to position function produced all of the above features of clinical neglect subjects' line bisection behaviour. Neglect may be conceived of as damage to brain systems performing mappings between stimulus characteristics (such as spatial location) and salience. PMID- 8673497 TI - Beyond unilateral neglect. AB - When required to set the endpoints of an imaginary horizontal line of a given length on the basis of its midpoint printed on a sheet of paper, left neglect patients most frequently misplaced endpoints leftwards. Though giving rise to the very same disproportion usually found with these patients on canonical line bisection tasks, this behaviour cannot be accommodated by current explanations of unilateral neglect. When the task was executed during leftward optokinetic stimulation (OKS), a manoeuvre known temporarily to improve neglect symptoms, the disproportion increased instead of vanishing. We therefore suggest that unilateral neglect is a manifestation of a disorder primarily implying a horizontal anisometry of space representation and that manipulations such as OKS may remove neglect without normalizing the representational medium itself. PMID- 8673498 TI - Diagonistic dyspraxia. Clinical characteristics, responsible lesion and possible underlying mechanism. AB - We present three patients who showed, in addition to signs of callosal interruption, a variety of abnormal motor behaviour of the left hand dissociated from conscious volition, in the absence of pathological grasping phenomena. The abnormal movements of the left hand consisted of (i) antagonistic movements to the right; (ii) non-antagonistic, irrelevant movements to the right; (iii) symmetric movements to the right in which the left hand sometimes preceded the right, and (iv) occasional inability to move at will during a bimanual task. From these observations and a review of previous publications, we propose that, in most right-handed subjects; diagonistic dyspraxia could be defined as abnormal motor behaviour of the left hand activated by voluntary movements of the right hand. Motor phenomena similar to diagonistic dyspraxia but attributable to impulsive groping movements induced by medial frontal lobe pathology should be excluded from diagonistic dyspraxia. Comparison of MRIs of the three patients with those of five patients who developed no diagonistic dyspraxia following an infarction of the corpus callosum, with or without medial hemispheric involvement, revealed that damage to the ventral part of the posterior end of the body of the corpus callosum was crucial for the development of diagonistic dyspraxia. Since the commissural fibres between the superior parietal lobules pass through the caudal part of the body of the corpus callosum, and also since there is accumulating evidence that the human superior parietal lobule is concerned with selection of movement based on the integration of visual and/or somatosensory information, we infer that diagonistic dyspraxia is produced by a disconnection of the right superior parietal lobule from the left which is dominant for volitional control of movement in most right-handed subjects. PMID- 8673499 TI - Tactile agnosia. Underlying impairment and implications for normal tactile object recognition. AB - In a series of experimental investigations of a subject with a unilateral impairment of tactile object recognition without impaired tactile sensation, several issues were addressed. First, is tactile agnosia secondary to a general impairment of spatial cognition? On tests of spatial ability, including those directed at the same spatial integration process assumed to be taxed by tactile object recognition, the subject performed well, implying a more specific impairment of high level, modality specific tactile perception. Secondly, within the realm of high level tactile perception, is there a distinction between the ability to derive shape ('what') and spatial ('where') information? Our testing showed an impairment confined to shape perception. Thirdly, what aspects of shape perception are impaired in tactile agnosia? Our results indicate that despite accurate encoding of metric length and normal manual exploration strategies, the ability tactually to perceive objects with the impaired hand, deteriorated as the complexity of shape increased. In addition, asymmetrical performance was not found for other body surfaces (e.g. her feet). Our results suggest that tactile shape perception can be disrupted independent of general spatial ability, tactile spatial ability, manual shape exploration, or even the precise perception of metric length in the tactile modality. PMID- 8673500 TI - An event-related potential study of recognition memory with and without retrieval of source. AB - Event-related potentials (ERPs) were recorded during the test phase of a recognition memory task in two experiments. In both experiments subjects made initial old/new judgements to visually presented words, and for words judged old, indicated in which of two voices (male/female) the words had been heard at study. In the second experiment only subjects had the option to signal that they were uncertain about the status of a test word. Two positive-going ERP effects differentiated the ERPs evoked by correctly recognized old words from those evoked by words correctly judged new. The two effects differed in their scalp topography and time course, and were both of greater magnitude in the ERPs evoked by recognized words for which a correct voice judgement was made. The findings are consistent with the view that multiple neural systems underlie the ability to recognize an item and to recall its study context. However, the findings offer little support for the view, articulated in certain 'dual-process' models of recognition memory, that recognition judgements with and without retrieval of study context depend upon qualitatively different memory processes or systems. PMID- 8673501 TI - Functional neuroanatomy of verbal self-monitoring. AB - The neural correlates of verbal self-monitoring were examined by measuring the response to alterations in auditory verbal feedback while subjects read aloud. Six normal subjects were studied with PET, using H2(15)O as a tracer of regional CBF. There was no difference between the temporal cortical response to reading aloud (and hearing one's own speech) and reading silently while hearing the words spoken by someone else. Distortion of subjects' speech (by pitch elevation) while they read aloud led to a bilateral activation of lateral temporal cortex, with a greater response on the right side than the left. A similar pattern of activation was evident when subjects read aloud, but the words they heard were spoken by someone else. These data suggest that (i) self-and externally generated speech are processed in similar regions of temporal cortex, and (ii) the monitoring of self-generated speech involves the temporal cortex bilaterally, in areas associated with the processing of speech which has been generated externally. PMID- 8673502 TI - Hearing and saying. The functional neuro-anatomy of auditory word processing. AB - The neural systems involved in hearing and repeating single words were investigated in a series of experiments using PET. Neuropsychological and psycholinguistic studies implicate the involvement of posterior and anterior left perisylvian regions (Wernicke's and Broca's areas). Although previous functional neuroimaging studies have consistently shown activation of Wernicke's area, there has been only variable implication of Broca's area. This study demonstrates that Broca's area is involved in both auditory word perception and repetition but activation is dependent on task (greater during repetition than hearing) and stimulus presentation (greater when hearing words at a slow rate). The peak of frontal activation in response to hearing words is anterior to that associated with repeating words; the former is probably located in Brodmann's area 45, the latter in Brodmann's area 44 and the adjacent precentral sulcus. As Broca's area activation is more subtle and complex than that in Wernicke's area during these tasks, the likelihood of observing it is influenced by both the study design and the image analysis technique employed. As a secondary outcome from the study, the response of bilateral auditory association cortex to 'own voice' during repetition was shown to be the same as when listening to "other voice' from a prerecorded tape. PMID- 8673503 TI - Location of lesions in stroke patients with deficits in syntactic processing in sentence comprehension. AB - Sixty patients, 46 with left-hemisphere strokes and 14 with right-hemisphere strokes, and 21 normal control subjects were tested for the ability to use syntactic structures to determine the meaning of sentences. Patients enacted thematic roles (the agent, recipient and goal of an action) in 12 examples of each of 25 sentence types, which were designed to test a wide variety of syntactic operations. Both right-and left-hemisphere damaged patients performed worse than control subjects on syntactically complex sentences, and left hemisphere patients performed worse than right-hemisphere patients. Eighteen patients with left-hemisphere strokes underwent CT scanning to image the perisylvian association cortex. There was no difference between the performance of patients with anterior and posterior lesions, and no correlation between the degree of impairment and the size of lesions in different regions of the perisylvian cortex. These results are consistent with the view that syntactic processing involves an extensive neural system, whose most important region is the left perisylvian cortex. When these results are combined with those of other studies, the picture that emerges is one in which, within this cortical region, this system manifests features of both distributed and localized processing. PMID- 8673504 TI - Bilateral effects of unilateral visual cortex lesions in human. AB - We studied the vision of 12 patients with unilateral lesions of the visual cortex. All had a VI-type scotoma located in the contralateral visual fields, as expected, and visual acuity of 20/30 or better. Our aim was to test the hypothesis that they also had a visual deficit in their ipsilesional or 'good' visual fields. The first experiment tested the subjects' ability to respond to transient signals presented at unpredictable temporal intervals and spatial locations amongst many spatially random and identical distracter elements. The results showed that, compared with controls, the lesion group had a significantly reduced sensitivity to signal and increased response times affecting both hemifields. In a second experiment, we tested the useful field of view (UFOV) in two of the patients under conditions of differing attention demand. Both showed bilateral constriction, compatible with the results of the first experiment. One possible explanation for the bilateral effects of unilateral occipital lobe lesions is damage to interhemispheric connections along their presplenial course, affecting the synthesis of visual information from both hemifields (i.e. the interhemispheric diaschisis effects put forth by von Monakow). The trouble is task dependent and can be construed as a global reduction in visual attention capacity. It is subtle in comparison with the contralesional V1-type scotoma that Holmes measured, yet may account for unexplained complaints of reduced performance in some patients, particularly in tasks with high visual information processing demands, such as reading and automobile driving. PMID- 8673505 TI - Childhood generalized and mesial temporal epilepsies demonstrate different amounts and patterns of hippocampal neuron loss and mossy fibre synaptic reorganization. AB - In this study, we determined whether childhood seizures were associated with hippocampal neuron loss and mossy fibre synaptic reorganization and if hippocampal sclerosis evolved from longer seizure histories. Children undergoing surgical treatment for catastrophic epilepsy were grouped into the following pathology categories: (i) those with generalized seizures and extra-hippocampal congenital pathologies (i.e. prenatal cortical dysplasia; n = 17); (ii) cases of generalized seizures and extra-hippocampal acquired lesions. (i.e. postnatal ischaemic injuries and encephalitis; n = 7); (iii) children with complex partial hippocampal epilepsy (n = 4). Further, to determine whether the epileptogenic location influenced hippocampal pathology, the seizure focus was classified as (i) hippocampal, (ii) temporal (n = 13) or (iii) extra-temporal (n = 11). Surgical and autopsy (n = 23) hippocampi were studied for (i) fascia-dentata (FD) and Ammon's horn (AH) neuron densities; (ii) thickness; height or length of the FD molecular layer, stratum granulosum (SG) and stratum pyramidale; and (iii) grey value (GV) densities of supragranular neo-Timm's staining. Statistically significant results (P < 0.05) showed the following. (i) Autopsy hippocampal neuron densities for the hilus (H), AH and prosubiculum (Pro) decreased logarithmically at the same time as the thickness of the stratum pyramidale and Pro increased. By contrast, autopsy granule cell densities and thickness did not significantly change with age; however, the SG lengthened-expanding around the enlarging H. Further, the supragranular molecular layer height increased logarithmically, and took longer than the increase in stratum pyramidale thickness. (ii) Compared with age-matched autopsies, young children with a history of hippocampal seizures showed decreased granule cell, hilar and regio superior neuron densities similar to adults with hippocampal sclerosis (average loss 70%). By contrast, children with extra-hippocampal congenital or acquired pathologies showed only decreased granule cell densities, along with a thinner and shorter SG. Compared with extra-temporal locations, those with temporal lobe lesions showed decreased hilar and AH neuron densities, but averaged 20-30% less than autopsies and not in the pattern typical of hippocampal sclerosis. (iii) The neo-Timm's GV densities, when compared with autopsies, showed supragranular mossy fibre sprouting in children with congenital pathologies and temporal lobe lesions; however, the greatest GVs were in children with hippocampal seizures. (iv) Of the children with extra-hippocampal congenital or acquired pathologies there were no statistical correlations between longer duration of seizures with changes in neuron densities, hippocampal heights, or mossy fibre sprouting. These results indicate the following. (i) In the human there is anatomical evidence for postnatal maturation of the hippocampus and our results are consistent with the notion that AH pyramids are a stable population; however, there are probably increases in granule cell numbers. Further, compared with the AH, dendritic maturation of the FD granule cells appears to take longer. (ii) Extra-hippocampal childhood seizures whether from prenatal or postnatal aetiologies are associated with moderate FD and minimal AH neuron losses and signs of aberrant mossy fibre sprouting. (iii) By contrast, young children with the syndrome of mesial temporal epilepsy show patterns of neuron loss and mossy fibre sprouting, typical of hippocampal sclerosis. (iv) Repeated extra-hippocampal childhood seizures are not associated with progressive evolution of hippocampal damage or mossy fibre sprouting. These findings support the hypothesis that childhood seizures can damage or alter the postnatally developing granule cells of the human hippocampus, and that early neuron loss and aberrant axon circuits may contribute to chronic hippocampal seizures. However, repeated childhood generalized seiz PMID- 8673506 TI - The running down phenomenon in temporal lobe epilepsy. AB - We compared 100 patients with temporal lobe epilepsy, who exhibited the running down phenomenon following temporal resections, with two groups of patients: 100 patients who became seizure-free, and 100 patients who continued to have frequent seizures following temporal resection. We found a significant correlation between prognosis and the size of the epileptogenic area as defined; patients with smaller epileptogenic areas had the best prognosis (seizure-free group). Patients exhibiting the running down phenomenon had intermediate size epileptogenic areas, while those patients who continued to have seizures had the largest epileptogenic areas often involving the lateral temporal and posterior temporal cortex. Other factors predictive of good outcome were: a history of febrile seizures, predominantly unilateral interictal spiking, anterior temporal localization, extent of resection of the mesial temporal structures, surgery under the age of 30 years, and the absence of habitual seizures in the immediate postoperative period. Patients with history of head trauma, encephalitis, posterior temporal localization and bitemporal spiking had a worse outcome. The frequency and types of aurae, and laterality of resection did not correlate with outcome. PMID- 8673507 TI - Mitochondrial cytopathy presenting as hereditary sensory neuropathy with progressive external ophthalmoplegia, ataxia and fatal myoclonic epileptic status. AB - We present six adult patients from three separate families, with a remarkably uniform heredo-ataxic syndrome, developing in three stages and ending in early death. The initial stage is determined by severe sensory neuropathy. The second stage is characterized further by progressive external ophthalmoplegia (PEO), probably caused by ocular myopathy, and progressive ataxia. During a short last stage there is epilepsia, and particularly myoclonic status epilepticus, of which four patients died unexpectedly. Sural nerve biopsies showed severe loss of myelinated fibres in a rather early stage of disease. Skeletal muscle biopsies (and a specimen of ocular muscle) revealed ragged-red fibres. Autopsy examination in two patients revealed multisystemic involvement of the nervous system, with, in particular, degeneration of spinal dorsal columns and spinocerebellar tracts. Pedigree data were compatible with an autosomal recessive disorder. Additional findings, particularly elevation of CSF lactate, suggested mitochondrial cytopathy as an essential feature of the multisystem degeneration in these patients. PMID- 8673508 TI - Morquio syndrome: a rehabilitation perspective. AB - Morquio Syndrome (mucopolysaccharidosis type IV A) is a rare inherited connective tissue disorder characterized by skeletal dysplasia, restrictive pulmonary disease and normal intelligence. Tetraplegia secondary to subluxation of C1 over C2 because of odontoid dysplasia is a common occurrence in these patients but there are limited descriptions regarding their specific physiatric management. Two patients (aged 20 and 17 years) were admitted to a pediatric rehabilitation facility after cervical spine stabilization following recurrent tetraplegia (C4 ASIA C and C4 ASIA D). Following surgery, patients were ventilator dependent and aphonic. One patient was successfully weaned off the ventilator to nocturnal BiPAP, while the other was able to tolerate three hours of ventilator free time despite being ventilator dependent for ten years. At discharge, both patients showed significant improvement in mobility, self care skills and communication abilities. Functional independence was encouraged through use of various assistive devices for mobility, activities of daily living (ADL) and communication. Group counseling and peer support were extremely helpful in their adjustment to disability. Physiatric intervention is essential and requires understanding of the unique impairments encountered by tetraplegics with Morquio Syndrome. PMID- 8673509 TI - Benefits of rehabilitation for traumatic spinal cord injury: a case report. AB - Many studies report significant functional improvements in tetraplegic patients during rehabilitation. The majority of these studies, obviously, are limited by the lack of control groups. Thus, it has always been difficult to differentiate between effects of a rehabilitation program and natural muscle recovery or independent learning. In this case report, a 25 year old man with right C7 motor, left C8 motor, C6 sensory complete tetraplegia was admitted to a tertiary care rehabilitation facility 16 months after discharge from an acute care hospital. Following a comprehensive inpatient rehabilitation program, this patient's functional status improved from near complete dependence to virtual independence in most areas of self care and mobility as scored by the Functional Independence Measure (FIM), without any change in motor or sensory function. This case, in which the patient served as his own control, illustrates the effectiveness and importance of aggressive inpatient rehabilitation following spinal cord injury. PMID- 8673510 TI - Surgery of the sympathetic nervous system. AB - This article reviews the innervation of the arterial system of the lower extremity, lumbar sympathectomy in vascular surgery, lumbar sympathectomy for digital gangrene and in the prevention of major amputation of the lower extremity and substance P's role in neurogenic inflammatory modulation. Long-term results of lumbar sympathectomy and direct arterial bypass surgery have also been reviewed. In addition to the pilomotor, sudomotor and vasomotor actions of the sympathetic nervous system via its neurotransmitters, the molecular basis of the chronic neurogenic inflammatory reaction have been addressed with special attention to the discovery of substance P in the lumbar sympathetic chain and ganglia of human beings. PMID- 8673511 TI - Magnetic resonance imaging examinations of gluteal decubitus ulcers in spinal cord injury patients. AB - The purpose of our study was to use magnetic resonance imaging (MRI) to determine deep changes in soft tissues and bones underlying decubitus ulcers which occur in spinal cord injury (SCI) patients. By diagnosing these deep changes adjacent to decubitus ulcers, MRI can facilitate proper clinical management and prevent contraindicated surgery. MRI evaluation was performed on 37 male SCI patients for a total of 44 diagnostic studies. The studies were evaluated by the following criteria: 1) the presence of an adjacent fluid collection, 2) bone involvement raising the possibility of osteomyelitis and 3) heterotopic bone formation. Results demonstrated 11 patients (29.7 percent) with fluid collection in the deep soft tissues underlying the decubitus ulcer and eight patients (21.6 percent) with abnormal adjacent bone marrow signal. Four patients (10.8 percent) had heterotopic bone formation near the ulcer. We conclude that MRI is helpful in determining the depth and extent of soft tissue involvement underlying decubitus ulcers including underlying fluid collections, heterotopic bone formation and evidence of adjacent bone marrow edema. This is beneficial in planning proper therapy. PMID- 8673512 TI - Neuroarthropathy: an overuse injury of the shoulder in quadriplegia. AB - The shoulder joint of the spinal cord injured patient is the primary joint used for transfer and wheelchair propulsion. In addition to ordinary use, the shoulder is subject to overuse injury with resultant functional impairment. Frequent overuse injuries of the shoulder include subdeltoid bursitis, bicipital tendonitis, rotator cuff tear and secondary degenerative arthritis. Neuroarthropathy of the shoulder, an overuse injury of an insensate shoulder girdle, has been rarely described in the literature. The case presented is that of an active 47 year old, right hand dominant, C7 complete quadriplegic male with a one week history of painless right shoulder girdle swelling. Radiologic evaluation documented right proximal humerus destruction. Magnetic Resonance Imaging (MRI) confirmed syringomyelia. The pathophysiology of neuroarthropathy is presented here and limited treatment options are discussed. PMID- 8673513 TI - Need for occupational and environmental health training. PMID- 8673514 TI - Paresthesias and sensory neuropathy due to 1,1,1-trichloroethane. PMID- 8673515 TI - Prevalence of antibodies to hepatitis B and C among fire department personnel prior to implementation of a hepatitis B vaccination program. PMID- 8673516 TI - Prevalence of antibodies to hepatitis B and C among fire department personnel prior to implementation of a hepatitis B vaccination program. PMID- 8673517 TI - Risk of nervous system cancer among workers exposed to lead. AB - Experimental animal studies suggest that lead compounds may increase the risk of gliomas. To study whether occupational exposure to lead increases the risk, we followed nervous system cancer incidence among 20,741 employees biologically monitored for their blood lead (B-Pb) concentrations. We also performed a nested case-referent study, comprising 26 male cases of nervous system cancer (16 of which had gliomas). Those cases a B-Pb > or = 1.4 mumol/L had a twofold increase in the odds ratio of nervous system cancer as compared with those employees whose B-Pb had not exceeded 0.7 mumol/L. The excess was confined to gliomas (odds ratio 11, 95% confidence interval 1.0 to 630 for B-Pb > or = 1.4 mumol/L; overall P value for trend, 0.037). We obtained lifetime information on exposure and potential confounders for 58% of the cases. The odds ratio of glioma was associated with indices of lifetime exposure to lead, and potential confounders seemed not to explain the effects. The results suggest that there may be an association between occupational lead exposure and the risk of gliomas. No firm conclusions can be drawn because of the small number of cases and loss of material. PMID- 8673518 TI - Comparison of spirometric reference values for Caucasian and African American blue-collar workers. AB - Interpretation of lung-function test results, specifically the forced vital capacity and forced expiratory volume in one second, generally involves the comparison of these parameters with reference values based on an individual's age, height, sex, and race. Such comparisons are often used to make important decisions concerning an individual, such as job placement or disability rating. Several studies have shown that predicted values for African Americans are approximately 15% less than those for Caucasians, most likely because of the use of standing height to estimate the size of the thorax. When an adjustment for race is applied to reference values based on a Caucasian population, a single value (15%) is usually applied to all individuals. When using a group of blue collar workers (766 Caucasian and 633 African-American subjects) without any race adjustment, 10.2% of the Caucasians and 37.4% of the African-American subjects were below the lower limit of normal. When a single adjustment factor was used, 11.5% of the African-American subjects were below the lower limit of normal. Between-subject variability within an ethnic group was far greater than variability between groups. Our results suggest that although a difference between Caucasian and African-American test results for forced vital capacity and forced expiratory volume in one second exists, an application of a single adjustment factor universally applied to all individuals, regardless of their age, sex, and height, is not optimal, and alternative approaches are needed. PMID- 8673519 TI - Medical surveillance for ethylene oxide exposure: practices and clinical findings in Massachusetts hospitals. AB - The medical surveillance requirements of the Occupational Safety and Health Administration's (OSHA) ethylene oxide (EtO) standard became effective in 1985. However, little is known about the nature of the response of EtO users to this regulatory requirement. In an effort to begin to understand this, we conducted a survey of EtO health and safety in Massachusetts hospitals (n = 92). We determined the cumulative incidence of provision of EtO medical surveillance, the characteristics of the surveillance interventions provided, and the clinical findings of EtO medical surveillance efforts in Massachusetts hospitals. From 1985 to 1993, medical surveillance for EtO exposure was provided one or more times in 62% of EtO-using hospitals. Sixty-five percent of EtO medical surveillance providers reported performance of all five medical surveillance procedures required by OSHA's EtO standard. Medical surveillance provider certification in occupational medicine or nursing, and a greater extent of coverage of written medical surveillance policies, were related to higher likelihoods of fulfillment of OSHA-required procedures. Twenty-seven percent of medical surveillance providers reported detection of EtO-related symptoms or conditions, ranging from mucous membrane irritation to peripheral neuropathy. These findings reveal wide-spread implementation of OSHA-mandated EtO medical surveillance, with concomitant incomplete fulfillment of OSHA-specified procedures. From the provider-based survey, we estimate that one or more workers at 19% of EtO-using Massachusetts hospitals have experienced EtO-related health effects. PMID- 8673520 TI - Determinants of the provision of ethylene oxide medical surveillance in Massachusetts hospitals. AB - An in-depth survey of ethylene oxide (EtO) health and safety was conducted in Massachusetts hospitals (n = 92) to investigate the determinants of the provision of medical surveillance for EtO exposure. We have evaluated the relationships between provision of EtO medical surveillance and (1) activating OSHA-specified triggers for providing EtO medical surveillance, (2) worker training on EtO health and safety, and (3) various public policy, organizational, group, and individual characteristics. Among the Occupational Safety and Health Administration's (OSHA) five specified triggers for provision of EtO medical surveillance, only accidental worker exposures were related to provision of surveillance (RR = 2.56, P < 0.001). Exceeding the Action Level for 30 or more days, one of OSHA's EtO triggers that is also used in a number of other standards, was not related to provision of surveillance (RR = 0.84, P = 0.714). Reports of coverage of EtO medical surveillance issues in worker training were also correlated with the provision of EtO medical surveillance (RR = 3.68, P < 0.001), supporting OSHA's premise that worker training plays an important role in medical surveillance implementation. The presence of detailed written EtO medical surveillance policies was positively related to the provision of EtO medical surveillance (RR = 1.81, P < 0.001). The relationships between these potential determinants and provision of medical surveillance were also validated in multivariate analyses. Implications for improvement of OSHA medical surveillance implementation through revised trigger schemes, improved worker training efforts, and other measures are discussed. Findings are relevant to the future development of medical surveillance and exposure monitoring policies and practices in both substance-specific and generic contexts. PMID- 8673521 TI - What role does occupational and environmental health law have in graduate and continuing medical education? AB - A two-stage survey that used the Delphi technique was performed to determine the attitudes and needs of physicians that practice occupational and environmental medicine (OEM) regarding continuing medical education (CME) and Master of Public Health (MPH) curriculum in the area of health law. Forty-six of the 80 subjects (58%) responded to the first survey, and 39 of these 46 (85%) responded to the follow-up survey. The results showed that most subjects agreed with the need for CME to devote approximately 14 hours over the next two years (1993-1995) to occupational/environmental health laws and regulations. Interest was also expressed in some practical business law that would be helpful to medical practices. The survey's results showed agreement on the need for a three-credit hour MPH course for OEM residents. The differences between the subgroups of academic faculty-post-1990 graduates of MPH or occupational medicine residencies, pre-1990 graduates, and those with no formal OEM education-were also investigated. Pre-1990 graduates consistently desired more hours of CME for the topics surveyed. This study should be helpful for planners of OEM CME courses and for residency directors. PMID- 8673522 TI - Lung function and respiratory symptoms related to changes in smoking habits in asbestos-exposed subjects. AB - The purpose of this study was to examine respiratory symptoms and lung function (forced vital capacity [FVC] and forced expiratory volume in 1 second [FEV1]) as related to changes in smoking habits in subjects previously exposed to asbestos. The study was linked to a smoke-ending program among asbestos-exposed males. Subjects were recruited from a population-based survey, and 231 smokers met for the baseline consultation. The baseline prevalences of cough, chronic cough, and dyspnea among smokers were 68.0%, 44.6%, and 42.4%, respectively. Both smoke ending (n = 10) and tobacco reduction (n = 52) during the 2-year follow-up resulted in remission of cough and chronic cough, whereas dyspnea was unaffected. When the 2-year measurements of FVC and FEV1 were adjusted for the respective baseline measurements, FEV1 tended to improve in subjects who had quit during the study, relative to the continuing smokers. It was concluded that both smoke ending and reduction of tobacco consumption resulted in reduction of cough and chronic cough, but not of dyspnea. The study further suggests a possible positive effect of smoking cessation on FEV1, but not merely by reduction of tobacco consumption. PMID- 8673523 TI - Effectiveness of nicotine patches in a workplace smoking cessation program. An eleven-month follow-up study. AB - Transdermal nicotine patches are widely prescribed as part of smoking cessation programs, but their efficacy beyond 6 months is not well established. We evaluated the efficacy of a 70-day treatment regimen among 75 subjects in an industrial setting where follow-up was conducted for 11 months. The median time free of cigarettes was 73 days, and the overall smoking abstinence rate was 9% after 11 months of follow-up. Smoking abstinence was significantly higher among those subjects who completed the full course of treatment than among those who did not (25 vs 6%, respectively). Smoking abstinence was also higher among subjects who started smoking after age 17 than among those who started at younger ages and was higher among male than female subjects. We conclude that transdermal nicotine patches are of limited efficacy in achieving long-term smoking cessation and that the relative costs and benefits of this treatment are not adequately specified. PMID- 8673524 TI - Reproducibility of a questionnaire for assessment of physical load during work and leisure time. Stockholm MUSIC I Study Group. MUSculoskeletal Intervention Center. AB - A self-administered questionnaire on physical load in lifetime occupational work, in present job, and in present leisure activities was tested for reproducibility with the test-retest method in 126 male and 217 female workers from 30 occupations. The questionnaire contained 92 questions and nine different response scales. The results indicated that questions concerning physical activity retrospectively and in the present job, vibrations in the present job, working postures involving the whole body, and questions concerning specific leisure activities (eg ball games, skiing, etc) seem to offer sufficient reproducibility to be worth testing for validity, at least at a 5-point ordinal level. Questions concerning working postures involving parts of the body, including awkward postures, and questions concerning manual materials handling seem to offer too poor reproducibility to be used in studies in which the aim is to quantify duration in proportions of a typical working day and frequencies in times per hour. Questions concerning level of physical activity and exertion in domestic work seem to offer too poor reproducibility to be used at a 5-point ordinal level. Gender, age, and musculoskeletal complaints did not influence the reproducibility to any great extent. PMID- 8673526 TI - A human monoclonal antibody to HIV-1 gp41 with neutralizing activity against diverse laboratory isolates. AB - A potential component that may be useful for passive immunotherapy for HIV-1 is human monoclonal antibodies (HumAbs) possessing potent anti-HIV-1 activity that is directed against conserved regions of the envelope glycoprotein. Such antibodies would, in principle, have the ability to neutralize diverse isolates of HIV-1. To develop such reagents, hybridomas were derived by initial Epstein Barr virus transformation of peripheral blood mononuclear cells (PBMCs) from an asymptomatic HIV-1 seropositive donor followed by fusion with heteromyelomas, and secreted anti-HIV-1 antibodies were further characterized. The specificity of one HumAb, designated as clone 3, was determined by enzyme-linked immunosorbent assay (ELISA) and Western blotting analyses that indicated reactivity to the transmembrane envelope glyco-protein gp41. Synthetic pentadecapeptides overlapping by 10 amino acids were utilized for epitope mapping of clone 3; a decapeptide GCSGKLICTT in the transmembrane gp41 was identified as the epitope. Clone 3 bound to SupT1 cells infected with HTLV-IIIB in fluorescent activated cell sorting analysis. In addition, in vitro biological assays demonstrated that clone 3 possessed neutralization reactivity against diverse laboratory isolates as well as an AZT-resistant isolate. Therefore, clone 3 reactivity defines a conserved neutralizable site on the HIV-1 transmembrane glycoprotein. Clone 3 and the conserved immunogenic epitope on gp41 could be useful in passive and active immunotherapy for the acquired immunodeficiency syndrome (AIDS). PMID- 8673525 TI - Influence of N-linked glycans in V4-V5 region of human immunodeficiency virus type 1 glycoprotein gp160 on induction of a virus-neutralizing humoral response. AB - One of the functions of N-linked glycans of viral glycoproteins is protecting otherwise accessible neutralization epitopes of the viral envelope from neutralizing antibodies. The aim of the present study was to explore the possibility to obtain a more broadly neutralizing immune response by immunizing guinea pigs with gp160 depleted of three N-linked glycans in the CD4-binding domain by site-directed mutagenesis. Mutant and wild type gp160 were formulated into immunostimulating complexes and injected s.c. into guinea pigs. Both preparations induced high serum antibody response to native gp120 and V3 peptides. Both preparations also induced antibodies that bound equally well to the V3 loop or the CD4-binding region, as determined by a competitive enzyme linked immunosorbent assay (ELISA). The sera from animals, immunized with mutated glycoprotein, did not neutralize nonrelated HIV strains better than did sera from animals, immunized with wild type glycoprotein. Instead, a pattern of preferred homologous neutralization was observed, i.e., sera from animals, immunized with mutant gp160, neutralized mutant virus better than wild type virus, and vice versa. These data indicated that elimination of the three N-linked glycans from gp160 resulted in an altered local antigenic conformation but did not uncover hidden neutralization epitopes, broadening the immune response. PMID- 8673527 TI - T-cell homeostasis, competition, and drift: AIDS as HIV-accelerated senescence of the immune repertoire. AB - The observation that the density of CD8+ T-lymphocytes increases as the density of CD4+ T-cells declines in adult HIV-1/AIDS patients, together with evidence that the total density of T-cells is regulated (homeostasis) has led to the suggestion that competition between lineages, and classes of T-cells contributes to the pathology of HIV. We use a mathematical model of the interactions between populations of T-cells, HIV, and other parasites to explore the effects of T-cell homeostasis and competition on the progression to AIDS. We demonstrate that as a consequence of parasite-mediated T-cell replication, of competition within and between different T-cell clones, and random processes (T-cell drift), some CD4+ lineages will be represented by relatively few cells, dearths, and some lineages may be lost, leaving holes in the immune repertoire. By killing CD4+ T lymphocytes, HIV accelerates the rate at which these dearths and holes accumulate and leads to an early breakdown of the immune control of HIV and other parasites, AIDS. When this model allows for intense, but not complete, competition between the CD4+ and CD8+ T-cell populations, it can account for most of the features of an HIV-1 infection in adults, including the gradual decline in CD4+ T-cell densities and concomitant increase in HIV density, as well as the variability in time from infection to AIDS and the decline in the time from infection to AIDS in older patients. PMID- 8673528 TI - Switching from zidovudine to didanosine in patients with symptomatic HIV infection and disease progression. ddI Iberian Study Group. AB - This study evaluated the efficacy of switching to didanosine in patients who were clinically or immunologically progressing despite zidovudine therapy. This multicenter, open-label study involved 400 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC), who had tolerated zidovudine for at least 12 weeks and had signs of clinical or immunological disease progression. They were randomly assigned to receive 600 mg/d of zidovudine (n=133), 500 mg/d of didanosine (n=131), or 200 mg/d of didanosine (n=136). The primary end point was a new AIDS-defining event or death. The study was prematurely terminated, after the first interim analysis, mainly owing to results of two controlled studies demonstrating that a change to didanosine was associated with an improved outcome in patients with advanced HIV-1 disease. The median duration of follow-up was 53 weeks. The primary end point rates were 41, 58, and 59 (per 100 person-years) in the didanosine 500 mg, didanosine 200 mg, and zidovudine groups (zidovudine vs. didanosine 500 mg, relative risk 1.28, 95% confidence interval, 0.88-1.86, p = 0.19; didanosine 200 vs. 500 mg, relative risk 1.24, 95% confidence interval, 0.85-1.79, p = 0.26). In subjects with a baseline CD4 count of 100/mm3 or more, the primary end point rates were 8, 29, and 25 (per 100 person-years) in the didanosine 500 mg, didanosine 200 mg, and zidovudine groups, respectively (zidovudine vs. didanosine 500 mg, relative risk 2.96, 95% confidence interval 0.91-9.62, p = 0.07). No difference was seen in survival. In the didanosine 500 mg group, more patients had a 50% increase in CD4 cells (10% vs. 1% in zidovudine group, p = 0.01) and an increase of > or = 2.5 kg in body weight (2% versus 3%). Fatal pancreatitis developed in one patient assigned to didanosine 500 mg and in one to zidovudine. Our data suggest that switching from zidovudine to currently recommended doses of didanosine in subjects with ARC or AIDS who show evidence of clinical and laboratory disease progression can be associated with improvements in clinical outcome as well as in surrogate markers of HIV disease progression. This effect tended to be greater among individuals with higher CD4 counts (>100/mm3). PMID- 8673529 TI - Prenatal care and birth outcomes of a cohort of HIV-infected women. AB - Adequate prenatal care has been linked to improved birth outcomes in general populations but has not been assessed in HIV-infected women. We examined longitudinal claims files and vital statistics records for women in the New York State Medicaid HIV/AIDS data base delivering a singleton from 1985 through 1990. Adequacy of the self-reported number of prenatal visits was assessed by the Kessner index. In logistics models, we estimated the association of prenatal care, illicit drug use, and other maternal characteristics with three outcomes; low birth weight, preterm birth, and small-for-gestational-age. Of 2,254 singletons delivered by this HIV-infected cohort, 28% were low birth weight, 23% were preterm birth, and 20% were small for gestational age. Two-thirds had inadequate prenatal care. Non-drug users had 57 and 26% lower adjusted odds of low birth weight and preterm delivery than drug users. The adjusted odds of low birth weight and preterm birth for women with an adequate number of prenatal visits were, respectively, 48 and 21% lower than for women with inadequate care. Adequate prenatal care was also associated with a 43% reduction in the odds of small-for-gestational-age. An adequate number of prenatal visits by women in this HIV cohort was associated with a significant reduction in all three adverse birth outcomes, but most had inadequate prenatal care. These data support strengthening efforts to bring pregnant, HIV-infected women into care. PMID- 8673530 TI - No evidence of a higher risk of progression to AIDS in patients with HIV-1 related severe thrombocytopenia. AB - The prognostic role of platelet (PLT) counts was evaluated in a cohort of 1,533 HIV-1-infected subjects followed for a median of 21 months. Thrombocytopenia (TCP), defined as a PLT count < or = 100 x 10(9)/L was present at enrollment in 11.2% of cases, with counts < or = 50 x 10(9)/L (severe TCP) in 5.3%. With the subjects with normal PLT counts (PLT >150 x 10(9)/L) as the reference group, the relative risk of developing acquired immunodeficiency syndrome (AIDS) was 0.8 [95% confidence interval (CI) 0.5-1.3, p = 0.4] for subjects with severe TCP, 2.1 (95% CI 1.4-3.1, p = 0.002) for those with PLT counts ranging from 51 to 100 x 10(9)/L (moderate TCP), and 1.6 (95% CI 1.2-2.1, p = 0.0004) for those with borderline PLT values (PLT ranging from 101 to 150 x 10(9)/L). Most of the risk increase associated with moderate TCP and borderline PLT values was explained by a higher prevalence of subjects with an older age and lower CD4+ cell counts. However, at multivariable analysis considering age, sex, risk group, and zidovudine (ZDV) treatment, the risk for subjects with severe TCP remained significantly lower than that for subjects with moderate TCP and borderline values. These results suggest the existence of different types of HIV-1 associated TCP and also suggest that severe TCP (which often arises in the early phases of infection) is not related to disease progression. PMID- 8673531 TI - Increased numbers of granzyme-B-expressing cytotoxic T-lymphocytes in the small intestine of HIV-infected patients. AB - The objective of this study was to determine whether granzyme B-expressing cells, which identify activated cytotoxic lymphocytes, are present in the small intestinal mucosa of human immunodeficiency virus (HIV)-infected patients with and without diarrhea. Therefore, duodenal biopsy specimens from 29 HIV-infected patients (11 with diarrhea and 18 without diarrhea) and 15 control patients were stained for the presence of granzyme B expressing cells. In HIV-infected patients, a significantly increased expression of granzyme B in the lamina propria was observed (p = 0.00001): In 22 of 29 patients, at least 5-10 cells per high-power field were counted. In contrast, in 13 of 15 control patients, granzyme B was not expressed or minimally so, and in two others a maximum of five granzyme-B-expressing cells could be detected per high-power field. No significant difference was found between the HIV-infected patients with and without diarrhea. Double staining revealed that the granzyme-B-expressing cells were mainly CD3 positive. These data show that activated cytotoxic T lymphocytes (CTLs) are present in the duodenal mucosa of HIV-infected patients. No relation between the number of CTLs and the presence of diarrhea was demonstrated. CTLs are known to be involved in the pathogenesis of HIV infection and in the production of tissue injury, but their functional role in intestinal HIV-related pathology has yet to be elucidated. PMID- 8673532 TI - Risk behavior and HIV seroincidence among out-of-treatment injection drug users: a four-year prospective study. AB - We monitored trends in HIV risk behaviors and seroconversion among out-of treatment injection drug users (IDUs) receiving street-based outreach intervention. Beginning in 1988, 641 HIV-seronegative IDUs were recruited by targeted sampling methods to reflect broader IDU populations and were followed for 4 years (1988-1992). All were active injectors not in treatment when recruited. Cohort members were targets of HIV-prevention outreach. The intervention was guided by the Indigenous Leader Outreach Model: Exaddicts deliver HIV-prevention services targeting IDU social networks in community settings. Primary outcome measures were HIV seroconversion and HIV risk behaviors. Observed incidence of HIV infection decreased, from 8.4 to 2.4 per 100 person-years. Prevalence of drug risk behaviors also decreased, from 100 to 14%. Seroconversion was associated with injection risk behavior [risk ratio (RR) = 9.8]. Sex risk behavior also decreased, but less dramatically, from 71 to 45%. Out-of-treatment IDUs in Chicago have reduced their rates of new HIV infection by reducing their injection risk behavior. New infections were strongly associated with injection risk behavior but not with sex risk behavior. PMID- 8673533 TI - Acceptability of interventions to reduce mother-to-child transmission of HIV-1 in west Africa. AB - Would HIV-1-positive pregnant African women use interventions of AIDS testing, medication (oral or vaginal), and vaginal disinfection to reduce the likelihood of HIV-1 transmission to their child? In this pilot study in two west African cities (Abidjan, Cote d'Ivoire and Bobo-Dioulasso, Burkina Faso), social workers gave a native-language questionnaire to 607 pregnant women at four Maternal and Child Health Centers. The women were asked about their perception of the HIV test; consequences of testing and counseling; choice of medical intervention to protect the future child; and feelings about being in a randomized, placebo controlled, clinical trial. Most accepted the principle of an AIDS test, said they wanted the agreement of their regular partner before being tested, and would use interventions to reduce the risk of vertical transmission. The researchers concluded that although concepts of informed consent, randomization, and placebo are difficult to understand, the study results are promising and encourage the evaluation of clinical trials to reduce mother-to-child transmission of HIV-1 in Africa. PMID- 8673534 TI - Tuberculosis among AIDS patients in the United States, 1993. AB - To evaluate the demographic characteristics, risk factors, and reported mortality of adults and adolescents with AIDS and tuberculosis (TB), we analyzed surveillance reports of persons with AIDS from state, territorial, and local health departments. Of 72,306 persons with AIDS diagnosed in 1993, 3,589 (5%) were reported with TB; of these, 2,782 (78%) with pulmonary TB, 552 (15%) with extrapulmonary TB, and 255 (7%) with both pulmonary and extrapulmonary TB were reported. In multivariate analysis, black [odds ratio (OR) 3.3, 95% confidence interval (CI) 2.9-3.7] and Hispanic (OR 2.5, 95% CI 2.2-2.9) persons had a higher risk of TB than white persons; injecting drug users (IDUs: OR 2.3, 95% CI 2.0 2.5) and persons exposed to HIV by heterosexual contact (OR 1.4, 95% CI 1.2-1.7) had a higher risk than men who have sex with men, and persons who were foreign born (OR 2.1, 95% CI 1.8-2.4) had a higher risk than those born in the United States. The highest proportions of AIDS patients with TB were in New York (11%), Illinois (7%), Florida (6%), Georgia (6%), and Texas (5%). The 1-year mortality rate among AIDS patients with pulmonary TB only (26%) and among those with extrapulmonary TB only (28%) was lower than among those with other AID-defining illnesses (38%) (p<0.001 and p<0.001, respectively). The high rate of TB among persons with AIDS, particularly in specific areas of the country and HIV exposure groups, emphasizes the need for continued support of strong TB control measures among persons infected with HIV. PMID- 8673535 TI - Sequence variation and subtyping of human and simian T-cell lymphotropic virus type I strains from South Africa. AB - We report on the subtyping of South African primate T-cell lymphotropic virus type I (PTLV-I) strains by investigating the LTR region using sequence analysis and restriction fragment length polymorphism (RFLP) techniques. DNA from either uncultured peripheral blood mononuclear cells (PBMCs); cultured PBMC or cell lines of eight human T-cell lymphotropic virus type I (HTLV-I); and two simian T cell lymphotropic virus type I (STLV-I) strains (Cercopithecus aethiops pygerythrus) were amplified by polymerase chain reaction (PCR), cloned, and sequenced. The samples originated from different geographical regions in South Africa. Phylogenetic relationships were estimated using the neighbor-joining method. The South African HTLV-I strains were of Cosmopolitan origin and similar to each other. RFLP analysis confirmed this subtyping. A divergence of 0.3 to 1.6% between the Cosmopolitan strains was observed, while the divergence between the HTLV-I and STLV-I strains ranged from 6.3 to 7%. The STLV-I strains were closely related to that of a chimpanzee, providing evidence of interspecies transmission. PMID- 8673536 TI - Delayed-type hypersensitivity testing in Tanzanian adults with HIV infection. AB - Delayed-type hypersensitivity (DTH) testing and total lymphocyte counts as measures of cell-mediated immune function were assessed for medical patients in Dar es Salaam, Tanzania. DTH testing was performed with the Multitest CMI device which simultaneously administers seven antigens. Of 201 patients completing DTH testing, 90 were HIV seropositive. Anergy occurred more frequently among HIV seropositive patients (39 of 90) as compared with HIV-seronegative patients (17 of 111). DTH skin test reactivity, measured by anergy, the number of positive antigens, and the combined DTH response induration, was significantly related to the clinical stage of HIV disease. Median total lymphocyte counts were significantly lower in HIV-seropositive patients than in HIV-seronegative patients (1,130 vs. 1,680 lymphocytes x 10(6)/L). Total lymphocyte counts decreased with increasing severity of HIV disease. In multivariable analysis, the number of positive antigens in DTH testing and lymphopenia significantly predicted HIV infection. The findings suggest that DTH testing and total lymphocyte counts may be useful, inexpensive tests of immune function in African patients with HIV disease. PMID- 8673539 TI - Hyperuricemia and progression of HIV disease. PMID- 8673537 TI - Replacing time since human immunodeficiency virus infection by marker values in predicting residual time to acquired immunodeficiency syndrome diagnosis. Multicenter AIDS Cohort Study. AB - It is widely assumed that the time since human immunodeficiency virus (HIV) infection is an important indicator of HIV disease stage, yet for most infected individuals the date of infection is unknown. We consider whether marker values, such as CD4 lymphocyte number or percent and levels of serum beta2 microglobulin or serum neopterin, render time since infection unimportant for predicting the residual time to acquired immunodeficiency syndrome (AIDS) diagnosis. The Multicenter AIDS Cohort Study (MACS) contains a subsample of homosexual men whose date of HIV seroconversion is known within +/-6 months and who provide data for this analysis. From this subsample, we extract two overlapping data subsets. The first subset consists of 370 persons whose 3,723 study visits include complete data on the cellular markers CD4 lymphocyte number and percent for a period of 9 years. The second consists of 272 persons whose 1,593 visits include complete information on cellular markers and on the serological markers beta2 microglobulin and neopterin for a period of 5 1/2 years. We model the residual time to AIDS diagnosis with a regression model, in which cellular and serologic markers are the explanatory covariates (independent variables) and the residual time to AIDS is the responses variable (dependent variable). A robust estimate of the variance-covariance matrix corrects for the dependence of repeated measurements in the same individual. In the case of CD4 number and percent, the results indicate that time since infection is of none or at most little importance if the marker value is known, suggesting that time since infection can be adequately replaced by the combination of marker values. However, the serological markers alone do not eliminate the importance of the time since infection. PMID- 8673538 TI - Konzo, an epidemic spastic paraparesis in Africa, is not associated with antibodies to HTLV-I, HIV, or HIV gag-encoded proteins. PMID- 8673540 TI - Effects of human immunodeficiency virus type 1 infection on programmed cell death in the presence or absence of Bcl-2. AB - The effect of human immunodeficiency virus (HIV-1) infection on the programmed cell death of CD4+ lymphocytes was studied by using Jurkat cells stably expressing high levels of the Bcl-2 protein (Jurkat-Bcl2) or control cells (Jurkat-P). Both Jurkat-Bcl2 and Jurkat-P cells exhibited surface CD4 expression adequate to support HIV-1 infection. We observed no differences between HIV-1 infected Jurkat Bcl2 cells and control cells with respect to kinetics of virus replication, protein expression, and processing. Severe cytopathic effects, which were typical of acute HIV-1 infection and consisted of syncytium formation followed by single-cell lysis, were observed in both cell types. However, several lines of evidence, such as cell viability analysis by trypan blue dye exclusion, chromosomal DNA laddering, and morphologic analysis by acridine orange/ethidium bromide or Giemsa staining, indicated that HIV-1 did not induce a significant amount of programmed cell death in either cell type. These results suggest that apoptosis is at most a minor element in HIV-1-induced cytopathicity in Jurkat lymphocytes. PMID- 8673542 TI - Inhibition of HIV replication by sense and antisense rev response elements in HIV based retroviral vectors. AB - The life cycle of human immunodeficiency virus type 1 (HIV-1) is critically dependent on the transregulatory proteins Tat and Rev. Tat increases the production of HIV-specific mRNAs by direct binding to the transactivation response (TAR) element located at the 5' end of all HIV transcripts. In contrast, Rev uses a complex RNA stem loop structure, the Rev response element (RRE), which is found in full-length and singly spliced HIV transcripts. Rev is required for the cytoplasmic expression of full-length mRNAs encoding Gag, Pol, and Env structural proteins. The complex intracellular interactions between Tat, Rev, host cell factors, and their respective RNA response elements should be susceptible to interdiction by genetic therapies designed to introduce and express novel genetic information. We show that the expression of antisense RREs inhibited the cytoplasmic expression of RRE containing HIV-1 transcripts. HIV based retroviral vectors containing either the antisense (-) or sense (+) RREs inhibited HIV replication in transient transfections. The production of full length HIV mRNA was also decreased significantly by the expression of RREs in either orientation. Interestingly, there was a paradoxic increase in HIV p24 gag production at low levels of inhibitor; this effect may have been the result of encapsidation of RRE-containing HIV-based retroviral vectors. The data suggest that the introduction and inducible expression of RRE-containing, HIV-based retroviral vectors may have therapeutic value in HIV infection. PMID- 8673541 TI - Transcriptional effects of superinfection in HIV chronically infected T cells: studies in dually infected clones. AB - We had previously shown that chronically infected ACH-2 cells (HIVLAI) could be superinfected with HIVRF, that the frequency of superinfection increased with time, and that the transcription of the superinfecting virus exceeded that of the host HIVLAI provirus. In contrast, ACH-2 cells superinfected with a nef substituted neomycin-resistant (proNEO) provirus were not detectable by DNA polymerase chain reaction (PCR) until geneticin (G418) was added, suggesting that the ability to propagate progressively in culture may be HIV strain specific. Clonal populations of ACH-2 superinfected with proNEO did not demonstrate preferential transcription of the superinfecting virus. However, clones of ACH-2 superinfected with HIVRF (ACH2/RF) showed a preponderance of HIVRF transcripts similar to that seen in bulk populations. Induction of the superinfecting virus by phorbol ester (PMA) occurred more rapidly than the hose provirus and did not equalize transcriptional activity. PCR-derived long terminal repeat (LTR) fragments and Tat cDNAs from A3.01 cells acutely infected with HIVRF or from ACH 2 cells were sequenced and tested for transactivation. The HIVLAI LTR was two to three times more Tat-responsive than the HIVRF LTR. TatRF was two to three times more transcriptionally active on either LTR than TatLAI. Demethylation with 5 azacytidine did not significantly affect HIV expression from the HIVLAI host provirus of superinfected ACH2/RF cell clones. These data suggest that the mechanism of preferential transcription in HIVRF superinfected ACH2/RF may be attributed to the Tat/TAR axis and the effect of the specific locus of host proviral integration. PMID- 8673543 TI - Molecular cloning of full-length HIV-1 genomes directly from plasma viral RNA. AB - Human immunodeficiency virus type 1 (HIV-1) in plasma reflects the replicating virus population at any point in time in vivo. Studies of the relationship of the complete HIV-1 genome to pathogenesis therefore need to focus on plasma virions. Since dual infections and recombination can occur in vivo, cloning an intact plasma virus genome as a single full-length molecule is desirable. For these reasons, we developed an efficient method to clone full-length HIV-1 genomes directly from plasma viral RNA. This method used reverse transcription and long polymerase chain reaction (PCR) amplification. Virion-associated RNA was isolated from plasma samples and then reverse-transcribed to make cDNA for PCR amplification. Two different strategies were employed to amplify the full-length genome: one amplified a 9-kb fragment, and the other amplified two overlapping 5 kb fragments. Although both strategies were successful, the second was preferable for amplifying HIV-1 genomes from samples with low viral titers. By directly ligating the PCR-derived fragments into a phagemid vector, we constructed clones that comprised full-length HIV-1 RNA genomes. Using this technique, we have constructed hundreds of clones containing full-length HIV-1 genomes derived from the plasma of HIV-1-infected individuals, some of whom had low HIV-1 titers. Different HIV-1 molecular species were cloned from a single clinical sample, as demonstrated by restriction site polymorphism. This method provides a tool for studying complete HIV-1 genomes in relation to pathogenic processes. PMID- 8673544 TI - Early clinical markers and CD4 percentage in subjects with human immunodeficiency virus infection. AB - In a clinical trial involving asymptomatic, HIV-seropositive subjects treated with either the HIV-1 immunogen (an inactivated, gp120-depleted HIV-1 virus in incomplete Freund's adjuvant) or an adjuvant control, we examined the relationship between changes in the percentage of CD4 cells over time and early clinical markers of HIV disease progression. Subjects who had an early clinical event were more likely to have a greater decline in the percentage of CD4 cells than those subjects who did not have a clinical event (p = 0.054). The greatest decline in CD4 percentage occurred within 10 weeks prior to a clinical event (mean 11% decrease from baseline). Subjects from the quartile with the greatest decline in CD4 percentage had a fivefold greater risk of having a clinical event than subjects from the quartile with the second largest decline (p = 0.045). These results demonstrate a relationship between changes in the percentage of CD4 cells and early clinical events. Further validation of this association may be useful in clinical monitoring and in evaluating therapies to treat HIV infection. PMID- 8673545 TI - Phase 1 study of combination therapy with L-697,661 and zidovudine. The ACTG 184 Protocol Team. AB - We performed a pilot study that examined the clinical and pharmacokinetic interactions between zidovudine (ZDV) and a pyridinone derivative, L-697-661. The results indicate that the drugs were well tolerated, with no important pharmacokinetic interactions, when administered concomitantly for as long as 8 weeks. Although the number of study participants was small, we noted rapid emergence of resistance to L-697,661 among ZDV-naive study subjects who were administered L-697,661 as monotherapy but did not observe isolates of human immunodeficiency virus type 1 (HIV-1) resistant to L-697,661 among those who were administered concomitant ZDV. These results suggest a potential interaction between development of resistance to L-697,661 and ZDV. Although the clinical development of L-697,661 has been halted, our results support the need for further studies to test whether specific interactions among antiretroviral agents administered in combination and the molecular target can delay the emergence of isolates that exhibit resistance to all drugs in the regimen. PMID- 8673546 TI - Lifetime cost of human immunodeficiency virus-related health care. AB - Estimates of the lifetime cost of illnesses are needed for temporal and international comparisons and for assessment of the efficiency of prevention strategies. The goal of the present study was to estimate the average present value, at both the time of diagnosis and the time of seroconversion, of the lifetime cost of health care for HIV infection. Australian data on the monthly cost of HIV-related health care for homosexual men were linked with published data on disease progression using survival analysis methods. Future costs were discounted at 5% per annum. For a patient diagnosed when his CD4+ count fell below 500 x 10(6)/L, the average present value in 1992-1993 of lifetime cost was approximately $93,000, of which 49% was for drugs and 32% was for hospital bed days. For a man infected in 1992-1993 and diagnosed when his CD4+ count falls below 500 x 10(6)/L, the average present value of lifetime cost at the time of seroconversion is approximately $70,000. These estimates are lower than the lifetime cost of $119,000 reported recently in the United States. However, when the U.S. figure was adjusted to make discounting of future costs consistent between the two studies, lifetime costs were approximately 17% lower in the United States. The lower American costs appear to be due to lower rates of hospitalization and drug prescribing, possibly because of reduced access to health services, but underestimation of costs due to study methodology might also explain the difference. PMID- 8673547 TI - Predictors of resource utilization for hospitalized patients with Pneumocystis carinii pneumonia (PCP): a summary of effects from the multi-city study of quality of PCP care. AB - To determine whether patient and hospital characteristics were significantly associated with variations in Pneumocystis carinii (PCP) care and outcomes, we analyzed the use of diagnostic tests, intensive care units (ICUs), anti-PCP medications for persons hospitalized with human immunodeficiency virus (HIV) related PCP, and hospital discharge status. We conducted retrospective chart reviews of a cohort of 2,174 patients with PCP hospitalized in 1987-1990. Outcomes included process of care for PCP and in-hospital mortality rates. Persons with PCP who were more severely ill at admission were more likely to have early medical care, to receive care in an intensive care unit, and to die in hospital. After we adjusted for differences in this severity of illness, we noted that Medicaid patients, injection drug users (IDUs), and patients treated at VA or county hospitals were significantly less likely than others to have diagnostic bronchoscopies and that persons covered by Medicaid, with a previous diagnosis of acquired immunodeficiency syndrome (AIDS), who did not receive prior zidovudine (AZT) or who received care in a VA hospital had the highest chances of in hospital death. Insurance and risk group characteristics, severity of illness, and hospital characteristics appear to be the most important determinants of the intensity and timing of medical care and outcomes among patients hospitalized with PCP. PMID- 8673548 TI - Pilot randomized controlled trial of Chinese herbal treatment for HIV-associated symptoms. AB - We wished to determine the short-term safety and efficacy of a Chinese medicinal herb preparation in treating symptoms of human immunodeficiency virus (HIV) infection in a 12-week randomized, double-blind, placebo-controlled clinical trial in a University-affiliated acquired immunodeficiency syndrome (AIDS) clinic at a public general hospital. Thirty adults with symptomatic HIV infection, no previous AIDS-defining diagnosis, and CD4+ counts of 0.200-0.499 x 10(9)/L (200 499/mm3) received 28 tablets each day of either a standardized oral preparation of 31 Chinese herbs or a cellulose placebo. Primary outcome measures were changes in life satisfaction, perceived health, and number and severity of symptoms. Other outcomes included adherence, and changes in weight, CD4+ count, depression, anxiety, physical and social function, and mental health. Two placebo- and no herb-treated subjects had mild adverse events (AE). Subjects on both arms reported taking 94% of prescribed tablets. No differences between treatment groups reached the p < 0.05 level. Life satisfaction improved in herb-treated [+0.86, 95% confidence interval (CI): +0.29, +1.43] but not in placebo-treated subjects (+0.20, 95% CI -0.35, + 0.75). Number of symptoms was reduced in subjects receiving herbs (-2.2, 95% CI -4.1, -0.3) but not in those receiving placebo (-0.3, 95% CI -3.2, +2.7). There were trends toward greater improvements among herb-treated subjects on all symptom subscales except dermatologic. Believing that one was receiving herbs was strongly associated with reporting that the treatment had helped (p < 0.005), but not with changes in life satisfaction or symptoms. There were improvements in life satisfaction and symptoms among subjects receiving the herbal therapy. Whether Chinese herbs are effective in the management of symptomatic HIV infection can be adequately addressed only by larger trials of longer duration. PMID- 8673549 TI - Analysis of an HIV-infected cohort followed for as long as 15 years after seroconversion. AB - Data from a cohort of 62 HIV-positive individuals with hemophilia or von Willebrands disease infected for a maximum period of 15 years were analyzed. The relation between CD4+ and total lymphocyte counts and their rate of decline was analyzed with respect to age at seroconversion, time of seroconversion, and development of disease and subsequent death. As expected, the CD4+ and total lymphocyte population decline correlated with increased probability of disease and death. The patients fell into two distinct categories with respect to this decline: those whose cell count declined steadily (single slope) and those whose cell count remained steady or decreased very slowly for a variable period and then declined sharply (double slope). Within this cohort, the presence of a double slope appears to indicate a poorer prognosis, as 9 of 18 of the patients who have died showed this pattern, whereas only 6 of 42 of the remaining patients have this pattern even though more than half of this group have CD4+ lymphocyte counts < 0.2 x 10(9)/L. In addition, the ratio of CD4+ lymphocyte count to total lymphocyte count decreased with increasing cumulative frequency of the cumulative incidence of disease and death and the overall probability of death in this cohort was lower than expected, being 30% 12 years after seroconversion. PMID- 8673550 TI - Characteristics of HIV-infected pregnant women in the Bahamas. AB - The Commonwealth of the Bahamas has one of the highest rates of acquired immunodeficiency syndrome (AIDS) in the English-speaking Caribbean. A seroprevalence study of pregnant women attending antenatal clinics in New Providence in 1990-91 showed that of 3,914 pregnant women tested, 2.9% were human immunodeficiency virus (HIV) infected. Women born in the Bahamas constituted 79.2% of the women tested; 17.7% were born in Haiti. The rate of HIV infection was 2.5% in the Bahamian women as compared with 4.5% in those born in Haiti. The highest incidence was in women aged 25-34 years and in women who had multiple pregnancies. There was a significant association with a history of crack cocaine use by the Bahamian women. There was also a significant association between a lack of education and HIV infection in this group. There was a lower rate of condom use among women with less education and also among women in common-law relationships, but the association of lack of condom use and HIV infection did not reach statistical significance. PMID- 8673551 TI - Interest among gay/bisexual men in greater Boston in participating in clinical trials of preventive HIV vaccines. AB - To estimate interest in HIV preventive vaccine trials, we administered questionnaires to two otherwise demographically similar cohorts of older (mean 40 years) and younger (mean 23 years) gay men in Boston. Questionnaire responses were linked to concurrent behavioral and demographic data. Univariate analyses, performed separately for older and younger cohorts, identified factors that distinguished participants who were "very interested" from those who were "not at all interested". Multivariate logistic regression analyses were used to adjust for confounding. Among all 630 participants, 215 (34%) were "not at all" interested in participating, 306 (49%) were "somewhat" interested, and 102 (16%) were "very" interested. Older men were significantly more likely than younger men to be "very" interested and less likely to be "not at all interested." Among both older and younger men, perceived peer willingness to enroll in vaccine trials predicted interest after adjusting for confounding. Among older men, optimism about success in vaccine development also predicted interest. In the younger cohort, men recruited in community settings (e.g., bars, nightclubs) were more interested in vaccine trial participation than were those recruited by outreach workers and word of mouth on college campuses. Vaccine-induced seroconversion evoked significant concern. PMID- 8673552 TI - Costs of HIV+/AIDS at CD4+ counts disease stages based on treatment protocols. AB - We report treatment protocols for HIV+/AIDS patients by CD4+ counts (T-lymphocyte cells/mm3: > or = 500, 499-200, 199-50, and < 50) as a tool to provide better definition and to project annual costs (total charges for services) and lifetimes costs for HIV+/AIDS. The treatment protocols, derived from the literature and an HIV+/AIDS Physician Panel, defined the resource use associated with antiretroviral therapy and opportunistic disease prophylaxis and treatment. Resource use costs were derived from the published literature, insurance database, Medicare fee schedules, surveys, and the Physician Panel. At CD4+ counts, the rates of opportunistic diseases were derived from the Physician Panel experience; the mean occupancy times were derived from the literature. The sensitivity analysis indicated stability of the lifetime costs to variation in mean occupancy times, rates of opportunistic diseases, rates of adverse events (AE), and costs. The total annual costs (1995 dollars) of HIV+/AIDS patients ranged from $1,934 (> or = 500), $6,015 (200-499), and $9,031 (50-199), to $25,239 ( < 50). The annual costs of opportunistic diseases are esophageal candidiasis (EC) ($2,194), tuberculosis (TB) ($2,924), cryptococcal meningitis (CM) ($17,264), toxoplasmosis ($17,631), Mycobacterium avium complex (MAC) (+20,153), Non-Hodgkin's lymphoma (NHL) ($22,329), wasting syndrome ($26,676), central nervous system (CNS) lymphoma ($27,333), Pneumocystis carinii pneumonia (PCP) [mild ($3,545), moderate ($4,889), and severe ($32,609)], Kaposi' sarcoma (KS) [mild/moderate ($5,902), and severe ($10,744)], and cytomegalovirus (CMV) retinitis ($100,337). The projected lifetime costs of HIV+/AIDS are $94,726 (annual costs $7,645). Our lower lifetime costs as compared with recent estimates may be due to including resources only for HIV+/AIDS-related treatment and not for non-HIV+/AIDS conditions, as well as reduced resource use resulting from more efficient diagnostic and therapeutic techniques and earlier prophylaxis provided by experienced HIV+/AIDS physicians. Nonetheless, our estimates are consistent with decreasing costs of HIV+/AIDS due to a reduction in the average length of stay and frequency of hospitalizations as well as to replacement of inpatient care by outpatient services. PMID- 8673553 TI - Performance of a modified HIV-1 p24 antigen assay for early diagnosis of HIV-1 infection in infants and prediction of mother-to-infant transmission of HIV-1 in Dar es Salaam, Tanzania. AB - The aim of this study was to determine the utility of an amplified human immunodeficiency virus type 1 (HIV-1) p24 antigen (ag) assay using heated plasma or serum samples for the early diagnosis of HIV-1 infection in infants and for the prediction of the risk of mother-to-infant (MTI) transmission of HIV-1 in Dar es Salaam, Tanzania. The study included 125 samples from 76 infants positive for HIV-1 DNA by the polymerase chain reaction (PCR), 106 samples from 101 PCR negative infants and 116 and 160 samples from seropositive and seronegative mothers, respectively. Samples were boiled to dissociate immune complexes and tested for HIV-1 p24 ag using a p24 ag amplification assay. Reactive samples were confirmed by a neutralization assay. Altogether, 123 of 125 samples from 76 PCR positive infants were positive for p24 ag (sensitivity = 98.7%). HIV-1 p24 ag was found in all 18 samples collected at 1-8 weeks, in 35 of 36 samples collected at 9-26 weeks, in all 40 samples collected at 27-52 weeks, and in 30 of 31 samples collected > 52 weeks after birth. Detection of HIV-1 p24 ag was significantly more common in transmitting mothers (12 of 29, 41.4%) than in nontransmitting mothers (nine of 87, 10.3%) (p < 0.001). Among mothers with p24 antigenemia, the vertical transmission rate was significantly higher (12 of 21, 57%) than in mothers without p24 antigenemia (17 of 95, 18%) (p < 0.001). All samples from 101 PCR-negative children and 160 seronegative mothers were negative for p24 ag (specificity = 100%). We conclude that using heated plasma or serum increases the sensitivity of the p24 ag assay significantly. This modified simple test may be sufficient for the early diagnosis of HIV-1 infection in infants in settings with limited laboratory facilities. It is also useful for prediction of the risk of MTI transmission of HIV-1. PMID- 8673554 TI - Correlation of HIV-1 RNA levels in plasma and heterosexual transmission of HIV-1 from infected transfusion recipients. PMID- 8673555 TI - HTLV-I/II indeterminate serology and natural killer cell expansion. PMID- 8673556 TI - Prevalence of and risk factors for HTLV-I and HTLV-II infection among patients at a hospital in the south Bronx, New York. PMID- 8673557 TI - The Yin and Yang of oxidation in the development of the fatty streak. A review based on the 1994 George Lyman Duff Memorial Lecture. AB - Recent data support the hypothesis that the fatty streak develops in response to specific phospholipids contained in LDL that become trapped in the artery wall and become oxidized as a result of exposure to the oxidative waste of the artery wall cells. The antioxidants present within both LDL and the microenvironments in which LDL is trapped function to prevent the formation of these biologically active, oxidized lipids. Enzymes associated with LDL and HDL (eg, platelet activating factor acetylhydrolase) or with HDL alone (eg, paraoxonase) destroy these biologically active lipids. The regulation and expression of these enzymes are determined genetically and are also significantly modified by environmental influences, including the acute-phase response or an atherogenic diet. The balance of these multiple factors leads to an induction or suppression of the inflammatory response in the artery wall and determines the clinical course. PMID- 8673558 TI - On quantifying plaque size and intima-media thickness in carotid and femoral arteries. Comments on results from a prospective ultrasound study in patients with familial hypercholesterolemia. AB - The aim of the present analysis in an ongoing observational study was to evaluate the possibility of measuring plaque size in ultrasound images from carotid and femoral arteries and the usefulness of quantitative plaque measurements in such a prospective study. Twenty-five patients with carotid plaques were identified in a group of patients with familial hypercholesterolemia (n = 50) compared with 7 subjects in a low-risk control group (n = 47). Only 20 of the 32 recorded plaques were accessible for quantitative follow-up measurements of area, base length, and thickness, which represents only 21% of all subjects investigated. In contrast, paired observations of intima-media thickness in the common carotid artery were available in 98% and in the carotid bulb in 87% of the subjects investigated. In those with paired observations of plaque area available, the data indicated a close relationship between the 2-year change recorded in plaque area and the 2 year change in intima-media thickness measured in a 10-mm-long predefined section of the carotid bulb (r = .81, P < .001, n = 19). The corresponding relationship between change in plaque area and change in a 10-mm-long section of the common carotid artery was r = .38 and P < .05 (n = 20). Quantitative measurements of plaques in the femoral arteries were also performed, but the results from these measurements were in most cases judged not to be useful. However, measurements of intima-media thickness in a 15-mm-long predefined section of the common femoral artery may be performed in a reproducible way in most patients. We conclude that the usefulness of plaque area measurements in prospective studies of the carotid artery seems limited because plaques available for quantitative measurements are present in only a small proportion of subjects. However, reproducible measurements of intima-media thickness in a predefined section of the carotid bulb are achievable in most subjects, and our data indicate that the changes recorded over time in the carotid bulb closely mirror changes occurring in the size of atherosclerotic plaques within the carotid artery region. In addition, present data indicate that measurements of intima-media thickness in the common carotid artery complement measurements performed in the carotid artery bulb in the study of early atherosclerosis. PMID- 8673559 TI - Ultrasound morphology classification of the arterial wall and cardiovascular events in a 6-year follow-up study. AB - A 6-year follow-up based on an arterial morphology classification defined with an ultrasound assessment of carotid and femoral artery bifurcations was conducted on 2322 asymptomatic subjects. Four morphology classes were considered. When 2000 subjects (86% of total subjects; 1124 males, 876 females) completed a 6-year follow-up, the study was terminated. At 6 years, no cardiovascular events were observed in subjects who were in class I (80.05% of the population sample) at inclusion; there were 69 events in classes II, III, and IV (19.95% of the population; incidence, 17.3%); 59 events, including the five deaths, occurred in classes III and IV (10.85% of the population), producing an event incidence of 27.2%. The increased event rate in classes II, III, and IV was significant (log rank test; P < .05, P < .025, and P < .025, respectively). Thus, the arterial morphology classification identified 19.95% of the population (subjects in classes II, III, and IV) in which all events occurred. There was a higher (P < .05) rate of progression of altered arterial morphology in 6 years in classes III (26.5% of subjects progressed) and IV (41.9% progressed) than in classes I and II. The total number of cigarette-years was higher (P < .05) in classes II, III, and IV than in class I. In conclusion, the ultrasound-based arterial classification was useful in selecting from the population sample 80.05% of subjects (class I) who remained event-free for 6 years. All events occurred in class II, III, and IV subjects (19.95%), and all five deaths (0.25% of the population) occurred in classes III and IV (10.85% of the sample). PMID- 8673560 TI - Angiotensin II-induced progression of neointimal thickening in the balloon injured rat carotid artery is AT1 receptor mediated. AB - To investigate the relative importance of AT1 and AT2 receptors in angiotensin II (Ang II)-induced restimulation of neointimal smooth muscle cell (SMC) DNA synthesis and increased neointimal cross-sectional area (CSA), male Wistar rats were subcutaneously infused for 2 weeks with Ang II and losartan, an AT1 receptor antagonist, or Ang II and PD123319, an AT2 receptor antagonist, during the third and fourth week after balloon injury of the left common carotid artery. Concomitantly, all rats received 5-bromo-2'-deoxyuridine to label DNA synthesizing SMCs. Neointimal CSAs and SMC DNA synthesis were compared with control groups that received Ang II, 0.9% NaCl, losartan, or PD123319. Systolic blood pressure (SBP) was measured at different times during the infusion. Ang II induced an increase in SBP that was significantly different from the SBP in the NaCl group. Infusion of Ang II together with losartan reduced the Ang II-induced increase in SBP to levels comparable with those obtained in the NaCl group. Infusion of Ang II+PD123319 caused an increase in SBP that was comparable with the increase in SBP of the Ang II group and significantly different from the SBP of the NaCl group. Infusion of losartan or PD123319 alone did not affect SBP. Ang II significantly enhanced neointimal CSA (47%, P < .05) compared with the control group infused with NaCl. Losartan significantly reduced Ang II-induced neointimal thickening (neointimal CSA, -37%, P < .05). Infusion of PD123319 together with Ang II did not affect Ang II-induced neointimal thickening. Losartan or PD123319 alone did not reduce neointimal thickening, since the neointimal CSAs in these groups did not differ from the neointimal CSA of the NaCl group. Comparable effects were found for SMC DNA synthesis in the neointima. Ang II infusion increased neointimal SMC DNA synthesis. Addition of losartan reduced the fraction of DNA-synthesizing neointimal SMCs from 23.7 +/- 2.1% in the Ang II group to 12.8 +/- 1.8% in the Ang II+losartan group, whereas the labeling fraction in the neointima remained 26.6 +/- 3.1% in the Ang II+PD123319 group. The labeling fractions in the neointimas of the groups that received losartan or PD123319 alone did not differ from the labeling fraction in the NaCl group. These data indicate that AT1 but not AT2 receptors mediate the progression of neointimal thickening induced by delayed application of Ang II in the injured left carotid artery in the rat. Furthermore, these data suggest that AT1 and AT2 receptors are not involved in the regulation of normal growth of a neointima in the third and fourth week after balloon injury. PMID- 8673561 TI - Antithrombin and atherosclerosis in the Rotterdam Study. AB - Antithrombin is a potent inhibitor of thrombotic tendency. Whether atherosclerotic disease is associated with high or low antithrombin is unclear. Studies of the relation between antithrombin and presence of arterial disease have shown contrasting results. In the Rotterdam Study, a single-center, population-based cohort study of 7983 subjects aged 55 years and older, the association between atherosclerosis and antithrombin was evaluated. The ratio of ankle to arm blood pressure is a graded marker for atherosclerosis and provides the opportunity to investigate nonlinear associations. In the first 1427 participants of the Rotterdam Study who did not use anticoagulants, both antithrombin and the ratio of ankle to arm blood pressure were measured. In men the association between the two was quadratic: antithrombin activity was increased in men with moderate peripheral arterial atherosclerosis compared with those without, and in men with more severe atherosclerosis it was decreased. In women the association was linear: a decreased ratio of ankle to arm pressure was associated with increased antithrombin activity. These associations were independent of smoking, body mass index, serum lipids, fibrinogen, and factor VIIc. We propose that antithrombin activity rises in response to increased risk of cardiovascular disease and also in response to the presence of atherosclerosis, whereas antithrombin may decrease with increasing severity of the atherosclerotic process in men. This may explain the contrasting results found in previous studies. Changes in antithrombin over time might be useful in predicting the risk of cardiovascular disease and progression. PMID- 8673562 TI - Uptake of vWF-anti-vWF complexes by platelets in suspension. AB - Efforts to identify the translocation of glycoprotein (GP) Ib/IX receptors, either bound to von Willebrand factor (vWF) or not, from exposed surfaces to interior membranes of thrombin-activated platelets in suspension have been unsuccessful. To observe vWF uptake by platelets, we added an anti-vWF antibody and staphylococcal protein A-gold (to act as a marker for the antibody) to an incubation medium containing washed platelets and bovine plasma vWF or ristocetin activated human vWF. Thin sections of platelets incubated for 10, 20, or 30 minutes with vWF but without antibody revealed no internalization and minimal changes in the original discoid form. Over the same 30-minute period with anti vWF, however, GPIb/IX-vWF-anti-vWF complexes were cleared from cell exteriors to channels of the open canalicular system. Engorgement of the open canalicular system with vWF multimers resulted in changes in shape, internal transformation, and degranulation. Physical changes associated with anti-vWF-induced uptake of vWF are not seen in platelets that are involved in hemostatic plug formation or clot retraction. PMID- 8673563 TI - Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. AB - Modest elevations of circulating homocyst(e)ine are common in patients with vascular disease. We explored in normal and coronary artery disease (CAD) populations the distribution of a mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene that results in enzyme thermolability and reduced activity and in homocyst(e)ine elevation to assess its relevance to risk. We identified the C to T substitution at the MTHFR locus and compared the distributions of genotypes in 565 patients aged < or = 65 years without and with angiographically documented CAD and in 225 healthy subjects. In the patients, we also assessed interrelations between genotypes and CAD occurrence and severity, as well as standard risk factors. The frequency of homozygotes for the mutation was the same in patients with and without CAD and in healthy subjects (11.6%, 11.0%, and 10.7%, respectively: P > .5 for each). There was also no excess among the 419 patients with severe disease (ie, one or more vessels with > 50% luminal obstruction) compared with those with no or mild CAD (odds ratio: 1.004; 95% confidence interval: 0.59 to 1.70). Homozygosity for the mutation was also not associated with a history of myocardial infarction or the presence or severity of angina. However, body mass index increased linearly with the presence of the mutant allele (P = .005), and the mutation and hypertension were weakly associated (P = .036). We conclude that the MTHFR genotype is not a risk factor for coronary disease in this Australian population but that the strong association found with body mass index should be explored further. PMID- 8673564 TI - Antibodies to CD36 (GPIV) inhibit platelet adhesion to subendothelial surfaces under flow conditions. AB - The membrane glycoprotein CD36 (glycoprotein [GP] IV) has previously been shown to accelerate the initial interaction of platelets with purified type I collagen in both static and flow systems. In the present study, the role of CD36 on platelet interaction with physiologically relevant collagenous surfaces was addressed. Using arterial subendothelium (SE) and endothelial cell extracellular matrix (ECM), studies were performed under flow conditions with annular and parallel-plate perfusion chambers, respectively, at a shear rate of 800 s-1 for 2, 5, and 10 minutes. Perfusates consisted of citrated normal blood samples incubated with Fab fragments of a monospecific polyclonal anti-CD36 antibody or with each of three new anti-CD36 monoclonal antibodies (MoAbs) that inhibit platelet adhesion to purified type I collagen in a static system (131.4, 131.5, and 131.7). Perfusions over SE were also carried out using citrated blood samples from a Naka-negative donor, whose platelets lack CD36. Morphometric evaluation of the perfused samples showed that polyclonal anti-CD36 Fab and the three monoclonal anti-CD36 antibodies inhibited platelet adhesion to the two substrates by 40% after 2 minutes of perfusion and by 30% after 5 minutes (P < .005 on SE and P < .01 on ECM), but at 10 minutes, significant inhibition was seen only on SE with polyclonal anti-CD36 Fab. Similar inhibitions were seen with Naka negative platelets on SE. These studies demonstrate that CD36 plays a role in the early stages of platelet adhesion to physiologically relevant subendothelial surfaces. PMID- 8673565 TI - Selective recruitment of ApoB-48 for the assembly of VLDL in rat triacylglycerol enriched hepatocytes. AB - Primary rat hepatocyte cultures were enriched in cellular triacylglycerol (TAG) by exposure to extracellular oleate for 3 days. Control cells were cultured for the same time without oleate. The large increase in TAG secretion into the medium of TAG-enriched cells during the final 24 hours (225 +/- 30 versus 40 +/- 10 micrograms/mg cell protein [control cells], P < .01) was not accompanied by a similar change in apolipoprotein B (apoB) secretion (4.22 +/- 0.94 versus 3.72 +/ 0.75 micrograms/mg per 24 hours, respectively). Instead, TAG-enriched cells recruited a larger proportion of apoB for the synthesis of very low density lipoprotein (VLDL), the secretion of which was substantially higher under these circumstances (1.46 +/- 0.39 versus 0.34 +/- 0.06 microgram apoB per milligram cell protein per 24 hours, P < .05). The increase in VLDL assembly was accompanied by a selective 2.5-fold increase (P < .05) in the specific recruitment of apoB-48. There was no significant increase in the amount of apoB 100, which appeared in the VLDL fraction when cells were enriched with TAG. Under these circumstances there was an increase in net cellular synthesis of apoB-48 (5524 +/- 667 versus 2505 +/- 598 disintegrations per minute per milligram protein per hour, P < .05). The net cellular synthesis of apoB-100 was unchanged compared with that observed in control cell cultures (1548 +/- 237 versus 2000 +/ 897 dpm/ mg per hour, respectively). A large proportion of the total secreted apoB was associated with small particles of density higher than VLDL, even when VLDL output was maximally stimulated, suggesting that apoB was oversecreted and in excess of the cells' requirement to transport TAG. PMID- 8673566 TI - The effect of bicycling helmets in preventing significant bicycle-related injuries in children. AB - OBJECTIVE: To identify bicycle-related injuries in children and the effect of helmet use on injury patterns and prevention. DESIGN: A prospective cohort of injured children with case-control design looking at serious head injuries and helmet use. SETTING: A tertiary care childrens' hospital emergency room. PATIENTS: All patients presenting between April 1, 1991 and September 30, 1993, between the ages of 3 and 16 years, with bicycle-related injuries were included. INTERVENTION: The Childrens' Hospital Injury Research and Prevention Program (CHIRPP) Database was used. Standardized information collected on each child included age and sex of the child; nature, location, and time of accident/injury; whether any safety devices were being used at the time of the accident; and the attending physician's determination of the injury(s) and treatment rendered. MAIN OUTCOME MEASURES: Injuries were categorized as major or minor, based upon a consensus of the authors, in a retrospective fashion. RESULTS: Separate bicycle accidents (n = 699) were recorded resulting in 856 injuries. Only 13.7% of the children were wearing helmets at the time of their accidents. Seventy-six serious head injuries were recorded. The risk of serious head injury was significantly greater when a helmet was not worn (chi 2 0.01 < p < 0.05) This represents an odds ratio of 3.12 [confidence interval (CI) = 95% 1.13-8.75]. There was no significant difference in terms of serious injuries overall comparing helmeted and nonhelmeted children (odds ratio = 1.11, 95% CI = 0.72-1.72). CONCLUSIONS: Helmets afford a protective effect with respect to serious head injuries. PMID- 8673567 TI - Checking from behind in ice hockey: a study of injury and penalty data in the Ontario University Athletic Association Hockey League. AB - OBJECTIVE: In this study we investigated the association between the introduction of the checking-from-behind rule (CFB) in the Ontario University Athletic Association (OUAA) hockey league and player safety. DESIGN: Injury and penalty data were collected for the 3 years prior to and the 3 years following the introduction of the CFB rule in 1989. PARTICIPANTS: There were 653 injury records and 389 penalty records for 3 OUAA teams that had complete records for the 6 years. MAIN OUTCOME MEASURE: In the absence of any a priori evidence, the null hypotheses of no association between the CFB rule and injuries or penalties, apart from a logical assumption that there would be a pre-/post difference in CFB penalties, were tested. RESULTS: Although the injury rates for each of the body segments (heat/neck, back, shoulder) demonstrated a significant independence (chi 2 = 56.66, df = 2, p < 0.001) from each other in relation to the pre-/post rule period, only the CFB penalty rates exhibited significant independence (chi 2 = 16.58, df = 2, p < 0.001) from body contact and stick-related penalties. CONCLUSIONS: These findings suggest that the introduction of the CFB rule was related to a safer playing environment as reflected by a pre-/post rule decrease in two of three categories of injury, increased CFB penalty rates, and the absence of significant association between the CFB rule and the decreases in body contact penalties and stick-related infractions. It appears that the medical community, with the supporting clinical data demonstrating CFB-related injuries, has helped create enhanced safety without significantly changing player behavior. PMID- 8673568 TI - Physician factors affecting patient willingness to comply with exercise recommendations. AB - OBJECTIVE: To evaluate how physician factors such as weight, exercise habits, and humanistic traits could influence patient willingness to comply with exercise recommendations. DESIGN: Survey questionnaire. SETTING: University-based Family Medicine Clinic. PATIENTS: 411 consecutive established patients of the Family Medicine Clinic. MAIN OUTCOME MEASURES: Selected Physician characteristics that patients believed would increase their willingness to comply with exercise recommendations. Results were compared with patient demographics to determine possible effects of physician characteristics on patients acceptance of exercise recommendations. RESULTS: Patients with higher education levels could be positively influenced by a physician being of appropriate weight, a regular exerciser, and a nonsmoker, and enlisting use of other experts, negotiating an exercise program, providing exercise counseling, and being their primary provider. Patients with higher income levels could be positively related to a physician's being of appropriate weight, and a nonsmoker, negotiating an exercise program, and enlisting use of other experts. Female patients could be positively influenced by physicians being well groomed, well dressed, accessible, and good listeners. Patients who regularly exercise could be positively influenced by a physician's appropriate weight and exercise regimen. CONCLUSIONS: Physicians may have a positive impact on patient willingness to comply by prescribing exercise and providing education and detailed guidance for all candidates. The study also showed that physicians' negotiating exercise programs and being good "exercise" role models is very important. PMID- 8673569 TI - Screening adolescent athletes for exercise-induced asthma. AB - OBJECTIVE: To pilot test an exercise-induced asthma (EIA) screening program using a submaximal step-test and pulmonary function test (PFT) to identify athletes with EIA and to determine if a physical examination or self-reported history could be used to predict the existence of EIA. DESIGN: Screening and diagnostic testing using a convenience sample. SETTING: Birmingham, Alabama, during athletic preparticipation examination (PPE). SUBJECTS: Fifty-two African-American, male football players aged 14-18 years being evaluated for participation in scholastic athletics. No athlete refused participation. Four were excluded because of need for further evaluation unrelated to any pulmonary condition. INTERVENTION: Each athlete completed a medical history, allergy history, physical examination, preexercise pulmonary function test (PFT), submaximal step-test, and a series of postexercise PFTs. MAIN OUTCOME MEASURES: Major outcome measurements were changes in forced expiration volume in 1s (FEV1) or peak expiratory flow rate (PEFR) after completing an exercise challenge. RESULTS: Seventeen of 48 athletes had a > or = 15% decrease in PEFR after exercise. Nine of 48 athletes had a > or = 15% decrease in FEV1 after exercise. The only self-reported item that differentiated subjects with normal and abnormal PFTs was a personal history of asthma (p < 0.05). CONCLUSION: Many athletes can be identified as having abnormal PFTs by use of a submaximal step-test as an exercise challenge. Self-reporting questionnaires and PPEs do not appear to be sensitive enough to identify athletes with this condition. If validated by future studies, this protocol could be used for the diagnosis of EIA. PMID- 8673570 TI - Fractures of the lateral process of the talus: a clinical review. "Snowboarder's ankle". AB - OBJECTIVE: This is a review article discussing the incidence, aetiology, investigation, and management of fractures of the lateral process of the talus, an uncommon but increasingly recognised complication of snowboarding. DATA SOURCES: The data regarding aetiology, investigation, and management of these fractures were obtained through a comprehensive literature review utilising the Medline, Sport discus, Medline Orthopaedic, and Cinahl databases. Injury data were obtained through published prospective epidemiological studies of snowboarding injuries. STUDY SELECTION: All studies of talar fractures, particularly of the lateral process, were included in the review. All prospective and retrospective studies of snowboarding injuries were reviewed. DATA SYNTHESIS: The mechanism of this injury appears to be a combination of dorsiflexion and inversion of the ankle. The combination of soft-shell snowboarding boots and aerial maneuvers increase the likelihood of injury. Clinically these injuries resemble severe ligamentous ankle sprains and are commonly misdiagnosed. The fractures can be classified into three subtypes based on the severity of the bony injury. The management of each injury subtype differs and although no prospective treatment trials have been performed the published risk of long term degenerative subtalar joint damage warrant aggressive early management of this injury. CONCLUSIONS: With the increasing popularity of snowboarding, the possibility of this injury should be considered in all ankle injuries related to this sport. Once diagnosed, management guidelines should be followed in order to minimise long term problems. PMID- 8673571 TI - Hip arthroscopy for posttraumatic loose fragments in the young active adult: three case reports. AB - PURPOSE. To demonstrate the usefulness of arthroscopy in the management of posttraumatic loose fragments of the hip in the young active adult. CASE SUMMARY. Operative arthroscopy of the hip has been performed successfully in 30 consecutive cases, with the patient supine. Three of these procedures were performed for posttraumatic loose fragments in young athletic males. All three underwent debridement. The age ranged from 17 to 28 years (average 23 years). Follow-up ranged from 14 to 33 months (average 22 months). Although each case was unique, each had a successful outcome. RELEVANCE. This reflects the merits of arthroscopic techniques in the assessment and management of specific disorders about the hip. The technique is safe and reproducible. PMID- 8673573 TI - Determining the presence of scaphoid fracture with a day 4 bone scan. PMID- 8673572 TI - Risk factors for ankle injury in college-aged athletes. PMID- 8673574 TI - Natural history of untreated anterior cruciate tears. PMID- 8673575 TI - Smoking habits and long-term decline in physical fitness and lung function in men. PMID- 8673576 TI - Immunologic changes associated with strenuous exercise. PMID- 8673577 TI - Influence of aerobic versus anaerobic exercise on male reproductive hormones. PMID- 8673578 TI - The risk of heat stress in Atlanta '96. PMID- 8673579 TI - Clinical sports medicine training and accreditation: the United States experience. PMID- 8673580 TI - Effects of rapid weight loss and wrestling on muscle glycogen concentration. AB - OBJECTIVE: To examine the effect of energy restriction and wrestling on muscle glycogen content in highly-trained male wrestlers. DESIGN: Randomized, unblinded intervention trial. SETTING: McMaster University Nutrition and Metabolism Research Laboratory. PARTICIPANTS: Twelve highly trained male wrestlers volunteered as subjects and were randomly assigned to one of two groups (Group A, n = 6; Group B, n = 6) as defined below. ASSESSMENT OF RISK FACTORS: All subjects were free of medical conditions that would preclude participation in the study and all had performed rapid weight loss at least three times/year with no medical complications. INTERVENTIONS: Group A: simulated wrestling tournament, four 5-min wrestling bouts ( > 7 h) following a 5% body weight loss and 17 h repletion period; Group B: 5% weight loss through energy restriction (1,141 kcal/day), exercise, fluid restriction, and dehydration methods (sauna) > 72 h. MAIN OUTCOME MEASURES: Group A: muscle glycogen content before and after wrestling tournament and plasma lactate after each bout; Group B: muscle glycogen before and after weight loss. RESULTS: Group A: no significant effect on muscle glycogen concentration, yet large increases were observed in blood lactate concentrations (up to 14.7 mmol/L); Group B: weight loss resulted in a 54% (p < 0.018) reduction in muscle glycogen concentration. CONCLUSIONS: The weight loss methods commonly performed by wrestlers resulted in large decreases in muscle glycogen concentration that were largely reversed during the 17-h repletion period between weigh-in and the start of the competition; participation in a wrestling tournament did not have a significant impact upon biceps brachii glycogen concentration when ad libitum feeding is allowed between matches. PMID- 8673581 TI - Stress fractures: a review of 180 cases. AB - OBJECTIVE: To review the cases of stress fracture seen over a 2-year period at a sports medicine clinic. DESIGN: One hundred and eighty cases diagnosed as stress fractures on the basis of clinical picture and radiological evidence were reviewed. The following features of each stress fracture were noted: age, sex, site, sport/activity. SETTING: A sports medicine centre in Melbourne, Australia. PATIENTS: The average age was 21.8 years. Seventy eight of these stress fractures were seen in women, 102 in men. RESULTS: The most common sites of stress fractures were the metatarsal bones (n = 42), tibia (n = 36), fibula (n = 30), tarsal navicular (n = 26) and pars interarticularis (n = 17). The most common sport was track (n = 54). Other common sports activities were jogging/distance running (n = 35), dance (n = 32) and Australian football (n = 14). The distribution of sites of stress fractures varied from sport to sport. Among the track athletes (n = 54), navicular (n = 19), tibia (n = 14) and metatarsal (n = 9) were the most common stress fracture sites. The distance runners (n = 35) predominantly sustained tibia (n = 15), and fibula (n = 8) stress fractures, while metatarsal stress fractures (n = 18) were the most common among dancers. The distribution of sports varied with the site of the stress fracture. In the metatarsal stress fractures (n = 42), dance was the most common activity. Distance running (n = 15) and track (n = 14) were the most common sports in the group to have sustained tibia stress fractures (n = 36). Track athletes (n = 14) were particularly prevalent in the navicular stress fracture group (n = 26). CONCLUSION: The distribution of sites of stress fractures in this study shows some differences from previously published studies. PMID- 8673583 TI - Incidence and severity of injuries resulting from amateur boxing in Ireland. AB - OBJECTIVE: To determine the incidence, pattern, and severity of injuries resulting from participation in amateur boxing. DESIGN: A prospective 5-month survey of injuries which occurred during competitive amateur boxing and training. SETTING: Amateur boxing competitions held in Dublin between November 1992 and March 1993, and the six largest amateur boxing clubs in Dublin. PARTICIPANTS: All the competitors in the tournaments and the > 16 year old members of the boxing clubs. INTERVENTIONS: Participation in competitive amateur bouts and/or boxing training. MAIN OUTCOME MEASURES: Incidence, pattern, and severity of injuries sustained in competition and training. RESULTS: The incidence of injuries in competition was 0.92 injuries per man-hour of play (or 0.7 injuries per boxer per year), while the incidence in training was 0.69 injuries per boxer per year. Cerebral injuries were reported only in competition, most of these being mild concussion. Hand, wrist and facial injuries were related to direct impact and occurred more frequently in competition than training, while injuries to other body parts were predominantly chronic and training-associated. Shoulder and knee injuries were the most debilitating injuries seen. CONCLUSIONS: The yearly risk of injury resulting from participation in amateur boxing is relatively low when compared with other sports. Cerebral injuries, which occur almost exclusively in competition, are predominantly mild concussions. PMID- 8673582 TI - Controlled prospective neuropsychological assessment of active experienced amateur boxers. AB - OBJECTIVE: To use a practical battery of eight neuropsychological tests for the detection of an association between amateur boxing and chronic traumatic encephalopathy. DESIGN: A controlled prospective neuropsychological study over a 15-18-month period. SETTING: Dublin, Ireland. March 1992 to September 1993. PARTICIPANTS: Twenty experienced actively competing amateur boxers and 20 controls matched for age and socioeconomic status. INTERVENTIONS: Participation in competitive amateur boxing and training. MAIN OUTCOME MEASURES: Absolute scores, and changes in scores, in the neuropsychological tests. RESULTS: At the end of the study period, the boxers performed significantly better then the controls in both the Trail-Making Tests A and B (TMT-A, TMT-B), whereas the control group's scores for the Finger Tapping Tests (FTT) were significantly higher than those of the boxers. The boxer's scores for the dominant-hand FTT showed a significant deterioration, but there was no association between this change and boxing exposure. CONCLUSIONS: There was no evidence of neuropsychological impairment in the boxers as compared with socioeconomically, educationally and age-matched controls, and there was no association between boxing exposure and performances in any of the neuropsychological tests used. There is accumulating evidence that amateur boxing is not associated with chronic traumatic encephalopathy but longer term prospective studies are needed. PMID- 8673584 TI - Hearing protection and cast saw noise. AB - Cast saw noise was measured and found to be within the limit where employee hearing protection was not required by current Occupational Safety and Health Administration standards. Wearing of hearing protectors was found useful in diminishing anxiety associated with cast removal, especially in pediatric patients. PMID- 8673585 TI - Injured stable knee with acute effusion: MRI evaluation. AB - This study was done to evaluate the magnetic resonance imaging (MRI) findings in acute traumatic effusions of the knee without ligament instability or radiographic abnormality other than the effusion. On reviewing the charts of 927 patients who had MRI of the knee, we found 114 patients who met the following criteria for inclusion in this study: (1) acute effusion by examination or history, (2) ligament stability on examination, and (3) normal findings on radiographs (excluding effusion). The total of 144 pathologic diagnoses made by MRI included bone injury (53%), disruption of the anterior cruciate ligament (19%), sprain of the medial collateral ligament (12%), medial meniscus tear (11%), lateral meniscus tear (5%), and rupture of the posterior cruciate ligament ( < 1%). Eight studies (7%) were read as normal. These MRI data are significantly different from data of previous studies using arthroscopy to evaluate acute knee injuries without ligament instability. The findings more accurately reflect the injury pattern seen in this setting because MRI can show both bone and soft tissue injury. From this study, we conclude that bone injury is the most common cause of acute effusion in the patient with ligament stability and normal radiographs. PMID- 8673587 TI - Effective management of osteomyelitis after grade III open fractures. AB - We report results and follow-up on a series of 34 patients who had chronic osteomyelitis resulting from complex open fractures. Treatment included debridement followed by cancellous bone grafting and simultaneous free flap transfer for coverage and revascularization. Thirty-one patients remained in the final study. For the 24 patients with lower extremity injuries, follow-up averaged 45.4 months (range, 10 to 84 months). There was a 4% recurrence rate of osteomyelitis (1 of 24 patients). Follow-up on the 7 patients with upper extremity injuries averaged 39.8 months (range, 22 to 60 months). There were no recurrences in this group. Serial debridement followed by simultaneous bone grafting and free flap transfer may be the most effective method available for the treatment of chronic osteomyelitis after grade III open fractures. This method produces the same results currently reported in the literature, but with one less operation. PMID- 8673586 TI - Cryopreserved anterior cruciate ligament allografts in a canine model. AB - This study was done to determine the clinical and biomechanical properties of cryopreserved anterior cruciate ligament allografts at 3, 6, 9, and 24 months after transplantation. A companion study of autografts was done to evaluate the effects of the surgical procedure and preservation on the tissue. The knee joints of 69 mongrel dogs (allograft n = 34, autograft n = 35) weighing 17 kg to 25 kg were grafted. Biomechanical results showed that maximum load was less in allografts than in autografts at each time interval. Deformation and slope were not significantly different between allograft and autograft. An apparent delay in revascularization and cellular repopulation was found in allografts compared with autografts, and collagen type I/type III ratios were similar in both grafts. DNA analysis indicated complete replacement of DNA in the graft by the host. Allografts provide adequate functional stability for daily activities in the canine model up to 2 years after transplantation. Biomechanical properties were relatively poor in allografts, which may lead to failure under more strenuous activity. The biologic similarity to autografts may indicate future remodeling potential. PMID- 8673588 TI - Cold extremities: investigation and management of Raynaud's phenomenon. AB - Since Raynaud's description in 1862 of triphasic color changes in the digits, little progress has been made in diagnosis and treatment of this entity. Recent technologic advances such as laser Doppler fluxmetry and isolated cold stress testing offer promise in diagnosis and measuring response to various drugs. We review the pathophysiology and the clinical and laboratory evaluation of Raynaud's phenomenon, as well as medical and nondrug management. PMID- 8673589 TI - MR imaging of knee ligaments. AB - MR imaging is an excellent modality with which to diagnose injuries of the major knee ligaments preoperatively. Strict attention to the mechanism of injury and physical examination findings and to MR imaging acquisition and section selection are essential to diagnostic success. PMID- 8673590 TI - Treatment of screw hole defects using bone graft materials: a histologic and biomechanic study. AB - We surgically applied compression plates, secured with cortical screws, to the anterolateral surface of each radius in 20 dogs. Five weeks later, the plates and screws were removed. The dogs were then divided into four groups of 5, and each group had the screw holes in the left radii filled with a different form of bone graft material. The screw holes in the right radii received no graft material and served as controls. Five weeks later the dogs were euthanized, and the radii were removed and torqued to failure. All bones failed through a previous screw hole. An analysis of variance comparing all grafted radii to the ungrafted controls revealed no significant difference in torque to failure. This suggests that both grafted and ungrafted screw holes still increase stress at 5 weeks, and any period of protection after plate removal should be longer than 5 weeks. However, histology revealed that the holes filled with graft material had, in every case, more bone in the screw holes than did the holes in the ungrafted controls. PMID- 8673591 TI - Imaging of pelvic trauma. PMID- 8673592 TI - Congenital constriction band syndrome. PMID- 8673593 TI - Swiss-Prot out of the fire. PMID- 8673594 TI - Not just your average structures. PMID- 8673595 TI - Balancing ATP in the cell. PMID- 8673596 TI - The complexity of a respiratory complex. PMID- 8673597 TI - Extending molecular systematics to the third dimension. PMID- 8673598 TI - Nucleoside-analogue resistance involves the p66 subunit of HIV-1 RT. PMID- 8673599 TI - Picture story. The helix from which the arch was made. PMID- 8673600 TI - The three-dimensional structure of the first domain of neural cell adhesion molecule. PMID- 8673601 TI - Structural basis for specificity of Grb2-SH2 revealed by a novel ligand binding mode. PMID- 8673602 TI - Combining Laue diffraction and molecular dynamics to study enzyme intermediates. AB - Two separate techniques, Laue diffraction and computational molecular dynamics (MD) simulations, have been independently developed to allow the visualization and assessment of transient structural states. Recent studies on isocitrate dehydrogenase show that computational MD simulations of an enzymatic Michaelis complex are consistent with difference Fourier electron density maps of the same structure from a Laue experiment. The use of independent MD studies during crystallographic refinement has allowed us to assign with confidence a number of additional contacts and features important for hydride transfer. We find that unrestrained independent MD simulations provides a very useful method of cross validation for highly mobile atoms in regions of experimental density that are poorly defined. Likewise, information from Laue difference maps provides information about substrate conformation and interactions that greatly facilitate MD simulations. PMID- 8673603 TI - A novel mode of carbohydrate recognition in jacalin, a Moraceae plant lectin with a beta-prism fold. AB - Jacalin, a tetrameric two-chain lectin (66,000 Mr) from jackfruit seeds, is highly specific for the tumour associated T-antigenic disaccharide. The crystal structure of jacalin with methyl-alpha-D-galactose reveals that each subunit has a three-fold symmetric beta-prism fold made up of three four-stranded beta sheets. The lectin exhibits a novel carbohydrate-binding site involving the N terminus of the alpha-chain which is generated through a post-translational modification involving proteolysis, the first known instance where such a modification has been used to confer carbohydrate specificity. This new lectin fold may be characteristic of the Moraceae plant family. The structure provides an explanation for the relative affinities of the lectin for galactose derivatives and provides insights into the structural basis of its T-antigen specificity. PMID- 8673604 TI - De novo design and structural analysis of a model beta-hairpin peptide system. AB - We have designed de novo a simple, context-free, model linear peptide system to fold into a regular beta-hairpin structure, with three-residue beta-strands connected by a type I' beta-turn. CD and NMR analysis of this peptide in aqueous solution show that the peptide folds into the expected conformation. Structural characterization of three peptide variants in which some of the strand side chains have been substituted by alanine, demonstrates that inter-strand side chain-side chain interactions are essential for beta-hairpin formation. This simple model system will help to isolate the factors behind beta-sheet formation, and contribute useful information about de novo protein design. PMID- 8673605 TI - Refolding and unfolding kinetics of the equilibrium folding intermediate of apomyoglobin. AB - Little is known about the kinetic process in which stable intermediates in protein folding are formed: whether their folding is highly cooperative (two state) or weakly cooperative is controversial. We report here that the folding and unfolding kinetics of the pH 4-stable intermediate (I1) of apomyoglobin are measurable, in the millisecond time range, when monitored by stopped-flow measurements of tryptophan fluorescence. The kinetics confirm that folding of I1 is strongly cooperative, but there is a burst phase (missing amplitude) in unfolding. If the faster steps in unfolding of I1 can be measured directly by suitable fast-reaction methods, they will give information about the nature of the folding transition. PMID- 8673606 TI - The three-dimensional structure of apopain/CPP32, a key mediator of apoptosis. AB - Cysteine proteases related to mammalian interleukin-1 beta converting enzyme (ICE) and to its Caenorhabditis elegans homologue, CED-3, play a critical role in the biochemical events that culminate in apoptosis. We have determined the three dimensional structure of a complex of the human CED-3 homologue CPP32/apopain with a potent tetrapeptide-aldehyde inhibitor. The protein resembles ICE in overall structure, but its S4 subsite is strikingly different in size and chemical composition. These differences account for the variation in specificity between the ICE- and CED-3-related proteases and enable the design of specific inhibitors that can probe the physiological functions of the proteins and disease states with which they are associated. PMID- 8673607 TI - A ligand-gated, hinged loop rearrangement opens a channel to a buried artificial protein cavity. AB - Conformational changes that gate the access of substrates or ligands to an active site are important features of enzyme function. In this report, we describe an unusual example of a structural rearrangement near a buried artificial cavity in cytochrome c peroxidase that occurs on binding protonated benzimidazole. A hinged main-chain rotation at two residues (Pro 190 and Asn 195) results in a surface loop rearrangement that opens a large solvent-accessible channel for the entry of ligands to an otherwise inaccessible binding site. The trapping of this alternate conformational state provides a unique view of the extent to which protein dynamics can allow small molecule penetration into buried protein cavities. PMID- 8673608 TI - Substrate-assisted catalysis in cytochrome P450eryF. AB - A highly conserved threonine in the active site of cytochromes P450 has been proposed to participate in O2 binding and cleavage. Cytochrome P450eryF is unusual in having alanine in place of this threonine and an ordered active site water molecule (Wat 519) which is hydrogen bonded to the substrate 5-hydroxyl group and is in position to operate as an acid catalyst required for cleaving dioxygen. To asses the role of this alanine residue and Wat 519 in catalysis, two mutant forms of P450eryF (Ala --> Ser,Ala --> Thr) and a substrate analogue lacking a 5-hydroxyl group were examined using kinetic, spectral and crystallographic techniques. In each case decreased catalytic activity was correlated with a loss or repositioning of Wat 519. These findings suggest that P450eryF utilizes the substrate to assist in the acid-catalysed dioxygen bond cleavage reaction. PMID- 8673610 TI - Historical and contemporary aspects of communicable disease control. PMID- 8673609 TI - Bacterial chitobiase structure provides insight into catalytic mechanism and the basis of Tay-Sachs disease. AB - Chitin, the second most abundant polysaccharide on earth, is degraded by chitinases and chitobiases. The structure of Serratia marcescens chitobiase has been refined at 1.9 A resolution. The mature protein is folded into four domains and its active site is situated at the C-terminal end of the central (beta alpha)8-barrel. Based on the structure of the complex with the substrate disaccharide chitobiose, we propose an acid-base reaction mechanism, in which only one protein carboxylate acts as catalytic acid, while the nucleophile is the polar acetamido group of the sugar in a substrate-assisted reaction. The structural data lead to the hypothesis that the reaction proceeds with retention of anomeric configuration. The structure allows us to model the catalytic domain of the homologous hexosaminidases to give a structural rationale to pathogenic mutations that underlie Tay-Sachs and Sandhoff disease. PMID- 8673611 TI - Cholera: outlook for the twenty-first century. PMID- 8673612 TI - The tuberculosis story: from Koch to the year 2000. PMID- 8673613 TI - Smallpox and measles in Mali: contrasting control strategies and outcomes. PMID- 8673614 TI - An epidemiologic analysis of the ten plagues of Egypt. PMID- 8673615 TI - Construction of a self-complementary nucleoside from deoxyguanosine. AB - The 8-hydroxyguanine:adenine mispairing scheme that spontaneously occurs in vivo through oxidative metabolism of DNA was edited to obtain a pair closely fitting the Watson-Crick geometry in which 2 purine bases of identical structure but oppositely rotated in the syn and anti configurations are hydrogen-bonded. The structure thus designed, 2-amino-8-hydroxypurine, was synthesized as a DNA precursor from deoxyguanosine in 8 steps by oxidation at carbon 8 of guanine followed by reduction at carbon 6. Polydeoxynucleotides embodying this self complementary base are expected to undergo direct copying processes through polymerase catalysis. PMID- 8673616 TI - What parameters can be used for individual acoustic recognition by the greater flamingo? AB - The greater flamingo Phoenicopterus ruber is a colonial bird for which acoustic communication plays a great role, in particular during the mating period. The study of contact calls emitted by the adults allow enables identification of some acoustic parameters which may be used for individual recognition. It appears that the frequential values of the harmonics, the distribution of energy in the spectrum as well as beats (mimicking amplitude modulations) are susceptible to represent individual markers. On the contrary, the coding of the individual identity does not depend on frequency modulation since this latter is practically lacking. These results are remarkably similar to those obtained from another colonial bird species, the emperor penguin Aptenodytes forsteri, and may correspond to signal adaptations to special acoustic constraints of the colonial way of life. PMID- 8673617 TI - Polarized microscopy study of an antennal sensillum of Triatoma infestans: an ordered distribution of chitin fibrils and associated components. AB - Aspects of the molecular organization of the antennal sensilla trichodea of Triatoma infestans have been investigated with the use of both polarization and scanning electron microscopy. The sensilla have a smooth surface with minute bulbs on the tapered end. They showed strong positive birefringence, irrespective of the refractive index of the imbibing medium. The plotting of a form birefringence (FB) curve for native material showed slight increases in the retardation values with increases of the refractive index and at least 2 inflection points. On the other hand, a FB curve constructed for alkali-treated structures reveals higher values for the form birefringence and slight decreases in retardation values with raising refractive index. These results demonstrate that chitin fibrils are preferentially aligned with the sensilla long axis. Interestingly, the alkali treatment introduced no alterations in the retardation values measured at n = 1,435, which corresponds to the intrinsic birefringence of chitin. It is suggested that components removed by alkali-treatment have electronic transitions disposed perpendicularly to the chitin filaments and that the ill definition of the form birefringence curve of chitin is associated with the incomplete removal of chitin-associated components, which keep chitin fibrils apart from but strongly bound to each other. In addition, it is apparent from the results that cross-linking in a system with a parallel array of the chitin fibrils occurs predominantly perpendicular to the chitin fibrils. PMID- 8673618 TI - Specific detection of the microsporidia Encephalitozoon intestinalis in AIDS patients. AB - The microsporidia Encephalitozoon intestinalis is an opportunistic pathogen responsible for severe gastrointestinal diseases and disseminated infection in AIDS patients. No light-microscopical method allows the specific detection of this unicellular parasite and up to this date, only electron microscopy could confirm the diagnosis of the species. We propose a method combining the non specific labelling of microsporidian spores by the fluorochrome Uvitex 2B and an indirect immunofluorescent assay with a polyclonal antibody specifically directed against E. intestinalis. Preliminary data demonstrate the specificity of this antibody. This method enables the distinction between E. intestinalis and Enterocytozoon bieneusi an other microsporidian also associated with gastrointestinal infection. Due to the precocious detection of E. intestinalis patients will be treated earlier with albendazole which is potentially active against this species. PMID- 8673619 TI - [Generation of a trans-complementable defective recombinant provirus and loading a transgene]. AB - This work was aimed at generating a novel system for gene transfer to tumor cell, combining the advantages of non-viral gene transfer methods with those of transfer by recombinant retroviruses. We replaced the env gene of an infectious Moloney murine leukemia provirus with the gene coding for the thymidine kinase of Herpes Simplex Virus 1 (HSV1-TK). The sole transfection of this construction allows the production of viral particles, and the encapsidation of a viral genome carrying transgene. We show that this gene is expressed at a level sufficient for conferring sensitivity to ganciclovir, a nucleoside analog that is metabolised in a toxic compound by HSV1-TK. We also show that the complementation of this recombinant defective provirus with a gene coding for a retroviral envelope, either expressed constitutively by the transduced cell, or by co-transfection, leads to the formation of infectious viral particles capable of transducing HSV1 TK into tumor cells. PMID- 8673620 TI - Modelization of coordinated changes of adenylate energy charge and ATP/ADP ratio: application to energy metabolism in invertebrate and vertebrate skeletal muscle. AB - Regulation of the coordinated adenylate energy charge (AEC) and ATP/ADP ratio variations was studied with the aid of computer-made simulations. When the equilibrium state for the adenylate kinase-catalyzed reaction has been assumed, the function describing the coordinated AEC and ATP/ADP ratio variations can be simply derived from the formulas describing these 2 parameters. The model was used to analyze incidence of AMP deamination in the coordinated regulation of cellular energy metabolism. PMID- 8673621 TI - [Cloning of genes coding for 3-alpha-hydroxysteroid dehydrogenase and for (3-17) beta-hydroxysteroid dehydrogenase from Pseudomonas testosteroni]. AB - A genomic library of Pseudomonas testosteroi total DNA constructed from SauIIIA digests ligated to a lambda gt11 vector was probed with different polyclonal antibodies raised against purified 3 alpha-HSD and (3 beta-17 beta)-HSD. Two different clones reacting with one antibody were selected. The clone reacting with (3-17)beta-HSD antibody contained a 2,661-base pair insert and was found to contained an open reading frame of 765 base pair that corresponds to a protein of 254 amino-acid residues. A 1,492-base pair was inserte in pBR 322 plasmid vector; the recombinant bacterie over expressed the (3-17)beta-HSD gene. The clone reacting with 3 alpha-HSD antibody contained a 1746 base pair insert which contained an open reading frame of 696 base pairs that corresponds to a protein of 231 amino-acid residues. A search for homologous proteins was performed. Distant similarities were found between (3-17)beta-HSD and members of the short chain alcool dehydrogenase (SCAD) family but no similarity was observed between 3 alpha-HSD and proteins of this family. PMID- 8673622 TI - [Genetics and endocrinology of male sex differentiation: application to molecular study of male pseudohermaphroditism]. AB - The various processes involved in sexual differentiation have been considerably clarified over the last few years through advances in biochemistry and molecular genetics. The cloning of the gene responsible for testicular determination SRY, of the anti-Mullerian hormone and anti-Mullerian hormone receptor genes, of the several steroidogenic enzymes genes, of the 5 alpha-reductase type 2 gene and of the androgen receptor gene has permitted to elucidate the molecular defects causing abnormal sexual differentiation. These data have brought a substantial impact on the understanding of human male sexual differentiation and its main disorders. PMID- 8673623 TI - [Applications of luminescence reactions in life science]. AB - Bioluminescence and chemiluminescence have emerged in the last decade as a major tool for biochemical and biological studies. Several very sensitive assays have been developed in our laboratory such as enzymatic assays, immunoassays and detection of nucleic acids. The use of a new instrumentation allowing to dimensional photon counting has permit the emergence of new investigations at the cellular level. In addition to the advantages of sensitivity and the real-time non-invasive nature of this detection system, the imaging potential of using low light and photon counting video cameras has been particularly influential in establishing its ascendence over more traditional systems. This review provides a reflection in this field through several applications in life sciences. PMID- 8673624 TI - [Modulation of cellular response expression during prolonged treatment with antiestrogens]. AB - The effects of a prolonged antiestrogen treatment on two estrogen-dependent responses and an AP-1 response were studied on two cell lines derived from MCF-7 cells. 1) Hydroxytamoxifen specifically provoked an irreversible inactivation of a chimeric estrogen-dependent gene expression in less than 30 days. This process was estrogen receptor mediated and led to a cellular heterogeneity that was induced by the treatment and was not due to a cell selection process. A similar heterogeneity was also observed for the progesterone receptor expression but after a longer treatment time. The mechanism underlying this phenomenon is currently investigated. 2) After a four day treatment of cells with an antiestrogen, the phorbol ester inducible expression of a chimeric AP-1 response was stimulated by a factor 3-4. This stimulation was antiestrogen dose-dependent and suppressed by the presence of estradiol, which strongly suggested that estrogen receptor was involved. This was confirmed by the fact that the phenomenon was not observed in a cell line devoid of estrogen receptor. This result suggests a yet unknown mechanism by which an antiestrogen could have an agonistic property allowing hormone independence to appear. Both these phenomena show that new activities of antiestrogens may be evidenced after prolonged treatments with unexpected consequences on endocrine therapy. PMID- 8673625 TI - [Modulation by some fatty acids of protein kinase C-dependent NADPH oxidase in human adherent monocyte: mechanism of action, possible implication in atherogenesis]. AB - It is largely admitted nowadays that the early stage of the atherosclerotic lesion involves formation of oxidized (and minimally oxidized) low-density lipoprotein. Their properties are briefly reviewed. It is recalled that a lipolytic process also takes place both at the lumenal surface and in the subendothelial space of the vessels implying lipoprotein lipase (LpL) activity. Recent studies emphasize the role of LpL in accumulating LDL in the vascular tissue (Rutledge & Golberg, J. Lipid Res., 1994, 35, 1152-1160), but the role of LpL-generated unesterified fatty acids (UEFA) in these two locations and their possible implication in atherogenesis are largely neglected. Physiological and pathophysiological significance of UEFA in the human adherent monocyte modulation of the superoxide anion (O2.-) production has been examined by our group, leading to a possible mechanism of modulation of LDL oxidative modification. The O2.- production-modulating effect of a 30-min UEFA preincubation has been studied in intact human adherent monocytes (HAM) after stimulation by a direct effector of protein kinase C (PKC). It has been established that UEFA alone (in the absence of PKC effectors) were not able to modulate the O2.- production of HAM whereas they had such a capacity in the presence of PKC effectors, phorbol myristate acetate (PMA) or diacylglycerol (DAG). In this case inhibitors of PKC such as GF 109203 X suppressed the modulating effect. UEFA have also been shown to possess a bimodal action in the presence of PKC effectors: they depressed or enhanced O2.- production at micromolar or nanomolar concentrations, respectively. All these results contrasted with others obtained in neutrophils or nonadherent monocytes, suggesting an absolute requirement of PKC for the phagocyte-NADPH oxydase (PHOX) activation especially in the case of HAM. In HAM, the maximal enhancing effects were obtained with monomethyl ramified saturated (MMRS) and linear unsaturated (LU) FAs such as arachidonic, eicosapentaenoic and docosahexaenoic acids (with exception of oleic, linoleic and linolenic acids which were without effect), whereas the maximal depressing effects were obtained with MMRS-FAs and LU-FAS such as oleic, linoleic and docosahexaenoic acids. Further investigations in HAM led us to examine the UEFA capacity at modulating the translocation of PKC, on the one hand, and the endogenous phosphorylation and membrane translocation of p47phox, on the other, in the presence of PMA or DAG. Using 13-methyl myristic (iso15:0) as FA model, it has been established that i) it was able to amplify or diminish PKC translocation at nanomolar and micromolar concentrations, respectively (this was also the case with arachidonic acid) ii) it enhanced and depressed the endogenous phosphorylation and the membrane translocation of p47phox at nanomolar/micromolar concentrations and iii) it was inactive in the absence of PMA or DAG. Taken together, our results strongly suggest that the active UEFA act directly on the monocyte PKC, modifying its kinase activity through interactions with PMA/DAG binding site of the regulatory domain of the protein. This leads to modulate the phosphorylation and translocation of p47phox, which in turn allows the assembling of the active PHOX complex and triggers the O2.- production. The direct action of UEFA on the PKC regulatory-domain known to strongly interact with the membrane lipids was also supported by the fact that linear saturated FAs that have already been reported to be unable to penetrate a lipid layer were devoided of effect on monocytic O2.- production. The free form of oleic and linoleic acids and, to a lesser extent, docosahexaenoic acid (in the case of oral administration of fish oil) are present at micromolar concentrations in the plasma.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 8673626 TI - [Essential fatty acids and prematurity: a triple experimental approach]. AB - Previous studies in our laboratory have shown that in fetal plasma arachidonic (AA) and docosahexaenoic acid (DHA) levels are higher (about two fold) than in maternal plasma whereas the reverse situation was observed for the levels of their C18 precursors linoleic acid (AL) and alpha-linolenic acid (AAL) (13). This paradoxical situation raises the questions of the origin of the long chain polyunsaturated fatty acids (PUFAs) and of the ability of fetal liver to desaturate and elongate C18 precursors since placenta was shown not to be able to desaturate fatty acids. This question should be answered for the rationale of formula feeding supplementation either with long chain PUFAs or with their C18 precursors. Three experimental approaches can contribute to elucidate this dilemna: nutritional studies with formula supplementation, investigations on hepatic enzymes in vitro, in vivo experiments using stable isotopes. Supplementation of formulas with AAL in precise conditions (AL/AAL ratio: 6.4/1 and AL intake: 4.95% of total energetic supply) was done in a multicentric study including 88 premature newborns (32 weeks post conceptional age) for five weeks. The plasma phospholipid and red blood cell DHA status was found to be closer to human milk feeding than with standard formula feeding and most of the n-6 pathway was preserved. The data suggests that in premature newborns a significant conversion of AAL into DHA is possible provided an equilibrium is respected between AL and AAL supplies. This conversion is confirmed both by in vitro and in vivo studies: in fetal livers (obtained from therapeutic abortion) significant delta 6 and delta 5 desaturase activities were measured by a radiochemical method using reverse phase HPLC separation of [1-14C] labelled substrates and products in the n-6 and in the n-3 series. Substrate inhibition was observed especially at delta 5 desaturation and the maximum velocities were relatively limited mainly in the n-6 pathway which was slower than in the n-3 serie. These data are in agreement with recent preliminary data obtained in different laboratories with stable isotopes in vivo but in infants born in term: experiments using either 13C or deuterium labelled fatty acids concluded to the conversion of C18 essential fatty acids into AA and DHA justifying (AAL) formula supplementation for sustaining DHA status in preterm newborns. PMID- 8673627 TI - [Nitric oxide and lipid peroxidation]. AB - Nitric oxide (NO) is a free radical produced enzymatically in biological systems from the guanidino group of L-arginine. Its large spectrum of biological effects is achieved through chemical interactions with different targets including oxygen (O2), superoxide (O2o-) and other oxygen reactive species (ROS), transition metals and thiols. Superoxide anions and other ROS have been reported to react with NO to produce peroxynitrite anions that can decompose to form nitrogen dioxide (NO2) and hydroxyl radial (OHo). Thus, NO has been reported to have a dual effect on lipid peroxidation (prooxidant via the peroxynitrite or antioxydant via the chelation of ROS). In the present study we have investigated in different models the in vitro and in vivo action of NO on lipid peroxidation. Copper-induced LDL oxidation were used as an in vitro model. Human LDL (100 micrograms ApoB/ml) were incubated in oxygene-saturated PBS buffer in presence or absence of Cu2+ (2.5 microM) with increasing concentrations of NO donnors (sodium nitroprussiate or nitroso-glutathione). LDL oxidation was monitored continuously for conjugated diene formation (234 nm) and 4-hydroxynonenal (HNE) accumulation. Exogenous NO prevents in a dose dependent manner the progress of copper-induced oxidation. Ischaemia-reperfusion injury (I/R), characterized by an overproduction of ROS, is used as an in vivo model. Anaesthetized rats were submitted to 1 hour renal ischaemia following by 2 hours of reperfusion. Sham-operated rats (SOP) were used as control. Lipid peroxidation was evaluated by measuring the HNE accumulated in rats kidneys in presence or absence of L-arginine or D-arginine infusion. L-arginine, but not D-arginine, enhances HNE accumulation in I/R but not in SOP (< 0.050 pmol/g tissue in SOP versus 0.6 nmol/g tissue in I/R), showing that, in this experimental conditions, NO produced from L-arginine, enhances the toxicity of ROS. This study shows that the pro- or antioxydant effects of NO are different in vivo and in vitro and could be driven by environmental conditions such as pH, relative concentrations of NO and ROS, ferryl species. PMID- 8673628 TI - [Inflammation cytokines and peroxidation of low density lipoproteins (LDL)]. AB - The effect of the inflammatory cytokins TNF-alpha, oncostatin M and interleukine 1 (IL1) on low density lipoprotein (LDL) oxidative modification have been studied on UNA endothelial cells or U937 monocytes in culture, by measuring the end products of lipid peroxydation (TBARS) and the relative electrophoretic mobility of the particle. TNF-alpha as well as oncostatin M stimulated in a dose-dependent manner the LDL peroxidation induced either by endothelial cells or U937 monocytes, and induced an increase in the uptake of modified LDL by J774 macrophages. Both TNF-alpha and oncostatin enhanced the superoxide anion production by endothelial cells or monocytes. In contrast, IL1 did not influence LDL cellular oxidation, but increased cholesterol esterification by stimulating the Acyl coenzyme A: cholesterol-0-acyltransferase (ACAT) activity of J774 macrophages. If IL1 acts on cholesteryl ester deposition by a mechanism differing from those of TNF-alpha or oncostatin M, all the studied cytokins may increase cholesteryl ester deposition. These results point at the potential promoting action of inflammatory processes in the progress of atherogenesis. PMID- 8673629 TI - [From cholesterol to oxysterols. Current data]. AB - Oxysterols, a class of cholesterol oxidation products exhibit several important biological activities. Some of these natural compounds are potent inhibitors of the enzyme HMG-CoA reductase, a key enzyme in the cholesterol biosynthetic pathway. Many studies have been directed towards to the verification of the hypothesis that some oxysterols are endogenous intracellular regulators of cholesterol homeostasis. In adition to oxysterols derived directly from oxidation of cholesterol, several others are formed from squalene dioxide. It is presently well established that, in addition to the classical cholesterol biosynthetic pathway, there exists an alternate bifurcation from squalene oxide. The cyclisation of squalene dioxide leads to a series of new oxysterols. Thus, several types of oxysterols and several molecular targets are involved in the regulation of steroid biosynthesis. Many oxysterols, particularly those obtained from the oxidations of phytosterols and tetracyclic triterpenes are potent cytotoxic agents. They are selectively cytotoxic against tumorous cells. This cytotoxicity depends markedly on the specific structure of each oxysterol. Some structures are very cytotoxic, while their stereoisomers are inactive. The activity depends on the tumor cells which are used in the assay system: some compounds display inhibitory activity towards hepatoma cells but are inactive against lymphoma cells while others act in the opposite manner. Free oxysterols do not depress tumor growth in living animals. However, several water soluble prodrugs of oxysterols are able to depress different type of tumors in vivo. Clinical trial studies are presently conducted in order to learn the therapeutic values of these oxysterols. PMID- 8673630 TI - [Biosynthesis and functions of eicosanoids. Recent data]. AB - Eicosanoids are oxygenated derivatives from 20-carbon polyunsaturated fatty acids. Among these, arachidonic acid is the reference precursor from which most metabolic pathways have been described. These pathways correspond to the biosynthesis of prostanoids with a recent revival interest after the discovery of an inducible form of prostaglandin H synthase, the formation of lipoxygenase products catalyzed by three different enzymes according to the initial carbon position of the oxygenation, and the oxygenation into epoxides and into hydroxy derivatives by the cytochrome P450 family. In addition to these enzyme pathways, the formation of prostaglandin isomers by radical-induced oxygenation and cyclization has been recently described and named isoprostanes. Finally, it is noteworthy to state the interest for two fatty acids of marine origin, namely eicosapentaenoic acid, an arachidonic acid analogue competing with it in different metabolic pathways, and docosahexaenoic acid, precursor of few docosanoids and transcriptional regulator of several activities. PMID- 8673631 TI - [Elastolysis, aging and atherogenesis]. AB - In order to explore the potential role and importance of elastin fiber degradation in atherogenesis we determined in more than 1,400 individuals (males and females between 59 and 71 years of age), [the EVA epidemiological study] serum parameters related to elastin fiber degradation: serum elastase activity, circulating elastin peptides and serum elastase inhibitor titers. Significant correlations were found these between parameters and several other serum constituents considered as risk-factors of atherogenesis--essentially serum lipid parameters and glycemia as well as several other biological factors. These correlations confirm the validity of the underlying hypothesis concerning the interest of the clinical determinations of these elastin-related parameters and the potential role of the permanent activation of the endothelial elastin receptor in atherogenesis. PMID- 8673632 TI - [Antioxidant and anti-inflammatory protection of vascular endothelial cells by new synthetic mimics of glutathione peroxidase]. AB - New selenium-containing compounds behave as GPx mimics and protect endothelial cells (HUVEC) from damage upon exposure to 55 microM linoleic acid hydroperoxide or to 200 microM hydrogen peroxide. The simultaneous presence of the GPx mimic and the hydroperoxyde is not necessary, since a pre-treatment of endothelial monolayers with 1 to 10 microM of such compounds, preserves their morphology, their cell density and their longer-term viability. The compounds which are most efficient in this model of oxidative stress also protect endothelial monolayers which have been incubated with an excess (10:1) of polymorphonuclear neutrophils (PMN) and with 1 ng/ml of TNF-alpha, if such monolayers are pre- and co-treated (10 microM). They inhibit the adhesion of activated neutrophils which show-up as polymorphous and very dense particles, in the vicinity of which endothelial alterations can be seen. The inhibition of leucocyte adhesion and that of endothelial activation/alteration have been quantified by means of immunoassays of myeloperoxidase and von Willebrand factor (vWf). The lead-compound BXT-51072 is not a direct inhibitor of the NADPH oxidase of PMN. TNF-alpha alone induces the endothelial release of Interleukin-8 (Il-8) as well as the expression of P- and E-selectin. The extent and the kinetics of inhibition of such processes by compound BXT-51072 would explain several of the effects observed in the presence of PMN. The GPx mimics also inhibit the endothelial production of Il-8 which is induced by Interleukin-1 alpha. Finally, compound BXT-51072 inhibits the endothelial expression of the adhesion factor VCAM-1 which is more slowly induced by TNF-alpha. Such antioxidant catalysts therefore protect endothelial cells from the toxic effects of TNF-alpha through mechanisms which include a down-regulation of cytokines and cell-adhesion factors. PMID- 8673633 TI - [Role of lipid transfers in intravascular lipoprotein metabolism in human]. AB - Human lipoproteins after their intestinal or hepatic synthesis undergo within vascular compartment important remodeling through the agency of endothelial lipases, Lecithin: Cholesterol Acyl Transferase and lipid transfer proteins, Cholesteryl Ester Transfer Protein (CETP) and Phospholipid Transfer Protein (PLTP). Following CETP and PLTP characteristics presentation, transfer proteins activities and role were described specifying notably mechanism and kinetic models of cholesteryl ester transfer reaction (shuttle and ternary collision complex mechanisms). Comparative study of Phospholipid Transfer Activities mediated by CETP and PLTP has shown that phospholipid transfer activities of PLTP and CETP are different and might rely on distinct mechanisms. PLTP mediated phospholipid transfers modulate cholesteryl ester transfer activity of CETP. In vivo PLTP is responsible for the net mass transfer of phospholipid from triglyceride rich lipoprotein towards HDL. Whereas PLTP has no intrinsic cholesteryl ester transfer activity, it enhances the transfer of cholesteryl ester from HDL to VLDL and LDL. Thus PLTP might be a determinant factor in modulating the CETP mediated redistribution of cholesteryl esters between pro (LDL) and anti-(HDL) atherogenic lipoproteins. PMID- 8673634 TI - [The important role of apolipoprotein C-III in lipoprotein metabolism]. AB - Apolipoprotein C-III (apo C-III) is present in the plasma in apo B containing lipoprotein (apo C-III-LpB) and in non apo B containing lipoprotein (apo C-III-Lp non B). Apo C-III inhibits the lipolysis of triglyceride riche particles and the apo B containing lipoprotein binding to the LDL receptor. A clinical study in myocardial infarction survivors (ECTIM study) shows that apo C-III-LpB is a good marker of atherogenesis. Hypolipidemic drugs as fenofibrate and Maxepa decrease the apo C-III-LpB particles. These studies demonstrate that apo C-III presents an important role in apo B containing lipoprotein particles metabolism and atherogenesis. Furthermore apo C-III levels may be reduced by hypolipidemic drugs. PMID- 8673635 TI - [Liver mechanisms for the elimination of lipoproteins of intestinal origin]. AB - This article critically examines the concept of the putative chylomicron remnant receptor (CMR). The molecular nature of this second lipoprotein receptor remains disputed. Indeed, two proteins, the low density lipoprotein receptor-related protein (LRP) and the lipolysis stimulated receptor (LSR) have been proposed as candidates for this function. The LRP bears significant structural homology with the LDL receptor and mediates the internalisation of beta-VLDL enriched with apo E. In addition, LRP binds several ligands not related to the lipoprotein system. Thus, LRP's contribution to the clearance of CMR has been questioned. The precise biochemical structure of LSR remains unclear. However, a series of observations support the hypothesis that LSR is the CMR receptor. LSR, which is activated by free fatty acis (FFA), the products of lipolysis, is present in primary cultures of rat hepatocytes. It displays the highest affinity for triglyceride-rich lipoproteins and is inhibited by lactoferrin. The existence of a strong inverse correlation in rats between the apparent number of hepatic LSR and the plasma triglyceride concentration measured in the post-prandial state, indicate that LSR represents a rate-limiting step for the removal of triglyceride-rich lipoproteins. Moreover, the ability of MAXEPA to enhance the expression of LSR in parallel with its well documented hypotriglyceridemic effect indicates that, contrary to popular belief, the putative CMR receptor represents a target for pharmacological management of hyperlipidemia. PMID- 8673636 TI - [Genetic aspects of primary atherogenic dyslipoproteinemia]. AB - Large progress have been made in the last 15 years about knowledge of genetic of atherogenic dyslipoproteinemias. The genes of apolipoproteins, lipoprotein receptors and enzymes of lipoprotein metabolism are now located and their structures are known. Many gene defects are described and are responsible of definite diseases such as familial hypercholesterolemia, familial dysbetalipoproteinemia, familial hypoalphalipoproteinemia. Beside this pure genetic disorders, other atherogenic dyslipoproteinemias are result of interactions of genetic and environmental factors. This new physio-pathological approach gives a better comprehension of the clinical features than phenotype classification based on plasma cholesterol and triglycerides levels and lipoprotein electrophoretic pattern. PMID- 8673637 TI - [Insulin, diabetes and cholesterol metabolism]. AB - Cholesterol metabolism is altered in diabetic states. Three main mechanisms seem to be involved in these alterations: a) an increased glycation of cholesterol rich lipoproteins, b) an insulin-resistant state which is mainly present in overweight type 2 diabetic patients, and c) changes in insulin secretion which depends on the clinical type of diabetes. Insulin per se exerts beneficial effects on the metabolism of cholesterol binding lipoproteins. Despite insulin has a stimulatory influence on the endogenous cholesterol synthesis from Acetyl CoA, this hormone tends to decrease the LDL cholesterol concentrations through two additional effects: a diminution in the ApoB VLDL synthesis and an increase in the LDL catabolism. In well controlled diabetic patients, plasma concentrations of cholesterol binding lipoproteins are generally found within the normal range. These patients exhibit usually a normal sensitivity to insulin in the liver and peripheral tissues. In this case, the VLDL production is generally decreased, the LDL catabolism is either increased or normal, and therefore the endogenous cholesterol synthesis from Acetyl-CoA remains setted at a normal level. In poorly controlled and/or in insulin resistant diabetic patients, both VLDL cholesterol production and cholesterogenesis are increased, mainly as a consequence of the insulin-resistant state. The excessive glycation of LDL results in a diminution of their catabolism and therefore in an increase of their plasma concentrations. The reverse cholesterol transport pathway is also altered, the modifications being characterized by a diminution in HDL cholesterol concentrations, especially in the HDL2 subfraction. All these changes are certainly involved in the accelerated development of cardio-vascular complications encountered in diabetic patients. PMID- 8673638 TI - [Casein-derived peptides can promote human LDL oxidation by a peroxidase dependent and metal-independent process]. AB - The results of the present study revealed that peptides derived from bovine casein hydrolysates can promote peroxidase-dependent oxidation of human low density lipoproteins (LDL). The reaction was independent of the free metal ions but required casein-derived peptides with tryosyl-residues, implying that the tyrosyl radical is a diffusible catalyst that conveys oxidizing potential from the active site of the heme enzyme to LDL lipids. This mechanism is independent of the peroxidase used to oxidize tyrosyl residues since myeloperoxidase and horseradish peroxidase mediate a similar LDL peroxidating process. Vitamin E, ascorbic acid, butylated hydroxytoluene and reduced glutathione delayed LDL oxidation and were consumed during the reaction, they transfered hydrogen to repair tyrosine. PMID- 8673639 TI - Age differences in stress, coping, and appraisal: findings from the Normative Aging Study. AB - Controversies exist concerning the influence of age on the stress and coping process, in part due to differences in methods across studies. We examined age differences in stress, appraisal, and coping, using both semistructured interview questions and a coping checklist in middle-aged, young-old, and old-old men. Despite extensive probing, nearly a quarter of the old-old reported having had no problems and they expended less coping effort even when they did have problems. The types of problems reported varied systematically with age. Middle-aged men were more likely to appraise their problems both as challenges and as annoyances than the older men. Different age patterns emerged from the coping interviews vs the checklists, but controlling for type of problem significantly attenuated age differences. However, there were no age differences in perceived stressfulness of the problem, appraisals of harm/loss, or helpless appraisals, number of emotions reported, or coping efficacy. One interpretation of these results is that the nature of stress changes with age, from episodic to chronic, which in turn affects appraisal and coping processes. PMID- 8673640 TI - Behavioral slowing with age: boundary conditions of the generalized slowing model. AB - One hundred and twenty-two adults ranging in age from 20 to 83 years participated in this study of visual discrimination and recognition. The simultaneous-matching to-sample (discrimination) and delayed-matching-to-sample (recognition) paradigms used identical stimuli for spatial frequency, luminance, spatial localization, orientation, pattern, trajectory, and velocity matching. Linear regression analyses indicated that increased age slowed reaction time on the simultaneous matching tasks. This relationship was not found, however, when subjects were required to match the stimuli after a delay. When older adults' reaction times were regressed on those of adults in their 20s, very different patterns of age related slowing emerged from the data as a function of task requirements. The results from the simultaneous-matching paradigm replicate previous reports of general slowing on nonlexical tasks, but this was not true for the results from the delayed-matching paradigm, which used similar stimuli but also involved short term memory. PMID- 8673641 TI - Aging and filtering by movement in visual search. AB - We examined the ability of younger and older adults to selectively process moving items and ignore stationary items in a task that required the search for a target defined by a conjunction of movement and form (i.e., search for a moving X among moving Os and stationary Xs) in displays of 5, 9, 17, and 25 stimuli (Experiment 1) and displays of 5, 10, and 20 stimuli (Experiment 2). We also investigated subjects' performance in two feature search tasks, the search for a target defined by movement or form. Finally, we examined the influence of practice on feature and conjunction search. Younger and older adults searched the displays at similar rates in the feature and conjunction search tasks. Older and younger adults also benefited equivalently from practice. These data suggest age equivalence in the processes which underlie feature search in dynamic environments as well as those processes responsible for the segregation of moving and stationary objects in the visual field. PMID- 8673642 TI - The effects of preclinical dementia on estimates of normal cognitive functioning in aging. AB - Individuals with preclinical dementia have begun to decline cognitively, but still perform within normal limits on cognitive testing. As a group, subjects with preclinical dementia have lower scores on neuropsychological tests than their dementia-free counterparts. This study examines the effects of preclinical dementia on estimates of normal cognitive function in the aged using data from a longitudinal study. Individuals with preclinical dementia at baseline were retrospectively identified based on subsequent development of dementia. Age adjusted norms were computed using baseline data for the Selective Reminding Test and the WAIS verbal and performance scores, both including (conventional norms) and then excluding (robust norms) preclinical cases. The results indicate that by failing to exclude preclinical dementia, conventional normative studies underestimate the mean, overestimate the variance, and overestimate the effect of age on cognitive measures. Methods are discussed for selecting robust elderly samples that are relatively free of contamination by preclinical dementia. PMID- 8673644 TI - Age differences in episodic memory, semantic memory, and priming: relationships to demographic, intellectual, and biological factors. AB - This study examined age differences in episodic memory, semantic memory, and priming using a random sample of 1,000 men and women from 10 age groups (35, 40, 45, . . . 80 years). The main purpose was to determine whether an age effect existed after differences on various demographic, intellectual, and biological factors had been controlled for. The simple correlations of age with episodic and semantic memory performance were found to be significant, whereas no relationship was found between age and levels of priming. After controlling for differences on the background factors, age predicted episodic but not semantic memory performance. It is proposed that the failure to account for the age effect on episodic memory is because it is caused by age-related neuronal changes. PMID- 8673643 TI - The effects of list-making on recall in young and elderly adults. AB - This study examined the effects of list-making, and specific aspects of list making such as intent (whether one expects to refer back to one's list at the time of recall) and organization, on memory performance in young and old adults. Young and old adults were randomly assigned to a list-making or a non-list-making condition. In both conditions, subjects performed two memory tasks in which they were presented with a word list followed by written recall and recognition tests. On one task, subjects were informed that they would not be allowed to refer to the list at the time of testing (internal-intent). On the other task, subjects were informed that they would be allowed to refer back to the list (external intent), but actually were not allowed to. Planned comparisons found that list making significantly improved older adults' performance on the recall tasks. Additionally, while the old performed significantly worse than the young in the non-list-making internal-intent recall task (the traditional memory test condition), these significant differences were not found on either of the list making recall tasks. Both young and old list-makers who spontaneously organized their lists while studying the words recalled more items than subjects who did not organize their lists. These findings suggest future directions for both theoretical and applied research in the area of memory and aging. PMID- 8673645 TI - Research on disability: where is it leading? PMID- 8673646 TI - Disentangling the disablement process. AB - A model was proposed to assess the premise that functional limitations are an intermediary stage between risk factors (e.g., sex and frequency of walking a mile), pathology/impairments (e.g., musculoskeletal problems), and the onset and course of Instrumental Activities of Daily Living (IADL) disability. Analyses were based on two random subsamples (each with n = 524) of Longitudinal Study of Aging respondents who were nondisabled at baseline (1984) and reinterviewed in 1988 and 1990. The model's central premise was supported in two ways. The main influence of age, frequency of walking, and musculoskeletal problems was on the onset of functional limitations, rather than the onset of IADL disability. And, onset of lower body functional limitations influenced future disability (1990) through its relationship with disability in 1988 and functional limitations in 1990. The results underscore the value of clinical trials which focus on minimizing functional limitations as a strategy for preventing disability. PMID- 8673647 TI - Self-efficacy, physical decline, and change in functioning in community-living elders: a prospective study. AB - This study examines whether high self-efficacy is protective against a decline in functional status in community-residing elderly persons. Data came from a sample of 1,103 subjects aged > or = 72 years who were ambulatory within the household and who received in-home assessments at baseline and 18 months later to obtain information on sociodemographic, psychosocial, and health status variables, including physical performance tests. Functional status was based on six basic self-care tasks (ADLs). Using OLS regression, lower self-efficacy was marginally related to decline in functional status, after controlling for sociodemographic and health-related variables. As hypothesized, there was a significant interaction effect between self-efficacy and change in physical performance, suggesting that low self-efficacy was particularly predictive of functional decline among older individuals who showed a decline in physical performance at follow-up. These findings provide support for the buffering effect of self efficacy on functional decline in the face of diminished physical capacity. PMID- 8673648 TI - Social network characteristics and onset of ADL disability: MacArthur studies of successful aging. AB - The relationship between social network structural and support characteristics and onset of new or recurrent activities of daily living (ADL) disability was examined in a cohort of older men and women. No significant protective effects were found for network structural or support characteristics. However, greater frequency of instrumental support was associated with significantly increased risk of ADL disability among men; a similar though nonsignificant pattern was seen among women. These findings indicate that receipt of more instrumental support may not have uniformly beneficial effects on functional status. They serve to underscore the need for more comprehensive research, examining both the positive and negative effects of social interactions on health and functioning. PMID- 8673649 TI - Trends in mortality in older women: findings from the Nun Study. AB - During this century, Catholic sisters have remained constant in many life-style characteristics such as smoking and reproduction (Catholic sisters are nonsmoking and nulliparous). It is therefore of interest to compare trends in the health of elderly Catholic sisters to those in the general population. In this study, mortality rates at ages 50 to 84 years in a population of 2,573 Catholic sisters were compared to those in the general population during the years 1965 to 1989. The Catholic sisters had a mortality advantage that increased dramatically over calendar time, and from early to more recent birth cohorts. This coincided with increases in smoking by U.S. women, while during the same time period the Catholic sisters had very low rates of mortality from smoking-related diseases. The Catholic sisters had high rates of mortality from cancers of the breast and reproductive organs, suggesting an effect of nulliparity manifested in older women. PMID- 8673650 TI - Aggregating poor and near-poor elderly under different resource definitions. AB - The large number of near-poor relative to poor elderly persons in the United States may be recharacterized as a high-prevalence, low-intensity type of poverty. The present study investigates how this characterization is affected by accounting for assets and non-cash transfers in addition to cash income in resources available for current-year consumption. The Foster, Greer, Thorbecke (FGT) poverty index is used to separately and jointly analyze prevalence and intensity of poverty. Estimation is from 1984 Survey of Income and Program Participation data. Adding the annuity value of assets removes many elderly persons from the ranks of the poor and near-poor, while adding non-cash transfers moves many elderly persons from poverty into near-poverty. Their combined effect reinforces a high-prevalence, low-intensity characterization of poverty. Large total poverty reduction effects are missed by income-only resource definition, and large poverty-intensity reduction effects are missed by prevalence-only aggregation. PMID- 8673651 TI - Age and the sense of control among older adults. AB - Older adults are expected and frequently found to report less control than younger adults. In this study, we decompose this negative relationship between age and sense of control using nested multivariable linear regression models that serially introduce sociodemographic characteristics, socioeconomic factors, health status, and subjective religiosity and religious beliefs in a sample of 1,051 older adults attending the general medicine clinics of a major medical center. The results indicate that the effect of age is suppressed in the bivariable model. In the final multivariable model, educational attainment has the largest relative effect (i.e., beta; .253), followed by age (-.210), mental health (.174), subjective religiosity (.113), being an African American (-.100), perceived health (.082), and being Catholic (.068). Future research should focus on the inflection point in the relationship between age and the sense of control that apparently occurs at about 50 years of age. PMID- 8673653 TI - Interventions fail to enhance appropriateness of care near life's end. PMID- 8673652 TI - Thrombolytic therapy can aid recovery from acute ischemic stroke, say researchers. PMID- 8673654 TI - Guidelines address management of gastroesophageal reflux disease. PMID- 8673655 TI - Standards set for COPD management. PMID- 8673656 TI - Ordering out for a pharmacy newsletter. PMID- 8673657 TI - Thalidomide for aphthous ulcers in patients infected with the human immunodeficiency virus. PMID- 8673658 TI - Prostate cancer: current and evolving strategies. AB - The staging, screening and diagnosis, and treatment of prostate cancer are discussed. Prostate cancer kills about 40,000 men in the United States each year. Signs and symptoms range from dysuria to features of advanced metastatic disease. The American Urological System of staging prostate cancer designates four stages, A through D. The tumor is graded histologically with the Gleason scale. Methods used in the screening and diagnosis of prostate cancer include digital rectal examination, the prostate-specific antigen (PSA) assay, biopsy, transrectal ultrasonography, and determination of PSA density, velocity, and age specificity. The value of screening and treatment remains controversial because tumors are generally slow-growing and conclusive data showing an effect on survival time are lacking. Treatment methods consist of prostatectomy, radiation therapy, and hormonal drug therapy or bilateral orchiectomy. The choice is influenced primarily by the stage of the disease but also by the patient's age, physical condition, and response to prior therapy. Patients with stage A or B disease are considered for prostatectomy or radiation therapy. The primary treatment for stage C disease is radiation therapy. For stage D, the main approaches are watchful waiting and bilateral orchiectomy or hormonal drug therapy to reduce androgenic stimulation of prostate tissue. Long-term survival rates are high for stages A and B and considerably lower for stages C and D. Prostate cancer responds to estrogens, but adverse effects are frequent and potentially severe. Luteinizing hormone-releasing hormone agonists (leuprolide and goserelin) are as effective as estrogens but have less toxicity; a disadvantage of these agents is an initial flaring of the disease. Other hormonal agents used include antiandrogens-progestins, flutamide, and bicalutamide. Secondary hormonal treatments (aminoglutethimide and ketoconazole) are less effective than initial hormonal therapy. Antineoplastic agents have little or no effectiveness in prostate cancer. Although the value of screening for and treating prostate cancer continues to be debated, many experts recommend annual screening for all men over 50. Research to identify more effective drugs for treating advanced disease continues. PMID- 8673659 TI - Work activities at an ambulatory care pharmacy with an integrated model of pharmacy practice. AB - Activities performed by pharmacists and technicians in an ambulatory care pharmacy were evaluated by work sampling to determine circumstances in which pharmacist time was used ineffectively. Over a two-week period, pharmacists and technicians in the outpatient pharmacy at University of Utah Hospitals and Clinics recorded their activities at random intervals during the workday. The data were analyzed by using descriptive statistics and an institution-specific index of pharmacist efficiency. During the study, 1565 pharmacist observations and 1465 technician observations of work activities were collected. Pharmacists spent 50% of their shifts on clinical and professional activities, while technicians spent 50% of their shifts processing prescriptions and 30% of their shifts directly supporting pharmacists clinical and professional activities. The efficiency with which pharmacists used the available work time for patient care was 56% (100% would mean that they spent all available work time on patient care activities). During a shift, 2.3 minutes per prescription per pharmacist was available for professional and clinical activities. Self-reported work sampling enabled the ambulatory care pharmacy staff to identify staff use of time. PMID- 8673660 TI - Quality-assurance testing of staff pharmacists handling cytotoxic agents. AB - Competency-based simulation testing was used to improve staff pharmacists' handling of cytotoxic agents. Pharmacists were asked to prepare a simulated liquid cytotoxic agent (fluorescein sodium 0.5 mg/ml.) according to the pharmacy service standard operating procedures. Participants were observed throughout the preparation to assess proper safety and aseptic technique, waste disposal, and labeling. Ultraviolet light was used to assess surface contamination. After the test, errors were discussed with each participant. All participants then received scheduled annual training on preparation of cytotoxic agents, and they took the simulation test again three months later. Thirteen staff members completed all testing. Simulation test scores improved from 61% to 84%. Evidence of surface contamination was found for 92% of these pharmacists during the pretest and only 23% during the posttest. Written test scores improved, but not significantly, from 85% to 89%. Each simulation and feedback session took 30 minutes. Simulation testing significantly improved competence in preparation of cytotoxic agents. PMID- 8673661 TI - Stability of flucytosine in an extemporaneously compounded oral liquid. AB - The stability of flucytosine in an oral liquid prepared from capsules was studied. Flucytosine 10-mg/ml oral liquid was prepared from 500-mg capsules (with distilled water as the diluent) and transferred to 10 glass and 10 plastic amber bottles. Five of each type of bottle were stored at 4 degrees C and five of each at 25 degrees C. Samples were taken at 0, 7, 14, 28, 42, 56, 70, and 91 days, and flucytosine concentration was measured by stability-indicating high-performance liquid chromatography. Flucytosine was stable in the liquid formulation for at least 70 days under all the study conditions. The physical appearance of the liquid stored at 4 degrees C did not change during the study period. Flocculation was observed both in glass and in plastic bottles stored at 25 degrees C on day 14 and thereafter. Flucytosine 10 mg/mL in an extemporaneously prepared oral liquid was stable for 70 days in glass or plastic prescription bottles kept at 4 or 25 degrees C. PMID- 8673662 TI - Appropriateness of therapy with angiotensin-converting-enzyme inhibitors in elderly outpatients. PMID- 8673663 TI - Safety of an extemporaneously prepared injection. PMID- 8673664 TI - Pharmacy without walls. AB - Attributes of excellence in pharmacy management are described: big-picture thinking, the ability to exploit change, and willingness to take risks. Big picture thinking means understanding trends that are shaping health care in order to determine where pharmacy fits. Health systems look beyond inpatient care and use case managers to maximize resource use; pharmacists might serve as case managers. Managed care has caused physicians to be more receptive to resource management strategies, such as clinical pathways; pharmacists can collaborate in the development of clinical pathways. Pharmacists can serve as physician extenders; for example, by conducting anticoagulation or hypertension clinics. Pharmacists need flexibility to adapt to changes in the internal organization of acute care institutions; they will need to learn about the clinical, behavioral, operational, and fiscal aspects of managing the total patient. New reporting relationships give pharmacists the opportunity to demonstrate to other members of the health care team their role in preventing, managing, and resolving drug related problems throughout the continuum of care. Risk-taking can mean setting ambitious goals. By setting and achieving ambitious goals for products and services, pharmacists can raise patients' and other health care providers' expectations for pharmacy services. Pharmacists' success will depend on their willingness to experiment with new services and discard services that do not substantially advance patient care. Pharmacists must monitor changes in the provision of health care, determine the implications for their practice and seek opportunities for participation outside the walls within which they have traditionally practiced. PMID- 8673665 TI - Introducing formulary drug selection in Russia. PMID- 8673666 TI - Thalidomide in diseases associated with human immunodeficiency virus infection. PMID- 8673667 TI - Stability of cefmetazole sodium and famotidine. PMID- 8673668 TI - Bias in observation of medication errors. PMID- 8673669 TI - Concomitant use of antipsychotics with risperidone. PMID- 8673670 TI - Role of pharmacy benefit management companies in integrated health care systems. PMID- 8673671 TI - Contributions of pharmacy management to systems' success: Scott & White Hospital, Clinics & Health Plan. PMID- 8673672 TI - Contributions of pharmacy management to systems' success: Abbott Northwestern hospital. PMID- 8673673 TI - Contributions of pharmacy management to systems' success: Fallon Healthcare System. PMID- 8673674 TI - Developing pharmacy's role in ambulatory care: Parkland Health and Hospital System. PMID- 8673675 TI - Opportunity for pharmacy leadership in integrated health care systems. PMID- 8673676 TI - Developing pharmacy's role in ambulatory care: Cedars-Sinai Medical Center. PMID- 8673677 TI - Negotiating innovative relationships with pharmaceutical companies: the pharmaceutical industry's perspective. PMID- 8673678 TI - Negotiating innovative relationships with pharmaceutical companies: integrated health systems' perspective. PMID- 8673679 TI - Integrated health care systems: current status and future outlook. PMID- 8673680 TI - Pharmacy factors that influence the success of integrated health care systems. PMID- 8673681 TI - Medical care in Russia in 1995: a state of transition. PMID- 8673682 TI - Urticaria and angioedema: a clinical spectrum. AB - OBJECTIVE: The objective of this review is to give the reader a global insight into the spectrum of urticaria, focusing on differential diagnosis and pathogenic mechanisms. This review will define the role of the mast cell, explore a possible autoimmune basis for urticaria, and examine the purported role of food allergy in chronic urticaria. Last, the work-up and treatment of urticaria will be discussed in the context of the histologic diagnosis. STUDY SELECTION: The relevant past medical literature will be reviewed in the context of new and novel research into the mechanisms of chronic urticaria. RESULTS: Urticaria can be classified histopathologically into the following three categories: (1) neutrophilic vasculitis, (2) polymorphous perivascular infiltrate, and (3) sparse perivascular lymphocytic infiltrate. Each of the above histologic patterns correlates with a distinct clinical entity and the work-up and treatment of urticaria will be related to each of the above histologic types. CONCLUSIONS: Urticaria and angioedema are frustrating problems for both physicians and their patients; however, the problem can best be approached by considering urticaria as a symptom that may be part of a larger clinical spectrum. The physical examination and medical history remain the two most important pieces of information. The allergist frequently overlooks the value of a skin biopsy as an aid in sorting out the pathophysiology of urticaria and the biopsy results may help to classify urticaria into subgroups which respond differently to treatment. PMID- 8673683 TI - An erythematous rash preceding ulcerative oral lesions in a 41-year-old woman. PMID- 8673684 TI - Comparison of ebastine to cetirizine in seasonal allergic rhinitis in adults. AB - BACKGROUND: Second-generation histamine H1-receptor antagonists are accepted first-line systemic therapy for seasonal allergic rhinitis. Ebastine is a new histamine H1-receptor blocker that may differ in efficacy from currently used second-generation agents. OBJECTIVE: To compare the efficacy of daily treatment with ebastine, 10 mg, ebastine, 20 mg, or cetirizine, 10 mg, for relieving symptoms of seasonal allergic rhinitis in adults. METHODS: In this multicenter, double-blind study, outpatients were randomized to one of three parallel treatment groups: ebastine, 10 mg, ebastine, 20 mg, or cetirizine, 10 mg once daily in the morning for a 2-week period. Patients were evaluated clinically according to symptoms, discomfort, and a global assessment at baseline and on days 8 and 15 of treatment. The total symptom score, defined as the sum of the total morning score on the day of evaluation and the total evening score on the preceding day, was the primary efficacy parameter. RESULTS: Ebastine, 20 mg (n = 111), ebastine, 10 mg (116), and cetirizine, 10 mg (116), were all effective for improving nasal and ocular symptoms. There was, however, a general trend towards more rapid relief of symptoms with ebastine, 20 mg, and this reached statistical significance in some efficacy parameters after the first week of treatment. In a subpopulation of 158 patients who presented with more severe symptoms, statistically significantly greater improvement was seen with ebastine, 20 mg, compared with ebastine, 10 mg, as indicated by the mean change from baseline in the total symptom score averaged over the treatment period (-13.7 +/- 4.7 vs 11.8 +/- 3.8; P =.027) and in the morning symptom score (-6.7 +/- 2.7 vs -5.7 +/- 2.2; P = .042). All three treatments were well tolerated. Dry mouth, headache, and somnolence were the most common adverse events. CONCLUSION: Ebastine (10 mg), cetirizine (10 mg), and ebastine (20 mg) administered orally once daily for 2 weeks all appear to be effective for relieving the symptoms of seasonal allergic rhinitis. Ebastine, 20 mg, may have advantages over ebastine, 10 mg, and cetirizine, 10 mg, in terms of a reduced time to achieve maximal efficacy and a superior level of efficacy in patients with more severe symptoms. PMID- 8673685 TI - An intervention program to reduce the hospitalization cost of asthmatic patients requiring intubation. AB - BACKGROUND: Asthma is the single disease that accounts for the largest proportion of total health care cost in the US. OBJECTIVE: To analyze whether an asthma management program affected the cost of subsequent asthma care for patients in whom intubation had been necessary. METHODS: We evaluated patients with asthma who (1) had required intubation for treatment of status asthmaticus; (2) were 45 years old or younger; (3) had regular follow-up visits in our clinic for 1 year after initial evaluation; and (4) had complete medical records 1 year before and 1 year after the intervention for our evaluation. Medical costs of asthma treatment for each patient were determined for 1 year before and 1 year after intervention. The program included patient education, regular outpatient visits, specialist care, and access to the Allergy Immunology emergency call service. The outcome measures were the total cost of care, inpatient hospitalizations, outpatient services, emergency services, and medicine costs. RESULTS: Nine patients [mean age 19.6 years (SD = 9.9)] fulfilled the criteria (six women and three men). The mean duration of asthma was 14.0 years (SD = 9.7). The mean total cost of care decreased from $43,066 to $4,914 (t = -4.53, P < .001) and inpatient hospitalization costs decreased from $40,253 to $1,926 (t = -4.50, P <.001). There was, however, no significant difference in the mean pre-intervention versus post-intervention cost of emergency services, outpatient services, or medicine costs. CONCLUSIONS: The intervention--which included education, specialist care, regular outpatient visits, and access to an emergency call service--significantly reduced the cost of asthma care in our population of patients intubated for asthma. PMID- 8673686 TI - Measurement of natural rubber proteins in latex glove extracts: comparison of the methods. AB - BACKGROUND: Health care workers and individuals with frequent contact with latex are at risk for latex protein allergy. OBJECTIVE: The purpose of this study was to compare several established methods for measuring protein in extracts from latex-containing medical devices. METHODS: Extracts from latex gloves were analyzed for natural rubber proteins using a modified Lowry assay and two different immunochemical assays. The immunochemical methods were competitive inhibition assays that employed either immune rabbit serum or human serum with antibodies directed against natural rubber proteins. RESULTS: Seventy extracts representing five different brands of gloves from four manufacturers were analyzed. A good linear correlation (R = 0.88) was found between the immunoassay methods. Correlation to the modified Lowry method was not possible because many of the samples were below the limit of detection for the Lowry assay. Reference extracts and antisera were further characterized by Western blot analysis. The data demonstrate that the proteins recognized by rabbit antisera and the proteins recognized by human IgE are similar. The greatest difference in the immunochemical assays appears to be the relative binding of the antibody sources to high and low molecular weight natural rubber proteins in the reference extracts. CONCLUSIONS: The immunochemical assays are specific for latex proteins and provide a more sensitive and biologically relevant method for determining protein levels in latex medical products. PMID- 8673687 TI - Analysis of a family containing three members with common variable immunodeficiency. AB - BACKGROUND: Common variable immunodeficiency (CVID), a diverse immunodeficiency syndrome characterized by low immune globulin levels and recurrent infections, has been observed in families with the HLA A1 B8 DR3 haplotype. METHODS: We report a two-generation family with three members affected by CVID. Immunoglobulin levels, antibody titers, lymphocyte marker analyses, T cell proliferation assays, and HLA typing were performed on the affected family members. RESULTS: Studies of the affected patients revealed low levels of immunoglobulin G and A; normal tetanus, rubella and rubeola antibody titers; low B cell numbers; normal T cell numbers; normal CD4/CD8 ratios and normal lymphocyte proliferation studies. HLA typing did not reveal the HLA A1 B8 DR3 haplotype previously associated with familial CVID. CONCLUSION: We report a family with a unique presentation of CVID involving possible genetic inheritance other than the HLA A1 B8 DR3 haplotype and possessing lymphocyte characteristics distinct from those usually seen in sporadic CVID. PMID- 8673688 TI - Immediate hypersensitivity to human recombinant granulocyte-macrophage colony stimulating factor associated with a positive prick skin test reaction. AB - BACKGROUND: Recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF), also known as sargramostim, is used to accelerate myeloid recovery following bone marrow transplantation or cytotoxic chemotherapy. "Anaphylactic" reactions to sargramostim have been reported on a limited basis and are poorly characterized. OBJECTIVE: It is the purpose of this report to describe an adverse reaction to sargramostim treatment involving palmar itching, urticaria, angioedema, and throat tightness and to demonstrate the utility of prick skin testing to determine type I sensitization. METHODS: Prick skin testing with 100 and 250 micrograms/mL sargramostim and 300 micrograms/mL rhu G-CSF (filgrastim) was performed in the patient and four control subjects. RESULTS: The patient experienced an immediate wheal and flare reaction with both concentrations of sargramostim while the control subjects demonstrated no reaction. There was also no reaction with filgrastim (rhu G-CSF) in either group and the patient subsequently tolerated filgrastim therapy. CONCLUSION: Prick skin testing with rhu GM-CSF and rhu G-CSF may be useful to demonstrate type I sensitization. Additional studies are needed to determine the incidence and prevalence of skin test reactions in larger numbers of patients with cytokine therapy exposure. PMID- 8673689 TI - Effect of dilution, temperature, and preservatives on the long-term stability of standardized inhalant allergen extracts. AB - BACKGROUND: Although documented stability of allergens used for diagnosis is important, research in this area has been limited. Most studies on extract stability have been of limited duration and discrepancies have been reported between stability test results of in vivo and in vitro methods. OBJECTIVE: In this study we determined the stability of allergenic extracts, comparing the intracutaneous test and enzymallergosorbent test inhibition method and determining the effect of temperature, dilution, and preservatives. METHODS: Three formulations of timothy pollen, birch pollen, house dust mite (D. pteronyssinus) and cat dander extracts, as used for bronchoprovocation, skin prick testing and intracutaneous testing, were stored for 24 months at 6 degrees C. The influence of temperature on various formulations was determined using the enzymallergosorbent test inhibition technique during storage for up to 36 months. RESULTS: Most formulations were found to be stable for 24 (intracutaneous test) or 36 (enzymallergosorbent test inhibition) months at 6 degrees C. At 25 degrees C, most formulations showed a decrease in relative potency, which remained above the limit of 0.3 times the in-house-reference for the bronchoprovocation formulation of timothy pollen, birch pollen, and house dust mite and for the skin prick test formulation of cat dander. CONCLUSIONS: Cat dander was remarkably stable at 6 and 25 degrees C in glycerine and birch pollen was very susceptible to phenol. This destructive effect of phenol could be prevented by adding human serum albumin. The discrepancy between in vivo and in vitro tests reported by others was confirmed for house dust mite and timothy pollen. PMID- 8673690 TI - Cross-reactivity of cephalosporins with penicillin. PMID- 8673691 TI - Role of theophylline in asthma. PMID- 8673692 TI - Malignant melanoma: perspectives on incidence and its effects on awareness, diagnosis, and treatment. PMID- 8673693 TI - Prevention and control of melanoma: the public health approach. PMID- 8673694 TI - Surgical management of primary cutaneous melanoma. PMID- 8673695 TI - Vaccine therapy for malignant melanoma. PMID- 8673696 TI - The management of clinically localized prostate cancer: guidelines from the American Urological Association. PMID- 8673697 TI - Asbestos-related cancer. PMID- 8673698 TI - Carcinogens and the workplace. PMID- 8673699 TI - Upstream-downstream: CD28 cosignaling pathways and T cell function. PMID- 8673700 TI - Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. AB - T lymphocyte receptor CTLA-4 binds costimulatory molecules CD80 (B7-1) and CD86 (B7-2) with high avidity and negatively regulates T cell activation. CTLA-4 functions at the cell surface, yet is primarily localized in intracellular vesicles. Here, we demonstrate cycling of CTLA-4 between intracellular stores and the cell surface. Intracellular vesicles containing CTLA-4 overlapped with endocytic compartment(s) and with perforin-containing secretory granules. Cell surface expression of CTLA-4 was rapidly increased by raising intracellular calcium levels. During T cell activation, intracellular and cell surface CTLA-4 became focused towards sites of TCR activation. Cycling and directional control of CTLA-4 expression may regulate its functional interaction with APCs bearing peptide-MHC complexes of appropriate specificity and avidity. PMID- 8673701 TI - CD4 T cell tolerance to nuclear proteins induced by medullary thymic epithelium. AB - Thymic epithelium is involved in negative selection, but its precise role in selecting the CD4 T cell repertoire remains elusive. By using two transgenic mice, we have investigated how medullary thymic epithelium (mTE) and bone marrow (BM)-derived cells contribute to tolerance of CD4 T cells to nuclear beta galactosidase (beta-gal). CD4 T cells were not tolerant when beta-gal was expressed in thymic BM-derived cells. In contrast, CD4 T cells of mice expressing beta-gal in mTE were tolerized. Tolerance resulted from presentation of endogenous beta-gal by mTE cells but not from cross-priming. mTE cells presented nuclear beta-gal to a Th clone in vitro, while thymic dendritic cells did not. The data indicate that mTE but not thymic BM-derived cells can use a MHC class II endogenous presentation pathway to induce tolerance to nuclear proteins. PMID- 8673702 TI - Dual function of Drosophila cells as APCs for naive CD8+ T cells: implications for tumor immunotherapy. AB - With unseparated mouse spleen cells as responders, Drosophila cells expressing MHC class I (L(d)) molecules alone lead to peptide-specific responses of CD8+ cells in the absence of exogenous cytokines. Under these conditions, DNA released from dying cells stimulates the B cells in spleen to up-regulate costimulatory molecules; these activated B cells then provide bystander costimulation for CD8+ cells responding to class I-peptide complexes on the Drosophila APCs. By stimulating B cells and presenting antigen to T cells, Drosophila cells thus serve two different functions in promoting primary responses of CD8+ cells in vitro. With this system, we show that Ld-transfected Drosophila cells are able to induce autologous spleen cells to respond to a tumor-specific peptide in vitro and, after transfer, cause tumor rejection in vivo. PMID- 8673703 TI - Evidence that a single peptide-MHC complex on a target cell can elicit a cytolytic T cell response. AB - Using a chemically homogeneous radiolabeled peptide of high specific activity (125I-QLSPYPFDL, 3.5 x 10(18) cpm per mole) we show that at a peptide concentration (5 pM) causing half-maximal lysis of target cells by a cytolytic T lymphocyte (CTL) clone that recognizes the peptide in association with Ld, a class I MHC protein, only 3 peptide molecules on average are bound by Ld per target cell. From the distribution of Ld on the target cells, we suggest that a single peptide-MHC complex per target cell can trigger activation of the T cell cytolytic response. PMID- 8673704 TI - DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. AB - Intercellular adhesion molecules play an important role in the generation of T lymphocyte-mediated immune responses. Here, we describe a novel accessory molecule, DNAX accessory molecule-1 (DNAM-1), that is constitutively expressed on the majority of peripheral blood T lymphocytes. DNAM-1 is a 65 kDa transmembrane glycoprotein consisting of 318 aa including two immunoglobulin-like domains. Anti DNAM-1 monoclonal antibody (MAb) inhibits T and NK cell-mediated cytotoxicity against a variety of tumor cell targets and blocks cytokine production by alloantigen-specific T cells. In addition, DNAM-1 is a tyrosine-phosphorylated signal-transducing molecule that participates in primary adhesion during cytotoxic T lymphocyte (CTL)-mediated cytotoxicity. PMID- 8673705 TI - A novel gene product that couples TCR signaling to Fas(CD95) expression in activation-induced cell death. AB - Cross-linking the TCR in T cell hybridomas induces cell apoptosis following activation. This activation-induced apoptosis has been used as a model for clonal deletion of thymocytes or peripheral T cells. Anti-TCR-induced apoptosis of T cell hybridomas requires de novo macromolecular synthesis, including up regulation of Fas and FasL. The Fas-FasL interaction then activates the apoptosis program. To study apoptosis-specific signaling processes, we generated a mutant T cell hybridoma line defective in induction of apoptosis, but competent to induce activation, upon TCR triggering. Subsequently, we cloned the gene TDAG51, which restored activation-induced apoptosis when transfected into the mutant cell line, and showed that TDAG51 expression was required for Fas expression. Thus, TDAG51 plays an essential role in induction of apoptosis by coupling TCR stimulation to Fas expression. PMID- 8673706 TI - Vav and SLP-76 interact and functionally cooperate in IL-2 gene activation. AB - T cell antigen receptor (TCR) stimulation induces tyrosine phosphorylation of many intracellular proteins, including the proto-oncogene Vav, which is expressed exclusively in hematopoietic and trophoblast cells. Vav is critical for lymphocyte development and activation. Overexpression of Vav in Jurkat T cells leads to potentiation of TCR-mediated IL-2 gene activation. However, the biochemical function of Vav is unknown. Here, we demonstrate that the major induced tyrosine phosphoprotein associated with Vav is the hematopoietic cell specific SLP-76. The Vav SH2 domain is required for this interaction and for TCR mediated Vav tyrosine phosphorylation. Similar to Vav, overexpression of SLP-76 markedly potentiates TCR-mediated NF-AT and IL-2 gene activation. Furthermore, overexpression of both Vav and SLP-76 synergistically induces basal and TCR stimulated NF-AT activation. These results suggest that a signaling complex containing Vav and SLP-76 plays an important role in lymphocyte activation. PMID- 8673707 TI - Normal human IgD+IgM- germinal center B cells can express up to 80 mutations in the variable region of their IgD transcripts. AB - Somatic hypermutation in immunoglobulin variable region genes occurs within germinal centers. Here, we describe a subset of germinal center dark zone centroblasts that express only sIgD and have accumulated up to 80 mutations per heavy chain variable region (IgVH delta gene). Over half of the hypermutated IgVH delta sequences were found to be clonally related. This level of mutation is not observed in either IgVH gamma transcripts from the same sample or IgVH delta transcripts from peripheral blood, suggesting that these cells neither undergo isotype switch nor mature into circulating memory B cells. Optimal growth of these cells in vitro depends on CD40 ligand, T cell cytokines, and a fibroblast stroma, a combination possibly mimicking the dark zone microenvironment. Our hypothesis is that these cells may be sequestered within germinal centers, where their somatic mutation machinery is triggered. The isolation of these hypermutated B cells may represent a critical step for studying both the biology and biochemistry of somatic hypermutation. PMID- 8673708 TI - Basic principles of MR contrast agents. AB - Although familiar for CNS enhancement, contrast agents for body MR applications are both similar and different. This short summary emphasizes the basics of tissue relaxation and the added influences of paramagnetic or superparamagnetic pharmaceuticals. An overview of safety and cost considerations is included. PMID- 8673709 TI - Contrast-enhanced MR imaging of the kidneys and adrenal glands. AB - Technical developments including motion artifact compensation and the use of paramagnetic contrast agents have substantially improved the performance of MR imaging of the kidneys and adrenal glands. MR imaging allows one to assess morphologic alterations of the kidneys as well as perfusion and functional derangements. MR imaging is the best noninvasive method for distinction of benign from malignant adrenal masses. PMID- 8673710 TI - Body MR angiography with gadolinium contrast agents. AB - Gadolinium-enhanced MR angiography provides contrast arteriograms without the risks of arterial catheterization or iodinated contrast. Although this technique is in the early stages of development, already it has yielded promising images of large vascular structures without degradation from flow artifacts. As the technique is developed and further optimized, higher resolution and greater arterial detail will become possible. PMID- 8673711 TI - Contrast-enhanced MR imaging of gynecologic disorders. AB - Although standard MR imaging techniques can provide most of the important diagnostic information needed for studies of the female pelvis, intravenous contrast and bowel contrast agents can provide critical ancillary information in selected patients. Imaging techniques and diagnostic principles related to the use of these agents for gynecologic disorders are discussed. PMID- 8673712 TI - Contrast-enhanced MR imaging of the bladder and prostate. AB - The staging of both bladder and prostate carcinoma is important to determine appropriate therapy. Routine clinical staging of these tumors, however, has only limited accuracy. This article reviews the literature on contrast-enhanced MR of both bladder and prostate cancer, including technique optimization and potential benefits of contrast-enhanced studies. PMID- 8673714 TI - Gastrointestinal contrast agents for MR imaging. AB - This article reviews the current status of gastrointestinal contrast agents being developed for MR imaging. The need for a bowel marker in MR imaging and the characteristics of an ideal agent are discussed. The major enteric MR agents are classified and reviewed with emphasis on their relative advantages and disadvantages. Finally, the future role of these agents is considered. PMID- 8673713 TI - Targeted contrast agents in MR imaging. AB - The use of target specific MR contrast agents can dramatically improve information obtained by MR imaging. This review outlines the various components of target specific MR contrast agents, including various carriers (e.g., monoclonal antibodies, peptides, proteins, polysaccharides, polymers, liposomes, and cells) as well as magnetic labels (e.g., metal ion chelates, free radicals, and iron oxides) and focusses on some promising clinical applications. PMID- 8673715 TI - Liver I: Currently available gadolinium chelates. AB - To use currently available gadolinium chelates most effectively, the liver should be imaged repetitively after contrast agent injection during hepatic arterial, portal vein, and delayed phases. Metastases usually demonstrate early as transient enhancement, which is often rim-shaped. Cavernous hemangiomas, however, demonstrate gradual clump-by-clump enhancement. Detection of hepatocellular carcinomas can be improved by use of dynamic scanning techniques. These and other principles of the use of currently available gadolinium chelates are reviewed in this article. PMID- 8673716 TI - Liver. II: Iron oxide-based reticuloendothelial contrast agents for MR imaging. Clinical review. AB - Iron oxide-based compounds are a new class of MR contrast agents that have a wide range of clinical applications. The biodistribution and subsequent influence on the MR image depends on the particle size. Iron oxides can be used to increase contrast-to-noise ratio, facilitating the visibility of focal liver lesions. Other applications include blood-pool imaging and targeting the reticuloendothelial system and cell surface receptors. PMID- 8673717 TI - Liver. III: Gadolinium-based hepatobiliary contrast agents (Gd-EOB-DTPA and Gd BOPTA/Dimeg). AB - Gd-EOB-DTPA and Gd-BOPTA/Dimeg are two paramagnetic contrast agents that are unlikely ECF contrast agents but that are selectively taken up by hepatocytes and yield a selective enhancement of the liver parenchyma on T1-weighted images. Gd EOB-DTPA yields hepatocellular specific uptake within the biliary excretion rate of 50% of the injected dose. Gd-BOPTA/Dimeg is taken up by hepatocytes in a small portion (2%-4%); however, its high relaxivity provides a significant and sustained increase of signal intensity of the normal liver. Both compounds have demonstrated a safe pharmacologic and toxicologic profile on preclinical evaluation and phase I clinical trials. Preliminary results demonstrate that these contrast agents may improve the MR imaging capability to detect focal liver lesions, with a dramatic and selective increase of liver signal-to-noise ratio and lesion-liver contrast-to-noise ratio. The wide imaging window, allowed by the sustained enhancement achieved after injection also provides flexibility in selecting an imaging sequence. PMID- 8673718 TI - Mangafodipir trisodium injection (Mn-DPDP). A contrast agent for abdominal MR imaging. AB - Mangafodipir trisodium (Mn-DPDP) is one of several recently developed targeted hepatobiliary agents. Contrast-to-noise measurements have shown favorable results for Mn-DPDP-enhanced MR as compared with nonenhanced T1- and T2-weighted images. An improved capability for lesion detection and the ability to characterize tumors of hepatocellular origin have been demonstrated. The prolonged enhancement obtained with Mn-DPDP provides an extended window of time during which effective contrast is maintained as compared with traditional extracellular contrast agents. This report details the experimental and initial clinical experience with Mn-DPDP-enhanced MR imaging of the abdomen. PMID- 8673719 TI - Contrast-enhanced MR imaging of the pancreas. AB - Recent MR techniques such as breath-hold imaging, fat suppression, and dynamic imaging after intravenous administration of gadolinium chelates have reduced artifacts in the abdomen, resulting in an increased role of MR imaging in the evaluation of pancreatic disease. The extracellular contrast agent gadolinium chelate has been shown to enhance normal pancreatic tissue in a homogeneous fashion. Contrast between normal pancreatic tissue and tumor tissue on T1 weighted images may be improved after administration of gadolinium. Because of the lesser vascularization of pancreatic ductal cancers as compared to the normal glandular tissue, the differences in signal intensity are often greatest in the capillary phase immediately after contrast administration. In addition, the hypervascular nature of islet cell tumors, results in good definition of primary tumor and liver metastases on immediate post-gadolinium images. PMID- 8673720 TI - Intracellular transport and maturation of nascent low density lipoprotein receptor is blocked by mutation in the Ras-related GTP-binding protein, RAB1B. AB - The relationship between the Ras-related GTP-binding protein, Rab1B, and intracellular transport of nascent low density lipoprotein (LDL) receptor was studied in cultured human embryonic kidney cells (line 293) cotransfected with plasmids encoding the LDL-receptor and either wild-type Rab1B or a Rab1B mutant (N121I) known to act as a dominant suppressor of endogenous Rab1B function. [35S]Methionine pulse-chase analysis of immunoprecipitated LDL-receptor indicated that coexpression with Rab1BN121I, but not Rab1BWT, impaired its conversion from the Endo-H-sensitive 120-125 kDa form to the O-glycosylated 160-170 kDa form, consistent with a block in ER-->Golgi trafficking of the nascent receptor. In cells expressing Rab1BN121I, the newly synthesized LDL-receptor was unable to reach the cell surface as evidenced by its inaccessibility to sulfo-NHS-biotin added to the cultures. These observations provide a direct demonstration of Rab protein involvement in LDL receptor trafficking and lend support to the concept of Rab1B as a universal mediator of ER-->Golgi transport of membrane glycoproteins in mammalian cells. PMID- 8673722 TI - Insulin receptor transmembrane signaling: evidence for an intermolecular oligomerization mechanism of activation. AB - To evaluate the mechanism of ligand activation of the insulin receptor we have generated mutant receptor cDNAs which encode proteins with oligopeptide linkers between the carboxy terminus of the extracellular domain and the transmembrane domain of the molecule. Mutant cDNAs encoding a rigid alpha helical insert (HIR NQDVD) or a flexible polyglycine insert (HIR G12) were expressed in CHO Kl cells. Both basal and insulin stimulated autophosphorylation in vitro and in vivo of the expressed receptors were indistinguishable from those of wild type receptor expressed in the same cells. These findings suggest that ligand binding can activate the insulin receptor by an intermolecular dimerization mechanism. PMID- 8673721 TI - Actions of terazosin and its enantiomers at subtypes of alpha 1- and alpha 2 adrenoceptors in vitro. AB - Terazosin and its enantiomers, antagonists of alpha 1-adrenoceptors, were studied in radioligand binding and functional assays to determine relative potencies at subtypes of alpha 1- and alpha 2-adrenoceptors in vitro. The racemic compound and its enantiomers showed high and apparently equal affinity for subtypes of alpha 1 adrenoceptors with Kl values in the low nanomolar range, and showed potent antagonism of alpha 1-adrenoceptors in isolated tissues, with the enantiomers approximately equipotent to the racemate at each alpha 1-adrenoceptor subtype. At alpha 2b sites, R(+) terazosin bound less potently than either the S(-) enantiomer or racemate. R(+) terazosin was also less potent than the S(-) enantiomer or the racemate at rat atrial alpha 2B receptors. These agents were not significantly different in their potencies at alpha 2a or alpha 2A sites. Since the high affinity for alpha 2B sites of quinazoline-type alpha-adrenoceptor antagonists has been used to differentiate alpha 2-adrenoceptor subtypes, the low affinity of R(+) terazosin for these sites was unexpected. Because terazosin or its enantiomers are approximately equipotent at alpha 1-adrenoceptor subtypes, the lower potency of R(+) terazosin at alpha 2B receptors indicates a somewhat greater selectivity for alpha 1-compared to alpha 2B adrenoceptor subtypes. The possible pharmacological significance of this observation is discussed. PMID- 8673723 TI - Characterization of a low affinity binding site for N6-substituted adenosine derivatives in rat testis membranes. AB - The binding characteristics of radiolabeled N6-(cyclohexyl)adenosine ([3H]CHA), N6-(R-phenylisopropyl)adenosine ([3H]R-PIA), 5'-N-ethyl-carboxamidoadenosine ([3H]NECA), and 2-[4-(2-carboxyethyl)phenyl]ethyl-amino-5'-N ethylcarboxamidoadenosine ([3H]CGS 21680), to rat testis membranes were investigated. Specific binding of [3H]CGS 21680, a selective agonist for the A2a adenosine receptor, was very modest whilst the nonselective agonist [3H]NECA bound to rat testis membranes showing high binding capacity. At least two types of binding sites for [3H]NECA could be identified in rat testis membranes: high affinity sites and high capacity sites. Selective agonists for the A1 adenosine receptor, [3H]CHA and [3H]R-PIA bound with high affinity to a single class of binding sites. This high affinity binding site showed the typical pharmacological specificity of the A1 adenosine receptor with a potency order for agonists of CHA > or = R-PIA > NECA > N6-(S-phenylisopropyl)adenosine (S-PIA). In order to detect the presence of the A3 adenosine receptor in these membranes we selectively blocked the A1 receptor with a large molar excess of a xanthine antagonist, either 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) or xanthine amine congener (XAC). In the presence of an antagonist a low affinity binding site for [3H]CHA and [3H]R-PIA was detected. This low affinity binding site showed a different pharmacological specificity than the high affinity binding site. In fact the potency order for agonists was CHA > or = NECA = R-PIA > S-PIA. This finding suggests that the low affinity binding site represents the A3 adenosine receptor. PMID- 8673724 TI - Characterization of interleukin-13 receptor in carcinoma cell lines and human blood cells and comparison with the interleukin-4 receptor. AB - The interleukin-13 receptor is characterized by ligand-binding and crosslinking studies and compared with the interleukin-4 receptor. Crosslinking of radio labeled hIL-4 and hIL-13 to the receptors on human carcinoma and mast cell lines demonstrated a predominant subunit at 130 kDa with two other minor bands of lower molecular mass (75 kDa and 65 kDa) in autoradiography. All binding of 125I-IL-13 was specifically blocked when the carcinoma cell suspensions were incubated with an excess of unlabeled hIL-4. However, unlabeled hIL-13 was unable to completely displace 125I-hIL-4 from the 130 kDa protein. In addition, 125I-hIL-13 showed no binding to mouse fibroblast cells transfected with human 130 kDa hIL-4 receptor c DNA. Using weighted nonlinear computer modeling of the data from several equilibrium binding studies with human mast cells, a model of two binding sites for IL-4 (Kd = 50 and 190 pmol/L) and one site for IL-13 (Kd = 100 pmol/L) fitted better than a one site model with a very high level of significance (F = 10.66, P < 0.0001). It can be concluded that human IL-4R and hIL-13R are similar but distinct. This conclusion is supported here for the first time by a strong statistical criterion. PMID- 8673725 TI - Isolation and characterization of neurokinin A receptor cDNAs from guinea-pig lung and rabbit pulmonary artery. PMID- 8673726 TI - The helix-loop-helix gene SCL: implicated in T-cell acute lymphoblastic leukaemia and in normal haematopoietic development. AB - The SCL gene encodes a member of the helix-loop-helix family of transcription factors and was first identified through its involvement in a chromosomal translocation in a human leukaemic cell line. SCL is now recognized to be aberrantly expressed in most human T-cell leukaemias. In around 25% of cases SCL overexpression is associated with identifiable chromosomal abnormalities but in other cases the mechanism of ectopic expression has not yet been identified. SCL is normally expressed in haematopoietic progenitor cells, erythroid cells, mast cells and megakaryocytes. Gene delivery experiments using haematopoietic cell lines and the recent creation of mice with a null mutation of the SCL gene have demonstrated that SCL plays a crucial role in haematopoietic commitment and differentiation. PMID- 8673727 TI - Insulin-like growth factor-binding proteins (IGFBPs) and their regulatory dynamics. AB - The IGFBPs are a family of homologous proteins that have co-evolved with the IGFs and that confer upon the IGF regulatory system both functional and tissue specificity. IGFBPs are not merely carrier proteins for IGFs, but hold a central position in IGF ligand-receptor interactions through influences on both the bioavailability and distribution of IGFs in the extracellular environment. In addition, IGFBPs appear to have intrinsic biological activity independent of IGFs. The current status of research on IGFBPs is reviewed herein. Following a brief introduction to the entire IGF/IGFBP system, separate sections for each of the six cloned mammalian IGFBPs, the most extensive for IGFBP3, cover selected topics that emphasize the dynamics of IGFBPs--that is, their regulation in cells, their functionally important post-translational modifications, and their interactions in the cellular microenvironment--and how these dynamics influence physiological function. PMID- 8673728 TI - Calcium phosphate transfection and cell-specific expression of heterologous genes in primary fetal rat hepatocytes. AB - In order to study transcriptional regulation of hepatic genes during development, a method for transfer of fusion genes to primary cultures of fetal hepatocytes was required. The aim of this study was to assess currently available transfection methods and optimize the best method for use with cultured fetal hepatocytes. The Rous sarcoma virus 5' long terminal repeat controlling transcription of the beta-galactosidase reporter gene (pRSV lac Z II) was used to assess electroporation, lipofection, DEAE-dextran and calcium phosphate transfection in cultured primary fetal hepatocytes. The success of transfection was determined by histochemical detection and quantitation of beta-galactosidase activity. Results showed that calcium phosphate transfection was optimal for fetal hepatocytes with respect to beta-galactosidase activity and cell survival. For maximum transfection of cells, 10 micrograms/ml DNA, HEPES buffered saline transfection buffer at pH 7.05 and a 24 hr expression period for the reporter gene were employed. Glycerol shock did not increase transfection efficiency significantly. The method was simplified by adding calcium chloride solution to DNA diluted in transfection buffer and the resulting co-precipitate added directly to the medium covering the cells. Transfection 24 hr after initial culture and a precipitate incubation time of 20 hr were optimal. The suitability of this method was confirmed with a liver-specific promoter controlling beta galactosidase and chloramphenicol acetyltransferase expression. In conclusion this study shows that a modified calcium phosphate transfection method is most effective for transferring DNA to primary cultured fetal hepatocytes. It is concluded that this method is appropriate for use with fetal hepatocytes and will facilitate studies of gene regulation during liver development. PMID- 8673730 TI - Inner membrane anion channel and dicarboxylate carrier in brown adipose tissue mitochondria. AB - In brown adipose tissue mitochondria, the anion transport proteins should respond to regulatory mechanisms controlling the thermogenic or resting state. We re evaluated the role of transport of organic/metabolite anions in these mitochondria, namely with regards to delta pH-regulation and substrate specificity. Valinomycin-induced osmotic swelling in potassium salts indicated by light scattering either directly on a fluorometer, or as the reciprocal absorbance, was used to characterize the anion uniport. A delta pH "jump" was thus created in respiring mitochondria and the delta pH-driven transport was studied. The two major features are reported: (1) existence of the inner membrane anion channel exhibiting the same full spectrum of anion and inhibitor specificity as in liver; and (2) existence of dicarboxylate carrier, so far disputed in brown adipose tissue mitochondria. The inner membrane anion channel was activated either by elevating delta pH in respiring mitochondria or by depleting matrix Mg2+ at alkaline pH. Dicarboxylate carrier was activated by elevated delta pH under conditions when the channel was blocked. A specific delta pH regulation could explain this activation and silence of the carrier in early studies. In conclusion, wide substrate specificity makes the inner membrane anion channel suitable for the regulation of volume homeostasis and a feed-back control between the delta psi-driven and the delta pH-driven transport. The delta pH activated dicarboxylate carrier is essential in the coupled state for malate uptake which enables fatty acid synthesis, while, in the uncoupled state, inaccessibility of dicarboxylates favors oxidation of fatty acids or pyruvate. PMID- 8673729 TI - Elevation of acid glycosidase activities in thyroid and gastric tumors. AB - Numerous investigators have suggested that cell glycoconjugates are modified by the development of cancer and the progression of this to a malignant form. Accordingly, in the present work, beta-D-galactosidase, alpha-L-fucosidase, beta N-acetyl-D-glucosaminidase and beta-N-acetyl-D-galactosaminidase activities were studied in human thyroid and gastric tumours. Samples were obtained from human gastric mucosa and thyroid gland tumours together with a part of the surrounding normal tissue (control). Enzyme activity was determined spectrophotometrically based on the release of p-nitrophenol from suitable p-nitrophenyl-derivative substrates. Results showed that beta-D-galactosidase, alpha-L-fucosidase, beta-N acetyl-D-glucosaminidase and beta-N-acetyl-D-galactosaminidase activities were detected in tumour and control samples from thyroid and gastric tissues. The gastric mucosa also showed alpha-L-mannosidase activity. The specific activities of these glycosidases were higher (two- or three-fold) in tumour tissues as compared with their controls. beta-D-galactosidase, beta-N-acetyl-D glucosaminidase and beta-N-acetyl-D-galactosaminidase activities from thyroid and gastric tumours showed a significant increase in V(max) as compared with their respective controls (P < 0.05 or P < 0.001). Thyroid alpha-L-fucosidase activity showed a statistically and significantly increased affinity (lower K(m)) in tumour samples as compared to normal tissue. In conclusion both gastric and thyroid tumours showed enhanced glycosidase activity as compared with enzyme activity observed in normal tissue. These results are in agreement with the notion of a markedly raised degradation within lysosomes of tumour cells. PMID- 8673731 TI - The primary structure and enzymic properties of porcine prochymosin and chymosin. AB - Preliminary investigations by N-terminal sequence analysis showed that pig and calf chymosin possessed 80% amino acid sequence identity but showed considerable differences in their enzymatic properties. A comparison of their structures may therefore contribute to an understanding of the significance of the amino acid residues responsible for the differences in these properties. Pig chymosis was extracted from the stomachs of pigs of less than 3 weeks of age, and was purified by ion exchange chromatography. Half of the primary structure was determined by amino acid sequencing and the complete structure was deduced from a cloned chymosin cDNA. Results showed that the zymogen showed 81% sequence identity with calf prochymosin and 57% identity with pig pepsinogen A. The size of the propart and location of the residue which becomes the N-terminus in the active molecule were the same in the prochymosins. The maximum general proteolytic activity at pH 3.5 of pig chymosin was 2-3% of that of the activity of pig pepsin A at pH 2, whereas the milk clotting activity relative to the general proteolytic activity of pig chymosin was much higher than that of calf chymosin. Agar gel electrophoresis at pH 5.3 of stomach extracts of individual pigs showed the existence of two predominant genetic variants of zymogen and enzyme. The two variants could not be distinguished by amino acid composition or N-terminal sequencing, and no differences in the enzymatic properties of the genetic variants were observed. It was concluded that of the residues that participate in the substrate binding, calf and pig chymosin differ in the following positions (pig pepsin numbering, subsites in parentheses): Ser 12 Thr (S4), Leu 30 Val (S1/S3), His 74 Gln (S'2), Val 111 Ile (S1/S3), Lys 220 Met (S4). With regard to the low general proteolytic activity of pig chymosin, the substitution Asp 303 Val relative to calf chymosin may contribute to an explanation of this. PMID- 8673732 TI - Evidence for secretion of cytosolic CuZn superoxide dismutase by Hep G2 cells and human fibroblasts. AB - The role so far ascribed to intracellular CuZn superoxide dismutase is that of an intracellular scavenger of oxygen radicals. However, other functions of cytosolic CuZn superoxide dismutase have been hypothesized. For example, CuZn superoxide dismutase incubated with rat hepatocyte cells in culture inhibits 3-hydroxy 3methylglutaryl CoA reductase, thereby reducing cholesterol synthesis. We recently demonstrated the presence of surface membrane receptors for CuZn superoxide dismutase, suggesting possible autocrine or paracrine activities. The aim of the present study was to investigate whether cytosolic CuZn superoxide dismutase can be secreted by human hepatocarcinoma and fibroblast cells lines. Proteins in human hepatocellular carcinoma (Hep G2) cells and human fibroblasts were biosynthetically labelled with [35S]-cysteine; then cell lysates and media were immunoprecipitated with rabbit polyclonal anti-human CuZn superoxide dismutase antibodies and separated by 12% polyacrylamide gel electrophoresis. Both Hep G2 cells and human fibroblasts produce and secrete CuZn superoxide dismutase which was detectable in cells and medium as a single protein band with the same electrophoretic mobility as human erythrocyte CuZn superoxide dismutase. These data suggest that CuZn superoxide dismutase, an enzyme thus far considered to be located exclusively intracellularly is secreted by at least two cell lines. This is consistent with autocrine or paracrine roles for CuZn superoxide dismutase. PMID- 8673733 TI - Identification of a glycosylphosphatidylinositol-anchored glycoprotein with nucleoside phosphatase activity on the membrane of pig pancreatic zymogen granules. AB - The molecular events between the second messenger-mediated triggering of regulated exocytosis and the subsequent fusion of the secretory granules with the apical plasma membrane are unclear. The glycoprotein GP-2, the most abundant of the very few proteins of the pancreatic zymogen granule membrane has been cloned and sequenced in dog and rat, but no (enzymatic) function has so far been ascribed to it. Nucleoside phosphatase activities associated with the pig zymogen granule membrane were recently assumed to be related to GP-2. To identify the protein(s) carrying these activities we have used a novel combination of native and denaturing one- and two-dimensional polyacrylamide gel electrophoresis in the detergents CHAPS, Triton X-100 or SDS. Histochemical examination on the gels and incubation with lectins and phosphatidylinositol phospholipase-C have allowed characterization of the protein with the nucleoside di- and tri-phosphatase activities. SDS-PAGE of the single protein spot with nucleoside phosphatase activity excised from Triton X-100 2-dimensional gels showed the presence of 92 kDa and 67 kDa glycoproteins. The isolated protein had an isoelectric point of 5.2, formed high molecular weight complexes, was shown to be glycosylphosphatidylinositol-anchored and contained complex carbohydrate structures. It hydrolyses di- and tri-phosphate nucleotides in dependence of the glycosylphosphatidylinositol anchor and is sensitive to non-mitochondrial diphosphohydrolase inhibitors. In summary, this paper identifies GP-2 as a nucleoside phosphatase within the zymogen granule membrane, suggesting it may be involved in energy-requiring processes on the cytosolic side of the granules. PMID- 8673734 TI - Effect of three novel polyamine oxa-analogues (MTR-OSPD, DIP-SPN and APPO-TFA) on the growth and proliferation of Swiss 3T3 cells. AB - In order to investigate their biological function on cellular polyamine content, cell growth and proliferation, three novel polyamine oxa-analogues, 5-(4-methoxy 2,3,6-trimethylbenzenesulfonyl)-6-oxa-spermidine (MTR-OSPD); 6,9-dioxa-5,10-di (2,2,5,7,8-pentamethylchroman-6-sulfonyl) spermine (DIP-SPN) and 3-aminopropyl N (3-phthalimidopropyloxy) trifluoroacetimidate (APPO-TFA) were tested for their ability to stop or slow down the growth of Swiss 3T3 cells. Cells at 50-60% confluency were grown for 24 or 48 hr in the presence of a wide range of polyamine oxa-analogue concentrations and the number of cells counted. To determine whether the drugs were cytotoxic or cytostatic, the analogue-containing medium in some vials was replaced with fresh culture medium after 48 hr and the cells incubated for a further 24 hr. Cellular protein, RNA, DNA, polyamine contents and the activities of ornithine decarboxylase, S-adenosyl-L-methionine decarboxylase and spermidine/spermine N1-acetyltransferase were also determined at the lowest effective analogue concentration. All three inhibitors stopped cell proliferation at concentrations over 100 microM. Both MTR-OSPD and DIP-SPN were cytotoxic, since the cells could not be revived by removing the inhibitor from the medium, whereas APPO-TFA was only cytostatic. At the lowest effective concentration the analogues had little effect on protein, RNA and DNA content of the cells, but had varying effects on polyamine metabolism. The most interesting analogue was APPO-TFA. This drug showed concentration-dependent growth inhibition between concentrations of 5 nM and 5 microM. These novel analogues may be of value in elucidating the precise functions of polyamines in cellular metabolism. Their exact mode of action is now under investigation. PMID- 8673735 TI - A mass screening device of genome by polymerase chain reaction-restriction fragment-single strand conformation polymorphism analysis. AB - We have developed a new genome screening method and named it as polymerase chain reaction-restriction fragment-single strand conformation polymorphism (PCR-RF SSCP) analysis. This method consists of three steps: (1) amplification of long DNA by PCR; (2) digestion of the amplified PCR products by restriction enzyme(s) and labelling the restriction sites; (3) polyacrylamide gel electrophoresis under non-denaturating conditions (SSCP analysis) and under denaturating conditions containing 8M urea. Theoretically, this method enables us to detect even a base substitution, deletion or insertion in up to 22,000 base pairs amplified from genomic DNA by PCR in one analysis. The procedures are very simple, reproducible and require no special apparatus. This method is applicable to any genes already known and we believe that this method is very useful for mass screening of the genome. PMID- 8673736 TI - Simplified riboprobe purification using translucent straws as gel tubes. AB - Gel purification of radioactive riboprobes enhances the quality of the ribonuclease protection assay. A simple and effective method for riboprobe purification is described. The method uses acrylamide gels in plastic tubes to achieve electrophoretic separation of the RNA polymerase products. PMID- 8673737 TI - A recombinant PCR approach requiring only three non-chimeric primers to generate a minigene of interest. AB - The recombinant PCR allows construction of chimeric molecules. Here we describe this approach utilizing non-chimeric primers. Unlike previous recombinant PCR methods, this approach eliminates the need of multiple sets of primers and multiple rounds of PCR making it an economical and expeditious alternative. We have used this approach to generate an FGF-1 minigene. PMID- 8673738 TI - Efficient preparation of short DNA sequence ladders potentially suitable for MALDI-TOF DNA sequencing. AB - Duplex probes with five-base single-stranded overhangs were developed for positional sequencing by hybridization [Broude et al., Proc Natl Acad Sci USA 91:3072-3076, 1994]. The partially duplex probes can be employed to capture single-stranded oligonucleotide targets and form primer-template complexes. Recently we showed that partially duplex probes can prime Sanger sequencing reactions on immobilized, but non-ligated long single-stranded targets (approximately 500 nucleotide) [Fu et al., Proc Natl Acad Sci, in press]. Here immobilized, non-ligated partially duplex probes were used to capture and sequence short single-stranded targets. This strategy is capable of rapidly preparing large numbers of samples for future mass spectrometric DNA sequencing. PMID- 8673739 TI - Northern analysis of highly folded goat alpha S1 casein mRNA. AB - Northern blotting using glyoxal to denature a highly folded mRNA, such as goat alpha S1-Casein E, can lead to the detection of multiple incompletely denatured forms. Formaldehyde appears to be the most suitable agent for Northern blotting due to its effective denaturing capacity and lower toxicity than methylmercuric hydroxide. PMID- 8673740 TI - Differential expression of AF4/FEL mRNA in human tissues. AB - This manuscript reports the differential expression of the AF4 gene among human tissues. AF4 mRNA is highly expressed in normal placental tissue which correlates with the newborn age of patients presenting with leukemia characterized by the MLL/AF4 gene rearrangement. PMID- 8673741 TI - From hybridization image to numerical values: a practical, high throughput quantification system for high density filter hybridizations. AB - Hybridization to sets of bacterial colonies or PCR products arrayed on high density filters is used in a number of experimental schemes. In many cases it is desirable to collect quantitative information ('hybridization signatures') rather than indications on 'positive' and 'negative' colonies. We present a practical system, based on an imaging plate analyser and a customized version of commercial software, that makes such quantification feasible, and define its performance in terms of reproducibility and linearity. The system is far superior to methods based on autoradiography and should be useful in many projects that involve the increasingly popular high density filter format. PMID- 8673742 TI - Coronary stenting: has the rubicon been crossed? PMID- 8673743 TI - Class III Antiarrhythmics: put to the SWORD? PMID- 8673744 TI - Syncope and salt. PMID- 8673745 TI - The physics of left ventricular filling: exploring the seemingly obvious. PMID- 8673746 TI - Training for academic cardiovascular medicine. PMID- 8673747 TI - New training guidelines: what are the implications for cardiological research? AB - The recognition of the importance of research experience is welcomed; committed research supervisors should be identified for each trainee and research planning should start as early as possible in the traineeship. It would be welcome if employing authorities and postgraduate deans were to provide personal support for up to one year and modest research expenses for trainees undertaking research. In the absence of such support, application would need to be made to grant-giving bodies well in advance. Certain posts may need to be earmarked for the training of future clinical scientists. Academic units should regard themselves as challenged, but not necessarily threatened, by the new proposals. With appropriate consultation and involvement, and a modest allocation of funding, the overall result should enhance the quality of both service and academic communities. PMID- 8673748 TI - Coronary Palmaz-Schatz stent implantation in acute myocardial infarction. AB - OBJECTIVE: To investigate the feasibility of coronary stenting in acute myocardial infarction. DESIGN: Prospective observational study. PATIENTS: 80 patients undergoing direct balloon angioplasty for acute myocardial infarction who had coronary Palmaz-Schatz stents implanted during a 3 year study period. Indications for stenting were abrupt reocclusion, large dissection with threatened reocclusion, and failure to achieve brisk flow of contrast by angioplasty alone. INTERVENTIONS: After stenting, 50 patients were treated by conventional anticoagulation and 30 patients received antiplatelet therapy with aspirin and ticlopidine. MAIN OUTCOME MEASURES: Death and subacute reocclusion within two weeks. RESULTS: Coronary stenting fully restored vessel patency in 79 patients (98.8%). 10 of 14 patients with symptoms of Killip class IV on admission were discharged from hospital alive. Three of the 66 patients with symptoms of Killip classes I-III died in hospital. Repeat angiography in 59 of these patients, showed 3 symptomatic and 2 silent reocclusions (reocclusion rate 8.5%). No stent thromboses were detected in patients treated with ticlopidine. CONCLUSIONS: Coronary stenting is a safe and effective treatment for complicated direct balloon angioplasty in acute myocardial infarction. In patients with symptoms of Killip classes I to III the risk of subacute reocclusion is comparable to that of bail-out stenting after elective balloon angioplasty. PMID- 8673749 TI - Assessment of coronary artery stenosis by magnetic resonance imaging. AB - OBJECTIVE: The findings of magnetic resonance and x-ray angiography were compared for assessment of coronary artery stenosis in this validation study. BACKGROUND: Magnetic resonance angiography of the coronary arteries has recently been described, but there has been no comparison with x-ray angiography of localisation or assessment of important characteristics of coronary stenosis. METHODS: A breath hold, segmented k-space, 2D gradient echo imaging technique incorporating fat suppression was used in 39 patients (55 coronary stenoses) with known coronary artery disease. RESULTS: Overall, 47 stenoses (85%) were assessed by magnetic resonance (29 of 33 stenoses in the left anterior descending artery, one of one in the left main stem, 14 of 17 in the right coronary artery, and three of four in the left circumflex artery were detected). There was close agreement between magnetic resonance and x-ray angiography for the distance of the stenosis from the arterial origin (magnetic resonance mean (SD) 27 (16) mm versus x-ray angiography 27 (16) mm, P = NS, mean difference -0.2 mm). The distance to 39 stenoses (83%) agreed to within 5 mm, with increased scatter for more distal stenoses. The severity of magnetic resonance signal loss, assessed visually at the site of stenosis, varied significantly according to the percentage diameter stenosis (F = 30, P < 0.0001); stenosis severity with severe signal loss was 89 (7)%, with partial signal was 70 (16)%, and with irregular wall only 37 (11)%, with significant differences among the three groups (P < 0.001). A significant correlation was found between the proportional magnetic resonance signal loss at the stenosis and the percentage diameter stenosis severity (r = -0.67, P < 0.0001). The length of stenosis measured by magnetic resonance (6 (3) mm) was greater than by x-ray angiography (5 (2) mm, P < 0.006, mean difference +1.1 mm). Spearman's rank test showed that there was significant overestimation of stenosis length by magnetic resonance as stenosis severity increased (rs = 0.34, P < 0.02). CONCLUSIONS: Accurate localisation of coronary stenosis and a qualitative assessment of stenosis severity are possible by magnetic resonance, but stenosis length is overestimated as severity increases, probably because of disturbed patterns of flow with turbulence distal to severe stenoses. Reasonable results for the detection of coronary artery stenosis by magnetic resonance were achieved in this highly selected population, but further progress in imaging techniques is necessary before moving towards appreciable clinical application. PMID- 8673750 TI - Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope. AB - OBJECTIVE: To determine whether in patients presenting with posturally related syncope administration of salt increases plasma volume and improves orthostatic tolerance. Patients with poor tolerance of orthostatic stress tend to have lower than average plasma and blood volumes. DESIGN: A double blind placebo controlled study in 20 patients and an open study in 11 of the effects of giving 120 mmol/day of sodium chloride. PATIENTS: 31 patients presenting with episodes of syncope who had no apparent cardiac or neurological disease. Plasma volume was determined by Evans blue dye dilution, orthostatic tolerance by time to presyncope in a test of combined head-up tilt and lower body suction, and baroreceptor sensitivity by the effect of neck suction on pulse interval. RESULTS: 8 weeks after treatment, 15 (70%) of the 21 patients given salt and three (30%) of the placebo group showed increases in plasma and blood volumes and in orthostatic tolerance, and decreases in baroreceptor sensitivity. Improvement was related to initial salt excretion in that patients who responded to salt had a daily excretion below 170 mmol. The patients in the placebo group who improved also showed increases in salt excretion. CONCLUSIONS: In patients with unexplained syncope who had a relatively low salt intake administration of salt increased plasma volume and orthostatic tolerance, and in the absence of contraindications, salt is suggested as a first line of treatment. PMID- 8673751 TI - Time course of platelet alpha granule release in acute myocardial infarction treated with streptokinase. AB - OBJECTIVE: To determine the time course of platelet alpha granule release in patients with acute myocardial infarction treated with streptokinase. DESIGN: A prospective study. SETTING: Coronary care unit. PATIENTS: Nine with myocardial infarction treated with both streptokinase and aspirin, and nine with acute chest pain but without myocardial infarction, who were treated with aspirin only. METHODS: All patients received 250 mg aspirin on admission and 150 mg once daily thereafter. All patients who fulfilled the indications for streptokinase received 1.5 megaunits, in a single infusion. After the initial medication, serial measurements of plasma beta thromboglobulin and plasma platelet factor 4 were performed at fixed intervals after the onset of chest pain. The primary endpoint sought was the peak value of beta thromboglobulin and platelet factor 4 in each individual. RESULTS: The median peak plasma beta thromboglobulin in the infarction group was substantially higher than in those without infarction, at 37 (range 12 to 210) v 15 (9 to 36) mg/litre, P < 0.01. The corresponding values for plasma platelet factor 4 were 4.6 (2.4 to 60.0) v 2.2 (< 2 to 8.5) mg/litre, P < 0.01. Increased values were seen only within the first 12 h after onset of chest pain, and after 12 h there was no difference between the patients with myocardial infarction and those without. Aspirin treatment did not abolish alpha granule release. CONCLUSIONS: In patients with acute myocardial infarction treated with streptokinase the content of the alpha granules is released within the first 12 h after the onset of chest pain. Aspirin apparently does not abolish this release. PMID- 8673752 TI - Release of endogenous vasopressors during and after cardiopulmonary resuscitation. AB - OBJECTIVE: To assess whether plasma endothelin, adrenaline, noradrenaline, arginine vasopressin, adrenocorticotropin, and cortisol concentrations were higher during cardiopulmonary resuscitation in patients in whom resuscitation was successful than in those in whom it failed, and to measure the concentrations of these hormones in the immediate post-resuscitation phase. DESIGN: Prospective, descriptive study. SETTING: Emergency medical service at a university hospital. PATIENTS: 60 patients with cardiac arrest out of hospital. INTERVENTIONS: Blood samples were drawn and blood pressure and heart rate were measured during cardiopulmonary resuscitation, before and after the first dose of adrenaline was given and at 5, 15, 30, and 60 minutes after the restoration of spontaneous circulation. Plasma hormone concentrations were measured by radio-immunoassays. RESULTS: 24 of the 60 patients were successfully resuscitated and admitted to hospital: 36 were not. During cardiopulmonary resuscitation before adrenaline was given, the plasma concentration of endothelin (mean (SEM)) in resuscitated and in not resuscitated patients was 4.3 (0.9) pg/ml and 5.5 (0.4) pg/ml respectively (NS), adrenaline was 14.1 (2.0) ng/ml and 25.3 (3.6) ng/ml (P < 0.01), noradrenaline was 5.0 (0.9 ng/ml) and 8.4 (1.1 ng/ml) (P < 0.05), arginine vasopressin was 193 (28) pg/ml and 70 (9) pg/ml (P < 0.001), adrenocorticotropin was 128 (34) pg/ml and 57 (6) pg/ml (P < 0.05), and cortisol was 18 (3) microgram/dl and 15 (2) microgram/dl (NS). During cardiopulmonary resuscitation after adrenaline was given endothelin in resuscitated and in not resuscitated patients was 4.0 (1.0) pg/ml and 5.3 (0.5) pg/ml (NS), adrenaline was 145 (16) ng/ml and 201 (21) ng/ml (P < 0.05), noradrenaline was 3.9 (0.9) ng/ml and 8.3 (1.1) ng/ml (P < 0.01), arginine vasopressin was 177 (27) pg/ml and 58 (9) pg/ml (P < 0.001), adrenocorticotropin was 234 (92) pg/ml and 85 (9) pg/ml (P < 0.001), and cortisol was 17 (2) microgram/dl and 13 (2) microgram/dl (NS). CONCLUSIONS: Despite a tremendous adrenosympathetic response, the lower arginine vasopressin and adrenocorticotropin concentrations during cardiopulmonary resuscitation in patients in whom resuscitation failed may influence vital organ perfusion and hence the success of resuscitation. Plasma concentrations of arginine vasopressin and adrenocorticotropin may have a more important effect on outcome than previously thought. PMID- 8673753 TI - Effect of acute alterations in afterload on left ventricular function in patients with combined coronary artery and peripheral vascular disease. AB - OBJECTIVE: To assess the effect of acute alterations in afterload by aortoiliac clamping, during peripheral vascular surgery, on left ventricular function. DESIGN: Prospective examination of the left ventricular long axis and transmitral Doppler flow preoperatively and intraoperatively; before aortic clamping, during clamping and 5 min, 15 min, and 5 days after unclamping. SETTING: A tertiary referral centre for cardiac and vascular disease equipped with invasive and non invasive facilities. PATIENTS: 20 patients (11 men; mean (SD) age 61 (8) years) with significant aortoiliac disease and documented coronary artery disease and 21 normal controls of similar age. RESULTS: Preoperatively: long axis function was abnormal compared with that in normal controls. In systole total long axis excursion and peak shortening rate were reduced, onset of shortening delayed, and there was pre-ejection lengthening (P < 0.001). In diastole there was abnormal shortening during isovolumic relaxation, delaying the onset of long axis lengthening (P < 0.001). Peak lengthening rate was also reduced and A wave excursion increased (P < 0.001). Transmitral Doppler showed increased A wave velocity and reduced peak E/A diastolic flow velocities ratio (P < 0.001). Intraoperatively: preclamping results did not differ from those before operation. With clamping the extent of systolic and diastolic abnormalities promptly increased as to a lesser extent did those of transmitral flow velocity, although heart rate and blood pressure did not change significantly. Total long axis excursion and A wave amplitude were more reduced by aortic than iliac clamping, whereas the onset of lengthening was more delayed and the lengthening velocity more reduced with iliac clamping. Some 5 min after unclamping systolic long axis function had already returned towards normal; total excursion increased, as did the peak shortening rate, and the onset of shortening became less delayed (P < 0.001). In diastole the delayed onset of lengthening regressed, its lengthening velocity increased, and A wave excursion fell (P < 0.001). Early diastolic transmitral flow velocity also increased. This improvement in systolic and diastolic long axis function had progressed 15 min after unclamping but showed no further change at 5 days. At 5 days after operation, however, systolic and diastolic measurements had improved compared with those preoperatively. CONCLUSION: Resting left ventricular long axis function is abnormal in patients with combined coronary artery disease and peripheral vascular disease. It is unaffected by anaesthesia but deteriorates with aortic or iliac clamping, although blood pressure remains unchanged. It promptly improves with unclamping after successful peripheral arterial reconstruction. Thus, even in apparently stable coronary artery disease, resting subendocardial function is labile, showing pronounced alterations with changing after-load, even when arterial pressure itself does not change. PMID- 8673754 TI - Effects of lacidipine on peak oxygen consumption, neurohormones and invasive haemodynamics in patients with mild to moderate chronic heart failure. AB - OBJECTIVE: To evaluate the efficacy and safety of the second generation dihydropyridine calcium channel blocker lacidipine in patients with heart failure. DESIGN: Placebo controlled, parallel group, double blind study over 8 weeks. SETTING: General community hospital in Breda, The Netherlands. PATIENTS: A random sample was studied of 25 outpatients with symptoms of mild to moderate heart failure, despite treatment with diuretics, digoxin, and angiotensin converting enzyme inhibitors. Their mean age was 65 years, with mean left ventricular ejection fraction of 0.24 and a peak oxygen consumption of 14.4 ml/min/kg. Two patients dropped out on lacidipine, one patient on placebo. INTERVENTION: Treatment with lacidipine 4 mg once daily or placebo for eight weeks. MAIN OUTCOME MEASURE: Cardiopulmonary exercise testing, invasive haemodynamics, and plasma neurohormones. RESULTS: Treatment with lacidipine 4 mg once daily, as compared to placebo treatment, significantly improved peak oxygen consumption (P < 0.02), cardiac index (P < 0.01), and stroke volume (P < 0.03) paralleled by a decrease in systemic vascular resistance (P < 0.03) and arteriovenous oxygen content difference (P < 0.01). Plasma noradrenaline, plasma renin activity, and aldosterone values did not differ between lacidipine and placebo. CONCLUSIONS: This second generation dihydropyridine may be of value as an adjunct to standard treatment in congestive heart failure patients. PMID- 8673756 TI - Acute pulmonary vasodilatory properties of amlodipine in humans with pulmonary hypertension. AB - OBJECTIVE: Calcium antagonists are the only oral vasodilators shown to influence mortality in primary pulmonary hypertension, but the high doses required are often poorly tolerated. Amlodipine is a novel, relatively well tolerated, calcium antagonist. It has not been previously tested in humans with pulmonary hypertension. DESIGN: Calcium antagonists are claimed to be of benefit in the 20 30% of patients who respond--that is, whose mean pulmonary artery pressure and pulmonary vascular resistance decreased by 20% after acute administration. Increasing oral doses of amlodipine (up to 40 mg) were given and haemodynamic measurements were obtained by the use of indwelling pulmonary artery catheters 12 h after each dose. SETTING: Large teaching hospital, primary referral centre. PATIENTS: Six patients (four women; age range 37-78 years) with pulmonary hypertension (one with primary pulmonary hypertension, five with thromboembolic disease. MAIN OUTCOME MEASURES: Mean pulmonary artery pressure and pulmonary vascular resistance decreased by greater than 20% in two patients, mean pulmonary artery pressure decreased by greater than 20% in one patient with a pulmonary vascular resistance reduction of 19%. Thus, two of six patients responded to amlodipine and one partially responded. RESULTS: The whole group mean (SEM) pulmonary artery pressure decreased from 47.7 (4.2) to 41.7 (4.4) mm Hg and mean pulmonary vascular resistance from 8.6 (2.1) to 7.1 (1.8) Wood units. Cardiac output rose by a mean (range) of 4% (-20.8 to+20.8), heart rate by 8.8% (-10 to +33), and systemic systolic blood pressure decreased by 12% (-29.2 to -5.8) and diastolic blood pressure by 6.8% (-28.2 to+20.0). There were no symptoms of systemic hypotension. CONCLUSION: These results show that oral amlodipine can produce acute pulmonary vasodilatation in patients with pulmonary hypertension. Further studies are required, but amlodipine may prove to be of value in the treatment of primary pulmonary hypertension. PMID- 8673757 TI - Demographic characteristics of patients undergoing aortic valve replacement for stenosis: relation to valve morphology. AB - OBJECTIVE: To determine the relative importance of the different causes of isolated aortic valve stenosis in a surgical series, and to relate these to patient characteristics including the rate of insertion of bypass grafts for coronary artery disease. DESIGN: Survey of the clinical and pathological data on patients undergoing aortic valve replacement for isolated stenosis. SETTING: Tertiary care cardiothoracic surgical unit. PATIENTS AND METHODS: 465 adult patients undergoing aortic valve replacement representing a consecutive series in one surgical unit. Retrospective review of patients records and classification of cause of aortic stenosis based on pathological examination of excised valve cusps. RESULTS: 63.7% patients had calcific bicuspid valves, 26.9% tricuspid calcific valves, and 5.4% rheumatic, 2.6% mixed pathology and 1.5% unicommissural valves. The ratio of males to females for bicuspid valves was 1.85:1 and for tricuspid calcific valves 0.76:1. The mean age of patients with bicuspid valves was 64.9 years compared with 73.4 years for those with tricuspid valves. Some 22.3% of patients with bicuspid valves and 44.8% of those with tricuspid valves had sufficient coronary artery disease to necessitate insertion of coronary bypass grafts. The differential rate of insertion of coronary bypass grafts was independent of age. CONCLUSIONS: Bicuspid calcified aortic valves are the predominant cause of isolated aortic valve stenosis followed by tricuspid calcified aortic valves. The sex and age distribution of bicuspid and tricuspid calcific aortic valve stenosis is different. The higher rate of insertion of vascular grafts in tricuspid calcific aortic valves may indicate that risk factors for atherosclerosis enhance cusp calcification in these patients. PMID- 8673755 TI - Drug-induced narrowing of the width of the zone of entrainment as a predictor of the subsequent non-inducibility of reentrant ventricular tachycardia after an additional dose of an antiarrhythmic drug. AB - BACKGROUND: The efficacy of drugs used to treat inducible monomorphic sustained ventricular tachycardia (VT) has been assessed by investigating their ability to suppress inducibility, but the mechanism of the drug action remains to be determined. OBJECTIVES: To determine electrophysiological variables that predict inducibility, divided doses of class I antiarrhythmic drugs were given and their effects were analysed, particularly the ability of the final dose to suppress inducibility. METHODS: The excitable gap was estimated by the zone of entrainment, which was defined as the difference between the cycle length of VT and the longest paced cycle length that interrupted VT during entrainment of VT with rapid pacing at paced cycle lengths in decrements of 10 ms. The cycle length of VT, the block cycle length, and the zone of entrainment were measured in the drug free state and after intermediate and final doses of procainamide, disopyramide, cibenzoline, and mexiletine. RESULTS: Sustained monomorphic VT with a mean (SD) cycle length of 285 (43) ms was induced in 8 patients. It was entrained and interrupted at the block cycle length of 231 (31) ms. The width of the zone of entrainment was 54 (23) ms. In 8 studies VT was not inducible at final doses of procainamide in 4, cibenzoline in 1, and mexiletine in 3. In another 10 studies (procainamide in 4, disopyramide in 1, cibenzoline in 2, and mexiletine in 3), VT remained inducible at the intermediate dose and at the final dose. The cycle length of VT was prolonged to a similar degree in studies of effective and ineffective drugs, but the cycle length that blocked VT was longer at the intermediate dose of the effective drugs. Consequently, the width of the zone of entrainment was significantly narrowed at the intermediate dose of effective drugs and the width of the zone of entrainment was narrower than when ineffective drugs were given (22 (13) ms v 76 (18) or 75 (37) ms at the intermediate and final doses respectively (P < 0.02). CONCLUSION: Drugs that narrowed the zone of entrainment were associated with non-inducibility of VT after the final dose of the drug was given. The baseline variables did not predict the responses to class I antiarrhythmic drugs. PMID- 8673758 TI - Changes in coronary sinus pH during dipyridamole stress in patients with hypertrophic cardiomyopathy. AB - OBJECTIVES: The presence of angina pectoris and myocardial scarring in patients with hypertrophic cardiomyopathy (HCM) suggests that myocardial ischemia is a factor in the pathophysiology of the disease. The clinical evaluation of ischaemia is problematic in HCM as baseline electrocardiographic abnormalities are frequent and thallium-201 perfusion abnormalities correlate poorly with anginal symptoms. Coronary sinus pH measurement using a catheter mounted pH electrode is a validated sensitive technique for the detection of myocardial ischaemia. METHODS AND RESULTS: 11 patients with HCM and chest pain (eight men; mean (SD) (range) age 36 (11) (19-53) years) and six controls (two men; mean (SD) (range) age 49 (11) (31-62) years) with atypical pain and normal coronary angiograms were studied. Eight patients with HCM had baseline ST segment depression of > or = 1 mm and four had reversible perfusion defects during stress 201TI scintigraphy. A catheter mounted hydrogen ion sensitive electrode was introduced into the coronary sinus and pH monitored continuously during dipyridamole infusion (0.56 mg/kg over four min). The maximal change in coronary sinus pH during dipyridamole stress was greater in patients with HCM than in controls (0.082 (0.083) (0 to -0.275) v 0.005 (0.006) (0 to -0.012), P = 0.02). In six patients (four men; mean (SD) (range) age 29 (9) (19-40 years) the development of chest pain was associated with a gradual decline in coronary sinus pH (mean 0.123 (0.089)), peaking at 442 (106) s. There were no relations among left ventricular dimensions, maximal wall thickness, and maximum pH change. In patients with HCM there was a correlation between maximum pH change and maximum heart rate during dipyridamole infusion (r = 0.70, P = 0.02). CONCLUSION: This study provides further evidence that chest pain in patients with HCM is caused by myocardial ischaemia. The role of myocardial ischaemia in the pathophysiology of the disease remains to be determined but coronary sinus pH monitoring provides a method for quantifying and prospectively assessing its effects on clinical presentation and prognosis. PMID- 8673759 TI - Collagen network remodelling and left ventricular function in constrictive pericarditis. AB - OBJECTIVE: To investigate whether patients with constrictive pericarditis have changes in collagen content and architecture that could influence left ventricular function. DESIGN: Cohort study. SETTING: University teaching hospital. PATIENTS: Biopsy specimens of myocardium from 13 patients admitted consecutively for treatment of chronic constrictive pericarditis were compared with normal heart tissue taken at necropsy from 15 patients free of cardiac disease. INTERVENTION: Pericardiectomy through median sternotomy. Biopsy specimens (4 or 5) were taken from the left ventricular free wall. MAIN OUTCOME MEASURES: Biochemical and histological assessment of total collagen content, relative proportion of type I and III collagen, and amount of orthogonal collagen fibre meshwork (crosshatching) in the left ventricular tissue. RESULTS: There was more collagen in the myocardium of patients with constrictive pericarditis than in controls when measured either biochemically by hydroxyproline content (89.4 v 50.4 mg/g dry weight) or by histological measurement of the collagen fraction of the myocardium (2.4% v 7.0%). Neither of these measurements, however, correlated with left ventricular ejection fraction, pulmonary wedge pressure, or right ventricular end diastolic pressure. The thickness of the fibrous trabeculae in the myocardium was, however, inversely related to both left ventricular ejection fraction (r = -0.76) and deceleration time (r = -0.68). Trabecular thickening was also related to NYHA class, with those in class III and IV having the greatest thickening. CONCLUSION: Changes in collagen content and architecture may contribute to impaired ventricular function in patients with chronic constrictive pericarditis. PMID- 8673760 TI - Outcome of isolated congenital complete heart block diagnosed in utero. AB - OBJECTIVE: To establish identifiable prenatal factors in fetal heart block which might predict death in utero, the need for intervention, or the probability of pacemaker requirement. SETTING: Tertiary referral unit for fetal echocardiography. SUBJECTS: 36 fetuses with congenital complete heart block and structurally normal hearts identified between 1980 and 1993. METHODS: Maternal anti-Ro antibody status was documented. Prenatal variables examined included absolute heart (ventricular) rate, change in rate, and development of hydrops fetalis. Postnatally, heart rate, need for pacing, and the indications for pacing were detailed. RESULTS: Of the total of 36 patients, there are 24 survivors; 11 are paced. Of those fetuses which died, two were electively aborted for severe hydrops, seven died in utero, two were immediate postnatal deaths, and one was an unrelated infant death. The trend was for the heart rate to decrease during fetal life and postnatally. Fetuses with deteriorating cardiac function did not always show the lowest heart rates. Bradycardia of less than 55 beats/min in early pregnancy or rapid decrease in heart rate prenatally were poor prognostic signs. Hydrops was also associated with bad outcome, 10 out of the 12 hydropic fetuses dying (83%). Of 10 fetuses presenting with a heart rate above 60/min, nine survived of whom three required pacing. Of seven presenting with heart rates of 50/min or less, only three survived and two of these required pacing. Of the two fetuses with negative maternal anti-Ro antibody status one died in utero and one required heart transplantation after pacemaker insertion. CONCLUSIONS: Isolated complete heart block identified in fetal life does not always have a good prognosis. An individual heart rate does not accurately predict the outcome in utero or the need for postnatal pacing. Regular, careful monitoring during pregnancy is required in order to optimise care and timing of any interventions. PMID- 8673761 TI - Out-of-hospital cardiac arrest due to coronary heart disease: a comparison of survival before and after the introduction of defribrillators in ambulances. AB - OBJECTIVE: To assess the actual impact on coronary mortality of equipping ambulances with defibrillators. DESIGN: Retrospective analysis of routine medical and legal records of all those who had a cardiac arrest attributed to coronary heart disease occurring outside hospital in a defined population before and after the introduction of Heartstart. SETTING: City of Glasgow, North of the River Clyde, 1984 and 1990. PATIENTS: 296 and 267 men and women aged 25-64 inclusive in 1984 and 1990 respectively who had a cardiac arrest outside hospital which was attributed to coronary heart disease (International Classification of Diseases codes 410-414, ninth revision). RESULTS: The impact on coronary mortality in 1990 of equipping ambulances with defibrillators concurred with the earlier prediction of less than 1% of all coronary deaths. The circumstances of cardiac arrest were largely unchanged; most occurred outside hospital in the victim's home and the principal witnesses were members of the victim's family. A call for help before cardiac arrest was made in very few cases and cardiopulmonary resuscitation was attempted by laypersons in less than a third of the deaths they witnessed. There was a significant increase in the number of cardiopulmonary resuscitation attempts made by ambulance crews (16% v 32%, P < 0.01). Ambulance crews, however, still attended less than half of all cases (44% and 47%). CONCLUSION: The impact of equipping ambulances with defibrillators will remain small unless strategies are introduced that focus on improving the public's response to coronary emergencies by calling for help promptly and initiating cardiopulmonary resuscitation before the arrival of the emergency services. PMID- 8673762 TI - Physician variation in the management of patients with atrial fibrillation. AB - OBJECTIVE: To investigate variations in the management of patients with atrial fibrillation among consultant physicians. DESIGN: Questionnaire survey. SUBJECTS: Consultant physicians in England, Wales, and Scotland. RESULTS: 214 consultant physicians (88 cardiologists and 126 non-cardiologists) were surveyed between May and July 1994. Most physicians (47.7%) reported that they saw one to five patients with atrial fibrillation weekly. Some 52% of cardiologists and 40% of non-cardiologists considered that the main factor influencing their decision of whether or not to anticoagulate was the clinical history--that is, heart failure, valve disease, or stroke. When encountering a patient admitted acutely with new onset atrial fibrillation, significantly more cardiologists (66% v 52%, chi 2 = 6.89, P = 0.03) would immediately start anticoagulant treatment, most favouring intravenous heparin. Most physicians would also introduce antiarrhythmic treatment or digoxin, but more cardiologists would attempt immediate pharmacological (39% v 18% of non-cardiologists, P < 0.001) or later electrical (86% v 69%, chi 2 = 11.7, P = 0.003) cardioversion to sinus rhythm, while non cardiologists tended to prefer "rate control" with digoxin. Although many physicians would not continue antiarrhythmic treatment post-cardioversion, more cardiologists than non-cardiologists would do so (the commonest choice being class III agents) (31% v 17%, P = 0.04). Fewer non-cardiologists would continue anticoagulant treatment post-cardioversion (27% v 69% of cardiologists, chi 2 = 39.8, P < 0.0001). When treating patients with atrial fibrillation, decisions about anticoagulation were usually related to the perceived relative risk of thromboembolism versus haemorrhage derived for each of six case management scenarios in the questionnaire. There was, however, general agreement between cardiologists and non-cardiologists in the use of antithrombotic treatment in the management of lone atrial fibrillation, paroxysmal atrial fibrillation, and patients with atrial fibrillation and mitral valve disease or thyrotoxicosis. CONCLUSION: There is considerable variation in the management of atrial fibrillation, with more cardiologists than non-cardiologists considering cardioversion to sinus rhythm (and the use of antiarrhythmic and anticoagulant treatment post-cardioversion) and thrombo-prophylaxis with anticoagulation. Guidelines on the management of this common arrhythmia are clearly required. PMID- 8673763 TI - Follow up after spontaneous coronary artery dissection: a report of five cases. AB - Five cases of spontaneous coronary artery dissection (SCAD) are reported, three in women and two in men (mean age 44 years; range 28-65), all of whom suffered a myocardial infarction. Common risk factors for coronary artery disease were present in the two men; in the female group one patient was taking an oral contraceptive, one was in the postpartum period, and the third was a smoker. Only the three women received intravenous alteplase and their ejection fraction was normal; both men had impaired left ventricular function. Two patients had SCAD of the left anterior descending coronary artery and three of the right coronary artery. Only the two men had angiographic features of coronary atherosclerotic involvement. No patients required surgical revascularisation or percutaneous transluminal coronary angioplasty. At a mean follow up of 27 months (range 6 to 40) all patients were alive and all but one were asymptomatic. PMID- 8673764 TI - Endovascular stent placement for pulmonary venous obstruction after Mustard operation for transposition of the great arteries. AB - Stenting of the left pulmonary venous baffle obstruction was successfully performed in a 6 year old girl after the Mustard operation for transposition of the great arteries. She also had stent implantation in both the superior vena cava and inferior vena cava baffle junctions. These procedures were followed by sustained clinical improvement. Angiography showed that all three stents were fully patent a year after the procedure. PMID- 8673765 TI - Squatting revisited: comparison of haemodynamic responses in normal individuals and heart transplant recipients. PMID- 8673766 TI - Serum lipids four weeks after acute myocardial infarction are a valid basis for lipid lowering intervention in patients receiving thrombolysis. PMID- 8673767 TI - Aortic distensibility measured by magnetic resonance imaging in patients with Marfan's syndrome. PMID- 8673768 TI - Is aspirin safe for patients with heart failure? PMID- 8673769 TI - The inappropriateness of "appropriateness". PMID- 8673770 TI - Captopril in acute pulmonary edema: measuring the benefit. PMID- 8673771 TI - A challenge in injury prevention--the Hispanic population. PMID- 8673772 TI - What is the role of diphenhydramine in local anesthesia? PMID- 8673773 TI - Visual aids for communicating information to patients: an excellent second step. PMID- 8673774 TI - Funding avenues for research in emergency medicine at the National Institutes of Health and the National Heart, Lung, and Blood Institute. AB - There are opportunities for research in EM at the NIH, which may be appropriate for a variety of Institutes, depending on the topic area. Most NIH-funded research is through investigator-initiated grant applications, and the PHS 398 application packet is a source of more information. RFAs and RFPs, which have set aside funding, are released for specific topic areas when an Institute identifies an area requiring multiple studies or multicenter research. PAs, which do not have set-aside funding, announce areas of interest for an Institute. The NIH Guide to Grants and Contracts announces RFAs, RFPs, and PAs. It is important to become expert in a field of research to be successful in achieving research funding, whether investigator- or institute-initiated. PMID- 8673775 TI - Rapid improvement of acute pulmonary edema with sublingual captopril. AB - OBJECTIVE: To test the hypothesis that sublingual captopril produces a more rapid improvement of acute pulmonary edema (APE) than does placebo, when added to a standard regimen of O2, nitrates, morphine, and furosemide. METHODS: Prospective, randomized, double-blind, placebo-controlled clinical trial in an urban teaching hospital ED. Adults brought to the ED with APE were given captopril or placebo sublingually. Every 5 minutes a clinical APE distress score (APEX) was obtained. RESULTS: Over the first 40 minutes of treatment, the mean APEXs were significantly better for the patients given captopril [p < 0.001, F = 14.5, one way (repeated-measures) analysis of variance (ANOVA)]. At 30 minutes, the patients given captopril had a mean APEX improvement of 43% (i.e., to 57% of initial distress); the group given the current standard regimen plus placebo improved only 25% (i.e., to 75% of initial distress; p = 0.03, multiway ANOVA). In addition, there was less respiratory failure necessitating mechanical ventilation in the captopril patients (9%) vs the placebo patients (20%), which did not achieve significance (p = 0.10, Fisher's exact test). CONCLUSION: In APE, the addition of sublingual captopril to the standard regimen of O2, nitrates, morphine, and furosemide produces more rapid clinical improvement than does the standard regimen alone. PMID- 8673776 TI - Pediatric trauma: enabling factors, social situations, and outcome. AB - OBJECTIVES: 1) To determine, for severely injured pediatric patients, which enabling factors and social situations are associated with the most severe and costly injuries; 2) to determine which subsets of patients are affected by particular enabling factors; and 3) to determine which enabling factors are associated with death. METHODS: Retrospective chart review of patients included in a pediatric trauma registry at a level I trauma center, plus review of medical examiner reports for deaths declared at the scene for one year. Abstracted data included age, gender, enabling factors (e.g., abuse/assault, neglect, endangerment, and nonuse of safety measures), mechanisms of injury, Injury Severity Scale (ISS) score, length of stay, need for intensive care unit (ICU) care, and expense. RESULTS: Records were reviewed for 336 identified children. There was a 2:1 male-to-female ratio; 9.5% died, 3.5% at the scene. Active endangerment or neglect was associated with death (p = 0.0004). However, the nonuse of safety devices was more common and resulted in a higher absolute number of deaths. Similarly, while inadvertent gunshot wounds, intentional injury, and environmental mishaps were more commonly lethal, motor vehicle crashes (MVCs) were more common and claimed the most lives. Cost was highest for the patients aged 14-16 years, in part reflecting the larger number of MVCs. CONCLUSION: The severity of pediatric trauma is largely influenced by the mechanism of injury. Our data highlight the importance of enabling factors for such injuries overall and as a function of age group (reflecting developmental status). While injury prevention education for caregivers is necessary, the incorporation of passive safety measures also is vital for decreasing injuries and their severity. PMID- 8673777 TI - Analysis of Hispanic motor vehicle trauma victims in Illinois, 1991-1992. AB - OBJECTIVE: 1) To develop a profile of Hispanic motor vehicle trauma victims in Illinois, 2) to ascertain whether differences exist between Hispanic and general Illinois-population motor vehicle trauma victims, and 3) to identify potential target areas for future injury intervention programs. METHODS: A retrospective analysis of Illinois motor vehicle trauma patients admitted from July 1991 to June 1992 was made. Participants were motor vehicle trauma victims (drivers and passengers) who presented to one of 73 level I or level II trauma centers throughout Illinois and were entered into the Illinois Trauma Registry (ITR) from July 1, 1991, through June 30, 1992. RESULTS: Of the 12,299 motor vehicle trauma victims in the ITR, 771 (6.3%) were Hispanic, 8,979 (73.0%) were white, 1,115 (9.1%) were black, and 1,434 (11.6%) were other. When compared with the other racial groups, the group of Hispanic victims were younger (25.2 vs 33.2 years), had higher male predominance (72.8% vs 60.9%), and had the lowest rate of safety equipment/occupant restraint use (21.7% vs 34.7%). A high alcohol use rate (30.7%) and high mean serum ethanol levels (44 mmol/L; 0.2 mg%) were noted. When contrasted with other racial/ethnic groups, the Hispanic victims had lower Injury Severity Scale scores (p < 0.001), but mean hospital charges tended to be higher, with fewer alternative sources of payment (p < 0.001). CONCLUSION: Using age adjusted data from the ITR, Hispanic motor vehicle trauma victim features differ significantly from those of other racial groups. Effective health maintenance and injury prevention strategies should address the basis for these differences. PMID- 8673778 TI - Comparison trial of four injectable anesthetics for laceration repair. AB - OBJECTIVES: To compare four injectable anesthetics (buffered 1% lidocaine, buffered 1% lidocaine with epinephrine, plain 1% lidocaine with epinephrine, and 0.5% diphenhydramine with epinephrine) for pain of infiltration and effectiveness of anesthesia during suturing of minor lacerations. METHODS: A prospective, randomized, double-blind, comparison trial of the above agents was performed in an urban ED; adults with simple linear lacerations without vascular compromise were enrolled. Physicians and patients ranked the pain of injection and suturing according to a 10-cm visual analog scale (VAS). Fisher's exact and Kruskal-Wallis tests were used to compare demographic data, and Kruskal-Wallis and Newman-Keuls tests were used in analysis of VAS rankings. The power of the study was 0.8 to detect a 1.4-cm difference in VAS readings, and 0.9 to detect a 1.7-cm difference. RESULTS: Seven of 200 enrolled patients were excluded due to improper data collection and 13 were removed from final statistical analysis due to need for additional anesthetic (treatment failures), leaving 180 subjects for final analysis. Demographic data were similar for the four groups (p > 0.05). Diphenhydramine with epinephrine was significantly more painful to inject than was buffered lidocaine or buffered lidocaine with epinephrine, according to both the patients (p = 0.0003) and the physicians (p = 0.0037). The two buffered compounds were slightly less painful to inject than was lidocaine with epinephrine, but statistical comparisons did not reach significance. For anesthesia effectiveness, lidocaine with epinephrine and buffered lidocaine with epinephrine were statistically better than buffered lidocaine or diphenhydramine with epinephrine (p = 0.0001 for the patients and the physicians). CONCLUSIONS: Buffered lidocaine with epinephrine and lidocaine with epinephrine were more effective anesthetics during suturing, according to both the physicians and the patients. There was a tendency toward less pain with infiltration in buffered solutions, compared with plain lidocaine with epinephrine, but the comparisons did not reach statistical significance. Diphenhydramine with epinephrine was more painful to inject than were buffered lidocaine with epinephrine and lidocaine with epinephrine, and was less effective anesthetically than the other three solutions. PMID- 8673779 TI - The use of propofol for sedation in the emergency department. AB - OBJECTIVE: To evaluate the effectiveness of propofol and fentanyl when used by emergency physicians (EPs) for systemic sedation and analgesia in the ED. METHODS: Over an eight-month period, a convenience sample of consenting patients at an urban teaching hospital ED who required sedation for painful procedures were enrolled in a descriptive study of therapeutic propofol sedation. After receiving 2 micrograms/kg of fentanyl i.v. the patients received a continuous infusion of propofol at 0.21 mg/kg/min i.v. to the desired level of sedation. A maintenance infusion of 3-6 mg/kg/hr was administered during the remainder of the procedure. Sedation time, total procedure time, and recovery time were recorded and the presence of side effects was noted. The patients and the physicians rated their satisfaction with the technique on a 100-mm visual analog scale. The patients were contacted at 24 hours for follow-up information. RESULTS: Twenty patients (aged 19-62 years) received propofol infusion for procedures that included ten abscess incision and drainages, eight orthopedic reductions, one chest tube placement, and one wound exploration. The mean (+/- SD) total dose of propofol was 200 +/- 160 mg. The mean time to onset of sedation was 6.6 +/- 3.2 min, the mean procedure interval was 9.6 +/- 6.3 min, and the mean interval until recovery was 6.1 +/- 4.1 min. The median patient satisfaction score was 97 mm (range 40-100 mm); the median rating by physicians was 88 mm (range 4-100 mm). Side effects were noted in six patients: three had pain on injection, one had pain on injection and brief (< 1 min) hypotension (systolic blood pressure = 80 mm Hg), and two had apnea (< 30 sec). Seven patients had some recall of the procedure immediately afterwards, but only five had any recall at 24 hours. All 20 patients stated they would be willing to receive the same sedation again for a future procedure. CONCLUSION: Propofol appears to be an effective agent to provide systemic sedation and analgesia when used in conjunction with fentanyl for procedures in the ED. Given its rapidity of onset and elimination, it may become a useful agent to EPs for i.v. sedation in the ED. PMID- 8673780 TI - Identification of hazardous/harmful drinking among subcritically injured patients. AB - OBJECTIVES: To examine the relationship between a saliva alcohol test (SAT) and hazardous/harmful drinking, as measured by the Alcohol Use Disorders Identification Test (AUDIT), among a sample of subcritically injured patients. METHODS: Patients (n = 78) seeking treatment for a subcritical injury were saliva tested for alcohol and interviewed regarding their drinking behaviors and related difficulties. Associations of SAT values with AUDIT results were determined. RESULTS: SAT results and hazardous/harmful drinking were not independent events (p < 0.001). Estimates of sensitivity and specificity (using a dichotomous SAT result [> or = 4 mmol/L] to identify positive AUDIT patients) were 65.2% and 83.6%, respectively. SAT-positive people had significantly higher AUDIT scores than did SAT-negative individuals (p < 0.0001). Patients experiencing assault type injuries were much more likely to be SAT-positive than were patients incurring other types of injury. Discriminant function analysis suggests that AUDIT scores can successfully identify SAT-positive and SAT-negative patients; the analysis accounted for 42.5% of the variance and correctly classified 84.6% of the sample. CONCLUSIONS: The use of an easy-to-administer, noninvasive, routine SAT, among patients presenting for a subcritical injury in a hospital ED, provides a mechanism for the identification of individuals with a history of hazardous/harmful drinking. However, since discrimination of hazardous/harmful drinking is imperfect, some caution is warranted when conducting such screening activities. PMID- 8673781 TI - Domestic violence: diurnal mismatch between need and availability of services. AB - OBJECTIVE: To determine whether a diurnal discordance exists between need and availability of services for victims of domestic violence. METHODS: A consecutive sample of women presenting to a municipal hospital ED with physical injuries suspected to be related to domestic violence were entered into a registry. Date and time of presentation and perceived need for services information were collected from all patients who answered affirmatively a screening question for domestic violence and whose conditions did not preclude administration of the data collection instrument. The Social Service Departments of all of the 53 911 receiving hospitals in New York City were contacted to ascertain availability of social services for victims of domestic violence by time of day. RESULTS: Twenty eight of 32 (88%; 95% CI: 71%, 97%) victims of domestic violence presented to the ED during hours other than weekday 9 AM to 5 PM. Of these, 63% desired counseling, 32% lacked a safe place to go, and 82% had children. Of those who had children, 48% were concerned for the children's safety. In-hospital social services were universally available weekday daytime (9 AM to 5 PM) but were available in only 11% of hospital (95% CI: 4%, 23%) at other times. CONCLUSION: Approximately nine of ten victims of domestic violence presented to the ED during hours when only about one hospital in ten can provide the special services these patients require. A marked diurnal mismatch appears to exist between availability of domestic violence services in New York City and the need for these services as measured by a representative sample drawn from an ED population. PMID- 8673782 TI - "Inappropriate" emergency department use: a comparison of three methodologies for identification. AB - OBJECTIVE: To determine the level of agreement between the rates of "inappropriate" ED visits assigned to a cohort of ambulatory patients based on three methods of defining ED use appropriateness. METHODS: Ambulatory adult patients seen at one urban, university-based teaching hospital ED between 8 AM and midnight during select days from April to June 1994 were assessed regarding the appropriateness of their ED visits. Patients triaged to acute resuscitation rooms in the ED were excluded. Eligible patients were asked to complete a 90 question survey including demographics and health service use (response rate 81%). The appropriateness of ED use was assessed for consenting respondents by 1) application of a list of 51 non-emergent complaints that have been used by managed care providers and previously published (TRIAGE), 2) use of ten explicit criteria (e.g., need for parenteral medication) from prior publications (EXPLICIT), and 3) the consensus of two emergency physicians (EPs) reviewing the records of ED patients (PHYS). All three methods were applied at the time of retrospective chart review. The agreement between methods was evaluated using kappa scores. RESULTS: Of the 892 eligible respondents, 64% were white, 54% were employed, 50% were female, and 29% were uninsured. Of the respondents, 26% had no regular source of ambulatory care and 25% considered the ED their regular source of care. The assigned rates of "inappropriate" visits using the three definitions were TRIAGE, 58%; PHYS, 47%; and EXPLICIT, 42%. Of those deemed "inappropriate" by the EXPLICIT criteria, 81% also were judged as "inappropriate" by the TRIAGE criteria, and 72%, by the PHYS criteria. Of those patients deemed "inappropriate" by the TRIAGE criteria, 59% also were judged as "inappropriate" by the EXPLICIT criteria, and 66%, by the PHYS criteria. Levels of agreement (kappas) were TRIAGE/EXPLICIT, 0.39; TRIAGE/PHYS, 0.42; and EXPLICIT/PHYS, 0.42. CONCLUSION: There is only moderate agreement between different methods of determining appropriateness of ED use. Until further refinement is made in triage assessment, managed care organizations and EPs should remain cautious when implementing a protocol that defines and restricts "inappropriate" ED visits. PMID- 8673783 TI - Continuous quality improvement reduces length of stay for fast-track patients in an emergency department. AB - OBJECTIVE: To demonstrate how continuous quality improvement (CQI) can identify rational and effective means to reduce length of stay for minor illness/injury in an ED. METHODS: A CQI team documented the process of fast-track (FT) patient flow and prioritized the causes of delay. In Phase I, two solutions were implemented. In this Phase II of the study, three changes were implemented, including expansion of the FT area, realignment to provide a full-time FT nurse, and a detailed, stricter triage classification. The outcome was assessed by examining the interval from presentation to release from the ED (length of stay; LOS). Differences were ascertained by analysis variance for consecutive FT patients not requiring radiography, ECG, or blood testing. Intervals from three pre-Phase II intervention 48-hour periods and one post-Phase II intervention 48-hour period were analyzed. RESULTS: Before the Phase I changes, the mean +/- SD LOS was 92 +/ 46 min. After the Phase I changes, the LOS was 67 +/- 31 min. After the Phase II changes, this was reduced to 57 +/- 34 min (p < 0.05). CONCLUSION: The formal application of CQI techniques in the ED can change patient flow and reduce LOS for FT patients. PMID- 8673784 TI - Communicating information to patients: the use of cartoon illustrations to improve comprehension of instructions. AB - OBJECTIVE: To evaluate the effect of cartoon illustrations on patient comprehension of and compliance with ED release instructions. METHODS: A prospective, randomized, controlled study of consecutive patients who presented to the ED of a community teaching hospital with lacerations necessitating wound repair during a three-month study period. At ED release, the patients were randomly assigned to receive wound care instructions with or without cartoon illustrations. Three days later, the patients were followed up by telephone. A blinded investigator asked a series of questions designed to test the patient's recall of, understanding of, and compliance with wound care instructions. RESULTS: A total of 234 patients were successfully contacted by telephone; 105 (45%) had been given ED release instructions with cartoons, 129 (55%), without cartoons. There was no significant difference in age, gender, level of education, or satisfaction with the ED visit between the two groups. The patients given cartoon instructions were more likely to have read the instructions (98% vs 79%, p < 0.001), were more likely to answer all wound care questions correctly (46% vs 6%, p < 0.001), and were more compliant with daily wound care (77% vs 54%, p < 0.01). Subset analysis of those patients who had less than a high school education (n = 57) demonstrated even larger differences between the two treatment groups in terms of comprehension of and compliance with ED release instructions. CONCLUSION: Cartoon illustrations are an effective strategy for conveying information and may improve patient compliance with ED release instructions. PMID- 8673785 TI - Inability to follow up ED patients by telephone: there must be 50 ways to leave your number. AB - OBJECTIVE: To determine the ability to complete follow-up home telephone calls to ED patients. METHODS: A retrospective review of the ability to reach 4,741 patients called during a posttreatment patient satisfaction survey of visits to a suburban community hospital ED. RESULTS: Only 54.9% of all patients called could be contacted after three or fewer phone calls. Of the 2,139 (45.1%) who could not be reached, there was no answer for 1,260 (58.9%), despite three telephone calls to a number currently in service. A significant minority (21.1%) had given nonworking numbers. Another 12.4% indicated that no one by the name of the patient lived at the number called and 2.9% of the respondents alleged that the patient was deceased. CONCLUSIONS: Almost half of the patients who present to the ED and supply home telephone numbers give telephone numbers at which they cannot be reached in follow-up. Using telephone follow-up alone to reach patients seen in the ED may be an unreliable method of communication. PMID- 8673786 TI - Research Directions Conference: Research directions in emergency medicine. January 20-21, 1995. AB - The goal of EM is to improve health while preventing and managing disease and illness in patients seeking emergency medical care. Improvements in emergency medical care and the delivery of this care can be achieved through credible and meaningful research efforts. Improved delivery of emergency medical care through research requires careful planning and the wise use of limited resources. To achieve this goal, EM must provide appropriate training of young investigators and attract support for their work. Promotion of multidisciplinary research teams will help the specialty fulfill its goals. The result will be the improvement of emergency medical care, which will benefit not only the patients whom EPs serve, but also, ultimately, the nation's health. PMID- 8673787 TI - The interface of health care reform and academic medicine. PMID- 8673788 TI - A skeletal model for the efficacy of automobile safety restraints. PMID- 8673789 TI - Interpersonal violence estimate. PMID- 8673790 TI - Thrombolysis "door-to-drug" interval. PMID- 8673791 TI - Thrombolysis "door-to-drug" interval. PMID- 8673792 TI - Falsely elevated carboxyhemoglobin levels secondary to fetal hemoglobin. PMID- 8673793 TI - Venereal and cannibalistic ways of Borrelia burgdorferi sensu lato exchange between males and females of Ixodes persulcatus (Ixodidae, Acarina). AB - Borrelia burgdorferi sensu lato (s. l.) infection rate in Ixodes persulcatus Shulze maintained in different relative humidity gradient in male and female pairs and separately by sex were compared. Ticks collected in the St. Petersburg Region of Russia during 1992-1994 temperate and 1995 hot seasons. We observed that the infection rate among specimens maintained as sexual pairs were 1.2-2.5 times higher than among ticks maintained separately. Rate of borrelia infection in tick couples was a bit higher among specimens collected within a hot spring summer period than among ticks collected during the seasons with temperate temperatures. This pathogen interchange was thought to result from a venereal or cannibalistic (omovampiric) mode of borreliae transmission. Traces of male bites (scars) on the female bodies were checked more often during a hotter seasons. borrelia burgdorferi s.l. was determined to be present in 22.9-29.3% whereas infection occurred in 12-20% of single specimens. Our data indicate the importance of isolating ticks sexually during disease investigations with borreliae as well as tick-borne encephalitis and probably other tick-borne pathogens. PMID- 8673794 TI - Bionomical and ecological characteristic of ticks (Acari:Ixodida) of significant medical importance on the territory of Poland. AB - Among Polish ticks species the most common in our country Ixodes ricinus has the biggest medical importance. Argasidae: Argas reflexus, A. polonicus and Ixodidae: Ixodes trianguliceps, I. hexagonus and Dermacentor reticulatus have significant medical meaning. Argasidae are nests and burrows dwelling species having multi host development cycle, they are mainly synanthropic and semisynanthropic, nocturnal active, with the peak seasonal activity in the middle of summer, dwelling semihumid or dry habitats (50-70% RH). The most of Polish Ixodidae species are burrows and nests dwelling parasites, more common species are out of nest-dwelling, having three-host development cycle, they are basically polixenic, active during the warm season of the year, normally with two peaks of activity- in spring and at the end of summer, beginning of autumn; dwelling in most cases forest, humid but not marshy habitats (80-100% RH). PMID- 8673795 TI - Prevalence of antibodies to Borrelia burgdorferi in European bison (bison bonasus) from Bialowieza Primeval Forest. AB - To estimate the prevalence of antibodies to borrelia burgdorferi in European bison from Bialowieza Primeval Forest, a total of 79 serum samples were collected from April 1989 until December 1994. Specific antibodies to B. burgdorferi antigen were assayed using inhibition ELISA. Borrelia antibodies were possibly present in 16.4% of examined bisons (inhibition between 20 and 30%). However, higher level of antibodies, over 30% of inhibition, was found only in two animals: no. 382 and no. 273 (2.5% from 79). European bison may be a host for B. burgdorferi and this may have implications for epidemiology of Lyme borreliosis in the areas were bisons and ixodes ricinus coexist. PMID- 8673796 TI - Human babesial infections in Europe. AB - The tick transmission of Babesia from infected animals to human has been clearly demonstrated. Including the first case described by Skaraballo in 1957 in Yugoslavia, 22 cases of human babesiosis have been reported in Europe. B. divergens, which is the most common pathogen for cattle, was involved in 17/22 cases. France, British Isles and Ireland accounted for more than half of the cases, occurring especially between May and October, the period of maximal activity of Ixodes ricinus, considered as the major vector. Splenectomy was the main factor of risk which was found in 86% of the patients. Clinically, babesial infections appeared suddenly with a non periodic high fever, shaking chills, sweat, headache, myalgia and jaundice induced by intravascular hemolysis. The mortality rate was higher than 50%. Treatment should be promptly initiated with a massive blood exchange, followed by intravenous clindamycin (600 mg) three time daily. For prophylaxis, attenuated vaccines could provide effective protection in cattle, but no vaccine is available for human protection. PMID- 8673797 TI - Epidemics of Q fever in Poland in 1992-1994. AB - From 1992 till the end of 1994, three epidemics of Q fever among people have been recognised in Poland. In 1992 the outbreak of Q fever was detected at the farm near Jawor in Legnica district. Coxiella burnetii infection was recognized serologically in 25 persons (27 tested). Titres of serum antibodies ranged from 8 to 256. It has been found that cattle were the source of human infection. C. burnetii strain has been isolated from the bull semen. In the same year, Q fever was recognized among 18 workers of the tannery in Myslenice, in Krakow district. Antibodies to C. burnetii, in titres from 8 to 2048, were detected in all 18 persons who had a contract with imported skins of wild animals. Serological tests performed again in 1994 showed that elevated titres of serum antibodies persisted in 10 of 14 persons and 9 of them developed phase I antibodies also. Since 1993 several cases of Q fever have been observed among people living in various regions of the country. Epidemiological investigations have revealed that infected patients are seasonal workers employed during the shearing time in Spain. Specific serum antibodies reached titre 512. The strains of C. burnetii were isolated from urine and semen of 2 patients. PMID- 8673798 TI - Unknown species of rickettsiae isolated from Ixodes ricinus tick in Walcz. AB - Ticks Ixodes ricinus have been harvested in park down-town Walcz in June 1994. Presence of Borrelia burgdorferi and rickettsiae has been tested with PCR. B. burgdorferi and Coxiella burnetii have not been detected in any tick whereas characteristic for other rickettsiae DNA fragment of gene encoding citrate synthase has been found. Bacterial strain has been cultured from the tick. Biochemical properties of isolated strain has strongly suggested that these bacteria belong to genus Bartonella (Rochalimaea). Further identification of bacterial DNA with RFLP-PCR (restriction fragment length polymorphism-PCR) has shown characteristics of Bartonella bacilliformis species not recognised in Poland until recently. PMID- 8673800 TI - Epidemiology of tick-borne encephalitis in Poland. AB - Tick-borne encephalitis are connected with existence of natural foci in environment, where virus circulation between natural host (rodents, wood mammals) and virus vectors does occur independently from humans. In Poland the first confirmed cases of tick-borne encephalitis occurred in following voivodships: bialostockie, olsztynskie, opolskie in 1948-1952. Between 1970 and 1993-816 cases of tick-borne encephalitis have been reported and annual morbidity has been from 0.01 to 0.6/100,000. In 1993 a sharp 30 fold-increase of reported cases occurred in comparison with previous year. In this year 249 cases were reported were reported and 94% of them and serological confirmation. Most of them were notified in following voivodships: bialostockie, opolskie, ostroleckie. In 1994-181 cases were reported mainly from endemic areas in the north-eastern territories of Poland. PMID- 8673799 TI - Tick-borne borreliosis in west Africa: recent epidemiological studies. AB - Tick-borne borreliosis in West Africa is classically considered a rare disease whose geographic distribution is limited to Saharan and Sahelian regions. We report results of epidemiological investigations which indicate that tick-borne borreliosis is endemic in all regions of Senegal north to the 13 degrees 30'N latitude and is a major cause of morbidity in these areas. Our findings indicate a considerable range extension for the vector tick Alectorobius sonrai and suggest that the persistence of Subsaharan drought is responsible for a large spread of tick-borne borreliosis in West Africa. PMID- 8673801 TI - Tick-borne encephalitis (TBE) epidemiology in the Brest Province of the Republic of Belarus. AB - Prevalence of tick-borne encephalitis (TBE) and number of TBE infected ticks was analysed in the Brest Province since 1955. They revealed increasing tendency, which reached the highest values in the last years. TBE incidence was the highest in June and it was observed predominantly in people between 30 and 39 of age. The studies of TBE incidence rate regularities have disclosed its cyclical nature. PMID- 8673802 TI - Clinical picture of tick-borne encephalitis among patients hospitalized in 1994 in the Department of Infectious Diseases Medical School Bialystok. AB - In 1994 20 patients of the Department of Infectious Diseases, Medical School Bialystok were diagnosed to have tick-borne encephalitis. The etiologic agent was identified by serologic studies of the serum and cerebrospinal fluid (FSME IgM ELISA Immuno Austria). 12 patients (60%) reported a tick bite preceding the disease. Following clinical manifestations were found in the analyzed groups of patients: fever > 37.5 degrees C-20 patients (100%), headache--20 patients(100%), nuchal rigidity-14 patients (70%), abdominal pain -3 patients (15%), arthralgia and myalgia-3 patients (15%), drowsiness and mental confusion -3 patients(15%). Total cell count in CSF ranged from 18 to 348 cells (mean-175). Lymphocytes predominated in 13 cases (68%). The FSME-IgM antibodies were present in serum of 19 patients (95%) and in CSF of only 4 patients (20%). The hospitalization lasted 12-58 days (mean 24 days). In one case the disease was complicated by acute psychosis requiring psychiatric treatment. Severe neurologic complications have been not observed. The prognosis in all cases was good. Our study confirms that tick-borne encephalitis is a current problem in north-eastern Poland. Noteworthy is the fact that only a part of patients give the history of tick bite. PMID- 8673803 TI - Tick-borne encephalitis and concomitant infection with Borrelia burgdorferi. AB - Concomitant tick-borne encephalitis and Borrelia infection in 43 year old farmer living in a village on the border of the Knyszyn Forest was described. Diagnosis was based on anamnesis and objective examination, and was confirmed by serological tests. PMID- 8673804 TI - Vaccination against tick-borne encephalitis--distant evaluation. AB - In 94 our of 2570 individuals vaccinated against tick-borne encephalitis (TBE) with FSME-Immun the level of IgG antibodies to TBE virus were tested. The examination was performed before and 2.5 years after the first dose of full cycle vaccination, which according to the manufacturer, consists of three doses. The maintenance of specific seroconversion was detected in 91.9% of the studied subjects. No statistically significant differences in antibody levels were found in the different age groups. None of the immunized subject developed TBE up to the present time. PMID- 8673805 TI - Differentiation of Borrelia burgdorferi sensu lato strains isolated from skin biopsies and tick by pulsed-field gel electrophoresis. AB - Fifteen isolates of Borrelia burgdorferi sensu lato from skin biopsies (8) and ticks (7) were investigated for species differentiation by pulsed-field gel electrophoresis (PFGE). The skin isolates were further characterized by plasmid profile as well as SDS-PAGE and revealed six Borrelia afzelii-, one Borrelia burgdorferi sensu stricto-, and one Borrelia garinii species. The tick isolates showed three Borrelia afzelii--and four Borrelia garinii species. The skin isolates could be further discriminated by plasmid profile analysis--all strains showed an individual pattern. The SDS-PAGE of whole-cell lysates obtained from skin isolate showed a different protein pattern for each of the skin isolates. PMID- 8673806 TI - Lyme borreliosis--tick borne spirochaetosis among children. AB - The clinical picture of Lyme borreliosis in children in an early stage of the disease was presented. Treatment with Amoxicillin or Doxycycline led to the regression of clinical symptoms and elimination of specific antibodies within a three-month period of therapy in all cases. PMID- 8673807 TI - Lyme disease--on the basis of our observations. PMID- 8673808 TI - Our experience with Lyme arthritis. AB - Since 1975, when first described, Lyme disease becomes more and more interesting and complicated medical problem. One of the "classical features" of the disease is arthritis. Based upon our own experience we described and discuss the diagnosis, treatment and outcome of three patients with Lyme arthritis. PMID- 8673809 TI - Study on clinical picture of erythema migrans. AB - Clinical picture of erythema migrans (EM) was evaluated in 83 patients from north eastern Poland. Patients were in mean age of 42,8. Most of patients (71%) were women. Tick bite remembered 64% patients. Mean incubation period of EM was 33 days. The mean diameter of the skin lesions was 14.8 cm. They persisted for 2-270 (mean-54) days. Lesions were located mostly on the skin of lower extremities. The largest lesions were found on trunk and the smallest on lower extremities. EM of diameter exceeding 20 cm were observed in patients with longer history of the disease. Specific antibodies were found in 53% of cases and were present more frequently (78%) in patients with shorter incubation period (< 30 days). PMID- 8673810 TI - Enzyme immunoassay in the diagnosis of Lyme borreliosis. AB - Comparison of serological EIA tests available in Poland, used in diagnostics of Lyme borreliosis: VIDAS Lyme Screen II (LYT II)-bioMerieux (France), Lyme Borreliosis-Dako (Denmark), Borrelia Recombinant-Biomedica (Austria) was carried out in sera of 112 persons: 39 inhabitants of Bialowieza area-Lyme borreliosis endemic region, 43 persons with Lyme borreliosis (first of all erythema migrans and neuroborreliosis), 27 healthy persons (control group), 3 persons with serologically confirmed rheumatoid arthritis. Compatibility of results in all tests was 73%, and it was the highest in control group (78%) and in neuroborreliosis patients (76%). Sensitivity of all tests was similar and varied from 77% (Dako) up to 81% (Biomedica). The highest specificity (93%), positive (94%) and negative (74%) predictive values demonstrated bioMerieux test. The lowest error of method for positive results showed bioMerieux (2,48%) and Dako IgG (2,94%), whereas for negative Biomedica-IgG (0). There were no positive (false) results in sera of patients with rheumatoid factor dependent on cross reaction. PMID- 8673811 TI - Cross-reactivity between Borrelia burgdorferi and "arthrogenic" bacteria in sera from patients with reactive arthritis. AB - The occurrence of specific antibodies for "arthrogenic bacteria" and Borrelia burgdorferi was analysed in sera samples from 30 patients with reactive arthritis. The control group consisted of 30 healthy blood donors. Our data showed that 66.6% (20) of the 30 examined patients had positive tests for Borrelia burgdorferi antigens and of all the patients, most of them (85%) had increased antibody levels against Salmonella antigens, 30% had increased levels of antibodies against Shigella antigens and 10% had antibodies for Yersinia antigens. Our findings indicated that the presence of antibodies to Borrelia burgdorferi and "arthrogenic enteric bacteria" in sera samples of patients with REA is evidence of wide cross-reactivity between these microorganisms. PMID- 8673812 TI - Seasonal prevalence of antibodies against Borrelia burgdorferi in Bialowieza inhabitants. AB - The aim of the study was evaluation of seasonal variability in presence of specific antibodies against Borrelia burgdorferi in Bialowieza area, as an endemic region of Lyme borreliosis. Specific IgM and IgG antibodies against 41 kDa antigen of Borrelia burgdorferi B31 strain were investigated with an enzyme immunoassay in sera of 300 Bialowieza inhabitants between September 1993 and May 1994. The highest prevalence of IgM antibodies was observed in September 1993 (43.4%), with decrease during winter and spring (down to 15.7% in April) and accompanying the highest prevalence of IgG antibodies (17.7% in April 1994). Quantitative determination of antibodies level expressed as corrected optical density revealed similar tendency. From 33 persons, that revealed IgM antibodies in September 1993, 26 (79%) had no IgM or IgG antibodies. Specific IgG antibodies found in 7 persons in September, were still present in 4. PMID- 8673813 TI - Change and continuity in tropical medical science and international health. PMID- 8673814 TI - Exploring the interface between first and second level of care: referrals in rural Africa. AB - The studies aimed to determine the referral rate, the characteristics of patients referred, the reasons for referral and, in a sub-sample, its outcome. Study I recorded data on 602 patients referred to hospital from 13 rural clinics; follow up interviews were conducted with a sub-sample of 57 referred patients. Study II interviewed 97 consecutive outpatients seeking care at Meru District Hospital. Both studies were carried out in a rural area of Meru district in central Kenya. The 602 referred cases represent between 0.3 and 1.8% of all new patients at the respective clinic with a mean of 0.5%, or 8.7 referrals annually per 1000 catchment area population. More than half of the referrals were for treatment only while 13% were for investigation, 63% were considered urgent, and 85% were referred in writing. Of the 57 subsequently interviewed, all except one had complied, and 52 patients, mostly with infections, injuries or obstetric disorders, reported improvement at the time of interview. The second study found that only 19 (20%) of the 97 outpatients had been referred (II in writing and 8 verbally). Rates of formal clinic-to-hospital referral were very low. Reasons included poor access to transport; patient inability to pay user fees, transport outlays, and other expenses; time constraints in emergency situations; and lack of feedback information from hospital to clinic. Verbal referral was common. Further research should focus on the selection of patients for referral, on follow-up of cases referred, on the communication between institutions involved, and on options for the financing of emergency transport to hospital. PMID- 8673815 TI - Malaria control and fever management in Henan Province, China, 1992. AB - Henan Province, which once had the highest malaria prevalence in China, had only 318 reported cases in 1992. Our purpose was to investigate this late 'consolidation phase' of malaria control in Henan with reference to malaria surveillance. We conducted a questionnaire survey of village doctors in Shang Shi Qiao Township during the transmission period of 1992. Of the 732 recorded fever cases, 16 were probable malaria cases by clinical and treatment response criteria, but only one received a full course of antimalarials. Of the 732 patients, 61% had fever every day, 37% went for treatment the first day, 52% waited 2-3 days and 10% waited longer. One hundred and twenty-eight patients took self-medication before seeing the doctor. Blood examination was carried out in 526 (71%) fever cases but only four were positive, all for Plasmodium vivax. Our findings highlight problems relating to patient behaviour and motivation of village doctors, malaria treatment, surveillance and microscopy, rural migration, economic development and malaria transmission. All need to be considered for reforming the malaria control strategy in Henan Province. PMID- 8673816 TI - Guinea worm disease in Ayod, Upper Nile Province, southern Sudan: a cross sectional study. AB - Upper Nile Province is one of the four main endemic areas for Guinea worm disease in the Sudan. In December 1994, a survey was conducted in the village of Ayod where the disease is endemic, to investigate morbidity and local knowledge of transmission and prevention. Interviews were conducted in households selected by standard cluster sampling procedures and of the 759 people examined, 156 (20.6%) had Guinea worm lesions. Adjusted odds ratios were used to estimate the relative risk for people with different personal or household characteristics in a multivariate analysis. After controlling for the possible confounding effects of other study variables, having a filter in the household, gender, and lack of knowledge about transmission and about prevention, were not associated with lesions. Only two variables were significantly associated with Guinea worm disease: getting water from a source other than a well increased the risk by a factor of 2.3, and being aged 5 years or more increased the risk by a factor of 31.1. This study demonstrates the clear association between the source of water for drinking and Guinea worm disease found elsewhere. We suggest the provision of reliable sources of pure drinking water and health education are the most suitable long-term preventive measures. The Sudan now represents the greatest challenge to the goal of global eradication of Guinea worm disease, following the reduction in cases in Nigeria. The continuing civil war and insecurity in southern Sudan hinder the implementation of an effective water programme and other control measures, but the potential benefits through reduced incapacity and improved agricultural productivity are considerable. PMID- 8673817 TI - A randomized trial of chloroquine, amodiaquine and pyrimethamine-sulphadoxine in Gambian children with uncomplicated malaria. AB - The increasing occurrence of chloroquine-resistant Plasmodium falciparum in sub Saharan Africa makes it essential to reconsider current recommendations for the treatment of uncomplicated P.falciparum malaria. In an open, randomized trial, we have compared chloroquine (CQ), amodiaquine (AQ), and pyrimethamine-sulphadoxine (PS) in rural Gambian children with uncomplicated P.falciparum malaria. Three hundred children were randomly assigned at the time of consultation (Do) to oral treatment with 25 mg/kg CQ, 25 mg/kg AQ (both given over 3 days), or 1.25/25 mg/kg PS. They were reviewed on day 7 (D7) and day 28 (D28) for symptoms, malaria parasitaemia, and packed cell volume (PCV). Significantly more children treated with PS compared to CQ (17 vs 7%, P = 0.03) or AQ (17 vs 3%, P = 0.001) returned with clinical complaints during the first 3 days after treatment. Five of these patients had a generalized convulsion (1 from the AQ group, 4 from the PS group), of whom 4 developed cerebral malaria. At D7, significantly more patients treated with CQ compared to AQ (25 vs 7%, P = 0.0009) or PS (25 vs 4%, P = 0.0001) were parasitaemic. By D28, the cumulative number of parasitological failures was significantly higher in the CQ group compared to the AQ group (65 vs 35%, P = 0.0001), and significantly higher in the AQ group compared to the PS group (35 vs 14%, P = 0.001). Overall, 91% of parasitological failures observed during the study period were symptomatic and were consequently treated with an alternative antimalarial drug. Over the 28-day study period the mean PCV increased significantly less in the CQ group than in the PS group (1.2 vs 3.8%, P = 0.016) and was lower in the CQ group than in the AQ group (1.2 vs 2.7%, P = 0.12, not significant). These results suggest that PS acts more slowly than 4 aminoquinolines in controlling the clinical features of malaria, and that AQ can be considered as an interim alternative to CQ in the first-line therapy of uncomplicated malaria in African areas of high CQ resistance. PMID- 8673818 TI - Population growth in the 21st century: cause for crisis or celebration? AB - Between now and the end of the next century, the population of the planet is projected to grow from 5.7 billion to somewhere between 9 and 16 billion. In the next 25 years, continued rapid growth is inescapable because of the youthful age structures of many countries. Beyond that point much depends on fertility trends in the coming decades. Continued population growth does not make inevitable any global catastrophe but it will exacerbate greatly problems of underemployment. The prognosis for further fertility declines is good, because the communications revolution is hastening the spread of new ideas and political attitudes are becoming favourable. PMID- 8673819 TI - The public and domestic domains in the transmission of disease. AB - This paper discusses the distinction between the transmission of infectious diseases within the domestic domain (the area normally occupied by and under the control of a household) and that in the public domain, which includes public places of work, schooling, commerce and recreation as well as the streets and fields. Whereas transmission in the public domain can allow a single case to cause a large epidemic, transmission in the domestic domain is less dramatic and often ignored, although it may account for a substantial number of cases. Statistical methods are available to estimate the relative importance of the two. To control transmission in the public domain, intervention by public authorities is likely to be required. Two examples show how environmental interventions for disease control tend to address transmission in one or the other domain; interventions are needed in both domains in order to interrupt transmission. PMID- 8673820 TI - The impact of HIV-1 infection on child health in sub-Saharan Africa: the burden on the health services. AB - HIV-1 infection in sub-Saharan Africa is resulting in substantial child mortality and an increase in the number of sick children presenting to health services. Many of the sick children come to health centres and hospitals, inflating numbers on paediatric wards. The presentations of childhood HIV-1 infection are many and varied so that HIV-1 infection is the new "great imitator' of other conditions. Some other infections are more severe in HIV-1 infected children (specifically bacterial infections and measles). However, there is no clear evidence of consequent rises in the incidence of other childhood infections, though this is likely to be the case of tuberculosis. HIV-1 infected children with other infections often respond to locally available anti-microbials, but may require longer courses. Treatment is problematic because of the impossibility of distinguishing infected from uninfected children and because of shortages of medicines, which are being intensified further by the child and adult HIV-1 epidemics. Severe HIV disease in adult family members is adding to child morbidity and creating substantial orphanhood. Staff fear nosocomial infection, while simultaneously experiencing falling personal incomes and lacking resources to care for their patients. Substantial numbers of trained staff are being lost because of HIV-1 caused disease and death. The reality of HIV-1 infection through breast-feeding is not yet appreciated. When this becomes generally apparent, there is a risk that a lethal increase in bottle feeding could occur in some areas. Reduction in the number of new paediatric HIV-1 infections in sub-Saharan Africa can be achieved only by ameliorating the adult HIV-1 epidemic, reducing unnecessary blood transfusions and ensuring a safe blood supply. PMID- 8673821 TI - Case report and review of disseminated histoplasmosis in South-East Asia: clinical and epidemiological implications. AB - The South-East Asian region is not known to be a major endemic area for histoplasmosis. We have recently diagnosed several cases of disseminated histoplasmosis in patients from this region. We report on a well documented indigenous case of disseminated histoplasmosis in a 62-year-old poultry farmer and review the literature for other reported cases of clinical histoplasmosis in the South-East Asian region. Sporadic cases of indigenous chronic pulmonary and non-meningeal disseminated histoplasmosis in immunocompetent hosts have been reported as well as examples of disseminated histoplasmosis in immunocompromised hosts. These reports suggest that histoplasmosis is endemic to certain areas in South-East Asia and that there may be a large number of undiagnosed and subclinical cases. The recent advances in diagnostic tests for histoplasmosis are also reviewed with reference to the experience of using these tests in the reported case. PMID- 8673822 TI - Sustainability of a nutrition education programme to prevent night-blindness in Bangladesh. AB - Cross-sectional surveys were conducted to assess prevalence of night-blindness and dietary habits prior to intervention (in 1986), after 3 years of intervention (in 1989) and 3 years after the termination of active intervention (in 1992), in the northern part of Bangladesh. The prevalence of night-blindness per thousand children decreased from 1986 to 1989 (during intervention) and rose from 1989 to 1992, but remained significantly lower in 1992 than the 1986 prevalence. Household income declined from 1989 to 1992, and lower consumption of beta carotene rich food, protein items and vitamin A capsules was registered in 1992 despite almost the same level of awareness relating to the prevention of night blindness in the community during the period 1989-1992. The results indicate that the long-term impact of a health education programme to prevent night-blindness is uncertain. Improvement in socioeconomic conditions, in addition to relevant knowledge, is probably a precondition for maintaining a sustainable impact of health education. PMID- 8673823 TI - A community trial of ivermectin for onchocerciasis in Sierra Leone: compliance and parasitological profiles after three and a half years of intervention. AB - We have studied the compliance patterns and the long-term effects of repeated ivermectin at various dosing intervals in a randomized controlled trial. The setting for the trial was six neighbouring communities hyperendemic for onchocerciasis in southern Sierra Leone. A total of 335 subjects attended a survey 18 months after the fifth treatment round. Of those randomized to ivermectin, over 85% had received at least three doses. There was no evidence that women of childbearing age were consistently under-treated, despite the criteria for exclusion from treatment. An intention-to-treat analysis showed that a 6-monthly ivermectin treatment regime satisfactorily suppressed microfilarial loads. Microfilarial repopulation was significantly slower over an 18-month period after multiple doses compared to a single dose. Further analysis of microfilarial repopulation suggests that there is a cumulative suppressive effect after at least the first three doses of ivermectin, and that an annual treatment interval is as effective for short-term microfilarial suppression as a 6-monthly interval. PMID- 8673824 TI - Sleeping sickness in Zaire: a nested polymerase chain reaction improves the identification of Trypanosoma (Trypanozoon) brucei gambiense by specific kinetoplast DNA probes. AB - Blood samples collected in the sleeping sickness focus of Boma, Zaire, from human patients and domestic animals were analysed by polymerase chain reaction (PCR) for the presence of trypanosome DNA. The comparison of PCR and miniature anion exchange centrifugation technique (m-AECT) results clearly shows that in domestic animals mixed infections (Trypanozoon/Trypanosoma [Nannomonas] congolense) are more frequently diagnosed by PCR than by m-AECT. Trypanozoon positive blood samples were further analysed for Trypanosoma (Trypanozoon) brucei gambiense. For that purpose amplified minicircle kinetoplast DNA (minicircle kDNA) was differentiated in gambiense and non-gambiense by hybridization with DNA probes. To analyse blood samples, especially those with low parasite numbers, the amplification step had to be improved by a nested PCR. Subsequent hybridization was done with kDNA probes generated by PCR from blood samples which had been obtained from a human patient infected with T.(T.) b. gambiense and a pig infected with Trypanozoon. The hybridization results clearly show that at least two genotypes of Trypanozoon parasites occur in the sleeping sickness focus of Boma, Baz-Zaire. One obviously corresponds to T.(T.) b. gambiense and was present in humans and two domestic animals (pig, dog). The other genotype seems to be associated with T.(T.) b. brucei and could be detected only in the blood of domestic animals. This is the first time that field samples could be analysed by a technique which facilitates the molecular identification of T.(T.) b. gambiense without prior cloning, propagation, and/or isolation of the parasites. Therefore, this technique seems to be a promising tool to elucidate the significance of the animal reservoir for the epidemiology of the gambiense sleeping sickness in Africa. PMID- 8673825 TI - [Motivation to acquire and use impregnated mosquito nets in a stable malaria zone in Burundi]. AB - In Burundi, the purchase, acceptance and utilization of impregnated bed nets sold at a promotion price (2 $US) were evaluated in a stable malaria area (South-Imbo, district of Nyanza Lac) where this method of protection was previously unknown to the inhabitants. The sale of the impregnated nets differed between the administrative subdivisions (so-called 'collines') of the area with a coverage varying from 10 to 70% of families. Moreover, in one of these collines with a high overall coverage rate (62%) a difference was also found between the three administrative regions (so-called 'sous-collines') which were socially and economically similar. However, these sous-collines (SC) differed in their geographical location and were found at different altitudes. The real coverage corresponding with the percentage of families showing at least one installed bed net, was calculated for each SC. This coverage was 77% in the SC-1 situated in the low wet area and decreased gradually to 14% in the SC-3 at the highest altitude. The purchase of a bed net does not necessarily mean that people will use them. About 30% of the bed nets bought at the promotion price could not be found and most of them were resold in the neighbouring country (Tanzania). Between 7 (SC-I) and 47% (SC-3) of the bed nets were still packed and not in use. The motivation for buying and using impregnated nets appears to depend essentially on the nuisance level caused by mosquitoes, as shown by the abundance of the mosquitoes in the SC-1 situated in the low wet area (75 bites/man/night) compared to that observed in the SC-2 located at a higher altitude (i bite/man/night). The authors conclude that appropriate health education and information should be developed and promoted by health staff, local authorities and teachers in order not only to improve comfort by decreasing the insect nuisance, but also to decrease the considerable malaria burden in the community. PMID- 8673826 TI - Post-natal incidence of HIV-I infection among children in a rural Ugandan population: no evidence for transmission other than mother to child. AB - We conducted a prospective cohort study to determine the post-natal incidence of and possible transmission routes for HIV-I infection in rural Ugandan children. The cohort consisted of the population of a cluster of 15 villages in Masaka District, south-west Uganda, and was enrolled in 1989-1990 through a demographic and serological survey. During the period 1991-1993 the population was resurveyed annually. A total of 5492 children aged 0-12 years were enrolled; of these, 41 (0.7%) were seropositive infants. A total of 3941 (72%) children were HIV negative on enrolment and had at least one follow-up specimen. During 8596 person years of observation only I seroconversion was observed, an incidence rate of 0.12 (95% CI 0.00-0.35) per 1000 years of observation. The transmission of HIV was most probably through breast milk. The case corresponds to a rate of 1.1 per 1000 in households with one or more HIV-positive adults (874 years of observation); no incident case was observed in households with only seronegative adults (6423 years of observation). Thus, HIV infection among children aged 0-12 years in this population is virtually exclusively the result of mother-to-child transmission. No infections were observed attributable to parenteral exposure, non-sexual casual or household contact, or insects. PMID- 8673827 TI - The El Nino Southern Oscillation and the historic malaria epidemics on the Indian subcontinent and Sri Lanka: an early warning system for future epidemics? AB - The recurrent great malaria epidemics which occurred in the Punjab province of former British India and Ceylon before the introduction of residual insecticides have been related to excessive and failing monsoon rains respectively. In the arid Punjab, rainfall facilitated breeding and increased the lifespan of the mosquito vector and, in the wet part of Ceylon, failing monsoon rains caused rivers to pool, creating more favourable breeding conditions. The periodic fluctuations in monsoon rainfall and epidemic malaria are here explained in relation to the El Nino Southern Oscillation. In the Punjab, epidemic malaria between 1868 and 1943 correlates significantly (r = 0.34, P < 0.005) with the sea surface temperature anomalies in the Eastern Equatorial Pacific, a parameter of the oscillation, and epidemics were significantly more prevalent in a year with a wet monsoon following a dry El Nino year than in other years. In Ceylon, epidemics were significantly more prevalent during El Nino years, when the same south-west monsoon tends to fail. With the reduced reliance on residual insecticides and the recurrence of epidemic malaria on the Indian subcontinent, advances made in predicting El Nino events may be used to forecast high and low risk years for future malaria epidemics. PMID- 8673828 TI - Isolation and characterization of a new subtype A variant of human immunodeficiency virus type I from Nigeria. AB - We have isolated a new variant of HIV-1 from Nigeria, Africa. The virus was recovered from the peripheral blood mononuclear cells (PBMCs) of an apparently healthy 23-year-old male from Ibadan, Nigeria. The in vitro studies indicated that the virus was highly cytopathic and replicated well in normal PBMCs, established T-cell lines and the monocytic cell line U937. The highest replicative titre of the virus was obtained in freshly isolated primary macrophage/monocyte cells which also showed the least cytopathology. Most other cultures showed single-cell cytolysis and giant cells, and syncytia were not induced in the HTLV-1 infected MT-2 cells. Since no HIV strain has been isolated from Nigeria, we obtained cDNA clones containing the env gene, to further characterize the Nigerian virus. Based on the DNA sequence analysis of 14 clones containing the coding region for its gp 120 protein, the Nigerian HIV isolate has been classified as HIV-1 subtype A. Only one subtype A virus from Rwanda has been characterized and this virus has not been shown to exhibit extreme cytopathicity in various cell types as was observed with the Nigerian strain. Further, the ability of this virus to grow well in lymphocytes, monocytes and macrophages and to exhibit cytopathicity without causing syncytia are uncommon properties distinguishing the Nigerian virus from other HIV-1 strains. Since most macrophage tropic viruses have been associated with 'neurotropism', the isolation of an HIV 1 strain from the blood of an individual with no known neurological disorder indicates that this rapidly replicating cytopathic virus, with a broad host range, may play an important role in the pathogenesis of HIV disease. This represents the first report of an HIV-1 isolate from Nigeria. PMID- 8673829 TI - Community financing or cost recovery: empowerment or social dumping? PMID- 8673830 TI - Potential interventions for preventing pneumonia among young children in developing countries: promoting maternal education. AB - The views of various disciplines on the role of education in improving the health and survival of young children in developing countries are discussed, as well as the factors and processes explaining this impact of education and the influence which education could have on risk factors especially relevant to acute respiratory infections (ARI) and pneumonia. This is by reviews of the available evidence on the impact of maternal education on mortality and morbidity. Since there are hardly any data dealing with the impact of education on pneumonia mortality, we focus on post-neonatal mortality, assuming that it is a suitable proxy for pneumonia mortality. Evidence is summarized on several processes or mechanisms which could explain why there is such an impact of education on ARI mortality (and morbidity) in children below 5. An attempt is made to quantify the reduction in pneumonia mortality which has occurred during the past 10-15 years as a result of improvement in women's education. This will also give an indication of the magnitude of the potential benefits of education for health and survival in the years ahead. Throughout this report we define maternal education as the regular schooling received by women during their youth. Some may have followed additional adult education classes before they became mothers. PMID- 8673831 TI - HIV and India: looking into the abyss. AB - Serosurveillance of high risk groups started in India in October 1985. The first positive cases were detected in 1986. As of mid-1994, official figures stood at 15000 HIV positive cases and 559 cases of AIDS. This is most certainly an underestimate because of under reporting. Among high risk groups, prevalence has risen rapidly. Between 1986 and 1994, prevalence has risen from 1.6 to 40.0% in sex workers, 1.4 to 40% in STD clinics and 0 to 70% in i.v. drug abusers in various studies. The penetration into the general population is uncertain. As in Africa, infection has been mainly by heterosexual intercourse, with commercial sex workers, long distance truck drivers and migrant labour serving as vehicles of spread. Other routes of infection are transfusion of blood and blood products and i.v. drug use. Dependence on professional blood donors is the main cause of infected blood supplies. Ninety per cent of cases with HIV infection are aged between 15 and 45 years and belong to socioeconomically disadvantaged groups. The male to female ratio is 5:1, with female cases being mainly sex workers. The predominant virus is HIV-1 but cases with HIV-2 and mixed infection are being reported from port cities. The present situation in India is similar to the early pattern in Africa where a sharp increase in seroprevalence among high risk groups was followed by spread to the general population. Clinical AIDS is still infrequent. From experience so far, pulmonary tuberculosis has been the most common clinical presentation. So far AIDS associated tuberculosis has responded to standard therapy but the development of multi-drug resistant mycobacteria and their spread to the large tuberculous population in the country is a potential threat. Key factors of AIDS/HIV prevention are public education and counselling about the infection and safe sex practices, especially in high risk groups; STD control; promotion of voluntary blood donation and adequate screening of blood products and general and equitable progress in the economic development of the country and its people-much high risk behaviour is driven by poverty. PMID- 8673832 TI - Treatment practices for degedege, a locally recognized febrile illness, and implications for strategies to decrease mortality from severe malaria in Bagamoyo District, Tanzania. AB - Malaria remains one of the chief causes of mortality among young children in sub Saharan Africa. Verbal autopsies for cases of childhood mortality in Bagamoyo District, Tanzania demonstrated that degedege, a locally defined illness of children characterized by fever and convulsions, is frequently treated by traditional healers. To investigate this further, an ethnographic study was carried out in one village that included in-depth interviews with 14 traditional healers and 3 focus groups with parents. Parents and traditional healers were unanimous in their conviction that degedege requires traditional treatments, at least initially, and that these treatments are effective. While traditional healers do refer cases that are not improving to the District Hospital, this frequently occurs late in the course of the illness, after one or more stages of traditional treatments. The prognosis will thus be poor for those children who are suffering from severe malaria. Consideration should be given to enlisting the support of traditional healers in efforts to improve treatment for severe malaria, including teaching them how to distinguish febrile convulsions from cases of severe malaria. PMID- 8673833 TI - Prevalence of blindness and visual impairment in the region of Segou, Mali. A baseline survey for a primary eye care programme. AB - A community-based cross-sectional study on the prevalence and causes of blindness and visual impairment was conducted between July and August 1990 in three rural districts in Segou region, Mali. The study population consisted of 5871 villagers. In the study area, the overall prevalence of bilateral blindness was 1.7% (standardized rate for age 2.0% +/- 0.4%), of bilateral visual impairment 1.7% (2.1% +/- 0.4%), of unilateral blindness 1.7% (2.2% +/- 0.4%) and of unilateral visual impairment 1.0% (1.2 +/- 0.3%). No important differences were found between districts. Cataract was the most common cause of visual loss (54%) and was most prevalent among those over 50 years of age. In 43%, unilateral blindness was associated with trauma. Other major eye diseases accounting for high percentages of visual impairment were trachoma and glaucoma. Xerophthalmia appeared to be a major public health problem among children in the age group 0-5. It was concluded that blindness is a major public health problem in this region. Some recommendations are given for strengthening integrated primary eye care at the district level in Segou region. PMID- 8673834 TI - Field tests of a village-based mollusciciding programme for the control of snail hosts of human schistosomes in Cameroon. AB - The feasibility of using unskilled workers at the district or village level to perform mollusciciding activities in arid regions of northern Cameroon was investigated. A simplified procedure for application to temporary ponds, the principal sites of schistosomiasis transmission in that region, was tested. This consisted of mixing the required quantity of niclosamide (Bayluscide, Bayer AG, Leverkusen) with pond water in a plastic watering can and applying the mixture around the circumference. To aid dispersion, the can was repeatedly swept from the perimeter toward the centre of the pond. Two ponds each were treated once near the end of the rainy season at 1 of 3 concentrations: 0.5, 1.0 and 1.5 p.p.m. Following treatment, 100% snail mortality was recorded at all concentrations. A simple, rapid method for determining the quantity of niclosamide needed to treat temporary ponds was also devised. Physical characteristics were determined for 16 potential schistosomiasis transmission sites in the region. An integration of those characteristics was used to develop a simplified scale indicating the quantity of niclosamide needed to treat ponds based on their circumference. The operational feasibility of a village based mollusciciding programme using those simplified procedures was then evaluated in 2 villages. Village health workers demonstrated a high accuracy (87%) in identifying potential schistosomiasis transmission foci and snail host populations were virtually eliminated from treated sites. PMID- 8673835 TI - Introducing insecticide impregnated bednets in an area of low bednet usage: an exploratory study in north-east Ghana. AB - To find out the acceptability of the use of insecticide impregnated bednets before launching a large-scale trial to evaluate their impact on child mortality, 96 permethrin impregnated bednets were distributed in 4 communities within the Kassena Nankana district of the Upper East Region of Ghana, where previously only 4% of the people had owned a mosquito net. The nets were readily accepted and used by the recipients. The major benefit perceived by the users was the reduction of the nuisance effect of mosquitoes and other insects. The people in the study area normally sleep on mats in either an open courtyard or a sleeping room depending on the weather but this did not deter them from using the nets. The white nets distributed for this study became dirty with use, and users thought they needed to be washed. In order to discourage this, it is recommended that dark coloured nets be used in the main intervention trial. After having used the nets for a year, the community members expressed willingness to buy the nets if they were made available after the harvest season when they had sold their crops and had enough money to pay for them. The results of this study have been used to plan and conduct a large intervention trial. PMID- 8673836 TI - Drinking water sources, mortality and diarrhoea morbidity among young children in northern Ghana. AB - In the Upper East Region of Ghana, considerable resources have been invested in the provision of boreholes. As part of the Ghana Vitamin A Supplementation Trials' Survival Study which was carried out in one of the districts of the Upper East Region between January 1989 and December 1991, data were collected over a period of one calendar year on the drinking water sources used by approximately 13,000 mothers/guardians of over 20,000 children and on the morbidity and mortality experiences of these children. These data were used to describe seasonal and geographical variations in drinking water sources; to look for other predictors of water source use; and to establish whether the drinking water source was associated with the risk of child death or the period prevalence of diarrhoea among young children. Boreholes were used as the main source of drinking water by about 60-70% of respondents. They were used slightly more frequently in the dry season. In the rainy season, the use increased of more traditional sources such as rainwater or holes dug in stream beds. The use of boreholes was greatest in the northern zone of the study area and was more common in those who had had some formal education and were of higher socioeconomic status. Some association was found between reported drinking water source and diarrhoeal morbidity, although this association appeared to be seasonal. No significant association was found between drinking water source and child mortality. PMID- 8673837 TI - A follow-up study on visual outcome after camp-based intracapsular cataract extraction. AB - The visual outcome of 164 intracapsular cataract extractions (ICCE) performed in 158 patients at an eye-camp was evaluated. 93.3% had a preoperative visual acuity of less than 3/60. On the 4th/5th post-operative day, 39.3% had a visual acuity between 6/18 and 6/36; 84.7% had vision better than 3/60. Six weeks post operatively, 44.1% had visual acuity better than 6/18 and a total of 84.1% better than 3/60. The vision of 40.7% improved between the 4th/5th post-operative day and the follow-up visit at 6 weeks. 46.4% of patients had post-operative corrected visual acuity better than 6/18, 24.3% had vision between 6/18 and 6/36, and a total of 84.3% had vision better than 3/60. The patients' satisfaction in terms of improvement in mobility and ability to do housework at 6 weeks after the operation correlated better with the improvement in vision in terms of the number of Snellen's lines than with the actual post-operative visual acuity. PMID- 8673838 TI - Histopathological observations in new and classic models of experimental Schistosoma haematobium infections. AB - The authors present marsh rat Holochilus brasiliensis, jirds Meriones shawi and M. unguiculatus as new models of Schistosoma haematobium infection. Histological findings were compared with those of classic models mouse Mus and hamster Mesocricetus. In new models, embryonated eggs were seen in the stool from 90 days post infestation (DPI) and active disease developed from 117 to 175 DPI. Seven out of 10 rodents presented granulomatous and/or chronic cystitis, fibrosis, polyps and urothelial changes: squamous metaplasia, precancerous dysplasia and squamous cell carcinoma of the urinary bladder. In the digestive tract of all new models, granulomas eroded the mucosa, formed inflammatory polyps, infiltrated the wall and accumulated into bilharziomas. In the liver, granulomatous hepatitis surrounded by bilharzial pigment deposit was apparent. Pipe-stem fibrosis involved 4 rodents with precirrhotic changes in 1 and portal hypertension in 2. One female Meriones suffered from granulomatous endometritis and salpingitis. All new models developed pulmonary granulomatosis with associated vascular lesions: giant cell arteritis in 1 rodent, thromboses in 3 and pulmonary hypertension in 4 others. In classic models, 1 Mus presented a squamous cell carcinoma of the urinary bladder while Mesocricetus displayed diverse lesions in digestive and genital tracts, liver and lungs. All tissue lesions, resembling those seen in humans in all points, were far more frequent and severe in new models than in classic ones. Those involving the urinary bladder have never been reported in other models such as monkeys: Pan troglodytes, Cercopithecus aethiops and Cebus apella. A comparison was carried out between different models on the basis of experimental conditions: definitive hosts, number of cercariae used, type and duration of infection. This study clearly demonstrated that Holochilus brasiliensis, Meriones shawi and M. unguiculatus are perfectly adequate models in terms of laboratory facilities. They are helpful in investigating the pathogenic mechanism of some disorders in S. haematobium infection, particularly tumours of the urinary bladder, and this may enhance therapeutic assays. PMID- 8673839 TI - Vaccination generates serum-mediated protection against Onchocerca lienalis microfilariae in the mouse. AB - Mice vaccinated with an aqueous extract of Onchocerca lienalis microfilariae (mf) plus adjuvant exhibited 51% protection against challenge with live mf. Protection was ablated by prior treatment of the extract with heat or proteinase K, indicating the involvement of proteinaceous epitope(s). A 54% level of protection was conferred on naive mice by passive transfer of serum from vaccinated donors, suggesting that host resistance was principally mediated by humoral components of the immune response. In contrast, the protection induced by sensitization of mice with living mf is transferable with cells, but not serum. Western blot data reveal different antigen recognition profiles for serum antibodies from these two groups of mice. These results indicate that vaccination and infection activate distinct protective mechanisms against Onchocerca mf in the mouse. PMID- 8673840 TI - Topical chemotherapy for experimental African trypanosomiasis with cerebral involvement: the use of melarsoprol combined with the 5-nitroimidazole, megazol. AB - Megazol, one of a number of related 5-nitroimidazoles, can be dissolved in dimethylsulphoxide and the solution can be converted into a gel by the addition of hydroxypropylcellulose which facilitates the ease and accuracy of administration. This megazol gel, when used in combination with melarsoprol (3.6%) in propylene glycol gel, will cure experimental CNS-trypanosomiasis in mice. A single application of 0.1 ml of melarsoprol (3.6%) gel plus 0.1 ml of either 8 or 16 mg/ml megazol gel successfully treated experimental CNS trypanosomiasis while two consecutive days' treatment with 0.05 ml melarsoprol and 0.1 ml of 16 or 32 mg/ml megazol gels also produced satisfactory cures. PMID- 8673841 TI - MR findings in human fascioliasis. AB - Fasciola hepatica is a trematode of herbivorous mammals, and man is infected by accidental ingestion of contaminated raw aquatic vegetables or water. There have been many reports on computed tomographic and cholangiographic features of human fascioliasis. However, findings of magnetic resonance (MR) imaging have not been reported. Hepatic fascioliasis produces three types of lesions in MR images arranged in tract-like fashion. The outermost area presents as an iso-signal area in T1WI, with slightly higher signal intensity in T2WI and diffuse enhancement after i.v. contrast. The second type presents as a well defined low signal area in T1WI, not enhanced, and also shows low signal intensity in T2WI. The third type has low signal intensity in T1WI, is not enhanced, and has high signal intensity in T2WI which is similar to fluid-containing inflammatory lesions such as pyogenic abscess. These findings suggest various changes associated with traumatic hepatitis caused by the migration of the worm in the liver. This diverse signal intensity can be a suggestive finding of fascioliasis. PMID- 8673842 TI - Direct amplification and species determination of microsporidian DNA from stool specimens. AB - Microsporidia are recognized as a major aetiological agent in chronic diarrhoea of immunocompromised patients. Their detection by light microscopy is hampered by the small size of the spores. A simple and rapid DNA extraction method has been developed for the detection of microsporidian DNA by PCR directly from stool specimens. It can be performed at room temperature in a 1.5-ml microcentrifuge tube format in less than 1 hour. The subsequent nested polymerase chain reaction permits the detection of 3-100 spores in a 0.1-g stool sample. The amplification products can be verified and the species Enterocytozoon bieneusi, Encephalitozoon cuniculi and Encephalitozoon (Septata) intestinalis distinguished by a simple restriction endonuclease digest. PMID- 8673843 TI - Plasmodium berghei mouse model: antimalarial activity of new alkaloid salts and of thiosemicarbazone and acridine derivatives. AB - Sixteen compounds were synthesized and evaluated on Plasmodium berghei in CD1 mouse. The nature of the salt associated to the active principle can give some advantages in the field of activity, bioavailability and toxicity. beta Resorcylic acid was chosen in this study because of its previously described antimalarial activity and its expected enhancement of quinine antimalarial activity. While treatment with subcutaneous quinine sulphate at 1 mmol/kg cured 6/10 mice, quinine beta-resorcylate cured all the mice under identical conditions. Although such a result appeared promising, in vitro investigation should be performed to draw clear conclusions regarding a synergy between quinine and beta-resorcylate. Cinchonidine beta-resorcylate was also active; all mice were cured at 1 mmol/kg and the mean survival time was 13.8 +/- 2.4 days after a subcutaneous treatment at 0.5 mmol/kg in a single dose. In the series of acridines, (N-alpha, sigma-dioxopentyl)-5-amino-1,2,3,4-tetrahydroacridine cured all mice at 50 mumol/kg under the same conditions. The maximum tolerated doses in mice ranged from 100 to 150 mumol/kg for these acridine derivatives. The chemotherapeutic index of (N-alpha, sigma-dioxopentyl)-5-amino-1,2,3,4 tetrahydroacridine was estimated at 2-3. Other salts expected to reduce the toxicity, such as alpha-ketoglutarate and p-chlorophenoxyacetate, did not enhance the activity of the active principles. These results prompt us to further investigations including plasma kinetic evaluation in rats and in vitro on Plasmodium falciparum. PMID- 8673844 TI - Impact of a mass vaccination campaign against a meningitis epidemic in a refugee camp. AB - Serogroup A meningococcus epidemics occurred in refugee populations in Zaire in August 1994. The paper analyses the public health impact of a mass vaccination campaign implemented in a large refugee camp. We compared meningitis incidence rates from 2 similar camps. In Kibumba camp, vaccination was implemented early in the course of the epidemic whilst in the control camp (Katale), vaccination was delayed. At a threshold of 15 cases per 100 000 population per week an immunization campaign was implemented. Attack rates were 94 and 134 per 100,000 in Kibumba and Katale respectively over 2 months. In Kibumba, one week after crossing the threshold, 121,588 doses of vaccine were administered covering 76% of all refugees. Vaccination may have prevented 68 cases (30% of the expected cases). Despite its rapid institution and the high coverage achieved, the vaccination campaign had a limited impact on morbidity due to meningitis. In the early phase in refugee camps, the relative priorities of meningitis vaccination and case management need to be better defined. PMID- 8673845 TI - Vibrio cholerae O139: how great is the threat of a pandemic? AB - The emergence of the new strain Vibrio cholerae O139 and its rapid spread in Bangladesh and India together with its detection in several other countries, have raised the question whether this constitutes the beginning of the eighth pandemic of cholera, and if so, how large a threat it poses. In an attempt to answer this question, epidemic spread patterns of Vibrio cholerae O139 strain in Bangladesh were studied. Initially the epidemic moved quickly and affected the entire coastal and estuarine tidal plains of southern Bangladesh. In the flood plains of the northern regions it affected mostly the north-eastern and north-central areas, at a slower pace than in the southern areas. In the beginning the new strain totally displaced both biotypes (classic and El Tor) of Vibrio cholerae O1. Nearly 2 years after its initial detection, striking differences in the distribution of V. cholerae O139 and O1 were observed. In most northern areas, the new strain was replaced by V. cholerae O1, whereas in the southern coastal regions, the O139 strain continues to dominate epidemics. The study suggests that the O139 strain may become endemic in the coastal ecosystem. The threat of a pandemic, therefore, may not be as large as it first seemed. PMID- 8673846 TI - Reduction of food intake during pregnancy in rural south India. AB - A common custom in developing countries is reduction of food intake during pregnancy, especially in the last trimester. In the research area in South India, women mentioned that they reduce food intake late in pregnancy. This paper explores whether the reported reduction could be confirmed by quantitative data on food intake; by how much intake was reduced; and whether all women ate less. A group of 186 women in a rural area of Karnataka were followed throughout pregnancy. Most did not achieve the daily food intake recommended by the Indian Council of Medical Research (ICMR), not even that of non-pregnant women. Their average daily energy intake during pregnancy was 1700 kcal. A trend of declining daily energy intake within subjects over the whole period of pregnancy was observed, the biggest change taking place between month 5/6/7 and month 8/9. The major determinant of change in energy intake turned out to be prepregnancy nutritional status, i.e. chronic energy deficiency (CED), measured by body mass index (BMI). Results indicate that women who were better nourished before they became pregnant were more likely to reduce energy intake during pregnancy. PMID- 8673847 TI - Prevalence of antibodies to human herpesviruses 6 and 7 in early infancy and age at primary infection. AB - Sera from a sample of children aged 3 months to 6 years and from cord blood were tested in an indirect immunofluorescence assay (IFA) for reactivity to human herpesviruses 6 (HHV-6) and 7 (HHV-7). HHV-6 seropositivity values rose from 19% to 79.3% in the first 18 months of life, while HHV-7 seroprevalence reached a similar value (75.9%) in children aged 3-6 years. These results show that HHV-7, like HHV-6, is a prevalent virus in infancy. In cord blood sera, assayed to study infant humoral situation at birth, similar values for the two viruses (78.9% for HHV-6 and 76.3% for HHV-7) were found. HHV-6 and HHV-7 IgG antibody affinity to the corresponding antigens was assessed by the end point antibody titration in the presence and absence of urea 8M. This test distinguishes antibodies of recent (low affinity) or past (high affinity) production. Together, the data on seroprevalence and antibody affinity suggest that HHV-6 primary infection generally precedes that by HHV-7. These results are discussed in the light of a different pathogenetic role of the two viruses. PMID- 8673848 TI - Modulatory effects of hen egg-white lysozyme on immune response in mice. AB - The effect of her egg-white lysozyme (HEWL) on immune response was evaluated by measuring antibody-producing cells and circulating antibodies in mice inoculated with the test antigen (SRBC or BSA) and HEWL at the same time but in a separate body area. HEWL caused a premature decline in SRBC-specific plaque forming cells (PFC) and a reduction in the total amount of these cells. HEWL inhibited antibody production against BSA in the primary response, but was devoid of any effect on the secondary response elicited in the same mice by a second inoculation of the test antigen. The inhibitory effect of HEWL was dose-dependent, being maximal with 300 micrograms, required an enzymatically active protein and was not shown by other basic proteins. HEWL also abolished the enhancing effect of LPS and CFA on anti-BSA antibody production. The inhibitory activity of HEWL was further increased by hydrolyzed peptidoglycan. These results suggest that HEWL modulates the immune response in mice and performs this function through activation of non specific suppression mechanisms. PMID- 8673849 TI - Lysozyme inhibitors enhance immune response in mice. AB - The effect of hen egg-white lysozyme (HEWL) inhibitors (such as heparin, histidine methylester, chitotriose, chitobiose) on immune response was evaluated by measuring antibody-producing cells and circulating antibodies in mice inoculated with these substances and the test antigen (SRBC or BSA). It was found that these compounds have an immuno-enhancing effect which is directly proportional to their inhibitory activity on HEWL. Conversely, HEWL inhibited the immunoenhancing effect of these compounds when injected together with these and the test antigen. The results suggest that one possible mechanism by which adjuvants stimulate immune response may be the inhibition of endogenous lysozyme. PMID- 8673850 TI - Evaluation of a competitive enzyme immunoassay in screening for syphilis. AB - A competitive immunoenzymatic method has been developed and evaluated for the serological screening of syphilis. The method detects both anti-Treponema Pallidum IgG and IgM. The kit, commercially known as "Syphilis Screen", is produced by DIESSE Diagnostica Senese (Siena, Italy); all the required reagents are included and are ready for use. The test is performed on undiluted serum and a single incubation step is necessary. The method can be easily automated, and the results do not require a subjective interpretation. A good correlation was found with the Treponema Pallidum Haemagglutination (TPHA) technique: only 14 out of 2350 samples tested (2090 non reactive and 260 reactive) were found to be in disagreement. This test can be considered an alternative to the TPHA method in screening for syphilis. PMID- 8673851 TI - Protective role of the pefloxacin-IFN-gamma association in Leishmania major infected mice. AB - Four groups of female Balb/c mice were inoculated in the left hind footpad with 30 microliters of RPMI 1640 medium containing 10(7) Leishmania major amastigotes/ml. One group was injected sc with 200 microliters of RPMI 1640 containing 180 micrograms of pefloxacin for 20 days, a second group with the same amount of medium containing 100 units of recombinant murine interferon gamma (rmIFN-gamma). The third group was treated with the association, while the fourth group received plain medium in an identical regimen. Pefloxacin or IFN-gamma significantly decreased the size of primary lesions, while their association was significantly more efficient in this respect, in reducing the incidence of metastatic lesions, and in clearing parasites from the spleen. We also investigated the effect of pefloxacin on the activation of mouse spleen cells by Concanavalin A (Con A) in vitro, without detecting any interference on the proliferative response or IFN-gamma production. PMID- 8673852 TI - Susceptibility to toxoplasmosis: correlation between macrophage function, brain cyst formation and mortality in rats. AB - Rats are resistant to Toxoplasma infection, and in contrast to mice do not form cysts in their tissues. Because rats treated with beta adrenergics, corticosteroids or 60cobalt are more susceptible to toxoplasmosis, we conducted experiments to investigate if the impaired resistance of drug-treated rats is related to macrophage function or induction of cystogenic capacity. Our experiments in 0.7 or 1.2 mg/kg-corticosteroid or 12 Gy-60cobalt-treated rats indicated that the decreased survival rate (P < 0.001 to P < 0.0001, compared to infected-untreated or infected-unirradiated animals) was associated with a decrease of both macrophage toxoplasmastatic activity and intracellular killing (P < 0.05 each group), compared to infected-untreated or infected-unirradiated rats. However in 9 Gy-60cobalt-treated animals the decreased survival rate (P < 0.001, compared with control rats) was accompanied only by a decrease of the toxoplasmastatic activity in comparison to macrophages of the control animals. Moreover in these animals, the release of NO2- by these macrophages was poorly detectable (P < 0.05) or completely inhibited (P < 0.01) in comparison with infected-untreated or infected-unirradiated rats. In contrast, in all groups of rats treated with high doses of beta adrenergic, the decreased survival (P < 0.001 to P < 0.0001, compared with untreated rats) was accompanied by values of intracellular killing and intracellular proliferation of Toxoplasma parasites that did not significantly (P = ns each group) differ from macrophages of infected-untreated rats. Furthermore in the high beta adrenergic treated groups only small amounts of NO2- were detectable (P < 0.05) in comparison with control animals. In addition, our data in rats treated with 0.7 or 1.2 mg/kg of corticosteroid or 12 Gy of 60cobalt indicated that the increased mortality was correlated to the presence of a small number of cysts in their brains (P < 0.05; P = ns; P < 0.01 respectively) in comparison to infected-untreated or infected unirradiated rats. These results suggest that the susceptibility of drug immunosuppressed rats is not due exclusively to a deficient macrophage function, but is probably also linked to immune mechanisms involved in the process of cystogenesis. PMID- 8673853 TI - A one-year survey of respiratory and urinary pathogens and their antimicrobial susceptibility. AB - A one-year (1993) survey of the distribution of pathogens causing respiratory and urinary infections and their antimicrobial susceptibility was performed. The most common bacteria isolated from the lower respiratory tract of patients in a district general hospital were Pseudomonas aeruginosa (35.9%) and Staphylococcus aureus (21.4%). About half of the Pseudomonas strains revealed a resistance to imipenem and gentamicin, whereas almost all Staphylococcus strains were resistant to penicillin G. The most common isolates from urine of in and out-patients were Escherichia coli (32.3% and 39.8%) and Enterococcus faecalis (16.6% and 14.2%). Escherichia coli strains were largely susceptible to almost all chemoantibiotics tested, whereas Enterococcus faecalis demonstrated a high resistance pattern. Pseudomonas aeruginosa isolated from urine were more sensitive to chemoantibiotics than respiratory strains and the susceptibility of Staphylococcus aureus isolated from hospitalized or out-patients was different. A periodic monitoring system devised to give information about the circulation of bacteria and the chemoantibiotic resistance in a local context would be useful to assess the local trends and select drugs for therapy. PMID- 8673854 TI - Heterotrophic bacteria in the Ross Sea (Terra Nova Bay, Antarctica). AB - Microbial research on temporal variation of bacterial densities was carried out on seawater samples collected from two field stations at different depths during the Antarctic summer (oceanographic campaign 1989/1990). Bacterial densities evaluated on Marine Agar 2216 (Difco) and on TCBS Agar (Difco) after incubation at +4 degrees C for 21 days respectively ranged from 0 to 7.9 x 10(2) CFU/ml for heterotrophic bacteria and from 0 to 5.7 x 10(2) CFU/100ml for "presumptive vibrios". During the period of observation, Vibrio densities showed a higher variability than those of total heterotrophic bacteria. A high percentage of gelatinolytic and chitinolytic vibrios was observed. The qualitative composition of heterotrophic bacterial communities was studied on 38 morphological and biochemical characteristics of 152 strains isolated from the stations. The data were subsequently used to determine the structure and metabolic potentialities of bacterial communities in the two sites. Almost all the heterotrophic, psychrotrophic isolates were non fermentative Gram-negative rods, belonging to the genera Pseudomonas/Alcaligenes, Flavobacterium/Cytophaga. The bacterial communities in the two coastal habitats investigated were clearly different. PMID- 8673855 TI - Influence of environmental adaptation on the sensitivity of micromycetes to pentachlorophenol toxicity in microcosms. AB - The search for fungal strains capable of pentachlorophenol degradation led to the isolation and identification of 98 different micromycetes. When these strains were submitted to toxicity tests in aquatic microcosms at concentrations of 10 mgL-1 and 100 mgL-1 PCP, inhibition of growth was 57% and 36% respectively of the total isolated and identified strains. Among the strains inhibited at 10 mgL-1, 6 can serve as bioindicators of PCP pollution while the strains resistant can be regarded as potential PCP biodegraders. It was confirmed that fungal strains isolated from sites contaminated by chemically different products manifest different levels of sensitivity to PCP toxicity and probably different biodegradation potentials. PMID- 8673856 TI - Radio immune Western blotting: a possible solution to indeterminate conventional Western blotting results for the serodiagnosis of HIV infections. AB - Western blot is used worldwide as a confirmatory assay after a positive or doubtful ELISA result in the serodiagnosis of HIV infections. Despite the use of this test some results may be not definitive due to the presence in Western blot of only few or a single band to HIV protein. This result has been defined as indeterminate. To resolve indeterminate results obtained with conventional Western blotting (WB) we used radio immune Western blotting (RIWB), a method capable of detecting antibodies to HIV-1 proteins with greatly increased sensitivity with respect to conventional WB. We used RIWB to perform a retrospective survey on 20 sera belonging to individuals undergoing HIV serodiagnosis (not blood donors) with positive or borderline EIA results, and indeterminate WB results who only later fully seroconverted. Fifteen of the sera tested by RIWB showed a positive result which clarified any doubtful indeterminate WB result; all bands present in conventional WB were enhanced in intensity using RIWB and new bands, absent in the WB assay, were highlighted using RIWB. RIWB may resolve most indeterminate WB results. PMID- 8673857 TI - An epidemiological study on viral infantile diarrhoea in Tirana. AB - During the period May 1993-April 1994, an epidemiological survey was conducted on enteric viruses which cause gastroenteritis in infants and young children in Tirana, Albania. Specimens from 321 cases were screened by direct electron microscopy and by an enzyme-linked immunosorbent assay specific for rotavirus group A antigen. By ultrastructural analysis, rotaviruses were detected in 10.3% of cases and adenoviruses in 0.6%, whereas small round structured viruses and small round viruses were found in 2.8% and 2.2% of cases, respectively. Different percentages of rotavirus excretors were revealed by enzyme-linked immunosorbent assay (12.15%) and electron microscopy. Samples rotavirus-positive in at least one of these assays were also analyzed by agglutination of latex particles and electron microscopy results were confirmed. Analysis of electron microscopy positive samples by rotaviral RNA polyacrylamide gel electrophoresis showed five different long electropherotypes of rotavirus among which a single, largely predominant electropherotype (65.5%) was observed. PMID- 8673858 TI - Detection of immunoglobulin G to a Sindbis-related virus by a membrane antigen enzyme immunoassay. AB - We determined the seroprevalence of a Sindbis-related virus isolated for the first time in 1975 from ticks in south-east Sicily and typed by Gresikova et al. in 1978. An indirect enzyme immunoassay based on viral membrane antigen for coating microtiter strips was used for the detection of immunoglobulin G to the Sindbis-related virus. The method appeared more sensitive than a similar enzyme immunoassay based on crude lysate antigen. Comparison of the results obtained from sera tested both by membrane antigen enzyme immunoassay and microneutralization test showed 92% agreement, while the agreement between microneutralization test and crude antigen enzyme immunoassay was 76%. An overall elevated seroprevalence (63.66%) was found in a population group living in and around the area of first isolation and seroprevalence in different age groups was also studied. PMID- 8673859 TI - Recommendations for the registration of new chemical entities used in the prevention and treatment of osteoporosis. PMID- 8673860 TI - Guidelines for the clinical utilization of bone mass measurement in the adult population. Society for Clinical Densitometry. PMID- 8673861 TI - Biochemical bone markers compared with bone density measurement by dual energy X ray absorptiometry. AB - In contrast to medical imaging, the biochemical markers allow a more frequent determination and are not as invasive as histomorphometric methods. We investigated biochemical markers of type I collagen compared with bone density measurements in 85 females between 41 and 89 years of age (median: 57 years). The bone density measurements were performed by dual energy X-ray absorptiometry (DXA) on the lumbar spine (L1-4). The bone density measurements were stated as a percentage of the norm. All patients were divided into three groups: I = <80%; II = 80-130%; III = >120%. Based on this classification the median concentration of the I-carboxyterminal propeptide of type I collagen in serum (S-PICP) as an anabolic marker of type-I collagen increased significantly with rising bone density: I 65.0 micrograms/liter (interquartile range: 52.1-78.0 micrograms/liter); II 85.9 micrograms/liter (52.1-115.5 micrograms/liter); III 81.4 micrograms/liter (62.0-101.0 micrograms/liter);P < 0.05. The concentration of urinary pyridinolines (U-PYR) as a marker for degradation of type I collagen decreased. The I-carboxyterminal telopeptide (S-ICTP) and osteocalcin (S-BGP) did not change. The multivariate regression analysis showed no relationship between between bone density and biochemical bone markers. Only the age significantly correlated negatively with bone density measurement. For a better assessment of type I collagen metabolism we created a "b-quotient" by dividing the sum of S PICP and S-BGP by U-PYR. The median b-quotient increased significantly: I 1.55 (0.97-2.04); II 2.09 (1.57-2.86): III 2.46 (1.58-3.22); P < 0.05. Changes in bone metabolism cannot be identified by the determination of a single marker. However, the improved biochemical diagnostic measurement using the b-quotient may provide early information about the progression of a metabolic disorder within the interval of imaging. PMID- 8673862 TI - Analysis of relationships between sex hormone dynamics and bone metabolism and changes in bone mass in surgically induced menopause. AB - A 3-year follow-up study was performed of bone metabolism and bone changes induced by surgical menopause as a consequence of hysterectomy and oophorectomy (OVX) is 52 nonmenopausal women. We investigated 22 bone parameters and determined seven bone indices as indicators of bone mineral content by dual energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT), and microdensitometry (MD). The significant correlations between levels of sex hormones and/or bone parameters and bone indices demonstrated that marked sex steroid deficiency after surgical menopause induced bone uncoupling during high bone turnover and subsequent rapid bone loss on the early period after OVX. Principal component analysis using correlation coefficients suggested a seven loading-factor matrix composed of bone parameters and a two-loading-factor matrix composed of bone indices. Two groups of parameters--estradiol and estriol, and androstenedione together, and luteinizing hormone and follicle stimulating hormone together--indicated that the rate of bone loss was greater in the trabecular bone than in the cortical bone. Three other groups of parameters- urine calcium, urine hydroxyproline, and serum bone Gla-protein together; serum alkaline phosphatase, serum calcium, and 1,25-dihydroxycholecalciferol [1,25(OH)2D] together; and plasma tartrate-resistant acid phosphatase--indicated that bone uncoupling, with a prevalence of resorption over formation of bone, was greater in trabecular bone than is cortical bone and also that magnitude and rate of bone loss in the axial vertebrae surpassed those in the appendicular metacarpals after OVX. Two other groups of parameters, namely, trabecular bone mineral density (Dd) and bone mineral content (Dc), both measured by DXA, and bone mineral density (L2, L3), measured by QCT, together; and the cortical thickness index (MCI), cortical bone mineral density (sigmaGS/D), and the ratio of GSmin/max, measured by MD, indicated that the relative rates of bone reduction at the 3-year follow-up were greater in the axial vertebrae than in the appendicular metacarpals. Thus, bone change in the trabecular bone was associated with rapid loss during the early phase after OVX, whereas that in the cortical bone was slow during the late phase. PMID- 8673863 TI - Ultrasound, densitometry, and extraskeletal appendicular fracture risk factors: a cross-sectional report on the Saunders County Bone Quality Study. AB - The Saunders Bone Quality Study was designed to determine the feasibility of ultrasonic bone measurement, at the patella, as a predictor of low-trauma fractures in a rural population-based study. At the first visit of this 4-year longitudinal study, anthropometric and clinical measurements and medical, surgical and fracture histories were obtained for the 1428 participants 9899 women and 529 men). Explored risk factors for low-trauma fractures included age, sex, calcium intake, alcohol and caffeine ingestion, tobacco use, body mass and grip strength, age of menopause, estrogen replacement therapy, propensity to fall, distal radius and ulna bone mineral content, and bone density. Forward multivariate logistic regression analysis showed that lower ultrasound values are more consistently associated with reported low-trauma appendicular fractures than the commonly reported forearm absorptiometry measures of radius mineral content and density. When ultrasound, age, and the extra skeletal risk factors were included in an additional multivariate model, only age and ultrasound were significantly associated with appendicular fracture history in women (P = 0.0003), whereas only ultrasound was associated in the men (P = 0.001). We conclude that ultrasound is a better measure as association with reported low trauma fractures than the commonly reported forearm SPA measures. Even after adjustment for many of the extra skeletal risk factors, low AVU is highly associated with low-trauma fracture status for both men and women. PMID- 8673864 TI - Beta-2-microglobulin in diseases with high bone remodeling. AB - Beta2-microglobulin has been observed to behave as a biological marker of bone remodeling. We measured beta2-microglobulin and tartrate-resistant acid phosphatase (TRAP), a specific biological marker of bone remodeling, in 225 women: healthy premenopausal controls, healthy postmenopausal control, and patients with diseases characterized by enhanced bone turnover (postmenopausal osteoporosis, primary hyperparathyroidism, primary hyperthyroidism, polyostotic Paget's bone disease), and in other Paget's group before and after calcitonin treatment. Beta2-microglobulin levels differed significantly between the healthy premenopausal women (n = 20) compared with all the other groups. However, beta2 microglobulin levels did not differ significantly between healthy postmenopausal women (n = 38) and patient's with Paget's bone disease (n = 40)(P = 0.5095), or between women with postmenopausal osteoporosis (n = 30) and women with hyperthyroidism (n = 20)(P = 0.7890). TRAP concentrations differed significantly in all the groups paired except for women with Paget's bone disease and women with either hyperparathyroidism or hyperthyroidism (P = 0.5179 and 0.6993, respectively); likewise, TRAP levels did not differ significantly between the women with hyperparathyroidism and those with hypothyroidism (P = 0.7804). After calcitonin treatment, there was a 22% increase in beta2-microglobulin, a 17% decrease in TRAP, and a 39% decrease in alkaline phosphatase, all of which were significant at P < 0.0001. Our findings indicate that serum beta2-microglobulin, like osteocalcin, behaves as a biological marker of remodeling in a number of diseases with enhanced bone remodeling but not in Paget's bone disease. PMID- 8673865 TI - The anatomy of bone sialoprotein immunoreactive sites in bone as revealed by combined ultrastructural histochemistry and immunohistochemistry. AB - Bone sialoprotein was immunolocalized at the EM level in thin Lowicryl K4M sections of rat bone. Because of the unconventional EM morphology of the bone matrix seen in thin demineralized acrylate sections, the pattern of immunolabeling was compared with detailed structural images of demineralized bone obtained using an en bloc treatment of tissue samples with the cationic electron 'dye,' Malachite Green (MG), which provides stabilization and retention of anionic material throughout specimen processing. A system of structures corresponding to the sites of bone sialoprotein (BSP) immunoreactivity, as seen in Lowicryl K4M this sections, could be readily identified in the MG-treated, epoxy thing sections. This system includes the cement lines, and aggregates of similar material within mineralized bone and mineralizing osteoid. The virtual identity of BSP distribution with the arrangement of the MG-visualized material indicates that a BSP-enriched, noncollagenous phase can be demonstrated using different, unrelated tissue preparation and imaging protocols for EM. Besides improving our understanding of the distribution of bone sialoprotein in bone, these data assign a previously unrecognized structural dimension to noncollagenous material in the bone matrix. PMID- 8673866 TI - Microsomal casein kinase II in endoplasmic reticulum- and Golgi apparatus-rich fractions of ROS 17/2.8 osteoblast-like cells: an enzyme that modifies osteopontin. AB - Osteopontin is an acidic phosphoprotein containing casein kinase II (CKII) phosphorylatable sites and an acidic amino acid cluster. The metabolically 32P labelings of both serines and threonines in vitro in osteopontin immunoprecipitated from rat osteoblast-like ROS 17/2.8 cells may suggest that casein kinase II catalyzes this modification. The enzyme occurs in microsomal fractions of rat osteoblast-like ROS 17/2.8 cells. Subcellular fractions containing endoplasmic reticulum and Golgi apparatus were isolated by differential centrifugation and were identified according to their ultrastructures and the presence of marker enzymes such as glucose-6-phosphatase and thiamine pyrophosphatase, respectively. both fractions phosphorylated the partially dephosphorylated osteopontin and the specific substrate peptide RRREEETEEE. Endoplasmic reticulum-catalyzed peptide phosphorylation was 2.7 times lower than that of Golgi although both endoplasmic reticulum- and Golgi-catalyzed peptide reactions were 50% inhibited by 20 and 100 ng/ml heparin, respectively. Western blot analysis revealed that both fractions contained osteopontin and microsomal CKII. Furthermore, microsomal CKII was immunogold-labeled in endoplasmic reticulum and Golgi apparatus. Heparin inhibition and utilization of [gamma-32P]GTP as a phosphate donor by both fractions confirmed their capacity to phosphorylate osteopontin. The results suggest that microsomal CKII modifies the acidic matrix proteins during transportation. These matrix phosphoproteins may participate in the mineralization process of hard tissues. PMID- 8673868 TI - Mechanisms of cellular recruitment in aseptic loosening of prosthetic joint implants. AB - The association of macrophages engaged in polymethylmethacrylate (PMMA) particle phagocytosis with pockets of inflammatory cells is a pathognomonic feature of the aseptically loose interface not present at the well-fixed interface. The mechanism by which the presence of PMMA particles leads to cellular recruitment, bone resorption, and ultimate loosening is poorly understood. Granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin 6 (IL-6), cytokines released by osteoblasts, stimulate the recruitment of macrophages into sites of inflammation. We show that exposure of macrophages to PMMA particles stimulated release of tumor necrosis factor (TNF), but no increase in prostaglandin E2 (PGE 2) or interleukin 1. Incubation of osteoblasts with conditioned medium from macrophages exposed to PMMA particles led to release of GM-CSF, IL-6, and PGE-2. Incubation of the PMMA/macrophage medium with antibodies to TNF prior to osteoblast exposure inhibited release of GM-CSF, IL-6, and PGE-2 by the osteoblasts. Our data demonstrate that exposure of macrophages to PMMA particles leads to the release of TNF which then stimulates osteoblasts to produce GM-CSF, IL-6 and PGE-2. Based upon the results of this study , we propose that the process of cellular recruitment in aseptic loosening is initiated when the mechanical failure of the cement mantle leads to the production of PMMA particles. These particles are phagocytized by macrophages leading to the production of TNF. TNF stimulates surrounding osteoblasts to produce GM-CSF, IL 6, and PGE-2 which leads to recruitment of macrophages and osteoclasts into the area of the bone-cement interface. The recruitment of these cells potentiates this process leading to bone resorption and ultimately, clinical loosening of prosthetic joint implants. PMID- 8673867 TI - Vitamin E stimulates trabecular bone formation and alters epiphyseal cartilage morphometry. AB - The effects of dietary vitamin E (VIT E) and lipids on tissue peroxidation and fatty acid composition, epiphyseal growth plate cartilage development, and trabecular bone formation were evaluated in chicks. A 2 x 2 factorial design was followed using two levels (30 and 90 IU/kg of diet) of dl-alpha-tocopheryl acetate and two different dietary lipids. The basal semipurified diet contained one of the following lipid treatments: anhydrous butter oil (40 g/kg) + soybean oil (60 g/kg), [BSO], or soybean oil (100 g/kg), [SBO]. After 14 days of feeding, the level of alpha tocopheryl in plasma was higher and thiobarbituric acid reactive substances (TBARS) were less in plasma and liver of chicks supplemented with 90 IU of VIT E compared with those given 30 IU of VIT E. Body weights and tibiotarsal bone lengths were not affected by the dietary treatments. Saturated fatty acids (14:0, 15:0, 16:0, 17:0, and 18:0) were increased in the tibiotarsal bone of chicks fed the BSO diet. In contrast, total polyunsaturated fatty acids and the ratio unsaturated fatty acids/saturated fatty acids were higher is plasma of chicks fed SBO compared with the values from chicks fed BSO. The thickness of the entire growth plate cartilage and the lower hypertrophic chondrocyte zone was significantly greater in chicks fed 90 IU/kg of VIT E. Kinetic parameters on bone histomorphometry indicated that mineral apposition rate was higher in chicks fed 90 IU of VIT E. The interaction effect between the VIT E and BSO treatments led to the highest trabecular bone formation rate among the groups. These data suggest that VIT E protects against cellular lipid peroxidation in cartilage to sustain normal bone growth and modeling. PMID- 8673869 TI - Use of TCA as a decalcifying agent for laminin immunohistochemistry. PMID- 8673870 TI - The IIIrd Workshop on Osteobiology. Mattinata, Foggia, Italy, July 1-3, 1995. Abstracts. PMID- 8673871 TI - [The dynamics of the intoxication indices during the performance of the preoperative preparation of patients with disseminated progressive destructive pulmonary tuberculosis]. PMID- 8673872 TI - [Angiodysplasia of the large intestine in children]. PMID- 8673873 TI - [Surgical treatment of Payr's disease in children]. PMID- 8673874 TI - [The short bowel syndrome in children]. PMID- 8673875 TI - [Diagnostic criteria of pancreatic diseases in children based on ultrasonic study data]. PMID- 8673876 TI - [Tumors and tumor-like formations of the liver in children]. PMID- 8673877 TI - [The use of a low-frequency magnetic field and intraorganic electrophoresis in treating peritonitis in children]. PMID- 8673878 TI - [The choice of a treatment method in pulmonary hypoplasia in children]. PMID- 8673879 TI - [Intra-ureteral plastic repair in ureterocystoneostomy]. PMID- 8673881 TI - [Ways to decrease the frequency of performing nephrectomy in treating congenital and acquired diseases of the kidneys and urinary tract]. PMID- 8673880 TI - [The use of the artificial pancreas apparatus (Biostator) in the diagnosis and surgical treatment of insuloma patients]. PMID- 8673882 TI - [The use of retrograde dynamic measured urethrocystography in the diagnosis of infravesical obstruction in men]. PMID- 8673883 TI - [Changes in the generation of free oxygen radicals in shock and their significance in the irreversibility of a pathological process]. PMID- 8673884 TI - [Adjuvant chemotherapy of colonic cancer]. PMID- 8673886 TI - [Simulation modelling in the training of students in senior courses in surgery]. PMID- 8673885 TI - [The use of polyplatilen in patients with malignant tumors of the skin and locomotor apparatus]. PMID- 8673887 TI - [Multistage surgical treatment of severe closed trauma to the abdominal cavity organs complicated by hemobilia in an 8-year-old child]. PMID- 8673888 TI - [Difficulty in diagnosing acute appendicitis in a nursing infant]. PMID- 8673889 TI - [Use of the contact laser scalpel in thoracoscopic operations]. PMID- 8673890 TI - [Electrical testing using the Myotest in the radical correction of anorectal defects in children]. PMID- 8673891 TI - [Repeat operations for pulmonary hypoplasia in children]. PMID- 8673892 TI - [Ambulatory laser therapy of bite wounds in children]. PMID- 8673894 TI - [The treatment of extensive wounds in children]. PMID- 8673893 TI - [A nonparasitic splenic cyst in a child]. PMID- 8673896 TI - [Two cases of perforated ulcer in young patients]. PMID- 8673895 TI - [Extensive thymolipoma with lipomatosis of the trunk in an adolescent]. PMID- 8673897 TI - [The use of autologous blood in treating urinary incontinence after performing a transurethral operation]. PMID- 8673898 TI - [Congenital phimosis]. PMID- 8673899 TI - [Torsion of the greater omentum]. PMID- 8673900 TI - [The use of cryogenic destruction in the treatment of gallbladder neoplasms]. PMID- 8673901 TI - [The potentials of ultrasonic dopplerography in the prognosis of the course of hemorrhagic stroke and in the choice of procedure for its treatment]. PMID- 8673902 TI - Loss of specialists hurts research. PMID- 8673903 TI - A male contraceptive pill. PMID- 8673904 TI - A male contraceptive pill. PMID- 8673905 TI - The Hippocratic oath on the move. PMID- 8673906 TI - A broader role for leptin. PMID- 8673907 TI - p53 activity and chemotherapy. PMID- 8673908 TI - Plasminogen and wound healing. PMID- 8673909 TI - . . . but new plans for surveillance are still being proposed. PMID- 8673910 TI - One doctor against managed care. PMID- 8673911 TI - Developing essential scientific capability in countries with limited resources. PMID- 8673912 TI - Refractive surgery--the cutting edge. PMID- 8673913 TI - Controlled release of a therapeutic protein. PMID- 8673914 TI - Clues to B-cell memory. PMID- 8673916 TI - Brain TNF: damage limitation or damaged reputation? PMID- 8673915 TI - Oddball p53 in testicular tumors. PMID- 8673917 TI - HOX gene mutations--the wait is over. PMID- 8673918 TI - Preventing cervical cancer. PMID- 8673919 TI - Progress towards a vaccine to prevent sexual transmission of HIV. PMID- 8673920 TI - Extensive polymorphisms observed in HIV-1 clade B protease gene using high density oligonucleotide arrays. AB - Naturally occurring mutations in HIV-1-infected patients have important implications for therapy and the outcome of clinical studies. However, little is known about the prevalence of mutations that confer resistance to HIV-1 protease inhibitors in isolates derived from patients naive for such inhibitors. In the first clinical application of high-density oligonucleotide array sequencing, the sequences of 167 viral isolates from 102 patients have been determined. The DNA sequence of USA HIV-1 clade B proteases was found to be extremely variable and 47.5% of the 99 amino acid positions varied. This level of amino acid diversity is greater than that previously known for all worldwide HIV-1 clades combined (40%). Many of the amino acid changes that are known to contribute to drug resistance occurred as natural polymorphisms in isolates from patients who had never received protease inhibitors. PMID- 8673921 TI - Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. AB - Analysis of the HIV protease gene from the plasma of HIV-infected patients revealed substitutions at nine different codons selected in response to monotherapy with the protease inhibitor ritonavir. Mutants at valine-82, although insufficient to confer resistance, appeared first in most patients. Significant phenotypic resistance required multiple mutations in HIV protease, which emerged subsequently in an ordered, stepwise fashion. The appearance of resistance mutations was delayed in patients with higher plasma levels of ritonavir. Early mutants retained susceptibility to structurally diverse protease inhibitors, suggesting that dual protease inhibitor therapy might increase the duration of viral suppression. PMID- 8673922 TI - Protective mucosal immunity elicited by targeted iliac lymph node immunization with a subunit SIV envelope and core vaccine in macaques. AB - Prevention of sexually transmitted HIV infection was investigated in macaques by immunization with a recombinant SIV (simian immunodeficiency virus) envelope gp 120 and core p27 vaccine. In two independent series of experiments, we used the novel targeted iliac lymph node (TILN) route of immunization, aiming close to the iliac lymph nodes draining the genitorectal mucosa. Rectal challenge with the SIVmac 32H J5 molecular clone in two series induced total protection in four out of seven macaques immunized by TILN, compared with infection in 13 of 14 unimmunized macaques or immunized by other routes (P = 0.025). The remaining three macaques showed either a decrease in viral load ( > 90%) or transient viremia, indicating that all seven TILN-immunized macaques showed total or partial protection (P = 0.001). Protection was associated with significant increase in the iliac lymph nodes of IgA antibody-secreting cells to p27 (P < 0.02), CD8-suppressor factor (P < 0.01), and the chemokines RANTES and MIP-1 beta (P < 0.01). PMID- 8673923 TI - H-cadherin, a novel cadherin with growth inhibitory functions and diminished expression in human breast cancer. AB - A newly identified gene, H-cadherin, is reported. H-cadherin encodes a protein related to the cadherin superfamily of cell adhesion molecules, and its expression is shown to be significantly reduced in human breast carcinoma cell lines and breast cancer specimens. H-cadherin was localized to chromosome 16q24 and is highly expressed in the heart. Introduction of H-cadherin cDNA markedly diminished tumor cell growth and resulted in a significant change from invasive morphology to a normal cell-like morphology in the Matrigel outgrowth assay. These studies indicate that downregulation of H-cadherin may be frequent in the breast malignant progression and suggest that it may have prognostic value as a marker for breast cancer development. PMID- 8673924 TI - Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. AB - Microtubule-associated protein tau becomes abnormally hyperphosphorylated in Alzheimer's disease (AD) and accumulates as tangles of paired helical filaments in neurons undergoing degeneration. We now show that in solution normal tau associates with the AD hyperphosphorylated tau (AD P-tau) in a nonsaturable fashion, forming large tangles of filaments 3.3 +/- 0.7 nm in diameter. These tangles, which are not detected in identically treated normal tau or AD P-tau alone, are made up of filaments several microns in length and are labeled with tau antibodies. Dephosphorylation with alkaline phosphatase abolishes the ability of AD P-tau to aggregate with normal tau and prevents tangle formation. AD P-tau disassembles microtubules assembled from normal tau and tubulin. These data provide insight into how the hyperphosphorylation of tau might lead to the formation of the neurofibrillary tangles and the degeneration of the affected neurons in AD. PMID- 8673925 TI - Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. AB - Brain injury, as occurs in stroke or head trauma, induces a dramatic increase in levels of tumor necrosis factor-alpha (TNF), but its role in brain injury response is unknown. We generated mice genetically deficient in TNF receptors (TNFR-KO) to determine the role of TNF in brain cell injury responses. Damage to neurons caused by focal cerebral ischemia and epileptic seizures was exacerbated in TNFR-KO mice, indicating that TNF serves a neuroprotective function. Oxidative stress was increased and levels of an antioxidant enzyme reduced in brain cells of TNFR-KO mice, indicating that TNF protects neurons by stimulating antioxidant pathways. Injury-induced microglial activation was suppressed in TNFR-KO mice, demonstrating a key role for TNF in injury-induced immune response. Drugs that target TNF signaling pathways may prove beneficial in treating stroke and traumatic brain injury. PMID- 8673926 TI - A month-long effect from a single injection of microencapsulated human growth hormone. AB - An injectable sustained-release form of human growth hormone (hGH) was developed by stabilizing and encapsulating the protein, without altering its integrity, into biodegradable microspheres using a novel cryogenic process. A single injection of microspheres in monkeys resulted in elevated serum levels of recombinant hGH (rhGH) for more than one month. Insulin-like growth factor-I (IGF I) and its binding protein IGFBP-3, both of which are induced by hGH, were also elevated for four weeks by the rhGH containing microspheres to a level greater than that induced by the same amount of rhGH administered by daily injections. These results show that, by using appropriate methods of stabilization and encapsulation, the advantages of sustained-release formulations previously demonstrated for low-molecular-weight drugs can now be extended to protein therapeutics. PMID- 8673927 TI - Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. AB - The presence of obesity increases the risk of thrombotic vascular diseases. The role of fat accumulation and its effect on plasminogen activator inhibitor-1 (PAI 1) levels was investigated in humans and animals. Plasma PAI-1 levels were closely correlated with visceral fat area but not with subcutaneous fat area in human subjects. PAI-1 mRNA was detected in both types of fat tissue in obese rats but increased only in visceral fat during the development of obesity. These data suggest that an enhanced expression of the PAI-1 gene in visceral fat may increase plasma levels and may have a role in the development of vascular disease in visceral obesity. PMID- 8673928 TI - A functionally inactive p53 protein in teratocarcinoma cells is activated by either DNA damage or cellular differentiation. AB - Testicular teratocarcinomas never contain p53 gene mutations even though these tumors express high levels of nuclear p53 protein. We have characterized two murine teratocarcinoma cell lines and find no evidence that endogenous p53 regulated genes are correspondingly upregulated. Differentiation of these teratocarcinoma cells with retinoic acid results in a marked decrease in p53 protein levels but is accompanied by a marked increase in p53-mediated transcriptional activity. Together these results support the hypothesis that the p53 protein in undifferentiated teratocarcinoma cells is transcriptionally inactive and accounts for the lack of selection for p53 gene mutations in this tumor type. These teratocarcinoma cells undergo p53-mediated apoptosis in response to DNA damage, which may explain the routine cures of human testicular tumors with combination chemotherapy. PMID- 8673929 TI - Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. AB - The mechanisms causing resistance to chemotherapeutic drugs in cancer patients are poorly understood. Recent evidence suggests that different forms of chemotherapy may exert their cytotoxic effects by inducing apoptosis. The tumor suppressor gene P53 has a pivotal role inducing apoptosis in response to cellular damage. In vitro investigations have shown intact p53 to play a critical role executing cell death in response to treatment with cytotoxic drugs like 5 fluorouracil, etoposide and doxorubicin. Recently, mutations in the P53 gene were found to confer resistance to anthracyclines in a mouse sarcoma tumor model, and overexpression of the p53 protein (which, in most cases, is due to a mutated gene) was found to be associated with lack of response to cisplatin-based chemotherapy in non-small cell lung cancer. Previous studies have shown mutations in the P53 gene or overexpression of the p53 protein to predict a poor prognosis, but also a beneficial effect of adjuvant radiotherapy or chemotherapy in breast cancer. In this study we present data linking specific mutations in the P53 gene to primary resistance to doxorubicin therapy and early relapse in breast cancer patients. PMID- 8673930 TI - Bradykinin-evoked sensitization of airway sensory nerves: a mechanism for ACE inhibitor cough. AB - Cough accompanied by an increased sensitivity of the cough reflex is the most common symptom of inflammatory airway disease. This symptom is also frequently reported in patients receiving angiotensin-converting enzyme (ACE) inhibitors as therapy for heart failure or hypertension, although the underlying mechanism is unknown. We have investigated the possibility that the inflammatory peptide bradykinin, normally degraded by ACE, causes sensitization of airway sensory nerves and an enhancement of the cough reflex in conscious guinea pigs. Treatment of guinea pigs for two weeks with captopril led to an increased cough response to inhaled citric acid, which was prevented by concomitant treatment with the bradykinin receptor antagonist icatibant. A similar icatibant-sensitive enhancement of citric acid-evoked cough was seen in untreated animals after prior inhalation of bradykinin, although cough evoked by hypertonic saline was unaffected. In electrophysiological studies performed in vitro, responses of single vagal C fibers to capsaicin, applied to receptive fields of single-fiber units in the trachea, were also markedly increased after perfusion with bradykinin, whereas A delta fiber responses to hypertonic saline were unaffected. These results indicate that bradykinin-evoked sensitization of airway sensory nerves may underlie the pathogenesis of ACE-inhibitor cough. Bradykinin receptor antagonists may be of benefit in treating chronic cough seen with this and other inflammatory conditions. PMID- 8673932 TI - Tissue engineering using synthetic extracellular matrices. PMID- 8673931 TI - Light activatable antibodies: models for remotely activatable proteins. AB - The ability to activate biological macromolecules remotely, at specific locations and times, will allow the manipulation of a wide range of cellular activities and give rise to many practical applications. Interest has been shown in the theoretical possibility of accomplishing this by means of photochemical approaches. Photochemical changes of the guest-binding cavity of cyclodextrins has been suggested; however, these changes require organic solvent. What is needed is a widely and readily applicable method allowing activation under physiological conditions. We have developed such a method. This is based on our demonstration that relatively large amounts of the a-methyl substituted 2 nitrobenzyl alcohol, namely, 1-(2-nitrophenyl)ethanol (NPE) can be coupled to proteins using diphosgene. Previous work involved "caging" of small molecules such as ATP (ref. 5-9) and blocking amino acids in peptide synthesis with 2 nitrobenzyl compounds. For large molecules, site-specific reversible inactivation of T4-lysozyme has been reported following introduction of an aspartyl beta nibenzyl ester into its active site by mutagenesis. In contrast, the present simple procedure allows an existing protein to be deactivated and then, when and where required, reactivated by exposure to ultraviolet-A (UV-A) light. We have employed antibodies as models for both receptors and ligands and have successfully modulated: antibody binding sites for antigen; antigen binding sites for antibody, and antibody Fc binding sites for Protein A. PMID- 8673933 TI - Bacteria and periodontitis. PMID- 8673934 TI - An open letter to all Canadian Periodontists. PMID- 8673935 TI - Recognition of medically necessary oral health care. PMID- 8673936 TI - Going up or down? PMID- 8673938 TI - Effects of a chlorhexidine varnish on the gingival status of adolescents. AB - The purpose of this blind study was to determine the effect of a two-stage chlorhexidine varnish, after three months, on the gingival status of 11- to 15 year-old children attending a school in Rio de Janeiro, Brazil. Subjects participating in the study were randomly allocated to control (C) and treatment (T) groups, n = 53 and n = 57, respectively. All subjects were matched at baseline on age, salivary levels of mutans streptococci, and caries scores. After elimination of carious lesions, a prophylaxis was given to both groups. The chlorhexidine varnish was then painted on the entire dentition of Group T subjects only. Prior to caries elimination, and again after three months, the gingival index was used to assess the gingival status of study subjects. An average of 106.6 +/- 8.9 and 107.7 +/- 6.2 gingival sites per subject (four sites per tooth) in Groups C and T, respectively, were examined by the same calibrated examiner on two occasions. For statistical purposes, data were dichotomized [(0,1) (2,3)] for the gingival index. Independent t-tests and paired t-tests were used to analyze the data. The percentage of sites per subject with scores of two or three at the baseline were balanced between study groups (3.7 +/- 7.1 for T; 1.8 +/- 3.2 for C; p = 0.08). After three months, a statistically significant decrease in the average percentage of sites with scores of two or three was demonstrated in the T group (0.7 +/- 2.4, T, p < 0.0001; 1.3 +/- 3.0, C, p < 0.25). The authors concluded that the application of a chlorhexidine varnish significantly improved the gingival health of T subjects for up to three months. A significant improvement in the gingival health could not be demonstrated in the C group. PMID- 8673939 TI - The dentist and prescription drug abuse. AB - Because dentists are authorized to prescribe narcotic drugs to their patients, they may be sought out by "drug seeking individuals" (DSI), disguised as patients, who are engaged in the illegal diversion of pharmaceutical-quality drugs to the street market. Two common methods of gaining illegal access to pharmaceutical-quality narcotics for resale on the street are: forgery and verbal misrepresentation, and multiple doctoring. The diversion of such drugs can produce a very high rate of return for DSIs, with only a minimal risk of arrest and conviction. This paper discusses the problem of DSIs, and how dentists can reduce the risk of becoming involved in the illegal diversion of narcotics. Prudent judgment and responsible prescribing by the dentist will increase the effectiveness of his or her practice, and help to abate a growing social problem. PMID- 8673937 TI - Efficacy of ketorolac in the management of pain associated with root canal treatment. AB - Patients requiring root canal treatment were randomly assigned to one of three groups. The first group received Ketorolac oral 10 mg at six hour intervals for 24 hours, the second group received Ketorolac (Toradol) injectable 10 mg at the height/depth of the buccal vestibule of the tooth to be treated, and the third group received no assigned medication. Significantly better pain relief was achieved when Ketorolac injectable or oral was used then when no drug was administered. Some of the patients in the Ketorolac injectable group felt that an additional dose of medication would have been helpful at the six- to eight-hour postoperative period. However, there was no significant difference in pain relief between the two groups treated with different drug regimens. PMID- 8673940 TI - Diagnostic tests. PMID- 8673941 TI - Attitudes and behavior of HIV-infected patients concerning dental care. AB - This preliminary, descriptive study investigated the behavior and attitudes of HIV-infected patients concerning dental care. A self-administered, anonymous questionnaire was completed by 101 of 102 consecutive HIV-infected adults (mean age 36 years). Since the diagnosis of HIV infection, 81 respondents reported that they had sought dental care; 54 reported visiting a dentist at least once a year; 41 had changed dentists; and 62 reported current mouth problems, for which 45 were receiving treatment. Forty per cent of all respondents were receiving treatment in a hospital dental department. The use of hospital facilities was not associated with advanced HIV disease. Seventy per cent of participants were satisfied with the dental treatment they had received since they were diagnosed with HIV (18 per cent had no opinion, and 12 per cent were dissatisfied). Twelve per cent were concerned that their HIV seropositivity would not be kept confidential. While 87 per cent of participants had disclosed their HIV seropositivity to their current dentist, 29 per cent believed that the dentist could be reluctant to provide treatment if they did so. Some patients reported changing dentists or not seeking care based on their fear that dentists would be reluctant to provide treatment. Fifteen per cent of patients who had sought dental care reported that they were refused treatment because they had HIV. Participants were more likely to have received dental care within the previous year if they reported being able to afford treatment, or had dental insurance (p < 0.01). Because more than 33 per cent of respondents had incomes below the poverty line, it is likely that economic factors limit the access to dental care for patients with HIV. More research is required using a larger sample and a random selection of participants. PMID- 8673942 TI - Multiple porcelain veneers: a temporization innovation--the peripheral seal technique. AB - Porcelain veneers, despite all appearances to the contrary, rank as one of the most demanding and technique sensitive applications in esthetic restorative dentistry. Given the minute dimensions of these restorations and the partial nature of coverage, the temporization of multiple veneers provides clinicians with a notable challenge. The optimum placement of porcelain veneers depends on the clinician establishing and maintaining the patient's gingival health during the provisional treatment phase, so that there is no opportunity for inflamed sulcular tissues to compromise the final adhesive effort. This is best achieved using provisional restorations with the correct emergence profile, as well as accurate and amply sealed restorative margins. The purpose of this paper is to introduce a new temporization technique for multiple veneers that assures predictable marginal fidelity, allowing for a "temporary" yet adequate seal of the acrylic facing the dental substrate, and elective detachment at the definitive bonding appointment. PMID- 8673943 TI - [Use of dental services and the percentage of persons possessing private dental insurance in Quebec]. AB - The utilization of dental health services and the percentage of adult members of a private health dental insurance plan are generally lower in Quebec than in the other Canadian provinces. In this study, results of a telephone survey of a representative sample of Quebec adults aged 18 and over (N = 8,042) show that 58 per cent of interviewed individuals visited a dentist (53 per cent) or a denturologist (five per cent) during the 12 months preceeding the interview. A multivariate analysis indicates that the most strongly associated factors related to the utilization of dental health services are, in decreasing order, edentulousness, income and level of education. About one third (36 per cent) of those surveyed had dental insurance coverage. Age and income are the most strongly associated factors concerning the membership to a dental health insurance plan. Finally, among those with dental insurance coverage, 71 per cent had visited a dentist or a denturologist during the last 12 months compared to 51 per cent of those not insured. PMID- 8673944 TI - [Canadian Society of Cardiology Consensus Conference on Atrial Fibrillation. 1994, 1995]. PMID- 8673945 TI - [Prognosis of auricular fibrillation]. PMID- 8673946 TI - [Antithrombotic treatment of atrial fibrillation]. PMID- 8673947 TI - [Control of heart rate and atrial fibrillation]. PMID- 8673948 TI - [Long term drug therapy for the prevention of recurrence in atrial fibrillation]. PMID- 8673949 TI - [Restoration of the sinus rhythm in atrial fibrillation]. PMID- 8673950 TI - [Cardiac stimulation and atrial fibrillation]. PMID- 8673951 TI - [Post-heart surgery auricular fibrillation]. PMID- 8673952 TI - [Atrial fibrillation and flutter in children and young adults with congenital cardiopathies]. PMID- 8673953 TI - [Non-chemical treatment of atrial fibrillation]. PMID- 8673954 TI - [Auricular fibrillation: future orientation]. PMID- 8673955 TI - [Auricular fibrillation and flutter]. PMID- 8673956 TI - [Study of auricular fibrillation]. PMID- 8673957 TI - Reciprocal inhibition in hemiplegia: correlation with clinical features and recovery. AB - BACKGROUND: Previous reports have described changes in reciprocal Ia inhibition in hemiplegic patients, but correlations between the amount of Ia inhibition and the clinical deficits have not been well established. METHODS: We studied reciprocal inhibition between ankle flexors (tibialis anterior) and extensors (soleus) in 16 hemiplegic patients at various stages following a stroke and in 26 control subjects. The amount of disynaptic Ia inhibition was determined from the short latency suppression of the soleus or tibialis anterior H-reflexes by conditioning stimulation of the antagonistic muscle nerves. RESULTS: Disynaptic Ia inhibition from peroneal nerve afferents to soleus motoneurones was increased in patients who showed good recovery of function with mild spasticity. However, it was not changed, or even sometimes diminished, in patients who made a poor recovery and had more marked extensor spasticity. In patients where serial recordings were obtained there was an increase in Ia inhibition during the recovery period following stroke. Ia inhibition to the tibialis anterior motoneurones tended to be greater in the poor recovery patients with marked spasticity than in the good recovery patients. The late (D1) inhibition, presumably due to presynaptic inhibition, was decreased in the patients, although consistent correlations between the amount of this inhibition and the clinical features were not clearly demonstrated. CONCLUSIONS: Changes in excitability of Ia inhibitory pathways can be correlated with some of the clinical features seen in hemiplegia. Increased Ia inhibition of soleus motoneurones during recovery may be a mechanism to compensate for loss of descending motor commands. PMID- 8673958 TI - Vagal nerve complex in normal development and sudden infant death syndrome. AB - BACKGROUND: Although the pathogenesis of sudden infant death syndrome (SIDS) is not understood, one of the major hypotheses is that a subtle defect in respiratory circuitry is an important underlying factor. The vagus nerve is a critical component of respiratory control, but its neuroanatomic complexity has limited its investigation in human disease. METHODS: Correlating developmental studies on different parts of the vagus nerve allows a more comprehensive assessment of its maturation process. Comparison of the normal developing vagus nerve with nerves examined in SIDS patients suggests alterations in the nucleus tractus solitarius and dorsal vagal nucleus as well as in the peripheral vagus nerve. RESULTS AND CONCLUSIONS: The persistence of dendritic spines and lack of appropriate axonal growth implies delays in vagal maturation. Since nodose ganglia can be examined in vitro from autopsy material, perturbation to this system can be explored to evaluate further the mechanism involved in terminal vagal maturation. Although the reason for the delayed vagal maturation in SIDS is not apparent, the presence of astrogliosis in the region of the vagal nuclei is consistent with an exposure to hypoxic-ischemic events some time before death. PMID- 8673959 TI - Kinematics of initiating a two-joint arm movement in patients with cerebellar ataxia. AB - OBJECTIVE: To characterize kinematically any systematic aberration in multi-joint movements in cerebellar ataxia. METHODS: Nine patients with cerebellar degeneration and nine normal subjects, mobile only at the shoulder and elbow of the right arm, were required to produce left-to-right cross-body linear hand trajectories on the horizontal surface of a digitizing tablet. Nonlinearity indicated failure of precise coordination of the two joints. A wide range of hand speeds was studied. Data analysis was restricted primarily to the first 130 ms of movement. RESULTS: As hand velocities increased, normal subjects and, especially, patients produced misdirected, curved paths. Normal subjects had significant curvature when peak speeds exceeded 100 cm/s and a trend toward significant bi directional angular deviation at velocities greater than 300 cm/s. In patients, peak path curvature was significantly greater than normal at peak velocities of 50 to 200 cm/s. By 3.3 cm, their paths deviated significantly outward at all but the slowest speeds. Overall, patients' maximal hand velocities and shoulder angular velocities, as well as maximal angular accelerations at both joints, were significantly lower than normal. CONCLUSIONS: The patients' trajectory aberrations were attributed to a deficient rate of rotation at the shoulder relative to that at the elbow. Relative to task requirements, their rate of torque development was apparently deficient at both joints. but to a greater degree at the shoulder. Joint torque-rate impairment may contribute to the ataxia in both multi- and single-joint movements of patients with cerebellar disorders. A similar, but smaller impairment may produce milder nonlinearity in high velocity movements of normal subjects. PMID- 8673960 TI - Stereotactic management of bacterial brain abscesses. AB - BACKGROUND: CT and MR guided stereotactic techniques have provided promising results in the management of brain abscesses. We reviewed our results of stereotactic management of brain abscesses in 20 consecutive patients with 28 abscesses from 1986 to 1993. METHODS: 13 abscesses were in the cerebral hemispheres, 12 in the cerebellum, 2 in the pons and 1 in the thalamus. The bacterial organism was isolated in 12 of the 20 cases. All patients, except one who had a tuberculous abscess, were on antibiotics for less than 7 weeks. RESULTS: Although there were 3 patients in coma before surgery, the mortality rate was zero and 17 patients had an excellent recovery with 3 patients having a persistent mild neurologic disability. Stereotactic aspiration of the largest lesion in the patients with multiple brain abscesses combined with intravenous antibiotic therapy was sufficient for the resolution of all lesions. Two of our patients treated with antibiotics alone showed abscess progression with neurologic worsening. CONCLUSION: Stereotactic aspiration is safe, accurate, and when combined with the appropriate antibiotics, should be considered the procedure of choice in the management of brain abscesses. PMID- 8673961 TI - Acute hydrocephalus following aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Acute hydrocephalus is a potentially treatable cause of early neurological deterioration after aneurysmal subarachnoid hemorrhage (SAH). METHODS: A retrospective study of 105 consecutive cases of aneurysmal SAH was undertaken to determine those factors significantly related to the development of acute hydrocephalus. Acute hydrocephalus was diagnosed when the bicaudate index was greater than the 95th percentile for age on a CT scan within 72 hours of the ictus. RESULTS: Thirty-one percent of the patients developed acute hydrocephalus. Grade of SAH was a significant factor for the development of acute hydrocephalus on univariate analysis as 87% of patients with acute hydrocephalus (29/32) presented with at least grade 3 (Hunt-Hess) SAH (P < 0.05). In addition, posterior circulation aneurysms on univariate analysis were associated with acute hydrocephalus (p < 0.05). Both premorbid hypertension and intraventricular blood (p < 0.05) were predictors for acute hydrocephalus, whereas intracisternal blood, age and sex were not. On multivariate linear regression analysis, factors found to be significantly associated with acute hydrocephalus were premorbid hypertension, intraventricular blood, CSF diversion and definitive shunt procedures. External ventricular drainage was not associated with any instances of rebleeding. Thirty-seven percent (10/27) of patients with acute hydrocephalus who survived were improved by pre-operative external ventricular drainage. CONCLUSIONS: Patients with acute hydrocephalus following SAH can be safely treated with external ventricular drainage. Multiple factors can be identified to predict those patients who will develop acute hydrocephalus post aneurysmal rupture. Approximately 30% of those patients with acute hydrocephalus will require definitive shunt placement. Acute hydrocephalus occurred in 31% of aneurysmal SAH patients in this series. PMID- 8673962 TI - Tirilazad prevention of reperfusion edema after focal ischemia in cynomolgus monkeys. AB - BACKGROUND: The purpose of the present investigation was to determine if post ischemic treatment with the 21-aminosteroid lipid peroxidation inhibitor tirilazad mesylate (U-74006F) could affect reperfusion brain edema during the first 3h following a 3h period of middle cerebral artery occlusion-induced focal ischemia in cynomolgus monkeys. METHODS: Adult female cynomolgus monkeys (N = 14) were subjected under halothane anesthesia to a 3h period of middle cerebral artery occlusion, followed by 3h of reperfusion. U-74006F, 3.0 mg/kg i.v. or citrate vehicle, was administered 10 min before beginning reperfusion. Multiple spin-echo (8 echoes: TE = 26.3 msec; TR = 3.0 secs; 2.35 Tesla) magnetic resonance imaging was performed every 30 min, beginning at 1h after reperfusion. Transverse relaxation rates (T2) for the caudate, putamen, cortex, insular cortex, parietal cortex and central white matter were calculated as an index of focal brain edema. After the final images, corresponding regions were removed for determination of water content by the wet weight/dry weight method. RESULTS: The T2 measurements strongly suggested the presence of post-reperfusion edema in all gray matter, but not white matter, regions at 1h after reperfusion in vehicle treated animals. Significant attenuation of edema development was seen in the putamen and insular cortex in U-74006F-treated animals. An effect was also observed in the parietal cortex, but none in the caudate. The measurement of water content at 3h after reperfusion yielded similar results. CONCLUSIONS: These results showing the ability of U-74006F to attenuate post-reperfusion brain edema support the concept that lipid peroxidation is a significant mediator of reperfusion brain edema after focal ischemia. The therapeutic window for U 74006F's anti-edema effect appears to be at least 3h after the onset of focal ischemia since delaying treatment until just before reperfusion largely prevented subsequent edema in cortical regions and the putamen. The effects of U-74006F on edema may play a mechanistic role in the compound's reported neuroprotective efficacy in a variety of focal ischemia models. PMID- 8673963 TI - Symptomatic dystonias associated with structural brain lesions: report of 16 cases. AB - BACKGROUND: Symptomatic (secondary) dystonias associated isolated lesions in the brain provide insight into etiopathogenesis of the idiopathic form of dystonia and are a basis for establishing the possible correlation between the anatomy of a lesion and the type of dystonia according to muscles affected. METHODS: In 358 patients with differently distributed dystonias, a group of 16 patients (4.5%) was encountered in whom dystonia was associated with focal brain lesions. RESULTS: Of the 16 patients, 3 patients had generalized, 3 segmental and 4 hemidystonia, while the remaining 6 patients had focal dystonia. The most frequent etiologies were infarction in 7, and tumor in 4 patients. These lesions were usually found in the lenticular and caudate nucleus, thalamus, and in the case of blepharospasm in the upper brainstem. CONCLUSIONS: Our results support the suggestion that dystonia is caused by a dysfunction of the basal ganglia. PMID- 8673964 TI - Prior intra-operative hypotension is not a risk factor for development of Alzheimer's disease. AB - OBJECTIVE: A retrospective, population-based, case-control study was carried out to evaluate episodes of prior intra-operative hypotension as a potential risk factor for Alzheimer's disease (AD). METHODS: Patients were all incident cases of AD from 1975-1984 who resided for 40 years or more in Olmsted County prior to their onset of dementia (N = 252). One age and gender-matched control for each case was selected from all registrations for care at Mayo Clinic during the year of onset in the incident case. Each case and control group had 252 individuals. RESULTS: Of these, 27 cases and 32 controls had at least one ten minute or longer episode of intra-operative hypotension of a systolic blood pressure of less than 90 mm Hg prior to the year of onset of dementia in the matched AD patient. We did not find a significantly increased risk of AD for hypotensive episodes of less than 75 or 90 mm Hg. CONCLUSIONS: It is unlikely that intra-operative hypotensive events of this degree increase the risk of AD. PMID- 8673965 TI - Narcolepsy secondary to fourth ventricular subependymoma. AB - BACKGROUND: Secondary (symptomatic) narcolepsy is rare. We report a subependymoma of the fourth ventricle associated with narcolepsy. The patient was a 50-year old woman with a long history of narcolepsy who died of colonic carcinoma with no cerebral metastasis. She was positive for HLA-DR2. At autopsy there was a tumour dorsal to the fourth ventricle which involved the midbrain tectum and rostral pons. Histologic examination of the tumour confirmed it to be a subependymoma. METHODS: Review of the previous cases of secondary narcolepsy was made with particular reference to the anatomical location of the lesions. RESULTS: Most of the lesions were found around the third ventricle and rostral brainstem. CONCLUSIONS: Knowing the anatomical localization of the pathological changes in secondary narcolepsy could be important in improving our understanding of its pathogenesis. PMID- 8673966 TI - A history of neurology in Toronto 1892-1960: Part II. PMID- 8673967 TI - On the names of Babinski. AB - The 100th anniversary of the discovery of the extensor plantar response will be celebrated in 1996. It was Joseph Francois Felix Babinski who became known worldwide for the sign that bears his name. In order to help Joseph in establishing his career, brother Henri gave up his aspirations and abandoned engineering. Clovis Vincent, "father' of French neurosurgery and pupil of Joseph, stated: "Joseph Babinski lived for science, and Henri lived for his brother; without Henri Babinski, Joseph would not have accomplished that much". However, Henri's name became famous in all Paris for a cookbook Gastronomie Pratique written under the pseudonym of "Ali-Bab.' Throughout Joseph's career his surname remained distorted despite his own efforts to spell and pronounce it correctly. Several people can claim the name Babinski, but in neurology and neurosurgery there is only one, Joseph. PMID- 8673968 TI - George A. Savoy, visionary benefactor of Canadians with epilepsy, and the history of the Savoy Foundation for Epilepsy. AB - George A. Savoy was born in Cohoes, New York, in 1873. He left the U.S.A. in 1921 to manage the Canadian branch of a large manufacturer of ledgers and looseleaf registers. This company was asked to supply Professor Jasper's laboratory with rolls of plain unlined paper and it was George Savoy who later developed fanfolded and lined EEG paper, which was first used at the Montreal Neurological Institute. He also had personal contacts with Wilder Penfield concerning their mutual interest in the needs of patients with epilepsy. He was a successful industrialist involved with several charitable organizations funding programmes for people with epilepsy. He was opposed to the sectarianism then prevalent in Quebec, which was unfamiliar to him, and in reaction built his own institution, Dieppe House, a home for people with epilepsy, later renamed <>. It was to operate without regard to race, language or religion. In 1971, his son Harold and other generous donors decided to create a foundation to support research in epilepsy. The Foyer Savoy was sold in 1988 and the proceeds used to increase the endowment of the foundation. His grandson George M. Savoy is the current president. The fourth generation is also represented by Caroline Savoy, daughter of the president, who joined the board of directors in 1992. The foundation will distribute from $300,000 to $400,000 yearly to researchers from many different countries working in the field of epilepsy in universities and hospitals throughout Canada. PMID- 8673969 TI - Northern Ontario MDs seek solution to region's huge accidental-death toll. AB - A recently published study discussed the trauma-related death toll that plagues northeastern Ontario, which has a much higher death rate from nonintentional trauma than the rest of the province Dr. Gary Bota, one of the study authors hates calling these tragedies accidents because that implies a random, act-of-God nature that he does not accept. "They're not accidents," he maintains. "They're patterns, just like infectious diseases." PMID- 8673970 TI - Treatment of psychiatric problems a growth industry in midst of Chile's booming economy. AB - Five years after an elected government took over from a military regime, Chile has enjoyed booming economic growth and some measure of political stability but the scars of the legacy left by the regime of Augusto Pinochet run deep. Alcohol and drug abuse, family violence, depression and other mental-health problems are reported by a large proportion of the population. Fear is one of the permanent consequences of the military regime, says one sociologist. PMID- 8673971 TI - Politician, MDs offer educators opinions on managing unprecedented health care change. AB - Three leaders in Canada's health care debate recently told medical educators that the Canada Health Act needs to be revamped, but each had different views about how the change should be managed. Different perspectives were provided by Alberta Premier Ralph Klein, National Forum on Health member Dr. Tom Noseworthy and CMA President-Elect Judith Kazimirski. PMID- 8673972 TI - Suicide totals for MDs sad reminder of stresses facing medicine, conference told. AB - A recent conference on physician health cosponsored by the CMA and American Medical Association provided some sobering news. One physician reported on the suicides of physicians practising in the US. Another reported that inroads being made by managed health care is affecting physician morale. "Physicians' lifetime calling of caring for the sick is being called into question," said Dr. Patricia Tighe. "They have become like factory workers who can't take pride in their work and are denied a sense of belonging. They are part of a corporate enterprise, to be dispensed with when they are not profitable, and subjected to penalties if their work doesn't measure up". PMID- 8673973 TI - Costs of noncompliance disputed. PMID- 8673974 TI - Family physicians: what do we do? PMID- 8673975 TI - Care provided to Madeleine. PMID- 8673976 TI - Reasonable "door-to-needle" time for thrombolytic therapy. PMID- 8673977 TI - Tools for determining appropriateness of care. PMID- 8673978 TI - Ethical dilemma of medical abortion. PMID- 8673979 TI - Issues raised by medical abortion. PMID- 8673980 TI - Issues raised by medical abortion. PMID- 8673981 TI - NIH statement on cochlear implants. PMID- 8673982 TI - Selecting your surgeon an advantage Canada has over the UK. PMID- 8673984 TI - Neurosurgery workforce in Canada, 1996 to 2011. Canadian Neurosurgical Society. AB - OBJECTIVE: To determine the number of neurosurgeons in clinical practice in Canada on Jan. 1, 1996, and their practice profile and to determine requirements for 2001 and 2011. DESIGN: Telephone survey and national mail survey. SETTING: Canada. PARTICIPANTS: All 174 neurosurgeons in Canada engaged in active clinical practice on Jan. 1, 1996, and all residents enrolled in neurosurgery training programs in Canada during the 1995-96 academic year. OUTCOME MEASURES: Demographic characteristics, full-time equivalents, workload, attrition, reasons for exit, vacancies, supply and shortfall. RESULTS: All 174 neurosurgeons responded to the survey. There is a chronic shortage of 25 neurosurgeons in Canada. Sixty-two established neurosurgeons will have stopped practice by 2001 and 181 by 2011. They will need to be replaced, for a total requirement of 87 and 206 neurosurgeons by 2001 and 2011 respectively. Canadian neurosurgery training programs can currently generate only up to 69 and 177 graduates by 2001 and 2011 respectively. During the period 1985-95, 50% of neurosurgery graduates emigrated from Canada within 2 years of obtaining certification, creating potential deficits of up to 52 and 117 neurosurgeons by 2001 and 2011 respectively. CONCLUSIONS: Strategies need to be developed quickly to address not only the chronic shortfall but also the attrition of established neurosurgeons. Strategies to increase and retain the number of Canadian neurosurgery graduates are also needed. PMID- 8673985 TI - The XI International Conference on AIDS: at the crossroads of hope and urgency. AB - This month Canada will host the largest conference ever held on the worldwide epidemic of AIDS. More than 12,000 participants from over 130 countries are expected to convene in Vancouver from July 7 to 12 for the XI International Conference on AIDS. As at previous conferences, the program will be organized along four tracks: basic science, clinical science, epidemiology and public health, and social and behavioural science. The author notes that although in each of these areas there is reason to take heart, we must not become complacent in the fight against HIV infection and AIDS. The pandemic is still growing at an alarming rate, and governments need to be reminded that a failure to commit funding and resources to the extension of programs for AIDS research, prevention and care is both cynical and unwise. Now is the time to redouble our efforts, not to abandon them. PMID- 8673986 TI - Travel statement on jet lag. PMID- 8673983 TI - Guidelines for the emergency management of asthma in adults. CAEP/CTS Asthma Advisory Committee. Canadian Association of Emergency Physicians and the Canadian Thoracic Society. AB - OBJECTIVE: To develop a set of comprehensive, standardized evidence-based guidelines for the assessment and treatment of acute asthma in adults in the emergency setting. OPTIONS: The use of medications was evaluated by class, dose, route, onset of action and optimal mode of delivery. The use of objective measurements and clinical features to assess response to therapy were evaluated in relation to the decision to admit or discharge the patient or arrange for follow-up care. OUTCOMES: Control of symptoms and disease reflected in hospital admission rates, frequency of treatment failures following discharge, resolution of symptoms and improvement of spirometric test results. EVIDENCE: Previous guidelines, articles retrieved through a search of MEDLINE, emergency medical abstracts and information from members of the expert panel were reviewed by members of the Canadian Association of Emergency Physicians (CAEP) and the Canadian Thoracic Society. Where evidence was not available, consensus was reached by the expert panel. The resulting guidelines were reviewed by members of the parent organizations. VALUES: The evidence-based methods and values of the Canadian Task Force on the Periodic Health Examination were used. BENEFITS, HARMS AND COSTS: As many as 80% of the approximate 400 deaths from asthma each year in Canada are felt to be preventable. The use of guidelines, aggressive emergency management and consistent use of available options at discharge are expected to decrease the rates of unnecessary hospital admissions and return visits to emergency departments because of treatment failures. Substantial decreases in costs are expected from the use of less expensive drugs, or drug delivery systems, fewer hospital admissions and earlier return to full activity after discharge. RECOMMENDATIONS: Beta2-agonists are the first-line therapy for the management of acute asthma in the emergency department (grade A recommendation). Bronchodilators should be administered by the inhaled route and titrated using objective and clinical measures of airflow limitation (grade A). Metered-dose inhalers are preferred to wet nebulizers, and a chamber (spacer device) is recommended for severe asthma (grade A). Anticholinergic therapy should be added to beta 2 agonist therapy in severe and life-threatening cases and may be considered in cases of mild to moderate asthma (grade A). Aminophylline is not recommended for use in the first 4 hours of therapy (grade A). Ketamine and succinylcholine are recommended for rapid sequence intubation in life-threatening cases (grade B). Adrenaline (administered subcutaneously or intravenously), salbutamol (administered intravenously) and anesthetics (inhaled) are recommended as alternatives to conventional therapy in unresponsive life-threatening cases (grade B). Severity of airflow limitation should be determined according to the forced expiratory volume at 1 second or the peak expiratory flow rate, or both, before and after treatment and at discharge (grade A). Consideration for discharge should be based on both spirometric test results and assessment of clinical risk factors for relapse (grade A). All patients should be considered candidates for systemic corticosteroid therapy at discharge (grade A). Those requiring corticosteroid therapy should be given 30 to 60 mg of prednisone orally (or equivalent) per day for 7 to 14 days; no tapering is required (grade A). Inhaled corticosteroids are an integral component of therapy and should be prescribed for all patients receiving oral corticosteroid therapy at discharge (grade A). Patients should be given a discharge treatment plan and clear instructions for follow-up care (grade C). VALIDATION: The guidelines share the same principles of those from the British Thoracic Society and the National Institutes of Health. Two specific validation initiatives have been undertaken: (a) several Canadian centres have been involved in the collection of comprehensive administrative data to assess compliance and outcome measures and (b) a survey of Canadian emergency physicians conducted to gather baseline informaton of treatment patterns, was conducted before development of the guidelines and will be repeated to re-evaluate emergency management of asthma. PMID- 8673988 TI - Regulations govern semen donations. PMID- 8673989 TI - The reality of despair: AIDS in Malawi. AB - While completing a recent medical elective in the Central African country of Malawi, medical student Dale Needham learned firsthand that HIV/AIDS represents a true pandemic in Africa. By the end of 1993, Malawi had the continent's highest per capita number of cumulative reported AIDS cases. Although Canadian physicians have had their own struggles helping patients with HIV/AIDS, many more battles are being fought in countries like Malawi, where financial resources are limited. In Africa, HIV-positive people of all ages suffer incredibly from diseases such as protein energy malnutrition, tuberculosis and cryptococcal meningitis. Primary health care programs, education in the primary schools and community awareness and support are partial answers to the pandemic. PMID- 8673990 TI - Prepare for more collaboration with other professionals, Manitoba FPs told. AB - During the recent scientific assembly of the Manitoba chapter of the College of Family Physicians (CFPC), a session was devoted to the ways health care reform has affected family medicine. Doctors listened to guest speakers from the CFPC, Manitoba Medical Association and provincial Ministry of Health, and there was a stimulating discussion about the critical issues facing FPs. PMID- 8673987 TI - An evidence-based approach to prescribing NSAIDs in musculoskeletal disease: a Canadian consensus. Canadian NSAID Consensus Participants. AB - OBJECTIVE: To make recommendations for the long-term use of nonsteroidal anti inflammatory drugs (NSAIDs) in primary care practice, particularly for patients at high risk for NSAID-induced complications. OPTIONS: The use of misoprostol to prevent gastrointestinal ulceration and other unwanted NSAIDs effects was considered. The role of cyclooxygenase-2 (COX-2) versus COX-1 inhibiting agents was also examined. OUTCOMES: Reduction of complications associated with long-term use of NSAIDs. EVIDENCE: Evidence was gathered in late 1995 from published research studies and reviews. Position papers were prepared by faculty and advisory board members and discussed at the Canadian NSAID Consensus Symposium in Cambridge, Ont., Jan. 26 and 27, 1996. VALUES: Recommendations were based on randomized, placebo-controlled clinical trials (level I evidence) and case control studies (level II evidence) involving NSAID use when such evidence was available. When the scientific literature was incomplete or inconsistent in a particular area, recommendations reflect the consensus of the participants at the symposium (level III evidence). Physicians were recruited from across Canada for their expertise in rheumatology, gastroenterology, epidemiology, gerontology, family practice, and clinical and basic scientific research. BENEFITS, HARMS AND COSTS: Although a reduction in complications due to inappropriate NSAID use should reduce costs of additional investigations, admissions to hospital and time lost from work, definitive cost analysis studies are not yet available. RECOMMENDATIONS: Currently, no NSAID is available that lacks potential for serious toxicity; therefore, long-term use of NSAIDs should be avoided whenever possible, particularly in high-risk patients (e.g., those who are elderly, suffer from hypertension, congestive heart failure, renal or hepatic impairment or volume depletion, take certain concomitant medications or have a history of peptic ulcer disease) (level I evidence). If NSAIDs are to be used in patients with gastric or nephrotoxic risk factors, the lowest effective dose of NSAID should be used (level III evidence); NSAIDs that are weak COX-1 inhibitors may be preferred (level II evidence). In addition, concomitant administration of misoprostol is recommended in patients at increased risk for upper gastrointestinal complications (level I evidence). However, the clinical judgement of the practising clinician must always be part of any therapeutic decision. VALIDATION: These recommendations are based on the consensus of Canadian experts in rheumatology, gastroenterology and epidemiology, and have been subjected to external peer review. PMID- 8673991 TI - Adoptive immunotherapy for nonsmall cell lung carcinoma. A fourth treatment modality, complicated radiation sensitizer, or none of the above. PMID- 8673992 TI - Prophylactic colectomy for gene carriers in hereditary nonpolyposis colorectal cancer. Has the time come? PMID- 8673993 TI - Prognostic value of paranasopharyngeal extension of nasopharyngeal carcinoma. A significant factor in local control and distant metastasis. AB - BACKGROUND: This study was conducted to evaluate the prognostic value of paranasopharyngeal extension in local control and distant metastasis in patients with nasopharyngeal carcinoma. METHODS: Three hundred and sixty-four patients with newly diagnosed nasopharyngeal carcinoma without distant metastasis were reviewed. Patients were staged according to Ho's staging system. Using a semiquantitative method, tumor extension into the paranasopharyngeal space was graded as: 0: no extension; 1: extension to the retrostyloid space; 2: extension to the prestyloid space; and 3: extension to the anterior part of the masticator space. All patients received radiotherapy as primary treatment. Median follow-up time was 45 months (range, 4.7 to 76.5 months). Relapse free, local relapse free, and distant metastasis free survival were estimated using the Kaplan-Meier method. Cox regression was also performed to adjust for prognostic factors. RESULTS: The incidence of paranasopharyngeal extension was high (72.5%). Of these patients, 65.5% had Grade 2 or 3 extension. The 5-year relapse free survival rates for Grade 0, 1, 2, and 3 extension were 76%, 70%, 46%, and 43%, respectively. The main difference was between Grade 0/1 and Grade 2/3 extension, the latter having a lower 5-year local control rate (86% in Grade 0/1 vs. 72% in Grade 2/3; P < 0.0001) and distant metastasis free survival rate (87% in Grade 0/1 vs. 68% in Grade 2/3; P = 0.0002). Multivariate analysis showed that Grade 2/3 paranasopharyngeal extension was an independent factor in predicting overall relapse, local relapse, and distant metastasis. Advanced T classification (T3) was another independent factor in predicting overall and local relapse, whereas advanced N classification (N3) was another independent factor in predicting overall relapse and distant metastasis. CONCLUSIONS: Extensive paranasopharyngeal extension (Grade 2/3) was an independent prognostic factor associated with poorer treatment outcome, both in local control and distant metastasis. Ho's T2 disease should be further subclassified into T2a and T2b, which include Grade 0/1 and Grade 2/3 paranasopharyngeal disease, respectively. PMID- 8673995 TI - Preoperative treatment of patients with locally advanced unresectable rectal adenocarcinoma utilizing continuous chronobiologically shaped 5-fluorouracil infusion and radiation therapy. AB - BACKGROUND: This study was designed to determine the efficacy and maximally tolerated dose of 5-fluorouracil when administered by chronobiologically shaped prolonged infusion in combination with radiation therapy in patients with both locally advanced and unresectable rectal carcinoma. METHODS: Eighteen sequential patients determined clinically to have either locally advanced or unresectable rectal carcinoma were treated by 4500 centigray (cGy) or 5580 cGy, respectively, combined with continuous chronobiologically modulated 5-FU infusion starting at 250 mg/m2/day, with the dose escalating in each cohort of 5 patients if no Grade 3 or higher toxicity was observed in each cohort. Imaging studies were obtained prior to and after completion of treatment. RESULTS: All 18 patients completed the full course of radiation therapy and all were subsequently resectable for potential cure. The maximum tolerated dose of 5-FU was 275/m2/day for 5 weeks. Seven patients had a sphincter-sparing procedure, and ten patients underwent an abdominoperineal resection, all with clear margins. Five complete pathologic responses (28%) were obtained. The average follow-up time was 12 months with a range of 6 to 37 months. With the exception of two patients, one of whom declined surgery and one of whom died of widespread disease, all of the patients have remained free of disease. CONCLUSIONS: The combination of radiation therapy and continuous chronobiologically shaped 5-FU infusion at a dose of up to 275/m2/day is well tolerated and appears to be more effective in downsizing and possibly downstaging locally advanced and unresectable rectal carcinoma than radiation therapy alone. Longer follow-up will determine whether ultimate disease free and overall survival are improved by this method. PMID- 8673994 TI - Treatment of patients with advanced gastric carcinoma with the combination of etoposide plus oral tegafur modulated by uracil and leucovorin. A phase II study of the ONCOPAZ Cooperative Group. AB - BACKGROUND: Both the biochemical modulation and the continuous administration of 5-fluorouracil (5-FU) have achieved promising results in patients with gastric carcinoma. Conversely, several studies on gastric carcinoma have demonstrated that the combination of etoposide (VP-16), leucovorin (LV), and 5-FU (ELF) is efficacious and moderately toxic. UFT is a combination of uracil and tegafur (ftorafur) in a 4:1 molar ratio. It can be administered orally for several weeks, thus stimulating the effects of a continuous infusion of 5-FU. Its combination with LV increased the efficacy of UFT. We conducted a Phase II study on patients with gastric carcinoma using the combination VP-16-LV-UFT. This combination is administered mainly orally (p.o) and could yield a good response rate and low toxicity. METHODS: Forty-six patients with bidimensionally measurable disease were entered into the study. Patients received VP-16 100 mg/m2 IV on Day 1 and 200 mg/ m2 p.o. on Days 2 and 3; LV 500 mg/m2 administered intravenously (i.v.) on Day 1, followed by p.o. LV 15 mg every twelve hours on Days 2 to 14. Patients also received UFT p.o. 390 mg/m2/day on Days 1 to 14. Treatment was repeated every 28 days for a minimum of 3 courses per patient. All courses were given on an outpatient basis. RESULTS: Four patients (9%) had a complete response, and 12 a partial response (26%) for an overall response rate of 35% (95% confidence interval: 22-51%). The median duration of response was 10 months. The median overall survival was 9 months. The main side effects were gastrointestinal. Grade 3 to 4 toxicity was encountered as follows: diarrhea in 17% of the patients, nausea/vomiting in 11%, anemia in 13%, mucositis and leukopenia in 4% each, and thrombocytopenia in 2%. One patient died of sepsis and neutropenia. CONCLUSIONS: VP-16-LV-UFT has an activity comparable to that of other schemes and a low incidence of side effects. Furthermore, since it is administered mainly orally, hospitalization is avoided, which makes this scheme suitable for patients with advanced gastric carcinoma. PMID- 8673996 TI - Angiogenesis as an unfavorable prognostic factor in human colorectal carcinoma. AB - BACKGROUND: Angiogenesis is reportedly correlated with metastasis, relapse, and prognosis in some types of tumors. Hematogenous or lymph node metastasis and local recurrence are the main elements related to the death of patients with colorectal carcinoma. Thus, the authors examined the microvessel count in colorectal carcinoma to determine how angiogenesis correlates with clinicopathologic factors and prognosis. METHODS: Paraffin embedded sections from 166 patients with primary colorectal carcinomas that had been completely removed were analyzed for angiogenesis. Vessels were stained with anti-factor VIII polyclonal antibody, and areas with the most discrete microvessels were counted in a 400x field. RESULTS: Tumor size was significantly correlated with microvessel count. Microvessel counts from patients with lymph node metastasis, lymphatic vessel invasion, venous vessel invasion, or relapse were significantly higher than those without. Furthermore, microvessel count was an independent prognostic factor (P = 0.007), whereas the Dukes stage had more significant prognostic value (P < 0.001) according to the multivariate Cox hazard analysis. CONCLUSIONS: This study suggested that angiogenesis assessed by the microvessel count was a marker of relapse and prognosis of patients with colorectal carcinoma. PMID- 8673997 TI - Telomerase as a tool for the differential diagnosis of human hepatocellular carcinoma. AB - BACKGROUND: Telomerase activation is thought to be essential for the immortality of cancer cells. We measured telomerase activity in human liver samples, including hepatocellular carcinoma (HCC), and evaluated this assay as a tool for the diagnosis of HCC using 21-gauge (21-G)-needle biopsy specimens. METHODS: Ninety-four liver samples (27 HCC, 27 liver cirrhosis, 37 chronic hepatitis, and 3 normal liver) that were surgically resected or biopsied with a 12-gauge Silverman needle and 13 HCC samples that were biopsied with a 21-G needle were analyzed for telomerase activation. RESULTS: Eleven of 29 (38%) tumor-bearing liver samples were weakly telomerase-positive, whereas telomerase activity was observed infrequently in nontumor-bearing liver samples (6 of 35; 17%) and in normal liver samples (0 of 3; 0%). The positivity of surgical samples for well differentiated, moderately differentiated, and poorly differentiated HCC was 88% (7 of 8), 87% (13 of 15), and 0% (0 of 2), respectively. In telomerase-positive HCC, 43% (3 of 7) of well differentiated samples were weakly positive, whereas 92% (12 of 13) of moderately differentiated samples were strongly positive. The difference in the tumor sizes and viral marker status did not affect the activity. The telomerase activity of the 21-G-needle biopsied specimens showed no significant difference from that of the surgical samples. The positive incidence of 21-G specimens was 80% (8 of 10) and 100% (2 of 2) in well differentiated HCC and moderately differentiated HCC, respectively. CONCLUSIONS: An incremental positivity of telomerase was observed during hepatocarcinogenesis. The use of this assay in 21-G-needle biopsy specimens may be useful in clinical examination. PMID- 8673999 TI - A randomized trial of adoptive immunotherapy with tumor-infiltrating lymphocytes and interleukin-2 versus standard therapy in the postoperative treatment of resected nonsmall cell lung carcinoma. AB - BACKGROUND: A previous pilot study from our group suggested that: (1) adoptive immunotherapy (A1) with tumor-infiltrating lymphocytes (TIL) and recombinant interleukin-2 (rIL-2) may be applied with safety to more than 80% of the patients who had surgery for Stage III nonsmall cell lung carcinoma (NSCLC); and (2) AI could be useful in patients with locally advanced disease. The present randomized study was planned to assess the efficacy of AI in the postoperative treatment of Stage II, IIIa, or IIIb NSCLC: METHODS: TIL were expanded in vitro from tissue samples obtained from the surgically removed specimens of 131 patients. Eighteen cultures yielded no growth of TIL. The remaining 113 patients were stratified according to disease stage and randomized to receive AI or standard chemoradiotherapy. TIL were infused intravenously 6 to 8 weeks after surgery, rIL 2 was administered subcutaneously at escalating doses for 2 weeks, and then at reduced doses for 2 weeks and then for 2 to 3 months. RESULTS: Three-year survival was significantly better (P < 0.05) for patients who underwent AI than for controls. AI was of no benefit to patients with Stage II NSCLC, potentially useful to patients with Stage IIIa NSCLC (P = 0.06), and significantly advantageous to patients with Stage IIIb (T4) NSCLC (P < 0.01). For patients with Stage III NSCLC, local relapse (but not distant relapse) was significantly reduced following AI (P < 0.05). CONCLUSIONS: AI should be considered when designing future adjuvant therapy protocols for the treatment of NSCLC: PMID- 8673998 TI - Serum tumor markers and cyst fluid analysis are useful for the diagnosis of pancreatic cystic tumors. AB - BACKGROUND: This study was performed to evaluate the utility of serum and cyst fluid analysis for enzymes (amylase and lipase) and tumor markers (carcinoembryonic antigen, CA 19-9, CA 125, and CA 72-4) in the differential diagnosis of cystic pancreatic lesions. METHODS: Serum and cyst fluid were obtained from 48 patients with pancreatic cysts (21 pseudocysts, 14 mucinous cystic neoplasms, 6 ductal carcinomas, and 7 serous cystadenomas), observed between 1989 and 1994. RESULTS: Serum CA 19-9 levels were significantly higher in ductal carcinomas (all > 100 U/mL) and mucinous cystic neoplasms (P < 0.05). CA 72-4 cyst fluid levels were significantly higher in mucinous cystic tumors (P < 0.005), with 95% specificity and 80% sensitivity in detecting mucinous or malignant cysts. A combined assay of serum CA 19-9 and cyst fluid CA 72-4 correctly identified 19 of 20 (pre-) malignant lesions (95%), with only 1 false positive result (3.6%). Cytology showed a sensitivity of 48% and specificity of 100%. CONCLUSIONS: Any pancreatic cyst with high serum CA 19-9 values, positive cytology, or high CA 72-4 in the fluid should be considered for resection. PMID- 8674000 TI - Reliability of computer image analysis of pigmented skin lesions of Australian adolescents. AB - BACKGROUND: The diagnosis of melanomas at an early stage is associated with improved survival, so the recognition of changes in pigmented skin lesions over time is important. We have developed a computer imaging system with the aim of assisting clinicians in differentiating early melanomas from benign pigmented skin lesions. The objective of this study was to investigate the system's reliability over time in measuring diagnostic characteristics of pigmented skin lesions, including their color, size, shape, and distinctness of boundary. METHODS: We captured video images of 5 lesions, all larger than 2 mm in greatest dimension, on each of 66 Australian adolescents on 2 occasions approximately 1 month apart. Features extracted by computer image analysis included area, perimeter, and regularity of outline of the lesions, the mean and standard deviation of reflectance at red, green, and blue wavelengths, and the mean and standard deviation of the gradients of red, green, and blue reflectance at the lesion boundary. RESULTS: All measurements showed moderate to high reliability (intraclass correlation coefficients 0.66-0.94), except for the standard deviations of the color gradients, whose reliability improved to moderate levels (0.68-0.71) when the mean of 5 lesions was considered. For most outcomes, reasonable within subject reliability was achieved when five lesions per subject were measured. CONCLUSIONS: These results, in combination with previous work demonstrating the reasonable ability of this computer imaging system to discriminate between malignant melanomas and other pigmented lesions, indicates that the system has the potential to become a useful tool for clinicians in following people with pigmented lesions over time to detect early malignant changes. PMID- 8674001 TI - Subsequent breast carcinoma risk after biopsy with atypia in a breast papilloma. AB - BACKGROUND: Risk of breast cancer after biopsy demonstrating a papilloma has long been variously interpreted on the basis of histologic pattern of multiplicity of papillomas. METHODS: A nested case control study was performed on women with surgical breast biopsies evidencing papillomas; cases who subsequently developed invasive carcinoma were compared with controls who did not. Presence of atypical hyperplasia (AH) within the papilloma as well as areas of AH in the surrounding parenchyma were evaluated in both cases and controls. The entire cohort (not tested) was separately evaluated for all variables except for atypia within papillomas. RESULTS: The relative risk of invasive carcinoma for women with papillomas containing AH was > 4x that of papillomas without AH within or surrounding the papilloma. This risk may be greater with added atypical hyperplasia outside the papilloma and most strikingly, most of the subsequent invasive carcinomas developed in the same breast and probably near the site of the original papilloma. However, ordinary patterns of epithelial hyperplasia lacking specific features of AH within the papilloma do not add to the risk of subsequent carcinoma development over papillomas without hyperplasia. CONCLUSIONS: This study indicates that women having papillomas with AH have a similar or greater cancer risk than others with specifically defined patterns of atypical hyperplasia within the breast parenchyma (4-5x relative risk). Most importantly, this risk is largely local in the region of the original papilloma. PMID- 8674002 TI - Serial serum c-erbB-2 levels in patients with breast carcinoma. AB - BACKGROUND: Recently, the extracellular domain of the c-erbB-2 oncogene product (HER-2/neu) has been reported to be elevated in the serum of one-fourth of patients with metastatic breast carcinoma. The role of serum c-erbB-2 as a tumor marker, however, is still poorly defined. The purpose of this study was to evaluate the utility of serial serum c-erbB-2 levels as a tumor marker in patients with metastatic breast carcinoma. METHODS: c-erbB-2 levels in the sera of patients with breast carcinoma were determined by an enzyme immunoassay that detects the extracellular domain of c-erbB-2. Serum c-erbB-2 levels were evaluated prior to treatment as well as throughout the course of treatment with second-line hormonal therapy employing either megestrol acetate or fadrozole, an experimental aromatase inhibitor. RESULTS: Fifty-eight of 300 patients (19.3%) had elevated pretreatment serum c-erbB-2 levels. Of these 58 patients with elevated pretreatment c-erbB-2, 48 had more than 1 visit which enabled us to quantitate serial c-erbB-2 levels throughout the course of treatment. Of these 48 patients, 28 (58.3%) had serial c-erbB-2 values that correlated with the clinical course. CONCLUSIONS: Serial serum c-erbB-2 levels did not show a high overall correlation with the clinical course in this group of patients with metastatic breast carcinoma treated with second-line hormonal therapy. PMID- 8674004 TI - Ovarian papillary serous tumors of low malignant potential (serous borderline tumors). A long-term follow-up study, including patients with microinvasion, lymph node metastasis, and transformation to invasive serous carcinoma. AB - BACKGROUND: The clinical outcome of patients with ovarian serous tumors of low malignant potential (LMP) remains controversial, especially for those with extraovarian disease. We retrospectively reviewed our experience to study this question further, to assess the safety of conservative management of patients with limited disease, and to determine whether exophytic ovarian surface tumor was predictive of tumor recurrence. METHODS: The clinical and pathologic records of 76 patients with ovarian serous LMP tumors accessioned at the Cleveland Clinic Foundation from 1979 to 1990 were reviewed. International Federation of Gynecology and Obstetrics (FIGO) staging was retrospectively assigned, follow-up information obtained, and clinicopathologic correlations made. RESULTS: An exophytic ovarian surface component was present in 39 of 76 patients (51%). Stage II or III disease was present in 28 of 74 staged patients (38%). Follow-up information was available on 66 patients, ranging from 8 to 264 months (mean, 99 months). Twenty-five patients of 66 patients with follow-up information (38%) received adjuvant therapy. Only 1 patient (1.5%) developed progressive disease; she died of widespread invasive serous carcinoma. Two of 18 conservatively managed patients (11%) developed "recurrent" disease, including 1 patient with a second primary serous LMP tumor of the preserved ovary and 1 patient with an incidentally discovered microscopic serosal implant. There were no other recurrences in the study group, which included four patients with stromal microinvasion and one with lymph node involvement. CONCLUSIONS: The long term outcome of serous LMP tumors is extremely favorable. Exophytic ovarian surface tumor did not serve as a predictor for subsequent peritoneal implants. Conservative surgical management in young patients with localized disease is supported and the use of adjuvant therapy in the initial management of patients with advanced tumors is further questioned. PMID- 8674003 TI - Prognostic value of immunohistochemically detected CD44 expression in patients with carcinoma of the vulva. AB - BACKGROUND: Overexpression of alternatively spliced CD44 isoforms has been reported to correlate with poor prognosis in several human malignancies. To the authors' knowledge, there are no studies concerning the prognostic value of CD44 isoform overexpression in patients with squamous cell carcinoma of the vulva. METHODS: Thirty cases of squamous cell carcinoma of the vulva with International Federation of Gynecology and Obstetrics Stage I to III were examined immunohistochemically for overexpression of CD44 isoforms. We used 3 different variant exon sequence-specific murine monoclonal antibodies to CD44 isoforms containing variant exons v5, v6, and v7 to -8, respectively. The correlation of CD44 overexpression with clinical stage, histologic grade, and disease free and overall survival was investigated. RESULTS: CD44 isoforms CD44v5, CD44v6, and CD44v7-8 were detected in 83% (25/30), 63% (19/30), and 27% (8/30) of the tumor samples, respectively. Patients with tumors overexpressing CD44v6 showed a significantly shorter relapse free (log rank test, P = 0.002) and overall survival (log rank test, P = 0.003) compared with patients with tumors lacking CD44v6 overexpression. Expression of CD44v5 and CD44v7 to 8 had no impact on patients' survival. Clinical stage and histologic grade did not correlate with CD44 overexpression. CONCLUSIONS: Immunohistochemically detected overexpression of CD44 isoforms containing variant exon v6 is correlated with a poor relapse free and overall survival in patients with carcinoma of the vulva. PMID- 8674005 TI - Alterations of retinoblastoma, p53, p16(CDKN2), and p15 genes in human astrocytomas. AB - BACKGROUND: Alterations of the suppressor genes, such as the retinoblastoma (RB), p53, p16(CDKN2), and p15 genes, have been reported in human gliomas. These genes have been suggested as the cell cycle regulatory genes at the G1-S checkpoint. METHODS: Alterations of the RB, p53, p16(CDKN2), and p15 genes in human astrocytomas were screened by single strand conformation polymorphism analysis of polymerase chain reaction products (PCR-SSCP analysis) and then confirmed by dideoxy sequencing. In addition, the expression of RB and p16 protein was examined by Western blot analysis. RESULTS: Aberrations of the RB gene were found in 3 of 23 surgical astrocytoma specimens (13%). Mutations were found at codon 754 in exon 22 (Val-->Gly), codon 519 in exon 17 (Thr-->Pro), and one base deletion at codon 903 resulting in stop codon at codon 905 in exon 26. These mutational locations were all near the regions associated with the functional domains of the RB gene. Aberrations of the p53 gene were found in 4 cases (17.4%). These mutations were found at codons 146 (Trp-->Gly) and 165 (Gln-->His) in exon 5, codon 73 (Val-->Glu) in exon 4, and codon 313 (Ser-->Asn) in exon 9. In addition, alterations of the p16(CDKN2) gene were found, with 5 cases (21.7%) having homozygous deletions, and 2 cases (8.7%) harboring point mutations. No p15 gene alteration was detected. The expression of p16 protein was undetectable in 10 cases (43.5%) by Western blot analysis, demonstrating an inverse correlation with the expression of RB protein. CONCLUSIONS: A few cases had overlapping alterations, and the incidence of one or more RB, p53, or p16(CDKN2) changes appeared to be relatively high in human astrocytomas. These results suggest that cell cycle regulatory gene alterations may play an important role in the development of gliomas. PMID- 8674006 TI - Comparison of costs for infusion versus bolus chemotherapy administration: analysis of five standard chemotherapy regimens in three common tumors--Part one. Model projections for cost based on charges. AB - BACKGROUND: The cost of infusional administration of cancer chemotherapy has been assumed to be more expensive than the traditional bolus schedule related to the use of durable medical equipment and other components of the delivery system. The objective was to develop a model of projected charges as a basis for the cost estimate for selected common chemotherapy regimens comparing the cost based on charges for bolus and infusional chemotherapy schedules. METHODS: Chemotherapy programs using either bolus or infusional delivery were selected representing standard or commonplace regimens for the treatment of patients with breast cancer (cyclophosphamide, methotrexate, fluorouracil [CMF] or CA); colon cancer (5 fluorouracil[5-FU] infusion vs. 5-FU bolus + leucovorin [LCVI] or lymphoma (cyclophosphamide, hydroxydaunomycin, Oncovin (vincristine), prednisone [CHOP] or CDE [cyclophosphamide, doxorubicin, etoposide]). Cost projections were estimated based on charges and were calculated in a model system using six charge (cost) centers including medical doctor [MD] and/or clinic visit; laboratory; drug cost based on average wholesale price (AWP); cost of disposables; and pump rental fee. Standard dosages were applied for each regimen using total mg/M2 for a 1.5 M2 person. RESULTS: Projected charges or chemotherapy for colon cancer (5-FU infusion vs. 5-FU + LCV) are variable depending on the LCV dose and the infusion duration. The longer infusion duration or higher doses of LCV result in a 40 to 50% increment in monthly charges excluding cost related to toxicity. For breast cancer, the charges for bolus or infusion administration CMF are similar, but for CA bolus charges are higher than infusion charges related to higher drug doses. For lymphoma, CHOP chemotherapy dosage costs are approximately half of those for CDE infusion related to the specific drug regimen and drug dosage used. CONCLUSIONS: The perception that infusional delivery of chemotherapeutic agents adds to the cost of cancer care is appropriate for some regimens but the absolute amount of cost increment is generally modest. The principle cost differences between bolus and infusional schedules relate to drug dosage and the toxicity profile. Generally, but not consistently, infusional schedules use lesser doses and are associated with lesser toxicity. Although the benefit of infusional delivery of chemotherapy in terms of response rates and survival are comparable to bolus schedules for 5-FU infusion and 5-FU + LCV in colon cancer, this has not been established for the regimens analyzed for breast cancer (CMF, CA) or lymphoma (CDE, CHOP). The misperception of cost advantages for bolus delivery should not preclude comparative trials of bolus versus infusional chemotherapy schedules and cost should be studied prospectively in clinical trials comparing different schedules of administration in addition to studies of quality of life and toxicity. PMID- 8674007 TI - Comparison of costs for infusion versus bolus chemotherapy administration--Part two. Use of charges versus reimbursement for cost basis. AB - BACKGROUND: The costs of infusion versus bolus administration of chemotherapy has been a point of controversy as has been the method of quantitating the cost. The present study analyzes the reimbursement for chemotherapy administration by infusion compared with bolus delivery based on reimbursement and relates this to cost based on projected charges and actual charges in a private practice setting. METHODS: Actual reimbursement records were retrieved for selected patients receiving infusion or bolus administration of specific chemotherapy regimens for three tumors: colon carcinoma, breast carcinoma, and lymphoma. All services were included except for radiology and hospitalization. Medicare reimbursement represented 90% of the treatment cycles analyzed. RESULTS: Actual reimbursement per month for each infusion regimen was as follows: colon carcinoma, $528 (5 fluorouracil [5-FU]); breast carcinoma, $621 (doxorubicin and cyclophosphamide [AC]) and $685 (cyclophosphamide, methotrexate, and fluorouracil [CMF]); and lymphoma, $603 (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]). Actual reimbursement per month for a bolus regimen was colon carcinoma, $393 (5-FU + leucovorin); breast carcinoma, $991 (AC) or $453 (CMF); and lymphoma, $749 (CHOP). Actual reimbursement represents 21-36% of actual charges. Projected charges based on the model system are generally less than the actual charges. CONCLUSIONS: The cost of chemotherapy as defined by reimbursement are substantially less than actual charges and are also less than projected costs based on charges. Data comparing bolus versus infusion reimbursement costs for colon carcinoma, breast carcinoma, and lymphoma indicate that differences between reimbursement for bolus and infusion administration are not substantial. PMID- 8674008 TI - Pregnancy-associated lymphomas. A clinicopathologic study. AB - BACKGROUND: The natural histories of Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHL) during pregnancy are not well understood. METHODS: All cases of HD and NHL diagnosed during pregnancy at Stanford University Medical Center since 1987 were reviewed and clinical follow-up was obtained. Various immunohistochemical studies and in situ hybridization for Epstein-Barr virus (EBV) encoded RNA were performed in a subset of cases. RESULTS: Seventeen cases of HD and 12 cases of NHL were accessioned (median age; 27 yrs). The HD cases were classified as 13 nodular sclerosis type, 3 mixed cellularity type, and 1 unclassified. Clinical follow-up revealed most of the patients had Stage II to III disease and were diagnosed on average at 22 weeks gestation. Most of the patients deferred therapy until after delivery and had no evidence of disease at the last follow-up except for one death with disease but not from it. NHL were classified according to the working formulation as high or intermediate grade lymphomas of various types, including both nodal and extranodal sites. Clinical follow-up revealed most had Stage II to IV disease and were diagnosed on average at 23 weeks gestation. Patients with HD tended to survive longer than those with NHL (raw mortality, P = 0.04). In situ hybridization failed to provide support for the presence of EBV in a subset of patients with NHL. CONCLUSIONS: The clinical behavior of these neoplasms during pregnancy does not appear to be significantly different from that outside of the setting of pregnancy. Treatment of selected HD patients apparently may be safely deferred until after delivery. Patients with NHL present with higher stage disease and have a poorer prognosis than those with HD. PMID- 8674009 TI - The treatment of neuroblastoma with intraspinal extension with chemotherapy followed by surgical removal of residual disease. A prospective study of 42 patients--results of the NBL 90 Study of the French Society of Pediatric Oncology. AB - BACKGROUND: Neuroblastoma is the most common malignant cause of spinal compression in the pediatric population. More than 30% of patients who are impaired prior to treatment remain impaired after the completion of therapy. Those who do not improve after decompressive laminectomy may go on to develop severe delayed spinal deformities. METHODS: To decrease the long term sequelae of routine neurosurgical intervention for all intraspinal extensions of neuroblastoma, the French NBL 90 Study was formulated to use chemotherapy as a first-line treatment for all nonmetastatic neuroblastomas with intraspinal extension. Neurosurgical decompression and excision was recommended only for patients demonstrating rapid neurologic deterioration. RESULTS: The overall survival of the 42 patients registered was 97%. Initial neurologic impairment was present in 27 patients (64%), including 11 with paraplegia. Thirty-two patients received chemotherapy as first-line treatment. Complete regression of the intraspinal component was observed in 13 patients and partial regression of greater than 50% of the initial volume in 5 patients. Of 19 evaluable patients presenting with a neurologic deficit and treated with primary chemotherapy, recovery was completed in 11 and partial in 3. Four patients failed to recover from long-standing pretreatment paraplegia. Only one patient worsened during therapy, and recovered completely after emergent neurosurgical intervention. Seven patients underwent initial neurosurgical procedures; six had a neurologic deficit and five recovered completely, including all three who presented with acute onset of paraplegia. Three patients had extraspinal surgery as exclusive treatment. Six patients (15%) suffered severe neurologic sequelae. Only one of the patients who underwent surgery required spinal stabilization for progressive deformity, but follow-up is limited. CONCLUSIONS: By treating patients with dumbbell neuroblastoma initially with chemotherapy, the authors were able to reduce the size of the intraspinal mass in 58% of patients, improve partial neurologic deficits in 92%, and avoid neurosurgical decompression in 60%. Neurologic deficits also improved in 83% of patients requiring emergent neurosurgical intervention. PMID- 8674010 TI - International consultation on prostatic intraepithelial neoplasia and pathologic staging of prostatic carcinoma. Rochester, Minnesota, November 3-4, 1995. PMID- 8674011 TI - The biologic dilemma of early carcinoma of the prostate. AB - BACKGROUND: The clinician has long been challenged by the diversity in clinical expression of carcinoma of the prostate. On one end of the spectrum is a disease that is phenotypically malignant but biologically not virulent. It is the prostate carcinoma that males die with rather than of. On the other end of the spectrum, there is a carcinoma of the prostate that is relentless and virulent, and has been resistant to our intervention efforts. Although all males are known to be at risk for the occurrence of carcinoma of the prostate, there is no means at present to predict the type and behavior of the disease they will experience. This is the conundrum faced upon recognition of premalignant and early microscopic disease. METHODS: This paper presents a conceptual framework of the evaluation of disease behavior along one of three distinctive pathways. In this trilogy of expression of carcinoma of the prostate, there are the indolent (Type I), the slowly progressive (Type II), and the virulent and systemic (Type III). These general patterns of behavior may be an expression of the tumor cell ("seed") and the factors that were its genesis, or the effect of the environment ("soil") in which the tumor cell finds itself. The more likely fact is that it is the product of both ("seed and soil"). RESULTS: Our goal is to identify tumors for which no therapy is warranted at their outset by molecular and biologic methods; age group in whom curative local therapy is feasible; and the carcinomas that require effective systemic therapy. CONCLUSIONS: The three general patterns of clinical expression provide a framework in which to identify the genetic, molecular, and cellular determinant of the biologic behavior of carcinoma of the prostate. Being able to correlate such parameters with likely behavior patterns would help us choose appropriate therapy. PMID- 8674012 TI - Prospective origins of prostate carcinoma. Prostatic intraepithelial neoplasia and atypical adenomatous hyperplasia. AB - BACKGROUND: The search for the precursor of prostatic adenocarcinoma has focused in recent years on two histopathologic findings: high grade prostatic intraepithelial neoplasia (PIN) and atypical adenomatous hyperplasia (AAH). This article describes the diagnostic criteria and clinical significance of PIN and AAH. METHODS AND RESULTS: PIN is the most likely precursor of prostate carcinoma. The continuum that culminates in high grade PIN and early invasive carcinoma is characterized by progressive basal cell layer disruption, loss of markers of secretory differentiation, nuclear and nucleolar abnormalities, increasing proliferative potential, increasing microvessel density, variation in DNA content, and allelic loss. Clinical studies suggest that PIN predates carcinoma by 10 years or more, with low grade PIN first appearing in men in their 30s. AAH is usually found in the transition zone, and shows a weak and inconclusive link to well differentiated adenocarcinoma of the transition zone. CONCLUSIONS: The significance of recognizing PIN is based on its strong association with prostatic carcinoma. PIN coexists with carcinoma in most cases, but retains an intact or fragmented basal cell layer, unlike carcinoma, which lacks a basal cell layer. High grade PIN in biopsies predicts the presence of carcinoma in subsequent biopsies, and PIN provides the highest risk ratio of all known predictive factors. This finding indicates the need for repeat biopsy and follow-up when PIN is identified in a biopsy, especially in patients with an elevated serum prostate specific antigen concentration. PIN also offers promise as an intermediate endpoint in studies of chemoprevention of prostatic carcinoma. Unlike PIN, AAH is weakly linked to carcinoma, and current data indicate that no follow-up is necessary for patients with this finding. PMID- 8674013 TI - Pathologic staging of prostate carcinoma. What are the issues? AB - BACKGROUND: Stage is a significant predictor of outcome for patients with carcinoma of the prostate. The American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) TNM staging system has gained general favor as the clinical staging system of choice for prostate carcinoma. With an increasing number of publications assessing prognostic markers for patients with carcinoma of the prostate, there is a need for the development of a uniform system of pathologic staging to support the clinical stage. METHODS: The literature related to pathologic prognostic markers for patients with carcinoma of the prostate, particularly with regard to staging, was reviewed. From this, issues important to the development of a pathologic correlate to the AJCC/ UICC TNM system were identified. RESULTS: A number of issues were identified related to the development of a pathologic staging system. For radical prostatectomy specimens some of the more important are whether or not subcategorization is needed in the pathologic classification of T2 tumors, definition and quantification of extraprostatic extension, and the reporting of positive surgical margins. CONCLUSIONS: There is a need for the development of a pathologic equivalent to the AJCC/UICC TNM clinical staging system for prostate carcinoma. Consensus needs to be reached on several important issues prior to the adoption and testing of such a system. PMID- 8674014 TI - Current prognostic factors for prostate carcinoma. AB - BACKGROUND: Prostate carcinoma provides a wide spectrum for risk of death from the disease and clinicians have long sought methods to predict the outcome accurately in individual patients. Traditional prognostic factors, such as histologic grade and stage, remain valuable. Additional clinical and laboratory studies may add to the precision of predicting the natural history of the disease or response to therapy. METHODS: A review of the literature on current, well accepted prognostic factors for prostate carcinoma and evolving methodology for the incorporation of new factors was conducted. RESULTS: The most widely used current prognostic factors for survival of patients with prostate carcinoma include clinical and pathologic stage, histologic grade, prostate specific antigen (PSA) level, age, and comorbidity. DNA ploidy has been extensively studied on radical prostatectomy specimens and appears valuable, but is not widely employed. The utility of DNA ploidy on biopsy specimens is less certain because of both methodologic issues and heterogeneity within the tumor. The statistical tools used to identify and validate new prognostic factors are critical and new techniques are sought to incorporate several independent factors into a prognostic score or index for an individual patient. CONCLUSIONS: Current prognostic factors for prostate carcinoma provide important information for patient care and research. However, new methods to define pretreatment prognosis and needed to assist clinicians and patients in making therapeutic choices for prostate carcinoma. The ideal method with which to incorporate the information attained from anatomic stage, histologic grade, PSA level, age, and comorbidity into a manageable prognostic score is uncertain and studies on this topic should be a high priority research objective. PMID- 8674015 TI - Quantitative microvessel density. A staging and prognostic marker for human prostatic carcinoma. AB - BACKGROUND: Accurate methods of predicting pathologic stage and malignant potential of carcinoma of the prostate are lacking. Such advances would represent major additions to our ability to recommend therapy and offer prognostic information. Quantitation of microvessel density (MVD) has been shown in a number of organ systems to predict tumor aggressiveness. METHODS: We and others have investigated this modality in preoperative assessment of pathologic stage and freedom from progression in patients with prostatic carcinoma. RESULTS: Unique and useful staging information has been provided and indeed quantitation of MVD has been shown to be a better predictor of the findings of radical prostatectomy than clinical stage, serum prostate specific antigen (PSA), and/or the Gleason score. Applying a variety of therapeutic modalities, quantitative MVD can be shown to provide additional information to predict who will or will not progress. Recent observations have demonstrated that quantitative MVD may be performed on a limited tissue sample provided by prostate core needle biopsy. CONCLUSIONS: Quantitative MVD may provide important staging and prognostic information for males with carcinoma of the prostate. The results may influence the recommendation for additional staging studies, provide stratification of patients for neoadjuvant or adjuvant therapy, assist in technical aspects of definitive therapy, and aid in defining optimum monitoring regimens. PMID- 8674016 TI - The diagnosis and reporting of adenocarcinoma of the prostate in core needle biopsy specimens. AB - BACKGROUND: There has been relatively little written on the diagnosis and reporting of adenocarcinoma of the prostate diagnosed in core needle biopsy specimens. METHODS: This article reviews issues concerning diagnosing, grading, and quantification of prostate carcinoma in core needle biopsy specimens. RESULTS: The diagnosis of prostate carcinoma in core needle biopsy specimens is discussed, including the relative frequency and utility of various architecture, cytologic, and ancillary features. Grading of prostate carcinoma in core needle biopsy specimens is evaluated along with the relationship of core needle biopsy grade to corresponding radical prostatectomy grade. The relationship between the extent of carcinoma in core needle biopsy specimens to extent of tumor in the radical prostatectomy is summarized. Finally, this article summarizes articles supporting the use of high molecular weight cytokeratin in the diagnosis of adenocarcinoma of the prostate in core needle biopsy specimens. CONCLUSIONS: Pathologists are not only called upon to diagnose limited cancer in core needle biopsy specimens, but also to quantify and grade these cancers accurately. Issues relating to this pathologic evaluation are critical for physicians treating men with adenocarcinoma of the prostate. PMID- 8674017 TI - Neuroendocrine differentiation in prostatic malignancy. AB - BACKGROUND: The prostatic neuroendocrine cell is a regulatory cell that produces serotonin and peptide hormones. This cell is part of a more widely dispersed diffuse neuroendocrine regulatory system known as the APUD system. Focal neuroendocrine differentiation is seen in virtually all prostate carcinomas to one degree or another. Specific malignancies that are purely neuroendocrine include small cell carcinoma and carcinoid/carcinoid-like tumors. A variety of studies suggest a possible prognostic significance of neuroendocrine differentiation in prostate carcinoma. METHODS: The literature on the prostatic neuroendocrine cell and neuroendocrine differentiation in prostate carcinoma is reviewed. RESULTS: Based on analogy with other better studied elements of the diffuse neuroendocrine regulatory system or APUD system, as well as the morphology and specific products produced by neuroendocrine cells, it is likely that they play an important regulatory role in the prostate. Neuroendocrine differentiation may be of prognostic significance in prostate carcinoma. Mechanisms are not well characterized at this point, but the known growth factor activity of the neuroendocrine cell products, an increase in proliferation in cells surrounding neuroendocrine cells, and a lack of androgen receptor expression in neuroendocrine cells, suggest mechanisms by which they may be of prognostic significance. CONCLUSIONS: Neuroendocrine differentiation in prostate carcinoma may be of prognostic significance, but better methods to define neuroendocrine, differentiation are necessary. The therapeutic implications of neuroendocrine differentiation in prostate carcinoma may be of significance and need to be explored further. PMID- 8674018 TI - Origins of prostate cancer. PMID- 8674019 TI - Staging and reporting of prostate cancer--sampling of the radical prostatectomy specimen. PMID- 8674020 TI - Current prognostic factors and their relevance to staging. PMID- 8674022 TI - Assessment of prostate carcinoma in core needle biopsy--definition of minimal criteria for the diagnosis of cancer in biopsy material. PMID- 8674021 TI - Exploration of new pathologic factors in terms of potential for prognostic significance and future applications. PMID- 8674023 TI - Differences in nausea, vomiting, and retching between younger and older outpatients receiving cancer chemotherapy. AB - The purpose of this study was to determine whether there were differences in the side effects of nausea, vomiting, and retching (N, V, and R) between younger ( < 65 years, n = 102) and older ( > or = 65 years, n = 25) persons receiving outpatient chemotherapy. A longitudinal 4-month study was used for the 127 participants recruited from 18 settings. Participants completed two questionnaires (Inventory of N, V, and R and Behavior Checklist) over the course of the study. The pattern between the younger and older patients' N, V, and R subscale scores was consistent in that the younger patients' scores were consistently (except on one occasion) higher than the older patients' scores, but this difference was statistically insignificant. This study furthers our understanding of N, V, and R and has several clinical implications. PMID- 8674025 TI - Psychological correlates of quality of life across the autologous bone marrow transplant experience. AB - A convenient sample of 24 patients was used to examine psychological response and quality of life (QOL) of patients undergoing autologous bone marrow transplantation (ABMT). The relationships among anxiety, depression, and quality also were examined. The study had a descriptive, correlational design. Instruments used to collect data were the Quality of Life Index (QLI), the Becks Depression Inventory, and the Spielberger State-Trait Anxiety Inventory. Data were collected 2 weeks before the patient's hospitalization for ABMT (baseline), 2 days before ABMT, and 5 and 20 days after ABMT. QOL and anxiety improved slightly after ABMT. Patients were significantly more depressed before ABMT (p < 0.05) than afterward. Analysis of QOL showed that health and functioning had the most negative impact on QOL, whereas family had the most positive impact on QOL. A strong negative relationship was found between depression and QOL (r = 0.79). PMID- 8674024 TI - Longitudinal study on quality of life and social support in cancer patients. AB - The aim of the present study is to acquire insight into the changes of quality of life, social networks, and social support of cancer patients during the first year after diagnosis, as well as into the relation between social support and the changes in quality of life. Newly diagnosed cancer patients (n = 51) were followed for 1 year. Semistructured personal interviews and questionnaires were used to gather data. On the average, patients' functioning improved and the amount of physical complaints decreased over the year. Psychological complaints and the global evaluation of life, however, did not change significantly over time. The patients were supported by small, dense networks, consisting mostly of family members. Size of the networks as well as the amount of emotional support showed some decrease over time. It appeared that emotional support was positively related to quality of life. Moreover, a tendency was found to indicate that patients with a deterioration in quality of life perceived a larger decrease in emotional support than patients with a positive course. The amount of perceived instrumental support did not change significantly. There is a tendency that patients who were functioning worse had a greater need for instrumental support. Although these findings indicate relations between types of support and quality of life, we cannot make statements on the causality of these relations. PMID- 8674027 TI - Mechanisms and management of gastric cancer. A comparison between the Japanese and U.S. experiences. AB - While gastric cancer is on the decline in the United States, this cancer has been the leading cause of death in Japan since 1981. Although the mechanisms underlying the development of gastric cancer are not completely understood, certain epidemiological factors, particularly diet, are associated with this disease. This article presents information on the differences in disease classification, diagnostic and screening procedures, treatment approaches, and mortality statistics between the United States and Japan. In addition, the clinical manifestations of gastric cancer are summarized, and the nursing care of the patient is outlined using a nursing diagnosis format. PMID- 8674026 TI - Psychosocial aspects of participation in early anticancer drug trials. Report of a pilot study. AB - Despite improvements in the treatment of many cancers, the need for effective new therapies is as great as ever. However, evaluating new drug treatments for cancer in clinical practice raises complex problems. Early trials of new drugs offer little in the way of therapeutic benefit, since their main aim is to identify toxic effects of the drug and subsequent doses for testing. The ethical and practical problems that these trials raise have received some attention in the literature. The main focus of previous studies has been the process of informed consent for trial participation, which has tended to reflect the perspective of the clinicians involved. Little attention has been given to patients' views in this context, and still less work has explored the total experience of clinical trial participation. In order to address these gaps in the literature, a research study was developed to explore the psychosocial aspects of participation in early anticancer drug trials from the perspective of the patient. This article reports the findings of a pilot study. The pilot study obtained the views of seven patients as they progressed through an anticancer drug trial. The informed consent process, the reasons behind decision-making concerning trial participation, and the impact of participation on the lives of the patients were explored, along with changing needs for information, care, and support as the trial progressed. Findings identify psychosocial aspects of clinical trial participation related to information, decision-making, and support from the perspective of those actually taking part. PMID- 8674028 TI - Factors influencing registered nurses teaching breast self-examination to female clients. AB - A university hospital-based study was conducted to explore factors that influence nurses teaching breast self-examination (BSE) to female clients, using the PRECEDE (Predisposing, Reinforcing, and Enabling factors in Educational Diagnosis and Evaluation) model as an organizing framework. Female registered nurses (N = 140) from adult inpatient and outpatient units completed a questionnaire that included items about frequency of BSE, knowledge of breast cancer screening and BSE technique, health motivation, confidence and competence in performing BSE, and teaching BSE. Data analysis compared the characteristics of nurses who reported teaching BSE with nurses who did not teach. Nurses in the teaching group had more work experience in nursing and were more likely to have a friend with breast cancer than were those in the nonteaching group. The teaching group had more knowledge about breast cancer screening and BSE technique and reported more confidence and competence in performing BSE. PMID- 8674029 TI - Information, support, and communication needs of women with a family history of breast cancer. AB - In this article, the role of information, support, and communication in promoting adaptation to the risk of breast cancer is reported. These variables emerged from an in-depth study of women at risk for breast cancer because of breast cancer in one or more of their primary (first degree) relatives. Fifty-five women with mothers, sisters, mother and sister, or mother and another primary relative were interviewed using in-depth semi-structured, tape-recorded interviews. After transcription, data were analyzed using qualitative analysis procedures. A three phase process of adaptation to the risk of breast cancer was uncovered, which was subsequently validated with two study participants. Information, support, and communication emerged as important factors in facilitating the adjustment of women throughout the three phases of the process: as women "lived" the breast cancer experience of their relative; as they developed a perception of their personal risk for breast cancer; and finally as they put the risk of breast cancer "in its place." Despite the importance of information and support, most women had difficulty meeting these needs. Also, communication patterns both within the family and with health professionals were generally not helpful for these women. Issues related to the ill relative as "manager" of cancer-related information, the "ownership style" of the woman at risk, and the accessibility and availability of resources influenced women's adaptation to feelings of risk. Women's needs for information, support, and communication and facilitating factors are described in detail, and recommendations for clinical practice and research offered. PMID- 8674030 TI - Programmed instruction: Cancer therapy. Associated late effects. PMID- 8674031 TI - Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. AB - Flavopiridol (L86-8275), a N-methylpiperidinyl, chlorophenyl flavone, can inhibit cell cycle progression in either G1 or G2 and is a potent cyclin-dependent kinase (CDK) 1 inhibitor. In this study, we used MCF-7 breast carcinoma cells that are wild type for p53 and pRb positive and contain CDK4-cyclin D1 and MDA-MB-468 breast carcinoma cells that are mutant p53, pRb negative, and lack CDK4-cyclin D1 to investigate the G1 arrest produced by Flavopiridol. Recombinant CDK4-cyclin D1 was inhibited potently by Flavopiridol (Kiapp, 65 nM), competitive with respect to ATP. Surprisingly, CDK4 immunoprecipitates derived from Flavopiridol-treated MCF-7 cells (3 h, 300 nM Flavonolpiridol) had an approximately 3-fold increased kinase activity compared with untreated cells. Cyclin D and CDK4 levels were not different at 3 hr, but cyclin D levels and CDK4 kinase activity decreased thereafter. The phosphorylation state of pRb was shifted from hypercoincident to hypocoincident with the development of G1 arrest. Asynchronous MDA-MB-468 cells were inhibited in cell cycle progression at both G1 and G2 by Flavopiridol. Flavopiridol inhibited the in vitro kinase activity of CDK2 using an immune complex kinase assay (IC50, 100 nM at 400 microM ATP). Immunoprecipitated CDK2 kinase activity from either MCF-7 or MDA-MB-468 cells exposed to Flavopiridol (300 nM) for increasing time showed an initial increased activity (approximately 1.5-fold at 3 h) compared with untreated cells, followed by a loss of kinase activity to immeasurable levels by 24 h. This increased immunoprecipitated kinase activity was dependent on the Flavopiridol concentration added to intact cells and was associated with a reduction of CDK2 tyrosine phosphorylation. Cyclin E and A levels were not altered to the same extent as cyclin D, and neither CDK4 nor CDK2 levels were changed in response to Flavopiridol. Inhibition of the CDK4 and/or CDK2 kinase activity by Flavopiridol can therefore account for the G1 arrest observed after exposure to Flavopiridol. PMID- 8674032 TI - Identification of a novel protein (VBP-1) binding to the von Hippel-Lindau (VHL) tumor suppressor gene product. AB - The tumor suppressor VHL gene product (pVHL), recently reported to bind to elongins B and C, is thought to regulate transcription elongation. To establish whether the VHL gene may have other functions, we here searched for additional cellular protein(s) that might bind to pVHL using a two-hybrid system and identified seven independent clones, including elongin C, but not elongin B. Three clones (unknown, imidopeptidase, and unknown) presumably bind to the N terminal nonconserved region, whereas the four other clones [elongin C, the HIV tat-binding protein, the actin-binding protein Filamin (ABP280), and the HIBBJ46 (named VBP-1)] were found to bind to the wild-type pVHL but not to a C-terminal 156-amino acid deletion mutant. Interestingly, the HIV tat-binding protein and Filamin could bind to C-terminal 26-amino acid deleted pVHL, but elongin C and VBP-1 failed to do so. Thus, elongin C and VBP-1 require the C-terminal end of pVHL for binding. It was also established that epitope-tagged pVHL strongly forms complexes with VBP-1 in vivo using immunoprecipitation Western blotting analysis. VBP-1 was widely expressed in various cell lines tested, in which VHL mRNA can be detected. When the VBP-1 protein was solely expressed, it located to the cytoplasm and did not localize to the nucleus. However, when coexpressed with VHL, it can translocate to the nucleus. These results indicate that VBP-1 can form a complex with VHL protein in vivo and hence VHL affects the intracellular localization of VBP-1 protein. PMID- 8674033 TI - Elevated p16 at senescence and loss of p16 at immortalization in human papillomavirus 16 E6, but not E7, transformed human uroepithelial cells. AB - CDKN2/p16 inhibits the cyclin D/cyclin-dependent kinase complexes that phosphorylate pRb, thus blocking cell cycle progression. We previously reported that p16 levels are low to undetectable in normal human uroepithelial cells (HUCs) and in immortalized uroepithelial cells with functional pRb, whereas p16 levels are markedly elevated in immortal HUCs with altered pRb (T. Yeager et al., Cancer Res., 55: 493-497, 1995). We now report that elevation of p16 levels occurs at senescence in HUCs, including HUCs transformed by human papillomavirus 16 E7 or E6, whose oncoprotein products lead to functional loss of pRb and p53, respectively. We also report that six of six independently immortalized E7 HUCs show high levels of p16 similar to those observed at HUC senescence, whereas p16 is undetectable in five of five immortal E6 HUCs. Four of the five independent E6 HUCs that lost p16 at immortalization showed hemizygous deletion of the 9p21 region. However, no homozygous CDKN2 deletions were detected, and only one CDKN2 mutation was identified. For the first time, these data associate elevated p16 with senescence in human epithelial cells. These data also suggest that a component of immortalization may be abrogation, either by pRb inactivation (as in the E7-transformed HUCs) or by p16 inactivation (as in the E6-transformed HUCs), of a p16-mediated senescence cell cycle block. PMID- 8674034 TI - Overexpression of tissue inhibitor of metalloproteinases-2 retroviral-mediated gene transfer in vivo inhibits tumor growth and invasion. AB - We have demonstrated previously that overexpression of tissue inhibitor of metalloproteinases-2 (TIMP-2), an inhibitor of matrix-degrading metalloproteinases, not only inhibits the invasive and metastatic behavior of tumor cells but also significantly decreases tumor growth in vivo (Y. A. DeClerck et at, Cancer Res., 52: 701-708, 1992). This latter effect was found to be dependent on the ability of TIMP-2 to prevent the degradation of the collagen matrix (A. M. Montgomery et al., Cancer Res., 54: 5467-5473, 1994). In this report, we have overexpressed TIMP-2 in tumor tissue by retroviral-mediated gene transfer into tumor cells by co-injecting s.c. in nude mice tumorigenic c-Ha-ras transfected rat embryo fibroblasts with irradiated packaging cells producing high titer retroviral vectors containing the human TIMP-2 cDNA. The growth rate of tumors derived from cells co-injected with the TIMP-2 vector producer cells was significantly slower than the growth rate of tumors derived from cells co injected with packaging cells producing a retrovirus containing the Escherichia coli beta-galactosidase gene. The transduction efficiency was estimated at 13%, and the production of a functional human TIMP-2 in tumor cells transduced with the TIMP-2-containing vector was documented. Furthermore, histological analysis of tumors derived from tumor cells co-injected with the TIMP-2 vector producer cells revealed the presence of a thick connective tissue capsule and a lack of local invasion. The data indicate that retroviral-mediated transduction of TIMP-2 cDNA into a limited population of tumor cells in vivo is sufficient to increase the accumulation of connective tissue proteins in tumor tissue, to inhibit growth, and to prevent local invasion. PMID- 8674035 TI - Inability of low- or high-fat diet to modulate late stages of colon carcinogenesis in Sprague-Dawley rats. AB - The main objective of the present proposal was to investigate the effect of feeding a low- or high-fat diet in the early and late stages of colon carcinogenesis. Sprague-Dawley male rats were injected with azoxymethane (20 mg/kg/week) for 2 weeks. One week later they were randomly allocated to eat a low fat (4% beef tallow + 1% corn oil) or a high-fat (18.6% beef tallow + 4.7% corn oil) diet (LF or HF). After 10 weeks of feeding, 10 animals per group were killed, and their colons were evaluated for tumors. The remaining animals in each group were divided further into LF and HF groups. The four experimental groups consisted of groups receiving LF or HF diet throughout the study (LF-LF or HF-HF) and the groups fed LF or HF diet for the first 10 weeks, then assigned the alternate diet for the remainder of the duration (LF-HF or HF-LF). By week 26, the remaining animals were killed, and their colons were evaluated for the number, location and size of tumors. The tumor incidence in the HF-HF and HF-LF groups were higher than the LF-LF and LF-HF groups (81.6 and 84.8% versus 71.4 and 60.0%). Tumor multiplicity ranged from 1.86 +/- 0.26 to 2.54 +/- 0.33 in all groups. The average size of tumors and total tumor area/rat were affected significantly by the time at which the diet was fed. Average size and total tumor area in the animals fed HF diet during early stages (HF-HF and HF-LF) were significantly higher than those fed the LF diet during the early stages. Late intervention by specific diets did not affect tumor outcome. Sequential enumeration of aberrant crypt foci of different growth features representing early preneoplastic stages corroborated the findings of the tumor outcome. It was concluded that early preneoplastic stages were more sensitive than their advanced counterparts to the dietary interventions of the present study. PMID- 8674036 TI - Microvessel count predicts survival in uveal melanoma. AB - Microvessel density has become established as an important prognostic indicator for many tumor types. This study investigates the microvessel density as a prognostic factor for survival in patients with uveal melanoma, which is the commonest intraocular tumor and has a clear tendency for metastatic spread to the liver. Factor VIII-related antigen was identified immunohistochemically in bleached sections from 123 tumors. Maximum blood vessel density in an area of 0.25 mm2 was recorded, along with other accepted prognostic information. Microvessel density was the single most important prognostic factor on univariate testing, and in a Cox proportional hazard model, tumor size was the only other variable to be entered. No other accepted prognostic factor entered the model. We conclude that microvessel density is an important prognostic factor for survival in patients with uveal melanoma and allows the identification of high-risk patients for whom adjuvant therapy should be considered. PMID- 8674037 TI - H19 gene overexpression in atypical multidrug-resistant cells associated with expression of a 95-kilodalton membrane glycoprotein. AB - The multidrug resistance phenotype of human breast carcinoma MCF-7/AdrVp cells is characterized by overexpression of a 95-kilodalton membrane glycoprotein (p95), accompanied by a marked reduction in intracellular anthracycline accumulation, without overexpression of P-glycoprotein or the multidrug resistance protein. We discovered that the mRNA of the H19 gene is overexpressed in MCF-7/AdrVp cells relative to parental MCF-7 cells or drug-sensitive MCF-7/AdrVp revertant cells. H19 is an imprinted gene with an important role in fetal differentiation, as well as a postulated function as a tumor suppressor gene. Another p95-overexpressing multidrug-resistant cell line, human lung carcinoma NCI-H1688, also displays high levels of H19 mRNA. In contrast, several multidrug-resistant cell lines that overexpress P-glycoprotein or the multidrug resistance protein do not have higher levels of H19 mRNA than their drug-sensitive counterparts. This is the first report of H19 gene overexpression accompanying any form of drug resistance. The association of H19 and p95 gene expression in drug resistance warrants further study. PMID- 8674038 TI - Evidence for an important role of neutrophils in the efficacy of photodynamic therapy in vivo. AB - To investigate the role of neutrophils in the efficacy of photodynamic therapy (PDT) in rhabdomyosarcoma-bearing rats, the number of these circulating phagocytes was decreased or increased before interstitial PDT by use of rabbit anti-rat neutrophil serum or granulocyte colony-stimulating factor, respectively. After administration of the antiserum, the number of circulating neutrophils decreased by 99.9%. However, the number of monocytes, lymphocytes, and platelets decreased as well (by 100%, 80%, and 25%, respectively). Under these conditions, PDT did not retard tumor growth at all. However, after cessation of the antiserum treatment 5 days after PDT, a striking decrease in the growth rate occurred subsequent to an increase above the normal range of the number of circulating neutrophils. Administration of the granulocyte colony-stimulating factor led to a specific 4-fold increase in the number of circulating neutrophils. In these rats, the tumor growth at day 2 after PDT was retarded as compared with PDT-treated rats that received saline only. Statistical evaluation of both experimental conditions showed that the efficacy of PDT, expressed as the percentage of change in tumor volume at day 2 after treatment, was dependent on the number of circulating neutrophils present at the day of PDT (P = 0.001; r2 = 0.482). Apparently, neutrophils are indispensable for successful PDT in vivo. PMID- 8674039 TI - Detection of germline BRCA1 mutations in breast cancer patients by quantitative messenger RNA in situ hybridization. AB - Mutations in the breast cancer susceptibility gene 1 (BRCA1) may account for one half of all familial breast cancers. Because of the wide spectrum of different germline mutations, identification of BRCA1 mutation carriers using current techniques is laborious and difficult. The majority of the identified mutations, however, lead to aberrant expression of the gene product in tumor tissue, potentially allowing the detection of BRCA1-linked breast cancers using simple histochemical techniques. We performed quantitative mRNA in situ hybridization analysis on archival paraffin-embedded tumor specimens from 25 patients with characterized germline BRCA1 mutations or linkage and from 29 patients with sporadic breast cancers. BRCA1 mRNA levels were invariably low in tumors from BRCA1 mutation carriers. Normal breast epithelium surrounding the BRCA1 tumors showed higher mRNA levels than the tumor tissue, indicating that the low mRNA levels were due to somatic inactivation of the wild-type BRCA1 allele in the tumor tissue. The expression levels in the sporadic tumors were, on average, six times higher than in the BRCA1 tumors (P < 0.0001). The difference allowed identification of BRCA1-mutated and sporadic tumors with more than 95% specificity and sensitivity. We conclude that the analysis of BRCA1 gene expression by mRNA in situ hybridization may be useful in screening for patients with BRCA1-linked breast cancer. PMID- 8674040 TI - High-density marker analysis of 11p15.5 in non-small cell lung carcinomas reveals allelic deletion of one shared and one distinct region when compared to breast carcinomas. AB - The presence of a non-small cell lung carcinoma (NSCLC)-related gene or genes on chromosome band 11p15.5 is of particular interest, given the specific loss of heterozygosity (LOH) measured in this region for lung as well as many other pediatric and adult neoplasms. We have undertaken high-density polymorphic marker analysis in 30 matched normal and NSCLC tumor samples using 11 PCR-based polymorphic markers positioned approximately every 2-3 cM throughout 11p15.5. These studies have confirmed the presence of two distinct regions of LOH for NSCLC in 11p15.5. In 9 of 13 (69%) tumors with measurable LOH, allelic deletion was restricted to 11p15.5, indicating that whole chromosome 11 loss is not a common event in NSCLC. Furthermore, one-half of these tumors showed independent deletion events for each LOH region, while the remaining tumor regions of LOH extended to include all four markers in between. Only two tumors showed LOH for the more telomeric region alone. Furthermore, the location of these two potentially distinct tumor suppressor genes has been significantly refined to a 3 cM area in the telomeric region between D11S1363 and tyrosine hydroxylase (TH) and a 10-cM area in the more proximal part of 11p15.5 between D11S988 and D11S926. Interestingly, the telomeric region of LOH in NSCLC overlaps with the reported location of one of two breast carcinoma-related tumor suppressor genes, but the proximal allelic deletion area for these two tumor types are clearly distinct. Our studies suggest that chromosome band 11p15.5 harbors a minimum of three separate loci, the loss of which is implicated in these two common adult neoplasms. PMID- 8674041 TI - MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis. AB - Accelerated intestinal tumorigenesis is probable in hereditary nonpolyposis colorectal cancer, a condition associated with germ line DNA mismatch repair (MMR) gene defects, and is believed to be caused by rapid accumulation of replication errors in critical genes, such as the APC (adenomatous polyposis coli) tumor suppressor gene. To study the potential contribution of MMR genes to accelerated intestinal tumorigenesis, we crossed the Min mouse, heterozygous for a germ line mutation of Apc, with an MMR gene (Msh2)-deficient mouse. MSH2 deficiency resulted in the development of many colonic aberrant crypt foci, as well as reduced survival of the mice, secondary to both a greater number and more rapidly developing adenomas. The mechanism of inactivation of the wild-type Apc allele depended on MSH2 status. In the presence of functional MSH2, all tumors demonstrated loss of heterozygosity. In contrast, whereas all adenomas were APC negative by immunostaining, only 5 of 34 adenomas from Apc+/-/Msh2-/- mice demonstrated loss of heterozygosity of the wild-type Apc allele, suggesting that somatic Apc mutations are responsible for the additional tumors. These findings provide evidence for the important role of MMR genes in accelerated intestinal tumorigenesis, thus supporting more aggressive surveillance strategies to prevent colorectal cancer in hereditary nonpolyposis colorectal cancer. PMID- 8674042 TI - Allelic losses at chromosomes 1p, 2p, 6p, 10p, 13q, 17p, and 21q significantly correlate with the chromophobe subtype of renal cell carcinoma. AB - We analyzed 50 sporadic renal cell carcinomas (RCCs) for loss of heterozygosity (LOH) at the chromosomal regions 1p, 2p, 6p, 7q, 10p, 11p, 13q, 14q, 17p, 21q, and 22q. Histologically, the tumors were distinguished into clear cell, chromophilic, and chromophobe carcinomas. Whereas LOH at 14q was identified in 42 64% of all three tumor types, only the chromophobe tumors showed high frequencies of LOH (73-91%) at 1p, 2p, 6p, 10p, 13q, 17p, and 21q. These findings provide substantial evidence that the chromophobe subtype of RCC represents a distinct genetic entity. Thus, specific LOH patterns may define the histogenesis and oncogenesis of chromophobe RCC and may be useful in tumor diagnosis and clinical prognosis. PMID- 8674043 TI - Increased sensitivity to cisplatin by nm23-transfected tumor cell lines. AB - We report a functional link between expression of the metastasis suppressor gene nm23 and cancer cell sensitivity to the alkylating agent cisplatin. Cisplatin was 2-15-fold more inhibitory to the growth in vitro of nm23 transfectants of the K 1735 TK murine melanoma, MDA-MB-435 human breast carcinoma, and OVCAR-3 human ovarian carcinoma cell lines as compared to matched control transfectants. Administration of a single dose of cisplatin i.v. after injection of control- or nm23-1-transfected K-1735 TK melanoma cells resulted in a more pronounced inhibition of pulmonary metastatic colonization by the nm23-1 transfectants. The mechanism of nm23-dependent sensitivity to cisplatin is unknown, but was correlated with increased formation of interstrand DNA cross-links in nm23-H1 transfected breast carcinoma cells. These data suggest that elevation of tumor cell nm23 expression may be considered as a potential therapeutic strategy in combination with cisplatin treatment. PMID- 8674044 TI - Evaluation of the FHIT gene in colorectal cancers. AB - A variety of studies suggests that tumor suppressor loci on chromosome 3p are important in various forms of human neoplasia. Recently, a chromosome 3p14.2 gene called FHIT was discovered and proposed as a candidate tumor suppressor gene in colorectal and other cancers. We evaluated the FHIT gene in a panel of colorectal cancer cell lines and xenografts, which allowed a comprehensive mutational analysis. A transcript containing the complete coding sequence was found to be expressed at robust levels in 29 of 31 cancers tested. The complete sequence of the coding region of the gene was determined and found to be normal in all 29 of these cases. These studies suggest either that FHIT is inactivated by an unusual mechanism or that it plays a role in relatively few colorectal tumors. PMID- 8674045 TI - p53-dependent cell cycle arrests are preserved in DNA-activated protein kinase deficient mouse fibroblasts. AB - p53 is involved in at least three cell cycle checkpoints in normal cells: two in G1, activated by either DNA damage or by ribonucleotide pool depletion in the absence of damage, and one in metaphase/anaphase activated by an incomplete mitotic spindle. We tested whether any of these checkpoints require the DNA activated protein kinase (DNAPK), since data indicate that it is activated by damaged DNA to modify p53 in cultured cells and in cell-free systems. Fibroblasts isolated from mice with severe combined immune deficiency (SCID) were used because the sole genetic defect underlying this syndrome lies within the DNAPK gene. This report shows that age-matched SCID and isogenic wild-type embryonic fibroblasts arrested in response to DNA damage, ribonucleoside triphosphate depletion, and spindle poisons, whereas p53-/- fibroblasts failed to do so. Therefore, DNAPK-deficient scid cells preserve normal p53-dependent cell cycle checkpoints. The data provide one explanation of why scid mice are not tumor prone though they are deficient in double-strand break repair. PMID- 8674046 TI - Accelerated degradation of PML-retinoic acid receptor alpha (PML-RARA) oncoprotein by all-trans-retinoic acid in acute promyelocytic leukemia: possible role of the proteasome pathway. AB - Acute promyelocytic leukemia (APL) is associated with a chromosomal translocation t(15;17) and successfully differentiated by all-trans-retinoic acid (ATRA) in vivo as well as in vitro. The PML-retinoic acid receptor alpha (RARA) oncoprotein, which is generated by the translocation, blocks the differentiation, and ATRA is thought to modulate the dominant negative function of PML-RARA. However, the molecular effect of ATRA on PML-RARA is unknown. In this study, we showed by means of immunoblotting that the expression of PML-RARA decreased within 12 h in APL cells treated with ATRA at concentrations greater than 0.1 microM. The decrease of PML-RARA was associated with restoration of the normal subcellular PML localization. PML-RARA transcripts were not down-regulated by ATRA. However, lactacystin, a specific inhibitor of the proteasome, almost completely inhibited the decrease of PML-RARA. These data indicate that the PML RARA degradation is accelerated by pharmacological concentrations of ATRA, suggesting that ATRA allows APL cells to differentiate by relieving the differentiation block. PMID- 8674047 TI - Fetal- and tumor-specific regulation of growth hormone receptor messenger RNA expression in human liver. AB - Eight different 5'-untranslated region variants of the human growth hormone receptor (hGHR) mRNA have been identified in adult liver (V1-V8). We have compared the expression of two of these variants (V1 and V3) in several human fetal and postnatal tissues (including liver) as well as in hepatoblastomas (HBs) and hepatocellular carcinomas (HCCs). Using reverse transcription-PCR assays, followed by Southern blotting to confirm the specificity of the amplified fragments, we found that V3 was expressed in all fetal and postnatal liver (n = 13 fetal and 5 postnatal), kidney (n = 4 fetal and 4 postnatal), lung (n = 4 fetal and 2 postnatal), intestine (n = 8 fetal and 4 postnatal), skeletal muscle (n = 1 fetal and 1 postnatal), and adrenal (n = 1 fetal and 1 postnatal) samples. In contrast, V1 was expressed only in postnatal liver. We then screened for V1 and V3 in HBs (n = 17, ages 6-36 months, including 5 with paired normal liver), and HCCs (n = 4, ages 50-75 years, with paired normal liver). V1 was undetectable in 15 of 17 HBs, including all HBs paired with (V1-expressing) normal liver; the absence of V1 did not correlate with patient age, sex, HB subtype, +/- chemotherapy, exon 3-retaining and -deficient hGHR mRNA isoform pattern, or loss of heterozygosity at 11p, 1p, and 1q. The four HCCs showed marked (>20-fold; n = 2) or complete (n = 2) suppression of V1 as compared to paired normal liver. V3 was expressed in all HBs, HCCs, and paired normal livers. Interestingly, V3, but not V1, was detected in two Wilms' tumor and paired normal kidney specimens. Our findings suggest that, in the human, there is tissue-, fetal- and tumor-specific regulation of V1 hGHR mRNA. PMID- 8674048 TI - Phenethyl isothiocyanate, a natural chemopreventive agent, activates c-Jun N terminal kinase 1. AB - Phenethyl isothiocyanate (PEITC) and other structurally related compounds are potent chemopreventive agents in a number of experimental models of cancer in animals. The mechanisms of cancer protection by these agents are not clear but may involve the regulation of gene expression, such as that by Phase II detoxifying enzymes. To unveil the upstream signaling events that lead to the potential transcriptional activation of genes, we studied the involvement of mitogen-activated protein kinase, c-Jun N-terminal kinase 1 (JNK1), and extracellular signal-regulated kinase 1 and 2 cascades, which have been shown to mediate numerous types of extracellular signals. On treatment of human ovarian HeLa cells with PEITC, JNK1 activity was strongly induced in a dose- and time dependent manner, whereas the activation of extracellular signal-regulated kinase 1 and 2 was not substantial. Furthermore, activation of JNK1 by PEITC was inhibited by pro-oxidants hydrogen peroxide and diamide, although these two pro oxidants by themselves had opposing effects on JNK1 activity. Pretreatment with an antioxidant, N-acetyl-L-cysteine, had no effects on PEITC activation of JNK1. When comparing the kinetics of JNK1 activation by different isothiocyanates, PEITC elicited a sustained activation, whereas 3-phenylpropyl isothiocyanate and 4-phenylbutyl isothiocyanate stimulated transient activations. The responsiveness of JNK1 to PEITC, 3-phenylpropyl isothiocyanate, and 4-phenylbutyl isothiocyanate suggests the involvement of JNK1 in the regulation of Phase II detoxifying enzyme gene expression. Furthermore, different patterns of JNK1 induction by these isothiocyanates may contribute to their distinct chemopreventive efficacies in some animal tumor model studies. PMID- 8674049 TI - Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide. AB - To date, the structure of the autocrine motility factor (AMF), a tumor-secreted cytokine which stimulates cell migration in vitro and metastasis in vivo, is unknown. Here, AMF secreted by Gc-4 PF murine fibrosarcoma into a protein-free conditioned media was isolated, purified, and microsequenced. The results demonstrate that AMF is the previously cloned cytokine and enzyme designated as neuroleukin, and phosphohexose isomerase (PHI), which has been independently implicated in cell motility, and to be a cancer progression marker. PHI catalyzes isomerization of glucose 6-phosphate to fructose 6-phosphate and is specific for both sugars. Murine AMF exhibits the enzymatic properties of PHI and rabbit heart PHI-stimulated mouse fibrosarcoma cells' motility similar to those of the endogenous AMF. Specific PHI inhibitors (carbohydrate phosphates) inhibited enzymatic activity and AMF-induced cell motility. PMID- 8674050 TI - Metabolic characterization of human soft tissue sarcomas in vivo and in vitro using proton-decoupled phosphorus magnetic resonance spectroscopy. AB - We applied 1H-decoupling and nuclear Overhauser enhancement to obtain well resolved 31P magnetic resonance spectra accurately localized to 20 soft tissue sarcomas in vivo, using three-dimensional chemical shift imaging. Fifteen spectra had large phosphomonoester signals (21% of total phosphorus) that contained high amounts of phosphoethanolamine (compared to those of phosphocholine) but no signals from glycerophosphoethanolamine, and glycerophosphocholine was detected in only four cases. Prominent nucleoside triphosphates (52% of phosphorus) and low inorganic phosphate (10% of phosphorus) indicated that a large fraction of these 15 sarcomas contained viable cells, and this impression was confirmed histologically in 13 of the sarcomas. High-resolution in vitro 31P spectra of extracts of surgical specimens of four of the sarcomas studied in vivo and six additional sarcomas confirmed the in vivo assignments of metabolites and revealed considerable inter- and intratumoral variations of metabolite concentrations associated with histological variations in the relative amounts of cells and of matrix materials or spontaneous necrosis. Seven sarcomas, all high grade with pleomorphic or round cells rather than spindle cells, contained an unidentified phosphodiester signal in vivo; its absence in the extract spectra indicates that it may be from an abnormally mobile membrane component. We have documented a means to obtain new information about in vivo metabolism in human sarcomas and to provide a basis on which to examine the uses of 31P magnetic resonance spectroscopy in the clinical management of sarcomas. PMID- 8674051 TI - Activation of chemically diverse procarcinogens by human cytochrome P-450 1B1. AB - A human cytochrome P-450 (P450) 1B1 cDNA was expressed in Saccharomyces cerevisiae and the microsomes containing P450 1B1 were used to examine the selectivity of this enzyme in the activation of a variety of environmental carcinogens and mutagens in Salmonella typhimurium TA1535/pSK1002 or NM2009 tester strains, using the SOS response as an end point of DNA damage. We also determined and compared these activities of P450 1B1 with those catalyzed by recombinant human P450s 1A1 and 1A2, which were purified from membranes of Escherichia coli. The carcinogenic chemicals tested included 27 polycyclic aromatic hydrocarbons and their dihydrodiol derivatives, 17 heterocyclic and aryl amines and aminoazo dyes, three mycotoxins, two nitroaromatic hydrocarbons, N nitrosodimethylamine, vinyl carbamate, and acrylonitrile. Among the three P450 enzymes examined here, P450 lB1 was found to have the highest catalytic activities for the activation of 11,12-dihydroxy-11,12-dihydrodibenzo[a,l]pyrene, 1,2-dihydroxy-1,2-dihydro-5-methylchrysene, (+)-7,8-dihydroxy-7,8 dihydrobenzo[a]pyrene, 11,12-dihydroxy-11,12-dihydrobenzo[g]chrysene, 3,4 dihydroxy-3,4-dihydrobenzo[c]phenanthrene, 3-amino-1,4-dimethyl-5H-pyrido[4,3 b]indole, 2-aminoanthracene, 3-methoxy-4-aminoazobenzene, and 2-nitropyrene. P450 1B1 also catalyzed the activation of 2-amino-3,5-dimethylimidazo[4,5-f]quinoline, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 2-amino-3-methylimidazo[4,5 f]quinoline, 2-aminofluorene, 6-aminochrysene and its 1,2-dihydrodiol, (-)-7,8 dihydroxy-7,8-dihydrobenzo[a]pyrene, 1,2-dihydroxy-1,2-dihydrochrysene, 1,2 dihydroxy-1,2-dihydro-5,6-dimethylchrysene, 2,3-dihydroxy-2,3 dihydrofluoranthene, 3,4-dihydroxy-3,4-dihydro-7,12-dimethylbenz[a]anthracene, and 6-nitrochrysene to appreciable extents. However, P450 1B1 did not produce genotoxic products from benzo[a]pyrene, trans- 3,4-dihydroxy-3,4 dihydrobenzo[a]anthracene, trans-8,9-dihydroxy-8,9-dihydrobenzo[a]anthracene, 7,12-dimethylbenz[a]anthracene and its cis-5,6-dihydrodiol, 5-methylchrysene, 11,12-dihydroxy-11,12-dihydro-3-methylcholanthrene, 1,2-dihydroxy-1,2-dihydro-6 methylchrysene, benzo[c]phenanthrene, 2-amino-6-methyldipyridol[1,2-a:3',2' d]imidazole, 2-acetylaminofluorene, benzidine, 2-naphthylamine, aflatoxin B1, aflatoxin G1, sterigmatocystin, N-nitrosodimethylamine, vinyl carbamate, or acrylonitrile in this assay system. P450 1B1 is expressed constitutively in extrahepatic organs, including fetal tissue samples, and is highly inducible in various organs by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds in experimental animal models. Thus, activation of procarcinogens by P450 lB1 may contribute to human tumors of extrahepatic origin. PMID- 8674052 TI - Karyotypic changes in a multistage model of chemical hepatocarcinogenesis in the rat. AB - Karyotypic analysis of the stages of rat hepatocarcinogenesis has been facilitated by the development of an initiation-promotion-progression (IPP) protocol that permits separation and characterization of morphologically normal and altered hepatocytes in each of these three stages. The expression of the membrane antigen gamma-glutamyl transpeptidase (GGT) during the promotion and progression stages of rat hepatocarcinogenesis permits the isolation, culture, analysis, and comparison of hepatocytes in the two stages, which express this marker of carcinogenesis. Female rats were administered 10 mg diethylnitrosamine/kg at 5 days of age. One group of initiated rats was maintained on dietary phenobarbital admixed into a laboratory chow diet at 0.05% for 9 months after weaning (promotion protocol). This initiation-promotion (IP) group was compared with one subjected to the complete IPP protocol. The IPP group was initiated with diethylnitrosamine, maintained on phenobarbital for 6 months after weaning, and then subjected to a 70% partial hepatectomy and administered 100 mg ethylnitrosourea/kg 24 h later. These rats on the IPP protocol were then maintained on phenobarbital for an additional 3 months prior to sacrifice. At sacrifice, single hepatocyte suspensions were obtained and separated into populations of cells expressing or not expressing GGT. These hepatocyte populations were cultured separately and subjected to standard cytogenetic analysis. At least five animals per treatment and 100 metaphase spreads of good morphology per animal were examined. Although GGT- cells from the IP protocol were 80% tetraploid and 20% diploid, the GGT+ hepatocytes were greater than 90% diploid. The GGT+ cells from this protocol had a low rate of random aneuploidy (4.0 +/- 1.3%) compared with corresponding cells from the IPP protocol, but a higher level of background aneuploidy compared with GGT- cells from the IP protocol. The GGT+ hepatocytes from animals on the IPP protocol had a 35% incidence of aneuploidy. In addition, the GGT+ population had a 28 +/- 5% incidence of chromosomal breakage and a 17 +/- 5% incidence of chromosomal rearrangements. The primary nonrandom chromosomal changes observed in cells from the IPP protocol included duplication of all or part (1q37-43) of chromosome 1 and the loss of chromosomes 3p and/or 6q. These studies indicate that rat hepatocytes in the stage of promotion are euploid, whereas those in the stage of progression exhibit considerable genetic instability. The presence of multiple copies of chromosome 1 or a duplication of a region of this chromosome indicates that alteration of gene dosage for one or more of the genes present in this region is critical to the neoplastic conversion of rat hepatocytes, whereas the loss of all of 3p and the last light band of 6q may indicate the presence of tumor suppressor genes. Thus, the IP and IPP protocols coupled with the ability to isolate GGT+ and GGT- hepatocytes permit the differential cytogenetic characterization of the stages of promotion and progression in rat hepatocarcinogenesis. PMID- 8674053 TI - Cytogenetic analysis of three rat liver epithelial cell lines (WBneo, WBHa-ras, and WBrasIIa) and correlation of an early chromosomal alteration with insulin like growth factor II expression. AB - Cytogenetic changes that occur during the progression of rat hepatocarcinogenesis were assessed with three rat liver epithelial cell lines derived from WB cells. Previously characterized WBneo, WBras, and WBrasIIa cells were grown in culture and analyzed for structural and numerical chromosomal integrity by banded karyotype analysis. The WBneo cells had a low level of aneuploidy with a consistent loss of the Y chromosome by passage 7. The ras-transfected cell line selected for growth in soft agar, WBras, had acquired a loss of chromosome 3 (12%) or 3p (34%), a trisomy of chromosome 1, as well as the chromosome Y loss. The cell line produced from tumors generated by injection of the WBras cells into a syngeneic F344 rat, WBrasIIa, contained additional chromosomal changes. The WBrasIIa line comprised cells retaining a trisomy of chromosome 1 (55%) and cells with two copies of chromosome 1, with a minimal duplication of 1q3.7 to 1q4.3 (45%). This tumor-derived cell line contained, in addition, a higher percentage of cells with a loss of all or part of chromosomes 3 and 6, indicating the possible presence of tumor suppressor genes in this region. The smallest region of duplication of chromosome 1 was bands 1q3.7-4.3. The insulin-like growth factor II (IGF-II) gene is located within the region of duplication on chromosome 1. Because IGF-II is both a rat liver mitogen and an inhibitor of apoptosis, its expression was examined in these three rat liver epithelial cell lines. Northern blot analysis demonstrated an increase in IGF-II mRNA expression in the WBras and WBrasIIa cell lines relative to the WBneo control cell line. Several IGF-II transcripts analogous to those detected in fetal rat liver were observed. An additional IGF-II transcript that migrates above the 28S ribosomal marker was also observed. These results were confirmed at the protein level by immunohistochemical and Western blot analysis. This increased expression of IGF II may confer a selective growth advantage to rat liver epithelial cells with a duplication of 1q3.7-4.3. This growth advantage may be enhanced by the further sequential loss of putative tumor suppressor genes on chromosomes 3 and 6. PMID- 8674054 TI - p53-independent apoptosis during mammary tumor progression in C3(1)/SV40 large T antigen transgenic mice: suppression of apoptosis during the transition from preneoplasia to carcinoma. AB - Alterations in apoptosis and associated mechanisms during mammary tumor progression were investigated in transgenic mice expressing the SV40 large T antigen (T(AG)) driven by the rat prostatic steroid-binding protein C3(1) 5' flanking region. Apoptosis levels, assessed by in situ end labeling, were low in normal mammary epithelial cells, highest in atypical hyperplasias (preneoplastic lesions), and less pronounced in adenocarcinomas. Preneoplastic cells maintain the ability to undergo apoptosis as a mechanism of tumor growth suppression, but this critical control of apoptosis is lost as these lesions progress to carcinomas. These alterations in apoptosis occur during mammary tumor progression in mice containing wild-type p53+/+ genotype as well as in mice with the p53-/- genotype. Thus, apoptosis in this tumor model occurs through a p53-independent mechanism. Because other studies have demonstrated p53-dependent apoptosis in T(AG)-induced choroid plexus tumors of transgenic mice, we propose that the role of p53 in apoptosis may be tissue-specific. In addition, bcl-2 protein was not expressed in any mammary lesions. SV40 T(AG) expression, which correlated with the nuclear p53 protein at all stages of tumor progression, was low in normal mammary epithelial cells, moderately high in atypical hyperplasias, and strongly expressed in adenocarcinomas. No p53 mutations were found at any stage of mammary adenocarcinoma development, suggesting that tumor progression does not require a dominantly acting p53 mutation in this transgenic model. p2l(Waf1/Cip1), a cyclin dependent kinase inhibitor, was expressed in normal mammary tissue but was not detected in the mammary carcinomas, despite high nuclear accumulation of wild type p53 protein, suggesting functional loss of p53 due to binding of SV40 T(AG), to p53. These findings suggest that suppression of apoptosis during the transition from atypical hyperplasia to adenocarcinoma appears to be a critical event for mammary cancer development in C3(1)/T(AG) transgenic mice and occurs by p53- and bcl-2-independent pathways. PMID- 8674055 TI - Expression of vascular permeability factor/vascular endothelial growth factor in human hepatocellular carcinoma. AB - Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) is unique in its ability to promote vascular permeability and endothelial cell growth, and its role in tumor development has received considerable attention. In this report, we describe the elevation of VPF/VEGF transcript expression in human hepatocellular carcinoma. Surgical samples of 23 patients with hepatocellular carcinoma were studied using reverse transcription-PCR analysis. The oligonucleotide primers were designed to amplify all four known splicing variants that could be expressed in the samples studied. Sixteen cases showed VPF/VEGF transcript expression in the tumor (16/23, 69.6%), whereas only 9 of the 23 patients showed it in the corresponding nontumoral part. There was no difference between the pattern of expression of VPF/VEGF isoforms in tumoral and nontumoral tissues. VPF/VEGF mRNA expression in the liver tumors was associated with fibrous capsule formation and septal formation (P < 0.05 respectively, Fisher's exact P test). In situ hybridization confirmed the presence of VPF/VEGF mRNA expression in tumor cells and less intensely in hepatocytes of nontumoral liver. We also found that VPF/VEGF expression in the tumor cell was increased in the area adjacent to necrotic regions (presumably hypoxic regions). As a regulator of vascular permeability and endothelial cell growth factor, VPF/VEGF may play an important role in the development of hepatocellular carcinoma. PMID- 8674056 TI - Methods to detect P-glycoprotein-associated multidrug resistance in patients' tumors: consensus recommendations. AB - Multidrug resistance (MDR), especially that associated with overexpression of MDR1 and its product, P-glycoprotein (Pgp), is thought to play a role in the outcome of therapy for some human tumors; however, a consensus conclusion has been difficult to reach, owing to the variable results published by different laboratories. Many factors appear to influence the detection of Pgp in clinical specimens, including its low and heterogeneous expression; conflicting definitions of detection end points; differences in methods of sample preparation, fixation, and analysis; use of immunological reagents with variable Pgp specificity and avidity and with different recognition epitopes; use of secondary reagents and chromogens; and differences in clinical end points. Also, mechanisms other than Pgp overexpression may contribute to clinical MDR. The combined effect of these factors is clearly important, especially among tumors with low expression of Pgp. Thus, a workshop was organized in Memphis, Tennessee, to promote the standardization of approaches to MDR1 and Pgp detection in clinical specimens. The 15 North American and European institutions that agreed to participate conducted three preworkshop trials with well-characterized MDR myeloma and carcinoma cell lines that expressed increasing amounts of Pgp. The intent was to establish standard materials and methods for a fourth trial, assays of Pgp and MDR1 in clinical specimens. The general conclusions emerging from these efforts led to a number of recommendations for future studies: (a) although detection of Pgp and MDR1 is at present likely to be more reliable in leukemias and lymphomas than in solid tumors, accurate measurement of low levels of Pgp expression under most conditions remains an elusive goal; (b) tissue-specific controls, antibody controls, and standardized MDR cell lines are essential for calibrating any detection method and for subsequent analyses of clinical samples; (c) use of two or more vendor-standardized anti-Pgp antibody reagents that recognize different epitopes improves the reliability of immunological detection of Pgp; (d) sample fixation and antigen preservation must be carefully controlled; (e) multiparameter analysis is useful in clinical assays of MDR1/Pgp expression; (f) immunostaining data are best reported as staining intensity and the percentage of positive cells; and (g) arbitrary minimal cutoff points for analysis compromise the reliability of conclusions. The recommendations made by workshop participants should enhance the quality of research on the role of Pgp in clinical MDR development and provide a paradigm for investigations of other drug resistance-associated proteins. PMID- 8674057 TI - Phase I clinical trial with a human major histocompatibility complex nonrestricted cytotoxic T-cell line (TALL-104) in dogs with advanced tumors. AB - The human TALL-104 cell line is endowed with a uniquely potent MHC nonrestricted tumoricidal activity across several species. In view of the potential applicability of TALL-104 cells as an anticancer agent, this study was conducted to evaluate the possible toxicity and efficacy of this new cell therapy in a superior animal model with spontaneous tumors. Nineteen canine cases with advanced, refractory malignancies of various histological types were entered in the study. All dogs had failed all other available treatments and had very limited life expectancy. Cyclosporin A was administered p.o. (10 mg/kg/day) starting from the day before TALL-104 cell administration throughout the treatment to prevent rejection of the xenogeneic effectors. Lethally irradiated (40 Gy) TALL-104 cells (10(8)/kg) were administered systemically following two treatment schedules. In the first schedule, the cells were given every other day for 2 weeks in a row and then once a week for 3 additional weeks; in the second schedule, TALL-104 cells were administered daily for a total of 5 days. None of the 19 cases showed significant clinical or laboratory toxicity; in addition, none of the dogs had to be withdrawn from the study because of immediate adverse reactions to the infusions. The severe side effects usually associated with classical lymphokine-activated killer therapy in association with high doses of interleukin 2, such as "capillary leak syndrome," were absent in this study. Remarkably, TALL-104 therapy induced various degrees of antitumor effects in 7 of the 19 dogs, including 1 complete response (continuing at +13 months), three partial responses (duration of 2 months, 3 months, and continuing at +2 months), and three transient responses. Clinical responses and immunological parameters correlated well in each case. Taken together, these data indicate that systemic administration of lethally irradiated TALL-104 cells in the absence of exogenous interleukin 2 may be regarded as a safe and promising adjuvant type of treatment for advanced cancer patients. PMID- 8674058 TI - Deoxynucleotide pool depletion and sustained inhibition of ribonucleotide reductase and DNA synthesis after treatment of human lymphoblastoid cells with 2 chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine. AB - The action of the new adenine nucleoside analogue 2-chloro-9-(2-deoxy-2-fluoro beta-D-arabinofuranosyl)adenine (Cl-F-ara-A) on DNA synthesis was evaluated both in whole cells and in vitro assay systems with purified DNA polymerases. [3H]Thymidine incorporation into DNA in human lymphoblastoid CEM cells was inhibited by Cl-F-ara-A in a concentration-dependent manner that was not reversed 72 h after removal of Cl-F-ara-A from the medium. Deoxynucleotide pools were depressed after incubation of Cl-F-ara-A for 3 h and only partially recovered following washing the cells into drug-free medium. The most pronounced decrease occurred in the dCTP pool, quantitatively followed by the dATP, dGTP, and dTTP pools. This was in concordance with the results of in situ assays of ribonucleotide reductase, which demonstrated profound inhibition of CDP reduction in cells incubated with Cl-F-ara-A; reduction of ADP, GDP, and UDP were affected to lesser extents. Reductase activity was inversely correlated with the cellular Cl-F-ara-ATP level, and inhibition of the enzyme was saturated when cellular Cl-F ara-ATP reached 25 microM. In vitro DNA primer extension assays indicated that Cl F-ara-ATP competed with dATP for incorporation into A sites of the extending DNA strand catalyzed by both human DNA polymerases alpha and epsilon. The incorporation of Cl-F-ara-AMP into DNA inhibited DNA strand elongation; the most pronounced effect was observed at Cl-F-ara-ATP:dATP values >1. The sustained inhibition of ribonucleotide reductase and the consequent depletion of deoxynucleotide triphosphate pools result in a cellular concentration ratio of dATP to Cl-F-ara-ATP, which favors analogue incorporation into DNA, an action that has been strongly correlated with loss of viability. PMID- 8674059 TI - Antitumor effects of an adenovirus expressing antisense insulin-like growth factor I receptor on human lung cancer cell lines. AB - Insulin-like growth factors (IGFs) are often essential for the maintenance of the malignant phenotype, and in lung cancer the IGF-I receptor (IGF-Ir) is often expressed at high levels. Stable transfection of antisense plasmids expressing the first 300 bp of the IGF-Ir reduces the tumorigenicity of a variety of tumor cell lines and has been reported to induce systemic antitumor effects on established, non-gene-modified tumors in animal model systems. We have constructed an adenovirus expressing an antisense IGF-Ir (Ad-IGF-Ir/as) in an attempt to develop these observations into a clinical therapeutic approach. A single transduction by Ad-IGF-Ir/as (at a multiplicity of infection of 10:1) decreased the IGF-Ir number by about 50% in human lung cancer cell lines NCI H460 and SCC5, as measured by an 125I-labeled IGF-I competitive binding assay. After the transduction of these human lung cancer cell lines by Ad-IGF-Ir/as, the soft agar clonogenicity was reduced by 84%. The i.p. treatment of nude mice bearing established i.p. NCI H460 cells resulted in prolonged survival compared to that of nude mice treated with a reporter virus. These results suggest that Ad-IGF Ir/as has a therapeutic effect on established human lung cancer xenografts and may represent an effective and practical cancer gene therapy strategy. PMID- 8674060 TI - CWR22: the first human prostate cancer xenograft with strongly androgen-dependent and relapsed strains both in vivo and in soft agar. AB - Most patients' prostate cancers respond to androgen deprivation but relapse after periods of several months to years. Only two prostate cancer xenografts, LNCaP and PC-346, have been reported to be responsive to androgen deprivation and to relapse subsequently. Both of these tumors shrink slightly, if at all, and relapse less than 5 weeks after androgen withdrawal. After androgen withdrawal, the human primary prostate cancer xenograft CWR22 regresses markedly, and prostate-specific antigen (PSA) falls up to 3000-fold in the blood of mice. PSA usually returns to normal. In some animals, the tumor relapses and is then designated CWR22R. In these animals, PSA starts to rise approximately 2-7 months, and tumor begins to grow 3-10 months after castration. Animals with CWR22 need to be euthanized because of large tumors 6-12 weeks after the transplantation of CWR22. Androgen withdrawal prolongs life approximately 3-4-fold. PMID- 8674061 TI - Adenovirus-mediated transfer of a wild-type p53 gene and induction of apoptosis in cervical cancer. AB - In most cervical cancers, the function of p53 is down regulated. To explore the potential use of p53 in gene therapy for cervical cancer, we introduced wild-type p53 into cervical cancer cell lines via a recombinant adenoviral vector, Ad5CMV p53, and analyzed its effects on cell and tumor growth. The transduction efficiencies of all cell lines were 100% at a multiplicity of infection of 100 or greater. The p53 protein was detected in Ad5CMV-p53-infected cells. Protein expression peaked at day 3 after infection and lasted 15 days. The Ad5CMV-p53 infected cells underwent apoptosis, and cell growth was greatly suppressed. The Ad5CMV-p53 treatment significantly reduced the volumes of established s.c. tumors in vivo. These results indicate that transfection of cervical cancer cells with the wild-type p53 gene via Ad5CMV-p53 is a potential novel approach to the therapy of cervical cancer. PMID- 8674063 TI - Processing of antibodies bound to B-cell lymphomas and other hematological malignancies. AB - In an attempt to recognize general patterns in the processing of Abs (antibodies) bound to the surface of tumor cells, eight monoclonal antibodies were tested on 10 hematological malignancies of various histological types. The results were compared with previous findings obtained with carcinomas, melanomas, and gliomas, using some of the same antibodies. The data demonstrated that some B-cell lymphomas appear to be unusual in that Abs were unable to bind to them irreversibly; except for those Abs that were rapidly internalized, none of the Abs tested was able to bind irreversibly to the B-cell lymphomas Raji or RL. In contrast, most Abs bound irreversibly to the tumors of other histological types, including other hematological tumors. Irreversible Ab binding to B-cell lymphomas was achieved by cross-linking the Abs on the cell surface. Such differences between cell lines may be due to differences in the supramolecular structure of the surface membrane, which affect the frequency or stability of bivalent Ab binding. The Ab binding interaction could not be described in terms of "functional affinity." These results may lead to improvements in the use of Abs for tumor immunotherapy and for other purposes. PMID- 8674062 TI - Minibody: A novel engineered anti-carcinoembryonic antigen antibody fragment (single-chain Fv-CH3) which exhibits rapid, high-level targeting of xenografts. AB - A novel engineered antibody fragment (VL-VH-CH3, or "minibody") with bivalent binding to carcinoembryonic antigen (CEA) was produced by genetic fusion of a T84.66 (anti-CEA) single-chain antibody (scFv) to the human IgG1 CH3 domain. Two designs for the connecting peptide were evaluated. In the T84.66/212 LD minibody, a two-amino acid linker (generated by fusion of restriction sites) was used to join VH and CH3. In the T84.66/212 Flex minibody, the human IgG1 hinge plus an additional 10 residues were used as the connecting peptide. Size exclusion chromatography of purified minibodies demonstrated that both proteins had assembled into Mr80,000 dimers as expected. Furthermore, analysis by SDS-PAGE under nonreducing conditions was consistent with disulfide bond formation in the hinge of the T84.66 Flex minibody. Purified minibodies retained high affinity for CEA (KA, 2 x 10(9) M(-1)) and demonstrated bivalent binding to antigen. Tumor targeting properties were evaluated in vivo using athymic mice bearing LS174T human colon carcinoma xenografts. 123I-labeled T84.66 minibodies demonstrated rapid, high tumor uptake, reaching 17% injected dose/gram (%ID/g) for the LD minibody and 33%ID/g for the Flex minibody at 6 h following injection. Radioiodinated minibody also cleared rapidly from the circulation, yielding high tumor:blood uptake ratios: 44.5 at 24 h for the LD minibody and 64.9 at 48 h for the Flex minibody. Rapid localization by the T84.66/212 Flex minibody allowed imaging of xenografts at 4 and 19 h after administration. PMID- 8674064 TI - Synthesis of alpha-galactosyl epitopes by recombinant alpha1,3galactosyl transferase for opsonization of human tumor cell vaccines by anti-galactose. AB - The immunogenicity of tumor-associated antigens in autologous tumor vaccines is limited because of insufficient uptake by antigen-presenting cells (APC). Anti Galactose (Gal) IgG, abundantly produced in humans, can serve as a natural adjuvant increasing the uptake of vaccinating autologous tumor cell membranes by APC. Anti-Gal interacts with the alpha-galactosyl epitope (Ga1alpha1-3Galbeta1 4GlcNAc-R), which is normally absent in humans. This epitope is produced in large amounts in nonprimate mammals and New World monkeys due to the intracellular activity of the glycosylation enzyme alphal,3galactosyltransferase. alpha Galactosyl epitopes were synthesized in vitro on human tumor cells by soluble recombinant alphal,3galactosyltransferase. Anti-Gal binding to these epitopes induces the effective uptake of the tumor cells by APC with Fc receptors that interact with the Fc portion of this natural antibody. It is suggested that synthesis of alpha-galactosyl epitopes on freshly isolated human tumor cell membranes, followed by their administration back to the patient, will result in the in situ opsonization of the membranes by anti-Gal, thereby improving the uptake, processing, and presentation of autologous tumor-associated antigens by APC with Fc receptors. PMID- 8674065 TI - Multiple features of advanced melanoma recapitulated in tumorigenic variants of early stage (radial growth phase) human melanoma cell lines: evidence for a dominant phenotype. AB - The vast majority of primary human cutaneous melanomas undergo a slow and gradual progression from a clinically indolent, curable radial growth phase (RGP) to a malignant vertical growth phase. We sought to develop a way of isolating genetically related malignant variants from a benign RGP human melanoma, called WM35. The parent and variants were then used as a model system to examine to what extent the expression of clinically and biologically relevant phenotypic features characteristic of advanced melanomas are associated with (and thus perhaps causative of) such a malignant conversion. Such a model system could also be used as a means of eventually identifying genetic alterations and cellular changes involved in the malignant switch in melanoma progression. To develop such a model, we subjected WM35 cells to retroviral insertional mutagenesis, which was followed by selection for progressive growth of solid tumors in nude mice. Highly aggressive and phenotypically stable tumorigenic variants were derived which contained at least four integrated proviruses. In contrast to the parental WM35 cells, these cell lines expressed several phenotypic features characteristic of naturally derived, advanced-stage malignant melanoma cells. Thus, in addition to tumor-forming ability in nude mice, the variants were growth factor and anchorage independent, overexpressed the MUC18 adhesion molecule, and lost responsiveness to the growth-inhibitory effect of several cytokines, including interleukin 6, transforming growth factor beta, interleukin 1beta, and tumor necrosis factor alpha. Tumorigenicity and "multicytokine resistance" were dominant traits since in somatic cell hybrids between the parental cells and a tumorigenic subline no suppressive effect of the former cell population was observed. These findings suggest that one or more dominantly acting genetic alterations might be involved in this progression of RGP melanoma cells. The identity of such alterations remains to be determined. PMID- 8674066 TI - Loss of DNA mismatch repair in acquired resistance to cisplatin. AB - Selection of cells for resistance to cisplatin, a well-recognized mutagen, could result in mutations in genes involved in DNA mismatch repair and thereby to resistance to DNA-alkylating agents. Parental cells of the human ovarian adenocarcinoma cell line 2008 expressed hMLH1 when analyzed with immunoblot. One subline selected for resistance to cisplatin (2008/A) expressed no hMLH1, whereas another (2008/C13*5.25) expressed parental levels. Microsatellite instability was readily demonstrated in 2008/A cells but not in 2008 and in 2008/C13*5.25 cells. In addition, the 2008/A cells were 2-fold resistant to methyl-nitro nitrosoguanidine and had a 65-fold elevated mutation rate at the HPRT locus as compared to 2008 cells, both of which are consistent with the loss of DNA mismatch repair in these cells. To determine whether the loss of DNA mismatch repair itself contributes to cisplatin resistance, studies were carried out in isogenic pairs of cell lines proficient or defective in this function. HCT116, a human colon cancer cell line deficient in hMLH1 function, was 2-fold resistant to cisplatin when compared to a subline complemented with chromosome 3 and expressing hMLH1. Similarly, the human endometrial cancer cell line HEC59, which expresses no hMSH2, was 2-fold resistant to cisplatin when compared to a subline complemented with chromosome 2 that expresses hMSH2. Therefore, the selection of cells for resistance to cisplatin can result in the loss of DNA mismatch repair, and loss of DNA mismatch repair in turn contributes to resistance to cisplatin. PMID- 8674067 TI - Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping. AB - A newly developed method of comparative genomic hybridization (CGH) employing quantitative statistical comparisons was applied to DNA from two different types of advanced prostate cancer tissue. Multiple CGH analyses were obtained for each chromosome in each tumor, and the results of point-by-point comparison of the mean tumor:normal color ratio to a control normal:normal color ratio in each of 1247 evenly distributed data channels constituting the entire human genome were interpreted as loss, gain, or no change in copy number in the tumor genome. Group I tissue was obtained from prostate cancer metastases from 20 patients, 19 of whom had received no prior prostate cancer treatment. This DNA also was analyzed by Southern and microsatellite allelotyping at 53 different loci on 20 different chromosome arms. CGH results agreed with allelotyping results at 92% of the informative loci studied. These samples, which contained highly enriched tumor DNA, showed the highest rates of alteration yet reported in several chromosomal regions known to be altered frequently in prostate cancer: 8q gain (85%), 8p loss (80%), 13q loss (75%), 16q loss (55%), 17p loss (50%), and 10q loss (50%). Group II tissue was obtained predominately from primary or recurrent tumor from 11 patients who had been treated with long-term androgen-deprivation therapy and developed androgen-independent metastatic disease. Quantitative CGH analysis on DNA from these tissues showed chromosomal alterations that were very similar to those found in group I, suggesting that untreated metastatic tumors contain the bulk of chromosomal alterations necessary for recurrence to occur during androgen deprivation. In the entire data set, a number of previously undetected regions of frequent loss or gain were identified, including losses of chromosomes 2q (42%), 5q (39%), 6q (39%), and 15q (39%) and gains of chromosomes 11p (52%), 1q (52%), 3q (52%), and 2p (45%). Chi-squared analysis showed a significantly higher frequency of gain of the 4q25-q28 region in tumors from African-American patients, indicating a possible oncogene whose activation may play a role in the higher rate of progression seen in this ethnic group. Additional study of these frequently altered regions may provide insight into the mechanism of prostate cancer progression and lead to important tools for tumor-specific prognosis and therapy. PMID- 8674068 TI - Involvement of integrin alphavbeta3 in cell adhesion, motility, and liver metastasis of murine RAW117 large cell lymphoma. AB - The molecules that mediate metastatic cell homing to specific organ sites remain largely unidentified. As a target organ for metastasis, the liver is a unique environment characterized by fenestrated sinusoidal endothelium, lack of a complete basement membrane, and production of serum components, including fibronectin and vitronectin. We examined a series of marine RAW117 large cell lymphoma variants selected in vivo for liver-colonizing properties (H10 >> L17 > P). Compared with L17 or P cells, the highly liver-colonizing H1O cells expressed much higher levels of surface integrin alphavbeta3, as shown by affinity chromatography, immunoprecipitation, and flow cytometry. H10 cells adhered at higher rates to vitronectin and fibronectin than to fibrinogen, fibrin, laminin, and type I collagen. Among the RGD peptides, H10 cells adhered at significantly higher rates to the polymeric RGD peptide (glycyl-arginyl-glycyl-aspartyl serine)4 than to monomeric RGD peptides. H10 cells were able to spread on immobilized vitronectin with highly polarized morphology but not on fibronectin. In contrast, the poorly liver-metastatic P and L17 cells did not adhere or spread well on vitronectin or fibronectin. H10 cells also migrated toward vitronectin concentration gradients. Blocking cell surface alphavbeta3 molecules with specific anti-beta3 monoclonal antibodies resulted in significant decreases in the adhesion of H10 cells to vitronectin and (glycyl-arginyl-glycyl-aspartyl serine)4 and significant inhibition of the formation of experimental liver metastases. These data suggest an important role of integrin alphavbeta3 in the metastasis of RAW117 cells to the liver. PMID- 8674069 TI - Identification of differentially expressed messenger RNAs in human melanocytes and melanoma cells. AB - The phenotype of malignant lesions is a reflection of genetic events altering the RNA and protein expression patterns of normal cells. We have investigated RNA expression patterns distinguishing normal melanocytes (FM 902), a primary melanoma cell line (WM 793), and its variant cell line (1205-LU), selected for metastatic phenotype in athymic mice. Using mRNA differential display, we identified 42 different cDNA PCR products with cell line-specific expression patterns. Direct sequence analysis matched approximately 50% of the cDNA PCR products with gene sequences accessible in DNA databases. Among the known genes, two functionally distinct groups were recognized: (a) genes encoding ribosomal and mitochondrial proteins that were predominantly up-regulated in the malignant cells; and (b) genes encoding modulators of the immune response. Among the immunomodulators, the T-cell antigen MART-1 and the protease inhibitor alpha2 macroglobulin were detected in the melanocyte cell line but not in the tumor cells. By contrast, mRNAs for the complement inhibitor CD59 and the cytokine IL 1beta were found to be overexpressed in the malignant melanoma cells. RNA slot blot hybridization on a larger panel of melanocyte and melanoma cell lines confirmed differential expression of 15 of 42 genes including MART-1, alpha2 macroglobulin, and CD59. This molecular screening approach identified also three partially characterized and three novel sequences with differential expression patterns in normal and malignant melanocytes. PMID- 8674070 TI - Expression of and response to interleukin 6 (IL6) in human mammary tumors. AB - Multifunctional cytokines play important and only partially defined roles in mammary tumor development and progression. Normal human mammary epithelia] cells (MECs) constitutively produce interleukin (IL) 6, IL8, and a nonsecreted form of tumor necrosis factor. MEC transformation by different oncogenes is frequently associated with alterations of cytokine/growth factor production and responsiveness. This seems particularly true in the case of IL6. Histochemical studies showed that expression of immunoreactive IL6, as compared to normal tissue and to in situ lesions, is significantly reduced in invasive ductal carcinoma. Conversely, the expression of IL6 in invasive lobular carcinoma was enhanced. Expression of TGF-beta1 in mammary neoplasia was in general less intense than that seen in the normal mammary gland. In vitro studies partially supported the in vivo findings: expression of IL6 and TGF-beta1 was significantly down-regulated in cultures derived from both ductal carcinoma and peritumoral tissue. Similarly, responsiveness to IL6 and TGF-beta1 was significantly reduced in neoplastic MECs. The data suggest that alterations of cytokine pathways are present not only in mammary neoplasia, but also in pathologically unaffected breast tissues. PMID- 8674071 TI - Plasminogen activator inhibitor 1 messenger RNA expression and molecular evidence for del(7)(q22) in uterine leiomyomas. AB - We analyzed the expression of plasminogen activator inhibitor 1 (PAI-1) in 16 leiomyomas and adjacent myometrium of women who underwent a hysterectomy while in the proliferative (n = 8) and secretory phases (n = 8) of the menstrual cycle. We localized the PAI-1 and its mRNA expression in smooth muscle and vessel endothelial cells of uterine tissues using immunocytochemistry and in situ hybridization. The expression of PAI-1 mRNA was higher in 11 (68.75%) of 16 leiomyomas compared with the adjacent myometrium (leiomyoma/myometrium ratio, 1.4 3.0; mean, 2.045). The leiomyoma:myometrium ratio of PAI-1 mRNA expression did not change during the proliferative (Phase I) and secretory (Phase II) phases of the menstrual cycle. In the remaining five samples, the leiomyoma:myometrium ratio of PAI-1 mRNA expression was close to 1 (0.8-1.2; mean, 0.92). Because the locus of the PAI-1 gene is on chromosome 7q22, we screened for loss of heterozygosity (LOH) in these samples using the PAI-1 marker and D7S471, an anonymous marker 12 cM telomeric to PAI-1. Four of five samples with low leiomyoma:myometrium ratio had LOH for the PAI-1 and/or D7S471 markers. The fifth sample demonstrated a noninformative analysis for these markers but had LOH for the D7S515, D7S666, and D7S518 markers, all centromeric to PAI-1. Because del(7)(q22), associated with a relatively low PAI-1 mRNA expression, can deregulate matrix proteinases and growth factors' activity in leiomyomas, it is conceivable that del(7)(q22) results in heterogeneous leiomyoma biology. PMID- 8674072 TI - Mutant p53-induced immortalization of primary human mammary epithelial cells. AB - Mutations of the p53 gene are the most frequent genetic lesions in breast cancer, suggesting a critical role for p53 protein in normal mammary cell growth control. Indeed, the p53-targeting human papillomavirus oncogene E6 induces efficient immortalization of normal human mammary epithelial cells (MECs). To assess whether selective loss of p53 is sufficient for MEC immortalization, we introduced seven missense mutants and one single-amino acid deletion mutant (del239) of p53 into the 76N normal MEC strain. Although the missense mutants failed to immortalize MECs, the del239 mutant reproducibly immortalized these cells. The immortal cells were anchorage dependent and nontumorigenic, indicating a preneoplastic transformation. Gamma-irradiation of these cells failed to induce G1 cell cycle arrest and did not lead to an increase in WAF1 and mdm-2 mRNA levels, demonstrating a loss of the endogenous p53 function. These results demonstrate that selective ablation of p53 function by a dominant-negative mutant is sufficient for immortalization of MECs. Availability of an immortalizing as well as several nonimmortalizing p53 mutants should help identify functions critical for cell growth control by p53 in mammary epithelial cells. PMID- 8674073 TI - Hyaluronate-independent metastatic behavior of CD44 variant-expressing pancreatic carcinoma cells. AB - Several studies have demonstrated a correlation between the expression of CD44 variant isoforms and the ability of tumor cells to metastasize. The CD44 proteins carry amino acid sequence motifs that confer the ability to bind to the extracellular matrix component hyaluronate (HA). In this study, we investigated whether a CD44 variant previously shown to stimulate metastasis in a rat pancreatic carcinoma model (BSp73AS) is capable of binding to HA, and whether such binding is critical for metastasis. We show that transfection of this CD44 variant into BSp73AS cells increases the HA-binding capacity of the cells in a dose-dependent manner. Transfection of the same CD44 variant isoform into BDX2 cells also conferred strong HA-binding properties on these cells, but was insufficient to cause them to metastasize. Transfection of a surface-bound hyaluronidase into metastasizing BSp73AS cells bearing variant CD44 efficiently ablated the ability of these cells to bind to HA. However, in metastasis assays, these hyaluronidase-transfected cells showed patterns of metastasis similar to those of the parental cell line. We also show that the HA-binding capacity of a variety of tumor cells is not correlated with their metastatic proclivity, and that an antibody previously shown to block metastasis of the pancreatic carcinoma cells does not interfere with their ability to bind to HA. We conclude that although CD44 variant expression does promote metastasis formation, HA binding by tumor cells is not rate limiting for metastasis in the BSp73AS system and probably also in other metastasizing tumors. Furthermore, for metastasis by CD44 variant-expressing BSp73AS cells to occur, contact of the CD44 variant protein with a ligand other than HA Is required. PMID- 8674074 TI - Integrin VLA-2 (alpha2beta1) function in postextravasation movement of human rhabdomyosarcoma RD cells in the liver. AB - It is now known that members of the selectin and integrin families are critical in the initial interaction of cells in circulation with endothelial surfaces. Also, platelet/endothelial cell adhesion molecule-1 has been shown to be involved in transendothelial migration of extravasating cells. Little is known about adhesion molecules involved in subsequent postextravasation events. In this study, the significance of VLA-2 (alpha2beta1) integrin in the movement of human rhabdomyosarcoma RD cells in the liver was characterized by in vivo videomicroscopy. Results show that after extravasation, the mock-transfected RDpF cells were able to migrate to the subcapsular region of the liver. Although the RDX2C2 transfectant expressing VLA-2 integrin extravasated equally well, a majority of RDX2C2 cells remained in close proximity to blood vessels and failed to reach the subcapsular region. The functional involvement of VLA-2 in affecting the ability of RD cells to reach the subcapsular region was verified by the preparation of an RD transfectant [RDX2C2(I-)] expressing a nonfunctional variant of VLA-2 lacking the inserted (I)-domain of alpha2 subunit. In vivo microscopy showed that RDX2C2(I-) cells migrated in a manner similar to control RDpF cells. To demonstrate that RDX2C2 cells that remained in dose proximity to blood vessels were due to VLA-2 function, a blocking monoclonal antibody against VLA-2 (BHA2.1) was prepared. Mice were injected with BHA2.1 or control monoclonal antibody P3 at the time when RDX2C2 cells completed their extravasation. Treatment with BHA2.1 increased the number of RDX2C2 cells that reached the subcapsular region and subsequently formed tumor foci. Therefore, VLA-2 integrin expression has major roles in postextravasation movement and affects tumor foci formation at the liver surface. PMID- 8674075 TI - Safety and effectiveness of an acellular pertussis vaccine in subjects with Down's syndrome. AB - We evaluated the reactogenicity and immunogenicity of an acellular pertussis vaccine in 24 subjects affected by Down's syndrome and in 10 normal infants. Neither general nor local adverse reactions were observed in either group of subjects. The new acellular vaccine administration elicited protective levels of antibodies in all the subjects with Down's syndrome, although the geometric mean titres of IgG antibodies against Bordetella pertussis in these subjects were significantly lower than in normal controls. PMID- 8674076 TI - Pineal ganglioglioma with premature thelarche. Report of a case and review of the literature. AB - We report a case of a 6-year-old girl with a ganglioglioma in the pineal region presenting with a rare clinical picture of premature thelarche. Intracranial gangliogliomas are rare, especially in the pineal region. Their character, origin, treatment, and prognosis remain controversial. The pathophysiology of precocious puberty associated with pineal ganglioglioma is discussed. PMID- 8674077 TI - Rapidly growing calcified cerebellar astrocytoma in infants. AB - We report the case of an infant with a cerebellar astrocytoma that showed marked calcification within only 6 months. In general, only slow-growing tumors tend to calcify. To our knowledge, no other case of such rapid calcification in cerebellar astrocytoma has been reported. PMID- 8674079 TI - Cervical kyphotic myelopathy in a child with Morquio syndrome. AB - A child with Morquio syndrome developed severe cervical kyphosis causing myelopathy. Decompression of the spinal cord was accomplished by an anterior approach using multilevel corpectomies and stabilization with calvarial bone grafts and halo immobilization. The case reported is unique in that cervical cord compression resulted from an uncommon degree of cervical kyphosis rather than the usual atlantoaxial instability seen in patients with Morquio syndrome. The operative procedure described shows another example of the usefulness of calvarial bone grafts for cervical spine fusions in children. PMID- 8674078 TI - Central nervous system dysmyelination in PIBI(D)S syndrome: a further case. AB - This is a report of new case of PIBI(D)S, a rare autosomal recessive syndrome characterized by photosensitivity, ichthyosis, brittle sulfur-deficient hair (trichothiodystrophy), impaired intelligence, decreased fertility, and short stature. Bilateral cataract and axial osteosclerosis were also detected. Magnetic resonance imaging (MRI) revealed diffuse central nervous system dysmyelination, a finding also described in the only three other reported cases in which MRI was performed. The paper also considers certain similarities in neurological signs and neuroradiological findings between PIBI(D)S, Cockayne syndrome, and xeroderma pigmentosum--all of which are inherited diseases characterized by photosensitivity and DNA repair defect. PMID- 8674080 TI - Craniocerebral birth trauma caused by vacuum extraction: a case of growing skull fracture as a perinatal complication. AB - A case of growing skull fracture following birth trauma and caused by vacuum extraction is reported in order to emphasize the incidence of this peculiar head injury at the beginning of extrauterine life and to point out its relation to possible neuropsychological disturbances that may appear later in childhood. Delivery by vacuum extraction increases the incidence of perinatal injuries and consequently the incidence of neurological deficits in children. Neurosurgical repair is advocated as the appropriate treatment, with the aim not only of cosmetically correcting the lesion's typical subgaleal protuberance with cranioplasty, but also of performing a water-tight closure of the dura, enabling the cerebral cortex to "fill in" the intracerebral lesion. The surgical technique and gross pathology of the lesion are described together with radiological findings before and after surgery. Reports by other authors are reviewed in an attempt to identify the conditioning factors and pathological features of this traumatic injury to skull and brain in neonates and infants. The literature on cranial fractures associated with intracerebral lesions at this age shows a significant difference in recovery and outcome from that after similar lesions in older children. PMID- 8674081 TI - Neonatal diagnosis of tuberous sclerosis. AB - Intracranial tumors are rare in the neonatal period, and generally the most common histological types are astrocytoma, medulloblastoma, choroid plexus papilloma and neuroectodermal tumors. The early diagnosis of these tumors is often very difficult. The authors report a case of a full-term newborn who presented with opisthotonus. A subependymal mass was detected by cerebral ultrasonography, and when the child was 1 month of age depigmentations appeared on the trunk and on the right leg, confirming the suspicion of tuberous sclerosis. At 3 months of age the child suffered infantile spasm with hypsarrhythmia. The developmental delay, the marked progressive neurological deterioration and the daily seizures suggested surgical resection. Histologic studies showed a subependymal giant cell astrocytoma such as typically occurs in tuberous sclerosis. PMID- 8674082 TI - The future perspectives of pediatric neurosurgery. AB - Pediatric neurosurgery as a subspecialty dealing primarily with such congenital and perinatal pathology as the dysraphic state, and various clinical entities having in common ventriculomegaly, is fast disappearing from the scene of neurosurgery in the industrialized world. Pari passu with this, one observes ever closer collaborative work between pediatric neurosurgeons and specialists in other pediatric disciplines such as oncology, radiology, orthopedics, and maxillofacial surgery: truly multidisciplinary activities. In addition, paramedical and specialized nursing personnel are participating actively, even in the decision-making and treatment-delivery aspects of pediatric neurosurgical care. The pediatric neurosurgeon is no longer the sole decision-maker, nor the automatic captain of the ship. Very probably, as in the whole history of human activities, new instrumentation will change somewhat what we do and with whom we collaborate. However, for the immediate future the major changes most probably will be expressions of socioeconomic readjustments, of ethical redefinitions, and of the to-and-fro movement into and out of pediatric neurosurgery by both neurosurgeons and ancillary medical personnel. PMID- 8674083 TI - Late MR follow-up of hypothalamic hamartomas. AB - The absence of changes over time in the diagnostic features of suspected hypothalamic hamartomas is of paramount importance. Since magnetic resonance (MR) imaging is very sensitive to modifications in the brain parenchyma, a late MR follow-up study was performed in five children. In all cases, the diagnosis of hypothalamic hamartoma has been suspected on the basis of the association of central precocious puberty and the presence of a mass in the inferior aspect of the hypothalamus, demonstrated on previous MR studies. Late MR evaluation (after a mean of 39 months) demonstrated stability of the lesions in shape, size, and signal intensity. In three cases the lesions demonstrated a rim of isointense signal with a hyperintense center on T2-weighted sequences. In two cases a Chiari I malformation was found in association with the hypothalamic malformation. In one case a pineal cyst was demonstrated. These unusual findings are discussed. Late MR follow-up showed the absence of changes in the lesions over time, allowing the diagnosis to be confirmed. PMID- 8674084 TI - The effectiveness of O2 administration for transient ischemic attacks in moyamoya disease in children. AB - Moyamoya disease is a cerebrovascular obstructive disease of unknown etiology. The rebuild-up phenomenon, slowing of waves on electroencephalogram (EEG) seen after cessation of hyperventilation (HV), is one of the characteristic phenomena of the disease and is thought to be related to a development of its symptoms. Therefore, we investigated the mechanism involved in the rebuild-up phenomenon to clarify the mechanism of development of transient ischemic attack (TIA) in moyamoya disease. Ten patients with moyamoya disease were studied; they ranged in age from 7 to 17 years. The power spectra of the EEGs in the occipital region were obtained with a Berg Fourier EEG analyzer for quantitative analysis. Arterial blood gas change (pH, PaO2, PaCO2), respiratory pattern (abdominal and nasal), tidal volume and respiratory rate were analyzed simultaneously every 30 s 1 min before, during, and after HV. The slow wave power spectrum (rebuild-up) increased and symptoms of TIA developed as a result of the sharp decrease in PaO2 (PaO2 60.5 +/- 15.4 mmHg) after cessation of HV. Based on the fact that hypoxemia was playing a main role, 100% oxygen was administered at a rate of 0.5 l/min in 4 cases where the rebuild-up phenomenon was clear. The EEG power spectra and arterial blood gas were analyzed during rebuild-up with and without O2 administration. The effectiveness of O2 administration at the beginning of rebuild-up as measure to prevent the symptoms was checked by a recovery rate of slow wave power percentage, a recovery time of slow wave power percent and by clinical observation. The recovery rates were 11.8 +/- 4.2%/min and 5.5 +/- 4.0%/min with and without O2 inhalation, respectively (P < 0.001). Recovery times of slow wave power percentage were 4.3 +/- 1.8 min and 8.1 +/- 1.2 min with and without O2 inhalation, respectively (P < 0.01). Thus, oxygen administration soon after the cessation of HV was shown to be effective in eliminating the rebuild-up phenomenon and hence in abolishing its symptoms. PMID- 8674085 TI - p53 expression in four human medulloblastoma-derived cell lines. AB - p53 is a tumor suppressor gene found on the short arm of chromosome 17. Loss of one p53 allele and alteration of the other is found in a variety of tumors, including highgrade glial tumors. Point mutations in the remaining allele occur in a highly conserved region of the gene encompassing exons 5-8. Although 40-50% of medulloblastomas lose sequences on the short arm of chromosome 17, alteration of p53 in these tumors is infrequent. To further characterize genetic alteration of p53 in medulloblastoma, we performed a mutational analysis of four medulloblastoma-derived cell lines established by our laboratory. Using two variable-number tandem repeat markers which map distally to p53, we found evidence indicating loss of sequences on the distal end of chromosome 17p in all four lines. However, no gross alterations of the p53 gene were detected. Northern analysis revealed expression of equivalent amounts of full-length p53 messenger RNA in each cell line. Using the polymerase chain reaction to amplify exons 5-8 of the p53 gene, we directly sequenced the amplified fragments and detected no mutations in any of the cell lines. Our results demonstrate that loss of p53 function through gene deletion and/or recessive mutation is not required for growth in our cell lines. PMID- 8674086 TI - Preoperative and postoperative analysis of visual and auditory memory in children with cerebellar tumors. AB - Motivated by the extensive clinical and experimental evidence that links the cerebellum to cognitive processes, we analyzed the auditory and visual memory of nine children with cerebellar tumors. Five patients had midline lesions and four had cerebellar hemispheric tumors. The patients were tested before and after surgery. One of the patients was also tested at 4 and 24 months after surgery. A third group constituted by four children, siblings of some of the patients, served as control. Statistically significant differences (P < 0.05) were found in the test of auditory memory, in which children with cerebellar tumors made a higher number of errors than their normal counterparts. Surgery performed according standard techniques did not increase significantly the number of errors in any of the tested categories. Location of the tumor (hemispheric vs midline) was not a determinant of the performance of the children. The patient tested up to 2 years after surgery demonstrated a progressive improvement in the performance of visual and auditory memory tasks. Our results provide further evidence that the cerebellum plays a role in the integration of auditory stimuli. PMID- 8674087 TI - CNS-85 trial: a cooperative pediatric CNS tumor study--results of treatment of medulloblastoma patients. AB - Between 1985 and 1989, 38 children with newly diagnosed medulloblastoma entered our therapeutic protocol. After surgery and postoperative staging assessments, patients were assigned to risk groups. Eleven with "standard-risk" (SR) tumors were treated with radiation therapy alone, while 27 with "high-risk" (HR) tumors received radiation therapy plus adjuvant chemotherapy with vincristine, methotrexate, VM-26, and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). After a minimum follow-up of 5 years (range 5-9 years) 21/38 children had developed a recurrence or progression of their disease and 19/38 patients had died. Five-year event-free survival rates and 5-year total survival rates for all 38 patients were 47.4% and 50% respectively. The event-free survival rates at 5 years for SR and HR patients separately were 27.3% and 55.6%, respectively. The corresponding 5-year total survival rates were 27.3% and 59.3%. The differences were not statistically significant. Univariate analysis showed age at diagnosis to be the most important prognostic factor. Infants aged 5 years or less had a significantly shorter event-free survival time than older patients (P = 0.00897). Similar effects were found when total survival time was considered. There were significant differences in outcome in patients receiving different doses of radiation, suggesting a dose-response relationship. A Cox stepwise multivariate analysis showed age at diagnosis as the only independent prognostic factor. Variables relating to treatment entered the model, suggesting that chemotherapy could play an important role in determining outcome. PMID- 8674088 TI - Concentration of malonic dialdehyde in the cerebrospinal fluid as a measure of the intensity of lipid peroxidation processes in intracranial hypertension in small children. AB - The authors analyzed the concentration of malonic dialdehyde (MDA) in the cerebrospinal fluid (CSF) of children with intracranial hypertension. For the control group an intracranial pressure (ICP) of 250 mm H2O was taken as a reference point. The concentration of MDA was determined by a method using thiobarbituric acid. In a group of children with ICP values greater than the limiting value, the concentration of malonic dialdehyde was 0.629 mmol/mg protein, while in the control group with an ICP below 250 mm H2O, this value was 0.610 mmol/mg protein. The differences between the two groups were not statistically significant. from the results obtained it can be concluded that the concentration of MDA, as an isolated parameter, does not constitute a good measure of intensity of the lipid peroxidation processes in central nervous system (CNS) tissues, taken as an indicator of their disintegration in cases of hydrocephalus with intracranial hypertension. PMID- 8674089 TI - [Neutrophilic leukocytes, thrombotic risk factors in vascular diseases]. PMID- 8674090 TI - Timing of adult cardiac transplantation. PMID- 8674091 TI - Interatrial, internodal, and dual reentrant atrioventricular nodal pathways: an anatomical update of arrhythmogenic substrates. PMID- 8674092 TI - [Facilitating effect of propafenone pretreatment in the interruption of atrial flutter by transesophageal pacing]. AB - Transesophageal atrial pacing is effective in the interruption of atrial flutter, and being simple and minimally invasive, is easily performed even on outpatients. The influence of antiarrhythmic drugs on this procedure is controversial. We investigated whether the administration of oral propafenone may facilitate the procedure. Thirty patients with type I atrial flutter were randomized into two groups in which transesophageal pacing was attempted, respectively, without treatment (Group A) and after oral administration of propafenone 600 mg (Group B). Transesophageal pacing was effective in interrupting atrial flutter in 53% (8/15) of patients in Group A and in 85% (13/15) of patients in Group B. A significant lengthening of the flutter cycle was observed in patients treated with propafenone (261 +/- 23 vs 217 +/- 25 ms, p < 0.01). Sinus rhythm resumed at a shorter paced cycle in patients of Group A (166 +/- 13 vs 187 +/- 14 ms, p < 0.01). The transesophageal threshold for stable atrial capture was significantly lower in Group A (20.5 +/- 0.2 vs 23.3 +/- 1.2 mA, p < 0.01). In no patient the threshold for atrial capture was higher than the pain threshold. We did not observe abrupt enhancement of atrioventricular conduction. We can conclude that propafenone is effective and safe when used with transesophageal pacing in the termination of atrial flutter. The depressing effect of the drug on intraatrial conduction and the possible stabilizing effect on the reentry circuit appear to be outweighed by the positive effect of propafenone on the excitable gap of the circuit, facilitating its capture and account for the beneficial effect of the drug on arrhythmia termination. PMID- 8674093 TI - [Effect of platelets and leukocytes on in vitro proliferation of muscle cells: role of platelet-derived chemical mediators]. AB - Some evidence indicate that platelets (PLTs) and leukocytes might contribute to the development of neointimal hyperplasia following arterial injury, via release of several growth factors. To study the relative contribution of these cells and of growth factors released in consequence of activation, smooth muscle cells (SMCs), isolated from the aorta of New Zealand White rabbits, were grown in Dulbecco's medium containing 10% fetal calf serum (FCS). At 70% confluence, SMCs were made quiescent by removing FCS from the medium. Twenty-four hours later, the cells were stimulated with activated platelets, neutrophils, lymphocytes+monocytes, whole leukocytes and platelets + whole leukocytes. Then, 1 microCi of O3H-thymidine were added to SMC cultures to evaluate the degree of proliferation. Relative contribution of different PLT-derived mediators to SMC growth was evaluated by adding either ketanserin, a 5-HT2 receptor antagonist, ridogrel, a thromboxane A2 (TxA2) receptor antagonist, BN52021, a platelet activating factor (PAF) receptor antagonist, and trapidil, a platelet-derived growth factor (PDGF) receptor antagonist, or all antagonists together. SMC proliferation was significantly increased by platelet activation. This effect was reduced by adding either ketanserin, ridogrel, BN 52021 or trapidil. Neutrophils, lymphocytes + monocytes and whole leukocytes also increased SMC proliferation. Simultaneous stimulation of SMCs by platelets and whole leukocytes was associated with a significant increase in SMC proliferation as compared to platelets or leukocytes alone. Thus, TxA2, 5-HT, PAF, and PDGF all contribute to SMC proliferation in vitro. Adding all antagonist together resulted in an additive antiproliferative effect. Leukocytes are also important in SMC proliferation. Interaction between platelets and leukocytes may play a pivotal role in the modulation of this phenomenon. PMID- 8674094 TI - [Prevention of coronary disease in clinical practice. Recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension]. PMID- 8674095 TI - [From "Braunwald" to cardiologic practice]. PMID- 8674096 TI - [Ejection fraction]. PMID- 8674098 TI - [Coronary angioplasty or drug therapy. Reading "between the lines" of major trials]. PMID- 8674097 TI - [Management of patients with sustained ventricular arrhythmia: anti-arrhythmia agents or defibrillator?]. PMID- 8674099 TI - Sympathetic nervous system as a coronary risk factor in hypertension. PMID- 8674100 TI - [Endothelial function and coronary microcirculation in arterial hypertension]. PMID- 8674101 TI - [Coronary arteriography: much more than a simple morphologic test]. PMID- 8674102 TI - [Introduction to ischemic preconditioning of the heart]. PMID- 8674103 TI - [Activation and role of the tumor necrosis factor-alpha in congestive heart failure]. AB - Recently, an activation of the immune system has been demonstrated in congestive heart failure (CHF). Aim of this study was to evaluate the effects of CHF on the activation of alpha tumor necrosis factor (TNF-alpha), a pleiotropic cytokine. Since the soluble forms of the TNF membrane receptors, sTNF-RI and sTNF-RII, have been shown to modulate TNF-alpha biological activity, we determined antigenic TNF alpha, bioactive TNF-alpha, sTNF-RI and sTNF-RII in 52 patients with varying degrees of CHF (NYHA functional class II, III, IV). The etiology of CHF was coronary artery disease in 51% of the patients, idiopathic dilated cardiomyopathy in 38% and valvular disease in 11%. All patients were treated with ACE inhibitors, digoxin and inotropic agents. Antigenic TNF-alpha was significantly increased in NYHA functional class IV patients (from 12.1 +/- 7.6 to 38.5 +/- 12.4 pg/ml, p < 0.001) whereas cytotoxic activity was always under the detection limit of the assay (100 pg/ml). Soluble TNF receptors were significantly elevated in NYHA functional class IV patients: sTNF-RI increased from 1.27 +/- 0.48 to 4.54 +/- 2.11 ng/ml (p < 0.001) and sTNF-RII from 2.25 +/- 0.55 to 7.78 +/- 2.13 ng/ml (p < 0.001). The possible modulation of TNF-alpha biological activity by the soluble receptors was investigated by means of spiking experiments after addition of 625 pg/ml human recombinant TNF-alpha to each serum sample. The biological activity of the added TNF-alpha was significantly inhibited by the high levels of soluble receptors present in the sera of NYHA functional class IV patients (from 625 to 249 +/- 176 pg/ml, p < 0.001). The results show that TNF alpha and its soluble receptors are activated in severe CHF. The high concentration of soluble TNF receptors circulating in CHF patients are likely to play a protective role against TNF-alpha biological activity. PMID- 8674104 TI - [Hemodynamics and clinical data in chronic coronary disease with severe left ventricular systolic dysfunction]. AB - To elucidate how symptoms and signs of chronic heart failure are related to the filling pressure and cardiac output at rest, 58 patients (55 males, 3 females, mean age 57 +/- 9 years, range 30-75) with left ventricular ejection fraction (LVEF) < or = 30% and a lesion > or = 50% on a major coronary branch have been selected from patients submitted in 1985-1993 to a complete right and left cardiac catheterization including ventriculography and coronary angiography. Patients with recent myocardial infarction (MI), unstable angina, associated heart diseases or recent changes in body weight and in diuretic therapy were excluded. Clinical data were obtained at cardiac catheterization time from history, physical examination, chest X-ray and ECG. Patients with angina as limiting symptom were excluded from NYHA functional classification. Pulmonary venous congestion (PVC) was defined on X-ray as: absent, venous redistribution, interstitial pulmonary edema (IPE). Mean pulmonary capillary wedge pressure (PCWP) was recorded under fluoroscopy and cardiac index was measured by the Fick method. On the whole group, 96% of patients had had one or more MI (on ECG necrosis was anterior in 58%, inferior in 9%, anterior and inferior in 26%), 69% were in NYHA functional class III or IV, 54% had IPE and 45% had mitral regurgitation. 71% were under treatment with digitalis, 74% with diuretics and 39% with ACE-inhibitors. PCWP was correlated with LVEDV (r = 0.34; p < 0.001) but neither with LV mass nor with LV mass/volume ratio. It was significantly higher (p < 0.01) in patients with mild-moderate mitral regurgitation, in patients with necrosis involving both anterior and inferior walls (26 +/- 6 vs 21 +/- 8 mmHg in patients with single wall necrosis, p < 0.05) and in patients with multiple MI (26 +/- 7 vs 20 +/- 8 mmHg in patients with no or single MI, p < 0.02). Moreover, it was neither correlated with functional classification nor with PVC: of patients with PCWP > 24 mmHg, 14% were in II NYHA functional class and 21% had no PVC while of patients with PCWP < 15 mmHg, 36% were in NYHA functional class IV and 7% had IPE. Cardiac index was reduced below 2.3 l/min/m2 in 21% of patients: these patients had increased pulmonary (p < 0.0002) and systemic (p < 0.0001) vascular resistance, increased systolic (p < 0.001) and diastolic (p < 0.01) pulmonary artery pressure and reduced LVEF (p < 0.01) and right ventricular ejection fraction (p < 0.03). Furthermore, on the whole patients an inverse correlation was found between cardiac index and functional classification (r = 0.42; p < 0.01). The reliability of NYHA functional class IV, physical signs of heart failure and IPE for estimating PCWP > 24 mmHg and cardiac index < 2.3 l/min/m2 was rather limited although high specificity was shown for gallop sounds (92 and 97%) and jugular vein distension (88 and 97%). In conclusion, in coronary patients with chronic severe LV systolic dysfunction a mismatch between clinical data and central hemodynamics is not rare. The reliability of functional class, X ray PVC and physical signs to predict central hemodynamics in fairly limited. PMID- 8674105 TI - [Mitral valve bioprosthesis from bovine pericardium. Color Doppler echographic study and long-term follow up]. AB - Pericardial heart valve bioprostheses have been utilized for 20 years. In spite of encouraging initial results, long-term follow-up showed a higher incidence of structural failures and primary tissue failures than porcine bioprostheses. Pericarbon represents the newest generation of bovine pericardial bioprostheses. Aim of this study is the long-term evaluation with echocardiographic and color Doppler technique of an innovative bioprostheses, in particular, its morfological and functional characteristics. From 1985 to 1989, 78 consecutive patients (21 males, 57 females, mean age 56.5 +/- 8.16 years) underwent mitral valve replacement with Pericarbon 29, by the same operator, who preserved the mitral posterior leaflet. One month after operation, 21 of these patients underwent echo color Doppler evaluation, in normalized hemodynamic conditions (normality ranges). In 1995, at the end of the followup, 30 of the remaining 54 patients underwent new echo-color Doppler evaluation and these data were compared with normality ranges values. Leaflets' thickness increased from 0.98 +/- 0.09 to 2.87 +/- 0.73 mm (anterior leaflet; p < 0.0001) and from 1.02 +/- 0.08 to 2.71 +/- 0.45 mm (posterior leaflet; p < 0.0001) 43.3% of anterior leaflet and 53.3% of posterior leaflet showed fibrocalcic lesions. Mean transvalvular gradient increased from 3.4 +/- 0.2 to 6.6 +/- 3.4 mmHg (p < 0.0001); also functional area decreased (p < 0.0001). We have found no paraprosthetic regurgitation and a very low number of central prosthetic regurgitation. Left ventricular function, evaluated by ejection fraction and regional kinesis, remained substantially preserved. PMID- 8674106 TI - [Transcatheter radiofrequency bundle branch ablation in bundle branch reentry ventricular tachycardia: report of a case]. AB - Two patients with branch to branch ventricular tachycardia (BBVT) are reported: successful radiofrequency catheter ablation of BBVT was performed in both, delivering energy distally to the point where the maximum amplitude of His deflection occurred, so that a wide ventricular deflection was obtained without any atrial electrogram. No significant conduction delay appeared but a right bundle branch block. HV intervals during BBVT resulted equal or longer than in sinus rhythm: whether this was secondary to anatomical or functional variations or to the possibility that the His bundle may be "bystander" in BBVT, is discussed. PMID- 8674107 TI - [Valve homograft in the reconstruction of left ventricular outflow in adults]. PMID- 8674108 TI - The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. AB - Mutations of the BRCA1 gone in humans are associated with predisposition to breast and ovarian cancers. We show here that Brca1+/- mice are normal and fertile and lack tumors by age eleven months. Homozygous Brca1(5-6) mutant mice die before day 7.5 of embryogenesis. Mutant embryos are poorly developed, with no evidence of mesoderm formation. The extraembryonic region is abnormal, but aggregation with wild-type tetraploid embryos does not rescue the lethality. In vivo, mutant embryos do not exhibit increased apoptosis but show reduced cell proliferation accompanied by decreased expression of cyclin E and mdm-2, a regulator of p53 activity. The expression of cyclin-dependent kinase inhibitor p21 is dramatically increased in the mutant embryos. Buttressing these in vivo observations is the fact that mutant blastocyst growth is grossly impaired in vitro. Thus, the death of Brca1(5-6) mutant embryos prior to gastrulation may be due to a failure of the proliferative burst required for the development of the different germ layers. PMID- 8674109 TI - Gene transpositions in the HoxD complex reveal a hierarchy of regulatory controls. AB - Vertebrate Hox genes are activated following a temporal sequence that reflects their linear order in the clusters. We introduced two Hoxd transcription units, labeled with lacZ, to an ectopic 5' position in the HoxD complex. Early expression of the relocated genes was delayed and resembled that of the neighboring Hoxd-13. At later stages, locus-dependent expression in distal limbs and the genital eminence was observed, indicating that common regulatory mechanisms are used for several genes. These experiments also illustrated that neighboring genes can share the same cis-acting sequence and that moving genes around in the complex induces novel regulatory interferences. These results suggest that high order regulation controls the activation of Hox genes and highlight three important constraints responsible for the conservation of Hox gene clustering. PMID- 8674110 TI - Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment. AB - Sterol regulatory element binding proteins (SREBPs) are transcription factors attached to the endoplasmic reticulum. The NH2-segment, which activates transcription, is connected to membranes by a hairpin anchor formed by two transmembrane sequences and a short lumenal loop. Using H-Ras-SREBP-2 fusion proteins, we show that the NH2-segment is released from membranes by two sequential cleavages. The first, regulated by sterols, occurs in the lumenal loop. The second, not regulated by sterols, occurs within the first transmembrane domain. The liberated NH2-segment enters the nucleus and activates genes controlling cholesterol synthesis and uptake. Certain mutant Chinese hamster ovary cells are auxotrophic for cholesterol because they fail to carry out the second cleavage; the NH2-segment remains membrane-bound and transcription is not activated. PMID- 8674111 TI - Tertiary structure of destrin and structural similarity between two actin regulating protein families. AB - Destrin is an isoprotein of cofilin that regulates actin cytoskeleton in various eukaryotes. We determined the tertiary structure of destrin by triple-resonance multidimensional nuclear magnetic resonance. In spite of there being no significant amino acid sequence homology, we found that the folding of destrin was strikingly similar to that of repeated segments in the gelsolin family, which resulted in a new protein fold group. Sequential dissimilarity of the actin binding helix of destrin to that of gelsolin explains the Ca2+-independent actin binding of destrin. Possible mechanisms of phosphorylation-sensitive phosphoinositide-competitive actin binding, of pH-dependent filament severing, and of nuclear translocation with actin in response to stresses, are discussed on the basis of the tertiary structure. PMID- 8674112 TI - Hydration and DNA recognition by homeodomains. AB - A 2-nanosecond molecular dynamics (MD) simulation of an Antennapedia homeodomain DNA complex in explicit solvent water at ambient temperature and pressure was performed to supplement experimental nuclear magnetic resonance (NMR) data on the structure and dynamics of this complex. In addition to direct protein-DNA contacts, the MD trajectory attributes an essential role for specific DNA recognition to hydration water molecules that mediate intermolecular contacts. The simulation provides a detailed description of the pathways of hydration water molecules exchanging in and out of the protein-DNA interface and indicates that the residence times of these "interior" waters are on the nanosecond time scale, near the lower end of the range determined by NMR. PMID- 8674113 TI - Crystal structures of a complexed and peptide-free membrane protein-binding domain: molecular basis of peptide recognition by PDZ. AB - Modular PDZ domains, found in many cell junction-associated proteins, mediate the clustering of membrane ion channels by binding to their C-terminus. The X-ray crystallographic structures of the third PDZ domain from the synaptic protein PSD 95 in complex with and in the absence of its peptide ligand have been determined at 1.8 angstroms and 2.3 angstroms resolution, respectively. The structures reveal that a four-residue C-terminal stretch (X-Thr/Ser-X-Val-COO(-)) engages the PDZ domain through antiparallel main chain interactions with a beta sheet of the domain. Recognition of the terminal carboxylate group of the peptide is conferred by a cradle of main chain amides provided by a Gly-Leu-Gly-Phe loop as well as by an arginine side chain. Specific side chain interactions and a prominent hydrophobic pocket explain the selective recognition of the C-terminal consensus sequence. PMID- 8674114 TI - Site-specific ribose methylation of preribosomal RNA: a novel function for small nucleolar RNAs. AB - Eukaryotic cells contain many fibrillarin-associated small nucleolar RNAs (snoRNAs) that possess long complementarities to mature rRNAs. Characterization of 21 novel antisense snoRNAs from human cells followed by genetic depletion and reconstitution studies on yeast U24 snoRNA provides evidence that this class of snoRNAs is required for site-specific 2'-O-methylation of preribosomal RNA (pre rRNA). Antisense sno-RNAs function through direct base-pairing interactions with pre-rRNA. The antisense element, together with the D or D' box of the snoRNA, provide the information necessary to select the target nucleotide for the methyltransfer reaction. The conclusion that sno-RNAs function in covalent modification of the sugar moieties of ribonucleotides demonstrates that eukaryotic small nuclear RNAs have a more versatile cellular function than earlier anticipated. PMID- 8674115 TI - p53 Protein exhibits 3'-to-5' exonuclease activity. AB - Highly purified p53 protein from different sources was able to degrade DNA with a 3'-to-5' polarity, yielding deoxynucleoside monophosphates as reaction products. This exonuclease activity was dependent on Mg2+ and inhibited by addition of 5 mM nucleoside monophosphates. This exonuclease activity is intrinsic to the wild type p53 protein: it copurified with p53 during p53 preparation; only purified wild-type p53, but not identically purified mutant p53 proteins displayed exonuclease activity; the exonuclease activity could be reconstituted from SDS gel-purified and urea-renatured p53 protein and mapped to the core domain of the p53 molecule; and finally, purified p53 protein could be UV-cross-linked to GMP. A p53-intrinsic exonuclease activity should substantially extend our view on the role of p53 as a "guardian of the genome." PMID- 8674116 TI - Structure of bacteriophage T4 RNase H, a 5' to 3' RNA-DNA and DNA-DNA exonuclease with sequence similarity to the RAD2 family of eukaryotic proteins. AB - Bacteriophage T4 RNase H is a 5' to 3' exonuclease that removes RNA primers from the lagging strand of the DNA replication fork and is a member of the RAD2 family of eukaryotic and prokaryotic replication and repair nucleases. The crystal structure of the full-length native form of T4 RNase H has been solved at 2.06 angstroms resolution in the presence of Mg2+ but in the absence of nucleic acids. The most conserved residues are clustered together in a large cleft with two Mg2+ in the proposed active site. This structure suggests the way in which the widely separated conserved regions in the larger nucleotide excision repair proteins, such as human XPG, could assemble into a structure like that of the smaller replication nucleases. PMID- 8674117 TI - GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR alpha, a novel receptor for GDNF. AB - We report the expression cloning and characterization of GDNFR-alpha, a novel glycosylphosphatidylinositol-linked cell surface receptor for glial cell line derived neurotrophic factor (GDNF). GDNFR-alpha binds GDNF specifically and mediates activation of the Ret protein-tyrosine kinase (PTK). Treatment of Neuro 2a cells expressing GDNFR-alpha with GDNF rapidly stimulates Ret autophosphorylation. Ret is also activated by treatment with a combination of GDNF and soluble GDNFR-alpha in cells lacking GDNFR-alpha, and this effect is blocked by a soluble Ret-Fc fusion protein. Ret activation by GDNF was also observed in cultured embryonic rat spinal cord motor neurons, a cell type that responds to GDNF in vivo. A model for the stepwise formation of a GDNF signal transducing complex including GDNF, GDNFR-alpha, and the Ret PTK is proposed. PMID- 8674118 TI - Meiotic pachytene arrest in MLH1-deficient mice. AB - Germ line mutations in DNA mismatch repair genes including MLH1 cause hereditary nonpolyposis colon cancer. To understand the role of MLH1 in normal growth and development, we generated mice that have a null mutation of this gene. Mice homozygous for this mutation show a replication error phenotype, and extracts of these cells are deficient in mismatch repair activity. Homozygous mutant males show normal mating behavior but have no detectable mature sperm. Examination of meiosis in these males reveals that the cells enter meiotic prophase and arrest at pachytene. Homozygous mutant females have normal estrous cycles and reproductive and mating behavior but are infertile. The phenotypes of the mlh1 mutant mice are distinct from those deficient in msh2 and pms2. The different phenotypes of the three types of mutant mice suggest that these three genes may have independent functions in mammalian meiosis. PMID- 8674119 TI - The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. AB - We examined the ability of chemokine receptors and related G protein-coupled receptors to facilitate infection by primary, clinical HIV-1 isolates. CCR5, when expressed along with CD4, the HIV-1 receptor, allowed cell lines resistant to most primary HIV-1 isolates to be infected. CCR3 facilitated infection by a more restricted subset of primary viruses, and binding of the CCR3 ligand, eotaxin, inhibited infection by these isolates. Utilization of CCR3 and CCR5 on the target cell depended upon the sequence of the third variable (V3) region of the HIV-1 gp120 exterior envelope glycoprotein. The ability of various members of the chemokine receptor family to support the early stages of HIV-1 infection helps to explain viral tropism and beta-chemokine inhibition of primary HIV-1 isolates. PMID- 8674120 TI - A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. AB - Here, we show that the beta-chemokine receptor CKR-5 serves as a cofactor for M tropic HIV viruses. Expression of CKR-5 with CD4 enables nonpermissive cells to form syncytia with cells expressing M-tropic, but not T-tropic, HIV-1 env proteins. Expression of CKR-5 and CD4 enables entry of a M-tropic, but not a T tropic, virus strain. A dual-tropic primary HIV-1 isolate (89.6) utilizes both Fusin and CKR-5 as entry cofactors. Cells expressing the 89.6 env protein form syncytia with QT6 cells expressing CD4 and either Fusin or CKR-5. The beta chemokine receptors CKR-3 and CKR-2b support HIV-1 89.6 env-mediated syncytia formation but do not support fusion by any of the T-tropic or M-tropic strains tested. Our results suggest that the T-tropic viruses characteristic of disease progression may evolve from purely M-tropic viruses prevalent early in virus infection through changes in the env protein that enable the virus to use multiple entry cofactors. PMID- 8674121 TI - Kinesin-related proteins at mitotic spindle poles: function and regulation. PMID- 8674122 TI - TGFbeta signaling: receptors, transducers, and Mad proteins. PMID- 8674123 TI - Morphogens, compartments, and pattern: lessons from drosophila? PMID- 8674124 TI - From transcript to protein. PMID- 8674125 TI - The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4. AB - The molecular basis for the distinctive cytokine expression of CD4+ T helper 1 (Th1) and T helper 2 (Th2) subsets remains elusive. Here, we report that the proto-oncogene c-maf, a basic region/leucine zipper transcription factor, controls tissue-specific expression of IL-4. c-Maf is expressed in Th2 but not Th1 clones and is induced during normal precursor cell differentiation along a Th2 but not Th1 lineage. c-Maf binds to a c-Maf response element (MARE) in the proximal IL-4 promoter adjacent to a site footprinted by extracts from Th2 but not Th1 clones. Ectopic expression of c-Maf transactivates the IL-4 promoter in Th1 cells, B cells, and nonlymphoid cells, a function that maps to the MARE and Th2-specific footprint. Furthermore, c-Maf acts in synergy with the nuclear factor of activated T cells (NF-ATp) to initiate endogeneous IL-4 production by B cells. Manipulation of c-Maf may alter Th subset ratios in human disease. PMID- 8674126 TI - The Fc(epsilon)RIbeta subunit functions as an amplifier of Fc(epsilon)RIgamma mediated cell activation signals. AB - The high affinity IgE receptor (Fc(epsilon)RI) plays a central role in the initiation of allergic responses. Fc(epsilon)RI is multimeric and is expressed as either (alpha)(gamma2) trimers or (alpha)(beta)(gamma2) tetramers. Recently, polymorphisms of the beta chain gene have been associated with the development of various allergic phenotypes. Until now, the role of beta in Fc(epsilon)RI dependent signaling was largely unknown. For that reason, we compared the signaling characteristics of various wild-type and mutant (alpha)(gamma2) and (alpha)(beta)(gamma2) Fc(epsilon)RI complexes. These studies demonstrate that the gamma dimer functions as an autonomous activation module, while beta functions as an amplifier that provides a gain of 5- to 7-fold, as measured by Syk activation and calcium mobilization. PMID- 8674127 TI - Differential requirements for alpha4 integrins during fetal and adult hematopoiesis. AB - Mice chimeric for the expression of alpha4 integrins were used to dissect the roles of these receptors in development and traffic of lymphoid and myeloid cells. During fetal life, T cell development is alpha4 independent, but after birth further production of T cells becomes alpha4 dependent. Precursors for both T and B cells require alpha4 integrins for normal development within the bone marrow. In contrast, monocytes and natural killer cells can develop normally without alpha4 integrins. Thus, there are lymphocyte-specific, developmentally regulated requirements for alpha4 integrins in hematopoiesis in the bone marrow. We also show that alpha4 integrins are essential for T cell homing to Peyer's patches, but not to other secondary lymphoid organs, including spleen, lymph nodes, and intestinal epithelium. PMID- 8674128 TI - Retinoids as Ig isotype-switch modulators. The role of retinoids in directing isotype switching to IgA and IgG1 (IgE) in association with IL-4 and IL-5. AB - The role of retinoids was analyzed in directing isotype switching to IgA and IgG1 (IgE) by LPS-stimulated murine mu(+)B-cells in the presence of two Th2-type cytokines, IL-4 and IL-5. All trans retinoic acid (RA) enhanced the production of IgA at high concentrations (10-100 nM) in the presence of IL-5. Addition of IL-4 to the system modulated the IgA response in a dose-dependent manner. Namely, IL-4 inhibited the response at concentrations higher than 250 u/ml, but showed slight enhancement at lower concentrations (130 u/ml). IL-4 alone, which is considered to be an IgE isotype-switch inducer, strongly enhanced the IgG1 and IgE responses. Addition of IL-5 to the system showed a synergistic effect which could be attenuated by addition of low concentrations of RA (about 1 nM). Thus, the presence of switch modulators such as IL-4 and IL-5, their concentration ratios, and concentrations of retinoids are crucial factors in initiating and directing isotype switching to IgA and IgG1 (IgE). PMID- 8674129 TI - Fascins, a family of actin bundling proteins. AB - Fascin is an actin-bundling protein that was first isolated from cytoplasmic extracts of sea urchin eggs [Kane, 1975: J. Cell Biol. 66:305-315] and was the first bundling protein to be characterized in vitro. Subsequent work has shown that fascin bundles actin filaments in fertilized egg microvilli and filopodia of phagocytic coelomocytes [Otto et al., 1980: Cell Motil. 1:31-40; Otto and Bryan, 1981: Cell Motil. 1:179-192]. Fifteen years later, the molecular cloning of sea urchin fascin [Bryan et al., 1993: Proc. Natl. Acad. Sci. U.S.A. 90:9115-9119] has led to the identification and characterization of homologous proteins in Drosophila [Cant et al., 1994: J. Cell Biol. 125:369-380], Xenopus [Holthuis et al., 1994: Biochim. Biophys. Acta. 1219:184-188], rodents [Edwards et al,. 1995: J. Biol. Chem. 270:10764-10770], and humans [Duh et al., 1994: DNA Cell Biol. 13:821-827; Mosialos et al., 1994: J. Virol. 68:7320-7328] that bundle actin filaments into structures which stabilize cellular processes ranging from mechanosensory bristles to the filopodia of nerve growth cones. Fascin has emerged from relative obscurity as an exotic invertebrate egg protein to being recognized as a widely expressed protein found in a broad spectrum of tissues and organisms. The purpose of this review is to relate the early studies done on the sea urchin and HeLa cell fascins to the recent molecular biology that defines a family of bundling proteins, and discuss the current state of knowledge regarding fascin structure and function. PMID- 8674130 TI - Structural and biological consequences of increased vimentin expression in simple epithelial cell types. AB - Cytoskeletal intermediate filaments (IFs) constitute a diverse family of proteins whose members are expressed in tissue-specific patterns. Although vimentin IFs are normally restricted to mesenchyme, a variety of cell types express vimentin alone or together with cell-specific IFs during growth, differentiation, and neoplasia. In this study, we have investigated the influence of increased vimentin expression on the simple epithelial cell phenotype. An expression vector encoding a human vimentin cDNA was transfected into murine HR9 endoderm and F9 embryonal carcinoma cell lines, which serve as models for early extraembryonic epithelial differentiation. Stable clones that expressed varying levels of human vimentin were characterized by human vimentin were characterized by immunofluorescence and biochemical analysis. A relatively high level of vimentin expression in HR9 and differentiated F9 epithelial cells resulted in aberrant vimentin structures with co-collapse of keratin K8/K18 filaments and lowered amounts of keratin protein. In F9 epithelial cells, the desmosomal proteins DP I/II did not appear to localize to cell surface desmosome s but rather but rather co-aggregated with the perturbed IFs. Although overall cell morphology was not dramatically altered, individual nuclei were distorted by excess intracellular vimentin. Furthermore, cell proliferation as well as the cell spreading response time were slowed. Ther appears to be a threshold effect regarding overall vimentin levels as cells that expressed lower amounts of the human vimentin exhibited no obvious structural nor biological effects. Our results demonstrate that wild-type vimentin can act as a "mutant" protein when present at high intracellular levels, inducing a variety of phenotypic changes. PMID- 8674131 TI - Genomic structure of a cytoplasmic dynein heavy chain gene from the nematode Caenorhabditis elegans. AB - We report the cloning and sequencing of genomic DNA encoding a cytoplasmic dynein heavy chain from the nematode Caenorhabditis elegans. In a contiguous stretch of 35,103 bp of DNA from the left arm of linkage group I, we have found a gene that is predicted to encode a protein of 4,568 amino acids. This gene is composed of 15 exons and 14 relatively short introns, and it has significant homology to the other dynein heavy chains in the databases. The deduced molecular mass of the derived polypeptide is 512,624 Da. As with other dynein heavy chains that have been sequenced to date, it contains four GXXGXGK(S/T) motifs that form part of a consensus sequence for the nucleotide triphosphate-binding domains. Comparison of the axonemal and cytoplasmic dynein heavy chains shows that regions of homology among all dyneins are clustered in the carboxyl terminal two-thirds of the polypeptide, whereas the amino terminal one-third of the heavy chains may contain domains that specify functions that differ between the axonemal and cytoplasmic forms of the dynein heavy chain. PMID- 8674132 TI - Characterization of adhesion plates induced by the interaction of Entamoeba histolytica trophozoites with fibronectin. AB - Entamoeba histolytica trophozoites are pleiomorphic and highly motile cells. Although scarce fibrous material can be identified in the cytoplasm as elements of an organized cytoskeleton, clearly defined actin-containing structures are formed at the site of cell-matrix contact upon the interaction of trophozoites with fibronectin (FN) and other cellular matrix substrates. The structures are reminiscent of the adhesion plaques or focal contacts found in higher eukaryotic cells, where actin filament bundles insert into specialized regions of the plasma membrane and function as signal transduction organelles. Thus, the formation of adhesion plates in this parasitic ameba could be related to the specific signaling responses involved in its invasive behavior. Here, we report the isolation of amebic adhesion plates and the results of their structural and molecular analyses. Filaments, with the characteristic diameter of F-actin, radiating from an electron-dense matrix, are the main feature. Actin is one of the main protein components of the plate; other proteins identified are a FN binding protein--previously reported as a "putative" FN receptor--the actin binding proteins myosin II, myosin I, alpha-actinin, vinculin, and tropomyosin. The presence of the isolated plates of several proteases and protein kinases, in particular pp125FAK, is also demonstrated. our results suggest that adhesion plates in amebas are dynamic membrane-cytoskeletal complexes participating not only in the attachment to FN substrates but also providing the structural basis for their involvement in parasite locomotion and invasiveness. PMID- 8674133 TI - Regulatory role of nucleotides in axonemal function. AB - Axonemal sliding involves both sliding velocity and the extent of sliding, that is how many doublets slide. It is clear that axonemes cannot beat if all doublets were to slide simultaneously, thus sliding extent is important. Using the turbidimetric assay of sliding disintegration of Tetrahymena axonemes, we examined the sliding extent and th effect of APD, ATP, and ATP analogs on the sliding extent. Of course, ATP is necessary to produce sliding disintegration, but ATP alone did not produce extensive sliding disintegration. The additions of higher ATP concentration even in the presence of ADP inhibited sliding disintegration. We also observed sliding disintegration using ribose-modified ATP analogs, anthraniloylATP, and methylanthraniloylATP. The extent of sliding disintegration was proportional to the analog concentration. Thus in contrast to ATP, higher analog concentration was not inhibitory. These results indicate that high ATP concentration acts to inhibit the extent of sliding disintegration and that ADP relieves this inhibition. We propose a model in which the affinity of of multiple cooperative active sites are regulated by the binding of ATP or ADP to a regulatory site. This model provides a mechanism by which nucleotides regulate the extent of sliding necessary for effective axonemal bending. PMID- 8674134 TI - Centrin in the photoreceptor cells of mammalian retinae. AB - Photoreceptor cells of vertebrate retinae are highly specialized ciliary cells. Their non-motile ciliated structure is restricted to the so-called connecting cilium at the joint between the light sensitive outer segment and the metabolically active inner segment. Extensive bidirectional intracellular transport between both segments is forced to occur through this tight connecting cilium. In the present study it is shown that the CA2+-binding, phospho-protein centrin is present in mammalian retinae. Western blot and immunoprecipitation reveal that anti-centrin antibodies react with purified photoreceptor cell fractions of retinae in bands at a molecular weight of 20 kDa, the molecular weight of centrins found in other cells. Indirect immunofluorescence analysis of cryosections through retinae of different mammalian species show that centrin is present only in centrosomes and basal bodies but also more extensively at the linkage between the inner and the outer segment of the photoreceptor cells. Immunocytological studies on isolated rod cells and immunoelectron microscopy clearly demonstrate a unique presence of centrin in the connecting cilium of photoreceptor cells. High molecular identity between centrins in lower eukaryotes and mammals indicates that centrin may play a role in cellular motility and/or in microtubule severing in the mammalian retina. PMID- 8674135 TI - Multiple protein kinase activities required for activation of sperm flagellar motility. AB - A specific peptide inhibitor of the cyclic AMP (cAMP)-dependent protein kinase (PKI-peptide) is a very effective inhibitor of the cAMP-dependent activation of motility of Ciona spermatozoa, when PKI-peptide is present at the beginning of incubation of demembranated spermatozoa with cAMP and ATP. Under conditions where approximately 120 sec is required for full activation of motility, the window of sensitivity to the PKI-peptide lasts for only 25-30 sec. Examination of sperm pellet proteins labeled with 32P ATP during activation reveals a major 25 kDa phosphoprotein and 2 minor phosphoproteins whose phosphorylation is highly sensitive to to inhibition by the PKI-peptide and essentially complete during this early phase. These sperm proteins appear to be immediate substrates for cAMP dependent protein kinase, and phosphorylation of one or more of these appears to be requires, but not sufficient, for activation of motility. The phosphorylation of other proteins is reduced or eliminated when PKI-peptide is present at the beginning of incubation, but is unaffected by later addition of PKI-peptide. Some of these substrates appear to be likely candidates for axonemal proteins that must be phosphorylated during the later stages of incubation in order to complete the activation process. This selection is based upon a high degree of inhibition by inclusion of PKI-peptide or other inhibitors at the start of the incubation process, on near-completion of their phosphorylation by the end of the 2 min incubation period required for the activation of motility, and evidence that these proteins are phosphorylated during in vivo activation of motility. Although these observations suggest the presence of a second kinase activity that is upregulated by the initial activation of the cAMP-dependent protein kinase, assays using exogenous substrates have not yet been able to identify such a kinase activity. PMID- 8674136 TI - Utrophin-dystroglycan complex in membranes of adherent cultured cells. AB - In skeletal muscle, dystrophin binds to an oligomeric, transmembrane complex (DAGc; dystrophin-associated glycoprotein complex) which interacts with laminin in the extracellular matrix. We now present biochemical evidence for an association between utrophin (dystrophin-related protein, DRP) and a major DAGc component, beta-dystroglycan (43DAG) in cultured cell lines which contain little if any dystrophin. We have shown also that utrophin and beta-dystroglycan co localise at or near the plasma membrane and that they co-sediment in large complexes on sucrose density gradients. On the lower plasma membrane, in contact with the substratum, part of the utrophin and beta-dystroglycan staining co localised with alpha-actinin in a punctate distribution outside classical vinculin-rich focal adhesions. beta-dystroglycan, utrophin, syntrophin (59DAP), and alpha-actinin were found in all adhesion-competent cell lines studied, but levels of the last three proteins were greatly reduced in myeloma cells, which cannot readily attach to substrata. Possible roles for utrophin in cultured cells are considered in the light of recent evidence for involvement of utrophin glycoprotein complexes in muscle in signal transduction and recruitment of acetylcholine receptors to neuromuscular junctions. PMID- 8674137 TI - Improved preparation and swimming behavior of Triton-extracted models of Didinium nasutum. AB - An improved method for the preparation of Triton X-100 extracted models of Didinium nasutum was established. Didinium models prepared by treatment with a Triton X-100 solution, containing specific proteolysis inhibitors and dimethyl sulfoxide, maintained an intact shape at 25 degrees C for a longer time than models prepared by treatment with a Triton X-100 solution not containing the proteolysis inhibitors and dimethyl sulfoxide. The improved Didinium models were reactivated so as to swim forward in the presence of Mg2+ and ATP or ADP. They did not swim backward in response to Ca2+, in contrast to well-known Paramecium models. However, the improved Didinium models showed circular swimming and spinning in response to 10(-6) M or higher concentrations of Ca2+. This observation suggests that the quick directional change as well as the spinning, which are characteristic of live Didinium, are due to an increase in the endoplasmic Ca2+ concentration around the ciliary system. The response of the Didinium ciliary system to Ca2+ may differ from the response of the Paramecium ciliary system to Ca2+. PMID- 8674138 TI - Localization of kinesin and cytoplasmic dynein in cultured melanophores from Atlantic cod, Gadus morhua. AB - In this study we have analyzed pigment translocation in cultured melanophores from the cold-tempered Atlantic cod, Gadus morhua. The transport process was found to be cold-adapted, as it proceeded at low temperatures. Both the typical morphology of the melanophores with long cytoplasmic processes, and the ability to translocate pigment granules, were found to be highly dependent on microtubules. Microtubules in melanophores were relatively stable to vinblastine treatment compared to microtubules in other skin cells. Extensive posttranslational modifications of tubulin were found. Detyrosinated and polyglutamylated microtubules were frequent, while acetylated microtubules only comprised a subpopulation or domains of microtubules. Both cod kinesin and dynein were distributed in a punctate pattern throughout the melanophores in close proximity to microtubules. The motors accumulated together with pigment granules during aggregation and were dispersed during translocation of pigment granules to the periphery. Individual melanosomes were occasionally found to rapidly change direction during translocation. Our data raise the interesting possibility that both kinesin and dynein are bound to pigment granules. This is of functional significance, since pigment granules are transported back and forth in the melanophores, and may be activated differently during aggregation and dispersion to generate translocation. PMID- 8674139 TI - Cold-treated centrosome: isolation of centrosomes from mitotic sea urchin eggs, production of an anticentrosomal antibody, and novel ultrastructural imaging. AB - A novel isolation of centrosomes is described and it was used to both generate a centrosome-specific monoclonal antibody and to image with high-resolution low voltage scanning electron microscopy the surface details of the isolated centrosome. At first mitotic prometaphase, sea urchin zygotes are chilled on ice overnight. While most of the microtubules disassemble, the mitotic centrosomes collapse into aggregated masses. These centrosomes have been isolated, and used to generate a monoclonal antibody, designated 4D2, which is reactive with interphase and mitotic centrosomes. 4D2 staining of centrosomes is similar, but not identical, to that of other centrosomal antibodies like Ah6 and 5051. Centrosomal material is detected as a compact sphere after cold treatment; upon recovery the sphere expands and undergoes the shape changes previously described [Mazia et al., 1987: J. Cell Biol. 105:206a] to eventually reorganize a normal mitotic apparatus. PMID- 8674140 TI - Calcium-independent effects of cadmium on actin assembly in mesangial and vascular smooth muscle cells. AB - Several metal ions are known to cause depolymerization of the actin cytoskeleton under some circumstances. We found that in renal mesangial and vascular smooth muscle cells, micromolar concentrations of Cd2+ result in loss of phalloidinstainable filamentous (F-) actin. The decrease in F-actin was not accompanied by a corresponding increase in G-actin. The decrease in total actin could be accounted for in part by an inhibition by Cd2+ of total protein (and actin) synthesis after 6 to 8 h without an effect on actin degradation, and the equilibrium between F- and G-actin was shifted to maintain near-constant levels of G-actin. However, Cd2+ caused significant decreases in F-actin at earlier times, indicating effects on the polymerization equilibrium independent of those on actin synthesis. Only picomolar concentrations of free intracellular Cd2+ occur in these experiments. However, it is this Cd2+ pool which is responsible for F-actin depolymerization because equal cellular concentrations of cadmium delivered as Cd-metallothionein have no effect. The effect is also very specific for Cd2+ and under the same conditions neither Mg2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, nor Hg2+ result in any loss of F-actin. Addition of Cd2+ to mesangial and vascular smooth muscle cells had no immediate effect on free intracellular calcium concentrations ([Ca2+]i) even though Ca(2+)-signalling pathways were intact as shown with vasopressin and endothelin. Exposure to 10 microM CdCl2 for 8 h nevertheless caused an increase in [Ca2+]i to > 250 nM and increases in [Ca2+]i achieved with ionophores alone were sufficient to decrease F-actin concentrations. However, a rise in [Ca2+]i is not necessary for actin depolymerization. Depletion of cellular Ca2+ by treatment with thapsigargin did not protect F-actin against Cd2+; the effect of Cd2+ was enhanced in cells unable to increase their [Ca2+]i. We conclude that depolymerization of F-actin by Cd2+ in smooth muscle and mesangial cells is metal-specific, Ca(2+)-independent, and accompanied by a depletion of total actin protein. PMID- 8674141 TI - Low molecular weight rat fibroblast tropomyosin 5 (TM-5): cDNA cloning, actin binding, localization, and coiled-coil interactions. AB - Previous studies have shown that three distinct genes encode six isoforms of tropomyosin (TM) in rat fibroblasts: the alpha gene encodes TM-2, TM-3, TM-5a, and TM-5b, the beta gene encodes TM-1, and the TM-4 gene encodes TM-4. Here we report the characterization of a cDNA clone encoding the most recent rat fibroblast TM to be identified, herein referred to as TM-5, that is the product of a fourth gene that is homologous to the human hTMnm gene, herein referred to as the rat slow-twitch alpha TM gene. The cDNA clone is approximately 1.7 kb and encodes a protein of 248 amino acids. Using two-dimensional gel electrophoresis, the TM-5 protein was found to co-migrate with fibroblast TM-5a and 5b. Comparison of the amino acid sequences of TM-5 to other fibroblast isoforms encoded by the alpha, beta, and TM-4 genes revealed a high degree of homology, although there were regions of divergence among the different isoforms. The gene encoding TM-5 is expressed in all tissues examined including skeletal muscle, stomach, heart, liver, kidney, uterus, spleen, brain, and diaphragm. However, Northern blot and RNase protection analyses revealed the presence of different mRNAs in fibroblasts, striated muscle (skeletal and diaphragm), and brain, which are expressed via alternative RNA splicing and the use of alternative promoters. The TM-5 protein was expressed in a bacterial system and tested for its ability to bind actin in vitro and in vivo. The apparent TM association constant (Ka) was taken as the free concentration at half saturation and was found to be 3 microM for TM-5 compared to 2 microM for TM-5b at an F-actin concentration of 42 microM. When fluorescently-labeled TM-5 was microinjected into living rat fibroblasts, it localized to the stress fibers and ruffles of the leading lamella. The coiled coil interactions of TM-5 with other low and high molecular weight TM isoforms were studied. TM-5 and TM-4 were capable of dimerizing with each other as well as with other low molecular weight isoforms (TM-5a and TM-5b), but not with the HMW isoforms (TM-1, TM-2, and TM-3). In addition, TM-5a and TM-5b were unable to heterodimerize with each other. The implications of these results in understanding the role of TM diversity in cytoskeletal dynamics are discussed. PMID- 8674142 TI - The human intestinal immune system: basic cellular and humoral mechanisms. AB - Adaptive immune protection of mucous membranes is provided mainly by secretory IgA (SIgA) antibodies. This first-line defence is accomplished through an ingenious cooperation between the mucosal B-cell system and the epithelial glycoprotein called secretory component (SC). This is quantitatively the most important receptor of the immune system because it is responsible for external transport of locally produced polymeric IgA (pIgA), which is the major humoral mediator substance of the whole immune system. Transmembrane SC belongs to the Ig supergene family and functions as a general pIg receptor, also translocating pentameric IgM externally to form secretory IgM. The B-cells responsible for local pIg production are initially stimulated in lymphoepithelial structures, particularly the Peyer's patches in the distal small intestine, from which they migrate as memory cells to exocrine tissues all over the body. Mucous membranes are thus furnished with secretory antibodies in an integrated way, ensuring a variety of specificities at every secretory site. There is currently great interest in exploiting this integrated or "common' mucosal immune system for oral vaccination against pathogenic infectious agents and also to induce therapeutic peripheral tolerance to ameliorate T-cell-mediated autoimmune diseases. Much remains to be learnt about antigen uptake and processing necessary to elicit stimulatory or suppressive mucosal immune responses, and how normal homeostasis is maintained in the intestinal mucosa. Considerable information has accumulated about various types of immune deviation that may lead to local or extraintestinal hypersensitivity reactions against luminal antigen, but the crucial mechanisms remain obscure. PMID- 8674143 TI - Aetiological agents and immune mechanisms in enterogenic reactive arthritis. AB - Reactive arthritis is triggered by an infection, either of the genitourinary or gastrointestinal tracts; the common triggering bacteria in enteric ReA include salmonella, shigella, yersinia, and campylobacter. It is still not clear how such different bacteria can lead to a similar clinical picture and have a similar association with the MHC class I antigen HLA-B27. Common both to enterogenic and urogenic bacteria is the type of peripheral joint involvement. However, this is not so different from other bacteria-associated arthritides and is probably the consequence of bacteria persistent inside the joint. What is unique to these bacteria is the HLA-B27-association and the nearly exclusively B27-linked clinical manifestations as sacroiliitis and iritis. Shigella-induced ReA has the highest B27-association while in salmonella- and chlamydia-induced ReA a lower association can be found. Mucosal entry of enterogenic bacteria give easy access to macrophages which might be important for the transport into the joint. Although bacteria-specific antibodies are of diagnostic value, the humoral immune response does not explain the immunopathogenesis and MHC-association of this disease. Bacteria-specific T-cells have been constantly found in the synovial fluid from ReA patients and have been further analysed. The identification of immunodominant antigens of these bacteria is of great importance to understand the pathogenesis. Although an antigen shared by all bacteria has not been identified until now progress is being made in this field. We have also to consider the possibility that these bacteria are not only driving the immune response themselves but rather work as a trigger for autoimmunity. PMID- 8674144 TI - Spondylarthropathies: from gut to target organs. AB - Recent studies strongly support the concept that gut and joint inflammation are closely related. Progress also has been made in identifying individual mechanisms that contribute to the pathogenesis of joint disease in IBD and in undifferentiated SpAs. However, the interrelationship of these mechanisms that result in chronic disease manifestations at a site distant from the initiating event remain to be elucidated. The local absence of homing molecule receptors in the gut wall combined with an expression of these receptors in target organs can be responsible for the transformation of the synovial membrane and/or the enthesis into an aberrant tertiary lymphoid organ of the gut. PMID- 8674145 TI - Course of gut inflammation in spondylarthropathies and therapeutic consequences. AB - Gut inflammation plays a crucial role in the pathogenesis of spondylarthropathies (SpA) since ileocolonoscopic studies have demonstrated the presence of gut inflammation in different forms of this concept: in ankylosing spondylitis (AS) (60%), in enterogenic (90%) and urogenital reactive arthritis (20%), in undifferentiated SpA (65%), in the pauciarticular and axial forms of psoriatic arthritis (16%), in late onset pauciarticular juvenile chronic arthritis (80%) and in acute anterior uveitis (66%). The strong relationship between gut and joint inflammation was demonstrated by performing a second ileocolonoscopy: remission of the joint inflammation was always connected with a disappearance of gut inflammation, whereas persistence of locomotor inflammation was mostly associated with the persistence of gut inflammation. During further evolution 20% of the non-ankylosing spondylitis SpA patients can develop AS. About 6% of the total group SpA patients, in whom inflammatory bowel disease (IBD) was excluded, developed Crohn's disease 5 to 9 years later. All these patients initially presented with gut inflammation, which indicates that this finding has prognostic value. The high prevalence of evolution to IBD in SpA patients confirms the thesis that both disease entities bear common pathogenic mechanisms, and confirms the place of IBD in the concept of SPA. Sulphasalazine (SASP), a successful drug in the treatment of IBD, has demonstrated its effectiveness in the treatment of SpA. The beneficial effect of the drug in this disease entity could be due to its anti-inflammatory effect on the gut wall, by normalizing its permeability and by preventing the entrance of antigens through the defective gut wall. However, SASP could not prevent the evolution to IBD. PMID- 8674146 TI - Influence of anti-rheumatic drugs on gut permeability and on the gut associated lymphoid tissue. AB - There is great interest in the association between intestinal inflammation and the various arthropathies. However, most studies assessing intestinal function in these diseases are confounded by the fact that non-steroidal anti-inflammatory drugs (NSAIDs) have profound effects on the small intestine. Hence NSAIDs cause quite distinct and severe biochemical damage during drug absorption (uncoupling of mitochondrial oxidative phosphorylation proving to be most important) which results in increased intestinal permeability. All commonly used NSAIDs, apart from aspirin and nabumetone, are associated with increased intestinal permeability in man. Whilst reversible in the short term, it may take months to improve following prolonged NSAID use. Increased intestinal permeability appears to be the central mechanism of converting the biochemical damage to an inflammatory tissue reaction (NSAID enteropathy). The inflammatory enteropathy is not, however, unique to NSAIDs but similar changes are found with other permeability breakers. In intestinal infections and in diseases associated with reduced mucosal defence, suggesting that the small intestinal inflammation represents a common final pathway for a number of intestinal injuries. Spondylarthropathies are associated with a high prevalence of terminal ileitis, but as most patients have been receiving NSAIDs it has been difficult to dissociate the effects of NSAIDs on intestinal function from that of the ileitis itself. Nevertheless, two studies suggest that increased intestinal permeability in spondylarthropathies occur independently of NSAID ingestion. Whilst these findings may have implications for the development of arthritis, the permeability changes in spondylarthropathy do not differ quantitatively or qualitatively from that of NSAIDs or other permeability breakers. NSAID enteropathy can be differentiated from spondylarthropathic enteropathy by differences in location of disease and lack of predilection of certain HLA types. However, as the two may coexist both enteroscopy and ileocolonoscopy may be necessary for this distinction. PMID- 8674147 TI - The gut associated addressins: lymphocyte homing in the gut. AB - The process of lymphocyte trafficking is mainly regulated by receptors that belong to a group of molecules referred to as adhesion molecules. These molecules can be divided, according to their molecular structure, into three broad families: the integrins; the selectins; and the immunoglobulin superfamily members. The alpha 4 beta 7 integrin is expressed on some lymphocytes with hallmarks of gut tropism. alpha 4 beta 7, among others, serves as a ligand for the mucosal vascular addressin MadCAM-1, which is selectively expressed on mucosal lymphoid organ high endothelial venules and on gut lamina propria venules. It is tempting to believe that related integrin receptors play a crucial role in the recirculation of activated lymphocytes between the gut mucosa and the synovial membrane. PMID- 8674148 TI - Oral tolerance: mechanisms and possible role in inflammatory joint diseases. AB - Decreased systemic immune responsiveness to a specific antigen following exposure to that antigen by the enteric route is termed 'oral tolerance.' Oral tolerance is revealed when attempts are made to parenterally immunize the host to the same antigen that was previously administered orally or intragastrically. A similar phenomenon is also seen following antigen exposure via the nasal mucosa and a related phenomenon is seen following antigen exposure in the upper respiratory tract. There has been a marked renewal of interest in the mechanisms that underlie oral tolerance because of its potential role for preventing and treating autoimmune and inflammatory diseases and IgE-mediated allergic disorders. The specific factors that determine whether or not the host develops mucosal tolerance to an antigen administered by the mucosal route are also of substantial importance for those involved in mucosal vaccine development. Furthermore, putative abnormalities in the ability of the host to develop mucosal tolerance may play a pathogenetic role in certain autoimmune and allergic diseases and disorders. Several well-defined immunological mechanisms mediate oral tolerance. These include the induction, following mucosal antigen exposure, of regulatory populations of T-cells that can down-regulate specific immune responses (e.g. DTH) via the production of specific cytokines (e.g. TGF-beta 1, IL-10 and IL-4). In addition, clonal anergy, clonal deletion and antibody-mediated suppression can be shown to play a role in the induction and maintenance of mucosal tolerance in several experimental systems. In animal studies, the onset of collagen-induced, adjuvant-induced, antigen-induced and pristane-induced arthritis has been delayed and the severity of ongoing disease diminished following feeding collagen type II. Mucosal tolerance has been clearly demonstrated in humans and clinical studies have been undertaken to treat rheumatoid arthritis using a similar approach. Results of initial clinical studies in rheumatoid arthritis indicated a modest improvement and further studies are ongoing in this and other autoimmune diseases (e.g. multiple sclerosis, autoimmune uveitis and insulin-dependent diabetes). This approach, if successful, could offer a new and novel therapeutic modality for preventing autoimmune and allergic disorders, and modulating ongoing disease. PMID- 8674149 TI - Animal models of intestinal and joint inflammation. AB - Recent rodent models have been exploited to explore mechanisms of intestinal and joint inflammation. HLA-B27 transgenic rats develop colitis, gastritis, and arthritis when raised in a conventional environment, but have no evidence of inflammation under germfree (sterile) conditions. Metronidazole treatment attenuates gastrointestinal inflammation, suggesting that anaerobic bacteria are important. Experimental bacterial over-growth of predominantly anaerobic bacteria reactivates arthritis in Lewis rats which have been previously injected intra articularly with bacterial cell wall polymers. Reactivation arthritis is mediated by interleukin-1, tumour necrosis factor-alpha, and can be blocked by metronidazole. Intramural injection of the bacterial cell wall polymer, peptidoglycan-polysaccharide, leads to biphasic, chronic granulomatous enterocolitis and peripheral arthritis in Lewis rats, but only transient intestinal inflammation and no arthritis in Buffalo or MHC-matched Fischer rats. Chronic granulomatous inflammation is mediated by T lymphocytes and interleukin-1 and is dependent on persistent antigenic stimulation by poorly biodegradable bacterial polymers. Results in these models firmly incriminate resident normal enteric flora (especially anaerobes), bacterial products, and host genetic susceptibility in the pathogenesis of spondyloarthropathies. We suggest that increased uptake of luminal bacterial components across the inflamed mucosa leads to systemic distribution of these arthropathic products. The genetically susceptible host develops reactive arthritis due to defective downregulation of inflammation in response to immunologically active bacterial components. PMID- 8674150 TI - Human models: Whipple's disease, coeliac disease and jejunoileal bypass. PMID- 8674151 TI - Epidermal growth factor receptor-dependent cytotoxic effect by an EGF ribonuclease conjugate on human cancer cell lines--a trial for less immunogenic chimeric toxin. AB - Mammalian pancreatic ribonuclease (RNase) was conjugated chemically via a disulfide bond to human or murine epidermal growth factor (EGF). The conjugation between EGF and RNase was ascertained by SDS-PAGE using reduced and nonreduced conjugates. The EGF-RNase conjugate retained potent RNase activity and competed with 125I-EGF for binding to EGFR to the same extent as unconjugated EGF. Both the human and murine EGF-RNase conjugates showed dose-dependent cytotoxicity against EGFR-overexpressing A431 human squamous carcinoma cells with IC50 values of 3 x 10(-7) M and 6 x 10(-7) M, respectively, whereas free RNase had an IC50 of 10(-4) M. Against the EGFR-deficient small-cell lung cancer cell line H69, the EGF-RNase conjugate had no cytotoxic effect. The Human EGF-RNase conjugate showed dose-dependent cytotoxicity against other squamous carcinoma cell lines (TE-5, TE 1) and breast cancer cell lines (BT-20, SK-BR-3, MCF-7) and the cytotoxicity of the conjugate correlated positively with the level of expression of EGFR by each cell line. An unconjugated mixture of EGF and RNase had no greater effect than RNase alone on any cell line. Excess free EGF blocked EGF-RNase conjugate cytotoxicity against A431 cells. These results suggest that the EGF-RNase conjugate may be a more effective anticancer agent with less immunogenicity than coventional chimeric toxins. PMID- 8674152 TI - Chromosome aberrations and pharmacokinetics in patients receiving tauromustine as either a single or a repeated dose. AB - Tauromustine (TCNU) is an exploratory drug that has demonstrated activity in various solid tumors. We examined chromosome aberrations and plasma levels of the drug in two groups of patients receiving either a single dose of 130 mg/m2 or 40 mg/m2 on 3 consecutive days. Peak plasma concentrations (mean +/- SD) were obtained at a similar time after both treatments, i.e., at 38 +/- 25, 32 +/- 24, 28 +/- 14, and 40 +/- 26 min after administration of 130 mg/m2 on day 1 and after that of 40 mg/m2 on days 1, 2, and 3, respectively. In addition, the cumulative area under the curve (AUC value) determined after administration of 40 mg/m2 x 3 was similar to that noted after treatment with a single dose of 130 mg/m2, i.e., 180 and 179 micrograms min ml-1, respectively. Both treatments induced chromosome aberrations (CAs) in peripheral blood lymphocytes. A dose-dependent increase in the number of CAs was found, with 40 mg/m2 producing 5.5% CAs and 130 mg/m2 yielding 20.9% CAs at 24 h after treatment. In addition, although the drug concentration declined to a level under the detection limit between the daily treatments, drug-induced chromosome damage was cumulative, with the 90-min values increasing from 4.8% on day 1 to 14.3% CAs on day 3. In individual patients, no correlation was found between CAs and kinetic parameters; however, the total mean CA yield was in agreement with the total drug exposure (CAs, 14.3% and 14.6%, AUC 180 +/- 62.8 and 179 +/- 115 micrograms min ml-1, respectively. PMID- 8674153 TI - Histopathological changes in rabbit uterus carcinoma after transcatheter arterial embolization using cisplatin. AB - The effects of chemoembolization with cisplatin on gynecological malignancy were investigated using rabbit uterine tumors. A group of 20 rabbits were subjected to inoculation of the uterus with 5 x 10(7) VX2 carcinoma cells and 4 weeks later were divided into four groups, each consisting of five rabbits: an untreated control group, a group given cisplatin intraarterially (IA), a group subjected to transcatheter arterial embolization (TAE) with Gelfoam particles and a group subjected to transcatheter chemoembolization (TACE) with Gelfoam particles plus 1 mg/kg cisplatin. All groups were examined histologically 2 days after treatment. The untreated control group was further investigated 4 weeks after inoculation. In the untreated control group, the tumor cell nuclei varied in size and were irregular in form, and multiple nuclei and nuclear division were also observed. No necrotic zones were found up to 4 weeks after inoculation. The IA group showed no necrosis, but a few apoptotic cells were scattered throughout the tumor. In the TACE group, necrosis was observed in the center of the tumors, but proliferating cells persisted at the periphery. In the TACE group, necrosis was observed in the central part with many apoptotic cells surrounding the necrotic region in layers. The proliferating cell nuclear antigen (PCNA) index was 95.88% in the untreated control group, 86.6% in the IA group, and 8.62% in the TACE group, indicating a significant reduction in cell proliferation in the TACE group. These findings suggest that TACE results in more effective cytotoxicity than the other two treatments in uterine cancer tumor transplants. PMID- 8674154 TI - A randomized, double-blind comparison of single-dose and divided multiple-dose dolasetron for cisplatin-induced emesis. AB - PURPOSE: Intravenous dolasetron has been shown to be an effective antiemetic agent in patients receiving high-dose cisplatin-containing chemotherapy. Previous studies have suggested that 1.8 mg/kg is an optimal dose for achieving control of emesis and nausea. The objective of this study was to compare the efficacy and safety of a single intravenous (IV) dose of dolasetron with an equal divided multiple dose. METHODS: In this randomized, double-blind, parallel-group, multicenter study, the efficacy and safety of a single 1.8-mg/kg dose of dolasetron given 30 min prior to high-dose cisplatin ( > or = 80 mg/m2) chemotherapy was compared with the same total amount of dolasetron administered in three separate doses (0.6 mg/kg each) over a 12-h interval commencing 30 min prior to beginning chemotherapy and ending 11.5 h later. Antiemetic efficacy, safety, and tolerability were compared in 55 patients with various malignancies during the 24 h following the initiation of chemotherapy. The number of emetic episodes was the primary efficacy parameter. RESULTS: A single IV dose of dolasetron was generally more effective than a multiple-dose regimen in all measures of efficacy. There was a larger proportion of complete responders in the single-dose group compared with the multiple-dose group (48% vs 23%), although this difference did not reach statistical significance. Compared with the multiple-dose group, patients who received a single dose of dolasetron had a significantly (P = 0.034) longer median time to the first emetic episode (10.1 h vs > 24 h, respectively). Overall, 53% of patients had either a complete response or a major response to dolasetron, and only 40% of the total patient population received escape antiemetic medication in the 24 h after cisplatin administration. Except for headache, adverse events were similar with both regimens and were generally of mild or moderate intensity; no serious adverse events occurred. Neither dolasetron treatment regimen was associated with any clinically important events, trends in laboratory variables, or differences in safety profile. CONCLUSIONS: single-dose dolasetron was well tolerated and effectively controlled emesis and nausea in patients who received highly emetogenic, high-dose cisplatin chemotherapy. The greater antiemetic efficacy of a single prophylactic dose of dolasetron offers both convenience and potential cost savings, compared with a multiple-dose schedule of administration. PMID- 8674155 TI - Preclinical pharmacology of ecteinascidin 729, a marine natural product with potent antitumor activity. AB - Ecteinascidins are marine natural products with potent antiproliferative activity under evaluation as chemotherapeutic agents by the National Cancer Institute. Ecteinascidins bind the minor groove of DNA and may form covalent adducts with DNA by binding the N-2 of guanine in a fashion similar to saframycin antibiotics. The most potent ecteinascidin is ET-729 with antitumor activity observed following administration of 3.8 and 10 micrograms/kg to mice bearing P388 leukemia and B16 melanoma, respectively. A reverse-phase high-performance liquid chromatography (HPLC) assay and an L1210 cell bioassay were developed for ET-729 and utilized for stability and murine pharmacokinetic studies. HPLC analysis showed that ET-729 was stable in organic solvents, mobile phase and acidic buffer (t1/2 > 100 h). Stability was diminished under neutral and basic conditions (t1/2 < 14 h). Following a 48-h incubation with L1210 cells in growth medium in the absence and presence of 2.5% murine plasma, the 50% growth inhibitory concentrations (IC50) of ET-729 were 37 and 72 pM, respectively. Following intravenous administration of ET-729 to male CD2F1 mice, the disappearance of antiproliferative activity determined by the bioassay was described by a two compartment open model. The mean values of the elimination half-life and plasma clearance were 28 min and 39.7 ml/min per kg, respectively. Following intraperitoneal administration, peak plasma concentrations of antiproliferative activity were observed 6-15 min after injection and antiproliferative concentrations remained above 1 nM for longer than 1 h. Intraperitoneal bioavailability varied over a wide range (20-91%). Antiproliferative activity was detected in every urine sample following intravenous and intraperitoneal administration, but the total 48-h urinary recovery was less than 0.1%. PMID- 8674156 TI - Antitumor activity of prolonged as compared with bolus administration of 2',2' difluorodeoxycytidine in vivo against murine colon tumors. AB - 2',2'-Difluorodeoxycytidine (gemcitabine) is a cytidine analogue with established antitumor activity against several experimental tumor types and against human ovarian and non-small-cell lung cancer. Both preclinical studies and most clinical trials involving patients with solid tumors have focused on short-term administration schedules; however, mechanistic studies indicate that a continuous infusion schedule may be more effective. We determined the maximal tolerated dose (MTD) of gemcitabine in mice using various schedules. At these MTDs we observed considerably better antitumor activity of gemcitabine in two of three murine colon carcinoma lines using a prolonged administration as compared with a standard bolus protocol (i.p. 120 mg/kg q3d x 4). On the latter schedule, Colon 26-10 grown in BALB/c mice was the most sensitive tumor line, showing a growth delay factor (GDF, number of doubling times gained by the treatment) of 6.7, whereas Colon 38 (grown in C57/B16 mice) was the least sensitive tumor, displaying a GDF of 0.9. Prolonged treatment (q3d x 6) of Colon 26-10 at a lower dose (100 mg/kg) enhanced the antitumor activity (GDF 9.6) while producing similar toxicity. A similar weight loss was found following the continuous infusion (c.i.) of gemcitabine using Alzet osmotic pumps s.c. for 3 or 7 days (2 mg/kg), but the GDF increased to 2.4 in Colon 38 (C57/B16) as compared with that provided by the bolus injections. Continuous infusion of gemcitabine at 15 mg/kg per 24 h q7d x 2 i.v. via the tail vein was more effective than bolus injection against Colon 26-10, with the GDF being > 17.7 and 73% of the tumors regressing completely. However, against Colon 38 tumors this schedule was not effective (GDF 0.4), even with a 25% higher dose. The plasma pharmacokinetics of gemcitabine was determined after one bolus dose (120 mg/kg). The peak concentration of gemcitabine was 225 microM and that of the deaminated catabolite 2',2' difluorodeoxyuridine (dFdU) was 79 microM. The elimination of gemcitabine was much faster than that of dFdU, with the t1/2 beta values being 15 min and 8 h, respectively. For the c.i. schedules, plasma concentrations were below the detection limit of the assay (< 0.5 microM). Our results suggest that prolonged infusion of gemcitabine can give a better antitumor activity than bolus injections and shows promise of being active in clinical trials. PMID- 8674157 TI - Development and validation of a chiral high-performance liquid chromatography assay for rogletimide and rogletimide-N-oxide isomers in plasma. AB - The purpose of the present study was to develop and validate a stereo-specific high-performance liquid chromatography (HPLC) assay for rogletimide (Rog) and rogletimide-N-oxide (Nox) isomers in plasma. The assay was performed with a chiral cellulose-[4-methylbenzoate]ester column (Chiracel OJ). Optimal separation was achieved isocratically with a mobile phase consisting of n-hexane/anhydrous ethanol (65/35, v/v) at a flow rate of 0.9 ml/min, with the column being thermostated at +35 degrees C (UV detection at 257 nm). Under these conditions, retention times were approximately 17, 28, 31 and 76 min for R-Rog, S-Rog, R-Nox and S-Nox, respectively. S-aminoglutethimide (S-Ag) served as the internal standard (retention time 70 min). An extraction procedure from plasma samples was developed on Bond Elut RP8 500-mg cartridges; conditioning was performed with 5 ml methanol and 5 ml water, after which 1 ml plasma that had previously been spiked with 5 microM S-Ag was applied. Washing was done with 6 ml water and elution, with 4 ml methanol. After evaporation to dryness, residues were dissolved in 400 microliters anhydrous ethanol and 12-48 microliters was injected onto the HPLC system. Blank plasma from healthy donors showed the random presence of a small interference eluting at the retention time of R-Rog, precluding the accurate quantification of R-Rog concentrations below 2.5 microM. Reproducibility assays demonstrated the need to use an internal standard. Taking into account the internal standard, at 2.5 microM the intra- and inter-assay coefficients of variation were 10.5% and 21.0% for R-Rog 5.5% and 8.7% for S-Rog, 7.6% and 20.8% for R-Nox and 11.7% and 6.4% for S-Nox, respectively. The detection limit was 2.5 microM for R-Rog, 0.5 microM for S-Rog, 0.25 microM for R-Nox and 0.5 microM for S-Nox. Linearity was satisfactory at concentrations ranging from 2.5 to 10 microM for R-Rog, from 0.5 to 10 microM for S-Rog, from 0.25 to 2.5 microM for R-Nox and from 0.50 to 2.5 microM for S-Nox. This assay was applied to plasma obtained from rog-letimide-treated breast cancer patients receiving conventional oral doses and demonstrated its feasibility with regard to sensitivity. The preliminary pharmacokinetic results reported herein suggest for the first time that both the R-Rog and S-Rog isomers are metabolized into rogletimide-N-oxide. PMID- 8674158 TI - Enhancement of melphalan activity by inhibition of DNA polymerase-alpha and DNA polymerase-beta. AB - Our previous studies exploring melphalan resistance in the human rhabdomyosarcoma xenograft TE-671 MR revealed elevation of DNA polymerase-alpha and DNA polymerase beta. The present study evaluated the alteration of melphalan activity in TE-671 (melphalan-sensitive) and TE-671 MR (melphalan-resistant) subcutaneous xenografts in nude mice after DNA polymerase-alpha was inhibited using aphidicolin glycinate (AG) and DNA polymerase-beta was inhibited using dideoxycytidine (DDC). Administration of AG or DDC did not produce toxicity or demonstrate antineoplastic activity when given alone. AG (90 mg/m2) enhanced the activity of melphalan against TE-671, with growth delays increasing by 8.4, 15.8, and 21.2 days over the regimen with melphalan only. AG (180 mg/m2) only modestly increased melphalan activity against TE-671 MR, with the growth delays increasing from 9.6 and 12.1 days using melphalan alone to 12.1 and 14.5 days using melphalan plus AG. AG (180 mg/m2) plus melphalan (the dose lethal to 10% of animals) produced greater weight loss compared with melphalan alone, whereas DDC plus melphalan produced no additional toxicity. DDC modestly enhanced the activity of melphalan plus AG against TE-671 MR. AG plus O6-benzylguanine did not increase the activity of 1,3-bis(2-chloroethyl)-1-nitrosourea against TE-671 or TE-671 MR. AG (90 mg/m2 and 180 mg/m2) inhibited DNA polymerase-alpha to 80% and 72% of control in TE-671 and 64% and 37% in TE-671 MR, and DDC inhibited DNA polymerase-beta to 59% in TE 671 and 48% in TE-671 MR. These results suggest a role for AG-mediated enhancement of melphalan activity, particularly in the treatment of newly diagnosed, melphalan-sensitive tumors. PMID- 8674159 TI - Pharmacokinetics and whole-body distribution of the new chemotherapeutic agent beta-D-glucosylisophosphoramide mustard and its effects on the incorporation of [methyl-3H]-thymidine in various tissues of the rat. AB - beta-D-Glucosylisophosphoramide mustard (beta-D-Glc-IPM) is a new, potential chemotherapeutic agent currently under investigation. Its pharmacokinetics in plasma and elimination of the parent drug and its metabolites via urine, bile, and exhaled air were studied in female Sprague-Dawley rats after bolus injection of 315 mg/kg. Typically, the drug's disposition from plasma follows a linear two compartment model with half-lives (t1/2) of 1.8 (t1/2 alpha) and 32 min (t1/2 beta). The rate of clearance is 0.0046 (range 0.0030-0.0071) 1 min-1 kg-1, and the steady-state volume of distribution (Vss) is 0.18 (0.08-0.042) 1/kg (mean +/- inter-individual standard deviation). In human plasma, 28.1 +/- 2.6% (mean +/- SD) of the drug (concentration range 0.5-5 mg/ml) is bound to plasma proteins (predominantly to albumin). Biliary excretion of the parent drug accounts for 2.9 +/- 1.7% of the dose; its elimination in the form of 14CO2 via exhaled air is less than 1%. Within 24 h, 63.5 +/- 4.9% of the 14C-labeled drug is excreted unchanged in the urine, whereas 17.5 +/- 5.1% is excreted in the urine as metabolites. In addition, beta-D-Glc-[14C]-IPM was given as a bolus injection to female Sprague-Dawley rats at dose levels of 315 and 56.2 mg/kg. The distribution of radioactivity into tissue was examined qualitatively by whole-body autoradiography (WBA). Parallel experiments were carried out using the high dose of the L-derivative. After dosing with the D-compound, the highest levels of radioactivity were found in the liver, kidneys, thymus, thyroid gland, and central nervous system, including the brain. A similar distribution pattern was observed for the L-compound, except in the brain, which contained negligible levels of radioactivity. The distribution of the D-compound (high dose) was also investigated in male Copenhagen rats bearing a Dunning prostate tumor. The results were similar to those obtained in healthy Sprague-Dawley rats. Additionally, radioactivity was found in the tumor at 1 h after dosing with the drug and remained there even after 24 h. The effects of beta-D-Glc-IPM on the incorporation of [methyl-3H]-thymidine into the DNA of the liver, kidneys, thymus, spleen, esophagus, and bone marrow of the rat were examined following tissue excision and liquid scintillation counting at 2, 8, and 24 h after administration of the drug. beta-D-Glc-IPM showed no effect on the incorporation of [methyl-3H]-thymidine in the liver and an insignificant reduction in kidney DNA (maximal reduction: -27.3%). However, after 8 h there was a marked reduction in the incorporation rate in the thymus (-83.7%), spleen (-74.6%), and esophagus (-87.2%), with a tendency toward recovery within 24 h. In bone marrow cells a reduction of -75.5% (8 h) and -73.3% (24 h) was observed. PMID- 8674160 TI - A novel in vitro model system for studying the action of ara-C. AB - The antimetabolite 1-beta-D-arabinofuranosyl-cytosine (ara-C) has proven to be one of the most effective agents available for the treatment of acute leukemia. While ara-C has been implicated as a potent inhibitor of mammalian cell DNA replication, the specific mechanism by which ara-C kills cells is not known. In this report we describe the development of an in vitro model system to study the molecular mechanism of ara-CMP incorporation into DNA. This model system makes use of a recently described human cell multiprotein DNA replication complex (MRC) that is competent to replicate DNA in vitro. The MRC can successfully incorporate ara-CMP into replicating DNA at internucleotide positions. These results are similar to those described for studies using intact cells. This MRC-driven in vitro replication system may therefore serve as a powerful model for the study of anticancer agents that directly affect human cell DNA synthesis. PMID- 8674161 TI - Biological characterization of L-asparaginase liposomal formulations. AB - The biological properties of preselected liposomal formulations of L-asparaginase (L-ASNase) were studied. Pharmacokinetics studies showed that encapsulation in large liposomes (sDRV; median diameter 1,249 nm) decreased the circulation time of the enzyme, whereas encapsulation in small liposomes (VET: median diameter 158 180 nm) prolonged it by a factor of up to 10. Liposome encapsulation in either VET or sDRV prevents the induction of anti-asparaginase antibodies and mitigates the anaphylatic reaction, as no death occurred in animals presensitized and challenged with liposomal formulation, in contrast to animals treated with the free enzyme. The antitumor activity was also enhanced by liposome encapsulation. The survival of animals bearing P1534 tumors was prolonged by a factor of 2 after treatment with selected liposomal formulations as compared with free enzyme. PMID- 8674162 TI - Pharmacokinetic evaluation of high-dose etoposide phosphate after a 2-hour infusion in patients with solid tumors. AB - Etoposide phosphate, a water soluble prodrug of etoposide, was evaluated at levels potentially useful in transplantation settings in patients with malignancies. For pharmacokinetic studies of etoposide phosphate in this phase I study, 21 patients with solid tumors were treated with etoposide phosphate given as etoposide equivalents of 250, 500, 750, 1000 and 1200 mg/m2 infused over 2 h on days 1 and 2, and G-CSF 5 micrograms/kg per day starting on day 3 until WBC was > or = 10,000/microliters. Qualitative, quantitative, and pharmacokinetic analysis was performed as reported previously. Rapid conversion of etoposide phosphate into etoposide by dephosphorylation occurred at all dosage levels without indication of saturation of phosphatases. Plasma levels (C(pmax)) and area under the curve (AUC) of etoposide phosphate and etoposide demonstrated linear dose effects. For etoposide, plasma disposition demonstrated biphasic clearance, with mean T1/2 alpha of 2.09 +/- 0.61 h, and T1/2 beta of 5.83 +/- 1.71 h. An AUC as high as 1768.50 micrograms.h/ml was observed at a dose of 1200 mg/m2. The total body clearance (TBC) showed an overall mean of 15.72 +/- 4.25 ml/min per m2, and mean volume of distribution (VDss) of 5.64 +/- 1.06 l/m2. The mean residual time (MRT) for etoposide was 6.24 +/- 1.61 h. In urine, etoposide but not etoposide phosphate, was identified with large quantitative variations (1.83% to 33.45% of injected etoposide equivalents). These results indicate that etoposide phosphate is converted into etoposide with the linear dose-related C(pmax) and AUCs necessary for use of this agent at the high dosage levels needed in transplantation protocols. A comparison of pharmacokinetic parameters of high dose etoposide with the values observed in our study with etoposide phosphate revealed comparable values for the clinically important C(pmax) and AUCs, clearance, terminal T1/2 and MRT. In contrast to the use of etoposide, etoposide phosphate can be delivered in aqueous vehicles and therefore may offer the advantage of ease of administration. PMID- 8674163 TI - Multimodal biochemical modulation of 5-fluorouracil by leucovorin, methotrexate, and interferon alpha in patients with advanced colorectal cancer. AB - A total of 26 patients with advanced colorectal cancer received 60 mg/m2 methotrexate i.v. on days 1-4; 400 mg/m2 5-fluorouracil i.v. on days 2, 3, 5, and 6; and 100 mg/m2 6S-leucovorin i.v. on days 2, 3, 5, and 6. Interferon-alpha 2b at a dose of 3 million U was given i.m. daily for the 6 days of chemotherapy. Courses were repeated every 3 weeks. There were four partial responses for a response rate of 15% (95% confidence interval 2-28%): In all, 14 patients expressed grade 3 toxicity; 9 patients had diarrhea, 3 had stomatitis, and 2 developed leukopenia. In conclusion, multimodal biochemical modulation of 5 fluorouracil, at least on this schedule, does not seem to be effective, as it results in severe toxicity. PMID- 8674164 TI - Unchanged pharmacokinetics of etoposide given by intra-arterial hepatic infusion as compared with i.v. infusion. AB - We investigated the pharmacokinetics of etoposide given to a patient suffering from multifocal liver metastases from an unknown primary tumor. The drug was given either by i.v. infusion or by hepatic arterial infusion (HAI). The calculated pharmacokinetic parameters (mean values +/- SD) were similar after i.v. infusion and HAI, viz., 6.4 +/- 0.7 versus 6.5 +/- 0.2 h for the terminal elimination half-life (t1/2 beta), 98.5 +/- 1.3 versus 101.3 +/- 5.9 mg l(-1) h for the area under the plasma concentration-time curve (AUC), 21.2 +/- 0.3 versus 20.6 +/- 1.2 ml min-1 m-2 for clearance (Cl), 17.7 +/- 1.9 versus 18.1 +/- 2.6 mg/l for the peak concentration, and 11.7 +/- 1.3 versus 11.6 +/- 1.01/m2 for the volume of distribution (Vd), respectively. We therefore conclude that administration of etoposide by HAI does not result in a significantly higher liver extraction. Hepatic extraction of etoposide is determined by the fraction of non-protein-bound (free) drug present. The lack of a difference between the two administration routes suggests that under in vivo conditions the equilibrium between free and bound drug is established before the drug reaches the hepatic arterioles. Consequently, administration by HAI does not lead to an increased exposure of the tumor in the liver to free (active) etoposide. Furthermore, the overall exposure of the liver to total (bound + free) etoposide is increased only from about 100 to 120 mg l-1 h. These results do not favor the use of this more complex route of drug administration in the treatment of (metastatic) cancer located in the liver. PMID- 8674165 TI - Comparison of ethanol plasma-protein precipitation with plasma ultrafiltration and trichloroacetic acid protein precipitation for the measurement of unbound platinum concentrations. AB - Sample preparation for the measurement of non-protein-bound platinum was evaluated by precipitation of plasma proteins with cold ethanol. The method was compared with the routinely used plasma ultrafiltration and with trichloroacetic acid (TCA) protein precipitation. After incubation of human plasma samples with cisplatin or carboplatin, unbound platinum concentrations were determined applying Amicon Diaflo ultrafiltration membranes and Millipore ultrafree-MC filters. For protein precipitation, 1 ml of cold (-20 degrees C) pure ethanol was added to 0.5 ml of human plasma and the supernatant was collected after 2 h, or 0.5 ml of cold 20% TCA was added to 0.5 ml of plasma. Platinum was analyzed by atomic absorption spectrophotometry (AAS). There was no significant difference between the ethanol and ultrafiltration methods in the unbound platinum concentration. The protein content in the supernatant (1.00 +/- 0.20%) was slightly higher than that in the Amicon (0.58 +/- 0.05%) and Millipore (0.55 +/- 0.04%) ultrafiltrates. On average, the TCA and ethanol method seemed to be equally appropriate. The ethanol precipitation method is concluded to be simple, convenient, and reproducible and has negligible costs. PMID- 8674166 TI - 90th Anniversary of the development by Nikolai S. Korotkoff of the auscultatory method of measuring blood pressure. PMID- 8674167 TI - Noninvasive quantification of valvular regurgitation. Getting to the core of the matter. PMID- 8674168 TI - Sex-related differences in autonomic modulation of heart rate in middle-aged subjects. AB - BACKGROUND: Women have worse outcomes when they experience acute myocardial infarction (MI), but the reasons for this sex-related difference are not well understood. Because cardiovascular neural regulation plays an important role in cardiac mortality, we studied possible sex-related differences in the autonomic modulation of heart rate (HR) in middle-aged subjects without known heart disease. METHODS AND RESULTS: Baroreflex sensitivity (BRS) and HR variability were studied in randomly selected, age-matched populations of middle-aged women (n = 186; mean age, 50 +/- 6 years) and men (n = 188; mean age, 50 +/- 6 years) without hypertension, diabetes, or clinical or echocardiographic evidence of heart disease. BRS measured from the overshoot phase of the Valsalva maneuver was significantly lower in women (8.0 +/- 4.6 ms/mm Hg, n = 152) than in men (10.5 +/ 4.6 ms/mm Hg, n = 151) (P < .001), and the low-frequency component of HR variability measured from ECG recordings also was lower in women (P < .001), whereas the high-frequency component was higher in women than in men (P < .001). The ratio between the low-and high-frequency oscillations also was lower in the women (P < .001). The increase of HR and decrease of high-frequency component of HR variability in response to an upright posture were smaller in magnitude in women than in men (P < .01 for both). After adjustment for differences in the baseline-variables, such as blood pressure, HR, smoking, alcohol consumption, and psychosocial score, the sex-related differences in BRS and HR variability still remained significant (P < .001 for all). Women with estrogen replacement therapy (n = 46) had significantly higher BRS and total HR variance than the age-matched women without hormone treatment (P < .01 for both), and the BRS and HR variability of the women with estrogen therapy did not differ from those of the age-matched men. CONCLUSIONS: Baroreflex responsiveness is attenuated in middle aged women compared with men, but the tonic vagal modulation of HR is augmented. Hormone replacement therapy appears to have favorable effects on the cardiovascular autonomic regulation in postmenopausal women. PMID- 8674169 TI - Echocardiographic and radionuclide pulmonary blood flow patterns after transcatheter closure of patent ductus arteriosus. AB - BACKGROUND: Transcatheter occlusion of patent ductus arteriosus (PDA) has been associated with protrusion of the occluder device into the left pulmonary artery (LPA). This study was conducted to evaluate the significance of occluder protrusion and its implications for potential obstruction of the LPA and associated decrease of left lung perfusion. METHODS AND RESULTS: Fifty-two patients underwent successful transcatheter PDA occlusion over a period of 5 years. In this study, 49 were reexamined between March and June 1995. In addition to clinical and echocardiographic examination, lung scintigraphy was performed. Protrusion into the LPA was present in 5 of 49 patients (10%). In these patients, maximal flow velocity in the LPA was significantly (P < .01) increased. Decreased left lung perfusion, defined as < 40% of total pulmonary blood flow, was found in 7 of 49 patients (14%). Although mean left pulmonary perfusion was significantly (P = .02) decreased in patients with protrusion, there was considerable overlap with patients without protrusion, and only a weak correlation was found (r = .35, P = .01) between flow-velocity and left lung perfusion. CONCLUSIONS: Our results demonstrate that protrusion of the device in the LPA is an infrequent finding. If present, it is associated with increased maximal flow velocity in the LPA and diminished left lung perfusion. However, echocardiography and lung scintigraphy are weakly correlated: Increased maximal blood flow velocities in the proximal LPA proved to be a poor indicator or impaired left lung perfusion. Also, decreased perfusion occurs in the absence of echocardiographic evidence of device protrusion. PMID- 8674170 TI - Effects of L-arginine supplementation on endothelium-dependent coronary vasodilation in patients with angina pectoris and normal coronary arteriograms. AB - BACKGROUND: The pathogenesis of impaired endothelium-dependent coronary vasodilation in angina pectoris and normal coronary arteriograms (microvascular angina pectoris) is not known. We examined whether supplementation with L arginine, a precursor of endothelium-derived nitric oxide, improves endothelium dependent coronary vasodilation in patients with microvascular angina. METHODS AND RESULTS: The effect of intracoronary infusion of L-arginine (50 mg/mm) on acetylcholine-induced coronary vasomotion was studied in eight patients with microvascular angina and eight control subjects. The responses of the large epicardial coronary artery diameter and coronary blood flow were measured with coronary arteriography and an intracoronary Doppler catheter, respectively. Acetylcholine increased coronary blood flow with modest vasoconstriction of the large coronary artery without altering arterial pressure and heart rate. The acetylcholine-induced increases in coronary blood flow were significantly less (P < .01) in patients than in control subjects. L-Arginine significantly augmented the coronary blood flow responses to acetylcholine in patients, but not in control subjects. L-Arginine did not alter responses of the large coronary artery in either group. CONCLUSIONS: Study results suggest that L-arginine improved endothelium-dependent vasodilation of coronary microcirculation in patients with microvascular angina pectoris. PMID- 8674171 TI - Quality of life, employment status, and anginal symptoms after coronary angioplasty or bypass surgery. 3-year follow-up in the Randomized Intervention Treatment of Angina (RITA) Trial. AB - BACKGROUND: The Randomized Intervention Treatment of Angina (RITA) trial compares initial policies of percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft surgery (CABG) in 1011 patients with angina. This report assesses the impact of these revascularization procedures on angina, quality of life (according to the Nottingham Health Profile), and employment over 3 years of follow-up. METHODS AND RESULTS: Both interventions produced marked improvement in all quality-of-life dimensions (energy, pain, emotional reactions, sleep, social isolation, and mobility) and seven aspects of daily living. Patients with angina at 2 years had more quality-of-life impairment than angina free patients, whose perceived health was similar to population norms. This reflects the close link at baseline between angina grade and quality of life. The slightly greater impairment of quality of life in PTCA compared with CABG patients is a result of their significantly higher chances of having angina, especially after 6 months. Employment status was investigated mainly for men < or = 60 years old. PTCA patients returned to work sooner (40% at 2 months compared with 10% of CABG patients), but the latter caught up by 5 months. After 2 years, 22% and 26% of CABG and PTCA patients, respectively, were not working for cardiac reasons. Patients with angina at 2 years were much more likely to be unemployed than those without. CONCLUSIONS: The impact of angina on quality of life and unemployment is greatly alleviated by PTCA or CABG. Angina is avoided more successfully with CABG, but PTCA offers a speedier return to work. Both intervention strategies then produce similar benefits for quality of life and employment over several years. PMID- 8674172 TI - Cost-effectiveness of a coronary care unit versus an intermediate care unit for emergency department patients with chest pain. AB - BACKGROUND: Guidelines are not available for which patients with acute chest pain should be admitted to the coronary care unit and which patients can be reasonably triaged to monitored beds in lower levels of care. METHODS AND RESULTS: Clinical and resource utilization data from 12 139 emergency department patients with acute chest pain were used in a decision-analytic model to identify cost effective guidelines for the admission to a coronary care unit versus an intermediate care unit for initially uncomplicated patients without other indications for intensive care. The probability of clinical complications and death were derived from data on age-specific subsets of the population. Resource utilization estimates were based on cost data from a subset of 901 patients and length of stay data for the entire cohort. The survival benefit associated with initial triage to the coronary care unit instead of an intermediate care unit was assumed to be 15%. In the baseline analysis for 55- to 64-year-old patients, the probability of acute myocardial infarction (AMI) at which the coronary care unit had an incremental cost-effectiveness below $50 000 per year-of-life-saved was 29%. Triage to the coronary care unit was somewhat more cost-effective in elderly patients because their higher early complication rate more than offset their shorter life expectancy. CONCLUSIONS: This analysis indicates that the coronary care unit usually should be reserved for patients with a moderate (21% or more, depending on the patient's age) probability of AMI unless patients need intensive care for other reasons. Clinical data suggest that only patients with ECG changes of ischemia or infarction not known to be old have a probability of AMI this high. Intermediate care units are appropriate for patients whose risks are not high enough for a coronary care unit to be cost-effective but too high for other alternatives to be recommended for safety and effectiveness. PMID- 8674173 TI - Comparison of d,l-sotalol and implantable defibrillators for treatment of sustained ventricular tachycardia or fibrillation in patients with coronary artery disease. AB - BACKGROUND: Implantable cardioverter-defibrillators (ICDs) and d,l-sotalol are widely used to treat ventricular tachyarrhythmia and ventricular fibrillation (VT/VF). The purpose of this study was to compare the long-term efficacy of d,l sotalol and ICDs in patients with coronary artery disease. METHODS AND RESULTS: In a case-control study, 50 patients treated with oral d,l-sotalol were matched to 50 patients treated with ICDs. Both groups were matched for sex (82 men), age (58 +/- 10 years), ejection fraction (40 +/- 12%), extent of coronary artery disease, presenting arrhythmia, and year that treatment began. In all patients in the sotalol group, VT/VF was inducible in the drug-free electrophysiological study. Induction of sustained VT/VF was suppressed by d,l-sotalol (438 +/- 95 mg/d). In the ICD group, either VT/VF was not inducible (n = 5) or inducible sustained VT/VF was refractory to antiarrhythmic drug treatment (n = 45). Sotalol treatment led to a marked reduction in arrhythmic events. Whereas 83% of the patients in the sotalol group were free of sudden death and nonfatal VT at 3 years, only 33% of the ICD patients did not receive appropriate ICD therapies (P < .005). Actuarial rates for absence of sudden death at 3 years were 85% in the sotalol group and 100% in the ICD group (P < .005). Actuarial rates for overall survival at 3 years were 75% in the sotalol group and 85% in the ICD group (P = .02). CONCLUSIONS: In this case-control study, ICD therapy was more effective tha electrophysiologically guided antiar-rhythmic treatment with d,l-sotalol in prevention of sudden death and reduction of total morality in patients with coronary artery disease. Prospective studies are needed to confirm these results. PMID- 8674174 TI - In vitro flow mapping of regurgitant jets. Systematic description of free jet with laser Doppler velocimetry. AB - BACKGROUND: Color Doppler and magnetic resonance imaging give pictures of abnormal jets within which the respective contribution of fluid mechanics and image artifacts are difficult to establish because of current technical limitations of these modalities. We conducted the present study to provide numerical descriptions of the velocity fields within regurgitant free jets. METHODS AND RESULTS: Laser Doppler measurements were collected in rigid models with pulsatile flow conditions, giving several series of two-dimensional flow images. The data were studied with the use of two-dimensional or M-mode flow images as well as regular plots. Numerical descriptions validated in steady flow conditions were tested at the various times of the cycle. In these free jets, the momentum was conserved throughout the cycle. The transverse velocity profiles were approximately similar. A central laminar core was found at peak ejection and during the deceleration. Its length (l = 4.08 d-0.036 mm, r = .99) and its diameter (d) were proportional to the orifice diameter. At peak ejection, the velocity decay was hyperbolic, and the transverse velocity profiles were clearly gaussian. The different relations that were tested could be combined in a single formula describing the velocity field: V(x,y,t peak) = V(O,O,t peak).4.(d/x).10( 45(y/x)2) (r = .92). CONCLUSIONS: These in vitro measurements demonstrated the presence of a central laminar core and similar transverse velocity profiles in free turbulent jets. This allowed us to validate a series of numerical relations that can be combined to describe the velocity fields at peak ejection. On the other hand, further studies are needed to describe the various singularities often encountered in pathology. PMID- 8674175 TI - Influence of HLA matching on thoracic transplant outcomes. An analysis from the UNOS/ISHLT Thoracic Registry. AB - BACKGROUND: The benefit of matching donor organs and recipients for HLAs has been well established in renal transplantation and has been suggested for thoracic organ transplantation. To determine the effect of HLA matching in cardiac and single-lung transplantation, the following study was performed. METHODS AND RESULTS: Using the joint Thoracic Transplant Registry or the United Network for Organ Sharing and the International Society for Heart and Lung Transplantation, all adult primary heart and single-lung transplant procedures performed in the United States from October 1987 through December 1993 were analyzed to determine the effects of HLA matching on transplant mortality. Both total HLA matches and matches at individual HLA loci were considered. Including HLA matching, 16 potential risk factors for heart transplant outcome and 16 potential risk factors for lung transplant outcome were subjected to multivariate analysis. A total of 10752 heart transplants and 1239 lung transplants were included in the independent analyses for each organ. For heart transplantation, there was a progressive reduction in risk for greater matching (1 or 2 matches: risk ratio, 0.83; 3 matches: risk ratio, 0.67; 4 to 6 matches: risk ratio, 0.59; all P < or = .01). The primary benefit of matching appeared to be at the A and DR loci (risk ratios, 0.87 and 0.79, respectively; P < .001). For lung transplantation, any matching had an independent positive effect on outcome; however, the relationship between numbers of HLA matches and relative risk was not present and ranged from risk ratios of 0.71 to 0.87 (P = .01 and P = .47, respectively). In this analysis, only matching at the A locus appeared to statistically influence outcome (risk ratio, 0.76; P = .01). CONCLUSIONS: These data demonstrate that HLA matching independently impacts survival in both heart and single-lung transplantation. PMID- 8674176 TI - Different effects of estrogen and progesterone on experimental atherosclerosis in female versus male rabbits. Quantification of cellular proliferation by bromodeoxyuridine. AB - BACKGROUND: The aim of the present study was to compare the effect of estrogen and progesterone on the development of experimental atherosclerosis in female versus male rabbits to assess possible sex-specific differences. METHODS AND RESULTS: A total of 32 female and 32 male New Zealand White rabbits were ovariectomized or castrated. In addition to a 0.5% cholesterol diet, the rabbits received estradiol alone (1 mg/kg body wt [BW] per week), progesterone alone (25 mg/kg BW per week), or combined estradiol-progesterone in these dosages during 12 weeks. Ovariectomized female and castrated male rabbits served as control groups without hormone treatment. Before excision of the vessels, bromodeoxyuridine labeling was performed to determine the extent of cellular proliferation in the atherosclerotic lesions. The aortic arch was analyzed immunohistologically and morphometrically. An inhibitory effect of estrogen on intimal plaque size was found in female rabbits compared with the ovariectomized control group (0.7 +/- 0.5 versus 3.7 +/- 2.5 mm2, P < .002; proliferating cells, 3.1 +/- 1.8% versus 8.5 +/- 2.6%, P < .002). In combination with progesterone, however, estrogen was not able to reduce intimal plaque size or cellular proliferation. In contrast, estradiol in castrated male rabbits was not associated with an inhibitory effect on cellular proliferation or intimal thickening compared with controls (estrogen treatment, 7.6 +/- 2.1% proliferating cells and 2.8 +/- 1.0 mm2 neointima; control group, 7.2 +/- 2.1% cellular proliferation and 2.9 +/- 1.2 mm2 intimal thickening). CONCLUSIONS: Our data suggest that the atheroprotective effect of estrogen is probably due to a mechanism that is present in female rabbits only. PMID- 8674177 TI - Altered serotonin receptor subtypes mediate coronary microvascular hyperreactivity in pigs with chronic inhibition of nitric oxide synthesis. AB - BACKGROUND: We previously reported that chronic inhibition of nitric oxide synthesis by administration of N omega-nitro-L-arginine methyl ester (L-NAME) causes microvascular hyperreactivity to 5-hydroxytryptamine (5-HT) and vascular structural changes in pigs in vivo. In the present study, we investigated the relative contributions of 5-HT receptor subtypes to microvascular hyper reactivity in this animal model. METHODS AND RESULTS: Coronary vasomotor response was studied in 16 pigs treated with oral L-NAME for 4 weeks (L group) and in 11 control pigs (C group). Intracoronary administration of 5-HT at 30 micrograms/kg decreased coronary blood flow (CBF) in the two groups. The decrease in CBF by 5 HT was greater (P < .01) in the L group than in the C group. The decrease in CBF by 5-HT in the C group was blocked completely by pretreatment with ketanserin, a 5-HT2 antagonist. In contrast, the augmented decrease in CBF by 5-HT in the L group was only partly inhibited by ketanserin alone and was blocked completely by ketanserin and methiothepin, a 5-HT1/5-HT2 antagonist. The decrease in CBF caused by prostaglandin F2 alpha and the increase in CBF caused by nitroglycerin were comparable between the two groups and were not affected by the 5-HT antagonists. CONCLUSIONS: These results suggest that the 5-HT-induced microvascular hyperreactivity may be mediated by relative changes in affinity for 5-HT receptors or de novo expression of 5-HT1 receptors in microvascular smooth muscle cells in our animal model. PMID- 8674178 TI - Coronary artery spasm does not depend on the intracellular calcium store but is substantially mediated by the protein kinase C-mediated pathway in a swine model with interleukin-1 beta in vivo. AB - BACKGROUND: The intracellular mechanism for coronary artery spasm is still unknown. Since the protein kinase C (PKC)-mediated pathway and Ca2+ release from sarcoplasmic reticulum (SR) are important intracellular mechanisms of vascular smooth muscle contraction, we examined the possible role of these two mechanisms in the pathogenesis of coronary spasm in our swine model in vivo. METHODS AND RESULTS: In 25 pigs, interleukin-1 beta (IL-1 beta) was applied chronically to the coronary arteries from the adventitia to induce an inflammatory/proliferative lesion. Two weeks after the operation, either intracoronary serotonin or histamine repeatedly induced coronary spasm at the IL-1 beta-treated site. At those spastic sites, phorbol-12, 13-dibutyrate, a PKC-activating phorbol ester, also induced coronary spasm, which was blocked by pretreatment with the PKC inhibitors staurosporine and sphingosine. Serotonin- and histamine-induced coronary spasm was also significantly inhibited by pretreatment with staurosporine, sphingosine, or nifedipine (an L-type Ca2+ channel antagonist) but not by ryanodine (an inhibitor of Ca(2+)-induced Ca2+ release from SR) or thapsigargin (an inhibitor of Ca(2+)-ATPase of SR). Bay K 8644 (an L-type Ca2+ channel agonist) also induced coronary spasm at the IL-1 beta-treated site, which was significantly inhibited by pretreatment with staurosporine, sphingosine, and nifedipine. In contrast, coronary vasoconstriction induced by prostaglandin F2 alpha was not affected by pretreatment with staurosporine or sphingosine but was significantly inhibited by pretreatment with ryanodine, thapsigargin, or nifedipine. CONCLUSIONS: These results suggest that (1) PKC activation largely accounts for the serotonin- and histamine-induced coronary spasm; (2) at the spastic site, the calcium influx through L-type Ca2+ channels may be augmented via the PKC-mediated pathway; and (3) the Ca2+ release from the SR into the cytosol may not play a primary role in coronary spasm. PMID- 8674179 TI - Recombinant staphylokinase variants with altered immunoreactivity. I: Construction and characterization. AB - BACKGROUND: Recombinant staphylokinase offers promise for thrombolytic therapy in acute myocardial infarction, but it is immunogenic. Although reduced immunogenicity of heterologous proteinaceous drugs by protein engineering has not previously been reported, an attempt was made to achieve this in staphylokinase by site-specific mutagenesis. METHODS AND RESULTS: Biospecific interaction analysis of a panel of 17 murine monoclonal antibodies against recombinant staphylokinase (SakSTAR variant) identified three nonoverlapping immunodominant epitopes, two of which could be eliminated by substitution mutagenesis of clusters of two or three charged amino acids with alanine. Circulating anti staphylokinase antibodies elceted in patients by treatment with SakSTAR were incompletely (< 90%) absorbed by these mutants. Therefore, the combination variants K35A,E38A,K74A,E75A,R77A (SakSTAR.M38) and K74A,E75A,R77A,E80A,D82A (SakSTAR.M89) were constructed, expressed in Escherichia coli, highly purified by ion-exchange and hydrophobic interaction chromatography, and characterized. These variants had specific activities that were approximately half that of SakSTAR, and they combined the reduced reactivity with the panels of monoclonal antibodies of their parent molecules. Absorption of circulating antibodies elicited in patients by treatment with SakSTAR was incomplete in 13 of 16 patients (median values, 68% and 65% with SakSTAR.M38 and SakSTAR.M89, respectively). CONCLUSIONS: SakSTAR contains three immunodominant epitopes, two of which were eliminated by site-directed mutagenesis, yielding combination mutants with relatively maintained specific activities that were not recognized by a significant fraction of the antibodies elicited in patients by treatment with wildtype SakSTAR. These mutants appear to be suitable for more detailed investigation of their thrombolytic and antigenic properties. PMID- 8674180 TI - Recombinant staphylokinase variants with altered immunoreactivity. II: Thrombolytic properties and antibody induction. AB - BACKGROUND: The substitution variants K35A,E38A,K74A, E75A,R77A (SakSTAR.M38) and K74A,E75A,R77A,E80A, D82A (SakSTAR.M89) of recombinant staphylokinase (SakSTAR) with reduced antibody reactivity were assayed for thrombolytic potency and antibody induction in animal models and in patients. METHODS AND RESULTS: In a 125I-fibrin-labeled pulmonary embolism model in the hamster, the doses giving 50% clot lysis in 90 minutes were 25 micrograms/kg for SakSTAR, 85 micrograms/kg for SakSTAR.M38, and 90 micrograms/kg for SakSTAR.M89. In rabbits with 125I-fibrin labeled plasma clots incorporated into extracorporeal arteriovenous loops, lysis within 2 hours was 76 +/- 18% (mean +/- SD, n = 28) with 400 micrograms/kg SakSTAR, 53 +/- 13% (n = 8) with 1000 micrograms/kg SakSTAR.M38, and 39 +/- 13% (n = 6) with 800 micrograms/kg SakSTAR.M89. When groups of eight rabbits were immunized by intravenous administration of 0.2 to 1.0 micrograms/kg compound followed by subcutaneous injection of 0.4 mg in Freund's adjuvant at 2, 3, and 5 weeks, SakSTAR.M38 and SakSTAR.M89 elicited markedly less circulating neutralizing activity, compared with SakSTAR, when determined at 6 weeks (neutralizing 6.1 +/- 3.0 and 4.9 +/- 1.3 micrograms compound/mL plasma, respectively, versus 20 +/- 17 micrograms/mL; P = .02 and P = .01, respectively) and induced significantly less resistance to thrombolysis (residual thrombolytic potency producing 59 +/- 25% and 39 +/- 12% lysis, respectively, versus 8.5 +/- 5.7%; P = .008 and P = .006, respectively). In patients with peripheral arterial occlusion, intra-arterial administration of SakSTAR.M38 (n = 4) or SakSTAR.M89 (n = 4) induced significantly fewer circulating neutralizing antibodies (P = .03) and specific IgG (P = .01) at 2 to 3 weeks than SakSTAR (n = 8). CONCLUSIONS: SakSTAR.M38 and SakSTAR.M89 induce less antibody formation and might constitute preferred agents for thrombolytic therapy in humans. PMID- 8674181 TI - Rapid rates during bradycardia prolong ventricular refractoriness and facilitate ventricular tachycardia induction with cesium in dogs. AB - BACKGROUND: Bradycardia can promote the development of some ventricular techycardias (VTs). We investigated whether relative bradycardia per se or the transition from a rapid to a slower ventricular rate might be important in developing VT. METHODS AND RESULTS: We studied groups of anesthetized closed chest dogs that had AV produced by radiofrequency catheter ablation of the AV junction. One group had uninterrupted AV block; the other group underwent a period of rapid left ventricular pacing. Both groups then received incremental doses of CsCl until sustained VT resulted. We also measured ventricular effective refractory period (V-ERP) and QT interval in separate groups of dogs that had AV block for 1 week or 3 days with and without rapid pacing (pacing cycle length [PCL] = 500 or 250 ms) for 1 hour or 30 minutes. Finally, we investigated the effects of rapid pacing on V-ERP by testing the effects of verapamil and autonomic denervation on these changes. We found that CsCl induced larger early afterdepolarizations and a greater prevalence of VT in dogs with rapid pacing than in dogs without. In dogs that had AV block for 1 week, 1 hour of rapid pacing prolonged V-ERP and QT interval compared with V-ERP and QT interval before pacing. Changes persisted for at least 3 hours. Rapid pacing for only 30 minutes and at a PCL of 250 ms, as well as superimposition on sinus rhythm, each prolonged V-ERP but to a lesser extent. Only 3 days of complete AV block and autonomic denervation did not affect the prolongation of V-ERP produced by rapid pacing, whereas verapamil significantly blunted but did not eliminate the prolongation. CONCLUSIONS: At the same PCLs, the heart exposed to transient tachycardia superimposed on bradycardia exhibited a longer V-ERP, QT interval, and monophasic action potential duration and greater ease for developing VT than the heart exposed only to bradycardia. The prolongation of refractoriness lasted for at least 3 hours, and the delta-ERP was influenced by the heart rate before pacing, the duration of pacing, and the PCL. The mechanism for this response to rapid rates appears to involve calcium, at least in part. PMID- 8674182 TI - Late consequences of Kawasaki disease. PMID- 8674183 TI - Metabolism of anabolic androgenic steroids. AB - Anabolic androgenic steroids (AAS) are misused to a high extent in sports by athletes to improve their physical performance. Sports federations consider the use of these drugs in sports as doping. The misuse of AAS is controlled by detection of the parent AAS (when excreted into urine) and (or) their metabolites in urine of athletes. I present a review of the metabolism of AAS. Testosterone is the principal androgenic steroid and its metabolism is compared with that of AAS. The review is divided into two parts: the general metabolism of AAS, which is separated into phase I and phase II metabolism and includes a systematic discussion of metabolic changes in the steroid molecule according to the regions (A-D rings), and the specific metabolism of AAS, which presents the metabolism of 26 AAS in humans. PMID- 8674184 TI - Molecular diagnosis of Charcot-Marie-Tooth 1A disease and hereditary neuropathy with liability to pressure palsies by quantifying CMT1A-REP sequences: consequences of recombinations at variant sites on chromosomes 17p11.2-12. AB - The most frequent form of Charcot-Marie-Tooth disease (CMT1A; OMIM118.220) is the result of a duplication on chromosome 17 in pll.2-p12. This region contains PMP22, a gene expressed in peripheral myelin. The mutation results from an unequal crossing-over involving repeated sequences, CMT1A-REP, located on both sides of the duplicated region. The reciprocal product of this recombination is a deletion of the same region, which is associated with hereditary neuropathy with liability to pressure palsies (HNPP; OMIM162.500). Proximal and distal CMT1A-REP sequences can be distinguished by the presence of a variant EcoRI site. We quantified the number of these repeat sequences in 36 CMT1A and 40 HNPP patients. CMT1A-REP sequences are involved in almost all of the mutations. The majority of recombination breakpoints occur distally from the variant EcoRI site. However, a few have a breakpoint proximal to this site, which creates the risk of misinterpretation with respect to a duplicated/deleted status. PMID- 8674185 TI - Analytical performance and clinical validity of two free prostate-specific antigen assays compared. AB - We compared two recently introduced commercial assays (CanAg and Immulite) for measuring free prostate-specific antigen (f-PSA), total PSA (t-PSA), and the ratio of t-PSA/f-PSA (f-PSA%) in control materials and sera of 54 healthy men, 50 patients with benign prostatic hyperplasia (BPH), and 45 patients with prostate cancer (PCa). The lower detection limits for f-PSA were 0.038 microgram/L and 0.004 microgram/L for the CanAg and Immulite assays, respectively. The within-run and between-day precisions of the Immulite assay were < 5%; the CanAg assay showed a poorer precision. Whereas f-PSA values differed between controls and patients but not between BPH and PCa patients, the f-PSA% values were lower in PCa patients than in BPH patients and controls. The receiver-operating characteristic (ROC) curve showed an improved diagnostic power of f-PSA% compared with t-PSA to discriminate between BPH and PCa. Discrimination limits of 16% (CanAg assay), and 15% (Immulite assay) are recommended for f-PSA%. PMID- 8674186 TI - Immunofluorometric assay for sensitive and specific measurement of human prostatic glandular kallikrein (hK2) in serum. AB - Prostate-specific antigen (PSA) and human prostatic glandular kallikrein (hK2) have 79% identity with the primary structure. When we used recombinant hK2 protein, only 7 of 23 monoclonal anti-PSA IgGs (monoclonal antibodies, MAbs) cross-reacted with hK2, which enabled us to design a novel immunofluorometric MAb MAb assay for the specific detection of hK2. In the first incubation, an excess of MAb 2H11, which does not cross-react with hK2, is added to prevent both free and complexed PSA from reacting in subsequent immunoreactions. In the second incubation, biotinylated MAb H50, which cross-reacts with hK2 by an epitope overlapping with MAb 2H11, served to bind only hK2 to the microtitration wells coated with streptavidin. In the third step, Eu-labeled MAb H117, which cross reacts with hK2, detected the immobilized hK2. The hK2 assay was calibrated with recombinant hK2. The detection limit of the assay was 0.1 microgram/L, and the cross-reactivity with recombinant PSA was < or = 0.7%. The concentration of hK2 was measured in serum samples from 334 males with total PSA concentrations ranging from 1 to 3400 microgram/L. Most of the samples (57%) had hK2 concentrations below the detection limit. The proportions of hK2 relative to total PSA were 0-2% in 79%, 2-5% in 14%, 5-10% in 4%, and >10% in 3% of the samples. Gel filtration of 10 serum samples with increased hK2 concentrations showed a single peak of hK2 immunoreactivity with an apparent molecular size of approximately 30 kDa, corresponding to that of recombinant hK2 and free PSA. PMID- 8674187 TI - Prostaglandin D2 synthase: a component of human amniotic fluid and its association with fetal abnormalities. AB - Prostaglandin D2 (PGD2) synthase is responsible for PGD2 production in the brain. Western blot analysis of human amniotic fluid and probing with a polyclonal antibody against prostate-specific antigen (PSA) revealed a strong immunoreactive band with a molecular mass of 25 kDa. The immunoreactive species, which does not react with monoclonal anti-PSA antibodies, was purified to homogeneity from 1 L of amniotic fluid through successive cycles of gel filtration and ion-exchange chromatography. Amino acid sequence analysis (15 cycles) revealed that the protein was highly homologous or identical to PGD2 synthase. On semiquantitative analysis, PGD2 synthase concentration appears to increase dramatically during gestational weeks 12-25 and then declines slowly until term. PGD2 synthase concentration in amniotic fluid was altered in many abnormal pregnancies, most notably its decrease in trisomic fetuses and fetuses with renal abnormalities. PMID- 8674188 TI - Clinical validation of renin monoclonal antibody-based sandwich assays of renin and prorenin, and use of renin inhibitor to enhance prorenin immunoreactivity. AB - Newly developed IRMAs to measure the plasma concentrations of renin and prorenin were validated for clinical use and compared with a classical enzyme kinetic assay. The IRMAs involve two monoclonal antibodies, one that reacts equally well with renin and prorenin and one that recognizes renin well but prorenin only minimally. Prorenin reactivity with the second antibody was enhanced by adding the renin inhibitor, Remikiren, to plasma. The complex of prorenin with this active-site ligand undergoes a conformational change, whereby prorenin is converted into a form that cannot be differentiated from renin by the IRMA. The linear working range of the assay was 4.0-3000 mU/L. The concentration of prorenin was calculated by subtracting the assay result obtained without Remikiren (i.e., renin) from the result obtained with Remikiren (i.e., renin plus prorenin). No more than 2% of prorenin present in plasma was detected as renin. The interassay CVs for renin quantification were 18%, 13%, and 8% at low, medium, and high concentrations, respectively. The interassay CV for calculated prorenin was 8% at both low and high concentrations. The IRMA results were highly correlated with those of an enzyme kinetic assay in healthy subjects; in patients with such conditions as primary hyperaldosteronism, renovascular hypertension, and low-, medium-, and high-renin essential hypertension; and in women undergoing gonadotropin stimulation. PMID- 8674190 TI - Use of precision profiles to evaluate precision of the automated leukocyte differential. AB - The commonly used methods of assessing the precision of the automated leukocyte differential have certain drawbacks that affect the validity and comparability of results. In the present report, we introduce a procedure based on building precision profiles from a large number of within-run imprecision experiments. The profiles are fitted to the function for the CV of proportions, which yields the number of theoretically differentiated leukocytes. Differences between fitted curves are evaluated for statistical significance by the F-test. As an example, we compared the precision of two hematology analyzers, a flow-cytometric technique involving fluorescence-labeled monoclonal antibodies, and the manual differential. We were able to establish definite differences in precision between different analyzers and different leukocyte classes. Our data also indicated that conventional within-run imprecision studies may completely misjudge analyzer precision. Furthermore, we could demonstrate that the precision of analyzers that analyze a fixed amount of blood rather than a fixed number of leukocytes is strongly influenced by the leukocyte count of the sample, leading to high imprecision for leukopenic samples. We believe the proposed procedure is a useful addition to currently used protocols; it yields clear results and creates a statistical basis of comparison between various instruments and techniques of differentiation. PMID- 8674189 TI - High serum IgA concentrations in patients with diabetes mellitus: agewise distribution and relation to chronic complications. AB - In this study we investigated the agewise distributions of serum IgA concentrations in 1251 type 1 and 2224 type 2 diabetic patients, and the association between serum IgA concentration and diabetic complications (retinopathy, neuropathy, nephropathy, macroangiopathy, and hypertension). The IgA concentrations of all groups of diabetic patients were significantly higher than those of the corresponding subgroups of 943 control subjects, except for type 1 patients >60 years of age. High IgA concentrations were found in 23.1% of the whole diabetic group. The prevalence of high IgA was significantly greater in males than in females among type 1 patients (24.4% vs 18%). In conclusion, an increase in circulating IgA concentrations is a generalized phenomenon among diabetic patients; IgA concentrations above the reference range are more common among male than female diabetics; and diabetic complications are associated with a significant increase in serum IgA concentration. PMID- 8674191 TI - Preparation of samples with equally spaced concentrations through mixing. AB - Linearity, interference evaluations of the performance of clinical chemistry systems, mathematical model selection for nonlinear calibration, and other assessments often involve several human sample pools with equally spaced analyte concentrations. Sequential mixing of equal volumes, first of the low and high pools to produce the middle pool, then of the low and middle pools to produce the mid-low pool, and of the high and middle pools to produce the mid-high pool, is recommended in the NCCLS EP7-P guideline for interference studies. Proportional mixing of the low and high pools to produce all of the required pool concentrations is recommended in the NCCLS EP6-P guideline for linearity studies. Mathematical analysis and computer simulation show that the sequential mixing is much more accurate and precise than the proportional mixing. Therefore, we recommend sequential mixing for clinical chemistry application. PMID- 8674192 TI - Robust, reliable biosensor for continuous monitoring of urea during dialysis. AB - We developed a new urea sensor for the on-line monitoring of hemodialysis adequacy. The biosensor consisted of an immobilized urease cartridge placed between magnetoinductive conductivity cells. The biosensor output was taken as the conductivity difference between these cells. The device was placed on the ultrafiltrate line of a paired filtration dialysis system. The amount of urease present in the cartridge was sufficient for the complete conversion to ammonium carbonate of urea up to 35 mmol/L. Agreement was good between the urea concentration by the biosensor method and an automated analyzer for seven patients: range 8.07-30.3 mmol/L (22.6-84.8 mg/dL blood urea nitrogen, BUN); intercept 0.20 +/- 0.1 mmol/L (0.55 +/- 0.4 mg/dL BUN); slope 1.01 +/- 0.01; r 0.997; S(y/x) 0.40 mmol/L (1.11 mg/dL BUN). The device proposed meets the requirements of accuracy, cost, ruggedness, and ease of use (no calibration required) for a biosensor to be used for continuous monitoring of hemodialysis. PMID- 8674193 TI - Validation of HPLC-amperometric detection to measure serotonin in plasma, platelets, whole blood, and urine. AB - We describe an isocratic liquid-chromatographic method with amperometric detection for determination of serotonin by rapid sample preparation. Platelet poor plasma and platelets were injected after a single deproteinization step with perchloric acid. Addition of sodium borohydride to whole blood avoids oxidation of serotonin during the deproteinization step without any chromatographic interferences. We purified urinary serotonin by two successive cationic and anionic extraction steps. After urine dilution, urinary 5-hydroxyindoleacetic acid (5-HIAA) was measured under the same chromatographic conditions. Platelet serotonin concentrations correlated more closely with whole-blood serotonin concentrations after correction for platelet number than with concentrations expressed in nmol/L. This suggests that whole-blood serotonin measurements should be corrected for platelet count to eliminate the variability of circulating platelets. Combined determination of serotonin in whole blood and urine and of 5 HIAA in urine provides a useful tool for detecting and monitoring carcinoid tumors. PMID- 8674195 TI - Long-term stability of blood glutathione and cysteine in humans. AB - Glutathione (GSH) availability is an important factor in the maintenance of health. Accordingly, blood GSH has been proposed as an indicator of health status. To validate the use of blood GSH in population studies, we investigated the long-term intraindividual variation of blood GSH and cyst(e)ine (Cys and cystine) concentrations in healthy adults. In a longitudinal study of 10 subjects, GSH and cyst(e)ine were measured in blood samples collected weekly over 8 months. The average within-person CV for GSH was only 9.1% compared with an observed interindividual CV of 20%. Blood cyst(e)ine was more variable within individuals (mean CV 14.7%) than GSH, whereas the interindividual CV for cyst(e)ine was lower (8.6%). The results demonstrate the stability of blood GSH in free-living subjects and the utility of GSH measurements as an indicator of long-term GSH status. PMID- 8674194 TI - Evidence for presence of a reduced form of digoxin-like immunoreactive factor (dihydro-DLIF) in mammalian tissues. AB - Digoxin-like immunoreactive factor (DLIF) from adrenal glands is an endogenous ligand structurally related to the plant-derived cardiac glycoside digoxin. Cardiac glycosides regulate the activity of the sodium pump and thus play key roles in disease processes involving regulation of ion transport. We now report the discovery of an endogenous dihydro-DLIF analogous to dihydrodigoxin. We used HPLC, ultraviolet spectrophotometry, and cross-reactivity with two antibodies, one specific for digoxin and one for dihydrodigoxin, to support the hypothesis that dihydro-DLIF contains a chemically reduced lactone ring. The spectral absorbance maximum for dihydro-DLIF is at 196 nm, identical to dihydrodigoxin. DLIF and dihydro-DLIF are 975- and 2588-fold less immunoreactive than digoxin and dihydrodigoxin for their respective antibodies. The molar ratio of dihydro-DLIF to DLIF is approximately 5.3 in bovine adrenocortical tissue and approximately 0.38 in human serum. Dihydrodigoxin (reduced lactone ring) added to microsomes isolated from bovine adrenal cortex produced a 4.5-fold increase in digoxin-like immunoreactivity (oxidized lactone ring) after 3 h of incubation. The biotransformation is likely mediated by a cytochrome P-450 NADPH-dependent process. Our findings demonstrate the presence of a dihydro-DLIF in mammals and suggest a metabolic route for synthesis of endogenous DLIF in mammalian tissue. PMID- 8674196 TI - Rapid analysis of amplified double-stranded DNA by capillary electrophoresis with laser-induced fluorescence detection. PMID- 8674197 TI - Influence of delay in stool sampling on fecal occult blood test sensitivity. PMID- 8674198 TI - Nonisotopic detection of point mutations in CYP21B gene in steroid 21-hydroxylase deficiency. PMID- 8674199 TI - Immunoreactivity of prostate-specific antigen in plasma and saliva of healthy women. PMID- 8674200 TI - Four automated methods for plasma lactate assessed by comparison with capillary gas chromatography. PMID- 8674201 TI - Influence of hemoglobin S adducts on hemoglobin A2 quantification by HPLC. PMID- 8674202 TI - Improved procedure for eluting DNA from dried blood spots. PMID- 8674203 TI - Reference calibrators for IgG antibodies to beta2-glycoprotein I: preparation, properties and availability to investigators. PMID- 8674204 TI - Lipid peroxidation and vitamin E supplementation in experimental hyperthyroidism. PMID- 8674205 TI - Increased Clara cell protein in serum of firefighters. PMID- 8674207 TI - Discrepant blood concentrations of type I procollagen propeptides in active Paget disease of bone. PMID- 8674206 TI - Cardiac troponins in severe rhabdomyolysis. PMID- 8674208 TI - Meeting Report: First and Second Estradiol International Workshops. PMID- 8674209 TI - Effect of preanalytical conditions on measurements of free thyroxine and total triiodothyronine. PMID- 8674210 TI - Interference by thiocyanate on electrochemical biosensors for blood glucose. PMID- 8674211 TI - Renin and prorenin: advances and declines in methodology. PMID- 8674212 TI - DNA diagnostics for Charcot-Marie-Tooth disease and related inherited neuropathies. PMID- 8674214 TI - Quality of life assessment: integral to clinical practice. PMID- 8674213 TI - Anabolic steroids, athletic drug testing, and the Olympic Games. PMID- 8674215 TI - Recurrent epistaxis and nasal septal deviation in young adults. AB - Epistaxis is common in young adults but the aetiology is unknown in many cases. To investigate the possibility that septal deviations are associated with epistaxis, 54 servicemen with recurrent epistaxis were compared with 46 controls. The epistaxis group were significantly more likely to have a history of nasal trauma (P = 0.008) and radiologically-proven nasal fracture (P = 0.002); on clinical examination, they were more likely to have a deviated septum (P < 0.00001), maxillary spur (P = 0.00004) and nasal obstruction (P = 0.011); they were also more likely to have radiological evidence of a deviated septum (P = 0.020). Those patients able to locate their epistaxis to one side tended to do so to the side of their septal deviation. This study supports the hypothesis that septal deviation is associated with epistaxis. PMID- 8674216 TI - Treatment of facial synkinesis and facial asymmetry with botulinum toxin type A following facial nerve palsy. AB - Facial synkinesis and asymmetry commonly impair the outcome of facial nerve palsy. Botulinum toxin type A is a neurotoxin which prevents acetylcholine release at the neuromuscular endplate, paralysing skeletal muscle. This paper examines its use in 24 patients with synkinesis and asymmetry affecting the eye and mouth. Sixty-eight of 72 treatments produced improved cosmesis. Dose-related complications occurred in 26 treatments but were generally mild and transient. The total dosages of toxin used were analysed. The higher dose group compared with the lower dose group had no significant advantage in overall cosmetic improvement but the complication rate was significantly higher in the higher dose group (20/39) compared with the lower dose group (6/33) (chi 2 6.675, P > 0.05). PMID- 8674217 TI - The role of ultrasound in screening patients referred for sialography: a possible protocol. AB - In a prospective study, ultrasound examination of the salivary glands was performed in 31 consecutive patients referred for sialography. Good correlation between ultrasound and digital sialography was observed in 26 patients with only one false negative ultrasound in a patient with significant sialectasis. We recommend initial ultrasound examination in patients with symptoms suggesting an inflammatory lesion in the salivary glands. If this is normal or reveals a solid mass, sialography is not indicated. If ultrasound examination demonstrates the presence of calculi, duct dilatation, cystic elements or an enlarged gland, digital sialography should be performed to identify lesions in the main duct such as strictures or obstructing calculi. PMID- 8674218 TI - Small cavity mastoidectomy--5 year review. AB - It has been recognized that the traditional method of open mastoid surgery often produces a larger mastoid cavity than necessary. Small cavity mastoidectomy is advocated to reduce the size of the mastoid cavity by exteriorizing the cholesteatoma from the epitympanum backwards. When this operation is performed in a sclerotic mastoid bone, the resulting cavity is very small. The 5 year review of 39 ears with small cavity mastoidectomy is presented. Not only were the mastoid cavities small, they remained stable and trouble-free. It also enabled the patients to enjoy swimming and minimizing wax accumulation within the cavities. The hearing results after 5 years were comparable to that of the closed technique. Formation of cholesterol granuloma behind the concho-meatal flap was an uncommon complication. PMID- 8674219 TI - The pharmacological treatment of Meniere's disease. AB - The management of Meniere's disease often provides a formidable clinical challenge largely because its precise aetiology is unknown. There is no known 'cure' once the condition is established, but drugs may be helpful in treating both the acute attacks of vertigo, and in more long-term management, particularly in the earlier fluctuant stage. These remedies are largely symptomatic and there are few if any properly controlled studies of their efficacy. Suppressant drugs may act centrally at neurotransmitter sites, or peripherally on the labyrinth. Conventional diuretics and osmotically acting agents have been given to reduce the endolymph fluid volume. Histamine analogues directly reduce inner ear fluid pressure mainly by increasing the cochlear blood flow, and are probably the treatment of choice. Otovestibulotoxic drugs given systemically to cause chemical labyrinthine ablation are frequently effective in abolishing attacks of vertigo but often resulted in disabling oscillopsia and ataxia. There is now evidence that local administration by intratympanic injection may well be more efficacious resulting in selective partial end organ ablation. To date innovative immune modifying regimes have not proved helpful. PMID- 8674220 TI - The ENT manifestations of HIV infection in children. AB - This study identified the ENT symptoms of 66 HIV infected children over an 8 year period (1986-1993) at Great Ormond Street Hospital for Children. The incidence, nature and age of onset of ENT symptoms were investigated; 91% of the children had ENT symptoms, the most common being cervical lymphadenopathy, oro-oesophageal candidiasis and otitis media. The HIV infected children suffered from the common ENT diseases of childhood. They also presented with specific conditions such as diffuse parotid swelling. Therefore, their clinical features differed from HIV infected adults as well as non-infected children. An increasing incidence of paediatric HIV infection was demonstrated by the study. Most were due to vertical transmission. ENT surgeons are likely to see more HIV infected children in future, either with the usual ENT diseases of childhood (to which they seem more susceptible) or with HIV-specific conditions. Although the diagnosis of HIV may be known, the ENT condition could be the initial presentation suggestive of immunodeficiency. PMID- 8674221 TI - Extended supraglottic laryngectomy for primary base of tongue carcinomas. AB - A retrospective review of 56 patients with a primary base of tongue carcinoma was undertaken to determine the value of supraglottic laryngectomy. All the patients had a supraglottic laryngectomy and a total of 77 neck dissections. Forty-three (76.8%) patients received post-operative radiotherapy. The incidence of local recurrence was 23.2%, neck relapse being seen in 16.1% of patients. The 3 year survival was 47%. The overall survival of the whole series and by stage was not improved by combined therapy compared with surgery alone. PMID- 8674222 TI - Occupational laryngitis with immediate allergic or immediate type specific chemical hypersensitivity. AB - Reports of allergic laryngitis are sparse. In some reports allergy has been mentioned as an aetiological factor, but the diagnosis has not been confirmed with provocation tests. This paper reports on 20 patients in order to show that laryngitis can be caused by organic substances and chemicals with mechanisms of immediate allergy or immediate type specific hypersensitivity. The agents in the former group consisted of flours, obeche, plants and acid anhydrides, whereas these in the latter group included chemicals like formaldehyde, acrylate compounds, and chemicals used in hairdressing. All the cases were confirmed with provocation tests in which the patients displayed a change in vocal cord status. Thirteen patients had positive skin-prick test results with suspected causative agents. Eleven of these 13 patients had an elevated level of specific IgE antibodies to the same agents. PMID- 8674223 TI - Malignant tumours of the cervical oesophagus. AB - Forty-seven patients with malignancy of the cervical oesophagus are described and compared with a group of 647 patients with hypopharyngeal malignancy. There was a higher proportion of non-squamous malignancy in cervical oesophageal cancer compared with hypopharyngeal cancer. Cervical oesophageal malignancy tended to present earlier with significantly lower T stage and neck node metastases were relatively unusual at presentation. Patients with cervical oesophageal malignancy were frequently incurable at the time they are first seen and 21 had palliative treatment only, 26 patients had curative treatment, 12 underwent radical radiotherapy and 14 had surgery. Cervical oesophageal malignancy had a significantly worse prognosis than hypopharyngeal malignancy with an 18% 3 year survival compared with a 33% 3 year survival (chi (1)2 = 7.1089, P < 0.01). Those patients with oesophageal malignancy who were treated fared considerably better than the whole group with 30% being alive at 3 years (chi (1)2 = 10.5185, P < 0.01). PMID- 8674224 TI - The reproducibility of urinary growth hormone measurement in children undergoing adenotonsillectomy: a pilot study. AB - The reproducibility of urinary growth hormone levels in normal children and in children undergoing adenotonsillar surgery was investigated. Thirty normal children and 32 children pre- and post-adenotonsillectomy had overnight urinary growth hormone levels measured on two consecutive nights using the technique of immunoradiometric assay. There was no significant difference when levels in each of these groups were compared. Therefore, the results were pooled (n = 94) and the correlation coefficient comparing levels obtained on the first and the second consecutive nights sample was calculated, r = 0.644 (P < 0.001). This work suggests that studies of urinary growth hormone levels in children give reproducible results. Further investigation of this technique as a screening or diagnostic procedure in the clinical setting can now be more widely evaluated. PMID- 8674225 TI - Overnight pulse oximetry in normal children and in children undergoing adenotonsillectomy. AB - This study investigates the hypoxia that has been described during sleep in children admitted for adenotonsillectomy. Two hundred and twenty-two randomly selected children and 33 children awaiting adenotonsillectomy had overnight pulse oximetry performed at home. Children undergoing surgery had a second study in hospital on the eve of surgery and a third at home 3 months post-operation. Analysis of pulse oximetry data failed to detect a clinically significant difference in oxygen saturation levels between these populations. Snoring is reported in 76% of children undergoing adenotonsillectomy and 11% of the normal population. Sleep apnoeic episodes occur in 52% of children prior to surgery compared with 8% of the normal population. Overnight pulse oximetry has failed to differentiate children with symptoms suggestive of obstructive sleep apnoea from the normal population. Its use as a screening procedure should be used with caution until more is known about its ability to predict significant disease. PMID- 8674226 TI - Survival of adult patients with head and neck soft tissue sarcomas. AB - A retrospective review and survival analysis is presented of 58 adult patients referred between 1963 and 1993 for treatment of a head and neck soft tissue sarcoma. The 5 year overall and disease-free survival was 60% and 52% respectively. Univariate analysis indicated that age, positive margins, bone invasion, distant metastases, single modality treatment, histological grading, sites below the deep fascia and size might be predictors of survival. On multivariate analysis, age, histological grade, distant metastases, site and referral for recurrent disease emerged as prognostic factors known before treatment. By including variables known after treatment, age remained the most important independent prognostic factor followed by the presence of free margins, histological grading and distant metastases at presentation. PMID- 8674227 TI - Clinical and rhinostereometric assessment of nasal mucosal swelling during histamine challenge. AB - The correlation between the subjective sensation of nasal stuffiness and nasal mucosal swelling measured with rhinostereometry during histamine challenge was studied in 13 healthy subjects. To permit a study of the entire range from decongestion to maximal congestion, the mucosa was pre-treated with a local vasoconstrictor 1 h before it was challenged with eight doses of increasing concentrations of histamine applied to one side of the nose. Ten minutes after each application, the subject estimated stuffiness on the challenged side, using a 100 mm visual analogue scale. The amount of mucosal swelling was measured with rhinostereometry. In 12 of 13 individuals and in the group as a whole, there was a strong positive correlation between a feeling of nasal stuffiness and the degree of mucosal swelling with this nasal provocation model (R = 0.59; P < 0.001). PMID- 8674228 TI - Topical corticosteroids potentiate mucin secretion in the normal nose. AB - The exact mode of action of topical nasal corticosteroids is still uncertain. The aim of this study was to determine their effects on microvascular permeability and cellular and glandular secretion by measuring the levels of total protein, albumin, lysozyme and mucin recovered in nasal lavage fluid before and after 3 weeks of treatment with a topical nasal corticosteroid in 12 normal non-atopic subjects. Six subjects applied 200 micrograms fluticasone propionate and six applied 200 micrograms beclomethasone dipropionate to one nostril in each 24 h: matched placebo was applied to the other nostril. There was a significant rise in the level of mucin recovered compared with baseline values following fluticasone administration (baseline 76.2 micrograms/ml (mean) +/- 5.5 (SEM), fluticasone 118.3 micrograms/ml +/- 11.6 P = 0.015) and beclomethasone administration (baseline 64.3 micrograms/ml +/- 6.6, beclomethasone 87.2 micrograms/ml +/- 4.8, P = 0.041). There was no significant change in the levels of total protein, albumin or lysozyme following either active medication or placebo treatment. Topical corticosteroids appear to potentiate mucin secretion and do not alter serous secretion or microvascular permeability in the unchallenged non-atopic nose. PMID- 8674229 TI - Unusual presentations of acoustic tumours. AB - A series of 238 consecutive patients with acoustic neuromas, operated on in Paris has been studied to identify unusual presentations and varied symptomatology. The most common history was that of a progressive unilateral hearing loss (in 68.1%), with tinnitus (in 49.1%) or disequilibrium (in 49.1%) or both. Sudden hearing loss (in 14.7%) or fluctuating hearing loss (in 6.3%), and a single or repeated episodes of acute vertigo (in 8.8%) were seen less commonly. Headaches occurred as an associated symptom in 10.5%, tinnitus was the sole symptom in 2.8% and other uncommon symptoms included otalgia, facial nerve palsy, facial or ocular pain, altered sensation in the face or eye, or tingling of the tongue. Some 11.3% of patients presented with normal pure tone auditory thresholds and a 100% speech discrimination score and of these patients acoustic reflex thresholds were normal in 53% and brainstem auditory evoked responses were suggestive of the retro cochlear abnormality in only 76.2%. Amongst the less common presentations, the initial symptoms mimicked such diagnoses as Meniere's disease, benign positional vertigo, vertebro-basilar migraine, vertebro-basilar insufficiency, Bell's palsy and Trigeminal neuralgia. Overall, 20.6% of patients had unusual initial presenting symptoms, 36.5% of the symptoms were unusual and these were found in isolation in 11.8% of patients. An awareness of the spectrum of more subtle symptoms of acoustic tumours may lead to the correct diagnosis at an earlier stage. PMID- 8674230 TI - The nasal response to isometric exercise in non-eosinophilic intrinsic rhinitis. AB - The exact pathophysiology of intrinsic rhinitis is not fully understood. The generally held belief is that it is due to an imbalance between the outflow of the nasal sympathetic and parasympathetic nervous systems, perhaps due to excessive parasympathetic or reduced sympathetic activity. In this study the nasal airway response to a predominantly sympathetic stimulus, isometric exercise, was studied in 19 patients with intrinsic rhinitis and compared with 16 normal patients. Isometric exercise took the form of a handgrip stimulus using a hand dynomometer. Following sustained handgrip, a small fall of nasal resistance in the normal group (0.058 kPas/1) and a moderate rise in nasal resistance in the rhinitis group (0.242 kPas/1) was found. Pulse and blood pressure changes were the same in both groups with a significant rise in pulse rate and diastolic blood pressure. The study shows that there is an abnormal response to isometric exercise in intrinsic rhinitis, perhaps due to relative nasal sympathetic hyposensitivity. PMID- 8674231 TI - Complications of supraglottic laryngectomy for carcinomas of the supraglottis and the base of the tongue. AB - The medical records of patients with either a supraglottic carcinoma (n = 193) or a base of tongue carcinoma (n = 56) who underwent a supraglottic laryngectomy were studied. Because of aspiration total laryngectomy was required in 9.8% and 21.4% of patients with supraglottic and base of tongue carcinomas, respectively, being related to locally advanced stage of disease in the base of tongue and to an age older than 65 years in the case of supraglottic carcinomas. The non decannulation rates were 23.8% and 50% in supraglottic and base of tongue tumours respectively. Post-operative radiotherapy did not influence the decannulation rate, but advanced local disease and age did. Post-operative mortality in the first month after the operation was 2.6% in supraglottic tumours and 3.6% in base of tongue tumours. PMID- 8674232 TI - A comparison of computerized tomographic staging systems in chronic sinusitis. AB - A number of different systems exist for staging computerized tomography (CT) scans in rhinosinusitis. The aim of this study was to determine which of four selected staging systems, currently in common use facilitated the highest level of agreement. The systems studied were those by Jorgensen (1991), May and Levine (1991), Lund and Mackay (1993) and Newman (1994). Ten observers independently assessed 10 representative films. In our assessment, the Lund and Mackay system facilitated the highest level of both inter-observer and intra-observer agreement of the four systems tested. We recommend it be adopted as the standard method of measuring the extent of disease, as depicted by CT scanning for chronic. rhinosinusitis. PMID- 8674233 TI - DNA methylation: a potential pathway to abnormal autoreactive lupus B cells. PMID- 8674234 TI - Terminology: interleukin 16 (IL-16). PMID- 8674235 TI - Antibodies to phospholipid-binding plasma proteins and occurrence of thrombosis in patients with systemic lupus erythematosus. AB - There is accumulating evidence that anti-phospholipid (aPL) antibodies in the sera of patients with autoimmune diseases bind to a complex of anionic phospholipids and plasma phospholipid-binding proteins, namely beta 2 glycoprotein I (beta 2-GPI) and prothrombin. It has been suggested that a conformational change in beta 2-GPI, induced by binding either to anionic phospholipids or to the oxygen molecules on the irradiated microtiter plate, reveals cryptic antigenic epitope(s) in the native protein. We used an enzyme linked immunoassay for measuring antibodies against two phospholipid-binding proteins, i.e., beta 2-GPI and prothrombin, absorbed to an irradiated plate in an unselected series of 139 patients with systemic lupus erythematosus (SLE). Elevated levels of antibodies against beta 2-GPI were found in 49% of patients and antibodies against prothrombin in 34% of patients. Both antibodies were significantly associated with deep venous thrombosis in patients with SLE (P = 0.009 for both antibodies). Accordingly, testing of these antibodies seems to be clinically useful in evaluating the risk of thrombosis. PMID- 8674236 TI - The role of the innate immune system in the reconstituted SCID mouse model of herpetic stromal keratitis. AB - Herpetic stromal keratitis (HSK) has an immunopathological basis, thought primarily to involve a CD4+ T cell-mediated immune response to viral antigen. Other cell types, however, particularly those involved in nonspecific immunity, such as natural killer (NK) cells or neutrophils, may also contribute to tissue destruction in the cornea. The reconstituted SCID mouse model of HSK provides a powerful system in which to study the interactions of the innate and adaptive immune responses to herpes simplex virus type 1 corneal infection. In the present study, reconstituted SCID mice depleted of NK cells had a reduced incidence and severity of clinical and histopathological HSK. The levels of T cell cytokine protein and message in restimulated splenocytes and cytokine message in corneas did not differ between experimental groups. However, significantly fewer neutrophils were seen within the inflamed corneas of NK-depleted SCID mice. Therefore, endogenous NK cells may indirectly influence the severity of HSK in reconstituted SCID mice by affecting neutrophil migration into the cornea. PMID- 8674237 TI - CD26 surface molecule involvement in T cell activation and lymphokine synthesis in rheumatoid and other inflammatory synovitis. AB - T cell surface expression and the functional role of CD26 antigen (Ag), a surface ectoenzyme involved in T cell activation and migration across the extracellular matrix, were analyzed in the peripheral blood (PB) and synovial fluid (SF) from patients with inflammatory arthritides. CD26 membrane expression on T cells was detected by cytofluorometry using two different monoclonal antibodies, anti-Ta1 and anti-1F7, while cell proliferation and both IL-2 and IFN-gamma production were evaluated in anti-CD3- or anti-CD2-stimulated cell cultures after Ag surface modulation with anti-1F7. The results showed that Ta1 and 1F7 Ag expression were increased on T cells from PB of patients with active, but not inactive, rheumatoid arthritis (RA). Most SF T cells from RA or other inflammatory arthritides displayed the memory marker CD45R0 and the Ta1 Ag, but lacked the 1F7 molecule. In addition, in vitro 1F7 modulation, which enhanced RA PB T cell proliferation and both IL-2 and IFN-gamma synthesis, did not synergize with anti CD3 or anti-CD2 in inducing IL-2-dependent activation of SF T cells, but reduced IFN-gamma production. A spontaneous reappearance of 1F7 Ag on the SF T cell surface was seen after 2-5 days in culture. Phorbol myristate acetate, able to accelerate its reexpression, also restored a normal response of SF T cells to anti-1F7 comitogenic effects. These data confirm a role of the CD26 surface molecule in regulating T cell activation and lymphokine synthesis. This observation may have important implications in the regulation of T cell activity at the joint level during chronic inflammatory processes. PMID- 8674238 TI - Induction of V gamma 2 V delta 2 T cell proliferation by activated antigen specific CD4+ T cells and IL-2. AB - Human gamma delta T cells respond to a wide range of ligands including some T lymphocyte cellular antigens associated with viral infection. In the present study we examined the participation of gamma delta T cells in the proliferative response that is induced in human peripheral blood mononuclear cells (PBMC) by activated, antigen-reactive, CD4+ T cells. Activated, irradiated, myelin basic protein (MBP)-specific T cells stimulate brisk proliferation when cultured with freshly isolated, autologous PBMC. Determination of the phenotype of the responding PBMC T cells revealed a prominent expansion of gamma delta T cells, principally of the V gamma 2 subset. There was only minimal proliferation of PBMC following culture with irradiated, MBP-specific T cells that had not been recently activated. However, addition of rIL-2 to cultures of PBMC and nonstimulated MBP-specific T cells restored proliferation and the expansion of the gamma delta T cells. IL-2 alone did not mediate this effect. While MBP was a convenient antigen to use in these experiments, similar gamma delta T cell expansion in vitro was noted using activated, CD4+ T cells reactive with an exogenous antigen, Candida. In additional experiments, gamma delta-enriched T cell lines and certain V gamma 2 T cell clones continued to respond to activated but not to nonstimulated, CD4+ T cells. Overall, this study suggests that V gamma 2 V delta 2 T cells may proliferate as a consequence of the activation of CD4+ T cells. At least one ligand associated with T cell activation is required in addition to IL-2. PMID- 8674239 TI - Neutrophil attractant protein-1 interleukin 8 and its autoantibodies in IgA nephropathy. AB - Human neutrophil attractant protein-1/interleukin 8 (IL-8) has been shown to activate neutrophils to degranulate in vitro and to be a potent chemotactic agonist for neutrophils and lymphocytes in vitro and in vivo. There is accumulating evidence that neutrophils are involved in inflammatory injury in IgA nephropathy (IgAN). We studied the serum levels of IL-8 and its autoantibodies of the IgA or IgG class in 36 patients with IgAN in comparison with 31 healthy controls and 26 patients with other primary glomerulonephritides (CGN). Interleukin 8 was more frequently detected in sera of patients with IgAN and their serum levels were significantly higher than those of healthy controls. The free IL-8 autoantibodies of the IgA, but not IgG class, were more frequently detected in patients with IgAN and their serum levels were significantly elevated compared with both groups of controls. The complexed IL-8 autoantibodies of either class were not different among the three groups of subjects. Again the ratio of free to complexed IL-8 autoantibodies of the IgA class was raised in patients with IgAN. Histologic examination revealed increased polymorphs and monocyte/macrophage infiltration in IgAN compared with other glomerulonephritides. When the serum levels of IL-8 and IL-8 autoantibodies were compared between IgAN patients with milder pathology and those with more severe pathology, the latter group had significantly higher serum levels of free and complexed IL-8 autoantibodies of the IgA class. These observations suggest a possible role for IL-8 and its autoantibodies of the IgA class in the inflammatory process of IgAN. These autoantibodies may provide a clinically useful marker for the diagnosis of disease severity. PMID- 8674240 TI - Expression of selectins (CD62 E,L,P) and cellular adhesion molecules in primary Sjogren's syndrome: questions to immunoregulation. AB - Adhesion molecules are important signal transmitters of the immune system and may mediate the homing of leukocytes to sites of inflammation. The aim of this work was to examine the presence of selecting and cellular adhesion molecules on epithelial and endothelial cells in labial salivary glands (LSG) in Sjogren's syndrome (SS). LSG biopsies were obtained from patients with primary SS (n = 31) and normal subjects (n = 21). Cryostat sections were examined with indirect immunoperoxidase. Epithelial cells in LSG from both patients and controls expressed LFA-3 (CD58) and Hermes I (CD44). A significantly increased number of acinar and ductal epithelial cells in LSG from patients expressed class I MHC (74%, as mean percentage of ductal epithelial cells) (P < 0.05), HLA-DR (58%) (P < 0.0001), and HLA-DQ (11%) (P < 0.001). To a lesser extent limited ICAM-1 (CD54) epithelial expression (6%) was noted only in a few biopsies from patients but none of the controls. Epithelial cells did not express any of the selectins CD62 E, L, and P and sometimes they expressed sialyl Le(x) (a ligand for selectins). Although the number of endothelial structures expressing ICAM-1 (CD54), HLA-DR, HLA-DQ, and class I MHC (per surface area) was increased in patients (P < 0.05), this may be due to the total increase of number of endothelial structures (P < 0.05) (Von Willebrand factor +ve) as part of the chronic inflammatory process. A smaller proportion of endothelial structures expressed E-selectin (CD62 E) (32%) and to a lesser extent VCAM-1 (CD106) (approximately 7%) as detectable only in some LSG from patients. P-selectin (CD62 P) was demonstrated on about one-third of endothelial structures in LSG from patients. Infiltrating mononuclear cells expressed CD11a (68%), CD18 (73%), CD11b (13%), CD11c (21%), CD58 (13%), CD4 (44%), CD8 (17%), CD62L (L-selectin) (18%), CD49d (38%), CD49e (15%), CD2 (56%), and CD44 (77%). The relatively reduced number of CD62 L +ve lymphocytes may be due to shedding of that molecule after activation. Sialyl Le(x) was not detectable on infiltrating lymphocytes. Although infiltrating mononuclear cells were activated, as evidenced by their expression of HLA-DR (72%) and ICAM-1 (55%), they did not express IL-2Ralpha (CD25, confirmed by two antibodies 2A3 and ACT1) or IL-2Rbeta (CD122), except rarely (< or = 1%). In some biopsies, CD106 and CD11c were localized on lymphocytes at the central areas of periductal lymphoid follicles with the appearance of dendritic cells. We conclude that adhesion molecules probably play a major role in the pathogenesis of SS. The pattern of expression of these molecules demonstrates a regulated altered activation in the glands associated with this disease. The glands may be subject to specific regulatory factors, in addition to proinflammatory cytokines. PMID- 8674241 TI - Release of sIL-2R alpha from and activation of native human peripheral blood mononuclear cells by recombinant IL-15. AB - The cytokine interleukin (IL)-15 shares several activities with IL-2. Both cytokines induced expression of cell-surface IL-2R alpha (CD25) on freshly isolated human peripheral blood mononuclear cells (PBMC) in the absence of other exogenous stimuli. They also stimulated the release of soluble IL-2R alpha and induced proliferation of these cells in 1-week cultures in a time- and dose dependent manner. Recombinant IL-7 could also induce the expression of CD25, although sIL-2R alpha was released at only low levels. In monocyte-depleted PBMC the sIL-2R alpha release was minimal. When isolated T cells or non-T cells were stimulated by rIL-15 or rIL-2, cell surface CD25 was expressed, but released sIL 2R alpha was undetectable. On stimulation with rIL-15, more than 80% of all natural killer cells expressed CD25 and more CD8br+ lymphocytes were positive for CD25 compared to stimulation by rIL-2. These results may be clinically relevant because several diseases are associated with high serum levels of sIL-2R alpha which may he not only due to IL-2 but also due to IL-15 stimulation. PMID- 8674242 TI - Immunosuppressive effects of the cyclosporin derivative SDZ IMM 125 on kidney allograft in the dog and small bowel and pancreas allografts in the rat. AB - The efficacy of SDZ IMM 125 in preventing allograft rejection was evaluated in kidney transplantation in the dog and orthotopic small bowel and heterotopic pancreas transplantation in the rat. Seven groups (n = 6) were involved in dog kidney transplantation. Untreated recipients rejected kidney allografts with a mean survival time (MST) of 8.0 +/- 1.8 days. There was a graded dose response in SDZ IMM 125-treated groups: 10 mg/kg/day, MST 11.3 +/- 3.5 days, P = 0.065; 15 mg/kg/day, MST 44.8 +/- 10.8 days, P = 0.0001; and 20 mg/kg/day, MST 47.3 +/- 5.6 days, P = 0.0001, same as in cyclosporin A (CsA)-treated groups: 10 mg/kg/day, MST 25.8 +/- 13.7 days, P = 0.001; 15 mg/kg/day, MST 38.3 +/- 18.1 days, P = 0.002; and 20 mg/kg/day, MST 38.7 +/- 17.7 days, P = 0.002. Low dose of SDZ IMM 125 (10 mg/kg/day) was less effective in prolonging the graft survival than low dose of CsA. High dose (20 mg/kg/day) treatment of both SDZ IMM 125 and CsA led to abnormal recipient liver enzymes alanine aminotransferase and aspartate aminotransferase postoperatively. A histopathological study demonstrated fatty degeneration of hepatic cells in both 20 mg/kg/day SDZ IMM 125- and CsA-treated groups. We also tested the effect of SDZ IMM 125 in orthotopic small bowel transplantation with three combinations, namely host-versus-graft (HVG), graft versus-host (GVH), and combined HVG and GVH immune responses and pancreas transplantation in the rat with different doses. The results indicate that SDZ IMM 125 is a potent immunosuppressant to prolong the kidney allograft survival in the dog, to alleviate HVG and GVH responses in small bowel transplantation, and to delay pancreas allograft rejection in the rat. Low dose of SDZ IMM 125 is less effective than a similar dose of CsA to prevent kidney allograft rejection in the dog. PMID- 8674243 TI - Selective accumulation of anti-histone antibodies in glomeruli of lupus-prone lpr mice. AB - Immunoglobulins were eluted from glomeruli of 50 lupus-prone, lpr mice and their physicochemical properties and specificity were compared with those in sera pooled from the same mice. Although immunoglobulins in glomeruli had higher isoelectric points than those in sera, there were no appreciable differences in the relative contents of neutral and acidic immunoglobulins between them. The proportion of IgG3 subclass was slightly higher in glomerular than serum immunoglobulins. Both anti-single-stranded and anti double-stranded DNA antibodies were twofold higher in glomerular than serum immunoglobulins, while anti-Sm antibodies were not recovered in glomerular eluate despite their high activity in serum. Antibodies in glomerular eluate reacted most strongly with histones, especially with core histones, while those in sera bound preferentially with histone H1, Sm-B, -B', and -D antigens. Since histones are very basic, they would have a higher affinity for negatively charged glomerular constituents, leading to an in situ formation of immune complexes involving fixed histones and their binding with antibodies for the induction of nephritides. Otherwise, such immune complexes themselves might retain positive charges sufficient for an affinity with the glomerular basement membrane. These results indicate that histone-anti-histone antibody system may play a role in the perpetuation of murine lupus nephritis. PMID- 8674244 TI - VH and VL gene elements that encode human antibodies to DNA. AB - We have determined the cDNA sequence of variable regions of heavy and light chains of three antibodies with low affinity to DNA. The variable heavy chains were found to result from utilization of VH gene elements that have been identified previously in other low-affinity anti-DNAs. These VH gene elements, VH26 and VH1.9III, are expressed in association with different D gene-encoded CDR3s than in the other antibodies. The variable light chains were found to be encoded by VL gene elements that have not previously been identified in anti DNAs. The recurrent identification of only 10 germ line VH genes in 22 low affinity anti-DNAs indicates that there is a high probability that all of the VH gene elements that confer reactivity with DNA have been identified. Previous studies have suggested that high-affinity antibodies to DNA result from an antigen-driven process of affinity maturation. However, only 6 of 13 high affinity antibodies to DNA are derived from this set of low-affinity VHs, indicating that DNA is unlikely to be the driving antigen. PMID- 8674245 TI - Progressive deficiencies in blood T cells associated with a 10p12-13 interstitial deletion. AB - We report on a 8-year-old patient affected by a selective T-cell defect associated with mental retardation and dysmorphic signs. At birth thymic aplasia and hypoparathyroidism were noted, suggesting a DiGeorge-like anomaly. The immunological evaluation during the 8 years follow-up revealed a progressive decrease of CD3+CD4+ lymphocytes, which paralleled deficiencies of blood T cells. Chromosome analysis using GTL banding revealed an interstitial deletion of the short arm of chromosome 10. We next investigated whether the expression of IL-2R alpha chain and Nil-2-a genes, which are located on the short arm of chromosome 10, was affected by the deletion. Transcription of these two genes was normal, thus suggesting that the two regions were preserved. In situ hybridization studies with the painting libraries #G3A7 and #G9 confirmed that the two regions were preserved and allowed us to define the breakpoint as 10p12-10p13. Due to the similarities between DiGeorge and 10p syndromes, we suggest that the 10p13-10p12 region contains a gene(s) potentially related to gene products of the 22q11 region, frequently altered in patients with DiGeorge. PMID- 8674246 TI - Normal levels of allo- but increased levels of potentially autoreactive antibodies against ABO histo-blood group antigens in AIDS patients. AB - The aim of our study was to investigate the immune response of human immunodeficiency virus (HIV)-infected patients in relation to the naturally occurring ABO histo-blood group antibodies. Despite markedly elevated levels of total IgM/G/A, anti-A/B isotypes revealed no significant different mean levels in AIDS patients compared to controls. However, 12 A-type AIDS sera out of 17 (70%) had anti-A IgA levels that were increased by >2 SD above normal range; anti-A IgM and anti-A IgG were increased in 7/17 (41%) and 2/17 (12%) of A-type AIDS sera, respectively. We conclude that the specific response to ABO histo-blood group antigens remains at levels similar to normal and does not follow hypergammaglobulinemia. As yet, certain A-type AIDS patients may form auto-anti-A as suggested by a portion of our data. PMID- 8674247 TI - Inotropic therapy for the failing myocardium. PMID- 8674248 TI - Credentialing cardiologists who perform therapeutic cardiac interventions. PMID- 8674249 TI - Cardiovascular diagnosis: what is the best way to teach this complex subject? PMID- 8674250 TI - Vascular reactivity of arterial coronary artery bypass grafts--implications for their performance. AB - Specific properties of the vessel wall of arteries employed as coronary bypass grafts are thought to play an important role in the short- and long-term performance of these conduits. Heterogeneity in the endothelial and smooth muscle cell function between different arteries may provide particular vessels with properties which will favor them for use as bypass conduits. The aim of this review is to provide an insight into how the vascular reactivity of presently used arterial conduits varies and to discuss the clinical implications of these findings both in terms of flow modulation in response to physiologic and exogenous vasoactive mediators and long-term patency. PMID- 8674251 TI - Assessing the physiologic significance of coronary artery disease: role of Doppler methodology. AB - It is important to define both anatomic and functional significance of coronary artery stenoses. Quantitative angiography has decreased the inter- and intraobserver variability in interpreting the coronary angiogram, but it is less clinically applicable in assessing functional significance. The coronary Doppler catheter and guidewire can provide considerable information regarding the functional effects and pathophysiology of coronary stenosis in humans at the time of cardiac catheterization. Clinically, it is a simple and safe technique which makes it feasible in a clinical setting to use it as a tool to assess the physiologic significance of an intermediate stenosis or the functional result of an interventional procedure. Other uses for the intravascular Doppler method, such as the evaluation of cardiac transplant vasculopathy and rejection and evaluation of patients with chest pain syndromes and normal coronary angiograms, are being studied. However, the usefulness of this technique in decision-making has yet to be fully clarified. Future clinical studies should be directed toward comparing this method with noninvasive methods, that is, exercise treadmill test and thallium studies, and attempt to answer questions regarding its prognostic value. PMID- 8674252 TI - Credentialing cardiologists who perform therapeutic cardiac interventions. PMID- 8674253 TI - Noninvasive diagnostic tests to detect coronary artery disease. PMID- 8674254 TI - Atrial fibrillation in acute myocardial infarction: a prospective study based on data from a consecutive series of patients admitted to the coronary care unit. AB - Atrial fibrillation (AF) is a common and much-studied arrhythmia in patients with acute myocardial infarction (MI). However, documentation of its occurrence in temporal association with MI has been often neglected in the literature; also, its frequent occurrence with mere advanced age, or in the setting of various cardiac conditions or complications, has prevented the definition of an exact role for AF as a marker or determinant of outcome in patients with MI. The purpose of this study was to evaluate prospectively the frequency of AF (present or occurring subsequently) in a consecutive series of patients with MI admitted to the Coronary Care Unit, and to explore for variables associated with this arrhythmia; the role of AF in determining major clinical outcomes of the patients was also examined. A large data base of baseline, clinical, laboratory, and patient outcome variables was generated and continuously updated to examine correlates of AF and its possible role in determining prognosis. AF was found in 72 of 517 patients, of whom 58 experienced this arrhythmia anew. Univariate analyses detected a positive association of AF with age, pulmonary congestion, left ventricular hypertrophy, high admission Killip class, and a large array of complications including in-hospital mortality. Multivariate analyses showed, however, that AF correlated weakly with age and strongly with left ventricular hypertrophy and occurrence of ventricular tachycardia, but that it was not a determinant of ventricular fibrillation or in-hospital mortality. PMID- 8674255 TI - Prediction of in-hospital cardiac events using dipyridamole-thallium scintigraphy performed very early after acute myocardial infarction. AB - BACKGROUND AND HYPOTHESIS: Ischemic complications occur frequently during hospitalization after acute myocardial infarction. Dipyridamole-thallium scintigraphy performed early after admission can detect residual ischemia, may have additional prognostic value and be useful in the management of these patients. METHODS: Dipyridamole infusion and 201thallium imaging were performed on the third day of infarction in 114 consecutive patients. Coronary angiography was performed before hospital discharge in 90% of patients and exercise testing was performed at the time of discharge in patients without contraindications. RESULTS: Side effects occurred in 28 patients, but they were mild and transient or rapidly reversed with intravenous aminophylline. During hospitalization, three patients died and four had a nonfatal reinfarction. Patients with these major cardiac events had previously shown a higher prevalence of reversible perfusion defects during testing (71 vs. 31%, p < 0.05). In addition, 19 patients had early recurrent ischemia requiring early in-hospital revascularization. Overall, cardiac events defined as death, reinfarction, or early myocardial revascularization occurred in 22 patients. Of the patients with these events, 68% had thallium redistribution on initial myocardial scanning compared with 25% of patients without events (p = 0.0001). Patients with cardiac events also showed a higher number of myocardial segments with reversible perfusion defects (1.8 +/- 2.2 vs. 0.6 +/- 1.3, p = 0.001). Logistic regression analysis revealed that among all the other clinical, scintigraphic, and angiographic variables, the presence of thallium redistribution on the dipyridamole-thallium scan was the only independent predictor of cardiac events, increasing the risk by sixfold. Furthermore, during a 1-year follow-up, 14 other patients had ischemic events. Of these, 64% had previously shown thallium redistribution during early dipyridamole testing compared with 19% of patients without cardiac events (p < 0.001). CONCLUSIONS: Intravenous dipyridamole-thallium-scintigraphy performed very early after myocardial infarction is safe and useful to predict in-hospital ischemic events. PMID- 8674256 TI - Change of plasma leukotriene C4 during myocardial ischemia in humans. AB - Changes in leukotriene C4 levels during different degrees of myocardial ischemia in humans were examined by comparing radioimmunoassay measures of leukotriene C4 plasma levels obtained during transient and prolonged myocardial ischemia. Leukotriene C4 levels in systemic arterial and coronary sinus blood were determined in patients with chronic stable angina before and after myocardial ischemia induced either by exercise (supine bicycle ergometer exercise stress testing; n = 14; age, 52 +/- 8 years) or by coronary occlusion during angioplasty (n = 14; age 53 +/- 7 years). Temporal changes of leukotriene C4 were also followed in arterial and pulmonary artery blood within 24 h after the onset of chest pain (acute phase), and 1 day, 1 week, and 1 month later in 22 patients with acute myocardial infarction (AMI) (12 patients with thrombolytic therapy, age 61 +/- 10 years; 10 patients without thrombolytic therapy, age 60 +/- 11 years). Clinical characteristics, including coronary risk factors and the severity of coronary artery disease, were not significantly different among the groups. Exercise-induced myocardial ischemia and coronary occlusion did not induce any significant leukotriene C4 changes in the chronic stable angina patients, whereas AMI patients had significantly higher plasma leukotriene C4 levels in both arterial and pulmonary artery blood in the acute phase compared with those of chronic stable angina patients (arterial blood, 471 +/- 164 pg/ml and 477 +/- 235 pg/ml vs. 275 +/- 254 pg/ml or 240 +/- 66 pg/ml, p < 0.05; pulmonary artery blood in AMI, 543 +/- 162 pg/ml vs. 234 +/- 125 pg/ml or 225 +/- 64 pg/ml, coronary sinus blood in chronic stable angina, p < 0.05). These results suggest that leukotriene C4 is involved more in prolonged myocardial ischemia than in transient myocardial ischemia, and that leukocyte function might play a significant role in the pathogenesis of patients with AMI. PMID- 8674258 TI - Transesophageal echocardiography in the detection of inferior vena cava and cardiac metastasis in hepatocellular carcinoma. AB - Antemortem diagnosis of inferior vena cava (IVC) and cardiac metastasis of hepatocellular carcinoma (HCC) is difficult but important before consideration of curative resection. There are only a few cases of cardiac metastasis of HCC which have been diagnosed antemortem by echocardiography. Accordingly, 18 consecutive patients with HCC who were potential candidates for curative resection were studied by transthoracic (TTE) and transesophageal echocardiography (TEE). One (6%) and two (11%) patients had cardiac and IVC metastasis of HCC, respectively, which was detected by two-dimensional TTE. In contrast, by using TEE, four patients (22%) showed tumor invasion of the IVC, of whom two (11%) had tumor mass extending into the right atrium (RA). There was no significant difference in age, serum level of alpha-fetoprotein, and percentage of right liver lobar involvement between those with and without cardiac metastasis. Patients without cardiac metastasis detected on TTE or TEE had significantly longer mean duration of survival (5.0 +/- 2.1 vs. 2.1 +/- 1.0 months; p < 0.05). In summary, TEE may be more useful than TTE in the detection of cardiac metastasis of HCC, which occurred in 22% of patients whose primary tumor was considered to be surgically resectable in our series. This can be safely performed in patients with HCC and can provide optimal visualization of the IVC and RA. The high prevalence of subclinical cardiac metastasis in HCC mandates the use of TEE in all patients with HCC prior to surgical intervention. PMID- 8674259 TI - Reproducibility of head-up tilt test in patients with syncope. AB - As the head-up tilt test (HUT) is employed to verify the efficacy of undertaking a treatment, we prospectively evaluated the reproducibility of positive and negative results, as well as that of the response type in 64 consecutive patients (mean age 34.6 +/- 22.9 years) with syncope of unknown cause. Two HUTs (60 min, 75 degrees), separated by an interval of 9.77 +/- 8.21 days, were performed on each patient. Positive responses were reproduced in the second HUT in 54.5% of the patients. A greater reproducibility (84.3%) was observed for negative responses. Of the 31 patients with a negative first test, 5 had a positive response during the second HUT. Using a multivariate analysis, no clinical variable correlated with the reproducibility of positive or negative results. Likewise, neither arterial pressure nor heart rate observed during the test were correlated with reproducibility. Of 18 patients who reproduced positive responses, 12 (66.6%) did so with the same response modality. In three patients with documented monomorphic sustained ventricular tachycardia, which was hemodynamically well tolerated, and in one patient with temporal spike wave activity in the electroencephalogram, HUT was also positive. It was concluded that the low reproducibility of HUT limits its usefulness as a tool for evaluating treatment efficacy. The variability of the type of response suggests a common mechanism leading to cardioinhibitory and vasodepressor reactions. A positive result in only the second study shows the rationale of performing two tests when the first one is negative. PMID- 8674257 TI - Stress-induced hemodynamic and hemostatic changes in patients with systemic hypertension: effect of verapamil. AB - Stress-induced hemodynamic and hemostatic responses may acutely trigger atherosclerotic plaque disruption and thrombosis leading to myocardial infarction. This study was designed to evaluate the responses to three stressors and to determine if once-daily sustained release verapamil (Verelan) modified these responses. We studied 13 patients with mild to moderate hypertension in a randomized, double-blind, placebo-controlled crossover trial. After 4 weeks of therapy, patients were evaluated following assumption of the upright posture, mental stress, and cold pressor test. During placebo, the stressors produced an increase in systolic pressure (144 +/- 2 to 167 +/- 3 mmHg, p < 0.001), heart rate (70 +/- 2 to 77 +/- 2 beats/ min, p < 0.001), and platelet aggregability to adenosine diphosphate (threshold concentration fell from 2.8 +/- 0.4 to 1.9 +/- 0.1 microM, p = 0.05) and epinephrine (3.4 +/- 0.9 to 1.6 +/- 0.6 microM, p < 0.001). Verapamil lowered systolic pressure at baseline (144 +/- 2 to 134 +/- 2 mmHg, p < 0.001), and after stress (167 +/- 3 to 154 +/- 3 mmHg, p < 0.001), but did not alter the absolute increase with stress. During verapamil, platelet reactivity did not increase with stress, and the post-stress response to epinephrine was reduced (higher threshold concentration) compared with placebo (3.9 +/- 1.3 vs. 1.5 +/- 0.3 microM, p = 0.05). Verapamil also reduced the response to collagen (increased lag time) at baseline and after stress (111 +/- 9 vs. 91 +/- 3 s, p < 0.01). We conclude that verapamil blunted potentially harmful stress-induced hemodynamic and hemostatic changes. Further studies are required to determine whether these effects translate into a lower incidence of acute cardiovascular events. PMID- 8674260 TI - Assessment of posterior aortic wall motion using echocardiogram in patients with atrial fibrillation. AB - BACKGROUND AND HYPOTHESIS: Noninvasive evaluation of left ventricular (LV) diastolic function was performed on 12 patients with atrial fibrillation (AF) using posterior aortic wall echocardiogram and a parameter for determining the optimal heart rate in patients with chronic atrial fibrillation was considered. METHODS: Subjects were divided into two groups; one with no underlying cardiac disease (AF only group; n = 7) and the other with dilated cardiomyopathy (DCM group; n = 5). Left atrial emptying index (LAEI) obtained from the posterior aortic wall echocardiogram was used as the parameter of LV diastolic function, and R-R interval-LAEI relation and minimum R-R interval showing LAEI = 1.0 were investigated and compared between the two groups. RESULTS: There was a good correlation between R-R interval and LAEI until LAEI of 1.0 was obtained in all patients. Slope of the regression line was significantly steeper in the AF only group than in the DCM group, and minimum R-R interval showing LAEI = 1.0 was significantly shorter in the AF only group. CONCLUSION: Assessment of R-R interval-LAEI relation was useful for the noninvasive evaluation of LV diastolic function, and this parameter could be used for clinical application to determine the optimal heart rate in atrial fibrillation. PMID- 8674261 TI - Left ventricular outflow tract obstruction as a cause for hypotension and symptoms during dobutamine stress echocardiography. AB - BACKGROUND: Hypotension has been found to occur in more than one-third of patients during DBSE. Unlike traditional treadmill exercise stress testing, hypotension does not appear to be associated with significant coronary artery disease or left ventricular (LV) dysfunction. Several ischemic and nonischemic mechanisms such as dynamic LV intracavitary obstruction have been implicated in the pathogenesis of hypotension and the induction of symptoms during DBSE. HYPOTHESIS: The purpose of this study was the prospective evaluation of patients referred for dobutamine stress echocardiography (DBSE) to determine (1) the frequency of hypotension during DBSE, (2) the underlying mechanisms responsible for the induction of hypotension, and (3) to describe the cardiac chamber sizes and mass of patients in whom hypotension occurs. METHODS: Seventy-eight consecutive patients were studied during DBSE. Pulsed and continuous-wave Doppler echocardiography were performed at baseline and at each dobutamine infusion stage. Maximum velocities were recorded. Cardiac output was determined noninvasively at each stage in patients who developed an outflow tract gradient. Echocardiography was used to characterize LV dimensions and mass. RESULTS: During dobutamine infusion, 14 of 78 (18%) patients developed a left ventricular outflow tract (LVOT) velocity > or = 2.5 m/s. Pulsed Doppler echocardiography verified that the maximal velocity originated in the LVOT. Of the patients who developed an LVOT gradient, 57% had a concomitant hypotensive response to dobutamine compared with 33% of patients without a gradient (not significant). Four of nine patients had a simultaneous fall in cardiac output. Patients who developed an LVOT gradient had smaller LV dimensions and increased wall thicknesses compared with those who did not develop a gradient. CONCLUSIONS: Dobutamine stress echocardiography precipitates LVOT obstruction in certain patients. The development of a gradient corresponded with a fall in blood pressure and a decline in cardiac output in nearly half of the patients. These findings suggest that stress-induced LVOT obstruction may be responsible in part for the hemodynamic changes and symptoms experienced by these patients during exercise. PMID- 8674262 TI - Peripheral artery recanalization in humans using balloon and laser angioplasty. AB - The treatment of patients with complex peripheral arterial disease and those who have had previous unsuccessful attempted revascularization procedures can be clinically challenging. Initial treatment was begun using therapy by percutaneous balloon and laser angioplasty, then proceeding to bypass surgery if severe ischemia persisted. Both percutaneous and cut-down approaches were used to access totally occluded arteries. An attempt was made to cross the occlusion mechanically with either a guide wire or an activated laser probe. If laser recanalization was not successful, the patient underwent bypass surgery or was managed with medication unless an amputation was necessary. Following initial screening of 381 patients, 115 procedures were performed on 103 patients. In 31 procedures (28 patients), only balloon angioplasty was performed. In 84 procedures (75 patients), laser recanalization was attempted: 55 percutaneously and 29 by cut-down. Overall technical success (crossing the obstruction without perforation) was 86/115 (75%). Technically successful procedures were characterized by shorter arterial occlusions than were technical failures (8.4 +/ 1 cm vs. 14.3 +/- 1.9 cm; p < 0.004). Clinical success (residual stenosis < 50%, symptom relief, improved ankle brachial index > or = 0.15, and no complications) was achieved in 22/31 (71%) of balloon angioplasty procedures alone. The stenoses decreased from 98 +/- 4% to 31 +/- 24%, p < 0.00001. Combined percutaneous laser and balloon angioplasty had a technical success of 36/55 (65%). Stenoses were reduced from 99 +/- 2% to 56 +/- 14% after laser angioplasty, to 30 +/- 15% after balloon angioplasty, p < 0.0001. Laser angioplasty performed via a cut-down had a clinical success of 9/29 (31%). However, major complications were rare. Device staging for treatment of peripheral vascular disease provides additional options for patients who are at high surgical risk and/or in whom standard therapy has failed. PMID- 8674263 TI - Cost-effective management of heart failure. AB - Heart failure affects more than 2 million Americans, and about 400,000 new cases are diagnosed each year. The direct economic cost is over $10 billion/year. About 75% of this cost is spent on hospitalization, and almost 20% on nursing home care. Drugs such as angiotensin-converting enzyme (ACE) inhibitors reduce mortality and hospitalization and are thus very cost effective in the management of heart failure. Cost-effective strategies should focus on keeping patients out of the hospital. Additional savings can be obtained by more appropriate utilization of tests. PMID- 8674264 TI - Endocardial fibroelastosis and primary carnitine deficiency due to a defect in the plasma membrane carnitine transporter. AB - Endocardial fibroelastosis (EFE) has previously been shown to be associated with tissue carnitine deficiency, although the basis for the carnitine deficiency has not been documented. A patient with the classical features of EFE and marked deficiency of carnitine in heart muscle, skeletal muscle, and liver is presented in this report. Cultured skin fibroblasts from both parents demonstrated levels of carnitine uptake at 50% of the normal rate. This is consistent with heterozygosity for the plasma membrane carnitine transporter defect, indicating likely homozygosity for this recently recognized inborn error in the index patient. PMID- 8674265 TI - Clinical evaluation of algorithms for ST measurement during exercise test. AB - HYPOTHESIS: Computer processing of the exercise electrocardiogram (ECG) has many advantages, but the reliability of the analysis algorithms is not easily evaluable. No standard annotated database, nor recommended practice for testing and reporting performance results is available: thus, performance evaluation of such devices can be accomplished only by using a set of unannotated recordings, obtained in clinical practice. We evaluated the accuracy of an original microcomputer-based exercise test analyzer comparing the ST computer output with the measurements obtained by two experienced cardiologists. METHODS: Six hundred ECG strips were randomly selected from the exercise test recordings of 60 patients. The ST shift (at J + 80 ms) was blindly assessed by two observers (with the aid of a calibrated lens) and compared with computer measurements. Correlation coefficients, linear regression equations, percent of discrepant measurements, and 95% confidence limits of the mean error were calculated for all leads, peripheral leads, precordial leads, and "stress-test" leads (II, III, aVF, V4, V5, V6). RESULTS: The computer did not analyze five samples on a total of 600 (0.83%) ECG strips because of excessive noise or signal loss, while 51 (8.5%) were considered unreadable by both observers and 67 (11.2%) were rejected by at least one observer. Correlation between the measurements taken by computer and observer(s) measurements was statistically significant (p < 0.001 for all lead groups), no systematic measurement bias was found, and the mean difference was lower than human eye resolution. CONCLUSIONS: Our algorithms provide results as good as those provided by trained cardiologists in measuring ST changes occurring during exercise test. However, this study did not evaluate whether computer improvement of the signal-to-noise ratio would allow accurate measurements even on cardiologists' uninterpretable ECG. This potential advantage of computer assisted analysis could be assessed only by using a dedicated exercise test database, in which different patterns of noise are superimposed on noise-free recordings previously annotated for ST level. PMID- 8674266 TI - Retinal artery embolization: a rare presentation of calcific aortic stenosis. AB - Retinal artery embolization is an unusual but serious complication of calcific aortic stenosis. However, it is rare for retinal embolization to be the presenting feature of aortic stenosis. This report describes a young patient who presented with an acute retinal artery occlusion secondary to calcific aortic valve disease, and discusses the rationale for early surgical intervention. PMID- 8674267 TI - Postpericardiotomy syndrome and cardiac tamponade following transvenous pacemaker placement. AB - This is the first reported case of cardiac tamponade presumed to be caused by postpericardiotomy syndrome (PPS) following endocardial pacemaker placement. An 84-year-old woman developed fever and dyspnea 3 weeks after pacemaker placement. Physical examination revealed hypotension, tachycardia, and pulsus paradoxus. Auscultation revealed clear lungs and diminished heart sounds. The sedimentation rate was 60 mm/h. Echocardiography revealed a large pericardial effusion with signs of cardiac tamponade. Surgical drainage of the pericardial space resulted in complete resolution of symptoms. The pericardial fluid was culture- and cytologically negative. PPS is a common complication of cardiothoracic surgery and chest trauma. It rarely occurs after percutaneous procedures such as percutaneous transluminal coronary angioplasty and transvenous pacemaker placement. While usually having a benign, self-limited course, PPS can cause a serious complication as illustrated in this case report. PMID- 8674268 TI - Anomalous origin of the right coronary artery from the pulmonary trunk: is surgical reimplantation into the aorta a method of choice? AB - The origin of the right coronary artery (RCA) from the pulmonary trunk (PT) is a rare congenital anomaly. Although most of the patients remain asymptomatic, prophylactic reimplantation of the RCA into the aorta has been recommended to prevent an adverse outcome. The report describes postoperative results in two patients following uneventful RCA reimplantation. A 47-year-old man, with coexisting diffuse atherosclerotic involvement of the left coronary artery, remained symptomatic despite the establishment of a two-coronary system. The second patient, a 36-year-old woman, with isolated anomalous origin of the RCA from the PT, continued to present with myocardial ischemia on exertion. The original observation of an angiographic "slow-flow" phenomenon in the reimplanted RCA in both patients implies the impairment of myocardial microvessels. These findings give rise to the question of whether the reimplantation of the anomalous artery is really superior to simple ligation of its origin in order to relieve the "coronary steal" effect. PMID- 8674269 TI - Silent ischemic cardiomyopathy and left coronary ostial stenosis secondary to radiation therapy. AB - A 55-year-old woman presented with profound congestive heart failure 23 years following mediastinal radiation. Ejection fraction (EF) was 35%. Symptoms markedly improved and EF increased to > 55% following saphenous vein bypass for > or = 80% ostial left main stenosis. Radiation therapy, a known risk factor for coronary atherosclerosis, may present with reversible severe silent ischemia. PMID- 8674270 TI - Complete atrioventricular block due to large cell lymphoma: resolution with chemotherapy. AB - Malignant lymphoma commonly involves the heart. Previous studies have found cardiac metastases in up to 20% of patients dying with lymphoma. Cardiac signs and symptoms of lymphoma are relatively rare, however, and in most cases, the diagnosis is made either postmortem or too late to affect the clinical course. This report presents the first case of complete heart block due to lymphoma that responded to surgery and chemotherapy with return of normal atrial ventricular conduction. PMID- 8674271 TI - Wilfred Gordon Bigelow. PMID- 8674272 TI - Muscle cells produce a low molecular weight factor with anti-cancer activity. AB - The present study describes a new low molecular weight factor released by muscle cells, which inhibits proliferation of tumor cells in vitro and in vivo, is highly specific towards tumor cells, and has no observable effect on normal cells' proliferation. What first prompted us to investigate this factor was the observation that tumor metastases are extremely rare in striated muscles. Co culturing of striated muscle cells with malignant cells led to marked morphological alterations in the latter, in contrast to the same cells when incubated without muscle cells. A conditioned medium of striated muscle cells was prepared and its effect tested on a variety of cells. This conditioned medium (CM) inhibited proliferation of tumor cell lines of murine (B16 melanoma, Madison 109 lung carcinoma, MCA-105 sarcoma, ESB lymphoma), or of human origin (HTB-38 adenocarcinoma, T47D breast carcinoma, CX1 colon carcinoma). The proliferation of normal cells (bone marrow cells, fetal liver erythroid cells) was not affected by the CM. Flow cytometric analysis of B16 melanoma cells following incubation with the CM revealed that 63% +/- 12 of the cells were in the G0/G1 phase of the cell cycle, compared to 47.8% +/- 8 of cells incubated with a medium (not conditioned) only. The activity of the CM and of certain fractions thereof was also demonstrated in vivo: they prevented tumor growth in mice inoculated intraperitoneally with MCA-105 sarcoma cells. Partial purification of the CM revealed that the active component was a non-proteinaceous compound with a molecular weight of about 500 D. The results clearly suggest that muscle cells produce a low molecular weight factor which can selectively inhibit the proliferation of tumor cells in vitro and in vivo. This factor is neither species nor tumor specific. PMID- 8674274 TI - Microvessel density, expression of proto-oncogenes, resistance-related proteins and incidence of metastases in primary ovarian carcinomas. AB - Relationships between the incidence of metastatic spread and microvessel density, expression of proto-oncogene products, or expression of resistance-related proteins were investigated in human ovarian carcinomas by immunohistochemistry. Ovarian carcinomas with a high microvessel density showed a significantly increased formation of metastases (P = 0.005). Tumors with positive immunoreactivity of c-jun and c-myc products had a higher metastatic spread; however, these results were not statistically significant. A marginally significant correlation existed between the expression of erbB1 (EGFR) and metastatic spread (P = 0.05). No significant relationship was found between the expression of the resistance-related proteins P-glycoprotein or glutathione S transferase-pi and the incidence of metastases. Furthermore, no correlation was detected between expression of the heat shock protein 70 and the occurrence of metastases. PMID- 8674275 TI - Pathological findings suggestive of interclonal stabilization in a case of cutaneous melanoma. AB - Metastatic spread is a complex process based on manyfold interactions of the tumor cells with each other and with the surrounding stroma. In experimental systems tumor cell heterogeneity and presence of various subpopulations which interact with one another to stabilize their relative proportions within the population has been shown. Here we report a patient with melanoma, showing morphological evidence of two distinct tumor cell populations in the primary tumor and in all subcutaneous metastases. By image analysis, both populations were clearly characterized by minimal nuclear diameter and by nuclear form factor and were demonstrable in each specimen. The fact that these peculiar cell populations were present in all melanoma lesions removed from the patient might indicate that the populations require the presence of each other and that none of them is metastatically competent on its own. PMID- 8674273 TI - Induction of matrix metalloproteinase 9 expression in breast carcinoma cells by a soluble factor from fibroblasts. AB - Tumor-stromal interactions appear to play an important role in the induction of metalloproteinase expression in malignant tumors. We describe a tissue culture system in which expression of MMP-9 (gelatinase B or the 92 kDa type IV collagenase/gelatinase) was induced by co-cultivation of fibroblasts with breast cancer cell lines. While neither the breast cancer cells nor the normal rat embryo fibroblasts made MMP-9 alone in culture, human MMP-9 was made in the co cultures. The MMP-9 was secreted in a latent form. The induction occurred at least in part through increases in the MMP-9 mRNA levels in the breast cancer cells. These increases did not appear to require protein synthesis. Conditioned medium from the fibroblasts could duplicate the induction of MMP-9 in the breast cancer cell lines. The active factor in the medium was inactivated by heat or by trypsin suggesting that it was a protein. This protein was in the size range of 30-100 kDa. Thus, fibroblasts could secrete a factor which was able to regulate the expression of MMP-9 in breast cancer cells. PMID- 8674276 TI - In vivo therapeutic effects of interleukin-12 against highly metastatic residual lymphoma. AB - Despite considerable advancement in anticancer therapy, minimal residual disease (MRD) is still a major problem in the clinical management of cancer, including lymphoma. In this report, we have studied the antitumor effects of interleukin-12 (IL-12) against an aggressive liver metastatic murine RAW117-H10 lymphoma. Our results using three different doses of IL-12 (0.175, 0.35 and 0.7 micrograms/mouse) showed that a 0.35 micrograms dose is the most efficacious against lymphoma grown in intact mice. Furthermore, we have evaluated the therapeutic effects of IL-12 against residual lymphoma in a transplantation setting. BALB/c mice were treated with high-dose therapy (HDT) and transplanted with syngeneic bone marrow cells added with a known number of RAW117-H10 lymphoma cells to mimic the clinical situation of MRD. The mice were then treated with IL 12 (0.25 micrograms/mouse/day) alone or IL-12 plus activated cytotoxic effector cells. Our results showed that IL-12 had a significant (P < 0.05) antitumor therapeutic effect against liver metastatic lymphoma grown in intact mice as well as in lymphoma-bearing mice treated with HDT followed by stem cell transplantation as determined by survival period. The therapeutic effect of IL-12 was also demonstrated by a very significant decrease (P < 0.05) in the tumor burden in livers from the IL-12-treated mice. Mice that were treated with IL-12 following HDT and hematopoietic stem cell transplantation had a significant decrease in circulating white blood cells (P < 0.05), a significant increase in spleen weight and cellularity (P < 0.05), and hematopoietic progenitor cells (P < 0.05), a significant increase in the number of splenocytes expressing IL-2 alpha chain receptor (P < 0.05), and an increase in the frequency of natural killer cells in their spleens. These studies suggest that cytokines such as IL-12 may have the potential to mediate antitumor effects against residual lymphoma without compromising lymphohematopoietic recovery. PMID- 8674277 TI - Anti-metastatic prostacyclins inhibit the adhesion of colon carcinoma to endothelial cells by blocking E-selectin expression. AB - Prostacyclins have long been shown to have anti-metastatic activity. One hypothesis is their modulation of cell adhesion molecule (CAM) expression by target organ endothelial cells. We have postulated that prostacyclin, its analogs, and mechanistic mimics decrease colon carcinoma adhesion to cytokine stimulated endothelial cells by blocking endothelial expression of the adhesion molecule E-selectin, but not the vascular cell adhesion molecule-1 (VCAM-1). Cultured human microvascular endothelial cells (HDMEC) were pre-incubated with prostacyclin (PGI2), dibutyrl-cAMP (dbcAMP), forskolin (FOR), and/or iso methylbutylxanthine (IBMX) for 15 min, then co-incubated with the cytokine tumor necrosis factor (TNF) for 4 h. HDMEC surface expression of E-selectin and VCAM-1 was evaluated by flow cytometry and ELISA. Adherence of 51Cr-labeled colon carcinoma cells to HDMEC monolayers was then determined. In parallel assays, HDMECs were incubated with anti-E-selectin and anti-VCAM-1 monoclonal antibody (1:100) prior to the addition of tumor cells. Prostacyclins, its analogs, and mimics significantly reduced E-selectin expression by HDMEC, while the reduction of VCAM-1 expression was much less pronounced. Prostacyclins also significantly decreased colon carcinoma adherence to stimulated HDMECs. The inhibition of E selectin expression, but not VCAM-1 expression, corresponded to the reduction of tumor cell adherence. Prostacyclin's effects on tumor adhesion were nullified by pre-incubation with E-selectin antibody. The inhibition of colon carcinoma adherence to cytokine-stimulated endothelial cells treated with prostacyclin, its analogs, and mimics appears to result from blocking endothelial E-selectin, but not VCAM-1, expression. These data support the hypothesis that prostacyclins may exert their anti-metastatic effect, in part, by inhibiting CAM-mediated adherence of colon carcinoma to endothelial cells in metastatic target organs. PMID- 8674278 TI - Vitamin D3 analogs inhibit growth and induce differentiation in LA-N-5 human neuroblastoma cells. AB - The physiologically active metabolite of vitamin D3, 1,25 dihydroxycholecalciferol (D3), plays an important role in embryonic development and cell differentiation. Previously, we have demonstrated that D3 significantly induces differentiation and inhibits growth of LA-N-5 human neuroblastoma cells at concentrations of 24 nm and higher. In this study, we compared two D3 analogs, 20-epi-22oxa-25a,26a,27a-tri-homo-1,25-D3 (KH 1060) and 1,25-dihydroxy-22,24 diene, 24,26,27-trihomo (EB 1089), with D3 with respect to their effects on differentiation and growth inhibition. We report an inhibition of growth by 45 55% in cells treated with 0.24 nm EB 1089 and 0.24 nM KH 1060, similar to that seen in cells treated with 24 nM D3. At these concentrations, both EB 1089 and KH 1060 stimulate the differentiation of LA-N-5 neuroblastoma cells as shown by increased neurite outgrowth, decreased N-myc expression and decreased invasiveness in vitro. An increase in acetylcholinesterase activity, a functional measure of differentiation, was also exhibited. Previous reports have shown that treatment doses needed to achieve 24 nM serum concentrations of D3 in patients would result in hypercalcemia. EB 1089 and KH 1060 can cause the same in vitro effects on LA-N-5 human neuroblastoma cells at 1/100 of the concentration required of D3. These data suggest a potential clinical efficacy of EB 1089 and KH 1060 as biological response modifiers. PMID- 8674279 TI - Identification of genetic alterations associated with the process of human experimental colon cancer liver metastasis in the nude mouse. AB - Understanding the genetic elements controlling the process of tumor metastasis to distant organ sites such as the liver may be the key to improving survivorship from colon cancer. By using standard cytogenetic techniques in combination with comparative genomic hybridization, multiple genetic imbalances within three human colon cancer cell lines previously selected for differences in liver-metastatic behavior were identified. The entire genome of one poorly metastatic cell line (KM12C) was compared directly with that of two highly metastatic cell lines (KM12SM, KM12L4A) derived from it. A number of chromosomal gains (8q, 12q15, 20q11.2) and losses (5p13, 6p21.3, 18) were common to all three cell lines and are likely related to early tumor development rather than to the selection process used to generate cell lines of increased metastatic potential. Chromosomal imbalances detected only in the highly metastatic cell lines were also observed. KM12SM showed losses of portions of 2p22, 2q24.3--> 2q32.2, 4p15.3 -> cen, 4q24 without the 13q and 15q22.3 gains noted for KM12C. Both gains (1p31.3--> 1p21, 2q22--> 2q33, 3cen--> 3q26.2, 5q14--> 5q23, 6cen--> 6q23) and losses (16p, 17p, 17q 19p, 19q 22q) were observed for KM12L4A but not for the other two cell lines. Identification of these alterations provides valuable insight into the process of experimental liver metastasis and is a first step towards mapping genes linked to the terminal phases of human colon cancer progression. PMID- 8674282 TI - HLA antigens are candidate markers for prediction of lymph node metastasis in gastric cancer. AB - We investigated the association between human leucocyte antigen (HLA) antigens and lymph node metastasis in 724 gastric cancer patients. Among patients who had poorly differentiated adenocarcinoma with or without HLA-DR4 antigen, lymph node metastasis was detected in 80.8 and 54.9%, respectively (relative risk (RR) = 3.5, P = 0.0005, corrected P = 0.0285). It was more common in patients with a family history of cancer death (RR = 7.7). Among signet ring cell carcinoma patients with or without HLA-B52 antigen, lymph node metastasis was detected in 57.7 and 19.7%, respectively (RR = 5.6, P = 0.0001, corrected P = 0.0086). It was more common in patients who were smokers (RR= 8.3). Our findings suggest that HLA DR4 and HLA-B52 antigens are associated with lymph node metastasis in gastric cancer. PMID- 8674281 TI - Epidermal growth factor modulates cell attachment to hyaluronic acid by the cell surface glycoprotein CD44. AB - Cell adhesion to and migration through extracellular matrices (ECM) are critical events in tumor invasion and metastasis. Previous work by us had demonstrated that signaling of epidermal growth factor receptor (EGFR) confers an oncogenic phenotype on NR6 cells and that these cells when transfected with holo EGFR demonstrate greater motility and invasiveness than cells carrying a carboxy terminal truncated EGFR. Recently, a cell surface glycoprotein, CD44, has been implicated in cell-ECM adhesion involved in tumor cell migration, signal transduction, and metastasis. We investigated whether EGF regulates cellular interactions with ECM components, and in particular, hyaluronate, by modulating CD44 expression. In vitro cell attachment assays on hyaluronate-coated plates demonstrated similar basal level of binding (approximately 33%) for murine NR6 parental cells devoid of endogenous EGFR (P) or expressing wild-type EGFR (WT), while a time-dependent increase in binding was observed in WT cells stimulated with EGF. Additionally, utilizing monoclonal antibody blocking assays, CD44, but not EGFR, was shown to be directly involved in this attachment. Both WT and P cells possessed equivalent 95 kDa bands on immunoblots, corresponding to CD44. The existence of CD44 mRNA was verified by RT-PCR using synthetic oligonucleotides in which a 1.1 kb cDNA was detected in both cell lines and confirmed by DNA sequencing. After 24-h exposure to exogenous EGF, an increase in CD44 protein and mRNA expression was found in WT cells, but not in P cells, supporting the contention that a functional EGFR signaling pathway is required for CD44 regulation. Thus, EGF stimulates cell binding to hyaluronate in vitro by regulating CD44 expression. PMID- 8674280 TI - Inhibition of colony formation in agarose of metastatic human breast carcinoma and melanoma cells by synthetic glycoamine analogs. AB - We studied the influence of 10 synthetic glycoamine analogs on colony formation in 0.3 and 0.9% agarose by metastatic human breast carcinoma (MDA-MB-435) and melanoma (TXM-13) cells. Nine synthetic analogs significantly inhibited the colony formation in 0.9% agarose of MDA-MB-435 human breast carcinoma cells; five compounds caused a 73-83% reduction of colony formation. Seven synthetic glycoamines caused a significant inhibition of colony formation in 0.9% agarose by TXM-13 melanoma cells with the inhibitory effect ranging from 71 to 87%. The 50% inhibition (I50) doses and relative activity rank of the compounds were similar for both breast carcinoma and melanoma cell lines. The murine B16 melanoma cell aggregation assay was employed to elucidate the potential mechanism(s) of the inhibitory activity of synthetic glycoamines. The relative activity ranks of the compounds based on the independently determined I50 doses for both cell aggregation and clonogenic growth assays were very similar for the four most active synthetic analogs and clearly indicated the importance of hydrophobic amino acid in mediating the bioactivity of synthetic glycoamines. In both experimental systems (clonogenic growth in agarose and cell aggregation assay) the leading compound was N-(1-deoxy-D-fructos-1-yl)-D-leucine (Fru-D-Leu) and the least active analog was N-(l-deoxy-D-fructos-1-yl)-glycine (Fru-Gly). These results show that synthetic glycoamines may act by competing for specific carbohydrate-lectin interactions, particularly those involving beta-galactoside specific lectins expressed on metastatic cells. PMID- 8674283 TI - Morphotypic plasticity in vitro and in nude mice of epithelial mouse mammary cells (NMuMG) displaying an epithelioid (e) or a fibroblastic (f) morphotype in culture. AB - Transition from an epithelioid (e-) to a fibroblastic (f-) morphotype marks invasiveness in clinical and experimental cancer. To understand better the factors influencing such transitions, we have subcloned and manipulated mouse mammary gland (NMuMG) cell cultures and compared the invasive phenotype of multiple subclones in vitro and in vivo. Cell lines with an e-morphotype expressed E-cadherin homogeneously and were not invasive in vitro. Cells with an f-morphotype were E-cadherin-negative and became fully invasive in vitro upon expression of the ras oncogene. Invasive tumors were produced in node mice after subcutaneous injection of e-type or f-type cells. These tumors showed cystic, glandular and undifferentiated structures. Tumors from f-type cells were E cadherin-negative whereas e-type tumors stained heterogeneously in immunohistochemical preparations. Our observations demonstrate the impact of the micro-ecosystem on the invasive phenotype, with in vivo downregulation of E cadherin and stimulation of the e- to f-morphotype transition. PMID- 8674284 TI - Urokinase-type plasminogen activation in three human breast cancer cell lines correlates with their in vitro invasiveness. AB - In order to invade and spread cancer cells must degrade extracellular matrix proteins. This degradation is catalysed by the concerted action of several enzymes, including the serine protease plasmin. Several experimental studies have shown that inhibition of plasmin formation reduces cancer cell invasion and metastasis, indicating a critical role of this proteolytic pathway in these processes. In order to further study the role of plasmin in cancer progression, we have characterized urokinase-type plasminogen activator (uPA) mediated plasmin formation in three human breast cancer cell lines. Using monoclonal antibodies against uPA and its receptor uPAR, we have investigated the contribution of uPA and uPAR to invasive capacity in an in vitro invasion assay. MDA-MB-231 BAG cells were found to express high protein levels of uPA, uPAR and PAI-1. MDA-MB 435 BAG cells produced low amounts of uPA, PAI-1 and moderate amounts of uPAR, whereas MCF-7 BAG cells showed low levels of uPA, uPAR and PAI-1 protein. In a plasmin generation assay MDA-MB-231 BAG cells were highly active in mediating plasmin formation, which could be abolished by adding either an anticatalytic monoclonal antibody to uPA (clone 5) or an anti-uPAR monoclonal antibody (clone R3), which blocks binding of uPA to uPAR. The two other cell lines lacked the capacity to mediate plasmin formation. In the Matrigel invasion assay the cells showed activity in this order: MCF-7 BAG < MDA-MB-435 BAG < MDA-MB-231 BAG. Testing MDA MB-231 BAG cells in the Matrigel invasion assay revealed that invasion could be inhibited in a dose-dependent manner either by the clone 5 uPA antibody or by the clone R3 uPAR antibody, suggesting that the cell surface uPA system is actively involved in this invasive process. It is concluded that these three cell lines constitute a valuable model system for in vitro studies of the role of cell surface uPA in cancer cell invasion and has application in the search for novel compounds which inhibit mechanisms involved in uPA-mediated plasmin generation on cancer cells. PMID- 8674285 TI - Differential motility stimulation but not growth stimulation or adhesion of metastatic human colorectal carcinoma cells by target organ-derived liver sinusoidal endothelial cells. AB - Liver is the most common distant metastatic site for colorectal cancers and when blood-borne colorectal cancer cells reach the liver, they first encounter hepatic capillary and sinusoidal endothelial cells. Thus we studied differences between highly (HT-29LMM) and poorly (HT-29P) liver-metastatic sublines of human colorectal cancer cells by examining the interactions between tumor cells and liver microvessel endothelial cells. Using hepatic sinusoidal endothelial (HSE) and lung microvessel endothelial (MLE) cell-conditioned medium we measured the growth and motility stimulating activities released from these endothelial cells and adhesion of these cancer cells to the endothelial cells. Differences in the ability of HSE-conditioned medium (HSE-CM) or MLE-conditioned medium (MLE-CM) to stimulate HT-29 cell growth were not observed. There was a small but significant increase in the rate of adhesion of highly metastatic HT-29LMM cells to HSE cell monolayers than poorly metastatic HT-29P cells, but there was no difference in adhesion to MLE cell monolayers. HSE-CM stimulated the motility of highly metastatic colorectal cancer cells to a greater extent than the poorly metastatic cells. Motility-stimulating activity for the colorectal cancer cell lines was not detected in MLE-CM. The HSE-CM motility-stimulating activity for human HT-29 cells was not removed using antibodies against hepatocyte growth factor (HGF/SF), complement component C3 or laminin, indicating that it is not related to these known liver-derived motility factors. The results suggest that the ability of highly metastatic HT-29LMM colorectal cancer cells to colonize the liver is related to their ability to respond to liver sinusoidal endothelial cell-derived motility factors and to a lesser degree to adhere to liver sinusoidal endothelial cells. PMID- 8674287 TI - Value of SPECT imaging of the thoracolumbar spine in cancer patients. AB - The purpose of this study was to evaluate the usefulness of SPECT bone imaging in targeting the precise location of vertebral abnormalities to ascertain whether such knowledge would help in differentiating between metastatic and benign lesions. SPECT images of the thoracolumbar spine in 50 patients were correlated with plain x-rays, CT, MRI, PET, and bone scans and 6-month clinical follow-ups. SPECT images revealed 110 lesions, 35 of which were metastases. Twenty-four of 25 lesions involving the vertebral body with extension into posterior elements were metastases, as well as 10 of 39 lesions found in the vertebral body and 1 of 4 found in the spinous process. All lesions limited to the anterior aspect of the vertebral body (13/13), facet joints (23/23), and intervertebral disk space (6/6) were benign. In conclusion, SPECT imaging of the thoracolumbar spine is helpful in determining the precise anatomic location of vertebral abnormalities, and knowledge of the location can be used to determine whether these abnormalities in cancer patients are benign entities or metastases. PMID- 8674286 TI - Protein kinase A regulates Lewis lung carcinoma adherence to extracellular matrix components and spontaneous metastasis. AB - Tumor cell adhesion to and migration through the extracellular matrix (ECM) can influence their capacity to disseminate. Since prior studies with Lewis lung carcinoma (LLC) tumors had shown metastatic clones to have more protein kinase A (PKA) activity than nonmetastatic clones, the present study assessed if PKA regulates the interaction between tumor and the ECM, and how this may be associated with the metastatic capacity of the tumor cells. This was accomplished with the use of metastatic (LLC-LN7) and nonmetastatic (LLC-C8) variants that had been stably transfected to overexpress the PKA Calpha subunit or to have blocked PKA activity. Cells with increased PKA activity were less adherent to vitronectin, laminin, and collagen I, and could more readily migrate through these ECM components than could transfectants with reduced PKA activity. PKA did not regulate adhesion to or migration through fibronectin, and did not appear to be associated with changes in expression of surface integrins. In addition to modulating tumor adhesion and migration in vitro, PKA activation caused an increased formation of metastases from s.c. tumors, but did not regulate formation of experimental metastases by i.v. injected tumor cells. These results suggest that PKA signaling is important for modulating the tumor-ECM interaction and can facilitate tumor transit from the primary tumor site. PMID- 8674288 TI - Metastases seen on SPECT imaging despite a normal planar bone scan. AB - Although bone scintigraphy is an extremely sensitive method for the detection of focal bone disease, small lesions below the resolution of planar imaging may be missed. This is a report of a patient with carcinoma of the breast who showed tumor progression 1 year after initial treatment. Complete evaluation was performed in order to detect the origin of increased level of a tumor marker. Although planar bone scintigraphy could not demonstrate any lesion in the spine, multiple metastases were detected in the lumbar and the thoracic spines on SPECT imaging. Only some of these lesions were seen with MRI. Repeat planar bone imaging 6 weeks later showed multiple bone lesions in the lumbar and thoracic areas. PMID- 8674289 TI - Multiple flexion-stress vertebral end-plate fractures. An osteogenesis imperfecta presentation. AB - A 28-year-old woman underwent bone scintigraphy for a 7-day history of severe back pain of sudden onset. Intense linear accumulation of Tc-99m HDP was present in several lower thoracic and lumbar vertebrae without vertebral body deformity. Intense uptake was also present in other thoracic vertebrae with vertebral body changes. X-rays demonstrated osteopenia and dual photon densitometry studies confirmed a significant degree of osteoporosis. Endocrine assessment identified that she and other female members of the family had osteogenesis imperfecta, Sillence type 1. This disorder should be considered in all differential diagnoses of nonobvious traumatic fractures of the vertebrae in healthy young adults. PMID- 8674290 TI - Reflex sympathetic dystrophy of the patello-femoral joint. Diagnosis and relevance. AB - A 30-year-old man had severe left anterior knee pain after a trivial injury. A three-phase bone scan diagnosed this condition to be reflex sympathetic dystrophy, which was subsequently confirmed by sympathetic blockade. PMID- 8674291 TI - Bone scintigraphy and densitometry in children with osteopetrosis. AB - Bone scintigraphy and dual x-ray absorptiometry were performed in 18 children (8 males, 10 females) with clinical and radiologic diagnoses of osteopetrosis in order to demonstrate the scintigraphic features of this rare disorder and to measure the bone mineral density. Their mean age was 9 years (range, 3-16 years). Bone scintigraphy demonstrated characteristic features of a widened metaphysis of all long bones that showed increased tracer uptake, particularly in the distal femur and proximal tibia. Dual x-ray absorptiometry of the lumbar spine, three femoral sites, and total body showed a marked increase in bone mineral density. The mean values for bone density of the lumbar spine and greater trochanter were markedly elevated than were other sites. Compared with a normal group matched for age and gender, the increase in bone mineral density was 181% for the lumbar spine and 193% for the greater trochanter. The authors concluded that bone imaging and bone densitometry are useful in establishing the diagnosis of osteopetrosis by demonstrating increase tracer uptake in the widened metaphysis and increased bone density. Bone densitometry may be of prognostic value in follow-up, especially in monitoring the response to therapy. PMID- 8674292 TI - Clinical utility of In-111 leukocyte imaging in Crohn's disease. AB - Thirty six patients with Crohn's disease were studied with In-111 leukocyte imaging. There was a correlation of the presence of activity on early (4 hour) imaging (r = 0.516, P < 0.001) and on delayed 18-24 hour) imaging (r = 0.457, P < 0.003). In the total group of 36 patients, the results of imaging were useful in the immediate management of 13 patients (36.1%). These included four patients (11.1%) who refused to undergo colonoscopic examination and nine patients (25%), six of whom had previous intestinal resection. PMID- 8674293 TI - Scintigraphic diagnosis of protein losing enteropathy using Tc-99m dextran. AB - The authors performed abdominal scintigraphy using intravenously administered Tc 99m dextran in a patient with protein losing enteropathy. The study revealed abnormal leakage of the radiotracer in the left lumber area that moved over time in a pattern suggestive of small intestinal transit. Besides being a nonprotein and having long stay in intravascular compartment, the macromolecule may have many advantages over Tc-99m human serum albumin, the current radiotracer of choice for imaging intestinal protein loss. PMID- 8674294 TI - Scintigraphy in assessment of the feasibility of separation of a set of xipho omphalopagous conjoined twins. AB - An account is given of the assessment of a set of xipho-omphalopagous twins by means of Tc-99m microcolloid human serum albumin (HSA) and Tc-99m HIDA scintigraphy before their successful separation. The Tc-99m HSA examination showed the absence of connections between the two hearts and major vessels, as well as the independent vascularization of each liver parenchyma and absence of substantial intrahepatic shunts. Tc-99m HIDA disclosed bile secretion and the existence of intrahepatic ducts in both twins. In one, there was excretion into the intestine and the gallbladder and common bile duct were visualized, whereas in the other excretion was slow, either because of duct hypoplasia or as a result of the connections with the other twin. On separation, it was found that the liver parenchyma was composed of two fused parts (the livers of each twin). In one twin, cholangiography showed the gallbladder and intrahepatic and extrahepatic bile ducts with normal excretion into the intestine and excellent drainage, whereas in the other twin the gallbladder was absent, the common bile duct was hypoplastic, and excretion was poor. The two scintigraphic techniques employed provided evidence of bile duct function and enabled the separation to be planned, while intraoperative cholangiography gave a clear picture of the anatomical details before the reconstruction procedure. PMID- 8674295 TI - Ventilation/perfusion lung scan probability category distributions in university and community hospitals. AB - The criteria used in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study for the interpretation of ventilation/perfusion scans are widely used and the probability of pulmonary embolism is determined from these criteria. The prevalence of pulmonary embolism in the PIOPED study was 33%. To investigate the similarity of patient populations who have ventilation/perfusion scans at one of the medical centers that participated in the PIOPED study and a small community hospital, the authors evaluated the probability category distributions of lung scans at the two institutions. They retrospectively interpreted 54 and 49 ventilation/perfusion lung scans selected from January, 1991, to June, 1992, at Duke University Medical Center and at Central Carolina Hospital, respectively. Studies were interpreted according to the PIOPED criteria. The percentage of studies assigned to each category at Duke University Medical Center and Central Carolina Hospital were 17% and 27% normal or very low probability, 31% and 59% low probability, 39% and 10% intermediate probability, and 13% and 4% high probability, respectively. The different distribution of probability categories between university and community hospitals suggests that the prevalence of disease may also be different. The post-test probability of pulmonary embolism is related to the prevalence of disease and the sensitivity and specificity of the ventilation/perfusion scan. Because these variables may differ in community hospital settings, the post-test probability of pulmonary embolism as determined by data from the PIOPED study should only be used in institutions with similar populations. Clinical management based upon the results of the PIOPED study may not be applicable to patients who have ventilation/perfusion scans performed in a community hospital. PMID- 8674296 TI - A pulmonary metastasis from renal cell carcinoma seen on a lung perfusion scan. AB - A 75-year-old man with known pulmonary metastases from renal cell carcinoma had ventilation and perfusion scans to rule out a pulmonary embolism. The ventilation scan showed a round defect at the left lung base. The Tc-99m MAA perfusion scan revealed multiple areas of increased tracer activity, at least one of which corresponded to the patient's pulmonary metastases seen on chest radiograph. The most plausible explanation for this finding was that the tumor metastasis invaded the pulmonary artery causing shunting of the tumor vessels with the pulmonary artery. PMID- 8674297 TI - Brain SPECT, MRI, and CT in a closed head injury induced intracerebral hematoma. PMID- 8674298 TI - Scrotal lymphocele. Diagnosis by lymphoscintigraphy. PMID- 8674299 TI - Tc-99m sestamibi uptake and retention in a large hepatoma. PMID- 8674300 TI - Extraskeletal accumulation of Tc-99m HMDP in a tuberculous cold abscess. PMID- 8674301 TI - Persistent asymmetric pulmonary Tl-201 uptake in type III sarcoidosis. PMID- 8674302 TI - Intraluminal hematoma. Another potential cause of false-positive results with In 111 leukocyte scintigraphy. PMID- 8674304 TI - Pulmonary arteriovenous malformation diagnosed with radionuclide angiography. PMID- 8674303 TI - False-positive uptake of I-131 MIBG. PMID- 8674305 TI - Visualization of reflux from bladder to the duodenal portion of a pancreatic duodenal allograft. PMID- 8674306 TI - Ga-67 scintigraphy in a patient with adult T-cell leukemia/lymphoma. PMID- 8674308 TI - Incidental visualization of hepatic hemangioma during Tc-99m (v) DMSA, Tl-201, and Tc-99m MDP imaging. PMID- 8674307 TI - Bleeding from postoperative (hepato-jejunostomy--Roux en Y) anastomosis demonstrated by labeled RBCs. PMID- 8674309 TI - Incidental visualization of cadaveric kidney transplant before Tc-99m MAG3 evaluation of transplant renal function. PMID- 8674311 TI - Abdominal scintigraphy of CSF leak. PMID- 8674310 TI - Bone scan in patient with horseshoe-kidney mimicking skeletal lumbar metastasis. PMID- 8674313 TI - Current readings in nuclear medicine. PMID- 8674312 TI - Tumoral calcinosis-like metastatic calcification in a patient with renal osteodystrophy: CT and scintigraphic appearances. PMID- 8674314 TI - Back to the drawing board. PMID- 8674315 TI - Biochemical haruspex for acute respiratory distress syndrome. PMID- 8674316 TI - Medicine and Mephistopheles. PMID- 8674317 TI - Unraveling the mysteries of heatstroke. PMID- 8674318 TI - Presence and absence of nitric oxide synthase in sepsis. PMID- 8674319 TI - Solutions in search of problems. PMID- 8674320 TI - Society of Critical Care Medicine initiative to address care at the end of life. PMID- 8674321 TI - Uncoupling of biological oscillators: a complementary hypothesis concerning the pathogenesis of multiple organ dysfunction syndrome. AB - OBJECTIVE: To present a complementary hypothesis concerning the pathogenesis of the multiple organ dysfunction syndrome. DATA SOURCES: Primary reports and reviews published in peer-reviewed medical and scientific journals. HYPOTHESIS: We suggest that healthy organs behave as biological oscillators, which couple to one another during human development, and that this orderly coupling is maintained through a communications network, including neural, humoral, and cytokine components. We suggest that the systemic inflammatory response syndrome initiates disruption of communication and uncoupling, and further suggest that progression into the multiple organ dysfunction syndrome reflects progressive uncoupling that can become irreversible. Resolution of the inflammatory response and reestablishment of the communications network are necessary but may not be, by itself, sufficient to allow organs to appropriately recouple. This hypothesis is testable using existing laboratory and clinical tools. PMID- 8674323 TI - Sir Isaac Newton, sepsis, SIRS, and CARS. PMID- 8674322 TI - Experimental human endotoxemia increases cardiac regularity: results from a prospective, randomized, crossover trial. AB - OBJECTIVE: To determine whether human endotoxemia is associated with a loss of the physiologic beat-to-beat variability of heart rate. DESIGN: Prospective, randomized, crossover, single-blind study. SETTING: Clinical research center in a federal, nonuniversity hospital. SUBJECTS: Healthy volunteers. INTERVENTIONS: Intravenous administration of reference (Escherichia coli) endotoxin or saline placebo, with or without previous administration of oral ibuprofen. MEASUREMENTS AND MAIN RESULTS: Electrocardiograms were continuously recorded and digitized using series of 1000 beat epochs of R-R intervals over 8 hrs. Analyses included measures in the time domain (standard deviation), frequency domain (power spectra), and a measure of regularity (approximate entropy). Endotoxin administration was associated with loss of variability by all measures. This loss of variability remained significant even with administration of ibuprofen, which blocked the development of fever and endotoxin-related symptoms. CONCLUSIONS: Infusion of endotoxin into human volunteers causes loss of heart rate variability, as measured by standard deviation and power spectra, as well as an increase in heart rate regularity, as measured by approximate entropy. Changes in approximate entropy occurred earlier than changes in other heart rate variability measures and may be a useful means of detecting early sepsis. This reduction in regularity is consistent with a model in which the pathogenesis of multiple organ system dysfunction syndrome involves the physiologic uncoupling of vital organ systems. PMID- 8674324 TI - An increase in serum C18 unsaturated free fatty acids as a predictor of the development of acute respiratory distress syndrome. AB - OBJECTIVE: No means exist for predicting the acute respiratory distress syndrome (ARDS), which complicates sepsis, trauma, and a variety of clinical disorders. Because activation of phospholipid-signaling pathways involving the acyl chains oleate and linoleate may initiate and amplify the inflammatory response, and thereby lead to the development of ARDS, we examined whether serum concentrations of these bioactive lipids increase and are predictive of ARDS in at-risk patients. DESIGN: Part I: A prospective, single-blind trial. Part II: A prospective, randomized, double-blind trial. SETTING: General intensive therapy units in five university teaching hospitals. SUBJECTS: Part I: Thirty-nine healthy control patients were studied to determine normal distribution of serum acyl values, followed by 30 patients admitted with onset of sepsis, trauma, or development of ARDS (within 24 hrs of admission) over a 1-yr period. Part II: Eight patients admitted with sepsis syndrome over a 2-month period. INTERVENTIONS: Part II: Patients were randomized to receive the substituted methylxanthine, lisofylline (CT1501R), or an identically presented placebo. MEASUREMENTS AND MAIN RESULTS: We measured the serum free fatty acid concentrations in the 39 healthy control subjects, and then we prospectively examined the serum free fatty acid concentrations in 30 age-matched patients in samples obtained within 24 hrs from the onset of sepsis, trauma, or development of ARDS. We then prospectively studied eight septic, at-risk patients who were matched for age, Acute Physiology and Chronic Health Evaluation II scores, Multiple Organ Failure index, and Glasgow Coma Score, in a double-blind, placebo controlled, pilot study. These patients included four patients who received no treatment and four patients who received lisofylline, a compound that decreases serum unsaturated free fatty acids and diminishes acute lung injury in animals caused by sepsis and/or trauma. The calculated ratios of serum free fatty acids (Le., the ratio of C18 unsaturated fatty acids linoleate and oleate to fully saturated palmitate, C16:0) increased and predicted the development of ARDS in at risk patients. Serum samples from the 30 patients, obtained within 24 hrs from the onset of sepsis, trauma, or development of ARDS, had significantly increased mean acyl chain ratios (1.42 +/- 0.35 [SD]) compared with healthy control subjects (0.86 +/- 0.25; p < .01). Sera from 13 patients with sepsis or trauma who did not develop ARDS (group A [at-risk, non-pre-ARDS]) also had increased acyl ratios (1.23 +/- 0.27) compared with sera from healthy control subjects (0.86 +/- 0.25; p < .01). Sera from seven patients who subsequently developed ARDS (group B [at-risk, pre-ARDS]) had higher acyl ratios (1.70 +/- 0.21) than group A at-risk patients who did not develop ARDS (1.23 +/- 0.27; p < .01) or healthy control subjects (0.86 +/- 0.25; p < .001). Sera from ten group C patients with ARDS at the time of admission to the study had the highest acyl ratios (1.80 +/- 0.75), which exceeded values for healthy control subjects (p < .001) and group A at-risk patients without ARDS (p = .01), but were not significantly different then group B at-risk, pre-ARDS patients (p = .17). Prospective study of eight septic, at-risk patients demonstrated significantly (p < .05) increased serum acyl ratios in the four untreated patients (findings consistent with the first study) but a significantly (p = .02) reduced ratio in the four at-risk patients treated with lisofyline. CONCLUSIONS: Increases in unsaturated serum acyl chain ratios differentiate between healthy and seriously iII patients, and identify those patients likely to develop ARDS. Thus, the serum acyl ratio may not only prospectively identify and facilitate the assessment of new treatments in patients at highest risk for developing ARDS, but may also lead to new insights about the pathogenesis of ARDS. PMID- 8674325 TI - Inflammatory cytokine and nitric oxide responses in pediatric sepsis and organ failure. AB - OBJECTIVE: To examine the relationship of circulating proinflammatory and anti inflammatory cytokine concentrations to nitric oxide and organ failure in pediatric sepsis. DESIGN: Prospective study. SETTING: Pediatric intensive care unit (ICU), children's Hospital of Pittsburgh, University of Pittsburgh. PATIENTS: Nineteen patients with a diagnosis of sepsis admitted to the pediatric ICU. Twelve uninfected critically iII patients served as controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma interleukin (IL)-10, IL-6, and nitrite/nitrate concentrations were measured and compared with an index of organ failure daily for 3 days after presentation with the sepsis syndrome. Children with increased plasma IL-6 concentrations (n = 6) had increased plasma nitrite/nitrate concentrations (p < 0.01 on each day), increased organ failure scores (p < .05 on days 1 and 3), and the highest plasma IL-10 concentrations (p < .05 on days 1 and 3, p = .054 on day 2) when compared with children with sepsis and undetectable IL-6 concentrations. Children with sepsis and detectable IL-6 concentrations, and children with undetectable IL-6 concentrations, both had increased nitrite/nitrate concentrations (p < .005 on days 1 through 3) and increased IL-10 concentrations (p < .05 on days 1 and 2) compared with controls. Children with increased IL-6 concentrations had higher organ failure on each day (p < .01), and children with undetectable IL-6 concentrations had higher organ failure on days 1 and 2 only (p < .005) when compared with controls. Organ failure improved over time in the children with undetectable IL-6 concentrations (p < .005). CONCLUSIONS: Increased plasma nitrite/nitrates and increased organ failure scores occurred in the children with sepsis who had an exaggerated proinflammatory state, despite a pronounced anti-inflammatory response. When the anti-inflammatory response predominated and the proinflammatory state was dampened, organ failure status improved. PMID- 8674326 TI - Gastrointestinal permeability and absorptive capacity in sepsis. AB - OBJECTIVE: To assess gastrointestinal permeability and functional absorptive capacity in patients with sepsis. DESIGN: Case control study to analyze gastrointestinal permeability and functional absorptive capacity of septic patients by differential saccharide absorption (from an oral test solution) and excretion. SETTING: The intensive Therapy Unit of St. Thomas' Hospital, London, UK. PATIENTS: Twenty patients with a mean Acute Physiology and Chronic Health Evaluation (APACHE) II score of 18.4 who were admitted to the intensive care unit with a diagnosis of sepsis. All patients were on enteral feeding. Patients with abdominal pathology were excluded. INTERVENTIONS: An oral test solution containing 5 g of lactulose, 1 g of L-rhamnose, 0.5 g of D-xylose, and 0.2 g of 3 O-methyl-D-glucose dissolved in water to a final volume of 100 mL was administered to patients and controls. Urine was collected for 5 hrs starting immediately after administration of the test solution and the saccharide content of the urine was estimated and expressed as a percentage recovery of the oral test solution. MEASUREMENTS AND MAIN RESULTS: Septic patients had increased lactulose/L-rhamnose urine excretion ratios (0.23 +/- 0.19) compared with control subjects (0.03 +/- 0.01, p < .001), consistent with increased gastrointestinal permeability in sepsis. Septic patients had decreased L-rhamnose/3-O-methyl-D glucose urine excretion ratios (0.14 +/- 0.07) compared with normal controls (0.28 +/- 0.08, p < .001), consistent with decreased gastrointestinal functional absorptive capacity in sepsis. CONCLUSIONS: Patients with acute sepsis exhibit increased gastrointestinal permeability and decreased gastrointestinal functional absorptive capacity in comparison with healthy control subjects. These abnormalities may contribute to the pathophysiology of sepsis. PMID- 8674327 TI - Renal hemodynamics during norepinephrine and low-dose dopamine infusions in man. AB - OBJECTIVE: To characterize the effects of pressor doses of norepinephrine and low dose dopamine (3 micrograms/kg/min) on renal hemodynamics in man, as well as to determine the clinical relevance of combining dopamine with norepinephrine. DESIGN: Prospective, single-blind, randomized study. SETTING: Clinical research unit of a tertiary care hospital. SUBJECTS. Six healthy male volunteers ranging in age between 20 and 28 yrs. INTERVENTIONS: The subjects were assigned randomly to four treatments (1 wk apart) in which renal hemodynamics and electrolyte excretion were assessed. Treatments consisted of 180-min infusions of the following: a) 0.9% sodium chloride (control); b) pressor doses of norepinephrine; c) dopamine at 3 micrograms/kg/min; and d) pressor doses of norepinephrine and dopamine at 3 micrograms/kg/min. Pressor doses of norepinephrine was defined as doses required to increase mean arterial pressure (MAP) by 20 mm Hg. MEASUREMENTS AND MAIN RESULTS: Glomerular filtration rate and renal blood flow were derived from inulin and para-aminohippurate clearances, respectively. Urine output and urine solute excretion were also determined. The mean norepinephrine dose required to increase MAP by 22 +/- 2 mm Hg was 118 +/- 30 ng/kg/min (range 76 to 164). After the addition of dopamine, similar doses of norepinephrine resulted in an MAP increase of 15 +/- 4 mm Hg. Glomerular filtration rate and urine output were comparable under all conditions. The infusion of norepinephrine decreased renal blood flow from 1241 +/- 208 to 922 +/- 143 mL/min/1.73 m2 (p = .03). The addition of dopamine returned renal blood flow to baseline values. The clearance of urine sodium increased significantly with the infusion of dopamine alone (p = .03). All subjects completed the four treatment periods. Adverse events, manifested mostly as palpitations and flushing, were rare and self-limiting. CONCLUSIONS: The addition of dopamine (3 micrograms/kg/min) to pressor doses of norepinephrine normalized renal blood flow in healthy volunteers. These hemodynamic changes were not reflected in urine output and glomerular filtration rate; hence, these monitoring parameters may be unreliable indicators of renal function in the setting of vasopressor therapy. In addition, systemic effects were observed with dopamine (3 micrograms/kg/min), as indicated by a decrease in MAP. PMID- 8674328 TI - Microbial contamination of blood conservation devices during routine use in the critical care setting: results of a prospective, randomized trial. AB - OBJECTIVES: To compare microbial contamination of two different blood conservation devices; to determine if there was an association between contamination of the blood conservation devices and clinical infections; to determine if there was a significant user preference for either of the two devices. DESIGN: Prospective, randomized trial. SETTING: Medical, neurosurgical, and spinal cord intensive care units of an urban, university hospital. PATIENTS: Forty patients who required clinically indicated intrafierial catheters placed at new sites. INTERVENTIONS: The two most widely available blood conservation devices at the time of the study (Venous Arterial blood Management Protection system [VAMP], Baxter Edwards Critical-Care, Irvine, CA; and Safe Draw, Ohmeda, Madison, WI) were chosen for comparison. After the normal 48 to 72 hrs of device use, the blood conservation systems were removed and semi-quantitative and quantitative cultures were taken from comparable sites of the two devices. Positive cultures from the patients were recorded and correlated with cultures obtained from the devices. In order to assess preference for either device, a survey tool was administered to the nursing staff who participated in the study. MEASUREMENTS AND MAIN RESULTS: Quantitative cultures from all sites cultured in both groups demonstrated mean colony counts of < 10(3) colony-forming units (cfu)/mL. There were no statistically significant differences in the colony counts at any of the sites compared between the two groups. There were no statistically significant relationships between positive cultures and patient age, gender, duration of device utilization, frequency of device entry, or the intensive care unit in which the study was conducted. In no circumstance did positive cultures from any of the blood conservation devices correlate with positive culture results from any sites of clinical infection. The clinical survey demonstrated a statistically significant preference for the VAMP system, which persisted despite increased experience with the Safe Draw system. CONCLUSIONS: The levels of microbial contamination noted in these devices were not consistent with clinical infection (defined as 10(3) cfu/mL on quantitative cultures). There was no significant difference in degree or pattern of contamination between the two devices. When utilized and changed according to the Centers for Disease Control guidelines, blood conservation devices are not harbors of infection in the critical care setting. Blood conservation devices can be used as part of a comprehensive blood conservation program in the critical care setting without undue concern for exacerbating infectious processes. PMID- 8674329 TI - Evaluation of complete blood count results from a new, on-site hemocytometer compared with a laboratory-based hemocytometer. AB - OBJECTIVE: To compare point-of-care results obtained from an on-site hemocytometer with values provided by an institutional laboratory instrument. DESIGN: A prospective laboratory evaluation. SETTING: The central laboratory and cardiac surgical intensive care unit of a university-affiliated tertiary care center. PATIENTS: Normal range comparison was performed using blood specimens routinely obtained from 48 hospitalized patients for complete blood count analysis. The second evaluation was performed on blood specimens routinely obtained (in the intensive care unit) after cardiac surgery involving extracorporeal circulation in a series of 187 consecutive patients. MEASUREMENTS AND MAIN RESULTS: Hemoglobin concentration, platelet count, mean corpuscular volume, mean platelet volume, and red and white blood cell counts were measured with both on-site (MD 16, Coulter Electronics, Hialeah, FL) and laboratory (STKS, Coulter Electronics) instruments. Hematocrit and red cell distribution width were calculated using measured variables. Blood specimens were obtained from two distinct patients series. To evaluate measurement values within the normal range, a series of 48 routinely obtained blood specimens for complete blood count analysis in our institutional laboratory were utilized for concurrent analysis with the on-site hemocytometer. To evaluate measurement values out of the normal range, a second comparison involved measurements performed on blood specimens obtained in the cardiac surgical intensive care unit for complete blood count analysis. Linear regression demonstrated good correlations between on-site and laboratory hemoglobin concentration (r2 = .97), hematocrit (r2 = .95), platelet count (r2 = .97), mean corpuscular volume (r2 = .91), red cell distribution width (r2 = .80), and red (r2 = .95) and white (r2 = .96) blood cell count results. A marginal correlation was observed between mean platelet volume values (r2 = .47). Bias analysis (mean +/- 2 SD) demonstrated similar measurements between on-site and laboratory hemoglobin concentration, hematocrit, platelet count, red blood cell count, white blood cell count, mean platelet volume, mean corpuscular volume, and red cell distribution width. CONCLUSIONS: On-site hemoglobin concentration, hematocrit, white blood cell count, red blood cell count, red cell distribution width, and platelet count values compare well with those results obtained from the laboratory. The MD 16 hemocytometer (Coulter Electronics) provides on-site hematologic results that can provide an accurate and rapid quantitative assessment of platelets, and red and white blood cells. Rapid access to information obtained from this type of system may be clinically useful, especially in critically ill patients. PMID- 8674330 TI - Cost accounting of adult intensive care: methods and human and capital inputs. AB - OBJECTIVE: To cost adult intensive care by determining inputs to production, resource consumption per patient, and total cost per intensive care unit (ICU) stay. DESIGN: Prospective cost-accounting analysis of each patient stay in the ICU, over a 1-yr period. SETTING: An 11-bed, medical/surgical adult ICU, in a 932 bad urban teaching hospital. PATIENTS: All patients' admissions to an adult ICU over a 1-yr period, excluding those patients admitted solely for repeat hemodialysis. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Demographic information was collected, including age, gender, Acute Physiology and Chronic Health Evaluation (APACHE) II score, primary reason for ICU admission, operative (elective and emergency) and nonoperative status, ICU length of stay, and ICU outcome. Direct patient care costs were accounted to individual patients whose care generated those costs, and indirect patient care costs were averaged over all patients in the ICU on a daily basis. Costs were collected for human (nursing, medical, professional, and support staff) and capital (laboratory, diagnostic imaging, supplies, drugs, and equipment) resources. Cost information was available on 690 patients (43% female, 57% male). Cost/day/patient was $1,508 +/- 475 (1992 Canadian dollars) and the average cost per ICU stay was $7,520 +/- 11,606. Median cost/stay for all patients was $2,600. Cost per ICU stay was < $5,000 in 68% of patients, with an ICU survival rate of 85%. High cost was not a marker for poor survival. There was no relationship between age and cost categories. Across most diagnoses, cost/ day/patient was remarkably constant, approximating $1,500/day/ patient at existing labor rates. CONCLUSIONS: In order to develop strategies aimed at cost containment, it is first necessary to undertake a thorough examination of cost drivers. This detailed cost-accounting study determined inputs to production, resources consumed by individual patients, and costs incurred during ICU stay. PMID- 8674331 TI - Evidence for endothelial cell activation/injury in heatstroke. AB - OBJECTIVES: We treated the hypothesis that heatstroke is associated with endothelial cell activation/injury and examined the possibility that the markers of endothelial cell activation/injury may be associated with its severity and complications such as disseminated intravascular coagulation, lung injury, and renal dysfunction. DESIGN: Prospective analyses. SETTING: Heatstroke Center in Makkah, Saudi Arabia. PATIENTS: Twenty-two adult patients with heatstroke. INTERVENTIONS: The plasma concentration of endothelin, circulating intercellular adhesion molecule-1 (ICAM-1), and von Willebrand factor-antigen values were measured, respectively, by radioimmunoassay, enzyme-linked immunosorbent assay, and rocket electroimmunoassay, in heatstroke patients on admission (precooling) and after complete cooling (postcooling), and in ten normal control patients. MEASUREMENTS AND MAIN RESULTS: Precooling heatstroke patients (rectal temperature 40.9 +/- 1.1 [SD] degrees C) had increased circulating concentrations of endothelin, c-ICAM-1, and von Willebrand factor-antigen in 100%, 80%, and 77% of patients to 126.4 +/- 11.2 pmol/L, 523.1 +/- 154.4 ng/mL, and 3.85 +/- 2.3 U/mL, respectively (control values: 13.7 +/- 4.2 pmol/L [p < .001]; 247.4 +/- 68.2 ng/ml [p < .001]; and < 1.5 U/mL, respectively). There was a significant (r2 = .68, p < .01) correlation between circulating ICAM-1 and endothelin concentrations. Plasma endothelin concentration correlated negatively with temperature (r2 = .35, p < .05). Mean endothelin concentration was similar in patients with or without renal dysfunction, and mean von Willebrand factor antigen concentration was similar in patients with or without lung injury or disseminated intravascular coagulation. There were no significant correlations between circulating ICAM-1, endothelin, or von Willebrand factor-antigen concentration and the Simplified Acute Physiology core. After cooling, mean circulating ICAM-1 and endothelin concentrations decreased significantly to 400 +/- 109 ng/mL and 93 +/- 38.5 pmol/L, respectively, whereas the mean von Willebrand factor-antigen concentration increased to 5.55 +/- 2.18 U/mL (p > .05). CONCLUSIONS: Our findings of increased circulating concentrations of circulating ICAM-1, endothelin, and von Willebrand factor-antigen are consistent with the hypothesis that heatstroke is associated with endothelial cell activation/injury. Whether the endothelial cell activation/injury is implicated in the pathophysiology of this disorder merits further studies. PMID- 8674332 TI - Plasma antioxidant potential in severe sepsis: a comparison of survivors and nonsurvivors. AB - OBJECTIVE: To determine the plasma antioxidant potential of patients in the intensive care unit (ICU) with severe sepsis and secondary organ dysfunction and relate these findings to outcome. DESIGN: A prospective, cohort study. SETTING: A nine-bed ICU in a university teaching hospital. PATIENTS: Fifteen consecutive patients, who were within 16 hrs of development of severe sepsis and secondary organ dysfunction. INTERVENTIONS: Plasma samples were obtained within 16 hrs of the onset of secondary organ dysfunction and subsequently on days 2, 3, 4, 6, 8, 10, and 15 until patients either left the ICU or died. Plasma antioxidant potential was determined by an ultraviolet spectrophotometric technique. MEASUREMENTS AND MAIN RESULTS: The mean initial plasma antioxidant potential was lower than our range for healthy volunteers (p < .05). Survivors had an initial plasma antioxidant potential that was greater than nonsurvivors (p < .01), and serial subset analysis demonstrated that survivors, despite having a low initial plasma antioxidant potential rapidly attained normal or supranormal values. While plasma antioxidant potential also increased in nonsurvivors over time, values in this subset never reached the normal range and remained below values in survivors at all time points studied (p < .05). CONCLUSIONS: Plasma antioxidant potential is initially decreased in patients with sepsis who develop organ dysfunction, and it increases over time. While we have no clear evidence to prove that this reduction has a causal relationship, failure to achieve a normal plasma antioxidant potential is strongly associated with an unfavorable outcome. PMID- 8674333 TI - Effects of heat and moisture exchangers on minute ventilation, ventilatory drive, and work of breathing during pressure-support ventilation in acute respiratory failure. AB - OBJECTIVES: To evaluate the effect of two commonly used heat and moisture exchangers on respiratory function and gas exchange in patients with acute respiratory failure during pressure-support ventilation. DESIGN: Prospective, randomized trial. SETTING: Intensive care unit of a university hospital. PATIENTS: Fourteen patients with moderate acute respiratory failure, receiving pressure-support ventilation. INTERVENTIONS: Patients were assigned randomly to two treatment groups, in which two different heat and moisture exchangers were used: Hygroster (DAR S.p.A., Mirandola, Italy) with higher deadspace and lower resistance (group 1, n = 7), and Hygrobac-S (DAR S.p.A.) with lower deadspace and higher resistance (group 2, n = 7). Patients were assessed at three pressure support levels: a) baseline (10.3 +/- 2.4 cm H2O for group 1, 9.3 +/- 1.3 cm H2O for group 2); b) 5 cm H2O above baseline; and c) 5 cm H2O below baseline. Measurements obtained with the heat and moisture exchangers were compared with those values obtained using the standard heated hot water humidifier. MEASUREMENTS AND MAIN RESULTS: At baseline pressure-support ventilation, the insertion of both heat and moisture exchangers induced in all patients a significant increase in the following parameters: minute ventilation (12.4 +/- 3.2 to 15.0 +/- 2.6 L/min for group 1, and 11.8 +/- 3.6 to 14.2 +/- 3.5 L/min for group 2); static intrinsic positive end-expiratory pressure (2.9 +/- 2.0 to 5.1 +/- 3.2 cm H2O for group 1, and 2.9 +/- 1.7 to 5.5 +/- 3.0 cm H2O for group 2); ventilatory drive, expressed as P41 (2.7 +/- 2.0 to 5.2 +/- 4.0 cm H2O for group 1, and 3.3 +/- 2.0 to 5.3 +/- 3.0 cm H2O for group 2); and work of breathing, expressed as either power (8.8 +/- 9.4 to 14.5 +/- 10.3 joule/ min for group 1, and 10.5 +/- 7.4 to 16.6 +/- 11.0 joule/min for group 2) or work per liter of ventilation (0.6 +/- 0.6 to 1.0 +/- 0.7 joule/L for group 1, and 0.8 +/- 0.4 to 1.1 +/- 0.5 joule/L. for group 2). These increases also occurred when pressure support ventilation was both above and below the baseline level, although at high pressure support the increase in work of breathing with heat and moisture exchangers was less evident. Gas exchange was unaffected by heat and moisture exchangers, as minute ventilation increased to compensate for the higher deadspace produced in the circuit by the insertion of heat and moisture exchangers. CONCLUSIONS: The tested heat and moisture exchangers should be used carefully in patients with acute respiratory failure during pressure-support ventilation, since these devices substantially increase minute ventilation, ventilatory drive, and work of breathing. However, an increase in pressure support ventilation (5 to 10 cm H2O) may compensate for the increased work of breathing. PMID- 8674334 TI - Treatment of acute chloroquine poisoning: a 5-year experience. AB - OBJECTIVE: To describe various aspects of prognostic and therapeutic importance in patients treated for acute chloroquine poisoning. DESIGN: Retrospective study. SETTING: Toxicology intensive care unit (ICU) of a university hospital. INTERVENTIONS: None. PATIENTS: One hundred sixty-seven consecutive patients with acute chloroquine overdose admitted to our toxicology ICU. MEASUREMENTS AND MAIN RESULTS: The mean amount ingested by history was 4.5 +2- 2.8 g. and 43 (26%) of 167 patients ingested > 5 g. The mean blood chloroquine concentration on admission was 20.5 +/- 13.4 mumol/L The majority (87%) of our patients received at least one arm of a combination therapy regimen (epinephrine, mechanical ventilation, diazepam). cardiac arrest occurred in 25 patients before hospital arrival; In seven of these patients, cardiac arrest occurred immediately after injection of thiopental. The mortality rate was 8.4% overall, and was 9.3% in patients with massive ingestions (NS vs. the group as a whole). We did not find a meaningful correlation between the amount ingested as estimated by history and the peak blood chloroquine concentration; the latter was highly correlated with the mortality rate. CONCLUSIONS: The mortality rate in patients with acute chloroquine poisoning, including those patients sick enough to be referred to a specialty unit such as ours, can be limited to < or = 10%. This finding appears to be true even in patients with massive ingestions. We were not able to correlate mortality with amount ingested by history, although the mortality rate does correlate with blood chloroquine concentration. While early use of diazepam, epinephrine, and mechanical ventilation in most of our patients may have contributed to the excellent overall results, these elements, either singly or in combination, do not appear to have a truly antidotal effect in acute chloroquine poisoning. Thiopental, on the other hand, should be used with great caution, if at all, in such cases. PMID- 8674335 TI - Inflammatory cytokines in an experimental model for the multiple organ dysfunction syndrome. AB - OBJECTIVE: To investigate the alterations in circulating pro-inflammatory cytokines and cytokine production by peritoneal macrophages during the development of multiple organ dysfunction syndrome. DESIGN: Prospective, controlled laboratory study on zymosan-induced generalized inflammation in mice. Single intraperitoneal administration of zymosan induces, over a 12-day period, a triphasic illness in mice; the third phase, from day 6 onward, resembles multiple organ dysfunction syndrome. SETTING: Animal research laboratory. SUBJECTS: C57BL/6CRW mice received a single intraperitoneal dose of zymosan on day 0, and standard numbers of animals were killed at different time points up until day 12. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of interleukin (IL)-1 alpha and IL-1 beta, IL-6, and tumor necrosis factor (TNF)-alpha were measured from 3 hrs to 12 days after administration of zymosan. At the same time points, both lipopolysaccharide-stimulated and unstimulated production of these cytokines by peritoneal macrophages were measured in vitro. Plasma TNF and IL-6 concentrations transiently increased during the first 24 hrs after administration of zymosan. After 8 days, a prominent peak of biologically inactive TNF was observed. Both unstimulated and lipopolysaccharide-stimulated cytokine production by peritoneal cells showed profound changes during the experimental period. CONCLUSIONS: These findings seem to confirm our hypothesis that the macrophages are in a continuously activated state and altered in their function, when the animals develop multiple organ dysfunction syndrome. Further studies are needed to elucidate what happens with these cytokines at the tissue level, to better understand the pathophysiology of multiple organ dysfunction syndrome. PMID- 8674336 TI - High-dose recombinant endotoxin neutralizing protein improves survival in rabbits, with Escherichia coli sepsis. AB - OBJECTIVE: To assess the benefit of a recombinant endotoxin neutralizing protein from Limulus polyphemus in treating Gram-negative bacterial sepsis in rabbits. DESIGN: Prospective, blinded, controlled, laboratory trial. SETTING: Animal research laboratory. SUBJECTS: New Zealand White rabbits. INTERVENTIONS: We established a rabbit model of Escherichia coli peritonitis and bacteremia, with high mortality rate, despite treatment with gentamicin and ceftriaxone. Twenty five pairs of male New Zealand White rabbits were challenged intraperitoneally with E. coli O18ac K1 in 5% porcine mucin (mean 7 x 10(1) colony-forming units). All animals were treated with intravenous gentamicin (2.5 mg/kg) and ceftriaxone (100 mg/kg), and with either intravenous endotoxin neutralizing protein (50 mg/kg) or saline 1 hr after E. coli challenge. MEASUREMENTS AND MAIN RESULTS: All animals were bacteremic 1 hr after challenge (mean 3.6 x 10(5) colony-forming units/mL). Animals in both groups developed tachycardia, hypotension, and acidosis (NS). Geometric mean serum endotoxin and tumor necrosis factor (TNF) concentrations were significantly ( p < .001) higher 1 hr after challenge compared with baseline prechallenge concentrations in both groups. From 1 to 2 hrs after challenge, endotoxin concentrations increased 2.5-fold in control animals (95% confidence interval = 13.1 to 32.9 endotoxin units/mL, p = .024), whereas endotoxin concentrations increased only 1.2-fold in endotoxin neutralizing protein-treated animals (95% confidence interval = 20.4 to 23.6 endotoxin units/mL, NS). TNF concentrations increased significantly (p < .001) in both groups from 1 to 2 hrs after challenge. Eighteen (72%) of 25 endotoxin neutralizing protein-treated animals vs. 11 (44%) of 25 controls survived 24 hrs (p = .032). CONCLUSIONS: Treatment with endotoxin neutralizing protein had the following effects: a) the increase in serum endotoxin was blunted, but not TNF concentrations measured 1 hr after antibiotic treatment; and b) survival in rabbits with E. Coli sepsis was improved. PMID- 8674337 TI - Efficacy of perfluorocarbon partial liquid ventilation in a large animal model of acute respiratory failure. AB - OBJECTIVE: To demonstrate the efficacy of partial perfluorocarbon liquid ventilation in large animal model of acute respiratory failure. DESIGN: Prospective, randomized, controlled trial. SETTING: Animal laboratory at a university medical center. SUBJECTS: Ten adult sheep, weighing 53.0 +/- 2.8 kg. INTERVENTIONS: After assessment of baseline physiologic data, acute respiratory failure was induced by right atrial injection of oleic acid (0.2 mL/kg). Five animals (partial liquid ventilation group) underwent sequential intratracheal dosing of 10 mL/kg of perflubron at 30-min intervals to the following cumulative doses: 10, 20, 30, 40, and 50 mL/kg. The remaining five animals were gas ventilated (control group). Physiologic data were assessed at 30-min intervals in both groups for the 2.5-hr experimental period or until death. MEASUREMENTS AND MAIN RESULTS: When compared with control animals, intratracheal perfluorocarbon instillation resulted in significant improvements in arterial oxygen saturation (arterial oxygen saturation after 50 mL/kg: partial liquid ventilation, 96 +/- 3%; control, 55 +/- 8%; p = .001) and physiologic shunt (physiologic shunt after 50 mL/kg dose: partial liquid ventilation, 2 +/- 8%; control, 64 +/- 5%; p = .004). Oxygen delivery improved with perfluorocarbon instillation, but this improvement was not significant. No significant difference in pulmonary compliance was observed during partial liquid ventilation when compared with controls (pulmonary compliance: partial liquid ventilation, 0.43 +/- 0.04 mL/ cm H2O/kg; control, 0.53 +/- 0.03 mL/cm H2O/kg; p = .102). CONCLUSIONS: Partial liquid ventilation with perflubron provides effective improvement in gas exchange in an adult animal model of respiratory failure. PMID- 8674338 TI - Measurement of blood CO2 concentration with a conventional PCO2 analyzer. AB - OBJECTIVES: CO2 content can be determined from the Pco2 in an acidified (forces all CO2 into solution) and diluted blood sample. However, Pco2 concentrations measured in conventional blood gas analyzers are only correct for samples with a significant buffer capacity (such as whole blood), so that mixing with the Pco2 in the rinse solution and tubing walls does not significantly change the sample Pco2. This study describes a calibration method and validation data for the Radiometer Medical ABL2 CO2 electrode system to accurately measure unbuffered blood samples used in the determination of blood CO2 content (or other aqueous fluids). DESIGN: Prospective, criterion standard. SETTING: Laboratory. MEASUREMENTS AND MAIN RESULTS: Blood samples (0.4 mL) were acidified and diluted with 0.2 M lactic acid. After measuring Pco2, CO2 content was calculated using the CO2 solubility coefficient and the dilution factor of 20. CO2 content was determined in a series of sodium carbonate (Na2CO3) solutions spanning the physiologic range of CO2 content. Regression of the measured vs. the actual CO2 content data generated a straight line with a slope of 0.796 and y-intercept of 12.5 (r2 = .99; n = 48). These coefficients were successfully used to correct CO2 content determined in blood samples into which graduated amounts of sodium carbonate were added. CONCLUSIONS: This calibration procedure allows accurate measurement of Pco2 in aqueous samples using the Radiometer ABL2 electrode system, and should be applicable to other blood gas analyzers. Necessary syringes and chemicals are readily available, the method is fast and simple, and the sample volume is small. In the practice of critical care medicine, accurate Pco2 measurement in aqueous acidified and diluted blood provides direct determination of blood CO2 content (useful in calculations of modified Fick cardiac output or tissue CO2 production). Determinations of absolute CO2 content in blood requiring complex methodology are not necessary. In addition, accurate measurement of aqueous gastric Pco2 can help determine gastric pH, which is an important marker of tissue perfusion. PMID- 8674339 TI - Differential regulation of the constitutive and inducible nitric oxide synthase mRNA by lipopolysaccharide treatment in vivo in the rat. AB - OBJECTIVE: Endotoxin and cytokines have been reported to have both stimulatory and inhibitory effects on endothelial cell-derived nitric oxide release. The discrepancy may be explained by differential regulation of the endothelial and inducible type of nitric oxide synthase gene expression. This study aimed to investigate the differential effect of lipopolysaccharide treatment in vivo on the three isoforms (endothelial, brain-type, and inducible) of nitric oxide synthase gene expression in the rat. DESIGN: Prospective, controlled, animal trial. SETTING: Experimental laboratory of a postgraduate medical research institution. SUBJECTS: Normal, anesthetized rats. INTERVENTIONS: Animals were treated with lipopolysaccharide (15 mg/kg iP), saline (1 mL/kg ip), or lipopolysaccharide plus dexamethasone (3 mg/kg ip, 50 mins before lipopolysaccharide administration) in vivo 4 hrs before experimentation. MEASUREMENTS AND MAIN RESULTS: The expression of endothelial, brain-type, and inducible nitric oxide synthase mRNAs was quantified by Northern blot analysis using bovine, rat, and mouse cDNA probes, respectively. An endothelial nitric oxide synthase mRNA was detected at 4.3 kilobase in the heart, lung, and aorta, and a 10-kilobase brain-type nitric oxide synthase mRNA was detected in the brain. The endothelial and brain-type signals were strong in tissues from animals treated with saline, but were reduced by three- to four-fold in tissues from lipopolysaccharide-treated rats as estimated by optical density ratio. The 4.4 kilobase inducible nitric oxide synthase mRNA detected using the murine cDNA probe was absent or negligible in the heart, lung, and brain from saline-treated rats, but was markedly increased in the same tissues from lipopolysaccharide treated animals. Dexamethasone significantly inhibited lipopolysaccharide-induced inducible nitric oxide synthase mRNA expression, but had no effect on the down regulation of endothelial and brain nitric oxide synthase mRNAs. CONCLUSIONS: Rats treated with lipopolysaccharide in vivo display down-regulation of endothelial nitric oxide mRNA in the heart, lung, and aorta, and brain-type nitric oxide synthase mRNA in the brain There was a parallel up-regulation of inducible nitric oxide synthase mRNA in all tissues except in the aorta. Dexamethasone prevents the induction of inducible nitric oxide synthase mRNA. but has no effect on the down-regulation of endothelial and brain-type nitric oxide synthase mRNAs induced by lipopolysaccharide. Thus, endotoxin regulates constitutive and inducible nitric oxide synthase mRNA differentially. PMID- 8674340 TI - Cerebral effects of resuscitation with hypertonic saline and a new low-sodium hypertonic fluid in hemorrhagic shock and head injury. AB - OBJECTIVES: A 2400-mOsm/L hypertonic solution (isosal) with a lower sodium content, compared with conventional 7.5% hypertonic saline, was formulated using a mixture of sodium chloride, glucose, and mixed amino acids. This solution was developed to minimize hypernatremia during resuscitation. We assessed the effects of isosal on hemodynamics, brain edema, and plasma sodium concentration after head injury associated with hemorrhagic shock. DESIGN. Prospective, randomized laboratory study. SETTING: University research laboratory. SUBJECTS: Twenty-one adult female Suffolk sheep, weighing 39 to 49 kg. INTERVENTIONS: Animals were subjected to a 2-hr period of hemorrhagic shock to a mean arterial pressure (MAP) of 40 to 45 mm Hg in the presence of a freeze injury to the cerebral cortex. The hemorrhagic shock/head injury phase was followed by 2 hrs of resuscitation with isosal, a new 2400-mosm/L low-sodium hypertonic fluid, 2400 mosm/L of 7.5% hypertonic saline, or lactated Ringer's solution. Initial resuscitation was with a bolus injection of 8 mL/kg of the study solution; subsequent resuscitation in all three groups was with lactated Ringer's solution as needed to maintain baseline cardiac output. MEASUREMENTS AND MAIN RESULTS: Serial hemodynamics, intracranial pressure, electrolytes, and osmolarity were measured. AT the end of resuscitation, the animals were killed and brain water content (mL H2O/g dry weight) of the injured and uninjured areas was determined. Resuscitation volumes were significantly lower in the isosal (19 +/- 5 mL/kg) and 7.5% hypertonic saline (14 +/- 2 mL/mg) groups compared with the lactated Ringer's solution (35 +/- 5 mL/kg) group. Intracranial pressure after 2 hrs of resuscitation was significantly lower in the isosal (7 +/- 1 mm Hg) and hypertonic saline groups (4 +/- 1 mm Hg). Water content in all areas of the brain was significantly lower in the hypertonic saline group compared with the lactated Ringer's solution group. Brain water content in the isosal group was lower than in the lactated Ringer's solution group only in the cerebellum. Plasma sodium content was lower in the isosal group than in the hypertonic saline group. CONCLUSIONS: After combined head injury and shock, isosal and 7.5% hypertonic saline have similar effects on hemodynamics and intracranial pressure. Hypertonic saline induces a greater degree of brain dehydration; isosal resuscitation results in smaller increases in plasma sodium. PMID- 8674341 TI - Dopexamine maintains intestinal villus blood flow during endotoxemia in rats. AB - OBJECTIVE: To determine the influence of dopexamine, a synthetic catecholamine ligand for dopaminergic and beta 2-adrenergic receptors, on alterations of the intestinal villus microcirculation in a model of normotensive endotoxemia. DESIGN: Randomized, controlled trial. SETTING: Experimental laboratory. SUBJECTS: Twenty-one male Wistar rats. INTERVENTIONS: Rats were treated with a continuous infusion of dopexamine (2.5 micrograms/kg/min; N = 7; group A) or 0.9% saline (n = 7; group B) during a study period of 120 mins. Both groups were given endotoxin (Escherichia coli lipopolysaccharide; 1.5 mg/kg Iv) over 60 mins. Animals in the control group (n = 7; group C) received a volume-equivalent infusion of 0.9% saline. Total volume substitution in all groups was 15 mL/kg/hr. MEASUREMENTS AND MAIN RESULTS: Blood flow in the intestinal villi of the distal ileum was determined using in vivo videomicroscopy at baseline, and 60 and 120 mins after the endotoxin challenge. These blood flow determinations were done by an observer who was unaware of the previous treatment of the animals. In addition, mean arterial pressure was monitored at baseline, and 15, 30, 45, 60, 75, 90, 105, and 120 mins later. The administration of 1.5 mg/kg endotoxin alone (group B) resulted in a reduction of the intestinal villus blood flow to 74.8 +/- 9.5% of baseline after 60 mins, and to 61.1 +/- 8.5% of baseline after 120 mins (baseline: 7.4 +/- 0.6 nL/min; 60 mins: 5.3 +/- 0.8 nL/min; 120 mins: 4.4 +/- 0.5 nL/min; p < .05). This reduction of blood flow was associated with a decrease in the arteriolar diameters by 13.8 +/- 2.5% after 60 mins, and by 17.1 +/- 4.3% after 120 mins (p < .05 vs. baseline). In contrast, villus blood flow in the dopexamine group (group A) did not show statistically significant changes during the entire study period, despite the administration of endotoxin (baseline: 8.2 +/- 0.6 nL/min; 60 mins: 7.3 +/- 0.8 nL/min; 120 mins: 7.8 +/- 0.5 nL/min). No vasoconstriction of the villus arterioles was noted in this group. In control animals (group C), the blood flow (baseline: 8.1 +/- 1.6 nL/min; 60 mins: 7.6 +/- 1.4 nL/min: 120 mins: 7.8 +/- 1.4 nL/min) and the arteriolar diameters remained unchanged throughout the observation period. Mean arterial pressure did not differ between groups: it remained unaltered in all groups during the entire study period. CONCLUSIONS: Dopexamine maintains intestinal villus arterial perfusion and prevents the vasoconstriction in villus arterioles during early normotensive endotoxemia. Therefore, further studies in critically ill patients will have to determine whether the early prophylactic use of dopexamine can limit ischemia and prevent the development of multiple organ failure. PMID- 8674342 TI - Early inflammatory response correlates with the severity of injury. AB - OBJECTIVE: To determine if the early inflammatory response correlates with the severity of injury in a blunt trauma model in rats. DESIGN: Prospective, randomized, controlled trial. SETTING: Research laboratory. SUBJECTS: Male Sprague-Dawley rats, weighing 250 to 400 g. INTERVENTIONS: Twenty-two male Sprague-Dawley rats were divided randomly into single hindlimb fracture, bilateral hindlimb fracture, and no fracture groups. At 90 mins, all animals underwent midline laparotomy and aspiration of blood from the inferior vena cava. Venous blood gas, plasma lactate, and plasma concentrations of tumor necrosis factor (TNF), prostaglandin F(6-keto-PGF1 alpha), and interleukin (IL)-6 were sampled. Statistical analysis was done via one-way analysis of variance and Scheffe post hoc analysis. In a second part of this experiment, the effect of hemorrhage on the release of IL-6 was evaluated. Animals in this group were compared with control and bilateral hindlimb fracture animals, using the Student's t-test. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in venous pH or base deficit among the groups. Oxygen saturation was significantly decreased in the bilateral hindlimb fracture group when compared with the control group. In the hemorrhage plus bilateral fracture group, oxygen saturation was significantly decreased when compared with the bilateral fracture group. lactate concentrations in plasma were increased in both fracture groups as well as the hemorrhaged groups. Plasma TNF concentrations were increased in the injured groups but there was no significant difference between single and bilateral hindlimb fracture groups. The 6-keto-PGF1 alpha concentrations were increased in both of the fracture groups when compared with the control group and there was a significant difference between single and bilateral hindlimb fracture groups. Similarly, circulating IL-6 concentrations were significantly higher in the bilateral fracture group than in the single fracture group; both fracture groups were significantly higher than the control group. Hemorrhaged animals had even higher IL-6 concentrations. CONCLUSIONS: Plasma lactate and TNF concentrations were affected by injury, however their concentrations did not correlate with degree of injury. IL-6 concentrations were increased early postinjury and correlated with severity of injury. The 6-keto-PGF1 alpha concentrations in plasma also correlated with the severity of injury and this phenomenon may represent early endothelial activation which may be the source of IL-6 release. PMID- 8674344 TI - Partial liquid ventilation enhances surfactant phospholipid production. AB - OBJECTIVE: To study the effect of partial liquid ventilation on phospholipid metabolism. DESIGN: Prospective, controlled laboratory study. SETTING: University affiliated animal research facility. SUBJECTS: Mature New Zealand white rabbits (n = 17). INTERVENTIONS: The rabbits were sedated, anesthetized, and instrumented with tracheostomy and the insertion of an arterial catheter. The rabbits were sequentially assigned to receive conventional mechanical ventilation or partial liquid ventilation with Perflubron (18 mL/kg by bolus fill). Ventilator strategies were identical in both groups and consisted of an FiO2 of 0.5, positive end-expiratory pressure of 4 cm H2O, effective tidal volume of 8 to 13 mL/kg, and rate to maintain Pco2 of 30 to 40 torr (4.0 to 5.3 kPa). Phosphatidylcholine was labeled in vivo by injection of 3H-methylcholine (25 microCi/kg iv). Ventilation was continued for 5.5 hrs. MEASUREMENTS AND MAIN RESULTS: When animals were killed, phosphatidylcholine was extracted from the total lung lavage and from the pulmonary parenchyma. After the separation of phospholipids by thin-layer chromatography, the 3H activity was determined by liquid scintillation counting. Inorganic phosphorus was also determined to assess the enrichment of the phosphatidylcholine. The 3H-phosphatidylcholine activity in the partial liquid ventilation treated- vs. control rabbits demonstrated a 53% increase (p = .051) in the lavage and a 48% increase (p = .013) in the parenchyma for a net 50% (p = .012) total pulmonary increase. The phospholipid content of the partial liquid ventilation treated- vs. the control rabbits demonstrated a 78% increase (p = .046). CONCLUSIONS: We conclude that partial liquid ventilation with Perflubron appears to have no negative impact on phospholipid metabolism but rather enhances surfactant phospholipid synthesis and secretion. PMID- 8674343 TI - Cerebrospinal fluid and plasma nitrite and nitrate concentrations after head injury in humans. AB - OBJECTIVES: To measure cerebrospinal fluid and plasma nitrite and nitrate concentrations as indicators of nitric oxide production in adults after severe closed-head injury. To determine if there is an association between cerebrospinal fluid and plasma nitrite and nitrate concentrations, and cerebral blood flow, arterio-jugular oxygen content difference, injury severity, and outcome after severe closed-head injury. DESIGN: A prospective, clinical study. SETTING: Multidisciplinary intensive care unit. PATIENTS: Fifteen comatose (Glasgow Coma Scale score of < or = 7) adult patients with severe closed-head injury were studied during the prospective, randomized evaluation of the effect of moderate hypothermia (32 degrees C for 24 hrs) on neurologic outcome after closed-head injury. Seven patients were in the hypothermic group and eight patients were in the normothermic treatment group. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were examined sequentially, every 12 hrs for 2 days. Intraventricular cerebrospinal fluid was assayed for nitrite and nitrate concentrations. Cerebral blood flow was measured by the 133xenon intravenous method. Simultaneous blood samples were obtained for measurements of arterio jugular oxygen content difference and plasma nitrite and nitrate concentrations. Cerebral metabolic rate for oxygen was calculated. Cerebrospinal fluid nitrite and nitrate concentrations were highest at 30 to 42 hrs vs. 6 to 18, 18 to 30, and 42 to 54 hrs (26.4 +/- 3.3 vs. 17.3 +/- 2.1, 20.0 +/- 2.2, and 18.8 +/- 2.4 microM, respectively, p < .05). There was no difference over time in plasma nitrite and nitrate concentrations. Cerebral blood flow was increased and arterio jugular oxygen content difference was reduced at 18 to 30, 30 to 42, and 42 to 54 hrs vs. 6 to 18 hrs (p < .05). At 30 to 42 hrs, cerebrospinal fluid nitrite and nitrate concentrations were 80% higher in patients who died vs. survivors (36.4 +/- 3.2 vs. 20.2 +/- 3.6, p < .05). Using a generalized, multivariate, linear regression model, both plasma nitrite and nitrate concentrations and injury Severity Score independently predicted cerebrospinal fluid nitrite and nitrate concentrations (p < .00001 and p = .0053, respectively). Cerebral blood flow and arterio-jugular oxygen content difference were not associated with cerebrospinal fluid or plasma nitrite and nitrate concentrations using this model. Cerebrospinal fluid nitrite and nitrate concentrations were increased over time in hypothermic vs. normothermic patients. But, where this difference occurred could not be determined by multiple comparisons (p = .03). The hypothermic patients had lower admission Glasgow Coma Scale scores than normothermic patients (p = .04) and tended to have higher injury Severity Scores (p = .09). CONCLUSIONS: Increases in cerebrospinal fluid nitrite and nitrate concentrations peaked at 30 to 42 hrs after severe closed-head injury. This increase in cerebrospinal fluid nitrite and nitrate concentrations was greater in nonsurvivors. Also, cerebrospinal fluid and plasma nitrite and nitrate concentrations were associated with injury Severity Score, suggesting that increased nitric oxide production in the brain is associated with injury severity and death. Hypothermia did not prevent the increase in cerebrospinal fluid nitrite and nitrate concentrations. Further study is required to determine the source of this increase in cerebrospinal fluid nitrite and nitrate concentrations and to further define the relationship to outcome and the effect of hypothermia on this process. PMID- 8674345 TI - Mediastinal tube placement in children with pneumomediastinum: hemodynamic changes and description of technique. AB - OBJECTIVE: To describe the technique, hemodynamic response, and complication rate after the insertion of a percutaneous mediastinal tube for drainage of pneumomediastinum. DESIGN: A combined retrospective and prospective study in mechanically ventilated children with pneumomediastinum. SETTING: Multidisciplinary pediatric intensive care unit at a children's hospital. PATIENTS: The medical records and chest radiographs of 25 (15 retrospective and 10 prospective) patients who had placement of a mediastinal tube for drainage of pneumomediastinum from 1990 to 1995 were reviewed. Hemodynamic data were collected prospectively in the ten consecutive children from January 1994 to April 1995. INTERVENTION: Mediastinal tube placement: The subxyphoid area was cleansed with povidone-iodine and draped. An 18-gauge, thin-walled introducer needle was inserted 1 to 2 cm below the xyphoid process at an angle of 20 degrees from the anterior abdominal wall, directed at the substernal space. Either a 9-Fr or 11-Fr pericardiocentesis catheter was inserted over a wire and advanced to the third intercostal space. The catheter was secured and connected to 10 cm H2O suction, using a standard thoracostomy tube drainage device. MEASUREMENTS AND MAIN RESULTS: The size of the mediastinal air column on a lateral chest radiograph was measured before and after placement of the mediastinal tube. The mean change in the size of the mediastinal air column was -1.6 cm (median -1.5, p < .001). In the ten prospective patients, hemodynamic data were recorded immediately before and after placement of a mediastinal tube from previously placed arterial and central venous pressure catheters. The mean hemodynamic changes after the mediastinal tube placement were: heart rate -4 beats/min (median = -1, p = .14); systolic blood pressure 16 mm Hg (median = 10, p = .007); diastolic blood pressure 11 mm Hg (median = 11, p = .005); mean arterial pressure 12 mm Hg (median = 8, p = .005); and central venous pressure -2 mm Hg (median = 1, p = .04). In four patients with pulmonary artery thermodilution catheters, the mean increase in cardiac index immediately following placement of the mediastinal tube was 34%. No complications, including bleeding, cardiac puncture, or infection occurred. CONCLUSIONS: These findings suggest that hemodynamic compromise commonly accompanies pneumomediastinum in children. Decompression of the mediastinal space and drainage of the pneumomediastinum, using this simple bedside technique for continuous drainage, can be performed rapidly and safely in children, resulting in immediate hemodynamic improvement, and allowing for continuous drainage. PMID- 8674346 TI - An intrinsic positive end-expiratory pressure lung model, with and without flow limitation. AB - OBJECTIVE: To design an intrinsic positive end-expiratory pressure (PEEP) lung model that has the property of air flow limitation. DESIGN: Mechanical lung model study of intrinsic PEEP. SETTING: Lung models were set up in the research laboratory. INTERVENTIONS: Intrinsic PEEP lung models were created with and without flow limitation. In the model with flow limitation, intrinsic PEEP was created by replacing a portion of the expiratory circuit with a collapsible Penrose tube and by placing this portion the circuit under water. The expiratory circuit became a part of the respiratory airway, with flow limitation occurring at the Penrose drain. In the model without flow limitation, intrinsic PEEP was generated with a fixed linear resistor, which was inserted in the expiratory circuit to produce a similar level of intrinsic PEEP. Multiple levels of external PEEP, both above and below the initial intrinsic PEEP, were applied. MEASUREMENTS AND MAIN RESULTS: At each level of external PEEP, peak airway pressure, plateau airway pressure, isovolume air flow, internal lung pressure, and intrinsic PEEP were measured. Peak airway pressure, plateau pressure, and internal lung pressure were minimally affected if the external PEEP was less than the intrinsic PEEP in the lung model with flow limitation. Intrinsic PEEP was reduced with external PEEP. However, if intrinsic PEEP was induced without dynamic airway closure or flow limitation, any level of external PEEP caused an immediate increase in peak airway pressure, plateau airway pressure, and internal lung pressure and a decrease in isovolume flow. External PEEP has little effect on the levels of intrinsic PEEP. CONCLUSIONS: We demonstrated two different models of an intrinsic PEEP lung model. The interactions between intrinsic PEEP and externally applied PEEP were different. The lung model with collapsible tube closely simulated the human respiratory system with flow limitation. This lung model may be useful for the future study of intrinsic PEEP and pulmonary mechanics. PMID- 8674347 TI - Doxacurium-corticosteroid acute myopathy: another piece to the puzzle. PMID- 8674348 TI - Cisapride-induced dysrhythmia in a pediatric patient receiving extracorporeal life support. PMID- 8674349 TI - Multiple organ dysfunction score. PMID- 8674350 TI - Role of cerebral perfusion pressure in acute brain trauma. PMID- 8674351 TI - Role of cerebral perfusion pressure in acute brain trauma. PMID- 8674352 TI - Role of cerebral perfusion pressure in acute brain trauma. PMID- 8674353 TI - Teaching medical students. PMID- 8674354 TI - The effect of simple hypothermic preservation with Trolox and ascorbate on lipid peroxidation in dog kidneys. AB - Dog kidneys were preserved by simple hypothermic storage in UW-lactobionate organ preservation solution for 48 h and analyzed for evidence of lipid peroxidation. The antioxidant function of the UW solution was evident in stored kidney tissues which had significant reductions in conjugated dienes, lipid peroxides, and Schiff base content compared to fresh controls without vascular flushing. Aerobic incubation of kidney cortex homogenates at 37 degrees C for 60 min resulted in increases in conjugated dienes, lipid peroxides, and Schiff bases in UW-stored kidneys. Schiff base production was markedly higher in UW-stored kidneys during warm incubation than in controls. Addition of Trolox (200 microM) to UW solution resulted in significant reductions in Schiff base production during warm aerobic incubation after preservation. In contrast, adding ascorbate (1 mM) to UW solution potentiated oxidative stress during aerobic incubation, with significant increases in conjugated dienes, lipid peroxides, and Schiff bases which were only partially reversed by further addition of Trolox. Increased oxidative stress was correlated with decreased respiratory function (decreased uncoupled respiration rates and sensitivity to oligomycin inhibition) in aerobically incubated homogenates. This study showed that although the UW solution does have an antioxidant function during hypothermic preservation there remains an increased oxidative stress during warm reoxygenation even in optimally harvested kidneys. The antioxidant effect of the UW solution after preservation can be significantly enhanced using the water-soluble vitamin E analogue Trolox. Antioxidant supplementation of UW solution may be advantageous in preserving kidneys with increased oxidative stresses obtained from suboptimal donors in clinical practice. PMID- 8674355 TI - Actions of selected hepatotoxicants on freshly isolated and cryopreserved rat hepatocytes. AB - The present study compares the actions of the hepatotoxic agents allyl alcohol, acetaminophen, and carbon tetrachloride on energy metabolism in freshly isolated and cryopreserved rat hepatocytes. After 30 min incubation of freshly isolated hepatocytes at 37 degrees C to allow metabolic equilibration, hepatocytes were supplemented with cryoprotectants and cooled in a stepwise manner to liquid nitrogen temperature. Hepatocytes stored in liquid nitrogen for 2 weeks to 6 months were thawed and centrifuged through Percoll to remove damaged cells. Despite similarities in energy status as indexed by ATP content and the rate of urea synthesis in freshly isolated and cryopreserved hepatocytes, cryopreserved hepatocytes were more sensitive to hepatotoxicants. All three hepatotoxicants caused ATP and rates of urea synthesis to decline to a greater extent in cryopreserved than in freshly isolated hepatocytes. Rates of oxygen uptake were higher in cryopreserved cells than in freshly isolated hepatocytes and declined in cryopreserved cells but not in freshly isolated cells during the initial period of incubation. Rates of mitochondrial respiration stimulated with site specific substrates were comparable in freshly isolated and cryopreserved cells permeabilized with digitonin. Allyl alcohol and acetaminophen inhibited site specific respiration to the same extent in both groups of cells. Collectively, these results suggest that increased sensitivity to hepatotoxic agents and elevated oxygen consumption in cryopreserved hepatocytes recovered after storage in liquid nitrogen are related to higher demand for energy in these cells rather than to permanent injury caused by cryopreservation and irreversible uncoupling of oxidative phosphorylation. PMID- 8674356 TI - Viability analysis of cryopreserved rat pancreatic islets using laser scanning confocal microscopy. AB - We have developed a digital image analysis technique to assay the viability of frozen-thawed pancreatic islets by using laser scanning confocal microscopy (LSCM) in conjunction with double fluorescent staining [acridine orange/propidium iodide (AO/PI)]. Freshly isolated rat pancreatic islets were cultured for 18-24 h and then brought to a 2 M concentration of dimethyl sulfoxide (Me2SO) by serial addition at decreasing temperatures. Ice was nucleated in the islet suspension at a defined temperature (-10 degrees C), followed by a controlled period for equilibration and then cooling in a programmable bulk freezer at rates of 0.3, 1, 3, 10 and 30 degrees C/min to -70 degrees C. Samples were then stored in liquid nitrogen. Subsequent to rapid thawing and serial dilution with sucrose solution to remove Me2SO, AO/PI-stained individual islets were prepared for imaging on the LSCM. A series of optical sections through individual stained islets were obtained and processed to obtain high-contrast images at two different wavelengths; 488 nm and 514 nm for viable and damaged tissue, respectively. Image analysis algorithms consisted of template masking, generation of histograms of the pixel intensity profile, and gray level thresholding to obtain binary images. The total percentages of both types of tissue in the islet were computed by summing the two populations in each serial section. The spatial distributions of viable and damaged tissue were calculated from the three-dimensional (3-D) data base for both cultured (control) and cryopreserved islets. The 3-D spatial distributions of damaged and viable tissue in the islets were computed by determining the normalized distance of each viable/damaged voxel from the centroid of the islet volume to a mathematically estimated 3-D superquadric surface used to estimate the outer boundary of the islet. Further, each isolated damaged cell was identified and its volume determined. These studies indicate that cryopreserved islets exhibit shape distortion and a decrease in the numerical density of cells in comparison to unfrozen controls. Maximal survival was observed at the slower cooling rates. Accordingly, damage was found to occur throughout the 3-D islet volume in distinct spatial distributions for islets frozen at the slower and the faster cooling rates. Further, it was found that the volume of the majority of damaged cells identified was consistent with that of cells ranging in diameter from 5 to 9 micrometers. PMID- 8674357 TI - A two-step reversible-irreversible model can account for a negative activation energy in an Arrhenius plot. AB - Arrhenius plots of the rate of inactivation (killing) of mammalian cells and Drosophila embryos have "apparent negative" activation energies at low temperatures. This can be explained by assuming that the rate-limiting event resulting in killing is a two-step process or mechanism, where the first step is reversible and the second irreversible. Two examples, consistent with this model, are suggested as possible mechanisms of hypothermic killing: (i) a membrane lipid liquid crystalline-to-gel transition followed by a metabolic block or event which kills the cell and (ii) cold denaturation of a protein followed by protein aggregation. PMID- 8674358 TI - Cryopreservation of anchorage-dependent mammalian cells fixed to structured glass and silicon substrates. AB - This paper describes a procedure for the cryopreservation of anchorage-dependent cells in a predefined position on microstructured glass or silicon substrates. During freezing and thawing, cells retain their location on the substrate, and an individual comparison and identification of cells before and after preservation are possible. To utilize this advantage, a good adherence and a high survival rate are important. It can be shown that adhesion of mouse fibroblasts (NIH-3T3) to substrate strongly influences the survival rate: 94% of cells grown for 16 h before freezing were judged to be alive after thawing. Widely spaced cells are best suited to cryopreservation on substrates. The different patterns of adhesion of cells to substrates when incubated for 1, 3, 6, and 16 h, were visualized by total internal reflection microscopy (TIRM). PMID- 8674359 TI - Proton nuclear magnetic resonance spectroscopy of lactate production in isolated rat liver during cold preservation. AB - Lactate-edited 1H NMR difference spectra have been acquired from intact rat liver tissue following flushing and preservation in ice. A peak, initially at 1.26 ppm, was seen to increase in the liver tissue with preservation time. This peak was assigned to lactate, despite the fact that its chemical shift was initially shifted by approximately -0.1 ppm relative to an externally added standard. The assignment was based on the following: (a) the peak increased over a 24-h ischemic storage period; (b) it was coupled to a signal 2.78 +/- 0.02 ppm upfield; and (c) a parallel increase in lactate was noted in perchloric acid extracts of tissue from the same liver. An additional peak, assigned to alanine, was also observed during storage and was also shifted by approximately -0.1 ppm. Inclusion of dimethyl sulfoxide, which readily permeates liver tissue, demonstrated that this chemical shift alteration was a tissue-specific effect. These results demonstrate that 1H NMR spectroscopy of intact liver tissue during hypothermic ischemia is possible, though chemical shift assignments should be made with caution. PMID- 8674361 TI - Anal fistula surgery. Factors associated with recurrence and incontinence. AB - PURPOSE: This study was undertaken to assess results of surgery for fistula-in ano and identify risk factors for fistula recurrence and impaired continence. METHODS: We reviewed the records of 624 patients who underwent surgery for fistula-in-ano between 1988 and 1992. Follow-up was by mailed questionnaire, with 375 patients (60 percent) responding. Mean follow-up was 29 months. Fistulas were intersphincteric in 180 patients, transsphincteric in 108, suprasphincteric in 6, extrasphincteric in 6, and unclassified in 75. Procedures included fistulotomy and marsupialization (n = 300), seton placement (n = 63), endorectal advancement flap (n = 3), and other (n = 9). Factors associated with recurrence and incontinence were analyzed by univariate and multivariate regression analysis. RESULTS: The fistula recurred in 31 patients (8 percent), and 45 percent complained of some degree of postoperative incontinence. Factors associated with recurrence included complex type of fistula, horseshoe extension, lack of identification or lateral location of the internal fistulous opening, previous fistula surgery, and the surgeon performing the procedure. Incontinence was associated with female sex, high anal fistula, type of surgery, and previous fistula surgery. CONCLUSIONS: Surgical treatment of fistula-in-ano is associated with a significant risk of recurrence and a high risk of impaired continence. Degree of risk varies with identifiable factors. PMID- 8674360 TI - Preliminary studies on the effect of Anaplasma marginale antibodies ingested by Dermacentor andersoni ticks (Acari:Ixodidae) with their blood meal on infections in salivary glands. AB - The effect of Anaplasma marginale antibodies ingested with the tick blood meal was tested on infected male ticks that were allowed to feed on cattle immunized with the erythrocytic stage of A. marginale. The experiments were done in two trials. Trial 1 was done using splenectomized calves (two calves per treated and control groups) while ticks in trial 2 were fed on intact yearling cattle (four cattle per treated and control groups). The cattle were immunized with purified outer membrane proteins of erythrocyte-derived A. marginale using saponin (trial 1) or monophosphoryl lipid-A-trehalose dicorynomycolate adjuvant (trial 2). The corresponding control cattle received adjuvant only. All cattle were challenged using Dermacentor andersoni males infected as adults that were allowed to feed for 7 days. In trial 1, the ticks were allowed to feed a second time on susceptible calves to test whether exposure of ticks to immunized cattle affected their ability to transmit anaplasmosis. Infections in fed ticks were monitored by determining the infection rates in salivary glands with an A. marginale-specific RNA probe and light microscopy. Vaccine-derived antibodies ingested with the tick blood meal did not appear to affect the development of A. marginale in previously infected ticks. The infection rates in the salivary glands were not significantly different among ticks fed on immunized versus adjuvant control cattle. When the vaccine-exposed ticks in trial 1 were allowed to feed a second time on susceptible calves, the resulting clinical symptoms of anaplasmosis were similar to those of the controls. There was no statistically significant effect of tick exposure to the anti-erythrocytic stage antibody on the development of salivary gland infection or transmission of A. marginale by ticks. PMID- 8674363 TI - Use or misuse of colostomy to heal pressure ulcers. AB - PURPOSE: The purpose of this study is to evaluate the effectiveness of colostomy performed as an adjunct measure in the attempt to heal pressure ulcers by flap closure. METHODS: Twenty-seven consecutive patients who underwent colostomy for healing of pressure ulcers were studied by chart review and patient questionnaire. Fecal diversion was accomplished by colostomy in each case. RESULTS: There were four (15 percent) deaths. Twenty-three patients subsequently underwent flap closure of their ulcer. Of 19 patients available for follow-up, only 6 (32 percent) patients had completely healed, although most patients thought their quality of life improved because of the colostomy. None of the patients underwent colostomy closure. CONCLUSION: Our conclusions are that, although most patients will have an improved quality of life subsequent to diversion, the high mortality and low rate of pressure ulcer healing should temper enthusiasm for performing colostomy in this setting. PMID- 8674362 TI - Curative reoperations for locally recurrent rectal cancer. AB - PURPOSE: Our aims were to determine the morbidity, survival and its influencing factors, and patterns of failure for patients who underwent further surgery with the hope of cure for locally recurrent rectal cancer. METHODS: Between January 1981 and December 1988, 224 patients with a preoperative diagnosis of recurrent rectal cancer underwent additional surgery at Mayo Medical Center in Rochester, Minnesota. Of these, 65 underwent further surgery with the hope of cure, i.e., no gross/microscopic residual disease at tumor margins after reoperation. Factors assessed included type of original operation, time interval between operation for primary tumor and initial operation for recurrence, symptom status, degree of fixation, types of reoperations for recurrence, and adjuvant therapy. RESULTS: None of the patients died within 30 days of reoperation. Seventeen complications requiring hospitalization and/or surgical procedure were observed in 14 patients. Extended operations (involving partial or complete removal of surrounding organs/structures) required more time to perform, a greater number of transfusions, and a longer hospital stay than more limited operations. Three year, five-year, and median survival were 57, 34, and 44.7 months, respectively. Survival was greater after curative than after palliative resection (P < 0.001). Survival tended to be greater in females (P < 0.075) and in patients without pain (P < 0.065). Cumulative probability of local failure was 24, 41, and 47 percent at 1, 3, and 5 years, respectively. Cumulative risk of distant metastasis was 30, 51, and 62 percent at 1, 3, and 5 years, respectively. CONCLUSIONS: Our results indicate that complete excision of locally recurrent rectal cancer can provide a significant number of patients with long-term survival and can be accomplished safely in select patients. PMID- 8674364 TI - Hereditary susceptibility to colorectal cancer. Relatives of early onset cases are particularly at risk. AB - Close relatives of patients with colorectal cancer are at an increased risk of developing a colorectal malignancy themselves. PURPOSE. A study was conducted to compare risks in relatives of patients diagnosed at different ages. METHODS. Family histories were taken from two cohorts of patients with colorectal cancer: Group A, a population group of 65 patients diagnosed at or under 45 (median, 42) years; Group B, 212 patients of all ages (median, 68 years) treated in a single surgeon's practice. RESULTS. Overall relative risk of colorectal cancer in first degree relatives was 5.2 in Group A and 2.3 in Group B. There was familial clustering of colorectal cancers suggestive of hereditary nonpolyposis colorectal cancer in 13 (20 percent) families in Group A but in only 3 (1.5 percent) families in the second group. Cumulative incidence of colorectal cancer for relatives of the young cohort rose steeply from 40 years, reaching 5 percent at age 50 years and 10 percent at age 70 years. This contrasts with risk for relatives of older patients, in whom the shape of the curve resembles that of the overall population risk, reaching 5 percent at age 70 years and 10 percent at age 80 years. CONCLUSIONS. There appears to be a quantitative and qualitative increase in risk to relatives of patients diagnosed at a young age compared with those diagnosed later in life, at least part of which is likely to be the result of a hereditary susceptibility. Close relatives of early onset cases warrant more intensive endoscopic screening and at an earlier age than relatives of patients diagnosed at older ages. PMID- 8674365 TI - A pilot study of factors influencing bowel function after colorectal anastomosis. AB - PURPOSE: This study was undertaken to assess subjective bowel function after anterior resection and to search for clinical characteristics that might affect the functional results. METHODS: A total of 70 patients answered a questionnaire concerning bowel function a median of 65 months after anterior resection, and 40 patients responded to the same questionnaire a median of 60 months after colonic resection. RESULTS: Median frequency of bowel movement per 24 hours was two (range, 0.2-9) after rectal resection and one (range, 0.4-6) after colonic resection (P < 0.001). Incontinence for loose stools (P < 0.01), need to wear a pad (P < 0.05), and need to return to the toilet after defecation (P < 0.05) was more common in the rectal resection group. In the latter group, advanced age, use of descending or transverse colon for anastomosis, and large amount of intraoperative bleeding was associated with fecal incontinence (P < 0.05). Preoperative radiotherapy was correlated with a high bowel frequency (P = 0.003). CONCLUSIONS: These data indicate that alterations of subjective bowel function frequently observed after colorectal anastomosis may be affected by both surgical technique and adjuvant radiotherapy. PMID- 8674366 TI - Technetium-99m-labeled red blood cell scans in the investigation of gastrointestinal bleeding. AB - PURPOSE: Technetium-99m-labeled red blood cell scans (Tc99m RBC scan) are recommended to confirm gastrointestinal (GI) bleeding. It is controversial whether these scans are sufficient to localize the site of bleeding. This study evaluated the efficacy of RBC scans in confirming and localizing GI bleeding. Our hypothesis was that these scans were effective in localizing GI bleeding if positive within the continuous phase of imaging. METHOD: Tc99m RBC scans were performed on a total of 80 patients over a four-year period to localize GI bleeding (59 male, 21 female; age range 6-88 (mean, 48) years). Films of 75 of the 80 patients were reread by a nuclear medicine physician who was blinded to the original reading and identity and history of the patient. Results of scans were compared with confirmatory studies. RESULTS: A total of 21 patients had positive scans (28 percent). Of these, the site of bleeding in 16 of 21 patients (76 percent) was confirmed by angiography (4/16), endoscopy (10/16), surgery (10/16), or a combination of these. In 14 of the 16 confirmed studies (88 percent), RBC scan correctly localized site of bleeding by our rigid definition. In six patients (4 not confirmed, 2 erroneously localized), scans were positive only at greater than 15 hours. Ten of the 14 correctly localized studies and none of the incorrectly localized studies were positive in the continuous phase of imaging. CONCLUSION: Tc99m RBC scan is effective in localizing GI bleeding when positive within the continuous phase of imaging. In this population supplemental angiography or endoscopy for the purpose of localization would seem unnecessary. PMID- 8674367 TI - Anorectal function and morphology in patients with sporadic proctalgia fugax. AB - PURPOSE: The pathophysiology of sporadic proctalgia fugax remains unknown. This study investigates whether patients with this syndrome exhibit alterations in anal function and morphology. METHODS: Eighteen patients with sporadic proctalgia fugax and 18 sex-matched and age-matched healthy controls were studied. Manometric studies investigated anal resting and squeeze pressures, the rectoanal inhibitory reflex, rectal compliance, and smooth muscle response to edrophonium chloride administration. External and internal sphincter thickness was measured endosonographically. RESULTS: Patients had slightly higher (P = 0.0291) anal resting pressures (65.5 +/- 11.4 mmHg) than controls (56 +/- 9.9 mmHg). However, anal squeeze pressure, sphincter relaxation during rectal distention, and rectal compliance were similar in both groups, and no alterations were detected in external and internal anal sphincter thickness. Edrophonium chloride administration was followed by sharp postrelaxation contractions in two patients, whereas anal function remained unaltered in controls. Acute episodes of proctalgia, which occurred in two patients while under study, were associated with a rise in anal resting tone and an increase in slow wave amplitude. CONCLUSIONS: In the resting state, patients with proctalgia fugax have normal anorectal function and morphology. However, they may exhibit a motor abnormality of the anal smooth muscle during an acute attack. PMID- 8674369 TI - Patterns of anismus and the relation to biofeedback therapy. AB - PURPOSE: A study was undertaken to assess physiologic characteristics and clinical significance of anismus. Specifically, we sought to assess patterns of anismus and the relation of these findings to the success of therapy. METHODS: Sixty-eight patients were found to have anismus based on history and diagnostic criteria including anismus by defecography and at least one of three additional tests: anorectal manometry, electromyography, or colonic transit time study. Interpretation of defecography was based on the consensus of at least three of four observers. Anal canal hypertonia (n = 32) was defined when mean and maximum resting pressures were at least 1 standard deviation higher than those in 63 controls. There were two distinct defecographic patterns of anismus: Type A (n = 26), a flattened anorectal angle without definitive puborectalis indentation but a closed anal canal; Type B (n = 42), a clear puborectalis indentation, narrow anorectal angle, and closed anal canal. Outcomes of 57 patients who had electromyographybased biofeedback therapy were reported as either improved or unimproved at a mean follow-up of 23.7 (range, 6-62) months. These two types of anismus were compared with biofeedback outcome to assess clinical relevance. RESULTS: Patients with Type A anismus showed greater perineal descent at rest (mean, 5.1 vs. 3.5 cm; P < 0.01), greater dynamic descent between rest and evacuation (mean, 2.7 vs. 1.4 cm; P < 0.01), greater difference of anorectal angle between rest and evacuation (mean, 14.6 vs. -3.1 degrees; P < 0.001), higher mean resting pressure (mean, 77.1 vs. 62.8 mmHg; P < 0.05), lower mean squeeze pressure (58.8 vs. 80.7 mmHg; P < 0.05), and a higher incidence of anal canal hypertonia (69.2 vs. 33.3 percent; P < 0.01) than did patients with Type B anismus. Only 25 percent of patients who had Type A anismus with anal canal hypertonia were improved by biofeedback therapy. Conversely, 86 percent of patients with Type B anismus without anal canal hypertonia were successfully treated with biofeedback (P < 0.001; Fisher's exact test). CONCLUSIONS: These two distinct physiologic patterns of anismus correlate with the success of biofeedback treatment. Therefore, knowledge of these patterns may help direct therapy. PMID- 8674368 TI - Natural history of aberrant crypt foci. A surgical approach. AB - BACKGROUND: The aberrant crypt focus (ACF) appears to be an important early step in colorectal carcinogenesis. Our objectives were to determine the natural history of ACF in a surgical model. METHODS: The natural history of ACF was followed by marking the lesions in vivo with tattoos. Rats were given four weekly injections of azoxymethand (AOM; 20 mg/kg). One hundred days after the first injection of AOM, rats were anesthetized, and individual aberrant crypt focus was identified by staining with methylene blue. A 3 x 3 mm area, identifying one large (4-8 crypts) ACF was marked with a tattoo dye in each colon. Control animals received saline or AOM injections and were tattooed in areas without ACF. At 200 days, colons were examined for the presence of macroscopic lesions. RESULTS: A total of 54 tumors were found in the study group of 38 animals, and 21 of these were in the transverse and proximal descending colon. The marked areas (all in transverse and proximal descending colon) yielded 6 tumors and 2 ACF, but in 30 instances no abnormality was noted. Probability of observing a tumor in the 3 x 3 mm area of the colon that was identified as containing ACFs was 17 times greater than expected from the observed tumor rate in approximately the same zone (16 vs. 1.7 percent; 95 confidence interval, 10 to 22 and 0.5 to 1.3 percent). Twenty control animals receiving saline had no tumors of epithelial origin. Nine control animals that were carcinogen-treated and tattooed in areas without ACF had no tumors in the marked areas. CONCLUSION: Results thus show regression of many ACF identified early in the carcinogenesis process. Results also support the hypothesis that some ACF are precursor lesions for adenomas and cancers. PMID- 8674370 TI - Locally advanced rectal cancer: resection and intraoperative radiotherapy using the flab method combined with preoperative or postoperative radiochemotherapy. AB - PURPOSE: Surgery often fails to achieve local control in advanced rectal cancer. Additional measures are necessary to prevent local recurrence. The aim of this study was to evaluate intraoperative radiation therapy (IORT) (flab technique) combined with preoperative or postoperative radiochemotherapy. PATIENTS/METHODS: IORT is performed using a flexible flab containing hollow plastic tubes that are connected to a multichannel afterloading device with a 370 Gbq-192-Ir source. Patients receive an intraoperative dose of 15 Gy. Target volumes were measured in a cadaver experiment. From 1989 to 1993, 38 patients were included in this study. Nineteen patients were staged as T3 tumors by preoperative endosonography (Group I) and 19 as T4 tumors (Group II). Patients in Group I underwent resection (abdominoperineal resection (APR), 16; anterior resection, 3) and IORT, followed by postoperative radiochemotherapy (50 Gy/5-fluorouracil), whereas patients in Group II received preoperative radiochemotherapy (40 Gy/5-fluorouracil) followed by resection (APR, 18; anterior resection, 1) and IORT. Mean follow-up was 25.5 months. RESULTS: Operative radicality in Group I was RO (13), R1 (3), and R2 (3), and in Group II it was RO (14), R1 (3), R2 (2). R2 resections were attributable to preoperative undetected distant metastases. Perioperative mortality was 0 percent in Group I and 10.5 percent (n = 2) in Group II. Postoperative morbidity was 53 percent (n = 10) in Group I and 84 percent (n = 16) in Group II with delayed sacral wound healing being the predominant problem. Stenosis of the ureter occurred in two patients (Group II). Late or persistent therapy-related complications were seen in two patients in Group I and in six patients in Group II. Local recurrence developed in three patients in Group I (15.8 percent) and in two patients in Group II (10.5 percent). Survival data do not reach statistical significance between the two groups because of small numbers but show a favorable trend for the preoperative radiochemotherapy group. When compared with a matched historical control group of patients receiving resection only, adjuvant/neoadjuvant radiotherapy with resection/IORT improves survival significantly. CONCLUSION: The flab method is a simple but especially practical technique for IORT in the pelvis. Adjuvant/neoadjuvant therapy combined with resection/IORT is associated with high morbidity but acceptable mortality. Preliminary survival data are encouraging and call for a controlled prospective randomized trial. PMID- 8674371 TI - Anastomotic leak after double-stapled low colorectal resection. AB - PURPOSE: Anastomotic leaks after double-stapled low anterior resection were associated with a number of factors related to patient condition, level of anastomosis, and variety of surgery-related and antitumor therapy-related factors. This retrospective analysis of a group of patients with consistent length of rectal stump was undertaken to determine the risk factors of anastomotic leak after low colorectal resection related to surgery and to intraperitoneal chemotherapy. METHODS: A group of 165 patients treated with surgery only, surgery with early postoperative intraperitoneal chemotherapy, and surgery with hyperthermic intraoperative and early postoperative intraperitoneal chemotherapy. All patients underwent surgery that used the double-stapled technique with transection of the rectum through its middle third. In univariate and multivariate analysis, the relationship between anastomotic leak rate and extent of colon resection, length of residual colon, presence of left colon, and type of applied treatment was studied. RESULTS: With a full length of residual colon, leak rate was 1 percent but increased progressively with the extent of proximal colon resection. Removal of the left colon was associated with the 2.7 odds ratio for anastomotic disruption. Leak rate after surgery only was 6 percent; surgery with normothermic intraperitoneal chemotherapy was 5 percent; and surgery with heated intraperitoneal chemotherapy was 20 percent. CONCLUSIONS: In this group of patients with consistent length of residual rectum, the incidence of anastomotic disruption was related to extent of proximal colon resection. Anastomotic integrity was not compromised by normothermic intraperitoneal chemotherapy. Hyperthermic intraperitoneal chemotherapy was associated with high leak rate only when extensive resection of the colon was performed. Variables other than extent of rectal excision are important in causing a leak of colorectal anastomosis. PMID- 8674372 TI - Distribution and concentrations of 5-aminosalicylic acid in rectosigmoid biopsy specimens after rectal administration. AB - PURPOSE: Using the autofluorescent properties of 5-aminosalicylic acid (5-ASA), we studied the penetration and distribution of this molecule in human colonic biopsies at different time intervals after administration of 5-ASA enemas. METHODS: Fluorescence scores of rectosigmoidal biopsy specimens were compared with 5-ASA and acetyl-5-aminosalicylic (Ac-5-ASA) concentrations, determined by high-performance liquid chromatography, in adjacent biopsies and in serum samples. RESULTS: 5-ASA penetrates into the rectal mucosa and into the epithelial cells after local application by means of an enema. We found a characteristic 5 ASA staining of two intramucosal structures that need further identification: intraepithelial triangular configurations and "5-ASA scavengers" in the lamina propria. Fluorescence scores correlate well with 5-ASA concentrations in adjacent biopsies (r = 0.67; P < 0.005) and correlate even better with serum concentrations of 5-ASA (r = 0.84; P < 0.005) and Ac-5-ASA (r = 0.80; P < 0.005), hence reflecting the amount of systemically absorbed and metabolized 5-ASA. CONCLUSION: 5-ASA penetrates into the rectal mucosa after local application. Local availability, assessed by means of fluorescence microscopy, correlates well with serum concentrations. PMID- 8674374 TI - Differences in serum tumor markers between colon and rectal cancer. Comparison of CA 242 and carcinoembryonic antigen. AB - PURPOSE: We investigated whether there are differences in serum levels of CA 242 and carcinoembryonic antigen (CEA) between patients with colon and rectal cancer. METHODS: Preoperative serum levels of CA 242 and CEA were determined in 153 patients with colon cancer and in 107 patients with rectal cancer. RESULTS: At the recommended cut-off levels for CA 242 and CEA, the overall sensitivity of CA 242 was 39 percent for both colon and rectal cancer, whereas the sensitivity of CEA was 40 percent for colon and 47 percent for rectal cancer. A combination of CA 242 and CEA increased overall sensitivity to 57 percent in colon cancer and to 62 percent in rectal cancer, whereas specificity decreased by 10 percent, compared with CEA alone. In colon cancer either or both markers were elevated in 38, 46, 56, and 84 percent of patients with Dukes Stages A, B, C, and D, respectively. Corresponding figures for rectal cancer were 52, 46, 71, and 87 percent, respectively. CONCLUSIONS: CA 242 showed equal sensitivity for colon and rectal cancer. In Stages A, C, and D, sensitivity of CEA and of a combination of CEA and CA 242 was higher in rectal than in colon cancer, but the difference was not significant. Concomitant use of markers increased sensitivity sharply compared with use of a single marker both in colon and rectal cancer. PMID- 8674373 TI - Prospective comparative study of abnormal distal rectoanal excitatory reflex, pudendal nerve terminal motor latency, and single fiber density as markers of pudendal neuropathy. AB - PURPOSE: This study was undertaken to determine the role of abnormal distal rectoanal excitatory reflex (RAER) as a marker of pudendal neuropathy and to compare results with pudendal nerve terminal motor latency (PNTML) and single fiber density (SFD) estimation. METHODS: Fifteen female patients (mean age, 47.1 (range, 20-70) years) referred to the pelvic floor laboratory with pelvic floor disorders (fecal incontinence, 13 patients; constipation, 2 patients) were evaluated prospectively with neurophysiologic tests and balloon reflex manometry for evidence of pudendal neuropathy. RESULTS: Pudendal nerve terminal motor latency provided evidence of pudendal neuropathy in ten patients (67 percent) and was normal in five patients (33 percent). Increased SFD confirmed denervation of the external anal sphincter in 12 patients (80 percent), being normal in 3 patients (20 percent). Distal RAER was abnormal in 13 patients (87 percent) and was normal in 2 patients (13 percent). In ten patients (67 percent), the three diagnostic modalities were in complete agreement, correctly identifying neuropathy in nine patients (60 percent) and excluding nerve damage in one patient (7 percent). Distal RAER was normal despite prolonged PNTML and increased SFD in one patient (7 percent). In two patients (13 percent), distal RAER was abnormal or absent despite normal PNTML and SFD. Pudendal nerve terminal motor latency was normal in the presence of abnormal distal RAER and increased SFD on electromyography in two patients (13 percent). CONCLUSIONS: Abnormal distal RAER compares favorably with current neurophysiologic tests used to diagnose pudendal neuropathy. PMID- 8674375 TI - Postpolypectomy colonic hemorrhage. AB - PURPOSE: This study was undertaken to evaluate the incidence, diagnostic methods, and treatment of hemorrhage occurring after colonoscopic polypectomy. METHODS: A retrospective chart review was conducted of 12,058 patients who underwent colonoscopy at an academic referral center between January 1989 and July 1993. Of these, 6,365 patients required polypectomies or biopsies. RESULTS: After these procedures, 13 patients (0.2 percent) developed lower gastrointestinal hemorrhage requiring hospitalization. All bleeding episodes occurred within 12 days of polypectomy or biopsy (mean = 8 days). Twelve patients (92 percent) underwent technetium-tagged red blood cell scintigraphy, which localized bleeding in four patients (31 percent). In the eight patients with normal scintigrams, hemorrhage did not recur, and no further evaluation was performed. Five patients (38 percent) underwent arteriography. Arteriogram was positive in two of four patients with positive scintigrams, and bleeding was controlled with selective vasopressin infusion. The fifth patient had arteriography without prior diagnostic studies because of massive hemorrhage; the bleeding site was identified and controlled with selective vasopressin infusion. Three patients had lower gastrointestinal endoscopy, with endoscopic identification of bleeding site in two patients, and endoscopic electrocautery controlled the bleeding in one patient. In the 13 patients with hemorrhage, cessation of bleeding occurred with intestinal rest and hydration in nine patients (69 percent), selective vasopressin infusion in three patients (23 percent), and endoscopic electrocautery in one patient (8 percent). Eight patients (62 percent) required blood transfusion with a mean of 4.8 units (excluding one patient on warfarin sodium who required 14 units of blood). No patient required surgical intervention. CONCLUSIONS: Incidence of hemorrhage after colonoscopic polypectomy or biopsy is low, and in our series, hemorrhage resolved without the need for surgical intervention. Management includes initial stabilization followed by diagnostic evaluation. Technetium-tagged red blood cell nuclear scintigraphy identifies ongoing bleeding and identifies patients in whom additional invasive procedures (arteriography lower gastrointestinal tract endoscopy) are warranted. PMID- 8674376 TI - Surgical treatment of traumatic cloaca. AB - PURPOSE: This study was designed to evaluate the repair of traumatic cloaca and determine the satisfactory outcome as determined by improvement in the continence mechanism of patients. METHODS: Forty-four patients were entered in this study during a 14-year period. The majority of traumatic cloaca occurred secondary to obstetric injury, most frequently during the first childbirth. No definite medical illnesses precipitated the occurrence of traumatic cloaca. Only two patients had diabetes mellitus, and one patient had prior radiation. All patients underwent surgical repair using puborectalis interposition and sphincteroplasty and perineal body repair, approximating the internal and external sphincter fused bundles and transversus perinei muscles in a vest-over-pants manner. Average stay in the hospital was less than three days, and postoperative morbidity was minimal. One patient had minor postoperative bleeding, which was corrected with cauterization. One patient had a superficial subcutaneous infection, which was drained on the 15th postoperative day. RESULTS: Majority of patients regained excellent control of continence to both flatus and feces. Four patients had unsatisfactory control to passage of flatus. One patient had unsatisfactory control to passage of liquid stool in addition to flatus. All five patients improved, with very satisfactory results, following an exercise program and biofeedback therapy. Six of 12 patients who had perineal discomfort before the surgical procedure, with associated dyspareunia, were the most dissatisfied subgroup in the series. Exact mechanism for perineal discomfort is unclear at this point. PMID- 8674377 TI - Immunohistochemical evaluations of ultrashort-segment Hirschsprung's disease. Report of three cases. AB - PURPOSE: Unlike classic Hirschsprung's disease, short-segment and ultrashort segment varieties are usually found to be latent and milder. Ultrashort-segment Hirschsprung's disease may present as intractable chronic constipation in children over one year of age, adolescents, and adults. Anorectal myectomy has been shown in many instances to provide effective long-term treatment for certain patients with ultrashort-segment Hirschsprung's disease. Histologically, the affected segment in Hirschsprung's disease has been shown to have increased cholinergic nerves, lack of nitric oxide synthase-containing neuronal elements, and show moderate to severe loss of myenteric neurons. METHODS: Here, we report three cases that showed clinical and manometric evidence of ultrashort-segment Hirschsprung's disease. Two of the three patients responded well to myectomy. RESULTS: Detailed histologic and immunohistochemical evaluation of the internal anal sphincter and a comparison with three normal controls revealed absence of nitric oxide synthase-containing neurons in both cases that responded well to surgery and continued presence of these neurons in the patient who did not respond. A review of the current literature on various treatment modalities is included. CONCLUSIONS: Anorectal myectomy provides long-term relief of this chronic problem in a subgroup of patients with ultrashort-segment Hirschsprung's disease who lack nitrinergic neurons at the internal anal sphincter. PMID- 8674378 TI - Effectiveness of combined anticoagulant therapy for extending portal vein thrombosis in Crohn's disease. Report of a case. AB - PURPOSE: Portal vein thrombosis is a rare complication of Crohn's disease, and its precise cause and appropriate treatment are not known. We describe a patient with extending portal vein thrombosis in Crohn's disease who was successfully treated with combined anticoagulant therapy. METHOD: Urokinase and tissue plasminogen activator were administered from a catheter inserted into the superior mesenteric artery, and heparin and a serine protease inhibitor also were given intravenously. RESULTS: On admission, thromboembolic occlusion was observed throughout the entire portal venous system in association with massive ascites and remarkable intestinal edema. After administration of combined anticoagulant therapy, thrombus rapidly decreased in size, and color Doppler ultrasonography showed a gradual increase in portal venous flow. The patient had no recurrence of symptoms while receiving warfarin after resolution of thrombus. CONCLUSION: This case report suggests that combined anticoagulant therapy is effective for patients with severe portal vein thrombosis in Crohn's disease and that color Doppler ultrasonography is useful for evaluation of portal venous flow. PMID- 8674379 TI - Clarifying the technique of four-contrast defecography. PMID- 8674380 TI - Medical jive. PMID- 8674381 TI - Transanal endoscopic microsurgery for management of early invasive cancer. PMID- 8674382 TI - Gastrointestinal symptoms and psychiatric disorders in the general population. Findings from NIMH Epidemiologic Catchment Area Project. AB - High rates of psychiatric disorder have been documented in patients with functional bowel syndromes sampled from physicians' offices. Lifetime psychiatric disorder and/or current psychiatric symptoms are thought to be much more highly associated with current gastrointestinal bowel symptoms in clinical settings than in the community. The relationship of lifetime functional gastrointestinal symptoms to lifetime psychiatric disorders has not been examined systematically in randomly selected samples of general community populations. The current study reports findings from existing data on a large, randomly selected population sample that may help to clarify these associations. Epidemiologic Catchment Area (ECA) project data were analyzed to examine relationships of functional gastrointestinal symptoms and psychiatric diagnoses in the community. Individuals with two or more medically unexplained gastrointestinal symptoms had high rates of psychiatric disorders. This was also true for the subgroup in which abdominal pain was one of the two symptoms. The overwhelming majority of subjects reporting medically unexplained gastrointestinal symptoms said they had consulted physicians for those symptoms. General population ECA data indicate that women in the community report more functional gastrointestinal complaints than men, that individuals with lifetime gastrointestinal complaints have high rates of lifetime psychiatric disorders (not necessarily currently symptomatic), and most have contacted a physician regarding their gastrointestinal symptoms. These data complement studies showing that patients with current gastrointestinal symptoms often do not consult a physician, or when they do, such behavior is associated with active psychiatric symptoms. These present data are consistent with the hypothesis that patients with recurrent symptoms are those who routinely seek medical help and who have high rates of psychiatric disorders, whereas those with symptoms that resolve or are improved by a medical intervention do not maintain treatment-seeking behavior. PMID- 8674383 TI - Computed tomography and granulocyte scintigraphy in active inflammatory bowel disease. Comparison with endoscopy and operative findings. AB - The accuracy of computed tomography (CT) and [99mTc]HMPAO granulocyte scintigraphy (GS) for detection of bowel localization, inflammatory activity, and complications in acute inflammatory bowel disease (IBD) was prospectively studied in 32 patients. Of each bowel segment, findings on CT and GS were scored by one blinded observer. Findings on operation or endoscopy served as the gold standard. In Crohn's disease (CD, 17 patients), CT detected bowel pathology (sensitivity 71%, specificity 98%), abscesses (sensitivity and specificity 100%), and fistulas (sensitivity 80%, specificity 100%). In CD, GS had a sensitive of 79% and a specificity of 98% for detection of inflammatory activity. The detection of complications with GS was poor. Segmental inflammatory activity correlated with endoscopy-operative findings for CT (r = 0/86, P < 0.0001) and GS (r = 0.86, P < 0.0001). In ulcerative colitis (UC, 15 patients), GS predicted proximal extension of bowel involvement better than CT. In CD, CT is Superior to GS for localization of both active and fibrostenotic bowel disease, and in detection of the abscesses and fistulas. In UC, GS showed proximal extension more accurately than CT. PMID- 8674384 TI - Role of brush border Na+/H+ exchange in canine ileal absorption. AB - Na+/H+ exchanger isoforms have been identified in mammalian intestinal enterocytes and cloned: NHE1 on the basolateral membrane regulating intracellular pH; and NHE2 and NHE3 on the brush border serving transcellular absorption in Na+. NHE1 and NHE2 are much more sensitive to inhibition by amiloride than NHE3, their in vitro IC50s for amiloride being 1 microM, 1 microM and 39 microM, respectively. This study tested the hypothesis that the brush border NHE3 isoform plays the predominant role in basal and meal-stimulated ileal absorption. Absorption studies (N = 72) were performed in dogs with 25-cm ileal Thiry-Vella fistulae. Six groups were studied over 4 hr. Perfusion with [14C]PEG and 140 mM Na+ was used to calculate absorption of water, ions, and glucose. Luminal amiloride was administered from the second to the fourth hours at doses of 20 microM in groups 3 and 4 to inhibit NHE1 and NHE2, and 1mM in groups 5 and 6 to also inhibit NHE3. A 480-kcal canine meal was ingested after the second hour in groups, 2, 4, and 6. Meal ingestion was followed by significant increases in water and electrolyte absorption. Amiloride (1 mM) caused significant reductions in basal and meal-stimulated ileal absorption, while the 20 microM dose had no effect on either. These data are consistent with the hypothesis that NHE3, but not NHE2, is involved in basal and meal-stimulated ileal water and Na+ absorption. PMID- 8674385 TI - Expression of protooncogene-encoded mRNA by colonic epithelial cells in inflammatory bowel disease. AB - Protooncogenes are cell cycle-related genes that are involved in cell growth of proliferation. Alterations in the level of expression of these genes, or expression of aberrant gene productions, have been observed in tumors and precancerous conditions. To determine if expression of these genes is altered in patients with inflammatory bowel disease (IBD) --who are at risk for development of colon cancer--we assayed transcripts of 15 protooncogenes in colonic epithelial cells of IBD patients and controls. Nine of these genes (H-ras, c-myc, c-fos, c-jun, junB, N-myc, c-abl, c-yes, and p53) were expressed in epithelial cells, whereas two (RB1 and N-ras) were not. expression of four other genes (c src, K-ras, c-raf, and c-myb) was observed, but the intensity of these bands was too low for densitometric analysis. The steady-state levels of transcripts of H ras and five nuclear protooncogenes (c-myc, c-fos, c-jun, junB, and N-myc) were lower in epithelial cells from involved or uninvolved IBD samples than in normal epithelial cells from either sporadic colon cancer or diverticulitis patients. The level of c-fos mRNA was two- to threefold higher in involved than in uninvolved areas of the colons of two ulcerative colitis (UC) patients, but not in one Crohn's disease (CD) patient. Message abundance of c-abl transcripts was two- to threefold lower in UC epithelial cells than in either the CD or control samples. The steady-state level of c-yes-encoded mRNA was considerably higher in IBD patients resected for colon cancer than in patients resected for active chronic IBD or in controls. The level of p53 message was constant in these samples. Increased levels of c-fos mRNA in involved UC relative to uninvolved UC may be related to the disease process. Decreased expression of c-abl transcript in UC may be a diagnostic marker for UC and may be related to the rate of cell turnover in these diseases. Enhanced expression of c-yes in IBD patients with tumors compared to active chronic IBD and controls suggests that expression of this gene may be a marker for development of colon cancer in IBD. PMID- 8674386 TI - LFA-1 subunit expression in ulcerative colitis patients. AB - The adhesion molecule, lymphocyte function associated antigen (LFA-1) consisting of two subunits, CD11a and CD18, mediates lymphocyte migration into tissue and cell effector functions. Previous observations showed no differences in LFA-1 expression by circulating lymphocytes between inflammatory bowel disease patients and controls. The aim of the present work was to study subsets of circulating LFA 1+ lymphocytes in ulcerative colitis (UC) patients versus healthy controls. Peripheral blood mononuclear cells were obtained from 16 UC patients and 10 healthy volunteers. The percentages of CD11alo, CD11ahi, CD18lo, CD18hi T and B cells, as well as Cd25 expression on these cells were studied using double staining with monoclonal antibodies and panning procedures. The percentage of CD11hi and CD18hi T cells was significantly decreased in quiescent UC patients as compared to active disease patients and healthy controls (P < 0.05). The majority of CD25+ T cells were expressing CD11a and CD18 with low density. A detectable percentage, 2% (range 1-6%), of CD11ahiCD25+ (but not CD18hiCD25+) was found in UC patients with moderate to severe disease, but not in those with inactive UC to healthy controls. In conclusion, the percentage of CD11ahi+ and CD18hi+ T cells is decreased in peripheral blood of quiescent UC patients, which is probably associated with the effect of specific treatment. The percentage of CD11ahi+IL-2R alpha+ T cells is increased in peripheral blood of patients with active (moderate and severe) UC, which most likely reflects a sustained T-cell activation due to a persistent inflammatory process. PMID- 8674387 TI - Increased ileal proglucagon expression after jejunectomy is not suppressed by inhibition of bowel growth. AB - After jejunectomy, a rapid and sustained increase in the abundance of proglucagon mRNA occurs in residual ileum and is accompanied by increases in plasma intestinal proglucagon-derived peptides. This response may be a component of adaptive growth, or proglucagon-derived peptides may regulate adaptive growth. To distinguish these possibilities, rats were treated with difluoromethylornithine, blocking ornithine decarboxylase activity and thereby adaptive bowel growth. Three groups fed ad libitum were compared: (1) resect: rats with 80% proximal small bowel resection; (2) resect + difluoromethylornithine: resected rats given difluoromethylornithine in drinking water; and (3) transect: transected controls. Six days after surgery, the resect + difluoromethylornithine group demonstrated inhibition of adaptive bowel growth. Abundance of ileal proglucagon mRNA in resect and resect + difluoromethylornithine groups was double that in the transect group (P < 0.02), whereas ornithine decarboxylase mRNA levels did not differ. Plasma enteroglucagon and glucagon-like peptide-I levels were greater in resect than transect groups (P < 0.002) and did not differ between resect and resect + difluoromethylornithine groups. The rise in ileal proglucagon mRNA after proximal small bowel resection is not inhibited by difluoromethylornithine despite blocking bowel growth and, therefore, is not merely a component of adaptive growth. Proglucagon-derived peptides are possible modulators of adaptive bowel but cannot stimulate growth when ornithine decarboxylase activity is inhibited. PMID- 8674388 TI - Demonstration of efficacy of combining corticosteroids and colchicine in two patients with idiopathic sclerosing mesenteritis. AB - Sclerosing mesenteritis is an uncommon condition of unknown etiology. It is likely to be the fibrous evolution of mesenteric panniculitis. It often has an indolent course but may be complicated by progressive bowel obstruction. The treatment of the symptomatic forms is not well established. The observations of two women (20 and 65 years old) with a relentless downhill course of biopsy proved sclerosing mesenteritis are described. A treatment regimen with corticosteroid therapy (initially 1 mg/kg/day) and colchicine (1 mg/day) led, in both cases, to a rapid improvement. Abdominal computer tomography showed reduction in the tumor size. The combination of corticosteroids and colchicine is helpful in the management of symptomatic sclerosing mesenteritis. Follow-up with abdominal computed tomography is useful in evaluating the therapeutic impact. PMID- 8674390 TI - Antral axial forces postprandially and after erythromycin in organic and functional dysmotilities. AB - Our aims were to measure antral axial forces in patients with suspected upper gut dysmotilities and to compare the number of antral contractions detected by an axial force catheter and by manometric sensors in the distal antrum and pylorus. Fifteen patients (2 men, 13 women; mean age 42 years) underwent studies for 3 hr fasting, 2 hr postprandially, and up to 60 min after intravenous erythromycin (3mg/kg). Seven patients had gastroparesis or chronic intestinal pseudoobstruction, five functional disease, and three subacute obstruction. Postprandially, the number of peaks detected by the two methods was not significantly different; however, after erythromycin, the axial catheter detected more contractions (P = 0.02). Erythromycin significantly increased the number of postprandial axial forces (from 1.2 +/- 0.3/min to 2.5 +/- 0.3/min, P < or = 0.01) in the whole group and in the organic dysmotility group (P = 0.01). Erythromycin significantly increases the number of axial forces in functional and organic upper gut dysmotilities, but the axial force catheter is not advantageous over manometry for postprandial measurements of antral motility. PMID- 8674389 TI - Impaired accommodation of proximal stomach to a meal in functional dyspepsia. AB - In patients with functional dyspepsia, scanning by a novel ultrasonographic method was carried out to investigate postprandial accommodation of the proximal stomach. Twenty patients with functional dyspepsia and 20 controls were scanned fasting in a sitting position after drinking 500 ml meat soup. Images were recorded up to 25 min after the ingestion period using an ultrasound sector scanner with a 3.25-MHz transducer. The area in a sagittal section and the maximal diameter in a oblique frontal section were chosen as the main variables for calculating the emptying fraction of the proximal stomach, defined as: (aV2.5min - aVactual/aV2.5min. All subjects were asked to score total symptoms (1 9) provoked by the meal. From 7.5 to 25 min after the ingestion period the patients exhibited both smaller area in the sagittal section (P < 0.018) and shorter diameter in the frontal section (P < 0.046) compared with the healthy controls, and they suffered more symptoms in response to the meal (P = 0.002). Dyspeptic patients revealed higher emptying fractions (P = 0.0005, ANOVA), and H. pylori status did not influence the emptying fractions. Diagnostic sensitivity of the method at 20 min postprandially was 70% and the specificity was 65%. Patients with functional dyspepsia have impaired accommodation of the proximal stomach to a meal, temporarily related to symptom induction. PMID- 8674391 TI - Recovery of gastrointestinal motility following open versus laparoscopic colon resection in dogs. AB - The recovery of gastrointestinal motility was compared in dogs undergoing either laparoscopic or open sigmoidectomy. During surgery, bipolar recording electrodes were placed on the proximal and distal antrum, mid- and distal colon, and the rectum. Fasting myoelectric data were recorded postoperatively. Scintigraphic gastric emptying studies employing a solid test meal were performed before and after [postoperative day (POD) 2] operation. Ten radiopaque markers were given just before operation and retained markers were counted daily by abdominal x-ray. Gastric emptying on POD 2 was significantly delayed in the open group at 120 min compared with preoperative studies for the open group and compared with the laparoscopic group on POD 2 (P < 0.05 and P < 0.01, respectively). A significant difference in the number of retained markers was observed between the groups on POD 4 (P < 0.05). There were no significant differences in slow-wave frequency, presence of dysrhythmias in the proximal and distal antrum, or presence of either discrete or continuous electrical response activity in the colon and rectum between groups on any days. We conclude that using a laparoscopic approach results in more rapid recovery of fed-state gastrointestinal motility following colon resection. These data also suggest that myoelectric activity alone is not a sensitive enough parameter to detect these differences in recovery in this animal model. PMID- 8674392 TI - Functional characteristics of canine pylorus in health, with pyloroplasty, and after pyloric reconstruction. AB - The aim was to determine whether pyloroplasty decreases the strength of pyloric contractions and speeds gastric emptying of solids, while subsequent pyloric reconstruction restores these abnormalities to the control. In conscious dogs, pyloroplasty decreased the strength of pyloroduodenal pressure waves measured with a perfused sleeve sensor [mean +/- SEM pyloroduodenal motility index: control (N = 7) = 1116 +/- 351 mm Hg x sec/10 min; pyloroplasty (N = 7) = 43 +/- 19 mm Hg x sec/10 min; P < 0.05], and caused rapid gastric emptying of solids measured scintigraphically (mean +/- SEM half-emptying time: control = 246 +/- 14 min, pyloroplasty = 176 +/- 16 min; P < 0.05). The frequencies of pyloroduodenal waves and gastric emptying of liquids, however, were unchanged. Pyloric reconstruction restored the postpyloroplasty patterns to the control. In conclusion, pyloroplasty decreased the strength of pyloroduodenal contractions and sped gastric emptying of solids, while pyloric reconstruction restored the altered patterns to the control. PMID- 8674393 TI - Effects of prostaglandins E2 and F2 alpha on electromyogram of cat colon in vitro. AB - Prostaglandins cause diarrhea, and their production by the gut increases in diarrheal states. We studied the effects of PGF2 alpha and PGE2 on the electromyogram recorded from the cat colon in vitro to determine if these prostaglandins might produce electromyographic changes similar to those seen in diarrheal states. PGF2 alpha decreased slow wave frequency and uncoupled slow wave propagation in the proximal colon. It increased the frequency of migrating spike bursts. PGE2 had no effect on slow waves, but increased the frequency of the migrating spike burst. PGF2 alpha produced electromyographic changes similar to those recorded from the colon of cats with spontaneous diarrhea or after exposure to diarrhea-producing agents such as ricinoleate or quinidine. Some diarrhea-producing agents are likely to act by increasing prostaglandin production. PMID- 8674395 TI - New noninvasive tests for Helicobacter pylori gastritis. Comparison with tissue based gold standard. AB - The current gold standard for diagnosing H. pylori gastritis requires antral biopsy for urease test (eg, CLOtest) and/or history. We compared this gold standard to a new low-dose capsule-based 1 microCi [4C]urea breath test (UBT) and a rapid serum test for anti-H. pylori antibodies (FlexSure HP) in 50 consecutive patients undergoing upper endoscopy. Antral biopsies within 3 cm of the pylorus were used for CLOtest and were stained with H&E and thiazine. Slides were reviewed by a single, blinded pathologist (Review) and compared to the pathology department report (Report). A true positive was defined as a positive CLOtest or Review. The prevalence of H. pylori infection by each test was: CLOtest 32%, Review 36%, gold standard 42%, UBT 38%, FlexSure HP 44%, Report 44%. UBT had sensitivity = 90%, specificity = 96%, positive predictive value = 95%, and negative predictive value = 93% and accurately determined H. pylori status in a subgroup of 10 patients who had completed treatment. The one false positive breath test occurred in a patient with 2+ chronic inflammation on biopsy and a positive antibody test. There were two false negative breath tests. Each had both negative CLOtests and negative antibody tests. FlexSure HP had sensitivity = 74%, specificity = 89%, positive predictive value = 88%, and negative predictive value = 77% in patients not previously treated, but had a high false-positive rate in the 10 patients after treatment. Pathology department Report and blinded pathologist Review had only 84% agreement, kappa = 0.67. Both CLOtest and UBT agreed better with Review (86%, 87%, kappa = 0.68, 0.73, respectively) than Report (78%, 77%, kappa = 0.53, 0.53, respectively) suggesting that Review is more accurate than Report. When biopsy is done, we recommend that a CLOtest be performed followed by histological examination if the CLOtest is negative to ensure adequate sensitivity. However, interpretation of histological slides has significant interobserver variability even in experienced hands and may be inaccurate at times. FlexSure HP has good PPV but inadequate sensitivity to rule out active infection and is not useful in patients after treatment. UBT is an excellent noninvasive test that should be considered in cases where EGD is otherwise not indicated. PMID- 8674396 TI - Biochemical effects of oral sodium phosphate. AB - Our objective was to monitor serum and urine biochemical changes after oral sodium phosphate cleansing in a prospectively designed study. The study subjects were seven healthy, asymptomatic adults. Sodium phosphate 45 ml diluted in 45 ml water was given orally at baseline and 12 hr later. Calcium, ionized calcium, phosphorus, sodium, potassium, creatinine, and PTH were analyzed at 2, 4, 6, 9, 12, 14, 16, 18, 21 and 24 hr after the first challenge. Urinary calcium, phosphorus, sodium, potassium, and cyclic AMP were analyzed at baseline and every 2 hr after oral sodium phosphate. Blood pressure, pulse, and respiratory rate were recorded every 2 hr and symptom questionnaires using visual analog scales were completed. A marked rise in phosphorus (peak range 3.6-12.4 mg/dl, P < 0.001) and falls in calcium (P < 0.001) and ionized calcium (P < 0.001) were seen. Rises seen in PTH and urinary cAMP confirmed the physiologic significance of the biochemical effect. There were no significant changes in other serum and urine laboratory or clinical assessments. Reported significant symptoms included bloating, cramps, abdominal pain, and nausea. Significant hypocalcemia and hyperphosphatemia after oral sodium phosphate raises concern about its use in normal individuals. Oral sodium phosphate should not be administered in patients with cardiopulmonary, renal, or hepatic disease. PMID- 8674394 TI - Butyrate and the colonocyte. Implications for neoplasia. AB - Butyrate is produced in the colon of mammals as a result of microbial fermentation of dietary fiber, undigested starch, and proteins. Butyrate may be an important protective agent in colonic carcinogenesis. Trophic effects on normal colonocytes in vitro and in vivo are induced by butyrate. In contrast, butyrate arrests the growth of neoplastic colonocytes and inhibits the preneoplastic hyperproliferation induced by some tumour promoters in vitro. We speculate that selective effects on G-protein activation may explain this paradox of butyrate's effects in normal versus neoplastic colonocytes. Butyrate induces differentiation of colon cancer cell lines. It also regulates the expression of molecules involved in colonocyte growth and adhesion and inhibits the expression of several protooncogenes relevant to colorectal carcinogenesis. Additional studies are needed to evaluate butyrate's antineoplastic effects in vivo and to understand its mechanism(s) of action. PMID- 8674397 TI - Placebo-controlled trial of cisapride in postgastrectomy patients with duodenogastroesophageal reflux. AB - Medical treatment of duodenogastroesophageal reflux in postgastrectomy patients has been disappointing. Using ambulatory esophageal bilirubin monitoring, we evaluated the efficacy of cisapride in this disorder. Ten chronically symptomatic partial gastrectomy patients (5 Billroth I, 5 Billroth II; 8 men; average age 57) with duodenogastroesophageal reflux were randomized to four weeks of either placebo or cisapride (20 mg four times a day) in a double-blind crossover study. Significantly improved patients continued to take cisapride for an additional four months. Duodenogastroesophageal reflux was assessed at baseline and after four weeks on each therapy. Daily diary recorded symptoms and mean monthly scores were determined. Global symptom improvements were assessed at the end of each treatment period. Compared to placebo, cisapride significantly (P < 0.05) decreased duodenogastroesophageal reflux. Overall symptom improvements were assessed at the end of each treatment period. Compared to placebo, cisapride significantly (P < 0.05) decreased duodenogastroesophageal reflux. Overall symptoms improved in 70% of patients on cisapride compared to 10% on placebo (P < 0.01). Mean monthly scores significantly (P < 0.05) improved for abdominal pain, regurgitation, and belching. These symptoms remained improved after four months of chronic therapy. We conclude that cisapride significantly reduces duodenogastroesophageal reflux and results in short- and long-term symptom improvements in postgastrectomy patients and that cisapride offers the first successful medical therapy for duodenogastroesophageal reflux in postgastrectomy patients. PMID- 8674398 TI - Inclusion of supine period in short-duration pH monitoring is essential in diagnosis of gastroesophageal reflux disease. AB - Prolonged esophageal pH monitoring is the most accurate method for detecting abnormal gastroesophageal reflux (GER) in patients with gastroesophageal reflux disease (GERD). However, some investigators have found that short-duration postprandial pH monitoring in the upright position is also useful, while others have failed to find such results. Therefore, we have compared a 6-hr period of pH monitoring (3-hr postprandial period after daytime meal and 3-hr supine period) with a total 24-hr period in detecting abnormal gastroesophageal reflux. Sixty five patients (44 men, mean age 41.3 years) with GERD and 16 healthy volunteers (11 men, mean age 34.3 years) underwent 24-hr pH monitoring according to a standard protocol. Various reflux parameters during 24-hr pH monitoring were compared with reflux parameters during the 6-hr period. Abnormal GER was detected in 56 patients presenting with typical symptoms of GERD (sensitivity 86.2%). These patients could be further divided into upright (N = 18), supine (N = 15), and combined (N = 23) refluxers, depending on the posture in which abnormal reflux occurred. Esophageal pH monitoring during the 3-hr postprandial upright period showed abnormal reflux in only 35 patients (sensitivity 53.8%; P < 0.00005, compared with the 24-hr pH monitoring period). Abnormal GER was identified in 13 of 18 upright, 19 of 23 combined, and only one of 15 supine refluxers, as well as in two of nine patients with normal 24-hr pH-metry. However, inclusion of the 3-hr supine monitoring period in the 3-hr postprandial upright period improved detection of abnormal GER to 78.5% (51 patients; P = NS compared with 24-hr pH monitoring period). This was related mainly to improved detection of abnormal GER in supine refluxers (11 of 15; 73.3%). Esophageal acid exposure time correlated significantly with severity of esophagitis only during the total and supine periods of both the 24- and 6-hr periods and not during the upright period. Esophageal acid clearance correlated significantly with increasing grades of esophagitis for the supine and total periods only. We conclude that 3-hr postprandial pH monitoring, as has been conventionally practiced, is not appropriate in the detection of abnormal GER; inclusion of a supine period in the short-duration pH monitoring schedule increases the detection of pathological reflux. We therefore recommend that a supine period should be included in short-duration pH monitoring schedules. We also found that supine reflex was the most important factor in the development of esophagitis. PMID- 8674399 TI - Overexpression of transforming growth factor-alpha alters differentiation of gastric cell lineages. AB - Overexpression of transforming growth factor-alpha (TGF-alpha) in the gastric fundic mucosa of metallothionein promoter/enhancer-TGF-alpha(MT-TGF-alpha) transgenic mice produces a phenotype of foveolar hyperplasia similar to that observed in Menetrier's disease. We have investigated the dynamics involved in the alterations of gastric mucosal morphology in the MT-TGF-alpha mouse model. The fundic mucosa of MT-TGF-alpha mice and nontransgenic littermates was evaluated in animals treated with cadmium sulfate. To mark the mucosal proliferative zone, 8-bromodeoxyuridine (BrdU) was administered 2 hr prior to killing. Gastric mucosa was examined by diastase-resistant, periodic acid-Schiff positive (DR-PAS) staining and immunohistochemistry for H/K-ATPase an BrdU. MT TGF-alpha mice demonstrated increased numbers of DR-PAS-staining mucous cells and lower parietal cell numbers per gland unit. While the proliferative zone in nontransgenic mice was located in the upper half of the gland, the zone in MT-TGF alpha mice was located in the basal region. Overexpression of TGF-alpha in MT-TGF alpha mice leads to an alteration in the development of mucosal lineages from the fundic progenitor zone, which is biased towards the predominant differentiation of foveolar mucous cells. PMID- 8674400 TI - Capsaicin-sensitive sensory neurons are involved in bicarbonate secretion induced by lansoprazole, a proton pump inhibitor, in rats. AB - Lansoprazole, a proton pump inhibitor, exerts prominent antiulcer activity via both antisecretory and mucosal protective actions. Although the antisecretory action has been explained by inactivation of (H+, K+)-ATPase in parietal cells, the mode of mucosal protective action remains to be elucidated. In the present study, the effect of lansoprazole on duodenal bicarbonate secretion was studied in anesthetized rats to clarify the mode of the mucosal protective action. Lansoprazole (0.1 mM) applied topically to the duodenum significantly (P < 0.01) increased bicarbonate secretion by 0.36 +/- 0.11 microeq/15 min (21 +/- 5%) compared with the value in the vehicle control. Topical administration of capsaicin (10 mg/ml) in the duodenum and intravenous infusion of vasoactive intestinal peptide (10 micrograms/kg/hr) increased bicarbonate secretion. Five minute perfusion of the duodenal loop with 100 mM HCl increased bicarbonate secretion. Administration of lansoprazole (0.3 and 1 mg/kg, intravenously) 60 min before luminal acidification enhanced the acid-induced bicarbonate secretion dose dependently and significantly (P < 0.01). In the capsaicin-pretreated rats, the effects of lansoprazole on basal and acid-induced bicarbonate secretion were significantly (P < 0.05) decreased compared with that of control group. These results indicate that lansoprazole increases basal and acid-induced bicarbonate secretion in the duodenum in rats and that capsaicin-sensitive sensory neurons may be involved in the mode of action for these effects. PMID- 8674401 TI - Ethanol-induced gastrointestinal damage. Influence of endogenous antioxidant components and gender. AB - This study compared the effects of undiluted and 8% ethanol administered orally on gastrointestinal antioxidant components of male and female rats. Eight percent ethanol increased the activities of duodenal glutathione peroxide (29% in males, 14% in females) and superoxide dismutase in female gastric (24%) and male duodenal (15%) mucosa. This dose of ethanol also increased the glutathione content of gastric mucosa (12% in males, 13% in females). Undiluted ethanol decreased glutathione levels in gastric mucosa (22% in males, 11% in females) and increased glutathione peroxide activity in gastric mucosa (14% in males, 9% in females). Undiluted alcohol also produced decreases in the activity of glutathione reductase in stomach (14% in males, 9% in females) and duodenum (16% in males, 12% in females). Undiluted ethanol caused mucosal damage in the body of the stomach in both genders, accompanied by an increase in luminal pH and fluid accumulation in the stomach; these changes were absent in rats given 8% ethanol. The increase in gastrointestinal antioxidant capacity associated with the administration of 8% ethanol may be a factor in the reported cytoprotective effect of lower doses of ethanol. PMID- 8674402 TI - One-day combined therapy of children with Helicobacter pylori-associated peptic disease. PMID- 8674403 TI - Nonsteroidal antiinflammatory drugs and dyspepsia in the elderly. PMID- 8674404 TI - Enzymatic cytochemistry, DNA ploidy and AgNOR quantitation in hepatocellular nodules of uncertain malignant potential in liver cirrhosis. AB - Conventional histological examination of echo-guided biopsy specimens can be inconclusive in small nodular lesions in cirrhotic livers. We investigated the diagnostic potential of cytochemical analysis of dipeptidyl-peptidase IV (DPP IV), of image analysis of nuclear DNA content, and of interphase silver-stained nucleolar organizer regions (AgNORs) in 12 cases of small (13- to 29-mm in diameter) hepatic nodules visualized in cirrhotic patients by ultrasonography. All cases underwent an echo-guided liver biopsy at the time of detection and in none of them were histological signs of malignancy found. Characterization with the above-mentioned techniques was always done at the time of histological examination. These patients underwent a mean (+/- SD) follow-up of 27.0 (+/- 11.2) months after biopsy, with repeated ultrasound (US) examinations. In the seven patients with subsequent neoplastic growth, DPP IV score was altered in five of six; the fraction of mononucleated polyploid cells was altered in six of seven; and the AgNOR quantity exceeded the cutoff value of 4 microns2 in five of five cases. Among the five lesions whose US appearance remained unchanged during the follow-up, only one abnormality (AgNORs) was found in one case. The combined cytochemical analysis of DPP IV, nuclear DNA content, and quantitative evaluation of interphase AgNORs in biopsy samples may contribute to the differential diagnosis of hepatocellular nodules of uncertain type in the cirrhotic liver. PMID- 8674405 TI - Tauroursodeoxycholic acid for treatment of primary biliary cirrhosis. A dose response study. AB - Tauroursodeoxycholic acid, a highly hydrophilic bile acid, may be of therapeutic value for chronic cholestatic liver diseases. We performed a dose-response study on 24 patients with primary biliary cirrhosis who were randomly assigned to receive 500, 1000, or 1500 mg daily of tauroursodeoxycholic acid for six months. Biliary enrichment with ursodeoxycholic acid ranged from 15% to 48% and was not related with the dose. Serum liver enzyme levels decreased significantly after the first month of treatment with all the three doses. No significant difference among the three doses was found, although further reduction over time occurred with 1000 and 1500mg daily. Plasma total and HDL cholesterol significantly decreased in patients administered the two higher doses. Diarrhea was the only side effect. In conclusion, a dose of about 10mg/kg body wt/day of tauroursodeoxycholic acid should be used for long-term studies in patients with primary biliary cirrhosis. PMID- 8674406 TI - Splenic arteriovenous fistula. A rare lesion causing bleeding esophageal varices, ascites, and diarrhea. AB - We report the case of a 39-year-old woman with portal hypertension caused by a splenic arteriovenous fistula that was diagnosed by Doppler ultrasound and splenic arteriography. She presented with esophageal variceal hemorrhage and was initially treated with sclerotherapy. Ascites and secretory diarrhea then developed. At laparotomy portal pressure was 60 cm H2O but fell to 26 cm H2O after the fistula was resected with a splenectomy. All symptoms disappeared shortly thereafter, and the patient has remained well for the past two years. PMID- 8674407 TI - Subcellular localization of Suppressor of Hairless in Drosophila sense organ cells during Notch signalling. AB - During imaginal development of Drosophila, Suppressor of Hairless [Su(H)], an evolutionarily conserved transcription factor that mediates intracellular signalling by the Notch (N) receptor, controls successive alternative cell fate decisions leading to the differentiation of multicellular sensory organs. We describe here the distribution of the Su(H) protein in the wing disc epithelium throughout development of adult sense organs. Su(H) was found to be evenly distributed in the nuclei of all imaginal disc cells during sensory organ precursor cells selection. Thus differential expression and/or subcellular localization of Su(H) is not essential for its function. Soon after division of the pIIa secondary precursor cell, Su(H) specifically accumulates in the nucleus of the future socket cell. At the onset of differentiation of the socket cell, Su(H) is also detected in the cytoplasm. In this differentiating cell, N and deltex participate in the cytoplasmic retention of Su(H). Still, Su(H) does not colocalize with N at the apical-lateral membranes. These observations suggest that N regulates in an indirect manner the cytoplasmic localization of Su(H) in the socket cell. Finally, the pIIb, shaft and socket cells are found to adopt invariant positions along the anteroposterior axis of the notum. This raises the possibility that tissue-polarity biases these N-mediated cell fate choices. PMID- 8674408 TI - The maize mutant narrow sheath fails to establish leaf margin identity in a meristematic domain. AB - The maize mutant narrow sheath (ns) displays a leaf shape and plant stature phenotype that suggests the preprimordial deletion of a leaf domain. The ns mutant phenotype is inherited as a recessive, duplicate-factor trait, conditioned upon homozygosity for each of the two unlinked mutations narrow sheath-1 (ns1) and narrow sheath-2 (ns2). Mutant leaves are missing a large domain including the leaf margin, and mutant internodes are shortened on the marginal side of the stem. This domain deletion extends from the internode to beyond the longitudinal mid-length of the blade, and corresponds to an alteration in the organization of a specific region of the shoot apical meristem. The premargin region of mutant founder cells fail to down-regulate expression of Knox genes, markers of nonleaf meristematic identity. Our results indicate that leaf domains may acquire identity in the meristem itself, and that the subdivision of preprimordial developmental fields into differential domains is a common feature of both plant and animal organogenesis. PMID- 8674409 TI - Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis. AB - Epithelial-mesenchymal interactions are critical for the branching and differentiation of the lung, but the mechanisms involved are still unclear. To investigate this problem in mouse embryonic lung, we have studied the temporal and spatial expression of genes implicated in the morphogenesis of other organs. At 11.5 days p.c., hepatocyte nuclear factor-3beta (Hnf-3beta) is expressed uniformly throughout the epithelium, while Wnt-2 expression is confined to the distal mesenchyme. Sonic hedgehog (Shh) transcripts are found throughout the epithelium, with high levels in the distal tips of the terminal buds, while bone morphogenetic protein-4 (Bmp-4) transcripts are localized at high levels in the distal tips of the epithelium, with lower levels in the adjacent mesenchyme. Epithelial expression is also seen for Bmp-7, but transcripts are less dramatically upregulated at the distal tips. The Type I Bone morphogenetic protein receptor gene (Bmpr/Tfr-11/Brk-1) is expressed at low levels in the epithelium and in the distal mesenchyme. To investigate the role of Bmp-4 in lung development, we have misexpressed the gene throughout the distal epithelium of transgenic lungs using a surfactant protein C enhancer/promoter. From 15.5 days p.c., transgenic lungs are smaller than normal, with grossly distended terminal buds and, at birth, contain large air-filled sacs which do not support normal lung function. Labeling with BrdU reveals an inhibition of epithelia] proliferation in 15.5 days p.c. transgenic lungs. A small but significant stimulation of proliferation of mesenchymal cells is also observed, but this is accompanied by an increase in cell death. In situ hybridization with riboprobes for the proximal airway marker, CC10, and the distal airway marker, SP-C, shows normal differentiation of bronchiolar Clara cells but a reduction in the number of differentiated Type II cells in transgenic lungs. A model is proposed for the role of BMP4 and other signalling molecules in embryonic lung morphogenesis. PMID- 8674410 TI - Inhibition of testicular germ cell apoptosis and differentiation in mice misexpressing Bcl-2 in spermatogonia. AB - During normal spermatogenesis, more than half of the germ cells undergo apoptosis, but the physiological significance and molecular mechanisms of this programmed cell death are largely unknown. Because Bcl-2 functions as a death repressor, we have investigated the effect of misexpressing Bcl-2 in spermatogonia in transgenic mice using the human bcl-2 cDNA under the control of the human polypeptide chain elongation factor 1alpha (EF-1alpha) promoter. In the 2-week-old transgenic testes, exogenous Bcl-2 was expressed in spermatogonia and massive accumulation of spermatogonia was observed in seminiferous tubules by 4 weeks. At this time, only a few spermatocytes were apparent, and the accumulated cells degenerated, leading to vacuolization in some seminiferous tubules by 7 weeks. In older transgenic mice, abnormal accumulation of spermatogonia and degeneration of these germ cells was still observed, but some seminiferous tubules in which the level of Bcl-2 expression was reduced recovered normal spermatogenesis. These observations indicate that spermatogonial apoptosis is part of the normal program of mammalian spermatogenesis and is regulated by a pathway affected by Bcl-2. PMID- 8674411 TI - Regulation of dorsal-ventral patterning: the ventralizing effects of the novel Xenopus homeobox gene Vox. AB - The formation of the dorsal-ventral axis in Xenopus laevis is elicited by a signaling cascade on the dorsal side of the embryo initiated by cortical rotation. These early developmental events impart an initial axial polarity to the embryo. By the time gastrulation occurs, the embryo has established opposing dorsal and ventral regulatory regions. Through a dynamic process, the embryo acquires a definitive pattern that reflects the distribution of future cell fates. Here we present a novel homeobox gene, Vox, whose expression reflects this dynamic process. Vox is first expressed throughout the embryo and subsequently eliminated from the notochord and neural plate. Ectopic expression of Vox demonstrates that the normal function of this gene may be to suppress dorsal genes such as Xnot and chordin, and induce ventral and paraxial genes such as Bmp 4 and MyoD. Ectopic expression of BMP-4 ventralizes embryos and positively regulates the expression of Vox, suggesting that these genes are components of a reciprocal regulatory network. PMID- 8674412 TI - Expression and function of matrix metalloproteinases and their inhibitors at the maternal-embryonic boundary during mouse embryo implantation. AB - Gelatinase B, a matrix metalloproteinase (MMP) of high specific activity, is highly expressed and activated by mouse blastocysts in culture, and inhibition of this enzyme activity inhibits lysis of extracellular matrix (Behrendtsen, O., Alexander, C. M. and Werb, Z. (1992) Development 114, 447-456). Because gelatinase B expression is linked to invasive potential, we studied the expression of gelatinase B mRNA and protein in vivo, in implanting trophoblast giant cells, and found that it was expressed and activated during colonization of the maternal decidua. mRNAs for several other MMPs (stromelysin-1, stromelysin-3 and gelatinase A) and MMP inhibitors (TIMP-1 and TIMP-2) were expressed in the undifferentiated stroma toward the outside of the decidua, and TIMP-3 mRNA was expressed in primary and some mature decidual cells during their differentiation. Both mRNA and TIMP-3 protein were present at high concentrations transiently, and declined from 6.5 days post coitum onward, as the cells underwent apoptosis during the main period of gelatinase B expression and ectoplacental growth and expansion. To assess the function of MMPs during implantation and decidual development, we either injected a peptide hydroxamate MMP inhibitor into normal mice or studied transgenic mice overexpressing TIMP-1. In both cases, decidual length and overall size were reduced, and the embryo was displaced mesometrially. Embryo orientation was less strictly regulated in inhibitor-treated deciduae than in control deciduae. Morphogenesis and development of oil-induced deciduomas were also slowed in the presence of the inhibitor. We conclude that administration of MMP inhibitors retards decidual remodeling and growth, and we suggest that the MMPs expressed in precursor stromal cells promote their differentiation and expansion. PMID- 8674413 TI - Involvement of FGF-8 in initiation, outgrowth and patterning of the vertebrate limb. AB - Fibroblast Growth Factors (FGFs) are signaling molecules that are important in patterning and growth control during vertebrate limb development. Beads soaked in FGF-1, FGF-2 and FGF-4 are able to induce additional limbs when applied to the flank of young chick embryos (Cohn, M.J., Izpisua-Belmonte, J-C., Abud, H., Heath, J. K., Tickle, C. (1995) Cell 80, 739-746). However, biochemical and expression studies suggest that none of these FGFs is the endogenous signal that initiates limb development. During chick limb development, Fgf-8 transcripts are detected in the intermediate mesoderm and subsequently in the prelimb field ectoderm prior to the formation of the apical ectodermal ridge, structures required for limb initiation and outgrowth, respectively. Later on, Fgf-8 expression is restricted to the ridge cells and expression disappears when the ridge regresses. Application of FGF-8 protein to the flank induces the development of additional limbs. Moreover, we show that FGF-8 can replace the apical ectodermal ridge to maintain Shh expression and outgrowth and patterning of the developing chick limb. Furthermore, continuous and widespread misexpression of FGF-8 causes limb truncations and skeletal alterations with phocomelic or achondroplasia phenotype. Thus, FGF-8 appears to be a key signal involved in initiation, outgrowth and patterning of the developing vertebrate limb. PMID- 8674414 TI - Clustered arrangement of winged helix genes fkh-6 and MFH-1: possible implications for mesoderm development. AB - The 'winged helix' or 'forkhead' transcription factor gene family is defined by a common 100 amino acid DNA binding domain which is a variant of the helix-turn helix motif. Here we describe the structure and expression of the mouse fkh-6 and MFH-1 genes. Both genes are expressed in embryonic mesoderm from the headfold stage onward. Transcripts for both genes are localised mainly to mesenchymal tissues, fkh-6 mRNA is enriched in the mesenchyme of the gut, lung, tongue and head, whereas MFH-1 is expressed in somitic mesoderm, in the endocardium and blood vessels as well as the condensing mesenchyme of the bones and kidney and in head mesenchyme. Both genes are located within a 10 kb region (in mouse chromosome 8 at 5.26 +/- 2.56 cM telomeric to Actsk1. The close physical linkage of these two winged helix genes is conserved in man, where the two genes map to chromosome 16q22-24. This tandem arrangement suggests the common use of regulatory mechanisms. The fkh-6/MFH-1 locus maps close to the mouse mutation amputated, which is characterised by abnormal development of somitic and facial mesoderm. Based on the expression patterns we suggest that a mutation in MFH-1, not fkh-6 is the possible cause for the amputated phenotype. PMID- 8674416 TI - Complex expression of the zp-50 pou gene in the embryonic zebrafish brain is altered by overexpression of sonic hedgehog. AB - We report the characterization of the zebrafish zp-50 class III POU domain gene. This gene is first activated in the prospective diencephalon after the end of the gastrula period. During somitogenesis, zp-50 is expressed in a very dynamic and complex fashion in all major subdivisions of the central nervous system. After one day of development, zp-50 transcripts are present in the fore- and midbrain in several distinct cell clusters. In the hindbrain, zp-50 expression is found in two types of domains. Correct zp-50 expression in the ventral fore- and midbrain requires genes known to be involved in dorsoventral patterning of the zebrafish CNS. Transcripts of the sonic hedgehog (shh) gene encoding an intercellular signaling molecule are detected in the forming diencephalon shortly prior to the appearance of zp-50 mRNA. Correct expression in this region of both shh, and zp 50, requires a functional cyclops (cyc) locus: shh and zp-50 transcripts are likewise absent from the ventral rostral brain of mutant cyc-/- embryos. Injection of synthetic shh mRNA into fertilized eggs causes ectopic zp-50 expression at more dorsal positions of the embryonic brain. The close spatial and temporal coincidence of expression in the rostral brain, the similar response to the cyc- mutation, and the ectopic zp-50 expression in the injection experiments all suggest that zp-50 may directly respond to the reception of the Shh signal. PMID- 8674415 TI - Amphiregulin in lung branching morphogenesis: interaction with heparan sulfate proteoglycan modulates cell proliferation. AB - Epithelial and mesenchymal cells isolated from mouse embryonic lungs synthesized and responded to amphiregulin (AR) in a different fashion. Mesenchymal cells produced and deposited 3- to 4-fold more AR than epithelial cells, proliferated in the presence of exogenous AR, and their spontaneous growth was blocked by up to 85% by anti-AR antibodies. In contrast, epithelial cells exhibited a broad response to this growth regulator factor depending on whether they were supplemented with extracellular matrix (ECM) and whether this ECM was of epithelial or mesenchymal origin. AR-treated epithelial cells proliferated by up to 3-fold in the presence of mesenchymal-deposited ECM, remained unchanged in the presence of epithelial-deposited ECM, and decreased in their proliferation rate below controls in the absence of ECM supplementation. This effect was abolished by treatment with the glycosaminoglycan-degrading enzymes heparinase and heparitinase suggesting the specific involvement of heparan sulfate proteoglycan (HSPG) in AR-mediated cell proliferation. In whole lung explants, branching morphogenesis was inhibited by antibodies against the AR heparan sulfate binding site and stimulated by exogenous AR. Since during development, epithelial cells are in contact with mesenchymal ECM at the tips of the growing buds and alongside the basement membrane, focal variations in the proportion of epithelial and mesenchymal HSPG will focally affect epithelial proliferation rates. Therefore, AR-HSPG interaction may underlie the process of branching morphogenesis by inducing differential cell proliferation. PMID- 8674417 TI - Distinct mitogenic and cell fate specification functions of wingless in different regions of the wing. AB - Patterning and proliferation are coordinately controlled in the development of Drosophila imaginal discs. Localized expression of decapentaplegic (dpp) at the anterior-posterior and wingless (wg) at the dorsal-ventral compartment boundaries controls growth of the wing with respect to the A/P and D/V axes. The growth promoting effects of these organizers are thought to be indirect, since growth is dispersed throughout the disc, and is not localized near the sources of wg or dpp. wg has also been implicated in proximal-distal patterning of the wing hinge. In this report, we present evidence that wg is principally required for local cell proliferation in the hinge. Loss of wg expression leads to a local reduction in cell division, resulting in the deletion of a distinct set of wing hinge structures. Ectopic activation of the wg pathway in cells of the wing hinge leads to overproliferation without repatterning, indicating that wg acts as a mitogen in this part of the disc. By contrast, overexpression of wg in the wing blade leads to repatterning and only secondarily to proliferation. These results suggest that the Wg signal elicits very different responses in different regions of the wing imaginal disc. PMID- 8674418 TI - An inductive interaction in 4-cell stage C. elegans embryos involves APX-1 expression in the signalling cell. AB - During the 4-cell stage of C. elegans embryogenesis, the P2 blastomere provides a signal that allows two initially equivalent sister blastomeres, called ABa and ABp, to adopt different fates. Preventing P2 signalling in wild-type embryos results in defects in ABp development that are similar to those caused by mutations in the glp-1 and apx-1 genes, which are homologs of the Drosophila genes Notch and Delta, respectively. Previous studies have shown that GLP-1 protein is expressed in 4-cell stage embryos in both ABa and ABp. In this report, we show that APX-1 protein is expressed in the P2 blastomere and that a temperature-sensitive apx-1 mutant has a temperature-sensitive period between the 4-cell and 8-cell stages. We propose that APX-1 is part or all of the P2 signal that induces ABp to adopt a fate different than ABa. PMID- 8674419 TI - An HF-1a/HF-1b/MEF-2 combinatorial element confers cardiac ventricular specificity and established an anterior-posterior gradient of expression. AB - The molecular determinants that direct gene expression to the ventricles of the heart are for the most part unknown. Additionally, little data is available on how the anterior/posterior axis of the heart tube is determined and whether the left and right atrial and ventricular chambers are assigned as part of this process. Utilizing myosin light chain-2 ventricular promoter/beta-galactosidase reporter transgenes, we have determined the minimal cis-acting sequences required for ventricular-specific gene expression. In multiple independent transgenic mouse lines, we found that both a 250 base pair myosin light chain-2 ventricular promoter fragment, as well as a dimerized 28 bp sub-element (HF-1) containing binding sites for HF1a and HF1b/MEF2 factors, directed ventricular-specific reporter expression from as early as the endogenous gene, at day 7.5-8.0 post coitum. While the endogenous gene is expressed uniformly throughout both ventricles, the transgenes were expressed in a right ventricular/conotruncal dominant fashion, suggesting that they contain only a subset of the elements which respond to positional information in the developing heart tube. Expression of the transgene was cell autonomous and its temporospatial characteristics not affected by mouse strain/methylation state of the genome. To determine whether ventricular-specific expression of the transgene was dependent upon regulatory genes required for correct ventricular differentiation, the 250 base pair transgene was bred into both retinoid X receptoralpha and Nkx2-5 null backgrounds. The transgene was expressed in both mutant backgrounds, despite the absence of endogenous myosin light chain-2 ventricular transcript in Nkx2-5 null embryos. Ventricular specification, as judged by transgene expression, appeared to occur normally in both mutants. Thus, the HF-1 element, directs chamber specific transcription of a transgene reporter independently of retinoid X receptoralpha and Nkx2-5, and defines a minimal combinatorial pathway for ventricular chamber gene expression. The patterned expression of this transgene may provide a model system in which to investigate the cues that dictate anterior posterior (right ventricle/left ventricle) gradients during mammalian heart development. PMID- 8674420 TI - LOP1: a gene involved in auxin transport and vascular patterning in Arabidopsis. AB - We have taken a genetic approach to understanding the mechanisms that control vascular patterning in the leaves of higher plants. Here we present the identification and characterization of the lop1 mutant of Arabidopsis which is defective in basipetal transport of IAA. Mutant leaf midveins show disoriented axial growth, and bifurcation into twin veins that are frequently rotated out of the normal dorsal/ventral axis of the leaf. Mutant plants also display abnormal patterns of cell expansion in the midrib cortex and in the epidermis of the elongation zone of lateral roots. Lateral roots show abnormal curvature during initiation, sometimes encircling the primary root prior to growth in a normal downward direction. Mutant seedlings have normal levels of free IAA, and appear normal in auxin perception, suggesting that transport is the primary lesion. The abnormalities in vascular development, lateral root initiation and patterns of cell expansion observed in the lop] mutant are consistent with a basic disruption in basipetal transport of IAA. PMID- 8674421 TI - Activation of Fgf-4 and HoxD gene expression by BMP-2 expressing cells in the developing chick limb. AB - Bone morphogenetic protein-2 (BMP-2) has been implicated in the polarizing region signalling pathway, which specifies pattern across the antero-posterior of the developing vertebrate limb. Retinoic acid and Sonic Hedgehog (SHH) can act as polarizing signals; when applied anteriorly in the limb bud, they induce mirror image digit duplications and ectopic Bmp-2 expression in anterior mesenchyme. In addition, the two signals can activate Fgf-4 expression in anterior ridge and HoxD expression in anterior mesenchyme. We tested the role of BMP-2 in this signalling cascade by ectopically expressing human BMP-2 (hBMP-2) at the anterior margin of the early wing bud using a replication defective retroviral vector, and found that ectopic expression of Fgf-4 was induced in the anterior part of the apical ectodermal ridge, followed later by ectopic expression of Hoxd-11 and Hoxd 13 in anterior mesenchyme. This suggests that BMP-2 is involved in regulating Fgf 4 and HoxD gene expression in the normal limb bud. Ectopically expressed hBMP-2 also induced duplication of digit 2 and bifurcation of digit 3, but could not produce the mirror-image digit duplications obtained with SHH-expressing cells. These results suggest that BMP-2 may be involved primarily in maintenance of the ridge, and in the link between patterning and outgrowth of the limb bud. PMID- 8674422 TI - Expression of AmphiHox-1 and AmphiPax-1 in amphioxus embryos treated with retinoic acid: insights into evolution and patterning of the chordate nerve cord and pharynx. AB - Excess all-trans retinoic acid (RA) causes severe craniofacial malformations in vertebrate embryos: pharyngeal arches are fused or absent, and a rostrad expansion of Hoxb-1 expression in the hindbrain shows that anterior rhombomeres are homeotically respecified to a more posterior identity. As a corollary, neural crest migration into the pharyngeal arches is abnormal. We administered excess RA to developing amphioxus, the closest invertebrate relative of the vertebrates and thus a key organism for understanding evolution of the vertebrate body plan. In normal amphioxus, the nerve cord has only a slight anterior swelling, the cerebral vesicle, and apparently lacks migratory neural crest. Nevertheless, excess RA similarly affects amphioxus and vertebrates. The expression domain of AmphiHox-1 (homologous to mouse Hoxb-1) in the amphioxus nerve cord is also extended anteriorly. For both the amphioxus and mouse genes, excess RA causes either (1) continuous expression throughout the preotic hindbrain (mouse) and from the level of somite 7 to the anterior end of the nerve cord (amphioxus) or (2) discontinuous expression with a gap in rhombomere 3 (mouse) and a gap at the posterior end of the cerebral vesicle (amphioxus). A comparison of these expression patterns suggests that amphioxus has a homolog of the vertebrate hindbrain, both preotic and postotic. Although RA alters the expression of AmphiHox-1 expression in the amphioxus nerve cord, it does not alter the expression of AmphiHox-1 in presomitic mesoderm or of alkali myosin light chain (AmphiMlc-alk) in somites, and the axial musculature and notochord develop normally. The most striking morphogenetic effect of RA on amphioxus larvae is the failure of mouth and gill slits to form. In vertebrates effects of excess RA on pharyngeal development have been attributed solely to the abnormal migratory patterns of Hox-expressing cranial neural crest cells. This cannot be true for amphioxus because of the lack of migratory neural crest. Furthermore, expression of Hox genes in pharyngeal tissues of amphioxus has not yet been detected. However, the absence of gill slits in RA-treated amphioxus embryos correlates with an RA-induced failure of AmphiPax-1 to become down-regulated in regions of pharyngeal endoderm that would normally fuse with the overlying ectoderm. In vertebrates, RA might similarly act via Pax-1/9, also expressed in pharyngeal endoderm, to impair pharyngeal patterning. PMID- 8674423 TI - Cell fate determination in an annelid equivalence group. AB - In embryos of glossiphoniid leeches such as Helobdella triserialis and H. robusta, pairs of adjacent 'o/p' ectodermal blast cells are known to be developmentally equipotent and yet eventually contribute distinct sets of 'O' and 'P' progeny to the nervous system and epidermis of the mature leech. It has been thought that the fate-determining interactions in this 'O-P equivalence group' take place between the equipotent cells themselves. We show here that such intra group interactions are neither necessary nor sufficient. Instead, transient contact with cells in another ectodermal lineage is necessary and sufficient to induce o/p blast cells to assume the P fate. In the absence of this contact they assume the O fate. PMID- 8674424 TI - hedgehog, wingless and orthodenticle specify adult head development in Drosophila. AB - The adult head capsule of Drosophila forms primarily from the eye-antennal imaginal discs. Here, we demonstrate that the head primordium is patterned differently from the discs which give rise to the appendages. We show that the segment polarity genes hedgehog and wingless specify the identities of specific regions of the head capsule. During eye-antennal disc development, hedgehog and wingless expression initially overlap, but subsequently segregate. This regional segregation is critical to head specification and is regulated by the orthodenticle homeobox gene. We also show that orthodenticle is a candidate hedgehog target gene during early eye-antennal disc development. PMID- 8674425 TI - The Drosophila pipsqueak gene encodes a nuclear BTB-domain-containing protein required early in oogenesis. AB - Mutations at the pipsqueak locus affect early patterning in the Drosophila egg and embryo. We have cloned pipsqueak and found that it is a large and complex gene, encoding multiple transcripts and protein isoforms. One protein, PsqA, is absent in all of the mutants that we have examined. We show that PsqA is a nuclear protein present in the germ cells and somatically derived follicle cells throughout oogenesis and that it is required prior to stage one of oogenesis. PsqA contains a BTB (POZ) domain at its amino terminus; additionally, we have identified an evolutionarily conserved motif of unknown function present four times in tandem at the C terminus of the protein. PZ pipsqueak mutants produce a putative fusion protein containing the pipsqueak BTB domain fused to sequences resident on the PZ element (H. Horowitz and C. Berg, 1995 Genetics 139, 327-335). We demonstrate here that expression of this fusion protein in wild-type flies has a dominant effect, resulting in infertility and eggshell defects. These dominant phenotypes are discussed in light of current theories on the role of the BTB domain in protein-protein interactions. PMID- 8674427 TI - Cellular mechanisms of epiboly in leech embryos. AB - Gastrulation in leech embryos is dominated by the epibolic movements of two tissues: germinal bands, composed of segmental precursor cells, and an overlying epithelium that is part of a provisional integument. During gastrulation, the germinal bands move over the surface of the embryo and coalesce along the prospective ventral midline. Concurrently, the epithelium spreads to cover the embryo. We have begun to analyze the mechanisms involved in gastrulation in the leech by assessing the independent contributions of the epithelium and the germinal bands to these cell movements. Here we describe cellular events during epiboly in normal embryos and in embryos perturbed by either reducing the number of cells in the epithelium, or by preventing the formation of the germinal bands, or both. These experiments indicate that both the germinal bands and the epithelium are able to undergo epibolic movements independently, although each is required for the other to behave as in control embryos. PMID- 8674426 TI - Anteroposterior patterning in the zebrafish, Danio rerio: an explant assay reveals inductive and suppressive cell interactions. AB - We report the first extended culture system for analysing zebrafish (Danio rerio) embryogenesis with which we demonstrate neural induction and anteroposterior patterning. Explants from the animal pole region of blastula embryos ('animal caps') survived for at least two days and increased in cell number. Mesodermal and neural-specific genes were not expressed in cultured animal caps, although low levels of the dorsoanterior marker otx2 were seen. In contrast, we observed strong expression of gta3, a ventral marker and cyt1, a novel type I cytokeratin expressed in the outer enveloping layer. Isolated 'embryonic shield', that corresponds to the amphibian organizer and amniote node, went on to express the mesodermal genes gsc and ntl, otx2, the anterior neural marker pax6, and posterior neural markers eng3 and krx20. The expression of these genes defined a precise anteroposterior axis in shield explants. When conjugated to animal caps, the shield frequently induced expression of anterior neural markers. More posterior markers were rarely induced, suggesting that anterior and posterior neural induction are separable events. Mesodermal genes were also seldom activated in animal caps by the shield, demonstrating that neural induction did not require co-induction of mesoderm in the caps. Strikingly, ventral marginal zone explants suppressed the low levels of otx2 in animal caps, indicating that ventral tissues may play an active role in axial patterning. These data suggest that anteroposterior patterning in the zebrafish is a multi-step process. PMID- 8674428 TI - In vitro and transgenic analysis of a human HOXD4 retinoid-responsive enhancer. AB - Expression of vertebrate Hox genes is regulated by retinoids in cell culture and in early embryonic development. We have identified a 185-bp retinoid-responsive transcriptional enhancer 5' of the human HOXD4 gene, which regulates inducibility of the gene in embryonal carcinoma cells through a pattern of DNA-protein interaction on at least two distinct elements. One of these elements contains a direct repeat mediating ligand-dependent interaction with retinoic acid receptors, and is necessary though not sufficient for the enhancer function. The HOXD4 enhancer directs expression of a lacZ reporter gene in the neural tube of transgenic mouse embryos in a time-regulated and regionally restricted fashion, reproducing part of the anterior neuroectodermal expression pattern of the endogenous Hoxd-4 gene. Administration of retinoic acid to developing embryos causes alterations in the spatial restriction of the transgene expression domain, indicating that the HOXD4 enhancer is also a retinoid-responsive element in vivo. The timing of the retinoic acid response differs from that seen with more 3' Hox genes, in that it occurs much later. This shows that the temporal window of competence in the ability to respond to retinoic acid differs between Hox genes and can be linked to specific enhancers. Mutations in the direct repeat or in a second element in the enhancer affect both retinoid response in culture and developmental regulation in embryos, suggesting that co-operative interactions between different factors mediate the enhancer activity. These data provide further support for a role of endogenous retinoids in regulation and spatial restriction of Hox gene expression in the central nervous system. PMID- 8674429 TI - Salivary duct determination in Drosophila: roles of the EGF receptor signalling pathway and the transcription factors fork head and trachealess. AB - Organogenesis in Drosophila embryos begins at 4-5 hours of development as the expression of organ-specific genes is initiated. The salivary primordium, which occupies the ventral epidermis of parasegment 2, is among the earliest to be defined. It is soon divided into two distinct regions: the more dorsal pregland cells and the more ventral preduct cells. We show that it is the opposing activities of the Drosophila EGF receptor (DER) signaling pathway and the Fork head transcription factor that distinguish these cell types and set up the boundary between them. DER signaling acts ventrally to block fork head expression in the preduct cells, thereby restricting gland identity to the more dorsal cells. Fork head in turn blocks expression of duct-specific genes in the pregland cells, thereby restricting duct identity to the more ventral cells. A third regulatory activity, the Trachealess transcription factor, is also required to establish the identity of the preduct cells, but we show that it acts independently or downstream from the DER:fork head confrontation. In trachealess mutants, subdivision of the salivary primordium occurs normally and the dorsal cells form glands, but the ventral cells are undetermined. We present a model proposing that trachealess is the crucial duct-specific gene that Fork head represses to distinguish pregland from preduct cells. PMID- 8674430 TI - Renal agenesis and hypodysplasia in ret-k- mutant mice result from defects in ureteric bud development. AB - The c-ret gene encodes a receptor tyrosine kinase that is expressed in the Wolffian duct and ureteric bud of the developing excretory system. Newborn mice homozygous for a mutation in c-ret displayed renal agenesis or severe hypodysplasia, suggesting a critical role for this gene in metanephric kidney development. To investigate the embryological basis of these defects, we characterized the early development of the excretory system in mutant homozygotes, and observed a range of defects in the formation, growth and branching of the ureteric bud, which account for the spectrum of renal defects seen at birth. Co-culture of isolated ureteric buds and metanephric mesenchyme show that the primary defect is intrinsic to the ureteric bud. While the mutant bud failed to respond to induction by wild-type mesenchyme, mutant mesenchyme was competent to induce the growth and branching of the wild-type bud. Furthermore, the mutant metanephric mesenchyme displayed a normal capacity to differentiate into nephric tubules when co-cultured with embryonic spinal cord. These findings suggest a model in which c-ret encodes the receptor for a (yet to be identified) factor produced by the metanephric mesenchyme, which mediates the inductive effects of this tissue upon the ureteric bud. This factor appears to stimulate the initial evagination of the ureteric bud from the Wolffian duct, as well as its subsequent growth and branching. PMID- 8674431 TI - Reorganization of membrane contacts prior to apoptosis in the Drosophila retina: the role of the IrreC-rst protein. AB - The final step of pattern formation in the developing retina of Drosophila is the elimination of excess cells between ommatidia and the differentiation of the remaining cells into secondary and tertiary pigment cells. Temporally and spatially highly regulated expression of the irregular chiasmC-roughest protein, an adhesion molecule of the immunoglobulin superfamily known to be involved in axonal pathfinding, is essential for correct sorting of cell-cell contacts in the pupal retina without which the ensuing wave of apoptosis does not occur. Irregular chiasmC-roughest accumulates strongly at the borders between primary pigment and interommatidial cells. Mutant and misexpression analysis show that this accumulation of the irregular chiasmC-roughest protein is necessary for aligning interommatidial cells in a single row. This reorganisation is a prerequisite for the identification of death candidates. Irregular chiasmC roughest function in retinal development demonstrates the importance of specific cell contacts for assignment of the apoptotic fate. PMID- 8674432 TI - Isolation and characterization of two new morphogenetically active peptides from Hydra vulgaris. AB - Foot-specific differentiation processes in hydra are controlled by activating and inhibiting potentials. In an attempt to understand the molecular mechanisms underlying these processes, two substances were isolated from Hydra vulgaris that stimulate foot-specific differentiation measured as acceleration of foot regeneration. These substances were shown to be peptides of 13 and 21 amino acids, respectively, with sequences that bear no significant homology to known peptides or proteins. Polyclonal antibodies were raised against both peptides. The data obtained by biological and radioimmunoassays show that the shorter peptide, pedin, is an excellent candidate for a major component of the 'foot activating potential'. PMID- 8674434 TI - Activation of p90rsk during meiotic maturation and first mitosis in mouse oocytes and eggs: MAP kinase-independent and -dependent activation. AB - Mitogen-activated protein kinases (MAPK) become activated during the meiotic maturation of oocytes from many species; however, their molecular targets remain unknown. This led us to characterize the activation of the ribosomal subunit S6 kinase of Mr 82 X 10(3) - 92 X 10(3) (p90rsk; a major substrate of MAPK in somatic cells) in maturing mouse oocytes and during the first cell cycle of the mouse embryo. We assessed the phosphorylation state of p90rsk by examining the electrophoretic mobility shifts on immunoblots and measured the kinase activity of immunoprecipitated p90rsk on a S6-derived peptide. Germinal vesicle stage (GV) oocytes contained a doublet of Mr 82 x 10(3) and 84 x 10(3) with a low S6 peptide kinase activity (12% of the maximum level found in metaphase II oocytes). A band of Mr 86 x 10(3) was first observed 30 minutes after GV breakdown (GVBD) and became prominent within 2 to 3 hours. MAPK was not phosphorylated 1 hour after GVBD, when the p90rsk-specific S6 kinase activity reached 37 % of the M II level. 2 hours after GVBD, MAPK became phosphorylated and p90rsk kinase activity reached 86% of the maximum level. The p90rsk band of Mr 88 x 10(3), present in mature M II oocytes when S6 peptide kinase activity is maximum, appeared when MAPK phosphorylation was nearly complete (2.5 hours after GVBD). In activated eggs, the dephosphorylation of p90rsk to Mr 86 X 10(3) starts about 1 hour after the onset of pronuclei formation and continues very slowly until the beginning of mitosis, when the doublet of Mr 82 X 10(3) and 84 X 10(3) reappears. A role for a M-phase activated kinase (like p34cdc2) in p90rsk activation was suggested by the reappearance of the Mr 86 X 10(3) band during first mitosis and in 1-cell embryos arrested in M phase by nocodazole. The requirement of MAPK for the full activation of p90rsk during meiosis was demonstrated by the absence of the fully active Mr 88 X 10(3) band in maturing c-mos -/- oocytes, where MAPK is not activated. The inhibition of kinase activity in activated eggs by 6-DMAP after second polar body extrusion provided evidence that both MAPK- and p90rsk-specific phosphatases are activated at approximately the same time prior to pronuclei formation. PMID- 8674433 TI - Position-effect variegation in Drosophila depends on dose of the gene encoding the E2F transcriptional activator and cell cycle regulator. AB - A dominant mutation due to the insertion of a P-element at 93E on the third chromosome of Drosophila melanogaster enhances position-effect variegation. The corresponding gene was cloned by transposon tagging and the sequence of the transcript revealed that it corresponds to the gene encoding the transcriptional activator and cell cycle regulator dE2F. The transposon-tagged allele is homozygous viable, and the insertion of the transposon in an intron correlates with a strong reduction in the amount of transcript. A homozygous lethal null allele was found to behave as a strong enhancer when heterozygous. Overexpression of the gene in transgenic flies has the opposite effect of suppressing variegation. A link is established here, and discussed, between the dose of a transcriptional activator, which controls the cell cycle, and epigenetic silencing of chromosomal domains in Drosophila. PMID- 8674435 TI - Degeneration of vestibular neurons in late embryogenesis of both heterozygous and homozygous BDNF null mutant mice. AB - The generation of mice lacking specific neurotrophins permits evaluation of the trophic requirements of particular neuronal populations throughout development. In the present study, we examined the developing vestibulocochlear system to determine the time course of neurotrophin dependence and to determine whether competition occurred among developing cochlear or vestibular neurons for available amounts of either brain-derived neurotrophic factor (BDNF) or neurotrophin-4/5 (NT-4/5). Both cochlear and vestibular neurons were present in mice lacking NT-4/5. In contrast, vestibular neurons decreased in number beginning at mid-stages of inner ear development, in mice lacking BDNF. Early in development (E12.5-13), the size of the vestibular ganglion was normal in bdnf -/ mice. Decreased innervation to vestibular sensory epithelia was detected at E13.5-15, when progressive loss of all afferent innervation to the semicircular canals and reduced innervation to the utricle and saccule were observed. At E16.5 17, there was a reduction in the number of vestibular neurons in bdnf -/- mice. A further decrease in vestibular neurons was observed at P1 and P15. Compared to bdnf -/- mice, mice heterozygous for the BDNF null mutation (bdnf +/-) showed an intermediate decrease in the number of vestibular neurons from E16.5-P15. These data indicate a late developmental requirement of vestibular neurons for BDNF and suggest competition among these neurons for limited supplies of this factor. PMID- 8674436 TI - Mesoderm and endoderm differentiation in animal cap explants: identification of the HNF4-binding site as an activin A responsive element in the Xenopus HNF1alpha promoter. AB - The gene encoding the tissue-specific transcription factor HNF1alpha (LFB1) is transcriptionally activated shortly after mid-blastula transition in Xenopus embryos. We have now shown that the HNF1alpha protein is localized in the nuclei of the liver, gall bladder, gut and pronephros of the developing larvae. In animal cap explants treated with activin A together with retinoic acid, we induced HNF1alpha in pronephric tubules and epithelial gut cells, i.e. in mesodermal as well as in endodermal tissues. HNF1alpha can also be induced by activin A, but not by retinoic acid alone. To define the promoter element responding to the activin A signal, we injected various HNF1alpha promoter luciferase constructs into fertilized eggs and cultured the isolated animal caps in the presence of activin A. From the activity profiles of the promoter mutants used, we identified the HNF4-binding site as an activin-A-responsive element. As HNF4 is a maternal protein in Xenopus and localized in an animal-to-vegetal gradient in the cleaving embryo, we speculate that the activin A signal emanating from the vegetal pole cooperates with the maternal transcription factor HNF4 to define the embryonic regions expressing HNF1alpha. PMID- 8674437 TI - Alternatively spliced forms of the Drosophila alphaPS2 subunit of integrin are sufficient for viability and can replace the function of the alphaPS1 subunit of integrin in the retina. AB - The Drosophila inflated (if) gene encodes the alphaPS2 subunit of the PS family of integrins. The if transcript is spliced such that alphaPS2 is found in two alternative forms, alphaPS2(C) and alphaPS2(m8), which differ by 25 amino acid residues in a region shown to affect cation requirements and ligand specificity. In this study, we examine the functional significance of the protein isoforms of if by analyzing the ability of transgenes producing only one isoform to rescue developmental abnormalities associated with complete loss of PS2 integrin. We find that either form of alphaPS2 is sufficient to rescue if- animals to viability; however, the alphaPS2(C) form promotes higher survival of the organism. Furthermore, these studies suggest distinct roles for alphaPS2(C) and alphaPS2(m8) during development. When expressed in the developing wing, alphaPS2(m8) is more efficient at rescuing the if wing blister phenotype than is alphaPS2(C). Expression of alphaPS2(C) in the eye produces dominant disruption of photoreceptor organization. We have also examined the ability of alphaPS2 and alphaPS1 to maintain photoreceptor organization in the Drosophila retina. Clonal analysis of sectioned eyes suggests a requirement for alphaPS1, but not alphaPS2. However, ectopic expression of if(m8) or if(C) shows that either splice form Of alphaPS2 can functionally replace alphaPS1 and rescue the mew eye phenotype. PMID- 8674438 TI - [The cholesterol hypothesis has been proved true at last]. PMID- 8674439 TI - [Sauna and congenital malformations--the myth and how it started]. PMID- 8674440 TI - [Current genetic linkages of Alzheimer's disease]. PMID- 8674441 TI - [Alzheimer's disease and the association of genetic polymorphism of apolipoprotein E and liquor beta protein in Finns]. PMID- 8674442 TI - [Reconstructive surgery of the deep veins of the lower extremities]. PMID- 8674443 TI - [The problem of recognizing depression in primary care]. PMID- 8674444 TI - [Serum thymidine kinase in the monitoring of lymphoma patients]. PMID- 8674445 TI - [Progressive paraparesis]. PMID- 8674446 TI - [Ring chromosome 9]. PMID- 8674447 TI - [Growth retardation in an asthmatic child]. PMID- 8674448 TI - [Thrombosis of the internal jugular vein as a cause of neck pain]. PMID- 8674449 TI - [Endocarditis caused by Staphylococcus lugdunensis leading to death]. PMID- 8674450 TI - [Photosensitivity]. PMID- 8674452 TI - [Response to Kari Salmisen's letter]. PMID- 8674451 TI - [When should a child be suspected of having a malignancy?]. PMID- 8674453 TI - [100 years x-rays]. PMID- 8674454 TI - [Fibrin glue]. PMID- 8674455 TI - [Effect of home-based family counseling on the mental health of youths--15-year follow-up study]. PMID- 8674456 TI - [Treatment of caustic ingestion in children]. PMID- 8674457 TI - [A rare lymphoma of the skin of the ear canal in an old man using a hearing aid]. PMID- 8674458 TI - [Chronic sarcoidosis--generalized disease, difficult to diagnose]. PMID- 8674459 TI - [Undiagnosed liver cirrhosis and laparotomy]. PMID- 8674460 TI - [Rehabilitation's viewpoint on phoniatrics]. PMID- 8674461 TI - [Technology for the diagnosis and rehabilitation of patients with dysphonia]. PMID- 8674462 TI - [Work and voice]. PMID- 8674463 TI - [Stuttering]. PMID- 8674464 TI - [Children with speech disorders]. PMID- 8674465 TI - ["Kukia poimi ja kukia kana, te sepele nista ja omaiesi ana"--developmental dyslexia]. PMID- 8674466 TI - [Erythrocyte ketone reductase activity, total plasma haloperidol and acute psychoses]. AB - Haloperidol (HAL) is a widely used and clinically effective neuroleptic. Its metabolism differs in various animal species. In humans, reduced haloperidol (RHAL), a hydroxy metabolite of HAL, is produced by a cytosolic ketone reductase. Interconversion is known to occur whereby HAL is found in the plasma after administration of RHAL in vivo. Interconversion of HAL and RHAL has been observed in man. However, the capacity for reductive HAL is greater than its oxidation back from RHAL. RHAL, the resulting metabolite of HAL, is reported to be about 10 25% as active as HAL in an animal model. Large intersubject variation has been observed in the pharmacokinetics of HAL and RHAL. A wide variation in reductive drug-metabolizing has been observed in schizophrenic patients treated with HAL. Both high and low RHAL/HAL ratios or RHAL levels were reported to be linked to poor response in HAL-treated patients and might be correlated with the therapeutic window effect of HAL treatment. It is conceivable, therefore, that subjects with high reductive capacity relative to oxidative capacity may have less therapeutic response from the same dose of HAL than those with a low reductive capacity relative to oxidative capacity. This aim of this study was to investigate the HAL reduction among a sample of HAL-treated schizophrenic patients. Because ketone reductases are generally not tissue specific, we investigate the reductase activity in Red blood cells (as described by Inaba), before and during the treatment. Steady-state plasma drug levels during 2 weeks of treatment were quantified. We examined the relationships between fixed doses of HAL treatment, Red blood cells ketone reductase activity, plasma HAL and RHAL levels and the percentage of change of the Positive and Negative Syndrome Scale for Schizophrenia. The participants in this study were 15 inpatients consecutively being treated in the adult psychiatric wards of the University of Lille. All subjects met DSM III-R criteria for schizophrenia (paranoid form). Upon induction subjects were evaluated clinically by trained raters using the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). Subjects were required to score 40 or higher on the general psychopathology subscale of the PANSS to continue participation. All subjects were drug free. Haloperidol was administered orally at three times daily dose. Patients were randomized to treatment at three orally fixed doses: 6 mg per day, 10 mg per day and 15 mg per day. Patients were treated for 2 periods of one week. At the end of each period, dosages could be modified according to the clinic evolution of the patient. PANSS was repeated by the same raters blinded to the haloperidol dosage, plasma concentration and Rbc haloperidol ketone reductase activity, at the beginning and at the end of each period. Blood samples were collected on the same day that clinical assessment were made. Multiple regression analysis (forward stepwise) revealed that Red blood cells reductase activity at D0 is an important variable predicting haloperidol plasma levels at week 2. Similarly Red blood cells reductase activity at D0 and D7 predicted Reduced haloperidol plasma concentrations at week 2. In this sample, no parameter was found to be consistency predicted the percentage change in the PANSS positive subscale from baseline, at week 2. Nevertheless, Red blood cells reductase activity at D0, Reduced haloperidol/haloperidol ratio at week 2, haloperidol plasma levels at week 2 and the dose of haloperidol at week 1 were important variables predicting the percentage change in the PANSS general subscale from baseline at week 2. These results suggest that the knowledge of reductase activity could predict the treatment response in acute schizophrenic patients. PMID- 8674467 TI - [Evaluation of autonomy in chronic mental patients. Problems, assessment tools, results]. AB - The autonomy of adult patients suffering from chronic psychiatric disorders is a notion in which we need to take an interest due to evolutions in patient care. The tendency of deinstitutionalization in the United States, in Italy and to a lesser degree in France has generated certain perverse effects when: capacities for self sufficiency, learning abilities to be developed, and substitutes to be set up, were not correctly evaluated from the outset. Many methods conceived mainly in the United States and in Canada were elaborated with such a diversity of approaches that, even today, for self-sufficiency, an instrument for evaluation which is universally prevalent and used, still does not exist in the way that has been possible for other clinical dimensions. The ability to accomplish the daily tasks for survival, the ability to reach decisions in life, the ability to enter into and sustain relationships with others do not embrace the dimensions explored by the scales of general psychopathology, of functional repercussions or of the quality of life. Moreover, the evaluation of these abilities is highly dependent on cultural characteristics. To adapt the existing methods to the French sociological realities or to conceive and elaborate simple and reliable procedures from our practices in professional and social reinsertion is a compulsory step in developing research in this field. Public Authorities and the teams on the ground should grasp the characteristics for innovation and its abilities for raising the hopes of patients, every bit as much as the actual progress in therapeutic practice. PMID- 8674468 TI - [Translation and validation of the Revised Social Anhedonia Scale (SAS Social Anhedonia Scale, M.L. Eckblad, L.J. Chapman et al., 1982). Study of the internal and concurrent validity in 126 normal subjects]. AB - The Revised Social Anhedonia Scale (SAS) with 40 items (Eckblad et al., 1982) which studies the social dimension of anhedonia has been validated in the United States (Mishlove & Chapman, 1985). However, no french translation and validation of this scale has been made to date. This work presents the french translation of the Social Anhedonia Scale and its validation. After a back-translation and final adjustment, it has been submitted to a sample of 126 control subjects from the general population. Furthermore, they were asked to fill two other scales: the Chapman Physical Anhedonia (PAS) with 61 items and the Fawcett Pleasure Scale (36 items), both of them exploring the subjects answer in terms of anhedonia/hedonia towards social, sensorial and/or physical experiences. The internal validity has been determined on the one hand by the Cronbach alpha coefficient which showed a strong unidimensional characteristic (0.80) and the other hand by the correlation of each item with the total score using the point biserial coefficient which ranged from .204 to .559. The concurrent validation has been determined by the Pearson correlation coefficient between the french version of social anhedonia scale and the french version of physical anhedonia scale. The values were .42, p = .001. Furthermore, this two scales are significant inversely correled to the french version of the pleasure scale: r = -.22, p = .0125 for the first, and r = .26, p = .0027 for the second. The internal and concurrent validity of the french version of the revised social anhedonia scale should allow to improve our understanding of anhedonia in psychiatry and psychopathology. PMID- 8674470 TI - [Anhedonia in schizophrenia]. AB - A study on 61 subjects who meet Spitzer's Research Diagnosis Criteria of schizophrenia and on 56 normal subjects has been conducted to explore anhedonia. Anhedonia was evaluated by two rating scales, the Physical Anhedonia Scale (PAS) and a sub-scale of physical pleasure (FCPCS-PP) extracted from the pleasure scale of Fawcett. The reliabilities of the scales were studied in the schizophrenic group by the Cronbach alpha and the Kuder Richardson (KR 20) coefficient and by the correlation between the two scales (concurrent validity). The Cronbach alpha was 0.77 for the FCPCS-PP and the KR 20 was 0.82 for the PAS. The correlation between the two scales was -0.37 (p < 0.01). The schizophrenics were significantly more anhedonic than normals with higher score on the PAS and with a lower score on the FCPCS-PP. Using the Beck Depression Inventory to rate depression in the schizophrenic group and to dichotomize these subjects into depressed schizophrenics and no depressed schizophrenics, we failed to find significantly differences concerning anhedonia scales between these two sub groups of schizophrenics. There was no difference between in and outpatients concerning the anhedonia scales. Our results suggest that anhedonia would be a possible marker of schizophrenic disease. The distribution of the anhedonia scales in the schizophrenic group is normal or unimodal and it doesn't support the hypothesis of a qualitative sub-group of schizophrenics characterised by severe anhedonia. PMID- 8674469 TI - [The dopamine transporter: characterization and physiopathologic implications]. AB - The dopamine transporter (DAT) is the carrier protein that transports dopamine across the presynaptic membrane. The DAT terminates the action of dopamine (DA) in the synapse via reuptake and thus regulates DA neurotransmission. The transporter has been studied by direct binding techniques using a variety of ligands which are inhibitors of DA transport. DAT binding, both in vivo (positron emission tomography) and in vitro (post mortem) may serve as a presynaptic marker to measure altered DA innervation in several neuropsychiatric diseases such as idiopathic Parkinson's disease, Tourette's disease, schizophrenia or cocaine addiction. In Parkinson's disease, a reduction in the density of binding sites could be due either to a degeneration of the terminal dopaminergic projections or to a compensatory readjustment in the level of dopamine synaptic transmission. This dopaminergic cell specific marker could also aid in attempts to elucidate the rate at which dopaminergic cells are lost in this disease. MPTP (a neurotoxin which induces a parkinsonian-like syndrome after conversion in MPP+) uses DAT to enter the neuron and exert its toxic effect which may be prevented by pretreatment with DA uptake blockers. In cocaine abuse, DAT mediates the addictive properties of cocaine. Cocaine binding sites on the carrier may be distinct from DA binding sites allowing the development of medication sparing the DA function but impairing the cocaine effects. In schizophrenia, functional DA uptake was reported to be increased in the striatum in post mortem brains, whereas the kinetic parameters of the uptake sites were unchanged using different transporter labeling ligands. Thus, this marker does not provide any evidence for the dopaminergic hypothesis, but an impairment of the DAT itself could possibly be involved in the etiology of schizophrenia. However, the possible interaction of drugs such as L-Dopa or neuroleptic treatment with transporter binding may be taken into account in the results analysis. Finally, the DAT gene is also an important candidate gene for psychiatric diseases such as schizophrenia or cocaine abuse. PMID- 8674471 TI - [Treatment of generalized anxiety: new pharmacologic approaches]. AB - First defined as a residual diagnostic category in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM), Generalized Anxiety Disorder (GAD) was until recently one of the least studied and least clearly conceptualized of the anxiety disorders. The clinical definition of GAD has however improved up to the fourth edition of the DSM where the disorder is now characterized as a chronic state of apprehensive expectation and uncontrollable worry concerning multiple daily life events or activities and accompanied with at least 3 symptoms belonging to a list of six common manifestations of psychic or motor tension. Clinical research demonstrating the stability and the specificity of somatic symptoms clearly support the validity of the diagnosis of GAD despite possible difficulties in the differential diagnosis with other chronic conditions or axis II disorders such as dysthymia or mixed anxiety-depressive disorder. After benzodiazepines (BZD) and 5-HT1A agonists like buspirone, several other types of new anxiolytic drugs have been developed for the treatment of GAD. Partial agonists at GABA-BZD receptor sites may offer the advantage of a better efficacy vs side-effects ratio over classical BZDs; however, systematic comparative clinical trials will have to demonstrate the clinical relevance of the encouraging results obtained with these drugs, at the experimental level, during studies in healthy volunteers and during the first placebo-controlled trials. Furthermore, the recent description of GABA-receptor's subunits clearly suggest that the development of drugs acting at this level and devoided of psychomotor or withdrawal side-effects is a target that is worth pursuing. On the other hand, the development of 5-HT2 and 5-HT3 antagonists is also of interest for the treatment of GAD since it could provide new anxiolytic drugs without these side-effects and thus easier to administer on a long-term basis corresponding to the chronicity of GAD. However, it will also be important to know if wether or not the efficacy of these new drugs, like that of buspirone, is associated with some effects on depressive symptomatology, develops only progressively over time and is different in previous BZD users compared to GAD patients who did not receive BZD before the new drug. Among these drugs in development for GAD, the most likely to reach the market in a near future are a BZD partial agonist (abecarnil), 5-HT1A agonists like ipsapirone and 5-HT3 antagonists like ondansetron. However, another area of new developments concerning the drug treatment of GAD is the use of antidepressants, which have demonstrated efficacy in this indication even in patients without depressive features or panic attacks symptoms. Considering the chronic nature of GAD, these drugs, like those acting on the 5-HT-system, would be more adapted than BZD for the long-term management of this condition. If confirmed by clinical trials involving antidepressants other than tricyclics, the efficacy of these drugs in GAD may suggest that common neurobiological mechanisms are involved in the pathogenesis of both anxiety and depressive disorders. Despite the potential interest of these new treatments of GAD, recent years have shown that the development of new anxiolytic drugs often appears limited by high-rates of placebo response in numerous clinical trials. This phenomenon may be related--in part--to the increasingly sophisticated designs used in such trials, such as extensive diagnostic workups, repeated evaluations and inclusion criteria selecting the less severe types of anxiety. As emphasized by other authors, much more research needs to be done to establish what effects various ways of conducting a trial have on the trial's results in order to facilitate the emergence of new psychopharmacological approaches in the treatment of GAD. PMID- 8674472 TI - [Porphyria variegata. Apropos of a case]. AB - A patient hospitalized because of somatic disturbances without any sign of detectable cerebral organicity and because of secondary anxiety disorder and major depression presents different clinical pictures with a neurological aspect. All this pictures, that evoke the diagnostic of hysteria conversion in particular, are complicated by a tetraplegia with emission of red urine that enable us to think of a diagnostic of hepatic-porphyria (variegata). Hereditary metabolic diseases, which categories of bioclinic symptoms (that enable us to evoke the diagnostic and to prevent the complications that are breeded by the prescription of forbidden drugs for ill subject) are reminded. PMID- 8674473 TI - [Electroconvulsive therapy and aortic aneurysm: apropos of a case]. AB - The adverse effects of electroconvulsive therapy (ECT) become rare due to the increased progress specially in avoiding cardiovascular side effects. In fact, several studies report ECT treatment performed with success and without side effects, in depressive patients presenting serious cardiovascular diseases (aortic anevrysm, cerebral venous angioma, cerebral infarct, aortic dissection...). Occurrence of cardiovascular complications can be prevented if an elevation of blood pressure or an arythmia occurring during the seizure are previously and correctly detected and managed. Hence an adequate anaesthetic premedication must be implemented. Usual protocols use atropine, hydralazine and hydro-chlorothiazide. However, ECT treatment should be avoided in patients requiring urgent surgical correction of their cardiovascular abnormalities. Also, patients and families must be informed on the benefit derived from ECT treatment and reassured on the therapeutic issue when ECT treatment is correctly managed. This case report concerns an 89 year old woman presenting a melancholic depressive state complicated with an aortic anevrysm, successfully treated with ECT. PMID- 8674474 TI - [Capgras syndrome in adolescence: a review apropos of one case]. AB - The author report a case of Capgras' syndrome in a 12-years-old girl, who had been hospitalized for attacks of abdominal pain. These symptoms had gone on for two years and led twice to surgical interventions which did not find any organic etiology. Interviews with the girl showed that the abdominal pains were related to symptoms of typical panic attacks which lasted about 20 minutes. In some on them, she experienced multiple autoscopy and the "illusion des sosies", described by Capgras. Long-term evolution showed that Capgras' syndrome disappeared with improvement of the panic attacks, but ten years later the patient is still suffering from generalized anxiety. To our knowledge, no case, even in adult patients, was previously described in the context of panic attacks. Furthermore, Capgras' syndrome is particularly rare at adolescence. Our review of literature exhibits only 19 cases under 18. Diagnosis was available in 16 cases, and consisted of schizophrenia or schizophreniform psychosis in 62.5% of the cases. The others involved acute psychosis (2 cases), post-partum psychosis (1 case), drug-induced-psychosis (1 case), psychotic major depression (1 case), and post varicella encephalitis (1 case). The doubles (out of the 15 cases where relevant detail is available) included at least a parent in 92.9% of patients, a brother or sister in 35.7%, a member of the medical team in 21.4% and a grand-parent in 14.3%. PMID- 8674475 TI - [Is there a correlation between postpartum depression and parity?]. PMID- 8674476 TI - [Possible combination of clozapine and specific serotonin reuptake inhibitors?]. PMID- 8674477 TI - [French translation of the Social and Physical Anhedonia Scale of Chapman]. PMID- 8674479 TI - Symptom prevalence and worry about high voltage transmission lines. AB - Few studies have documented public perceptions of environmental health risks from exposure to overhead transmission lines. In particular, little information has been provided on the impact of worry on symptom prevalence in residents living adjacent to high voltage transmission lines. The current study assessed symptom prevalence and worry in 152 Orange County female residents living either adjacent to overhead transmission lines or one block away. Forty-five percent of the respondents were either very worried or somewhat worried about the transmission lines and 55% were slightly worried or not worried at all. Results indicated that for those who did not live on the easement level of worry did not affect the prevalence of health problems. For those who lived on the easement, the most worried respondents were more likely to report health problems. Disclosure of health problems may depend more on individuals' level of worry about rather than proximity to overhead transmission lines. Possible limitations of this study include personality variables such as hypochondriasis which were not assessed, recall bias, and social desirability. The homogeneity of subjects may also limit the generalizability of findings. PMID- 8674478 TI - Temperature, ambient ozone levels, and mortality during summer 1994, in Belgium. AB - The number of daily deaths, temperature, relative humidity, and 24-hr concentrations of main air pollutants observed during a heat wave (June 27-August 7, 1994) in Belgium were compared with those recorded before and after this heat wave. All these variables were averaged over the country. Expected mortality was calculated from daily deaths observed during the summers of 1985-1993. The influence of meteorological and air pollution variables on daily mortality was analyzed using generalized least-squares method. Mortality recorded during the heat wave was higher than expected: it increased by 9.4% in the age group 0-64 years (236 excess deaths; P < 0.001) and by 13.2% in the elderly (1168 excess deaths; P < 0.001). After the heat wave, mortality in the elderly was lower than expected (178 deficit deaths; P< 0.05); the net excess of mortality in the whole population amounted to 1226 deaths when accounting for this deficit. This increased mortality was associated with unusually high outdoor temperatures (range of daily mean: 15.3-27.5 degrees C) and elevated ozone levels (range of 24 hr concentration: 34.5-111.5 microg/m3). The duration of the ozone overexposure during the heat wave was also uncommon: half-hour concentrations of ozone exceeded, on an average, 100 microg/m3 for 8 consecutive hr. The number of daily deaths was mostly correlated with the mean daily temperature and 24-hr ozone concentration, both measured the day before. A synergy between temperature and ozone in their effects on mortality was also highlighted in both age groups. The product of the logarithm of temperature by the logarithm of ozone concentration, both measured the day before, contributed to 39.5% of the variance of the logarithm of daily deaths in elderly and to 4.5% in the age group 0-64 years. In conclusion, elevated outdoor temperatures combined with high ozone concentrations were assumed to be the likely cause of the important excess mortality observed in Belgium during the summer, 1994. PMID- 8674480 TI - On the association between canine malignant lymphoma and opportunity for exposure to 2,4-dichlorophenoxyacetic acid. AB - In response to criticisms raised regarding a case-control study of canine malignant lymphoma, the results of several ancillary analyses are reported. The case-control study demonstrated a significant association between risk for canine malignant lymphoma and the opportunity for exposure to 2,4-dichlorophenoxyacetic acid herbicides. It is demonstrated that risk estimates do not vary by type of control group (i.e., tumor control or nontumor control group), by method of response (i.e., self-administered or telephone interview), or by geographic area. Questions related to the potential for referral bias, supposed inconsistencies in subject responses regarding frequency of herbicide use, and ambiguities regarding exposure classification are also examined. PMID- 8674482 TI - Lead in house dust: relationships between exposure metrics. AB - This paper examines the quantitative relationships between dust loading, lead loading, and lead concentration in house dust. Bare floor, interior sill, and carpet dust samples were collected in 216 Jersey City, New Jersey, homes using quantitative wipe and vacuum sampling techniques. Comparison of wipe and vacuum sample distributions for these homes indicated that lead loading was more variable than dust loading or lead concentration measured on floors, sills, or carpets. These data also indicated that increased lead loading on carpets relative to sills or floors was due to higher dust loading on carpets. Correlation analysis of wipe samples indicated that dust loading was more strongly correlated with lead loading on floors (r = 0.73) than on sills (r = 0.53), that dust loading was not correlated with lead concentration on either surface, and that lead loading and lead concentration were more strongly correlated in samples collected from sills (r = 0.81) than from floors (r = 0.65). Most importantly, carpets and rugs served as large reservoirs for house dust and consequently were a large potential source of dust exposure in children's common microenvironments. PMID- 8674481 TI - Effects of simulated nuclear fuel particles on the histopathology and CYP enzymes in the rat lung and liver. AB - We studied both short-term (3 and 30 days) and long-term (3-24 months) effects of simulated nuclear fuel particles (neutron-activated UO2) on the rat lung and liver histopathology and cytochrome P450 (CYP) activities. In the short-term study, after a single intratracheal instillation with neutron-activated particles (administered activity 36 kBq), the lung histology revealed inflammation and a decrease in several lung testosterone hydroxylation levels. Liver exhibited normal histology but hepatic testosterone 7alpha-hydroxylase (T7alphaOH) was decreased by 30% at 3 days treatment with neutron-activated particles (9.3 kBq). At 30 days after treatment, hepatic T7alphaOH and testosterone 15alpha hydroxylase activities were enhanced by 70 and 40%, respectively. At the long term follow-up, benign and malignant lung tumors were observed but in the livers only slightly increased inflammation was found. At the 1.5-year follow-up (cumulated lung dose 0.4-0.66 Gy, 131 and 182 kBq), decreases in lung testosterone 6beta-hydroxylase (60%) and testosterone 6alpha-hydroxylase (30%) activities were found. In contrast to lungs, hepatic testosterone 16alpha hydroxylase activity decreased by 60-75% with both nonactivated and neutron activated particles. These findings indicate that when lung is exposed to nonactivated UO2 or beta-emitting UO2 particles they have differential effects on CYP enzymes in both the primary target organ (lung) and secondary tissue (liver). PMID- 8674483 TI - Analysis of induced sputum after air and ozone exposures in healthy subjects. AB - Exposure of healthy subjects to ozone is associated with increases in cellular and biochemical markers of inflammation in bronchoalveolar lavage fluid. To determine if analysis of induced sputum might similarly reveal the pulmonary inflammatory effects of ozone exposure, we performed cellular and biochemical analysis of induced sputum collected 4 hr after air and ozone (0.4 ppm for 2 hr) exposures from 10 healthy subjects (age 30.0 +/- 5.0 years; 5 females) in a randomized crossover study in which exposures were separated by 2 weeks. We found that the total number of nonsquamous cells was significantly higher after ozone exposure than after air exposure (7.4 vs 3.9 x 10(5)/ml, P < 0.05) as was the percentage of the nonsquamous cells that were neutrophils (80.0 +/- 7.0% vs 51.0 +/- 20.0%, P < 0.05) and the levels of myeloperoxidase in the sputum fluid phase (1.6 +/- 0.6 vs 1.3 +/- 0.6 microg/ml, P < 0.05). In addition, IL-6 and IL-8 levels were higher after ozone than after air exposures, but not significantly so (44.5 +/- 32.4 pg/ml vs 26.8 +/- 30.7 pg/ml, P = 0.11; 1.5 +/- 0.5 ng/ml vs 1.1 +/- 0.6 ng/ml, P = 0.09). Mucin-like glycoprotein levels were also not significantly different between exposures (1.6 +/- 0.9 mg/ml vs 1.3 +/- 1.0 mg/ml, P = 0.26). We conclude that analysis of induced sputum is a useful noninvasive method for studying the pulmonary response to ozone exposure in healthy subjects. PMID- 8674484 TI - Increased limbic system symptomatology and sensitizability of young adults with chemical and noise sensitivities. AB - We previously hypothesized that individual differences in (a) limbic system reactivity and (b) central nervous system sensitizability underlie vulnerability to environmental stimuli, not only in the controversial clinical condition multiple chemical sensitivity (MCS), but also in the general population. Earlier research has shown overlaps in the characteristics of persons who report noise and air pollutant sensitivities. This study assessed questionnaire responses of 897 young adult college students who reported high versus low frequency of illness from several environmental chemical odors and concomitantly high versus low sensitivity to environmental noise. Subjects who reported increased rates of illness from chemical odors with or without noise sensitivity scored significantly higher (P < 0.0001) on a measure of limbic system symptomatology derived from ictal sensory, somatic, mnemonic, and behavioral manifestations of temporal lobe epilepsy. The group rating high both for illness from chemicals and for noise sensitivity had characteristics predictive of heightened sensitizability from the animal research on time-dependent sensitization (progressive response amplification to repeated, intermittent stimuli over time): i.e., higher female to male ratio (gender risk factor), increased rates of drug abuse problems in blood relatives (genetic risk factor), trait shyness (hyperreactivity to novelty), and increased carbohydrate craving. Despite the increased family histories of drug abuse and levels of personal anxiety and depression, the chemical- and noise-sensitive group reported the lowest rates of current smoking or personal drug abuse problems and the highest frequency of illness from drinking a small amount of alcohol. Taken together, the findings suggest that limbic system dysfunction associates more with chemical than with noise sensitivity; that individuals with both chemical and noise sensitivity may be the most sensitizable subset of the population for prospective studies, and that, in their substance use patterns, young adults with both chemical and noise sensitivity are more similar to MCS patients than are their peers with chemical or noise sensitivity alone. PMID- 8674485 TI - Fine particulate air pollution and mortality in two Southern California counties. AB - Several epidemiologic studies have reported associations between respiratory disease and particulate matter less than 2.5 microns in diameter (PM2.5) or fine particles. However, since daily fine particulate data from ambient monitors are seldom available, many studies have used estimates of PM2.5 based on visual range observed at local airports. This paper examines the impact of visibility-based estimates of PM2.5 on mortality from 1980 through 1986 in San Bernardino and Riverside Counties, located in the Los Angeles metropolitan area. Multiple regression analysis was used to isolate the effects of estimated fine particles on mortality while controlling for covariates, including season, day of week, maximum temperature, and dew point. The results are dependent on season. During the summer quarters, there was a small but statistically significant association of estimated fine particles with both total mortality (RR = 1.03, 95% CI = 1.00 1.05, evaluated at the mean PM2.5 value of 32.5 microg/m3) and respiratory specific mortality. However, for the year taken as a whole, estimated fine particles were not associated with mortality (RR = 1.00; 95% CI = 0.99-1.02). The use of estimated fine particles introduces additional measurement error into the analysis. During the summer quarters, an effect of ozone on mortality was also detected, but this association could be due to confounding with temperature. Sensitivity analysis indicated that the fine particulate association found during the summer quarters was robust to alternative estimates deriving fine particles from visual range, alternative regression specifications, functional forms, and exposure averaging times. These findings are consistent with another recent study of mortality in Los Angeles County and add to the other findings of associations between particulate matter and various respiratory diseases outcomes. PMID- 8674486 TI - Anthropometric measurements of the Nilotic tribes in a refugee camp. AB - The heights and weights of 2,233 randomly selected adult Nilotic immigrants from Southern Sudan (50.8% Dinkas, 43.8% Nuers, 3.4% Anuaks and 2.0% Shilluks) that have settled in Itang, Southwestern Ethiopia were measured. The mean height, weight and body mass index [BMI = weight(kg)/the square of height(m2)] of men (N = 1,1618) were 175.9 + 9 cm) (+/- SD), 59.7 +/- 8 kg, and 19.4 +/- 2, respectively, and those of women (N = 615) were 169.0 +/- 7 cm, 54.0 +/- 8 kg, and 19.1 +/- 3, respectively. The mean height of Dinka men (176.4 +/- 9 cm) and Nuer men (175.7 +/- 9 cm) were significantly higher than that of Anuak men (171.7 +/- 8 cm) and Shilluk men (172.6 +/- 6.1 cm). The Nuer women's mean height, weight and BMI were significantly lower than those of the other tribes'. This study confirms that the Nilotics in Southern Sudan have slender bodies and are amongst the tallest in the world, and may attain greater height if priviledged with favourable environmental conditions during early childhood and adolescence, allowing full expression of the genetic material. PMID- 8674487 TI - Assessment of hospital management needs. AB - During 1993/94, a study was done through a mailed self-administered questionnaire to identify specific hospital management needs. Out of 73 hospitals, 29 (39.7%) were covered in the study. Of the 29 medical directors, 16 (55.2%) were general practitioners and 25 (86.2%) did not have any formal training in hospital management. Lack of financial resource, shortage of medical supplies and equipment and low motivation of health personnel were considered top problems. The need for improving hospitals by providing appropriate training, involving communities, developing strong supervision and control are suggested. PMID- 8674489 TI - The efficacy of oxamniquine in selective population chemotherapy in Ethiopia. AB - Oxamniquine, at 40 mg/kg body weight, was used in a pilot schistosomiasis control programme in an endemic community in Ethiopia. After mass screening of the population using Kato's thick smear method, 1556 positive patients were treated in divided doses over two consecutive days. However, only 1183 (76%) persons completed the total dose. Three months later stool examination of about 20% of those who completed the total dose showed a cure rate of 68% and a significant reduction in the geometric mean egg counts. In those still positive redistribution of grades of infection took place; heavy infection, > 800 egg count per gram (epg), was reduced from 22.7% to 7.9% (p < .001) and light infection increased from 27.7% to 57.3% (p < .001) and light infection increased from 27.7% to 57.3% (p < .0001). The implications of this experience in the control of schistosomiasis in Ethiopia is discussed. PMID- 8674488 TI - Sociodemographic profile of children affected by AIDS in Addis Abeba. AB - A survey was conducted in Addis Abeba between October 2, 1993 and December 10, 1993 to assess orphanhood due to AIDS deaths. It was possible to trace only 1,047 AIDS cases among residents of Addis Abeba. During the survey, 59% of the cases and 16% of their spouses were already dead. The total number of children born to the index cases were 2186, among which, 883 (40.4%) were below 15 years of age. Two hundred eighty (30.4%) of these children had lost either one or both parents. Other social problems include ill health in 10.5% among which 3.9% had AIDS; 14.1% were school dropouts. There were also children who faced abandonment, displacement and who lacked medical care at the time of their illness. The existing coping mechanism seems to be relying on the extended family, which is an important social support system. However, there is a need to raise community awareness and strengthen the system to enhance the effort in protecting and supporting children affected by AIDS. PMID- 8674490 TI - Intensity of infection and reinfection rate of A. lumbricoides in a rural farming village, Dembia district, northwest Ethiopia. AB - The purpose of this study was to determine the intensity of infection and reinfection rate of A. lumbricoides at a village in Dumbia District, Northwest Ethiopia. It was done in June 1992 and repeated in June 1993. Among 192 examined for intestinal parasites, the prevalence rate was 60.9%. Infection with A. lumbricoides was 34.4%. Children in the age-group 1-4 years had the highest egg count (arithmetic mean of 3040 eggs per gram of stool) for A. lumbricoides. Reinfection rate after 11 months among those treated against A. lumbricoides was 53%. The study has an important implication in understanding the local epidemiology of A. lumbricoides and in the design of community-based control programmes. PMID- 8674491 TI - Rupture of pregnant uterus in Shashemene General Hospital, south Shoa, Ethiopia (a three year study of 57 cases). AB - This study was carried out to determine the frequency of occurrence and outcome of treatment of uterine rupture in a rural hospital. Fifty seven patients with uterine rupture were admitted to Shashemene General Hospital (SGH) from September 1989 to August 1992. The age, parity, type of operation, outcome of treatment, site of rupture, post operative complications and duration of hospitalization of these cases were analyzed. Two thousand one hundred eighty five deliveries were conducted over the study period. The frequency of occurrence of uterine rupture was 2.6% or 1 in 38 deliveries. There were 9 deaths giving a case fatality rate of 15.8%. The mean duration of hospitalization among those who survived was 13 days (Range: 6 hours to 20 days). Fifty four (94.7%) of the cases were para 3 and above. Left lateral wall rupture was found in 28 (49%) of the cases. The commonest causes of rupture were neglected shoulder presentation (63.2%), brow and face presentations (29.8%). The age of the patients ranged from 16 to 59 years, with a peak incidence (42 (73.7%)) occurring between 25 and 34 years. Three patients had repair operation and fifty four had hysterectomy. The antibiotics used for treatment of associated infections were crystalline penicillin, ampicillin and chloramphenicol since other drugs were not available. PMID- 8674494 TI - Post menopausal vaginal bleeding due to vaginal wall leech infestation. PMID- 8674493 TI - Pseudotumor cerebri (toxic effect of the "magic bullet"). AB - A 10 year-old female patient presented to the outpatient unit of the ophthalmology department of Menelik II Hospital with complaints of inward deviation of the left eye, of three weeks' duration. The patient was on a mega dose of vitamin A 200,000 I.U. (the "magic bullet") daily for two months prior to the onset of the present illness. Physical examination revealed left sixth nerve palsy and bilateral papilloedema in an alert and oriented patient without localizing neurologic findings. The cerebrospinal fluid pressure ( > 250 mm water) was increased and skull X-ray findings were suggestive of increased intracranial pressure (IIP). This case meets the modified Dandy criteria except that a highly likely cause, hypervitaminosis A, is associated. Therefore, a diagnosis of Idiopathic Intracranial Hypertension (IIH) or Pseudotumor Cerebri was made. This disorder and its management is discussed and literature reviewed. The serious and potentially blinding toxic effect of Vitamin A, if consumed in excessive amounts, is emphasized. PMID- 8674495 TI - Determination of the human blood index of some anopheline mosquitos by using ELISA. AB - To determine the human blood index, 1253 anopheline mosquitos collected from Arbaminch, Awassa, Metahara and Ziway were tested by the blood meal ELISA, based on anti-human IgG. Higher positivity for human blood were observed in anopheline mosquitos collected from mixed dwellings (range, 26-92%) while those from animal shelters had the lowest positivity (range, 9-48%). The human blood index for A. arabiensis, a principal malaria vector in most parts of the country, from mixed dwelling collections was 88% while it was 43% for those collected from animal shelters. For A. pharoensis, it was 84% and 9%, and for A. coustani, it was 26% and 15% for the respective sites of collection. The human blood index of A. marshalli was 40%; for A. demeilloni, it was 36%; and for A. christyi, 91% for collections from mixed dwellings, while 35% for A. tenebrosus was determined for those collected from animal shelters. Out of the 15 A. funestus and the 11 A. longipalpis tested, 13 and 8 were positive for human blood, respectively. As the feeding and resting preference of the mosquitos varied, malaria control measures must be based on integrated measures in order to reduce man-mosquito contact. PMID- 8674492 TI - Colonization of irrigation canals by Bulinus abyssinicus and upsurge of urinary schistosomiasis in the middle Awash Valley of Ethiopia. AB - The current status of urinary schistosomiasis and snail intermediate 1 hosts in the middle Awash Valley was assessed. Examination of urine by the filtration method for one camp (Assoba) in the Amibara Irrigation scheme showed high human prevalence (70%) and snail infection (7%). Of interest is the fact that now B. abyssinicus, the snail intermediate host of urinary schistosomiasis, has started colonizing the irrigation canals and that our of the infected individuals, 30.3% are itinerant population, possible irrigation workers. The immediate measures to be taken are suggested. PMID- 8674496 TI - Seroepidemiological and leishmanin skin test surveys of visceral leishmaniasis in south and southwest Ethiopia. AB - Sero-epidemiological and leishmanin skin test surveys of visceral leishmaniasis were carried out in eight localities of South and Southwest Ethiopia between the July 1989 and June 1992. A total number of 4870 subjects comprising semi-pastoral nomads, peasants and farm labourers were included in the study. Areas of high and low leishmanin skin test positivity were identified, with rates varying from 1.0 80.5%. An enzyme-linked immunosorbent assay was used to determine prevalence of antileishmanial antibodies. The rates varied from 1.8% to 27.8%. Age and sex related serological and leishmanin skin test profiles are described. Correlation analysis of serological and leishmanin skin test was made for data in each locality. The relationships between seroprevalence, leishmanin skin test rates and prevalence of active visceral leishmaniasis and the implications on degrees of endemicity and patterns of transmission are discussed. PMID- 8674497 TI - HIV/AIDS awareness, knowledge and practice in patients with sexually transmitted diseases. AB - Patients diagnosed to have sexually transmitted diseases in one month at the Adigrat Health Centre were interviewed to determine knowledge about means of transmission and prevention of HIV/AIDS and practice of high risk behaviour. In this study done in October and November 1992, of a total of 812 patients aged between 15-45 years, 60 patients (7.4%) had sexually transmitted diseases. Male to female ratio was 1.7:1. Fifty nine out of sixty patients (98.3%) knew the sexual route of HIV/AIDS transmission. 43 patients (71.7%) knew the preventive role of condoms, and 34 patients (56.7%) knew the preventive role of monogamous relationships. Only 12 patients (20%) knew nothing of the mode of transmission. An association between the knowledge of preventive methods of HIV/AIDS transmission and their practice was found only for condoms: 14/43 (33%) out of the aware group, 1/17 (6.5%) in the unaware group used condoms occasionally (P = 0.0457), whereas there was no difference between single partner-aware and single partner-unaware group in the percent with single sexual partner (41.2% vs 30.8%, P = 0.57). Though there is awareness of the existence of HIV/AIDS, its main route of transmission, and methods of prevention to some extent, a problem lies in the difficulty of changing individual sexual behavior. With the epidemic of HIV/AIDS sweeping the country, health education programmes must be evaluated for success in bringing about sexual behavioural change in the population as well as for success in imparting knowledge. PMID- 8674498 TI - Visceral leishmaniasis in Gambela, western Ethiopia. AB - Active case finding, leishmanin skin test and serological surveys of visceral leishmaniasis were carried in selected localities in Gambela, Western Ethiopia, through the years 1989-1993. Active case detection surveys were made among 1456 Sudanese refugees, 646 Ethiopian Nuers and Anuaks, 651 resettlers at Baro-Abol and 165 patients from health centres in Itang. Fugnido and Kermi and Gambela hospital. Leishmanin skin test and sero-epidemiological studies were also conducted. A total of seven cases of visceral leishmaniasis were detected among refugees and none among resettlers, natives or 156 patients attending health centres and a hospital in Gambela. Positive leishmanin rates varied from 34.4% among refugees to 7.6% and 1.7% among Ethiopian Nuers and Anuaks and resettlers, respectively. Seroprevalence rates were also determined to be 18.1%, 7.3% and 8.1% respectively for the above order of study populations. Results are discussed in view of the currently ongoing leishmaniasis epidemic in the Upper Nile Province of the Sudan. The study emphasizes on the potential risk of imported visceral leishmaniasis being established in Western Ethiopia, where the disease is not known to be endemic until now. PMID- 8674499 TI - Cryptosporidiosis in children seen at the children's clinic of Yekatit 12 Hospital, Addis Ababa. AB - The stools of 214 children under five years of age with diarrhoea were examined for Cryptosporidium oocysts using the Modified Ziehl Nelson Technique. Twelve (5.6%) of the children had Cryptosporidium oocysts in their faeces. All of these were above 6 months of age and were either partially or fully weaned. There were 15 exclusively breast fed children of whom 11 were less than 6 months of age. None of these cases had the evidence of Cryptosporidial infection. The present study indicates the importance of Cryptosporidium as a possible etiologic agent in patients with diarrhoeal diseases. However, a comprehensive investigation is needed in order to rule out other enteropathogens. PMID- 8674500 TI - Decline of urinary schistosomiasis in Kurmuk town, western Ethio-Sudanese border, Ethiopia. AB - Urine examination of the residents of Kurmuk town, Western Ethio-Sudanese border, done in April 1993, showed that Schistosoma haematobium infection has now declined to 5.7% from 30.2% in 1981. The current intensity of infection is also as low as 20 eggs/10 ml urine. However, the finding of infected Bulinus africanus indicates resurgence of urinary schistosomiasis in the town. Possible factors that may have contributed to the decline and measures required to contain the disease are discussed. PMID- 8674501 TI - Fatal reaction to urografin. AB - A 40 year old female who came to Radiology Department of Tikur Anbessa Hospital on November 15, 1994 for intravenous pyelography and died suddenly after intravenous injection of 15 cc of 76% Urografin is discussed. The clinical condition and progress of the event with brief review of literature will be presented. PMID- 8674503 TI - Changes in mandibular tooth alignment during adulthood from 18 to 50 years. PMID- 8674504 TI - Benzoporphyrin-lipoprotein-mediated photodestruction of intraocular tumors. AB - Benzoporphyrin derivative (BPD), a sensitizer currently in clinical trials, was evaluated for the treatment of experimental Greene melanoma implanted in the rabbit iris. To improve tumor targeting, BPD was complexed with low-density lipoprotein (LDL) representing an endogenous carrier system for BPD as previously described. Twelve tumors were irradiated at a sensitizer dose of 2 mg kg-1 body weight using a dye laser at 692 nm. Tumor responses were documented by photography, angiography and light and electron microscopy. All tumors treated with 80 J cm-2 regressed irreversibly. The principal mechanism of tumor necrosis was thrombosis following disruption of endothelial membranes. Ultrastructure data suggested tumor cell damage, although evidence for this being the result of direct PDT-mediated tumor cell death was less clear. These data suggest that BPD LDL may be used to improve the selectivity of photodynamic tumor therapy possibly by the increased uptake of lipoprotein-delivered sensitizer to neovascular endothelial cells. PMID- 8674502 TI - Stimulation of bone formation in the expanding mid-palatal suture by transforming growth factor-beta 1 in the rat. AB - The most intense endogenous transforming growth factor (TGF)-beta 1 expression was detected in osteoblasts and fibroblasts in the mid-palatal suture 24 hours after the start of palatal expansion with an immunohistochemical technique. Based on these data, local effects of transforming growth factor-beta 1 (TGF-beta 1) in the expanding mid-palatal suture of the rat were examined. Single doses of human recombinant (rhu) TGF-beta 1 (40 and 200 ng, and 1 microgram) were injected into the expanding mid-palatal suture 24 hours after expansion started. Calcein was also injected immediately, and 6 and 12 days after expansion. The width of each calcein label was measured to evaluate bone formation along the suture with bone histomorphometry. In the experimental groups, bone formation during the 12-day expansion period was stimulated significantly (P < 0.05), in a dose-dependent manner, compared with that in the control group. Furthermore, bone formation during the later stage (6-12 days) of the 12-day expansion period, was still significantly higher than that in the control group. In addition, the amount of bone formation in response to a course of 3 injections of 200 ng rhu TGF-beta 1 on days 3, 6, and 9 was almost equal to that induced by a single injection of 200 ng rhu TGF-beta 1 on day 1. These results suggest that TGF-beta 1 may play an important role in bone formation at the active site of the suture in response to rapid palatal expansion and application of TGF-beta 1 during the early stages may induce rapid bone formation. PMID- 8674505 TI - Schlemm's canal and primary open angle glaucoma: correlation between Schlemm's canal dimensions and outflow facility. AB - The purpose of the study was to examine the correlation between outflow facility and morphometric measurements of Schlemm's canal (SC) in normal and glaucomatous human eyes. Outflow facility was measured in ten normal and five glaucomatous (POAG) human eyes prior to perfusion-fixation at a pressure of 15 mmHg. Two separate sections per quadrant (eight sections per eye) were analysed using a morphometric analysis system. SC cross sectional area, perimeter, and inner wall length were measured. Inner wall endothelial nuclei were counted. When pooled data were examined, a statistically significant correlation was found between facility and SC area (P < or = 0.01). Most importantly, POAG eyes had a significantly smaller SC cross-sectional area, SC perimeter and SC inner wall length compared to normal eyes. If examined as a reduction in SC filtering area, this decrease in SC inner wall length alone could account for approximately 41 55% of the difference in outflow facility observed between normal and POAG eyes. The dimensions of Schlemm's canal in glaucomatous human eyes were significantly smaller than those in normal eyes. This reduction in SC dimensions may account for approximately half of the decrease in outflow facility observed in POAG eyes. PMID- 8674506 TI - Effect of selected anti-cataract agents on opacification in the selenite cataract model. AB - A systematic study of the anti-cataract activity of 14 reagents was conducted using the selenite model. The reagents or their derivatives were identified from literature reports of their potential effectiveness against cataract formation. The effects of each reagent were measured on the phase separation temperature, Tc, of lens homogenate in vitro. Tc is a direct measure of molecular interactions leading to protein aggregation. The protective effect of a single subcutaneous injection of each reagent [at a dose of 1.5 mmol (kg body weight)-1] on lens opacification was evaluated in vivo using rats administered selenite [at a dose of 19 mumol (kg body weight)-1] to initiate cataract formation. The strongest effects on lens opacification in vivo were observed with reagents having the strongest effect on Tc, in vitro. The weakest effects in vivo were observed with the reagents having the weakest effect on Tc, in vitro. The results were suggestive of a relationship between the effect of a reagent on Tc and protection against cataract formation in vivo. PMID- 8674507 TI - Sequence and expression of chicken beta A2- and beta B3-crystallins. AB - Crystallins are a diverse group of proteins that contribute to the transparency and refractive properties of the eye lens. Previously, the chicken orthologs of four out of the six known bovine beta-crystallin genes have been cloned and sequenced. In the present study, cDNAs corresponding to the chicken orthologs of beta A2- and beta B3-crystallin, the two previously unidentified chicken beta crystallins, have been isolated. In addition, sequence analysis of three independent chicken beta B2-crystallin cDNAs yielded a deduced connecting peptide sequence which is considerably shorter than that reported previously. Thus, direct homologs of all of the known bovine beta-crystallins are expressed in the chicken lens. This demonstrates that the duplications giving rise to the known vertebrate beta-crystallins occurred over 300 million years ago. beta B2- and beta B3/A1-crystallin are the most highly conserved of the beta-crystallins suggesting that these genes may be important for other functions besides their refractive role in the lens. By Northern blot hybridization analysis, both beta A2- and beta B3-crystallin were shown to be lens-specific in the chicken embryo. The relative levels of beta A2-crystallin remained stable from five days of embryogenesis until adulthood, while the relative amounts of beta B3-crystallin increased until hatching and were appreciably lower in the adult lens. Approximately equal relative amounts of beta A2-crystallin mRNA were found in the lens epithelia and fibers of 5 day embryonic chicken embryos; by contrast, beta B3-crystallin mRNA was detected preferentially in the lens fibers. These data in combination with previous studies suggest that beta-crystallin genes are regulated independently from each other in the developing chicken lens. The elucidation of the primary structures for all seven chicken beta-crystallin polypeptides will facilitate future studies on the structure/function relationships responsible for lens transparency and on the molecular basis for beta-crystallin gene expression during development. PMID- 8674508 TI - Laminin isoform distribution in the human optic nerve head. PMID- 8674510 TI - Transport of circulating reduced glutathione at the basolateral side of the anterior lens epithelium: physiologic importance and manipulations. AB - Transport of circulating reduced glutathione (GSH) was studied at the basolateral side of the lens epithelium by using an in situ vascular eye perfusion technique in guinea-pigs with rapid sampling to ensure detecting initial uptakes. The unidirectional transport rates of [35S]-GSH (4 nM) from plasma and aqueous into the epithelial cytosol were 0.046 +/- 0.003 and 6.88 +/- 0.39 min-1, respectively. HPLC analysis indicated that over 94% of [35S]-GSH remained intact in the epithelium and cortex in the presence or absence of gamma-glutamyl transpeptidase inhibitor, serine borate. Simultaneous infusion of [35S-cysteine] GSH and [3H-glycine]-GSH confirmed the non-involvement of gamma-glutamyl transpeptidase in GSH transport across the lenticular membranes by showing that 35S/3H ratio in the epithelium and cortex was the same as in the aqueous and plasma. GSH epithelial influx was reduced by 53% (P < 0.01) by 0.3 mM sulphobromophtalein-GSH, a GSH conjugate that does not inhibit the facilitative GSH transporter, RcGshT, recently found in the lens. At physiologic concentration of circulating GSH at 30 microM, GSH epithelial influx was 0.77 nmol min-1 g-1; a t1/2 of 85.4 hr was estimated if endogenous epithelial GSH had to be replaced exclusively by plasma-derived GSH. The level of GSH in the epithelium was increased by 38% (P < 0.05) by 1 hr arterial infusion of GSH at 20 mM. The aqueous concentration of GSH under these conditions was 1.2 mM so that accumulation in the epithelium occurred a greater than six-fold concentration gradient. It is concluded that: (a) transport of GSH at the basolateral side of the epithelium is mediated by a concentrative mechanism distinct from RcGshT: (b) circulating GSH may represent a major source for epithelial GSH under physiologic conditions; and (c) the level of GSH in the epithelium can be manipulated by exogenous GSH. PMID- 8674509 TI - Nitric oxide synthase inhibitors exert differential time-dependent effects on LPS induced uveitis. AB - Nitric oxide (NO) is a highly reactive radical which plays an integral role in physiological and pathophysiological processes. NO is produced endogenously in small amounts by a constitutive NO synthase (cNOS) as a regulator of vascular tone and neurotransmission. NO can also be produced in large amounts by an inducible NOS (iNOS) in response to endotoxin and cytokines, and has been reported to be a mediator of lipopolysaccharide (LPS)-induced uveitis in rats. The purpose of the present study was to investigate the effects of NOS inhibitors with different NOS isoform specificities in the rabbit model of endotoxin-induced ocular inflammation. LPS and/or inhibitors of NOS. NG-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine (AG), were injected intravitreally and the eyes observed by slit lamp for 24 hr. Coinjection of LPS with L-NAME inhibited anterior inflammation in rabbits. Iridal hyperemia (IH) and aqueous flare (AF) were completely abolished in eight out of nine rabbits in a dose-dependent manner. In addition, total cell counts were significantly suppressed (7393 +/- 697 vs. 325 +/- 188, P < 0.05) and aqueous protein levels were reduced to near control levels (25 +/- 0.75 vs. 1.72 +/- 0.36, P < 0.05). Similar suppression was seen with AG (cell counts = 351 +/- 246 and proteins = 3.1 +/- 1.2). Administration of L-NAME 0.5 hr after LPS injection suppressed inflammation to a lesser extent than coinjection. In contrast, administration of L-NAME 6 hr after LPS injection was not inhibitory, and in fact significantly increased cellular infiltration. However, AG given 6 hr after LPS had a remarkably different effect, since it significantly decreased both protein extravasation and cellular infiltration into the aqueous humor. In fact, our results suggest that cNOS may play a greater role in the earlier stages of this developing inflammatory response. These results extend others' observations that NO is a key mediator in uveitis, that induction of iNOS plays a critical role in experimental uveitis, and suggest that NO has a complex role in the ocular inflammatory process. Inhibitors of NOS can abort the LPS-induced inflammatory response if administered early enough, but could potentially exacerbate an established inflammatory episode. PMID- 8674511 TI - Decreased 3 alpha-hydroxysteroid dehydrogenase activity in peripheral blood lymphocytes from patients with primary open angle glaucoma. AB - The purpose of the present study was to determine whether peripheral blood lymphocytes (PBL) from primary open angle glaucoma (POAG) patients have reduced 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) activity as was previously found in POAG-derived cultured trabecular meshwork cells. The availability of PBL from both POAG and control patients makes this a useful system for studying the association of decreased 3 alpha-HSD activity with POAG. PBL were isolated from the venous blood of 17 POAG patients and 22 non-glaucoma controls and assayed for 3 alpha-HSD activity with tritiated 5 beta-dihydrocortisol as a substrate. The mean 3 alpha-HSD activity +/- S.E.M., expressed in comparable units of specific activity, of the POAG derived PBL was 13.8 +/- 1.3 U as compared to 32.8 +/- 2.0 U for control cells. This reduction (> 50%) was statistically significant (P < 0.001). Quantitative immunoblot analysis of PBL indicated that the POAG and control cells, despite their difference in 3 alpha-HSD activity, had nearly identical amounts of 3 alpha-HSD protein. The molecular weight of PBL 3 alpha-HSD from both groups of patients was 38,000, the same as previously reported for human liver. The results of this study show an association of decreased PBL 3 alpha-HSD activity and POAG which was not related to antiglaucoma therapy. The reduced levels of 3 alpha-HSD activity in the readily obtainable PBL may serve as a marker for POAG or those at risk for developing the disease. PMID- 8674512 TI - Lipid-protein interactions in human and bovine lens membranes by Fourier transform Raman and infrared spectroscopies. AB - In other systems, proteins have been shown to alter the molecular structures of lipids in the cell membrane bilayer. We wished to determine if proteins altered the structure of lens lipids. The structure of lipid hydrocarbon chains in urea purified human lens membrane vesicles containing intrinsic, hydrophobically bound proteins was compared to the structure of lipids in vesicles without protein. Fourier transform Raman spectroscopy was used to characterize lipid and protein structure. To study lipid interactions with extrinsic, surface bound proteins, the lipid structure was compared in bovine lipid vesicles with and without alpha crystallin bound to the surface of the membrane. Lipid structure was studied using Fourier transform infrared spectroscopy. No change in lipid structure was detected even at protein/lipid weight ratios of two to one. Human lens intrinsic proteins contained a high amount of a helical structure (60%), but did not alter hydrocarbon chain interactions. PMID- 8674513 TI - Normally occurring loss of single cells and repair of resulting defects in retinal pigment epithelium in situ. AB - The retinal pigment epithelial cells, which form a monolayer between the choroid and photoreceptor cell layer of the eye, generally do not divide after birth. There is, however, a gradual loss of retinal pigment epithelial cells die and the mechanism by which the integrity of retinal pigment epithelium is maintained after cell death has not been examined. Confocal laser scanning microscopy of whole mounts of retinal pigment epithelium of 12 to 16 day old chick embryos showed that among the great majority of retinal pigment epithelial cells which were regular in size and hexagonal in shape, single, scattered, irregularly shaped, dying cells are present. The distribution of the dying retinal pigment epithelial cells, their morphology and the presence of apoptotic bodies, including pyknotic and fragmented nuclei, above such defects suggests that the death occurs by apoptosis. The defects created by the dying or dead cells were repaired by spreading of the surrounding normal retinal pigment epithelial cells and a series of stages in the repair of the defects could be identified. During the repair of the defects, fine microfilament bundles running parallel to the edge of the defect in each of the surrounding retinal pigment epithelial cells could be detected by confocal laser scanning microscopy giving a 'spider-web' appearance to the region around the defect. Since induction of proliferation in retinal pigment epithelial cells during healing of the defect requires cell migration, we would not expect the spreading of retinal pigment epithelial cells into the single cell defects to trigger cell proliferation. The death of single cells and the spreading of adjacent ones in the absence of cell proliferation would however explain at least in part the increase in the average size of retinal pigment epithelial cells with age. PMID- 8674514 TI - Phenotypic heterogeneity of retinal pigment epithelial cells in vitro and in situ. AB - We have previously developed methods based upon differential cell adhesion to select for cells of two different phenotypes, epithelioid and fusiform, from cultures of human RPE. Here we considered whether the differences in cell shape correlated with differences in protein tyrosine phosphorylation since it is known that elevated phosphorylation perturbs the stability of the adherens junction, a major determinant of epithelial phenotype. In cultures of both phenotypes we found low tyrosine phosphorylation levels in postconfluent cultures, and the same complement of tyrosine phosphoproteins after treatment with a phosphatase inhibitor. However, in contrast to epithelioid cells, fusiform RPE failed to localize the phosphoproteins to junctional sites on the cell periphery. We also re-evaluated primary and passaged RPE cultures for additional cell shape variants. Several discrete phenotypes were identified within the same cultures. They required several weeks at confluency to develop in primary as well as in passaged cultures, but after developing they remained stable for months. Since explanted RPE cells manifest several shape variants in an identical culture environment we examined bovine RPE cells in situ to determine whether the cells were heterogenous with regards to some cell surface and cytoskeletal proteins that might contribute to cell shape. Circumferential actin microfilament bundles and the occluding junction protein ZO-1 had fairly uniform distributions among cells in the monolayer, but the intermediate filament protein vimentin and the pericellular expression of phosphotyrosine varied among individual cells. Therefore, despite its grossly homogeneous appearance, the RPE monolayer in situ might be considered a mosaic of structurally heterogeneous cells which can give rise to phenotypically-distinct subpopulations when propagated in vitro. PMID- 8674516 TI - Retinal pigment epithelium topography in the mature quokka, Setonix brachyurus. AB - In this paper we describe cell topography of the retinal pigment epithelium (RPE) for the mature marsupial wallaby, the quokka, Setonix brachyurus. RPE topography was analysed in bleached and stained whole mounted retinae, sampling from the entire surface area. The mature adult quokka RPE has a distinct topography in terms of both cell density and the distribution of multinucleate cells. Peripheral RPE demonstrates the lowest cell density and the greatest proportion of multinucleate cells. In an annulus surrounding central retina, corresponding to equatorial retina, RPE cell density is relatively high and multinucleate cells are at the lowest frequency. Cell density is highest in central temporal retina, in the regions adjacent to some of the highest densities in the neural retina. Other regions of central retina exhibit moderate cell densities. A small proportion of central cells are multinucleate. The RPE topography may result from, or account for, regional differences in susceptibility of this tissue to environmental influences and stressors. Understanding of this topography may throw light on the marked localization of certain human retinal diseases inherent to this tissue. PMID- 8674515 TI - Delay or inhibition of rat lens opacification using pantethine and WR-77913. AB - Pantethine and the amino phosphorothioate, WR-77913, protected lenses against increased light scattering and opacification during cataract formation in five animal models: (1) radiation, (2) selenite, (3) galactose, (4) streptozotocin and (5) Royal College of Surgeons. In the radiation or selenite models, each test reagent was administered 15 to 30 min prior to initiation of cataract by a single injection of Na2SeO3 or a single exposure to 15 Gy (gray) gamma radiation. In the galactose, streptozotocin and Royal College of Surgeons models where the cataractogenic insult was continuous, repeated administrations of pantethine and WR-77913 were necessary. The results suggested that protein aggregation and lens opacification associated with a variety of physiological and biochemical mechanisms can be delayed or inhibited using a systemic administration of pantethine or WR-77913. PMID- 8674518 TI - John Weakland: a personal note. PMID- 8674519 TI - Training to think culturally: a multidimensional comparative framework. AB - A multidimensional, comparative training framework is designed to integrate culture with all aspects of family therapy. Culture is viewed as occurring in multiple contexts that create common "cultural borderlands" as well as diversity; unpredictability and possibility, as well as regularity and constraint. The framework proposes a search for basic parameters to help therapists think comparatively and pluralistically about families' cultural configurations and meanings. Further, the parameters chosen--ecological context, migration/acculturation, organization, and life cycle--are used to heighten therapists' awareness about the "situated knowledge" of their own professional and personal culture. This approach recognizes the potential complexity of both the family's and the therapist's cultural location or ecological niche, and encourages curiosity in the therapeutic conversation rather than reliance on potentially stereotyping, ethnic-focused information. PMID- 8674517 TI - A study of aqueous humor dynamics in keratoconus. AB - Clinical observations suggest that patients with keratoconus have lower intraocular pressures, on average, than normal subjects. Our purpose was to determine whether differences in aqueous production and outflow facility could account for differences in intraocular pressure between a group of patients with keratoconus and a group of normal, age-matched control subjects. Aqueous humor dynamics were determined by the use of fluorophotometry in one eye of seven patients with keratoconus and ten age-matched normal subjects. Intraocular pressure was measured by applanation tonometry. Keratoconus patients had a statistically significant lower mean intraocular pressure than normal control subjects (11.3 +/- 1.6 mmHg vs. 16.6 +/- 2.8 mmHg, P = 0.0004). The difference in mean intraocular pressure remained significant even after correcting for possible errors in applanation tonometry due to thin corneal stroma. There was no difference in mean aqueous humor flow rates in the keratoconus patients as compared to controls (2.29 +/- 0.53 microliter min-1, P = 0.73). The mean apparent outflow facility was 0.21 +/- 0.07 microliter min-1 mmHg-1 for keratoconus patients compared to 0.14 +/- 0.03 microliter min-1 for controls (P = 0.02). Lower mean intraocular pressure in keratoconus patients appears to be due to increased outflow facility as compared to normal subjects. PMID- 8674520 TI - The value of curiosity and naivete for the cross-cultural psychotherapist. AB - Therapists today face a dramatic increase in the cultural diversity of their client populations. Cultural literacy, long the dominant model for preparing to do cross-cultural therapy, advocates study of the prospective client's history and culture. This model, however, poses logistical problems, emphasizes scholarship over the experiential and phenomenological, and risks seeing clients as their culture and not as themselves. In this essay, we argue that teaching culture alone can obscure therapists' view of human diversity. To balance the cognitive model of preparation, a process-oriented approach is considered, whereby the therapists' attitudes of cultural naivete and respectful curiosity are given equal importance to knowledge and skill. We begin from a concern with clients' vulnerability in the power distribution that inevitably exists in therapy, especially with immigrant and marginalized populations. The use of acculturation narratives, which the therapist explores with naivete and curiosity, helps clients to find their voices. PMID- 8674521 TI - Critical interaction therapy: couples therapy in combat-related posttraumatic stress disorder. AB - There is a need for family therapy interventions that are specific to the conditions found in families of traumatized people such as combat veterans. In these families, the historically "real" event of the trauma often continues to exert influence on the family system despite collusive arrangements that serve to keep it hidden. In families of combat veterans, a situation develops whereby the veteran becomes triangulated with a dead buddy without the spouse's knowledge. The discrepancy between past and present emerges in what we call the critical interaction between the spouses. This article outlines a method of couples therapy that attempts to demystify this critical interaction, and begins to integrate the discrepant narratives of each spouse. The establishment of a nascent mutuality of perspective within the couple releases energies that can be directed toward support rather than symptom-formation in the family system. PMID- 8674523 TI - A self psychologist in couplesland: multisubjective approach to transference and countertransference-like phenomena in marital relationships. AB - This essay introduces the reader to some basic self psychological concepts that have useful applications to couples therapy. Two points are highlighted. First, the therapist must be constantly aware of the narcissistic vulnerability of each of the participants. Second, the working through of transference and countertransference-like experiences within the marital dyad is just as central to an understanding of the curative process in couples treatment as it is within the patient/therapist dyad in individual treatment. PMID- 8674522 TI - Counseling caregivers of relatives with schizophrenia: themes, interventions, and caveats. AB - As part of a controlled study of the effectiveness of a counseling program for family caregivers of patients with schizophrenia, we conducted a comprehensive examination of the process. The particular foci were on themes that arose during sessions, principal therapeutic interventions offered, and caveats for counselors working in the field. The most striking finding was the diverse range of themes, covering personal, coping, family, and social aspects of the caregiving experience. This required a correspondingly broad array of interventions. The implications are clear: confining counseling for caregivers to such traditional dimensions as education or attempts to reduce emotional expressiveness denies them the opportunity to deal with other equally relevant concerns. PMID- 8674525 TI - Stability and change in family-of-origin recollections over the first four years of parenthood. AB - This article, one of several from a longitudinal family study, examines stability and change in family-of-origin recollections. Family-of-origin data were collected by means of a questionnaire from both husbands and wives prior to the birth of their first child and 41/2 years later. The questionnaire probed the subjects' recollections of their relationships with their mothers and fathers and of their parents' marital relationships. With median correlations for the women and men of .70 and .72, family-of-origin recollections appear relatively stable over this 41/2-year period. One exception to the relative stability was that women recalled their fathers and the closeness of their parent's marriage less positively after 4 years of parenthood. These changes in women's recollections were related to contemporaneous experiences with husbands' depression and qualities of the husband's parenting. PMID- 8674524 TI - The excitation-adaptation model of pediatric chronic illness. AB - This article examines the value of the psychosomatic family model for the study of chronically ill children. Four conceptual problems arise in the discussion of this model: the unidirectional causality of the model; the function of the sick child for the family system; the pathology of the family characteristics; and the disease type. In the present study, we propose (a) that a distinction be made between uncontrolled and controlled forms of disease, and (b) that the family characteristics of "cohesion" and "adaptation" be examined in relation to the parental capacity for problem solving and the acceptance or rejection of the child by the parents. This is shown by means of empirical research. In this empirical study, 20 families with a child suffering from controlled asthma are compared with 20 families with a child suffering from uncontrolled asthma. Contrary to the assumptions derived from the psychosomatic family model, the results show significantly more cohesion and structure in the group with a child suffering from controlled asthma. The findings from this study are integrated in a new model for the study of chronic childhood illness--"the excitation adaptation model." In this model, two circular processes are emphasized involving (a) the progress of the illness and the way in which parents and child deal with medication and medical advice (therapy compliance), and (b) the factors influencing the therapy compliance on the part of the parents, the family, and the child. By studying these factors in connection with the management of the illness, it should become clear whether family characteristics are adaptive or pathological. PMID- 8674526 TI - Polemic or dialogue. PMID- 8674527 TI - The stiffness of the crossbridge is a function of the intrinsic protein osmotic pressure generated by the crossbridge itself. AB - A model is presented that makes it possible to determine the stiffness of the crossbridge from protein osmotic stress experiments. The model was elaborated while studying the osmotic properties of F-actin and of myosin subfragment-1 F actin. These studies showed that the elastic modulus by bending of the monomer is directly related to the intrinsic protein osmotic pressure of the system. At a protein osmotic pressure of 1.8 x 10(5) dynes/cm2, the physiological protein osmotic pressure of frog skeletal muscle, it was found that the elastic moduli by bending of the monomer in F-actin and in the myosin subfragment-1 decorated F actin are 6.5 X 10(7) and 3.3 X 10(8) dynes/cm2, respectively. The value of the elastic modulus by bending of the monomer in the myosin subfragment-1 decorated F actin compares favorably with the values of the elastic modulus by stretching determined in skeletal muscle fibres. PMID- 8674529 TI - Interferon-gamma inhibits 35S incorporation in heparan sulfate synthesized by human skin fibroblasts. AB - Glycosaminoglycans synthesized by human skin fibroblasts were simultaneously radiolabelled with D-[1-(3H)]glucosamine and Na2(35)SO4. Considering 3H incorporation, we found that IFNgamma increased the production of glycosaminoglycan synthesis, including hyaluronic acid, heparan and chondroitin/dermatan sulfate. In contrast, the production of heparan and chondroitin/dermatan sulfate was slightly decreased on the basis of the 35S signal. Furthermore, when heparan sulfate was treated with nitrous acid, the release of free 35S was greater in control than in treated cells, although the 3H patterns of depolymerization with this agent were similar. These data demonstrate that IFNgamma inhibits the incorporation of sulfate from extracellular medium into heparan sulfate. PMID- 8674528 TI - X-ray structure analysis of an engineered Fe-superoxide dismutase Gly-Ala mutant with significantly reduced stability to denaturant. AB - We have refined the X-ray structure of a site-directed G152A mutant of the iron dependent superoxide dismutase from Mycobacterium tuberculosis at 2.9 angstroms resolution. The mutation which replaces a glycine residue in a surface loop with alanine was designed to alter the conformation of this loop region which has previously been shown to play a crucial structural role in quaternary interactions within the SOD tetramer. Gly-152 was targeted as it has dihedral angles (phi = 83.1 degrees, psi = -0.3 degrees) close to the left-handed alpha helical conformation which is rarely adopted by other amino acids except asparagine. Gly-152 was replaced by alanine as it has similar size and polarity, yet has a very low tendency to adopt similar conformations. X-ray data collection on crystals of this mutant at 2.9 angstroms resolution and subsequent least squares refinement to an R-value of 0.169 clearly establish that the loop conformation is unaffected. Fluorescence studies of guanidine hydrochloride denaturation establish that the mutant is 4 kcal/mol less stable than the wild type enzyme. Our results indicate that strict conformational constraints imposed upon a region of polypeptide, due for example to interactions with a neighbouring subunit, may force an alanine residue to adopt this sterically hindered conformation with a consequent reduction in stability of the folded conformation. PMID- 8674530 TI - Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. AB - Expression of the leptin receptor gene has been examined in mouse hypothalamus and other brain regions by in situ hybridization. With a probe recognizing all the known splice variants, receptor mRNA was evident in several brain regions (cortex, hippocampus, thalamus), with strong expression in the hypothalamus (arcuate, ventromedial, paraventricular and ventral premammillary nuclei), choroid plexus and leptomeninges. A probe specific to the long splice variant of the leptin receptor (Ob-Rb), containing the putative intracellular signaling domain, again revealed strong expression in the hypothalamus; there was, however, minimal hybridization to choroid plexus and leptomeninges. These results indicate that the hypothalamus is a key site of leptin action, although other brain regions are also targeted. PMID- 8674531 TI - Zfp60, a mouse zinc finger gene expressed transiently during in vitro muscle differentiation. AB - The complete cDNA coding sequence of the zinc finger gene Zfp60 is reported. The predicted amino acid sequence of the Zfp60 protein has been found to contain 19 zinc finger motives clustered at the C-terminus. At its N-terminus, Zfp60 shares with other members of the zinc finger gene family two additional conserved amino acid modules named Kruppel Associated Boxes (KRAB). The expression patterns of Zfp60, MyoD and MHC mRNAs have been followed during in vitro myogenic differentiation of C2 cells. We show that the bacterial produced Zfp60 protein binds DNA only in presence of zinc ions. Zfp60 locus has been mapped in chromosome 7, where other Zfp loci are localised. PMID- 8674532 TI - Two bacteriorhodopsin M intermediates differing in accesibility of the Schiff base for azide. AB - Glutaraldehyde treatment leads to the inhibition (i) of the M intermediate decay in wild-type bacteriorhodopsin (bR) and (ii) of the azide-facilitated M decay in the D96N mutant bR. LuCl3 is shown to be a more potent inhibitor of both processes. Glycerol and sucrose are also inhibitors. None of these agents change the linearity of the azide concentration dependency of the M decay in the D96N mutant but they do shift this dependency to higher azide concentrations. It is concluded that the two M forms are in equilibrium. These M forms differ in the accessibility of the Schiff base for azide and, probably, also for water molecules. The above-mentioned agents shift the equilibrium toward the less accessible M form. The data obtained are in line with the model of azide action as the penetrating proton donor and can hardly be realized within the framework of the model of Le Coutre et al. [(1995) Proc. Natl. Acad. Sci. USA 92, 4962 4966] which assumes that a bound anionic form of azide catalyzes proton transfer to the Schiff base. PMID- 8674534 TI - The ternary complex of DNase I, actin and thymosin beta4. AB - We have recently described a method for identifying contact sites between actin and thymosin beta4 (Tbeta4) by following spectrophotometrically the extent and kinetics of distinct, thiol-specific crosslinking reactions between appropriate derivatives of the two proteins [Reichert et a]. (1996) J. Biol. Chem. 271, 1301 1308]. In the present study this method was used to show that such crosslinking, which is indicative of complex formation, occurs to the same extent with the actin-DNase I complex as with pure actin, although at a somewhat lower rate. Further evidence for the formation of the ternary complex was given by gel electrophoresis. From fluorescence spectroscopy the KD value of Tbeta4 from the actin-DNase I complex was found to be identical to that from pure actin. In line with these data, the capacity of actin for inhibiting DNase I was not affected by the addition of Tbeta4. In conclusion, DNase I and Tbeta4 are independent of each other in their interaction with actin, suggesting that the binding sites of thymosin beta4 and DNase I on actin do not overlap. A ternary complex of DNase I, actin and Tbeta4, if obtained in crystalline form, could thus provide an approach for studying the interface of Tbeta4 and actin by X-ray analysis. PMID- 8674533 TI - The inhibitor protein of phosphorylated nitrate reductase from spinach (Spinacia oleracea) leaves is a 14-3-3 protein. AB - The inhibitor protein (IP) that inactivates spinach leaf NADH:nitrate reductase (NR) has been identified for the first time as a member of the eukaryotic 14-3-3 protein family based on three lines of evidence. First, the sequence of an eight amino acid tryptic peptide, obtained from immunopurified IP, matched that of a highly conserved region of the 14-3-3 proteins. Second, an authentic member of the 14-3-3 family, recombinant Arabidopsis GF14omega, caused inactivation of phospho-NR in a magnesium-dependent manner identical to IP. Third, an anti-GF14 monoclonal antibody cross-reacted with IP and anti-IP monoclonal antibodies cross reacted with GF14omega. PMID- 8674535 TI - The irreversible inactivation of ribonucleotide reductase from Escherichia coli by superoxide radicals. AB - The expression of superoxide dismutase in all aerobic living organisms supports the concept that superoxide radicals are toxic species. However, because of the limited chemical reactivity of superoxide, the mechanisms of this toxicity are still uncertain. Protein R2, the small component of ribonucleotide reductase, a key enzyme for DNA synthesis, is shown here to be irreversibly inactivated during incubation with an enzymatic generator of superoxide radicals, at neutral pH. During inactivation the essential tyrosyl radical of protein R2 is irreversibly destroyed. Full protection is afforded by superoxide dismutase. It is proposed that coupling between superoxide radicals and the radical protein R2 generates oxidized forms of tyrosine, tyrosine peroxide and 3,4-dihydroxyphenylalanine. PMID- 8674536 TI - Reconstitution of GTP-gamma-S-dependent phospholipase D activity with ARF, RhoA, and a soluble 36-kDa protein. AB - For activation of kidney membrane phospholipase D (PLD), cytosol is absolutely needed in addition to GTP-gamma-S. The active component of cytosol consists of three protein factors: ADP-ribosylation factor, RhoA, and a soluble 36-kDa protein. Any combination of these two factors synergistically activates PLD to some extent, but the presence of the three factors causes full activation. The 36 kDa protein is stable at 60 degrees C but inactivated at 80 degrees C for 10 min. Tissue distribution of the 36-kDa protein roughly coincides with that of PLD, suggesting physiological relevance of the protein in the regulation of PLD. PMID- 8674538 TI - Combined effects of ATP and its analogs on the membrane permeability in transformed mouse fibroblasts. AB - Extracellular ATP (0.6 mM) induces a marked decrease in the membrane potential, followed by an increase in cell membrane permeability in transformed mouse fibroblasts. The effects of the ATP analogs, p[CH2]ppA and p[NH]ppA (0.6 mM), on the membrane potential and permeability are much less pronounced. ATP at 0.05 mM has no effect by itself, but markedly increases the analog-induced membrane potential dissipation and permeability. The data suggest that ATP-induced membrane permeation is composed of two processes: One is common to ATP and its analogs and appears to be a receptor-mediated process. The second is unique for ATP, effective even at low concentration (0.05 mM), and might be mediated by cell surface enzymes, for which ATP, but not its analogs, serves as a substrate. PMID- 8674537 TI - Calcium/calmodulin-dependent protein kinase II phosphorylates tau at Ser-262 but only partially inhibits its binding to microtubules. AB - PHF-tau, which is phosphorylated at 10 Ser/Thr-Pro and 11 non-Ser/Thr-Pro sites, is unable to promote microtubule assembly. Phosphorylation of the non-Ser/Thr-Pro site, Ser-262, is reported to be primarily responsible for this. The identities of kinase(s) responsible for Ser-262 phosphorylation are still to be clarified. In this study we have used the monoclonal antibody 12E8, which recognizes P-Ser 262 and P-Ser-356 on tau, to survey different kinases for their abilities to phosphorylate Ser-262 on human tau 3L (tau410). In decreasing order of effectiveness we found that Ser-262 and Ser-356 phosphorylation can be catalyzed by CaM kinase II >> C-kinase >> GSK-3 approximately = A-kinase >> CK-1. CaM kinase II and C-kinase were shown to phosphorylate both Ser-262 and Ser-356. The binding of tau to taxol-stabilized microtubules was decreased by 35 and 42% after phosphorylation by CaM kinase II and C-kinase, respectively. Of the fraction of tau that bound to microtubules, about 50% was phosphorylated at Ser-262 and Ser 356. These results suggest that Ser-262 and Ser-356 are very good substrates for CaM kinase II but their phosphorylations are not sufficient to achieve maximal inhibition of tau binding to microtubules. PMID- 8674540 TI - Selective control of cytosolic glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase mRNA stability by selenium supply. AB - Selenium depletion of H4 hepatoma cells reduced cytosolic glutathione peroxidase (cGSH-Px) mRNA abundance but had no effect on phospholipid hydroperoxide glutathione peroxidase (PHGSH-Px) mRNA abundance. Actinomycin D chase experiments showed that selenium depletion had no effect on the stability of PHGSH-Px mRNA but decreased the stability of cGSH-Px mRNA. In Se-replete cells puromycin decreased the stability of both cGSH-Px and PHGSH-Px mRNAs. The results suggest that when selenium supply is limiting PHGSH-Px mRNA translation is maintained more than that of cGSH-Px mRNA, and thus more cGSH-Px mRNA is released from polysomes and degraded. PMID- 8674542 TI - Efficient expression, processing and secretion of a biologically active mammalian protein by Vibrio cholerae. AB - The use of Vibrio cholerae as a secretory expression system for the expression of a mammalian protein, namely human growth hormone, under the control of the heat labile enterotoxin chain B signal sequence is reported. The protein is efficiently expressed and processed. The mature protein is exported to the periplasm after which it is secreted to the extracellular milieu. The expressed and secreted hGH actively binds to its receptor as established by its receptor binding activity. The biological activity of the protein is demonstrated in vitro in a Nb2 proliferation assay. PMID- 8674539 TI - Molecular cloning of a mouse homologue for the Drosophila splicing regulator Tra2. AB - We report the identification of a mouse cDNA, SIG41, encoding a protein of 288 amino acids that is 45% identical (58% similar) to the Drosophila splicing regulator Tra2. SIG41 cDNA contains four polyadenylation signals whose alternative use gives rise to four types of transcripts (2.1, 2.0, 1.5, and 1.4 kb) in mouse cells. Northern analysis and RT-PCR assays showed that SIG41 mRNA is present in virtually all the cell lines and tissues studied, with remarkable levels of expression in uterus and brain tissues. Differential stability of the SIG41 mRNAs was detected in mouse macrophage cells. PMID- 8674543 TI - Oxidant-mediated proteolytic activation of Ca(+)-ATPase in microsomes of pulmonary smooth muscle. AB - Treatment of bovine pulmonary artery smooth muscle tissue microsomes with H2O2 (1 mM) markedly stimulated protease activity tested with a synthetic substrate N benzoyl-DL-arginine p-nitroanilide (BAPNA), and also enhanced Ca(2+)-ATPase activity. ATP-dependent Ca(2+) uptake was found to be stimulated upon treatment of the microsomes with H2O2. Pretreatment of the microsomes with vitamin E and aprotinin prevented the H2O2-induced stimulation of Ca(2+)-ATPase activity and also ATP-dependent Ca(2+) uptake. In contrast, H2O2-induced inhibition of Na(+) dependent Ca(2+) uptake was reversed by vitamin E and aprotinin. PMID- 8674544 TI - Inhibitory mechanisms of H(+)-ATPase inhibitor bafilomycin A1 and carbonic anhydrase II inhibitor acetazolamide on experimental bone resorption. AB - The effects of the vacuolar-type H(+)-ATPase inhibitor bafilomycin A1 (baf.A1) and the carbonic anhydrase II inhibitor acetazolamide (AZ) on bone resorption and procathepsin L secretion of rat osteoclasts were investigated using the bone slice assay method, pit formation test. Baf.A1 completely suppressed osteoclastic bone resorption stimulated by parathyroid hormone (PTH), but did not affect procathepsin L secretion, while AZ suppressed both bone resorption and procathepsin L secretion. These findings suggest that bone resorption by procathepsin L secretion and its processing are regulated by proton production and proton secretion. PMID- 8674541 TI - Drosophila melanogaster SL2 cells contain a hypoxically inducible DNA binding complex which recognises mammalian HIF-binding sites. AB - Nuclear extracts from Drosophila SL2 cells were found to contain a hypoxically inducible complex capable of binding to hypoxia response elements from mammalian genes. This complex (HIF-D) resembled mammalian hypoxia inducible factor (HIF-1) in DNA sequence specificity, abrogation of induction by cycloheximide, induction by desferrioxamine and redox sensitivity of DNA binding. However, HIF-D was not induced by cobalt and was less sensitive to phosphatase than HIF-1. Endogenous phosphoglycerate kinase mRNA in SL2 cells showed similar inducible characteristics to HIF-D. These findings are evidence that the mammalian HIF-1 dependent system of oxygen regulated gene expression has a functional homologue in Drosophila. PMID- 8674545 TI - Single point mutations in Met4p impair the transcriptional repression of MET genes in Saccharomyces cerevisiae. AB - Transcription of MET genes in Saccharomyces cerevisiae depends on a transcriptional activator, the MET4 gene product (Met4p). Using in vitro mutagenesis, we isolated two mutant MET4 alleles encoding [Pro215]Met4p and [Ser156]Met4p. These mutations impeded Met4p's responsiveness to methionine in the media, and yeast cells carrying mutant alleles exhibited enhanced transcription of MET genes under repressing conditions. The enhanced transcription was dependent on the CBF1 gene, but did not compete with an excess of wild-type Met4p, suggesting that some changes in the affinity of Met4p to other factors might be involved in S-adenosylmethionine-mediated transcriptional regulation. PMID- 8674548 TI - Characterisation of glucose transport in the hyperthermophilic Archaeon Sulfolobus solfataricus. AB - Sulfolobus solfiataricus is a hyperthermophilic Archaeon growing at 80 degrees C, pH 3. The glucose transport system of this organism has been characterised kinetically at this temperature and pH using 2-deoxy-D-glucose: the sugar analogue is transported into the cells with a Km = 1.8 +/- 0.3 microM and a Vmax = 3.6 +/- 0.1 nmol min(-1) (mg protein)(-1), with an intracellular accumulation of up to 200-fold over the extracellular concentration. Transport was significantly reduced at pH 5. Inhibition of 2-deoxy-D-glucose transport was investigated using a variety of sugars and sugar analogues; D-glucose, D galactose and D-mannose showed the highest affinity for the transporter, with D glucose possessing a Ki = 120 +/- 20 nM. PMID- 8674546 TI - cDNA cloning of p42, a shared subunit of two proteasome regulatory proteins, reveals a novel member of the AAA protein family. AB - We have employed cDNA cloning to deduce the complete primary structure of p42, a protein previously identified as a common subunit of two proteasome regulatory proteins: PA700, a 700000-Da multisubunit complex that binds to the proteasome and promotes the ATP-dependent degradation of ubiquitinated proteins, and modulator, a 250000-Da PA700-dependent proteasome activator. Computer analysis reveals that p42 is a novel member of a large protein family characterized by a conserved 200 amino acid domain which contains a consensus sequence for ATP binding. Five other members of this family, termed AAA proteins (ATPases associated with a variety of cellular activities) are also subunits of PA700. Gel filtration chromatography was employed to determine the qualitative and quantitative distribution of p42 in crude soluble lysates of bovine red blood cells. These studies demonstrated that p42 was found in two multi-protein complexes: the 26S proteasome (formed from the 20S proteasome and PA700) and the modulator. These results establish the identity of a new protein involved in the regulation of proteasome function and indicate that this protein is found in at least two different protein complexes. PMID- 8674549 TI - Acetylcholinesterase from Bungarus venom: a monomeric species. AB - The venom of Bungarus fasciatus, an Elapidae snake, contains a high level of AChE activity. Partial peptide sequences show that it is closely homologous to other AChEs. Bungarus venom AChE is a non-amphiphilic monomeric species, a molecular form of AChE which has not been previously found in significant levels in other tissues. The composition of carbohydrates suggests the presence of N-glycans of the 'complex' and 'hybrid' types. Ion exchange chromatography, isoelectric focusing and electrophoresis in non-denaturing and denaturing conditions reveal a complex microheterogeneity of this enzyme, which is partly related to its glycosylation. PMID- 8674547 TI - Reverse transcription, amplification and sequencing of poliovirus RNA by Taq DNA polymerase. AB - A model for virion RNA of the poliomyelitis virus, which does not pass the stage of DNA copies during biogenesis, demonstrates that Taq DNA polymerase is capable of synthesizing 960-bp cDNA with the specific primer. When comparing the nucleotide sequence of the starting virion RNA and recombinant DNAs, isolated from several independent clones, copying and amplification of virion RNA appear accurate (one substitution per 960 bp). A comparison of Taq and Tth DNA polymerases in RT/PCR indicates that the sensitivity of Taq polymerase seems to be two orders of magnitude higher than that of Tth polymerase. The RNA detection level under the chosen conditions approached 10(4) RNA copies per test. The present investigation indicates the great versatility of Taq polymerase, which promoted the reverse transcription reaction of RNA, cDNA amplification, screening of recombinant clones as well as sequencing of recombinant DNA. Thus application of Taq polymerase is rather promising not only to detect nucleic acids in biological samples, but also for isolating and cloning individual genes, encoded on DNA and/or on RNA templates. PMID- 8674550 TI - Comparison of proline and N-methylnorleucine induced conformational equilibria in cyclic pentapeptides. AB - The cyclic, imido acid containing pentapeptides cyclo(Asp-Trp-(NMe)Nle-Asp-Phe) (cpp[NMeNle(3)]) and cyclo(Asp-Trp-Pro-Asp-Phe) (cpp[Pro(3)]) have been investigated by 1H-NMR spectroscopy in DMSO and by restrained molecular dynamics methods. The spectra indicate the existence of at least four cis/trans isomers for cpp[NMeNle(3)] and two cis/trans isomers for cpp[Pro(3)]. In addition to the imido peptide bonds, cpp[NMeNle(3)] shows cis/trans isomerization of the Asp4 Phe5 and Phe5-Asp1 peptide bonds whereas only the Phe5-Asp1 peptide bond isomerizes in the Pro-containing peptide. In cpp[Pro(3)] all cis bonds are centred in betaVIb turns. Also, cpp[NMeNle(3)] prefers backbone angles around the cis bonds which are rather similar to the angles of a betaVIb turn. The higher number of cis/trans isomers and slight deviations in the backbone angles of comparable isomers of both peptides are caused by an enhanced flexibility of cpp[NMeNle(3)] due to the possibility of the phi-(NMe)Nle rotation. PMID- 8674551 TI - [News from the front: Highlights of the 1995 AMA interim meeting]. PMID- 8674552 TI - Annual scientific program summary Medical Society of Delaware Saturday, November 18, 1995. PMID- 8674553 TI - Why should physicians worry about patient satisfaction? Applying some of the principles used in the emergency department to hospital and office-based practices. PMID- 8674554 TI - The shape of things to come. PMID- 8674555 TI - Is cancer screening always good for patients? PMID- 8674556 TI - Street drug use in Delaware. PMID- 8674557 TI - Professional aspects of OB/GYN in Germany. PMID- 8674558 TI - Computerized fetal heart rate analysis in labour based on 2-s sampling. Can it proceed with confidence? PMID- 8674559 TI - Urinary cGMP levels during pregnancy with and without uterine contractions. AB - OBJECTIVE: The purpose of this study was to investigate the nitric oxide-cGMP (NO cGMP) system by urinary cGMP level determinations in pregnant women with and without uterine contractions. DESIGN AND SUBJECTS: cGMP expressed in nmol/mmol of creatinine was performed by radio immuno-assay (Amersham UK) in urine samples obtained from 94 pregnant women with non-complicated pregnancies. Population A without contractions (n = 62) was divided into three groups according to the gestational age (group I, < or = 15 weeks; group II, 16-33 weeks; group III, > 33 weeks). The group III from A population was compared to B population (of the same gestational age) presenting uterine contractions (n = 32). RESULTS: In A population, no significant urinary cGMP level differences were observed whatever the gestational age. Nevertheless, the comparison between patients with or without uterine contractions (A III and B populations) showed a significant difference by a variance analysis (P < 0.05). Lower levels of cGMP were seen when uterine contractions occurred. CONCLUSION: Urinary cGMP levels are significantly decreased in pregnant women with uterine contractions, without any difference from early to late pregnancy. These results, completed by more precise investigations, could suggest that the NO-cGMP system might be implicated in uterine quiescence. PMID- 8674560 TI - Immunoreactive parathyroid hormone-related protein: its association with preterm labor. AB - OBJECTIVE: Parathyroid hormone-related protein (PTHrP) is a 141 amino acid protein which contains a 1-36 N-terminal domain resembling parathyroid hormone which has smooth muscle relaxant activity and a mid (67-86) domain which reportedly alters placental calcium transport. Using specific antibodies to these regions of PTHrP, the objective of this study was to determine changes in the levels and localization of the peptides in placenta and membranes that might be indicative of their biological activity and role during term and preterm labor. STUDY DESIGN: Placenta and fetal membranes were collected from patients with preterm delivery (PTL) (n = 16), term cesarean section in the absence of labor (n = 10) and term vaginal delivery (n = 5). Immunohistochemistry was performed with specific antisera visualized by the avidin-biotin peroxidase method and the staining intensity was quantified with an image analysis system MCID. RESULTS: Immunoreactive (ir)-PTHrP(1-34) and ir-PTHrP(67-86) were localized to the amnionic epithelium chorionic trophoblasts, decidual cells and placental syncytiotrophoblast. Intense immunostaining was observed for ir-PTHrP(67-86) but not for ir-PTHrP(1-34) in the endothelial lining of the villous capillaries. Ir PTHrP(1-34) staining was lower in placenta and fetal membranes of PTL patients compared with term cesarean section in the absence of labor (P < 0.05 Mann Whitney test). In contrast, there was no difference in ir-PTHrP [67-86] staining intensity between delivery categories. CONCLUSION: These results showing differential localization of PTHrP(1-34) and PTHrP(67-86) suggest cell specific processing of PTHrP precursor in the human placenta. Moreover, the changes in ir PTHrP(1-34) but not ir-PTHr(67-86) with labor are indicative of a particular role for this peptide in the delivery process. PMID- 8674561 TI - Cigarette smoking and urinary incontinence in women--a new calculative method of estimating the exposure to smoke. AB - The aim of the study was to investigate the relation between cigarette smoking and urinary incontinence. A group of 80 women with incontinence (Group A) were tested urodynamically and compared with a group of 80 continent women (Group B). Patients were divided into smokers (S) and non-smokers (NS) with the incontinent ones classified as suffering from stress (SI) or motor in-continent (UI). The assessment of the smoking behavior of each individual focused upon the tar and nicotine content of each cigarette. The overall exposure to smoke was assessed as follows: tar/nicotine content in mg per cigarette x consumed cigarettes per day x duration of smoking intervals in years. According to the obtained data smokers were divided into current smokers (cs) and stop/start smokers (sss), whereas the current smokers were subdivided into heavy current smokers (hcs) and light current smokers (lcs). Significantly, more S were observed in Group A compared with Group B (48/80 vs. 11/32, P < 0.0005), whereas significantly more SI was found in NS compared with S (21/32 vs. 19/48, P < 0.0025). Particularly hcs developed more frequently UI than SI, although this difference had no statistical significance. According to our data smoking women are more likely to develop incontinence, especially motor incontinence, than non-smokers. Heavy smokers seem to tend more to UI. PMID- 8674562 TI - Modulation of expression of p53 and cell proliferation in locally advanced cervical carcinoma after neoadjuvant combination chemotherapy. AB - OBJECTIVE: In the present study, we investigated changes of p53 expression and the cell proliferation index detected with MIB 1 in tumors before and after neoadjuvant combination chemotherapy with respect to the outcome of the disease. Our aim was to define more appropriately the significance of chemotherapy in locally advanced cervical carcinoma. MATERIALS AND METHODS: Our study included 17 women with locally advanced squamous cervical carcinoma who had been admitted to the Institute of Gynecology and Obstetrics Ancona University, between January 1990 and December 1994. The patients received neoadjuvant combination chemotherapy consisting of three cycles of cisplatin (80 mg/m2) and bleomycin (30 mg/m2). After chemotherapy, radical surgery was performed. Bioptic specimens were obtained from cervical tumors before and after chemotherapy and processed for immunohistochemical staining with a monoclonal antibody against p53 and with the monoclonal antibody MIB 1. RESULTS: Thirteen patients (76.5%) showed a clinical response (4 complete and 9 partial), while of the remaining 4 cases (23.5%) 3 had no change and 1 showed progression after neoadjuvant combination chemotherapy. A significant relationship was observed between the overexpression of p53 and the sensitivity to chemotherapy; responder patients showed a higher frequency of p53 positive cells than non-responders (P = 0.03). No significant relationship with MIB 1 index was observed. Both expression of p53 protein (P < 0.001) and reaction with MIB 1 (P = 0.003) significantly decreased after chemotherapy. The decrease in expression of p53 protein and staining with antibody MIB 1 was particularly evident in patients who responded to chemotherapy. DISCUSSION: In tumors, p53 protein and index of proliferating cells as determined with MIB 1 showed a significant modulation after treatment, suggesting an association with sensitivity to chemotherapy. However, the limited number of our series of patients does not permit a statement on the clinical implication of expression of p53 and cell proliferation in patients undergoing neoadjuvant combination chemotherapy for locally advanced cervical carcinoma. PMID- 8674563 TI - A prospective randomised study of the effects of prophylactic antibiotics on the incidence of bacteraemia following hysteroscopic surgery. AB - OBJECTIVE: To study the effect of prophylactic antibiotics on the incidence of bacteraemia following hysteroscopic surgery. DESIGN: Prospective randomized study. SETTING: Aberdeen Royal Infirmary. SUBJECTS: One hundred and sixteen women about to undergo either endometrial laser ablation (ELA) or transcervical resection of the endometrium (TCRE). INTERVENTION: Fifty-five women were randomised to receive 1.2 g of Augmentin (co-amoxiclav) i.v. at induction of anaesthesia. Sixty-one women received no antibiotic prophylaxis. Blood cultures were obtained at the end of the surgical procedure. RESULTS: Incidence of bacteraemia in the non-antibiotic group (16%) was significantly higher than that in the antibiotic group (2%) (95% confidence interval for difference from 5% to 25%). The majority of organisms were of dubious clinical significance and contamination could not be excluded in 7 cases out of 10. CONCLUSION: There is no convincing evidence that antibiotics are of value in this clinical setting. PMID- 8674565 TI - Gynaecological aspects of primary Sjogren's syndrome. AB - Female patients affected with Sjogren's Syndrome (SS) frequently describe symptoms such as vaginal dryness and dyspareunia; however, only a few controlled studies have regarded clinical involvement of the female external genitalia. OBJECTIVE: The present study was undertaken in order to: (1) Evaluate the involvement of external genitalia in a large number of female patients affected with primary SS (pSS) by semi-quantitative methods covering subjective symptoms and clinical evaluation. (2) Compare pSS patients with a matched healthy control group (pre- and post-menopausal women were separately studied). (3) Correlate the gynaecological involvement with salivary and lacrimal abnormalities in pSS patients. METHODS: We evaluated 36 patients with primary SS (18 pre- and 18 post menopausal women) and 43 healthy controls using a questionnaire regarding vulvar and vaginal dryness and a complete gynaecological examination. Subsequently, three scores related to vulvar and cervical status plus a global score were obtained. In primary SS patients, salivary and lacrimal involvement was also evaluated. RESULTS: Dyspareunia was present in 61% and vaginal dryness in 55% of SS patients versus 39% and 33% of healthy controls. No significant differences regarding gynaecological scores were found between SS patients and controls, in both pre- and post-menopausal women, nor correlation was observed between gynaecological and lacrimal or salivary involvement. CONCLUSIONS: Our data suggest that although SS patients frequently complain of dyspareunia and vaginal dryness they do not greatly differ from healthy subjects in regard to some major gynaecological aspects. PMID- 8674564 TI - Endometrial leukocyte subpopulations in women with endometriosis. AB - The aim of this study was to investigate whether the endometrium of women with endometriosis differs immunologically from the endometrium of normal fertile women. Endometrial biopsies were obtained from 18 normal fertile women who were requesting sterilisation or reversal of sterilisation and 21 infertile women who had laparoscopically diagnosed pelvic endometriosis. The endometrial biopsies were obtained from both groups during the either early, mid or late luteal phase of the menstrual cycle. A panel of 11 monoclonal antibodies and immuno histochemical techniques were employed to characterise the endometrial stromal leukocytes in frozen sections. Image analysis was used for semi quantitation of leukocytes. In both groups, the number of endometrial granulated lymphocytes (CD56+ CD38+ cells) and macrophages (CD68+ cells) increased significantly between the early and late luteal phase of the menstrual cycle. Compared with fertile controls, women with endometriosis had fewer T-suppressor/cytotoxic (CD8+) cells and endometrial granulated lymphocytes but more T-helper/inducer (CD4+) cells, CD68+ cells and CD16+ cells. None of these differences reached a statistically significant level. This study has shown that the endometrial lymphoid tissue of women with endometriosis does not differ qualitatively or quantitively from that of normal fertile controls. However, functional differences of endometrial leukocytes between the two groups cannot be excluded. PMID- 8674566 TI - p53 tumor suppressor gene protein expression in cervical cancer: relationship to prognosis. AB - OBJECTIVE: Mutation of the p53 gene can be found in several human tumors. We tested the hypothesis whether overexpression of p53 protein is a parameter of more aggressive disease in patients with cervical cancer. STUDY DESIGN: In this study, we describe the effects of p53 overexpression in 156 patients with cervical cancer (Figo stage IB-IV) by assessing expression patterns of the p53 gene product using a monoclonal anti-p53 antibody (DO7). RESULTS: Overexpression of p53 tumor suppressor gene protein was observed in 30.2% of the tumors, low expression in 30.7% and 39.1% of the tumors showed no p53 immunoreactivity. With increase in stage, p53 overexpression raised from 20.1% in stage IB to 60% in stage IV. A significant correlation between p53 overexpression and disease-free survival of patients was observed, however, after stratification for stage, this effect disappeared. CONCLUSIONS: The p53 mutation expressed as p53 tumor suppressor gene protein overexpression is a late event in cervical cancer genesis and does not appear to be of prognostic significance in cervical cancer. PMID- 8674568 TI - Ovarian malignancies in childhood and adolescence. AB - We retrospectively reviewed all cases of ovarian malignancies during a 10-year period at the Department of Obstetrics and Gynecology, University Medical School of Debrecen, Hungary. The experience with 16 cases: three epithelial tumors, one granulosa cell tumor, 11 germ cell tumors (six dysgerminoma, four teratoma, one endodermal sinus tumor), and one metastatic ovarian cancer is discussed. Malignant ovarian tumors can best be treated with conservative surgery, followed by adjuvant chemotherapy. Survival mainly depends on tumor type and stage at the time of diagnosis. PMID- 8674567 TI - Treatment of Bartholin's cyst and abscess: excision versus silver nitrate insertion. AB - In a prospective randomized study, intracavitary silver nitrate (AgNO3) stick insertion (n = 25) was compared to the conventional excision technique (n = 25) for Bartholin's cyst or abscess. Two groups were similar with regard to age, previous Bartholin's cyst/abscess and size of the cyst. Operation and healing time was significantly shorter in the AgNO3 group (P < 0.001, P < 0.001, respectively). Chemical burning in the vulva was observed in one patient in the AgNO3 group, whereas hematoma on the operation site occurred in two patients in the excision group. Scar formation was found in two patients in whom excision was performed. Patients were followed for a period of 2 years and recurrence was not found in any of the cases in both groups. We conclude that, AgNO3 insertion treatment for Bartholin's cyst and abscess is as effective as excision and is associated with fewer complications. Because it is simple and inexpensive, it is an attractive alternative treatment modality for this common gynecological disease. PMID- 8674569 TI - Estrogen and progesterone receptor content of GnRH analogue pretreated and untreated uterine leiomyomata. AB - OBJECTIVES: The steroid receptor concentration and the histological morphology of uterine leiomyomata in premenopausal patients undergoing myomectomy therapy with and without a preoperative GnRH analogue, was analysed to evaluate whether the GnRH analogue therapy leads to important hormonal receptor changes, histomorphological changes and a significant shrinkage of the leiomyomata. STUDY DESIGN: Sixty-one GnRH analogue pretreated leiomyomata and 28 untreated leiomyomata were analysed. To determine the estrogen and progesterone receptor concentrations, immunohistochemical techniques were used and quantified with the immuno-reactive score (IRS-score). The leiomyomata were divided into cellular rich, normal, hyaline or cystic degenerated and necrotic according to their histology. RESULTS: The GnRH analogue pretreated leiomyomata group showed higher levels of estrogen and progesterone receptors than the untreated group (37.7% of the GnRH analogue group had a high positive and 29.5% a moderate positive estrogen receptor status whereas high levels of estrogen receptor could be found in only 14.3% of the untreated group). The leiomyomata of both groups with the exception of the necrotic ones, were estrogen and progesterone receptor positive. CONCLUSIONS: Our study suggests that pretreatment of uterine leiomyomata leads to a significant increase in the hormonal receptor concentration of these benign tumors. If pretreated leiomyomata are not removed surgically immediately after the therapy, a rapid regrowth can occur and again cause clinical symptoms. PMID- 8674570 TI - Congenital cytomegalovirus infection. AB - OBJECTIVE: Congenital cytomegalovirus is the most common viral infection affecting approximately 1% of newborns. The virus can be transmitted to the fetus during both primary and recurrent infection. Although most of the infants are asymptomatic at birth, up to 15% develop late complications. The annual cost of treating cytomegalovirus infection complications in the USA is two billion US dollars. Many issues regarding cytomegalovirus infection such as routine screening, antenatal diagnosis and vaccination during pregnancy are unsettled and disputed. The aim of this article is to review the current literature on the subject and to draw some conclusions. DESIGN: Review of the current literature. CONCLUSIONS: At present, it appears that there is no indication for routine prenatal screening, while other issues, such as the most accurate method for antenatal diagnosis and the indications for pregnancy termination are, as yet, unsettled. PMID- 8674572 TI - Comparative aspects of placental exchange functions. AB - The anatomic structure of the placenta varies widely at the macroscopic and microscopic levels, and these differences are often reflected in differences in exchange mechanisms. For example, placental iron transfer proceeds by three distinct mechanisms each associated with a distinctive anatomic feature. A number of factors also affect the exchange capacity per unit of placental tissue, these include boundary properties and the arrangement and rates of fetal and maternal placental blood flows. Generally, the exchange rate of a substrate is limited principally by the membranes or by blood flow but these interact in a complex fashion. When exchange occurs by relatively slow passive diffusion, the barrier thickness and exchange area per gram of placenta are most important. The T diagram reveals that a counter- or crosscurrent arrangement of blood streams is most efficient. However, relatively few placentas make use of these high efficiency designs. It is suggested that only in animals such as rodents and shrews where a large fetus is produced in a short time by a small placenta does placental exchange capacity need to be pushed to its theoretical limits. We define an index termed the 'turbo factor' (= term fetal weight/[placental weight x days of gestation]) to express the extent to which growth taxes the placenta. A value of > 0.2 seems to require a placenta of the high-efficiency type and may predict that, in a given species, the placenta makes use of the most efficient arrangement of blood flows. PMID- 8674571 TI - The effect of intermittent steroid therapy on anti-sperm antibody levels. AB - Sperm-bound antisperm antibody levels were measured in 10 males in subfertile partnerships who were treated with high dose intermittent prednisolone therapy over a period up to 9 months. Antibody levels fell in all patients during therapy, although a transient rise occurred after 2-4 months. There were low treatment complication rates. Four pregnancies occurred during the treatment of the 10 patients. There was no correlation between pregnancy and change in antibody. PMID- 8674573 TI - Delayed interval delivery after intrauterine infection and immature birth of twin 1--a case report and literature review. AB - We report a case of delayed interval delivery in a twin pregnancy complicated by rupture of membranes, intrauterine infection and birth of one twin at 21 weeks gestation. Tocolysis combined with antibiotics and corticosteroids successfully prolonged pregnancy for 73 days, allowing the second twin to mature and reach viability. At 31.5 weeks gestation, a 1890 g healthy male neonate was born with good Apgar scores. His postnatal course was uneventful. A literature review of several other cases of delayed interval delivery is presented. When multifetal pregnancies are complicated by immature birth of one fetus, delayed interval delivery may offer survival chances and favourable outcome for the remaining fetus(es). PMID- 8674574 TI - Pelvic kidney: a rare cause of obstetrical obstruction. AB - This case report presents a patient with a pelvic kidney. The child was delivered by caesarean section because of obstruction of the birthcanal. A relation with amyoplasia congenita in the newborn is presumed. The literature of the pelvic kidney and its implications in pregnancy is reviewed. PMID- 8674575 TI - Gas embolism complicating obstetric or gynecologic procedures. Case reports and review of the literature. AB - Gas embolism is a rare life-threatening complication of obstetric or gynecologic procedures, arising as a result of gas bubbles being introduced into the circulation via severed blood vessels. Extensive brain damage and acute cardiovascular collapse will lead to a fatal outcome. A favourable outcome depends on early diagnosis and prompt treatment. Hyperbaric oxygenation, which reduces bubble size and increases the supply of oxygen to hypoxic tissues, is the definitive treatment for gas embolism. We report four cases of gas embolism complicating obstetric or gynecologic procedures which were treated at the Israel Naval Medical Institute followed by an updated review of the literature. PMID- 8674576 TI - Viruses in the RNA world. PMID- 8674577 TI - Activation of NF kappa B and potentiation of TNF-induced NF kappa B activation by ceramide analogues in leukemic cell lines despite the absence of an observed sphingomyelinase signalling event. PMID- 8674578 TI - Crystal structures of a ferredoxin: NADP+ reductase and of a complex with NADP+. PMID- 8674579 TI - Characterization of the sea urchin egg receptor for sperm. PMID- 8674580 TI - Secretory properties of clonal insulin-secreting BRIN-BG5 cells, produced by electrofusion. PMID- 8674581 TI - Quantitative measurement of sulphated glycosaminoglycans in urine. PMID- 8674582 TI - Glycosaminoglycan accumulation in amniotic fluid during early pregnancy. PMID- 8674583 TI - Modification of the glycosyl groups of collagen: effects on fibril assembly. PMID- 8674584 TI - Molecular evolution and substrate specificity of acyl-CoA dehydrogenases: chimaeric "medium/long' chain-specific enzyme from medium-chain acyl-CoA dehydrogenase. PMID- 8674585 TI - Analysis of mutations at the adenine phosphoribosyltransferase gene locus in wild type and thymidine kinase-deficient Friend cells. PMID- 8674587 TI - The 3'untranslated region of the human estrogen receptor gene post transcriptionally reduces mRNA levels. PMID- 8674586 TI - Cloning of an Atlantic salmon transcription factor. PMID- 8674588 TI - A novel genetic assay for mutations which affect post-embryonic development or the behaviour of adult flies. PMID- 8674589 TI - The chromosomal organisation of the alcohol dehydrogenase region of the genome of Drosophila melanogaster. PMID- 8674590 TI - Affinity precipitation of dehydrogenases with bis-NADH derivatives. PMID- 8674591 TI - Expression of the serpin genes squamous cell carcinoma antigen and leupin in human tissues. PMID- 8674594 TI - Reduction of MTT as an index of electropermeabilization in spermatozoa. PMID- 8674593 TI - Cloning sequencing and expression of the serpin ovalbumin gene Y. PMID- 8674592 TI - Molecular recognition in protein complexes involved in electron transfer. PMID- 8674595 TI - A spectrophotometric assay of intercellular communication. PMID- 8674596 TI - The functional role of the gamma-chain cysteine in Fc gamma RI-mediated phagocytosis using co-transfected COS-7 cells. PMID- 8674597 TI - The use of biotinylation in the detection and purification of affinity labelled Glut-1. PMID- 8674599 TI - Post dialysis fluid (CAPD) increases 3H cholesterol efflux from human skin fibroblasts. PMID- 8674598 TI - NMR studies of flavoproteins. PMID- 8674601 TI - The effect of oligomycin on the adhesion strength of cultured Chinese hamster lung (CHL) cells. PMID- 8674600 TI - Investigation of glucocorticoid modulation of apolipoprotein mRNA transcription. PMID- 8674602 TI - Rapid purification of heart muscle enzymes using dye affinity aqueous two-phase systems. PMID- 8674603 TI - Expression and analysis of the gene for the catalytic beta subunit of the sodium translocating NADH-ubiquinone oxidoreductase of Vibrio alginolyticus. PMID- 8674604 TI - Rapid enrichment of poly (ADP-ribose) polymerase using magnetic DNA affinity beads. PMID- 8674605 TI - AMP-succinate lyase in lymphocytic leukemia. PMID- 8674607 TI - The effect of high frequency ultra sound on cell adhesion. PMID- 8674606 TI - Regulation of the redox potentials of flavodoxins: modification of the flavin binding. PMID- 8674608 TI - Using computers to teach undergraduates about biological molecules. PMID- 8674609 TI - The CTI Centre for Biology: network-based information services for biochemists. PMID- 8674610 TI - The simulation of substantial conformational transitions of proteins: progress in the application of path energy minimization in internal coordinate space. PMID- 8674611 TI - Improving the engineered activity of mutants of clostridial glutamate dehydrogenase towards monocarboxylic substrates: substitution of Ala163 with glycine. PMID- 8674613 TI - A peptide molecular dynamics study correlates structure with function. PMID- 8674612 TI - Unifying concepts in flavin-dependent catalysis. AB - Flavin-dependent proteins can be involved in a wide variety of biochemical reactions. Among these reactions are electron transfer, oxidase activity, dehydroxygenase activity and mono- and dioxygenations. Furthermore, the oxygenation steps may proceed by either electrophilic or nucleophilic reaction mechanisms. The present paper focuses on aromatic hydroxylation by a nucleophilic C(4a) hydroperoxyflavin cofactor. The reactivity of this intermediate is highly dependent on its actual protonation state as well as on the (de)protonation of the substrate to be converted. Electrophilic attacks by the peroxyflavin intermediate on the substrate and favoured by a protonated C(4a) hydroperoxyflavin and a (partially) deprotonated hydroxyl moiety in an aromatic substrate. Thus, the actual mechanism of enzyme catalysis is basically that the enzyme provides possibilities for the coexistence of (de)protonation states of cofactor and substrate that would normally not be possible in one solution at one pH value. Another concept presented in this paper, originating from results obtained in molecular orbital studies on flavin-dependent mono-oxygenation reaction by phenol hydroxylase and 4-hydroxybenzoate-3-hydroxylase, questions the actual unifying concept found in some biochemical textbooks that proposes that enzymes accelerate chemical reactions by stabilization of the transition state only. The results of the present study demonstrate that increasing the reactivity of the substrate and/or cofactor may be another important mechanism to decrease the activation barrier of a chemical reaction. PMID- 8674614 TI - The lysopine and octopine dehydrogenase activities of Mytilus edulis are catalysed by a single enzyme. PMID- 8674615 TI - The synthesis and characterisation of a glyoxal inhibitor of chymotrypsin. PMID- 8674616 TI - Oxidation of NADH catalysed by human xanthine oxidase: generation of superoxide anion. PMID- 8674617 TI - 1H-NMb spectroscopy of beta-thiocyanatoalanine. PMID- 8674619 TI - A study of the pH dependence of the reaction of benzyloxycarbonyltryptophanylchloromethane with chymotrypsin. PMID- 8674618 TI - A study of the stabilization of semiquinones by the Escherichia coli quinol oxidase cytochrome bd. PMID- 8674620 TI - Proof that serine hydroxymethyltransferase retains its specificity for the pro-2S proton of glycine in the absence of tetrahydrofolate. PMID- 8674621 TI - Function of the two mannose 6-phosphate receptors in lysosomal enzyme transport. PMID- 8674622 TI - Enzymatic synthesis of alpha-deuterated amino acids. PMID- 8674623 TI - Kinetic analysis of the exchange of the alpha-protons of amino acids by pyridoxal phosphate-dependent enzymes. PMID- 8674624 TI - A 1H-NMR study of the histidine resonance's of native subtilisin and of subtilisin inhibited by benzyloxycarbonylglycylglycylphenylalanyl-chloromethane. PMID- 8674625 TI - Insulin-like growth factor II/cation-independent mannose 6-phosphate receptor and lysosomal enzyme recognition. PMID- 8674626 TI - In vitro construction of inter-subunit hybrids in Clostridium symbiosum glutamate dehydrogenase. PMID- 8674627 TI - Simulation of voltage-dependent insertion of alpha-helical peptides into lipid bilayers. PMID- 8674628 TI - Molecular dynamics simulations on solvated M2 helix bundles of nicotinic receptors. PMID- 8674629 TI - Water dynamics in model transbilayer pores. PMID- 8674630 TI - Role and oxidation state of the pterin molybdenum cofactor of molybdenum enzymes: studies of a Drosophila melanogaster xanthine dehydrogenase (rosy) variant, G1011E. PMID- 8674631 TI - Simulation of the packing of transmembrane alpha-helices. PMID- 8674632 TI - Galectins in mouse embryogenesis. PMID- 8674633 TI - Rationalisation of the C-S lyase activity of aspartate amino transferase. PMID- 8674634 TI - TGF beta 1 alters the production of collagen types I and III by human gingival fibroblasts. PMID- 8674635 TI - Quantum mechanical model assembly calculations of energetics of binding of ligands to protein receptors. PMID- 8674636 TI - Domain swap chimeras to study the binding of IgG by Fc gamma RI, the high affinity receptor for IgG. PMID- 8674637 TI - Effects of dietary sucrose and cortisone on hepatic acetazolamide-resistant carbonic anhydrase. PMID- 8674638 TI - Ca(2+)-dependent sugar recognition by animal lectins. PMID- 8674639 TI - The role of GTP binding proteins in the release of gonadotrophin by alpha T3-1 cells. PMID- 8674640 TI - Interactions of proteins with dyes conjugated to soluble polymers. PMID- 8674641 TI - Development of a model system for investigating cell/surface affinity interactions. PMID- 8674642 TI - Preliminary functional studies of mutant D114N of Clostridium symbiosum glutamate dehydrogenase. PMID- 8674643 TI - Cyclin from sea urchins to HeLas: making the human cell cycle. PMID- 8674644 TI - On the molecular basis of inhibition by excess substrate in wild-type and Y143F flavocytochrome b2. PMID- 8674646 TI - Investigation of the inhibition of complement mediated cell death. PMID- 8674645 TI - Sialoadhesin and related cellular recognition molecules of the immunoglobulin superfamily. PMID- 8674647 TI - Crystallisation of the flavodoxin from Megasphaera eldenii . PMID- 8674648 TI - FTIR spectroscopic structural analysis of the CHIP28 water channel protein. PMID- 8674650 TI - Functional uncoupling between flavin and heme domains in flavocytochrome b2 by a monoclonal antibody. PMID- 8674649 TI - C-type lectins of natural killer cells: carbohydrate ligands and role in tumour cell lysis. PMID- 8674651 TI - The dopamine D1 receptor family: structural and functional aspects. PMID- 8674652 TI - Expression of newly cloned brain dopamine receptors in peripheral organs. PMID- 8674653 TI - Inhibition of flavin reoxidation in P450 BM3 by diphenyliodonium chloride. PMID- 8674654 TI - Effects of glutamate antagonists on nigral dopamine release in the reserpine treated rat. PMID- 8674655 TI - Dopamine receptor multiplicity: "D1-like'-"D2-like' interactions and " D1-like" receptors not linked to adenylate cyclase. PMID- 8674656 TI - Formation of flavin semiquinone during the reduction of P450 BM3 reductase domain with NADPH. PMID- 8674657 TI - D2 receptor agonists and partial agonists: relationship between receptor binding measures and functional activity. PMID- 8674658 TI - The binding of agonists and antagonists to dopamine receptors. PMID- 8674659 TI - Deflavination of cytochrome P450 BM3 by treatment with guanidinium chloride. PMID- 8674660 TI - Functional models for the dopamine D3 receptor. PMID- 8674661 TI - Elucidation of D3 receptor function in vivo: do D3 receptors mediate inhibition of dopamine neuronal activity? PMID- 8674662 TI - Mechanism of NF kappa B activation by interleukin-1 and tumour necrosis factor in endothelial cells. PMID- 8674663 TI - Reversibility of inhibition of human type II nitric oxide synthase. PMID- 8674664 TI - Dopamine receptors and schizophrenia. PMID- 8674665 TI - Interleukin I receptors and signal transduction. PMID- 8674666 TI - Reactivity of sulfhydryl groups of Rhodotorula gracilis D-amino acid oxidase. PMID- 8674667 TI - Can n-3 polyunsaturated fatty acids be used as immunomodulatory agents? PMID- 8674668 TI - A chimeric iron-sulfur flavoprotein endowed with NADPH-cytochrome c reductase activity. PMID- 8674669 TI - Membrane molecules and macrophage endocytosis: scavenger receptor and macrosialin as markers of plasma-membrane and vacuolar functions. PMID- 8674670 TI - Intervention in the complement system: a therapeutic strategy in inflammation. PMID- 8674671 TI - Anti-oxidants and apoptosis. PMID- 8674672 TI - The purification and characterisation of flavin adenine dinucleotide phosphohydrolase from Brevibacterium ammoniagenes. PMID- 8674673 TI - Intraislet expression of inducible nitric oxide synthase and islet cell death. PMID- 8674674 TI - The TOR signalling pathway and growth control in yeast. PMID- 8674675 TI - The effects of pH on the absorption spectrum of the hydroquinone of flavodoxin from Desulfovibrio vulgaris. PMID- 8674676 TI - Phosphoinositide 3-kinase and CD28-mediated T-cell co-stimulation. PMID- 8674677 TI - Simulations of enzymic reactions. PMID- 8674678 TI - Comparison of the N-terminal sequence of NADH oxidase from Thermus aquaticus with those of other flavoenzymes. PMID- 8674679 TI - Brownian dynamics simulations of enzyme-substrate encounter. PMID- 8674680 TI - Simulations on the activation of the bradykinin B2 receptor. PMID- 8674681 TI - Chemical synthesis of 8-bromo(adenine)-FAD by direct bromination of FAD. PMID- 8674682 TI - Quantum mechanical/molecular mechanical approaches to transition state structure: mechanism of sialidase action. PMID- 8674683 TI - Force field development and conformational search strategy in the simulation of biomolecular recognition processes. PMID- 8674684 TI - Purification and partial characterisation of the E14K mutant of flavodoxin from Megasphaera elsdenii. PMID- 8674685 TI - ProMod and Swiss-Model: Internet-based tools for automated comparative protein modelling. PMID- 8674686 TI - The redox potentials of flavodoxin from Desulfovibrio vulgaris and ferredoxin NADP+ reductase from Spinacia oleracea and their complexes. PMID- 8674687 TI - Molecular recognition by proteins: protein-ligand interactions from a structural perspective. PMID- 8674689 TI - The Caenorhabditis elegans genome project. C. elegans Genome Consortium. PMID- 8674688 TI - Mapmakers--progress in the human genome project. PMID- 8674690 TI - The purification and crystallisation of 2,5-diketocamphane 1,2-monooxygenase and 3,6-diketocamphane 1,6-monooxygenase from Pseudomonas putida NCIMB 10007. PMID- 8674691 TI - From DNA sequence to biological function: the new "Voyage of the Beagle'. PMID- 8674692 TI - The use of computers in the teaching of biochemistry: support for learning the qualitative differences. PMID- 8674693 TI - The Bionet project--beyond writing courseware. PMID- 8674694 TI - Inhibition of NF kappa B activity by oxidative processes in intact cells mechanism of action of pyrolidine dithiocarbamate and diamide. PMID- 8674695 TI - Reaction of apoflavodoxin from Desulfovibrio vulgaris with 5,5'-dithio-bis-(2 nitrobenzoic acid). PMID- 8674696 TI - Issues arising from the transnational evaluation and dissemination of Teaching and Learning Technology Programme materials. PMID- 8674697 TI - Crystallisation of the flavodoxin from Megasphaera eldenii. PMID- 8674698 TI - Engineering and expression in Drosophila melanogaster of a xanthine dehydrogenase (rosy) variant. PMID- 8674699 TI - Purification of flavocytochrome b558: comparison between octylglucoside and a perfluoralkyl detergent. PMID- 8674700 TI - Kinetic characterization of Anabaena ferredoxin-NADP+ reductase mutants. PMID- 8674702 TI - The signal transduction pathway leading from the toll receptor to nuclear localization of dorsal transcription factor. PMID- 8674701 TI - Structural investigation on recombinant riboflavin synthase from E. coli. PMID- 8674703 TI - Biosynthesis of riboflavin. Bifunctional pyrimidine deaminase/reductase of Escherichia coli and Bacillus subtilis. PMID- 8674704 TI - Characterization of two recombinant forms of ferredoxin-NADP+ reductase from Anabaena PCC 7119 (presentation reference 204). PMID- 8674705 TI - Structure and mechanism of GTP cyclohydrolase I of Escherichia coli. PMID- 8674706 TI - Binding of NO to the oxygen reaction site of cytochrome bd from Azotobacter vinelandii. PMID- 8674707 TI - Rel signalling pathway and the melanotic tumour phenotype of Drosophila. PMID- 8674708 TI - Quantitative analyses of control exerted by overt carnitine palmitoyltransferase over hepatic fatty acid oxidation and ketogenesis in suckling rats. PMID- 8674709 TI - Early response gene expression in Ras oncoprotein signalling. PMID- 8674710 TI - Cyanylation of the thiol of the cysteine of flavodoxin from Anabaena PCC 7119. PMID- 8674711 TI - Activation of (ADP-ribose)polymerase by complexes of oligodeoxynucleotides. PMID- 8674712 TI - Human plasma carboxypeptidase N; stability of enzyme activity following collection. PMID- 8674713 TI - Oscillatory NADH-oxidase activity of horseradish peroxidase. PMID- 8674714 TI - The alpha-amylase of Bacillus coagulans. PMID- 8674715 TI - The actions of cyclosporin A and FK506 on T-lymphocyte activation. PMID- 8674716 TI - Initial studies on an amylopullulanase from Bacillus sp. DSM 405. PMID- 8674717 TI - Amino acid sequence alignment of a "small' citrate synthase from Pseudomonas aeruginosa PAC 514, with other citrate synthase sequences. PMID- 8674718 TI - Approach to development of tentacle affinity matrices. PMID- 8674719 TI - Endo 5'-nucleotidase in healthy peripheral blood lymphocytes. Inhibition by alpha beta methylene adenosine 5'-diphosphate. PMID- 8674720 TI - A yeast transcription factor activating G1 cyclin expression has similarity to bacterial signal transduction proteins. PMID- 8674721 TI - Expression of the 5'-nucleotidase gene in the peripheral blood lymphocytes from B chronic lymphocytic leukemia. Evaluation of mRNA. PMID- 8674722 TI - Regulation of Id-HLH transcription factor function in third messenger signalling. PMID- 8674723 TI - Ecto 5'-nucleotidase in B-cell lymphocytic leukemia. PMID- 8674724 TI - Purine nucleotide metabolism in lymphocytic leukemia. Behavior of principle enzymes. PMID- 8674726 TI - Allosteric regulation of rat and human dopamine receptor subtypes: evidence for two binding states for [3H]spiperone. PMID- 8674725 TI - Brain cytochrome P450 in the rat. PMID- 8674727 TI - E2F and the molecular mechanisms of early cell-cycle control. AB - This is an exciting era in cell-cycle research. We are now uncovering the molecular details of a critical pathway which regulates early cell-cycle progression by integrating signals emanating from proteins that drive the cell cycle with the transcription apparatus and the consequent control of target genes. Molecules that function to positively regulate, such as cyclin-cdk complexes, and negatively regulate, such as the cdk inhibitors, converge on the pathway and, in turn, regulate the activity of pRb and related proteins. A principal role of pRb is in the regulation of the E2F family of transcription factors, and activity of which determines cell-cycle progression. Importantly, many of the proteins in this pathway are encoded by genes which are frequently mutated in tumour cells, a feature which emphasizes the pathway's critical role in orchestrating early cell-cycle control. In fact, it seems likely that the pathway is, at some point, aberrantly regulated in most, if not all, human tumour cells. It is principally E2F that pRb seeks out to exert its effect on the cell cycle. However, it is unclear why there is such a plethora of E2F/DP heterodimers under the E2F umbrella: different genes, different targets or different pathways of control? In human tumour cells, why is Rb so frequently mutated, whereas the genes encoding p107 and p130 apparently not so? Does this imply that the physiological roles of p107 and p130 are of overwhelming importance that cells cannot accommodate mutation in either gene, or do they take on such minor roles that their mutation in tumour cells would be of incidental consequence? These questions, and many others, remain to be resolved. Finally, we should never forget that the increasing knowledge of cell-cycle control has profound implications for the treatment of proliferative disease. The progress and insights into the physiological pathways which regulate cell-cycle progression offer a new and exciting range of realistic targets through which oncogenesis may, in the near future, be effectively treated. The mechanistic and structural information that is rapidly accumulating offers new promise in the search for small-molecule clinically viable drugs. PMID- 8674728 TI - Protein kinase C modulation of phosphoinositidase C in 1321N1 human astrocytoma cells. PMID- 8674729 TI - Stimulation of prostacyclin release by endothelial ATP receptors requires activation of protein kinase C and tyrosine kinases. PMID- 8674730 TI - Protein kinase C isoforms in endothelial cells: role in agonist stimulated prostacyclin release. PMID- 8674731 TI - Comparison of agonist potencies at human dopamine D2 and D3 receptors, expressed in the same cell line, using the Cytosensor Microphysiometer. PMID- 8674732 TI - Inositol 1,4,5-trisphosphate perfusion of electropermeabilised SH-SY5Y neuroblastoma cells produces quantal calcium uptake and release. PMID- 8674733 TI - Properties of some peptides related to amyloid beta-peptide. PMID- 8674734 TI - Sustained c-fos expression is associated with excitotoxicity during the development of neuronal cells in vitro. PMID- 8674735 TI - The interaction of 1-methyl-4-phenylpyridinium (MPP+) with bovine adrenal medulla chromaffin vesicle ghosts. PMID- 8674736 TI - Protein engineering of domains in flavoprotein disulphide oxidoreductases: contributions to folding and assembly. PMID- 8674737 TI - Nicotinamide derivatives and mitochondrial respiration. PMID- 8674738 TI - The effects of 1-methyl-4-phenylpyridinium ion on biogenic amine levels in rat substantia nigra. PMID- 8674739 TI - Substrate specificity of human platelet monoamine oxidase B activity Parkinson's and Alzheimer's disease. PMID- 8674740 TI - Nitrocatechol derivatives as inhibitors of catechol-O-methyltransferase. PMID- 8674741 TI - Vascular smooth muscle cells from spontaneously hypertensive rats exhibit increased MAPK response to angiotensin II and phorbol ester stimulation. PMID- 8674742 TI - Lack of inhibition of phosphoinositide 3-kinase enzyme activity by FKBP12/rapamycin. PMID- 8674743 TI - A glutathione reductase-like flavoenzyme of the malaria parasite Plasmodium falciparum: structural considerations based on the DNA sequence. PMID- 8674744 TI - Investigation of the role of protein kinase C and tyrosine kinases during the rapid and sustained release of superoxide from adherent human neutrophils. PMID- 8674745 TI - Lipoprotein lipase expression in human monocyte-derived macrophages. PMID- 8674746 TI - Stimulation of signal transduction pathways by MCP-1 in human monocytes and THP-1 cells. PMID- 8674748 TI - Integrin triggered Ca2+ signalling in human neutrophils. PMID- 8674747 TI - Early response genes activated by stimulation of human B lymphocytes through different cell surface receptors. PMID- 8674749 TI - An investigation of the response of lymphoblastoid cells to hydrogen peroxide derived oxidative stress. PMID- 8674750 TI - Investigation into the mechanisms of complement mediated cytotoxicity in pancreatic beta cells. PMID- 8674751 TI - Flavocytochrome b2: an ideal model system for studying protein-mediated electron transfer. PMID- 8674752 TI - Inhibition of nitric oxide induced cytotoxicity in pancreatic b-cells. PMID- 8674753 TI - Investigation into the effects of adrenaline and/or lipopolysaccaride on nitrite production by murine macrophages. PMID- 8674754 TI - The effect of antioxidant supplementation on the oxidant-induced stress response in human lymphocytes. PMID- 8674755 TI - A possible mechanism for the inhibition of blood platelet aggregation by pyridoxal-5'-phosphate. PMID- 8674756 TI - The chemical mechanism of flavoprotein-catalysed alpha-hydroxy acid dehydrogenation: a mutational analysis. PMID- 8674757 TI - The effect of varying the omega-6: omega-3 ratio of the diet upon immune function in the rat. PMID- 8674758 TI - Glutamine requirement of proliferating T lymphocytes. PMID- 8674759 TI - Tyrosine phosphorylation in inflammatory neutrophils. PMID- 8674760 TI - Photoinactivation of glutathione reductase by hematoporphyrin and Al phthalocyanine tetrasulfonate. PMID- 8674761 TI - Wortmannin enhances tumour necrosis factor alpha-stimulated neutrophil apoptosis. PMID- 8674763 TI - Effect of pertussis toxin and PGE2 on the functioning of the IL-2 promoter in interleukin-1 treated EL4.NOB-1 thymoma cells. PMID- 8674762 TI - Investigation into the role of protein kinase C in IL1 and PMA signalling in EL4.NOB-1 thymoma cells. PMID- 8674764 TI - Differential stimulation of IL-6 secretion following apical and basolateral presentation of IL-1 on epithelial cell lines. PMID- 8674765 TI - Escherichia coli chorismate synthase. PMID- 8674766 TI - Heat-shock proteins (Hsps)-reactive T-cells in inflammatory disease. PMID- 8674767 TI - Do heat-shock proteins (Hsps)65-reactive lymphocytes in rheumatoid arthritis, Hashimoto's thyroiditis & systemic lupus erythematosus implicate Hsp65 in autoimmunity? PMID- 8674768 TI - Electrophoretic analysis of rainbow trout (Oncorhynchus mykiss) mucus. PMID- 8674769 TI - Characterisation of a serine/threonine kinase which mediates CD28 phosphorylation following activation by B7.1. PMID- 8674770 TI - Involvement of phosphatidylinositol 3-kinase in the activation of p70 S6 kinase by the T cell costimulatory molecule CD28. PMID- 8674771 TI - Biosynthesis of riboflavin: structure and mechanism of lumazine synthase. PMID- 8674772 TI - Rapamycin-resistant human lymphoid cell lines. PMID- 8674773 TI - The oxidative and reductive half reactions of subunit interface mutants of Escherichia coli glutathione reductase. PMID- 8674774 TI - Effects of cyclolinopeptide A on T lymphocyte activation and peptidyl prolyl isomerase activity. PMID- 8674775 TI - Role of p70 S6 kinase in lymphocyte activation. PMID- 8674776 TI - Near membrane Ca2+ changes in neutrophils. PMID- 8674777 TI - A role for RANTES in T lymphocyte proliferation. PMID- 8674778 TI - Heterogeneous expression of UDP-glucuronosyltransferases in periportal and perivenous hepatocytes. PMID- 8674779 TI - Glutamate synthase: a complex iron-sulphur flavoprotein. PMID- 8674780 TI - Effect of pyridoxal-5'-phosphate on aggregation of platelets from stored human concentrates induced by arachidonic acid. PMID- 8674781 TI - Fish-odour syndrome and impaired N-oxidation. PMID- 8674782 TI - V region connectivity vs mimicry in the selection of T-cell repertoire. PMID- 8674783 TI - Secondary structures in water of chondroitin-4-sulphate and dermatan sulphate. Implications in the formation of tertiary structures. PMID- 8674784 TI - Recent studies on xanthine oxidase and related enzymes. PMID- 8674785 TI - Molecular modelling analyses of the C-type lectin domain in human aggrecan. PMID- 8674786 TI - Speculations on the influence of electromagnetism on genomic and associated structures. AB - Recent clinical and experimental works in the area of bioelectromagnetics are reviewed and considered from a physical viewpoint. An equation relating the intrinsic (or 'rest') energy of a charged particle with its energy of interaction in an externally applied magnetic field is proposed. This equation is intended to represent an initial basic physical interaction which may be part of a more complex biological mechanism that may explain the potential effects of externally applied magnetic fields. Speculations are presented on the potential use of magnetic fields for the non-invasive treatment of such diverse conditions such as cancer, AIDS and neurological disorders. PMID- 8674787 TI - Clinical evaluation of roxithromycin in patients with acne. AB - On the basis of reports that erythromycin is effective in the treatment of acne, we investigated whether roxithromycin (ROM), a new derivative of erythromycin, might also be effective in treating acne. Roxithromycin was administered to 30 patients with acne for 8 weeks. General improvement was assessed 8 weeks after the initiation of the therapy with a six-graded scale as follows; 1: good improvement, 2: moderate improvement, 3: slight improvement, 4: no change, 5: worsening, and 6: no assessment. The percentage of good or moderate improvement was 73.3%, and that of good improvement alone was 20.0%. Our results suggest that ROM is effective in the treatment of acne. PMID- 8674788 TI - Granulocyte-colony stimulating factor and erythropoietin therapy in children with human immunodeficiency virus infection. AB - To determine whether granulocyte-colony stimulating factor and erythropoietin are effective in the therapy of neutropenia and anaemia related to human immunodeficiency virus (HIV) infection and to anti-retroviral agents, we recruited 11 HIV-infected children (mean age 4 years 10 months). All the children were given granulocyte-colony stimulating factor at a dosage of 5 micrograms/kg twice or three times a week while erythropoietin was administered additionally to three patients at a dosage of 50 U/kg twice a week. Both agents were administered subcutaneously for at least 4 months. Leukocyte and neutrophil counts significantly increased during the treatment (after 1 months, P = 0.003 and P = 0.009, respectively). Erythropoietin prevented blood transfusions and increased haemoglobin levels in the three children treated. No side-effects were recorded during the administration of either agent. Granulocyte-colony stimulating factor and erythropoietin appear to be safe and useful agents in the management of HIV infected children. PMID- 8674789 TI - Activity of nadifloxacin against methicillin-resistant Staphylococcus aureus isolated from skin infections: comparative study with seven other fluoroquinolones. AB - The in vitro susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) to nadifloxacin and seven other fluoroquinolones (norfloxacin, ofloxacin, enoxacin, ciprofloxacin, lomefloxacin, tosufloxacin and sparfloxacin) was evaluated. The MRSA isolates were isolated from 114 skin infections between 1991 and 1994. Nadifloxacin exhibited the lowest minimum inhibitory concentration and there were no MRSA isolates resistant to nadifloxacin, while there were some resistant to all of the other seven fluoroquinolones. The minimum concentrations of these drugs needed to cause 50% inhibition of the isolates increased dramatically from 1991 to 1992, but has hardly changed since 1992. PMID- 8674790 TI - Diversity of the neuropathies in patients with non-insulin-dependent diabetes mellitus. AB - The relationships between cardiac autonomic neuropathies, diabetic somatic neuropathy, metabolic parameters, general parameters (such as age and duration of illness) and diabetic microangiopathy and macroangiopathy were investigated in 103 patients with non-insulin-dependent diabetes mellitus (NIDDM). Spearman's correlation coefficients were calculated for the comparisons of all the parameters of the neuropathies with all the other parameters. Variables were selected using a stepwise procedure and multiple regression analysis was carried out using these variables. The results of the regression analysis show that diabetic neuropathy is correlated with vascular parameters including blood pressure and pulse-wave velocity, as well as with parameters of sugar and lipid metabolism. The results confirm the diversity of the clinical characteristics of the neuropathies in patients with NIDDM and confirm that these neuropathies do not always occur in parallel. PMID- 8674791 TI - Treatment of chronic hepatitis C infection with interferon alpha-2a in a Turkish population. AB - Recombinant interferon (IFN) alpha has been shown to normalize the aminotransferase levels in approximately half of patients with chronic hepatitis C virus (HCV) infection. Twenty four patients with chronic HCV infection were treated with IFN alpha-2a subcutaneously, three times a week for 6 months. All patients responded to IFN therapy with a decrease of alanine aminotransferase (ALT) level. Thirteen out of 24 cases (54.2%) had normal ALT levels at the end of the sixth month of therapy. However, four of these complete responders (30.8%) relapsed during the 12 month follow-up. Relapse was high in the partial responder group (45.5%). Overall relapse rate was 37.5% at 6 months. HCV genotype II, which is associated with a low response rate to IFN was prevalent (85-87%) in our patient population. This study shows that interferon therapy can be effective in reducing transaminase levels in patients with chronic hepatitis C in a population with a high prevalence of HCV type II. The relapse rate after discontinuation of treatment, however, remains a problem. PMID- 8674792 TI - Antihypertensive and metabolic effects of doxazosin in hypertensive patients with concomitant non-insulin-dependent diabetes mellitus. AB - In this multicentre, non-randomized clinical study, 35 hypertensive patients with concomitant non-insulin-dependent diabetes mellitus were treated with the selective alpha 1 adrenoceptor blocker doxazosin mesilate for 24 weeks, either alone or together with existing antihypertensive therapy. The effects of the drug on blood pressure, glucose and lipid metabolism were examined. Daily administration of 0.5-8 mg doxazosin caused a significant reduction in both systolic and diastolic blood pressure decreased from 172 +/- 15/90 +/- 11 mmHg at the beginning, to 149 +/- 19/80 +/- 12 mmHg at the end of the trial. Heart rate was not affected. The plasma glucose level showed no change, whereas the haemoglobin A1c level decreased significantly from 7.4 +/- 1.2% to 7.1 +/- 1.2% (P < 0.01). Total and high-density lipoprotein cholesterol levels remained unchanged. The triglycerides level, however, decreased from 113 +/- 54 mg/dl at the beginning to 98 +/- 49 mg/dl at the end of the trial (P < 0.05). In a subgroup of patients, who showed hypercholesterolaemia ( > or = 220 mg/dl, n = 9) at the beginning, the total cholesterol level decreased from 252 +/- 33 mg/dl to 220 +/- 33 mg/dl (P < 0.05). Two patients complained of abdominal fullness or diarrhoea, but both were easily manageable. The results indicate that doxazosin is effective and safe in the treatment of hypertension in non-insulin-dependent diabetics and does not affect glucose metabolism. As for lipid metabolism in non insulin-dependent diabetic patients, doxazosin seems to have a beneficial effect. PMID- 8674793 TI - Plasmapheresis for a schizophrenic patient with drug-induced lupus anti coagulant. AB - A 59-year-old patient with schizophrenia developed Sjogren's syndrome. She also presented with the lupus anticoagulant attributed to long-term medication with chlorpromazine. Serial plasmapheresis treatments were performed to decrease the anti-coagulant activity. As a result, the activated partial thromboplastin time was temporarily improved, but the lupus anti-coagulant activity did not change. Because of her unstable emotional state, she continued to require chlorpromazine, but took a low dose of aspirin (87 mg/day) and never manifested any signs of thrombotic events. In view of the potential anti-thrombotic effects of chlorpromazine, it may not be necessary to use plasmapheresis in an attempt to reduce anti-coagulant activity among patients with chlorpromazine-induced lupus anti-coagulant. PMID- 8674795 TI - Use of an alpha-glucosidase inhibitor to synchronize sugar absorption with delayed insulin secretion in a patient with non-insulin-dependent diabetes mellitus. AB - The case of a 67-year-old women with non-insulin-dependent diabetes mellitus is described. Diabetes was first diagnosed when the woman was aged 55; a diet of 1440 kcal daily was recommended and 500 mg tolbutamide daily was prescribed. Hypoglycaemia was improved for a while but the blood-sugar concentration gradually increased until a tolbutamide dose of 2000 mg/day was needed. The patient eventually came to an out-patient clinic for diabetes control due to continuous hyperglycaemia. Her diabetes proved difficult to control, probably due, in part, to excessive eating and lack of exercise, despite appropriate education and glibenclamide treatment. After 15 months, an alpha-glycosidase inhibitor, at a dosage of 0.75 mg/day, was added to the treatment with glibenclamide at 7.5 mg/day and the glycosylated haemoglobin level was reduced to normal levels within 2 months. After a further 6 months the glibenclamide dose was reduced to 3.75 mg/day with no ill effects during the subsequent 4 weeks, up to the present day. PMID- 8674794 TI - Eosinophilic gastro-enteritis associated with protein-losing enteropathy and protein C deficiency. AB - Reported below is a case of eosinophilic gastro-enteritis involving the colon, stomach and duodenum in a patient who was also found to have marked hypoalbuminaemia and protein C deficiency due to severe protein-losing enteropathy. The most recent literature is reviewed and the challenging differential diagnosis of the disease is discussed. PMID- 8674796 TI - Bacterial translocation in experimental intestinal obstruction. AB - In this study, bacterial translocation to the mesenteric lymph nodes (MLN), liver and spleen and the histopathological changes in the intestine MLN, liver and spleen were investigated in Wistar Albino rats with intestinal obstruction. The subjects were divided into three main groups: the control group, simple obstruction group and loop obstruction group. Each group was further subdivided into two sub-groups: those who underwent repeat laparotomy at 12 h or at 24 h. No bacterial translocation was observed in the control group. The incidences of bacterial translocation to the MLN, livers and spleens of the rats with loop obstruction who underwent repeat laparotomy at 24 h were the highest. According to the cultured bacteria growth results, Escherichia coli was most abundant (48%). Most histopathological changes were observed in the MLN, livers, spleens and intestines of the rats with loop obstruction who underwent second laparotomy at 24 h. PMID- 8674797 TI - The effect of roxithromycin on the generation of reactive oxygen species in vitro. AB - The effect of roxithromycin (ROM), a new oral semi-synthetic macrolide, on the generation of reactive oxygen species (ROS), using human neutrophils and a cell free, xanthine-xanthine oxidase system was examined. The species investigated were the superoxide radical anion (O2-), hydrogen peroxide (H2O2), and the hydroxyl radical (OH.). ROM effectively inhibited the generation of O2-, H2O2 and OH. by human neutrophils. On the other hand, the drug did not markedly affect the ROS levels generated in the xanthine-xanthine oxidase system. The present study indicates that ROM may exert an anti-inflammatory action by inhibiting neutrophil oxygen radical generation at the sites of inflammation. PMID- 8674798 TI - Beneficial effects of allopurinol on glutathione levels and glutathione peroxidase activity in rat ischaemic acute renal failure. AB - The protective effect of allopurinol, an inhibitor of the enzyme, xanthine oxidase, against the renal ischaemia-reperfusion of the rat was investigated. Rats were subjected to renal ischaemia by clamping of the left renal artery and vein for 45 min, and were then reperfused for 24 h; these animals were randomized to receive either saline (n = 10) or allopurinol (n = 10) at a dose of 50 mg/kg bolus intraperitoneally 5 min before reperfusion. The control group comprised seven healthy rats not exposed to ischaemia or reperfusion. The blood urea nitrogen and plasma creatinine levels were increased in the allopurinol group, but the increase was less than that in the placebo group, compared with the controls. The kidney glutathione level was significantly reduced in the placebo group but not in the allopurinol group compared with the controls. The glutathione peroxidase activity in the kidney tissues was reduced more than two fold in the placebo group compared with the controls, but the reduction in glutathione peroxidase was considerably less in the allopurinol group. Renal tissue lactate dehydrogenase, aspartate amino-transferase, gamma-glutamyl transferase and alkaline phosphatase activities were reduced almost two-fold in the placebo group, but allopurinol treatment maintained these enzyme activities close to the control activities. These results provide evidence that allopurinol treatment may have beneficial effects on antioxidant defences against ischaemia reperfusion injury of rat kidneys. PMID- 8674800 TI - Estimated urinary albumin index: a predictor of microalbuminuria in type 2 diabetes. AB - This study examined factors contributing to the development of microalbuminuria in diabetic patients. A total of 236 patients with Type 2 diabetes were studied: 143 were normoalbuminuric and 86 were also normotensive. Multiple regression analysis was used to identify factors influencing the urinary albumin index (UAI), an index of proteinuria based on urinary albumin adjusted for urinary creatinine. Significant factors (retinopathy, systolic blood pressure, and glycosylated haemoglobin) were used to generate a formula for estimating the log(e) UAI. Target values for systolic blood pressure and glycosylated haemoglobin to maintain the urinary albumin index at or below 22 were determined for different degrees of retinopathy. Normoalbuminuric patients were followed for 3 years to evaluate their progression to microalbuminuria. Each month, blood pressure, urinary albumin and creatinine, and glycosylated haemoglobin were measured. In normotensive, normoalbuminuric patients, initial urinary albumin index and log(e) UAI were significantly higher in patients who subsequently developed microalbuminuria. Patients with initial log(e) UAI > 3.09 or initial glycosylated haemoglobin > 6.0% also showed greater progression to microalbuminuria. Hyperglycaemia was an independent factor for the development of microalbuminuria in Type 2 diabetes. The urinary albumin index was most significantly affected by retinopathy, systolic blood pressure, and glycosylated haemoglobin. The estimated loge UAI calculated from these factors is a useful predictor of progression to microalbuminuria. PMID- 8674799 TI - Effect of glutathione depletion on haemoglobin and membrane integrity of red blood cells of rats. AB - The effects of streptozocin (streptozotocin) and water-soluble menadione (menadione bisulphite, sodium salt) on the haemoglobin content and membrane integrity of red blood cells were investigated. Both menadione bisulphite and streptozocin significantly depleted glutathione but menadione bisulphite was much more effective in reducing glutathione than was streptozocin. Menadione bisulphite, at concentrations above 0.1 mM, caused substantial conversion of oxygenated haemoglobin into methaemoglobin while streptozocin did not alter the haemoglobin content of the red blood cells at concentrations of up to 100 mM. Both agents demonstrated only a modest ability to haemolyse the red blood cells, even at concentrations up to 300 mM. These results suggest that depletion of glutathione by menadione causes the conversion of oxyhaemoglobin to methaemoglobin. In contrast, streptozocin-induced glutathione depletion does not seem to be well correlated with alterations in haemoglobin content. PMID- 8674801 TI - The protective effects of long-acting recombinant human pancreatic secretory trypsin inhibitor (R44S-PSTI) in a rat model of cerulein-induced pancreatitis. AB - The effects of pancreatic secretory trypsin inhibitor (PSTI) on cerulein-induced pancreatitis were studied in a rat model. Arg44 of PSTI was replaced by Ser using site-directed mutagenesis (R44S-PSTI). R44S-PSTI has a longer half-life than the natural form. Pancreatitis was induced by four intramuscular injections of cerulein (50 microgram/kg at 1 h intervals). Continuous intravenous infusion of R44S-PSTI began at a dose of 20 micrograms/kg/h 30 min before the first cerulein injection, and was completed 3 h after the last cerulein injection. Tumour necrosis factor (TNF-alpha) production by isolated peritoneal macrophages from rats with cerulein-induced pancreatitis increased following lipopolysaccharide stimulation, compared to control rats (P < 0.01). R44S-PSTI administration significantly decreased the TNF-alpha production by peritoneal macrophages from rats with cerulein-induced pancreatitis (P < 0.05). In addition, R44S-PSTI significantly reduced serum amylase activity (P < 0.01) and pancreatic wet weight after pancreatitis induction (P < 0.05). Histological examination revealed marked acinar cell vacuolization, interstitial oedema, and cellular infiltration in cerulein-induced pancreatitis, but a lesser degree of histological change in rats that were treated with R44S-PSTI. Prophylactic use of intravenous R44S-PSTI infusion may reduce the severity of acute pancreatitis either histologically or serologically. PMID- 8674802 TI - A novel enzymatic assay for the quantification of skin surface lipids. AB - The applicability of a novel enzymatic assay for quantifying skin surface lipids was investigated experimentally. The standard curves for the assays of glycerol esters, free fatty acids, and cholesterol and its esters were linear over a wide range of lipid concentrations, which ensures the accuracy of measurements. The assay system also showed good simultaneous reproducibility. There were significant positive correlations (P < 0.001) between the quantities of glycerol esters, free fatty acids, and cholesterol and its esters sampled from the skin surface of women when measured by the enzymatic assay compared with the gas chromatographic method. The enzymatic assay was applied to studies of the relationships between age, acne and menstrual cycle, and skin surface lipids in women. The quantities of glycerol esters and free fatty acids reached peaks in females in their twenties and thirties. Increased quantities of glycerol esters, free fatty acids, and cholesterol and its esters were observed in women with acne compared with women without acne. Among the women with acne, those in the premenstrual phase of the menstrual cycle showed increased levels of glycerol esters, free fatty acids, and cholesterol and its esters compared with those in the menstrual phase. The results suggest that the enzymatic method is a satisfactory new technique for the quantification of skin surface lipids. PMID- 8674803 TI - Do non-steroidal anti-inflammatory drugs induce sister chromatid exchanges in T lymphocytes? AB - The genetic toxicity of non-steroidal anti-inflammatory drugs was investigated using the sister chromatid exchange technique in cultured human lymphocytes. A total of 48 patients were treated with non-steroidal anti-inflammatory drugs (ibuprofen, ketoprofen, naproxen, indomethacin, diclofenac or acetylsalicylic acid) for 2 weeks. The average numbers of sister chromatid exchanges in cultured lymphocytes from the patients, before and after treatment with these drugs, did not differ significantly (P > 0.05). These results indicate that treatment with non-steroidal anti-inflammatory drugs for 2 weeks does not induce sister chromatid exchanges in T lymphocytes. PMID- 8674804 TI - Comparison of roxatidine and famotidine on nocturnal gastric juice secretion. AB - Adult patients with symptoms of gastric disease were randomly assigned to two treatment groups (roxatidine group, n = 115; famotidine group, n = 113) or untreated control group (placebo, n = 111). The treatment groups randomly received 75 mg of roxatidine or 20 mg of famotidine at 9 pm, and 12 - 13 h later gastric juice secretion was measured with gastric X-ray films in both groups. Mean gastric juice secretion was significantly lower in the treated groups (roxatidine, 16.1 ml/12 h; famotidine, 19.9 ml/12 h) than in the untreated controls (placebo, 49.5 ml/12 h). Gastric juice suppression by roxatidine and by famotidine, respectively, was 82% and 37% in patients with gastric ulcer; 71% and 39% in patients with duodenal ulcer; 70% and 64% in patients with gastritis; and 68% and 86% in patients with no evidence of disease. It is concluded that roxatidine was more effective than famotidine for gastric juice suppression in patients with peptic ulcer. In patients with no evidence of gastric disease, however, famotidine was more effective than roxatidine. PMID- 8674805 TI - Relationship between cardiac autonomic neuropathy and diabetic microangiopathies and macroangiopathy in patients with non-insulin-dependent diabetes mellitus. AB - The relationship between cardiac autonomic neuropathy and diabetic microangiopathies and macroangiopathy was investigated in 103 patients with non insulin-dependent diabetes mellitus. Cardiac autonomic nerve function was assessed by determining the uptake of [123I]metaiodobenzyl-guanidine into the myocardium. Cardioparasympathetic nerve function was assessed by comparing electrocardiographically the expiratory and inspiratory respiratory rate (RR) interval ratios, during a period of deep breathing, and the coefficients of variation of the RR intervals. Nerve conduction velocity measurements were used to assess diabetic somatic neuropathy, and measurement of pulse-wave velocity provided an indication of the extent of aortic sclerosis. The only correlations between the parameters of cardiac autonomic neuropathy and parameters of diabetic microangiopathies and macroangiopathy were between the expiratory to inspiratory RR interval ratio and both the conduction velocity of the tibial nerve and pulse wave velocity, and between the heart to lung ratio (cardiac autonomic nerve function) and nephropathy. These correlations may have occurred by chance; alternatively they may indicate a difference in the onset mechanisms of cardiac parasympathetic and sympathetic neuropathies in diabetics. PMID- 8674806 TI - Significance of metabolic and blood pressure factors in relation to microangiopathy and macroangiopathy in patients with non-insulin-dependent diabetes mellitus. AB - We are actively seeking methods to prevent and to limit the progression of angiopathy in patients with non-insulin-dependent diabetes mellitus (NIDDM). In the present study, we conducted a clinical and epidemiological survey to clarify the clinical factors responsible for the development and progression of diabetic microangiopathy (MI) and macroangiopathy (MA). A total of 107 patients (58 female and 49 male) were randomly selected from 145 NIDDM patients. Twenty-four patient variables were selected for analysis. We identified PWV, UAI, RETINOP, MCV-T, SCV S, MCV-P, SBP, and DBP as responsible factors and carried out stepwise multiple regression analyses. The following explanatory variables were found to be significant: age > SCV-S (P < 0.0001) for the criterion variable PWV, BUN > HbA1c > MCV-P > HT-drug > HDL-C (P < 0.0001) for log(e) UAI, DM-thera > SBP (P < 0.0001) for RETINOP, MCV-P (P < 0.0001) for MCV-T, IRI > SBP > MCV-P > S-CR (P < 0.0002) for SCV-S, MCV-T > SCV-S > DM-thera (P < 0.0001) for MCV-P, DBP > HT-drug > BUN > MCV-P (P < 0.0001) for SBP, and SBP > PWV > sex (P < 0.0001) for DBP. In summary, responsible factors for MI and MA in NIDDM had metabolic and blood pressure factors in common. Moreover, MI was a responsible factor for MA, which becomes a responsible factor for MI because it is a responsible factor for blood pressure factors. Thus, all the responsible factors for MA represented by MI and PWV had metabolic and blood pressure factors in common. The results of this study suggest that metabolic and blood pressure factors must be controlled to prevent and to limit the progression of diabetic MI and MA in NIDDM patients. PMID- 8674807 TI - The moulting hormone ecdysone is able to recognize target elements composed of direct repeats. AB - In Drosophila melanogaster, three temporally distinct ecdysone-responsive puff sets, the so-called intermoult, early and late puffs, have been described on the salivary gland polytene chromosomes. We have analyzed in detail a DNA segment of the 3C polytene region, from which the originates one of the most prominent intermoult puffs, with the aim of identifying ecdysone response elements (EcREs). Here we report that two putative EcREs of identical sequence are located at this puff site. Interestingly, these elements display a novel structural feature, being composed of directly repeated half-sites. Our results show that the EcR/USP heterodimer known to constitute the ecdysone functional receptor complex is able to bind to and transactivate through target elements composed of directly repeated half-sites. In addition, we show that these elements are also able to bind efficiently USP alone, suggesting that USP and EcR/USP could compete for their binding to DNA. PMID- 8674808 TI - Functional properties of a mutant T3 receptor beta (R338W) identified in a subject with pituitary resistance to thyroid hormone. AB - Previously, we identified a point mutation of the T3 receptor (TR) beta gene (R338W) in a patient with pituitary resistance to thyroid hormone (PRTH). The mutation existed in one of two hot spot areas in TRbeta gene where clusters of mutations have been found in subjects with generalized resistance to thyroid hormone (GRTH). Interestingly, R338W induces the phenotypical features responsible for PRTH. In the present study, we examined the functional properties of R338W in comparison with those of a GRTH-mutant, K443E. The levels of thyroid hormones and inappropriately elevated TSH (SITSH) were similar between subjects with K443E and R338W. Transcriptional activities and dominant negatives potencies were measured by CAT assay in CV1 cells transfected with each mutant TRbeta1 or along with wild-type TR. When a reporter gene containing T3-responsive elements (TRE), TRE-pal2, DR4 or myosin heavy chain alpha subunit, was used, transcriptional activation induced by R338W was higher than that by K443E. At 50 nM T3, K443E decreased the transcriptional activity of wild-type TRbeta1 on TRE pal2 by 31.5%, while R338W reduced by 13.6% (n = 15, P < 0.05). Co-expression of retinoid X receptor (RXR) alpha increased transcriptional activity of R338W and K443E, but not of wild-type TRbeta1. Dominant negative activity on TRE-TSHalpha subunit of R338W was milder than that of K443E. When T3-binding activities of mutant TRbeta1s expressed in the cells were assayed under the same cell conditions for CAT assay, both mutant TRbeta1 showed remarkably reduced activity with no difference between the two. Gel mobility shift assay using TRE-DR4 showed poor homodimer formation of R338W. Heterodimerization with RXRalpha was similar between R338W, K443E and wild-type TRbeta1. The result of the present study suggested that R338W had relatively mild transcriptional and dominant negative activities on several TREs including TRE-TSHalpha subunit. We also showed poor homodimerization of R338W, which might be related to its weak dominant negative potency. PMID- 8674809 TI - Hormonal regulation of the female enriched GH receptor/binding protein mRNA in rat liver. AB - At least two classes of mRNA for the GH receptor (GHR) and GH binding protein (GH BP) with different 5' untranslated first exons exist in the rat. One such class, the GHR1 is predominantly expressed in the liver of female rats. The hepatic expression of the GHR1 mRNA in normal and hypophsectomized rats of both sexes was studied by employing an RNase protection/solution hybridization assay. Normal females expressed 10-fold more GHR1 mRNA than males, hypophysectomy of female rats decreased the GHR1 level to that observed in male rats. Continuous GH treatment of hypophysectomized male and female rats for 6 days increased the expression of GHR1 mRNA to levels found in normal females, whereas intermittent GH treatment without effect. Bovine GH(bGH) induced the GHR1 expression in a time and dose-dependent manner in primary cultures of adult rat hepatocytes as determined by solution hybridization. Maximal induction was achieved after 72 h of treatment with 50 ng bGH/ml medium. Female enriched expression of receptor and binding protein mRNAs raises the possibility that they participate in determining the ability of the liver to respond differently to the male and female GH secretory patterns. Our in vitro model utilizing cultures of primary adult rat hepatocytes could be used to address this issue as well as explore a hormonal interplay in regulation of GHR1 expression. PMID- 8674810 TI - Impaired cyclic AMP response to stimuli in glucose-desensitized rat pancreatic islets. AB - Isolated islets were either studied immediately after isolation (fresh; F), or were cultured for 6 days at 11 mM glucose (desensitized; D), or were incubated for 2 h at 5.5 mM glucose following D (recovered; R). Glucose-stimulated insulin secretion in D islets was reduced compared with F and R islets. In the presence of 3-isobutyl-1-methylxanthine, glucose also increased cyclic adenosine monophosphate (cAMP) levels in F islets, but failed to affect cAMP generation in R or D islets. Glucagon alone or in the presence of glucose stimulated insulin release in F and R islets, but the response was blunted in D islets. Glucagon like peptide 1 (GLP) potentiated insulin secretion in R islets, but not in D islets. Glucagon (0.01-0.1 microM) did not increase cAMP levels in D islets, whereas GLP (0.1 microM) increased cAMP as much as 4.5-fold. R islets recovered adenylyl cyclase responsivity to glucagon, and GLP increased cAMP levels as much as 9-fold. In F islets pretreated with forskolin for 2 h, the cAMP responses to glucose and GLP were inhibited. The cAMP response to forskolin stimulation was similarly inhibited in D islets and in islets pretreated for 2 h with forskolin. Forskolin pretreatment significantly attenuated the islet insulin release response to glucose, although the combined stimulus of glucose and GLP restored insulin release to control values. Insulin secretion in response to glucose and cAMP analogue (Sp)5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole-3'-5'-cyclic monophosphorothioate was lower than that observed in F islets. In conclusion, beta-cell cAMP accumulation in response to several stimuli acting through different mechanisms is impaired following continuous glucose stimulation. However, cAMP levels are not the definitive second messenger in the recovery of glucose-sensitive insulin secretion in glucose desensitized islets. PMID- 8674811 TI - Functional ovarian and placental isoforms of porcine aromatase. AB - Functional isoforms of porcine aromatase cytochrome P-450 were cloned from placenta, and ovarian theca interna and granulosa tissues, and full length cDNAs were expressed in vitro. Porcine theca and granulosa expressed an identical form of P-450arom. This ovarian cDNA encoded for a protein of 501 amino acids, two amino acids shorter at the N-terminal end than placental P-450arom isoform (503 residues). Overall, the two isoforms exhibited 93% nucleotide and 87% amino acid identity with each other, and both were highly homologous, at the nucleotide and amino acid levels, to human and bovine P-450arom, also 503 amino acid proteins. Analysis of the predicted amino acid sequence further suggested that the regions of the cDNAs, corresponding to presumed exons III, V and IX, assuming conservation of intron-exon boundaries with the human P-450arom gene, were conserved in the porcine placental and ovarian enzymes, while sequence variance occurred in all other putative exons. In vitro expression indicated that the cDNA encoding porcine placental P-450arom was almost 10-fold more active in the synthesis of estrone from androstenedione than was the ovarian isoform which synthesized more 19OH-androstenedione than estrone. Western analysis of transfected Cos1 cells suggested that the differences in activity were not due to levels of expression of the cDNAs since similar levels of immunodetectable protein were observed in cells transfected with each construct. Both isoforms were sensitive to inhibition of activity by the specific aromatase inhibitors, 4OH-androstenedione and CGS16949A. In addition, activity of the enzyme encoded by the ovarian P-450arom cDNA was suppressed by etomidate, an inhibitor of cytochrome P-450 11beta-hydroxylase, but the placental P-450arom isoform was not. These functional differences were consistent with observations made in similar experiments involving P-450arom activity in freshly homogenized tissues. These data provide evidence of the existence of distinct, intraspecies isoforms of P 450arom, the first described in any species and suggest that pigs possess a unique mechanism for regulating androgen metabolism. PMID- 8674812 TI - Bacterial expression of human chorionic gonadotropin alpha subunit: studies on refolding, dimer assembly and interaction with two different beta subunits. AB - Human chorionic gonadotropin (hCG) is a member of a family of heterodimeric glycoprotein hormones that have a common alpha subunit but differ in their hormone-specific beta subunit. The common alpha subunit contains two asparagine (N)-linked oligosaccharides. To study the function of carbohydrates on in vitro refolding of alpha subunit and dimer assembly, we generated recombinant non glycosylated hCG alpha subunit (rNGl-hCGalpha) from E. coli. The expression vector was constructed by inserting hCGalpha cDNA coding for the mature form in frame into a pQE-30 vector, which contains a 6 x His sequence immediately before the 5'-end of hCGalpha cDNA for subsequent purification of rNG-hCGalpha. The rNG hCGalpha expressed in inclusion bodies was efficiently purified by immobilized metal chelate affinity chromatography on Ni-NTA resin. SDS-PAGE, solid-phase binding assay and immunoblotting demonstrated the expression of rNG-hCG. Its alpha molecular weight on SDS-PAGE was 14.7 kDa under reducing conditions and 15 kDa for a monomer accompanied with some higher molecular weight oligomer under non-reducing conditions. Reconstitution of rNG-hCGalpha with native hCGbeta and oFSHbeta occurred in very low yield under standard conditions. However, the oxidation-reduction system cystamine (1.34 mM) and cysteamine (7.3 mM) facilitated both the refolding of rNG-hCGalpha and reconstitution of rNG-hCGalpha with native hCGbeta to regain partially correct conformation. These were revealed by conformationally sensitive antibody and receptor binding assays. Cystamine and cysteamine were more effective in the recombination of rNG-hCGalpha with oFSHbeta as indicated by a 22-36-fold decrease in the amount required to cause a 50% competitive inhibition in radioreceptor assay. They have no effect on assembly of rNG-hCGalpha with oLHbeta. Our results suggest the carbohydrate moieties confer greater conformational flexibility to the backbone of the beta subunit and the relative rigidity of the beta subunit may serve as a conformational template of the alpha subunit. The present approach has made it possible to prepare the non glycosylated gonadotropin alpha subunit in adequate amounts for further study on their biological and topographical features in complete absence of carbohydrate. PMID- 8674813 TI - Effect of phospholipids on the reconstitution and thermal stability of delipidated rat ovarian luteinizing hormone/human chorionic gonadotropin receptors in proteoliposomes. AB - The role of lipids and a possible structure-functional alteration of delipidated LH/hCG receptor reconstituted into proteoliposomes was analyzed by thermal perturbation techniques. Delipidated receptor lost to a great extent its binding activity and thermal stability. The LH/hCG receptor was almost fully reactivated by the reconstitution into proteoliposomes with phosphatidylcholine (PC) and sphingomyelin (SpM) and partly with phosphatidylethanolamine (PE) and phosphatidic acid (PA). The heat inactivation profile of delipidated LH/hCG binding sites was shifted to a lower temperature by about 4 degrees C (T50 values). Thermal inactivation of the receptor by delipidation was entirely inverted by treatment with soybean PC, dioleoyl PC and dipalmitoyl PC and partially with SpM. The presence of negatively charged phospholipids, phosphatidylserine (PS), phosphatidylglycerol (PGl) and PA, did not change the heat-inactivation profile of the LH/hCG receptor modified the differential scanning calorimetric profile and the quenching of protein fluorescence characteristic for control proteoliposomes. Delipidation increased membrane lipid rigidity. Reconstitution of delipidated proteoliposomes with soybean PC, dioleoyl PC, PGl, PS and PA decreased, and that of dipalmitoyl PC, lysoPC, SpM and cholesterol increased the degree of fluorescence polarization of DPH of proteoliposomes. The different action of phospholipids on the reconstitution, thermal inactivation of the receptor and membrane lipid fluidity in proteoliposomes suggests that lipid fluidity is not related to the stabilizing action of phospholipids on the LH/hCG receptor. PMID- 8674814 TI - Repression of somatostatin gene transcription mediated by two promoter silencer elements. AB - We report that expression of the somatostatin gene in pancreatic islets and in non-islet cells is negatively regulated by two proximal silencer elements, PS1 and PS2. Transient transfection assays showed that PS1 decreases somatostatin gene promoter activity stimulated by an upstream enhancer in the islet D-cell line RIN-1027-B2, but not in the islet B-cell line RIN-1046-38, whereas PS2 inhibits gene transcription both B- and D-cell lines. In BHK fibroblasts, both PS1 and PS2 independently inhibit somatostatin gene in non-islet cells. DNA binding studies revealed that both PS1 and PS2 bind similar nuclear protein complexes in islet and non-islet cells (120 and 130 kDa). PS1 also binds a 100 kDa protein present in islet B- and D-cell lines. In addition, both PS1 and PS2 bind three D-cell-specific proteins (40, 43 and 45 kDa). These observations support a direct involvement of both positive and negative transcriptional control mechanisms in the regulation of the islet cell-specific expression of the somatostatin gene. PMID- 8674816 TI - Initiation of insulin secretion in glucose-free medium by activin A. AB - Activin A is a multifunctional protein known to stimulate insulin secretion (Yasuda H et al., (1993) Endocrinology 133, 624-630). The present study was conducted to determine whether activin A augments insulin secretion in the absence of ambient glucose. In the presence of 2.7 mM glucose, and 1.25 mM calcium, activin A induced a biphasic secretory response of insulin. In the absence of glucose in perifusate, activin A induced a small but significant release of insulin. The effect of activin A was monophasic in the absence of glucose. In contrast, glucagon-like peptide-1 (GLP-1) had no effect on insulin secretion under the same conditions. However, GLP-1 could enhance insulin secretion induced by activin A in glucose-free medium. Activin A induced a transient increase in cytoplasmic-free calcium concentration, [Ca2+]c, in a fura 2-loaded islet superfused with glucose-free buffer. Again, GLP-1 was without effect on [Ca2+]c by itself in glucose-free buffer. In the presence of activin A, however, GLP-1 could induce an elevation of [Ca2+]c. Finally, GLP-1, but not activin A, increased cAMP content in islets incubated in glucose-free medium. These results indicate that activin A, but not GLP-1, induces insulin secretion in glucose-free medium. Activin A is able to reproduce partly the effect of glucose to support the action of GLP-1 in glucose-free medium. PMID- 8674815 TI - Wortmannin and LY294002 inhibit the insulin-induced down-regulation of IRS-1 in 3T3-L1 adipocytes. AB - The insulin receptor substrate-1 (IRS-1) is expressed in 3T3-L1 adipocytes and is involved in at least some insulin responses, notably mitogenesis. Chronic exposure to insulin down regulates IRS-1 in these cells by stimulating its degradation (Rice, K.M., Turnbow, M.A. and Garner, C.W. (1993) Biochem. Biophys. Res. Commun. 190, 961-967). This insulin response was completely inhibited by wortmannin and LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one), two inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase). Neither wortmannin nor LY294002 had any effect on the calcium-dependent degradation of IRS-1 in vitro nor did they inhibit the phosphorylation of IRS-1 in vitro. In addition, neomycin, a cationic aminoglycoside antibiotic that binds to phosphoinositides, inhibited the insulin-induced down-regulation of IRS-1 in 3T3-L1 adipocytes and, also, the C8-PIP3-stimulated degradation of IRS-1 in vitro. These results suggest that PI 3-kinase and its 3-phosphoinositide products mediate the insulin-induced down-regulation of IRS-1 in 3T3-L1 adipocytes. PMID- 8674817 TI - Identification of DNA sequences that bind retinoid X receptor-1,25(OH)2D3 receptor heterodimers with high affinity. AB - Vitamin D3 receptors (VDR) bind as heterodimers with retinoid X receptors (RXR) to vitamin D response elements (VDRE) and transactivate gene expression in a 1,25(OH)2D3-dependent manner. These elements are tandem direct repeats (DRs) of the hexamer RGGTCA separated by three nucleotides (DR3). We determined whether this DR3 was the optimal and/or only recognition sequence, by PCR-mediated binding site selection with reticulocyte lysate-expressed hVDR and mRXRalpha, and a pool of random sequences. We derived a consensus binding site for RXR-VDR heterodimers, RGGTCANN RRGTTCAB, and analyzed 10 of the 45 sequences slected by EMSA, methylation interference and transfection experiments: all the sequences were specific and acted as positive VDREs; the underlined purine of the spacer interacted with the heterodimer; the mutation of the third T in the second motif to a G did not influence VDRE activity. Thus, the selectivity of vitamin D pathway involving heterodimerization rather than VDR-homodimerization is not due to internal sequence variations. Except for mouse osteopontin VDRE, the natural VDREs would be efficient, only when helped by adjacent sequences and/or transactivators other than VDR and RXR. PMID- 8674818 TI - The post-translational processing and intracellular sorting of carboxypeptidase H in the islets of Langerhans. AB - The post-translational processing and intracellular sorting of the proinsulin converting enzyme carboxypeptidase H (CPH) was studied in isolated rat islets of Langerhans. Pulse-chase-radiolabelling experiments using sequence-specific antisera showed that CPH was synthesized initially as a 57-kDa glycoprotein which was processed to a 54-kDa mature form by proteolytic processing at the N terminus. Processing of the CPH precursor occurred rapidly (t(1/2) = 30) after an initial delay of 15-30 min and the enzyme was secreted in parallel with the insulin-related peptides in response to glucose-stimulation within 1 h after radiolabelling. This indicated that the proteins were packaged into nascent secretory granules at approximately the same rate following synthesis. Conversion of proinsulin and the 57-kDa form was inhibited markedly by chase incubation of islets at 20 degrees C, indicating that maturation of both proteins occurs in a post-Golgi compartment. Affinity purification of the enzyme from insulinoma subcellular fractions showed that the 57-kDa form was associated with endoplasmic reticulum or Golgi elements, and the 54-kDa form was present in secretory granules. Structural analysis showed that the granule form of the enzyme had an N terminal amino acid sequence beginning at residue 42 of rat CPH, thereby implicating cleavage of the precursor after the fourth Arg in a site containing five consecutive Arg residues. These findings indicate that post-translational processing of CPH is mediated by an endoprotease which cleaves at sites containing multiple basic amino acid residues upon segregation of the enzyme to the secretory granules. PMID- 8674819 TI - Regulation of alpha-subunit mRNA transcripts by pituitary adenylate cyclase activating polypeptide (PACAP) in pituitary cell cultures and alpha T3-1 cells. AB - Pituitary adenylate cyclase activating polypeptide (PACAP) increases glycoprotein hormone alpha-subunit mRNA levels suggesting a role for PACAP in maintaining the high levels of alpha-subunit protein characteristic of the pituitary. The present study used primary pituitary cell cultures and the alpha T3-1 pituitary cell line to investigate how PACAP affects alpha-subunit mRNA transcripts. Stimulation of cultured pituitary cells with 10 nM PACAP38, 10 nM GnRH, or the combination, for 24 h increased alpha-subunit mRNA levels 1.5-fold, whereas GnRH more effectively (P<0.01) stimulated alpha-subunit protein release than did PACAP38 (3.2- vs. 2.0 fold). alpha-Subunit mRNA levels in alphaT3-1 cells were also increased by PACAP38 and by GnRH to maximum values at 12 h (P<0.05), and alpha-subunit protein secretion rose proportionately and in parallel with alpha-subunit mRNA levels. PACAP38 was a 100-fold more potent stimulator of alpha-subunit mRNA than was VIP, and a VIP-antagonist failed to block the stimulatory effect of PACAP38, suggesting an effect via type PACAP 1 receptors. Type I receptor mRNA transcripts were identified by Northern analysis in alphaT3-1 cells. Depletion of PCK activity by PMA failed to block the stimulatory effect of PACAP38, but prevented GnRH from increasing alpha-subunit mRNA levels and alpha-subunit secretion. PACAP38, like 8Br-cAMP and forskolin, stimulated (P<0.05) luciferase (LUC) activity in alphaT3-1 cells transfected with a plasmid containing the first 846 of 180 base pairs of the 5'-flanking region of the human alpha-subunit gene linked upstream to a LUC reporter gene. Finally, experiments using the transcription inhibitor DRB reveal that PACAP does not appreciably change alpha subunit mRNA half-life. These findings are consistent with the proposal that PACAP contributes to the high levels of alpha-subunit protein characteristic of the pituitary by activating Type I receptors and stimulating alpha-subunit gene transcription in part by the cAMP/PKA pathway. PMID- 8674820 TI - Differential alternative splicing of PACAP receptor in pituitary cell subpopulations. AB - The capability of rat pituitary cells to express receptors for pituitary adenylate cyclase activating polypeptide (PACAP) and VIP was evaluated by binding studies and measurement of adenylate cyclase activity on whole gland preparations and by reverse transcriptase-polymerase chain reaction (TR-PCR) using specific primers on preparations from isolated cell populations enriched in PRL- and GH producing cells. Data obtained on whole gland preparations indicated that selective PACAP receptors (PACAP Type I) predominated. The mRNA coding for PACAP Type I and for the non-selective PACAP receptors Type II VIP2 (but not VIP1) were identified. The mRNA coding for four different spliced variants of the PACAP Type I receptor were detected. In PRL producing cells, three variants and the VIP2 mRNA were detected, whereas in GH-producing cells the mRNA coding for the variant having a 28-amino acid insert (termed HOP) in the third intracellular loop was the only present. PMID- 8674821 TI - Gene expression and peptide localization for epidermal growth factor receptor and its ligands in porcine luteal cells. AB - The present study was undertaken to determine the expression of the genes for epidermal growth factor receptor (EGF-R), and two of its ligands, epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) in isolated large (LLC) and small (SLC) porcine luteal cells by reverse transcription polymerase chain reaction (RT-PCR), and to localize their peptides in whole corpora lutea (CL) as well in isolated LLC and SLC by immunocytochemistry. RT-PCR revealed strong cDNA signals for EGF-R and EGF in both LLC and SLC, and for TGF alpha in LLC. The signal for TGF-alpha message in SLC was relatively weaker but detectable. Immunocytochemistry revealed intense EGF-R staining in LLC and SLC in both isolated and intact CL preparations. On the other hand, immunoreactive EGF and TGF-alpha appeared to be present only in LLC in intact CL sections, and isolated luteal cell preparations confirmed their presence in LLC and absence in SLC. These results suggest an autocrine/paracrine role for EGF and TGF-alpha in luteal functions. PMID- 8674822 TI - The role of estrogen receptor in modulation of chromatin conformation in the 5' flanking region of the rat prolactin gene. AB - To determine whether the estrogen receptor (ER) has a role in the modification of chromatin structure, we developed cell lines to model discrete stages in the estrogen response. Each cell line carries a population of stably expressed papillomavirus-based minichromosomes containing the 5' flanking region of the rat prolactin gene. We examined ER effects at the distal enhancer domain of the rat prolactin promoter, using DNaseI to probe for alterations of the nucleoprotein complex. Within 1 h after the start of estrogen treatment, modifications in the chromatin state of the distal enhancer region were detected in a pituitary derived, permissive cell line (GH3G1J). In rat-1 fibroblast cell lines that maintain the same stably expressed papillomavirus-based minichromosomes in the absence of ER or pituitary-specific transcription factors (Rat-1.2A2; non permissive), no estrogen-induced modifications in the chromatin state were detected at 1 or 24 h. In rat-1 fibroblast cell lines that also contained ectopically expressed, functional ER (Rat-1 + ER.8A1), no estrogen-induced modifications in the chromatin state were detected at 1 h, but a 24 h a specific modification in the local structure was induced. These data support a model in which the ER interacts with chromatin to modify local structure in such a way as to induce a permissive state for interactions of transcription factors necessary for hormone-induced activation of gene transcription. PMID- 8674823 TI - The Neuro-2a neuroblastoma cell line expresses [Met]-enkephalin and vasopressin mRNA and peptide. AB - Mouse neuroblastoma Neuro-2a cells were examined for the expression of pro enkephalin mRNA, protein, and Met-enkephalin ([Met]-Enk) peptide. Reverse transcriptase/polymerase chain reaction (RT/PCR) and in situ hybridization demonstrated the presence of pro-enkephalin mRNA in these cells. Immunocytochemistry using an antibody which recognizes pro-enkephalin and high pressure liquid chromatography (HPLC) followed by radioimmunoassay indicated that pro-enkephalin was synthesized in these cells and processed to yield the bioactive pentapeptide, [Met]-Enk. Furthermore, release studies showed that the [Met]-Enk was secreted from these cells with high K+ stimulation. Using double labeling, in situ hybridization combined with immunocytochemistry, we demonstrated that prohormone convertase 2 (PC2) mRNA is colocalized with pro enkephalin in the same Neuro-2a cells, suggesting that this enzyme may be responsible for processing this precursor. we also showed the presence of vasopressin mRNA and arginine-vasopressin peptide in these cells using in situ hybridization and immunocytochemistry, respectively. Thus, the Neuro-2a cells are a multiple neuropeptide-producing cell line and an excellent model for studying the mechanisms involved in the synthesis, intracellular targeting and processing of endogenous pro-enkephalin and pro-vasopressin, as well as other transfected neuropeptide precursors. PMID- 8674824 TI - Expression of transcripts encoding steroid UDP-glucuronosyltransferases in human prostate hyperplastic tissue and the LNCaP cell line. AB - The UDP-glucuronosyltransferase (EC 2.4.1.17) enzymes transform many lipophilic compounds to more water-soluble products via conjugation with glucuronic acid. This conversion is responsible for enhancing the excretion of endogenous aglycones such as steroids. To date, several distinct isoforms of steroid UDP glucuronosyltransferases (UGTs) have been isolated in the human liver. Among these UGTs, UGT2B7 is specific for estriol and 3,4-catechol estrogens, UGT2B15 glucuronidates 17beta-hydroxy-C19 steroids while UGT2B10 has as yet an undescribed activity. To further demonstrate the presence of UGTs in peripheral tissues we studied the expression of these enzymes in human prostate hyperplastic tissue and the LNCaP cell line. Metabolism studies using intact LNCaP cells in culture indicate the presence of UGT activities involved in the glucuronidation of 3alpha-hydroxysteroids (androsterone) and 17beta-hydroxysteroids (testosterone and dihydrotestosterone). Northern blot analysis of poly(A+) RNA from LNCaP cells and prostate using a UGT2B15 cDNA probe revealed two bands of 2.0 and 2.3 kb. In order to identify more specifically the mRNAs detected in Northern blot analysis we used RNase protection and RT-PCR, although, these approaches did not allow detection of UGT2B7 transcripts. Our studies demonstrate the presence of two UGT activities and at least two types of UGT transcripts in both the human prostate and the LNCaP. PMID- 8674825 TI - Follicle-stimulating hormone regulates the expression of cyclic protein 2/cathepsin L messenger ribonucleic acid in rat Sertoli cells in a stage-specific manner. AB - Cyclic protein-2/cathepsin L (CP-2) is secreted by Sertoli cells in a highly stage-specific manner, maximally during stages VI-VII of the rat seminiferous epithelial cycle. We investigated FSH regulation of CP-2 mRNA expression of its cellular localization in isolated staged seminiferous tubular segments. FSH induced a significant increase of CP-2 mRNA expression and its cellular localization in isolated staged seminiferous tubular segments. FSH induced a significant increase of CP-2 mRNA levels in stages IX-I, whereas in stages II VIII, the levels of CP-2 mRNA were reduced. A similar effect was produced by two cAMP analogs, dbcAMP (0.2 mM) and Sp cAMP (20 microM). FSH and cAMP did not affect on the levels of SGP-2 mRNA during the seminiferous epithelial cycle. The magnitude of the response was time- and dose-dependent; the maximum was obtained with 100 ng/ml of FSH. It is likely that FSH regulates Cp-2 gene transcription, since de novo RNA synthesis was required for the stimulatory FSH effect on CP-2 mRNA levels, while ongoing protein synthesis was not. In conclusion, the data suggest that FSH, via cAMP-mediated pathway, regulates CP-2/cathepsin L gene transcription in rat Sertoli cells and modulated the stage-specific expression pattern. PMID- 8674826 TI - Analysis of cytochrome P-450 side-chain cleavage gene promoter activation during trophoblast cell differentiation. AB - Trophoblast giant cell differentiation is accompanied by transcriptional activation of the cytochrome P-450 side-chain cleavage (P450scc) gene. The Rcho-1 trophoblast cell line has the capacity to differentiate along the trophoblast giant cell lineage and has been used to study trophoblast-specific P450scc gene expression. In this report, P450scc gene promoter activities in trophoblast specific P450scc gene expression. In this report, P450scc gene promoter activities in trophoblast cells have been mapped and the involvement of known modulators of steroid hydroxylase gene expression, the cyclic AMP/protein kinase A pathway and steroidogenic factor-1 (SF-1), evaluated. Comparisons were made with Y-1 adrenal and R2C Leydig cells. The cumulative results from transient and stable transfection experiments implicate the region between -428 and -511 bp of 5'-flanking DNA in the developmental activation of the P450scc promoter during trophoblast giant cell differentiation. Differences in basal activities of the P450scc promoter constructs were also observed in Y-1 adrenal and R2C Leydig cells; however, the magnitude of the differences was modest. Activators of the protein kinase A pathway stimulated P450scc promoter activity in Y-1 cells, whereas similar treatment of Rcho-1 trophoblast cells did not stimulate but actually inhibited P450scc promoter activity. The inhibitory activity was localized between -639 and -894 bp of the P450scc promoter. SF-1 mRNA and protein were detected in adrenal and gonadal cells but not in rat placenta or Rcho-1 trophoblast cells by Northern and Western blotting, respectively. Thus, P450scc gene activation during trophoblast cell differentiation involves an 83-bp region of its 5'-flanking DNA between -428 and -511 but does not appear to involve cyclic AMP-activated pathways or SF-1. In conclusion, the mechanism of P450scc gene activation during trophoblast cell differentiation appears different from the regulation of P450scc gene activation in other steroidogenic tissues. PMID- 8674827 TI - Somatostatin receptors in prostate tissues and derived cell cultures, and the in vitro growth inhibitory effect of BIM-23014 analog. AB - We investigated somatostatin receptors (SSTRs) in surgical specimens of prostate cancer and benign prostate hyperplasia (BPH), a normal immortalized epithelial cell line (PNT1), epithelial cancer cell lines, and stromal cells in short-term culture derived from normal and BPH biopsies. Cross-linking studies with 125I Tyr11-SRIF-14 (125I-SRIF) and the SRIF analog 125I-BIM-23104 identified one major 57-kDa band both in surgical specimens and in epithelial and stromal cells cultures. In membrane-enriched fractions and whole stromal cells from a normal prostate and from one BPH, a single type of SSTR was characterized (Kd = 6.10(-9) and 10(-8) M, respectively, Bmax = 1.6 pmol per mg of proteins). mRNA for SSTR1 was detected in all epithelial and stromal cells tested except for PNT1, while SSTR2 mRNA was detected in one BPH stromal cell culture. BIM-23104 had no effect on the in vitro growth of the epithelial cells tested. Conversely, 10(-10) M BIM 23104 induced >50% growth inhibition of stromal cells after 6 days in culture. These results may have implications for therapeutic strategies using SRIF analogs in BPH and prostate cancer. PMID- 8674828 TI - Inhibition of chondrocyte cathepsin B and L activities by insulin-like growth factor-II (IGF-II) and its Ser29 variant in vitro: possible role of the mannose 6 phosphate/IGF-II receptor. AB - Lysosomal enzymes and IGF-II both bind to the mannose 6-phosphate (M6P)/IGF-II receptor. This receptor targets newly synthesized lysosomal enzymes to lysosomes. The functional meaning of IGF-II binding to this receptor is not well known. We have postulated that IGF-II, the Ser29 IGF-II variant (vIGF-II) and IGF-I on lysosomal cathepsin B and L activities from post-natal rabbit chondrocytes in vitro. This effect was compared with the ability of each peptide to stimulate chondrocyte-sulfated proteoglycan synthesis. The sulfating dose-response relationship of the IGF peptides corresponded to their relative binding affinities for the type I-IGF receptor (IGF-I > IGF-II > vIGF-II). The intracellular cathepsin B and L activities were inhibited in a time- and dose dependent manner by IGF-II or vIGF-II. Maximal inhibition of cathepsin B and L activities (40 and 30% below controls, respectively) was found after an 8 h treatment with 100 ng/ml IGF-II or vIGF-II. By contrast, IGF-I up to 1 micrograms/ml or insulin up to 2 micrograms/ml had no inhibitory effect. The relative potency pattern corresponded to the binding profile of each ligand for the M6P/IGF-II receptor. A treatment of chondrocytes with IGF-I or insulin transiently increased the binding of radiolabelled IGF-II at the cell surface to approximately 120% of controls, whereas IGF-II or vIGF-II had no effect. Thus, it is unlikely that the inhibition of lysosomal enzyme activities by IGF-II peptides could result from a redistribution of M6P/IGF-II receptors from intracellular compartments to the plasma membrane. We hypothesize that internalized IGF-II peptides could occupy the intracellular M6P/IGF-II binding sites required for targeting of cathepsins B and L to lysosomes. PMID- 8674829 TI - The growth hormone (GH)-independent growth of the obese Zucker rat is not due to increased levels of GH receptor messenger RNA in the liver. AB - Obese Zucker rats maintain normal rates of linear growth and circulating concentrations of insulin-like growth factor-I (IGF-I) and of IGF-binding protein 3 (IGFBP-3) in spite of low GH secretion. The mechanisms underlying this GH independent growth in obesity are unknown. To assess whether the liver expression of the GH receptor (GHR) messenger RNA (mRNA) is increased and/or if the liver expression of IGFBP-3 mRNA is maintained in the obese, Zucker rats of both genders and phenotypes (four groups, n = 6/group) were studied at 12 weeks of age. By Northern analysis, mRNA levels for GHR and GHBP were not increased in obese rats compared to their sex-matched lean littermates; the expression of these two transcripts was sexually dimorphic and the changes in GHBP mRNA/GHR mRNA ratios associated with obesity were sex-specific. In both genders, IGFBP-1 and IGFBP-3 mRNAs were decreased in the obese. We concluded that the GH independent growth of obese Zucker rats is not due to increased GHR mRNA or to maintained IGFBP-3 mRNA levels in the liver. PMID- 8674830 TI - Splicing variants of the human growth hormone mRNA: detection in pituitary, mononuclear cells and dermal fibroblasts. AB - The human growth hormone/human chorionic somatomammotropin (hGH/hCS) gene cluster contains five genes: hGH-N, hGH-V, hCS-B, and hCS-L. In this study, the nature of splicing products of their primary transcripts (except hCH-L) was analyzed by nuclease mapping as well as by reverse transcription-polymerase chain reaction (RT-PCR) experiments All the previously described hGH-N mRNAs encoding the normal 22-K growth hormone, the 20-K variant as well as a transcript lacking the third exon were found in pituitary tissue and pituitary tissue and in transiently transfected human 293-S cells. In addition, splicing products lacking either exons 3 and 4 exons 2,3 and 4 were found in both tissues. In accordance to previously reported data, the hGH-V, the hCS-A and the hCS-B genes which are expressed in placental tissue give rise to the 22-K mRNA but not to 20-K mRNA. Furthermore, no hCS mRNA arising from skipping of exon 3 was present, whereas mRNAs arising from ligation of exon 2 to exon 5 and of exon 1 to exon 5 were clearly detectable. The various hGH cDNas were expressed in vivo and screened for lactogenic activity. Only the 22-K and the 20-K variant were active in this assay. All of the hGH-N-derived differentially processed RNAs were found in cell lines of lymphoid (Hut-78) and of myelomonocytic type (U937), which had been recently described to secrete growth hormone. Interestingly, RT-PCR analysis allowed the determination of hGH-N transcripts in dermal fibroblasts. This finding underlines the importance of growth hormone in influencing immune system development and further suggests possible autocrine/paracrine regulatory loops in skin tissue. PMID- 8674831 TI - Contrasting patterns of expression of thyroid hormone and retinoid X receptor genes during hormonal manipulation of Xenopus tadpole tail regression in culture. AB - The precocious induction of amphibian metamorphosis is an ideal system for analyzing the developmental action of TH, while the hormonal activation of tadpole tail regression offers the further advantage of studying programmed cell death. One of the striking features of thyroid hormone (TH)-induced tail regression (as with morphogenetic responses of all tadpole tissues) in Xenopus is the rapid autoinduction of TRbeta gene, but it is not known how TH would affect the expression of the genes encoding TR's heterodimeric partner, retinoid X receptor (RXR). Here we first show that the synthetic glucocorticoid dexamethasone (Dex) potentiates and prolactin (PRL) suppresses, 3,3',5 triiodothyronine (T3)-induced regression of pre-metamorphic Xenopus tadpole tails in organ culture. T3 strongly upregulated (11-35-fold) the concentration of Xenopus TRbeta (xTRbeta) mRNA in these cultures while downregulating by 50% that of Xenopus RXRgamma (xRXRgamma) mRNA in the same samples of tail RNA. DEX and PRL enhanced or diminished the T3-regulated expression of these two transcripts, respectively, which parallels their other effects in whole tadpoles or cultured tails. The contrasting effects of the three hormones on the steady-state levels of xTRbeta and XRXRgamma mRNAs were time- and dose-dependent. T3 and DEX also strongly upregulated the transcription of xTRbeta gene transfected into Xenopus XTC-2 cells but PRL failed to prevent this autoinduction. The actions of these three hormones involved in amphibian metamorphosis, as judged by the expression of xTRbeta and xRXRgamma genes, reveal a new facet of hormonal interplay underlying their developmental actions. PMID- 8674832 TI - Developmental pattern and regulation by androgens of androgen receptor expression in the urogenital tract of the rat. AB - Distribution and regulation of androgen receptor expression during fetal and neonatal virilization of the rat fetus was assessed by immunohistochemistry. In mesonephric duct derivatives the androgen receptor expression became evident first in the efferent ductules and epididymis (on fetal day 14), subsequently in the vas deferens and finally in the seminal vesicle. Mesenchymal cells of the urogenital tubercle were positive for androgen receptors from fetal day 14 onwards. In the mesenchymal cells of the prostate anlagen, androgen receptor positive cells were found first on fetal day 16. Administration of 5alpha dihydrotestosterone to pregnant rats from day 11 to day 20 of gestation caused a stabilization of the wolffian duct in female fetuses. The androgen receptor expression pattern became similar as found in mail fetuses, and showed an increase in density and in frequency of androgen receptor positive cells. Administration of the androgen antagonist flutamide during the same interval caused a reduction in density and frequency of androgen receptor positive cells in male fetuses. These findings indicate that androgens enhance the expression of androgen receptors in the developing rat genital tract by induction of androgen receptor positive cells, and by increasing the frequency. The developmental pattern of androgen receptor expression in the rat mesonephric duct system reflects the androgen-responsiveness of the ducts, and is consistent with induction of the androgen receptor along the ducts by testosterone reaching these structures in an exocrine fashion. PMID- 8674833 TI - Avian muscle cells as targets for the secosteroid hormone 1,25-dihydroxy-vitamin D3. PMID- 8674834 TI - Differential expression of islet amyloid polypeptide (amylin) and insulin in experimental diabetes in rodents. AB - An increased ratio of islet amyloid polypeptide (IAPP) to insulin for mRNA and peptide content in pancreatic extracts and for secretion has been observed in experimental diabetes, suggesting a differentially regulated IAPP and insulin expression. Therefore, we investigated the islet expression of IAPP and insulin in streptozotocin and alloxan diabetic rats and mice, using in situ hybridization and immunocytochemistry. A low dose of streptozotocin equivalently reduced IAPP and insulin mRNA levels to approximately 45% of controls. In contrast, a high dose of streptozotocin or alloxan reduced IAPP mRNA levels significantly less than those of insulin mRNA (streptozotocin: 24 vs. 15%, P = 0.011; alloxan: 15 vs. 6%, P < 0.0001). In situ hybridization and immunocytochemistry revealed expression of IAPP in experimental diabetes to occur predominantly in insulin cells. Thus, IAPP and insulin gene expression are differentially regulated in experimental diabetes in rodents and IAPP is predominantly expressed in insulin cells. PMID- 8674835 TI - Endothelin-1 regulates human decidual cells through both A- and B-type receptors. AB - The aims of this study were to investigate the effects of endothelin-1 (ET-1) on first trimester human decidual cells, identify the ET receptor sub-types through which these effects are mediated and assess the role of cyclic AMP in any effects of ET-1. ET-1 increased prostaglandin production by first trimester decidual cells, which was consistent with similar studies in third trimester decidual cells. The endothelin A-type receptor (ETA) was coupled to the increased prostaglandin production from first trimester cells, as shown by the inhibitory effects of BQ610, an ETA receptor antagonist. The time course of this effect was unusual, with a rapid increase peaking after 6 h of stimulation, followed by a longer effect over 12-24 h, which was paralleled by changes in cyclic AMP production. No evidence was obtained for any involvement of cyclic AMP in mediating the effects of ET-1 on prostaglandin production. ET-1 also increased decidual prolactin production with a maximum effect after 6 h of stimulation. This was mediated through the ETB receptor and may be linked to increased cyclic AMP production, indicating that the ETA and ETB receptors were coupled to different second messenger systems and affected decidual cell function in different ways. PMID- 8674836 TI - Basic and acidic fibroblast growth factor increase prolactin mRNA in a dose dependent and specific manner in GH3 cells. AB - In the present report we have studied the effects of acidic and basic molecular forms of the fibroblast growth factor (aFGF, bFGF) on prolactin (PRL) mRNA production and PRL secretion in GH3 cells, a rat pituitary cell line, and their interactions with 17 beta-estradiol (beta E2). To meet this purpose we measured mRNA levels in the cells by both Northern blot and dot blot hybridization analysis, and rPRL immunoreactivity in the culture medium by specific RIA. We observed a marked increase in PRL mRNA levels following 24 h incubation with both basic and acidic FGF. This effect was dose-dependent, with maximal responses ranging between 300 and 600% above the control values. bFGF appeared to be much more potent than aFGF (10-50 times), considering the ED50 of the dose-response curves. Prior incubation with beta E2 (10(-8) M) produced an enhancement in the responses to low doses of bFGF and aFGF, but not to high doses, as revealed by dot-hybridization analysis. Northern blot analysis showed also that both aFGF and bFGF, may have a partially additive effect with beta E2, upon the mature form (1 kb) of rPRL mRNA in GH3 cells. Considering that bFGF is present at high levels in the pituitary, our results suggest that FGF could be a physiological regulatory factor for prolactin production and secretion. PMID- 8674837 TI - Effect of cAMP on GnRH stimulated LH secretion from individual pituitary gonadotropes. AB - Enhanced responsiveness of the pituitary gland to GnRH is a fundamental step required for secretion of the proestrous LH surge, and is achieved primarily by the actions of ovarian steroid hormones on the gonadotropes. The mechanisms involved are still unclear but the cAMP second messenger pathway can mediate some of these activities. The present study was undertaken to determine the effects of in vitro cholera toxin (CTX; increases cAMP) pretreatment of pituitary cells from proestrous and diestrous 1 rats relative to their LH secretory response to GnRH using a reverse hemolytic plaque assay. The number of gonadotropes that secrete LH in the group treated with CTX increased at low doses of GnRH and also in the absence of the peptide, but decreased at high doses, showing a dual effect: stimulation of some gonadotropes and inhibition of others. The inhibition was achieved within 3 h of pretreatment in proestrous cells but it was not seen until 20 h in diestrous 1 cells. This suggests the existence of at least two subpopulations of gonadotropes, one of which is stimulated by cAMP and another which is inhibited. PMID- 8674838 TI - Cloning and expression of the rat adrenal cytochrome P-450 11B3 (CYP11B3) enzyme cDNA: preferential 18-hydroxylation over 11 beta-hydroxylation of DOC. AB - The biosynthesis of glucocorticoids and mineralocorticoids in the rat adrenal cortex requires the action of two different cytochrome P450 11 beta-hydroxylases, CYP11B1 and CYP11B2, which are distributed in the zona fasciculata and glomerulosa, respectively. The existence of another cytochrome P450-11 beta gene, CYP11B3, was recently reported. Although CYP11B3 has similar gene structure and great homology to the CYP11B1 and -B2 genes, the CYP11B3 mRNA was not originally detected by reverse transcription-polymerase chain reaction (RT-PCR) and has only recently been cloned and detected from neonatal rat adrenals. Herein we demonstrate RT-PCR detection of CYP11B3 mRNA expressed in adult rat adrenal and brain tissues. The whole coding region of the CYP11B3 enzyme cDNA was cloned and sequenced. When transiently expressed in COS-7 cells the CYP11B3 converted deoxycorticosterone (DOC) to corticosterone and 18-hydroxydeoxycorticosterone, but not to 18-hydroxycorticosterone or aldosterone. It produced more 18-OH-DOC than corticosterone. A single mutation in CYP11B3 in which Gly-59 was replaced by Ser, reduced the enzymatic activity 5-6-fold. Furthermore, CYP11B3 mRNA expression is greater in neonatal, compared to adult rat adrenal glands. PMID- 8674839 TI - Estradiol and triiodothyronine increase production of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) by GH4C1 rat pituitary tumor cells. AB - The main purpose of this study was to examine the effect of 17 beta-estradiol (E2) on the production of insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding proteins (IGFBP) by GH4C1 cells, a pituitary tumor cell line that displays many phenotypic properties of the anterior pituitary lactotroph. At a low population density (10,500 cells/cm2), E2 stimulated production of IGF-I by 4.2-fold. At this density, the antiestrogen tamoxifen (TAM) had no significant effect, whereas triiodothyronine (T3), which has been demonstrated to increase the level of IGF-I mRNA in the parental GH3 cell line, stimulated IGF-I production by 3.3-fold. Both E2 and T3 also stimulated GH4C1 cell proliferation at this population density. At a four-fold higher population density (42,000 cells/cm2), E2, TAM and T3 had little effect on IGF-I production. E2 failed to stimulate proliferation of GH4C1 cells at high density, and T3 stimulated proliferation to a lesser extent than observed at the low density. At the low population density, E2 and T3 stimulated production of IGFBP-3 by 6- and 11-fold, respectively. At high density, the abilities of E2 and T3 to stimulate IGFBP-3 production were somewhat reduced. TAM had no effect on IGFBP-3 production at either population density. These data indicate that E2 and T3 stimulate production by GH4C1 cells of IGF-I through a mechanism that is sensitive to changes in population density. PMID- 8674840 TI - Effect of exogenous chicken growth hormone (cGH) administration on insulin-like growth factor-I (IGF-I) gene expression in domestic fowl. AB - The effects of chicken growth hormone (cGH) infusion on insulin-like growth factor (IGF-I) gene expression in rapidly-growing, meat-type chickens was investigated. Chicken GH was infused either continuously or in a pulsatile fashion to 8-week-old birds during a 7-day period. Following cGH infusion, both IGF-I peptide and IGF-I mRNA content were measured in selected tissues. Steady state IGF-I mRNA abundance was determined by a solution hybridization nuclease protection assay using total cellular RNA obtained from liver, heart, kidney, spleen, epiphyseal growth plate cartilage, gastrocnemius and pectoralis muscles. Continuous infusion of cGH elicited a two-fold increase in IGF-I peptide concentration in the kidney (P < 0.05), while all other tissues remained unchanged by cGH treatment under this infusion pattern. Pulsatile cGH infusion produced a two-fold increase in IGF-I peptide content in the liver, gastrocnemius, and pectoralis muscles (P < 0.05). In contrast with the levels of IGI-I peptide, relative steady-state IGF-I mRNA content was two-fold higher in liver and spleen of birds treated continuously with cGH, but was decreased to 35 and 55% of control birds in heart and pectoralis muscle. Pulsatile cGH infusion resulted in a 64% increase in IGF-I mRNA in the liver and remained unchanged in other tissues. Under both patterns of administration, changes in IGF-I mRNA were not reflected by changes in tissue IGF-I peptide levels. Overall correlations between tissue IGF-I mRNA and peptide levels were low and not significant in the tissues studied, except for liver under pulsatile infusion, in which IGF-I peptide levels paralleled changes in IGF-I mRNA. We conclude that, in chickens, exogenous cGH treatment stimulates hepatic IGF-I transcription and translation only when the pattern of infusion mimics the natural episodic pattern of GH secretion. The low correlation between IGF-I peptide and mRNA levels in extra hepatic tissues may indicate differential responsiveness to GH in birds, and that in some tissues IGF-I levels are under GH-independent transcriptional controls. PMID- 8674841 TI - Effect of dietary chloride on aldosterone synthase induction and angiotensin II receptors in rat adrenals. AB - Effects of dietary chloride ions on the levels of both cytochrome P-450aldo (CYP11B2) and angiotensin II receptors were examined in rat adrenals. Capsular adrenal CYP11B2 protein levels significantly increased in previously chloride depleted animals treated with either ammonium- or choline chloride. No changes in CYP11B2 protein levels were detected in previously chloride-depleted rats replenished with either ammonium acetate or choline bromide. The induction of CYP11B2 by chloride-repletion was not concurrent with either increased plasma renin activity or elevated serum potassium levels. None of the above dietary manipulations affected angiotensin II receptor number and affinity, respectively. Treatment of chloride-repleted animals with an angiotensin II receptor antagonist (TCV116) significantly attenuated the increase of CYP11B2 protein levels. In addition, chloride-repletion of previously chloride-depleted animals increased mRNA levels encoding angiotensin II type 1B receptor, but decreased mRNA levels encoding the type 1A form of the receptor. Thus, the presented data are supportive of the notion that the regulation of CYP11B2 expression in the capsular portion of the rat adrenal is, in part, mediated via induction of the angiotensin II type 1B receptor. PMID- 8674843 TI - Modulation of macrophage proliferation by hyperglycemia. AB - Macrophages have been show to be of importance in three areas of pathology in the diabetic state: (a) in the destruction of the beta cells of the pancreas; (b) in the pathogenesis of the microvascular lesions; and (c) in the atherosclerotic lesion which is a common complication of diabetes. However, there is only scanty information on the behavior of the macrophage in the hyperglycemic environment. The present study investigates the growth of WEHI-3 monocytes/macrophages and the proliferative response of splenic macrophages to colony stimulating factor-1 when cultured in media containing high glucose concentrations. The results of the study show that hyperglycemia increases the proliferation of these macrophages; this effect is not mediated by the effect of osmolality since mannitol and L glucose failed to produce a similar result. These findings suggest that alterations of macrophage physiology may be an important component of the diabetic state; such alterations may have a role in the production of some of the lesions found in diabetes mellitus. PMID- 8674842 TI - Angiotensin II receptor subtypes in the adrenals of pregnant rats. AB - During human and rat pregnancy, several hemodynamic and endocrine processes are markedly modified. These include activation of the renin-angiotensin system (RAS) and increase of plasma aldosterone. However, the rise of plasma aldosterone is greater than expected from the elevation of RAS activity. Gestational alterations in angiotensin II receptors (AT receptor) in the adrenal could explain this apparent hyperaldosteronism. This study was conducted to determine differences between AT receptor subtypes in the adrenal glands of non-pregnant and pregnant (22 days) rats. Using plasma membrane preparations from adrenal glomerulosa and medulla, we determined receptor density and affinity with 125I-angiotensin II (ANG II); the AT receptor subtypes were assessed by displacement of 125I-ANG II binding with subtype-specific antagonists (DuP753 and PD123319). In zona glomerulosa of non-pregnant and pregnant rats, AT1 receptors predominated (approximately 80%) with no statistical difference in receptor density (Bmax) and affinity (Kd) and the ratio of receptor subtypes between the two groups of rats. In adrenal medulla of both groups of rats, the major portion of 125I-ANG II binding (60-70%) was displaced by the AT2 receptor antagonist, PD123319. Neither Bmax nor Kd differed in this tissue during gestation. The results for AT1 receptor density were confirmed by Western blot. Northern blot analysis showed that AT1 mRNA level in the adrenal is not modified by gestation. These results indicate that the number, the affinity and the transcription of the AT1 receptor in the adrenal are not altered during pregnancy, indicating that the rise in aldosterone secretion during pregnancy could not be explained by increase of AT1 receptors in the zona glomerulosa, or modification of AT1/AT2 ratio. PMID- 8674844 TI - Multihormonal control of vitellogenin mRNA expression in the liver of frog, Rana esculenta. AB - In Rana esculenta in an in vitro system, hepatic vitellogenin synthesis can be induced by growth hormone in both sexes. In this study: (1) the ability of this hormone to induce transcription of the VTG gene was determined, and (2) this ability was compared with that of estradiol-17 beta. The results indicate that growth hormone stimulates VTG mRNA transcription both in vivo and in vitro, in both sexes. The levels of mRNA are related to protein levels in the medium. In addition, seasonal variation occurs in the VTG gene transcription under growth hormone and estradiol-17 beta; indeed the more active inducer was growth hormone during the reproductive period and estradiol-17 beta during the preproductive phase. PMID- 8674845 TI - Basic fibroblast growth factor binding and processing by human glioma cells. AB - Tumor cells of glial origin express high levels of basic fibroblast growth factor (bFGF) which stimulates their proliferation in an autocrine manner. In the present study we examined bFGF receptor (FGFR) expression and 125I-bFGF binding and processing in a human glioma cell line. RT-PCR demonstrated the co-expression of bFGF and FGFR mRNAs in five glioma cell lines examined. The high-affinity FGFR was visualized in U87-MG glioma cells by crosslinking with 125I-bFGF and by Western blotting with anti-receptor antisera. Both techniques identified a discrete 110-kDa moiety associated with the cell membrane, consistent with the reported size of one of the FGFR-1 isoforms. Western blotting also identified an intracellular receptor pool which was not accessible with exogenous 125I-bFGF. Suramin treatment induced a 2-fold increase in immunoreactive FGFR and a 1.5-fold increase in 125I-bFGF binding sites, indicating that FGFRs are chronically down regulated by endogenous bFGF in U87-MG cells. Removal of extracellular bFGF with heparin resulted in a rapid, cycloheximide-sensitive increase in high-affinity bFGF binding sites. At 37 degrees C, receptor-bound 125I-bFGF was internalized and subjected to limited proteolytic cleavage over 12 h. U87-MG cells also contained abundant low-affinity bFGF binding sites which were removed by digestion with heparinase III but not by chondroitinase ABC. The presence of heparin (25 micrograms/ml) in the binding reaction eliminated the association of 125I-bFGF with the heparin-like sites but did not prevent binding to the high affinity receptor. Scatchard binding analysis in the presence of heparin revealed a single class of high-affinity sites in U87-MG cells (Kd = 4.9 +/- 0.9 pM; 10-12 x 10(3) sites per cell). Neither heparin nor heparinase digestion prevented the binding of 125I-bFGF to the detergent-extractable high-affinity receptor, although both treatments significantly reduced the extent of 125I-bFGF association with the receptor. These findings indicate that in U87-MG cells, heparan sulfate proteoglycans may be involved in presentation of bFGF to the high affinity receptor, but are not essential for high-affinity binding to occur. PMID- 8674846 TI - A 338-bp proximal fragment of the glucose transporter type 2 (GLUT2) promoter drives reporter gene expression in the pancreatic islets of transgenic mice. AB - The high Km glucose transporter GLUT2 is a membrane protein expressed in tissues involved in maintaining glucose homeostasis, and in cells where glucose-sensing is necessary. In many experimental models of diabetes, GLUT2 gene expression is decreased in pancreatic beta-cells, which could lead to a loss of glucose-induced insulin secretion. In order to identify factors involved in pancreatic beta-cell specific expression of GLUT2, we have recently cloned the murine GLUT2 promoter and identified cis-elements within the 338-bp of the proximal promoter capable of binding islet-specific trans-acting factors. Furthermore, in transient transfection studies, this 338-bp fragment could efficiently drive the expression of the chloramphenicol acetyl transferase (CAT) gene in cell lines derived from the endocrine pancreas, but displayed no promoter activity in non-pancreatic cells. In this report, we tested the cell-specific expression of a CAT reporter gene driven by a short (338 bp) and a larger (1311 bp) fragment of the GLUT2 promoter in transgenic mice. We generated ten transgenic lines that integrated one of the constructs. CAT mRNA expression in transgenic tissues was assessed using the RNAse protection assay and the quantitative reverse transcribed polymerase chain reaction (RT-PCR). Overall CAT mRNA expression for both constructs was low compared to endogenous GLUT2 mRNA levels but the reporter transcript could be detected in all animals in the pancreatic islets and the liver, and in a few transgenic lines in the kidney and the small intestine. The CAT protein was also present in Langerhans islets and in the liver for both constructs by immunocytochemistry. These findings suggest that the proximal 338 bp of the murine GLUT2 promoter contain cis-elements required for the islet specific expression of GLUT2. PMID- 8674847 TI - Immortalized anterior pituitary alpha T3 gonadotropes contain functional luteinizing hormone/human chorionic gonadotropin receptors. AB - Immortalized alpha T3 gonadotropes contain a major 5.0-kb and minor 3.6-, 2.4- and 1.6-kb luteinizing hormone/human chorionic gonadotropin (LH/hCG) receptor transcripts and an 80-kDa receptor protein which can specifically bind 125I-hCG. The relative abundance of the receptors in alpha T3 cells is, however, lower than in gonadal tissues. Culturing alpha T3 cells with highly purified hCG resulted in a dose- and time-dependent and hormone-specific increase in steady-state levels of LH-alpha subunit mRNA. Culturing alpha T3 cells with hCG also resulted in a concomitant increase in the LH-alpha protein levels. As expected, culturing with GnRH also resulted in an increase of LH-alpha subunit mRNA and protein levels. In summary, we conclude that alpha T3 cells contain LH/hCG receptors which are functionally coupled to the up-regulation of LH-alpha subunit gene expression. PMID- 8674848 TI - Ontogeny of immunoreactive and bioactive microsomal steroidogenic enzymes during adrenocortical development in rats. AB - The functional development of the neonatal rat adrenal cortex is characterized by a triphasic response to adrenocorticotropic hormone (ACTH), with a nadir in responsiveness around neonatal day 10 (d10). In this study, the hypothesis was tested that hyporesponsiveness to ACTH partly results from deficiencies in steroidogenic enzyme content. Immunoreactive (ir) levels of mitochondrial cytochrome P450 enzymes (side chain cleavage (P450scc) and 11 beta-hydroxylase (P450c11)) did not change during neonatal development. Immunoreactive levels of microsomal 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta-HSD), however, were significantly and comparably lower in both day 1 (d1) and d10 neonates compared to adult rats. Activity of 3 beta-HSD did not parallel changes in ir 3 beta-HSD content. Enzyme activity was low on d1 (approximately 39% of adult activity), but by d10 was statistically equivalent to that of microsomes from adult adrenal glands. Immunoreactive levels of microsomal cytochrome P450 21 alpha-hydroxylase (P450c21) were significantly lower in d1 glands than in adult glands (by approximately 50%), but by d10 were statistically indistinguishable from adults. On the other hand, P450c21 activity was equivalent on d1 and d10 and both were significantly lower compared to adults (approximately 62% of adult activity). ACTH injections from d3-d10 facilitated the adrenocortical steroidogenic response to ACTH on d10. This treatment increased levels of ir 3 beta-HSD, but not ir P450c21. The results suggest that rat adrenocortical 3 beta HSD and P450c21 are developmentally and differentially regulated, and that ir levels of the proteins are not correlated with enzyme activity during the neonatal period. One possible explanation for these observations is that multiple isoforms of the two enzymes, with different antigenic and enzymatic properties, may be expressed during development at different times. In addition, the combined decreased activities of these two enzymes can almost entirely account for the decreased steroidogenic output of rat adrenocortical cells on d1, but not during the later neonatal period. PMID- 8674849 TI - Growth hormone inhibits differentiation of avian epiphyseal growth-plate chondrocytes. AB - The effect of chicken growth hormone (cGH) on the proliferation and differentiation of avian growth-plate chondrocyte was evaluated in culture. In culture, addition of ascorbic acid to the culture media caused cell differentiation. Treatment of proliferating chondrocytes with cGH caused a time dependent increase in collagen type II gene expression together with a decrease in the appearance of osteopontin (OPN) in the medium. In addition, the ascorbic acid-dependent increase in alkaline phosphatase (AP) activity was inhibited by cGH. IGF-I, on the other hand, caused an increase in AP activity in the ascorbic acid-treated chondrocytes. In the presence of ascorbic acid, cGH did not affect collagen type II gene expression or the appearance of OPN in the medium. Proliferation of avian growth-plate chondrocytes, in contrast to mammalian chondrocytes, was not stimulated by GH alone, although the presence of cGH was essential for chondrocyte survival in long-term culture. cGH in combination with epidermal growth factor (EGF) stimulated cell proliferation. These results suggest that GH inhibits differentiation in avian growth-plate chondrocytes, thereby sustaining their proliferative state and maintaining their sensitivity to growth factors such as EGF. PMID- 8674851 TI - Establishment of immunological probes to study human gonadotropin-releasing hormone receptors. AB - Monoclonal antibodies were raised to a synthetic peptide corresponding to amino acids 1-29 of the human gonadotropin-releasing hormone (GnRH) receptor. One of the two antibodies was found to recognise GnRH receptors on human pituitary gonadotrophs as determined by immunohistochemistry and supported by Western blotting. The antibody also bound to T47D human breast carcinoma cell line as determined by flow cytometric analysis. PMID- 8674850 TI - Growth hormone (GH) and prolactin (PRL) regulate IGFBP-3 gene expression in rat beta-cells. AB - We examined the effects of growth hormone (GH), prolactin (PRL) and insulin-like growth factor-I (IGF-I) on DNA synthesis, and insulin-like growth factor binding protein 3 (IGFBP-3) gene expression, in a rat beta-cell line INS-1. GH and PRL were equally effective in increasing DNA synthesis and IGFBP-3 gene expression. IGF-I also stimulated DNA synthesis, but its effect on IGFBP-3 mRNA accumulation was moderate. The GH activities in this cell line were not mediated by IGF-I production: (1) no IGF-I mRNA could be detected in poly-A RNA preparation, and IGF-I level was very low; (2) neither IGF-I mRNA nor the protein, were increased upon GH treatment; (3) DNA synthesis stimulatory activities of GH and IGF-I were additive; (4) the GH-induced IGFBP-3 mRNA increase was not inhibited by cycloheximide treatment. Thus, the activities of GH in this cell line are not mediated by a protein synthesis. PMID- 8674852 TI - Characterization of site-directed antibodies to the LH receptor in functionally active gonadal cells and their differential effects on LH-stimulated signal transduction in Leydig tumour (MA10) cells. AB - In this study site-directed antibodies have been used to investigate the structure/activity relationships of the LH receptor in functionally active gonadal cells. Polyclonal antibodies were raised in rabbits against synthetic peptides corresponding to regions within both the extracellular N-terminal domain (antibodies 1 and 2 against residues 48-65 and 187-206, respectively) and the cytoplasmic C-terminal domain (antibody 3 against residues 622-636) of the LH receptor. Following affinity purification by chromatography on columns of immobilised peptides the antibodies were demonstrated to be peptide specific both by ELISA and by dot-blotting assays. On Western blots of membranes proteins prepared from superovulated rat ovaries, mouse Leydig tumour (MA10) cells, and rat testes, all three antibodies recognised a single broad band of apparent M(r) 95,000-100,000 corresponding to the putative LH receptor. The protein of apparent M(r) 95,000-100,000 also bound 125I-hCG on ligand blots, and binding was displaced by excess unlabelled hCG. The binding of 125I-hCG in the ligand blots was completely inhibited by excess unlabelled hCG. The two N-terminal antibodies (antibodies 1 and 2 (10 micrograms/ml)) also inhibited 125I-hCG binding to a greater extent than the C-terminal antibody (antibody 3 (10 micrograms/ml)). Antibody 1 (1 and 10 micrograms/ml) also potently inhibited the binding of 125I hCG to MA10 cells. A lesser but still significant inhibition of binding was produced by antibody 2 (with 10 micrograms/ml), whereas at the concentrations tested antibody 3 exerted no greater inhibition than that yielded by pre-immune IgG. At 0.1 micrograms/ml antibody 1 significantly inhibited and at 10 micrograms/ml completely inhibited LH-stimulated cAMP and progesterone production by MA10 cells. With antibody 2, 10 micrograms/ml was required to give a significant inhibition, whereas neither antibody 3 nor pre-immune IgG had a significant effect. The antibodies had no effect on cAMP or progesterone production when added to the MA10 cells in the absence of LH. These results indicate that binding of antibody 1 and, to a lesser extent, antibody 2 interferes with ligand binding which consequently affects signal transduction. In view of the ability of the antibodies to recognise the LH receptors both in the ovary and the testis and in more than one rodent species, and their greater apparent potency than previously available antisera, the anti-peptide antibodies raised in the present study will therefore be useful to study LH receptors in normal, functionally active gonadal cells. PMID- 8674853 TI - Effects of retinoic acid and estrogens on oxytocin gene expression in the rat uterus: in vitro and in vivo studies. AB - We and others have previously identified functional estrogen (E) and retinoic acid (RA) response elements in the human and rat oxytocin (OT) gene promoters. Whereas there is no direct evidence for a significant role of E or RA in the regulation of rat hypothalamic OT gene expression, we have recently demonstrated that in vivo administration of E strongly stimulates uterine OT gene expression. Here, we show that in vivo administration of RA similarly induces a significant increase in uterine OT gene expression. Moreover, we report that the E and RA effects are reproducible in vitro. Using short-term uterine organ explant cultures derived from 18-day pregnant rats, we found that E (50 nM) and RA (0.4 nM) increased OT mRNA levels 5.2- and 3-fold, respectively, suggesting a direct action of these agents on uterine OT gene expression. Finally, we analyzed uterine E and RA receptor gene expression during pregnancy. Using semi quantitative Northern blot analysis, we found that mRNAs encoding the E receptor, the RA receptor alpha and RA receptor beta are present in rat uterus and that their levels rise by 3.7-, 3.6- and 5.8-fold, respectively, between day 14 of gestation and term. Taken together, the data suggest that, at term, the rat uterus has an increased capacity to respond to E and RA, and that both agents may be involved in mediating the dramatic increase of OT mRNA accumulation observed in the uterus at term. PMID- 8674854 TI - The major promoter of the rat insulin-like growth factor-I gene binds a protein complex that is required for basal expression. AB - IGF-I gene transcription is regulated by two promoters--the major promoter which is active in all tissues and regulates transcription of IGF-I mRNAs that contain exon 1 and a second promoter which regulates transcription of IGF-I mRNAs that contain exon 2 and from which significant transcription is restricted to the liver. The major promoter is a TATAA-less promoter that lacks both a CAAT box and SP1 binding sites and that utilizes multiple transcription initiation sites. The current studies were designed to delineate the functional elements of the major promoter. Transient transfection assays using rat C6 glioma cells and rat dermal fibroblasts in primary culture demonstrated that basal activity of the major promoter was located between -18 (with +1 defined as the most 5' transcription initiation site in exon 1) and +78 of exon 1. DNase I footprinting, which was performed using nuclear extracts from rat C6 glioma cells, demonstrated protein binding to a sequence that extended from -10 to +9 (termed IGFI-FP1). In gel shift assays, binding of C6 cell nuclear proteins to a 34-basepair (bp) oligonucleotide that contained IGFI-FP1 resulted in the formation of three specific protein-DNA complexes. The functional role of protein binding to IGFI FP1 was examined by mutating the sequences between either -4 and -2 or -9 and -7 in IGF-I-luciferase fusion genes that contained either 412 or 18 bp of 5' flanking region and 302 bp of exon 1. Both of these mutations altered protein binding to IGFI-FP1 as demonstrated by gel shift analysis. Transfection of the wild-type and mutant fusion genes into C6 glioma cells demonstrated that mutation of the nucleotides between -4 and -2 decreased luciferase activity to approximately 50% of wild-type activity, whereas mutation of the nucleotides between -9 and -7 decreased luciferase activity to 11-35% of wild-type activity. These data demonstrate that: (i) basal activity of the major promoter of the rat IGF-I gene is localized to the region between -18 and +78 of exon 1; (ii) protein binding sites are present within this region of the major promoter; and (iii) protein binding to this region contributes to basal expression of the IGF-I gene. PMID- 8674855 TI - Two consecutive nucleotide substitutions resulting in the T3 receptor beta gene resulting in an 11-amino acid truncation in a patient with generalized resistance to thyroid hormone. AB - We identified unusual mutations in the T3 receptor (TR) beta gene in a 6-year-old Japanese girl with generalized resistance to thyroid hormone. Two consecutive base substitutions, T to A and C to A at nucleotide positions 1637 and 1638, respectively, changed the 451st codon coding for Phe(TTC) to stop codon (TAA), resulting in an 11-amino acid carboxyl(C)-terminus truncation. The patient was a heterozygote. Western blotting using an anti-TR antibody demonstrated the truncated receptor protein. The patient showed severe mental retardation (IQ41), disturbance in speech development, and attention deficit hyperactivity disorder. Thyroid functional status by clinical evaluation was considered within the normal range in spite of high serum thyroid hormone levels (T4 725.9 nmol/l, T3 12.7 nmol/l, FT4 166.0 pmol/l). TSH increased from 0.6 to 24 mU/L after TRH (150 micrograms) injection. TSH secretion as well as 123I-uptake was suppressed only partially by T3 (75 micrograms/day for a week). Close examination of thyroid functions and TR beta gene analysis were not possible in the family, except for paternal grandmother and one of her two sisters who showed no abnormality. The patient's truncated TR beta showed very low T3 binding activity (Ka = 0.1 x 10-10 M), transcriptional activity, and a very strong dominant negative effect. When co expressed with wild-type TR beta at the molar ratio 1:1 in CV-1 cells, the mutant receptor inhibited the wild-type TR beta transcriptional activity by 74% at 10 nM T3. Even 1 microM T3 could not normalize these impaired functions. PMID- 8674856 TI - Functional activity of the human prolactin receptor and its ligands. AB - Prolactin receptors (PRLR) have been identified in a number of human tissues and cell lines, although little is known about the human receptor protein. The cloning of the human PRLR cDNA has enabled further characterization of the receptor protein in transfected cells. Since the human cDNA is expressed at lower levels than the rat cDNA, we have constructed a hybrid cDNA (pECE r5'hPRLR) containing nucleotides of the 5' untranslated region and signal peptide of the rat PRLR and the protein coding and 3' untranslated portion of the human receptor. Expression of the hybrid receptor was increased more than two-fold compared to the human receptor as detected by specific binding of 125I-human growth hormone (GH) to transfected COS-7 cells. The relative molecular mass of the receptor was 93,000 Da, as determined by chemical cross-linking studies. Transcriptional assays were used to show the human PRLR was able to activate two milk protein genes; ovine beta-lactoglobulin and rat beta-casein. Transfected cells expressing the human PRLR receptor, treated with human GH or prolactin (PRL), induced a dose-dependent increase in transcriptional activation of the beta-casein/luciferase fusion gene. Glycosylated, and non-glycosylated human PRL, and ovine PRL were equally effective in activating the beta-casein promoter. Human placental lactogen and bovine PRL could also induce a greater than 10-fold induction, whereas insulin did not significantly stimulate the beta-casein promoter. The results show that the human PRLR can activate both beta lactoglobulin and beta-casein milk gene promoters and that these reporter genes can be used to evaluate the functional activity of agonists and antagonists of the human PRLR. PMID- 8674857 TI - Preparation and characterization of recombinant prolactin receptor extracellular domain from rat. AB - Complementary (c)DNA of the extracellular domain of rat prolactin receptor (rPRLR ECD) was cloned in the prokaryotic expression vector pTrc99A, and expressed in Escherichia coli following induction with isopropyl-b-D-thiogalactopyranoside. The expressed rPRLR-ECD protein, contained within the refractile body pellet was solubilized in 4.5 M urea, refolded and purified on a Q-Sepharose column by stepwise elution with NaCl. Only approximately 10% of the expressed protein refolded as a monomeric fraction, yielding 5-6 mg/l of induced culture. The purified protein was over 98% homogeneous, as shown by SDS-PAGE in the presence or absence of reducing agent, and by chromatography on a Superdex column. Its molecular mass, determined by SDS-PAGE in the absence of reducing agent, was 28 kDa, and by gel filtration, 25.6 kDa. Binding experiments indicated high affinity for bovine placental lactogen (bPL) and human growth hormone (hGH) as compared to ovine (o) or rat PRLs. Gel filtration was used to determine the stoichiometry of rPRLR-ECD's interaction with these hormones. At a 5 microM initial concentration of the hormones, formation of 2:1 (ECD:ligand) complexes was detected with bPL, hGH and oPRL whereas only 1:1 complex was formed with rPRL. Dilution (25-fold) of these complexes did not affect the stoichiometry with bPL, whereas with hGH a clear tendency towards dissociation of the initial 2:1 complex to 1:1 complex was observed. This tendency was even stronger in the case of oPRL. Although all four hormones exhibited nearly identical activities in the Nb2-11C lymphoma cell bioassay, the ability of the purified rat or rabbit PRLR-ECD to inhibit hormonal mitogenic activity generally reflected their affinity for the respective hormones. In view of these and former results, we suggest that unlike in the GH:GHR-ECD interaction, the inability of lactogenic hormones to form a 1:2 complex with soluble recombinant PRLR-ECDs does not necessarily predicts lack of biological activity. PMID- 8674858 TI - Stimulation of ecdysteroidogenesis by small prothoracicotropic hormone: role of calcium. AB - Insect prothoracic glands are regulated by neuropeptide prothoracicotropic hormones (PTTH). In Manduca sexta PTTH exists as two size variants, big PTTH (approximately 25.5 kDa) and small PTTH (approximately 7 kDa). Previous studies indicate that both size variants employ cAMP as a second messenger and that stimulation of ecdysteroid secretion by big PTTH is Ca(2+)-dependent. In the present study, experiments were performed to assess the role of Ca2+ in small PTTH-stimulated ecdysteroid secretion by prothoracic glands from fifth instar larvae. Basal ecdysteroid secretion was not affected by Ca2+ channel blockers (verapamil or lanthanum) or by omission of Ca2+ from the incubation medium. Treatment of glands with a Ca2+ ionophore (A23187 or ionomycin) produced a concentration-dependent stimulation of ecdysteroid secretion. Stimulation of ecdysteroid secretion by small PTTH was suppressed (1) by Ca2+ channel blockers and (2) in Ca(2+)-free medium. A cAMP analog (Sp-cAMPS) stimulated ecdysteroid secretion in the presence of a Ca2+ channel blocker (verapamil) and in Ca(2+) free incubation medium, and ionophore-induced ecdysteroid secretion appeared to be suppressed by a cAMP antagonist (Rp-cAMPS). The combined results indicate that basal ecdysteroid secretion is not dependent on external Ca2+, and suggest that small PTTH-stimulated ecdysteroid secretion is mediated by an influx of Ca2+ that precedes cAMP formation. PMID- 8674859 TI - Characterization of the Pacific salmon gonadotropin-releasing hormone gene, copy number and transcription start site. AB - Multiple forms of gonadotropin-releasing hormone (GnRH) have been shown to exist in all vertebrates examined except recently-evolved placental mammals. To study the origin and regulation of the GnRH genes in a Pacific salmon (Oncorhynchus nerka), we isolated and sequenced the salmon form of GnRH. The Southern blot shows a single band that strongly hybridizes to a probe for the gene reported here and weaker bands that may represent genes for related forms of GnRH. There is strong conservation of sequence in the hormone coding region and of the gene organization between fish and mammals. However, the GnRH-associated peptide (GAP) shows very little sequence identity with the mammalian GAPs, questioning its physiological role. We also show for the first time the transcriptional start site for a GnRH gene in a non-mammalian species. Interestingly, a large segment of 1152 nucleotides in the promoter region of the Pacific salmon GnRH gene is missing compared with the Atlantic salmon (Salmo salar) gene. These gene rearrangements suggest that these two salmonid species, which have been geographically separated for 8-15 million years, have evolved promoters with different mechanisms for control and transcription of GnRH. PMID- 8674860 TI - Glucose-dependent insulinotropic peptide (GIP) gene expression in the rat salivary gland. AB - Previous studies have indicated that following nutrient ingestion, GIP is released principally from the upper small intestine. In addition to its presence in the rat small intestine, GIP transcripts have also been localized to the submandibular salivary gland (SSG). The present studies were directed to further characterize expression of the GIP gene in the SSG. Pregnant rats were sacrificed at gestational days 18 and 20, followed by the removal of rat fetuses. The duodenum pancreas, and SSG were then excised from the fetuses, as well as from neonatal pups at ages 1, 3, 7, 10, 14, and 21 days. RNA was extracted and measured by Northern blot analysis using specific rat GIP probes. GIP transcripts were first detected in the duodenum in the 18-day fetus and reached maximum levels at birth. In contrast, GIP mRNA was not observed in the SSG until 10 days postnatally and was not detected at all in either the fetal or neonatal pancreas. In situ hybridization of the SSG using an 35S-labelled antisense GIP RNA probe demonstrated expression of the GIP gene to be limited to ductal cells, with no transcripts present in acini. In separate experiments, rats fasted overnight were given water or 10% glucose. While no changes were detected in water-fed rats following oral glucose ingestion, small, but significant increases in SSG GIP gene expression were detected at 60 and 240 min. The results of these initial studies suggest the possibility of a functional role for GIP in the rat salivary gland by the demonstration of GIP mRNA in the SSG by Northern analysis and in situ hybridization, as well as by an increase in SSG GIP gene expression following a glucose meal. PMID- 8674861 TI - Canine kidney glucagon receptor: evidence for a structurally-different, tissue specific variant of the glucagon receptor. AB - 125I-Glucagon was directly cross-linked to its receptor sites on the MDCK plasma membranes using a UV irradiation procedure. Analysis of the affinity labeled membranes by SDS-PAGE and autoradiography, demonstrated the presence of a single band at 74 kDa. The incorporation of radiolabeled glucagon into this band was abolished by the presence of excess unlabeled hormones, thus indicating a specificity of labeling. Also this band was observed in affinity labeled dog kidney plasma membranes. The size of the MDCK and the dog kidney glucagon receptors were consistently larger than that of the dog liver receptor as judged by electrophoretic mobility. Treatments with neuraminidase, endoglycosidase F, or N-glycanase failed to convert the renal form into the hepatic form of the receptor. Proteolytic mapping of the MDCK and the dog liver glucagon receptors revealed that major domains of both proteins are remarkably similar, yet transient variations in the size of the fragments could be detected after short duration digestions. Overall the data presents evidence that the dog renal receptor represents a structurally unique isoform of the glucagon receptor. PMID- 8674862 TI - Regulation of eicosanoid synthesis in fibroblasts from inflamed gallbladders. AB - Gallbladder cell cultures obtained from rabbits subjected to sham or 72 h of bile duct ligation (72 h BDL, cholecystitis model) were incubated with calcium ionophore (A23187), dibutyryl cAMP (cAMP), and phorbol 12,13-diacetate (phorbol) to determine the intracellular signal transduction mechanisms responsible for increased inflamed gallbladder eicosanoid synthesis. Incubation of sham and 72 h BDL cell cultures with A23187 or phorbol significantly increased, whereas cAMP decreased, release of 6-keto-PGF1 alpha, PGE2, thromboxane B2 (measured by enzyme immunoassay) in a dose-related manner. Seventy-two-hour BDL cell cultures contained a specific 2-fold increased level of prostacyclin synthase compared to sham cell cultures which was not altered by preincubation with A23187, phorbol or cAMP. These findings suggest that increased PGI2 release in the sham and inflamed cell cultures following A23187 and phorbol stimulation was mediated in part via the inositol triphosphate pathway and protein kinase C activation and was not associated with altered cyclooxygenase or prostacyclin synthase content. PMID- 8674863 TI - Cytochromes CYP1A1 and CYP1B1 in the rat mammary gland: cell-specific expression and regulation by polycyclic aromatic hydrocarbons and hormones. AB - Cultured rat mammary cells express both CYP1A1 and CYP1B1 in response to polycyclic aromatic hydrocarbons (PAH) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a cell type-specific manner. The expression of each P450 was determined functionally (regioselective PAH metabolism), as apoprotein (immunoblots) and as mRNA (Northern hybridization). The epithelial rat mammary cells (RMEC) expressed CYP1A1, however only after PAH or TCDD treatment. CYP1B1 protein was scarcely detected in these induced RMEC but was surprisingly active as a participant in 7,12-dimethylbenz[a]anthracene (DMBA) metabolism shown through selective antibody inhibition (40% of total activity). CYP1B1 was selectively expressed in the stromal fibroblast population of rat mammary cells to the exclusion of CYP1A1. In the rat mammary fibroblasts (RMF), CYP1B1 protein and associated activity were each present at low levels constitutively and were highly induced by benz[a]anthracene (BA) to a greater extent than by TCDD (12- versus 6-fold). However, BA (10 microM) and TCDD (10 nM) stimulated the 5.2-kb CYP1B1-specific mRNA equally. These increases are consistent with the involvement of the aryl hydrocarbon (Ah) receptor in the transcription of the CYP1B1 gene and with the additional stabilization of CYP1B1 protein by BA, previously observed in embryo fibroblasts. Exactly this regulation of CYP1B1-dependent activity was seen in RMEC suggesting that this arises from exceptionally active CYP1B1 in a small proportion (5%) of residual RMF. The constitutive expression and PAH inducibility of CYP1B1 and CYP1A1 proteins in RMF and RMEC, respectively, were each substantially decreased (approximately 75%) by a hormonal mixture (17 beta estradiol (0.2 microM) progesterone (1.5 microM) cortisol (1.5 microM) and prolactin (5 micrograms/ml)). Progesterone and cortisol, added singly to RMF suppressed CYP1B1 protein expression (approximately 80%) in both untreated and BA induced cells, while cortisol also suppressed the 5.2-kb CYP1B1 mRNA. In contrast, 17 beta-estradiol stimulated constitutive expression of CYP1B1 protein (50-75%) and mRNA level (2- to 3-fold), but did not affect CYP1B1 expression in BA-treated RMF. The expression of CYP1A1 and CYP1B1 is therefore highly cell specific even though each is regulated through the Ah receptor. Each P450 exhibits a surprisingly similar pattern of hormonal regulation even though expressed in different cell types. PMID- 8674864 TI - Neural and hormonal regulation of growth of corpora allata in the cockroach, Diploptera punctata. AB - DNA synthesis and mitosis in the corpora allata (CA) of adult Diploptera punctata males were investigated with total cell count after 5'-bromo-2'-deoxyuridine immunodetection and colchicine arrestment both in vivo and in vitro. The CA exhibited a single wave of DNA synthesis followed by cell division during the first 4 days after the imaginal ecdysis. A second mitotic wave was experimentally induced after the nervous connections between the CA and the brain were severed on day 4. Spontaneous mitosis was abolished in cockroaches treated with a juvenile hormone (JH) analog. This inhibitory regulation in vivo appeared to act through brain neurosecretory cells since in the denervated CA mitotic activity was unaffected by JH treatment. An in vitro system supporting growth of the corpus allatum was established to study direct hormonal effects. By using continuous bromodeoxyuridine labeling in vitro for 6 days, we showed that DNA synthesis of corpus allatum cells was unaffected by direct contact with JH. In contrast, 20-hydroxyecdysone exerted direct mitogenic action on allatal cells. These and previous results suggest that CA cells alternate between JH synthesis and a proliferative state in which they divide in a self-renewing fashion to yield differentiated progeny. We propose that in newly enclosed adult Diploptera punctata males, low JH titer and high ecdysteroid titer promote mitosis in CA cells. As the ecdysteroid titer declines, JH produced by the CA acts on brain neurosecretory cells which dispatch inhibitory signals through nerves to prevent continuous proliferation of CA cells. PMID- 8674865 TI - Melatonin and arylalkylamine N-acetyltransferase activity in the silkworm, Bombyx mori. AB - Melatonin (N-acetyl-5-methoxytryptamine) was identified in the head and hemolymph of the silkworm, Bombyx mori, using reversed-phase high-performance liquid chromatography coupled with fluorometric detection and radioimmunoassay. In addition, evidence of arylakylamine (serotonin) N-acetyltransferase (NAT) a key enzyme controlling the synthesis of melatonin in vertebrates, was found in the head of the silkworm. Melatonin levels in the head and hemolymph and the NAT activity in the head were significantly higher during the dark period than during the light period of a 12-h light/12-h dark cycle. The day-night changes persisted in constant darkness but were suppressed by constant light. The results suggest that the synthesis and release of melatonin in the silkworm head occur as a circadian rhythm that is entrained by environmental light/dark cycles, as it is in the pineal gland of vertebrates. Melatonin in the silkworm head may function as a neurochemical mediator of photoperiodic control of developmental events such as molting, eclosion and diapause. PMID- 8674866 TI - Binding properties of coumestrol to expressed human estrogen receptor. AB - We have studied the binding of coumestrol, an inherently fluorescent analog of 17 beta-estradiol, to human estrogen receptor (hER) in extracts of transfected cultured cells. The binding of coumestrol to the hER as well as its dissociation from the receptor can be directly determined by the change in fluorescence intensity of the probe. In agreement with previous studies using calf uterine extracts, we find that coumestrol binds to the receptor with a ten-fold lower affinity than 17 beta-estradiol. However, the rate of dissociation appears to be close to that of the native ligand. Coumestrol can accept energy from Trp residues in the excited state and, using a C530W hER mutant, we have confirmed that residue 530 is close to the ligand-binding pocket. We also find that the presence of saturating amounts of the specific DNA binding sites (ERE) did not significantly alter the binding affinity of coumestrol to either wild type hER or the C530W mutant. PMID- 8674867 TI - Prothoracicotropic hormone-regulated expression of a hsp 70 cognate protein in the insect prothoracic gland. AB - In Manduca sexta, ecdysteroids coordinate molting and metamorphosis of insects and are produced by the prothoracic glands under the acute control of the brain neuropeptide prothoracicotropic hormone (PTTH). PTTH stimulates rapid ecdysteroidogenesis accompanied by specific increases in the synthesis and accumulation of three proteins, including one with M(r) = 70 kDa. This 70-kDa protein is a constitutively expressed member of the heat shock protein 70 family (hsc 70). Levels of this hsc 70 vary in a prothoracic gland-specific manner during development as does its PTTH-stimulated synthesis when assayed in vitro. The accumulation of hsc 70 may be regulated by abrupt changes in its turnover rate. The PTTH-stimulated increase in hsc 70 synthesis is dependent upon both translational and transcriptional events. Hsc 70 expression in the prothoracic gland may be required for changes in gland growth, e.g., protein content, that underlie alterations in ecdysteroid production. PMID- 8674868 TI - Expression of extracellular domain peptides of the FSH receptor and their effect on receptor-ligand interactions in vitro. AB - Follicle-stimulating hormone receptor (FSH-R) displays considerable homology to luteinizing hormone receptor (LH-R) in structure and amino acid sequence. Comparison of the sequences of the extracellular domains (ECD) of the receptors reveals two regions (amino acids 4-56 and 265-319 in FSH-R) that share relatively little amino acid sequence similarity. This suggests that these variable regions may be important in providing specificity of ligand binding. We have expressed overlapping ECD peptides containing one or both of these regions (RFI, amino acids 5-125; RF2, amino acids 201-319; and RF3, amino acids 5-319) as fusion proteins in E. coli using pRSET vector. The presence of polyhistidine at the N terminal end allowed substantial purification of the expressed proteins by a single step of affinity chromatography. The purified peptides were characterized for direct binding of hormone and their ability to block the binding of FSH and LH to the receptors. None of the peptides bound labelled hormone, while all peptides inhibited the binding of FSH to its receptor in a dose-dependent manner. However, only RF2 peptide inhibited ligand binding in a hormone-specific manner. These data suggest there is a site between amino acids 201-319 of the FSH-R ECD that is involved in FSH binding. PMID- 8674869 TI - Differential gene regulation by estrogen and progesterone in the primate endometrium. AB - During the shift from a proliferative to a secretory endometrium in the rhesus menstrual cycle, progesterone action causes massive metabolic and structural remodelling. In order to identify genes whose expression is potentially important for the change from estrogen (E) to progesterone (P) dominance we have initiated a study of specific gene regulation using semiquantitative, reverse transcription polymerase chain reaction (RT-PCR). PolyA+ RNA was isolated from both E-dominant (days 9-13 of artificial menstrual cycles [AMCs]) and P-dominant (days 21-23) rhesus monkey endometria. The two pools of mRNA were converted to cDNA, end ligated to double-stranded oligonucleotide adaptors and amplified by PCR using an adaptor-complementary primer. This procedure resulted in the production of E- and PcDNA template populations for cDNA-specific screening and comparative quantitation by PCR. Initial analysis showed that placental protein 14 (PP14) was P-dependent and human complement 3 (HC3) was up-regulated in E-dominant tissue, whereas the housekeeping genes B-actin and glyceraldehyde-3-phosphate dehydrogenase (G-3-PDH) were expressed at equivalent levels under E and P dominance. Expression of the E receptor (ER), P receptor (PR), epidermal growth factor receptor (EGFR) and insulin-like growth factor (IGF-I) was equivalent under E or P dominance. Expression of epidermal growth factor (EGF) and retinoblastoma (RB) was down-regulated in P-dominant tissue. Conversely IGF-1 receptor (IGF-1-R), transforming growth factor-beta 2 (TGFB-2), TGFB-2 receptor (TGFB-2-R), 17 beta-hydroxysteroid dehydrogenase (17-B-HSD) and leukemia inhibitory factor (LIF) levels were up-regulated in PcDNA. Among these factors, PP14, LIF, IGF-1-R TGFB-2 and 17-B-HSD were also detectable in PCR in a P dependent cDNA library isolated by subtractive hybridization. These data provide evidence for hormonal regulation of specific gene products that may play important roles in the normal maturation of the primate endometrium in preparation for implantation. PMID- 8674870 TI - Proceedings of the 15th International Diabetes Federation Satellite Symposium on Diabetes and Macrovascular Complications. Suita City, Osaka, Japan, 12-13 November 1994. PMID- 8674871 TI - The clinical features and treatment of arteriosclerosis obliterans with diabetes. AB - The objective of this study was to clarify the differences, if any, in the clinical features between diabetic and nondiabetic patients with arteriosclerosis obliterans (ASO) and to select the optimal treatment for diabetic patients with ASO. The 171 patients with ASO studied were classified into nondiabetic and diabetic groups. Each group was subdivided into an intermittent claudication (IC) group and ulcer and necrosis (ULC) group. The frequency of complications with cardiac and cerebral vascular diseases and risk factors of arteriosclerosis were analyzed. Ankle and brachial blood pressure and ankle/brachial pressure index (API) were measured, and blood rheological parameters of filterability using Nuclepore filter membrane and viscosity of whole blood and plasma were measured. Three indexes of walking distance were measured by our ASO-Treadmill protocol to evaluate quantitatively the effect of treatment. There were 95 diabetic patients with ASO and 76 nondiabetic patients. Of the nondiabetic patients, 81 had IC and 14 had ULC, and of the diabetic patients, 63 had IC and 13 had ULC. The diabetic group showed more frequent complications with coronary heart disease (56.5 vs. 25.6%), but the two groups showed the same frequency of cerebrovascular diseases (30%). The diabetic ULC subgroup showed higher fasting plasma glucose than the diabetic IC subgroup. The API of the ULC subgroup was significantly lower than that of the IC subgroup in the nondiabetic patients, whereas that of the ULC subgroup was not significantly lower than that of the IC subgroup in the diabetic patients. Stenotic lesions of arteriography in both the nondiabetic and diabetic ULC subgroups demonstrated a tendency toward multisegmental and below-knee lesions compared with the two IC subgroups. For blood rheology-related factors, the diabetic ASO subgroup demonstrated a significantly elevated fibrinogen level compared with the normal control value, for patients of average age. After walking exercise treatment, a significant increase in the walking distance was obtained. After treatment with Cilostazol, prostaglandin I2 analog, and LDL apheresis, the rheological indexes were significantly improved, while the API did not change. We conclude that therapeutic improvement of blood rheological properties would be effective for prolongation and improvement of the quality of life for diabetic patients with ASO. PMID- 8674872 TI - Biochemical and molecular mechanisms in the development of diabetic vascular complications. AB - Hyperglycemia is the major causal factor in the development of diabetic vascular complications. The mechanism by which hyperglycemia causes the complications is not clear; however, it is very likely that hyperglycemia is mediating its adverse effects through multiple mechanisms. We have summarized some of these mechanisms in this review, with particular attention to the effect of hyperglycemia on the activation of diacylglycerol (DAG)-protein kinase C (PKC) pathway. We have reviewed existing information regarding various vascular tissues that show increased DAG and PKC levels. In addition, the mechanism by which hyperglycemia increases DAG as well as the cellular physiological consequences on the activation of PKC have been reviewed. PMID- 8674873 TI - Mechanism on disorders of coagulation and fibrinolysis in diabetes. AB - Determination of various important parameters of coagulation and fibrinolysis, clinical characteristics, and levels of serum lipid were compared in 193 patients with NIDDM and 50 control subjects. Levels of fibrinogen, tissue factor pathway inhibitor (TFPI), thrombin-anti-thrombin complex, and plasminogen activator inhibitor 1 in plasma increased significantly in the diabetic patients. Levels of TFPI correlated significantly with levels of total cholesterol. In the patients with coronary heart disease or cerebral infarction, levels of lipoprotein(a) increased significantly. From these results, we have concluded that there is a thrombotic tendency or at least an imbalance between the hemostatic and thrombosis-protecting system in diabetic patients, especially in patients with angiopathy. PMID- 8674874 TI - Prostacyclin-stimulating factor, novel protein, and diabetic angiopathy. AB - We recently purified and cloned a new protein that stimulates the synthesis of prostacyclin (PGI2) by the vascular endothelial cells (ECs). We have termed this protein "PGI2-stimulating factor" (PSF). The present study evaluated the expression of PSF mRNA in tissues of Wistar rats, including the kidneys of rats with streptozotocin-induced diabetes, and in cultured cells. Furthermore, we evaluated the presence of PSF in human sera and the immunohistochemical localization of PSF in tissues of patients obtained at autopsy. The latter included a coronary atherosclerotic lesion of a patient who died of acute myocardial infarction. PSF was observed by Northern blot analysis to be expressed in all rat tissues examined (brain, lung, liver, kidney, skeletal muscle, and fat tissue) and was expressed in cultured vascular ECs, smooth muscle cells (SMCs), and fibroblast cells (FCs). A decreased expression of PSF was observed in the kidneys of diabetic rats versus those of normal rats. The presence of PSF in human serum was confirmed by Western blot analysis. In humans, PSF was mainly localized in vascular ECs and SMCs of arterial media and in SMCs of bronchi. Reduced staining for PSF was found in an atherosclerotic versus a normal coronary artery of humans. PSF may be involved in the production of PGI2 in the vessel wall and may participate in the maintenance of vascular homeostasis. PSF abnormalities may be involved in the development of such vascular lesions as atherosclerosis and diabetic angiopathy. PMID- 8674875 TI - Human arterial smooth muscle cell proliferation in diabetes. AB - In the present study, we focus on the proliferation of human arterial smooth muscle cells (SMCs) from NIDDM patients (DM-SMCs) to clarify the reactivity to the growth factor(s) in fetal calf serum (FCS) and the factor(s) secreted by T cells. The proliferation of DM-SMCs was significantly greater than SMCs from nondiabetic patients (nonDM-SMC). DM-SMC conditioned medium (DM-condMed) increased the growth of nonDM-SMCs. These results suggest that the growth factor is secreted from DM-SMCs as an autocrine system, which increases the proliferation of nonDM-SMCs. T-cells increased DNA synthesis of SMCs, and DM-SMCs strikingly reacted to T-cells. The present results support a function of T-cells in stimulating SMC growth. In conclusion, human arterial SMC proliferation is increased in diabetes in the same fashion as in experimentally induced diabetes in animals through responses to growth factors and an increased autocrine system. These results provide a mechanism for the increase in atherosclerotic disease in diabetes. PMID- 8674876 TI - Vitamin E normalizes diacylglycerol-protein kinase C activation induced by hyperglycemia in rat vascular tissues. AB - Hyperglycemia, a major cause of vascular complications in diabetes, has been shown to activate the diacylglycerol (DAG)-protein kinase C (PKC) pathway in vascular tissues. We have found that D-alpha-tocopherol (vitamin E) treatment reversed the adverse effects of hyperglycemia both in vitro and in vivo. In aortic smooth muscle cells (ASMCs), the PKC specific activity from the membranous fraction and total DAG were increased by 31 +/- 4% (P < 0.05) and 50 +/- 7% (P < 0.05), respectively, when the glucose levels were changed from 5.5 to 22 mmol/l. D-alpha-tocopherol prevented the glucose-stimulated increases in DAG level and PKC activity as well as the amount of PKC beta II isoform in ASMCs cultured with elevated glucose levels. Comparing streptozotocin-induced diabetic rats after 2 weeks of disease to controls, specific membranous PKC activities and total DAG levels were increased in aorta (162%, P < 0.05; 60%, P < 0.05). Intraperitoneal injection of D-alpha-tocopherol (40 mg/kg) every other day resulted in a significant decrease of the elevated membranous PKC specific activity and total DAG levels in parallel with a significant increase of D-alpha-tocopherol content in the aorta. These findings suggested that D-alpha-tocopherol can prevent the activation of PKC in the vascular cells and aorta induced by hyperglycemia by normalizing the elevated levels of DAG. PMID- 8674877 TI - Criteria for metabolic control and intervention in diabetes. AB - Guidelines for optimal management of diabetes advocate comprehensive strategies to treat all established risk factors for coronary heart disease (CHD). The targets for treatment should be optimization of glycemic control, weight reduction, lowering of elevated blood pressure, correction of lipid abnormalities, and stopping smoking. Recently, strong evidence has emerged to demonstrate that poor glycemic control is a powerful predictor for excess CHD risk. The fact that dyslipidemia and hypertension are frequent in NIDDM patients at the time of diagnosis indicates that these risk factors may cause damage for years before the actual diagnosis of NIDDM. This article highlights the current background knowledge for the guidelines of therapeutic strategies for dyslipidemias in NIDDM. PMID- 8674878 TI - Hypertriglyceridemia and low HDL cholesterol in Japanese patients with NIDDM. AB - Diabetes is frequently associated with the combination of hypertriglyceridemia and low HDL cholesterol level, a known risk factor for cardiovascular disease. We evaluated the frequency of elevated serum triglyceride and the reduced HDL cholesterol levels in Japanese male NIDDM patients. Hypertriglyceridemia (>1.69 mmol/l) and low HDL cholesterol level (<0.91 mmol/l) were frequently found in Japanese male (NIDDM patients (30.4 and 14.2%, respectively). The combined abnormality, i.e., hypertriglyceridemia with concomitant low HDL cholesterol level, was more common in patients with poor glycemic control. We observed that inpatient diet therapy markedly reduced serum triglyceride but serum HDL cholesterol did not change significantly. This is in marked contrast to primary hypertriglyceridemia, in which HDL cholesterol level generally increases in parallel with a reduction in serum triglyceride level. We discuss the defective removal of triglyceride-rich lipoproteins and ineffective HDL production caused by lipoprotein lipase (LPL) deficiency. We also discuss possible correction of this combined abnormality by certain maneuvers that increase LPL activity. PMID- 8674879 TI - Infrainguinal reconstruction in diabetes. AB - Dramatic changes have occurred in the efficacy of infrainguinal reconstruction in diabetic patients. Enhanced limb salvage resulted from comprehensive understanding of patterns of macrovascular involvement, better perioperative control of sepsis and hyperglycemia, and advances in techniques for limb salvage. This report summarizes the applicability of recently evolving surgical techniques. Advances in pattern recognition have eliminated the misconception that microvascular involvement of the foot precludes successful reconstruction. A decreasing incidence of amputation in diabetic patients is currently seen. Interventions applicable to the usual patterns of diabetic macroangiopathy include femorodistal bypass to ankle or foot and popliteal distal bypass using autogenous vein usually in situ. In the absence of usable vein (a rare occurrence), the authors have observed intermediate patency using polytetrafluoroethylene to a vein cuff and anticoagulation. Initially, successful bypasses in diabetic and nondiabetic patients exhibit comparable longterm patency. Local toe or foot amputations are used more frequently to maintain bipedal gait. With careful management, a high rate of limb salvage is practical for nonsmoking, nonuremic diabetic patients. PMID- 8674880 TI - Transgenic mouse and gene therapy. AB - In the transgenic mouse, a specific gene can be transduced or deleted to study its function and relation to human diseases. Recently, various lines of transgenic mice that overexpress or lack a specific gene have been established and are available to study the pathophysiology of human diseases, including atherosclerosis, diabetes, and hyperlipidemia. We have established transgenic mouse lines with an integrated rat apolipoprotein (apo) E gene under control of the metallothionein promoter. Overexpression of apoE in the liver reduced plasma cholesterol and triglyceride levels and prevented diet-induced hypercholesterolemia. Another transgenic model with overexpression of apoE under control of the H2 Ld promoter in the arterial wall was established. In this model, the formation of fatty streak lesions was markedly inhibited, suggesting that apoE has antiatherogenic actions. Finally, we discuss gene therapy, which will be an important therapeutic approach to correct genetic abnormalities found in metabolic diseases. PMID- 8674881 TI - Diabetes and cardiovascular disease in a prospective population survey in Japan: The Hisayama Study. AB - To elucidate the effect of glucose intolerance on cardiovascular disease in the current Japanese population, we performed a 75-g oral glucose tolerance test in 2,427 Hisayama residents aged 40-79 years in 1988, who were free from a previous history of stroke or myocardial infarction, and followed them prospectively for 5 years. The prevalence of diabetes (NIDDM) among men was 13% and that of impaired glucose tolerance (IGT) was 20%; the corresponding values for women were 9 and 19%, respectively. The age- and sex-adjusted incidence of cerebral infarction (6.5 per 1,000 person-years, P < 0.01) and coronary heart disease (5.0 per 1,000 person-years, P < 0.05) was significantly higher in subjects with NIDDM than in those with normal glucose tolerance (1.9 and 1.6 per 1,000 person-years, respectively). In addition, subjects with IGT and NIDDM had a higher risk of cardiovascular disease including stroke and coronary heart disease than did those with normal glucose tolerance after adjustment for age and sex, namely the relative risk for IGT was 1.9 (95% CI 1.2-3.2), and the relative risk for NIDDM was 3.0 (95% CI 1.8-5.2). These associations remained significant even after controlling for six other risk factors including hypertension in multivariate analysis. Our data suggest that NIDDM is a significant risk factor for both cerebral infarction and coronary heart disease and also that IGT itself is a risk factor for cardiovascular disease in the general Japanese population today. PMID- 8674882 TI - Coronary heart disease and NIDDM in Japanese-Americans. AB - Glucose intolerance is associated with increased risk of coronary heart disease (CHD) in Japanese-Americans, especially in men. Intra-abdominal fat, assessed by computed tomography, is increased in those with both NIDDM and CHD. Increased intra-abdominal fat (visceral adiposity) with CHD is independent of NIDDM or impaired glucose tolerance. The association between NIDDM and CHD may be explained by the association of each of these conditions with visceral adiposity. However, hyperinsulinemia is associated with CHD only in the presence of diabetes, whereas triglyceride levels are elevated with CHD independent of glucose tolerance category. These findings suggest that factors other than insulin levels, such as lipids, may mediate the relationship between visceral adiposity and CHD. Moreover, these relationships are influenced by gender. PMID- 8674883 TI - Risk factor analyses for macrovascular complication in nonobese NIDDM patients. Multiclinical Study for Diabetic Macroangiopathy (MSDM). AB - To examine the characteristic features of risk factors for macroangiopathy (MA) in nonobese Japanese NIDDM patients, 899 NIDDM patients with and without MA were registered from 40 facilities. Of these, 386 subjects were identified as having any form of MA (total MA); these included 211 with ischemic heart disease (IHD), 163 with cerebrovascular disease (CVD), and 77 with peripheral vascular disease (PVD). Univariate analyses revealed the following common risk factors for total MA, IHD, CVD, and PVD: age, hypertension, systolic blood pressure (sBP) or diastolic blood pressure (dBP), duration of diabetes, diabetic microangiopathy (retinopathy, nephropathy, and neuropathy), low HDL cholesterol level, and higher LDL cholesterol/HDL cholesterol ratio. Additional significant risk factors for specific conditions were also identified, respectively, as male sex for total MA, IHD, and PVD, smoking for IHD and PVD, and high fasting plasma glucose level for total MA and CVD. With stepwise multivariate logistic regression analysis, older age, duration of diabetes, smoking, and low LDL cholesterol/HDL cholesterol ratio were identified as significant and independent risk factors for total MA, IHD, CVD, and PVD. Other risk factors identified were high dBP for IHD, CVD, and PVD, high sBP for total MA, and low BMI for PVD. These results clearly demonstrated that duration of diabetes, smoking, hypertension, and dyslipidemia are major risk factors for MA in NIDDM patients. Since the mean BMI was similar for both groups (approximately 23 kg/m2) and there were no significant differences in immunoreactive insulin levels before and after 75-g oral glucose challenge testing, obesity and hyperinsulinism at the time of the analyses were not considered to play an important role for the pathogenesis of MA in Japanese NIDDM patients. By using the chi 2 test, cutoff points were determined for six of the most commonly measured risk factors. The cutoff point was the level beyond which a significantly higher prevalence of MA occurred. The cutoff points (rounded slightly upward in some cases) for fasting plasma glucose, sBP, dBP, serum total cholesterol level, serum triglyceride level, and BMI were 140 mg/dl, 140 mmHg, 80 mmHg, 180 mg/dl, 120 mg/dl, and 23 kg/m2, respectively. When these cutoff points were used as control criteria, the prevalence of MA was significantly lower in subjects whose risk factor measurements remained under the proposed control criteria for four or more of the six variables. In conclusion, in nonobese NIDDM patients, age, hypertension, and dyslipidemia were found to be risk factors for MA. Duration of diabetes was also demonstrated as an independent risk factor, indicating the close association of deranged glucose metabolism with the pathogenesis of MA in NIDDM patients. It seems to be crucial to control these risk factors for the prevention of MA in NIDDM patients. PMID- 8674884 TI - Hyperinsulinemia and triglyceride-rich lipoproteins. AB - Hypertriglyceridemia is the most frequent form of hyperlipidemia seen in diabetes. Because hypertriglyceridemia and hyperinsulinemia often coexist in the general population and because patients with NIDDM generally are hyperinsulinemic, we have undertaken a series of in vivo studies to examine the effects of hyperinsulinemia on VLDL production. These studies showed that chronic hyperinsulinemia is accompanied by increased VLDL production and that this occurs even when plasma free fatty acid (FFA) levels have fallen. By contrast, acute hyperinsulinemia is accompanied by a reduction in VLDL production, and this reduction is, at least in part, mediated by an associated reduction in the availability of plasma FFAs as a substrate for VLDL-triglyceride (TG). The studies also raise the possibility that the difference in the dependence of VLDL production on plasma FFAs in acute versus chronic hyperinsulinemia results from an increase in hepatic lipogenic enzymes and from the availability of an alternate substrate such as fructose. The overall effect of hyperinsulinemia on VLDL production is postulated to reflect both the effect of insulin on apolipoprotein B production and the hepatic synthesis of TG from either plasma FFAs or newly made fatty acids. PMID- 8674885 TI - Diabetic dyslipidemia: basic mechanisms underlying the common hypertriglyceridemia and low HDL cholesterol levels. AB - Elevated levels of plasma triglycerides (TG) and reduced concentrations of HDL cholesterol are very common in patients with diabetes, particularly NIDDM. Although regulation of the plasma concentrations of VLDL, the major TG-rich lipoprotein is extremely complex, it is clear from in vivo kinetic studies that increased rates of secretion of VLDL into plasma is almost uniformly present in patients with NIDDM and hypertriglyceridemia. Recent studies at the cellular level indicate that increased fatty acid flux to the liver, also common in NIDDM (and other insulin-resistant states associated with elevated plasma TG levels), will stimulate the assembly and secretion of apoprotein (apo) B-containing lipoproteins by targeting apoB for secretion rather than intracellular degradation. Increased rates of secretion of VLDL into plasma appears to drive the exchange of TG from these lipoproteins for HDL cholesteryl ester. This exchange, which occurs in plasma, is facilitated by cholesteryl ester transfer protein, and generates a TG-enriched HDL that is a substrate for either hepatic lipase or lipoprotein lipase. When the TG in HDL is hydrolyzed, the resultant particle is smaller, and this appears to affect the binding of the major HDL protein, apoA-I. ApoA-I dissociates from the smaller, lipid-poor HDL, and the free apoA-I (molecular weight 28,000) can be filtered by the glomerulus in the kidney and most likely is degraded in renal tubular cells after reabsorption. Thus, increased free fatty acid transport in plasma, a common abnormality in insulin-resistant states, may be the underlying driving force for the two common lipid abnormalities seen in diabetes. PMID- 8674886 TI - Quantitative and qualitative derangement of apolipoprotein B-containing lipoproteins as a risk factor for diabetic macroangiopathy in nonobese NIDDM subjects. AB - Cholesterol, triglyceride (TG), and apolipoprotein (apo) B were determined in plasma and in lipoprotein subfractions (VLDL, intermediate-density lipoproteins [IDL], LDL, and HDL) in nonobese NIDDM subjects, who were classified into well controlled, fairly controlled, or poorly controlled states with or without macrovascular complications (macroangiopathy [MA]). The same analyses were also performed on subjects who had coronary artery disease (CAD) with stable angina pectoris (SA) or unstable angina pectoris (UA) and acute myocardial infarction, cerebrovascular disease (CVD) with atherothrombotic or lacunar infarction, and arteriosclerosis obliterans (ASO). In nonobese NIDDM subjects, the number of apoB containing lipoproteins (VLDL, IDL, and LDL) increased. This alteration was more prominent in subjects with poorly or fairly controlled disease as well as in subjects with MA, but not in those with well-controlled NIDDM. Cholesterol/apoB in LDL decreased in subjects with poorly or fairly controlled diabetes or with MA and was correlated with low HDL cholesterol. The disorder is characterized by hyperbetalipoproteinemia with elevated LDL cholesterol and small dense LDL. In obese NIDDM subjects, the similar disorder was more pronounced. Glycemic control had less effect and hyperinsulinemia, if present, aggravated the lipid disorder. In those with CAD, the number of IDLs increased and the LDL fraction had the properties of small dense LDL. HDL cholesterol decreased. In those with UA, the LDL number increased without elevation of LDL cholesterol, indicating typical hyperbetalipoproteinemia. The subjects with atherothrombotic brain infarction, an increased number of small-sized LDLs was noted. In those with ASO, the number of VLDL and IDL increased with small LDL. HDL cholesterol decreased in those with CAD, cerebrovascular disease, and ASO. Since similar quantitative and qualitative alterations of apoB-containing lipoprotein have been observed in NIDDM patients as well as in those with macrovascular diseases, diabetic patients are thought to be more susceptible to the initiation and progression of atheromatous lesions in coronary, brain, and peripheral arteries. PMID- 8674887 TI - Atherogenic modified LDL in diabetes. AB - This paper summarizes the recent findings on LDL atherogenic modifications in diabetic patients. LDL from diabetic patients, unlike LDL from healthy subjects, caused a significant increase in cholesterol content of cells cultured from unaffected human aortic intima, i.e., produced a direct atherogenic effect. LDL was divided into two fractions (nonbound and bound) by affinity chromatography on Ricinus communis agglutinin-agarose. The amount of bound LDL was significantly higher in diabetic patients compared with healthy subjects. Bound LDL was characterized by significantly lowered sialic acid content and a significantly increased fructosyl lysine level compared with unbound LDL, i.e., was desialylated and nonenzymatically glycosylated lipoprotein. The bound (desialylated), but not unbound (sialylated), LDL subfraction induced cholesterol accumulation in cultured cells. Bound LDL was also characterized by a significantly lowered content of neutral lipids and demonstrated increased electrophoretic mobility on agarose gel electrophoresis. Bound and nonbound LDL differed significantly in hydrated density and particle size, as was determined by density gradient ultracentrifugation and native polyacrylamide gradient gel electrophoresis. The results of this study have shown that the in vivo modified atherogenic LDL subfraction in the blood of diabetic patients is represented by small, dense, more electronegative, desialylated, and glycated LDL. PMID- 8674888 TI - Cytokines, modified lipoproteins, and arteriosclerosis in diabetes. AB - Modified lipoproteins, particularly different forms of oxidized LDL (ox-LDL), have been reported to elicit humoral immune responses both in experimental animals and humans. In diabetes, glycation and oxidation processes coexist and lead to the formation of glycoxidation products. Ox-LDL has been demonstrated in atheromatous lesions, anti-ox-LDL antibodies have been detected in circulation and in atheromatous plaques, and immune complexes (ICs) formed with LDL and anti LDL (LDL-IC) have been isolated from the serum of patients with manifestations of atherosclerosis. In addition, in vitro formed LDL-ICs and ICs isolated from patients have been demonstrated to cause intracellular accumulation of cholesteryl esters (CEs) in human macrophages and fibroblasts. The accumulation of CEs in macrophages exposed to LDL-ICs is unique to this type of IC and is associated with paradoxical overexpression of LDL receptor and with increased synthesis and release of interleukin 1 beta and tumor necrosis factor (TNF) alpha. The overexpression of LDL receptors is higher in LDL-IC-stimulated macrophages that release markedly high amounts of TNF-alpha than in macrophages that release low amounts of TNF-alpha into the medium. The release of cytokines in the subendothelial space may have a significant role in promoting the interaction of endothelial cells with mononuclear cells, causing endothelial cell damage directly or indirectly, and also in inducing smooth muscle cell proliferation. Thus, in view of the above data, it can be concluded that humoral autoimmunity may play a significant role in the pathogenesis of atherosclerosis in diabetes. PMID- 8674889 TI - Hyperinsulinemia and atherosclerosis. AB - For more than 25 years, there has been an expansion in the clinical and experimental evidence linking hyperinsulinemia with cardiovascular disease and atherosclerosis. Assessment of the evidence under the headings of the strength of the association, dose response, temporality, consistency, specificity, and plausibility supports the concept that hyperinsulinemia has a causal role in atherogenesis. Evidence that reducing insulin levels prevents atherosclerosis is lacking. The evidence available is strong enough to support preventive measures to lower insulin levels such as regular physical exercise and avoidance of obesity. PMID- 8674890 TI - Effects of insulin and IGF-I on vascular smooth muscle glucose and cation metabolism. AB - Data is accumulating indicating that impaired insulin action predisposes to increased vascular smooth muscle (VSM) tone, the hallmark of hypertension associated with diabetes. During the last several years, it has been established that VSM is an insulin-sensitive tissue like skeletal muscle and adipocytes. Investigators have shown that insulin regulates VSM intracellular cation metabolism through attenuating effects on inward calcium (Ca2+) currents and by direct effects on VSM cells (VSMCs) Na+, K(+)-ATPase pump expression and activity and that insulin and IGF-I stimulate glucose uptake in VSMCs. Furthermore, recent data suggest that IGF-I, like insulin, attenuates cytosolic calcium [Ca2+]i transients and vasoconstrictive responses. IGF-I, like insulin, also stimulates the production of nitric oxide from both the endothelium and VSMCs. IGF-I and insulin are structurally related, share receptors, and have similar postreceptor actions. Unlike insulin, which must transverse the endothelium before acting on VSMCs in vivo, IGF-I is synthesized by VSMCs. Thus, it is likely that IGF-I has more relevance than insulin in regulating physiological parameters in VSMCs. PMID- 8674891 TI - Mechanism and clinical implication of insulin resistance syndrome. AB - The insulin resistance syndrome has been noted as an interesting and important new risk factor for coronary artery disease. The syndrome consists of hypertension, glucose intolerance, and dyslipidemia, all of which are likely to be derived from insulin insensitivity. In subjects with nonobese and nondiabetic essential hypertension, steady-state plasma glucose (SSPG) was higher than in normotensive subjects during an insulin sensitivity test, indicating reduced insulin sensitivity to glucose metabolism in the hypertensive group. SSPG correlated with the percentage decrease of branched chain amino acids, free fatty acids, and serum potassium during the insulin sensitivity test. With a 2-h insulin infusion, serum norepinephrine, epinephrine, plasminogen activator inhibitor 1, and intraplatelet Ca2+ decreased significantly, but 6-keto prostaglandin (PG) F1 alpha and PGE2 did not change. Insulin resistance decreased by using antihypertensive treatments with bunazosin, cilazapril, amlodipine, and benidipine in hypertensive subjects. Diagnostic criteria for the insulin resistance syndrome, including clinical values for each risk factor, were developed. Lowered insulin sensitivity and hyperinsulinemia were demonstrated in subjects with both vasospastic and coronary artery stenotic angina. The insulin resistance syndrome together with hyperinsulinemia is likely to induce atherosclerotic changes, possibly through reduced rather than excessive action of insulin. PMID- 8674892 TI - Augmented contractile function and abnormal Ca2+ handling in the aorta of Zucker obese rats with insulin resistance. AB - To investigate the role of hyperinsulinemia/insulin resistance in vasomotor tone regulation, we studied the effects of vasoactive substances on tension and intracellular free calcium concentration ([Ca2+]i) of aortic smooth muscle derived from rats that were made hyperinsulinemic by insulin infusion and from Zucker obese rats with insulin resistance. The tension and [Ca2+]i of fura 2 loaded aortic strip preparations without endothelium were simultaneously measured by using a fluorimeter. Ten male Wistar rats received a continuous subcutaneous infusion of insulin (18 nmol x kg(-1) x day(-1)) for 2 weeks with osmotic minipumps (INS group). A control group of 10 rats received vehicle. The plasma immunoreactive insulin concentration in the INS group increased to 930 +/- 54 pmol/l. The increase in [Ca2+]i and tension by KCl and phenylephrine (PE) were lower in the INS group without alteration of the [Ca2+]i-tension relationship. The responses to serotonin (5-HT) in the INS group were similar to those in the control group. In contrast, responses to KCl, PE and 5-HT were markedly enhanced in Zucker obese rats compared with those in Zucker lean rats. The pretreatment of aortic preparations from lean rats with Bay K8644 significantly enhanced the responses to KCl to the level observed in the preparations from obese rats; however, Bay K 8644 failed to affect the responses to KCl in obese rats. These results suggest that enhanced vascular contractile responses to vasoactive substances, possibly due to altered function of the voltage-dependent Ca2+ channel in vascular smooth muscle, may play an important role in the pathogenesis of hypertension in the insulin resistance syndrome. PMID- 8674893 TI - The role of insulin resistance in Korean patients with coronary atherosclerosis. AB - To determine whether dietary modification improves insulin resistance and coronary atherosclerosis, we randomly assigned 14 Korean patients to an experimental group (low-fat, low-cholesterol diet, high polyunsaturated/saturated fatty acid ratio, and calorie restriction) or to a control group (no dietary change). Coronary artery lesions were analyzed by quantitative coronary angiography, and postglucose insulin responses were measured. At baseline, there were no significant differences in body weight, BMI, waist-to-hip ratio (WHR), and plasma lipid and insulin levels between the two groups. After completion of the 1-year diet program, the experimental group showed significant reductions in body weight (66.0 +/- 3.2 to 61.6 +/- 3.8 kg [means +/- SE], P < 0.01) and WHR (O.96 +/- 0.01 to 0.93 +/- 0.01, P < 0.05). Total cholesterol (5.45 +/- 0.45 to 4.50 +/- 0.44 mmol/l, P < 0.05), LDL cholesterol (3.71 +/- 0.36 to 2.98 +/- 0.37 mmol/l, P < 0.05), and triglyceride (1.91 +/- 0.28 to 1.29 +/- 0.17 mmol/l, P < 0.05) were also significantly reduced in the experimental group. The mean insulin response during an oral glucose tolerance test was also significantly decreased (258.6 +/- 26.4 to 181.8 +/- 6.6 pmol/l, P < 0.05). In contrast, there were no significant changes in these parameters in the control group. When only coronary artery lesions > 50% stenosed were analyzed, the average percentage diameter stenosis regressed from 63.2 to 56.8% in the experimental group. However, there were no significant changes in the control group. Our trial suggests that decreases in body weight and WHR and an improvement in insulin resistance with a low-fat, low cholesterol diet and caloric restriction may reduce risk factors and reverse coronary atherosclerotic lesions in 1 year. PMID- 8674894 TI - Diabetes and coronary heart disease in American Indians: The Strong Heart Study. AB - Coronary heart disease (CHD) is the leading cause of death among American Indians. However, information on the prevalence of CHD and its association with known risk factors is limited. The purpose of the Strong Heart Study is to quantify CHD and its risk factors among three geographically diverse groups of American Indians. The population consists of 4,549 adults between 45 and 74 years of age in 13 Indian communities in Arizona, Oklahoma, and South and North Dakota. The phase I examination (1989-1991) revealed very high prevalence rates of diabetes that ranged from 33 to 72% in men and women in the three centers. Prevalence rates of definite myocardial infarction (MI) and definite CHD were higher in men than in women in all three centers (P < 0.0001) and in those with diabetes (P = 0.002 and P = 0.0003 in women and men respectively). Diabetes was associated with a relatively greater increase in prevalence of MI (prevalence rate = 3.8 vs. 1.9) and CHD (prevalence rate = 4.6 vs. 1.8) in women than in men. Logistic regression analysis indicated that the prevalence of CHD among American Indians was significantly related to age, diabetes, hypertension, albuminuria, percentage of body fat, smoking, high concentrations of plasma insulin, and low concentrations of HDL cholesterol. Lower prevalence rates of CHD were found in Arizona despite higher rates of diabetes, obesity, hypertension, and albuminuria; these lower rates may be in part related to lower smoking frequency and lower concentrations of total and LDL cholesterol. These findings from the baseline Strong Heart Study examination emphasize the relative importance of diabetes and its associated variables as risk factors for CHD among American Indian populations. PMID- 8674895 TI - Insulin suppresses endothelial secretion of C-type natriuretic peptide, a novel endothelium-derived relaxing peptide. AB - We have previously reported that C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, is produced in vascular endothelial cells (ECs) and acts as an endothelium-derived relaxing peptide. We further demonstrated the detection of the gene transcripts of CNP and atrial natriuretic peptide (ANP) B receptor, a specific receptor for CNP, in human blood vessels. We thus propose the existence of a vascular natriuretic peptide system (NPS). CNP secretion was also demonstrated to be stimulated by various growth factors and cytokines. To clarify the significance of vascular NPS in proliferative vascular complications associated with diabetes, hypertension, or atherosclerosis, in the present study we examined the effect of insulin on CNP secretion from cultured ECs. Insulin at a concentration in the physiological range (10(-10)-10(-7) mol/l) potently suppressed CNP secretion, whereas insulin at the same concentration did not suppress endothelin (ET) secretion from EC. IGF-I had no significant effect on CNP secretion. Insulin, therefore, can be a potent inhibitor of CNP secretion through the activation of insulin receptor. Since CNP has been shown to be a potent inhibitor of vascular smooth muscle cell proliferation, the present study suggests the possibility that attenuated activity of vascular NPS is associated with hyperinsulinemia, which might result in proliferative vascular lesions. PMID- 8674896 TI - Recent progress in advanced glycation and diabetic vascular disease: role of advanced glycation end product receptors. AB - Advanced glycosylation end products (AGEs) form principally from the rearrangement of early glycation products, i.e., Amadori products, which produce a class of stable moieties that possess distinctive chemical crosslinking and biological properties. It has been generally believed that proteins with half lives of longer than a few weeks are most susceptible to advanced glycosylation and that the highest levels of AGEs occur on proteins that comprise the long lived structural components of connective tissue matrix and basement membrane. PMID- 8674897 TI - The mechanism of collagen cross-linking in diabetes: a puzzle nearing resolution. AB - Considerable interest has been focused in recent years on the mechanism of collagen cross-linking by high glucose in vitro and in vivo. Experiments in both diabetic humans and in animals have shown that over time collagen becomes less soluble, less digestible by collagenase, more stable to heat-induced denaturation, and more glycated. In addition, collagen becomes more modified by advanced products of the Maillard reaction, i.e., immunoreactive advanced glycation end products and the glycoxidation markers carboxymethyllysine and pentosidine. Mechanistic studies have shown that collagen cross-linking in vitro can be uncoupled from glycation by the use of antioxidants and chelating agents. Experiments in the authors' laboratory revealed that approximately 50% of carboxymethyllysine formed in vitro originates from pathways other than oxidation of Amadori products, i.e., most likely the oxidation of Schiff base-linked glucose. In addition, the increase in thermal stability of rat tail tendons exposed to high glucose in vitro or in vivo was found to strongly depend on H2O2 formation. The final missing piece of the puzzle is that of the structure of the major cross-link. We speculate that it is a nonfluorescent nonultraviolet active cross-link between two lysine residues, which includes a fragmentation product of glucose linked in a nonreducible bond labile to both strong acids and bases. PMID- 8674898 TI - Advanced glycation end products and their recognition by macrophage and macrophage-derived cells. AB - Modification of proteins by long-term incubation with glucose leads to the formation of advanced glycation end products (AGEs). AGE proteins are taken up by macrophages via the AGE receptor, which is similar to the macrophage scavenger receptor (MSR). In the present study, we compared the ligand specificity of the AGE receptor with that of MSR by three different experiments. The endocytic uptake of 125I-acetyl-LDL by RAW cells was effectively inhibited by unlabeled AGE bovine serum albumin (BSA), whereas the inhibitory effect of acetyl-LDL on 125I AGE-BSA was partial. Polyanions showing an effective inhibition for endocytic uptake of AGE-BSA were not always inhibitory for endocytic degradation of acetyl LDL. These data, together with those obtained by three-dimensional fluorescence activated cell sorter analysis, indicate that AGE proteins are recognized by more than two receptors, of which MSR is at least one. Finally, we examined whether MSR could mediate the endocytic uptake of AGE proteins by Chinese hamster ovary cells overexpressing bovine type II MSR (CHO-SRII cells). 125I-AGE-BSA underwent endocytic degradation by CHO-SRII cells, and this was effectively inhibited by unlabeled acetyl-LDL. These results clearly show that MSR mediates the endocytic uptake of AGE proteins, suggesting a new role of MSR in biological recognition of AGE in vivo. PMID- 8674899 TI - RAGE: a novel cellular receptor for advanced glycation end products. AB - Exposure of proteins to reducing sugars results in nonenzymatic glycation with the ultimate formation of advanced glycation end products (AGEs). One means through which AGEs modulate cellular functions is through binding to specific cell surface acceptor molecules. The receptor for AGEs (RAGE) is such a receptor and is a newly identified member of the immunoglobulin superfamily expressed on endothelial cells (ECs), mononuclear phagocytes (MPs), and vascular smooth muscle cells (SMCs) in both vivo and in vitro. Binding of AGEs to RAGE results in induction of cellular oxidant stress, as exemplified by the generation of thiobarbituric acid-reactive substances, expression of heme oxygenase type I, and activation of the transcription factor NF-kB, with consequences for a range of cellular functions. AGEs on the surface of diabetic red cells enhance binding to endothelial RAGE and result in enhanced oxidant stress in the vessel wall. By using reagents to selectively block access to RAGE, the role of this receptor in AGE-mediated perturbation of cellular properties can be dissected in detail. PMID- 8674900 TI - Involvement of glycation and oxidative stress in diabetic macroangiopathy. AB - Under diabetic conditions, the Maillard reaction facilitates the production of reactive oxygen species, and the activity of antioxidant enzymes such as Cu,Zn superoxide dismutase is decreased, resulting in a remarkable increase of oxidative stress. The oxidative stress attacks DNA, lipids, and proteins and is also thought to be involved in the pathogenesis of diabetic complications, including the progression of macroangiopathy. Proliferation of smooth muscle cells (SMCs) is known to be associated with progression of macroangiopathy and is modulated by several growth factors. At least three mitogens for SMCs, platelet derived growth factor (PDGF), fibroblast growth factor, and heparin-binding epidermal growth factor-like growth factor (HB-EGF), are known to be produced by SMCs themselves and are considered to be the most potent growth factors in the progression of macroangiopathy as seen in diabetes. HB-EGF, but not PDGF, is regulated at the transcriptional level by 3-deoxyglucosone (3-DG), a major and highly reactive intermediate in the glycation reaction. The induction seems to be triggered by the increase of reactive oxygen species produced by 3-DG. Taken together, glycation reactions under diabetic conditions may be highly associated with the pathogenesis of diabetic macroangiography by enhancing the gene expression of HB-EGF. PMID- 8674901 TI - Glycation, oxidative stress, and scavenger activity: glucose metabolism and radical scavenger dysfunction in endothelial cells. AB - It has been reported that oxidative stress is increased in vivo in the diabetic state. Increased oxidative stress is caused not only by accelerated production of oxygen-free radicals but also by decreased scavenging of those molecules. Endothelial cells are extremely sensitive to oxidative stress, resulting in impairments of various endothelial cell function. In this report, we studied the association of intracellular glucose metabolism and oxygen radical scavenging function via the glutathione redox (GR) cycle in cells exposed to high-glucose conditions using cultured human umbilical vein endothelial cells. Glutathione dependent H2O2 degradation in cells exposed to 33 mmol/l glucose (HG) for 5-7 days was reduced by 48% vs. 5.5 mmol/l glucose (NG). This impairment under the oxidative stress was D-glucose-specific and concentration-dependent and was also associated with a 42% decrease in intracellular NADPH content. Exposure of cells to 200 micromol/l H2O2 stimulated the GR cycle and the pentose phosphate pathway (PPP) at the same time. In the HG condition, activation of PPP was reduced by 50%, which was consistent with a decrease in NADPH content. Inhibition of glycolysis by H2O2 was less marked in HG cells versus NG cells. Activation of polyol pathway in HG cells is not responsible for the decrease in intracellular NADPH content. These results indicate that activation of the PPP and NADPH supply to the GR cycle is impaired in HG cells exposed to H2O2, which may result in increased oxidative stress to endothelial cells. PMID- 8674902 TI - Intensive insulin therapy in type II diabetes: rationale and collaborative clinical trial results. AB - The rationale for intensive insulin therapy and results from major clinical trials in diabetes are reviewed. The Diabetes Control and Complications Trial (DCCT) has shown that intensive insulin therapy will prevent or delay the onset of retinopathy, nephropathy, and neuropathy in type I diabetes. The University Group Diabetes Program (UGDP) and the U.K. Prospective Diabetes Study (UKPDS) have addressed the issue of insulin versus oral agent or diet therapy in people with recently diagnosed type II diabetes. The UGDP showed that effective glycemic control could be achieved with intensive insulin therapy, but no effect on vascular end points was seen. Early data from the UKPDS also suggest that intensive insulin therapy may be more effective in lowering HbA1c toward normal than oral agents or diet. A pressing clinical problem is the question of the use of intensive insulin therapy in type II diabetic individuals who remain hyperglycemic despite pharmacological therapy. A Veterans Affairs Cooperative Study explored the feasibility of using intensive insulin therapy in 153 male type II diabetic patients with these characteristics. A 2% lowering of HbA1c was seen, with no increase in weight gain or in hypoglycemia. However, 40 of 153 patients (26.1%) had cardiovascular events during the 27-month trial; no difference in cardiovascular event rates was seen between the two treatment groups. A long-term multicenter collaborative trial is needed to assess the benefit:risk ratio of intensive insulin therapy for type II diabetic patients in whom pharmacological therapy failed to provide glycemic management. PMID- 8674903 TI - Diabetic macroangiopathy and atherosclerosis. AB - In the present study, we have compared and analyzed published data related to the pathogenesis of the large vessel disease in diabetes. The prevailing opinion appears to be that diabetes accelerates the mechanism that leads to the development of classical atherosclerosis. However, as an alternative, we have amassed data that point to the presence of a diabetic macroangiopathy. This phenomenon comprises a constellation of nonatherosclerotic large vessel abnormalities. Today, we know that accumulation of periodic acid-Schiff (PAS) positive material, as laminin, fibronectin, and type IV collagen, occurs together with hyaluronic acid and various types of connective tissue and calcium deposition. All these changes occur independent of the presence of atherosclerosis in the large vessels of diabetic patients. It seems to us that these observations emphasize that the concept of a specific diabetic macroangiopathy is a more fruitful working hypothesis than the usual theory of a link between atherosclerosis and diabetes. It provides a causal relationship (although the mechanism is unknown) between such changes and the abnormal metabolism in diabetes and a background for research strategy and tactics, aiming finally at the possibility of prevention and/or treatment of this common and dangerous disease. PMID- 8674904 TI - Diabetes and brain ischemia. AB - Diabetes influences brain ischemia in a number of different ways. Diabetes causes and exacerbates macroangiopathies, increases the severity of ischemia, and increases stroke mortality. Unfortunately, few studies have examined in sufficient depth the influence of diabetes on the various vascular lesions that cause brain ischemia. These can be divided into: 1) cardiac-origin brain embolism; 2) atherosclerosis of the aorta and the large extracranial arteries- the internal carotid arteries (ICAs) and the vertebral arteries (VAs); 3) atherosclerosis of the large intracranial arteries--ICAs, anterior, middle, and posterior cerebral arteries, the VAs, and the basilar artery; 4) intracranial atheromatous branch disease of macroscopically visible branches of the intracranial arteries enumerated in 3; and 5) degenerative abnormalities such as lipohyalinosis and fibrinoid changes within penetrating artery branches visible only microscopically. The last three types of disorders all can cause deep subcortical brain infarcts, the predominant type of brain infarction found in Japan. PMID- 8674905 TI - Asymptomatic cerebral small infarcts (lacunae), their risk factors and intellectual disturbances. AB - This study examines the relationship between cerebral small infarcts (lacunae) and the multiple risk factors of diabetes, age, hypertension, hyperlipidemia, and atherosclerosis in asymptomatic NIDDM patients and nondiabetic subjects by comparing brain magnetic resonance imaging (MRI) findings to these risk factors. Brain MRI was performed on 155 asymptomatic NIDDM and 39 asymptomatic nondiabetic patients, using a Shimazu SMT-150, 1.5-T instrument. Among the diabetic patients, 65 showed evidence of lacunae. The incidence of lacunae was significantly higher in older diabetic patients, but it did not significantly differ in those with or without the risk factors of atherosclerosis. We also correlated the results of a freehand cube-drawing test with the incidence of lacunae. Cube-drawing is a good indicator of spatial cognition ability supported by wide association areas of the brain. Drawing ability was tested in 56 diabetic and 39 nondiabetic subjects. Correlations of lacuna incidence with deformity in drawing and with age were high in the diabetic group. Correlation of lacunae with deformity in drawing was also significant in nondiabetic subjects. The incidence of lacunae was highly correlated with intellectual impairment. PMID- 8674906 TI - Lessons from clinical research: adverse events or complications? PMID- 8674907 TI - The long-term effects of children's early-onset disability on marital relationships. AB - To investigate the long-term effects of a child's chronic illness or severe physical or intellectual disability on parents and their marital relationship, the parents of 89 children, aged 14-17, years were interviewed. The parents returned a questionnaire and a social worker interviewed them. One-fifth of the respondents had experienced the child's disability as contributing positively to the marital relationship, 25% reported impairment in some areas of the marital relationship, while only 7% felt that they had drawn apart from each other. A higher level of occupational education, insecurity at onset, heavy daily demands for care of the child, unequal distribution of tasks between the spouses and a lack of time for leisure activities were found to be risk factors for impaired marital satisfaction. Adequate information, a realistic notion of the illness or disability and practical advice for everyday life seemed to be the protective factors for the marital relationship. PMID- 8674908 TI - The management of febrile seizures in the Mersey Region. AB - The management of children with febrile seizures admitted to hospital within the Mersey region was evaluated by case note review. The patient groups were demographically similar in all the participating hospitals. Most children were admitted for less than 48 hours and nearly all received paracetamol as an antipyretic. There was a marked variation in the number of investigations performed in each hospital, with venepunctures for blood cultures and white blood cell counts ranging from 6 to 56% and from 8 to 70%, respectively. The majority of children had a urinalysis. 23 to 78% of children were prescribed antibiotics. Further studies are required on the value of hospital admission and the appropriate use of investigations and antibiotics in children with febrile seizures. PMID- 8674909 TI - Measurement of oxygen consumption in disabled children by the Cosmed K2 portable telemetry system. AB - Measurement of the energy cost of walking in children with cerebral palsy or spina bifida is difficult due to the cumbersome nature of equipment used to assess oxygen consumption. Such information collected with a lightweight telemetric system, the Cosmed K2, correlated well with that from a non-portable breath-by-breath system associated with a treadmill. The K2 did not significantly affect regular gait pattern as measured by gait analysis, and repeatability was satisfactory. Measurement of the energy cost of walking in the individual is unreliable in detecting differences of less than 10%; comparison between groups is more useful. PMID- 8674910 TI - Handedness in very-low-birthweight (VLBW) children at 12 years of age: relation to perinatal and outcome variables. AB - The authors assessed 137 VLBW children and 162 controls for laterality by observation and questionnaire at 12 years of age. A significantly higher proportion of the VLBW children were either left-handed or mixed-handed. A number of motor cognitive and educational outcome variables were measured. Impaired manual dexterity was found to be significantly more common in VLBW non-right handers. This group was also found to be more at risk of poor near vision. No cognitive or educational outcomes were associated with handedness. The results seem to support the theory that at least in a proportion of VLBW children, non right-handedness has a pathological basis, but the relationship to perinatal events remains obscure. PMID- 8674911 TI - Bullying, physical disability and the paediatric patient. AB - This study compared the rates and types of bullying in two groups of paediatric outpatients: those attending the Child Development Centre with conditions affecting their appearance or gait and a control group of those attending a general paediatric outpatient clinic with conditions not associated with visible abnormality. The children completed Olweus' self report bullying questionnaire anonymously. Using logistic regression analysis, the most important variables found to increase a child's chance of being bullied were having fewer friends, being alone at playtime, being male and requiring extra help in school. Significantly more of the group from the Child Development Centre were bullied during the term. However, there was no indication that the children attending the Child Development Centre with a visible disability were more likely to be victims than the control group once these four factors were taken into account. PMID- 8674912 TI - The Cambridge Language and Speech Project (CLASP). I . Detection of language difficulties at 36 to 39 months. AB - A community-based investigation of the nature, characteristics and evolution of speech and language delay in a sample of 3-year-olds is being carried out in Cambridgeshire. 1936 parents completed a preschool language checklist (PLC) to identify children at risk of language difficulties. Two hundred and seventy-seven children at risk together with 148 controls completed a series of preliminary face-to-face standard language tests to determine expressive, receptive and phonological skills. Concordance between the Cambridge Language and Speech Project (CLASP) identification and speech therapy involvement suggests that the overall (CLASP) screening procedure identified a number of children that current surveillance had missed and support the conclusion that the PLC may be a useful adjunct for child health care services as an aid in prioritising children for referral to speech therapy services. Children with scores of 1 to 3 at 36 months should be reviewed at 39 months, and those with 4 or more should be a high priority for referral. Preliminary examination of the impairment profile suggests that children with language impairments rather than pure speech impairments at 36 and 39 months are more likely to have a broader range of overall language-related deficit. PMID- 8674914 TI - Marinesco-Sjogren syndrome: clinical and magnetic resonance imaging features in three children. AB - The authors describe clinical and MRI features of a girl and two boys, aged 9, 17 and 19 years, respectively, with Marinesco-Sjogren syndrome. The clinical findings included the major features of the syndrome, including growth deficiency, ataxia, cataracts, hypogonadism (in two) and seizures (in two). Truncal hypotonia (in three), microcephaly (in two) and leg spasticity (in two) were also present. MRI showed a very small cerebellar vermis in all three patients, various supratentorial abnormalities, an apparently small anterior pituitary gland in two and the absence of a posterior pituitary gland in all three. The MRI features are similar to the few reported pathologic findings for persons with Marinesco-Sjogren syndrome. MRI may be helpful in the early diagnosis of the disorder. PMID- 8674913 TI - X-linked hydrocephalus masquerading as spina bifida and destructive porencephaly in successive generations in one family. AB - The authors report a case of X-linked hydrocephalus which presented as a destructive porencephaly. There was asymmetric dilatation of the ventricles of prenatal onset, and neuro-imagining studies were suggestive of infection or haemorrhage. The child was profoundly handicapped but did not have adducted thumbs. Two of his mother's brothers had been stillborn, and postmortem reports revealed that the diagnosis had been isolated hydrocephalus and not spina bifida as reported by the family. Despite serial ultrasound scans, recurrence of X linked hydrocephalus in the mother's subsequent pregnancy was not detected until 26 weeks gestation, when the ventricles became grossly dilated. The diagnosis was confirmed in this family by identification of a mutation within the LICAM gene. PMID- 8674915 TI - Life-span intellectual development of people with mental retardation. PMID- 8674916 TI - Infantile spasms and haemophilia A. PMID- 8674917 TI - Longevity of people with tuberous sclerosis. PMID- 8674918 TI - Prognosis of esophageal cancers preoperatively staged to be locally invasive (T4) by endoscopic ultrasound (EUS): a multicenter retrospective cohort study. AB - BACKGROUND: Endosonography is a significant advance in the preoperative staging (TNM classification) of esophageal cancer. Its accuracy for evaluating depth of tumor invasion is over 80%. METHODS: A multicenter retrospective cohort study of patients with esophageal carcinomas defined to be invasive (T4) by endosonography was performed to compare the survival of surgically and nonsurgically treated patients. Median survival time, overall mortality, and Kaplan-Meier survival curves were compared by treatment group. Univariate and Cox regression analysis were used to evaluate the effects of various prognostic factors and treatment on the risk of death. RESULTS: A total of 79 patients were studied. The surgical group (Group I, n = 42) was significantly younger and had more distal tumors (adenocarcinomas) than the nonsurgical group (Group II, n = 37). Endosonography was significantly more accurate than CT scanning in identifying tumor invasion (87.5% versus 43.8%, respectively, p = .0002). Overall mortality rate was not significantly different between treatment groups; 59.5% of the surgical group and 64.9% of the nonsurgical group were dead at follow-up (p = 0.65). Similarly, the median survival times of Group I and Group II patients were similar (5.2 and 7.0 months, respectively, p = 0.50). Survival curves for the two groups were almost overlapping (log rank test, p = 0.84). Even after adjusting for age, histologic diagnosis, tumor location, and regional lymph node status, surgical treatment did not significantly influence survival (p = 0.24). CONCLUSIONS: Endosonography accurately identifies patients with invasive T4 tumors who have a poor prognosis. This prognosis is independent of mode of therapy. PMID- 8674919 TI - Photodynamic therapy with porfimer sodium versus thermal ablation therapy with Nd:YAG laser for palliation of esophageal cancer: a multicenter randomized trial. AB - BACKGROUND: Photodynamic therapy (PDT) is a different type of laser treatment from Nd:YAG thermal ablation for palliation of dysphagia from esophageal cancer. METHODS: In this prospective, multicenter study, patients with advanced esophageal cancer were randomized to receive PDT with porfimer sodium and argon pumped dye laser or Nd:YAG laser therapy. RESULTS: Two hundred thirty-six patients were randomized and 218 treated (PDT 110, Nd:YAG 108) at 24 centers. Improvement in dysphagia was equivalent between the two treatment groups. Objective tumor response was also equivalent at week 1, but at month 1 was 32% after PDT and 20% after Nd:YAG (p < 0.05). Nine complete tumor responses occurred after PDT and two after Nd:YAG. Trends for improved responses for PDT were seen in tumors located in the upper and lower third of the esophagus, in long tumors, and in patients who had prior therapy. More mild to moderate complications followed PDT, including sunburn in 19% of patients. Perforations from laser treatments or associated dilations occurred after PDT in 1%, Nd:YAG 7% (p < 0.05). Termination of laser sessions due to adverse events occurred in 3% with PDT and in 19% with Nd:YAG (p < 0.05). CONCLUSIONS: Photodynamic therapy with porfimer sodium has overall equal efficacy to Nd:YAG laser thermal ablation for palliation of dysphagia in esophageal cancer, and equal or better objective tumor response rate. Temporary photosensitivity is a limitation, but PDT is carried out with greater ease and is associated with fewer acute perforations than Nd:YAG laser therapy. PMID- 8674920 TI - Proximal migration of biliary stents: attempted endoscopic retrieval in forty-one patients. AB - BACKGROUND: Proximal migration of a biliary stent is an uncommon event, but its management can present a technical challenge to the therapeutic endoscopist. METHODS: We reviewed the methods that have been used for retrieval of proximally migrated biliary stents in a referral endoscopy center. RESULTS: Forty-four cases were identified; 38 stents (86%) were extracted successfully. Half of the stents were retrieved after first passing a guide wire through the stent lumen. Various accessories were then used to withdraw the stents, the Soehendra device being the most popular. Nearly one third were retrieved by grasping the stents directly, usually with a wire basket or forceps. The remainder were recovered after using a stone retrieval balloon alongside the stents to provide traction indirectly. Interventional radiology techniques were needed in two cases, and surgery in one. CONCLUSIONS: Cannulating the stent lumen with a wire is often the best approach in patients with a biliary stricture or a nondilated duct. An over-the-wire accessory can then be used to secure the stent. In patients with a dilated duct, indirect traction with a balloon or direct grasping of the stent with a wire basket, snare, or forceps is usually successful. Using these techniques, most proximally migrated biliary stents can be retrieved endoscopically. PMID- 8674921 TI - Endoscopic retrograde forceps biopsy and brush cytology of biliary strictures: a prospective study. AB - BACKGROUND: Nonsurgical pathologic confirmation of malignant bile duct strictures is desirable for defining subsequent treatment and prognosis. Endoscopic retrograde cholangiopancreatography is frequently performed in patients suspected of having pancreaticobiliary obstruction, but there exists no standardized method for defining the nature of obstructing lesions by ERCP. METHODS: We prospectively evaluated the yields of endoscopic retrograde brush cytology and biopsy for the diagnosis of malignant bile duct strictures. Fluoroscopically guided endobiliary biopsy and brush cytology (52) or cytology alone (42) were performed during endoscopic retrograde cholangiopancreatography in 94 consecutive patients, 64 with malignant strictures and 30 with benign strictures. A single cytopathologist classified the results of these studies as positive or negative for malignancy. RESULTS: The sensitivities of the two procedures were identical (53%) and the gain achieved by combining the two techniques (61%) was small. Specificity proved excellent for both methods. One major complication that occurred was perforation of the common hepatic duct with leakage of bile, which was managed by surgical oversewing. This complication was ascribed to biopsy and untimely removal of the nasobiliary drain by the patient herself. CONCLUSIONS: This study indicates that endoscopic retrograde brush cytology alone may be sufficient in daily practice, at least in centers that have access to experienced cytopathologists. We recommend use of forceps biopsy in selected cases where brush cytology is negative. PMID- 8674922 TI - Diagnostic and therapeutic endoscopic retrograde cholangiography after liver transplantation. AB - BACKGROUND: We report our current experience using endoscopic retrograde cholangiography in the management of post-transplantation biliary tract complications. METHODS: Twenty-three patients among 109 adult liver transplant recipients underwent retrograde cholangiography because of cholestasis (18 patients) or bile leaks (5 patients). RESULTS: Eleven of 18 patients developed anastomotic strictures, all successfully dilated by plastic stents; one patient required Roux-en-Y revision due to recurrent cholangitis while stented. Three had biliary calculi extracted following sphincterotomy. Two developed intrahepatic ductal strictures secondary to severe rejection. One patient had hepatic artery thrombosis with a hilar stricture. One cholangiogram was normal. Three patients developed bile peritonitis following T-tube removal, all treated by sphincterotomy and nasobiliary drainage. Choledochal perforation resulting from an impacted T-tube limb was detected in two patients, both treated with sphincterotomy and nasobiliary drainage. CONCLUSIONS: Strictures within 3 months of surgery required 3 months of stenting; those occurring later required longer periods of time to respond. Bile leaks responded uniformly and rapidly to drainage. Endoscopic retrograde cholangiography is a useful diagnostic and therapeutic intervention for post-transplantation biliary tract complications. PMID- 8674923 TI - Endoscopic variceal ligation versus conservative treatment for patients with hepatocellular carcinoma and bleeding esophageal varices. AB - BACKGROUND: Endoscopic variceal ligation (EVL) is currently a favored treatment for control of bleeding from esophageal varices. However, little is known about the treatment of bleeding varices in hepatocellular carcinoma. METHODS: EVL was performed in 16 patients with bleeding esophageal varices due to concomitant hepatocellular carcinoma. Treatment results were compared with those of another 23 patients who were conservatively treated. RESULTS: Comparing the two groups, ligation significantly reduced the risk of fatal bleeding (44% vs 70%; P < 0.05). Significantly fewer patients in the ligation group died at the time of the index hemorrhage (11% vs 52%; P < 0.05). Rebleeding occurred in 44% of the ligation group and 73% in the control group (P > 0.05). The mean days of survival were 40 +/- 20 (range, 7 to 103) in the ligation group and 20 +/- 30 (range, 1 to 136) in the control group (P = 0.08). In the absence of portal vein thrombosis, ligation significantly reduced the rebleeding rate (17% vs 50%, P < 0.05) and the mortality rate (0% vs 100%, P < 0.05). CONCLUSION: EVL is a good choice for palliation in patients with esophageal variceal bleeding and hepatocellular carcinoma. Aggressive use of EVL may be tried in those patients without portal venous thrombosis. PMID- 8674924 TI - Postoperative screening for anastomotic recurrence of esophageal carcinoma by endoscopic ultrasonography. AB - BACKGROUND: The usefulness of endoscopic ultrasonography (EUS) in the preoperative staging of esophageal carcinoma is well established. Alternatively, the role of EUS in the early diagnosis of anastomotic recurrence is less well accepted. METHODS: EUS was used to evaluate 30 asymptomatic and 10 symptomatic patients (i.e., with dysphagia) who had previously undergone resection of esophageal carcinoma. RESULTS: There were 3 (10%) unsuspected anastomotic recurrences in the asymptomatic group. EUS correctly identified locally recurrent cancer in all cases, whereas endoscopy confirmed the presence of only one anastomotic recurrence. Computed tomography was not diagnostic in any of the three recurrences. Sensitivity of EUS for recurrence of esophageal carcinoma was 100% compared with 33% for endoscopic diagnosis while the specificity was 96% for EUS compared with 100% for endoscopic biopsy. There was one false positive diagnosis of recurrence by EUS because of postoperative fibrosis resulting in concentric hypertrophy of the esophageal wall near the surgical anastomosis. Of the 10 symptomatic patients, 4 were diagnosed with tumor recurrence. EUS correctly predicted recurrences in all symptomatic patients (100% sensitivity and specificity), as did upper endoscopy with biopsy. CONCLUSIONS: EUS is more sensitive than upper endoscopy and CT scan for the evaluation of anastomotic recurrence of esophageal carcinoma and should be considered as an adjunctive modality to conventional endoscopy for the postoperative surveillance of these patients. PMID- 8674925 TI - High-resolution endoluminal sonography in achalasia. AB - BACKGROUND: Imaging of the lower esophageal sphincter in patients with achalasia using 7.5 and 12 MHz ultrasound transducers has shown variable results. METHODS: A 20 MHz radial ultrasound transducer was used to quantitatively compare the lower esophageal sphincter in patients with achalasia to that of normal volunteers. The transducer, housed in a 6.2F catheter, was placed at the level of the lower esophageal sphincter in 29 patients with achalasia and 19 normal subjects. Videotaped images from the lower esophageal sphincter were digitized and the width of the circular smooth muscle, longitudinal smooth muscle, and total muscularis propria were measured. A mean width for each muscle layer was calculated. RESULTS: All muscle layers were found to be significantly thickened at the lower esophageal sphincter in patients with achalasia when compared with those in normal subjects: circular smooth muscle (0.206 cm +/- 0.137 cm vs 0.124 cm +/- 0.038 cm, p < 0.017); longitudinal smooth muscle (0.128 cm +/- 0.077 cm vs 0.088 cm +/- 0.028 cm, p < .041); and total muscle thickness (0.317 +/- 0.180 cm vs 0.224 cm +/- 0.049 cm, p < 0.033). CONCLUSION: Although high-resolution endoluminal sonography cannot be used to differentiate patients with achalasia from normal controls, this study quantitatively demonstrates that both the mean longitudinal and mean circular smooth muscle layers at the lower esophageal sphincter are wider in patients with achalasia than in a group of normal subjects. PMID- 8674926 TI - Endoscopic sphincterotomy-induced hemorrhage: a study of risk factors and the role of epinephrine injection. AB - BACKGROUND: We studied the incidence and relative risk factors for postsphincterotomy bleeding and the efficacy of epinephrine injection in hemostasis. METHODS: We retrospectively analyzed the incidence of postsphincterotomy bleeding in 983 consecutive patients with sphincterotomy for common duct stones and risk factors for such bleeding, i.e., presence of coagulopathy, stone impaction, periampullary diverticulum, extension of previous sphincterotomy, and use of needle knife precut sphincterotomy in sphincterotomy induced bleeding. Epinephrine irrigation was performed for mild bleeding, and injection with 1:10,000 epinephrine was performed to control more severe bleeding. RESULTS: 119 patients (12.1%) developed postsphincterotomy bleeding; 114 patients had immediate bleeding and 5 had delayed hemorrhage. Stone impaction at the papilla, periampullary diverticulum, and extension of a previous sphincterotomy were independent variables that increased the risk of bleeding. Forty-six percent of 119 patients with mild bleeding responded to epinephrine irrigation. The remaining required injection therapy with 1:10,000 epinephrine. Initial hemostasis was achieved in all. Rebleeding occurred in 5 patients but all responded to conservative management. None required emergency surgery and there was no mortality related to uncontrolled hemorrhage. CONCLUSION: Epinephrine injection is a safe treatment for sphincterotomy-induced bleeding. PMID- 8674927 TI - Descriptive features of gastric ulcers: do endoscopists agree on what they see? AB - BACKGROUND: Little is known about the interobserver variation between endoscopists on descriptive morphologic features. METHODS: This study describes the agreement among 10 endoscopists on their description of 12 morphologic features, using 10 photographs of gastric ulcers, and on their eventual interpretation. The endoscopists used a form with predefined options for description. RESULTS: Kappa value was on average 0.36 for descriptive features and 0.31 for interpretation. The proportion of endoscopists agreeing on descriptive features was on average 84%, and 81% on interpretations. The chance of an endoscopist describing all 12 morphologic features of an ulcer on a photograph exactly the same as a colleague ranged from 4% to 46% (average 15%). A positive correlation between agreement in description and interpretation (0.75, p < 0.05) was found. CONCLUSIONS: These results indicate a poor agreement between endoscopists in their translation of visual observations into descriptive terms. The positive correlation between agreement in description and interpretation suggests disagreement in description as an important cause for disagreement in interpretation. We believe that the use of more explicit descriptive terms will improve agreement in description and in subsequent interpretation. PMID- 8674928 TI - Intraoperative small bowel enteroscopy in familial adenomatous and familial juvenile polyposis. AB - BACKGROUND: In familial adenomatous polyposis and juvenile polyposis, polyps can occur throughout the gastrointestinal tract. METHODS: We report seven patients with familial adenomatous polyposis and two patients with juvenile polyposis who underwent small bowel enteroscopy at the time of exploratory celiotomy either for colectomy or other pathology. RESULTS: Polyps in the jejunum and/or ileum were noted in five of nine (56%) patients at enteroscopy. In three of nine (33%) patients these polys were adenomatous. Two of these patients had polyps in the jejunum and in the ileum, whereas one patient had jejunal adenomas alone. These polyps were from 3 mm to 30 mm in size. The remaining two patients with polyps had lymphoid hyperplasia in the ileum. All three patients who had adenomas at intraoperative small bowel enteroscopy had duodenal adenomas at esophagogastroduodenoscopy. At the age of 14 years, one patient had an intramucosal carcinoma in a small bowel juvenile polyp. CONCLUSION: Baseline small bowel enteroscopy should be considered at the time of surgical exploration in patients with asymptomatic familial adenomatous polyposis and juvenile polyposis. In patients with duodenal polyps, enteroscopy should be performed at the time of surgery. Biopsy and/or excision of larger polyps should be performed because these polyps may harbor a carcinoma. PMID- 8674929 TI - Value of endobiliary brush cytology and biopsies for the diagnosis of malignant bile duct stenosis: results of a prospective study. AB - BACKGROUND: Before considering a nonsurgical method of management of a bile duct stenosis, a tissue diagnosis is highly desirable. In a prospective study we have evaluated the feasibility and reliability of endobiliary brush cytology and biopsies performed at the time of endoscopic retrograde cholangiography. METHODS: Two hundred thirty-three consecutive patients underwent an attempt at endobiliary brush cytology and biopsies of bile duct stenosis when no mass was detected on ultrasound and CT scan. RESULTS: The material for cytology was sufficient for analysis in 210 cases (90%) and biopsies were obtained in 128 cases (55%). One hundred fifteen patients had both cytology and biopsies (49%). For the diagnosis of malignant stenosis, the sensitivity was 35% for cytology, 43% for biopsies, and 63% for the combination of cytology and biopsies. For both cytology and biopsies, the specificity was 97%. In the cases of cancer primarily involving the bile ducts, the sensitivity was 86% when combining both cytology and biopsies. CONCLUSIONS: Endobiliary sampling is technically difficult and has a limited sensitivity for the diagnosis of malignant biliary stenosis. Biopsies should be combined with cytology to increase the sensitivity. PMID- 8674930 TI - Randomized controlled study of injury in the canine right colon from simultaneous biopsy and coagulation with different hot biopsy forceps. AB - BACKGROUND: Monopolar hot biopsy forceps (HBF), bipolar HBF, and cold biopsy forceps (CBF) followed by bipolar electrocoagulation are used clinically to simultaneously perform a biopsy and coagulate diminutive colon polyps and angiomata. Our purpose was to conduct a randomized, controlled study to evaluate the safety of these different techniques in the canine right colon. METHODS: After right colotomy in 8 mongrel dogs, colonic mucosa was grasped en face, tented, and biopsy performed in randomized order. The dogs were sacrificed after nine days and the biopsy sites were identified and histologically examined. RESULTS: Monopolar HBF caused an overall mean rate of acute serosal whitening of 29% compared with 0% for bipolar HBF and CBF and 6% for CBF/bipolar probe. Histologically confirmed transmural injury 9 days after biopsy occurred in 44% of monopolar HBF compared with 5% of bipolar HBF, 0% of CBF, and 50% of CBF/bipolar probe. CONCLUSIONS: Monopolar HBF had significantly higher rates of acute serosal whitening and histologic transmural damage than bipolar HBF or cold biopsy alone. On the basis of these results, monopolar HBF should be avoided for coagulation of small or flat right colon lesions such as diminutive polyps or angiomata. PMID- 8674931 TI - Use of corticosteroids in the prevention of post-ERCP pancreatitis. AB - BACKGROUND: Pancreatitis frequently complicates diagnostic and therapeutic ERCP. A variety of causes have been implicated. A number of different agents have been used, without success, in an attempt to prevent pancreatitis. METHODS: In the current study, 824 patients with a history of iodine sensitivity were given preprocedure corticosteroid therapy (651 oral steroids and 173 intravenous steroids) in an attempt to prevent allergic reactions. These patients were retrospectively studied in an attempt to determine if corticosteroid administration prevents ERCP-related pancreatitis. Two control groups were used for comparison, including 1000 patients during the same study period (Control Group I) and 1954 patients from the Midwest Pancreaticobiliary Group (Control Group II). RESULTS: There was a significant difference in the overall incidence of post-ERCP pancreatitis in the corticosteroid treated group (4.6%) compared with either control group (Control Group I = 7.4% and Control Group II = 9.1%). Of those patients undergoing therapeutic ERCP, results were even more significant in favor of the steroid-treated group (5.2%) compared with Control Group I (9.7%) and Control Group II (11.2%). CONCLUSIONS: These results demonstrate that the administration of corticosteroids prior to ERCP results in a decreased incidence of post-ERCP pancreatitis. A prospective, randomized, controlled trial is warranted. PMID- 8674932 TI - A video baby cholangioscope. PMID- 8674933 TI - An easily constructed device for removal of laser plume and bodily fluid leakage from the biopsy ports of endoscopes. PMID- 8674934 TI - Spontaneous gastrosplenic fistula revealing high-grade centroblastic lymphoma: endoscopic findings. PMID- 8674935 TI - Successful use of an internal biliary stent in Caroli's disease. PMID- 8674936 TI - Endoscopic ultrasonography for esophageal cancer staging: impact on patient outcome. PMID- 8674937 TI - Style and substance in Gastrointestinal Endoscopy. PMID- 8674938 TI - Anesthesia for pediatric endoscopy. PMID- 8674939 TI - Enteroliths and Crohn's disease stricture treated by transendoscopic balloon dilation. PMID- 8674940 TI - Colonic anastomotic ulcers. PMID- 8674941 TI - Technology assessment status evaluation: balloon dilation of gastrointestinal tract strictures. American Society for Gastrointestinal Endoscopy. AB - Balloon dilation is an acceptable modality for the dilation of stenoses at various sites in the gastrointestinal tract. In the esophagus its reported efficacy and safety is similar to bougienage; in other sites it offers an alternative to surgical treatment, in most cases as the definitive therapy. PMID- 8674942 TI - Technology Assessment status evaluation: endoscopic feeding tubes. American Society for Gastrointestinal Endoscopy. PMID- 8674943 TI - Technology assessment status evaluation: monitoring equipment for endoscopy. American Society for Gastrointestinal Endoscopy. AB - An understanding of the principles and limitations of monitoring devices is valuable for their appropriate use and interpretation. Reliable monitoring de available as an adjunct to skilled personnel to detect changes in patient condition during endoscopy. Combination units that provide pulse oximetry, automated sphygmomanometry and ECG monitoring appear to be the most convenient and cost effective products. PMID- 8674945 TI - Position statement. Maintaining competency in endoscopic skills. American Society for Gastrointestinal Endoscopy. AB - This statement addresses the maintenance of endoscopic competence by physicians who have attained initial competence by endoscopic training in a formal fellowship or residency in gastroenterology or surgery, as defined in the ASGE "Statement of Endoscopic Training." PMID- 8674944 TI - Technology assessment status evaluation: disposable endoscopic accessories. American Society for Gastrointestinal Endoscopy. AB - Data supporting the preferential use of disposable endoscopic accessories is limited. These devices have been widely disseminated without careful evaluation of their impact on the environment and medical costs. In addition, current facility reimbursement for endoscopic procedures does not adequately cover the costs of these accessories. Re-use of accessories labelled "for single use only" as a potential means to reduce costs has not been carefully evaluated. More prospective data comparing the efficacy, safety, and cost effectiveness of disposable versus reusable accessories is needed. PMID- 8674946 TI - Guideline for the management of ingested foreign bodies. American Society for Gastrointestinal Endoscopy. AB - This guideline is intended to aid the endoscopist in the management of adult patients with possible foreign object ingestion and/or food bolus impaction. A literature search was performed on the Medline using Medlars II, the National Library of Medicine's National Interactive Retrieval Service. This search generated 181 citations. References chosen for review were English-language citations from the gastroenterology, otolarygology, general surgical, and radiological literature. As little or no data exist from well-designed prospective trials, emphasis was given to results from large series, and reports from recognized experts. In preparing this guideline several drafts were distributed to the members of the ASGE Standards of Practice Committee, to the practice committees of the AGA, ACG, and SAGES, and to national experts on this subject for critical review. A final draft was then reviewed by the ASGE Governing Board. The final guideline reflects the input from this review process. PMID- 8674947 TI - Sedation and monitoring of patients undergoing gastrointestinal endoscopic procedures. American Society for Gastrointestinal Endoscopy. AB - Every available means to insure the safety of patients during endoscopic procedures is mandatory. This begins with a fully trained and knowledgeable endoscopist, thorough preparation of the unit to handle endoscopic procedures and potential adverse outcomes, appropriate patient preparation, skilled assistants, and monitoring of the patient's well-being before, during and after the procedure. The relative risks involved can be estimated from patient and procedural factors and should be determined for each procedure. The level and type of monitoring during endoscopic procedures is dependent upon a thorough understanding and assessment of the risk to the patient. Monitoring of patients undergoing endoscopic procedures is mandatory and prudent. The ultimate responsibility for protecting patients lies with the endoscopist and cannot be assigned to an assistant or electronic monitoring device. However, both may greatly improve the ability to detect patient distress at a time when intervention will prevent an otherwise adverse outcome. PMID- 8674948 TI - Antibiotic prophylaxis for gastrointestinal endoscopy. American Society for Gastrointestinal Endoscopy. AB - This is one of a series of statements discussing the practice of gastrointestinal endoscopy in common clinical situations. It is intended to aid endoscopists in determining the appropriate use of antibiotic prophylaxis for patients undergoing gastrointestinal endoscopic procedures. Guidelines for the appropriate practice of endoscopy are based on a critical review of the available data and expert consensus. Controlled clinical studies are needed to clarify aspects of this statement, and revision may be necessary as new data appear. Clinical consideration may justify a course of action at variance from these recommendations. Recommendations on prophylaxis against infective endocarditis were developed in conjunction with the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease of the Council of Cardiovascular Disease in the Young of the American Heart Association. PMID- 8674949 TI - [Sensible use of CO2 laser therapy on the lower genital tract of the woman]. PMID- 8674950 TI - [Management of mother and child--ethical, surgical and institutional aspects of the history of obstetrics]. PMID- 8674951 TI - [Needs and expectations of cancer patients from their physicians: what do patients expect?]. PMID- 8674952 TI - [Tumor documentation system of the Working Group of German Tumor Centers]. PMID- 8674953 TI - [Chemical condoms supposed to prevent HIV infection]. PMID- 8674954 TI - [Balloon dissection of the cavum retzii--an innovative preparatory technique for endoscopic, extraperitoneal Burch colposuspension-plasty]. AB - Colposuspension is known as "Gold Standard" in incontinence surgery; however, a variety of different techniques exist for performing this measure. Minimal invasive surgery offers new treatment possibilities. Besides the intraperitoneal approach, there is also an extraperitoneal technique for the Burch procedure. We describe an innovative technique, namely, balloon dissection, which is well known in endoscopic hernioplasty for an atraumatic approach to the cavum retzii. This technique that was used in six patients with urinary stress incontinence has the following advantages: minimal blood loss, better visualisation of the operative field, and a shortened hospital stay and recovery period than with abdominal colposuspension. PMID- 8674955 TI - [Preperitoneal pelviscopic Burch colposuspension using the "Nottingham needle"]. AB - By 40 women with stress incontinence II.-III. degrees we performed a preperitoneal pelviscopic colposuspension (Burch) modified by Gill with the "Nottingham Needle". An urodynamic and sonographic assessment before and 6-9 months after the pelviscopic operation were done. In 38 cases from the 40 women (95%) we saw a good result. The new modification of the pelviscopic colposuspension showed us a low intra- and postoperative morbidity and we consider it a big advantage for obese women. PMID- 8674956 TI - [The VIVA urethral plug: a sensible expansion of the spectrum for conservative therapy of urinary stress incontinence?]. AB - OBJECTIVE: To evaluate applicability, acceptance, side effects and complications and the possible curative effect on female stress urinary incontinence of the treatment with the urethral plug VIVA (Braun Melsungen, Germany). DESIGN: Part I: Prospective clinical study. Part II: Ongoing prospective-longitudinal study. Additionally two case reports. SUBJECTS: Part II: 156 consecutive patients of the urodynamic out patient clinic. Part II: 21 patients with urinary stress incontinence (SUI). MAIN OUTCOME MEASURES: Part I: Ability to hold the plug while walking and standing, acceptance rate of plug therapy. Part II: Subjective improvement of SUI, pad-weighing test, cough test, urinary tract infections, other complications during four months of plug treatment. RESULTS: Part I: 62% of 156 patients were able to hold the plug. 40% of 53 patients with SUI accepted the plug treatment. Part II: 14 patients completed the study. 4 pat. were subjectively and objectively cured, 3 were improved, 7 unchanged. The cured patients all had a low grade SUI with a urine loss of 3 g in the pad-weighing test before treatment. 12/21 pat, showed 1-2 urinary tract infections and 1 patient dropped out from the study because of recurrent urinary tract infections. In one patient a plug migrated into the bladder and was removed cystoscopically. In two case reports the possibility of symptomatic plug treatment for patients with severe stress incontinence after surgical and radiological treatment of cervical cancer is demonstrated. CONCLUSIONS: Plug treatment is a broadening of the spectrum of conservative treatment of SUI as a symptomatic treatment in pat. with contraindications to anti-incontinence surgery and as a curative treatment in low grade SUI. PMID- 8674957 TI - [Observation of an increase in "aggressive tumor forms" in increasing incidence of breast carcinoma]. AB - Between 1986 and 1990 23% more patients with carcinomas of the breast were treated in the Gynaecological Hospital of the Municipal Hospital (Stadt. Krankenanstalten) of Krefeld than during the comparative period between 1976 and 1980. Simultaneously, an increase of carcinomas metastasising the further course of the disease were observed. When analysing the possible reasons it can be noticed that in the first group (1986 to 1990) compared to the second group (1976 to 1980) multifocal and lobular carcinomas were observed more frequently with regard to their statistical significance. The same applies to the metastatic involvement of axillary and infraclavicular lymphodes. It was noticed that in the first group, lymphangiosis and hemangiosis carcinomatosa were seen more frequently than in the second group. The collected data suggest that in case of an increase in carcinomas of the breast, a larger number of tumours with prognostically unfavourable tumour criteria is seen. PMID- 8674958 TI - [Does the risk of complications after amniocentesis depend on the indications for intervention? An evaluation of 2,066 punctures]. AB - Data from 2066 amniocenteses were analysed retrospectively to test the hypothesis whether the indications for amniocentesis influence the risk of post-procedural complications. Compared to the reference group of 35-39 year-old gravidae, the complication rates were similar in women with a previous child with chromosomal abnormality, in cases with maternal disease, abnormal biochemical markers, maternal anxiety, and translocation carriers. If the maternal age was 40 years and over, only the percentage of pregnancy terminations for fetal abnormalities was higher than in the reference group; high parental age was associated with a significantly decreased fetal loss rate. In the group of amniocenteses performed for sonographic evidence of fetal malformation, the highest total complication rates and the highest fetal loss rates were observed. PMID- 8674959 TI - [Quality of prenatal data in the Hessian Perinatal Registry. A comparison with data from maternal health record and results of a pregnancy survey]. AB - In the Federal State of Hesse, Germany, pregnancy and delivery related data are collected in a central perinatal registry called "Hessische Perinatalerhebung" (HEPE) since 1981, the objective being to enforce quality assurance and to contribute to a reduction in perinatal mortality and morbidity. The delivery unit compiles these data based on the antenatal record called "Mother Passport" and the actual delivery. In order to check on the quality of data, information on risk factors obtained from the perinatal register was compared to information from antenatal records and from a questionnaire administered to pregnant women prior to delivery. The study population comprised 1978 women who delivered at the maternity unit of the Municipal Hospital of Wiesbaden, the Dr. Horst Schmidt Kliniken, in 1990 and 1991. Comparison of the three data sources revealed substantial differences: Almost all risk factors were most frequently mentioned by the mothers themselves, less by the antenatal record and even less by the perinatal register. These differences were less pronounced for data on previous pregnancies and pre-existing disease and on abnormal positioning. Considerable differences were found in relation to pregnancy induced hypertension, intra uterine growth retardation, incapacity of the cervix, preterm labour and bleeding. Risk factors related to the social environment and personal habits like psycho-social stress and smoking were found to be extremely under-reported in the antenatal records as well as in the perinatal register. The following factors could be identified as major reasons for the different risk profiles obtained from the various data sources: [1] Data loss through the transfer of data from the antenatal record to the record form of the perinatal register or to the computer, [2] selective recording of those risk factors considered by doctors to be particularly relevant, [3] missing definition of some risk factors and [4] recording of antenatal data for the perinatal register by the delivery unit after knowing the pregnancy outcome. Antenatal data in the perinatal register of Hessen are doubtful and should not be used uncritically for comparative studies and the assessment of relative risks. The extreme under-reporting of some risk factors may even lead to giving some interventions undue priority. In future, regular validity studies should become routine. A reduction of the data losses as well as a clear separation of antenatal data and delivery data could be achieved if antenatal data would be transferred from the doctor providing antenatal care direct to the perinatal register. PMID- 8674960 TI - [Male subfertility and conventional in vitro fertilization in Germany 1990 to 1993]. AB - A retrospective study was carried out to compare the results of in vitro fertilisation (IVF) in 20936 patients with different sperm parameters who underwent IVF in Germany between 1990 and 1993. The study was designed to evaluate prognostic factors for IVF outcome, such as sperm parameters and pre treatment diagnosis. The percentage of subfertile sperm parameters ( < 10 millions sperm per ml and/or < 30% progressive mobility and/or < 30% normal morphology) increased from 31.4% in 1990 to 51.1% in 1993. The fertilisation rate per puncture varied between 87.9% in patients with normozoospermia and 38.7% in patients with severe oligo-astheno-teratozoospermia (OAT). The fertilisation rate in patients with tubal indication was significantly higher than in patients with male indication and comparable spermatozoa. The pregnancy rate per embryo transfer was 23% in patients with normozoospermia and 13.8% in patients with "severe OAT syndrome" in the IVF semen parameters. On the other hand, patients with male sterility as pre-treatment diagnosis showed significantly higher chances of pregnancy than patients with a tubal factor (24% versus 20%, p < 0.05). Comparing percoll and swim-up preparation techniques, we found significantly higher fertilisation rates in normozoospermia and significantly higher pregnancy rates in subfertile patients after percoll sperm preparation. The results of the study demonstrated that patients with moderate subfertile sperm parameters have good chances of fertilisation and pregnancy following conventional IVE. It seems reasonable to set the boundary at a sperm count of 10 millions sperm/ml with 30% progressive motility and 30% normal morphology. Below these limits intracytoplasmic sperm injection shows better IVF outcome. PMID- 8674961 TI - [Highly purified FSH for stimulation of down regulated cycles in the in vitro fertilization program]. AB - Highly purified FSH (Fertinorm HP) was used for follicle stimulation during one cycle of IVF in each of 112 women. In all cases, stimulation was begun with 150 IU FSH per day s.c. after pituitary down-regulation with a GnRH analogue in a Long protocol. Sixteen (14.3%) of the 112 treatment cycles started were stopped before follicle aspiration. The reasons for stopping stimulation were elevated progesterone values with premature luteinisation in 9 (8.0%) patients, inadequate follicle stimulation in 4 (3.6%) cases and threatened overstimulation in 3 (2.7%) cases. The mean duration of stimulation was 11.8 days with 7.8 oocytes obtained per aspiration by the transvaginal rute. Embryo transfer was possible in 77 (68.7%) patients, with a mean of 2.3 embryos per transfer. A total of 23 clinical pregnancies resulted, with a pregnancy rate of 20.5% and 29.9% per cycle and embryo transfer, respectively. There were three cases of multiple pregnancy (13.0%), two (8.7%) miscarriages occurred and one patient (4.3%) had a tubal pregnancy. The rate of successful pregnancies was thus 17.9% per cycle. Five patients (5.2%) required treatment for overstimulation. There were not other treatment complications. These results show that highly purified FSH can also be used successfully in IVF after pituitary down-regulation. The remaining endogenous LH activity in these cases may be regarded as sufficient for follicular development and steroid synthesis. Highly purified FSH can therefore be used for all stimulation protocols in patients with normal gonadotrophin levels. The relatively low rate of miscarriages with this treatment is noteworthy. PMID- 8674962 TI - [Successful treatment of drug refractory uterine atony by fundus compression sutures]. AB - Postpartum atony remains the most common cause life-threatening haemorrhage in obstetrics. In a case of postpartum atony unresponsive to medical treatment after Caesarean section haemorrhage was controlled and satisfactory uterine tonus was achieved by inverted sutures of the uterine fundus. Imminent hysterectomy could thus be avoided. PMID- 8674963 TI - [Struma ovarii--a case report]. AB - A 43-year old women was admitted to our hospital for investigation and treatment of a right ovarian tumour. Presenting symptoms and signs included recurrent pelvic pain since half a year, nervousness and intercurrent insomnia. At operation a solid cystic tumour was found arising from the right ovary. Histologically a combination tumour was found to consist of a multilocular cystadenoma and a true struma ovarii as a rare neoplasia of teratomatous nature. PMID- 8674964 TI - [Initial manifestation of tuberculoid leprosy in pregnancy. Guidelines for diagnosis and therapy]. AB - Pregnancy has long been associated with the first presentation of clinical leprosy or aggravation of the existing disease. In Germany leprosy has been diagnosed in 107 patients since 1980. A 27-year-old Singhalese female, gravida 2 at 14 weeks' gestation was admitted with well defined, elevated, erythematous lesions on her cheeks and nose. Clinical examination revealed central anaesthesia in the lesions. No further signs of leprosy in the skin, the mucosae and the peripheral nerves were found. Fite-Faraco staining of the skin biopsy showed sporadic acid-fast bacilli and confirmed an active subpolar tuberculoid leprosy (TTs). Outpatient treatment was immediately initiated with oral rifampin 600 mg monthly and dapsone 100 mg daily. During the 4-month treatment cycle the skin lesions vanished completely. Additional leprosy reactions did not occur and the medication was well tolerated. However, in the 32nd gestational week the patient was readmitted with premature labour and 3 weeks later Caesarean section was performed because of cardiotocographic pathology. Polymerase chain reaction (PCR) for M. leprae of placental tissue was negative. Antibodies against phenolic glycolipid 1 (PGL 1) of M. leprae (IgM-Elisa and Dot-Elisa) from cord blood, maternal and newborn blood were not found. On the fifth postpartal day the healthy mother and her baby were discharged. In conclusion, leprosy in pregnancy can be treated safely and successfully by combined drug therapy. PMID- 8674965 TI - Regulation and organization of the groE and dnaK operons in Eubacteria. AB - groEL and dnaK are the most highly conserved protein-coding genes known. Most groEL operons and several dnaK and dnaJ operons contain a highly conserved inverted repeat (IR) sequence in their regulatory region. So far, this IR has been found only as part of the groE, dnaK and dnaJ operons and genes. In most cases, the IR is part of the operon transcript, and is involved in the regulation of expression at both the DNA and mRNA levels. A detailed analysis of groE and dnaK operons indicates that the organization of the groE operons is highly conserved. They contain only the groES and groEL genes and always in the same order. In contrast, the organization of the dnaK operons has changed during evolution: genes have been added and deleted from it, and the gene order within the operon is variable. PMID- 8674966 TI - A new set of primers for the detection of Toxoplasma gondii in amniotic fluid using polymerase chain reaction. AB - A new PCR system including a pair of primers, a probe and an internal control were designed from the B1 gene of Toxoplasma gondii. The system described allowed the detection of less than 10 tachyzoites of the RH strain of T. gondii. Among 21 amniotic fluid samples, this system diagnosed the cases of congenital toxoplasmosis which were simultaneously diagnosed using mice inoculation, in vitro culture, and serology from both amniotic fluid and fetal blood. These results show that these new primers allow for a highly sensitive detection of T. gondii DNA. PMID- 8674967 TI - Rapid, direct extraction of DNA from soils for PCR analysis using polyvinylpolypyrrolidone spin columns. AB - Polyvinylpolypyrrolidone spin columns were used to rapidly purify crude soil DNA extracts from humic materials for polymerase chain reaction (PCR) analysis. The PCR detection limit for the tfdC gene, encoding chlorocatechol dioxygenase from the 2,4-dichlorophenoxyacetic acid degradation pathway, was 10(1)-10(2) cells/g soil in inoculated soils. The procedure could be applied to the amplification of biodegradative genes from indigenous microbial populations from a wide variety of soil types, and the entire analysis could be performed within 8 h. PMID- 8674968 TI - Adherence and invasive capacities of the fish pathogen Pasteurella piscicida. AB - Pasteurella piscicida strains were weakly or moderately adherent to cell lines, the levels of attachment being variable depending on the cells employed. All the isolates exhibited the highest binding capacity to CHSE-214 cells. Adhesive capacities were affected by heat and sugars but not by proteinase K or by treatment with antisera raised against the lipopolysaccharides of P. piscicida, implicating components of glycoprotein(s) as ligands in the adhesion process. The isolates showed a great binding capacity to intestines from the marine fish hosts gilthead sea bream, sea bass and turbot, with values ranging from 10(4) to 10(5) bacteria/g. Although the P. piscicida strains showed a weak invasiveness in the poikilothermic cell lines employed as in vitro model, the bacteria remained viable inside the infected cells at least for 2 days. The invasion process was inhibited by cytochalasin D indicating the active participation of the host cytoskeleton in the internalization of P. piscicida. PMID- 8674969 TI - Relationship between stress response toward bile salts, acid and heat treatment in Enterococcus faecalis. AB - Stress tolerance and cross-protection in Enterococcus faecalis ATCC19433 were examined after exposure to bile salts, acid or heat shock. Bile salts and heat adapted cells demonstrated induced homologous tolerance and cross-resistance. No cross-protection of heat adapted cells against acid stress is observed and pretreatment with bile salts even sensitized the cells to this challenge. Whole cell protein extract analysis revealed that each treatment induced a battery of stress proteins. Some of these polypeptides are induced by more than one treatment. The greatest overlap is observed between bile salts and heat treatments. Eighteen stress proteins, including DnaK and GroEL, are common between these stresses. PMID- 8674970 TI - A peptidoglycan binding domain in the porin-associated protein (PAP) of Rhodospirillum rubrum FR1. AB - The porin-associated protein of Rhodospirillum rubrum FR1 was found to contain a peptidoglycan binding motif. A partial fragment of 179 amino acids, obtained by cleavage of PAP with trypsin, Asp-N protease, and CNBr, was sequenced. Substantial sequence homology was found of the C-terminal part (residues 126-179) of porin-associated protein with OmpA, the peptidoglycan-associated lipoprotein of several bacteria, protein F of Pseudomonas aeruginosa, and PIII of Neisseria gonorrhoeae, the latter being also a porin-associated protein. The 179 amino acid fragment comprised about 67% of the mass spectrometrically determined total mass of PAP of 27850 Da. PMID- 8674971 TI - The respiratory chain of Helicobacter pylori: identification of cytochromes and the effects of oxygen on cytochrome and menaquinone levels. AB - The quinone and cytochrome components of the respiratory chain of the microaerophilic bacterium Helicobacter pylori have been investigated. The major isoprenoid quinone was menaquinone-6, with traces of menaquinone-4; no methyl substituted or unusual menaquinone species were found. Cell yield was highest after growth at 10% (v/v) oxygen and menaquinone levels (per dry cell mass) were maximal at 5-10% (v/v) oxygen. Helicobacter pylori cells and membranes contained b- and c-type cytochromes, but not terminal oxidases of the a- or d-types, as judged by reduced minus oxidised difference spectra. Spectra consistent with the presence of a CO-binding terminal oxidase of the cytochrome b- or o-type were obtained. The soluble fraction from disrupted cells also contained cytochrome c. There were no significant qualitative differences in the cytochrome complements of cells grown at oxygen concentrations in the range 2-15% (v/v) but putative oxidases were highest in cells grown at 5-10% (v/v) oxygen. PMID- 8674972 TI - Isolation, characterization and crystallization of an iron-superoxide dismutase from the crenarchaeon Sulfolobus acidocaldarius. AB - An iron containing superoxide dismutase from the cytosol of the thermoacidophilic crenarchaeon Sulfolobus acidocaldarius (DSM 639) has been purified to electrophoretic homogeneity. It comprises at least 11% of the cytosolic protein. The isolated protein consists of two identical subunits with an apparent molecular mass of 22.4 kDa. It contains one iron atom per dimer. The protein shows the typical EPR spectrum of a S = 3/2, rhombic high-spin iron center. It is extremely resistant against thermal and chemical denaturation. Simultaneous treatment with heat and detergent resulted in the conversion into a more active tetrameric form. Similar enzymes appear to be present in the cytosol of other members of the Sulfolobaceae. The dimeric form of the protein from S. acidocaldarius has been crystallized. PMID- 8674973 TI - Quantitative analysis of gene expression in sexual structures of Aspergillus nidulans by sequencing of 3'-directed cDNA clones. AB - We constructed a 3'-directed cDNA library of cleistothecia and Hulle cells of Aspergillus nidulans to examine gene expression patterns of the sexual structures and to have probes necessary to isolate sexual structure-specific genes. Sequencing of 360 randomly selected cDNA clones yielded 272 expressed sequence tags (ESTs), most of which probably represent frequently or less expressed genes in sexual structures of A. nidulans. Among the 272 ESTs, 33 ESTs (87 cDNA clones) appeared more than once and 2 ESTs appeared 6 times; 9 ESTs matched GenBank entries. When compared with sequences obtained from a mycelial 3'-directed cDNA library of A. nidulans, 28 out of 33 ESTs seem to be sexual structure-specific. Northern blot analyses of 20 ESTs showed that 17 are sexual structure-specific. The remaining three ESTs also hybridized with RNA isolated from vegetative mycelia. These results suggest that analyses of ESTs from different cell types or tissues can readily demonstrate gene expression patterns of specific cell types and identify cell type-specific cDNA probes. PMID- 8674974 TI - Immunochemical characterization of two new O serotypes of Serratia marcescens (O27 and O28). AB - In an earlier study of the distribution of O-serotypes among clinical isolates of Serratia marcescens, two apparently new serotypes were identified, represented by strains S1254 and S3255. Studies using ELISA, immunoblotting and the Quellung reaction have shown that they qualify for inclusion in the O-antigenic typing scheme on three counts: (1) they possess chemically distinct O-antigenic repeating units, (2) the O-antigens are serologically distinguishable from all others, and (3) they are found in a significant proportion of clinical S. marcescens strains (13% and 6% respectively). S1254, the type strain for serotype O27, is an acapsular strain which expressed a glucorhamnan with a disaccharide repeating unit as its lipopolysaccharide side chain. It cross-reacts with serotype O4, the O antigen of which is an O-acetylated form of the O27 glucorhamnan, but this cross-reaction can be eliminated by reciprocal cross absorption. S3255, the type strain for serotype O28, has a mannose homopolymer as its O-antigen and is the only S. marcescens serotype with a trimeric repeating unit structure. However, it cross-reacts with the O5 serotype strain due to similarities in their acidic capsular polysaccharides. Cross-absorption and the production of serum to an acapsular variant of serotype strain O28 produced typing reagents which could differentiate serotypes O5 and O28. PMID- 8674975 TI - Analysis of the adaptive oxidative stress response of Candida albicans. AB - Treatment of Candida albicans with low concentrations of either hydrogen peroxide or menadione (a superoxide generating agent) induces an adaptive response which protects cells from the lethal effects of a subsequent challenge with higher concentrations of these oxidants. Pre-treatment with either menadione or hydrogen peroxide is protective against cell killing by either oxidant. This suggests that the pathogenic yeast C. albicans (unlike the budding yeast Saccharomyces cerevisiae which has separate responses) possesses an adaptive response that responds to both these oxidants. In addition, we found that C. albicans showed a greater level of resistance to oxidants, both H2O2 and redox-cycling agents, compared to that observed with S. cerevisiae. In an attempt to characterise the oxidative stress response in more detail we have analysed the effect of oxidants on the activities of a number of enzymes with known antioxidant activity. PMID- 8674976 TI - Prevotella intermedia and Prevotella nigrescens serotypes, ribotypes and binding characteristics. AB - Type strains and 62 clinical isolates of Prevotella intermedia and Prevotella nigrescens were typed with the use of genomic DNA fingerprints and rRNA gene probes. The strains were further serotyped with monoclonal antibodies and characterized with SDS-PAGE, enzymatic activities, hemolysis and hemagglutination and coaggregation with Streptococcus and Actinomyces spp. P. intermedia and P. nigrescens were found to have distinct ribotype patterns which correspond to previously defined serotyupes I and II/III, respectively. No clear phenotypic difference related to hemolysis, hemagglutination and coaggregation with streptococcus and actinomyces species, or expression of aminopeptides and lipase was found between P. intermedia and P. migrescens. PMID- 8674977 TI - An iron dioxygenase from Alcaligenes faecalis catalyzing the oxidation of pyruvic oxime to nitrite. AB - An enzyme which participated in the oxidation of hydroxylamine to nitrite from was partially purified Alcaligenes faecalis, and some of its properties were studied. The enzyme oxidized aerobically pyruvic oxime to nitrite in the presence of hydroxylamine or ascorbate. As molecular oxygen equimolar to nitrite formed was consumed in the enzymatic oxidation of pyruvic oxime to nitrite, the enzyme was thought to be a dioxygenase. It was an iron protein, and a reducing reagent was required to keep the iron in the ferrous state for the action of the enzyme. PMID- 8674978 TI - Immunological crossreactivity to the catabolite control protein CcpA Bacillus megaterium is found in many gram-positive bacteria. AB - The catabolite control protein CcpA from Bacillus megaterium was overproduced as a fusion protein to a 6xhis affinity tag and purified to homogeneity. Polyclonal antibodies of high affinity and specificity were raised against the purified protein. The serum did not crossreact with purified Lac repressor despite the fact that CcpA and LacI belong to the same protein family. Using this antiserum we identified proteins that share antigenic determinants with CcpA in many Gram positive bacteria, including bacilli, staphylococci, lactic acid bacteria, and some actinomycetes. PMID- 8674979 TI - Salmonella typhimurium cob mutants are not hyper-virulent. AB - It was previously reported that Salmonella typhimurium LT2 cob mutants defective in the biosynthesis of vitamin B12 (cobalamin) are more virulent than the wild type in mice. Here we show that the strains used previously are non-isogenic and that the proposed increase in virulence of the cob mutant strain results from an uncharacterized mutation in the "wild type" which attenuates virulence, most likely by decreasing expression of the spv genes on the virulence plasmid. As a result the cob mutant will appear as hyper-virulent. Examination of the virulence of reconstructed wild-type and cob mutant strains showed that their growth rates were similar in mice, and we conclude that vitamin B12 does not affect the virulence of S. typhimurium LT2. PMID- 8674980 TI - Regulation of the yeast vacuolar aminopeptidase Y gene (APY1) expression. AB - The steady-state levels of the aminopeptidase Y (APY1) transcript and the level of assayable aminopeptidase Y activity were measured under a variety of nutritional conditions. Specific APY1 mRNA is less abundant in cells grown in minimal medium than in cells grown in rich medium, while active enzyme levels follow just the opposite pattern. Aminopeptidase Y activity decreases when cells are deprived of glucose without a concomitant fall in mRNA levels. Production of aminopeptidase Y is not markedly affected by nitrogen regulation. APY1 gene expression is not disturbed in heat-shocked cells. Our data support the idea that the main control event in vacuolar aminopeptidase Y expression is a post transcriptional step. PMID- 8674981 TI - Isolation, characterisation and expression of the bacterioferritin gene of Rhodobacter capsulatus. AB - The nucleotide sequence of the Rhodobacter capsulatus bacterioferritin gene (bfr) was determined and found to encode a protein of 161 amino acids with a predicted molecular mass of 18,174 Da. The molecular mass of the purified protein was estimated to be 18,176. +/ 0.80 Da by electrospray mass spectrometry. The bfr was introduced into an expression vector, and bacterioferritin was produced to a high level in Escherichia coli. The amino acids which are involved in haem ligation, and those provide ligands in the binuclear metal centre in bacterioferritin from E. coli are conversed in the R. capsulatus protein. The sequences of bacterioferritins, ferritin-like proteins, and proteins similar to Dps of E. coli are compared, and membership of the bacterioferritin family re-evaluated. PMID- 8674982 TI - The arsenical resistance operon of IncN plasmid R46. AB - The arsenical resistance operon of the IncN plasmid R46 consists of 4696 bp and starts with predicted transcriptional control and initiation signals, followed by five genes, arsD, arsA, and arsC. The corresponding Escherichia coli chromosomal ars operon and two staphylococcal ars operons lack arsA and arsD genes. The R46 system contains only the second known versions of arsA and arsD, after those of plasmid R773. Western blot analysis identified the R46 proteins using antibodies against R773 ArsA, ArsD and ArsR. PMID- 8674983 TI - Production of an autoinducer of growth by norepinephrine cultured Escherichia coli O157:H7. AB - Escherichia coli O157:H7 were cultured in the presence of norepinephrine to generate conditioned media. The presence of a growth-inducing factor(s) in the conditioned media was examined by measurements of the ability of conditioned media to support the growth of fresh cultures of E coli O157:H7. Supplementation of fresh cultures with as little as 0.024% (v/v) norepinephrine conditioned medium resulted in increased growth as compared to controls, thereby indicating the presence of an autoinducer of growth. Analysis of the production kinetics for the autoinducer during the generation of conditioned media indicates that it differs from other more well characterized autoinducers. It is proposed that the neurohumoral environment of the host may contribute to the production of bacterial growth factors. PMID- 8674984 TI - A family of halobacterial transducer proteins. AB - A DNA probe to the signaling domain of a halobacterial transducer for phototaxis (HtrI) was used to clone and sequence four members of a new family of transducer proteins (Htps) in Halobacterium salinarium potentially involved in chemo- or phototactic signal transduction. The signaling domains in these proteins have 31 43% identity when compared with each other or with their bacterial analogs, the methyl-accepting chemotaxis proteins. An additional region of homology found in three of the Htps has 31-43% identity with HtrI. The Htps contain from 0 to 3 transmembrane helices and Western blotting showed that HtpIII is soluble. The arrangement of the domains in these Htps suggests a modular architecture in their construction. PMID- 8674985 TI - Suppressor mutations in alpha-subunit of RNA polymerase for a mutant of the positive regulator, OmpR, in Escherichia coli. AB - The OmpR protein is a positive regulator specific for the Escherichia coli ompF and ompC genes. This protein functions in a phosphorylation-dependent manner through a presumed interaction with RNA polymerase. We previously isolated OmpR mutants which were suggested to be defective in transcription activation, but not in DNA binding (the so-called positive control (PC) mutant). In this study we isolated mutants of the alpha-subunit of RNA polymerase which can suppress one of the putative PC mutants of OmpR. A crucial amino acid substitution was identified as [V264G] in the alpha-subunit, which is located in the helix H1 of the C terminal domain, which has been claimed, based on mutational and structural analyses, to be involved in the interaction with other positive regulators including the well-characterized cAMP receptor protein. PMID- 8674986 TI - The gene encoding ammonia monooxygenase subunit A exists in three nearly identical copies in Nitrosospira sp. NpAV. AB - The gene encoding ammonia monooxygenase subunit A (AmoA) was found in three copies of the genome of the chemolithotrophic soil bacterium, Nitrosospira sp. NpAV. The open reading frame and flanking regions of the three copies were isolated from digested size fractionated genomic DNA using oligodeoxyribonucleotide primers and polymerase chain reaction. The three gene copies of amoA were sequenced and the sequences compared to each other. The open reading frames and the upstream and downstream flanking regions were nearly identical in the three copies. All three copies were expressed in recombinant Escherichia coli strains from the indigenous promoter producing a product of approximately 30 kDa. All amoA copies encode 274 amino acid polypeptides which have similarity to the ammonia monooxygenase acetylene-binding protein from Nitrosomonas europaea. PMID- 8674987 TI - RcsC-mediated induction of colanic acid by secretion of streptokinase in Escherichia coli K-12. AB - The introduction of a plasmid containing skc (streptokinase-coding gene) fused with ompA signal sequence into Escherichia coli K-12 strains, rendered the bacteria mucoid. Measurement of the synthesis of beta-galactosidase from a cps lacZ fusion (lacZ fusion to a gene necessary for capsule synthesis) showed that the mucoid phenotype was due to induction of the capsular polysaccharide colanic acid synthesis. The introduction of a plasmid carrying skc fused with malE (gene encoding maltose-binding protein) also induced cps-lacZ expression, but intracellular expression of streptokinase in E. coli did not. The cps expression by secretion of streptokinase was diminished to the basal level in a cps-lacZ strain carrying a rcsC mutation. These results show that the secretion of streptokinase in E. coli induces colanic acid synthesis through the RcsC dependent pathway. PMID- 8674988 TI - Interaction of lysozyme with a surface protein antigen of Streptococcus mutans. AB - The interaction of salivary lysozyme with the surface protein antigen (PAc) of Streptococcus mutans and the interaction of lysozyme with the pathogen were examined by ELISA using S. mutans MT8148 (PAc+) and the PAc-defective mutant EM-2 (PAc-). The lysozyme clearly bound to the S. mutans wild type but not to the S. mutans mutant. Furthermore, lysozyme bound directly in the fluid phase to the rPAc, of which the binding kinetics were determined (Kon = 3.63 +/- 0.04 x 10(3) M-1 s-1, K(off) = 1.72 +/- 0.04 x 10-5 s-1 and Kon/K(off) = 2.11 x 10(8) M-1) using surface plasmon resonance. The kinetics of both association and dissociation were relatively slow. In addition, anti-lysozyme antibody significantly inhibited the binding of salivary components to the rPAc. The present findings indicate that lysozyme is one of the major salivary components interacting with S. mutans PAc. PMID- 8674989 TI - Isolation of an Ustilago maydis ERG11 gene and its expression in a mutant deficient in sterol 14 alpha-demethylase activity. AB - A gene (ERG11) encoding cytochrome P450 sterol 14 alpha-demethylase (P450(14DM)) was isolated from the maize pathogen, Ustilago maydis, by amplifying part of the coding region of the gene using PCR and by employing the amplified DNA fragment as a hybridization probe to recover the complete gene from an U. maydis lambda EMBL3 genomic library. The deduced amino acid sequence of the U. maydis gene showed homology to P450(14DM)s from other organisms and contained specific motifs which were hallmarks of P450s. Expression of the gene in an U. maydis mutant (A20) deficient in P450(14DM) led to only a partial restoration of P450(14DM) activity. Accumulation of ergosta-7,22-dienol and ergost-7-enol in A20 transformants containing the ERG11 gene implied that an additional mutation affecting sterol delta 5,6-desaturase activity accompanied the P450(14DM) lesion. PMID- 8674990 TI - Energy production and peptidase activity in Eikenella corrodens. AB - Eikenella corrodens 33EK(L), a clinical isolate, was assayed for its ability to utilise amino acids as substrates in the reduction of nitrate to nitrite. The metabolism of proline, glutamate, serine and glutamine was found to result in relatively high rates of nitrate reduction. The ability of cells to metabolise these amino acids from a variety of small peptides was also determined. E. corrodens was found to possess a relatively specific proline aminopeptidase as well as a putative carboxypeptidase activity for glutamate. Energy production in this organism appears to be via oxidative deamination of these key amino acids linked to a respiratory chain, with nitrate acting as the ultimate electron acceptor. PMID- 8674991 TI - Characterisation of the Aspergillus nidulans frA1 mutant: hexose phosphorylation and apparent lack of involvement of hexokinase in glucose repression. AB - Hexose phosphorylation was studied in Aspergillus nidulans wild-type and in a fructose non-utilising mutant (frA). The data indicate the presence of at least one hexokinase and one glucokinase in wild-type A. nidulans, while the frA1 mutant lacks hexokinase activity. The A. nidulans gene encoding hexokinase was isolated by complementation of the frA1 mutation. The absence of hexokinase activity in the frA1 mutant did not interfere with glucose repression of the enzymes involved in alcohol and L-arabinose catabolism. This suggest that, unlike the situation in yeast where mutation of hexokinase PII abolishes glucose repression, the A. nidulans hexokinase might not be involved in glucose repression. PMID- 8674993 TI - Immunological detection of the GerA spore germination proteins in the spore integuments of Bacillus subtilis using scanning electron microscopy. AB - To clarify the molecular mechanisms that trigger spore germination of Bacillus subtilis, the location of GerA proteins (GerAA, GerAB and GerAC), which were reported to be putative gene products of a receptor for one of the germinants, L alanine, was investigated by immunological techniques using anti-GerA peptide antibodies. Four antibodies were raised against the corresponding epitopes, two in GerAA, one in GerAB and the other in GerAC molecules. The binding of all four antibodies to the inner surface of the cortex-less spore coat fragments could be seen by scanning immunoelectron microscopy with colloidal gold particles. The result agreed with the fact, previously reported, that the colloidal gold particles were visualized just inside the spore coat layer by transmission immunoelectron microscopy using another anti-GerAB peptide antibody. PMID- 8674992 TI - Characterization of a novel SHV beta-lactamase variant that resembles the SHV-5 enzyme. AB - An SHV type beta-lactamase frequently found in enterobacteria isolated in Greek hospitals was analyzed. The enzyme (SHV-5a) conferred resistance to ceftazidime and aztreonam. The DNA sequence of the structural gene was determined. The deduced amino acid sequence showed that positions 70-73 were occupied by the active site tetrad Ser-Thr-Phe-Lys. As in SHV-5, Ser-238 and Lys-240 were present. However, one deletion (Gly-54) and three substitutions (Arg-140 for Ala, Asn-192 for Lys and Val-193 for Leu) differentiate SHV-5a beta-lactamase from SHV 5. Asn-192 and Val-193 have been reported to date only in the R974 plasmid mediate SHV-1 beta-lactamase. Hydrolysis studies with SHV-5a and SHV-5 showed that the enzymes behaved similarly. Additional evidence that they are functionally indistinguishable was provided by the similar MICs of beta-lactams when the enzymes were expressed under isogenic conditions. The sequence differences, however, indicate that they are derived from different ancestors. PMID- 8674994 TI - A Myxococcus xanthus cell density-sensing system required for multicellular development. AB - Progression through early Myxococcus xanthus multicellular fruiting body development requires the generation of and response to extracellular A signal. Extracellular A signal is a specific set of amino acids at an extracellular concentration greater than 10 muM. It functions as a cell density signal during starvation that allows the cells to sense that a minimal cell density has been reached and development can proceed. The generation of extracellular A signal requires the products of three asg genes. They have recently been identified as AsgA, a fused two-component histidine protein kinase and response regulator; AsgB, a putative DNA-binding protein; and AsgC, the M, xanthus major sigma factor. Other elements of the A signaling pathway map to the sasB locus and appear to be A signal transducers. These elements are regulators of the earliest A signal-dependent gene, whose promoter is a member of the sigma-54 family. Continued study of the A signaling pathway is expected to identify additional components of this network required for the complex behavioural response of fruiting body formation. PMID- 8674995 TI - The O:34-antigen lipopolysaccharide as an adhesin in Aeromonas hydrophila. AB - We compared the ability of different Aeromonas hydrophila strains from serogroup O:34 grown at different temperatures to adhere to Hep-2 cells. We found a high level of adhesion when the strains were grown at 20 degrees C but not when they were grown at 37 degrees C. We previously described that these strains were able to form the O-antigen lipopolysaccharide when they grow at low temperature but not at high temperature. We also obtained by transposon mutagenesis mutants only devoid of the O-antigen lipopolysaccharide (rfb mutants), and they showed significantly lower levels of adhesion to Hep-2 cells than the smooth strains. All these results prompted us to conclude that the O-antigen LPS, in these strains, is an important adhesin. PMID- 8674996 TI - The anatomy of intelligence. AB - In this article, traditional concepts of intelligence are challenged. It is proposed that IQ tests, which largely measure the functioning of the postrolandic cerebrum, are not a good measure of intelligence, which reflects the functioning of the prerolandic cerebrum, especially the prefrontal cortex. Intelligence is defined as an active, transformational process in which sensory data are synthesized into the simplest possible representation for the purpose of maximizing behavioral efficiency. Quantum physics and Eastern psychology are discussed as they are related to intelligence. Intelligence is also investigated from a cultural and neuropsychological perspective. Culture and IQ tests are regarded as inseparable, making culture-free intelligence tests impossible. It is also proposed that intelligent behavior cannot be separated from the influence of paleocerebral functions such as emotions and compulsions. PMID- 8674997 TI - The development of visual preferences in art-trained and non-art-trained schoolchildren. AB - Measures of four dimensions of visual preference (preferences for symmetry, simplicity, uniformity, and expressiveness) and a standardized test of visual arts achievement were administered to art-trained and non-art-trained children in kindergarten, Grade 3, Grade 7, and high school. The art and non-art groups were matched at the school level on family income, English-language and ethnic backgrounds, school attendance, and school neighborhoods. The results showed effects for age and instruction, but the effects for instruction did not increase after Grade 3. The relative independence of the visual-preference dimensions from visual arts learning suggests they may measure individual differences that take shape early in development and are related to visual arts performance. PMID- 8674998 TI - Effect of group status on physical attractiveness preferences--from the Japanese case to a general cognitive perspective. AB - The development of intergroup physical attractiveness preferences and the effect of national status on physical attractiveness judgments were examined. Study 1 reveals that ranking of national status and physical attractiveness are correlated. Study 2 shows that national labels attached to persons affect the ratings of their attractiveness. The results of Study 3 demonstrate that people tend to connect attractive people with nations of higher status. The author suggests that perceptions of national attractiveness derive from a categorization process linking status and appearance, as well as from indigenous dispositions toward certain physical features related to the preference of an ingroup mate. PMID- 8674999 TI - Phylogeny and systematics of 18 Colletotrichum species based on ribosomal DNA spacer sequences. AB - The potential use of the ribosomal DNA internal transcribed spacer (ITS) sequences in understanding the phylogeny and systematics of Colletotrichum species has been evaluated. Sequence data from a limited number of isolates revealed that in Colletotrichum species the ITS 1 region (50.3% variable sites) shows a greater degree of intra- and inter-specific divergence than ITS 2 (12.4% variable sites). Nucleotide sequences of the ITS 1 region from 93 isolates representing 18 Colletotrichum species were determined. Data for 71 of these isolates where molecular and morphological identities concurred were used for phylogenetic analysis. The size of the ITS 1 region varied from 159 to 185 base pairs. Maximum intraspecific divergence was recorded with C. acutatum (5.8%), and C. capsici showed the greatest level of interspecific divergence (8.9-23.3%). Parsimony and distance analyses gave similar tree topologies. The bootstrapped consensus parsimony tree divided the 18 Colletotrichum species into six phylogenetic groups, designated 1-6. These groups, however, are not congruent with species clusterings based on spore shape. For example, the straight cylindrical spored species were represented both in groups 1 and 6; group 6 also included the falcate fusiform spored species C. capsici. The molecular evidence suggests refinement of the species concepts of some of the taxa examined. In group 6, divergence between C. gloeosporioides and C. fuscum (0.6-3.0%) or C. kahawae (0.6-3.0%) or C. fragariae (0.6-4.2%) overlap the divergence (3.6%) within C. gloeosporioides. It is suggested that C. fuscum as well as C. kahawae and C. fragariae fall within the group species C. gloeosporioides. ITS 1 data enabled clear distinction (7.1%) of Colletotrichum isolates from maize and sorghum into C. graminicola and C. sublineolum, respectively (group 2). Species such as C. acutatum, C. coccodes, C. dematium, and C. trichellum can be clearly distinguished based on ITS 1 sequence divergence, but C. destructivum cannot be confidently separated (98% homology) from C. linicola. Colletotrichum dematium f. truncatum is distinct (12.9%) from C. dematium and should probably be called C. truncatum. PMID- 8675000 TI - Directional dominance and a developmental model for the expression of the Tda testis-determining autosomal trait of the mouse. AB - The POSCH-2 Y chromosome from the poschiavinus variety of Mus musculus domesticus causes incomplete testis development in the recessive autosomal background of the C57BL/6J laboratory mouse strain. Testis development is normal with the POSCH-2 Y in its native strain background as well as in some strains of the laboratory mouse such as DBA/2J. The phenotype or expression of XY gonadal hermaphroditism in a C57BL/6J strain, which was constructed to be consomic for the POSCH-2 Y, is a threshold trait in which liability is normally distributed and thresholds in the development of the testis define the probability of observing XY embryos with different combinations of ovaries, ovotestes, and testes. The difference in this testis-determining autosomal or Tda trait between the C57BL/6J and DBA/2J strain pair has been demonstrated to be multigenic. We conducted a survey among different strains of the laboratory mouse by test mating females with C57BL/6J.Y POS males that are consomic for the POSCH-2 Y. We identified five groups of strains with significantly different response of XY gonadal hermaphroditism in their XY-POS F1 test embryos. In test embryos, four groups of strains produced gonadal hermaphroditism with different distributions of the types of gonad that appear to have the same variance or shape of a normally distributed liability, but the means of the distributions are at different locations on a scale of gonadal development. The fifth group of strains produced only tests in the test embryos. Several additional matings produced results suggesting that a model of dominance, in the direction of more complete testis development, could interpret the strain differences. The differences in response to the POSCH-2 Y chromosome among the five groups of strains may represent the phenotypes of the genetic recombinants in the Tda trait that were suggested previously by a segregation analysis between C57BL/6J and DBA/2J. The strains may also provide the tools to further dissect the allelic differences and locus determinants of the Tda trait. PMID- 8675001 TI - Useful DNA polymorphisms are identified by snapback, a midrepetitive element in Tribolium castaneum. AB - The red flour bettle, Tribolium castaneum, is both a pest of stored grain products and an important experimental organism. To improve its facility as a genetic model, we are developing DNA fingerprinting methods for this insect. A Tribolium DNA fragment, snapback-1 (SBI), identified among sequences that reassociate before a Cot of 0.03 mol.s/L, was found to produce a banding pattern in restriction endonuclease digested genomic DNA that is characteristic of a midrepetitive element. DNA fingerprints of individual beetles demonstrated that unvarying inherited DNA polymorphism is revealed, and that polymorphism is inherited in a dominant Mendelian fashion. Linkage between bands was minimal. The sequence of SBI was determined, and hybridization experiments indicated that SBI is a fragment of a larger midrepetitive element. Fingerprinting individuals with known inbreeding coefficients indicated that SBI loci have relatively high mutation rates. The possibility that SBI is a fragment of a transposable element is discussed. PMID- 8675002 TI - Regional and racial specificities in sorghum germplasm assessed with DNA markers. AB - Three different molecular marker technologies were used to determine the relatedness of 84 different lines of sorghum. Both racial characterization and geographical origin were found to be correlated with relatedness. In some cases, the region of origin was the more significant factor, where samples of different races from the same locality were more closely related than were samples of the same race from different localities. Wild sorghums were shown to have few novel alleles, suggesting that they would be poor sources of germplasm diversity. The results also indicated that Chinese sorghums are a narrow and distinctive group that is most closely related to race bicolor. PMID- 8675003 TI - The Afrotropical Drosophila montium subgroup: Balbiani ring 1, polytene chromosomes, and heat shock response of Drosophila vulcana. AB - A detailed photographic map of the salivary gland polytene chromosomes of Drosophila vulcana, an Afrotropical species of the montium subgroup of the melanogaster group, is presented, along with chromosomal rearrangements, such as reverse tandem duplications and inversions, the well-formed Balbiani ring 1, and the most prominent puffs during normal larval and white prepupal development and after ecdysone treatment. In addition, the heat inducible protein and puffing pattern and the loci of the major heat shock genes, namely, hsp70, hsp83, the "small" hsps, and a putative hsp68, of this species were studied. In the light of the data revealed by the above studies, phylogenetic relationship among the montium subgroup species are attempted. PMID- 8675004 TI - A PCR assay for detection of a 2RL.2BS wheat-rye chromosome translocation. AB - A 2RL.2BS wheat-rye translocation, present in the wheat germplasm line Hamlet, carries a gene for resistance to Hessian fly biotype L, one of the most virulent biotypes presently encountered in wheat production environments. Unlike several other wheat-rye chromosome translocations common in wheat breeding programs, 2RL lacks genes encoding storage proteins or other easily selected markers. Oligonucleotide primers synthesized from published sequences derived from the R173 family of moderately repetitive rye DNA were used in the DNA polymerase chain reaction (PCR) to identify specific markers for 2RL. The same primers, when used with DNA extracted from additional wheat-rye translocation lines of importance to the wheat breeding community, gave distinctive PCR products for each genotype. The single primer pair, PAWS5 and PAWS6, may, therefore, have wide applicability for the identification of wheat-rye chromosomal translocations presently encountered in wheat breeding populations. PMID- 8675005 TI - MyoD is required for myogenic stem cell function in adult skeletal muscle. AB - To investigate the function of MyoD in adult skeletal muscle, we interbred MyoD mutant mice with mdx mice, a model for Duchenne and Becker muscular dystrophy. Mice lacking both MyoD and dystrophin displayed a marked increase in severity of myopathy leading to premature death, suggesting a role for MyoD in muscle regeneration. Examination of MyoD mutant muscle revealed elevated numbers of myogenic cells; however, myoblasts derived from these cells displayed normal differentiation potential in vitro. Following injury, MyoD mutant muscle was severely deficient in regenerative ability, and we observed a striking reduction in the in vivo proliferation of myogenic cells during regeneration. Therefore, we propose that the failure of MyoD-deficient muscle to regenerate efficiently is not caused by a reduction in numbers of satellite cells, the stem cells of adult skeletal muscle, but results from an increased propensity for stem-cell self renewal rather than progression through the myogenic program. PMID- 8675006 TI - The c-ros tyrosine kinase receptor controls regionalization and differentiation of epithelial cells in the epididymis. AB - The c-ros gene was originally identified in mutant form as an oncogene. The proto oncogene encodes a tyrosine kinase receptor that is expressed in a small number of epithelial cell types, including those of the epididymis. Targeted mutations of c-ros in the mouse reveal an essential role of the gene in male fertility. Male c-ros -/- animals do not reproduce, whereas the fertility of female animals is not affected. We demonstrate that c-ros is not required in a cell autonomous manner for male germ cell development or function. The gene, therefore, does not affect sperm generation or function in a direct manner. The primary defect in the mutant animals was located in the epididymis, showing that c-ros controls appropriate development of the epithelia, particularly regionalization and terminal differentiation. The epididymal defect does not interfere with production or storage of sperm but, rather, with sperm maturation and the ability of sperm to fertilize in vivo. Interestingly, sperm isolated from c-ros -/- animals can fertilize in vitro. Our results highlight the essential role of the epididymis in male fertility and demonstrate a highly specific function of the c ros receptor tyrosine kinase during development of distinct epithelial cells. PMID- 8675007 TI - Patterning of cells in the Drosophila eye by Lozenge, which shares homologous domains with AML1. AB - The lozenge (lz) gene encodes a transcription factor involved in prepatterning photoreceptor precursors in the developing Drosophila eye. The central region of the predicted Lz protein product is homologous to AML1, a transcription factor associated with human leukemias, and to the Drosophila protein Runt. We show here that Lz plays a crucial role in governing the fate of two groups of cells that are born in a single round of mitosis in the larval eye disc. Lz helps define a subset of these cells as an equipotential group that is competent to respond to the Sevenless developmental signal. This is achieved by negative regulation of seven-up, a member of the steroid hormone receptor superfamily in these cells. In contrast, in a second group of cells, the Lz protein confers proper photoreceptor identity by positively regulating the homeo box gene Bar. Additionally, our genetic analysis suggests that Lz interacts with the Ras pathway to determine photoreceptor cell fate. This study suggests that the strategies involved in cell fate determination in the Drosophila eye are remarkably similar to those utilized during vertebrate hematopoietic development and require the coordinate action of growth factor and AML1-like pathways. PMID- 8675008 TI - RBF, a novel RB-related gene that regulates E2F activity and interacts with cyclin E in Drosophila. AB - Genetic studies have shown that cyclin E and dE2F are critical regulators of S phase entry during Drosophila embryogenesis. Whereas the ectopic expression of cyclin E activates dE2F-dependent transcription, it has been proposed that cyclin E does not act directly on dE2F but targets a negative regulator of E2F activity. Such a regulator might be analogous to the family of RB-related proteins (pRB, p107, and p130) that associate with E2F in humans; however, extensive efforts have failed to find such homologs in Drosophila. We have developed a two-hybrid approach that allows transcription activators to be used as bait for interacting proteins. From a screen using Drosophila E2F (dE2F and dDP) as bait, we identified a novel gene, RBF. RBF combines several of the structural features of pRB, p107, and p130, suggesting that it may have evolved from a common ancestor to the three human genes. RBF associates with dE2F and dDP in vivo and is a stoichiometric component of E2F DNA-binding complexes. RBF specifically repressed E2F-dependent transcription and suppressed the phenotype generated by ectopic expression of dE2F and dDP in the developing Drosophila eye. RBF was phosphorylated by a cyclin E-associated kinase in vitro, and loss-of-function cyclin E mutations enhanced an RBF overexpression phenotype, consistent with the idea that the biological activity of RBF is negatively regulated by endogenous cyclin E. The properties of RBF suggest that it is the intermediary factor that was proposed to allow cyclin E induction of E2F activity. These findings indicate that RBF plays a critical role in the regulation of cell proliferation in Drosophila and show that analogous pathways regulate S-phase entry in a diverse range of species. PMID- 8675009 TI - The XPB and XPD DNA helicases are components of the p53-mediated apoptosis pathway. AB - The molecular pathway of p53-dependent apoptosis (programmed cell death) is poorly understood. Because p53 binds to the basal transcription-repair complex TFIIH and modulates its DNA helicase activities, we hypothesized that TFIIH DNA helicases XPB and XPD are members of the p53-mediated apoptotic pathway. Whereas transfer of a wild-type p53 expression vector by microinjection or retroviral infection into primary normal human fibroblasts resulted in apoptosis, primary fibroblasts from individuals with xeroderma pigmentosum (XP), who are deficient in DNA repair and have germ-line mutations in the XPB or XPD gene, but not in the XPA or XPC gene, have a deficiency in the apoptotic response. This deficiency can be rescued by transferring the wild-type XPB or XPD gene into the corresponding mutant cells. XP-D lymphocytes also have a decreased apoptotic response to DNA damage by adriamycin, indicating a physiologically relevant deficiency. The XP-B or XP-D mutant cells undergo a normal apoptotic response when microinjected with the Ich-L, and ICE genes. Analyses of p53 mutants and the effects of microinjected anti-p53 antibody, Pab421, indicate that the carboxyl terminus of p53 may be required for apoptosis. Direct microinjection of the p53 carboxy terminal-derived peptide (amino acid residues 319-393) resulted in apoptosis of primary normal human fibroblasts. These results disclose a novel pathway of p53 induced apoptosis. PMID- 8675010 TI - A protein that shuttles between the nucleus and the cytoplasm is an important mediator of RNA export. AB - The connection between RNA and protein export from the nucleus was examined in the budding yeast Saccharomyces cerevisiae. NPL3 encodes an RNA-binding protein that shuttles in and out of the nucleus. Export of poly(A)+ RNA has been shown previously to be blocked in np13-1 mutants. To understand the role of Np13p in RNA export, we have developed a novel assay that effectively uncouples nuclear protein export from reimport. With this assay, we show that Np13p satisfies several of the predicted requirements for a protein carrier for mRNA export. Temperature-sensitive mutations in the RNA recognition motifs of Np13p result in nuclear accumulation of poly(A)+ RNA. One such mutation prevents nuclear export of Np13p. Moreover, Np13p export depends on ongoing RNA polymerase II transcription. Export ceases in either the presence of the RNA synthesis inhibitor thiolutin or in a temperature-sensitive RNA polymerase (rpb1) mutant. Together, these findings support a model in which Np13p exits the nucleus in association with poly(A)+ RNA, deposits the RNA in the cytoplasm, and is rapidly reimported for another cycle of export. PMID- 8675011 TI - Repression domain of the yeast global repressor Tup1 interacts directly with histones H3 and H4. AB - Repression of yeast a cell-specific genes by the global repressor Ssn6/Tup1 has been linked to a specific organization of chromatin. We report here that Tup1 directly interacts with the amino-terminal tails of histones H3 and H4, providing a molecular basis for this connection. This interaction appears to be required for Tup1 function because amino-terminal mutations in H3 and H4 that weaken interactions with Tup1 cause derepression of both a cell-specific and DNA damage inducible genes. Moreover, the Tup1 histone-binding domain coincides with the previously defined Tup1 repression domain. Tup1/histone interactions are negatively influenced by high levels of histone acetylation, suggesting a mechanism whereby the organization of chromatin may be modulated in response to changing environmental signals. PMID- 8675012 TI - Promoter specificity mediates the independent regulation of neighboring genes. AB - Although enhancers can exert their influence over great distances, their effect is generally limited to a single gene. To discern the mechanism by which this constraint can he mediated, we have studied three neighboring Drosophila genes: decapentaplegic (dpp), SLY1 homologous (Slh) and out at first (oaf). Several dpp enhancers are positioned close to Slh and oaf, and yet these genes are unaffected by the dpp elements. However, when a transposon is located within the oaf gene, the dpp enhancers activate the more distant transposon promoters while still ignoring the closer Slh and oaf start sites. To test whether this promoter specificity accounts for the regulatory autonomy normally found for the three genes, we used in vivo gene targeting to replace the oaf promoter with a dpp compatible one in an otherwise normal chromosome. Strikingly, this chimeric gene is now activated by the dpp enhancers. Thus, the properties of the promoters themselves are sufficient to mediate the autonomous regulation of genes in this region. PMID- 8675013 TI - Intracellular receptors use a common mechanism to interpret signaling information at response elements. AB - The glucocorticoid receptor (GR) activates transcription in certain glucocorticoid response element (GRE) contexts, and represses or displays no activity in others. We isolated point mutations in one GRE, plfG, at which GR activated transcription under conditions in which the wild-type element was inactive or conferred repression, implying that GREs may carry signals that are interpreted by bound receptors. Consistent with this notion, we identified a mutant rat GR, K461A, which activated transcription in all GRE contexts tested, implying that this residue is important in interpretation of GRE signals. In a yeast screen of 60,000 GR mutants for strong activation from plfG, all 13 mutants isolated contained substitutions at K461. This lysine residue is highly conserved in the zinc-binding region (ZBR) of the intracellular receptor (IR) superfamily; when it was mutated in MR and RARbeta, the resulting receptors similarly activated transcription at response elements that their wild-type counterparts repressed or were inactive. We suggest that IR response elements serve in part as signaling components, and that a critical lysine residue serves as an allosteric "lock" that restricts IRs to inactive or repressing configurations except in response element contexts that signal their conversion to transcriptional activators. Therefore, mutation of this residue produces altered receptors that activate in many or all response element contexts. PMID- 8675014 TI - Ptx1, a bicoid-related homeo box transcription factor involved in transcription of the pro-opiomelanocortin gene. AB - The pituitary gland contains six distinct hormone-producing cell types that arise sequentially during organogenesis. The first cells to differentiate are those that express the pro-opiomelanocortin (POMC) gene in the anterior pituitary lobe. The other lineages, which appear later, include cells that are dependent on the POU factor Pit-1 and another POMC-expressing lineage in the intermediate pituitary lobe. Using AtT-20 cells as a model for early expression of POMC in the anterior pituitary, we have defined a regulatory element conferring cell specificity of transcription and cloned a cognate transcription factor. This factor, Ptx1 (pituitary homeo box 1), contains a homeo box related to those of the anterior-specific genes bicoid and orthodenticle in Drosophila, and Otx-1 and Otx-2 in mammals. Ptx1 activates transcription upon binding a sequence related to the Drosophila bicoid target sites. Ptx1 is the only nuclear factor of this DNA binding specificity that is detected in AtT-20 cells, and it is expressed at high levels in a subset of adult anterior pituitary cells that express POMC. However, Ptx1 is expressed in most cells of Rathke's pouch at an early time during pituitary development and before final differentiation of hormone-producing cells. Thus, Ptx1 may have a role in differentiation of pituitary cells, and its early expression pattern suggests that it may have a role in pituitary formation. In the adult pituitary gland, Ptx1 appears to be recruited for cell-specific transcription of the POMC gene. PMID- 8675015 TI - Identification of a biologically significant DNA-binding peptide motif by use of a random phage display library. AB - A peptide library approach was used to identify peptides that could bind to different DNA structures. A 23-mer random peptide library was displayed in the context of the pIII protein of M13 filamentous phage. Double-stranded (ds) oligodeoxyribonucleotides (oligos) were immobilized in 96-well plates using either chemical conjugation or a biotin-avidin linking method. Individual phage clones capable of binding to immobilized oligos were selected from the phage library. Using a plaque dilution assay for rapid screening of binding preferences, four groups of oligo-binding (OB) phage were tentatively identified as showing preference for: (1) single-stranded (ss) oligos irrespective of sequence; (2) ds oligos irrespective of sequence; (3) sequence-specific binding to ss oligos; and (4) weak non-specific binding to all types of oligos tested. A quantitative solution-phase competition assay was used to confirm the ability of certain phage to discriminate ss from ds oligos. A consensus motif, FGRA, was found in those phage clones that preferentially bound ss oligos; this motif has previously been noted in the binding domains of several ribonucleoproteins and ss DNA-binding proteins. Peptides based on the FGRA motif, but not scrambled controls, were able to inhibit the binding of appropriate phage clones or of Escherichia coli ss DNA-binding protein to oligos. This suggests that amino acid sequences that are capable of affecting biologically significant protein-DNA interactions can be identified from random peptide libraries using phage display techniques. PMID- 8675016 TI - Cloning, sequencing and expression of the uvrA gene from an extremely thermophilic bacterium, Thermus thermophilus HB8. AB - One of the most important DNA repair systems is the nucleotide (nt) excision repair system. The uvr A gene, which plays an essential role in the prokaryotic excision repair system, was cloned from an extremely thermophilic eubacterium, Thermus thermophilus (Tt) HB8, and its nt sequence was determined. In the amino acid (aa) sequence of Tt UvrA, a characteristic duplicated structure, two nt binding consensus sequences (Walker's A-type motif) and two zinc finger DNA binding motifs were found. The aa sequence showed 73% homology with that of Escherichia coli (Ec). These features suggest that Tt has the same excision repair system as Ec. Upon comparison of the Tt and Ec UvrA, some characteristic aa substitutions were found. The numbers of Arg and Pro residues were increased (from 66 to 81 and from 47 to 55, respectively), and the numbers of Asn and Met residues were decreased (from 33 to 18 and from 18 to 11, respectively) in Tt. The Tt uvr A gene was expressed in Ec under control of the lac promoter. Purified UvrA was stable up to 80 degrees C (at neutral pH) and at pH 2-11 (at 25 degrees C). PMID- 8675017 TI - Structural and functional conservation of human and yeast HCP1 genes which can suppress the growth defect of the Saccharomyces cerevisiae ire15 mutant. AB - The Saccharomyces cerevisiae ire15 mutant has a defect in the expression of the IN01 gene, showing an inositol auxotrophic phenotype. The growth defect of this mutant is suppressed by human cDNAs such as for the TGF-beta receptor-encoding gene (TGFR) [Nikawa, Gene 149 (1994) 367-372]. Here, we isolated a new human cDNA, HCP1, which suppresses the ire15 mutation by genetic complementation. Sequencing analysis revealed that HCP1 encodes 360 amino acid residues (40,515 Da). The product of HCP1 is highly conserved among species and the yeast homolog was also found to suppress the ire15 mutation. Northern blot analysis revealed that multicopies of the yeast and human HCP1, as well as TGFR, resulted in an increase in the IN01 mRNA level in the yeast mutant. These results clearly indicate that the products of human and yeast HCP1 are structural and functional homologs, and are involved in expression of genes such as of IN01. PMID- 8675018 TI - Cloning of the gene encoding the mitochondrial adenine nucleotide carrier of Schizosaccharomyces pombe by functional complementation in Saccharomyces cerevisiae. AB - We describe the isolation and sequencing of both cDNA and genomic clones encoding the mitochondrial ADP/ATP carrier (Anc) of Schizosaccharomyces pombe (Sp). The cDNA clone was isolated from a cDNA library of this fission yeast by complementation of a Saccharomyces cerevisiae (Sc) strain defective in adenine nucleotide carrier. The predicted amino acid (aa) sequence (322 aa) shared similarity with the known Anc sequences. It is more closely related to Neurospora crassa (Nc) Anc than to ScAnc1, 2, or 3 or Kluyveromyces lactis (Kl) Anc. Hybridization experiments with ordered libraries of Sp genomic DNA led to the physical mapping (chromosome II, NotI-B region) and the isolation of the Sp ANC1 gene. We also conclude that a single-copy gene encodes the Sp Anc. PMID- 8675019 TI - Amiloride toxicity in the fission yeast Schizosaccharomyces pombe is released by thiamine and mutations in the thiamine-repressible gene car1. AB - Amiloride (Am) inhibits growth in the fission yeast Schizosaccharomyces pombe. We show that the toxic effect of this drug is relieved by low concentrations of thiamine (Th) and that the pyrimidine moiety of the Th molecule is responsible for growth inhibition release. A putative membrane protein encoded by the car1 gene is the target for Am action. It is responsible for Am sensitivity and is involved in the utilization of Th and its biosynthetic precursor, 4-amino-5 hydroxymethyl-2-methylpyrimidine. Its expression is repressed by Th and is under the genetic control of the genes, thi1, tnr1, tnr2 and tnr3, which have previously been shown to be responsible for the transcriptional control of genes involved in the biosynthesis and dephosphorylation of Th. PMID- 8675020 TI - Isolation and characterization of a cDNA from Trichoderma harzianum P1 encoding a 14-3-3 protein homolog. AB - A full-length cDNA close, Th1433, (GenBank accession No. U24158), was isolated and characterized from the filamentous fungus, Trichoderma harzianum. The deduced amino acid (aa) sequence showed an acidic 30-kDa protein homologous to the 14-3-3 proteins, a family of putative kinase regulators originally characterized in mammalian brain tissue. The greatest homology, 71% identical aa, was found to BMH1, the corresponding protein from Saccharomyces cerevisiae and to the epsilon isoform from sheep brain. Southern analysis of genomic DNA indicated that Th1433 is a member of a small genomic family. At least two genes encoding 14-3-3-like proteins exist in T. harzianum. Northern analysis showed the highest level of expression during the first day after inoculation of the culture with conidial spores. PMID- 8675021 TI - EcoRI variant N199H has enhanced specific activity. AB - The Asn199 residue of the EcoRI restriction endonuclease has been replaced with other amino acids to investigate whether it mediates nucleotide recognition or catalytic activity. Cassette mutagenesis gave variants of EcoRI: N199D, N199H, N199L, N199R, N199S and N199V. Their relative cleavage rates were found to be in the following order: N199H > EcoRI (wild type; wt) > N199L > N199V > N199S > N199R > N199D. In particular, EcoRI variant N199H showed about a twofold higher specific activity than that of the wt enzyme. PMID- 8675022 TI - Sequences of the Salmonella typhimurium mglA and mglC genes. AB - The nucleotide sequences of the mglA and mglC genes of Salmonella typhimurium (St) LT2 have been determined. The deduced amino acid (aa) sequences of MglA and MglC are 506 and 302 aa long with predicted molecular masses of 56,484 and 31,551 Da, respectively. The aa sequences of St MglA and MglC are homologous to the corresponding Mgl proteins of Escherichia coli, Haemophilus influenzae, Treponema pallidum and Mycoplasma genitalium. The order of the St mgl operon is mglBAC. PMID- 8675023 TI - Plasmids with erythromycin resistance and catechol 2,3-dioxygenase- or beta galactosidase-encoding gene cassettes for use in Neisseria spp. AB - Four new plasmids containing the ermC' (encoding a methyltransferase which confers resistance to erythromycin), xylE-ermC' (xylE, encoding catechol 2,3 dioxygenase) and lacZ-ermC' cassettes have been constructed. The 10-bp gonococcal uptake sequence has been placed downstream from ermC' to facilitate the delivery of these cassettes into pathogenic Neisseria spp. Several restriction sites have been placed to flank the cassettes to allow their excision and directional cloning. These plasmids will provide valuable tools for constructing insertional mutants and transcriptional fusions in Neisseria spp. or other bacteria. PMID- 8675024 TI - Gene organization in the ada-rplL region of Streptomyces virginiae. AB - The gene organization of a 7.4-kb region of the Streptomyces virginiae (Sv) chromosome was determined. The predicted open reading frames (ORFs) and their predicted products, in sequence order, were (i) ada, encoding adenosine deaminase [EC 3.5.4.4], (ii) aat, encoding a protein homologous to aspartate aminotransferase [EC 2.6.1.1], (iii) secE, encoding a protein involved in protein secretion, (iv) vbrA, encoding a NusG-like protein involved in antitermination of transcription as described by Okamoto et al. [J. Biol. Chem. 267 (1992) 1093 1098], and (v) rplKAJL, encoding the large subunits of the ribosomal proteins L11, L1, L10 and L12. Six of the ORFs (secE-rplL) were oriented in the same direction, but the other two (ada and aat) had the opposite orientation. The gene organization of the secE-rplL region in Sv was identical to that in Escherichia coli. PMID- 8675025 TI - Sequence analysis and characterization of the hmw gene cluster of Mycoplasma pneumoniae. AB - Mycoplasma pneumoniae (Mp) cytadherence requires the proper anchoring of cytadhesin proteins in the mycoplasmal membrane at an attachment organelle through their interaction with a cytoskeleton-like network of accessory proteins that includes HMW1 and HMW3. Approximately 8.25 kb of Mp DNA was sequenced, beginning at the 3' end of the hmw3 gene and continuing through hmw1. Comparison of the resulting deduced amino acid (aa) sequence with N terminus and internal peptide aa sequences from purified HMW1 permitted definitive identification of hmw1. HMW1 was characterized with respect to structure, hydrophobicity, possible phosphoacceptor sites and expression of the Mp recombinant protein in Escherichia coli. In addition, HMW1 membrane topography was examined for antibody accessibility on the mycoplasmal surface. hmw3 and hmw1 flank four open reading frames (ORFs) spanning approximately 4.3 kb and in the same orientation as the hmw genes. The sequences of their deduced products were evaluated for likely structural features and comparison with protein data banks. Finally, the Mp rpsD analog was identified immediately downstream from hmw1. PMID- 8675026 TI - A novel cross-phylum family of proteins comprises a KRR1 (YCL059c) gene which is essential for viability of Saccharomyces cerevisiae cells. AB - We demonstrate here that the open reading frame (ORF) YCL059c, discovered during the systematic sequencing of chromosome III [Oliver et al., Nature 357 (1992) 38 46], codes for a protein essential for yeast: neither spore germination nor cell division occur in strains deleted for this gene. We have cloned the wild-type (wt) gene and shown that it complements the deletion. A relatively abundant RNA transcript corresponds to the gene. The protein has no similarity to proteins of known function. Interestingly, however, it is homologous to several expressed sequence tags (EST) of unknown function from Caenorhabditis elegans, Oryza sativa and Homo sapiens. Thus, a novel family of proteins of presumably nuclear localization, with a characteristic highly basic motif, KRR-R, transcends various phyla, and plays an important role in cellular processes. We propose to call this essential gene KRR1. PMID- 8675027 TI - A new Saccharomyces cerevisiae ankyrin repeat-encoding gene required for a normal rate of cell proliferation. AB - We have characterized a new ankyrin (ANK) repeat-containing Saccharomyces cerevisiae gene, YAR1, located between the HSP82 and SUI3 genes on chromosome XVI. YAR1 encodes a 200-amino-acid (aa) protein with two ANK repeat motifs and an acidic C terminus rich in PEST-like sequences. The Yar1 ANK repeats are most similar to the conserved ANK repeats in the yeast cell cycle transcription factor, Swi6. We show that YAR1 is transcribed as an 800-nucleotide (nt) poly(A)+ mRNA from a promoter lacking a consensus TATA sequence. YAR1 is transcribed in both haploid and diploid cells, and in haploid cells arrested in G1 with alpha factor or in S phase with hydroxyurea. YAR1 shares an intergenic region with HSP82, and while HSP82 transcription is induced 15-fold by heat shock, transcription of YAR1 is transiently repressed by heat shock. We show that YAR1 is not an essential gene, but that haploid cells bearing a yar1 deletion grow significantly more slowly than do isogenic wild-type cells, especially at low temperature. PMID- 8675028 TI - A putative new membrane protein, Pho86p, in the inorganic phosphate uptake system of Saccharomyces cerevisiae. AB - The PHO84 gene in Saccharomyces cerevisiae encodes the P(i) transporter Pho84p. The other three genes, GTR1, PHO86 and PHO87, are also suggested to be involved in the P(i) uptake system. We cloned and sequenced PHO86 and found that it encodes a 34-kDa protein consisting of 311 amino acid residues with two strongly hydrophobic segments in its N-terminal half. Western blotting analysis of cell extracts revealed that Pho86p, tagged with c-Myc, was fractionated into a water insoluble fraction. Disruption of PHO86 did not affect cell viability even in combination with the pho84 and/or pho87 disruptions. The triple disruptants showed high levels of constitutive rAPase synthesis and arsenate resistance similar to the pho84 mutant, but showed slower cell growth than the pho84 mutant. PHO86 has two putative binding sites for the transcriptional activator, Pho4p, at nucleotide positions -191 and -497 relative to the ATG start codon, and showed substantial levels of transcription under high-P(i) conditions and more enhanced levels in low-P(i) medium. PMID- 8675029 TI - New vectors for peptide display on the surface of filamentous bacteriophage. AB - We have modified the genome of the filamentous bacteriophage fd and also constructed a number of new vectors for the purpose of displaying peptides on the surface of the virion. These vectors facilitate the directional cloning of DNA encoding a peptide of interest at or near the N terminus of the major coat protein, the product of the bacteriophage gene VIII, and the construction of hybrid capsids in which the modified coat protein is interspersed with wild-type coat protein subunits. PMID- 8675030 TI - Location and sequence analysis of a 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoate hydrolase-encoding gene (bpdF) of the biphenyl/polychlorinated biphenyl degradation pathway in Rhodococcus sp. M5. AB - The 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoate (HOPD) hydrolase-encoding gene (bpdF) in the biphenyl (BP)/polychlorinated biphenyl (PCB)-degrading bacterium, Rhodococcus sp. M5 (M5), was found to be located within a 4.5-kb HindIII-BamHI genomic DNA that was 5.4 kb downstream from the bpdC1C2BADE gene cluster. The deduced amino acid (aa) sequence of bpdF revealed that the hydrolase contains 297 aa (32679 Da) that was verified by expression in the Escherichia coli T7 RNA polymerase/promoter system. Unlike previously known HOPD hydrolases, the aa sequence of BpdF appears unique. Interestingly, all HOPD hydrolases and related proteins from the phenol and toluene/xylene degradation pathways, were found to have a bias in the codon usage in the catalytic Ser within the conserved VGNS(M/F)GG motif. PMID- 8675031 TI - Cloning, sequence and expression in Escherichia coli of the gene encoding phosphofructokinase from Bacillus macquariensis. AB - A chromosomal DNA fragment containing the Bacillus macquariensis (Bm) ATP dependent phosphofructokinase-encoding gene (pfk) was cloned from a subgenomic library in pUC19 using a PCR-derived probe. The region containing pfk, including flanking sequences, was sequenced and the deduced amino acid sequence (aa) was found to be homologous to other PFK, but it contained two single-aa changes conserved in a range of other organisms from pro- and eukaryotic origins. Enzymatic studies with PFK purified from overproducing Escherichia coli (Ec) host cells showed that the Bm enzyme is similar to B. stearothermophilus (Bs) PFK in many respects and that it is relatively cold stable. PMID- 8675033 TI - pUCS75, a stable high-copy-number Streptomyces--Escherichia coli shuttle vector which facilitates subcloning from pUC plasmid and M13 phage vectors. AB - A new Streptomyces-Escherichia coli shuttle vector, pUCS75, has been constructed to permit facile subcloning of DNA from the multiple cloning sites of the pUC plasmid and M13 phage vectors. In contrast to other commonly used shuttle vectors, pUCS75 retains the primary site for second-strand synthesis (ssi) of the parental streptomycete replicon, pIJ101. This sequence can not only enhance structural stability of the plasmid, but also confers on it an elevated copy number when replicated in Streptomyces. Consequently, the vector is useful for cloning sequences containing repeat structures and for allowing the high-level expression of cloned genes. PMID- 8675032 TI - Identification of an amino acid signature sequence predictive of protein G inhibitable IgG3-binding activity in group-A streptococcal IgG-binding proteins. AB - Sequence comparison of six known group-A streptococcal IgG-binding proteins, sharing the common property of protein G-inhibitable IgG3-binding-activity, identified a highly conserved 35-amino-acid (aa) sequence (74-100% similarity) within an EQ-rich central conserved core region of each protein. A search of aa sequence databases identified four additional proteins with > 50% similarity to this consensus sequence. All of these proteins demonstrated protein G-inhibitable IgG3-binding activity. Taken together, these results identify a signature sequence that predicts the presence of a protein G-inhibitable IgG3-binding domain(s) in group-A streptococcal IgG-binding proteins. PMID- 8675034 TI - Identification of bldA mutants of Streptomyces griseus. AB - The bldA gene (encoding tRNA(UUA)Leu) from Streptomyces griseus (Sg) was cloned by hybridization with bldA from Streptomyces coelicolor (Sc). Introduction of Sg bldA into Sc bldA mutants restored sporulation and actinorhodin production. Sporulation of a subset of Sg bald mutants, which produce no aerial mycelium or spores, was restored in the presence of bldA from Sc or Sg. The nucleotide sequences of the bldA alleles from two such bald mutants revealed point mutations in the anticodon stem and the T psi C stem. PMID- 8675035 TI - The P200 protein of Mycoplasma pneumoniae shows common features with the cytadherence-associated proteins HMW1 and HMW3. AB - The gene coding for the P200 protein of the bacterium, Mycoplasma pneumoniae (Mp), was cloned and sequenced. The sequence-derived data and biochemical data indicated that P200 has several features in common with the well characterized cytadherence-associated proteins, HMW1 and HMW3. These features consist of abnormal migration in SDS-PAGE, a central acidic domain with a high Pro content, repeated peptide blocks within the Pro-rich domain and P200 partitioning similar to HMW1 and HMW3 in the insoluble fraction after extraction of Mp with the detergent Triton X-100. PMID- 8675036 TI - Phylogeny based on elongation factor Tu reflects the phenotypic features of mycoplasmas better than that based on 16S rRNA. AB - A universal phylogenetic tree of organisms from all kingdoms was constructed by the use of elongation factor Tu (EF-Tu) as the marker molecule. As in the 16S ribosomal RNA (16S rRNA)-based phylogeny, the EF-Tu tree divides eukaryotes, archaebacteria, and prokaryotes into three main branches. Furthermore, the EF-Tu based tree shows, in contrast to the 16S rRNA tree, some interesting evolutionary relationships between mycoplasmas, better reflecting phenotypic features of these organisms. PMID- 8675037 TI - The s29x gene of symbiotic bacteria in Amoeba proteus with a novel promoter. AB - Gram-symbiotic bacteria (called X-bacteria), present in the xD strain of Amoeba proteus as required cell components, synthesize and export a large amount of a 29 kDa protein, S29x. S29x is exported into the host's cytoplasm across the bacterial membranes and the symbiosome membrane. The complete nucleotide (nt) sequence of the s29x gene of X-bacteria has been determined, and the promoter sequence and tsp have also been identified. The gene has a nonconventional promoter with putative nt sequences different from the known consensus sequences. When Escherichia coli cells are transformed with s29x, the gene is expressed and the product is secreted into the culture medium. Functions of S29x are not fully known, but it is suspected that S29x plays an important role in the symbiotic relationship between amoebae and X-bacteria. PMID- 8675038 TI - Mobilization of vancomycin resistance by transposon-mediated fusion of a VanA plasmid with an Enterococcus faecium sex pheromone-response plasmid. AB - A striking feature of recent outbreaks of vancomycin-resistant (VmR) enterococci is the apparent horizontal dissemination of resistance determinants. The plasmids pHKK702 and pHKK703 from Enterococcus faecium clinical isolate R7 have been implicated in the conjugal transfer of VmR. pHKK702 is a 41-kb plasmid that contains an element indistinguishable from the glycopeptide-resistance transposon Tn1546. pHKK703 is an approx. 55-kb putative sex pheromone-response plasmid that is required for conjugative mobilization of pHKK702. During experiments in which strain R7 was used as a donor, a highly conjugative VmR transconjugant was isolated that formed constitutive cellular aggregates. Restriction analyses and DNA hybridizations revealed that the transconjugant harbored a single plasmid of approx. 92 kb and this plasmid (pHKK701) was composed of DNA from both pHKK702 and pHKK703. Results from DNA sequence analyses showed that a 39-kb composite transposon (Tn5506) from pHKK702 had inserted into pHKK703. The left end of Tn5506 contained a single insertion sequence (IS) element, IS1216V2, whereas the right end was composed of a tandem IS structure consisting of the novel 1065-bp IS1252 nested within an IS1216V1 element. Transposition of Tn5506 from pHKK702 to pHKK703 created an 8-bp target sequence duplication at the site of insertion and interrupted an ORF (ORFX) that was 91% identical to that of prgX, a gene proposed to negatively regulate sex pheromone response of the E.faecalis plasmid, pCF10. We propose that the interruption of ORFX by Tn5506 led to the constitutive cellular aggregation phenotype and thereby enhanced the efficiency with which VmR was transferred. Similar IS1216V-mediated transposition events may contribute to the horizontal spread of glycopeptide resistance among enterococci in nature. PMID- 8675039 TI - The unique organization of the rpoB region of Spiroplasma citri: a restriction and modification system gene is adjacent to rpoB. AB - A 6.5-kb DNA fragment containing the gene (rpoB) encoding the RNA polymerase (RNAP) beta subunit, from the mollicute Spiroplasma citri (Sc), was cloned and sequenced. The classical eubacterial organization, with the genes (rplK, A, J and L) encoding ribosomal proteins L11, L1, L10 and L12 located immediately upstream from rpoB, was not found in the Sc DNA. Instead, an open reading frame (hsdS) potentially encoding a component of a type I restriction and modification system was identified upstream from rpoB, and sequences showing similarities with insertion elements were found between hsdS and rpoB. PMID- 8675040 TI - Cloning and sequencing of a gene encoding a new member of the tetratricopeptide protein family from magnetosomes of Magnetospirillum magnetotacticum. AB - A gene encoding the 22 kDa protein (MAM22) which was localized in the magnetosomes isolated from the magnetotactic bacterium, Magnetospirillum magnetotacticum, was cloned and sequenced. MAM22 was composed of 220 amino acids (aa) with a molecular weight of 24,186 Da. The deduced aa sequence exhibited significant homology with a number of proteins that belong to the tetratricopeptide repeat (TPR) protein family, including mitochondrial protein import receptors and peroxisomal protein import receptors. The presence of three repeats of a degenerate 34-aa consensus sequence, suggest that MAM22 localized in magnetosome membranes may interact with the cytoplasmic proteins containing similar TPR motifs. PMID- 8675042 TI - End-of-life care: 'merit' of suffering questioned by reader. PMID- 8675041 TI - The dangers of physician-assisted suicide. Will we choose to provide a right to euthanasia for the few or palliative care for the many? PMID- 8675043 TI - Nursing home reviews can be frustrating to dedicated staff. PMID- 8675044 TI - Which came first: the itch or the rash? Patient's scratching may be unrelated to a primary skin disease. PMID- 8675045 TI - Perils of polypharmacy: 10 steps to prudent prescribing. AB - A focused, systematic intervention by the primary care physician can often remedy the problem of polypharmacy in older patients. Such an approach includes medication disclosure, drug identification, side effect recognition, treatment review, and a thoughtful, well-monitored reduction in the numbers and doses of medicines. By developing skillful prescribing habits, the physician can resolve drug side effects, prevent future adverse reactions, reduce pharmacy expenditures, and improve medication compliance. Prudent prescribing is one way to improve quality of life for the older patient. PMID- 8675046 TI - The older driver: a handy tool to assess competence behind the wheel. AB - Predicting with certainty which older patient will have driving problems is not possible, as standardized guidelines do not exist. In the absence of guidelines, the mnemonic SAFE DRIVE outlined in this article can help you identify important risk factors for unsafe driving. Risk factors included in SAFE DRIVE are problems with vision and reaction time, intellectual impairment, a poor safety record, alcohol abuse, use of certain medications, poor attentional skills, impaired executive functions, and a family report of driving problems. Most of these factors can be identified with a careful history, physical examination, in-office tests of cognitive function and alcohol use, and an interview with family member(s). PMID- 8675047 TI - Coping with stress: a physician's guide to mental health in aging. AB - The mental and emotional health of people of all ages is related to how well they cope with or adapt to the stresses and changes in their lives. Although risks to health do increase with advancing age, stress is not an inevitable consequence of old age. However, two transitional stressors that are more common with increased age are the onset of illness and/or physical impairment and the death of loved ones. As recently as 1987, less than 1.5% of community-based mental health care went to persons over age 65. The elderly consistently report that when they do seek help with emotional problems, they first consult with their primary care physicians. Therefore, these physicians need to be knowledgeable about mental health in aging and familiar with mental health services their patients could use. PMID- 8675048 TI - [Hygienic assessment of dust and gas factors at the enterprises using phosphoric acid production wastes]. AB - The process of phosphor-gyps is associated with the pollution of the working environment by aerosols containing Ca, Fe, Si, P, fluorides, and other substances. Sanitary measures for the working environment and studies of the aerosol effects on human health are proposed. PMID- 8675049 TI - [Organization, structure and rationalization of nutrition of school children in Syktyvkar]. AB - The characteristics of Syktyvkar schoolchildren' diets were studied. The specific features of their alimentary status were used to improve children nutrition. PMID- 8675050 TI - [Relationship between physical development and the immune status of children and adolescents]. AB - The paper gives the data from studies of the physical development, health status, and immunity of 6- and 11-year-old children and 15-year-old adolescents. Correlations between the physical development and immune status of children and adolescents were studied. Negative immunological changes were more profound in children with severe physical developmental abnormalities. PMID- 8675051 TI - [Automated information system for controlling the sociopsychological adaptation of junior grade schoolchildren during learning activities]. AB - An automatic information system (AIS) was developed to assess the mental status and sociopsychological adaptation of junior schoolchildren. AIS contains functional units for automatic testing, assessment, individual and group analysis of the schoolchildren's status. PMID- 8675052 TI - [Study of risk factors of enterobiasis in schoolchildren and development of a prognostic table for primary screening]. AB - Risk factors for enterobiasis were qualitatively and quantitatively assessed by a questionnaire given to 277 health schoolchildren and 277 schoolchildren who suffered from enterobiasis. A prognostic table was developed for primary screening of risk groups. Preventive measures are recommended in the paper. PMID- 8675053 TI - [Hygienic standardization of the length of children's work using personal computers]. PMID- 8675054 TI - [Assessment of radioactive irradiation of Kamensk-Uralski inhabitants and its impact on their descendants' health]. AB - The radioactive radiation of the inhabitants of the town of Kamensk-Uralsky, Sverdlovsk Region, was studied for its impact on the health of their descendants. The radiation of parents was found to be a risk factor for increasing the high incidence of frequent respiratory diseases of their children. The dietary deficiency of vitamins in children and other factors are also causes of frequent respiratory diseases. PMID- 8675055 TI - [Hygienic regulation of combined effects of a complex mixture of sulfurous anhydride, hydrogen fluoride and nitrogen dioxide in the environmental air]. PMID- 8675056 TI - [Comparative hazards of polychlorinated biphenyls and their substitutes by the indicators of material and functional accumulation]. PMID- 8675057 TI - [A mathematical model of mercury metabolism in the human body]. PMID- 8675058 TI - [Use of antimicrobial materials containing sangviritrin in the prevention of nosocomial infections]. PMID- 8675059 TI - [Blood content of lead and cadmium in adults of the City of Chansha, People's Republic of China]. PMID- 8675060 TI - [Physiological and hygienic problems of the implementation of the U.N. Convention on Child's Rights (the 5th anniversary of Russia's joining the Convention)]. PMID- 8675062 TI - [Providing the Sverdlovsk Region population with good-quality drinking water]. PMID- 8675061 TI - [History of the establishment and development of the Department of Child and Adolescent Health, Russian Medical Academy of Postgraduate Training]. PMID- 8675063 TI - [A conceptual model of students' health promotion at a Teaching Institute]. PMID- 8675064 TI - [Assessment of bottom sediments of the Uriup River in the area of open coal pit sewage accumulation]. AB - The levels of greater than 20 chemicals were determined in the bottom sediments of the Uryup river. The characteristics of bottom river sediments before and after sewage accumulator outlet were compared. No negative changes in the chemical sediments in the river were revealed. PMID- 8675065 TI - [Methods of drinking water conservation in autonomous objects (review)]. AB - The purpose of this study was to analyse literature on the use of different methods for conserving the quality of drinking water in autonomous objects. The analysis showed that the use of silver ions, impulsive electric discharges and their combinations are the best methods for conservation of water. It is necessary to make further research to develop new methods for drinking-water conservation. PMID- 8675066 TI - [Levels of serotonin in plasma and activity of monoamine oxidase in serum and blood platelets of women with EPH gestosis]. AB - The study was performed on 70 pregnant women, divided into two groups: normal or EPH gestosis. The concentration of serotonin in plasma was determined according to Manuchin et al., the activity of monoamine oxidase was determined using the radioisotope method of Yuodim. Daily urinary excretion of 5-hydroxyindoleacetic acid was established with the method of Udenfriend et al. It was found that women with EPH gestosis have significantly higher (p < 0.01) plasma concentration of serotonin and significantly lower activities of MAO (p < 0.001) in serum and in blood platelets and urinary excretion of 5-hydroxyindoleacetic acid (p < 0.05) than normal pregnant women. PMID- 8675067 TI - [Comparison of mortality and morbidity in newborns treated with ambroxol prenatally and postnatally]. AB - The effect of Ambroksol given pre- and postnatal on infant mortality and morbidity was performed. In particular we found a statistically significant differences in reduction of mortality in the group A treated with Ambroksol pre- and postnatal vs. group B treated only postnatal. The other parameters of morbidity had no significantly importance but sepsis, which was more often diagnosed in group A than in group B (17.5% vs. 11.1%). We connect this fact with higher frequency of PROM in the group A. PMID- 8675068 TI - [Evaluation of peritoneal fluid in women with endometriosis]. AB - An analysis of the peritoneal fluid in women with endometriosis was undertaken. Peritoneal fluid was collected during laparoscopy from the Douglas pouch. The quantity, color of the fluid as well as macrophages number, concentration and activity were assessed. Conclusion is that no one of the listed parameters of peritoneal fluid could be considered as an endometriosis marker. PMID- 8675070 TI - [Fibronectin gene expression in preneoplastic states and female genital neoplasms]. AB - In this paper the fibronectin gene expression level (Northern blotting) in 33 endometrial samples (residua post abortum, endometrium proliferativum, secretivum and involutivum, hyperplasia glandularis endometrii, adenocarcinoma endometrii) was measured and compared. Higher level of fibronectin gene expression level in endometrial hyperplasia and carcinoma than in other endometrial samples was found. Strong correlation between high fibronectin gene expression level in endometrial hyperplasia and carcinoma was found. PMID- 8675069 TI - [Evaluation of endometrial changes in women with cyclical mastalgia]. AB - Cyclical mastalgia which almost 40% of women suffer from is caused by inadequate ovarian hormones secretion. There are reports regarding increased number of endometrial steroid receptors in this group of women. The possibility of higher risk of endometrial cancer development in these women is very probable. 119 women with cyclical mastalgia aged 16-55 (means age 35.4 years) were investigated. Anovulatory cycles occurred in 63%. Increased estrogen action in vaginal smears was found in 24.1%, also decreased progesterone effect had been seen in 20.3% of our cases. Serum estradiol levels were elevated in 10.6% and 39.1% of the patients had lower serum progesterone levels. Mean progesterone--estrogen luteal index value was decreased to 0.99. Irregular uterine bleedings occurred in 16.8 of women (aged 41-48 years). Histological endometrium examinations revealed changes due to insufficient progesterone action. PMID- 8675071 TI - [The value of hysterosalpingoscintigraphy in examining the patency and activity of oviducts]. AB - As many as 15 patients have been examinedby hysterosalpingoscintigraphy by administration of albumin macroaggregates labelled with Te99m (HAMA) into posterior vaginal fornix and external orifice of uterine cervix. Gamma camera was used to observe the transportation of molecules through the cervical canal, uterine cavity as well as oviducts to peritoneal cavity. The results were compared with HSG examination and salpingochromotubation. is 93%. Hysterosalpingoscintigraphy allows us to estimate both the anatomical patients after reconstructive operations involving oviducts. PMID- 8675073 TI - [Effect of electro-conization involving the vaginal part of the uterine cervix on cervical mucus parameters]. AB - Parameters of cervical mucus and its penetration by spermatozoa were evaluated in 36 women prior to and after conisation of the vaginal part of uterine cervix. After the procedure: complete absence of fecund mucus was revealed in 9 women (25% of cases); in 23 the mucus parameters and the penetration test results were not significantly changed (63.8% of cases) and 4 women became pregnant (11% of cases). The results of studies indicate that in the majority of cases this procedure fails to influence the parameters of mucus, although in a part of cases it may lead to its complete disappearance. PMID- 8675072 TI - [Fertility of women after microsurgical resection of intraperitoneal adhesions of uterine adnexa]. AB - The aim of the paper was to evaluate the results of microsurgical resections of periadnexal adhesions and those within the pelvis, with taking into consideration the index of intraperitoneal adhesions, coexisting endometriosis and possible adhesions within the fimbriae of oviducts with their patency being preserved. Among 40 women operated on, intrauterine pregnancy terminating in delivery occurred in 42.5% of cases, miscarriage in 7.5%, and oviductal pregnancy in 5% of cases. The highest percentage of pregnancies was obtained with the index of adhesion up to 30 points. Above that value the number of obtained pregnancies decreased dramatically. In the group of patients with coexisting endometriosis the percentage of pregnancies was 13.3%, while 33.3% were scored in the group of women, in whom resection of adhesions within fimbriae was carried out. Active endometriosis and changes within fimbriae of oviducts exert unfavourable influence effects of surgical procedure. PMID- 8675074 TI - [Effect of blood flow velocity on umbilical vessels in twin pregnancy]. AB - The authors did analyzed Doppler indices in 26 twin pregnancies recognized by ultrasound in the first trimester, 20% of them resulted in singleton birth. There were disturbances of arterial and venous flow in cases of fetal demise occurring in the second and third trimester. PMID- 8675076 TI - [A rare case of concurrent endometrial carcinoma and PCO syndrome]. AB - A case of PCO syndrome associated with carcinoma of the endometrium was described at woman of 40 years old. Endometrial carcinoma was superficial and well differentiated. PMID- 8675075 TI - [Breast cancer during pregnancy]. AB - Approximately 2-3% of all breast cancers coincide with pregnancy or lactation and this tumour affects one to four out of 10000 pregnant women. Breast cancer associated with pregnancy (BCAP) has generally been believed to have a particularly grim prognosis. Several recent studies suggest however, that survival in BCAP does not substantially differ from that of non-pregnant, age and stage matched patients. BCAP may managed with standard methods. Surgery should be considered in all patients deemed to be operable. Therapeutic abortion does not need to be routinely performed, unless adjuvant chemotherapy or radiotherapy is to be applied or the patient necessitates systemic therapy for advanced disease. Prophylactic ovarian ablation does not influence significantly the course of BCAP and should be undertaken only in case of progressive or recurrent disease. PMID- 8675077 TI - [A case of advanced vulvar cancer treated with combination therapy]. AB - Presented is a patient with advanced vulvar cancer involving the vagina, the perineum and the anus, with metastases to inguinal lymph nodes. The patient received irradiation and next, an artificial sigmoidal anus was made, with simultaneous vulvectomy performed with an electrosurgery. The patient's survival of 3 years and 3 months encourages to consider in such cases an attempt at applying aggressive surgical treatment combined with external radiotherapy. PMID- 8675078 TI - Why is epidermal growth factor present in the gut lumen? AB - The jury is still out on the role of luminal EGF in the normal gastrointestinal tract. Recent evidence, however, suggests that its major function is to act as a 'luminal surveillance' peptide, which is available to stimulate repair and that it is not of major importance in maintaining normal gut growth. Recombinant EGF administered via the gut lumen could still prove a valuable tool for the treatment of gastrointestinal ulceration. Perhaps the old term for EGF, 'epidermal healing factor' or EHF, was more appropriate after all! PMID- 8675079 TI - Age related changes in gut physiology and nutritional status. AB - Few gastrointestinal functions decline to an important extent as a result of old age alone and there is little clinical evidence that significant malnutrition occurs in any normal elderly person as a result of the aging process itself. Nevertheless, decreased gastrointestinal reserve makes older people highly sensitive to minor insults and decompensation can rapidly occur. Drugs appreciably affect taste sensation, which is already blunted and psychological as well as physical disability can have a major impact on appetite. Malabsorption can be caused by gastric hypochlorhydria with small bowel bacterial overgrowth and while gastrointestinal dysmotility can be caused by subclinical hypothyroidism, it can improve in response to physical exercise. Evidence is now mounting that thorough investigation of gastrointestinal disturbances in elderly patients coupled with intensive nutritional support can make a very real impact on their outcome. Gastroenterologists should therefore seek out and actively treat gastrointestinal disorders in the elderly and not just ascribe them to old age. PMID- 8675080 TI - Effects of cisapride on gastric emptying of oil and aqueous meal components, hunger, and fullness. AB - To evaluate the effects of cisapride on gastric emptying of extracellular fat and hunger and fullness 10 volunteers consumed a meal consisting of 60 ml technectium 99m (99mTc)-V-thiocyanate labelled olive oil and 290 ml indium-113m (113mIn) labelled soup after taking cisapride (10 mg four times daily orally) and placebo, each for four days, in randomised, double blind fashion. Gastric emptying was quantified scintigraphically. Hunger and fullness before and after the meal were evaluated using visual analogue scales. Cisapride accelerated gastric emptying of oil and aqueous components by reducing the lag phase mean (SEM) (20.3 (7.0) min v 40.7 (4.1) min (p < 0.05) for oil and 4.1 (2.5) min v 10.0 (3.1) min (p < 0.05) for aqueous). Cisapride had no effect on the post-lag emptying rate of oil. Treatment with cisapride was associated with reduced retention of oil in the proximal stomach (p < 0.05). Subjects were more hungry before ingestion of the meal while receiving cisapride (6.7 (0.9) v 3.9 (0.7), p < 0.001). The scores for hunger at 120 and 180 minutes were inversely related to gastric emptying of oil on both cisapride (r > -0.62, p < 0.05) and placebo (r > -0.86, p < 0.001). Fullness increased after the meal while receiving placebo (p < 0.01), but not cisapride and postprandial fullness was less with cisapride at (30 min; 0.4 (0.3) v 3.3 (1.0), p < 0.05). With placebo, but not cisapride, the score for fullness at 15 minutes was inversely related to emptying of the aqueous phase (r = 0.68, p < 0.05). These results show that in normal volunteers after ingestion of an oil/aqueous meal: (a) postprandial hunger is inversely related to gastric emptying of oil, while fullness is inversely related to gastric emptying of the aqueous phase, (b) cisapride affects the intragastric distribution and accelerates gastric emptying of both oil and aqueous meal components, and (c) cisapride increases preprandial hunger and reduces postprandial fullness. PMID- 8675081 TI - Risk assessment after acute upper gastrointestinal haemorrhage. AB - The aim of this study was to establish the relative importance of risk factors for mortality after acute upper gastrointestinal haemorrhage, and to formulate a simple numerical scoring system that categorizes patients by risk. A prospective, unselected, multicentre, population based study was undertaken using standardised questionnaires in two phases one year apart. A total of 4185 cases of acute upper gastrointestinal haemorrhage over the age of 16 identified over a four month period in 1993 and 1625 cases identified subsequently over a three month period in 1994 were included in the study. It was found that age, shock, comorbidity, diagnosis, major stigmata of recent haemorrhage, and rebleeding are all independent predictors of mortality when assessed using multiple logistic regression. A numerical score using these parameters has been developed that closely follows the predictions generated by logistical regression equations. Haemoglobin, sex, presentation (other than shock), and drug therapy (non steroidal anti-inflammatory drugs and anticoagulants) are not represented in the final model. When tested for general applicability in a second population, the scoring system was found to reproducibly predict mortality in each risk category. In conclusion, a simple numerical score can be used to categorize patients presenting with acute upper gastrointestinal haemorrhage by risk of death. This score can be used to determine case mix when comparing outcomes in audit and research and to calculate risk standardised mortality. In addition, this risk score can identify 15% of all cases with acute upper gastrointestinal haemorrhage at the time of presentation and 26% of cases after endoscopy who are at low risk of rebleeding and negligible risk of death and who might therefore be considered for early discharge or outpatient treatment with consequent resource savings. PMID- 8675082 TI - Reversal of osteopenia with diet in adult coeliac disease. AB - To evaluate the effects of a gluten free diet on bone mineral density in untreated adult patients with coeliac disease, 63 patients (17-79 years, 35 women) were examined at diagnosis and after one year taking a gluten free diet. Bone mineral density was measured in the forearm using single photo absorptiometry and in the lumbar spine, femoral neck, and trochanter using dual energy x ray absorptiometry. The values for each patient were compared with those of 25 healthy controls, matched for sex, age, and menopausal state. Before being given a gluten free diet bone mineral density in the total group was reduced at all sites (p < 0.001). Age adjusted bone mineral density was inversely correlated with age. During the first year taking a gluten free diet bone mineral density increased at all sites (p < 0.01). This was seen in patients of all ages and in patients who were without symptoms of malabsorption (weight loss or diarrhoea) before treatment. Low bone mineral density in patients with untreated coeliac disease increases rapidly when treatment with a gluten free diet is followed. These findings emphasise the importance of early diagnosis and treatment in all patients with coeliac disease. PMID- 8675083 TI - Local entrapment of interferon gamma in the recovery from Shigella dysenteriae type 1 infection. AB - In healthy controls (n = 8) living in shigella endemic areas, accumulation of interferon gamma (IFN gamma) in the epithelial lining was seen in the rectal tissues. At the single cell level, however, few or no IFN gamma protein producing cells or mRNA expressing cells were detected at that site indicating the involvement of the whole large intestine in the production of IFN gamma in controls. Persistent numbers of IFN gamma producing cells were detected in the rectum of patients with Shigella dysenteriae type 1 infection (n = 8) throughout the course of disease with a tendency to increase in the convalescent stage. A significantly increased extra cellular deposition of secreted IFN gamma in tissue was seen in convalescence when compared with the acute stage (p < 0.05). In addition, enzyme immunoassay showed increased stool concentration of IFN gamma in patients at the convalescent stage as well as in healthy controls. In situ hybridisation confirmed the results by showing increased frequency of IFN gamma mRNA containing cells at the late stage of the disease (p < 0.05). Extensive message for IFN gamma was evident in cells in the lamina propria with no detectable transcripts in the surface epithelium. A colocalisation of IFN gamma with the IFN gamma receptor expression, predominantly found in the epithelial lining was detected by immunohistochemistry. Semiquantitative evaluation by computerised image analysis showed a gradual increased expression of IFN gamma and its corresponding receptor in the convalescent stage of shigellosis. This suggested progressive entrapment and binding of IFN gamma to its specific receptor at the local site. The enhanced surface expression of IFN gamma receptor evident at the convalescent stage of shigellosis was comparable to the constitutive level of expression in the healthy subjects. Thus, immunity to shigellosis correlated to up-regulation of IFN gamma production and expression of IFN gamma receptor. PMID- 8675084 TI - Effect of Clostridium difficile toxin A on human intestinal epithelial cells: induction of interleukin 8 production and apoptosis after cell detachment. AB - Clostridium difficile is the aetiological agent of pseudomembranous colitis, and animal studies suggest the essential role of secreted toxin A in inducing disease. This study examined the biological responses to toxin A by human intestinal epithelial cells. Confluent monolayers of Caco2, HT29, and T84 cells and primary epithelial cells in organ cultures of human colonic biopsy specimens and after detachment with EDTA were studied. Interleukin 8 was assayed using enzyme linked immunosorbent assay (ELISA). Purified C difficile toxin A induced cell rounding and detachment of monolayers of the epithelial cell lines. Cells in detached monolayers initially remained viable while adherent to each other. Subsequently, an increasing number of apoptotic cells appeared in suspension. Exposure to toxin A for 24 hours induced interleukin 8 production in T84 and HT29 cells. Toxin A also induced epithelial cell rounding, detachment, and apoptosis in organ cultures of human colonic biopsy specimens. During culture (in medium only), EDTA detached colonic epithelial cells produced interleukin 8 and cell death occurred by apoptosis. Colonic disease by C difficile may be initiated by toxin A mediated induction of epithelial cell interleukin 8 production and apoptosis after cell detachment from the basement membrane. Studies on isolated (toxin untreated) colonic epithelial cells suggest that interleukin 8 production and apoptosis occur as a consequence of cell injury and detachment. PMID- 8675085 TI - In vivo IgA coating of anaerobic bacteria in human faeces. AB - The bacterial flora in the human colon, although extremely diverse, has a relatively stable composition and non-infectious anaerobic bacteria are dominant. The flora forms a pool of numerous different antigens separated from mucosal immunocompetent cells by just a single layer of epithelial cells. Despite this thin barrier, however, the colonic mucosa is physiologically only mildly inflamed. This study looked at the mucosal humoral immune response against faecal anaerobes. By flow cytometric analysis the in vivo immunoglobulin coating of anaerobic bacteria in faecal samples of 22 healthy human volunteers was determined. In a previous study flow cytometric analysis of faecal bacteria has been found to be a very sensitive method to detect immunoglobulins on faecal bacteria. This technique showed that in vivo many bacteria are coated with IgA (24-74%) and less with IgG and IgM. The presence of many bacteria coated with IgA implies that IgA coating does not result in permanent removal of the species from the colon. The absence of immunoglobulin coating suggests that there is immunological unresponsiveness for anaerobic bacterial antigens. It is concluded that both immunological unresponsiveness and preferential coating with IgA are responsible for the relative absence of colonic mucosal inflammation. PMID- 8675086 TI - Platelet activating factor: release from colonic mucosa in patients with ulcerative colitis and its effect on colonic secretion. AB - Inflammatory mediators have been implicated in the pathophysiology of ulcerative colitis. They may stimulate intestinal secretion and contribute to the production of diarrhoea. Platelet activating factor (PAF) may be responsible for a high proportion of this secretory response. Biopsy specimens from inflamed and quiescent mucosa of patients with ulcerative colitis and normal human colonic mucosa were cultured or co-cultured. The release of PAF, prostaglandin E2, and leukotriene D4 into the culture medium was measured and the ability of this culture medium, from inflamed and normal tissues, to influence secretion in rat colonic mucosa was assessed. PAF was liberated by inflamed tissue. Its release from quiescent but not normal tissue was stimulated by medium in which inflamed mucosal biopsy tissues had been cultured and by exogenous bradykinin and 5 hydroxytryptamine, but not by histamine. PAF stimulated eicosanoid production. The rise in short circuit current produced in vitro by inflamed tissue culture medium was inhibited by the PAF receptor antagonist (CV 6209) (46%) (32.4 (2.9) v 17.5 (1.19) muA.cm-2, p < 0.005) and further by combined cyclooxygenase and lipoxygenase inhibition (indomethacin plus ICI 207968) (58%) (32.4 (2.9) v 13.6 (1.9) muA.cm-2, p < 0.005). Mepacrine and hydrocortisone attenuated considerably the electrical response evoked by medium from inflamed mucosa to a similar extent (32.4 (2.9) v 6.3 (1.2) v 5.1 (0.9) muA.cm-2, p < 0.001). These data suggest that PAF accounted for 46% of the culture medium secretory effect. Thus, any attempt to block its release in patients with ulcerative colitis may have only a partial effect on their symptoms. PMID- 8675087 TI - Smoking may prevent pouchitis in patients with restorative proctocolectomy for ulcerative colitis. AB - Epidemiological studies have shown an increased risk of ulcerative colitis (UC) in non-smokers and particularly recent ex-smokers. Patients with UC have an increased risk of pouchitis following ileal pouch-anal anastomosis, which may be a manifestation of the original disease susceptibility. The aim of this study was to test the hypothesis that smoking habit may influence the incidence of pouchitis. All patients with a functioning pouch > or = 12 months at one centre were assessed. Patients were excluded if (a) the original indication was not UC (n = 5), (b) the excised pouch showed histology diagnostic of Crohn's disease (n = 2), and (c) data were inadequate (n = 4). Smoking data were collected by questionnaire, or direct interview, or both. Ex-smokers were those who had stopped smoking < 7 years before colectomy. Non-smokers included ex-smokers who had stopped > 7 years before colectomy. Pouchitis was defined as an increase in stool frequency > 8/day with acute inflammation on biopsy specimen histology. Each presentation requiring treatment was regarded as an episode. For comparison smoking habit was assessed with regard to three other adverse outcomes - haemorrhage, sepsis, and pouch excision. Of 72 non-smokers (mean follow up 3.5 years) 18 had 46 episodes of pouchitis. Of 12 ex-smokers (mean follow up 3.3 years) four patients have had 14 episodes of pouchitis. Only one smoker from 17 has had a single episode of pouchitis. This shows that smokers have significantly less episodes of pouchitis compared with non-smokers (p = 0.0005) and ex-smokers (p = 0.05). There was no association of smoking habit with other adverse outcomes. PMID- 8675089 TI - Seasonal variations in the onset of ulcerative colitis. AB - Several retrospective studies have reported seasonal variations in the relapse of ulcerative colitis, and two studies have found seasonality in the onset of ulcerative colitis, with a peak from August to January. This study was designed to investigate possible seasonal variations of onset of ulcerative colitis (UC) and Crohn's disease (CD). Patients with symptoms of one year or less were recruited from a prospective study of the incidence of inflammatory bowel disease, and the onset of symptoms was recorded month by month for four consecutive years. A total of 420 patients with UC and 142 patients with CD were included. There was monthly seasonality (p = 0.028) in symptomatic onset in December and January for UC but not for CD. It was found that environmental agents with known seasonality can be of importance for the seasonal variations of disease onset in UC. PMID- 8675088 TI - Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria. AB - In contrast with normal subjects where IgA is the main immunoglobulin in the intestine, patients with active inflammatory bowel disease (IBD) produce high concentrations of IgG from intestinal lymphocytes, but the antigens at which these antibodies are directed are unknown. To investigate the specificities of these antibodies mucosal immunoglobulins were isolated from washings taken at endoscopy from 21 control patients with irritable bowel syndrome, 10 control patients with intestinal inflammation due to infection or ischaemia, and 51 patients with IBD: 24 Crohn's disease (CD, 15 active, nine quiescent), 27 ulcerative colitis (UC, 20 active, seven inactive). Total mucosal IgG was much higher (p < 0.001) in active UC (median 512 micrograms/ml) and active CD (256 micrograms/ml) than in irritable bowel syndrome controls (1.43 micrograms/ml), but not significantly different from controls with non-IBD intestinal inflammation (224 micrograms/ml). Mucosal IgG bound to proteins of a range of non pathogenic commensal faecal bacteria in active CD; this was higher than in UC (p < 0.01); and both were significantly greater than controls with non-IBD intestinal inflammation (CD p < 0.001, UC p < 0.01) or IBS (p < 0.001 CD and UC). This mucosal IgG binding was shown on western blots and by enzyme linked immunosorbent assay (ELISA) to be principally directed against the bacterial cytoplasmic rather than the membrane proteins. Total mucosal IgA concentrations did not differ between IBD and controls, but the IgA titres against faecal bacteria were lower in UC than controls (p < 0.01). These experiments show that there is an exaggerated mucosal immune response particularly in active CD but also in UC directed against cytoplasmic proteins of bacteria within the intestinal lumen; this implies that in relapse of IBD there is a breakdown of tolerance to the normal commensal flora of the gut. PMID- 8675090 TI - High frequency of helicobacter negative gastritis in patients with Crohn's disease. AB - The frequency of gastric Crohn's disease has been considered low. This study was undertaken to determine the prevalence of chronic gastritis and Helicobacter pylori infection in patients with Crohn's disease. Oesophagogastroduodenoscopy was performed on 62 consecutive patients suffering from ileocolonic Crohn's disease. Biopsy specimens from the antrum and corpus were processed for both histological and bacteriological examinations. H pylori antibodies of IgG and IgA classes were measured in serum samples by enzyme immunoassay. Six patients (9.7%) were infected with H pylori, as shown by histology, and in five of them the infection was also verified by serology. Twenty one patients (32%) had chronic H pylori negative gastritis (negative by both histology and serology) and one of them also had atrophy in the antrum and corpus. Granulomas were found in four patients. The characteristic appearance of H pylori negative gastritis was focal and mostly mild inflammation resembling the inflammatory changes seen in the gut in Crohn's disease. Patients with H pylori negative chronic gastritis had a significantly more active disease in their gut than those with normal gastric mucosa (p < 0.01). It is concluded that H pylori positive gastritis is rare, while H pylori negative gastritis is relatively common in patients with Crohn's disease. H pylori negative 'Crohn's gastritis' seems to be associated with active Crohn's disease. PMID- 8675091 TI - Importance of antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis and ulcerative colitis: prevalence, titre, and IgG subclass. AB - Antineutrophil cytoplasmic antibodies (ANCA) have been reported in up to 87% of patients with primary sclerosing cholangitis with or without ulcerative colitis (PSC +/- UC) and in 68% of those with UC only. Compared with other liver and diarrhoeal diseases, ANCA have high specificity for PSC (+/- UC) and UC only. This study aimed to determine the prevalence and significance of ANCA in these two diseases and whether the ANCA titre or IgG subclass, or both, could distinguish between PSC + UC and UC only. Subjects included 63 patients with PSC, 85 with UC, 17 with coeliac disease, and 10 with dermatitis herpeteformis and 36 normal subjects. ANCA was detected using the immunoalkaline phosphatase method. The IgG subclass of ANCA was determined in 27 PSC + UC and 30 UC only patients using a panel of mouse monoclonal antibodies specific for the IgG subclasses. At a serum dilution of 1:5, ANCA had a diagnostic sensitivity of 65% for all PSC and 45% for UC only. For PSC + UC the sensitivity was 70% at 1:5 (p = 0.004 v UC only). At 1:50, the sensitivity values were 54% and 25% respectively for PSC + UC and UC only (p = 0.0006). In PSC, ANCA positivity was significantly associated with extensive involvement of the biliary tree but not with other clinical parameters. In UC only, the median disease duration was significantly greater in ANCA positive patients. The PSC + UC ANCA showed increased IgG3 compared with UC only ANCA (p < 0.05), together with increased IgG2 and IgG4 (p = NS). ANCA is a diagnostic marker in PSC and UC. While the higher titres and different IgG subclass distribution of ANCA in PSC + UC patients compared with those with UC only may reflect differences in underlying immune regulation, determination of the ANCA titre and IgG subclass is unlikely to have a role in distinguishing between PSC + UC and UC only ANCA. Future identification of the antigen(s) for ANCA should allow the development of a more sensitive and specific test for the diagnosis of these two conditions and also determine if ANCA is associated with UC or PSC. PMID- 8675092 TI - Characterisation of inorganic microparticles in pigment cells of human gut associated lymphoid tissue. AB - Macrophages at the base of human gut associated lymphoid tissue (GALT), become loaded early in life with dark granular pigment that is rich in aluminium, silicon, and titanium. The molecular characteristics, intracellular distribution, and source of this pigment is described. Laser scanning and electron microscopy showed that pigmented macrophages were often closely related to collagen fibres and plasma cells in GALT of both small and large intestine and contained numerous phagolysosomes, previously described as granules, that are rich in electron dense submicron sized particles. Morphological assessment, x ray microanalysis, and image electron energy loss spectroscopy showed three distinct types of microparticle: type I - spheres of titanium dioxide, 100-200 nm diameter, characterised as the synthetic food-additive polymorph anatase; type II - aluminosilicates, < 100-400 nm in length, generally of flaky appearance, often with adsorbed surface iron, and mostly characteristic of the natural clay mineral kaolinite; and type III - mixed environmental silicates without aluminium, 100 700 nm in length and of variable morphology. Thus, this cellular pigment that is partly derived from food additives and partly from the environment is composed of inert inorganic microparticles and loaded into phagolysosomes of macrophages within the GALT of all human subjects. These observations suggest that the pathogenicity of this pigment should be further investigated since, in susceptible individuals, the same intracellular distribution of these three types of submicron particle causes chronic latent granulomatous inflammation. PMID- 8675093 TI - Effect of longterm placebo controlled calcium supplementation on sigmoidal cell proliferation in patients with sporadic adenomatous polyps. AB - A longterm, double blind intervention trial was undertaken in patients with sporadic adenoma treated by polypectomy to investigate the putative role of calcium as a protective factor in colon carcinogenesis. The aim of the study was to assess the effect of a daily dietary supplementation of 2 g calcium over nine months on cell proliferation measured as proliferation index in colonic mucosa. A total of 48 patients were entered into the study of which 30 were fully compliant. After intervention proliferation index % (mean (SEM) in colonic epithelium was decreased in both the calcium (13.5 (1.5) to 11.4 (1.2)) and the placebo group (13.7 (0.9) to 10.8 (1.1)). The difference in the change between the two groups was not significant (p = 0.7). Changes in proliferation index % of crypt compartments were also not significantly different between the two groups. A significantly positive correlation between soluble calcium in faeces and the total proliferation index % in colonic epithelium at baseline and after intervention (r = 0.54, p < 0.01, r = 0.50, p < 0.01 respectively) suggests that an increase of free luminal calcium alone is insufficient for inhibition of cellular proliferation. PMID- 8675094 TI - p53 tumour suppressor gene expression in pancreatic neuroendocrine tumour cells. AB - Neuroendocrine pancreatic tumours grow slower and metastasise later than ductal and acinar carcinomas. The expression of the p53 tumour suppressor gene in pancreatic neuroendocrine tumour cells is unknown. Pancreatic neuroendocrine cell lines (n = 5) and human tumour tissues (n = 19) were studied for changed p53 coding sequence, transcription, and translation. Proliferative activity of tumour cells was determined analysing Ki-67 expression. No mutation in the p53 nucleotide sequence of neuroendocrine tumour cell was found. However, an overexpression of p53 could be detected in neuroendocrine pancreatic tumour cell lines at a protein level. As no p53 mutations were seen, it is suggested that post-translational events can also lead to an overexpression of p53. PMID- 8675095 TI - Folate status of gastrointestinal epithelial cells is not predicted by serum and red cell folate values in replete subjects. AB - Localised folate deficiency has been implicated in colonic carcinogenesis and supplementation has been proposed for certain populations at risk. However, identifying those groups that may benefit is difficult as the relation between blood folate and gut epithelial cell values is unknown. The aim of this study was to define this relation. Epithelial cells mean (SEM) (sigmoid: 5.35 (0.56) x 10(6) cells, caecum: 6.6 (0.71) x 10(6) cells, duodenum: 4.0 (0.62) x 10(6) cells) were isolated from four endoscopic mucosal biopsy specimens (n = 25) by incubation with dithiothreitol (three hours) and EDTA (one hour). Lamina propria contamination was < 1%, with < 6% intraepithelial lymphocytes. Folate assay of isolates showed sigmoid colon folate content to be 20.1 (1.8) pg/micrograms DNA (10.2-46.6). In the same subject, caecal folate concentrations were lower (p < 0.01, n = 11) than sigmoid values, whereas duodenal isolates mirrored those of the sigmoid (19.4 (2.9) v 20.5 (3.2), n = 5). Sigmoid folate values were consistent over one to three weeks (n = 3). In a single case with blood folate deficiency, colonic values were normal. Serum folate and red cell folate correlated poorly with sigmoid epithelial cell folate content (r = 0.41, p = 0.063 and r = 0.17, p > 0.05 respectively). This study reports a modified ion chelation isolation method for colonic biopsy specimens that yields large numbers of viable epithelial cells. Cell folate values remain constant with time though vary with intestinal region. The inability of serum or red cell folate values to predict those of the sigmoid epithelium suggests that they cannot identify those patients that might benefit from folate supplements. PMID- 8675097 TI - Family based colorectal cancer screening in a district hospital. AB - Colorectal cancer (CRC) screening using family history to define a group at increased risk is gaining support. Three hundred and ninety six subjects aged over 25 with at least one first degree affected relative have been screened using a single slide, immunological faecal occult blood test (FOBT), and family history data to select the highest risk group. Compliance was 64.9% but was significantly better if contact was made within one year of diagnosis of the index relative (75% v 62.1%, chi 2 = 5.7, p < 0.05). Twelve subjects (13.2%) of those who had a colonoscopy) bearing adenomas have been detected, three of which were at high risk of malignant transformation. No cancers have been diagnosed. Most subjects undergoing screening were less than 55 years of age (67.8%). These accounted for most colonoscopies (68.1%) but only one large adenoma was diagnosed in this group. The FOBT was particularly useful, enabling the detection of five large adenomas. Family based CRC screening is practical in a district hospital setting. Although labour intensive, it meets a population demand and can detect significant numbers of adenomas. Screening, even in those at moderately increased risk, could be focused on the older age groups, probably those aged over 40. PMID- 8675096 TI - Induction of NGAL synthesis in epithelial cells of human colorectal neoplasia and inflammatory bowel diseases. AB - In inflammatory and neoplastic disorders of the colon a defect barrier function of the mucosa may result in absorption of bacterial products from the intestinal lumen. These products may further recruit inflammatory cells and thus augment the inflammatory response. A novel lipocalin in neutrophils, neutrophil gelatinase associated lipocalin (NGAL), with the ability to bind bacterial formylpeptides, has been described and therefore it is of interest to investigate the expression of this protein in diseases of the colon. Expression of NGAL was investigated by immunohistochemistry and by mRNA in situ hybridisation in normal colon and in neoplastic and inflammatory colorectal diseases. A very high expression of NGAL was seen in colonic epithelium in areas of inflammation, both in non-malignant epithelium (diverticulitis, inflammatory bowel disease, and appendicitis) as well as in premalignant and malignant neoplastic lesions of the colon. In adenocarcinoma, the NGAL expression was especially abundant in the transitional mucosa and in the superficial ulcerated area. On the other hand, no NGAL expression could be detected in lymph node metastases from these adenocarcinomas. A weak expression of NGAL in some epithelial cells was only occasionally seen in normal colon. In conclusion, NGAL synthesis is induced in epithelial cells in inflammatory and neoplastic, colorectal diseases. NGAL may serve an important anti-inflammatory function as a scavenger of bacterial products. PMID- 8675098 TI - K-ras gene mutation in gall bladder carcinomas and dysplasia. AB - Epithelial dysplasia of gall bladder is an important precancerous lesion of gall bladder carcinogenesis. To investigate the frequency of K-ras gene mutation in gall bladder carcinoma and dysplasia, K-ras codon 12 mutations were investigated by the polymerase chain reaction/restriction enzyme based method following direct sequencing. Mutation was detected in 59% (30 of 51) of gall bladder carcinomas, in 73% (8 of 11) of gall bladder dysplasia in gall stone cases, and in 0% of the normal gall bladder epithelium. There was, however, no correlation between K-ras mutation and clinicopathological factors of gall bladder carcinoma. K-ras gene mutation occurs even in gall bladder dysplasia at an incidence similar to that in carcinomas, suggesting that testing for K-ras gene mutation may prove useful as an adjunct to bile cytological or biopsy analysis. PMID- 8675099 TI - Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumours. AB - Antiproliferative treatment of patients with metastatic endocrine gastroenteropancreatic tumours (GEP) is based mainly on chemotherapeutic protocols whereby drug toxicity is a major handicap. Octreotide is the first choice in the control of hormone mediated symptoms. From retrospective and a few prospective studies it has been suggested that octreotide exhibits antiproliferative properties. The prospective German Sandostatin multicentre phase II trial investigated the effects of 200 micrograms octreotide thrice daily for one year on tumour growth and endocrine abnormalities in 103 patients. Octreotide treatment was continued in those patients responding to the drug until tumour progression occurred. In 28 of those with tumour progression during 200 micrograms thrice daily octreotide dose was increased to 500 micrograms thrice daily. The study sample consisted of 52 patients with computed tomography confirmed tumour progression and 13 patients with stable disease before octreotide treatment, whereas no preobservation period was available in 38 patients. Nineteen patients (36.5%) with computed tomography confirmed tumour progression experienced stabilisation of tumour growth lasting for at least three months. Median duration of stable disease was 18 months. At month 12, stable disease continued in 12 patients, declined after 24 months to nine patients, and after 36 months to five patients. Tumour regression has not been seen in this or other subgroups. In the subgroup with stable disease before octreotide, stable disease continued in 53.8% of patients over 12 months. Increase of octreotide dose to 500 micrograms thrice daily did not influence progression seen during the lower dose with the exception of one patient in whom tumour progression changed to stable disease. No association of tumour size response and patients' characteristics could be detected. The results suggest that octreotide inhibits tumour growth in patients with metastasised endocrine GEP tumours. The antiproliferative effect is, at least in some patients, longlasting. Currently, octreotide can only be recommended as an antiproliferative drug if patients with clearly progressive disease show stabilisation after treatment for three to six months. PMID- 8675100 TI - Metabolism of orally administered tauroursodeoxycholic acid in patients with primary biliary cirrhosis. AB - The metabolism of tauroursodeoxycholic acid orally administered and its effects on the bile acid pool of patients with asymptomatic/mildly symptomatic primary biliary cirrhosis is described. Patients were randomly assigned 500, 1000, or 1500 mg/day of tauroursodeoxycholate for six months. Biliary and serum bile acids were measured before and during treatment by gas chromatography-mass spectrometry and by high performance liquid chromatography. During tauroursodeoxycholate administration, the proportion of total ursodeoxycholate in bile reached mean (SEM) 34.4 (4.5)%, 32.8 (2.8)%, and 41.6 (3.0)% with doses of 500, 1000, and 1500 mg/day, respectively. Significant decreases in the proportions of chenodeoxycholate and cholate resulted. The glycine/taurine ratio of the biliary bile acid pool decreased from 1.9 at baseline, to 1.1 with the highest dose. Ursodeoxycholate in bile was conjugated with glycine and taurine, indicating that tauroursodeoxycholate undergoes significant deconjugation and reconjugation during its enterohepatic recycling. The proportion of lithocholate in bile remained unchanged. Fasting serum conjugated ursodeoxycholate concentration positively correlated with the tauroursodeoxycholate dose, and the increased proportion of ursodeoxycholate was accompanied by substantial decreases in the endogenous bile acids. Compared with previously published data for ursodeoxycholic acid therapy, these findings indicate that the shift toward a more hydrophilic bile acid pool is greater and potentially more favourable with tauroursodeoxycholate, and this is because of the reduced intestinal biotransformation of tauroursodeoxycholate. PMID- 8675101 TI - Increased concentrations of tumour necrosis factor (TNF) and soluble TNF receptors in biliary obstruction in mice; soluble TNF receptors as prognostic factors for mortality. AB - Systemic tumour necrosis factor (TNF) is present in jaundiced mice. Two soluble TNF receptors, sTNFr-P55 and sTNFr-P75 are reported to play a part in the natural defence against TNF. This study investigated the properties of circulating TNF and sTNFr in jaundiced mice. The data show that TNF in these mice is biologically inactive and that an increase of both sTNFr is seen (p < 0.001). Surgical trauma in jaundiced mice is known to be accompanied by a high mortality (36%) and increased TNF concentrations. This study shows that both systemic TNF and sTNFr concentrations are increased after surgical trauma in jaundiced mice and that sTNFr concentrations rather than TNF concentrations were found to be correlated with mortality. In line with this finding this study showed that lactulose pretreatment before a surgical trauma in these mice significantly reduces postoperative concentrations of sTNFr-P75 (p < 0.005) and mortality (0%; p < 0.05) without reducing TNF concentrations, while anti-TNF antibodies were ineffective. In conclusion, these data suggest that TNF in biliary obstruction is rapidly inactivated by increased concentrations of sTNFr. Furthermore, sTNFr concentrations rather than TNF concentrations show a good correlation with mortality after surgery in obstructive jaundice. The positive effect of lactulose on mortality could be caused by a decreased inflammatory status. PMID- 8675103 TI - A national training programme for gastroenterology and hepatology. PMID- 8675102 TI - Acute liver damage and ecstasy ingestion. AB - Eight cases of ecstasy related acute liver damage referred to a specialised liver unit are described. Two patients presented after collapse within six hours of ecstasy ingestion with hyperthermia, hypotension, fitting, and subsequently disseminated intravascular coagulation with rhabdomyolysis together with biochemical evidence of severe hepatic damage. One patient recovered and the other with evidence of hyperacute liver failure was transplanted but subsequently died, histological examination showing widespread microvesicular fatty change. Four patients presented with acute liver failure without hyperthermia. All four fulfilled criteria for transplantation, one died before a donor organ became available, and two died within one month post-transplantation of overwhelming sepsis. Histological examination showed submassive lobular collapse. Two patients presented with abdominal pain and jaundice and recovered over a period of three weeks; histological examination showed a lobular hepatitis with cholestasis. Patients developing jaundice or with evidence of hepatic failure particularly encephalopathy and prolongation of the international normalised ratio, or both, whether or not preceded by hyperthermia, should be referred to a specialised liver unit as liver transplantation probably provides the only chance of recovery. PMID- 8675104 TI - The quiet pleasure of browsing through vital statistics. PMID- 8675105 TI - The nurse endoscopist. PMID- 8675106 TI - Why use Buscopan during diagnostic upper gastrointestinal endoscopy? PMID- 8675107 TI - Measurement of morphokinetic status in experiments on intestinal adaptation. PMID- 8675108 TI - Experimental colitis is ameliorated by inhibition of nitric oxide synthase activity. PMID- 8675109 TI - Heartburn in patients with achalasia. PMID- 8675110 TI - [Progress of lymphoproliferative disease associated with disseminated Kaposi's sarcoma]. AB - A 73-year-old woman with a lymphoproliferative disorder had successive stages of reactive lymphadenopathy in sequence, a multifocal type of Castleman's disease and angioimmunoblastic lymphadenopathy. The disease ran an aggressive course and was associated with disseminated Kaposi's sarcoma. The linkage between the various types of lymphoproliferative disorders that presented in the same patient, as well as the association with Kaposi's sarcoma, are discussed. PMID- 8675111 TI - [Bleeding due to platelet dysfunction as a presenting symptom of systemic lupus erythematosus]. AB - A 32-year-old woman was admitted for evaluation of fever, blurred vision in the left eye, nasal and gingival bleeding and arthralgia. There was a macular hemorrhage, a tender mass in the left lower abdomen and edema of both legs. She also had anemia, mild thrombocytopenia, platelet function abnormalities, kidney dysfunction, and albuminuria. Serology was positive for antinuclear antibodies and double-stranded DNA; complement level was low, and circulating anticoagulants were present. Kidney biopsy established the diagnosis of systemic lupus erythematosus (SLE). Abdominal sonography demonstrated perisplenic and pelvic bleeding. A pulse therapy of corticosteroids with low-dose oral cyclophosphamide, along with platelet transfusions and infusions of deamino-d-arginine vasopressin resulted in symptomatic and laboratory improvement. Bleeding stopped, platelet function became normal, kidney function tests returned to normal and she became seronegative. It is emphasized that platelet function abnormalities are rare in SLE. The thrombocytopenia was too mild to cause spontaneous bleeding, and lupus anticoagulant is usually associated with thromboembolic complications and not with spontaneous bleeding. It is therefore conceivable that in this case platelet function abnormalities were responsible for the spontaneous bleeding, the presenting sign which led to establishing the diagnosis. PMID- 8675112 TI - [Percutaneous feeding gastrostomy]. AB - In the past 3 years 71 procedures for insertion of a percutaneous gastrostomy for enteral feeding were performed under X-ray control. The indication for gastrostomy was inability or refusal of the patient to swallow food, in the absence of mechanical obstruction of the gastrointestinal tract. The age range was 66-93 years (mean 82). Most patients had suffered strokes and some had dementia or Parkinson's disease. The procedure was successful in 69/71 patients (97%). 9 (12.6%) died within 30 days of causes related to their underlying condition, rather than to the procedure; 1 developed peritonitis and 6 (8.4%) developed minor infections at the site of entry of the gastrostomy tube. This is the first account of this technique to appear in the Hebrew medical literature. In our opinion the technique should be adopted as the preferred method for forming a gastrostomy, as it is quicker, safer and cheaper than the operative method, and even easier to perform than endoscopic percutaneous gastrostomy. PMID- 8675113 TI - [Primary malignant melanoma of the rectum]. AB - Primary malignant melanoma of the rectum is a very aggressive tumor with a 5-year survival rate of 6%. Most reports include cases of both anal and of rectal melanoma together. We report 2 women with primary melanoma of the rectum, aged 67 and 72 years, who underwent abdominoperineal resection and survived 5 and 7 months respectively. PMID- 8675114 TI - [Angina pectoris as a symptom of gastric volvulus]. AB - Angina pectoris is a common complaint in any emergency service, but it rarely is of extracardiac origin. A rare case of gastric volvulus which presented a recurrent angina pectoris in a 47-year-old man is reported. Repeated episodes of angina pectoris in a patient with a negative cardiac investigation should alert the physician to the possibility of extracardiac pathology. PMID- 8675115 TI - [A case of Job's syndrome]. AB - An 8-year-old boy had been followed in our clinic for recurrent abscesses of his thigh and buttocks. Serum levels of IgE greater than 2000 IU/ml and impaired leukocyte chemotactic response led to the diagnosis of Job's syndrome (hyperimmunoglobulin E syndrome), which is characterized by markedly elevated serum IgE, impaired neutrophil chemotaxis, chronic dermatitis, and recurrent pyogenic infections. Children with this syndrome are much more likely to develop opportunistic infections. An accurate etiological diagnosis and treatment of this specific infection in these children is mandatory. We report the first successful treatment of this syndrome with cyclosporin A. We therefore suggest that to diagnose this syndrome, quantitative IgE levels be routinely performed in children with recurrent skin or other suppurative infections. PMID- 8675116 TI - [Conservative therapy in carpal tunnel syndrome]. AB - A prospective study was designed to determine which patients with carpal tunnel would respond to conservative therapy (splinting and local injection of corticosteroids). The study included 50 hands of 34 patients, aged 25-80 years, with a mean follow-up of 18 months. Conservative therapy was effective in 82% of hands after 8 weeks, but symptoms subsequently recurred, so that by the end of a year only 20% remained asymptomatic. Failure of conservative therapy was predicted by long duration of symptoms, older age, permanent paresthesia, 2-point discrimination threshold above 6 mm, positive Phalen test within 30 seconds, and long motor and sensory distal latency. PMID- 8675118 TI - [Vaccination against measles--are we victims of our success?]. PMID- 8675117 TI - [Impingement syndrome following direct injuries of the shoulder joint]. AB - Impingement is the most common cause of pain and limitation of movement in the shoulder, with painful arc syndrome its major clinical sign. It usually becomes manifest at between 70 degrees-120 degrees of abduction, but in severe cases, this may be reduced to only 50 degrees-70 degrees. We studied 22 patients who had developed shoulder impingement following direct injuries and who had been treated by anterior acromioplasty and decompression, with an average follow-up of 32 months. 5 had sustained fractures of the greater tuberosity of the humerus at the time of injury, 14 had tears of the rotator cuff of various sizes (1 in both shoulders) and 3 had developed fibrotic scars of the subacromial bursa. Excellent or good results were achieved in 86.6%. Healing time was shorter, and there was return of full range of shoulder movement in those with subacromial scars, undisplaced fractures of the greater tuberosity, or those with a small tear of the rotator cuff. Recovery took longer in those with larger tears of the rotator cuff and in those with displaced fractures of the greater tuberosity. Recovery time was proportional to the size of the rotator cuff tear. It is concluded that direct trauma to the shoulder bears a direct relationship to the development of impingement syndrome, and that at surgery a concomitant tear in the rotator cuff is seen more than 2/3. Because of the high rate of success in surgical treatment of this syndrome, operation is indicated when a few months of physical therapy and analgesics fail to provide relief. In the presence of fractures, decompression surgery should be postponed until the fracture has united. PMID- 8675119 TI - [Clinical trials in Israel--the need for good clinical practice guidelines]. PMID- 8675120 TI - [Insomnia in infancy and childhood--causes, significance, assessment and approach to treatment]. PMID- 8675121 TI - [Axillary lymph node dissection in breast cancer--is it always necessary?]. PMID- 8675122 TI - [Estrogen replacement therapy and malignant tumors of the female genital tract]. PMID- 8675124 TI - [Conversion nonepileptic seizures]. PMID- 8675123 TI - [Diagnostic and therapeutic approaches to interstitial cystitis]. PMID- 8675125 TI - [Treatment of status epilepticus--1995]. PMID- 8675126 TI - [Lactic acidosis associated with biguanides]. PMID- 8675127 TI - [Management of psoriatic arthritis]. PMID- 8675128 TI - [Can we determine attitudes towards "right to die" among Israeli doctors?]. PMID- 8675129 TI - [Acute gastric dilation in a diabetic patient]. PMID- 8675130 TI - "ADAM' or "EVE'?--a toxicological conundrum. AB - The 3,4-methylenedioxy ring-substituted amphetamines, including "ADAM' and "EVE', are currently popular drugs of abuse. Adverse reactions are reported in the clinical literature but few fatal cases are documented and little toxicological data is available to guide those determining the cause or manner of death in such cases. We report two deaths presenting in a similar manner and with similar clinical features. Various body fluid samples were analysed for amphetamines by gas chromatography/mass spectrometry. In one case, amphetamine alone was detected at levels of 1.54 mg/l and 1.47 mg/l in postmortem blood and admission serum, respectively. The other involved several 3,4-methylenedioxy ring-substituted amphetamines, namely MDA, MDMA and MDEA, at levels of 0.25 mg/l, 0.43 mg/l and 0.3 mg/l, respectively in postmortem femoral blood and 0.24 mg/l, 0.55 mg/l and 0.49 mg/l in admission blood. The interpretation of these toxicological results and some novel legal issues are discussed. PMID- 8675131 TI - Drug addict deaths in the Nordic countries: a study based on medicolegally examined cases in the five Nordic countries in 1991. AB - The study includes medicolegally examined deaths among drug addicts in 1991 in the five Nordic countries: Denmark, Finland, Iceland, Norway and Sweden. A common definition of 'drug addict' was applied by the participating countries. The greatest number of drug addict deaths per 10(5) inhabitants was observed in Denmark followed, in descending order by Norway, Sweden, Finland and finally Iceland with only four deaths. The main difference between the countries was found in the number of fatal poisonings. The distribution according to geographical regions showed that about half of all drug addict deaths occurred in the metropolitan areas. Of the capitals, the greatest number of fatal poisonings per 10(5) inhabitants was seen in Oslo, followed by Copenhagen with a similar number, Stockholm with only the half, and Helsinki with a quarter. Heroin/morphine dominated as cause of death in fatal poisonings in Norway and Sweden. In Denmark, heroin/morphine caused about half of the fatal poisonings only, and nearly one third of the fatal poisonings was caused by methadone. Except for two cases in Sweden, methadone deaths were not seen in the other Nordic countries. Amphetamine caused one tenth of the fatal poisonings in Sweden. In Finland only one tenth of the deaths were caused by heroin/morphine and more by codeine, ethylmorphine and different drugs and poisons not classified in Single Convention on Narcotic Drugs 1961 or the International Convention on Psychotropic Substances 1971. A widespread use of alcohol, cannabis and benzodiazepines, diazepam especially, was seen in all the countries. PMID- 8675132 TI - Drugs usage of drivers suspected of driving under the influence of alcohol and/or drugs. A study of one week's samples in 1979 and 1993 in Finland. AB - The extent of drug use among drivers suspected of driving under the influence of alcohol and/or drugs in Finland was studied. All blood samples submitted to the laboratory during 1 week in two study periods, in 1979 (n = 298) and 1993 (n = 332), were analyzed for alcohol and psychotropic drugs. Drugs classified as hazardous to traffic safety were detected in 7.0% of the samples in 1979 and 26.8% in 1993. Benzodiazepines were the most frequently found drugs in both years: 6.0% of the cases in 1979 and 22.9% in 1993. Illegal drugs were found in 4% of the cases in 1993. Of the samples tested, 296 in 1979 and 317 in 1993 were from drivers suspected of driving under the influence of alcohol only. In 1979 every fourteenth and in 1993 every fourth of these suspected drunken drivers had drugs in their blood. Drugs, other than alcohol, were found six times more often than expected by the police. The results indicate that the trend of drug use, multidrug use and drug abuse is increasing among cases suspected of driving under the influence of alcohol/drugs. PMID- 8675133 TI - Identification of osteocalcin as a permanent aging constituent of the bone matrix: basis for an accurate age at death determination. AB - Age at death determination based on aspartic acid racemization in dentin has been applied successfully in forensic odontology for several years now. An age dependent accumulation of D-aspartic acid has also recently been demonstrated in bone osteocalcin, one of the most abundant noncollagenous proteins of the organic bone matrix. Evaluation of these initial data on in vivo racemization of aspartic acid in bone osteocalcin was taken a step further. After purification of osteocalcin from 53 skull bone specimens, the extent of aspartic acid racemization in this peptide was determined. The D-aspartic acid content of purified bone osteocalcin exhibited a very close relationship to age at death. This confirmed identification of bone osteocalcin as a permanent, 'aging' peptide of the organic bone matrix. Its D-aspartic acid content may be used as a measure of its age and hence that of the entire organism. The new biochemical approach to determination of age at death by analyzing bone is complex and demanding from a methodologic point of view, but appears to be superior in precision and reproducibility to most other methods applicable to bone. PMID- 8675134 TI - Traumatic ponto-medullary tear: a case report. AB - The aim of this report is to demonstrate the correlation between an extremely short time acting but strong force leading to incomplete rupture of the ponto medullary junction (PMJ) accompanied by rupture of the basilar artery. Potential mechanisms involved in a combined hyperextension and axial torsion of the head followed by characteristic lesions at the PMJ are discussed. A 33-year-old male suffered a blunt head injury following a blow to the head, i.e. a head-butt. Resuscitation was performed for 45 min without success. At post mortem, there was a superficial periorbital haematoma on the right and a deep soft tissue bruise in the right fronto-parieto-temporal area, but no evidence of skull or dens axis fracture. A deep tear at the ponto-medullary junction was identified with rupture of the basilar artery, whereas at the tip of the tear, i.e. the floor of the IVth ventricle, only a thin tissue layer of about 2 mm remained intact. In contrast to the severity of these lesions, only mild subarachnoid hemorrhage was observed, but the ventricular system was filled with blood clot resulting from the retrograde flow of subarachnoid hemorrhage. PMID- 8675135 TI - Fatal poisoning with the antidepressive agent opipramol. AB - An ingestion of an unknown quantity ( < or = 3000 mg) of opipramol dihydrochloride in a suicide case is described. Quantitation of opipramol and its deshydroxyethyl metabolite was performed simultaneously after liquid-liquid extraction from alkalinized samples prior to HPLC analysis. Postmortem concentrations of opipramol and of the metabolite in body fluids and organs are given. The distribution pattern of opipramol in tissue was comparable to findings from animal studies. The results showed the high uptake of opipramol in parenchymal tissues resulting in a low blood concentration. A possibly low contribution of deshydroxyethyl opipramol to the antidepressive effect may be concluded as the concentration was considerably lower in brain compared to other organs. PMID- 8675136 TI - Solid phase extraction of morphine and its metabolites from postmortem blood. AB - A simple and rapid high-performance liquid chromatographic method is described for the determination of morphine-3-glucuronide, morphine-6-glucuronide, normorphine and morphine in postmortem blood. A solid phase extraction technique employing C18 Sep-Pak cartridges was used to recover morphine and its metabolites from 0.5 ml of blood. Reverse phase ion-pair chromatography was used to achieve separation with a C18 bonded column. The mobile phase consisted of acetonitrile, lauryl sulphate and sodium dihydrogen orthophosphate buffer at low pH. Electrochemical detection (ECD) in series with ultraviolet (UV) spectrophotometric detection (210 nm) was used for quantitation. The lower limit of detection using ECD was 10 ng/ml for all analytes and a linear response was observed to 5000 ng/ml. Coefficients of variation for all analytes ranged between 3-13% for both intra- and inter-assay. This method is reproducible, quick and easy to perform and allows morphine conjugates and morphine to be measured simultaneously in postmortem blood. PMID- 8675138 TI - [Emigration of German psychiatrists to England. 1: England as a refuge for psychiatrists]. AB - During Nazi time some 100 German psychiatrists emigrated to the U.K. and worked there for the rest of their lives or a number of years. An approximately equal number of them came into close contact with (a) the developing modern British psychiatry and (b) with psychoanalysis, which had already been established for a long time. With the exception of the Maudsley Hospital and the British Psychoanalytic Society, no groups have been established, so that there are many individual life histories of the former German psychiatrists in the U.K. in a series of papers we intend to review the movement and its consequences. Long before the emigration movement began there were already convergent evolutions in the British and German psychiatry. The current paper studies the historical conditions encountered by the psychiatric clinicians and classical-psychiatric immigrants on their arrival in Britain. PMID- 8675139 TI - [Research into premorbid personality in psychiatry in German-speaking countries: the last 3 decades]. AB - The empirical research in premorbid personality of psychiatric patients has markedly advanced in German speaking countries since adequate research methods were introduced in the middle of the sixties. Among the various results are the following: Kretschmer's typological conception of human constitution were largely refuted and replaced by other conceptions on a methodologically more solid ground; Tellenbach's concept of the "melancholic type" as the premorbid structure of the majority of patients suffering from a unipolar affective disorder with melancholic features could be convincingly validated; this concept was supplemented by that of the "manic type" of personality as the premorbid correlate of the amount of a predisposition to manic episodes within the course of an affective disorder; the premorbid deviations of personality in schizophrenics and neurotics were shown to possess little nosological specificity; furthermore, similar deviations could be demonstrated in the personality of (still healthy) relatives of patients with severe mental disorders; the complex relationships of (premorbid) personality, personality disorders and mental disorders were partly clarified. PMID- 8675137 TI - Characteristics of fire victims in different sorts of fires. AB - We studied retrospectively 286 cases of fire deaths from a 10 year period. The victims were classified according to the type of fire. Among the victims of smouldering fire, 80% had lethal HbCO saturations, whereas only 30% had such saturations when an accelerant had been used. The third group consisted of victims of fires in which the type of fire was, for various reasons, undetermined. HbCO saturations were not influenced by sex, age, concomitant disease or blood alcohol concentration. In eight cases neither respiratory soot nor HbCO was detected in spite of evidence that the deceased was alive as the fire broke out. The material included nine cases of homicide and 22 cases of suicide. PMID- 8675140 TI - [12 patients with extended suicide--psychology, personality, motivation, previous history and psychosocial conflict environment]. AB - 12 unselected female patients of extended suicide examined for an expertise testimony (4 schizophrenics, 4 endogenous depressives, 3 personality disorders, 1 psychogenic reaction) were investigated. With the exception of one all schizophrenic patients killed their victims under the influence of hallucinations and/or delusion. In two of the melancholic patients showing personality traits in the sense of the melancholic type (Tellenbach) a duty-bound motive for killing the other, characterized as a hypernomic motive, was found. Apart from this, in these patients a psychotic identification with the victim was given, which induced them to kill the other like themselves with the motive of an unworthy existence. In all patients with a personality disorder and psychogenic reaction the motive of killing others was connected with egocentric personality traits. In all of these patients the killing of the victim or the attempt of killing was precipitated by an event. Two of the patients were addicts. The notion of extended suicide as well as the question of the altruistic motive of killing others are discussed. PMID- 8675141 TI - [Chronic progressive spinobulbar spasticity (primary lateral sclerosis)]. AB - This paper presents an account of chronic-progressive Spinobulbar Spasticity (SBS) or Primary Lateral Sclerosis (PLS), a rare syndrome involving degeneration of the upper motoneuron, on the basis of 6 clinically examined cases. Individuals of both sexes can be affected. Onset of the syndrome occurs around the age of 54, but may sometimes be before 50. Early symptoms of the disease are spasticity on one leg and disturbance of motor skills in one hand. The symptoms generalize within two to three years into tetraspasticity accentuated in the legs, accompanied by pseudo-bulbar dysarthria and dysphagia, which, however, may also be present at the onset of the disease. Compulsive laughing and crying, optokinetic disturbances and facial stiffness develop as additional, though inconstant symptoms. Disease courses of 25 years were observed. Therapy is symptomatic. Fasciculation and muscular atrophy, which would indicate a transition to Amyotrophic Lateral Sclerosis (ALS), were not observed even if the disease was of longstanding. SBS differs from spastic spinal paralysis by virtue of its greater mean age of incidence, its tetraspasticity in conjunction with pseudobulbar signs, and-so far as can be established to date-its apparent non hereditariness. An influence of exotoxic factors has not been demonstrated so far. The clinical syndrome results from a selective degeneration of the corticospinal and cortico-bulbar tracts up to the motor cortex, where loss of original pyramidal cells has been shown to occur (Pringle et al., 1992). The paper includes a survey of the clinical and neuropathological findings in cases of SBS published so far. Extensive anamnestic and clinical records including TCMS studies, PET and NMR-CT scans performed in the parasagittal plane are essential for early diagnosis of the syndrome. PMID- 8675142 TI - Inhibition of hepatitis B virus replication by targeted pretreatment of complexed antisense DNA in vitro. AB - We have shown that antisense oligonucleotides can be targeted to hepatitis B virus (HBV)-infected cells, resulting in specific inhibition of viral protein synthesis and replication in vitro. The targeting system was based on the internalization of DNA complexes by highly selective receptors for galactose terminal glycoproteins, asialoglycoproteins, on the surface of hepatocytes. Our objective in this study was to determine whether antisense DNA could be targeted to hepatocytes to prevent subsequent infection by HBV. A 21-mer phosphorothioate linked oligo DNA complementary to the HBV polyadenylation signal and 5'-upstream sequences was complexed to a targetable DNA carrier consisting of asialoglycoprotein coupled to polylysine. Pretreatment of Huh7, asialoglycoprotein receptor (+) cells, with antisense complexes before lipofection with an HBV-plasmid at a level of 6.5 x 10(6) copies of plasmid per cell inhibited the amount of newly synthesized, core-associated viral DNA in Huh7 cells to undetectable levels, less than 0.1 pg, as assessed by quantitative polymerase chain reaction (PCR). Hepatitis B viral RNA transcripts were decreased by 60% compared with controls as detected by RNase protection assays, and HBV surface antigen (HBsAg) accumulation was inhibited by 97%. The inhibition lasted for 6 days and was dose dependent. Controls consisting of antisense alone and a random oligo complex showed no significant effect on any of the parameters under identical conditions. We conclude that preexposure of cells to targeted complexed antisense DNA can substantially block viral gene expression and viral replication after transfection of HBV DNA. PMID- 8675144 TI - Frequent expression of MUC1 apomucin on biliary epithelial cells of damaged small bile ducts in primary biliary cirrhosis and chronic viral hepatitis: an immunohistochemical study. AB - MUC1 apomucin is a specific target tumor antigen recognized by cytotoxic T cells in a major histocompatibility complex (MHC) unrestricted fashion in patients with pancreatic and breast cancer. This T-cell-mediated immune mechanism against MUC1 apomucin expressing cells has not been evaluated in nonneoplastic immune-mediated diseases. Therefore, we immunohistochemically surveyed the expression of MUC1 apomucin on biliary epithelial cells of small bile ducts in various hepatobiliary diseases, including primary biliary cirrhosis (PBC). MUC1 apomucin was detected using the monoclonal antibody DF3 and the streptavidin-biotin complex, in livers from 31 patients with PBC, 67 with chronic viral hepatitis (CH) with or without cirrhosis, 31 with extrahepatic biliary obstruction (EBO), 30 with hepatolithiasis, and from 23 normal individuals. MUC1 apomucin was infrequently and focally expressed in the biliary epithelial cells of the small bile ducts in 3 of 23 normal livers. In contrast, MUC1 apomucin was frequently and strongly expressed on the luminal surface of biliary epithelia] cells of small bile duct, in 22 of 31 patients with PBC, and in 50 of 67 patients with CH. In particular, high levels of MUC1 apomucin were expressed in bile ducts showing chronic nonsuppurative destructive cholangitis (CNSDC) in PBC and hepatitic duct injuries in CH. In EBO and hepatolithiasis, MUC1 apomucin was focally and weakly expressed in 29% and 30% of livers examined, respectively. More MUC1 apomucin was expressed in PBC and CH than in EBO, hepatolithiasis, and normal liver (P < .01, respectively). Frequent and high luminal expression of MUC1 apomucin on biliary epithelial cells in damaged small bile ducts in PBC and CH may be related to T cell-mediated immunologic mechanisms in these diseases, probably by an MHC unrestricted recognition process. PMID- 8675143 TI - Activation of fetal promoters of insulinlike growth factors II gene in hepatitis C virus-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma. AB - Increased prevalence of hepatitis C virus (HCV) infection has been found in patients with hepatocellular carcinoma (HCC). The expression of insulinlike growth factor II (IGF-II) has been linked to hepatocarcinogenesis in the experimental animal and in humans. Since reactivation of fetal IGF-II transcripts has been observed in human HCC, we have analyzed the levels of adult P1 and fetal P3 and P4 IGF-II promoter-derived transcripts in the liver of patients with HCV related chronic active hepatitis (CAH), cirrhosis, and HCC by means of a semiquantitative reverse-transcription polymerase chain reaction (RT-PCR) assay. Transcripts derived from adult P1 promoter were increasingly expressed from normals to patients with CAH and cirrhosis, but were undetectable in the tumorous area of 5 of 7 HCC patients and present at low levels in the nontumorous area of all HCC patients. Transcripts derived from fetal P3 promoter were not detectable in normal subjects, while they were expressed abundantly in most CAH and all cirrhotic patients. Transcripts from fetal P4 promoter were detected at high levels in 3 of 9 CAH patients and in the majority of cirrhotic patients. Increased expression of fetal promoter-derived transcripts was also found in the liver of HCC patients, although levels were lower than in cirrhosis. Also, the activity of fetal P3 and P4 promoters was higher in the nontumorous than in the tumorous area of the liver of HCC patients. The expression of IGF-II transcripts was correlated with the rate of cell mitotic activity by measuring the expression of the proliferating cell nuclear antigen (PCNA) gene. PCNA messenger RNA (mRNA) levels progressively increased from normals to CAH and to cirrhotic patients, and persisted at a high level in the tumorous and in the nontumorous area of HCC subjects, thus showing that the increase of IGF-II transcripts in CAH and cirrhosis is accompanied by an activation of cell mitosis in these samples. These data suggest that the activation of IGF-II gene expression from adult and fetal promoters may play a role in premalignant proliferation observed in HCV-related chronic liver disease. PMID- 8675145 TI - Hepatic expression of hepatitis C virus RNA in chronic hepatitis C: a study by in situ reverse-transcription polymerase chain reaction. AB - Hepatitis C virus (HCV) replicates at a low rate and this makes its detection and intrahepatic localization difficult. To evaluate the clinical implications and effect of interferon alfa (IFN-alpha) therapy on hepatic expression of HCV RNA, HCV RNA was detected by in situ reverse-transcription polymerase chain reaction (IS-RT-PCR) in formalin-fixed paraffin-embedded liver sections from 26 patients with chronic hepatitis C. Results were compared with RT-PCR of HCV RNA extracted from liver sections/tissue. Twenty-four paired post-IFN-alpha treatment biopsy specimens were also assessed. Using RT-PCR of the extracted RNA as a positive standard and non-HCV liver sections as the negative standard, the sensitivity and specificity of IS-RT-PCR were 69% and 100%, respectively. HCV RNA was detected in the cytoplasm of hepatocytes (median, 5% hepatocytes positive; range, 0 to 35%) and very occasionally in infiltrating mononuclear cells. There was no correlation between hepatic expression of HCV RNA and the clinical, biochemical parameters, total and activity scores of histology activity index. Presence of HCV RNA in liver as detected by IS-RT-PCR was associated with higher serum HCV RNA levels (4.9 x 10(6) vs. 0.4 x 10(6) genome Eq/mL, P < .01). There was no difference in the pretreatment proportion of HCV RNA-positive hepatocytes among patients with different biochemical responses to IFN-alpha therapy. In the posttreatment samples, HCV RNA was undetectable by IS-RT-PCR in 16 of 24 patients (P < .01), including all 4 patients who had complete and sustained response (SR). We conclude that HCV RNA was detected by IS-RT-PCR in 0 to 35% of hepatocytes in patients with chronic HCV infection, detection of HCV RNA in liver by IS-RT-PCR was associated with higher viremia levels and IFN-alpha therapy reduced hepatocytic expression of HCV RNA. PMID- 8675146 TI - Non-neoplastic liver disease associated with chronic ground squirrel hepatitis virus infection. AB - We examined 95 ground squirrels to compare the histological appearance of liver sections from animals that were chronically infected with ground squirrel hepatitis virus (GSHV) (n = 29), uninfected (n = 42), or had recovered from infection (n = 24). We studied the effects of long-term infection because these animals had been infected with GSHV for up to 10 years. Chronic infection generally produced a mild, persistent hepatitis characterized by light lymphocytic and plasmacytic portal infiltrates with occasional individual necrotic hepatocytes and small aggregates of Kupffer cells or mononuclear inflammatory cells in the parenchyma. In a few of the portal tracts from each of the more inflamed livers (grade 2), the inflammatory infiltrate penetrated the limiting plate and extended into the adjacent parenchyma. Hepatitis (grades 1 or 2) was detected more often in chronically infected animals (17 of 29) than in recovered (4 of 24) or uninfected ground squirrels (7 of 42). Fibrosis was generally not increased, but fine strands of collagen extended from the portal tracts and central veins into the parenchyma of about one quarter of the infected and recovered animals. Cytoplasmic pigment accumulation and variation in the size of hepatocyte nuclei appeared to be related to aging, not infection. Serum levels of aspartate and alanine transaminases (AST and ALT) were mildly elevated in samples from seven infected animals compared with seven control animals. Despite many years of chronic infection, liver injury was similar to that reported in previous studies on animals infected for shorter intervals, indicating that liver injury is not progressive in GSHV-infected ground squirrels. PMID- 8675147 TI - Serum levels of hepatitis C virus core protein in patients with chronic hepatitis C treated with interferon alfa. AB - The quantitation of hepatitis C virus (HCV) viremia can be helpful in the diagnosis, therapy, and monitoring of patients with chronic hepatitis C. A sensitive and quantitative fluorescence enzyme immunoassay (FEIA) has recently been developed for assaying HCV core protein in serum. To assess the utility of measurements of serum HCV core protein during the course of treatment of chronic hepatitis C, we studied 27 patients who were treated with a single schedule of interferon alfa (IFN-alpha) (9 million units per dose for 24 weeks; total dose, 720 million units). Eleven of the 27 patients responded with clearance of HCV RNA and fall of aminotransferase to normal; 16 patients did not respond to treatment. Before therapy, HCV core antigen was detectable in 25 of the 27 patients (93%). The initial serum concentration of HCV core protein was significantly (P < .01) higher in the nonresponders versus the responders. Two weeks after initiating IFN alpha therapy, HCV core protein was not detectable in any of the 11 responders, but was detected in 8 of 16 nonresponders (P < .01). All responders, but none of the nonresponders, remained negative for core protein after IFN-alpha therapy. The measurement of HCV core protein by FEIA may be useful for predicting the response to IFN-alpha and for monitoring its therapeutic efficacy. PMID- 8675148 TI - The long-term pathological evolution of chronic hepatitis C. AB - Most patients infected with hepatitis C virus (HCV) develop chronic hepatitis. Unfortunately, the pathological evolution of this disease over time is not completely understood. We studied 70 HCV-positive patients, from whom 2 to 10 liver biopsy specimens (mean, 3.9) had been obtained during an interval of 1 to 26 years (mean, 8.8 years). Each biopsy specimen was evaluated independently by four pathologists who each provided a numerical score for the grade of portal/periportal necroinflammation (0-4), grade of lobular necroinflammation (0 4), their sum (final grade), and the stage of fibrosis (1-4). The scores were correlated with progression of disease, if any, and transition to cirrhosis. During follow-up, 35 patients (50%) developed cirrhosis. Cirrhosis developed in all patients with a high final grade (> or = 5) of necroinflammation on initial biopsy who were followed for 10 years and in 96% of patients with an intermediate final grade (3.5-4.9) who were followed for 17 years. Only 30.4% of patients with low final grade (< or = 3.4) on initial biopsy developed cirrhosis after 13 years. All patients with evidence of septal fibrosis with incomplete nodularity (stage 3.0-3.4) in the initial biopsy progressed to unequivocal cirrhosis by 10 years. The rate of progression to cirrhosis was accelerated in patients whose initial biopsies showed high-grade and -stage lesions. This study demonstrates the importance of grading and staging liver biopsy lesions in chronic hepatitis C, particularly for patients with high-grade necroinflammation, septal fibrosis, and regions of modularity on initial biopsy who are at high risk of developing advanced cirrhosis in the ensuing decade. PMID- 8675149 TI - Expression of immunoreactive matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in human normal livers and primary liver tumors. AB - Matrix metalloproteinases (MMPs) play an important role in cancer cell invasion by degrading extracellular matrix proteins. However, little is known about the in situ expression of MMP in human normal livers and primary liver tumors. In this study, we therefore examined the in situ expression of immunoreactive MMP and tissue inhibitors of MMP (TIMP) in 10 normal livers, 11 surgically resected intrahepatic cholangiocarcinomas (CCs), and 6 surgically resected hepatocellular carcinomas (HCCs). In normal livers, MMP and TIMP were infrequently and faintly expressed in bile ducts, but were not expressed in hepatocytes. In the 11 CCs, MMP-1, MMP-2, MMP3, MMP-9, TIMP-1, and TIMP-2 were expressed in tumor cells and/or tumor stroma in 11 (100%), 5 (45%), 8 (73%), 3 (27%), 9 (82%), and 9 (82%), respectively. The expression of MMP and TIMP in tumor cells was located in the cytoplasm with a diffuse or granular pattern; that in the tumor stroma was situated in fibroblasts, leukocytes, and extracellular matrix. Their expression was stronger in CC cases with severe invasion than in CC cases with mild invasion. In contrast, MMP and TIMP were not expressed in any cases of HCC. These results show that intrahepatic bile duct cells may neoexpress or overexpress MMP and TIMP after malignant transformation but that hepatocytes do not, and suggest that MMP and TIMP play an important role in CC cell invasion by degrading extracellular matrix proteins. PMID- 8675150 TI - The hepatocyte growth factor regulates the synthesis of acute-phase proteins in human hepatocytes: divergent effect on interleukin-6-stimulated genes. AB - Our study addressed the role of the human hepatocyte growth factor (HGF), a potent mitogen for mature rat and human hepatocytes, in the regulation of specific hepatic genes. The experimental evidence obtained in primary cultured human hepatocytes indicates that HGF regulates the synthesis of plasma proteins in a dose-response fashion. It stimulates the synthesis of the negative acute phase proteins albumin, transferrin, and fibronectin, decreases that of alpha1 antichymotrypsin (ACT) and haptoglobin, and stimulates that of alpha2 macroglobulin (AMG), which in man is insensitive to inflammatory mediators. HGF had no effect on C-reactive protein (CRP) synthesis. These effects differ from those elicited by interleukin-6 (IL-6). The effects of HGF on fibrinogen and alpha1-antitrypsin were, however, similar to those induced by IL-6. The effects of HGF were also observed at the messenger RNA (mRNA) level. Time-course induction experiments showed that the effects of HGF on protein synthesis were delayed by about 48 to 72 hours, in contrast with the 12-hour lag found after IL 6 stimulation. Although the presence of glucocorticoids was not absolutely necessary for HGF to affect plasma protein synthesis, it moderately extended the effects. In pulse-chase experiments, it was found that the action of HGF was not due to an alteration of the rate of secretion of the proteins. The effects of HGF on the synthesis of albumin, transferrin, fibronectin, alpha1-antichymotrypsin, and haptoglobin could be counteracted by the simultaneous presence of IL-6 in the incubation media. A clear additive effect was observed only in the case of fibrinogen. No interaction was observed in the cases of CRP and AMG. The results of this study indicate that the effects of HGF on human hepatocytes may not simply be limited to its mitogenic activity, but that it also regulates hepatic specific genes and antagonizes, in part, the action of IL-6. PMID- 8675151 TI - Chemical mediators released by primary-cultured human hepatic macrophages in patients with and without cirrhosis: a study in tumor-bearing patients. AB - To elucidate the possible role of chemical mediators in modulating the host defense activity of patients with cirrhosis, primary-cultured human hepatic macrophages (HHMphi) were obtained from cirrhotic and noncirrhotic patients who received liver resections because of the presence of malignant liver tumors. The cirrhotic and noncirrhotic groups consisted of patients with similar malignancies: noncirrhotic patients had normal liver function and normal liver histology for nontumorous portions. The cultured HHMphi were analyzed for their ability to release chemical mediators with specific activities in the host defense system. Dose-dependent increases in superoxide release, interleukin-1 (IL 1) release, and, within a relatively narrow range, prostaglandin-E2 (PGE2) release were observed in opsonized zymosan (oz)-stimulated HHMphi derived from both cirrhotic and noncirrhotic patients. The release of O2- and PGE2 from HHMphi derived from cirrhotic patients was significantly less than HHMphi derived from noncirrhotic patients, whereas the release of IL-1 was significantly greater. Although, because of the limited sample availability, only tumor-bearing patients were studied, the mediator-releasing ability of HHMphi derived from cirrhotic patients was significantly different from the ability of HHMphi derived from noncirrhotic patients with similar malignancies. This phenomenon may be related to altered host defenses in patients with cirrhosis. PMID- 8675152 TI - Gene therapy for alpha-fetoprotein-producing human hepatoma cells by adenovirus mediated transfer of the herpes simplex virus thymidine kinase gene. AB - We have developed a recombinant replication-defective adenovirus containing human alpha-fetoprotein (AFP) promoter/enhancer to direct cell type-specific expression of the herpes simplex virus thymidine kinase (HSVtk) gene to AFP-producing hepatocellular carcinoma (HCC) cells. After an in vitro infection by a recombinant adenovirus carrying the lacZ gene under the control of human AFP promoter/enhancer (AdAFPlacZ), an expression of the lacZ gene was demonstrated efficiently in AFP-producing HuH-7 and HepG2 cell lines, but not in AFP nonproducing HLE and HLF cell lines, although lacZ gene expression was demonstrated in all these cell lines when infected with adenovirus vector carrying lacZ gene driven by the beta-actin-based promoter. Expression of the HSVtk gene by adenovirus, from AFP promoter/enhancer (AdAFPtk) induced the cells sensitive to ganciclovir (GCV) in the AFP-producing cell line efficiently, but not in AFP-nonproducing HLF hepatoma cells. An in vitro bystander effect was observed when only 10% of the cells were infected with AdAFPtk. These findings suggest that the AFP promoter/enhancer sequence can provide the tumor-specific activity for the therapeutic gene expression, and that the AdAFPtk vector induces the selective growth inhibition by GCV in the adenovirus-infected human hepatoma cells in vitro. Recombinant adenovirus transfer of the HSVtk gene under the control of tumor-specific promoter followed by GCV may have promise as a targeted in situ treatment for solid neoplasms. PMID- 8675153 TI - Features of autoimmune hepatitis in primary sclerosing cholangitis: an evaluation of 114 primary sclerosing cholangitis patients according to a scoring system for the diagnosis of autoimmune hepatitis. AB - Overlapping features between primary sclerosing cholangitis (PSC and autoimmune hepatitis (AIH) have previously been noted. To assess systematically similarities between these disorders, we have evaluated 114 PSC patients (36 women; 78 men), all confirmed by endoscopic retrograde cholangiography (ERC), according to a scoring system proposed by The International Autoimmune Hepatitis Group for the diagnosis of AIH. The scoring system attributes positive or negative scores to the parameters sex, ratio of elevation of serum levels of alkaline phosphatase (ALP) vs. aminotransferase, serum levels of immunoglobulins and autoantibodies, viral markers, history of drug and alcohol intake, genetic factors, liver histology, and response to therapy. Two of the PSC patients (2%) obtained scores above 15 before treatment, satisfying the diagnostic criterion of "definite" AIH. Thirty-eight patients (33%) scored between 10 and 15 points and could be classified as "probable" AIH. The serum level of immunoglobulin G (IgG) was elevated in 68 patients (61% of 111 cases tested), and positive titers of antinuclear antibodies (ANA) or smooth muscle antibodies (SMA) were detected in 24 patients (22% of 111 cases tested). Thirty-five of the PSC patients (33% of 105 evaluable biopsy specimens) obtained positive scores for histological features similar to those of AIH, but the total score for histology was in the negative range in 72 patients (69%) because of the presence of biliary changes. The frequent finding of high scores in PSC patients underlines the similarities PSC may have with AIH. A modification of the scoring system, in particular by increasing the negative score for histological biliary changes, would improve its potential to discriminate between AIH and PSC. PMID- 8675154 TI - High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: relationship to endotoxemia. AB - The aim of this study was to evaluate whether there is endothelial dysfunction in patients with cirrhosis and to detect the mechanism that may account for it. We measured plasma levels of von Willebrand factor (vWF), a marker of endothelial perturbation, and endotoxin, which releases vWF from endothelial cells in vitro, in 32 patients (18 men, 14 women, aged 39-70 years) with cirrhosis classified as mild (class A, n = 10), moderate (class B, n = 16), or severe (class C, n = 6) according to Child-Pugh's classification. vWF antigen (P < .0001) and endotoxemia (P < .0001) progressively increased from A to class C; but the increase of vWF antigen was not strictly related to liver failure, as shown by the lack of correlation between vWF and several indexes of liver protein synthesis. Analysis of the vWF subunit showed no sign of proteolytic fragmentation of the molecule. Multimeric analysis indicated intact vWF multimeric structure. In all patients, there was a strong correlation between vWF antigen and endotoxemia (rho = .92; P = .0001). In 20 selected patients, vWF antigen and endotoxemia were measured before and after 7 days of standard therapy (n = 10) or standard therapy plus nonabsorbable antibiotics. There was a significant decrease of vWF antigen (P < .02) concomitantly with the decrease of endotoxemia (P < .006) in patients taking nonabsorbable antibiotics. Human umbilical vein endothelial cells incubated in vitro with 125 to 500 pg/mL endotoxin released vWF antigen into the medium dose dependently. These results demonstrate that there is endothelial perturbation in cirrhosis and that endotoxemia may play a key role in its occurrence. PMID- 8675156 TI - Intensive care unit admissions with cirrhosis: risk-stratifying patient groups and predicting individual survival. AB - Prognosis for acutely ill patients with cirrhosis is influenced by the severity of hepatic abnormalities and by dysfunction of other organ systems. The purpose of this study was to examine the usefulness of the Acute Physiology, Age, and Chronic Health Evaluation (APACHE III) prognostic system for risk-stratifying groups of intensive care unit (ICU) patients with cirrhosis and in predicting individual survival. We used data for 17,440 ICU admissions at 40 American hospitals to select 117 of the 537 patients with a history of cirrhosis who were ventilated on ICU day 1, a group known to have a high mortality rate. We then calculated each patient's probability of hospital death on ICU days 1 through 7, using seven previously validated multivariate equations. Hospital mortality was 63% for the 117 study patients. The most important determinants of risk for hospital death on ICU day 1 were the acute physiology score of APACHE III, ICU admission diagnosis, and operative status. Daily changes in the acute physiology score caused a rise or fall in the probability of hospital mortality and was useful in assessing individual response to therapy. APACHE III accurately risk stratifies critically ill patients with cirrhosis because it accounts for many of the factors known to influence prognosis. This capability can be used to assess severity of illness and risk-stratify patients with cirrhosis during clinical trials. Daily prognostic estimates based on physiological changes over time reflect patient response and can help physicians to assess the incremental benefit of therapy. PMID- 8675155 TI - Quantitation of alpha-fetoprotein and albumin messenger RNA in human hepatocellular carcinoma. AB - To analyze gene expression of alpha-fetoprotein (AFP) and albumin in hepatocellular carcinoma (HCC), messenger RNAs (mRNAs) of these proteins in six human hepatoma cell lines and in 30 cases of HCC were quantitatively analyzed by competitive reverse transcription (RT) followed by polymerase chain reaction (PCR). The transcriptional levels of both AFP and albumin genes in HepG2 and Huh 7 cell lines were 10(10) copies/microgram RNA, in contrast to approximately 10(5) copies/microgram RNA in HLE and HLF cell lines. AFP and albumin mRNA levels in three normal livers were 10(5) and 10(10) transcripts/microgram RNA, respectively. In 30 cases with HCC AFP mRNA level in neoplasm was 10 to 10(5) fold enhanced as compared with that of nonneoplastic portion, and correlated with serum AFP level and tumor size (P < .01). In contrast, albumin mRNA level was not reduced in the neoplasms presenting enhanced AFP mRNA levels, indicating that AFP and albumin gene expression in situ is not necessarily mutually exclusive. Prospective analysis revealed that an increased serum AFP was shown at the time of recurrence among patients with enhanced AFP mRNA levels in neoplasm only, indicating that AFP mRNA levels in neoplasm could be a clinically predictable tool. PMID- 8675157 TI - Biochemical epidemiology of gallbladder cancer. AB - To evaluate the a priori hypotheses that an increased level of glyco and tauro lithocholic acid, perhaps because of a decreased capacity for hepatic sulfation, contributed to the biochemical epidemiology of gallbladder cancer, a case-control study was undertaken at four hospitals in La Paz, Bolivia, and at one hospital in Mexico City, Mexico. Eighty-four cases with newly diagnosed histologically confirmed gallbladder cancer were compared with 264 controls with cholelithiasis or choledocholithiasis in the absence of cancer and with 126 controls with normal biliary tracts. All study subjects were undergoing abdominal surgery. Interview data were collected for all study subjects, as well as blood, bile, and gallstone specimens when feasible. Sera were analyzed for carcinoembryonic antigen, cholesterol concentration, and total bile acids. Bile specimens were analyzed for carcinoembryonic antigen; and for concentration of bile salts; cholesterol; phospholipids; and the glycine and taurine conjugates of cholic, ursodeoxycholic, chenodeoxycholic, deoxycholic, and lithocholates; sulfoglycolithocholate; and sulfotaurolithocholate. Gallstone specimens were analyzed for the percentage of cholesterol content, the percentage of calcium bilirubinate content, and the percentage of calcium carbonate content. Serum bile acids were increased in cases versus the two control groups (median 11.7 nmol/mL vs. 9.3 nmol/mL for stone controls and 8.2 nmol/L for nonstone controls, P < or = .02 for each pairwise comparison). Biliary bile acids were markedly decreased in the cases (median 3.98 micromol/mL vs. 33.09 micromol/mL, and 154.0 micromol/L, respectively, P < or = .0001 for each comparison), even after excluding those with a serum bilirubin higher than 2.0 mg/dL. Bile cholesterol was lower for the cases as well (median 1.70 micromol/mL vs. 4.90 micromol/mL, and 16.81 micromol/ mL, respectively, P < or = .02), as was the concentration of bile phospholipids (median 2.97 micromol/mL vs. 6.26 micromol/mL, and 52.69 micromol/mL, P = .1 and .0004, respectively). Contrary to our a priori hypothesis, there was no difference between the cases and either control group in their bile concentrations of lithocholate, the proportion of bile acids which were sulfated, or the concentration of nonsulfated lithocholate. However, the cases had a higher concentration of ursodeoxycholate (UDC) (P < .004 for both control groups), especially glycoursodeoxycholate (P < .001 for both control groups). A previously published suggestion that gallstone size differed between cases and controls was not confirmed. In conclusion, cases with gallbladder cancer differed from controls with stones and from controls with normal biliary tracts in their serum and bile biochemistries. These findings may be a reflection of the disease process, or may provide useful clues to its pathogenesis. PMID- 8675158 TI - Liver function in early Lyme disease. AB - To evaluate the frequency, pattern, and severity of liver function test abnormalities in patients with Lyme disease associated with erythema migrans (EM), 115 individuals with no other identifiable cause for liver function test abnormalities who presented with EM between July 1990 and September 1993 were prospectively evaluated. For individuals with abnormal liver function tests, common causes of hepatitis, including hepatitis A, B, and C, were excluded. A local control group was used for comparison. Forty-six (40%) patients had at least one liver test abnormality, and 31 (27%) had more than 1 abnormality compared with 19 (19%) and 4 (4%) of controls, respectively (P < .01 for each comparison). gamma-Glutamyl transpeptidase (28%) and alanine transaminase (ALT) (27%) were the most frequently elevated liver function tests among Lyme disease patients. Anorexia, nausea, or vomiting was reported by 30% of patients, but did not occur more frequently in patients with elevated liver function tests compared with those with normal values. Patients with early disseminated Lyme disease were more likely to have elevated liver function studies (66%) compared with patients with localized disease (34%) (P = .002). After antibiotic treatment, elevated liver function tests improved or resolved in most patients. Liver function test abnormalities are common in patients with EM but were mild, most often not associated with symptoms, and improved or resolved by 3 weeks after the onset of antibiotic therapy in most patients. PMID- 8675159 TI - Effect of venovenous bypass on perioperative renal function in liver transplantation: results of a randomized, controlled trial. AB - Although venovenous bypass (VVBP) has been suggested to protect the kidneys during liver transplantation and its systematic use has therefore been recommended, this beneficial effect of VVBP has not been clearly demonstrated. In a prospective, randomized, controlled trial, 77 patients receiving liver transplants for chronic liver disease were allocated to be supported with VVBP (group 1, 38 patients) or not (group 2, 39 patients). Both groups were similar in relation to preoperative clinical and laboratory data and operative transfusion requirements. Inulin clearance and urinary beta(2)-microglobulin and N-acetyl beta-D-glucosaminidase (NAG) excretion (to determine glomerular filtration rate and tubular damage, respectively) were measured at different perioperative periods (anesthesia induction, hepatectomy, anhepatic phase, biliary anastomosis, and 24 hours after surgery). A significant decrease in inulin clearance and increase in tubular damage markers were observed in the anhepatic phase, which only partly improved in the subsequent phases. No significant differences were observed between groups 1 and 2 at any perioperative phase, except during the anhepatic phase, in which a more marked renal function impairment occurred in group 2 patients. However, renal function on the 7th postoperative day and the need for hemodialysis/ hemofiltration during the 1st week were similar in both groups. Among 40 variables analyzed, only low mean arterial pressure at anesthesia induction was identified as an independent predictor for early postoperative severe renal failure (inulin clearance < 10 mL/min/1.73 m(2) at the 24th postoperative hour), with no significant relationship between this complication and the use of venovenous bypass. Renal function markedly deteriorates during liver transplantation, and renal impairment persists during the early postoperative period. Because VVBP support is not associated with any clear benefit in renal function, its systematic use does not seem to be justified. PMID- 8675160 TI - The caffeine breath test does not identify patients susceptible to tacrine hepatotoxicity. AB - Therapy with tacrine, a promising new treatment for Alzheimer's disease, must be discontinued in up to 15% of patients because of hepatocellular toxicity. Recent studies using human liver microsomes have suggested that a single liver enzyme, cytochrome P450 1A2 (CYP1A2), catalyzes the major route of metabolism and elimination of tacrine, and also catalyzes the pathway(s) involved in the generation of reactive metabolites capable of covalent protein binding and cytotoxicity. Because CYP1A2 activity has been shown to vary up to 60-fold among patients, we proposed that a convenient measure of CYP1A2 activity, the [(13)C 3 methyl] caffeine breath test (CBT), might be clinically useful in identifying patients most susceptible to tacrine liver toxicity. To test this hypothesis, we administered the CBT to 37 patients with Alzheimer's disease before they began treatment with tacrine. Twenty patients received 2 mg/kg of [(13)C 3-methyl] caffeine. The remaining 17 patients received the commercially available CBT kit, which employs a constant 200-mg dose. The activities of two other major drug metabolizing enzymes (cytochrome P450 3A4 and 2D6 [CYP3A4 and CYP2D6]) were also measured in these 17 patients. We found that the results obtained from the CBT protocol did not predict the peak serum alanine transaminase (ALT) observed in the patients. The measured CYP3A4 and CYP2D6 activities also failed to predict the susceptible patients. However, the result of the standardized-dose CBT correlated well with the logarithm of the steady-state plasma tacrine level obtained in 10 patients (R(2) = .69, P = .003). We conclude that the CBT will not be clinically useful in determining the subset of patients most susceptible to tacrine hepatotoxicity. However, the correlation we observed between CBT results and tacrine blood levels is the first evidence supporting a critical role for CYP1A2 activity in the disposition of the drug in vivo. PMID- 8675161 TI - Liver abscess formation after local treatment of liver tumors. AB - Our goal was to determine a subset of patients at high risk of developing liver abscesses after local treatment of liver tumors (LTLT) and establish guidelines for the conduct of LTLT in the safest conditions in such patients. Five hundred sixty-one LTLT, 489 transhepatic arterial chemoembolizations (TAC, 10 hepatic embolizations, and 62 percutaneous intratumor injections (PIT), were retrospectively reviewed for liver parenchyma necrosis and abscess formation. Four patients developed abscesses, three after TAC and one after PIT. Despite broad-spectrum antibiotherapy, percutaneous drainage, and surgery, two patients died. A left hepatectomy was required in the other two patients for cure. All four patients had a carcinoid or a neuroendocrine pancreatic tumor. Three out of four patients had bilioenteric anastomoses, and the fourth had recently undergone cholecystectomy and papillotomy. A Lipiodol/doxorubicin mixture without any particulate embolization was injected in the three patients who developed abscesses after TAC. LTLT in patients with bilio enteric anastomosis or papillotomy and/or neuroendocrine or carcinoid tumor should be performed with strict precautions during the procedure and for peri-procedural care. PMID- 8675162 TI - Expression of epithelial cadherin and alpha- and beta-catenins in nontumoral livers and hepatocellular carcinomas. AB - Expression of the cell adhesion molecule, epithelial cadherin (E-CD) and its binding proteins, alpha- and beta-catenins, in normal liver, chronic liver diseases, and hepatocellular carcinomas (HCCs) was investigated immunohistologically. In normal liver, weak immunostaining of E-CD and catenins was observed at the lateral membranes of the hepatocytes, whereas at the interlobular bile duct epithelia, they stained strongly. No immunoreactions were seen in sinusoidal Kupffer cells. Similar results were observed in the majority of livers from chronic hepatitis and cirrhosis sufferers; however, hepatocytes undergoing regeneration and rosette formation, as well as Hering canals and proliferating ductules, showed markedly increased molecular expression. Analysis of 66 HCC lesions revealed that the majority (64.3-96.6%) of thin trabecular- and pseudoglandular-type tumors preserved or overexpressed E-CD and catenins, whereas thick trabecular-type HCCs frequently showed low E-CD and alpha-catenin expression (56.5-65.2% reduction), suggesting that the thick trabecular histology represented diffuse tumor cell growth. Likewise, the E-CD and catenin expression levels correlated with the HCC cell differentiation grades. These collective results indicate that intercellular adhesion mediated by the E-CD-catenin system plays a role in morphological changes in nonmalignant and malignant hepatic diseases. PMID- 8675163 TI - Fulminant hepatitis in a tropical population: clinical course, cause, and early predictors of outcome. AB - The profiles of patients with fulminant hepatic failure (FHF) from developing countries have not been reported earlier. The current study was conducted prospectively, at a single tertiary care center in India, to document the demographic and clinical characteristics, natural course, and causative profile of patients with FHF as well as to define simple prognostic markers in these patients. Four hundred twenty-three consecutive patients with FHF admitted from January 1987 to June 1993 were included in the study. Each patient's serum was tested for various hepatotropic viruses. Univariate Cox's regression for 28 variables, multivariate Cox's proportional hazard regression, stepwise logistic regression, and Kaplan-Meier survival analysis were done to identify independent predictors of outcome at admission. All patients presented with encephalopathy within 4 weeks of onset of symptoms. Hepatotropic viruses were the likely cause in most of these patients. Hepatitis A (HAV), hepatitis B (HBV), hepatitis D (HDV) viruses, and antitubercular drugs could be implicated as the cause of FHF in 1.7% (n= 7), 28% (n= 117), 3.8% (n= 16), and 4.5% (n= 19) patients, respectively. In the remaining 62% (n= 264) of patients the serological evidence of HAV, HBV, or HDV infection was lacking, and none of them had ingested hepatotoxins. FHF was presumed to be caused by non-A, non-B virus(es) infection. Sera of 50 patients from the latter group were tested for hepatitis E virus (HEV) RNA and HCV RNA. In 31 (62%), HEV could be implicated as the causative agent, and isolated HCV RNA could be detected in 7 (19%). Two hundred eighty eight (66%) patients died. Approximately 75% of those who died did so within 72 hours of hospitalisation. One quarter of the female patients with FHF were pregnant. Mortality among pregnant females, nonpregnant females, and male patients with FHF was similar (P > .1). Univariate analysis showed that age, size of the liver assessed by percussion, grade of coma, presence of clinical features of cerebral edema, presence of infection, serum bilirubin, and prothrombin time prolongation over controls at admission were related to survival (P < .01). The rapidity of onset of encephalopathy and cause of FHF did not influence the outcome. Cox's proportional hazard regression showed age > or = 40 years, presence of cerebral edema, serum bilirubin > or = 15 mg/dL, and prothrombin time prolongation of 25 seconds or more over controls were independent predictors of outcome. Ninety three percent of the patients with three or more of the above prognostic markers died. The sensitivity, specificity, positive predictive value, and the negative predictive value of the presence of three or more of these prognostic factors for mortality was 93%, 80%, 86%, and 89.5%, respectively, with a diagnostic accuracy of 87.3%. We conclude that most of our patients with FHF might have been caused by hepatotropic viral infection, and non-A, non-B virus(es) seems to be the dominant hepatotropic viral infection among these patients. They presented with encephalopathy within 4 weeks of the onset of symptoms. Pregnancy, cause, and rapidity of onset of encephalopathy did not influence survival. The prognostic model developed in the current study is simple and can be performed at admission. PMID- 8675164 TI - Acute reactant cytokines and neutrophil adhesion after warm ischemia in cirrhotic and noncirrhotic human livers. AB - Animal studies suggest that acute phase reactant cytokines and polymorphonuclear leukocytes (PMN) may play a critical role in ischemia-reperfusion injury. To evaluate whether similar mechanisms are operative in human liver, six cirrhotic and nine noncirrhotic patients undergoing right hepatectomy were randomized for utilization of hepatic vascular exclusion (HVE) as a model of ischemia reperfusion injury. Portal and systemic levels of acute reactant cytokines (interleukin 6 [IL-6], interleukin 1 [IL-1], tumor necrosis factor alpha [TNF alpha]) and neutrophil adhesion in serial liver biopsy specimens were studied. Correlations among mediators, leukocyte adhesion, and markers of liver injury were also evaluated. Hepatic vascular exclusion resulted in substantial and reproducible changes in portal and arterial IL-6 levels in both cirrhotic and noncirrhotic patients. Portal and systemic cytokine levels were comparable in most instances, whereas levels were usually higher in cirrhotic patients than in noncirrhotic patients. Negative correlations were found between IL-6 levels at the time of reperfusion and later TNF-alpha levels. IL-6 levels correlated negatively with numerous markers of hepatocellular injury and the number of postoperative complications. Hepatic vascular exclusion increased neutrophils adhesion after reperfusion in cirrhotic patients but not in noncirrhotic patients. In cirrhotic patients, the degree of leukocyte adhesion after reperfusion correlated with several postoperative markers of liver injury. This study in humans shows that acute reactant cytokines are released during liver ischemia and, interestingly, that IL-6 levels strongly correlate with clinical and laboratory measures of injury. Further studies to evaluate possible causal relationship with hepatic injury are warranted, with emphasis on the role of IL-6 and PMN adhesion. PMID- 8675165 TI - Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. AB - Non-alcohol-induced steatohepatitis (NASH) is characterized by elevated serum aminotransferase activities with hepatic steatosis, inflammation, and occasionally fibrosis that may progress to cirrhosis. No established treatment exists for this potentially serious disorder. Our aim was to conduct a pilot study to evaluate the safety and estimate the efficacy of ursodeoxycholic acid (UDCA) and clofibrate in the treatment of NASH. Forty patients were diagnosed with NASH based on a compatible liver biopsy with other causes of liver disease, including alcohol abuse, excluded by history, serum tests, and use of ultrasound. Twenty-four patients received 13 to 15 mg/kg/d of UDCA for 12 months. Sixteen patients with hypertriglyceridemia were placed on clofibrate, 2 g/day for 12 months. Twenty-five women and 15 men entered the study. Six of 40 patients (15%) withdrew because of side effects. Four additional patients were withdrawn because of noncompliance; one of them later required liver transplantation. In the UDCA group, the decreases in mean serum levels of alkaline phosphatase, alanine transaminase (ALT), and gamma-glutamyl transpeptidase (GGT) as well as histological grade of steatosis were significant. Among the patients treated with clofibrate, no change from baseline was found in mean ALT, aspartate transaminase (AST), GGT, bilirubin, triglycerides, and cholesterol, or in histological grade of steatosis, inflammation, or fibrosis after 12 months of treatment as compared with entry. Alkaline phosphatase activities decreased significantly from baseline. Despite the known lipid-lowering effects of clofibrate, it did not appear to be of clinical benefit in the treatment of NASH in this 1-year pilot study. However, treatment of NASH with UDCA for 12 months resulted in significant improvement in alkaline phosphatase, ALT, GGT, and hepatic steatosis. The possible benefit of UDCA therapy should be further investigated in the context of a randomized, controlled trial. PMID- 8675166 TI - Hepatocyte proliferative activity in chronic liver damage as assessed by the monoclonal antibody MIB1 Ki67 in archival material: the role of etiology, disease activity, iron, and lipid peroxidation. AB - Hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related liver damage is linked to an increased risk of hepatocellular carcinoma, but the mechanisms underlying hepatitis C viral activity are not known. We therefore compared hepatocellular proliferative activity in chronic C virus-related hepatitis and in liver damage of other etiology. Hepatocyte proliferation rate was investigated in 56 patients with chronic hepatitis using the Ki67 MIB1 monoclonal antibody in archival material. According to etiology, the patients were subgrouped as follows: HCV (34), HBV (11), Alcohol (4), HCV + Alcohol (4), and Hemochromatosis (3). Proliferation rate was correlated with age, sex, etiology, disease activity, liver iron storage, free-radical production, and glutathione levels by regression and discriminant analysis. HCV-positive patients had significantly more MIB1 positive hepatocytes in the periportal area (P < .011) and in the low proliferating perivenular area (zones 2 and 3) (P < .05). The number of MIB1 positive cells correlated directly with alanine transaminase (ALT) levels, Knodell index (KI), and, inversely, with iron saturation. By stepwise discriminant analysis, ALT levels and etiology were identified as single independent variables. These data suggest that HCV infection induces increased and abnormal hepatocyte proliferation, which might be related to the increased risk of hepatocellular carcinoma in patients with HCV-related liver damage. PMID- 8675167 TI - FK506 inhibits human lymphocyte migration and the production of lymphocyte chemotactic factors in liver allograft recipients. AB - The macroglide immunosuppressant FK506 is effective at preventing and reversing hepatic allograft rejection. The establishment of graft rejection is dependent upon an influx of lymphocytes from the circulation into the graft in response to locally secreted chemotactic factors. Thus, inhibition of lymphocyte migration might be an additional mode of action of FK506 that could block lymphocyte recruitment to rejecting liver allografts. In the present study, we provide evidence to support this hypothesis because we have demonstrated, using in vitro migration assays, that FK506 can inhibit the migration of lymphocytes, including CD4+ and CD8+ T-cells, to structurally diverse chemotactic factors that are present during human liver allograft rejection. In addition, FK506 acts on lymphocytes in patients with graft rejection to inhibit migration and to block the secretion of chemotactic factors in vitro. Thus, FK506 might reverse established graft rejection by inhibiting lymphocyte recruitment to the graft in vivo. PMID- 8675168 TI - Ursodeoxycholic acid for liver disease associated with cystic fibrosis: a double blind multicenter trial. The Italian Group for the Study of Ursodeoxycholic Acid in Cystic Fibrosis. AB - Liver disease is increasingly recognized as a major cause of morbidity in cystic fibrosis (CF). Preliminary data suggest that ursodeoxycholic acid (UDCA) may be beneficial for treatment of this manifestation. We performed a double-blind, multicenter trial in these patients to establish efficacy and safety of UDCA in terms of the improvement of clinical and nutritional indicators besides standard liver function tests. We also intended to establish whether taurine supplementation has a beneficial effect in patients receiving UDCA. From June to December 1990, we enrolled in 12 centers 55 CF patients with liver disease (39 male subjects; median age, 13.8 years). They were randomly assigned to receive for 1 year one of the following treatments: UDCA (15 mg/kg body weight daily) plus taurine (30 mg/kg body weight daily), UDCA plus placebo, placebo plus taurine, or double placebo. Clinical and laboratory evaluations were performed every 3 months. After 1 year, deterioration of overall clinical conditions, as indicated by the Shwachman-Kulczycki score (SKS), occurred in patients who received placebo but not in those who received UDCA (P = .025). Patients treated with UDCA also showed an improvement in gamma-glutamyl transpeptidase (GGT) (P = .004) and 5'-nucleotidase (P = .006) levels. Treatment with taurine was followed by a significant increase in serum prealbumin levels (P = .053), a trend toward a reduction in fat malabsorption, and no effect on the biochemical profile. No severe side effects occurred with any treatment. Thus, we concluded that UDCA administration improves clinical and biochemical parameters in CF patients with liver disease. Taurine supplementation may be indicated in patients with severe pancreatic insufficiency and poor nutritional status. PMID- 8675169 TI - Nonlinear kinetics after high-dose omeprazole caused by saturation of genetically variable CYP2C19. AB - Nonlinear kinetics of omeprazole and its metabolites were investigated after treatment with repeated high doses. Extensive metabolizers relating to cytochrome P450 2C19 (CYP2C19) activity received for 1 week either omeprazole at 40 mg/d (n = 14) or 60 mg/d omeprazole twice daily (n = 8). Five poor metabolizers (PMs) received 40 mg/d for 1 week. Comparison of omeprazole plasma kinetics between extensive metabolizers (EMs) and PMs after 40-mg treatment revealed a dominant role of CYP2C19 over cytochrome P450 3A CYP3A in omeprazole metabolism. Comparing the omeprazole doses of 40 mg and 60 mg in eight EMs on day 7 of treatment showed that CYP2C19-dependent plasma clearance of omeprazole and omeprazole sulfone was reduced from 19.0 to 8.4 L/h (P < .001) and from 19.8 to 9.2 L/h (P = .012), respectively. Similarly, formation half-life of 5'-hydroxyomeprazole increased from 0.58 to 1.45 hours (P = .025) with the higher dose. CYP3A-dependent metabolic routes remained unaffected. Thus, high-dose treatment with omeprazole uncovers saturation kinetics for CYP2C19 pathways in EMs, and CYP3A becomes the predominant enzyme of omeprazole elimination. Moreover, these individuals may be at risk for side effects due to high omeprazole concentrations if high-dose omeprazole treatment is combined with drugs inhibiting CYP3A activity. PMID- 8675171 TI - Coagulation factor V levels as a prognostic indicator in fulminant hepatic failure. AB - Data reported by Bernuau et al. have strongly supported the measurement of coagulation factor V as the best prognostic indicator in fulminant hepatic failure (FHF) and as the test on which selection for urgent liver transplantation should be made. In this study, we have measured plasma factor V in 110 patients with FHF, in grades I-IV coma, in 88 of whom the etiology was acetaminophen overdose. On admission, patients who did not survive had significantly lower factor V levels (median, 5%; range, 1-27; n = 49), compared with those who did (median, 10%; range, 2-70; P < .001). In the 81 patients with acetaminophen induced FHF who did not receive a transplant, there was no cutoff level of factor V that clearly separated the patients. On statistical analysis, a positive predictive value (the mortality in patients predicted to have a poor prognosis) of 0.49 was calculated for factor V <20% and 0.57 for factor V < 10%. If the prognostic criteria included deep coma (grades III and IV) as well as factor V <20%, a positive predictive value of 0.73 was calculated. This compared with a value of 0.92 for the well-established King's prognostic criteria based on pH, and a combination of international normalized ratio (INR), renal failure, and coma. In the 17 mixed, nonacetaminophen group of patients who did not receive a liver graft, the positive predictive value was 0.85 for a factor V level <20% and 1.00 for factor V <10%, compared with 0.93 for the King's criteria for that etiologic group. This study demonstrates that the predictive accuracy of plasma factor V level is much less effective than the well-validated King's criteria in the selection of patients with acetaminophen-induced FHF needing liver grafting, although it may be useful in patients with FHF due to other causes. PMID- 8675170 TI - Cloning of variable regions of an antibody that reacts with the soluble fraction of human liver cells and its possible value in chronic liver disease. AB - A gene encoding the variable regions of the heavy and light chains of a mouse monoclonal antibody designated H2, which specifically reacts with human liver cells, was cloned into a phagemid vector. The clone of the variable region was designed to be expressed as a separate protein, the structure of which is the same as that of the mouse antibody. The cloned phage protein specifically reacted with anti-idiotypic antibodies produced in rabbits against the original mouse antibody, and this reaction was specifically blocked by the original antibody. The soluble protein, expressed as a fusion protein, was detected as a single 30 kd band on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and specifically bound to an anti-H2 idiotypic antibody as determined by Western blot analysis. Sera of patients with various diseases were assayed for antibodies to anti-H2 by sandwich enzyme-linked immunosorbent assay (ELISA). Only sera from patients with chronic liver disease reacted strongly. This binding was specifically blocked by the cloned soluble protein. The nucleotide sequences of the variable regions were determined by the dideoxy chain-termination method, and the sequences were approximately 95% identical to those of other mouse immunoglobulins. These findings suggest that a human antibody with the same idiotype as a mouse monoclonal antibody that reacts with human liver cells, can be detected in patients with chronic liver disease, suggesting that autoimmunity may be partly responsible for these diseases. PMID- 8675172 TI - Transferrin receptor-independent uptake of differic transferrin by human hepatoma cells with antisense inhibition of receptor expression. AB - The hepatic uptake of transferrin-bound iron by a nontransferrin receptor (NTR) mediated process was investigated using the human hepatoma cell line HuH7. Because HuH7 cells also acquire iron from transferrin by a receptor (TR)-mediated process, TR expression was inhibited by transfecting the cells with a plasmid containing human TR complementary DNA in antisense orientation relative to a human cytomegalovirus promoter/enhancer element. Cell clones were obtained that expressed a 50% to 60% reduction in cell surface TR, leading to a corresponding decrease in transferrin and iron uptake compared with wild-type cells. Uptake of transferrin by a second process was nonsaturable and not inhibited by a 100-fold excess of unlabeled transferrin. The amounts of transferrin taken up by the wild type and antisense cells by this process were similar, showing that it did not involve TR. The proteolytic enzyme Pronase reduced the uptake of transferrin, suggesting that the NTR-mediated process entailed the nonsaturable binding of transferrin to plasma membrane proteins. This process, like the TR-mediated one, involved the internalization and recycling of transferrin, leading to accumulation of iron with time. Iron uptake mediated by NTR process was saturable and displaced by 100-fold excess unlabeled transferrin and reduced by weak bases and metabolic inhibitors. Therefore, the NTR-mediated process entailed transferrin adsorption to membrane-bound proteins, internalization, and release of iron from transferrin by a pH-dependent step followed by the intracellular transport of iron into ferritin and heme by a saturable carrier-mediated mechanism. PMID- 8675173 TI - Hepatic sinusoidal endothelium heterogeneity with respect to mannose receptor activity is interleukin-1 dependent. AB - Using fluorescein isothiocyanate-conjugated ovalbumin (OVA-FITC), 125I-mannan, or 125I-invertase as specific ligands for the mannose receptor, we have quantified its activity in mouse and rat hepatic sinusoidal endothelium (HSE), under both basal conditions and after lipopolysaccharide (LPS) or human recombinant interleukin-1beta (IL-1beta) stimulations. Mouse treatment for 4 hours with 5 microg/kg IL-1beta significantly increased OVA-FITC uptake by HSE. Ligand uptake exhibited a sublobular compartmentalization: In control mice as well as in IL 1beta-stimulated mice, the ligand distributed preferentially in the periportal and septal areas; no OVA-FITC was observed in the perivenous sinusoids. In vitro exposure of mouse HSE to 100 pg/mL LPS or 1 ng/mL IL-1beta for 6 hours significantly (P < .01) increased OVA-FITC uptake. Blocking IL-1 receptors in HSE by addition of 100 ng/mL IL-1 receptor antagonist (IL-1Ra) before stimulation with LPS or IL-1beta abrogated the increase in mannose receptor-mediated uptake. In vitro endocytosis assays showed that rat HSE uptake of 125I-mannan or 125I invertase progressively increased with both exposure time and concentration of added IL-1beta. Upregulation of mannose receptor-mediated uptake in response to IL-1beta or LPS was also blocked by previous addition of IL-1Ra to rat HSE. Flow cytometric analysis showed a significant HSE heterogeneity in mannose receptor mediated endocytosis in response to IL-1beta treatment: type I endothelial cells (EC-I, defined by their small size and high cytoplasmic density) significantly (P < .01) increased OVA-FITC uptake compared with type II endothelial cells (EC-II, defined by their large size and low cytoplasmic density). In addition, the subset of EC-I contained three times more IL-1beta-binding cells than the EC-II subset. Because EC-I and EC-II are preferentially located in the periportal and perivenous segments of hepatic sinusoids, respectively, these results suggest that IL-1beta, apart from upregulating mannose receptor activity, contributes to the sublobular compartmentalization of this endothelial cell function. PMID- 8675174 TI - Insulin-like growth factor II/mannose 6-phosphate-receptor expression in liver and serum during acute CCl4 intoxication in the rat. AB - The liver is reported to be the main source of soluble insulin-like growth factor II/mannose 6-phosphate (IGF-II/M6P) receptor in adults. In view of the role of this receptor in the activation of transforming growth factor beta (TGF-beta) during hepatic fibrogenesis, we have investigated the correlation between serum levels and tissue expression of the receptor during acute CCl4 intoxication of the rat. Sixteen hours after CCl4, injection, the level of the soluble receptor in serum, as measured by radioimmunoassay (RIA), increased threefold. At 24 hours, values almost returned to normal, but increased again by twofold at 48 hours. By 96 hours, nearly normal values were obtained. Northern blot analysis showed peaks in tissue IGF-II/M6P receptor messenger RNA (mRNA) levels at 24 hours and at 48 hours. In normal liver, immunostaining for IGF-II/M6P receptor showed weak positivity in parenchymal cells. CCl4-induced hydropic changes appeared in centrilobular parenchymal cells (PCs) at 8 hours. These changes extended to the midzonal region at 16 hours. Hydropic cells were devoid of receptor staining. The hydropic wave became extinct at 32 hours. At 48 hours, we observed a collapse of PCs in the centrilobular zone, coinciding with strongly positive staining for IGF-II/M6P receptor in fat-storing cells (FSCs), identified by dual IGF-II/M6P receptor and desmin immunostaining. Between 48 and 72 hours, the liver gradually regained its normal appearance. As shown by Western blotting, in vitro differentiated FSCs released soluble receptor in the medium. Northern blot analysis showed this release to be preceded by an increased receptor-mRNA expression, whereas immunostaining showed an increase of intracellular receptor. In conclusion, we have shown that acute CCl4 intoxication induces two peaks in serum levels of soluble receptor. While the first peak at 16 hours coincides with the loss of receptor-staining in hydropically damaged PCs, the second peak at 48 hours is paralleled by an increase in positive staining in FSCs and tissue mRNA level. Differentiated FSCs shed soluble receptor in vitro. As a consequence, these cells might contribute to the serum levels of soluble receptor in vivo. These results indicate that measuring serum soluble IGF-II/M6P receptor might useful in the diagnosis of early acute liver damage. PMID- 8675175 TI - Comparison of glial fibrillary acidic protein and desmin staining in normal and CCl4-induced fibrotic rat livers. AB - Fat-storing cells are the major producers of extracellular matrix in the liver. A good immunocytochemical marker is, however, still lacking for this cell type. Desmin, frequently used by most investigators, fails to stain many pericentral fat-storing cells in normal rat liver. The aim of the present study is to evaluate glial fibrillary acidic protein (GFAP) as an alternative marker of fat storing cells. In normal rat liver, immunostaining of GFAP revealed numerous fat storing cells with characteristic cytoplasmic extensions. Unlike desmin, which was preferentially expressed in periportal fat-storing cells, GFAP-positive fat storing cells were distributed more evenly in the lobules. In a narrow periportal zone, however, GFAP-positive cells were occasionally absent. Dual GFAP/desmin staining revealed colocalization of these markers, but fat-storing cells positive only for GFAP or desmin were also present. Chronic carbon tetrachloride exposure induced a spatial change in the expression of GFAP and desmin. At 3 weeks, accumulation of GFAP/desmin double-positive cells was observed in developing fibrotic septa. At 8 weeks, the GFAP positivity in the septa persisted but became weak, while desmin expression became stronger. In contrast, the expression of GFAP within the lobule was gradually decreased as fibrosis progressed. We conclude that GFAP is expressed by a subpopulation of fat-storing cells, which differs partially from the population that expresses desmin. Because in normal rat liver desmin-negative fat-storing cells can be identified by GFAP staining and vice versa, dual GFAP/desmin staining allows more complete identification of fat-storing cells. In chronically injured liver, GFAP may not be as useful as in normal rat liver. The coexpression of GFAP/desmin in developing septa and the subsequent downregulation of GFAP in an advanced stage of fibrosis may reflect different stages of fat-storing cell activation. Further investigation is required to determine the functional significance of alteration of GFAP expression in fat-storing cells. PMID- 8675176 TI - Expression of c-fos and c-jun during hepatocellular remodeling following ischemia/reperfusion in mouse liver. AB - The expression of the immediate early genes (IEGs) c-fos and e-jun have been hypothesized to potentially play key roles in mediating cellular responses following injury to the liver. In this study, we sought to evaluate the potential involvement of c-jun and c-fos as determinants either of cellular regeneration or programmed cell death following ischemia/reperfusion (I/R) in mouse liver. To this end, we have analyzed the in situ messenger RNA (mRNA) expression patterns of c-jun and c-fos following lobar I/R in mouse liver. The expression patterns of c-jun and c-fos were correlated with four criteria for tissue repair and injury, including: 1) morphological determinations of regeneration using immunocytochemical detection of proliferating cell nuclear antigen (PCNA), 2) programmed cell death (apoptosis) using the in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method, 3) histopathologic assessment of hepatocellular necrosis, and 4) serum glutamic pyruvic transaminase (GPT) levels. Increasing lengths of lobar ischemia for 3, 60, and 90 minutes followed by reperfusion directly correlated with the extent of liver injury as determined by serum transaminases and hepatocellular necrosis. PCNA expression in the liver was elevated at 1 to 6 hours following liver reperfusion and returned to baseline levels by 20 hours in both ischemic and nonischemic lobes. In contrast, apoptotic responses peaked only in ischemic lobes at 6 hours' postreperfusion and remained elevated out to 20 hours. Two distinct patterns of c-jun and c-fos expression were observed during the acute (1-3 hours) and subacute (6-20 hours) phases of liver responses to I/R including: 1) coexpression of c-jun and c-fos mRNA within damaged regions of the liver at 1 to 3 hours' postreperfusion, and 2) a decline in c-fos expression with sustained high levels of c-jun expression within a subset of cells bordering necrotic/apoptotic regions of the liver at 6 to 20 hours' postreperfusion. These findings suggest that coexpression of both c-jun and c-fos may be involved in mediating early tissue repair processes in liver remodeling following I/R. In contrast, the onset of hepatocellular apoptosis correlated with sustained c-jun expression, in the absence of c-fos, and suggests that these changes in the molecular profile of immediate early gene expression may regulate cellular responses that signal hepatocytes for programmed cell death. PMID- 8675177 TI - Effects of ethanol administration on components of the ubiquitin proteolytic pathway in rat liver. AB - Hepatic protein accumulation during ethanol administration may result partly from an ethanol-elicited decline in hepatic protein degradation, which we have previously shown. We conducted the current studies to examine the effects of ethanol administration on the levels of hepatic ubiquitin, an 8.5-kd protein which is an important mediator of extralysosomal protein catabolism. Rats were pair-fed liquid diets containing either ethanol (36% of calories) or isocaloric maltose-dextrin for 1 to 5 weeks. Ubiquitin was immunochemically quantified by competitive enzyme-linked immunosorbent assay (ELISA) in crude cytosol fractions from whole liver and in 12,000g supernatants of hepatocyte lysates. Ubiquitin levels in hepatic cytosol fractions of ethanol-fed rats exceeded those of controls by about 30%. Isolated hepatocytes from ethanol-fed animals also showed a 40% to 75% elevation of ubiquitin above that in cells of pair-fed controls and this difference exceeded the relative rise in hepatocellular protein. In hepatocyte lysates subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting, we detected monomeric ubiquitin and higher molecular mass ubiquitin-protein conjugates. However, the immunoblot analyses revealed no quantitative changes in the level of either free or conjugated ubiquitin. The ubiquitin conjugating activity of crude and diethyl aminoethyl-fractionated liver cytosols of ethanol-fed rats had equal capacities to those from controls in catalyzing the formation of ubiquitin-protein conjugates. Our findings indicate that chronic ethanol consumption increased the level of immunoreactive ubiquitin in rat liver. This may have resulted from enhanced ubiquitin production because of an ethanol-elicited stress response and/or decreased catabolism of ubiquitin and its conjugates. Our findings also provide no indication that the ethanol-elicited reduction in hepatic proteolysis is because of a ubiquitin-mediated mechanisms. PMID- 8675178 TI - Modulation of basal hepatic glycogenolysis by nitric oxide. AB - We perfused livers from fed rats with a balanced salt solution containing 1 mmol/L glucose. Under these conditions a low steady rate of glycogenolysis was observed (approximately 1.7 micromol glucose equivalents/g/min; 20% of the maximal glycogenolytic activity). Nitric oxide (NO) transiently stimulated hepatic glucose production. A maximal response (on average doubling basal glucose output) was observed with 34 micromol/L NO. The same concentration of nitrite (NO2-) was ineffective. Half-maximal effects were seen at 8 to 10 micromol/L NO, irrespective of the flow direction (portocaval or retrograde). This glycogenolytic response to NO corresponded to a partial activation of phosphorylase. The NO effect was not additive to maximal stimulation of glycogenolysis (7.7 +/- 0.2 micromol hexose equivalents/g/min; n = 4) by 100 micromol/L dibutyryl cyclic adenosine monophosphate (Bt2cAMP). The requirement for activation of phosphorylase was also evidenced by the ineffectiveness of NO in phosphorylase-kinase-deficient livers of gsd/gsd rats. The NO effect was blocked by co-administration of cyclooxygenase inhibitors (50 micromol/L ibuprofen, 50 micromol/L indomethacin, or 2 mmol/L aspirin), suggesting a mediatory role of prostanoids from nonparenchymal cells. This conclusion was confirmed by the fact that NO did not activate phosphorylase in isolated hepatocytes. Moreover, NO was no longer glycogenolytic in livers perfused with Ca2+-free medium, in agreement with the known mediatory role of Ca2+ in prostanoid-mediated responses. Surprisingly, in Ca2+-free medium NO inhibited the basal glucose production. This coincided with an increased elution of cyclic guanosine monophosphate (cGMP). Inhibition of glycogenolysis by NO under these conditions was blocked by 1 mmol/L theophylline, suggestive for involvement of cGMP-stimulated cAMP phosphodiesterase. However, we could not confirm that an increase in cGMP resulted in a drop in cAMP. In conclusion, NO recruits opposing mechanisms with respect to modulation of basal hepatic glycogenolysis. In the presence of Ca2+, activation of phosphorylase with stimulation of glycogenolysis dominates. Cyclooxygenase inhibitors abolish this effect. Activation by NO of the cyclooxygenase in nonparenchymal cells is a distinct possibility. In the absence of Ca2+, inhibition of basal glycogenolysis becomes observable. It remains to be established whether this results from cGMP-mediated stimulation of hydrolysis of cAMP. PMID- 8675179 TI - Possible roles of nonparenchymal cells in hepatocyte proliferation induced by lead nitrate and by tumor necrosis factor alpha. AB - A single intravenous injection of lead nitrate (LN) to rats induces liver cell proliferation without causing cell necrosis (direct hyperplasia). We suggested that liver cell proliferation in this model may be triggered by the induction of liver tumor necrosis factor alpha (TNF-alpha). Because administration of TNF alpha in vivo has been shown to induce proliferation of both parenchymal and nonparenchymal cells of the liver, we analyzed the temporal sequences of DNA synthesis in both cell populations following LN and recombinant TNF-alpha treatment by 5-bromo-2-deoxyuridine (BrdU) immunohistochemistry. The patterns of cell proliferation induced by these agents were further compared with those induced by a single dose of nafenopin (NAF), a direct mitogen which does not induce liver TNF-alpha messenger RNA (mRNA). In male Wistar rats given a single dose of LN (100 micromol/kg), BrdU incorporation of hepatocytes and nonparenchymal cells (Kupffer cells, endothelial cells and periportal nondescript cells) became evident 12 hours after the treatment. The labeling of all cell types reached a peak after 36 hours and declined thereafter. Rats given a single intravenous injection of human recombinant TNF-alpha (46 microg/rat) showed an increase of BrdU labeling in nonparenchymal cells after 24 hours, whereas the labeling of hepatocytes became evident at 36 hours. A single intragastric administration of NAF resulted in a rapid increase in the number of labeled hepatocytes with no substantial labeling of nonparenchymal cells. These results add further support to the notion that LN-induced liver cell proliferation is mediated by TNF-alpha, and suggest that different cell populations are involved in the initial proliferative response of the liver to mitogens, depending on the capacity of the mitogens to stimulate TNF-alpha production. PMID- 8675180 TI - Influence of continuous interleukin-2 administration via the portal vein on liver regeneration following partial hepatectomy in rats. AB - We have reported the efficacy of intraarterial-combined immunochemotherapy including interleukin-2 (IL-2) for unresectable hepatocellular carcinoma (HCC). To further test this therapy for prevention of intrahepatic recurrence after hepatectomy, the influence of IL-2 on liver regeneration was examined using mitotic index (MI) and the bromodeoxyuridine (BrdU) labeling index (LI) in 70% hepatectomized Donryu rats. In addition, gap junction appearance, which may change during liver regeneration, was analyzed using a monoclonal antibody (HAM8). Serum albumin, alanine transaminase, and total bilirubin (TB) levels were also evaluated. IL-2 (45,000 Japanese reference units [JRU]/d) or saline was administered continuously via the portal vein immediately after hepatectomy using an infusion pump. We also examined the influence of IL-2 on liver regeneration after hepatectomy with splenectomy. No difference in the weight of the liver, serum albumin, alanine transaminase, or TB was observed in any groups at 1, 2, or 4 days after hepatectomy. Neither IL-2 nor splenectomy influenced MI and BrdU LI at all three points. Gap junctions began to disappear after hepatectomy and reached a minimum on day 2 in all groups. Four days after hepatectomy, the density of the reappearing gap junctions was markedly lower in groups treated with IL-2 than in those receiving saline with or without splenectomy. However, the density returned to close to preoperative levels 6 days after hepatectomy in all groups. Continuous portal infusion of IL-2 transiently disturbed gap junction reappearance during liver regeneration. However, no other parameters of liver regeneration or liver functions differed. These results suggest that the liver regeneration after partial hepatectomy may be suppressed by the administration of IL-2, even though the suppression may not be harmful for overall recovery of the resected liver. However, it seems that hepatic IL-2 administration can be performed without serious complications after hepatectomy. PMID- 8675182 TI - The translational inhibitor cycloheximide represses growth factor depletion induced apoptosis in an alb-SV40T transgenic rat liver cell line. AB - A transgenic rat line carrying the alb-SV40A transgene has been described by this laboratory. Several cell lines have been established from the livers of two of these rats. One of these cell lines, L37, exhibits a large nuclear/cytoplasmic ratio and a well-differentiated cytoplasm containing numerous organelles. When L37 cells are placed into culture medium lacking necessary growth factors, cellular proliferation continues for 48 hours after medium change. Subsequent to the initial 48 hours, cells begin to shrink and lose contact with adjacent cells, eventually sloughing off the culture plate surface, with most cell deaths occurring between 48 and 96 hours after medium change. Microscopic examination of sloughing cells indicates they possess highly convoluted and blebbed plasma membranes, a morphological characteristic of apoptosis. Ultrastructural studies demonstrate the ubiquitous presence of apoptotic bodies. When DNA isolated from growth factor-depleted cells is resolved on agarose gels, DNA fragmentation ladders are observed at times of maximum apoptotic change. Quantitative analysis of L37 cells between 48 and 96 hours after the removal of the culture medium shows that 59% +/- 2% of the cells undergo apoptosis. When cycloheximide, puromycin, or actinomycin D is added to the L37 cultures, only cycloheximide is able to repress apoptosis, indicating that the mechanism of apoptosis in the L37 liver-derived cell line requires a cycloheximide-sensitive translational event. The extremely high rate of apoptosis, together with the maintenance of hepatocellular characteristics, indicates the usefulness of this cell line as a model in which to study the mechanisms of hepatocellular apoptosis. PMID- 8675181 TI - Decreased ureagenesis from alanine, but not from ammonia and glutamine, in the perfused rat liver after partial hepatectomy. AB - Ureagenesis from ammonia, alanine, and glutamine in the liver after partial hepatectomy (PH) was determined by using the liver-perfusion system. The maximum rate of ureagenesis from ammonium chloride (10 mmol/L) in hepatectomized (HX) rats at 24 hours after surgery was obtained in the presence of ornithine, lactate, and pyruvate, and it was almost identical to that in sham-operated (SO) rats. The rate of urea production from glutamine (1 mmol/L or 10 mmol/L) in HX rats was significantly lower than that of SO rats with a concomitant decrease in hepatic glutaminase activities. However, the rate of urea synthesis from glutamine (1 mmol/L) in the presence of added ammonia (0.5 mmol/L) was accelerated approximately 10-fold, and the significant difference in the rate of urea formation between HX and SO rats was abolished. This result indicates that there is enough glutaminase to generate ammonia from glutamine in the liver of HX rats. The rate of urea production from alanine (1 mmol/L or 10 mmol/L) in HX rats was significantly decreased at 24 hours following surgery, while that of SO rats was increased. The decreased formation of urea from alanine was not seen at 72 and 120 hours after the operation. These results suggest that during the proliferation phase of liver regeneration, a reduction of ureagenesis from alanine facilitates the remnant liver to make nonessential amino acids such as aspartate. This metabolic alteration might be related to the proliferation of liver cells. PMID- 8675183 TI - Effect of tumor necrosis factor alpha on intrahepatic bile duct epithelial cell of rat liver. AB - Tumor necrosis factor alpha (TNF-alpha), which is primarily produced by macrophages, is a cytokine with various biological activities. Macrophage infiltration often accompanies experimental cholangitis in rats, and chronic cholangitis in humans. The pathophysiologic significance of TNF-alpha in cholangitis is not known. We used cultured, polarized intrahepatic bile duct epithelial cells (IBDECs) from rat liver to determine whether TNF-alpha directly affects the organization of IBDEC monolayers. The addition of recombinant TNF alpha (rTNF-alpha) to culture media at concentrations from 10 to 200 U/mL lacked cytotoxicity to the IBDECs as judged by trypan blue exclusion and lactate dehydrogenase (LDH) release. rTNF-alpha transiently reduced transepithelial electrical resistance in a dose-dependent manner. During this decrease in resistance, the cellular tight junctions became leaky, allowing horseradish peroxidase (HRP) penetration. rTNF-alpha, at concentrations up to 200 U/mL, did not detach IBDECs from Matrigel, an artificial basement membrane. Electron microscopy and immunohistochemistry for F-actin showed a well-preserved cell structure and organization of IBDECs. Results suggest that TNF-alpha is nontoxic to IBDECs, and that it increases the permeability of tight junctions. TNF-alpha may thus disturb the barrier function of the bile duct. PMID- 8675184 TI - Critical involvement of interferon gamma in the pathogenesis of T-cell activation associated hepatitis and regulatory mechanisms of interleukin-6 for the manifestations of hepatitis. AB - A single intravenous injection of concanavalin A (Con A) induces T-cell activation and an acute hepatitis in mice. This study investigated the role of interferon gamma (IFN-gamma) in the pathogenesis of this hepatitis model. Striking increases in the plasma levels of various cytokines, including tumor necrosis factor (TNF), interleukin-2 (IL-2), and IFN-gamma, were detected before the increase in plasma aminotransferase levels induced by Con A injection. TNF levels peaked within 2 hours, whereas IFN-gamma levels peaked at 6 hours after Con A injection. In contrast to a sharp peak of TNF levels, high IFN-gamma levels were detected for a more prolonged period. Passive immunization with anti-IFN gamma monoclonal antibody (MAb) conferred a dose-dependent protection against liver injury in this model. This protection was observed when anti-IFN-gamma MAb was administered at least 30 minutes before Con A injection but not when given 1 hour after Con A injection. The protection from Con A-induced hepatitis was also induced by administration of rIL-6 before Con A injection. rIL-6 treatment induced significant albeit incomplete inhibition of IFN-gamma and TNF production, whereas this regimen did not affect IL-2 production. Despite striking protective effects of rIL-6 or anti-IFN-gamma MAb, comparable levels of cellular (both T cell and polymorphonuclear cell) infiltration were detected in liver sections from animals untreated, or treated with either rIL-6 or anti-IFN-gamma MAb. Moreover, electron microscopic examination showed that infiltrating T cells exhibited a blastoid appearance in all groups. These results indicate that IFN gamma plays a critical role in the development of Con A-induced acute hepatitis and suggest that IL-6 administration can regulate the manifestation of hepatitis through mechanisms including the reduced production of inflammatory cytokines such as IFN-gamma. PMID- 8675185 TI - Thalidomide inhibits tumor necrosis factor alpha, decreases nitric oxide synthesis, and ameliorates the hyperdynamic circulatory syndrome in portal hypertensive rats. AB - A hyperdynamic circulatory state frequently is observed in portal hypertension with liver failure or extensive portal-systemic shunting. Tumor necrosis factor alpha (TNF) causes marked hypotension in mammals by inducing nitric oxide synthesis and has been shown to play a role in the development of the hemodynamic changes observed in portal hypertension. Thalidomide selectively inhibits TNF production by enhancing messenger RNA degradation. We investigated the systemic and portal hemodynamic effects of thalidomide in a prehepatic model of portal hypertension and evaluated whether suppressing TNF synthesis decreases NO production. Portal hypertension was induced by partial ligation of the portal vein (PVL). Animals received thalidomide (T) (50 mg/kg/d) + water or water alone (W), orally, daily for 2 days before and 13 days after PVL operation, at which time hemodynamic studies were performed and TNF plasma levels were obtained. Sham operated animals were studied identically. In an additional group of PVL animals, 24-hour urinary excretion of NO2- and NO3- was measured during treatment. PVL animals receiving T presented with a significantly higher mean arterial pressure and systemic vascular resistance and significantly lower portal pressure, TNF plasma levels, and 24-hour urinary excretion of NO2- and NO3-, in comparison with rats receiving W. A significant correlation (r = -0.61) was observed between TNF plasma levels and mean arterial pressure among PVL animals. Thalidomide did not have any significant effects on sham rats. Thalidomide inhibits TNF synthesis and reduces NO production, blunts the development of the hyperdynamic circulation, and decreases portal pressure in PVL-operated rats. PMID- 8675186 TI - Platelet-activating factor augments lipopolysaccharide-induced nitric oxide formation by rat Kupffer cells. AB - Acute endotoxic shock is accompanied by an increase in the production of nitric oxide (NO) by several different hepatic cell types. Platelet-activating factor (PAF) is a potent proinflammatory mediator with many pathophysiological actions and, in fact, elevated plasma and tissue levels of PAF are observed in animal models of endotoxic shock. The current study demonstrates that PAF induced nitrite formation, the end product of nitric oxide synthesis, by Kupffer cells in a dose- and time-dependent manner. Moreover, PAF was seen to initiate NO synthase gene expression and protein synthesis. PAF augmented lipopolysaccharide (LPS) induced expression of inducible nitric oxide synthase messenger RNA (mRNA), protein, nitrite and cyclic guanosine monophosphate (cGMP) levels in Kupffer cells. Treatment of Kupffer cells with actinomycin D or cycloheximide inhibited PAF- and LPS-stimulated nitrite and nitric oxide synthase protein formation confirming that de novo synthesis of the enzyme occurred. In Kupffer cells, the presence of an arginine analog, NG-methyl-L-arginine, attenuated nitrite formation induced by PAF and LPS alone or in combination. L-arginine is the principal substrate for nitric oxide synthase. PAF and LPS individually and in combination induced a time-dependent uptake of L-[3H]-arginine into the Kupffer cell, and this response was sensitive to cycloheximide. The current study indicates that exogenous PAF contributes to the induction of nitric oxide synthase by LPS in cultured rat Kupffer cells. PMID- 8675187 TI - Use of an asialoglycoprotein receptor-targeted magnetic resonance contrast agent to study changes in receptor biology during liver regeneration and endotoxemia in rats. AB - The hepatic asialoglycoprotein receptor is responsible for rapid clearance of desiaylated glycoproteins from the circulation by receptor-mediated endocytosis. Previous in vitro studies in hepatocyte preparations from rats subjected to partial hepatectomy (PH) of 70% to stimulate hepatic regeneration showed decreased asialoglycoprotein (ASGP) receptor binding. We used an ASGP receptor targeted hepatic magnetic resonance imaging (MRI) agent, BMS 180550, to demonstrate similar changes in receptor biology in vivo. BMS 180550 is an arabinogalactan-coated ultrasmall superparamagnetic iron oxide preparation. Arabinogalactan is a ligand for the ASGP receptor and, thereby, targets the contrast agent exclusively to hepatocytes. Hepatic uptake of BMS 180550 was assessed by sequential precontrast and post-contrast MRI in rats subjected to PH of 70%. In regenerating liver 1 and 3 days after PH, the maximum decrease in hepatic signal intensity (62.2% +/- 6.1 and 59.4% +/- 3.8, respectively) was significantly less than the maximum decrease seen in sham-operated animals at 1 and 3 days postsurgery (39.5% +/- 2.5 and 44% +/- 1.0, respectively). The time necessary to reach 80% of the maximum decrease in hepatic signal intensity, (t80), was less than 2 minutes in control rats and increased to 7.5 +/- 1.3 min and 11.0 +/- 2.3 minutes at 1 and 3 days post-PH, respectively. By 7 days post PH, contrast-enhanced MRI no longer detected a difference in regenerating liver. Because BMS 180550 is taken up exclusively by the liver, clearance of the agent from the blood was used as a measure of hepatic clearance. Concentration-time curves constructed by measuring changes in blood T2 after an intravenous dose of BMS 180550 were used to determine clearance of the agent. Blood clearance of BMS 180550 in normal liver (15.4 +/- 1.08 mL/min) obeyed first-order kinetics and did not vary over the dose range tested (10 to 100 micromol/L/kg iron). One, 3, 7, and 14 days post-PH, clearance varied with dose, suggesting ASGP receptor saturation. As regeneration proceeded, the dose of contrast agent needed to cause a deviation from first-order kinetics increased, suggesting gradual recovery of ASGP receptor function. Hepatic relaxation was determined by in vitro spectroscopy 60 minutes after administration of graded doses of BMS 180550 and showed dose-dependent increases in relaxation. Kinetic analysis at 1 day post-PH demonstrated a decrease in the apparent k(m) and the maximum response, R(max), suggesting a decrease in the number of functional asialoglycoprotein receptors with concomitant increase in receptor affinity. Systemic endotoxemia, which normally accompanies hepatic regeneration induced by PH, also decreased clearance of BMS 180550 and slowed hepatic uptake of the contrast agent. Altered BMS 180550 pharmacokinetics in endotoxin-treated rats was enhanced by prior administration of small doses of competing ligand. Our studies document the value of BMS 180550 in following changes in ASGP function that accompany PH or systemic endotoxemia. This agent may be useful in assessing the degree of hepatic regeneration in patients with clinical liver disease. PMID- 8675189 TI - Biosynthesis and degradation of hyaluronan by nonparenchymal liver cells during liver regeneration. AB - Hepatic stellate cells (HSC) and endothelial cells of the liver sinusoids synthesize and degrade hyaluronan, respectively. The roles of these cell types in the biosynthesis and degradation of hyaluronan were studied during regeneration following partial hepatectomy. Pure cultures of HSC and liver endothelial cells (LEC) were obtained from regenerating liver at different stages using a Nycodenz gradient followed by discontinuous Percoll gradient. The HSC that established 3 or 4 days after partial hepatectomy synthesized large amounts of hyaluronan when cultured in the presence of fetal calf serum (FCS) or platelet-derived growth factor B-chain homodimer (PDGF)-BB. These cells, as well as LEC, expressed active PDGF beta-receptors. Furthermore, the ability of LEC to degrade hyaluronan was decreased at early stages of liver regeneration. The increased synthesis of hyaluronan by HSC and the failure of LEC to catabolize the polysaccharide resulted in elevated hyaluronan concentrations in the blood. PMID- 8675188 TI - Evidence that interference with binding to hepatic cytosol binders can inhibit bile acid excretion in rats. AB - We previously identified that Y' bile acid binders (3alpha-hydroxysteroid dehydrogenases) interact with bile acids in intact rat hepatocytes using [3beta 3H, C24-14C]bile acids and that indomethacin, a competitive inhibitor of 3alpha hydroxysteroid dehydrogenase, inhibits 3H-loss from the C3-position of bile acids as well as inhibits hepatic bile acid removal and excretion. To study the kinetics of these inhibitory effects, glycocholate transport was studied in the absence and presence of indomethacin in the single-pass perfused rat liver. Indomethacin decreased net hepatic glycocholate uptake in the perfused liver, which was confirmed in isolated hepatocytes and basolateral liver plasma membrane vesicles. However, indomethacin markedly increased the sinusoidal efflux and decreased the biliary excretion of glycocholate in the perfused liver. These observations indicate that the effect of indomethacin to delay biliary glycocholate excretion is related to either intracellular or canalicular glycocholate transport. The latter possibility seemed unlikely because indomethacin did not inhibit electrogenic or adenosine triphosphate (ATP) dependent glycocholate uptake by canalicular liver plasma membrane vesicles. Thus, the current data support an important role for binding of bile acids to cytosolic proteins in overall hepatic transport and suggest that specific interference with cytosolic binding can interfere with the excretion of bile acids. PMID- 8675190 TI - Involvement of platelet-activating factor in cytokine production and neutrophil activation after hepatic ischemia-reperfusion. AB - Although platelet-activating factor (PAF) is implicated as an important mediator in the pathogenesis of hepatic ischemia-reperfusion (IR) injury, the precise mechanism of its action has not been studied. We examined the hypothesis that PAF may influence neutrophils by promoting the production of tumor necrosis factor alpha (TNF-alpha) and cytokine-induced neutrophil chemoattractant (CINC), a member of the interleukin-8 (IL-8) family, and may be associated with liver and lung injury during the early phase of reperfusion after total hepatic ischemia. Rats pretreated with a specific PAF receptor antagonist exhibited suppression of the increase in plasma TNF-alpha and CINC levels, as well as the priming of peripheral neutrophils for superoxide production after reperfusion when compared with animals pretreated with physiological saline. These effects resulted in a reduction of plasma liver enzymes and of hepatic and pulmonary neutrophil sequestration, as well as an increased survival rate. There was a strong correlation between the time course of CINC release and hepatic or pulmonary neutrophil sequestration. We concluded that PAF activates neutrophils, either directly or by promoting the production of TNF-alpha and CINC, and is involved in hepatic IR injury. PMID- 8675191 TI - Slow intestinal transit: a motor disorder contributing to cholesterol gallstone formation in the ground squirrel. AB - Impaired gallbladder motility is an established factor in cholesterol gallstone formation. We assessed whether altered small intestinal smooth muscle contractility with slow transit might potentiate gallstone formation by further impeding enterohepatic cycling of bile acids. Ground squirrels were fed a 1% or a trace (controls) cholesterol diet. Small intestinal transit was evaluated from 51Cr distribution in conscious, fasted animals 20 minutes after infusion into the proximal jejunum. Small intestinal and gallbladder smooth muscle contractility was determined in vitro. Biliary lipid secretion was measured from the cannulated common duct and the bile salt pool size calculated by isotope dilution. Gas liquid chromatography (GLC) assessed bile salt profile. In animals on the 1% cholesterol diet, aboral transit was significantly delayed, the maximal contractile response to bethanechol was markedly increased (P <.05) with no change in median effective concentration in either circular or longitudinal muscle strips from both the jejunum and ileum, and the gallbladder contractile responses to bethanechol and cholecystokinin (CCK) were decreased. Cholesterol saturation index and the fraction of deoxycholic acid in the pool doubled, whereas the total bile salt pool size remained unchanged in cholesterol-fed animals. In this model, a high-cholesterol diet is associated with altered small intestinal smooth muscle contractility and prolonged small intestinal transit, in addition to diminished gallbladder contractility. The resulting sluggish enterohepatic cycling of bile salts, associated with expanded deoxycholate pool, contributes to cholesterol gallstone formation. PMID- 8675192 TI - Dexamethasone alters messenger RNA levels but not synthesis of collagens, fibronectin, or laminin by cultured rat fat-storing cells. AB - Glucocorticoids have been shown to suppress collagen synthesis and gene expression by fibroblasts. However, little is known about their effects on fat storing cells, the major matrix-producing cells in liver fibrosis. In this study we investigated the effect of dexamethasone on the extracellular matrix expression by cultured rat fat-storing cells. Fat-storing cells were isolated from male Wistar rats by collagenase/pronase digestion and purified by density gradient centrifugation. Fat-storing cells in early primary culture (3-day-old, representing a relatively quiescent phenotype) and in subculture (one passage, about 2-week-old, representing an activated phenotype) were treated with 10(-6) mol/L dexamethasone for messenger RNA (mRNA) study or with 10(-8) to 10(-6) mol/L dexamethasone for protein study. Expression of collagen type I, III, IV, fibronectin, and laminin was analyzed at the mRNA level by Northern hybridization, and at the protein level by metabolic labeling and immunoprecipitation. Dexamethasone had a variable effect on the expression of collagen alpha1(I) mRNA level. While a tendency for modest suppression was observed (5%-50%) in primary cells, the difference was not statistically significant. Variable response was observed in subcultured cells. Collagen alpha1(III) mRNA level showed a tendency for stimulation. Dexamethasone stimulated the expression of collagen alpha1 (IV), fibronectin, and laminin B1 mRNA levels by 1.4-, 2.4-, and 1.6-fold respectively, in primary fat-storing cells. Subcultured cells showed a similar response, but the magnitude of stimulation was more variable than that of primary cells. Unexpectedly, at the protein level dexamethasone had no effect on the expression of these proteins. Our results indicate that glucocorticoids do not possess a net suppressive effect on extracellular matrix synthesis by fat-storing cells. Beneficial effects of glucocorticoids may be attributable to other mechanisms of action, such as their anti-inflammatory effect. PMID- 8675193 TI - Biliary atresia: current concepts and research directions. Summary of a symposium. AB - Biliary atresia (BA) is the end result of a destructive, inflammatory process that affects intra- and extrahepatic bile ducts, leading to fibrosis and obliteration of the biliary tract with the development of biliary cirrhosis. It is the commonest cause of chronic cholestasis in infants and children, and therefore is the most frequent indication for liver transplantation in this age group. The disease occurs worldwide, affecting an estimated 1 in 8,000 to 12,000 live births. At present, there is no specific therapy for BA; however, sequential surgical therapy begins with creation of a hepatoportoenterostomy (HPE); in those with end-stage liver disease, liver transplantation is indicated. Since most candidates are young children of small size, there is a shortage of size-matched donors for liver transplantation. At present, an increased awareness to ensure early diagnosis and development of methods to prevent progressive fibrosis are needed. These considerations are dependent on detailed studies of the pathogenesis of BA. Recent studies have focused on normal and altered bile duct morphogenesis and the role of various factors (infectious or toxic agents and metabolic insults) in isolation or in combination with a genetic or immunologic susceptibility in the etiology of BA. PMID- 8675194 TI - Biliary atresia into the 21st century: a historical perspective. PMID- 8675195 TI - The daunting challenges of gene therapy for malignant disease. PMID- 8675196 TI - Endothelin in hepatic fibrosis--friend or foe? PMID- 8675197 TI - Alcohol and iron: a radical combination? PMID- 8675198 TI - Transforming growth factor beta and liver regeneration: the stage may be set, but what's the script? PMID- 8675199 TI - Familial prevalence of gallstone in first-degree relatives of patients with gallstones. PMID- 8675200 TI - Detection of albumin messenger RNA in blood is not restricted to hepatocellular carcinoma. PMID- 8675201 TI - Randomized trial comparing three different regimens of interferon alfa 2a in chronic hepatitis C. PMID- 8675202 TI - Prevalence of chronic liver disease in northern Italy. PMID- 8675203 TI - Constitutive and inducible expression of interleukin-6 by Langerhans cells and lymph node dendritic cells. AB - During the induction phase of contact sensitization and other cutaneous immune responses a proportion of epidermal Langerhans cells (LC) is induced to leave the skin and migrate via afferent lymphatics to lymph nodes draining the site of exposure. The cells that accumulate in draining nodes have acquired the characteristics of immunostimulatory dendritic cells and effectively present antigen to responsive T lymphocytes. In the present study we have questioned whether LC in the epidermis and the lymph node dendritic cells into which they develop express interleukin-6 (IL-6), a cytokine that has been shown to serve as an important costimulator of T lymphocyte activation. In situ immunocytochemical analyses using a biotin-streptavidin staining technique revealed that dendritic cells resident in the epidermis of untreated mice constitutively express this cytokine. Keratinocytes expressed detectable IL-6 only following local exposure to the contact allergen oxazolone. Such treatment also appeared to enhance the expression by epidermal dendritic cells of this cytokine. Analyses of unfractionated and LC-enriched and -depleted populations of epidermal cells revealed a close correlation between major histocompatibility complex (MHC) class II (Ia) antigen expression and staining for IL-6, implicating LC as the sole or major source of this cytokine in unstimulated epidermis. Finally, compared with tissue isolated from mice treated with vehicle alone, draining lymph nodes prepared from animals 18 hr following sensitization with oxazolone displayed a substantial increase in both the frequency of dendritic cells and the number of IL-6+ cells within the paracortex. These data demonstrate that resident epidermal LC and the dendritic cells into which they develop are important sources of IL-6. Their constitutive and inducible expression of this cytokine will facilitate the induction of cutaneous immune responses. PMID- 8675204 TI - Upregulation of MHC class II antigen on dendritic cells from hepatitis B virus transgenic mice by interferon-gamma: abrogation of immune response defect to a T cell-dependent antigen. AB - The experiments presented here were performed to see whether the level of expression of major histocompatibility complex (MHC) class II antigen (Ia antigen) on dendritic cells, one of the most critical antigen presenting cells (APC), influences the humoral immune response in hepatitis B virus (HBV) transgenic mice. We have reported that transgenic mice had a low responsiveness in specific antibody production to keyhole limpet haemocyanin (KLH), a T-cell dependent, HBV-unrelated antigen compared with the age, sex, and major histocompatibility-matched normal mice, due to a significantly lower T-cell stimulatory capacity of transgenic mice-derived dendritic cells, possibly as a result of significantly lower level of Ia antigen. Immunohistochemical staining has shown that treatment of transgenic mice with mouse recombinant interferon gamma (IFN-gamma), daily for six consecutive days resulted in an increased expression of Ia antigen on splenic dendritic cells. Again, flow cytometric analyses have further confirmed the significant increase in the expression of Ia antigen on dendritic cells, isolated from transgenic mice treated with IFN-gamma compared with the same from the untreated or phosphate-buffered saline (PBS) treated transgenic mice. Transgenic mice immunized with two optimum doses of KLH (5 micrograms/mouse) could not produce anti-KLH antibodies in sera, but injecting transgenic mice with the same doses of KLH together with IFN-gamma resulted in the production of anti-KLH antibodies in sera. Again, KLH-primed normal mice derived T/B lymphocytes produced anti-KLH antibody, when cultured with dendritic cells from IFN-gamma-treated transgenic mice expressing a higher level of Ia antigen, but not with the same from PBS-treated or untreated transgenic mice. Treatment of transgenic mice with IFN-gamma resulted in a reduced level of hepatitis B virus (HBV) DNA in liver and in sera. These experiments have shown that the level of expression of Ia antigen on dendritic cells is a critical factor for its APC capability and its modulation of IFN-gamma may be used for immune therapy in HBV carriers. PMID- 8675205 TI - Chimpanzee dendritic cells with potent immunostimulatory function can be propagated from peripheral blood. AB - We have established dendritic cell (DC) cultures from chimpanzee peripheral blood mononuclear cells (PBMC) by using recombinant human (rh) granulocyte-macrophage colony-stimulating factor (GM-CSF) and rh interleukin-4 (IL-4) and demonstrate that these cells have all the characteristics of DC as described for other species. We consistently can obtain 1 x 10(7) DC per 100 ml of blood, a yield of 5% DC as compared to 0.1 to 0.5% DC reported in fresh human PBMC. The cultured DC have a varied morphology with typical cytoplasmic extensions. Phenotypically, the blood-derived DC lack expression of most lineage antigens, but express CD83, an antigen specifically expressed on human blood DC. Chimpanzee DC express very high levels of major histocompatability complex class II antigens, adhesion and costimulatory molecules. Consistent with this phenotype of a powerful antigen presenting cell, chimpanzee DC generate allogeneic mixed leukocyte responses 15 to 20 times more potent than that elicited by macrophages, Epstein-Barr virus transformed lymphoblasts and fresh PBMC. In addition, chimpanzee DC very efficiently present tetanus toxoid to PBMC-derived CD4+ T cells as compared to macrophages and PBMC. The DC generated by culturing chimpanzee PBMC with rhGM-CSF and rhIL-4 thus closely resemble human blood-derived DC propagated in the same manner. This technology provides a powerful animal model with which to apply DC to clinical studies with relevance to human disease. In particular, chimpanzee DC can be tested as immunotherapeutic agents for cancer, and be studied in relation to the pathogenesis of human immunodeficiency virus (HIV) infection. PMID- 8675206 TI - Comparative immunophenotypic analysis of human mast cells, blood basophils and monocytes. AB - Mast cells (MC), blood basophils (Ba) and monocytes (Mo) are of haemopoietic origin. Lineage-relationships and transdifferentiation between MC and Mo, or MC and Ba, have been considered, based on common expression of antigens. In this study, comparative phenotypic analyses on MC, Ba and Mo and on respective cell lines were performed using monoclonal antibodies (mAb) to previously defined and novel CD antigens (CD1-130). By cluster analysis, the overall (all 130 CD) phenotypic relationships (given as similarity indices, SI), between primary cells (MC, Ba and Mo) and corresponding cell lines (HMC-1, KU-812, U937) were 0.716, 0.779 and 0.757, respectively. When primary cells were compared, lower SI values were found (MC versus Ba, 0.509; MC versus Mo, 0.625; Mo versus Ba, 0.698). More distant relationships were found between MC versus Ba and MC versus Mo, compared with Ba versus Mo, for adhesion receptor (R)-, complement R- and cytokine R profiles. Analysis of cytokine R revealed most significant dissimilarities between MC versus Ba and MC versus Mo (SI < 0.2). Moreover, in contrast to other CD subgroups and other lineages, MC and HMC-1 differed from each other in cytokine R expression (SI = 0.286). Cytokine R detectable on HMC-1 but not MC were granulocyte-macrophage colony-stimulating factor (GM-CSFR)alpha(CD116), CD40, Apo-1/FAS(CD95) and gp130(CD130). Cytokine R detectable on Ba but not MC, were interleukin-3 (IL-3)R alpha(CD123), IL-1RII(CD121b), IL-2R alpha(CD25) and CD40. In summary, MC, Ba and Mo display a unique CD profile with MC being the most distantly related cell. The most significant mismatch within a given lineage is the loss of cytokine R on mature MC as compared with normal myeloid progenitors and HMC-1 cells. PMID- 8675207 TI - Dynamic production of tumour necrosis factor-alpha (TNF-alpha) messenger RNA, intracellular and extracellular TNF-alpha by murine macrophages and possible association with protein tyrosine phosphorylation of STAT1 alpha and ERK2 as an early signal. AB - Tumour necrosis factor-alpha (TNF-alpha), an important mediator in both immune and inflammation responses, is one of the major cytokines released by activated macrophages. The present study shows that, during macrophage activation, protein tyrosine phosphorylation of STAT1 alpha and ERK2 occurred as an immediate early signal, whereas maximum TNF-alpha mRNA transcription appeared at 3 hr, precursor TNF-alpha formation at 3 to 4 hr, and TNF-alpha release at 5 to 6 hr after stimulation of an RPMI-1640-based induction medium containing lipopolysaccharide (100 ng/ml), interferon-gamma (100 U/ml), and 0.5% bovine serum albumin. Herbimycin A, a tyrosine kinase inhibitor, suppresses protein tyrosine phosphorylation of STAT1 alpha and ERK2 and also blocks TNF-alpha production by resident peritoneal macrophages from BALB/c mice, suggesting a possible association between protein tyrosine phosphorylation of STAT1 alpha and ERK2 and macrophage activation resulting in TNF-alpha production. PMID- 8675208 TI - Differential regulation of tumour necrosis factor-alpha mRNA degradation in macrophages by interleukin-4 and interferon-gamma. AB - Interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) have been reported previously to mediate similar as well as antagonistic effects on murine macrophage functions. One effect common to both is the enhancement of tumour necrosis factor-alpha (TNF-alpha) secretion in macrophages. To assess further the effects of these two lymphokines on macrophage TNF-alpha production, we investigated the role of these lymphokines in the induction and stability of TNF alpha messages along with interleukin-1 (IL-1) as a comparison. IFN-gamma and IL 4 increased lipopolysaccharide (LPS)-induced TNF-alpha, IL-1 steady-state message levels. In contrast to IL-1 messages, whose degradation was not significantly affected by either lymphokine, the stability of TNF-alpha messages differed after IFN-gamma and IL-4 treatment. Although IL-4 treatment increased the TNF-alpha transcription rate, an increase in the degradation rate of TNF-alpha mRNA in the IL-4-treated cells resulted in a lower level of steady-state mRNA than in the IFN gamma-treated cells. Additionally, a 18,000 MW cytoplasmic factor was found to have specific binding activity to the AU-rich sequences of the TNF-alpha message in peritoneal macrophages. Although the binding activity of this factor was not affected by either IFN-gamma or IL-4, the binding of the factor to AU-rich sequences appeared to be important in the rapid degradation of TNF-alpha messages. Thus IFN-gamma and IL-4 may differentially affect the post transcriptional control of TNF-alpha gene expression. And this lymphokine mediated post-transcriptional control of the TNF-alpha gene does not appear to involve the alteration of binding activity of the 18,000 MW AU-rich sequence binding factor. PMID- 8675209 TI - Differential regulation of tissue-specific lymph node high endothelial venule cell adhesion molecules by tumour necrosis factor and transforming growth factor beta 1. AB - Lymphocytes migrate from blood into lymph nodes (LN) of rats specifically at segments of venules lined by high endothelium (HEV). We have previously shown that pretreatment of LN HEV cells with pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), augments their adhesiveness for thoracic duct lymphocytes (TDL). Here we report that a mouse monoclonal antibody, 3C10, recognized tissue-specific endothelial determinants on rat LN HEV cells and blocked their adhesiveness for TDL and EL-4J cells transfected with rat L-selectin. In contrast, 3C10 antibody did not inhibit lymphocyte attachment to Peyer's patch (PP) frozen sections or cultured PP HEV cells. The antibody immunoprecipitated from LN HEV cells two proteins with apparent molecular weights of 90,000 and 50,000. The expression of 3C10 antigen on LN HEV cells was increased by incubation with TNF-alpha or IFN-gamma. Furthermore, pretreatment of cytokine-stimulated LN HEV cells with 3C10 antibody blocked TDL binding in a dose-dependent manner. In contrast, 3C10 antigen expression on LN HEV cells was significantly decreased following incubation of cells with transforming growth factor-beta 1 (TGF-beta 1). In addition, TGF-beta 1 also abrogated the adhesiveness of LN HEV cells stimulated with TNF-alpha, IFN gamma or both cytokines. Together, these data suggest that endothelial determinants recognized by the 3C10 antibody are tissue-specific ligands for lymphocyte adhesion and cytokines such as TNF-alpha and TGF-beta differentially regulate their expression and function. PMID- 8675210 TI - Involvement of LFA-1/ICAM-2 adhesive interactions and PKC in activation-induced cell death following SEB rechallenge. AB - Ligation of T-cell receptor (TCR) causes mature T cells to proliferate or, on re exposure to antigen, can cause them to die by activation-induced cell death (AICD). In proliferative responses, costimulatory and adhesive interactions are required and activation of protein kinase C (PKC) has been shown to be essential. Whether or not interactions involving costimulatory signals and PKC have a role in facilitating AICD remains unclear. Here we have examined the role of CD28/B7 and leucocyte function associated antigen-1 (LFA-1)/intracellular adhesion molecule (ICAM) mediated interactions in AICD triggered by staphylococcal enterotoxin B (SEB) in murine lymph node T cells. We show that, after a primary proliferative response to SEB, LFA-1/ICAM-2 adhesive interactions can play a part in AICD following SEB rechallenge, while B7 and ICAM-1 mediated interactions are not essential for this process. In addition, using a highly selective PKC inhibitor, Ro31.8425, we show that PKC activation is essential for the regulation of AICD by SEB rechallenge. PMID- 8675211 TI - Altered patterns of migration of cytokine-producing T lymphocytes in skin-grafted naive or immune mice following in vivo administration of anti-VCAM-1 or -ICAM-1. AB - Naive or preimmunized (to B10.BR or BALB.k) C3H/HeJ mice received skin grafts from multiple minor histoincompatible B10.BR or BALB.k mice following antigen specific portal venous (p.v.) pretransplant transfusion, a protocol known to produce prolongation of graft survival in naive animals. In addition, groups of mice received intravenous (i.v.) infusion following transplantation with a mixture of monoclonal antibodies (mAb) to vascular adhesion molecule-1L: very late activation antigen-4 (VCAM-1:VLA-4) or intracellular adhesion molecule 1:lymphocyte function-associated antigen-3 (ICAM-1:LFA-1). Cells were harvested from different tissues of the grafted mice at various times post grafting. RNA was extracted and analysed, using polymerase chain reaction, for expression of different cytokines potentially involved in the regulation of graft rejection [interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumour necrosis factor-alpha, interferon-gamma and transforming growth factor-beta]. In addition, using limiting dilution analysis, we investigated the frequency of allo-specific and third-party reactive cells producing IL-2 and IL-4 in vitro in different tissues of grafted mice following these treatments. The mAb treatment protocol which produced optimum increases in graft survival in naive versus immune mice was different, with anti-LFA-1:ICAM-1 superior for naive mice compared with anti-VLA 4:VCAM-1, and vice versa for immune animals. However, in each case, increased survival was associated with increases local to the graft in the frequency of occurrence of antigen-specific type-2 cytokine-producing cells. PMID- 8675212 TI - HIV-1 upregulates Fas ligand expression in CD4+ T cells in vitro and in vivo: association with Fas-mediated apoptosis and modulation by aurintricarboxylic acid. AB - CD4+ T-lymphocyte apoptosis has been associated with human immunodeficiency virus (HIV)-1 infection in vitro, paralleling the expression of Fas (APO-1, CD95) on peripheral blood mononuclear cells from patients with HIV disease. However, the link between Fas induction, T-cell activation, and cell death is unclear. We document, for the first time, marked upregulation of expression of mRNA for the ligand for Fas in peripheral blood mononuclear cells from HIV seropositive individuals, and demonstrate the ability of HIV infection to induce such expression in CD4+ T cells in vitro. We also define the relevance of this expression to HIV-mediated CD4+ T cell death. Our ability to downregulate Fas ligand message and suppress HIV-mediated apoptosis with aurintricarboxylic acid, a clinically used protease inhibitor with known activity against programmed cell death in other systems, may open up a new area of therapy for HIV infection. PMID- 8675213 TI - Effects of antigen presentation on superantigen-induced apoptosis mediated by Fas/Fas ligand interactions in human T cells. AB - Stimulation of T cells with bacterial superantigens has several distinct functional outcomes including proliferation, anergy and apoptosis. At present however, the mechanisms that dictate whether activation, anergy, or apoptosis predominate are unclear. In this study we have investigated the effects of superantigen presentation to mature superantigen-reactive human T-cell lines. Despite expressing major histocompatibility complex (MHC) class II molecules, these lines failed to proliferate in response to superantigen in the absence of antigen-presenting cells (APC) but proliferated when minimal APC were added. In the absence of APC a significant proportion of the T cells underwent apoptosis. This response was rapid, antigen dependent and largely abolished by the addition of cyclosporin A. Interestingly the response was not blocked by the addition of a number of antibodies to cell surface molecules including MHC class II and intracellular adhesion molecule-1. Using both a bioassay and messenger RNA analysis we were able to demonstrate that stimulation of these T cells with superantigen resulted in the induction of Fas-ligand expression on the T cells and furthermore, the ability of these cells to induce apoptosis was inhibited by the addition of blocking Fas antibodies as well as a Fas-Fc fusion protein. These data demonstrate that stimulation of T cells with staphylococcal enterotoxin B induces expression of Fas-ligand resulting in T-cell apoptosis; however, the final outcome of proliferation or apoptosis is determined by the presence of APC. PMID- 8675214 TI - Venom immunotherapy modulates interleukin-4 and interferon-gamma messenger RNA expression of peripheral T lymphocytes. AB - The mechanism by which specific immunotherapy exerts its beneficial effect remains unclear. In order to evaluate the influence of venom immunotherapy on the T-cell cytokine pattern of allergic reactions, we studied interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) mRNA expression of peripheral T lymphocytes from 12 patients undergoing rush venom desensitization, before treatment at Day 0 (D0), at Day 15 (D15) and Day 90 (D90) after treatment, and from seven controls. Antigen-specific T-cell proliferation was also determined. Cytokine mRNA expression was evaluated using in situ hybridization, 24 hr after culture of peripheral T cells with medium, venom, or an unrelated allergen. Allergen-induced T-cell proliferation decreased at D15 and D90 of rush immunotherapy (P < or = 0.02). In venom-stimulated cultures of the patient group, there was a decrease in IL-4 mRNA-positive cells at D15 and D90 (P < or = 0.001). Before desensitization, IFN-gamma mRNA expression was lower in patients than in controls and did not increase after in vitro allergen stimulation. In contrast, after immunotherapy, spontaneous IFN-gamma mRNA expression increased, but only at D90 (P < or = 0.001). The cytokine pattern observed at D90 after immunotherapy was similar to that observed in control subjects. In conclusion, venom immunotherapy induced an altered cytokine mRNA pattern in allergen-stimulated T cells which was dissociated from the early changes of allergen-induced T-cell responsiveness. PMID- 8675215 TI - Expression of RANTES in human airway epithelial cells: effect of corticosteroids and interleukin-4, -10 and -13. AB - RANTES is a C-C chemokine with strong chemoattractant and activating properties for eosinophils, basophils and T lymphocytes. We investigated the expression of RANTES in human airway epithelial cells and its modulation. Epithelial cells obtained from tracheas of donor lungs were stimulated with interleukin-1 beta (IL 1 beta), tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) or with a mixture of the three cytokines ('cytomix'). Levels of mRNA and protein were assayed by Northern blot and radioimmunoassay, respectively. Each individual cytokine produced a small increase in RANTES protein: IL-1 beta 24 +/- 1 pM, TNF alpha 13 +/- 7 pM and IFN-gamma 29 +/- 7 pM, but cytomix increased protein to 236 +/- 22 pM (P < 0.002) and mRNA expression by > 20-fold (P < 0.002). Both RANTES protein and mRNA expression were inhibited by dexamethasone (10(-6) M) (38 +/- 5%, P < 0.05 and 55 +/- 8%, P < 0.007, respectively), and by IL-4 (42 +/- 7%, P < 0.03 and 19 +/- 1%, not significant, respectively). No inhibitory effect was observed with IL-10 or IL-13. We also demonstrated in vivo expression of RANTES protein by epithelial cells in human airways using immunohistochemistry. Our data show that human airway epithelial cells can be stimulated to express and release RANTES, an effect that is inhibited by corticosteroids and IL-4, but not by IL-10 and IL-13. PMID- 8675216 TI - Reduced primary antigen-specific T-cell precursor frequencies in neonates is associated with deficient interleukin-2 production. AB - Clinical evidence has indicated that the neonatal cell-mediated immune response to primary infection is delayed when compared to that of adults with the same primary infection. The mechanisms regulating the development of antigen-specific T-cell immunity in neonates remain to be elucidated. We examined the primary immune response to the non-recall antigen, keyhole limpet haemocyanin (KLH) in adults and neonates in vitro. We report here that conventional bulk culture methods show reduced proliferative responses in neonates although statistical significance was not achieved. Using limiting dilution analysis, the frequencies of KLH-specific T lymphocytes were 10-100-fold lower in neonates when compared to adults. Interleukin-2 (IL-2) production was significantly lower in the supernatants of neonatal mononuclear cells (MNC) stimulated with KLH when compared to adults. Addition of exogenous IL-2 increased precursor frequencies twofold in both adult and newborn cultures. In contrast to the secreted IL-2 levels, IL-2 mRNA expression was higher in antigen-stimulated neonatal MNC preparations, even though proliferation was lower. These observations indicate differential in vitro responsiveness in neonates and adults to primary antigenic challenge. Since no IL-2 was detected in cell lysates, the presence of high levels of IL-2 mRNA and low IL-2 production suggests inability by neonatal MNC to translate IL-2. This deficiency in IL-2 production may explain the reduced precursor frequencies, suggesting failure to recruit T lymphocytes in order to expand the KLH-specific T-cell response. These observations are important for the understanding of the development of primary immune responses and immunological maturation in neonates. PMID- 8675217 TI - Expression of functional molecules by human CD3- decidual granular leucocyte clones. AB - Cell surface and cytoplasmic antigen expression by 35 CD3- decidual granular leucocyte (DGL) clones, derived from human endometrial tissue in the first trimester of pregnancy, has been compared with both that of fresh CD3- decidual leucocytes and that of CD3- peripheral blood natural killer (PBNK) cell clones (n = 12). The majority of DGL clones retained the antigenic phenotype of fresh cells, although CD103 (HML-1) was expressed on 50% of DGL clones but only 17% of fresh DGL. Both cytoplasmic CD3 zeta and CD3 epsilon chains were detected in > 90% of DGL clones in the absence of cell surface CD3. Cytoplasmic CD3 zeta was present in almost all fresh CD3- DGL, whereas CD3 epsilon was not. Most DGL clones did not express surface Fc gamma receptors I-III (CD64, -32 and -16, respectively) and complement receptors (CR) types 1 and 2 (CD35 and 21, respectively), but 43% expressed CR3 (CD11b/18); in contrast, all PBNK clones were CR3+. The NK cell-associated molecules Kp43 (CD94) and the p58 molecule recognized by the HP3E4 monoclonal antibody were both present on a higher proportion of CD3- PBNK (91% and 50%, respectively) than DGL clones (31% and 14%, respectively), despite expression of CD94 by > 90% of fresh CD56+ decidual leucocytes. Five of 35 CD3- DGL clones expressed cytoplasmic CD3 zeta in the absence of expression of CD2, CD16 or the p58 molecule recognized by HP3E4. These variations between CD3- DGL and PBNK cell clones in expression of functional molecules may be related to previously reported differences in major histocompatibility complex-non-restricted cytotoxic activities between these two cell types. PMID- 8675218 TI - Porcine CD3 epsilon: its characterization, expression and involvement in activation of porcine T lymphocytes. AB - The cloning, characterization and expression of porcine CD3 epsilon and establishment of its role in T-cell activation using an anti-porcine CD3 epsilon monoclonal antibody, as described here, provides a first step towards a greater understanding of the porcine immune response. Porcine CD3 epsilon was cloned from a porcine T-cell cDNA library by polymerase chain reaction and found to have up to 72% identity with other CD3 epsilon chains, retaining all the necessary primary structural motifs for correct functioning of porcine CD3 epsilon. When expressed in COS7 cells porcine CD3 epsilon was an intracellularly localized, monomeric 23,000 MW protein exhibiting no evidence of N-glycosylation. A monoclonal antibody, PPT3, recognized expressed porcine CD3 epsilon and activated porcine T cells as demonstrated by stimulation of calcium mobilization, an increase in protein tyrosine phosphorylation and proliferation. These results further reaffirm and identify CD3 epsilon as an important cell surface protein involved in signal transduction of activation signals in porcine T cells. PMID- 8675219 TI - Ligation of CD40 with soluble CD40 ligand reverses anti-immunoglobulin-mediated negative signalling in murine B lymphoma cell lines but not in immature B cells from neonatal mice. AB - Ligation of surface immunoglobulin (sIg) on certain murine B-lymphoma lines has been shown to initiate a programme leading to growth arrest and death of the cells by apoptosis. The cell lines WEHI 231 and CH33 which respond in this way to receptor cross-linking have phenotypic characteristics resembling those of immature normal B cells, and their responses have been taken to model those responsible for clonal deletion or anergy. Cross-linking of sIg on normal neonatal B cells has also been shown to inhibit their responsiveness to polyclonal activators. We have examined the ability of various co-stimuli to modify the response of growth-inhibitable B lymphoma lines to sIg cross-linking. Our findings indicate that cell-cell contact between cells of the WEHI 231 or CH33 lines and activated T cells rescues these cells from growth arrest and apoptosis. Cell-free supernatants from some T-cell lines were also protective although recombinant IL-4 had no effect. Analysis of the most effective signals and timing for inducing this protection suggested that it might, in part, be mediated by CD40 ligand (CD40L) expressed on or secreted by activated T cells. Using a soluble recombinant CD40L-CD8 fusion protein we have now shown that co ligation of CD40 is sufficient to rescue WEHI231 and CH33 cells from anti-Ig induced apoptosis. In contrast, the inhibitory effect of anti-Ig antibodies on the lipopolysaccharide (LPS)-driven proliferation of neonatal B cells was not relieved by co-ligation of CD40 with CD40L. These findings bring into question the usefulness of 'immature' B-cell lines as models for tolerance induction. PMID- 8675220 TI - In vivo treatment with anti-interleukin-13 antibodies significantly reduces the humoral immune response against an oral immunogen in mice. AB - Interleukin-13 (IL-13) is a cytokine which significantly enhances the proliferation and differentiation of B lymphocytes. We therefore evaluated its role in the formation of a humoral immune response in vivo. Upon oral immunization with the B subunit of Escherichia coli heat-labile enterotoxin (LT B), rapid up-regulation of IL-13 mRNA expression in the mesenteric lymph nodes of LT-B intubated mice occurred. This result suggested that IL-13 might be involved in the formation of a mucosal antibody response against LT-B if this cytokine was in fact secreted. To test this possibility, the coding region for murine IL-13 was cloned into the pFLAG-1 expression vector. Recombinant murine IL-13 was purified from bacterial lysates and used as an immunogen to produce polyclonal anti-IL-13 antibodies. Groups of BALB/c mice treated in vivo with anti-IL-13 antibody 2 days before and on the day of oral immunization with LT-B had significantly reduced intestinal IgA and serum IgG and IgA anti-LT-B antibody responses when compared to mice treated with control antibody. Furthermore, groups of mice primed with LT-B and then treated with anti-IL-13 antibody prior to oral immunization with a second dose of LT-B also had significantly reduced intestinal IgA and serum IgG and IgA anti-LT-B antibody titres compared to controls. In vitro LT-B restimulation experiments using splenic mononuclear leucocytes isolated from LT-B primed mice treated with anti-IL-13 antibody demonstrated decreased expression of IL-4 and IL-13 mRNA and decreased IL-4 secretion when compared to controls. Together these results demonstrate an important role for IL-13 in the formation of a humoral immune response at mucosal surfaces. PMID- 8675222 TI - Differential localization of allograft nitric oxide synthesis: comparison of liver and heart transplantation in the rat model. AB - Nitric oxide (NO) is a free radical with a diversity of cellular origins and potential functions. Within the realm of solid organ transplantation, NO has been the focus of much attention. Discordant reports have documented both suppression and potentiation of the alloimmune response. In addition to questions regarding its functional role, little is known of the cellular origins of NO in acute rejection of vascularized allografts. To address this question, acute rejection models of rat heterotopic heart and orthotopic liver transplantation were chosen. When compared with naive controls and isografted animals, acute rejection in both heart and liver transplantation was associated with elevated systemic levels of the NO metabolite, nitrite. This was accompanied by increased graft content of iNOS protein as determined by immunoblot analysis of protein extracts. Expression of iNOS mRNA was localized with in situ hybridization. In both heart and liver transplantation, iNOS mRNA was found in the inflammatory infiltrate accompanying acute rejection. In addition, hepatocytes also expressed iNOS mRNA in the rejecting liver allograft. In contrast, cardiac myocytes in the rejecting heart allograft did not stain for iNOS mRNA. These results indicate that organ specific, differential cellular expression of iNOS occurs in the acutely rejecting allograft. Transcriptional regulation of iNOS may vary among various organs according to the local cellular milieu. In addition, there may be a variable allograft specific response to acute rejection which may modify the associated immunologic biology. PMID- 8675221 TI - Acceleration of IgE responses by treatment with recombinant interleukin-3 prior to infection with Trichinella spiralis in mice. AB - Treatment of mice with recombinant interleukin-3 (rIL-3) accelerated an IL-4 dependent IgE production following infection with Trichinella spiralis. When mice were treated with a total of 1.5 x 10(4) units rIL-3 for 5 days before infection with 400 muscle larvae, the serum IgE level increased prominently on day 5. Acceleration of IgE responses was dependent on the dose of rIL-3 injected. Treatment of mice with a total of 10(3) units rIL-3 could accelerate IgE responses. IgE responses were detected by a sandwich enzyme-linked immunosorbent assay at least from day 3 in mice treated with rIL-3. Acceleration of IgE responses was inhibited by anti-IL-4 monoclonal antibody. In contrast to this, IgG1 and IgG2a responses were not suppressed by the anti-IL-4 treatment. IL-3 treatment could up-regulate IgE and IgG1 responses but not the IgG2a response. IL 3 treatment could also accelerate IgE responses in W/Wv mice infected with the parasites. These results suggest that IL-3 is involved in regulation of IgE responses in mice and that mast cells do not play an essential role in acceleration of IgE responses induced by rIL-3 treatment in this system. PMID- 8675223 TI - Agalactosyl IgG and beta-1,4-galactosyltransferase gene expression in rheumatoid arthritis patients and in the arthritis-prone MRL lpr/lpr mouse. AB - Reduced galactosylation of immunoglobulin G (IgG) is well documented in rheumatoid arthritis (RA), but the reason for this defect is still unknown. There is some evidence supporting a defect in the biosynthetic pathway, and a reduction in the level of beta-1,4-galactosyltransferase (beta-1,4-GalTase) enzyme activity. Since glycosyltransferases are, in general, regulated at the level of transcription, we have measured the level of beta-1,4-GalTase gene expression in B cells from patients with RA and normal control individuals. We found no significant difference in mRNA levels for the transferase in these two groups (P > 0.7). MRL/Mp-lpr/lpr (MRL-lpr) mice develop a spontaneous arthritis with increased levels of agalactosyl IgG (G0). In spite of a significant reduction in the level of beta-1,4-GalTase mRNA in total spleen lymphocytes from MRL-lpr mice compared with the congenic MRL/Mp-(+/+) (MRL-(+/+) mice and with CBA/Ca mice, we found comparable levels of the beta-1,4-GalTase mRNA in purified B cells from both spleen and lymph nodes of the three strains. Amongst the lymphoid compartments examined, the spleen and peripheral blood were found to be the major contributors of G0 in MRL-lpr mice. These data indicate that in neither human RA, nor in an animal model of this disease, is reduced IgG galactosylation caused by impaired expression of the beta-1,4-GalTase gene in B lymphocytes. Furthermore, splenic B cells, which have normal levels of beta-1,4-GalTase mRNA, appear to be a major source of G0 in MRL-lpr mice. PMID- 8675225 TI - Lectin-activated CD4+CD45RA+ T-lymphocytes have no ability to kill monocytes. AB - Monocytes are eliminated from cell culture by antigen or mitogen activated cytotoxic CD4+ T-lymphocytes. In this report we asked the question whether CD4+CD45RA+ and CD4+CD45RO+ subpopulations differ in the ability to kill monocytes in pokeweed mitogen (PWM)-activated cultures. Data are presented that although CD4+CD45RA+ vigorously proliferate in the presence of PWM, they do not kill monocytes or secrete IFN gamma. PMID- 8675224 TI - Cleavage of human complement component C5 by cysteine proteinases from Porphyromonas (Bacteroides) gingivalis. Prior oxidation of C5 augments proteinase digestion of C5. AB - Since severe periodontitis is characterized by an acute inflammatory response with cellular infiltration and microbial overgrowth, plasma proteins could be exposed to both proteinases and oxidants released from the granulocytes, as well as to proteinases from the microorganisms. When human complement component C5 was digested by cysteine proteinases (i.e. gingipain-R and gingipain-K) from Porphyromonas gingivalis, limited cleavage of the C5 molecule was observed. If C5 was first oxidized by hydroxyl radicals, these gingipains converted modified C5 to fragments that exhibited significantly greater pro-inflammatory activity than did digests of unmodified C5. After cleavage of oxidized C5 by gingipain-R, the digest exhibited measurably greater neutrophil enzyme release and chemotaxis of human polymorphonuclear leukocytes (PMNs) compared with the activities of unoxidized C5 digests. Gingipain-K generates virtually no polarization or chemotactic activity of human PMNs from C5, nor is enzyme release stimulated by these C5 digests. However, when oxidized C5 was digested by gingipain-K, human PMNs were stimulated for polarization, chemotaxis and enzyme release indicating that an active fragment had been generated. Proteolysis of oxidized C5 evokes greater neutrophil activation than does proteolysis of unoxidized protein, a fact which supports the hypothesis that oxidation and proteolysis may be coupled to enhance the destructive effects of the inflammatory process. These results, in which digests of both oxidized and unmodified complement component C5 were evaluated, support the general concept that oxidation and proteolysis may participate cooperatively in amplifying both the severity and duration of the inflammatory reaction. PMID- 8675226 TI - HLA-DQ3 is associated with Graves' disease in African-Americans. AB - HLA heterogeneity occurs in various ethnic groups and has been significantly associated with Graves' disease. In this study we have determined that DQ3 is associated with Graves' disease in African-Americans. Human leukocyte antigen (HLA) typing of D-region antigens in 139 controls and 45 Graves' disease patients reveals significant differences for HLA-DR2, DR9, DQ1, and DQ3. The latter remained significant after correction. Increases in HLA-DR9 and DR3 are associated with increases in DQ3 and DQ2, respectively. The decrease in DR2 is associated with a decrease in DQ1. The associated increases and decreases in DR with DQ antigens probably reflect linkage disequilibrium. Patients were evaluated for autoantibodies against microsomal antigens and/or against thyroglobulin. All of the normal control volunteers were negative for thyroid antibodies and thirteen percent of patients produced autoantibodies. No significant associations were detected for antibody production, type of treatment required, age of onset, family history of Graves', status of T3, T4 levels, goiter and/or ophthalmopathy. PMID- 8675227 TI - T cell receptor V-segment frequencies in aged individuals. AB - The T V alpha and V beta cell specificities repertoire usage in aging subjects was studied by the use of seven different monoclonal antibodies specific for defined regions of the T cell receptor (TCR). Except for the V beta 8 subfamily, no differences were observed in the frequency of T cells bearing selected V alpha beta epitopes, between old and control subjects. PMID- 8675228 TI - Interleukin 10 induced c-fos expression in human B cells by activation of divergent protein kinases. AB - IL-10 is a potent mediator of human B cell growth and plasma cell formation. However, signal transduction of IL-10 in B cells is poorly understood. In this study the effect of IL-10 on the expression of the protooncogene c-fos was investigated, because Fos plays a potential role in the regulation of B cell proliferation and differentiation. B cells were purified from buffy coat preparations of healthy blood donors by positive selection using an anti CD20 monoclonal antibody and a MiniMACS separation unit. B cells were prestimulated with SAC for 48 hrs. Then, cells were incubated with medium or IL-10 (100 ng/ml) for 10 to 120 min. RNA was extracted by phenol/chloroform and c-fos expression was analyzed by PCR assisted mRNA assay. A significant 2-4 fold increase of c-fos expression was observed within 30 min of stimulation with IL-10 (p < 0.01). After 2 hrs c-fos expression declined to basal levels. The effect of IL-10 was dose dependent with a maximum stimulation using 100 ng/ml of IL-10. The IL-10 effect on c-fos expression was not blocked by polymyxin B. Using the tyrosine kinase inhibitor genistein (10 microM) a complete inhibition of IL-10 induced c-fos expression was observed. In addition, H-7 (10 microM), a specific inhibitor of serine/threonine kinases, significantly blocked IL-10 mediated c-fos expression (p < 0.05). In conclusion, these data show that IL-10 induces c-fos expression in human B-cells by activation of tyrosine and serine/threonine kinases. Since this is the first report on IL-10 induced signal transduction, these data may help to identify the intracellular mechanisms by which IL-10 stimulates human B-cells. PMID- 8675229 TI - Growth regulatory effects of transforming growth factor-beta 1 and interleukin-2 on IL-2 dependent CD4+T lymphoblastoid cell line. AB - Transforming growth factor-beta 1 (TGF-beta 1) is an immuno-modulatory cytokine which has been shown to modulate the activity of T and B cells. We show here that human TGF-beta 1 inhibited stationary cultures of IL-2 dependent CD4+ bovine lymphoblastoid T cells (BLTC) by down-regulating their IL-2 receptor (IL-2R) expression, arresting cells in the G0/G1 compartment of the cell cycle, and inducing these cells to undergo apoptosis. These events were reversed by the addition of a minimal concentration of IL-2 (2U/ml). In the presence of exogenous IL-2, TGF-beta 1 was found to augment the proliferative response of BLTC through up-regulation of IL-2R expression, allow progression of normal cell cycle, and significantly prevent apoptosis. Our data clearly show that IL-2 and TGF-beta 1, when present alone, have contrasting effects on BLTC. TGF-beta 1 down regulates events that are associated with IL-2 mediated signal. But when present together, IL-2 and TGF-beta 1 upregulate activation signals and proliferation of rapidly dividing CD4+T cells. PMID- 8675230 TI - Cytokines and cell surface markers in prediction of cardiac allograft rejection. AB - Endomyocardial biopsy is generally used to quantify heart allograft rejection and guide immunotherapy. Biopsy, however, is invasive, costly, and risky. Since rejection requires lymphocyte activation, the purpose of this study was to assess alternative methods to evaluate rejection dynamics by investigating serum levels of cytokines and cell surface markers after heart transplantation. Interleukin-2 receptor bearing CD4+T (IL-2R/CD4) cell levels were higher in the peripheral blood of human transplant recipients with rejection grade 2 (p < 0.02). HLA DR/CD3 levels were somewhat higher in rejection grade 2. There was no correlation between biopsy scores and serum levels of tumor necrosis factor (TNF-alpha), IL 2, or percentage of T cell, NK cell, B cell, CD4+T cell, CD8+T cell, HLA-DR/CD4, HLA-DR/CD8, IL-2R/CD3, IL-2R/CD8. Interleukin-1 (IL-1 beta) was not detectable in all of the samples. The current studies suggest that monitoring lymphocyte IL 2R/CD4 and HLA-DR/CD3 levels is useful in predicting cardiac transplant rejection. PMID- 8675231 TI - alpha-Interferon treatment of patients with chronic fatigue syndrome. AB - Thirty patients who fulfilled clinical criteria defined by the CDC for Chronic Fatigue Syndrome were treated with alfa 2a interferon or placebo in a double blind crossover study. Outcome was evaluated by Natural Killer (NK) cell function, lymphocyte proliferation to mitogens and soluble antigens, CD4/CD8 counts and a 10 item Quality of Life (QOL) survey. Although mean NK function rose from 87.8 +/- 19.6 to 129.3 +/- 20.7 lytic untis (LU; p < .05) with 12 weeks of interferon therapy, there was no significant change in the other immunologic parameters or QOL scores. When the 26 patients who completed the study were stratified according to their baseline NK function and lymphocyte proliferation, 4 groups were identified: 3 patients had normal NK cell function and lymphocyte proliferation when compared to normal, healthy controls, 9 had isolated deficiency in lymphocyte proliferation, 7 had diminished NK function only, and 7 had abnormalities for both parameters. QOL scores were not significantly different for the four groups at baseline. After 12 weeks of interferon therapy, QOL score significantly improved in each of the seven patients with isolated NK cell dysfunction (mean score, 16.3 +/- 7.9) compared to baseline (39.7 +/- 12.1; p < .05). In these patients the mean NK function increased from 35.1 +/- 11.7 to 91.5 +/- 22.7 LU (p < .01). Significant improvement was not recorded for QOL in the other three groups. Thus, therapy with alpha interferon has a significant effect on the QOL of that subgroup of patients with CFS manifesting an isolated decrease in NK function. PMID- 8675232 TI - Binding reactivity of monoclonal anti-carcinoembryonic antigen (CEA) antibodies with cell membrane-bound CEA and with free CEA in solution. AB - Binding reactivities of 62 anti-CEA MAbs from 10 different research groups with cell membrane-bound CEA and with free CEA in solution were compared by inhibition of MAb binding to CEA-expressing tumor cells by free CEA. Bindings of 30 MAbs to the cell membrane-bound CEA (280 ng CEA/2 x 10(5) cells) were inhibited by approximately equal amounts of free CEA, indicating that binding affinities of about half the MAbs for cell membrane-bound CEA are similar to those for free CEA, respectively. Bindings of 15 MAbs to the cell membrane-bound CEA were easily inhibited by free CEA of less than half the amount of the cell membrane-bound CEA, while inhibition of bindings of the remaining 17 MAbs required twice more free CEA than the amount of cell membrane-bound CEA, showing that about one fourth of the MAbs have higher affinities for free CEA and the remaining about one-fourth of the MAbs possess higher affinities for cell membrane-bound CEA. These results help form the basis for selecting the anti-CEA MAbs for use in clinical applications, such as serum CEA assay, tumor imaging and immunotherapy. PMID- 8675233 TI - IFN-gamma treatment increases insulin binding and MHC class I expression in erythroleukemia cells. AB - We have investigated if interferon-gamma (IFN-gamma) treatment of human K562 tumor cells, which upregulates the expression of MHC class I antigens (MHC-I), simultaneously would influence insulin binding. Treatment of K562 cells with recombinant human IFN-gamma for 48 h caused a significant increase of insulin binding at 37 degrees C. Recombinant human tumor necrosis factor-alpha (TNF alpha) alone had no effect but acted synergistically with IFN-gamma, leading to a two-fold increase of insulin binding. No change in affinity, number of binding sites or cell surface expression of insulin receptors (IR) after IFN-gamma treatment could be detected. The increased insulin binding observed at 37 degrees C was not seen at 4 degrees C, suggesting alteration of insulin internalization. The dose-response curve, as well as the time curve, for the increase in insulin binding after IFN-gamma treatment correlated with enhanced cell surface expression of MHC-I antigens. However, the correlation was not absolute. Our results show that IFN-gamma treatment alone or together with TNF-alpha, can alter the insulin binding to K562 cells without changing the expression or affinity of the IR. This correlates with the effect of IFN-gamma on MHC-I expression. These results support the findings that MHC-I molecules associate and interact with the IR at the cell surface. PMID- 8675234 TI - Quantification of leukocyte migration: improvement of a method. AB - Eighteen different permeable membrane supports with and without confluent endothelial cell monolayers were incubated with normal donor derived neutrophils in the upper chambers of a 24 multiwell double chamber system. In order to study transmembrane or transendothelial leukocyte migration leukocytes were stimulated by chemoattractants, or endothelial cells were activated by IL-1. After coincubation the membrane supports building the upper chambers were discarded. Using this technique, leukocytes that had migrated into the lower chamber were exposed to the fluorescent dye calcein AM without additional washing or transfer steps. Absolute cell counts were determined computer assisted using dilution series of calcein AM labeled leukocytes as standards. Serial dilutions of neutrophils exposed to calcein AM showed reproducible linear fluorescence intensity, and relative fluorescence intensity correlated significant with cell counts (r2 = 0.974, p < 0.0001). Out of 18 membrane supports only one was suitable for our assay set up. Best technical and optical performance was achieved with a membrane made of polyethylene terephtalate with a pore size of 3 mm at a pore density of 0.8 x 10(6)/cm2. Stimulation of leukocytes or endothelium by FMLP or IL-1 revealed an increase of transendothelial migration to 7.2 +/- 1.8 x 10(5) PMN and 5.1 +/- 0.7 x 10(5) PMN respectively if compared with medium (0.6 +/- 0.2 x 10(5) PMN). IL-1 induced migration of neutrophils was inhibited by anti IL-1 autoantibodies derived from chronic renal failure patients (IL-1: 100% of PMN migrated, anti IL-1 antibody: 39% of PMN migrated, control antibody: 84% of PMN migrated). In summary, a simple fluorimetric assay was established for the quantification of transmembrane and transendothelial leukocyte migration. PMID- 8675235 TI - Apoptosis as a mechanism of lectin-dependent monocyte-mediated cytotoxicity. AB - In this study we investigated the mechanisms of cytotoxicity mediated by pokeweed mitogen (PWM)-activated human peripheral blood monocytes. By using DNA electrophoresis and propidium iodide (PI)-DNA staining flow cytometry, we demonstrated that apoptotic cell death of target U937 cells and Raji cells was induced in lectin (PWM)-dependent monocyte-mediated cytotoxicity (LDMC). The LDMC mediated DNA fragmentation in U937 cells and Raji cells was induced in lectin (PWM)-dependent monocyte mediated cytotoxicity(LDMC). The LDMC-mediated DNA fragmentation in U937 cells was completely inhibited by anti-TNF alpha monoclonal antibody (mAb), but not by the addition of monosaccharide (N-acetylglucosamine, GlcNAc, a sugar specifically recognized by PWM and a lectin-like receptor on monocytes). In contrast, GlcNAc inhibited the DNA fragmentation in Raji cells induced by LDMC which the anti-TNF alpha mAb had no effect. PWM was found to stimulate the production of nitric oxide (NO) from monocytes. The NO-production was enhanced in the presence of target Raji cells, while the enhancement was abolished by the treatment with GlcNAc. By flow cytometry, we found that PWM bound to tumour cells as well as monocytes, and inhibited the expression of HLA DR antigen on tumour cells. These results suggest that the presence of lectin molecules on the surface of monocytes and tumour cells may bring the two cells together, thus facilitating the induction of apoptosis in target cells by triggering the production of cytolytic factors (TNF and NO) and the modification of target cell surface antigen (HLA-DR). PMID- 8675236 TI - Induction of LFA-1 independent human B cell proliferation and differentiation by binding of CD40 with its ligand. AB - Engagement of CD40 on resting B cells in the presence of IL-4 triggers B cell proliferation, differentiation and homotypic adhesion. This study was designed to investigate the role of LFA-1/ICAM-1 interactions in homotypic adhesion and proliferation of CD40-activated human B lymphocytes. Freshly isolated B cells were cultured in vitro in the presence of IL-4 and of L cells expressing CD40L, the CD40 ligand. The addition to the culture medium of LFA-1 and ICAM-1 antibodies inhibited homotypic B lymphocyte adhesion. However, these antibodies failed to affect B lymphocyte proliferation and antibody production. These results indicate that aggregation and proliferation are independent events although both induced by CD40 activation. PMID- 8675237 TI - Polyethylene glycol precipitates of serum contain a large proportion of uncomplexed immunoglobulins and C3. AB - High pressure liquid chromatography (HPLC) was used to fractionate redissolved polyethylene glycol (PEG) precipitates isolated from the sera of normal volunteers and from patients with IgA nephropathy (IgAN) and systemic lupus erythematosus (SLE), 2 diseases characterized by elevated levels of circulating immune complexes. The individual fractions were analyzed by solid phase ELISA for IgA, IgM, C3, IgG, and complexes of IgG-IgA and IgG-C3. Although PEG precipitates were enriched for high molecular weight IgA and IgG (presumably bound within CIC), significant amounts of IgM, unbound IgG and C3 were also present. The quantities of the PEG-precipitable proteins did not correlate with their serum concentrations. IgG-IgA and IgG-C3 complexes were found in all precipitates examined, but the levels of complexes were higher in both patient groups. These results indicate that PEG precipitates a considerable quantity of proteins not bound in immune complexes. There appeared to be greater protein precipitation from sera of the patient groups compared to the amount precipitated from the normal sera. These results suggest that an understanding of the mechanism of PEG precipitation may be important in defining abnormalities in IgAN, SLE and perhaps other diseases characterized by elevated levels of CIC. In addition, the possibility of undetected CIC in PEG precipitable material must be considered. PMID- 8675238 TI - Measles & malnutrition. AB - Measles is an important acute childhood viral infection having severe consequences on the nutritional status. The adverse nutritional effects of measles are experienced by both the well-nourished and the malnourished children. However, the severe nutritional deficiencies like kwashiorkor/marasmus are precipitated only in children who are already malnourished. As high as 3-4 per cent of children with measles suffered from these clinical nutritional syndromes in their post-measles period. Though malnutrition is widespread among Asian children also, measles appears to run a milder course with low mortality rates in developing Asian countries, as compared to African children. The associated secondary infections which apparently complicate the primary illness in malnourished children might be responsible for higher mortality and could be due to socioeconomic and environmental causes that are associated with poverty and malnutrition rather than due to malnutrition or measles per se. Measles related blindness is of multifactorial aetiology. While acute measles triggers corneal ulceration through viral proliferation in the cornea, nutritional keratomalacia is often the cause of blindness in the post-measles period. Measles vaccination is the major preventive measure. However, timely use of local antibiotic therapy to the eyes and administration of vitamin A supplements offer protection to the child who already has measles. Response of malnourished children to live attenuated measles vaccine has been found to be safe and effective. Neither malnutrition nor tuberculosis which are widespread among malnourished children of developing countries appear to be contraindications for measles vaccination. Thus, the beneficial effects of the measles vaccination should be fully exploited by adequate supply of potent vaccine and coverage of all susceptible children. PMID- 8675239 TI - Diet, nutrition & cancer--the Indian scenario. AB - Cancer continues to be a major health problem despite advances in medical technology for its diagnosis and treatment. Hence prevention strategies are needed to decrease the burden of the disease. Of all the environmental factors, dietary components appear to play an important role in the initiation/progression of the disease. Nutrients and non-nutrients in the diet can influence the carcinogenic process at various stages, from initiation to overt manifestation. The National Institute of Nutrition has conducted studies on several aspects of diet-cancer inter-relationships. These include studies on metabolic susceptibility, case-control approach to determine the risk factors and intervention studies to determine the role of nutrients and non-nutrient components on preneoplastic events. Extensive work has been carried out demonstrating the antimutagenic/anticarcinogenic potential of some commonly consumed spices and vegetables such as turmeric, mustard, green leafy and allium species of vegetables. Dietary intervention for cancer prevention is needed to control the disease besides avoiding risk factors such as smoking and alcoholism and exposure to genotoxicants. Public education and awareness about the beneficial effects of consuming a healthy diet including plenty of fresh vegetables and fruits with spices such as turmeric in adequate amounts to prevent cancer are required. PMID- 8675240 TI - Zinc status of Indian children. AB - Zinc is a trace metal essential for human health and its deficiency is found to cause severe growth retardation in children. Information on the zinc status of Indian children is meagre perhaps due to lack of a reliable parameter. However, in view of the role of zinc in promoting growth, it has become common practice to prescribe zinc supplements to young children and newborns, particularly preterm infants. It is now clearly established that zinc confers no additional benefits to an individual with adequate zinc status while it can potentially lead to harmful effects by disturbing the milieu of other trace metals in the body. Estimation of thymulin levels in circulation is found to be a sensitive indicator of zinc status and using this parameter we found that apparently normal children have adequate zinc status. Children suffering from severe protein energy malnutrition however had very low levels of the hormone besides low leukocyte and plasma zinc levels indicating zinc deficiency. Such children showed improvement in their zinc status when zinc supplements were provided along with rehabilitation diets. Pregnant women and term newborns showed no evidence of zinc deficiency. Preterm infants had higher leukocyte zinc levels during early infancy and the breast milk of their mothers also had higher zinc content which could cater to the higher requirements of the rapidly growing preterm infant. All breast-fed infants showed decline in the zinc status gradually over the initial 4 months of life and regained adequate zinc status after appropriate weaning. These studies thus do not support the view of routine zinc supplements to pregnant women or children. However, Infants solely fed formula milk from birth had significantly impaired zinc status till the time of weaning. The functional significance of severe zinc inadequacy in such infants needs to be established. PMID- 8675241 TI - Strategies for control of micronutrient malnutrition. AB - Micronutrient malnutrition, particularly vitamin A deficiency (VAD), iron deficiency anaemia (IDA) and iodine deficiency disorders (IDD), poses a serious threat to the health of vulnerable segments of population. Dietary Inadequacy is the primary cause of VAD and IDA, while poor iodine content of soil and water due to environmental iodine deficiency is the main determinant of IDD. Three major intervention strategies are available for the control of micronutrient malnutrition: supplementation of the specific micronutrients; fortification of foods with micronutrients; and horticulture intervention to increase production and nutrition education to ensure regular consumption of micronutrient rich foods. In India currently the national nutrition programmes being implemented for preventing these deficiencies are based on short term supplementation like periodic mega dosing of vitamin A, distribution of iron and folic acid tablets, and salt iodisation. Though these have been in operation for over two decades, there has been no perceptible biological impact on the prevalence of micronutrient malnutrition. Among the constraints, the most important are: lack of coordination, shortage of resources and manpower, inadequate and irregular supplies, lack of proper orientation and training to the functionaries, poor monitoring and supervision and absence of nutrition education. Integrated and multi-sectoral approaches are required to achieve the goals set under the National Nutrition Policy. These should include community-friendly nutrition education to increase awareness and motivation; active people's participation; food fortification; nutrient supplementation; nutrition oriented horticulture programmes; orientation of functionaries, and establishment of integrated micronutrient surveillance. Concerted and focussed efforts are needed to combat micronutrient malnutrition by the 2000 AD. PMID- 8675242 TI - Role of goitrogens in iodine deficiency disorders & brain development. AB - Although iodine deficiency has primarily been implicated in the causation of goitre, the significant role played by food goitrogens in the etiology of iodine deficiency disorder (IDD) is being increasingly recognized. Impaired brain development is the major cause of concern in IDD. Detailed experimental studies were undertaken to ascertain various biochemical changes associated with developing brain in response to treatment with a goitrogens--thiocyanate. Addition of thiocyanate to food deprived of KI brought down significantly the circulating levels of thyroxine (T4) in rats. Nucleic acids and protein content in different regions of brain were significantly lowered in rat pups exposed to thiocyanate. The rate of microtubule assembly, which is detrimental for neurite growth was considerably lowered, thereby influencing both myelin deposition and synaptogenesis in developing brain. Goitrogen intake not only caused an adaptive increase in the activity of type II 5'-deiodinase, which governs availability of triiodothyronine (T3) in brain, it also increased the latter's binding to brain nuclear receptors under conditions of thiocyanate induced hypothyroid state. Addition of adequate quantities of KI mitigated thiocyanate induced alterations by restoring circulating level of thyroxine. These investigations suggest that goitrogens play a significant role in influencing biochemical events unique to developing brain. PMID- 8675243 TI - Human requirements of iodine & safe use of iodised salt. AB - Iodine deficiency is the most common preventable cause of mental deficiency. Remarkable success has been achieved by the use of iodised salt to correct this deficiency in many industrialised countries since 1920. The Government of India has adopted a strategy to iodise all edible salt in the country to overcome iodine deficiency. Universal salt iodisation is the principal public health measure for eliminating iodine deficiency disorders. Daily iodine intakes of up to 1000 micrograms, appear to be entirely safe. In India, the likelihood of exceeding this level is quite small. Iodised salt does not cause any side effects. Iodine in iodised salt does not carry risks for persons who are already iodine sufficient. iodisation of salt at the current level of fortification (15 30 ppm iodine) keeps intakes well within a safe daily range for all populations, irrespective of their iodine status. PMID- 8675244 TI - Nutrition & health implications of palm oil in Indian diets. AB - To boost the edible oil production and attain self-sufficiency, one of the long term strategies undertaken by the Indian government is promotion of palm oil production through oil palm cultivation. Compared to other traditional oils (except coconut oil) used in India, palm oil and palmolein have high saturated fatty acids and low linoleic acid levels. Studies conducted to evaluate the nutritional and health implications of substituting other oils with palmolein show that despite having low linoleic acid, the use of palm oil may not adversely affect the linoleic acid status of Indian population. Substitution of groundnut oil with palmolein in cereal based lactovegetarian diets providing about 30 per cent total fat calories, doubles the saturated fatty acids and reduces by half the linoleic acid content. The effects of this substitution in volunteers from the middle income group did not raise serum cholesterol and aggregability of platelets indicating that palm oil may not produce the deleterious effects associated with saturated fatty acids. The tocols present in palm oil are natural biological antioxidants and can therefore augment the antioxidant potential of Indian diets. Red palm oil is the richest natural source of carotenes which are powerful biological antioxidants. The major carotene in red palm oil is beta carotene. Therefore, red palm oil can be used to prevent vitamin A deficiency which is widespread in India. PMID- 8675245 TI - Nutritional significance of rice bran oil. AB - India is the second largest producer of rice in the world and has the high potential to produce rice bran oil (RBO), a by-product of the rice milling industry. Since RBO is, an unconventional oil, the chemical composition, nutrient evaluation and toxicological safety were assessed. The fatty acid composition RBO is very close to that of groundnut oil (GNO). Though RBO has high unsaponifiable matter (4.2%), it is rich In minor constituents such as phytosterols, triterpene alcohols, tocopherols and tocotrienols. Experimental as well as human studies have demonstrated the hypolipidaemic effects of RBO. Further, It was established that minor constituents present in unsaponifiable fraction of RBO were responsible for its hypolipidaemic effects. Nutritional evaluation studies, carried out with 10 per cent RBO and 20 per cent protein, indicated that growth, feed efficiency and mineral balance were comparable to GNO-fed animals. Toxicological studies had shown that there were no abnormalities In animals fed either RBO or GNO. The reproductive performance was also found to be normal as compared with that of GNO-fed animals in all three generations. In addition, neither RBO nor the foods deepfried in it showed any mutagenicity as judged by Ames test. In view of its safety and hypolipidaemic activity, RBO could be considered as an alternative source of edible oil. PMID- 8675246 TI - Health & nutritional implications of food colours. AB - Colour is a vital constituent of food which imparts distinct appearance to the food product. Artificial colouring becomes a technological necessity as foods tend to lose their natural shade during processing and storage. Most of the food colours tested in the conventional toxicity experiments showed toxic effects at a very high level of intake i.e., 1-5 per cent in the diet. However, such levels of intake are not normally encountered. Human studies indicated that food colours, (natural or synthetic) can induce wide range of allergic reactions only in sensitive or atopic individuals. Most of the foodborne diseases reported are due to the consumption of non-permitted textile colours or abuse of colours. The Government is pressurised periodically to place a total ban on the use of food colours due to their possible ill effects. It should be realised that surveillance should go hand in hand with legal actions. PMID- 8675247 TI - Intervention trials: concerns and publishing pitfalls. PMID- 8675248 TI - Angiotensin-(1-7) inhibits vascular smooth muscle cell growth. AB - Although angiotensin II (Ang II) and the heptapeptide Ang-(1-7) differ by only one amino acid, the two peptides produce different responses in vascular smooth muscle cells. We previously showed that Ang II stimulated phosphoinositide hydrolysis, whereas Ang II and Ang-(1-7) released prostaglandins. We now report that Ang II and Ang-(1-7) differentially modulate rat aortic vascular smooth muscle cell growth. Ang-(1-7) inhibited [3H]thymidine incorporation in response to stimulation by fetal bovine serum, platelet-derived growth factor, or Ang II. The reduction in serum-stimulated thymidine incorporation by Ang-(1-7) depended on the concentration of the heptapeptide over the range of 1 nmol/L to 1 mumol/L, with a maximal inhibition of 60% by 1 mumol/L Ang-(1-7). Ang-(1-7) also inhibited the serum-stimulated increase in cell number to a maximum of 77% by 1 mumol/L Ang (1-7). The attenuation of serum-stimulated thymidine incorporation by Ang-(1-7) was unaffected by antagonists selective for angiotensin type 1 (AT1) or type 2 (AT2) receptors; however, [Sar1,Ile1]Ang II and [Sar1,Thr2]Ang II were effective antagonists, indicating that growth inhibition by Ang-(1-7) was a result of angiotensin receptor activation. In contrast, Ang II stimulated [3H]thymidine incorporation in cultured vascular smooth muscle cells over the same concentration range, with a maximal stimulation of 314% at 1 mumol/L Ang II. Ang II also increased the total number of cells (to 145% of control), suggesting that enhanced thymidine incorporation was associated with vascular smooth muscle cell proliferation. The AT1 antagonist losartan or L-158,809 but not AT2 antagonists blocked [3H]thymidine incorporation by Ang II. These results suggest that Ang-(1 7) and Ang II exhibit opposite effects on the regulation of vascular smooth muscle cell growth. The inhibition of proliferation by Ang-(1-7) appears to be mediated by a novel angiotensin receptor that is not inhibited by AT1 or AT2 receptor antagonists. PMID- 8675249 TI - Comparison of nifedipine alone and with diltiazem or verapamil in hypertension. AB - Receptor binding studies suggest that combinations of calcium channel blockers may result in either enhanced or diminished pharmacological effects, but clinical data in hypertension are incomplete. In this study, we compared blood pressure reductions using nifedipine alone, nifedipine plus diltiazem, and nifedipine plus verapamil and determined whether combinations alter nifedipine pharmacokinetics. After determination of baseline blood pressures. 16 subjects with essential hypertension (12 men, 4 women; mean age, 48 years) received 30 mg/d open-label, sustained release nifedipine for 2 weeks. If still hypertensive (n = 16), they were randomized (double-blind) to receive either additional sustained release diltiazem or sustained release verapamil, both 180 mg/d, for 2 weeks and were then crossed-over for the final 2 weeks of the study. All medications were once daily, extended-release formulations. Blood pressures and nifedipine plasma concentrations were measured during the final day of each treatment. Overall, each combination lowered mean systolic and diastolic pressures more than nifedipine alone. Mean supine diastolic pressures were significantly lower at 8 hours (77.6 versus 84.6 mm Hg, P = .001) and 12 hours (81.5 versus 87.1 mm Hg, P = .04) with nifedipine plus diltiazem than nifedipine plus verapamil. Mean nifedipine concentrations were inversely correlated with mean blood pressures. Mean nifedipine area under the curve values were greater with diltiazem than verapamil (1430 versus 1134 ng.h/mL, P = .026), with each greater than nifedipine alone (957 ng.h/mL). Nifedipine plus diltiazem had a greater antihypertensive effect than nifedipine plus verapamil. Diltiazem caused greater increases in nifedipine plasma concentrations than did verapamil. These data suggest that combined calcium channel blockers result in additive antihypertensive effects, perhaps because of a pharmacokinetic interaction. PMID- 8675250 TI - Reduced distensibility of the common carotid artery in patients treated with ergotamine. AB - To investigate the effect of vascular smooth muscle contraction on mechanical vessel wall properties of proximal "elastic" arteries, we investigated the effect of the vasoconstrictor ergotamine on the distensibility of the common carotid artery in 10 migraine patients with ergotamine intake, in 10 control patients with migraine headache but no prior ergotamine intake, and in 10 healthy control subjects. The patients and control subjects were matched for age, blood pressure, and sex. In the ergotamine group, 2.2 +/- 1.4 mg ergotamine tartrate (0.25 to 6 mg) was taken within 12 hours before investigation. Differences in mean 24-hour blood pressure between the study groups were excluded by 24-hour blood pressure recording and differences in arterial wall thickness by high-resolution and differences in arterial wall thickness by high-resolution B-mode ultrasound. A multigate Doppler system was used for measurement of vessel wall movements by M mode Doppler analysis. Blood pressure was determined by sphygmomanometry. The end diastolic diameter of the common carotid artery was insignificantly reduced in the ergotamine group compared with the healthy control subjects and control patients (healthy control subjects, 6.6 +/- 0.4 mm; control patients, 6.7 +/- 0.5 mm; patients with ergotamine intake, 6.3 +/- 0.4 mm; P = NS). Arterial distensibility was significantly lower in the patients with ergotamine intake (17.4 +/- 4.0 10(-3)/kPa) than in the healthy control subjects (22.3 +/- 5.1 10( 3)/kPa) and control patients (22.8 +/- 3.6 10(-3)/kPa) (one-way ANOVA, P = .014). The results show that ergotamine reduces the distensibility of the common carotid artery. The data suggest that vascular smooth muscle contraction can modulate the buffering function of the arterial system independently of blood pressure changes. PMID- 8675251 TI - Insulin-resistant lipolysis in abdominally obese hypertensive individuals. Role of the renin-angiotensin system. AB - Resistance to the capacity of insulin to suppress lipolysis may be an important link in the association between abdominal obesity and hypertension. Furthermore, a more active renin-angiotensin system in adipose tissue may contribute to insulin-resistant lipolysis in abdominally obese hypertensive subjects. We determined nonesterified fatty acid concentrations and turnover as well as lipid oxidation under basal conditions and during steady-state euglycemia with two levels of insulinemia (72 and 287 pmol/L) in lean normotensive, abdominally obese normotensive, and abdominally obese hypertensive subjects. To assess the role of the renin-angiotensin system in determining non-esterified fatty acid turnover, we repeated studies in the abdominally obese hypertensive subjects after double blind random assignment to placebo or enalapril for 1 month each. The main findings were the following: (1) Nonesterified fatty acid flux was significantly higher in abdominally obese hypertensive subjects at both levels of insulinemia than in either abdominally obese normotensive or lean normotensive subjects and correlated significantly with both mean blood pressure and total systemic resistance during the higher level of insulinemia. (2) Enalapril significantly improved insulin-resistant lipolysis in the abdominally obese hypertensive subjects. The improvement in insulin suppressibility of nonesterified fatty acid flux at the high hormonal concentrations correlated positively with the magnitude of reduction in blood pressure. (3) Basal lipid oxidation and suppression in response to insulin were similarly impaired in both obese groups. Resistance to the antilipolytic actions of insulin is thus a characteristic feature in abdominally obese hypertensive subjects and may be linked to the elevated blood pressure in these individuals. A more active renin-angiotensin system may partly explain the insulin-resistant lipolysis in this form of hypertension. PMID- 8675252 TI - Insulin resistance, elevated glomerular filtration fraction, and renal injury. AB - The development of insulin resistance may be an early step in the development of hypertension; however, the mechanism for this process is not known. The worsening of insulin resistance and hypertension could increase both systemic and glomerular capillary pressures and predispose an individual to renal injury. The purpose of this study was to examine the relationship of insulin resistance to glomerular hemodynamics and dietary salt intake in 10 older (68 +/- 6 years), obese (body mass index, 31 +/- 4 kg/m2), mildly hypertensive (151 +/- 8/82 +/- 2 mm Hg), sedentary subjects without clinical evidence of diabetes or renal disease. They were studied on separate days with radioisotopic renal clearances (glomerular filtration rate by 99mTc-diethylenetriaminepentaacetic acid urinary clearance; renal plasma flow by 131I-hippuran serum disappearance) and a two-dose (40 and 100 mU/m2 per minute) hyperinsulinemic euglycemic clamp for measurement of glucose disposal after 2 weeks of a 3-g and 2 weeks of a 10-g sodium diet. Glomerular filtration rate (68.1 +/- 7.7 to 78.0 +/- 6.6 mL/min per 1.73 m2, P = .08) and glomerular filtration fraction (0.21 +/- 0.02 to 0.22 +/- 0.02, P = .5) did not change significantly after dietary salt was increased. During low dietary salt intake, there was an inverse relationship between glomerular filtration fraction and glucose disposal rate (milligrams per kilogram fat-free mass per minute) at both low (r = -.70, P = .04) and high (r = -.83, P = .006) insulin levels. However, these relationships were attenuated during salt loading. This suggests that a greater degree of insulin resistance, not increased dietary salt, may predispose older mildly hypertensive subjects to renal injury by worsening renal hemodynamics through the elevation of glomerular filtration fraction and resultant glomerular hyperfiltration. PMID- 8675253 TI - Residual pressor effects of chronic alcohol in detoxified alcoholics. AB - Although research in population studies has indicated that recent alcohol intake is positively correlated with blood pressure, there is a need to study the relationship of blood pressure to measures of lifetime alcohol intake in alcoholics. To this end, we assessed systolic and diastolic pressures and lifetime alcohol intake through structured interviews with 253 normotensive recovering alcoholics. Blood pressures were first corrected with multiple linear regression for the influence of confounding or modifying variables and then were regressed against alcohol consumption measures. Systolic pressure was significantly correlated (positively) with only a few measures of recent alcohol intake, and the correlations were not high (r2 = .05 to .11, P < .05). Diastolic pressure was found to be highly and positively correlated with the duration of the drinking career, but more so in blacks than in whites. The total lifetime dose of alcohol was found to be positively correlated with diastolic but not systolic pressure, but only in black male alcoholics. The steeper slope of the regression of blood pressure versus lifetime total alcohol or duration of the drinking career in black alcoholics suggests greater cardiovascular susceptibility to alcohol toxicity as lifetime doses increase and as the drinking career lengthens. PMID- 8675254 TI - High sodium sensitivity implicates nocturnal hypertension in essential hypertension. AB - We investigated the relationship between sodium sensitivity and diurnal variation of blood pressure in patients with essential hypertension. Twenty-eight inpatients with essential hypertension were maintained on high sodium (12 to 15 g NaCl per day) and low sodium (1 to 3 g NaCl per day) diets for 1 week each. Twenty-four-hour blood pressure and urinary sodium excretion were measured at the end of each diet period, and the sodium sensitivity index was calculated as the ratio of the change in mean arterial pressure to the change in urinary sodium excretion rate by sodium restriction. Patients whose average mean arterial pressure was lowered more than 10% by sodium restriction were assigned to the sodium-sensitive group (n = 16); the remaining patients, whose mean arterial pressure was lowered by less than 10%, were assigned to the non-sodium-sensitive group (n = 12). In the non-sodium-sensitive group, mean arterial pressure and heart rate fell during the nighttime, and average values of systolic, diastolic, and mean arterial pressures during the night were significantly lower than those during the day during both low and high sodium diets. On the other hand, in the sodium-sensitive group, there was no nocturnal fall in mean arterial pressure, and none of the systolic, diastolic, and mean arterial pressure values during the nighttime was different from the respective pressure values during the daytime during either sodium diet. The sodium sensitivity index was positively correlated with the fall in mean arterial pressure during the nighttime during a high sodium diet (r = .55, P < .01). These results indicate that in patients with sodium sensitive essential hypertension, blood pressure fails to fall during the night. High sodium sensitivity may be a marker of greater risk of renal and cardiovascular complications, as has been found in nondippers, patients whose blood pressure fails to fall during the night. PMID- 8675255 TI - Altered cerebrovascular response to a potassium channel opener in hypertensive rats. AB - We examined whether the effect of Y-26763, an ATP-sensitive potassium channel opener, on cerebral blood flow is altered in stroke-prone spontaneously hypertensive rats (SHRSP) and, if altered, whether long-term antihypertensive treatment with cilazapril, an angiotensin-converting enzyme inhibitor, is capable of preventing the change. Cerebral blood flow during intracarotid infusion of Y 26763 was measured in anesthetized SHRSP and normotensive Wistar-Kyoto rats (WKY) as control. Y-26763 increased cerebral blood flow in a dose-dependent manner in WKY, and glibenclamide, a selective inhibitor of ATP-sensitive potassium channels, inhibited the Y-26763-induced increase in cerebral blood flow. In contrast, the response to Y-26763 in SHRSP was significantly impaired compared with that in WKY. Antihypertensive treatment with cilazapril lowered blood pressure toward normal and prevented the impaired response in cerebral blood flow to Y-26763 in SHRSP. These findings suggest that (1) ATP-sensitive potassium channels contribute to the regulation of cerebral blood flow in rats, (2) the response to an ATP-sensitive potassium channel opener is markedly diminished in hypertensive rats, and (3) the altered response to an ATP-sensitive potassium channel opener during chronic hypertension can be prevented by long-term antihypertensive treatment. PMID- 8675256 TI - Inhibition of hypertension by peripheral administration of antisense oligodeoxynucleotides. AB - We administered liposome-encapsulated antisense oligodeoxynucleotide targeted to angiotensinogen mRNA peripherally to spontaneously hypertensive rats to test whether peripheral angiotensinogen reduction would lower their hypertensive blood pressures and to determine the role of peripheral angiotensinogen in the modulation of hypertension. Using in vitro translation techniques, we tested the sequence specificity of the antisense sequence. The selected antisense sequence decreased angiotensinogen production in vitro, enabling us to distinguish between specific and nonspecific effects. To increase the efficiency of peripheral and hepatic antisense delivery, oligonucleotides were liposome encapsulated and intra arterial administration. Confocal microscopy was used for determination of the hepatic distribution of fluorescently labeled antisense. Encapsulated antisense molecules were seen to be distributed within liver tissue 1 hour after injection; however, little or no uptake was observed with the unencapsulated oligonucleotides. We also determined the physiological effects of antisense oligodeoxynucleotide targeted to liver angiotensinogen mRNA. Administration of liposome-encapsulated antisense significantly decreased hypertensive blood pressures to normotensive levels compared with scrambled control oligonucleotides, unencapsulated antisense, and empty liposomes (P = .013). These data were supported by biochemical changes elicited by the antisense treatment. Rats receiving liposome-encapsulated antisense had significantly lowered peripheral angiotensinogen and angiotensin II levels compared with control groups (P < .05). No significant heart rate changes were observed in the antisense or control groups. These results suggest that peripheral angiotensinogen plays a role in the maintenance of hypertensive blood pressure in this model of hypertension and that peripheral administration of antisense molecules is possible with organ-targeted delivery mechanisms. PMID- 8675257 TI - Dispersion of the QT interval and autonomic modulation of heart rate in hypertensive men with and without left ventricular hypertrophy. AB - Left ventricular hypertrophy is an independent risk factor for sudden cardiac death in hypertension, but the mechanisms of electrical instability associated with hypertrophy are not well known. We studied dispersion of the QT interval, an index of inhomogeneity of repolarization, and heart rate variability, a measure of cardiac autonomic modulation, in a randomly selected population of 162 men with systemic hypertension and made comparisons between the patients with echocardiographic evidence of left ventricular hypertrophy (left ventricular mass index > or = 131 g/m2, n = 44) and those without hypertrophy (left ventricular mass index < 131 g/m2, n = 118). The heart rate-corrected QT dispersion (67 +/- 37 versus 53 +/- 21 milliseconds, P < .05) and QT apex dispersion (55 +/- 22 versus 44 +/- 16 milliseconds, P < .01) were significantly longer in the patients with left ventricular hypertrophy than in those without hypertrophy. Thirteen of the 44 patients (30%) with hypertrophy versus 7 of the 118 patients (6%) without hypertrophy had an abnormally long QT apex dispersion ( > 70 milliseconds) (P < .001). The time and frequency domain measures of heart rate variability did not differ significantly between the patient groups with and without left ventricular hypertrophy. The measures of heart rate variability were not related to QT dispersion or left ventricular mass index but had a negative correlation with blood pressure values (eg, r = -.30 between the low-frequency component of heart rate variability and systolic pressure, P < .001). Age, body mass index, antihypertensive medication, and the other demographic variables were similar between the groups, but the patients with left ventricular hypertrophy had higher systolic (P < .01) and diastolic (P < .01) pressures compared with the patients without hypertrophy. Left ventricular hypertrophy in hypertensive men is associated with inhomogeneity of the early phase of ventricular repolarization, favoring susceptibility to reentrant ventricular tachyarrhythmias. Abnormalities in cardiac autonomic function, which may trigger a spontaneous onset of arrhythmias, are related to elevated blood pressure but not specifically to left ventricular hypertrophy. PMID- 8675259 TI - Association of carotid atherosclerosis with electrocardiographic myocardial ischemia and left ventricular hypertrophy. AB - Patients with carotid atherosclerosis have an increased risk of coronary events and an increased prevalence of echocardiographic left ventricular hypertrophy. However, little is known regarding the association between electrocardiographic abnormalities and carotid atherosclerosis. The relationship of electrocardiographic evidence of myocardial ischemia and left ventricular hypertrophy to the presence of carotid atherosclerosis was prospectively studied in 349 asymptomatic subjects who underwent echocardiography and carotid ultrasonography. Myocardial ischemia on the electrocardiogram was defined by the presence of localized T-wave inversions, and electrocardiographic hypertrophy was defined by the product of Cornell voltage and QRS duration. Carotid atherosclerosis was present in 21% (72/ 349) of subjects and was associated with older age, higher systolic and pulse pressures, and greater left ventricular mass. Both ischemia and hypertrophy on the electrocardiogram were strongly associated with carotid plaque. Carotid atherosclerosis was more than three times more prevalent in subjects with electrocardiographic ischemia (69% [11/16] versus 18% [61/333], P < .0001) or electrocardiographic left ventricular hypertrophy (78% [7/9] versus 19% [65/340], P = .0003) than in subjects without these findings. Logistic regression analysis, including standard risk factors, revealed that both ischemia and hypertrophy on the electrocardiogram remained significant independent predictors of the presence of carotid atherosclerosis, along with age and echocardiographic left ventricular mass. These findings suggest that the associations of ischemia and left ventricular hypertrophy with carotid atherosclerosis may contribute to the increased incidence of coronary events in patients with carotid atherosclerosis. PMID- 8675258 TI - Relationship between left ventricular geometry and natriuretic peptide levels in essential hypertension. AB - Previous studies have shown that plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are increased in essential hypertension. However, whether left ventricular geometry affects plasma ANP and BNP levels remains unknown. To investigate the effect of left ventricular geometry on plasma ANP and BNP levels in essential hypertension, we measured plasma ANP and BNP levels in 90 patients with essential hypertension. All patients were hospitalized, and fasting blood samples were obtained in the early morning after 30 minutes of bed rest. Plasma ANP and BNP levels were measured by immunoradiometric assay. Hypertensive patients were classified into four groups according to echocardiographic findings that showed normal geometry, concentric remodeling, eccentric hypertrophy, or concentric hypertrophy. Mean plasma ANP and BNP levels in all essential hypertensive patients were higher than those in age matched normotensive control subjects. Plasma ANP levels in hypertensive patients with concentric remodeling, eccentric hypertrophy, and concentric hypertrophy were higher than in normotensive control subjects, although there were no differences between normotensive subjects and hypertensive patients with normal geometry. Plasma BNP levels tended to be higher in hypertensive patients with normal geometry, concentric remodeling, and eccentric hypertrophy than in normotensive control subjects; however, the differences were not significant. Plasma BNP levels and BNP/ANP ratio were specifically higher in concentric hypertrophy. There were significant correlations between ANP and left ventricular mass index, relative wall thickness, interventricular septal thickness, posterior wall thickness, and mean arterial pressure. Plasma BNP levels significantly correlated with relative wall thickness, interventricular septal thickness, posterior wall thickness, and left ventricular mass index but not with mean arterial pressure. In addition, plasma BNP levels were well correlated with ANP levels, and the slope for the linear regression model was steeper in concentric hypertrophy than in the other four groups. These results show that plasma ANP and BNP levels are increased in essential hypertensive patients with left ventricular hypertrophy. Furthermore, BNP secretion is augmented to a greater extent in concentric hypertrophy. Thus, measurement of plasma ANP and BNP levels may be useful for the detection of concentric left ventricular hypertrophy in patients with essential hypertension. PMID- 8675260 TI - Prognostic value of invasive hemodynamic measurements at rest and during exercise in hypertensive men. AB - In 1994, we ascertained the outcome of 143 hypertensive men in whom invasive hemodynamic measurements were performed at rest and during graded bicycle exercise during the period 1972-1982 to assess (1) which of the hemodynamic components of blood pressure is associated with the incidence of cardiovascular events and total mortality, and (2) whether the hemodynamic response to dynamic exercise adds prognostic precision to the data at rest. During 2186 patient years of follow-up, 38 patients suffered at least one fatal or nonfatal cardiovascular event and 17 patients died. Cox regression analysis showed that systolic pressure and systemic vascular resistance measured at rest, during submaximal exercise (50 W), and at peak effort were significant (P < .01) predictors of the age-adjusted incidence of cardiovascular events and total mortality. However, exercise blood pressure did not significantly predict the incidence of cardiovascular events over and above pressure at rest; by contrast, exercise systemic vascular resistance added prognostic precision to vascular resistance at rest (P < .01). As for total mortality, systolic pressure and systemic vascular resistance at peak exercise carried prognostic information that was independent of the results at rest (P < .05); this was not the case for measurements during submaximal exercise. We conclude that the prognostic importance of blood pressure is related to systemic vascular resistance. The prognostic precision of exercise pressure, on top of pressure at rest, is limited. Exercise systemic vascular resistance, however, provides prognostic information beyond that available from measurements at rest, particularly for the incidence of cardiovascular events. PMID- 8675261 TI - Correlates of the hemodynamic determinants of blood pressure. AB - The purpose of this study was to investigate the association of sex, race, lean body mass, and fat mass with the hemodynamic determinants of blood pressure, including stroke volume, heart rate, and total peripheral vascular resistance. The study included 201 subjects aged 6 to 17 years, 105 of whom were male and 98 of whom were black. Lean body mass and fat mass were both significant (P < .05) independent determinants of stroke volume, cardiac output, and total peripheral vascular resistance. However, the direction of the effect of lean body mass was opposite for stroke volume and cardiac output compared with that of total peripheral vascular resistance. The direct relationship of lean body mass with systolic blood pressure (SBP) and diastolic blood pressure (DBP) (regression coefficients, 0.55 +/- 0.05 for SBP and 0.47 +/- 0.05 for DBP) indicates that the effect of lean body mass on cardiac output may predominate. Lean body mass explained substantially more of the variance of the hemodynamic variables than did fat mass. After control for the effects of body size, male subjects had higher heart rate and cardiac output, and female subjects had higher vascular resistance. White subjects had higher stroke volume and cardiac output, and black subjects had higher peripheral vascular resistance. This study demonstrates that lean body mass is a more important correlate of the hemodynamic determinants of blood pressure than is fat mass and that sex and race have significant independent relationships with the hemodynamic determinants of blood pressure in children and adolescents. PMID- 8675262 TI - Orthostatic hypertension due to vascular adrenergic hypersensitivity. AB - Autoregulatory mechanisms ensure relatively small fluctuations of blood pressure with postural changes in healthy people. Although orthostatic hypotension is well recognized and commonly encountered, there are only a few reports of orthostatic hypertension. Most of the reported cases of orthostatic hypertension were related to excessive venous pooling, with an initial drop in cardiac output followed by overcompensation with an excessive release of catecholamines, or to nephroptosis with orthostatic activation of the renin-angiotensin system. We describe a 44 year-old woman with normal supine blood pressure and severe orthostatic hypertension who did not demonstrate an initial decrease in cardiac output and had normal plasma and urinary catecholamines and renin release. Pharmacological tests of autonomic nervous system function showed an increased pressor sensitivity to norepinephrine (11 to 14 times normal), normal sensitivity to isoproterenol, diminished baroreceptor reflex sensitivity, and exquisite sensitivity to alpha-adrenergic blockers. This unusual case of orthostatic hypertension appears to be secondary to vascular adrenergic hypersensitivity. PMID- 8675263 TI - Effect of hypertension on aortic root size and prevalence of aortic regurgitation. AB - Although early reports suggested that hypertension predisposed to aortic root enlargement and consequent aortic regurgitation, more recent pathological and M mode echocardiographic studies have not found an association between hypertension and aortic enlargement when age is considered. These discrepancies may partially reflect methodological shortcomings in the accuracy and reproducibility of aortic and blood pressure measurements. Therefore, we measured two-dimensional echocardiographic diameters of the aortic root at four locations and compared findings with ambulatory and resting blood pressures and measures of body size in 110 normotensive and 110 hypertensive men and women matched for age and sex. Aortic diameters at the anulus (2.41 +/- 0.29 versus 2.34 +/- 0.24 cm, P = .06) and sinuses (3.47 +/- 0.44 versus 3.37 +/- 0.36 cm, P = .08) were marginally higher, whereas diameters at the supra-aortic ridge (2.94 +/- 0-38 versus 2.81 +/ 0.32 cm, P < .01) and ascending aorta (3.26 +/- 0.45 versus 3.11 +/- 0.32 cm, P < .01) were significantly increased in hypertensive subjects. Aortic diameters increased with increasing quartiles of diastolic and systolic pressures, particularly at the supra-aortic ridge and ascending aorta. In multivariate analyses, blood pressure remained an independent determinant of distal aortic diameters after body size and age were considered. Aortic regurgitation was seen in 5 normotensive and 7 hypertensive subjects and did not differ in severity. Thus, hypertension is associated with a slight increase in aortic root size, most notably of the supra-aortic ridge and proximal ascending aorta. Although dilatation at the commissural attachment might be expected to predispose to an increase in aortic regurgitation, we did not detect such a difference in this population of healthy, asymptomatic individuals. PMID- 8675264 TI - Activation of heat shock transcription factor 1 in rat aorta in response to high blood pressure. AB - We have previously demonstrated that acute hypertension induces heat shock protein gene expression in rat arterial wall. Here we provide evidence that this induction is mediated through the activation of heat shock transcription factor 1 in response to high blood pressure. Rats subjected to restraint or immobilization stress displayed an acute elevation in systolic pressure accompanied by an increase in heat shock protein 70 mRNA expression. Consistent with the rapid time course of mRNA induction, an increase in binding activity to an oligonucleotide encompassing a consensus heat shock element sequence was seen in protein extracts from aorta of restrained rats as assessed with gel mobility shift assays. A similar increase in DNA binding activity was also observed in aortic extracts from rats treated with various hypertensive agents, including phenylephrine, angiotensin II, and vasopressin. That the DNA binding activity was attributed to heat shock factor 1 was shown through use of antibodies to the transcription factor that retarded the DNA-protein complexes in gel mobility supershift assays. Western blot analysis of heat shock factor 1 protein expression in aortic extracts showed a slower mobility form of the protein in hypertensive rats, indicative of an activated, presumably phosphorylated, form of the transcription factor. These findings support the view that heat shock factor 1 is responsible for induction of heat shock protein 70 in the arterial wall during acute hypertension, a response that is likely to play an important role in protecting arteries during hemodynamic stress. PMID- 8675265 TI - Benidipine improves endothelial function in renal resistance arteries of hypertensive rats. AB - We studied the effects of long-term antihypertensive treatment on endothelial function in renal resistance arteries from spontaneously hypertensive rats (SHR). Wistar-Kyoto rats (WKY) were used as a normotensive reference. Adult SHR were treated with benidipine (a calcium antagonist) or ecarazine (a vasodilator) for 10 weeks; the drugs caused similar reductions in blood pressure. Changes in isometric tension of rings prepared from the third-order branches of the renal arteries were recorded. Endothelium-dependent relaxations induced by acetylcholine in rings contracted with norepinephrine were smaller in SHR than in WKY. The impaired relaxation was improved by benidipine treatment, but ecarazine had no significant effect. In vitro treatment with meclofenamic acid, a cyclooxygenase inhibitor, did not alter the differences in the relaxations. In the presence of meclofenamic acid, N omega-nitro-L-arginine methyl ester slightly reduced the relaxations; the relaxation was smaller in SHR than in WKY and was not affected by benidipine treatment. In rings contracted with 40 mmol/L. KCI, the relaxations induced by acetylcholine in the presence of meclofenamic acid were smaller than those in rings contracted with norepinephrine. The relaxation was smaller in SHR than in WKY but was normalized by benidipine treatment. Thus, acetylcholine relaxes rat renal resistance arteries by releasing nitric oxide and endothelium-derived hyperpolarizing factor from the endothelium, which is impaired in SHR. Long-term benidipine treatment improves the impaired relaxation in SHR by enhancing nitric oxide-mediated relaxation. PMID- 8675266 TI - Role of prostaglandins in acetylcholine-induced contraction of aorta from spontaneously hypertensive and Wistar-Kyoto rats. AB - Evidence in support of prostaglandin (PG) H2 as the endothelium-derived contracting factor released in response to acetylcholine in vessels from adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) is to a large degree indirect. Therefore, the purpose of the present study was to test the hypothesis that a prostaglandin or prostaglandins other than PGH2 may serve as the endothelium-derived contracting factor that mediates acetylcholine-induced contraction in these vessels. Acetylcholine-induced contraction of endothelium intact aorta from 7- to 12-month-old SHR and WKY in the presence of the nitric oxide synthase inhibitor N omega-nitro-L-arginine was abolished by indomethacin and only partially decreased by the thromboxane (Tx) A2/PGH2 receptor antagonist SQ29548. Contraction induced by the TxA2/ PGH2 receptor agonist U46619 was abolished by SQ29548. These findings suggest that in endothelium-intact aorta from SHR and WKY, acetylcholine causes the release of a cyclooxygenase product other than PGH2 that induces contraction independently of TxA2/PGH2 receptor activation. To investigate which prostaglandin or prostaglandins could be responsible for the TxA2/PGH2 receptor-independent component, we challenged endothelium-denuded aorta from SHR and WKY with various prostaglandins in the presence of SQ29548. In SQ29548-treated aorta from 7- to 12-month-old rats, maximal contractions to PGF2 alpha, PGE2, and carbacyclin (a PGI2 analogue) were greater than the magnitude of acetylcholine-induced contraction. These findings suggest that PGF2 alpha, PGE2, and/or PGI2 could serve as mediators of the TxA2 receptor-independent component of the acetylcholine-induced contraction. However, in studies with SQ29548-treated aorta from 4- to 6-week-old SHR and WKY (an age at which acetylcholine-induced contraction is known to be absent), maximal contraction to PGF2 alpha and PGE2 was also greater or equivalent to that of SQ29548-treated aorta from 7- to 12-month-old rats, whereas carbacyclin induced negligible contraction. Thus, unlike PGE2 and PGF2 alpha, the age-dependent pattern of contraction induced by carbacyclin closely resembles the pattern induced by acetylcholine. We also measured the levels of PGI2 released in response to acetylcholine and found that they are sufficient to account for the TxA2 receptor-independent component of the acetylcholine-induced contraction. Thus, we propose that PGI2 released in response to acetylcholine may serve as the endothelium-derived contracting factor that elicits the TxA2/PGH2 receptor independent and dependent components of the acetylcholine-induced contraction. PMID- 8675267 TI - Mediators of arachidonic acid-induced relaxation of bovine coronary artery. AB - Bovine coronary arteries relax in response to bradykinin, methacholine, sodium nitroprusside, isoproterenol, and arachidonic acid in a concentration-dependent manner. The relaxations to methacholine, bradykinin, and arachidonic acid are lost when endothelium is removed. Indomethacin, a cyclooxygenase inhibitor, attenuated the relaxations to methacholine, bradykinin, and arachidonic acid and shifted the EC50 (control versus indomethacin) to each (1 x 10(-7) versus 3 x 10( 7) mo1/L, 3 x 10(-10) versus 2 x 10(-9) mo1/L, and 3 x 10(-7) versus 2 x 10(-6) mo1/L, respectively). Nitro-L-arginine, a nitric oxide synthase inhibitor, also attenuated the relaxations to methacholine, bradykinin, and arachidonic acid and shifted the EC50 (control versus nitro-L-arginine) to each (1 x 10(-7) versus 3 x 10(-7) mo1/L, 3 x 10(-10) versus > 10(-9) mo1/L, and 3 x 10(-7) versus > 10(-6) mo1/L, respectively). The combination of indomethacin and nitro-L-arginine blunted the relaxations to these agents and also shifted the EC50 values (control versus indomethacin plus nitro-L-arginine) to each (1 x 10(-7) versus 5 x 10(-7) mo1/L, 3 x 10(-10) versus > 10(-9) mo1/L, and 3 x 10(-7) versus > 10(-6) mo1/L, respectively). Methacholine, bradykinin, and arachidonic acid stimulated the release of prostaglandin I2, measured as 6-keto-PGF1 alpha. Indomethacin, but not nitro-L-arginine, inhibited arachidonic acid-induced release of 6-keto-PGF1 alpha. Vascular cGMP content was unchanged by arachidonic acid but was significantly elevated by bradykinin. Relaxations to prostaglandin I2 and sodium nitroprusside, but not 8,9-epoxyeicosatrienoic acid or isoproterenol, were inhibited by nitro-L-arginine. We conclude that the endothelium-dependent relaxations to methacholine, bradykinin, and arachidonic acid are partly due to prostaglandin I2 release. The remainder of the responses to these agents is due to the release of other relaxing factor or factors. Since bradykinin increased cGMP and nitro-L-arginine partially inhibited its relaxant effects, nitric oxide also appears to participate in the bradykinin-induced effect. Since the combination of indomethacin and nitro-L-arginine failed to completely block the relaxations to methacholine, bradykinin, and arachidonic acid, another endothelial factor must contribute to their vascular effects. Surprisingly, nitro L-arginine attenuated the relaxations to arachidonic acid; however, L-arginine failed to reverse the effects of nitro-L-arginine on arachidonic acid-induced relaxations. In addition, arachidonic acid failed to increase cGMP. Nitro-L arginine also reduced the responses to prostaglandin I2 and sodium nitroprusside. These data indicate that these arginine analogues may have effects other than competitive inhibition of nitric oxide synthase. PMID- 8675268 TI - Utility of new electrocardiographic models for left ventricular mass in older adults. The Cardiovascular Health Study Collaborative Research Group. AB - Several multivariate statistical models have recently been introduced for estimation of left ventricular mass from standard 12-lead electrocardiographic measurements. The validity of these algorithms has not been adequately evaluated. The objective of this investigation was to compare the associations between echocardiographic and electrocardiographic left ventricular mass values with clinical and subclinical indexes of coronary heart disease. The evaluation was performed with participants of the Cardiovascular Health Study, a population based sample of 5201 men and women aged 65 years and older. Echocardiographic M mode measurements of left ventricular mass were performed from videotape recordings with the use of a strictly standardized protocol. Electrocardiographic algorithms of the Novacode program and new algorithms derived from the Cardiovascular Health Study population were used for left ventricular mass prediction. Echocardiographic and electrocardiographic determinations of left ventricular mass were technically successful in 3410 (65.6%) and 5013 (96.4%) participants, respectively. The Novacode model overestimated echocardiographic left ventricular mass. Compared with the Novacode model, the new Cardiovascular Health Study electrocardiographic model, which includes adjustment for body weight, eliminated left ventricular mass prediction bias and improved the correlation between echocardiographic and electrocardiographic left ventricular mass from .33 to .54 in women and from .46 to .51 in men. Echocardiographic and electrocardiographic models both demonstrated similar and about equally strong associations with overt and subclinical disease and with risk factors for left ventricular hypertrophy. These observations demonstrate the potential utility of electrocardiographic models for left ventricular mass estimation. PMID- 8675269 TI - Aberrant adenylyl cyclase/cAMP signal transduction and G protein levels in platelets from hypertensive patients improve with antihypertensive drug therapy. AB - We have previously demonstrated a decreased expression of Gi alpha 2 protein in platelets from spontaneously hypertensive rats that was associated with an altered responsiveness of adenylyl cyclase to hormone stimulation and inhibition. In the present studies, we have used platelets from hypertensive patients and examined the hormonal regulation of adenylyl cyclase as well as the levels of G proteins and their modulation by antihypertensive drug therapy. We performed these studies in platelets from four groups of subjects: normotensive subjects (group 1), untreated mildly essential hypertensive patients (group 2), and treated moderately to severely hypertensive patients whose blood pressure was uncontrolled (group 3) or controlled with drug treatment (group 4). GTP gamma S, 5'-(N-ethylcarboxamido)adenosine (NECA), and prostaglandin E1 stimulated adenylyl cyclase activity to a greater extent in hypertensive patients (group 2). This effect was partially corrected (by approximately 50% to 80%) in the patients under antihypertensive drug therapy (groups 3 and 4). In addition, inhibition of adenylyl cyclase mediated by a ring-deleted analogue of atrial natriuretic factor (C-ANF4.23) observed in control normotensive subjects was blunted in hypertensive patients (group 2) and was not corrected in treated patients. Gi alpha levels determined by immunoblotting were in the same range for the four groups, whereas Gi alpha 2 and Gi alpha 3 levels were decreased by 70% and 60%, respectively, in hypertensive patients (group 2) compared with normotensive subjects. Antihypertensive drug therapy (groups 3 and 4) partially restored Gi alpha 2 levels toward normal (group 1) by about 60% and 70%, respectively; however, the reduced Gi alpha 3 levels in group 2 hypertensive patients were not improved in group 3 but were raised toward normal levels in group 4 by about 55%. These results suggest that the altered responsiveness of platelet adenylyl cyclase to hormones in hypertension and the normalization of the response with antihypertensive drug therapy could partly be due to the ability of the latter to modulate Gi alpha protein expression. These effects on platelet function may underlie the beneficial effects of antihypertensive agents on some of the complications of hypertension. PMID- 8675270 TI - Angiotensin II type 2 receptor mRNA expression in the developing cardiopulmonary system of the rat. AB - Recent studies have shown that angiotensin II has a trophic action on the heart. The presence of two types of angiotensin II receptors, type 1 (AT1) and type 2 (AT2), has been reported in the rat heart. This in situ hybridization study describes the tissue and cell location of AT2 receptor mRNA in the developing rat cardiopulmonary system, from 15 days of gestation to adulthood. Expression of AT1A receptor mRNA was studied in parallel for direct comparison. The aortic arch and pulmonary artery expressed high levels of AT2 receptor mRNA from 15 days of gestation up until 15 days postpartum, whereas expression of this mRNA was observed only just before and after birth in the coronary arteries. AT2 receptor mRNA was not detected in any cardiac muscle of the fetus, neonate, or adult. The annulus of all four heart valves expressed AT2 mRNA from 21 days of gestation until 10 days postpartum, but no labeling was seen in the valve leaflets. The subendocardial atrial tissue showed a high level of AT2 receptor mRNA expression during the early postnatal period, but no expression was observed in the atrial myocytes from fetal stages to adulthood. The bronchi and trachea, but not the lung parenchyma, showed a high level of AT2 receptor mRNA expression starting from 17 days of gestation until 10 days postpartum. AT2 receptor mRNA expression in the cardiopulmonary system is therefore transient, developmentally regulated, and mostly located in vascular structures. By these three characteristics, its expression contrasts with that of AT1A, which is continuously expressed in the cardiac muscle to adulthood. This spatiotemporal pattern of expression of angiotensin II receptor mRNAs during development suggests a possible role for angiotensin II in organogenesis. PMID- 8675271 TI - Angiotensin I-converting enzyme genotypes and angiotensin II receptors. Response to therapy. AB - In the present study, we studied angiotensin II type 1 (AT1) and type 2 (AT2) receptor messengers by quantitative reverse transcriptase-polymerase chain reaction. We examined peripheral blood mononuclear cells from 30 healthy subjects and 50 subjects with primary hypertension, in whom angiotensin I-converting enzyme genotype was determined, before and after 15 days of treatment with different antihypertensive drugs. The medication included a calcium channel antagonist, an angiotensin I-converting enzyme inhibitor, and a beta 1-blocker. We also studied the relationship between AT1 receptor gene expression and biochemical parameters of the renin-angiotensin system. AT1 receptor messenger levels were positively correlated with plasma renin activity in both normotensive and untreated hypertensive subjects. Increases of this messenger and plasma angiotensin II levels were correlated with the D allele in the same individuals. AT1 receptor messenger levels decreased significantly with angiotensin I converting enzyme inhibitor treatment in subjects with the DD genotype, and a significant decrease was observed in subjects with the II and ID genotypes treated with a calcium antagonist. No changes were observed in mRNA with the beta 1-blocker. We conclude that the AT2 receptor is not expressed in peripheral leukocytes and that AT1 receptor messenger levels vary in relation to angiotensin I-converting enzyme genotype and pharmacological treatment. These results suggest that angiotensin I-converting enzyme genotype may be an important factor when deciding on antihypertensive therapy in individuals with primary hypertension. PMID- 8675273 TI - Who owns the problem of the uninsured? PMID- 8675272 TI - Deja vu. PMID- 8675274 TI - What role for hospitals in the health care endgame? PMID- 8675275 TI - C. Rufus Rorem Award Lecture. Big question for the Blues: where to from here? PMID- 8675276 TI - Economic and organizational determinants of HMO mergers and failures. AB - This study analyzed data from all operational health maintenance organizations (HMOs) in the United States from 1986 through 1993. Eighty HMOs disappeared through mergers and 149 failed over that period. We estimated a multinomial logit model to predict whether an HMO would merge and survive, merge and disappear, or fail, relative to the probability of no event. We found that enrollment and profitability play a critical role in explaining HMO mergers and failures: large and profitable HMOs were more likely to merge and survive, but less likely to merge and disappear or fail. These results explain why HMO merger and failure rates fell after 1988, as most surviving HMOs became larger and more profitable. Among several market-area variables in the model, state anti-takeover regulations had a negative impact on mergers. Mergers were more likely in markets with more competing HMOs, but the overall market penetration of HMOs had no effect on mergers. This result may have important implications for the current debate over the future of the competitive health care strategy. If public policy successfully stimulates the development of large numbers of new HMOs, another wave of mergers and failures is likely to occur. But it appears that growth in overall HMO penetration will not lead inevitably to increased market concentration. PMID- 8675277 TI - Mandatory high-risk pooling: an approach to reducing incentives for cream skimming. AB - Risk-adjusted capitation payments (RACPs) to competing health insurers are an essential element of market-oriented health care reforms in The Netherlands. Crude RACPs are inadequate, especially because they encourage insurers to select against people expected to be unprofitable--a practice called cream skimming. However, implementing improved RACPs does not appear to be straightforward. This paper analyzes an approach that, given a system of crude RACPs, reduces insurers' incentives for cream skimming in the market for individual health insurance, while preserving incentives for efficiency and cost containment. Under the proposed system of Mandatory High-Risk Pooling (MHRP), each insurer would be allowed to periodically predetermine a small fraction of its members whose costs would be (partially) pooled. The pool would be financed with mandatory, flat-rate contributions. The results suggest that MHRP is a promising supplement to RACPs. PMID- 8675278 TI - Health plan satisfaction and risk of disenrollment among social/HMO and fee-for service recipients. AB - Health plan satisfaction among the elderly is affected by multiple individual and locational factors. We used a general behavioral framework of predisposing, enabling, and service use factors to produce adjusted satisfaction scores. These then were included in a logistic analysis to determine the effect of satisfaction on continued membership in social health maintenance organizations (S/HMOs) or continued participation in fee-for-service care. S/HMO members, after one year in the plan, generally reported satisfaction scores comparable to Medicare beneficiaries in fee-for-service care. Satisfaction with perceived physician quality and interpersonal relationships with the providers reduced the risk of disenrollment. Functional impairment reduced the likelihood of disenrollment, but this effect varied by community. Being impaired was protective in communities with established HMOs. In markets where HMOs were emerging or where intensive HMO competition was beginning, disability increased the likelihood of changing current coverage. S/HMO membership, after adjusting for the market area's general disenrollment propensities, had varying effects. Being a newly formed plan was not a consistent predictor of higher disenrollment rates. PMID- 8675279 TI - Judging hospitals by severity-adjusted mortality rates: the case of CABG surgery. AB - In many health care marketplaces, outcomes assessment is central to monitoring quality while controlling costs. Comparing outcomes across providers generally requires adjustment for patient severity. For mortality rates and other adverse outcomes comparisons, severity adjustment ideally aims to control for patient characteristics prior to the health care intervention. A variety of severity methodologies, specifically for hospitalized patients, are commercially available. Some have been adopted by state or regional initiatives for publicly comparing hospital outcomes. We applied 14 common severity measures to the same data set to determine whether judgments about risk-adjusted hospital death rates are sensitive to the specific severity method. We examined 7,765 patients undergoing coronary artery bypass graft (CABG) surgery at 38 hospitals. Unadjusted death rates ranged from 0% to 11.2% across hospitals. Comparisons of relative hospital performance were relatively insensitive to the severity adjustment method. PMID- 8675280 TI - Physician service to the underserved: implications for affirmative action in medical education. AB - Affirmative action is under increasing scrutiny. In medicine, the observation that minority physicians disproportionately serve minority patients has been one rationale for affirmative action. Using two large physician surveys, we find that minority and women physicians are much more likely to serve minority, poor, and Medicaid populations. Weaker, but significant association exists between physician and patient socioeconomic background. Service patterns are sustained over time and are generally consistent with physician career preferences. Ending affirmative action in medicine may imperil access to care. Results do not support affirmative action based on economic disadvantage instead of race, ethnicity, and sex. PMID- 8675281 TI - Matching physician supply and requirements: testing policy recommendations. AB - Managed care has been growing and likely will increase market share. This movement will require fundamental alterations in the number and specialty distribution of physicians. Under current production, future supply does not appear well-matched with requirements. Although the adequacy of generalist supply is of concern, the oversupply of specialists is the overriding problem. Neither reducing the number of first-year residents nor increasing the generalist output alone would bring both generalist and specialist supply within requirement ranges. Combining an increase in generalist production to 50% with a reduction in first-year residents to 110% of the number of U.S. medical graduates would minimize the projected specialty surplus while maintaining generalist supply within the requirement range. PMID- 8675282 TI - The design of the community tracking study: a longitudinal study of health system change and its effects on people. PMID- 8675283 TI - Bacterial collagenases and collagen-degrading enzymes and their potential role in human disease. PMID- 8675284 TI - Antibody-mediated shift in the profile of glycoprotein A phenotypes observed in a mouse model of Pneumocystis carinii pneumonia. AB - It is well established that Pneumocystis carinii has the molecular capability for variation of a major surface antigen, glycoprotein A (gpA). However, the extent of expression of gpA variation among P. carinii organisms infecting a single host and whether this variation has any impact on host-parasite immunological interactions is unknown. Using a mouse model of P. carinii pneumonia, we were able to demonstrate the expression of more than one gpA phenotype in a closed population of infected mice. Administration of monoclonal antibody (MAb) 2B5, which is specific for one of the gpA phenotypes, resulted in a marked diminution in the frequency of this particular gpA phenotype in the population of organisms. This effect was due to a loss of trophozoites bearing the specific epitope recognized by MAb 2B5; cysts bearing the same epitope appeared unaffected. Interestingly, P. carinii was unable to introduce a new phenotype into the population to compensate for the loss of trophozoites bearing the epitope recognized by MAb 2B5. Discontinuing administration of MAb 2B5 allowed the MAb 2B5-binding phenotype to reemerge. This finding suggests that the phenotype recognized by MAb 2B5 was continually produced even when MAb 2B5 was present. Thus, although P. carinii exhibited a form of antigenic variation, it did not appear able to rapidly introduce new phenotypes into the population in response to destruction by antibodies. PMID- 8675285 TI - Evaluation of purified UspA from Moraxella catarrhalis as a vaccine in a murine model after active immunization. AB - Moraxella catarrhalis causes otitis media, laryngitis, and respiratory infections in humans. A high-molecular-weight outer membrane protein from this bacterium named ubiquitous surface protein A (UspA) is present on all isolates. A monoclonal antibody (MAb) to UspA that recognizes a conserved epitope of this protein has been shown to promote pulmonary clearance of bacteria in passively immunized mice. In the present study, M. catarrhalis heterologous isolates were screened by dot blot with a panel of four additional MAbs specific for surface exposed epitopes of UspA from M. catarrhalis isolate 035E. Three of the MAbs were specific for 035E, and the fourth reacted with 17 (74%) of the 23 isolates tested. Thus, UspA contains highly conserved, semiconserved, and variable surface exposed epitopes. The UspA was purified from the 035E isolate by ion-exchange and size-exclusion chromatography, formulated with the adjuvant QS-21, and used to immunize BALB/c mice. Upon pulmonary challenge with either 035E or the heterologous isolate TTA24, significantly fewer bacteria were recovered from the lungs of immunized mice 6 h postchallenge than from control mice. The immune sera from mice or guinea pigs contained high titers of antibodies to the homologous isolate and heterologous isolates in a whole-bacterial-cell enzyme-linked immunosorbent assay. Sera against UspA, whether prepared in mice or guinea pigs, had complement-dependent bactericidal activity toward homologous and 11 heterologous M. catarrhalis isolates. These results indicate that the conserved epitopes of the UspA are highly immunogenic and elicit broadly reactive and biologically functional antibodies. UspA may offer protection against M. catarrhalis infections and is being further evaluated as a vaccine candidate. PMID- 8675286 TI - Lipoteichoic acid preparations of gram-positive bacteria induce interleukin-12 through a CD14-dependent pathway. AB - Interleukin 12 (IL-12) strongly augments gamma interferon production by natural killer (NK) and T cells. IL-12 also promotes effective cell-mediated immune responses, which are particularly important against intracellular bacteria such as Listeria monocytogenes. While the lipopolysaccharide (LPS) of gram-negative bacteria induces monocyte production of IL-12, the relevant gram-positive components which induce IL-12 production are uncharacterized. We used the human monocytic cell line THP-1 to study IL-12 induction by gram-positive bacteria. Muramyl dipeptides as well as the major muramyl tetrapeptide component of Streptococcus pneumoniae were inactive for inducing IL-12. In contrast, lipoteichoic acid (LTA), a predominant surface glycolipid of gram-positive bacteria, potently induced IL-12 p40 gene expression. A competitive LPS antagonist, Rhodobacter sphaeroides LPS, inhibited LTA-induced IL-12 production, suggesting a common pathway for LPS and LTA in IL-12 activation. Pretreatment of cells with anti-CD14 monoclonal antibody blocked both LPS and LTA induction of IL 12 p40 expression. LTA also induced Thl development in naive CD4 T cells by an IL 12-dependent mechanism, indicating direct induction of physiologic levels of IL 12. Together, these results show that LTA is a potent surface structure of gram positive bacteria which induces IL-12 in monocytes through a CD14-mediated pathway. PMID- 8675287 TI - Substitution of cysteine 192 in a highly conserved Streptococcus pyogenes extracellular cysteine protease (interleukin 1beta convertase) alters proteolytic activity and ablates zymogen processing. AB - Virtually all strains of the human pathogenic bacterium Streptococcus pyogenes express a highly conserved extracellular cysteine protease. The protein is made as an inactive zymogen of 40,000 Da and undergoes autocatalytic truncation to result in a 28,000-Da active protease. Numerous independent lines of investigation suggest that this enzyme participates in one or more phases of host parasite interaction, such as inflammation and soft tissue invasion. Replacement of the single cysteine residue (C-192) with serine (C192S mutation) resulted in loss of detectable proteolytic activity against bovine casein, human fibronectin, and the low-molecular-weight synthetic substrate 7-amino-4-trifluoromethyl coumarin. The C192S mutant molecule does not undergo autocatalytic processing of zymogen to mature form. Taken together, these data support the hypothesis that C 192 participates in active-site formation and enzyme catalysis. PMID- 8675288 TI - Pathogenicity of the diffusely adhering strain Escherichia coli C1845: F1845 adhesin-decay accelerating factor interaction, brush border microvillus injury, and actin disassembly in cultured human intestinal epithelial cells. AB - The diffusely adhering Escherichia coli strain C1845 harboring the fimbrial F1845 adhesin can infect cultured human intestinal epithelial cells. The mechanism by which E. coli C1845 induces diarrheal illness remains unknown. This study investigated the injuries of cultured human intestinal cells promoted by E. coli C1845. Membrane-associated decay accelerating factor was identified as the intestinal receptor for the F1845 fimbrial adhesin of the E. coli C1845 strain by using purified F1845 adhesin, antibody directed against the F1845 adhesin, and monoclonal antibodies directed against the decay accelerating factor. Using monolayers of Caco-2 cells apically infected with E. coli C1845 and examined by scanning and transmission electron microscopy, we observed that strain C1845 induced injury to microvilli (MV) characterized by elongation and nucleation of the MV. We observed that infection of T84 and Caco-2 cells by E. coli C1845 was followed by disassembly of the actin network in the apical and basal cell domains. MV injury was differentiation related: E. coli C1845 promoted MV injury only when the cells were fully differentiated. The disassembly of the actin network occurred in poorly differentiated and fully differentiated Caco-2 cells but not in undifferentiated cells. Moreover, apical actin disassembly was observed in fully differentiated Caco-2 cells infected with the laboratory strain E. coli HB101(pSSS1) expressing the F1845 adhesin. In conclusion, E. coli C1845 promotes MV lesion in human epithelial intestinal cells, resulting from disassembly of the actin network. PMID- 8675290 TI - In vitro simulation of immunosuppression caused by Trypanosoma brucei: active involvement of gamma interferon and tumor necrosis factor in the pathway of suppression. AB - Experimental infections of mice with the African trypanosome Trypanosoma brucei lead to a profound state of T-cell unresponsiveness in the lymph node cell (LNC) compartment. This suppression is mediated by macrophage-like cells which inhibit interleukin 2 (IL-2) secretion and down-regulate IL-2 receptor expression (M. Sileghem, A. Darji, R. Hamers, M. Van de Winkel, and P. De Baetselier, Eur. J. Immunol. 19:829-835, 1989). Similar suppressive cells can be generated in vitro by pulsing 2C11-12 macrophage hybridoma cells with opsonized T. brucei parasites (2C11-12P cells). Cocultures of 2C11-12P cells and LNCs secrete higher levels of gamma interferon (IFN-gamma), and the hyperproduction of IFN-gamma was found to be confined to CD8+ lymphoid cells. Elimination of CD8+ cells from cocultures of 2C11-12P cells and LNCs restores the T-cell proliferative response. Furthermore, addition of neutralizing anti-IFN-gamma antibodies to the cocultures reduces the level of suppression and concomitantly restores the level of IL-2 receptor expression. Hence, IFN-gamma plays a cardinal role in this in vitro model for T. brucei-elicited immunosuppression. Cocultures of LNCs and 2C11-12P cells in a two chamber culture system further demonstrated that cell-cell contact is required for hyperproduction of IFN-gamma and, moreover, that IFN-gamma cooperates with a 2C11-12P-derived diffusible factor to exert its suppressive activity. Finally, tumor necrosis factor alpha (TNF-alpha produced by 2C11-12P cells was found to be implicated in the hyperproduction of IFN-gamma, since addition of neutralizing anti-TNF-alpha antibodies to cocultures reduced the level of suppression and concomitantly abrogated the hyperproduction of IFN-gamma. Collectively, our findings indicate that T. brucei-elicited suppressive 2C11-12 macrophage cells differentially influence T-cell subpopulations: (i) CD8+ cells are signaled via cell-cell contact to produce IFN-gamma, and TNF-alpha is implicated in this process, and (ii) locally produced IFN-gamma and macrophage-released factors act in concert to inhibit CD4+ and CD8+ T-cell proliferative responses. PMID- 8675289 TI - The ActA polypeptides of Listeria ivanovii and Listeria monocytogenes harbor related binding sites for host microfilament proteins. AB - The surface-bound ActA polypeptide of the intracellular bacterial pathogen Listeria monocytogenes acts as a nucleator protein, generating the actin cytoskeleton around intracellularly motile bacteria. In this work, we examined the functional similarity of ActA from Listeria ivanovii (iActA) ATCC 19119 to its L. monocytogenes counterpart. The amino acid sequence of iActA predicts a molecular mass of 123 kDa and harbors eight proline-rich repeats. For functional analysis, various iActA derivatives and hybrid constructs of L. ivanovii and L. monocytogenes ActA polypeptides were transiently expressed in epithelial cells and examined for recruitment of host microfilament proteins by a mitochondrial targeting assay. As has been demonstrated with ActA, iActA also spontaneously inserted into the surface of mitochondria and induced recruitment of actin, alpha actinin, and the vasodilator-stimulated phosphoprotein (VASP) to these subcellular organelles. By comparison of amino-terminally truncated iActA derivatives for their ability to recruit cytoskeletal proteins, a region essential for actin filament accumulation was identified between amino acid residues 290 and 325. Such derivatives, however, retained their ability to bind VASP. Replacement of the proline-rich repeats in ActA with those of iActA also resulted in VASP recruitment. Hence, despite the limited overall sequence homology between ActA and iActA, the two molecules consist of at least two similar domains: a highly positively charged N-terminal domain that is directly involved in actin filament recruitment and a proline-rich repeat region required for VASP binding. PMID- 8675291 TI - Cytotoxic-T-lymphocyte-mediated cytolysis of L cells persistently infected with Chlamydia spp. AB - Persistent chlamydial infections have been proposed as a means whereby chlamydiae evade immune resolution of infection. Such a mechanism would require evasion not only of the humoral immune responses but also of cell-mediated immune responses. We hypothesized that if such a mechanism is important, persistently infected cells should not be recognized by cytotoxic T cells. Persistent infections were simulated in vitro by treatment of Chlamydia trachomatis- or Chlamydia psittaci infected cells with gamma interferon (IFN-gamma), penicillin, or tryptophan depletion. Cultures were examined for induction of a chlamydial stress response (measured by transcription of groesl RNA) and for the effects on viability, infectivity, morphology, and immune recognition. Although both IFN-gamma and penicillin induced aberrant chlamydial morphology and growth, we did not find evidence that these treatments elicited a classical stress response. In addition, T-cell-mediated lysis of Chlamydia-infected target cells treated with IFN-gamma or penicillin or grown in tryptophan-deficient media was examined. The immune cell-mediated lysis of these treated infected cells demonstrated that despite the effects of these compounds on chlamydial growth and development, the infected cells continued to be efficiently recognized and killed by cytotoxic T cells. Thus, it seems unlikely that these in vitro models of persistence represent functional mechanisms to evade immune clearance. PMID- 8675292 TI - The conserved 18,000-molecular-weight outer membrane protein of Haemophilus ducreyi has homology to PAL. AB - Haemophilus ducreyi expresses an 18,000-molecular-weight outer membrane protein that contains a conserved surface-exposed epitope recognized by monoclonal antibody 3B9. Monoclonal antibody 3B9 cross-reacts with proteins of similar molecular weight found in many Haemophilus sp. strains, including P6, a candidate vaccine for Haemophilus influenzae. The gene encoding the 18,000-molecular-weight outer membrane protein was identified by screening a lambdagt11 genomic library with 3B9. The coding sequence of the gene was localized to a 471-bp open reading frame, designated pal (peptidoglycan-associated lipoprotein). Translation of pal predicted a mature polypeptide with a molecular weight of 15,000 that had extensive homology with P6 and Escherichia coli PAL. The predicted signal peptide had features characteristic of a prokaryotic lipoprotein, and processing of PAL was sensitive to globomycin in H. ducreyi. The sequences encoding mature H. ducreyi PAL were subcloned into the vector pRSET B and expressed as a polyhistidine-containing fusion protein that bound 3B9. In Western blot (immunoblot) analysis, serum samples obtained from healthy subjects and patients with chancroid or other genital ulcer diseases contained antibodies to purified PAL. Antibodies that bound to PAL were removed by absorption with a lysate of Haemophilus sp. antigens, suggesting that patients with chancroid do not develop an H. ducreyi-specific antibody response to PAL. PMID- 8675293 TI - Iron starvation causes release from the group A streptococcus of the ADP ribosylating protein called plasmin receptor or surface glyceraldehyde-3 phosphate-dehydrogenase. AB - In many pathogenic bacteria, iron starvation serves as an environmental signal that triggers the expression of virulence factors, many of which are found on the cell surface or secreted into the culture supernatant. Using the chelating agent nitrilotriacetic acid, we have established conditions for iron starvation of the important human pathogen Streptococcus pyogenes (the group A streptococcus) and determined that iron limitation results in the specific appearance of several new proteins in the culture supernatant. One of these supernatant proteins is the ADP ribosylating protein known as streptococcal plasmin receptor (Plr) or as the streptococcal surface glyceraldehyde-3-phosphate-dehydrogenase because of its other activities. Upon iron starvation, Plr is specifically released into the culture supernatant in a time-dependent manner, and its appearance in the supernatant is not accompanied by induction of plr mRNA synthesis. Release of Plr from the bacteria may be important for the virulence of group A streptococci and the manifestation of diseases. PMID- 8675294 TI - Interleukin-12 mediates resistance to Trypanosoma cruzi in mice and is produced by murine macrophages in response to live trypomastigotes. AB - Host resistance to infection by Trypanosoma cruzi is dependent on both natural and acquired immune responses. During the first week of infection in mice, NK cell-derived gamma interferon (IFN-gamma) is involved in controlling intracellular parasite replication, mainly through the induction of NO biosynthesis by activated macrophages. Interleukin-12 (IL-12) has been shown to be a powerful cytokine in inducing IFN-gamma synthesis by NK cells, as well as in mediating resistance to different intracellular protozoa. We have therefore studied the ability of T. cruzi to elicit IL-12 synthesis by macrophages and the role of this cytokine in controlling parasite replication during acute infection in mice. Our results show that macrophages cultured in the presence of live trypomastigote forms (but not epimastigotes) release IL-12 that can induce IFN gamma production by normal spleen cells. IL-12 was detected in as little as 12 h after the addition of the trypomastigotes, and the level of IL-12 peaked at 48 h after the initial macrophage-parasite incubation. The addition of anti-IL-12 monoclonal antibody to macrophage-trypomastigote supernatants dose-dependently inhibited IFN-gamma production by naive splenocytes. Finally, the in vivo role of IL-12 in resistance to infection by T. cruzi was analyzed. Mice treated with anti IL-12 monoclonal antibody had significantly increased parasitemia and mortality in comparison with those of control infected mice treated with control antibody. Together, these results suggest that macrophage-derived IL-12 plays a major role in controlling the parasitemia in T. cruzi-infected mice and that the animal's resistance during the acute phase of infection may, at least in part, be a consequence of postinfection levels of IL-12. PMID- 8675295 TI - Elevated levels of Legionella pneumophila stress protein Hsp60 early in infection of human monocytes and L929 cells correlate with virulence. AB - Legionella pneumophila 2064 was selectively radiolabelled in mouse L929 cells and human monocytes to identify proteins expressed early in the course of infection. Polypeptide profiles (sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography) of adherent or intracellular bacteria indicated that a 60-kDa stress protein (Hsp60) was preferentially synthesized. Hsp60 synthesis was not induced by medium alone. The synthesis of many polypeptides, including OmpS (major outer membrane protein), diminished over the 1-h period postinfection. However, by 17 h postinfection OmpS and Hsp60 were the dominant proteins synthesized by 2064. To establish whether induction of Hsp60 was a correlate of virulence, an isogenic avirulent strain (2064M) of 2064 was isolated following selection on a nonpermissive medium. 2064M did not exhibit a stress response when adherent or intracellular in L929 cells or in human monocytes and failed to abrogate phagosome-lysosome fusion. When grown in vitro, 2064M exhibited no deficiencies in the heat shock response and its polypeptide profile resembled that of 2064. Immunogold electron microscopy was used to localize Hsp60 in L. pneumophila-infected L929 cells. There was an increase in the number of gold particles associated with phagosomes for phagosomes harboring single 2064 bacteria compared with those harboring 2064M. Moreover, by 1 h postinfection, a sixfold increase in the number of gold spheres associated with the membranes of phagosomes was observed for phagosomes harboring 2064 compared with those harboring 2064M. These studies indicate that virulent, but not NaCl-tolerant avirulent, strains of L. pneumophila respond to host-cell-associated environmental signals early in the course of infection. This response includes increased synthesis and possibly extracellular secretion of Hsp60 concomitant with repression of the expression of other genes, including ompS. PMID- 8675296 TI - The second capsule gene of cryptococcus neoformans, CAP64, is essential for virulence. AB - The extracellular polysaccharide capsule produced by Cryptococcus neoformans is essential for its pathogenicity. We have isolated and characterized a gene, (AP64, which is required for capsule formation. An encapsulated strain created by complementation of the cap64 mutation produced fatal infection of mice within 25 days, while the cap64 acapsular strain was avirulent. Gene deletion of CAP64 from a wild-type strain resulted in the loss of capsule as well as virulence. Contour clamped homogeneous electric field gel analysis indicates that CAP64 is located on chromosome III which is different from the localization of another capsule related gene, CAP59. The nonlinkage between CAP64 and CAP59 was also supported by classical recombinational analysis. Database searches did not reveal any sequence with high similarity to CAP64. We also found that the CAP64 locus is contiguous to a convergently transcribed gene which has significant similarity to the gene encoding the yeast proteasome subunit, PRE1. The distance between the cDNA ends of these two genes is only 22 bp. This study confirms the previous molecular genetic evidence that capsule is an essential factor for the virulence of C. neoformans in the murine model. PMID- 8675297 TI - Proteolytic inactivation of the leukocyte C5a receptor by proteinases derived from Porphyromonas gingivalis. AB - The anaerobic bacterium Porphyromonas gingivalis has been implicated as a primary causative agent in adult periodontitis. Several proteinases are produced by this bacterium, and it is suggested that they contribute to virulence and to local tissue injury resulting from infection by P. gingivalis. Cysteine proteinases with specificities to cleave either Arg-X or Lys-X peptide bonds (i.e., gingipains) have been characterized as predominant enzymes associated with vesicles shed from the surface of this bacterium. It has recently been demonstrated that these proteinases are capable of degrading the blood complement component C5, resulting in the generation of biologically active C5a. By using an affinity-purified rabbit antibody raised against residues 9 to 29 of the C5a receptor (C5aR; CD88), we demonstrate that noncysteinyl proteinases associated with vesicles obtained from P. gingivalis cleave the C5aR on human neutrophils. Proteolytic attack of the C5aR by enzymes from the P. gingivalis vesicles was inhibited by TPCK (tolylsullonyl phenylalanyl chloromethyl ketone), PMSF (phenylmethylsulfonyl fluoride), and dichloroisocoumarin, suggesting that serine proteinases are primarily responsible for this degradative activity. The purified vesicle proteinase Lys-gingipain but not Arg-gingipain also cleaved the N terminal region of the C5aR on the human neutrophils. Lys-gingipain activity was essentially resistant to these inhibitors but was inhibited by TLCK (Nalpha-p tosyl-L-lysine chloromethyl ketone) and iodoacetamide. A synthetic peptide that mimics the N-terminal region of C5aR (residues 9 to 29; PDYGHY DDKDTLDLNTPVDKT) was readily cleaved by chymotrypsin but not by trypsin, despite the presence of two potential trypsin (i.e., lysyl-X) cleavage sites. The specific sites of cleavage in the C5aR 9-29 peptide were determined by mass spectroscopy for both chymotrypsin and Lys-gingipain digests. This analysis demonstrated that the C5aR peptide is susceptible to cleavage at both potential Lys-gingipain sites (i.e., between residues 17 and 18 [K-D] and 28 and 29 [K-T]) and at two chymotrypsin sites (between residues 14 and 15 [Y-D] and 20 and 21 [L-D]), respectively. These studies suggest that P. gingivalis contains at least two enzymes capable of cleaving the C5aR, Lys-gingipain and a second nontryptic serine proteinase that is distinct from either Arg- or Lys-gingipain. PMID- 8675298 TI - Molecular cloning and characterization of the Coccidioides immitis complement fixation/chitinase antigen. AB - Detection of anti-Coccidioides complement-fixing (CF) antibody is a valuable diagnostic and prognostic aid in coccidioidomycosis. The CF antibody response is directed against a heat-labile antigen that has chitinase activity, hereafter referred to as the CF/chitinase protein. To identify and clone this immunoreactive enzyme, we constructed a Coccidioides immitis cDNA lambda ZAP expression library from spherule RNA and detected fusion peptides expressing CF epitopes by immunoscreening. A cDNA clone consisting of 1,623 bp was identified, sequenced, and found to contain a single open reading frame that encodes a protein of 47 kDa with 427 amino acids. Deduced amino acid sequence analyses showed that the cloned CF/chitinase cDNA contains a 35-amino-acid region, beginning at Ser-18 and ending at and ending at Arg-52 which has 92% homology with the reported N-terminal amino acid sequence of authentic CF/chitinase protein. The first 17 amino acids in the deduced sequence of the cloned cDNA are not present on the mature CF/chitinase protein, suggesting that it may be a signal peptide. Expression of the CF/chitinase cDNA insert by using the pGEX-4T-3 vector yields a fusion peptide that bears CF-specific epitopes and shows chitinase activity. The CF/chitinase clone will enable large-scale production of the recombinant CF antigen for use in immunoassays and facilitate studies on the role of chitinase in the morphogenesis of C. immitis. PMID- 8675299 TI - CR3-dependent resistance to acute Toxoplasma gondii infection in mice. AB - Studies were performed to determine whether resistance to acute Toxoplasma gondii infection in mice depends on a mechanism involving CR3, the type 3 complement receptor. Nineteen of 22 mice (86%) given multiple injections of the anti-CR3 monoclonal antibody, 5C6, prior to and after intraperitoneal inoculation of cysts of the ordinarily mildly virulent ME49 strain of T. gondii died within 8 to 12 days, whereas control antibody-treated mice survived. All (five of five) anti-CR3 treated BALB/c mice infected via the natural peroral route died within 8 days of infection. Flow cytometric analysis of cells recovered from peritoneal lavages of anti-CR3-treated T. gondii-infected mice revealed that the percentage of Thy-1+ CD4- CD8- cells was reduced to about 50% of that of control antibody-treated mice and to about 20% of the number of such cells in controls. The numbers of macrophages, polymorphonuclear leukocytes, and lymphocytes recovered from the peritoneal cavities of T. gondii-infected mice were all reduced in anti-CR3 treated mice to about 40% of those of controls. In addition, anti-CR3-treated mice had less than 25% of the induced NK cell activity of the controls, and gamma interferon was reduced to undetectable levels. Thus, the rapid death of anti-CR3 treated mice was probably caused by impaired preimmune defenses. Histological examination of anti-CR3-treated T. gondii-infected mice revealed extensive liver pathology compared with that of infected mice given a control antibody or uninfected mice given anti-CR3. The inflammation, degeneration, and necrosis in most of the anti-CR3-treated mice were severe enough to account for the observed mortalities. PMID- 8675300 TI - Hyper-immunoglobulin G2 production by B cells from patients with localized juvenile periodontitis and its regulation by monocytes. AB - Localized juvenile periodontitis (LJP) runs in families, and a predisposition to develop disease appears to be inherited in an autosomal dominant fashion. Patients with LJP have elevated levels of serum immunoglobulin G2 (IgG2), and this is most striking in black LJP patients. We hypothesized that the markedly elevated serum IgG2 levels related to LJP status and race may be attributable to a fundamental difference in the response of black LJP leukocytes. To test this possibility, leukocytes from black LJP patients, black non-periodontitis (NP) controls, and white NP controls were cultured with a nonspecific mitogen (pokeweed mitogen) which stimulates immunoglobulin production. The levels of IgG2 produced were measured using an enzyme-linked immunosorbent assay. The results revealed that the serum IgG2 level differences among black LJP patients and white and black NP subjects were reproducible in peripheral blood leukocytes in vitro. Analysis revealed that B cells from the LJP patients appeared to be predisposed to produce high levels of IgG2. Further analysis supported the concept that the high IgG2 responses of B cells from black LJP patients were regulated by monocytes. Replacing the monocytes in cultures from white NP subjects with LJP monocytes from black patients resulted in production of IgG2 at levels that were comparable with those produced by the LJP B cells from black patients. In short, B cells from black LJP patients produce elevated levels of IgG2 in vitro, and at least part of this elevation appears to be attributable to regulation via the LJP monocytes. PMID- 8675301 TI - Biochemical characterization and protein kinase C dependency of monokine-inducing activities of Toxoplasma gondii. AB - Previous reports have indicated that the early induction of interleukin-12 (IL 12), tumor necrosis factor alpha (TNF-alpha), IL-1beta, and IL-10 is crucial for the establishment and regulation of host cell-mediated immunity to the intracellular protozoan parasite Toxoplasma gondii. In this study, we demonstrate that a soluble tachyzoite extract (soluble tachyzoite antigen) can trigger the expression of these four monokines by murine inflammatory macrophages. Further characterization revealed that the parasite molecules in soluble tachyzoite antigen responsible for monokine induction are heat stable at 100 degree C but differ in sensitivity to protease digestion. Thus, the tachyzoite factors that stimulate TNF-alpha and IL-to expression were found to be more resistant to treatment with proteinase K than those responsible for IL-12 and IL-10 induction. Similarly, while the factors responsible for the induction of all four monokines were found to be sensitive to periodate oxidation, the TNF-alpha-stimulating activity was partially resistant to treatment with the compound at a low concentration (1 mM). A further dichotomy in monokine induction signals was inferred from experiments with isoquinoline sulfonamide protein kinase inhibitors. The latter work suggested that the pathways for TNF-alpha and IL 1beta are protein kinase C dependent, while expression of IL-12 and expression of IL-10 share distinct signal transduction mechanisms involving other kinases. Together, these data argue that monokine induction by T. gondii is mediated by glycoproteins that may belong to distinct groups in terms of their biochemical properties and intracellular signaling pathways. PMID- 8675302 TI - Identification of a domain in Rck, a product of the Salmonella typhimurium virulence plasmid, required for both serum resistance and cell invasion. AB - Rck is encoded on the Salmonella typhimurium virulence plasmid and is a member of a family of related 17- to 19-kDa outer membrane proteins of Enterobacteriaceae, including Ail (Yersinia enterocolitica) and PagC (S. typhimurium). Structural models for these proteins predict eight membrane-spanning domains alternating with hydrophilic inner and outer loops. When expressed in Escherichia coli, Rck and Ail, but not PagC, confer high-level resistance to the bactericidal activity of complement as well as the ability to adhere to and invade mammalian cell lines. To identify functional domains of Rck, we made and screened random mutations in Rck for decreased bioactivity. We found that a single amino acid substitution (glycine to aspartic acid) in the putative third outer loop greatly reduced Rck-mediated serum resistance and eukaryotic cell invasion. We then constructed two chimeric proteins between Rck and PagC. Substitution of the C terminal half of Rck with the corresponding PagC fragment containing both the third and the fourth outer loops abolishes the Rck-mediated serum resistance and invasion phenotypes. Substitution of Rck with a smaller C-terminal portion of PagC containing the fourth outer loop did not affect the invasive phenotype or serum resistance. These data reveal that the third putative outer membrane loop region is important for the virulence-associated properties of the Rck protein and suggest a similarity between the mechanism of serum resistance and epithelial cell invasion involving the same domain of Rck. PMID- 8675303 TI - Expression of the CopB outer membrane protein by Moraxella catarrhalis is regulated by iron and affects iron acquisition from transferrin and lactoferrin. AB - The amino acid sequence of the cell-surface-exposed, 81-kDa CopB outer membrane protein of Moraxella catarrhalis was found to be similar to those of TonB dependent outer membrane proteins of other gram-negative bacteria. Expression of CopB was affected by the availability of iron in the growth medium, and the extent of overexpression of CopB in response to iron limitation varied widely among the M. catarrhalis strains tested. Wild-type M. catarrhalis strains were found to be able to utilize ferric citrate, transferrin, lactoferrin, and heme as sources of iron for growth in vitro. However, an isogenic copB mutant was severely impaired in its ability to utilize transferrin and lactoferrin as sole sources of iron for growth, whereas this same mutant grew similarly to the wild type parent strain when supplied with ferric citrate as the iron source. The copB mutant was not significantly different from its wild-type parent strain in its ability to bind transferrin and lactoferrin. In addition, the wild-type parent strain and the copB mutant exhibited equivalent rates of uptake of 55Fe from ferric citrate. However, the copB mutant was markedly less able than the wild type strain to take up 55Fe from transferrin and lactoferrin. These results indicate that lack of expression of the CopB protein exerts a direct or indirect effect on the ability of M. catarrhalis to utilize iron bound to certain carrier proteins. PMID- 8675304 TI - Potential role of molecular mimicry between Helicobacter pylori lipopolysaccharide and host Lewis blood group antigens in autoimmunity. AB - Helicobacter pylori is involved in gastritis, gastric and duodenal ulcers, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. Earlier studies already suggested a role for autoimmune phenomena in H. pylori-linked disease. We now report that lipopolysaccharides (LPS) of H. pylori express Lewis y, Lewis x, and H type I blood group structures similar to those commonly occurring in gastric mucosa. Immunization of mice and rabbits with H. pylori cells or purified LPS induced an anti-Lewis x or y or anti-H type I response, yielding antibodies that bound human and murine gastric glandular tissue, granulocytes, adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma cells. Experimental oral infections in mice or natural infection in humans yielded anti-Lewis antibodies also. The beta chain of gastric (H+,K+)-ATPase, the parietal cell proton pump involved in acid secretion, contained Lewis y epitopes; gastric mucin contained Lewis x and y antigenic determinants. Growth in mice of a hybridoma that secretes H. pylori-induced anti-Lewis y monoclonal antibodies resulted in histopathological evidence of gastritis, which indicates a direct pathogenic role for anti-Lewis antibodies. In conclusion, our observations demonstrate that molecular mimicry between H. pylori LPS and the host, based on Lewis antigens, and provide understanding of an autoimmune mechanism for H. pylori-associated type B gastritis. PMID- 8675305 TI - Inability of the Francisella tularensis lipopolysaccharide to mimic or to antagonize the induction of cell activation by endotoxins. AB - We studied the ability of the lipopolysaccharide (LPS) extracted from a vaccine strain of Francisella tularensis (LPS-Ft) to mimic LPSs from other gram-negative bacteria for activation of various murine cell types or to antagonize the effects of other LPSs. We found that activation of macrophages for the production of tumor necrosis factor alpha and NO, of pre-B lymphocytes for the expression of surface immunoglobulins, and of bone marrow cells for the expression of LPS binding sites was either undetectable with LPS-Ft or required concentrations 100 to 1,000 times higher than for standard LPSs. Preexposure of macrophages to LPS Ft also failed to trigger down-regulation of tumor necrosis factor alpha (desensitization) or up-regulation of NO responses to an endotoxin challenge. In contrast to other atypical LPSs, LPS-Ft was also unable to antagonize any of the endotoxin-induced cellular responses mentioned above, suggesting that this LPS does not interact with LPS receptors. PMID- 8675306 TI - Nucleotide sequence and expression of the gene encoding the major 25-kilodalton outer membrane protein of Brucella ovis: Evidence for antigenic shift, compared with other Brucella species, due to a deletion in the gene. AB - The nucleotide sequences encoding the major 25-kDa outer membrane protein (OMP) (omp25 genes) of Brucella ovis 63/290, Brucella melitensis 16M, Brucella suis 1330, Brucella canis RM6/66, and Brucella neotomae 5K33 (all reference strains) were determined and compared with that of Brucella abortus 544 (P. de Wergifosse, P. Lintermans, J. N. Limet, and A. Cloeckaert, J. Bacteriol. 177:1911-1914, 1995). The major difference found was between the omp25 gene of B. ovis and those of the other Brucella species; the B. ovis gene had a 36-bp deletion located at the 3' end of the gene. The corresponding regions of other Brucella species contain two 8-bp direct repeats and two 4-bp inverted repeats, which could have been involved in the genesis of the deletion. The mechanism responsible for the genesis of the deletion appears to be related to the "slipped mispairing" mechanism described in the literature. Expression of the 25-kDa outer membrane protein (Omp25) in Brucella spp. or expression from the cloned omp25 gene in Escherichia coli cells was studied with a panel of anti-Omp25 monoclonal antibodies (MAbs). As shown by enzyme-linked immunosorbent assay (ELISA) and immunoelectron microscopy, Omp25 was exported to the outer membrane in E. coli expressing either the truncated omp25 gene of B. ovis or the entire omp25 genes of the other Brucella species. Size and antigenic shifts due to the 36-bp deletion were demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting and by the differences in binding patterns in ELISA of the anti-Omp25 MAbs at the cell surface of E. coli cells harboring the appropriate gene and of cells of B. ovis and other Brucella species. In particular, MAbs directed against discontinuous epitopes of the entire Omp25 showed the absence of, or a significant reduction in, antibody reactivity with the B. ovis truncated Omp25. The results indicated that, as defined by the MAbs, exported Omp25 probably presents similar topologies in the outer membranes of E. coli and Brucella spp. and that the short deletion found in the omp25 gene of B. ovis has important consequences for the expression of surface B-cell epitopes which should be considered for the development of vaccines against B. ovis infection. PMID- 8675307 TI - Conservation of the sporozoite p67 vaccine antigen in cattle-derived Theileria parva stocks with different cross-immunity profiles. AB - Immunity to Theileria parva infection in cattle is often parasite stock specific. The antigenic diversity which is expressed at the schizont stage of the parasite together with a wild reservoir of the organism in buffalo has complicated the development of effective disease control by immunization. We have previously shown that about 70% of cattle inoculated with recombinant forms of p67, a sporozoite stage-specific surface antigen from the cattle-derived Muguga stock of the parasite, are immune to a homologous challenge. Thus, immune responses to p67 can play a role in immunity. The genes encoding this protein in five other parasite stocks have been sequenced. Here, we report that the p67 molecule encoded by four cattle-derived parasite stocks (Boleni, Uganda, Mariakani, and Marikebuni) that fall into different cross-immunity groups is identical in sequence to Muguga p67. The protein encoded by a buffalo-derived parasite exhibits 95% sequence identity with Muguga p67, the major difference being the presence of a 43-residue peptide insert. As predicted by these data, cattle inoculated with recombinant p67 can resist a heterologous cattle-derived parasite challenge. Seven of 12 cattle receiving a homologous Muguga challenge and 6 of 11 cattle receiving a heterologous Marikebuni challenge were immune to East Coast fever. These results extend earlier data suggesting that p67 is a conserved molecule and confirm its potential as a broad-spectrum vaccine antigen for the control of T. parva infection. PMID- 8675308 TI - An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of nonreplicating persistence. AB - It was demonstrated previously that abrupt transfer of vigorously aerated cultures of Mycobacterium tuberculosis to anaerobic conditions resulted in their rapid death, but gradual depletion of available O2 permitted expression of increased tolerance to anaerobiosis. Those studies used a model based on adaptation of unagitated bacilli as they settled through a self-generated O2 gradient, but the model did not permit examination of homogeneous populations of bacilli during discrete stages in that adaptation. The present report describes a model based on culture of tubercle bacilli in deep liquid medium with very gentle stirring that keeps them in uniform dispersion while controlling the rate at which O2 is depleted. In this model, at least two stages of nonreplicating persistence were seen. The shift into first stage, designated NRP stage 1, occurred abruptly at a point when the declining dissolved O2 level approached 1% saturation. This microaerophilic stage was characterized by a slow rate of increase in turbidity without a corresponding increase in numbers of CFU or synthesis of DNA. However, a high rate of production of glycine dehydrogenase was initiated and sustained while the bacilli were in this state, and a steady ATP concentration was maintained. When the dissolved O2 content of the culture dropped below about 0.06% saturation, the bacilli shifted down abruptly to an anaerobic stage, designated NRP stage 2, in which no further increase in turbidity was seen and the concentration of glycine dehydrogenase declined markedly. The ability of bacilli in NRP stage 2 to survive anaerobically was dependent in part on having spent sufficient transit time in NRP stage 1. The effects of four antimicrobial agents on the bacilli depended on which of the different physiologic stages the bacilli occupied at a given time and reflected the recognized modes of action of these agents. It is suggested that the ability to shift down into one or both of the two nonreplicating stages, corresponding to microaerophilic and anaerobic persistence, is responsible for the ability of tubercle bacilli to lie dormant in the host for long periods of time, with the capacity to revive and activate disease at a later time. The model described here holds promise as a tool to help clarify events at the molecular level that permit the bacilli to persist under adverse conditions and to resume growth when conditions become favorable. The culture model presented here is also useful for screening drugs for the ability to kill tubercle bacilli in their different stages of nonreplicating persistence. PMID- 8675309 TI - Prevalence of cytolethal distending toxin production in Campylobacter jejuni and relatedness of Campylobacter sp. cdtB gene. AB - Campylobacter jejuni produces a toxin called cytolethal distending toxin (CDT). The genes encoding this toxin in C. jejuni 81-176 were cloned and sequenced. The nucleotide sequence of the genes revealed that there are three genes, cdtA, cdtB, and cdtC, encoding proteins with predicted sizes of 30,11-6, 28,989, and 21,157 Da, respectively. All three proteins were found to be related to the Escherichia coli CDT proteins, yet the amino acid sequences have diverged significantly. All three genes were required for toxic activity in a HeLa cell assay. HeLa cell assays of a variety of C. jejuni and C. coli strains suggested that most C. jejuni strains produce significantly higher CDT titers than do C. coli strains. Southern hybridization experiments demonstrated that the cdtB gene is present on a 6.0-kb ClaI fragment in all but one of the C. jejuni strains tested; the cdtB gene was on a 6.9-kb ClaI fragment in one strain. The C. jejuni 81-176 cdtB probe hybridized weakly to DNAs from C. coli strains. The C. jejuni 81-176 cdtB probe did not hybridize to DNAs from representative C. fetus, C. lari, C. "upsaliensis," and C. hyointestinalis strains, although the HeLa cell assay indicated that these strains make CDT. PCR experiments indicated the probable presence of cdtB sequences in all of these Campylobacter species. PMID- 8675310 TI - CD4+ T-helper lymphocyte responses against Babesia bigemina rhoptry-associated protein I. AB - A multigene family of 58- to 60-kDa proteins, which are designated rhoptry associated protein 1 (RAP-1) and which come from the parasites Babesia bigemina and Babesia bovis, is a target for vaccine development. The presence of multiple gene copies and conserved sequences and epitopes of RAP-1 implies that these proteins are functionally important for the survival of these parasites. Furthermore, it was previously shown that B. bigemina RAP-1 induced partial protection against challenge infection. However, the lack of correlation between protective immunity to B. bigemina infection and antibody titers against a merozoite surface-exposed, neutralization-sensitive epitope of B. bigemina RAP-1 indicated the potential importance of RAP-1-specific T helper (Th) cells in the observed protection. To begin to understand the mechanism of RAP-1-induced protective immunity, RAP-1-specific T-cell responses were characterized in cattle. Vigorous and sustained proliferative responses of peripheral blood mononuclear cells from native RAP-1-immunized cattle were observed. The anamnestic response in immunized cattle was specific for B. bigemina RAP-1 and predominantly comprised CD4+ T cells, which upon cloning expressed type 1 cytokine mRNA profiles and high levels of gamma interferon protein. The T cells responded to both native and recombinant forms of RAP-1, indicating the potential to use recombinant protein or epitopes derived therefrom as a vaccine that could evoke specific recall responses after exposure to natural infection. The differential responses of peripheral blood mononuclear cells and seven Th-cell clones derived from RAP-1-immunized cattle to different Central American strains of B. bigemina indicated the presence of at least one conserved and one variable Th-cell epitope. The lack of response to B. bovis RAP-1 indicated that a strictly conserved 14-amino-acid peptide shared by the two babesial species was not immunogenic for Th cells in these experiments. However, the Th-cell epitope conserved among strains of B. bigemina may be a useful component of a RAP-1 subunit vaccine. PMID- 8675312 TI - Mixed infection with Porphyromonas gingivalis and Fusobacterium nucleatum in a murine lesion model: potential synergistic effects on virulence. AB - These studies determined the characteristics of tissue destruction in a murine abscess model elicited by mixed infection with the periodontopathogens Fusobacterium nucleatum and Porphyromonas gingivalis. The interbacterial effects of this synergism, the kinetics of the relationship of the bacterial interaction, and the characteristics of the bacteria required for the tissue destruction were studied. Infection of mice with P. gingivalis and F. nucleatum strains elicited lesions of various sizes as a function of infective dose. Primary infection with F. nucleatum plus P. gingivalis at various ratios (i.e., <1:1) resulted in a significantly greater lesion size (P < 0.001) compared with that resulting from primary infection with P. gingivalis alone. At F. nucleatum/P. gingivalis ratios of > or = 1:1, spreading lesion formation and progression were significantly (P < 0.001) decreased, suggesting that bacterial interaction (i.e., coaggregation) may have inhibited the spread of the P. gingivalis infection to a site distant from the initial injection. Infection with F. nucleatum and P. gingivalis simultaneously (at different sites) or F. nucleatum administered within 4 h prior to or 1 h following P. gingivalis infection significantly enhanced the ability of P. gingivalis to form large phlegmonous lesions. Chemical inhibition of the P. gingivalis trypsin-like protease activity or the use of a trypsin-negative P. gingivalis strain abrogated tissue destruction either alone or in combination with F. nucleatum. Therefore, it was possible to examine aspects of virulence of these pathogens in a murine lesion model by either altering bacterial ratios, manipulating the time of infection, or targeting vital bacterial virulence factors. PMID- 8675311 TI - Construction and characterization of a Yersinia enterocolitica O:8 high temperature requirement (htrA) isogenic mutant. AB - The high-temperature requirement (HtrA) family of stress response proteins are induced by different environmental stress conditions in a variety of bacteria and have been shown to contribute to the pathogenicity of some of these species. In this study, the htrA gene from Yersinia enterocolitica O:8 was amplified, cloned, and sequenced. Analysis of the deduced amino acid sequence predicted that the putative HtrA homolog contains a serine protease active site and a catalytic triad characteristic of trypsin-like serine proteases, structural features characteristic of previously described HtrA proteins. In order to evaluate the biological functions of Y. enterocolitica HtrA, an isogenic mutant was constructed by a reverse-genetics PCR-based approach. Characterization of the mutant provided evidence supporting a stress response function for the Y. enterocolitica htrA gene product. In contrast to the parent strain, the mutant showed increased sensitivity to killing by H2O2, O2- and temperature stress (50 degrees C). The mutant was avirulent in the murine yersiniosis injection model and offered partial protection to mice challenged with the parent strain. Further studies with the Y. enterocolitica htrA mutant should increase our knowledge of the host-pathogen interactions which occur during Yersinia infections. PMID- 8675313 TI - Hypothermic response of mice to ornithine-containing lipids and to endotoxin. AB - The hypothermic response of mice to ornithine-containing lipids (Orn-Ls) of the form alpha-N-(3-acyloxyacyl)-ornithine and to endotoxin (Escherichia coli 0111:B4 lipopolysaccharide [LPS]) was studied. After the administration of Orn-L or LPS to C3H/HeSlc mice, body temperature decreases were determined at 30-min intervals by inserting a thermistor into the rectum of each mouse. When Orn-L (750 microg) or LPS (70 microg) was injected into the mice, body temperature decreases of 0.8 and 2.0 degrees C, respectively, occurred 1.8 to 2.0 h later. These body temperature decreases were completely suppressed by the preadministration of indomethacin. When anti-tumor necrosis factor alpha (TNF-alpha) antibody was administered before the administration of Orn-L or LPS, only the body temperature decrease by LPS was suppressed. The body temperature decrease by Orn-L was suppressed by anti-interleukin-1beta (IL-1beta) antibody preadministration. Next, in order to study IL-1beta and TNF-alpha mRNA expression in macrophages, peritoneal macrophages were collected 40 min after the administration of Orn-L or LPS to mice. The expression of IL-1beta mRNA by stimulation with Orn-L was as strong as that by stimulation with LPS, but the expression of TNF-alpha mRNA by stimulation with Orn-L was very weak. Our previous studies of in vitro macrophage activation by Orn-L proved that strong induction of IL-1 and prostaglandin E2 generation by Orn-L occurred (Y. Kawai and K. Akagawa, Infect. Immun. 57:2086 2091, 1989). From these experiments, the weak body temperature decrease in mice caused by Orn-L was found to be mediated by cytokines different from those which mediate the strong body temperature decrease caused by LPS. Namely, it was caused by prostaglandin E2 being mediated by IL-1 but not by TNF-alpha. PMID- 8675314 TI - Differential secretion of interleukin-8 by human epithelial cell lines upon entry of virulent or nonvirulent Yersinia enterocolitica. AB - Epithelial cells of the intestinal mucosa are among the first cells encountered by invasive pathogens. Bacterial invasion of the mucosa gives rise to an inflammatory response, characterized by the influx of polymorphonuclear leukocytes. The chemotactic stimulus responsible for this accumulation is unknown, but several in vitro studies have demonstrated that epithelial cells secrete the chemokine interleukin-8 (IL-8), a potent chemoattractant of polymorphonuclear leukocytes, upon bacterial entry. In this study we analyzed the secretion of IL-8 by human intestinal (T84) and cervical (HeLa) epithelial cell lines in response to infection with the enteric pathogen Yersinia enterocolitica. IL-8 was secreted by T84 and HeLa cells in response to invasion by Y. enterocolitica. Virulent Y. enterocolitica induced a significantly lower level of IL-8 secretion than nonvirulent Y. enterocolitica. Subsequent analysis employing a mutant defective in Yop secretion and various yop mutants showed that the reduced secretion of IL-8 is due to the presence of Yop proteins. Our data suggest that YopB and YopD are required for the suppressive effect. PMID- 8675315 TI - scbA from Streptococcus crista CC5A: an atypical member of the lraI gene family. AB - A new member of the lraI family of putative adhesin genes was cloned, from Streptococcus crista CC5A, and sequenced. The gene, scbA appears to be part of an ABC transport operon and encodes a putative peptide of 34.7 kDa. The protein contains a signal sequence with residues 17 to 21 (L-A-A-C-S) matching the consensus sequence for the prolipoprotein cleavage site of signal peptidase II. ScbA is 57 to 93% identical, at the amino acid level, with the five previous sequenced members of the LraI family. Surprisingly, ScbA does not exhibit adhesion properties characteristic of the other LraI proteins. Strain CC5A bound poorly to saliva-coated hydroxyapatite and did not coaggregate with Actinomyces naeslundii PK606. An scbA insertion-duplication mutation that abolished expression (of ScbA was created. There was no difference in fibrin binding between this mutant and wild-type CC5A. Since it is possible that ScbA could play a role in corncob formation between S. crista and Fusobacterium nucleatum, this property was examined. The mutant strain retained the ability to form corncobs. On the basis of the lack of adhesin properties it appears that ScbA is an atypical member of the LraI family. PMID- 8675316 TI - Identification of a fibronectin-binding protein (GfbA) in pathogenic group G streptococci. AB - Attachment to eukaryotic cell surfaces is an essential step in the establishment of colonization and infection by bacterial pathogens. This report examines the adherence capabilities of pathogenic group G streptococci and demonstrates that certain group G streptococcal clinical isolates express a fibronectin-binding protein. This protein, termed GfbA for group G streptococcal fibronectin-binding protein, mediates adherence to human skin fibroblasts (HSF). The gene encoding this protein, gfbA, was isolated, and the complete DNA sequence of gfbA was determined. From this sequence GfbA was predicted to be a 580-amino-acid protein (molecular weight = 64,979) with significant amino acid identity to the group A streptococcal fibronectin-binding proteins SfbI and protein F (PrtF) (76 and 78% identity, respectively). GfbA contains regions with notable identity to the fibronectin-binding repeat domains of PrtF. gfbA(+) strains were able to bind to HSF, and preincubation of the gfbA(+) strains with fibronectin blocked this adherence. In addition, gfbA(+) strains were able to bind radiolabeled fibronectin, and this binding was inhibited with addition of excess unlabeled fibronectin. gfbA-negative strains were not able to bind either the HSF or radiolabeled fibronectin. DNA homologous to gfbA was found in 36% of the group G streptococcal isolates examined. Since not all group G streptococcal strains examined contained gfbA, this suggests there might be other tissue-specific adherence molecules expressed by these pathogenic strains. PMID- 8675317 TI - Cloning and characterization of Pseudomonas aeruginosa fliF, necessary for flagellar assembly and bacterial adherence to mucin. AB - Pseudomonas aeruginosa adheres to the mucosal surfaces of the lungs. This process appears to be mediated by nonpilus adhesins which bind to mucin. To find this nonpilus adhesin(s), mutagenesis of a nonpiliated mutant of P. aeruginosa with transposon Tn5G, followed by a screen for mucin adhesion, was used to isolate a series of mutants unable to adhere to mucin. All of these mutants were also found to be defective in motility. One such mutant, PAK-RR20, is characterized here. The site of the transposon insertion in PAK-RR20 was localized to a gene which is homologous to the fliF gene of other organisms and was flanked by other motility related genes, fliE and fliG. Both adhesion and motility defects in PAK-RR20 were complemented by providing the fliF gene in trans. Since complementation could have been due to the presence of an internal promoter in the fliF gene or in the Tn5G transposon, which allowed the transcription of the downstream genes, another chromosomal mutant of the fliF gene was constructed by insertional inactivation with an antibiotic resistance cassette. This mutant was also nonmotile and nonadhesive. However, the two defects in this new mutant could not be complemented by the fliF gene in trans, consistent with the interpretation that there is no internal fliF promoter but possibly a functional promoter in the Tn5G transposon. The complete nucleotide sequences of the fliE and fliF genes and a partial nucleotide sequence of the fliG gene of P. aeruginosa were determined. Control of the promoter upstream of the fliE gene was analyzed by construction of a fliE-lacZ fusion and the introduction of this construct into strains of P. aeruginosa with mutations in several regulatory genes. Beta-Galactosidase expression measurements indicated that the fliE promoter does not utilize RpoF (sigma(28)) or RpoN (sigma(54)) sigma factors. The characterization of this gene as being responsible for the loss of adhesion indicates that basal body structures are probably important for localization of the adhesin. PMID- 8675318 TI - Cholera toxin induces synthesis of phospholipase A2-activating protein. AB - The mechanism of cholera toxin (CT)-stimulated arachidonate metabolism was evaluated. CT caused rapid in vitro synthesis of prostaglandin E2 (PGE2) in murine smooth muscle-like cells (BC3H1), reaching maximal levels within 3 to 4 min. In comparison, cyclic AMP (cAMP) levels were unchanged, and addition of dibutyryl cAMP did not affect PGE2 synthesis. CT-induced PGE2 synthesis was prevented by actinomycin D or cycloheximide, indicating a need for de novo protein synthesis. Northern blot analysis of total RNA from BC3H1 cells revealed that exposure to CT resulted in an increase in abundance of mRNA encoding phospholipase A2 (PLA2)-activating protein (PLAP). PLAP is a regulatory protein that increases the enzymatic activity of cellular PLA(2), which in turn causes increased hydrolysis of arachidonate from membrane phospholipids. Furthermore, CT evoked the accumulation of PLAP mRNA in J774 (murine monocyte/macrophage) and Caco-2 (human intestinal epithelial) cells in vitro, but the responses were more delayed than that of BC3H1 cells. A protein band of approximately 35 kDa, which corresponded to the size of PLAP, was observed in sodium dodecyl sulfate extracts of Caco-2 cells by Western blot (immunoblot) analysis using affinity-purified antibodies to PLAP synthetic peptides. Synthesis of PLAP protein was increased after 2 h of exposure to CT. Exposure of mouse intestinal loops to either CT or live Salmonella typhimurium for 3 h increased mucosal PLAP mRNA levels. The role of PLAP in CT-induced PGE2 synthesis provides an attractive explanation for the reported suppression of CT-induced intestinal secretion by inhibitors of protein synthesis. PMID- 8675319 TI - Synthesis of hybrid molecules between heat-labile enterotoxin and cholera toxin B subunits: potential for use in a broad-spectrum vaccine. AB - Three variants of the cholera toxin B subunit (CTB) were generated by site specific mutagenesis in which regions of the mature protein were altered to the composition found at the corresponding positions of the closely related B subunit of the heat-labile enterotoxin of enterotoxigenic Escherichia coli (LTB). The mutant proteins were expressed in Vibrio cholerae and purified from the growth medium. In the first of the mutant proteins, the first 25 amino acids corresponded to the sequence found in LTB, and in the second, changes were made at positions 94 and 95 of the mature protein. The third mutant protein combined the changes made in the first two. Analysis of the immunological properties of these novel proteins by using monoclonal antibodies and absorbed polyclonal antiserum demonstrated that they had acquired LTB-specific epitopes. Immunizations with the mutant proteins resulted in antisera containing LTB specific as well as CTB-specific and cross-reactive antibodies. The sera were also found to be more strongly cross-reactive in the in vitro neutralization of both cholera toxin and heat-labile enterotoxin than were antisera raised against either CTB or LTB. The results suggest that such hybrid CTB-LTB proteins may be useful in a broad-spectrum vaccine against enterotoxin-induced diarrhea. PMID- 8675320 TI - Inhibition of Giardia lamblia excystation by antibodies against cyst walls and by wheat germ agglutinin. AB - Although excystation is crucial to the initiation of infection by Giardia lamblia, little is known about the regulation of this important process. We have been able to reliably induce excystation in vitro by mimicking cyst passage through the stomach and upper small intestine by the exposure of in vitro-derived cysts to an acidic, reducing environment (stage I) followed by protease treatment at a slightly alkaline pH (stage II). Preexposure of cysts to polyclonal rabbit antiserum against purified cyst walls (PCWs) or to wheat germ agglutinin (WGA) inhibited excystation by > 90%. Adsorption of either ligand with PCWs eliminated inhibition, demonstrating specificity for cyst wall epitopes. Inhibition by WGA was reversed by either chitotriose or sialic acid, while inhibition by polyclonal antibodies against PCWs (anti-PCW) was reversed only by sialic acid, which also inhibited binding of both ligands to intact cysts and to cyst wall antigens in immunoblots. Binding of anti-PCW did not affect acidification of cyst cytoplasm during stage I. Exposure of cysts to anti-PCW and WGA prior to, but not after, stage II was sufficient to inhibit excystation, and inhibition could be partially reversed by increasing the protease concentration during stage II. A 7- to 10 fold higher proportion of WGA- and anti-PCW-treated cysts than control cysts remained intact after stage II. Our results suggest that these ligands, which bind cyst wall epitopes, inhibit excystation, most likely by interfering with proteolysis of cyst wall glycoproteins during stage II. PMID- 8675321 TI - Intranasal immunization with SAG1 protein of Toxoplasma gondii in association with cholera toxin dramatically reduces development of cerebral cysts after oral infection. AB - SAG1 protein of Toxoplasma gondii was evaluated as a protective antigen in mucosal immunization with cholera toxin as an adjuvant. CBA/J mice intranasally immunized with a combination of SAG1 and cholera toxin exhibited significantly fewer cysts in the brain after oral infection with the 76K strain of T. gondii than control mice. This acquired protection lasted at least 5 months. Protected mice developed high levels of serum anti-SAG1 immunoglobulin G antibodies as well as an enhanced systemic cellular response, as assessed by the proliferation of splenocytes in response to SAG1 restimulation in vitro. This cellular proliferation was associated with an increase of interleukin-2 and interleukin-5 synthesis and with barely detectable gamma interferon production. Splenic immune T cells were shown to convey modest protection to recipients against development of brain cysts following oral infection with T. gondii. Significant production of anti-SAG1 immunoglobulin A was induced in intestinal secretions of protected mice. These results indicate that intranasal immunization with SAG1 and cholera toxin can induce mucosal and systemic immune responses and affords partial and long-lasting resistance against the establishment of chronic toxoplasmosis. PMID- 8675322 TI - In vivo cytokine response to Escherichia coli alpha-hemolysin determined with genetically engineered hemolytic and nonhemolytic E. coli variants. AB - Alpha-hemolysin is an Escherichia coli exotoxin that enhances bacterial virulence, has profound effects on leukocytes in vitro, and induces the release of interleukin-1 (IL-1) but not tumor necrosis factor (TNF) from human monocytes in vitro. The purpose of this study was to examine alpha-hemolysin's influence on virulence and TNF and IL-1 production in vivo. Two genetically engineered, isogeneic strains of E. coli were used; one variant produces alpha-hemolysin, and the other does not. Male BALB/c mice were injected with either of the two variants and serum TNF and IL-1 were assayed. These results were compared with those obtained from the injection of either of two serotypes of lipopolysaccharide (LPS). The nonhemolytic E. coli strain produced no mortality and no significant elevation of serum TNF or IL-1 levels. In contrast, equal inocula of the hemolytic E. coli strain produced significant mortality and elevation of serum IL-1 levels. No significant elevation of TNF levels was detected in this group despite high-level mortality. A pattern of induction of mortality and elevation of serum IL-1 levels without elevation of serum TNF levels is distinct from the pattern typical of LPS. In these experiments, both serotypes of LPS caused elevations of TNF and IL-1 levels whether or not mortality was induced. Thus, alpha-hemolysin produces a cytokine response in vivo that is similar to that previously demonstrated in vitro by Bhakdi et al. (S. Bhakdi, M. Muhly, S. Korom, and G. Schmidt, J. Clin. Invest. 85:1746-1753, 1990) and appears to induce mortality independently of serum TNF. PMID- 8675323 TI - Antibodies to a conserved-motif peptide sequence of the Plasmodium falciparum thrombospondin-related anonymous protein and circumsporozoite protein recognize a 78-kilodalton protein in the asexual blood stages of the parasite and inhibit merozoite invasion in vitro. AB - Athrombospondin-related anonymous protein (TRAP) of the human malaria parasite Plasmodium falciparum shares highly conserved amino acid sequence motifs with the circumsporozoite protein of all plasmodia sequenced so far, as well as with unrelated proteins like thrombospondin and properdin. Although it was first described as an asexual blood stages protein, there has been some controversy about its expression in these stages. Pursuant to our interest in the conserved sequences within the malaria antigens, we synthesized an 18-residue peptide (18 mer) representing a conserved motif of TRAP and raised polyclonal antibodies against it. In an immunoblot assay in which we probed proteins from the asexual blood stages of the parasite, we found that this antibody recognized predominantly a 78-kDa protein in the whole parasite lysate. Furthermore, in another immunoblot, the recombinant TRAP constructs containing the conserved motif sequence were distinctly recognized by the antipeptide antibodies, whereas a construct lacking the motif sequence was not, suggesting that the antibodies specifically cross-reacted with a protein which might be a TRAP-like protein present in the asexual blood stages of the parasite. Also, in an immunofluorescence assay, this antibody brightly stained the acetone-fixed trophozoites of the parasite. Most significantly, anti-18-mer immunoglobulin G, as well as antipeptide antibody against a smaller (nonamer) construct representing the most conserved motif within the 18-mer, inhibited the merozoite invasion of erythrocytes in a dose-dependent manner. These results provide evidence of the expression of TRAP or a TRAP-like protein in the asexual blood stages of the parasite and of a possible role of the conserved motifs in the parasite-host cell interaction during the process of invasion. PMID- 8675324 TI - Fraction 1 capsular antigen (F1) purification from Yersinia pestis CO92 and from an Escherichia coli recombinant strain and efficacy against lethal plague challenge. AB - As a first step in formulating an improved plague vaccine, we developed a simple purification strategy that produced high yields of pure cell-associated and culture supernatant-derived fraction 1 capsular antigen (F1) from both avirulent Yersinia pestis C092 (Pgm- Lcr-) and an Escherichia coli F1-producing recombinant strain. Cell-associated F1 was partially purified by sequential ammonium sulfate precipitations of a sodium chloride extract of acetone-dried bacteria harvested from broth cultures. Cell-free F1 was precipitated directly from culture supernatants with a single application of 30% ammonium sulfate. By exploiting the aggregative property of F1, large quantities of purified high-molecular-weight F1 species from both cell extracts and supernatants were isolated in the void volume of a preparative gel filtration column. Highly purified, endotoxin-free F1, combined with two different adjuvants, induced very high F1 titers in mice and protected them against either subcutaneous (70 to 100% survival) or aerosol (65 to 84% survival) challenge with virulent organisms. This protection was independent of the source of the antigen and the adjuvant used. F1-induced protection against both subcutaneous and aerosol challenge was also significantly better than that conferred by immunization with the licensed killed whole-cell vaccine. Our results indicate that F1 antigen represents a major protective component of previously studied crude capsule preparations, and immunity to F1 antigen provides a primary means for the host to overcome plague infection by either the subcutaneous or respiratory route. PMID- 8675325 TI - Deletion of purE attenuates Brucella melitensis infection in mice. AB - We previously showed that a purE mutant (delta purE201) of Brucella melitensis 16M is attenuated for growth in cultured human monocytes (E. S. Drazek, H. H. Houng, R. M. Crawford, T. L. Hadfield, D. L. Hoover, and R. L. Warren, Infect. Immun. 63:3297-3301, 1995). To determine if this strain is attenuated in animals, we compared the growth of the delta purE201 mutant with that of strain 16M in BALB/c mice. The number of bacteria in the spleen and spleen weight peaked for both strains between 1 and 2 weeks postinfection (p.i.), though the number of delta purE201 cells was significantly less than the number of 16M cells recovered from the spleens of infected mice. During the next 6 weeks, delta purE201 was essentially eliminated from infected mice (three of five mice sterile; < 100 CFU in two of live mice at 8 weeks p.i.), whereas bacteria persisted at a high level in the spleens of 16M-infected mice (about 106 CFU per spleen). The number of bacteria in the livers and lungs of mice infected with either strain paralleled those in the spleen. Mice infected with 16M had a strong inflammatory response, developing dramatic and prolonged splenomegaly (five to eight times normal spleen weight) and producing serum interleukin-6. In contrast, mice infected with delta purE201 developed only mild, transient splenomegaly at 1 week p.i. and produced no interleukin-6 in their serum. We further characterized the host response to infection by measuring changes in immune spleen cell populations by flow cytometry. CD4- and CD8-positive lymphocytes declined by I week in both experimental groups, while MAC-1-positive cells increased. T-cell subpopulations remained low or declined further, and MAC-1 cells increased to three times normal levels during 8 weeks of infection with 16M but returned to normal by 4 weeks after infection with delta purE201. These results document infectivity and attenuation of delta purE201 and suggest that it should be further evaluated as a potential vaccine. PMID- 8675327 TI - Passive transfer of poly-(1-6)-beta-glucotriosyl-(1-3)-beta-glucopyranose glucan protection against lethal infection in an animal model of intra-abdominal sepsis. AB - Previous studies have established the efficacy of soluble polymers of poly-(1-6) beta-glucotriosyl-(1-3)-beta-glucopyranose (PGG) glucan, a biological-response modifier, in protecting against mortality associated with experimentally induced peritonitis in a rat model. PGG glucan-treated animals showed increases in total leukocyte counts and enhanced bacterial clearance from blood. To further explore the mechanisms) by which this agent confers protection, studies were performed to examine whether protection could be transferred from PGG glucan-treated animals to naive recipients via spleen cells (SC), SC lysates, or serum. Passive-transfer experiments indicated that the responsible factor(s) was transferable by whole SC and SC lysates, as well as by peripheral leukocytes or serum from animals treated with PGG glucan. The transferable factor(s) was resistant to pronase and trypsin digestion, was heat stable at 56 or 80 degrees C, and was not removed by NH4SO4 precipitation. The protective effect of PGG glucan was abrogated by treatment with indomethacin, a potent inhibitor of prostaglandin synthesis. Administration of a purified prostaglandin extract from the sera of PGG glucan-treated animals protected against mortality in the peritonitis model. Furthermore, treatment of rats with exogenous synthetic prostaglandin E2 also conferred protection against mortality. These results suggest that the protective effect exhibited by PGG glucan in the rat peritonitis model is mediated, at least in part, by prostaglandins. PMID- 8675326 TI - DNA sequencing and gene expression of the emm gene cluster in an M50 group A streptococcus strain virulent for mice. AB - The strain B514, an M serotype 50 strain, is capable of causing a natural upper respiratory infection leading to death in mice, as reported by Hook et al. in 1960 (E. W. Hook, R. R. Wagner, and R. C. Lancefield, Am. J. Hyg. 72:111-119, 1960). Thus, this strain was of interest for use in developing an animal model for group A streptococcal colonization and disease. The emm gene cluster for this strain was examined by PCR mapping and found to contain three emm family genes and cluster pattern 5. PCR-generated fragments corresponding to the SF4 (mrp50), SF2 (emmL50), and SF3 (enn50) genes were cloned and the entire gene cluster was sequenced. The gene cluster has greater than 97% DNA identity to previously sequenced regions of the gene cluster of the M2 strain T2/44/RB4 if two small divergent regions that encode the mature amino terminus of the SF-2 and SF-3 gene products are not included. If expressed, the genes encode proteins which bind human immunoglobulin G (Mrp50 and EmmL50) or immunoglobulin A (Enn50). However, in isolates taken directly after passage in mice, the surface proteins arising from these genes were barely detectable. The transcription of each gene in the B514 strain was investigated by Northern (RNA) hybridization, and mRNA transcripts were detected and quantitated relative to those of the recA gene, a housekeeping gene. Transcription of all three emm family genes was found to be over 30-fold attenuated relative to transcription of the same genes in strain T2/44/RB4. This suggests that the positive regulator, Mga, either is not expressed in this strain or has a different requirement for activation; it also suggests that the capsule may be sufficient to inhibit phagocytosis under these circumstances. PMID- 8675329 TI - Role of manganese superoxide dismutase in a mucoid isolate of Pseudomonas aeruginosa: adaptation to oxidative stress. AB - Chronic infection by alginate-producing (mucoid) Pseudomonas aeruginosa is a leading cause of morbidity among cystic fibrosis (CF) patients. In the lungs of CF patients, the bacteria are exposed to activated oxygen species produced by the phagocytes of the host or resulting from the metabolism of oxygen. Two isoforms of superoxide dismutase are synthesized by P. aeruginosa; they differ by the metal present at their active site, which is either iron or manganese. To evaluate the role of manganese-containing superoxide dismutase (MnSOD), encoded by sodA, we have isolated a sodA mutant of the mucoid P. aeruginosa strain CHA isolated from the bronchopulmonary tract of a CF patient. The sodA mutant exhibited an increased sensitivity to oxidative stress generated by paraquat and was less resistant to oxidative stress in the stationary phase of growth compared with its parental strain. It was observed that MnSOD was expressed in the parental strain solely during the stationary phase of growth and that cells of the sodA mutant taken at the stationary phase resumed growth with a longer delay than the sodA+ cells when reinoculated in a new medium, especially in the presence of paraquat. These results suggest that MnSOD may participate in the adaptation of mucoid strains of P. aeruginosa to the stationary phase of growth in the lungs of CF patients. PMID- 8675328 TI - Leishmania major-human macrophage interactions: cooperation between Mac-1 (CD11b/CD18) and complement receptor type 1 (CD35) in promastigote adhesion. AB - It has been suggested that the developmental maturation of Leishmania major promastigotes can affect their interaction with human complement receptors. To study this, we measured the adhesion of metacyclic and logarithmic-phase L. major promastigotes to complement receptors expressed on primary macrophages, to recombinant receptors expressed on transfected cells, or to purified complement receptors in a cell-free system. We demonstrate that complement-opsonized promastigotes can bind to both Mac-1 and complement receptor type 1 (CR1) and that the transition of promastigotes from the noninfectious logarithmic phase of growth to the infectious metacyclic stage does not affect this interaction. Furthermore, we show that Mac-1 and CR1 can cooperate to mediate the efficient adhesion of complement-opsonized metacyclic promastigotes to cells expressing both receptors. On human monocyte-derived macrophages, Mac-1 appears to make a quantitatively greater contribution to this adhesion than does CR1, since blocking macrophage Mac-1 diminishes metacyclic promastigote adhesion to a greater extent than does blocking CR1. In addition, bovine monocytes lacking Mac 1 exhibit a dramatic decrease in complement-dependent promastigote adhesion, relative to normal monocytes. The predominance of Mac-1 in these interactions is due, at least in part, to the factor I cofactor activity of CR1, which facilitates the conversion of C3b to iC3b. The stable adhesion of complement opsonized metacyclic promastigotes to Mac-1 is a prerequisite for phagocytosis by human monocyte-derived macrophages. Blocking Mac-1 on macrophages abrogates the majority of the complement-dependent phagocytosis of promastigotes, whereas blocking CR1 has no detectable effect on phagocytosis. In addition, bovine monocytes lacking Mac-1 exhibit a dramatic reduction in promastigote phagocytosis relative to normal bovine monocytes. We conclude, therefore, that the two complement receptors, Mac-1 and CR1, can cooperate to mediate the initial complement-dependent adhesion of metacyclic promastigotes to human monocyte derived macrophages and that Mac-1 is the predominant complement receptor responsible for the phagocytosis of complement-opsonized metacyclic promastigotes. PMID- 8675330 TI - Preclinical immunoprophylactic and immunotherapeutic efficacy of antisera to capsular polysaccharide-tetanus toxoid conjugate vaccines of Vibrio vulnificus. AB - Vibrio vulnificus is an oyster-associated bacterial pathogen that causes life threatening fulminating septicemia and necrotizing wound infections in humans. The capsular polysaccharide of V. vulnificus (VvPS) is critical for virulence. Previously we showed that active immunization of mice with a VvPS-tetanus toxoid (VvPS-TTa) conjugate vaccine conferred significantly higher protection against subsequent lethal challenge than immunization with VvPS alone. In the current study, we examined the utility of immunoprophylaxis or immunotherapy with hyperimmune antisera elicited by VvPS-TTa and VvPS-TTb conjugate vaccines prepared by different synthetic schemes. First we demonstrated that the Ribi adjuvant significantly enhanced the murine antibody response (P < or = 0.02) to both conjugates. Subsequently, high-titered polyclonal antisera were raised to VvPS-TTa and VvPS-TTb conjugate vaccines by using Ribi adjuvant or Freund's adjuvants. Antisera were observed to have protective effects when administered before and after acute lethal infection. All animals receiving prophylactic antisera intraperitoneally 24 h before lethal challenge with homologous carbotype 1 were protected, while 73 to 100% of control mice succumbed. Immunotherapy was also effective, with survival rates of 60 to 73% seen among mice when antisera were administered 2 h after bacterial challenge, at a time when symptoms of infection were already apparent. The protective effect of capsular antiserum appeared to be serotype specific. Antisera to the, carbotype 1 VvPS-TTa vaccine did not confer cross-protection against lethal challenge with carbotype 2 V. vulnificus despite partial structural similarity and a weak serological cross reaction between the two carbotypes. Immune globulins induced by a potential multivalent VvPS conjugate vaccine composed of clinically prevalent carbotypes may have utility in the management of V. vulnificus infections and deserve further evaluation. PMID- 8675331 TI - Truncated enterohemorrhagic Escherichia coli (EHEC) O157:H7 intimin (EaeA) fusion proteins promote adherence of EHEC strains to HEp-2 cells. AB - Intimin, the product of the eaeA gene in enterohemorrhagic Escherichia coli O157:H7 (EHEC), is required for intimate adherence of these organisms to tissue culture cells and formation of the attaching and effacing lesion in the gnotobiotic pig. Because of the importance of intimin in the pathogenesis of EHEC O157:H7 infection in this animal model, we began a structure-function analysis of EaeA. For this purpose, we constructed amino-terminal fusions of the intimin protein with six histidine residues to form two independent fusions. The longer fusion, RIHisEae, contained 900 of the 935 predicted amino acids and included all but the extreme amino terminus. The second fusion, RVHdHisEae, consisted of the carboxyl two-thirds of the protein. Purified extracts of either construct enhanced binding of wild-type 86-24 to HEp-2 cells and conferred HEp-2 cell adherence on 86-24eaeDelta10, an eaeA deletion mutant, and B2F1, an EHEC O91:1 121 eaeA mutant strain. When 86-24eaeDelta10 was transformed with either of the plasmids encoding the intimin fusion proteins, the transformant behaved like the wild-type parent strain and displayed localized adherence to HEp-2 cells, with positive fluorescent-actin staining. In addition, polyclonal antisera raised against RIHisEae reacted with both fusion constructs and recognized an outer membrane protein of the same mass as intimin (97 kDa) in EHEC and enteropathogenic E. coli but not E. coli K-12. The intimin-specific antisera also blocked adherence of EHEC to HEp-2 cells. Thus, intimin (i) is a 97-kDa outer membrane protein in EHEC that serves as a requisite adhesin for attachment of the bacteria to epithelial cells, even when the protein is truncated by one-third at its amino terminus and (ii) can be added exogenously to specifically facilitate HEp-2 cell adherence of EHEC but not E. coli K-12. PMID- 8675332 TI - Outer surface protein C (OspC), but not P39, is a protective immunogen against a tick-transmitted Borrelia burgdorferi challenge: evidence for a conformational protective epitope in OspC. AB - Outbred mice were immunized with the soluble fraction of a crude Escherichia coli lysate containing either recombinant outer surface protein C (OspC or P39 of Borrelia burgdorferi B31 (low passage). Following seroconversion, the mice were challenged with an infectious dose of B. burgdorferi B31 via the natural transmission mode of tick bite. Three mice immunized with P39 were not protected; however, all 12 of the recombinant OspC-immunized mice were protected from infection as assayed by culture and serology. Although OspC has been shown to be a protective immunogen against challenge with in vitro-cultured borrelia administered by needle, this study is the first to demonstrate OspC effectiveness against tick-borne spirochetes. Following feeding, all ticks still harbored B. burgdorferi, suggesting that the mechanism of protection is not linked to destruction of the infectious spirochete within the tick. In a separate experiment, groups of four mice were immunized with protein fractions from B. burgdorferi B31 purified by preparative gel electrophoresis in an attempt to identify potential protective antigens. Many of these mice developed high-titer antibody responses against OspC, but curiously the mice were susceptible to B. burgdorferi infection via tick bite. These results suggest that the protective epitope(s) on OspC is heat sensitive/conformational, a finding which has implications in vaccine development. PMID- 8675333 TI - Relationship between phase variation in colony morphology, intrastrain variation in cell wall physiology, and nasopharyngeal colonization by Streptococcus pneumoniae. AB - Streptococcus pneumoniae undergoes phase variation in colony morphology, which has been implicated as a factor in the pathogenesis of pneumococcal disease. Phenotypic differences between opaque and transparent colony forms correlate with differences in rates of autolysis. This study examined whether differences in autolysis are caused by differences in expression of the major amidase, LytA, or the structure of its peptidoglycan substrate. No significant difference was detected by high-pressure liquid chromatography analysis of stem peptides released after treatment of purified peptidoglycan with amidase. Differences in the rate of digestion of purified cell walls, furthermore, did not correlate with susceptibility to autolysis. Lower levels of autolysis in opaque variants, however, was associated with decreased levels of immunodetectable LytA on colony immunoblots and Western blots (immunoblots). Diminished cell-surface-associated LytA in opaque variants was also demonstrated by whole-cell inhibition enzyme linked immunosorbent assay. Since transparent variants have been shown both to colonize the nasopharynx more efficiently in an animal model and to express more surface-exposed LytA, it was determined whether LytA contributes to colonization in a neonatal rat model of pneumococcal carriage. Defined mutants in the lytA gene were used to show that there was no significant contribution by LytA to nasopharyngeal colonization in this model. Although the expression of LytA was shown to undergo phase variation in association with colony morphology, lytA mutants are still capable of phenotypic variation in colony morphology, which suggests that other factors are responsible for intrastrain differences which affect colonization. PMID- 8675335 TI - Molecular characterization of the tia invasion locus from enterotoxigenic Escherichia coli. AB - Enterotoxigenic Escherichia coli (ETEC) shares with other diarrheal pathogens the capacity to invade epithelial cell lines originating from the human ileum or colon, although the role of invasion in ETEC pathogenesis remains undefined. Two distinct loci (tia and tib) that direct noninvasive E. coli to adhere to and invade intestinal epithelial cell lines have previously been isolated from cosmid libraries of the classical ETEC strain H10407. Here, we report the molecular characterization of the tia locus. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of cellular fractions of E. coli DH5alpha carrying the tia-positive cosmids and recombinant plasmid subclones revealed that this locus directs the production of a 25-kDa protein (the Tia protein) that is localized to the outer membrane. The tia locus was subcloned to a maximum of 2 kb and mutagenized with bacteriophage Mud. Synthesis of this protein was directly correlated with the ability of subclones and Mud transposon mutants to adhere to and invade epithelial cells. Sequencing of the tia locus identified a 756-bp open reading frame. All transposon insertions resulting in an invasion-negative phenotype mapped to this open reading frame. The open reading frame was amplified and directionally cloned behind the lac promoter of pHG165. This construct directed DHalpha to express a 25-kDa protein and to adhere to and invade epithelial cells. The role of the tia gene in directing epithelial adherence and invasion was further assessed by the construction of chromosomal tia deletion derivatives of the parent ETEC strain, H10407. These tia deletion strains were noninvasive and lacked the ability to adhere to human ileocecal cells. The tia gene shares limited homology with the Yersinia ail locus and significant homology with the hra1 agglutinin gene cloned from a porcine ETEC strain. Additionally, tia probes hybridized to geographically diverse ETEC strains, as well as some enteropathogenic E. coli, enteroaggregative E. coli, and Shigella sonnei strains. PMID- 8675334 TI - Alterations in Vibrio cholerae motility phenotypes correlate with changes in virulence factor expression. AB - Motility is thought to contribute to the virulence of Vibrio cholerae, but the role it plays in pathogenesis is not completely understood. To investigate the influence of motility on virulence gene expression and intestinal colonization, we have isolated mutants with altered swarming abilities in soft agar medium. Both spontaneous hyperswarmer (exhibiting faster swarm rates) and spontaneous or transposon-induced nonmotile mutants of strain 0395 were obtained. Surprisingly, we found that two of three classes of hyperswarmer mutants were defective in autoagglutination, a phenotype associated with expression of toxin-coregulated pili (TCP), an essential ToxR-regulated colonization factor of V. cholerae. In contrast, nonmotile mutants exhibited autoagglutination under growth conditions that normally repress this phenotype. Further characterization of mutant strains revealed differences in the expression of other virulence determinants. Class I hyperswarmer mutants were defective in production of TCP, cholera toxin, and a cell-associated hemolysin but showed increased levels of protease and fucose sensitive hemagglutinin. All nonmotile mutants examined, including those with insertions in a sequence homologous to motB, exhibited increased expression of TCP pilin, cholera toxin, and cell-associated hemolysin but dramatically decreased levels of fucose-sensitive hemagglutinin and HEp-2 adhesins. In general, nonmotile mutants displayed few or no defects in intestinal colonization, while class I hypermotile mutants were highly defective in colonization. These results suggest that the motility phenotype of V. cholerae is tightly coupled to the expression of multiple ToxR-regulated and non-ToxR regulated virulence determinants. PMID- 8675336 TI - A new fimbrial antigen harbored by CAZ-5/SHV-4-producing Klebsiella pneumoniae strains involved in nosocomial infections. AB - We purified and characterized a new fimbria termed KPF-28 (Klebsiella pneumoniae fimbria with a fimbrin molecular mass of 28 kDa) involved in K. pneumoniae adherence to the human carcinoma cell line Caco-2. Electron microscopy of bacterial surface protein preparations and immunogold labeling of bacterial cells showed that KPF-28 was a long, thin, and flexible fimbria about 4 to 5 nm in diameter and 0.5 to 2 microm long. The N-terminal amino acid sequence of the KPF 28 major fimbrial subunit showed no homology with type 1 and type 3 pili of K. pneumoniae but showed 61.7% identity with residues 6 to 19 of the N-terminal amino acid sequence of PapA, the Pap major pilus subunit expressed by uropathogenic Escherichia coli strains. Total amino acid content determination showed that the KPF-28 major subunit composition was close to that of the GVVPQ fimbrial family major subunits expressed by pathogenic E. coli strains. The study of the prevalence of KPF-28 among K. pneumoniae strains involved in nosocomial infections revealed that KPF-28 was found in the great majority of the K. pneumoniae strains producing the CAZ-5/SHV-4 extended-spectrum beta-lactamase. As shown by curing and mating experiments, the R plasmid encoding the CAZ-5/SHV-4 enzyme was found to be involved in but not solely responsible for KPF-28 expression. Hybridization experiments using an oligonucleotide probe corresponding to the N-terminal part of the 28-kDa protein revealed that the structural gene encoding the KPF-28 major subunit was localized on this R plasmid. KPF-28 is a putative colonization factor of the human gut, since the ceftazidine-sensitive derivative strain CF914-1C no longer adhered and since the Fab fragments of antibodies raised against KPF-28 inhibited adhesion of K. pneumoniae CF914-1 to the Caco-2 cell line. PMID- 8675337 TI - Immunogenicity and protection studies with recombinant mycobacteria and vaccinia vectors coexpressing the 18-kilodalton protein of Mycobacterium leprae. AB - The activation of antigen-specific T lymphocytes is essential for the control of leprosy infection in humans and experimental animals. T cells recognize a variety of protein antigens from Mycobacterium leprae, including the 18-kDa protein, which is limited in distribution among mycobacteria and which is absent from Mycobacterium tuberculosis and the vaccine strain, Mycobacterium bovis BCG. Adjuvant preparations of mycobacterial protein antigens have had limited protective efficacy for experimental infections in animals. Since recombinant vectors may elicit more effective T-cell responses than adjuvant preparations, recombinant vaccinia virus (VV18) and M. bovis BCG (BCG18) vectors expressing the 18-kDa protein of M. leprae were prepared. Both VV18 and BCG18 stimulated anti-18 kDa protein antibody and lymphocyte proliferative responses. Sequential immunization with VV18 followed by BCG18 induced higher levels of specific immunoglobulin G2a antibodies than immunoglobulin G1 antibodies, in contrast to immunization with VV18 or BCG18 alone. The protective efficacy of immunization with VV18 from a challenge with BCG18 was examined in two murine models of mycobacterial infection. After intravenous challenge, mice immunized with recombinant vaccinia virus exhibited lower initial levels of replication and earlier clearance of BCG18 from their spleens than mice immunized with vaccinia virus expressing an unrelated protein. After footpad infection in a dissemination model, there was earlier clearance of BCG18 from specifically immunized mice. However, immunization of mice with VV18 did not prevent a productive mycobacterial infection. PMID- 8675338 TI - Hemin-induced modifications of the antigenicity and hemin-binding capacity of Porphyromonas gingivalis lipopolysaccharide. AB - Previous studies have shown that the physical, biochemical, and antigenic properties of the bacterial outer membrane are profoundly influenced by the growth environment. In the present study, the effects of growth in hemin-replete (H+) and hemin-depleted (H-) media on the lipopolysaccharide (LPS) of the oral pathogen Porphyromonas gingivalis were investigated. Our studies show that LPS from P. gingivalis cultured in H+ media (H+LPS) expressed additional low molecular-mass antigens, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot (immunoblot) analysis. Particularly evident was a 26-kDa antigen (26 LPSC) that was lost from the LPS upon transfer of P. gingivalis into H- media. The loss of the 26 LPSC was accompanied by a marked reduction in the hemin-binding capacity of the LPS. The 26 LPSC was refractory to Coomassie blue staining and proteinase K digestion. H+LPS from strain W50/BE1, a nonpigmented pleiotropic strain, lacked the 26 LPSC and did not bind hemin. Polyclonal antiserum raised to whole-cell antigens of P. gingivalis A7436, W83, and HG405 grown in H+ media, but not in H- media, recognized the 26 LPSC in the purified H+LPS from any of the three strains. The immunoreactivities of sera from humans with (n = 24) or without (n = 25) periodontitis to the 26 LPSC and other H+LPS determinants were analyzed by Western blot. Overall, 75% of adult periodontitis patient sera reacted with multiple bands in the H+LPS stepladder, particularly in the range of 14 to 27 kDa. In contrast, only 20% of control sera reacted faintly with H+LPS bands in the range 27 to 34 kDa. The 26 LPSC was recognized by over 40% of sera from adult patients with periodontitis and none of the healthy control sera. Taken together, these results suggest that the antigenicity and hemin-binding properties of P. gingivalis LPS can be modified by growth in H+ media. PMID- 8675339 TI - Relationship between cytotoxicity and corneal epithelial cell invasion by clinical isolates of Pseudomonas aeruginosa. AB - We have reported that some strains of Pseudomonas aeruginosa can enter corneal epithelial cells during experimental murine eye infection and when the cells are cultured in vitro. Following invasion, both the host cell and the intracellular bacteria can remain viable for up to 24 h. Others have reported that toxin mediated damage of epithelial cells contributes to the pathogenesis of P. aeruginosa keratitis. To clarify the relationship between cell invasion and cytotoxicity, fourteen P. aeruginosa isolates were compared for their capacity to enter epithelial cells and for their ability to induce cytotoxicity. Bacterial invasion was quantified by gentamicin survival assays both in vivo and in vitro. Cytotoxicity was examined qualitatively by trypan blue exclusion assays and quantitatively by chromium release assays in vitro. A significant inverse correlation was found between the ability to induce cytotoxicity and epithelial cell invasion as measured by gentamicin survival assays. Both cytotoxic and noncytotoxic strains were identified among corneal and noncorneal isolates; all isolates that were not cytotoxic were capable of epithelial cell invasion. Efficient host cell invasion could not be demonstrated for cytotoxic strains; however, the gentamicin survival assay relies upon host cells retaining viability in order to yield useful results, and this may limit the effectiveness of this assay for testing epithelial cell invasion by cytotoxic strains. Since all of the corneal isolates that were tested were virulent in vivo, the results show that there are at least two different types of P. aeruginosa-induced disease, one caused by strains that are cytotoxic and the other involving bacteria that can enter epithelial cells and survive intracellularly without killing the host cell. PMID- 8675340 TI - Infection of cesarean-derived colostrum-deprived 1-day-old piglets with Arcobacter butzleri, Arcobacter cryaerophilus, and Arcobacter skirrowii. AB - Neonatal piglets have been used as models to study human campylobacteriosis and helicobacteriosis. The purpose of this study was to determine the relative pathogenicities, on the basis of the duration of fecal shedding and colonization of tissues, of three Arcobacter species in 1-day-old cesarean-derived colostrum deprived piglets. Two experiments were conducted. In experiment 1, two piglets each were infected per os with either Arcobacter butzleri ATCC 49616, Arcobacter cryaerophilus 1B ATCC 43159, Arcobacter skirrowii CCUG 10374, or the three field strains of A. butzleri (approximately 5 X 10(9) CFU per piglet). Rectal swab samples were taken prior to infection and daily thereafter for up to 7 days. Arcobacter spp. were detected at least once in rectal swab samples of all but one of the experimentally infected piglets but not in the control. At necropsy, A. butzleri was recovered from the lung, kidney, ileum, or brain tissues of the four infected piglets which had received either the field strain or the ATCC type strain of A. butzleri. A. cryaerophilus 1B was detected in rectal swab samples for up to 7 days postinfection but was not cultured from tissues at necropsy. Arcobacters were detected in the rectal swab sample of the A. skirrowii-infected piglet only on day 3 postinfection; no isolates were obtained from tissues at necropsy. No gross pathological lesions were consistently noted in the experimentally infected piglets. In experiment 2, two piglets each were infected per os with A. butzleri ATCC 49616, A. cryaerophilus 1A ATCC 43158, A. skirrowii CCUG 10374, or the single A. butzleri field strain Yard J/c (approximately 5 X 10(9) CFU per piglet). Arcobacter spp. were cultured from rectal swab samples of all but one of the experimentally infected piglets at least once. At necropsy Arcobacter spp. were cultured from the liver, kidney, ileum, or brain tissues of two of the four A. butzleri-infected piglets. However, no severe gross pathology was noted. These data suggest that Arcobacter spp., especially A. butzleri, can colonize neonatal pigs. PMID- 8675341 TI - A model of genital Chlamydia trachomatis infection using human xenografts in severe combined immunodeficiency mice. AB - We developed a new model of human genital Chlamydia trachomatis infection in order to characterize the pathogen-host relationship in a clinically relevant system using a human strain of C. trachomatis instead of the commonly employed mouse biovar (MoPn). Human endometrial tissue was xenografted into the skin of mice homozygous for the mutation severe combined immunodeficiency and inoculated with C. trachomatis serovar K. C. trachomatis efficiently infected the endometrium as shown by cell culture and immunofluorescence microscopy and persisted for more than 6 weeks. Chlamydial inclusions detected by direct immunofluorescence and electron microscopy appeared to be smaller than those produced by in vitro cell culture-grown chlamydiae. A pattern of localized mild infection prevailed, and infiltrative uncontrolled spread of chlamydiae was observed in only 1 of 10 infected grafts. This might correspond to the well-known tendency of the agent to cause asymptomatic infections. This model allows the study of a human genital infection resembling the clinical situation and offers the possibility to better characterize the host-parasite relationship with respect to pathogenicity and therapy. PMID- 8675342 TI - Contribution of YopB to virulence of Yersinia enterocolitica. AB - The 70-kb virulence plasmid, pYV, of Yersinia enterocolitica encodes a number of secreted proteins (Yops) which are essential for virulence. YopD, the 33-kDa product of the lcrGVHyopBD operon, appears to be involved in delivering YopE and YopH (the Yersinia protein tyrosine phosphatase) into target cells. These proteins then act in concert to cause cytotoxicity in host cells. Previously, we reported that bacteria carrying transposon insertions in yopD are not cytotoxic for macrophages, show impaired tyrosine phosphatase activity in host cells, and are avirulent for mice (E. L. Hartland, S. P. Green, W. A. Phillips, and R. M. Robins-Browne, Infect. Immun. 62:4445-4453, 1994). trans complementation of yopD mutants of Y. enterocolitica with the yopD gene restores all these properties. In this study, we show that polar mutations in proximal genes of the lcrGVHyopBD operon also abrogated bacterial virulence and the capacity to induce cytotoxicity in mouse bone marrow-derived macrophages and HEp-2 epithelial cells. Moreover, trans complementation of a yopBD mutant with the yopD gene alone was not sufficient to restore the ability of the bacteria to cause cytotoxicity. Further work showed that YopB was required for cytotoxicity, dephosphorylation of host proteins, and virulence for mice. These findings indicate that YopB and YopD may serve a related function in Y. enterocolitica and that they may act together to deliver intracellularly acting Yops to their respective targets in host cells. PMID- 8675343 TI - Experimental genital mycoplasmosis: time of infection influences pregnancy outcome. AB - Genital infection of rats with Mycoplasma pulmonis causes adverse pregnancy outcome and can result in in utero spread of infection to the fetus. The current study was designed to determine whether the stage of pregnancy when infection occurs influences pregnancy outcome. Rats were inoculated with 3 X 10(7) CFU of M. pulmonis at 10 days prior to breeding (-10) or at gestational day (gd) 11 or 14 and were necropsied at gd 11, 14, or 18 or within 24 h of parturition (term). Control rats received sterile broth. M. pulmonis was isolated from the placenta, amniotic fluid, or fetal tissues only from rats infected prior to breeding (P < 0.001). All infected rats had significantly more loss of pups than did control rats (P < 0.006), but rats infected prior to breeding or at the beginning of the third trimester (gd 14) were much more likely to have fetal losses. Rats infected in the early second trimester after implantation (gd 11) did not experience severe losses. Litter sizes, total litter weight, and individual pup weight from all infected rats, regardless of gestational stage when infected, were significantly smaller than those of control rats (P < 0.001). On the basis of the results of this study, we conclude that the time of infection plays a major role in determination of pregnancy outcome and spread of infection from the genital tract to the respiratory tract. PMID- 8675345 TI - Changes in Helicobacter pylori ultrastructure and antigens during conversion from the bacillary to the coccoid form. AB - In vitro, Helicobacter pylori converts from a bacillary to a full coccoid form via an intermediate U-shaped form. Organisms with a full coccoid form keep a double membrane system, a polar membrane, and invagination structures. Western blots (immunoblots) of sera from colonized patients show that some high-molecular mass antigenic fractions are expressed only in coccoids. Conversely, fractions of 30 and 94 kDa were more intensively detected in the bacillary forms. These results suggest that (i) coccoid conversion is not a degenerative transformation and (ii) antigens specific to the coccoid forms are expressed in vivo. PMID- 8675344 TI - Molecular cloning and sequence analysis of the gene encoding LipL41, a surface exposed lipoprotein of pathogenic Leptospira species. AB - We report the cloning of the gene encoding a surface-exposed leptospiral lipoprotein, designated LipL41. In a previous study, a 41-kDa protein antigen was identified on the surface of Leptospira kirschneri (D. A. Haake, E. M. Walker, D. R. Blanco, C. A. Bolin, J. N. Miller, and M. A. Lovett, Infect. Immun. 59:1131 1140, 1991). We obtained the N-terminal amino acid sequence of a staphylococcal V8 proteolytic-digest fragment in order to design an oligonucleotide probe.A Lambda ZAP II library containing EcoRI fragments of L. kirschneri DNA was screened, and a 2.3-kb DNA fragment which contained the entire structural lipL41 gene was identified. The deduced amino acid sequence of LipL41 would encode a 355 amino-acid polypeptide with a 19-amino-acid signal peptide, followed by an L-X-Y C lipoprotein signal peptidase cleavage site. A recombinant His6-LipL41 fusion protein was expressed in Escherichia coli in order to generate specific rabbit antiserum. LipL41 is solubilized by Triton X-114 extraction of L. kirschneri; phase separation results in partitioning of LipL41 exclusively into the detergent phase. At least eight proteins, including LipL41 and the other major Triton X-114 detergent phase proteins, are intrinsically labeled during incubation of L. kirschneri in media containing [3H] palmitate. Processing of LipL41 is inhibited by globomycin, a selective inhibitor of lipoprotein signal peptidase. Triton X 100 extracts of L. kirschneri contain immunoprecipitable OmpL1 (porin), LipL41, and another lipoprotein, LipL36. However, in contrast to LipL36, only LipL41 and OmpL1 were exposed on the surface of intact organisms. Immunoblot analysis of a panel of Leptospira species reveals that LipL41 expression is highly conserved among leptospiral pathogens. PMID- 8675346 TI - Influence of opsonization conditions on C3 deposition and phagocyte binding of large- and small-capsule Cryptococcus neoformans cells. AB - Previous studies demonstrated that, following opsonization with normal human serum (NHS), phagocytes bind greater numbers of small-capsule Cryptococcus neoformans cells than yeast cells with large capsules. The present study tested the hypothesis that suboptimal deposition of opsonic C3 fragments contributes to this disparity. C neoformans was grown under conditions promoting large or small capsules and was incubated at various concentrations in NHS. At low concentrations of yeast cells (125 cells per microl of NHS), the deposition of C3 fragments per unit of capsule volume and the binding of yeast cells to cultured human monocytes were similar for yeast cells having large and small capsules. However, at higher cell concentrations, large-capsule cells exhibited suboptimal coating with C3 fragments and markedly diminished monocyte binding compared with small-capsule cells. Thus, the inverse correlation between capsule size and phagocyte binding can be overcome by conditions promoting optimal C3 deposition. PMID- 8675347 TI - Binding of hemoglobin to the envelope of Porphyromonas gingivalis and isolation of the hemoglobin-binding protein. AB - The binding activity of the Porphyromonas gingivalis envelope and hemoglobin was examined over a wide range of pH values from 4.5 to 9.0. The binding activity in low-pH buffers was much higher than that at high pH; the optimum pHs for the binding were found to be 4.5 and 5.0. Since the hemoglobin bound to the envelope was found to dissociate in the pH 8.5 and 9.0 buffers, the binding is reversible. We hypothesized that hemoglobin-binding protein (HbBP), responsible for the binding to hemoglobin, exists in the envelope and confirmed its presence by dot blot determination with peroxidase-conjugated hemoglobin. Then we attempted to isolate HbBP from the solubilized (by a detergent) materials of the envelope by affinity chromatography. The molecular mass of HbBP was 19 kDa, and the isoelectric point was 4.3. PMID- 8675348 TI - The O4 specific antigen moiety of lipopolysaccharide but not the K54 group 2 capsule is important for urovirulence of an extraintestinal isolate of Escherichia coli. AB - Group 2 capsules and lipopolysaccharides are regarded as important virulence factors in extraintestinal isolates of Escherichia coli, but their specific contributions to bladder and renal infections, if any, are unknown. Proven isogenic derivatives deficient in the K54 antigen alone (CP9.137), the O4 antigen alone (CP921), or both the K54 and O4 antigens (CP923) were compared with their wild-type parent (CP9 [O4/K54JH5]) for growth in human urine in vitro and for virulence in vivo in a mouse model of ascending urinary tract infection (UTI). Growth of CP9.137 and CP921 was equivalent to that of CP9 in human urine. CP923 demonstrated a small but reproducible decrease in log-phase growth but achieved the same plateau density. In the mouse model of UTI, the isogenic mutant deficient in the 04 antigen alone (CP921) and, to a greater degree, the derivative deficient in both the K54 and O4 antigens (CP923) were significantly less virulent in nearly all parameters measured. In contrast, the K54 knockout derivative was as virulent as its parent, CP9, in causing bladder infection and nearly as virulent in causing renal infection. These results demonstrate an important role for the O4 antigen moiety of lipopolysaccharide in the pathogenesis of UTI. The possibility that the K54 antigen also plays a minor role cannot be excluded. PMID- 8675349 TI - Haemophilus ducreyi hemolysin acts as a contact cytotoxin and damages human foreskin fibroblasts in cell culture. AB - Haemophilus ducreyi, which causes the sexually transmitted disease chancroid, produces several factors that damage human cells. We used isogenic mutants of H. ducreyi 35000 to demonstrate that the hemolytic activity and the cytotoxic effect of H. ducreyi on human foreskin fibroblasts are due to the same toxin. PMID- 8675350 TI - Comparison of haemophilus influenzae type b interaction with respiratory mucosa organ cultures maintained with an air interface or immersed in medium. AB - Haemophilus influenzae type b infection of immersed and air interface organ cultures for 24 h caused significant epithelial damage. Bacterial association with mucus, damaged epithelium, and unciliated cells was significantly higher in air interface than immersed organ cultures, and total bacterial association was 55.8 times greater. Bacteria exhibited tropism for mucus only on explants maintained with an air interface. We conclude that immersion of nasopharyngeal tissue in medium may influence bacterial interaction with the mucosal surface. PMID- 8675351 TI - Neutralizing monoclonal antibodies against listeriolysin: mapping of epitopes involved in pore formation. AB - Six different mouse monoclonal antibodies (MAbs) and a specific rabbit polygonal antibody were raised against listeriolysin. Four of the MAbs also recognized seeligeriolysin, and five cross-reacted with ivanolysin. The hemolytic activity could be neutralized by the polygonal antibody as well as by five of the MAbs. None of the neutralizing antibodies interfered with the binding of listeriolysin to the cellular membrane. The epitopes recognized by the MAbs were localized by using overlapping synthetic peptides between positions 59 and 279, a region hitherto not implicated in mediating hemolytic activity. PMID- 8675352 TI - Listeriolysin O activates mitogen-activated protein kinase in eucaryotic cells. AB - Infection with Listeria monocytogenes induces the activation of mitogen-activated protein (MAP) kinase in several tissue culture cell lines (P.Tang, I. Rosenshine, and B. B. Finlay, Mol. Biol. Cell 5:455-464, 1994). After various mutants were examined, the bacterial factor responsible for MAP kinase activation was identified as listeriolysin O (LLO). Growth supernatant containing LLO or purified LLO alone can induce MAP kinase tyrosine phosphorylation in HeLa cells. Single-amino-acid mutations in LLO that do not affect its membrane binding capacity but reduce its cytolytic activity also reduced its ability to induce MAP kinase activity in HeLa cells. Streptolysin O, another sulfhydryl-activated hemolysin, and the detergent saponin are also able to activate MAP kinase in target cells. Thus, the increased MAP kinase activity observed in L. monocytogenes-infected cells is most likely a result of the permeabilization of the host cell membrane by LLO and may not be linked with invasion. PMID- 8675353 TI - New evidence for an inflammatory component in diarrhea caused by selected new, live attenuated cholera vaccines and by El Tor and Q139 Vibrio cholerae. AB - Using a lactoferrin latex agglutination assay, we have compared the inflammatory responses to a cholera vaccine candidate, CVD 110, in which all known toxin genes have been deleted or mutated yet still produced significant diarrhea, with a less reactive vaccine strain and wild-type El Tor and 0139 Vibrio cholerae strains. Data suggest that diarrhea due to attenuated and wild-type El Tor V. cholerae, and to a lesser extent 0139 V. cholerae, involves an inflammatory response. Further study is required to further elucidate the mechanism of the process(es) involved. PMID- 8675355 TI - Phosphorylation of myosin light chain at distinct sites and its association with the cytoskeleton during enteropathogenic Escherichia coli infection. AB - Myosin light chain, the most prominent host cell phosphoprotein during adhesion of enteropathogenic Escherichia coli to cultured HEp-2 cells, was shown to be distributed between cytosolic and cytoskeletal cell fractions; its association with the cytoskeletal fraction increased with time of enteropathogenic E. coli incubation. Phosphopeptide mapping indicated cytosolic and cytoskeletal myosin light chain phosphorylation at different sites by protein kinase C and myosin light chain kinase. PMID- 8675354 TI - The predicted amino acid sequence of the Salmonella typhimurium virulence gene mviAA(+) strongly indicates that MviA is a regulator protein of a previously unknown S. typhimurium response regulator family. AB - The Salmonella typhimurium virulence gene mviA+ has a predicted amino acid sequence with homology to the N-terminal 112-amino-acid sequence of response regulator proteins. A previously described mutant allele (mviA), which restores virulence to avirulent LT2 strains, was shown to contain a point mutation which would be predicted to cause a single amino acid change, V-102-->G (W. H. Benjamin, Jr., J. Yother, P. Hall, and D. E. Briles, J. Exp. Med. 1,74:1073-1083, 1991). A comparison of the nucleotide sequence of mviA+ with that of the Escherichia coli and Salmonella typhi genes revealed a high degree of conservation. PMID- 8675356 TI - Acute renal failure and membranes. Some medical and ethical questions. PMID- 8675357 TI - Low dose megestrol increases serum albumin in malnourished dialysis patients. AB - To evaluate the efficacy of low dose megestrol on malnourished dialysis patients we treated 16 dialysis patients with persistent hypoalbuminemia ( < 3.5 gm/dl for 2 consecutive months) and adequate dialysis at a dose of 20 mg orally twice daily. Twelve patients on peritoneal dialysis and 4 on hemodialysis were followed for 4.3 +/- 0.6 m (2-11 m). Within one month serum albumin rose from 2.7 +/- 0.1 to 3.0 +/- 0.2 gm/dl (p < 0.05) and remained elevated at the end of follow-up (3.1 +/- 0.2, p < 0.05 vs. pre-treatment levels). In the 12 responders (increase of albumin > 0.3 gm/dl), all of whom reported improved appetite, the maximal increase of serum albumin in 2 months was 0.8 +/- 0.1 gm/dl (range: 0.3-1.2). Four patients did not respond (change of albumin: -0.05 +/- 0.18, range: -0.6 0.2) because of encephalopathy, amyloidosis, depression or noncompliance. One patient stopped megestrol because of vaginal bleeding from uterine leiomyoma. Three patients died from causes unrelated to the megestrol. Our preliminary study suggests that low dose megestrol (40 mg per day) increases serum albumin levels in 75% of dialysis patients with malnutrition. It is well tolerated but may cause vaginal bleeding from uterine tumors. PMID- 8675358 TI - Estimated versus predicted creatinine generation as an indicator of compliance with the prescribed dose of continuous peritoneal dialysis. AB - The expression (Estimated-Predicted)/Predicted creatinine generation ?(E-P)/P? has been proposed as an index of compliance in continuous peritoneal dialysis (CPD). We attempted to define an (E-P)/P value that can be used as a cut-off for non-compliance and to characterize the relation of (E-P)/P to serum albumin. In 324 clearance studies, (E-P)/P had a normal distribution with a mean of +0.094 and an SD of 0.357. In these studies, there was a weak correlation between (E P)/P and serum albumin (r = 0.12, P < 0.05), but (E-P)/P was not a predictor of serum albumin by logistic regression. In 34 CPD patients, who had an increase in the dose of CPD resulting in an increase in measured creatinine clearance from 43.8 +/- 14.0 to 66.1 +/- 17.6 L/1.73 m2 weekly (P < 0.001), (E-P)/P increased correspondingly from +0.018 +/- 0.284 to +0.153 +/- 0.369 (P = 0.018), although all subjects should be in a steady state of creatinine excretion in the second study. The rise in (E-P)/P was statistically significant in the subgroup of 17 subjects who had a decrease in serum albumin, but not in the subgroup of 14 subjects who had an increase in serum albumin from the first to the second clearance study. The (E-P)/P cut-off for a definitive diagnosis of CPD non compliance may be around +0.400 or +0.500. The findings of this study suggest that non-compliance, as indicated by (E-P)/P, has an adverse effect on serum albumin and that non-compliance increases after a prescribed increase in the dose of CPD. PMID- 8675359 TI - Modulation of CD11b/CD18 on monocytes and granulocytes following hemodialysis membrane interaction in vitro. AB - We studied the generation of CD11b/CD18 mobilizing factors in serum after incubation with dialysis membrane fragments of different chemical composition. We also evaluated the relative importance of the alternative and classical pathways of the complement system in the generation of such factors. Monocytes and granulocytes from healthy blood donors were incubated in normal human serum (NHS) and in NHS that had been preincubated with Cuprophan (CU) membrane (NHS-CU), Hemophan (HE) (NHS-HE) or polysulfone (PS) (NHS-PS). NHS-CU caused the highest up regulation of the CD11b/CD18 receptor on monocytes and granulocytes. The rank in capacity to mobilize CD11b/CD18 on granulocytes was CU > HE > PS (p < 0.001), CU > HE (p < 0.05) and HE > PS (p < 0.001). The rank in capacity to mobilize CD11b/CD18 on monocytes was CU > HE > PS (p < 0.001), CU > HE (p < 0.05) and HE > PS (p < 0.01). NHS-PS induced a lower up-regulation of CD11b/CD18 compared to NHS which indicates that serum factors with the ability to mobilize the CD11b/CD18 receptor on monocytes and granulocytes are deposited on or absorbed by PS. In order to study the relative contribution of the alternative and classical pathways of the complement system in the generation of CD11b/CD18 mobilizing factors in serum, three different serum preparations (1. both pathways intact. 2. only the alternative intact and 3. only the classical pathway intact) were used. The CU membrane activated the classical pathway to a larger extent than the PS membrane (p < 0.01). When only the alternative pathway was intact no difference in the generation of CD11b/CD18 mobilizing factors between the CU and PS membranes was observed. These studies show that CD11b/CD18 mobilizing serum factors are generated after incubation with CU membranes and that such factors are probably adsorbed by PS. The classical pathway of complement activation seems to contribute to the generation of CD11b/CD18 mobilizing factors in serum. PMID- 8675360 TI - Prerenal azotemia: differentiation of hyperureagenesis from renal hypoperfusion using urinary urea nitrogen data. AB - Blood urea nitrogen (BUN) rises disproportionately to serum creatinine in patients with prerenal azotemia whether due to impaired hemodynamics or excessive ureagenesis. To determine whether urinary urea nitrogen excretion rates can distinguish between these caused of hyperuremia we performed a cross-sectional observational study to compare urinary urea nitrogen excretion rates in a highly selected group of patients with prerenal azotemia. Patients who had stable serum creatinine levels, BUN: serum creatinine ratios exceeding 20:1, and progressive azotemia were identified from the hospital laboratory data base. Using conventional clinicolaboratory criteria, 27 patients were diagnosed with either renal hypoperfusion (group I; n = 17) or hyperureagenesis ((group II; n = 10). Random urine sampling for electrolytes, osmolality, creatinine, and urea nitrogen was followed by 24 h collection for creatinine clearance and urinary urea nitrogen. There were no significant differences in age, gender, absolute levels of BUN, or BUN: serum creatinine ratios between the groups. Creatinine clearance (ml/min/1.73 m2) (ml/s/1.73 m2) was lower in group I than in group II (21 +/- 16 vs 36 +/- 13; p < 0.05) (0.35 +/- 0.27 vs 0.60 +/- 0.22; p < 0.05). Twenty-four hour urinary urea nitrogen levels were significantly different (group I, 4.8 +/- 2.9 vs. group II, 13.6 +/- 3.2 gm; p < 0.001) (group I, 171 +/- 300 vs. group II, 486 +/- 114 mmol; p < 0.001). Random urine urea excretion indices were less discriminating but nevertheless still capable of separating the groups. Timed as well as random urine urea nitrogen determinations may assist in differentiating prerenal azotemia due to renal hypoperfusion from hyperureagenesis. Differentiation of these causes of prerenal azotemia might prevent iatrogenic overhydration of patients with azotemia incorrectly attributed to hemodynamic disturbances. PMID- 8675362 TI - Small pore size microporous membrane oxygenator reduces plasma leakage during prolonged extracorporeal circulation: a case report. AB - Plasma leakage has been regarded as the main technical problem during prolonged extracorporeal circulation (ECC) with microporous membrane oxygenators (MMOs). We report the case of a 15 year old male who underwent long term ECC for ARDS and in whom, by using new MMOs with reduced pore size, we were able to achieve prolonged artificial gas exchange efficiency with minimal plasma leakage. We conclude that reduced pore size MMOs might represent a valuable technical advance in extracorporeal oxygenation therapy. PMID- 8675363 TI - Variation in artificial heart acceleration and sound production with prosthetic valve selection in vitro. AB - In an attempt to explore methods to reduce total artificial heart (TAH) acceleration and sound production, in vitro measurements of TAH acceleration and sound were made when using a variety of prosthetic valves in a test ventricle. A miniature, uniaxial, high fidelity accelerometer was glued to the housing of a UTAH-100 left ventricle adjacent to the inflow and outflow ports and parallel to the axis of diaphragm excursion. A miniature, high fidelity contact microphone was glued to the opposite side of the ventricular housing between the inflow and outflow ports. Data was collected over a range of heart rates, ventricular filling volumes and control modes while using tilting disc valves (TDV) and polymer trileaflet valves (PTV). For both valve types, the peak systolic acceleration impulse was lower (approximately equal to 50%) when the ventricle was fully rather than partially filled and the peak diastolic acceleration impulse was lower (approximately equal to 50%) when the ventricle was fully rather than partially ejected. The magnitude of the acceleration with PTVs was approximately equal to 20x less than the TDVs (0.5 to 2.2 g vs. 10 to 49g). The magnitude of the sound production was also considerably less with the PTVs (28 to 49 db vs. 50 to 64 db). Diastolic acceleration and sound production was approximately twice the systolic value for the TDVs; the reserse was true for PTV sound production. These data demonstrate the substantial reduction in TAH impulse acceleration and sound production by selecting PTVs over TDSs. With PTVs, the TAH impulse acceleration is the same as the natural heart. Consequently, this ability to lower TAH acceleration and sound production to the level of the natural heart may lead to a reduction in component wear, patient discomfort and other undesirable consequences of TAH implantation. PMID- 8675361 TI - Design of a physiologic pulsatile flow cardiopulmonary bypass system for neonates and infants. AB - Cardiopulmonary bypass surgical techniques that allow a surgeon to operate on the infant's heart use an extracorporeal circuit consisting of a pump, oxygenator, arterial and venous reservoirs, cannulae, an arterial filter, and tubing. The extracorporeal technique currently used in infants and neonates is sometimes associated with neurologic damage. We are developing a modified cardiopulmonary bypass system for neonates that has been tested in vitro and in one animal in vivo. Unlike other extracorporeal circuits which use steady flow, this system utilizes pulsatile flow, a low prime volume (500 ml) and a closed circuit. During in vitro experiments, the pseudo patient's mean arterial pressure was kept constant at 40 mmHg and the extracorporeal circuit pressure did not exceed a mean pressure of 200 mmHg. In our single in vivo experiment, the primary objective was to determine whether physiologic pulsatility with a 10 F (3.3 mm) aortic cannula could be achieved. The results suggest that this is possible. PMID- 8675364 TI - A new automatic cardiac output control algorithm for moving actuator total artificial heart by motor current waveform analysis. AB - A new automatic cardiac output control algorithm for an implantable electromechanical total artificial heart (TAH) was developed based on the analysis of motor current waveform without using any transducer. The basic control requirements of an artificial heart can be described in terms of three features: preload sensitivity, afterload insensitivity, and balanced ventricular output. In previous studies, transducers were used to acquire information on the hemodynamic states for automatic cardiac output control. However, such a control system has reliability problems with the sensors. We proposed a novel sensorless automatic cardiac output control algorithm (ACOCA) providing adequate cardiac output to the time-varying physiological demand without causing right atrial collapse, which is one of the critical problems in an active filling device. In vitro tests were performed on a mock circulatory system to assess the performance of the developed algorithm and the results show that the new algorithm satisfied the basic control requirements of the cardiac output response. PMID- 8675365 TI - Peripheral nerve and muscle function in the aging Fischer 344/brown-Norway rat. AB - This study was designed to define the age-related changes that occur in the F1 cross of the male Fischer 344 and brown Norway rats and to determine if these findings were associated with electrophysiologic abnormalities indicative of motor neuron loss. Contractility, morphologic, and histochemical studies were performed on the tibialis anterior muscles (TA) from 25 male rats at ages 6, 18 and 30-32 months. Tibialis anterior weight was 17% greater in the 18-mo vs 6-mo old animals, but at age 32 months mean TA weight was 20% less than at 18 months. Other changes at 32 months included a 12% decrease in specific tension and reduced contractile/relaxation velocities of isometric twitches and maximal tetanic tension; findings associated with a 40% decrease in type IIb fiber cross sectional area. Electrophysiologic studies on 15 rats revealed prolonged H-reflex latencies at 18 and 32 months. Needle electromyography demonstrated abnormal spontaneous activity consistent with peripheral axonal, not motor neuron loss. These findings demonstrate age-related changes in muscle mass and strength that are associated with changes in the peripheral nervous system. These findings are consistent with previous work in homozygous, inbred strains and help to establish the F1 cross of the Fischer 344 and brown Norway strains as a potentially useful rodent model in gerontologic studies of the neuromuscular system. PMID- 8675367 TI - Comparative embryonic development in chickens with different patterns of postnatal growth. AB - We compared embryonic development of two lines of chickens that exhibit different patterns of postnatal growth. Classical staging techniques and morphological measurements of bone, cartilage, feather and intestines were used to test the hypothesis that differences in postnatal growth would be reflected in patterns of embryonic tissue partitioning. During the second quarter of incubation, the line with higher postnatal growth staged significantly earlier (i.e., was less developed overall) than the line with lower postnatal growth. Embryos from the line with higher postnatal growth exhibited less (i.e., allocated away from), bone growth (beak length, ossification of long bones), feather growth (number of feather papillae, length of primary), and eye development (number of lens sclera). There were no differences in gut development between the two lines. Our results show that different postnatal growth patterns are associated with changes in the pattern of embryonic reallocation between tissue types, even when gross morphological differences are not evident at hatching. We suggest that these differences in development represent periods when the embryo is allocating to hyperplastic growth of tissues such as muscle, as a means of increasing posthatching growth potential. PMID- 8675366 TI - Effects of bovine growth hormone analogs on mouse skeletal muscle structure. AB - Skeletal muscles of transgenic mice expressing altered bovine growth hormones (bGH) have been compared with those of nontransgenic mice to determine whether muscle fiber type-specific responses or histopathologies are associated with the altered gene. The slow soleus and predominantly fast gastrocnemius muscles were prepared for myofibrillar ATPase activity (to determine muscle fiber type) and histological examination from mice that were either giant (M4 line), larger than normal (M11 line), dwarf (G119K line), or nontransgenic (NTC). No histopathology was observed in any of the muscles. Although body weights were significantly different between all four lines of mice, only the giant M4 mice had significantly larger muscle fibers than the other lines of mice, while neither the G119K nor M11 lines were significantly different from the NTC for either muscle. No fiber type-specific differences were noted. These results suggest that the different muscles are the product of differences in numbers of muscle fibers expressed in the G119K and M11 lines of mice; the increase in body mass matched the fiber size growth only in the giant M4 line. Therefore, the altered bGH genes may be acting on fetal liver and myoblast/myotube GH receptors to change the GH and IGF-I regulated pattern of muscle development, and eventually, to determine the adult muscle fiber numbers. PMID- 8675368 TI - Thymic weight changes and endocrine relationships during maturation in cattle: effects of age, sex, and castration. AB - Elucidation of cause and effect relationships between gonadal and thymic function can be particularly challenging due to the complexity of interactions among various hormones on thymic function, many of which are largely unknown. To monitor gonadal-thymic interaction with the endocrine changes associated with maturity, bulls, steers, heifers, and ovariectomized heifers were slaughtered at 4, 6, 10, 12, or 14 months of age (n = 5-7/sex/age). Steers and ovariectomized heifers were castrated before 1 week of age. Thymic weights were increased in castrated animals as early as 4 months of age (p < 0.01), and differences were more pronounced in males. Thymic secretory peptide, thymosin beta4, increased up to six months of age in all groups (p < 0.05) and then decreased with age, similar to the pattern of growth hormone. Prepuberal testosterone concentrations increased to 10-12 months of age and then decreased in both bulls and heifers (p < 0.05), coordinate with decreases of thymosin beta4 at 10 months of age. Growth hormone concentrations increased up to 6 months of age in all groups (p < 0.01) and then declined. Concentrations of prolactin peaked at 10 months of age (p < 0.01) but were not different between groups. Relationships of luteinizing hormone (LH) were highly related to thymosin beta4 changes in heifers during maturation. Changes of thymosin beta4 and LH were coordinate in ovary-intact heifers and inversely related in ovariectomized heifers. Gonadal effects on thymic weight were evident as early as 4 months of age, and no abrupt declines in thymic weight were detected at puberty. PMID- 8675370 TI - Allele capture by selection for flanking markers: a new method for analyzing multigenic traits. PMID- 8675369 TI - Posthatching growth and pectoralis muscle development in broiler strain chickens, bantam chickens and the reciprocal crosses between them. AB - Body weight, pectoralis muscle weight, pectoralis protein and DNA concentration, and plasma GH and IGF-I concentrations of broiler chicks (BrBr), bantam chicks (BaBa) and reciprocal crosses between them (BaBr and BrBa) were measured between 0 and 42 days after hatching. At hatch, body weight and pectoralis weight of the two types of chicks from broiler eggs (BrBr and BaBr) were equal to each other but greater than the two types of chicks from bantam eggs (BaBa and BrBa), which were not different from each other. BrBr chicks grew more rapidly than crossbreds and BaBa chicks grew more slowly. Weights of the reciprocal crosses (BaBr and BrBa) were markedly different at day of age, but converged by day 14. The increase in pectoralis muscle mass of BrBr chicks exceeded that of the reciprocal crosses which in turn exceeded that of BaBa chicks. The increase in pectoralis DNA content and protein content followed the same pattern. The DNA unit size, as expressed by the protein:DNA ratio, was markedly lower in pure bantam chicks from 14 to 42 days of ages, whereas the unit size did not differ between the intermediate sized reciprocal crosses and the large bodied broiler chicks. Differences in muscle mass were primarily achieved by differences in the number of DNA units although a difference in unit size was also a factor. There were no clear relationships between growth and plasma growth hormone or insulin-like growth factor I concentrations. Thus while satellite cell proliferation is primarily responsible for genotypic differences in muscle mass, the plasma growth hormone-IGF-I axis does not appear to be regulating their proliferation. PMID- 8675371 TI - Lines of mice selected for reproductive longevity. AB - Two lines of mice selected for reproductive longevity were compared with one unselected control line to examine longevity and lifetime performance such as number of parturitions during lifetime. Mice were pair mated at about 8 weeks of age and cohabited throughout life. Litter size was reduced to eight at birth in selected line 121 and unselected control line 221, but not in selected line 141. At generation 16, the average number of days from mating to the last parturition was 240.8, 243.0 and 134.6 for lines 121, 141 and 221, respectively. Selected lines 121 and 141 had 80% and 93%, respectively, greater number of parturitions during their lifetimes than the control line. Mean litter size at the early stage of reproduction was similar in the selected and control lines, but persistency of reproduction differed markedly. The average number of young born alive per breeding pair during a lifetime was 77.2, 82.8 and 45.9 for lines 121, 141 and 221, respectively. Data from the short-lived half of the mouse lines showed that mean lifespan was 17% longer in the selected lines 121 and 141 (377.5 and 436.5 days, respectively) than the control line 221 (346.8 days), and phenotypic and genetic correlations between reproductive longevity and lifespan were in the neighbourhood of 0.75 and 0.25, respectively. It was concluded that reproductive longevity was improved through selective breeding and lifespan increased as a correlated response to selection for increased reproductive longevity. The mouse lines derived from this study represent a unique mammalian model for studying various aspects of aging and longevity. PMID- 8675372 TI - Ontogeny of 17B-estradiol (E2)- and estrogen receptor (ER)- immunostained cells in the hypothalamus and adenohyophyseal pars distalis of the chick embryo. AB - Brain sections of 6.5-18.5 day-old (stages 30-45: Hamburger and Hamilton, 1951) male and female chick embryos were examined immunocytochemically for the presence of 17B-estradiol (E2)- and estrogen receptor (ER)-containing cells in the hypothalamus and adenohypophyseal pars distalis. Single (E2 or ER)- and double (E2 and ER)-immunostained cells were observed in five nuclei of the anterior-, mid-, and posterior-hypothalamus and in the rostral and caudal pars distalis. The number of E2-immunostained cells were determined in each of these brain areas from Days 10.5 through 18.5 (stages 37 through 45); during this time period no differences were noted between the cell counts of males and females. In both sexes there was a significant increase (P<0.05) from Days 10.5 through 12.5-13.5 (stages 37 through 39-40) in the mean number of E2-immunoreactive cells. These findings agree with the observations of Wilson and Glick (1970) that prior to the 13th day of embryonic development E2 contributes, via its effect on the hypothalamic neural circuitry (organization) to posthatch mating behavior. PMID- 8675373 TI - The relationship of hospital process variables to patient outcome post-myocardial infarction. AB - This study examined the hospital process variables of nursing care, medical care, information, and hospital environment, as evaluated by patients, in relation to their outcome post-myocardial infarction (MI). The sample included 68 hospitalized men and women, aged 29-92, who were diagnosed with an MI. At the time of discharge, they responded to four subscales of the Patient Judgment of Hospital Quality Questionnaire, which measured the hospital process variables, and the Revised Haussman and Hegyvary Outcome Criteria Instrument for Acute Myocardial Infarction, which measured patient outcome post-MI. Data also were collected from patient charts and nurses. Correlational analyses revealed statistically significant relationships between nursing care and patient outcome, and between hospital environment and patient outcome; neither medical care nor information correlated appreciably with patient outcome post-MI. Regression analysis indicated that nursing care was the only significant predictor of patient outcome post-MI. PMID- 8675374 TI - Factors influencing nurses' handling and control of peripheral intravenous lines- an interview study. AB - The purpose of the study was to describe how nurses (n = 37) planned, took care of, and documented peripheral intravenous (vein) cannulae (PIV) and what controls their way of action. Knowledge, experience, and routine were said to govern the care and handling of PIV. The nurses' intention was that a PIV should be inserted for 1-3 days, but all of them were aware of PIV being inserted considerably longer, the reasons being forgetfulness, carelessness, mistake, no one to take responsibility, bad routines and stress. Patients who had received drugs or solutions daily were given less information and furthermore the same PIV-entry was used for drugs, solutions and blood. Only one nurse documented the insertion and the removal of a PIV. The nurses' personal comments were that the area was neglected and there were great variations in the care and handling of PIV. Their task is to systematically identify the patients' needs and risk factors, and to analyse, diagnose, plan, implement and evaluate the care given. Using a standardised guide could be a way to reduce the frequency of complications in the daily care of PIV. PMID- 8675375 TI - Nurses' infection-control practice: hand decontamination, the use of gloves and sharp instruments. AB - Infection is an acknowledged hospital problem. Micro-organisms are disseminated mainly via hands but there is evidence that hand decontamination, the most important means of prevention, is performed too seldom, and not always after activities likely to result in heavy contamination. Nurses themselves are exposed to risks of infection, chiefly through contact with blood and body fluids, yet it has also been reported that gloves are not always worn during contact with patients' secretions and that the handling and disposal of sharp instruments may be performed unsafely. The study reported in this paper documents nursing behaviour in relation to hand decontamination, the use of gloves and sharps, taking into consideration a number of variables which could influence practice: availability of the expertise afforded by an infection-control nurse, clinical setting, nursing workload, knowledge and the resources available to control infection. Hands were decontaminated after 28.78% of patient contacts. Hands were decontaminated after 49.85% of activities likely to result in heavy contamination. Performance was related to nursing workload and the availability of hand decontaminating agents, especially when the nurses became busy. Use of gloves when they were available also proved good, with little evidence of wasteful use. The handling and disposal of sharps were commendable for most subjects but a few grossly unsafe incidents were nevertheless witnessed, apparently not associated with any of the variables examined. PMID- 8675376 TI - Structured clinical preparation time for culturally diverse baccalaureate nursing students. AB - In 1987, the City College School of Nursing revised its curriculum. One of the changes in a course entitled "Health Care of Adult II" was to alter its instruction methods in the clinical setting. A standardized form of clinical preparation and assignment, with emphasis on the elements of the nursing process, replaced the previous time and method of assigning student tasks, which had varied from instructor to instructor. This change in instruction methods stresses that clinical preparation must be guided and overseen by the instructor in order to reach maximum effectiveness as a tool for teaching. To evaluate the effectiveness of the structured clinical preparation time, a questionnaire was administered to the first two groups of students enrolled in "Health Care of Adult II" who were exposed to this new approach of clinical preparation. A total of 61 students participated in the survey. On a five-point Likert scale, the respondents were asked to rate six statements. Possible responses ranged from strong agreement to strong disagreement. The majority of the respondents agreed that the structured clinical preparation time helped them to: improve their skills in collecting relevant data and in formulating nursing diagnoses; develop and implement a client care plan based on a priority nursing diagnosis; and become more familiar with the equipment to perform psychomotor skills safely. The results also indicate that the structured clinical preparation time helped to diminish students' anxiety in going to the clinical setting and that the time allotted for preparation was sufficient. PMID- 8675377 TI - Reflective practice: reviewing the issues and refocusing the debate. AB - Reflective practice has emerged in the U.K. and beyond as an important issue not just in nursing but in many other professions. However, it remains problematic; it is difficult to conceptualize and many aspects of it are open to debate. Reflective practice is also contentious because, at a fundamental level, it raises a number of important issues for professional practitioners and the way they view their practice. The intention of this paper is to: explore some of the issues that have emerged as the profession of nursing and other professions have gained a better understanding of reflective practice; broaden the scope of the debate and refocus it; raise issues which are in need of further research. PMID- 8675378 TI - The effects of a discharge information intervention on recovery outcomes following coronary artery bypass surgery. AB - This quasi-experimental study tested the effects of a discharge information intervention on physical and psychological outcomes 1 month following coronary artery bypass surgery (CABG). Recovery outcomes were compared between two groups of patients: those receiving an audiotape of information focusing on expected physical symptoms and their management in addition to usual care, and those receiving a usual cardiac discharge information protocol. The nonprobability sample of 82 patients were men and women and had a mean age of 64 years. The outcome measurements included psychological distress, measured by the Profile of Mood States, and physical functioning, measured by the Sickness Impact Profile. The audiotape intervention produced positive effects on physical functioning [F(1,80) = 6.37, p < 0.01]; the effects were maintained when age and post operative length of stay were statistically controlled. No differences in psychological distress were found. Findings suggest that audiotapes containing discharge information about expected recovery experiences are a feasible and effective approach to enhancing the physical recovery of CABG patients. PMID- 8675379 TI - Nursing diagnosis: a critical analysis of underlying assumptions. AB - The nursing diagnosis movement has now reached many European countries and is rapidly being accepted as a method with which to advance the professional status of nursing as well as to define, structure, standardize and systematize nursing care. It is necessary that the import of Anglo-Saxon nursing concepts, theories and models are critically examined for cultural, contextual and philosophical appropriateness. In this article, we articulate and critically examine some of the assumptions implicit in nursing diagnosis, using examples from our clinical research in Sweden. PMID- 8675380 TI - Nurses' awareness of restraint use with elderly people in Greece and the U.K.: a cross-cultural pilot study. AB - The use of restraints in hospitalised elderly people is a contentious but poorly documented issue and many gaps remain in the literature. Despite the growth of the elderly population, there has been little attempt to safeguard their rights in relation to appropriate care whilst in hospital. Furthermore, little is known about the attitudes of nurses in the U.K. towards the use of restraints in the older population, and there is an almost total absence of cross-cultural studies. The current study is a small pilot study of nurses' attitudes towards and knowledge of restraint use with older patients. A structured questionnaire was given to 39 U.K. and 11 Greek trained nurses who were working in acute care settings where elderly patients were cared for, with the aim of identifying their perceptions and experiences of the use of restraints in their clinical settings. Although numbers were small, a number of differences between the two groups were found, and there were indications of further differences. These issues are examined, with particular reference to the need for education, restraint policies and multidisciplinary decision-making about restraint use. Some major principles which should be included in cross-cultural studies are also discussed. PMID- 8675381 TI - Cultural perspectives of meals expressed by patients in geriatric care. AB - The aim of this study was to investigate cultural values and ideas concerning table manners and food habits expressed by patients in geriatric care. The research approach was ethnographic. The findings exposed conflicts related to three themes. The first, "Mind your manners", demonstrated problems in managing food and objects, keeping clean, and conduct at table. The second, "Appetite for food", was connected to tradition and taste, healthy food and the need not to waste food. The third, "Be contented and do not complain", illustrated the elderly patients' socialized manners in talking about meals and food. PMID- 8675382 TI - A study of the official records of seclusion. AB - The official records of seclusion on one locked ward in a city hospital were analysed. In the first instance we examined the frequency of seclusion, the sex and type of the patients secluded over a 4-year period. Following the introduction of a new recording system, a more detailed analysis of all the official records of seclusion over a 2-year period was then carried out (n = 225). The findings are presented here as simple frequency counts and provide a detailed picture of the use of seclusion in this particular area. They include details about the way in which seclusion was used on the ward and the reasons staff provided for secluding patients. The use of official records as research data illustrate how important insights into the daily care of psychiatric patients may be explored in a fruitful manner. PMID- 8675389 TI - Developmental neurotransmitters. Signals for shaping neuronal circuitry. PMID- 8675390 TI - Visual stabilization of posture in persons with central visual field loss. AB - PURPOSE: To determine whether people with central visual field loss (CFL) show a smaller visual contribution to posture stabilization than people with normal vision and to determine the visual factors that predict the magnitude of visual stabilization in people with central visual field loss. METHODS: Posture information was recorded in 19 subjects with CFL and in 20 subjects with normal vision. Data were collected as the subject stood in a dark environment and also as he or she viewed a stationary visual display. In both conditions, somatosensory feedback was concurrently altered. The central visual fields of the subjects with CFL were measured by static perimetry with the confocal scanning laser ophthalmoscope. Binocular visual acuity and contrast sensitivity were measured on all subjects using the ETDRS and Pelli-Robson charts, respectively. Image-displacement thresholds were measured in a subset of the subjects. RESULTS: On average, subjects with central field loss showed a smaller visual contribution to posture stabilization than subjects with normal vision. The reduction in sway caused by visual stimuli was only 29% for the subjects with CFL compared to 41% for the subjects with normal vision. Displacement thresholds accounted for 45% of the variance in the visual stabilization magnitude of the subjects with CFL. No other visual factor significantly increased the coefficient of determination. CONCLUSIONS: The visual self-motion cues generated by small body oscillations may be undetectable and, thus, unusable as cues to postural sway by people with central field loss. PMID- 8675391 TI - Psychophysics of reading. XV: Font effects in normal and low vision. AB - PURPOSE: Little is known about the effect of font on low-vision reading. In this study, the authors measured the influence of font in reading with normal and low vision. METHODS: Reading acuity, maximum reading speed, and critical print size (the smallest print that can be read with maximum speed) were measured in 50 normal subjects and 42 subjects with low vision. Data were collected using versions of the MNREAD Acuity Chart printed with the Times (proportionally spaced) and Courier (fixed-width) fonts. RESULTS: Reading acuity scores obtained with Courier were better than those obtained with Times for both normal (mean difference, 0.05 logMAR, P < 0.001) and subjects with low vision (0.09 logMAR, P < 0.001). Similarly, critical print sizes measured with Courier were smaller than those measured with Times (mean difference, 0.06 logMAR for normal subjects and subjects with low vision, P < 0.002). Maximum reading speeds for normal subjects were 5% faster with Times than with Courier (P < 0.001), but for subjects with low vision, maximum reading speeds were 10% slower with Times than with Courier (P < 0.05). For print smaller than the critical print size, the reading speeds of normal subjects and subjects with low vision were substantially slower (by as much as 50%) for Times than for Courier. CONCLUSIONS: There are small, but significant, advantages of Courier over Times in reading acuity, critical print size, and reading speed for subjects with low vision. For normal subjects, the differences are slighter, with an advantage in reading speed for Times. However, for print sizes close to the acuity limit, choice of font could make a significant difference in both normal and low-vision reading performance. PMID- 8675392 TI - Isoforms of Na,K-ATPase in rat lens epithelium and fiber cells. AB - PURPOSE: The lens epithelium is thought to conduct Na-K transport for the entire lens cell mass. Lens fibers have a poor ion transport capacity. The authors tested whether different Na,K-ATPase polypeptides are expressed in the two cell types and whether both cells have the machinery needed for ongoing Na,K-ATPase expression as judged by the presence of mRNA for the Na,K-ATPase alpha subunit. METHODS: Membranes were isolated from adult rat lens epithelium or fibers, and Western blot experiments were conducted for Na,K-ATPase alpha 1, alpha 2, and alpha 3 polypeptides. Total RNA was isolated from adult rat lens epithelium or fiber cells, and Northern analysis was conducted for Na,K-ATPase alpha 1, alpha 2, and alpha 3 mRNA. Some experiments were conducted using fiber cells from neonatal (3-day-old) rat lenses. RESULTS: Multiple isoforms of Na,K-ATPase were detected in adult rat lens epithelium. Judged by Northern blot band intensity, mRNA for Na,K-ATPase alpha 1 and alpha 2 was more abundant than for alpha 3 mRNA. By Western blot, Na,K-ATPase alpha 1, alpha 2, and alpha 3 polypeptides were observed as sharp bands at 100 to 108 kDa. In fiber cells, only Na,K-ATPase alpha 1 immunoreactive polypeptide was detected. Judged by immunoblot density, the amount of alpha 1 polypeptide was similar in both epithelium and fiber cell material. However, Na,K-ATPase alpha subunit mRNA was not found in adult lens fibers. To test whether Na,K-ATPase synthesis takes place during fiber cell growth, Northern blot analysis was conducted with RNA from neonatal (3-day-old) lens fibers; Na,K-ATPase alpha 1 mRNA was clearly visible. CONCLUSIONS: Adult rat lens epithelium expresses more than one isoform of Na,K-ATPase catalytic subunit, whereas only the alpha 1 isoform can be detected in fiber cells. In adult rat lens fiber cells, the observation of alpha 1 polypeptide, but no alpha 1 mRNA, suggests that ongoing alpha 1 synthesis is low. Based on the detection of alpha 1 mRNA in neonatal lens fibers, Na,K-ATPase synthesis by lens fibers may be higher during cell elongation and growth. PMID- 8675393 TI - Inhibition of transforming growth factor-beta-induced cataractous changes in lens explants by ocular media and alpha 2-macroglobulin. AB - PURPOSE: To investigate the ocular media for the presence of inhibitors of transforming growth factor-beta (TGF beta) using a lens epithelial explant system in which TGF beta induces cataractous changes. The effect of alpha 2 macroglobulin, an inhibitor of TGF beta in other systems, also was assessed. METHODS: Explants prepared from 21-day-old rats were cultured with TGF beta 2 with and without 50% bovine aqueous or vitreous or alpha 2-macroglobulin. alpha 2 macroglobulin was added to an aqueous concentrate, shown to contain endogenous TGF beta activity by blocking with anti-TGF beta. Explants were monitored by phase-contrast microscopy for 5 days and assessed in terms of capsule wrinkling, spindle-cell formation, blebbing, and cell loss. alpha 2-macroglobulin in the ocular media was assessed by enzyme-linked immunosorbent assay and Western blot analysis. RESULTS: At 50% strength, neither aqueous nor vitreous demonstrated TGF beta-like activity; however, aqueous partially and vitreous completely prevented cataractous changes induced by 25 and 100 pg/ml TGF beta 2, respectively. alpha 2 macroglobulin (50 to 200 micrograms/ml) also protected against these changes, with complete inhibition of TGF beta 2 or aqueous-derived TGF beta activity at the highest concentration. A threefold higher concentration of alpha 2 macroglobulin was detected in vitreous than aqueous. CONCLUSIONS: Both aqueous and vitreous contain molecule(s) that inhibit TGF beta 2 activity. alpha 2 macroglobulin has been identified in the ocular media and shown to block cataractous changes induced by TGF beta. Maintaining appropriate levels of alpha 2-macroglobulin or similar molecules in the ocular media may protect lens cells from the damaging effects of TGF beta, and reduced levels may predispose to cataract. PMID- 8675394 TI - Acuity and contrast sensitivity in monkeys after neonatal intraocular lens implantation with and without part-time occlusion of the fellow eye. AB - PURPOSE: The authors used a monkey model to evaluate intraocular lenses (IOLs) for the treatment of infantile cataract in humans. Specifically, they sought to assess the effectiveness of IOLs, with and without occlusion therapy, in preventing amblyopia. METHODS: A diffuser contact lens was placed on one eye each of 11 neonatal monkeys to simulate an infantile cataract. A unilateral lensectomy, combined with the implantation of an IOL, was performed on the same eye 1 to 2 weeks after birth. Clear contact lenses were used to adjust the optical correction of the pseudophakic eyes to a near point, and opaque lenses were used to maintain daily part-time (70%) occlusion of the fellow eyes of half the subjects. Behavioral methods were used to assess grating acuity, optotype acuity (Landolt C), and contrast sensitivity. RESULTS: In five of the animals, complications that developed in the eye with the implant were severe enough to interfere with visual function. The authors present only behavioral outcomes obtained before or in the absence of surgical complications. In monkeys that underwent daily 70% occlusion, grating acuity in the pseudophakic eyes eventually matured to normal adult levels. Grating acuity was significantly poorer in animals with no occlusion therapy. Even in animals with normal grating acuity, assessments of optotype acuity revealed amblyopic deficits; contrast sensitivity was impaired as well at middle and low spatial frequencies. CONCLUSIONS: The current study demonstrates that if there are no complications secondary to surgery, normal grating acuity can be obtained in neonatal monkey eyes that undergo IOL implantation, optical correction of the pseudophakic eye to a near point, and 70% occlusion of the fellow eye. However, these good outcomes for grating acuity cannot be attained without occlusion therapy. In addition, optotype acuity and sensitivity to contrast always are impaired. PMID- 8675395 TI - The critical period for surgical treatment of dense congenital unilateral cataract. AB - PURPOSE: Early treatment of dense congenital unilateral cataract is associated with better acuity outcomes. It is unclear whether there is a gradual worsening of prognosis with delay of treatment from the time of birth (linear model) or whether there exists an early window of time during which treatment is maximally effective, followed by declining success (bilinear model). The aim of the current study was to determine which model better describes the response to treatment. METHODS: A maximum likelihood procedure that permits statistical comparison between linear and bilinear models was applied to acuity outcomes from a group of 45 children 5 to 8 years of age with a history of dense congenital unilateral cataract diagnosed at 1 to 10 days of age. Contrast sensitivity and vernier acuity data from a subset of these children were evaluated with nonparametric statistical methods. RESULTS: The bilinear model provided a significantly better fit to the acuity outcome data. The line fitted to the initial portion of the function had a shallow slope that was not significantly different from 0.0. The intersection of the two linear functions occurred at 5.6 weeks and was followed by a steep decline in visual acuity outcomes. Contrast sensitivity and vernier outcome measures over a range of spatiotemporal conditions showed better outcomes were obtained with early treatment. CONCLUSIONS: Intervention before 6 weeks of age may minimize the effects of congenital unilateral deprivation on the developing visual system and provide for optimal rehabilitation of visual acuity. PMID- 8675397 TI - Ascorbic acid and glucose oxidation by ultraviolet A-generated oxygen free radicals. AB - PURPOSE: To determine the relative rate of oxidation of ascorbic acid (ASA) and glucose under conditions used for glycation reactions in vitro and by ultraviolet A (UVA)-generated oxygen free radicals using human lens sensitizers. METHODS: ASA and [14C]glucose were incubated in 0.1 M phosphate buffer, and the rate of oxidation was determined by absorbance at 265 nm and by thin-layer chromatography, respectively. Oxidation also was measured during the UVA irradiation of 2 mg/ml solutions of human lens water-insoluble proteins. The role of individual reactive oxygen species was determined by the protective effects of superoxide dismutase, catalase, and sodium azide. RESULTS: ASA was oxidized rapidly in 0.1 M phosphate buffer. This loss was prevented by the addition of a metal chelator, by previous chelex resin treatment of the buffer, or by the addition of lens proteins. Glucose was not oxidized under any of the above conditions. UVA irradiation with 2 mg/ml human lens protein as sensitizer oxidized 1 mM ASA after several hours but oxidized, at most, only 2 microM glucose even after 8 hours of irradiation. Superoxide anion was responsible for 24%, and singlet oxygen for 40%, of the ASA oxidized. UVA-generated H2O2 caused little or no oxidation of ASA. H2O2 did accelerate the oxidation of ASA in phosphate buffer, but this was almost completely prevented by the addition of either a chelating agent or lens proteins. CONCLUSIONS: The conditions used for glycation reactions in vitro rapidly oxidized ASA, but not glucose. The UVA dependent generation of oxygen free radicals also oxidized ASA at a 10(3) faster rate than glucose. Superoxide anion and singlet oxygen were identified as the principal oxidants of ASA in this process. These data argue that ASA may be the primary glycating agent in aging normal lenses. PMID- 8675396 TI - The role of prostaglandins E2 and F2 alpha in ultraviolet radiation-induced cortical cataracts in vivo. AB - PURPOSE: Previous work has shown that exposure of lens epithelial cells or rabbit eyes in vivo to ultraviolet B (UVB) radiation enhanced prostaglandin (PG)E2 synthesis. Such enhanced PGE2 synthesis was related to the increased DNA synthesis that followed UVB exposure. The current study examined the relationship between enhanced prostaglandin synthesis and UVB-induced cataract formation. METHODS: Seventy albino (New Zealand white) rabbit eyes were exposed to UVB radiation in vivo. Fluence of radiation at the cornea was 2.8 J/cm2, 5.6 J/cm2, or 11.2 J/cm2. Eyes were examined 24 hours after UVB exposure and for as long as 10 days by slit lamp biomicroscopy. Mass spectrometry was used to measure PGE2, PGF2 alpha, and 6-keto-PGF1 alpha content of the lens and iris-ciliary body using authentic standards. To determine the effect of inhibition of prostaglandin synthesis on UVB-induced cataract formation, animals were given indomethacin intraperitoneally. Other pharmacologic agents, such as PGE2, PGF2 alpha, and misoprostol, were applied topically to the eye. The effect of UVB on K+ pump was determined by incubating isolated lenses with [86Rb+]. RESULTS: Twenty-four hours after UVB exposure, PGE2 and PGF2 alpha concentrations in aqueous humor were increased by 100- and 30-fold, respectively. Lens PGE2 and PGF2 alpha increased by 6- and 4-fold, respectively, after UVB radiation exposure. Pretreatment of animals with indomethacin prevented the rise in lens and aqueous humor PGE2 and PGF2 alpha levels. Furthermore, indomethacin was partially protective against UVB cataract formation and lowered cataract severity from stage 3 to stage 1, but it did not prevent UVB-induced lens changes completely. Topical application of PGE2 before UVB exposure completely prevented cataract formation in the UVB-exposed eye. In contrast, topical administration of PGF2 alpha increased cataract severity. UVB-induced cataract formation preceded changes in [86Rb]+ uptake in lenses subsequently incubated in K(+)-free Tyrode's. CONCLUSIONS: Enhanced synthesis of cyclooxygenase products of arachidonic acid metabolism in the lens is associated with UVB-induced cataract formation in albino rabbit eyes, and inhibition of cyclooxygenase by indomethacin decreased the severity of cataracts. PGE2, the principal arachidonic acid metabolite, appears to have a protective role because pretreatment of the eye with topical PGE2 completely prevented UVB induced cataract formation, whereas PGF2 alpha increased the severity of the cataract. The evidence presented for a role of PGF2 alpha in the development of cataract suggests that caution be exercised in the use of PGF2 alpha derivatives in the therapy of glaucoma. PMID- 8675398 TI - Liquefaction of cortical tissue in diabetic and galactosemic rat lenses defined by confocal laser scanning microscopy. AB - PURPOSE: To investigate whether a histologic link exists between osmotic fiber cell swelling and cortical tissue liquefaction in experimentally induced diabetic and galactosemic cataractogenesis of the rat lens. METHODS: Confocal laser scanning microscopy, in conjunction with specific membrane labels and correlative transmission electron microscopy, was used to image large cortical areas with precise definition of the individual cells. RESULTS: In both cataract models, tissue liquefaction--defined as the disintegration of tissue and the appearance of large fluid-filled spaces--typically was limited to a discrete zone in the lens cortex. The borders of the liquefaction zone were characterized by transitions between normal-appearing cells and swollen cells, which gained in size as plasma membranes ruptured and cytoplasmic contents fused and ultimately burst, thereby contributing to the formation of large fluid-filled spaces. During cataractogenesis, before tissue liquefaction became evident, selected fiber cells appeared swollen and accumulated specifically in the zone destined for tissue liquefaction. With increasing duration of diabetes or galactosemia, swollen fiber cells in this zone became more frequent and enlarged, resulting first in tissue disorder and then in tissue disintegration and the formation of large fluid filled spaces. CONCLUSIONS: New imaging protocols strongly support a direct involvement of lens fiber cell swelling in the liquefaction of cortical tissue. The appearance of swollen fiber cells in the lens cortex, therefore, can be used as an early indicator of the histopathology of sugar cataractogenesis. PMID- 8675399 TI - Expression of cell cycle-associated proteins in human and rabbit corneal endothelium in situ. AB - PURPOSE: It is unknown why human corneal endothelium exhibits limited capacity to divide while the endothelia of other species, such as rabbit, divide in vivo at wounding and in culture. A potentially valuable source of information concerning why human endothelium has such a limited proliferative capacity lies in elucidating any differences in the molecular events governing the cell cycle of these two species. A recent study of the relative expression of cell cycle associated proteins in donor corneas suggests that human corneal endothelial cells in vivo have not exited the cell cycle but are arrested in G1-phase. The purpose of the current study was to identify differences in cell cycle protein expression in human and rabbit endothelium that would explain the difference in their relative proliferative capacities. Specifically, the authors first ascertained the relative proliferative status of rabbit corneal endothelial cells in vivo. The expression and intracellular distribution of G1-phase regulatory proteins was then determined in both species, and the results were compared. METHODS: Corneas from New Zealand white rabbits (weight range, 2 to 3 kg) and from human donors (age range, 6 months to 67 years) were fresh frozen, cryostat sectioned, and prepared for indirect immunofluorescence microscopy using an established protocol. The following monoclonal antibodies were localized in rabbit corneal endothelium only: cyclins D, E, A, and B1; protein kinase p34cdc2; and Ki67, a marker of actively cycling cells. Localization patterns for the following G1-phase regulatory proteins were compared in both human and rabbit corneal endothelia: the tumor suppressors, pRb, p53, and p16INK4, and the transcription factor, E2F. Reverse transcription-polymerase chain reaction studies were conducted to detect mRNA for Ki67 in human and rabbit corneal cells. RESULTS: Cyclins D, E, and A were localized in the cytoplasm of rabbit corneal endothelium, whereas cyclins B1 and p34cdc2 were detected in the nucleus. No Ki67 protein or mRNA expression was detected in the endothelium of either species. In human and rabbit endothelia, p53 and p16INK4 were localized to the cytoplasm, whereas pRb was detected in the nucleus. E2F exhibited a nuclear and a cytoplasmic localization in each species. CONCLUSIONS: The corneal endothelium of rabbits stained positively for cyclins D, E, and A and did not stain for Ki67, suggesting that, as in humans, rabbit corneal endothelium in vivo is arrested in G1-phase upstream from Ki67 synthesis. Cyclin E was located in the cytoplasm of rabbit cells, whereas it was found in the nucleus in human endothelium. The apparent difference in cellular distribution of cyclin E in these two species may be significant because this cyclin is active during the G1-/S-phase transition. It is possible that in situ human and rabbit corneal endothelial cells are arrested at different points within G1-phase and/or that the difference in relative proliferative capacity exhibited by the corneal endothelium in these two species may be caused by differences in their relative ability to overcome G1 phase arrest. PMID- 8675400 TI - Generation of complement membrane attack complex in normal human corneas. AB - PURPOSE: To determine whether complement-derived SC5b-9, the soluble nonlytic fluid phase of the membrane attack complex, can be generated in normal human corneas when they are injured with lipopolysaccharide (LPS), ribitol teichoic acid (RTA) immune complexes, acid, or alkali. METHODS: The experimental cornea of each donor pair was injected with 50 microliters of sterile saline containing 0.5 mg of LPS or 50 microliters of sterile saline containing 250 micrograms of RTA immune complexes. Other experimental corneas were treated topically for 35 seconds with either 200 microliters of 1N HCl or 2N NaOH. The control cornea of each donor pair was injected with 50 microliters of sterile saline or was treated topically for 35 seconds with 200 microliters of sterile saline. After injury, all corneas were incubated in medium 199 for 6 hours at 37 degrees C in 5% CO2, then eluted for 24 hours in phosphate-buffered saline with 10 mM ethylenediaminetetraacetic acid. Each corneal eluate was collected and stored at 70 degrees C until assayed for SC5b-9 by an enzyme immunoassay. RESULTS: Compared with control corneas, SC5b-9 levels were increased significantly in corneas injected with LPS or RTA immune complexes. However, when compared with controls, SC5b-9 levels were decreased significantly in corneas treated with HCl or NaOH. CONCLUSIONS: Normal human corneas injured immunologically with LPS or RTA immune complexes activate the classical or alternate pathway and generate SC5b-9. Corneas injured chemically with acid or alkali do not produce SC5b-9. PMID- 8675402 TI - Changes in beta 4 integrin expression and localization in vivo in response to corneal epithelial injury. AB - PURPOSE: To determine whether production and localization of beta 4 integrin is altered during in vivo corneal epithelial cell migration in response to debridement wounding. METHODS: Rat corneas were wounded and animals were killed at times ranging from 3 hours to 14 days. At various time points, corneal epithelial integrins were quantitated by gel electrophoresis and immunoblotting of epithelial extracts and then were localized by immunohistochemistry. RESULTS: As early as 6 hours after wounding, an increase in the amount of the beta 4 integrin subunit expressed per microgram of total protein was observed. The level of beta 4 continued to increase until wound closure. By 14 days after wounding, beta 4 expression returned to control levels. The level of expression of beta 1 and alpha (v) integrins were found not to change significantly throughout migration. Immunohistochemical analyses using antibodies against either the beta 4 integrin subunit or HD1, a hemidesmosomal plaque component, showed that in control sections, beta 4 integrin and HD1 codistributed in a linear staining pattern above the basement membrane. As early as 4 hours after wounding, beta 4 was present in both basal and suprabasal epithelial cells, and HD1 was retained at the basal aspect of the epithelial basal cells. CONCLUSIONS: These data show that changes in expression and localization of beta 4 integrin occur in the corneal epithelium in response to debridement wounding in vivo. Previously, we had shown that quantitative changes in beta 4 integrin expression do not occur in an in vitro organ culture model used for the study of corneal epithelial cell migration. Increased beta 4 expression may not be required for migration per se, but it may be play a role in either stabilizing cell:cell or cell:substrate adhesion in vivo or in preparing cells to undergo mitosis during restratification. PMID- 8675403 TI - Contrast-enhanced magnetic resonance imaging confirmation of an anterior protein pathway in normal rabbit eyes. AB - PURPOSE: Contrast-enhanced proton magnetic resonance imaging (1H MRI) has been used as a quantitative, noninvasive method to corroborate a pathway for the diffusion of plasma-derived protein into the aqueous humor in the normal rabbit eye. METHODS: T1-weighted magnetic resonance images were produced over 1- to 3 hour periods after the intravenous injection of gadolinium diethylenetriamine pentaacetic acid. RESULTS: Analysis of the images yielded the time dependence of signal enhancements within the areas of interest. The ciliary body showed an immediate sharp increase, followed by a gradual decrease in signal enhancement with time. Although a gradual increase in signal enhancement was found in the anterior chamber, no significant change occurred in the posterior chamber. A similar MRI experiment with an owl monkey produced parallel, though smaller, signal enhancements in the ciliary body and anterior chamber. Again, however, no significant change was found in the posterior chamber. CONCLUSIONS: These results support and extend those of recent fluorophotometric, tracer-localization, and modeling studies demonstrating that in the normal rabbit and monkey eye, plasma derived proteins bypass the posterior chamber, entering the anterior chamber directly via the iris root. PMID- 8675401 TI - The Fas-Fas ligand system and other modulators of apoptosis in the cornea. AB - PURPOSE: Previous studies have suggested that the disappearance of anterior keratocytes after injury to the overlying epithelium is mediated by apoptosis. The authors examined the expression of the apoptosis-related modulators, Fas (receptor), Fas ligand, Bax, Bcl-2, Bcl-XL, and interleukin-1 beta converting enzyme (ICE) in corneal cells as candidate mediators of this response and tested the effect of Fas receptor-stimulating antibody on corneal stromal fibroblast cells in vitro. METHODS: Reverse-transcription-polymerase chain reaction was used to detect FAS, FAS ligand, Bax, Bcl-2, Bcl-XL, and ICE mRNA expression in primary cultures of human corneal epithelial, stromal fibroblast, and endothelial cells. Immunohistochemistry was applied to detect Fas and Fas ligand proteins in fresh frozen sections of normal human cornea. The effect of FAS-stimulating monoclonal antibody on first-passage stromal fibroblasts was studied using a DNA fragmentation assay, the live-dead assay with fluorescent microscopy, toluidene blue staining with light microscopy, and electron microscopy. RESULTS: FAS, Fas ligand, Bax, Bcl-2, Bcl-XL, and ICE mRNAs are expressed in all three major cell types of the cornea. Fas protein is expressed in corneal epithelial, keratocyte, and endothelial cells in fresh-frozen human cornea. Fas ligand protein, however, was detected in corneal epithelial and endothelial, but not keratocyte, cells. Fas-stimulating antibody induced first-passage stromal fibroblast cell death with morphologic changes and DNA fragmentation consistent with apoptosis. CONCLUSIONS: The Fas system (Fas and Fas ligand) modulators and final common pathway mediators of apoptosis are expressed in corneal cells. The distribution of Fas (epithelial, keratocyte, and endothelial cells) and Fas ligand (epithelial and endothelial cells) protein expression in fresh-frozen corneal tissue suggests that Fas ligand expressed in corneal epithelial and endothelial cells modulates functions in keratocyte cells and, possibly, autocrine-juxtacrine functions in epithelium and endothelium. The Fas-Fas ligand system is expressed in the cornea and could have important functions in normal corneal physiology and in the pathophysiology of corneal disease, including modulation of keratocyte apoptosis after epithelial injury. PMID- 8675404 TI - Patients with ocular hypertension have abnormal point scotopic thresholds in the superior hemifield. AB - PURPOSE: To compare light- and fully dark-adapted thresholds at loci within the central visual field in patients with ocular hypertension and glaucoma. METHODS: Eighteen patients with chronic open angle glaucoma, 13 patients with ocular hypertension, and 24 age-matched normals were studied. The Humphrey automated perimeter with the standard background illumination of 31.5 apostilbs was used to determine photopic thresholds at 18 loci within 20 degrees of fixation. Fully dark-adapted thresholds were measured at the same loci after 30 minutes of dark adaptation by automatic, static campimetry. RESULTS: The glaucoma group showed elevated scotopic thresholds. Scotopic defects also were found in a significantly higher proportion of patients with ocular hypertension than in normals. These scotopic defects were predominantly in the superior hemifield. CONCLUSIONS: Scotopic threshold campimetry may identify the subgroup of patients with ocular hypertension who progress to develop glaucomatous field loss identifiable by standard photopic and mesopic perimetry. PMID- 8675405 TI - Chronic low-dose glutamate is toxic to retinal ganglion cells. Toxicity blocked by memantine. AB - PURPOSE: It is well known that acute exposure to high concentrations of glutamate is toxic to central mammalian neurons. However, the effect of a chronic, minor elevation over endogenous glutamate levels has not been explored. The authors have suggested that such chronic exposure may play a role in glaucomatous neuronal loss. In the current study, they sought to explore whether a chronic, low-dose elevation in vitreal glutamate was toxic to retinal ganglion cells and whether this toxicity could be prevented with memantine, a glutamate antagonist. METHODS: Rats were injected serially and intravitreally with glutamate to induce chronic elevations in glutamate concentration. A second group of rats was treated with intraperitoneal memantine and glutamate. Control groups received vehicle injection with or without concurrent memantine therapy. After 3 months, the animals were killed, and ganglion cell survival was evaluated. RESULTS: Intravitreal injections raised the intravitreal glutamate levels from an endogenous range of 5 to 12 microM glutamate to 26 to 34 microM. This chronic glutamate elevation killed 42% of the retinal ganglion cells after 3 months. Memantine treatment alone had no effect on ganglion cell survival. However, when memantine was given concurrently with low-dose glutamate, memantine was partially protective against glutamate toxicity. CONCLUSIONS: These data suggest that minor elevations in glutamate concentration can be toxic to ganglion cells if this elevation is maintained for 3 months. Furthermore, memantine is efficacious at protecting ganglion cells from chronic low-dose glutamate toxicity. PMID- 8675406 TI - A model of angiogenesis in the mouse cornea. AB - PURPOSE: The study of angiogenesis depends on reliable and reproducible models for the stimulation of a neovascular response. The purpose of this research was to develop such a model of angiogenesis in the mouse cornea. METHODS: Uniformly sized Hydron pellets containing either basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) and sucralfate were prepared and implanted into the stroma mouse cornea adjacent to the temporal limbus. RESULTS: Neovascularization of the corneal stroma began on day 3 and was sustained through day 8. The bFGF-induced neovascularization was consistent and dose dependent in C57B1/6, as well as in severe combined immune deficient, beige natural killer cell-deficient, and nude mouse strains. Biomicroscopic and histologic examination of bFGF- and VEGF-induced angiogenesis was notable for the absence of corneal edema or substantial inflammation. CONCLUSIONS: This noninflammatory model of corneal neovascularization is especially advantageous because it is reproducible, economical, and facilitates investigation of angiogenesis in various murine tumor models as well as in genetically defined murine strains. PMID- 8675407 TI - Captopril ameliorates the decreased Na+,K(+)-ATPase activity in the retina of streptozotocin-induced diabetic rats. AB - PURPOSE: To examine the effect of captopril, an angiotensin-converting enzyme (ACE) inhibitor, on the activity of retinal sodium-potassium ATPase (Na,K-ATPase) and the activity of ACE in the serum and retina of streptozotocin (STZ)-induced diabetic rats. METHODS: Experimental diabetes was induced in male Long-Evans rats by a single intraperitoneal injection of STZ (55 mg/kg body weight). Some groups of normal and diabetic animals were treated with captopril (10 mg/kg per day) added to the drinking water for either a week or a month. After 2 and 4 months of diabetes, the specific activity of retinal total Na,K-ATPase was determined. The components of the activity of Na,K-ATPase caused by the alpha 1 and alpha 3 isoforms were pharmacologically separated by their different sensitivity to ouabain. The activity of ACE in the serum and retina was measured by radioassay using benzoyl-gly-gly-gly as substrate (10(5) cpm, 5 mM). RESULTS: The total Na,K ATPase activity was decreased significantly after 2 (16%, P < 0.02) and 4 months (15%, P < 0.02) of diabetes. At both time points examined, the activities of the alpha 1-low-ouabain-affinity isoform and the alpha 3-high-ouabain-affinity isoform of retinal Na,K-ATPase were significantly reduced compared to those of age-matched controls (alpha 1, 9% to 14%, P < 0.05; alpha 3, 14% to 19%, P < 0.05 and P < 0.02 respectively). After 1 month of captopril administration, the activities of both Na,K-ATPase isoforms were at control level in 2-month diabetic rats, whereas they were restored only partially in 4-month diabetic rats. In age matched normal animals, 1 month of captopril treatment did not alter the specific activities of either Na,K-ATPase isoform. One week or 1 month of captopril administration to diabetic rats did not change the activities of retinal Na,K ATPase isoforms. Serum ACE activity was elevated significantly in both groups of untreated STZ rats (55% and 40%, respectively). One month of captopril administration further increased the ACE levels in 2- and 4-month diabetic rats (101% and 94%, respectively) and also enhanced significantly the serum ACE activity in normal animals (131%) versus the basal values. In contrast, retinal ACE activity was decreased significantly in both groups of untreated STZ rats (approximately 37%). Captopril exerted a significant inhibitory effect on the retinal ACE activity in 2- and 4-month diabetic rats (37% and 31%, respectively) compared to untreated diabetic animals as well as in normal rats (29%). CONCLUSIONS: These data suggest that stimulation of retinal Na,K-ATPase activity in diabetes is most likely one of the mechanisms through which captopril can improve retinal complications. The effect of captopril seems to be related to local effects in the retina. Whether the inhibition of retinal ACE is part of the mechanism of action of captopril requires further study. PMID- 8675408 TI - Selective visualization of choroidal neovascular membranes. AB - PURPOSE: Laser-targeted angiography has unique advantages over conventional angiography of the fundus. Its efficacy in visualizing choroidal neovascular membranes was tested in a rat model and compared to that of fluorescein angiography. METHOD: Laser-targeted angiography was performed in rats with choroidal neovascularization (CNV) by injecting heat-sensitive carboxyfluorescein liposomes intravenously, locally releasing a bolus of dye in the choroid with a weak laser pulse, and recording advancement of the bolus on a video camera. Conventional fluorescein angiography also was performed. RESULTS: Laser-targeted angiography revealed CNV as an abnormal pattern of brightly fluorescent vessels. The flow pattern of the bolus and histology, performed in some cases, confirmed the choroidal nature of the vessels. The angiographic visualization was not dependent on dye leakage through the vessels or staining of their walls. Laser targeted angiography also provided visualization of new vessels that could not be diagnosed by fluorescein angiography. It demonstrated that blood flow was typically more sluggish in CNV than in normal choriocapillaris. Fluorescein angiography failed to demonstrate flow dynamics in all cases of CNV. CONCLUSIONS: This study, in an animal model of CNV, shows that laser-targeted angiography demonstrates CNV and its flow dynamics in a manner not provided by conventional fluorescein angiography. It holds clinical promise as a method to delineate CNV considered difficult or impossible to detect by fluorescein angiography. The method also may permit selective photocoagulation of feeding vessels in the choroid, thereby limiting damage to the overlying retina. PMID- 8675409 TI - Developmental expression of laminin beta 2 in rat retina. Further support for a role in rod morphogenesis. AB - PURPOSE: The authors previously hypothesized that laminin beta 2 (S-laminin) plays a role in directing photoreceptor development. The aim of this study was to examine the temporal and spatial expression pattern of beta 2 laminins in rat retina to test this hypothesis. METHODS: Retinas from Sprague-Dawley rats were harvested on embryonic days (E) 14, 16, and 21, as well as on postnatal days (P) 2, 5, and 10. Cryostat sections were probed with antibodies directed against beta 2 laminin, laminin-1 (alpha 1-beta 1-gamma 1), and von Willebrand factor. RESULTS: At the onset of rod photoreceptor birth (E14), laminin beta 2 surrounds the cells of the retinal pigmented epithelium (RPE) and is present on the apical surface of the retinal neuroepithelium. At E16, laminin beta 2 persists on the apical surface of the neuroepithelium and the subjacent apical surface of the RPE. At birth, laminin beta 2 fills the matrix between the juxtaposed surfaces of the RPE and neuroepithelium; moreover, laminin beta 2 immunoreactivity penetrates the neural retina. Throughout postnatal development, laminin beta 2 immunoreactivity surrounds maturing inner and outer segments. Laminin beta 2 also is found in association with blood vessels in the neural retina itself, as well as with choroidal blood vessels; in both places, it is co-localized with an endothelial marker, von Willebrand factor, and laminin-1. CONCLUSIONS: The spatial and temporal expression of laminin beta 2 is consistent with its hypothesized role in rod development. Laminin beta 2 is in a unique position to interact with mitotically active cells (in early retinal development), uncommitted progenitors (in late embryonic development), developing rods (in early postnatal development), and mature outer segments (throughout adulthood). Together with our earlier functional data, these data support our hypothesis that this molecule is an important component of the interphotoreceptor matrix. PMID- 8675410 TI - Photoreceptor function in heterozygotes with insertion or deletion mutations in the RDS gene. AB - PURPOSE: To understand the pathophysiology of human retinal degenerations caused by mutations in the peripherin/RDS gene. METHODS: Three families with autosomal dominant retinal degeneration were found to have mutations in the peripherin/RDS gene. There were two frameshift mutations: a 1-base pair (bp) insertion at codon 32 and a 2-bp deletion at codon 193. For these mutations, the predicted proteins would be truncated by 303 and 131 amino acids, respectively. The third mutation would result in an 8-bp substitution for five nucleotides involving codons 67-69 and would be predicted to disrupt the second transmembrane domain of the protein. Heterozygotes were examined clinically and with rod and cone perimetry, dark adaptometry, and rod- and cone-isolated electroretinograms (ERGs). RESULTS: Rod and cone sensitivity losses were present with perimetric testing in most patients; patients with advanced disease in all three families showed more pericentral than peripheral field dysfunction. The kinetics of dark adaptation were abnormal in all patients. Rod and cone ERG a-waves were normal in maximum amplitude in three younger patients but were reduced in all others; phototransduction was normal in most patients. There was equal loss of rod and cone a-wave amplitudes and equal elevation of rod and cone thresholds. CONCLUSIONS: Heterozygotes with these different peripherin/RDS gene mutations showed variation in clinical presentation but a similar pattern of receptor abnormalities. Results of visual function tests were consistent with a normal amount of rod and cone outer segment membrane in early disease, progressing to reduced outer segments at later stages. There was an equal effect on rod and cone photoreceptor function at all stages of disease. This functional phenotype may represent the human analogue of the rds/+ mouse. PMID- 8675411 TI - Constructing retinal fundus photomontages. A new computer-based method. AB - PURPOSE: To develop computer algorithms for reconstructing 24-bit color, wide angle composite retinal fundus images from a set of adjacent 45 degrees fundus slides. The authors present the description, technical details, and results of the image reconstruction technique. METHODS: Patients with retinal degeneration underwent fundus photography with a 45 degrees field-of-view fundus camera. Individual photographic slides were digitized for creating fundus montages. Background variations in individual 45 degrees images were modeled to first- or second-order two-dimensional polynomial functions to generate a background image. The background image was subtracted from the original image to obtain background corrected image. Background corrected images were registered and spatially transformed using a first- or second-order two-dimensional polynomial warp model to reconstruct a composite retinal fundus montage. RESULTS: The authors successfully reconstructed 24-bit color, 100 degrees field-of-view, composite retinal fundus images. The computer-reconstructed montages are an improvement over manually generated montages because computer analysis can be performed on the computer-based montages. In addition, background variations and discontinuities between individual photographs observed in manually generated montages are reduced greatly in computer-generated montages. Most important, the computer-generated montages are better aligned than the manually generated photomontages. CONCLUSIONS: This method of reconstructing a wide-angle composite retinal fundus image from a set of adjacent small- and wide-angle fundus slides is a new tool for creating montages as large as 100 degrees field of view. The computer-generated montages may be used for documenting and quantifying retinal findings. This can greatly assist studies of retinal manifestations of diseases, such as gyrate atrophy, retinitis pigmentosa, sickle cell disease, and acquired immune deficiency syndrome. PMID- 8675412 TI - Expression of secretory mucin genes by human conjunctival epithelia. AB - PURPOSE: To determine whether human conjunctival epithelium expresses any of the human mucin genes designated MUC2 through MUC7. METHOD: Northern blot analysis was performed using total RNA isolated from surgically removed conjunctival tissues. Complementary DNA or oligonucleotides to the tandem repeat region of each mucin gene were labeled and hybridized to conjunctival RNA. In situ hybridization also was performed to determine the distribution of mucin mRNA. RESULTS: Only MUC4 and MUC5 probes hybridized to conjunctival RNA by Northern blot analysis. Both probes bound in a polydispersed pattern, which is characteristic of mucin genes. Using in situ hybridization, MUC4 mRNA was detected in the cells of the stratified conjunctival epithelium, whereas MUC5 mRNA expression was limited to goblet cells MUC4 or MUC5 probes did not hybridize to sections of corneal epithelium. CONCLUSIONS: The mucins MUC4 and MUC5 are expressed by the human conjunctiva. These mucins may play an important role in forming the tear-film layer at the air and ocular surface epithelium interface. PMID- 8675413 TI - The relationship between visual field size and electroretinogram amplitude in retinitis pigmentosa. AB - PURPOSE: To determine to what degree visual field size is correlated with electroretinogram (ERG) amplitude among patients with the common forms of retinitis pigmentosa (RP). METHODS: Visual field equivalent diameter to the V4e white test light of the Goldmann perimeter was correlated with log ERG amplitude elicited by 0.5 Hz or 30 Hz full-field flashes of white light. Primary analyses were conducted on data from 583 patients with the common forms of RP. Subset analyses were performed on data from patients with ERG responses with different ranges of amplitude to assess to what extent the correlation depends on ERG amplitude, as well as on data from patients of a given genetic type to determine whether the correlation depends on the mode of transmission. Data from patients with the rhodopsin, Pro23His mutation (n = 38) or with the rhodopsin, Pro347Leu mutation (n = 24) were analyzed to determine the correlation between visual field size and ERG amplitude for patients with the same mutation. RESULTS: Visual field size was significantly correlated with ERG amplitude for every comparison (P < or = 0.0003). Correlations generally were higher for ERGs elicited by 30 Hz flashes (r = 0.62 for the entire sample) than they were for those elicited by 0.5 Hz flashes (r = 0.53 for the entire sample). They were lower for truncated ranges of ERG amplitude, higher for patients with dominant or recessive disease than for patients with x-linked disease or for patients of all genetic types combined, and strong for patients with the same rhodopsin mutation (reaching a value of 0.87). CONCLUSIONS: Visual field size is significantly correlated with ERG amplitude for patients with RP. Correlation depends on the range of ERG amplitudes, the inheritance type, and, particularly, on whether the analysis is confined to a single gene mutation. PMID- 8675414 TI - Location and severity of cortical opacities in different regions of the lens in age-related cataract. AB - PURPOSE: To examine the distribution of cortical opacities across the lens in the Italian-American Natural History Study of Age-Related Cataract and to study the association between an index of sunlight exposure and the location of cortical cataract within the lens. METHODS: Lens photographs of one eye of 731 persons with cortical opacities (503 with pure and 228 with mixed types of opacity) were included in the analysis. A radial grid superimposed on the photographs was used to assess presence, location, and severity of wedge-shaped cortical opacities. RESULTS: Both the prevalence and the extent of cortical opacities were highest in the inferior-nasal quadrant and lowest in the superior-nasal quadrant of the lens. In polychotomous logistic regression, persons with the greatest excess areal involvement in the inferior half of the lens were more likely to have high exposure to sunlight, as measured by a sunlight index, than persons with excess involvement in the superior half of the lens (odds ratio, 1.73; 95% confidence interval 1.03, 2.93). Excess areal involvement of the inferior lens also was associated with the pure type of cortical cataract and with the total extent of the opacity. CONCLUSIONS: Age-related cortical opacities occur more frequently inferiorly than superiorly and, to a lesser extent, nasally than temporally. Possibly higher exposure of these lens segments to sunlight may explain this preferential location of cortical opacities. PMID- 8675416 TI - Performance in simple visual search at threshold contrasts. AB - PURPOSE: Visual search for a target, orthogonal to distractors (nontargets) in orientation, has been shown to be independent of the number of distractors (set size). This finding has been thought to indicate that the search occurs spatially in parallel and without capacity limitations. The current study was designed to test whether an orientation difference of 90 degrees between the target and distractor gratings would produce a set-size effect when performance was measured at contrast threshold, that is, whether the threshold contrast at which the target was detected among distractors increased as a function of the number of distractors. The second question studied was whether signal-position uncertainty could explain the possible set-size effect. METHODS: The observer searched for a horizontal Gabor patch target in a two-interval, forced-choice task. In the search condition, the target patch was among seven vertical distractor Gabors, all positioned along an isoeccentric circle. The number of possible display locations monitored by the observer varied, and, before each block, he was informed which locations were relevant. In the single-element condition, the target appeared alone, but the number of possible target locations varied as above. RESULTS: In both conditions, the contrast thresholds almost doubled when the number of possible target locations increased from 1 to 8. CONCLUSIONS: Even though the orientation difference between target and distractors was maximal, a set-size effect was found. The effect could be explained by positional uncertainty. PMID- 8675415 TI - Confirmation of the identity of the major phospholipid in human lens membranes. AB - PURPOSE: To confirm the identity of the major component of the human lens membranes proposed in 1994 to be dihydrosphingomyelin (DH-SPH). METHODS: DH-SPH was prepared by catalytic hydrogenation of the double bond between carbons 4 and 5 of sphingomyelin (SPH). DH-SPH was characterized by phosphorus-31 (31P) and proton (1H) nuclear magnetic resonance (NMR) spectroscopy at different reaction times. The spectroscopic data were compared to those of the major component extracted from human lens membranes. RESULTS: Both the 1H NMR and the 31P NMR spectral resonances of the prepared DH-SPH matched those for the once "unknown phospholipid" that constitutes approximately half the human lens phospholipids. CONCLUSIONS: The match of the spectroscopic NMR data obtained for the DH-SPH prepared by hydrogenation of SPH and those for the major phospholipid isolated from the human lens membranes confirms the identity of this sphingolipid as D erythro-4,5-dihydrosphingomyelin. PMID- 8675417 TI - Decreased intraocular pressure induced by nitric oxide donors is correlated to nitrite production in the rabbit eye. AB - PURPOSE: To evaluate the effect of intraocular administration of nitric oxide (NO) donors in the rabbit eye on intraocular pressure (IOP), inflammation, and toxicity. METHODS: Intravitreal and intracameral injections of two NO donors, SIN 1 and SNAP, and SIN-1C and BSS were performed. Clinical examination, IOP measurements, protein evaluation in aqueous humor, and histologic analysis of the ocular globes were realized. Nitric oxide release was demonstrated by nitrite production in the aqueous humor and in the vitreous using the Griess reaction. RESULTS: The drastic decrease of IOP, observed after a single NO donor injection, was correlated directly with nitrite production and, thus, to NO release. Injection of inactive metabolite of SIN-1, SIN-1C, which is not able to release NO, did not modulate IOP. When administered in the aqueous humor or in the vitreous, NO did not diffuse from one segment of the eye to another. No inflammation or histologic damage was observed as a result of a single NO donor administration. CONCLUSIONS: Nitric oxide is implicated directly in the regulation of IOP and its acute, and massive release into the rabbit eye did not induce inflammation or other growth toxic effects on the ocular tissues. PMID- 8675418 TI - Phosphorus-31 nuclear magnetic resonance spectroscopy of the spinal cord in the pig, rat, and rabbit. AB - RATIONALE AND OBJECTIVES: To ensure that contamination-free phosphorus-31 nuclear magnetic resonance (31P-NMR) spectra of the spinal cord could be obtained, a porcine model was adopted that provided a large cord sample and a greater area free from adjacent muscle tissue. METHODS: Phosphorus-31 NMR spectra were acquired from the porcine spinal cord under in vivo conditions using a 4.7-T spectrometer. Spectra also were collected from perchloric acid and lipid extracts, and excised freeze trapped samples of the rat, rabbit, and pig spinal cord. RESULTS: The in vivo spectrum showed resonances corresponding to adenosine triphosphate, phosphocreatine, inorganic phosphate, phosphomonoesterase, and phosphodiesterase as confirmed by extracts. In addition, a broad resonance was observed that was assigned to myelin phospholipids. CONCLUSION: Phosphorus-31 NMR spectra of the spinal cord revealed resonances common to brain tissue. Importantly, the existence of a previously undetected resonance, which is likely to correspond to myelin phospholipids, also is reported. This resonance may prove important in future studies monitoring changes in myelin in response to trauma and ischemia. PMID- 8675419 TI - Optimal beam quality for chest computed radiography. AB - RATIONALE AND OBJECTIVES: Optimal x-ray beam quality for chest computed radiography (CR) has not been determined. To investigate the optimal beam quality for chest CR, the authors measured the radiographic contrasts and compared the image quality of chest CR and screen-film (SF) radiographs using various x-ray tube voltages. METHODS: Chest CR and SF radiographs were obtained on a phantom lung and human volunteers with or without a variety of simulated lung opacities using various x-ray tube voltage levels. Exposures were set to maintain identical patient exposure doses for all images. The contrast between peripheral lung and rib or heart was measured on these images and the differences were compared. The quality of the images of each simulated opacity was evaluated by five radiologists using a five-point grading scale. RESULTS: Contrast between peripheral lung and rib or heart increased on CR images obtained by lowering the tube voltage from 140 to 80 kV, but the degree of increase was less than half the increase on SF images. The CR images of the simulated opacities obtained using a lower tube voltage were judged to be superior to those obtained with a higher tube voltage. Scattered radiation was reduced on CR images with a lower tube voltage. CONCLUSION: The image quality of chest CR was improved by using a lower tube voltage than that used for conventional SF chest radiography. Considering the problem of tube loading in clinical applications, a tube voltage of 100 kV is recommended for chest CR. PMID- 8675421 TI - Evaluation of selected two-dimensional segmentation techniques for computed tomography quantitation of lymph nodes. AB - RATIONALE AND OBJECTIVES: As contrast agents that selectively target normal lymph nodes are undergoing development and evaluation, it has become important to accurately and reproducibly determine nodal boundaries to study the agents and determine such values as lymph node area or mean nodal contrast concentration. This study was performed to evaluate the accuracy of different two-dimensional computer segmentation methods, tested on acrylic phantoms constructed to imitate the appearance of lymph nodes surrounded by fat. METHODS: Five segmentation techniques (manual tracing, semiautomatic local criteria threshold selection, Sobel/watershed technique, interactive deformable contour algorithm and thresholding) were evaluated using phantoms. Subsequently, the first three methods were applied to the images of enhanced lymph nodes in rabbits. RESULTS: Minimum errors in phantom area measurement (< 5%) and interoperator variation (< 5%) were seen with the Sobel/watershed technique and the interactive deformable contour algorithm. These two techniques were significantly better than thresholding and semiautomated thresholding based on local properties. CONCLUSION: Methods based on Sobel edge detection offer more objective tools than thresholding methods for segmenting objects similar to lymph nodes in computed tomography images. Both methods, Sobel/watershed and interactive deformable contour algorithm, are fast and have simple user interfaces. PMID- 8675420 TI - Granulocyte accumulation in the transplanted liver does not correlate with clinical and histologic evidence of dysfunction. AB - RATIONALE AND OBJECTIVES: To evaluate the role of granulocytes in reperfusion injury after liver transplantation. The authors injected radiolabeled granulocytes to determine if human liver graft outcome could be correlated with granulocyte accumulation. MATERIALS AND METHODS: Pure granulocyte suspension was prepared from eight patients 12 to 24 hours after orthotopic liver transplantation. The granulocytes were labeled with indium-111 (111In) oxine and reinjected. Total body radionuclide images were performed. Liver uptake of granulocytes was compared with biochemical and histologic evidence of liver injury. RESULTS: No correlation was found between liver uptake of granulocytes, as measured by geometric mean counts, and the biochemical or histologic measures of liver injury. Liver uptake of 111In was 9.6% for the patient who had liver dysfunction and 10.4% mean of the study group. This technique did not detect early signs of liver dysfunction. CONCLUSIONS: This investigation supports the premise that granulocytes do not play a major role in reperfusion injury of the newly transplanted liver graft. PMID- 8675422 TI - Computerized identification of suspicious regions for masses in digitized mammograms. AB - RATIONALE AND OBJECTIVES: A simple and effective computerized detection scheme was developed to identify suspicious mass regions in digitized mammograms. METHODS: This method identifies a maximum of five suspicious mass regions per image and was tested with a database of 510 images, including 162 verified masses. It includes a series of five rule-based processes that select one region with each of the following characteristics: 1) a global minimum of optical density in a smoothed image; 2) a local minimum of optical density in the original image; 3) a local minimum of optical density in a filtered image; 4) a small "mass" of low contrast; and 5) a small "mass" of high contrast. RESULTS: This multi-stage process achieved a sensitivity of 95% while limiting false positive detection rates to below an average of two per image. CONCLUSION: Because this method limits the initial number of suspicious mass regions while retaining high sensitivity, it may be applicable to clinically usable computer aided diagnosis schemes. PMID- 8675423 TI - Functional hepatobiliary imaging with gadolinium-EOB-DTPA. A comparison of magnetic resonance imaging and 153gadolinium-EOB-DTPA scintigraphy in rats. AB - RATIONALE AND OBJECTIVES: Gadolinium-EOB-DTPA (Gd-EOB-DTPA) is a hepatobiliary magnetic resonance (MR) imaging contrast medium designed to detect focal liver lesions. The objective of this study was to evaluate dynamic Gd-EOB-DTPA-enhanced MR imaging as a new method for assessing liver excretory function and to compare it with a scintigraphic method, the gold standard. METHODS: Changes in scintigraphic liver activity or MR liver signal intensity were intraindividually monitored over time after intravenous injection of 50 mumol Gd/kg of Gd-EOB-DTPA in controls and rats with common bile duct obstruction or L-ethionine-induced fatty liver (n = 6). RESULTS: A comparison of liver scintigraphy and MR imaging revealed that elimination half-lives of Gd-EOB-DTPA were significantly longer in rats with common bile duct obstruction (scintigraphy: 100 +/- 27 minutes; MR imaging: 59 +/- 18 minutes) or fatty liver (scintigraphy: 94 +/- 30 minutes; MR imaging: 72 +/- 32 minutes) than in controls (scintigraphy: 20 +/- 2 minutes; MR imaging: 18 +/- 3) (P < 0.05). CONCLUSIONS: Like liver scintigraphy, functional MR liver imaging using Gd-EOB-DTPA is feasible and can differentiate normal controls from models of biliary and hepatocyte disease. PMID- 8675424 TI - A model for the modulation transfer function of cardiovascular x-ray systems. AB - RATIONALE AND OBJECTIVES: To derive a theoretical model for the modulation transfer function (MTF) of the complete imaging chain of a cardiovascular x-ray system. A sufficiently accurate MTF model may be used in quantitative coronary arteriographic applications to decrease the systematic overestimation of small coronary vessels. The model could be used to restore blurred images in image restoration applications and also may be used for image quality assurance measurements. METHODS: Digital images of a step wedge phantom were acquired at different modes (5-, 7-, and 9-inch) of the image intensifier and at different kilovolt levels of the x-ray generator. From these images the MTFs that were used to estimate the parameters of the model were assessed. RESULTS: The total MTF of the cardiovascular x-ray imaging chain consisting of image intensifier, video camera, optical elements, and analog/digital converter can be modeled by the simple formula MTF = e-(w/f)R, where w is the frequency in linepairs per millimeter. The constants frequency f and the device index n are parameters that can be derived for an individual x-ray system using the phantom. In this formula, the contribution from the focus of the x-ray source has been excluded. The mean square error (MSE) between the measured values and those assessed from the theoretical model of the MTF for the horizontal direction was found to be equal to 0.00003 for the 5-inch mode of image intensifier, and for the vertical resolution at the 9-inch mode this MSE was equal to 0.00038. In addition, we have demonstrated that the contributions of the video camera and the image intensifier to the total MTF can be replaced by an imaginary electron-optical device. CONCLUSION: An accurate representation for the MTF of a cardiovascular x-ray system has been derived. This MTF model can be used in x-ray image quality assurance measurements and in quantitative image processing applications. PMID- 8675425 TI - Doppler ultrasound of the hepatic artery and vein performed daily in the first two weeks after orthotopic liver transplantation. Useful for the diagnosis of acute rejection? AB - RATIONALE AND OBJECTIVES: To analyze changes in Doppler ultrasound variables in relation to liver biopsy findings for the diagnosis of acute rejection after orthotopic liver transplantation (OLT), the authors performed in a prospective study 316 Doppler ultrasound examinations in the first 2 weeks after OLT on 23 patients. METHODS: Recordings were obtained daily from the hepatic artery (resistive index [RI]) and hepatic vein (damping index [DI]). Correlations were explored between the Doppler ultrasound findings and histologic data. The chi square test was used to analyze differences in Doppler ultrasound variables in patients with and without acute rejection. RESULTS: Serial Doppler ultrasound examinations showed a significant increase in the RI in 11 of 22 patients (50%); the 23rd patient was excluded because of hepatic artery thrombosis. Despite an agreement in 15 of 22 patients (68%) no statistically significant correlation could be found (positive predictive value 6/11 = 55%; negative predictive value 9/11 = 82%; chi-square = 3.14; P > 0.05). A significant increase in the DI was observed in 14 of 23 patients (61%). However, no statistically significant correlation could be found as well with this parameter (positive predictive value 6/14 = 43%; negative predictive value 6/9 = 67%; chi-square = 0.00; P > 0.05). CONCLUSION: Serial Doppler ultrasound examinations were not helpful in predicting acute rejection. PMID- 8675426 TI - Effect of hyperbaric oxygen on the immunoreactivity to substance P in the nasal mucosa of cluster headache patients. AB - Exposure to hyperbaric oxygen has been shown to be effective in cluster headache, but the mechanism of the action is still not clear. Primary nociceptive neurons, containing neuropeptides such as substance P and particularly those innervating the nasal mucosa, could be involved in the pathogenesis of cluster headache. The present study evaluated the effect of an exposure to hyperbaric oxygen on the content of substance P in the nasal mucosa of patients affected by cluster headache. The results were compared with those observed in another group of cluster headache patients who underwent a placebo procedure. The samples of nasal mucosa were analyzed by immunocytochemical methods. A qualitative analysis of the slides was carried out by an operator under "blinded conditions". A marked decrease in the content of immunoreactivity for substance P was found in the patients exposed to hyperbaric oxygen. The decrease was statistically significant when compared with the findings of the placebo procedure. The results of the present study indicate that an influence on the content of peripheral neuropeptides could be involved in the mechanism of action of the beneficial effect of hyperbaric oxygen in cluster headache. PMID- 8675427 TI - Pediatric headaches: what do the children want? AB - One hundred consecutive children (aged 3 to 17 years), drawn from primary care pediatric clinics, with a greater than 3-month history of headaches completed surveys to determine the type and associated features of their headache and to query their reasons for wanting to see a physician. Additionally, the children were asked to draw pictures of how they felt when they had a headache to assess their nonverbal perceptions. Over 90% of the headaches were migrainous (65% common, 23% classic, 5% basilar). The children wanted three answers from the physician: what was the cause of their headache, what would make it better, and reassurance that they had no life-threatening illness. Furthermore, 33% of the children's illustrations disclosed depressive features of helplessness, frustration, and anger. Over 20% of the adolescents depicted themselves as dead, dying, or about to be killed by their headache. PMID- 8675428 TI - IHS criteria for migraine and tension-type headache in children and adolescents. AB - We investigated the influence of age on the IHS criteria for migraine and tension type headache in 437 consecutive children and adolescents and found the following age-associated statistically significant differences: migraine duration, occurrence of migraine aura, and bilateral location of tension-type headache were more often fulfilled by adolescents, whereas aggravation of headache by physical activity (in migrainous disorder) and photophobia (in migraine with aura) were more often fulfilled by children. Accordingly, there are only a few differences concerning the fulfillment of the IHS criteria for migraine and tension-type headache in children and adolescents. Independent of age, the intensity of headache and the presence or absence of nausea are most important for differentiating the two major types of idiopathic headache. The sensitivity of the IHS criteria for migraine could be increased by reducing the minimum duration of migraine and by allowing the diagnosis of migraine when severe headache is associated with nausea, even though the criteria of location, quality, and aggravation by physical activity are not fulfilled. PMID- 8675429 TI - Divalproex sodium: migraine treatment and monitoring. AB - Divalproex sodium is an effective drug for the treatment of migraine. Most adverse drug events are transient and not of great clinical concern. Although rare, well-documented examples of liver toxicity have been reported in children under 2 years of age on polypharmacy. Additional cases occur in children under 10 who are receiving polypharmacy, particularly those who have intractable seizures and degenerative central nervous system disease. Clinicians who treat migraineurs with divalproex sodium do not need to be overly preoccupied with monitoring of drug levels and liver function tests. The most valuable test is clinical observation of the patient. PMID- 8675430 TI - Outdoor pollution and headache. AB - The aim of this study was to clarify a possible relationship between pollution and worsening of headache in the industrial city of Turin. From October 1992 to June 1993, we examined a group of 32 patients suffering from various headache types. During these months, they kept a daily record of their headaches and associated disturbances. Changes in pain frequency and severity were recorded every hour of the day and compared hour to hour with the various degrees of pollution recorded in the main streets by a monitoring station. The influence of meteorological parameters was also taken into consideration. During winter, carbon monoxide and nitrogen dioxide showed a simultaneous hyperconcentration on the same days and the same hours. Increased incidence of headache attacks and increase in severity corresponded to the same hours, days, and months. The findings were statistically significant (P = 0.008, Student's t-test). An isolated increase in nitrogen dioxide only (without an increase in carbon monoxide which was only recorded once) induced headache a couple of hours after the peak concentration was reached. Among the meteorological factors, only the highest values in wind velocity were shown to exert a significant influence on worsening headache frequency and severity. PMID- 8675431 TI - Descriptive features and causal attributions of headache in an Australian community. AB - The reported characteristics and causes of headache differ across individuals and between groups. Such differences are of interest from an epidemiological point of view. This study set out to identify the main descriptive features and causal attributions of headache within an Australian urban community. A sample of 261 subjects reporting headache volunteered to participate in the survey. Subjects completed a self-report questionnaire for assessing demographic variables, headache parameters (intensity, duration, etc), headache medication habits, and perceived causes of one's headache (as in the UK headache survey by Blau, 1990). Results revealed that the typical headache sufferer was a middle-aged employed individual. Migraine versus tension headache were equivalent in number, and on the average, subjects experienced moderate intensity, day-long headaches that recurred about nine times per month. With regard to causal attributions, the prevalence of headaches due to mental stress was higher than that due to any other single stimulus (eg, noise, exercise), and alcohol was the most frequent dietary cause of headache. These findings are generally consistent with those from previous surveys, although some interesting departures emerge which may be accounted for by demographic differences in the populations studied. PMID- 8675432 TI - Benign Valsalva's maneuver-related headache: an MRI study of six cases. AB - Cough headache is not infrequent, but there have not been any series studied with current neuroimaging techniques, and effective therapy has seldom been reported. In a large series from an outpatient clinic of a general hospital, we have studied, with MRI, eight cases of headache related to situations provoking sudden increase of intrathoracic pressure (cough, straining, stooping), similar to that elicited by a Valsalva's maneuver. One case showed hindbrain herniation and another showed isolated hydrocephalus. Symptoms did not differ between these two cases and the six cases without MRI abnormality. Initial symptoms presented between 49 and 67 years of age, and headache was of variable location and duration, mostly global and short-lasting. During a mean follow-up of 13.3 months, one patient became spontaneously asymptomatic, one improved on indomethacin, and two improved after treatment with propranolol. We propose the eponym, benign Valsalva's maneuver-related headache (as more appropriate than the equivalent "cough headache"), for cases in which headache is related to such situations and structural lesions are excluded by MRI or similar tests. PMID- 8675433 TI - Exclusion of 5-HT2A and 5-HT2C receptor genes as candidate genes for migraine. AB - Several lines of investigation suggest that the serotonergic system may be involved in the pathogenesis of migraine. In particular, drugs which block 5-HT2 receptor subtypes appear to be effective migraine prophylactic agents. Therefore, chromosomal DNA regions overlapping the 5-HT2A (13q14-q22) and 5-HT2C(Xq22-25) receptor loci were analyzed for possible linkage to the clinical diagnosis of migraine. No evidence for linkage to either chromosomal region was found, although a small subset of migrainous families showed positive likelihood of odds (LOD) scores. However, a homogeneity (HOMOG) analysis provided no statistical evidence for locus heterogeneity. The coding region of the 5-HT2A and 5-HT2C receptor genes was also analyzed in migraine patients and unaffected controls using polmerase chain reaction and direct sequencing. No mutations were found in the deduced amino acid sequence of either receptor in the sample of migraineurs tested. These results indicate that DNA-based mutations in the 5-HT2A and 5-HT2C receptors are not generally involved in the pathogenesis of migraine. PMID- 8675434 TI - Clusterlike headache as a first sign of brain metastases of lung cancer. AB - We report on a patient with clusterlike headache and multiple brain metastases of lung cancer. Initially, cluster headache was suggested clinically by characteristic symptoms without any focal central nervous system signs. However, magnetic resonance imaging demonstrated multiple brain metastases. It is possible that tumor necrosis factor may have played a role in initiating the clusterlike headache. PMID- 8675436 TI - Using physician claims to identify postoperative complications of carotid endarterectomy. AB - OBJECTIVE: This study develops a methodology for identifying complications following carotid endarterectomy, using physician claims data. DATA SOURCES/STUDY SETTING: We selected a random 20 percent sample of Medicare patients undergoing carotid endarterectomy in 1991 (n = 8,345) and extracted all of their claims. STUDY DESIGN: Project neurologists identified the following services as indicative of complications following carotid endarterectomy if they were provided within 30 days of surgery: head CT, head MRI, and surgical exploration of the neck for hemorrhage, thrombosis, or infection. DATA COLLECTION/EXTRACTION METHODS: Total costs were calculated from all claims associated with the hospitalization and the 30-day postoperative period. Outcomes included mortality (obtained from Medicare eligibility files), length of stay, discharge to an institution, and readmission to an acute care hospital (the latter obtained from claims data). PRINCIPAL FINDINGS: Surgical complications were identified in one out of every ten endarterectomy patients (10.3 percent). Patients with complications were significantly more likely to die within 30 days of surgery (8.9 percent, compared with 1.1 percent of those not experiencing complications). They also were significantly more likely to be discharged to an institutional setting (24.9 percent versus 2.9 percent), and more likely to be readmitted to acute care hospitals (26.8 percent versus 8.2 percent). Patients with postoperative complications also were significantly more expensive: $22,187 versus $10,892. CONCLUSION: Our findings suggest that physician claims could be used by PROs or similar entities as a screening tool to identify potential problem hospitals or problem surgeons. First, however, the methodology would need to be clinically validated. PMID- 8675435 TI - Demographic variation in the rate of knee replacement: a multi-year analysis. AB - OBJECTIVE: The aim of this study is to describe the practice variation of knee replacements (KRs) in the elderly ( > or = 65) over time from 1985-1990 in terms of the number of primary, bilateral, and revision KRs; the extent of large area variation in performance rates; and the degree to which demographic variables are the determinants of area rates. DATA SOURCES/STUDY SETTING: Data analyzed are from every hospital in the United States that performed a KR on a Medicare patient during the study period. Data were obtained from the MEDPAR, HISKEW, and denominator files of the Medicare Statistical System. STUDY DESIGN: This is a cohort study of all Medicare beneficiaries who received a KR between 1985 and 1990. The dependent variable in the analyses was the count of the KRs performed in each area. DATA COLLECTION/EXTRACTION METHODS: This is a population-based sample of Medicare enrollees in the United States. All hospitalizations for Medicare-reimbursed KRs were included in the initial data set. Exclusion criteria were used to identify the Medicare covered population with a definite KR. These criteria resulted in 7.3 percent exclusions and a final set of 414,079 KR hospitalizations. PRINCIPAL FINDINGS: The number of Medicare-funded KRs increased in each of the study years corresponding to an annual rate of increase of 18.45 percent. The likelihood of receiving a KR was a function of age, gender, and race. For each year, KRs were almost-twice as likely to be performed on women than on men. The odds of whites getting the surgery were over 1.5 times greater than for blacks. Even after adjusting for demographic factors, significant regional variation remained. CONCLUSIONS: Much about area variation and the rate of growth in KR rates remains unexplained. For answers to emerge, better data and different types of studies are required. PMID- 8675437 TI - Measuring hospital use without claims: a comparison of patient and provider reports. AB - OBJECTIVE: We compared the validity of hospital admission and length of stay reports from patients, outpatient providers, and hospitals, and we examined possible sources of error. DATA SOURCES: Data were collected from people enrolled in a randomized trial of treatment for severe mental illness and substance use disorders, from community mental health centers (CMHCs), and from hospitals. Reports for each of the 74 study participants covered two-year time periods beginning and ending at various times between 1989 and 1993. STUDY DESIGN: We compared reports from the various sources and constructed a hybrid with data from all three sources. Using parametric and non-parametric statistics, we compared patient, CMHC, and hospital reports with each other and with the hybrid source. In subsequent regression analyses we explored correlates of reporting accuracy. PRINCIPAL FINDINGS: Single-source reports underestimated hospital use, but when patient and CMHC reports were combined, results were very similar to those obtained by the more laborious hybrid method. Patient reports became less accurate as the time between discharge and reporting increased; people with bipolar disorders reported admissions with greater accuracy than did people with schizophrenia. CMHC reporting accuracy decreased as the distance to the admitting hospital increased and were less accurate for people with more severe psychiatric symptoms. CONCLUSIONS: Reports from single sources are likely to underestimate hospital use for different reasons. Combining carefully collected data from patients and outpatient providers produces estimates of hospital use that are substantially the same as those developed through methods that are more laborious and costly. PMID- 8675438 TI - Reactions of salaried physicians to hospital decline. AB - OBJECTIVE: To examine the Exit, Loyalty, Voice, and Neglect (ELVN) reactions of full-time salaried physicians to the decline of their employing hospital, and to explore factors possibly associated with the choice of reactions. DATA SOURCE: The study analyzes data collected in a larger survey of work attitudes of 703 hospital physicians, constituting a representative national sample of (every tenth) salaried hospital physicians in Israel. DATA COLLECTION: Data were collected through a self-administered mail questionnaire with return envelopes attached. STUDY DESIGN: A survey design was used. Survey questionnaires included composite measures of the ELVN reaction as well as of the main predictors of reaction choice: job satisfaction, hospital commitment, job investment, alternatives, tenure, and managerial and senior positions. PRINCIPAL FINDINGS: The reactions of salaried physicians to hospital decline include the whole range of ELVN reactions. The choice of each reaction was found associated with a different set of disposition, situation, and position predictors. CONCLUSIONS: The ELVN typology is relevant for examining physicians' reactions to hospital decline, which appear to extend beyond the simple stay/leave dichotomy commonly used. The reactions of Exit, Loyalty, Voice, and Neglect are different in nature, and appear to reflect the different sets of circumstances that salaried physicians may face. Implications of these results for coping with hospital decline, hospital-physician relationships, and integration strategies are discussed. PMID- 8675439 TI - Physician impact on hospital admission and on mortality rates in the Medicare population. AB - OBJECTIVE: We assess the effect of variations in the supply and specialty distribution of physicians on admission rates for ambulatory care-sensitive conditions (ACS) and for all causes, and on mortality rates among Medicare beneficiaries of various health care service areas (HCSA). DATA SOURCES: For the Medicare beneficiaries, sources were the Health Care Financing Administration's 1992 enrollment and impatient (Part A) files for a 5 percent sample of that population; for the overall populations and for the medical resources of the HCSAs, the Area Resource File. STUDY DESIGN: This observational, cross-sectional study employed multiple linear regression to assess the influence of population characteristics and of the supply of physicians on hospital admissions, and Poisson regression in the analysis of the factors that affect mortality. PRINCIPAL FINDINGS: Physician supply levels vary nearly fourfold or more when comparing the top and bottom deciles of the HCSAs, Medicare admissions for ACS conditions vary about threefold, and admission rates for all causes and mortality rates vary about 1.5-fold. Physician supply levels and distributions have very little influence on ACS admission rates, and even less on the admissions for all causes and on mortality, except in HCSAs with very low physician supply levels (one-fourth the national average or less). However, these HCSAs account for only about 1 percent of the U.S. population. CONCLUSIONS: Physician supply levels and the proportions of specialists and generalists have negligible effects on health status as measured by mortality rates and by rates of admission for all causes and for conditions presumed to be sensitive to the adequacy of ambulatory care. Reductions in admissions for such conditions are not likely to be achieved through broadening of insurance to levels that exist under Medicare, nor through increases in the supply of physicians, nor, conversely, through a reduction in any presumed oversupply of physicians. PMID- 8675440 TI - Mobile technology in rural hospitals: the case of the CT scanner. AB - OBJECTIVE: This study evaluates the relationship between hospital and regional characteristics and the prevalence of mobile computed tomography in rural hospitals. DATA SOURCES AND STUDY SETTING: Primary data were gathered from all rural hospitals in eight northwestern states (n = 471) in 1991. Secondary data sources include the AHA Annual Survey, the Area Resource File, and HCFA's PPS data sets for 1987-1990. STUDY DESIGN: Primary data are a single observation taken in the summer of 1991. Key hospital characteristics include patient volume, distance to the nearest referral center, distance to the nearest hospital, financial performance, and medical staff size. Key regional variables include beds per unit area, hospitals per unit area, and physician supply. DATA COLLECTION: A structured telephone interview was conducted with the hospital administrator at each hospital. For many hospitals, detailed information was gathered with additional calls to hospital personnel. PRINCIPAL FINDINGS: Where hospitals are closely spaced, mobile CT suppliers are more readily available, and hospitals are more likely to choose mobile CT than in areas where hospitals are farther apart. Hospitals may realize economies of scale and scope in their decisions about CT adoption. CONCLUSIONS: Transportation costs are an important determinant of hospital decisions about acquiring CT, but may be less important for higher-priced medical technologies. There is no support for the proposition that rural hospitals compete with referral centers for patients by purchasing technological equipment. PMID- 8675441 TI - Localization of the telomeric (TTAGGG)n sequences in chromosomes of some domestic animals by fluorescence in situ hybridization. AB - Fluorescence in situ hybridization analysis was carried out on metaphase preparations of a variety of domestic animal species, viz. pigs, cattle, sheep, river buffaloes, swamp buffaloes, horses, and reindeers, using a PCR generated human telomere repeat probe (TTAGGG)n. Three protocols with different hybridization/washing stringencies were applied. Distinct double spots representing the telomeric sites were observed on either ends of the chromosomes in all the species studied, confirming that one-armed chromosomes are not completely telocentric. In pigs, an interstitial telomeric signal was observed on the 6q22 band of all the individuals examined. Although a random variation in the intensity of signals was observed, it was interesting to note that in one of the five cattle studied, very strong hybridization signals were seen on at least three pairs of chromosomes. In sheep, river buffaloes, and swamp buffaloes, where the biarmed chromosomes are considered to be the result of the fusion of 2-3 one armed chromosomes of the cattle karyotype, no interstitial telomeric signals were observed. PMID- 8675442 TI - Cytological evaluation of global DNA methylation in mouse testicular genome. AB - Global methylation of DNA from different testicular cell types has been studied by DNA end-labeling and nick translation of fixed chromatin (in situ), following digestion with cytosine methylation-sensitive restriction enzymes. Both at the level of chromatic (chromosome) and naked DNA, there is extensive methylation of the genome. Although the extent of methylation was nearly the same among different cell types in the MspI, HpaII, and HhaI digested end-labelled DNA, in the chromosome preparations the digestion patterns varied in cell type-specific manner, pachytene being the most sensitive and spermatids and sperm the most resistant. The differential sensitivity is attributable to the difference in the chromatin organisation in different testicular cell types though no specific region could be identified as particularly more sensitive or resistant to the enzymes. Pachytene bivalents do not reveal a consistent segmental pattern of digestion, but the perichiasmate regions of diplotene/diakinesis and metaphase I chromosomes show hypersensitivity to the enzymes. PMID- 8675443 TI - Developing microsatellite markers for insect population structure: complex variation in a checkerspot butterfly. AB - We isolated and characterized two microsatellite markers from the genome of the endangered checkerspot butterfly Melitaea cinxia L. In Finland, this species only survives on the Aland islands, where it exhibits a highly fragmented metapopulation structure on small meadows. Four alleles were observed at the locus CINX1 and nine at CINX4; the total gene diversities at the two loci were HT = 0.34 and 0.80, respectively. A pilot survey showed moderate gene frequency differentiation among meadows (local populations; FLM = 0.1) and among metapopulations c. 30 km apart (FMT = 0.2). Contrary to prior expectation, distinct feeding larval groups collected in the spring did not represent offspring of single females. There was a conspicuous excess of homozygotes within local populations (FIL = 0.35), which can hardly be attributed to population structure alone; this urges caution in straightforward interpretation of microsatellite phenotype data. PMID- 8675445 TI - The social "instinct". PMID- 8675444 TI - Psychodynamics and neurobiology: an integrated approach. PMID- 8675446 TI - The application of psychotherapeutic and self psychology principles to hostage negotiations. AB - Self psychology provides valuable insights into the dynamics that underlie hostage situations and negotiations. Recognition of the similarities between negotiations and psychotherapy further clarifies the complex interactions that occur. The importance of empathy and the development of selfobject relationships will have a significant impact on the resolution of the incident. Recognition of selfobject transferences and the indicators of self fragmentation will help to guide the negotiator and mental health consultants in their conduct of the negotiations. The complex relationships that develop between hostage-taker, hostages, and negotiators can all be understood within the framework of self psychology, leading to the more effective management of these situations. PMID- 8675447 TI - The moral perspective and the psychoanalytic quest. PMID- 8675448 TI - The psychoanalytic treatment of ulcerative colitis revisited. AB - A review of the literature indicates that very little is known about the role of psychological factors in the etiology, exacerbation, and treatment of ulcerative colitis. Most phenomenological consensus seems to take place around recognizing that the patient has great difficulty in expressing aggression and is frightened of loss of control. Episodes of ulcerative colitis are often related to the sudden loss of an important love-object and/or severe narcissistic wounding. Chronic narcissistic rage is not at the center of the psychological phenomena as I (Chessick, 1985) have described it in narcissistic psychosomatic disorders. In ulcerative colitis, acute episodes of object loss, narcissistic wounding, or bitter disappointment, along with a sense of entrapment and helplessness, produce the threat of an explosion of uncontrollable rage. Such an explosion would result in disruption of the patient's life and expulsion from significant and needed relationships. This produces an acute internal conflict, hopelessness, and despair, with the danger of resolution by paranoid projection. Why in these patients these events seem to be followed by changes in the colonic mucosa is simply unknown, nor is it clear whether they are related to these changes directly or indirectly. The defensive inability to feel the archaic rage at early significant caretakers or their later life substitutes is clearly an important determinant of the psychosomatic condition. I believe that the treatment problems raised by the patient presented here are fairly typical of what will be encountered in any effort to psychoanalyze a patient with ulcerative colitis. Perhaps because of the failure of Alexander's specificity hypothesis, there has been a loss of interest in the psychoanalytic treatment of such patients, and this is regrettable because at least some of them, like the present case, respond well and it makes a vital difference in their future. One certainly cannot say that psychoanalytic treatment represents any sort of "cure" for ulcerative colitis, but it seems clear that resolving underlying psychopathology to whatever extent is possible lessens the chance for ulcerative colitis to be exacerbated by stressful events, such as severe narcissistic wounding or substantial unexpected object loss, because the ego has been strengthened and the patient has an improved tension-reduction capacity. Psychoanalysts should not be afraid to consider the treatment of such patients as long as they are not in the acute phase of the disease. Acute manifestations require active medical, pharmacological, and supportive psychological intervention. PMID- 8675449 TI - Psychoanalysis and empirical research: the example of patients who lack psychological mindedness. PMID- 8675450 TI - Value issues involving western psychoanalysts with Asian patients. PMID- 8675451 TI - "The 'Bad Mother' Freud has never seen": Otto Rank and the birth of object relations theory. PMID- 8675452 TI - George Bernard Shaw's Pygmalion: a creative response to loss after early childhood trauma. PMID- 8675453 TI - Multilateral transference relationship and therapeutic regression-a case report. AB - In this work, we have presented the treatment of a young woman with a psychotic character disorder, and we have described the multilateral transference configuration that derived from the treatment of this disorder. We have described some of the manifestations of this multivalent transference, and have described some aspects of its role in the patient's treatment. The theoretical background has been outlined. Although this transference configuration is relatively unique, we think that the nature of the treatment team that arose in this situation might have treatment implications for others with this disorder. PMID- 8675454 TI - The impact of contemporary genetics on psychoanalysis. PMID- 8675455 TI - The WHO recommendations on BSE: what they mean to the United States. PMID- 8675456 TI - Reopening Russia's doors to US poultry: the team approach pays off. PMID- 8675457 TI - Microbial carcass reduction technologies count. PMID- 8675458 TI - Reminder on effects of DDT. PMID- 8675459 TI - Another opinion on xenotransplantation. PMID- 8675460 TI - Total quality management in veterinary medicine--a blinding flash of the obvious. PMID- 8675461 TI - The immorality of nonhuman animal research. PMID- 8675462 TI - Veterinarians are not all created equal. PMID- 8675463 TI - What is your diagnosis? Severe cranioventral alveolar lung disease and generalized megaesophagus, with gastric dilatation and duodenal obstruction. PMID- 8675464 TI - ECG of the month. Respiratory sinus arrhythmia and wandering pacemaker in a cat. PMID- 8675465 TI - Animal behavior case of the month. A cat was referred for evaluation of self mutilation. PMID- 8675467 TI - Updating the art of leadership. PMID- 8675466 TI - Veterinary nutritional management of amphibians and reptiles. PMID- 8675468 TI - Restrictive covenants: recent cases, court modification, and statutory provisions. PMID- 8675469 TI - Postexposure rabies prophylaxis and preexposure rabies vaccination failure in domestic animals. AB - OBJECTIVES: To determine the effectiveness of postexposure rabies prophylaxis (PEX) recommendations, as mandated by the state of Texas, and to investigate PEX and preexposure rabies vaccination failures. DESIGN: Retrospective study. ANIMALS: 1,345 unvaccinated domestic animals that had received PEX and 6 animals that had preexposure rabies vaccination failure. PROCEDURE: Zoonotic incident case report forms from 1979 through 1994 were reviewed for information about unvaccinated domestic animals that received PEX after exposure to a rabid animal, according to state protocol; the reports were also reviewed for information about preexposure rabies vaccination failures. From 1979 through 1987, the PEX protocol was to immediately vaccinate the animal against rabies, isolate it for 6 months, and administer a booster vaccination 1 month prior to release from isolation. From 1988 through 1994, the protocol was to immediately vaccinate the animal against rabies, isolate it for 90 days, and give booster vaccinations during the third and eighth weeks of the isolation period. RESULTS: From 1979 through 1987, 713 animals received PEX; 2 failures were recorded. From 1988 through 1994, 632 animals received PEX; 3 failures were recorded. From 1991 through 1994, 6 preexposure rabies vaccination failures were recorded. CLINICAL IMPLICATIONS: An effective PEX schedule for domestic animals includes immediate rabies vaccination, with a minimum of 1 booster vaccination, and 90 days' strict isolation. PMID- 8675470 TI - Chemical restraint and anesthesia of sea otters affected by the oil spill in Prince William Sound, Alaska. PMID- 8675471 TI - Evaluation of shelf arthroplasty as a treatment for hip dysplasia in dogs. AB - OBJECTIVE: To evaluate effects of shelf arthroplasty on coxofemoral joint laxity and progression of degenerative joint disease in young dogs with hip dysplasia. DESIGN: Prospective, controlled study. ANIMALS: 10 dogs between 10 and 24 months old and weighing between 20 and 27 kg. All dogs had bilateral coxofemoral joint laxity (i.e., an Ortolani's sign). PROCEDURE: In all dogs, shelf arthroplasty was performed on the right coxofemoral joints, and a sham procedure was performed on the left. Dogs were evaluated before and after surgery by means of lameness assessment, coxofemoral joint palpation and goniometry, thigh circumference measurement, and radiography. RESULTS: There were no significant changes in coxofemoral joint mobility, range of motion, joint laxity, degree of degenerative joint disease, or thigh circumference during the study. A greater amount of periacetabular bone formed on the right side than on the left side; however, dogs did not develop large bony shelves, and the amount of periarticular bone decreased over time. The polymer implants remained in their original position and were encapsulated by fibrous tissue. There was no histologic evidence of osteoconduction by the implants. CLINICAL IMPLICATIONS: The polymer implants used in this procedure do not appear to be osteoconductive. Shelf arthroplasty was associated with minimal morbidity and was not associated with serious adverse sequelae in this study, but the procedure did not alter the progression of hip dysplasia in these dogs. We cannot advocate shelf arthroplasty using this polymer as a treatment for dogs with hip dysplasia. PMID- 8675472 TI - Magnetic resonance imaging of the brain for diagnosis of neurocysticercosis in a dog. AB - Neurocysticercosis was diagnosed in a 2-year-old spayed Whippet by use of magnetic resonance imaging. The dog was evaluated because of a 3-month history of slowly progressive balance and directional abnormalities, which were indicative of brain stem disease. Magnetic resonance imaging of the brain and CSF analysis were chosen as the best diagnostic modalities for determination of the primary disease. Results of CSF analysis were within reference ranges. Examination of T1 weighted, contrast-enhanced, 3-mm-thick axial, sagittal, and coronal views of the brain revealed multiple cyst-like lesions. The cysts had high-signal-intensity, ring-like peripheral margins and were located in the subdural portion of the left occipital lobe and the dorsal midline and right dorsolateral aspect of the brain stem. A tentative diagnosis of neurocysticercosis was made on the basis of similar findings in human beings with this disease. Treatment with albendazole and prednisone was initiated, and clinical signs resolved during the following weeks. Repeat magnetic resonance imaging confirmed resolution of the disease. PMID- 8675473 TI - Multiple extrahepatic portosystemic shunts in dogs: 30 cases (1981-1993). AB - OBJECTIVE: To describe the long-term outcome in dogs with naturally developing multiple extrahepatic portosystemic shunts (PSS). DESIGN: Retrospective case series. ANIMALS: 30 dogs with multiple PSS. PROCEDURE: Medical records of dogs with multiple PSS were reviewed. Follow-up data were obtained by 1 or more of the following methods: recheck at the veterinary teaching hospital (n = 6) or telephone contact with the referring veterinarian (n = 18) or owner (n = 10). The chi 2 or Mann-Whitney rank sum test was used to determine the association of clinical factors with long-term outcome. Survival curves were generated by the Kaplan-Meier product limit method. RESULTS: Median age at diagnosis was 1 year. Findings on exploratory surgery in 25 dogs included ascites; numerous tortuous vessels connecting the portal vein with systemic veins; a small, misshapen liver; and an enlarged portal vein. The most common lesions on histologic evaluation of hepatic tissue specimens were hepatocellular atrophy, portal vascular duplication, cirrhosis, inflammation, and bile duct proliferation. Twelve dogs were treated surgically with vena caval banding, whereas 13 dogs were treated conservatively with dietary restriction of protein and administration of antibiotics, diuretics, and other drugs. Long-term survival and quality of life were similar in dogs from both treatment groups. Median follow-up interval in dogs that survived hospitalization was 24 months (range, 1 to 54 months). CLINICAL IMPLICATIONS: On the basis of these findings, vena caval banding in dogs with multiple PSS is not superior to medical and nutritional treatment. PMID- 8675474 TI - Factors associated with perioperative mortality in dogs with surgically managed gastric dilatation-volvulus: 137 cases (1988-1993). AB - OBJECTIVE: To evaluate factors associated with perioperative mortality in dogs with gastric dilatation-volvulus and to determine the influence of treatment differences between university and private specialty practices on outcome. DESIGN: Retrospective analysis of medical records. ANIMALS: 137 dogs with gastric dilatation-volvulus. PROCEDURE: Signalment; frequency of preoperative and postoperative treatments and complications; intraoperative findings; surgical technique; and hematologic, serum biochemical, and electrocardiographic results were recorded, evaluated for association with mortality, and compared between institutions. RESULTS: Mortality did not differ between institutions, and overall mortality was 18% (24/137). Surgical techniques differed between institutions, but were not associated with mortality. Gastric necrosis was associated with significantly higher mortality (46%; 13/28). When partial gastrectomy or splenectomy was performed, mortality (35 and 32% or 8/23 and 10/31, respectively) was significantly increased. Splenectomy was performed in 11 of 23 dogs requiring partial gastrectomy, and when both procedures were performed, mortality (55%; 6/11) was significantly increased. Preoperative cardiac arrhythmias were associated with significantly higher mortality (38%; 6/16). Mortality in dogs > 10 years old was not significantly greater than that in younger dogs. CLINICAL IMPLICATIONS: Patient management differences between practices did not seem to influence survival in dogs with surgically managed gastric dilatation-volvulus. Signalment, including age, did not influence mortality. Gastric necrosis, gastric resection, splenectomy, and preoperative cardiac arrhythmias were associated with mortality > 30%. PMID- 8675476 TI - Rattlesnake venom poisoning in horses: 32 cases (1973-1993). AB - OBJECTIVE: To determine the clinical manifestations, morbidity, mortality, and treatment methods for rattlesnake venom poisoning in horses. DESIGN: Retrospective analysis of medical records. ANIMALS: 27 horses with acute venom poisoning attributable to prairie rattlesnakes, and 5 with chronic problems subsequent to a rattlesnake bite. RESULTS: Most horses were bitten on or near the muzzle while on pasture, resulting in head swelling, dyspnea, and epistaxis. Additional manifestations of acute poisoning included fever, tachycardia, tachypnea, cardiac arrhythmia, hemolytic anemia, thrombocytopenia, hemorrhage, thrombosis of venipuncture sites, colic, diarrhea, and prehensile and masticatory dysfunction. Chronic problems included cardiac disease, pneumonia, laminitis, pharyngeal paralysis, and wound complications. The most common chronic problem was cardiac disease. The most commonly used treatments were antibiotics, nonsteroidal anti-inflammatory drugs, tetanus prophylaxis, and airway support. Mortality in the 27 acutely affected horses was 18.5%; the overall mortality was 25%. CLINICAL IMPLICATIONS: Horses bitten by prairie rattle-snakes may develop multiple, often severe, acute or chronic manifestations of poisoning involving various organ systems. Thorough clinical evaluation, effective treatment, supportive care, and close observation are indicated in horses with rattlesnake venom poisoning. PMID- 8675475 TI - Hyperkalemic periodic paralysis episode during halothane anesthesia in a horse. AB - A 7-month-old Quarter Horse filly was admitted for surgical repair of a right olecranon fracture. Anesthesia was achieved with xylazine hydrochloride, guaifenesin, ketamine hydrochloride, and halothane. Two and a half hours after induction of anesthesia, myotonia, muscle fasciculations, and sweating, concurrent with high serum potassium concentration and associated electrocardiographic changes consistent with hyperkalemic periodic paralysis, were observed. Treatment included intermittent positive-pressure ventilation, changing intravenous administration of fluids from lactated Ringer's solution to 0.9% NaCl solution, and administration of calcium gluconate, glycopyrrolate, dopamine, and sodium bicarbonate. Clinical signs resolved with the return of serum potassium concentrations to the reference range. The horse was confirmed to be heterozygous for hyperkalemic periodic paralysis by DNA testing. PMID- 8675477 TI - Associations between subclinical paratuberculosis and milk production, milk components, and somatic cell counts in dairy herds. AB - OBJECTIVE: To determine associations between subclinical Mycobacterium paratuberculosis infection and milk production, milk components, and somatic cell counts of dairy cattle. DESIGN: Cross-sectional epidemiologic survey. ANIMALS: 23 dairy herds in Wisconsin containing 1,653 adult cows were studied. The herds had above average milk production and a history of bovine paratuberculosis in the herd within the previous 12 months. PROCEDURE: All adult cows in the herds were tested for paratuberculosis by use of an absorbed ELISA. Milk yield, fat, protein, and somatic cell count data were retrieved electronically from Dairy Herd Improvement Association records. RESULTS: 147 ELISA-positive and 1,506 ELISA negative cows were identified. ELISA-positive cows had a mature-equivalent milk production of 376 kg (829 lb)/lactation less than that for ELISA-negative herdmates. Significant difference was not found in lactation average percent-ages of fat and protein, or somatic cell count linear score. When comparing ELISA positive and -negative cow's current mature equivalent milk with all previous lactations, significant difference was found only from the immediate-preceding lactation. When this difference was examined by parity group, significant difference was confined to cows in the second lactation. CLINICAL IMPLICATIONS: Subclinical paratuberculosis infections, as determined by ELISA, are associated with a 4% reduction in milk yield and add to the already substantial costs of clinical M paratuberculosis infection in the dairy industry. PMID- 8675478 TI - Epidemiologic study of on-farm management practices associated with prevalence of Mycobacterium paratuberculosis infections in dairy cattle. AB - OBJECTIVE: To use an on-farm recording form to quantity the effect of specific management practices on apparent prevalence of Mycobacterium paratuberculosis in dairy cattle herds. DESIGN: Epidemiologic survey. ANIMALS: 26 commercial Wisconsin dairy farms. PROCEDURES: An instrument was developed on the basis of literature review and expert interviews to quantify on-farm management practices associated with increased apparent prevalence of M paratuberculosis. On-farm visits were conducted to assess how specific management practices were conducted. Apparent prevalence of M paratuberculosis infection was measured for all animals > 20 months old on all farms, using a commercial ELISA. Regression analysis was used to identify management variables that were significantly associated with apparent prevalence of M paratuberculosis. RESULTS: Regression analysis (R2 = 0.90) identified that high scores for environmental conditions, newborn calf care, grower calf care, bred heifer care, and manure handling were significantly associated with M paratuberculosis apparent prevalence in Wisconsin dairy herds. CLINICAL IMPLICATIONS: Environmental conditions, newborn calf care, grower calf management, bred heifer management, and manure handling factors may serve as a prioritized checklist for instructing owners and managers where to place emphasis in changing management practices to limit M paratuberculosis prevalence. Likewise, the factors identified as having low association with apparent prevalence may be de-emphasized in control programs, allowing dairy managers to focus time and finances on more effective components of an M paratuberculosis control program. PMID- 8675479 TI - Postoperative complications of elective surgeries in dogs and cats determined by examining electronic and paper medical records. AB - Postoperative complications (POC) that developed in dogs and cats that underwent elective ovariohysterectomy, castration, and declaw at a veterinary teaching hospital were determined by examining the computerized abstracts of the medical records and by examining a random sample of the paper medical records. When the computerized abstracts were examined, POC were found to have occurred in 62 (6.1%) of 1,016 dogs. One dog died and 6 others developed major complications. Postoperative complications were found to have occurred in 38 (2.6%) of 1,459 cats. Two cats died and 1 was euthanatized. Four other cats developed major complications. Complete paper medical records for 218 dogs and cats were examined. When the paper medical records were examined, the proportions of dogs and cats with POC were 19.4% and 12.2%, respectively. These proportions were 4 to 7 times higher than when the computerized abstracts were the data source. Results of this study indicate that the frequency of clinically relevant POC of elective surgeries in dogs and cats is substantial. Examination of the computerized abstracts of medical records at this hospital allowed us to rapidly identify cases that could be included in the study but the frequency of POC would be significantly underestimated if paper records were not also assessed. PMID- 8675480 TI - Cross-reactivity of antibodies raised to Pseudomonas fluorescens protease with extracellular proteins produced by meat-spoiling pseudomonads. AB - The cross-reactivity patterns of antibodies to Pseudomonas fluorescens protease with the extracellular proteins produced by a number of meat-spoiling pseudomonads were studied. Immunoblotting studies showed that purified IgG to Ps. fluorescens protease cross-reacted with extracellular proteins in the cell culture supernatant fluids of Pseudomonas spp., including Ps. fragi and Ps. lundensis. In the case of Ps. lundensis and Pseudomonas spp. 11390, the cross reactive moieties were of similar molecular weight to the Ps. fluorescens protease (46 kDa). However, in Ps. fragi the cross-reactive moiety was a lower molecular weight protein (8 kDa). This may represent a fragment of the active enzyme. These results indicate the presence of common antigenic determinants among the proteases of meat spoiling pseudomonads. PMID- 8675481 TI - Phylogenetic characterization of a novel salt-tolerant Bacillus species: description of Bacillus dipsosauri sp. nov. AB - The taxonomic position of a novel halophilic endospore-forming bacterium previously isolated from a desert iguana was investigated by 16S rRNA gene sequencing. Comparative sequence analyses showed the unidentified bacterium to be phylogenetically loosely associated with some other spore-forming (Bacillus pantothenticus, Sporosarcina halophila) and non-spore-forming (Marinococcus albus) halotolerant bacteria. Based on the phenotypic and phylogenetic distinctiveness of the unidentified bacterium, it is proposed that it is classified in the genus Bacillus as a new species, Bacillus dipsosauri. PMID- 8675482 TI - Antimicrobial activity of lactic acid bacteria isolated from goat's milk and artisanal cheeses: characteristics of a bacteriocin produced by Lactobacillus curvatus IFPL 105. AB - A total of 203 lactic acid bacteria isolated from raw goat's milk and artisanal cheese were tested for antibacterial activity. Only two strains of Lactococcus lactis, one strain of Enterococcus faecalis and one strain of Lactobacillus curvatus were shown to produce a bacteriocin-like substance. Lactobacillus curvatus IFPL105 produced a heat-stable bacteriocin, which was hydrolysed by alpha-chymotrypsin, proteinase K and pancreatin and exhibited a broad spectrum of inhibitory activity. The bactericidal activity of the bacteriocin was more potent when sensitive strains were in the logarithmic growth phase, inducing cell lysis, as observed by decreases in optical density and release of intracellular marker enzymes. Curing experiments resulted in variants that lacked both bacteriocin activity and immunity to the bacteriocin. Plasmid profile analysis of the parental strain and the bacteriocin-negative variants indicated that a plasmid of about 46 kbp may be involved in bacteriocin production and immunity to this antibacterial compound. PMID- 8675483 TI - Influence of 1,10-phenanthroline and its analogues, other chelators and transition metal ions on dipeptidase activity of the rumen bacterium, Prevotella ruminicola. AB - Prevotella ruminicola plays a prominent role in the breakdown of peptides in the rumen, a process which contributes to excessive ammonia production and inefficient nitrogen retention in ruminants. Various metal ions and chelators were examined to assess how the metal ion-dependent dipeptidase activity of P. ruminicola M384 might be inhibited. Using sonicated extracts, Cu2+, Cr2+ and Hg2+ were most inhibitory, decreasing Ala2 breakdown to 15, 15 and 5% of control activity, whereas Co2+, Mn2+ and Zn2+ stimulated activity by 189, 30 and 26%, respectively. The chelators, EDTA, EGTA, TPEN and 1,10-phenanthroline, were inhibitory, as were several phenanthroline analogues. Among the stereoisomers of 1,10-phenanthroline tested, derivatives methylated on C-2 and C-9 were less effective than the parent molecule, but 3,4,7,8-tetramethyl-1,10-phenanthroline (TMP) was more inhibitory. Titration of the most effective inhibitors showed that EDTA, TPEN and TMP had similar potency and were effective at 0.1 mmol l-1 and above. Thus some metal ions and chelators are potent inhibitors of P. ruminicola dipeptidase, although they are unlikely to be sufficiently specific to peptide metabolism to be useful in vivo. PMID- 8675484 TI - Inhibitory effects of sucrose monolaurate, alone and in combination with organic acids, on Listeria monocytogenes and Staphylococcus aureus. AB - The effects of sucrose esters of fatty acids, alone and in combination with ethylenediaminetetraacetic acid (EDTA), acetic acid, lactic acid and citric acid, on survival, growth and thermal inactivation of Listeria monocytogenes and Staphylococcus aureus were determined. The presence of sucrose monocaprate (400 micrograms ml-1) in tryptose phosphate broth (TPB) or tryptic soy broth (TSB) did not inhibit the growth of L. monocytogenes or Staph. aureus, respectively. However, significantly (P < or = 0.05) lower populations of L. monocytogenes were detected in TPB containing as little as 100 micrograms ml-1 sucrose monolaurate (SML) during the logarithmic growth phase compared to populations detected in TPB containing no SML. At 400 micrograms ml-1, SML was lethal to L. monocytogenes. Less marked inhibitory effects were observed with Staph. aureus. The addition of EDTA to broth containing SML had a synergistic effect on the inhibition of both organisms. The chelator alone had no effect at 100 micrograms ml-1 on either pathogen but was inhibitory at 200 micrograms ml-1. Inhibition of L. monocytogenes was more pronounced as the incubation temperature was decreased from 30 degrees C to 15 or 5 degrees C. The addition of 0.1% acetic or lactic acid to TPB minimized the inhibitory effect of 100 and 200 micrograms ml-1 SML during the first 32 h of incubation. Staphylococcus aureus behaved similarly, but not as dramatically, to L. monocytogenes when cultured in TSB supplemented with SML alone or SML and organic acids. A synergistic inhibitory effect of SML and EDTA on heat inactivation of L. monocytogenes was evident but the reverse phenomenon was observed with Staph. aureus. The effectiveness of SML in controlling the growth of L. monocytogenes and Staph. aureus in foods most likely to be contaminated with these pathogens should be further investigated. PMID- 8675485 TI - The lethal effects of biguanides on cysts and trophozoites of Acanthamoeba castellanii. AB - The effects of a range of biocides on trophozoite and encysted forms of Acanthamoeba castellanii were investigated. Viable acanthamoebae were enumerated by a plaque assay technique. The cyst form of Acanthamoeba castellanii was more resistant to all biocides tested than the trophozoite form. Of the biocides tested, chlorhexidine diacetate (CHA) and polyhexamethylene biguanide (PHMB) were the most effective. Their lethal effects were time- and concentration-dependent. CHA was very effective when formulated in 0.1% EDTA combined with Tris buffer pH 7.8 whereas PHMB activity was reduced by 0.1% EDTA. Three per cent dimethylsulphoxide (DMSO) enhanced the activity of CHA but not of PHMB. PMID- 8675486 TI - Update: newborn screening for galactosemia. PMID- 8675487 TI - Third generation plasminogen activators in the treatment of acute myocardial infarction. PMID- 8675488 TI - Legionellosis and serological interpretations. PMID- 8675489 TI - Radiological case of the month. Spontaneous intracranial hypotension. PMID- 8675490 TI - The nude in medical photography: a historical perspective, with modern legal ramifications. AB - Taking medical photographs of nude patients was common in the nineteenth century and was related to the diagnostic promises of photography. Nude photography today, while just as diagnostically important, is a carefully thought out practice fraught with serious legal ramifications especially when dealing with children and adolescents. As members of the human race, we are diverse in our practices and not only on a country wide but a regional level. What is acceptable in New York is not necessarily acceptable in central Kansas. Unfortunately, in many circumstances, it is difficult to measure intent. Vintage medical photographs have become valued as art, as well as historic and cultural documents. Nude vintage medical photographs fully expose the human condition and have become among the most valued of historic medical photographs. The implications for the future treatment of nude medical photography is well established. The passage of time, nostalgia, and, most importantly, the attempt to learn the secrets of life and means of death in past epochs will result in preserving and valuing these most important clinical photographs. PMID- 8675491 TI - Nudity in clinical photography: a literature review and the quest for standardization. PMID- 8675492 TI - Internet for the allergist. PMID- 8675493 TI - Increased spontaneous production and generation of superoxide anion by blood neutrophils in patients with asthma. AB - Spontaneous production and PMA- and opsonized zymosan- stimulated generation of superoxide anion by blood cells in asthmatic patients were compared with those in normal volunteers and chronic obstructive pulmonary disease (COPD) patients using a lucigenin-dependent chemiluminescence method. Superoxide anion generation by 100 microl of blood in patients with asthma and/or COPD was significantly greater than that in normal subjects [asthma: 5684 +/- 253 chemiluminescence (CL); COPD: 4994 +/- 240 CL; normal: 2543 +/- 213CL]. This is consistent with the increased superoxide generation per leukocyte (PMN) in these patients (Asthma: 1.56 +/- 0.08 CL/PMN; COPD: 1.31 +/- 0.08 CL/PMN; normal: 0.83 +/- 0.07 CL/PMN. However, spontaneous production of superoxide by individual PMNs was increased only in asthmatic patients, compared with that in normal subjects (Asthma: 0.14 +/- 0.02 CL/PMN; COPD: 0.07 +/- 0.01 CL/PMN; normal: 0.07 +/- 0.01 CL/PMN. These results indicate that the respiratory burst is enhanced in both asthmatic patients and COPD patients, and that superoxide production by resting neutrophils is also increased in asthmatic patients, but not in COPD patients, compared with normal subjects. PMID- 8675494 TI - Asthma, health behaviors, social adjustment, and psychosomatic symptoms in adolescence. AB - The association of health behaviour, indicators of social adjustment, and psychosomatic symptoms with diagnosed asthma was assessed in a community-based sample of 4550 adolescents in South Western Sydney, Australia. The results of this survey found an asthma prevalence among 11-15-year-olds of 17.5%, being consistent with previous studies. Tobacco use and alcohol consumption were higher among asthmatic compared with nonasthmatic adolescents. Asthmatics reported feeling lonely more often, having a number of negative social perceptions and feelings, and having more frequent psychosomatic symptoms. The findings of the study suggest that adolescents with asthma represent an important vulnerable group of school children. Asthma education may need a greater life-style change focus, besides asthma self-management training. PMID- 8675495 TI - Improving the treatment of nocturnal asthma: use of an office questionnaire to identify nocturnal asthma symptoms. AB - Nocturnal asthma is a major problem in many asthma patients and it is important to recognize and treat it. We previously reported the incidence of nocturnal asthma in our practice (1); the current study was done to try to improve upon the incidence of nocturnal asthma in our patients. After our previous survey, which indicated a 67% incidence of nocturnal asthma in our practice, we instituted a previsit questionnaire regarding nocturnal asthma to be filled out by all follow up asthma patients in our office. After a period of time, we mailed a nocturnal asthma questionnaire to all asthma patients to see if the intervention had improved our incidence of nocturnal asthma. This questionnaire was identical to the one used in our prior study and was mailed to 2019 patients. We had 602 responders, 560 of whom had asthma. A total of 328 of these patients (59%) had nocturnal asthma. This was similar to the results of our previous survey, and our initial conclusion was that the new in-office questionnaire that we instituted had not improved the situation. Then we discovered that the in-office questionnaire had inadvertently been distributed only to the patients of one or our physicians (Dr. A). His patients were then compared with those of the other two doctors (Drs. B and C), and it was found that Dr. A's patients had fewer nocturnal symptoms than did the patients of the other doctors. The percent of asthmatics with nocturnal asthma 4-7 nights per week (more than half the nights in a week) for Dr. A was 16%, for Dr. B 47%, and for Dr. C 39%. The use of a short office questinnaire for asthma patients before they see the doctor for follow-up visits leads to greater recognition and better treatment of nocturnal asthma. PMID- 8675496 TI - Comparison between incremental and single-dose allergen administration in bronchial provocation tests. AB - To study the effect of different schedules of allergen administration on the early (EAR) and late allergic reaction (LAR), 15 asthmatic patients with dual response after allergen challenge were submitted to two consecutive bronchoprovocation tests (BPT). BPT1 was carried out with semilogarithmic increases of allergen doses until a FEV1 drop of 20% was recorded. BPT2 was performed 2 weeks later using the highest allergen dose that had elicited the dual reaction in BPT1. Both EAR and LAR were very similar for a given patient. As the allergen dose used in BPT2 is smaller than the cumulative allergen dose administered in BPT1, this protocol takes into account a possible influence on BPT2 of bronchial hyperreactivity induced by BPT1 performed 2 weeks before. PMID- 8675497 TI - Sudden death from asthma in 108 children and young adults. AB - To identify factors that may contribute to asthma mortality, 108 acute asthma deaths were reviewed. Information was obtained from medical records, next-of-kin, and autopsy records. The fatal asthmatic was characterized by early-onset asthma, severe disease requiring systemic corticosteroids, and prior hospitalization. Risk factors associated with gender, season, employment, and region were also identified. The fatal attack was characterized by an identifiable trigger, delay in seeking medical attention, and rapid deterioration in clinical status. Death due to asthma was confirmed in 95% of autopsied cases. Adrenal cortical abnormalities were recorded for 18.7% of cases. We conclude that, in addition to established risk factors, complications associated with the use of systemic steroids may contribute to the risk for sudden death in this age group. PMID- 8675498 TI - The prevalence of asthma and respiratory symptoms among young adults: is it increasing in Australia? AB - The objective of this study was to determine the prevalence of self-reported asthma and respiratory symptoms among young adults and whether there had been any change since a previous survey. A cross-sectional postal community survey was conducted in three parliamentary electorates in the inner South East region of Melbourne, Australia. A total of 4500 individuals aged between 20 and 44 years were randomly selected from the electoral roll. After three mailings and telephone follow-up, an adjusted response rate of 79% was achieved. No intervention was performed. Self-reported asthma and respiratory symptoms were recorded from the European Community Respiratory Health Survey screening questionnaire. Respondents were most likely to report nasal allergies (41%), nocturnal cough (28.6%), and wheeze in the last 12 months (28.1%). Nocturnal cough was more common in females than males. The prevalence of wheeze, nocturnal chest tightness, and use of asthma medications decreased with age. An attack of asthma in the last 12 months was reported by 9.7% of young adults, and this fell to 8.2% after correction for nonresponse bias. The prevalence of current asthma had not increased significantly since a previous postal survey in 1990. However the prevalence of nocturnal chest tightness, nocturnal cough, and use of asthma medications had increased significantly over a 2-year period. Further research is required to investigate why asthma is so prevalent in Australia and why some features are increasing in prevalence. PMID- 8675499 TI - STAT3beta, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription. AB - The 89-kDa STAT3 protein is a latent transcription factor which is activated in response to cytokines (interleukin (IL)-5 and -6) and growth factors (epidermal growth factor). Binding of IL-5 to its specific receptor activates JAK2 which leads to the tyrosine phosphorylation of STAT3 proteins. Here we report the cloning of a cDNA encoding a variant of the transcription factor STAT3 (named STAT3beta) which was isolated by screening an eosinophil cDNA library. Compared to wild-type STAT3, STAT3beta lacks an internal domain of 50 base pairs located near the C terminus. This splice product is a naturally occurring isoform of STAT3 and encodes a 80-kDa protein. We found by reconstitution of the human IL-5R in COS cells that like STAT3, STAT3beta is phosphorylated on tyrosine and binds to the pIRE from the ICAM-1 promoter after IL-5 stimulation. However, STAT3beta fails to activate a pIRE containing promoter in transient transfection assays. Instead, co-expression of STAT3beta inhibits the transactivation potential of STAT3. These results suggests that STAT3beta functions as a negative regulator of transcription. PMID- 8675500 TI - The effect of an arginine-glycine-aspartic acid peptide and hyaluronate synthetic matrix on epithelialization of meshed skin graft interstices. AB - Keratinocytes and fibroblasts interact with proteins of the extracellular matrix such as fibronectin and vitronectin through RGD (arginine-glycine-aspartic acid) cell-attachment sequences. This study evaluated the ability of a provisional synthetic matrix composed of an RGD peptide and hyaluronic acid to accelerate the epithelialization of the interstices of meshed, human, split-thickness skin when placed on full-thickness wounds of athymic mice. Full-thickness skin defects, sparing the panniculus carnosus, were created on athymic mice and 3:1 meshed, human skin was placed on them. The grafts had four central, isolated interstices, which epithelialized by migration of human keratinocytes. Conditions were either the addition to the wound of the synthetic matrix or a matrix of hyaluronic acid alone. The time to closure of the graft interstices was decreased (p < 0.02) in the wounds treated with the RGD peptide-hyaluronic acid provisional matrix. The resultant epithelium of the closed interstices was significantly thicker 8 days after surgery for the RGD-treated wounds. Basement membrane proteins (laminin and type IV collagen) were also found to be present at the dermoepidermal junction earlier in the RGD-treated wounds. These results imply that use of the RGD peptide conjugate to effect cell-matrix interactions may have clinical significance in the field of wound healing. PMID- 8675501 TI - Influence of allogeneic blood transfusion on natural killer cell activity in burn injured mice. AB - Allogeneic blood transfusion (Allo/BT) and burn injury modify the cellular immune response in patients under a variety of circumstances. We designed this study to investigate the influence of Allo/BT, burn injury, and the combination of the two on in vivo natural killer (NK) cell activity in a murine model. This study demonstrated significant enhancement of in vivo NK cell activity in noninjured BALB/c mice receiving Allo/BT from C3H mice when compared to both the control and syngeneic blood transfusion group at posttransfusion day 5. When burn-injured mice were compared to sham-stressed mice, the burn-injured mice showed significant suppression of in vivo NK cell activity. Furthermore, in this strain combination model, Allo/BT modulated the suppressive effect of burn injury on in vivo NK cell activity at posttransfusion day 5 and postburn day 7. PMID- 8675502 TI - Clinical evaluation of an acellular allograft dermal matrix in full-thickness burns. AB - A multicenter clinical study assessed the ability of an acellular allograft dermal matrix to function as a permanent dermal transplant in full-thickness and deep partial-thickness burns. The study consisted of a pilot phase (24 patients) to identify the optimum protocol and a study phase (43 patients) to evaluate graft performance. Each patient had both a test and a mirror-image or contiguous control site. At the test site, the dermal matrix was grafted to the excised wound base and a split-thickness autograft was simultaneously applied over it. The control site was grafted with a split-thickness autograft alone. Fourteen-day take rates of the dermal matrix were statistically equivalent to the control autografts. Histology of the dermal matrix showed fibroblast infiltration, neovascularization, and neoepithelialization without evidence of rejection. Wound assessment over time showed that thin split-thickness autografts plus allograft dermal matrix were equivalent to thicker split-thickness autografts. PMID- 8675503 TI - Sequential excision and grafting of the burn injuries of 1507 patients treated between 1967 and 1986: end results and the determinants of death. AB - The development of a more aggressive approach to burn wound management, leading to complete excision within 72 hours after burn, has led some to conclude that total early excision is a major force behind improved survival rates. We have summarized the results of treatment of 1507 patients with burn injuries treated between 1967 and 1986. Wounds were managed with use of standard topical therapy, occlusive dressings, and staged excision and grafting of full-thickness injury or deep dermal injury (not healed by 21 days). Data were analyzed with use of a logistic-regression model because, with the exception of older patient cohorts, the data did not fit the probit model. The major determinants predicting death were the percentage of body surface area burned, age, smoke inhalation, and the percentage of full-thickness burn. Concordance was 97%. These data show that aggressive sequential wound excision and grafting produces end results comparable with those achieved with complete early burn wound excision for similar age ranges and injury. Early harvest of available donor sites in patients with large burns may be more important to survival than complete early wound excision. PMID- 8675504 TI - Persistent peripheral nerve pathologies in patients with electric burns. AB - Clinical and electrodiagnostic evaluations were performed in 25 patients with electric burns who were injured 2 to 13 years before the study. Abnormal motor nerve conduct findings were detected in 12 of the patients. In nine patients, abnormalities were observed in more than one nerve. There was a positive relation noted between age and nerve lesions. Weakness was the most prominent clinical finding. PMID- 8675505 TI - Elbow anchylosis due to postburn heterotopic ossification. AB - In a retrospective study performed on 2280 patients that had had major thermal injuries, six patients experienced elbow anchylosis due to heterotopic ossification (two of them bilaterally). In every patient the ossification was localized at the posterior-medial aspect of the elbow. The treatment of this complication consisted of resection of the bone mass and transposition of the ulnar nerve. Mobilization was begun early, and rehabilitation was kept up for at least 4 months. The results obtained have been evaluated following the criteria of Merle d'Aubigne and Canadell, who consider a very good result a gain of more than 60% in the arch of flexion-extension of the elbow; good, between 40% and 60%; fair between 20% and 40%; and poor, a gain of less than 20%. In five of the patients (six elbows), the result was very good with an average gain of 73.6% (minimum, 61.5%, maximum, 84.6%). In one patient the result was poor with gain of less than 20%. The incidence of this complication, its treatment, and the results obtained are analyzed. PMID- 8675506 TI - Does the architectural design of burn centers comply with the Americans with Disabilities Act? AB - Title III of the Americans with Disabilities Act (ADA) requires that hospitals and burn centers be designed and constructed so that all public and common-use areas are accessible. At least 10% of patient bedrooms and toilets must be accessible to persons with mobility disorders. The purpose of this study was to determine whether four hospitals with burn centers complied with Title III of the ADA. The burn centers agreed to participate in this study only if they were first assured anonymity, because of the Health Care Financing Administration of the U.S. Department of Health and Human Services requires that each hospital comply. With use of the ADA accessibility guidelines, we developed a survey instrument that was validated by a state government building inspector. This tool was used to inspect the burn center facility and common use areas in four hospitals with burn centers. In the four hospitals, numerous architectural barriers to persons with disabilities were noted. No burn center had a designated accessible room for persons with disabilities. The bedrooms, bathrooms, sinks, bathtubs, and toilets were not accessible to persons with disabilities. The common-use areas in the hospitals, in contrast, had few architectural barriers to persons with disabilities. Only one burn center had plans to eliminate architectural barriers in its hospital. Because the four hospitals with burn centers had numerous architectural barriers for persons with disabilities, it can be concluded they do not comply with Title III of the ADA and are subject to severe penalty from the Health Care Financing Administration and the U.S. Department of Justice. PMID- 8675507 TI - Rehabilitation of the burned hand: questionnaire results. AB - Burns to the hand can cause anatomical and functional limitations due to burn sequelae and treatment obstacles that arise during the rehabilitation process. A questionnaire consisting of four open-ended questions was distributed at the 1993 American Burn Association Breakfast Session, "Rehabilitation of the Burned Hand." The questionnaire was designed to gather information regarding common postburn deformities and treatment obstacles that occur in the acute and postacute phase of burn rehabilitation. Information was collected from 38 respondents and frequency distributions were compiled. The deformities and treatment obstacles are discussed in relation to the current literature and clinical management of hand burns. PMID- 8675508 TI - The revised burn diagram and its effect on diagnosis-related group coding. AB - Diagnosis-related group (DRG) codes for burn injuries are defined by thresholds of the percentage of total body surface area and depth of burns, and by whether surgery, debridement, or grafting or both occurred. This prospective study was designed to determine whether periodic revisions of the burn diagram resulted in more accurate assignment of the International Classification of Diseases and DRG codes. The admission burn diagrams were revised after admission and after each surgical procedure. All areas grafted (deep second-and third-degree burns) were diagrammed as "third-degree," after the current convention that both are biologically the same and require grafting. The multiple diagrams from 82 charts were analyzed to determine the disparities in the percentage of total body surface area burn and the percentage of body surface area third-degree burn. The revised diagrams differed from the admission diagrams in 96.5% of the cases. In 77% of the cases, the revised diagram correctly depicted the percentage of body surface area third-degree burn as confirmed intraoperatively. In 7.3% of the cases, diagram revision changed the DRG code. Documenting wound evolution in this manner allows more accurate assignment of the International Classification of Diseases and DRG codes, assuring optimal reimbursement under the prospective payment system. PMID- 8675509 TI - Computer-assisted evaluation of hand and arm function after thermal injury. AB - Comprehensive care of the burned upper extremity requires accurate and complete evaluation of function, including two-point discrimination, active and passive range of motion, and grip strength. These evaluations, when performed serially during a course of therapy, are time-consuming and manpower-intensive. We tested the utility and accuracy of a commercially available computer-assisted impairment evaluation system when used to automate and standardize measurement of upper extremity function. The function of 80 upper extremities was evaluated with both the conventional and the computer-assisted methods. The time required to perform a complete examination with each method was recorded, and measurements of grip strength and total active motion made with both methods were compared. Complete upper-extremity evaluation required an average of 20.3 minutes with the computer assisted method, compared to 62.9 minutes with conventional means. Measurements of extremity function with computer-assisted and conventional methods had correlation coefficients of 0.984 for grip strength and 0.996 for total active motion. The computer-assisted impairment evaluation system was found to be a useful and accurate adjunct in the acute and rehabilitative management of burned upper extremities. PMID- 8675510 TI - Home health care and burn care: an educational and economical program. AB - Changes in health care reimbursement have challenged providers of health care to work smarter instead of harder, with more efficient and effective use of resources. Patients with burn injuries remain hospitalized for dressing changes that could be completed in the home environment by health care professionals. An early discharge for a select group of patients from a resource-intensive hospital stay to a quality, cost-effective home care program was achieved. An educational program was developed to provide home care nurses the necessary knowledge and skill to care for the patient with burn injuries at home. This program combines didactic classroom lectures with a clinical orientation for home care registered nurses. The outcome for patients is a well-integrated continuity of care with a decreased length of hospital stay. PMID- 8675511 TI - Burns due to flammable solvents ignited with floor buffers. AB - Three patients, employed by janitorial service agencies, were burned severely while buffing floors. A solvent to remove floor lacquer was used in one case, and a solvent to remove glue that held carpet to the floor was used in the other two cases. The solvent used in each case is flammable and was ignited when a floor buffer was used near it. The floor buffers are specifically labeled as unsafe to operate near flammable liquids. The patients' injuries were severe. All three patients survived. This represents a rather unusual and unsafe industrial practice that should be avoided. PMID- 8675512 TI - Burn incidence and medical care use in the United States: estimates, trends, and data sources. AB - Recent estimates related to annual burn incidence and medical care use in the United States include 5500 deaths from fire and burns (1991), 51,000 acute hospital admissions for burn injury (1991 to 1993 average), and 1.25 million total burn injuries (1992). Time trends from 1971 to 1991 reveal significant declines in each estimate. Taking into account the 25% increase in the U.S. population during this period, the rates of decline in deaths attributed to fire and burns and acute hospitalization for burn injury are both about 50%. The rates of decline are similar in sample statistics for all burns receiving medical care and for all burns above a reportable level of severity. In addition to providing current and time-series estimates, this article discusses burn injury coding issues and describes the data sources from which national and state estimates can be derived. The principal objective is to establish and describe a set of burn injury data baselines in a manner that will facilitate future tracking of burn incidence and medical care use at the national and state level by practitioners and researchers. PMID- 8675513 TI - The impact of thrombolytic therapy on arterial and graft occlusions: a critical analysis. AB - BACKGROUND: The indications for intraarterial thrombolytic therapy of lower extremity native arterial and synthetic graft occlusions prior to vascular reconstructions requires further refinement before firm conclusions can be made. STUDY DESIGN: A retrospective review of 55 patients undergoing 81 lytic treatments with high dose urokinase from February 1989 to February 1993 was performed. The cases were divided into three groups: Group I: successful thrombolysis with residual defects followed by surgical reconstruction or percutaneous transluminal angioplasty (PTA); Group II: successful thrombolysis alone; and Group III: failure of thrombolysis requiring reconstruction or leading to amputation. No effort was made to analyze the particular type of reconstruction. Follow-up ranged from 1 to 1627 days (4 years and 5 1/2 months). RESULTS: One, two, and three year patency rates were 47%, 24%, and 8% for Group I; 57%, 46%, and 46% for Group II; and 24%, 10%, and 10% for Group III respectively. The one, two and three year limb salvage rates were 92%, 76%, and 76% for Group I; 82%, 82%, and 82% for Group II; and 48%, 37%, and 37% for Group III respectively. Forty-one complications occurred in 35 of the 81 (43%) lytic treatments. CONCLUSIONS: Intraarterial thrombolytic therapy can be regarded as a possible consideration in the initial management of acute lower extremity arterial and synthetic graft occlusions especially in patients with multiple prior vascular reconstructions. Unsuccessful thrombolysis results in a poor outcome despite surgical reconstruction in the majority of cases. PMID- 8675515 TI - Rupture of true profunda femoris artery aneurysms. Two new cases. AB - Atherosclerotic aneurysms of the deep femoral artery are very rare. We report the first 2 published Scandinavian cases. Both were present in elderly smoking men. They presented with acute local pain, swelling and circulatory collapse. Ultrasonography and angiography demonstrated femoral aneurysm but it was only at operation that the relation to the deep femoral artery was established. Simple ligation of the deep femoral artery was performed in one case. The other patient had a 6 mm PTFE graft interpositioned. Both made an uneventful recovery. PMID- 8675514 TI - Peroneal arteriovenous fistula as a complication of above-knee femoropopliteal polytetrafluorethylene graft thrombectomy with the Fogarty catheter. AB - The Fogarty catheter is an invaluable tool in the surgical practice of a vascular surgeon. Arteriovenous fistula is an unusual but potentially dangerous complication of its use. We present the case of a man who suffered a peroneal arteriovenous fistula as a result of an above-knee femoropopliteal polytetrafluorethylene graft thrombectomy. As the fistula compromised the viability of the extremity, surgical correction was warranted. It was performed without further complications to the patient. The few cases reported in the literature are reviewed. We conclude that this complication should be repaired as soon as it is detected. PMID- 8675516 TI - Traumatic pseudoaneurysm of the superficial temporal artery associated with facial nerve palsy. AB - Aneurysms of the superficial temporal artery as a result of trauma occur rarely. These pseudoaneurysms tend to present 2 to 6 weeks following initial injury with a painless swelling which may be associated with a headache, ear discomfort or other vague symptoms. Neurological complications are very rare. A thorough history and physical examination are essential. Investigations such as duplex scanning, angiography or CT scanning may be helpful in difficult cases. The most common treatment is surgical. Embolization may prove to be an alternative to surgery in some cases. We review a rare case of superficial temporal artery aneurysm associated with a facial nerve palsy which was treated surgically. A thorough review of the literature is presented. PMID- 8675517 TI - Time limitation of postural retrograde cerebral perfusion during cerebral hypothermic circulatory arrest. A report of an unsuccessful case. AB - We report an unsuccessful case with ruptured aortic arch aneurysm using deep hypothermia with postural retrograde cerebral perfusion by simply elevating central venous pressure in the Trendelenburg position. Ninety-three minutes of cerebral circulatory arrest by this method caused irreversible global cerebral damage. Ninety minutes may be over the time limit of this method. PMID- 8675518 TI - Three-dimensional intracoronary ultrasound imaging. Methodology and clinical relevance for the assessment of coronary arteries and bypass grafts. AB - Three-dimensional (3-D) reconstruction of intracoronary ultrasound (ICUS) images has an increasing application as the applicability of systems of on-line analysis provides a superior guidance by coupling the advantages of a high-resolution cross-sectional imaging with an overview of stenosis and reference segments. Detection of the external contour of the vessel which is a prerequisite for measurements of coronary plaques is currently not provided by the algorithms for automated on-line analysis. Thus, off-line reconstruction is required for studies aiming at the assessment of progression/regression of atherosclerosis and of mechanisms of interventions or restenosis. Various 3-D reconstruction methods with specific advantages and limitations are able to meet the different requirements concerning applicability, quality of visualization, and accuracy of quantification. The use of 3-D ICUS in the assessment of cardiac transplant recipients permits a more reliable and accurate quantification of intimal hyperplasia as seen in cardiac allograft arteriopathy. In patients undergoing bypass surgery it may influence the therapeutic decision, since it allows to determine the longitudinal extent of calcification and frequently discovers atherosclerosis in angiographically normal segments. Vessel stenoses both of native coronary arteries and bypass grafts can be studied by 3-D ICUS and additional information can be obtained during catheter based interventions. Despite some remaining technical limitation 3-D reconstruction of ICUS images has the potential of becoming a practical tool to simplify the interpretation and quantification of ICUS images. PMID- 8675519 TI - Pre-clamp cardioprotection by protein kinase C (PKC) inhibitor improves left ventricular function following canine normothermic arrest. AB - Since protein kinase C (PKC) has been proven to be a mediator of neutrophil activation and of intracellular calcium homeostasis, its inhibition could protect the myocardium from the deleterious effects of ischemic/reperfusion inury (IRI). The principal objective of this study was to evaluate the efficacy of the PK inhibitor SPC-100270 (2S,3S)-2-amino, 3-octadecanediol in a canine model of IRI. A double-blind study was conducted in which 19 coonhound dogs received either SPC 100270 or a vehicle before going on cardiopulmonary bypass (CPB). After 60 minutes of global normothermic (37 degree C) cardiac arrest (cross-clamp time 65 81 minutes for SPC-100270 and 65-72 minutes for control) and discontinuation of CBP, an epicardial short axis view echocardiogram was performed and reviewed by a double-blinded observer to determine the ejection fraction (EF). EF value exceeded 20% in 5 out of 9 SPC-100270 animals (27%-44%) and in 0 of 10 controls (0%-16%). These data show that SPC-10027 significantly (p=0.01 by Fisher's Exact Test) increased the probability that the animals would exhibit an EF greater than 20%. PMID- 8675520 TI - Transversal trans-septal biatrial approach for mitral valve surgery. AB - A surgical approach to the mitral valve is very important to visualize all valvular and subvalvular structures. We have used a transversal trans-septal biatrial approach in some mitral procedures. From January 1994 to May 1994, 11 patients were operated on using this technique. Patient ages ranged from 28 to 74 years. Five cases (45.5%) were cardiac reoperations and six (54.5%) were first operations. Three case (27.3%) were mitral reconstructions, 3 (27.3%) were mitral replacement due to mechanical mitral valve thrombosis, 1 (9.1%) as a result of bioprosthetic mitral valve degeneration, 4 (36.4%) were mitral valve replacements for calcified mitral valve disease one case (9.1%) was tricuspid valve replacement due to severe tricuspid insufficiency. There were 4 case (36.4%) of tricuspid valvuloplasties besides the mitral procedures. There was no operative mortality, and all patients preserved their preoperative cardiac rhythm. No important bleeding or supra-ventricular arrhythmias were seen in any case. Aortic cross-clamping and extracorporeal circulation times were comparable with the traditional approach through the left atrial alone. So, we think that this is a very easy and useful technique to expose the mitral valve during some procedures above it, overall when the left atrium is small and total visualization of the mitral is not possible with the traditional approach through the left atrial alone. PMID- 8675521 TI - Modified Blalock-Taussig shunt: statistical analysis of potential factors influencing shunt outcome. AB - From January 1986 to December 1991, 100 modified Blalock-Taussig Shunts (MBTS) using PTFE (polytetrafluoroethylene) grafts were performed on 86 patients with complex cyanotic congenital cardiac malformations at this hospital. The ages of patients ranged from 15 days to 22 years. Thirty-seven were operated upon in infancy and one in the neonatal period. Varying sizes of grafts were used: 3 mm in 3 cases, 4 mm in 18, 5 mm in 44, 6 mm in 34 and 8 mm in one. The mean follow up period was 13.5 months (ranged from one to 50 months). There were one hospital mortality and one morbidity. One year shunt patency rate was 90%. Univariate analysis showed the age of the patient operated upon and graft size were risk factors for shunt patency. With an encouraging 90% early shunt patency rate, we can now adopt MBTS as an alternative without hesitancy. Yet, the surgical technique and perioperative care of those cyanotic neonates receiving this palliation still remain a challenge. PMID- 8675522 TI - The association between rhabdomyolysis and acute renal failure in patients undergoing cardiopulmonary bypass. AB - OBJECTIVE: The authors describe 9 cases of rhabdomyolytic acute renal failure (ARF) as a complication of cardiopulmonary bypass. EXPERIMENTAL DESIGN: Retrospective research between June 1992 and March 1994. SETTING: Department of Cardiac Surgery. PATIENTS: 931 consecutive patients undergoing major cardiac surgery. INTERVENTIONS: Patients affected by rhabdomyolytic ARF were treated with pharmacological therapy and/or plasmapheresis/continuous arteriovenous hemofiltration. In seven patients indirect cannulation of the femoral artery was used. MEASURES: Incidence, risk factors of syndrome results obtained with pharmacological treatment, CAVH and plasmapheresis were evaluated. Statistical analysis was performed with ANOVA, Tukey Kramer test and chi2 test (p<0.05 as significant). RESULTS: The syndrome occurred in 0.96% (9/931 patients) of the total cases; 11.3% (6/53 -p<0.0000) in patients undergoing a direct femoral artery cannulation for cardiopulmonary bypass and 9.5% (2/21, p<0.01) in patients in which the aortic balloon pump was used. Six patients develop acute anuric renal failure and underwent plasma exchange and hemodialysis (1 case) or CAVH (5 cases); 3 patients underwent early medical treatment and developed developed acute renal failure (ARF) with preserved diuresis. Early medical therapy appeared to prevent the evolution towards anuric ARF. The indirect cannulation of the femoral artery does not seem to produce a rhabdomyolytic ARF syndrome. In patients with direct femoral artery cannulation risk factors appear to be: arteriopathy (p<0.001), prolonged extra corporeal circulation (p<0.001), low cardiac output syndrome (p<0.001), continuous i.v. infusion of epinephrine (p<0.0001). CONCLUSIONS: Rhabdomyolytic acute renal failure is a severe complication, early identification of patients ?at risk? is most important. The preventive measures and the therapy adopted proved efficient. PMID- 8675523 TI - Coronary bypass after ascending aorta to femoral graft placement running head: CABG after ascending aorta-bifemoral graft. AB - A 73-year-old woman had undergone ascending aorta-bifemoral bypass 9 years previously and now required coronary artery bypass for unstable angina. The technical considerations for the operation had never been described. We successfully completed the operation by mobilization of the pre-existent graft as it exited the thorax and by intermittent aortic root perfusion of the graft. Postoperatively she had no lower extremity complications, despite what was likely a graft dependent circulation. The same technique for coronary bypass can likely be used for all extra-anatomic bypass grafts originating from the ascending aorta. An alternate theoretical method is also discussed. PMID- 8675524 TI - Right atrial lipoma. Case report. AB - The authors report the successful excision of a right atrial lipoma in an adult male. The rarity of this lesion, clues to diagnosis and its management are discussed. PMID- 8675526 TI - Congenital diaphragmatic eventration: treatment and postoperative evaluation. AB - Three patients with congenital diaphragmatic eventration have been reported. The diagnosis was established by chest radiography which showed an abnormally elevated diaphragm. Additionally fluoroscopy, ultrasonography and pulmonary function tests were used. Diaphragmatic plication was performed in order to restore normal pulmonary parenchymal volume and the diaphragm was replaced in its normal localization. All the patients had been discharged in good condition following uneventful postoperative courses. In this study we discussed the etiology, diagnosis, treatment and postoperative courses of diaphragmatic eventration. PMID- 8675525 TI - Results of surgical treatment of stage I and II lung cancer. AB - Pulmonary resection remains the most appropriate treatment for localised bronchogenic carcinoma, since prognosis and outcome are currently dependent on surgical resectability. A retrospective analysis of our experience with three hundred and thirteen stage I (n=250) and stage II (n=63) patients treated surgically form the basis of this report. The initial pulmonary resection was lobectomy in 173 patients, bilobectomy in 38, sleeve lobectomy in 12, pneumonectomy in 59, wedge excision or segmentectomy in 31. The overall operative mortality was 3.2%; 4.03% for lobectomy and 1.6% for pneumonectomy. Morbidity was observed in 21 (6.7%) patients. Four out of sixteen small cell carcinoma patients had postoperative adjuvant chemotherapy. Survival in patients with stage I tumours was 71% at 5 years and 61% at 10 years compared with 41% at 5 years and 35% at 10 years for patients with stage II disease. The five year survival after pneumonectomy was significantly (p<0.05) better for both stage I and stage II lung cancer than after lobectomy. Five year survival in stage I carcinoma was not influenced by histological type, while there was statistically significant difference (p<0.05) in survival between adenocarcinoma (0%) and squamous cell carcinoma (46%) in stage II disease. We conclude that an aggressive surgical approach can provide an excellent prognosis for recovery and long term cure in most patients with early stage lung cancer. PMID- 8675528 TI - The use of intrapleural clonidine for postoperative pain control. AB - While the potent analgesic properties of clonidine, a centrally-acting antihypertensive agent, in humans is well described, its analgesic effect when administered into the pleural cavity is largely unknown. We have used intrapleural clonidine as a primary analgesic agent for postoperative pain control in two patients who had undergone cholecystectomy. Clonidine was instilled into the pleural space at the end of the operation via a silastic catheter placed through the seventh intercostal space. Oral pain medications were resumed within 48 hours after removal of the intrapleural catheter. In both patients, there was a substantial improvement in pulmonary function correlating with adequate pain control. No complications were noted secondary to the use of intrapleural clonidine. We conclude that intrapleurally administered clonidine is sufficient to provide adequate postoperative analgesia following abdominal surgery. PMID- 8675527 TI - Relaxation of human isolated pulmonary arteries by amrinone. AB - Amrinone, a selective phosphodiesterase III inhibitor, has been developed as a nonglycoside, noncatecholamine agent with positive inotropic effect. In this study, we examined the effect of amrinone on human pulmonary arterial strips in vitro to understand its action on human pulmonary circulation. Amrinone (10(-5) 10(-3) g/ml) caused dose-dependent relaxation of human pulmonary arterial strips precontracted with 60 mM KCl. Preincubation with either meclofenamate (3.1 microM), a cyclooxygenase inhibitor, or L-N(G)-nitroarginine (100 microM), a competitive inhibitor of EDRF/NO, failed to inhibit amrinone-induced pulmonary vasodilation. The cyclic AMP (cAMP) levels in the supernatant of the lung vessel homogenates increased after incubation with amrinone (10(-3) g/ml). These findings indicate that amrinone causes vasodilation of human pulmonary artery in vitro, and suggest a possible role for cAMP in the mechanisms of amrinone-induced pulmonary vasodilation. Because it is suggested that amrinone has not only positive inotropic effect but also pulmonary vasodilative effect in human in this study, we speculate that amrinone could be an useful agent for the treatment of an increase in right heart afterload and consequent pulmonary hypertension and right heart failure after lung resection in human. PMID- 8675529 TI - Traumatic rupture of the pericardium. Case report and literature review. AB - Rupture of the pericardium due to blunt thoracic trauma is a rare pathology with a range of mortality between 30 and 64% according to different authors. We review 40 cases which have been reported in the literature in the last decade and report a case of our own. We have found that 82% of the patients with traumatic rupture of the pericardium were men with a mean age of 45 years. In 80% of the cases the cause was a motor vehicle accident, 17% were due to falls and only 1 case was associated with a crush. The commonest location of the tear was the left pleuropericardium (62%) followed by the diaphragmatic portion of the pericardium (22%). In 80% of the cases the diagnosis was achieved in the course of a surgery performed for associated lesions. None of the cases was diagnosed in a post mortem study. The traumatic rupture of the pericardium is a disease which often remains undiagnosed, especially when one does not have a high index of suspicion. Nevertheless, this is a disease which can threaten the life of the patient and we should keep it in mind to diagnose and treat it as soon as possible. It is known that an early and aggressive management of these patients implies a much better prognosis with a significant reduction of the mortality. In this article we want to give useful clues to allow a preoperative diagnosis and an early and adequate management. PMID- 8675530 TI - Laceration of the phrenic artery. A life-threatening complication after repair of pectus excavatum. AB - We report a case of life-threatening hemothorax three months after surgical repair of pectus excavatum. Angiography revealed the hemorrhage to originate from a laceration of the phrenic artery secondary to dislodgment of the metal strut used for the repair. Awareness of this rare complication in patients after repair of pectus excavatum is required. PMID- 8675531 TI - Pediatric Morgagni hernia. Report of two cases. AB - Morgagni hernia is a rare condition in childhood, and it may be asymptomatic or produce respiratory symptoms. Two cases with Morgagni hernias are presented. Both patients had occasionally respiratory infection, coughing and fever. The diagnosis was made with a chest radiograph taken for respiratory infection. They were treated surgically and they were discharged in uneventful condition. PMID- 8675532 TI - Pericardial cyst. Surgical resection in two symptomatic cases. AB - Two cases of surgical resection of symptomatic pericardial cysts are reported. Pathological aspects, diagnostic methods and alternatives of management in these benign lesions are discussed. Other excised cases are also mentioned. The authors recommend excision of these cysts in all patients with a low risk in order to: 1) eliminate the tumour mass, 2) relieve symptoms and 3) allow histological examination. PMID- 8675534 TI - Endoscopic ultrasound: improving GI diagnosis. AB - At present, the technique--which incorporates fiberoptic imaging--is best used for local staging of esophageal, pancreatic, and rectal cancer, characterization of submucosal gastrointestinal masses, and detection of common bile duct stones. Potential uses being investigated include transintestinal fine needle puncture to aspirate lymph nodes or tumors and assistance with various therapies. PMID- 8675535 TI - Resistant bacteria in nursing homes: a rational approach. PMID- 8675533 TI - Autoregulation of renal and splanchnic blood flow following infra-renal aortic clamping is mediated by nitric oxide and vasodilator prostanoids. AB - OBJECTIVE: This study examines the hypothesis that nitric oxide and vasodilator prostanoids contribute to the autoregulation of renal artery and superior mesenteric artery (SMA) blood flow following infra-renal aortic clamping. EXPERIMENTAL DESIGN: Renal and SMA artery blood flow were measured in anesthetized rats. The rats received bolus injection of saline carrier, L-NAME (25 mg/kg) or indomethacin (15 mg/kg) prior to sham or infra-renal aortic occlusion. In vivo blood flow was measured 1, 30 and 60 minutes during aortic occlusion and 1, 30, and 60 minutes following release of the aortic cross clamp. RESULTS: Aortic occlusion transiently increased SMA blood flow but did not alter renal artery blood flow. Aortic clamp release resulted in a 40% decrease in both SMA and renal artery blood flow. L-NAME or indomethacin pretreatment decreased both SMA and renal artery blood flow at 60 minutes following infrarenal aortic occlusion. Indomethacin decreased SMA blood flow at 1 minute following unclamping of the aorta and L-NAME decreased SMA blood flow at 30 and 60 minutes following aortic clamp release. Both L-NAME and indomethacin markedly decreased renal artery blood flow at all time periods following aortic clamp release. CONCLUSIONS: These data suggest that renal and splanchnic vascular beds utilize endogenous vasodilator eicosanoids and nitric oxide to maintain blood flow during cross clamping and unclamping of the infra-renal aorta. PMID- 8675536 TI - Primary care diagnosis of thyroid disease. AB - Recent diagnostic advances include sensitive thyroid-stimulating hormone (TSH) assays, more accurate free thyroxine assays, and fine-needle aspiration biopsy. The workup of patients with suspected thyroid dysfunction generally begins with a TSH assay; guidelines are provided for subsequent thyroid tests. Aspiration biopsy is appropriate for those with a nodular goiter. PMID- 8675537 TI - Stroke in a young woman with a history of gonorrhea. PMID- 8675538 TI - PSA: to screen or not to screen. PMID- 8675539 TI - An introduction to HEDIS. PMID- 8675540 TI - Chronic bruising in a 40-year-old woman. PMID- 8675541 TI - Case in point. Primary biliary cirrhosis. PMID- 8675542 TI - Atrial systolic failure in a 46-year-old man. PMID- 8675543 TI - Dyspnea and tachycardia in a young man after a cold. PMID- 8675544 TI - Acute chest pain in a tall, thin woman. PMID- 8675546 TI - Allergic rhinoconjunctivitis: current therapy. AB - Seasonal allergic rhinoconjunctivitis can be incapacitating, but an extensive therapeutic arsenal is available. The author describes the advantages and disadvantages of various oral, intranasal, and ophthalmic medications and discusses when they should be prescribed and how they may be combined. Options for circumventing side effects, satisfying patient preferences, and controlling even severe symptoms are reviewed. PMID- 8675545 TI - Addressing the spectrum of hypercholesterolemia. AB - The past decade has seen a major shift in management: Trials of HMG-CoA reductase inhibitors have suggested that cholesterol reduction offers greater protection against coronary artery disease than does antihypertensive therapy. Five patient vignettes provide guidelines for initiating therapy. The agents should be prescribed with restraint, often not until other measures have been exhausted. PMID- 8675547 TI - Primary care of the somatizing patient: a collaborative model. AB - Somatizing patients can be frustrating to treat, and their lengthy diagnostic workups represent a huge drain on health care resources. Cure of somatoform disorders is elusive; however, cost-effective, compassionate management is possible through collaboration between primary care physicians and psychiatrists or behavioral health care groups. PMID- 8675548 TI - Transcription factors and inflammatory disease. AB - DNA-binding proteins enable extracellular signals to influence cellular manufacture of substances implicated in chronic inflammation. Cross-talk between the nuclear messenger pathways subserving such regulation accounts for differences among inflammatory diseases. It also explains much of the efficacy of current therapies and may be the basis for novel, more specific approaches to treatment. PMID- 8675550 TI - Determination of L-buthionin (SR)-sulfoximine, gamma-glutamylcysteine synthetase inhibitor in rat plasma with HPLC after prelabeling with dansyl chloride. AB - L-(SR)-Buthionin sulfoximine (L-(SR)-BSO) is a potent and specific inhibitor of gamma-glutamylcysteine synthetase, which catalyzes the first reaction of glutathione biosynthesis. A selective, sensitive, and simple high-performance liquid chromatographic method was developed for the determination of L-(SR)-BSO in rat plasma. After the compound was labeled with dansyl chloride (Dns-Cl) under optimal conditions, it was separated in a Zolbax-ODS column with a mobile phase that consisted of 0.01M phosphate buffer, methanol, and acetonitrile (8:1:3, v/v). The compound was detected with a fluorescence detector at an excitation wavelength of 335 nm and an emission wavelength of 525 nm using a xenon lamp. The coefficients of variation (DV) from the interassay in the low and high concentrations (10 and 500 micrograms/mL of L-(SR)-BSO in rat plasma) were 2.5 and 4.8%, respectively. The CVs from the intra-assay in the low and high concentrations were 3.2 and 5.6%, respectively. The minimum concentration of L (SR)-BSO that could be determined was 10 micrograms/mL when 100-microL serum samples were used. The detection limit was 50 ng per injection volume. This method enables pharmacokinetic and pharmacodynamic studies in rats. PMID- 8675549 TI - A full evaporation headspace technique with capillary GC and ITD: a means for quantitating volatile organic compounds in biological samples. AB - The full evaporation technique (FET), which is a variant of headspace analysis used to overcome matrix effects, was combined with capillary gas chromatography (GC) and ion-trap detection (ITD). The aim was to enable quantitative tests of volatile organic compounds (VOCs) in blood and postmortem tissue samples. FET was applied to sample sized less than 35 mg whose VOCs were released from the matrix at an equilibration temperature of 130 degrees C. A capillary column with a nonpolar stationary phase was used for GC, and ITD was performed with the mass spectrometer run in full-scan mode. The potential of FET-GC-ITD was studied for the analysis of blood samples spiked with low concentrations of ethanol, acetone, 2-propanol, and 2-butanone and on brain tissue that contained methyl tert-butyl ether (MTBE), Benzene, toluene, ethylbenzene, o-, m-, and p-xylene, and propylbenzene. Samples were obtained from the bodies of victims who had inhaled smoke during an arson or accidental fire. There was a linear relationship between peak area and sample size, which indicates that the conditions of full evaporation were met and that the matrix effect was negated. The total analyte amount in the test sample at the limit of quantitation was in the range of 0.4-1 nmol for polar VOCs in blood and 0.03-0.1 nmol for nonpolar VOCs in brain tissue. Data on precision and accuracy of the method are reported. PMID- 8675551 TI - Determination of synthetic estrogens in illegal veterinary formulations by HPTLC and HPLC. AB - To determine the actual amount of diethylstilbestrol, hexestrol, and dienestrol in formulations such as pellets and oily injections that are illegally available on the Brazilian market, a simple methanol extraction is used for the analysis of the pellets and an ether extraction with Sephadex columns (for clean-up) is used for the oily injections. High-performance thin-layer chromatography is used for identification (as a qualitative and semiquantitative method), and high performance liquid chromatography is used for quantitation. The results of the analysis show that all the formulations are not in accordance with the information listed on their labels. PMID- 8675552 TI - Clinical review 81: Gonadotropin-releasing hormone analogs in ovulation induction: current status and perspectives. PMID- 8675553 TI - Tibolone as an alternative to estrogen for the prevention of postmenopausal osteoporosis in selected postmenopausal women. PMID- 8675554 TI - Tibolone: prevention of bone loss in late postmenopausal women. AB - The aim of the study was to assess the effects of 2 yr of treatment with two dose levels of tibolone on bone mineral density and bio-chemical markers of bone metabolism in late postmenopause. Ninety-one healthy women, more than 10 yr after menopause, entered a 2-yr double blind, randomized, placebo-controlled study of treatment with either 1.25 mg/day (n = 36) or 2.5 mg/day (n = 35) Tibolone or placebo (n = 20). Densitometry and determinations of biochemical markers of bone metabolism in serum and urine were performed before randomization and every 3 months during the study. The results revealed a steady and equal increase in bone mineral density in both tibolone groups at the bone sites studied. Gains in BMD spine of 5.9 +/- 0.9% in the 1.25 mg group, 5.1 +/- 0.9% in the 2.5 mg group, and 0.4 +/- 1.1% in the placebo group were found. In the forearm, increases of 2.2 +/ 0.7% in the 1.25 mg group and 1.9 +/- 1.1% in the 2.5 mg group were detected, whereas the placebo group lost 2.1 +/- 1.0%. This was fully supported by changes in biochemical markers of bone resorption (urinary excretion of fragments from the osteoclastic degradation of the alpha 1-chain of the C telopeptides of type 1 collagen and hydroxyproline) and bone formation (serum osteocalcin), respectively. In conclusion, within 2 yr of treatment, tibolone increases bone mass in the spine and prevents bone loss in the forearm in late postmenopausal women determined by densitometry and several biochemical parameters of bone turnover. Tibolone at two doses (1.25 and 2.5 mg/day) had similar effects, indicating that even lower doses may be efficacious. PMID- 8675556 TI - A 73-year-old man with hyperglycemia, skin rashes, anemia and weight loss. PMID- 8675555 TI - Maximal dose glyburide therapy in markedly symptomatic patients with type 2 diabetes: a new use for an old friend. AB - No consensus exists as to the best approach for treating markedly symptomatic patients with new-onset (or diet-treated) type 2 diabetes. Therefore, based on the experience of one successful case, further studies were undertaken to determine the safety and efficacy of maximal dose glyburide (10 mg, twice daily, in patients < 65 yr of age) or half the dose (10 mg, daily, in patients > or = 65 yr of age) for treating these patients. Fifty-five patients with polyuria, polydipsia, nocturia, involuntary weight loss, and blood glucose concentrations of 300 mg/dL or greater were treated following protocols that used maximal dose ( < 65 yr of age) or half-maximal dose ( > or = 65 yr of age) sulfonylurea agent therapy. Data were collected retrospectively in 30 patients and prospectively in 25. Patients in the prospective group differed only in that more laboratory measurements were obtained, and less strict guidelines for using insulin were adopted. Data were collected in both groups at baseline and 1 week and 4 months after starting the sulfonylurea agent therapy. Patients responded rapidly with a fall in blood glucose levels from 456 +/- 12 mg/dL at baseline to 202 +/- 10 mg/dL at 1 week to 120 +/- 5 mg/dL at 4 months. Glycated hemoglobin levels fell from 18.1 +/- 0.4% at baseline to 8.1 +/- 0.2% ( P < 0.0001) at 4 months. Most patients had symptomatic improvement within 3 days. Seventeen patients had positive (small or larger) urinary ketones, and 5 had positive serum ketones. Insulin to glucose and C peptide to glucose ratios improved maximally at 1 week, indicating rapid reversal of glucotoxicity on the beta-cell. At 4 months, 11 patients were receiving diet therapy alone, 29 were receiving submaximal dose sulfonylurea agent therapy, 6 remained on maximal dose sulfonylurea agent therapy, and only 3 were receiving insulin therapy. Six patients were lost to follow-up. No patient experienced hypoglycemia in the first 2 weeks of treatment. Maximal dose sulfonylurea agent therapy is a safe and effective method for treating patients with markedly symptomatic type 2 diabetes. Patients improve rapidly and are able to avoid the immediate institution of long term insulin therapy. PMID- 8675557 TI - Mutations in G proteins and G protein-coupled receptors in endocrine disease. PMID- 8675558 TI - Cellular characterization of adipose tissue from various body sites of women. AB - Adipose tissue is the primary site of estrogen biosynthesis in postmenopausal women. The two main histologic components of adipose tissue are mature adipocytes and fibroblasts. Aromatase P450 expressed in the fibroblast component of adipose tissue is responsible for catalyzing conversion of C19 steroids to estrogens. We previously have demonstrated that in women, aromatase expression in adipose tissue of various body sites increases with age and that aromatase expression in the hip is markedly higher than in the abdomen. To determine whether this age- and regional-dependent variation in aromatase expression is caused by an alteration in the ratio of fibroblasts to mature adipocytes, we collected sc adipose tissue samples from 19 women (age range: 21-93 yr) at the time of autopsy. Using a computerized image analysis system, we determined by morphometry the proportions of adipocytes, fibroblasts, and vascular endothelial cells within histologic sections of adipose tissue from midabdomen, both breasts, and both hips. The percentage of each cell component at each body site was expressed as the mean of triplicate replicates. Statistical analysis of our results did not indicate any correlation between advancing age and fibroblast to adipocyte ratios in the breast, abdomen, or hip. Fibroblast to adipocyte ratios were found to be significantly higher in the breast and abdomen compared with the hip ( P < 0.05). No statistical differences were found between the breast and abdomen. These findings suggest that the increase in aromatase expression with advancing age and the higher aromatase expression in the hip compared with the abdomen in women may be caused by alterations in specific signal transduction mechanisms rather than a simple increase in local adipose fibroblast numbers. PMID- 8675559 TI - Low density lipoprotein particle size in hypopituitary adults receiving conventional hormone replacement therapy. AB - Adults receiving conventional replacement therapy for hypopituitarism are known to have increased cardiovascular mortality. The aim of this study was to assess the lipid profiles of 30 hypopituitary adults compared with 2 case control groups, 1 matched for age, sex, and body mass index (BMI) and the second matched for age and sex only with a BMI representative of the general population. Fasting lipids, lipoproteins, and apoproteins (Apo) were determined by routine methods. Low density lipoprotein (LDL) particle size was determined by nondenaturing gradient gel electrophoresis. LDL size was significantly smaller in the hypopituitary group (25.9 +/- 0.1 nm) than in the BMI-matched (26.2 +/- 0.1 nm; P < 0.05) and standard control (26.3 +/- 0.1 nm; P < 0.01) groups. High density lipoprotein cholesterol levels in the hypopituitary group were significantly lower than those in the BMI-matched control group (1.13 +/- 0.06 vs. 1.34 +/- 0.06 mmol/L; P < 0.05) and the standard control group (1.38 +/- 0.06 mmol/L; P < 0.005). Apo A1 levels were also lower compared with those in the BMI-matched (122 +/- 6 vs. 137 +/- 4 mg/dL; P < 0.05) and the standard (143 +/- 4 mg/dL; P < 0.005) control groups. There was a trend toward higher triglyceride levels when the hypopituitary subjects were compared with the standard control group [1.4 (95% CI, 1.3-2.2) vs. 1.0 (95% CI, 0.9-1.4) mmol/L; P = 0.06]. These differences were more marked in the female subjects studied. No significant differences were noted in total cholesterol, LDL cholesterol, or Apo B levels. We conclude that hypopituitary patients receiving conventional replacement therapy have an atherogenic lipid profile characterized by small dense LDL, decreased high density lipoprotein cholesterol, and increased triglyceride levels, which may contribute to the excess cardiovascular mortality in this group. PMID- 8675560 TI - Glutamic acid decarboxylase antibodies in relation to other autoantibodies and genetic risk markers in children with newly diagnosed insulin-dependent diabetes. Childhood Diabetes in Finland Study Group. AB - To study the frequency of antibodies to glutamic acid decarboxylase (GAD65A) at the diagnosis of insulin-dependent diabetes mellitus (IDDM) and to evaluate the relation of these antibodies to other IDDM-associated autoantibodies and genetic risk markers of the disease, we analyzed 747 newly diagnosed diabetic children younger than 15 yr of age (mean, 8.4 yr) for GAD65A, islet cell antibodies, insulin autoantibodies, and human leukocyte antigen DR alleles. GAD65A were detected in 73.2% of the children, with a higher frequency in females than in males (77.1% vs. 70.1%; P = 0.04) and in index cases aged 10 yr or older than in younger children (79.0% vs. 68.7%; P = 0.004). The index cases positive for GAD65A had higher levels of islet cell antibodies (median, 40 vs. 34 Juvenile Diabetes Foundation units; P = 0.003) and insulin autoantibodies (median, 55 vs. 43 nU/mL; P = 0.03) than those testing negative for GAD65A. Human leukocyte antigen DR3/non-DR4 children had the highest GAD65A levels, whereas DR2-positive cases had levels of GAD65A similar to those found in other subjects. One third of the index cases (33.9%) tested positive for all three autoantibodies, 43.1% for two antibodies, and 18.2% for one antibody, whereas 4.8% were triple negative. The females had multiple antibodies (at least two antibodies) more often than the males (81.3% vs. 73.5%; P = 0.01). There was a significant trend for a higher frequency of multiple antibodies in young children (83.0% in those under 5 yr and 73.2% in those 10 yr or older; P = 0.02) and a higher frequency in DR3/4 heterozygous children than in those with DR3/non-DR4 (83.3% vs. 63.2%; P = 0.02). The results show that GAD65A antibodies are more frequent in girls and adolescents with newly diagnosed IDDM and suggest that DR3/non-DR4 subjects have increased GAD65A levels. Multiple antibodies in diabetic children are associated with young age, female sex, and DR3/4 heterozygosity. PMID- 8675561 TI - An amplitude-specific divergence in the pulsatile mode of growth hormone (GH) secretion underlies the gender difference in mean GH concentrations in men and premenopausal women. AB - Although many studies have discerned higher serum GH concentrations in women than in men, based on measurements of single random blood samples or integrated 24-h means, the neuroendocrine mechanisms that underlie such gender differences have not been defined. Such mechanisms might entail an increase in GH-secretory burst frequency, amplitude, or duration, heightened interpulse basal GH release, or a prolonged half-life of GH. These mechanisms can be distinguished by deconvolution analysis of appropriate GH time series. Earlier studies employed RIA or IRMA with sensitivities of 0.1-0.5 microgram/L, which result in frequently undetectable serum GH concentrations. To address these limitations, we undertook blood sampling at 10-min intervals for 24 h and applied a high-sensitivity immunofluorometric assay of GH (sensitivity 0.0115 microgram/L). Multiparameter deconvolution analysis was used to estimate specific features of GH secretion, while simultaneously calculating the half-life of endogenous GH. Eleven men and 11 premenopausal women from the same community were studied. Discrete peak detection by Cluster was employed as a complementary half-life-independent technique to assign variations in serum GH into pulsatile and basal fractions over 24 h. Cluster revealed significantly higher mean serum GH concentrations over 24 h in women (0.78 +/- 0.08 microgram/L) compared with in men (0.27 +/- 0.03 microgram/L, P < 0.00005). Women exhibited significantly higher maximal serum GH concentration peak values than men (2.08 +/- 0.34 microgram/L in women, 0.67 +/- 0.11 microgram/L in men, P = 0.0008), which could be, in turn, attributed to a significantly increased incremental serum GH peak amplitude (1.85 +/- 0.33 microgram/L in women vs. 0.60 +/- 0.10 microgram/L in men, P = 0.0021) and a longer peak duration (114 +/- 8 min in women, 86 +/- 4 min in men, P = 0.008). The mean area under the serum GH concentration peak was significantly (3 fold) higher in women than in men (98 +/- 17 micrograms/L.min in women, 34 +/- 8 micrograms/L.min in men, P = 0.0046). Serum GH peak frequency was similar in women (9.7 +/- 0.8 peak/24 h) and men (10.7 +/- 1.1 peak/24 h, P = NS). The mechanisms underlying the increase in serum GH concentration pulse amplitude, duration, and area were investigated further by deconvolution analysis. Deconvolution analysis disclosed equivalent secretory pulse frequencies in women and men (13 +/- 0.9 bursts/day in women, 10.5 +/- 1.3 bursts/day in men,P = NS), and statistically indistinguishable mean interburst intervals of 106 +/- 8 min in women and 150 +/- 26 min in men (P = NS). GH-secretory burst mass was significantly higher in women by approximately 2.4-fold (P = 0.0013) compared with in men, which was attributed to a greater burst amplitude. Only low levels of basal GH release were inferred in women (5%) and men (9%), which did not differ significantly between genders. Moreover, the calculated half-life of endogenous GH was no different in women compared with in men: 15.8 +/- 0.7 min vs. 17.1 +/- 0.8 min, respectively (P = NS). The calculated daily secretion rate was 3-fold higher in women (47 +/- 4.8 micrograms/L.24 h) than in men (15 +/- 1.8 micrograms/L.24 h) (P < 0.001). In summary, discrete peak-detection analysis of serum GH concentration profiles collected at 10-min intervals over 24 h in men and premenopausal women discloses significantly different mean serum GH concentrations that are accounted for by higher maximal and incremental serum GH peak amplitudes. Deconvolution analysis demonstrated that the mechanism supporting the amplitude-specific difference in women was an augmentation of the GH-secretory burst mass caused by a higher GH-secretory burst amplitude. These gender differences were highly specific because the frequency of detectable GH secretory bursts, the calculated endogenous half-life, and the estimated basal GH release were no different in women than in men. PMID- 8675562 TI - Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. AB - Data from rodent studies indicate that cumulative stress exposure may accelerate senescence and offer a theory to explain differences in the rate of aging. Cumulative exposure to glucocorticoids causes hippocampal defects, resulting in an impairment of the ability to terminate glucocorticoid secretion at the end of stress and, therefore, in increased exposure to glucocorticoids which, in turn, further decreases the ability of the hypothalamo-pituitary-adrenal axis to recover from a challenge. However, the consensus emerging from reviews of human studies is that basal corticotropic function is unaffected by aging, suggesting that the negative interaction of stress and aging does not occur in man. In the present study, a total of 177 temporal profiles of plasma cortisol from 90 normal men and 87 women, aged 18-83 yr, were collected from 7 laboratories and reanalyzed. Twelve parameters quantifying mean levels, value and timing of morning maximum and nocturnal nadir, circadian rhythm amplitude, and start and end of quiescent period were calculated for each individual profile. In both men and women, mean cortisol levels increased by 20-50% between 20-80 yr of age. Premenopausal women had slightly lower mean levels than men in the same age range, primarily because of lower morning maxima. The level of the nocturnal nadir increased progressively with aging in both sexes. An age-related elevation in the morning acrophase occurred in women, but not in men. The diurnal rhythmicity of cortisol secretion was preserved in old age, but the relative amplitude was dampened, and the timing of the circadian elevation was advanced. We conclude that there are marked gender-specific effects of aging on the levels and diurnal variation of human adrenocorticotropic activity, consistent with the hypothesis of the "wear and tear" of lifelong exposure to stress. The alterations in circadian amplitude and phase could be involved in the etiology of sleep disorders in the elderly. PMID- 8675563 TI - Regulation of the insulin-like growth factor system by insulin in burn patients. AB - The aim of the present investigation was to determine whether there is a net uptake of insulin-like growth factor I (IGF-I) or IGF-binding proteins (IGFBPs) by the leg after burn injury and to elucidate the regulatory role of insulin exerted on this system under in vivo conditions in burn patients. Studies were performed on nine patients after burn injury (approximately 60% body surface area). Each patient was studied twice during a continuous infusion of a carbohydrate-rich enteral diet. Blood was collected simultaneously from the femoral artery and vein for the measurement of various elements of the IGF system after 7 days of enteral diet alone (basal period) and after 7 days of the enteral diet plus the infusion of insulin (insulin period). Data from these patients were compared to values in age-matched fed healthy volunteers. During the basal period, burn patients demonstrated a significant reduction in the venous concentration of IGF-I and an increase in both IGFBP-1 and -2 compared to control values. Insulin produced a significant 15% increase in the IGF-I concentration in burn patients, but decreased the circulating levels of IGFBP-1 by 50%. The IGF-I and IGFBP-1 concentrations at the end of the insulin period were still significantly different from those in control subjects. Burn patients also exhibited a marked reduction in intact IGFBP-3 and the acid-labile subunit under basal conditions, and these alterations were not reversed by insulin. Under basal conditions, all burn patients had a positive arterio-venous (A-V) difference for IGF-I across the leg. The A-V difference was increased 50% in response to insulin. The net uptake of IGF-I by the leg was 2.4 micrograms/min under basal conditions, and as leg blood flow also tended to increase in response to insulin, IGF-I uptake was elevated more than 3-fold during the insulin period. No A-V difference across the leg was detected for IGFBP-1, -2, or -3 in burn patients. In conclusion, burn injury in humans produces dramatic and sustained alterations in various components of the IGF system that persist despite adequate nutritional support. Our data indicate the presence of a net uptake of IGF-I by the leg in burn patients that may serve to counteract the catabolic state. PMID- 8675565 TI - Somatostatin pretreatment enhances growth hormone (GH) responsiveness to GH releasing hormone: a potential new diagnostic approach to GH deficiency. AB - Despite the availability of numerous testing procedures to evaluate GH secretion in short children, there is still controversy about the most reliable test in the diagnosis of GH deficiency. We have recently demonstrated that in normal short children, priming with the long-acting somatostatin analog. SMS 201-995 (SMS), significantly potentiates their GH response to subsequent GHRH challenge. In the present study, we used the combined SMS + GHRH test in patients with GH deficiency to validate the hypothesis that this test would better discriminate between normal short children and those with truly diminished GH secretion. We studied 24 children classified into three groups according to their GH peak response to up to four conventional tests: 1) children with normal short stature and normal GH response (NSSA: GH peak > or = 10 micrograms/L, n = 6); 2) children with normal short stature with borderline GH response (NSSB: GH peak > or = 7 micrograms/L but < 10 micrograms/L, n = 4); and 3) GH-deficient children (GHD: GH peak < 7 micrograms/L, n = 14). Two study protocols were performed in all subjects: SMS (1 microgram/kg, sc) was randomly administered or omitted (control test) a 0800 h and GHRH (1 microgram/kg, iv) was given 5 h later. Plasma GH levels were measured every 30 min from 0800 h until 2 h after the GHRH injection. Pretreatment with SMS significantly augmented the GH peak response and the GH area under the GH concentration curve over 2 h after GHRH injection in the NSSA group, compared with control tests, but had no effect in the other two groups. While there was wide overlap of individual peak GH values to both the conventional tests and to the GHRH injection in the control test among the three groups of children, pretreatment with SMS resulted in complete discrimination between GHD and normal short children; the mean GH peak response to GHRH after SMS pretreatment was 8- to 9-fold lower in the GHD subjects (5.2 +/- 0.8 micrograms/L) compared with both the NSSA (44.0 +/- 14.3 micrograms/L; P < 0.01) and NSSB (42.9 +/- 5.0 micrograms/L; P < 0.01) groups and, more importantly, there was no overlap in the individual GH responses between GHD and normal short children. These results demonstrate that the combined SMS + GHRH test clearly discriminates normal short children from those with GHD. In view of its testing economy, safety, and accuracy, this combined test could become the test of choice to establish a diagnosis of GH deficiency in the slowly growing child. PMID- 8675564 TI - Genomic sequence of the DAX1 gene: an orphan nuclear receptor responsible for X linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. AB - The gene responsible for X-linked adrenal hypoplasia congenita, DAX1, encodes a member of the nuclear hormone receptor superfamily. We sequenced 8851 bp that contained the DAX1 genomic region. The DAX gene was composed of two exons and one 3.4-kilobase intron. Putative TATA and GC boxes and a putative steroidogenic factor 1 response element were present in the 5'-flanking region. Two potentially polymorphic short tandem repeats were identified. The first exon encoded two putative novel zinc finger motifs within a putative DNA binding domain and part of the ligand binding domain, and the second exon encoded the remainder of the ligand binding domain. Although the putative DNA binding domain of DAX1 does not contain substantial sequence similarity to other nuclear hormone receptor superfamily members, the putative ligand binding domain had remarkable similarity to other family members. Single-strand conformational polymorphism analysis permitted identification of three new mutations in DAX1. In conclusion, single strand conformational polymorphism analysis facilitates identification of mutations in the DAX1 gene, and the short tandem repeats may permit linkage analysis in families in which mutations are not yet identified. We speculate that DAX1 may be the most primitive member of the nuclear hormone receptor superfamily identified in mammals. PMID- 8675566 TI - Cellular localization and sex steroid regulation of insulin-like growth factor binding protein messenger ribonucleic acids in the primate myometrium. AB - Insulin-like growth factors (IGF)-I and -II are abundant in the primate myometrium and are implicated in the sex steroid-induced growth of this tissue. To evaluate the potential for modulation of IGF action in the primate myometrium by locally produced IGF binding proteins (IGFBPs), we examined the cellular localization and sex steroid regulation of IGFBPs 1-5 in the nonhuman primate uterus. Ovariectomized rhesus monkeys were treated with placebo, estradiol (E2), or E2 and progesterone (P4) (E2 and P4) for 2 weeks, after which their uteri were removed and cut into thin serial sections for analysis by in situ hybridization. IGFBP-1 messenger RNA (mRNA) was not detected in control or E2-treated uteri but was found in a few unidentified cells in the E2 and P4-treated group. IGFBP-2, 3, -4, and -5 mRNAs were all expressed by myometrial smooth muscle cells but each displayed distinctive patterns of regulation by sex steroids. IGFBP-2 was barely detectable in control myometrium, was significantly increased by E2 and even more significantly by E2 and P4. IGFBP-4 and 5 mRNAs were readily detectable in control myometrium and significantly increased by E2 treatment. The addition of P4 to E2 treatment did not produce a significantly greater augmentation in IGFBP 4 or 5mRNA level compared with E2 alone. IGFBP-3 mRNA was abundant in the control myometrium, but in contrast to other IGFBPs was significantly reduced by approximately 75% in smooth muscle cells by E2 and by E2 and P4 treatment. Interestingly, however, IGFBP-3 mRNA was increased in the uterine vascular endothelium by E2 and by E2 and P4 treatment. In summary, this study has shown that four of the six known IGFBPs are highly expressed in the primate myometrium, and that their expression is differentially regulated by sex steroids. The cellular and sex steroid-regulated pattern of IGFBP-2 gene expression is very similar to that of IGF-I, as previously determined in these same myometrial samples. Both IGF-I and IGFBP-2 are dependent on E2 for significant myometrial expression, and both are further augmented by the addition of P4 to E2 treatment. Uterine smooth muscle IGFBP-3 mRNA levels are negatively regulated, whereas IGFBP 4 and -5 mRNA levels are positively regulated by E2: none of these myometrial IGFBPs appears sensitive to the effects of P4. The present observations, together with our previous data from the same animals, demonstrate that the primate myometrial smooth muscle cell expresses mRNAs for IGF-I and -II, IGF-I and -II receptors, as well as expresses mRNAs for IGFBP-2, -3, -4, and -5. These data provide evidence for complex local interactions between IGF system components regulated by estrogen and progesterone. PMID- 8675567 TI - Pulsatile thyrotropin secretion in patients with Addison's disease during variable glucocorticoid therapy. AB - The inhibitory action of physiological to pathophysiological serum cortisol levels on TSH secretion were investigated in 12 patients with Addison's disease on 3 occasions. 1) In continuation of the conventional hydrocortisone (HC) substitution, a medium dose of HC (0.5 mg/kg) was infused over 23 h. 2) After 24 h withdrawal of HC, the patients had placebo infusion over 23 h. 3) After 5 days of dexamethasone (1.5 mg/day), a high dose of HC (2.0 mg/kg) was infused over 23 h. Blood sampling was performed every 10 min during the last 10 h of the study period, followed by a TRH test (10 micrograms, iv), To mimic the normal diurnal rhythm for serum cortisol, HC was infused in graduated doses, and during medium dose infusion, the serum cortisol level and the TSH pulsatility pattern were similar to those seen in normal controls. The TSH mean level was 1.0 +/- 0.5 mU/L during medium doses of HC, increasing significantly (P < 0.05) to 2.0 +/- 1.6 mU/L during the low cortisol state and was significantly (P < 0.05) suppressed to 0.4 +/- 0.2 mU/L during high doses of glucocorticoids, when the pulse frequency was also significantly reduced (P < 0.01). Together with a dose-dependent inhibitory action of glucocorticoids on the TSH response to TRH, our data indicate that even physiological serum levels of cortisol have an influence on endogenous TSH secretion, probably caused by regulation of the pituitary sensitivity to TRH. PMID- 8675568 TI - Treatment of prostate cancer with gonadotropin-releasing hormone analogue: effect on lipoprotein[a]. AB - Because of its association with cardiovascular disease, lipoprotein[a] (Lp[a]) has attracted the interest of the medical community. Even though serum concentrations of Lp[a] are mainly controlled by the apolipoprotein[a] gene locus, hormonal and metabolic factors, including manipulations of sex hormone levels, have been associated with changes in Lp[a] levels. We report here that the GnRH analog buserelin reduced concentrations of Lp[a] by 48% in elderly males suffering from cancer of the prostate. In contrast, apolipoprotein B levels increased during treatment, whereas other lipid factors, including serum cholesterol, triglyceride, high and low density lipoprotein cholesterol, and apolipoprotein A-I, were not affected. Although the study does not exclude a specific Lp(a)-lowering effect of buserelin, our results suggest that GnRH analogs may reduce Lp[a] levels in the circulation. PMID- 8675569 TI - Delayed diagnosis of psychological erectile dysfunction because of the presence of macroprolactinemia. AB - Idiopathic hyperprolactinemia can be found in men with either normal or low serum testosterone (T) levels. The explanation for the differing effects on T of similar PRL levels has not been found. Macroprolactinemia, as a clinical entity, has been reported mostly in women. These macromolecules are biologically less active and/or are transported less easily across the capillary bed than the 22 kDa molecules. Therefore, women with elevated PRL levels retain normal menses and fertility. We studied six men, aged 28-53 yr (mean, 45 yr), in whom hyperprolactinemia was initially considered to be the cause of their erectile dysfunction. PRL levels ranged from 25-92 ng/mL (normal, 2-15 ng/mL), but T and gonadotropin levels were normal, suggesting that PRL was not disrupting gonadotropin and gonadal steroid function. The results of magnetic resonance imaging studies of the pituitary gland were normal. Separation by Sephadex G-100 column chromatography showed a predominance (85-90%) of big (60 kDa) and big big ( > 150 kDa) PRL, in contrast to the predominance of 22-kDa PRL in normal subjects. Nocturnal tumescence testing was normal, supporting the diagnosis of psychogenic impotence in these subjects, and potency returned after counseling. Hence, the biologically inactive macroprolactinemia did not cause any organic derangement in erectile function. It further obscured and delayed the appropriate diagnosis and treatment of these individuals. PMID- 8675570 TI - Acute and chronic regulation of serum sex hormone-binding globulin levels by plasma insulin concentrations in male noninsulin-dependent diabetes mellitus patients. AB - This study was undertaken to investigate the relationship of the serum sex hormone-binding globulin (SHBG) levels with the plasma insulin concentration and with the insulin resistance in male subjects with noninsulin-dependent diabetes mellitus (NIDDM). This investigation comprised 12 patients with NIDDM and 16 normal subjects matched for age, sex, and body mass index (BMI). There was a significant increase in insulin levels (P < 0.03) and a decrease in SHBG levels (P < 0.01) in the diabetic group as compared with those of the normal group. The sex hormone and plasma insulin levels were measured in NIDDM patients undergoing exercise and dietary therapy. Insulin sensitivity was evaluated by the hyperinsulinemic euglycemic clamp technique expressed as the glucose infusion rate (GIR) before and after the treatment. The SHBG levels correlated significantly with the insulin concentrations (r = -0.643, P < 0.05) and with the GIR (r = 0.615, P < 0.05) before the treatment. The SHBG levels (P < 0.02) and GIR (P < 0.01) increased, and the insulin concentrations (P < 0.01) decreased significantly during the treatment. The SHBG levels showed a negative and significant correlation with the plasma insulin concentrations at the end of the clamp study before (r = -0.615, P < 0.05) and after (r = -0.626, P < 0.05) the treatment. These findings suggest that, in the hyperinsulinemic state, plasma insulin has a direct effect on the SHBG levels. SHBG levels decreased significantly during the clamp study before (P < 0.02) and after (P < 0.01) the treatment. This may represent the acute effect of insulin on the SHBG levels. Briefly, these results suggest that insulin may directly affect the SHBG levels and that SHBG may constitute an index of the insulin resistance only in the hyperinsulinemic state. PMID- 8675571 TI - Effect of sodium valproate on luteinizing hormone secretion in pre- and postmenopausal women and its modulation by naloxone infusion. AB - The synchronized activity of the GnRH neurons can be modulated through both excitatory and inhibitory circuits: one such inhibitory modulator is gamma aminobutyric acid (GABA), but this has been little studied in humans. The aim of this study was to examine whether acute or chronic modulation of the GABA-ergic system with the drug sodium valproate (VPA) affects gonadotropin secretory frequency and/or amplitude in a steroid-dependent manner, and whether any such modulation might interact with endogenous opioids. Sixty postmenopausal women (age range 50-60 yr, group I), 50 postmenopausal women who had been on estrogen replacement therapy (group II), and 30 women in the luteal phase of their regular menstrual cycle (age range 25-40 yr, group III) were studied. VPA was administered acutely using doses of 300, 600, and 1200 mg orally. Samples for serum gonadotropins were taken at intervals over 24 h. Each dose of VPA caused significant LH suppression in group I. The maximum degree of suppressibility was the same with the three doses of VPA (14-20%). However, no dose had any effect on gonadotropin levels in group II. In group III, the single high dose of 1200 mg VPA significantly suppressed serum LH levels. The efficacy of chronic VPA administration in the three groups studied was assessed by measuring LH pulsatility (10-min samples) over 6 h, before and after 1 month's treatment with VPA. No change in either mean basal LH or in the LH pulsatility parameters was found. Naloxone infusion (1.6 mg/h for 6 h) had no effect on LH pulsatility in group I. When 1200 mg of VPA was administered before naloxone infusion, the level of LH suppression was 18% and was associated with a significant decrease in LH pulse frequency (P < 0.01). Naloxone infusion alone significantly increased mean serum LH and LH pulse frequency in group II patients (P < 0.01), and this elevation was antagonized by VPA pretreatment. Naloxone infusion alone significantly increased mean LH levels and LH pulse frequency in patients in group III, and this was also blocked by VPA pretreatment. These results suggest that an acute increase in GABA-ergic tone may inhibit gonadotropin secretion in the estrogen-deprived state, or when endogenous opioid inhibition is blocked in postmenopausal women on estrogens, as well as during the luteal phase of the menstrual cycle. It is possible that GABA-ergic pathways interact with opioids in the inhibitory modulation of gonadotropins in the human female. PMID- 8675572 TI - Critical relationship between autoantibody recognition and thyrotropin receptor maturation as reflected in the acquisition of complex carbohydrate. AB - Generation of large amounts of recombinant TSH receptor (TSHR) protein capable of recognition by TSHR autoantibodies is a goal of clinical importance. We expressed in Chinese hamster ovary cells the human TSHR ectodomain (ECD) with a carboxyl terminus six-histidine tag. After transgene amplification, expressing clones were selected by nickel chelate chromatography in combination with [35S] methionine precursor labeling. An approximately 74-kDa protein was detected in the culture medium, and larger quantities of an approximately 68-kDa protein were found in the cell soluble fraction. Immunoblot analysis with a rabbit antiserum revealed that most of the TSHR-ECD was not secreted, but was retained within the soluble fraction of the cell. Nickel chelate chromatography was not effective in purifying significant quantities of this material. In contrast, with Concanavalin A, but not with wheat germ agglutinin, an approximately 50-fold purification of TSHR-ECD was achieved from the cell soluble fraction. Surprisingly, this affinity enriched TSHR, containing high mannose carbohydrate, was not recognized by human TSHR autoantibodies in sera from six individuals. By ion exchange chromatography, the autoantibody-neutralizing TSHR in the cell supernatant fraction was found to be nonidentical with TSHR-ECD protein recognized by antisera from immunized animals. The present data indicate the critical relationship between autoantibody recognition and TSHR maturation as reflected in the acquisition of complex carbohydrate. Nonsecretion of the TSHR-ECD appears to be related to the specific protein rather than to the glycosylation apparatus of the host cell. Antibodies from immunized animals may be ineffective in monitoring purification of autoantigen-competent TSHR. Finally, the data explain why soluble recombinant TSHR generated in many expression systems is not recognized satisfactorily by human autoantibodies. PMID- 8675573 TI - Relationship between circulating insulin-like growth factor components and sex hormones in a population-based sample of 50- to 80-year-old men and women. AB - There is a large body of evidence that points to a systemic link between the somatotropic axis and sex hormones, but epidemiologic data on the interactions between the two hormonal systems are still missing. We examined here the associations between the plasma levels of insulin-like growth factor (IGF) I, IGF II, IGF-binding protein 3 (IGFBP-3), and sex hormones in a population-based sample of 486 men and women, aged 50-80 yr. The strongest association was an age independent inverse correlation between all three circulating IGF components and sex hormone-binding globulin (SHBG), the major testosterone-binding protein in plasma. Consistent with this, bio-available (non-SHBG-bound) but not total testosterone levels were positively associated with the IGF system in men, and 3 alpha-androstanediol glucuronide was positively correlated with circulating IGFs in women. Moreover, part of the correlation between the circulating IGF system and bone mineral density at the femur and the calcaneus could be accounted for by SHBG. Our data suggest that sex hormones and the GH/IGF system are significantly interrelated in the elderly population. These hormonal interactions may play an important role in human aging and the pathogenesis of age-related diseases. PMID- 8675574 TI - Octreotide scintigraphy in patients with differentiated thyroid carcinoma: contribution for patients with negative radioiodine scan. AB - Somatostatin receptor scintigraphy (SRS) was evaluated in 25 differentiated thyroid carcinoma (DTC) patients. All DTC patients had elevated thyroglobulin levels. A total body scan (TBS) was performed 4 and 24 h after injection of indium-111-DTPA-Phe-octreotide. Group 1 included 16 patients with negative 131I TBS; group 2 had 9 patients with positive 131I TBS. SRS results were compared to the results of conventional imaging methods in group 1 and to 131I TBS in group 2. 131I TBS was performed after administration of a therapeutic dose of 131I in all patients except one. SRS was positive in 20 of 25 (80%) patients. In group 1, SRS was positive in 12 of 16 patients; in the 3 patients with no previously known tumor site, SRS visualized one abnormal neck focus of uptake in two. In the other 13 patients, SRS disclosed unknown mediastinal foci in 2, but visualized less organ involvements and a smaller number of tumor sites than conventional imaging methods. In group 2, SRS was positive in 8 of 9 patients and visualized an identical (7 patients) or a smaller number (1 patient) of involved organs than 131I TBS; in 2 patients, SRS allowed the discovery of 1 abdominal and 1 bone tumor site. We suggest than SRS should guide imaging modalities in DTC patients with negative 131I TBS and be an alternative to 131I TBS in DTC patients unable to withdraw T4 treatment. PMID- 8675575 TI - "Add-back" estrogen reverses cognitive deficits induced by a gonadotropin releasing hormone agonist in women with leiomyomata uteri. AB - Treatment of women with uterine myomas with GnRH agonists results in symptoms of hypoestrogenism which can be prevented by concurrent "add-back" estrogen administration. We took advantage of these induced endocrine changes to investigate their effects on cognitive functioning in young women with myomas. Nineteen women with uterine myomas were tested before treatment. They all received the GnRH agonist, leuprolide acetate depot (LAD), every 4 weeks for 12 weeks and were then randomized to receive LAD plus estrogen or LAD plus placebo every 4 weeks for 8 additional weeks. Levels of all sex hormones decreased after 12 weeks of LAD treatment (P < 0.01), and only estradiol (E2) levels increased (P < 0.01) following 8 weeks of subsequent treatment in the group that received LAD plus E2. Scores on neuropsychological tests of verbal memory decreased from pretreatment to 12 weeks posttreatment with LAD (P < 0.05). These memory deficits were reversed in the group that received LAD plus E2 for 8 weeks coincident with an increase in plasma E2, whereas memory scores remained depressed in the group that received LAD plus placebo. These findings are consistent with those from studies on surgically menopausal women and strongly suggest that estrogen serves to maintain verbal memory in women. These results provide support for the efficacy of add-back estrogen regimens in women treated with GnRH agonists and also imply that estrogen may be important for maintaining memory in the postmenopause. PMID- 8675576 TI - Gemfibrozil treatment of endogenous hypertriglyceridemia: effect on insulin mediated glucose disposal and plasma insulin concentrations. AB - Gemfibrozil or placebo was administered for 3 months to 24 individuals with endogenous hypertriglyceridemia and normal glucose tolerance. Mean ( +/- SEM) fasting plasma triglyceride (TG) concentrations decreased (4.01 +/- 0.55 to 1.34 +/- 0.12 mmol/L; P < 0.001) and high density lipoprotein cholesterol concentrations increased (0.54 +/- 0.03 to 0.67 +/- 0.04 mmol/L; P < 0.001) in gemfibrozil-treated patients, associated with lower (P < 0.01-0.001) plasma free fatty acid and TG concentrations when measured at hourly intervals in response to breakfast (0800 h) and lunch (1200 h). However, day-long plasma glucose and insulin responses to meals in the 2 groups were similar before and after treatment, as were the steady state plasma glucose and insulin concentrations at the end of a 180-min infusion of somatostatin, insulin, and glucose. Thus, marked decreases in both plasma TG and free fatty acid concentrations seen in association with gemfibrozil neither enhanced insulin-mediated glucose disposal nor lowered ambient plasma insulin concentrations in patients with endogenous hypertriglyceridemia. PMID- 8675577 TI - Absence of mutations in parathyroid hormone (PTH)/PTH-related protein receptor complementary deoxyribonucleic acid in patients with pseudohypoparathyroidism type Ib. AB - To clarify the mechanism of resistance to PTH in patients with pseudohypoparathyroidism (PHP) type Ib, the complementary DNA (cDNA) for PTH/PTH related protein (PTHrP) receptor was analyzed in skin fibroblasts from three patients with PHP Ib and compared with those from a patient with PHP Ia and a normal subject. We have divided the full coding region of PTH/PTHrP receptor cDNA into five parts and amplified the cDNA by reverse transcription-coupled PCR. There was no difference in the size of PCR products among these patients and the normal control. Single strand conformation polymorphism analysis of the PCR products also showed no aberrant bands in PHP Ib patients. Furthermore, no mutation in PTH/PTHrP receptor cDNA was found by direct sequencing of the PCR products from these patients. These results demonstrate that there is no mutation in PTH/PTHrP receptor cDNA from skin fibroblasts at least in the examined patients with PHP Ib. In addition, the expression of PTH/PTHrP receptor messenger ribonucleic acid was reduced in two patients but was increased in one patient with PHP Ib, suggesting that a reduction in PTH/PTHrP receptor expression cannot explain the resistance to PTH in all patients with PHP Ib. Elucidation of the pathogenesis of PHP Ib may require examination of tissue-specific abnormality in the PTH signal transduction system in the kidney. PMID- 8675578 TI - Although DR3-DQB1*0201 may be associated with multiple component diseases of the autoimmune polyglandular syndromes, the human leukocyte antigen DR4-DQB1*0302 haplotype is implicated only in beta-cell autoimmunity. AB - Human leukocyte antigen (HLA)-DRB1 and -DQB1 alleles were analyzed using a PCR based sequence-specific priming technique in 16 patients with autoimmune polyglandular syndrome type I (APS-I), 31 patients with APS-II, and 110 patients with component diseases of APS-II, including 9 patients with isolated Addison's disease, 43 patients with Hashimoto's thyroiditis, 22 patients with Graves' disease, and 36 patients with vitiligo. No significant associations was observed between HLA and APS-I patients in our data set, nor was sharing of HLA haplotypes by sibling pairs affected by APS I significantly different from the random expectation. Thus, HLA-DRB1 and -DQB1 genes are probably not involved in APS-I. To delineate the associations between HLA-DRB1, DQB1, and APS-II, we analyzed APS II patients with or without beta-cell autoimmunity [i.e. insulin-dependent diabetes (IDD) and/or islet cell or glutamic acid decarboxylase autoantibodies]. Our results suggest that the association between DR4-DQB1*0302 and APS-II was entirely due to the presence of pancreatic beta-cell autoimmunity, since this haplotype was otherwise not significantly associated with APS-II or with any other of its component diseases. In contrast, the DR3-DQB1*0201 haplotype was associated not only with IDD, but also with APS-II in the absence of pancreatic beta-cell autoimmunity, as were several its component diseases, including isolated Addison's disease, Graves' disease, and Hashimoto's thyroiditis. Interestingly, the frequency of DQB1*0602, a dominantly protective allele against IDD, was not significantly decreased in the APS-II patients with IDD or beta-cell autoimmunity, albeit the patient numbers were small. This phenomenon may suggest that the development of autoimmunity to nonpancreatic endocrine glands may predispose autoimmunity to the pancreatic beta-cells and involve genes other than those of the MHC. PMID- 8675579 TI - A novel mutation in the deoxyribonucleic acid-binding domain of the vitamin D receptor causes hereditary 1,25-dihydroxyvitamin D-resistant rickets. AB - Mutations in the vitamin D receptor (VDR) result in hereditary 1,25 dihydroxyvitamin D3-resistant rickets (HVDRR), an autosomal recessive disease caused by target organ resistance to the action of 1,25-dihydroxyvitamin D3 [1,25 (OH)2D3]. In this study, we investigated the molecular basis of HVDRR in a child from Saudi Arabia who was previously shown to be resistant to 1,25-(OH)2D3 action, but whose cultured skin fibroblasts exhibited normal [3H]1,25-(OH)2D3 binding. Using the PCR, exons 2 and 3 of the VDR gene that encode the DNA-binding region of the receptor were amplified and sequenced. A novel point mutation at nucleotide 252 in exon 2 of the VDR was identified. This missense mutation (GGC to GAC) resulted in the conversion of glycine to aspartic acid at amino acid position 46 (G46D), located at the base of the first zinc finger. This single base change was introduced into wild-type VDR complementary DNA by site-directed mutagenesis, and the mutant VDR was then expressed in COS-1 cells. The expressed mutant VDR displayed a normal binding affinity (Kd = 1.2 x 10(-10) mol/L) for [3H]1,25-(OH)2D3 as determined by Scatchard analysis. However, the mutant VDR was shown to have reduced binding affinity for DNA by DNA-cellulose chromatography. In COS-7 cells cotransfected with a vitamin D response element-chloramphenicol acetyltransferase reporter construct and the mutant VDR complementary DNA expression vector, the mutant VDR was unable to activate gene transcription in cells treated with up to 100 nmol/L 1,25-(OH)2D3. Restriction fragment length polymorphism analysis using MwoI restriction digests of exon 2 demonstrated that the affected child is homozygous for the mutation, whereas the child's father is heterozygous and a carrier of the defective allele. In conclusion, a new mutation was identified in exon 2 of the VDR gene. This mutation, which occurs in the first zinc finger of the DNA-binding domain of the receptor, blocks 1,25-(OH)2D3 action and leads to the syndrome of HVDRR. PMID- 8675580 TI - Fluoride at mitogenic concentrations increases the steady state phosphotyrosyl phosphorylation level of cellular proteins in human bone cells. AB - This study was designed to test the hypothesis that treatment of human bone cells with mitogenic concentrations of fluoride would lead to an increase in the steady state level of tyrosyl phosphorylation of specific cellular proteins. With an immunoblot assay method, it was found that mitogenic concentrations of fluoride (i.e. 50-200 mumol/L) induced a dose- and time-dependent increase in the level of tyrosyl phosphorylation of at least 13 cellular proteins in both normal human bone cells and human TE85 osteosarcoma cells. Time-course studies revealed that a statistically significant increase in tyrosyl phosphorylation of these 13 cellular proteins in human bone cells was observed after 3-6 h of fluoride treatment and was sustained for up to 24 h. This time course was not compatible with a direct activation of tyrosyl kinases, as epidermal growth factor, which activates tyrosyl kinase activity, induced an immediate and acute response that was rapidly reversible within 1 h. Although fluoride increased the steady state tyrosyl phosphorylation of the cellular proteins in human bone cells, the same micromolar doses of fluoride had no effect on human skin fibroblasts, which are fluoride-nonresponsive cells. The effects of fluoride were rapidly reversible in the absence of fluoride and could be acutely potentiated by pretreatment with epidermal growth factor. In summary, we have shown for the first time that mitogenic concentrations (i.e. 50-200 mumol/L) of fluoride increased the steady state level of tyrosyl phosphorylation of at least 13 cellular proteins in human bone cells, and that the increases were relatively show in onset and sustained. In conclusion, these findings are consistent with the hypothesis that the osteogenic actions of fluoride are mediated at least in part by an inhibition of the activity of one or more fluoride-sensitive phosphotyrosyl protein phosphatases in human bone cells. PMID- 8675581 TI - Measurement of corticotropin-releasing factor (CRF), CRF-binding protein (CRF BP), and CRF/CRF-BP complex in human plasma by two-site enzyme-linked immunoabsorbant assay. AB - The actions of human corticotropin-releasing factor (hCRF) in brain, pituitary, and plasma are modulated by a 37-kDa protein [CRF-binding protein (CRF-BP)] that binds to hCRF and neutralizes the peptide's biological activity, suggesting that only the free unbound peptide is biologically active. To accurately predict the biological consequences resulting from changes in total hCRF levels, we have developed two-site enzyme-linked immunosorbent assays (ELISAs) for hCRF-BP, free hCRF, and the hCRF-BP/hCRF complex. The assays were validated by measuring each factor in 1) maternal plasma at times when CRF and hCRF-BP levels are altered, and 2) plasma from normal elderly human subjects who have undergone a hCRF stimulation test. The hCRF-BP ELISA has a sensitivity of 2.7 fmol and a range of detection from 2.7-8000 fmol. Both the hCRF and hCRF-BP/ hCRF assays have a sensitivity of 0.4 fmol, with a useful range of detection from 0.4-40 fmol. Maternal plasma hCRF-BP levels remained unaltered between the 16-21 and 34-39 month gestational age groups. However, levels rose from 0.88 +/- 0.069 nmol/L in the 16-21 month gestational age group to 1.01 +/- 0.09 nmol/L in the 28-33 month gestational age group. Bound hCRF levels dramatically rose from undetectable at 16-21 months of gestation to 200 +/- 69 and 442 +/- 106 pmol/L in the 28-33 and 34-39 month gestational age groups, respectively. In comparison, free hCRF levels remained low throughout gestation, but dramatically rose to 318 +/- 120 pmol/L from 34-39 months of gestation. Binding site occupancy on the hCRF-BP decreased when bound and free hCRF levels were elevated. After treating the third trimester plasma sample with the high affinity hCRF-BP ligand, alpha-helical CRF-(9-41), all of the bound hCRF was displaced from the binding protein, and free hCRF levels rose from 87 to 284 pmol/L. The plasma hCRF-BP level was 0.9 +/- 0.08 nmol/L in normal human volunteers (10 men and 9 women; mean +/- SD age, 74.2 +/- 7.7 yr), decreased to 60% of basal levels 15 min after a bolus injection of 1 microgram/kg synthetic hCRF, and gradually returned to preinjection levels after 120 min. Conversely, bound and free hCRF levels increased from undetectable levels before hCRF injection to 0.58 +/- 0.03 nmol/L at 15 min and then rapidly decreased to undetectable levels at 120 min. These data validate the ELISAs in combination with high affinity hCRF-BP ligands for measuring bound and free hCRF in human plasma and suggest the utility of these assays for further determining alterations in peripheral CRF in conditions such as pregnancy. PMID- 8675582 TI - Aberrant properties of alkaline phosphatase in patient fibroblasts correlate with clinical expressivity in severe forms of hypophosphatasia. AB - The markedly variable clinical expressivity of hypophosphatasia was explored by examining biochemical properties of alkaline phosphatase (ALP) in fibroblasts cultured from 16 patients with severe autosomal recessive forms of this metabolic bone disease. Outcome ranged from death in utero to survival into childhood. Mean ALP activity in patients was 4.3% of controls. Gel filtration analysis indicated a mixture of dimeric and tetrameric ALP in both subject groups. Control cells produced levels of bone ALP cross-reacting material that correlated strongly with ALP activity. Patient bone ALP cross-reacting material levels averaged 41% of the control mean with a wide range of individual values that did not correlate with ALP activity. Control ALP activity was stable in 3% SDS and during electrodialysis. Patient ALP activity was generally unstable under both conditions but with a considerable range of individual values. Fibroblast ALP from every patient exhibited some aberrancy in physicochemical and immunoreactive properties. These data strongly correlated (r = 0.95) with clinical severity. There appeared to be specific associations of tissue nonspecific (bone/liver/kidney isoenzyme) ALP (TNSALP) gene mutations with aberrant enzyme properties and disease severity. We conclude that a spectrum of aberrant biochemical properties of the TNSALP enzyme, caused by different combinations of TNSALP gene missense mutations, reflects the variable clinical expressivity of hypophosphatasia. PMID- 8675583 TI - Antibody-dependent cell-mediated cytotoxicity in autoimmune thyroid disease: relationship to antithyroperoxidase antibodies. AB - Thyroid antibody-dependent cell-mediated cytotoxicity (ADCC) has been reported in autoimmune thyroid disease, and its relationship with antithyroperoxidase antibodies (TPOAb) questioned. We studied the effect of highly purified human thyroperoxidase (TPO) on thyroid ADCC activity elicited by serum from patients with autoimmune thyroid disease. ADCC promoted by a pool of Graves' disease sera could be inhibited by the addition of TPO in a dose-dependent manner. TPO at 40 micrograms/mL decreased the ADCC observed in the presence of this serum pool by 50%. In the presence of 40 micrograms/mL TPO, ADCC was significantly reduced (P < 0.0005) from 39.6 +/- 10.6% (mean +/- SD) to 14.0 +/- 12.9% for the 18 Graves' disease sera tested and from 39.1 +/- 10.5% to 6.1 +/- 1.7% for the 16 thyroiditis sera tested. Purified thyroglobulin had no effect. Immunoaffinity purified TPOAb could mediate ADCC in a dose-dependent manner, whereas purified antithyroglobulin antibodies could not. Three TPOAb-positive, but ADCC-negative, sera appear to contain an activity able to protect thyroid cells from ADCC. This protective effect is also observed on human fibroblasts. In conclusion, TPO is the major antigen involved in thyroid ADCC. PMID- 8675584 TI - Glucocorticoids and interferon-alpha in the acquired immunodeficiency syndrome. AB - Some patients with acquired immunodeficiency syndrome (AIDS) develop glucocorticoid resistance characterized by low receptor affinity (Kd) for glucocorticoids in mononuclear, cells and high values of ACTH and cortisol. As glucocorticoids regulate interferon-alpha (IFN alpha) production, we hypothesized that IFN alpha, a cytokine produced predominantly by monocytes in AIDS, should be increased in cortisol-resistant AIDS, attributing the lack of cortisol inhibition to IFN alpha production. Therefore, we examined glucocorticoid receptor characteristics on monocytes by [3H]dexamethasone binding and measured IFN alpha, cortisol, and ACTH in AIDS patients with (AIDS-GR) or without glucocorticoid resistance (AIDS-C) and controls (C). Monocytes of AIDS-GR patients had a receptor Kd of 10.5 +/- 4.2 nmol/L that was higher than that in the AIDS-C group (2.9 +/- 0.8 nmol/L) and normal subjects (2.0 +/- 0.8 nmol/L; P < 0.01). IFN alpha levels were increased in the AIDS-GR group (17 +/- 6 vs. 4 +/- 1 U/mL in the AIDS-C group and 2 +/- 0.5 U/mL in the C group; P < 0.01). Correlations were found between plasma IFN alpha and receptor Kd on monocytes of AIDS-GR (r = 0.77) and between IFN alpha and plasma cortisol in the same group (r = 0.74). The poly(I)-poly(C)-induced IFN alpha production by monocytes was inhibited by glucocorticoids in the C and AIDS-C groups (approximately 80% inhibition in both groups); the effect was reversed by the receptor antagonist RU-38486. By contrast, glucocorticoids failed to inhibit IFNalpha production from AIDS-GR monocytes (approximately 20% inhibition). In conclusion, elevated IFN alpha levels in AIDS-GR may be due to the lack of inhibitory effect of cortisol on IFN alpha production due to cortisol resistance in monocytes. PMID- 8675585 TI - Antitumor actions of cytokines on new human papillary thyroid carcinoma cell lines. AB - To investigate the in vitro effects of cytokines on the growth of human papillary thyroid carcinoma (PTC) cells, we established six new PTC cell lines, designated BHP 5, 14, 15, 17, 18, and 19, from different patients. We studied the antiproliferative actions of cytokines by using BHP cells, NP cells (PTC cell line), and ARO cells (anaplastic thyroid carcinoma cell line). These cells were treated with various concentrations of tumor necrosis factor-alpha (TNF alpha), interferon-gamma (IFN gamma), interleukin-1 beta (IL-1 beta), and transforming growth factor-beta 1 (TGF beta 1), alone and in combination. Cell proliferation was assessed by [3H]thymidine incorporation and cell number measurement. In BHP cell lines, IFN gamma, IL-1 beta, and TGF beta 1 inhibited [3H]thymidine incorporation and decreased cell number, but TNF alpha stimulated [3H]thymidine incorporation. In NP cells, treatment with each cytokine decreased [3H]thymidine incorporation and cell number. In contrast, the proliferation of ARO cells was either stimulated by or resistant to TNF alpha, IL-1 beta, and TGF beta 1. The effects of these cytokines on [3H]thymidine incorporation were additive in these cell lines. The results suggest that IL-1 beta and TGF beta 1 play a pivotal role in growth inhibition of PTC cells, and the escape from negative control of IL-1 beta and TGF beta 1 may be a step toward anaplastic changes. The additive effects of these cytokines suggest that they act through different pathways. PMID- 8675586 TI - Immunofunctional assay of human growth hormone (hGH) in serum: a possible consensus for quantitative hGH measurement. AB - Confirmation of the diagnosis of GH deficiency in adults and children involves provocative testing for human (h) GH. Different commercially available immunoassays yield largely discrepant results in the measurement of GH levels in human serum. These discrepancies result in doubtful relevance of cut-off levels proposed for GH provocative testing. We have developed an immunofunctional assay method that allows quantitation of only those GH forms in circulation that possess both binding sites of the hormone for its receptor and thus can initiate a biological signal in target cells. An anti-hGH monoclonal antibody recognizing binding site 2 of hGH is immobilized and used to capture hGH from the serum sample. Biotin-labeled recombinant GH-binding protein in a second incubation step forms a complex with those hGH molecular isoforms that have both binding sites for the receptor. The signal is detected after a short third incubation step with labeled streptavidin. The assay is sensitive (detection range, 0.1-100 micrograms/L) and has average inter- and intraassay precisions of 10.3% and 7.3% respectively. Endogenous GH-binding protein does not interfere with the hGH result; placental lactogen slows no detectable cross-reaction in this immunofunctional assay. The degree of immunofunctionally active hGH forms in serum samples, calculated by comparison of immunofunctional assay and RIA results, varied between 52-93%. We propose this immunofunctional assay for GH measurement as a new reference method for hGH quantitation in serum. The immunofunction assay translates only hGH forms into an assay signal that are capable of dimerizing GH receptors and, thus, of initiating a biological effect in target cells. PMID- 8675587 TI - High-dose but not low-dose dexamethasone impairs glucose tolerance by inducing compensatory failure of pancreatic beta-cells in normal men. AB - The diabetogenic effects of glucocorticoids appear to be dose dependent. To determine the effects of different doses of dexamethasone on glucose metabolism, we performed frequently sampled intravenous glucose tolerance tests in 20 healthy young men. Glucose kinetics were analysed by the minimal model. Ten subjects received low-dose dexamethasone (2 mg/day) for 3 days, and the other 10 received high-dose dexamethasone (6 mg/day) for 3 days. The rate of glucose disappearance (KG) did not decrease in the low-dose group (2.46 +/- 0.20 to 2.19 +/- 0.11% min 1, P = 0.35). In contrast, KG in the high-dose group did decrease significantly (2.43 +/- 0.29 to 1.81 +/- 0.11% min-1, P < 0.05). The factor responsible for the decline in KG in the high-dose group was not glucose effectiveness because these values did not change in either group. The insulin sensitivity decreased significantly, by 46% in the low-dose group and 69% in the high-dose group [17.1 +/- 2.7 to 9.2 +/- 1.5 and 18.5 +/- 3.7 to 5.8 +/- 0.9 x 10(-5) min-1 (pmol/L)-1, P < 0.001 and P < 0.01, respectively]. The insulin area (0-20 min) increased significantly, by 104% in the low-dose group and 114% in the high-dose group [3412.6 +/- 609.7 to 6972.7 +/- 1450.1 and 4086.7 +/- 864.5 to 8750.0 +/- 1451.6 (pmol/L) min, P < 0.01 and P < 0.01, respectively]. Insulin sensitivity x insulin area as an estimate of insulin-dependent glucose uptake and insulin's action to suppress hepatic glucose production decreased significantly in the high-dose group (0.588 +/- 0.112 to 0.441 +/- 0.073, P < 0.05), but did not change in the low-dose group (0.436 +/- 0.050 to 0.484 +/- 0.032, P = 0.77). Therefore, the decline in KG in the high-dose group may be associated with the compensatory failure of pancreatic beta-cells against for the insulin resistance. PMID- 8675588 TI - Ethanol decreases nocturnal plasma levels of thyrotropin and growth hormone but not those of thyroid hormones or prolactin in man. AB - Previous studies on the effects of ethanol on circulating pituitary hormones have been carried out mostly during daytime when the secretion of these hormones is generally at a nadir. Therefore, we studied the effects of ethanol on the nocturnal secretion of GH, PRL, TSH, and thyroid hormones (protocol I, nine healthy subjects, five women) and on the TSH and PRL responses to synthetic TRH (protocol II, healthy subjects, four women). Ethanol was given in doses of 0, 0.5 or 1.0 g/kg of BW(protocol I) and 0 or 1.0 g/kg (protocol II) and ingested po at 1900-1945 h. In protocol I, plasma GH rose from 0.6 +/- 0.2 microgram/L (mean +/- SE) at 2200 h to 25.0 +/- 4.3 micrograms/L at 0100 h in control subjects and was almost completely inhibited at 4.5 +/- 1.7 micrograms/L at 0100 h in subjects receiving 1.0 g/kg ethanol (P < 0.01). In subjects receiving 0.5 g/kg ethanol, the inhibition was also significant (P < 0.01), plasma GH being 8.2 +/- 2.5 micrograms/L at 0100 h. Plasma GHRH was measured after solid phase separation in RIA, but it did not show any ethanol-related changes. Plasma PRL exhibited a clear diurnal rhythm in control subjects and rose from 77 +/- 16 at 1800 h to 248 +/- 62 micrograms/L at 0700 h (P < 0.01). The plasma PRL profile was not affected by ethanol. Plasma TSH was 1.4 +/- 0.2 mU/L at 1800-2200 h and rose to 2.3-2.4 mU/L for 0100-0700 h (P < 0.001) in the control subjects. Ethanol 1.0 g/kg suppressed plasma TSH to 1.4 +/- 0.2 mU/L (P < 0.05 at 0100 h and P < 0.01 at 0200 h). According to the area under the curve analyses, the suppression in the nocturnal TSH was 32% in the 0.5 g/kg group and 45% in the 1.0 g/kg group (P < 0.05 for both cases). Circulating free or total T3 and T4 did not show any statistically significant changes that could explain the ethanol-induced inhibition in the nocturnal TSH peak. In protocol II, synthetic TRH (1 microgram/kg BW) was given intravenously, and blood samples were collected before, at 20 and 60 min. TRH significantly stimulated plasma TSH and PRL, but ethanol (1.0 g/kg BW) had no effect on these responses. In conclusion, small amounts of ethanol have unexpectedly great effects on nocturnal surges of TSH, and especially on those of GH, that are apparently mediated by suprapituitary mechanisms. On the other hand, ethanol did not affect the nocturnal PRL surge. These inhibitory effects of ethanol may have unfavorable effects on growth and metabolism in adolescent drinkers. PMID- 8675589 TI - Hormonal regulation of serum lipoprotein (a) levels: effects of parenteral administration of estrogen or testosterone in males. AB - When given orally, estrogens, as well as androgens, lower serum lipoprotein (a)[Lp(a)]levels. To determine whether these effects occur also after parenteral administration of steroids, Lp(a) levels were determined in two groups of elderly males suffering from prostatic carcinoma, who were randomized to treatment with parenteral estrogen (n = 8) or orchidectomy (n = 6). One group of healthy male volunteers (n = 9) was studied after parenteral administration of testosterone. Estrogen was given as im polyestradiol phosphate, 240 mg twice monthly, and testosterone was given as im injections, 250 mg/week. In the orchidectomized subjects, Lp(a) levels increased by 20% by month 3 after treatment (P < 0.05). In spite of drastic changes in serum hormone levels, no change in Lp(a) levels was observed in the estrogen-treated subjects. Concomitantly, low-density lipoprotein cholesterol levels were lowered by 15% and high-density lipoprotein cholesterol levels increased by 20%. Testosterone administration lowered Lp(a) levels by 20% (P < 0.05). No significant changes in serum lipid levels were observed in the testosterone-treated subjects or in the orchidectomy group. Thus, during parenteral administration of estrogens or androgens, diverging effects on Lp(a) and serum lipoproteins were observed. In particular, the mode of administration of estrogen influenced the response in Lp(a) levels. This suggests that the regulatory role of sex hormones on serum Lp(a) levels may depend on their capability to influence hepatic metabolic pathways of Lp(a). PMID- 8675590 TI - Somatostatin analog octreotide inhibits the growth of differentiated thyroid cancer cells in vitro, but not in vivo. AB - Somatostatin and its analogs are antiproliferative in a wide range of normal and neoplastic tissues. In this study we investigated the effect of octreotide (SMS 201-995) on the invasion and growth of three follicular thyroid cancer (FTC) cell lines from one patient in vitro and in vivo. FTC133 was established from the primary tumor, FTC236 from a cervical lymph node metastasis, and FTC238 from a lung metastasis. Invasion was the ability of tumor cells to penetrate 8-microns pore polycarbonate membranes coated with Matrigel. Invasion and proliferation were analyzed using the MTT assay. For in vivo experiments, athymic nude mice were sc inoculated with 500,000 calls of FTC133. The animals were treated twice daily with octreotide sc (100-300 micrograms/kg). RIA studies yielded dose dependent high plasma levels of octreotide (3.43-6.5 ng/mL). Octreotide had a biphasic effect, enhancing growth at low concentrations (1-10 nmol/mL) and inhibiting it at high concentrations (100 nmol to 1 mumol/mL). Octreotide had also a dose-dependent biphasic effect on the invasion of FTC, inhibiting the invasion of all follicular thyroid cancer lines at high concentrations. However, it affected invasion less than growth. Octreotide (10 nmol/mL) stimulated the invasion of FTC133 by 13%, whereas stimulation was lower in both FTC metastases (FTC236, 6%; FTC238, 7%; P < 0.01). At higher concentrations (100 nmol to 1 mumol/mL), octreotide inhibited invasion of FTC133 by 17% (FTC236, 15%; FTC238, 17%; P < 0.01). During a 3-week treatment period, octreotide had no antiproliferative effect on the growth of FTC133 cells in nude mice. In conclusion, octreotide at low concentrations stimulates and at high concentrations inhibits the growth and invasion of follicular thyroid cancer cells in culture. However, it has no effect on the growth of FTC cells in animal experiments. Thus, the value of octreotide as an antitumoral agent in follicular thyroid cancer must be critically questioned. PMID- 8675591 TI - Spectrum of pituitary disease in multiple endocrine neoplasia type 1 (MEN 1): clinical, biochemical, and radiological features of pituitary disease in a large MEN 1 kindred. AB - Prolactinomas and somatotropinomas are reported to be the pituitary lesions most frequently associated with multiple endocrine neoplasia type 1 (MEN 1). However, few reports have documented the full spectrum of pituitary disease in this condition. We report herein the clinical, biochemical (PRL, alpha-subunit, insulin-like growth factor-I, cortisol, and thyroid function), and radiological (magnetic resonance imaging and computerized tomography scan) characteristics of pituitary disease occurring in a single MEN 1 pedigree containing 165 MEN 1 affected members. Pituitary lesions were detected in 30 (18%) of 165 patients overall. In the subgroup of MEN 1 patients (n = 131) living after recognition of MEN 1 in the kindred, pituitary lesions were detected in 25 (19%). In 76% of patients with pituitary lesions, the diagnosis was made by prospective screening; the remainder sought medical attention for symptomatic pituitary disease. Prolactinomas accounted for 76%, and nonfunctioning adenomas accounted for the remaining 24%. alpha-Subunit elevation was observed in 29% of 41 patients tested, and an aggressive alpha-subunit secreting macroadenoma developed in 1 subject with a previously documented prolactinoma. Progression of pituitary disease occurred in 47% of patients with prolactinoma. There were no cases of Cushing's disease, thyrotropinoma, or somatotropinoma. We conclude that 1) in addition to prolactinomas, nonfunctioning pituitary tumors are common in MEN 1; 2) alpha subunit hypersecretion is frequent in MEN 1; 3) comprehensive screening may identify many clinically significant but asymptomatic pituitary lesions; and 4) prolactinomas occurring in MEN 1 may behave more aggressively than sporadic prolactinomas. PMID- 8675592 TI - Risk factors and long-term outcome in pituitary-dependent Cushing's disease. AB - Although transphenoidal pituitary microsurgery has become the treatment of choice in Cushing's disease, other procedures, such as bilateral adrenalectomy and pituitary irradiation, are currently in use in its management. Indeed, no treatment has proven to be fully satisfactory for this condition. The rates of cure and recurrence after pituitary surgery or irradiation and the incidence of Nelson's syndrome after bilateral adrenalectomy are still open issues. A population of 162 patients with pituitary-dependent Cushing's disease was studied at 1 institution and had a follow-up of at least 2 yr after treatment (median, 7 yr). Patients were divided in subgroups according to the type of treatment: transsphenoidal pituitary microsurgery, bilateral adrenalectomy, or pituitary irradiation. Survival analysis was employed to characterize the outcome of treatment in each subgroup. Predictive factors for success of pituitary surgery were also evaluated. The estimated cumulative percentage of patients remaining in remission after successful pituitary surgery (n = 79) was 93.7% after 2 yr, 80.6% after 5 yr, 78.5% after 7 yr, and 74.1% after 10 yr. Of 8 risk factors examined, the following attained statistical significance: age, clinical severity, presence of major depression, pre- and posttreatment urinary cortisol levels, and posttreatment ACTH level. Pituitary surgery was successful in 79 of 103 patients (76.7%). Surgical failure was significantly associated with lack of pituitary adenoma and the clinical severity and presence of major depression. Of patients treated by bilateral adrenalectomy (n = 63), the estimated cumulative percentage remaining free of Nelson's syndrome was 87.1% after 2 yr, 79.3% after 7 yr, and 71.2% after 10 yr. The occurrence of Nelson's syndrome was significantly related to the pretreatment urinary cortisol level and the presence of pituitary adenoma at previous pituitary surgery. After cure by pituitary irradiation (n = 23), the estimated cumulative percentage of patients remaining in remission was 100% after 2 yr, 81.8% after 5 yr, 71.6% after 7 yr, and 65.1% after 10 yr. Previous pituitary surgery, although unsuccessful, appeared to be a protective factor for relapse. The results indicate that relapse after cure by either pituitary surgery or irradiation is a considerable clinical problem that increases over time. Our findings ascribe new importance to the clinical presentation of patients and indicate subgroups that are at high risk for relapse after pituitary surgery or irradiation and for developing Nelson's syndrome after bilateral adrenalectomy. PMID- 8675593 TI - Insulin-like growth factors stimulate the release of insulin-like growth factor binding protein-3 (IGFBP-3) and degradation of IGFBP-4 in nonsmall cell lung cancer cell lines. AB - Insulin-like growth factors (IGFs) are potent mitogens for lung cancer cells. Their proliferative activity is influenced by their binding proteins (IGFBPs). We report here on the regulatory effects of IGF-I and IGF-II on the production and release of IGFBPs by nonsmall cell lung cancer cell lines (NSCLC). The nine NSCLC cell lines used in this study showed messenger ribonucleic acid (mRNA) expression of all six IGFBPs known, as determined by PCR, and protein secretion of IGFBP-1, 2, -3, -4, and -5, as analyzed by Western immunoblots. The addition of IGFs to a serum-free medium showed divergent effects on IGFBP-3 and IGFBP-4 levels in a conditioned medium (CM). IGF-I and IGF-II, but not insulin, led to a much higher concentration of IGFBP-3 in the CM of all tested NSCLC cell lines, whereas the level of immunologically detected membrane-associated IGFBP-3 was decreased. Furthermore, Northern analysis of mRNA isolated from A549 revealed that IGFBP-3 specific mRNA was not changed by IGF-I or IGF-II, suggesting that the IGF-induced effects on IGFBP-3 depend on the release of cell-associated IGFBP-3. In contrast, IGFBP-4 levels were diminished by increasing concentrations of IGFs in the CM of the NSCLCs A549, NCI-H157, and U1752, with no response to insulin or the IGF-I analog, whereas IGFBP-4-specific mRNA was not changed by IGF-I or IGF-II, as determined by Northern analysis. The same effects were seen in a cell-free system after incubation of the CM with IGFs. The decrease in IGFBP-4 concentrations was prevented by coincubation of the CM with the IGFs and either ethylenediamine tetraacetate or 1,10-phenanthrolene, but not with other protease inhibitors. We suggest that IGFs may either activate an IGFBP-4-specific metalloprotease present in NSCLC CM or that the binding of IGFs to IGFBP-4 may enhance the susceptibility of IGFBP-4 to proteolytic degradation. Based on these data, we present evidence that IGFs may regulate their own availability both by releasing IGFBP-3 from cell membrances and through proteolytic degradation of IGFBP-4. PMID- 8675594 TI - Growth hormone synthesized and secreted by human thymocytes acts via insulin-like growth factor I as an autocrine and paracrine growth factor. AB - There is increasing evidence that GH can influence immune function and that it is secreted by lymphocytes. In the present study we investigated the endogenous synthesis and secretion of GH and insulin-like growth factor I (IGF-I) from human thymocytes and evaluated the autocrine/paracrine effects of GH and IGF-I on T cell and thymic epithelial cell proliferation. First, the presence of thymic GH and IGF-I was detected by RIA of thymocyte extracts. Next, using a hormonal enzyme-linked immunoplaque assay, we found that thymocytes secreted GH and IGF-I. Further, we documented the endogenous synthesis of GH by human thymocytes using [35S]methionine labeling followed by immunoprecipitation, gel electrophoresis, and autoradiography. We then evaluated the physiological role of endogenously generated GH and IGF-I. Using an affinity-purified-GH polyclonal antibody, we observed a marked inhibition (P < 0.04) of phytohemagglutinin-stimulated thymocyte proliferation, suggesting an autocrine/paracrine role for the secreted GH. Further, we observed significant (P < 0.001) increases in thymocyte proliferation in cultures stimulated with varying doses of GH and IGF-I. Also, conditioned medium of human thymocytes (1 x 10(5) cells) stimulated with GH for 48 h contained a significant (P < 0.001) amount of IGF-I. Thymocyte proliferation stimulated by GH was significantly (P < 0.01) inhibited by monoclonal as well as polyclonal human IGF-I antisera. Finally, we studied the paracrine effect of thymocyte-secreted GH on human primary thymic epithelial cell (TEC) cultures. A significant (P < 0.05) increase in [3H]thymidine uptake in TEC cultures after GH addition was observed, which was abolished by GH antiserum. Polyclonal and monoclonal IGF-I antisera significantly (P < 0.05) inhibited GH-stimulated TEC proliferation. In summary, human thymocytes synthesize and secrete GH and IGF-I. Further, GH functions as an autocrine/paracrine growth factor in the human thymus via locally synthesized IGF-I. PMID- 8675595 TI - Twenty-four-hour energy expenditure: the role of body composition, thyroid status, sympathetic activity, and family membership. AB - The present study assessed the possible familial effect in 71 healthy Caucasian siblings on each of the variables determining the inter-individual variations in energy expenditure (EE) measured under standardized conditions. We found that the 24-h EE measured in respiration chambers of 71 siblings from 32 different families was positively correlated with fat-free mass, which explained 82% of the variation between subjects (P < 0.00001). An additional 10% of the total variation was explained by differences in spontaneous physical activity (P < 0.00001), fat mass (P < 0.00001), plasma concentration of free T3 (P < 0.003), and norepinephrine (P < 0.002), whereas plasma values of epinephrine and androgen hormones did not correlate with 24-h EE. After adjustment for gender, there was a familial aggregation of both 24-h and sleeping EE, as indicated by intraclass correlation coefficients (r) of 0.44 (P < 0.02) and 0.58 (P < 0.01), respectively. The familial effect on gender-adjusted 24-h EE was explained mainly by a familial resemblance of fat-free mass (ri = 0.48; P < 0.015) and fat mass (ri = 0.40; P < 0.03), whereas spontaneous physical activity and plasma concentrations of T2 and norepinephrine did not correlate in families. It is concluded that the familial aggregation of EE in Caucasians is mediated mainly through familial resemblance of body composition; even though plasma concentrations of free T3 and norepinephrine, independent of body composition, explain an additional proportion of the variation in EE, they do not contribute to the familial correlation. PMID- 8675596 TI - Regulation of human placental trophoblast low-density lipoprotein uptake in vitro by estrogen. AB - In the present study, human trophoblast cells were studied in culture to determine the effect of estrogen on low-density lipoprotein (LDL) uptake and progesterone formation. Cytotrophoblasts were obtained from term human placentas and incubated for 72 h with 10% FBS to stimulate formation of syncytia. Syncytiotrophoblasts were then incubated for an additional 48 h with estradiol and/or LDL protein. Estradiol plus LDL stimulated progesterone to a level that was 133% greater (P < 0.05) than control (314 +/- 69 ng/mg protein) or LDL alone, suggesting that estrogen stimulated progesterone formation via an increase in LDL uptake and utilization. To examine this possibility, trophoblast cells were cultured with estradiol for 48 h as above, then incubated for 12 h with 6-200 micrograms/mL [125I]LDL. Mean (+/- SE) specific uptake of [125I]LDL (ng/mg cell protein) was approximately 50% greater (P < 0.01) with estradiol (638 +/- 23) than with vehicle (429 +/- 54). Scatchard analysis demonstrated that the dissociation constant for LDL uptake was similar in the presence (2.9 +/- 0.4 x 10(-6)M) and absence (2.8 +/- 0.6 x 10(-8)M) of estradiol, indicating that estrogen increased LDL receptor number without affecting affinity. LDL uptake was increased (P < 0.05) by incubating trophoblast with as little as 0.10 ng/mL estradiol (approximately 10(-9) M). We conclude that estrogen regulates placental trophoblast cell uptake of LDL and, thus, the availability of cholesterol for progesterone bio-synthesis during human pregnancy. PMID- 8675597 TI - The expression of insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) genes in the human placenta and membranes: evidence for IGF-IGFBP interactions at the feto-maternal interface. AB - The placenta synthesizes insulin-like growth factors (IGFs) and their binding proteins (IGFBPs), which are believed to regulate its growth and development in an autocrine/paracrine manner. To delineate the cellular sites of expression of IGP and IGFBP messenger ribonucleic acids (mRNAs) in human placenta throughout pregnancy, we used in situ hybridization histochemistry with 35S-labeled IGF and IGFBP complementary RNA probes on human placentas and fetal membranes of gestational ages 6 weeks to term (40 weeks). In placental regions where trophoblasts (fetal) or decidua (maternal) coexist (e.g. basal plate), the identity was delineated by their cytokeratin or vimentin immunoreactivity, respectively. Except for IGF-II, mRNAs encoding peptides of the IGF system were expressed in a similar spatial pattern and relative abundance throughout gestation. Both IGF mRNAs showed similar tissue distribution, but the IGF-II mRNA was more abundant than IGF-I mRNA at all gestational ages. IGF-II mRNA was expressed in the chorionic mesoderm of placental villi and chorionic plate in moderate abundance, and it decreased with gestation. It was also expressed in the trophoblasts of the cytotrophoblastic shell and Langhan's layer of placental villi only in the first trimester, suggesting an autocrine role for IGF-II in early cytotrophoblastic proliferation and/or differentiation. IGF-II mRNA was expressed most abundantly in the columns of intermediate trophoblasts in the anchoring villi and chorionic and basal plates. A gradient of IGF-II mRNA abundance was observed in the trophoblasts of the cytotrophoblastic column, with greater IGF-II mRNA levels in those at the invading front, suggesting a role for IGF-II in trophoblastic invasion. In the fetal membranes, IGF-II mRNA was identified in the amnion and chorion laeve. IGF-I receptor mRNA was expressed in low abundance in all cell types of the placenta. All six IGFBP mRNAs were identified in variable abundance in the decidualized stromal cells of the maternal decidua basalis and parietalis, with IGFBP-1 mRNA being expressed in the greatest abundance. The spatial pattern of expression of each IGFBP mRNA also differed among decidual cells, with IGFBP-1, IGFBP-2, IGFBP-4, and IGFBP-6 mRNAs being expressed in most cells, whereas IGFBP-3 and IGFBP-5 mRNAs were expressed in only some cells. IGFBP-1 mRNA was expressed initially in the epithelium of endometrial glands and in a population of decidualized stromal cells in early gestation, and subsequently in the majority of decidualized stromal cells. IGFBP 3 mRNA was expressed in both the decidua and certain intermediate trophoblasts of the basal plate and anchoring villi of placenta and in amnion and chorion laeve of fetal membranes. IGFBP-4 and IGFBP-5 mRNA were expressed additionally in low abundance in the chorionic mesoderm. IGFBP-6 was expressed in greater abundance in the decidua parietalis than in decidua basalis, although the general level of expression was low. The spatial pattern and relative abundance of expression of IGFBP mRNAs suggest IGFBP-1 to be the predominant IGFBP synthesized by the maternal decidual cells, interacting with the IGF-II that synthesizes fetal intermediate trophoblasts. Presumably, IGF-II and IGFBPs are used for cell to cell communication between fetal trophoblasts and maternal decidual cells at the feto-maternal interface for placental development and/or function. PMID- 8675598 TI - Pulsatile growth hormone secretion in older persons is enhanced by fasting without relationship to sleep stages. AB - Spontaneous secretion of GH decreases with aging. To investigate whether fasting increases pulsatile GH secretion in older as it does in younger subjects, we studied six subjects (four postmenopausal women and two men, aged 55-81 yr; body mass indexes, 22-24 kg/ m2). Blood was obtained every 5 min for 24 h on a control (fed) day and on the second day of a fast. Serum GH concentrations, measured by an immunoradiometric assay, were analyzed with a multiple parameter deconvolution method to stimultaneously resolve endogenous GH secretory and clearance rates. Two days of fasting induced a 4-fold increase in the 24-h GH production rate (38 +/- 25 vs. 166 +/- 42 micrograms/L distribution volume; P = 0.003) and a 2-fold increase in the amount of GH secreted per pulse (2.4 +/- 1.4 vs. 5.5 +/- 1.2 micrograms/L distribution volume; P = 0.02). The latter was a result of increased secretory burst amplitudes with unchanged secretory burst durations. The number of detectable GH secretory bursts per 24 h was also increased by fasting (13 +/- 1.4 vs. 30 +/- 1.1; P = 0.0004); the GH pulse frequency may have been underestimated in the fed state, as 33 +/- 4.9% of the samples had undetectable ( < 0.2 microgram/L) serum GH concentrations compared to 5.2 +/- 2.6% of the samples on the fasting day (P = 0.004). The t1/2 of endogenous GH was not significantly altered by fasting. The fold increase in GH secretion with fasting was similar to that previously observed in young men, although absolute levels of GH secretion were approximately 50% lower in both fed and fasted conditions. Fasting decreased the proportion of sleep time spent in rapid eye movement sleep (4.7 +/- 1.3 vs. 15 +/- 2.1%; P = 0.005), but did not significantly increase slow wave (stages 3 and 4) sleep. In both fed and fasted conditions, mean GH secretion rates were similar during daytime wakefulness, nocturnal wakefulness, rapid eye movement sleep, and stages 1, 2, and 3 of sleep. We conclude that hyposomatotropism associated with aging is partially reversed by fasting, and the enhancement of GH secretion by fasting is not related to changes in slow wave sleep. These data indicate that GH secretion in older persons can be enhanced by physiological interventions. PMID- 8675599 TI - Immunological evidence for the expression of the Fas antigen in the infant and adult human ovary during follicular regression and atresia. AB - Immunohistochemical localization of the Fas antigen in the infant and adult human ovary during follicular growth, regression, and atresia was examined by the avidin/biotin immunoperoxidase method with a monoclonal antibody to the Fas antigen. Western blotting was used to confirm the presence of the Fas antigen protein. In primordial and primary follicles within the normal adult ovary, only the oocyte showed moderate immunostaining for the Fas antigen. In secondary and antral follicles, only the oocyte showed weak staining for the Fas antigen, while in preovulatory follicles, neither the oocyte nor the granulosa and theca cells were immunostained for the Fas antigen. In corpora lutea, the Fas antigen staining became apparent in the granulosa lutein cells during the early luteal phase and intensified during the mid luteal phase, while the theca lutein cells became positive for the Fas antigen staining during the mid luteal phase. During the late luteal phase, the staining intensity of the Fas antigen in the regressing corpora lutea further increased. As the regressing corpora lutea were converted into corpora albicans, the staining intensity decreased, and the corpora albicans and stromal cells were negative for the Fas antigen. In atretic primordial and primary follicles, only the degenerating oocyte showed the Fas antigen staining. By contrast, in atretic antral follicles, the Fas antigen staining was profound in the degenerating granulosa cells at the early stage of atresia, and at the mid stage of atresia it was intensified in the cell surface of the scattered granulosa cells and became apparent in the theca cells. At the late stage of atresia the Fas antigen remained only in the hypertrophied theca cells. In the infant ovary, only the oocyte in primordial and primary follicles exhibited intense staining for the Fas antigen. In the postmenopausal ovary, the Fas antigen staining was entirely negative. Western blot analysis revealed the presence of the Fas antigen protein with a molecular mass of 45 kDa in luteal tissues. On the basis of the recent evidence, that the Fas antigen mediates an apoptotic signal in a variety of cells, the abundant expression of the Fas antigen in the regressing corpora lutea and atretic follicles suggests that the Fas antigen participates in luteal regression and follicular atresia through the apoptotic process. Furthermore, notable expression of the Fas antigen in the oocyte of primordial and primary follicles within the infant and adult human ovary followed by the decrease in the Fas antigen expression in the oocyte with the advance of follicular maturation suggests that the Fas antigen expression in the oocyte may play a role in follicular selection. PMID- 8675600 TI - Role of the RET proto-oncogene in sporadic hyperparathyroidism and in hyperparathyroidism of multiple endocrine neoplasia type 2. AB - Parathyroid tumors occur either sporadically or as part of inherited syndromes such as multiple endocrine neoplasia (MEN) types 2A and 2B. The development of both of these familial syndromes has been related to specific germline gain-of function mutations predominantly in exons 10 and 11 (MEN 2A) and 16 (MEN 2B) of the RET proto-oncogene. The same mutations have also been implicated in the pathogenesis of sporadic medullary thyroid carcinoma and sporadic pheochromocytoma. The RET mutations are thought to have a transforming effect only in cells of neural crest origin such as thyroid parafollicular (C-cells) and adrenal chromaffin cells, which normally express the RET proto-oncogene. Expression of RET messenger RNA has not yet been studied in the parathyroid, however, we demonstrate in this study by a sensitive, semiquantitative RT-PCR technique and in situ hybridization, that RET is expressed in MEN 2A parathyroid tumors and in sporadic adenomas. Although DNA from a parathyroid tumor of a MEN 2A patient displayed an expected mutation, none of the previously described MEN 2A or 2B mutations were found in DNA of 34 sporadic adenomas. Our data suggest that parathyroid disease is an integral part of the MEN 2A syndrome, but that MEN 2 mutations in RET rarely play a part in the pathogenesis of sporadic parathyroid tumors. PMID- 8675601 TI - Angiotensin II receptors and angiotensin II stimulation of ciliary activity in human fallopian tube. AB - Using an antibody (6313/G2) directed against a specific sequence in the extracellular domain of the type 1 angiotensin II receptor (AT1), we demonstrated the presence of angiotensin II (AII) receptors in human fallopian tube. Immunoperoxidase staining for AT1 receptor showed positive staining in the epithelium of the tubal mucosa. The intensity of staining varied depending upon the hormonal status at the time of salpingectomy, being strongest in the proliferative phase of the ovarian cycle and weakest after menopause. Ligand binding assay confirmed that the AII receptor concentration was highest in the mucosa of fallopian tubes from premenopausal women. Mucosa from the ampullary segment had higher concentrations of AII receptor than the fimbrial and isthmic segments in both premenopausal and postmenopausal women. Displacement studies using specific AII receptor subtype antagonists showed that approximately 60% of the total activity could be displaced by CGP42112B (type 2 specific) and 40% by losartan (AT1 specific). Immunoblotting confirmed that the antibody detected a protein of approximately 60 kDa. Functional studies showed that AII had a stimulatory action on tubal ciliary beat frequency, but had no significant effect on myosalpingseal activity. This effect was achieved at nanomolar concentrations of AII; further increases in the AII concentration were without additional effect. The stimulatory effect of AII was inhibited by the specific AT1 antagonist losartan, whereas the type 2 antagonist, CGP42112B, had no effect. The data demonstrate that AII may play an important role in ovum transport and fertility. PMID- 8675602 TI - Expression of the cell death-inducing gene bax in carcinomas developed from the follicular cells of the thyroid gland. AB - The expression of apoptosis-regulating proteins, Bcl-2, Bax, Mcl-1, and Bcl-X, was evaluated by immunohistochemical methods in 39 cases of thyroid carcinomas. Normal thyroid tissues showed a consistent expression of Bcl-2 and Mcl-1 whereas Bax and Bcl-X proteins were essentially absent from most follicular thyroid cells. Bax expression was observed in all papillary carcinomas (n = 23) and in 8 of 10 follicular carcinomas. The intensity of Bcl-2 immunostaining was generally higher in follicular tumors (n = 10) than in papillary carcinomas (n = 21 of 23). However, in undifferentiated tumors, both Bax and Bcl-2 were weakly expressed. Mcl-1 protein expression was similar to that of Bax in papillary and follicular tumors, but was also frequently detectable in undifferentiated tumors. Bcl-X immunostaining was seen in all undifferentiated tumors (n = 6), in 22 of 23 papillary tumors, and in 5 of 10 follicular tumors. Our findings show that the regulation of bcl-2 family gene expression is different in normal thyroid tissue compared to that of its neoplastic counterpart and varies with the tumor subtype. In particular, unlike normal thyroid epithelium, the apoptosis-blocking gene bcl X and the apoptosis-inducing gene bax are frequently expressed in thyroid carcinomas derived from the follicular cells. Thus, alterations in the expression of these bcl-2 family genes may contribute to the pathogenesis of thyroid carcinomas. PMID- 8675603 TI - C618R mutation in exon 10 of the RET proto-oncogene in a kindred with multiple endocrine neoplasia type 2A and Hirschsprung's disease. AB - The cosegregation of multiple endocrine neoplasia (MEN) type 2A with Hirschsprung's disease (HSCR), two diseases associated with mutation of the RET proto-oncogene, is infrequent. A 30-yr-old man was referred for screening of MEN 2A. Surgery for HSCR was performed at 4 yr of age. Basal and pentagastrin stimulated calcitonin levels were abnormal. Histological examination of the thyroid confirmed bilateral medullary thyroid carcinoma. Screening of family members revealed six subjects with medullary thyroid carcinoma or abnormal pentagastrin-stimulated calcitonin test; one had an unilateral pheochromocytoma and two were affected with HSCR. DNA sequence analysis showed a heterozygote C618R mutation in exon 10 of the RET proto-oncogene in the proband and his mother, as well as in second-degree relatives with MEN 2A phenotype or HSCR. In this study, we report on a novel kindred with MEN 2A and HSCR phenotype associated with a point mutation (C618R) in one of the cysteine codons at the extracellular domain of the RET proto-oncogene. PMID- 8675604 TI - Obesity in childhood craniopharyngioma: relation to post-operative hypothalamic damage shown by magnetic resonance imaging. AB - OBJECTIVE: To quantify the extent of hypothalamic damage after surgery for craniopharyngioma using magnetic resonance imaging (MRI) and to relate the findings to changes in body mass index (BMI). PATIENTS: Sixty-three survivors (36 males, 27 females) of childhood cramopharyngioma were treated surgically between 1973 and early 1994. METHODS: Cranial MRI was performed at a structured follow-up assessment 1.5-19.2 yr after the initial surgery. Hypothalamic damage was scored as 0 (no visible damage), 1 (intermediate), or 2 (severe). RESULTS: After surgery there was an increase in BMI standard deviation (SD) from diagnosis to study assessment in all but 7 patients. However, patients with MRI scores of 2 (n = 17) had a significantly greater increase in median BMI SD score at follow-up (+5.5 SD score), compared with +2.5 SD score and +1.1 SD score for patients with MRI scores of 1 or 0, respectively. Of the 17 cases with MRI scores of 2, 10 had a history of extreme weight loss or weight gain at presentation; preoperative neuroimaging demonstrated extensive hypothalamic infiltration by tumor in these cases. CONCLUSION: MRI gives sufficient anatomical definition to allow assessment of the extent of hypothalamic damage and, thereby, prediction of the patients most at risk for severe post-operative weight gain. PMID- 8675605 TI - Human skin contains luteinizing hormone/chorionic gonadotropin receptors. AB - Normal human skin contains a major 4.5 kb and several minor mRNA transcripts and a 66 kDa protein of luteinizing hormone (LH)/chorionic gonadotropin (hCG) receptors which are capable of binding exogenous 125I-hCG. The distribution of receptor transcripts and receptor protein are the highest in epidermis followed by hair follicles, sebaceous and sweat glands. LH/hCG receptors are co-localized with androgen receptors in all the skin appendages. These data are the first demonstration of skin containing LH/hCG receptors and would suggest that LH and hCG may regulate skin functions. PMID- 8675606 TI - Decreased inhibin B secretion is associated with the monotropic FSH rise in older, ovulatory women: a study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles. AB - This study sought to compare circulating and follicular fluid (FF) concentrations of dimeric inhibin A and B utilizing specific two-site ELISAs for these hormones in normal older and younger ovulatory women. METHODS. Normally ovulating women age 40-45 (n = 10) and 20-25 (n = 13) were studied throughout the follicular phase with daily blood sampling, transvaginal ultrasound examinations, and dominant follicle aspiration. When the dominant follicle reached a mean diameter of 16 mm or serum estradiol (E2) was > or = 550 pmol/L, 10,000 IU of hCG was administered intramuscularly followed 32 hours later by transvaginal follicle aspiration. Serum and FF samples were analyzed for E2, FSH, and inhibin A and B. Daily hormone levels were compared by ANOVA, and mean results were compared using t-tests. RESULTS: Older women developed a dominant follicle sooner, meeting criteria for hCG cycle day 10.6 +/- 0.4 vs. 14.5 +/- 1.0 p < 0.001. As expected, the older group had higher maximal serum FSH concentrations compared to the younger women (11.4 +/- 0.5 vs. 8.0 +/- 0.4 IU/L, p < 0.001). We compared hormone concentrations from days-1 to 3 (where day 0 = day of maximal FSH concentration). E2 concentration was higher in the older women (p = 0.002), and there was no significant difference in inhibin A secretion (p = 0.61). In contrast, mean inhibin B concentration was significantly lower in the older women (p = 0.04). On the day of aspiration of the dominant follicle, serum inhibin B was decreased in the older subjects (42.6 +/- 6.5 vs. 153.1 +/- 53 pg/ml, p = 0.02), whereas older subjects had higher levels of inhibin A (106 +/- 16 vs. 60.4 +/- 9.4 pg/ml, p = 0.04) and similar E2 levels (665 +/- 35.2 vs. 687 +/- 92 pmol/L, p = 0.83). There were no differences in FF concentrations of inhibin B (164 +/- 31 vs. 174 +/- 37 ng/ml, p = 0.85), inhibin A (317.7 +/- 38 vs. 248 +/- 57 ng/ml, p = 0.16), or E2 (2074 +/- 294 vs. 2474 +/- 338 nmol/L, p = 0.82) in the older and younger women. CONCLUSION. Follicular phase inhibin B secretion is decreased in older ovulatory women who demonstrate a monotropic FSH rise, whereas inhibin A secretion is similar to that in younger women. The dominant follicle in these older women appears to be normal in terms of FF E2 and inhibin content. We speculate that decreased inhibin B secretion most likely reflects a diminished follicular pool in older women and may be an important regulator of the monotropic FSH rise. PMID- 8675607 TI - ACTH receptor, CYP11A1, CYP17 and CYP21A2 genes are expressed in skin. AB - Evidence is provided that mRNA for ACTH (MC-2) receptor and mRNAs for three obligatory enzymes of steroid synthesis including cytochromes P450scc, P450c17 and P450c21 are expressed in normal and pathologic human skin. Thus, molecular elements of the distal loop of the "pituitary-adrenal axis" such as the MC-2, CYP11A1, CYP17 and CYP21A2 genes are expressed in the skin. PMID- 8675608 TI - Outcome of severe congenital hypothyroidism. New England Congenital Hypothyroidism Collaborative. PMID- 8675609 TI - Disparate effects of weight reduction by diet on serum dehydroepiandrosterone sulfate levels in obese men and women. PMID- 8675610 TI - High androgen levels in chronic fatigue patients. PMID- 8675611 TI - Effects of MSG on the neuroendocrine system. PMID- 8675612 TI - Detailed staging of inbred C57BL/6 mice between Theiler's [1972] stages 18 and 21 (11-13 days of gestation) based on craniofacial development. AB - A detailed staging table of inbred C57BL/6 embryonic mice was developed to facilitate a study of the stage-by-stage cellular and molecular mechanisms underlying cranial skeletal development and elucidation of the developmental mechanisms potentially involved in evolutionary changes in cranial skeletal morphology exhibited by different inbred strains of mice. Mice were mated for only 2 hr and embryos were recovered every 2 or 4 hr between 11 and 13 days of gestation. Theiler's [1972] stages 18 through 21 were divided into substages and divisions based on the development of five external structures--the frontonasal area, eyes, auditory meatus, mandibular and hyoid auricular hillocks/pinna, and vibrissae--and three internal histological structures--eyes, tongue, and vibrissae. Each substage and division was designated with a decimal point: e.g., substage 20.1 and division 20.11. Embryos were staged using the staging table and the relationship of the substages and divisions with days of gestation was examined. The results showed considerable intra- and inter-litter variation in stages of embryos, suggesting that days of gestation are not a good indicator for staging embryos. Our staging table offers a more reliable and precise method to standardize embryonic development. Regression analyses of substages on days of gestation showed that the duration of stages increased from stages 18 to 21. Estimated durations were 3.5 hr for stages 18 and 19, 8.8 hr for stage 20, and 38.8 hr for stage 21. Our staging table also provides baseline information on development of the frontonasal area (muzzle) and vibrissae and development and the transformation of the auricular hillocks into the pinna. The developmental sequence of mystacial and labial vibrissae indicated highly regulated differentiation and morphogenesis of vibrissal development at stages 20 and 21. Three hyoid auricular hillocks transiently became four hillocks at stage 19.1 before transforming to the pinna during stage 21. The second and third hyoid auricular hillocks were the major contributor to the pinna before stage 21.2, whereas mandibular auricular hillocks contributed to the pinna from stage 21.32 onward. The staging table has already served to demonstrate stage-specific skeletogenesis of the first arch cartilages in inbred C57BL/6 mice and to reveal differences in the onset of timing of skeletogenesis among inbred C57BL/6, C3H/He and CBA/J mice. PMID- 8675613 TI - Stage-specific onset of condensation and matrix deposition for Meckel's and other first arch cartilages in inbred C57BL/6 mice. AB - Condensation is a multistep process, involving cell recruitment, cell-to-cell contact by cell adhesions, and concomitant changes in cell shape. Condensation of prechondrogenic cells down-regulates and/or inactivates cell proliferation and enhances the activities of cartilage-specific genes. Timing of onset and duration of condensation are thus important regulatory processes mediating cellular and molecular events during chondrogenesis. The present study was undertaken to examine timing of onset and duration of condensation and onset of matrix formation for first arch cartilages in inbred C57BL/6 mice. Because timing can only be reliably assessed in very precisely staged embryos, mice were mated for only 2 hr, pregnancy was determined by weight increase, and embryos were assigned to substages and divisions of Theiler's [1972] stages on the basis of external development of the frontonasal area, eyes, vibrissae, mandibular and hyoid auricular hillocks (pinna) and some internal structures [Miyake et al., 1996]. Condensation and matrix formation were determined using PNA lectin histochemistry, type II collagen immunohistochemistry, Mallory's trichrome, Hall and Brunt's quadruple and toluidine blue stains on serially sectioned embryos, and 3-D reconstruction. A single, continuous, first arch chondrogenic condensation was identified. It consisted of three components: 1) a rostral component for the symphysis; 2) a core component for the major portion of Meckel's cartilage; and 3) a caudal component for the caudo-lateral area of Meckel's cartilage and the two ear cartilages, the malleus and incus. The caudal component was further divided into rostral and caudal subcomponents which gave rise to the malleus and incus, respectively. Cellular arrangement differed among the three components, probably reflecting major axes of matrix growth. The condensation was only weakly recognized by peanut agglutinin lectin (PNA), unless sections were pretreated with neuraminidase, showing the masking effects of sialic acid. The core and caudal components of the condensation appeared at stage 20.12 and ended at stage 21.14 and 21.32, respectively. The symphysial component began at stage 20.2 and ended at stage 21.32. Deposition of sulfated proteoglycans began at stage 21.14 in the core component of the condensation- preceding slightly deposition of type II collagen--and at stage 21.32 in the symphysial and caudal components. PMID- 8675614 TI - Distribution of basement membrane components in the mouse primary palate. AB - Laminin, type IV collagen, and fibronectin are major components of the basement membrane of epithelial tissues. The purpose of this study was to characterize their distributions as the epithelial seam of the primary palate is disrupted and the mesenchymal bridge forms and enlarges. The distributions of these molecules were studied with indirect immunofluorescence in day 11 (9-20 tail somites), noncleft CD1 mice. During epithelial seam formation at 9-11 tail somites (TS), all three molecules were intensely localized in the basement membrane of the seam and adjacent stomodeal and nasal epithelia. During epithelial seam replacement by mesenchymal tissues at 12-18 TS, basement membrane components were first fragmented along the seam, then absent at the site of the mesenchymal bridge. At 19-20 TS, basement membrane components were intact around the margins of the primary palate. These results show that disruption of basement membrane components occurs rapidly and simultaneously with mesenchymal bridge formation in the primary palate. PMID- 8675615 TI - Craniosynostosis with autosomal dominant transmission in New Zealand white rabbits. AB - Although great strides have been made recently in determining the etiology of a number of human craniosynostotic syndromes, pathogenic mechanisms for these conditions are still unclear, in part because of the lack of a genetic animal model with primary craniosynostosis. Recently, we developed an inbred colony of rabbits with congenital coronal suture synostosis. The present study describes long term breeding demographics, karyotypes, and pedigree analysis from this colony in an effort to characterize the genotype and mode of inheritance of craniosynostosis for future etiopathogenic studies. Seventy-six consecutive back- and intercrosses resulted in 46 fetal and term litters and produced 135 normal offspring and 163 affected offspring with either partial or complete coronal suture synostosis. Conception rate, litter size, and gestation length were normal, and karyotype analysis revealed no gross chromosomal abnormalities. Pedigree analysis of the segregation rates observed for each rabbit litter suggests that the craniosynostosis seen in this pedigree is inherited in an autosomal dominant fashion with reduced penetrance and variable expression. Results revealed that the mode of inheritance and phenotypic variability noted in this colony closely parallel the human craniosynostotic condition and several possible candidate gene families are discussed. The utility of developing such a congenital animal model is evident and may lead to a better understanding of gene expression, normal suture morphogenesis, and the pathogenesis of craniosynostosis. PMID- 8675616 TI - Good and laudable pus. PMID- 8675617 TI - Why there is an IRS. PMID- 8675618 TI - Gene therapy for cystic fibrosis: challenges and future directions. PMID- 8675619 TI - Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes. AB - Lipoprotein lipase (LPL)-deficient mice have been created by gene targeting in embryonic stem cells. At birth, homozygous knockout pups have threefold higher triglycerides and sevenfold higher VLDL cholesterol levels than controls. When permitted to suckle, LPL-deficient mice become pale, then cyanotic, and finally die at approximately 18 h of age. Before death, triglyceride levels are severely elevated (15,087 +/- 3,805 vs 188 +/- 71 mg/dl in controls). Capillaries in tissues of homozygous knockout mice are engorged with chylomicrons. This is especially significant in the lung where marginated chylomicrons prevent red cell contact with the endothelium, a phenomenon which is presumably the cause of cyanosis and death in these mice. Homozygous knockout mice also have diminished adipose tissue stores as well as decreased intracellular fat droplets. By crossbreeding with transgenic mice expressing human LPL driven by a muscle specific promoter, mouse lines were generated that express LPL exclusively in muscle but not in any other tissue. This tissue-specific LPL expression rescued the LPL knockout mice and normalized their lipoprotein pattern. This supports the contention that hypertriglyceridemia caused the death of these mice and that LPL expression in a single tissue was sufficient for rescue. Heterozygous LPL knockout mice survive to adulthood and have mild hypertriglyceridemia, with 1.5-2 fold elevated triglyceride levels compared with controls in both the fed and fasted states on chow, Western-type, or 10% sucrose diets. In vivo turnover studies revealed that heterozygous knockout mice had impaired VLDL clearance (fractional catabolic rate) but no increase in transport rate. In summary, total LPL deficiency in the mouse prevents triglyceride removal from plasma, causing death in the neonatal period, and expression of LPL in a single tissue alleviates this problem. Furthermore, half-normal levels of LPL cause a decrease in VLDL fractional catabolic rate and mild hypertriglyceridemia, implying that partial LPL deficiency has physiological consequences. PMID- 8675620 TI - Autoantibodies against heat shock protein 60 mediate endothelial cytotoxicity. AB - Stress or heat shock proteins (hsp) are a family of approximately two dozen proteins with a high degree of amino acid sequence homology between different species, ranging from prokaryotes to humans, and are representative of a generalized response to environmental and metabolic stressors. Our previous studies showed increased expression of human hsp60 on endothelial cells of arterial intima with atherosclerotic lesions, and elevated levels of serum antibodies (Ab) against hsp65/60 in subjects with carotid atherosclerosis. To investigate the possible involvement of anti-hsp65/60 Ab in endothelial injury, specific hsp-Ab were isolated from human high titer sera by affinity chromatography and probed on heat-shock human umbilical vein endothelial cells. Purified human anti-hsp65/60 Ab reacted specifically with mycobacterial hsp65, human hsp60, and a 60-kD protein band of heat-shocked endothelial cells. High levels of hsp60 mRNA expression in endothelial cells were found between 4 and 12 h after 30 min treatment at 42 degrees C. In immunofluorescence tests, positive staining of heat-stressed endothelial cells was observed not only in the cytoplasm but also on the cell surface. Furthermore, only heat-stressed, but not untreated, Cr-labeled endothelial cells were lysed by anti-hsp65/60 Ab in the presence of complement (complement-mediated cytotoxicity) or peripheral blood mononuclear cells (antibody-dependent cellular cytotoxicity). Control Abs, including human anti-hsp65/60 low titer antiserum, human Ig fraction deprived of hsp65/60 Ab, and mAbs to Factor VIII, alpha-actin, hsp70, and CD3 showed no cytotoxic effect. In conclusion, human serum anti-hsp65 antibodies act as autoantibodies reacting with hsp60 on stressed endothelial cells and are able to mediate endothelial cytotoxicity. Thus, a humoral immune reaction to hsp60 may play an important role in the pathogenesis of atherosclerosis. PMID- 8675621 TI - Endogenous production of interleukin 15 by activated human monocytes is critical for optimal production of interferon-gamma by natural killer cells in vitro. AB - Natural killer (NK) cells are large granular lymphocytes that constitutively express functional IL-2 receptors. We have shown that recombinant human IL-15 uses the IL-2 receptor to activate human NK cells and can synergize with recombinant human IL-12 to stimulate NK cell production of IFN-gamma in vitro. IFN-gamma production by NK cells is critical in the prevention of overwhelming infection by obligate intracellular microbial pathogens in several experimental animal models. Herein, we demonstrate that human monocytes produce IL-15 protein within 5 h of activation with LPS. Using an IL-15-neutralizing antiserum in a coculture of LPS-activated monocytes and NK cells, we demonstrate that monocyte derived IL-15 is critical for optimal NK cell production of IFN-gamma. Endogenous IL-15 activates NK cells through the IL-2 receptor, and with endogenous IL-12, regulates NK cell IFN-gamma after monocyte activation by LPS. These in vitro studies are the first to characterize a function for endogenous IL-15, and as such, suggest an important role for IL-15 during the innate immune response. IL 15 may be an important ligand for the NK cell IL-2 receptor in vivo. PMID- 8675622 TI - Sustained inhibition of intimal thickening. In vitro and in vivo effects of polymeric beta-cyclodextrin sulfate. AB - Intimal thickening after vascular injury may be modulated in part by heparin binding growth factors. We hypothesized that placement of a therapeutic polymer in the periadventitial space capable of tightly binding growth factors might alter the vascular response to injury. We first demonstrated that incubation of rat aortic smooth muscle cells with an insoluble, sulfated polymer of beta cyclodextrin (P-CDS) was associated with a dose-dependent inhibition of proliferation induced by fetal calf serum, fibroblast growth factor-2 (FGF-2), platelet-derived growth factor BB, or epidermal growth factor. Preincubation studies of P-CDS with FGF-2 revealed a very rapid removal of mitogenic activity. Using radiolabeled FGF-2 (0.25 microg/ml), we observed a very rapid association rate (0.34 +/- 0.07 min-1, n=4) and a very slow dissociation rate (3.3 +/- 0.2 X 10(-7) min-1) at 37 degrees C, suggesting a high affinity interaction. Using both Transwell and linear under-agarose assays, we demonstrated a significant inhibition of random migration (chemokinesis) by P-CDS. Unsulfated polymeric beta cyclodextrin (P-CD) had little if any of these effects, suggesting that the high negative charge density of P-CDS was important for the effects. Finally, rats undergoing carotid artery balloon injury were randomized to treatment with periadventitial P-CDS or no treatment, and were killed at 4 (n=20), 14 (n=59), and 88 d (n=14). Morphometric analysis demonstrated significant and sustained inhibition of intimal thickening in P-CDS-treated rats at 14 (P < 0.01) and 88 d (P < 0.05) using absolute intimal area or intima/media area ratios. No inhibition was seen in a group of rats treated with P-CD. In P-CDS-treated rats, bromodeoxyuridine labeling studies revealed fewer labeled smooth muscle cells in the intima at 14 d (P=0.01), while staining with Evans blue revealed enhanced late endothelial cell regrowth. Thus, periadventitially applied sulfated beta cyclodextrin polymer, which can tightly bind heparin binding growth factors, inhibits intimal thickening in vivo in a sustained fashion without using an additional delivery system. These studies suggest that cellular processes mediated by heparin binding growth factors may be modulated by P-CDS. PMID- 8675623 TI - Expression of plasminogen activator inhibitor type 1 by human prostate carcinoma cells inhibits primary tumor growth, tumor-associated angiogenesis, and metastasis to lung and liver in an athymic mouse model. AB - Expression of urokinase-type plasminogen activator (uPA) by malignant cells correlates with an aggressive phenotype, including increased invasiveness, tumor associated angiogenesis, and metastases. Plasminogen activator inhibitor type 1 (PAI-1) is undetectable in cells of some aggressive malignancies, but present in the stroma of tumor-associated microvasculature. This analysis of an athymic mouse model of prostate carcinoma further defines the role of the uPA/PAI 1/plasmin system in primary growth and metastasis. A marked increase in PAI-1 expression was induced in clones of the aggressive human prostate carcinoma line, PC-3, by stable transfection. Primary PC-3 tumors, in mice, were significantly smaller when derived from PAI-1 expressing versus control cells. PAI-1 expression reduced the density of tumor-associated microvasculature by 22-38%. Microscopic metastases were quantitated using stable expression of the chromogenic label (beta-galactosidase) in control and PAI-1 expressing cells. PAI-1 expression resulted in a significant inhibition of lung metastases, and liver metastases. Expression of PAI-1 by malignant prostate cells resulted in a less aggressive phenotype, presumably by inhibition of uPA activity, suggesting pharmacologic or molecular inhibition of uPA activity as a potential therapeutic target. PMID- 8675624 TI - Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia. AB - Overexpression of plasma apolipoprotein CIII (apo CIII) causes hypertriglyceridemia in transgenic mice. A genetically variant form of the human apo CIII promoter, containing five single base pair changes, has been shown to be associated with severe hypertriglyceridemia in a patient population. In animals and in cultured cells the apo CIII gene is transcriptionally downregulated by insulin. In this study we demonstrate that, unlike the wild-type promoter, the variant promoter was defective in its response to insulin treatment, remaining constitutively active at all concentrations of insulin. The loss of insulin regulation was mapped to polymorphic sites at -482 and -455, which fall within a previously identified insulin response element. Loss of insulin regulation could result in overexpression of the apo CIII gene and contribute to the development of hypertriglyceridemia. The variant apo CIII promoter is common in the human population and may represent a major contributing factor to the development of hypertriglyceridemia. PMID- 8675625 TI - Serum IgG autoantibodies directed against the alpha chain of Fc epsilon RI: a selective marker and pathogenetic factor for a distinct subset of chronic urticaria patients? AB - While it is well established that acute allergic urticaria is caused by degranulation of skin mast cells occurring after allergen/IgE-dependent cross linking of high affinity IgE receptors (FcepsilonRI), the pathophysiologic mechanisms operative in chronic urticaria (CU) are less well understood. Some evidence points to the existence of histamine-releasing activity in the serum of CU patients which possibly acts via triggering of FcepsilonRI. In this study, we aimed to better characterize this anti-FcepsilonRIalpha reactivity of CU patients using affinity-purified, IgE-depleted IgG fractions of such individuals (CU-IgG). Using immobilized, recombinant soluble FcepsilonRIalpha as a a reaction target for Western blot studies, we found that 12/32 (37%) CU-IgG serum samples exhibited IgG autoreactivity against FcepsilonRI- alpha. These findings were confirmed by experiments demonstrating that immunoblot-reactive, but not immunoblot-nonreactive, CU-IgG preparations precipitated the FcepsilonRIalpha from FcepsilonRI- alphagamma-transfected cells. No anti-FcepsilonRIalpha reactivity was observed in IgG fractions from atopic dermatitis (AD) patients (0/15) or healthy control individuals (CO:0/15). As opposed to the selective occurrence of IgG anti-Fc epsilon RI alpha autoantibodies in CU patients, IgG anti-IgE antibodies were detected in all groups investigated (CU: 69%; AD: 73%; CO: 26%). While both types of autoantibodies can exhibit histamine-releasing properties, not all of the autoantibodies proved to be functional in vitro. Our results indicate that the occurrence of IgG anti-FcepsilonRIalpha reactivity defines an autoimmune-mediated subentity of CU and provide a basis for the development of new diagnostic procedures and, perhaps, therapeutic strategies for this disease. PMID- 8675626 TI - Cholesterol efflux potential of sera from mice expressing human cholesteryl ester transfer protein and/or human apolipoprotein AI. AB - The ability of whole serum to promote cell cholesterol efflux and the relationships between apoprotein and lipoprotein components of human serum efflux have been investigated previously (de la Llera Moya, M., V. Atger, J.L. Paul, N. Fournier, N. Moatti, P. Giral, K.E. Friday, and G.H. Rothblat. 1994. Arterioscler. Thromb. 14:1056-1065). We have now used this experimental system to study the selective effects of two human lipoprotein-related proteins, apoprotein AI (apo AI) and cholesteryl ester transfer protein (CETP) on cell cholesterol efflux, when these proteins are expressed in transgenic mice. The percent efflux values for cholesterol released in 4 h from Fu5AH donor cells to 5% sera from the different groups of mice were in the order: background = human apo AI transgenic (HuAITg) > human CETP transgenic (HuCETPTg) > human apo AI and CETP transgenic (HuAICETPTg) >> apo AI knockout mice. In each group of mice a strong, positive correlation (r2 ranging from 0.64 to 0.76) was found between efflux and HDL cholesterol concentrations. The slopes of these regression lines differed between groups of mice, indicating that the cholesterol acceptor efficiencies of the sera differed among groups. These differences in relative efficiencies can explain why cholesterol efflux was not proportional to the different HDL levels in the various groups of mice. We can conclude that: (a) HDL particles from HuAITg mice are less efficient as cholesterol acceptors than HDL from the background mice; (b) despite a lower average efflux due to lower HDL cholesterol concentrations, HDL particles are more efficient in the HuCETPTg mice than in the background mice; and (c) the coexpression of both human apo AI and CETP improves the efficiency of HDL particles in the HuAICETPTg mice when compared with the HuAITg mice. We also demonstrated that the esterification of the free cholesterol released from the cells by lecithin cholesterol acyltransferase in the serum was reduced in the HuAITg and AI knockout mice, whereas it was not different from background values in the two groups of mice expressing human CETP. PMID- 8675628 TI - Inhibition of neointimal proliferation in rabbits after vascular injury by a single treatment with a protein adduct of nitric oxide. AB - Endothelium-derived relaxing factor is important for vascular homeostasis and possesses qualities that may modulate vascular injury, including vasodilation, platelet inhibition, and inhibition of smooth muscle proliferation. S nitrososerum albumin is a naturally occurring adduct of nitric oxide (NO) with a prolonged biologic half-life and is a potent vasodilator and platelet inhibitor. Given the avidity of serum albumin for subendothelial matrix and the antiproliferative effects of NO, we investigated the effects of locally delivered S-nitroso-bovine serum albumin (S-NO-BSA) and a polythiolated form of bovine serum albumin (pS-BSA) modified to carry several S-nitrosothiol groups (pS-NO BSA) on neointimal responses in an animal model of vascular injury. Locally delivered S-NO-BSA bound preferentially to denuded rabbit femoral vessels producing a 26-fold increase in local concentration compared with uninjured vessels (P = 0.029). pS-NO-BSA significantly reduced the intimal/medial ratio (P = 0.038) and did so in conjunction with elevations in platelet (P < 0.001) and vascular cGMP content (P < or = 0.001). pS-NO-BSA treatment also inhibited platelet deposition (P = 0.031) after denuding injury. Comparison of BSA, S-NO BSA, pS-NO-BSA, and control revealed a dose-response relationship between the amount of displaceable NO delivered and the extent of inhibition of neointimal proliferation at 2 wk (P < or = 0.001). Local administration of a stable protein S-nitrosothiol inhibits intimal proliferation and platelet deposition after vascular arterial balloon injury. This strategy for the local delivery of a long lived NO adduct has potential for preventing restenosis after angioplasty. PMID- 8675627 TI - Molecular basis of spectrin deficiency in beta spectrin Durham. A deletion within beta spectrin adjacent to the ankyrin-binding site precludes spectrin attachment to the membrane in hereditary spherocytosis. AB - We describe a spectrin variant characterized by a truncated beta chain and associated with hereditary spherocytosis. The clinical phenotype consists of a moderate hemolytic anemia with striking spherocytosis and mild spiculation of the red cells. We describe the biochemical characteristics of this truncated protein which constitutes only 10% of the total beta spectrin present on the membrane, resulting in spectrin deficiency. Analysis of reticulocyte cDNA revealed the deletion of exons 22 and 23. We show, using Southern blot analysis, that this truncation results from a 4.6-kb genomic deletion. To elucidate the basis for the decreased amount of the truncated protein on the membrane and the overall spectrin deficiency, we show that (a) the mutated gene is efficiently transcribed and its mRNA abundant in reticulocytes, (b) the mutant protein is normally synthesized in erythroid progenitor cells, (c) the stability of the mutant protein in the cytoplasm of erythroblasts parallels that of the normal beta spectrin, and (d) the abnormal protein is inefficiently incorporated into the membrane of erythroblasts. We conclude that the truncation within the beta spectrin leads to inefficient incorporation of the mutant protein into the skeleton despite its normal synthesis and stability. We postulate that this misincorporation results from conformational changes of the beta spectrin subunit affecting the binding of the abnormal heterodimer to ankyrin, and we provide evidence based on binding assays of recombinant synthetic peptides to inside-out vesicles to support this model. PMID- 8675629 TI - Impaired activity and gene expression of hexokinase II in muscle from non-insulin dependent diabetes mellitus patients. AB - After entering the muscle cell, glucose is immediately and irreversibly phosphorylated to glucose-6-phosphate by hexokinases (HK) I and II. Previous studies in rodents have shown that HKII may be the dominant HK in skeletal muscle. Reduced insulin-stimulated glucose uptake and reduced glucose-6-phosphate concentrations in muscle have been found in non-insulin-dependent diabetes mellitus (NIDDM) patients when examined during a hyperglycemic hyperinsulinemic clamp. These findings [correction of finding] are consistent with a defect in glucose transport and/or phosphorylation. In the present study comprising 29 NIDDM patients and 25 matched controls, we tested the hypothesis that HKII activity and gene expression are impaired in vastus lateralis muscle of NIDDM patients when examined in the fasting state. HKII activity in a supernatant of muscle extract accounted for 28 +/- 5% in NIDDM patients and 40 +/- 5% in controls (P = 0.08) of total muscle HK activity when measured at a glucose media of 0.11 mmol/liter and 31 +/- 4 and 47 +/- 7% (P = 0.02) when measured at 0.11 mmol/liter of glucose. HKII mRNA, HKII immunoreactive protein level, and HKII activity were significantly decreased in NIDDM patients (P < 0.0001, P = 0.03, and P = 0.02, respectively) together with significantly decreased glycogen synthase mRNA level and total glycogen synthase activity (P = 0.02 and P = 0.02, respectively). In the entire study population HKII activity estimated at 0.11 and 11.0 mM glucose was inversely correlated with fasting plasma glucose concentrations (r = -0.45, P = 0.004; r = -0.54, P < 0.0001, respectively) and fasting plasma nonesterified fatty acid concentrations (r = -0.46, P = 0.003; r = -0.37, P = 0.02, respectively). In conclusion, NIDDM patients are characterized by a reduced activity and a reduced gene expression of HKII in muscle which may be secondary to the metabolic peturbations. HKII contributes with about one-third of total HK activity in a supernatant of human vastus lateralis muscle. PMID- 8675631 TI - Inhibitory effect of porcine surfactant on the respiratory burst oxidase in human neutrophils. Attenuation of p47phox and p67phox membrane translocation as the mechanism. AB - Surfactant has been shown to inhibit the production of reactive oxygen intermediates by various cells including alveolar macrophages and peripheral blood neutrophils. Superoxide O2-. production by the respiratory burst oxidase in isolated plasma membranes prepared from PMA-treated human neutrophils was significantly attenuated by prior treatment with native porcine surfactant. The effect was concentration dependent with half-maximal inhibition seen at approximately 0.050 mg surfactant phospholipid/ml. Kinetic analyses of the membrane-bound enzyme prepared from neutrophils stimulated by PMA in the presence or absence of surfactant demonstrated that surfactant treatment led to a decrease in the maximal velocity of O2-. production when NADPH was used as substrate, but there was no effect on enzyme substrate affinity. Immunoblotting studies demonstrated that surfactant treatment induced a decrease in the association of two oxidase components, p47phox and p67phox, with the isolated plasma membrane. In contrast, surfactant treatment of the cells did not alter the phosphorylation of p47phox. A mixture of phospholipids (phosphatidylcholine and phosphatidylglycerol in a 7:3 ratio) showed similar inhibition of the PMA-induced O2-. generation. Taken together, these data suggest the mechanism of surfactant induced inhibition of O2-. production by human neutrophils involves attenuation of translocation of cytosolic components of the respiratory burst oxidase to the plasma membrane. The phospholipid components of surfactant appear to play a significant role in this mechanism. PMID- 8675630 TI - Clusterin promotes the aggregation and adhesion of renal porcine epithelial cells. AB - The function of clusterin, a heterodimeric glycoprotein markedly induced in renal and other organ injuries, is unclear. Since renal injury is accompanied by alterations in cell attachment, it is possible that clusterin functions to promote cell-cell and cell-substratum interactions. In this study, a single cell suspension of renal epithelial (LLC-PK1) cells was treated with purified human clusterin, resulting in time- and dose-dependent cell aggregation. Electron microscopy of the cell aggregates demonstrated cell junction and lumen formation. To determine the effect of clusterin on cell adhesion, tissue culture plates were coated with clusterin, fibronectin, PBS, or albumin. Clusterin and fibronectin promoted cell adhesion to the same extent. The adhesion to clusterin was dose dependent and specific, as a monoclonal antibody against clusterin inhibited cell adhesion to clusterin but not fibronectin. Perterbations of the cytoskeleton may underlie the alterations in cell attachment which occur in renal injury. Induction of clusterin mRNA was seen after disruption of both microtubules and microfilaments and after inhibition of cell-substratum interactions. In conclusion, clusterin is a potent renal epithelial cell aggregation and adhesion molecule. We speculate that clusterin functions to promote cell-cell and cell substratum interactions which are perturbed in the setting of renal injury, thereby preserving the integrity of the renal epithelial barrier. PMID- 8675632 TI - Regulation of bovine endothelial constitutive nitric oxide synthase by oxygen. AB - Oxygen (O2) may regulate pulmonary vascular resistance through changes in endothelial nitric oxide (NO) production. To determine whether constitutive NO synthase (cNOS) is regulated by O2, we assessed cNOS expression and activity in bovine pulmonary artery endothelial cells exposed to different concentrations of O2. In a time-dependent manner, changes in O2 concentration from 95 to 3% produced a progressive decrease in cNOS mRNA and protein levels resulting in 4.8- and 4.3-fold reductions after 24h, respectively. This correlated with changes in cNOS activity as determined by nitrite measurements. Compared with 20% O2, cNOS activity was increased 1.5-fold in 95% O2 and decreased 1.9-fold in 3% O2. A decrease in O2 concentration from 94 to 3% shortened cNOS mRNA half-life from 46 to 24 h and caused a 20-fold repression of cNOS gene transcription. Treatment with cycloheximide produced a threefold increase in cNOS mRNA at all O2 concentrations, suggesting that cNOS mRNA expression is negatively regulated under basal condition. We conclude that O2 upregulates cNOS expression through transcriptional and post-transcriptional mechanisms. A decrease in cNOS activity in the presence of low O2 levels, therefore, may contribute to hypoxia-induced vasoconstriction in the pulmonary circulation. PMID- 8675633 TI - Decreased type II/type I TGF-beta receptor ratio in cells derived from human atherosclerotic lesions. Conversion from an antiproliferative to profibrotic response to TGF-beta1. AB - Atherosclerosis and postangioplasty restenosis may result from abnormal wound healing. The present studies report that normal human smooth muscle cells are growth inhibited by TGF-beta1, a potent wound healing agent, and show little induction of collagen synthesis to TGF-beta1, yet cells grown from human vascular lesions are growth stimulated by TGF-beta1 and markedly increase collagen synthesis. Both cell types increase plasminogen activator inhibitor-1 production, switch actin phenotypes in response to TGF-beta1, and produce similar levels of TGF-beta activity. Membrane cross-linking of 125I-TGF-beta1 indicates that normal human smooth muscle cells express type I, II, and III receptors. The type II receptor is strikingly decreased in lesion cells, with little change in the type I or III receptors. RT-PCR confirmed that the type II TGF-beta1 receptor mRNA is reduced in lesion cells. Transfection of the type II receptor into lesion cells restores the growth inhibitory response to TGF-beta1, implying that signaling remains responsive. Because TGF-beta1 is overexpressed in fibroproliferative vascular lesions, receptor-variant cells would be allowed to grow in a slow, but uncontrolled fashion, while overproducing extracellular matrix components. This TGF-beta1 receptor dysfunction may be relevant for atherosclerosis, restenosis and related fibroproliferative diseases. PMID- 8675634 TI - Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell-derived carbon monoxide. AB - CO is produced in vascular smooth muscle cells (VSMC) by heme oxygenase-1 (HO-1). CO increases cGMP levels in VSMC; however, its possible additional roles in the vasculature have not been examined. We report that a product of HO, released from VSMC and inhibited by hemoglobin, has paracrine effects on endothelial cells: it increases endothelial cGMP content and decreases the expression of the mitogens, endothelin-1 (ET-1) and platelet-derived growth factor-B (PDGF-B). This product has the characteristics of CO, and its production is increased sevenfold under hypoxia. The VSMC-derived CO caused a fourfold rise in endothelial cell cGMP. In addition, it inhibited the hypoxia-induced increases in mRNA levels of the ET-1 and PDGF-B genes. Inhibitors of HO, and hemoglobin, a scavenger of CO, prevented the rise in cGMP and also restored the hypoxic response of these genes. The inhibition of ET-1 and PDGF-B mRNA by CO resulted in decreased production of these endothelial-derived mitogens, and in turn, inhibition of VSMC proliferation. These findings suggest an important physiologic role for VSMC derived CO in modulating cell-cell interaction and cell proliferation in the vessel wall during hypoxia. PMID- 8675635 TI - Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism. AB - Familial benign hypercalcemia (FBH) and neonatal hyperparathyroidism (NHPT) are disorders of calcium homeostasis that are associated with missense mutations of the calcium-sensing receptor (CaR). We have undertaken studies to characterize such CaR mutations in FBH and NHPT and to explore methods for their more rapid detection. Nine unrelated kindreds (39 affected, 32 unaffected members) with FBH and three unrelated children with sporadic NHPT were investigated for mutations in the 3,234-bp coding region of the CaR gene by DNA sequencing. Six novel heterozygous (one nonsense and five missense) mutations were identified in six of the nine FBH kindreds, and two de novo heterozygous missense mutations and one homozygous frame-shift mutation were identified in the three children with NHPT. Our results expand the phenotypes associated with CaR mutations to include sporadic NHPT. Single-stranded conformational polymorphism analysis was found to be a sensitive and specific mutational screening method that detected > 85% of these CaR gene mutations. The single-stranded conformational polymorphism identification of CaR mutations may help in the distinction of FBH from mild primary hyperparathyroidism which can be clinically difficult. Thus, the results of our study will help to supplement the clinical evaluation of some hypercalcemic patients and to elucidate further the structure-function relationships of the CaR. PMID- 8675636 TI - Effects of the apolipoprotein E polymorphism on uptake and transfer of cell derived cholesterol in plasma. AB - The reverse cholesterol transport is initiated by the uptake of cholesterol into minor subfractions of high density lipoproteins (HDL) which contain either apolipoprotein (apo) A-I or apoE as their only apolipoproteins. From these initial acceptors, which are termed prebeta1-LpA-I and gamma-LpE, respectively, cell-derived cholesterol is transferred to LDL via the bulk of HDL termed alpha LpA-I. In this study we analyzed the effect in plasma of the genetically determined apoE polymorphism on the formation of gamma-LpE, uptake and transfer of cell-derived cholesterol to LDL. Gamma-LpE was immunologically detectable in plasmas of individuals carrying at least one apoE3-allele but not in apoE3-free plasmas. During one minute incubation with [3H]cholesterol-labeled fibroblasts, gamma-LpE of plasmas from apoE3/3 subjects accumulated 7 and 13-fold more radioactivity than the respective fractions in plasmas from apoE2/2- and apoE4/4 subjects, respectively. Totally, 30% less [3H]cholesterol was released into plasmas of apoE2/2 and apoE4/4-individuals as compared with plasmas of apoE3/3 subjects. Moreover, plasmas of apoE3/3 individuals accumulated 50% and 65% more cell-derived [3H]cholesterol in alpha-LpA-I2 than plasmas of apoE4/4 and apoE2/2 subjects, respectively. These results indicate that the apoE-polymorphism is an important determinant of the uptake and transfer of cell-derived cholesterol in plasma. PMID- 8675637 TI - The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. AB - Tryptase, a protease produced by all mast cells, was evaluated as a clinical marker of systemic mastocytosis. Two sandwich immunoassays were evaluated, one which used the mAb G5 for capture, the other which used B12 for capture. The B12 capture assay measured both recombinant alpha- and beta-tryptase, whereas the G5 capture assay measured primarily recombinant beta-tryptase. G5 binds with low affinity to both recombinant alpha-tryptase and tryptase in blood from normal and nonacute mastocytosis subjects, and binds with high affinity to recombinant beta tryptase, tryptase in serum during anaphylaxis, and tryptase stored in mast cell secretory granules. B12 recognizes all of these forms of tryptase with high affinity. As reported previously, during systemic anaphylaxis in patients without known mastocytosis, the ratio of B12- to G5-measured tryptase was always < 5 and approached unity (Schwartz L.B., T.R. Bradford, C. Rouse, A.-M. Irani, G. Rasp, J.K. Van der Zwan and P.-W.G. Van der Linden, J. Clin. Immunol. 14:190-204). In this report, most mastocytosis patients with systemic disease have B12-measured tryptase levels that are elevated (> 20 ng/ml) and are at least 10-fold greater than the corresponding G5-measured tryptase level. Most of those subjects with B12-measured tryptase levels of < 20 ng/ml had only cutaneous manifestations. The B12 assay for alpha-tryptase and beta-tryptase, particularly when performed in conjunction with the G5 assay for beta-tryptase, provides a more precise measure of mast cell involvement than currently available assessments, a promising potential screening test for systemic mastocytosis and may provide an improved means to follow disease progression and response to therapy. PMID- 8675638 TI - Anti-thrombotic effects of a nitric oxide-releasing, gastric-sparing aspirin derivative. AB - Effects of a nitroxybutylester derivative of aspirin (NCX 4215) on platelet aggregation and prostanoid synthesis were compared to the effects of aspirin. NCX 4215 was approximately seven times more potent than aspirin as an inhibitor of thrombin-induced human platelet aggregation in vitro, but did not inhibit platelet thromboxane synthesis or gastric prostaglandin synthesis. NCX 4215 released nitric oxide when incubated in the presence of platelets and increased platelet levels of cGMP within 10 min of exposure, while aspirin did not. The anti-aggregatory effects of NCX 4215 in vitro were significantly attenuated by 10 microM hemoglobin. In ex vivo studies of ADP- or collagen- or thrombin-induced rat platelet aggregation, aspirin and NCX 4215 had comparable inhibitory effects 3 h after administration. Aspirin (10-120 mg/kg) caused extensive hemorrhagic erosion formation in the stomach of the rat within 3 h of oral administration, while NCX 4215 did not produce significant damage at doses of up to 300 mg/kg, nor when given daily for two weeks at 166 mg/kg. NCX 4215 did not alter systemic arterial blood pressure when administered intravenously to the rat. These studies demonstrate that NCX 4215 has comparable or enhanced anti-thrombotic activity to that of aspirin, but does not cause gastric damage or alter systemic blood pressure. The anti-thrombotic actions of NCX 4215 are, at least in part, due to generation of nitric oxide. PMID- 8675639 TI - Expression and localization of inducible and endothelial nitric oxide synthase in the rat ovary. Effects of gonadotropin stimulation in vivo. AB - Nitric oxide is reportedly involved in the regulation of several ovarian processes, yet the isoforms of nitric oxide synthase (NOS) expressed in the ovary are unknown. Our purpose was to identify and localize NOS isoenzymes in the rat ovary and to examine++ if mRNA expression of NOS isoenzymes change after gonadotropin stimulation. Using reverse transcriptase-PCR, we demonstrated that inducible (iNOS) and endothelial (eNOS), but not neuronal, NOS mRNAs are expressed in the ovary. In a gonadotropin-stimulated rat model, unstimulated ovaries had the highest levels of iNOS mRNA as quantified by ribonuclease protection assay. After gonadotropin injection, iNOS mRNA declined to undetectable levels in ovaries containing ovulatory follicles before increasing slighty in ovaries containing copora lutea. In situ hybridization studies localized iNOS to granulosa cells of secondary follicles and small antral follicles. Western blots of unstimulated ovaries demonstrated iNOS protein. In contrast to iNOS, eNOS mRNA levels, determined by quantitative PCR, increased after gonadotropin stimulation and peaked in ovaries containing ovulatory follicles before declining in the luteal phase. eNOS protein was localized to blood vessels in the ovary by immunohistochemistry. We conclude that two isoforms of NOS are expressed in the ovary and the mRNA levels for these isozymes are differentially regulated. PMID- 8675640 TI - Polysaccharide-mediated protection against abscess formation in experimental intra-abdominal sepsis. AB - Abscess formation is a major complication of intra-abdominal sepsis that causes significant morbidity and mortality. In such cases, Bacteroides fragilis is the predominant anaerobic isolate. In a rat model of intra-abdominal sepsis, the capsular polysaccharide complex (CPC) from B. fragilis promotes abscess formation and when administered sub-cutaneously, protects against this host response by a T cell-dependent immune mechanism. In the present study, the polysaccharide A (PS A) component of CPC protected animals against challenge with live heterologous bacterial species (mixtures of anaerobes and facultative organisms) that are most commonly isolated from intra-abdominal abscesses in humans. Protection against heterologous bacterial challenge was transferred by T cells. Administration of PS A shortly before or even after challenge with B. fragilis protected against this host response. In experiments designed to simulate fecal contamination of the human peritoneal cavity, PS A protected animals against abscess formation induced by a rat cecal contents inoculum. The surprisingly broad protective activity of PS A indicates that this molecule is likely suppressing a nonspecific host tissue reaction that forms in response to a variety of abscess-inducing organisms and that it might be useful in preventing abscess formation associated with intra abdominal sepsis in the clinical setting. PMID- 8675641 TI - Immunoglobulin kappa chain allotypes (KM) in onchocerciasis. AB - GM and KM allotypes, powerful tools for genetic characterization of human populations, have been shown to play an important role in genetic predisposition to some infectious diseases. Two diverse racial groups--Afro-Ecuadorians and Amerindians--living in a single restricted geographical area of Ecuador, appear to have different risk factors for acquisition and clinical expression of onchocerciasis, a disease caused by the filarial parasite Onchocerca volvulus. In this study, GM and KM allotypes were determined in 25 Afro-Ecuadorians and 24 Amerindians infected with Onchocerca volvulus (INF) and in putative immune individuals (PI). In Afro-Ecuadorians, the frequency of the homozygous KM 3 phenotype was significantly decreased in INF as compared with the PI group (20 vs. 68%; P= 0.0012), while the frequency of the heterozygous KM 1,3 phenotype was increased in INF as compared with the PI subjects (48 vs. 9%; P= 0.0044). These results suggest that in Afro-Ecuadorians KM 3 is associated with a lower relative risk (resistance), whereas KM 1,3 is associated with an increased risk (susceptibility) of onchocerciasis. PMID- 8675642 TI - Short-term alterations in carbohydrate energy intake in humans. Striking effects on hepatic glucose production, de novo lipogenesis, lipolysis, and whole-body fuel selection. AB - Short-term alterations in dietary carbohydrate (CHO) energy are known to alter whole-body fuel selection in humans, but the metabolic mechanisms remain unknown. We used stable isotope-mass spectrometric methods with indirect calorimetry in normal subjects to quantify the metabolic response to six dietary phases (5 d each), ranging from 50% surplus CHO (+50% CHO) to 50% deficient CHO (-50% CHO), and 50% surplus fat (+50% fat). Fasting hepatic glucose production (HGP) varied by > 40% from deficient to surplus CHO diets (1.78 +/- 0.08 vs 2.43 +/- 0.09 mg/kg per min, P < 0.01). Increased HGP on surplus CHO occurred despite significantly higher serum insulin concentrations. Lipolysis correlated inversely with CHO intake as did the proportion of whole-body lipolytic flux oxidized. Fractional de novo hepatic lipogenesis (DNL) increased more than 10-fold on surplus CHO and was unmeasurable on deficient CHO diets; thus, the preceding 5-d CHO intake could be inferred from DNL. Nevertheless, absolute hepatic DNL accounted for < 5g fatty acids synthesized per day even on +50% CHO. Whole-body CHO oxidation increased sixfold and fat oxidation decreased > 90% on surplus CHO diets. CHO oxidation was highly correlated with HGP (r2= 0.60). HGP could account for 85% of fasting CHO oxidation on +25% CHO and 67% on +50% CHO diets. Some oxidation of intracellular CHO stores was therefore also occurring. +50% fat diet had no effects on HGP, DNL, or fuel selection. We conclude that altered CHO intake alters HGP specifically and in a dose-dependent manner, that HGP may mediate the effects of CHO on whole-body fuel selection both by providing substrate and by altering serum insulin concentrations, that altered lipolysis and tissue oxidation efficiency contribute to changes in fat oxidation, and that surplus CHO is not substantially converted by the liver to fat as it spares fat oxidation, but that fractional DNL may nevertheless be a qualitative marker of recent CHO intake. PMID- 8675643 TI - Genetic instability in patients with Hodgkin's disease undergoing chemotherapy. AB - We have studied the effect of chemotherapy on the level of a particular kind of genetic instability in patients with Hodgkin's disease. The particular type of genetic instability assayed is exemplified by trans-rearrangements between two (rather than within one) T cell antigen receptor. 16 patients were studied during their course of treatment. Presentation samples were available for 13 of these patients; 9 of them showed an increase in the level of trans-rearrangements during their exposure to chemotherapeutic agents (P < 0.043). All patients for whom posttherapy samples were available (10 out of 16) showed a return to baseline levels of trans-rearrangements 1-5 mo after completion of therapy (P < 0.03). Thus, this assay appears to be a marker for the "destabilizing" effects of certain chemotherapeutic agents. PMID- 8675644 TI - rENaC is the predominant Na+ channel in the apical membrane of the rat renal inner medullary collecting duct. AB - The terminal nephron segment, the inner medullary collecting duct (IMCD), absorbs Na+ by an electrogenic process that involves the entry through an apical (luminal) membrane Na+ channel. To understand the nature of this Na+ channel, we employed the patch clamp technique on the apical membrane of primary cultures of rat IMCD cells grown on permeable supports. We found that all ion channels detected in the cell-attached configuration were highly selective for Na+ (Li+) over K+. The open/closed transitions showed slow kinetics, had a slope conductance of 6-11 pS, and were sensitive to amiloride and benzamil. Nonselective cation channels with a higher conductance (25-30 pS), known to be present in IMCD cells, were not detected in the cell-attached configuration, but were readily detected in excised patches. The highly selective channels had properties similar to the recently described rat epithelial Na+ channel complex, rENaC. We therefore asked whether rENaC mRNA was present in the IMCD. We detected mRNA for all three rENaC subunits in rat renal papilla and also in primary cultures of the IMCD. Either glucocorticoid hormone or mineralocorticoid hormone increased the amount of alpha-rENaC subunit mRNA but had no effect on the mRNA level of the beta-rENaC or gamma-rENaC subunits. From these data, taken in the context of other studies on the characteristics of Na+ selective channels and the distribution of rENaC mRNA, we conclude that steroid stimulated Na+ absorption by the IMCD is mediated primarily by Na+ channels having properties of the rENaC subunit complex. PMID- 8675645 TI - Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures. AB - We previously reported that high density lipoprotein (HDL) protects against the oxidative modification of low density lipoprotein (LDL) induced by artery wall cells causing these cells to produce pro-inflammatory molecules. We also reported that enzyme systems associated with HDL were responsible for this anti inflammatory property of HDL. We now report studies comparing HDL before and during an acute phase response (APR) in both humans and a croton oil rabbit model. In rabbits, from the onset of APR the protective effect of HDL progressively decreased and was completely lost by day three. As serum amyloid A (SAA) levels in acute phase HDL (AP-HDL) increased, apo A-I levels decreased 73%. Concomitantly, paraoxonase (PON) and platelet activating factor acetylhydrolase (PAF-AH) levels in HDL declined 71 and 90%, respectively, from days one to three. After day three, there was some recovery of the protective effect of HDL. AP-HDL from human patients and rabbits but not normal or control HDL (C-HDL) exhibited increases in ceruloplasmin (CP). This increase in CP was not seen in acute phase VLDL or LDL. C-HDL incubated with purified CP and re-isolated (CP-HDL), lost its ability to inhibit LDL oxidation. Northern blot analyses demonstrated enhanced expression of MCP-1 in coculture cells treated with AP-HDL and CP-HDL compared to C-HDL. Enrichment of human AP-HDL with purified PON or PAF-AH rendered AP-HDL protective against LDL modification. We conclude that under basal conditions HDL serves an anti-inflammatory role but during APR displacement and/or exchange of proteins associated with HDL results in a pro-inflammatory molecule. PMID- 8675646 TI - Alteration of growth responses in established cardiac pressure overload hypertrophy in rats with aortic banding. AB - We examined the acute effects of elevated wall stress, norepinephrine, and angiotensin II on cardiac protein synthesis as well as protooncogene expression in hearts with established pressure overload left ventricular hypertrophy. Isolated rat hearts with chronic hypertrophy (LVH) were studied 12 wk after ascending aortic banding when systolic function was fully maintained. New protein synthesis (incorporation of [3H]phenylalanine [Phe]) was analyzed in isolated perfused rat hearts after a 3-h protocol; c-fos, c-jun, c-myc, and early growth response gene-1 (EGR-1) mRNA levels (Northern blot) were studied over a time course from 15 to 240 min of perfusion. Under baseline conditions (i.e., before mechanical or neurohormonal stimulation), [3H]-Phe-incorporation (280 nmoles/gram protein/h) and protooncogene mRNA levels were similar in age-matched control and LVH hearts. However, hearts with chronic LVH were characterized by a markedly blunted or absent [3H]-Phe-incorporation after acute imposition of isovolumic systolic load (90 mmHg/gram left ventricle), as well as norepinephrine (10(-6)M), or angiotensin II infusion (10(-8)M plus prazosin 10(-7)M) compared with nonhypertrophied control hearts. Similarly, stimulation of LVH hearts with acute systolic load or norepinephrine was associated with a significantly blunted increase of protooncogene mRNA levels relative to control hearts. The blunted induction of c-fos mRNA in LVH hearts was not due to feedback inhibition, since cycloheximide perfusion of hearts exposed to elevated wall stress further increased the differences between age-matched control and LVH hearts. The data suggest that acute molecular growth responses to mechanical or neurohormonal stimulation are altered in rat hearts with established LVH relative to nonhypertrophied control hearts. This alteration of molecular adaptations in hearts with compensatory hypertrophy may prevent inappropriate excess cardiac growth in response to mechanical and neurohormonal stimuli. PMID- 8675647 TI - Breast cancer selective gene expression and therapy mediated by recombinant adenoviruses containing the DF3/MUC1 promoter. AB - The high molecular weight mucin-like glycoprotein, DF3 (MUC1), is overexpressed in the majority of human breast cancers. Here we demonstrate that replication defective recombinant adenoviral vectors, containing the DF3 promoter (bp -725 to +31), can be used to express beta-galactosidase (Ad.DF3-betagal) and the herpes simplex virus thymidine kinase (HSV-tk) gene (Ad.Df3-tk) in DF3 positive breast carcinoma cell lines. In vivo experiments using breast tumor implants in nude mice injected with Ad.DF3-betagal demonstrated that expression of the beta galactosidase gene is limited to DF3-positive breast cancer xenografts. Moreover, in an intraperitoneal breast cancer metastases model, we show that i.p. injection of Ad.DF3-tk followed by GCV treatment results in inhibition of tumor growth. These results demonstrate that utilization of the DF3 promoter in an adenoviral vector can confer selective expression of heterologous genes in breast cancer cells in vitro and in vivo. PMID- 8675648 TI - A unique genetic and biochemical presentation of fish-eye disease. AB - This paper describes a novel genetic defect which causes fish-eye disease in four homozygous probands and its biochemical presentation in 34 heterozygous siblings. The male index patient presented with premature coronary artery disease, corneal opacification, HDL deficiency, and a near total loss of plasma lecithin:cholesterol acyltransferase (LCAT) activity. Sequencing of the LCAT gene revealed homozygosity for a novel missense mutation resulting in an Asp131 - Asn (N131D) substitution. Heterozygotes showed a highly significant reduction of HDL cholesterol and apolipoprotein A-I levels as compared with controls which was associated with a specific decrease of LpA-I:A-II particles. Functional assessment of this mutation revealed loss of specific activity of recombinant LCAT(N131D) against proteoliposomes. Unlike other mutations causing fish-eye disease, recombinant LCAT(N131D) also showed a 75% reduction in specific activity against LDL. These unique biochemical characteristics reveal the heterogeneity of phenotypic expression of LCAT gene defects within a range specified by complete loss of LCAT activity and the specific loss of activity against HDL. The impact of this mutation on HDL levels and HDL subclass distribution may be related to the premature coronary artery disease observed in the male probands. PMID- 8675649 TI - Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle. Implications for glucose toxicity. AB - Glucosamine (Glmn), a product of glucose metabolism via the hexosamine pathway, causes insulin resistance in isolated adipocytes by impairing insulin-induced GLUT 4 glucose transporter translocation to the plasma membrane. We hypothesized that Glmn causes insulin resistance in vivo by a similar mechanism in skeletal muscle. We performed euglycemic hyperinsulinemic clamps (12 mU/kg/min + 3H-3 glucose) in awake male Sprague-Dawley rats with and without Glmn infusion at rates ranging from 0.1 to 6.5 mg/kg/min. After 4h of euglycemic clamping, hindquarter muscles were quick-frozen and homogenized, and membranes were subfractionated by differential centrifugation and separated on a discontinuous sucrose gradient (25, 30, and 35% sucrose). Membrane proteins were solubilized and immunoblotted for GLUT 4. With Glmn, glucose uptake (GU) was maximally reduced by 33 +/- 1%, P < 0.001. The apparent Glmn dose to reduce maximal GU by 50% was 0.1 mg/kg/min or 1/70th the rate of GU on a molar basis. Control galactosamine and mannosamine infusions had no effect on GU. Relative to baseline, insulin caused a 2.6-fold increase in GLUT 4 in the 25% membrane fraction (f), P < 0.01, and a 40% reduction in the 35%f, P < 0.05, but had no effect on GLUT 4 in the 30% f, P= NS. Addition of Glmn to insulin caused a 41% reduction of GLUT 4 in the 25%f, P < 0.05, a 29% fall in the 30%f, and prevented the reduction of GLUT 4 in the 35% f. The 30%f membranes were subjected to a second separation with a 27 and 30% sucrose gradient. Insulin mobilized GLUT 4 away from the 30%f, P < 0.05, but not the 27% f. In contrast, Glmn reduced GLUT 4 in the 27%f, P < 0.05, but not the 30%f. Thus Glmn appears to alter translocation of an insulin-insensitive GLUT 4 pool. Coinfusion of Glmn did not alter enrichment of the sarcolemmal markers 5'-nucleotidase, Na+/K+ATPase, and phospholemman in either 25, 30, or 35% f. Thus Glmn completely blocked movement of Glut 4 induced by insulin. Glmn is a potent inducer of insulin resistance in vivo by causing (at least in part) a defect intrinsic to GLUT 4 translocation and/or trafficking. These data support a potential role for Glmn to cause glucose induced insulin resistance (glucose toxicity). PMID- 8675650 TI - Skeletal muscle membrane lipid composition is related to adiposity and insulin action. AB - The cellular basis of insulin resistance is still unknown; however, relationships have been demonstrated between insulin action in muscle and the fatty acid profile of the major membrane structural lipid (phospholipid). The present study aimed to further investigate the hypothesis that insulin action and adiposity are associated with changes in the structural lipid composition of the cell. In 52 adult male Pima Indians, insulin action (euglycemic clamp), percentage body fat (pFAT; underwater weighing), and muscle phospholipid fatty acid composition (percutaneous biopsy of vastus lateralis) were determined. Insulin action (high dose clamp; MZ) correlated with composite measures of membrane unsaturation (% C20-22 polyunsaturated fatty acids [r= 0.463, P < 0.001], unsaturation index [r= 0.369, P < 0.01]), a number of individual fatty acids and with delta5 desaturase activity (r= 0.451, P < 0.001). pFAT (range 14-53%) correlated with a number of individual fatty acids and delta5 desaturase activity (r= -0.610, P < 0.0001). Indices of elongase activity (r= -0.467, P < 0.001), and delta9 desaturase activity (r= 0.332, P < 0.05) were also related to pFAT but not insulin action. The results demonstrate that delta5 desaturase activity is independently related to both insulin resistance and obesity. While determining the mechanisms underlying this relationship is important for future investigations, strategies aimed at restoring "normal" enzyme activities, and membrane unsaturation, may have therapeutic importance in the "syndromes of insulin resistance." PMID- 8675651 TI - Basic fibroblast growth factor augments podocyte injury and induces glomerulosclerosis in rats with experimental membranous nephropathy. AB - Podocyte injury is believed to contribute to glomerulosclerosis in membranous nephropathy. To identify the factors involved, we investigated the effects of basic fibroblast growth factor (bFGF), a cytokine produced by podocytes, on rats with membranous nephropathy (passive Heymann nephritis [PHN]). All rats received a daily i.v. bolus of 10 microg bFGF or vehicle from days 3-8 after PHN induction. In proteinuric PHN rats on day 8, bFGF injections further increased proteinuria. Podocytes of bFGF-injected PHN rats showed dramatic increases in mitoses, pseudocyst formation, foot process retraction, focal detachment from the glomerular basement membrane, and desmin expression. bFGF injections in PHN rats did not alter antibody or complement deposition or glomerular leukocyte influx. bFGF-injected PHN rats developed increased glomerulosclerosis when compared with control PHN rats. Also, bFGF induced proteinuria and podocyte damage in rats injected with 10% of the regular PHN-serum dose. None of these changes occurred in bFGF-injected normal rats, complement-depleted PHN rats or rats injected with 5% of the regular PHN serum dose. These divergent bFGF effects were explained in part by upregulated glomerular bFGF receptor expression, induced by PHN serum. Thus, bFGF can augment podocyte damage, resulting in increased glomerular protein permeability and accelerated glomerulosclerosis. This bFGF action is confined to previously injured podocytes. Release of bFGF from glomerular sources (including podocytes themselves) during injury may represent an important mechanism by which podocyte damage is enhanced or becomes self sustained. PMID- 8675652 TI - Glucose transport in cultured human skeletal muscle cells. Regulation by insulin and glucose in nondiabetic and non-insulin-dependent diabetes mellitus subjects. AB - A primary human skeletal muscle culture (HSMC) system, which retains cellular integrity and insulin responsiveness for glucose transport was employed to evaluate glucose transport regulation. As previously reported, cells cultured from non-insulin-dependent diabetic (NIDDM) subjects displayed significant reductions in both basal and acute insulin-stimulated transport compared to nondiabetic controls (NC). Fusion/differentiation of NC and NIDDM HSMC in elevated media insulin (from 22 pM to 30 microM) resulted in increased basal transport activities but reduced insulin-stimulated transport, so that cells were no longer insulin responsive. After fusion under hyperinsulinemic conditions, GLUT1 protein expression was elevated in both groups while GLUT4 protein level was unaltered. Fusion of HSMC under hyperglycemic conditions (10 and 20 mM) decreased glucose transport in NC cells only when combined with hyperinsulinemia. Hyperglycemia alone down-regulated transport in HSMC of NIDDM, while the combination of hyperglycemia and hyperinsulinemia had greater effects. In summary: (a) insulin resistance of glucose transport can be induced in HSMC of both NC and NIDDM by hyperinsulinemia and is accompanied by unaltered GLUT4 but increased GLUT1 levels; and (b) HSMC from NIDDM subjects demonstrate an increased sensitivity to impairment of glucose transport by hyperglycemia. These results indicate that insulin resistance in skeletal muscle can be acquired in NC and NIDDM from hyperinsulinemia alone but that NIDDM is uniquely sensitive to the additional influence of hyperglycemia. PMID- 8675653 TI - Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. AB - We have studied whether, or not, tissue-specific regulatory mechanisms provide normal 3,5,3'-triiodothyronine (T3) concentrations simultaneously in all tissues of a hypothyroid animal receiving thyroxine (T4), an assumption implicit in the replacement therapy of hypothyroid patients with T4 alone. Thyroidectomized rats were infused with placebo or 1 of 10 T4 doses (0.2-8.0 micrograms per 100 grams of body weight per day). Placebo-infused intact rats served as controls. Plasma and 10 tissues were obtained after 12-13 d of infusion. Plasma thyrotropin and plasma and tissue T4 and T3 were determined by RIA. Iodothyronine-deiodinase activities were assayed using cerebral cortex, liver, and lung. No single dose of T4 was able to restore normal plasma thyrotropin, T4 and T3, as well as T4 and T3 in all tissues, or at least to restore T3 simultaneously in plasma and all tissues. Moreover, in most tissues, the dose of T4 needed to ensure normal T3 levels resulted in supraphysiological T4 concentrations. Notable exceptions were the cortex, brown adipose tissue, and cerebellum, which maintained T3 homeostasis over a wide range of plasma T4 and T3 levels. Deiodinase activities explained some, but not all, of the tissue-specific and dose related changes in tissue T3 concentrations. In conclusion, euthyroidism is not restored in plasma and all tissues of thyroidectomized rats on T4 alone. These results may well be pertinent to patients on T4 replacement therapy. PMID- 8675654 TI - IL-6 and IL-8 production from cultured human endothelial cells stimulated by infection with Rickettsia conorii via a cell-associated IL-1 alpha-dependent pathway. AB - Mediterranean spotted fever due to infection by Rickettsia conorii, is characterized by a general vasculitis. This vasculitis is thought to be due to a direct injury to endothelial cells induced by R. conorii. However, production and activity of cytokines on endothelial cells is an important pathway in inflammation, and part of the underlying mechanism of vasculitis. In the present studies, human umbilical vein endothelial cells (HUVEC) infected with R. conorii actively secrete high levels of IL-8 and IL-6 (P < 0.002, and P < 0.03, respectively, compared with uninfected cells). IL-1alpha, IL-1beta, or TNFalpha were not detected in the culture supernates. Nevertheless, IL-6 and IL-8 production was due, in a large part, to a cell-associated form of IL-1 alpha expressed on R. conorii-infected HUVEC, since production of these cytokines was suppressed by 80% (P = 0.0001) and 85% (P < 0.04) by the addition of IL-1 receptor antagonist, or anti-IL-1alpha antibodies (60% inhibition, P < 0.01 and 65% inhibition, P < 0.05, respectively) and IL-1alpha was measured after lysis of R. conorii-infected HUVEC but not in uninfected cells (P < 0.01). Rickettsial lipopolysaccharide does not seem to be involved, since polymyxin B did not reduce cytokine secretion. On the contrary, infection by intracellular R. conorii appears to be necessary to induce IL-1alpha and subsequently IL-8, since formalin fixed R. conorii did not induce cytokine production. These observations demonstrate that R. conorii-infected HUVEC secrete IL-6 and IL-8 via the induction of cell-associated IL-1alpha, providing a possible mechanism for the vasculitis observed in Mediterranean spotted fever. PMID- 8675655 TI - In vivo demonstration of red cell-endothelial interaction, sickling and altered microvascular response to oxygen in the sickle transgenic mouse. AB - Intravascular sickling, red cell-endothelium interaction, and altered microvascular responses have been suggested to contribute to the pathophysiology of human sickle cell disease, but have never been demonstrated under in vivo flow. To address this issue, we have examined a transgenic mouse line, alphaHbetaSbetaS-Antilles [betaMDD] which has a combined high (78%) expression of beta S and beta S-Antilles globins. In vivo microcirculatory studies using the cremaster muscle preparation showed adhesion of red cells, restricted to postcapillary venules, in transgenic mice but not in control mice. Electron microscopy revealed distinct contacts between the red cell membrane and the endothelium surface. Some red cells exhibiting sickling were regularly observed in the venular flow. Infusion of transgenic mouse red cells into the ex vivo mesocecum vasculature also showed adhesion of mouse red cells exclusively in venules. Under resting conditions (pO2, 15-20 mmHg), there were no differences in the cremaster microvascular diameters of control and transgenic mice; however, transgenic mice showed a drastic reduction in microvascular red cell velocities (Vrbc) with maximal Vrbc decrease (> 60%) occurring in venules, the sites of red cell adhesion and sickling. Local, transient hyperoxia (pO2, 150 mmHg) resulted in striking differences between control and transgenic mice. In controls, oxygen caused a 69% arteriolar constriction, accompanied by 75% reduction in Vrbc. In contrast, in transgenic mice, hyperoxia resulted in only 8% decrease in the arteriolar diameter and in 68% increase in VrBC; the latter is probably due to an improved flow behavior of red cells as a consequence of unsickling. In summary, the high expression of human sickle hemoglobin in the mouse results not only in intravascular sickling but also red cell-endothelium interaction. The altered microvascular response to oxygen could be secondary to blood rheological changes, although possible intrinsic differences in the endothelial cell/vascular smooth muscle function in the transgenic mouse may also contribute. These sickle transgenic mice could serve as a useful model to investigate vasoocclusive mechanisms, as well as to test potential therapies. PMID- 8675656 TI - Aberrant hepatic processing causes removal of activation peptide and primary polymerisation site from fibrinogen Canterbury (A alpha 20 Val --> Asp). AB - A novel mechanism of molecular disease was uncovered in a patient with prolonged thrombin time and a mild bleeding tendency. DNA sequencing of the fibrinogen A alpha chain indicated heterozygosity for a mutation of 20 Val --> Asp. The molar ratio of fibrinopeptide A to B released by thrombin was substantially reduced at 0.64 suggesting either impaired cleavage or that the majority of the variant alpha chains lacked the A peptide. The latter novel proposal arises from the observation that the mutation changes the normal 16R G P R V20 sequence to R G P R D creating a potential furin cleavage site at Arg 19. Synthetic peptides incorporating both sequences were tested as substrates for both thrombin and furin. There was no substantial difference in the thrombin catalyzed cleavage. However, the variant peptide, but not the normal, was rapidly cleaved at Arg 19 by furin. Predictably intracellular cleavage of the Aalpha-chain at Arg 19 would remove fibrinopeptide A together with the G P R polymerisation site. This was confirmed by sequence analysis of fibrinogen Aalpha chains after isolation by SDS PAGE. The expected normal sequence was detected together with a new sequence (D V E R H Q S A-) commencing at residue 20. Truncation was further verified by nonreducing SDS-PAGE of the NH2-terminal disulfide knot which indicated the presence of aberrant homo- and heterodimers. PMID- 8675657 TI - Damage to type II collagen in aging and osteoarthritis starts at the articular surface, originates around chondrocytes, and extends into the cartilage with progressive degeneration. AB - Enhanced denaturation of type II collagen fibrils in femoral condylar cartilage in osteoarthritis (OA) has recently been quantitated immunochemically (Hollander, A.P., T.F. Heathfield, C. Webber, Y. Iwata, R. Bourne, C. Rorabeck, and A.R. Poole. 1994. J. Clin. Invest. 93:1722-1732). Using the same antibody that only reacts with denatured type II collagen, we investigated with immunoperoxidase histochemistry (results were graded for analysis) the sites of the denaturation (loss of triple helix) of this molecule in human aging (at autopsy, n= 11) and progressively degenerate (by Mankin grade [MG]) OA (at arthroplasty, n= 51) knee condylar cartilages. Up to 41 yr, most aging cartilages (3 of 4) (MG 0-4) showed very little denaturation. In most older cartilages, (4 of 7) (MG 2-4), staining was observed in the superficial and mid zones. This pattern of collagen II denaturation was also seen in all OA specimens with increased staining extending to the deep zone with increasing MG. Collagen II staining correlated directly both with MG and collagen II denaturation measured by immunoassay. Cartilage fibrillation occurred in OA cartilages with increased penetration of the staining for collagen II denaturation into the mid and deep zones and where denaturation was more pronounced by immunoassay. Thus in both aging and OA the first damage to type II collagen occurs in the superficial and upper mid zone (low MG) extending to the lower mid and deep zones with increasing degeneration (increasing MG). Initial damage is always seen around chondrocytes implicating them in the denaturation of type II collagen. PMID- 8675658 TI - beta-Adrenergic modulation of the inwardly rectifying potassium channel in isolated human ventricular myocytes. Alteration in channel response to beta adrenergic stimulation in failing human hearts. AB - The beta-adrenergic modulation of the inwardly-rectifying K+ channel (IK1) was examined in isolated human ventricular myocytes using patch-clamp techniques. Isoproterenol (ISO) reversibly depolarized the resting membrane potential and prolonged the action potential duration. Under the whole-cell C1- -free condition, ISO applied via the bath solution reversibly inhibited macroscopic IdK1. The reversal potential of the ISO-sensitive current was shifted by approximately 60 mV per 10-fold change in the external K+ concentration and was sensitive to Ba2+. The ISO-induced inhibition of IK1 was mimicked by forskolin and dibutyrl cAMP, and was prevented by including a cAMP-dependent protein kinase (PKA) inhibitor (PKI) in the pipette solution. In single-channel recordings from cell-attached patches, bath applied ISO could suppress IK1 channels by decreasing open state probability. Bath application of the purified catalytic sub-unit of PKA to inside-out patches also inhibited IK1 and the inhibition could be antagonized by alkaline phosphatase. When beta-adrenergic modulation of IK1 was compared between ventricular myocytes isolated from the failing and the nonfailing heart, channel response to ISO and PKA was significantly reduced in myocytes from the failing heart. Although ISO inhibited IK1 in a concentration dependent fashion in both groups, a half-maximal concentration was greater in failing (0.12 microM) than in nonfailing hearts (0.023 microM). These results suggest that IK1 in human ventricular myocytes can be inhibited by a PKA-mediated phosphorylation and the modulation is significantly reduced in ventricular myocytes from the failing heart compared to the nonfailing heart. PMID- 8675659 TI - Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein. AB - Our group has previously demonstrated that oxidized phospholipids in mildly oxidized LDL (MM-LDL) produced by oxidation with lipoxygenase, iron, or cocultures of artery wall cells increase monocyte-endothelial interactions and this sequence of events is blocked by HDL. To obtain further insight into the mechanism by which HDL abolishes the activity of MM-LDL we investigated the effect of the HDL-associated ester hydrolase paraoxonase (PON). Treatment of MM LDL with purified PON significantly reduced the ability of MM-LDL to induce monocyte-endothelial interactions. Inactivation of PON by pretreating HDL with heat or EDTA reduced the ability of HDL to inhibit LDL modification. HPLC analysis of phospholipids isolated from MM-LDL before and after treatment with purified PON showed that the 270 nm absorbance of phospholipids was decreased, while no effect was observed on 235 nm absorbance. Oxidized 1-palmitoyl-2 arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC) and specific fractions of Ox-PAPC isolated by HPLC induced the same monocyte-endothelial interactions as did MM-LDL. Biologically active and inactive HPLC fractions of Ox-PAPC were compared by fast atom bombardment-mass spectrometry which revealed that active fractions possessed ions with a mass to charge [correction of change] ratio greater than native PAPC by multiples of 16 D suggesting the addition of 3 and 4 oxygen atoms to PAPC. Comparison of Ox-PAPC by fast atom bombardment-mass spectrometry before and after PON treatment showed that PON destroyed these multi oxygenated molecules found in biologically active fractions of Ox-PAPC. These results suggest that PON in HDL may protect against the induction of inflammatory responses in artery wall cells by destroying biologically active lipids in mildly oxidized LDL. PMID- 8675660 TI - Temporal correlation between maximum tetanic force and cell death in postischemic rat skeletal muscle. AB - To gain insight into the mechanisms responsible for muscle dysfunction after ischemia-reperfusion, a rat spinotrapezius muscle preparation was developed which enabled sequential measurements of in vivo maximum tetanic force production and cell death assessed using digital microfluorographic determination of propidium iodide (PI) staining. After 60 min of no-flow ischemia, maximum tetanic force fell significantly during 90 min of reperfusion compared with control, nonischemic muscles. The most striking fall was evident within 30 min of reperfusion and occurred concomitant with an explosive increase in PI-positive myocyte nuclei. Treatment with the oxygen radical scavenger, dimethylthiourea, attenuated both the fall in force and increased PI staining. Indeed, the rise in PI-positive nuclei correlated closely (r= 0.728) with the reduction of maximum tetanic force developed following ischemia and reperfusion under all conditions. Superoxide dismutase also attenuated the rise in PI-positive nuclei. Assessment of mitochondrial inner membrane potential (deltapsi) using Rhodamine 123 fluorescence revealed that myocytes with the lowest initial mitochondrial membrane potential were subject to the greatest injury after 90 min of reperfusion (r= 0.828). These results support the hypothesis that myocyte injury, as visualized by PI-staining, reflects an impaired contractile function in fibers with a low oxidative potential which is likely mediated by oxygen radicals. PMID- 8675661 TI - Neutrophil adhesion in leukocyte adhesion deficiency syndrome type 2. AB - We have previously reported a newly discovered congenital disorder of neutrophil adhesion, leukocyte adhesion deficiency syndrome type 2 (LAD II). The clinical manifestations of this syndrome are similar to those seen in the classic leukocyte adhesion deficiency syndrome, now designated type 1 (LAD I), but the two syndromes differ in the molecular basis of their adhesion defects. LAD I is caused by a deficiency in the CD18 integrin adhesion molecules while LAD II patients are deficient in expression of sialyl-Lewis X (SLeX), a carbohydrate ligand for selectins. In this report we demonstrate that neutrophils from a LAD II patient bind minimally or not at all to recombinant E-selectin, purified platelet P-selectin, or P-selectin expressed on histamine-activated human umbilical vein endothelial cells, but have normal levels of L-selectin and CD11b/CD18 integrin, and adhere to and migrate across endothelium when CD11b/CD18 is activated. We compare LAD I and LAD II patient neutrophil function in vitro, demonstrating that integrin and selectin adhesion molecules have distinct but interdependent roles in neutrophil adhesion during an inflammatory response. PMID- 8675662 TI - Carbonic anhydrase IV expression in rat and human gastrointestinal tract regional, cellular, and subcellular localization. AB - Carbonic anhydrase IV (CA IV) is a glycosylphosphatidylinositol-linked isozyme previously identified on the surface of renal tubular epithelium and certain populations of vascular endothelium. This report identifies the regional, cellular, and subcellular localization of CA IV in the rat gut. Northern blot and RT-PCR analyses demonstrated little CA IV expression in stomach or proximal small intestine, but abundant expression in distal small and large intestine. In contrast, CA II mRNA was abundant in stomach, decreased in proximal small intestine, low in distal small intestine, and abundant in large intestine. CA I mRNA was detected only in large intestine. The regional distribution of CA IV activity correlated with distribution of CA IV mRNA. Immunohistochemistry localized CA IV to the apical plasma membrane of the mucosal epithelium in distal small intestine and large intestine. Signal intensity was greatest in colon. CA IV was additionally found in submucosal capillary endothelium of all gastrointestinal regions. Immunohistochemical findings in human stomach and colon paralleled those in the rat. These studies demonstrate pre-translational isozyme specific regulation of CA expression along the cranial-caudal axis of the gastrointestinal tract. The regional, cellular, and subcellular localizations are consistent with participation of CA IV in the extensive ion and fluid transport in the distal small and large intestine. PMID- 8675664 TI - Activation of the Fas receptor on lung eosinophils leads to apoptosis and the resolution of eosinophilic inflammation of the airways. AB - While considerable progress has been made in understanding the events by which eosinophils accumulate in various pathophysiological conditions, the mechanisms controlling the resolution of eosinophilic inflammation are poorly understood. In the present study, we demonstrate that lung eosinophils obtained by bronchoalveolar lavage (BAL) after aerosol allergen provocation of immunized mice expressed the Fas receptor. Stimulation of purified eosinophils in vitro with a monoclonal anti-Fas mAb (1 ng-1 microg/ml) induced a dose/time dependent loss of cell viability from 24-72 h. Measurement of DNA fragmentation with propidium iodide confirmed that anti-Fas induced eosinophil death by apoptosis. While incubation with IL-3, IL-5, or GM-CSF prevented spontaneous apoptosis, these factors failed to prevent anti-Fas induced apoptosis. Administration of anti-Fas mAb to the lungs after the induction of a lung eosinophilia increased the number of peroxidase positive macrophages in BAL fluid 4-12 h later which was followed by a marked reduction in the number of eosinophils in the airways. Importantly, Fas-mediated resolution of eosinophilic inflammation occurred in the absence of any overt secondary inflammatory changes in the lungs. We speculate that defects in this pathway may at least in part explain the chronic eosinophilic inflammation often observed in the lungs of asthmatic individuals. PMID- 8675663 TI - Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. AB - The brown fat-specific mitochondrial uncoupling protein (UCP) provides a mechanism for generating heat by uncoupling respiration and oxidative phosphorylation. It has been suggested that this system of thermogenesis can provide a defense against obesity. To test this idea, we created a transgenic mouse in which the fat-specific aP2 gene promoter directed Ucp expression in white fat and provided for the constitutive expression of Ucp in brown fat. Transgenic mice showed both Ucp mRNA and immunoreactive UCP in white fat at 2-10% the level normally measured in brown fat. A reduction in subcutaneous fat of aP2 Ucp C57BL/6J mice was observed at 3 mo of age. When the transgene was expressed in Avy genetically obese mice reductions in total body weight and subcutaneous fat stores were observed. Female transgenic Avy mice at 13 mo of age weighed 35 grams, a weight indistinguishable from nontransgenic C57BL/6J mice. Gonadal fat showed an increase in a novel adipocyte derivative that did not accumulate lipids and that constituted approximately 80% of the mass of the tissue in Avy transgenic. A major effect of aP2-Ucp in brown fat was to reduce endogenous gene expression by as much as 95%. The results suggest that UCP synthesized from the aP2 gene promoter is thermogenically active and capable of reducing fat stores. PMID- 8675665 TI - A genetic model for absent chylomicron formation: mice producing apolipoprotein B in the liver, but not in the intestine. AB - The formation of chylomicrons by the intestine is important for the absorption of dietary fats and fat-soluble vitamins (e.g., retinol, alpha-tocopherol). Apo B plays an essential structural role in the formation of chylomicrons in the intestine as well as the VLDL in the liver. We have developed genetically modified mice that express apo B in the liver but not in the intestine. By electron microscopy, the enterocytes of these mice lacked nascent chylomicrons in the endoplasmic reticulum and Golgi apparatus. Because these mice could not form chylomicrons, the intestinal villus enterocytes were massively engorged with fat, which was contained in cytosolic lipid droplets. These mice absorbed D-xylose normally, but there was virtually no absorption of retinol palmitate or cholesterol. The levels of alpha-tocopherol in the plasma were extremely low. Of note, the absence of chylomicron synthesis in the intestine did not appear to have a significant effect on the plasma levels of the apo B-containing lipoproteins produced by the liver. The mice lacking intestinal apo B expression represent the first genetic model of defective absorption of fats and fat-soluble vitamins and provide a useful animal model for studying nutrition and lipoprotein metabolism. PMID- 8675666 TI - Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation. AB - Elevated levels of endogenous angiotensin can cause hypertensive nephrosclerosis as a result of the potent vasopressor action of the peptide. We have produced by gene targeting mice homozygous for a null mutation in the angiotensinogen gene (Atg-1-). Postnatally, Atg-1- animals show a modest delay in glomerular maturation. Although Atg-1- animals are hypotensive by 7 wk of age, they develop, by 3 wk of age, pronounced lesions in the renal cortex, similar to those of hypertensive nephrosclerosis. In addition, the papillae of homozygous mutant kidneys are reduced in size. These lesions are accompanied by local up-regulation of PDGF-B and TGF-beta1 mRNA in the cortex and down-regulation of PDGF-A mRNA in the papilla. The study demonstrates an important requirement for angiotensin in achieving and maintaining the normal morphology of the kidney. The mechanism through which angiotensin maintains the volume homeostasis in mammals includes promotion of the maturational growth of the papilla. PMID- 8675667 TI - Adenovirus-mediated gene transfer into normal rabbit arteries results in prolonged vascular cell activation, inflammation, and neointimal hyperplasia. AB - Adenovirus vectors are capable of high efficiency in vivo arterial gene transfer, and are currently in use as therapeutic agents in animal models of vascular disease. However, despite substantial data on the ability of viruses to cause vascular inflammation and proliferation, and the presence in current adenovirus vectors of viral open reading frames that are translated in vivo, no study has examined the effect of adenovirus vectors alone on the arterial phenotype. In a rabbit model of gene transfer into a normal artery, we examined potential vascular cell activation, inflammation, and neointimal proliferation resulting from exposure to replication-defective adenovirus. Exposure of normal arteries to adenovirus vectors resulted in: (a) pronounced infiltration of T cells throughout the artery wall; (b) upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in arterial smooth muscle cells; (c) neointimal hyperplasia. These findings were present both 10 and 30 d after gene transfer, with no evidence of a decline in severity over time. Adenovirus vectors have pleiotropic effects on the arterial wall and cause significant pathology. Interpretation of experimental protocols that use adenovirus vectors to address either biological or therapeutic issues should take these observations into account. These observations should also prompt the design of more inert gene transfer vectors. PMID- 8675668 TI - Antibody facilitation of multiple sclerosis-like lesions in a nonhuman primate. AB - In the human disease multiple sclerosis (MS), the immune mechanisms responsible for selective destruction of central nervous system myelin are unknown. In the common marmoset Callithrix jacchus, a unique demyelinating form of experimental allergic encephalomyelitis resembling MS can be induced by immunization with whole myelin. Here we show that the MS-like lesion can be reproduced by immunization against the extracellular domain of a single myelin protein, myelin/oligodendrocyte glycoprotein (MOG). By contrast, immunization against the quantitatively major myelin proteins myelin basic protein or proteolipid protein results in inflammation but little or no demyelination. Furthermore, in the presence of encephalitogenic (e.g., disease-inducing) T cells, the fully demyelinated lesion is reconstructed by systemic administration of IgG purified from whole myelin-, or MOG-immunized animals, and equally by a monoclonal antibody against MOG, but not by control IgG. Encephalitogenic T cells may contribute to the MS-like lesion through disruption of the blood-brain barrier that permits access of demyelinating antibody into the nervous system. The identification of MOG as a major target antigen for autoimmune demyelination in a nonhuman primate should facilitate development of specific immunotherapies for human MS. PMID- 8675669 TI - Angiotensin converting enzyme as a genetic risk factor for coronary artery spasm. Implication in the pathogenesis of myocardial infarction. AB - It has been reported that individuals with the D allele of an insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene are at greater risk for myocardial infarction (MI), especially among subjects normally considered to be at low risk. However, little is known about the mechanism by which the ACE polymorphism affects the risk of MI. Coronary artery spasm (CAS) is considered to be one possible mechanism for developing MI. We therefore examined the ACE polymorphism relation to CAS to determine if this was the mechanism by which the DD genotype influences MI. We studied 150 angiographically assessed Japanese males, all more than 60 yr old. CASs were detected using intracoronary injection of ergonovine maleate. Subjects were divided into three groups: those with CAS (group 1), those without CAS, but with fixed organic stenosis (group 2); and those without CAS and no organic stenosis (group 3). DD subjects were significantly represented in group 1 when compared with groups 2 (P = 0.002) and 3 (P = 0.026). These results suggest that the DD genotype relates to the greater risk for MI in the patients with CAS. PMID- 8675670 TI - Targeted tumor killing via an intracellular antibody against erbB-2. AB - Specific killing of erbB-2-overexpressing tumor cells can be achieved using expression of an intracellular antibody directed against the erbB-2 oncoprotein. We have developed a strategy using a recombinant adenovirus encoding an anti-erbB 2 single chain antibody to achieve targeted tumor cell killing in vivo and can show significantly prolonged survival of animals carrying a human ovarian carcinoma tumor burden within their peritoneal cavities. This strategy of gene therapy for ovarian carcinoma offers the potential to achieve highly specific, targeted killing of human tumor cells and thus establishes the rationale to undertake human clinical trials on this basis. PMID- 8675671 TI - Immune tolerance to autoantibody-derived peptides delays development of autoimmunity in murine lupus. AB - Mechanisms that initiate and maintain autoantibody (autoAb) production in individuals with autoimmune diseases like SLE are poorly understood. Inadequate suppression of autoreactive T cells and/or unusual activation of T and B cells may underlie the persistence of pathogenic autoAbs in lupus. Here, we examine the possibility that in mice with lupus, autoAb molecules may be upregulating their own production by activating self-reactive T cells via their own processed peptides; downregulation of this circuit may decrease autoAb production and delay the development of lupus. We found that before the onset of clinical disease, lupus-prone (NZB/NZW) F1 [BWF1] (but not MHC-matched nonautoimmune mice) developed spontaneous T cell autoimmunity to peptides from variable regions of heavy chains (VH) of syngeneic anti-DNA mAbs but not to peptides from the VH region of an mAb to an exogenous antigen. Tolerizing young BWF1 mice with intravenous injections of autoAb-derived determinants substantially delayed development of anti-DNA antibodies and nephritis and prolonged survival. Thus, in such an autoAb-mediated disease, the presence of autoreactive T cells against VH region determinants of autoAbs may represent an important mechanism involved in the regulation of autoimmunity. Our findings show that tolerizing such autoreactive T cells can postpone the development of an autoimmune disease like SLE. PMID- 8675672 TI - Genotypic analysis of respiratory mucous sulfation defects in cystic fibrosis. AB - Intracellular dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) has been proposed to alter endosomal acidification. The most widely studied consequence of this defect has been alterations in the biochemical properties of cystic fibrosis (CF) respiratory mucus glycoproteins. However, studies confirming the existence of mucous processing defects in CF have been hindered by the lack of in vivo animal models by which to test these hypotheses in the absence of secondary effects of chronic bacterial infection. The human bronchial xenograft model has been useful in evaluating the pathophysiologic differences between CF and non-CF airway epithelium, in the absence of secondary disease effects such as goblet cell hyperplasia. In this study we sought to compare the extent of sulfation within secreted mucus glycoproteins from CF and non-CF human bronchial xenografts. Cumulative results of xenografts generated from 13 independent CF tissue samples demonstrated a statistically significant higher level of sulfation (1.7 +/- 0.18, P < 0.026) as compared to non-CF paired controls. Such findings add to the growing body of knowledge that primary defects in sulfation exist in CF respiratory mucin. Correlation of genotype with the extent of mucus sulfation revealed two categories of CF tissues with statistically different mucus sulfation profiles. Results from these studies demonstrated a 2.0 +/- 0.15-fold higher level of mucus sulfation produced from xenografts of five defined CF genotypes as compared to non-CF controls (P < 0.004, n= 10). Interestingly, three CF samples for which one mutant allele remained undefined (deltaoff8/unknown or G551D/unknown) demonstrated no statistical difference in the level of sulfation as compared with matched non-CF controls (n= 3). This as yet unknown allele was not identified within a screen for the 26 most common CF mutations. These results provide preliminary evidence for allelic variation within the CF population which may begin to elucidate the structure-function of CFTR with regards to intracellular mucus processing defects. PMID- 8675673 TI - A variant of human paraoxonase/arylesterase (HUMPONA) gene is a risk factor for coronary artery disease. AB - Coronary artery disease (CAD) is a complex trait caused by a number of genetic and environmental factors. Recently, paraoxonase/arylesterase (PONA) enzyme has been implicated in the pathogenesis of atherosclerosis. There is a 10-40-fold variability in the activity of this enzyme among individuals. This variability is due to the presence of an A/G polymorphism in the coding region of the gene (HUMPONA). The A and G alleles code for glutamine (A genotype) and arginine (B genotype), respectively. Individuals with A genotype have a lower enzymatic activity than those with B genotype. We determined the HUMPONA genotypes and alleles in 223 patients with angiographically documented CAD and in 247 individuals in the general population. The distribution of genotypes were in Hardy-Weinberg equilibrium in patients and in controls. Genotypes A and B were present in 120 (49%) and 28 (11%) individuals in controls and in 68 (30%) and 40 (18%) patients with CAD, respectively (chi squared= 16.5, P= 0.0003). The frequency of the A allele was 0.69 in controls and 0.56 in patients (OR= 1.7, P= 0.0001). There were no differences in the distribution of HUMPONA genotypes in the subgroups of patients with restenosis, myocardial infarction, or any of the conventional risk factors for CAD as compared with corresponding subgroups. In summary, variants of the HUMPONA gene are involved in predisposition to coronary atherosclerosis. PMID- 8675674 TI - A new subgroup of lectin-bound biliary proteins binds to cholesterol crystals, modifies crystal morphology, and inhibits cholesterol crystallization. AB - Biliary proteins inhibiting or promoting cholesterol crystallization are assumed to play a major role in cholesterol gallstone pathogenesis. We now report a new group of biliary proteins that bind to cholesterol crystals, modify crystal morphology, and inhibit cholesterol crystallization. Various glycoprotein mixtures were extracted from abnormal human gallbladder bile using lectin affinity chromatography on concanavalin A, lentil, and Helix pomatia columns and were added to supersaturated model bile. Independent of the protein mixtures added, from the cholesterol crystals harvested, the same four GPs were isolated having molecular masses of 16, 28, 63, and 74 kD, respectively. Each protein was purified using preparative SDS-PAGE, and influence on cholesterol crystallization in model bile was tested at 10 microg/ml. Crystal growth was reduced by 76% (GP63), 65% (GP16), 55% (GP74), and 40% (GP28), respectively. Thus, these glycoproteins are the most potent biliary inhibitors of cholesterol crystallization known so far. Evidence that the inhibiting effect on cholesterol crystallization is mediated via protein-crystal interaction was further provided from scanning electron microscopy studies. Crystals grown in presence of inhibiting proteins showed significantly more ordered structures. Incidence of triclinic crystals and regular aggregates was shifted from 30 to 70% compared with controls. These observations may have important implications for understanding the role of biliary proteins in cholesterol crystallization and gallstone pathogenesis. PMID- 8675675 TI - Cholesteryl ester transfer protein: friend or foe? PMID- 8675676 TI - Genetics reveals importance of platelet activating factor in asthma and possibly other inflammatory states. PMID- 8675677 TI - Sticky business: cytoskeleton and Na+ transport. PMID- 8675678 TI - Bisphosphonates: mechanisms of action. PMID- 8675679 TI - Altered expression of glomerular heat shock protein 27 in experimental nephrotic syndrome. AB - Although nephrotic syndrome is a very common kidney disease, little is known about the molecular changes occurring within glomerular capillary loops during development of disease. The characteristic histologic change is retraction (effacement) of the distal "foot" processes of glomerular epithelial cells (GEC) which surround the capillary loops. The GEC foot processes are an essential part of the kidney's filtration barrier, and their structure is regulated primarily by actin microfilaments, cytoskeletal proteins present in high concentrations in foot processes. Actin polymerization has been reported to be regulated via phosphorylation of the low molecular weight heat shock protein, hsp27. We localized hsp27 within normal rat GECs using immunofluorescence and immunoelectron microscopy. Induction of nephrotic syndrome and GEC foot process effacement using the puromycin aminonucleoside rat model resulted in significant increases in: (a) renal cortical hsp27 mRNA expression (826 +/- 233%, x +/- SEM, P < 0.01 vs. control); (b) glomerular hsp27 protein expression (87 +/- 2%, P < 0.001 vs. control); and (c) glomerular hsp27 phosphorylation (101 +/- 32%, P < 0.05 vs. control). These findings support the hypothesis that hsp27, by regulating GEC foot process actin polymerization, may be important in maintaining normal foot process structure, and regulating pathophysiologic GEC cytoskeletal changes during development of nephrotic syndrome. PMID- 8675680 TI - The effect of non-insulin-dependent diabetes mellitus and obesity on glucose transport and phosphorylation in skeletal muscle. AB - Defects of glucose transport and phosphorylation may underlie insulin resistance in obesity and non-insulin-dependent diabetes mellitus (NIDDM). To test this hypothesis, dynamic imaging of 18F-2-deoxy-glucose uptake into midthigh muscle was performed using positron emission tomography during basal and insulin stimulated conditions (40 mU/m2 per min), in eight lean nondiabetic, eight obese nondiabetic, and eight obese subjects with NIDDM. In additional studies, vastus lateralis muscle was obtained by percutaneous biopsy during basal and insulin stimulated conditions for assay of hexokinase and citrate synthase, and for immunohistochemical labeling of Glut 4. Quantitative confocal laser scanning microscopy was used to ascertain Glut 4 at the sarcolemma as an index of insulin regulated translocation. In lean individuals, insulin stimulated a 10-fold increase of 2-deoxy-2[18F]fluoro-D-glucose (FDG) clearance into muscle and significant increases in the rate constants for inward transport and phosphorylation of FDG. In obese individuals, the rate constant for inward transport of glucose was not increased by insulin infusion and did not differ from values in NIDDM. Insulin stimulation of the rate constant for glucose phosphorylation was similar in obese and lean subjects but reduced in NIDDM. Insulin increased by nearly twofold the number and area of sites labeling for Glut 4 at the sarcolemma in lean volunteers, but in obese and NIDDM subjects translocation of Glut 4 was attenuated. Activities of skeletal muscle HK I and II were similar in lean, obese and NIDDM subjects. These in vivo and ex vivo assessments indicate that impaired glucose transport plays a key role in insulin resistance of NIDDM and obesity and that an additional impairment of glucose phosphorylation is evident in the insulin resistance of NIDDM. PMID- 8675681 TI - Hereditary hepatic and systemic amyloidosis caused by a new deletion/insertion mutation in the apolipoprotein AI gene. AB - We report a Spanish family with autosomal-dominant non-neuropathic hereditary amyloidosis with a unique hepatic presentation and death from liver failure, usually by the sixth decade. The disease is caused by a previously unreported deletion/insertion mutation in exon 4 of the apolipoprotein AI (apoAI) gene encoding loss of residues 60-71 of normal mature apoAI and insertion at that position of two new residues, ValThr. Affected individuals are heterozygous for this mutation and have both normal apoAI and variant molecules bearing one extra positive charge, as predicted from the DNA sequence. The amyloid fibrils are composed exclusively of NH2-terminal fragments of the variant, ending mainly at positions corresponding to residues 83 and 92 in the mature wild-type sequence. Amyloid fibrils derived from the other three known amyloidogenic apoAI variants are also composed of similar NH2-terminal fragments. All known amyloidogenic apoAI variants carry one extra positive charge in this region, suggesting that it may be responsible for their enhanced amyloidogenicity. In addition to causing a new phenotype, this is the first deletion mutation to be described in association with hereditary amyloidosis and it significantly extends the value of the apoAI model for investigation of molecular mechanisms of amyloid fibrillogenesis. PMID- 8675682 TI - Human natural killer cells produce abundant macrophage inflammatory protein-1 alpha in response to monocyte-derived cytokines. AB - Once infected by obligate intracellular pathogens, monocytes/macrophages release cytokines that activate natural killer (NK) cells. NK cells in turn produce and secrete monocyte/macrophage activating factors such as interferongamma (IFN gamma), which are important in the early control of these infections. Here we demonstrate that human NK cells are potent producers of another monocyte/macrophage-activating factor, macrophage inflammatory protein-1 alpha (MIP-1 alpha). Fresh NK cells produce negligible amounts of MIP-1 alpha after stimulation with the monocyte-derived cytokines IL-12, TNF-alpha, IL-1 beta, or IL-10, while stimulation with IL-15 alone results in modest MIP-1 alpha production. Abundant NK cell production MIP-1 alpha is seen after costimulation with IL-12 and IL-15, and is dose-dependent. Combinations of IL-12, with TNF alpha, IL-1 beta, or IL-10 are substantially less effective inducers of MIP-1 alpha production by NK cells. NK cell MIP-1 alpha mRNA transcripts were detectable within 1 h after costimulation with IL-12 plus IL-15 and steadily increased over 24 h, with a concomitant increase in protein production detectable at 12 h. Resting NK cells constitutively express mRNA transcript for a MIP-1 alpha receptor, and costimulation with IL-12 and IL-15 upregulates its level of expression. Equilibrium binding studies with radioiodinated MIP-1 alpha were consistent with the induction of a single class of high affinity MIP-1 alpha receptors on NK cells costimulated with IL-12 and IL-15. Addition of exogenous MIP-1 alpha to resting NK cells did not enhance cytokine production, but did increase NK cytotoxic activity. The requirement for IL-15 as a critical cofactor for NK cell production MIP-1 alpha suggests a potentially unique role for this monocyte-derived cytokine in combination with IL-12. As MIP-1 alpha is known to potentiate the action of IFN-gamma on monocytes and to suppress human immunodeficiency virus replication, the NK cell's production of MIP-1 alpha may be important during the innate immune response to infection. PMID- 8675683 TI - Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat. AB - We asked whether the well known starvation-induced impairment of glucose stimulated insulin secretion (GSIS) seen in isolated rat pancreas preparations also applies in vivo. Accordingly, fed and 18-24-h-fasted rats were subjected to an intravenous glucose challenge followed by a hyperglycemic clamp protocol, during which the plasma-insulin concentration was measured. Surprisingly, the acute (5 min) insulin response was equally robust in the two groups. However, after infusion of the antilipolytic agent, nicotinic acid, to ensure low levels of plasma FFA before the glucose load, GSIS was essentially ablated in fasted rats, but unaffected in fed animals. Maintenance of a high plasma FFA concentration by coadministration of Intralipid plus heparin to nicotinic acid treated rats (fed or fasted), or further elevation of the endogenous FFA level in nonnicotinic acid-treated fasted animals by infusion of etomoxir (to block hepatic fatty acid oxidation), resulted in supranormal GSIS. The in vivo findings were reproduced in studies with the perfused pancreas from fed and fasted rats in which GSIS was examined in the absence and presence of palmitate. The results establish that in the rat, the high circulating concentration of FFA that accompanies food deprivation is a sine qua non for efficient GSIS when a fast is terminated. They also serve to underscore the powerful interaction between glucose and fatty acids in normal beta cell function and raise the possibility that imbalances between the two fuels in vivo could have pathological consequences. PMID- 8675684 TI - Role of lysophosphatidylcholine in the inhibition of endothelial cell motility by oxidized low density lipoprotein. AB - Endothelial cell (EC) movement is required for the development and repair of blood vessels. We have previously shown that LDL oxidized by transition metals almost completely suppressed the wound-healing migratory response of vascular EC in vitro. We now report that lysophosphatidylcholine (lysoPC), a lipid component of oxidized LDL, has an important role in the antimigratory activity of the lipoprotein. Purified 1-palmitoyl lysoPC inhibited movement with a half-maximal activity at 12-15 micrometers, and near complete inhibition at 20 micrometers; the inhibitory concentration of lysoPC was consistent with its abundance in oxidized LDL. The inhibition was not due to cytotoxicity since protein synthesis was unaffected and since EC movement was restored after removal of lysoPC. Lysophospholipid activity was dependent on lipid structure. LysoPC's containing 1 position C16 or C18 saturated fatty acids were antimigratory, but those containing C < or = 14 saturated fatty acids or polyunsaturated fatty acids were not. The activity of 1-palmitoyl lysolipids with various head groups was examined. Lysophosphatidylinositol was more antimigratory than lysophosphatidylglycerol and lysophosphatidylcholine, which were more potent than lysophosphatidylserine and lysophosphatidylethanolamine. Monoglyceride was inactive while lysophosphatidate had promigratory activity. These results are consistent with head group size rather than charge as a critical determinant of activity. To show that lysophospholipids within an intact lipoprotein were active, LDL was treated with bee venom phospholipase A2 (PLA2). The modified lipoprotein inhibited EC movement to the same extent as iron-oxidized LDL and antimigratory activity correlated with the amount of lysoPC formed. To determine antimigratory activity of lysoPC present in oxidized LDL, lipid extracts from oxidized LDL were fractionated by normal phase HPLC. The fraction comigrating with lysoPC had nearly the same activity as the total extract confirming that lysoPC (or a co-eluting lipid) was a major antimigratory molecule in oxidized LDL. These studies demonstrate that lysoPC in oxidized LDL limit EC wound healing responses in vitro, and suggest a possible role for lysolipids in limiting endothelial regeneration after a denuding injury in vivo. PMID- 8675685 TI - Dopamine decreases expression of type-1 angiotensin II receptors in renal proximal tubule. AB - Systemic and/or locally produced angiotensin II stimulates salt and water reabsorption in the renal proximal tubule. In vivo, dopamine (DA) may serve as a counterregulatory hormone to angiotensin II's acute actions on the proximal tubule. We examined whether dopamine modulates AT1 receptor expression in cultured proximal tubule cells (RPTC) expressing DA1 receptors. Dopamine decreased basal RPTC AT1 receptor mRNA levels by 67 +/- 7% (n = 10; P < 0.005) and decreased 125I-angiotensin II binding by 41 +/- 7% (n = 4; P < 0.05). The DA1 specific agonist, SKF38393 decreased basal AT1 receptor mRNA levels (65 +/- 5% inhibition; n = 5; P < 0.025), and the DA1-specific antagonist, SCH23390 reversed dopamine's inhibition of AT1 receptor mRNA expression (24 +/- 10% inhibition; n = 8; NS) and angiotensin II binding (5 +/- 15%; n = 4; NS). DA2-specific antagonists were ineffective. In rats given L-DOPA in the drinking water for 5 d, there were decreases in both proximal tubule AT1 receptor mRNA expression (80 +/- 5%; n = 6; P < 0.005) and specific [125I] Ang II binding (control: 0.74 +/- 0.13 fmol/mg pro vs. 0.40 +/- 0.63 fmol/mg pro; n = 5; P < 0.05). In summary, dopamine, acting through DA1 receptors, decreased AT1 receptor expression in proximal tubule, an effect likely mediated by increased intracellular cAMP levels. Local dopamine production also led to decreased AT1 receptor expression, suggesting dopamine may reset sensitivity of the proximal tubule to angiotensin II. PMID- 8675686 TI - A mouse model of gyrate atrophy of the choroid and retina. Early retinal pigment epithelium damage and progressive retinal degeneration. AB - Gyrate atrophy (GA) of the choroid and retina is a blinding chorioretinal degeneration caused by deficiency of ornithine delta-aminotransferase (OAT). The phenotype of GA is characterized by progressive concentric reduction of the visual fields and ornithine accumulation. To understand better the pathogenesis of GA and to develop a model to test therapeutic strategies, we produced an OAT deficient mouse by gene targeting. Like human GA patients, adult OAT-deficient mice exhibit chronic hyperornithinemia to levels 10-15-fold above normal and massive ornithinuria. Slowly progressive retinal degeneration is reflected by a gradual decline in electroretinogram amplitudes over the first 12 mo of life. At 2 mo, the retinal pigment epithelium is histologically normal, but electron microscopy reveals sporadic degeneration of scattered pigment epithelial cells. By 6 mo there are more diffuse abnormalities of the pigment epithelium with accumulation of large phagosomes and crystalloid inclusions. Although morphologically normal at 2 mo, the photo-receptor outer segments become highly disorganized and shortened to 60% of control length by 10 mo. Additionally, there is cumulative loss of the photoreceptor cells, which reaches 33% by 10 mo and is most pronounced in the central region of the retina. Our results indicate that retinal pigment epithelial cells are the initial site of insult in GA and that the OAT-deficient mouse is an excellent animal model of GA in human patients. PMID- 8675687 TI - Rat renal arcade segment expresses vasopressin-regulated water channel and vasopressin V2 receptor. AB - The arcades are long, branched renal tubules which connect deep and mid-cortical nephrons to cortical collecting ducts in the renal cortex. Because they are inaccessible by standard physiological techniques, their functions are poorly understood. In this paper, we demonstrate that the arcades are a site of expression of two proteins, aquaporin-2 (the vasopressin-regulated water channel) and the V2 vasopressin receptor, that are important to regulated water transport in the kidney. Using a peptide-derived polyclonal antibody to aquaporin-2, quantitative ELISA in microdissected segments showed that aquaporin-2 is highly expressed in arcades and that the expression is increased in response to restriction of fluid intake. Immunocytochemistry revealed abundant aquaporin-2 labeling of structures in the cortical labyrinth in a pattern similar to that of the Na(+)-Ca2+ exchanger and kallikrein, marker proteins expressed in arcades but not in cortical collecting ducts. RT-PCR experiments demonstrated substantial aquaporin-2 and V2 receptor mRNA in microdissected arcades. In situ hybridization, using 35S-labeled antisense cRNA probes for the V2 receptor demonstrated strong labeling of both arcades and cortical collecting ducts. Thus, these results indicate that the arcades contain the specific proteins associated with vasopressin-regulated water transport, and may be a heretofore unrecognized site of free water absorption. PMID- 8675688 TI - Identification and characterization of glima 38, a glycosylated islet cell membrane antigen, which together with GAD65 and IA2 marks the early phases of autoimmune response in type 1 diabetes. AB - Immunoprecipitating IgG autoantibodies to glutamic acid decarboxylase, GAD65, and/or a tyrosine phosphatase, IA2, are present in the majority of individuals experiencing pancreatic beta cell destruction and development of type 1 diabetes. Here we identify a third islet cell autoantigen, a novel 38-kD protein, which is specifically immunoprecipitated with sera from a subset of prediabetic individuals and newly diagnosed type 1 diabetic patients. The 38-kD autoantigen, named glima 38, is an amphiphilic membrane glycoprotein, specifically expressed in islet and neuronal cell lines, and thus shares the neuroendocrine expression patterns of GAD65 and IA2. Removal of N-linked carbohydrates results in a protein of 22,000 Mr. Glima 38 autoantibodies were detected in 16/86 (19%) of newly diagnosed patients, including three very young children, who had a rapid onset of disease, and in 6/44 (14%) of prediabetic individuals up to several years before clinical onset. The cumulative incidence of GAD65 and glima 38 antibodies in these two groups was 83 and 80%, respectively, and the cumulative incidence of GAD65, glima 38, and IA2 antibodies in the same groups was 91 and 84%, respectively. GAD65, IA2, and glima 38 represent three distinct targets of immunoprecipitating IgG autoantibodies associated with beta cell destruction and type 1 diabetes. PMID- 8675689 TI - Platelet-activating factor acetylhydrolase deficiency. A missense mutation near the active site of an anti-inflammatory phospholipase. AB - Deficiency of plasma platelet-activating factor (PAF) acetylhydrolase is an autosomal recessive syndrome that has been associated with severe asthma in Japanese children. Acquired deficiency has been described in several human diseases usually associated with severe inflammation. PAF acetylhydrolase catalyzes the degradation of PAF and related phospholipids, which have proinflammatory, allergic, and prothrombotic properties. Thus, a deficiency in the degradation of these lipids should increase the susceptibility to inflammatory and allergic disorders. Miwa et al. reported that PAF acetylhydrolase activity is absent in 4% of the Japanese population, which suggests that it could be a common factor in such disorders, but the molecular basis of the defect is unknown. We show that inherited deficiency of PAF acetylhydrolase is the result of a point mutation in exon 9 and that this mutation completely abolishes enzymatic activity. This mutation is the cause of the lack of enzymatic activity as expression in E. coli of a construct harboring the mutation results in an inactive protein. This mutation as a heterozygous trait is present in 27% in the Japanese population. This finding will allow rapid identification of subjects predisposed to severe asthma and other PAF-mediated disorders. PMID- 8675690 TI - Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice. AB - The salient feature of solid tumor growth is the strict dependence on local angiogenesis. We have previously demonstrated that IL-8 is an angiogenic factor present in freshly isolated specimens of human non-small cell lung cancer (NSCLC). Using a model of human NSCLC tumorigenesis in SCID mice, we now report that IL-8 acts as a promoter of human NSCLC tumor growth through its angiogenic properties. Passive immunization with neutralizing antibodies to IL-8 resulted in more than 40% reduction in tumor size and was associated with a decline in tumor associated vascular density and angiogenic activity. IL-8 did not act as an autocrine growth factor for NSCLC proliferation. The reduction in primary tumor size in response to neutralizing antibodies to IL-8 was also accompanied by a trend toward a decrease in spontaneous metastasis to the lung. These data support the notion that IL-8 plays a significant role in mediating angiogenic activity during tumorigenesis of human NSCLC, thereby offering a potential target for immunotherapy against solid tumors. PMID- 8675691 TI - Transcription of human herpesvirus-like agent (HHV-8) in Kaposi's sarcoma. AB - Recently, DNA sequences of what appear to be a unique human herpesvirus-like agent (HHV-8) have been detected in different types of Kaposi's sarcoma (KS) tumors (Chang, Y., E.C. Cesarman, M.S. Pessin, F. Lee, J.C. Culpepper, D.M. Knowles, and P.S. Moore. 1994. Science (Wash. DC). 266:1865-1869). To further elucidate the possibility that HHV-8 plays a role in the pathogenesis of KS, the expression of HHV-8 RNA was examined in fresh KS tissue specimens which were found to harbor HHV-8 DNA by polymerase chain reaction (PCR). The transcription of HHV-8 RNA was detected by RT-PCR in 26 of 29 specimens (89.7%) of the KS tumors including 2 of 3 CKS and 24 of 26 AIDS-KS. No positive signal was detected in eight biopsy specimens of normal skin from healthy donors. By Northern blot analysis, the expression of HHV-8 was detected in 2 of 10 KS tumors examined. Furthermore, the RNA transcripts were observed in endothelial cells lining the irregular vascular spaces and perivascular spindle-shaped cells histologically characteristic of KS in 2 out of 8 different KS specimens examined by in situ hybridization using an antisense probe specific of HHV-8. The detection of RNA expression of HHV-8 in KS tumors further supports the possible etiopathogenic role of this virus in the development of KS. PMID- 8675692 TI - Changes in aquaporin-2 protein contribute to the urine concentrating defect in rats fed a low-protein diet. AB - Low-protein diets cause a urinary concentrating defect in rats and humans. Previously, we showed that feeding rats a low (8%) protein diet induces a change in urea transport in initial inner medullary collecting ducts (IMCDs) which could contribute to the concentrating defect. Now, we test whether decreased osmotic water permeability (Pf) contributes to the concentrating defect by measuring Pf in perfused initial and terminal IMCDs from rats fed 18 or 8% protein for 2 wk. In terminal IMCDs, arginine vasopressin (AVP)-stimulated osmotic water permeability was significantly reduced in rats fed 8% protein compared to rats fed 18% protein. In initial IMCDs, AVP-stimulated osmotic water permeability was unaffected by dietary protein. Thus, AVP-stimulated osmotic water permeability is significantly reduced in terminal IMCDs but not in initial IMCDs. Next, we determined if the amount of immunoreactive aquaporin-2 (AQP2, the AVP-regulated water channel) or AQP3 protein was altered. Protein was isolated from base or tip regions of rat inner medulla and Western analysis performed using polyclonal antibodies to rat AQP2 or AQP3 (courtesy of Dr. M.A. Knepper, National Institutes of Health, Bethesda, MD). In rats fed 8% protein (compared to rats fed 18% protein): (a) AQP2 decreases significantly in both membrane and vesicle fractions from the tip; (b) AQP2 is unchanged in the base; and (c) AQP3 is unchanged. Together, the results suggest that the decrease in AVP-stimulated osmotic water permeability results, at least in part, in the decrease in AQP2 protein. We conclude that water reabsorption, like urea reabsorption, responds to dietary protein restriction in a manner that would limit urine concentrating capacity. PMID- 8675693 TI - Hypertension-associated point mutations in the adducin alpha and beta subunits affect actin cytoskeleton and ion transport. AB - The adducin heterodimer is a protein affecting the assembly of the actin-based cytoskeleton. Point mutations in rat adducin alpha (F316Y) and beta (Q529R) subunits are involved in a form of rat primary hypertension (MHS) associated with faster kidney tubular ion transport. A role for adducin in human primary hypertension has also been suggested. By studying the interaction of actin with purified normal and mutated adducin in a cell-free system and the actin assembly in rat kidney epithelial cells (NRK-52E) transfected with mutated rat adducin cDNA, we show that the adducin isoforms differentially modulate: (a) actin assembly both in a cell-free system and within transfected cells; (b) topography of alpha V integrin together with focal contact proteins; and (c) Na-K pump activity at V(max) (faster with the mutated isoforms, 1281 +/- 90 vs 841 +/- 30 nmol K/h.mg pt., P < 0.0001). This co-modulation suggests a role for adducin in the constitutive capacity of the epithelia both to transport ions and to expose adhesion molecules. These findings may also lead to the understanding of the relation between adducin polymorphism and blood pressure and to the development of new approaches to the study of hypertension-associated organ damage. PMID- 8675694 TI - Differential expression in glioblastoma multiforme and cerebral hemangioblastoma of cytoplasmic proteins that bind two different domains within the 3' untranslated region of the human glucose transporter 1 (GLUT1) messenger RNA. AB - The glucose transporter 1 (GLUT1) protein is underexpressed in human glioblastoma multiforme and is overexpressed in human cerebral hemangioblastoma. To gain in sight into possible posttranscriptional mechanisms regulating the expression of the GLUT1 protein in human brain tumors, cytosolic proteins were prepared from these two tumors and used in RNase T1 protection assays that employed [32P]human GLUT1 synthetic RNA prepared from transcription plasmids. Gel shift mobility assays and ultra-violet light cross-linking studies demonstrated the formation of specific RNA/protein complexes that migrated with a mol mass of 120, 44, and 41 kD. RNase T1 mapping and oligodeoxynucleotide competition studies showed that the 120 kD complex was comprised of an RNA fragment that localized to nucleotides 2186-2203 of the GLUT1 mRNA. The 44 kD complex contained an adenosine-uridine rich RNA fragment that localized to nucleotides 1885-1906 of the human GLUT1 mRNA, and the formation of this complex was inhibited by synthetic RNA enriched in adenosine-uridine sequences. The 44 kD complex was selectively downregulated in hemangioblastoma as compared to glioblastoma multiforme. These studies demonstrate that human brain tumors have differential regulation of cytosolic proteins that specifically interact with two different domains in the 3' untranslated region of the GLUT1 mRNA, which may serve to mediate the posttranscriptional regulation of GLUT1 gene expression in these tumors. PMID- 8675695 TI - Paradoxical effects of a synthetic metalloproteinase inhibitor that blocks both p55 and p75 TNF receptor shedding and TNF alpha processing in RA synovial membrane cell cultures. AB - We have previously hypothesized that the pro-inflammatory cytokine TNF alpha has a pivotal role in the pathogenesis of rheumatoid arthritis (RA). It mediates its effects by cross-linking surface p55 TNF receptors (TNF-R), which can be proteolytically cleaved to yield soluble fragments. Upon binding TNF alpha soluble TNF-R (sTNF-R) can inhibit its function. We investigated the enzymatic nature of the proteases involved in TNF-R cleavage, and found that this process is blocked by a synthetic inhibitor of matrix metallo-proteinase activity (MMP), BB-2275. Inhibition of TNF-R cleavage was observed in a number of different cell types, as detected by retention of surface bound TNF receptor and by less sTNF-R released into the cell supernatant. The augmentation of surface TNF-R expression was of biological relevance as TNF alpha-mediated necrosis of human KYM.1D4 rhabdosarcoma cells was enhanced approximately 15-fold in the presence of BB 2275. The addition of BB-2275 to rheumatoid synovial membrane cell cultures totally inhibited MMP activity and also significantly reduced the levels of soluble TNF alpha (P < 0.006), p55 sTNF-R (P < 0.006), and p75 sTNF-R (P < 0.004). Paradoxically, despite the reduction in soluble TNF alpha levels, the production of IL-1 beta, IL-6, and IL-8, cytokines whose production was previously demonstrated to be inhibited by the addition of neutralizing anti-TNF alpha antibody were not down-regulated by BB-2275. These results raise the interesting possibility that a close relationship exits between the enzyme(s) which process membrane-bound TNF alpha, and those involved in surface TNF-R cleavage. Furthermore our observations suggest that hydroxamate inhibitors of MMP activity which block TNF alpha secretion and TNF-R cleavage may not modulate down stream effects of TNA alpha, and as such suggest that the precise specificity of these compounds will be highly relevant to their clinical efficacy in inflammatory diseases. PMID- 8675696 TI - Altered cardiac troponin T in vitro function in the presence of a mutation implicated in familial hypertrophic cardiomyopathy. AB - Familial hypertrophic cardiomyopathy (HCM) can be caused by dominant missense mutations in cardiac troponin T (TnT), alpha-tropomyosin, C-protein, or cardiac myosin heavy chain genes. The myosin mutations are known to impair function, but any functional consequences of the TnT mutations are unknown. This report describes the in vitro function of troponin containing an IIe91Asn mutation in rat cardiac TnT, corresponding to the HCM-causing Ile79Asn mutation in man. Mutant and wild-type TnT cDNAs were expressed in bacteria and the proteins purified and reconstituted with the other troponin subunits, the mutation had no effect on troponin's affinity for tropomyosin, troponin-induced binding of tropomyosin to actin, cooperative binding of myosin subfragment 1 to the thin filament, CA(2+)-sensitive regulation of thin filament-myosin subfragment 1 ATPase activity, or the CA2+ concentration dependence of this regulation. However, the mutation resulted in 50% faster thin filament movement over a surface coated with heavy meromyosin in in vitro motility assays. The increased sliding speed suggests an unexpected role for the amino terminal region of TnT in which this mutation occurs. The relationship between this faster motility and altered cardiac contraction in patients with HCM is discussed. PMID- 8675697 TI - Immunization with T cell receptor V beta chain peptides deletes pathogenic T cells and prevents the induction of collagen-induced arthritis in mice. AB - Collagen-induced arthritis (CIA) in susceptible strains of mice is an animal model of T cell-mediated inflammatory polyarthritis. Analysis of T cell receptor (TCR) V beta gene usage in cells isolated from arthritic joints of BUB/BnJ (BUB) mice (H-2q, TCR V beta a) showed that TCR V beta chain gene usage was limited to TCR V beta 3 and V beta 10 gene families. All of the BUB mice immunized with a mixture of TCR V beta 3 and TCR V beta 10 peptides, but not with control TCR V beta 14 peptide, were refractory to the induction of CIA. Immunization with TCR V beta 3 and V beta 10 peptides completely blocked the development of clinical and subclinical inflammation, formation of pannus and synovial hyperplasia, and the erosion of cartilage and bone. Further studies revealed that preimmunization of BUB mice with V beta 10 peptide alone was sufficient to render the mice resistant to CIA. Analysis of TCR V beta chain gene expression in lymph node cells from arthritic and arthritis-protected mice showed the expression of TCR V beta 10 subfamily in all of the arthritic mice, but not in arthritis-protected mice. Immunization with TCR V beta peptides did not diminish the humoral responses to chicken type-II collagen and also elicited significant levels of anti-V beta 3 and anti-V beta 10 peptide antibodies. Antibodies cross-reactive with mouse chicken type-II collagen were detected in both the arthritic and arthritis protected mice. Adoptive transfer of serum from arthritis-protected BUB mice significantly delayed the onset (P < 0.005) of arthritis in recipient BUB mice. In contrast, mice injected with serum from arthritic mice had early onset of arthritis. These results demonstrate that immunization of BUB mice with TCR V beta chain peptides elicited antibodies reactive with the self-TCR and prevented the induction of collagen-induced arthritis by eliminating or downregulating pathogenic T cells and consequently blocking the development of humoral immune response. These findings may have clinical applications in treating human autoimmune diseases characterized by common TCR gene usage. PMID- 8675698 TI - Mechanism of free fatty acid-induced insulin resistance in humans. AB - To examine the mechanism by which lipids cause insulin resistance in humans, skeletal muscle glycogen and glucose-6-phosphate concentrations were measured every 15 min by simultaneous 13C and 31P nuclear magnetic resonance spectroscopy in nine healthy subjects in the presence of low (0.18 +/- 0.02 mM [mean +/- SEM]; control) or high (1.93 +/- 0.04 mM; lipid infusion) plasma free fatty acid levels under euglycemic (approximately 5.2 mM) hyperinsulinemic (approximately 400 pM) clamp conditions for 6 h. During the initial 3.5 h of the clamp the rate of whole body glucose uptake was not affected by lipid infusion, but it then decreased continuously to be approximately 46% of control values after 6 h (P < 0.00001). Augmented lipid oxidation was accompanied by a approximately 40% reduction of oxidative glucose metabolism starting during the third hour of lipid infusion (P < 0.05). Rates of muscle glycogen synthesis were similar during the first 3 h of lipid and control infusion, but thereafter decreased to approximately 50% of control values (4.0 +/- 1.0 vs. 9.3 +/- 1.6 mumol/[kg.min], P < 0.05). Reduction of muscle glycogen synthesis by elevated plasma free fatty acids was preceded by a fall of muscle glucose-6-phosphate concentrations starting at approximately 1.5 h (195 +/- 25 vs. control: 237 +/- 26 mM; P < 0.01). Therefore in contrast to the originally postulated mechanism in which free fatty acids were thought to inhibit insulin-stimulated glucose uptake in muscle through initial inhibition of pyruvate dehydrogenase these results demonstrate that free fatty acids induce insulin resistance in humans by initial inhibition of glucose transport/phosphorylation which is then followed by an approximately 50% reduction in both the rate of muscle glycogen synthesis and glucose oxidation. PMID- 8675699 TI - Mechanisms of drug-induced lupus. II. T cells overexpressing lymphocyte function associated antigen 1 become autoreactive and cause a lupuslike disease in syngeneic mice. AB - Current theories propose that systemic lupus erythematosus develops when genetically predisposed individuals are exposed to certain environmental agents, although how these agents trigger lupus is uncertain. Some of these agents, such as procainamide, hydralazine, and UV-light inhibit T cell DNA methylation, increase lymphocyte function-associated antigen 1 (LFA-1) (CD11a/CD18) expression, and induce autoreactivity in vitro, and adoptive transfer of T cells that are made autoreactive by this mechanism causes a lupuslike disease. The mechanism by which these cells cause autoimmunity is unknown. In this report, we present evidence that LFA-1 overexpression is sufficient to induce autoimmunity. LFA-1 overexpression was induced on cloned murine Th2 cells by transfection, resulting in autoreactivity. Adoptive transfer of the transfected, autoreactive cells into syngeneic recipients caused a lupuslike disease with anti-DNA antibodies, an immune complex glomerulonephritis and pulmonary alveolitis, similar to that caused by cells treated with procainamide. These results indicate that agents or events which modify T cell DNA methylation may induce autoimmunity by causing T cell LFA-1 overexpression. Since T cells from patients with active lupus have hypomethylated DNA and overexpressed LFA-1, this mechanism could be important in the development of human autoimmunity. PMID- 8675700 TI - Transgenic expression of tpr-met oncogene leads to development of mammary hyperplasia and tumors. AB - Receptor tyrosine kinases are important in cell signal transduction and proliferation. Abnormal expression of tyrosine kinases often leads to malignant transformation. C-met is a tyrosine kinase receptor and its ligand is hepatocyte growth factor (HGF). HGF/c-met plays diverse role in regulation of cell growth, shape and movement. Constitutively activated met, such as tpr-met, is a potent oncogene in vitro, but its carcinogenic role in vivo remains unclear. Our study demonstrates that expression of tpr-met leads to development of mammary tumors and other malignancies in transgenic mice, and suggests that deregulated met expression may be involved in mammary carcinogenesis. PMID- 8675701 TI - Endogenous production of angiotensin II modulates rat proximal tubule transport. AB - There is evidence that angiotensin II is synthesized by the proximal tubule and secreted into the tubular lumen. This study examined the functional significance of endogenously produced angiotensin II on proximal tubule transport in male Sprague-Dawley rats. Addition of 10(-11), 10(-8), and 10(-6) M angiotensin II to the lumen of proximal convoluted tubules perfused in vivo had no effect on the rate of fluid reabsorption. The absence of an effect of exogenous luminal angiotensin II could be due to its endogenous production and luminal secretion. Luminal 10(-8) M Dup 753 (an angiotensin II receptor antagonist) resulted in a 35% decrease in proximal tubule fluid reabsorption when compared to control (Jv = 1.64 +/- 0.12 nl/mm.min vs. 2.55 +/- 0.32 nl/mm.min, P < 0.05). Similarly, luminal 10(-4) M enalaprilat, an angiotensin converting enzyme inhibitor, decreased fluid reabsorption by 40% (Jv = 1.53 +/- 0.23 nl/mm.min vs. 2.55 +/- 0.32 nl/mm.min, P < 0.05). When 10(-11) or 10(-8) M exogenous angiotensin II was added to enalaprilat (10(-4) M) in the luminal perfusate, fluid reabsorption returned to its baseline rate (Jv = 2.78 +/- 0.35 nl/mm.min). Thus, addition of exogenous angiotensin II stimulates proximal tubule transport when endogenous production is inhibited. These experiments show that endogenously produced angiotensin II modulates fluid transport in the proximal tubule independent of systemic angiotensin II. PMID- 8675702 TI - Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. AB - To reconstruct the mechanisms for the vasoobliteration that transforms diabetic retinopathy into an ischemic retinopathy, we compared the occurrence of cell death in situ in retinal microvessels of diabetic and nondiabetic individuals. Trypsin digests and sections prepared from the retinas of seven patients (age 67 +/- 7 yr) with .9 +/- 4 yr of diabetes and eight age- and sex-matched nondiabetic controls were studied with the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) reaction which detects preferentially apoptotic DNA fragmentation. The count of total TUNEL+ nuclei was significantly greater in the microvessels of diabetic (13 +/- 12 per one-sixth of retina) than control subjects (1.3 +/- 1.4, P = 0.0016), as were the counts of TUNEL+ pericytes and endothelial cells (P < 0.006). The neural retinas from both diabetic and nondiabetic subjects were uniformly TUNEL-. Retinal microvessels of rats with short duration of experimental diabetes or galactosemia and absent or minimal morphological changes of retinopathy, showed TUNEL+ pericytes and endothelial cells, which were absent in control rats. These findings indicate that (a) diabetes and galactosemia lead to accelerated death in situ of both retinal pericytes and endothelial cells; (b) the event is specific for vascular cells; (c) it precedes histological evidence of retinopathy; and (d) it can be induced by isolated hyperhexosemia. A cycle of accelerated death and renewal of endothelial cells may contribute to vascular architectural changes and, upon exhaustion of replicative life span, to capillary obliteration. PMID- 8675703 TI - Apoptosis in pressure overload-induced heart hypertrophy in the rat. AB - Pressure overload induces cardiac growth in the rat, which implies the hypertrophy of cardiac muscle cells and proliferation of nonmuscle cells. The cardiac cell loss observed in parallel has generally been attributed to necrosis. Using an in situ assay, we demonstrated a phase of apoptosis or programmed cell death during the first 7 d after pressure overload with a peak at day 4 while cardiac growth continued for over 30 d. The increase in apoptosis was confirmed by quantification of 180-1500-bp DNA oligonucleosomes with agarose gel electrophoresis and in situ labeling via 3'-terminal deoxynucleotidyl transferase assay. While some apoptosis was observed in the basal state in nonmuscle cells, pressure overload induced apoptosis mainly in cardiomyocytes. These data suggest that cardiac hypertrophy is initiated by a wave of apoptosis of cardiomyocytes. Thus, apoptosis may be involved in the pathogenesis of heart remodeling. PMID- 8675704 TI - Expression of uncoupling protein in skeletal muscle and white fat of obese mice treated with thermogenic beta 3-adrenergic agonist. AB - The mitochondrial uncoupling protein (UCP) is usually expressed only in brown adipose tissue (BAT) and a key molecule for metabolic thermogenesis. The effects of a highly selective beta 3-adrenergic agonist, CL316,243 (CL), on UCP expression in skeletal muscle and adipose tissues were examined in mice. Daily injection of CL (0.1 mg/kg, sc) to obese yellow KK mice for two weeks caused a significant reduction of body weight, associated with a marked decrease of white fat pad weight and hypertrophy of the interscapular BAT with a sixfold increase in UCP content. Clear signals of UCP protein and mRNA were detected by Western and Northern blot analyses in inguinal, mesenteric and retroperitoneal white fat pads, and also in gastrocnemius and quadriceps muscles, whereas no signal in saline-treated mice. The presence of UCP mRNA in muscle tissues was also confirmed by reverse transcription-PCR analysis. Weaker UCP signals were also detected in control C57BL mice treated with CL, but only in inguinal and retroperitoneal fat pads. Immunohistochemical examinations revealed that UCP stains in the white fat pads were localized on multilocular cells quite similar to typical brown adipocyte, and those in the muscle tissues on myocytes. The mitochondrial localization of UCP in myocytes was confirmed by immunoelectron microscopy. In addition to UCP protein, UCP mRNA was also detected in myocytes by in situ hybridization analysis. Thus, chronic stimulation of the beta 3 adrenergic receptor induces ectopic expression of UCP in adipose tissues conventionally considered as white fat and even in skeletal muscle, which probably contributes to the potent anti-obesity effect of the beta 3-adrenergic agonist. PMID- 8675705 TI - Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis. AB - Polymyositis (PM) and dermatomyositis (DM) are the prototypical inflammatory diseases of skeletal muscle. In PM, CD8+ T cells invade and destroy muscle fibers, whereas humoral effector mechanisms prevail in DM. We studied the expression of the cytotoxic mediator perforin in inflammatory cells in PM and DM muscle by semiquantitative PCR, immunohistochemistry and confocal laser microscopy. Similar levels of perforin mRNA were expressed in PM and DM, and abundant perforin-expressing CD3+CD8+ and CD3+ CD4+ T cells were observed in both diseases. However, there was a striking difference in the intracellular localization of perforin. In DM, perforin was distributed randomly in the cytoplasm of the inflammatory T cells. In contrast, 43% of the CD8+ T cells that contacted a muscle fiber in PM showed perforin located vectorially towards the target muscle fiber. The results suggest (a) that the random distribution of perforin in the cytoplasm of muscle-infiltrating T cells observed in DM reflects nonspecific activation, and (b) that the vectorial orientation observed only in PM reflects the specific recognition via the T cell receptor of an antigen on the muscle fiber surface, pointing to a perforin- and secretion-dependent mechanism of muscle fiber injury. PMID- 8675706 TI - Expression of naked DNA in human, pig, and mouse skin. AB - The insertion and expression of genes in the epidermis may have a variety of therapeutic uses, including the treatment of skin diseases. Here we show that when both human skin organ cultures and human skin grafts on immunocompromised mice are injected with naked DNA, the DNA is taken-up and genes are expressed in the epidermis in a manner similar to both pig skin injected in vivo and injected pig skin organ cultures. In contrast, DNA injected into mouse skin is expressed not just in the epidermis, but also in the dermis and underlying fat and muscle tissue, and is expressed at lower levels. These findings suggest that genes can be expressed in human skin, after injection of naked DNA, and indicate that pig skin is an appropriate model for the study of DNA uptake and gene expression in human skin. The organ cultures of human and pig skin may be useful in understanding how naked DNA is internalized and expressed after in vivo injections. Additionally, skin obtained from patients with skin disease may be studied as skin grafts and organ cultures to help optimize genetic approaches for the treatment of skin diseases prior to clinical trials, by determining if the injected gene can provide a therapeutic benefit. PMID- 8675708 TI - Maternal discipline of young children: context, belief, and practice. AB - This report describes maternal discipline of infants and toddlers, focusing on how the context of the misbehavior affects maternal beliefs and practices. Mothers of 1- to 4-year-old children were interviewed using a 20-minute, structured questionnaire at two practice sites: (1) an inner-city teaching hospital pediatric clinic (n = 104) and (2) a private pediatrician's office in a nearby suburban neighborhood (n = 100). Measures were constructed to assess beliefs and practices about three kinds of discipline (teaching, spanking, and removing) and about two approaches to discipline (positive or negative). We found that mothers believe significantly (p < .001) more strongly in all three kinds of discipline for dangerous misbehavior compared with annoying ones. Belief in teaching, spanking, and negative approach increase with age; belief in removing decreases (p < .001); and belief in positive approach remains stable. Belief in spanking starts earlier than belief in teaching, and belief in negative tone increases with age. Mothers seem to have better formulated beliefs about spanking and negative and positive approach to discipline than about teaching or removing. Eighty-five percent believe time-out is at times appropriate for 2 year old, but only 67% had practiced it in the past week. Belief and practice of time-out varied by the age of the child and practice site. Explaining, distracting, and praising were practiced frequently, whereas bribing was less common. Less than half (44%) reported that they had ever discussed discipline with their child's physician, although 85% thought that their physician could give good advice. There is evidence that mothers change their minds about the appropriateness of time-out as their child gets older, but beliefs about other kinds of discipline remain relatively constant. We conclude that the type of misbehavior and the age of the child affect a mother's beliefs about discipline. These findings suggest a role for pediatricians in exploring and broadening parents' concepts of discipline. PMID- 8675709 TI - Differential diagnosis of chronic fatigue in children: behavioral and emotional dimensions. AB - A battery of self-report questionnaires and structured diagnostic interviews was administered to 20 children and adolescents who presented to a pediatric specialty clinic with chronic fatigue. Matched groups of healthy and depressed control subjects (aged 8 to 19 years) were also studied. Criteria were established to identify those items in the assessment battery that reliably differentiated among the three groups. Analysis of item content suggested several clusters of characteristics that discriminated among the subject groups, including life changes, cognitive difficulties, negative self-attributions, social relationship disruption, and somatic symptom presentation. The results suggest that certain psychological factors can discriminate chronic fatigue from depressive symptomatology, as well as normal functioning. Items discriminating among groups are presented in an organized questionnaire format to assist with the understanding and assessment of pediatric chronic fatigue cases. PMID- 8675707 TI - Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. AB - Plasma high density lipoprotein (HDL) levels are strongly genetically determined and show a general inverse relationship with coronary heart disease (CHD). The cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to other lipoproteins and is a key participant in the reverse transport of cholesterol from the periphery to the liver. A high prevalence of two different CETP gene mutations (D442G, 5.1%; intron 14G:A, 0.5%), was found in 3,469 men of Japanese ancestry in the Honolulu Heart Program and mutations were associated with decreased CETP (-35%) and increased HDL chol levels (+10% for D442G). However, the overall prevalence of definite CHD was 21% in men with mutations and 16% in men without mutations. The relative risk (RR) of CHD was 1.43 in men with mutations (P < .05); after adjustment for CHD risk factors, the RR was 1.55 (P = .02); after additional adjustment for HDL levels, the RR was 1.68 (P = .008). Similar RR values were obtained for the D442G mutation alone. Increased CHD in men with mutations was primarily observed for HDL chol 41-60 mg/dl; for HDL chol > 60 mg/dl men with and without mutations had low CHD prevalence. Thus, genetic CETP deficiency appears to be an independent risk factor for CHD, primarily due to increased CHD prevalence in men with the D442G mutation and HDL cholesterol between 41 and 60 mg/dl. The findings suggest that both HDL concentration and the dynamics of cholesterol transport through HDL (i.e., reverse cholesterol transport) determine the anti-atherogenicity of the HDL fraction. PMID- 8675710 TI - Is there an association between season of birth and reading disability? AB - Reported associations between season of birth and reading failure suggest medical causation and prevention. The relationship between season of birth and two measures of reading outcome in two cohorts of children (n1 = 2411 and n2 = 1972) was studied using chi2 tests. None was significant. Logistic regression was used to investigate the joint associations of gender, age at school entrance, and season of birth with reading outcome. A significant interaction between reading failure and age category (overage at school entrance vs correct age) by season of birth was observed. It was shown that this significant interaction was probably caused by kindergarten entrance cutoff birth dates. Although 67.8% of all overage children had summer births, only 15.3% failed in reading, which is not statistically different from the percentage of summer-born, correct-age low readers (13.6%). Results suggest that reported associations may be attributed to selective samples rather than the total population of school children who experience reading failure. PMID- 8675711 TI - Otitis media, communication style of primary caregivers, and language skills of 2 year olds: a preliminary report. AB - The association between early otitis media, styles of primary caregivers, and language development was prospectively examined in 26 2-year-old children from lower socioeconomic backgrounds (of mixed perinatal status) followed prospectively since birth. Based on otoscopic evaluations during the first year of life, there were 14 children who were classified as bilaterally otitis-free (OM-) and 12 children who were classified as bilaterally otitis-positive (OM+). At 2 years of age, all children were administered standardized measures of cognitive and language function along with a 20-minute videotaped play session with one of their primary caregivers. The language of both the children and caregivers was analyzed. Results indicate that caregivers of OM+ and OM- children used language nearly identically when interacting with their children. However, caregivers of OM+ children whose communication style was marked by a high percentage of directives and a corresponding low percentage of both questions and information-giving had the children with the lowest scores on all measures of naturalistic language. Controlling for neonatal illness did not alter the relationships found. The results suggest that caregiver language may compensate for some of the auditory deprivations associated with otitis media. PMID- 8675712 TI - To be or not to be ... noncategorical. PMID- 8675713 TI - Beyond infant colic. AB - Some of the most interesting cases in pediatric practice evolve through time. What may begin as a clear, well defined problem with a predictable natural history and an accepted intervention strategy may develop into a more complex, multi-faceted set of problems. It is these children who potentially provide clinicians with new insights into behaviors. This case of a colicky infant illustrates the wide spectrum of behavioral and physiological symptoms that emerge from a specific underlying behavioral phenomenon. It also emphasizes the significant benefit derived from a longitudinal perspective of developmental events. PMID- 8675714 TI - Family and parental functioning in cystic fibrosis. AB - This article reviews 31 recent articles that describe the functioning of families and/or parents of children with cystic fibrosis (CF), compares them to families of healthy children, pinpoints factors that predict quality of adjustment, or evaluates interventions designed to improve functioning. Commonly cited concerns included the difficulty of the treatment regimen, the terminal nature of CF, and the disruption of intrafamilial relationships. Parents of children with CF experienced greater stress and burdens than parents of healthy children, yet parenting behavior and family functioning were quite similar in CF and healthy control groups. Higher levels of distress, an avoidant coping style, and low levels of family support were associated with poor psychological adjustment. Recommendations for future research include: using multiple informants; using detailed, illness-specific measures and conceptual frameworks; and conducting studies of individual variation and interventions. Practitioners might consider performing periodic updates of how the family is managing as a whole. PMID- 8675715 TI - Cosleeping and early childhood sleep problems: effects of ethnicity and socioeconomic status. AB - This study examined ethnic differences in the relationship between cosleeping and sleep problems in the United States, taking socioeconomic status (SES) into consideration. The sample consisted of 186 urban families with a healthy 6- to- 48-month-old child and was grouped as follows: white lower SES (n = 40), white higher SES (n = 54), black lower SES (n = 43), and black higher SES (n = 47). Regular cosleeping was associated with increased night waking and/or bedtime protests among lower SES white children and higher SES black children. Among families who coslept, white parents were more likely than black parents to consider their child's sleep behavior to be a problem, i.e., stressful, conflictual, or upsetting as well as regularly occurring. One explanation is that differing childrearing attitudes and expectations influenced how parents interpreted their children's sleep behavior. PMID- 8675716 TI - The empirical status of the clinical application of eye movement desensitization and reprocessing. AB - The published reports of the clinical application of eye movement desensitization and reprocessing (EMDR) are reviewed in terms of empirical validity. Case studies, single-subject experiments and group design experiments on clinical problems are evaluated for the effectiveness of the protocol, component effects, comparative effects and treatment fidelity. Classification of disorders and measurement issues are addressed. The protocol frequently reduces verbal report and independent observer ratings of distress--strikingly in some instances. Psychophysiologic measures show little effect of treatment. There is little empirical evidence to indicate the effect of treatment on motoric or behavioral indices. Eye movements do not appear to be an essential component of treatment, and there have been no substantial comparisons with other treatments. No studies have adequately controlled for nonspecific (placebo) effects of treatment. Suggestions are made for applying improved methodological controls for future applications of EMDR to clinical disorders. PMID- 8675717 TI - Synthesizing animal and human behavior research via neural network learning theory. AB - Animal and human research have been "divorced" since approximately 1968. Several recent articles have tried to persuade behavior therapists of the merits of animal research. Three reasons are given concerning why disinterest in animal research is so widespread: (1) functional explanations are given for animals, and cognitive explanations are given for humans; (2) serial symbol manipulating models are used to explain human behavior; and (3) human learning was assumed, thereby removing it as something to be explained. Brain-inspired connectionist neural networks, collectively referred to as neural network learning theory (NNLT), are briefly described, and a spectrum of their accomplishments from simple conditioning through speech is outlined. Five benefits that behavior therapists can derive from NNLT are described. They include (a) enhanced professional identity derived from a comprehensive learning theory, (b) improved interdisciplinary collaboration both clinically and scientifically, (c) renewed perceived relevance of animal research, (d) access to plausible proximal causal mechanisms capable of explaining operant conditioning, and (e) an inherently developmental perspective. PMID- 8675718 TI - Cognitive mediators of situational fear in agoraphobia. AB - The aim of this study was to examine cognitive mediators of situational fear in agoraphobia. Patients suffering from panic disorder with moderate or severe agoraphobia were randomly assigned to receive either cognitive therapy or guided mastery therapy in a 6-week inpatient group program. The results were consistent with a self-efficacy model of agoraphobia. Across test occasions, and when the other cognitive variables were controlled for, self-efficacy made a significant contribution to the prediction of situational fear or changes in situational fear in 5 out of 5 cases. Catastrophic beliefs were related to situational fear in 1 of the 5 cases. PMID- 8675719 TI - Eye movement desensitization of public-speaking anxiety: a partial dismantling. AB - Forty college students suffering from public speaking anxiety and having experienced a specific traumatic speech-related event were exposed to either a standard EMD protocol with eye movements; a moving audio stimulus in place of the eye movements; a protocol with eyes resting on the hands in place of the eye movement, or a no-treatment control condition. The results revealed that EMD is comparable in limited effectiveness to the other procedures and that the eye movements are not a crucial component of the treatment with this population. PMID- 8675720 TI - Eye movement desensitization and reprocessing in the treatment of test anxiety: a study of the effects of expectancy and eye movement. AB - Eye Movement Desensitization and Reprocessing (EMDR) is a recently invented technique acclaimed as a major breakthrough for a range of anxiety-related symptoms. To determine the importance of the eye movement and expectancy variables, we conducted a one-hour session with 41 undergraduate subjects (11 males and 30 females) with test anxiety. A 2 (eye movement vs no eye movement) x 2 (high expectancy vs low expectancy) analysis of variance was performed on three dependent measures: (1) Subjective Units of Disturbance Scale (SUDs). (Wolpe, The Practice of Behavior Therapy, 1982); (2) Validity of Cognition Scale (VOC) (Shapiro, 1992); and (3) the Test Anxiety Inventory (TAI) (Spielberger, TestAnxiety Inventory Preliminary Professional Manual, 1977). The data indicate that all subjects, regardless of treatment condition, showed a significant decrease in anxiety on the TAI. Subjects in the eye-movement condition reported feeling less anxious (SUDs) than those in the no-eye-movement condition. We found no significant main effect or interactions for any of the dependent measures for expectancy. PMID- 8675721 TI - Association between stereotypic behavior and polydipsia in chronic schizophrenic patients. AB - We assessed temporal associations between polydipsia and motor stereotypies in chronic schizophrenia. Subjects included: (a) a polydipsic patient with marked stereotypies; (b) a polydipsic patient with no history of stereotypy; (c) a nonpolydipsic patient. Stereotyped grooming and pacing were significantly associated with drinking for polydipsic patients only (polydipsic patients evidenced a 87% and 66% concordance between excessive grooming and drinking versus 12% in the control). Our findings provide the first empirical demonstration that polydipsia is temporally associated with other repetitive behaviors. The use of behavioral assessment to examine etiological theories suggesting that polydipsia stems from interacting environmental, biological, and pharmacological variables is discussed. PMID- 8675722 TI - A self-report diagnostic measure of generalized anxiety disorder. AB - The present study tested the reliability of a self-report diagnostic measure of generalized anxiety disorder (GAD) based on DSM criteria. Among two samples of undergraduate students, 47-80% of the GAD diagnoses by questionnaire were confirmed by diagnostic interview, with the higher rate being associated with DSM IV criteria. Categorization of a participant as Non-GAD by questionnaire was found to be 100% reliable by interview. Given these findings as well as prior empirical support for the validity of the measure, this questionnaire has utility for identifying analogue GAD and Non-GAD participants from undergraduate populations for use in preliminary investigations of the mechanisms and functions associated with chronic worry and GAD. PMID- 8675723 TI - Inaccuracies in the estimation of functional relationships using self-monitoring data. AB - When evaluating self-monitoring data, most behavior therapists form subjective estimates of the magnitude of the functional relationships between controlling factors and target behaviors. These estimates are, however, subject to correlation misestimation. In this study, upper-level clinical psychology graduate students were asked to estimate the magnitude of correlations between a set of controlling variables and target behaviors for a hypothetical client. The findings suggested that intuitive correlation estimates among controlling factors and target behaviors are generally inaccurate. PMID- 8675724 TI - Exposure therapy in the treatment of vaginal penetration phobia: a single-case evaluation. AB - A 25-year-old woman with a specific phobia related to vaginal penetration fears was effectively treated with graduated exposure therapy involving self-conducted and partner-assisted homework exercises. Treatment produced a complete resolution of the problem within 12 sessions. This behavior therapy regimen followed the client having received several periods of psychodynamic therapy which did not yield symptomatic improvement. PMID- 8675725 TI - The relevance of the anxiety literature to research on eye movement desensitization. PMID- 8675726 TI - Near patient testing: is it here to stay? PMID- 8675727 TI - How to develop and use a Bayesian Belief Network. PMID- 8675728 TI - Do histopathology reports of primary cutaneous melanoma contain enough essential information? AB - AIMS: To audit the content of primary cutaneous malignant melanoma histopathology reports with special reference to Breslow thickness and lateral excision margins. METHODS: The Trent Regional Cancer Registry was asked to provide details of primary cutaneous malignant melanomas for the most recent year available (1990). Histopathology departments were then requested to provide copies of the relevant reports, which were then analysed. RESULTS: In total, 178 reports were obtained from 16 departments. Breslow thickness was present in 87.1% (155/178) and a comment had been made on lateral excision in 85.4% (152/178). A specific clearance measurement was recorded in 5.6% (10/178), and in 9.6% (17/178) tumour was stated to extend to the margin. In 4.5% (8/178) neither thickness nor a comment on excision was recorded. Clinical advice on excision was offered in 12.4% (22/178). A macroscopic description was absent in 6.7% (12/178). CONCLUSIONS: Deficiencies were identified in the quality of malignant melanoma histopathology reports in Trent Region. There is no reason to believe that significant improvements have occurred since 1990 or that other regions are performing differently. A national standard for reporting primary cutaneous malignant melanoma is recommended. As a minimum, all reports should include Breslow thickness and a specific measurement of lateral clearance. This will facilitate prognostic evaluation, clinical management and audit. This standard would not exclude the reporting of other information, depending on local policy. As with all standards, continual review must be undertaken and consideration given as to whether other more recent parameters, such as growth phase, also warrant future inclusion. PMID- 8675729 TI - VS38 immunostaining in melanocytic lesions. AB - AIMS: To investigate the immunoreactivity of a range of melanocytic lesions, both benign and malignant, with the monoclonal antibody VS38. This was recently described as a marker of reactive/neoplastic plasma cells and, therefore, is useful in the diagnosis of plasmacytoma/myeloma and lymphomas with plasmacytic differentiation. This study was prompted by the recent observation that a plasmacytoid melanoma arising in the nasal cavity was strongly immunoreactive with VS38, which was therefore a potential source of major diagnostic error. METHODS: The Streptavidin-peroxidase complex technique was used on paraffin wax embedded sections of 167 melanocytic lesions. Diaminobenzidine (DAB) was used as chromogen for non-pigmented or lightly pigmented lesions and nickel/DAB for more heavily pigmented lesions. RESULTS: Positive immunostaining for VS38 was seen in 14.5% (10/69) of benign naevi (including 40% (four of 10) of Spitz naevi), 10.5% (two of 19) of dysplastic naevi/in situ melanomas, 92% (35/38) of primary cutaneous melanomas, 100% (four of four) of primary mucosal melanomas, 91.7% (33/36) of recurrent/metastatic melanomas, and 100% (one of one) of clear cell sarcomas of soft tissues. CONCLUSIONS: VS38 immunostaining is frequently positive in primary and recurrent/metastatic malignant melanoma and is also reactive less commonly with benign naevi. These results should be borne in mind when this recently described marker of normal/neoplastic plasma cells is used to identify tumour lineage, particularly in tumours arising at unusual sites, such as in the nasal cavity. The possibility of malignant melanoma should be actively considered and excluded in any undifferentiated tumour which shows VS38 immunoreactivity. PMID- 8675730 TI - Association between sarcoidosis and lymphoma revisited. AB - AIMS: To investigate the relation between sarcoidosis and lymphoma. METHODS: The hospital notes of five patients with sarcoidosis and a lymphoproliferative disorder were reviewed. Histological material on which the diagnoses of sarcoidosis and lymphoma were made was re-analysed. RESULTS: Four of the five patients had well documented sarcoidosis preceding the development of lymphoma by 18 months to 28 years; the fifth patient had lymphoplasmacytic lymphoma with a reactive granuloma reaction. Two patients had chronic sarcoidosis and three were treated with prednisolone. The types of lymphoma were: Hodgkin's disease (n = 1), B cell lymphoma (n = 2) (mantle cell and lymphoplasmacytic/local plasmacytoma) and large granular lymphocyte leukaemia (T cell) (n = 1). CONCLUSIONS: The association between sarcoidosis and lymphoma is confirmed, suggesting that sarcoidosis may be a predisposing factor for the development of a lymphoid malignancy due to disturbance of the immune system. All types of lymphoma may develop. The first case of T cell granular lymphocytic leukaemia in a patient with sarcoidosis has been documented. PMID- 8675732 TI - Funeral directors, mortuaries and necropsies: implications for necropsy consent rates and the prevention of infection. AB - AIM: To evaluate the attitudes and experiences of funeral directors in relation to necropsies. METHODS: All 1631 members of the National Association of Funeral Directors were surveyed by postal questionnaire about the purposes of necropsies, the technical and administrative problems associated with necropsied cases and their relations with relatives, mortuaries and pathology departments. RESULTS: In total, 123 funeral directors completed the questionnaire (8% response rate). Workload, proportion of cases necropsied and type of mortuary did not influence answers. Necropsies were considered important for the assessment of treatment outcome, identification of inherited disease and junior pathologist training, but not for medical audit. There was strong support for more education about necropsies. The areas of necropsy practice most frequently discussed with relatives related to concerns about funeral delay and the involvement of the coroner or equivalent authority. Funeral directors occasionally counselled relatives for or against giving necropsy consent. The commonest technical problems associated with necropsies were difficulties in embalming, leakage of body fluids and scalpel penetration in visible areas. Few administrative problems were reported; the commonest was inflexibility in body collection times. There was strong support for a national code of practice to cover relations between funeral directors and mortuaries despite general satisfaction with relations with local pathology departments. CONCLUSIONS: Although the relation among the funeral profession, mortuaries and pathology departments is largely satisfactory, a national code of practice for funeral directors and mortuaries is desirable. PMID- 8675733 TI - Germ cell tumour as a diagnostic pitfall of metastatic carcinoma. AB - AIM: Testicular germ cell tumours may present as metastases in cervical lymph nodes, yet the primary tumours remain clinically occult. The aim of the study is to alert pathologists and clinicians to this uncommon but important presentation and highlight the clues and the diagnostic adjuncts to its correct diagnosis. METHODS: The clinical, cytological, histological, and immunohistochemical features of two patients with germ cell tumour initially presenting as cervical lymphadenopathy were described and analysed. RESULTS: Both patients were young adult males, who were found to have metastatic undifferentiated carcinoma on fine needle aspiration of the enlarged cervical lymph nodes. The tumour cells in both cases were positive for placental alkaline phosphatase (PLAP) and negative for epithelial membrane antigen (EMA). CONCLUSIONS: Clinicians and pathologists should be aware of the possibility of germ cell tumour when encountering a young adult male with metastatic poorly differentiated carcinoma. Positivity for PLAP and negativity for EMA are helpful adjuncts in arriving at the correct diagnosis. PMID- 8675731 TI - Information on death certificates: cause for concern? AB - AIMS: To assess the frequency with which the cause of death on death certificates included the relevant details requested of certifying doctors, especially in deaths due to malignant disease, but also including certain other deaths where specific information would be expected to be included. METHODS: Consecutive series of certificates attributing death to malignancy, pneumonia, an acute cerebrovascular event, and renal failure were inspected and compared with the categories identified in the International Classification of Disease. Review of clinical notes and of laboratory data was used to determine the number of cases in which detailed histological diagnoses were available. RESULTS: A histological diagnosis was available in 79.1% of cases of deaths due to malignancy, but was recorded on only 23.6% of certificates. Haematologists performed best (69.6%) and general surgeons worst (2.8%). The sites of primary tumours were recorded in detail in only 23 of 89 cases of tumours of the large bowel (22/36), lung (1/35) and stomach (0/18). In cases of pneumonia the causative organism was recorded in only 4 of 330. In cases of an acute cerebrovascular event one of 70 was recorded as being due to haemorrhage. A distinction between cerebral or precerebral arterial occlusion (embolism/thrombosis) and cerebral haemorrhage was not recorded in any of the other cases. In cases of renal failure a cause was not recorded in 75 of 95. CONCLUSIONS: Despite consistent encouragement to record all relevant details on death certificates this study shows that doctors fail to do so in most cases. Such a failure diminishes information available to the Office of Population Censuses and Surveys, affecting mortality statistics and gives further cause for concern about standards of certification. Means by which the standard of certification might be improved are discussed, including screening of certificates by a medically qualified person prior to registration. PMID- 8675734 TI - Adequacy of bone marrow trephine biopsy specimens in children. AB - AIMS: To evaluate success in obtaining adequate bone marrow trephine biopsy cores from children. METHODS: Sections of trephine biopsy cores submitted by 25 centres from children with neuroblastoma over a five year period were reviewed centrally. In cores containing no tumour adequacy was defined as 0.5 cm of well preserved bone marrow after processing. Occasional smaller cores containing obvious tumour were also considered adequate. RESULTS: Of 822 biopsy specimens, 139 (17%) were inadequate. In 13 centres submitting at least 20 cores failure rates ranged from 2.6 to 50%. There was no improvement over the five years of the study. There was no practically important correlation between the numbers of cores submitted and success in obtaining adequate specimens. Although a lower rate of inadequate biopsy specimens was found when haematologists rather than paediatricians (13 v 29%) were the predominant operators this should not be overinterpreted, not least because of the potentially confounding association between haematologist operators and larger numbers of biopsy specimens, and because the arbitrary subdivision of centres according to operator specialty was crude. The skill of individual operators could not be assessed. CONCLUSIONS: Many operators do not obtain adequate bone marrow biopsy specimens from children. Improvement is necessary because this is an invasive investigation, often performed under general anaesthesia. Reporting pathologists are well placed to influence practice by pointing out inadequacies in the specimen and suggesting retraining or even a change in operator. Improvement would almost certainly occur if this investigation was restricted to locally recognised successful operators, whatever their specialty. Most centres should review their practice and devise strategies to improve their ability to obtain adequate cores. PMID- 8675735 TI - Chronic hepatitis C in long term survivors of haematological malignancy treated in a single centre. AB - AIMS: To investigate the impact of hepatitis C virus (HCV) infection in long term survivors of haematological malignancy treated before the introduction of blood donor screening in September 1991. METHOD: Patients were tested for evidence of HCV infection by third generation enzyme linked immunosorbent assays, a recombinant immunoblot assay and reverse transcriptase polymerase chain reaction. Serum aspartate aminotransferase activities were measured. The number and type of blood component units received by each patient were recorded. RESULTS: Forty two patients were studied who had received a total of 7143 blood component units. Two patients (4.8%) were found to have HCV infection, both had histological evidence of chronic active hepatitis, and one is now receiving treatment with alpha interferon. Both of these patients had been missed by the ongoing look-back programme which aims to detect recipients of all known HCV infected blood components. CONCLUSION: Although HCV infection affects a minority of long term survivors of haematological malignancy, infected patients may benefit from alpha interferon treatment. The screening of all patients treated for haematological malignancy before September 1991 is advocated. PMID- 8675736 TI - Electron microscopy and immunocytochemistry in the assessment of renal biopsy specimens: actual and optimal practice. AB - AIMS: To determine the variation in practice of British renal histopathologists in the use of immunohistochemistry and electron microscopy in the investigation of renal biopsy specimens; to attempt to identify a consensus on what acceptable practice should be; and to satisfy requests from laboratories which have found immunoperoxidase methods unreliable on renal biopsy specimens, by disseminating methods from laboratories which have had success. METHODS: A questionnaire was sent to all 58 laboratories which participate in the UK National Renal Pathology External Quality Assessment Scheme. RESULTS: A response rate of 88% was achieved. Most laboratories use immunocytochemistry and electron microscopy to investigate most renal biopsy specimens, but a few use these methods only rarely and one, never. There is a widespread wish to switch from immunofluorescence to immunoperoxidase, but this is frustrated by the unreliability of the method. This seems to be mainly because of the need to tailor the time of enzyme pretreatment to each biopsy specimen. CONCLUSIONS: The majority view is that electron microscopy and immunocytochemistry are necessary in the investigation of most native renal biopsy specimens, and the few pathologists who report renal biopsy specimens without these methods risk accusations of negligence. Difficulty in using fixed renal tissues for immunocytochemistry stem largely from variations in the requirement for enzyme pre-digestion. Even where immunoperoxidase methods are usually successful, the occasional use of immunofluorescence in parallel to check that false negatives are not occurring is advocated. In all cases it is wise to keep some frozen cortex in reserve in case there is an unexpected or inconsistent immunoperoxidase result. PMID- 8675737 TI - Glomerular vascular cell adhesion molecule-1 expression in renal vasculitis. AB - AIMS: To study the expression of cell adhesion molecules in the renal biopsy specimens of patients with systemic vasculitis and Henoch-Schonlein purpura (HSP); to correlate this with the severity of glomerular inflammation. METHODS: Renal biopsy specimens obtained from eight patients with untreated systemic vasculitis (four with Wegener's granulomatosis and four with microscopic polyarteritis), eight with HSP and nine controls (four with normal histopathology and five with thin glomerular basement membrane disease) were stained using the alkaline phosphatase anti-alkaline phosphatase method with monoclonal antibodies directed against intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. RESULTS: Biopsy specimens of normal kidneys expressed ICAM-1 in glomerular endocapillary cells, Bowman's capsule epithelium, interstitial cells and interstitial vascular endothelium, and VCAM-1 in Bowman's capsule epithelium, proximal tubular epithelium and interstitial vascular endothelium. No staining with antibody directed against E-selectin was seen in any of the biopsy specimens. Biopsy specimens of patients with a vasculitic glomerulonephritis (segmental necrotising glomerulonephritis) expressed VCAM-1 in glomerular endocapillary cells (four of eight patients with systemic vasculitis; two of eight patients with HSP). In patients with a systemic vasculitis glomerular VCAM-1 expression was associated with a more severe renal lesoin (44, 50, 60, and 65% of glomeruli involved) than in those not showing glomerular VCAM-1 expression (3, 3, 11, and 39% of glomeruli involved). CONCLUSION: Expression of VCAM-1 by glomerular endocapillary cells in renal biopsy specimens raises the possibility that recruitment of VLA-4 bearing leucocytes may contribute to glomerular injury in Wegener's granulomatosis and microscopic polyarteritis. PMID- 8675738 TI - Distribution of varicella zoster virus and herpes simplex virus in disseminated fatal infections. AB - AIMS: To study the cutaneous and visceral distribution of herpes simplex virus (HSV) and varicella zoster virus (VZV) in fatal infections. METHODS: Standard histology, immunohistochemistry (monoclonal antibodies VL8 and VL2 and polyclonal antibody IE63 directed against VZV; monoclonal antibodies IBD4 and HH2 and polyclonal antibodies directed against HSVI and HSVII) and in situ hybridisation (anti-HSV and anti-VZV probes) were applied to formalin fixed, paraffin wax sections. RESULTS: On histological examination, Herpesviridae infection was evident in various organs including the lungs, liver and skin. In addition, immunohistochemistry and in situ hybridisation revealed the presence of HSV and VZV antigens and nucleic acids in several cell types and tissues showing no cytopathological alterations suggestive of Herpesviridae infection. The organs with histological evidence of infection also contained VZV or HSV antigens and their genes. CONCLUSIONS: These findings suggest that organ failure in disseminated VZV and HSV infections is primarily caused by HSV or VZV induced cell damage and lysis. They also indicate that immunohistochemistry and in situ hybridisation can provide an accurate, type-specific diagnosis on formalin fixed, paraffin wax embedded tissue even when classic histological and cytological characteristics are lacking. PMID- 8675739 TI - Effect of pH changes in cerebrospinal fluid specimens on bacterial survival and antigen test results. AB - AIMS: To determine the effect of pH changes occurring in cerebrospinal fluid (CSF) after sampling on the viability of meningitis causing bacteria, and on the performance of agglutination assays used for the rapid detection of bacterial antigens. METHODS: The pH of CSF collected via lumbar puncture was measured by various methods, and the effects of the following different incubation conditions on subsequent changes were determined: air at 4 degrees C; air at room temperature (22 degrees C); air at 37 degrees C; and air with 5% CO2 at 37 degrees C. The growth/survival in pooled CSF of 15 bacterial isolates collected from 74 patients with meningitis was assessed in these incubation conditions over 24 hours. The effects of pH changes in the CSF on the sensitivity of two latex agglutination and one co-agglutination kits for detecting Haemophilus influenzae, Neisseria meningitidis groups B and C, and Streptococcus pneumoniae were determined. RESULTS: The measured pH of CSF was highly affected by the method used and particularly the time delay between patient sampling and assay. Measured pH values at the time of sampling (mean 7.5) increased rapidly within 60 seconds by about one unit. CSF pH continued to increase during incubation in all tested conditions (up to approximately pH 10), with the exception of in air with 5% CO2 at 37 degrees C where pH changes were reversible and near physiological values were attained. Bacterial survival for all species tested was poorest in CSF incubated in air at 37 degrees C and best following exposure to air with 5% CO2 at 37 degrees C. Agglutination in rapid antigen detection kits with CSF incubated in air as opposed to air with 5% CO2 generally took longer to occur and in some instances was less prominent. In one case a false negative result was obtained with CSF seeded with N meningitidis group B incubated in the former but not the latter conditions. CONCLUSIONS: CSF pH increases after patient sampling are minimised and/or mostly reversed by incubation in an atmosphere containing 5% CO2. CSF samples should ideally be placed in such an atmosphere as soon as possible after collection, and left there until laboratory processing occurs, to reduce the detrimental effects of pH stress on bacterial survival. pH increases may also reduce the likelihood of obtaining a positive result in rapid antigen detection assays. PMID- 8675740 TI - Hepatitis C virus seroconversion by a third generation ELISA screening test in blood donors. AB - The significance of seroconversion as detected by an ELISA screening test for hepatitis C virus (HCV) antibody with a negative supplemental/confirmatory recombinant immunoblot assay (RIBA) result was investigated. Of 118,220 established West Midlands blood donors with at least one negative HCV antibody screen, 43 had seroconverted in 1994 according to the ELISA but had negative RIBA 3 results. The paired archive serum samples of the pre- and postseroconversion donations of 29 seroconverting donors were tested by nested polymerase chain reaction (PCR) for the detection of HCV RNA. All 58 samples were negative by PCR. The absence of detectable viraemia in all tested seroconverting donors suggests that HCV infection was not responsible for seroconversion by ELISA. PMID- 8675741 TI - Microbiological and serological investigations of oral lesions in Papillon Lefevre syndrome. AB - Microbiological and serological (enzyme linked immunosorbent assay) investigations were carried out, including karyotyping, on two Asian children with Papillon-Lefevre syndrome. In case 1, a girl aged four years, the most prevalent putative periodontopathogens were Eikenella corrodens, Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella intermedia (deciduous dentition) and Bacteroides gracilis, E corrodens and F nucleatum (permanent dentition). In case 2, a boy aged nine years, they were F nucleatum, P intermedia and P loeschii and E corrodens. Serum from case 2 showed a raised specific IgG antibody response to Actinomyces actino-mycetemcomitans serotype b. Thus, a wider range of species than hitherto reported may be associated with Papillon-Lefevre syndrome, including A actino-mycetemcomitans and F nucleatum. PMID- 8675742 TI - OCT embedded sections of pathological specimens as a source of high quality RNA for reverse transcriptase/polymerase chain reaction. AB - OCT embedded cryostat sections of stored pathological specimens of non-Hodgkin's lymphoma were used to provide RNA. After reverse transcription to produce cDNA, the polymerase chain reaction was performed with primers for standard and variant forms of the CD44 molecule. Using Southern transfer and hybridisation with a probe specific for exon 4 of the CD44 gene, both standard and variant forms were visualised by autoradiography. This method was shown to be applicable to other gene products by using primers specific for the abl and bcr genes. This technique permits retrospective analysis of RNA from small amounts of stored pathological samples. PMID- 8675743 TI - Small cell variant of Ki-1 lymphoma associated with myelofibrosis and a novel constitutional chromosomal translocation t(3;4) (q13;q12). AB - An unusual case of small cell variant of Ki-1 non-Hodgkin's lymphoma diagnosed one year after an original diagnosis of idiopathic myelofibrosis is reported. On the second occasion, the patient presented with fever, lymphadenopathy and hepatosplenomegaly. A lymph node biopsy specimen confirmed a diagnosis of small cell variant of Ki-1 lymphoma. A repeat bone marrow biopsy specimen showed myelofibrosis with no evidence of lymphomatous infiltration, but cytogenetic studies on blood, bone marrow and skin fibroblasts revealed a novel chromosomal translocation t(3,4)(q13;q12). PMID- 8675744 TI - Langerhans cell histiocytosis forming an asymptomatic solitary nodule in the spleen. AB - A case of solitary Langerhans cell histiocytosis (LCH) in the spleen of a 29 year old Chinese man, discovered incidentally at necropsy, is reported. This is the first documented case of LCH confined to the spleen and suggests that LCH should be included in the differential diagnosis of space occupying lesions in the spleen. PMID- 8675745 TI - Lymphocyte infiltration in oesophageal carcinoma: lack of correlation with MHC antigens, ICAM-1, and tumour stage and grade. AB - Infiltration by T lymphocytes into oesophageal carcinomas was assessed immunohistochemically, total T lymphocyte numbers by staining for CD3 and activated T lymphocytes by staining for CD25. Five squamous carcinomas and seven adenocarcinomas, resected without neoadjuvant treatment, were studied. Computer aided quantitation showed that total numbers of tumour infiltrating CD3 positive cells were highly variable (range 48-1673 cells/mm2). They were located largely in the stromal (87.9-99.2%) rather than intratumoral regions. Up to 84% of tumour infiltrating T lymphocytes were CD25 positive, although the median figure was 33%. There was no correlation between T lymphocyte infiltration or activation and expression of class I and II histocompatibility antigens, intercellular adhesion molecule-1, tumour stage or grade. These results imply that the local inflammatory response in oesophageal carcinomas is deregulated, which may be a factor contributing to the aggressive nature of the tumours. PMID- 8675746 TI - Sudden death due to a glial cyst of the pineal gland. AB - Asymptomatic cysts of the pineal gland are found frequently by radiological examination of the brain or at postmortem examination. Symptomatic cysts are rare, and may require surgical intervention. Sudden death due to a cystic lesion of the pineal gland is very rare. A case of a 22 year old man who collapsed and died unexpectedly is reported. Postmortem examination revealed a glial cyst of the pineal gland and evidence of chronic obstructive hydrocephalus. Deaths from colloid cysts and pineal gland cysts are rare, but should be considered where no other cause of death is evident, especially with a history of headaches. Their small size, and their possible rupture on dissection can make them difficult to detect if a careful examination is not undertaken. PMID- 8675747 TI - EBNA expression in Reed-Sternberg like cells in post-transplant lymphoproliferative disorders. PMID- 8675748 TI - Which proliferation markers for routine immunohistology? PMID- 8675749 TI - Observation of encapsulated lactic acid bacteria using confocal scanning laser microscopy. AB - The confocal scanning laser microscope allows direct observation of milk and cultured milks in their natural state. The microscope was used to observe the capsules of lactic acid bacteria growing in milk. Capsule production was confirmed by microscopic observation of cells suspended in latex beads. Some strains of Streptococcus thermophilus were surrounded by a capsule 4 to 5 microns in diameter, and others by capsules 2 microns in diameter. Lactobacillus delbrueckii ssp. bulgaricus strains showed capsule sizes from 1.5 to 3 micron in diameter. Of four strains of lactococci tested, three were unencapsulated, and one had capsule sizes of 1.5 and 2 microns around some cells. Encapsulated strains produced less acid in milk than did unencapsulated strains. Growth in Elliker's broth produced smaller capsules than did growth in milk. Capsules acted as a barrier to acid diffusing from the cell. PMID- 8675750 TI - Application of capillary electrophoresis in the identification of phenotypes containing the beta-lactoglobulin C variant. AB - A method for the separation of the beta-LG variants A, B, and C was developed using free zone capillary electrophoresis. A separation buffer consisting of 50 mM 2-(N-morpholino)ethane sulfonic acid (pH 8.0) and polyoxyethylene (20) sorbitan monolaurate was used for the separation. Milk samples from 424 Jersey cows were phenotyped using this method, and the gene frequencies for beta-LG A, B, and C were .41, .53, and .06, respectively. These frequencies were different from those found in studies of Jersey populations in other countries, where the beta-LG B allele had a significantly higher frequency, and the beta-LG A allele a significantly lower frequency, than those of this present study. The frequency of the beta-LG C allele was intermediate to those of other studies. The concentration of beta-LG in the milk was different among the beta-LG phenotypes and was, from greatest to least: AA, AB, AC, BB, and BC. PMID- 8675751 TI - The effect of mammary gland expression of human lysozyme on the properties of milk from transgenic mice. AB - Transgenic mice were used as model systems to evaluate the impact of human lysozyme expression in the mammary gland. We previously generated two lines of transgenic mice that express human lysozyme mRNA in the mammary gland under the tissue-specific and developmentally correct control of the bovine gene promoter for alpha s1-casein. Concentrations of human lysozyme protein in milk of transgenic mice varied from .25 to .71 micrograms/microliters of milk. Human lysozyme secreted into mouse milk retained its antimicrobial activity, as determined by a denaturing polyacrylamide gel activity assay. The physical and functional properties of the milk were also altered, because mouse milk containing human lysozyme had a 35% decrease in rennet clotting time, a smaller median micelle size (157 nm vs. 172 nm), and a 2.5- to 3-fold greater gel strength than control milk. From these results, we conclude that the use of transgenic animals producing lysozyme in the milk is feasible and potentially useful to the dairy industry. PMID- 8675752 TI - Characterization of multiply phosphorylated peptides selectively precipitated from a pancreatic casein digest. AB - Anticariogenic phosphopeptides, released during the hydrolysis of casein with trypsin, contain the cluster sequence Ser(P)-Ser(P)-Ser(P)-Glu-Glu and have commercial potential as toothpaste, mouthwash, and food additives for the prevention of dental caries. To develop a commercial-scale process for the production of these peptides, we have comprehensively characterized casein phosphopeptides that were selectively precipitated using Ca2+ and ethanol from an acid-clarified (pH 4.6) pancreatic casein hydrolysate. Casein was hydrolyzed using pancreatin at 50 degrees C for 2 h. The precipitate contained a series of casein phosphopeptides that were slightly truncated relative to tryptic casein phosphopeptides. The major casein phosphopeptides released by pancreatin were beta-CN-4P(f7-24), alpha s1-CN-5P(f61-78), and alpha s1-CN-5P(f59-78), all containing the cluster sequence. The truncation of the tryptic peptides beta-CN 4P(1-25) and alpha s1-CN-5P(f59-79) resulted from the chy-motryptic and carboxypeptidase activities of the pancreatin. The peptides containing the cluster sequence constituted 77.8 +/- 6.7 mol/100 mol of the total peptides that were selectively precipitated. This composition was not significantly different from that of casein phosphopeptides produced under identical conditions using trypsin. In conclusion, pancreatin should be a suitable enzyme preparation for the production of anticariogenic casein phosphopeptides on a commercial scale. PMID- 8675753 TI - In vivo parathyroid hormone stimulates in vitro bone resorption by bovine monocytes. AB - Cells of the monocyte-macrophage lineage have been thought to play a role in bone resorption. We examined the effects of in vivo administration of parathyroid hormone and 1,25-dihydroxyvitamin D3 on the ability of monocytes to degrade bone in vitro. Administration of parathyroid hormone for 4 d resulted in sustained hypercalcemia and a transient 1-d increase in plasma 1,25-dihydroxyvitamin D3. Parathyroid hormone significantly stimulated bone degradation by monocytes 2.6 times more than that of pretreatment controls. Parathyroid hormone treatment significantly enhanced (threefold) release of superoxide anion by monocytes stimulated with phorbol 12-myristate 13-acetate and increased migration of monocytes to bone particles in vitro. Continuous 7-d infusion of 1,25 dihydroxyvitamin D3 (50 micrograms/d) elevated plasma 1,25-dihydroxyvitamin D3 until infusions were discontinued. Increased 1,25-dihydroxyvitamin D3 was associated with hypercalcemia, which continued for several days postinfusion. In vivo administration of 1,25-dihydroxyvitamin D3 did not affect in vitro ability of monocytes to degrade bone. We concluded that in vivo administration of parathyroid hormone enhanced in vitro responsiveness of isolated monocytes in a manner consistent with a role for monocytes in bone remodeling. Furthermore, these data suggested that circulating monocytes could be a useful experimental model for further studies on parathyroid hormone responsiveness and bone resorption for the cow with milk fever. PMID- 8675754 TI - Influence of prepubertal dietary regimen on mammary growth of Holstein heifers. AB - One hundred-sixteen Holstein heifers (mean BW, 175 kg) were randomly assigned to diets of alfalfa silage or corn silage and were fed to gain approximately 725 or 950 g/d in order to study the influence of prepubertal diet and rate of gain on mammary growth and milk production. Blood was collected before puberty for hormone determination, and 8 heifers per group were killed at puberty for evaluation of tissue variables. Serum growth hormone was reduced, and IGF-I was increased, in the group of heifers reared at a high rate of gain on the corn silage diet. Accompanying the decline in growth hormone, total mammary parenchymal DNA and RNA was reduced in heifers reared at a high rate of gain on the corn silage diet. Mammary parenchyma in heifers of the latter group contained a greater volume of adipocytes and a lower volume of epithelial cells than did mammary parenchyma in heifers of other groups. Data are consistent with previous investigations that showed a deleterious effect of prepubertal rapid weight gain on mammogenesis when accompanied by excess body fat deposition. However, this effect did not cause a decline in subsequent milk production. PMID- 8675755 TI - Relationship between frequent milking or suckling in early lactation and milk production of high producing dairy cows. AB - Groups of 9 or 10 cows were assigned to one of three treatments 1) machine milking three times daily, 2) machine-milking six times daily, and 3) suckling three times daily in addition to machine- milking three times daily. Treatments were conducted during the first 6 wk postpartum; thereafter, all cows were milked three times daily. During treatment, milk production was highest for suckled cows and lowest for cows milked three times daily. The DMI were similar for suckled cows and cows milked three times daily but higher for those milked six times daily. Body weight loss was greatest for suckled cows and least for cows milked three times daily. During wk 7 to 18 postpartum, cows milked six times daily exhibited a carry-over effect on milk production that was greater than that of other groups, During treatment, plasma growth hormone and IGF-I concentrations were elevated for suckled cows and, to a lesser extent, for cows milked six times daily. Prolactin and oxytocin similarly increased, but insulin decreased in suckled cows and, to a lesser extent, in cows milked six times daily. Posttreatment differences persisted for insulin and IGF-I, but not for the other hormones. Increased frequency of udder emptying increased milk production, and suckling was superior to machine-milking. High milk production was associated with elevated growth hormone, IGF-I, prolactin, and oxytocin, although cause and effect could not be established. The failure of suckled cows to increase feed intake to match output requires further investigation. PMID- 8675756 TI - Serum immunoglobulin concentrations and health of dairy calves in two management systems from birth to 12 weeks of age. AB - Fifteen dairy calves were kept with their dams for 5 d after birth and thereafter were fed milk from a nipple pail in individual pens (nursed calves). Another 15 calves were separated from their dams immediately after birth, placed in individual pens, and fed from an open pail (weaned calves). These calves received colostrum for the first three feedings. Serum Ig concentrations and the health of the calves were monitored from birth to 12 wk of age. The serum Ig concentrations developed identically for calves in both groups. A 30-min delay in intake of first colostrum decreased total Ig concentrations in serum by about 2 mg/mL. Occurrence of diarrhea was three times greater for the weaned calves than for the nursed calves. Serum Ig concentrations did not explain the differences in the diarrhea occurrence between the groups. In conclusion, the newborn calves in both management systems acquired equal passive immunity, although the time of first colostrum consumption played an important role. Open pail feeding may increase the incidence of prolonged diarrhea compared with that from nipple feeding. PMID- 8675757 TI - Antigenic crossreactivity and lipopolysaccharide neutralization properties of bovine immunoglobulin G. AB - We investigated a possible mechanism by which immunization against core and lipid A determinants of lipopolysaccharide reduced clinical cases of mastitis and symptoms commonly associated with heterologous Gram-negative IMI. The IgG fraction of sera from cows immunized with either Escherichia coli J5 bacterin, E. coli J5 lipopolysaccharide conjugate vaccine, or unimmunized controls was purified by precipitation with caprylic acid and ammonium sulfate. The degree of IgG crossreactivity with Gram-negative bacteria that were isolated from clinical quarters was greater than that with Gram-positive isolates of Staphylococcus aureus. The highest magnitude of crossreactivity was against smooth strain E. coli isolates, followed by heterologous species of Enterobacter, Serratia, and Klebsiella isolates. Serum IgG from cows immunized with conjugate was highly crossreactive to E. coli J5, E. coli O111:B4, Serratia marcescens, Klebsiella pneumoniae, and Salmonella typhimurium lipopolysaccharides. The magnitude of antibody crossreactivity with lipopolysaccharides coincided with the ability of IgG to suppress the mitogenic effect of lipopolysaccharides on bovine lymphocytes. PMID- 8675758 TI - Relationship between somatic cell count and intramammary infection of the half udder in dairy ewes. AB - A total of 1382 milk samples from half udders of three breeds of ewes (686 Assaf, 422 Churra, and 274 Castellana) were collected aseptically at midlactation from 18 flocks in the Castile-Leon region of Spain. Bacteriological tests were carried out on the samples to ascertain the status and type of IMI. Somatic cell counts were determined for all samples after bacteriological analysis. Analysis of variance showed significant effects of breed, IMI status, flock nested within breed by milking type, organism within IMI status, and interactions of breed by milking type and of breed by organism. The most frequent bacterial groups were staphylococci, especially coagulase-negative staphylococci, followed by streptococci, micrococci, and yeasts. The SCC response was related to the bacterial group involved in the IMI; coagulase-negative staphylococci showed significantly lower SCC values than those for coagulase-positive staphylococci and streptococci. Highest percentages of IMI by major pathogens and highest SCC, both in the absence of IMI and in staphylococcal IMI, were in Assaf ewes. The threshold of 300,000 cells/ml allowed 81% of the half udders to be correctly classified according to IMI status. However, the existence of breed differences in SCC response and IMI type could make the use of specific SCC thresholds for each breed advisable. PMID- 8675759 TI - Methane and carbon dioxide emissions from dairy cows in full lactation monitored over a six-month period. AB - Methane and CO2 emissions from a herd of 118 lactating cows were measured directly by continuous monitoring with an infrared gas analyzer from 24 gas sampling locations. A total of 112 d of gas output was recorded between June 1993 and November 1993. Recordings were integrated at .5-h intervals, so that there were 48 data points for each 24-h period. The mean 24-h CH4 emission per cow was 587 +/- 61.3 L; the range was 436 to 721 L. The mean 24-h CO2 emission per cow was 6137 +/- 505 L, and the range was 5032 to 7427 L. These values were not corrected for gas emissions from stored manure, which contributed 5.8 and 6.1%, respectively, to CH4 and CO2 output under conditions of this experiment. PMID- 8675760 TI - Responses of early lactation cows fed winter and summer annual forages and undegradable intake protein. AB - Twenty-four multiparous Holstein cows were divided into six blocks of 4 cows based on their previous 305-d mature equivalent milk yield and were used in a 2 x 3 factorial experiment for the first 84 DIM. Objectives were to determine the effects of forage and RUP supplementation of DM and nutrient intakes and digestibilities, milk yield and composition, BW change, and plasma concentrations of insulin, triiodothyronine, thyroxine, cortisol, NEFA, urea N, and protein. One cow from each block was assigned to wheat or sorghum silage plus one of three concentrates. Protein treatments were 1) all supplemental CP from soybean meal; 2) 33.3% of supplemental CP from heat soybean meal, fish meal, and corn gluten meal; and 3) protein treatment 2 plus an additional 4.6% CP from soybean meal. Intakes of DM, CP, NDF, ADF, NEL, and RUP were higher in cows fed sorghum silage; RUP tended to increase DMI. Milk and 3.5% FCM yields were higher for cows fed sorghum silage than for those fed wheat silage (42.3 vs. 40.0 kg/d and 41.2 vs. 38.7 kg/d, respectively). Milk protein, lactose, and SNF were increased by RUP. Insulin was increased, cortisol was decreased, and thyroid hormones were unaffected by RUP. Concentrations of NEFA were highest at wk 4. For early lactation cows fed diets containing sorghum or wheat silage, RUP is a necessity. PMID- 8675761 TI - Lipid metabolism in adipose tissue of cows fed high fat diets during lactation. AB - The adaptations of fat synthesis in adipose tissue to lactational state, rate of milk production, and dietary fat intake were determined for dairy cows. Lipogenesis and esterification were determined in cows of average or high genetic merit for milk production and fed either a control TMR of corn silage, alfalfa, and concentrate (2.5% fat; 1.47 Mcal of NEL/kg); a TMR with whole cottonseeds replacing 12% of the concentrate (4.4% fat; 1.49 Mcal NEL/kg); or a TMR with 12% cottonseeds and 2.7% of Ca salts of fatty acids (6.0% fat; 1.53 Mcal of NEL/kg). Dietary treatments began on d 17 of lactation and continued for 288 d. Lipogenesis and esterification decreased equally from 15 d prepartum to 15 d postpartum in all groups. Cows of high merit had lower rates of lipogenesis and esterification at d 60 than did low merit cows but had higher rates of lipogenesis at d 120. Rates of lipogenesis were decreased by dietary fat treatments. Esterification rates were lowest on the intermediate fat TMR and highest on the highest fat TMR. Lipogenesis was decreased logarithmically by dietary fat intake; this effect was greater as lactation progressed. Adipocyte size and body fat mass decreased during early lactation and then increased for all treatment groups. Supplemental dietary fat reduces de novo synthesis of fatty acid, and this effect increases as lactation progresses. PMID- 8675762 TI - Lipolysis and biohydrogenation of soybean oil in the rumen in vitro: inhibition by antimicrobials. AB - This experiment attempted to lower rumen lipolytic activity, biohydrogenating activity, or both using antimicrobial compounds. In vitro incubations were carried out with rumen fluid, 80 mg of soybean oil, and .5 g of commercial concentrates as substrate. Unless stated otherwise, the final concentrations of the additives in the incubation was 20 ppm. Lipolysis and biohydrogenation were determined by separation of triacylglycerols and FFA by TLC; the fatty acid composition of each was determined by GLC before and after incubation and with or without additive. With some of the antibiotics, lipolysis was inhibited 10 to 20%, and the most potent inhibitors were ionophores and amoxicillin. Biohydrogenation (including C18:1) decreased only for lasalocid, but no additive could prevent hydrogenation of linolenic acid liberated from triacylglycerols. Some additives decreased hydrogenation of linoleic acid, but only slightly. Lipolytic activity decreased VFA production more than the other potent additives (amoxicillin, avoparcin, lasalocid sodium, monensin, and salinomycin sodium). This result could indicate a more specific toxic effect on lipolytic microbes. Finally, different antimicrobials influenced fermentation patterns differently (VFA proportions and CH4 production), but shifts were always in accordance with stoichiometric principles. PMID- 8675763 TI - Interactions of ruminally protected methionine and lysine with protein source or energy level in the diets of cows. AB - Interactions between supplementation with ruminally protected Met and Lys and the nature of protein or energy concentration of the diet were studied using 16 and 12 multiparous lactating dairy cows in two trials of 8 and 12 wk, respectively, commencing on approximately d 40 of lactation. In trial 1, cows received a semicomplete diet plus concentrates. The diet consisted of 62 to 63% corn silage, 2.2% corn gluten meal, .4% urea, 11% soybean meal (untreated or treated with formaldehyde), and 23 to 24% barley. In trial 2, cows received a complete diet with corn silage, untreated and formaldehyde-treated soybean meal, and barley in the ratio 78:12:9:0 or 49:13:4:33. All treatments were replicated in a 4 x 4 Latin square design. In both trials, Met plus Lys (10 g/d of intestinally available Met and 30 g/d of Lys) has no significant effect on DMI, milk yield, fat content, casein as a percentage of true protein, or urea content of the milk. Mean increase of milk protein yield was 46 g/d with Met plus Lys, and mean increase of true protein content was 1.1 g/kg of milk. The increase in content of milk true protein was greater for cows receiving the low energy diet. Protein source had no effect on milk yield or composition. Glucose, urea, NEFA, BHBA, and total free AA in plasma were unaffected by supplementation of ruminally protected Met plus Lys. However, concentrations of Met and Lys in blood were slightly, but not significantly, higher in supplemented cows. PMID- 8675764 TI - Lack of association between calf morbidity and subsequent first lactation milk production in 25 New York Holstein herds. AB - The association of owner-diagnosed calfhood diseases with first lactation milk production was evaluated using data collected prospectively for 728 heifers from 25 New York dairy herds. Cows diagnosed with one or more occurrences of dullness, respiratory disease, or scours within 90 d of birth had first lactation milk production that was similar to that of unaffected herdmates. Estimates for the effects of dullness, respiratory disease, and scours on second test milk production were -1.0, 1.0, and .4 kg/d, respectively (adjusted for season and age at calving, times milked per day, study month on birth, sire PTA for milk production, and the other two calfhood diseases). Estimates for the effects on 305-day mature equivalent production were -139, 123, and 158 kg for dullness, respiratory disease, and scours, respectively (adjusted for study month of birth, sire PTA for milk production, and the other two calfhood diseases). These results were based on data of heifers that were selected as replacements and remained in the herd long enough to have milk production recorded. There was no significant detrimental effect of owner-diagnosed calfhood disease on first lactation milk production, but affected heifers had higher mortality before calving and were less likely to enter the milking herd. PMID- 8675765 TI - A study of the use of milk replacers for dairy calves in the United States. AB - This study focused on aspects of the National Dairy Heifer Evaluation Project that involved neonatal feeding practices and types of milk replacers utilized on dairy farms. Types of milk replacers and the management practices associated with their feeding were studied. Nearly 60% of US dairy farms use milk replacers for some or all of the feeding program for neonatal calves. Regional differences existed in the types of liquid feeds and milk replacers fed to calves. Western producers fed less milk replacer, and western and northeast producers fed replacers with less total CP. Many characteristics of management utilized along with these products reflect accepted management and nutrition practices. During the study period from 1991 to 1992, 11.2% of replacers contained casein. A greater proportion of these were found in the West during the first 6 mo of the study, reflecting changes in the milk replacer formulations during that time. PMID- 8675766 TI - Effect of administration of bifidobacteria and lactic acid bacteria to newborn calves and piglets. AB - The effect of oral administration of bifidobacteria and lactic acid bacteria on newborn livestock was investigated. Oral administration of Bifidobacterium pseudolongum or Lactobacillus acidophilus to calves improved BW gain and feed conversion over that of untreated controls. The frequency of diarrhea occurrence was decreased in the group fed probiotics. However, there was no significant difference between calves administered B. pseudolongum and those administered L. acidophilus. Under conditions of feeding without antibiotics, the frequency of diarrhea was decreased markedly by administration of probiotics. The BW gain of piglets was significantly greater during both the suckling and weaning periods for the group fed probiotics than for the control group. The effect was more evident during the suckling period than during the weaning period. Under conditions of feeding without antibiotics, the frequency of piglet mortality was decreased markedly by administration of probiotics. The probiotics tested here had useful effects, including improved BW gain, feed conversion, and fecal condition of both newborn calves and piglets. PMID- 8675767 TI - Estimation of genetic parameters for test day records of somatic cell score. AB - The present study estimated variance components for test day records of somatic cell score and production traits. Data consisted of 235,100 test day observations recorded between 1986 and 1994 on lactations 1 to 3 of 15,922 Holstein cows from 143 herds. Records were considered as repeated observations within a lactation and as different traits across lactations. The multiple-trait animal model for analysis included random animal additive genetic and permanent environment effects by lactation. Fixed effects included herd test date and a set of four covariables for days in lactation, estimated by parity, age, and season, which accounted for the shape of the lactation curve. Gibbs sampling chains were carried out separately for somatic cell score and milk production and fat and protein yields. Heritabilities of somatic cell score for lactations 1 to 3 were .09, .09, and .11, respectively. Genetic correlations between lactations were high (.88, .79, and .95 between lactations 1 and 2, 1 and 3, and 2 and 3, respectively). Correlations between permanent environment effects were smaller (.29, .19, and .46 between lactations 1 and 2, 1 and 3, and 2 and 3, respectively). Heritabilities and correlations between permanent environment effects were higher for production traits than for somatic cell score. Genetic correlations between lactations for production traits were similar to those for somatic cell score. Variances between lactations differed significantly, indicating that observations from different lactations should no be considered as repeated observations of the same trait. PMID- 8675768 TI - Genetic evaluation for somatic cell score with a test day model for multiple lactations. AB - A multiple lactation model for test day data was applied to predict genetic merit for somatic cell scores of Canadian Holsteins. The model for genetic evaluation included a fixed effect for herd test date, fixed regressions on functions of days of lactation, random effects of permanent environment within lactation, random genetic effects on animal, and residual effects. Records from the first three lactations were used and treated as different traits. Procedures for this model, developed for national genetic evaluation for somatic cell score in Canada, were found to be practical. Use of starting values from the previous genetic evaluation reduced the number of rounds necessary to reach convergence. Test day models were compared with several single-trait models based on lactation average of somatic cell score in terms of computing efficiency and ranking of animals. Differences between EBV from the test day model and EBV from a repeatability model for lactation average were small for bulls with many daughters, but differences were large with EBV from a single-trait model for first lactation average of somatic cell count. Association were desirable for EBV for somatic cell score with EBV for some udder conformation traits, but undesirable for EBV for milk and protein yield. PMID- 8675769 TI - Multiphasic analysis of reproductive efficiency of dairy bulls. AB - Reproductive efficiency of dairy bulls is usually measured by nonreturn rate. Nonreturn is a compound trait that is a result of two events, conception and gestation, that lead to calving. Nonreturn rates can be used to derive more elementary biological measures for reproductive efficiency, such as conception rate and calving rate, which separately might be more reliable than nonreturn rate itself to evaluate the fertility of a bull or the performance of an AI technician. The challenge of this study was to examine the decline in nonreturn rate in light of the theory of multiphasic analysis. A multiphasic logistic function was developed to model decline in nonreturn rate by estimating conception rate, calving rate, and characteristics of the first two estrous cycles. The model is illustrated with data on daily nonreturn rates to 120 d. From the proportion of cows that conceived but failed to complete gestation because postsignal embryonic death, the model estimates conception rate and calving rate. From the proportion of cows that failed to conceive or that conceived but failed to complete gestation because of presignal embryonic death, the model estimates the proportion of returns, or probability of detecting estrus, duration of nonreturns, and time of maximum decline in nonreturn rate for the first two cycles. Using the proposed model, conception rate and calving rate estimated from daily nonreturn rates might be more reliable for evaluation of performance of an AI technician and fertility of a bull than nonreturn rates at arbitrarily chosen days after insemination. PMID- 8675770 TI - Visualization of inheritance patterns from graphic representation of additive and dominance relationships between animals. AB - Evaluation of pedigrees of normal and affected individuals help to suggest possible patterns of inheritance. Because large numbers of individuals are involved in studies of genetic disease, classic two-dimensional family tree charts are difficult to draw. Instead, DFA plots of graduated circles, weighted by dominance relationships, inbreeding, and additive relationships between individuals can be plotted above, on, and below the diagonal. Base animals without phenotypic measurements contribute information for computation of approximate dominance relationship, inbreeding, and additive relationships, but are not explicitly in the graph. Plotting only a set of randomly selected animals for each combination of phenotypes improves the visualization effect, especially when pedigrees are large or when computer resources are limited. For deficiency of uridine monophosphate synthase and interdigital hyperplasia, DFA plots showed higher densities of additive and dominance relationships among affected animals. However, DFA plots did not show clear patterns of inheritance for heel erosion, laminitis, or sole ulcers because environmental effects were important for those traits. Grouped graduated circles also improved visualization. The function of DFA plots is comparable with statistical scatter plots that display data to help examine statistical approaches. The DFA plots serve as a first approach to evaluate genetic hypotheses before a more complex model is fit. PMID- 8675771 TI - Bias and accuracy of single milking testing schemes to estimate daily and lactation milk yield. AB - This study evaluated the adequacy of an alternate a.m.-p.m. testing scheme for milk yield in comparison with the official test method based on weighing two milkings within 24 h. A total of 88,558 single test day milking weights from 15,670 Italian Friesian cows in 610 herds in the province of Milano (Italy) were collected between September 1991 and October 1992. Ratios were computed for daily milk yield to a.m. and p.m. milking weights (direct yield ratios) and ratios of a.m and p.m. milking weights to daily milk yield (inverse yield ratios). Analysis of variance indicated that the milking interval is the most important source of variation for yield ratios. Factors for estimating daily milk yield from single milking weights adjusted for milking intervals were derived through regression analysis of direct and inverse yield ratios on the length of the milking interval. Daily milk yield was estimated more precisely and accurately when adjustment factors were used than when single milking weights were doubled. The doubling of a.m. and p.m. milking weights overestimated and underestimated (5% on average) daily milk yield, respectively. For 305-d lactation yield, accuracies of these methods were comparable. In conclusion, alternate recording of a.m. and p.m. milking weights led to reliable estimates of milk yield. Effects of the alternate a.m.-p.m. testing scheme on estimates of milk components and genetic evaluations of dams of sires should be investigated. PMID- 8675772 TI - Effects of nicotinamide on milk composition and production in dairy cows fed supplemental fat. AB - Thirty-two cows, averaging 112 DIM, were assigned to four dietary treatments: 1) control, 2) Ca salts of fatty acids, 3) nicotinamide, and 4) Ca salts of fatty acids blended with nicotinamide during manufacture. Preliminary studies showed that nicotinamide survives blending with Ca salts of fatty acids during manufacture and that a blended mixture of nicotinamide and Ca salts of fatty acids gave results similar to those from nicotinamide plus Ca salts of fatty acids supplemented separately. Calcium salts of fatty acids increased milk fat percentage, decreased milk protein percentage, but had no effect on production of milk, FCM, fat, or protein. Nicotinamide increased production of milk and protein, decreased fat percentage, but had no effect on either production of FCM and protein or percentage of protein. Calcium salts of fatty acids increased NEFA in blood, and dietary nicotinamide increased concentrations of nicotinamide in blood, but glucose and BHBA in blood were unaffected by either dietary ingredient. Therefore, in these midlactation cows, the decreased milk protein percentage caused by supplemental dietary fat was prevented by nicotinamide. Supplementation with only nicotinamide increased total production of milk protein. PMID- 8675773 TI - Influence of by-product feeds and tallow on lactation performance of Holstein cows during two seasons. AB - Experiments were conducted to evaluate the impact of fibrous by-product feeds and tallow on lactation performance and ruminal fermentation. Diets were arranged as a 2 x 2 factorial of low and high NDF with or without added tallow. Corn and soybean meal were replaced with corn gluten feed, soyhulls, wheat middlings, and high moisture, whole ear corn. Forty-eight Holstein cows were used in two seasonal replicates of a randomized block design. Addition of tallow decreased intake of the low fiber diet, but not the high fiber diet, during winter. Intake was unaffected by diet during summer. Dietary NDF percentage did not change DMI. Milk production was unaffected by addition of tallow but was more persistent for cows fed low fiber diets. Tallow reduced milk protein percentage but did not change milk fat percentage. Fibrous feeds did not influence milk composition. Four fistulated cows were used in a 4 x 4 Latin square design. Fibrous by-product feeds decreased total VFA concentration. Acetate to propionate ratio increased when tallow was added to high fiber diets but decreased when tallow was added to low fiber diets. Tallow and fibrous by-product feeds can be used to support milk production. PMID- 8675774 TI - Duodenal flow of microbial and feed nitrogen in sheep fed normal soybean meal or soybean meal treated with modified zein. AB - The effect of protecting soybean meal from microbial degradation in the rumen on duodenal flow of microbial N and feed N was studied with sheep. The soybean meal was protected with chemically modified zein. Two groups of four wethers, each equipped with a ruminal cannula and a duodenal reentrant cannula, were fed a diet based on corn silage (1 kg of DM/d) that contained either a normal or protected soybean meal supplement. The results showed no appreciable differences between the two supplements in ruminal fluid pH, total N, and NAN concentrations; however, the concentration of total VFA was lower for protected soybean meal than for normal soybean meal. Although the flow of NAN into the duodenum was not affected, bacterial N flow was 18% lower, and feed N flow was 195% higher, for protected soybean meal than for normal soybean meal. The digestibilities of OM, ADF, and N in the digestive tract were not affected by the type of supplement. The treatment of soybean meal decreased the degradability of total feed N in the stomach by 22 percentage points, but the increased supply of feed N into the small intestine because of the treatment was at the expense of decreased bacterial synthesis of protein in the rumen, probably because of a shortage of RDP in the diet. PMID- 8675775 TI - Bioavailability of copper proteinate and copper carbonate relative to copper sulfate in cattle. AB - Two experiments were conducted to determine the relative bioavailabilities of Cu proteinate, CuCO3, and CuSO4. In Experiment 1, 30 heifers that had been depleted of Cu were us 1. Treatments were control, Cu proteinate A, Cu proteinate B, CuCO3, and CuSO4. Sources provided 50 mg of Cu/d. Supplementation increased plasma Cu by d 21, but there were no differences among the sources. Heifers supplemented with Cu had greater liver Cu concentrations on d 21 than did controls. Heifers receiving CuCO3 had lower liver Cu concentrations than the other heifers. In Experiment 2, 40 heifers were fed diets containing 0.15% of added S and 5 mg of added Mo/kg of DM. Treatments were control, CuSO4, CuCO3, and Cu proteinate A. All sources provided 5 mg of added Cu/kg of DM. Controls and heifers supplemented with CuSO4 had declining plasma Cu concentrations. Supplementation with CuCO3 or Cu proteinate A maintained plasma Cu concentrations. Heifers supplemented with Cu proteinate A had smaller decreases in liver Cu concentrations than did heifers supplemented with other Cu sources. In the absence of high Mo, Cu proteinates were similar in bioavailability to CuSO4. In the presence of high Mo, Cu proteinate A appeared to have a greater bioavailability than CuSO4. Copper carbonate increased or maintained plasma Cu concentrations but was not stored in the liver efficiently. PMID- 8675776 TI - Correlations of neutrophil phagocytosis for proven bulls with traits of economic importance of their daughters. AB - Neutrophil phagocytic parameters, measured on 25 AI Canadian Holstein bulls, were investigated for evidence of association with production and type traits, SCC, and survival of dairy cows. An animal model and REML methodologies were used to evaluate the bulls for their neutrophil potential phagocytic activity and capacity. A total of 42,103 first lactation records, collected from 1985 through 1993 for 2919 Quebec dairy herds, were used to obtain EBV for SCC and log SCC for 697 sires. From the same population of cows, 32,900 lactation records were used to calculate EBV for survival after first lactation for 338 sires. Correlations of EBV for SCC and log SCC with all other traits were not significant. Official Canadian ETA for type traits related to the mammary system tended to be positively correlated with phagocytosis parameters. Official Canadian ETA for production traits tended to be negatively correlated. The ETA for milk protein had a significant negative correlation with potential phagocytic activity. Survival after first lactation was significantly associated with ETA for dairy character, milk fat, and fat percentage. PMID- 8675777 TI - Effect of variance of interaction effects of sire and herd on selection for milk and fat yield. AB - The animal model for genetic evaluations of dairy cattle by the USDA currently includes a term for interaction effects of sire and herd. The relative magnitude of the variance of that effect was established in the 1960s as 14% of the total variance, but recent research has shown that the proportion is 2% or less. This report compared EBV using either the 14% or the actual estimate from 20 samples of records from herds in California, New York, and Pennsylvania. From 6 to 22% of bulls or cows selected for milk and fat yields based on evaluation with 14% of the total variance would not be selected using the sample estimates, depending on selection intensity, region, and whether only first or up to three lactations were used in the evaluations. Nevertheless, the average EBV of the bulls and cows selected based on 14% of the total variance were only slightly less than for those selected on 2%. This pilot research suggests that further study of the national data be done to establish the appropriate proportion of variance from interaction effects of sire and herd to use with national evaluations. Kinds of evaluations of bulls and ages of cows and bulls should be considered. PMID- 8675778 TI - Alkaline phosphatase activity in Penicillium roqueforti and in blue-veined cheeses. AB - The Penicillium roqueforti mold exhibits alkaline phosphatase activity. Therefore, blue mold-ripened cheeses made from properly pasteurized milk test positive for phosphatase. Because microbial phosphatases are considered to be more resistant to heat than is milk phosphatase, a statutory control test recommends the repasteurization of cheese at 66 degrees C for 30 min to inactivate selectively the native milk enzyme. However, because of thermal lability of Penicillium roqueforti phosphatase, this control test leads to confusion of the fungal enzyme with native milk alkaline phosphatase and does not confirm whether the milk used to make cheese has been pasteurized. PMID- 8675779 TI - Beta-casomorphins: analysis in cheese and susceptibility to proteolytic enzymes from Lactococcus lactis ssp. cremoris. AB - Commercial cheese products were surveyed for beta-casomorphin peptides. Two extraction methods were compared: 1) water and 2) chloroform and methanol. Peptide profiles were determined using reverse-phase HPLC and multiple wavelength detection. beta-Casomorphin standards were used for comparison with cheese peptide profiles. Results indicated that peptides were present in cheeses with HPLC elution times that were similar to those for beta-casomorphins. However, comparison of absorbancies of the peaks at multiple wavelengths did not indicate peptides similar to beta-casomorphins. Therefore, beta-casomorphins were absent, or concentrations were below the HPLC detection threshold for beta-casomorphin of 2 micrograms/ml of cheese extract. The susceptibility of beta-casomorphins to the proteolytic system of a commercial strain of Lactococcus lactis ssp. cremoris was investigated. beta-Casomorphin standards were incubated at 4 degrees C with bacterial cell lysate at pH 5.0, 5.2, 5.4, and 5.7. Salt concentrations varied among 0, 1.5, and 5%. The concentration of added beta-casomorphins and the degradation products were monitored over 15 wk using HPLC. Enzymatic degradation of beta-casomorphins was influenced by the combination of pH and salt concentrations at cheese ripening temperatures. Therefore, if formed in cheese, beta-casomorphins may be degraded under conditions common for Cheddar cheese. PMID- 8675781 TI - Effect of foot lesions on milk production by dairy cows. AB - Individual curves for milk production of 428 cows affected by foot lesions were compared with control curves drawn from data of healthy lactating cows. First, differences were classified into patterns of milk loss, and their distribution was analyzed among the patterns with regard to breed, season, parity, stage of lactation, and milk production. Then, individual milk losses were estimated and analyzed according to the same factors. During early lactation, as during mid to late lactation, no marked modifications of the lactation curves occurred for about one-half of the cases. In 25% of the cases, milk production was affected for an expanded period (medians were 17 wk for early lactation and 12 wk for mid to late lactation). Corresponding median milk losses were 440 and 270 kg, respectively. Summer foot lesions were more severe than winter lesions, regardless of stage of lactation. Milk production at foot lesion onset was a determining factor of the amount and pattern of milk loss only for cases occurring during mid to late lactation. PMID- 8675780 TI - Modulation of proliferation, second messenger levels, and morphotype expression of the rat intestinal epithelial cell line IEC-6 by fermented milk. AB - Trophic effects of milk fermented with Lactobacillus helveticus, Lactobacillus paracasei ssp. paracasei, Bifidobacterium sp., or the combination of Lactobacillus bulgaricus and Streptococcus thermophilus (yogurt) were studied on the IEC-6 intestinal epithelial cell line. Incorporation of [methyl-3H]thymidine, mitochondrial dehydrogenase activities, cyclic AMP production, and differentiation of levels of the IEC-6 strain were evaluated between the 15th and 30th passage in culture. All fermented and unfermented milks enhanced trophic responses of IEC-6 cells in a dose-dependent manner. Compared with the corresponding milks, supernatant fractions were more effective in stimulating mitochondrial dehydrogenase response. Fermented milk supernatants were also more effective than the corresponding unfermented fractions. Increases in DNA synthesis and cyclic AMP confirmed the activation observed with mitochondrial dehydrogenase. Yogurt induced the more trophic response with an increased number of the more differentiated cell morphotype. Fermentation with L. casei also demonstrated an important trophic adaptation of IEC-6 cells. Milk processing by lactic acid bacteria enhanced trophic and proliferation responses of intestinal epithelial cell line IEC-6. These results suggested that IEC-6 cells could represent an accurate and easy in vitro model for testing the trophic quality of various nutrients and for an optimization of physiological digestive functions. PMID- 8675782 TI - Evaluation of a stochastic dynamic replacement and insemination model for dairy cattle. AB - An approach to evaluating results from a stochastic, dynamic model for insemination and replacement of dairy cattle was devised using sensitivity and behavioral analyses. Sensitivity analysis was defined as the quantification of the various outputs resulting from uncertain price and production inputs. Behavioral analysis determined how outputs changed when model specifications were changed. The variation in outputs that were identified by sensitivity analysis was used as an objective measure to assess variation caused by behavioral analysis scenarios. A contemporary model was modified, and a base run was defined using Florida values for input variables. The model specifications that were varied were decision horizon, number of milk production levels, and number of days open classes. Effects of including seasonality of milk production, milk price, and conception rate were examined. The necessary decision horizon was shorter than other works would suggest. Optimal policies were influenced greatly by the number of days open classes, but not by the number of milk production levels. Removal of seasonality of milk production and conception rate resulted in meaningful changes in seasonal patterns of all outputs measured. Our results suggest that model specifications could affect results and should be evaluated objectively when models are being developed. PMID- 8675783 TI - Mathematical modeling to estimate efficacy of postmilking teat disinfection in split-udder trials of dairy cows. AB - A mathematical model was used to estimate the efficacy of postmilking teat disinfection from observations in split-udder trials with natural exposure. Data were studied from an outbreak of Staphylococcus aureus IMI during a split-udder trial in a commercial herd with low SCC. The efficacy of postmilking teat disinfection was similar when calculated based on incidence density rates or on transmission rates of IMI in dipped and control quarters. If, however, first and subsequent S. aureus IMI in a cow were not assumed to be independent and were therefore treated separately in the models, the efficacy of post-milking teat disinfection was calculated as being higher with the modeling procedure. The analysis using mathematical modeling, which includes the effect of the number of existing IMI on the number of new IMI, is presented and discussed. This analysis also allows estimation of the basic reproduction ratio. The impact of postmilking teat disinfection on transmission of pathogens is quantified, and proposals for additional preventive measures can be generated. We concluded that efficacy estimations from split-udder trials, assuming quarters to be independent observations, might underestimate the effect of postmilking teat disinfectants on udder pathogens. PMID- 8675784 TI - alpha-Tocopherol concentrations in milk and plasma during clinical Escherichia coli mastitis. AB - Eighteen cows were challenged by intramammary infusion with Escherichia coli 727 to determine the effects of acute clinical mastitis on alpha-tocopherol concentrations in plasma and milk. Cows were fed diets supplemented with 1000 IU of vitamin E/d from calving through the experimental period. At challenge, geometric mean DIM was 33 d. Each mammary quarter was diagnosed with an IMI and clinical mastitis at 24 and 48 h after challenge. The alpha-tocopherol concentrations in milk from challenged quarters were approximately 60% greater by 24 and 48 h after challenge than concentrations at prechallenge and 168 h postchallenge. Plasma alpha-tocopherol concentrations did not change after intramammary challenge. The alpha-tocopherol in plasma and milk was correlated at 48 and 168 h postchallenge but not at prechallenge or 24 h postchallenge. Milk alpha-tocopherol and SCC were correlated positively across all sample periods. Milk fat and milk alpha-tocopherol concentrations were correlated at each sample period except 24 h postchallenge. Increases in milk alpha-tocopherol during clinical mastitis were not correlated to milk production, DMI, or BSA concentration in milk. Changes in milk alpha-tocopherol concentration during clinical mastitis were similar to the dynamics of milk SCC. PMID- 8675785 TI - Mastitis-causing Escherichia coli: serum sensitivity and susceptibility to selected antibacterials in milk. AB - A total of 169 Escherichia coli strains were isolated from cows with cases of clinical mastitis. beta-Glucuronidase production, serum sensitivity, and susceptibility to selected antibacterials were analyzed using the fluorometric beta-glucuronidase assay. About 89% (150 of 169) of the isolates tested positive for beta-glucuronidase. Of these isolates producing beta-glucuronidase, 102 (68%) were resistant or moderately resistant to bovine serum. The antibacterial susceptibility of 96 isolates was tested in broth and milk. There was a significant shift from lower fluorometric minimum inhibitory concentration for tetracycline, sulfadoxin-trimethoprim, enrofloxacin, and gentamicin in broth to higher fluorometric minimum inhibitory concentration in milk. Serum sensitivity and susceptibility to tested antibacterials in broth or in milk were not related. Gentamicin and sulfadoxin-trimethoprim seemed to be more potent in mastitic milk than in normal milk, suggesting a possible synergistic effect between these exogenous antibacterials and the indigenous antibacterial agents in mastitic milk. PMID- 8675786 TI - Detection of clinical mastitis by changes in electrical conductivity of foremilk before visible changes in milk. AB - Mastitis was induced by the direct infusion of Staphylococcus aureus or Streptococcus uberis into the mammary gland of lactating cows. Changes in electrical conductivity of foremilk indicated the establishment of bacteria, increased SCC, increased clotting of milk, and, hence, disease, in advance of visible changes in the milk that could be diagnosed by a herdsperson. Clinical mastitis was detectable by changes in electrical conductivity of foremilk, 90% of cases were detectable when clots first appeared in foremilk, and 55% of cases were detectable up to 2 milkings prior to the appearance of clots. All subclinical infections from Staph. aureus were detected, but subclinical infections from Strep. uberis were not detected. The results suggested that clinical mastitis caused by these two major pathogens could be detected earlier by measuring changes in electrical conductivity of milk than by waiting for a herdsperson to detect visible changes in milk. Earlier detection would permit earlier treatment. However, the handheld sensor used in this experiment is impractical for commercial application, and reliable automated sensors and decision-making algorithms are required. PMID- 8675787 TI - Effects of chemical treatment of whole canola seed on digestion of long-chain fatty acids by steers fed high or low forage diets. AB - The objective was to evaluate the effectiveness of alkaline H2O2 treatment of whole canola seed as a means of weakening the seed coat while simultaneously protecting long-chain unsaturated fatty acids from ruminal biohydrogenation without hindering their digestion in the lower gut. Six ruminally and duodenally cannulated beef steers were offered six isonitrogenous diets for ad libitum intake twice daily in a 6 x 6 Latin square design. Treatments were arranged as a 2 x 3 factorial with two forage percentages (70 vs. 30% of dietary DM as corn silage) and three forms of canola seed supplementation, including no canola seed or canola seed added at 10% of dietary DM as treated whole seed or as crushed seed. Canola seed contributed 5% added fat to the total diet. Treated whole canola seed was superior to crushed seed in increasing the amounts of C18:1, C18:2, and C18:3 flowing to the duodenum and the amounts digested postruminally. However, digestibilities of these long-chain fatty acids (as percentages of the amounts entering the small intestine) did not differ between diets containing canola seed as treated whole seed or crushed seed. Results suggest that chemically treated whole canola seed can be used as a means of postruminal delivery of digestible long-chain unsaturated fatty acids, especially C18:1, which contributes 62% of the total fatty acids in canola seed. Results also suggest that treated whole canola seed may be more beneficial when fed with low than with high forage diets. PMID- 8675788 TI - Effects of forage percentage and canola seed on ruminal protein metabolism and duodenal flows of amino acids in steers. AB - The objective was to determine the effects of dietary forage percentage and fat supplementation on ruminal N metabolism, duodenal flows of AA, and digestion of N. Six ruminally and duodenally cannulated steers were offered six isonitrogenous diets for ad libitum intake twice daily in a 6 x 6 Latin square design. Treatments were arranged as a 2 x 3 factorial with two forage percentages (70 vs. 30% of dietary DM as corn silage) and three forms of canola seed supplementation, including no canola seed or canola seed added at 10% of dietary DM as whole seed treated with alkaline H2O2 or as crushed seed. No interactions between dietary forage percentage and canola seed supplementation occurred for any of the measurements. Duodenal flows of NAN and AA were greater for diets containing low forage than for diets containing high forage. However, duodenal flows of total N and NAN did not differ among diets when corrected for differences in intake. Efficiency of bacterial protein synthesis and duodenal flows of bacterial N and AA were increased when treated whole canola seed was supplemented. Apparent total tract digestibility of N was not altered by dietary forage percentage or canola seed supplementation. Results indicate that fat supplementation from canola seed (at 5% of dietary DM), in either form, had no effects on ruminal N metabolism or flows of AA to the duodenum and suggest that treated whole canola seed may stimulate ruminal bacterial protein synthesis. PMID- 8675789 TI - Dental materials: 1994 literature review. PMID- 8675790 TI - The use of panoramic radiology in dental practice. AB - OBJECTIVES: Approximately 1.5 million panoramic radiographs are taken annually in the general dental service in England and Wales. The aim of this review was to assess the clinical role of panoramic radiology in the diagnosis of diseases associated with the teeth and to consider its value in routine screening of patients. METHOD: This was carried out by critical review of the literature. RESULTS: In addition to common problems with radiographic technique and processing, there are limitations in image quality inherent to panoramic radiology. These factors contribute to a reduced diagnostic accuracy for caries diagnosis, demonstration of periodontal bone support and periapical pathology when compared with intraoral radiography. Routine screening is unproductive for large proportions of dentate and edentulous populations, while in those cases where pathology is detected the diagnostic accuracy can be questioned. Furthermore, the "detection' of asymptomatic anomalies may have no effect on patient management. Attempts to develop and test panoramic radiographic selection criteria are reviewed. CONCLUSIONS: New, high-yield selection criteria for panoramic radiography are proposed as a means of reducing unnecessary examinations, limiting radiation doses and reducing financial costs to patients and health service providers. However, research is indicated to develop further and to test such selection criteria. PMID- 8675791 TI - Five-year performance of high-copper content amalgam restorations in a multiclinical trial of a posterior composite. AB - PURPOSE: This paper reports the 5-year performance of the restorations of the high-copper content dental amalgam alloys included in the worldwide programme of clinical trials of Occlusin, including unique data on wear. METHODS: The methods employed are common to those previously reported for the multiclinical evaluation of Occlusin. Analysis of the data is limited to simple statistical procedures. RESULTS: The findings lend support to existing knowledge concerning the favourable performance of restorations of high-copper content dental amalgam alloys, notably in relation to restorations in moderate- to large-sized Class II preparations in permanent molar teeth. Analysis of the data sheds new light on the influences of variables, including type of tooth restored, size and class of restoration and the presence or absence of occlusal contact(s) on performance. CONCLUSION: Conclusions are drawn regarding ways in which protocols for future evaluations of the type reported should be expanded, and, together with suggestions for further work, it is concluded that this paper is a timely reminder of the value of existing dental amalgam alloys. PMID- 8675792 TI - Effects of acidic conditioners on dentine demineralization and dimension of hybrid layers. AB - OBJECTIVES: This study was aimed at investigating the relationships between dentine conditioning for different durations with different acids and (1) the resulting depth of dentinal demineralization and (2) the rebounding capacity of collapsed collagen due to primer and adhesive resin penetration. METHODS: Two commercial and four experimental acids were tested directly by light microscopic evaluation of the depth of decalcification of dentine, and indirectly by determination of the hybrid layer thickness and the total depth of demineralization effects on perpendicular sections through Gluma bonded composite resin specimens. RESULTS: Depths of demineralization increased by both acid concentrations and conditioning times following a logarithmic relationship. There was good agreement between the results of the direct and the indirect procedures. Thirty seconds' conditioning with 20% phosphoric-acid gel resulted in 10-microns hybrid layer thickness. This 20% compound was considered a suitable compromise as a uni-etch conditioner since 30-s etch duration also generated an effective enamel retentive pattern and at the same time a frosted enamel appearance for visual control of extent and efficacy of enamel conditioning. PMID- 8675793 TI - Shear bond strength of four dentinal adhesives applied in vivo and in vitro. AB - OBJECTIVES: The purpose of this study was to determine whether dentine bonding performed under clinical conditions is as reliable as laboratory bonding. METHODS: Freshly cut dentine was used in vivo or in vitro as a substrate for the bonding of various adhesive systems. Bond strength was measured in shear loading. RESULTS: Clearfil Liner Bond, Optibond and All Bond 2 showed better results when applied in vivo than in vitro. Scotchbond Multipurpose showed the opposite effect but the bond strength was, for both conditions, superior to the other three products. Only All Bond 2 presented statistically significant differences in bond strength between in vivo and in vitro applied bonding. CONCLUSIONS: The results indicate that, with the new hydrophilic dentine bonding systems, in vitro application does not lead to substantially different results when compared with, in vivo application. PMID- 8675794 TI - Laboratory evaluation of three visible light-cured resinous liners. AB - OBJECTIVES: The aim of the present study was to evaluate the composition and the laboratory performance of three visible light-cured resinous liners (Cavalite, Ionoseal and Timeline). METHODS: Monomers were separated from fillers and were analysed by HPLC. Set pastes were analysed by FTIR spectroscopy and diametral strengths and water solubility were measured. RESULTS: The monomers identified in the liners were BisEMA/2-HEMA (Cavalite), BisDMA/BisGMA (Ionoseal) and UEDMA (Timeline). Significant variations were found in the filler content but the mechanical response as assessed by the diametral tensile strength showed no statistical differences. The curing efficiency ranged from 24.2 to 31.0% (top surfaces) to 26.0-54.0% (bottom surfaces) of remaining C = C bonds. No positive correlations were found between curing efficiency and optical properties. The bond strength of the liners to dentine was negligible compared with that to composite. All the liners demonstrated extensive gap formation and debonding at the liner-dentine interfaces in marginal adaptation testing. Statistical differences were noticed in the water absorption and water solubility values of the products. Ionoseal showed extensive hydrolytic degradation compared with the other liners. No evidence of acid-base reaction was found in the set products. PMID- 8675795 TI - The impact of language on our perceptions as dental researchers: who do we remove "plaques" from teeth but add them to our walls? PMID- 8675796 TI - Role of adhesion in microbial colonization of host tissues: a contribution of oral microbiology. PMID- 8675797 TI - Does an incremental filling technique reduce polymerization shrinkage stresses? AB - It is widely accepted that volumetric contraction and solidification during the polymerization process of restorative composites in combination with bonding to the hard tissue result in stress transfer and inward deformation of the cavity walls of the restored tooth. Deformation of the walls decreases the size of the cavity during the filling process. This fact has a profound influence on the assumption--raised and discussed in this paper--that an incremental filling technique reduces the stress effect of composite shrinkage on the tooth. Developing stress fields for different incremental filling techniques are simulated in a numerical analysis. The analysis shows that, in a restoration with a well-established bond to the tooth--as is generally desired--incremental filling techniques increase the deformation of the restored tooth. The increase is caused by the incremental deformation of the preparation, which effectively decreases the total amount of composite needed to fill the cavity. This leads to a higher-stressed tooth-composite structure. The study also shows that the assessment of intercuspal distance measurements as well as simplifications based on generalization of the shrinkage stress state cannot be sufficient to characterize the effect of polymerization shrinkage in a tooth-restoration complex. Incremental filling methods may need to be retained for reasons such as densification, adaptation, thoroughness of cure, and bond formation. However, it is very difficult to prove that incrementalization needs to be retained because of the abatement of shrinkage effects. PMID- 8675798 TI - Correlative transmission electron microscopy examination of nondemineralized and demineralized resin-dentin interfaces formed by two dentin adhesive systems. AB - The resin-dentin interface formed by two dentin adhesives, Optibond (OPTI, Kerr) and Scotchbond Multi-Purpose (SBMP, 3M), was ultramorphologically examined by transmission electron microscopy (TEM). Ultrastructural information from nondemineralized and demineralized sections was correlated. It was hypothesized that the different chemical formulations of the two adhesives would result in a different morphological appearance of the hybrid layer. Ultrastructural TEM examination proved that each of the two dentin adhesive systems was able to establish a micromechanical bond between dentin and resin with the formation of a hybrid layer. However, the interfacial hybridization process that took place to produce this resin-dentin bond appeared to be specifically related to the chemical composition and application modes of both systems. OPTI consistently presented with a hybrid layer with a relatively uniform ultrastructure, electron density, and acid resistance. These three parameters were found to be more variable for the hybrid layer formed by SBMP. Characteristic of SBMP was the identification of an amorphous phase deposited at the outer surface of the hybrid layer. Although both adhesive systems investigated follow a total-etch concept, their specific chemical formulations result in different interfacial ultrastructures that are probably related to different underlying bonding mechanisms. The clinical significance of these morphological findings, however, is still unknown. PMID- 8675799 TI - Effects of different magnitudes of tension-force on alkaline phosphatase activity in periodontal ligament cells. AB - Alkaline phosphatase (ALP) activity is involved in the process of calcification in various mineralizing tissues, and it is found at much higher levels in the periodontal ligament (PDL) than in other connective tissues. Since the PDL lies between hard tissues and functions as a cushion mitigating mechanical stress, such as occlusal and orthodontic forces, this stress may modulate ALP activity in PDL cells, which themselves may affect adjacent alveolar bone metabolism. The objective of this study was to determine the level of ALP activity and the gene expression of liver/bone/kidney (L/B/K) ALP in human PDL fibroblasts in response to cyclic tension-forces. Human PDL cells were cultured on flexible-bottomed plates and placed on a Flexercell Strain Unit. Cells were flexed at 6 cycle/min (5 sec strain, 5 sec relaxation) at 6 levels of tension-force (9%, 12%, 15%, 18%, 21%, and 24% increase in surface area) for 5 days. There was no significant difference in cell proliferation between the cells subjected to the tension-force and the controls. There was a 10% and 42% decrease, respectively, in the ALP activity in PDL cells exposed to low (9%) and high (24%) tension-forces, and these decreases were dependent on the magnitude of the tension-force. The finding of inhibited ALP activity in response to tension-force was consistent with the observation that L/B/K ALP mRNA levels were decreased in response to cyclic tension-force. These results suggest that tension-force may affect PDL metabolism, depending on the functional role of ALP. PMID- 8675800 TI - Functional characteristics of gingival and periodontal ligament fibroblasts. AB - In periodontal surgery, healing after guided tissue regeneration (GTR) may be explained by differences in functional activities of gingival and periodontal ligament fibroblasts (GF and PDLF). Several studies in vitro have supported this hypothesis, but much remains to be defined. In the present work, gingival and periodontal ligament fibroblasts derived from five healthy subjects were isolated and compared in vitro. The morphology of the cells was observed under scanning electron microscopy (SEM). Several extracellular matrix components (ECM) were studied to compare the effects on fibroblast attachment, proliferation, and protein synthesis. Several biochemical markers were examined in both cellular extract (CE) and conditioned medium (CM). We also examined the muscle differentiation markers alpha-smooth muscle actin, desmin, and smooth-muscle myosin. Finally, we studied the effects of epithelial cells on the proliferation and protein synthesis of the two types of fibroblasts. GF and PDLF appeared identical under the SEM. All ECM components enhanced attachment; however, while collagen types I and IV promoted the attachment of GF, gelatin, laminin, and vitronectin promoted that of PDLF. Most ECM components increased the proliferation rate of GF and the biosynthetic activity of PDLF. The biochemical markers were similarly distributed between the two cell types, except for alkaline phosphatase, which was detected only in the CE of PDLF. Both GF and PDLF strongly expressed alpha-smooth-muscle actin and were negative for desmin; only PDLF were positive for smooth-muscle myosin. Epithelial cells increased the proliferation of both GF and PDLF but had no effect on their biosynthetic activity. These in vitro results may better explain the in vivo functional differences between GF and PDLF. PMID- 8675801 TI - Agents with periodontal regenerative potential regulate cell-mediated collagen lattice contraction in vitro. AB - A variety of pharmaceutical agents has been proposed for use in periodontal therapy to inhibit loss of alveolar bone and to promote regeneration of tissues lost to disease. The purpose of this study was to determine the effects of such agents on periodontal cell-mediated gel contraction, an in vitro process considered representative of wound contraction and remodeling in vivo. Human gingival fibroblasts were cultured in a type I collagen lattice, and contraction was quantified by means of a computer-assisted video imaging system. Cell-gel combinations were prepared with cells both pre-exposed and non-exposed to agents; non-anchored cell-gels were then incubated with agents for various time periods. Agents tested included Demecolcine (an inhibitor of cytoskeletal contraction), growth factors (i.e., TGF-beta 1, PDGF, and IGF-1), and non-steroidal anti inflammatory drugs (NSAIDs) (indomethacin, ibuprofen, naproxen, and flurbiprofen). While Demecolcine inhibited gel contraction, TGF-beta 1 (1-20 ng/mL), PDGF (100 ng/ML), IGF-1 (1000 ng/mL), and [PDGF + IGF], all of which have been reported to enhance wound healing in vivo, promoted lattice contraction in this system. In contrast, NSAIDs inhibited cell-gel contraction. Ethanol, used to solubilize two specific NSAIDs, also inhibited cell proliferation and gel contractile ability, even at very low concentrations. These findings indicate that periodontal cells respond differently to various agents in vitro and may be adversely affected by alcohol. Furthermore, the results of this study suggest that the cell-lattice contraction system holds potential as a method for screening agents for positive or negative effects on cell activity. PMID- 8675802 TI - Re-epithelialization of human oral keratinocytes in vitro. AB - Re-epithelialization involves interactions between keratinocytes and the extracellular matrix upon which these cells move. It is hypothesized that keratinocytes are activated when wounded, and the resultant phenotypic change directs re-epithelialization. We have adapted organotypic cultures, in which oral gingival keratinocytes are fully differentiated, to study re-epithelialization following wounding. To elucidate keratinocyte behavior and phenotype during re epithelialization, we have investigated this process in the presence and absence of the growth factor TGF-beta 1 and have monitored expression of MMP-1 (Type I collagenase) mRNA by in situ hybridization. In addition, we have followed proliferation and migration of wound keratinocytes by genetically marking these cells with a retroviral vector and by measuring their proliferative index. We found that keratinocytes grown without TGF-beta 1 were hyperproliferative in response to wounding, and re-epithelialization was complete by 24 h. However, 2.5 ng/mL TGF-beta 1 induced a transient delay in re-epithelialization, a reduction in proliferation, and fewer clusters of genetically marked cells. Keratinocytes expressed MMP-1 mRNA only when they covered the wounded surface, suggesting that the cells acquire a collagenolytic phenotype during re-epithelialization and that contact with different ECM components may modulate keratinocyte expression of MMP 1. We conclude that the phenotype of oral keratinocytes is altered during re epithelialization in vitro and that this process is modulated by TGF-beta 1. Re epithelialization occurs as keratinocytes are activated to move over the wound bed. Understanding the phenotype of wounded keratinocytes may facilitate treatment of chronic oral wounds and periodontal disease. PMID- 8675803 TI - Effects of dexamethasone and cell proliferation on the expression of matrix metalloproteinases in human mucosal normal and malignant cells. AB - Matrix metalloproteinases (MMPs) have an important role in many biological processes, such as tumor metastasis, wound healing, and inflammation. The regulation of MMPs and their inhibitors is still not known in detail, and the aim of this study was to investigate the effects of dexamethasone on cultured oral benign and malignant cell lines. The expression of MMPs in culture was studied: in four gingival (GF) and one periodontal ligament (PLF) fibroblast cell lines; in six gingival keratinocyte (GK) cell lines; and in UNR (UNR-108, rat osteogenic sarcoma) and SCC (SCC-25, human tongue squamous cell carcinoma) cell lines. In the GFs, PLFs, and UNR cells, only MMP-2 (72 kDa gelatinase) was detected by gelatin zymography, while in most of the GK cell lines only MMP-9 (92 kDa gelatinase) was observed. In confluent SCC cultures, both MMP-2 and MMP-9 were found, while only MMP-2 was seen in rapidly growing SCC cells, demonstrating that cell proliferation influenced gelatinase expression in these cells, but not in the other cell lines studied. Dexamethasone at concentrations of 10(-5) mol/L and 10(-7) mol/L decreased the production of gelatinases in the GFs and PLFs, but not in the GKs, SCC, or UNR cells. The expression of mRNAs for matrix metalloproteinases (MMP-1 [interstitial collagenase] and MMP-2) and their inhibitors (TIMP-1 and TIMP-2) was also studied in the GFs by Northern hybridization. Dexamethasone markedly decreased the amount of MMP-2 mRNA in the GFs. The mRNA level of MMP-1 decreased even more in the same GFs. The mRNA levels for TIMP-1 and TIMP-2 were also decreased by dexamethasone in the GFs. Cell proliferation influenced the degree to which dexamethasone decreased these mRNA levels. The results indicate that glucocorticoids decrease the levels of MMPs and TIMPs in oral fibroblastic cells, whereas they do not appear to affect the production of gelatinases in either normal or malignant oral epithelial cell lines. PMID- 8675804 TI - Induction of lymphocytes cytotoxic to oral epithelial cells by Streptococcus mitis superantigen. AB - The preparation of a superantigenic fraction F-2 from the culture supernatant of Streptococcus mitis 108, a fresh isolate from human tooth surfaces, was reported previously. Now, to determine the possible pathogenic role of the superantigen in oral mucosal diseases, we examined the cytotoxic effects of human peripheral blood T-cells activated with F-2 on human oral epithelial cells. T-cells activated with F-2 were cytotoxic to the human squamous carcinoma HO-1-N-1 cells derived from the oral mucosa, similar to those activated with Staphylococcus aureus enterotoxin B (SEB). This cytotoxic effect was increased in a dose dependent manner by the addition of the respective stimulant, F-2 or SEB, to the cytotoxic assay system. F-2 endowed mainly CD8+ T-cells with cytotoxic activity. Pretreatment with human interferon gamma increased the sensitivity of the HO-1-N 1 cells to the cytotoxic effects of F-2-activated T-cells. The F-2-activated T cells were also cytotoxic to human keratinocytes derived from gingiva. There was no correlation between the degree of cytotoxicity and the levels of tumor necrosis factor alpha in co-cultures of F-2-activated T-cells and HO-1-N-1 cells. A double-chamber plate experiment revealed no cytotoxic effects when the F-2 activated T-cells were separated from the HO-1-N-1 cells. Supernatants of the co cultures of target and effector cells were not cytotoxic to HO-1-N-1 cells. These findings suggest that the cytotoxic effects of the F-2-activated T-cells on HO-1 N-1 cells were mediated not by soluble factors but by the direct interaction between the activated T-cells and the target cells. The cytotoxicity of the F-2 activated T-cells against HO-1-N-1 cells was markedly inhibited by monoclonal antibodies (MAbs) against CD11a and CD54, but was only slightly inhibited by MAbs against human leukocyte antigen (HLA)-DR and CD2. Thus, the interaction between lymphocyte-function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) was crucial for the F-2-dependent T-cell-mediated cytotoxicity against oral epithelial cells, while HLA-DR and CD2 molecules are not necessarily involved in the cytotoxicity observed. PMID- 8675805 TI - A regulatory role in mammalian salivary glands for 5-hydroxytryptamine receptors coupled to increased cyclic AMP production. AB - Although a functional role for serotonin (5-hydroxytryptamine, 5-HT) has been defined in the salivary glands of some lower species, relatively few data supporting a role for 5-HT in the regulation of mammalian salivary glands have been presented. Our initial results from polymerase chain reaction studies in cells of mammalian submandibular gland origin using consensus sequence primers from G protein-coupled receptors suggested the presence of mRNA for a 5-HT receptor in these cells. Based on this observation, the question of a role for 5 HT in mammalian submandibular gland function was re-addressed, using isolated, perfused rat submandibular glands and dispersed-cell aggregates from this gland. In perfused glands, 5-HT decreased the rate of saliva flow initiated by acetylcholine by about 50% and increased the amount of protein in the saliva two fold. In dispersed-cell aggregates, 5-HT elicited a concentration-dependent increase in the accumulation of adenosine 3',5' monophosphate (cyclic AMP; EC50 = 660 +/- 110 nM). In addition, functional studies, as well as radioligand binding experiments, indicated that the effects of 5-HT are independent of beta adrenoceptors. Accumulation of cAMP in gland cells was consistent with a direct action of 5-HT on adenylyl cyclase. Similar cyclic AMP responses to 5-HT were observed in cells isolated from mouse and opossum submandibular glands and rat sublingual and parotid glands. Our findings suggest the presence of a 5-HT receptor in mammalian salivary glands coupled to the stimulation of adenylyl cyclase and, at least in rat submandibular gland, involved in modifying the volume and protein content of saliva. PMID- 8675806 TI - A quantitative morphological comparison of cat lingual nerve repair using epineurial sutures or entubulation. AB - Since lingual nerves may be transected during a variety of oral surgical procedures, including third molar removal, we have investigated two possible methods of repair. Quantitative morphological observations were made on feline chorda tympani and lingual nerves proximal and distal to transection injuries repaired either by epineurial suturing or by insertion of the cut ends into a perforated silicon tube. Proximal to the repair, the most prominent difference was an increase in the number of myelinated axons in the lingual nerve following epineurial suturing but not entubulation. Proximal to the repair site, the number of nonmyelinated axons increased in comparison with controls in both chorda tympani and lingual nerves after both procedures, though the difference was statistically significant only in the lingual nerve proximal to entubulation. Distal to the injury, both types of repair showed a reduction in the number, size, and sheath thickness of myelinated axons in comparison with unoperated controls, but the difference in numbers was statistically signIficant only distal to repair by entubulation. The number of non-myelinated axons distal to the repair sites was much higher than that in controls, the difference being greater distal to entubulation repair. There were more axons per Remak bundle distal to entubulation repair than to epineurial suturing, suggesting, perhaps, that fewer axons would ultimately become myelinated. Though the morphological differences between the two repair techniques are not as striking as the parallel electrophysiological differences reported previously (Smith and Robinson, 1995a,b), they are consistent with them and support the conclusion that, for transected lingual and chorda tympani nerves, epineurial suturing is the preferred approach. PMID- 8675807 TI - Transmission electron microscopy of cementum crystals correlated with Ca and F distribution in normal and carious human root surfaces. AB - Root-surface caries, like enamel caries, develops as a subsurface type of mineral loss. Very little is known about the composition of the surface zone covering the body of the lesion, and the ultrastructure and composition of carious cementum are not known. The aim of this study was to correlate the ultrastructure and arrangement of the cementum crystals with the distribution of fluoride and calcium in root cementum from human teeth with sound, unexposed, or exposed root surfaces as well as in early stages of root-surface caries. Microradiographically, unexposed specimens showed a relatively homogeneous mineral distribution contrasting with the formation of an apparently highly mineralized surface layer in exposed and, in particular, in carious cementum. The electron-probe findings showed a substantial fluoride peak corresponding to the surface layers in carious tissues in particular, whereas the calcium profile in the surface did not reflect the apparent increase in mineralization. A substantial increase in size of the cementum crystals was found in specimens with formation of the fluoride-rich, well-mineralized surface zone. The crystal lattice intervals when observed along the (001) plane showed a hydroxyapatite spacing. The findings indicated that a significant crystal growth can be achieved in human cementum concomitant with fluoride accumulation. PMID- 8675808 TI - Symposium on self-reported assessments of oral health outcomes. Introduction. PMID- 8675809 TI - An overview of self-reported outcome assessment in dental research. PMID- 8675810 TI - Applications of self-reported assessments of oral health outcomes. PMID- 8675811 TI - Associations among different assessments of oral health outcomes. PMID- 8675813 TI - Reactor paper. PMID- 8675812 TI - Demands and opportunities for development of self-reported assessments of oral health outcomes. PMID- 8675814 TI - Dental education and the primary oral health care clinic model. PMID- 8675815 TI - Death, dying, and bereavement education in dental schools. PMID- 8675816 TI - Student operator-assistant pairs. PMID- 8675817 TI - Complementary laboratory course in cariology. PMID- 8675818 TI - Thrombospondin receptor (CD36) expression of human keratinocytes during wound healing in a SCID mouse/human skin repair model. AB - Using a human skin/severe combined immunodeficient (SCID) chimeric mouse model, we examined the keratinocyte expression of the thrombospondin receptor (CD36) and its ligand thrombospondin-1 (TSP1) in acute uninflamed wounds. Positive suprabasal keratinocyte expression of CD36 was observed as early as 30 minutes after wounding in the adjacent, intact epidermis; it disappeared 4 days later. Keratinocytes of the freshly re-epithelised wounds and those of the surrounding epidermis remained TSP1-negative throughout the whole observation period of 7 days. Our results indicate that CD36-positive keratinocytes, probably in connection with activated, TSP1-positive thrombocytes, may play an important role in the early phase of wound healing. PMID- 8675819 TI - Anti-lipase activity of Kampo formulations, coptidis rhizoma and its alkaloids against Propionibacterium acnes. AB - Anti-lipase activity of Kampo formulations, Coptidis Rhizoma (CR), and its alkaloids against Propionibacterium acnes were examined in vitro. The amounts of propionic and butyric acids in the medium were measured as growth and lipase activity of P. acnes, respectively. In tributyrin-PYG medium with each concentration of Kampo formulation, CR, or the alkaloids added, the production of propionic acid was suppressed remarkably more than that of butyric acid. The suppression of production of these acids by CR was higher than that of the alkaloids. Furthermore, no lipase-negative colonies were found on the medium to which Kampo formulations were added. From these observations, we concluded that not only Kampo formulations and CR, but also their alkaloids, showed suppression of growth of P. acnes, which reduced anti-lipase activity. Furthermore, it was suggested that Kampo formulations and Kampo crude drugs with anti-lipase activity to P. acnes should be synergistic when their ingredients are combined. PMID- 8675820 TI - Counts of common and atypical melanocytic nevi in Korean young men: assessment of their risks and correlations with associated factors. AB - Two hundred and thirty-five Korean young men were examined for the count of melanocytic nevi (MN). The mean count of common MN of at least 2 mm diameter was 16.1. Three subjects had more than 50 common MN and another four had clinically atypical MN. We determined skin phototype by interview with questionnaires in the same persons as proposed by Fitzpatrick. All subjects were classified with respect to skin phototype and the number of previous sunburns. The correlations between common MN and the skin phototype or the number of previous sunburns were statistically analyzed. The skin phototype showed the correlation with the number of common MN, which means if skin phototype of any subject belongs to type I, he could to be predicted to have many more common MN than subjects with darker phototypes, like type VI. The correlation between number of previous sunburns and number of common MN was not statistically significant. This study shows persons at moderate risk of cutaneous melanoma (CM) do exist and skin phototype is associated with the prevalence of common MN in Koreans. PMID- 8675821 TI - Extramammary Paget's disease: a report of 22 cases in Chinese males. AB - Extramammary Paget's disease (EMPD) is more frequently seen in Caucasian females than in males (3.2:1 female:male ratio). During the past 14 year period, we have collected 22 patients, all Chinese males, with EMPD. They presented with eczema like lesions in the early stages in the genital or perianal regions. Histological sections showed Paget cells within the epidermis or skin appendages and even within the dermis. No underlying adnexal carcinoma or adjacent internal carcinoma could be detected after thorough examinations. Mode of therapy and outcome are presented. EMPD seems to affect more males than females in Orientals. The incidence of concomitant malignancy in Chinese male patients with genital Paget's disease seems to be much lower than that in Caucasians. However, if EMPD involves the glans penis or perianal area, a search for internal malignancy is still warranted. PMID- 8675822 TI - Coexistence of plaque-type blue nevus and congenital melanocytic nevi. PMID- 8675823 TI - Giant basal cell carcinoma associated with systemic amyloidosis. AB - A large basal cell carcinoma, 39 x 26 cm in size, is presented as second in size only to the largest basal cell carcinoma documented (40 x 30 cm), reported by Beck and co-workers (1). A 61-year-old Japanese male visited our clinic with a huge ulcerating tumor on the back. He had hidden the tumor for the previous 30 years. The tumor was histologically confirmed as basal cell carcinoma. The condition was associated with anemia, hypoproteinemia, and dyspnea, and with systemic amyloidosis in the skin, in the lymph nodes, and in the intestinal canal. On admission, the tumor had metastasized to the regional lymph nodes, and, about two years after the first operation, there were metastases to bone and lung, leading to death due to respiratory failure. PMID- 8675824 TI - Solitary mastocytoma treated with tranilast. AB - Two infants with solitary mastocytoma were treated with 5 mg/kg/day of tranilast [N-(3',4'-dimethoxycinnamoyl)anthranilic acid], a mast cell stabilizing compound extracted from Nandina domestica. Tranilast was administered orally in three divided doses. In one infant, a topical corticosteroid was also applied in combination with the oral tranilast. Patients experienced symptomatic relief, and nodules resolved almost completely after eight weeks of treatment. Tranilast therapy was continued for six months. No relapses were observed after discontinuation of therapy. We speculated that tranilast not only inhibited mast cell degranulation but also reduced the number of mast cells. PMID- 8675825 TI - Successful treatment of a therapy-resistant severely pruritic skin eruption of malignancy-associated dermatomyositis with high-dose intravenous immunoglobulin. AB - Malignancy-associated dermatomyositis developing in a middle-aged Japanese female was successfully treated by removal of her gastric cancer. However, five years later, concomitant with catching a cold, her severely pruritic skin lesions recurred on exposed areas. Six years after the start of corticosteroid therapy for her annoying skin lesion, we started to treat her with high-dose intravenous immunoglobulin (IVIG) infusion therapy because of the difficulty of reducing the dosage of oral prednisone, that had secondarily induced adverse effects. After five courses of the therapy, her recalcitrant, pruritic, erythematous skin lesions improved dramatically, enabling a satisfactory reduction in the dosage of oral prednisone. There were no significant adverse side effects with IVIG. PMID- 8675826 TI - Progressive systemic sclerosis sine scleroderma which developed after exposure to epoxy resin polymerization. AB - Progressive systemic sclerosis (PSS) sine scleroderma is well known as a special form of scleroderma. Because of its rarity, its pathogenesis has not yet been elucidated. We experienced a 33-year-old man who developed PSS sine scleroderma while working with epoxy resin polymerization. He had short white frenulum linguae, diffuse hyperpigmentation and facial telangiectasia, positive antinuclear antibody, and pulmonary dysfunction, but not acrosclerosis or sclerodactylia. Modest dermal collagen proliferation in the forearm skin confirmed PSS sine scleroderma. Epoxy resin polymerizer appears to be a potent causative agent for PSS sine scleroderma as well as for generalized morphea-like PSS. PMID- 8675827 TI - Antiphospholipid syndrome associated with progressive systemic sclerosis. AB - We report a case of secondary antiphospholipid syndrome (APS) occurring in a progressive systemic sclerosis (PSS) patient who took herbal medication. Clinical findings compatible with APS included positive IgM anticardiolipin antibody (ACL), thrombocytopenia, and obstruction of the left radial artery on digital subtraction angiography (DSA). Clinical findings compatible with PSS included sclerodactyly and digital ulcers, Raynaud's phenomenon, pulmonary fibrosis and pulmonary hypertension, proteinuria and renal mesangial reaction, and myocarditis. PMID- 8675828 TI - A case of stasis papillomatosis associated with psoriasis vulgaris. AB - A markedly obese, 41-year-old Japanese man who had suffered from psoriasis vulgaris for several years visited us with elephantiasis-like swelling of his lower legs of three months' duration. His right lower leg showed marked papillomatosis with thick scales, and the left lower leg was eroded and papillomatous. Although direct lymphography of his lower extremities showed no abnormality, indirect lymphography revealed local lymphatic damage in the involved skin. Histological examination showed hyperkeratosis, marked papillomatosis, proliferation of capillaries in the upper dermis, and lymphectasia in the lower dermis. The lesions were much improved by washing and topical use of corticosteroids for two months. It was suspected that obesity and the preceding psoriatic lesions caused local lymphatic disturbances, followed by the development of stasis papillomatosis. PMID- 8675829 TI - Pustular psoriasis induced by hydroxychloroquine: a case report and review of the literature. AB - A variety of pharmacologic agents have been known to induce pustular psoriasis. We describe a patient with a positive personal and family history of psoriasis who developed an extensive annular pustular eruption 3 weeks after starting hydroxychloroquine (Plaquenil) for arthritis. The drug was discontinued, and she received 3 weeks of systemic and topical corticosteroids; in spite of the therapeutic intervention, showers of new lesions appeared daily, and progressed to involve 75% of the body. The development of new lesions stopped, and the older lesions began to clear after one dose of 7.5 mg of methotrexate. Subsequently, methotrexate therapy was stopped because of mild transaminase elevation; the pustular lesions then flared. New lesions stopped appearing after four doses of weekly methotrexate. The patient remains clear of lesions 6 months later. PMID- 8675830 TI - Modified Thiersch grafting in stable vitiligo. AB - Medical management of vitiligo usually gives complete repigmentation in up to 60 to 90% of cases (4, 7). Modified Thiersh grafting, in which psoralen without UVA or solar radiation was used successfully, is described. PMID- 8675831 TI - Immunohistochemical detection of p53 tumor suppressor protein in porokeratosis. AB - We examined 9 Japanese cases of porokeratosis (4 of the plaque type, 2 of disseminated superficial actinic porokeratosis, 2 of disseminated superficial porokeratosis, and one of giant porokeratosis) for the expression of p53 tumor suppressor protein immunohistochemically, using two anti-p53 antibodies, CM1 and DO1. The same results were obtained with both antibodies. The epidermis central to the cornoid lamellae was positive in 8 of 9 specimens. On the other hand, the peripheral epidermis was positive in 2 of the 9 cases. The epidermis beneath the cornoid lamellae was positive in 3 of the 9 cases. The frequency of p53 positivity was significantly higher in the epidermis central to cornoid lamellae over that beneath or peripheral to them (Fisher's exact probability test, p < 0.05). The majority of squamous cell carcinoma cells arising on giant porokeratosis stained with CM1 and DO1. These data may suggest that the abnormal p53 expression has some relevance to the skin carcinogenesis of porokeratosis. PMID- 8675832 TI - Giant mixed tumor of the face. AB - A 35-year-old Japanese man consulted our clinic with an eight year history of a 6 cm diameter subcutaneous tumor on the left cheek. Hematoxylin and eosin staining of the resected section showed histology corresponding to a benign chondroid syringoma. Keratin was positive in most of the constituent cells, and S-100 protein was positive in the cells distant from the lumens and in myxomatous cells. A benign chondroid syringoma of this size has only been very rarely reported in the literature. PMID- 8675833 TI - Multiple sebaceous hyperplasia in a patient with Senear-Usher syndrome under immunosuppressive therapy. PMID- 8675834 TI - An artificial neural network for sound localization using binaural cues. AB - A three-layer neural network is used to estimate the direction of a sound source from the signals detected by two directional, spatially separate receivers. Although the implemented system does not require any specific knowledge about acoustical parameters or propagation properties, a model of the acoustical environment is used to generate simulated data for training the network. The neural network is trained according to the multiple extended Kalman algorithm (MEKA), which provides fast convergence and does not require intervention for adjustment of the learning parameters. Lower bounds on estimation are computed and compared with simulations using the neural network. PMID- 8675835 TI - Error bounds on ultrasonic scatterer size estimates. AB - Precision errors that occur in estimating the average scatterer size from pulse echo ultrasound waveforms are examined in detail. The method-independent lower bound on estimation error is found from the Cramer-Rao inequality for comparison with the predicted error for the measurement technique currently used to estimate scatterer sizes in soft biological tissues. The probability density function for the estimate is also derived. From these statistical analyses, strategies for designing experiments that minimize the error are discussed. It is shown that compared with biological variability, measurement errors in scatterer size estimates are relatively large. Consequently, there is reason to continue searching for more efficient estimators. Although the analysis and results are derived for Gaussian correlation models that have been used to study the function and structure of kidneys, generalization to include correlation models for other tissues is straightforward. PMID- 8675836 TI - Sound transmission to and within the human ear canal. AB - Sound transmission to the eardrum from various points in the external ear was measured by means of probe microphone technique. Twelve human subjects participated, and three directions of sound incidence were included. For the major part of the audio frequency range the transmission to the eardrum proved independent of direction from points at the centerline of the ear canal, including the entrance (open or blocked). The results further suggested that the region with independent transmission extends some millimeters outside the entrance plane. The transmission from the free field to the eardrum was divided into a directional-dependent part and two directional-independent parts: (1) the transmission from the free field to the blocked entrance, (2) a pressure division between the radiation impedance and the ear-canal input impedance, and (3) the transmission along the ear canal. All parts of the transmission were seen to be highly individual. The first part was shown to be uncorrelated with any of the other parts, whereas mutual dependence of parts (2) and (3) resulted in a smaller variation in the combined transmission than for the parts in separate. The standard deviation between subjects for head-related transfer functions (HRTFs) measured at the eardrum, the open entrance, and the blocked entrance was studied, and the lowest values were found for the blocked-entrance HRTFs. It is concluded, that the blocked entrance is the most suitable point for measurements of HRTFs and for binaural recordings, since sound at this point includes the complete spatial information, and in addition to that the minimum amount of individual information. PMID- 8675837 TI - Development of the cochlear amplifier. AB - The development of the cochlear amplifier was examined in gerbils aged 14 days after birth (dab) to adult, for stimulus frequencies from 1 to 48 kHz. Distortion product otoacoustic emissions (DPOAEs) were employed to determine the characteristics of active emissions associated with cochlear amplifier operation. DPOAEs were also used to determine the characteristics of "passive" emissions remaining when the cochlear amplifier operation was interrupted by acute furosmide intoxication. The input-output functions of the passive emissions, and of the active emissions at low stimulus levels, could be approximated by parallel straight lines. The horizontal distance between these parallel lines, i.e., the increase in stimulus level required to obtain a passive emission amplitude equal to the active emission, is an estimate of the gain of the cochlear amplifier. Further, the lowest stimulus level at which active and passive emissions become approximately equal defines a passive threshold level. At 14 dab, the cochlear amplifier gain was already at adult levels for the midfrequencies (4-8 kHz), but no emissions were detected at the extremes (at 1 kHz, and 24 kHz and above). During the period over which the endocochlear potential (EP) is known to increase most sharply (14 to 18 dab), the gain at all frequencies increased. At low frequencies there was little or no gain in the youngest age group, but matured by 23 dab. The gain at the middle frequencies subsequently decreased, resulting by 30 dab in a gain that was remarkably flat across frequency from 1 to 32 kHz. The passive thresholds generally improved with age at all frequencies, but most dramatically at the high frequencies. Results are consistent with the view that the elements of the cochlear amplifier are functional in the base of the cochlea at all ages, but that auditory function is primarily limited by the lower passive base cutoff frequency at younger ages. The proposed increase in passive base cutoff frequency with age accounts for the known place code shift. PMID- 8675838 TI - Two-tone rate suppression boundaries of cochlear ganglion neurons in normal chickens. AB - The purpose of the present study was to provide a quantitative description of two tone rate suppression boundaries in normal chickens. The boundaries were measured in 249 cochlear ganglion neurons using a tone 20 dB above threshold at the characteristic frequency (CF). The boundaries were present in 90.4% of neurons either on both sides or only one side of CF but more frequently above CF than below CF. The best suppression thresholds were positively correlated with and, on the average, 19-25 dB higher than CF thresholds. The boundary was farther from CF and shallower below CF than above CF. The boundary slope varied slightly with CF threshold and the tuning curve slope. These results are generally consistent with previous reports from mammals except that: (1) the boundary below CF did not follow and lie above the tuning curve flank; (2) the average best suppression threshold was slightly lower below CF than above CF; (3) the boundaries below and above CF were not particularly asymmetrical. PMID- 8675839 TI - One-tone suppression in the frog auditory nerve. AB - Sixty-seven fibers of a sample of 401 in the auditory nerve of grassfrogs (Rana temporaria) showed one-tone suppression, i.e., their spontaneous activity was suppressed by tones. All fibers were afferents from the amphibian papilla with best frequencies between 100 and 400 Hz. Best suppression frequencies ranged from 700 to 1200 Hz. Spontaneous activities for the fibers showing one-tone suppression ranged from 3 to 75 spikes/s. Spontaneous activities above 40 spikes/s and the phenomenon of one-tone suppression itself has not been reported previously for frogs. The population of fibers showing one-tone suppression comprises 81% of all fibers with best frequencies below 400 Hz and spontaneous activities higher than 3 spikes/s, indicating that the mechanism underlying the suppression is quite general. PMID- 8675840 TI - Variable effects of click polarity on auditory brain-stem response latencies: analyses of narrow-band ABRs suggest possible explanations. AB - The auditory brain-stem responses (ABRs) to rarefaction and condensation clicks were obtained for 12 normal-hearing subjects in quiet, and high-pass masking at 8, 4, 2, 1, and 0.5 kHz. Derived narrow-band wave V latency differences were analyzed with respect to (1) stimulus polarity, (2) absolute differences irrespective of polarity. The analyses revealed no significant stimulus polarity effects on latency for the derived bands. Absolute latency differences regardless of polarity tended to be greater for those derived bands having lower characteristic frequencies (CFs). However, these differences were smaller than the expected half-period of the theoretical CF. Further analyses in three additional subjects using repeated runs of the same polarity indicate that this increase in absolute latency difference with lower derived band CF does not reflect a simple half-period change owing to polarity, but rather to the increase variability in measuring the peak latency of the lower CF derived bands. The variability is consistent with variability of eighth nerve PST histograms behavior observed in animal work [Kiang et al., "Discharge patterns of single fibers in the cat's auditory nerve," Research Monograph No. 35 (MIT, Cambridge, MA, 1965)]. Thus claimed polarity effects observed in other ABR work using absolute values may have been affected by this variability. It appears from these current data that half-period latency shifts of wave V owing to stimulus polarity differences are not observed in derived bands responses initiated from frequency specific regions of the cochlea. PMID- 8675841 TI - Recalibrating the perception of loudness: interaural transfer. AB - Previous research, using both magnitude-scaling and direct-comparison methods, has shown the perception of loudness to be contingent on the distribution of tonal stimuli varying in sound frequency as well as SPL: When a low-frequency signal, f1, is presented at low SPLs and a high-frequency signal, f2, at high SPLs, loudness at f1 is great relative that at f2; reversing the association of SPL with frequency reverses the loudness relation. These shifts in relative loudness, recently termed "recalibration" [Marks, J. Exp. Psychol: Hum. Percept. Perf. 20, 382-396 (1994)] [corrected], are consistent with the operation of frequency-specific, fatiguelike processes at f1 and f2. Experiment 1 combined both scaling (magnitude estimation) and matching (direct-comparison) methods and showed that exposing one ear to recalibrating stimuli (500 and 2500 Hz) led to substantial shifts not only in the ipsilateral ear but also in the contralateral ear (albeit smaller ones). Experiment 2 used a selective-exposure procedure and gave similar results. Thus the processes underlying recalibration of loudness appear to involve central mediation; consequently, it is possible that processes of auditory fatigue rely on central as well as peripheral mechanisms. PMID- 8675842 TI - Binaural masking level differences in the inferior colliculus of the guinea pig. AB - The binaural masking level difference (BMLD) is a striking and well-documented psychophysical effect which relates to the ability to use the phase of low frequency sounds to dissociate them from masking noise. When identical tones and noise are presented to both ears, detectability is improved by up to 15 dB simply by inverting the phase of either the tone or noise in one ear. Measurements of BMLDs were made in single delay-sensitive neurones in the inferior colliculus of the guinea pig. These have confirmed and extended an earlier report [D. M. Caird, A. R. Palmer, and A. Rees, Hear. Res. 57, 91-106 (1991)] by demonstrating that when signals are optimized for the frequency, level, and interaural delay sensitivities of each neurone, BMLDs can be measured which are in a direction, and of a magnitude, consistent with appropriate psychophysical observations in human subjects. In addition, BMLDs were found to be consistent with the delay sensitivities of the neurones to the signal and masker, the major determinant of the masked threshold for optimized signals being the activity evoked in the neurone by the masking noise. Within-channel signal-to-noise (S/N) ratios at masked threshold for single neurones varied from +20 to -7 dB, depending on the binaural configuration and the units' delay sensitivities. In single neurones, the size of the BMLD for optimized signals increased with the level of the noise. The BMLD increased by 5 dB over a 40-dB range of noise, consistent with psychophysical observations. This came about because as noise level increased, masked threshold for optimized tones increased more slowly in Npi noise than in N0 noise. For all binaural comparisons, both positive (pi signals more detectable, as in the psychophysics) and negative BMLDs were observed, often in the same neurone, a result entirely consistent with the sensitivity to the interaural delay of the noise and tone signals. For 500-Hz signals in zero and pi phase masked by identical noise the majority of BMLDs determined with the PEST procedure was negative, a result which is taken to indicate that increases in spike rate may not be an appropriate cue for masked threshold under these conditions. PMID- 8675843 TI - Effect of otoacoustic emissions on just-noticeable differences for intensity in normally hearing subjects. AB - Measurements of spontaneous and click-evoked otoacoustic emissions (OAEs) were used to classify listeners with normal hearing into one of two categories--those with spontaneous emissions (SOAEs) and high-level transiently evoked emissions (TEOAEs) in both ears (strong emissions) and those with no SOAEs and low-level TEOAEs in either ear (weak emissions). Just-noticeable differences (jnd's) in intensity for 1-kHz pure tones presented at either 60, 40, or 20 dB SL were determined for these two groups using a continuous pedestal technique. Mean jnd's for intensity for the two groups did not differ significantly. Intratest variability was compared and the group with strong emissions had significantly higher variability for presentation levels of 20 dB SL and lower variability at 60 dB SL. Additional testing of intensity jnd's was performed in individuals with strong emissions using pure tones 30 Hz lower than a targeted SOAE frequency. Large interindividual differences were present without a specific pattern. It is concluded that OAE activity level does not affect the mean jnd for intensity discrimination. Individuals with strong emissions have less variance when performing the test at higher levels and more variance for lower level stimuli than do individuals with weak emission characteristics. Because an ear's OAE characteristics can alter performance on psychoacoustic tasks, knowledge of such characteristics is desirable when psychoacoustic results are acquired and reported. PMID- 8675844 TI - Pitch of iterated rippled noise. AB - Iterated rippled noise (IRN) stimuli are generated by a cascade of delay (d), gain (g), and add networks. The matched pitch of IRN stimuli was determined as a function of the type of network used to generate IRN stimuli, the delay (d = 2, 4, and 8 ms), the number of iterations (n = 1,2,3,4,6,8) of the delay and add networks, and whether the delayed noise was added (g = 1) to or subtracted (g = 1) from the undelayed noise. The matched pitch of IRN stimuli did not depend on the type of network. When g = 1 (addition), the matched pitch did not depend on the number of stages of iterations (n) and was always equal to the reciprocal of the delay (1/d). When g = -1 (subtraction), the match pitch depended on n. When n = 1, the matched pitch of IRN stimuli was ambiguous having two pitches in the region of 1/d +/- 10%. When n = 8, the match pitch was equal to 1/2d. This change in the pitch occurred between n = 2 and 6. The results are discussed in terms of spectral and temporal models of complex pitch processing. A temporal model based on autocorrelation was able to provide quantitative predictions for the pitch of these IRN stimuli. However, a spectral type of model can also account for the pitch of these IRN stimuli. PMID- 8675845 TI - Cochlear hearing loss and the processing of modulation: effects of temporal asynchrony. AB - Temporal coincidence and envelope correlation among components of a complex sound are informative cues for the perceptual organization of that sound. Listeners with hearing loss of cochlear origin often exhibit reductions in temporal processing of stimuli with randomly fluctuating envelopes. The purpose of this study was to examine the performance of such listeners on auditory grouping tasks which rely on temporal cues. The first experiment examined temporal asynchrony effects in a comodulation masking release (CMR) task. Performance was poorer than normal and appeared to be associated with reduced frequency selectivity. However, the pattern of asynchrony effects was the same as normal. The second experiment examined temporal asynchrony effects in a task based on envelope comparison interference. On this task, performance was similar to that for normal-hearing listeners. It was concluded that listeners with hearing loss of cochlear origin are comparable to normal-hearing listeners in their ability to make use of relatively gross temporal asynchrony cues. PMID- 8675846 TI - Adaptive psychophysical procedures and imbalance in the psychometric function. AB - One class of adaptive psychophysical procedures was studied, using simulated and human observers. These procedures are those which require an increase in stimulus intensity after an incorrect response, and a decrease after k successive correct responses. This paper analyzes how step size and the value of k affect the mean and standard deviation of threshold estimates based on a k-down 1-up adaptive procedure. Computer simulations are used to study the bias in threshold estimates, which are most evident when larger step size and small values of k are used. The adaptive procedure can be characterized by a function called the imbalance of the track, the relative probability of adjusting the stimulus either up or down at equal stimulus distances from the equilibrium point. These imbalance functions can be used to understand the threshold biases obtained in the computer simulations. The computer simulations also show that the average number of reversals obtained per trial is dependent on different values of k, but are largely independent of step size. The standard error of the threshold estimates, however, varies systematically with step size, but are nearly independent of k. Finally, we compare the stability of threshold estimates for human listeners using two very different sets of parameters: a very large step size (approximately half the range of the psychometric function) with k = 4, and the conventional k = 3 with an initial 4-dB and a final 2-dB step size. PMID- 8675847 TI - Vocal tract area functions from magnetic resonance imaging. AB - There have been considerable research efforts in the area of vocal tract modeling but there is still a small body of information regarding direct 3-D measurements of the vocal tract shape. The purpose of this study was to acquire, using magnetic resonance imaging (MRI), an inventory of speaker-specific, three dimensional, vocal tract air space shapes that correspond to a particular set of vowels and consonants. A set of 18 shapes was obtained for one male subject who vocalized while being scanned for 12 vowels, 3 nasals, and 3 plosives. The 3-D shapes were analyzed to find the cross-sectional areas evaluated within planes always chosen to be perpendicular to the centerline extending from the glottis to the mouth to produce an "area function." This paper provides a speaker-specific catalogue of area functions for 18 vocal tract shapes. Comparisons of formant locations extracted from the natural (recorded) speech of the imaged subject and from simulations using the newly acquired area functions show reasonable similarity but suggest that the imaged vocal tract shapes may be somewhat centralized. Additionally, comparisons of the area functions reported in this study are compared with those from four previous studies and demonstrate general similarities in shape but also obvious differences that can be attributed to differences in imaging techniques, image processing methods, and anatomical differences of the imaged subjects. PMID- 8675848 TI - Perception of the place of articulation of French stop bursts. AB - This paper deals with the perception of French natural stop bursts and with the role played by the following vowel in this perception. The first experiment verified the ability of listeners to identify long stimuli containing the burst and part of the subsequent vowel. The second and third experiments investigated the identification of stop bursts with and without a priori knowledge of the following vowel. In order to determine the discriminating power of spectral characteristics of the burst, these experiments used fixed-length burst stimuli of 25-ms duration with all traces of vocalic segment cut off. The bursts of initial voiceless stops were extracted from CVC isolated words. The burst provided very reliable information about stop place since listeners identified correctly 87% of the stops, without a priori knowledge of the following vowel. Performance however was context-dependent. Knowing the identity of the vowel led to a slight but statistically significant improvement in stop identification. Nevertheless, the effects of this knowledge were selective and varied with context. Finally, the first experiment proved that a near perfect identification of stops can be achieved only when all main cues (burst spectrum, burst duration, and onset of vocalic formant transitions) were present simultaneously. PMID- 8675849 TI - A cross-language comparison of vowel perception in English-learning and German learning infants. AB - Studies of cross-language consonant discrimination have shown a shift from a language-general to a language-specific pattern during the first year of life. Recently, the same pattern of change was observed for English-speaking infants' discrimination of two non-native vowel contrasts (Polka and Werker, 1994). The present study was designed to provide a more direct assessment of language specific influences on infant vowel contrast perception. In experiment 1 adults were tested on a German (non-English) contrast, /dut/ versus /dyt/, and an English (non-German) contrast, /d epsilon t/ versus /daet/. English and German adults discriminated both contrasts with high levels of accuracy in a categorial AXB task. However, results of an identification and rating task showed that, within each non-native vowel contrast, one vowel perceptually matched a native vowel category better than the other. In experiment 2 discrimination of /dut/ versus /dyt/ and /d epsilon t/ versus /daet/ was examined in English- and German learning infants in two age groups (6-8 months and 10-12 months) using the conditioned headturn procedure. English and German infants did not differ in their discrimination of either contrast and there were no age differences in discrimination of either contrast for the German or for the English infants. However, in both language groups at both ages, there were clear differences in performance related to the direction in which the vowel change was presented to the infants. For the German contrast, discrimination was significantly poorer when the contrast changed from /dut/ to /dyt/. For the English contrast, discrimination was significantly poorer when the contrast changed from /daet/ to /d epsilon t/. The directional asymmetries observed here and in other infant vowel studies point to a language-universal perceptual pattern which suggests that vowels produced with extreme articulatory postures serve as perceptual attractors in infant vowel perception. PMID- 8675850 TI - Speechreading enhancement: a comparison of spatial-tactile display of voice fundamental frequency (F0) with auditory F0. AB - In two experiments, subjects repeated video-recorded sentences presented via speechreading with and without enhancement by a sensory input derived from the acoustic speech signal. Enhancement was measured as percentage increase in recognized words. In experiment 1, tactile presentation of fundamental frequency (F0) provided, after training, for three of four postlingually deafened adults a mean enhancement of 11%. In experiment 2, using six hearing adults, the auditory presentation of F0 provided a mean enhancement of 50%. This value fell, but only to 37%, when the F0 signal was derived from the processor of the tactile aid used in experiment 1. From these experiments it can be concluded that the unexpectedly small enhancement found in experiment 1 is probably due both to the fact that this tactile aid was not providing effective access to all of the information available in the F0 contour and to limitations related to the tactile processing ability of the kinaesthetic system. PMID- 8675851 TI - Cepstral representation of speech motivated by time-frequency masking: an application to speech recognition. AB - A new spectral representation incorporating time-frequency forward masking is proposed. This masked spectral representation is efficiently represented by a quefrency domain parameter called dynamic-cepstrum (DyC). Automatic speech recognition experiments have demonstrated that DyC powerfully improves performance in phoneme classification and phrase recognition. This new spectral representation simulates a perceived spectrum. It enhances formant transition, which provides relevant cues for phoneme perception, while suppressing temporally stationary spectral properties, such as the effect of microphone frequency characteristics or the speaker-dependent time-invariant spectral feature. These features are advantageous for speaker-independent speech recognition. DyC can efficiently represent both the instantaneous and transitional aspects of a running spectrum with a vector of the same size as a conventional cepstrum. DyC is calculated from a cepstrum time sequence using a matrix lifter. Each column vector of the matrix lifter performs spectral smoothing. Smoothing characteristics are a function of the time interval between a masker and a signal. DyC outperformed a conventional cepstrum parameter obtained through linear predictive coding (LPC) analysis for both phoneme classification and phrase recognition by using hidden Markov models (HMMs). Compared with speaker dependent recognition, an even greater improvement over the cepstrum parameter was found in speaker-independent speech recognition. Furthermore, DyC with only 16 coefficients exhibited higher speech recognition performance than a combination of the cepstrum and a delta-cepstrum with 32 coefficients for the classification experiment of phonemes contaminated by noises. PMID- 8675852 TI - The dynamics of expressive piano performance: Schumann's "Traumerei" revisited. AB - Ten graduate student pianists were recorded playing Robert Schumann's "Traumerei" three times on a Yamaha Disclavier. Their expressive dynamics were analyzed at the level of hammer (MIDI) velocities. Individual dynamic profiles were similar across repeated performances, more so for the right hand (soprano and alto voices) than for the left hand (tenor and bass voices). As expected, the soprano voice, which usually had the principal melody, was played with greater force than the other voices, which gained prominence only when they carried temporarily important melodic fragments. Independent of this voice differentiation, there was a tendency for velocity to increase with pitch, at least in the soprano and alto voices. While there was an overall tendency for velocities to increase with local tempo, there were salient local departures from this coupling. Individual differences in expressive dynamics were not striking and were only weakly related to individual differences in expressive timing. PMID- 8675853 TI - The relevance of the Dutch system of maternity care to the United Kingdom. AB - The Dutch system of maternity care is occasionally held up as an example to be emulated by health care providers in the United Kingdom. There are, however, certain differences between maternity care in the two countries which prevent the direct transfer of a system of maternity care from the Netherlands to the UK. The countries are different in terms of their geography and social class distribution. The organizational frameworks within which maternity care is provided demonstrate important differences. The midwives are from a different background, undergo a different preparation and face crucially different working arrangements. There are also certain, largely cultural, differences between mothers in the two countries. Despite these discrepancies, much may be learned by those involved in maternity care in the UK from their Dutch counterparts and the Dutch system of care. PMID- 8675854 TI - Maternal behaviour during spontaneous and directed pushing in the second stage of labour. AB - It has become custom and practice within the midwifery and obstetric professions in the English-speaking western world for women to be required to follow very specific instructions on how to push in the second stage of labour. There is very little literature on the behaviour of women using spontaneous pushing in the second stage of labour. In a pilot study of a randomized controlled trial comparing spontaneous (n = 15) with directed (n = 17) pushing, the behaviour of the women was observed and recorded. The findings from the observational part of the study are reported in this paper. When pushing spontaneously women do not instinctively take a deep breath, they do not start expulsive effort with the commencement of the contraction, and they use both open and closed glottis pushing. In order to assist women in the second stage of labour, those caring for them should be aware of what is normal behaviour when women are using spontaneous expulsive effort. PMID- 8675855 TI - Postoperative morbidity following Caesarean delivery. AB - The current study was designed to determine the postoperative morbidity associated with Caesarean section and to compare the morbidity with the timing of the operation: elective versus emergency Caesarean section; subgroups of women delivered by emergency Caesarean section; women delivered during the first stage of labour versus those delivered during the course of the second stage. A retrospective review was conducted of the obstetric case record and the midwifery notes of all women delivered by Caesarean section over a 1-year period in a university teaching hospital (n = 619). The variables used to measure postoperative morbidity included: wound infection, intrauterine infection, urinary tract infection, chest infection, pyrexia, urinary catherization and postnatal blood transfusion. Only 9.5% of the women had no recorded morbidity in the postnatal period. Women delivered by emergency Caesarean section experienced a greater number of postnatal problems, an increased incidence of febrile morbidity, more blood transfusions in the postnatal period and a higher proportion had a urinary catheter left in situ after surgery. The incidence of wound infection, intrauterine infection and chest infection was higher in the emergency group and this resulted in an increased proportion of the women requiring antibiotic therapy in the postnatal period. The study found that there was considerable postoperative morbidity associated with Caesarean delivery, particularly if the operation was carried out as an emergency procedure. PMID- 8675856 TI - Outcomes management in neonatal nursing clinical practice. AB - One approach for evaluating the quality and cost of patient care is through outcomes management. Outcomes management in a neonatal environment will be described within a structure-process-outcome framework. Outcomes will be presented from three perspectives: administrative, economic and clinical. The relevance and implications of outcomes management will be discussed. PMID- 8675857 TI - Reflection and critical incident analysis: ethical and moral implications of their use within nursing and midwifery education. AB - Despite the dearth of rigorous empirical investigation, reflection and reflective practice have become buzz words in nursing and midwifery education. Reflection and critical incident analysis may be tools which can facilitate the integration of theory and practice. It is proposed that in the absence of explicit and thorough preparation of lecturers and students, together with very careful curriculum planning, these activities may be counter-productive or even harmful. In the absence of structure, reflection and associated critical incident analysis may lead to student disaffection or, worse, the potential for actual psychological disturbance. Empirical studies on the use of identified models of reflection and critical incident analysis are urgently needed to assist nursing and midwifery lecturers and students to achieve predictable learning outcomes for this potentially valuable activity. PMID- 8675858 TI - Partnership nursing: influences on involvement of informal carers. AB - Factors influencing family involvement in the care of children in hospital were explored in a survey of 243 inpatients in two hospitals. Eighty-five per cent of the children were receiving some or all of their care from a family member, usually the mother. Significant influences on the amount and type of involvement included acuity, type of illness, length of stay and the language spoken by the family. Other social factors, such as distance from the hospital, number of dependent siblings, social class and ethnicity were not significant influencing factors in this population. The influence of language on involvement, and conclusions from related literature, suggest that characteristics of the interaction such as communication and nursing style are more significant than social structural factors. A typology of nursing approaches to informal carers is proposed which could apply beyond the paediatric context. Further work is needed to test the hypothesis that such approaches are characterized by nurses excluding the carer, or permitting, making assumptions about, or negotiating carer involvement. PMID- 8675859 TI - Home treatment of patients with cystic fibrosis using the 'Intermate': the first year's experience. AB - Home treatment of patients with cystic fibrosis has many attractions and is becoming increasingly popular. The investigators have studied the use, results and costs of the first year of operation of a home-care intravenous antibiotic service using the 'Intermate' infusion device in a prospective study using questionnaires, spirometric and weight measurements. Ninety-three patients received 166 courses of intravenous antibiotics in full or in part at home during 1991. The average length of treatment was 12.5 days and on average 70% of the treatment was given at home. The mean percentage predicted FEV1 and FVC improved after treatment and the mean improvement was not significantly different to that produced by hospital treatment. Breathlessness, sputum volume, appetite, ability to sleep, mood, energy and overall well-being, as assessed by questionnaire, showed significant improvements after home treatment. The median time spent mixing and administering drugs was 10-19 hours and visiting the hospital was 7-12 hours. The median number of days of lost income to patients or their carers was 0 days. The majority of the patients were extremely satisfied with the treatment and supervision that they received. Using the home care service, 1442 inpatient days were saved. The investigators conclude that home care using 'Intermates' improves a patient's lung function and quality of life. PMID- 8675860 TI - The transformational experience of liver transplantation. AB - Liver transplantation is now the treatment of choice for patients with end-stage chronic liver disease. However, few studies have examined the recovery of liver transplant patients and no qualitative research studies have examined the experiences of these patients. Therefore the purpose of this study was to explore and describe the experiences of liver transplantation from the patient's perspective. In-depth focused interviews with 10 liver transplant patients were carried out. Grounded theory data collection and data analysis methods were used. A theoretical framework of the transformational experience of liver transplantation is presented. The process of transformation involves moving through a five-stage trajectory of: receiving the transplant, improving in hospital, improving at home, feeling well again, and reciprocating. PMID- 8675861 TI - Comforting: exploring the work of cancer nurses. AB - In a study to identify and describe nurses' use of comforting strategies, techniques of qualitative ethology were used to analyse videotaped recordings of nurse-patient interactions on an active cancer treatment ward. Comforting strategies nurses were observed to use included gentle humour, physical comfort measures, emotionally supportive statements, and comforting and connecting touch. In addition they increased physical proximity, provided patients with information, supported patients' active participation in decisions regarding their care, and offered opportunities for patients to engage in social exchange. These strategies appeared to play a major role in helping cancer patients endure the discomforts associated with their illness and/or treatment. Various combinations of comforting strategies were used in four different contexts, including: helping patients put experiences into perspective; helping them stay in control; providing opportunities to function as normally as possible; and providing emotional support. The findings of this study support conceptualizations of comforting that extend beyond measures related to symptom control and indicate that comforting strategies used by cancer nurses comprise a significant part of their work. PMID- 8675862 TI - An overview of the oral complications of adult patients with malignant haematological conditions who have undergone radiotherapy or chemotherapy. AB - The aim of this review is to look at mouth-care in adult patients with malignant haematological conditions and in particular those with disturbed immunity or bone marrow depression due to radiotherapy or chemotherapy. The oral assessment tools available will be discussed. Different products used and research to support their use will be examined, as well as any staging systems for their introduction to the patient's schedule. The awareness of the nurses who use them will also be investigated. Patient education has been found to be the most important aspect of mouth-care in the haematology patient undergoing radiotherapy or chemotherapy. Further research into the area of developing a specific tool for use with haematology patients with oral problems is highlighted here, as is further liaison with dental hygienists. Aspects of this review may apply more generally to other patients undergoing radiotherapy or chemotherapy. PMID- 8675863 TI - Living with a venous leg ulcer: a descriptive study of patients' experiences. AB - This study aimed to describe the experience of living with a venous leg ulcer from the patient's perspective, to answer the question 'What is it like to live with a venous leg ulcer?' Investigating the experience of illness is important in understanding how disease processes affect people, how they understand and cope with these processes, and how care may be given most effectively. Little research was identified which examined these areas with reference to people with leg ulceration. A qualitative approach was taken in the following study, using phenomenological methods to describe the experience of venous leg ulceration. Informal unstructured interviews were conducted with 13 informants, guided by their descriptive priorities. Tape recordings were then transcribed and analysed for recurrent themes and their meanings. It was found that certain symptoms of ulceration, principally pain, were the overwhelming feature of the experience. These symptoms caused significant restrictions in people's lives, particularly in their ability to walk and go out. Treatment was not described as being efficacious in ameliorating these symptoms, but nevertheless great confidence and trust was placed in the expertise of nurses. People coped with the experience mainly by a process of normalizing its components. It is concluded that if treatment is to meet the needs of those suffering venous leg ulceration, then symptom control must be the highest priority. PMID- 8675864 TI - Living with haemophilia and HIV/AIDS: support and coping. AB - This paper describes sources and types of support, appraisal of support, and use of social support as a strategy for coping with Acquired Immune Deficiency Syndrome (AIDS)-related stresses. Thirty people with haemophilia, 23 family caregivers and 17 bereaved relatives participated. The study was conducted in two stages: individual interviews and mailed questionnaires. The key coping strategies used were 'normalizing personal relationships' and 'seeking informational support'. Informational support was provided by health professionals and practical aid by relatives. Respondents reported insensitivity, prejudice and avoidance from others. Participants needed peers for emotional and affirmational support, and professionals for informational support. The preferred intervention was support groups, co-led by professionals and peers. PMID- 8675865 TI - Using video and conversational analysis to train staff working with people with learning disabilities. AB - Through analysis of video data of interaction between staff and clients with learning disabilities and limited vocal skills, it was possible to demonstrate that clients used gaze and body orientation to display a readiness that was often not responded to by staff. Yet staff could recognize that readiness from the videos. Video analysis was therefore developed as a medium for education and training where staff were helped to become more aware of strategies for non-vocal communication, which could help them achieve their policies of supporting clients more successfully. The study also allowed development of methodology in the field of services for people with learning disabilities. PMID- 8675866 TI - Patient suffering: a taxonomy from the nurse's perspective. AB - Using the ethnoscientific method, a taxonomy depicting types of suffering experienced by patients was developed. Nurses were asked to describe patients' suffering and, from this data, the differing types were identified. The four major domains identified were 'to bear it', 'to stay in control', 'to protect', and 'to strengthen'. Under these broad domains, nurses identified 24 different types of suffering, such as peaceful, meaningful, self-absorbed, silent, stoic, flaunted, martyr-like, 'in limbo', and hopeless. Implications for nurses are that: (a) patients expend much energy in their suffering and this should be considered when giving care, (b) nurses' personal evaluation of patient suffering should not preclude individualized care, (c) patients need personal space periodically, (d) some patients do not want their suffering alleviated, and (e) hidden reasons for patient behaviour are likely to exist. PMID- 8675867 TI - A research study exploring the patient's view of quality of life using the case study method. AB - A research study into the patient's perspective of quality of life is outlined. This phenomenon had not been explored at the time when the study was in process. However, late in 1993 towards the end of the study a paper was published by Bertero & Ek in which the findings of a similar study were discussed. The findings of this study reinforced and expanded upon those of Bertero & Ek. After a brief outline of the research study this paper explores validity in qualitative research, the case study method, method triangulation and the application of the hermeneutic cycle. The latter two of these were strategies adopted within this study to promote validity. The paper ends with a discussion of the main findings from this study and conclusions. PMID- 8675868 TI - Professional caring: the moral dimension. AB - The concept of caring, its intentions, actions and its achievements, as it relates to nursing is a concept on which many nurses' minds have been focused. The concern and at times a major preoccupation with the need to explore and explain caring among the nursing body is a concern which is rooted in socio political and cultural phenomena related to the evolution of nursing. The need to explore and explain caring through philosophical discourse is a necessary and an ongoing part of this evolutionary process. This paper represents an attempt to partake in such discourse. More precisely, the paper undertakes an analysis of the concept of caring as it happens in both nonprofessional and in professional caring contexts and represents an attempt to characterize professional caring. In an effort to do this the author considers the moral-ethical dimension of caring in the light of important theoretical positions on social morality. When considered against these theories of social morality and against the professionally derived imperatives which guide caring actions, professional caring may be construed as a distinct mode of caring. PMID- 8675869 TI - Linguistic entrapment: medico-nursing biographies as fictions. AB - This paper argues that in their trainings health professionals are encouraged to use language naively as if it were a transparent medium of scientific communication. We contend that language use, particularly in the field of mental health care, should be studied in terms of its social functions and attention should be paid to the inevitably constructive nature of language in patients' records, in order that a 'fictional distance' opens up between patients and their records. Recent developments in literary theory and narrative analysis can be deployed as theoretical frameworks to understand this process, and we suggest that more attention to the use of language should be included in the educational programmes for health care professionals to counteract the risk of 'linguistic entrapment' or 'incarceration'. PMID- 8675870 TI - Organizational environment and the support of patient autonomy in nursing home care. AB - This study examined how patient autonomy is associated with the organizational environment in nursing homes, particularly the organizational climate, organization of work and selected staff characteristics, such as age and experience of health care. Staff from 13 nursing homes in the county of Stockholm, Sweden, were included. The organizational climate was described by staff from two of the nursing homes that, on the basis of staff judgement, were rated as creative, and from two of the nursing homes that were rated as lacking innovation. Regarding organization of work, which included the number of patients who required to be fed, together with the incidence of pressure sores and indwelling urinary catheters, there appeared to be no difference in care from both types of nursing home. The statistical analyses showed that nursing homes characterized as significantly creative supported patient autonomy to a high degree, and that the staff's experience with health care was associated with the organizational climate. PMID- 8675871 TI - Health promotion: a concept analysis. AB - Health promotion is a concept which is frequently used, but is often ill defined. Current health care trends, and the emphasis on the nurse of the future as a promoter of health suggest that it would be useful to attempt to clarify the concept. This paper develops a conceptual analysis of health promotion using the process developed by Rodgers (1989). Attributes, antecedents, consequences and references are described following an examination of the ongoing debate in the literature surrounding the meaning of the concept. Empirical work is also reviewed which suggests that nurses' understandings of the concept are firmly embedded in the more traditional approach rather than the more modern or new paradigm approach to health promotion. A model case is described, and the analysis results in a proposed definition of health promotion which it is hoped will stimulate further discussion. PMID- 8675872 TI - The development of a clinical learning environment scale. AB - Within nursing, there is a strong demand for high-quality, cost-effective clinical education experiences that facilitate student learning in the clinical setting. The clinical learning environment (CLE) is the interactive network of forces within the clinical setting that influence the students' clinical learning outcomes. The identification of factors that characterize CLE could lead to strategies that foster the factors most predictive of desirable student learning outcomes and ameliorate those which may have a negative impact on student outcomes. The CLE scale is a 23-item instrument with five subscales: staff student relationships, nurse manager commitment, patient relationships, interpersonal relationships, and student satisfaction. These factors have strong substantive face validity and construct validity, as determined by confirmatory factor analysis. Reliability coefficients range from high (0.85) to marginal (0.63). The CLE scale provides the educator with a valid and reliable instrument to evaluate affectively relevant factors in the CLE, direct resources to areas where improvement may be required, and nurture those areas functioning well. It will assist in the application of resources in a cost-effective, efficient, productive manner, and will ensure that the clinical learning experience offers the nursing student the best possible learning outcomes. PMID- 8675874 TI - Nursing informatics: state of the science. AB - The phenomena of interest in nursing informatics are nursing data, nursing information and nursing knowledge. The current state of knowledge related to these phenomena suggests four implications for the development of systems to support nursing. First, research has provided evidence that knowledge and experience is related to the quality of nursing assessment, diagnosis or clinical inference, and planning of nursing care, and also that knowledge is task specific. Information technology can provide access to a variety of information resources, such as knowledge bases and decision support systems, to increase the level of knowledge of the nurse decision-maker. Second, structured patient assessment forms with linkages to knowledge bases of diagnoses have the potential to improve the quality of the patient assessment and the accuracy of the diagnosis or clinical inference. Third, studies on planning care have demonstrated the complexity of the task when a number of options are potentially appropriate. Model-based decision support applications such as decision analysis and multi-attribute utility theory can assist the clinicians and patients to analyse and compare the treatment alternatives in a systematic manner. Fourth, there is modest support for demonstrating the relationship between the process and outcomes of clinical decision making. Large databases built upon nursing data are needed to further examine this relationship. PMID- 8675873 TI - The validity of Qualpacs. AB - The validity of the quality assessment instrument Qualpacs is discussed. The literature reviewed addresses the sensitivity, scoring and scope of the instrument, operational decisions and cost and policy implications. Specific attention is given to the reliability and validity of Qualpacs and methodological challenges of convergent validity testing. The study, which was funded by the Department of Health, England, employed a multiple triangulation research design to assess the validity of the instrument. Qualpacs was compared to two other instruments (Monitor and Senior Monitor) and to other quality of nursing care data derived from: observation of patients' activities and nurse-patient interaction, and interviews with patients and nurses on their perceptions of quality of care. The results support Qualpacs as a relatively valid instrument in that it displayed greater convergent validity than Monitor or Senior Monitor. Convergent validity was stronger when compared to Senior Monitor and the Monitor DG3 schedule than the other Monitor schedules. Comparison with the observation of nurse and patient activities and interactions supported Qualpacs for medical and surgical wards but not for elderly care wards. Congruence between Qualpacs' items and the views of patients and nurses provides evidence in support of construct validity of the instrument. PMID- 8675875 TI - Staffing levels and seclusion use. AB - In this paper the role of staffing levels as a determinant of seclusion use in one psychiatric hospital is examined. A detailed review of the official records of seclusion over a 2-year period was completed (n = 225). The staffing levels on shifts when seclusions were initiated were compared with similar shifts when seclusions were not used on the same ward. Statistical analysis revealed a highly significant difference between the levels of staffing: Wilcoxon matched pairs signed-ranks test, Z = -5.8675, two-tailed, P = 0.001. This finding suggests that staffing levels play a crucial role in the practice of seclusion. However, the overall staffing level must be considered along with other factors in the makeup of the staff group, including the ratio of female to male staff and the experience level of those staff. These findings have important implications for those involved in the management and practice of seclusion as well as the patients who are secluded. PMID- 8675876 TI - Valid arguments? a consideration of the concept of validity in establishing the credibility of research findings. AB - Validity is an important concept in establishing the credibility of research findings. However, the current debate about the criteria used to substantiate claims for the validity of research evidence is largely based on a set of distinctions between qualitative and quantitative methodology which are outdated and misleading. This paper argues that validity is an epistemological concept, whose application depends upon some fundamental positions taken about the nature of truth, representation and scientific methodology. There remain important, unresolved questions about the meaning and application of the concept of validity which have a crucial bearing on what criteria are used to establish the credibility of research evidence. PMID- 8675877 TI - Nursing practice in Canada: the influence of current and proposed legislation. AB - Nursing practice in Canada is regulated by separate acts in each of the 10 provinces and two territories. These acts grant self-governance to the nursing profession, define a scope of practice, and establish mechanisms for registration and quality assurance. The Canada Health Act 1984, the Agreement on Internal Trade (1994) between provinces, and the North American Free Trade Agreement have potentially great effects on Canadian nursing by altering the regulation of professionals within the various jurisdictions. PMID- 8675878 TI - Chaos and evolution in nursing research. PMID- 8675879 TI - The social body and the biomechanical body: can they coexist in nurse education? AB - The curricula of tertiary nursing courses usually involve a number of complementary strands. These include biological sciences, social sciences, behavioural sciences, other support subjects and clinical units. These different strands each, to some extent, present the nursing student with a dilemma as they may present entirely different models of the body. Explorations of this dilemma show that students are also being presented with different models of illness and different conceptions of appropriate health care response to illness. The question is then raised as to which of these approaches most accurately reflects the realities of nursing practice. PMID- 8675880 TI - Psychoneuroimmunology: an emerging framework for nursing research. AB - Psychoneuroimmunology (PNI) is concerned with the mechanisms of bidirectional communication between the neuroendocrine and immune systems. Investigators in other disciplines have used this framework to guide the examination of possible relationships between behavioural factors and the progression of immunologically mediated illnesses and to evaluate the role of immune products in central nervous system disturbances. Nurse scientists have an opportunity to make unique contributions to the growing field of PNI. Unlike basic science research, which has as its goal the generation of fundamental knowledge concerning biological or behavioural processes, nursing research is driven by the need to promote excellence in nursing science as a guide for nursing practice. Although a few nurse scientists have conducted PNI research to date, additional studies are needed to generate new knowledge concerning mind-body interactions in health and illness and to develop strategies that promote mental and physical well-being in persons at risk for immune dysfunction. This paper highlights the few recently conducted nursing studies grounded in a PNI framework to illustrate the utility of PNI in advancing nursing science. PMID- 8675881 TI - Intuition and expertise: comments on the Benner debate. AB - The rift between "science' and "phenomenology' in current nursing theory is explored through an examination of two recent evaluations of the work of Patricia Benner, who has proposed a model of skill acquisition, latterly within a Heideggerian framework. English offers a critique of Benner's ideas from the perspective of cognitive psychology; while Darbyshire defends them against what he describes as a "positivist' attack. No attempt is made, in this paper, to evaluate Benner's work directly, but Darbyshire's response to the "critique' is analysed; and it is noted that, in making his defence, he invokes a network of concepts which he ascribes to a "traditional notion of objective science', and accuses English of subscribing to it. It is suggested that this "Cartesian' worldview is an outmoded myth, superseded by the philosophy of science during the last 30 years, and based on the rhetoric rather than the reality of scientific practice. Nursing is not, therefore, obliged to choose between "positivism' and a philosophy whose chief virtue is that it represents a "challenge' to positivism. It could instead build a scientific basis for research and theory by drawing, not on mid-century thinking, but on a more contemporary understanding of the nature of science. PMID- 8675882 TI - Critical aspects of nursing in aged and extended care. AB - An ageing Australian population and improving medical retrieval technology have led to an increasing need for nurses to manage complex and acute health issues of ageing and chronic disability. In a study of aged and extended care involving nurses, residents, allied health professionals and family members, investigators used semi-structured interviews to identify critical aspects of nursing. The aim of the study was to begin to identify and illustrate a theoretical framework of "critical' nursing activities for aged and extended care. Two important themes to emerge were the structure of the health care setting and the characteristic behaviours of people associated with it. These themes reinforce the importance of treating people as individuals and of describing caring criteria in ways which reinforce holism. PMID- 8675883 TI - A nursing perspective on the interrelationships between theory, research and practice. AB - This paper is concerned with the interrelationships between the three concepts of theory, research and practice. In the course of discussing the interrelationships between these concepts, research is identified as the link between theory and practice on both a formal (explicit) and informal (tacit) level. The role of formal and informal research in the development of nursing expertise is also given some consideration. PMID- 8675884 TI - The theory/practice "gap': taking issue with the issue. AB - Theory/practice issues have a long-standing history in nurse education, and are a chronic source of controversy to which there is no easy or perfect solution. We have argued that it is the tension between theory and practice and research which can be usefully exploited in teaching and research. Students need to be introduced to the debates surrounding the genesis and generation of nursing knowledge. They need to gain an appreciation of what counts as nursing knowledge at different points in time and the politics which drive the legitimation of nursing theory and practice. Such an approach has much to offer in helping students deal with reality shock and make sense of their experience as they confront the ambiguities, uncertainties and contradictions that characterize the stock-in-trade of professional life. PMID- 8675885 TI - The research basis of health care decision making. AB - Regarding health care services, the decision-making process occurs at three primary levels: macro (national), mid-range (hospital) and micro (individual practitioner). The research basis for this process at each of these levels is briefly discussed, with an emphasis concerning which type of data is and/or should be utilized. The paradigm assumptions behind data generation are also explored with reference to methodologies which seek to combine different types of data. The nursing profession, within the changing structure of the NHS, needs to take account of data generation if it is to play an active research role, and therefore be able to influence the health care decision-making process. PMID- 8675886 TI - An exploration of the influence of managerial factors on research utilization in district nursing practice. AB - This paper reports a small study which explored the management arrangements of the providers of community services in five health districts and the influence these had on the way research findings were utilized by nurses in their clinical practice. Insights were sought into the nature of the organizations in which district nurses worked. With the co-operation of the service managers, all the nurses had previously been involved in testing a model of dissemination of research information. The study reported here arose from that original research and explored the links between management arrangements and research utilization in clinical practice. Interviews using a semi-structured schedule are reported from 22 service managers in the five health districts. Data on managers' professional roles and backgrounds, the organizational structures and processes and external social and political factors were collected and analysed. A selection of findings is discussed in relation to influence on research utilization in clinical practice. PMID- 8675887 TI - Hermeneutic phenomenology: philosophical perspectives and current use in nursing research. AB - The wise choice of the postmodern tradition of hermeneutic phenomenology for nursing research is partly dependent upon an awareness of that tradition's base of philosophical hermeneutics. The origins of this philosophy within the work of Heidegger and especially Gadamer are detailed with an explanation of some major concepts intrinsic to their hermeneutic writings. Subsequently an analysis is offered of the ontological, epistemological and methodological perspectives of the tradition which is considered thereby to reside within an interpretivist/constructivist paradigm of inquiry. The contemporary use within the discipline of nursing of hermeneutic phenomenology is discussed, and the growing trend for using the tradition, across continents, is identified. However the question is posed as to whether all such research is accurately identified as belonging to the tradition. A further analysis suggests that hermeneutic phenomenology will increasingly be applied to the research of nursing phenomena. PMID- 8675888 TI - Using the diffusion of innovation model to influence practice: a case study. AB - There continue to be suggestions within the nursing literature that research findings are not being utilized in clinical practice. The reasons for this are well documented. However, less emphasis is given to ways to facilitate utilization. It seemed possible that non-utilization could be due not only to lack of knowledge, but also to the method of implementing change towards research based practice. The "top-down', authoritarian, approach to dissemination of information within the NHS may have been a block to research use. Could staff be motivated to consider research-based change through use of a different approach? An "action research' approach seemed a possible way to attempt to facilitate research-based practice. Within this study one ward was used with all staff as the participants. The staff identified the area to be studied (devising a protocol for preoperative information-giving). The instruments used were semi structured interviews and informal discussions and field notes. Rogers' diffusion of innovation model was used to organize data collection and to analyse results. Although the results may not be generalizable, the use of this model provides a useful framework for others interested in an alternative approach to achieving research-based practice. PMID- 8675889 TI - Processes in the creation and diffusion of nursing knowledge: an examination of the developing concept of family-centred care. AB - The creation of a knowledge base to underpin and direct nursing practice has been the pursuit of nurse academics, educationists and practitioners over recent decades. Much of this work has concerned the explication of major theories of nursing, whilst some has sought to elucidate specific areas of knowledge. This paper outlines processes of creation and diffusion, considering the influence of factors from both within and without the nursing profession on the epistemology of its knowledge base. An examination of the developing concept of family-centred care is utilized to illustrate the convolutionary process of knowledge creation. PMID- 8675890 TI - Agency and research team co-operation: an exploration of human territoriality. AB - The purpose of this paper is to alert researchers and agency staff to potential conflicts that may arise during research projects conducted in busy community based agencies. Within a framework of human territoriality, key factors in avoiding such conflicts are explored. Territoriality is the defence against intruders of an area of land which is considered to be owned. For humans, something owned includes space, objects, ideas, privileges or rights. Key territoriality concepts explored in the paper are: the private domain, encompassing a privacy retreat and personal space; and the public arena which includes psychological space and action territory. Examples of violation of the types of territory are examined and suggestions for prevention of conflicts are provided. PMID- 8675891 TI - Parent participation: a concept analysis. AB - Parent participation has become a central tenet of paediatric nursing in the United Kingdom. The purpose of this paper is to explore the meaning of parent participation, to clarify the concept to benefit children and their families, and to increase understanding among practitioners. The concept analysis utilized was directed by Rodgers' "evolutionary approach' that views concept development as an ongoing dynamic process. A review of British literature and research studies indicated that parent participation is a complex and multi-dimensional concept. In the evolution of parent participation, the terminology changed from "parental involvement' to "partnership in care', to "care-by-parent' and finally to "family centred care'. The analysis reveals a lack of coherence in the descriptions, with the terminology changing but the underlying theme remaining parent participation. Parent participation can be conceptualized as a composite of attributes that relate to the family, the nurse and their relationships. Those attributes include: negotiation, control, willingness, competence and autonomy. The concept of family-centred care is gradually assuming importance in the literature. This acknowledgement of the family is long overdue. However the concept remains poorly defined and urgent clarification is needed in this area. To adopt a family centred care approach, a radical paradigm shift is required. PMID- 8675892 TI - The subculture of adolescence: beliefs about care, health and individuation within Leininger's theory. AB - The purpose of this ethnonursing investigation, which was part of a larger study, was to describe and explain the meanings and experiences of adolescents in relation to their care and health within their peer subculture and family contexts. Data were collected using observation-participation and interviews with adolescents in southwestern Ontario, Canada. Interviews were tape recorded, coded and entered on to a computer. The following themes were abstracted from the verbatim descriptors and patterns. (a) Care for adolescents meant "being there' for listening in confidence, helping, gift giving, humour and demonstrating love in time of need. (b) Health for adolescents meant well-being, absence of illness, being fit, dealing with problems, and taking responsibility. (c) The adolescents valued family, friends, education, money, sports, and honesty. (d) Clothes, hair and music were metaphors for adolescents' emerging identities. PMID- 8675893 TI - Measuring patients' satisfaction with nursing: 1990-1994. AB - Assessing patients' satisfaction with the care they receive is assuming greater importance in the new-style National Health Service. This paper reviews recent developments in the measurement of patients' satisfaction with nursing, including new approaches and taking into account increased interest in users' opinions. Studies published since 1990 generally demonstrate lack of clarity with regard to the purpose and intent of the study, as well as a lack of conceptual rigour and methodological investment. However, several new approaches were found upon which future nursing research could build. PMID- 8675894 TI - Social support and the patient with cancer: a consideration of the literature. AB - Although the nature, meaning and measurement of social support are still being debated in the literature, it has been claimed to have positive effects on a variety of outcomes, including physical health, mental well-being and social functioning. However, an intention to help on the part of the support provider is not sufficient to ensure that one is actually supportive, either as a professional or within one's own personal network. Past research indicates that social support is beneficial to cancer patients in adjusting to the stress of the disease and yet, because of the intense fears and stigma associated with it, those who have cancer may be especially likely to experience problems in obtaining adequate support. Without an appreciation of the complexity of support elicitation and support provision, nurses caring for patients with cancer and for their relatives may, however unintentionally, undermine one of the strongest potential resources people have in coping with the disease-the social relationship. PMID- 8675895 TI - Nursing assessment of clients at risk of deep vein thrombosis (DVT): the Autar DVT scale. AB - Deep vein thrombosis (DVT) poses a threat to hospitalized clients' recovery. It is preventable and the cost of treating this problem is considerably more than that of preventative practices. Accurate DVT risk assessment facilitates the application of the most appropriate venous thromboprophylaxis. Founded on Virchow's triad of risk factors in the genesis of deep vein thrombosis, the Autar DVT scale was developed as a predictive index. The DVT scale is composed of the following seven risk categories: increasing age, build and body mass index (BMI), immobility, special DVT risk, trauma, surgery and high risk disease. The DVT scale was tested on two trauma wards and the study was essentially a data generating exercise. Clinical data were gathered on 21 clients to validate the reliability, sensitivity and specificity of the DVT scale. Pearson moment correlation coefficient (r) and total percentage agreement (T%) measurement yielded a value of r at 0.98 and a T% ranging between 70% and 87% respectively for both reliability studies. Predictive validity of the scale calculated from a threshold score of 16 achieved 100% sensitivity and 81% specificity. The Autar DVT scale has produced some interesting results and holds considerable promise as a predictive index. However, as this was a small study further testing in diverse clinical areas of a large client population is recommended. PMID- 8675896 TI - Case study of a female client on a regional secure unit. AB - Reported in this paper is a single-case experimental design study on the behaviour of a 32-year-old schizophrenic female inpatient, presenting with maladaptive behaviours necessitating care in a medium secure environment. A baseline of her observed behaviour on the unit was taken. The information gathered was used to assist in deciding the differential effects of psychosis vs. behavioural manipulation on her presentation and to assist in planning her immediate and future management/treatment. Situational factors portrayed as likely indicators of maladaptive behaviours proved difficult to influence, owing to the nature of the subject's environment. Cognitions and learnt behaviours were targeted. Recent research indicates that for some schizophrenics cognitive behavioural treatment of hallucinations/delusions using a focusing strategy is effective in reducing the symptoms' frequency. Frequency of the behaviours was recorded whilst this cognitive approach to symptom reduction was used. A marked decrease in her maladaptive behaviours was noted. PMID- 8675897 TI - Abortion: the antithesis of womanhood? AB - The debate regarding the practice and role of abortion has been an enduring and problematic area of discourse within the nursing literature, with a tendency towards a polarized and inevitably simplistic analysis of what, for many practitioners, women and families, remains a highly complex and morally fraught concept. This paper attempts to explore the concept of abortion from within a feminist epistemology, to present a review of the literature as regards women's reproductive health and responsibilities, and thereby to contribute to the process of better understanding the role of abortion within contemporary health care practice. In order to facilitate the study it has been necessary to explore the wide spectrum of historical, philosophical, legal, moral and political imperatives pertaining to the meaning of abortion as represented within contemporary society, not only in relation to women and their reproductive health, but to feminism, women's well-being and self-determinism per se. PMID- 8675898 TI - Chronic illness and the family life-cycle. AB - Chronic illness is currently the outstanding health issue in the United States. It creates increased family stress, requires constant adaptation by the family members and poses a challenge to nurses to better understand and meet the needs of the family as well as the individual. This paper presents a psychosocial typology of chronic illness and discusses the importance of time phasing of the chronic illness. A conceptual framework for analysing the interaction of chronic illness with family and individual life-cycles is outlined. Knowledge of life cycle stressors is essential for nurses to better delineate the relationship between the vertical and horizontal life stressors which affect the family system. PMID- 8675899 TI - Caring for a parent with Alzheimer's disease: process of daughter caregiver stress. AB - This study aimed to explore the process of caregiver stress associated with the care of a parent with Alzheimer's disease, the perception of the relationship with the parent, the image of the caregiver role, and the contextual aspects of coping and social support relationships. The grounded theory method was used to analyse the daughter caregiving process for 17 women. Findings included substantive theory and 13 hypotheses. This study provides an expanded awareness of the interrelationship between caregiver stress and the contextual aspects of social support, coping, and the nature of the prior filial relationship. PMID- 8675900 TI - Ongoing work of older adults at home after hospitalization. AB - This paper describes the hospital-to-home transition process as experienced by elderly people with a medical diagnosis of congestive heart failure. Qualitative data were collected in semi-structured interviews with a sample of 25 older adults within 2 weeks following discharge. Constant comparative data analysis procedures were used. The findings suggest that at 2 weeks post-hospitalization the situation could be described as tentative. The core variable for this study was conceptualized as "a tentative situation', characterized by three key processes: ups and downs associated with managing the illness, caregiver issues, and quality of life challenges. These elders were in need of a post-hospital plan which provided them with ongoing information, additional resources and supportive assistance. To emphasize the changing, uncertain nature of this chronic illness, and the necessity of the health care team developing an ongoing plan of care with the client and family, the trajectory was graphed using the trajectory phasing scheme as described by Corbin & Strauss. The changing nature of congestive heart failure in these participants noted as well as the need for a continuum of care. PMID- 8675901 TI - Considering nursing resource as "caring time'. AB - The present constrained economic climate faced by health care agencies underscores the need for nurse administrators to have an in-depth appreciation of how nursing services are being used. The purpose of this investigation was to increase the understanding of nursing as a resource. Using phenomenological research methodology, the investigator purposefully selected six patients and a chain sample of 14 professionals responsible for their care, including nurses, nurse managers and physicians. Data collection methods included in-depth interviews, document reviews, and participant observation. The inductive interpretation depicts the nature of nursing resource to be "caring time'. Caring was understood primarily in terms of time and was experienced by all participants as "spending time'. Caring time was spent through "being with' and "doing to/doing for' the patient. Study participants experienced tension with regard to how best to spend precious "caring time'. Nursing resource was inextricably linked to both quantitative and qualitative expressions of nursing, and "being with' patients was a highly valued, under-allocated, and unintentionally provided component of nursing resource. The researcher concluded that nursing administrators, nurse managers and practitioners all have leadership roles to play in achieving recognition, allocation and promotion of caring time within their agencies. PMID- 8675902 TI - The effect of ward design on the well-being of post-operative patients. AB - Changes in the design of hospital wards have usually been determined by architects and members of the nursing and medical professions; the views and preferences of patients have seldom been sought directly. The Hospital Anxiety and Depression scale and the Disturbance Due to Hospital Noise questionnaire were administered to 64 female patients on bay and Nightingale wards together with a questionnaire designed for this study. Perceptions of social and physical factors of ward design were examined, and their relationship to psychological well-being and sleep patterns. The results show that the bay ward seemed to offer a more favourable environment for patients but some of the disadvantages of bay wards are balanced by better staffing levels and better and more modern facilities. Visibility to nurses was lower on the bay ward. The Nightingale ward was perceived as significantly noisier than the bay ward and noise levels were significantly correlated to anxiety scores. Paradoxically the increase in noise levels appeared to improve the perceived level of privacy on the Nightingale ward. Seventy-five per cent of patients were found to prefer the bay ward design, and since neither design appears to have major disadvantages their continued introduction should be encouraged. However, recommendations are made concerning the optimizing of patients' well-being within the bay ward setting. PMID- 8675903 TI - Is there a relationship between job satisfaction and absenteeism? AB - This study attempted to address the problem of stress and burnout in hospital nurses by exploring factors which affect job satisfaction and the relationship between these and absence rates. Fifty nurses working in the elderly care unit of a district general hospital were asked to complete a job satisfaction questionnaire, specifically developed to include factors appropriate to the study, together with Maslach's burnout inventory and Beck's hopelessness scale. The hypothesis that job satisfaction is related to absenteeism was not supported. However, significant correlations between some variables were isolated. These correlations were tested using Spearmans risk correlation co-efficient. It is hoped that the job satisfaction questionnaire will become a useful instrument in screening those at risk of burnout, and a diagnostic aid to help consider the factors which affect job satisfaction. The implications of the study point to the need for the prevention of stress from environmental factors by the adoption of organizational strategies to promote positive working conditions, and the development of coping strategies in the form of stress awareness seminars, regular staff support groups and counselling services. PMID- 8675904 TI - The lived experience of clinical educators. AB - This phenomenological study was undertaken to discover the everyday meanings which clinical educators of pre-registration Bachelor of Nursing students attached to their experiences as clinical educators. The researcher employed a qualitative design using audiotaped in-depth interviews with four registered nurses employed as clinical educators in four different schools of nursing in Victoria, Australia. Using hermeneutics, thematic analysis revealed five themes of meaning central to the lived experiences of clinical educators. They are:(a) being human, (b) having standards, (c) developing own teaching style, (d) learn as you go, and (e) not belonging. The first three themes are described in the literature on clinical education, however, the latter two are unique to this research. The results of this study indicate there is need for extensive preparation and on-going support of clinical educators. The researcher, who is respectful of the enormity of the task which educators face in preparing students for practice, speculates whether clinical educators are the vanguards of student learning in the clinical field. It is evident that the participants of this study did not possess many of the role requirements of clinical educators identified in the literature. Further studies are needed which explore the link between student learning and clinical educator support. PMID- 8675905 TI - Qualitative research in health and social care. National conference held at Wessex Hotel, Bournemouth, England, 28-29 September 1995, organized by the Institute of Health and Community Studies, Bournemouth University. PMID- 8675906 TI - The flavor of food? It's all in your head!. Interview by Nancy I. Hahn. PMID- 8675907 TI - Cost-effectiveness of medical nutrition therapy. PMID- 8675908 TI - Uses of the recommended dietary allowances: a commentary. PMID- 8675909 TI - Diet quality and dietary diversity in France: implications for the French paradox. AB - OBJECTIVES: Assessing the quality of the total diet is a relatively new focus of studies in nutritional epidemiology. New indexes of healthful eating patterns have been largely limited to US populations. This study used evaluative criteria developed in the United States to assess diet quality and dietary diversity of French adults. METHODS: Habitual dietary intakes of a representative sample of 837 adults (361 men and 476 women) in the Val-de-Marne Departement were evaluated. Evaluative measures of diet quality included a modified diet quality index (DQI), a dietary diversity (DD) score, and a dietary variety score (DVS). The 5-point DQI assessed compliance with the key guidelines of the US Department of Agriculture (USDA) for healthy people. The DD score counted the number of major food groups consumed whereas the DVS counted the total number of foods consumed on a regular basis. RESULTS: Few French adults consumed diets consistent with the USDA dietary recommendations. Only 14% of respondents derived less than 30% of energy from fat and only 4% derived less than 10% of energy from saturated fat. As a result, 63% of the sample had DQI scores of either 0 or I. In contrast, close to 90% of respondents scored a maximum of 5 in DD. Persons whose diets met US dietary recommendations also had the lowest DVSs. CONCLUSIONS: Methodologic factors and cultural biases may account for some of the observed differences between French and US data. Nevertheless, studies of diet quality and diversity are a promising new approach to the study of the total diet and associated health outcomes and may provide new insight into the French paradox. PMID- 8675911 TI - Pattern of growth in children with cerebral palsy. AB - OBJECTIVE: To provide a growth reference standard for children with quadriplegic cerebral palsy (QCP). Growth references specific to children with cerebral palsy would facilitate uniformity in clinical appraisal of their growth and nutritional status and would simplify comparative interpretation of growth data. DESIGN: Weights and lengths were obtained according to standardized procedures. Measurements were taken at time of visit to an orthopedic clinic and from retrospective review of charts. SUBJECTS: Three hundred sixty children with QCP. Growth data were based on 1,630 observations. ANALYSIS: Growth curves representing the 10th, 50th, and 90th percentiles were estimated using a smoothing splines technique. Statistical bootstrapping was performed to confirm significant differences from the growth charts of the National Center for Health Statistics (NCHS). RESULTS: Growth charts were constructed for boys and girls, aged 0 to 120 months, depicting length for age, weight for age, and weight for length. Average differences in length for age, weight for age, and weight for length between children with QCP and NCHS standards were -2.3 z, -2.4 z, -1.3 z for boys, and -2.1 z, -2.1 z, -1.1 z for girls. Children with QCP fell progressively behind in stature and weight. Compared with their NCHS counterparts, they were 5% shorter at 2 years of age and more than 10% shorter at 8 years of age. APPLICATION: Charts representing the pattern of growth in children with QCP should be accessible to parents and health care professionals to facilitate evaluation and monitoring of nutritional status. PMID- 8675910 TI - Low-fat diet practices of older women: prevalence and implications for dietary assessment. AB - OBJECTIVE: To evaluate the importance of information on low-fat diet practices and consumption of reduced-fat foods for accurate assessment of energy and fat intakes using a semiquantitative food frequency questionnaire (FFQ). SUBJECTS: Subjects were 7,419 women, aged 50 to 79 years, who filled out an FFQ as part of eligibility screening for a diet modification component and/or a hormone replacement trial in a multicenter study of chronic disease prevention in postmenopausal women (Women's Health Initiative). STATISTICAL ANALYSIS: For 26 FFQ questions, we recoded the low-fat diet choices of participants to a high-fat counterpart and recalculated energy and fat intakes. We then determined the decrease in energy and nutrient estimates attributable to adding low-fat options to the FFQ. RESULTS: Low-fat diet practices were widespread in this population. For example, 69% of respondents rarely or never ate skin on chicken, 76% rarely or never ate fat on meat, 36% usually drank nonfat milk, 52% usually ate low-fat or fat-free mayonnaise, 59% ate low-fat chips/snacks, and 42% ate nonfat cheese. These low-fat choices had substantial effects on energy and nutrient estimates. Absolute decreases (and mean percentage decreases) for energy and nutrient measures attributable to adding low-fat diet options to the FFQ were 196 kcal (11.4%) energy, 9 percentage points in percentage energy from fat (22.3%), 23.2 g fat (29.0%), and 9.6 g saturated fat (32.5%). Black and Hispanic women and women of lower socioeconomic status reported significantly fewer low-fat diet practices than white women and women of higher socioeconomic status. CONCLUSION: Failure to collect information on low-fat diet practices with an FFQ will result in an upward bias in estimates of energy and fat intake, and the amount of error will vary by the personal characteristics of respondents. PMID- 8675912 TI - The Gustaf study: repeated, telephone-administered 24-hour dietary recalls of obese and normal-weight men--energy and macronutrient intake and distribution over the days of the week. AB - OBJECTIVE: A dietary survey of obese and control men was conducted through 24 hour dietary recalls administered by telephone at 12 times selected randomly over a period of 3 months. Energy and macronutrient intake and distribution were studied for all days of the week. SUBJECTS: Eighty-six obese men, 20 to 60 years old, body mass index (BMI) = 37.7 +/- 4.4 (mean +/- standard deviation) from the waiting list of the outpatient clinic and 6I normal-weight (BMI = 23.0 +/- 1.9), age-matched men selected randomly from the Stockholm County Census Bureau. MAIN OUTCOME MEASURES: Energy and macronutrient intake, intakes by energy tertiles, and distribution over the days of the week. STATISTICAL ANALYSES: Nonparametric tests were used because of skewed distribution of most food data. RESULTS: A median daily energy intake of 2,700 kcal was found in both groups. The obese men reported a higher protein (P < .001) and a lower alcohol (P < .001) intake than the control subjects. Both groups reported a maximum intake of energy and macronutrients on Saturdays. When separated into tertiles according to reported energy intake, the obese men in tertile 3 reported a higher intake from fat (% energy, P < .001) and a lower intake from protein (P < .01) compared with men in tertile 1. Normal-weight men intertile 3 reported a higher intake fat (% energy, P < .01) compared with men intertile 1. CONCLUSIONS: When reported energy intake was compared with calculated total daily energy expenditure, there was a greater discrepancy in the obese group than in the control group. The normal-weight men may have had a special interest in food and health, and this group may not reflect the population at large. PMID- 8675913 TI - Update on the biological characteristics of the antioxidant micronutrients: vitamin C, vitamin E, and the carotenoids. AB - Under normal circumstances, free radicals that are produced through biological processes and in response to exogenous stimuli are controlled by various enzymes and antioxidants in the body. Laboratory evidence suggests that oxidative stress, which occurs when free radical formation exceeds the ability to protect against them, may form the biological basis of several acute medical problems, such as tissue injury after trauma, and chronic conditions, such as atherosclerosis and cancer. A potential role for the antioxidant micronutrients (vitamin C, vitamin E, and the carotenoids) in modifying the risk for conditions that may result from oxidative stress has stimulated intense research efforts, increased interest in micronutrient supplements, and heightened consumer interest in these compounds. Much remains to be learned, however, about the bioavailability, tissue uptake, metabolism, and biological activities of these micronutrients. These biological characteristics will ultimately determine their clinical usefulness in modulating oxidative stress. Also, whether the antioxidant mechanism explains their relationship with risk for acute and chronic disease in epidemiologic studies remains to be determined. Increased knowledge in this area of nutrition science will have an impact on both clinical dietetics practice and public health nutrition guidelines. PMID- 8675914 TI - Discrepancies between perceived dietary changes and 4-day food records in older adults with diabetes. PMID- 8675915 TI - Underreporting of energy intake in biracial children is verified by doubly labeled water. PMID- 8675916 TI - Questionable dieting behaviors are used by young adults regardless of sex or student status. PMID- 8675917 TI - Family factors and fat consumption of college students. PMID- 8675918 TI - President's page: managing managed care--a mission impossible? PMID- 8675919 TI - Continuing education needs for public health nutritionists. PMID- 8675920 TI - Individual sulfonylureas and serious hypoglycemia in older people. AB - OBJECTIVE: To compare the risk of serious hypoglycemia associated with the use of individual sulfonylureas in older people. DESIGN: A retrospective cohort study. SETTING: The Tennessee Medicaid Program. PATIENTS: A total of 13,963 Medicaid enrollees, aged 65 years or older, who were prescribed one of six sulfonylureas from 1985 to 1989. MAIN OUTCOME MEASURE: Hospitalization, emergency room admission, or death associated with neuroglycopenic or autonomic symptoms, myocardial infarction, stroke, or injury, with a concomitant blood glucose determination of less than 2.8 mmol/L (50 mg/dL). RESULTS: We identified 255 persons with a first episode of serious hypoglycemia during 20,715 person-years of sulfonylurea use. The crude rate (per 1000 person-years) of serious hypoglycemia was highest in glyburide users, 16.6 (95% confidence interval [CI], 13.2 to 19.9 and lowest among users of tolbutamide, 3.5 (95% CI, 1.2 to 5.9). Users of tolbutamide, tolazamide, and glipizide had lower risks of serious hypoglycemia than users of chlorpropamide, whereas the risk of serious hypoglycemia among glyburide users did not differ from that of chlorpropamide users. Among second generation sulfonylureas, the adjusted relative risk of severe hypoglycemia among glyburide users, compared with glipizide users, was 1.9 (95% CI, 1.2 to 2.9). An increased risk of serious hypoglycemia associated with use of glyburide compared with glipizide occurred in all strata, including those defined by gender, race, nursing home residence, dose, and duration of use. CONCLUSIONS: Significant differences in risk of serious hypoglycemia were observed among users of individual agents. This may be explained by duration, timing, or potency of hypoglycemic action. These data confirm previous findings that chlorpropamide use is associated with high risk of hypoglycemia and indicate that among second generation sulfonylureas, glipizide is less associated with hypoglycemia than is glyburide. More information comparing the effectiveness of glycemic control among individual sulfonylureas is needed to assist prescribers in selecting a specific agent for use in clinical practice. PMID- 8675921 TI - Impact of a 12-month exercise program on the physical and psychological health of osteopenic women. AB - OBJECTIVE: To describe the effect of a supervised physical activity program on the physical and psychological health of osteopenic women. DESIGN: A randomized controlled trial. SETTING: Sherbrooke, Quebec, Canada. PARTICIPANTS: A total of 124 community-living postmenopausal women, between 50 and 70 years of age, with low bone mass took part in the study. INTERVENTION: Subjects allocated to the experimental group performed weight-bearing exercises (walking, stepping up and down from benches), aerobic dancing, and flexibility exercises for 60 minutes, three times a week, over a period of 12 months. All subjects were invited to attend bi-monthly educational seminars covering topics related to osteoporosis. OUTCOME MEASURES: Spinal and femoral bone mineral density (BMD), functional fitness (flexibility, coordination, agility, strength/endurance, cardiorespiratory endurance), psychological well-being, back pain intensity, and self-perceived health. RESULTS: Spinal BMD stabilized in the exercisers while decreasing significantly in the controls (P = .031). No change in femoral BMD was observed in either group (P = .597). Four of the five parameters chosen to evaluate functional fitness, namely flexibility, agility, strength, and endurance, were affected positively by the exercise program (all P < .01). Adjusting for prescores by means of an analysis of covariance revealed a significant difference between the groups in psychological well-being, which favored the exercisers (P = .012). After 12 months, back pain reported by exercisers was lower than that reported by controls (P = .008). Finally, self perceived health increased in the exercise group, whereas no difference was observed in the control group (P = .790). CONCLUSION: These results suggest that after 12 months, exercising can produce a significant increase above initial levels in the functional fitness, well-being, and self-perceived health of osteopenic women. Intensity of back pain can also be lowered by exercise. The exercise program succeeded in stabilizing spinal BMD but had no effect on femoral BMD. PMID- 8675922 TI - Pulmonary aspiration in a long-term care setting: clinical and laboratory observations and an analysis of risk factors. AB - OBJECTIVE: To determine the incidence and risk factors associated with aspiration in a high risk group in a long-term care setting. DESIGN: A prospective study of demographic, nutritional, clinical, dental, and survival characteristics in 69 patients who suffered 98 aspirations events from May 1, 1990, to December 31, 1990. Demographic and nutritional data from 192 patients who did not aspirate were collected from September 1991 to December 1991. SETTING: A long-term care VA facility. PATIENTS: Long-term care residents, most of whom were neurologically debilitated. MEASUREMENTS: The incidence of aspiration was measured and the clinical and microbiological characteristics of aspiration-associated nosocomial pneumonia described. Mortality and demographic, clinical, and nutritional characteristics were compared between patients who aspirated and those who did not. MAIN RESULTS: Twenty-five percent of the study group aspirated during the 8 month observational period, and 56% of the aspiration events progressed to roentgenographically proven cases of nosocomial pneumonia. Six bacteremic episodes were documented, and results of sputum cultures were consistent with mixed Gram-positive and Gram-negative infections. During the study period, patients who aspirated were at three times the risk of dying compared with patients who did not aspirate. Three years later, only 17% of the original group of patients who aspirated were still alive compared with 60% of the patients who had not aspirated. Multivariate analysis identified tube feeding, presence of a hyperextended neck or contractions, malnutrition, and the use of benzodiazepines and anticholinergics as risk factors. CONCLUSIONS: Pulmonary aspiration is a common and serious event in neurologically impaired long-term care patients. Some risk factors are amenable to change. PMID- 8675923 TI - Attitudes toward use of nursing homes and home care in older Japanese-Americans. AB - OBJECTIVE: A cohort of 1142 older Japanese Americans was identified to study preferences and attitudes regarding use of long-term care (nursing home or home care). DESIGN: Prospective cohort study. PARTICIPANTS AND SETTING: Older Japanese Americans in King County, Washington. RESULTS: Subjects were asked to consider hypothetical situations in which they were temporarily disabled by hip fracture or permanently disabled by dementing illness. If they fractured a hip, only 12% intended to use a nursing home; 29% intended to recover at home with the help of family or friends; another 54% intended to use paid home health care. If they became demented, the majority (53%) intended to use a nursing home; only 11% intended to rely on family or friends for care, and another 29% intended to use paid home health care. Similar responses were observed when subjects were asked what most members of their family or friends would wish them to do; however, they tended to value the perceived wishes of religious figures or the Japanese American community-at-large less than those of family or friends. Significant correlates with intention to enter nursing homes were lack of social support (unmarried, few or no close relatives or housemates), female gender, and high levels of acculturation into American society (never lived in Japan, English speaking only). Other factors that were not significantly correlated were health perceptions, satisfaction and life control scales, and health care utilization (hospitalizations and MD visits). In multivariate logistic regression, marital status and level of acculturation were the most powerful independent predictors of intention to enter nursing homes. Age and female gender were predictors of intention to use home care. In the base population of subjects, the prevalence of nursing homes use (5%) was similar to that of the general US older population. CONCLUSIONS: We conclude that older Japanese Americans in the Pacific Northwest often intend to enter nursing homes if they became disabled by dementing illness. Actual use is similar to other older populations. This may be attributable largely to the existence of an ethically appropriate nursing home which is strongly supported by, and familiar to, this close-knit community. Intention to use long-term care services appears to be dependent primarily on the level of social supports and acculturation into American society. PMID- 8675924 TI - Prevalence and persistence of sleep complaints in a rural older community sample: the MoVIES project. AB - OBJECTIVES: To determine the prevalence and 2-year persistence of subjective sleep complaints in a rural older population. DESIGN: A prospective epidemiological study of an age-stratified random community sample. SETTING: The mid-Monongahela Valley, a rural area of Southwestern Pennsylvania. PARTICIPANTS: A total of 1050 individuals with a mean age of 74.4 years (range, 66-97; SD = 5.5); 57.2% were women. MEASUREMENTS: Subjective responses to questions about sleep complaints, classified as "never" experienced versus "sometimes" or "usually"; these questions reflected difficulty falling asleep (DFA), sleep continuity disturbance (SCD), early morning awakening (EMA), and uncontrollable daytime somnolence (DaSom). Subjects were also asked about snoring. Frequencies of these complaints were used to calculate their prevalence; those who remained in the study 2 years later were asked the same questions again to determine the persistence of sleep complaints. On the first occasions, subjects were also asked for "usual" estimates of how long they took to fall asleep, how many times they wakened during the night, and how many hours of sleep they obtained per night. RESULTS: With regard to prevalence, 385 (36.7%) subjects reported DFA, 301 (28.7%) reported SCD, 201 (19.1%) reported EMA, and 198 individuals (18.9%) reported DaSom. Of those who knew whether they snored, 334 (40.0%) reported snoring loudly during sleep. Within the age range of this group, age was not associated with complaints of insomnia or somnolence; however, older age was associated with a significantly lower prevalence of snoring (P < .001). All three insomnia complaints were significantly more common among women (P < .001). Snoring was significantly more common among men (P < .005), but there was no gender difference in DaSom. With regard to subjective estimates, of those reporting DFA, 49.2% reported that sleep latency exceeded an hour; of those reporting SCD, 26.2% reported waking three or more times per night; and of the entire sample, 11.8% reported 5 hours or less, whereas 12.7% reported 9 to 12 hours, of sleep per night. Approximately 2 years later, among those who had reported insomnia previously and participated in the follow-up wave, the persistence of DFA was 74.9%, that of SCD 68.9%, that of EMA 47.3%, and that of known snoring was 59.6%. The persistence of DaSom, however, was only 5.7%; only DaSom was significantly (P = .049) associated with mortality. CONCLUSIONS: Sleep complaints were common among these older individuals. Because these data were collected prospectively, they also provide objective evidence that insomnia is relatively persistent or chronic among older adults. This finding has implications for the diagnosis and long-term management of sleep disorders in older people. Derivation from a random community-based sample rather than from samples of patients or volunteers makes these data more generalizable to the general older population. Finally, these data describe a rural older populations, a group which, in general, is medically underserved and understudied. PMID- 8675925 TI - A method to communicate patient preferences about medically indicated life sustaining treatment in the out-of-hospital setting. AB - OBJECTIVE: Patient preferences for life-sustaining treatment are frequently unknown at critical moments, which often results in clinicians providing treatment that is not medically indicated and/or may not be consistent with patient desires. A consortium of Oregon health care professionals developed the Medical Treatment Coversheet (MTC) to standardize documentation of patient preferences in the out-of-hospital setting by having corresponding physician orders available at the patient's location. We describe a unique process of development, evaluation, and implementation of the MTC. DESIGN: First, we conducted focus groups of providers to help draft the MTC. Second, the accuracy of MTC interpretation was determined by cohorts of acute and long-term care providers by indicating their treatment approach to three hypothetical written scenarios. They responded to the same scenarios twice, with and without the MTC. Responses were compared with each other and with ideal responses (most medically appropriate and in agreement with patient preferences) as defined by an expert panel. Finally, we are instituting pilot projects and developing a plan for statewide voluntary implementation of the MTC. SETTING: Urban and rural long-term care facilities and emergency medical service systems in Oregon. PARTICIPANTS: Focus groups included 28 general internists practicing in urban and rural settings and five nurses working in a long-term care facility. In addition, 87 providers (19 primary care physicians, 20 emergency physicians, 26 paramedics, and 22 long-term care nurses) participated in the evaluation of the form by responding to hypothetical scenarios. Providers in long-term care facilities in both an urban and rural area helped with pilot implementation of the MTC. Use of the MTC in noninstitutional settings was not evaluated. MAIN OUTCOME MEASURES: Suggestions from focus groups were incorporated into the form. For the hypothetical scenario responses, ideal appropriateness scores were analyzed, with a total possible score of 30 for each acute care provider and 15 for each long term care provider. Statistically significant differences were determined using a paired t test. We report the experience of providers who helped with the pilot implementation of the form. RESULTS: Focus groups would use the MTC and believed it would be useful for their patients. Comparing responses to the hypothetical scenarios without the MTC to those with the MTC, 37% of treatment decisions changed for acute care and 29% changed for long-term care providers. Changes were attributable overwhelmingly to withholding treatments consistent with patient preferences. Compared with the ideal, decisions were more appropriate for all specific treatments across all scenarios and clinician groups with the MTC, with one exception: some advanced emergency treatments were withheld inappropriately by 18% of acute care providers with the MTC, (chi-square = 15.94, P < .0001). For all scenarios combined, appropriateness scores increased significantly with the MTC for both acute care (16.4 to 22.3, P < .0001) and long-term care providers (8.8 to 12.2, P < .0001). Overall, providers helping with the pilot implementation were satisfied with the document, organizational endorsements, and available informational resources. CONCLUSION: We describe our process for development, initial evaluation, and implementation of the MTC. In clinical scenarios overall, the MTC improves the appropriateness of clinicians' decisions about life-sustaining treatments. We are planning statewide implementation of the MTC after appropriate education of clinicians. PMID- 8675926 TI - Cross-discipline disparities in perceptions of mental disorders in a long-term care facility. AB - OBJECTIVES: This study compared prevalence rates of mental disorders in a single long-term care facility as perceived by three professional disciplines and compared professionals' perceptions with two standardized measures of psychopathology. DESIGN: Comparison of (1) prospective standardized psychiatric evaluations performed by psychiatrists, (2) chart reviews of mental disorders as documented by primary care physicians, and (3) interviews of nurses. SETTING: The residential health care facility at Monroe Community Hospital in Rochester, New York. PARTICIPANTS: A 20% random sample of adult residents, stratified by ward (n = 80). MEASUREMENTS: Prevalence rates of psychopathology as determined by each data collection method: psychiatric diagnoses as determined by psychiatrists and primary care physicians, the Brief Psychiatric Rating Scale, and the Psychogeriatric Dependency Rating Scale. RESULTS: Prevalence rates of psychopathology ranged from 60 to 91% across discipline-specific data collection methods. Using psychiatrists' diagnoses as the benchmark, primary care physicians and nurses underestimated the prevalence of mental disorders, particularly organic mental disorders. All disciplines agreed on the presence of personality and developmental disorders. The Brief Psychiatric Rating Scale and Psychogeriatric Dependency Rating Scale validated perceptions of psychopathology by psychiatrists and nurses, but not by primary care physicians' chart diagnoses. CONCLUSION: Disparities in perceptions of mental disorders across disciplines pose a threat to patient care and suggest a need for more reliable incorporation of mental health expertise in the long-term care setting. PMID- 8675927 TI - Atrophy of the corpus callosum in Alzheimer's disease versus healthy aging. AB - OBJECTIVE: To investigate the specificity of atrophic changes in the corpus callosum (CC) compared with the cerebellum and pons in patients with Alzheimer Disease (AD), healthy elderly subjects (HE), and a sample of prospectively studied subjects who have developed cognitive decline or "incipient dementia" (ID). DESIGN: Cross-sectional comparison by age using quantitative MRI. SETTING: Ambulatory research unit. PARTICIPANTS: Sixty HE subjects (mean age 78.2 years; range 66-95), 20 ID subjects (mean age 88.1 years; range 78-98) and 39 AD subjects (mean age 72.2 years; range 52-91) were enrolled in longitudinal studies of healthy aging or AD. The population was selected for optimal health; all were examined to exclude medical, neurological and psychiatric illness. MEASUREMENTS: Brain atrophy by quantitative MRI. RESULTS: AD subjects had smaller CC than HE or ID subjects, who did not differ from each other. All three sectors of the CC were smaller in AD than in HE or ID subjects. The cross sectional area of the cerebellum and pons did not differ between groups. HE and ID subjects showed a significant decline in CC size with age. No age-related decline was found for AD subjects. The regional atrophy of the CC in AD subjects was significantly related to cognitive function but not to disease duration. CONCLUSIONS: Atrophy of the CC differentiates HE and ID from AD subjects and tracks the cognitive decline of this disease. In addition, optimally healthy subjects show an age-related decline in callosum size. The atrophy is specific to the CC, a cortical projection system, and does not occur in cerebellum or pons. PMID- 8675928 TI - Do neural factors underlie age differences in rapid ankle torque development? AB - OBJECTIVES: Rapid torque development is substantially slower in healthy old adults compared with young adults, but the underlying cause of this age-related loss remains unclear. Measurements of myoelectric signals in ankle dorsi- and plantarflexor muscles during rapid exertions were used to explore the extent to which the loss might be attributed to neural factors. METHODS: Myoelectric signals were measured in a laboratory setting in 24 healthy young and 24 healthy old adult volunteers during rapid isometric and isokinetic torque development. Premotor times, muscle activation rates, and myoelectric activity levels of agonistic and antagonistic muscles were quantified. RESULTS: There were few marked age differences in the premotor times or in the onset rates or magnitudes of agonistic muscles activities during maximum isometric and during isokinetic exertions. Premotor times were statistically associated with age but, in the mean, were only approximately 10 to 25 ms longer in the old. Age effects on agonist muscle activity magnitudes were significant only in the lateral gastrocnemius. Small decreases in antagonistic muscle activity levels with age were found. CONCLUSIONS: Given the outcomes of this study, the differences observed previously in rapid torque development abilities in healthy older adults, compared with healthy younger adults, seem attributable largely to differences in muscle contraction mechanisms rather than to differences in speeds of stimulus sensing or central processing of motor commands, or to differences in muscle recruitment strategies. PMID- 8675929 TI - Postural hypotension and dizziness in a general aged population: a four-year follow-up of the Helsinki Aging Study. AB - OBJECTIVE: To evaluate the frequency, risk factors, and prognostic significances of postural hypotension (PH) and dizziness on postural testing (DPT). DESIGN: A prospective cohort study. SETTING: General community, The Helsinki (Finland) Aging Study. SUBJECTS: Persons of three age cohorts (75, 80, and 85 years, n = 569) were chosen randomly and followed for 4 years. MEASURES: Postal questionnaires, structured interview, extensive clinical and laboratory examinations, blood pressure (BP) changes in a postural test using different definitions for PH, history of dizziness, dizziness on testing postural blood pressure reactions (DPT), and date of death during a 4-year follow-up. RESULTS: The frequency of a fall in systolic blood pressure greater than 20 mm Hg or a fall in diastolic pressure greater than 10 mm Hg (PH-I) was 30.3%. Both criteria occurred simultaneously (PH-II) in 7.5%, and if dizziness on postural testing (DPT) was an additional symptom (PH-III), the prevalence was 2.6%. The overall prevalence of DPT was 19.7%. PH-I, PH-II, and DPT were also frequent among the healthy aged (26.6%, 6.6%, and 17.3%, respectively). The postural change in BP correlated inversely with the initial supine BP levels (systolic r = -.149, P < .001 and diastolic r = -.218, P < .001), but in persons with isolated systolic hypertension PH was rather less frequent (21.9% and 2.3%). DPT was more common in the subjects with heart failure (26.3%, P < .05), impaired exercise tolerance (NYHA III-IV) (33.7%, P < .05), and PH-II (37.2%, P < .05) compared with the healthy controls (17.3%). The 1-year mortality was higher in subjects with than without DPT (7.1% vs 4.8%, P < .05), but the difference was not significant after controlling for age and gender. PH-I, PH-II, and PH-III were not significantly related to 4-year mortality. CONCLUSIONS: In this study of older people in Helsinki, Finland, asymptomatic hypotensive postural BP reactions and DPT were found frequently among healthy older people, and they tended to be increased in people with some diseases. Neither PH nor DPT were of prognostic significance for mortality in this population. PMID- 8675930 TI - The "co-pilot" driver syndrome. PMID- 8675931 TI - The effects of hormone replacement therapy, lipoprotein cholesterol levels, and other factors on a clock drawing task in older women. AB - OBJECTIVES: To assess the associations of a clock drawing task with hormone replacement therapy and other factors in older women. DESIGN: Group comparisons. SETTING: Leisure World Laguna Hills, retirement community in southern California. PARTICIPANTS: Two hundred ninety-two postmenopausal women who were analyzed for lipoprotein levels in 1987-88 were contacted by postal survey, which included a clock drawing task, in 1992; 168 women who drew normal clocks were compared with 46 who drew abnormal or blank clocks. MEASUREMENTS: Clock drawings; lipoprotein cholesterol levels; serum progesterone, estrone, estradiol, and steroid hormone binding globin levels; self-reported data on smoking, alcohol intake, prior medical diagnoses, and use of certain medications including hormone replacement therapy and analgesics. RESULTS: Women with normal clocks had significantly lower total cholesterol (P = .01), LDL cholesterol (P = .03), and serum progesterone levels (P = .03). They weighed, on average, 5 more pounds at the time of last menstrual period (P = .05), were more likely to use combined hormonal replacement therapy (P = .06), and were less likely to use acetaminophen daily (P = .02) than women with abnormal clocks. Serum estrone and estradiol levels did not differ significantly between women with normal and abnormal clocks. CONCLUSION: The associations found here suggest that high serum cholesterol and progesterone levels might have a negative effect on clock drawing performance. Acetaminophen may also be related to worse performance on this task. PMID- 8675932 TI - Systemic oxidative stress and its relationship with age and illness. Associazione Medica "Sabin". AB - OBJECTIVE: It has recently been proposed that increased oxidative stress may play a role in the aging process and age-associated degenerative diseases. DESIGN AND MEASUREMENTS: A cross-sectional study was carried out to assess the relationship of circulating antioxidants, namely vitamins E and C, beta-carotene, proteic thiols (P-SH) and ceruloplasmin, and of lipid peroxides, with both aging and aging with disability, i.e., unsuccessful aging. PARTICIPANTS: One hundred healthy free living and 62 disabled octo-nonagenarians and 91 healthy adults were enrolled in the study. RESULTS: Free living and disabled older adults had lower antioxidant and higher lipid peroxide levels than healthy adults, as well as the disabled older adults compared with free living older persons. Using logistic regression, we observed that plasma concentrations of vitamins E and C, P-SH, and lipid peroxides were independently associated with either aging or aging with disability, apparently representing biochemical indicators of patient status. In particular, aging and unsuccessful aging were associated with higher levels of lipid peroxides independently of circulating levels of vitamins C and E, suggesting that the increased oxidative stress was not merely an effect of a lower dietary intake of antioxidants. Serum ceruloplasmin was significantly higher in free living older adults than in healthy adults, and in the disabled compared with free living octo-nonagenarians. CONCLUSIONS: Our findings are consistent with the presence of systemic oxidant load in older adults, and this phenomenon is far more evident in unsuccessful aging. PMID- 8675933 TI - Cognitively impaired spouses as primary caregivers for demented elderly people. AB - OBJECTIVE: To describe problems of dementia patients whose spousal caregivers are also cognitively impaired. DESIGN: Retrospective chart review. SETTING: The geriatric assessment clinic at University of California, San Diego, which is one center for the California State sponsored Alzheimer's Disease Diagnosis and Treatment Center Program. PATIENTS: During the period from January 1992 through May 1994, 65 patients completed the assessment and met the entry criteria of being demented and having a spousal caregiver. Twelve of the spouses scored six or more error points on the Katzman Short Orientation-Memory-Concentration Test. MEASUREMENTS: Patient data included age, living situation, other caregivers, use of formal and informal support systems, profiles of medical, cognitive, and functional ability, caregivers interactions, and recommendations from the evaluation. MAIN RESULTS: Dementia patients with cognitively impaired spouses utilized fewer community resources (P = .021) and experienced difficulty with medication compliance (P = .041) more often than those with cognitively normal spousal caregivers. CONCLUSIONS: Older caregivers of patients suffering from dementia should be screened for cognitive problems. PMID- 8675934 TI - A clinical approach to "idiopathic" normocytic-normochromic anemia. AB - OBJECTIVES: Normocytic-normochromic anemia is frequently found in patients with chronic disorders. The pathogenesis, epidemiological and clinical characteristics of normocytic normochromic anemia of unknown cause are not well established. We evaluated the role of bone marrow examination and the clinical course of patients with "idiopathic" normocytic-normochromic anemia. DESIGN: Patients with normocytic-normochromic anemia underwent a noninvasive evaluation according to a predetermined protocol. Bone marrow aspiration and biopsy were performed in those patients in whom no explanation for the anemia was found. They were later followed at 3 to 6 month intervals. RESULTS: Thirty-one patients (23 females and 8 males) with "idiopathic" normocytic-normochromic anemia (mean hemoglobin concentration was 10.0 + 0.6 g/dL) were detected. No patient had symptoms related to the anemia. Twenty-nine bone marrow aspirations and 21 biopsies were performed. Iron deficiency and mild myelofibrosis were found in one patient each. The rest of the bone marrow examinations were normal. During 15.5 +/- 10.3 months of follow-up, the hemoglobin level rose marginally to 10.9 + 1.0 g/dL (P < .0002). No changes in clinical or laboratory variables that could be ascribed to anemia were detected. CONCLUSION: Normocytic-normochromic anemia of unknown cause is encountered infrequently in clinical practice and is found mainly in older patients. The evaluation should be noninvasive to exclude correctable causes of the anemia. Bone marrow examination is only rarely contributive in this setting. The prognosis of these patients is excellent. PMID- 8675935 TI - Looking inside the black box of comprehensive geriatric assessment: a classification system for problems, recommendations, and implementation strategies. AB - OBJECTIVE: To develop and test the inter-rater reliability of a coding system for geriatric problems identified through Comprehensive Geriatric Assessment (CGA) of hospitalized older persons, recommendations generated by the assessment, and implementation strategies for these recommendations. DESIGN: Validation study. SETTING: A health maintenance organization and a geriatrics academic program. PARTICIPANTS: A total of 49 hospitalized older persons, who met at least 1 of 13 inclusionary "targeting" criteria, two geriatricians, and one social worker who coded forms. MEASUREMENTS: Standardized coding of CGA consultation sheets into (1) geriatric problems identified, (2) recommendations, and (3) implementation strategies; inter-rater reliability testing of coding system using two physicians and a social worker. RESULTS: On average, each assessed patient had 4.8 recommendations. The largest percentages of recommendations were for non physician referrals (18.2%), advance directives (13.4%), medication adjustments (11.5%), diagnostic evaluation/monitoring (11.5%), and community services (10.9%). The proportions of agreement between raters in coding problems ranged from 0.77 to 0.90, in coding recommendations from 0.69 to 0.86, and in coding implementation strategies from 0.68 to 0.83. CONCLUSION: A classification system for measuring some components of the process of care of CGA has satisfactory inter-rater reliability, can be adapted for other settings, and may provide valuable insight into determining which components of CGA confer health benefits. PMID- 8675936 TI - Cross-validation of the Delirium Rating Scale in older patients. AB - OBJECTIVE: To cross-validate the Delirium Rating Scale (DRS). DESIGN: Cross sectional. SETTING: Geriatric medicine and geriatric psychiatry assessment units and consultation services. PARTICIPANTS: A total of 104 older patients on the above services. MEASUREMENTS: Mini-Mental State Examination (MMSE) score, Barthel Index score, DRS score, Blessed Dementia Scale score, clinical diagnoses using DSM-III-R criteria. MAIN RESULTS: The mean DRS score was highest in the delirium group. Cronbach's alpha was .90, and inter-rater reliability of total scores was .91 (intra-class correlation). Receiver Operating Characteristic curve analysis showed that the area under the curve for the DRS was significantly higher than the MMSE as a test for delirium. At its published cutpoint of 10, the sensitivity of the DRS is .82 and the specificity is 94. The value at which the sensitivity of the DRS is .90 is 8, at which specificity is .82. CONCLUSIONS: The DRS appears to a feasible instrument. In a sample with a high proportion of delirious patients, it has acceptable measurement properties when used by expert observers. PMID- 8675937 TI - A 67-year-old woman with a progressive gait disturbance. PMID- 8675938 TI - The effectiveness and efficiency of outpatient geriatric evaluation and management. AB - OBJECTIVE: To compare the effectiveness of geriatric evaluation and management (GEM) with usual primary care (UPC). DESIGN: A 2 x 3 randomized controlled group design. SETTING: A 450-bed Department of Veterans Affairs Medical Center (VAMC) that provides general medical and surgical care to eligible veterans. PARTICIPANTS: One-hundred sixty male subjects (mean age = 72 years), who were above average users of VAMC outpatient clinics and who had at least two Activity of Daily Living (ADL) or Instrumental Activity of Daily Living (IADL) impairments, were assigned to GEM (n = 80) or UPC (n = 80). MEASUREMENTS: Data were collected about patients' (1) health and functional status, (2) psychosocial well-being, (3) quality of health and social care, (4) health care utilization, and (5) health care costs. Data were obtained before randomization, and again at 8 and 16 months. RESULTS: The results indicated that GEM was more effective than UPC in improving some aspects of the quality of health and social care and in increasing patient satisfaction with care. GEM also reduced emergency room use, and showed a trend toward decreasing acute admissions. It was not effective, however, in improving patients' psychosocial well-being. Except for a short-term survival advantage, it was also not effective in preventing deterioration in their health and functional status. Further, GEM did not reduce overall utilization of outpatient or inpatient services, and it significantly increased total outpatient health care costs. CONCLUSIONS: Outpatient GEM improves patient satisfaction and some aspects of the quality of care patients' receive but does not reduce the cost of outpatient or inpatient care. Longer-term follow-up studies are needed to determine whether reductions in emergency room use and inpatient admissions persist over time and result in reductions in the overall cost of care. PMID- 8675939 TI - Hippocampal and neocortical involvement in normal brain aging and dementia: morphological and neurochemical profile of the vulnerable circuits. PMID- 8675940 TI - Is there a role for estrogen replacement therapy in the prevention and treatment of dementia? AB - Studies in experimental animal models provide a convincing rationale for a role for ERT in the treatment and prevention of dementia. These studies establish the role of estrogen in the regeneration and preservation of neuronal elements within the CNS that are analogous to those regions of the brain most sensitive to the neurodegenerative changes associated with AD. Furthermore, behavioral studies in these animals establish a correlation between the hormone dependent changes in the neuronal architecture and learning and memory. However, extrapolation of these studies to post-menopausal women must be done with caution. Surgical and natural loss of ovarian function does not result in a clinically relevant decline in cognitive function over the short term (1 to 2 decades) or ever in some women. The modest changes that are observed may relate to the hormone's effect on neurotransmitter levels or their receptors. Although Singh et al. noted changes in neurotransmitter concentrations 5 weeks after ovariectomy, changes in cognitive performance in their rat model did not become significant until 28 weeks after ovariectomy--the equivalent of approximately 2 decades of human life. Except for the familial forms of the disease, AD is rarely seen in the first 2 decades after the menopause. However, by the third decade after the menopause, 50% of women can be expected to manifest the histopathological changes of AD. Approximately half of these women are without clinical evidence of disease. Thus, the neurodegenerative process of AD probably precedes by many years the age of onset of the disease. We do not know what factors contribute to the selective neuronal injury which, over time, eventually leads to the neuronal loss and reduced synaptic density that result in the cognitive impairment of AD. At this time we can only speculate as to estrogen's role in modifying this process. Data from experimental animal models suggest that estrogen deficiency would selectively increase the vulnerability of estrogen-responsive neural elements, for example, the cholinergic neurons of the basal forebrain and hippocampus- offulnerability mediated perhaps by the reduced expression of neurotrophic factors, decreased clearance of the amyloid protein, and/or reduced cerebral blood flow that are associated with estrogen deficiency. The brain's ability to adapt to the neuronal loss by stimulating axonal and synaptic regeneration would also be impaired by estrogen deficiency as suggested by estrogen's ability to restore the synaptic density of lesioned brains of ovariectomized animals. Thus, estrogen deficiency, like the apolipoprotein E4 allele, can be considered not a cause of AD but one of perhaps several factors modifying the neuronal injury and loss leading to AD. The limited epidemiologic data and intervention trials currently available are consistent with this interpretation. Because of the urgency and enormity of the problem of dementia in our aging society, there would now appear to be sufficient reason to allocate the resources needed to conduct the appropriate clinical trials to determine estrogen's efficacy in both the treatment and prevention of this devastating condition. These trials are needed so that women and their physicians can adequately weigh the risks and benefits of hormone replacement for the treatment and, more importantly, the prevention of dementia. PMID- 8675941 TI - Using pharmacoepidemiological findings to guide clinical practice: sulfonylureas and hypoglycemia in older adults. PMID- 8675942 TI - Oxidative stress and aging: still a hypothesis. PMID- 8675943 TI - Should Alzheimer's disease patients be allowed to drive? A medical, legal, and ethical dilemna. PMID- 8675944 TI - Hormone replacement therapy and its potential relationship to dementia. PMID- 8675945 TI - Myocardial infarction and antihypertensive drug therapy. PMID- 8675946 TI - Diurnal variation in language tests and relevance to early detection of dementia: disruption of time dependency in dementing subjects. PMID- 8675947 TI - Decline of hemoglobin is accelerated in older subjects with a high lipoprotein (a) concentration. PMID- 8675948 TI - Hypoalbuminemia in older people is attributable to barriers against food accessibility rather than the burden of disease. PMID- 8675949 TI - Isolated external jugular vein thrombosis in older people. PMID- 8675950 TI - Continuous bladder irrigation with vancomycin for the treatment of methicillin resistant Staphylococcus aureus. PMID- 8675951 TI - Thumb cellulitis attributable to group G streptococcus. PMID- 8675952 TI - Factor structure and validity of the Dutch version of the Cohen-Mansfield Agitation Inventory (CMAI-D) PMID- 8675953 TI - A plug-in minielectrode for measurements in stirred photometric cuvettes. AB - A device is described to perform potentiometric measurements with ion-sensitive electrodes in stirred photometric cuvettes. Its design allows to make additions to the reaction medium with microliter syringes during measurements. Originally, this plug-in electrode was designed to register the free Ca2+ concentrations in the incubation medium of mitochondrial suspensions during measurements of the free matrix Ca2+ concentration with a permeant fluorescent Ca2+ indicator. However, numerous other applications can be easily realized, such as the combination of mitochondrial light-scattering measurements and ion-transport measurements, the combination of the permeabilized cell technique with fluorescence measurements of intracellular organelles or simply the calibration of the fluorescence of Ca2+ indicators with a Ca2+ ion-sensitive minielectrode. Compared with the use of a second fluorescent indicator the use of an electrode has the advantage that the signal can be transformed into ion concentrations already during the measurements. PMID- 8675955 TI - Application of a chromogenic bioassay procedure for the measurement of the proliferation of endothelial cells in vitro under the influence of the effects of steroid hormones and growth factors. AB - Development of in vitro procedures which permit the measurement of the synergistic biological influences of polypeptide growth factors and steroid hormones on cellular processes represents an important objective in reaching an understanding of the molecular basis of many physiological events, including those associated with the proliferation of endothelial cells and the subsequent angiogenesis which occurs, for example, during the estrous cycle and wound repair. The present investigations were undertaken to examine the use of nonradioisotopic procedures for the bioassay of polypeptide growth factors, such as basic fibroblast growth factor (bFGF), known to exert effects on the proliferation and migration of endothelial cells, and to overcome some of the recognised sensitivity limitations with endothelial cell proliferation assays based on the [3H]thymidine uptake methods due to the cell passage number and culture conditions. The experimental results confirm these objectives with establishment of a simplified chromogenic procedure for the sensitive determination of the effects of the steroid hormones, estradiol and progesterone, on the proliferation of endothelial cells in culture, either directly or via mediation of the effects of bFGF at low concentration levels. This procedure has provided experimental data suggesting that a hitherto unrecognised synergy may exist between these steroids and bFGF, with both estradiol and progesterone significantly antagonising the bFGF-stimulated proliferative response with bovine aortic endothelial cells (BAEC) in culture. Progesterone alone was also capable of directly stimulating BAEC proliferation, albeit transiently. Neither estradiol or progesterone affected the proliferation of the control 3T3 fibroblast cell population, in the presence or absence of a stimulatory dose of bFGF. PMID- 8675954 TI - NMR study of dideoxynucleotides with anti-human immunodeficiency virus (HIV) activity. AB - The molecular structures of 3'-azido-2',3'-dideoxyribosylthymine 5'-triphosphate (AZTTP), 2',3'-dideoxyribosylinosine 5'-triphosphate (ddlTP), 3'-azido-2',3' dideoxyribosylthymine 5'-monophosphate (AZTMP) and 2',3'-dideoxyribosyladenine 5' monophosphate (ddAMP) have been studied by NMR to understand their anti-HIV activity. For ddAMP and ddITP, conformations are almost identical with their nucleoside analogues with sugar ring pucker equilibriating between C3'-endo (approximately 75%) and C2'-endo (approximately 25%). AZTMP and AZTTP on the other hand show significant variations in the conformational behaviour compared with 3'-azido-2',3'-dideoxyribosylthymine (AZT). The sugar rings for these nucleotides have a much larger population of C2'-endo (approximately 75%) conformers, like those observed for natural 2'-deoxynucleosides and nucleotides. The major conformers around C5'-O5', C4'-C5' and the glycosidic bonds are the beta 1, gamma + and anti, respectively. PMID- 8675956 TI - Bulk acoustic wave sensor for investigating hemorheological characteristics of plasma and its coagulation. AB - A method of using a bulk acoustic wave (BAW) device to study the hemorheological phenomena is proposed. By measuring the resonant resistance of a BAW device, the dependence of the plasma viscosity on its composition is investigated. It has been found that during the process of the plasma coagulation, the frequency response of a BAW device is dominated by the change in plasma viscoelasticity, and useful information such as the coagulation time and the viscoelasticity of coagulated plasma can be obtained from the curve of frequency response. Based on the BAW quartz detection system, effects of fibrinogen, thrombin and some drugs on the plasma coagulation are investigated. The results show that the BAW device based on the oscillator method possesses some advantages, such as high sensitivity, simplicity of use, cost effectiveness and small sample volume for clinical hemorheological study. PMID- 8675957 TI - Determination of surfactant critical micelle concentration by a novel fluorescence depolarization technique. AB - A novel method using fluorescence depolarization to determine the critical micelle concentrations (CMC) of surfactants was developed. Fluorescence anisotropies of Triton X-100, sodium dodecyl sulfate, and sodium cholate were measured using 1,6-diphenyl-1,3, 5-hexatriene as a fluorescence probe. Fluorescence anisotropy decreased with increasing surfactant concentrations below the CMC and leveled off above the CMC. The depolarization method does not depend on the concentration of DPH and is largely immune to light-scattering problems encountered in turbid aqueous systems. PMID- 8675958 TI - Solid-state CP/MASS 13C-NMR spectroscopy: a sensitive method to monitor enzymatic hydrolysis of chitin. AB - The time-course hydrolysis of colloidal chitin by the chitinase complex isolated from Myrothecium verrucaria was monitored using solution and solid-state 13C-NMR spectroscopy. The solution NMR studies showed the presence of N-acetylglucosamine (GlcNAc) as the sole product of hydrolysis. Solid-state 13C CP/MASS studies, on the other hand, indicated the presence of high molecular weight oligomers as well as GlcNAc. The linewidth of the C1 carbon of the oligomers obtained after hydrolysis is found to be less than that of the unhydrolyzed sample. The linewidths calculated from the spin-spin relaxation times (T2) of colloidal chitin and its products of hydrolysis were in the restricted range of 40-50 Hz, compared with the observed linewidths of 143-123 Hz. Peak area measurement on monomer to polymer/oligomer indicated an initial slow formation of the monomer, GlcNAc. From the NMR data, the involvement of endo-enzymes in the initial phase of hydrolysis is suggested. PMID- 8675959 TI - Porous zirconia: a new support material for enzyme immobilization. AB - Four different proteases (trypsin, chymotrypsin, papain and pepsin) were covalently attached to the surface of a new type of porous zirconia, as well as a conventional porous silica, activated with 3-isothiocyanatopropyltriethoxy silane (NCS-silane). The immobilization efficiency onto the porous zirconia material was evaluated in terms of the amount of enzyme attached to the particles and from the biological activity remaining after the immobilization step. The results were compared with the corresponding experiments with a porous silica of similar surface area/g support material. In addition, the storage stability of the modified zirconia and silica biocatalysts were evaluated. These results indicated that specific immobilized enzyme biocatalysts can be achieved with this new zirconia support material which exhibits different properties to those observed with the more conventional silica-based materials. Moreover, the results with the enzyme-zirconia biocatalysts also indicate different characteristics when compared with data for the same enzymes immobilized under similar buffer conditions to organic support materials as previously described by various other investigators. The advantages of zirconia-based immobilized enzyme biocatalysts in terms of their density and chemical robustness are also described relative to other alternative support materials currently in use. PMID- 8675960 TI - An affinity method for the purification of mannose 6-phosphate receptor proteins (MPR 215) from rat tissues and goat liver. AB - An affinity matrix (Sepharose 6B-divinyl sulfone-pentaphosphomannan) has been developed which can be efficiently used for the purification of the MPR 215 from different tissues of rat as well as from goat liver. The matrix developed is relatively easy to prepare compared with the available procedures, and can be used for the purification of similar receptor proteins from other sources. PMID- 8675961 TI - Sodium dodecyl sulfate (SDS)-based whole-mount in situ hybridization of Xenopus laevis embryos. AB - We describe a streamlined whole-mount in situ hybridization protocol that utilizes high concentrations of the detergent sodium dodecyl sulfate (SDS). Our results suggest that SDS is an effective blocking agent in Xenopus laevis embryos which permeabilizes membranes without disrupting morphology. Consequently, riboprobes appeared to disperse uniformly within the embryo and several arduous and/or laborious steps of conventional procedures could be eliminated without compromising the technique. PMID- 8675962 TI - Microcalorimetric study of mitochondria isolated from fish liver tissue. AB - We determined the thermogenesis curves of mitochondria isolated from fish liver tissue by using an LKB 2277 Bioactivity Monitor. After isolation from the fish liver, mitochondria still have activity and can live for a long time by using the stored nutrients. We calculated the recovery rate constants of mitochondria. We found that the thermogenesis curves of mitochondria are similar to those obtained from prokaryotic cells, but not similar to those obtained from eukaryotic cells. We determined the metabolic thermogenesis curves of mitochondria isolated from two kinds of carp liver tissue, scattered-scaled mirror carp and harvest carp. There are some important similarities and some important differences between these thermogenesis curves. PMID- 8675963 TI - Steady-state two-dimensional maps of very alkaline proteins in an immobilized pH 10-12 gradient, as exemplified by histone types. AB - Two-dimensional steady-state patterns of histones are here reported for the first time. The first dimension run consists in nonlinear immobilized pH gradients, spanning the pH 10-12 range. The second dimension run is a standard SDS-PAGE in a constant concentration (15% T) gel slab, in presence of a 6% T stacking gel. All the histone fractions analysed (II-AS, VI-S, VII-S and VIII-S) exhibit pI values between pH 11 and 12. The M(r) values range from 13 to 32 kDa, with the heaviest distribution around 18 kDa. When running all different histone fractions in a single mixture, and analysing the 2-D gel by computerized image data acquisition, a total of 35 individual spots is detected. PMID- 8675964 TI - Enzyme reactions in a multicompartment electrolyzer with isoelectrically trapped enzymes. AB - The possibility of performing bioconversions under an electric field is here reported. A system is described by which the enzyme is trapped by an isoelectric mechanism between two zwitterionic membranes having pI values encompassing the isoelectric point of the enzyme. The enzyme is loaded into a multicompartment electrolyzer and kept operating under an electric field, which will continuously harvest the reaction product. Since, under focusing conditions, all buffering ions will vacate the reaction chamber at steady state, the buffering ion is trapped into the enzyme chamber by using amphoteric buffers co-isoelectric with the enzyme. As an example of such "isoelectrically immobilized' reactor, the enzyme beta-hydroxysteroid dehydrogenase is blocked into an isoelectric trap delimited by a pI 8.0 and a pI 6.5 membranes. 100 mM histidine (pI 7.47) is co immobilized by the same isoelectric mechanism into the enzyme chamber. The dehydrocholic acid substrate (3,7,12-trioxo-5 beta-cholanoic acid) and reduced co factor (NADH) are continuously infused into the enzyme chamber and the product (3 beta-hydroxy-7,12-dioxo- 5 beta-cholanoic acid, a compound of pharmaceutical interest) and the oxidized co-factor (NAD+) collected, separately, into the two neighbouring chambers at the anodic side. ADVANTAGES: in a soluble form, the enzyme maintains the reaction kinetics of the free soluble form. Additionally, the reaction product and exhausted co-factor can be recovered by electrophoretic transport. PMID- 8675965 TI - Sertraline 50 mg daily: the optimal dose in the treatment of depression. AB - The dose regimen for sertraline in the treatment of depression has been well established. The starting dose, 50 mg/day, is the usually effective therapeutic dose, and the optimal dose when considering both efficacy and tolerability for most patients. For patients who do not show an adequate therapeutic response within 24 weeks, the dose of sertraline can be increased in 50 mg/day increments at no less than weekly intervals to a maximum of 200 mg/day. Sertraline is generally given as a single daily dose and may be administered at any time of the day. In contrast to other selective serotonin reuptake inhibitors, there is no need for altered dose recommendations in the elderly. PMID- 8675966 TI - Effects of various factors on steady state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine. AB - Effects of various factors on steady state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine (mCPP) were studied in 43 depressed patients (19 males, 24 females) receiving trazodone 150 mg at bedtime for 1-3 weeks. Sixteen cases were smokers, and 19 cases were also receiving various benzodiazepines. The means (and ranges) of plasma concentrations of trazodone and mCPP, and the mCPP/trazodone ratio were 619 (251-1059) ng/ml, 59 (32-139) ng/ml and 0.100 (0.044-0.219), respectively. Smokers had significantly (p < 0.05) lower plasma concentrations of trazodone and higher mCPP/trazodone ratios than non-smokers. Age, sex and co-administration of benzodiazepines did not affect any plasma concentrations or the mCPP/trazodone ratio. In 11 cases where the dose was increased to 300 mg, neither plasma concentration/dose ratios nor the mCPP/trazodone ratio changed significantly. The present study thus suggests that: (1) there is a large Interindividual variation in the metabolism of trazodone; (2) smoking enhances the metabolism, but age, sex and co administration of benzodiazepines do not affect it; (3) trazodone and mCPP have linear kinetics. PMID- 8675967 TI - Cerebrospinal fluid 5-hydroxyindolacetic acid and aggression: a critical reappraisal of the clinical data. AB - Over the past 15 years several clinical studies have been published dealing with the hypothesis that disturbances in central serotonergic functioning could be related to outward directed aggression and impulsivity. Close reading of the 22 relevant reports, however, raises doubt about the unequivocality of the results across diagnostic boundaries and in comparison with normal controls. Only eight of the studies are methodologically acceptable and seem to support the hypothesis. Taking all data together, it is concluded that some relationship exists between decreased serotonin metabolism, as reflected by lowered cerebrospinal fluid 5-hydroxyindolacetic acid, and certain aspects of aggressive behavior in a subgroup of young, male, personality-disordered subjects with seriously deviant behavior. PMID- 8675968 TI - Structural validity of MADRS during antidepressant treatment. AB - In order to assess the internal structure of MADRS, a principal component analysis was performed in a group of 137 patients suffering from DSM-III major depression (MADRS score at baseline > 20) receiving a 4 week treatment in three double-blind drug trials (medifoxamine vs clomipramine, imipramine or amineptine). Prior to antidepressant treatment, three factors could be identified with 32 %, 12 % and 11.5 % of explained variance. The first factor corresponded to the global severity of depression whereas the second, with sleep and appetite items scoring high, could be postulated as a somatic factor. After 28 days of antidepressant treatment (mean MADRS total score = 13.3), only one factor could be substantiated, representing 66% of total variance. The study was primarily based on data obtained without rotation, which ensures the independence of the different factors. The good internal consistency of MADRS accounts for the high correlation of all items with the first factor (r = 0.95). MADRS appears as a unidimensional scale more oriented towards psychic as opposed to somatic aspects of depression. PMID- 8675969 TI - Naltrexone use in the treatment of anorexia nervosa and bulimia nervosa. AB - Our auto-addiction model suggests that opiate blockade may be therapeutically useful in anorexia nervosa and bulimia nervosa. Naltrexone was administered to out-patient subjects in double-blind clinical trials with randomized cross-over designs. Reduction in binge-purge symptomatology was evident in the naltrexone period over placebo for 18 out of 19 subjects with either bulimia or anorexia nervosa of the bulimic subtype. In every case, the decoding of drug or placebo double blinding confirmed the assessments of both the investigator and the subjects, based on the blind analysis of the data and on their therapeutic response, respectively. Statistical analysis done on the total population and two diagnostic subgroups found highly significant differences. PMID- 8675970 TI - A detailed longitudinal analysis on the use of naltrexone in the treatment of bulimia. AB - In accord with our auto-addiction opioid model, naltrexone was previously reported to be effective in the treatment of bulimia in a controlled double-blind clinical trial with a randomized cross-over design. This is a detailed longitudinal analysis over a 16 month period of one subject from that study. Attenuation in bulimic symptoms in two-drug as compared to no-drug periods was demonstrated. The duration for which the drug was needed was also addressed. The subject is an illustration of a therapeutic response on multiple parameters including binges, purges, urges to perform both behaviors, eating patterns, scaled feelings and Eating Disorder Inventory questionnaire scores. A rare allergic reaction to the drug is reported. It appeared to be heat and photosensitive, even in the presence of sun screen, occurred after a delay and did not appear immediately on skin testing. Use of naltrexone after desensitization is also reported. PMID- 8675971 TI - Physiological responses to d-fenfluramine and ipsapirone challenge correlate with indices of aggression in males with personality disorder. AB - Hormonal responses to challenge with the 5-HT2A/2C probe d-fenfluramine and hormonal and thermal responses to challenge with the 5-HT1A probe ipsapirone were correlated with self-report and historical assessments of aggression in a pilot sample of eight male personality-disordered individuals. Prolactin responses to d fenfluramine and cortisol responses to ipsapirone challenge were inversely correlated with self-reported assaultiveness. Thermal responses to ipsapirone were inversely correlated with a historical assessment of aggression. Since none of these physiological indices of 5-HT system function were intercorrelated, it is possible that simultaneous assessment of these 5-HT indices may yield a more comprehensive assessment of the relationship between central 5-HT system function and aggressive behavior in humans. PMID- 8675972 TI - Benzodiazepines for depression? A review of the literature. AB - The English language literature on the use of benzodiazepines: in depressive disorders was reviewed. We selected double-blind random assignment studies in which benzodiazepines; were compared with reference drugs and/or placebo. Comparative studies with classical (non-triazolo) benzodiazepines in major depression show that these agents do not alleviate the core symptoms of depression, although they do have an effect on sleep and anxiety. Classical benzodiazepines show some efficacy in minor depression, but this conclusion could be related to efficacy in patients suffering from anxiety disorders rather than depression. Triazolo-benzodiazepines, mainly alprazolam, have been found to be effective in mild to moderate depression, although they turned out to be inferior to tricyclic antidepressants (TCAs) in patients with endogenous or melancholic depression. Furthermore it is questionable whether triazolo-benzodiazepines cause amelioration of the core symptoms of depression. With regard to combination therapy benzodiazepines may contribute to antidepressant response in the first weeks, because of a faster onset of effect than TCAs and/or because of effects on different symptoms. Beyond the first weeks of treatment combination therapy does not seem superior to monotherapy with TCAs. PMID- 8675973 TI - Isoniazid, tricyclics and the "cheese reaction". AB - Isoniazid is an antitubercular drug with some monamine oxidase (MAO) inhibition. Perhaps because this is only weak inhibition, a few clinicians consider dietary or drug restrictions for their patients on isoniazid. However recent reports suggest the combination of isoniazid and antidepressants may cause adverse events possibly related to isoniazid's MAO inhibition activity. The mechanism of the tyramine reaction and recommendations for cautious combinations of tricyclic antidepressants and isoniazid are discussed. PMID- 8675974 TI - Recurrent priapism as a side effect of zuclopenthixol decanoate. AB - Priapism has been described as a rare side effect of certain phenothiazine antipsychotics with high alpha1-adrenergic blocking potential. We describe a patient who in the course of clinical treatment with the thioxanthene antipsychotic zuclopenthixol (Clopixol) decanoate had several episodes of priapism. Although the alpha-blocking potential of zuclopenthixol is only moderate, it seems that in sufficient dose, or in combination with other antipsychotics, this drug is capable of inducing priapism. PMID- 8675975 TI - The effective treatment of severe repetitive behaviour with fluvoxamine in a 20 year old autistic female. AB - The case of a 20 year old autistic woman with disabling repetitive behaviour that responded dramatically to treatment with fluvoxamine is reported. The connection between repetitive symptoms in autism and obsessive-compulsive disorder is considered, and the need for further evaluation of selective serotonin reuptake inhibitors in autism is discussed. PMID- 8675976 TI - Managed care needs proactive physicians. Interview by Bob Carlson. PMID- 8675977 TI - How solo physicians view their practices. PMID- 8675979 TI - Answers to your questions on Medicaid managed care. PMID- 8675978 TI - New Medicaid laws bring regulatory relief. PMID- 8675980 TI - Statewide medical education in Indiana. PMID- 8675981 TI - Response of bidimensionally measurable metastases to flutamide withdrawal in a patient with advanced prostate cancer. PMID- 8675982 TI - Museum exhibit features history of radiology. PMID- 8675983 TI - The medical properties of food in the eighteenth century. PMID- 8675984 TI - Homeopathy's early Dutch conquests: the Rotterdam clientele of Clemens von Bonninghausen in the 1840s and 1850s. PMID- 8675985 TI - The gorilla and the question of human origins: the brain controversy. PMID- 8675986 TI - The physician automobilist. PMID- 8675987 TI - Comparison of 35S and chemiluminescence for HPV in situ hybridization in carcinoma cell lines and on human cervical intraepithelial neoplasia. AB - For in situ hybridization (ISH), development of sensitive, nontoxic alternatives to the use of radioactivity is a constant concern. In this trend, and close to chromogenes and fluorophores, chemiluminescence appears an attractive method. A first positive experience in immunocytochemistry and in ISH, by using the enhanced luminol as luminogene substrate for horseradish peroxidase (HRP) led us to compare the sensitivity of 35S autoradiography and chemiluminescence. For this purpose, we used three human carcinoma cell lines, CaSki [400-600 copies of human papilloma virus (HPV) 16], HeLa (10-50 copies of HPV 18), and SiHa (1-5 copies of HPV 16), and 40 biopsy specimens of human cervical preneoplastic and neoplastic lesions. We performed ISH by using HPV cDNA biotin-labeled probes, detected by a two-step immunocytochemical reaction, the secondary antibodies being either 35S labeled for autoradiography or HRP-labeled for chemiluminescence. An intensified CCD camera allowed acquisition of the luminescent signal. After only 10 min of photon accumulation, on cell line smears as well as on serial tissue sections, chemiluminescence gave comparable results to those obtained by a 3-week exposure for 35S autoradiography. A quantitative approach on cervical biopsy specimens confirmed this similar level of sensitivity by measuring the area of 35S- or chemiluminescence-stained nuclei. Our results indicate that chemiluminescence is a credible and perfectible alternative to radioisotopes for in situ detection of nucleic acids by hybridization. PMID- 8675988 TI - Expression of thyroid transcription factor-1(TTF-1) in fetal and neonatal human lung. AB - We assessed the immunohistochemical localization of thyroid transcription factor 1 (TTF-1) in the lungs of 24 human fetuses (11-23 weeks), three infants without pulmonary pathology (36-42 weeks), and 24 infants (2 days-6.5 months) with hyaline membrane disease (HMD) or bronchopulmonary dysplasia (BPD). TTF-1 was detected in fetal lung epithelial cell nuclei by 11 weeks' gestation. Budding tips of terminal airways had prominently labeled nuclei. By 17 weeks, labeling was present in scattered nonciliated columnar and cuboidal cells. Throughout gestation, TTF-1 nuclear staining was prominent in airways abutting pleural, peribronchial, or perivascular connective tissue, being less prominent in centers of lobules. By 23 weeks, many cells in cuboidal but not columnar cell-lined airways had labeled nuclei. At term, TTF-1 was detected primarily in Type II epithelial cells. In HMD with alveolar hemorrhage, edema, or airway collapse, little or no TTF-1 was present except in open terminal airways. In BDP lungs, TTF 1 was absent in areas of alveolar collapse or infection, being present in regenerating open airways. The temporal-spatial distribution of TTF-1, in general, follows patterns of distribution of surfactant protein-B in developing and pathological lungs, consistent with its role in the regulation of epithelial cell gene expression in the lung. PMID- 8675989 TI - Cellular localization of P-glycoprotein in brain versus gonadal capillaries. AB - P-glycoprotein, the multidrug resistance protein that actively transports a wide variety of lipophilic substrates out of cancer cells, has recently been described in some normal tissues, including the endothelium of the brain and testes. Here we show that P-glycoprotein is also expressed in ovarian endothelium. In ovarian capillaries, the immunolabeled protein was detected with two monoclonal antibodies to P-glycoprotein. It was shown to be membrane-bound and to transport a known P-glycoprotein substrate. Expression of P-glycoprotein in endothelial cells suggests that this transport protein plays a role in enhancing or restricting vascular permeability to lipophilic molecules. If it does, then its role may be predicted from its site of expression on the luminal or abluminal face of the capillary wall. In the region of the endothelial nucleus, endothelial membranes are sufficiently far apart that they can be distinguished at the light microscopic level. Confocal examination of tissue sections double labeled for P glycoprotein and nuclei confirmed that, in brain, P-glycoprotein is expressed only on luminal membranes. This location is consistent with its putative role in protecting the neuropil from circulating lipophilic molecules. In both testicular and ovarian endothelium, however, P-glycoprotein is expressed on both luminal and abluminal membranes. This localization suggests that it acts to exclude P glycoprotein substrates from the endothelial cells themselves. PMID- 8675990 TI - Topographical distribution of phospholipids in boar sperm plasma and intracellular membranes as revealed by freeze-fracture cytochemistry. AB - We used fracture-label and label-fracture cytochemistry in conjunction with the phospholipase A2-colloidal gold (PLA2-CG) technique to study the distribution of phospholipids in ejaculated boar spermatozoa. These techniques provide visualization of the topographical distribution of phospholipids in freeze fractured sperm membranes in a three-dimensional view. In various freeze fractured boar sperm membranes and crossfractured cytoplasmic structures, quantitative analysis revealed that the nuclear envelope membranes and the nuclear content possessed the highest labeling density of PLA2-CG. Moderate labeling was detected over acrosomal membranes, especially the inner acrosomal membrane. Replicas of both protoplasmic and exoplasmic fracture faces of the plasma membrane of boar sperm head showed a relatively low density of PLA2-CG labeling. Moreover, a differential distribution of phospholipids was seen over the protoplasmic face of the plasma membrane domains of the sperm head, which showed the highest concentration of gold particles in the postacrosomal region, followed by the equatorial segment and the anterior acrosome region. The PLA2-CG labeling densities over the post-acrosomal region and the equatorial segment were significantly higher than that over the anterior acrosome region. In the flagellum, an intense labeling was also seen over crossfractured mitochondria, dense fibers, and fibrous sheath. The protoplasmic fracture face of the plasma membrane over the middle piece, the annulus, and the principal piece was moderately labeled by PLA2-CG. No significant difference in mean labeling density of PLA2-CG was detected among the three membrane domains. In label-fracture preparations, exoplasmic halves of the plasma membrane of the head and the middle piece of the tail were uniformly labeled with PLA2-CG. However, the annulus and principal piece were devoid of PLA2-CG binding sites. These results indicate that differential distribution of phospholipids associated with the boar sperm membranes may reflect phospholipid composition of membrane domains characteristic of special physiological functions. PMID- 8675991 TI - Regulation of Na+,K+-ATPase in submandibular glands of hypophysectomized male mice by steroid and thyroid hormones. AB - The effects of thyroid hormone, androgen, glucocorticoid, and mineralocorticoid on Na+,K+-ATPase activity and on levels of its alpha-subunit protein (alpha 1 isoform) in mouse submandibular gland (SMG) were studied by enzyme assay for ouabain-sensitive ATP hydrolysis, by quantitative densitometric scanning of Western blots, and by immunohistochemistry. To define the specific regulatory effects of various pituitary-dependent hormones on expression of Na+,K+-ATPase in the SMG, we treated hypophysectomized (hypox) male mice with triiodo-L-thyronine (T3), 5 alpha-dihydrotestosterone (DHT), dexamethasone (Dex), and aldosterone (Ald), injected singly or in combination. Na+,K+-ATPase was confined to the duct system of the SMG. In intact mice there was a gender difference in SMG Na+,K+ ATPase, with levels of the enzyme's activity and of its alpha 1-subunit being less in the glands of males. In males, hypophysectomy caused a rise in levels of Na+,K+-ATPase activity and in levels of the alpha 1-subunit protein of this enzyme, and in intensity of immunocytochemical staining for this subunit but there were no such changes in the SMG of hypox females. Changes caused by hormonal replacement to hypox males in Na+,K-ATPase activity, levels of its alpha 1-subunit, or the intensity of immunocytochemical staining for this subunit were complex. Ald had no effect. T3 or dexamethasone, given alone, induced Na+,K+ ATPase activity above control values (hypox males) and increased levels of its alpha 1-subunit protein and immunohistochemical staining for this subunit. By contrast, DHT did not cause a decline in any of these parameters. However, when treatment with T3 was combined with administration of Dex or DHT, enzymatic activity of Na+,K+-ATPase decreased but levels of the alpha 1-subunit protein and immunohistochemical staining for this subunit increased. Therefore, inductions of the alpha 1-subunit of this enzyme are not always correlated with increases in levels of activity of Na+,K+-ATPase, and we propose that both enzymatic and immunochemical analyses are essential for evaluation of hormonal regulation of Na+,K+-ATPase in salivary gland and in other tissues. PMID- 8675992 TI - In vivo modulation of proliferating cell nuclear antigen in growth plate chondrocytes from normal, hypophysectomized, growth hormone-treated hypophysectomized rats: a comparative immunohistochemical study with image analysis. AB - Growth hormone (GH) regulates the proliferation and maturation of chondrocytes in the epiphyseal growth plate, in which a temporal dimension is superimposed on the septal organization of the tissue. In this study we investigated the in vivo effects of hypophysectomy (Hypox) and injection of GH into Hypox animals (Hypox + GH) on the proliferative activity of the growth plate chondrocytes. We assessed the immunohistochemical expression of proliferating cell nuclear antigen (PCNA) in paraffin-embedded tissues, using monoclonal antibody PC 10 against PCNA combined with immunogold-silver staining. We subjected the immunostained sections to computer-based image analysis by ACAS 570 interactive laser cytometry employing a conventional microscopic light source. Hypox was carried out on 20 rats at 8 weeks of age, half of which received a hypodermic injection of human GH at a dose of 1 IU/kg twice a day for 1 week after the operation. Another group of five rats of the same age were used as normal controls. In normal rats, a distinct PCNA immunoreaction was observed in the proliferative zone, whereas a remarkable diminution of the number of immunoreactive cells in this zone was apparent in Hypox animals. On the other hand, marked hyperplasia of PCNA-positive cells was seen in the proliferative zone of the Hypox + GH rat growth plate. The immunoreactive cells of this zone in Hypox + GH animals exhibited increased nuclear size and staining intensity of PCNA compared with those in normal and Hypox rats. These findings were further confirmed by computer-based image analysis of the specimens in terms of cell integrated value, area, perimeter, and shape factor. These different patterns of PCNA expression may imply that GH specifically promotes the proliferation phase of the chondrocytes in the proliferative zone. The data also suggest that GH influences not only cell replication activity but also cell kinetics of chondrocytes in the growth plate during their lifespan. PMID- 8675993 TI - Lamina propria macrophages in the human gastrointestinal mucosa: their distribution, immunohistological phenotype, and function. AB - In this study we systematically investigated the cellular distribution, immunohistochemical phenotype, and mucosal disposal function of macrophages in the lamina propria of the human gastrointestinal mucosa (lamina propria macrophages; LPMs). In all tissues examined, most of these LPMs accumulated beneath the epithelial layer that covered the apex of the lamina propria of the mucosa. These cells expressed normal levels of common macrophage markers such as CD68, LN5, lysozyme, ferritin, and alpha 1-anti-chymotrypsin. In addition, they expressed high levels of 25F9 (a market for a certain subpopulation of macrophages), MHC Class II molecules, and CD74 (MHC Class II-associated invariant chain). Interestingly, LPMs possessed some epithelial cell-associated antigens such as cytokeratin, carcinoembryonic antigen (CEA), and Ber-Ep4 in their cytoplasm. Ultrastructurally, these antigens were associated with cellular debris ingested by LPMs, which were recognized as apoptotic fragments by in situ end labeling. Furthermore, double positive-labeled granules were seen in LPMs by double staining for epithelial cell-associated antigens and in situ end-labeling. These observations suggest that one of the major functions of LPMs is the disposal of apoptotic epithelial cells and that LPMs may be involved in the regulation of mucosal epithelial renewal. PMID- 8675994 TI - Internalization of styryl dye FM1-43 in the hair cells of lateral line organs in Xenopus larvae. AB - We used a fluorescent dye, FM1-43 to investigate mechanotransduction mechanisms in the hair cells of lateral line organs of Xenopus larvae. FM1-43 specifically labeled the hair cells. The photo-oxidation technique was performed with election microscopy to examine the labeling sites and their mechanisms. The results showed that the labeling sites were mitochondria and rough endoplasmic reticulum throughout the cytoplasm. Endocytic activity of the hair cells was limited to endosomes and small granules located at the apical part of the cells. Blockers of the mechanosensitive cation channel (neomycin, gentamicin, streptomycin, and amiloride) effectively inhibited FM1-43 labeling. One of the blockers, amiloride, was found to bind to hair cells when its fluorescence was examined. Divalent cations such as Mg2+ and Ca2+, but not monovalent cations such as Na+ and K+, inhibited FM1-43 labeling when they were added in excess amounts. These results suggest that FM1-43 internalizes hair cells via the putative mechanosensitive cation channel in the plasma membrane. PMID- 8675995 TI - Possible association of chaperonin 60 with secretory proteins in pancreatic acinar cells. AB - Assembly and folding of newly synthesized polypeptides, acquisition of their biological active form, and their translocation in different cellular compartments are processes assisted by molecular chaperones. Because particular chaperones have been found to be present along the RER-Golgi-granule secretory pathway in pancreatic acinar cells, we presume that they should play important roles in secretion. In the present study, applying double immunogold labeling at the electron microscopic level on rat exocrine pancreas, we have revealed the existence of a topographical association between Hsp60 and particular pancreatic enzymes along the secretory pathway. The highest association was found for amylase, lipase, and chymotrypsinogen, whereas trypsinogen and carboxypeptidase B showed much lower association values. Immunoprecipitation of isolated zymogen granule content with an anti-Hsp60 antibody appears to confirm the morphological data, since amylase and lipase were found to co-precipitate with Hsp60. These findings support the hypothesis that Hsp60 is associated with certain pancreatic proteins along the secretory pathway. Hsp60 would assist the proper folding and assembly of pancreatic secretory proteins and could also prevent their autoactivation before secretion. PMID- 8675996 TI - Distinct distribution of protein disulfide isomerase family proteins in rat tissues. AB - We investigated the distribution of protein disulfide isomerase (PDI) family proteins PDI, ERp72, and ERp61 in rat tissues and compared their localization by immunohistochemical double staining. The extent of their expression was diverse in different cell types, although they were ubiquitously distributed in a wide variety of cell types. Prominent staining for all three proteins was detected in thyroid follicular epithelia, tracheal mucous gland cells and chondrocytes, and chief cells and mucous neck cells of the stomach. Hepatocytes, neuronal cells in brain and spinal cord, and pancreatic acinar cells were also consistently and uniformly stained, but with low intensity. On the other hand, distinct differences were observed for the expression of the three proteins in plasma cells, pancreatic islet cells, goblet cells, and Paneth's cells of intestines, seminiferous epithelia, and salivary gland ductal epithelia. The similarities and differences in the distribution of the three proteins provide helpful clues to their biological functions. PMID- 8675997 TI - Immunohistochemical detection of thrombospondin-1 in formalin-fixed, paraffin embedded tissue. AB - Thrombospondin-1 (TSP) is a 450-KD glycoprotein that was initially discovered in the platelet alpha-granule. It now appears that TSP is intimately involved in the regulation of a variety of cellular functions and cell-to-cell interactions. Recently, it has been demonstrated that TSP functions as a p53-dependent inhibitor of angiogenesis in cultured fibroblasts from Li-Fraumeni patients and therefore may be an important factor involved with tumor invasion and metastasis. It has previously been demonstrated that TSP can be detected in frozen tissue sections by immunohistochemical methods. Our objective in this study was to determine the optimal antigen retrieval (AR) protocol for detection of TSP in formalin-fixed, paraffin-embedded tissue by using tissue sections from patients with invasive transitional cell carcinoma of the bladder. The optimal AR protocol was determined utilizing a variety of heating conditions and antigen retrieval buffers. Our results demonstrate that TSP can be reliably detected in paraffin embedded tissue by immunohistochemical techniques that utilize AR with high temperature microwave heating and a low-pH Tris-HCI buffer. The importance of this method is that it allows the reliable detection of TSP in archival tissue. This should facilitate further investigation into TSP's role in the regulation of cellular processes, including its influence on tumor angiogenesis and metastasis. PMID- 8675998 TI - Retrieval of leukocyte antigens in paraffin-embedded rat tissues. AB - We compared the immunohistochemical reactivity of various rat leukocyte antigens in frozen and paraffin-embedded thymus, spleen, abdominal lymph node, liver, and brain tissues of healthy Sprague-Dawley rats, fixed in various fixatives. Immune reactivity after fixation in Methacarn was superior to that of 4% neutral buffered formalin, a mercury-based fixative (B-5), or Carnoy. Microwave (MW) antigen retrieval (AR) enhanced antigen reactivity. Ten of the 11 leukocyte antigens studied could be retrieved in Methacarn-fixed, paraffin-embedded sections with a reactivity comparable to that obtained on frozen sections. PMID- 8675999 TI - Effect of hypertonic glucose in thermotolerant rat BT4An gliomas treated with combined hyperthermia and BCNU in vivo. AB - The influence of hypertonic glucose i.p. on development of thermotolerance and thermochemosensitivity with BCNU in thermotolerant tumours, and on intratumoural pH alterations in previously unheated and thermotolerant tumours, was investigated in BT4An tumours grown on the hind foot of BD IX rats. Thermotolerance was induced with local waterbath hyperthermia (44 degrees C/45 min) 24 h before start of test treatment. Hypertonic glucose immediately after priming hyperthermia did not inhibit development of thermotolerance, despite a significant reduction of pH by glucose. The pH reduction was less in thermotolerant tumours. Glucose administered before treatment of thermotolerant tumours did not change the growth rate of tumours treated with hyperthermia (44 degrees C/45 min), BCNU (20 or 25 mg/kg i.p.) or thermochemotherapy with a low or high dose BCNU (10 or 20 mg/kg), in contrast to previous results, where glucose enhanced thermochemosensitivity of non-thermotolerant tumours. PMID- 8676000 TI - HSP27 and HSP70 increase the survival of WEHI-S cells exposed to hyperthermia. AB - Exposure of cells to hyperthermia and various other stress conditions induces synthesis of a small group of proteins, the heat shock proteins (HSPs). Synthesis of HSPs correlates with the development of thermotolerance, but little is known about the role of individual HSPs in this phenomenon. Using stably transfected WEHI-S murine fibrosarcoma cells we show that overexpression of either HSP27 or HSP70 clearly protects these cells from the toxic effect of elevated temperatures. Moreover, a clone expressing HSP70 mRNA in antisense orientation, and thereby reduced levels of endogenous HSP70 protein, is more thermosensitive than transfection control cells. Using indirect immunofluorescence we show that following heat treatment exogeneous HSP27 and HSP70 are relocated from the cytoplasm to the nucleus and nucleoli respectively. A similar pattern of localization was seen for the endogenous HSPs. Taken together, these results indicate that both HSP27 and HSP70 protect cells from heat mediated killing. PMID- 8676001 TI - Comparison of tumour blood flow changes induced by step-up and step-down heating. AB - The changes in the blood flow in SCC-VII tumours after step-down and step-up heating (SDH and SUH) were compared. SDH was carried out by initial treatment of tumours in a water bath at 44.5 degrees C for 10 min, immediately followed by heating at 41.5 degrees C for 60 min. For SUH, the sequence of these high- and low-temperature treatments was reversed. Tumour perfusion was evaluated by laser Doppler flowmetry (LDF) at 1, 2, and 24h after finishing the hyperthermia. It was shown that the decrease in the blood flow in tumours was more substantial after SDH than after SUH; in the former case, the drop in LDF values was both faster and larger than in the latter. It is concluded that such a "physiological' component may be involved in the difference in the antitumour effect between SDH and SUH. PMID- 8676002 TI - Antitumour effect of irradiation followed by hyperglycemia and hyperthermia: the dependence on tumour size and blood flow. AB - The interrelationship of three tumour parameters-volume, blood flow and growth delay-was evaluated after irradiation alone or combined with hyperglycemia (HG) and hyperthermia (HT). The experiments were performed on Ehrlich carcinoma tumours 5, 7 or 9 days after intramuscular implantation when they reached a mean volume of approximately 0.17, 0.46 or 0.90 cm3, respectively. Tumours were irradiated at a dose of 12.5 Gy. In groups of trimodality therapy, induction of HG (5i.p. injections of glucose during a 2-h period, total dose of glucose 10.4 g/kg) was started immediately after irradiation, and HT (water bath, 43 degrees C, 30 min) was given 3 h later. Regardless of the method of therapy, blood flow in the central part of each tumour was measured 4 and 7 h after irradiation by 133Xe clearance technique. It was shown that if tumours were treated by irradiation alone, both tumour blood flow and growth delay declined with increasing tumour volume. There was no correlation between individual values of tumour blood flow intensity and growth delay within each size group, and only all the data pooled together showed a significant direct relationship between these two parameters. In contrast, for radiotherapy with HG and HT, the antitumour effect increased with tumour volume. Blood flow was strongly inhibited by radio modifiers; the larger tumours, the lower levels of perfusion were observed. There was a pronounced trend of increased tumour growth delay with decreased blood flow for tumours of the same volume, and these parameters were highly correlated if all individual data were analysed together regardless of tumour size. It was concluded that postirradiation blood flow inhibition plays a significant role in the tumouricidal effect of irradiation with HG and HT. The monitoring of tumour perfusion may be useful for the prediction of the effectiveness of such postirradiation modification, which is especially attractive in radiotherapy of large advanced tumours. PMID- 8676003 TI - Drug delivery to the brain using thermosensitive liposome and local hyperthermia. AB - We investigated the possibilities of drug delivery to the brain using thermosensitive liposomes and hyperthermia. Thermosensitive liposomes are small vesicles containing some drugs, which are designed to release the drugs in response to hyperthermia. The first experiment consisted of four groups: (1) received free Cisplatin: cis-diamminedichloroplatinum (CDDP); (2) received free CDDP and above 41 degrees C local brain heating for 30 min; (3) received liposomes containing CDDP (CDDP-liposome); and (4) received CDDP-liposome and above 41 degrees C local brain heating for 30 min. Brain CDDP levels were significantly higher in (4), while those on the other groups were undetectable. In the second experiment, we studied the distribution of Evans blue (Eb) in the artificially heated region of mongrel dogs' brain. One group received free Eb and the other group received liposomes containing Eb (Eb-liposome). While the extravasation of free Eb was localized in regions heated > 44 degrees C, that of Eb-liposome was extended up to the regions heated at 41 degrees C. We concluded that the use of thermosensitive liposomes and hyperthermia not only contributes to the brain tumour killing as direct thermal killing does but also helps to increase the concentration of chemotherapeutic drugs into the tumour invaded zones with mild local hyperthermia of 41 degrees C. PMID- 8676004 TI - The effects of hyperthermia in bone marrow purging of breast cancer. AB - The number of autologous bone marrow transplants done for solid tumours, particularly breast cancer, has risen steadily over the last ten years. The role of bone marrow or peripheral blood progenitor cell purging in transplantation is incompletely understood. Theoretically, the reinfusion of untreated bone marrow containing tumour cells might result in relapse in some patients treated with high-dose chemotherapy and hematopoietic support. Therefore, safe and effective purging techniques may increase long-term, disease-free survivorship. In this study, hyperthermia was evaluated for its ability to purge CAMA-1 breast cancer cells from normal human bone marrow. Between two and nine trials of a range of temperatures (42-45 degrees C) and durations of treatment (1-4 h) were performed. The effect of hyperthermia on normal bone marrow alone and in mixes with breast cancer cells was also evaluated. Hyperthermia (45 degrees C, 4 h) produced > 5 logs of CAMA-1 cell kill. Exposures of 45 degrees C for 2 h and 44 degrees C for 4 h resulted in approximately three logs of cell kill, corresponding to < 1% survival of clonogenic cells. Normal bone marrow was considerably more vulnerable to heat treatments, however, with approximately 1% of progenitors remaining clonogenic after exposure of 43 degrees C for 2 h and 44 degrees C for 1 h. Therefore, although hyperthermia is able to achieve adequate CAMA-1 breast cancer cell kill, it remains more toxic to normal bone marrow as a purging method. To make hyperthermia useful in purging systems, mechanisms to selectively alter thermal sensitivity must be pursued. PMID- 8676005 TI - Hyperthermia as an adjuvant to radiation therapy of recurrent or metastatic malignant melanoma. A multicentre randomized trial by the European Society for Hyperthermic Oncology. AB - The ESHO protocol 3-85 is a multicentre randomized trial investigating the value of hyperthermia as an adjuvant to radiotherapy in treatment of malignant melanoma. A total of 134 metastatic of recurrent malignant melanoma lesions in 70 patients were randomized to receive radiotherapy alone (3 fractions in 8 days) or each fraction followed by hyperthermia (aimed for 43 degrees C for 60 min). Radiation was given with high voltage photons or electrons. Tumours were stratified according to institution and size (above or below 4 cm) and randomly assigned to a total radiation dose of either 24 or 27 Gy to be given with or without hyperthermia. The endpoint was persistent complete response in the treated area. A number of 128 tumours in 68 patients were evaluable, with an observation time between 3 and 72 months. Sixty-five tumours were randomized to radiation alone and 63 to radiation + heat. Sixty received 24 Gy and 68 tumours received 27 Gy, respectively. Size was < or = 4 cm in 81 and > 4 cm in 47 tumours. Overall the 2-year actuarial local tumour control was 37%. Univariate analysis showed prognostic influence of hyperthermia (rad alone 28% versus rad + heat 46%, p = 0.008) and radiation dose (24 Gy 25% versus 27 Gy 56%, p = 0.02), but not of tumour size (small 42% versus large 29%, p = 0.21). A Cox multivariate regression analysis showed the most important prognostic parameters to be: hyperthermia (odds ratio: 1.73 (1.07-2.78), p = 0.02), tumour size (odds ratio: 0.91 (0.85-0.99), p = 0.05) and radiation dose (odds ratio: 1.17 (1.01-1.36), p = 0.05). Analysis of the heating quality showed a significant relationship between the extent of heating and local tumour response. Addition of heat did not significantly increase the acute or late radiation reactions. The overall 5-year survival rate of the patients was 19%, but 38% in patients if all known disease was controlled, compared to 8% in the patients with persistent active disease. PMID- 8676006 TI - Effects of hyperthermal stress on the fibrinolytic system. AB - The effects of hyperthermal stress on the coagulation and fibrinolytic systems were examined in five healthy subjects who took a 3-min 47 degrees C hot-spring bath. After a 3-min 47 degrees C bath, the sublingual temperature was transiently increased about 1.8 degrees C, returning to the baseline level within 60 min. The plasma level of plasminogen activator inhibitor-1 antigen (PAI-1) was transiently increased 15 min after the start of bathing and returned to the pre-bathing level 360 min later. The plasma levels of tissue plasminogen activator antigen, alpha 2 plasmin inhibitor activity, plasmin-antiplasmin complex, thrombin-antithrombin III complex, and thrombomodulin antigen were not influenced by the bath. The in vivo result correlated well with the in vitro result that PAI-1 was released from cultured endothelial cells by heating. These findings suggest that the increase in plasma PAI-1 level may be due to the direct hyperthermal action of the very hot hot-spring bath on the endothelial cells and that acute hyperthermal stress may decrease the fibrinolytic capacity, leading to the occurrence of thrombotic events. PMID- 8676007 TI - Preoperative thermochemotherapy of oral cancer using magnetic induction hyperthermia (Implant Heating System: IHS). AB - Eight patients with primary cancer of the oral cavity were preoperatively treated by combined treatment with hyperthermia and chemotherapy. They received two courses of chemotherapy, which included intra-arterial infusion of 100 mg of cisplatin (CDDP) and 25 mg of peplomycin (PEP) via the superficial temporal artery. The patients also received interstitial hyperthermia for 45 min once a week using the Implant Heating System (IHS) with chemotherapy. IHS consists of ferromagnetic implant, induction coil and generator to produce high frequency magnetic field. The ferromagnetic implant is made of Fe-Pt alloy (Fe: 73%, Pt: 27%), and has a Curie temperature of 68 degrees C. As a result, clinical complete response (CR) was observed in seven patients and partial response (PR) in one, and postoperative pathological examination showed no residual tumour cells in any specimen. Combined interstitial hyperthermia by IHS and chemotherapy is thus found to be an effective therapeutic method for treating oral cancers. PMID- 8676008 TI - Temperature control and light penetration in a feedback interstitial laser thermotherapy system. AB - The aim of this study was to describe the performance of a closed loop interstitial laser thermotherapy system in processed liver and to demonstrate its suitability for treating a vascularized tumour in vivo. The thermotherapy system consisted of an Nd: YAG laser and a temperature feedback circuit including an automatic thermometry system and thermistor probes. Experiments in processed liver were performed with a sapphire probe and temperature control at a distance of 10 mm. In most experiments at 1-2 W, and in half of the experiments at 3 W, there was no carbonization, a moderate change in the light penetration and excellent control of the temperature. In experiments with output powers of 4-5 W there was carbonization with rapid deterioration of light penetration and impaired control of the temperature. Carbonization affected the distribution of temperatures, which were lower below, and higher above, the laser tip in experiments with carbonization as compared to experiments without carbonization. Treatment of an adenocarcinoma implanted into rat liver was performed at 2 W with a bare fibre and without blood inflow occlusion. The feedback thermistor probe was placed 3 mm outside the margin of the tumour (largest diameter 9.5 +/- 0.3 mm (mean +/- SEM)). Temperature control and light penetration characteristics were similar to those found in vitro. No tumour could be demonstrated at sacrifice 6 days later. It is concluded that a closed loop feedback system can produce stable and reproducible local hyperthermia, that it performs better when carbonization is avoided and light penetration is preserved and that it has a great potential for interstitial thermotherapy of malignant tumours. PMID- 8676009 TI - Hyperthermia treatment planning and temperature distribution reconstruction: a case study. AB - While a great deal of effort has been applied toward solving the technical problems associated with modelling clinical hyperthermia treatments, much of that effort has focused on only estimating the power deposition. Little effort has been applied toward using the modelled power depositions (either electromagnetic (EM) or ultrasonic) as inputs to estimate the hyperthermia induced three dimensional temperature distributions. This paper presents a case report of a patient treated with hyperthermia at the Duke University Medical Center where numerical modelling of the EM power deposition was used to prospectively plan the treatment. Additionally, the modelled power was used as input to retrospectively reconstruct the transient three-dimensional temperature distribution. The modelled power deposition indicated the existence of an undesirable region of high power in the normal tissue. Based upon this result, amplitudes and phases for driving the hyperthermia applicator were determined that eliminated the region of high power and subsequent measurements confirmed this. The steady-state and transient three-dimensional temperature distributions were reconstructed for four out of the seven treatments. The reconstructed steady-state temperatures agreed with the measured temperatures; root-mean-square error ranged from 0.45 to 1.21 degrees C. The transient three-dimensional tumour temperature was estimated assuming that the perfusion was constant throughout the treatment. Using the computed three-dimensional transient temperature distribution, the hyperthermia thermal dose was computed. The equivalent minutes at 43 degrees C achieved by 50% (T50Eq43) of the tumour volume was computed from the measured data and the three dimensional reconstructed distribution yielding T50Eq43 = 40.6 and 19.8 min respectively. PMID- 8676010 TI - The development and magnitude of thermotolerance during chronic hyperthermia in murine granulocyte-macrophage progenitors: II. AB - We have previously reported that murine granulocyte-macrophage progenitors (CFU GM) are capable of developing thermotolerance during chronic hyperthermia at temperatures of 40 to 42 degrees C. However, a differential profile of intrinsic thermal response and, in particular, the capability of developing thermotolerance during chronic heating was identified between CFU-GM and macrophage colony forming units (CFU-M) stimulated respectively, by lung conditioned medium (LCM) and L929 cell conditioned medium (CCM). Nucleated marrow cells treated in vitro were cultured in McCoy's 5A medium plus 15% fetal bovine serum (FBS) in semisolid agar with 10% of CCM. Two different treatment protocols were used in this study to determine the kinetics of thermotolerance in CFU-M: (1) nucleated marrow from mouse tibia and femur were chronically heated in vitro at temperatures of 40, 41 and 42 degrees C (up to 480 min) or (2) nucleated marrow cells were heated over a period of 90 min stepwise from 37 to 42 degrees C, at a heating rate of 0.056 degrees C/min, before exposure to 42 degrees C. The amount of thermotolerance developed was analysed at various times after chronic incubation at 40-42 degrees C by a challenge with 15 min at 44 degrees C. In contrast to CFU-GM, the surviving fraction of CFU-M heated with 15 min at 44 degrees C did not increase during chronic hyperthermia at 40 degrees C for up to 480 min indicating failure to develop thermotolerance. However, CFU-M were able to develop thermotolerance during prolonged incubation at 41 and 42 degrees C, although to a much less extent than observed in CFU-GM. In other words, there was much less development of thermotolerance in murine CFU-M compared to that in CFU-GM. Furthermore, a slow temperature transit from 37 to 42 degrees C over 90 min before exposure to 42 degrees C induced CFU-M to develop thermotolerance. The thermotolerance ratio (TTR, the ratio of the surviving fraction at maximum tolerance versus normotolerance) increased from a maximum of 3.5 after 180 min at 42 degrees C (no warm-up) to a maximum of 4.1 after 60 min at 42 degrees C when the cells received a slow warm-up to 42 degrees C. This implies that in the murine bone marrow granulocyte/macrophage lineage, CFU-M does not normally develop thermotolerance during hyperthermia and that the colony forming unit-granulocyte (CFU-G) and CFU GM play a more critical role than CFU-M in the initiation and promotion of thermotolerance during chronic hyperthermia. However, in a situation that simulates the slow heat-up used clinically in wholebody hyperthermia, e.g., the 90 min slow warm-up from 37 to 42 degrees C, stimulated CFU-M to develop greater thermotolerance more rapidly than during rapid heating. PMID- 8676011 TI - The development and magnitude of thermotolerance during chronic hyperthermia in murine bone marrow granulocyte-macrophage progenitors: I. AB - Murine bone marrow granulocyte-macrophage progenitors (CFU-GM) are capable of developing thermotolerance during exposure to temperatures < 42.5 degrees C. Bone marrow from the tibia and femora was heated to 40-42 degrees C (i.e. chronic hyperthermia), and challenged immediately with 15 min at 44 degrees C at regular intervals during treatment (step-up heating). CFU-GM were heated and cultured in McCoy's 5A medium + 15% FBS (fetal bovine serum) and lung-conditioned medium (source of colony stimulating factor) in semisolid agar. The kinetics of thermotolerance development and decay, and the magnitude of the thermotolerance during chronic heating with temperatures of 40-41.5 degrees C were similar. Survival increased rapidly to a maxima by approximately 120 min of hyperthermia (temperatures of 40-41.5 degrees C) and thereafter decreased with a slope similar to the controls. Normalization for cell killing by chronic hyperthermia that occurred during "step-up' heating permitted analysis of thermotolerance in the surviving cells. The surviving fraction after 15 min at 44 degrees C, during incubation at 40, 41 and 41.5 degrees C increased from 0.13 to maxima of 0.56 +/- 0.04, 0.71 +/- 0.03 and 0.82 +/- 0.03 respectively, by 150 min and did not decrease for up to 480 min during chronic hyperthermia. The surviving fraction after 15 min at 44 degrees C during incubation at 42 degrees C increased more slowly than during incubations at 40-41.5 degrees C. The survival of thermotolerant cells after exposure to 15 min at 44 degrees C during 42 degrees C chronic hyperthermia was maximal at 0.87 +/- 0.08 by 120 min and then decreased after approximately 150 min of exposure to 42 degrees C. The thermotolerance ratios (TTR's) were 4.0, 5.4, 6.7 and 6.9 for temperatures of 40, 41, 41.5 and 42 degrees C respectively. The results suggest that chronic hyperthermia temperatures (i.e. 40-42 degrees C) induce rapid thermotolerance development in CFU-GM during the thermal exposure and protect this normal marrow progenitor during whole body hyperthermia or ex vivo purging of leukaemic cells. PMID- 8676012 TI - Step-down heating enhances the cytotoxicity of human tumour necrosis factor on murine and human tumour cell lines in vitro. AB - The response of tumour necrosis factor (TNF)-sensitive murine L929 cells to TNF was enhanced approximately 1000-fold after step-down heating (SDH) for 30 min at a sensitizing temperature (ST) of 43 degrees C and a subsequent 24 h incubation at a test temperature (TT) of 40.5 degrees C, compared to continuous treatment at 37 degrees C. The TNF-resistant phenotype of murine EMT-6 mammary adenocarcinoma cells could be overcome by 24 h heating at a TT of 40.5 degrees C, and their sensitivity to TNF could be further increased by preheating at the ST for up to 60 min. The response of TNF-sensitive HCT-15 human colon adenocarcinoma cells was somewhat similar to that of L929 cells except that there was u approximately 2.5 log increase in TNF-sensitivity due solely to heating at 40.5 degrees C. The response of TNF-resistant DLD-1 human colon adenocarcinoma cells was similar to that of EMT-6 cells. In contrast, three normal cell lines demonstrated greater resistance to any TNF/SDH treatment examined. Our results suggest that SDH may overcome the resistance or enhance the response of tumour cells to TNF while minimizing cytotoxic effects on normal cells. PMID- 8676013 TI - Pre-operative distraction lengthening for radial longitudinal deficiency. AB - Patients treated for total radial aplasia have been reviewed. It was possible to re-align the carpus by radialization in five out of six limbs treated with pre operative distraction, but in only one out of six treated without distraction. The average improvement in radial angulation in the non-distraction group was 19 degrees and in the distraction group 38 degrees. The average improvement in radial translation was 16 mm and 17 mm in the two groups respectively. Pre operative distraction with the Kessler device permits re-alignment of the hand without skeletal resection or excessive tension on the radial neurovascular structures. PMID- 8676014 TI - Carpal tunnel syndrome in children and adolescents with no history of trauma. AB - Four cases of carpal tunnel syndrome in children and adolescents with no history of trauma are discussed. The pertinent literature and a classification of the different causes of carpal tunnel syndrome in this age group is presented. PMID- 8676015 TI - Dupuytren's disease in children. AB - Although Dupuytren's disease of the hand has been reported in teenagers, it is generally considered to be a disease of adults. A series of nine children who developed Dupuytren's disease of the hand before the age of 13 years is presented. Eight had surgical removal of the diseased tissue and histological confirmation of the diagnosis before the age of 13 years and one at 14 years of age. The presence of the condition in young children and teenagers is discussed and the literature summarized. PMID- 8676016 TI - Congenital neuroepithelioma in an infant hand. AB - We describe a congenital peripheral neuroepithelioma of the hand in an infant aged 6 weeks. This primitive malignant tumour of neuroepithelial origin is extremely rare in neonates. Peripheral neuroepitheliomas of the hand have not been described in the literature previously. Specific diagnosis and the current therapeutic approaches are discussed. PMID- 8676017 TI - Infantile haemangiopericytoma of the hand. AB - Infantile haemangiopericytomas (IHP) are rare subcutaneous tumours arising from pericytes. Clinically they are difficult to diagnose and pathologically they appear to be locally invasive, but they have a better prognosis than adult haemangiopericytomas. We report a case of IHP affecting the hand of a 7-week-old child that required urgent treatment. PMID- 8676018 TI - The first multi-disciplinary obstetrical brachial plexus clinic in Saudi Arabia. PMID- 8676019 TI - Giant cell tumour of metacarpal with pulmonary and skeletal metastases. AB - A case of giant cell tumour of the left fifth metacarpal with pulmonary and skeletal metastases is reported with follow-up of 14 years. The pulmonary metastases were treated by chemotherapy, but the size of the metastatic nodules continued to increase, and no further treatment was given. The pulmonary metastatic nodules started to regress 8 years after the diagnosis without any treatment, and had disappeared after 14 years. The skeletal metastases were unchanged at the latest follow-up. Both pulmonary and skeletal metastases have been asymptomatic for the 14 years after they were diagnosed. It is suggested that pulmonary metastases of benign giant cell tumour has a good long-term prognosis and these patients should be kept under observation only, avoiding extensive lobectomy, chemotherapy or radiotherapy. PMID- 8676020 TI - Ulnar nerve compression at the elbow caused by a prominent medial head of the triceps and an anconeus epitrochlearis muscle. AB - A number of musculo-tendinous variations around the medial epicondyle have been alleged to cause ulnar nerve compression. Subluxation of the ulnar nerve, a "snapping" separate medial head of triceps, a prominent medial head of triceps covering the ulnar nerve, anconeus epitrochlearis, Osborne's band, and the ligament of Struthers have been implicated. We present a case of clearcut compression of the ulnar nerve at two levels just at and posterior to the epicondyle by a tightly applied prominent head of the triceps, and at a more distal level beneath an anconeus epitrochlearis muscle. PMID- 8676021 TI - Dorsally displaced epiphyseal fracture of the phalangeal base. AB - A dorsally displaced epiphyseal fracture of the middle phalanx (Salter-Harris Type I) is described. The epiphyseal fragments were attached to the central slip of the extensor tendon and collateral ligaments. The articular surface of the PIP joint was intact and smooth. The epiphysis was reduced and fixed without cutting the central slip or the collateral ligaments 8 months after injury. This kind of fracture can occur in the PIP and DIP joints, and presents special diagnostic difficulties. Open reduction is evidently necessary to correct the displacement. PMID- 8676022 TI - Radio-lunate arthrodesis for distal radial intraarticular malunion. AB - Eleven cases of symptomatic distal radial intraarticular malunion were treated by radio-lunate arthrodesis from 1983 to 1991. The mean age was 35.3 years. There were 11 men, all manual workers. The mechanism was usually a high velocity injury. The time elapsed since injury was a mean 23 months (2-109 months). The range of motion was, on average, flexion 39 degrees, extension 27 degrees, radial deviation 10 degrees and ulnar deviation 20 degrees. Pain was present on light work and grip strength was 45% of the opposite side. The average step-off was 4.4 mm. The scapho-lunate gap was greater than 3 mm in three cases and 5 mm in one case. An ulnar translation of the carpus greater than 4 mm was present in four cases. Posterior subluxation was significant in three cases. The distal radio ulnar joint (DRUJ) was totally destroyed in three cases, and incongruent in five. Radio-lunate arthrodesis is performed by a posterior approach. Other procedures were combined, mainly on the DRUJ. The average follow-up was 28.5 months (8-79 months). Healing was achieved in ten out of 11 cases in 45 to 90 days. Pain was absent or moderate after 4 months. The range of motion was 33 degrees in flexion, 39 degrees in extension, 17 degrees in radial deviation and 29 degrees in ulnar deviation. The average post-operative strength was 57% of the opposite side (19 kg/33). Eight patients returned to their previous work and two to lighter work. PMID- 8676023 TI - Triradiate skin incision for dorsal approach to the wrist. AB - A new triaradiate skin incision is presented as an approach to the wrist. Centred over Lister's tubercle, it consists of one longitudinal proximal and two oblique distal rays, making three 120 degrees skin flaps. These provide an excellent triangular operating field to the distal radius, the radiocarpal joint and the carpus itself, allowing for most procedures in this region. There have been no complications in 32 patients, and the cosmetic appearance has been excellent in most of them. PMID- 8676024 TI - Experimentally induced ulno-carpal instability. A study on 13 cadaver wrists. AB - This experimental work studies the role of ligamentous structures in suspending the carpal bones from the radius and ulna. Thirteen human cadaver wrists underwent a distal radio-ulnar arthrodesis in a neutral position and an arthrodesis between the three bones of the first carpal row. Progressive postero anterior forces in a palmar direction were applied to the fused carpal bones. Displacement was measured by two dial gauges before and after sequential section of the different fibrous structures. The largest absolute average displacement (both, dorso-palmar and induced rotational displacement) was observed after section of the ulnar styloid process. No significant differences were observed after section of the extensor retinaculum, extensor carpi ulnaris sheath, posterior ulno-carpal and posterior radio-carpal ligaments. This work suggests that the carpus is suspended not only from the radius, but also from the distal ulna and particularly at the ulnar styloid and the structures which insert onto it. PMID- 8676025 TI - Synovial osteochondromatosis of the distal radio-ulnar joint. AB - Synovial osteochondromatosis is an uncommon lesion characterized by cartilagenous and osseous metaplasia of joint synovium. It is typically monarticular, affecting large joints such as the knee and hip, although it has also been described in the ankle, elbow and shoulder. It is exceptionally rare in the hand, but has been reported involving the tenosynovium of the digits and the wrist. We report a rare case of synovial osteochondromatosis involving the distal radio-ulnar joint in a 16-year-old man. PMID- 8676026 TI - Corrective osteotomy for post-traumatic malunion of the phalanges in the hand. AB - Rotation, angulation, deviation, shortening or a combination of deformities can occur due to phalangeal malunion and can lead to impairment of hand function. A historical cohort study of 57 patients who had phalangeal corrective osteotomies for posttraumatic malunion between 1978 and 1990 was undertaken. 59 rotational, radial/ulnar deviation, flexion/extension, length adjustment procedures, and combinations thereof were performed, using rigid internal fixation. Concurrent tenocapsulolysis was done in 50% of the cases. Satisfactory correction was obtained in 76% of the patients. Bony union was obtained in all cases. A net gain in active range of motion was achieved in 89% of the patients. Excellent and good results were obtained in 96% of the patients who had corrective osteotomies for malunion involving only the bone and in 64% of the patients who had corrections for malunion with involvement of multiple structures (P < 0.01). PMID- 8676028 TI - Rotation-angulation osteotomy in the hand. AB - The use of a single osteotomy combining both rotation and angulation is described, with a means of achieving the correct angle and direction of the osteotomy. Patients who have been treated by this method are presented. PMID- 8676027 TI - The epidemiology and management of upper limb peripheral nerve injuries in modern practice. AB - This paper reports an epidemiological and clinical study of 813 patients with 1,111 peripheral nerve injuries who were treated for upper limb trauma, which included nerve injury, at two plastic surgery units in south-east England, predominantly between the years 1982 and 1991. The frequency distributions of the levels of nerve injury, and the causes of nerve injury in the sample, are presented, together with the surgical management and timing of nerve repair in these patients. 1,018 clinically suspected nerve injuries in 730 patients (91.6% of nerves, 89.8% of patients) were treated by primary nerve repair, elective delayed nerve repair or primary surgical exploration alone. Divisions of 93 nerves in 83 patients (8.3% of nerves, 10.2% of patients) were treated other than by primary repair or elective delayed repair, due to delayed referral from accident and emergency departments, resulting from missed or uncertain diagnosis at presentation or otherwise unaccounted delay in the initial referral. PMID- 8676030 TI - Sciatic nerve regeneration in the rat after frozen muscle grafting. A comparative study using somatosensory evoked potentials. AB - In an experimental study, somatosensory evoked potentials were used to evaluate sciatic nerve regeneration in the rat after 12 mm-long conventional nerve grafting, vascularized nerve grafting and frozen muscle grafting. This experimental method was found to be technically easy and highly reproducible. No statistical difference was found between the three groups concerning amplitude of the negative electrical wave recorded at the cortex level after distal stimulation. Conduction velocities were found to be significantly higher in both the vascularized nerve group and the frozen muscle group, compared with the conventional nerve grafting group. The frozen muscle grafting technique is valuable as it gives good experimental results, is easy to carry out and causes minimal damage to the donor site. PMID- 8676029 TI - Long-term results of vein grafts interposed in arterial defects using the telescoping anastomotic technique and fibrin glue. AB - Fibrin glue has been applied in the anastomosis of vein grafts placed in rat femoral arteries using the telescoping technique at both ends of the graft. 34 out of 35 grafts which were patent 1 to 3 weeks post-operatively were kept for 3 months to assess the long-term patency, and the effect of the glue on the diameters of the graft and femoral artery. All 34 grafts were patent 3 months post-operatively. Excessive enlargement of the graft diameter was alleviated by the fibrin glue without affecting the diameter of the femoral artery. The diameter at the proximal anastomosis was 66% and that at the distal anastomosis was 87% of the diameter of the femoral artery. PMID- 8676031 TI - Innervation of the lumbrical muscles. AB - It has long been recognized that the first and second lumbricals are normally innervated by the median nerve, whereas the third and fourth lumbricals are innervated by the ulnar nerve (Sunderland and Ray, 1946). However, the courses of the motor nerves, particularly to the first two lumbricals and their loci of insertion, have not been clearly described. Because this information may be useful to a surgeon operating in the palm, we undertook a cadaver study to define more precisely the pathways of innervation of the lumbrical muscles. PMID- 8676032 TI - Upper arm fasciotomy. A new approach. PMID- 8676033 TI - Surgical treatment of the divided flexor digitorum profundus tendon in zone 2, delayed more than 6 weeks, by tendon grafting in 50 cases. AB - The surgical treatment of the divided FDP tendon, more than 6 weeks old, in zone 2 is reviewed in 50 patients. The method used was the excision of the divided FDP tendon and the insertion of a thin tendon graft. There were 50 patients in this study; 36 were male and 14 female, aged from 18 to 60 years. All patients were markedly disabled because of loss of strength of the involved finger. Follow-up ranged from 1 to 25 years following tendon grafting. In 35 patients plantaris tendon was used and in 15 patients palmaris longus. Definite advantages were found in using the tendon grafting procedure; strength, dexterity, pinch and grasp were markedly improved. Functional results were evaluated by the Boyes method, with the Pulvertaft method as a secondary assessment. Among the 50 patients, 80% had excellent and good results (excellent 32%, good 48%) and 20% fair. PMID- 8676034 TI - The effects of a shortened postoperative mobilization programme after flexor tendon repair in zone 2. AB - The effects of a shortened post-operative mobilization programme following flexor tendon repair in zone 2 in the hand were examined in a prospective, randomized study. 91 digits in 82 patients were included in the study. All injured tendons were repaired within 24 hours and all patients were subjected to the same mobilization programme during the first 6 weeks using a passive flexion-active extension regime. After 6 weeks the patients were randomized into two groups; in group A full activity was allowed after 8 weeks while in group B unrestricted use of the injured hand was not allowed until 10 weeks after the tendon repair. Functional results were compared using the Louisville, Tsuge and Buck-Gramcko assessment systems. Grip-strength was measured 16 weeks after repair, subjective assessment of hand function was recorded on a visual analogue scale, and absence from work was registered. No significant differences were observed between the groups regarding functional results, rupture rates, grip strength or subjective assessment, but absence from work was reduced by 2.1 weeks with the shorter mobilization programme. Using the described regime, full activity can be encouraged 8 weeks after flexor tendon repair in zone 2 of the hand without adverse effects on functional results or increased risk of rupture of the repair. PMID- 8676035 TI - Reconstruction of the flexor tendon sheath. An experimental study in rabbits. AB - The role of the tendon sheath in flexor tendon healing was investigated in rabbits. Tendon sheath was reconstructed with syngeneic parietal peritoneum or a non-tanned processed porcine collagen membrane. Resection of the tendon sheath led to adhesions. Reconstruction of the sheath with either graft resulted in a synovial-like lining, resembling a neo-tendon sheath. Even when combined with tendon repair a neo-tendon sheath was seen after reconstruction with both grafts, without adhesions. Subcutaneously implanted processed porcine collagen membrane was completely resorbed in less than 3 months. PMID- 8676036 TI - Human composite flexor tendon allografts. A report of two cases. AB - We report two cases in whom human composite flexor tendon allografts were used, and followed-up for more than 5 years. The results show a real improvement in function, without any complications. PMID- 8676037 TI - Histopathology of Kienbock's disease. Correlation with magnetic resonance and other imaging techniques. AB - Histopathological studies of extracted whole lunate bones obtained from 10 patients with Stage 3 Kienbock's disease at surgery for tendon-ball replacement were correlated with magnetic resonance imaging (MRI), computed tomography (CT) and tomography images made prior to surgery. A reforming zone, or a reactive interface between the reactive new bone and granulation tissue formation, and new vascularization were observed surrounding the bone necrosis area showing empty lacunae, fatty necrosis, and disappearance of osteoid. Findings of CT, tomography and microradiography of slices of extracted lunate bone confirmed that fractures of the articular cartilage and the subchondral bone occurred secondarily by overloading, and showed the extent of the collapsed area of the lunate. MRI showed complete loss of signal intensity in T1 images of the lesion of the lunate in advanced Stage 3 Kienbock's disease. MRI is at present unable to distinguish bone necrosis, the histological reactive interface or surrounding hyperaemia in detail. However, the low-intensity arc, or the reactive interface present on MRI in early Stage 3, sometimes correlates with the histological findings of osteoid and granulation zones. PMID- 8676038 TI - A neurovascular island flap for volar-oblique fingertip amputations. Analysis of long-term results. AB - A neurovascular island flap has been developed to reconstruct volar-oblique fingertip amputations. This study analyzes the data collected on 16 patients who were treated with this flap and had at least 2 years follow-up. The average active/passive range of motion was 54/55 degrees at the DIP joint, 96/98 degrees at the PIP joint, and 83/83 degrees at the MP joint. Twelve out of 16 flaps (75%) had two-point discrimination better than 10 mm. Moderate and severe problems included cold intolerance (six patients), hypersensitivity (three patients), stiffness (three patients), and numbness (two patients). Out of the 16 patients treated with this technique, 14 were satisfied with their surgical outcome. In experienced hands, this technique is a safe and reliable method with which to reconstruct volar-oblique fingertip amputations. PMID- 8676039 TI - Mechanical strength of scaphoid fixation. AB - We have investigated five devices suitable for scaphoid fixation (ASIF 2.7 mm and 3.5 mm cannulated screws, Herbert, Herbert-Whipple, and Howmedica Universal Compression Screw). The biomechanical properties tested were compression and resistance to cantilever bending. There was no statistically significant difference in compression between devices. There were significant differences in resistance to cantilever bending, with the Howmedica screw being strongest in both failure mode and in ultimate failure strength. PMID- 8676040 TI - Molecular mechanisms of glucocorticoid resistance. PMID- 8676041 TI - Sodium channel heterogeneity in the apical membrane of porcine thyroid epithelial cells. AB - Porcine thyroid epithelial cells cultured as a monolayer with their apical membranes facing the medium are known to absorb Na+ and secrete Cl-. Two types of Na+ channels were found in cell-attached patches of apical membrane. A low conductance Na+ channel (conductance g = 4 picosiemens (pS)) remained open for seconds and showed a high selectivity for Na+ compared with K+. In contrast, a high conductance Na+ channel (g = 10 pS) flickered rapidly and had reduced selectivity. Both types of Na+ channel became more prevalent when the cells were exposed to Na(+)-free medium, though only the high conductance channel increased in prevalence on addition of prostaglandin E2, a stimulator of adenylate cyclase which increases Na+ absorption in this cultured epithelium. Two minority types of channel were also found: a non-selective small conductance cation channel which had been reported previously, and an intermediate conductance channel found only in Na(+)-free medium. It was concluded that passage of Na+ across the apical membrane of thyroid cells is mediated by typical epithelial Na+ channels, but that the two types of channel are differentially regulated. PMID- 8676042 TI - A V1-type receptor for mediating the neurohypophysial hormone-induced ACTH release in trout pituitary. AB - We analysed the effects of specific neurohypophysial analogues for pharmacological characterization of the type of vasotocin receptor involved in the control of the adrenocorticotrophin hormone (ACTH) release from the perifused pituitary in the rainbow trout, Oncorhynchus mykiss. Mammalian corticotrophin releasing factor (CRF) and teleostean neurohypophysial peptides (arginine vasotocin (AVT) and isotocin (IT)) stimulated ACTH release. Analysis of concentrations giving half-maximal effects (D50) showed that these peptides affected ACTH release in the following order of potency: CRF (8 x 10(-13) M) > AVT (2 x 10(-10) M) > IT (10(-7) M). Maximal responses (Dmax) were obtained for hormonal concentrations of 10(-10) M, 10(-8) M and 10(-6) M respectively. This suggests that AVT and IT have different roles in the control of ACTH release. The values obtained for AVT and IT were in agreement with the circulating levels we previously found for these peptides. Specific V1 or V2 agonists or antagonists (with reference to vasopressin in mammals) were used to define the specificity of the neurohypophysial peptide receptor involved in this stimulation. The V1 agonist, [Phe2, Orn8]-oxytocin, stimulated ACTH release while the V2 agonist, [deamino1, Val4, D-Arg8]-vasopressin, had no such effect. Maximal and half maximal responses were obtained in the presence of the V1 agonist with 10(-7) M and 7 x 10(-9) M respectively, and were in the range of values obtained with natural peptides. The V1 antagonist, [d(CH2)5(1), O-Me-Tyr2, Arg8]-vasopressin, and the V2 antagonist, [d(CH2)5(1), D-Ile2, Ile4, Arg8, Ala9]-vasopressin, maximally reversed the 10(-9) M AVT-stimulated ACTH release by 60% and 25% respectively, for a 5 x 10(-10) M concentration of the analogues and a D50 approximately 2 x 10(-11) M. These results demonstrated the presence of only one V1-type receptor in fish pituitary, with some of the structural and functional peculiarities typically displayed by the mammalian V1a-type receptor, but distinct from it. In this sense, the fish pituitary vasotocin receptor may represent a novel type of neurohypophysial hormone receptor, more closely related to the mammalian V1b-type. PMID- 8676043 TI - Expression levels of the insulin-like growth factor-II gene (IGF2) in the human liver: developmental relationships of the four promoters. AB - We have studied the insulin-like growth factor-II gene (IGF2) promoter usage in normal human liver from fetal to late adult life by quantifying the specific transcripts by RNase protection assays using exon-specific probes. While the fetal liver uses only three promoters (P2, P3, P4) for the transcription of IGF2, all four promoters can be used from the age of 2 months after birth. The levels of the individual promoter transcripts vary substantially during development and the P3 promoter, which is a highly active fetal promoter, was not used by all the investigated adult patients but was detected in 30% of the adult group as a whole. The P1 promoter, which has previously been considered as the only one responsible for IGF2 transcription in the postnatal/adult liver, displayed a trend of increasing relative and absolute activity throughout life, but in some adult cases it was found to be less active than the P4 promoter. The P4 promoter displayed an age-related trend of decreasing activity from a very high fetal level, but individual exceptions were apparent. The P2 promoter transcript, peaking at the age of 2 months, showed a relatively even absolute amount from 18 months onwards. Thus, while P2 and P3 were both found to reach their highest activity after birth, the P4 promoter displayed its highest transcription at the fetal stage. The total IGF2 transcription, primarily from P2, P3 and P4, was found to peak shortly after birth. After this age, the P3 promoter transcript declined most rapidly and a low or zero amount was detected in adulthood. From the age of 18 months to old adulthood the total IGF2 mRNA, derived primarily from P1, P2 and P4, displayed a relatively even amount (approximately one tenth) of that seen at the peak at 2 months. This data may be important in relation to translatability of the various IGF2 transcripts. PMID- 8676044 TI - Pulsatile and diurnal secretion of GH and IGF-I in the chronically catheterized pig fetus. AB - The ontogeny of GH and IGF-I secretion was investigated in the fetal pig. Pulse studies were performed to describe the pattern of GH release. Twenty-four-hour profiles were recorded to examine possible diurnal variations in these hormones. (I) PULSE STUDIES: Blood samples were obtained at 15-min intervals for 2-h periods from 24 male and 20 female fetuses at various gestational ages (fetal day 89-113; term 113 +/- 1 S.D.). Fetuses revealed a pulsatile GH release. The GH pulse frequency did not vary with gestational age in either sex (0.95 +/- 0.19 pulses/h). In males the GH pulse amplitude decreased with increasing fetal age (r = -0.41; P < 0.02). In female fetuses no significant correlation could be calculated. Mean GH concentrations fell significantly in male fetuses 3 to 4 days before delivery (P < 0.05) and the same tendency was observed in females (P < 0.06). Between fetal days 94 and 98 GH pulse amplitude and GH and IGF-I concentrations were higher in males than in females (P < 0.01, P < 0.001 and P < 0.02 respectively). Fetal IGF-I secretion showed no ontogenetic changes in both sexes. However, maternal IGF-I concentrations increased with progressing gestation (r = 0.46; P < 0.001). (II) 24-H PROFILES: Eight male and four female late-gestational fetuses (fetal days 104-108) were studied. Blood samples were taken at 30-min intervals over 24 h. Dams and fetuses showed an episodic GH secretion over the 24-h period but no diurnal rhythm was observed. Whereas maternal IGF-I secretion was constant, fetal IGF-I release was characterized by marked fluctuations over the 24 h. In half of the fetuses (n = 6) the fluctuations appeared at regular intervals. Again no diurnal rhythm existed. These data demonstrated that: (1) porcine fetal GH secretion is pulsatile and decreases shortly before birth; (2) a sex difference in GH and IGF-I concentrations exists between fetal days 94 and 98, suggesting that IGF-I is at least partially under the control of GH before birth; (3) fetal GH and IGF-I secretion is episodic over 24 h, but does not vary diurnally; and (4) fetal and maternal GH and IGF-I secretion are regulated independently. PMID- 8676045 TI - Age-related endocrine deficiencies and fractures of the proximal femur. II implications of vitamin D deficiency in the elderly. AB - In the United Kingdom, as many as 60% of institutionalized people who are not taking vitamin D supplements may be deficient. Both impaired mineralization and a hyperparathyroidism-related increase in bone turnover have been identified in the presence of vitamin D deficiency. Recent interventional data have confirmed the role of vitamin D deficiency in the pathogenesis of senile osteoporosis and indicated the need to maintain serum cholecalciferol levels within the normal range in elderly people. PMID- 8676046 TI - Functional heterogeneity of human term cytotrophoblasts revealed by differential sensitivity to extracellular Ca2+ and nucleotides. AB - We have prepared purified cytotrophoblasts from human term placentas and examined the sensitivity of fura-2 loaded cells to the nucleotides ATP and UTP and to changes in extracellular Ca2+ concentration ([Ca2+]o). Purified cytotrophoblasts were obtained by collagenase digestion and separation according to density using self-generated Percoll gradients. The cytotrophoblast fraction was free of red cell and largely free of white cell contamination (as assessed by uniformly negative staining for vimentin and the failure of > 90% of fura-2 loaded cells to respond to the chemotactic peptide fMet-Leu-Phe). Purified cells secreted progesterone in a linear fashion over several hours in the presence of 25 hydroxycholesterol. The cells ranged in size from approximately 7.5 to 50 microns in diameter as described previously for purified cytotrophoblasts, and an analysis of cells for sensitivity to [Ca2+]o or nucleotides suggested functional heterogeneity within the cytotrophoblast population. Small cells (7.5-10 microns) were negative for cytokeratin-8 and, after loading with fura-2, were insensitive to extracellular nucleotides but sensitive to elevations in [Ca2+]o. Medium-sized cells (12-20 microns) were largely cytokeratin-positive (70% of cells) and sensitive to both ATP and UTP but largely insensitive to [Ca2+]o. Large cells (25 50 microns) were uniformly cytokeratin-positive (100% of cells) and, after fura-2 loading, sensitive to both [Ca2+]o and extracellular ATP or UTP. We examined the likely origin of small, medium and large cytotrophoblasts using an immunomagnetic cell sorting procedure that separates villous cytotrophoblasts (which do not express major histocompatibility class I antigens) from extravillous cytotrophoblasts. This procedure resulted in the selective sedimentation of almost all medium and large cells, leading to the conclusion that the small cells were villous cytotrophoblasts whereas medium and large cells were predominantly extravillous in origin. The data suggest that small, medium and large cytotrophoblasts have distinct roles in the function of the term placenta. PMID- 8676047 TI - Fluorescence-activated cell sorted rat islet cells and studies of the insulin secretory process. AB - Studies of individual cell types in the islets of Langerhans are complicated by the cells' functional coupling by gap junctions and paracrine interaction. Access to purified alpha and beta cells is therefore desirable. We present a simplified and optimized method for fluorescence-activated cell sorting of endocrine pancreatic rat islets. For dispersion of the islets, dispase was superior to trypsin, as the number of vital single cells was higher (1.1 +/- 0.1 x 10(3) vs 0.6 +/- 0.1 x 10(3)/islet, P < 0.05). The purity of the sorted cells was 96.7 +/- 1.2% for the non-beta cells and 97.8 +/- 0.6% for the beta cells (numbers in percentages of endocrine cells). In culture, isolated beta cells, non-beta cells and mixtures of beta and non-beta cells formed aggregates, but not at low temperature (4 degrees C) and not in medium with low serum content (2%). Finally, in pure beta cell aggregates, glucose stimulated changes in cytoplasmic free Ca2+ concentration although both glucose- and arginine-induced insulin secretion was much reduced. We conclude that alpha cells are necessary for insulin secretion but not for glucose sensing. PMID- 8676048 TI - Ca2+ entry in gonadotrophs and alpha T3-1 cells: does store-dependent Ca2+ influx mediate gonadotrophin-releasing hormone action? AB - In pituitary gonadotrophs GnRH causes biphasic (spike and plateau) increases in cytosolic Ca2+ ([Ca2+]i) and gonadotrophin release. The spike phases reflect mobilization of stored Ca2+ and the plateau responses are attributed, in part, to Ca2+ influx via voltage-sensitive Ca2+ channels. In recent years, store-dependent Ca2+ influx (SDCI), in which depletion of the intracellular inositol 1,4,5 trisphosphate-mobilizable pool stimulates Ca2+ influx, has emerged as a major form of Ca2+ entry activated by phosphoinositidase C-coupled receptors in non excitable cells. More recent evidence also indicates a role for SDCI in excitable cells. We have used dynamic video imaging of [Ca2+]i in alpha T3-1 cells (a gonadotroph-derived cell line) and manipulation of the filling state of the GnRH mobilizable Ca2+ pool to test the possible role of SDCI in GnRH action. In Ca(2+) containing medium, GnRH caused a biphasic increase in [Ca2+]i whereas in Ca(2+) free medium only a transient increase occurred. The response to a second stimulation with GnRH in Ca(2+)-free medium was reduced by > 95% (demonstrating that Ca2+ pool depletion had occurred) and was recovered after brief exposure to Ca(2+)-containing medium (which enables refilling of the pool). Ionomycin (a Ca2+ ionophore) and thapsigargin (which inhibits the Ca(2+)-sequestering ATPase of the endoplasmic reticulum) also transiently increased [Ca2+]i in Ca(2+)-free medium and depleted the GnRH-mobilizable pool as indicated by greatly reduced subsequent responses to GnRH. Pool depletion also occurs on stimulation with GnRH in Ca(2+) containing medium because addition of ionomycin and Ca(2+)-free medium during the plateau phase of the GnRH response caused only a reduction in [Ca2+]i rather than the transient increase seen without GnRH. To deplete intracellular Ca2+ pools, cells were pretreated in Ca(2+)-free medium with thapsigargin or GnRH and then, after extensive washing, returned to Ca(2+)-containing medium. Pretreatment with thapsigargin augmented the increase in [Ca2+]i seen on return to Ca(2+) containing medium (to two- to threefold higher than that seen in control cells) indicating the activation of SDCI, whereas pool depletion by GnRH pretreatment had no such effect. To ensure maintained pool depletion after Ca2+ re-addition, similar studies were performed in which the thapsigargin and GnRH treatments were not washed off, but were retained through the period of return to Ca(2+) containing medium. Return of GnRH-treated cells to Ca(2+)-containing medium caused an increase in [Ca2+]i which was inhibited by nicardipine, whereas the increase seen on return of thapsigargin-treated cells to Ca(2+)-containing medium was not reduced by nicardipine. The quench of fura-2 fluorescence by MnCl2 (used as a reporter of Ca2+ influx) was increased by GnRH and thapsigargin, indicating that both stimulate Ca2+ influx via Mn2+ permeant channels. The GnRH effect was abolished by nicardipine whereas that of thapsigargin was not. Finally, depletion of intracellular Ca2+ pools by pretreatment of superfused rat pituitary cells with GnRH or thapsigargin in Ca(2+)-free medium did not enhance LH release on return to Ca(2+)-containing medium. The results indicate that (a) thapsigargin stimulates SDCI in alpha T3-1 cells via nicardipine-insensitive Ca2+ channels, (b) in spite of the fact that GnRH depletes the hormone-mobilizable Ca2+ pool, it fails to stimulate SDCI, (c) GnRH stimulates Ca2+ entry predominantly via nicardipine-sensitive channels, a route not activated by SDCI and (d) in rat gonadotrophs, GnRH-stimulated LH release is not mediated by SDCI. PMID- 8676049 TI - Characterization of transforming growth factor-alpha receptors in the avian ovary: alterations in ligand binding to granulosa cells during follicular maturation. AB - The presence of epidermal growth factor receptors (EGF-R) and the ligands epidermal growth factor/transforming growth factor-alpha (EGF/TGF alpha) have been reported in mammalian ovaries where they are implicated in folliculogenesis and steroidogenesis. Evidence is presented to show that authentic EGF/TGF alpha receptors are expressed by the avian granulosa cells. The TGF alpha receptors (TGF alpha-R) from chicken granulosa cells were characterized by specific binding of 125I-human TGF alpha. In this study, competition with human EGF, human TGF alpha, human IGF-I, human basic fibroblast growth factor (bFGF) and insulin for 125I-human TGF alpha binding demonstrated that the avian granulosa cell TGF alpha R binds human EGF with 300-fold lower affinity than human TGF alpha. IGF-I, bFGF and insulin did not displace bound 125I-TGF alpha. Scatchard analysis showed that a single class of high-affinity binding sites is present on the granulosa cells (Kd 0.23 +/- 0.009 nM). However, the number of binding sites altered during follicular maturation with a significant decline in the most mature follicle. These results go some way to explaining the basis for the changing sensitivity of avian granulosa cells to EGF/TGF alpha stimulation as they mature. In addition, the gonadotrophins, LH and FSH, increased the number of receptors in cultured granulosa cells and may therefore partially influence folliculogenesis and steroidogenesis through this route. PMID- 8676050 TI - Influence of nutrition on hepatic IGF-I mRNA levels and plasma concentrations of IGF-I and IGF-II in meat-type chickens. AB - We have examined the influence of nutrition on plasma IGF-I, IGF-II and IGF binding protein (IGFBP) levels and on hepatic IGF-I gene expression in young meat type chickens. Plasma IGF concentrations were measured by using RIA with recombinant chicken IGFs as standards. In chickens fed the control diet containing 200 g/kg dietary protein ad libitum for 7 days, plasma IGF-I concentrations increased significantly from those found in the initial control group. Food restriction for either 4 or 7 days decreased plasma IGF-I by 30% from the initial control. When chickens were refed ad libitum for 3 days after 4 days of restricted feeding, plasma IGF-I levels recovered to those of the control birds fed ad libitum. In chickens eating a low protein diet (100 g/kg protein), the plasma IGF-I tended to be lowered but the decrease was not significant. Although the intensity of IGF-I and beta-actin mRNA bands protected in the RNase protection assay was changed by nutrition, no statistical effect of nutrition on the ratio of IGF-I to beta-actin was observed. The nutritional treatments had no effect on plasma IGF-II concentrations. Western ligand blot and chromatographic analyses were used to investigate the influence of nutrition on IGFBP profiles. Both IGF-I and IGF-II ligands in the Western ligand blot revealed the most intense binding at 30 kDa for plasma obtained from chickens with restricted food intake. The 30 kDa band also appeared at a lower intensity in the group fed a low protein diet but not in any other groups. These observations were confirmed by neutral gel chromatography. The chicken IGF-II ligand revealed an intensely labelled band corresponding to 75 kDa and this was not affected by nutrition. IGF I and IGFBP concentrations in the plasma of young broiler chickens were influenced by nutritional state but IGF-II concentrations were not. The lack of a response in circulating IGF-II levels may have been due to the presence of high concentrations of a 75 kDa specific binding protein which did not respond to nutrition in this experiment. PMID- 8676051 TI - Pituitary lactotrope expresses transforming growth factor beta (TGF beta) type II receptor mRNA and protein and contains 125I-TGF beta 1 binding sites. AB - Transforming growth factor beta 1 (TGF beta 1) has recently been shown to be produced in the prolactin (PRL)-secreting lactotropes of the pituitary gland. TGF beta 1 inhibits lactotropic secretion and proliferation, and the production of TGF beta 1 in lactotropes is reduced during lactotropic growth following estrogen treatment in ovariectomized rats. In many estrogen-responsive tissues, TGF beta 1 has been shown to exert its effect by binding to TGF beta 1 type II receptors (T beta R II) at the cell surface. In this study, we sought to ascertain whether T beta R II is involved in TGF beta 1 action on lactotropes by determining the changes of T beta R II mRNA and protein levels and specific 125I-TGF beta 1 binding sites on the lactotropes during estrogen-induced proliferation of lactotropes in Fischer 344 rats. Double immunohistochemical procedures were employed to identify immunoreactive T beta R II in PRL-reactive cells. The majority of T beta R II-reactive cells in the anterior pituitary were observed to be lactotropes. Dual immunohistochemistry and in situ hybridization procedures also indicated that lactotropes were the major cell types containing T beta R II mRNA hybrids. Both the levels of immunoreactive T beta R II protein and in situ T beta R II mRNA hybrids in the pituitary were significantly decreased in ovariectomized rats after 15 days of estrogen treatment. Determination of 125I TGF beta 1 binding sites in lactotropes by double immunohistochemistry and receptor autoradiography also revealed specific binding sites of 125I-TGF beta 1 in lactotropes in the anterior pituitary. 125I-TGF beta 1 binding in the anterior pituitary was also reduced following estrogen treatment in ovariectomized rats. These data suggest that down-regulation of T beta R II may be an important mechanism of estrogen action on lactotropic cell growth and PRL secretion, and further support the notion that TGF beta 1 controls lactotropic function by autocrine/paracrine mechanisms. PMID- 8676052 TI - Median charge of gonadotrophin isoforms in the pituitary gland and in the circulation of sheep fetuses from mid- to late gestation. AB - The heterogeneity of LH and FSH in the sheep fetus was studied by determining the median charge of pituitary and circulating isoforms. Pituitary extracts from male and female fetuses at days 75, 95, 120 and 135 of gestation were subjected to agarose suspension electrophoresis. For all fetuses except the day 75 age group, the median mobility of the gonadotrophin isoforms in matching serum samples from the individual fetuses were also determined. LH and FSH in extracts, peripheral samples and column eluates were measured using sensitive and specific sandwich fluoroimmunoassays for ovine gonadotrophins. The median charge of pituitary LH became more basic (P < 0.001) with gestational age, whereas for pituitary FSH more acidic forms (P < 0.001) were present in the older groups. The female fetuses had more basic pituitary isoforms of LH than the males (P < 0.01) between days 95 and 135, and for FSH at day 75 (P < 0.05). In the matching serum samples, the median charge of the LH (P < 0.001) and FSH (P < 0.05) isoforms were more acidic than those in the pituitary gland. No significant effects of age or sex were detected in the median charge of the gonadotrophin isoforms in serum, but in a number of instances the median charge could not be determined due to low serum concentrations which affected the group sizes. These data show that in the sheep fetus LH and FSH are differentially regulated in qualitative as well as quantitative terms, and that the charge of fetal gonadotrophin isoforms changes according to the age and sex of the fetus. PMID- 8676053 TI - Expression of insulin-like growth factors in two bovine oviductal cultures employed for embryo co-culture. AB - We have investigated the patterns of expression and cellular localization of polypeptides and mRNAs encoding IGF-I and IGF-II in intact bovine oviduct and two bovine oviductal primary cultures (monolayers and vesicles) which are utilized for supporting development in vitro. IGF-I and IGF-II polypeptides were localized by immunocytochemistry in intact oviduct and in both primary cultures for an 8 day culture interval, but IGF-II polypeptide displayed a more restricted distribution in day 8 monolayer cultures. IGF-I and IGF-II mRNAs were localized in both oviductal cell cultures as assessed by in situ hybridization. We were unable to detect IGF-I and IGF-II mRNAs in intact oviduct by in situ hybridization; however, transcripts encoding IGF-I and IGF-II mRNAs were detected in intact oviduct cell preparations and all primary culture samples by reverse transcription-PCR methods. The origin and phenotypic stability of these cultures was assessed by immunostaining with antibodies raised against vimentin (mesenchymal cell marker) and cytokeratin (epithelial cell marker). Over the culture period, the proportion of vimentin-immunoreactive cells increased in the monolayer cultures but remained at a low level in the vesicle cultures which were predominantly composed of cytokeratin-positive cells. The results suggest that oviductal cell co-culture may facilitate early mammalian development, in part, by the establishment of paracrine growth factor circuits. PMID- 8676054 TI - The testis is not the major source of circulating follistatin in the ram. AB - The aims of this study were to determine the plasma concentrations of follistatin in rams and to assess if the testis contributes to circulating follistatin and if there is uptake or production of follistatin by the head in rams. Catheters were inserted in the carotid artery, jugular vein and spermatic vein of intact rams during the non-breeding season (experiment 1; n = 5) and breeding season (experiment 2; n = 4). In experiment 1, blood samples were collected from 5 rams every 10 min for 4 h, commencing 20-60 min after surgery. After 2 h of sampling 1 microgram gonadotrophin-releasing hormone (GnRH) was injected intravenously. In experiment 2, blood samples were collected from 4 of the rams used in experiment 1 by venipuncture 30 and 15 min before surgery and every 15 min throughout surgery. Commencing 1 h after surgery, matched samples were taken from each of the vessels every 10 min for 4 h (1-4 h after surgery), then every hour for 20 h (4-24 h after surgery) and then every 10 min for 4 h (24-28 h after surgery). In both experiments, follistatin secretion was non-pulsatile and there were no significant differences between the concentrations of follistatin in any of the vessels. There was a significant (P < 0.05) increase in the concentrations of follistatin in each of the vessels throughout the 4 h of 10-min sampling in both experiments. In experiment 2 plasma concentrations of follistatin in the jugular vein were significantly (P < 0.05) lower before surgery than at other stages of the experiment. During the non-breeding season (experiment 1) the concentrations of follistatin in all vessels were about 2-fold higher (P < 0.001) than during the breeding season (experiment 2). Concentrations of follistatin were measured in the testicular tissue of the ram, bull, monkey and rat and were found to be 13.6, 2.1, 2.5, 0.8 ng/g testis respectively. In experiment 3, blood samples were collected every 15 min for 4 h from castrated rams (n = 6) in the absence of treatment with testosterone propionate (TP) and after 7 days of treatment with a physiological dose of TP during the breeding and non-breeding seasons. There was no effect of stage of breeding season or TP on the plasma concentrations of follistatin and these concentrations in the castrated rams were similar to the concentrations in the intact rams in experiment 2. In experiment 4, the function of Leydig cells was stimulated by administration of human chorionic gonadotrophin but this had no effect on plasma concentrations of follistatin. These experiments show that the concentrations of follistatin in the plasma of rams are measurable, that the testis is not the major contributor to circulating follistatin and that there is no significant uptake or production of follistatin by the head in rams. It appears that the contribution of the testis to circulating follistatin may vary with the stage of the breeding season, being greater during the non-breeding season than the breeding season. The gonadotrophins and testosterone do not appear to have a direct effect on the secretion of follistatin in rams. The increase in concentrations of circulating follistatin during surgery and more frequent blood sampling suggest a stress-related effect on the production of follistatin. PMID- 8676055 TI - The effects of N-methyl-D,L-aspartic acid and aspartic acid on the plasma concentration of gonadotrophins, GH and prolactin in the ewe. AB - Aspartic acid is a neurotransmitter in the central nervous system that acts via the glutamate receptor and the analogue, N-methyl-D,L-aspartic acid (NMA) is an agonist that stimulates GnRH secretion. Under normal dietary conditions, the plasma concentration of aspartic acid in ewes is low and if increased by improved nutrition may increase the brain concentration of aspartic acid leading to increased gonadotrophin secretion. In two experiments we investigated the effects of NMA on pituitary hormone concentrations and the effects of aspartic acid on ovulation rate and pituitary hormone concentrations. The intravenous injection of NMA into cycling ewes resulted in an immediate (within 15 min) release of a pulse of LH and of GH and a prolonged (up to 1 h) suppression of prolactin secretion. There were marked differences in responsiveness to NMA between individual ewes. The intravenous infusion of aspartic acid for 5 days in the late luteal phase of the oestrous cycle did not affect ovulation rate but reduced the mean LH (P < 0.05) and FSH (P < 0.05) concentrations in plasma. The frequency of LH pulses also tended to be lower (P < 0.1) in ewes infused with aspartic acid. It is suggested that the decrease in gonadotrophin secretion in ewes infused with aspartic acid is due to effects on the hypothalamus or the anterior pituitary gland which are not related to increased levels of ovarian feedback. These changes are likely to involve decreased GnRH secretion. PMID- 8676056 TI - Age-related endocrine deficiencies and fractures of the proximal femur. I implications of growth hormone deficiency in the elderly. AB - Growth hormone activates osteoblasts to increase local synthesis of IGF-I, which acts in an autocrine or paracrine way to enhance bone matrix apposition, suggesting a role in the preservation of bone mass. Growth hormone deficiency in the elderly may therefore be of pathogenetic significance in senile osteoporosis. However, critical evidence does not yet support the concept that the decreased activity of the growth hormone-IGF-I axis alters bone remodelling, and the extent to which geriatric hyposomatotropism contributes to the age-related femoral bone loss remains to be elucidated. Despite the fact that biochemical estimates of bone turnover indicate that (short-term) administration of rhGH and IGF-I stimulates bone metabolism in non-osteoporotic older people, no significant changes have been observed in bone mineral density at the proximal femur. Additional studies are needed to assess the therapeutic potential for rhGH in attenuating or reversing bone loss in elderly people. Moreover, data on long-term adverse side effects of rhGH therapy are not yet available. Because of the known mitogenic action of IGF-I, the neoplastic potential of long-term rhGH therapy needs to be considered. PMID- 8676057 TI - Acute effect of thyroid hormone in the rat heart: role of calcium. AB - Several observations provide some clues as to the possible mode of the regulatory action of thyroid hormone (TH) in the heart, indicating delayed action at the level of the nucleus and acute effects on the plasma membrane. Here we present evidence for a direct and rapid stimulatory effect of TH in the intact normal heart. In the isolated perfused rat heart, 3,5,3'-tri-iodothyronine (T3) produced a positive inotropic effect increasing both the left ventricular peak systolic pressure (P) and +dP/dt values, but had no significant effect on heart rate. This effect of T3 was: (1) very rapid in onset (starting after 15 s) and transient, increasing gradually to reach a maximum (80% above control) at about 20 min, and declining progressively 20 to 30 min later; (2) dose-related and biphasic, occurring at physiological concentrations as low as 1 pM (+dP/dt) and 10 pM (P), reaching a maximum at 1 nM, and decreasing at higher concentrations; and (3) thyroid hormone specific, as shown by the effects of several TH analogs (L-T3 > L thyroxine (T4) = D-T3 > D-T4; 3,3',5'-tri-iodothyronine (rT3), 3,5,-L-di iodothyronine and DL-thyronine had no effect). The calcium blockers nifedipine and verapamil, at concentrations of 10(-8) - 10(-5) M given before or after the addition of T3 (10(-9) - 10(-6) M), inhibited the T3-induced increase in cardiac inotropic activity in a time- and dose-related fashion. We suggest that the acute effect of TH in the heart is plasma membrane-mediated and calcium-dependent. PMID- 8676058 TI - GH regulation of the Type 2 IGF receptor in regenerating skeletal muscle of rats. AB - GH enhances skeletal muscle growth, and IGF-II peptide is highly expressed during regeneration. We have therefore investigated the effect of GH administration on IGF-II binding and expression in regenerating rat skeletal muscle using the techniques of receptor autoradiography and in situ hybridisation. Notexin, a myotoxin, was injected into the right M. biceps femoris (day 0), causing affected fibres to undergo necrosis followed by rapid regeneration. Animals were administered either GH (200 micrograms/100 g body weight) or saline vehicle daily. Contralateral muscles were used as regeneration controls. GH administration during regeneration resulted in significant increases in body weight, and damaged and undamaged muscle weights (P < 0.001). IGF-II expression, which was examined in regenerating fibres, survivor fibres and undamaged fibres, varied according to tissue type (P < 0.001). Specifically, IGF-II expression in regenerating fibres was elevated relative to control and survivor fibres after day 3 (P < 0.05), with a peak on day 9 (P < 0.001). GH did not affect IGF-II message levels. 125I-IGF-II binding in regenerating muscle was examined in the same fibre types as well as in connective tissue. 125I-IGF-II binding in regenerating fibres was higher (P < 0.001) than in other tissue types on day 5. GH administration increased 125I-IGF-II binding in all damaged muscle tissues on day 5 (P < 0.001, regenerating fibres; P < 0.01, others). We believe that this shows for the first time an effect of GH on the Type 2 IGF receptor in regenerating skeletal muscle. PMID- 8676059 TI - Inhibin-related proteins in rat prostate. AB - Inhibin and activin are members of the transforming growth factor beta (TGF beta) family which can regulate cell proliferation in a number of tissues. The presence of inhibins and the related proteins, activins, in the prostate has been implicated by the detection of activin type II receptors. The aim of this study was to determine whether or not immunoactive (ir) inhibin and ir-activin are present in the rat prostate and to study the acute regulation by androgens. The results showed that mRNAs for the alpha and beta inhibin subunits were detected in rat prostate by reverse transcription-PCR together with ir-inhibin and ir activin in prostate cytosols. The levels of ir-activin in the prostate (223 +/- 44 ng/gland) were greater than the levels of ir-inhibin (6.89 ng/gland), and activin immunoreactivity was localised to the epithelial cells. The presence of these proteins and the subunit mRNAs suggests that these proteins are produced in the prostate and may have a role in prostate function. The study of the effect of androgen withdrawal on the levels of ir-activin and ir-inhibin in these tissues showed no change in the content of ir-inhibin or ir-activin (ng/g tissue) after 3 days of castration or following the administration of the cytotoxic drug ethane dimethane sulphonate (EDS), although there was a significant (P < 0.01) decline in prostate weight. Fourteen days after EDS treatment, as the prostate weight fell significantly lower, the amount of ir-inhibin and ir-activin per prostate gland was significantly (P < 0.01) reduced although the concentration was unaffected. These data demonstrate, for the first time, that inhibin alpha and beta subunit mRNA and ir-inhibin and ir-activin are present in the prostate; the role of these proteins in prostate function remains to be established. PMID- 8676060 TI - Is interleukin 17, an inducible cytokine that stimulates production of other cytokines, merely a redundant player in a sea of other biomolecules? PMID- 8676061 TI - Is IL-6 both a cytokine and a neurotrophic factor? PMID- 8676062 TI - Chemokines active on eosinophils: potential roles in allergic inflammation. PMID- 8676063 TI - The immunosuppressant 15-deoxyspergualin [correction of 1,5-deoxyspergualin] reveals commonality between preT and preB cell differentiation. AB - 15 [correction of 1,5] deoxyspergualin (DSG) is a potent immunosuppressant whose mechanism of action is still somewhat of a mystery. We have studied the generation of lymphocytes in mice treated with this drug. The differentiation of T cells in the thymus was blocked at an important early control point: the CD4-8- --> CD4+8+ transition, known to depend on the expression of a preTCR complex that includes the variable TCR-beta, but not TCR-alpha, chain. In clear contrast, a later control point, the CD4+8+ --> CD4+8- or CD4-8+ transition, dependent on the display of a conventional alpha:beta TCR complex, appeared unaffected, as did activation of mature T cells both in vitro and in vivo. Interestingly, preB cell differentiation in the bone marrow was blocked at a precisely equivalent point: the A-C --> C' transition, controlled by expression of a pre-receptor complex containing the Ig heavy, but not light, chain. Mature B cells seemed unperturbed. These findings have theoretical implications, suggesting common signaling pathways in early lymphocytes that are distinct from those employed by more mature cells, and are also of practical interest, to be considered in the design of DSG treatment protocols. PMID- 8676065 TI - Selective activation of Fas/Fas ligand-mediated cytotoxicity by a self peptide. AB - To study how MHC-associated self antigens may regulate the function of T cells in the periphery, we generated CD8+ T cell lines specific for a single residue variant of a self peptide. The self peptide (GAYEFTTL) was isolated from H-2-Kb class I MHC molecules immunopurified from tumor cells. CD8+ CTL lines from H-2b mice were generated against a variant peptide, pE4R, (arginine for glutamic acid at the TCR contact position 4). In short-term 51Cr-release assays, these CTL lysed H-2Kb targets that were pulsed with picomolar levels of pE4R but did not lyse target cells coated with the self peptide at micromolar levels. However, in overnight assays the CTL lysed Fas-positive target cells in the presence of nanomolar levels of the self peptide. This killing was shown to be entirely Fas/Fas ligand mediated by blocking with anti-Fas antibody and Fas-Fc chimeric molecules. While the self peptide was unable to induce serine esterase release from the CTL, it did induce secretion of IFN-gamma. By these criteria then, the unmodified self ligand served as a partial agonist for the CTL raised against a single-residue variant. CD8+ T cell lines raised by in vitro stimulation with the self peptide were likewise unable to kill self peptide-coated targets via the perforin pathway but did lyse targets via Fas. These and similar data from other groups show that self antigens (i.e., MHC/peptide complexes) may be recognized by mature peripheral T cells. The T cell population is tolerant of the self antigen in the sense that they do not respond to physiological levels of the MHC/peptide complex. However, when the level of self antigen is increased (by using synthetic peptide loading) CD8+ T cells may respond by proliferation, IFN-gamma secretion, Fas ligand upregulation, and Fas-mediated cytolysis but are still unable to respond by perforin-mediated cytolysis or granzyme release. The physiological significance of such partial activation in regulation of the immune system remains to be demonstrated. PMID- 8676064 TI - Molecular cloning and characterization of a human eotaxin receptor expressed selectively on eosinophils. AB - The chemokine eotaxin is unusual in that it appears to be a highly specific chemoattractant for eosinophils. Ligand-binding studies with radiolabeled eotaxin demonstrated a receptor on eosinophils distinct from the known chemokine receptors CKR-1 and -2. The distinct eotaxin binding site on human eosinophils also bound RANTES (regulated on activation T expressed and secreted) and monocyte chemotactic protein (MCP)3. We have now isolated a cDNA from eosinophils, termed CKR-3, with significant sequence similarity to other well characterized chemokine receptors. Cells transfected with CKR-3 cDNA bound radiolabeled eotaxin specifically and with high affinity, comparable to the binding affinity observed with eosinophils. This receptor also bound RANTES and MCP-3 with high affinity, but not other CC or CXC chemokines. Furthermore, receptor transfectants generated in a murine B cell lymphoma cell line migrated in transwell chemotaxis assays to eotaxin, RANTES, and MCP-3, but not to any other chemokines. A monoclonal antibody recognizing CKR-3 was used to show that eosinophils, but not other leukocyte types, expressed this receptor. This pattern of expression was confirmed by Northern blot with RNA from highly purified leukocyte subsets. The restricted expression of CKR-3 on eosinophils and the fidelity of eotaxin binding to CKR-3, provides a potential mechanism for the selective recruitment and migration of eosinophils within tissues. PMID- 8676066 TI - Nucleosomal peptide epitopes for nephritis-inducing T helper cells of murine lupus. AB - Nucleosome-specific T helper (Th) cells provide major histocompatibility complex class II-restricted, cognate help to nephritogenic antinuclear autoantibody producing B cells in lupus. However, the lupus Th cells do not respond when components of the nucleosome, such as free DNA or histones, are individually presented by antigen-presenting cells. Thus critical peptide epitopes for the pathogenic Th cells are probably protected during uptake and processing of the native nucleosome particle as a whole. Therefore, herein we tested 145 overlapping peptides spanning all four core histones in the nucleosome. We localized three regions in core histones, one in H2B at amino acid position 10-33 (H2B(10-33)), and two in H4, at position 16-39 (H4(16-39)) and position 71-94 (H4(71-94)), that contained the peptide epitopes recognized by the pathogenic autoantibody-inducing Th cells of lupus. The peptide autoepitopes also triggered the pathogenic Th cells of (SWR x NZB)F1 lupus mice in vivo to induce the development of severe lupus nephritis. The nucleosomal autoepitopes stimulated the production of Th1-type cytokines, consistent with immunoglobulin IgG2a, IgG2b, and IgG3 being the isotypes of nephritogenic autoantibodies induced in the lupus mice. Interestingly, the Th cell epitopes overlapped with regions in histones that contain B cell epitopes targeted by autoantibodies, as well as the sites where histones contact with DNA in the nucleosome. Identification of the disease-relevant autoepitopes in nucleosomes will help in understanding how the pathogenic Th cells of spontaneous systemic lupus erythematosus emerge, and potentially lead to the development of peptide-based tolerogenic therapy for this major autoimmune disease. PMID- 8676067 TI - Regulated expression of telomerase activity in human T lymphocyte development and activation. AB - Telomerase, a ribonucleoprotein that is capable of synthesizing telomeric repeats, is expressed in germline and malignant cells, and is absent in most normal human somatic cells. The selective expression of telomerase has thus been proposed to be a basis for the immortality of the germline and of malignant cells. In the present study, telomerase activity was analyzed in normal human T lymphocytes. It was found that telomerase is expressed at a high level in thymocyte subpopulations, at an intermediate level in tonsil T lymphocytes, and at a low to undetectable level in peripheral blood T lymphocytes. Moreover, telomerase activity is highly inducible in peripheral T lymphocytes by activation through CD3 with or without CD28 costimulation, or by stimulation with phorbol myristate acetate (PMA)/ionomycin. The induction of telomerase by anti-CD3 plus anti-CD28 (anti-CD3/CD28) stimulation required RNA and protein synthesis, and was blocked by herbimycin A, an inhibitor of S pi protein tyrosine kinases. The immunosuppressive drug cyclosporin A selectively inhibited telomerase induction by PMA/ionomycin and by anti-CD3, but not by anti-CD3/CD28. Although telomerase activity in peripheral T lymphocytes was activation dependent and correlated with cell proliferation, it was not cell cycle phase restricted. These results indicate that the expression of telomerase in normal human T lymphocytes is both developmentally regulated and activation induced. Telomerase may thus play a permissive role in T cell development and in determining the capacity of lymphoid cells for cell division and clonal expansion. PMID- 8676068 TI - Induction of unresponsiveness and impaired T cell expansion by staphylococcal enterotoxin B in CD28-deficient mice. AB - We used CD28-deficient mice to analyze the importance of CD28 costimulation for the response against Staphylococcal enterotoxin B (SEB) in vivo. CD28 was necessary for the strong expansion of V beta 8+ T cells, but not for deletion. The lack of expansion was not due to a failure of SEB to activate V beta 8+ T cells, as V beta 8+ T cells from both CD28-/- and CD28+/+ mice showed similar phenotypic changes within the first 24 h after SEB injection and cell cycle analysis showed that an equal percentage of V beta 8+ T cells started to proliferate. However, the phenotype and the state of proliferation of V beta 8+ T cells was different at later time points. Furthermore, in CD28-/- mice injection with SEB led to rapid induction of unresponsiveness in SEB responsive T cells, indicated by a drastic reduction of proliferation after secondary SEB stimulation in vitro. Unresponsiveness could also be demonstrated in vivo, as CD28-/- mice produced only marginal amounts of TNF alpha after rechallenge with SEB. In addition CD28-/- mice were protected against a lethal toxic shock induced by a second injection with SEB. Our results indicate that CD28 costimulation is crucial for the T cell-mediated toxicity of SEB and demonstrate that T cell stimulation in the absence of CD28 costimulation induces unresponsiveness in vivo. PMID- 8676069 TI - Reduction of otherwise remarkably stable virus-specific cytotoxic T lymphocyte memory by heterologous viral infections. AB - Experimental analyses of the acute cytotoxic T lymphocyte (CTL) response to viruses have focused on studying these infections in immunologically naive hosts. In the natural environment, however, viral CTL responses occur in hosts that are already immune to other infectious agents. To address which factors contribute to the maintenance and waning of immunological memory, the following study examined the frequencies of virus-specific CTL precursor cells (pCTL) not only using the usual experimental paradigm where mice undergo acute infections with a single virus, and in mice immune to a single virus, but also in immune mice after challenge with various heterologous viruses. As determined by limiting dilution assays, the pCTL frequency (p/f) per CD8+ T cell specific for lymphocytic choriomeningitis virus (LCMV), Pichinde virus (PV), or vaccinia virus (VV) increased during the acute infections, peaking at days 7-8 with frequencies as high as 1/27-1/74. Acute viral infections such as these elicit major expansions in the CD8+ T cell number, which has been reported to undergo apoptosis and decline after most of the viral antigen has been cleared. Although the decline in the total number of virus-specific pCTL after their peak in the acute infection was substantial, for all three viruses the virus-specific p/f per CD8+ T cell decreased only two- to fourfold and remained at these high levels with little fluctuation for well over a year. The ratios of the three immunodominant peptide specific to total LCMV-specific clones remained unchanged between days 7 and 8 of acute infection and long-term memory, suggesting that the apoptotic events did not discriminate on the basis of T cell receptor specificity, but instead nonspecifically eliminated a large proportion of the activated T cells. However, when one to five heterologous viruses (LCMV, PV, VV, murine cytomegalovirus, and vesicular stomatitis virus) were sequentially introduced into this otherwise stable memory pool, the stability of the memory pool was disrupted. With each successive infection, after the immune system had returned to homeostasis, the memory p/f specific to viruses from earlier infections declined. Reductions in memory p/f were observed in all tested immunological compartments (spleen, peripheral blood, lymph nodes, and peritoneal cavity), and on average in the spleen revealed a 3 +/- 0.4-fold decrease in p/f after one additional viral infection and an 8.4 +/- 3-fold decrease after two additional viral infections. Thus, subsequent challenges with heterologous antigens, which themselves induce memory CTL, may contribute to the waning of CTL memory pool to earlier viruses as the immune system accommodates ever-increasing numbers of new memory cells within a limited lymphoid population. This demonstrates that virus infections do not occur in immunological isolation, and that CD8+ T cell responses are continually being modulated by other infectious agents. PMID- 8676070 TI - A mutated HLA-A2 molecule recognized by autologous cytotoxic T lymphocytes on a human renal cell carcinoma. AB - Many human tumor cells have been shown to express antigens that are recognized by autologous cytotoxic T lymphocytes (CTL) and the molecular nature of a number of melanoma antigens has been defined recently. Here we describe the characterization of an antigen recognized on a renal cell carcinoma by autologous CTL clones. This antigen is encoded by the HLA-A2 gene present in the tumor cells. The sequence of this gene differs from the HLA-A2 sequence found in autologous peripheral blood lymphocytes by a point mutation that results in an arginine to isoleucine exchange at residue 170, which is located on the alpha helix of the alpha 2 domain. Transfection experiments with the normal and mutated HLA-A2 cDNA demonstrated that this amino acid replacement was responsible for the recognition of the HLA-A2 molecule expressed on the tumor cells. The mutant HLA A2 gene was also detected in the original tumor tissue from the patient, excluding the possibility that the mutation had appeared in vitro. Thus, HLA class I molecules carrying a tumor-specific mutation can be involved in the recognition of tumor cells by autologous CTL. PMID- 8676071 TI - Autoreactive cytotoxic T lymphocytes in human immunodeficiency virus type 1 infected subjects. AB - A subtractive analysis of peptides eluted from major histocompatibility complex (MHC) class I human histocompatibility leukocyte antigen (HLA)-A2.1 molecules purified from either human immunodeficiency virus type-1 (HIV-1)-infected or uninfected cells was performed using micro high-performance liquid chromatography and mass spectrometry. Three peptides unique to infected cells were identified and found to derive from a single protein, human vinculin, a structural protein not known to be involved in viral pathogenesis. Molecular and cytofluorometric analyses revealed vinculin mRNA and vinculin protein overexpression in B and T lymphocytes from HIV-1-infected individuals. Vinculin peptide-specific CTL activity was readily elicited from peripheral blood lymphocytes of the majority of HLA-A2.1+, HIV+ patients tested. Our observations suggest that atypical vinculin expression and MHC class I-mediated presentation of vinculin-derived peptides accompany HIV infection of lymphoid cells in vivo, with a resultant induction of antivinculin CTL in a significant portion of HIV+ (HLA-A2.1+) individuals. PMID- 8676072 TI - Binding and cooperative interactions between two B cell-specific transcriptional coactivators. AB - The class II transactivator (CIITA) and B cell octamer-binding protein 1/octamer binding factor 1/Oct coactivator from B cells (Bob1/OBF-1/OCA-B) represent two B cell-specific transcriptional coactivators. CIITA and Bob1 interact with proteins that bind to conserved upstream sequences in promoters of class II major histocompatibility genes and octamer-binding transcription factors Oct-1 and Oct 2, respectively. Both CIITA and Bob1 increase the expression from the DRA promoter, which is a prototypic class II promoter. Moreover, in the presence of CIITA, interactions between class II promoters and Bob1 are independent of the octamer-binding site. Using in vivo and in vitro binding assays, we confirm that Bob1 binds to CIITA. Thus, CIITA not only activates the expression of class II genes but recruits another B cell-specific coactivator to increase transcriptional activity of class II promoters in B cells. PMID- 8676073 TI - Constitutive expression of bcl-2 in B cells causes a lethal form of lupuslike autoimmune disease after induction of neonatal tolerance to H-2b alloantigens. AB - The bcl-2 protooncogene has been shown to provide a survival signal to self reactive B cells, but it fails to override their developmental arrest after encounter with antigen. Furthermore, constitutive expression of bcl-2 in B cells does not promote the development of autoimmune disease in most strains of mice, indicating that signals other than those conferred by bcl-2 are required for long term survival and differentiation of self-reactive B cells in vivo. To further examine the factors that are required for the pathogenesis of autoimmune disease, we have assessed the effect of bcl-2 overexpression on the development of host versus-graft disease, a self-limited model of systemic autoimmune disease. In this model, injection of spleen cells from (C57BL/6 x BALB/c)F1 hybrid mice into BALB/c newborn parental mice induces immunological tolerance to donor tissues and activation of autoreactive F1 donor B cells through interactions provided by allogeneic host CD4+ T cells. BALB/c newborns injected with spleen cells from (C57BL/6 x BALB/c)F1 mice expressing a bcl-2 transgene in B cells developed high levels of anti-single-stranded DNA and a wide range of pathogenic autoantibodies that were not or barely detectable in mice injected with nontransgenic spleen cells. In mice injected with transgenic B cells, the levels of pathogenic autoantibodies remained high during the course of the study and were associated with long-term persistence of donor B cells, development of a severe autoimmune disease, and accelerated mortality. These results demonstrate that bcl-2 can provide survival signals for the maintenance and differentiation of autoreactive B cells, and suggest that both increased B cell survival and T cell help play critical roles in the development of certain forms of systemic autoimmune disease. PMID- 8676074 TI - CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. AB - While interactions between CD28 and members of the B7 family costimulate and enhance T cell responses, recent evidence indicates that the CD28 homologue CTLA 4 plays a downregulatory role. The mechanism by which this occurs is not clear, but it has been suggested that CTLA-4 terminates ongoing responses of activated T cells, perhaps by induction of apoptosis. Here we demonstrate that CTLA-4 engagement by antibody cross-linking or binding to B7 inhibits proliferation and accumulation of the primary T cell growth factor, IL-2, by cells stimulated with anti-CD3 and anti-CD28. This inhibition is not a result of enhanced cell death. Rather it appears to result from restriction of transition from the G1 to the S phase of the cell cycle. Our observation that upregulation of both the IL-2R alpha chain and the CD69 activation antigen are inhibited by CTLA-4 engagement supplies further evidence that CTLA-4 restricts the progression of T cells to an activated state. Together this data demonstrates that CTLA-4 can regulate T cell activation in the absence of induction of apoptotic cell death. PMID- 8676075 TI - CTLA-4 ligation blocks CD28-dependent T cell activation. AB - CTLA-4 is a CD28 homologue believed to be a negative regulator of T cell function. However, the mechanism of this downregulatory activity is not well understood. The present study was designed to examine the effect of CTLA-4 ligation on cytokine production, cell survival, and cell cycle progression. The results demonstrate that the primary effect of CTLA-4 ligation is not the induction of apoptosis. Instead, CTLA-4 signaling blocks IL-2 production, IL-2 receptor expression, and cell cycle progression of activated T cells. Moreover, the effect of CTLA-4 signaling was manifested after initial T cell activation. Inhibition of IL-2 receptor expression and cell cycle progression was more pronounced at late (72 h) time points after initial activation. The effects of anti-CTLA-4 mAbs were most apparent in the presence of optimal CD28-mediated costimulation consistent with the finding that CTLA-4 upregulation was CD28 dependent. Finally, the addition of exogenous IL-2 to the cultures restored IL-2 receptor expression and T cell proliferation. These results suggest that CTLA-4 signaling does not regulate cell survival or responsiveness to IL-2, but does inhibit CD28-dependent IL-2 production. PMID- 8676076 TI - Differential cytokine effects on primitive (CD34+CD38-) human hematopoietic cells: novel responses to Flt3-ligand and thrombopoietin. AB - A high proportion of the CD34+CD38- cells in normal human marrow are defined as long-term culture-initiating cells (LTC-IC) because they can proliferate and differentiate when co-cultured with cytokine-producing stromal feeder layers. In contrast, very few CD34+CD38- cells will divide in cytokine-containing methylcellulose and thus are not classifiable as direct colony-forming cells (CFC), although most can proliferate in serum-free liquid cultures containing certain soluble cytokines. Analysis of the effects of 16 cytokines on CD34+CD38- cells in the latter type of culture showed that Flt3-ligand (FL), Steel factor (SF), and interleukin (IL)-3 were both necessary and sufficient to obtain an approximately 30-fold amplification of the input LTC-IC population within 10 d. As single factors, only FL and thrombopoietin (TPO) stimulated a net increase in LTC-IC within 10 d. Interestingly, a significantly increased proportion of the CFC produced from the TPO-amplified LTC-IC were erythroid. Increases in the number of directly detectable CFC of > 500-fold were also obtainable within 10 d in serum-free cultures of CD34+CD38- cells. However, this required the presence of IL-6 and/or granulocyte/colony-stimulating factor and/or nerve growth factor beta in addition to FL, SF, and IL-3. Also, for this response, the most potent single-acting factor tested was IL-3, not FL. Identification of cytokine combinations that differentially stimulate primitive human hematopoietic cell self-renewal and lineage determination should facilitate analysis of the intracellular pathways that regulate these decisions as well as the development of improved ex vivo expansion and gene transfer protocols. PMID- 8676077 TI - Interleukin-12 primes human CD4 and CD8 T cell clones for high production of both interferon-gamma and interleukin-10. AB - Interleukin-12 (IL-12) induces differentiation of T helper 1 (Th1) cells, primarily through its ability to prime T cells for high interferon-gamma (IFN gamma) production. We now report that the presence of IL-12 during the first several days of in vitro clonal expansion in limiting dilution cultures of polyclonally stimulated human peripheral blood CD4+ and CD8+ T cells also induces stable priming for high IL-10 production. This effect was demonstrated with T cells from both healthy donors and HIV+ patients. Priming for IL-4 production, which requires IL-4, was maximum in cultures containing both IL-12 and IL-4. IL-4 modestly inhibited the IL-12-induced priming for IFN-gamma, but almost completely suppressed the priming for IL-10 production. A proportion of the clones generated from memory CD45RO+ cells, but not those generated from naive CD45RO- CD4+ T cells, produced some combinations of IFN-gamma, IL-10, and IL-4 even in the absence of IL-12 and IL-4, suggesting in vivo cytokine priming; virtually all CD4+ clones generated from either CD45RO(-) or (+) cells, however, produced high levels of both IFN-gamma and IL-10 when IL-12 was present during expansion. These results indicate that each Th1-type (IFN-gamma) and Th2-type (IL-4 and IL-10) cytokine gene is independently regulated in human T cells and that the dichotomy between T cells with the cytokine production pattern of Th1 and Th2 cells is not due to a direct differentiation-inducing effect of immunoregulatory cytokines, but rather to secondary selective mechanisms. Particular combinations of cytokines induce a predominant generation of T cell clones with anomalous patterns of cytokine production (e.g., IFN-gamma and IL-4 or IFN-gamma and IL-10) that can also be found in a proportion of fresh peripheral blood T cells with "memory" phenotype or clones generated from them and that may identify novel Th subsets with immunoregulatory functions. PMID- 8676078 TI - Enhancement of Antigen-specific functional responses by neutrophils from allergic patients. AB - It has been demonstrated that neutrophils from healthy donors or from patients with inflammatory disorders can bind immunoglobulin (Ig) E proteins through binding to Mac-2/epsilon bp. Functional responses to allergens were assessed by measuring the respiratory burst and intracellular Ca2+ levels, and binding of allergens to neutrophils was assessed by flow cytometry analysis and fluorescence microscopy. In this article, we demonstrate that neutrophils sensitized to specific allergens (from allergic patients), but not from healthy donors, are sensitive to allergens of the same type as those that produce clinical allergic symptoms. The activation of neutrophils was analyzed by the induction of a respiratory burst that was detected with luminol-dependent chemiluminescence. Intracellular Ca2+ levels increased parallel to those of the inducing allergens. In addition, the specific binding of allergens on the cell surface was revealed by flow cytometry and allergen-FITC-labeled staining analyses. The present data suggest a restricted recognition of allergen by sensitive neutrophils, probably associated with the specific binding of the allergen to its corresponding IgE molecule, which is bound to the Mac-2/epsilon bp structure. These findings demonstrate a functional role of allergen-associated neutrophils during the allergic state. PMID- 8676079 TI - The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures. AB - Interleukin (IL)-11 is a multifunctional cytokine whose role in osteoclast development has not been fully elucidated. We examined IL-11 production by primary osteoblasts and the effects of rat monoclonal anti-mouse glycoprotein 130 (gp130) antibody on osteoclast formation, using a coculture of mouse osteoblasts and bone marrow cells. IL-1, TNF alpha, PGE2, parathyroid hormone (PTH) and 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3) similarly induced production of IL-11 by osteoblasts, but IL-6, IL-4, and TGF beta did not. Primary osteoblasts constitutively expressed mRNAs for both IL-11 receptor (IL-11R alpha) and gp130. Osteotropic factors did not modulate IL-11R alpha mRNA at 24 h, but steady-state gp130 mRNA expression in osteoblasts was upregulated by 1 alpha,25(OH)2D3, PTH, or IL-1. In cocultures, the formation of multinucleated osteoclast-like cells (OCLs) in response to IL-11, or IL-6 together with its soluble IL-6 receptor was dose-dependently inhibited by rat monoclonal anti-mouse gp130 antibody. Furthermore, adding anti-gp130 antibody abolished OCL formation induced by IL-1, and partially inhibited OCL formation induced by PGE2, PTH, or 1 alpha,25(OH)2D3. During osteoclast formation in marrow cultures, a sequential relationship existed between the expression of calcitonin receptor mRNA and IL-11R alpha mRNA. Osteoblasts as well as OCLs expressed transcripts for IL-11R alpha, as indicated by RT-PCR analysis and in situ hybridization. These results suggest a central role of gp130-coupled cytokines, especially IL-11, in osteoclast development. Since osteoblasts and mature osteoclasts expressed IL-11R alpha mRNA, both bone forming and bone-resorbing cells are potential targets of IL-11. PMID- 8676080 TI - T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. AB - Analysis of the cDNA encoding murine interleukin (IL) 17 (cytotoxic T lymphocyte associated antigen 8) predicted a secreted protein sharing 57% amino acid identity with the protein predicted from ORF13, an open reading frame of Herpesvirus saimiri. Here we report on the cloning of human IL-17 (hIL-17), the human counterpart of murine IL-17. hIL-17 is a glycoprotein of 155 amino acids secreted as an homodimer by activated memory CD4+ T cells. Although devoid of direct effects on cells of hematopoietic origin, hIL-17 and the product of its viral counterpart, ORF13, stimulate epithelial, endothelial, and fibroblastic cells to secrete cytokines such as IL-6, IL-8, and granulocyte-colony-stimulating factor, as well as prostaglandin E2. Furthermore, when cultured in the presence of hIL-17, fibroblasts could sustain the proliferation of CD34+ hematopoietic progenitors and their preferential maturation into neutrophils. These observations suggest that hIL-17 may constitute (a) an early initiator of the T cell-dependent inflammmatory reaction; and (b) an element of the cytokine network that bridges the immune system to hematopoiesis. PMID- 8676081 TI - Experimental granulomatous colitis in mice is abrogated by induction of TGF-beta mediated oral tolerance. AB - In previous studies we showed that a chronic colitis associated with a Th1 T cell response can be induced by the rectal administration of the haptenizing reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). We report here that oral administration of haptenized colonic proteins (HCP) before rectal administration of TNBS effectively suppresses the ability of the latter to induce colitis. This suppression (oral tolerance) appears to be due to the generation of mucosal T cells producing TGF-beta and Th2-type cytokines after oral HCP administration. Peyer's patch and lamina propria CD4+ T cells from HCP-fed animals stimulated with anti-CD3/anti-CD28 had a 5-10-fold increase in their production of TGF-beta and secreted increased amounts of IL-4 and IL-10 but lower levels of IFN-gamma in comparison to T cells from ovalbumin-fed control animals. In addition, the colons of HCP-fed mice showed strikingly increased TGF-beta but decreased IL-12 expression by immunohistochemical studies and isolated mononuclear cells from HCP fed animals secreted less IL-12 heterodimer. Finally, and most importantly, the suppressive effect of orally administered HCP was abrogated by the concomitant systemic administration of anti-TGF-beta or rIL-12 suggesting a reciprocal relationship between IL-12 and TGF-beta on tolerance induction in TNBS-induced colitis. In parallel studies we demonstrated that TNBS-induced colitis can be transferred to naive recipient animals with purified CD4+ T cells from the colon of TNBS-treated animals and that such animals develop lethal pancolitis when exposed to very low doses of TNBS. Feeding of HCP suppressed this sensitivity to TNBS, indicating that oral feeding can suppress the response of pre-committed T cells in vivo. These studies suggest for the first time that TGF-beta production can abrogate experimental granulomatous colitis even after such colitis is established, and thus, that regulation of TGF-beta levels may have relevance to the treatment of human inflammatory bowel disease. PMID- 8676082 TI - Antigen compartmentation and T helper cell tolerance induction. AB - The process of antigen recognition depends in part on the amount of peptide antigen available and the affinity of the T cell receptor for a particular peptide-major histocompatibility complex (MHC) molecule complex. The availability of self antigen is limited by antigen processing, which is compartmentalized such that peptide antigens presented by MHC class I molecules originate in the cytoplasm, whereas peptide antigens presented by MHC class II molecules are acquired from the endocytic pathway. This segregation of the antigen-processing pathways may limit the diversity of antigens that influence the development and selection of, e.g., CD4-positive, MHC class II-specific T cells. Selection in this case might involve only a subset of self-encoded proteins, specifically those that are plasma membrane bound or secreted. To study these aspects of immune development, we engineered pigeon cytochrome for expression in transgenic mice in two forms: one in which it was expressed as a type II plasma membrane protein, and a second in which it was targeted to the mitochondria after cytoplasmic synthesis. Experiments with these mice clearly show that tolerance is induced in the thymus, irrespective of antigen compartmentation. Using radiation bone marrow chimeras, we further show that cytoplasmic/mitochondrial antigen gains access to the MHC class II pathway by direct presentation. As a result of studying the anatomy of the thymus, we show that the amount of antigen and the affinity of the TCR affect the location and time point of thymocytes under-going apoptosis. PMID- 8676083 TI - Accelerated Nerve Regeneration in Mice by upregulated expression of interleukin (IL) 6 and IL-6 receptor after trauma. AB - In this study we aimed to examine a role for interleukin 6 (IL-6) and its receptor (IL-6R) in peripheral nerve regeneration in vivo. We first observed that cultured mouse embryonic dorsal root ganglia exhibited dramatic neurite extension by simultaneous addition of IL-6 and soluble IL-6R (sIL-6R), a complex that is known to interact with and activate a signal transducing receptor component, gp130. After injury in the hypoglossal nerve in adult mice by ligation, immunoreactivity to IL-6 was upregulated in Schwann cells at the lesional site as well as in the cell bodies of hypoglossal neurons in the brain stem. In the latter, upregulation of the immunoreactivity to IL-6R was also observed. Regeneration of axotomized hypoglossal nerve in vivo was significantly retarded by the administration of anti-IL-6R antibody. Surprisingly, accelerated regeneration of the axotomized nerve was achieved in transgenic mice constitutively expressing both IL-6 and IL-6R, as compared with nontransgenic controls. These results suggest that the IL-6 signal may play an important role in nerve regeneration after trauma in vivo. PMID- 8676084 TI - HLA-DR4-IE chimeric class II transgenic, murine class II-deficient mice are susceptible to experimental allergic encephalomyelitis. AB - To investigate the development of HLA-DR-associated autoimmune diseases, we generated transgenic (Tg) mice with HLA-DRA-IE alpha and HLA-DRB1*0401-IE beta chimeric genes. The transgene-encoded proteins consisted of antigen-binding domains from HLA-DRA and HLA-DRB1*0401 molecules and the remaining domains from the IE(d)-alpha and IE(d)-beta chains. The chimeric molecules showed the same antigen-binding specificity as HLA-DRB1*0401 molecules, and were functional in presenting antigens to T cells. The Tg mice were backcrossed to MHC class II deficient (IA beta-, IE alpha-) mice to eliminate any effect of endogenous MHC class II genes on the development of autoimmune diseases. As expected, IA alpha beta or IE alpha beta molecules were not expressed in Tg mice. Moreover, cell surface expression of endogenous IE beta associated with HLA-DRA-IE alpha was not detectable in several Tg mouse lines by flow cytometric analysis. The HLA-DRA-IE alpha/HLA-DRB1*0401-IE beta molecules rescued the development of CD4+ T cells in MHC class II-deficient mice, but T cells expressing V beta 5, V beta 11, and V beta 12 were specifically deleted. Tg mice were immunized with peptides, myelin basic protein (MBP) 87-106 and proteolipid protein (PLP) 175-192, that are considered to be immunodominant epitopes in HLA-DR4 individuals. PLP175-192 provoked a strong proliferative response of lymph node T cells from Tg mice, and caused inflammatory lesions in white matter of the CNS and symptoms of experimental allergic encephalomyelitis (EAE). Immunization with MBP87-106 elicited a very weak proliferative T cell response and caused mild EAE. Non-Tg mice immunized with either PLP175-192 or MBP87-106 did not develop EAE. These results demonstrated that a human MHC class II binding site alone can confer susceptibility to an experimentally induced murine autoimmune disease. PMID- 8676085 TI - The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice. AB - The role of cell-mediated cytotoxicity in the complex pathophysiology of graft versus-host disease (GVHD) has remained poorly defined for several decades. We transplanted T cells from Fas-ligand (FasL)-defective and perforin-deficient mutant donor mice into lethally irradiated MHC-matched allogeneic recipient mice to characterize the role of cell-mediated cytotoxicity in GVHD. Although recipients of allogeneic FasL-defective donor T cells underwent severe GVHD associated cachexia, they exhibited only minimal signs of hepatic and cutaneous GVHD pathology. Recipients of perforin-deficient allogeneic donor T cells developed signs of acute GVHD, but the time of onset was significantly delayed. These findings demonstrate that Fas-mediated anti-recipient cytotoxicity may be critical for the development of hepatic and cutaneous GVHD, but is not required for GVHD-associated cachexia. In addition, perforin-mediated anti-recipient cytotoxicity appears to play an important role in the kinetics of GVHD pathophysiology, but is not required for GVHD-associated tissue damage. PMID- 8676086 TI - The pulmonary alveolar proteinosis in granulocyte macrophage colony-stimulating factor/interleukins 3/5 beta c receptor-deficient mice is reversed by bone marrow transplantation. AB - Mice mutant for granulocyte macrophage colony-stimulating factor (GM-CSF) or the common receptor component (beta c) for GM-CSF, interleukin (IL)-3, and IL-5 exhibit a lung disorder similar to human pulmonary alveolar proteinosis, a rare disease with congenital, infantile, and adult forms. Bone marrow transplantation and hematopoietic reconstitution of beta c mutant mice with wild-type bone marrow reversed the established disease state in the lungs, defining this disease as hematopoietic in nature. It is likely that the disease involves alveolar macrophages, as donor myeloid cell engraftment into the lungs of mutant recipient mice correlated with reverting both the disease and an abnormal macrophage morphology seen in the lungs of affected animals. Recombination Activating Gene-2 mutant donor bone marrow, which lacks the potential to develop lymphocytes, reversed the pathology in the lungs to the same extent as whole bone marrow. These data establish that certain lung disorders, if of cell-autonomous hematopoietic origin, can be manipulated by bone marrow transplantation. PMID- 8676087 TI - IL-10 is necessary and sufficient for autoimmune diabetes in conjunction with NOD MHC homozygosity. AB - Contrary to expectations based on in vitro experiments, we previously found that pancreatic IL-10 did not inhibit autoimmune diabetes but accelerated it in an MHC dependent manner. Therefore, the ability of IL-10 to overcome the absence of all non-MHC diabetes susceptibility (Idd) alleles was studied in transgenic mice expressing pancreatic IL-10 backcrossed to B10.H2g7 congenic mice, which have no Idd alleles other than NOD MHC (H2g7). IL-10 transgenic backcross 1 (BC1) mice with H2g7/g7 haplotype developed clear-cut insulitis and diabetes, but neither transgenic mice with the H2g/b haplotype nor nontransgenic BC1 mice did so. Further implicating IL-10 in autoimmune diabetes, anti-IL-10 antibody treatment inhibited the development of insulitis in NOD mice. These results suggest that IL 10 may be necessary and sufficient for producing autoimmune diabetes in conjunction with NOD MHC homozygosity and that some Idd genes may be related to the regulation of IL-10. PMID- 8676088 TI - A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. AB - A T helper type 1 (Th1)-mediated colitis with similarities to inflammatory bowel disease in humans developed in severe combined immunodeficiency mice reconstituted with CD45RB(high) CD4+ splenic T cells and could be prevented by cotransfer of CD45RB(low) CD4+ T cells. Inhibition of this Th1 response by the CD45RB(low) T cell population could be reversed in vivo by an anti-transforming growth factor (TGF) beta antibody. Interleukin (IL) 4 was not required for either the differentiation of function of protective cells as CD45RB(low) CD4+ cells from IL-4-deficient mice were fully effective. These results identify a subpopulation of peripheral CD4+ cells and TGF-beta as critical components of the natural immune regulatory mechanism, which prevents the development of pathogenic Th1 responses in the gut, and suggests that this immunoregulatory population is distinct from Th2 cells. PMID- 8676089 TI - Protection against lethal toxic shock by targeted disruption of the CD28 gene. AB - Toxic shock syndrome (TSS) is a multi system disorder resulting from superantigen mediated cytokine production. Nearly 90% of the clinical cases of TSS arise due to an exotoxin, toxic shock syndrome toxin-1 (TSST-1), elaborated by toxigenic strains of Staphylococcus aureus. It is clearly established that besides antigen specific signals a variety of costimulatory signals are required for full T cell activation. However, the nature and potential redundancy of costimulatory signals are incompletely understood, particularly with regards to superantigen-mediated T cell activation in vivo. Here we report that CD28-deficient mice (CD28-/-) are completely resistant to TSST-1-induced lethal TSS while CD28 (+/-) littermate mice were partially resistant to TSST-1. The mechanism for the resistance of the CD28 (-/-) mice was a complete abrogation of TNF-alpha accumulation in the serum and a nearly complete (90%) impairment of IFN-gamma secretion in response to TSST 1 injection. In contrast, the serum level of IL-2 was only moderately influenced by the variation of CD28 expression. CD28 (-/-) mice retained sensitivity to TNF alpha as demonstrated by equivalent lethality after cytokine injection. These findings establish an essential requirement for CD28 costimulatory signals in TSST-1-induced TSS. The hierarchy of TSST-1 resistance among CD28 wild-type (CD28+/+), CD28 heterozygous (CD28+/-), and CD28-/- mice suggests a gene-dose effect, implying that the levels of T cell surface CD28 expression critically regulate superantigen-mediated costimulation. Finally, as these results demonstrate the primary and non-redundant role of CD28 receptors in the initiation of the in vivo cytokine cascade, they suggest therapeutic approaches for superantigen-mediated immunopathology. PMID- 8676090 TI - Recombinant human stem cell factor (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo. AB - Stem cell factor (SCF), also known as mast cell growth factor, kit ligand, and steel factor, is the ligand for the tyrosine kinase receptor (SCFR) that is encoded by the c-kit proto-oncogene. We analyzed the effects of recombinant human SCF (r-hSCF, 5-50 micrograms/kg/day, injected subcutaneously) on mast cells and melanocytes in a phase I study of 10 patients with advanced breast carcinoma. A wheal and flare reaction developed at each r-hSCF injection site; by electron microscopy, most dermal mast cells at these sites exhibited extensive, anaphylactic-type degranulation. A 14-d course of r-hSCF significantly increased dermal mast cell density at sites distant to those injected with the cytokine and also increased both urinary levels of the major histamine metabolite, methyl histamine, and serum levels of mast cell alpha-tryptase. Five subjects developed areas of persistent hyperpigmentation at r-hSCF injection sites; by light microscopy, these sites exhibited markedly increased epidermal melanization and increased numbers of melanocytes. The demonstration that r-hSCF can promote both the hyperplasia and the functional activation of human mast cells and melanocytes in vivo has implications for our understanding of the role of endogenous SCF in health and disease. These findings also indicate that the interaction between SCF and its receptor represents a potential therapeutic target for regulating the numbers and functional activity of both mast cells and cutaneous melanocytes. PMID- 8676091 TI - In vitro correction of JAK3-deficient severe combined immunodeficiency by retroviral-mediated gene transduction. AB - Mutations affecting the expression of the Janus family kinase JAK3 were recently shown to be responsible for autosomal recessive severe combined immunodeficiency (SCID). JAK3-deficient patients present with a clinical phenotype virtually indistinguishable from boys affected by X-linked SCID, a disease caused by genetic defects of the common gamma chain (gamma c) that is a shared component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. The specific interaction of JAK3 and gamma c represents the biochemical basis for the similarities between these two immunodeficiencies. Both forms of SCID are characterized by recurrent, severe infections leading to death in infancy unless successfully treated by allogeneic bone marrow transplantation. Because of the potentially lethal complications associated with allogeneic bone marrow transplantation and the frequent lack of suitable marrow donors, the development of alternative forms of therapy is highly desirable. To this end, we investigated a retroviral-mediated gene correction approach for JAK3-deficiency. A vector carrying a copy of JAK3 cDNA was constructed and used to transduce B cell lines derived from patients with JAK3-deficient SCID. We demonstrate restoration of JAK3 expression and phosphorylation upon IL-2 and IL-4 stimulation. Furthermore, patients' cells transduced with JAK3 acquired the ability to proliferate normally in response to IL-2. These data indicate that the biological defects of JAK3-deficient cells can be efficiently corrected in vitro by retroviral-mediated gene transfer, thus providing the basis for future investigation of gene therapy as treatment for JAK3-deficient SCID. PMID- 8676092 TI - A novel anti-Vpre-B antibody identifies immunoglobulin-surrogate receptors on the surface of human pro-B cells. AB - Vpre-B and lambda 5 genes, respectively, encode V-like and C-like domains of a surrogate immunoglobulin light chain (psi L). Such psi L complex is expressed in early progenitor B (pro-B) cells, before conventional immunoglobulin heavy (microH) and light (L) chains are produced. We raised a wide panel of monoclonal antibodies (mAbs) against soluble recombinant Vpre-B proteins to study early events in human B cell development. One of these antibodies, B-MAD688, labeled surrogate Ig-complexes on the surface of microH- pro-B cell lines and normal bone marrow cells in immunofluorescence assays. Immunoprecipitations using surface labeled pro-B cells and B-MAD688 mAb indicated that human psi L is associated with high molecular weight components homologous to the surrogate heavy (psi H) chains described in mouse. Using B-MAD688 and SLC2 mAbs, we were able to distinguish between psi H psi L and microH psi L complexes on the surface of human pro-B and later precursor, pre-B, cells. The finding of psi H psi L complexes in mouse and man lead us to hypothesize a role for psi H-containing receptors in B cell development. PMID- 8676093 TI - The multidrug resistance phenotype confers immunological resistance. AB - Multidrug resistance (MDR), which is due, in part, to the overexpression of P glycoprotein, confers resistance to a variety of natural product chemotherapeutic agents such as daunorubicin, vincristine, and colchicine. RV+ cells are a P glycoprotein overexpressing variant of the HL60 myeloid leukemia cell line. In addition to classic MDR, RV+ cells displayed relative resistance to complement mediated cytotoxicity with both immunoglobulin G and M antibodies against different cell surface antigens, but not to antibody-dependent cellular cytotoxicity and lymphokine-activated killing. Complement resistance was reversed both by treatment with verapamil and with specific monoclonal antibodies (mAbs) capable of binding to P-glycoprotein and blocking its function. To further confirm that the resistance of RV+ cells was not a consequence of the selection of the cells on vincristine, a second system involving P-glycoprotein infectants was also investigated. K562 cells infected with the MDR1 gene, which were never selected on chemotherapeutic drugs, also displayed relative resistance to complement-mediated cytotoxicity. This MDR1 infection-induced resistance was also reversed by mAbs that bind to P-glycoprotein. Therefore, the MDR phenotype as mediated by P-glycoprotein provides resistance to complement-mediated cytotoxicity. The increased intracellular pH and the decreased membrane potential due to the MDR phenotype may result in abnormal membrane attack complex function. This observation may have implications for the possible mechanisms of action of P glycoprotein and for a possible physiologic role for P-glycoprotein in protection against complement-mediated autolysis. PMID- 8676094 TI - Cloning and characterization of 5E6 (Ly-49C), a receptor molecule expressed on a subset of murine natural killer cells. PMID- 8676095 TI - Developmental biology of the vertebrate heart. AB - This paper summarizes the development of the heart from the formation of the heart mesoderm to cardiac septation. A brief account of morphological changes is provided, but attention is focused on mechanisms rather than on morphologic descriptions. Heart induction and differentiation, and the expression of cardiac specific proteins, are reviewed. New developments in these areas include the possible role of cell surface proteins and peptide growth factors in the segregation of the splanchnic mesoderm and in cardiac commitment. Past and recent experiments indicate that the heart morphogenetic information is engraved in the precardiac mesoderm. In spite of this, specific differentiative signals can be overriden experimentally demonstrating the unstability of the cardiac phenotype at the early heart tube stage. The relationship between differentiation and morphogenesis is analyzed. While cardiac differentiation appears to be a prerequisite for morphogenesis, a number of experiments indicate that differentiation can proceed in the absence of any morphogenesis. Formation of the heart loop is separated into two different components; looping itself and the acquisition of handedness. Late heart morphogenesis is explained in terms of differential tissue growth and tissue remodeling. This not only includes morphogenetic changes intrinsic to the heart but the addition of new cell types (neural crest, epicardium, vessels, nerves) that become integrated into the developing heart. The contribution of specific mechanisms to our understanding of heart development, such as cell death and hemodynamics is also analyzed. PMID- 8676096 TI - Gravity, blood circulation, and the adaptation of form and function in lower vertebrates. AB - Gravitational force influences musculoskeletal systems, fluid distribution, and hydrodynamics of the circulation, especially in larger terrestrial vertebrates. The disturbance to hydrodynamics and distribution of body fluids relates largely to the effects of hydrostatic pressure gradients acting in vertical blood columns. These, in turn, are linked to the evolution of adaptive countermeasures involving modifications of structure and function. Comparative studies of snakes suggest there are four generalizations concerning adaptive countermeasures to gravity stress that seem relevant to lower vertebrates generally. First, increasing levels of regulated arterial blood pressure are expected to evolve with some relation to gravitational stresses incurred by the effects of height and posture on vertical blood columns above the heart. Second, aspects of gross anatomical organization are expected to evolve in relation to gravitational influence incurred by habitat and behavior. Third, natural selection coupled to gravitational stresses has favored morphological features that reduce the compliance of perivascular tissues and provide an anatomical "antigravity suit." Fourth, natural selection has produced gradients or regional differences of vascular characteristics in tall or elongated vertebrates that are active in high gravity stress environments. Consideration or awareness of these principles should be incorporated into interpretations of structure and function in lower vertebrates. PMID- 8676097 TI - Distribution and molecular forms of urotensin II and its role in cardiovascular regulation in vertebrates. PMID- 8676098 TI - Epilogue: comparative cardiovascular biology of lower vertebrates. PMID- 8676099 TI - Ultrasonography characterization of heart morphology and blood flow of lower vertebrates. AB - Echocardiography is an noninvasive technique that utilizes high frequency ultrasound to evaluate structural, functional, and hemodynamic status of the cardiovascular system. With all the inherent potentials of this technique, its application has not been explored on lower vertebrates. The objective of our work was to apply ultrasonography technique, with an available commercial equipment (Echo camera--Aloka SSD 830 and Toshiba using probes of 5 and 7.5 MHz frequency emission) and to identify and characterize cardiac structures and blood flow in lower vertebrates. Specimens studied were Lophius piscatorius, Halobatrachus didactylus, and Bufo bufo. The probe was applied on the ventral middle line over heart chambers. Two-dimensional images were obtained from long and short axis incidences at various levels of cardiac chambers. During each cardiac cycle and for every specimen it was possible to identify the relation between each structure, to measure longitudinal and transversal diameters, to identify blood fluxes, and measure their velocities. The work we describe and discuss in our preliminary experience and data concerning the ultrasound study of some lower vertebrates. The cardiovascular apparatus of the different species we studied was a dynamic, phasic, and efficient contraction and relaxation mechanism. The phenomena could be well documented with two-dimensional echocardiography. The effect of the coupling phenomena of contraction and relaxation was also studied through the application of pulsed and color Doppler ultrasound. Two-dimensional and Doppler echocardiography can be easily applied to the study of the anatomy, morphology, and physiology of lower vertebrates. Well defined structures and cardiac chambers were displayed with this noninvasive imaging technique. Echo Doppler ultrasonography is a reliable technique in these lower vertebrate specimens, to study cardiac structure and kinetics, and to identify and measure blood flow velocity. It can be used as an experimental model for cardiac function. PMID- 8676100 TI - Anatomy, histology, and development of the cardiac valvular system in elasmobranchs. AB - We report here on the anatomy, histology, and development of the three sets of cardiac valves in embryonic and adult elasmobranch fishes. The sinus venosus is the first segment of the heart to receive blood, and a pair of sinoatrial (SA) valves prevent backward flow of blood into the sinus venosus. The SA valves derive from two dorsolateral infoldings of the cardiac wall and consist of a simple endocardium covering transverse sheets rich in collagen. The SA valves are simple flaps of tissue without papillary muscles or chordae tendineae. Blood from the atrium passes the atrioventricular (AV; semilunar) valves, which are attached to papillary muscles in the ventricle by way of the chordae tendineae. A series of rows of conal or pocket valves (CV) in the conus arteriosus, equipped with chordae tendineae but no papillary muscles, prevent blood from reentering the ventricle. Chordae tendineae form in a similar fashion in both chambers. Elevations from the chamber wall emerge as a sheet covered on both surfaces with endocardium and separated by a core of connective tissue. Endocardial cells extend basal projections toward the opposing epithelium through their basal laminae. Basal cell projections make contact to create perforations that enlarge to produce spaces between the nascent chordae. Fibroblasts in the core of the chordae enlarge and strengthen the chordae by producing linear arrays of collagen fibers. PMID- 8676101 TI - Mechanism of zinc homeostasis. AB - Homeostatic equilibrium of a nutrient is characteristic of a healthy body. For zinc, phytate has been shown to alter that equilibrium in several monogastric species including man. The pancreas is an important organ in the maintenance of zinc homeostasis. Elevated calcium has been shown to be a synergistic agent in affecting the rate of onset and rate of homeostatic change. In the studies described, rats were depleted of zinc to differing extents, zinc was injected intraperitoneally to label the endogenous zinc pool. Phytate- and nonphytate containing protein diets were fed and feces were collected. Feces were counted for radioactivity. The ratios of radioactivity (phytate:nonphytate) indicated that the major effect of phytate was on the endogenous secreted pool. Evidence is included to indicate that two, pancreatic labile pools of zinc are secreted, one is stable complexes not affected by phytate and two, a labile pool of zinc readily available for complexation. A mathematical model is included that fits all nutritional models for zinc homeostasis. PMID- 8676102 TI - Reaction of metallothionein with ethylenediamine-N,N,N',N'-tetraacetic acid. AB - The reactions of various rabbit MTs (Cd7Th, Zn7Th, Hg7Th, Bi7Th, Pb7Th) with EDTA were studied at different pH and EDTA concentrations, and were determined to be pseudo-first-order reactions. The reactions were all divided into two steps: one faster and EDTA-dependent, and the other EDTA-independent. The mechanism is also described in detail. Based on obtained results, the varied induction behaviors of MT formation for those metals are discussed. PMID- 8676103 TI - Metal-ion binding properties of the transferrins: a vanadium-51 NMR study. AB - Transferrins can bind a wide range of di- and trivalent metal ions. They have a bilobal structure where each domain contains a deep cleft that binds a metal ion along with a synergistic anion. In this work, the binding of vanadate as VO2+ to the transferrins was studied by 51V quadrupolar central transition (QCT) NMR. Information about differences in the symmetry and motion of the bound metal ion was obtained from chemical shift and line width differences for serotransferrin (sTf), lactoferrin (lTf), and ovotransferrrin(oTf). The effects of pH, ionic strength, and temperature on the 51V QCT NMR spectra of the bound VO2+ cations showed that the N-lobe binding site of sTf is unique as compared to the other proteins. Properties of the quadrupolar central transition were also investigated, revealing that temperature, magnetic field strength, and NMR pulse angle all induce predictable changes on the second-order dynamic frequency shift, spectral line width, and optimal pulse angle in the 51V NMR spectra. Analysis of NMR spectra of V(V)2-oTf and V(V)2-sTf at three magnetic fields allowed an estimation of the quadrupolar coupling constants for these binding sites. This indicates that the degree of coordination symmetry in the binding sites is as follows: sTf N < sTf C < oTf N, C. Carbon-13 NMR studies revealed that VO2+ binding, in contrast to di- and trivalent metal ions, has no requirement for a synergistic anion. PMID- 8676104 TI - The inhibition of bovine xanthine oxidase activity by Hg2+ and other metal ions. AB - The inhibition of the activity of bovine xanthine oxidase (XO) by divalent mercury and other metal ions has been investigated by optical spectroscopy and stop-flow kinetic measurements. The study shows that Hg2+ ion completely inhibits the activity of XO, while other metal ions such as Zn2+, Mg2+, Co2+, and Ni2+ inhibit the activity only marginally (approximately 10%). The inhibition by the Hg2+ ion was found to be monophasic and noncompetitive with strong affinity for binding to XO. The pH-dependent study of the inhibition indicates that at least two ionizing groups of XO are involved in the binding of the Hg2+ ion. PMID- 8676105 TI - Unusual reactivity of cisplatin analogs that bear o-phenylenediamine ligands: insights for the design of more effective cytotoxic agents. AB - The stabilities of dichloro(o-phenylenediamine)platinum(II) (1) and several 4,5 disubstituted analogs [i.e., with: Cl (2), Br (3), Me (4), or MeO (5)] were investigated under various aqueous conditions. The Pt complexes 1-5- decomposed by reactions which were independent of the amount of chloride in the medium. The poor aqueous stabilities of 1-5 were attributed to two factors: 1) The compounds underwent facile oxidation reactions in aqueous solution at pH 7.4 and 37 degrees C, resulting in the formation of intensely colored Pt-species as well as H2O2. Compounds 2 and 3 oxidized considerably faster than 1, 4, and 5. Based on the redox behavior and UV-Vis spectra of the decomposition products, it is proposed that they are o-benzoquinonediimine Pt complexes. 2) Compound 4 underwent an unusually rapid substitution reaction with L-methionine, a component of the culture medium, whereby both of the chloro ligands of platinum were replaced by an N,S-chelated methionine. At an L-methionine concentration of 0.5 mM, the reaction ran to completion within 1 min. Thus, the weak growth inhibitory activities of 1-5 on human cancer cells in vitro was likely a result of their poor chemical stability in the culture medium. Based on a knowledge of the decomposition pathways, analogs were designed to be resistant to these types of reactions. Dichloro(o-aminomethylaniline)platinum(II) (6) and [bis 1,2(aminomethyl)benzene]-di-chloroplatinum(II) (7) were synthesized and their aqueous stabilities investigated. Both 6 and 7 were considerably more stable than 1-5 under aqueous conditions, as well as being more effective in inhibiting the growth of human cancer cells in vitro. PMID- 8676106 TI - Fixation of the acetabular component: the case for cement. PMID- 8676107 TI - Effect of medial displacement of the tibial tubercle on patellar position after rotational malposition of the femoral component in total knee arthroplasty. AB - A large Q angle induced by technical error such as an internally rotated femoral component causes patellar failure after total knee arthroplasty. The effect of medial displacement of the tibial tubercle to decrease the Q angle for patellar tracking was studied by evaluating the patellar position relative to the patellar groove on the femoral component in cadaver specimens. A 5 degrees internally rotated femoral component caused the patella to shift medially about 5 mm, and also caused the tibia to rotate internally about 3 degrees at full extension. With a 5 degrees externally rotated femoral component, normal patellar tracking occurred. The distance of medial displacement was determined so that the patellar tendon was parallel to the longitudinal axis of the tibia at full extension. This allowed the quadriceps tendon, the patella, and the patellar tendon to form a straight line. The average distance of medial transposition of the tibial tubercle was 9.32 mm. Medialization of the tibial tubercle caused the patella to shift about 2 mm medially from the patellar groove. The transfer also caused an external rotation of the tibia (2 degrees-5 degrees). Medial transfer of the tibial tubercle changes patellar kinematics and corrects the tendency toward lateral patellar dislocation caused by internally rotating the femoral component; however, it also creates minor patellar and tibial kinematic changes that may have a clinical effect. PMID- 8676108 TI - The Porous-Coated Anatomic total knee experience. Special emphasis on complications and wear. AB - One hundred sixty knees in 141 patients with the Primary Porous-Coated Anatomic prosthesis (Howmedica, Rutherford, NJ) were evaluated after a follow-up period of 5.6 years (range, 1-10 years). One hundred six knees were in the latest follow-up evaluation, including clinical examination and a defined standing radiograph with a follow-up period of 6.3 years (range, 3-10 years). Survivorship analysis regarding the cumulative revision rate (including completion with a patellar component) was 0.88 at the 8-year and 0.84 at the 10-year follow-up examination. The clinical result was satisfying/good, with a mean Hospital for Special Surgery score of 83 (range, 39-97). Five percent had thinning greater than 30% of the tibial component. The wear was calculated to be 1.0 mm (range, 0-9 mm), including three revised tibial components with heavy wear. Excluding the revised cases, the wear was 0.7 mm. PMID- 8676109 TI - Total hip arthroplasty complicated by tuberculous infection. AB - The case of a 66-year-old woman with tuberculous infection complicating a total hip arthroplasty that had been performed 4 years previously for degenerative arthritis is reported. The patient had no prior history of exposure to tuberculosis and no evidence of skeletal or nonskeletal tuberculous infection. The need for a high index of suspicion when dealing with unexpected arthroplasty failure is emphasized. Tuberculous cultures are recommended in these cases prior to revision surgery. PMID- 8676110 TI - Mycobacterium chelonae infection following a total knee arthroplasty. AB - Infection following total knee arthroplasty is a major cause of implant failure, with an incidence of infections between 1 and 12%. Although there have been no previously reported cases of infection with Mycobacterium chelonae following total knee arthroplasty, this mycobacterium appears to be a potential pathogen in arthroplasty. When infection following total knee arthroplasty is evident but standard cultures come back negative, atypical mycobacterium infection should be considered. Mycobacterium chelonae does not grow in the normally allotted culture time, so false negative results are common. Once identified, M. chelonae is difficult to treat because of its resistance to standard drug therapies. Details of the first reported successful diagnosis and treatment of an infection with M. chelonae following a total knee arthroplasty are reported. PMID- 8676111 TI - Tibial shaft fracture following tibial tubercle osteotomy. AB - Tibial tubercle osteotomy has been reported to be an excellent exposure for a very stiff primary or revision knee requiring total knee arthroplasty. In 1993, the Center for Hip and Knee Surgery performed 657 primary and 16 revision total knee arthroplasties, using tibial tubercle osteotomy in 9 cases, 2 of which sustained tibial shaft fractures, because of which the Center's experience is reviewed. PMID- 8676112 TI - Ultrasonically driven tools. AB - Ultrasonically driven tools have been employed extensively in revision hip surgery during the last 2 years at the Nuffield Orthopaedic Centre. In combination with hand revision instruments, the removal of cement, in particular the removal of the distal cement plug, has been made safer. One significant complication that has occurred with this device is reported and advice on its prevention offered. PMID- 8676113 TI - Acetabular wear. PMID- 8676114 TI - Cementless total knee arthroplasty in rheumatoid arthritis. A report on 51 AGC knees followed for 54 months. AB - Fifty-one primary consecutive cementless AGC 2000 (Anatomically Graduated Components, Biomet, Warsaw, IN) total knee arthroplasties were performed during 1985 through 1990 in 40 patients with rheumatoid arthritis. Forty-one knees (32 patients) were available for clinical and radiologic follow-up analysis after 24 to 76 months (median, 54 months). There was no pain in 33 knees and mild pain in the rest. Median range of motion was 110 degrees (range, 50 degrees-130 degrees). Median knee score was 90 (range, 71-97), and all knees were rated good or excellent. Radiolucencies greater than 1 mm were found under five tibial components, but no obvious migrations were seen. One tibial component was revised due to aseptic loosening. The cumulative success rate after 4 to 5 years was 97% (lower limit of 95% confidence interval, 91.8%). The medium-term results are considered to compare favorably with reported cemented series. PMID- 8676115 TI - Early radiographic results comparing cemented and cementless total hip arthroplasty. AB - In a randomized clinical trial of cemented and cementless total hip arthroplasty, 147 patients (76 cemented, 71 cementless) have had a minimum 4-year clinical and radiographic follow-up evaluation. No revisions have been done in either group. Two cemented acetabular components were considered definitely loose and 18 were probably loose; 7 cemented stems were possibly loose at last follow-up examination. One cementless socket was considered unstable. Although cementless femoral component subsidence occurred in 10 cases, the sinkage always stabilized within 6 months, and no stem was considered unstable at last follow-up examination. Significant femoral bone resorption was rare, and so-called "spot welds" were uncommon using this titanium stem. Distal cortical hypertrophy was common, but the cause is uncertain. Osteolysis was seen around 10 cementless and 6 cemented sockets. A small area of lysis occurred in the proximal medial femoral neck in 15 cemented stems and 1 cementless stem. No cases of distal femoral lysis were seen in either group. Despite excellent clinical results with no difference between groups, the high rate of early radiographic failure of this metal-backed acetabulum should preclude its use. Osteolysis will continue to be a problem in both groups, and its prevention should remain the focus of future studies. PMID- 8676116 TI - Fixation of the acetabular component: the case for cementless bone ingrowth modular sockets. PMID- 8676117 TI - Indications for total hip and total knee arthroplasties. Results of orthopaedic surveys. AB - A lack of consensus regarding the indications for total hip arthroplasty (THA) and total knee arthroplasty (TKA) has been cited as one reason for the variations in the rates of THA and TKA across the United States. The purposes of this study were to survey orthopaedists in a specific geographic area (New York City) regarding the candidacy of patients with osteoarthritis for THA or TKA and to compare indications for THA between orthopaedists at two academic medical centers, The Hospital for Special Surgery in the United States and McGill University in Canada. Orthopaedists were sent mail surveys asking about indications, factors affecting outcomes, and factors that might modify decisions for surgery. Approximately 45% of orthopaedists who performed THA and TKA in New York City in 1992 completed the surveys. Although there were wide variations among surgeons, most surgeons required at least severe pain daily, rest pain several days per week, transfer pain either several days per week (THA) or daily (TKA), and destruction of most of the joint space on radiograph. Younger age, comorbidity, technical difficulties, and lack of motivation modified the decision against surgery, whereas the desire to be independent and return to work swayed the decision for surgery. Most surgeons rated that patients with severe pain, osteoarthritis, or rheumatoid arthritis would have a high likelihood of an excellent outcome, whereas those with comorbidity and certain technical factors would have only a moderate likelihood of an excellent outcome. In the U.S. Canadian survey of THA, in which more than 90% of surgeons responded, Canadian surgeons tended to require more frequent pain and use of assistive devices for walking. Although there was a majority of opinion for several indications, there was no clear consensus among surgeons regarding the indications for THA and TKA. Possible explanations for this are that isolated indications are not as important as integrating and weighing several indications and that the patient's desire to proceed with THA or TKA is an important driving force in the decision to operate. PMID- 8676118 TI - Correlation of patient questionnaire responses and physician history in grading clinical outcome following hip and knee arthroplasty. A prospective study of 201 joint arthroplasties. AB - Questionnaires are commonly used in orthopaedic outcome studies. This study sought to determine if responses to a simple standardized questionnaire correlated with responses obtained during a physician interview in evaluation of clinical outcome following hip and knee arthroplasty. One hundred sixty-two patients with 201 hip and knee arthroplasties were asked to fill out a questionnaire prior to returning for routine follow-up evaluation. There was a highly significant correlation (P < .0001, r = .74) between scores calculated from patient responses on the questionnaire and those calculated from responses recorded during the subsequent physician visit. There was no significant difference between patient and physician clinical hip scores, but physicians gave significantly higher knee scores than patients for both long- ( > 4.5 years, P < .05) and short-term ( < or = 4.5 years, P < .0001) follow-up periods; however, 97% of patient responses were within one grade of physician-recorded answers to the same questions. Eight and one-half percent of scores differed in overall evaluation from good-excellent to fair-poor categories. This study both validates and defines more clearly the limitations of questionnaires for follow-up evaluation of clinical results following total hip and knee arthroplasty. PMID- 8676119 TI - Heterotopic ossification. Incidence in cemented versus cementless total hip arthroplasty. AB - To resolve the debate whether cementless total hip arthroplasty (THA) carries an increased risk of heterotopic ossification (HO) as compared with cemented THA, 100 patients undergoing primary cemented THA (both acetabulum and femur) were individually matched to 100 patients undergoing primary cementless THA. Preoperative, 6-week postoperative, and 2-year postoperative radiographs were reviewed for the presence of HO using the Brooker classification. No subject in either group received any postoperative prophylaxis for HO. The matching parameters were age ( +/- 10 years), sex, weight ( +/- 10 lb.), diagnosis (all were osteoarthritis), Charnley class (A/B), and surgical approach (trochanteric osteotomy or modified Hardinge). The overall incidence of HO was 68% in the cemented group and 65% in the cementless group. The extent of HO (grade III) was significant in 9% of the cemented group and 5% of the cementless group. There was no grade IV HO (bone ankylosis) in either group. Neither the overall incidence nor the incidence of grade III HO was statistically different between the two groups. Patient sex and surgical approach had no interactive effect with type of component fixation on the incidence of HO. Fear of HO should not be a factor in the choice of fixation for THA. PMID- 8676120 TI - Aspiration arthrography of the hip joint. Its uses and limitations in revision hip surgery. AB - Seventy-one patients undergoing revision hip surgery over a 5-year period from 1988 to 1993 had aspiration arthrography of the hip as a preoperative investigation. Sixteen hips were found to be infected at operation. Preoperative aspiration yielded positive cultures in 11 of these 16 hips. There was identical correlation between the organisms isolated on aspiration and during surgery. There were 5 false positive cultures from the aspirates of the remaining 55 noninfected hips. All of the hips from which a true positive culture was obtained had either clinical or radiologic evidence suggestive of infection. Aspiration arthrography does not have a major role to play as a routine investigation prior to all revision hip surgery. It is recommended that its use be reserved for those hips in which there is either clinical, hematologic, or radiologic evidence of infection. PMID- 8676121 TI - Influence of patellar thickness on patellar tracking and patellofemoral contact characteristics after total knee arthroplasty. AB - Although total knee arthroplasty (TKA) has become a very common procedure, patellar problems remain a major cause of disability. Patellar thickness is one of the most challenging factors. The influence of patellar thickness on patellofemoral kinematics and contact characteristics following TKA was investigated. Seven unembalmed whole-lower-extremity cadaveric specimens were used. The kinematics was measured with a magnetic tracking device (3Space Tracker System, Polhemus Navigation Sciences Division, Colchester, VT). Contact area was calculated from the kinematic data and the digitized joint surface geometrics based on a theoretical method. The patellofemoral joint contact force was measured directly using a uniaxial force transducer. Kinematically, the influence of patellar thickness on patellar flexion, rotation, and proximodistal shift was not significant. Orthopaedic surgeons are often challenged by derangement of the patellofemoral joint, especially following TKA. It is commonly assumed that restoration of overall patellar thickness is most desirable. A thin patella can reduce the contact force, but it also poses the potential risks of stress fracture and anteroposterior instability. Increasing patellar thickness might be expected to increase the effective quadriceps moment arm at low flexion angles of the knee, but potentially reduces the range of motion of the knee and predisposes to patellar subluxation. Either a thicker or a thinner patella had a smaller contact area than intact and normal-thickness patella. Therefore, the surgical technique of patellar resurfacing during TKA should attempt to reproduce the original patellar thickness. PMID- 8676122 TI - Survivorship analysis of cemented total condylar knee arthroplasty. A long-term follow-up report on 348 cases. AB - Survivorship analysis was used in the evaluation of 348 consecutive primary total condylar knee arthroplasties (total knee arthroplasties) performed on 253 patients in a 27-month period, with a maximum follow-up period of 12 years. The diagnosis was osteoarthrosis in 184 cases and rheumatoid arthritis in 164 cases. Ten patients (10 total knee arthroplasties) were lost to follow-up evaluation. The endpoint was defined as prosthesis not in situ. The variables considered were age, sex, body mass index, and diagnosis. The overall cumulative survival rate was 92%. The survival rate of the osteoarthrosis group was significantly higher (97%) than that of the rheumatoid arthritis group (87%). None of the other variables affected survival rate significantly. PMID- 8676123 TI - Total hip arthroplasty with shelf grafts using uncemented cups. A long-term follow-up study. AB - A series of 33 hips treated with cementless cups and structural autograft or allograft were reviewed at a minimum follow-up period of 5 years. Seventeen hips received a shelf autograft during primary hip arthroplasty and 16 received an allograft at revision. In the hips receiving autografts, the average preoperative hip score was 45.1 and the score at final review was 87.5, whereas in the revisions reconstructed with allografts, the average preoperative hip score was 44.4 and the score at final review was 82. Overall, only 2 of 33 hips were considered failures, giving a success rate of 94% at an average follow-up period of 6.6 years. Leg-length discrepancy greater than 2 cm was seen in 27 of 33 hips, and at final review only 4 of 33 hips had a leg-length discrepancy greater than 2 cm. All grafts united to host-bone. Resorption, when seen, was minor, with only three grafts showing moderate resorption. Our data support the use of cementless cups with structural allografts and autografts, provided the graft supports less than 50% of the cup. PMID- 8676124 TI - Revision total hip arthroplasty with shelf bulk allografts. A long-term follow-up study. AB - A series of 29 shelf ( < 50% of the acetabulum) structural allografts were done in conjunction with acetabular revision with a minimum follow-up period of 5 years (average, 7.1 years). At the latest follow-up examination, 86% of the hips were successful both clinically and radiologically. Only four patients required further surgery, with two of these being revised with no additional grafts. The use of bulk allograft in conjunction with acetabular revision is supported, provided that at least 50% support of the cup can be obtained with host-bone. This type of reconstruction provides support for the cup and restores anatomy, leg length, and bone stock should future revision be necessary. PMID- 8676125 TI - Treatment of type III acetabular deficiencies in revision total hip arthroplasty without structural bone-graft. AB - The use of structural bone allografts has been advocated for the reconstruction of type III acetabular defects, but the results reported for this method have shown revision rates from 20 to 30% and failure rates averaging 50% at short-, to intermediate-term follow-up periods. A prospective study was undertaken to determine the results of reconstructing type III defects without structural allograft and to compare the results using spherical components with the results using eccentric components. Quantitative inclusion criteria were developed and applied to all hips undergoing revision arthroplasty between 1987 and 1991. Twenty-one hips (20 patients) were identified and included in this study. An evaluation protocol including radiographs, and for defects greater than 30 mm, computed tomography scans and three-dimensional models, was used. At an average follow-up period of 46 months, 19 hips (18 patients) were evaluated. Hip scores of these patients improved from 46 to 75. The location of the hip center was improved to a greater degree in those hips with revised to eccentric components, but implant stability was poor. Overall, the mechanical failure rate was 26%, the clinical failure rate was 16%, and the revision rate was 11%. These results compare favorably with the results of reconstruction using structural graft at the same length of follow-up time. Good results can be achieved by reconstructing type III defects without structural allograft if a cementless spherical component can be placed in stable position on host-bone. PMID- 8676126 TI - Decreased posterior tibial slope increases strain in the posterior cruciate ligament following total knee arthroplasty. AB - The purpose of this study was to measure the strain in the posterior cruciate ligament as a function of knee flexion angle and posterior tibial slope following total knee arthroplasty with a posterior cruciate ligament-retaining design. Posterior cruciate ligament strain was measured in seven fresh-frozen cadavers for posterior tibial slopes of 10 degrees, 8 degrees, and 5 degrees. For all three levels of tibial slope tested, strain in the posterior cruciate ligament increased with increasing flexion angle to approximately 100 degrees and then decreased with increasing flexion. The strain measured at 8 degrees posterior tibial slope was greater than that measured at 10 degrees, but the difference was not significant. The strain measured at 5 degrees posterior slope was significantly greater than strain measured at both 8 degrees and 10 degrees. This increased strain may result in altered knee kinematics and reduced range of motion at higher flexion angles. PMID- 8676127 TI - Effects of various isoquinoline alkaloids on in vitro 3H-dopamine uptake by rat striatal synaptosomes. AB - Various alkaloids having an isoquinoline skeleton from different species of the Annonaceae, Fumariacae, and Aristolochiacae (aporphine, cularine, benzylisoquinoline, and bisbenzylisoquinoline derivatives) were tested for their ability to inhibit in vitro 3H-dopamine uptake by rat striatal dopamine D1 3H-SCH 23390 AND D2 3H-raclopride binding sites. Except for some aporphine derivatives (anonaine [1], norstephalagine [2], isopiline [3]) and some bisbenzylisoquinoline alkaloids (dimethylgrisabine [27], antioquine [28], obaberine [29], isotetrandrine [30]) that displayed affinities of the same order as the reference compounds (nomifensine [38], amineptine [39], dexamphetamine [40]), the other tested products had low, or no, affinity on the 3H-dopamine uptake since, in comparison, its affinity at dopamine D1 3H-SCH 23390 and D2 3H-raclopride binding sites was low. These data suggest that it could be possible to synthesize anonaine-like products displaying intense dopamine-uptake inhibitory properties, which could lead to a potential antidepressant activity. PMID- 8676128 TI - Phospholipase D inhibitors from a Myrsine species. AB - The phospholipase D-inhibitory activity of a methanol extract from the leaves of a New Zealand plant, Myrsine australis, has been attributed to two new saponins 1 and 2. Compound 1 was assigned as 3-0-[-beta-D-xylopyranosyl-(1-->2)-0-beta-D glucopyranosyl-(1-->4)- -[0-beta-D -glucopyranosyl-(1-->2)]-alpha-L-arabinosyl] 16alpha-hydroxy-+ ++13beta,28-epoxyoleanane and 2 as 3beta-0-[-beta rhamnopyranosyl-(1-->2)-0-beta-D-glucopyranosyl-(1-->4)-[ 0-beta-D-glucopranosyl] alpha-L-arabinopyranosyl]-16alpha -hydroxy-13beta, 28-epoxyleanane. Compounds 1 and 2 showed IC50 values of 3 and 2 microM, respectively, versus phorbol 12 myrisate-13-acetate-stimulated phosphlipase D in human promyelocytic leukemic (HL 60) cells. Compounds 1 and 2 also inhibited fMLP (formyl-Met-Leu-Phe) stimulated phospholipase D with IC50 values of 8 and 24 microM, respectively. PMID- 8676129 TI - 13-O-acetylvakhmatine, a new diterpenoid alkaloid from the seeds of Consolida ambigua. AB - Vakhmatine [1] and the new diterpenoid alkaloid 13-O-acetylvakhmatine [3] have been isolated from the polar alkaloidal fractions of the seeds of Consolida ambigua, together with ajacine, delcosine, gigactonine, and takaosomine. Structure 3 has been established on the basis of spectroscopic data and chemical correlation with 1. PMID- 8676130 TI - Asimilobin and cis- and trans-murisolinones, novel bioactive Annonaceous acetogenins from the seeds of Asimina triloba. AB - Three new bioactive Annonaceous acetogenins, asimilobin [1], cis-murisolinone [2], and trans-murisolinone [3], have been isolated from an ethanolic extract of the seeds of Asimina triloba by directing the fractionation with brine shrimp lethality. The structure were elucidated based on spectroscopic and chemical methods, In addition, cis- and trans-bullatacinone, which are known compounds, were obtained. Asimilobin [1] has adjacent bis-THF rings, located at C-10 to C-17 and having only one flanking hydroxyl group at C-18. Compounds 1-3 showed cytotoxicity values comparable with adriamycin against six human solid tumor cell lines. PMID- 8676131 TI - Oleanane triterpene saponins from the Chinese medicinal herb Clinopodium chinensis. AB - Four oleanne triterpene saponins, 3beta,16beta, 23-trihydroxy-keton-13beta,28 epoxyolean-9(11)-en-3-yl -[beta-D-glucopranosyl(1-->2)]-[beta-D-glucopyranosyl(1- >3)]-beta -D-fucopyranoside [1] (clinopodiside D), 16beta-propionyl-3beta,23 dihydroxyoleana-11-21-dien-3 -yl-[beta-D-glucopyranosyl(1-->2)]-[beta-D glucopranosyl(1-->3)]-b eta-D-fucopyranoside [2] (clinipodiside E), 3beta,16beta,21alpha,23,28-pentahydroxy-11-methoxyolean++ +-12-en-3-yl-[beta-D glucopyranolyl(1-->2)]-[beta-D-glucopyranosyl (1-->3)]-beta-D-fucopyranoside [3] (clinopodiside F), and 3beta,16beta,21beta,23,28-pentahydroxyoleana-11,13(18) dien-3-yl-[beta-D-glucopyranosyl(1-->2)]-[beta-D-glucopyranosyl(1 -->3)]-beta-D fucopyranoside [4] (clinopodiside G), were isolated and purified from the plant Clinopodium chinensis. Their structures were elucidated on the basis of interpretation of nmr and ms data and from chemical evidence. The results are of potential interest for medicinal reasons. PMID- 8676132 TI - Gummiferol, a cytotoxic polyacetylene from the leaves of Adenia gummifera. AB - A new polyacetylenic diepoxide compound, gummiferol [1] was isolated from the leaves of Adenia gummifera by KB cytotoxicity-guided fractionation. Compound 1 exhibited significant activity against the KB human cell line and a broad cytotoxic spectrum against other human cancer cell lines. The structure of 1 was established primarily on the basis of its spectral data. PMID- 8676133 TI - Triterpenoid saponins from Gypsophila oldhamiana. AB - Three new triterpenoid saponins were isolated from the roots of Gypsophila oldhamiana. Their structures were elucidated, using a combination of homonuclear and heteronuclear 2D nmr and fabms, as 3-0-beta-D-galactopyranosyl-(1-->2)-[beta D-xylopyranolyl-(1-->3)] -beta-D-glucuronopyranosyl quillaic acid methyl ester [1], 3-0-beta-D-galactopyranosyl-(1-->2)-[beta-D-xylopyranosyl-(1-->3)]-beta- D glucuronopyranosyl gypsogenin methyl ester [2], and 3-0-beta-D-galactopyranolsyl (1-->2)-[beta-D-xylopyranosyl-(1-->3) ]-beta-D-glucuronopyranosyl quillaic acid 28-[0-beta-D-fucopyranosyl(1-->4)-beta-D-glucopyranosyl(1-->3)]-alpha-L- rhamnopyranosyl] ester. PMID- 8676135 TI - Simple motor tics may be preceded by a premotor potential. AB - Obeso et al reported that simple motor tics in Tourette's syndrome were not associated with premotor potentials, which were present when patients mimicked their tics voluntarily, suggesting that spontaneous tics were not generated in the same manner as voluntary movements. Five patients with simple motor tics were studied using a similar paradigm. Premotor potentials were examined during spontaneous tics and during voluntary imitation of the tics. All patients had premotor negativity with the voluntary movements. As in the study of Obeso et al, spontaneous tics were not preceded by premotor potentials in three patients. However, premotor negativity was present with spontaneous tics in two patients and resembled the NS' segment of the premotor potential seen with self paced, voluntary movements. A similar premotor potential pattern has been reported with voluntary movements performed in response to external triggering stimuli. In patients with Tourette's syndrome, the eliciting signals could be internal sensations. PMID- 8676134 TI - Is chronic respiratory failure in neuromuscular diseases worth treating? PMID- 8676136 TI - Sensory deficits of a nerve root lesion can be objectively documented by somatosensory evoked potentials elicited by painful infrared laser stimulations: a case study. AB - Somatosensory evoked potentials (SEPs) in response to painful laser stimuli were measured in a patient with a unilateral sensory deficit due to radiculopathy at cervical levels C7 and C8. Laser evoked potentials (LEPs) were compared with SEPs using standard electrical stimulation of median and ulnar nerves at the wrist and mechanical stimulation of the fingertips by means of a mechanical stimulator. Early and late ulnar and median nerve SEPs were normal. Mechanical stimulation resulted in w shaped early SEPs from all five fingertips with some degree of abnormality at the fourth and fifth digits of the affected hand. Late LEPs were completely absent for stimulations at affected dermatomes and normal in the unaffected control dermatomes. The border between skin areas with normal or absent LEPs was very sharp and fitted the dermatomes of intact C6 and damaged C7 and C8 nerve roots. It is suggested that pain dermatomes are narrower than tactile dermatomes because thin fibres of the nociceptive system, activated by laser stimuli, probably do not overlap between adjacent spinal segments to the same extent as thick fibres of the mechanoreceptive system, activated by standard electrical or mechanical stimulation. PMID- 8676137 TI - Codon 200 mutation in a new family of Chilean origin with Creutzfeldt-Jakob disease. PMID- 8676138 TI - Calcification of the substantia nigra in a patient with an akinetic rigid syndrome. PMID- 8676139 TI - A sporadic case of dentatorubral pallidoluysian atrophy (DRPLA) with CAG repeat expansion but no clinical abnormalities in the father. PMID- 8676140 TI - Malignant distress on eye contact after severe head injury. PMID- 8676141 TI - Arrested progression of the cauda equina syndrome of ankylosing spondylitis after lumboperitoneal shunting. PMID- 8676142 TI - Diffuse neurofibrillary tangles with calcification in a non-demented woman. PMID- 8676143 TI - Neurology of adult alpha-mannosidosis. PMID- 8676144 TI - Electromyography of the serratus anterior and subscapularis muscles: description of a technique. PMID- 8676145 TI - Hemifacial spasm: treatment with pizotifen. PMID- 8676146 TI - Orthostatic hypotension caused by a localised dorsal medullary tumour. PMID- 8676147 TI - Tardive dystonia after neuroleptic treatment of Tourette's syndrome. PMID- 8676148 TI - Should patients with central core disease be screened for malignant hyperthermia? PMID- 8676149 TI - Multiple sclerosis in the north Cambridgeshire districts of East Anglia. PMID- 8676150 TI - Magnetic resonance imaging in Avellis' syndrome. PMID- 8676152 TI - Louis Charles Alfred de Musset (1810-57). PMID- 8676151 TI - Evidence of misery perfusion and risk for recurrent stroke in major cerebral arterial occlusive diseases from PET. AB - OBJECTIVES: In major cerebral arterial occlusive diseases, patients with inadequate blood supply relative to metabolic demand (misery perfusion) may be at increased risk for cerebral ischaemia. This study investigated whether patients showing misery perfusion on PET have a high risk of recurrent ischaemic stroke. METHODS: The relation between the regional haemodynamic status of cerebral circulation and the subsequent risk of recurrent stroke was prospectively evaluated in 40 patients with symptomatic internal carotid or middle cerebral arterial occlusive diseases who underwent PET. Patients were divided into two haemodynamic categories according to the mean hemispheric value of oxygen extraction fraction in the hemisphere supplied by the artery with symptomatic disease: patients with normal oxygen extraction fraction and those with increased oxygen extraction fraction (misery perfusion). All patients were followed up for at least 12 months. RESULTS: The one year incidence of ipsilateral ischaemic strokes for patients with normal oxygen extraction fraction and those with increased oxygen extraction fraction were two of 33 and four of seven patients respectively. A significantly higher incidence of ipsilateral strokes was found in patients with increased oxygen extraction fraction (Fisher's exact test; P = 0.005). In patients with increased oxygen extraction fraction, three of four strokes were watershed infarctions and the location of the infarction corresponded with the area of increased oxygen extraction fraction. CONCLUSION: These findings contradict conclusions of a previous study and suggest that patients with major cerebral arterial occlusive diseases and misery perfusion have a high risk for recurrent ischaemic stroke. PMID- 8676153 TI - Changes in cerebral tissue perfusion during the first 48 hours of ischaemic stroke: relation to clinical outcome. AB - BACKGROUND: One major therapeutic strategy to minimise the extent of infarction after ischaemic stroke is to improve early reperfusion using thrombolytic agents. However, reperfusion may be hazardous and the period during which reperfusion may have a beneficial effect on tissue and clinical outcome is not known. METHODS: Fifty three patients were studied with serial cerebral perfusion (99mTcHMPAO SPECT) during the first 48 hours of ischaemic stroke to determine if changes in tissue perfusion during this time were prognostically significant. Single and multiple linear regression non-parametric analyses were used to include other factors during the same period which may influence outcome. RESULTS: In univariate analysis age, neurological score at admission, SPECT perfusion defect size in the first 24 hours, and percentage change in cerebral tissue perfusion at 24-48 hours (all P < 0.01) correlated significantly with the Barthel score at three months. In multiple linear regression analysis only age (P < 0.01) and percentage change in cerebral tissue perfusion at 24-48 hours (P < 0.01) provided independent prognostic information at three months. CONCLUSIONS: Changes in cerebral tissue perfusion during the first 48 hours of ischaemic stroke are significant outcome predictors and therapeutic effort aimed at increasing perfusion during this period seem to be justified. PMID- 8676154 TI - Use of botulinum toxin in stroke patients with severe upper limb spasticity. AB - OBJECTIVES: Spasticity can contribute to poor recovery of upper limb function after stroke. This is a preliminary evaluation of the impact of botulinum toxin treatment on disability caused by upper limb spasticity after stroke. METHODS: Seventeen patients with severe spasticity and a non-functioning arm were treated with intramuscular botulinum A neurotoxin (median age at treatment 54.5 years; median time between onset of stroke and treatment 1.5 years). Baseline and assessments two weeks after treatment were compared to assess efficacy. The duration of improvement in disability was documented. Outcome measures used were; passive range of movement at the shoulder, elbow, wrist, and fingers; modified Ashworth scale to assess spasticity of biceps and forearm finger flexors; an eight point scale to assess the degree of difficulty experienced by the patient or carer for each functional problem defined before treatment; the presence of upper limb pain. The biceps, forearm finger flexors, and flexor carpiulnaris were treated with intramuscular botulinum toxin. Up to a total dose of 400-1000 mouse units (MU) of Dysport (Speywood) or 100-200 MU of BOTOX (Allergan) was used in each patient. RESULTS: Functional problems reported by the patients before treatment were difficulty with cleaning the palm, cutting fingernails, putting the arm through a sleeve, standing and walking balance, putting on gloves, and rolling over in bed. Hand hygiene improved in 14 of 17 patients; difficulty with sleeves improved in four of 16; standing and walking balance improved in one of four; shoulder pain improved in six of nine; wrist pain improved in five of six. Passive range of movement at shoulder, elbow, and wrist improved after treatment. Benefit was noted within two weeks and lasted one to 11 months. No adverse effects occurred. CONCLUSION: This preliminary study suggests that intramuscular botulinum toxin is a safe and effective treatment for reducing disability in patients with severe upper limb spasticity. PMID- 8676155 TI - Sciatica. PMID- 8676156 TI - Chronic dysimmune demyelinating polyneuropathy: a clinical and electrophysiological study of 93 patients. AB - OBJECTIVES: To identify clinical, electrophysiological, and immunological characteristics of chronic immune demyelinating polyneuropathy to define for each group the appropriate therapeutic strategies. METHODS: The clinical and electrophysiological data and the response to treatment of 93 patients with an acquired chronic dysimmune demyelinating polyneuropathy (CDDP) studied over a period of 10 years were reviewed. Two groups were identified: group 1, comprising 64 patients with an idiopathic CDDP, of whom 13 had serum monoclonal or polyclonal gammopathy without detectable antibodies directed against the "myelin associated glycoprotein" (MAG), and group 2, comprising 29 patients with an IgM monoclonal gammopathy of undetermined significance (MGUS) with antibodies binding to the MAG. RESULTS: Group 1 patients had either a progressive or relapsing course. The relapsing course had more pronounced distal slowing of motor conduction velocity. In group 1, there were no significant clinical or electrophysiological differences between patients with or without gammopathy. Patients with anti-MAG antibody (group 2) differed significantly from group 1 patients, especially on the basis of electrophysiological results. They had a more pronounced slowing of peroneal motor nerve conduction velocity, a lower frequency of conduction block, and a distal accentuation of conduction slowing, distinguishing them from those with idiopathic CDDP, Charcot-Marie-Tooth polyneuropathy type 1A, and control subjects. CONCLUSION: The idiopathic CDDP group is heterogeneous with probably different subgroups. Patients with IgM MGUS polyneuropathy and anti-MAG antibodies have characteristics which distinguish them significantly from other CDDP and suggest different immune mechanisms and responses to treatment. PMID- 8676158 TI - Slowing of central conduction in X-linked Charcot-Marie-Tooth neuropathy shown by brain stem auditory evoked responses. AB - BACKGROUND: The most common form of CMT with slow nerve conduction velocities (CMT type I) is CMT1A, caused by a submicroscopic duplication of a region of DNA on chromosome 17 including the PMP22 gene. This gene is expressed in peripheral nerve but not in the CNS. The second most common form is CMTX, caused by mutations in the connexin32 gene in the X chromosome. Connexin32 is expressed both in brain and in peripheral nerve. These molecular variants are difficult to distinguish clinically. METHODS: Brain stem auditory evoked responses (BAERs) were measured in patients with CTMX and CMT1A. RESULTS: BAERs showed central conduction slowing in male patients with CMTX which did not overlap the normal range. Patients with CMT1A had a delay in wave I latency but otherwise normal responses. These results are consistent with the pattern of expression of PMP22 in the peripheral portion of the eighth nerve (myelinated by Schwann cells) and of connexin32 in the central portion in the brainstem auditory pathways (myelinated by oligodendrocytes). This is the first evidence for central involvement in CMTX. CONCLUSION: BAERs are useful to distinguish CMTX from CMT1A and may assist selection of appropriate patients for connexin32 mutation analysis. PMID- 8676157 TI - How far are we in understanding the cause of Parkinson's disease? PMID- 8676159 TI - The A to G transition at nt 3243 of the mitochondrial tRNALeu(UUR) may cause an MERRF syndrome. AB - OBJECTIVE: To verify the phenotype to genotype correlations of mitochondrial DNA (mtDNA) related disorders in an atypical maternally inherited encephalomyopathy. METHODS: Neuroradiological, morphological, biochemical, and molecular genetic analyses were performed on the affected members of a pedigree harbouring the heteroplasmic A to G transition at nucleotide 3243 of the mitochondrial tRNALeu(UUR), which is usually associated with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). RESULTS: The proband was affected by a fullblown syndrome of myoclonic epilepsy with ragged red fibres (MERRF), severe brain atrophy, and basal ganglia calcifications, without the MRI T2 hyperintense focal lesions which are pathognomonic of MELAS. Oligosymptomatic relatives were variably affected by lipomas, goitre, brain atrophy, and basal ganglia calcifications. Muscle biopsies in the proband and his mother showed a MELAS-like pattern with cytochrome c oxidase hyperreactive ragged red fibres and strongly succinate dehydrogenase reactive vessels. Quantification of the A3243G mutation disclosed 78% and 70% of mutated mtDNA in the muscle of the severely affected proband and of his oligosymptomatic mother respectively. Nucleotide sequencing of the mitochondrial tRNALeu(UUR) and tRNALys in the proband's muscle failed to show any additional nucleotide change which could account for the clinical oddity of this pedigree by modulating the expression of the primary pathogenic mutation. CONCLUSION: So far, MERRF has been associated with mutations of the mitochondrial tRNALys, and MELAS with mutations of the mitochondrial tRNALeu(UUR). Now MERRF may also be considered among the clinical syndromes associated with the A to G transition at nt 3243 of the tRNALeu(UUR). PMID- 8676161 TI - Gerstmann's syndrome. PMID- 8676160 TI - Congenital unilateral perisylvian syndrome: radiological basis and clinical correlations. AB - DESIGN: Advances in neuroimaging have allowed correlations between radiological patterns and clinical features of brain malformations. This paper reports clinical, prognosis, and electroencephalographic features of six children with a previously unrecognised neuroimaging picture of unilateral widening and verticalisation of the sylvian fossa associated with an abnormal ipsilateral perisylvian cortex. RESULTS: All children had reduced hemisphere size and thalamostriatal hypoplasia ipsilateral to the cleft and hemiplegia. Cognitive development was mostly impaired. Epilepsy occurred in two patients and was mainly characterised by partial seizures. Studies with EEG showed hemispheric slowing of background activity homolateral to the perisylvian dysplasia. Occurrence of the malformation among their siblings was not found. CONCLUSION: Similar brain malformations occasionally reported in older patients confirm the clinical picture, sporadic occurrence, and prognosis found, allowing the validation of a unilateral perisylvian syndrome. PMID- 8676162 TI - Inflammatory cytokines in CSF in bacterial meningitis: association with altered blood flow velocities in basal cerebral arteries. AB - OBJECTIVE: To investigate the association between release of humoral inflammatory mediators in CSF and blood and alterations of cerebral blood flow in patients with bacterial meningitis. METHODS: Immunomodulatory (interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF alpha)) and vasoactive (thromboxane A, prostacyclin, endothelin-1) molecules of probable or confirmed leucocyte origin were determined in CSF and venous blood from 20 patients with bacterial meningitis, and matched control subjects. Their concentrations were related to the presence of increased blood flow velocities in the middle cerebral arteries, as recorded by transcranial Doppler sonography. RESULTS: Concentrations of proinflammatory cytokines and prostacyclin and leucocyte counts were significantly increased in meningitis, but concentrations of the vasoconstrictors thromboxane and endothelin-1 were not. Patients with high blood flow velocities ( > 140 cm/s) had significantly increased concentrations of IL-1 beta and IL-6 and raised cell counts in CSF. CONCLUSION: The increases of key mediators of inflammation and immunoactivation and of leucocyte count in the CSF of patients with high cerebral blood flow velocities suggest a role of excessive compartmentalised host defence in pathogenesis of disorders of cerebral blood flow in bacterial meningitis. PMID- 8676163 TI - Tinel's sign of formication. PMID- 8676164 TI - Central pain: clinical and physiological characteristics. AB - OBJECTIVES: To study the clinical and pathophysiological features of central pain due to damage to the CNS. METHODS: 156 patients (mostly with ischaemic strokes, some with infarct after subarachnoid haemorrhage and other cerebral conditions; one with bulbar and others with spinal pathology) with central pain have been investigated clinically and varying numbers instrumentally with respect to quantitative somatosensory perception thresholds and autonomic function. RESULTS: Pain onset was immediate in a minority; and from a week or two up to six years in > 60%. For those with supraspinal ischaemic lesions, the median age of onset was 59; dominant and non-dominant sides were equally affected. Two thirds of the patients had allodynia, including a previously undescribed movement allodynia apparently triggered from group I afferents. Most patients exhibited autonomic instability in that their pain was increased by physical and emotional stress and alleviated by relaxation; cutaneous blood flow and sweating may also be affected. Pain occurred within a larger area of differential sensory deficit. The critical deficit seems to be for thermal and pinprick sensations, which were more pronounced in areas of greatest than in areas of least pain; whereas low threshold mechanoceptive functions, if affected, did not vary between areas of greatest and least pain. Skinfold pinch (tissue damage) pain thresholds were only slightly affected in supraspinal cases, but greatly increased in patients with spinal lesions; thermal (heat) pain did not show this dissociation. CONCLUSION: The pathogenetic hypothesis which seems best to fit the findings is that there is up regulation or down regulation of receptors for transmitters, possibly mainly noradrenergic, over time. PMID- 8676165 TI - Quality of life in patients with Parkinson's disease: development of a questionnaire. AB - OBJECTIVES: To develop and test a questionnaire for measuring quality of life in patients with Parkinson's disease. METHODS: An item pool was developed based on the experience of patients with Parkinson's disease and of neurologists; medical literature on the problems of patients with Parkinson's disease; and other quality of life questionnaires. To reduce the item pool, 13 patients identified items that were a problem to them and rated their importance. Items which were most often chosen and rated most important were included in the Parkinson's disease quality of life questionnaire (PDQL). The PDQL consists of 37 items. To evaluate the discriminant validity of the PDQL three groups of severity of disease were compared. To test for convergent validity, the scores of the PDQL were tested for correlation with standard indices of quality of life. RESULTS: The PDQL was filled out by 384 patients with Parkinson's disease. It consisted of four subscales: parkinsonian symptoms, systemic symptoms, emotional functioning, and social functioning. The internal-consistency reliability coefficients of the PDQL subscales were high (0.80-0.87). Patients with higher disease severity had significantly lower quality of life on all PDQL subscales (P < 0.05). Almost all PDQL subscales correlated highly (P < 0.001) with the corresponding scales of the standard quality of life indices. CONCLUSION: The PDQL is a relevant, reliable, and valid measure of the quality of life of patients with Parkinson's disease. PMID- 8676166 TI - Emotional, neuropsychological, and organic factors: their use in the prediction of persisting postconcussion symptoms after moderate and mild head injuries. AB - BACKGROUND: After mild and moderate head injuries a range of postconcussion symptoms (PCS) are often reported by patients. Both organic and psychogenic factors can contribute to these. Full recovery from PCS usually occurs within three months of the injury. A significant minority, however, continue to experience symptoms beyond this time. To date, no means of identifying these patients early after injury has been reported. This study investigates whether a combination of neuropsychological, emotional, and traditional measures of severity of head injury taken early after the injury can help predict severity of PCS three months after injury. METHODS: 50 patients with mild or moderate head injury had a range of measures administered at 7-10 days after injury. These included three tests of divided attention, a PCS rating scale-the Rivermead postconcussion symptoms questionnaire (RPQ), the hospital anxiety and depression scale (HADS), the impact of event scale (IES), and post-traumatic amnesia. An RPQ was then completed by all patients three months after injury. RESULTS: Stepwise multiple regression analysis was performed with the RPQ score at three months as the dependent measure. A combination of eight of the scores from the early measures gave a multiple correlation coefficient of R = 0.86 accounting for 74% of the variance in RPQ scores. The most predictive individual measures were the HADS and IES. Regression analysis with RPQ score at 7-10 days as dependent measure showed that 10 of the scores gave a coefficient of R = 0.84 accounting for 71% of the variance. CONCLUSIONS: A combination of measures may significantly aid the prediction of persistent PCS. Five measures: HADS, post-traumatic amnesia, SOMC, PASAT, and RPQ are recommended for their predictive value and clinical utility. Independent cross validation studies are required before these results can be generally applied. They do, however, provide valuable indications regarding those measures that are most likely to demonstrate utility. PMID- 8676168 TI - Simple partial status epilepticus: causes, treatment, and outcome in 47 patients. AB - A retrospective case note review was conducted of 47 patients of 15 years and older who had sustained simple partial status epilepticus (SPSE) in The Netherlands between 1980 and 1987. In 46 patients the type of SPSE was somatomotor (in four adversive), and in one aphasic with visual and auditory hallucinations. SPSE was more common over the age of 50. Six of 27 patients with previous epilepsy had an acute symptomatic cause. In 20 patients without previous epilepsy stroke was the most frequent cause (75%). Outcome was determined by the underlying cause. In one patient the continuing epileptic activity may have caused neuronal damage. PMID- 8676167 TI - Psychiatric disorders in candidates for surgery for epilepsy. AB - OBJECTIVE: To provide a descriptive analysis of the prevalence and pattern of psychiatric morbidity among 300 consecutive epileptic patients refractive to treatment and admitted during a six year period for evaluation of their candidature for surgery. METHODS: Patients underwent detailed observation of their seizure and standardised psychiatric assessment. Patients were considered to be refractory to treatment if they continued to manifest seizures with an average frequency of at least once every month even with polytherapy using up to three different anti-convulsants for a period of at least two years. Of the 300 patients, 231 had a temporal lobe focus, 43 had a non-temporal lobe focus, and 26 patients had a generalised and multifocal seizure onset. RESULTS AND CONCLUSIONS: With the DSM-III-R criteria 142 (47.3%) patients emerged as psychiatric cases. A principal axis I diagnosis was made in 88 (29.3%), and an axis II diagnosis (personality disorder) in another 54 (18.0%) patients. The most common axis I diagnosis was anxiety disorders (10.7%). A schizophrenia-like psychosis was seen in 13 (4.3%). Most patients with personality disorders showed dependent and avoidant personality traits. There was a significantly higher psychotic subscore on the present state examination in the temporal than with the non-temporal group of patients. These findings were not significant when compared with patients with a generalised and multifocal seizure disorder. There were no significant findings between the different seizure focus groups on the neurotic subscores. The findings with regard to laterality of seizure focus and the neurotic or psychotic subscores were not significant. PMID- 8676169 TI - Non-convulsive status epilepticus: causes, treatment, and outcome in 65 patients. AB - The incidence of non-convulsive status epilepticus (NCSE) in The Netherlands is not known. Files of admissions in the years 1980-7 were studied from 40 adult patients (older than 15 years) with complex partial status epilepticus (CPSE) and 25 with absence status epilepticus (ASE). The clinical presentation sometimes made distinction between CPSE and ASE possible. Focal clinical signs were more frequent in CPSE; a fluctuating level of consciousness was more often present in ASE. All patients, but one, with ASE and most patients with CPSE (28) were known to have had previous epilepsy. Outcome in ASE was good in all. Outcome in CPSE depended on the underlying cause and quality of treatment. In three patients inadequate treatment probably contributed to morbidity. PMID- 8676170 TI - Palatal and pharyngeal reflexes in health and in motor neuron disease. AB - Palatal and pharyngeal sensation and motor responses, and volitional palatal movement, were tested in 171 healthy adults and 43 patients with motor neuron disease. In healthy adults palatal and pharyngeal sensation and volitional palatal elevation were present in all; the palatal and pharyngeal motor responses could not be elicited on first testing in two (1.1%) and seven (4.1%) subjects respectively. Pharyngeal motor responses were more easily elicited in older subjects and palatal responses were more easily elicited in women. Eye watering and retching were the most common accompanying features. In 57 normal subjects tested on five occasions there was considerable variation in the stimulus required to elicit the motor responses within subjects: in none of four subjects (7%) who initially had absent responses were they always absent. Pharyngeal motor responses were more easily elicited in patients with motor neuron disease than in matched normal subjects; within the motor neuron disease group pharyngeal motor responses elicited by tongue depression were associated with the symptom of food or drink "going down the wrong way" > 1/month and a reduction in average volume per swallow (ml) and swallowing capacity (ml/s). Volitional palatal elevation was absent in five patients (11.6%). In six of eight patients with motor neuron disease studied repeatedly (on between two and seven occasions) the palatal and pharyngeal responses were elicited with the same stimulus on each occasion. In healthy adults palatal and pharyngeal sensation and motor responses should be present although considerable variation occurs in the stimulus required. In patients with motor neuron disease features of impaired swallowing are associated with a brisk rather than a depressed pharyngeal response. PMID- 8676171 TI - Acute pandysautonomia: mass spectrometric and histopathological studies of the sympathetic nervous system during long term L-threo-3,4-dihydroxyphenylserine treatment. AB - Stable isotope labelled L-threo-3,4-dihydroxyphenylserine (L-DOPS) infusion tests and histopathological studies of the rectal autonomic nerves were performed in a patient with acute pandysautonomia. A pronounced increase in blood pressure occurred and stable isotope labelled noradrenaline appeared in the plasma during L-DOPS infusion in the acute stage, but decreased during the next three years. Noradrenergic nerve fibres in the rectal mucosa showed no recovery, and so clinical improvement had occurred without apparent significant regeneration of the peripheral autonomic nerves. PMID- 8676173 TI - Searching for an improved clinical comorbidity index for use with ICD-9-CM administrative data. AB - We studied approaches to comorbidity risk adjustment by comparing two ICD-9-CM adaptations (Deyo, Dartmouth-Manitoba) of the Charlson comorbidity index applied to Massachusetts coronary artery bypass surgery data. We also developed a new comorbidity index by assigning study-specific weights to the original Charlson comorbidity variables. The 2 ICD-9-CM coding adaptations assigned identical Charlson comorbidity scores to 90% of cases, and specific comorbidities were largely found in the same cases (kappa values of 0.72-1.0 for 15 of 16 comorbidities). Meanwhile, the study-specific comorbidity index identified a 10% subset of patients with 15% mortality, whereas the 5% highest-risk patients according to the Charlson index had only 8% mortality (p = 0.01). A model using the new index to predict mortality had better validated performance than a model based on the original Charlson index (c = 0.74 vs. 0.70). Thus, in our population, the ICD-9-CM adaptation used to create the Charlson score mattered little, but using study-specific weights with the Charlson variables substantially improved the power of these data to predict mortality. PMID- 8676172 TI - Metabolic risk factors for cardiovascular disease in a working population: a retrospective cohort study. AB - Risk factors for cardiovascular disease (CVD) appear to cluster in individuals, possibly because of a single, underlying metabolic disorder. We describe the prevalence of metabolic risk factors for CVD in a young working population and the tendency for individuals with some risk factors to acquire additional factors. This was a retrospective three-year follow-up study of baseline CVD risk factors assessing (1) incidence of risk factors and (2) fatal CVD. The study group consisted of 9,747 Eastman Kodak employees, who participated in a worksite based cardiovascular screening program in Rochester, New York, which included a medical history, physical examination, and laboratory evaluation. Abnormal metabolic risk factors were defined as (1) an abnormal glucose value (fasting blood sugar greater than 115 mg/dl); (2) abnormal lipids (high-density lipoprotein cholesterol under 35 mg/dl in men or under 45 mg/dl in women; or low density lipoproteins of 160 or greater; or triglycerides greater than 250 mg/dl), and (3) hypertension (blood pressure systolic above 160 mmHg; or diastolic above 90 mmHg). Subjects were classified as having none, one, two, or all three risk factors. Prevalence of single risk factors were: hypertension 9.8%, abnormal lipids 22.6%, and abnormal glucose 1.5%. Combinations of two risk factors were greater than expected by chance (p < 0.01). Individuals who started with one or more abnormal values tended to have an increased risk of developing others. The highest relative risk (RR) was for those with hypertension and a later diagnosis of abnormal glucose (RR 2.0; 95% CI = 0.87, 4.58). Seven employees of 4,263 with at least one risk factor died of CVD, compared with one of 5,484 employees with no factors (RR 9.0, 95% CI = 1.1, 73.2). In conclusion, this study suggests that young working individuals with CVD risk factors may continue to acquire additional factors. This clustering could be an indication of an underlying metabolic disorder and identify individuals at risk for negative CVD sequelae. PMID- 8676174 TI - Women and Mexican Americans receive fewer cardiovascular drugs following myocardial infarction than men and non-Hispanic whites: the Corpus Christi Heart Project, 1988-1990. AB - Mortality following myocardial infarction (MI) is greater among women than men and among Mexican Americans than non-Hispanic whites. Because therapy can affect mortality following MI, we examined differences in discharge therapy among these groups. Data regarding discharge therapy of 982 patients in the Corpus Christi Heart Project showed that women received fewer cardiovascular drugs than men, and Mexican Americans received fewer cardiovascular drugs than non-Hispanic whites. In multivariate analysis adjusting for age, cigarettes smoking, diabetes, hypertension, congestive heart failure, and serum cholesterol, the odds ratio for receipt of cardiovascular medications was 0.51 (95% CI: 0.28-0.93) for women versus men and 0.62 (0.3-1.15) for Mexican Americans versus non-Hispanic whites. Beta-blockers were prescribed rarely. Thus, treatment differences between ethnic and gender groups were observed following MI. Further research is needed to determine both the reasons for these differences and the extent to which these differences contribute to the observed survival patterns following MI. PMID- 8676175 TI - Evaluating pressure ulcer occurrence in long-term care: pitfalls in interpreting administrative data. AB - Administrative databases for long-term care frequently collect information on fixed dates of the calendar year, rather than for entire episodes of care. Patients discharged or dying prior to an evaluation date are lost to follow-up. We used one such database, the VA Patient Assessment File, to examine pressure ulcer occurrence in long-term care. Clinical studies have established that most pressure ulcers develop during the first several weeks following admission. In these data, however, pressure ulcer development was less common in patients assessed within 2 months following admission, as compared to those examined at 3 to 6 months. This finding appears to be related to the selective discharge of patients, which makes these patient populations noncomparable. These results highlight that care must be exercised when interpreting results obtained from such administrative data. PMID- 8676176 TI - Loglinear models using capture-recapture methods to estimate the size of a measles epidemic. AB - Cases of measles reported separately by doctors, hospitals, laboratories, and others are treated as separate captures and releases of the population of children aged up to 10 years who have been infected by measles in a recent epidemic. Loglinear models are used to assess the adequacy of fit of various models for capture-recapture and the size of the epidemic in different age groups is estimated. PMID- 8676177 TI - Self-report disability in an international primary care study of psychological illness. AB - We assessed the replicability of reliability and validity of a brief self-report disability scale, adapted from the Medical Outcomes Survey (short form), in a 15 center, cross-national, multilingual study of psychological illness among primary care patients (n = 5438). Across all 15 centers in the World Health Organization Collaborative Study of Psychological Problems in General Health Care, the reliability of the disability scale was high and individual items were responsive at similar levels of disability. Self-report disability was consistently correlated with disability in work role (including housework) as rated by interviewers according to the Groningen Social Disability Schedule, a semistructured method taking local norms into account. Disability as measured by the self-report questionnaire was also consistently correlated with depressive symptoms as measured by the General Health Questionnaire. At each center, the disability items formed a moderately to strongly hierarchical (Guttman-like) scale. These findings support the feasibility of using self-report disability scales in cross-national primary care research. PMID- 8676178 TI - Prevention-oriented life styles and diffusion of cholesterol screening and awareness: Massachusetts behavioral risk factor survey, 1987-1991. AB - Universal screening of the adult population for detection of elevated serum cholesterol has been recommended. We examined the relation of eight risk factors for morbidity and mortality (hypertension, overweight, inactivity, tobacco use, safety belt nonuse, binge alcohol consumption, driving after alcohol consumption, and chronic alcohol consumption) to adoption of cholesterol screening and to awareness of cholesterol level. Data were collected through the Massachusetts Behavioral Risk Factor Surveillance System between 1987 and 1991 (mean number of respondents interviewed annually, 1240). We compared trends in prevalence of cholesterol screening and awareness within risk groups defined on the basis of the presence or absence of each risk factor. Cholesterol screening prevalence increased from 46.8% in 1987 to 67.9% in 1991. Overweight and hypertensive respondents were more likely to have been screened than nonoverweight or normotensive respondents; for the other six risk factors, individuals at increased risk were less likely to have been screened. The difference in cholesterol screening prevalence between increased-risk and lower-risk respondents increased between 1987-1988 and 1990-1991 for four risk factors. Prevalence of awareness of cholesterol level increased from 7.8% in 1987 to 35.4% in 19991. Trends by risk status were comparable to those observed for cholesterol screening. Individuals already motivated toward a preventive life style appear to be those most likely to avail themselves of a new prevention possibility. PMID- 8676179 TI - A new measure of parent satisfaction with medical care provided in the neonatal intensive care unit. AB - The objective of this study was to develop a valid and reliable discriminative index that measures parent satisfaction with the medical care of their infant in the NICU. We developed an initial questionnaire (Item Reduction Questionnaire) by reviewing the literature, surveying 63 NICU clinicians, and interviewing 125 parents of infants in 2 tertiary level NICUs regarding what they liked and disliked about the medical care of their infants. We administered the Item Reduction Questionnaire, which included 154 items, to 60 parents, who rated the frequency and importance of these items. We included the items identified most frequently as sources of dissatisfaction and rated most important in a second, briefer instrument, the Neonatal Index of Parent Satisfaction (NIPS). To measure reliability we administered the NIPS to 47 parents twice, separated by a 1-week interval. We assessed validity by comparing actual to predicted correlations between NIPS scores and other measures: parent's global rating of satisfaction, medical caregiver ratings of mother's satisfaction, medical caregiver ratings of father's satisfaction, and parents' perception of their infant's health status. We also compared mean NIPS scores for parents who did and who did not report incidents when errors occurred in the medical care of the infant. Of 154 items generated, we included 27 in the NIPS. The intraclass correlation between two administrations of the NIPS to the same 47 parents was 0.71. As predicted, there was a high correlation (0.61) between the NIPS score and parent global rating of satisfaction, and much lower correlations with other variables. Mean NIPS scores for parents who did and who did not report errors differed significantly (difference, 14.6; 95% CI around difference, 5.8-23.5; p < 0.001). The NIPS is likely to be a useful measure for discriminating between parents who differ in terms of their satisfaction with the medical care of their infant in the NICU. PMID- 8676180 TI - An approach to measuring quality of midwifery care. AB - In perinatology "Outcome" is almost always defined in terms of mortality or serious morbidity. Evaluation of care for normal pregnancy and midwifery care in particular cannot rely only on outcome measures per se, but must also take the means and interventions by which these are achieved into account. Perinatal Background and Perinatal Outcome Indexes were developed for the assessment of midwifery care in women with low-risk pregnancies. These indexes were applied in a prospective study of midwifery care during labor and childbirth for a population of 1836 women with low-risk pregnancies in The Netherlands. The Perinatal Background Index confirmed that the study population was indeed a population at low risk of perinatal complications. The Perinatal Outcome Index gave an adequate description of both the result and process of childbirth, with a lower score indicating a further deviation from the optimal situation of "maximum outcome with minimal intervention." PMID- 8676181 TI - Reliability and validity of a comprehensive health status measure in a heterogeneous population of children admitted to intensive care. AB - This study assesses psychometric and empirical characteristics of the Multi Attribute Health Status Classification (MAHSC) in a heterogeneous population of children admitted to intensive care. The MAHSC encompasses six health domains (sensation, mobility, emotion, cognition, self-care, and pain), each with four or five hierarchic levels of dysfunction. The health status of 254 consecutively admitted children was determined independently by 3 different observers (parents, attending clinicians, and investigators). The proportion of children with health impairment varied between 13% (in sensation) and 58.7% (in mobility). Interrater reliability of domain scores, as analyzed by Spearman's rank, Pearson product moment, and intraclass correlations, was high, generally exceeding 0.80 for all pairs of observers. Intraclass correlation appeared to be highest in nonsurgical patients (range, 0.89-0.98) and lowest in cardiovascular surgery patients (range, 0.50-0.84). The validity of the classification was supported by (1) the presence of expected specific health status impairment in patient suffering from diseases with an acknowledged impact on specific domains and (2) the presence of a relation between health impairment and medical consumption. The absence of a relation between the average (chronic) health status preceding admission and the acute risk of mortality precipitating the admission confirmed their independent prominence in outcome assessment. We conclude that the MAHSC is a feasible, reliable, and valid measure for outcome assessment in a heterogeneous population of children within a demanding clinical situation. Excellent interrater reliability allows the use of various raters, adjusted to practical requirements. PMID- 8676182 TI - Type A behavior and metabolic syndrome precursors in young adults. AB - The association between type A behavior and a cluster of parameters of the metabolic syndrome was studied in 919 randomly selected healthy young adults. Type A behavior was measured using the Type A Behavior Questionnaire for the Finnish Multicenter Study and the Hunter Wolf A-B Rating Scale. The results showed that type A men scored higher on the "Metabolic Syndrome Precursors Factor," representing a metabolic entity, than did non-type A men. In addition, type A behavior had a moderating effect on the relationship between parameters of the metabolic syndrome, that is, interdependence of these somatic factors was stronger in type A men than in non-type A men. These findings were not true of women. It is discussed whether type A behavior might affect bodily functions through increased activity along the pituitary-adrenal system resulting in insulin resistance, compensatory hyperinsulinemia, and other characteristics of the metabolic syndrome. PMID- 8676184 TI - Trends in obesity differences by educational level in Spain. AB - Our objective was to study the trend in differences in the frequency of obesity by educational level in the general population 20 to 64 years of age. We used data from two cross-sectional health surveys carried out in 1987 and 1993 in representative samples of the Spanish population. We investigated the relation between obesity and educational level during the periods 1987 and 1993, taking into account the main factors confounding the relation. We used, as setting, the National Health Interview Surveys representative of the whole Spanish population. In both men and women, the highest odds ratios (ORs) for obesity were observed at lower educational levels. These differences increased in women between 1987 and 1993, while they decreased in men during the same period. Evidence of increased educational differences in the frequency of obesity indicates that future studies should focus on the evaluation and monitoring of this trend in the population. PMID- 8676183 TI - Does collecting repeated blood samples from each subject improve the precision of estimated steroid hormone levels? AB - Measuring levels of steroid hormones in epidemiologic studies is difficult because pulsatile release can cause the levels of many hormones to vary markedly over short intervals, leading to a loss of precision in between-subject comparisons. Clinicians often control this variation by collecting several samples from each subject at defined intervals and pooling these samples for assay. The number of samples per subject that would adequately control such variation in an epidemiologic study has not been fully investigated. This study examines the effects of collecting 1, 2, or 3 samples per subject on the variances of 11 hormones and sex hormone binding globulin in men and 6 hormones in women. Three samples were collected at 30-minute intervals from each of 20 men and 59 women and were assayed separately. Variances that would be obtained in studies collecting one, two, or three samples per subject were then estimated. Collecting more than one sample substantially reduced the variances of several hormones in men but not in women. PMID- 8676186 TI - Validity and reproducibility of the Spanish Version of the Sickness Impact Profile. AB - The Perfil de las Consecuencias de la Enfermedad (PCE), the Spanish version of the Sickness Impact Profile (SIP), was administered to 352 individuals who were grouped into 4 subsamples according to type and severity of illness. Differences among scores in the subsamples were used for assessing the discriminating ability of the PCE and correlation of PCE scores with theoretically comparable measures for convergent validity. Test-retest reliability was studied in a subgroup of 129 patients. The PCE scores correlated well with self-perceived overall health (0.53), self-assessment of sickness (0.51), self-assessment of dysfunction (0.63), the Index of Restricted Activity (0.54), and the Index of Activities of Daily Living (0.45). A poor correlation with clinicians' assessment of dysfunction (0.29) and speech therapists' assessment of speech pathology (0.23) was found. Reproducibility across illnesses (0.95-0.98), types of administration (0.96-0.98), and interviewers (0.93-0.99) was very high. The PCE is equivalent to the original instrument in terms of validity and reliability, which allows its use in international studies. PMID- 8676185 TI - Improving drug use through continuing education: a randomized controlled trial in Zambia. AB - The objective of this study was to evaluate the impact of three continuing education seminars (within a period of 4 months) on the quality of patient management and rational drug use. The study was designed as a randomized controlled trial. Prescribers in 16 general health centers were allocated to an intervention (eight health centers) or a control (eight health centers) group. A total of 5,685 patient cards was analyzed for quality of case management and rational drug use. In the intervention health centers the average number of drugs per patient decreased from 2.3 to 1.9 (p = 0.005) and the proportion of patients managed with nonpharmacological treatment increased from 1 to 13.2%. Recorded history taking, examination, and diagnosis improved in the intervention health centers. More drugs were correctly chosen in the intervention health centers compared to control health centers (p = 0.03). The proportion of patients prescribed antibiotics decreased and the proportion of patients adequately managed increased in the intervention health centers. Our conclusion is that continuing education in the form of repeated seminars is effective in influencing prescribers and in promoting rational drug use in primary care. PMID- 8676187 TI - A follow-up study of determinants of second tumor and metastasis among subjects with cancer of the oral cavity, pharynx, and larynx. AB - We conducted a follow-up study of 380 incident cases of cancer of the oral cavity, pharynx, or larynx, who had been included in a previous case-control study. Information pertaining to potential risk factors, clinical characteristics, and evolution of the tumor (vital status, metastases, and second primary tumors) was obtained. From a multivariate proportional hazard model including terms for risk factors and clinical variables, the incidence of metachronous second primary tumors occurring in the head and neck was positively associated with employment as a farmer as opposed to white collar (hazard ratio [HR] = 3.3) and with tobacco smoking before first tumor diagnosis (HR = 4.3 for heavy versus never or very light smoker). The risk of second primary tumor decreased with increasing dietary "beta-carotene" intake (HR = 0.4 for high versus low intake in tertiles). Less differentiated first primary tumors were followed more frequently by second tumors as compared to grade 1 tumors. The incidence of metastases was not associated with etiological factors of the first tumor, but with stage. PMID- 8676188 TI - Refusal and information bias associated with postal questionnaires and face-to face interviews in very elderly subjects. AB - Our objectives were (1) to analyze the refusal bias associated with postal questionnaires and face-to-face interviews and (2) to compare responses elicited from a postal questionnaire with those provided by a face-to-face interview in subjects over 75 years of age. Our methods included a postal questionnaire sent to a representative sample of community-dwelling elderly individuals (n = 842). All subjects were also invited to participate in an in-home interview conducted by a trained nurse. One hundred and six subjects (12.6%) were nonrespondents to the postal questionnaire. These nonrespondents were more cognitively impaired, more disabled, and showed a higher 1-year mortality rate (13.2 versus 5.2%) than respondents. Late respondents who needed a reminder letter were similar to nonrespondents. One hundred and eighty-seven subjects (22.2%) refused to participate in the home interview. These nonparticipants were similar to the participants on age, sex, 1-year mortality rate, and responses given to all but two postal questions. Comparison of postal questionnaire responses and face-to face responses revealed that agreement was substantial to moderate for factual information (kappa = 0.41 to 0.80) but poor for clinical information (depression, cognitive impairment, disability). A short index including age, sex, and six questions on disability was useful in identifying disabled subjects by a postal questionnaire. Our conclusion is that nonresponse bias is evidenced when postal questionnaires are utilized in the very elderly population and caution should be used when interpreting health data obtained by this technique. Refusal bias from face-to-face interviewing is less important in this population. PMID- 8676190 TI - Case-control evaluation of screening. PMID- 8676189 TI - Predominance of aortic calcification as an atherosclerotic manifestation in women: the Reykjavik study. AB - Since 1967 the Reykjavik study has monitored coronary artery disease and its risk factors in randomly selected cohorts. From 1979 to 1984, 3246 men and 3545 women aged 45-74 years were studied. Routine biplane chest X rays were assessed by a radiologist who noted the presence or absence of aortic calcification (AC), but had no detailed knowledge of the subjects. Overall, AC was diagnosed in 283 (8%) women, but in only 54 of the men (1.7%). In the women, the prevalence of AC increased from 2.0% at age 45-49 years to 17.1% at the age of 70-74 years, while in men it was 0 and 8.3%, respectively. In women, multivariate analysis of risk factors showed AC to be positively related to systolic and negatively related to diastolic blood pressure, indicating a potential relation to pulse pressure. Furthermore, AC was independently associated with age, drug treatment for hypertension, nonfasting blood sugar, use of antidiabetic drugs, total serum cholesterol levels, and the amount of smoking. Too few men had AC for multivariate assessment of risk factors. In addition, in women AC was also related to a previous myocardial infarction (p < 0.05), mortality from coronary artery disease (p < 0.01), and the presence of intermittent claudication (p < 0.01). In men, however, AC was related only to total mortality (p < 0.05). Thus, these data show AC to be more prevalent in women, independently associated with recognized atherosclerotic risk factors, and a potential marker for coronary and peripheral artery disease. PMID- 8676191 TI - Case-control evaluation of screening. PMID- 8676192 TI - White blood cell count and hypertension. PMID- 8676193 TI - Kit formulation for the preparation of radiolabeled iododeoxyuridine by demetallation. AB - The fastest and most reliable preparation of radiolabeled 5-iodo-2'- deoxyuridine (*IUdR) is accomplished by iododemetallation. METHODS: We describe a kit formulation for the preparation of *IUdR by demercuration whereby [123I/125I/131I]IUdR is synthesized virtually instantaneously following the incubation of an aqueous solution of the chloromercuric precursor with Na123I/125I/131I in the presence of lodogen. We also report the conditions for the radiosynthesis of IUdR by destannylation of the tributylstannyl precursor using hydrogen peroxide as the oxidant. RESULTS: In each case, the total procedure is completed in 5 min. HPLC indicates the total transformation of iodide into IUdR with no detectable UV-absorbing by-products. The metal content of the sample is low. The product, therefore, does not require purification. CONCLUSION: *IUdR can be prepared instantly, by either demercuration of ClHgUdR or destannylation of Bu3SnUdR. The use of a mercuric precursor favors a kit formulation since the metallic derivative is stable when kept in aqueous solution, aliquoted in vials coated with the oxidant, for up to 3 mo. PMID- 8676194 TI - Radiolabeled IUdR. Proceedings of a meeting. Boston, Massachusetts, October 4, 1994. PMID- 8676195 TI - Preclinical animal studies with radioiododeoxyuridine. AB - We examined the diagnostic and therapeutic potential of 5-iodo-2'- deoxyuridine (IUdR) radiolabeled with the Auger electron emitters 123I and 125I in several animal tumor models. METHODS: Experiments were conducted using mice bearing an intraperitoneal ovarian tumor (*IUdR by intracavitary injection), and rats bearing either bladder cancer (*IUdR by intravesical injection), brain gliosarcomas (intratumoral injection), or intrathecal gliosarcomas (intrathecal injection). RESULTS: After locoregional administration, [123I]IUdR and [125I]IUdR localize within tumor, clear rapidly from the rest of the body and are therapeutically effective. CONCLUSION: When labeled with the Auger electron emitter 123I or 125I, IUdR demonstrates therapeutic efficacy. In addition, [123I]IUdR has a potential role in the scintigraphic detection of cancer. PMID- 8676196 TI - Radiolabeled iododeoxyuridine: safety evaluation. AB - The emphasis of radiolabeled iododeoxyuridine (*IUdR) research at our institution to date has been to assess its safety as a potential therapeutic agent. Toward this goal, we have performed preclinical and clinical studies, using various routes of administration, to detect adverse changes in normal tissues in both humans and animals. As IUdR is rapidly dehalogenated by the liver, the intravenous route is unlikely to be successful in therapeutic efforts. We have therefore focused our attention on more "protected" routes: intra-arterial and intravesicular administration. METHODS: Studies were performed in farm pigs after multiple administrations of [125I]IUdR into the aorta, carotid artery and bladder. IUdR and metabolites were measured in venous blood samples at appropriate time intervals after administration, after which histologic examination of tissues was performed. Studies in human have been performed after intra-arterial administration of [123I]IUdR in patients with liver metastases and intravesicular administration in patients with bladder carcinoma, initially using [123I]IUdR and currently using both [123I]IUdR and [125I]IUdR. Blood samples for pharmacokinetics and metabolite analysis and tissue for autoradiography (when feasible) have been obtained. RESULTS: To date, no evidence of adverse effects on normal tissue or alteration of hematologic or metabolic indices have been seen in pigs or humans. When instilled in the bladder, there is little leakage of IUdR in the circulation. CONCLUSION: When [125I]IUdR is used as a therapeutic agent, we anticipate little or no effect on normal tissues. PMID- 8676197 TI - Tumor uptake and mitotic activity pattern of 5-[125I]iodo-2'- deoxyuridine after intravesical infusion in patients with bladder cancer. AB - In patients with bladder cancer, little is known about diffusion in the tumor mass of 5-iodo-2'-deoxyuridine (IUdR) administered intraluminally, although previous studies based on external scanning have shown promising tumor-targeting properties of IUdR instilled intravesically. This study compared the pattern of IUdR uptake by bladder cancer cells with the actual distribution of mitotic activity, as evaluated by incubation of ex vivo tumor specimens with tritiated thymidine. METHODS: The [125I]IUdR (2-13 MBq) was instilled over 1-3 hr in the bladder of four patients with bladder cancer scheduled for ablative surgery. Twenty-four hours later, surgical samples were assayed for radioactivity and processed for microautoradiography, while fresh tumor specimens were fragmented, incubated with [3H]thymidine and further processed for microautoradiography. The diffusion of labeled IUdR across the bladder wall was evaluated by blood sampling. RESULTS: Tumor incorporation of [125I]IUdR 24 hr after intravesical instillation was 0.002%-0.05% ID/g, while the average tumor-to-normal bladder ratio was about 20. Microautoradiography showed that [125I]IUdR incorporation was confined to tumor cells in the most superficial layers of the bladder, while incubation of the tumor fragments with [3H]thymidine demonstrated the presence of diffuse mitotic activity also in the deeper tumor mass. Diffusion of labeled IUdR in the general circulation was minimal. CONCLUSION: Poor diffusion in the tumor mass makes *IUdR unsuitable for intracavitary therapy of bladder cancer, but the role of such an approach in the postsurgical "sterilization" of cancer remnants floating in the bladder lumen after partial cystectomy should be explored. PMID- 8676198 TI - Intratumoral administration of 5-[123I]iodo-2'-deoxyuridine in a patient with a brain tumor. AB - We have initiated a study in which patients suspected of having primary gliomas are given a single intracerebral injection of the thymidine analog 5-[123I]iodo 2'-deoxyuridine ([123I]IUdR). The purpose of the study is to determine the biodistribution of the radiopharmaceutical and to calculate dose estimates to the tumor and normal tissues. METHODS: A patient with a cystic glioma was injected with [123I]IUdR. Whole-body scans and brain scans were obtained at various times after injection, and blood, urine and stools were collected and assayed for radioactivity to assess its biodistribution and clearance. RESULTS: Scintigraphic imaging demonstrated that the distribution of radiolabeled IUdR was mainly confined to the tumor (injection site), stomach and bladder. Disappearance from the tumor site and blood clearance were delayed probably due to collection in the cystic lesion. Eighty percent of the injected dose was recovered in the urine. CONCLUSION: The pharmacokinetics of [123I]IUdR locoregionally administered to a human glioma in situ resembled those observed in a rat glioma model where administration of the radiopharmaceutical radiolabeled with the Auger electron emitter 125I was therapeutically effective. PMID- 8676199 TI - Tumor targeting by intra-arterial infusion of 5-[123I]iodo-2'-deoxyuridine in patients with liver metastases from colorectal cancer. AB - We previously showed the tumor-targeting potential of the 125I-labeled thymidine analog 5-iodo-2'-deoxyuridine (IUdR) injected intratumorally in patients with high tumor-cell kinetics. In this study, we evaluated the tumor incorporation of [123I]IUdR infused intra-arterially in patients with liver metastases from colorectal cancer. METHODS: Iodine-123-IUdR (110-300 MBq, 3-8 mCi, specific activity, 150-200 Ci/mumole) was infused into the hepatic artery of 16 patients with inoperable liver metastases over 30-45 min through a permanent intra arterial catheter. A dynamic sequence during infusion, spot images, whole-body scans and SPECT acquisitions were recorded up to 42 hr. Blood and urine samples were obtained for biodistribution and HPLC analyses. RESULTS: In the 14 patients with adequate tumor perfusion patterns, tumor uptake reached 2%-17.6% ID at the end of infusion. After a washout phase that lasted 18-20 hr, incorporated radioactivity remained steadily associated with the tumor lesions until at least 42 hr after infusion (about 1.4%-11.1% ID). HPLC analysis indicated a virtually 100% first-pass hepatic deiodination of unincorporated [123I]IUdR (about 80%-95% ID recovered in the 42-hr urine). No significant uptake was detected in the bone marrow or in other normal dividing tissues. CONCLUSION: These results encourage further studies to enable dosimetric estimates, optimization of dose regimens, and examination of the therapeutic potential of Auger-electron-emitter-labeled IUdR in cancer therapy utilizing this type of approach. PMID- 8676200 TI - Pilot clinical trial of 5-[125I]iodo-2'-deoxyuridine in the treatment of colorectal cancer metastatic to the liver. AB - The thymidine analog, 5-iodo-2'-deoxyuridine (IUdR), is incorporated in the DNA of cells in the S phase. When incorporated into DNA, short-range Auger electrons emitted by 125I-labeled IUdR can cause double-strand breaks, delivering a lethal radiation dose to the cell. We conducted therapeutic trial to evaluate[125I/131I]IUdR pharmacokinetics in liver metastases from colorectal cancer. Dosimetry, safety, and therapeutic potential were assessed. METHODS: Four patients were each infused with 5 mCi [125I]IUdR and 10 mCi [131I]IUdR through the sideport of a hepatic artery pump. Iodine-131 images were quantitated and used for pharmacokinetic studies. The radioactivity in the DNA of biopsy samples of tumor, normal liver and bone marrow, obtained 24 or 48 hr after injection, was counted. RESULTS: All patients had [125I]IUdR and [131I]IUdR uptake in tumor, with a biexponential clearance. Repeat injections in individual patients showed little variation in tumor uptake, especially in the slow clearance component. On planar images, no long-term retention was seen in bone marrow or other actively dividing normal tissues. Radioactivity in all tumor DNA samples was greater than background, while that in normal liver cell DNA was at background levels. Radioactivity in the DNA of one marrow sample taken at 24 hr was above background, but in another taken at 48 hr it was equal to background levels. No side effects were noted, no hematologic toxicity was observed in any patients and no tumor responses were seen. CONCLUSION: There is persistent uptake of [125I]IUdR in hepatic tumors, thereby making hepatic artery infusion a suitable mode of delivery for therapy. Repeat injections will be needed because only 15% 50% of tumor cells are in the S phase. Based on results from this pilot study, a therapeutic regimen is being planned. PMID- 8676201 TI - Pharmacokinetics and dosimetry of iodine-125-IUdR in the treatment of colorectal cancer metastatic to liver. AB - The radiotoxicity of 125I is highly sensitive to the site of decay relative to nuclear DNA. This paper describes a new approach, based upon pharmacokinetic clearance of radioactivity from the tumor, with which to quantify the fraction of [125I]IUdR incorporated within the DNA of tumor cells. METHODS: Patients were injected with [125I]IUdR through the hepatic artery. Iodine-131-IUdR was used as a tracer for imaging and quantitation. Both conventional and DNA-level dosimetry were performed. RESULTS: We calculated that if 15% of the tumor cells were in S phase at the time of injection, there would be 250 decays of 125I in the DNA per tumor cell after an infusion of 5 mCi [125I]IUdR. According to in vitro data based on 5 x 10(8) cells per g tumor, 99% of these cells in S phase would be killed. CONCLUSION: The estimate of cell inactivation is strongly dependent on the number of cells per gram and the fraction of cells in S phase at the time of injection, which indicates that repeat injections would be necessary to achieve a therapeutic effect. PMID- 8676202 TI - Strategies for selective targeting of Auger electron emitters to tumor cells. AB - Strategies based on the use of Auger-emitting radionuclides require the targeting of genomic DNA. Iododeoxyuridine and its analogs, which target the process of DNA synthesis, are incorporated randomly in the genome. Alternative targeting agents are likely to assume a greater role in the future. One possibility is the use of triplex-forming oligonucleotides to target genomic DNA on a sequence-specific basis. METHODS: A model oligonucleotide-targeting system has been developed using a synthetic DNA target sequence based on the N-myc gene. This has been used to examine the ability of alternative oligonucleotides to form DNA triplexes with homopurine-homopyrimidine tract of the target sequence. RESULTS: Oligonucleotides consisting of G and A or G and T that were designed to bind in an antiparallel orientation to the homopurine strand of the target sequence formed triplexes. CONCLUSION: Triplex-forming oligonucleotides have potential as therapeutic agents for cytotoxic therapy. They may also have applications in the study of microradiobiological questions, such as the radiosensitivity of individual genes. Methods of synthesizing high specific activity triplex-forming oligonucleotides, probably using short half-life radionuclides such as 123I, are required. PMID- 8676203 TI - Radioiododeoxyuridine in cancer therapy: an in vitro approach to developing in vivo strategies. AB - Studies were undertaken to determine the relationship between IUdR concentration and the duration of radiolabeled IUdR treatment required to incorporate the equivalent of a D(o) dose in vitro and to estimate the treatment parameters necessary to incorporate a killing dose in vivo. METHODS: W138 (normal human) and HeLa (human cancer) cells were grown axenically or in co-culture. The three cultures were treated for 5 days with 18.5 kBq/ml [125I]IUdR. After treatment, the cells were subcultured and grown for 7 days in medium without [125I]IUdR. In separate experiments, Chinese hamster ovary cells (CHO) were labeled with various ratios of radiolabeled (125I) and nonradiolabeled IUdR and the mole rate of IUdR incorporation in double-stranded DNA was measured. Mitotically selected CHO cells were incubated without treatment until > 98% were in S phase. At this time, the cells were labeled for 15 min with several concentrations of either [123I]IUdR or [125I]IUdR and their colony survival was measured. RESULTS: After incubation with [125I]IUdR, selective eradication of HeLa cells from a co-culture of W138 and HeLa cells was achieved. The incorporation of IUdR into DNA of CHO cells, although the sum of a series of enzymatic steps, has the appearance of and can be analyzed as a Michaelis-Menton type curve. The maximum rate of IUdR incorporation (Vmax) is 4.424 x 10(-18) mol/min and the substrate concentration at 1/2 Vmax (K) is 3.717 x 10(-6) M IUdR. The Do dose rates for [123I]IUdR and [125I]IUdR, respectively, are 18.78 and 1.88 initial decays/cell/hr. CONCLUSION: The D(o) dose for *IUdR can be determined from survival curves versus the mole amount of *IUdR incorporated in DNA. To be effective as an in vivo treatment it will be necessary to manipulate the IUdR delivery time, concentration and volume in a manner that assures that the target cells incorporate a cytocidal dose of *IUdR. PMID- 8676204 TI - Teaching caring to nursing students. AB - This article reports on phenomenological research designed to discover how caring was taught in a nursing education program. The basic questions were: 1) What is the meaning of caring to the faculty and students; 2) How do the faculty communicate this meaning to the students; and 3) How does this meaning shape the experience of the students? Data were collected from a small associate degree nursing program using: a) semi-structured interviews with all faculty and a selected group of students, b) classroom observations, and c) review of documents. Data were analyzed for and found to have content explaining the meaning of caring, how caring was being taught, and what students were learning about caring as the essence of nursing. Implications derived speak to the need for faculty and administrators to have caring as a way of being if they wish to communicate caring as the essence of nursing to students. PMID- 8676205 TI - Nursing students' perspectives: experiences of caring and not-so-caring interactions with faculty. AB - The purpose of this study was to describe the meaning of baccalaureate nursing students' lived experience of caring and not-so-caring interactions with faculty. The research questions explored the phenomenon of being cared-for or not-cared for by asking, "What does being cared-for by faculty mean to baccalaureate nursing students?" Students were also asked to describe not-so caring interactions with faculty. Seventeen baccalaureate nursing students at a private liberal arts college and 15 baccalaureate nursing students at a public university were interviewed. Transcripts of the tape-recorded interviews were analyzed using Giorgi's technique. After reflection upon the content of the interviews, significant statements were identified, meaning units were developed, and themes were extracted which were then abstracted into categories of Recognition, Connection, and Confirmation/Affirmation. Finally, general structural descriptions of phenomena of a caring and of a not-so-caring interaction were constructed. Implications for teaching, research, and practice are described. PMID- 8676206 TI - A phenomenological study of faculty-student caring interactions. AB - Caring is an essential component in nursing that must be affirmed and nurtured. A National League for Nursing resolution in 1990 called for the incorporation of caring in nursing curriculum. Kelley's (1992) study of the major influences on senior nursing students' professional self-concept concluded that faculty were the dominant role models for caring. Nurse educators must determine effective ways of demonstrating caring. This study explored the perceptions of faculty caring behaviors as experienced by students at the practical nurse and nurses' aide levels. The research replicated a phenomenological study of baccalaureate nursing students (Beck, 1991). The results indicate that the participants perceived caring as recognition of their unique individuality and the sharing and giving of self and time by the faculty. Some unusual responses, deemed to be "positive-negatives" by the authors, are apparently unique to students at this entry level. The knowledge acquired in this study could be utilized by nursing faculty in order to reinforce or enrich caring interactions with students. PMID- 8676207 TI - Critical reflections about professional ethical stances: have we lost sight of the major objectives? AB - Increasingly, the professional literature reflects a call for the adoption of a (feminist) "ethic of caring" as a model for moral education is nursing. But what is not clear is the relationship between "care" and "ethics, " or between an "ethic of caring" and "moral education." Has ethics, and the issue of ethics education for nurses, become entangled with what may be a separate issue of an "ethic of caring" for the nursing profession? This article presents an overview of evolving ethical stances of three professions, and shows how the dichotomous views within philosophy and psychology have strongly influenced ethical thought in nursing. Major questions concerning the stances are raised. Nurse educators need to have a critical awareness of the scope and complexity of the discussion, and the ability to closely scrutinize conclusions reached by each profession's theorists. Viewpoints concerning what should comprise ethics education in nursing will depend on the particular ethical stance adopted. Ethics education for nurses will continue in its present confused state until there is focused and directed critical reflection about what is currently known regarding moral development, ethical thought, and the role of education in both. PMID- 8676208 TI - The RN-BSN student: developing a model of empowerment. AB - Nursing practice is being redefined. Today's graduating nurse is practicing in a tomorrow full of unknowns. The relevancy of traditional nursing education is being questioned in today's health care climate of crisis. In an attempt to prepare the graduating RN-BSN student to cope with these changes, nurse educators developed a process of empowerment. The framework for this effort was derived from the curriculum revolution, adult learning theory and empowerment research. The faculty defined empowerment as both an interpersonal process and an outcome. A graphic model has been created consisting of the four elements of empowerment: collegiality, communication, autonomy and accountability. Learning experiences are selected based upon these four elements. Teaching strategies are identified. Positive changes in student behavior have been reported anecdotally. The faculty are beginning the next phase: designing a research project to investigate behavior changes related to this empowerment model. PMID- 8676209 TI - A teacher looks back: the route to mastery. PMID- 8676210 TI - Caring as therapeutic in nursing education. AB - Caring outcomes in practice depend on a caring teaching-learning process. A transformation in thinking and practice in nursing education, that is congruent with the values of caring is essential to develop the kind of nurses that are needed in today's health care system. A project to implement caring as a nursing therapeutic with associate degree nursing students was initiated in a community college of Western New York in the fall of 1993. Watson's carative factors (1988) and Carper's ways of knowing (1978) were utilized as a framework to develop caring strategies to awaken a caring-consciousness among the students. The goals of the project were to provide a caring space for students to dialogue and share their stories and to experience themselves as caring and cared for; and to value and practice caring by implementing creative, knowledgeable, intentional actions for the ultimate good of the patient. PMID- 8676211 TI - Journal writing as a mode of thinking for RN-BSN students: a leveled approach to learning to listen to self and others. AB - Returning to academe, RNs are conceptualized as adult learners, as gendered authors, and as developing students. For most RNs prior learning has evolved from the rational-technical model from which they have learned to look at the world from a distance, relying on empirical evidence and negating or denying personal knowledge. Carefully constructed assignments in journal writing based on educational and developmental theory can be an effective means to assist RN-BSN students in social, cognitive, and professional development. Journal writing in response to assigned readings and clinical experiences provides a safe environment for RN-BSN students to explore critically the ideas of others, to look seriously at authorial intention and point of argument, and to articulate their own views of the world. Conceptually supported by student development and learning theories of Perry (1970) and Knowles (1984), and qualitative research with women's ways of knowing (Belenky, Clinchy, Goldberger, & Tarule, 1986), a leveled model of journal writing for RN-BSN students is described as a vehicle for the development of writing and thinking critically. PMID- 8676212 TI - Literary works as case studies for teaching human experimentation ethics. AB - Case studies are widely used as a teaching strategy for a variety of topics in various disciplines. They are particularly valued as a teaching strategy in the teaching of ethics because they provide a context for understanding the complexities of situations involving ethical dilemmas. This article describes the successful use of two literary works as case studies in teaching master's students about the ethical issues in human experimentation. Pygmalion and Flowers for Algernon were selected to exemplify the ethical considerations important in the conduct of research with human subjects. Students found the assignment both personally and professionally stimulating and recommended continued use of the assignment in the course. PMID- 8676213 TI - Estimation of daily minimum energy expenditure in free-moving rats and mice. AB - In this paper, we presented a new procedure to determine daily minimum energy expenditure (MEE) in free-moving rats and mice kept in a chamber. Energy expenditure was measured for 23 h period and averaged every 10 min. Data were sorted in ascending order. MEE was estimated from the regression line with the smallest slope and the biggest intercept among the regression lines calculated between the sorted energy expenditure and the data ranking. Among three duplicate measurements in individual animals, MEE gave the smallest coefficient of variation (2.2%) as compared with actual measured-values: either the single lowest value (4.0%) or the average of the 6 lowest values (2.5%). Judging from diurnal patterns of energy expenditure and locomotor activity and from video tape observation of the rat's performance, it was confirmed that MEE represented an energy expenditure at rest. MEE decreased with fasting from days 1 to 5. MEE per body weight also declined with age, but stayed around 71-72 kcal/day/kg3/4 at 18 and 34 weeks of age in male Wistar rats. MEE in mice increased at lower ambient temperatures between 16 and 32 degrees C, but stayed fairly constant at the same temperature in repeated experiments. Thus, MEE estimated by the present regression procedure was highly reproducible and valid to determine the fundamental value of daily energy expenditure under free-moving conditions. PMID- 8676214 TI - Profile of nucleotides and nucleosides of human milk. AB - The content of nucleotides and nucleosides of human milk was analyzed using a newly developed method for high performance liquid chromatography. By this method it is possible to analyze nucleotides and nucleosides simultaneously. Human milk was pooled according to season, lactation period, and geographical area. Three kinds of nucleosides--cytidine, uridine, and adenosine--and 6 kinds of nucleotides--5'-CMP, 5'-UMP, 5'-AMP, 5'-GMP, 5'-IMP, and 5'-CDP--were detected. Cytidine, 5'-CMP, and 5'-CDP predominated throughout lactation. Also there seemed to be geographical differences in nucleoside composition. The overall amounts of nucleotides and nucleosides were higher in winter than in summer. No nucleosides were detected in bovine milk, nor in bovine milk-based infant formula, and bovine milk contained much less nucleotides than human milk. These results suggest that nucleosides and nucleotides found in human milk may play some important roles in the development of infants. PMID- 8676215 TI - Characteristics of iron binding to solubilized brush border membrane of the rat intestine. AB - Characteristics of iron binding to the solubilized brush border membrane (BBM) of rat intestine were studied. Specific Fe(II) and Fe(III) binding sites were detected by iron binding assay using immobilized BBM from the upper intestine on a nitrocellulose sheet and the binding to Fe(II) was considerably higher than that to Fe(III). The dissociation constants for Fe(II) were 0.26+/-0.02 nm (M+/ SE) for high-affinity binding sites and 2.70+/-0.26 nm forlow-affinity binding sites. For Fe(II),the number of high-affinity binding sites was 0.35+/-0.04 x 10(16)/mg of protein (M+/-SE) and that of low-affinity binding sites was 1.07+/ 0.11 x 10(16)/mg of protein. Bound Fe(II) could not be replaced with Fe (II), Fe(III) or transferrin-bound iron and approximately 50% of bound Fe(II) was removed by chelators. The apparent molecular weights of Fe(II) binding peaks were 250 and 120 kDa by gel filtration. SDS-polyacrylamide gel electrophoresis (SDS PAGE) detected three bands with iron-binding activity. The distribution of the Fe(II) binding sites showed that the number of low-affinity sites was significantly higher in the proximal third of the intestine compared with the rest of the intestine. Iron deficiency increased the number of Fe(II) binding sites. These findings suggest that the Fe(II) binding sites might play a physiological role in iron absorption in the rat. PMID- 8676216 TI - Metabolism of essential amino acids in growing rats at graded levels of soybean protein isolate. AB - The metabolic fates of the carbon skeletons of essential amino acids were investigated in growing rats fed on diets containing graded percentages of protein calories (5, 10, 15, 20, 30, and 40 PC%) using soybean protein isolate at 4,100 kcal of metabolizable energy per kg of diet. The incorporation of 14C into the body protein 12 h after the intraperitoneal injection of labeled essential amino acids was more than 60% of the dose in the 5 to 10 PC% groups, but it began to decline gradually in the higher PC% groups. The expired 14CO2 production from labeled threonine, tryptophan, leucine, isoleucine, valine, phenylalanine, and lysine increased linearly with increasing levels of dietary soybean protein, but the rate of increase in the 14CO2 production was lower in the higher PC% groups. In comparison, the 14CO2 production from methionine, histidine, and arginine decreased in the 5 to 15 PC% groups, and it increased linearly in the higher PC% groups. The extent of 14CO2 production varied among the essential amino acids in each dietary group. These results indicate that the carbon skeletons of essential amino acids are mainly utilized for body protein synthesis, but significant amounts of their carbons are oxidized to expired carbon dioxide for energy production, and that the metabolic responses of these amino acids to dietary protein level change at around 20 PC%, where the growth rate reached its approximate maximum. The utilization of individual essential amino acids in rats fed on the soybean protein diets changed markedly as compared to those on purified whole egg protein diets, the results of which have been reported elsewhere. PMID- 8676217 TI - The role of macrophages in increased mitogen response of rat splenic lymphocytes following in vitro incubation with vitamin E. AB - The role of macrophages (M phi) in the enhancement of lymphocyte proliferation by alpha-tocopherol (VE) was investigated using rat splenocytes. The proliferation of whole splenocytes was significantly higher than that of M phi-depleted splenocytes at all concentrations of concanavalin A (Con A; 0.5-10 micrograms/ml). When whole and M phi-depleted splenocytes were preincubated with VE (2 micrograms/ml) for 24 h, the proliferation of whole splenocytes was significantly enhanced compared to that of whole splenocytes preincubated with medium alone. In contrast, M phi-depleted splenocytes did not show any increase of proliferation following in vitro pretreatment with VE. When the splenic: M phi pretreated with both VE (2 micrograms/ml) and Con A (10 micrograms/ml) for 24 h were further incubated with splenic lymphocytes, their proliferation was significantly enhanced compared to that of splenic lymphocytes cultured with splenic M phi pretreated with Con A. In this experiment, the medium containing 2 mercaptoethanol (2-ME) had the ability to enhance splenic lymphocyte proliferation, which masked the enhanced effect of VE on splenic: lymphocyte proliferation. Furthermore, in vitro treatment of VE could not decrease the production of prostaglandin E2, but could enhance the production of interleukin 1 from splenic M phi. These results suggest that M phi play an important role in the proliferation of splenic lymphocytes following in vitro incubation with VE, which is closely associated with the action of VE as an immunomodulator rather than antioxidant. PMID- 8676218 TI - c-myc mRNA is stabilized by deprivation of amino acids in primary cultured rat hepatocytes. AB - We investigated whether the expression of growth-related genes could be changed in primary cultured hepatocytes in response to changes in the nutritional environment. Hepatocytes were isolated from the liver of growing rats after collagenase perfusion and cultured in Williams' E medium (WE medium) containing 5% calf serum, 10(-7) M insulin and 10(-6) M dexamethasone for 24 h. When amino acids were removed from the culture, the level of c-myc mRNA increased more than 18-fold within 2-3 h, whereas replenishment of the amino acids to the medium caused rapid decrease in the mRNA level. We found that the half-life of the c-myc mRNA was prolonged more than 6-fold in the absence of amino acids. The mRNA levels of other proteins, such as ornithine decarboxylase, c-Ha-ras and actin, and their half-lives were not affected by amino acids. It is known that a short lived protein is involved in the degradation of c-myc mRNA. In fact, the addition of cycloheximide to cultured hepatocytes increased the level of c-myc mRNA either in the presence or absence of amino acids, though the levels of other mRNAs were not changed significantly. These results suggest that the synthesis of the short lived protein is suppressed and the c-myc mRNA is thereby stabilized in the absence of amino acids. PMID- 8676219 TI - Water-soluble viscous substance of Jew's mellow leaves lowers serum and liver cholesterol concentrations and increases fecal steroid excretion in rats fed a high cholesterol diet. AB - The effect of Jew's mellow leaf powder and its water soluble viscous substance on cholesterol metabolism in rats fed a high cholesterol diet was examined. When compared to the controls, total serum and liver cholesterol concentrations were significantly decreased or tended to decrease in the groups given dry powder of fresh Jew's mellow leaves, dry powder purchased from the market or residual powder after extracting with ethanol, whereas no difference was observed in those given residual powder after extracting with water. There were significant increases or increasing tendencies in the fecal excretion of bile acids, total neutral sterols and cholesterol in those fed the experimental diets when compared to the control group. Rats fed a diet containing a water-soluble viscous substance (1.7%, about 1% as dietary fiber) obtained from the dry powder of Jew's mellow leaves showed significant decreases in serum and liver cholesterol concentrations and increases in fecal excretions of bile acids and neutral sterols. Based on the above, the component of dry powder of Jew's mellow leaves that is effective in decreasing serum and liver cholesterol concentrations was found to be a soluble dietary fiber, and the mechanism was assumed to be largely due to the increased excretion of bile acids and neutral sterols. PMID- 8676220 TI - Effect of docosahexaenoic acid and sardine oil diets on the ultrastructure of hepatocytes in adult mice. AB - The influence of docosahexaenoic acid (DHA) on the ultrastructure of hepatocytes was studied. Adult male mice of Crj:CD-1 (ICR) strain were fed a fat-free purified diet supplemented with 5% (by weight) of purified DHA, refined sardine oil, and palm oil. The mice were fed the DHA diet or the palm oil diet for 7 days, and the sardine oil diet or the palm oil diet for one month. There were significant ultrastructural changes in the hepatocytes between the mice fed palm oil diet and the animals fed DHA and sardine oil diets. Many lipid droplets in the tissues of mice fed the palm oil diet were observed. Few lipid droplets were contained in the hepatocytes from the mice fed DHA and sardine oil diets, but electron-dense bodies were found in their tissues. These electron-dense bodies were mainly found near the region of the nucleus, blood sinusoids and bile canaliculi. These results suggest that the dense bodies found in the DHA and sardine oil diet groups may appear as a result of acceleration of lipid metabolism in the liver of mice. PMID- 8676221 TI - Effects of Platycodon grandiflorum feeding on serum and liver lipid concentrations in rats with diet-induced hyperlipidemia. AB - To study the effect of Platycodon grandiflorum (P.g.) feeding on serum and liver lipid concentrations, diet-induced hyperlipidemic rats were fed diets containing 5% and 10% P.g. powder for 3 weeks. The P.g. feeding markedly decreased both serum and liver lipid concentrations in hyperlipidemic rats. Especially, 5% P.g. diet significantly decreased the concentrations of total cholesterol and triglycerides in serum and liver as compared with those of the hyperlipidemic control group. Dietary P.g. also induced a reduction in low-density lipoprotein (LDL)-cholesterol as well as an increase in the concentration of high-density lipoprotein (HDL)-cholesterol in serum. Furthermore, the atherogenic index was also low in rats fed P.g. diet. These results indicated that dietary P.g. may have a beneficial effect on preventing hypercholesterolemia and hyperlipidemia. PMID- 8676222 TI - 4-oxo retinoic acid for refractory acute promyelocytic leukemia in children with all-trans retinoic acid therapy. AB - Therapy with all-trans retinoic acid (ATRA) achieves complete remission in a high proportion of patients with acute promyelocytic leukemia (APL), but the efficacy is reported to relate to plasma ATRA level after oral administration. The pharmacokinetics of ATRA and 4-oxo all-trans retinoic acid (4-oxo ATRA), a metabolite of ATRA, were studied in four children with APL at the time of initial oral administration. After administration of ATRA at a dose of 30 mg/m2, the peak plasma ATRA level was 20-741 ng/ml and was reached at 60-120 min. The patient with the lowest peak plasma level did not achieve complete remission and had a very high 4-oxo ATRA level compared to the patients with complete remission. These findings suggest that accelerated metabolism of ATRA plays a role in the failure of this agent in the patients without remission. PMID- 8676223 TI - The challenges of treating the elderly. PMID- 8676224 TI - The effect of local anesthesia with vasoconstrictor on gingival blood flow during Le Fort I osteotomy. AB - PURPOSE: In earlier studies, it has been documented that maxillary gingival blood flow (GBF) decreased significantly during the intraoperative course of a Le Fort I osteotomy. It was not clear, however, whether the observed decrease in GBF was caused by the osteotomy or by the use of local anesthetic with vasoconstrictor (LA + V). The purpose of this study was to measure the effect of LA + V on GBF during Le Fort I osteotomy using laser Doppler flowmetry (LDF). PATIENTS AND METHODS: Using a randomized clinical trial study design, patients undergoing Le Fort I osteotomy were assigned to either a treatment (group 1, LA + V used) or a control group (group 2, LA + V not used). The predictor variable was group assignment (LV + V used or not used). The outcome variable was mean maxillary GBF. Maxillary GBF was recorded at predetermined times during the operation. Other study variables included age, sex, single- or double-jaw surgery, estimated blood loss, direction and magnitude of maxillary movements, temperature, pulse, mean blood pressure, O2 saturation, and duration of operation. RESULTS: There were 19 patients in group 1 (LA + V used) and 15 patients in group 2 (LA + V not used). In both groups, mean maxillary GBF decreased significantly during the operation (group 1, 33.3 +/- 13.1 to 16.9 +/- 16.1 mL/ min/100 g tissue, P = .015; and group 2, 48.2 +/- 17.1 to 15.5 +/- 7.6 mL/min/100 g tissue, P = .001). The decrease in GBF occurred much earlier in group 1. By an average of 2.3 hours into the operation, the mean GBF was equivalent in both study groups (group 1, 10.6 +/- 8.6, and group 2, 13.1 +/- 9.4 mL/min/100 g tissue, P = .44). CONCLUSIONS: The results of this study confirm earlier findings that mean maxillary GBF decreases significantly during the intraoperative course of a Le Fort I osteotomy. In addition, LA + V significantly affects GBF during the early phase of the operation. Its effect, however, dissipates between the time of soft tissue dissection and maxillary downfracture. PMID- 8676225 TI - Prospective comparison of arthroscopy and arthrocentesis for temporomandibular joint disorders. AB - PURPOSE: A prospective, randomized study was undertaken to compare arthroscopy and arthrocentesis for treatment of temporomandibular joint disorders. PATIENTS AND METHODS: Nineteen patients with clinical and radiographic documentation of internal derangement of the temporomandibular joint(s) unresponsive to nonsurgical therapy were randomized to one of two surgical groups: arthroscopic lysis and lavage under general anesthesia or arthrocentesis, hydraulic distention, and lavage under intravenous sedation. Objective data were collected; including interincisal opening, lateral excursions, occlusal evaluation, deviation on opening, and tenderness to palpation. A questionnaire in the form of visual analog scales relating to pain, joint noise, jaw mobility, and dietary alterations was completed by each patient at 1 week, and 1, 3, 4, 12, and 26 months postoperatively. RESULTS: There was no statistically significant difference in outcome between the two groups for any parameter evaluated. Categorization of a particular subject into a successful outcome was based on statistically significant improvement in maximum incisal opening and pain scores; the overall success rate was 82% for arthroscopy and 75% for arthrocentesis. CONCLUSIONS: Therapeutic success was not significantly different for arthroscopy and arthrocentesis; both surgical modalities are useful for decreasing patient reports of pain while increasing functional mobility of the mandible. PMID- 8676226 TI - Location of the descending palatine artery in relation to the Le Fort I osteotomy. AB - PURPOSE: This study evaluated the positional relationship of the descending palatine artery to the Le Fort I osteotomy. MATERIALS AND METHODS: Three separate examinations were performed. In the first, 30 human skulls were used, and measurements were made of the greater palatine canal and foramen in relation to maxillary landmarks pertaining to the Le Fort I osteotomy. In the second, 40 patients with normal or minimal sinus mucosal thickening were selected from a pool of patients who underwent computed tomography (CT) scanning for sinus evaluation. These patients were scanned on a Somatome Plus spiral CT scanner as part of a routine sinus protocol, with the addition of an axial image 3 mm above the nasal floor where the Le Fort I osteotomy is usually performed. The distance from the greater palatine canal to the piriform rim was measured. In the third, eight fresh cadavers were used, and the distance from the internal maxillary artery to the nasal floor was measured. RESULTS: The internal maxillary artery enters the pterygopalatine fossa approximately 16.6 mm above the nasal floor and gives off the descending palatine artery. The descending palatine artery travels a short distance within the pterygopalatine fossa and then enters the greater palatine canal. It travels approximately 10 mm within the canal in an inferior, anterior, and slightly medial direction to exit the greater palatine foramen in the region of the second and third molars. CONCLUSION: Injury to the descending palatine artery during Le Fort I osteotomy can be minimized by not extending the osteotomy more than 30 mm posterior to the piriform rim in females. This distance can be extended to 35 mm in males. Pterygomaxillary separation should be made by closely adapting the cutting edge of a curved osteotome or right-angled saw to the pterygomaxillary fissure while avoiding excessive anterior angulation. Furthermore, the superior cutting edge of the osteotome or saw blade should be less than 10 mm above the nasal floor. PMID- 8676227 TI - Functional and morphologic changes after combined maxillary intrusion and mandibular advancement surgery. AB - PURPOSE: The purposes of this investigation were 1) to compare the morphology and function of patients with combined vertical maxillary excess (VME) and mandibular retrognathia with that of controls, and 2) to examine how these parameters change after combined maxillary intrusion and mandibular advancement surgery. PATIENTS AND METHODS: Fifteen female VME/retrognathic patients were compared with 26 female controls before and for up to 3 years after orthognathic surgery. Facial skeletal morphology, mandibular range of motion, maximum isometric bite force, and levels of electromyographic activity (EMG) in selected muscles of mastication were measured on all subjects. Where appropriate, one-way analysis of variance (ANOVA) or t-tests were used to compare the patients with controls. Univariate repeated-measures ANOVA was used to study longitudinal changes. RESULTS: Preoperatively, patients' morphologic measurements were characteristic of VME compounded by mandibular retrognathia. At surgery, the maxilla was elevated an average of 2.8 mm, and the mandible was lengthened by an average of 7.1 mm. All of the postoperative morphologic measurements were closer to normal values. The patients' masseter mechanical advantage was significantly lower than that of controls both before and after surgery. Surgically induced changes in mechanical advantage were very small. The patients' maximum range of motion and excursion during mastication were all lower than those of controls before surgery. All measurements of mobility decreased immediately after surgery, with a gradual return to preoperative values. However, even 3 years after surgery, all of the motion measurements remained smaller than those of the controls. Before surgery, the patients had maximum isometric bite forces significantly lower than those of controls. Bite forces increased significantly after surgery, approaching normal values within 2 years. The activity levels in the muscles of mastication during isometric bites were not significantly altered by surgery. CONCLUSIONS: This study confirms that VME/retrognathia patients suffer from substantial deficiencies in their oromotor function. Surgical correction of this particular type of dentofacial deformity improves both the morphologic and functional deficits. Although some changes were not statistically significant, all were toward normalization of the presurgical values. PMID- 8676229 TI - Endoscopic intracorporeal lithotripsy for sialolithiasis. AB - PURPOSE: This article describes a technique of salivary gland endoscopy using a 2.1-mm endoscope with a 1-mm working channel. The technique allows intracorporeal lithotripsy under endoscopic control. Two types of energy to produce calculi fragmentation were analyzed. PATIENTS AND METHODS: Of 39 patients who presented with obstructive sialoadenitis, endoscopic treatment was possible in 27. Eighteen had a diagnosis of sialolithiasis. Intracorporeal lithotripsy was done under endoscopic control in these patients. Laser energy was used to produce fragmentation in 3 cases and pneumobalistic energy in 9. In 6 cases, the calculi were extracted with forceps. RESULTS: Fifteen patients are free of stones and symptoms after a 6-month follow-up. Fragmentation and extraction of the calculi were not possible in 3 patients. Two of these patients required open surgery. The other patient is under observation. CONCLUSIONS: The use of endoscopes with a working channel allows irrigation to improve visibility during exploration. Both extraction of calculi and lithiasis fragmentation using different energies can be carried out through the channel. In this series, pneumoballistic energy (Lithoclast) has been shown to produce calculus fragmentation with more efficiency than lasertripsy (Dornier Impact). When dilation and placement of a cannula (Abocath 16 G) was done 2 days preoperatively, endoscopy was performed more easily. Postoperative drainage has proven effective in avoiding complications. PMID- 8676228 TI - A double-blind randomized comparison of midazolam alone and midazolam combined with ketamine for sedation of pediatric dental patients. AB - PURPOSE: The safety and efficacy of a new sedation technique for children having dental procedures under local anesthesia were evaluated. MATERIALS AND METHODS: One hundred children between the ages of 2 and 7 years who required sedation for dental procedures were administered either a combination of midazolam (0.35 mg/kg) and ketamine (5 mg/kg) or midazolam alone (1 mg/kg) rectally 30 minutes before removal to the dental chair. Pulse rate, respiratory rate, arterial pressure, oxygen saturation, adverse reactions, postoperative recovery, and behavior were recorded. RESULTS: Satisfactory sedation and anxiolysis were achieved with both drugs used in the study. When evaluating postoperative recovery, statistically significantly more children receiving midazolam alone were fully awake on admission to the recovery room and 30 minutes later. Results of physiologic monitoring, behavioral ratings, and adverse effects are reported. Excessive salivation occurred in 26% of children receiving the combination of drugs, compared with 14% receiving midazolam alone. Seven (14%) of the children receiving the combination of drugs hallucinated, compared with 21 (42%) receiving midazolam alone. Both drug groups had reliably good anxiolysis and sedation without loss of respiratory drive or protective airway reflexes. CONCLUSION: The use of a combination of midazolam and ketamine or midazolam alone is a safe, effective, and practical approach to managing children for minor dental procedures under local anesthesia. With this technique, advanced airway management proficiency is recommended. PMID- 8676230 TI - Predicting factors for distant metastases in head and neck carcinomas: an analysis of 103 patients with locoregional control. AB - PURPOSE: This study evaluated the ability of certain clinical and pathologic parameters to predict distant metastases (DMs) in patients with squamous cell carcinoma of the head and neck. MATERIALS AND METHODS: A total of 103 patients with histologically proven squamous cell carcinoma of the head and neck were studied. None had persistent or recurrent disease above the clavicle. Of these patients, 48 (47%) had metastatic lymph nodes. The relationships of tumor stage, primary site, clinical growth pattern, tumor differentiation, regional node status, and extranodal spread (ENS) with DMs were evaluated. RESULTS: Twenty-one (20%) of the 103 patients developed DMs as the initial treatment failure. The incidence of DMs was significantly higher in patients with neck metastases (40%) than in those without neck metastases (4%) (P < .001). The degree of histologic differentiation and the presence of ENS were also correlated with the subsequent occurrence of DMs. There was no statistical difference in the incidence of DMs based on sex, location, stage of the disease, and clinical growth pattern. On multivariate analysis, only pathologic nodal status and ENS proved to be independent cofactors of DMs. The most common site of DMs was the lungs (56%), followed by bone (16%) and skin (16%). CONCLUSION: The presence of pathologically positive nodes is the most critical factor to influence the eventual development of DMs. PMID- 8676231 TI - Analysis of reconstruction of mandibular defects using single stainless steel A-O reconstruction plates. AB - PURPOSE: This report reviews the results and complications of immediate reconstruction using a single stainless steel A-O plate after resection of mandibles invaded by malignant tumors. PATIENTS AND METHODS: Thirty-four patients were retrospectively evaluated. According to the extent of the tumor, hemimandibulectomy or segmental resection were performed in 4 and 30 cases, respectively. Five of 34 cases required a myocutaneous flap to close soft tissue defects. RESULTS: Nine of the 34 patients died during the follow-up period. Complications occurred in 7 of these patients: plate exposure was caused by local tumor recurrence (4 cases), screw loosening (1 case), and temporomandibular joint pain (2 cases). Twenty-five of the 34 patients (73.5%) were alive, with a mean follow-up of 47.4 months (range 6 to 115 months). Eighteen of the 25 surviving patients with the single A-O plate reconstruction did not show any complications. Thirteen of these (52%) patients had not undergone secondary reconstruction. Five of the 25 patients received secondary reconstruction for cosmetic or masticatory function reasons. Postoperative complications occurred in 7 of the 25 surviving patients (28%): extraoral plate exposure (2 cases), fracture of the plate (1 case), mandibular fracture (1 case), screw loosening (3 cases), and screw fracture (1 case). CONCLUSIONS: On the basis of the findings, it was concluded that a single A-O reconstruction plate can be used for temporary, or sometimes even permanent, reconstruction after mandibular resection. PMID- 8676232 TI - Treatment of mandibular angle fractures using one noncompression miniplate. AB - PURPOSE: This study evaluated the results in patients treated for fractures of the mandibular angle with a single miniplate. PATIENTS AND METHODS: Eighty-one patients with fractures of the mandibular angle were treated by open reduction and internal fixation using one noncompression miniplate with 2.0-mm self threading screws placed through a transoral incision. No patient was placed into postsurgical maxillomandibular fixation. They were prospectively studied for complications. RESULTS: Thirteen patients with angle fractures (16%) experienced complications requiring secondary surgical intervention. Most of the complications (n = 11), however, were minor and could be treated in the office. Most commonly, intraoral incision and drainage and later removal of the bone plate were required. All patients with minor complications had clinical union. Only two complications required hospitalization for intravenous antibiotics and further surgery. One of these patients had a fibrous union requiring a bone graft. CONCLUSIONS: The use of a single miniplate for fractures of the angle of the mandible is a simple, reliable technique with a relatively small number of major complications. PMID- 8676233 TI - Protein interactions with particulate Teflon: implications for the foreign body response. AB - PURPOSE: This study examined the nature of protein interactions with particulate polytetrafluoroethylene (PTFE, Teflon) to elucidate possible mechanisms involved in the foreign body response directed against failed Proplast/Teflon implants. MATERIALS AND METHODS: Fifty milligrams PTFE prepared to particle sizes ranging from < 32 microns to > 300 microns was incubated with newborn bovine serum. The total amount of protein adsorbed to the PTFE particles was determined using a standard colorimetric assay. The structural and functional integrity of the proteins adsorbed to PTFE was also examined. For these studies, xanthine oxidase was substituted for serum, and the enzymatic activity of xanthine oxidase adsorbed to PTFE was determined. Finally, primary interactions between protein and PTFE particles were assessed in experiments using water, 2 or 8 mol/L urea, 1 mol/L Nacl, or 1% sodium dodecyl sulfate in an attempt to dissociate bound protein from the surfaces of PTFE particles. RESULTS: Serum proteins bind almost instantly to the surface of PTFE particles. The effective surface area of PTFE increases dramatically with reduction of the material to small particles, as does the total amount of protein adsorbed by the particulate PTFE. Proteins bind to PTFE principally by hydrophobic interactions, and their three-dimensional structure is significantly perturbed by this interaction. In the case of xanthine oxidase, adsorption to PTFE distorts protein structure to the extent that biologic activity is eliminated. CONCLUSIONS: The amount of serum protein adsorbed to PTFE particles varies inversely with particle size for a constant mass of material. It is believed that the foreign body response directed against this material is related to the amount and relative distortion of proteins adsorbed to its surface. If so, it appears that reduction of an implant to small particles (typically 50 micron or less) will dramatically increase the biologic signal to local cell populations. Thus, the severity of the biologic response to PTFE debris may be dependent largely on the size of the debris particles. PMID- 8676235 TI - Part I. Mandibular reconstruction using vascularized bone grafts. PMID- 8676236 TI - Part II. Mandibular reconstruction using cancellous cellular bone grafts. PMID- 8676234 TI - Distribution and morphology of valves in the human external jugular vein: indications for utilization in microvascular anastomosis. AB - PURPOSE: This study examined the valves in the external jugular vein (EJV) that could affect microvascular anastomosis and increase the risk of thrombogenesis. MATERIALS AND METHODS: The EJVs of 57 sides from 36 cadavers aged 40 to 95 years (20 males and 16 females) were dissected. After opening the veins, the distribution and morphology of the valves were investigated using a stereoscopic microscope. The length of the valves and inner diameter of the vessels were measured and related to the location of the valves. RESULTS: Forty-nine (86%) of 57 EJVs were confluent with the subclavian vein. The EJV possessed bicuspid valves, and in 46 (93.9%) of the 49 specimens there were valves at the junction with the subclavian vein, whereas 44 (89.8%) contained valves in the middle portion of the specimen. The length of the valves was less than twice the inner diameter, and some were occasionally only rudimentary. CONCLUSION: Numerous valves exist in the middle portion of the EJV where microvascular anastomoses are performed. When valves are observed in the site of anastomosis, they can be avoided by resecting a length equal to approximately twice the inner diameter. PMID- 8676237 TI - Multiple, rapidly growing, submandibular masses. PMID- 8676238 TI - Nerve-sheath myxoma (neurothekeoma) of the oral cavity: a case report and review of the literature. PMID- 8676239 TI - Recurrent multifocal Langerhans cell eosinophilic granuloma of the jaws: report of a case. PMID- 8676240 TI - Lithium-induced diabetes insipidus in a surgical patient: report of a case and review of the literature. PMID- 8676241 TI - Horner's syndrome after vertical ramus osteotomy: report of a case. PMID- 8676242 TI - Intraoral lipoma of the tongue and submandibular space: report of a case. PMID- 8676243 TI - Perioperative angioedema in a patient on long-term angiotensin-converting enzyme (ACE)-inhibitor therapy. PMID- 8676244 TI - At odds about ratios and other statistics. PMID- 8676245 TI - Sharing our knowledge: the importance of international exchange of ideas in orthopaedic research. PMID- 8676246 TI - Transforming growth factor-beta 1 enhances bone healing to unloaded tricalcium phosphate coated implants: an experimental study in dogs. AB - Growth of bone into cementless prosthetic components is compromised after revision of failed joint prostheses and by osteoporosis, gaps, and micromotion. We studied the effects of recombinant human transforming growth factor-beta 1 adsorbed on ceramic coated implants on the improvement of mechanical fixation and bone growth on the implant. Unloaded cylindrical grit-blasted titanium alloy implants were inserted bilaterally into both the medial and lateral femoral condyles of 10 skeletally mature mongrel dogs. The implants measured 10 mm in length and 6 mm in diameter and were initially surrounded by a 2 mm gap. One implant had an uncoated titanium surface and three implants were coated with tricalcium phosphate and 0, 0.3, or 3.0 micrograms of recombinant human transforming growth factor-beta 1. The dogs were killed at 6 weeks. Mechanical testing showed a 3-fold increase in fixation for the 0.3 microgram dose of recombinant human transforming growth factor-beta 1 and a 2-fold increase for the 3.0 micrograms dose. Histological analysis of bone growth on the implant demonstrated that maximal stimulation occurred with the 0.3 microgram dose, but bone volume in the gap was maximally stimulated by the 3.0 micrograms dose and increased 2-fold over control values. The majority of tricalcium phosphate was resorbed after the 6-week observation period. This study suggests that recombinant human transforming growth factor-beta 1 adsorbed onto implants coated with tricalcium phosphate ceramic can enhance mechanical fixation and bone growth on the implant. The use of transforming growth factor-beta 1 on ceramic coated prosthetic components may help to improve the functional outcome of cementless total joint replacements. PMID- 8676247 TI - Porous ceramics as bone graft substitutes in long bone defects: a biomechanical, histological, and radiographic analysis. AB - Three porous ceramic bone graft materials were compared with regard to their ability to heal a 2.5 cm defect created surgically in a bilateral canine radius model. The ceramic materials were analyzed at 12 and 24 weeks after surgery and included tricalcium phosphate, hydroxyapatite, and collagen hydroxyapatite, which contained a mixture of 35% tricalcium phosphate and 65% hydroxyapatite with added collagen. Each material was evaluated alone and with added bone marrow aspirate. All the implants were compared with a graft of autogenous cancellous bone in the contralateral radius. Biomechanical testing and radiographic evaluation revealed that the addition of bone marrow aspirate was essential for tricalcium phosphate and hydroxyapatite to achieve results comparable with those of cancellous bone. Collagen hydroxyapatite performed well without the addition of bone marrow, although the addition of marrow did have a positive effect. Further qualitative radiographic and histological analysis demonstrated that tricalcium phosphate was the only ceramic that showed any sign of degradation at 24 weeks. This observed degradation proved to be an important factor in evaluating radiographs because the radiodensity of collagen hydroxyapatite and hydroxyapatite interfered with the determination of radiographic union. At 24 weeks, tricalcium phosphate with bone marrow was the material that performed most like cancellous bone. In this study, the biomechanical and radiographic parameters of tricalcium phosphate with bone marrow were roughly comparable with those of cancellous bone at 12 and 24 weeks. Tricalcium phosphate was the only implant that showed significant evidence of degradation at 24 weeks by both histological and radiographic evaluations, and this degradation took place only after a degree of mechanical competence necessary for weight-bearing was achieved. PMID- 8676248 TI - Differential effects of insulin-like growth factor-I on matrix and DNA synthesis in various regions and types of rabbit tendons. AB - Tendon healing and integration of tendon grafts may be site or donor specific. To determine if differences exist in sensitivity to growth factors that have the potential to influence tendon repair, we compared the effects of recombinant human insulin-like growth factor-I on various types of tendon segments. The dose response effects on proteoglycan, collagen, noncollagen protein, and DNA synthesis were investigated in short-term explant cultures of intrasynovial intermediate and proximal segments of deep flexor tendons extrasynovial segments of deep flexor tendons, and Achilles tendons of rabbits. The four different types of tendon segments cultured in media without recombinant human insulin-like growth factor-I synthesized similar amounts of each of the matrix components. Intrasynovial proximal segments synthesized 15 times less DNA than other tendon segments. Recombinant human insulin-like growth factor-I stimulated matrix and DNA synthesis of all tendon segments in a dose-dependent manner in intervals from 10 to 1,000 ng/ml. The potency (LogED50) of the stimulation did not differ between the segments. The estimated maximal stimulation (E(max)) of proteoglycan synthesis by recombinant human insulin-like growth factor-I was higher, and of collagen and noncollagen protein synthesis was lower, in intrasynovial proximal segments as compared with that of the other types of segments. In contrast, the estimated maximal stimulation of DNA synthesis by recombinant human insulin-like growth factor-I was 6-fold higher than controls in all types of tendons. These findings demonstrate differences in mitotic capacity between anatomical regions of tendons during culture without recombinant human insulin-like growth factor-I and in matrix synthesis after stimulation with it. PMID- 8676249 TI - Biomechanical effects of stress shielding of the rabbit patellar tendon depend on the degree of stress reduction. AB - A rabbit model was used to discover whether the effects of stress shielding on the mechanical properties of the patellar tendon depend on the degree of stress reduction. Ninety mature female Japanese White rabbits were divided into three groups: completely stress-shielded partially stress-shielded and sham-operation and contralateral controls. In the experimental groups, tension applied to the patellar tendon was 0%, approximately 30%, and 100% of the normal tension, respectively, with a polyester artificial ligament. Tensile tests were carried out on patella-patellar tendon-tibia complexes harvested 1, 2, 3, 6, or 12 weeks after surgery. The tensile strength decreased in comparison with the sham operation group to 50.2, 13.5, 9.7, and 20.7% in the completely stress-shielded group and to 75.2, 57.6, 59.6, 57.3, and 72.9% in the partially stress-shielded group. The tensile strength in the completely stress-shielded group was significantly less than that in the partially stress-shielded group at 1, 2, 3, and 6 weeks. The cross-sectional area of the patellar tendon significantly increased to 132, 206, 237, and 136% in the completely stress-shielded group and to 136, 170, 175, 155, and 127% in the partially stress-shielded group compared with the sham-operation group. The cross-sectional area of the completely stress shielded tendon was significantly larger than that of the partially stress shielded tendon at 1, 2, and 3 weeks. This study demonstrated that effects of stress shielding on the mechanical properties of the patellar tendon were dependent on the degree of stress shielding. PMID- 8676251 TI - Protective effect of hypothermia on contractile force in skeletal muscle. AB - The clinical success of limb replantation and tissue transfer is partly dependent on the duration of ischemia experienced by the amputated part. This study focused primarily on the damage that occurs during this ischemic period. An experimental system was implemented that allowed the observation of contractile function in totally isolated skeletal muscle after ischemia. Contractile function was selected as an indicator of ischemic damage because normal function is the ultimate goal of replantation. All experiments were performed on the rat extensor digitorum longus. The muscles were subjected to ischemic periods of 1.5, 3.0, and 5.0 hours and were stored in either a hypothermic (4 degrees C) or a room temperature (23 degrees C) environment during the ischemic interval. After the ischemic period, all muscles were transferred to a tissue bath and were subjected to contractility testing, followed by fatigue testing. In both groups, muscle function decreased as the ischemic interval was increased. A significant difference in function between the normal control and the muscles of both ischemic groups implied that ischemic injury had occurred in the hypothermic and room-temperature muscles, even with the relatively short 1.5-hour ischemic interval. After each ischemic interval however, the hypothermic muscles produced significantly greater contractile force than the room-temperature muscles in both the contractility and the fatigue tests. After 1.5 hours of ischemia, the contractile force in the hypothermic group was about three times as great as that observed in the room-temperature group. These results indicated that muscle function after a period of totally isolated ischemia is protected by hypothermic preservation. They also support the advisability of storage of amputated parts and free muscle flaps in hypothermic environments before replantation even after relatively brief intervals of ischemia. PMID- 8676250 TI - Distribution of cellular repopulation and collagen synthesis in a canine anterior cruciate ligament autograft. AB - Whether the central core of an anterior cruciate ligament autograft reconstruction is nutritionally compromised at a time when revascularization is known to be complete has not been determined by methods that detect matrix synthesis. In a canine model of anterior cruciate ligament reconstruction with patellar tendon autograft, the adequacy of the supply of metabolites for cellular matrix synthesis was determined by autoradiographic analysis. Total collagen synthesis and cellularity were also quantified. Total collagen synthesis was found to be significantly elevated (p = 0.014 by analysis of variance) in the ligament reconstructions as compared with normal anterior cruciate ligaments or patellar tendons but cellularity was not (p = 0.13 by analysis of variance). Autoradiography demonstrated even distribution of [3H]proline incorporation throughout the graft and normal tissue. When revascularization was complete there was an adequate supply of metabolites for cellular synthesis of protein macromolecules within all regions of the ligament reconstruction. At 3 months after reconstruction, the grafts were found to be actively remodeling their collagen matrix. Since the long-term function of an anterior cruciate ligament autograft is dependent on viable fibroblasts to maintain the collagen matrix the canine anterior cruciate ligament reconstruction contains living cells that are able to remodel the matrix under appropriate conditions. PMID- 8676253 TI - Expression of syndecan-3 and tenascin-C: possible involvement in periosteum development. AB - The development of cartilaginous elements of long bone during embryogenesis and postnatal bone repair processes is a complex process that involves skeletal cells and surrounding mesenchymal periosteal cells. Relatively little is known of the mechanisms underlying these processes. Previous studies from this and other laboratories have suggested that the extracellular matrix protein tenascin-C is involved in skeletogenesis. Using in situ hybridization and immunofluorescence, we extended those studies by comparing the expression of tenascin-C with that of syndecan-3, which belongs to a family of cell surface receptors with which tenascins are known to interact. We found that syndecan-3 transcripts at first were very abundant in the presumptive periosteum surrounding the diaphysis of early chondrocytic skeletal elements in chick limb. As the elements developed further, syndecan-3 gene expression decreased in the diaphyseal periosteum, whereas it became stronger around the early epiphysis and within the forming articular cells. However, as the diaphyseal periosteum initiated osteogenesis and gave rise to the intramembranous bone collar, syndecan-3 gene expression increased again. At early stages of skeletogenesis: the tenascin-C gene exhibited patterns of expression that were similar to and temporally followed, those of the syndecan-3 gene. At later stages, however, tenascin-C gene expression was markedly reduced during intramembranous osteogenesis around the diaphysis. In addition, although syndecan-3 gene expression was low in osteoblasts and osteocytes located deep into trabecular bone, tenascin-C gene expression remained strong. Thus, tenascin-C and syndecan-3 display distinct temporal and spatial patterns of expression in periosteum and during the development of long bone. Given their multidomain structure and specific patterns of expression, these macromolecules may regulate site-specific skeletal processes, including interactions between developing periosteum and chondrocytes and delineation of the early cartilaginous skeletal elements. PMID- 8676252 TI - Human breast cancer induces osteoclast activation and increases the number of osteoclasts at sites of tumor osteolysis. AB - The cellular mechanism through which osseous breast cancer metastases induce the focal destruction of bone (tumor osteolysis) is unknown. An athymic mouse model designed for the study of tumor osteolysis was developed and the influence of two human breast cancer tumors on bone was studied. Tumor-induced osteolysis occurred between 7 and 10 weeks after inoculation of mouse femora with MDA-MB-231 or MDA MB-435s breast cancer cells. An increase in osteoclast number and an increase in osteoclast size (area) were detected when tumor-bearing and sham-injected limbs were compared. In vitro analysis of the influence of the tumor-conditioned medium on osteoclast-mediated bone resorption revealed that this conditioned medium stimulated the resorption by increasing both the number of osteoclasts bound to bone and the number of bone resorption pits formed per osteoclast. In addition, in vitro analysis of the influence of breast cancer tumor cells on osteoclast formation or survival, or both, demonstrated that breast cancer cells induced a dramatic increase in the number of osteoclasts detected in culture. Taken in total these findings suggest that human breast cancer tumors induce osteolysis by enhancing osteoclast adherence to bone, stimulating osteoclast-mediated bone resorption and either prolonging the survival of osteoclasts or increasing osteoclast formation. PMID- 8676254 TI - Chondrocyte survival in cryopreserved osteochondral articular cartilage. AB - Fluorescent staining techniques were used in combination with confocal and conventional fluorescent microscopy to determine the location of viable chondrocytes in frozen and thawed osteochondral articular cartilage. The results showed that cell survival was confined to the superficial layer of the cartilage matrix. The addition of a cryopreservative agent (dimethyl sulfoxide) increased chondrocytes survival but only in the same layer. There was no evidence of cell survival in the middle or deep layers of the cartilage with or without the use of dimethyl sulfoxide. Under the conditions employed in this study, chondrocyte survival in a cryopreserved osteochondral allograft appears t be limited to the superficial layer of the articular cartilage. PMID- 8676255 TI - Swelling and fibronectin accumulation in articular cartilage explants after cyclical impact. AB - The objective of this study was to determine if repeated impact could damage living cartilage and lead to osteoarthritis-like changes in its biology. Canine cartilage explants were subjected to impacts of as much as 50 MPa once every 5 seconds for 30 minutes. On each impact cycle, the loading rate was 100 MPa/sec to the assigned peak stress, which was held for 1 second. After impact testing, the cartilage was kept in defined culture for as long as 10 days. Radiosulfate incorporation in the region that received direct impact varied with load 0-4 hours after impact, but it did not vary with load at 20-24 hours after impact. Even so, most explants were visibly damaged by 20 or 50 MPa, and there was subtle evidence of damage from impacts of 5 or 10 MPa. For example, ion-induced swelling in 0.01 M NaCl was increased, suggesting that the physical integrity of the matrix was reduced relative to controls. Self-diffusion of water, measured by proton magnetic resonance imaging was also increased in the deeper zones of the explant, consistent with changes in structure at the molecular level. Ten days after impact, the water content and the fibronectin content of the loaded region of the explant were both increased. In combination, these osteoarthritis-like changes suggested that the physical strength of normal cartilage limits its ability to withstand cyclical impact. PMID- 8676256 TI - Zone-specific cell biosynthetic activity in mature bovine articular cartilage: a new method using confocal microscopic stereology and quantitative autoradiography. AB - A new methodology was developed to measure spatial variations in chondrocyte/matrix structural parameters and chondrocyte biosynthetic activity in articular cartilage. This technique is based on the use of a laser scanning confocal microscope that can "optically" section chemically fixed, unembedded tissue. The confocal images are used for morphometric measurement of stereologic parameters such as cell density (cells/mm3), cell volume fraction (%), surface density (l/cm), mean cell volume (micron3), and mean cell surface area (micron2). Adjacent pieces of tissue are simultaneously processed for conventional liquid emulsion autoradiography, and a semiautomated grain counting program is used to measure the silver grain density at regions corresponding to the same sites used for structural measurements. An estimate of chondrocyte biosynthetic activity in terms of grains per cell is obtained by dividing the value for grain density by that for cell density. In this paper, the newly developed methodology was applied to characterize the zone-specific behavior of adult articular cartilage in the free-swelling state. Cylinders of young adult bovine articular cartilage were labelled with either [3H]proline or [35S]sulfate, and chondrocyte biosynthesis and structural parameters were measured from the articular surface to the tidemark. The results showed that chondrocytes of the radial zone occupied twice the volume and surface area of the chondrocytes of the superficial zone but were 10 times more synthetically active. This efficient and unbiased technique may prove useful in studying the correlation between mechanically induced changes in cell form and biosynthetic activity within inhomogeneous tissue as well as metabolic changes in cartilage due to ageing and disease. PMID- 8676257 TI - Topographic variation in biglycan and decorin synthesis by articular cartilage in the early stages of osteoarthritis: an experimental study in sheep. AB - Articular cartilage contains large molecular weight proteoglycans that aggregate with hyaluronic acid (aggrecan) and small species, particularly biglycan (dermatan sulphate proteoglycan-1) and decorin (dermatan sulphate proteoglycan 2), that do not. Mechanical stresses have been shown to profoundly influence the metabolism of aggrecan by articular chondrocytes; however, there are limited corresponding data on the metabolism of dermatan sulphate proteoglycans 1 and 2. The objective of this study was to examine the metabolism of aggrecan, biglycan, and decorin in articular cartilage from different weight-bearing areas of normal ovine stifle joints and in joints 6 months after menisectomy, a procedure that has been shown to induce early osteorthritic changes. [35S]proteoglycans synthesised by cartilage explants from eight different weight-bearing regions of unoperated and meniscectomised ovine stifle joints during 48 hours of culture were separated by size-exclusion chromatography, hydrophobic chromatography, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis and were quantitated by phosphor-screen autoradiography. The synthesis and degradation of the proteoglycans were expressed relative to the DNA content of the explants. In control joints, the cartilage exposed to high contact stress synthesised significantly less proteoglycan overall and more decorin than joint regions bearing less stress. Explants from high stress regions also released significantly greater amounts of resident proteoglycans (dimethylmethylene blue positive) into media during culture. After lateral meniscectomy, the lateral tibial and femoral cartilages showed elevated biosynthesis of both 35S-dermatan sulphate proteoglycans 1 and 2. This chondrocyte biosynthetic response was accompanied by increased catabolism of aggrecan and the release of its degradation products into culture media. These experiments revealed, in normal joints, a topographic variation in proteoglycan synthesis by articular cartilage that was related to the mechanical stress to which the tissues were subjected in vivo. This biosynthetic pattern changed when the load distribution of the joint was altered by unilateral meniscectomy. These data suggest that an altered chondrocyte phenotypic expression of proteoglycans in response to abnormal mechanical loading is an early event in osteoarthritis. PMID- 8676258 TI - In vitro bone biocompatibility of poly (anhydride-co-imides) containing pyromellitylimidoalanine. AB - Poly(anhydride-co-imides) are currently under study for applications involving bone. The cytotoxicity of a series of poly(anhydride-co-imides) with osteoblast like cells (MC3T3-E1) was evaluated. The imide component of the copolymers was based on pyromellitylimidoalanine and the anhydride component was based on either sebacic acid or 1,6-bis(carboxyphenoxy)hexane. Cell adhesion and proliferation on the surfaces of the polymer discs were observed by environmental scanning electron microscopy. During the first 24 hours of attachment, the cells showed normal morphology when cultured on copolymers containing 1,6 bis(carboxyphenoxy)hexane. The cells did not adhere to the polymers containing sebacic acid, probably due to the rapid degradation of the polymer surfaces. Concurrently, the effects of polymer breakdown products on osteoblast-like cells were evaluated by studying their proliferation (cell numbers), viability (dye exclusion), morphology (light microscopy), and phenotypic expression. The morphology of osteoblast-like cells cultured in the presence of the polymer breakdown products pyromellitylimidoalanine and pyromellitic acid was found to be similar to that of the same cells grown on tissue culture polystyrene and consisted of a characteristic polygonal shape. With use of a monoclonal antibody to osteocalcin, these cells were shown to demonstrate preserved osteoblast phenotype with growth over a 21-day period. In addition, the cells reached confluency after 3-4 days, similar to cells grown on tissue culture polystyrene. This in vitro evaluation showed that the poly(anhydride-co-imides) evaluated are non-cytotoxic and may be viable biomaterials for orthopaedic applications. PMID- 8676259 TI - Influence of biomaterial surface texture on bone ingrowth in the rabbit femur. AB - The purpose of this study was to examine both the histologic and the mechanical characteristics of bone apposition to an experimental surface, arc-deposited titanium, in a rabbit model and to compare them with those of four previously studied surfaces: one layer of cobalt-chromium beads, three layers of cobalt chromium beads, plasma-sprayed cobalt-chromium, and uncoated titanium alloy. Bilateral cylindrical implants were press-fit into the lateral femoral condyles of 70 adult New Zealand White rabbits, which were allowed unrestricted activity and then killed at 6 or 12 weeks. The distal femora were harvested, radiographed, and prepared for either mechanical or histologic evaluation. All of the implants with coated surfaces had significantly greater shear strength than the implants of grit-blasted titanium alloy after both 6 and 12 weeks. After 6 weeks, maximum bone apposition occurred in the beaded surfaces. After 12 weeks, the shear strengths and bone apposition of implants of arc-deposited titanium and of one and three layers of cobalt-chromium beads were significantly greater than those of implants of plasma-sprayed cobalt-chromium and grit-blasted titanium alloy. The histologic studies correlated with the mechanical results. After 12 weeks, the bone apposition and mechanical stability of arc-deposited titanium were similar to those of a single layer of beads. There appeared to be no advantage to multiple layers of beads, and the plasma-sprayed cobalt-chromium and grit-blasted titanium surfaces showed lower shear strength and bone apposition than the other groups. PMID- 8676260 TI - In vitro activation of human fibroblasts by retrieved titanium alloy wear debris. AB - Titanium-aluminum-vanadium wear particles isolated from the soft-issue membrane of a failed total hip arthroplasty were added to human fibroblasts in cell culture. The cellular response to particle challenge was determined by assaying for levels of interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, prostaglandin E2, basic fibroblast growth factor, platelet-derived growth factor AB, and transforming growth factor-beta. Collagenase and gelatinase activities were analyzed by zymography and [3H]collagen degradation. Cell viability was assessed by measuring the uptake of [3H]thymidine. Over the range of particle concentrations tested, cell viability, as demonstrated by [3H]thymidine uptake, remained unaffected. Fibroblasts exhibited a dose-dependent release of interleukin-6 in response to exposure to titanium-aluminum-vanadium particles. At 6 and 48 hours, the highest concentration of titanium alloy particles (0.189% [vol/vol]) resulted in 7-fold and 16-fold increases in interleukin-6 release, respectively, when compared with negative controls. Neither interleukin-1 beta nor tumor necrosis factor-alpha was detected in the culture medium at any particle concentration tested for both dermal and foreskin fibroblasts. The pattern of prostaglandin E2 release by fibroblasts mirrored the pattern of interleukin-6 release. Fibroblasts exposed to the highest concentration of titanium alloy particles showed an increase in collagenase activity, starting at 12 hours. When medium samples were treated with amino phenylmercuric acetate to activate latent enzymes, a statistically significant increase in collagenase activity was observed as early as 6 hours (p < 0.001). Substrate gel analysis of medium from fibroblasts stimulated by high particle concentrations also showed an increase in gelatinolytic activity when compared with unstimulated controls. Analysis of medium samples for growth factors showed an increase in basic fibroblast growth factor at low particle concentrations, beginning at 12 hours. Levels of platelet-derived growth factor-AB and transforming growth factor-beta were not detectable in the controls or at any particle concentration tested. The results of this study showed that fibroblasts exposed to titanium alloy wear particles become activated and release proinflammatory mediators that influence bone metabolism. These data support the hypothesis that direct activation of fibroblasts by particulate wear may play a role in particle-mediated osteolysis. Fibroblast activation coupled with the biologic response of macrophages to wear debris in the loosening membrane may have a synergistic effect on pathologic bone resorption. PMID- 8676261 TI - Bone formation and bone resorption in failed total joint arthroplasties: histomorphometric analysis with histochemical and immunohistochemical technique. AB - To elucidate the reactions of bone around aseptically loosened total joint arthroplasties, 24 interface tissues with adjacent bone were obtained in 17 revision operations (11 hips and six knees). The morphology of the bone surface next to the interface membrane was investigated with histochemical and immunohistochemical techniques and then histomorphometrically analysed. One-third of the total bone surface. 32.69 +/- 5.16% (mean +/- SE) (n = 24), showed positive alkaline phosphatase activity. The bone surface in contact with the cells positive for CD11b (a macrophage marker) amounted to 19.33 +/- 5.16% (n = 24). The proportion of the osteoclastic bone resorption estimated by vitronectin receptor expression was 7.67 +/- 1.82% (n = 21). Tissues retrieved from the sites where radiographic evidence of osteolysis was present (n = 12) had a significantly larger extent of the bone surface in contact with CD11b-positive cells than did the tissues from areas without osteolysis (n = 12, p = 0.0067, Mann-Whitney U test), whereas no significant difference was observed in the extent of osteoclastic bone resorption. These data demonstrate that active bone formation, regarded as a repair process, is the most common feature even in revised cases. They also highlight the role played by macrophages, not as cells producing inflammatory mediators that could activate osteoclasts, but as cells primarily responsible for the bone loss in osteolytic lesions. PMID- 8676262 TI - Curved beam model of the proximal femur for estimating stress using dual-energy X ray absorptiometry derived structural geometry. AB - The investigation of individual differences in hip strength requires a method to measure structural geometry in vivo and a valid analytical approach to calculate mechanical stress. We developed a method for deriving structural geometry of the femur from the proximal shaft through the femoral neck, using data from dual energy X-ray absorptiometry. The geometric properties are employed in a two dimensional curved beam model of the proximal femur to estimate stresses on the lateral and medial bone surfaces. Stresses calculated by this method are compared with those from the conventional flexure formula and with results produced from a cadaver femur with use of three-dimensional finite element analysis of computed tomography data. Loading conditions simulating a one-legged stance and a fall on the greater trochanter are employed. Stresses calculated by curved beam theory are in much better agreement with three-dimensional finite element analysis than are those for which the conventional straight beam formula was used. In simulation of a fall on the greater trochanter, all three methods show peaks of stress at the femoral neck but only the curved beam and finite element analysis methods show an additional peak at the medial intertrochanteric margin. Both neck and trochanter regions correspond to common failure sites for hip fractures in the elderly. The curved beam treatment of hip structure derived from dual-energy X-ray absorptiometry provides an approach for the in vivo engineering analysis of hip structure that is not practical by other methods. PMID- 8676263 TI - Type-I collagen mutation compromises the post-yield behavior of Mov13 long bone. AB - Despite recent advances in our understanding of the molecular basis of skeletal fragility, little is known about how these molecular alterations lead to whole bone brittleness. In the current study, we investigated the relationship between a type-I collagen mutation and post-yield behavior of whole bone in Mov13 transgenic mice by considering tissue-level organizational issues known to be important for normal bone fracture. Mechanical assays revealed that the post yield deflection of Mov13 femurs was reduced by 61% relative to littermate controls. Fractographic images revealed that lamellar interfaces which were important for dissipating energy during the failure process of control femurs, were not effective in Mov13 mice. Further investigation revealed that a 22% reduction in bone collagen content, a 2-fold increase in tissue porosity, and significant alterations in collagen organization interfered with normal energy dissipation mechanisms of Mov13 microstructure. Collectively, the results provided the first evidence that the reduced ductility associated with a type-I collagen mutation was mediated by alterations in intermediate structures that normally contribute to the post-yield behavior of cortical bone. The results suggest that, to better understand the pathogenesis of skeletal fragility, it is important to consider the effects of molecular alterations on higher-level structures, particularly those structures that contribute to the failure mechanisms in normal bone. PMID- 8676264 TI - Biomechanical comparison of calf and human spines. AB - Given the limited availability of human cadaveric specimens and their potential risk of infection, calf spines have been used as substitutes for human spines in the evaluation of spinal implants. Few biomechanical data comparing calf and human spines are available, however. The purpose of this study was to determine the biomechanical properties of the calf spine and to compare them with properties previously reported for the human spine. We determined the range of motion neutral zone, and stiffness of thoracic and lumbar calf spines (T6 to L6) under pure moment loading in flexion-extension, axial rotation, and lateral bending. These properties were shown to be similar to those of the human spine. The results suggest that the calf spine can be used as a substitute for the human spine in some in vitro tests. PMID- 8676265 TI - Role of aspartate in ischemic spinal cord damage. AB - To study the potentially different roles of the excitatory amino acids glutamate and aspartate in the development of ischemic injury of the spinal cord, we measured their release from cultured neurons and glial cells under ischemic conditions. We also examined changes in intracellular Ca2+ concentration and the damage elicited in cultured neurons by glutamate and aspartate. Hypoxic hypoglycemic treatment (in vitro ischemia) elicited a rapid release of the excitatory amino acids from cultured spinal cord neurons and glial cells, but the release was greater from glial cells than from neurons. The ischemia-induced glutamate release from glial cells was transient; the aspartate release lasted longer, although the peak level was smaller than that of glutamate. In cultured neurons, a remarkable elevation in intracellular Ca2+ concentration was induced by glutamate but not by a lower concentration (10 microM) of aspartate, which is below the neurotoxic dose. At the higher concentration (100 microM), both excitatory amino acids induced a marked elevation in intracellular Ca2+ concentration and neuronal death. These results indicate that aspartate is less potent than glutamate in eliciting excitatory neurotransmission under normal physiological conditions. However, under pathological conditions such as ischemia, the increased release of aspartate from glial cells may add to the damage to neighboring neurons. PMID- 8676266 TI - The effect of non-surgical periodontal and adjunctive minocycline-HCL treatments on the activity of salivary proteases. AB - The purpose of this investigation was to evaluate the effect of non-surgical periodontal treatment and adjunctive systemic minocycline therapy on the level of neutral protease activity in whole saliva of adults with periodontitis. A test group of 21 adult patients with moderate to severe periodontitis was compared to a control group of 5 adults with healthy periodontium. Four test groups were examined: 1) scaling and root planing (SRP), probing depth = 4 to 5 mm; 2) SRP, PD > or = 6 mm; 3) SRP and adjunctive systemic minocycline therapy, PD = 4 to 5 mm; 4) SRP and adjunctive systemic minocycline therapy, PD > or = 6 mm. Clinical parameters and levels of neutral protease in whole saliva were assessed at baseline and on the sixth week after the non-surgical periodontal treatment. Neutral protease activity was measured by spectrofluorimetric method. Statistical tests of Mann-Whitney and Spearman Rank correlation coefficient were used in the evaluation of the mean values of measurements. The mean values of protease activity were significantly higher in the test groups than in the control group at baseline. Six weeks after non-surgical therapy, patients with 4 to 5 mm probing depth had approximate values of protease activity comparable to the control group. Hence it can be argued that these patients did not need minocycline HCL as an adjunctive therapy. However, non-surgical therapy had limited effects on both clinical parameters and enzyme activities for subjects with > or = 6 mm probing depth; on the other hand, gingival inflammation and enzyme activities were reduced significantly by the usage of minocycline as adjunctive therapy in these patients. According to our results, neutral protease activity in saliva is related to probing depth and gingival bleeding index, and not related to age and epithelial cell number. For these reasons, systemic minocycline therapy might be useful as an adjunct to non-surgical therapy in the presence of deep pockets, especially for reinfected cases. Further investigations are needed to confirm this suggestion. PMID- 8676267 TI - Cervical cemental tears in older patients with adult periodontitis. Case reports. AB - This communication reports 5 cases of cervical and 1 apical cemental tears. The diagnosis of the cervical tears was made by a characteristic feature which presented radiographically as a prickle-like body. The fragment of cementum could be detached by root planing or during periodontal surgery and uneventful healing was obtained following these procedures. The process of aging in addition to continuous occlusal strain may lead to this phenomenon. Cervical cemental tear may be one of the contributing factors in the progress of adult periodontitis. PMID- 8676269 TI - Reduction of aerosols produced by ultrasonic scalers. AB - There is concern with decreased air quality and potential aerosol contamination in the dental operatory. This problem has been addressed by the Centers for Disease Control and Prevention, which recommends that all sources of blood contaminated splatter and aerosols be minimized. One of the major sources of potential aerosol contamination in the dental setting is the ultrasonic scaler. This study looks at the use of a high volume evacuator attachment for the ultrasonic scaler handpiece. Artificial teeth were mock-scaled for 1 minute with and without the evacuator attachment. The mock scaling was performed within a plastic enclosure that had a 1 cm grid laid out on 4 sides. Scaling was performed 10 times each by 2 operators. An erythrosin solution was used for the ultrasonic scaler coolant with a coolant volume of 17.5 ml/min. The number of squares containing a red erythrosin spot were counted and considered to represent aerosol contamination. The high volume evacuator attachment produced a 93% reduction in the number of contaminated squares (chi squared significant at P < 0.05). There was no increase in heat transfer to a tooth analogue when the high volume evacuator attachment was used with the ultrasonic scaler as compared to the scaler without the evacuator attachment. It is felt that the high volume evacuator attachment is capable of significantly reducing the amount of aerosol contamination produced within the test system without increased heat transfer to the tooth. PMID- 8676268 TI - Ultrastructural and histochemical features of the ground substance in cyclosporin A-induced gingival overgrowth. AB - The overgrowth-affected gingiva of patients treated with cyclosporin A after kidney transplant was examined with ultrastructural and histochemical methods to evaluate the involvement of connective tissue. Gingival overgrowth has the same clinical signs as local edema. The ultrastructural study showed that the dimensional increase was largely due to increased production of amorphous ground substance by fibroblasts, possibly resulting from an increased release of histamine by mast cells. The histochemical data revealed that the affected tissues contained higher levels of glycosaminoglycans and that cyclosporin A induced comparably high levels of glycosaminoglycans in in vitro cultures of fibroblasts obtained from normal gingiva. The combination of ultrastructural and histochemical data, therefore, strongly suggests that the response of the connective tissue in gingival overgrowth cannot be ignored and may be the main cause of the observed pathological condition. PMID- 8676270 TI - Periodontal disease in HIV seropositive patients and its relation to lymphocyte subsets. AB - This study was performed to determine the type of periodontal pathology found in a group of HIV+ patients and its relation to serum levels of CD4. The sample consisted of 101 individuals: intravenous drug users (84%), homosexuals (7%), and heterosexuals (10%). Each patient was examined clinically and radiographically. Periodontal clinical parameters included gingival index and probing depth and loss of attachment on four sites per tooth. Severity of disease was defined as the most severe lesion found: gingivitis, or early, moderate, or advanced periodontitis. CD4 counts were determined on 64 of these patients. Associations between severity of the disease and gender and CD4 counts were analyzed using the Mantel Haenszel chi square test, while associations between severity and age and CD4/CD8 ratio were analyzed using the Kruskal-Wallis test. No disease was found in 14.8% of the sample, gingivitis was found in 21.8%, early periodontitis in 43.6%, moderate periodontitis in 10.9%, and advanced periodontitis in 8.9%. Linear gingival erythema (LGE) was seen in 17.8% of all patients and necrotizing periodontitis (NUP) in 4.9%. No statistically significant differences were observed between the severity of the disease and CD4 counts. PMID- 8676271 TI - Gingival Langerhans' cells in type I diabetes mellitus. AB - Langerhans' cells (LCs) are intraepithelial immunocompetent cells. Changes in the number of LCs occur in inflammatory and autoimmune diseases. In this study, the number of gingival LCs in patients with type I diabetes mellitus was compared with those of normal individuals using immunohistochemical methods. Gingival biopsies were obtained from 20 type I diabetics and 10 healthy individuals. Anti CD1 positive LCs formed an intraepithelial network and showed a marked increase in type I diabetics. This increase was not related to diabetic age. The number of LCs was proportional to the density of subepithelial inflammatory cells. Our findings suggest that LCs may play a role in the development of diabetic gingivitis. PMID- 8676272 TI - Spatial resolution and angular alignment tolerance in radiometric analysis of alveolar bone change. AB - This pilot study was undertaken to determine the effect of x-ray beam alignment and spatial resolution on quantification of alveolar bone using radiometric techniques. Six (6) dry mandibles were radiographed at 70 kVp, 10 mA, 0.6 seconds using D-speed film, with a bone chip (2.64, 4.10, or 6.07 mg) present or absent at 7 x-ray beam alignments (0 degree, 2 degrees horizontal, 2 degrees vertical, 4 degrees horizontal, 4 degrees vertical, 6 degrees horizontal, 6 degrees vertical). This resulted in 28 radiographs per mandible. Radiographs were digitized using 50- and 200-microns pixel spatial resolution. Image gray levels were standardized using a simple look-up table shift. Regions of interest (ROIs) were positioned on the alveolar bone where the bone chips had been placed. Cumulative percent histograms (CPH) were calculated for those ROIs. Regression analysis was used to evaluate the relationships between CPH changes and bone chip size as x-ray beam angulation and spatial resolution was varied. The resulting R2 values for angulation ranges of 0 degree to 1.4 degrees, 1.5 degrees, to 2.4 degrees, and 2.5 degrees to 5.5 degrees were: 0.983, 0.941, 0.891 for 50-microns pixel images and 0.869, 0.909, and 0.774 for 200-microns pixel images. We conclude that 50-microns pixel spatial resolution is apparently superior to 200 microns pixel images if radiometric data is to be evaluated. With 50-microns pixel spatial resolution, alignment variations up to 5 degrees may be acceptable in clinical studies, depending on the magnitude of bone change that is to be detected. PMID- 8676273 TI - Repair of a defect following the removal of a maxillary adenomatoid odontogenic tumor using guided tissue regeneration. A case report. AB - Adenomatoid odontogenic tumors (AOT) make up 3% of odontogenic tumors. This tumor, most commonly found in the maxillary arch, mimics a follicular cyst associated with an impacted tooth. This is a case report of an AOT found in a 14 year-old female undergoing active orthodontic therapy. The surgical removal of the lesion resulted in the exposure of a large bony cavity surrounding the maxillary left canine. Placement of freeze-dried bone and coverage with an expanded polytetrafluoroethylene membrane resulted in rapid and complete healing of the lesion and restoration of osseous support. PMID- 8676274 TI - Tobacco use and the periodontal patient. AB - This position paper was prepared by the Research, Science and Therapy Committee of The American Academy of Periodontology and is intended for the information of the dental profession. The purpose of the paper is to provide the reader with a general overview of the relationship of tobacco use and periodontal diseases. This paper will review the epidemiological and clinical findings that have led to our understanding of the role of tobacco use in relation to periodontal diseases and their treatment. In addition, this paper will review the possible underlying mechanisms for these effects from tobacco use. The practitioner can use this information in treatment decisions and in giving advice to the patients who use tobacco products. PMID- 8676276 TI - New features of the Journal of Periodontology. PMID- 8676275 TI - Periodontal diseases of children and adolescents. AB - This position paper was prepared by the Committee on Research, Science and Therapy of The American Academy of Periodontology and is intended for the information of the dental profession and the public. It represents a brief summary of the current state of knowledge, about periodontal diseases in children and adolescents. PMID- 8676277 TI - Comparative study of a bioresorbable and a non-resorbable membrane in the treatment of human buccal gingival recessions. AB - Twelve patients with bilateral comparable gingival recessions were treated using a split mouth design, to compare the relative success of root coverage by two regenerative procedures. The areas of recession treated were Class I or II according to Miller's classification and caused either an esthetic problem and/or root sensitivity. The symmetrical defects, on the maxillary canines, 4 mm or deeper, were randomly assigned in each patient to surgical procedures with either a bioresorbable matrix barrier (test) or a non-resorbable expanded polytetrafluoroethylene membrane (control). Gingival recession, clinical attachment level, probing depth, and extension of keratinized tissue were measured at baseline and at 6 months postsurgically. Both procedures resulted in significant root coverage (P < 0.0001) and attachment gain (P < 0.0001). The gingival recession decreased from 4.75 +/- 0.22 mm to 0.83 +/- 0.24 mm and from 4.75 +/- 0.22 mm to 0.75 +/- 0.22 mm, corresponding to a mean root coverage of 82.4% and 83.2%, at the test and control sites respectively. The average clinical attachment gain was 4.33 +/- 0.44 mm at the test sites compared to 4.42 +/- 0.48 mm for the non-resorbable barrier. No significant changes were found for probing depth and keratinized tissue. Data analysis did not demonstrate any significant difference between the two procedures for any of the variables included. However, a questionnaire given to each patient revealed the single-step surgery to be the patients' choice. PMID- 8676278 TI - The panorama of cyclosporin research. PMID- 8676279 TI - Characterization and chillproofing activity of two enzymes from Streptomyces species. AB - Two enzymes, amylase and protease of Streptomyces species were purified by a combination of ion exchange chromatography and gel filtration and characterized. The amylase had an exoaction on starch yielding maltose as a major end product and was identified as beta-amylase. The purified amylase had a molecular weight of 48,000 and was maximally active at 35 degrees C and at pH 6.0. On the other hand, protease had a molecular weight of 21,000 and was most active at pH 10.0 and at a temperature of 30 degrees C. The Km or MICHAELIS constant of amylase for maize starch was 0.333 mg/ml while that of protease for casein was 2.5 mg/ml. The feasibility of using the purified protease for various industrial application especially in the chillproofing of beer is discussed. PMID- 8676281 TI - Fungal spore concentrations in the atmosphere at the Anatolia quarter of Istanbul, Turkey. AB - In this research, spore concentrations of Cladosporium, Alternaria, Epicoccum, Botrytis, Leptosphaeria, Polythrincium, ascospores, Aspergillus, Penicillium, basidiospores, uredospores, Ustilago, Torula, Erysiphe, Ganoderma, Hyaline indeterminate and others in the atmosphere have been determined, and comparisons have been made between locations with both low and high spore concentrations. The importance of these air-borne fungal spores which cause allergy and asthma are emphasized in the paper from the viewpoint of human health. PMID- 8676280 TI - Synthesis and secretion of recombinant penicillin G acylase in bacterial L-forms. AB - L-form strains of Proteus mirabilis and Escherichia coli lacking the cell wall represent an alternative prokaryotic cell system for the production of recombinant proteins (KLESSEN et al. 1988, LAPLACE et al. 1988a, 1989b). We could demonstrate that they are also able to synthesize the enzyme penicillin G acylase (PAC)1). PAC was processed and secreted into the medium by recombinant L-form strains. The synthesis of PAC was growth-associated and stably regulated. Expression, secretion, and processing were not temperature-dependent and occurred at 26 degrees C, 32 degrees C and even 37 degrees C. The expression vector pHC1 carried the pac gene under the control of the lac UV promotor and a kanamycin resistance gene. It could be maintained in L-form cells, showing low structural as well as segregational instability. The secretion of the biologically active enzyme into the medium indicated that the postranslational processing of the PAC molecule, including the excision of a 54 amino acid spacer peptide between the alpha and beta subunit, is not carried out in the periplasmic space, but occurs at the cytoplasmic membrane or autocatalytically. PMID- 8676282 TI - Bacterial diversity at surface water in three locations within the Baltic sea as revealed by culture-dependent molecular techniques. AB - Diversity of culturable bacteria inhabiting the Baltic sea surface waters was studied in three separate locations. Based on electrophoretically separated whole cell proteins the number of operational taxonomic units (OTU) within each sampling location was high. Most of the OTUs were unique to single locations. Within each sampling location 8-22% of isolates belonged to a single OTU. Rarefaction analysis revealed that the bacterial community was more divergent at a polluted location than at clean areas. Also the most common OTUs were different in clean locations compared to the polluted site suggesting that both diversity and species composition of the bacterial community is greatly affected by pollution. The partial 16S rRNA gene sequences of the isolates of the most common OTUs are unique. Intragroup variation and an OTU-specific bacteriocin system was observed among the isolates of the second common OTU. The bacteriocin activity was linked to restriction fragment length polymorphism grouping, although additional variation correlating to geographic origin of isolates was observed. PMID- 8676283 TI - Process optimization for continuous ethanol fermentation by alginate-immobilized cells of Saccharomyces cerevisiae HAU-1. AB - Continuous ethanol production by immobilized cells of Saccharomyces cerevisiae HAU-1 has been studied using synthetic and molasses based medium in column reactors. Immobilization of 30% yeast cells biomass (wet) in 1.5% calcium alginate gel resulted in the production of 20.8 g. l-1.h-1 alcohol at a dilution rate of 0.36 h-1 with approximately 1/3rd volume of the column reactor packed with gel beads. Optimum diameter of the beads was found to be 3.5 mm for efficient fermentation. The size of the column reactor (length to diameter ratio) also affected the productivity and fermentation efficiency due to gas hold-up and mass transfer effects. Molasses could also be fermented by this system but at a lower fermentation efficiency which could be improved, to some extent, by supplementation with nutrients. PMID- 8676285 TI - Helping the helper. PMID- 8676284 TI - Christianity or new age focus? PMID- 8676286 TI - Fire-setting from the viewpoint of an arsonist. AB - 1. Arsonists have more psychiatric symptoms, such as self-destructive behavior and alcohol dependency, than other criminal offenders. 2. Arsonists are found to have poor social competence with low social status and a high unemployment rate. 3. The act of arson could be like an attempted suicide, a cry for help. PMID- 8676287 TI - The characteristics of women who stay married to bipolar men. AB - 1. Although a body of knowledge allows intervention of and effective therapy for bipolar affective behavior, only a few mental health professionals treating them have focused on the quality of their marriages, or the specific attitudes of the well spouses toward marital problems or divorce. 2. The present results showed that women married to men with bipolar affective disorder have more problems with separation-individuation than women married to men who are not bipolar. 3. Unresolved anxiety about separation from a loved object, anxiety that dates back to early childhood, may need to be discussed in detail before any progress can be made in resolving the marital difficulties. PMID- 8676288 TI - Aggressive behavior on an inpatient geriatric unit. AB - 1. Violent or aggressive behavior may be a consequence of poor frustration tolerance, ineffective individual coping, impulsivity, and real or imagined threats to the individuals territory, body space, or life. 2. It is ironic that at the same time that the numbers of elderly are increasing, available services are decreasing and the number of beds in nursing homes and rest homes are lower than in the past. 3. Nurses must look at the environment in which these patients function to develop strategies and techniques to maximize independence while decreasing aggression. PMID- 8676289 TI - Somatization in Hispanics. AB - 1. Major psychological disorders are found universally, but their form and content are modified by culture. In addition, the expression of psychosocial distress is largely shaped by cultural values and beliefs. 2. Preliminary research indicates Hispanics are more likely to somatize than Anglos when experiencing psychosocial disorders or psychosocial distress. 3. Additional research is required into the sources of stress for hispanic women, especially those born in the United States, and its effect on their health. PMID- 8676290 TI - Does exercise help in the treatment of psychiatric disorders? AB - 1. Some researchers have stated that the perception of fitness and health may be a better predictor of psychological improvements than actual cardiovascular fitness. 2. It appears reasonable to encourage patients in psychotherapy to participate in a regular exercise program. 3. Adjunct treatments such as exercise may become increasingly important and helpful in the changing health care delivery and reimbursement environment where more short-term and self-help therapies are being strongly encouraged. PMID- 8676291 TI - Perils of the power of prescriptive authority. PMID- 8676292 TI - [Magnetic resonance imaging of the breast]. PMID- 8676293 TI - [Factors of image quality in spiral x-ray computed tomography]. AB - In helical CT, there are 4 mains factors of quality: The in-plane spatial resolution that is the same in conventional CT; The spatial resolution on the Z axis, which is the slice thickness. The increase factor of the slice thickness between a conventional and a helical CT depends on the pitch and the reconstruction algorithm. The value of the increase factor can be easily calculated; The signal to noise ratio which depends on the collimation, the mA, the KV and the reconstruction algorithm. The signal to noise ratio is not depending on the table speed; The reconstruction interval which can be less than the slice thickness. Then the contrast of small lesion is improved and stair-step artifacts are reduced in 3D reformations. PMID- 8676294 TI - [Comparative study of power Doppler and color Doppler in breast diseases]. AB - In order to evaluate the interest of power doppler in breast studies, we studied 27 breast lesions in 22 patients. This series includes 8 malignant lesions, 11 benign lesions, and 8 enlarged lymph nodes. We used a Esaote Biomedica ultrasound machine with a 7 MHz transducer. We compared power doppler and pulsed doppler for every lesion. Power doppler was more sensitive in 3 out of 8 malignant tumors, 8 out of 11 benign lesions, and 5 out of 8 lymph nodes involvement. This study shows the value of power doppler in breast studies. The increased sensitivity, however, is balanced by a decreased specificity. PMID- 8676295 TI - [Image data bases and multimedia works on server and CD-ROM in medical imaging. A French experience]. AB - The CD-ROM technology allows the production of multimedia works which costs far less than books do. The creation of Internet and the servers World Wide Web has the advantage of distributing those works world wide, without the difficulties and the delays related to books and magazines distribution. The Teachers' Council of Radiology of France (CERF) and the French Society of Radiology (SFR) have opted to use these new media and these information highways to spread a part of their radiology teaching work. Iconocerf is a software program which allows to create, store, read and to exchange digitized radiological cases. It's available free of charge, within the CERF and SFR. The CD-ROMs Iconocerf-Medimag contain 3,500 radiological files with 15,000 images, previously on the videodisc Medimag. The Server of the French Radiology is a W3 server which includes: the CERF directory, a guide for the teachers, the research workers and the students in Radiology and Medical Imaging. It also contains the teaching works on Radiology, and some Iconocerf clinical cases translated onto HTML. The aim of this project is to create an evaluation system for radiology. By using key words, this system allows to consult: radiological clinical cases, located on the server or on CD ROMs; reference texts; and to have access to the experts' addresses to be able to send them eventually a difficult case through electronic mail. PMID- 8676296 TI - [Evaluation of bladder volume by ultrasonography]. AB - The aim was to evaluate bladder volume measurement using computerized calculation in comparison with usual formulas. Twenty-eight volunteers underwent bladder ultrasonography, which was recorded for computerized measurement of bladder volume. From diameters and/or areas measurements, bladder volume was calculated using 12 different formula. True bladder volume was obtained from voided volume measurement. Computerized measurement was not more accurate than formulas. No formulas displayed association of low percentage error and standard deviation and good accuracy. The best accuracy was obtained with the combined formula F12 ([(DSc x DAPc x DT x 0.523) + (DT x AS)]/2). Formula (F4) using the three diameters, with reference to anterior bladder recessus and 0.625 correction factor displayed good results on the average. PMID- 8676297 TI - [Spinal cord compression disclosing rib hydatidosis]. AB - The authors report an exceptional case of spinal compression following an isolate rib hydatidosis. The CT scan has suspected the diagnosis. The authors recall the anatomoclinic features and specify the radiologic aspects of the osseous hydatidosis, especially the rib's localization which is very rare. MR imaging in addition of its diagnosis role showing a very evocative cyst images, is the exam of choice in order to appreciate the disease's extent and the degree of medular sufferance. PMID- 8676298 TI - [Left ventricular insertion of a permanent pacemaker (radiographic aspect)]. AB - We report a case of inadvertent transarterial permanent pacing of the left ventricule that was not diagnosed on routine chest radiography or ECG. The malposition was diagnosed because of the rupture of the mitral valve cordage 2 months after pacemaker implantation. We emphasize the radiographic appearance of this rare malposition. PMID- 8676299 TI - [Quid? Calcification of the inferior vena cava in an adult]. PMID- 8676300 TI - [MRI semiology of stress fractures]. PMID- 8676301 TI - The Department of Radiology of the Hospital of the University of Pennsylvania. PMID- 8676302 TI - [Illegal practice of medical radiology? A 35-year conflict between physicians and non physicians]. PMID- 8676303 TI - [Diagnostic case: pseudotumoral non specific subacute interstitial nephritis]. PMID- 8676304 TI - [Diagnostic case: infected cyst of the urachus]. PMID- 8676305 TI - [Diagnostic case: pseudotumoral tuberculous pyelonephritis]. PMID- 8676306 TI - [Diagnostic case: focal nodular hyperplasia]. PMID- 8676307 TI - [Diagnostic case: Erasmus syndrome associating silica exposure with silicosis and systemic sclerosis]. PMID- 8676308 TI - [Diagnostic case: rhabdomyosarcoma of the biliary tracts]. PMID- 8676309 TI - [Diagnostic case: sequelae of smallpox]. PMID- 8676310 TI - [Diagnostic case: intraductal mucinous hypersecreting tumor or intraductal mucinous ectasia]. PMID- 8676311 TI - I am sorry that we lost your leg. PMID- 8676312 TI - Chronic pain: time for epidemiology. PMID- 8676313 TI - All that palsies is not Bell's. PMID- 8676314 TI - Tracheostomy in children. AB - Tracheostomy is more hazardous in children than in adults, and carries special risks in the very young. The past 20 years have seen a large shift in the age distribution of tracheostomy. Whereas formerly the operation was done largely for management of epiglottitis and laryngotracheobronchitis, today the prime indication is subglottic stenosis in infants consequent upon intubation for respiratory distress syndrome and prematurity. We have reviewed experience with 57 tracheostomies in 56 children under 12 years old managed from a university hospital. All operations were done as elective procedures, in standard fashion, by otolaryngologists. Forty (70%) were in children under 1 year old, the indications being upper airways obstruction (41), failed extubation (11), and long-term assisted ventilation (5). Subglottic stenosis was the commonest cause of obstruction (21 operations). In 91.4 accumulated years with a tracheostomy there were 11 complications related to tracheostomy, one of which (a blocked tube) was fatal. Thirty-nine children were decannulated, the mean duration of cannulation being 21 months. In this series we suggest that the low morbidity and mortality rates were due to management by otolaryngologists; to postoperative intensive care; and, for the majority cared for at home, to careful education of parents and visits by specialist nurses. PMID- 8676315 TI - Smoking and menstrual problems in 16-year-olds. AB - The British Birth Cohort Study (BCS70) is a cohort study which follows all the people born in England, Scotland and Wales in the week of 5-11 April 1970. The data described here were from the postal questionnaires returned by 2181 young women aged between 16 and 16 1/2 in 1986. Thirty-nine per cent of the respondents had never smoked, 39% had smoked at some time and 22% were regular smokers. Most of the respondents indicated that they had one or more of the following symptoms associated with menstruation: pain, depression, irritability, headaches, cramps. Analysis of the data showed that regular smokers were significantly more likely than those who had never smoked to have all these symptoms. Whilst the percentage of 'sometime smokers' experiencing pain, depression and headaches fell between smokers and 'never-smokers', the percentage experiencing unpleasant symptoms in general, irritability and cramps was the same as for regular smokers. If causality could be demonstrated, messages about immediate health problems such as these might be more powerful health education to young women than information about long-term risks. PMID- 8676316 TI - Informed consent in Indian patients. AB - It is commonly believed that patients in India do not need to be told about their operations as they are unable to understand the complexities and forget the salient facts soon afterwards. Obtaining informed consent is therefore considered to be an unnecessary ritual. We studied 100 consecutive patients undergoing elective major abdominal operations and asked them 5 days after their operations to recall certain details about the procedure which had been explained to them preoperatively. Seventy per cent of the patients recalled the relevant data. The ability was the same in males and females (67% and 69%) but the older, less educated and poorer patients performed worse than the others. Ninety-eight per cent of the patients appreciated being given the information as it reduced their anxiety about the operation. Indian patients are able to comprehend and should be informed about the details of their operation. Particular care should be taken during explanation to the old, poor and illiterate. In these informed consent should be a continuous process rather than a single event and the information should also be given to a younger and more educated relative. PMID- 8676317 TI - Splenectomy in a general hospital. AB - Splenectomy is often performed in patients with malignant disease or trauma who are at a high risk of complications. In the long term, it increases the risk of infection by encapsulated bacteria. An audit was performed to determine the reasons for splenectomy in a district general hospital, to review the results and complications of surgery, and to see how often the patients were prescribed antibacterial prophylaxis. Twenty-eight patients underwent splenectomy in 3 years. The indication was haematological disease in 13 and trauma in four. In the remaining nine the spleen was removed either as part of a radical gastrectomy or during some other abdominal procedure. Six of the 28 patients had died, one within 30 days from disseminated intravascular coagulopathy following an emergency gastrectomy and splenectomy for haematemesis, two from progressive haematological malignant disease, two from non-haematological malignancy, and one from bronchopneumonia. Of the nine patients (32%) with complications, three required a further laparotomy. Most patients had been prescribed pneumococcal vaccine (85%) and prophylactic antibiotics (93%). PMID- 8676318 TI - Personal child health record and advice booklet programme in Tuzla, Bosnia Herzegovina. AB - Personal child health records, held by the parents, have potential advantages in times of civil disorder. Via health and community workers, 939 booklets (incorporating health records and health advice) were distributed to displaced and other families near Tuzla. Subsequently mothers were invited to bring their children for examination. Five hundred and seventy-one children with their booklets returned to the clinics. The survey revealed high rates of dental caries (305 cases), anaemia (36), and scabies (20). The war had not affected the duration of breast feeding, and the children's nutrition was generally satisfactory. Immunization status was generally good, though rates were unacceptably low in children from certain areas, reflecting not only deficient provision in their place of origin but also failings in the programme for displaced persons. An informal survey indicated that parents and older children appreciated the health-information content of the booklet. In a disaster of this sort, the personal child health record and advice booklet serves the combined purpose of yielding essential epidemiological data, providing a permanent health record, and meeting a need for health education material. PMID- 8676319 TI - Rev Harold Nelson Burden and Katherine Mary Burden: pioneers of inebriate reformatories and mental deficiency institutions. PMID- 8676320 TI - Biochemical investigation of unexplained diarrhoea. PMID- 8676321 TI - Selective venous catheterization and plasma catecholamine analysis in the diagnosis of phaeochromocytoma. PMID- 8676322 TI - Some unusual biochemical changes in diabetes mellitus. PMID- 8676323 TI - Secondary amenorrhoea. PMID- 8676324 TI - Familial adenomatous polyposis: an update. PMID- 8676325 TI - Diabetic retinopathy. PMID- 8676326 TI - Analgesia for venous cannulation. PMID- 8676327 TI - NSAID chemoprevention of colorectal adenomas and oesophageal metaplasia. PMID- 8676328 TI - Sam Johnson's lung not in Baillie's Atlas. PMID- 8676329 TI - Clinical ecologists. PMID- 8676330 TI - Prescribing patterns and costs. PMID- 8676331 TI - Economics and medical practice. PMID- 8676332 TI - Asbestos exposure and asbestosis. PMID- 8676333 TI - N-terminus urea-substituted chemotactic peptides: new potent agonists and antagonists toward the neutrophil fMLF receptor. PMID- 8676334 TI - Betulinic acid and dihydrobetulinic acid derivatives as potent anti-HIV agents. PMID- 8676335 TI - Carbohydrates in an acidic multivalent assembly: nanomolar P-selectin inhibitors. PMID- 8676336 TI - 4'-O-[2-(2-fluoromalonyl)]-L-tyrosine: a phosphotyrosyl mimic for the preparation of signal transduction inhibitory peptides. AB - Development of phosphotyrosyl (pTyr) mimetics which are stable to protein tyrosine phosphatases (PTPs), yet can retain biological potency when incorporated into peptides, is an active area of drug development. Since a majority of pTyr mimetics derive their "phosphofunctionality" from phosphorus-containing moieties, such as phosphonates, evolution of new inhibitors and modes of prodrug derivatization have been restricted to chemistries appropriate for phosphorus containing moieties. A new, nonphosphorus-containing pTyr mimetic has recently been reported, L-O-(2-malonyl)tyrosine (OMT,5), which can be incorporated into peptides that exhibit good PTP and Src homology 2 (SH2) domain inhibitory potency. For phosphonate-based pTyr mimetics such as phosphonomethyl phenylalanine (Pmp,2) introduction of fluorines alpha to the phosphorus has provided higher affinity pTyr mimetics. This strategy has now been applied to OMT, and herein is reported 4'-O-[2-(2-fluoromalonyl)]-L-tyrosine (FOMT,6) a new fluorine-containing nonphosphorus pTyr mimetic. Incorporation of FOMT into appropriate peptides results in good inhibition of both PTP and SH2 domains. In an assay measuring the inhibition of PTP 1B-mediated dephosphorylation of phosphorylated insulin receptor, the peptide Ac-D-A-D-E-X-L-amide exhibited a 10 fold enhancement in inhibitory potency for X = FOMT (19) (IC(50) = 10 microM) relative to the unfluorinated peptide, X = OMT (18) (IC(50) = 10 microM. Molecular modeling indicated that this increased affinity may be attributable to new hydrogen-bonding interactions between the fluorine and the enzyme catalytic site, and not due to lowering of pKa values. In a competition binding assay using the p85 PI 3-kinase C-terminal SH2 domain GST fusion construct, the inhibitory peptide, Ac-D-X-V-P-M-L-amide, showed no enhancement of inhibitory potency for X = FOMT (22) (IC(50) = 18 microM) relative to the unfluorinated peptide, X = OMT (21) (IC(50) = 14 microM). The use of FOMT would therefore appear to have particular potential for the development of PTP inhibitors. PMID- 8676337 TI - Structure-activity relationship for antineoplastic imidazoacridinones: synthesis and antileukemic activity in vivo. AB - Synthesis of several new 5-amino-substituted derivatives of 5-amino-6H imidazo[4,5,1-de]-acridin-6-one bearing in the benzene ring OH, OCH3, CH3, tert butyl, or OCH2O groups is described. 8-OH-substituted compounds or double substituted 7-OH-10-OCH3 compounds demonstrated potent in vivo activity against murine P388 leukemia. The highest activity was exhibited by 5-[[2-[[2 (diethylamino)ethyl]amino]ethyl]amino]-8-hydroxy-6H- imidazo[4,5,1-de]-acridin-6 one (4c). PMID- 8676338 TI - Time-dependent inactivation of aromatase by 6-alkylandrosta-1,4-diene-3,17 diones. Effects of length and configuration of 6-alkyl group. AB - Series of 6alpha- and 6beta-alkylandrosta-1,4-diene-3,17-diones (3 and 4) were synthesized and evaluated as time-dependent inactivators of aromatase in human placental microsomes to gain insights to the structure-activity relationship of varying the 6-n-alkyl substituents (C-1--C-7) to the time-dependent inactivation activity. All of the inhibitors synthesized were powerful to good competitive inhibitors of aromatase, with apparent Ki's ranging from 4.7 to 54 nM. The 6beta ethyl (4b) and 6beta-n-pentyl (4e) compounds were the most potent among them (Ki = 4.7 and 5.0 nM for 4b and 4e, respectively). In a series of the 6alpha-alkyl steroids, the inhibitors 3a-d having C-1--C-4 at the 6-position as well as the 6 alpha-n-heptyl (3g) compounds did not. In contrast, in the 6beta-alkyl steroid series, only the methyl analog 4a inactivated aromatase in a time-dependent manner, and the other alkyl steroids having more than two carbons at C-6beta did not. The inactivations were prevented by the substrate androstenedione, and no significant effects of L-cysteine on the inactivation were observed in each case. These results along with molecular modeling with the PM3 method indicate that both length and stereochemistry of a straight alkyl substituent at the C-6 position of androsta-1.4-diene-3,17-dione (3h) play an important role in the cause of a time-dependent inactivation of aromatase. No significant correlation between affinity for the enzyme and the inactivation ability in the 6 alkylandrosta-1,4-diene-3,17-diones is observed. PMID- 8676339 TI - 2,4-Diarylpyrrolidine-3-carboxylic acids--potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722. AB - We have discovered a novel class of endothelin (ET) receptor antagonists through pharmacophore analysis of the existing non-peptide ET antagonists. On the basis of this analysis, we determined that a pyrrolidine ring might replace the indian ring in SB 209670. The resultant compounds were readily prepared and amenable to extensive SAR studies. Thus a series of N-substituted trans,trans-2-(4 methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrroli din e-3- carboxylic acids (8) have been synthesized and evaluated for binding at ET(A) and ET(B) receptors. Compounds with N-acyl and simple N-alkyl substituents had weak activity. Compounds with N-alkyl substituents containing ethers, sulfoxides, or sulfones showed increased activity. Much improved activity resulted from compounds where the N-substituents were acetamides. Compound 17u (A-127722) with the N,N dibutylacetamide substituent is the best of the series. It has an IC(50)=0.36 nM for inhibition of ET-1 radioligand binding at the ET(A) receptor, with a 1000 fold selectivity for the ET(A) vs the ET(B) receptor. It is also a potent inhibitor (IC(50)=0.16 nM) of phosphoinositol hydrolysis stimulated by ET-1, and it antagonized the ET-1-induced contraction of the rabbit aorta with a pA(2)=9.20. The compound has 70% oral bioavailability in rats. PMID- 8676340 TI - Bisindolylmaleimides linked to DNA minor groove binding lexitropsins: synthesis, inhibitory activity against topoisomerase I, and biological evaluation. AB - The synthesis, characterization, inhibitory activity against topoisomerase I, and biological evaluation of a series of oligopeptide-substituted bisindolylmaleimides 7-12 are described. Compounds 7-9, which contain a basic C terminus function such as (dimethylamino)propyl and bind to DNA with C(50) values of 200, 160, and 135 microM, respectively, exhibited inhibition of topoisomerase I in a concentration dependent manner. Also, the relative order of observed topoisomerase I inhibition is 9 > 8 > 7 at < or = 100 microM concentration, corresponding to the increase of the number of pyrrole units in the oligopeptide moiety. Compounds 10-12, which contain an electrostatically neutral moiety, such as methyl ester, did not bind to DNA templates nor inhibit topoisomerase I. However, the cytotoxicity activities of these compounds were 1.5 times greater than those of compounds 7-9. PMID- 8676341 TI - Betulinic acid derivatives: a new class of human immunodeficiency virus type 1 specific inhibitors with a new mode of action. AB - A series of omega-undecanoic amides of lup-20(29)-en-28-oic acid derivatives were synthesized and evaluated for activity in CEM 4 and MT-4 cell cultures against human immunodeficiency virus type 1 (HIV-1) strain IIIB/LAI. The potent HIV inhibitors which emerged, compounds 5a, 16a, and 17b, were all derivatives of betulinic acid (3beta-hydroxylup-20(29)-en-28-oic acid). No activity was found against HIV-2 strain ROD. Compound 5a showed no inhibition of HIV-1 reverse transcriptase activity with poly(C).oligo(dG) as template/primer, nor did it inhibit HIV-1 protease. Additional mechanistic studies revealed that this class of compounds interfere with HIV-1 entry in the cells at a postbinding step. PMID- 8676342 TI - Betulinic acid derivatives: a new class of specific inhibitors of human immunodeficiency virus type 1 entry. AB - A novel series of omega-aminoalkanoic acid derivatives of betulinic acid were synthesized and evaluated for their activity against human immunodeficiency virus (HIV). The anti-HIV-1 activity of several members of this new series was found to be in the nanomolar range in CEM 4 and MT-4 cell cultures. The optimization of the omega-aminoalkanoic acid side chain is described. The presence of an amide function within the side chain was found important for optimal activity. RPR 103611 (14g), a statine derivative, was found to be inactive against HIV-1 protease, reverse transcriptase, and integrase as well as on gp120/CD4 binding. "Time of addition" experiments suggested interaction with an early step of HIV-1 replication. As syncytium formation, but not virus-cell binding, seems to be affected, betulinic acid derivatives are assumed to interact with the postbinding virus-cell fusion process. PMID- 8676343 TI - Hypoxia-selective antitumor agents. 12. Nitrobenzyl quaternary salts as bioreductive prodrugs of the alkylating agent mechlorethamine. AB - A series of benzene-substituted analogues of the novel hypoxia-selective cytotoxin N,N-bis(2-chloroethyl)-N-methyl-N-(2-nitrobenzyl)ammonium chloride (3a), together with three corresponding tetrahydroisoquinolinium "cyclic" analogues 21a-23a and two naphthalene derivatives (19a and 20a), have been prepared and evaluated for cytotoxicity in cultured mammalian tumor cells under aerobic and hypoxic conditions. The parent compound 3a has a one-electron reduction potential of -358 mV and undergoes reductively-induced fragmentation to release the nitrogen mustard mechlorethamine. The compounds were prepared by halogenation (SOCl2) of the corresponding quaternary diols, which in turn were synthesized from N-methyldiethalnolamine and substituted nitrobenzyl chlorides. The reduction potentials of the benzene-substituted compounds were generally well predicted by Hammett substituent relationships. All of the compounds were much more toxic toward repair-deficient UV4 cells than the corresponding wild-type AA8 cells, as expected if the active cytotoxic species as a DNA alkylating agent. They were also more toxic toward the human cell lines EMT6 and FME compared to AA8, but the reasons for this are not known. Analogues of 3a substituted in the phenyl ring with electron-donating substituents provided compounds with widely differing selectivities for hypoxic AA8 cells, ranging from no selectivity for the 3-Me compound 9a to 3000-fold (at least as great as that of the parent 3a) for the 4-OMe compound 14a. The naphthalene derivatives 19a and 20a and the tetrahydroisoquinolinium compounds 21a-23a showed no hypoxic selectivity. Selective chemical reduction of 22a and 23a with nickel boride resulted in isolation of the corresponding stable amino derivatives, indicating that reduction of these compounds does not result in fragmentation. The reason(s) for the marked differences in hypoxic selectivity of the nitrobenzyl quaternary mustards is unknown, but may reflect differences in radical chemistry, cell uptake, or sensitivity to enzymatic reduction. PMID- 8676344 TI - Toward a novel metal-based chemotherapy against tropical diseases. 2. Synthesis and antimalarial activity in vitro and in vivo of new ruthenium- and rhodium chloroquine complexes. AB - Chloroquine free base (CQ) reacts with [Rh(COD)Cl]2 (COD = 1,5-cyclooctadiene) and RuCl3.-3H2O/Zn to yield Rh(COD)(CQ)Cl (1) and [RuCl2(CQ)]2 (2), respectively. The two novel metal- CQ complexes, which were characterized mainly by 1D and 2D NMR spectroscopy, were tested against Plasmodium berghei. The in vitro activity of 1 was comparable to that of chloroquine diphosphate (CQDP), whereas 2 was about 5 times more active. In in vivo tests at equivalent concentrations of free CQ, CQDP reduced the parasitemia by 55%, while for complexes 1 and 2 the reduction reached 73% and 94%, respectively, without any sign of acute toxicity being observed up to 30 days after treatment. The Ru derivative 2 was further evaluated against two chloroquine-resistant strains of Plasmodium falciparum, and it was found to be 2-5 times more active than CQDP. PMID- 8676345 TI - New mustard prodrugs for antibody-directed enzyme prodrug therapy: alternatives to the amide link. AB - Antibody-directed enzyme prodrug therapy (ADEPT) is a two-step approach for the treatment of cancer which seeks to generate a potent cytotoxic agent selectively at a tumor site. In this work described the cytotoxic agent is generated by the action of an enzyme CPG2 on a relatively nontoxic prodrug. The prodrug 1 currently on clinical trial is a benzamide and is cleaved by CPG2 to a benzoic acid mustard drug 1a. We have synthesized a series of new prodrugs 3-8 where the benzamide link has been replaced by, for example, carbamate or ureido. Some of these alternative links have been shown to be good substrates for CPG2 and therefore new candidates for ADEPT. The active drugs 3a and 4a derived from the best of these prodrugs are potent cytotoxic agents (1-2 microM) some 100 times more than 1a. The prodrugs 3 and 4 are some 100-200-fold less cytotoxic, in a proliferating cell assay, than their corresponding active drugs 3a and 4a. PMID- 8676346 TI - Studies on the mechanism of phosphatidylinositol 3-kinase inhibition by wortmannin and related analogs. AB - Wortmannin, a fungal metabolite, was identified as a potent inhibitor (IC50 = 4.2 nM) of phosphatidylinositol 3-kinase (PI 3-kinase). Due to the importance of PI 3 kinase in several intracellular signaling pathways, structure-activities studies on wortmannin analogs were performed in an effort to understand the structural requirements necessary for PI 3-kinase inhibition. Since wortmannin is an irreversible inhibitor of PI 3-kinase, it was postulated that covalent attachment at the electrophilic C-21 site was a possible mode of action for PI 3-kinase inhibition. We have prepared various wortmannin analogs which address the possibility of this mechanism. Of particular interest are compounds which affect the C-21 position of wortaminnin either sterically or electronically. Our results support the conclusion that nucleophilic addition by the kinase onto the C-21 position of wortmannin is required for inhibition of PI 3-kinase by wortmannin analogs. Additionally, we have prepared several D-ring analogs of wortmannin, and their activities are reported herein. We conclude that the wortmannin D ring is an important recognition site since modifications have such a dramatic effect on inhibitor potency. Finally, the identification of 17beta-hydroxywortmannin represents the first reported subnanomolar inhibitor of PI 3-kinase. These studies, along with in vivo antitumor experiments, suggest that the mechanism of PI 3-kinase inhibition correlates to the associated toxicity observed with wortmannin-based inhibitors of PI 3-kinase. PMID- 8676347 TI - Nonpeptidic inhibitors of human neutrophil elastase. 7. Design, synthesis, and in vitro activity of a series of pyridopyrimidine trifluoromethyl ketones. AB - Using molecular modeling and the information derived from X-ray crystal structures of human neutrophil elastase (HNE) and porcine pancreatic elastase (PPE) complexed to peptidic ligands, we have developed a new series of nonpeptidic inhibitors of HNE, the pyridopyrimidine trifluoromethyl ketones (TFMKs). These bicyclic inhibitors were designed to extend the concept of the related pyridone trifluoromethyl ketones by incorporating a rigidly positioned carbonyl group to participate in a hydrogen bonding interaction with the backbone NH groups of Gly-218 and Gly-219 of the enzyme. In addition, the pyrimidine ring serves as a scaffold to vector substituents toward the S5-S4 subsites of the enzyme's extended binding pocket. Furthermore, the heteroatoms of the pyrimidine ring generally increase the aqueous solubility of the pyridopyrimidines relative to pyridone TFMKs. Pyridopyrimidine TFMKs containing a 6-phenyl substituent afforded potent inhibitors of elastase, and several inhibitors from this class of compounds possessed aqueous solubilities of > 0.1 mg/mL and Ki values of < or = 10 nM. PMID- 8676349 TI - Synthesis and biological evaluation of1',2'-seconucleo-5'- phosphonates. AB - A series of 1',2'-seconucleophosphonate analogues were prepared containing adenine, cytosine, thymine, and uracil as the nucleobase. The synthetic methodology is efficient and uses chloromethyl ethers derived from the chirons diethyl (3S)-(benzyloxy)-(2R)-hydroxybutane-phosphonate (1) and diethyl (3S),4 bis(benzyloxy)-(2R)-hydroxybutanephosphonate (2). Selected deblocked derivatives, i.e., two monoesters (13 and 14), four phosphonic acids (15-18), and one cyclic phosphonate (23), were screened for in vitro activity against certain RNA, adeno, and HIV viruses. All of them were found to be devoid of activity. PMID- 8676348 TI - 8-[4-[2-(1,2,3,4-Tetrahydroisoquinolinyl]butyl-8-azaspiro[4.5]decane-7,9-dione: a new 5-HT1A receptor ligand with the same activity profile as buspirone. AB - A new analog of buspirone (1), i.e., 8-[4-[2-(1,2,3,4 tetrahydroisoquinolinyl)]butyl]-8-azaspiro- [4.5]decane-7,9-dione (6a), was synthesized. In was demonstrated that buspirone and its analog 6a were equipotent 5-HT(1A) ligands. Several behavioral models showed that 6a had essentially the same functional profile at 5-HT(1A) receptors as buspirone. The obtained results permit a conclusion that the basic nitrogen atom and terminal, bulky cycloimide moiety, but not the 2-pyrimidinyl group, of buspirone are directly involved in the formation of the bioactive complex with 5-Ht1A receptors. PMID- 8676350 TI - Design, synthesis, and biological activities of cyclic lactam peptide analogues of dynorphine A(1-11)-NH2. AB - We previously have reported four possible binding conformation of dynorphin A (Dyn A) for the central kappa opioid receptors, induced by the address sequence, using a molecular mechanics energy minimization approach. The lowest energy conformation was found to exhibit an alpha-helical conformation in the cyclized address sequence. It was suggested that an alpha-helical conformation in the cyclized address sequence or a helical conformation induced by the conformational characteristics of the message sequence may be important for binding potency and kappa opioid receptor selectivity. Side chain to side chain lactam bridges between the i and i + 4 positions have been shown to stabilize alpha-helical conformation. Thus, a series of cyclic lactam analogues of dynorphin A(1-11)-NH2 have been designed, synthesized and evaluated by the guinea pig brain (GPB) binding assay and guinea pig ileum (GPI) bioassay to evaluate the conformational analysis prediction and, further, to investigate the conformational requirements for high potency and selectivity for kappa opioid receptors. Positions 2-6, 3-7, and 5-9 were chosen as the sites for incorporating cyclic conformational constraints. Cyclization between D-Asp(2) and Lys(6) in c[D-Asp(2),Lys(6)]Dyn A(1 11)-NH2 led to an analogue with pronounced potency and selectivity enhancement for the mu opioid receptor, whereas cyclization between D-Asp(3) and Lys(7) in c[D-Asp(3),Lys(7)]Dyn A(1-11)-NH2 led to a potent ligand (IC(50) 4.9 nM) with kappa receptor selectivity. The other analogues in the series proved to be less selective. The biological results led to the suggestion that the binding conformation for the kappa receptor may have structural requirements that are distinct from those of mu and delta receptors. Interestingly, analogues with a D Asp at position 2, 3, or 9 were found to be more potent for the kappa receptor than analogues with an L-Asp at the same positions. It is suggested that the incorporation of D-Asp into position 2, 3, or 9 of Dyn A(1-11)-NH2 may have stereochemical and conformational effects on the nearby amino acids which can help discriminate the preference between kappa, mu, and delta receptors. PMID- 8676351 TI - Antagonistic properties of centrally truncated analogs of [D-Trp(32)]NPY. AB - We have previously shown that [D-Trp(32)]NPY can competitively antagonize NPY induced feeding in rats (Balasubramaniam et al. J. Med. Chem. 1994, 37, 811-815). This peptide, however, did not bind to SK-N-MC cells with Y-1 receptors. Since centrally truncated NPY analogs have been shown to bind Y-1 receptors, we synthesized similar analogs of [D-Trp(32)]NPY and investigated their Y-1 (SK-N MC) and Y-2 (SK-N-BE2) receptor affinities and their properties in human erythroleukemia (HEL) cells. None of the analogs with D-Trp(32) mobilized intracellular calcium, [Ca2]i, in HEL cells. Although Des-AA(6-24)[Aoc(6)]NPY and the corresponding D-Trp(32) analog exhibited no affinity to Y-1 receptors, Des AA(7-24)[Aoc(6),D-Trp(32)] NPY(6) exhibited weak binding. Replacing Pro(5) in 6 with D-Ala to stabilize the central chain reversal, and hence the antiparallel alignment of the N- and C-terminal regions known to be important for Y-1 binding, resulted in an analog, Des-AA(7-24)[D-Ala(5),Aoc(6),D-Trp(32)]NPY (7), which exhibited moderate antagonist potency in attenuating NPY effects on cAMP and [Ca2+]i, in SK-N-MC and HEL cells, respectively. This analog also shifted the dose-response curve of NPY on blood pressure in anesthetized rats. Deletion of only the 7-17 and/or the incorporation of N-Me-Ala(5), superior beta-turn stabilizer, in 7 did not improve the Y-1 receptor affinity. Des-AA(7-24)[D Ala(5), Gly(6),D-Trp(32)]NPY exhibited an affinity similar to that of 7, suggesting that a long spacer arm is not necessary for efficient Y-1 receptor interaction. Locking the antiparallel alignment via a 2/26 or 2/27 lactam bridge did not improve the binding. Finally, replacement of D-Ala(5) in 7 with D-Trp dramatically increased both the binding and the antagonistic potencies. Modeling based on the avian pancreatic polypeptide X-ray structure suggested that analogs which have the N- and C-terminal regions in close proximity might exhibit good binding, and that the D-Trp(32) substitution may induce a beta-turn that could be important for exhibiting antagonism. A systematic investigation has resulted in the development of relatively potent Y-1 receptor antagonists. Further structure activity studies with these compounds and those previously reported by us and other investigators should result in the development of long-acting and receptor selective antagonists. PMID- 8676353 TI - Novel carbamates as potent histamine H3 receptor antagonists with high in vitro and oral in vivo activity. AB - The known histamine H3 receptor antagonists burimamide, thioperamide, clobenpropit, and a related homohistamine thioamide derivative were taken as templates in search for new leads. Novel histamine H3 receptor antagonists structurally described as carbamate derivatives of 3-(1H-imidazol-4-yl)propanol were prepared in high yields by treatment of the alcohol with corresponding isocyanates or carbamoyl chlorides and investigated for their H3 receptor antagonist activity. Different chain lengths and various substituents possessing different electronic and steric parameters were introduced and structure-activity relationships established. In different functional tests, the new antagonists showed high H3 receptor antagonist potencies in vitro (-log Ki values of 6.4-8.4) at synaptosomes of rat cerebral cortex and low activities at histamine H1 and H2 receptor subtypes. They were also screened for their central in vivo activity in mice after peroral administration. The most promising compounds (2, 16, 19) showed ED(50) values of about 1-2 mg/kg and thus are potential drugs for the therapy of H3 receptor dependent diseases. Some of the novel carbamate derivatives are H3 receptor selective compounds with high in vitro and in vivo activity. PMID- 8676352 TI - Nitric oxide-releasing polymers containing the [N(O)NO]- group. AB - Ions of structure X[N(O)NO]- display broad-spectrum pharmacological activity that correlates with the rate and extent of their spontaneous, first-order decomposition to nitric oxide when dissolved. We report incorporation of this functional group into polymeric matrices that can be used for altering the time course of nitric oxide release and/or targeting it to tissues with which the polymers are in physical contact. Structural types prepared include those in which the [N(O)NO]- group is attached to heteroatoms in low molecular weight species that are noncovalently distributed throughout the polymeric matrix, in groupings pendant to the polymer backbone, and in the polymer backbone itself. They range in physical form from films that can be coated onto other surfaces to microspheres, gels, powders, and moldable resins. Chemiluminescence measurements confirm that polymers to which the [N(O)NO]- group is attached can serve as localized sources of nitric oxide, with one prototype providing sustained NO release for 5 weeks in pH 7.4 buffer at 37 degrees C. The latter composition, a cross-linked poly-(ethylenimine) that had been exposed to NO, inhibited the in vitro proliferation of rat aorta smooth muscle cells when added as a powder to the culture medium and showed potent antiplatelet activity when coated on a normally thrombogenic vascular graft situated in an arteriovenous shunt in a baboon's circulatory system. The results suggest that polymers containing the [N(O)NO]- functional group may hold considerable promise for a variety of biomedical applications in which local delivery of NO is desired. PMID- 8676354 TI - Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives: potent and selective A(2A) adenosine antagonists. AB - A series of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives (10a o,q,r), bearing alkyl and aralkyl chains on positions 7 and 8, were synthesized in the attempt to obtain potent and selective antagonists for the A(2A) adenosine receptor subtype. The compounds were tested in binding and functional assays to evaluate their potency for the A(2A) compared with the A1 adenosine receptor subtype. In binding studies in rat brain membranes, most of the compounds showed affinity for A(2A) receptors in the low nanomolar range with a different degree of A(2A) versus A1 selectivity. Comparison of N(7) (10a-d,h-o)- and N(8) (10e-g) substituted pyrazolo derivatives indicates that N(7) substitution decreases the A1 affinity with the concomitant increase of A(2A) selectivity. Specifically, the introduction of a 3-phenylpropyl group at pyrazolo nitrogen in position 7 (101) increased significantly the A(2A) selectivity, being 210-fold, while the A(2A) receptor affinity remained high (Ki=2.4 nM). With regards to the affinity for A(2A) receptors, also the compound 10n, bearing in the 7-position a beta morpholin-4-ylethyl group, deserves attention (Ki=5.6 nM) even though the A2A selectivity (84-fold) was not as high as that of 101. Conversely, the compound 10m (N(7)-4-phenylbutyl derivative) showed a remarkable selectivity (A1/a(2A) ratio = 129) associated with lower A(2A) affinity (Ki = 21 nM). In functional studies, most of the compounds examined reversed 5'-(N-ethylcarbamoyl) adenosine induced inhibition of rabbit platelet aggregation inhibition which is a biological response mediated by the A2A receptor subtype. The compounds are potent and selective A2A antagonists which can be useful to elucidate the pathophysiological role of this adenosine receptor subtype. These compounds deserve to be further developed to assess their potential for treatment of neurodegenerative disorders such as Parkinson's disease. PMID- 8676355 TI - Structure-activity relationships of a series of substituted benzamides: potent D2/5-HT2 antagonists and 5-HT1a agonists as neuroleptic agents. AB - A series of substituted (4-(4-(1,2-benzisothiazol-3-yl)-1 piperazinyl)butyl)benzamide derivatives was prepared and evaluated as potential atypical antipsychotic agents. The target compounds were readily prepared from their benzoyl chloride, benzoic acid, or isatoic anhydride precursors, and they were evaluated in vitro for their ability to bind to dopamine D2, serotonin 5 HT2, and serotonin 5-HT1a receptors. To assess the potential antipsychotic activity of these compounds, we investigated their ability to inhibit the apomorphine-induced climbing response in mice. Selected compounds were evaluated further to determine their side-effect potentials. Structure-activity relationships of both mono- and polysubstituted benzamides are discussed herein. While several analogues had potent in vitro and in vivo activities indicative of potential atypical antipsychotic activity, anthranilamide 77 (1192U90) ddemonstrated a superior pharmacological profile. As a result of this investigation, 1192U90 (2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1 piperazinyl)butyl)ben zamide hydrochloride) was selected for further evaluation and is currently in phase I clinical trials as a potential atypical antipsychotic agent. PMID- 8676356 TI - Hepatitis C virus : prevalence in Lebanese blood donors and brief overview of the disease. AB - Hepatitis C virus (HCV) is recognized as the major cause of non-A, non-B hepatitis. Its prevalence in different patient populations and blood donors has been reported worldwide but not yet from Lebanon. This study was performed to determine the prevalence of HCV antibodies in 536 random Lebanese blood donors using three enzyme immunoassay kits: ETI-AB-HCVK (Sorin, Biomedica, Italy), UBI HCV EIA (Organon Teknika, Netherlands) and ORTHO HCV 2.0 ELISA (Ortho Diagnostic Systems, USA). The latter was also used as an arbitrator test. Though ETI-AB-HCVK and UBI HCV EIA kits gave higher initial positive results (5.8% and 3.7%, respectively) than ORTHO HCV 2.0 ELISA (1.1%), the over all prevalence of HCV antibody in these blood donors was 0.7%. A brief review of the HCV virus, its epidemiology, clinical features and diagnostic aspects is also presented. A similar testing approach was carried out on additional 3643 blood donors. Confirmatory testing based on CHIRON*RIBA*HCV 2.0 strip immunoblot assay (Ortho) revealed that the HCV antibody seroprevalence in random Lebanese blood donors is 0.11% and not 0.7% as found by ELISAs alone. PMID- 8676357 TI - Most common diseases treated in primary health care facilities in Lebanon. AB - The Lebanese Ministry of Health has requested public health experts to assess the most common health problems seen in Primary Health Care (PHC) facilities. This paper presents the results of this assessment conducted in a convenience sample of PHC centers. The assessment aimed at identifying areas of strength and gaps in the current system. Data were drawn from 23 PHC centers in various regions of Lebanon, in addition to an 8-year review of the experience of the Department of Family Medicine at the American University Hospital. In general, 46% of all visits to PHC centers did not include any kind of diagnosis. Most centers provided data on large categories of diseases without breakdown into specific entities. The most commonly identified health problems were hypertension, diabetes and asthma, in addition to eye and ear diseases, cardiologic conditions, and dermatologic problems. Other health problems included ill-defined signs and symptoms associated most likely with mental distress. Dental caries, skin and hair parasites, and respiratory tract infections topped the health problems among children. A qualitative synopsis of all data is presented. The paper highlights the limitations of the current health information system in Lebanon, and suggests corrective measures. It also presents a number of recommendations regarding the optimal use of PHC centers for health education and promotion and for disease prevention. PMID- 8676358 TI - Behcet's disease in Lebanon: report of 100 cases. AB - PURPOSE: To present clinical features of Behcet's disease in Lebanon and to evaluate the efficacy of treatment. PATIENTS AND METHODS: The 100 patients are seen at Hotel-Dieu de France Hospital of Beirut between 1980 and 1992. Diagnostic criteria are those of the Behcet Syndrome Research Committee of Japan. RESULTS: Recurrent oral ulcers are present in 95% of cases, genital ulcers in 78%, ocular manifestations are more frequent than those of several studies whereas skin lesions and vascular signs are less frequent. Joint involvement are recorded in 65% of cases and neurological one in 14%. The effectiveness of colchicine therapy is confirmed for mucocutaneous lesions and arthritis. Immunosuppressive agents are more beneficial than steroids alone on serious uveitis. An aggressive treatment with corticosteroids and immunosuppressive drugs improve the prognosis of meningoencephalitis. CONCLUSION: Behcet's disease doesn't have any specific characteristics in Lebanon despite some variation in the frequency of lesions. PMID- 8676360 TI - Contrast media nephropathy. PMID- 8676359 TI - The fibromyalgia syndrome. PMID- 8676361 TI - [Esophageal Abrikossof tumor: a case report]. AB - Systematic eso-gastric endoscopy allowed the discovery of a granular cell tumor. Also known as Abrikossof's tumor, the latter is a benign lesion, usually symptomless, unless it is large in size, or associated with a malignant tumor. Grossly it is a polypoid, submucosal tumor. Diagnosis is microscopic, confirmed by immunohistochemistry, unless biopsies are superficial, and show only the usually associated pseudo-carcinomatous hyperplasia. Therapeutic approach depends on the symptoms, mainly dysphagia, which is related to the size of the tumor. PMID- 8676362 TI - [Missions of medicine and the foundation of medical morals]. PMID- 8676363 TI - [Clinical pathology: myths and limits (or how to interpret a pathology report]. PMID- 8676364 TI - [Health in the third age]. PMID- 8676365 TI - [World AIDS year: final declaration]. PMID- 8676366 TI - [Megacolon: nineteen years using the Soave technique]. AB - Between 1972-1991, 44 cases of megacolon disease were treated at the Sacre-Coeur Hospital by the same surgical team. 13 cases were excluded because of negative biopsy or lost for follow-up. 30 cases were operated by Soave technique with 1 mortality by septicemia and 19 years of follow-up of 29 patients. 11 patients had minor complications and were treated successfully. One patient had a posterior myomectomy for a short segment. Results were excellent in 29 cases and considered to be cured. PMID- 8676367 TI - Cardiovascular applications of biomaterials and implants--an overview. AB - This paper was originally commissioned by the UK Department of Health as a contribution to the work of its Biomaterials and Implants Research Advisory Group. This group was set up under the Chairmanship of Professor Sir Colin Berry with the following terms of reference: (i) to identify recent advances in the field of biomaterials; (ii) to consider the future contribution of biomaterials in improving human health; (iii) to advise the Standing Group on Health Technology in areas where developments and assessment are needed; and (iv) to report to the Director of Research and Development (Professor Sir Michael Peckham) by October 1995. The cardiovascular field was one of several areas in biomaterials/implants considered by the Advisory Group. Amongst other areas considered were orthopaedics, dentistry, urology, wound repair and ophthalmology. Additionally, consideration was also given to such topics as chemical and biochemical sensors, drug release, hydrogels, membranes and artificial organs. The final report of the Advisory Group will be published at the end of this year. However, the Department has agreed that individual working papers such as the present one can be published independently in appropriate scientific journals. PMID- 8676368 TI - Noise coherence in closely-spaced electrodes: the implications for spatial averaged ECG recordings. AB - Ensemble signal averaging is conventionally used to reduce the noise content of ECG recordings. One shortcoming of this technique is that it removes the possibility of registering transient signals. As a consequence the simultaneous averaging of spatially related leads has been used. This relies on the recording electrodes receiving correlated signal components for reinforcement together with uncorrelated noise. We have developed a methodology for studying EMG noise reduction by spatial averaging and present results for different electrode spacings which suggest minimum separations for noise rejection. PMID- 8676369 TI - An automated system for the functional evaluation of oscillometric non-invasive blood pressure monitors. AB - Most of the automated non-invasive blood pressure (NIBP) monitors in clinical use rely on the oscillometric technique for measuring the blood pressures. The functional evaluation of these monitors has relied on comparison with intra arterial blood pressure measurements or comparison with 'standard' non-invasive blood pressure meters such as the Hawksley random zero sphygmomanometer. The commercial availability of simulated arm test instruments provides the opportunity for developing an alternative evaluation method. We describe the control of an NIBP simulator by a personal computer which is also linked to the NIBP monitor under test. An evaluation protocol is described and the data analysed to present graphically and in tabular form an assessment of the NIBP monitor. PMID- 8676370 TI - Topoisomerase II-mediated DNA cleavage: evidence for distinct regions of enzyme DNA contacts. AB - To determine the specific interaction sites of topoisomerase II within the DNA region defined by the footprint of the enzyme, we have investigated the cleavage reaction on double-stranded DNA substrates containing nicks and deletions. Topoisomerase II-mediated cleavage of the DNA substrates is suicidal as the enzyme is unable to religate the cleaved DNA due to diffusion of the small nucleotides 5' to the cleavage position. Thus, suicidal cleavage is obtained with substrates having one, two or three nucleotides 5' to the cleavage position. The enzyme requires interaction with three distinct regions of double-stranded DNA for cleavage to occur, one region spanning the eight nucleotides located around the cleavage position and two distal regions each spanning approximately six nucleotides. A model is proposed, where these data are taken to imply that two distinct regions of interactions exist between each topoisomerase II subunit and its DNA substrate. The model is discussed in relation to the recently solved three-dimensional structure of yeast topoisomerase II. PMID- 8676371 TI - Microtubule minus ends can be labelled with a phage display antibody specific to alpha-tubulin. AB - To investigate the orientation of alpha- and beta-tubulin heterodimers within microtubules, we cloned a phage display antibody to alpha-tubulin. The N-terminal 100 residues of alpha-tubulin were bacterially expressed and used to select clones from a large repertoire of antibody-expressing phagemid particles. One clone reacted with the expressed alpha-tubulin N terminus and native tubulin dimer but not with the expressed beta-tubulin N terminus. Electron microscopy showed 30 nm gold beads coated with the antibody binding to one end of brain microtubules. The beads bound to the minus ends of axonemes but not to the brain tubulin extensions from their plus ends. In sliding motility assays with a plus end directed motor, beads were pushed ahead of the microtubules. Our results indicate that an N-terminal epitope of alpha-tubulin is exposed only at the minus ends of microtubules. PMID- 8676372 TI - Subunit orientation in the filamentous virus Ff(fd, f1, M13). AB - The Ff filamentous viruses (fd, M13, f1) are important models for membrane protein assembly and are used extensively as cloning vectors and vehicles for peptide display. The thread-like virion (approximately 6 nm x 880 nm) comprises a single-stranded DNA genome sheathed by approximately 2700 copies of a 50-residue alpha-helical subunit (pVIII). The average inclination of pVIII subunits from the virion axis has been determined experimentally by polarized Raman microspectroscopy of oriented fd fibers, using the amide I Raman tensors obtained from a peptide single crystal. It is found that the average tilt angle, theta, between the pVIII alpha-helix and the virion axis falls within the range 13< theta <20 degrees. PMID- 8676374 TI - Protein fold recognition by mapping predicted secondary structures. AB - A strategy is presented for protein fold recognition from secondary structure assignments (alpha-helix and beta-strand). The method can detect similarities between protein folds in the absence of sequence similarity. Secondary structure mapping first identifies all possible matches (maps) between a query string of secondary structures and the secondary structures of protein domains of known three-dimensional structure. The maps are then passed through a series of structural filters to remove those that do not obey simple rules of protein structure. The surviving maps are ranked by scores from the alignment of predicted and experimental accessibilities. Searches made with secondary structure assignments for a test set of 11 fold-families put the correct sequence dissimilar fold in the first rank 8/11 times. With cross-validated predictions of secondary structure this drops to 4/11 which compares favourably with the widely used THREADER program (1/11). The structural class is correctly predicted 10/11 times by the method in contrast to 5/11 for THREADER. The new technique obtains comparable accuracy in the alignment of amino acid residues and secondary structure elements. Searches are also performed with published secondary structure predictions for the von-Willebrand factor type A domain, the proteasome 20 S alpha subunit and the phosphotyrosine interaction domain. These searches demonstrate how the method can find the correct fold for a protein from a carefully constructed secondary structure prediction, multiple sequence alignment and distant restraints. Scans with experimentally determined secondary structures and accessibility, recognise the correct fold with high alignment accuracy (86% on secondary structures). This suggests that the accuracy of mapping will improve alongside any improvements in the prediction of secondary structure or accessibility. Application to NMR structure determination is also discussed. PMID- 8676375 TI - P1 plasmid partition: a mutational analysis of ParB. AB - P1 plasmid partition to daughter cells requires plasmid proteins, ParA and ParB, and a centromere analog, parS, to which ParB binds. ParA and ParB decrease the loss frequencies of some low copy number plasmid vectors with parS inserts, as well as that of P1 itself, more than 100-fold. Unexpectedly, we find that Par proteins can actively destabilize other parS-plasmid constructs under similar conditions. Only ParB is required for this partition dysfunction. The destabilization can be dramatic; certain parS-plasmid constructs cannot even be maintained in the presence of ParB. We take advantage of this partition dysfunction to select parB mutants unable to destabilize a particularly ParB sensitive parS-plasmid. The mutations obtained are widely distributed in the gene. Several of the mutations affected binding of ParB to parS; others did not. Amino acid substitutions that affected binding without influencing dimerization were mapped to two separate regions of ParB. C-Terminal amino acid substitutions in ParB blocked its dimerization and binding to parS, as did deletions of the entire C-terminal part of the protein. These results are consistent with ParB binding to parS as a dimer and suggest that the C-terminal part is a dimerization domain of the protein. Cell extracts of a frameshift mutant analyzed contained, in addition to the expected truncated ParB, a second species of ParB with the normal C-terminal part. Apparently, a site of ribosomal frameshifting is encoded within parB, at which some ribosomes change reading frame in the mutant. All obtained mutant ParB proteins were unable to complement the partition defect of a parB null mutant mini-P1. This suggests that the initial reactions between ParB and parS leading to partition dysfunction and to partition function are similar. PMID- 8676373 TI - hnRNP A1 selectively interacts through its Gly-rich domain with different RNA binding proteins. AB - Heterogeneous nuclear ribonucleoproteins (hnRNPs) are abundant nuclear polypeptides, most likely involved in different steps of pre-mRNA processing. Protein A1 (34 kDa), a prominent member of the hnRNP family, seems to act by modulating the RNA secondary structure and by antagonizing some splicing factors (SR proteins) in splice-site selection and exon skipping/inclusion. A role of A1 in the nucleo-cytoplasmic transport of RNA has also been proposed. These activities might depend not only on the RNA-binding properties of the protein but also on specific protein-protein interactions. Here we report that A1 can indeed selectively interact, in vitro, both with itself and with other hnRNP basic "core" proteins. Such selective binding is mediated exclusively by the Gly-rich C terminal domain, where a novel protein-binding motif constituted by hydrophobic repeats can be envisaged. The same domain is necessary and sufficient to promote specific interaction in vivo, as assayed by the yeast two-hybrid assay. Moreover, an in vitro interaction with some SR proteins was also observed. These observations suggest that diverse and specific protein-protein interactions might contribute to the different functions of the hnRNP A1 protein in mRNA maturation. PMID- 8676376 TI - Carboxy-terminal residues of mouse thymidine kinase are essential for rapid degradation in quiescent cells. AB - The expression of murine thymidine kinase (TK) is highly dependent on the growth state of the cell. The enzyme is nearly undetectable in resting (G0) cells, but TK protein levels rise dramatically when serum-stimulated cells reach the G1/S boundary. To study post-transcriptional regulation of TK expression, Ltk- cells were stably transfected with the coding region of the TK cDNA under the control of a constitutive SV40 promoter. While TK mRNA levels were growth independent in this cell line, TK protein expression and enzyme activity were low in resting cells but increased strongly after growth stimulation by serum. Measurements of translation efficiency and protein stability by immunoprecipitation and pulse chase experiments indicated that a fourfold change in protein synthesis rate and a sevenfold rise in protein stability are responsible for the increase of TK expression. Progressive deletion of three, six, ten and 20 carboxy-terminal residues of the enzyme resulted in a stepwise loss of its growth-dependent regulation. In addition, a truncated protein lacking the last 30 amino acid residues was expressed at a level tenfold higher than the full-length polypeptide. Further analysis showed that removal of the C-terminal 30 residues did not affect the translation rate, but resulted in the drastic increase in protein half-life. These results demonstrate that residues at the carboxy terminus of the murine enzyme are essential for the growth-dependent regulation of TK protein stability. PMID- 8676377 TI - Electron-crystallographic refinement of the structure of bacteriorhodopsin. AB - Using electron diffraction data corrected for diffuse scattering together with additional phase information from 30 new images of tilted specimens, an improved experimental density map has been calculated for bacteriorhodopsin. The atomic model has then been rebuilt into this new map with particular attention to the surface loops. All the residues from 7 to 227 as well as ten lipid molecules are now included, although a few amino acid residues in three of the six surface loops, about half of the lipid hydrophobic chains and all of the lipid head groups are disordered. The model has then been refined against the experimental diffraction amplitudes to an R-factor of 28% at 3.5 angstrom resolution with strict geometry (0.005 angstrom) bond length deviation) using the improvement of the "free" phase residual between calculated and experimental phases from images as an objective criterion of accuracy. For the refinement some new programs were developed to restrain the number of parameters, to be compatible with the limited resolution of our data. In the final refined model of the protein (2BRD), compared with earlier co-ordinates (1BRD), helix D has been moved towards the cytoplasm by almost 4 angstrom, and the overall accuracy of the co-ordinates of residues in the other six helices has been improved. As a result the positions of nearly all the important residues in bacteriorhodopsin are now well determined. In particular, the buried, protonated Asp115 is 7 angstrom from, and so not in contact with, the retinal and Met118 forms a cap on the pocket occupied by the beta-ionone ring. No clear density exists for the side-chain of Arg82, which forms a central part of the extracellular half-channel. The only arginine side chain built into good density is that of Arg134 at the extracellular end of helix E, the others being disordered near one of the two surfaces. The interpretation of the end of helix F on the extracellular surface is now clearer; an extra loose helical turn has been built bringing the side-chain of Glu194 close to Arg134 to form a probable salt bridge. The model provides an improved framework for understanding the mechanism of the light-driven proton pumping. A number of cavities that could contain water molecules were found by searching the refined model, most of them above or below the Schiff base in the half-channels leading to the two surfaces. The ordered and disordered regions of the structure are described by the temperature factor distribution. PMID- 8676378 TI - Mutational analysis of the joining regions flanking helix P18 in E. coli RNase P RNA. AB - We have studied variants of Escherichia coli RNase P RNA with base exchanges in the joining regions flanking helix P18, which form part of the ribozyme core structure. Mutant RNase P RNAs were analyzed for: (1) specific tRNA binding by gel retardation; (2) catalytic performance in single turnover reactions; (3) structural perturbations utilizing Pb2+ -induced hydrolysis; and (4) in vivo function by complementation analysis in E. coli RNase P mutant strains. Our in vitro experiments revealed that the base moieties of nucleotides (nt) 303 and 331 to 333 neither significantly contribute to tRNA binding or structural stabilization of RNase P RNA nor to active site chemistry. Single base exchanges at nt 300, 301, and 330 reduced tRNA binding, while having little effect on the catalytic rate, which demonstrates that these nucleotides are involved in forming the high affinity (pre-)tRNA binding site. In contrast, point mutations at the strictly conserved positions nt 328, 329, 334 and 335 reduced tRNA binding affinity as well as the catalytic rate, suggesting that these mutations additionally disrupted important interactions in the catalytic center. Probing by Pb2+ revealed that particularly the mutations that affected catalytic function most strongly perturbed a more extended region (nt 248 to 335) known to be involved in tRNA binding. Under high salt conditions (> or = 0.8 M NH4+), catalytic defects of the mutant RNase P RNAs were much less pronounced, suggesting that structural perturbations leading to increased electrostatic repulsion between phosphate groups were the main cause for observed functional defects. Only mutant C334 retained a largely increased pre-steady-state K(m(pss)) under high salt conditions. We conclude that the base at position 334 is directly involved in a contact crucial to pre-tRNA binding. A complementation analysis demonstrated the important role in vivo of the joining regions flanking helix P18. None of the bases could be mutated without affecting bacterial viability. PMID- 8676380 TI - On the relative ability of centromeric GNA triplets to form hairpins versus self paired duplexes. AB - While tandem repeats of the human centromere DNA pentamer sequence TGRAA form stable "self-complementary" [TGRAATGRAA]2 duplexes (R = G or A) containing the GA bracketed unpaired purine stack motif, their phase-shifted variants NAATGNAATG (N = A, G, C, T) were found to exist in solution as an equilibrium mixture of a duplex containing the GA-bracketed unpaired stack motif and a hairpin containing a single-residue loop closed by a sheared G x A pair. The stability of the hairpin form relative to duplex form of GNA triplets was found to be GCA>GAA/GTA>>GGA, with the CAATGCAATG sequence mostly in the hairpin form and the GAATGGAATG sequence mostly in the [GAATGGAATG]2 duplex form. The chemical shifts of the H1' and H4' protons of the central N residue in GNA triplets were found to differ markedly in the duplex and hairpin forms and are diagnostic indicators of which conformation the oligonucleotide adopts. Comparison between the structures of the G x A-closed C loop motif and the G x A-bracketed unpaired G-stack [GGA]2 motif reveals remarkably similar stacking by the loop C residue and the intercalated G residue on the adjacent sheared G x A pair. The anomalous upfield chemical shifts of the H1' and H4' protons in [GGA]2 motifs and the H4' proton in GCA loops, and the different sugar conformations in these two motifs, can be explained by interstrand versus intrastrand stacking of the central (G or C) deoxyribose with the adenine base. Based on these studies, a DNA sequence GTGGAATGGAATGGAAC was designed and shown to form a duplex containing three [GGA]2 motifs, while its 9G-->9C analog GTGGAATGCAATGGAAC was found to adopt a stable hairpin containing a (GGA)2 motif in the stem and a G x A-closed single C-loop. PMID- 8676379 TI - Observation of the A-DNA to B-DNA transition during unrestrained molecular dynamics in aqueous solution. AB - A large challenge in molecular dynamics (MD) simulations of proteins and nucleic acids is to find the correct "experimental" geometry when a simulation is started a significant distance away from it. In this study, we have carried out four unrestrained approximately 1 ns length MD trajectories in aqueous solution on the DNA duplex d(CCAACGTTGG)2, two beginning in a canonical A-DNA structure and two beginning in a canonical B-DNA structure. As judged by root-mean-squared coordinate deviations, average structures computed from all four of the trajectories converge to within approximately 0.8 to 1.6 angstroms (all atoms) of each other, which is 1.3 to 1.7 angstroms (all atoms of the central six residues from each strand) and 3.1 to 3.6 angstroms (all atoms) away from the B-DNA-like X ray structure reported for this sequence. To our knowledge, this is the first example of multiple nanosecond molecular dynamics trajectories with full representation of DNA charges, solvent and long range electrostatics that demonstrate both internal consistency (two different starting structures and four different trajectories lead to a consistent average structure) and considerable agreement with the X-ray crystal structure of this sequence and NMR data on duplex DNA in aqueous solution. This internal consistency of structure for a given sequence suggests that one can now begin to realistically examine sequence dependent structural effects in DNA duplexes using molecular dynamics. PMID- 8676381 TI - Catalytic mechanism of the metal-dependent fuculose aldolase from Escherichia coli as derived from the structure. AB - The structure of L-fuculose-1-phosphate aldolase in a cubic crystal form has been determined with and without the inhibitor phosphoglycolohydroxamate at 2.4 and 2.7 angstrom (1 angstrom = 0.1 nm) resolution, respectively. This inhibitor mimics the enediolate transition state of the substrate moiety dihydroxyacetone phosphate. The structures showed that dihydroxyacetone phosphate ligates the zinc ion of this metal-dependent class II aldolase with its hydroxyl and keto oxygen atoms, shifting Glu73 away from the zinc coordination sphere to a non-polar environment. At this position Glu73 accepts a proton in the initial reaction step, producing the enediolate which is then stabilized by the zinc ion. The other substrate moiety L-lactaldehyde was modeled, because no binding structure is yet available. PMID- 8676382 TI - High-resolution crystal structures of two polymorphs of cytochrome c' from the purple phototrophic bacterium rhodobacter capsulatus. AB - The structures of two polymorphs of cytochrome c' from Rhodobacter capsulatus (RCCP) strain M110 have been determined by the molecular replacement method. Iron anomalous scattering data were used to confirm the molecular replacement solution. The structures were refined at 1.72 angstrom and 2.0 angstrom resolution to R-values of 15.0% and 16.3%, respectively. The RCCP molecule is a dimer and each of the identical 129 residue subunits folds as a four-helical bundle with a covalently bound heme group in the center. This structural motif resembles that of cytochromes c' reported from Rhodospirillum molischianum (RMCP), Rhodospirillum rubrum (RRCP), Chromatium vinosum (CVCP), Achromobacter xyloseoxidans (AXCP) and Alcaligenes denitrificans (ADCP). However, the architecture of the RCCP dimer, that is, the mode of association of subunits, differs substantially from that of the other cytochromes c'. In the RCCP dimer, the subunits are roughly parallel with each other and only helix B of each subunit participates in formation of the dimer interface. Measurement of the solvent-accessible surface area indicates that the dimer interface is smaller in RCCP than in the other cytochromes c'. In RMCP, CVCP, RRCP, AXCP and ADCP the subunits cross each other to form an X shape, and two helices, A and B, of each subunit interact across the dimer interface. These results are consistent with hydrodynamic measurements, which show that there is an equilibrium between monomers and dimer in RCCP, whereas the dimer is the predominant form in the other cytochromes c' for which structures have been determined. Structural comparison of the six cytochromes c' reveal that they can be divided into two groups. In group 1 cytochromes c', CVCP and RCCP, the amino acid sequences and the folding of subunits are arranged in such a way as to allow the formation of a deep channel between helices B and C with direct solvent accessibility to the heme sixth ligand position. There is no such channel in group 2 cytochromes c', RMCP, RRCP, AXCP and ADCP. This may account, in part, for the differences in carbon monoxide binding. PMID- 8676383 TI - Determination of the gene sequence and the three-dimensional structure at 2.4 angstroms resolution of methanol dehydrogenase from Methylophilus W3A1. AB - The DNA sequences for the genes encoding the heavy and light subunits of methanol dehydrogenase from Methylophilus methylotrophus W3A1 have been determined. The deduced amino acid sequence has enabled the structure of the enzyme to be refined at 2.4 angstrom resolution against X-ray data collected on a Hamlin area detector. The structure was refined using the programs PROFFT and X-PLOR with several model building step interspersed. The final model contains two heavy chains (571 amino acids), two light chains (69 amino acids), two molecules of pyrroloquinoline quinone, two Ca2+ and 521 solvent molecules. Each half molecule contains four disulfide linkages and four cis peptides. One of the disulfides is formed from two adjacent cysteine residues linked by a trans peptide which creates a novel eight-membered ring. The heavy subunit is an 8-fold beta propeller, each "blade" of which is a four-stranded antiparallel twisted beta sheet. The light chain is an elongated subunit stretching across the surface of the heavy subunit, with residues 1 to 32 containing four beta-turns and residues 33 to 62 forming a helix; however, it neither interacts with the active site, nor the other HL dimer and its functional role is obscure. Around the 8-fold beta propeller there is a repeating pattern of tryptophan residues located in the outer strand of seven of the eight beta-leaflets, each packed between adjacent leaflets. Each of these tryptophan residues is centered in the beta-strand and participates in the main chain hydrogen bonding of the sheet. Five of the seven tryptophan residues have closely similar interactions with the adjacent beta leaflet including stacking of the tryptophan indole rings against a peptide plane and formation of a hydrogen bond from NE1 of the indole ring to a main-chain carbonyl. This repeating pattern is conserved over a number of MEDH sequences. The PQQ is located on the pseudo 8-fold rotation axis of the heavy subunit, in a funnel-shaped internal cavity, sandwiched between the indole ring of Trp237 and the two sulfur atoms of the Cys103-Cys104 vicinal disulfide. A hexacoordinate Ca2+ is bound in the active site by one nitrogen and five oxygen ligands, three from the PQQ and the others from two protein side-chains. In the active site an isolated solvent molecule is bound to the O5 of PQQ and to a nearby aspartate side-chain; its position may be the binding site for methanol. The aspartate might than serve as a general base for proton abstraction from the substrate hydroxyl. The C5 atom of PQQ could be activated by electrophilic catalysis by a nearby argenine side-chain or by the calcium ion bound to PQQ. PMID- 8676384 TI - Structure of the IIA domain of the mannose transporter from Escherichia coli at 1.7 angstroms resolution. AB - The mannose transporter from Escherichia coli is a member of the phosphoenolpyruvate-dependent phosphotransferase system. The multi-subunit complex couples translocation across the bacterial inner membrane with phosphorylation of the solute. A functional fragment (IIA(Man), residues 2 to 133) of the membrane-associated IIAB(Man) subunit of the mannose transporter was expressed as a selenomethionine protein, and the unphosphorylated molecule was crystallized and its structure solved by X-ray crystallography. The protein consists of a central five-stranded beta-sheet covered by helices on either face. The order of the secondary structure elements is (beta alpha)4, alpha beta. Four beta-strands are arranged in a parallel manner with strand order 2134 and are linked by helices forming right-handed cross-over connections. The fifth strand that forms one edge of the sheet and runs antiparallel to the others is swapped between the subunits of the dimeric structure. Helices D and E form a helical hairpin. Histidine 10, which is transiently phosphorylated during catalysis, is located at the topological switch-point of the structure, close to the subunit interface. Its imidazole ring is hydrogen bonded to the buried side-chain of Asp67. It is likely that Asp67 acts as a general base and thus increases the nucleophilicity of the histidine. Modeling suggests that the covalently bound phosphoryl group would be stabilized by the macrodipole of helix C. Putative interactions between IIA(Man) and the histidine-containing phosphocarrier protein are discussed. PMID- 8676385 TI - The methanol-induced globular and expanded denatured states of cytochrome c: a study by CD fluorescence, NMR and small-angle X-ray scattering. AB - Methanol-induced conformational transitions of cytochrome c(cyt c) at acidic pH values were investigated with a combined use of far and near-UV CD, fluorescence, NMR spectroscopy and small-angle X-ray scattering. At pH 3.0 and 25 degrees C, two methanol-induced non-native states were characterized. First, addition of methanol up to 25% (v/v) induced a compact denatured conformer (I(M)). Further addition of methanol transformed this I(M) state into the expanded and highly helical denatured state (H). The existence of the I(M) state was shown by the discrepancy in transition curves obtained from the ellipticity at 222 nm, the ellipticity at 282 nm, the tryptophan fluorescence monitored at 350 nm and the native peak intensity of the (1)H NMR spectrum. These CD, fluorescence and NMR results showed that the I(M) state has no specific tertiary structure but has a secondary structural content and tryptophan environment similar to those in the native state. The radius of gyration of the I(M) state, 17.7 angstroms, obtained from the Guinier plot of the small-angle X-ray scattering data was significantly smaller than that of the acid-denatured state (30.1 angstroms) and was closer to that of the native state (14.6 angstroms), showing that the I(M) state is compact. The Kratky plot for the I(M) state exhibited a bell-shaped profile, indicating a globular conformation. These structural features indicate that the structure of the I(M) state is quite similar to that of the anion-induced molten globule state of this protein. Furthermore the alcohol-denatured state (H) of cyt C in 60% (v/v) methanol was structurally characterized. Though the H state had a helical content much higher than the native state monitored by far-UV CD spectroscopy, the radius of gyration, 31.7 angstroms, was similar to that of the acid-denatured state, showing that this H state is an expanded denatured state. The Kratky plot for the H state did not show a clear peak, indicating a chain like conformation. Thus we conclude that the H state has an expanded and chain like conformation with a high helical content. Finally, we constructed a phase diagram of cyt c involving the native, I(M), acid-denatured and H states against pH and the methanol concentration. The result indicates that the I(M) state is found in the pH range from 2.5 to at least 4.5 with a pH-dependent optimum methanol concentration of 10 to 40%. PMID- 8676386 TI - Three-dimensional solution structure and backbone dynamics of a variant of human interleukin-3. AB - The three-dimensional structure and backbone dynamics of a truncated and multiply substituted recombinant human interleukin-3 (IL-3) variant (SC-65369) have been determined from multidimensional heteronuclear nuclear magnetic resonance spectroscopic data. Sequential application of distance geometry and restrained molecular dynamics calculations produced a family of 25 convergent structures which satisfy a total of 1812 experimental constraints (1659 proton-proton NOEs, 75 backbone dihedral angle constraints, and 39 pairs of hydrogen bond constraints) with an average root-mean-square deviation from the mean coordinate positions of 0.88(+/- 0.15) angstroms and 1.37(+/- 0.13) angstroms for the backbone and all heavy atoms, respectively, of all residues except 28 to 39. The structure is a left-handed four-helix bundle (comprised of helices A through D) with two long overhand loops (designated as loops AB and CD). Loop AB contains a short fifth helix (helix A') which is closely packed against helix D in an approximately parallel fashion and which has multiple contacts with loop CD. The overall molecular tumbling time (6.5 ns) determined from the 15N relaxation data was consistent with a monomeric protein under the conditions of the experiment (1 mM protein, pH 4.6, 30 degrees C). The 15N relaxation data indicate that the helical regions of SC-65369 are quite rigid, while portions of loop AB, loop CD, and the C terminus undergo significant internal motions. Among the structurally related four-helical bundle cytokines, the structure of SC-65369 is most similar to those of granulocyte-macrophage colony stimulating factor (GM-CSF) and the single structural domain of interleukin-5 (IL-5), all of which share a common receptor subunit required for signal transduction and activation of their hematopoietic target cells. Indeed, the C(alpha) atoms in the four-helix core of these three proteins can be superimposed to 1.71 angstroms (SC-65369 and GM-CSF, 62 C(alpha) atoms) and 1.96 angstroms (SC-65369 and IL-5 single structural domain, 58 C(alpha) atoms), respectively. When the structures of the IL-3 variant, GM-CSF, and IL-5 were aligned, the conserved and conservatively substituted residues were found to be hydrophobic and buried, with the single exception of Glu-22 (IL-3 numbering), which is strictly conserved but nonetheless fully exposed to solvent. The most remarkable differences between the SC-65369 structure and that of GM-CSF occur in loop AB. This loop in GM-CSF crosses over the top of helix D and passes underneath loop CD on its way to helix B. In contrast, loop AB of SC-65369 passes in front of helix D, similar to the first crossover loop in human growth hormone and granulocyte colony-stimulating factor. In addition, helix A', which is interdigitated into the helical bundle in a manner similar to the helices in the CD loop of interferon-beta and interferon gamma, exists in a region where short stretches of beta-structure are found at analogous positions in GM-CSF and IL-5. These differences suggest that the structural elements within this region may be important for recognition by their cognate receptors. PMID- 8676387 TI - Thermodynamic and structural compensation in "size-switch" core repacking variants of bacteriophage T4 lysozyme. AB - Previous analysis of randomly generated multiple mutations within the core of bacteriophage T4 lysozyme suggested that the "large-to-small" substitution Leu121 to Ala (L121A) and the spatially adjacent "small-to-large" substitution Ala129 to Met (A129M) might be mutually compensating. To test this hypothesis, the individual variants L121A and A129M were generated, as well as the double "size switch" mutant L121A/A129M. To make the interchange symmetrical, the combination of L121A with A129L to give L121A/A129L was also constructed. The single mutations were all destabilizing. Somewhat surprisingly, the small-to-large substitutions, which increase hydrophobic stabilization but can also introduce strain, were less deleterious than the large-to-small replacements. Both Ala129 - > Leu and Ala129 --> Met offset the destabilization of L121A by about 50%. Also, in contrast to typical Leu --> Ala core substitutions, which destabilize by 2 to 5 kcal/mol, Leu121 --> Ala slightly stabilized A129L and A129M. Crystal structure analysis showed that a combination of side-chain and backbone adjustments partially accommodated changes in side-chain volume, but only to a limited degree. For example, the cavity that was created by the Leu121 to Ala replacement actually became larger in L121A/A129L. The results demonstrate that the destabilization associated with a change in volume of one core residue can be specifically compensated by an offsetting volume change in an adjacent residue. It appears, however, that complete compensation is unlikely because it is difficult to reconstitute an equivalent set of interactions. The relatively slow evolution of core relative to surface residues appears, therefore, to be due to two factors. First, a mutation in a single core residue that results in a substantial change in size will normally lead to a significant loss in stability. Such mutations will presumably be selected against. Second, if a change in bulk does occur in a buried residue, it cannot normally be fully compensated by a mutation of an adjacent residue. Thus, the most probable response will tend to be reversion to the parent protein. PMID- 8676388 TI - A microscopic view of helix propagation: N and C-terminal helix growth in alanine helices. AB - Molecular dynamics simulations with umbrella sampling are used to perform free energy simulations of C-terminal and N-terminal helix propagation in small helices of Ace-(Ala)n-NMe, with n= (4,5,10,15), in water. From the resulting free energy surfaces, computed as a function of the terminal psi dihedral angle, the roles of length and end effects in helix propagation are explored. An energetic analysis of the helices, both formed and partially formed, is used to develop a molecular rationalization for the observed trends in helix stability. We find that the microscopic helix propagation parameters vary significantly depending on the end and length of the helix in which the terminal hydrogen bond is forming. A model which considers propagation of the helices from either end as statistically independent yields Zimm-Bragg s parameters in the range of 0.5 to 1.5, depending on helical length. Analysis of the mechanism of helix propagation suggests that 3(10)-helix plays a role in helix formation but its population should be low in the helical state of these model peptides. PMID- 8676389 TI - The effect of nucleosome phasing sequences and DNA topology on nucleosome spacing. AB - The distances between the nucleosomes in eukaryotic chromatin that define the nucleosome repeat length are not universally constant, but vary between different cell types and activity states. We have previously established in a cell-free system that nucleosome spacing is essentially governed by electrostatic principles, most likely through charge neutralisation of linker DNA by cations either free in solution or on flexible histone domains. On the basis of the tight correlation between the parameters that affect nucleosome spacing and those that influence the folding of the nucleosomal fiber into higher order structures, we suggested that there is an intimate relationship between nucleosome spacing and chromatin folding. Here we describe DNA topology as a new parameter that influences nucleosome spacing in a predictable way. The effects of topology and cation concentrations integrate to define the final repeat length. The phenomenon of "nucleosome phasing" describes nucleosomal arrays that are generated through positioning of nucleosomes by the underlying DNA sequence. To determine the relative contribution of DNA sequence and the parameters intrinsic to physiological chromatin for nucleosomal positions, we created situations where these two principles were in conflict. We found that nucleosome repeats directed by a strong positioning sequence are dominated by the cation-induced spacing as well as by the effects of topology. We conclude that the DNA sequence effects nucleosome spacing only by "fine tuning" of nucleosome positions within the framework of a repeat pattern that is established by other principles. PMID- 8676390 TI - Sequence-specific DNA binding of the phage Mu C protein: footprinting analysis reveals altered DNA conformation upon protein binding. AB - The mom gene of bacteriophage Mu, which codes for a DNA modification function, is regulated in a complex manner at both transcriptional and translational levels. The phage-encoded C protein functions as an activator of mom transcription. The mom promoter has features of an activator-dependent weak promoter, and the C binding site is located upstream and overlapping the -35 region and includes the palindromic sequence TTAT(N)6ATAA. The interactions of this activator protein at its binding site in Pmom has been investigated using four different chemical footprinting reagents. The protein footprint spans a region of 18 to 25 bp, depending on the nature of the chemical reagent used. Dimethylsulfate protection experiments revealed the base-specific interactions. The protected guanines are separated by 15 bp and are located beyond the interrupted palindromic sequence. A tripartite footprint was observed with hydroxyl radical, generated by Fe(II) EDTA, which shows the binding of the protein to one face of the helix. The extent of protection conferred by the bound protein, however, is not uniform, suggesting that the interaction is asymmetric. The chemical nuclease 1,10-phenanthroline copper, a minor groove specific ligand, shows hyper-reactivity upon protein binding in the top strand nucleotide triplet CAC, again confirming the protein induced alterations in DNA conformation. Gel exclusion chromatography and chemical crosslinking experiment with the purified protein suggest that this mode of interaction is accomplished by a dimeric protein. This observation is supported by electrophoretic mobility shift assay using heterodimer of pure C protein and staphylococcal protein A-C fusion. The deletion analysis implicates a role for the carboxyl-terminal region of the protein in DNA binding. PMID- 8676391 TI - Nucleolin is a sequence-specific RNA-binding protein: characterization of targets on pre-ribosomal RNA. AB - Nucleolin is an abundant nucleolar protein, which plays an essential, but largely unknown role in ribosome biogenesis. Nucleolin contains four consensus RNA binding domains (CS-RBD), the presence of which suggests that the molecular function of this protein is likely reflected by its RNA-binding properties. Indeed, by immunocytological analysis performed on ribosomal transcription units, we have found several nucleolin molecules associated with nascent pre-rRNA. In mouse, two high-affinity binding sites with an apparent dissociation constant (Kd) of 50 to 100 nM have been mapped in the 5' ETS upstream from the early pre rRNA processing site. Interestingly, nucleolin of mouse origin has recognized analogous sequences in the 5' ETS of human pre-rRNA. In parallel, selection amplification (SELEX) experiments have identified an 18-nucleotide long RNA sequence that binds nucleolin with high affinity (Kd 5 to 20 nM) and shares a common UCCCGA motif with the characterized pre-rRNA binding sites. By mutagenesis and a structural analysis, we have characterized the nucleolin RNA binding site and found that it is constituted by a minimal 18-nucleotide long stem-loop structure. The sequence UCCCGA that is found within the hairpin loop is necessary for the specific interaction. Mutation of any of the C or G residues within this motif abolishes nucleolin interaction. Furthermore, point mutation in the stem that completely disrupt the hairpin structure also prevents nucleolin binding. By determining the minimal 5' and 3' ends of the RNA that is bound to the protein we concluded that nucleolin binding site is constituted by a short four to five-base pair stem and an eight-nucleotide loop. This structural motif is very similar to hairpins recognized by two other CS-RBD-containing proteins (U1 snRNP A and U2 snRNP B"). Possible functional implications of our findings are discussed. PMID- 8676392 TI - The Bacillus subtilis DNA replication terminator. AB - The recent discovery of the Bacillus subtilis plasmid terminator TerLS20 with bidirectional fork arrest activity has provided the opportunity to probe further the structural and functional features of B. subtilis replication terminators in general. The minimal TerI and TerLS20 terminators each comprise two 13 nt segments flanking a central trinucleotide, which is almost completely conserved in all terminators. It corresponds to the region of overlap of the two RTP binding sites (A and B) on the DNA. It has been shown that, despite this conservation, considerable variation in this trinucleotide region still allows fork arrest activity. Thus, the productive interaction of the RTP dimers, which presumably occurs in the vicinity of this trinucleotide region, is not dependent upon stringently defined contacts with the bases in this region. A completely synthetic and highly symmetrical terminator was constructed by replacing the 13 nt segment of the A site of TerI with an opposed segment identical to that in the B site. The efficient bidirectional activity of this new terminator, TerSymB, established more firmly the need for two opposed RTP binding sites in a functional terminator. TerSymB was used to investigate the effect of sequence deviation in one of the 13 nt segments, from that in the B site, on bidirectionality of the terminator. It was found that the deviations introduced converted the terminator significantly towards polarity of action. The partial symmetry within each of the 13 nt segments of TerSymB, and the presumed recognition of this symmetry in the binding of a symmetrical dimer of RTP to each overlapping site, suggest that the bound dimers are centred over positions in the DNA sequence separated by 15 nt. This separation distance has been used in conjunction with the mode of binding of RTP to DNA proposed by Bussiere et al., based on their crystal structure for RTP, to model the interaction of the two dimers of RTP with unbent B-form DNA. Increased separation of the two binding sites of TerSymB was performed by inserting an extra three, seven or ten nucleotides centrally within the TerSymB sequence. The effects of these insertions on RTP binding and fork arrest activity were consistent with the proposed positioning of the RTP dimers within the terminator sequence, and interaction between the dimers bound to TerSymB. A model to account for the generation of RTP-terminator complexes with bidirectional or polar fork arrest activity utilising TerSymB or TerI-VI is presented. PMID- 8676393 TI - A zinc-binding domain involved in the dimerization of RAG1. AB - Recombination-activating gene 1 (RAG1), as well as RAG2, are the only lymphoid specific genes required for V(D)J recombination. RAG1 protein contains a C3HC4 zinc-binding motif (zinc ring finger) that binds two zinc ions. We have found that RAG1 contains additional zinc-binding motifs in the form of two separate C2H2 zinc finger sequences. One of the zinc fingers, in combination with the C3HC4 subdomain, forms a highly specific dimerization domain. A combination of biophysical techniques has been used to determine the energetics of association, the overall shape of the dimerization domain, and the relative orientation of the monomeric subunits within the dimer. These results provide direct evidence that a C3HC4 motif is involved in a protein-protein interaction, in this case via homodimer formation. In addition, the observation that the dimerization domain includes multi-class zinc binding motifs, namely both a zinc finger and a C3HC4 subdomain, has important implications for other C3HC4-containing proteins. The position of this dimerization domain in the N-terminal third of the RAG1 sequence of 1040 amino acid residues may have a significant influence on the activities associated with the C-terminal domains of the protein. PMID- 8676394 TI - Three-dimensional structure of scaffolding-containing phage p22 procapsids by electron cryo-microscopy. AB - The procapsids of bacterial viruses are the products of the polymerization of coat and scaffolding subunits, as well as the precursors in DNA packaging. Electron cryo-microscopy has been used to study the three-dimensional structures of bacteriophage P22 procapsids containing wild-type and mutant scaffolding proteins. The scaffolding mutant structure has been resolved to 19 A resolution and agrees with the 22 A resolution wild-type procapsid reconstruction. Both procapsid reconstructions contain an outer icosahedral coat protein shell and an inner scaffolding protein core. The outer core protein forms a T = 7 icosahedral lattice with distinctive channels present at the centers of the pentons and hexons. In addition, the hexons display a prominent skew. Computational isolation of the skewed hexon shows the presence of a local 2-fold axis that reduces the number of unique conformations in the asymmetric unit to four at this resolution. We have classified the four unique subunits into three distinct classes, based upon the shape of the upper domain and the presence of a channel leading to the inner coat protein surface. In addition, at the inner surface of the coat protein, finger-like regions that extend towards the scaffolding protein core are present in two of the subunits. The finger-like regions suggest the presence of an ordered interaction between the inner coat protein and the scaffolding protein. However, an icosahedral scaffolding protein shell is not formed, and the innermost scaffolding protein core does not pack with icosahedral symmetry. PMID- 8676396 TI - Concurrent interactions contribute to the raised pKa of His18 in Barnase. AB - To understand the source of the stability due to a charged His side-chain located at the C terminus of an alpha-helix in barnase, we computed the stabilization free energy, upon ionization of the His side-chain, in the native protein, the Leu94 mutant, and a "pseudo-native" protein, using free energy molecular dynamics simulations. We show that there are a number of interactions that can individually stabilize the native protein. These interactions cannot be portrayed satisfactorily by a unique model such as: (1) the helix dipole model, in which there is a strong interaction between His+ and the helix dipole; or (2) the H bond model, in which His+ acts as a donor to either a carbonyl group at the C terminus of the helix or to the aromatic moiety of the neighbouring Trp94 residue. The protonated form of His18 in the native protein is computed to be more stable than the neutral form, in accord with the experimental observation. Part of this stabilization is due to the last turn of the alpha-helix. In the simulation of the folded proteins, the persistence of a H-bond between the His18 side-chain and a carbonyl group at the C terminus of the helix sustains the H bond model. However, it is difficult to perceive whether this helix-stabilizing interaction is stronger when the His side-chain is charged. It is shown, in agreement with experiment, that the Trp94 side-chain, in the vicinity of the charged His residue, stabilizes the protein. Water molecules hydrogen-bonded to His18 have longer residence times ( > 100 ps) in the native protein than in the Leu94 mutant ( < 50 ps). This observation might be indicative of the capacity of Trp94, by a mechanism not evident, for trapping water molecules in the vicinity of His18 and making the exchange of a water molecule, bound to His18, with bulk water more difficult. A conformational analysis of the native and Leu94 mutant proteins shows that the simulations reproduce fairly well features of the crystal and NMR structures of these proteins. PMID- 8676395 TI - Role of capsid structure and membrane protein processing in determining the size and copy number of peptides displayed on the major coat protein of filamentous bacteriophage. AB - Filamentous bacteriophage virions can be engineered to display small foreign peptides in the N-terminal regions of all 2700 copies of the major coat protein (pVIII), but larger peptides can be accommodated only in hybrid virions, in which modified and wild-type coat protein subunits are interspersed. The copy number of peptides accepted in hybrid virions is generally believed to be related to peptide size: the larger the insert, the lower the number of modified coat protein subunits in the assembled virion. However, we show here that some large peptides can be displayed at a much higher copy number than smaller ones and that some relatively small peptides are poorly displayed, if at all, in hybrid virions. X-ray diffraction studies of a recombinant virion together with model building experiments with peptide and protein epitopes of known structure demonstrated that it is feasible to accommodate much larger structures, without perturbation of the capsid protein packing, than it has proved possible to generate in vivo. We show further that the insertion of certain peptides greatly slowed or even prevented the processing of the pVIII pro-coat by leader peptidase at the inner membrane of the Escherichia coli cell. A good correlation was found between the effect of the insert on the rate of the processing of the pro-coat, an essential step in virus assembly, and the number of the mature but modified proteins in the subsequently assembled hybrid virion. These results have important implications for the design of peptide display systems based on filamentous bacteriophage. PMID- 8676397 TI - Do it right, do the right thing. PMID- 8676398 TI - Fluconazole increases bactericidal activity of neutrophils. AB - BACKGROUND: Candida infections after injury are associated with significant mortality. Death often results from gram negative sepsis. Because antifungal therapy lowers mortality seen with Candida infections, this study was undertaken to determine whether fluconazole (FCZ) augments host response against bacteria, specifically, the bactericidal activity of polymorphonuclear neutrophils (PMN). METHODS: PMN from 23 volunteers were incubated with phosphate-buffered saline or FCZ (20 micrograms/mL or 40 micrograms/mL). Bactericidal activity of these PMN, as well as FCZ alone, was determined using Escherichia coli and a colony forming unit protocol. RESULTS: PMN possess potent bactericidal activity while FCZ possesses minimal inherent bactericidal activity. PMN bactericidal activity is significantly augmented by preincubation with FCZ. This enhanced bactericidal state is greater than the combined individual bactericidal properties of either FCZ concentration and PMN. CONCLUSIONS: FCZ augments PMN bactericidal activity. This augmentation may help to explain the improved survival of critically injured patients receiving FCZ. PMID- 8676399 TI - Seat belt use, insurance status, and hospital bad debt. AB - OBJECTIVES: Previous studies have shown that not wearing a seat belt is associated with both increased injury severity and higher hospital charges. In this article, we examine whether unrestrained motorists are also more likely (a) to be medically uninsured, and (b) to leave their hospital bills unpaid. METHODS: We reviewed the hospital clinical and billing records for all occupants in motor vehicle collisions admitted to the Massachusetts General Hospital Emergency Department during a 2-month period (n = 265). Using data on seat belt use, insurance status, bad debt, admission to the hospital, driver or passenger status, age and sex, we performed simple correlation and multiple regression analyses to determine the association between (a) seat belt use and insurance status and (b) seat belt use and hospital bad debt. RESULTS: Unrestrained patients were more likely both to be uninsured and, holding insurance status and other factors constant, to generate bad debt for the hospital. CONCLUSIONS: Our findings are similar to previous studies that show that the public pays a significant share of the medical care charges associated with risk-taking behavior. Propitious selection, an economic theory, may explain such findings. It asserts that risk-taking individuals are least likely to buy insurance voluntarily and will also be the ones most likely to deliberately place themselves in dangerous situations. Our findings show that people who do not use seat belts are more likely to have outstanding hospital bills; the public effectively pays for these bills in higher taxes or insurance premiums. PMID- 8676400 TI - Blunt force injury of the abdominal aorta. AB - OBJECTIVE: To review the clinical presentation, diagnosis, and management of injury to the abdominal aorta after blunt force trauma. DESIGN: This study was a retrospective review. RESULTS: A total of 5,676 patients were admitted to the University of Michigan Medical Center with traumatic injury. Seven had injuries to the abdominal aorta after a blunt force mechanism. Five patients had operative repair of the aortic injury, of which four involved orthotopic graft placement and one had an extra-anatomic bypass. Two patients had the aortic injury repaired by endovascular stent placement in the angiography suite. One patient died, and lower extremity amputations were performed in three patients. CONCLUSIONS: Surgical repair of abdominal aortic injury is preferable for the unstable patient or those with threatened extremities. In the stable patient with viable limbs, treatment with radiologic placement of endovascular stents may provide a nonoperative option for management. PMID- 8676401 TI - Gastrointestinal perforations in children: a continuing challenge to nonoperative treatment of blunt abdominal trauma. AB - The present trend towards conservative management of hemodynamically stable pediatric trauma patients may be increasing the risk of delay in the diagnosis of traumatic hollow viscus perforations (HVP). The purpose of this study is to determine whether there is a delay in the diagnosis of HVP because of expectant management. A survey of factors leading to diagnostic delay was also made and the value of current diagnostic tools were reevaluated. In 1,283 trauma admissions between 1980-1994, 34 patients were operated for HVP caused by blunt abdominal trauma. Sites of perforation were; stomach (four), duodenum (five), jejunum (12), ileum (nine), and jejunum/ileum (four). Signs of peritoneal irritation were positive in 32 of 34 patients. There was free air in only six of 24 abdominal roentgenograms. Free peritoneal fluid without solid organ injury was detected in only four out of 13 patients with ultrasound. Peritoneal lavage was diagnostic in eight of nine patients. Time from admission to operating room averaged 24 +/- 4.1 (mean +/- standard deviation) hours. Eleven patients died after the operation mostly because of accompanying head injury. Only two of the deaths were the result of sepsis originating from the perforated bowel. There is an apparent delay in the diagnosis of traumatic HVP in this series. Signs of peritoneal irritation are the most consistent findings of HVP after blunt abdominal trauma in children. Persistence of abdominal signs indicates peritoneal lavage, which has a high diagnostic sensitivity for HVP compared to other diagnostic modalities. PMID- 8676402 TI - Airbag-induced eye injuries: a report of 25 cases. AB - OBJECTIVE: To acquire a better understanding of airbag-induced eye injuries, 25 cases are reviewed and an attempt is made to identify the causal mechanisms associated with each injury. DESIGN AND METHODS: The National Highway Traffic Safety Administration's National Accident Sampling System for the years 1984-1994 was accessed to identify automobile accidents that included airbag deployment and injury to the ocular region. The search provided 25 such cases with detailed studies of the accident scene and medical records of the injuries. The cases were comprehensively reviewed to determine the casual mechanisms associated with each group of injuries. RESULTS: The study determined that the injuries range from mild corneal abrasions to retinal detachment. Causation for each injury was determined and is detailed. The injuries were grouped according to location within the ocular region, and the distribution is shown. CONCLUSIONS: Most of the injuries were induced by impact with the fully deployed airbag, but the more severe ocular trauma resulted from the actively deploying airbag striking the occupant. Thus, ocular trauma from airbags can occur in very minor impacts. Additionally, the left eye seemed more vulnerable to injury than the right. Nontethered airbags have greater inflation distances that tend to increase the probability of injury. External parameters that may also increase the severity of eye injury include an unfastened seat belt, sitting too close to the steering wheel, or wearing glasses. PMID- 8676403 TI - Prognosis and clinical relevance of anisocoria-craniotomy latency for epidural hematoma in comatose patients. AB - OBJECTIVE: To determine whether the time between onset of anisocoria and surgery for hematoma evacuation in the head-injured patient is a useful prognostic variable for outcome in the comatose patient with an acute epidural hematoma. DESIGN: Prospective. MATERIALS AND METHODS: Twenty-one patients with an acute traumatic epidural hematoma and an admission Glasgow Coma Scale score of less than 8 were analyzed. RESULTS: Anisocoria was present in 14 (67%) patients. Mortality rate was three times higher in this group than in the patients without anisocoria; however, this difference was not statistically significant (p = 0.21, Fisher's exact test). None of the patients with an anisocoria-craniotomy latency of 70 minutes or less died and all of these patients had a good or reasonable outcome. Analysis of the anisocoria-craniotomy latency in ten patients revealed that a lapse of more than 90 minutes was associated with a greater mortality compared with patients with a latency of less than 90 minutes (p = 0.0238, Fisher's exact test). CONCLUSIONS: In patients with an acute epidural hematoma, reducing the anisocoria-surgery interval below 90 minutes is significantly associated with a better outcome (p = 0.0238, Fisher's exact test). PMID- 8676404 TI - Altered glutathione levels in ischemic and postischemic skeletal muscle: difference between severe and moderate ischemic insult. AB - The purpose of the present study was to investigate how the duration of ischemia and reperfusion affect the glutathione (GSH) levels in skeletal muscle and to assess the presence of oxidative stress by quantitating oxidized glutathione (GSSG) and the ratio of GSSG/GSH. The amounts of GSH and GSSG were quantitated in the tibialis anterior muscle of the rat hind limb after 2 and 4 hours of tourniquet ischemia and after 1 and 5 hours of reperfusion, and the levels were compared to those in nonischemic control tibialis anterior muscles. In muscles subjected to 2 hours of ischemia, the levels of GSH, GSSG, and the ratio GSSG/GSH did not differ significantly from those of nonischemic controls. After 4 hours of ischemia without reperfusion, the GSH levels were slightly increased, compared to controls (p < 0.05). After 1 hour of reperfusion following 4 hours of ischemia, the levels of GSH decreased by 50% compared to control (p < 0.01), and still after 5 hours of reperfusion the levels of GSH were 50% lower than control levels. The GSSG/ GSH ratio did not change during 1 and 5 hours of reperfusion compared to control. A major finding in this study was that, during reperfusion after severe ischemia of 4 hours, there was a marked depletion of glutathione, which was not seen after a moderate ischemic insult of 2 hours. PMID- 8676405 TI - Influence of percussion trauma on expression of intercellular adhesion molecule-1 (ICAM-1) by human cerebral microvascular endothelium. AB - OBJECTIVES: Brain injury is associated with the production of oxygen free radicals (OFR) and the accumulation of polymorphonuclear leukocytes (PMN) at the site of injury, both of which may be involved in the evolution of secondary cerebral injury. Intercellular adhesion molecule-1 (ICAM-1) is responsible for adherence of PMNs. We sought to determine whether percussion trauma altered the expression of ICAM-1 and to determine the effect of OFR scavengers on ICAM-1 expression after percussion trauma. DESIGN: Prospective controlled laboratory research using passage 2 human cerebral microvascular endothelium (HCME). MATERIALS AND METHODS: Cell lysates were collected over 24 hours and analyzed for ICAM-1 by enzyme-linked immunosorbent assay (ELISA) after trauma or incubation with tumor necrosis factor (TNF)-alpha. OFR scavengers were added immediately after trauma with or without previous incubation with TNF-alpha. MEASUREMENTS AND MAIN RESULTS: Sublethal percussion trauma did not alter ICAM-1 expression by HCME. TNF-alpha upregulated ICAM-1 in percussed and nonpercussed cells with maximal ICAM-1 expression at 24 hours (p < 0.01, ANOVA). However, percussion trauma significantly blunted the response of HCME to TNF-alpha. The addition of OFR scavengers after percussion trauma alone had no effect on ICAM-1 expression at 24 hours, but restored the response of percussed HCME to TNF-alpha. CONCLUSIONS: Percussion trauma alters the response of HCME to cytokine-induced ICAM-1 upregulation, and the normal response is restored by OFR scavengers. This suggests that HCME become dysfunctional after percussion trauma and this dysfunction may be mediated by OFR. PMID- 8676406 TI - Surgical exposure of the left subclavian artery by median sternotomy and left supraclavicular extension. AB - OBJECTIVE: To evaluate the feasibility of surgical exposure of the full length of the left subclavian artery using a median sternotomy and left supraclavicular extension. DESIGN: Anatomic study of five cadavers, and case review of four patients with blunt trauma to the proximal left subclavian artery. MATERIALS AND METHODS: A median sternotomy with left supraclavicular extension was performed on five cadavers and four patients. The depth of various portions of the subclavian artery was measured. Photographs of the dissections were used to document anatomic relationships and to serve as a basis for pen and ink drawings. The hospital records of four patients in which this exposure was used were reviewed for operative details. MEASUREMENTS AND MAIN RESULTS: The left subclavian artery was readily exposed from its origin on the aortic arch to its termination as the axillary artery in all cadaver dissections, including one who was more than 300% ideal body weight. The first portion of the subclavian artery lay at an average wound depth of 6.0 cm, with a mean length of 4.7 cm. The same surgical approach was used for the care of four patients who sustained blunt trauma to the first portion of the left subclavian artery and permitted expeditious control and excellent exposure for placement of a proximal subclavian interposition graft in two, a proximal subclavian to axillary artery graft in the third, and resection and end-to-end anastomosis in the fourth. CONCLUSIONS: Median sternotomy with left supraclavicular extension provides rapid, safe, and reliable exposure of all portions of the left subclavian artery without the morbidity associated with clavicular resection, thoracotomy, or a "trapdoor" incision. Furthermore, the ability to perform this procedure in the supine position allows access to the abdominal cavity, the neck, and the extremities, which often require concomitant operative intervention in a patient with multiple injuries. PMID- 8676407 TI - An atraumatic technique to fix the omentum after partial splenectomy. AB - During a partial splenectomy, the resultant bleeding of the remaining spleen is difficult to control; some techniques have been described to achieve complete hemostasis. The omentum has been traditionally used to promote hemostasis on raw surfaces of solid viscus, particularly during the repair of liver injuries. We present here a technique to fix the omentum to the spleen after partial resections; emphasis is made to perform it in an atraumatic way to avoid additional damage to the splenic capsule. PMID- 8676408 TI - Nonoperative treatment of traumatic pancreatic duct disruption using an endoscopically placed stent. PMID- 8676409 TI - Percutaneous placement of self-expanding stent for acute traumatic arterial injury. PMID- 8676410 TI - Primary aortoenteric fistula from a posttraumatic pseudoaneurysm. PMID- 8676411 TI - Surgical cricothyroidotomy in trauma patients: analysis of its use by paramedics in the field. AB - OBJECTIVE: To analyze the indications for and the success rate, complications, and neurologic outcomes of surgical cricothyroidotomy when performed in the field by ambulance paramedics. METHODS: The ambulance and hospital records of all trauma patients on whom a surgical cricothyroidotomy was attempted in the field by ambulance paramedics over a 5-year period were reviewed. A telephone survey of survivors was used to assess long-term complications and neurologic outcome. RESULTS: Surgical cricothyroidotomy was attempted on 50 patients, or 9.8% of those requiring definitive airway control. The most common indications were clenched teeth, blood or vomit obscuring visualization of the upper airway, severe maxillofacial injuries, and inaccessibility because the patient was trapped. Airway establishment was successful in 47 patients (94%). Major complications occurred in 2 patients (4%), where inadvertent dislodgement of the tube developed, requiring replacement. No patient developed significant subglottic stenosis. Nineteen patients (38%) survived and no patient died because of an inadequate airway. Evaluation of neurologic outcome revealed 12 patients (63%) with no significant deficits, 3 (16%) with moderate disability, 2 (10%) with severe disability, and only 2 in a persistent vegetative state. CONCLUSIONS: Surgical cricothyroidotomy can be performed on the critically injured patient in the field by ambulance paramedics with a high success rate and a low complication rate. The use of surgical cricothyroidotomy should be included in airway protocols for well-trained, ambulance Advanced Life Support paramedics. PMID- 8676412 TI - False aneurysm of a digital artery in a softball catcher evaluated by sonography: a case report. AB - A rare injury, a traumatic false aneurysm of ulnar proper digital artery of the left thumb in a softball catcher, is described. Noninvasive ultrasonographic evaluation led to an accurate diagnosis of the aneurysm, which was caused by blunt trauma by a softball. PMID- 8676413 TI - Compartment syndrome as a complication of skin traction in children with femoral fractures. AB - We report the history of two 3-year-old children with femoral shaft fractures, who developed severe compartment syndromes after skin traction. Both children were admitted in our department for treatment of their compartment syndromes. In both, important and permanent disability persisted. The causative role of the skin traction is proved since, in one infant, the compartment syndrome developed in the nonfractured limb. Cautious application of skin traction, conscientious observation, immediate diagnosis, and aggressive treatment of threatening compartment syndromes will prevent these tragic complications. PMID- 8676414 TI - The role of growth factors in wound healing. AB - Growth factors have many activities that make them attractive agents for stimulating tissue repair. Growth factors attract cells into the wound, stimulate their proliferation, and have profound influence on extracellular matrix deposition. Since developing the ability to mass-produce these cytokines by recombinant techniques, hundreds of studies have demonstrated that growth factors can augment all aspects of tissue repair in normal and impaired healing models. After demonstrating that growth factors augment healing, investigators have started to detect and measure growth factors in wounds and have found that wounding initiates the expression of various growth factors. Impaired healing has also been linked to altered growth factor production. These findings have prompted great interest in the use of growth factors to augment clinical healing. Preliminary clinical trials have not produced the results expected. Growth factor treatment has occasionally led to statistically significant improvements in tissue repair, but whether the results are clinically significant can be debated. It appears that to be cost effective, clinical trials must focus on targeting growth factors for specific types of impaired healing. Although growth factors have not been the panacea that was originally expected, they have the potential for making significant clinical improvements when targeted for specific problem wounds. PMID- 8676415 TI - Adequacy of hospital discharge data for determining trauma morbidity patterns. PMID- 8676416 TI - Death and dollars: the cost of dying in the surgical intensive care unit. PMID- 8676417 TI - Failure of nonoperative treatment of a gunshot wound to the liver predicted by computed tomography. PMID- 8676418 TI - Strangulation injuries in children. PMID- 8676419 TI - Utility of admission chemistry and coagulation profiles in trauma patients: a reappraisal of traditional practice. AB - To determine whether abnormal results of admission serum chemistry profiles (P7: sodium (Na), potassium (K), chloride (Cl), carbon dioxide content (CO2), blood urea nitrogen (BUN), creatinine (Cr), and glucose (GLU), amylase (AMY), and coagulation profiles (CP: prothrombin time (PT) and partial thromboplastin time (PTT) in trauma patients lead to clinical interventions, and to characterize frequency of abnormal results, we prospectively gathered laboratory data on 500 consecutive patients seen in our Level 1 trauma center. Clinicians were blinded to the study. Abnormal results were found in 93% of P7s, 7% of AMYs, and 59% of CPs. Interventions were made for < 1% of abnormal P7s, 0% of abnormal amylase, and 5% of patients with abnormal CP. We conclude that information provided by routine admission chemistry and coagulation profiles in trauma patients seldom lead to clinical interventions. These tests should not be ordered routinely on admission in trauma patients. PMID- 8676420 TI - Air ambulance trauma transport: a quality review. AB - OBJECTIVE: Provincial air ambulance transports of injured patients were quality reviewed prospectively to determine utilization and appropriateness of care. METHODS: All trauma air ambulance transports over a 2-month span were reviewed prospectively. Revised Trauma Score, Injury Severity Score, probability of survival, prehospital time, distance of transport, procedures performed, and outcome were determined. Quality control questions were asked of the sending and receiving physicians. RESULTS: The majority of air ambulance transports reviewed (N = 97) were indicated for mechanism and severity of injury. Economics and requirement for advanced medical care were indications in only 15%. Physicians tended to perform more advanced procedures, likely related to higher patient Injury Severity Score (23 vs. 15, p = NS). Four problems with air ambulance access were identified. The overtriage rate was 5%. Inappropriate patient care was documented in six (6%) cases; a physician was present for only one of these. CONCLUSIONS: A low overtriage rate was documented, raising concerns that the undertriage rate may be too high. Injured patients air transported without physician accompaniment more often received inappropriate care, suggesting that physician accompaniment is beneficial. PMID- 8676421 TI - The use of oxygen consumption and delivery as endpoints for resuscitation in critically ill patients. AB - OBJECTIVE: Oxygen consumption (VO2I) and delivery (DO2I) indices have been stated to be superior to conventional parameters as endpoints for resuscitation. However, another interpretation of published data is that inability to increase VO2I/DO2I given adequate volume resuscitation reflects inadequate physiologic reserve and poor outcome. DESIGN: Fifty-eight critically ill patients were randomized to two groups. In group 1 (27 patients) attempts were made to maintain VO2I > or = 150 or DO2I > or = 600 mL/min/m2. If DO2I was > 600, no attempt was made to increase VO2I even if it was < 150. Group 2 (31 patients) was resuscitated based on conventional parameters. Volume resuscitation protocols and goals for pulmonary capillary wedge pressure were the same in both groups. VO2I/DO2I were recorded in group 2, but physicians were blinded to this data. Age, Injury Severity Score, and Acute Physiology and Chronic Health Evaluation (APACHE II) score were not different between groups. MAIN RESULTS: Three patients in group 1 and two patients in group 2 died of organ failure (OF). One additional patient in group 2 died of refractory shock within 24 hours. Two of the patients in group 1 who died failed to meet VO2I/DO2I goals within 24 hours despite maximal resuscitation. Mortality was not different between the groups even with exclusion of the group 1 patients who failed to meet VO2I/DO2I goals (p = 0.66). After exclusion of the patient in group 2 who died of refractory shock, OF occurred in 18 of 27 (67%) in group 1 and in 22 of 30 (73%) in group 2 (p = 0.58). Length of ventilator support, intensive care unit stay, and hospital stay were not different between groups. When all patients were assessed, no difference was found in the incidence of OF between patients who attained the VO2I goal and those who did not. OF occurred in 20 of 34 (59%) patients who maintained a mean DO2I > or = 600 during the first 24 hours of the study and in 21 of 24 (88%) of those who did not (p < 0.02). CONCLUSIONS: No difference was found in the incidence of OF or death in patients resuscitated based on oxygen transport parameters compared to conventional parameters. These data suggest that given adequate volume resuscitation, oxygen-based parameters are more useful as predictors of outcome than as endpoints for resuscitation. PMID- 8676422 TI - Long-term outcomes after lower extremity trauma. AB - Previous studies have shown that over one-quarter of patients who were working before a severe lower extremity fracture had not returned to work by 12 months after injury. Disabilities also persisted in household management, recreation, and social interaction. The objective of this study was to determine whether recovery extended beyond 12 months. Three hundred nineteen patients who were previously working and were treated at three level I trauma centers for a severe lower extremity fracture were prospectively followed at 3, 6, and 12 months after injury. Patients were queried at each follow-up about their work status and completed the Sickness Impact Profile (SIP) at 6 and 12 months. The SIP is a widely used and well validated measure of general health status; it was used in this study to measure functional recovery across several domains of daily living. Patients who had not recovered by 12 months (i.e., 204 who were not working, working with limitations, or had limitations in performing other daily activities as measured by elevated scores on the SIP) were contacted again at 30 months and asked to complete an interview and the SIP. At 30 months, an estimated 82% of the study patients had returned to work (compared to 72% at 12 months). SIP scores improved only slightly from 6.4 at 12 months to 5.7 at 30 months. At 30 months, 64% of the patients had no disability (SIP scores less than 4), 17% had mild disability (SIP scores of 4 to 9), 12% had moderate disability (SIP scores of 10 to 19), and 7% had severe disability (SIP scores of 20 or higher). Although the majority of patients with persistent disabilities at 30 months had residual physical impairments at 12 months, the extent of impairment did not fully explain why some people had and had not recovered at 30 months after injury. The results confirm those of other studies that conclude that overall, outcomes after serious trauma are good when appropriate trauma and rehabilitation care are rendered. However, a minority of patients still report limitations at 30 months after injury, with one-fifth not returning to work. PMID- 8676423 TI - The relationship of oxygen consumption measured by indirect calorimetry to oxygen delivery in critically ill patients. AB - OBJECTIVE: The existence of oxygen supply dependency, defined as oxygen consumption (VO2) limited by oxygen delivery (DO2), is still questioned. This study examined the relationship between VO2 and DO2 in two groups of critically ill surgical patients 50 years and older in the first 24 hours of resuscitation after pulmonary artery catheter insertion. Group 1 patients had systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, and adult respiratory distress syndrome (ARDS). Group 2 patients had hemorrhagic shock. METHODOLOGY: Study methodology included (1) augmenting DO2 with fluids, blood, and vasopressors, (2) measuring VO2 by indirect calorimetry to avoid the problem of mathematical coupling with DO2 calculation, and (3) analyzing data during steady states of temperature, sedation, paralyzing agents, and vasopressors. RESULTS: Six to 18 measurements collected on all study patients during a period within the first 24 hours were analyzed using a linear regression analysis. Statistical significance was set at p < or = 0.05. Seven of nine patients in group 1 demonstrated positive, statistically significant relationships between VO2 and DO2. Of six patients in group 2, one patient demonstrated a positive, significant relationship of VO2 and DO2, three demonstrated inverse relationships, and two patients did not show a DO2/VO2 relationship. Supply dependency did not exist in all patients but was present in seven out of nine patients with systemic inflammatory response syndrome, sepsis, severe sepsis, septic shock, and adult respiratory distress syndrome in the first 24 hours of treatment. PMID- 8676424 TI - Allogeneic fibroblasts used to grow cultured epidermal autografts persist in vivo and sensitize the graft recipient for accelerated second-set rejection. AB - INTRODUCTION: Cultured epidermal autografts (CEAs) have been used for wound coverage in patients with massive burns and other skin defects. However, CEAs often display late breakdown, which may be immunologically mediated and initiated by persistent foreign fibroblasts used as a feeder layer to optimize keratinocyte growth. This study investigates whether these fibroblasts, previously shown to persist in vitro, survive after grafting and induce host sensitization to alloantigen. METHODS: CEAs from CBA donors (H-2k) were grown on allogeneic NIH 3T3 (H-2q) or syngeneic LTK (H-2k) fibroblasts, which were removed by trypsinization 7 days later. CBA mice (n = 85) were flank-grafted with NIH allografts (positive control), CEA/3T3s, CEA/LTKs, or CBA autografts (negative control). Hosts were challenged with second set NIH tail allografts 3 weeks later. Median graft survival was compared between groups by Wilcoxon rank and chi 2 analysis. Additional CBA mice (n = 15) received CEAs that were biopsied 0, 4, and 8 days after grafting. The presence of allogeneic fibroblasts was determined by Western immunoblotting, using KL295, a monoclonal antibody that recognizes H 2q (but not H-2k) class II histocompatibility antigens. RESULTS: Allogeneic fibroblasts persisted after grafting but decreased over time, as determined by alloantigen expression on Western immunoblots. Accelerated tail graft rejection occurred in hosts primed by NIH allografts (9 days, p < 0.05), as well as by CEAs growth with an allogeneic (10 days, p < 0.05) but not a syngeneic feeder layer (12 days, NS). Mice receiving flank autografts rejected second set tail allografts at 12 days. CONCLUSIONS: Immunogenic fibroblasts used to grow CEAs survive in vivo and sensitize the graft recipient for accelerated second-set rejection. These persistent cells may initiate an inflammatory response that may result in late graft breakdown and limit the utility of CEAs grown with a foreign fibroblast feeder layer. PMID- 8676426 TI - Magnetic resonance imaging of occult scaphoid fractures. AB - Occult fractures of the scaphoid bone occur frequently and may lead to nonunions. In a prospective blind study, we performed magnetic resonance imaging (MRI) examinations on 32 patients who had sustained a wrist injury and in whom a scaphoid fracture was clinically suspected, but could not be confirmed on the original set of two routine and four scaphoid view radiographs. The MRI examinations were performed an average time of 2.8 days after the trauma. This prospective study proved that MRI is able to diagnose occult scaphoid fractures without delay and without the use of radioactive diagnostic means. Sensitivity and specificity of MRI were 100%. This conventional method could save $7,200 (US) per 100,000 inhabitants in providing an immediate and correct diagnosis and avoiding unnecessary cast immobilization. Additional injuries that may be misdiagnosed by conventional radiographs are also detected with a specificity and sensitivity of 100%. PMID- 8676427 TI - Two-level burst fractures: clinical evaluation and treatment options. AB - Two-level burst fractures are rare. In a series of 180 surgically treated spinal fracture-dislocations, seven had such injuries, with an incidence of 3.9%. Four had fracture sites without contiguity: C4-T12 (one), L1-L4 (one), L2-L4 (one), and L2-L5 (one); and three with contiguity: T12-L1 (one), L1-L2 (one), and L2-L3 (one). L2 was the most frequently involved site, accounting for four in seven. Falling from height was the most common mechanism of injury, accounting for four in seven. Five in seven patients (71%) sustained multiple injuries. Chest traumas and extremity fractures were the ones most frequently associated. All of these patients had incomplete neurologic deficits at initial presentation. In the four discontiguous bursts, the neurologic levels corresponded to the cephalic ones. Six patients had follow-up periods of more than 2 years. Transpediculate systems were used in five, and at follow-up, two had screw breakages. In this series, the average neurologic recovery was 1.3 grades on the Frankel scale. In conclusion, it is mandatory to have a thorough organ system review when such patients are first seen. Then each fracture site would be judged seperately as either a stable or unstable burst preoperatively. Every effort should be made to treat any unstable segment via anterior, posterior, or combined approaches. PMID- 8676425 TI - Acute ethanol intoxication and endotoxemia after trauma. AB - To determine actions of acute intoxication on pathophysiologic responses to trauma, anesthetized and ventilated mongrel pigs received a 20% solution of ethanol (EtOH) by an intravenous (IV group; 2 g/kg, n = 8) or an oral (PO group; 3 g/kg, n = 12 x 60 minutes) route of administration, or the lactated Ringer's vehicle (LR group; n = 12). After 60 minutes, all were subjected to soft tissue injury and 30 to 35% hemorrhage, 60-minute shock, and then resuscitation, with shed blood plus supplemental LR. After 3 days, host defense was challenged with Escherichia coli lipopolysaccharide (LPS); (1 microgram/kg x 30-minutes IV). The supplemental resuscitation was identical (50-53 mL/kg/hours), but posttraumatic acidosis was observed in the IV group and the PO group (base deficit = 4.4 +/- 1.3 and 5.5 +/- 0.9 mEq/L) and not in the LR group. After 3 days, the acid-base equilibrium was restored, but a difference in host defense was unmasked by LPS. In the LR group, LPS-evoked pulmonary vasoconstriction was followed by decreased compliance and ventilation-perfusion mismatch, which was associated at 3 to 5 hours with a base deficit, reduced SVO2, and reduced PO2 (-0.5 +/- 0.2 mEq/L, 46 +/- 1%, 127 +/- 1 mm Hg). These changes were blunted in the PO group (2.0 +/- 0.1 mEq/L, 56 +/- 1%, 183 +/- 4 mm Hg) and potentiated in the IV group (-4.3 +/- 0.5 mEq/L, 40 +/- 2%, 60 +/- 2 mm Hg), even though more fluid was required to maintain systemic arterial and cardiac filling pressures following LPS administration in the IV (40 +/- 6 mL/kg/ hours) versus the LR or PO groups (31 +/- 5 or 23 +/- 3). The PO versus LR differences could not be attributed to enteral nutrition because an isocaloric solution of 50% dextrose had no effect versus LR solution. EtOH caused neutropenia following trauma, relative to LR solution, but the IV versus PO differences could not be discriminated on the basis of neutrophil or lymphocytes counts, nor CD18 receptor expression, nor renal or hepatic dysfunction. However, T4 lymphocytes and cortisol, a nonspecific index of inflammation, were higher for at least 24 hours after trauma with IV, relative to PO or LR. Blood EtOH was similar with IV or PO during resuscitation (100-120 mg/dL), but the kinetics were different prior to trauma. With PO, blood EtOH slowly accumulated to a steady state plateau, the level of which was higher with no anesthesia or no trauma. With IV, blood EtOH peaked at 275 mg/dL and then exponentially declined with a rate that was not influenced to a major extent by trauma or by anesthesia. Therefore: 1) EtOH absorption is impaired during trauma (in part because of reduced gut blood flow); 2) acute EtOH intoxication at the time of trauma altered neutrophils, plasma cortisol, and T4 lymphocytes during recovery and host defense to a superimposed LPS challenge. The apparently favorable effect of PO versus IV EtOH on the response to endotoxemia after trauma probably reflects differences in the kinetics of blood EtOH in the interval before reperfusion but a "first pass" effect (metabolism in the gut or liver) might also explain the data. PMID- 8676428 TI - A study of preventable trauma mortality in rural Michigan. AB - OBJECTIVE: To determine the preventable death rate (PDR) and the frequency and types of inappropriate medical care in a large, rural region of Michigan. DESIGN: A prospective study of all deaths caused by injury during a 1-year period. METHODS: Preventability of death and appropriateness of care were determined using a structured implicit review process and expert panel. A second panel was convened to confirm the reliability of the review process. MAIN RESULTS: One hundred fifty-five injury-related deaths underwent panel review. Four deaths (2.6%) were found to be definitely preventable and 16 (10.3%) possibly preventable, for a combined preventable death rate of 12.9%. Sixty-five deaths (41.9%) occurred in the emergency department or hospital; 18 of these (27.7%) were judged to be definitely preventable or possibly preventable. Forty-three episodes of inappropriate care were identified in 27 (17.4%) of the 155 cases reviewed. These occurred primarily in the emergency department and hospital rather than during prehospital care or transfer. CONCLUSIONS: A relatively small percentage of trauma fatalities in rural Michigan could have been prevented by more appropriate or timely medical care. Efforts to improve the care of injured persons in rural Michigan should be directed primarily at the emergency department and inpatient phases of trauma system care. PMID- 8676429 TI - Predicting survival from head trauma 24 hours after injury: a practical method with therapeutic implications. AB - OBJECTIVE: To develop a method to predict long-term outcome after head injury and determine if outcome can be accurately predicted 24 hours after injury. DESIGN: A retrospective review was performed on a study cohort of 672 head-injured patients admitted in coma (Glascow Coma Scale score < or = 8) who remained comatose for at least 6 hours, survived more than 24 hours, and had 6-month outcome data available. Stepwise logistic regression analysis was used to determine which clinical variables predicted 6-month outcome. Statistically significant clinical predictors were combined into a single examination variable (MPX score), which reflected a rank-ordering of examinations from worst to best, which was then further weighted by patient age. The relation between 6-month outcome and MPX score at admission and 24 hours was plotted and analyzed. MEASUREMENT AND MAIN RESULTS: Age, best motor score, and pupillary reactivity at admission and 24 hours were significant predictors of outcome; extraocular motility was predictive at 24 hours only. Age was the most important independent predictor, followed by best motor score, pupillary reactivity, and extraocular motility. Combining these predictors into MPX score resulted in a set of graphs that reliably predicted long-term outcome. The 24-hour MPX data were better predictors of 6-month outcome and were more specific in predicting negative outcomes than admission data. CONCLUSIONS: The method is simple to use, relying on bedside neurologic examination and a single graph, but appears to predict long-term outcome accurately as early as 24 hours after head injury. If validated on other large series of patients, this method could provide an objective and practical basis for terminating care in patients unlikely to survive a head injury. PMID- 8676430 TI - Occlusal vertical dimension in prosthodontics. AB - Occlusal vertical dimension is important in all aspects of prosthodontics. Unfortunately, there is no scientific method of determining the correct occlusal vertical dimension. The amount of interocclusal rest space (IRS) is a rough guide since muscle tone, which determines the space, is variable. IRS varies greatly from one patient to the next. It will automatically be correct when the occlusal vertical dimension is correct. IRS should not be interfered with regardless of its size. Many techniques have been used for determining occlusal vertical dimension in dentulous and edentulous patients. Regardless of the technique, the occlusal vertical dimension must be determined carefully by the dentist for a successful prosthesis. PMID- 8676431 TI - Detection of iron(III) chelate separated by reversed-phase high-performance liquid chromatography. AB - A reversed-phase high-performance liquid chromatographic method for the analysis of iron(III)-N, N'-trimethylenebis[2-(2-hydroxyl-5-ethyl-phenyl)glycine] (Fe(TM-5 ethyl-PHPG)-), which is potentially used as effective hepatobiliary magnetic resonance imaging (MRI) contrast agent, has been developed in this study. The effect of mobile phase, such as the varied pH values, ion-pairing agents and concentration of the ion-pairing agent on the capacity factor of the diastereomers and free ligand, were investigated to improve the separation and peak shape. HPLC in connection with a ion exchange column and a UV/VIS detector can be used to determine metal ion dissociated from this complex. This protocol can be successfully used in the quality assay of the synthesized potential MRI contrast agent of [Fe(TM-5-ethyl-PHPG)-]. PMID- 8676432 TI - Treatment of hepatocellular carcinoma smaller than 5 cm by transcatheter arterial chemoembolization. AB - To assess the effectiveness of transcatheter arterial chemoembolization (TACE) in the treatment of small hepatocellular carcinoma (HCC) and to analyze the prognostic factors, a total of 77 patients with histologically proven HCC, < or = 5 cm in diameter, were enrolled for the study and followed for more than 2 years, The overall cumulative 1-, 2-, and 3-year survival rates were 79.2%, 50.6% and 36.7%, respectively. The median survival time of Child-Pugh's A patients was 990 +/- 146 days, which was significantly better than the median survival time of Child-Pugh's B patients (450 +/- 82 days) Furthermore, positive HBeAg and alpha Fetoprotein (AFP) were factors close to statistically significant. In contrast, sex, age, HBsAg, Anti-HCV, tumor type, tumor size and tumor number were not related to the prognosis in small HCC who received TACE. PMID- 8676433 TI - Immunohistochemical pattern of P53 protein in human astrocytic tumors. AB - P53 immunohistochemistry in astrocytic tumors has usually been evaluated by the percentage of positive cells. However, in this study we analyzed the P53 immunopositive cells by their patterns of distribution. Formalin-fixed and paraffin-embedded sections from 38 patients with astrocytic tumors were examined. The distribution pattern of P53 immunostaining cells was divided into 3 types: negative, locally scattered, and diffuse clustering. There were 2 positive stains in 5 astrocytomas (40%), 12 positive in 24 anaplastic astrocytomas (50%), and 7 positive in 9 glioblastoma multiformes (78%). In astrocytomas, the positive cells were locally scattered. In anaplastic astrocytoma and GBM, the positive cells appeared locally scattered or as diffuse clustering. For the variant immunoreactive expression, the mean ages for patients with negative, locally scattered and diffusely clustered P53 immunostaining were as follows: 51.4, 52.6, and 28.4 years (P < 0.01), respectively. In anaplastic astrocytoma and GBM, the diffusely clustered pattern was more common in younger patients, whereas elderly patients in same groups tended to have few or no P53 immunopositive cells. Thus, our results implicate that clonal expansion of P53 immunopositive cells is associated with brain tumor progression. PMID- 8676434 TI - Abnormal gastric emptying in patients with liver cirrhosis. AB - Twenty-eight patients (aged: 44-76 years) with liver cirrhosis secondary to chronic hepatitis were included in this study. None of the patients had a history of gastric surgery, diabetes, hypothyroidism, or neurological or collagen vascular disease. The patients were divided into groups based on the presence or absence of the following conditions: (1) ascites, (2) splenomegaly, (3) esophageal varices. Radionuclide labelled solid meals were used to evaluate gastric emptying (GE). GE was represented by the gastric retention ratio of the solid meal at 90 min (RR90), and calculated by the following formula: RR90 = residual radioactivity within the region of interest (ROI) covered the whole stomach at 90 min divided by the initial radioactivity within the ROI at 0 min. The RR90 values of the patients were compared with the RR90 values of 25 normal control volunteers. If the RR90 was more than two standard deviations (SD) above the mean of the control group (> 0.687), GE was defined as abnormal. The results showed 71% (20/ 28) of the cirrhotic patients had abnormal GE. Patients with ascites, splenomegaly, or esophageal varices had higher RR90 values than patients without ascites, splenomegaly or esophageal varices. The differences in RR90 among patients with and without ascites, and patients with and without splenomegaly, were not significant (P values > 0.05). However, there were significant differences among the 2 patient groups separated according to the presence or absence of esophageal varices (P values < 0.05). In addition, poor correlations (R square values < 0.01) were found for RR90 and serum values of bilirubin and albumin. PMID- 8676435 TI - Diagnosis of prostatic intraepithelial neoplasia in whole mount sections of prostates. AB - Dysplasia of prostate or prostatic intraepithelial neoplasia (PIN) is associated with prostatic adenocarcinoma, which is quite common in elderly males. The presence of high grade PIN in biopsy of patients with clinically suspicious tumors is an indication of further search for malignancy. Whole mount sections of 48 prostates were studied. PIN was sought and graded. The morphology of other lesions including atrophy, adenosis and basal cell hyperplasia, and also seminal vesicle epithelium was studied. All 36 prostates resected for treatment of prostatic adenocarcinoma contained foci of PIN. The differential diagnosis of PIN, atrophy, adenosis, basal cell hyperplasia and seminal vesicle epithelium is quite easy when whole mount sections are studied. Whole mount sections of prostates are valuable teaching material for pathologists. PMID- 8676436 TI - I-cell disease: report of a case. AB - I-cell disease, or mucolipidosis type II (ML II), resembles Hurler syndrome but without the mucopolysacchariduria. I-cell disease is a slowly progressive disorder with onset at birth and fatal outcome in childhood. The neonate with I cell disease usually has a low birth weight. Unlike Hurler syndrome, there is no temporary acceleration of skeletal growth around one year of age. Instead, clinical characteristics included coarse face and skin, skeletal abnormalities, gum hypertrophy, and severe psychomotor retardation. Head size is proportional to stature. Psychomotor retardation is extreme in some patients but rather mild in others. The most frequent causes of death are bronchopneumonia and congestive heart failure. We report a 9 month-old male infant with characteristic clinical features of I-cell disease. Cytoplasmic inclusions were observed in cultured skin fibroblasts. Ultrastructural study of normal looking skin revealed numerous cytoplasmic inclusions with pleomorphic contents in the fibroblasts and Schwann cells. The diagnosis was confirmed by lysosomal enzyme assay in serum and fibroblasts. PMID- 8676437 TI - Elimination of false negative results in the two-hybrid system in the phagocyte NADPH oxidase. AB - The yeast two-hybrid system is finding increased use in the study of interactions between proteins. In this method, two polypeptides are expressed in yeast as fusion proteins to a transcriptional activator DNA-binding domain (bd) and activating domain (ad), respectively. Interaction between the two polypeptides reconstitutes function of a transactivator which controls expression of reporters. The phagocyte NADPH oxidase is a complex of membrane cytochrome b558 (comprised of subunits p22-phox and gp91-phox) and three cytosol proteins (p47 phox, p67-phox, and p21rac) that translocate to membrane and bind to cytochrome b558. This is the first report to demonstrate that two of cytosolic components of cytochrome b558, p47-phox binding to p67-phox each other. We encountered several methodological problems in the two-hybrid system which are the focus of this report. PMID- 8676438 TI - Genetic analysis of the activation domain of bovine papillomavirus protein E2: its role in transcription and replication. AB - The bovine papillomavirus protein E2 serves dual functions in viral transcription and in the initiation of viral replication. As a transcription factor, E2 can cooperatively interact with cellular proteins such as SP1 and stimulate transcription of distal promoters. In replication, E2 and the helicase El are the only viral proteins required for accurate replication of templates containing the viral origin. The amino terminus of E2 is a functionally separable domain critical for activation of both replication and transcription; its primary sequence is conserved between many strains of papillomavirus. We targeted conserved residues spanning the activation domain and constructed a series of 30 amino acid substitution mutants. These mutant E2 genes were analyzed for the ability to activate DNA replication and gene expression in cells. The majority of the substitutions affected the ability of E2 to support both viral replication and transcriptional activation, revealing substantial overlap of the functional determinants for these two processes. Replication and transcription activities are genetically separable, however, as mutations at amino acids 73 and 74 retained replication function but failed to activate transcription. Additionally, a mutation at position 39 substantially reduced replication activity but left transcriptional activation intact. Interestingly, over two-thirds of the mutations analyzed reduced function and protein accumulation, many in a temperature-dependent manner. The correspondence between the replication and transcription phenotypes of mutations spanning the activation domain may indicate that the entire region is folded into a single domain required for both functions. PMID- 8676439 TI - Identification of two amino acids in the hemagglutinin glycoprotein of measles virus (MV) that govern hemadsorption, HeLa cell fusion, and CD46 downregulation: phenotypic markers that differentiate vaccine and wild-type MV strains. AB - We have used site-directed mutagenesis of the hemagglutinin (H) glycoprotein of measles virus (MV) to investigate the molecular basis for the phenotypic differences observed between MV vaccine strains and recently isolated wild-type MV strains. The former downregulate CD46, the putative cellular receptor of MV, are positive for hemadsorption, and are fusogenic in HeLa cells, whereas the latter are negative for these phenotypic markers. CD46 downregulation in particular, could have profound consequences for the immunopathology of MV infection, as this molecule protects the cell from complement lysis. Mutagenesis of two amino acids, valine and tyrosine at positions 451 and 481, respectively, in the H protein from the vaccine-like Halle MV strain to their counterparts, glutamate and asparagine, in the H protein from the wild-type Ma93F MV strain (creating the V451E/Y481N double mutation) abrogated CD46 downregulation, HeLa cell fusion, and hemadsorption. The converse double mutagenesis of the Ma93F H protein (E451V/N481Y) transferred the CD46-downregulating, fusogenic, and hemadsorption functions to this protein. The data provide the first mapping study of the functional domains of MV H. The consequences of these results for MV vaccine design and the role of CD46 in MV infection are discussed. PMID- 8676440 TI - Hepatitis delta antigens enhance the ribozyme activities of hepatitis delta virus RNA in vivo. AB - The mechanism of regulation for the ribozyme activity of hepatitis delta virus (HDV) RNA in infected cells is unknown. Previously, we developed a direct assay capable of detecting the ribozyme activity of HDV dimer or trimer RNAs in vivo (K.-S. Jeng, A. Daniel, and M. M. C. Lai, J. Virol, 70:2403-2410, 1996). In this study, we used this method to examine the effects of hepatitis delta antigen (HDAg) on the ribozyme activities of HDV RNA in vivo. The HDV multimer cDNAs were cotransfected with plasmids encoding either HDV small delta antigen (SHDAg) or large delta antigen (LHDAg), and the self-cleavage of the primary transcripts from the HDV cDNA was analyzed at day 2 postransfection. The results were as follows. (i) Both HDAgs, particularly LHDAg, enhanced the self-cleavage activity of HDV RNA; however, HDAgs are not required for HDV RNA cleavage. (ii) HDAg could not restore the ribozyme activity of mutant HDV RNAs which have lost the ribozyme function. (iii) The enhancement of ribozyme activity by HDAg does not require HDV RNA replication. (iv) RNA-binding activity of HDAg is required for the enhancement of RNA cleavage. (v) The self-ligation activities of HDV ribozyme also were enhanced by HDAg. These results suggest that HDAg can regulate the cleavage and ligation of HDV RNA during the HDV life cycle. PMID- 8676441 TI - A new hepadnavirus endemic in arctic ground squirrels in Alaska. AB - We present evidence for a novel member of the hepadnavirus family that is endemic in wild arctic ground squirrels (Spermophylus parryi kennicotti) in Alaska. This virus, designated arctic squirrel hepatitis virus (ASHV), was initially detected in the livers of animals bearing large hepatic nodules by nucleic acid hybridization with hepadnavirus probes and in plasma by cross-reactivity with antibodies to hepadnavirus surface and core antigens. The complete nucleotide sequence of the 3,302-bp-long ASHV genome was determined and compared with those of ground squirrel hepatitis virus (GSHV) and woodchuck hepatitis virus (WHV); all sequences were organized into four open reading frames, designated pre-C/C, pre-S/S, pol, and X. Despite roughly equivalent variability among the three rodent hepadnaviruses (around 16% base and 19% amino acid exchanges), ASHV appeared to be more closely related to GSHV than to WHV in phylogenetic analysis. Accordingly, preliminary studies of the pathology of ASHV infection suggested that ASHV may be a less efficient oncogenic agent than WHV. About one-third of aged animals maintained in captivity, including virus-infected as well as uninfected squirrels, developed large liver nodules, consisting of hepatocellular adenomas or carcinomas or nonmalignant lesions characterized by drastic microvesicular steatosis. ASHV-infected arctic ground squirrels may serve as a new model with which to analyze the contribution of hepadnavirus- and host specific determinants to liver pathology and tumorigenesis. PMID- 8676442 TI - Cyclophilin A is required for the replication of group M human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus SIV(CPZ)GAB but not group O HIV-1 or other primate immunodeficiency viruses. AB - The human immunodeficiency virus type 1 (HIV-1) Gag polyprotein binds to cyclophilin A and incorporates this cellular peptidyl prolyl-isomerase into virions. Disruption of cyclophilin A incorporation, either by gag mutations or by cyclosporine A, inhibits virion infectivity, indicating that cyclophilin A plays an essential role in the HIV-1 life cycle. Using assays for packaging of cyclophilin A into virions and for viral replication sensitivity to cyclosporine A, as well as information gleaned from the alignment of Gag residues encoded by representative viral isolates, we demonstrate that of the five lineages of primate immunodeficiency viruses, only HIV-1 requires cyclophilin A for replication. Cloned viral isolates from clades A, B, and D of HIV-1 group M, as well as a phylogenetically related isolate from chimpanzee, all require cyclophilin A for replication. In contrast, the replication of two outlier (group O) HIV-1 isolates is unaffected by concentrations of cyclosporine A which disrupt cyclophilin A incorporation into virions, indicating that these viruses are capable of replicating independently of cyclophilin A. These studies identify the first phenotypic difference between HIV-1 group M and group O and are consistent with phylogenetic studies suggesting that the two HIV-1 groups were introduced into human populations via separate zoonotic transmission events. PMID- 8676443 TI - A conserved domain of the Epstein-Barr virus nuclear antigens 3A and 3C binds to a discrete domain of Jkappa. AB - EBNA-3C can affect the LMP-1 promoter in both a positive and a negative manner through distinct DNA sequence elements. The viral transactivator EBNA-2 normally binds DNA indirectly via Jkappa to activate transcription, but this activation is prevented in the presence of EBNA-3C. The DNA element recognized by Jkappa is both required and sufficient for this inhibition. Jkappa clones isolated in a yeast two-hybrid screen using EBNA-3C as bait allowed us to delineate the sequences of both proteins mediating the interaction. Two isoforms of Jkappa that differ in exon 1, Jkappa-1 and RBP-2N, interact with EBNA-3C, suggesting that exon 1 is not required for this interaction; indeed, clones with deletion of the N-terminal third of Jkappa interacted as efficiently with EBNA-3C as full-length Jkappa clones. A Jkappa domain as small as 56 amino acids was sufficient to bind to EBNA-3C. A 74-amino-acid domain of EBNA-3C, conserved in all three EBNA-3 family members, was sufficient to interact with Jkappa. A specific mutation in this conserved domain suppressed the ability of EBNA-3C to downregulate transcription. Accordingly, EBNA-3A was also able to interact with Jkappa and downregulate Jkappa-mediated transcription as efficiently as EBNA-3C. The ability of the EBNA-3 proteins to prevent Jkappa from binding to DNA in vitro and suppress transactivation via Jkappa DNA elements suggests that the EBNA-3 proteins act analogously to the Drosophila protein Hairless. PMID- 8676445 TI - Characterization of inhibition of M2 ion channel activity by BL-1743, an inhibitor of influenza A virus. AB - The influenza A virus M2 integral membrane protein has ion channel activity that can be inhibited by the antiviral drug amantadine. Recently, a spirene-containing compound, BL-1743 (2-[3-azaspiro (5,5)undecanol]-2-imidazoline), that inhibits influenza virus growth was identified (S. Kurtz, G. Lao, K. M. Hahnenberger, C. Brooks, O. Gecha, K. Ingalls, K.-I. Numata, and M. Krystal, Antimicrob. Agents Chemother. 39:2204-2209, 1995). We have examined the ability of BL-1743 to inhibit the M2 ion channel when expressed in oocytes of Xenopus laevis. BL-1743 inhibition is complete as far as can be measured by electrophysiological methods and is reversible, with a reverse reaction rate constant of 4.0 x 10(-3) s(-1). In contrast, amantadine inhibition is irreversible within the time frame of the experiment. However, BL-1743 inhibition and amantadine inhibition have similar properties. The majority of isolated influenza viruses resistant to BL-1743 are also amantadine resistant. In addition, all known amino acid changes which result in amantadine resistance also confer BL-1743 resistance. However, one BL-1743 resistant virus isolated, designated M2-I35T, contained the change Ile-35-->Thr. This virus is >70-fold more resistant to BL-1743 and only 10-fold more resistant to amantadine than the wild-type virus. When the ion channel activity of M2-I35T was examined in oocytes, it was found that M2-I35T is BL-1743 resistant but is reversibly inhibited by amantadine. These findings suggest that these two drugs interact differently with the M2 protein transmembrane pore region. PMID- 8676444 TI - Identification and characterization of a double-stranded RNA- reovirus temperature-sensitive mutant defective in minor core protein mu2. AB - A newly identified temperature-sensitive mutant whose defect was mapped to the reovirus M1 gene (minor core protein mu2) was studied to better understand the functions of this virion protein. Sequence determination of the Ml gene of this mutant (tsH11.2) revealed a predicted methionine-to-threonine alteration at amino acid 399 and a change from proline to histidine at amino acid 414. The mutant made normal amounts of single-stranded RNA, both in in vitro transcriptase assays and in infected cells, and normal amounts of progeny viral protein at early times in a restrictive infection. However, tsH11.2 produced neither detectable progeny protein nor double-stranded RNA at late times in a restrictive infection. These studies indicate that mu2 plays a role in the conversion of reovirus mRNA to progeny double-stranded RNA. PMID- 8676446 TI - Immune evasion properties of herpes simplex virus type 1 glycoprotein gC. AB - Herpes simplex virus type I (HSV-1) glycoprotein gC binds complement component C3b, and purified gC inhibits complement activation. Two HSV strains carrying mutations in the gC gene which rendered them unable to bind C3b were compared with wild-type and marker-rescued viruses to evaluate the role of gC on the virion in protecting HSV-1 from complement-mediated neutralization. The gC mutant viruses were markedly susceptible to neutralization by nonimmune human serum, showing up to a 5,000-fold decline in titer after 1 h of incubation with serum. In contrast, wild-type or marker-rescued viruses showed a twofold reduction in titer. Studies with hypogammaglobulinemic and immunoglobulin G-depleted serum supported the observation that neutralization occurred in the absence of antibody. Neutralization of gC mutant strains by nonimmune serum was rapid; their half-life was 2 to 2.5 min, compared with 1 h for wild-type virus. Ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA)-treated human serum or C4-deficient guinea pig serum failed to neutralize gC mutant strains, indicating a role for components of the classical complement pathway. gC had little additional effect on neutralization by the combination of antibody plus complement compared with complement alone. The results indicate that the magnitude of the protection offered by gC-1 is larger than previously recognized; that in the absence of gC-1, complement neutralization is rapid and is mediated by components of the classical complement pathway; and that gC mainly protects against antibody-independent complement neutralization, suggesting a probable role for gC early in infection, before antibodies develop. PMID- 8676447 TI - Enzymatic characterization of hepatitis C virus NS3/4A complexes expressed in mammalian cells by using the herpes simplex virus amplicon system. AB - The hepatitis C virus (HCV) NS3 protein possesses three enzymatic activities: an N-terminal serine protease activity, a C-terminal RNA-stimulated NTPase activity, and an RNA helicase activity. To characterize them, the full-length NS3(631)/4A and three C-terminal truncated proteases (NS3(201)/4A, NS3(181)/4A, and NS3(155)/4A were expressed in mammalian cells with HSV amplicon-defective viruses. Our results revealed that all of the NS3/4A proteins produced in mammalian cells (except NS3(155)/4A) are active in processing both cis and trans cleavage sites. Temperature optimization studies revealed that the protease is more active at temperatures ranging from 4 to 25 degrees C and is completely inactive at 42 degrees C. The RNA-stimulated ATPase activity was characterized with a partially purified NS3(631)/4A fraction and has a higher optimal temperature at 37 to 42 degrees C. The effects of detergents on both NS3 protease and RNA-stimulated ATPase were similar. Nonionic detergents such as Triton X-100, Nonidet P-40 and Tween 20 did not affect the activities, while anionic detergents such as sodium dodecyl sulfate and deoxycholic acid were inhibitory. Zwitterionic detergent such as 3-[(3-cholamidopropyl)- dimethyl-ammoniol-1-propanesulfonate (CHAPS) inhibited protease activity at a concentration of 0.5% (8 mM), which had no effect on ATPase activity. Finally, RNA-unwinding activity was demonstrated in the NS3(631)/4A fraction but not in the similarly purified NS3(181)/4A and NS3(201)/4A fractions. NS(363)/4A unwinds RNA duplexes with 3' but not 5' single stranded overhangs, suggesting that the NS3 RNA helicase functions in a 3'-to-5' direction. PMID- 8676448 TI - Hepatitis B virus nucleocapsid envelopment does not occur without genomic DNA synthesis. AB - Assembly of the enveloped hepatitis B virus (HBV) is initiated by packaging of the RNA pregenome and the viral reverse transcriptase-DNA polymerase into a nucleocapsid. The pregenome is then reverse transcribed into single-stranded minus-polarity DNA, which is subsequently replicated to double-stranded DNA. All replicative intermediates are observable in capsids within infected liver, but only relatively mature nucleocapsids containing partially double stranded DNA are found in secreted virions. This observation suggests that maturation of the genome within the capsid is required for envelopment and secretion. We show that the differential distribution of replicative intermediates between intracellular nucleocapsids and secreted virions is also observable in human hepatoma cells transfected with wild-type HBV genomes. However, nucleocapsids were not enveloped or secreted when they were produced by an HBV genome carrying a missense mutation in the DNA polymerase that eliminates all DNA synthesis. An HBV missense mutant defective in the RNase H activity of the polymerase which allowed minus-strand DNA synthesis but not formation of double-stranded DNA was able to form virion like particles. These experiments demonstrate that immature nucleocapsids containing pregenomic RNA are incompetent for envelopment and that minus-strand DNA synthesis in the interior lumen of the capsid is coupled to the appearance of a signal on the exterior of the nucleocapsid that is essential for its envelopment. PMID- 8676449 TI - Loss of resistance to murine hepatitis virus strain 3 infection after treatment with corticosteroids is associated with induction of macrophage procoagulant activity. AB - Activation of the immune coagulation system has been implicated in the pathogenesis of liver injury following infection of inbred mice with murine hepatitis virus strain 3 (MHV-3). Following MHV-3 infection, macrophages isolated from MHV-3-susceptible and -semisusceptible inbred strains of mice express increased procoagulant activity (PCA), whereas macrophages from resistant strains express no increase in PCA over basal levels. The PCA induced by MHV-3 is a prothrombinase, encoded by the gene Fgl-2, which encodes a fibrinogen-like protein (musfiblp). In this study, MHV-3-resistant A/J mice treated with methylprednisolone prior to infection with MHV-3 developed elevated levels of alanine aminotransferase in serum and died within 10 days of infection, with histological findings of fulminant hepatitis. In vitro, macrophages isolated from A/J mice and pretreated with methylprednisolone produced a marked increase in functional PCA following infection with MHV-3. The PCA was shown to be a prothrombinase by its ability to cleave 125I-prothrombin. Northern blot analysis of RNA transcripts from these macrophages demonstrated increased transcription of the Fgl-2 gene relative to that in macrophages which had not been pretreated with methylprednisolone prior to MHV-3 infection. Methylprednisolone pretreatment of MHV-3-infected macrophages stabilized the Fgl-2 mRNA. Thus, loss of resistance to MHV-3 secondary to methylprednisolone therapy is associated with increased transcription and stability of Fgl-2 mRNA resulting in expression of the Fgl-2 gene product, musfiblp. These results provide further insight into mechanisms of PCA regulation in response to MHV-3 infection in inbred strains of mice. PMID- 8676450 TI - Producer-cell modification of human immunodeficiency virus type 1: Nef is a virion protein. AB - Type 1 human immunodeficiency viruses encoding mutated nef reading frames are 10- to 30-fold less infectious than are isogenic viruses in which the nef gene is intact. This defect in infectivity causes nef-negative viruses to grow at an attenuated rate in vitro. To investigate the mechanism of Nef-mediated enhancement of viral growth rate and infectivity, a complementation analysis of nef mutant viruses was performed. To provide Nef in trans upon viral infection, a CEM derivative cell line (designated CLN) that expresses Nef under the control of the viral long terminal repeat was constructed. When nef-negative virus was grown in CLN cells, its growth rate was restored to wild-type levels. However, the output of nef-negative virus during the first 72 h after infection of CLN cells was not restored, suggesting that provision of Nef within the newly infected cell does not enhance the productivity of a nef-negative provirus. The genetically nef negative virions produced by the CLN cells, however, were restored to wild-type levels of infectivity as measured in a syncytium formation assay in which CD4 expressing HeLa cells were targets. These trans-complemented, genetically nef negative virions yielded wild-type levels of viral output following a single cycle of replication in primary CD4 T cells as well as in parental CEM cells. To define the determinants for producer cell modification of virions by Nef, the role of myristoylation was investigated. Virus that encodes a myristoylation negative nef was as impaired in infectivity as was virus encoding a deleted nef gene. Because myristoylation is required for both membrane association of Nef and optimal viral infectivity, the possibility that Nef protein is included in the virion was investigated. Wild-type virions were purified by filtration and exclusion chromatography. A Western blot (immunoblot) of the eluate fractions revealed a correlation between peak Nef signal and peak levels of p24 antigen. Although virion-associated Nef was detected in part as the 27-kDa full-length protein, the majority of immunoreactive protein was detected as a 20-kDa isoform. nef-negative virus lacked both 27- and 20-kDa immunoreactive species. Production of wild-type virions in the presence of a specific inhibitor of the human immunodeficiency virus type 1 protease resulted in virions which contained only 27-kDa full-length Nef protein. These data indicate that Nef is a virion protein which is processed by the viral protease into a 20-kDa isoform within the virion particle. PMID- 8676451 TI - Equine arteritis virus subgenomic mRNA synthesis: analysis of leader-body junctions and replicative-form RNAs. AB - In addition to the genomic RNA, a 3' coterminal nested set of six subgenomic mRNAs is produced in equine arteritis virus (EAV)-infected cells. The seven viral RNAs are also 5' coterminal, since they all contain a 206-nucleotide common leader sequence which is identical to the 5' end of the genome. A conserved penta nucleotide sequence motif, 5' UCAAC 3', was shown to be present at the junctions between the leader and body sequences in each of the mRNAs. In addition, two alternative junction sites were detected for mRNA 3. Seven replicative-form (RF) RNAs (RFs I to VII), corresponding to the genomic RNA and each of the subgenomic EAV mRNAs, could be prepared from lysates of infected cells. The minus-strand RNA contents of these RF RNAs were analyzed by using an RNase protection assay with an RNA probe containing the mRNA 2 leader-body junction. It was established that RF II contained a negative-stranded copy of mRNA 2, including a complementary leader sequence. The presence of subgenomic minus-strand RNA in RFs is indicative of a function as a transcription template during the production of EAV subgenomic mRNAs. PMID- 8676452 TI - Binding of the human immunodeficiency virus type 1 Gag polyprotein to cyclophilin A is mediated by the central region of capsid and requires Gag dimerization. AB - The cellular peptidyl-prolyl isomerase cyclophilin A (CyPA) is incorporated into human immunodeficiency virus type 1 (HIV-1) virions via direct contacts with the HIV-1 Gag polyprotein. Disruption of the Gag-CyPA interaction leads to the production of HIV-1 particles lacking CyPA; these virions are noninfectious, indicating that contacts between CyPA and Gag are necessary for HIV-1 replication. Here, we have used the yeast two-hybrid system in conjunction with an in vitro binding assay to identify the minimal domain of Gag required for binding to CyPA. Analysis of a panel of gag deletion mutants in the two-hybrid system indicated that a region spanning the central portion of the capsid (CA) domain was sufficient for interactions with CyPA, but discrepancies between results obtained in different fusion protein contexts suggested that multimerization of Gag might also be necessary for binding to CyPA. Consistent with a requirement for multimerization, the binding of Gag to CyPA in vitro required a region within the nucleocapsid (NC) domain shown previously to be important for Gag self-association. Substitution of a heterologous dimerization motif for the region from NC also promoted specific binding to CyPA, confirming that interactions with CyPA are dependent on Gag multimerization. Fusion of the heterologous dimerization motif to a 100-amino-acid domain from CA was sufficient for binding to CyPA in vitro. These results define the minimal CyPA-binding domain within Gag and provide insight into the mechanism by which CyPA is incorporated into HIV-1 virions. PMID- 8676453 TI - An endoplasmic reticulum-retained herpes simplex virus glycoprotein H is absent from secreted virions: evidence for reenvelopment during egress. AB - Although it is generally accepted that one of the first steps of herpesvirus egress is the acquisition of an envelope by nucleocapsids budding into the inner nuclear membrane, later events in the pathway are not well understood. We tested the hypothesis that the virus then undergoes de-envelopment, followed by reenvelopment at membranes outside the endoplasmic reticulum (ER), by constructing a recombinant virus in which the expression of an essential glycoprotein, gH, is restricted to the inner nuclear membrane-ER by means of the ER retention motif, KKXX. This targeting signal conferred the predicted ER localization properties on gH in recombinant virus-infected cells, and gH and gL polypeptides failed to become processed to their mature forms. Cells infected with the recombinant virus released particles with 100-fold less infectivity than those released by cells infected with the wild-type parent virus, yet the number of enveloped virus particles released into the medium was unaltered. These particles contained normal amounts of gD and VP16 but did not contain detectable amounts of gH, and these data are consistent with a model of virus exit whereby naked nucleocapsids in the cytoplasm acquire their final envelope from a subcellular compartment other than the ER-inner nuclear membrane. PMID- 8676455 TI - Therapeutic effect of Gag-nuclease fusion protein on retrovirus-infected cell cultures. AB - Capsid-targeted viral inactivation is a novel protein-based strategy for the treatment of viral infections. Virus particles are inactivated by targeting toxic fusion proteins to virions, where they destroy viral components from within. We have fused Staphylococcus nuclease (SN) to the C-terminal end of Moloney murine leukemia virus Gag and demonstrated that expression of this fusion protein in chronically infected chicken embryo fibroblasts resulted in its incorporation into virions and subsequent inactivation of the virus particles by degradation of viral RNA. Release of particles incorporating Gag-SN fusion proteins into the extracellular milieu activates the nuclease and results in destruction of the virion from within. By comparing the effects of incorporated SN and SN*, an enzymatically inactive missense mutant form of SN, on the infectivity of virus particles, we have clearly demonstrated that nucleolytic activity is the antiviral mechanism. Expression of Gag-SN fusion proteins as a therapeutic agent causes a stable reduction of infectious titers by 20- to 60-fold. The antiviral effect of capsid-targeted viral inactivation in our model system, using both prophylactic and therapeutic approaches, suggests that a similar anti-human immunodeficiency virus strategy might be successful. PMID- 8676454 TI - Separate functional domains of the herpes simplex virus type 1 protease: evidence for cleavage inside capsids. AB - The herpes simplex virus type 1 (HSV-1) protease (Pra) and related proteins are involved in the assembly of viral capsids and virion maturation. Pra is a serine protease, and the active-site residue has been mapped to amino acid (aa) 129 (Ser). This 635-aa protease, encoded by the UL26 gene, is autoproteolytically processed at two sites, the release (R) site between amino acid residues 247 and 248 and the maturation (M) site between residues 610 and 611. When the protease cleaves itself at both sites, it releases Nb, the catalytic domain (N0), and the C-terminal 25 aa. ICP35, a substrate of the HSV-1 protease, is the product of the UL26.5 gene. As it is translated from a Met codon within the UL26 gene, ICP35 cd are identical to the C-terminal 329-aa sequence of the protease and are trans cleaved at an identical C-terminal site to generate ICP35 e,f and a 25-aa peptide. Only fully processed Pra (N0 and Nb) and ICP35 (ICP35 e,f) are present in B capsids, which are believed to be precursors of mature virions. Using an R site mutant A247S virus, we have recently shown that this mutant protease retains enzymatic activity but fails to support viral growth, suggesting that the release of N0 is required for viral replication. Here we report that another mutant protease, with an amino acid substitution (Ser to Cys) at the active site, can complement the A247S mutant but not a protease deletion mutant. Cell lines expressing the active-site mutant protease were isolated and shown to complement the A247S mutant at the levels of capsid assembly, DNA packaging, and viral growth. Therefore, the complementation between the R-site mutant and the active site mutant reconstituted wild-type Pra function. One feature of this intragenic complementation is that following sedimentation of infected-cell lysates on sucrose gradients, both N-terminally unprocessed and processed proteases were isolated from the fractions where normal B capsids sediment, suggesting that proteolytic processing occurs inside capsids. Our results demonstrate that the HSV-1 protease has distinct functional domains and some of these functions can complement in trans. PMID- 8676456 TI - The leucine domain of the visna virus Tat protein mediates targeting to an AP-1 site in the viral long terminal repeat. AB - The visna virus Tat protein is a strong transcriptional activator and is necessary for efficient viral replication. The Tat protein regulates transcription through an AP-1 site proximal to the TATA box within the viral long terminal repeat (LTR). Previous studies from our laboratory using Tat-Gal4 chimeric proteins showed that Tat has a potent acidic activation domain. Furthermore, a region adjacent to the Tat activation domain contains a highly conserved leucine-rich domain which, in the context of the full-length protein, suppressed the activity of the activation domain. To further elucidate the role of this region, four leucine residues within this region of Tat were mutated. In transient-transfection assays using visna virus LTR-CAT as a reporter construct, the activity of this leucine mutant was dramatically reduced. Additionally, domain-swapping experiments using the N-terminal activation domain of VP16 showed that the leucine-rich domain of Tat confers AP-1 responsiveness to the chimeric VP16-Tat protein. A chimeric VP16-Tat construct containing the leucine mutations showed no increased AP-1 responsiveness in comparison with that of the VP16 activation domain alone. Furthermore, in competition experiments, a Gal4-Tat protein containing only the leucine region of Tat (amino acids 34 to 62) was able to inhibit by competition the activity of full-length Tat. These studies strongly suggest that this leucine-rich domain is responsible for targeting the Tat protein to AP-1 sites in the viral LTR. In addition, examination of the amino acid sequence of this region of Tat revealed a highly helical secondary structure and a pattern of residues similar to that in the leucine zippers in the bZIP family of DNA-binding proteins. This has important implications for the interaction of Tat with cellular proteins, specifically Fos and Jun, that contain bZIP domains. PMID- 8676457 TI - The hepatitis B virus posttranscriptional regulatory element is composed of two subelements. AB - The RNAs of the hepatitis B virus (HBV) contain a cis-acting regulatory element which facilitates the cytoplasmic localization of unspliced transcripts (J. Huang and T. J. Liang, Mol. Cell. Biol. 13:7476-7486, 1993, and Z. M. Huang and T. S. Yen, J. Virl. 68:3193-3199, 1994). Such localization is presumed to be mediated by cellular factors which interact with the element. The HBV posttranscriptional regulatory element (HBVPRE) can efficiently activate an RNA export reporter system in an orientation-dependent and position-independent manner. Deletion analysis reveals that the HBVPRE consists of two subelements which function synergistically. A synergistic effect was also observed when the 5' (PREalpha) or 3' (PREbeta) subelements were duplicated. The bipartite structure of the HBVPRE is reminiscent of reports that the high-affinity binding sites of the Rev-like proteins must be duplicated to function efficiently (M. Grone, E. Hoffmann, S. Berchtold, B.R. Cullen, and R. Grassmann, Virology 204:144-152, 1994; X. Huang, T.J. Hope, B.L. Bond, D. McDonald, K. Grahl, and T. G. Parslow, J. Virol. 65:2131 2134, 1991; and D. McDonald, T. J. Hope, and T. G. Parslow, J. Virol. 66:7232 7238, 1992). PMID- 8676458 TI - Transduction of human CD34+ hematopoietic progenitor cells by a retroviral vector expressing an RRE decoy inhibits human immunodeficiency virus type 1 replication in myelomonocytic cells produced in long-term culture. AB - Genetic modification of hematopoietic stem cells with a synthetic "anti-human immunodeficiency virus type 1 (HIV-1) gene" which inhibits replication of HIV-1 may allow production of mature lymphoid and monocytic cells resistant to HIV-1 growth after autologous transplantation. Because productive HIV-1 replication requires binding of the Rev protein to the Rev-responsive element (RRE) within the viral transcripts for the HIV-1 structural proteins, anti-HIV-1 gene products which interfere with Rev-RRE interactions may inhibit HIV-1 replication. One such strategy involves overexpression of the RRE sequences in transcripts derived from retroviral vectors to act as decoys to sequester Rev protein and prevent its binding to the RRE element in HIV-1 transcripts. We developed an in vitro model to test the efficacy of this gene therapy approach in primary human hematopoietic cells. Human CD34+ hematopoietic progenitor cells from normal bone marrow or umbilical cord blood were transduced with retroviral vectors carrying RRE decoy sequences as part of a long terminal repeat-directed transcript expressing the neo gene (L-RRE-neo) or with a control vector expressing only the neo gene (LN). The transduced progenitors were allowed to differentiate into mature myelomonocytic cells which were able to support vigorous growth of the monocytotropic isolate of HIV-1, JR-FL. HIV-1 replication was measured in unselected cell populations and following G418 selection to obtain uniformly transduced cell populations. Inhibition of HIV-1 replication in the unselected cell cultures was between 50.2 and 76.7% and was highly effective (99.4 to 99.9%) in the G418-selected cultures. Progenitors transduced by either the L-RRE-neo vector or the control LN vector were identical with respect to hematopoietic growth and differentiation. These findings demonstrate the ability of an RRE decoy strategy to inhibit HIV-1 replication in primary human myelomonocytic cells after transduction of CD34+ progenitor cells, without adverse effects on hematopoietic cell function. PMID- 8676459 TI - Resistance of previously infected chimpanzees to successive challenges with a heterologous intraclade B strain of human immunodeficiency virus type 1. AB - To test whether the protective effects of attenuated simian immunodeficiency virus vaccines in macaques were applicable to the human immunodeficiency virus type 1 (HIV-1)-chimpanzee system, two groups of animals, previously infected with HIV-1(IIIB) or HIV-1(SF2) were each challenged with a heterologous clade B virus, HIV-1(DH12). Following challenge, the parameters measured included virus isolation (from plasma, peripheral blood mononuclear cells, and lymph node tissue); quantitative DNA PCR using primers capable of distinguishing HIV 1(IIIB), HIV-1(SF2), and HIV-1(DH12) from one another; and serologic assays to monitor changes in binding and neutralizing antibodies. In contrast to an HIV-1 naive chimpanzee that rapidly became infected following the inoculation of HIV 1(DH12), the two chimpanzees previously infected with HIV-1(IIIB) resisted repeated and escalating inoculations of HIV-1(DH12), as monitored by virus isolation and PCR. The two animals previously infected with HIV-1(SF2) became infected with HIV-1(DH12) but in contrast to the case with the HIV-1-naive chimpanzee, no cell-free viral RNA was detected in the plasma by the branched DNA procedure and levels of peripheral blood mononuclear cell-associated viral DNA were reduced 35- to 50-fold. PMID- 8676460 TI - Roles of the sequence encoding tobacco etch virus capsid protein in genome amplification: requirements for the translation process and a cis-active element. AB - The roles of the capsid protein (CP) and the CP coding sequence of tobacco etch potyvirus (TEV) in genome amplification were analyzed. A series of frameshift stop codon mutations that interrupted translation of the CP coding sequence at various positions were introduced into the TEV genome. A series of 3' deletion mutants that lacked the CP coding sequence beyond each of the frameshift-stop codon mutations were also produced. In addition, a series of 5' CP deletion mutants were generated. Amplification of genomes containing either frameshift stop codon insertions after codons 1, 59, 103, and 138 or genomes containing the corresponding 3' deletions of the CP coding sequence was reduced by 100- to 1,000 fold relative to that of the parental genome in inoculated protoplasts. In contrast, a mutant containing a frameshift-stop codon after CP position 189 was amplified to 27% of the level of the parental virus, but the corresponding 3' deletion mutant lacking codons 190 to 261 was nonviable. Deletion mutants lacking CP codons 2 to 100, 2 to 150, 2 to 189, and 2 to 210 were amplified relatively efficiently in protoplasts, but a deletion mutant lacking codons 2 to 230 was nonviable. None of the amplification-defective frameshift-stop codon or deletion mutants was rescued in transgenic cells expressing TEV CP, although the transgenic CP was able to rescue intercellular movement defects of replication competent CP mutants. Coupled with previous results, these data led to the conclusions that (i) TEV genome amplification requires translation to a position between CP codons 138 and 189 but does not require the CP product and (ii) the TEV CP coding sequence contains a cis-active RNA element between codons 211 and 246. The implications of these findings on mechanisms of RNA replication and genome evolution are discussed. PMID- 8676461 TI - TM domain swapping of murine leukemia virus and human T-cell leukemia virus envelopes confers different infectious abilities despite similar incorporation into virions. AB - We investigated the influence of transmembrane protein (TM) domains on incorporation of retroviral envelopes into virions and on infectivity. We introduced complete, truncated, or chimeric Friend murine leukemia virus (F-MuLV) and human T-cell leukemia virus type 1 (HTLV-1) envelopes into an MuLV particle producing complementation cell line. As shown previously for HTLV-1 envelopes containing extracellular domains of F-MuLV TM (C. Denesvre, P. Sonigo, A. Corbin, H. Ellerbrok, and M. Sitbon, J. Virol. 69:4149-4157, 1995), reverse chimeric F MuLV envelopes containing the extracellular domain of HTLV-1 TM were not processed. In contrast, a chimeric MuLV envelope containing the entire HTLV membrane-spanning and cytoplasmic domains (FHTMi) was efficiently processed, fusogenic as tested in a cell-to-cell assay, and efficiently incorporated into MuLV particles. However, these MuLV particles bearing FHTMi envelope proteins could not infect mouse or rat cells which are susceptible to wild-type F-MuLV. Therefore, envelopes which are readily fusogenic in cell-to-cell assays and also efficiently incorporated into virions may not necessarily confer virus-to-cell fusogenicity. HTLV envelopes, whether parental, chimeric (containing the MuLV cytoplasmic tail) or with a truncated cytoplasmic domain, were incorporated into MuLV particles with equal efficiencies, indicating that the cytoplasmic tails of these envelopes did not determine their incorporation into virions. In contrast to FHTMi envelope, HTLV-1 envelopes with F-MuLV membrane-spanning and cytoplasmic domains, as well as wild-type HTLV-1 envelopes, conferred virion infectivity. These results help to define requirements for envelope incorporation into retroviral particles and their cell-free infectivity. PMID- 8676462 TI - Receptor-binding properties of a purified fragment of the 4070A amphotropic murine leukemia virus envelope glycoprotein. AB - A 208-amino-acid amino-terminal fragment of the 4070A amphotropic murine leukemia virus envelope glycoprotein contains all of the determinants required to recognize cell surface amphotropic receptors. This fragment was fused with a streptavidin-binding tag, expressed in Sf9 insect cells by using a baculovirus vector, and purified to homogeneity. The (125)I-labeled purified fragment (AS208) specifically bound various cell lines susceptible to amphotropic murine leukemia virus infection. The number of AS208-binding sites was in the range of 7 X 10(4) to 17 X 10(4) per cell. Quantitative analysis of binding revealed that AS208 binding sites are heterogeneous with regard to ligand binding affinity or that cooperativity exists between receptors. Competition experiments showed that the concentration of AS208 required to inhibit virus entry was lower than that required to inhibit the binding of virus particles at the cell surface. Taken together, these data suggested that amphotropic envelope-binding sites present at the cell surface do not act independently and do not participate equally in virus infection. PMID- 8676463 TI - Disruption of M-T5, a novel myxoma virus gene member of poxvirus host range superfamily, results in dramatic attenuation of myxomatosis in infected European rabbits. AB - Myxoma virus is a pathogenic poxvirus that induces a lethal myxomatosis disease profile in European rabbits, which is characterized by fulminating lesions at the primary site of inoculation, rapid dissemination to secondary internal organs and peripheral external sites, and supervening gram-negative bacterial infection. Here we describe the role of a novel myxoma virus protein encoded by the M-T5 open reading frame during pathogenesis. The myxoma virus M-T5 protein possesses no significant sequence homology to nonviral proteins but is a member of a larger poxviral superfamily designated host range proteins. An M-T5- mutant virus was constructed by disruption of both copies of the M-T5 gene followed by insertion of the selectable marker p7.5Ecogpt. Although the M-T5- deletion mutant replicated with wild-type kinetics in rabbit fibroblasts, infection of a rabbit CD4+ T-cell line (RL5) with the myxoma virus M-T5- mutant virus resulted in the rapid and complete cessation of both host and viral protein synthesis, accompanied by the manifestation of all the classical features of programmed cell death. Infection of primary rabbit peripheral mononuclear cells with the myxoma virus M-T5-mutant virus resulted in the apoptotic death of nonadherent lymphocytes but not adherent monocytes. Within the European rabbit, disruption of the M-T5 open reading frame caused a dramatic attenuation of the rapidly lethal myxomatosis infection, and none of the infected rabbits displayed any of the characteristic features of myxomatosis. The two most significant histological observations in rabbits infected with the M-T5-mutant virus were (i) the lack of progression of the infection past the primary site of inoculation, coupled with the establishment of a rapid and effective inflammatory reaction, and (ii) the inability of the virus to initiate a cellular reaction within secondary immune organs. We conclude that M-T5 functions as a critical virulence factor by allowing productive infection of immune cells such as peripheral lymphocytes, thus facilitating virus dissemination to secondary tissue sites via the lymphatic channels. PMID- 8676464 TI - In vivo blockade of gamma interferon affects the influenza virus-induced humoral and the local cellular immune response in lung tissue. AB - Influenza virus infection induces the local production of gamma interferon (IFN gamma) by T cells and non-T cells in the respiratory tract. To elucidate the possible functions of this cytokine, the humoral and local cellular immune responses to influenza virus were studied in BALB/c mice with or without in vivo neutralization of IFN-gamma by using monoclonal antibodies. Neutralization of IFN gamma led to a significant reduction in virus-specific titers of immunoglobulins G2a and G3 in serum but had little effect on other isotypes. Studies on cells isolated from the lung parenchyma itself revealed that at the height of the immune response the ability of these cells to produce cytokines after antigen or T-cell receptor/CD3 stimulation was not affected. Ex vivo cytolytic activity by lung parenchyma cells, which is induced by infection with this virus in normal mice, was also found to be undisturbed by this treatment, even though anti-IFN gamma antibody activity was recovered from lung lavage samples and sera at all days studied. Surprisingly, in vivo neutralization of IFN-gamma led to a significant reduction in the magnitude of the cellular infiltrate in the lung tissue which followed infection, suggesting an involvement of IFN-gamma in the mechanisms that regulate increased leucocyte traffic in the inflamed lung parenchyma. This conclusion was supported by findings of differences between mock treated and anti-IFN-gamma-treated mice in the number of CD8+ lung T cells expressing CD49d (alpha4-integrin) and CD62L at various times after influenza virus infection. This study therefore demonstrates that IFN-gamma affects the local cellular response in the respiratory tract as well as the systemic humoral response to influenza virus infection. PMID- 8676465 TI - Relative ability of different bovine leukocyte populations to support active replication of rinderpest virus. AB - Bovine peripheral blood mononuclear cells (PBMC) were infected with the pathogenic Saudi isolate of rinderpest virus (RPV) in order to identify the cell subpopulation(s) susceptible to active replication of this virus. Flow cytometry analysis, using a monoclonal antibody recognizing the H glycoprotein of RPV, showed that monocytes were the main subpopulation in which the virus replicated, whereas <2% of lymphocytes expressed viral antigen. The activation of PBMC with concanavalin A before infection resulted in an increase in the capacity of lymphocytes to support RPV replication; >90% of CD4+ and CD8+ T lymphocytes expressed viral antigen at 3 days postinfection, although < or = 40% of gamma/delta T cells were productively infected. B-lymphocyte activation with pokeweed mitogen also resulted in increased replication of this virus in these cells, involving up to 40% of B lymphocytes. An enhancement of lymphocyte susceptibility to infection and active replication by RPV was observed upon coculture of RPV-infected PBMC on bovine endothelial cells. Such enhancement was most marked with the B-cell and CD4+ T-cell subpopulations. Contact between lymphocytes and extracellular matrix components did not alter the capacity of RPV to replicate in lymphocytes. This intercellular contact with endothelial cells increased the viability of certain lymphocyte subpopulations, but it alone could not explain the increased sensitivity to RPV. Intercellular signalling, which resulted in interleukin-2 receptor upregulation, probably played a role. In summary, monocytes are the main target for active, productive infection by RPV. Similar replication in lymphocytes depends on their activation state and on contact with accessory cells such as endothelial cells. These characteristics have important implications for virus traffic in vivo and the pathogenesis of this disease. PMID- 8676466 TI - Activation of transcription factor NF-kappaB by the Tat protein of human immunodeficiency virus type 1. AB - A recombinant Tat protein was used to investigate the molecular mechanisms of transcriptional activation of the human immunodeficiency virus type 1 long terminal repeat (LTR). Liposome-mediated delivery of this protein to responsive cells results in dose-dependent LTR activation. As evaluated by mRNA quantitation with competitive PCR, the activation response is rapid and transient, peaking at 5 h after the beginning of Tat treatment. In vivo footprinting experiments at the LTR showed that transcriptional activation is concomitant with a modification of the protein-DNA interaction pattern at the downstream kappaB site of the enhancer and at the adjacent Sp1 boxes. The effects of Tat on the enhancer are mediated by Tat-induced nuclear translocation of NF-kappaB, which parallels the kinetics of transcriptional activation. This induction results from degradation of the inhibitor IkappaB-alpha, is blocked under antioxidant conditions and by a protease inhibitor, and occurs as a rapid response in different cell types. The functional response to Tat is impaired upon cell treatment with a kappaB site decoy or with sodium salicylate, an inhibitor of NF-kappaB activation. These results show that NF-kappaB activation by Tat is important for LTR transcriptional activation. Furthermore, they suggest that some of the pleiotropic effects of Tat on cellular functions can be mediated by induction of NF-kappaB. PMID- 8676468 TI - Transcription of a vaccinia virus late promoter template: requirement for the product of the A2L intermediate-stage gene. AB - Evidence is presented that a 26-kDa protein encoded by the vaccinia virus A2L open reading frame, originally shown to be one of three intermediate-stage genes that together can transactivate late-stage gene expression in transfection assays (J. G. Keck, C. J. Baldick, and B. Moss, Cell 61:801-809, 1990), is required for in vitro transcription of a template with a late promoter. The critical step in this analysis was the preparation of an extract containing all the required factors except for the A2L protein. This extract was prepared from cells infected with a recombinant vaccinia virus expressing the bacteriophage T7 RNA polymerase in the presence of the DNA synthesis inhibitor cytosine arabinoside and transfected with plasmids containing the two other known transactivator genes, A1L and G8R, under T7 promoter control. Reaction mixtures made with extracts of these cells had background levels of late transcription activity, unless they were supplemented with extracts of cells transfected with the A2L gene. Active transcription mixtures were also made by mixing extracts from three sets of cells, each transfected with a gene (A1L, A2L, or G8R) encoding a separate factor, indicating the absence of any requirement for their coexpression. To minimize the possibility that the A2L protein functions indirectly by activating another viral or cellular protein, this gene was expressed in insect cells by using a baculovirus vector. The partially purified recombinant protein complemented the activity of A2L-deficient cell extracts. Recombinant A1L, A2L, and G8R proteins, all produced in insect cells, together complemented extracts from mammalian cells containing only viral early proteins, concordant with previous in vivo transfection data. PMID- 8676467 TI - Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. AB - We have previously demonstrated that hepatitis C virus (HCV) core protein regulates cellular protooncogenes at the transcriptional level; this observation implicates core protein in the alteration of normal hepatocyte growth. In the present study, the transforming potential of the HCV core gene was investigated by using primary rat embryo fibroblast (REF) cells which were transfected with or without cooperative oncogenes. Integration of the HCV core gene resulted in expression of the viral protein in REF stable transformants. REF cells cotransfected with HCV core and H-ras genes became transformed and exhibited rapid proliferation, anchor-independent growth, and tumor formation in athymic nude mice. Results from these studies suggest that the core protein plays an important role in the regulation of HCV-infected cell growth and in the transformation to tumorigenic phenotype. These observations suggest a possible mechanism for this viral protein in the pathogenesis of hepatocellular carcinoma in HCV-infected humans. PMID- 8676469 TI - A role for urokinase-type plasminogen activator in human immunodeficiency virus type 1 infection of macrophages. AB - Urokinase-type plasminogen activator (uPA), a proteinase which activates plasminogen by cleaving at -CPGR(arrow downward)V-, was shown to cleave the V3 loop in recombinant gp120 of human immunodeficiency virus type 1 (HIV-1) IIIB and MN strains, as well as a synthetic, cyclized peptide representing the clade B consensus sequence of V3. Proteolysis occurred at the homologous -GPGR(arrow downward)A-, an important neutralizing determinant of HIV-1. It required soluble CD4 and was prevented by inhibitors of uPA but not by inhibitors of likely contaminating plasma proteinases. It was accelerated by heparin, a known cofactor for plasminogen activation. In immune capture experiments, tight binding of uPA to viral particles, which did not depend on CD4, was also demonstrated. Active site-directed inhibitors or uPA diminished this binding, as did a neutralizing antibody to V3. Addition of exogenous uPA to the laboratory-adapted IIIB strain of HIV-1, the macrophage-tropic field strains JR-CSF and SF-162, or a fresh patient isolate of indeterminate tropism, followed by infection of macrophages with the various treated viruses, resulted in severalfold increases in subsequent viral replication, as judged by yields of reverse transcriptase activity and p24 antigen, as well as incorporation, as judged by PCR in situ. These responses were reversible by inhibitors or antibodies targeting the proteinase active site or the V3 loop. We propose that uPA, a transcriptionally regulated proteinase which is upregulated when macrophages are HIV infected, can be bound and utilized by the virus to aid in fusion and may be an endogenous component that is critical to the infection of macrophages by HIV-1. PMID- 8676471 TI - Synergistic neutralization of human immunodeficiency virus type 1 by a chimpanzee monoclonal antibody against the V2 domain of gp120 in combination with monoclonal antibodies against the V3 loop and the CD4-binding site. AB - Synergistic neutralization of human immunodeficiency virus type 1 (HIV-1) was observed in studies using a chimpanzee anti-V2 monoclonal antibody (MAb), C108G, in combination with anti-V3 loop and anti-CD4 binding-site (bs) MAbs of different epitope specificities. C108G paired with either of two anti-V3 loop MAbs or either of two anti-CD4 bs MAbs synergistically neutralized both the uncloned IIIB and clonal HXB2 strains of virus in H9 target cells. Synergism was quantitated by calculation of combination indices. Significant synergy with a given MAb pair was seen over a range of MAb ratios, with the optimal effect centering around the ratio at which the MAbs were equipotent for a given HIV-1 strain (on the basis of the 50% neutralization titer). In preliminary experiments with monocytotropic strains of HIV-1 in peripheral blood mononuclear cell targets, significant synergism was also observed between anti-V2-anti-V3 and anti-V2-anti-CD4 bs MAb pairs. Synergism by all MAb pairs tested was greater against heterogeneous isolates of HIV-1 (IIIB and Ba-L) than against clonal isolates (HXB2 and NLHXADA), suggesting that strain broadening may be a component of the synergism observed against the heterogeneous isolates. In addition, conformational changes in gp120 upon binding of one or both MAbs may result in increased affinity or exposure of the epitope of one or both MAbs. Finally, a three-MAb combination of C108G, an anti-V3 MAb, and an anti-CD4 bs MAb was more effective in neutralizing the HXB2 strain of HIV-1 than any of the three two-MAb combinations within this trio, as determined by the dose reduction indices of each MAb required to achieve a given level of neutralization. This is the first report of synergistic neutralization of HIV-1 by a three-MAb combination composed of MAbs directed against the three major neutralization epitope clusters in gp120. Implications for vaccine design and for immunoprophylaxis and immunotherapy with a combination of MAbs are discussed. PMID- 8676470 TI - Functional implications of mutations within polyomavirus large T antigen Rb binding domain: effects on pRb and p107 binding in vitro and immortalization activity in vivo. AB - In this study, we have extensively modified the Rb-binding domain of polyomavirus large T antigen. Mutant polyomavirus large T antigens were tested for their ability to bind pRb and p107 in vitro and assayed for their capacity to immortalize primary rat embryo fibroblasts in vivo. Polyomavirus large T antigen bound pRb and p107 through a common region located between amino acids 141 to 158, containing the consensus Rb-binding sequence D/N-L-X-C-X-E. Substitution of any amino acid within the core Rb-binding sequence abolished pRb and p107 binding in vitro and immortalization activity in vivo. Substitution of amino acids outside the core Rb-binding sequence reduced pRb and p107 binding in vitro and decreased or abolished immortalization of rat embryo fibroblasts in vivo. Although duplication of the Rb-binding domain within the polyomavirus large T antigen results in a molecule that can bind at least twice as much pRb and p107 in vitro, this mutant displayed an essentially wild-type level of immortalization activity. More importantly, we found that the addition of acidic residues within the casein kinase II consensus phosphorylation region flanking the Rb-binding domain, or the deletion of amino acids 256 to 272, increased the immortalizing activity of the mutant polyomavirus large T antigen. These two mutants displayed a greater than wild-type level of pRb binding in vitro, while in contrast, a decreased affinity for p107 binding in vitro was observed. Together, these results indicate that while pRb binding appears to be an essential event for immortalization, there is no tight correlation between the frequency of immortalization and the absolute level of pRb binding in vitro, indicating that other large T antigen functions are important for cellular immortalization. PMID- 8676473 TI - Inhibition of human immunodeficiency virus type 1 integrase by the Fab fragment of a specific monoclonal antibody suggests that different multimerization states are required for different enzymatic functions. AB - We have characterized a murine monoclonal antibody (MAb 35), which was raised against human immunodeficiency virus type 1 (HIV-1) integration protein (IN), and the corresponding Fab 35. Although MAb 35 does not inhibit HIV-1 IN, Fab 35 does. MAb 35 (and Fab 35) binds to an epitope in the C-terminal region of HIV-1 IN. Fab 35 inhibits 3'-end processing, strand transfer, and disintegration; however, DNA binding is not affected. The available data suggest that Fab 35 inhibits enzymatic activities of IN by interfering with the ability of IN to form multimers that are enzymatically active. This implies that the C-terminal region of HIV-1 IN participates in interactions that are essential for the multimerization of IN. Titration of the various IN-mediated enzymatic activities suggests that different degrees of multimerization are required for different activities of HIV-1 IN. PMID- 8676472 TI - Characterization of human immunodeficiency virus type 1 p17 matrix protein motifs associated with mother-to-child transmission. AB - In order to determine if viral selection occurs during mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1), we used a direct solid-phase sequencing method to sequence the p17 matrix protein-encoding regions of viral isolates from 12 HIV-1-infected mother-and-child pairs, 4 infected infants, 4 transmitting mothers, and 22 nontransmitting mothers and compared the sequences. The blood samples were collected during the delivery period for the mothers and during the first month of life for most of the children. The p17 nucleic sequences were distributed among several clades corresponding to the HIV 1 A, B, and G subtypes. At the amino acid level, no significant differences within the known p17 functional regions were observed among the subtypes. Statistical analyses could be performed with the B subtype. Within the major p17 antibody binding site, a constant KIEEEQN motif (amino acids 103 to 109) was found in all mother-and-child isolates from the B subtype. On the other hand, 9 of 17 nontransmitting mother isolates were variable in this 103 to 109 region. Thus, this motif was significantly associated with the transmitting status (chi square, P = 0.0034). A valine residue at position 104 was significantly associated with the nontransmitting phenotype (chi square, P = 0.014), suggesting that it has a protective role during vertical transmission. The C-terminal end of p17 was globally conserved among nontransmitting mother isolates (chi square, P = 0.0037). These results might improve the understanding of the pathogenesis of HIV 1 vertical transmission and might allow the screening of seropositive mothers by a rapid molecular or peptide test. PMID- 8676474 TI - In vitro replication of adeno-associated virus DNA: enhancement by extracts from adenovirus-infected HeLa cells. AB - Previously we have described an in vitro assay for the replication of adeno associated virus type 2 (AAV2) DNA. Addition of the AAV2 nonstructural protein Rep68 to an extract from uninfected cells supports the replication of linear duplex AAV DNA. In this report, we examine replication of linear duplex AAV DNA in extracts from either uninfected or adenovirus (Ad)-infected HeLa cells. The incorporation of radiolabeled nucleotides into full-length linear AAV DNA is 50 fold greater in extracts from Ad-infected cells than in extracts from uninfected cells. In addition, the majority of the labeled full-length AAV DNA molecules synthesized in the Ad-infected extract have two newly replicated strands, whereas the majority of labeled full-length AAV DNA molecules synthesized in the uninfected extract have only one newly replicated strand. The numbers of replication initiations on original templates in the two assays are approximately the same; however, replication in the case of the Ad-infected cell extract is much more likely to result in the synthesis of a full-length AAV DNA molecule. Most of the newly replicated molecules in the assay using uninfected cell extracts are in the form of stem-loop structures. We hypothesize that Ad infection provides a helper function related to elongation during replication by a single-strand displacement mechanism. In the assay using the uninfected HeLa cell extract, replication frequently stalls before reaching the end of the genome, causing the newly synthesized strand to be displaced from the template, with a consequent folding on itself and replication back through the inverted terminal repeat, using itself as a template. In support of this conjecture, replication in the uninfected cell extract of shorter substrate molecules is more efficient, as measured by incorporation of radiolabeled nucleotides into full length substrate DNA. In addition, when shorter substrate molecules are used as the template in the uninfected HeLa cell assay, a greater proportion of the labeled full-length substrate molecules contain two newly replicated strands. Shorter substrate molecules have no replicative advantage over full-length substrate molecules in the assay using an extract from Ad-infected cells. PMID- 8676475 TI - Adenovirus interaction with distinct integrins mediates separate events in cell entry and gene delivery to hematopoietic cells. AB - A major impediment to the effective use of adenovirus vectors for gene therapy is a lack of knowledge of how these vectors interact with diverse cell types in vivo. Adenovirus attachment to most human cell types is mediated by the fiber protein, which binds to an as yet unidentified cell receptor. In contrast to this, we report that adenovirus type 2 (Ad2) attachment to hematopoietic cells is facilitated by interaction of the penton base protein with members of the beta2 integrin family. Adenovirus particles were capable of binding to human monocytic cells, which lack fiber receptors, and virus binding could be blocked by a soluble penton base or by a function-blocking monoclonal antibody to integrin alphaMbeta2. To confirm the role of alphaMbeta2 integrins in Ad2 binding to hematopoietic cells, we analyzed virus attachment and gene delivery to CHO cells expressing recombinant beta2 integrins. alphaMbeta2-expressing CHO cells supported 3- to 5-fold-higher levels of Ad2 binding and 5- to 10-fold-larger amounts of gene delivery than did nontransfected CHO cells, indicating that alphaMbeta2 facilitates adenovirus attachment to and infection of hematopoietic cells. While beta2 integrins promote Ad2 attachment to hematopoietic cells, further studies demonstrated that alphav integrins were required for the next step in infection, virus internalization into cell endosomes. These studies reveal a novel pathway of Ad2 infection of hematopoietic cells mediated by distinct integrins which facilitate separate events in virus entry. They also suggest a possible strategy for selective adenovirus-mediated gene delivery to hematopoietic cells. PMID- 8676476 TI - High-risk human papillomavirus E6 protein has two distinct binding sites within p53, of which only one determines degradation. AB - Human papillomavirus (HPV) E6 protein can inactivate tumor suppressor p53 by inducing its degradation. We now find that high-risk HPV E6 binds to p53 at two distinct sites; one is within the core structure of p53, and another is at the C terminus of p53. Binding to the core of p53 is required for E6-mediated degradation, as shown by deletion analysis and the properties of a point mutant at residue 135. Both low- and high-risk HPV E6 can bind to a C-terminal region of p53, but these interactions do not induce degradation. These results resolve previous seemingly contradictory findings that attributed the distinctive functional properties of high- and low-risk E6 proteins to either a difference in their abilities to associate with p53 or a difference in their N-terminal structures. PMID- 8676477 TI - Alpha/beta interferons increase host resistance to murine AIDS. AB - Murine AIDS (MAIDS) is caused by a defective retrovirus present in the LP-BM5 murine leukemia virus mixture. Strains of inbred mice differ in resistance to MAIDS development; some are susceptible (e.g., C57BL/6), while others are resistant (e.g., CBA and B10.BR). As an early block to viral replication in resistant mice has been demonstrated previously by PCR studies, we postulated that alpha/beta interferons (IFN-alpha/beta) may be involved in resistance to MAIDS. Susceptible C57BL/6 mice infected with LP-BM5 were treated with IFN alpha/beta or Newcastle disease virus. Newcastle disease virus induces high endogenous IFN-alpha/beta production in mice. Both treatments delayed the development of MAIDS, as assessed by splenomegaly and T- and B-cell proliferation. In addition, an IFN-alpha/beta response was detected by reverse transcription-PCR and dot blotting 3, 6, and 9 h after LP-BM5 infection in resistant mice but not in susceptible mice. These results suggest that the ability to produce IFN-alpha/beta in response to LP-BM5 infection may contribute to host resistance to MAIDS. PMID- 8676478 TI - Inhibition of topoisomerase II by ICRF-193 prevents efficient replication of herpes simplex virus type 1. AB - Cellular topoisomerase II is specifically inactivated by the drug ICRF-193. This compound turns topoisomerase II into a closed clamp that is unable to cleave DNA. We have investigated the effects of this inhibitor on the replication of herpes simplex virus type 1. We show that ICRF-193 at low multiplicities of infection dramatically inhibits viral DNA synthesis and the production of infectious virus. The inhibition is less efficient at high multiplicities of infection. In addition, inhibition of viral DNA synthesis was observed only when ICRF-193 was present during the first 4 h of the infectious cycle. The transient replication of plasmids containing a herpes simplex virus type 1 origin of DNA replication, oriS, was affected by ICRF-193 in the same way. In contrast, neither cellular DNA synthesis nor replication of plasmids containing a simian virus 40 origin of DNA replication was inhibited. The observed effect on herpes simplex virus DNA replication was not caused by a decreased transcription of replication genes inasmuch as the levels of UL8, UL9, UL29, and UL30 rmRNAs were unaffected by the drug. These results suggest that topoisomerase II plays a vital role during the replication of herpes simplex virus type 1 DNA. We speculate that topoisomerase II is involved in the decatenation of newly synthesized daughter molecules. PMID- 8676479 TI - Inducible human immunodeficiency virus type 1 packaging cell lines. AB - Packaging cell lines are important tools for transferring genes into eukaryotic cells. Human immunodeficiency virus type 1 (HIV-1)-based packaging cell lines are difficult to obtain, in part owing to the problem that some HIV-1 proteins are cytotoxic in a variety of cells. To overcome this, we have developed an HIV-1 based packaging cell line which has an inducible expression system. The tetracycline-inducible expression system was utilized to control the expression of the Rev regulatory protein, which in turn controls the expression of the late proteins including Gag, Pol, and Env. Western blotting (immunoblotting) demonstrated that the expression of p24gag and gp120env from the packaging cells peaked on days 6 and 7 postinduction. Reverse transcriptase activity could be detected by day 4 after induction and also peaked on days 6 and 7. Defective vector virus could be propagated, yielding titers as high as 7 x 10(3) CFU/ml, while replication-competent virus was not detectable at any time. Thus, the cell line should enable the transfer of specific genes into CD4+ cells and should be a useful tool for studying the biology of HIV-1. We have also established an inducible HIV-1 Env-expressing cell line which could be used to propagate HIV-1 vectors that require only Env in trans. The env-minus vector virus titer produced from the Env-expressing cells reached 2 x 10(4) CFU/ml. The inducible HIV-1 Env expressing cell line should be a useful tool for the study of HIV-1 Env as well. PMID- 8676480 TI - Constitutive phosphorylation of the vesicular stomatitis virus P protein modulates polymerase complex formation but is not essential for transcription or replication. AB - As a subunit of both the P-L polymerase complex and the P-N assembly complex, the vesicular stomatitis virus (VSV) P protein plays a pivotal role in transcription and replication of the viral genome. Constitutive phosphorylation of this protein is currently thought to be essential for formation of the P-L complex. We recently identified the three relevant phosphate acceptor sites in the VSV Indiana serotype P protein (R. L. Jackson, D. Spadafora, and J. Perrault, Virology 214:189-197, 1995). We now report the effects of substituting Ala at these acceptor sites on transcription reconstitution in vitro and replication of defective interfering virus (DI) templates in vivo. The singly substituted S60A, T62A, and S64A mutants and the doubly substituted S60A/T62A and T62A/S64A mutants, all of which retain some constitutive phosphorylation, were nearly as active as the wild type in both assays. Surprisingly, the nonphosphorylated S60A/S64A protein was also active in transcription (> or = 28%)) and replication (> or = 50%) under optimal conditions. However, this mutant was much less active in in vitro transcription (< or = 5% of wild type) at low P concentrations (<27 nM). In addition, S60A/S64A required higher concentrations of L protein than did the wild type for optimal DI replication in vivo. DI replication efficiency and intracellular accumulation of L, P, and N proteins in the transfected system were very similar to those in VSV-infected cells. We conclude that P protein constitutive phosphorylation is not essential for VSV RNA synthesis per se but likely plays an important role in vivo in facilitating P multimerization and possibly P-L complex formation. PMID- 8676481 TI - Recombinant subviral particles from tick-borne encephalitis virus are fusogenic and provide a model system for studying flavivirus envelope glycoprotein functions. AB - Recombinant subviral particles (RSPs) obtained by coexpression of the envelope (E) and premembrane (prM) proteins of tick-borne encephalitis virus in COS cells (S. L. Allison, K. Stadler, C. W. Mandl, C. Kunz, and F. X. Heinz, J. Virol. 69:5816-5820, 1995) were extensively characterized and shown to be ordered structures containing envelope glycoproteins with structural and functional properties very similar to those in the virion envelope. The particles were spherical, with a diameter of about 30 nm and a buoyant density of 1.14 g/cm3 in sucrose gradients. They contained mature E proteins with endoglycosidase H resistant glycans as well as fully cleaved mature M proteins. Cleavage of prM, which requires an acidic pH in exocytic compartments, could be inhibited by treatment of transfected cells with ammonium chloride, implying a common maturation pathway for RSPs and virions. RSPs incorporated [14C]choline but not [3H]uridine, demonstrating that they contain lipid but probably lack nucleic acid. The envelope proteins of RSPs exhibited a native antigenic and oligomeric structure compared with virions, and incubation at an acidic pH (pH <6.5) induced identical conformational changes and structural rearrangements, including an irreversible quantitative conversion of dimers to trimers. The RSPs were also shown to be functionally active, inducing membrane fusion in a low-pH-dependent manner and demonstrating the same specific hemagglutination activity as whole virions. Tick-borne encephalitis virus RSPs thus represent an excellent model system for investigating the structural basis of viral envelope glycoprotein functions. PMID- 8676483 TI - Covalently closed circular viral DNA formed from two types of linear DNA in woodchuck hepatitis virus-infected liver. AB - We found that livers from woodchucks chronically infected with woodchuck hepatitis virus (WHV) contained covalently closed circular DNA (cccDNA) molecules with deletions and insertions indicative of their formation from linear viral DNA by nonhomologous recombination, as we previously described for the duck hepatitis B virus (W. Yang and J. Summers, J. Virol. 69:4029-4036, 1995). However, evidence for two different types of linear precursors was obtained by analysis of the recombination joints in WHV cccDNA. Type 1 linear precursors possessed the structural properties that correspond to those of in situ-primed linear DNA molecules, which constitute between 7 and 20% of all viral DNA replicative intermediates synthesized in the liver. Type 2 linear precursors are hypothetical species of linear DNAs with a terminal duplication of the cohesive-end region, between DR1 and DR2. This type of linear DNA has not been previously described and was not detected among the DNA species present in nucleocapsids. A fraction of cccDNAs formed from both type 1 and type 2 linear DNAs are predicted to be functional for further DNA synthesis, and some evidence for the formation of two or more generations of cccDNA from linear DNA was observed. PMID- 8676484 TI - The human immunodeficiency virus Tat proteins specifically associate with TAK in vivo and require the carboxyl-terminal domain of RNA polymerase II for function. AB - Human immunodeficiency virus types 1 and 2 encode closely related proteins, Tat-1 and Tat-2, that stimulate viral transcription. Previously, we showed that the activation domains of these proteins specifically interact in vitro with a cellular protein kinase named TAK. In vitro, TAK phosphorylates the Tat-2 but not the Tat-1 protein, a 42-kDa polypeptide of unknown identity, and the carboxyl terminal domain (CTD) of RNA polymerase II (RNAP II). We now show that the 42-kDa substrate of TAK cochromatographs with TAK activity, suggesting that this 42-kDa polypeptide is a subunit of TAK. We also show that the Tat proteins specifically associate with TAK in vivo, since wild-type Tat-1 and Tat-2 proteins expressed in mammalian cells, but not mutant Tat proteins containing a nonfunctional activation domain, can be coimmunoprecipitated with TAK. We also mapped the in vivo phosphorylation sites of Tat-2 to the carboxyl terminus of the protein, but analysis of proteins with mutations at these sites suggests that phosphorylation is not essential for Tat-2 transactivation function. We further investigated whether the CTD of RNAP II is required for Tat function in vivo. Using plasmid constructs that express an alpha-amanitin-resistant RNAP II subunit with a truncated or full-length CTD, we found that an intact CTD is required for Tat function. These observations strengthen the proposal that the mechanism of action of Tat involves the recruitment or activation of TAK, resulting in activated transcription through phosphorylation of the CTD. PMID- 8676482 TI - Hepatitis B virus HBx protein activates transcription factor NF-kappaB by acting on multiple cytoplasmic inhibitors of rel-related proteins. AB - The HBx protein is a small polypeptide encoded by mammalian hepadnaviruses that is essential for viral infectivity and is thought to play a role in development of hepatocellular carcinoma during chronic hepatitis B virus infection. HBx is a transactivator that stimulates Ras signal transduction pathways in the cytoplasm and certain transcription elements in the nucleus. To better understand the activities of HBx protein and its mechanism of action, we have explored the manner by which HBx activates the transcription factor NF-kappaB during transient expression. We show that HBx induces prolonged formation, in a Ras-dependent manner, of transcriptionally active NF-kappaB DNA-binding complexes, which make up the family of Rel-related proteins, p50, p52, RelA, and c-Rel. HBx was found to activate NF-kappaB through two distinct cytoplasmic pathways by acting on both the 37-kDa IkappaBalpha inhibitor and the 105-kappaDa NF-kappaB1 precursor inhibitor protein, known as p105. HBx induces phosphorylation of IkappaBalpha, a three- to fourfold reduction in IKBalpha stability, and concomitant nuclear accumulation of NF-kappaB DNA-binding complexes, similar to that reported for human T-cell leukemia virus type 1 Tax protein. In addition, HBx mediates a striking reduction in cytoplasmic p105 NF-kappaB1 inhibitor and p50 protein levels and release of RelA protein that was sequestered by the p105 inhibitor, concomitant with nuclear accumulation of NF-kappaB complexes. HBx mediated only a slight reduction in the cytoplasmic levels of NF-kappaB2 p100 protein, an additional precursor inhibitor of NF-kappaB, which is thought to be less efficiently processed or less responsive to release of NF-kappaB. No evidence was found for HBx activation of NF-kappaB by targeting acidic sphingomyelinase- controlled pathways. Studies also suggest that stimulation of NF-kappaB by HBx does not involve activation of Ras via the neutral sphingomyelin-ceramide pathway. Thus, HBx protein is shown to activate the NF-kappaB family of Rel related proteins by acting on two distinct NF-kappaB cytoplasmic inhibitors. PMID- 8676485 TI - Functional domains of Moloney murine leukemia virus integrase defined by mutation and complementation analysis. AB - Retroviral integrases perform two catalytic steps, 3' processing and strand transfer, that result in the stable insertion of the retroviral DNA into the host genome. Mutant M-MuLV integrases were constructed to define the functional domains important for 3' processing, strand transfer, and disintegration by in vitro assays. N-terminal mutants had no detectable 3' processing activity, and only one mutant which lacks the HHCC domain, Ndelta105, had strand transfer activity. Strand transfer mediated by Ndelta105 showed preference for one site in the target DNA. Disintegration activity of N-terminal mutants decreased only minimally. In contrast, all C-terminal mutants truncated by more than 28 amino acids had no integration or disintegration activity. Activity on a single-strand disintegration substrate did not require a functional HHCC domain but did require most of the C-terminal region. Complementation analysis found that the HHCC region alone was able to function in trans to a promoter containing only the DD(35)E and C-terminal regions and to enhance integration site selection. Increasing the reducing conditions or adding the HHCC domain to Ndelta105 reaction mixtures restored the wild-type strand transfer activity and range of target sites. The reducing agent affected Cys-209 in the DD(35)E region. The presence of C-209 was required for complementation of Ndelta105 by the HHCC region. PMID- 8676487 TI - The GP64 envelope fusion protein is an essential baculovirus protein required for cell-to-cell transmission of infection. AB - To demonstrate the essential nature of the baculovirus GP64 envelope fusion protein (GP64 EFP) and to further examine the role of this protein in infection, we inactivated the gp64 efp gene of Autographa californica multicapsid nuclear polyhedrosis virus (AcMNPV) and examined the biological properties of this virus in vivo. To provide GP64 EFP during construction of the recombinant GP64 EFP-null AcMNPV baculovirus, we first generated a stably transfected insect cell line (SfpOP64-6) that constitutively expressed the GP64 EFP of Orgyia pseudotsugata multicapsid nuclear polyhedrosis virus (OpMNPV). The AcMNPV gp64 efp gene was inactivated by inserting the bacterial lacZ gene in frame after codon 131 of the gp64 efp gene. The inactivated gp64 gene was cloned into the AcMNPV viral genome by replacement of the wild-type gp64 efp locus. When propagated in the stably transfected insect cells (Sf9OP64-6 cells), budded virions produced by the recombinant AcMNPV GP64 EFP-null virus (vAc64z) contained OpMNPV GP64 EFP supplied by the Sf9OP64-6 cells. Virions propagated in Sf9OP64-6 cells were capable of infecting wild-type Sf9 cells, and cells infected by vAc64z exhibited a blue phenotype in the presence of X-Gal (5-bromo-4-chloro-3-indolyl-beta-D galactopyranoside). Using cytochemical staining to detect vAc64z infected cells, we demonstrated that this GP64 EFP-null virus is defective in cell-to-cell propagation in cell culture. Although defective in cell-to-cell propagation, vAc64z produces occlusion bodies and infectious occlusion-derived virions within the nucleus. Occlusion bodies collected from cells infected by vAc64z were infectious to midgut epithelial cells of Trichoplusia ni larvae. However, in contrast to infection by a control virus, infection by vAc64z did not proceed into the hemocoel. Analysis of vAc64z occlusion bodies in a standard neonate droplet feeding assay showed no virus-induced mortality, indicating that occluded virions produced from vAc64z could not initiate a productive (lethal) infection in neonate larvae. Thus, GP64 EFP is an essential virion structural protein that is required for propagation of the budded virus from cell to cell and for systemic infection of the host insect. PMID- 8676486 TI - Location, exposure, and conservation of neutralizing and nonneutralizing epitopes on human immunodeficiency virus type 2 SU glycoprotein. AB - Eleven rat monoclonal antibodies (MAbs) that recognize the SU glycoprotein of human immunodeficiency virus type 2 (HIV-2) ROD were produced and characterized. Binding sites for eight of these MAbs were mapped to epitopes within the Cl, V1/V2, C2, and V3 envelope regions. The three other MAbs defined at least two conformation-dependent, strain-specific epitopes outside Vl/V2, V3, and the CD4 binding site. The MAbs were used to probe the tertiary structure of oligomeric envelope glycoprotein expressed on the surfaces of infected cells. Epitopes at the apices of V2 and V3 were exposed on the native molecule, whereas other epitopes on V1/V2, Cl, and C2 were hidden. The MAbs defined three neutralization targets on exposed domains: two linear epitopes in the V2 and the V3 loops and one conformational epitope outside V1, V2, and V3. PMID- 8676488 TI - bc1-2 expression facilitates human immunodeficiency virus type-1 mediated cytopathic effects during acute spreading infections. AB - The cytopathic effects (CPE) resulting from the infection of CD4+ T cells by human immunodeficiency virus (HIV) have generally been characterized as single cell killing associated with apoptosis and/or the generation of syncytia resulting from the direct cell-to-cell transmission of the virus. Little is known, however, about the cellular factors influencing host cell susceptibility to HIV-mediated CPE. Because expression of the antiapoptosis gene, bcl-2, enhances cell viability after exposure to cytotoxic agents or stimuli, the effect of bcl-2 expression on HIV infection of stably transfected T-cell clones was investigated. Unexpectedly, bcl-2 expression by these cells accelerated the kinetics of an acute spreading HIV infection, as evidenced by a rapid loss of culture viability associated with the appearance of CPE and reverse transcriptase activity in the culture supernatant. This unexpected effect of bcl-2 expression results from the arrest of syncytial apoptosis, directly facilitating the cell-to cell transmission of HIV. In addition, bcl-2 expression is associated with enhanced HIV replication as determined by HIV type 1-specific Western blot (immunoblot) analysis. These results suggest that the inhibition of apoptosis is essential for this mode of viral transmission. PMID- 8676489 TI - Assemblons: nuclear structures defined by aggregation of immature capsids and some tegument proteins of herpes simplex virus 1. AB - In cells infected with herpes simplex virus 1 (HSV-1), the viral proteins ICP5 (infected-cell protein 5) and VP19c (the product of UL38) are associated with mature capsids, whereas the same proteins, along with ICP35, are components of immature capsids. Here we report that ICP35, ICP5, and UL38 (VP19c) coalesce at late times postinfection and form antigenically dense structures located at the periphery of nuclei, close to but not abutting nuclear membranes. These structures were formed in cells infected with a virus carrying a temperature sensitive mutation in the UL15 gene at nonpermissive temperatures. Since at these temperatures viral DNA is made but not packaged, these structures must contain the proteins for immature-capsid assembly and were therefore designated assemblons. These assemblons are located at the periphery of a diffuse structure composed of proteins involved in DNA synthesis. This structure overlaps only minimally with the assemblons. In contrast, tegument proteins were located in asymmetrically distributed structures also partially overlapping with assemblons but frequently located nearer to nuclear membranes. Of particular interest is the finding that the UL15 protein colocalized with the proteins associated with viral DNA synthesis rather than with assemblons, suggesting that the association with DNA may take place during its synthesis and precedes the involvement of this protein in packaging of the viral DNA into capsids. The formation of three different compartments consisting of proteins involved in viral DNA synthesis, the capsid proteins, and tegument proteins suggests that there exists a viral machinery which enables aggregation and coalescence of specific viral protein groups on the basis of their function. PMID- 8676490 TI - Direct interactions of coxsackievirus B3 with immune cells in the splenic compartment of mice susceptible or resistant to myocarditis. AB - In vitro replication of coxsackievirus B3 (CVB3) in cells of the immune system derived from uninfected adolescent A/J and C57BL/6J mice and replication of CVB3 in and association with immune cells from spleens of infected animals in vivo were assessed. Nonstimulated or mitogen-stimulated spleen cells were minimally permissive for viral replication during an 8-h period. Three days postinfection (p.i.), CVB3 RNA was localized in vivo to B cells and follicular dendritic cells of germinal centers in both A/J and C57BL/6J mice; however, extrafollicular localization was greater in C57BL/6J mice (P = 0.0054). Although the pattern of CVB3 RNA localization was different, the total load of infections virus (PFU per milligram of tissue) was not different. Splenic CVB3 titers (PFU per milligram of tissue) in both strains were maximal at day 3 or 4 p.i. and were back to baseline by day 7 p.i., with most infectious virus being non-cell associated. CVB3 titers (PFU per milligram of tissue) correlated directly with in situ hybridization positivity in splenic follicles and extrafollicular regions in both murine strains; however, follicular hybridization intensity was greater in A/J mice at day 5 p.i. (P = 0.021). Flow cytometric analysis demonstrated that 50.4% of total spleen cells positive for CVB3 antigen were B cells and 69.6% of positive splenic lymphocytes were B cells. Myocardial virus load in C57BL/6J mice was significantly lower than that in A/J mice at days 4 and 5 p.i. These data indicate that CVB3 replicates in murine splenocytes in vitro and in B cells and extrafollicular cells in vivo. PMID- 8676491 TI - A "humanized" green fluorescent protein cDNA adapted for high-level expression in mammalian cells. AB - We constructed gfph, a synthetic version of the jellyfish Aequorea victoria green fluorescent protein (gfp) cDNA that is adapted for high-level expression in mammalian cells, especially those of human origin. A total of 92 base substitutions were made in 88 codons in order to change the codon usage within the gfp10 coding sequence so that it was more appropriate for expression in mammalian cells. We also describe a series of versatile recombinant adeno associated virus and adenovirus vectors for delivery and expression of genes into mammalian cells and, using these vectors, demonstrate the efficient transduction and expression of the gfph gene in the human cell line 293 and also in vivo, within neurosensory cells of guinea pig eye. Cells infected with recombinant adeno-associated virus-GFPH can be readily sorted by fluorescence-activated cell sorting, suggesting that the newly designed gfph gene could be widely used as a reporter in many gene delivery technologies, including human gene therapy. PMID- 8676492 TI - Isolation and characterization of a Chinese hamster ovary mutant cell line with altered sensitivity to vaccinia virus killing. AB - The Chinese hamster ovary (CHO) cell line is nonpermissive for vaccinia virus, and translation of viral intermediate genes was reported to be blocked (A. Ramsey Ewing and B. Moss, Virology 206:984-993, 1995). However, cells are readily killed by vaccinia virus. A vaccinia virus-resistant CHO mutant, VV5-4, was isolated by retroviral insertional mutagenesis. Parental CHO cells, upon infection with vaccinia virus, die within 2 to 3 days, whereas VV5-4 cells preferentially survive this cytotoxic effect. The survival phenotype of VV5-4 is partial and in inverse correlation with the multiplicity of infection used. In addition, viral infection fails to shut off host protein synthesis in VV5-4. VV5-4 was used to study the relationship of progression of the virus life cycle and cell fate. We found that in parental CHO cells, vaccinia virus proceeds through expression of viral early genes, uncoating, viral DNA replication, and expression of intermediate and late promoters. In contrast, we detect only expression of early genes and uncoating in VV5-4 cells, whereas viral DNA replication appears to be blocked. Consistent with the cascade regulation model of viral gene expression, we detect little intermediate- and late-gene expression in VV5-4 cells. Since vaccinia virus is known to be cytolytic, isolation of this mutant therefore demonstrates a new mode of the cellular microenvironment that affects progression of the virus life cycle, resulting in a different cell fate. This process appears to be mediated by a general mechanism, since VV5-4 is also resistant to Shope fibroma virus and myxoma virus killing. On the other hand, VV5-4 remains sensitive to cowpox virus killing. To examine the mechanism of VV5-4 survival, we investigated whether apoptosis is involved. DNA laddering and staining of apoptotic nuclei with Hoechst 33258 were observed in both CHO and VV5-4 cells infected with vaccinia virus. We concluded that the cellular pathway, which blocks viral DNA replication and allows VV5-4 to survive, is independent of apoptosis. This mutant also provides evidence that an inductive signal for apoptosis upon vaccinia virus infection occurs prior to viral DNA replication. PMID- 8676493 TI - cis-acting elements in human immunodeficiency virus type 1 RNAs direct viral transcripts to distinct intranuclear locations. AB - Two distinct intranuclear locations were identified for alternatively spliced RNA transcripts expressed from the pNL4-3 infectious molecular clone of human immunodeficiency virus (HIV) type 1. Multiply spliced HIV RNA encoding tat was detected within the nucleus in large clusters; immunostaining and colocalization studies using laser-scanning confocal microscopy revealed that these structures contained the non-small nuclear ribonucleoprotein RNA processing factor, SC35. In contrast, unspliced gag RNA was detected in much smaller granules distributed throughout the nucleus, with little or no association with SC35-containing granules. Analyses of nuclear RNA expressed from recombinant plasmids encoding gag (pCMVgag-2) alone or tat (pCMVtat-2) alone revealed distributions corresponding to those obtained with pNL4-3, indicating that expression within the context of the HIV provirus was not required for the distinct RNA locations detected for these transcripts. The presence of unspliced gag RNA in small granules was confirmed in infections of H9 T-lymphocytic cells, indicating that gag localization was not restricted to transient expression systems. The intranuclear distribution of gag RNA was dependent on specific RNA sequences. Deletion of a portion of the gag gene of pCMVgag-2, containing a cis-repressing inhibitory region, resulted in redirection of unspliced gag RNA from small granules into large SC35-containing clusters. The addition of the Rev-responsive element, RRE, to the deleted pCMVgag-2 construct resulted in RNA transcripts which were no longer associated with SC35. We also identified a cellular intron, rabbit beta-globin-intervening sequence 2 (IVS-2) which, when introduced into pCMVgag-2, redirected unspliced gag RNA into SC35-containing granules and permitted rev-independent Gag expression. These findings suggest that redirecting intranuclear RNA localization may influence gene expression. Color micrographs from this article are available for view at http//128.231.216.2/lmmhome.htm. PMID- 8676494 TI - Murine coronavirus membrane fusion is blocked by modification of thiols buried within the spike protein. AB - The envelopes of murine hepatitis virus (MHV) particles are studded with glycoprotein spikes that function both to promote virion binding to its cellular receptor and to mediate virion-cell membrane fusion. In this study, the cysteine rich spikes were subjected to chemical modification to determine whether such structural alterations impact the virus entry process. Ellman reagent, a membrane impermeant oxidizing agent which reacts with exposed cysteine residues to effect covalent addition of large thionitrobenzoate moieties, was incubated at 37 degrees C with the JHM strain of MHV. Relative to untreated virus, 1 mM Ellman reagent reduced infectivity by 2 log(10) after 1 h. This level of inhibition was not observed at incubation temperatures below 21 degrees C, suggesting that virion surface proteins undergo thermal transitions that expose cysteine residues to modification by the reagent. Quantitative receptor binding and membrane fusion assays were developed and used to show that Ellman reagent specifically inhibited membrane fusion induced by the MHV JHM spike protein. However, this inhibition was strain specific, because the closely related MHV strain A59 was unaffected. To identify the basis for this strain specificity, spike cDNAs were prepared in which portions encoded either JHM or A59 residues. cDNAs were expressed with vaccinia virus vectors and tested for sensitivity to Ellman reagent in the fusion assays. The results revealed a correlation between the severity of inhibition mediated by Ellman reagent and the presence of a JHM-specific cysteine (Cys 1163). Thus, the presence of this cysteine increases the availability of spikes for a thiol modification that ultimately prevents fusion competence. PMID- 8676496 TI - Effects of modifying the tRNA(3Lys) anticodon on the initiation of human immunodeficiency virus type 1 reverse transcription. AB - tRNA(3Lys) is a primer for reverse transcription in human immunodeficiency virus type 1 (HIV-1), and the anticodon of tRNA(3Lys) has been implicated in playing a role in both its placement onto the HIV-1 genome and its interaction with HIV-1 reverse transcriptase (RT). In this work, the anticodon in a tRNA(3Lys) gene was changed from UUU to CUA (tRNA(3Lys)Su+) or, in addition, G-73 was altered to A (tRNA(3Lys)Su+G73A). COS-7 cells were transfected with either wild-type or mutant tRNA(3Lys) genes, and both the wild-type and mutant tRNA(3Lys) produced were purified by using immobilized tRNA-specific hybridization probes. Each mutant tRNA(3Lys) was tested for its ability to prime reverse transcription in vitro, either alone or in competition with wild-type tRNA(3Lys). Short RT extensions of wild-type and mutant tRNALys could be distinguished from each other by their different mobilities in one-dimensional single-stranded conformation polymorphism polyacrylamide gel electrophoresis. These reverse transcription products show that heat-annealed tRNA(3Lys)Su+ has the same ability as heat-annealed wild-type tRNA(3Lys) to prime RT and competes equally well with wild-type tRNA(3Lys) for priming RT. tRNA(3Lys)Su+G73A has 60% of the wild-type ability to prime RT but competes poorly with wild-type tRNA(3Lys) for priming RT. However, the priming abilities of wild-type and mutant tRNA(3) are quite different when in vivo-placed tRNA is examined. HIV-1 produced in COS cells transfected with a plasmid containing both the HIV-1 proviral DNA and DNA coding for tRNA(3Lys)Su+ contains both endogenous, cellular wild-type tRNA(3Lys) and mutant tRNA(3Lys). When total viral RNA is used as the source of primer tRNA placed onto the genomic RNA in vivo, only wild-type tRNA(3Lys) is used as a primer. If the total viral RNA is first heated and exposed to hybridizing conditions, then both the wild-type and mutant tRNA(3Lys) act as primers for RT. These results indicate that the tRNA(3Lys)Su+ packaged into the virions is unable to act as a primer for RT, and a model is proposed to explain the disparate results between heat-annealed and in vivo-placed primer tRNA. PMID- 8676495 TI - Selection of the bovine papillomavirus type 1 nucleotide 3225 3' splice site is regulated through an exonic splicing enhancer and its juxtaposed exonic splicing suppressor. AB - Alternative splicing is an important mechanism for the regulation of bovine papillomavirus type 1 (BPV-1) gene expression during the virus life cycle. However, one 3' splice site, located at nucleotide (nt) 3225, is used for the processing of most BPV-1 pre-mRNAs in BPV-1-transformed C127 cells and at early to intermediate times in productively infected warts. At late stages of the viral life cycle, an alternative 3' splice site at nt 3605 is used for the processing of the late pre-mRNA. In this study, we used in vitro splicing in HeLa cell nuclear extracts to identify cis elements which regulate BPV-1 3' splice site selection. Two purine-rich exonic splicing enhancers were identified downstream of nt 3225. These sequences, designated SE1 (nt 3256 to 3305) and SE2 (nt 3477 to 3526), were shown to strongly stimulate the splicing of a chimeric Drosophila doublesex pre-mRNA, which contains a weak 3' splice site. A BPV-1 late pre-mRNA containing the nt 3225 3' splice site but lacking both SE1 and SE2 was spliced poorly, indicating that this 3' splice site is inherently weak. Analysis of the 3' splice site suggested that this feature is due to both a nonconsensus branch point sequence and a suboptimal polypyrimidine tract. Addition of SE1 to the late pre-mRNA dramatically stimulated splicing, indicating that SE1 also functions as an exonic splicing enhancer in its normal context. However, a late pre-mRNA containing both SE1 and SE2 as well as the sequence in between was spliced inefficiently. Further mapping studies demonstrated that a 48-nt pyrimidine-rich region immediately downstream of SE1 was responsible for this suppression of splicing. Thus, these data suggest that selection of the BPV-1 nt 3225 3' splice site is regulated by both positive and negative exonic sequences. PMID- 8676497 TI - Characterization of the rubella virus nonstructural protease domain and its cleavage site. AB - The region of the rubella virus nonstructural open reading frame that contains the papain-like cysteine protease domain and its cleavage site was expressed with a Sindbis virus vector. Cys-1151 has previously been shown to be required for the activity of the protease (L. D. Marr, C.-Y. Wang, and T. K Frey, Virology 198:586 592, 1994). Here we show that His-1272 is also necessary for protease activity, consistent with the active site of the enzyme being composed of a catalytic dyad consisting of Cys-1151 and His-1272. By means of radiochemical amino acid sequencing, the site in the polyprotein cleaved by the nonstructural protease was found to follow Gly-1300 in the sequence Gly-1299-Gly-1300-Gly-1301. Mutagenesis studies demonstrated that change of Gly-1300 to alanine or valine abrogated cleavage. In contrast, Gly-1299 and Gly-1301 could be changed to alanine with retention of cleavage, but a change to valine abrogated cleavage. Coexpression of a construct that contains a cleavage site mutation (to serve as a protease) together with a construct that contains a protease mutation (to serve as a substrate) failed to reveal trans cleavage. Coexpression of wild-type constructs with protease-mutant constructs also failed to reveal trans cleavage, even after extended in vitro incubation following lysis. These results indicate that the protease functions only in cis, at least under the conditions tested. PMID- 8676498 TI - Cellular factors controlling the activity of woodchuck hepatitis virus enhancer II. AB - Woodchuck hepatitis virus (WHV) efficiently induces hepatocellular carcinoma in chronically infected hosts. A key step in hepatocarcinogenesis by WHV is insertional activation of the cellular N-myc gene by integrated viral DNA. WHV enhancer II (En II) is the major cis-acting element involved in this activation. Here we characterize this viral enhancer element and define the cellular factors involved in its activity. WHV En II activity is strongly liver specific and maps to an 88-nucleotide DNA segment (nucleotides 1772 to 1859) located 5' to the pregenomic RNA start site. Genetic analyses and electrophoretic mobility shift assays indicate that the enhancer contains three subregions important to its activity. The core elements of the enhancer are recognition sites for the liver enriched factors HNF1 and HNF4; together, these signals account for the bulk of En II activity as well as its strong liver specificity. Multimerization of either recognition site produced strong activity even in the absence of other En II sequences. 5' to these elements is a binding site for the ubiquitous Oct-1 transcription factor, which further augments enhancer activity ca. twofold. PMID- 8676499 TI - Prion protein PrPc interacts with molecular chaperones of the Hsp60 family. AB - Prions mediate the pathogenesis of certain neurodegenerative diseases, including bovine spongiform encephalopathy in cattle and Creutzfeldt-Jakob disease in humans. The prion particle consists mainly, if not entirely, of PrPSc, a posttranslationally modified isoform of the cellular host-encoded prion protein (PrPc). It has been suggested that additional cellular factors might be involved in the physiological function of PrPc and in the propagation of PrPSc. Here we employ a Saccharomyces cerevisiae two-hybrid screen to search for proteins which interact specifically with the Syrian golden hamster prion protein. Screening of a HeLa cDNA library identified heat shock protein 60 (Hsp60), a cellular chaperone as a major interactor for PrPc. The specificity of the interaction was confirmed in vitro for the recombinant proteins PrPc23-231 and rPrP27-30 fused to glutathione S-transferase with recombinant human Hsp60 as well as the bacterial GroEL. The interaction site for recombinant Hsp60 and GroEL proteins was mapped between amino acids 180 and 210 of the prion protein by screening with a set of recombinant PrPc fragments. The binding of Hsp60 and GroEL occurs within a region which contains parts of the putative alpha-helical domains H3 and H4 of the prion protein. PMID- 8676500 TI - The polymerase-like core of brome mosaic virus 2a protein, lacking a region interacting with viral 1a protein in vitro, maintains activity and 1a selectivity in RNA replication. AB - Brome mosaic virus (BMV), a member of the alphavirus-like super-family of positive-strand RNA viruses, encodes two proteins required for viral RNA replication: 1a and 2a. 1a contains m7G methyltransferase- and helicase-like domains, while 2a contains a polymerase (pol)-like core flanked by N- and C terminal extensions. Genetic studies show that BMV RNA replication requires 1a-2a compatibility implying direct or indirect 1a-2a interaction in vivo. In vitro, la interacts with the N-terminal 125-amino-acid segment of 2a preceding the pol-like core, and prior deletion studies suggested that this 2a segment was essential for RNA replication. We have now used protein fusions and deletions to explore possible parallels between noncovalent 1a-2a interaction and covalent fusion of similar protein domains in tobacco mosaic virus and to see whether the N-terminal 2a-1a interaction was the primary basis for 1a-2a compatibility in vivo. We found that 2a can function as part of a tobacco mosaic virus-like 1a-2a fusion and that a 2a segment (amino acids 162 to 697) comprising the pol-like core was sufficient to provide 2a functions in such a fusion. Unexpectedly, the unfused 2a core segment also supported RNA replication when it and wild-type la were expressed as separate proteins. Moreover, in gene reassortant experiments with the related cowpea chlorotic mottle virus, the unfused 2a core segment showed the same 1a compatibility requirements as did wild-type BMV 2a. Thus, the pol-like core of 2a must interact with la in a way that is selective and essential for RNA synthesis, and 1a-2a interactions are more complex than the single, previously mapped interaction of the N-terminal 2a segment with 1a. PMID- 8676501 TI - Ty3 integrase mutants defective in reverse transcription or 3'-end processing of extrachromosomal Ty3 DNA. AB - Ty3, a retroviruslike element in Saccharomyces cerevisiae, encodes an integrase (IN) which is essential for position-specific transposition. The Ty3 integrase contains the highly conserved His-Xaa(3-7)-His-Xaa(23-32)-Cys-Xaa(2)-Cys and Asp, Asp-Xaa(35)-Glu [D,D(35)E] motifs found in retroviral integrases. Mutations were introduced into the coding region for the Ty3 integrase to determine the effects in vivo of changes in conserved residues of the putative catalytic triad D,D(35)E and the nonconserved carboxyl-terminal region. Ty3 viruslike particles were found to be associated with significant amounts of linear DNA of the approximate size expected for a full-length reverse transcription product and with plus-strand strong-stop DNA. The full-length, preintegrative DNA has at each 3' end 2 bp that are removed prior to or during integration. Such 3'-end processing has not been observed for other retroviruslike elements. A mutation at either D-225 or E-261 of the Ty3 integrase blocked transposition and prevented processing of the 3' ends of Ty3 DNA in vivo, suggesting that the D,D(35)E region is part of the catalytic domain of Ty3 IN. Carboxyl-terminal deletions of integrase caused a dramatic reduction in the amount of Ty3 DNA in vivo and a decrease in reverse transcriptase activity in vitro but did not affect the apparent size or amount of the 55-kDa reverse transcriptase in viruslike particles. The 115-kDa viruslike particle protein, previously shown to react with antibodies to Ty3 integrase, was shown to be a reverse transcriptase-IN fusion protein. These results are consistent with a role for the integrase domain either in proper folding of reverse transcriptase or as part of a heterodimeric reverse transcriptase molecule. PMID- 8676502 TI - An enhancer of recombination in polyomavirus DNA. AB - Previous work from this laboratory has indicated that intramolecular homologous recombination of polyomavirus (Py) DNA is dependent upon promoter structure or function. In this report, we demonstrate that Py DNA contains not two but three binding sites for transcription factor YY1, all located on the late side of viral origin of replication (ori) and the third well within the VP1 coding sequence. This third site (Y3), which may or may not play a role in transcription regulation, is immediately adjacent to a previously described recombination hot spot (S1/S2). We found that Py replicons carrying an altered Y3 site recombined in a manner suggesting partial inactivation of the S1/S hot spot. Point mutations precluding the binding of YY1 to Y3 in vitro depressed hot spot activity in vivo; however, of the two reciprocal products reflecting recombination at this spot, only that carrying the mutated Y3 site arose at a reduced rate. These results are interpreted in light of a model assuming that recombination occurs within a transcriptionally active viral chromatin tethered to the nuclear matrix by YY1. PMID- 8676503 TI - Phenotypic changes in Langerhans' cells after infection with arboviruses: a role in the immune response to epidermally acquired viral infection? AB - The role of Langerhans cells (LC) in the initiation of an immune response to a viral infection remains unclear. In vivo epidermal infection with the arboviruses West Nile virus and Semliki Forest virus significantly increased the expression of major histocompatibility complex class II antigens, CD54, and CD80 on LC. Thus, during an epidermally acquired viral infection, local LC appear to mature to a phenotype approximating that of lymphoid dendritic cells. This change may be important in the activation of naive T cells and the subsequent clearance of viral infection. PMID- 8676504 TI - Proteins encoded by open reading frames 3 and 4 of the genome of Lelystad virus (Arteriviridae) are structural proteins of the virion. AB - Four structural proteins of Lelystad virus (Arteriviridae) were recognized by monoclonal antibodies in a Western immunoblotting experiment with purified virus. In addition to the 18-kDa integral membrane protein M and the 15-kDa nucleocapsid protein N, two new structural proteins with molecular masses of 45 to 50 kDa and 31 to 35 kDa, respectively, were detected. Monoclonal antibodies that recognized proteins of 45 to 50 kDa and 31 to 35 kDa immunoprecipitated similar proteins expressed from open reading frames (ORFs) 3 and 4 in baculovirus recombinants, respectively. Therefore, the 45- to 50-kDa protein is encoded by ORF3 and the 31- to 35-kDa protein is encoded by ORF4. Peptide-N-glycosidase F digestion of purified virus reduced the 45- to 50-kDa and 31- to 35-kDa proteins to core proteins of 29 and 16 kDa, respectively, which indicates N glycosylation of these proteins in the virion. Monoclonal antibodies specific for the 31- to 35-kDa protein neutralized Lelystad virus, which indicates that at least part of this protein is exposed at the virion surface. We propose that the 45- to 50-kDa and 31- to 35-kDa structural proteins of Lelystad virus be named GP3 and GP4, to reflect their glycosylation and the ORFs from which they are expressed. Antibodies specific for GP3 and GP4 were detected by a Western immunoblotting assay in swine serum after an infection with Lelystad virus. PMID- 8676505 TI - The transmissible gastroenteritis coronavirus contains a spherical core shell consisting of M and N proteins. AB - Coronaviruses are enveloped RNA viruses involved in a variety of pathologies that affect animals and humans. Existing structural models of these viruses propose a helical nucleocapsid under the virion envelope as the unique internal structure. In the present work, we have analyzed the structure of the transmissible gastroenteritis coronavirus. The definition of its organization supports a new structural model for coronaviruses, since a spherical, probably icosahedral, internal core has been characterized. Disruption of these cores induces the release of N-protein-containing helical nucleocapsids. Immunogold mapping and protein analysis of purified cores showed that they consist of M and N proteins, M being the main core shell component. This surprising finding, together with the fact that M protein molecules are also located in the virion envelope, indicates that a reconsideration of the assembly and maturation of coronaviruses, as well as a study of potential M-protein subclasses, is needed. PMID- 8676506 TI - Sequences within the VP6 molecule of bluetongue virus that determine cytoplasmic and nuclear targeting of the protein. AB - Genome segment 9 of bluetongue virus serotype 10 encodes the minor protein VP6. The protein is abundant with basic residues particularly in two regions of the carboxy half of the molecule. A series of amino- and carboxy-terminal deletion mutants was expressed in mammalian cells by using a vaccinia virus T7 polymerase driven transient expression system, and the intracellular fate of the products was monitored by both immunofluorescence staining and cell fractionation techniques. Data obtained indicated clearly that VP6 has nuclear transportation signals which may be correlated with positively charged domains of the molecule. In the intact molecule, though, these signals are masked and the protein is retained in the cytoplasm. The biochemical and immunofluorescence data obtained indicate that sequences in the region of residues 33 to 80 of the 328-amino acid protein are required for the retention of VP6 within the cell cytoplasm while amino acids 303 to 308 in the carboxy-terminal half of the molecule appear to possess nuclear localization capabilities. PMID- 8676507 TI - The Rep68 protein of adeno-associated virus type 2 stimulates expression of the platelet-derived growth factor B c-sis proto-oncogene. AB - Rep68 protein, encoded by adeno-associated virus type 2 (AAV), has been previously shown to bind to specific sequences within the viral genome and in human chromosome 19. The effect of AAV Rep protein on human cellular genes is of interest because AAV is being developed as a gene therapy vector. We have identified sequences related to the Rep recognition sequence in the AAV P5 promoter in or near the c-sis proto-oncogene and the genes coding for a hepatocyte glucose transporter, alpha-A-crystallin, and carcinoma marker GA733-1. The ability of Rep68 to bind to these sites was established by gel shift assays, and the effect of Rep68 on the expression of these genes was tested by semiquantitative reverse transcriptase PCR. Rep68 enhances the expression of the c-sis proto-oncogene, which codes for the B polypeptide of platelet-derived growth factor, a multifunctional growth factor that is involved in embryonic development, tissue regeneration, osteogenesis, fibrosis, atherosclerosis, and neoplasia. PMID- 8676508 TI - Human CD4+ T-cell recognition of influenza A virus hemagglutinin after subunit vaccination. AB - We have examined human CD4+ T-cell recognition of influenza A/Beijing/32/92 (H3N2) virus hemagglutinin following influenza virus HANA subunit vaccination. CD4+ T-cell repertoires were dominated by recognition of epitopes located in conserved regions of the molecule, in a major histocompatibility complex class II haplotype-dependent manner, analogous to that observed following natural infection. PMID- 8676510 TI - Synthesis of potato virus X RNAs by membrane-containing extracts. AB - Membrane-containing extracts isolated from tobacco plants infected with the plus strand RNA virus, potato virus X (PVX), supported synthesis of four major, high molecular-weight PVX RNA products (R1 to R4). Nuclease digestion and hybridization studies indicated that R1 and R2 are a mixture of partially single stranded replicative intermediates and double-stranded replicative forms. R3 and R4 are double-stranded products containing sequences typical of the two major PVX subgenomic RNAs. The newly synthesized RNAs were demonstrated to have predominantly plus-strand polarity. Synthesis of these products was remarkably stable in the presence of ionic detergents. PMID- 8676509 TI - Two amino acid residues confer type specificity to a neutralizing, conformationally dependent epitope on human papillomavirus type 11. AB - Characterization of virus binding by neutralizing antibodies is important both in understanding early events in viral infectivity and in development of vaccines. Neutralizing monoclonal antibodies (MAbs) to human papillomavirus type 11 (HPV11) have been described, but mapping the binding site has been difficult because of the conformational nature of key type-specific neutralization epitopes on the L1 coat protein. We have determined those residues of the L1 protein of HPV11 which confer type specificity to the binding of HPV11-neutralizing MAbs. Binding of three HPV11-specific neutralizing MAbs could be redirected to HPV6 L1 virus-like particles in which as few as two substitutions of corresponding amino acid residues from HPV11 L1 have been made, thus demonstrating the importance of these residues to MAb binding through the transfer of a conformationally dependent epitope. In addition, a fourth neutralizing MAb could be distinguished from the other neutralizing MAbs in terms of the amino acid residues which affect binding, suggesting the possibility that it neutralizes HPV11 through a different mechanism. PMID- 8676512 TI - Efficient generation of recombinant adenovirus vectors by homologous recombination in Escherichia coli. AB - Despite recent technical improvements, the construction of recombinant adenovirus vectors remains a time-consuming procedure which requires extensive manipulations of the viral genome in both Escherichia coli and eukaryotic cells. This report describes a novel system based on the cloning and manipulation of the full-length adenovirus genome as a stable plasmid in E. coli, by using the bacterial homologous recombination machinery. The efficiency and flexibility of the method are illustrated by the cloning of the wild-type adenovirus type 5 genome, the insertion of a constitutive promoter upstream from the E3 region, the replacement of the E1 region by an exogenous expression cassette, and the deletion of the E1 region. All recombinant viral DNAS were shown to be fully infectious in permissive cells, and the modified E3 region or the inserted foreign gene was correctly expressed in the infected cells. PMID- 8676511 TI - A bispecific antibody recognizing influenza A virus M2 protein redirects effector cells to inhibit virus replication in vitro. AB - Bispecific antibodies can be used to redirect cytotoxic T cells to kill virus infected cells, overriding the need for major histocompatibility complex restriction. We produced a bispecific antibody (3F12) which binds influenza virus M2 protein and the T-cell receptor and can redirect staphylococcal enterotoxin B activated T cells to kill influenza virus-infected cells and inhibit virus replication in vitro. PMID- 8676513 TI - Infection of class II-deficient mice by the DA strain of Theiler's virus. AB - The DA strain of Theiler's virus causes, in susceptible strains of mice, a persistent infection of the white matter of the spinal cord accompanied by chronic inflammation and primary demyelination. In resistant strains, including all H-2b strains, mice clear the infection after 1 to 2 weeks. We inoculated RHAbetao/o mice, an H-2b strain which does not express class II molecules. We found that they are susceptible to persistent infection and that they develop foci of chronic inflammation with demyelination. However, these foci are smaller and contain fewer demyelinated axons than those observed in susceptible SJL/J or beta2m-/- mice. PMID- 8676514 TI - Evidence that the nuclease activities associated with the herpes simplex type 1 DNA polymerase are due to the 3'-5' exonuclease. AB - We investigated nuclease activities associated with the catalytic subunit of herpes simplex virus type 1 DNA polymerase. We confirm that a 3'-5' exonuclease copurifies with this enzyme. Previous reports suggested that a 5' DNase was intrinsic to the polymerase. Our preparation lacks such activity. PMID- 8676515 TI - Characterization of a soluble stable human cytomegalovirus protease and inhibition by M-site peptide mimics. AB - The human cytomegalovirus (HCMV) protease is a potential target for antiviral chemotherapeutics; however, autoprocessing at internal sites, particularly at positions 143 and 209, hinders the production of large quantities of stable enzyme for either screening or structural studies. Using peptides encompassing the sequence of the natural M-site substrate (P5-P5', GVVNA/SCRLA), we previously demonstrated that substitution of glycine for valine at the P3 position in the substrate abrogates processing by the recombinant protease in vitro. We now demonstrate that introduction of the V-to-G substitution in the P3 positions of the two major internal processing sites, positions 143 and 209, in the mature HCMV protease renders the enzyme stable to autoprocessing. When expressed in Escherichia coli, the doubly substituted protease was produced almost exclusively as the 30-kDa full-length protein. The full-length V141G, V207G (V-to-G changes at positions 141 and 207) protease was purified as a soluble protein by a simple two-step procedure, ammonium sulfate precipitation followed by DEAE ion-exchange chromatography, resulting in 10 to 15 mg of greater than 95% pure enzyme per liter. The stabilized enzyme was characterized kinetically and was indistinguishable from the wild-type recombinant protease, exhibiting Km and catalytic constant values of 0.578 mM and 13.18/min, respectively, for the maturation site (M-site) peptide substrate, GVVNASCRLARR (underlined residues indicate additions to or substitutions from peptides derived from the wild-type substrate). This enzyme was also used to perform inhibition studies with a series of truncated and/or substituted maturation site peptides. Short nonsubstrate M site-derived peptides were demonstrated to be competitive inhibitors of cleavage in vitro, and these analyses defined amino acids VVNA, P4 through P1 in the substrate, as the minimal substrate binding and recognition sequence for the HCMV protease. PMID- 8676516 TI - Two separate envelope regions influence induction of brain disease by a polytropic murine retrovirus (FMCF98). AB - The major determinants involved in neurological disease induction by polytropic murine leukemia virus FMCF98 are encoded by the envelope gene. To map these determinants further, we produced four chimeras which contained neurovirulent FMCF98 envelope sequences combined with envelope sequences from the closely related nonneurovirulent polytropic virus FMCF54. Surprisingly, two chimeric viruses containing completely separate envelope regions from FMCF98 could both induce neurological disease. Clinical signs caused by both neurovirulent chimeras appeared to be indistinguishable from those caused by FMCF98, although the incubation periods were longer. One neurovirulence determinant mapped to the N terminal portion of gp7O, which contains the VRA and VRB receptor-binding regions, while the other determinant mapped downstream of both of the variable regions. Western blot (immunoblot) analyses and immunohistochemical staining of tissue sections indicated that the variations in neurovirulence of these viruses could not be explained by differences in either the quantitative level or the location of virus expression in the brain. PMID- 8676518 TI - Increased polymerase fidelity of E89G, a nucleoside analog-resistant variant of human immunodeficiency virus type 1 reverse transcriptase. AB - Nucleoside analog resistance in human immunodeficiency virus type 1 results from mutations in reverse transcriptase (RT) that allow the enzyme to discriminate against such analogs. To evaluate the possible impact of such mutations on the ability of human immunodeficiency virus RT to selectively incorporate Watson Crick base-paired deoxynucleotide triphosphates (dNTPs) over incorrectly paired dNTPs, we have measured the fidelity of dNTP insertion by the E89G variant of RT in in vitro reaction mixtures containing synthetic template primers. The E89G RT was previously shown to be resistant to several ddNTPs and to phosphonoformic acid. Our results show that the mutant enzyme displays a lower level of efficiency of misinsertion than did the wild-type RT for every mispair tested (ranging from 2- to 17-fold. PMID- 8676517 TI - Identification of a naturally occurring recombinant Epstein-Barr virus isolate from New Guinea that encodes both type 1 and type 2 nuclear antigen sequences. AB - In this report we describe an Epstein-Barr virus isolate, derived from the peripheral blood lymphocytes of a healthy adult from Papua New Guinea, that is a recombinant of the two major Epstein-Barr virus types, encoding type 1 Epstein Barr nuclear antigen 2 (EBNA2) sequences, and type 2 EBNA3, EBNA4, and EBNA6 sequences. PMID- 8676519 TI - C/EBPbeta is a negative regulator of human papillomavirus type 11 in keratinocytes. AB - We have evaluated the impact of the CCAAT enhancer-binding protein (C/EBP) transcription factors on human papillomavirus type 11 (HPV11). C/EBPbeta is in nuclei of cultured foreskin keratinocytes and binds its consensus sequence in HPV11 DNA. We have used the novel approach of depleting the availability of C/EBPs in vivo using nuclease-resistant oligomers containing C/EBP DNA binding sites. In cultured foreskin keratinocytes containing replicating HPV11 DNA, levels of both HPV11 transcripts and HPV DNA increase after treatment with oligomers; containing the C/EBPbeta DNA binding motif. These results indicate that C/EBPbeta is a repressor for HPV11 in keratinocytes. PMID- 8676520 TI - The role of interleukin-10 in the inhibition of T-cell proliferation and apoptosis mediated by parainfluenza virus type 3. AB - We have previously demonstrated that parainfluenza virus type 3 (PIV3), a significant respiratory pathogen, can markedly inhibit T-cell function in vitro. We now report that the virus potently induces interleukin-10 (IL-10) production by peripheral blood mononuclear cells. The IL-10 produced contributes to viral inhibition of T-cell proliferation and protects T cells from PIV3-mediated apoptosis. These findings suggest that IL-10 is likely to play an important immunoregulatory role in PIV3 infections. PMID- 8676521 TI - Epstein-Barr virus nuclear antigen 2 and latent membrane protein independently transactivate p53 through induction of NF-kappaB activity. AB - B-cell immortalization by Epstein-Barr virus (EBV) is dependent on permanent control of the cellular processes which normally regulate cell division and apoptosis, functions possessed by p53 in a number of normal cell types. In studies initiated to evaluate relationships between EBV latent genes and p53, p53 levels were found to increase approximately 10-fold 4 to 5 days after EBV infection of purified resting human B cells; the induced p53 was transcriptionally active. Latent membrane protein 1 and, to a lesser extent, EBV nuclear antigen 2 mediated the increase in p53 levels via activation of the NF kappaB transcription factor. PMID- 8676522 TI - Sequence determinants of 3A-mediated resistance to enviroxime in rhinoviruses and enteroviruses. AB - Using site-directed mutagenesis of the 3A coding region of rhinovirus 14, we have expanded our analysis of resistance to enviroxime. We have observed that high and low levels of drug resistance involve two domains within 3A and that the amino acid at position 30 is critical in determining resistance. PMID- 8676524 TI - Three retroviral sequences in amphibians are distinct from those in mammals and birds. AB - We isolated and characterized three endogenous retroviral fragments from the dart poison frog Dendrobates ventrimaculatus. These are the first retroviral sequences to be identified in amphibians, and consequently retroviruses have now been found in each of the five major vertebrate classes. Comparison of the amphibian retroviral fragments, termed DevI, DevII, and DevIII, with mammalian and avian isolates revealed significant differences between their nucleotide sequences. This suggested that they were only distantly related to the seven currently recognized retroviral genera. Additional analysis by phylogeny reconstruction showed that the amphibian retroviral fragments were approximately equally related to the Moloney leukemia-related viruses, the spumaviruses, and walleye dermal sarcoma virus. Hybridization experiments revealed that viruses closely related to DevI, DevII, and DevIII do not appear to be widespread in other vertebrates and that DevI, DevII, and DevIII are all present at high copy numbers within their amphibian hosts, typically at over 250 copies per genome. The viruses described here, along with two others which have recently been found in a fish and a reptile, indicate that there may be some major differences in the retroviruses harbored by different vertebrate classes. This suggests that further characterization of retroviruses of fish, reptiles, and amphibians will help in understanding the evolution of the whole retroviral family and may well lead to the discovery of retroviruses with novel biological properties. PMID- 8676523 TI - An African swine fever virus Bc1-2 homolog, 5-HL, suppresses apoptotic cell death. AB - Here, we show that the African swine fever virus 5-HL gene is a highly conserved viral gene and contains all known protein domains associated with Bcl-2 activity, including those involved with dimerization, mediating cell death, and protein binding functions, and that its protein product, p21, suppresses apoptotic cell death in the mammalian lymphoid cell line FL5.12. Thus, 5-HL is a true functional viral member of the Bcl-2 gene family. PMID- 8676526 TI - Bone loss and oral state in patients on home parenteral nutrition. AB - BACKGROUND: The purpose was to analyze changes in the mandible and the forearm bone mineral content and oral state in patients on home parenteral nutrition due to short bowel syndrome in relation to the bone mineral values and oral findings in a normal population. METHODS: The bone mineral content was measured by dual photon absorptiometry and the dental and periodontal state were studied in 15 adults patients (12 women, and 3 men, aged 26 to 65 years). All patients were on free oral intake as a supplement to the parenteral nutrition. RESULTS: Forty seven percent of the patients (2 males, 2 young and 3 elderly females) showed mandibular osteoporosis (Z-scores < -2.00), and all young females showed Z-scores < 0. Moreover, 34% of the patients showed osteoporosis in the forearm bones (Z scores < -2.00) and also radiographic signs of osteoporotic fractures of the columna. The dental and the periodontal state in the patients did not differ clearly from that of the normal Danish population of the same age. CONCLUSIONS: Such patients seem to have a high risk of developing systemic osteoporosis, including the jaws, but apparently do not show a higher risk for deterioration of the dental or periodontal state than age-matching normals from the same population. PMID- 8676525 TI - Inhibition of human immunodeficiency virus type 1 replication is enhanced by a combination of transdominant Tat and Rev proteins. AB - Mutation of either of two critical human immunodeficiency virus type 1 (HIV-1) regulatory proteins, Tat and Rev, results in marked defects in viral replication. Thus, inhibition of the function of one or both of these proteins can significantly inhibit viral growth. In the present study, we constructed a novel transdominant Tat mutant protein and compared its efficiency in inhibiting HIV-1 replication with that of transdominant mutant Rev M10 when these proteins were stably expressed either alone or in combination in T-lymphocyte cell lines. The transdominant Tat mutant protein alone resulted in a modest inhibition of HIV replication, but it was able to enhance the ability of the M10 Rev mutant protein to inhibit HIV-1 replication. These results suggest a possible synergistic effect of these transdominant mutant proteins in inhibiting HIV-1 replication. PMID- 8676528 TI - Case management in home total parenteral nutrition: a cost-identification analysis. AB - BACKGROUND: Home parenteral nutrition (HPN) requires intensive medical case management by practitioners with expertise in the provision of nutrition support. There is expenditure of considerable time and resources for management of these patients not covered by any of the traditional reimbursement mechanisms. The costs associated with this unreimbursed input and follow-up are most often borne by the Nutrition Support Team or individual practitioners. Reimbursement by home care agencies to physicians for management of patients after discharge cannot be done because this may be construed as a "kick-back" for referral of patients to particular home care agencies. METHODS: Time and costs associated with management of HPN patients after discharge from the hospital were assessed using a cost identification analysis of 24 different factors. Daily activity logs were kept by the Nutrition Support Team members over a 2-week period. Costs of space and furnishings were calculated. RESULTS: On average, a total of 25 h/d was spent by members of the Nutrition Support Team on our HPN patients. Variable activities accounted for 5640.1 hours of time with fixed support at 890.3 hours. This computes to a total annual personnel cost of $168,482 ($1982 per patient). If costs of furnishings and space are also included, the overall cost of all resources was $175,989 per year or $2070 per patient. CONCLUSION: Significant and currently nonreimbursed costs are involved in HPN patient management. These costs are most often absorbed by the Nutrition Support Team and should be considered when evaluating total costs of HPN. PMID- 8676527 TI - An evaluation of the safety of mixed micelles in healthy subjects. AB - BACKGROUND: Fat and water soluble vitamins are an essential part of i.v. nutrition (IVN). However, they are unstable in solution and may adhere to the bags and tubing containing the IVN. This study has examined the safety and side effect profile of mixed micelles (mixed bile-salt lecithin micelles) used to solubilize water and fat soluble vitamins for i.v. administration. METHODS: Two groups of six healthy male subjects received either placebo or mixed micelles daily for 5 days by i.v. infusion in a randomized crossover design with a 9-day washout period separating the two treatment periods. RESULTS: Infusion of mixed micelles resulted in a significant increase in serum glycocholic acid from a median of 26.5 micrograms/dL (interquartile range 18 to 38) to 115 micrograms/dL (70 to 155) postinfusion. Glycocholic acid may have a lytic effect on cell membranes; however, in this study there was no evidence of hemolysis or increase in serum transaminases during mixed micelle infusion. There was no increase in reported side effects during mixed micelle infusion compared with placebo. CONCLUSION: Mixed micelles can be used safely for the solubilization of fat- and water-soluble vitamins and drugs that are to administered by i.v. injection. PMID- 8676529 TI - Glucose response to discontinuation of parenteral nutrition in patients less than 3 years of age. AB - BACKGROUND: The effects of abrupt discontinuation and tapering of total parenteral nutrition (TPN) on glucose concentration were compared in patients < 3 years of age. METHODS: Serial glucose concentrations were measured over 120 minutes after abrupt discontinuation as compared with tapering (decreasing infusion rate by 50% for 1 hour before discontinuation). Serial insulin concentrations were measured after abrupt discontinuation. RESULTS: There was a significantly greater decrease in glucose concentration from baseline at 30 minutes after abrupt discontinuation as compared with tapering. Fifty-five percent (6/11) of the patients developed hypoglycemia (glucose concentration < 40 mg/dL) after abrupt discontinuation. Age, glucose infusion rate, and serum insulin concentrations were not predictive of the development of hypoglycemia. The tapering regimen did not prevent hypoglycemia, which developed in 20% (2/10). CONCLUSION: The high incidence of hypoglycemia after TPN discontinuation in children < 3 years of age requires monitoring of serum glucose concentration when initiating intermittent TPN until tolerance is documented. PMID- 8676530 TI - Neurologic symptoms due to possible chromium deficiency in long-term parenteral nutrition that closely mimic metronidazole-induced syndromes. AB - BACKGROUND: We previously described a patient on home parenteral nutrition (HPN) who developed glucose intolerance and neuropathy that only responded to an infusion of chromium. A patient on HPN who had neuropathy and glucose intolerance was studied. He was also on metronidazole, which could have caused the neuropathy, but the symptoms and signs persisted. METHODS: Baseline clinical examination, nerve conduction studies, serum vitamin and trace element levels, and glucose tolerance were measured. Then, 250 micrograms of trivalent chromium as the chloride salt was infused daily for 2 weeks. The above studies were repeated. RESULTS: The patient at baseline had peripheral neuropathy of the axonal type and was glucose intolerant. Serum chromium was raised in this patient above the reference range. Despite raised serum levels, the infusion of chromium resulted in clinical remission that was marked 4 days after starting the infusion. Normalization of nerve conduction also occurred within 3 weeks of the initial study. CONCLUSIONS: Neuropathy and glucose intolerance may occur despite increased serum chromium levels and respond to chromium infusion. The previous use of drugs such as metronidazole should not exclude chromium as a potential treatment for neuropathy in HPN patients. PMID- 8676531 TI - Isocaloric glutamine-free diet and the morphology and function of rat small intestine. AB - BACKGROUND: The importance of L-glutamine as metabolic fuel for enterocytes and its role in prevention of mucosal atrophy during total parenteral nutrition is well documented. No data are available to date that document whether a glutamine free complete enteral diet, requiring full energy expenditure for hydrolysis and absorption, is associated with changes in the morphology and function of the small intestine. Our aim was to examine the effect of such a diet during a 4-week period on the morphology and function of the small intestine of rats. METHODS: Three isocaloric solid rat food, containing 0%, 4%, and 8% of glutamate, respectively, were fed to three groups of rats. On the 7th and 28th days the morphology of the jejunum, the subcellular structure of enterocytes on transmission electron microscopy, enzyme activities, blood, and muscle glutamine were examined and compared in the three groups. RESULTS: The rats on the glutamine-free diet had significantly lower mucosal wet weight, protein and DNA content, and number of intraepithelial lymphocytes on the 7th day, whereas the number of mitoses in the Lieberkuhn's crypts was significantly less on the 28th day. The height of the enterocytes and villi was 20% higher on average in the glutamine-free group. Electron microscopy revealed either early (swelling of cristae) or terminal (swelling of matrix) mitochondrial degenerative changes, homogenization of apical cytoplasm, and degeneration and fragmentation of microvilli with loss of their rootlets. The Na+, K(+)-ATPase activity was markedly decreased in the glutamine-free group compared with that of the other groups, most likely because of a diminished energy supply. Among brush border membrane enzymes, lactase activity decreased markedly (p < .05) in the first week. The glutamine-free diet resulted in an increase of the lung glutamine synthetase activity and decrease in muscle glutamine content by the 28th day of the diet. CONCLUSIONS: Our study shows for the first time that a complete enteral diet, deficient only in glutamine, is associated with significant early morphologic and functional changes in the small intestine. The precise effect on intracellular events and the time of onset of these changes needs to be clarified in the future. PMID- 8676532 TI - Muscle protein synthesis rate decreases 24 hours after abdominal surgery irrespective of total parenteral nutrition. AB - BACKGROUND: Muscle protein synthesis rate is known to decrease postoperatively as a part of the catabolic response to trauma. Conventional total parenteral nutrition (TPN) in the postoperative period does not seem to counteract the decrease in protein synthesis. However, it is still unclear if ongoing TPN given continuously after surgery would inhibit this fall in muscle protein synthesis. METHODS: The rate of protein synthesis in skeletal muscle was determined before and 24 hours after open cholecystectomy, used as a standardized human model of trauma. Patients (n = 14) were randomized to receive either TPN continuously throughout the postoperative period or saline as postoperative fluid therapy. The protein synthesis rate was calculated from the increase in enrichment of labeled phenylalanine in protein after an IV flooding dose of [2H5] phenylalanine, 45 mg/kg body weight. RESULTS: The fractional synthesis rate decreased by 31% from 1.74 +/- 0.13% to 1.15 +/- 0.10% per 24 hours in the saline group (p < .02) and by 23% from 1.59 +/- 0.10% to 1.22 +/- 0.07% per 24 hours in the group receiving TPN (p < .01), showing no significant difference between the two groups. CONCLUSION: A continuous and ongoing infusion of conventional TPN started immediately after surgery did not counteract the obligatory decline of muscle protein synthesis, observed 24 hours postoperatively. PMID- 8676533 TI - Effects of xylitol on urea synthesis in normal humans: relation to glucagon. AB - BACKGROUND: Xylitol exerts a nitrogen-sparing effect in stress catabolic states with hyperglucagonemia, but the mechanism(s) is unknown. We examined the effects of xylitol on urea synthesis during physiologic glucagon concentrations and during hyperglucagonemia. METHODS: Urea synthesis was measured independently of blood amino acid concentration by means of functional hepatic nitrogen clearance (FHNC) (ie, the linear slope of the relation between urea synthesis rate and blood alpha-amino nitrogen concentration during infusion of alanine). FHNC was measured on four separate occasions in each of seven healthy subjects: during constant infusion of alanine alone, alanine superimposed on a constant infusion of xylitol (blood xylitol 1 mmol/L), alanine superimposed on infusion of glucagon, and alanine superimposed on infusions of xylitol and glucagon. RESULTS: During alanine infusion alone, plasma glucagon rose to -170 ng/L, and FHNC was (mean +/- sem) 27.9 +/- 1.3 L/h. Xylitol did not affect plasma glucagon and only moderately reduced FHNC to 24.3 +/- 1.0 L/h (p < .05). Glucagon infusion increased plasma glucagon to -450 ng/L and FHNC twofold to 50.9 +/- 6.2 L/h; this increase was totally prevented by the addition of xylitol that reduced FHNC to 27.4 +/- 2.6 L/h (p < .01). CONCLUSIONS: The results show that xylitol only inhibited FHNC minimally during spontaneous glucagon levels. In contrast, xylitol completely inhibits the increase in FHNC by glucagon. This suggests that the mechanism whereby xylitol reduces nitrogen loss in stress catabolic conditions with hyperglucagonemia involves an effect on liver metabolism. The mechanism is unknown but may be related to depletion of hepatocyte adenine nucleotides. PMID- 8676535 TI - Duodenojejunal motility after oral and enteral nutrition in humans: a comparative study. AB - BACKGROUND: Small bowel motility during enteral nutrition (EN) remains poorly known. Our aim was to compare, in six healthy volunteers, the duodenojejunal motor patterns after a 750-kcal meal either ingested or infused intraduodenally at two different infusion rates: 2 kcal/min for 6 hours (6-hour EN) or 1 kcal/min for 12 hours (12-hour EN). METHODS: In each volunteer, the three manometric studies were carried out in a random order with an interval of > or = 1 week between each recording. Number of phase III (PIIIs), their characteristics, number of waves (NW), and area under the curve (AUC) were determined. RESULTS: PIIIs were interrupted by each type of nutrition in every volunteer. In five of six during 6-hour EN and in six of six during 12-hour EN, the first PIII returned before the end of EN. The mean duration of the fed pattern was similar in the three studies. During the interruption of PIIIs after oral meal, duodenojejunal motility was characterized by uninterrupted random contractions. By contrast, in four of six during the 6-hour EN and in five of six during 12-hour EN, it was organized as regular short bursts of contractions separated by motor quiescence. In all studies during the disruption of PIIIs, NW and AUC values decreased progressively with time and were higher at the jejunum level than in the duodenum (p < .001). However, at each level of recording, NW and AUC values were similar in the three types of feeding. After the return of PIIIs, the number, duration, and propagation velocity of PIIIs, NW, and AUC values were similar in the three studies. CONCLUSIONS: EN interrupts PIIIs, but, in most cases, PIIIs reappear before the end of EN. During the interruption of PIIIs, the organization of the contractions is qualitatively different from the fed pattern observed after oral feeding. For the same caloric value of the meal, the quantitative duodenojejunal motor response is not affected by the infusion rate, and the more important jejunal, rather than duodenal motor response found after an oral meal, is observed during EN. During EN, after the return of PIIIs, despite the persistence of a nutrient infusion into the duodenum, the small bowel motor patterns are not qualitatively or quantitatively different from those recorded in fasting subjects. PMID- 8676534 TI - Evaluation of retinol, alpha-tocopherol, and carotenoids in serum of men with cancer of the larynx before and after commercial enteral formula feeding. AB - BACKGROUND: Both epidemiologic and in vitro studies have indicated the inverse correlation between intake and/or blood concentrations of different carotenoids, retinol, and tocoferol with different chronic and degenerative disturbances (cancer, cardiovascular diseases, cataracts, aging). The purpose of this study was to determine the fat-soluble vitamin and carotenoid levels in men with recently diagnosed cancer of the larynx (n = 51) who had undergone total or partial laryngectomy and compare them with those of an age- and sex-matched control group (n = 51). In addition, the effects of commercial enteral formula feeding were assessed in a subgroup of these patients (n = 35). METHODS: A validated high-performance liquid chromatography method was used to determine the concentrations of six carotenoids (lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, and beta-carotene), retinol, and alpha-tocopherol in serum. Commercial, rather than blender prepared, enteral formulas were supplied to the patients as the only food source for an average period of 12 days. The statistical analysis was based on nonparametric methods (Mann-Whitney and Wilcoxon). RESULTS: The levels of all compounds analyzed were significantly lower in men with laryngeal cancer than in the control group. Retinol and tocopherol increased significantly after enteral formula feeding, although they continued to be significantly lower than those of the controls. The carotenoid levels decreased after enteral nutrition. CONCLUSIONS: The retinol and carotenoid concentrations should be monitored on a routine basis in these patients because of their relationship to this type of cancer. Moreover, it would be of interest to assess the effects of the addition of carotenoids to enteral formulas because they may offer protection from oxidative damage and potentiate the immune system. PMID- 8676536 TI - Histologic development of the sheath that forms around long-term implanted central venous catheters. AB - BACKGROUND: Chronically implanted catheters often become covered with a thin, white adherent covering of tissue that has been referred to as a fibrin sheath. This tissue often interferes with catheter function. METHODS: To chronicle the development of this sheath, rats were implanted with silicone rubber central venous catheters. Five rats were euthanized at 3,7, and 60 days postimplantation so that gross necropsy and histology could be performed on the catheterized vessels. RESULTS: The coating that developed around the external portion of the catheter started as a dark red thrombus containing fibrin and progressed into vascularized, fibrous connective tissue. CONCLUSIONS: The translucent to white sheath that forms around chronically implanted catheters is not composed of fibrin and is therefore not likely to be dissolved by fibrinolytic agents such as urokinase, streptokinase, or tissue plasminogen activator. PMID- 8676537 TI - Overview of randomized clinical trials of oral branched-chain amino acid treatment in chronic hepatic encephalopathy. AB - BACKGROUND: The role of oral branched-chain amino acid supplements in the prevention and treatment of chronic hepatic encephalopathy is not yet established, and conflicting opinions are expressed in authoritative textbooks. We aimed to review and pool the published controlled studies by means of meta analytical techniques. METHODS: A computerized search of published papers identified nine studies, controlled against placebo, energy, alimentary proteins, or casein. Their quality score was calculated according to the protocol of Chalmers. The value of the portal-systemic encephalopathy index was chosen as main outcome, because of lack of more significant clinical outcomes. To cope with differences in trial design and data presentation, individual data were requested to authors. RESULTS: After 18 months, we received the individual data of only two studies, thus precluding any meta-analysis. Two studies, accounting for over 60% of total enrolled patients, were in favor of branched-chain amino acids. Their quality score was much better than that of the remaining seven negative small studies, carrying a significant risk of type II error. CONCLUSIONS: Based on the results of the two largest, long-term studies, the use of oral branched-chain amino acids in the prevention and treatment of chronic encephalopathy may only be proposed for patients with advanced cirrhosis, intolerant to alimentary proteins. Large, multicenter, long-term studies, considering more important clinical outcomes, are needed to provide definite answers to an aged question. PMID- 8676538 TI - Megestrol acetate in patients with AIDS-related cachexia. PMID- 8676539 TI - Energy-enriched hospital food to improve energy intake in elderly patients. AB - BACKGROUND: It was hypothesized that energy intake in hospitalized elderly patients could be improved by increasing the density of energy of the food and that the volume of food actually consumed, even with a higher energy content than the normal, would not change with servings of high energy-dense hospital food. METHODS: Thirty-six elderly patients (52 to 96 years) of both sexes, long-term treated at two comparable wards, participated in this study. The patients were given 6 weeks of regular hospital food (RHF, 1670 kcal/d, 7.0 MJ) and 6 weeks of high-energy food (HE, 2520 kcal/d, 10.5 MJ). The volume of food was kept constant. A crossover study design was used. Food intake, energy intake, body weight, and modified functional condition (Norton scale) were measured. RESULTS: Regardless of type of food (RHF or HE) and time of day (lunch or dinner), he food portion size (volume of food) intake was the same, approximately 80% of the portions consumed. HE led to a 40% increase in energy intake (from 25 +/- 1 during RHF to 35 +/- 2 kcal/kg/d, p < .0001), which resulted in a 3.4% increase in body weight (p < .001) after 3 weeks of HE. Only minimal changes in functional condition were found. The cost of HE was substantially lower (-85%) than any other mean available for improvement of energy intake. CONCLUSIONS: A significant increase in energy intake can be achieved by higher energy density in regular hospital food and that HE does not cause a decrease in the volume of the food consumed. These findings suggest that it is the volume of food rather than the energy that limits voluntary energy intake of hospital food in elderly hospitalized patients. PMID- 8676540 TI - Adhesive mucous gel layer and mucus release as intestinal barrier in rats. AB - BACKGROUND: Although it has been reported that total parenteral nutrition induces an increased intestinal permeability and a decreased mucous gel layer covering the intestinal epithelium, the role of mucous gel on intestinal permeability has not been well understood. We examined the in vivo effects of N-acetyl cysteine (NAC) as mucolytic agent and colchicine as suppressant of the mucus production on the intestinal transmission of fluorescein isothiocyanate dextran 70,000 (FITC dextran). METHODS: Rats were divided into four groups. In each group, FITC dextran (750 mg/kg) with or without NAC (3000 mg/kg) was injected into the small intestinal lumen 3 hours after intraperitoneal injection of saline or colchicine (Col, 10 mg/kg). Thirty minutes after injection of FITC-dextran, blood samples were taken from portal vein to analyze plasma fluorescein concentration by fluorescence spectrometry. Samples of small intestine were sectioned in a cryostat for fluorescence microscopy, and the identical sections were stained by periodic acid-Schiff reaction. RESULTS: Plasma FITC-dextran level in NAC group was higher than that in control group (p < .01), that in Col + NAC group was higher than that in Col group (p < .01) and that in Col + NAC group was higher than that in NAC group (p < .05). The spaces between villi were filled with mucous gel in the control and Col groups, whereas those were not entirely filled with mucous gel in NAC and Col + NAC groups. FITC-dextran and mucous gel showed complementary distribution in all rats. The villous interstitial edema was recognized in NAC group and the villi were disrupted in Col + NAC group. CONCLUSIONS: These results suggest that intestinal permeability is possibly affected not only by the mucous gel covering the intestinal epithelium but also by mucus release from goblet cells of the small intestine. PMID- 8676541 TI - Cross-bridge-dependent changes in the intracellular Ca2+ concentration in mammalian cardiac muscles. AB - A change in muscle length significantly alters the developed tension in mammalian cardiac muscle compared to that in skeletal muscle fibers. The intracellular mechanisms related to the length-dependent change in developed tension have been studied using Ca2+ indicators in intact preparations; a cross-bridge-dependent change in the affinity of troponin-C for Ca2+ is a possible mechanism. This hypothesis is further supported by the measurement of Ca2+ bound to troponin-C in skinned preparations. The molecular mechanism of the cross-bridge-dependent change in the affinity of troponin-C for Ca2+ is not fully understood although the studies which employ the substitution of troponin-C in skinned preparations, transgenic animals and in an animal model with heart disease have been performed. We reviewed the current studies by analyzing the intracellular mechanism responsible for the length-dependent change in tension development in mammalian cardiac muscle. PMID- 8676542 TI - Tubuloglomerular feedback. AB - The macula densa, a plaque of specialized tubular epithelial cells located in the distal tubule, monitors the NaCl concentration of the tubular fluid and sends an as of yet unidentified signal to control glomerular hemodynamics. In this mechanism, called tubuloglomerular feedback (TGF), an increase in NaCl concentration at the macula densa constricts the glomerular afferent arteriole and thus decreases the single-nephron GFR. Along with the myogenic response, TGF significantly contributes to renal autoregulation. In addition, the macula densa also controls the rate of renin release, and hence the level of angiotensin II. Studies indicate that an appropriate interaction between TGF and the renin angiotensin system is essential for body fluid and electrolyte homeostasis in the face of rather big variations in daily salt intake. Thus, alterations in TGF may play an important role in the pathogenesis/pathophysiology of various diseases such as hypertension, diabetes mellitus and congestive heart failure. PMID- 8676543 TI - Long-term outcome in single-vessel coronary artery disease in Japanese patients. AB - We assessed the long-term outcome of medical therapy in 453 patients who underwent coronary angiography in the period from September 1973 to February 1984, and who had a significant stenotic lesion (75% or more stenosis) in a single coronary artery. The mean follow-up period was 9.8 years. The 5- and 10 year survival rates were, respectively, 96.0% and 91.3% in these patients, and these survival rates were comparable to the cumulative survival rates in the age matched healthy male controls determined on the basis of overall death. Cardiac death occurred in 35/453 patients (7.7%) with single-vessel disease (SVD), and non-fatal myocardial infarction occurred in 17 patients (3.8%) during the follow up period. The incidence of cardiac events, which was defined as cardiac death and nonfatal myocardial infarction, was as low as 1.2% per year. The survival rates were compared in terms of the presence or absence of myocardial infarction, the type of the coronary artery with stenosis, and proximal versus distal location of the stenotic lesion in the left anterior descending artery (LAD). The survival rates were similarly high in both assessed groups, with no significant differences. Patients with SVD treated medically had a good prognosis, except for those patients with decreased left ventricular function (ejection fraction < or = 40%). These factors should be taken into consideration when selecting therapies for patients with SVD. PMID- 8676544 TI - Decreased glutathione levels in acute myocardial infarction. AB - Although experimental studies have demonstrated that reduced glutathione (GSH) is involved in cellular protection from deleterious effects of oxygen free radicals (OFRs) in ischemia and reperfusion, there are controversial data on the correlation between the levels of erythrocyte GSH and the ischemic process. To clarify, we determined the erythrocyte GSH levels in 21 patients with acute myocardial infarction (AMI), aged 39-70, who were not given thrombolytic therapy and 21 age- and sex- matched healthy controls. Samples of blood were taken on days 1, 3, 5 and 7 from AMI patients and on the same days from the controls. The GSH levels of patients with AMI were significantly depressed by 11.5% as compared to the controls on the second day after infarction (7.44 +/- 1.71 vs 8.41 +/- 1.54 U/gHb p < 0.05). Although the total mean of GSH levels for all days was lower (3.8%) in patients than in the controls, this finding did not reach statistical significance (7.41 +/- 1.71 vs 7.71 +/- 1.27 U/gHb, ns). There was no correlation between the erythrocyte GSH levels and cardiac enzyme concentrations, infarct localization, hemodynamic status according to Killip classification and the frequency of ventricular arrhythmias. This preliminary work suggests that depressed GSH levels may be associated with an enhanced protective mechanism to oxidative stress in AMI. Measurements of erythrocyte GSH can be helpful in the estimation of oxidative stress in the course of AMI. However, further research must be done to determine the primary scavenger in AMI by analyzing all the enzymes and substrates involved in the endogeneous system that controls the effects of OFRs. PMID- 8676545 TI - Long-term results of radiofrequency catheter ablation in non-ischemic sustained ventricular tachycardia with underlying heart disease. Nonuniform arrhythmogenic substrate and mode of ablation. AB - This study examined 12 VTs in 8 patients who underwent radiofrequency (RF) catheter ablation for ventricular tachycardia (VT) associated with non-ischemic underlying heart diseases, and who were followed-up for more than 24 months after ablation. The site of VT origin was determined to be within a narrow site (within 1.0 x 1.0 cm) in 5 VTs (4 patients), but VT originated from a wide origin (more than 1.0 x 1.0 cm) in the other 5 VTs (3 patients). The remaining patient had two macroreentrant VTs revolving around an anatomical obstacle in both the clockwise and counterclockwise directions. Two of 5 VTs originating from a narrow site were successfully ablated by 2-3 RF applications. In VT associated with a wide origin, two perpendicular linear RF lesions with 6.0 +/- 1.8 RF applications were required to ablate the VT. Eight of the 12 VTs (66.7%) were finally ablated by RF current (30-50 watts), and they did not recur during the follow-up period of 31.2 +/- 6.5 months. An excellent long-term outcome is expected, even in VT associated with non-ischemic underlying heart disease, if VT is successfully treated by RF ablation. PMID- 8676546 TI - Diagnostic value of endomyocardial biopsies of the right ventricular septum in arrhythmias originating from the right ventricle. AB - The aim of the study was to classify the value of endomyocardial biopsies taken from the right ventricular septum in patients with ventricular tachyarrhythmias originating from the right ventricle. In a cohort of 62 young patients (mean age 35.6 years) 4-5 endomyocardial biopsies were taken from the right ventricular septum and myocardial atrophy, fibrosis and lipomatosis were analysed qualitatively and semi-quantitatively. Much interest was focused on the arrangement and type of fibrosis. Lipomatosis, myocardial atrophy and a finer form of fibrosis surrounding individual myocytes or groups of myocytes were judged as the typical histopathological findings of arrhythmogenic right ventricular dysplasia. The cohort of patients was subdivided clinically into idiopathic right ventricular outflow tract tachycardia (n = 50) and arrhythmogenic right ventricular dysplasia (n = 12). In the group of arrhythmogenic right ventricular dysplasia pathological findings were found in 92% with typical fibrolipomatosis in two cases, severe fibrosis ( > 40% per biopsy) in 5 cases, a finer form of fibrosis surrounding individual myocytes without lipomatosis in two cases and a slight interstitial or subendocardial fibrosis in two cases. In only one patient the endomyocardial biopsy was normal. In right ventricular outflow tract tachycardia normal endomyocardial biopsy findings predominated (80%). In two cases lipomatosis without fibrosis was a more or less normal finding, and in two other cases a slight interstitial or subendocardial fibrosis was found. Fibrosis was judged to be moderate or severe with discrete signs of inflammation in only two cases; in a long-term follow-up these two patients developed typical features of idiopathic dilated cardiomyopathy. Endomyocardial biopsies taken exclusively from the right ventricular septum were able to distinguish between right ventricular outflow tract tachycardia and arrhythmogenic right ventricular dysplasia, although the typical finding of fibrolipomatosis in cases with arrhythmogenic right ventricular dysplasia was rare. Characteristics of fibrosis are the key to the correct diagnosis provided that histopathological analysis is based on experienced qualitative criteria (type and arrangement of fibrosis). In conclusion, qualitative and semi-quantitative analyses of endomyocardial biopsies are far better than computerized quantitative methods. Biopsies from the free right ventricular wall cannot be generally recommended if a correct definition of arrhythmogenic right ventricular dysplasia in endomyocardial biopsies from the right ventricular septum is used. PMID- 8676547 TI - The absolute voltage and the lead vector of Wilson's central terminal. AB - The absolute potential value of Wilson's central terminal was calculated at 2 msec intervals during a cardiac cycle in 60 clinical cases. Starting from the body surface potential data at 128 thoracic locations, the effect of immersion of the body into an infinite conductor on the surface potential was calculated to obtain values with reference to zero potential at infinity. The conductivity of the outside medium was then made to approach zero. Comparison of the result with the original map showed nearly a constant shift of the potential, corresponding to the voltage of Wilson's terminal. In addition, the cardiac vector was calculated as the first approximation of the cardiac electromotive force and the lead vector of Wilson's terminal was obtained in order that the scalar product of the cardiac vector and the lead vector approximated the observed voltage of Wilson's terminal. The results indicate that the voltage of the Wilson electrode depended on the surface voltage with a peak value near the maximal QRS force in most of the cases. The peak voltage of Wilson's terminal was either positive or negative, and was 0.15 mV in absolute value on average. Voltage variations of Wilson's terminal during a cardiac cycle were 0.20 mV as an average of all cases. The voltage of Wilson's terminal also depended on the direction of the equivalent cardiac vector. The lead vector of Wilson's terminal was found to be directed superiorly in most of the cases. The average magnitude of the lead vector of Wilson's terminal was 0.097 omega/cm, which corresponded to about 1/4 of that of lead I. PMID- 8676548 TI - The mechanism of the physiologic disappearance of the third heart sound with aging. AB - The third heart sound (S3) is often present in children and adolescents but is not present in most adults. Applying at the left ventricle a mathematical model, the mechanism of the disappearance of S3 was studied employing the frequency analysis of the sound and echocardiographic data. The existence of a significant correlation between the spectrum energy of S3 and the diameter and thickness of the left ventricle at the moment of S3 in 25 healthy subjects (aged 21 +/- 7 years) allowed us to interpret the origin of S3 based on a viscoelastic oscillating system. Once the left ventricle starts vibrating it behaves as a simple physical model composed of a mass (m), a spring (k) and a viscous element. The abrupt deceleration of the blood mass (m) against the left ventricular walls (k) triggers the vibration of the system according to the equation Fd = 1/2 pi.square root of k/m.square root of 1 - zeta 2, where Fd is the natural damped frequency and zeta is the damping factor. The equation shows that the vibrating system can oscillate only if zeta is < 1. During the growth of the individual the increased myocardial mass may lead to augmented viscous forces causing a gradual increase in zeta until the system becomes overdamped and consequently unable to vibrate causing the disappearance of S3. PMID- 8676549 TI - Noninvasive measurement of left atrial functions using transesophageal echocardiography. AB - The use of transesophageal pulsed Doppler echocardiography provides an ideal approach for determining both pulmonary venous flow and transmitral flow. This approach thus provides information about the flow of blood into and out of the left atrium. We designed a new method for separately evaluating left atrial functions on the basis of the time-velocity integrals of pulmonary venous flow and transmitral flow using transesophageal pulsed Doppler echocardiography, assuming that the cross-sectional areas of the mitral ring during the left ventricular diastolic phase and of the four pulmonary venous orifices throughout a cardiac cycle were constant and that the blood flows of the four pulmonary veins exhibited identical velocity profiles. Good correlation was observed between the indices of left atrial function (i.e. left atrial reservoir, conduit and forward contractile volume) using this new method of analysis of Doppler echocardiographic data and those of a conventional method using contrast angiography. In conclusion, transesophageal pulsed Doppler echocardiography provided satisfactory information about left atrial function, and our new method may be one of the most practical techniques for estimating individual left atrial functions. PMID- 8676550 TI - Electrocardiographic findings in children with spinal muscular atrophy. AB - Most of the patients in this study with spinal muscular atrophy were found to have tremors of the isoelectric line in the electrocardiogram (ECG) tracings. There were a total of 47 cases of SMA (mean age 40.8 months). All three types of SMA had a similar incidence (about 80%) of tremors in the tracings (p = 0.885). In 7 cases the ECG tremors had an intermittent pattern. ECG tremors were commonly found in the majority of SMA patients and this finding, though non-specific, may suggest a possible SMA diagnosis. PMID- 8676551 TI - Risk factors in heart transplantation. A statistical study of New Zealand cases. AB - The first heart transplantation in New Zealand was performed on December 2, 1987. This study covers all forty-five transplantations that were performed in New Zealand at Green Lane Hospital from that time through January 1994. Eleven patients from that group have died. The 30 day and 1, 2 and 4 year survival rates were found to be 91.1, 86.7, 80.0 and 75.6%, respectively. The mean waiting period of the patients for heart transplantation was 61.9 days. Only pulmonary vascular resistance was a statistically significant risk factor for early death after cardiac transplantation. Ischemic time was not a significant risk factor in this study. PMID- 8676552 TI - Effect of trichlormethiazide and captopril on nitric oxide synthase activity in the kidney of deoxycorticosterone acetate-salt hypertensive rats. AB - Nitric oxide (NO) production is reduced in patients with essential hypertension and in some experimental models. We have investigated the effect of trichlormethiazide and captopril on NO synthase (NOS) activity and glomerular damage in the kidney of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. DOCA-salt rats were induced with weekly injections of DOCA (30 mg/kg body weight (BW) and 1% saline in drinking water after right nephrectomy. As antihypertensive therapies, CAP (captopril, 40 mg/kg BW) and TCM (trichlormethiazide, 10 mg/kg BW) were given after induction of DOCA-salt hypertension. The increased blood pressure was significantly lowered by TCM, but not by CAP after 5 weeks. Nitrite production in kidney slices was suppressed in DOCA-salt rats, and immunoreactivity for both brain-type NOS (B-NOS) in macula densa and endothelial-type NOS (EC-NOS) in renal vessels was decreased. TCM significantly increased the nitrite production in the kidney slices and B-NOS immunoreactivity, whereas these changes were less in CAP. Glomerulosclerosis score was significantly higher in DOCA-salt rats, and TCM ameliorated renal damage more effectively than CAP. These results indicate that the reduced nitrite production in the kidney of DOCA-salt hypertensive rats was increased more effectively by trichlormethiazide than by captopril, via increased immunoreactivity for B-NOS in the macula densa, and prevented renal damage. PMID- 8676553 TI - Headache as a manifestation of myocardial infarction. AB - We report a 64-year-old man who complained of headache without chest pain at the onset of acute myocardial infarction (AMI). He had no history of chest pain or headache. Severe headache in this case was the first symptom of AMI. The headache was reproduced during stress test. During the angioplasty procedure, he also complained of headache without vasospastic change in the coronary artery. These findings suggest that the headache which accompanied AMI or myocardial ischemia in this case was due to referred pain rather than a generalized vasospastic disorder. PMID- 8676554 TI - Idiopathic ventricular fibrillation initiated by a short-coupled ventricular premature beat. AB - We report the case of a 38-year-old man who had idiopathic ventricular fibrillation (VF) which initiated by abnormally short-coupled ventricular premature beats. VF was successfully prevented by the combination of pilsicainide, propranolol, and verapamil. In particular, the effects of pilsicainide are assumed to exert an important effect in controlling this arrhythmia. Class Ic drugs may be effective for preventing VF initiated by short coupled VPBs. PMID- 8676555 TI - Suppression of fluid accumulation following pericardial inflammation in a patient with primary chylopericardium. AB - The patient was a 50-year-old woman with primary chylopericardium. Triglyceride rich chyloid fluid was continuously drained from the pericardial space through an indwelling catheter. A surgical procedure was scheduled since a medium chain triglyceride diet was insufficient to control the fluid accumulation. Before the operation, inflammatory signs were apparent around the indwelling catheter and the catheter was removed immediately. The inflammation was easily treated with antibiotics, and the pericardial effusion no longer accumulated during a follow up period of 10 months. The inflammatory process may have caused fibrin production and tissue adhesion in the pericardial cavity, and these might have prevented an accumulation of chyloid fluid and occluded the connection between the thoracic duct and the pericardial cavity. PMID- 8676556 TI - [Perspective of clinical pathology/laboratory medicine in Japan]. AB - More than 45 years' history of the Japan Society of Clinical Pathology was reviewed. The term of clinical pathology has been raising much confusion, particularly many anatomic pathologists being hesitant to accept the term as reported in non-English speaking European countries. The roles of clinical pathology/laboratory medicine were discussed from four different standpoints; 1) clinical pathology as a medical practice, 2) clinical pathology in medical education, including undergraduate, postgraduate and continuing educations, 3) clinical pathology in medical research, 4) guild activity in clinical pathology, including national and international activities. Future of clinical pathology will be characterized by continuing increase of needs in clinical medicine. In order for clinical pathologists and laboratory scientists to keep their active roles continuously in clinical medicine, they must be revolutionalized by themselves for their changing roles in the 21st century. PMID- 8676557 TI - [Bone turnover and clinical tests]. AB - Bone mass is the lifelong result of a balance between bone formation and bone resorption as shown in most metabolic bone diseases including involutional osteoporosis. To date, bone turnover has been precisely assessed by bone histomorphometry made by bone biopsy and also calcium kinetics and balance studies. However, bone histomorphometry is an invasive procedure requiring specialized laboratory for processing and evaluation, and calcium kinetics and balance studies require administration of radioisotopes and long periods of observation. Therefore, these procedures are not suitable for clinical tests of evaluation of bone turnover. Recently several biochemical parameters for bone turnover have been developed and also a number of noninvasive procedures such as single and dual photon absorptiometry, dual energy x-ray absorptiometry, computed tomography and ultrasound velocity, have been developed to quantitate bone mass more sensitively. In this symposium "Bone turnover and clinical tests" five symposists talked and discussed about some biochemical parameters for bone turnover and noninvasive procedures for measurement of bone mass. PMID- 8676558 TI - [Biochemical markers of bone formation in osteoporosis]. AB - We measured circulating bone Gla-protein(BGP) changes following short-term(2 weeks) active vitamin D treatment in elderly men with osteoporosis (73.0 +/- 9.4 years, n = 9) to evaluate osteoblastic function. We also measured serum levels of BGP(n = 245) and bone specific ALP(B-ALP) in women (n = 113) with normal lumbar bone mineral density, and evaluated the difference in clinical significance between these markers of bone formation. Serum BGP was significantly increased at the end of the first and 2nd week of daily oral 2 micrograms of 1 alpha(OH)D3 administration. BGP measurement is a clinically useful method to detect osteoblastic function after active vitamin D3 treatment. Significant positive correlations were found between age and BGP (r = 0.402, p < 0.01) or B-ALP (r = 0.494, p < 0.01). These markers were significantly higher in postmenopausal women compared with age-matched premenopausal women. The z-score of the difference in B ALP was 1.47 and that of BGP was 0.7. Although B-ALP and P1CP in sera remained stable even at room temperature for at least 4 hours, the BGP level was significantly lower when the blood sample was kept at room temperature for more than 1 hour. These findings suggest that B-ALP is a more sensitive and stable marker than BGP in evaluating bone formation, although both markers have significant correlations with each other, and BGP is useful to detect the active vitamin D3 effect on osteoblastic function. PMID- 8676559 TI - [Bone resorption markers]. AB - For many years, only two bone resorption markers, urinary hydroxyproline and serum tartrate-resistant acid phosphatase, have been clinically employed. However, these two markers have lacked the sensitivity and specificity to bone resorption. In the late 1980s, pyridinoline (Pyr) and deoxypyridinoline (Dpyr) which are mature crosslinks inter-molecular of collagen, were proposed as bone resorption markers. After newly synthesized collagen is incorporated into bone matrix, Pyr, Dpyr are synthesized by the post-translational modification of collagen molecules. Pyridinoline crosslinks occur in type I collagen at two sites, the carboxy- and amino- terminal telopeptides to helix. At the time of bone resorption, Pyr, Dpyr and amino-, and carboxy- terminal crosslinked telopeptides of type I collagen are excreted into the circulation through collagen degradation. Because the crosslinks and crosslinked telopeptides do not exist at the time of synthesis of collagen, the assay for the crosslinks and telopeptides are specific to bone resorption. Recently, novel assays for measuring crosslinked telopeptides have been developed. Amino-terminal pyridinolines crosslinked telopeptides (NTx) and carboxy-terminal telopeptide of type I collagen (CrossLaps) is assayed in urine, and carboxy-terminal pyridinolines crosslinked telopeptides (ICTP) is assayed in serum. Because those markers are specific to bone resorption, they are expected to reflect the minimum amount of bone resorption in postmenopausal women and osteoporosis. We reviewed the background of Pyr and cross-linked telopeptides markers and compared the performance of these bone resorption markers in the bone turnover in postmenopause and established osteoporosis. PMID- 8676560 TI - [Bone densitometry]. AB - Recently, several methods for measurement of bone density have been developed. Among them, dual X-ray absorptiometry (DXA) is now considered to be a standard method in bone densitometry. In most cases, values by DXA measurement reflect bone strength and thus measurements of lumbar spine and femoral neck by DXA are used for diagnosis of osteopenia or osteoporosis. In several clinical trials of new drugs, measurement of DXA proved to be very useful. Other methods such as DXA for os radius or os calcaneus are also useful for screening of general osteopenia and quantitative ultrasound is widely used for mass-screening of osteoporosis because of its convenience. Radiographic absorptiometry is also a convenient method, which can be performed only by taking an X-ray photograph with an aluminum phantom. Quantitative computed tomography (QCT) is a method which enables measurement of trabecular true bone density as well as an analysis of trabecular structure and peripheral QCT, aimed for measurement of peripheral bones, is also expected to be a sensitive method to monitor therapeutic responses. Since several methods are now available, it is important to choose a method which is the most suitable for the purpose of each bone mineral measurement. PMID- 8676561 TI - [Establishment of reference intervals and physiological parameters for 13 serum proteins in healthy Japanese adults]. AB - Using a nephelometry with a new calibrator in which values were assigned from EU/CRM470, a new international reference preparation, we have established for the first time the reference intervals of 13 different serum proteins in Japanese adults. Based on the NCCLS guideline C28-P, a new statistical and concrete procedure was revised and used for this study. It is clearly shown here that standardisation of serum proteins can be possible under the qualified assay system, making it possible to share the reference intervals among laboratories under well-controlled quality assurance. New aspects of serum protein variations were discovered in relation to physiologic changes and life styles. PMID- 8676562 TI - [Nucleotide sequences at intron 6 and exon 7 junction of fibroblast growth factor receptor 2 and rapid mutational analysis in Apert syndrome]. AB - Apert syndrome, acrocephalosyndactyly Type I, is an autosomal dominant craniosynostosis comprising acrocephaly, facial dysmorphism and severe syndactyly of the hands and feet. Missense mutations at codons 252 and 253 at 5'-end on exon 7 of fibroblast growth factor receptor (FGFR) 2 have been identified in a large number of patients with Apert syndrome. In this study, nucleotide sequences on the intron 6 were determined by vector ligation-PCR and direct sequencing. Five DNA samples from sporadic Apert syndrome were examined by non-RI SSCP and direct sequencing using a primer pair of intron 6 and exon 7. All cases of the syndrome showed abnormal banding pattern in the SSCP and missense mutations from Ser to Trp at codon 252 of the FGFR2 gene. The non-RI SSCP and direct sequencing of the FGFR2 exon 7 from genomic DNAs may be a useful and rapid molecular means for clinical diagnosis of Apert syndrome. PMID- 8676563 TI - [Frequent missense mutations of fibroblast growth factor receptor (FGFR) gene families in craniofacial syndromes in Japanese patients]. AB - Craniofacial syndromes, including Crouzon syndrome, Pfeiffer syndrome, Jackson Weiss syndrome, Apert syndrome and achondroplasia, have been indicated that syndromes were associated with mutations of fibroblast growth factor receptor (FGFR) gene families. In this report, seven Japanese patients with craniofacial syndromes, three Crouzon syndromes and four achondroplasias, were analyzed on FGFR2 and FGFR3 genes by non RI-SSCP (single strand conformation polymorphisms) and direct sequencing. Missense mutations of the FGFR3 exon 10, at codon 380 in two sporadic cases and codon 375 in two familial cases, were detected in all cases of achondroplasia. Mutations of the FGFR2 were noted in Crouzon and Apert syndromes. One of three Crouzon syndromes has a missense mutation at codon 342 on exon 9. Highly frequent mutations were clustered within some localized regions of the FGFR genes in craniofacial syndromes. Alterations in these receptors due to missense mutations would thus appear closely involved in pathogenesis of craniofacial syndrome. The non RI-SSCP and direct sequencing of the FGFR genes, shown in this report, may be an appropriate approach for diagnosis of these syndromes with extensive clinical application. PMID- 8676564 TI - [Measurement of serum catalase activity and its clinical significance]. AB - Catalase (CAT) is an enzyme to scavenge H2O2 and to protect peroxidation of cell wall lipid and lipoproteins. The increase in its activity has been observed in several diseases as an compensating reaction. The decrease in its activity may be related to some pathophysiologies of diseases. However, there has been few reports on the measurement of serum CAT activity. We formerly reported the method to measure CAT accurately with an automated analyzer. In the present experiment, we measured CAT in various kinds of diseases and healthy controls by this method. By an analysis of serum samples which were obtained from randomly selected 1,051 patients at Chibune Hospital for 12 months (from January to December, 1993), we obtained following results. The CAT of neuromuscular, cardiovascular and metabolic diseases were significantly high (p < 0.01). The CAT of psychiatric and otorhinopharyngologic diseases were significantly low (p < 0.01). There was significant relationship between CAT and some biochemical markers. CAT is thought as a protector against tissue injuries or circulatory insufficiencies. These results indicate that CAT increases in some kinds of diseases as a protection reaction to the injury, and that the decrease of CAT may cause some kinds of diseases. PMID- 8676565 TI - [Analysis of factors which affect the measurement of factor VIII inhibitor by Bethesda method]. AB - Factor VIII neutralizing antibody (factor VIII inhibitor) sometimes develops in the patients with hemophilia A who are treated with factor VIII concentrates and more rarely in non-hemophilic individuals as auto antibody. Factor VIII inhibitor titer is most commonly measured by Bethesda method in which the sample is mixed with normal pooled plasma as a source of factor VIII for 2-hour incubation followed by measurement of residual factor VIII activity. Because of its simplicity and accessibility of normal pooled plasma, Bethesda method is widely used in clinical laboratories. However, the reproducibility of the assay is not generally considered to be satisfactory and measurement of inhibitor units varies among laboratories. In the present study, the factors which affect the measurement of Bethesda method were assessed. The reproducibility of Factor VIII activity showed better in a factor VIII dose dependent manner and varies according to clotting threshold of the sample that is analyzed by an automated coagulation equipment and a desktop computer. The reproducibility of inhibitor measurement was worse in the inter-assay than in the intra-assay. The assay fluctuation of the measurement of lower inhibitor units tends to be more evident when the sample of 0.39 to 2.39 BU/ml were tested. The factor VIII content in the normal pooled plasma did not affect the measurement of factor VIII inhibitor units in the range of 0.8 to 1.2 U/ml. The buffers retained factor VIII in the control sample during the 2-hour incubation better in the order of imidazole buffer, bernard buffer, Tris-HCl buffer and saline. PMID- 8676566 TI - Multicenter evaluation of a colorimetric microplate antimycobacterial susceptibility test: comparative study with the NCCLS M24-P. AB - A colorimetric test method using the microplate culture technique for the determination of susceptibility of Mycobacterium tuberculosis against antimycobacterial agents was developed and evaluated by the multicenter study. The test method utilizes an oxidation-reduction dye, 2,3-diphenyl-5-thienyl-(2) tetrazolium chloride (STC), as an indicator of mycobacterial growth. When compared to the presently available test method, some modifications were also included; lower inoculum density (10-fold dilution), inclusion of an inoculum diluted 1:100 as a growth control, and the preparation of inoculum preincubated in Middlebrook 7H9 broth and spectrophotometrically adjusted to McFarland #1 turbidity. The test method evaluated was highly precise and reliable to detect antimycobacterial resistances when the ATCC reference strains were tested. Also, the interpretations of the test result were highly comparable to those determined by the method of NCCLS M24-P, the % agreements ranging from 76.1% (ethambutol) to 91.3% (streptomycin). The test results were also comparable to those determined by Ogawa media; > 90% agreed with susceptible, intermediate, or resistant. The appearance of mycobacterial colonies on the test media was easily read, and the test results were more comparable to those of NCCLS M24-P. With these results, it can be concluded that the colorimetric microplate susceptibility test method described will be more suitable for clinical mycobacteriology laboratories. PMID- 8676567 TI - [Antibiotic resistance of clinical isolates Streptococcus pneumoniae]. AB - Streptococcus pneumoniae is a major pathogenic organism of community-acquired bacterial pneumonia as well as otitis media and bacterial meningitis. Recently penicillin- or multiply resistant pneumococci have been isolated worldwide. In this study we examined the susceptibility tests of 11 antibiotics with the total of 63 clinically isolated pneumococci, using a broth microdilution method. Most of pneumococci were isolated from respiratory specimens. According to NCCLS standard, all these pneumococci were classified as follows: PCG-susceptible S. pneumoniae (PSSP, MIC < or = 0.06 micrograms/ml), PCG-intermediately resistant S. pneumoniae (PISP, 0.12 < or = MIC < or = 1.0 micrograms/ml), and PCG-highly resistant S. pneumoniae (PRSP, MIC > or = 2.0 micrograms/ml) were 45 (71.4%), 14 (22.2%) and 4 isolates (6.4%), respectively. Forty-four percent of isolates from children under 10 years and 29% from outpatients were PISP or PRSP. Resistance to erythromycin (EM) clindamycin (CLDM) or minocycline (MINO) was significantly recognized, but not correlated with that to PCG. On the other hand, the resistance to beta-lactam antibiotics were correlated with that to PCG. Seventeen isolates (27%) were resistant to two or more antibiotics among PCG, EM, MINO, ofloxacin (OFLX), and sulfamethoxazole-trimethoprim (ST). In pneumococcal infection, we always have to pay a careful attention to susceptibility test before we choose antibiotics. PMID- 8676568 TI - [Quick radioimmunoassay for plasma immunoreactive gastrin--application for localizing occult gastrinoma(s) during operation]. AB - A rapid method for determining gastrin, quick gastrin, has been developed. Separation/washing procedure has been improved and can be completed within three minutes. It required only 48 minutes for the assay of 22 blood samples. Quick gastrin is a RIA that uses magnetic particles. On magnetic particles, a goat anti rabbit IgG antibody is bound covalently. An anti-human gastrin rabbit antibody is bound to an anti-rabbit IgG antibody. Assay is started by adding the magnetic particles to a mixture of sample and 125I-gastrin. Following 30 minute incubation at 37 degrees C, the particles are sedimented in a magnetic field and washed. The gastrin content of the sample is then quantitated by counting radioactivity of the particles. Incomplete equilibration of antigen-antibody reaction is corrected using standard solution prepared from charcoal treated plasma. The immunoreactive gastrin values by quick gastrin correlated well with those by a commercial assay kit (Gammadab RIA kit; y = 1.01 x +4.3, r = 0.99). When compared to a reported conventional rapid assay, quick gastrin is easier and more accurate. Quick gastrin is sensitive enough to use for intra-operative determination of gastrin. We applied quick gastrin to the samples obtained from intra-operative secretin test in a gastrinoma patient. Twofold increases in gastrin after injection of secretin clearly indicated the existence of occult gastrinomas in her pancreas. When gastrin was assayed with the conventional rapid method, the increase in gastrin was less and did not reach the criteria for existence of gastrinoma. PMID- 8676569 TI - [Clinical significance of urinary free dopamine as a marker of renal function]. AB - Urinary free dopamine (DA) is derived from DA synthesized or converted from circulating DOPA in renal proximal tubules, and plays an important role for diuresis and natriuresis. As plasma free DA is in tiny amounts near detectable range, a large amount of free DA in urine is tubular origin, but not from circulating DA. In the present study, we hypothesized that urinary free dopamine (U-f-DA) can be used as the marker of renal function. We speculated that U-f-DA may decrease in the damage of renal tubules or renal disorder. To evaluate clinical significance of U-f-DA, we used serum creatinine levels as the index of renal function. As the urinary parameter of renal function, we measured U-f-DA, alpha(1)-microglobulin (U-alpha(1) MG), beta(2)-microglobulin (U-beta(2)MG) and N acetyl-beta-D-glucosaminidase (U-NAG) in spot urine samples of 154 outpatients (male; 76, female; 78). Each values are rectified by creatinine (Cr) concentration in urine. U-f-DA was negatively correlated with the serum level of creatinine, U-alpha(1)MG and U-beta(2)MG. The receiver operating characteristic (ROC) curve analysis was used for their comparison in evaluation of urinary marker of renal function. In this analysis, area under the curve (AUC) of U-f-DA is best among other markers of renal function. AUC of U-f-DA/Cr, U-alpha(1)MG/Cr, U-beta(2)MG/Cr, U-NAG/Cr were 0.82, 0.57, 0.72, 0.62 in male, 0.92, 0.72, 0.81, 0.57 in female, respectively. These results suggest that the measurement of U-f DA is superior marker of renal function to the determination of U-alpha(1)MG, U beta(2)MG and U-NAG. PMID- 8676570 TI - [Detection of p27/kip1 mRNA in blood cells by nonradioactive ribonuclease protection assay]. AB - Cyclin and cyclin-dependent kinase(cdk) complexes, and their inhibitors (CKIs) play important roles in growth regulation on the cells. p27/kip1 is a CKI associated with G1 arrest induced by cell to cell contact, transforming growth factor-beta and cyclic AMP. The abnormality of p27/Kip1 genes in human tumors usually appears as a steady level defect of expression, since mutations in them is rare. Thus it is important to estimate the expression level of this gene. To detect the change of p27/Kip1 mRNA level in blood cells, we developed the ribonuclease protection assay using nonradioactive riboprobe which was produced by reverse transcriptase-polymerase chain reaction (RT-PCR) with T7 promoter added antisense primer and the in vitro transcription system. Our assay may be useful for clinical evaluation of the mRNA level. PMID- 8676571 TI - Differential inhibitory mechanisms in VPL versus intralaminar nociceptive neurons of the cat: I. Effects of periaqueductal gray stimulation. AB - Nociceptive thalamic units receiving afferent input from the greater splanchnic nerve (SPL) were recorded from the nucleus ventralis posterolatealis (VPL) and intralaminar nuclei in urethane-chloralose anesthetized cats. The effects of stimulating the periaqueductal gray (PAG), or the nucleus raphe dorsalis (NRD) on responses of nociceptive thalamic units were investigated. Forty-eight nociceptive specific (NS) and 20 wide dynamic range (WDR) units with SPL input were found in the shell region of the caudal VPL. Following electrical stimulation of either the ventral PAG or the NRD, responses to SPL input were inhibited in all NS and WDR units tested. Responses of these units to electrical stimulation of spinothalamic tract fibers in the ventrolateral funiculus (VLF) were also inhibited following the PAG/NRD stimulation. These results suggest that PAG/NRD stimulation-produced inhibition of both NS and WDR units may be partially mediated by an ascending antinociceptive mechanism. Intralaminar nociceptive units with SPL input were found in the nuclei centralis lateralis (CL), paracentralis (Pc), and parafascicularis (Pf). The effects of conditioning electrical stimulation of either the ventral PAG or the NRD on responses of intralaminar nociceptive units were studied. Of 113 intralaminar nociceptive units studied, 68 units were unaffected, 23 units were excited and 22 units were inhibited following the conditioning stimulation. In the units in which responses to SPL stimulation were inhibited, responses elicited by electrical stimulation of the mesencephalic reticular formation (MRF) were also inhibited. These data suggest that although there is an ascending inhibitory pathway from PAG/NRD to intralaminar nuclei, this system is far less potent compared with the ascending inhibitory system acting upon the VPL. PMID- 8676572 TI - Differential inhibitory mechanisms in VPL versus intralaminar nociceptive neurons of the cat: II. Effects of systemic morphine and CCK. AB - In urethane-chloralose anesthetized cats, the effects of intravenous morphine on responses of thalamic nociceptive units were studied. In both nociceptive specific (NS) and wide dynamic range (WDR) units recorded from the nucleus ventralis posterolateralis (VPL), intravenous morphine suppressed unit responses to the greater splanchnic nerve (SPL) stimulation, but had little effect on responses to stimulation of spinothalamic tract fibers in the ventrolateral funiculus. In nociceptive units recorded from nuclei centralis lateralis (CL) and parafascicularis (Pf) of the intralaminar nuclei, intravenous morphine suppressed responses to stimulation of the mesencephalic reticular formation as well as to SPL stimulation. Intravenous cholecystokinin (CCK) antagonized the suppressive action of morphine on responses of VPL units, but did not antagonize the suppressive action of morphine on responses of intralaminar units. The results suggest that intravenous morphine inhibits synaptic transmission of nociceptive impulses in the intralaminar nuclei as well as in the spinal cord, but not in the VPL, and that CCK antagonizes the antinociceptive action of morphine in the spinal cord, but not in the intralaminar nuclei. PMID- 8676573 TI - Regulation of heat production of brown adipocytes via typical and atypical beta adrenoceptors in the rat. AB - Previous studies in our laboratory demonstrated that microcalorimetry is an appropriate method for estimating the physiological function of isolated rat brown adipocytes. In the present study, to elucidate the mode of action of typical and atypical beta-adrenoceptors on heat production of this cell, the effect of novel adrenergic beta 3-agonists was compared with that of other typical adrenergic reagents by direct microcalorimetry. Isoproterenol and beta 3 agonists, BRL37344, ICI215001, and CGP12177, increased heat production in a dose dependent manner, however, phenylephrine had no effect. Propranolol and pindolol did not increase the heat production but attenuated the effect of isoproterenol and BRL37344 in a dose-dependent manner. Molar IC50 values of propranolol and pindolol for BRL37344 were about 10(-5) and 3 x 10(-6) M, respectively, whereas those of the two antagonists for isoproterenol were about 3 x 10(-7)M. The pA2 values by Schild analysis of propranolol vs. isoproterenol and BRL37344 were 7.91 and 6.13, respectively. These results suggest that heat production may be regulated via both beta 3- and typical beta-adrenoceptors in brown adipocytes. PMID- 8676574 TI - Assessment of training-induced autonomic adaptations in athletes with spectral analysis of cardiovascular variability signals. AB - The purpose of this study was to assess the adaptive effects of endurance training on autonomic functions in athletes with spectral analysis of cardiovascular variability signals. Continuous ECG, arterial blood pressure (ABP), and respiratory signals were recorded from 15 athletes (VO2max > 55 ml/(kg.min)) and 15 nonathletes (VO2max < 45 ml/(kg.min)) in the sitting position during controlled respiration (tidal volume 700 ml and 15 cycles/min). The autonomic functions were assessed by the normalized low-frequency power (LF power: 0.06-0.14 Hz) and high-frequency power (HF power: the region of the respiratory frequency based on respiratory spectrum) obtained from the autospectra of the RR interval, systolic arterial pressure (SAP), and diastolic arterial pressure (DAP) variability signals. The spontaneous baroreflex sensitivity (BRS) was evaluated by the moduli, BRSLF and BRSHF, of the transfer function between the RR interval and SAP variability in LF and HF bands. The resting HR in athletes was significantly lower than that in nonathletes. In the case of RR interval spectra, the HF power was significantly higher in athletes than in nonathletes, whereas the LF power was significantly lower in athletes than in nonahtletes. These differences might reflect an alteration of sympathovagal interaction with a predominance of parasympathetic activity. However, there was no significant difference in the LF power of SAP and DAP autospectra, reflecting the sympathetic vascular control. The BRSLF and BRSHF were significantly higher in athletes as compared with nonathletes. These results indicate that endurance training induces autonomic imbalance (i.e., the enhanced vagal activities/the attenuated sympathetic tone), which may in part contribute to the resting bradycardia and an increase in the spontaneous BRS in athletes. PMID- 8676575 TI - Stimulated Ca2+ entry activates Cl- currents after releasing Ca2+ from the intracellular store in submandibular gland cells of the rat. AB - In order to examine whether Ca2+ entry is directly involved in controlling exocrine secretion, the Ca(2+)-activated Cl- currents were recorded in single and clusters of rat submandibular gland cells using the whole-cell patch-clamp method. Extracellularly applied acetylcholine (ACh, 10 nM) as well as intracellularly applied GTP gamma S and InsP3 caused repetitive transients of the Cl- currents activated by intracellular Ca2+. These responses occurred also in the absence of external Ca2+, but disappeared after several minutes. Readmission of Ca2+ to the extracellular solution restored the repetitive current transients, while introduction of Sr2+ failed to restore the current signals in spite of the presence of Sr2+ entry detected by microfluorimetry. On the other hand, direct application of Sr2+ to the cell inside caused activation of the Cl- currents although less effectively than Ca2+. When Ca2+ was introduced to the extracellular solution during an interruption of ACh stimulation after the ACh induced depletion of intracellular Ca2+ store, the Cl- current was not elicited. However, a subsequent challenge with ACh at the same concentration in the absence of extracellular Ca2+ caused repetitive transient Cl- currents. The results suggest that in this cell type the stimulated Ca2+ entry does not by itself activate the Cl- currents but activates them indirectly by triggering Ca2+ release from the intracellular Ca2+ store which may take up Ca2+ soon after the Ca2+ entry. PMID- 8676577 TI - Acute or chronic exercise alters angiotensin II-induced contraction of rat aorta. AB - Chronic exercise substantially shifted the dose-response curve for angiotensin II (ANG II)-induced contractions to the right with increases in the EC50 value in both endothelium-intact and endothelium-denuded aortae. An acute endurance exercise also caused a 3-fold increase in the EC50 value in both endothelium intact and endothelium-denuded aortae from sedentary control rats. Whereas, no substantial increase in the EC50 value was observed in trained rats after an acute endurance exercise. Thus, chronic exercise attenuates ANG II receptor mediated contraction of rat aortae. An acute exercise also caused the reduced responses to ANG II in sedentary control rats but not in chronically exercise trained rats. PMID- 8676576 TI - Influence of intracellular Mn on the contractile inhibition caused by db cAMP, forskolin, and porcine relaxin in the circular muscle of the estrogen-treated rat uterus. AB - Whether Mn ion permeates into circular muscle cells of the estrogen-treated rat uterus and how contractile inhibitions caused by db cAMP, forskolin, and relaxin are affected by treatment with Mn were examined. By exposing the muscle strip to 0.35 mM Mn added to Mg-free Krebs solution, the magnitude of phasic contractions evoked by electrical stimulation was reduced to 21.8 +/- 14.7% (n = 22) of control. Mn influx was measured by fura-2 fluorescence quenching at the Ca isosbestic excitation wavelength (360 nm). The contractile inhibitions caused by 30 microM db cAMP and 0.2 microM forskolin were enhanced after pretreatment with 0.35 mM Mn for 10 min, whereas the inhibition caused by 100 mU relaxin underwent enhancement or attenuation. These results are discussed in relation to those reported previously for the longitudinal muscle in which the influences of treatment with Mn were somewhat different. PMID- 8676578 TI - Adaptation to heat. PMID- 8676579 TI - Ventilatory depression during mild hypoxia in adult humans. PMID- 8676580 TI - Cardiac autonomic control and muscle sympathetic nerve activity during dynamic exercise. AB - We compared sympathetic outflow to the heart and skeletal muscle (MSNA) during dynamic exercise to test whether their mechanisms of control were the same. The sympathetic component to the heart was evaluated by heart rate variability analysis of the power spectrum. MSNA was recorded from the median nerve during graded leg cycling lasting 16 min at loads of 20, 40, 60, and 75% of maximal oxygen uptake (VO2max) in the sitting position. The R-R interval and heart rate variability as well as low (Pl) and high (Ph) power frequency decreased with increasing exercise intensity while no significant change was observed in total power (Pt). The indicator of the cardiac sympathetic component, Pl/Ph, and the parasympathetic component, Ph/Pt, increased and decreased relative to exercise intensities, respectively. MSNA, represented as burst frequency (BF), was suppressed by 21.4% at 20% VO2max, and thereafter BF increased with the exercise intensity by 23.5% and by 79.4% at 60 and 75% VO2max, respectively, compared to the baseline level. There was a close positive and negative correlation between changes in BF and those in Pl/Ph (r = 0.593, p < 0.002) and Ph/Pt (r = -0.681, p < 0.0001), respectively. These results indicate acceleration of the sympathetic component of heart rate and increase in sympathetic outflow to the skeletal muscle during graded exercise. However, the exact control mechanisms of these sympathetic responses to graded exercise in two different organs remain unclear. PMID- 8676581 TI - Changes of contractile properties of extensor digitorum longus in response to creatine-analogue administration and/or hindlimb suspension in rats. AB - Changes of contractile properties of extensor digitorum longus in response to hindlimb suspension and/or altered high-energy phosphate contents were studied in rats. A reduction of high-energy phosphates, especially phosphocreatine, was seen in rats fed creatine analogue beta-guanidinopropionic acid (beta-GPA), but they were elevated after 10-d supplementation of creatine. The one-half relaxation time was increased by feeding beta-GPA, but was normalized by creatine supply. The fatigue resistance of creatine-depleted muscle was significantly improved, but tended to decrease by suspension and creatine supply, although it was still better than that in the control diet group. It is indicated that the contractile properties of muscle are influenced by the high-energy phosphate content. It is also suggested that the endurance capacity may be influenced by the mitochondrial respiratory capacity, but not necessarily by the levels of high-energy phosphates. PMID- 8676583 TI - Geriatric ethics: responsibilities and conspiracies, Part I. PMID- 8676582 TI - Left ventricular mechanoenergetics under altered coronary perfusion in guinea pig hearts. AB - Coronary perfusion pressure (CPP) is well known to affect left ventricular (LV) mechanoenergetics (Gregg's phenomenon). The garden hose effect via the Frank Starling mechanism caused by coronary distension has long been considered to be the underlying mechanism of this phenomenon. However, recent studies have revealed a close correlation between CPP and the excitation-contraction coupling in myocytes. The aim of this study was to investigate the mechanoenergetic aspects of Gregg's phenomenon by the ventricular contractility (Emax) dependency of the myocardial oxygen consumption (VO2)-total mechanical energy (PVA, systolic pressure-volume area) relationship. Experiments were performed in the excised, cross-circulated guinea pig heart preparation. The protocol consisted of LV volume loading (VOL run), changing coronary perfusion pressure at a fixed LV volume (CPP run) and intracoronary calcium (Ca) infusion also at the same LV volume (Ca run). In all seven hearts, we obtained a linear VO2-PVA relation in VOL run. The VO2-PVA relations in CPP and Ca runs, which equally enhanced Emax, were highly linear and had no significant difference in their slopes, both significantly steeper than in VOL run. These findings suggest no significant difference in the oxygen cost of Emax between CPP and Ca runs. The enhanced LV mechanoenergetics under increasing CPP is characterized by increases in the VO2 component primarily for the excitation-contraction coupling to a greater degree than expected from the mechanical (garden hose) effect. PMID- 8676584 TI - Prevention of hepatitis A. PMID- 8676585 TI - Complications of intravenous heparin therapy for treatment of thromboembolic disease in joint arthroplasty patients. PMID- 8676586 TI - The provision of labor and delivery services by graduates of four Kansas family practice residencies. AB - The provision of labor and delivery services by family physicians is especially important in largely rural states such as Kansas. The decline in the number of family physicians offering labor and delivery services threatens those who depend on access to primary health care in rural areas. A survey was mailed to all 370 of the University of Kansas School of Medicine-Wichita (UKSM-W) family practice residency graduates. Two hundred sixty-five (72%) graduates responded, of whom 206 are in private practice. Eighty percent of responding graduates practice in communities of less than 100,000, and 72% of those physicians provide labor and delivery services. Although 48 of 206 graduates have ceased delivering babies, 131 still do so, averaging 41 deliveries per year. Sixty-five graduates perform C sections, averaging 12 per year. CONCLUSIONS. UKSM-W graduates afford rural patients considerable access to care. Income, work hours, and practice satisfaction were similar in all three groups (no delivery, delivery without cesarean section, and cesarean section). Policy makers are justified in expanding educational programs in family practice that emphasize complete care of the pregnant woman. PMID- 8676587 TI - Who'd a thought? PMID- 8676588 TI - Testicular seminoma: review and experience in northwest Kansas. PMID- 8676589 TI - Medical care and the criminal law. PMID- 8676590 TI - [Relation of pulmonary hemodynamics and ventilation to tissue hypoxia during exercise in patients with tuberculosis sequelae]. AB - We examined a relationship between tissue hypoxia and pulmonary hemodynamics or ventilatory capacity during rest and exercise in patients with tuberculosis sequelae. Nine patients performed exercise test until their symptom limit. Mean pulmonary arterial pressure (PPA) during exercise was plotted against cardiac index (C.I.) from rest to maximum exercise in each patient. In most of the patients, the changes of PPA showed linear relation with the C.I., and a slope (P F slope) was obtained from the regression equation in each patient, and it was used as an index of circulatory disability during exercise. At the same time a coefficient of oxygen delivery (COD) was calculated and mixed venous oxygen tension (PvO2) was measured to evaluate a tissue hypoxia at rest and during exercise. The changes of COD were similar to those of PvO2 during exercise. COD positively correlated with PvO2 (R = 0.873, P < 0.01) from rest to maximal exercise, indicating that the values of PvO2 depended on those of COD. P-F slope negatively correlated with S.I. (R = -0.887, P < 0.01), oxygen transport (R = 0.780, P < 0.01), COD (R = -0.827, P < 0.01) and PvO2 (R = -0.760, P < 0.01) at maximal exercise. Whereas no significant relationship between ventilatory variables and COD or PvO2 was noted at maximal exercise. In conclusion, the patients with pulmonary tuberculosis sequelae who had a step P-F slope showed low mixed venous oxygen tension during exercise as a result of limited oxygen transport in consequence of low stroke volume. PMID- 8676591 TI - [Video-assisted thoracic surgical (VATS) biopsy as a technique for differential diagnosis of indeterminate small pulmonary nodules]. AB - The authors experienced two cases of multiple pulmonary tuberculomas, which were suspected of metastatic lung tumors. First patient was a 63-years-old male, who was found to have multiple pulmonary nodular shadows on his check up chest X-ray film, suspected of pulmonary metastases of rectal cancer. VATS biopsy, performed for one of nodules revealed that it was caseating granuloma, suggestive of pulmonary tuberculosis. Second patient was a 55-years-old female with rheumatoid arthritis and a chest X-ray film showed multiple pulmonary nodules, which were thought to be metastatic lung tumor from unknown origin. VATS biopsy for a subpleural nodule showed epitheloid granuloma with caseous necrosis of lung, indicating pulmonary tuberculosis. VATS biopsy is, therefore, an useful technique for differential diagnosis of small pulmonary nodules of unknown origin. PMID- 8676592 TI - [A case of AIDS with bronchial tuberculosis]. AB - A case is 48 years-old Japanese man who had a history of frequent sexual contact with prostitutes in Thailand and the Philippines. He presented with chief complaint of chest discomfort in April 1995. His chest X-ray film showed right mediastinal lymph node swelling in other hospital and the sputum smear was strongly positive for acid fast bacilli. In May 1995, he was admitted to our hospital and serological tests for HIV were positive both by EIA and Western blot methods. The CD4 lymphocyte count was 167/microliters. He was diagnosed as a case of AIDS according to the criteria proposed by the AIDS surveillance committee of the Japanese Ministry of Health and Welfare. Although numerous tubercule bacilli were detected in sputum, the chest X-ray did not show abnormal shadow in lung fields. So the diagnosis of bronchial tuberculosis was suspected by these apparently contradictory findings and the bronchoscopy was performed. Biopsy specimen of the bronchial mucous membrane obtained by bronchoscopy confirmed the presence of acid fast bacilli by Ziehl-Neelsen's staining method, however, histological findings were atypical of tuberculosis. A month after the initiation of treatment with isoniazid, rifampicin and ethambutol and AZT, his clinical symptoms improved and the sputum smear and the culture tests for tubercule bacilli converted to negative. Complications of AIDS, (Pneumocystis carinii infection, Cytomegalo virus infection, Kaposi's sarcoma, etc) other than tuberculosis have not developed to date. In the past reports, we could not find reports of bronchial tuberculosis with AIDS. Tuberculous granuloma formation was scarce in this case, and it was suspected that bronchial tuberculosis with AIDS would show characteristic sign as same as pulmonary tuberculosis with AIDS. PMID- 8676593 TI - [A case of abdominal tuberculous lymphadenitis diagnosed by percutaneous needle biopsy under ultrasound control and followed up by ultrasound imaging]. AB - A case of abdominal tuberculous lymphadenitis diagnosed by percutaneous needle biopsy under ultrasound control and followed up by ultrasound imaging was reported. A 63 years-old male was admitted to a certain hospital complaining of dizziness and diplopia. Chest roentgenogram showed bilateral infiltrative shadows in the upper lung fields and Mycobacterium tuberculosis was detected in cultures from specimens of gastric aspiration. Abdominal ultrasound examination and computed tomography showed abdominal lymph nodes swelling. Needle biopsy under ultrasound control was performed, and the specimens showed necrosis and Mycobacterium tuberculosis was positive by culture. He was diagnosed as lung tuberculosis with abdominal tuberculous lymphadenitis and admitted to our hospital for anti-tuberculous chemotherapy. Ultrasound examination done every two weeks showed diminution in size of the lymph nodes after a month of anti tuberculous therapy. For the diagnosis of abdominal lymph node swelling, a needle biopsy under ultrasound control is safe and useful technique, and a ultrasound examination is also valuable to follow up the course of abdominal tuberculous lymphadenitis. PMID- 8676594 TI - [A case of posterior tuberculous spondylitis of the lumbar vertebra with the skull inoculated by acupuncture]. AB - A 77-year-old male consulted an orthopedist with complaints of lumbago and a lumbar swelling, and was treated with acupuncture. As the symptoms deteriorated, and smear of a specimen aspirated from the lumbar swelling was positive for acid fast bacilli which were later identified as Mycobacterium tuberculosis, he was hospitalized in the National Chiba Higashi Hospital. On admission to our hospital, CT-scan of lumbar vertebrae showed the destructive change of spinous process of the third lumbar vertebra accompanied by the abscess formation, and an occipital swelling with the destructive change of skull was also detected. Whole body examinations with CT-scan and bronchoscopy did not reveal any other abnormal findings suspective of tuberculous lesions. The above lesions were both gradually improved by antituberculous chemotherapy with INH, RFP, and EB. He was finally diagnosed as posterior tuberculous spondylitis of the lumbar vertebra with cold abscess, and also clinically diagnosed as skull tuberculosis caused presumably by the inoculation of tubercle bacilli from the lumbar lesion by acupuncture. PMID- 8676595 TI - [Hypersomnia in multiple sclerosis]. AB - A 13-year-old girl presented with hyersomnia and incontinence of urine. The clinical course was complicated by strabism, muscle weakness and coordination and balance disturbances. VEP recording were pathologic. Myelin basic protein in the cerebrospinal fluid was elevated. Nuclear resonance imaging of the brain revealed multiple areas of demyelination. These findings supported the diagnosis of multiple sclerosis. There was a marked disturbance of the sleep-waking-pattern during the acute phase of the illness. The hypnogram resembled the pattern of polysymptomatic narcolepsy. Regression of symptoms was noted with dexamethasone therapy. PMID- 8676596 TI - Value of clinical symptoms, intrathecal specific antibody production and PCR in CSF in the diagnosis of childhood Lyme neuroborreliosis. AB - Due to the wide spectrum of clinical manifestations of Lyme neuroborreliosis laboratory investigations are necessary to confirm the diagnosis. Serum and CSF antibodies against Borrelia burgdorferi (Bb) as well as mononuclear CSF pleocytosis are usually present in patients with suspected neuroborreliosis. In some cases, however, the results may be conflicting, causing difficulty for the clinician in making a therapeutic decision. We therefore analysed the value of clinical symptoms, the presence of intrathecal antibody production against Bb with a modified IFA and a capture ELISA test, and the presence of Bb in the CSF with PCR testing in eleven children with suspected neuroborreliosis. In six of eight children with probable neuroborreliosis we could demonstrate intrathecal antibody production against Bb. In only one of these cases could Bb be detected in the CSF with the PCR assay. In two children the clinical manifestations consisting of erythema chronicum migrans and facial palsy, the presence of mononuclear CSF pleocytosis, and the presence of Bb specific antibodies in serum supported the diagnosis of neuroborreliosis, despite the absence of intrathecal specific antibodies. Three additional children with possible neuroborreliosis based on the occurrence of nonspecific clinical symptoms along with high serum antibody titers to Bb were included in the study. Intrathecal antibodies against Bb could not be detected and the PCR result was negative; therefore the diagnosis of neuroborreliosis was not substantiated in these three patients. We conclude that in addition to clinical symptoms, serological evidence and CSF findings suggestive of neuroborreliosis, the demonstration of intrathecal specific antibody synthesis against Bb may be helpful in establishing a definitive diagnosis of neuroborreliosis. The absence of CSF antibodies, however, does not necessarily indicate a lack of CNS involvement, especially if the examination is performed early in the course of disease. PCR testing in CSF is not suitable for routine application in the diagnosis of Lyme neuroborreliosis. PMID- 8676597 TI - [Indirect genotype analysis in 2 families with early manifestation of autosome dominant polycystic nephropathy]. AB - Autosomal dominant polycystic kidney disease (ADPKD) is one of the commonest dominantly inherited disease with an estimated incidence of 1 in 1000. In the majority of cases the ADPKD gene locus is linked to chromosome 16p13.3-markers (PKD1). It has been estimated that approximately 2 percent of PKD1 gene carriers already present with severe clinical manifestation in childhood. In two families with early manifestation of ADPKD, DNA studies with markers of chromosome 16p allowed the determination of carrier status. A preclinical (predictive) DNA analysis of possible PKD gene carriers in childhood should not be performed as a routine examination. However, children of PKD gene carriers should be examined by pediatric nephrologists in order to allow early treatment of possible complications. PMID- 8676598 TI - [Bone density in children and adolescents with rheumatic diseases. Preliminary results of selective measurement of trabecular and cortical bone using peripheral computerized tomography]. AB - Selective measurements of bone mineral density (BMD) of trabecular and cortical bone at the ultradistal radius were made in 27 children with rheumatic diseases and in age- and sex-matched healthy controls using peripheral quantitative computed tomography (pQCT). RESULTS: Mineral density of trabecular bone (-34,5%) and total bone mineral density (-18,9%) differed significantly between patients and controls (p < 0.01). BMD of the cortical bone (-13,6%) did not differ significantly between the groups. There was no difference in BMD in patients with systemic or non-systemic diseases. BMD did not correlate with duration of disease or steroid medication. CONCLUSIONS: Total bone mineral density and trabecular bone density are decreased in children and adolescents with sytemic and non systemic rheumatic diseases. Age of onset of disease and steroid medication did not correlate with bone mineral density. PQCT has the advantages of low local and no total body radiation, high sensitivity, high reproducibility and selective measurement of different bone compartements. Because selective measurement can be made in metabolically active trabecular bone changes of BMD can be detected at an early stage before the whole bone is affected. With this method therapy for chronic diseases affecting bone density can be initiated and the course of the disease can be followed. PMID- 8676599 TI - [Long-term ursodeoxycholic acid treatment of cholestatic liver diseases in childhood--clinical and biochemical effects]. AB - BACKGROUND: In adults with chronic cholestatic liver disorders, controlled studies have shown a reduction of clinical, biochemical and possibly histological parameters during long-term medication with ursodeoxycholic acid (UDCA). It is not yet clear, however, whether similar effects can be achieved in children. Therefore, we retrospectively evaluated the use of UDCA in typical liver diseases of childhood. METHOD: 20 children were treated for at least 6 months (age at start of therapy 5-87, median 24 months; diagnosis: biliary atresia n = 10, Alagille's syndrome n = 4, intrahepatic biliary hypoplasia n = 3, Byler disease n = 3). Pruritus, liver cell injury, cholestasis, synthetic liver function and weight and height for age before medication with UDCA (7-26, mean 13 mg/kg BW/d) was compared to values after 3, 6, 12, 18 and 24 months of therapy, with special attention towards possible adverse effects. RESULTS: No adverse effects of UDCA necessitating modification of therapy were encountered. During the first year of medication, weight for age improved in 15 patients, but pruritus in only four. During UDCA treatment, GIDH and gamma GT decreased significantly. GOT and GPT declined in the majority of patients. No significant changes of bilirubin and parameters of liver synthesis were seen. CONCLUSION: Long-term medication with UDCA appears to be safe in children. Thus, controlled studies of UDCA medication in children are justified, and are urgently needed to further investigate the prognostic significance of the positive effects of UDCA identified in this retrospective analysis. PMID- 8676600 TI - [Therapy of iodine deficiency goiter in adolescents with iodine or a combination of iodine and levothyroxine with special reference to lipid parameters]. AB - The are various opinions about the optimal therapy of endemic goiter in adolescents. From 106 patients (75 girls) suffering from endemic goiter 50 patients (group A) were treated with 300 micrograms iodine per day and 56 patients (group B) with 100 micrograms iodine plus 100 micrograms levothyroxine per day. Before therapy and after 172 days of therapy on average the thyroid volume, the thyroid hormones (TSH, T3, T4) and the lipidparameters (cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides) were measured. Within the period of treatment the thyroid volume (measured by ultrasound) decreased by 11.3% in group A and by 23% in group B. The iodine deficiency was corrected completely in both groups. However, investigations in both groups proved that patients undergoing combined therapy excrete the iodine administered additionally. Analogously to studies of the intrathyreoidal iodine metabolism it can be concluded that combined therapy on the basis of the dose mentioned above does either not result in an increase in the intrathyreoidal iodine contents or in a minor increase only. Iodine treatment as well as combined treatment cause a decrease in TSH-levels and an increase in T4-levels. The changes are only significant in group B. In the total group the percentage of T3-increases was reduced from 45% to 33% during treatment. The initially elevated plasma concentration of cholesterol, LDL-cholesterol and triglycerides - compared to the control group - decreased significantly in both groups during therapy. Both groups does not differ significantly with respect to the decrease in lipids. It is to be concluded that combination therapy is preferable to iodine therapy with respect to the SD-volume reduction as well as the lipid metabolism. The primary cause of endemic goiter, i.e. the intrathyreoidal iodine deficiency, can presumably not be eliminated by means of the dose of 100 micrograms iodine combined with 100 micrograms LT4. PMID- 8676601 TI - [Carnitine deficiency and carnitine therapy in a patient with Rett syndrome]. AB - BACKGROUND: Rett syndrome can be diagnosed only clinically. Several biochemical abnormalities are known, but none of them is characteristic. To our knowledge only one study on carnitine deficiency and one case of successful carnitine therapy have been reported. PATIENT: A five years old girl with normal milestones in the first months of life became retarded in the second year with muscle hypotonia of unknown cause and loss of known abilities. Later on recurrent washing movements of the hands, hyperventilation and microcephaly were observed and the diagnosis of Rett syndrome was established. METHOD: A muscle biopsy was performed for the determination of enzymes of the respiratory chain and polarographic respirometry in permeabilized muscle fibres at the age of 3 1/2 years. Carnitine in plasma and urine was determined before and during a therapy with carnitine. RESULTS: The activities of some enzymes of the respiratory chain were slightly decreased as was oxygen consumption in the permeabilized muscle fibres. However muscle morphology and histochemistry were normal. With normal carnitine in the muscle plasma carnitine was clearly decreased but showed a normal ratio of acylcarnitine to free carnitine. Carnitine substitution was started at the age of 3 1/2 years with 75 mg/kg/day and was later increased to 150 mg/kg/day. The treatment showed not only a normalisation of plasma carnitine but also an improvement of physical activity, muscle hypotonia, communication and sleep time. A wash out for one month and resumption of therapy confirmed the efficacy of this regime. CONCLUSIONS: The reason for the carnitine deficiency in the patient with Rett syndrome is not known. A primary carnitine deficiency is excluded by normal muscle carnitine. An explanation for the efficacy of the carnitine therapy is not known, although one could speculate that carnitine provides a transport system for acetyl groups, stimulates acetylcholine formation in the brain and in this way improves the disturbance of the cholinergic system. PMID- 8676602 TI - [Prader-Willi syndrome in association with self-injury behavior and premature craniosynostosis]. AB - Report of an 18-years old mentally retarded patient with Prader-Willi syndrome, who exhibits severe disorders of behaviour including self-injurious behaviour. A psychic frontal lobe syndrome as the result of premature craniosynostosis is discussed. PMID- 8676603 TI - [X-chromosomal recessive hydrocephalus internus: a separate disease picture? 2 further case reports and review of the literature]. AB - Two patients with X-chromosomal hydrocephalus internus (aqueduct stenosis, clasped thumbs, mental retardation and spasticity) habe been described. In both cases the family history revealed further affected relatives. The intra- and interfamilial variability of this rare X-chromosomal recessive disease will be demonstrated. In this context differentialdiagnoses like X-linked MASA syndrome and X-linked spastic paraplegia have been discussed on the basis of a variable expressivity of different mutations in the same gene. PMID- 8676604 TI - [Extra-cerebral intracranial fluid collections in childhood: differentiation between benign subarachnoid space enlargement and subdural effusion using color coded duplex ultrasound]. AB - BACKGROUND: Extracerebral fluid collections in infancy are a common diagnostic problem, because by noninvasive imaging studies (including cranial ultrasonography, CT and NMR), no definite differentiation between two distinct pathological conditions can be found until today: An enlargement of the subarachnoid spaces in children with macrocephaly is a frequent observation of mostly unknown etiology but is known to be associated with a good prognosis. If surgery is necessary in these patients, ventricular shunting is required. On the other hand subdural effusions are often of traumatic origin and require frequently neurosurgical intervention (subdural shunting). Most reports on extracerebral fluid collections in infancy have not differentiated between both pathological conditions and therefore reveal confusing results. Recent studies using magnetic resonance imaging have shown that vascular flow phenomena in the arachnoid space can be used to a reliable diagnosis, whereas previous noninvasive neuroimaging attempts including high resolution computerized tomography (CT) have been useless. PATIENTS AND METHODS: We investigated a cohort of 20 patients aged 4 mths to 30 mths (mean 10.5 +/- 6.6 months) 16 with the history of macrocephaly and normal neurological development and 4 patients after head trauma and symptoms of an elevated intracranial pressure. RESULTS: In all 16 patients with the clinical diagnosis of benign subarachnoid space enlargement colour coded Doppler sonography detected archnoid vessels within the fluid collection, furthermore high resolution ultrasound demonstrated the dural border of of the arachnoidea as an echogenic membrane, an observation useful as a further sign of the subarachnoid location of the fluid collection. In the 4 patients with subdural hematoma the fluid collection showed an increased echogenity, no vascular structures and no surrounding border. CONCLUSION: Out of these observations we conclude that high resolution ultrasound and colour-Doppler sonography are able to reliably differentiate between a subdural and a subarachnoid fluid collection. An NMR investigation with its higher risks (sedation, anesthesia) focused on this target only seems therefore to be not necessary in these patients. PMID- 8676606 TI - The performance of Hospital Corporation of America and Healthtrust hospitals after leveraged buyouts. AB - The authors examine performance changes after two leveraged buyouts (LBOs) in the hospital industry, one an employee stock ownership plan (ESOP) and the other a managed buyout (MBO). The findings show that hospitals owned by HCA, the MBO firm, and Health Trust, the ESOP firm, did not increase revenues, decrease operating expenses, or improve profitability after the LBOs, relative to other hospitals in their local markets. Nor were the numbers or salaries of employees at these facilities decreased. Although performance incentives associated with LBOs did not change performance at the hospital level, incentives to meet debt payments did result in corporate changes. More specifically, the LBOs led to corporate downsizing through the sale of hospitals and subsidiaries. PMID- 8676607 TI - The impact of implementing a more restrictive prescription limit on Medicaid recipients. Effects on cost, therapy, and out-of-pocket expenditures. AB - On November 1, 1991, the Georgia Department of Medical Assistance reduced the maximum number of monthly reimbursable prescriptions from six to five. This policy change provided a natural experiment to investigate the recipient responses to a decrease in an existing prescription limit. The research design was a quasiexperimental, retrospective, 12-month interrupted time-series analysis of a cohort. The cohort consisted of 743 ambulatory recipients who were high prescription users. Complete Medicaid claims data were obtained, in addition to pharmacy-generated computer profiles for all cohort recipients to determine Medicaid and out-of-pocket prescriptions expenditures. Interrupted time-series analyses were performed to model the effect of the five-prescription limit on total, Medicaid-reimbursed, out-of-pocket, and prescription use across eight therapeutic categories. After the implementation of the five-prescription limit, total prescription use fell 6.6%, prescriptions reimbursed by Medicaid fell 9.9%, and prescriptions paid for out-of-pocket increased 9.7%. Abrupt, permanent decreases were observed for cardiovascular, miscellaneous, pulmonary, and palliative therapeutic drug categories (alpha = 0.05), whereas gastrointestinal, chemotherapy, hormone (insulin), and central nervous system prescription use remained constant. The implementation of a more restrictive prescription limit alters prescription regimens potentially predisposing elderly Medicaid recipients to clinical consequences. Further examination of the health outcomes of these recipients is necessary. PMID- 8676608 TI - Multiattribute utility function for a comprehensive health status classification system. Health Utilities Index Mark 2. AB - The Health Utilities Index Mark 2 (HUI:2) is a generic multiattribute, preference based system for assessing health-related quality of life. Health Utilities Index Mark 2 consists of two components: a seven-attribute health status classification system and a scoring formula. The seven attributes are sensation, mobility, emotion, cognition, self-care, pain, and fertility. A random sample of general population parents were interviewed to determine cardinal preferences for the health states in the system. The health states were defined as lasting for a 60 year lifetime, starting at age 10. Values were measured using visual analogue scaling. Utilities were measured using a standard gamble technique. A scoring formula is provided, based on a multiplicative multiattribute utility function from the responses of 194 subjects. The utility scores are death-anchored (death = 0.0) and form an interval scale. Health Utilities Index Mark 2 and its utility scores can be useful to other researchers in a wide variety of settings who wish to document health status and assign preference scores. PMID- 8676609 TI - Provider choice and continuity for the treatment of depression. AB - The role of specialist versus generalist providers regularly surfaces in health care reform debates about costs and quality of care. By changing incentives to seek and deliver care, different payments systems can affect both the probability of initial specialty care and the duration of this patient-provider relationship. The authors compare provider selection (psychiatrist, nonphysician mental-health specialist, general medical provider) and duration of this relationship among depressed patients in prepaid and fee-for-service plans. Regarding initial care, depressed patients in prepaid plans are significantly less likely to see a psychiatrist and more likely to see a nonphysician mental-health specialist than patients in fee-for-service plans. Although the mix of providers differs, patient demographic and clinical characteristics have similar effects on specialty in both payment systems, ie, there are no differences in who gets specialty care by type of payment, but in how many get specialty care. The average duration of a patient-provider relationship is significantly shorter in prepaid plans. Durations are significantly shorter for patients of both psychiatrists and general medical providers in prepaid plans, but do not differ by payments type for nonphysician therapists. In both payments systems, patients of nonphysician providers end the relationship sooner than patients of psychiatrists or general medical providers. Although the authors find provider switching to be associated significantly with discontinuing antidepressant medication, there is no significant direct effect on patient health outcomes. PMID- 8676611 TI - Outpatient asthma management. AB - Asthma is an inflammatory disease. Educated asthmatics can be involved in self managements strategies that focus on prevention and treatment of airway inflammation using environmental control and inhaled corticosteroids as the cornerstones of therapy. It is hoped that such an approach will reduce asthma morbidity and mortality rates. PMID- 8676612 TI - The beta-agonist controversy. AB - After many years of increasing morbidity and mortality, several avenues of scientific investigation now appear to be converging to offer an explanation for the asthma paradox and indicate that regular or long-term use of short-acting inhaled beta-agonist drugs is inappropriate. Pharmacoepidemiologic studies indicate a strong association between increased beta-agonist use and asthma deaths, which does not appear entirely related to confounding by severity. Clinical data, although still limited, show little evidence for symptomatic or functional improvement during long-term beta-agonist therapy and, in many instances, reveal significant adverse effects. Related investigations offer evidence of potential plausible mechanisms, notably increased bronchial responsiveness to inhaled allergen, to explain these findings. A radical revision of the therapeutic use of these drugs in asthma has been prompted by these findings. Beta-agonist drugs remain essential for the management of acute severe attacks. They are also useful on demand for the relief of breakthrough symptoms and for prophylaxis of exercise-induced symptoms. In chronic asthma, however, adequate anti-inflammatory therapy is the treatment of choice. Long-term treatment with short-acting beta-agonist, even in the presence of seemingly adequate anti-inflammatory therapy, may be associated with deterioration of asthma over the long-term. The effects of long-acting beta-agonists remain under review. To date, there are no data that clearly indicate a deleterious effect, and many clinical trials show benefits in symptom control and improved lung function associated with their regular use. The significance of tachyphylaxis remains to be defined. Their current role is still somewhat unclear, but they have been successfully used in subjects in whom, despite the use of moderate doses of inhaled corticosteroid, short-acting bronchodilator is still frequently required. The use of twice-daily long-acting beta-agonist appears preferable to frequent use of short-acting beta-agonists. PMID- 8676613 TI - Nonsensitizing causes of occupational asthma. AB - Irritant-induced asthma and RADS are related conditions that need further study focusing on the following questions: (1) Are there differences between the pathologic and functional features that follow single or multiple exposures to an irritant material? (2) What is the time course of the changes? (3) What are the physiologic correlates in terms of onset of airway hyperresponsiveness? (4) What are the risk markers (besides exposure)? (5) Are there means of modulating the reaction by using anti-inflammatory preparations? Developing an animal model of irritant-induced asthma and conducting prospective epidemiologic surveys in high risk workers may be most effective routes to provide satisfactory answers to these questions. Further examination of the physiopathology of such conditions as byssinosis, grain-dust-induced respiratory disease, and aluminum potroom asthma as well as of the differences from and similarities to OA is also warranted. PMID- 8676614 TI - AIDS and the lung. AB - Respiratory symptoms are common in HIV-infected persons. The challenge facing clinicians is to determine whether these respiratory symptoms are due to an opportunistic infection or to a chronic process, such as asthma, chronic bronchitis, bronchiectasis, or emphysema. This article reviewed the clinical presentation, diagnosis, and treatment of two important opportunistic infections, PCP and bacterial pneumonia. It also reviewed the current data on obstructive lung diseases as they relate to HIV. PMID- 8676615 TI - Obstructive sleep apnea. Diagnosis and treatment. AB - The studies cited in this article highlight the remarkable effectiveness of nasal CPAP therapy in reversing the clinical consequences of obstructive sleep apnea and underscore the importance of long-term compliance with therapy. This information should be shared with patients to impress on them to continue with their treatment. The economic cost of sleepiness and sleep-related accidents to society has been estimated to be in the billions of dollars. This estimate would be even higher if the costs of treating the secondary medical conditions were also included. Considerable cost savings could be realized if more people are convinced to seek medical help and receive appropriate therapy as early as possible. PMID- 8676616 TI - Obstructive lung disease and sleep. AB - There is a significant interaction between obstructive lung disease and sleep- sleep is associated with clinical deterioration in obstructive lung disease, and vice versa. Knowledge of the pathophysiology of deterioration in obstructive lung disease during sleep is essential to the understanding of the management of this problem. Recent information has helped to clarify this pathophysiology and has led to more aggressive treatment for deterioration of obstructive lung disease during sleep. Whether this newer and more aggressive treatment strategy improves survival or morbidity in these conditions is a challenge for future research. PMID- 8676618 TI - A UK Academy of Medicine: hot idea or hot air? PMID- 8676617 TI - Occupationally induced airways obstruction. AB - The studies reviewed in this article indicate the association of occupational exposure to a variety of organic and inorganic dusts and various gases and fumes with chronic bronchitis and decrements of FEV1. Usually an obstructive pattern was noted, although in some occupations a similar decrement in FVC was noted. The effect of smoking on chronic bronchitis, respiratory symptoms, and FEV1 was usually additive, although workers exposed to cotton dust in one study demonstrated an interaction between exposure and smoking, as did a study of a general population sample. In coal workers, exposure to dust in younger workers resulted in a greater decline in lung function than if the exposure occurred in older workers. Studies in coal miners and grain workers further suggest that occupational standards in effect are not sufficient to protect the working population from adverse effects. The magnitude of the effect of occupation on decrement in FEV1 is usually less than cigarette smoking. Studies in coal miners indicate, however, that a minority of workers could be more severely affected by exposure. When considered together with cigarette smoking, additional decrements in lung function because of occupational exposure could contribute to disability. Additional study is needed for better understanding of exposure-response relationships, host factors, potential interaction with cigarette smoking, and pathophysiology of the development of occupationally induced airway disease. PMID- 8676619 TI - Fludarabine in chronic leukaemia. PMID- 8676620 TI - Whole-population screening for carriers of cystic fibrosis gene. PMID- 8676621 TI - Detecting vulnerable coronary plaques. PMID- 8676622 TI - Of bites and body odour. PMID- 8676623 TI - Ruling out Ingelfinger? PMID- 8676624 TI - Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive disease with no effective treatment. In an initial study, riluzole decreased mortality and slowed muscle-strength deterioration in ALS patients. We have carried out a double blind, placebo-controlled, multicentre study to confirm those findings and to assess drug efficacy at different doses. METHODS: 959 patients with clinically probable or definite ALS of less than 5 years' duration were randomly assigned treatment with placebo or 50 mg, 100 mg, or 200 mg riluzole daily; randomisation was stratified by centre and site of disease onset (bulbar or limb). The primary outcome was survival without a tracheostomy. Secondary outcomes were rates of change in functional measures (muscle strength, functional status, respiratory function, patient's assessments of fasciculation, cramps, stiffness, and tiredness). The primary analysis was the comparison of the 100 mg dose with placebo by intention-to-treat. Drug-effect on survival was assessed before (log rank test) and after adjustment for known prognostic factors (Cox's model). FINDINGS: At the end of the study, after median follow-up of 18 months, 122 (50.4%) placebo-treated patients and 134 (56.8%) of those who received 100 mg/day riluzole were alive without tracheostomy (unadjusted risk 0.79, p = 0.076; adjusted risk 0.65, p = 0.002). In the groups receiving 50 mg and 200 mg riluzole daily, 131 (55.3%) and 141 (57.8%) patients were alive without tracheostomy (relative to placebo 50 mg adjusted risk 0.76, p = 0.04; 200 mg 0.61, p = 0.0004). There was a significant inverse dose response in risk of death. No functional scale discriminated between the treatment groups. The most common adverse reactions were asthenia, dizziness, gastrointestinal disorders, and rises in liver enzyme activities; they were commonest with the 200 mg dose. INTERPRETATION: Overall, efficacy and safety results suggest that the 100 mg dose of riluzole has the best benefit-to-risk ratio. This study confirms that riluzole is well tolerated and lengthens survival of patients with ALS. PMID- 8676625 TI - Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL. AB - BACKGROUND: Fludarabine seems to be a promising treatment for patients with advanced chronic lymphocytic leukaemia (CLL). We compared fludarabine therapy with the combination of cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of CLL in a randomised, multicentre prospective trial. METHODS: Patients older than 18 years of age were entered into the study if they presented with previously untreated B-cell lineage CLL (B-CLL) of Binet stages B or C or relapsed B-CLL pretreated with chorambucil or similar non-anthracycline containing regimens. Patients were randomly assigned to either fludarabine (25 mg/m2 per day on days 1-5) or CAP (cyclophosphamide 750 mg/m2 per day and doxorubicin 50 mg/m2 per day on day 1, and prednisone 40 mg/m2 per day on days 1 5), both given for six courses. FINDINGS: Of 196 evaluable patients, 100 were previously untreated whereas 96 patients had received prior therapy. Remission rates were significantly higher after fludarabine than CAP, with overall response rates of 60% and 44%, respectively (p = 0.023). A higher response rate to fludarabine was observed in both untreated (71% vs 60%, p = 0.26) and pretreated (48% vs 27%, p = 0.036) cases, although the difference was statistically significant only in pretreated cases. In the latter group, remission duration and survival did not differ between treatment groups with a median remission duration of 324 days after fludarabine and 179 days after CAP (p = 0.22) and median survival times of 728 days and 731 days, respectively. In untreated cases, on the other hand, fludarabine induced significantly longer remissions than CAP with the median not yet reached after fludarabine and a median of 208 days after CAP (p < 0.001). This effect also translated into a tendency towards longer overall survival after fludarabine (p = 0.087). Treatment-associated side-effects consisted in both regimens of predominantly myelosuppression and in particular granulocytopenia. CAP-treated patients had a higher frequency and severity of nausea and vomiting (25% vs 5%, p < 0.001) and alopecia (65% vs 2%, p < 0.001). INTERPRETATION: Fludarabine provided an effective and well-tolerated therapy for patients with advanced CLL, which compared favourably with CAP as one of the most effective standard regimens. In second-line therapy, fludarabine induced a significantly higher rate of complete and partial remissions, while in first-line therapy a significant prolongation of remission was obtained, which may translate into an improvement of overall survival. PMID- 8676626 TI - Comparison of acamprosate and placebo in long-term treatment of alcohol dependence. AB - BACKGROUND: About 50% of alcoholic patients relapse within 3 months of treatment. Previous studies have suggested that acamprosate may help to prevent such relapse. The aim of our study was to assess the efficacy and safety of long-term acamprosate treatment in alcohol dependence. METHODS: In this multicentre, double blind, placebo-controlled study, we recruited 455 patients, aged 18-65 years, with chronic or episodic alcohol dependence. Patients were randomly allocated treatment with acamprosate (1998 mg daily for bodyweight > 60 kg; 1332 mg daily for < or = kg) or placebo for 360 days. Patients were assessed on the day treatment started and on days 30, 90, 180, 270, and 360 by interview, self report, questionnaire, and laboratory screening. Patients were classified as abstinent, relapsing, or non-attending. Time to first treatment failure (relapse or non-attendance) was the primary outcome measure. FINDINGS: Seven patients were excluded from the intention-to-treat analysis because they did not attend on the first treatment day and therefore received no medication. The acamprosate (n = 224) and placebo (n = 224) groups were well matched in terms of baseline demographic and alcohol-related variables. 94 acamprosate-treated and 85 placebo treated patients completed the treatment phase: of those withdrawn, 104 (52 in each group) relapsed, 69 (33 vs 36, respectively) were lost to follow-up, 63 (31 vs 32) refused to continue treatment, 16 (15 vs 11) had concurrent illness, three (two vs one) died, ten (six vs four) had adverse side-effects, one (acamprosate treated) received the wrong medication, and three (placebo treated) were non compliant. The proportion without treatment failure was higher in the acamprosate than in the placebo group throughout the treatment period (p < 0.001, Mantel Cox). At the end of treatment, 41 (18.3%) acamprosate-treated and 16 (7.1%) placebo-treated patients had been continuously abstinent (p = 0.007). Mean cumulative abstinence duration was significantly greater in the acamprosate group than in the placebo group (138.8 [SD 137.5] vs 103.8 [119.0] days; p = 0.012). 148 patients (79 acamprosate, 69 placebo) completed 27 months follow-up: 27 (11.9%) acamprosate-treated and 11 (4.9%) placebo-treated patients remained continuously abstinent, and the mean cumulative abstinence duration was 230.8 days (259.1) and 183.0 days (235.2), respectively. Apart from occasional diarrhoea, there was no difference in side-effects between groups. INTERPRETATION: Acamprosate is an effective and well-tolerated pharmacological adjunct to psychosocial and behavioural treatment programmes for treatment of alcohol-dependent patients. PMID- 8676627 TI - Psychological impact of population-based carrier testing for cystic fibrosis: 3 year follow-up. UK Cystic Fibrosis Follow-Up Study Group. AB - BACKGROUND: The objective of this study was to show the long-term psychological effects of population-based screening for cystic fibrosis. METHODS: The sample comprised all carriers (n = 435) and, for each carrier, two matched screen negative individuals (n = 870) detected during screening programmes for cystic fibrosis in the general population and in antenatal populations carried out a median of 3 years earlier in six UK centres. Questionnaires were sent to all eligible participants, with reminders sent to non-responders. The main endpoints were understanding of test results, degree of anxiety, perceptions of health, and reproductive intentions, and behaviour. FINDINGS: 746 (62%) of 1201 questionnaires were returned. Recall of the meaning of test results was accurate in 225 (80%) of 280 carriers but only 200 (43%) of 466 screen-negative individuals. 46 (16%) of 280 proven carriers believed that their result meant that they were only likely, rather than definitely, to be a carrier; 232 (50%) of 466 of those with a screen-negative result erroneously believed that the result meant that they were definitely not carriers. There was no significant difference between carriers and screen-negative individuals in degree of general anxiety, although 16% of carriers reported feeling worried about their test results. Carriers had a poorer perception of their current health than did non-carriers, even though they had been told that carrier status confers no disadvantages to their own health. There were no differences between carriers and screen-negative individuals in reproductive intentions or behaviour. INTERPRETATION: We have shown that in the long-term, retention of the meaning of test results from cystic fibrosis screening is poor. Further research is needed to improve the performance of test-related counselling programmes to ensure that the main objectives of these programmes, to provide information on carrier status and to allow informed reproductive decisions, are met. PMID- 8676628 TI - Thermal detection of cellular infiltrates in living atherosclerotic plaques: possible implications for plaque rupture and thrombosis. AB - BACKGROUND: Atherosclerotic lesions are heterogeneous and prognosis cannot easily be predicted, even with intracoronary ultrasound and angioscopy. Serial angiographic and necropsy studies suggest that the risk of plaque rupture correlates only weakly with the degree of stenosis. Most ruptured plaques are characterised by a large pool of cholesterol or necrotic debris and a thin fibrous cap with a dense infiltration of macrophages. The release of matrix digesting enzymes by these cells is thought to contribute to plaque rupture. Other thromboses are found on non-ruptured but inflamed plaque surfaces. We postulated that both types of thrombotic events may be predicted by heat released by activated macrophages either on the plaque surface or under a thin cap. METHODS: To test the hypothesis, we measured the intimal surface temperatures at 20 sites in each of 50 samples of carotid artery taken at endarterectomy from 48 patients. The living samples were probed with a thermistor (24-gauge needle-tip; accuracy 0.1 degree C; time contrast 0.15 s). The tissues were then fixed and stained. FINDINGS: Plaques showed several regions in which the surface temperatures varied reproducibly by 0.2-0.3 degrees C, but 37% of plaques had substantially warmer regions (0.4-2.2 degrees C). Points with substantially different temperatures could not be distinguished from one another by the naked eye; such points could also be very close to one another (< 1 mm apart). Temperature correlated positively with cell density (r = 0.68, p = 0.0001) and inversely with the distance of the cell clusters from the luminal surface (r = 0.38, p = 0.0006). Most cells were macrophages. Infrared thermographic images also revealed heterogeneity in temperature among the plaques. INTERPRETATION: Living atherosclerotic plaques show thermal heterogeneity, which raises the possibility that an infrared catheter or other techniques that can localise heat or metabolic activity might be able to identify plaques at high risk of rupture or thrombosis. PMID- 8676629 TI - Effect of ambient solar ultraviolet radiation on incidence of squamous-cell carcinoma of the eye. AB - BACKGROUND: We have investigated the geographic distribution of squamous-cell carcinoma of the eye to assess whether solar ultraviolet light is a risk factor for this disease. METHODS: We used routinely collected population-based cancer incidence data and published measurements of ambient solar ultraviolet light in our analysis. FINDINGS: The incidence of squamous-cell carcinoma of the eye declined by 49% of each 10 degrees increase in latitude (p < 0.0001), falling from more than 12 cases per million per year in Uganda (latitude 0.3(0)) to less than O.2 per million per year in the UK (latitude > 50(0)). Solar ultraviolet radiation decreases with increasing latitude, and the incidence of squamous-cell carcinoma of the eye decreased by 29% per unit reduction in ultraviolet exposure (p < 0.0001). INTERPRETATION: Our results are compatible with the hypothesis that exposure to solar ultraviolet light is an important cause of squamous-cell carcinoma of the eye. PMID- 8676630 TI - Confusion over a missing social security cheque. PMID- 8676631 TI - Systemic sclerosis: current pathogenetic concepts and future prospects for targeted therapy. AB - Although there is no cure for systemic sclerosis, the disease is certainly treatable. And the more that is understood of its pathogenesis, the better the prospects for treatment. Excessive collagen deposition in the skin and viscera is responsible for the morbidity and mortality. The immune system plays a critical role in setting up the fibrotic process, but impaired regulation of collagen gene expression probably underlies the persistence of fibrosis. The development of effective antifibrotic drugs, in particular agents that inhibit transcription factors involved in the activation of type I collagen genes, is likely to be the way forward for treatment of the later stages of diffuse systemic sclerosis, with immunomodulatory therapy for the earlier stages. PMID- 8676632 TI - The Ingelfinger rule, embargoes, and journal peer review--part 2. PMID- 8676633 TI - Early infant diets and insulin-dependent diabetes. PMID- 8676634 TI - Medical response to operation Grapes of Wrath. PMID- 8676635 TI - Risk of untreatable infection is growing. PMID- 8676636 TI - US approves home HIV test. PMID- 8676637 TI - Mechanism-based medicine proposed for hypertension. PMID- 8676638 TI - Portable bone-growth stimulators go domestic in USA. PMID- 8676640 TI - Surgical research. PMID- 8676639 TI - Proposed US misconduct rules draw opposition. PMID- 8676641 TI - Surgical research. PMID- 8676642 TI - Surgical research. PMID- 8676643 TI - Surgical research. PMID- 8676644 TI - Surgical research. PMID- 8676645 TI - Surgical research. PMID- 8676646 TI - Surgical research. PMID- 8676647 TI - Surgical research. PMID- 8676648 TI - Chernobyl and hypothyroidism. PMID- 8676649 TI - Hantaan and Puumala virus antibodies in blood donors in Samara, an HFRS-endemic region in European Russia. PMID- 8676650 TI - Bronchoalveolar lavage in rapid diagnosis of leptospirosis. PMID- 8676651 TI - Localised lipoatrophy after acupuncture. PMID- 8676652 TI - Ondansetron: reasons to be restrictive. PMID- 8676654 TI - Melanoma. PMID- 8676653 TI - Angiotensin-converting enzyme inhibitor for epirubicin-induced dilated cardiomyopathy. PMID- 8676655 TI - Response to dexamethasone in patients with fluid retention after docetaxel. PMID- 8676656 TI - Diverse HIV-1 genetic subtypes in UK. PMID- 8676657 TI - Cuban doctors in South Africa. PMID- 8676658 TI - Cuban doctors in South Africa. PMID- 8676659 TI - What to do with spare embryos. PMID- 8676660 TI - What to do with spare embryos. PMID- 8676661 TI - What to do with spare embryos. PMID- 8676662 TI - The causes of diabetes: a non-geneocentric view. PMID- 8676663 TI - Assessing the effects of pallidotomy in Parkinson's disease. PMID- 8676664 TI - Absence of association between respiratory symptoms in young adults and use of gas stoves in Belgium. PMID- 8676666 TI - beta-Amyloid vasoactivity in Alzheimer's disease. PMID- 8676665 TI - Selective toxicity of vincristine against chronic lymphocytic leukaemia in vitro. The Tampere CLL Group. PMID- 8676667 TI - beta-Amyloid vasoactivity in Alzheimer's disease. PMID- 8676668 TI - BRCA1 mutations in young women with breast cancer. PMID- 8676669 TI - The Vellore vibrio watch. PMID- 8676670 TI - Hepatitis E antibodies and HIV status. PMID- 8676671 TI - Multi-disciplinary approach to control of tuberculosis. PMID- 8676672 TI - Oral poliomyelitis vaccines. PMID- 8676673 TI - Oral poliomyelitis vaccines. PMID- 8676674 TI - Oral poliomyelitis vaccines. PMID- 8676675 TI - Oral poliomyelitis vaccines. PMID- 8676676 TI - Tonsillectomy in 1913. PMID- 8676677 TI - Are both genetic and reproductive associations with rheumatoid arthritis linked to prolactin? AB - The risk of rheumatoid arthritis (RA) seems to be associated with reduced fecundity and with breastfeeding; these apparently contradictory risk factors can be explained by their association with high prolactin concentrations. The only consistent genetic association with RA is for genes encoded in the HLA complex, particularly HLA DR4. We have identified some data indicating that the effects of breastfeeding and nulliparity are modified by HLA DR4 status, suggesting an interaction between genetic and reproductive risk factors in the aetiology of RA. The prolactin gene is in close proximity to the HLA region on the short arm of chromosome six. We therefore propose the hypothesis that the associations between DR4 and reproductive risk factors in RA are due to linkage disequilibrium between DR4 and an abnormally regulated prolactin gene polymorphism. PMID- 8676678 TI - Why literature and medicine? PMID- 8676679 TI - Marketing clinical trials. PMID- 8676680 TI - Vancouver AIDS meeting highlights combination attack on HIV. PMID- 8676681 TI - HIV-1 group O infection identified in USA. PMID- 8676682 TI - High-power lasers help the ischemic heart. PMID- 8676683 TI - Treatment of severe dry eye. PMID- 8676684 TI - Relation between Glasgow Coma Scale and aspiration pneumonia. PMID- 8676685 TI - Late whiplash syndrome. PMID- 8676686 TI - Late whiplash syndrome. PMID- 8676688 TI - Thermal cycler from recycled printer. PMID- 8676687 TI - Late whiplash syndrome. PMID- 8676689 TI - Appendicectomy. PMID- 8676690 TI - Qualitative research. PMID- 8676691 TI - Qualitative research. PMID- 8676692 TI - Qualitative research. PMID- 8676693 TI - Non-invasive detection of endothelial dysfunction. PMID- 8676694 TI - Delayed reactivation of hepatitis B infection after cladribine. PMID- 8676695 TI - Ectopic pregnancy falls in Finland. PMID- 8676696 TI - Cutaneous T-cell lymphoma (mycosis fungoides) PMID- 8676697 TI - Childhood neoplasia and Haemophilus influenzae type b vaccine failure. PMID- 8676698 TI - The Ingelfinger rule. PMID- 8676699 TI - The Ingelfinger rule. PMID- 8676700 TI - The Ingelfinger rule. PMID- 8676701 TI - The Ingelfinger rule. PMID- 8676702 TI - The Ingelfinger rule. PMID- 8676703 TI - Controlling pain in cancer. PMID- 8676704 TI - Cuban doctors in Africa. PMID- 8676705 TI - Economic barriers for tuberculosis patients in Zambia. PMID- 8676706 TI - A woman who did her own caesarean section. PMID- 8676707 TI - Oestrogens and depression. PMID- 8676708 TI - Guidance on new therapies in multiple sclerosis patients. PMID- 8676709 TI - Differences in vitamin D receptor genotype and geographical variation in osteoporosis. PMID- 8676710 TI - Macronutrients and risk of breast cancer. PMID- 8676711 TI - Macronutrients and risk of breast cancer. PMID- 8676712 TI - Morphine's name. PMID- 8676713 TI - The persistence of mind. PMID- 8676715 TI - Impact of daytime sleepiness underrated. PMID- 8676714 TI - Neonatal extracorporeal membrane oxygenation--a bridging technique. PMID- 8676716 TI - Why the resistance to diagnostic imaging in childhood urinary tract infections. PMID- 8676717 TI - Is nephron-sparing surgery appropriate for a small renal-cell carcinoma? PMID- 8676718 TI - Is childhood hyperactivity the product of western culture? PMID- 8676719 TI - The message, the medium, and The Lancet. PMID- 8676720 TI - UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. UK Collaborative ECMO Trail Group. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a complex and expensive technology that can be used to provide temporary support during respiratory failure. Its value for mature newborn infants is controversial because of varying interpretation of the available evidence. We undertook a collaborative trial throughout the UK to assess whether a policy of referral for ECMO has a beneficial effect on survival to 1 year without severe disability in comparison with conventional management. METHODS: Between 1993 and 1995, 185 mature (gestational age at birth > or = 35 weeks, birthweight > or = 2 kg) newborn infants with severe respiratory failure (oxygenation index > or = 40) were enrolled from 55 hospitals in a randomised comparison of either referral to one of five specialist centres for consideration of ECMO or continued intensive conventional management at the original hospital. The most common diagnoses were persistent pulmonary hypertension due to meconium aspiration, congenital diaphragmatic hernia, isolated persistent fetal circulation, sepsis, and idiopathic respiratory distress syndrome. Of the infants allocated ECMO, 84% received this support. Recruitment to the trial was stopped early (November, 1995) by the trial steering committee on the advice of the independent data monitoring committee, because the data accumulated showed a clear advantage with ECMO. 124 children were enrolled before December, 1994; those who survived to 1 year of age have undergone neurological assessment at that age (by one of three developmental paediatricians unaware of treatment allocation). FINDINGS: Overall, 81 (44%) infants died before leaving hospital, and two are known to have died later. Death rates differed between the two trial groups; 30 of 93 infants allocated ECMO died compared with 54 of 92 allocated conventional care. The relative risk was 0.55 (95% Cl 0.39-0.77; p = 0.0005), which is equivalent to one extra survivor for every three to four infants allocated ECMO. The difference in survival applied irrespective of the primary diagnosis, disease severity, and type of referral centre. The benefit of ECMO was also found for the primary outcome measure of death or disability at 1 year (among 124 children enrolled before December, 1994). One child in each group has severe disability (overall Griffiths' developmental quotient < 50, or untestable), and 16 (ten ECMO, six conventional management) have impairments with a lesser degree of disability. INTERPRETATION: These preliminary results demonstrate the clinical effectiveness of a well-staffed and organised neonatal ECMO service. ECMO support should be actively considered for neonates with severe but potentially reversible respiratory failure. PMID- 8676721 TI - Outbreak of bronchiolitis obliterans associated with consumption of Sauropus androgynus in Taiwan. AB - BACKGROUND: In August, 1995, there was an outbreak in Taiwan of rapidly progressive respiratory distress associated with consumption of uncooked Sauropus androgynus, a vegetable with a claimed yet unconfirmed effect on weight control. We report on 23 patients with strikingly similar clinical presentations. METHODS: A structured questionnaire for clinical manifestations was completed. Radiographic findings, pulmonary physiological changes, immunological and microbiological studies, and pathological examination were evaluated. FINDINGS: All patients were young and middle-aged women (mean age 39 years [range 21-52]). They took uncooked S androgynus juice, generally mixed with guava or pineapple juice, for a mean duration of 10 weeks. Progressive dyspnoea and persistent cough were the main symptoms on presentation. Pulmonary function testing uniformly revealed moderate to severe airflow obstruction with mean forced expiratory volume in 1 s (FEV1) of 0.66 L (26% of predicted). No bronchodilator response was observed. Room-air arterial blood gas analysis showed hypoxaemia (mean PaO2 9.6 [SD 1.6] kPa). Chest radiographs were essentially normal. High-resolution computed tomography showed bilateral bronchiectasis and patchy low attenuation of lung parenchyma with mosaic perfusion. Ventilation-perfusion scintigraphic findings were compatible with obstructive lung disease. Histopathology of open lung biopsy specimens in four patients confirmed the presence of bronchiolitis obliterans. Immunohistochemical stains of the open lung biopsy specimens showed predominance of T cells over B cells. Immunofluorescent stains for IgG, IgM, IgA, C1q, C3, and C4 were negative. Serum concentrations of tumour necrosis factor alpha were higher than those of normal controls. Clinical response to prednisolone was limited. INTERPRETATION: We describe an unusual association between bronchiolitis obliterans and ingestion of the vegetable S androgynus. T cell mediated immunity may be involved in the pathogenesis. PMID- 8676722 TI - Scrub typhus infections poorly responsive to antibiotics in northern Thailand. AB - BACKGROUND: Rickettsia tsutsugamushi, the aetiological agent of scrub typhus, is common in Asia and readily infects visitors to areas where disease transmission occurs. Rapid defervescence after antibiotic treatment is so characteristic that it is used as a diagnostic test for R tsutsugamushi infection. Reports from local physicians that patients with scrub typhus in Chiangrai, northern Thailand responded badly to appropriate antibiotic therapy prompted us to do a prospective clinical evaluation and antibiotic susceptibility testing of human rickettsial isolates. METHODS: The clinical response to doxycycline treatment in patients with early, mild scrub typhus in northern Thailand was compared with the results of treatment in Mae Sod, western Thailand. Prototype and naturally occurring strains of R tsutsugamushi were tested for susceptibility to chloramphenicol and doxycycline in mice and in cell culture. FINDINGS: By the third day of treatment, fever had cleared in all seven patients from Mae Sod, but in only five of the 12 (40%) from Chiangrai (p < 0.01). Median fever clearance time in Chiangrai (80 h; range 15-190) was significantly longer than in Mae Sod (30 h; range 4-58; p < 0.005). Conjunctival suffusion resolved significantly more slowly in Chiangrai (p < 0.05). Antibiotics prevented death in mice infected by Chiangrai strains of R tsutsugamushi less often than after infection by the prototype strain (p < 0.05). Only one of three Chiangrai strains tested in cell culture was fully susceptible to doxycycline. INTERPRETATION: Chloramphenicol-resistant and doxycycline resistant strains of R tsutsugamushi occur in Chiangrai, Thailand. This is the first evidence of naturally occurring antimicrobial resistance in the genus Rickettsia. PMID- 8676723 TI - Specificity, sensitivity, and predictive value of apolipoprotein-E genotyping for sporadic Alzheimer's disease. AB - BACKGROUND: We aimed to determine the specificity, sensitivity, and predictive value of apolipoprotein E (APOE) genotyping in 67 consecutive patients with clinical diagnoses of sporadic Alzheimer's disease (AD) who underwent necropsy. METHODS: We studied patients who attended the Duke Memory Disorders Clinic and were diagnosed as having probable AD. These patients were followed up until they died. APOE genotyping was done during life in most cases, but in some brain tissue obtained at necropsy was used. Members of known AD families were excluded. FINDINGS: After neuropathological examination 57 (85%) of 67 of our patients were confirmed as having AD including all 43 who had at least one APOE-epsilon 4 allele. None of the patients found not to have AD carried an epsilon 4 allele. In this series, the specificity of the epsilon 4 allele was 100%, the sensitivity 75%, the positive predictive value 100%, and the negative predictive value 42%. In this necropsy-confirmed series, the epsilon 4/epsilon 4 genotype predicted AD with 100% accuracy. The epsilon 3/epsilon 4 and epsilon 2/epsilon 4 genotypes were also unexpectedly highly specific for AD. INTERPRETATION: Data from hundreds of necropsy-confirmed non-AD patients in other longitudinal necropsy series will allow the predictive value of APOE genotypes to be assessed with useful confidence limits. PMID- 8676724 TI - Visualisation and quantification of rates of atrophy in Alzheimer's disease. AB - BACKGROUND: Definitive diagnosis of Alzheimer's disease requires histological examination of brain tissue. In life, brain atrophy can be visualised by computed tomography or magnetic resonance (MR) imaging, but the atrophy due to the disease is difficult to distinguish from that caused by normal ageing. We have investigated use of accurate positional matching (registration) and digital subtraction of serially acquired MR brain scans to allow determination of rates of global and regional atrophy. METHODS: This technique was applied to eleven patients with clinically diagnosed Alzheimer's disease and eleven age-matched controls. Each individual had two scans approximately 1 year apart; scan intervals were matched between the groups. FINDINGS: The median rate of atrophy was significantly greater in the Alzheimer's disease group than in the control group (12.3 [range 5.8 to 23.6] vs 0.3 (-1.2 to 1.7) mL per year; p < 0.0001). There was no overlap between the groups. Furthermore, three non-demented individuals at risk of familial Alzheimer's disease had scans 6-14 months apart and showed greater rates of volume loss than the controls; these three individuals have subsequently developed symptoms. INTERPRETATION: This technique may be useful for the diagnosis of Alzheimer's disease, the assessment of disease progression, and the evaluation of potential treatments. PMID- 8676725 TI - An echo of the Spanish lady. PMID- 8676726 TI - Global burden of the HIV pandemic. AB - Within the global pandemic of HIV infection there are many different epidemics, each with its own dynamics and each influenced by many factors including time of introduction of the virus, population density, and cultural and social issues. Effective management strategies depend on knowledge of all these factors. By the year 2000, WHO projections are that 26 million persons will be infected with HIV, more than 90% of whom will be in developing countries. To control AIDS, countries must not only promote changes in individual behaviour but also address social issues such as unemployment, rapid urbanisation, migration, and the status of women. PMID- 8676727 TI - Lipids and atherosclerosis. PMID- 8676728 TI - Effects of enoxaparin, standard heparin, and streptokinase on the patency of anastomoses in severely crushed arteries. AB - The effects of topical irrigation with three antithrombotic agents on the patency of anastomosed arteries following crush injury were examined. Following an impact crush injury with a 25 kg crush load, the femoral arteries of rats were divided and then anastomosed. During anastomoses, the vessel lumina were topically irrigated with saline, streptokinase, standard heparin, or enoxaparin (a low molecular weight heparin). The results were evaluated by patency test and histology up to day 56. The thrombosis rate at days 1 and 7 was statistically lower (P < 0.05) in the standard heparin and the enoxaparin groups than in the other two groups. The difference between the standard heparin and the enoxaparin groups was not statistically significant. Histology at day 1 showed that thrombus in the occluded vessels adhered to the exposed adventitia in the crushed area or the adventitia was covered by fibrin, red blood cells, and platelet mesh in the patent vessels. The results showed that 1) topical irrigation with standard heparin or enoxaparin solution significantly reduced the thrombosis rate at the anastomosis site of the crushed arteries; and 2) enoxaparin was as effective an antithrombotic agent as standard heparin when topically applied during microvascular anastomoses. PMID- 8676729 TI - Blood flow in free muscle flaps measured by color Doppler ultrasonography. AB - Color Doppler ultrasonography, a noninvasive method for studying changes in blood flow, has been used to monitor 18 patients with free microvascular lower limb muscle flaps. The peak, mean, and minimum velocities, resistance indices, and diameters of the flap pedicle arteries and also of the limb recipient arteries proximal to the microvascular anastomoses were measured at 2 and 6 weeks and 3, 6, and 9 months after surgery. The peak velocities did not significantly differ from each other, but the mean velocity in the flap pedicle arteries was 12.5% higher than that in the recipient arteries throughout the study period. End diastolic velocity in the pedicle was positive (toward the ultrasound probe) at 2 weeks (mean, 2 cm/sec, SD 10), 6 weeks (mean, 5 cm/sec, SD 16), and 3 months (mean, 3 cm/sec, SD 13) after surgery and significantly higher (P < 0.05) than at 6 months (mean, 7 cm/sec, SD 11), when the pattern of blood flow was normal forward/backward flow during systole/diastole. The resistance indices of the pedicle at 2 weeks (Ri = 0.978), 6 weeks (Ri = 0.936), and 3 months (Ri = 1.001) were significantly lower (P < 0.05) than at 6 months (Ri = 1.108), when the pedicle and recipient artery indices were the same. The diameter of the pedicle arteries was 14% smaller than those of the recipient arteries, but did not change during follow-up. This prospective clinical study shows that blood flow in the pedicle of a free microvascular muscle flap is increased until 6 months after surgery, mainly due to the increased minimum velocity of the pedicle in diastole and decreased resistance index. These findings can be attributed to the loss of vessel tone after denervation and are in accordance with earlier studies showing that denervated muscles lose their autoregulation and that blood flow increases, but that these phenomena subside with time. Increased blood flow in free muscle flaps can explain the high success rate of microanastomoses and positive effect on wound healing. PMID- 8676730 TI - Value of a dynamic MR scan in predicting vascular ingrowth from free vascularized scapular transplant used for treatment of avascular femoral head necrosis. AB - We have treated three patients with avascular osteonecrosis using vascularized scapular bone graft. To predict blood perfusion in both the diseased femoral head and the transferred bone, all the hips were followed up using dynamic magnetic resonance (MR) scans, performed 1 and 7 months after surgery. In the present cases, it was shown that conventional enhanced MR imaging sometimes depicts increased intensity in bone marrow without blood perfusion due to the leakage of gadolinium-DTPA (Gd-DTPA) from the capillaries surrounding the avascular tissue. It was found that Gd-DTPA remaining in the dead bone marrow resulted in a false positive image. By contrast, the dynamic MR scan evaluated only those images taken before the leakage. This is one of the advantages of the dynamic study, which reflects actual blood flow in the bone. The fast rise in the time-intensity curve following bolus injection of Gd-DTPA indicates that there is fast blood perfusion in the bone. The dynamic MR scan has demonstrated that there is little blood perfusion in the diseased bone 1 month after the operation and that vascular ingrowth from the transferred bone flap proceeds gradually between 1 and 7 months after surgery. These findings indicate that the dynamic MR scan is very useful in demonstrating vascular ingrowth after surgery in avascular necrosis of the femoral head and can be a reliable monitoring technique for anastomotic patency of the vascularized bone flap. PMID- 8676731 TI - Experimental study on choline acetyltransferase activity measurement for brachial plexus injury. AB - We studied choline acetyltransferase (CAT) activity in a rat model of brachial plexus injury. In experiment 1, we found that the CAT activity was remarkably high in the anterior roots and low in the posterior roots. In experiment 2, nerve root segments were extracted and examined for CAT activity in the root avulsion group (group A) and the plexus severance group (group B). CAT activity decreased day by day in group A, reaching about 1/20 of the normal 5 days postoperatively. By contrast, in group B activity decreased only slightly, and even at 90 days postoperatively was about 6,000 cpm (one-half normal level). As a result, CAT activity enabled us to distinguish postganglionic from preganglionic injury of the cervical roots. Furthermore, it was a useful adjunct for minimizing nerve loss in intercostal nerve transfer, distinguishing motor and sensory branches of the intercostal nerve, and evaluating the motor nerve activity. PMID- 8676733 TI - Thumb reconstruction with a free neurovascular wrap-around flap from the big toe: long-term follow-up of thirty cases. AB - From March 1982 to December 1992, 30 cases of thumb reconstruction with a free neurovascular wrap-around flap from the big toe were performed at Korea University Hospital. Twenty-nine of a total of 30 cases were successful and obtained excellent functional and cosmetic results. Postoperative complications included 1 case of graft failure, 6 partial skin necroses, 1 malunion, and 15 cases of resorption of iliac bone graft including 1 case of fatigue fracture of grafted bone. Even for the first metacarpal neck amputations, thumb reconstruction with a free neurovascular wrap-around flap was possible; however, limitation of motion of the reconstructed thumb and resorption of the grafted bone occurred. Thumb reconstruction with a wrap-around free flap from the big toe gives excellent cosmetic and functional results and causes minimal morbidity on the donor site. PMID- 8676732 TI - Elongation of wallerian degenerating nerve with a tissue expander: a functional, morphometrical, and immunohistochemical study. AB - The purpose of this experimental study was to investigate the usefulness and mechanism of the expansion of wallerian degenerating nerve. The study consisted of two experiments: Experiment I, functional and morphometrical analysis, and Experiment II, immunohistochemical analysis. In Experiment I, the rat nerve crush model was used to assess the effects of mechanical expansion of wallerian degenerating nerves on axonal regeneration. In Experiment II, the rat sciatic nerve cut model was used to investigate the effects of nerve expansion on Schwann cell events in wallerian degenerating nerves. In both experiments, nerve expansion was carried out between days 5 and 9 after nerve injury, using a rubber tissue expander placed beneath the sciatic nerve. In Experiment I, rats were divided into the following three groups according to the volume of saline injected: control group (nerves were crushed, without saline injection); 8-ml injection group; and 11-ml injection group. Functional recovery was assessed using the sciatic functional index until 54 days after nerve injury. Rats in all three groups showed good functional recovery, and the morphometrical analysis revealed no significant differences among the three groups. In Experiment II, anti-S-100 protein polyclonal antibody and anti-proliferating cell nuclear antigen monoclonal antibody were used to identify proliferating Schwann cells. Rats were divided into two groups: control group (nerves were cut, without expansion) and nerve expansion group. In the control group, proliferating Schwann cells were observed only between days 3 and 7. By contrast, these cells continued to be seen in the expanded nerves until day 16. These results suggest that the expansion of wallerian degenerating nerve does not have a deleterious effect on the axon-promoting property of Schwann cell tubes and that the expansion is dependent not only on the viscoelasticity of the nerves but also on enhanced proliferation of Schwann cells. PMID- 8676734 TI - The versatility of free rectus femoris muscle flap: an alternative flap. AB - In the 10-year period from June 1985 to December 1994, 54 free rectus femoris muscle or musculocutaneous flaps were performed at our hospital. It has been one of the most frequently used free muscle flaps in our institution and forms 2% of all free tissue transfers (total, 2,769 cases). In 26 patients, it was used for large wound coverage following debridement or tumor ablation, and in 27 patients, as a functioning free muscle transplantation for brachial plexus palsy or traumatic muscle loss. In one patient the components of the deep aponeurosis, muscle, and overlying skin were used for reconstruction of an abdominal wall defect after neurilemmoma excision. There were two complete failures, one due to diabetic foot infection and one due to venous occlusion. Four had superficial marginal skin necrosis. No significant disability of the donor limb was encountered. Easy approach, rapid harvest, large and reliable overlying skin flap, a single dominant neurovascular pedicle (with large vessel diameter and long motor nerve), easy primary closure of the donor site, and minimal donor site morbidity all make the rectus femoris flap a good alternative flap for free tissue transfer, in addition to the gracilis, rectus abdominis, and latissimus dorsi muscle flap. PMID- 8676735 TI - One-stage treatment of infected bone defects of the tibia with skin loss by free vascularized osteocutaneous grafts. AB - Twenty-six patients who had an infected nonunion or segmental defect of the tibia with skin loss were treated in one stage with debridement and a free vascularized osteocutaneous fibula or iliac graft. Successful control of infection, closure of skin defects, and incorporation of bone union were achieved in all patients except one. In an average follow-up of 39 months, no recurrence of infection was seen. There were four stress fractures of the grafted fibula; these healed within 2 months with cast immobilization. Graft hypertrophy was common in the fibula grafts, but it took 1 1/2 years for hypertrophy of the graft to be strong enough to remove external supports without stress fracture or an additional cancellous bone graft. The use of a one-stage free vascularized osteocutaneous graft for the management of infected bone defects of the tibia with skin loss is effective because extensive debridement can remove all devitalized and infected tissue and can increase vascularity in the region of infection and osseous defect to enhance antibiotic delivery. PMID- 8676736 TI - Multivariate analysis of factors influencing the functional recovery after finger replantation or revascularization. AB - A multivariate statistical analysis was utilized to study the influence of the four preoperative (age, mechanism of injury, level of injury, and type of amputation) and one postoperative (rehabilitation) variables on the functional recovery of the replanted or revascularized finger. Statistically significant differences are summarized as follows. The young age group have a better functional recovery due to better sensory recovery than the old age group. The crush injury group have a better functional recovery, with better scores in motion and patient satisfaction, than the avulsion injury group. The middle phalangeal injury group have a better functional recovery, with better score in motion and sensation than the proximal phalangeal injury group. There is no statistically significant difference in functional recovery between the revascularized and replanted fingers, but there is a significantly better sensory recovery in the revascularized finger. The rehabilitation group has a better functional recovery, with better score in motion, subjective symptoms, and patient satisfaction, than the nonrehabilitation group. PMID- 8676737 TI - Phylogenetic history of LINE-1 among arvicolid rodents. AB - The extent of restriction fragment sharing among arvicolid rodents was examined following Southern blotting with a reverse transcriptase region probe from long interspersed nuclear element 1 (LINE-1 or L1). DNAs from 30 species belonging to nine genera were digested with 11 restriction endonucleases. Following hybridization discrete bands were scored with respect to their presence or absence and intensity, and both within- and between-species comparisons were conducted. Intraspecific analyses revealed low but detectable levels of variation. Interspecific comparisons revealed three groups of bands: those present in all 30 species (6 out of a total of 248 bands), those phylogenetically informative in two or more species (130 out of 248), and those unique to a single species (114 out of 248). A multistate data matrix consisting of species by codes representing the intensities of informative bands was analyzed by maximum parsimony. Further, distance values between species were converted to rates using estimated fossil divergence times. Both the parsimony and rate analyses revealed differences between species in the extent of band sharing and in the intensities of common bands, indicating that the amplification and movement of LINE elements has occurred in episodic bursts during the history of this group. Systematic interpretations of the evolutionary trees were concordant with those previously obtained using other data sets, suggesting that although the amplification of repetitive sequences may occur episodically in this taxonomic group, there do appear to be some constraints. PMID- 8676738 TI - Phylogenetic relationships within the aplocheiloid fish genus Rivulus (Cyprinodontiformes, Rivulidae): implications for Caribbean and Central American biogeography. AB - We examined the phylogenetic relationships of 16 northern species of the aplocheiloid genus Rivulus inhabiting the Caribbean, Central America, and South America. A total of 714 base pairs per taxon were sequenced from two segments of the mitochondrial genome, 12S rRNA and cytochrome b. Both parsimony and neighbor joining analyses suggest an ancient vicariant origin of the Greater Antillean taxa, in addition to a quite recent dispersal of species into the Lesser Antilles from the South American mainland. Combined analyses support the monophyly of the northern South American assemblage as the sister group of a Central American/Columbian biota. However, the monophyly of the Central American biota remains uncertain. Divergence estimates for the Central American taxa are calibrated from the Last Cretaceous separation of the proto-Antilles from the Americas. These data suggest that the extant Central American taxa represent the descendants of at least two separate invasions during the Cenozoic, prior to the closing of the Panamanian isthmus. Times are consistent with the extensive evidence for reptilian and mammalian exchange throughout the Cenozoic. PMID- 8676739 TI - Approximate methods for estimating the pattern of nucleotide substitution and the variation of substitution rates among sites. AB - We propose two approximate methods (one based on parsimony and one on pairwise sequence comparison) for estimating the pattern of nucleotide substitution and a parsimony-based method for estimating the gamma parameter for variable substitution rates among sites. The matrix of substitution rates that represents the substitution pattern can be recovered through its relationship with the observable matrix of site pattern frequences in pairwise sequence comparisons. In the parsimony approach, the ancestral sequences reconstructed by the parsimony algorithm were used, and the two sequences compared are those at the ends of a branch in the phylogenetic tree. The method for estimating the gamma parameter was based on a reinterpretation of the numbers of changes at sites inferred by parsimony. Three data sets were analyzed to examine the utility of the approximate methods compared with the more reliable likelihood methods. The new methods for estimating the substitution pattern were found to produce estimates quite similar to those obtained from the likelihood analyses. The new method for estimating the gamma parameter was effective in reducing the bias in conventional parsimony estimates, although it also overestimated the parameter. The approximate methods are computationally very fast and appear useful for analyzing large data sets, for which use of the likelihood method requires excessive computation. PMID- 8676740 TI - Asymmetric substitution patterns in the two DNA strands of bacteria. AB - Analyses of the genomes of three prokaryotes, Escherichia coli, Bacillus subtilis, and Haemophilus influenzae, revealed a new type of genomic compartmentalization of base frequencies. There was a departure from intrastrand equifrequency between A and T or between C and G, showing that the substitution patterns of the two strands of DNA were asymmetric. The positions of the boundaries between these compartments were found to coincide with the origin and terminus of chromosome replication, and there were more A-T and C-G deviations in intergenic regions and third codon positions, suggesting that a mutational bias was responsible for this asymmetry. The strand asymmetry was found to be due to a difference in base compositions of transcripts in the leading and lagging strands. This difference is sufficient to affect codon usage, but it is small compared to the effects of gene expressivity and amino-acid composition. PMID- 8676741 TI - Combining protein evolution and secondary structure. AB - An evolutionary model that combines protein secondary structure and amino acid replacement is introduced. It allows likelihood analysis of aligned protein sequences and does not require the underlying secondary (or tertiary) structures of these sequences to be known. One component of the model describes the organization of secondary structure along a protein sequence and another specifies the evolutionary process for each category of secondary structure. A database of proteins with known secondary structures is used to estimate model parameters representing these two components. Phylogeny, the third component of the model, can be estimated from the data set of interest. As an example, we employ our model to analyze a set of sucrose synthase sequences. For the evolution of sucrose synthase, a parametric bootstrap approach indicates that our model is statistically preferable to one that ignores secondary structure. PMID- 8676743 TI - Large-scale search for genes on which positive selection may operate. AB - We conducted a systematic search for the candidate genes on which positive selection may operate, on the premise that for such genes the number of nonsynonymous substitution is expected to be larger than that of synonymous substitutions when the nucleotide sequences of genes under investigation are compared with each other. By obtaining 3,595 groups of homologous sequences from the DDBJ, EMBL, and GenBank DNA sequence databases, we found that 17 gene groups can be the candidates for the genes on which positive selection may operate. Thus, such genes are found to occupy only about 0.5% of the vast number of gene groups so far available. Interestingly enough 9 out of the 17 gene groups were the surface antigens of parasites or viruses. PMID- 8676742 TI - Comparison of a vitellogenin gene between two distantly related rhabditid nematode species. AB - Three vitellogenin genes from the free-living nematode Caenorhabditis elegans have previously been characterized at the molecular level. In order to study evolutionary relationships within this poorly understood taxon, we have cloned a vitellogenin gene, CEW1-vit-6, from a distantly related species belonging to the same family as C. elegans. Screening of a genomic library with a probe to total poly(A+) RNA yielded three clones that hybridized more intensely than all others, and all three corresponded to a single gene homologous to C. elegans vit-6. Comparison of CEW1-vit-6 with Ce-vit-6 reveals both strong similarities and surprising differences. Life Ce-vit-6, the gene is about 5 kb long and contains four unusually small introns (38-41 nt), but only one interrupts the gene at the same location as a Ce-vit-6 intron. The promoter region contains five matches to Vitellogenin Promoter Element 1 (VPE1) and no matches to VPE2, both previously shown to be required for vit gene transcription in C. elegans. Codon usage is in general similar to that of the Ce-vit genes, but a few codon biases are quite different. Alignment of the CEW1-vit-6 protein with Ce-vit-6 and Ce-vit-2 products suggests the existence of two domains which have evolved at different rates. Sequence comparison shows that nematode vitellogenins are much more closely related to vertebrate than to insect vitellogenins. PMID- 8676744 TI - A complete sequence of the mitochondrial genome of the western lowland gorilla. AB - The complete mitochondrial DNA (mtDNA) molecule of the gorilla was sequenced. The entire sequence, 16,412 nucleotides, was determined by analysis of natural (not polymerase chain reaction) restriction fragments covering the whole molecule. The sequence was established from one individual and thus nonchimeric. After comparison with the COII gene of gorilla specimens with known geographical origin, the sequence was identified as characteristic of the Western lowland gorilla, Gorilla gorilla gorilla. With the exception of the NADH2 gene, all genes have a methionine start codon. The inferred start codon of NADH2 is ATT (isoleucine). The COIII, NASDH4, and cytochrome b genes are not terminated by a stop codon triplet, and the COI gene is probably terminated by an AAA triplet rather than by a regular stop codon. The great majority of genic sequences (rRNAs, peptide-coding genes, tRNAs) of the complete mtDNAs of Gorilla, Pan, and Homo show a greater similarity between Pan and Homo than between either of these genera to Gorilla. The analysis of the peptide-coding genes suggest that relative to comparison between Homo and Pan a certain degree of transition saturation has taken place in codon position 3 in comparisons between Gorilla to either Homo or Pan. PMID- 8676745 TI - Phylogenetic position of cetaceans relative to artiodactyls: reanalysis of mitochondrial and nuclear sequences. AB - By a maximum likelihood analysis of mitochondrial DNA sequences, we examine Graur and Higgins' hypothesis of the Ruminantia/Cetacea clade with Suiformes as an outgroup. Graur and Higgins analyzed these sequences by the neighbor-joining and parsimony methods, as well as by the maximum likelihood method under the assumption that the substitution rate is the same for all sites. The Ruminantia/Suiformes clade assumed by the traditional taxonomy was rejected strongly by this analysis and the Ruminantia/Cetacea clade was supported. Adoption of a more realistic model distinguishing among rates at different codon positions in the maximum likelihood analysis of the same data, however, grossly reduces the significance level on the Graur-Higgins hypothesis. Thus, although the Ruminantia/Suiformes grouping is indeed least likely from Graur and Higgins' data set of mitochondrial DNA, this traditional tree cannot be rejected with statistical significance under the new analysis, and more data are needed to settle the issue. In the same way, we examine Irwin and Arnason's suggestion of the Hippopotamus/Cetacea clade by using cytochrome b and hemoglobins alpha and beta, and it turn out that their suggestion is also fragile. This analysis demonstrates the importance of selecting an appropriate model among the alternatives in the maximum likelihood analysis and of using many different genes from many relevant species in order to make reliable phylogenetic inferences. PMID- 8676746 TI - Protein kinase C alpha, beta immunoreactivity in baker's yeast, lobster and wheat germ. AB - The immunoreactivity of PKC alpha (protein kinase C alpha) and PKC beta in wheat germ, lobster tail muscle and three strains of yeast was analysed by Western blotting with mouse anti-PKC active fragments. The potency of the immunoreactivity of PKC alpha activity was much greater than that of PKC beta. The occurrence of multiple bands may be due to PKC self-interactions and/or the interactions between PKC and other molecules. The evolutionary conservation of PKC alpha and PKC beta implies that these PKC isoenzymes may play important roles in Ca2+/lipid-dependent signal transduction and cell growth in these eukaryotes. PMID- 8676747 TI - Identification of new enzyme biotypes of Helicobacter pylori isolated in Japan. AB - The enzyme biotype of 86.5% of strains of Helicobacter pylori isolated in Japan could not be determined by the method used for the identification of the biotypes defined by Reina and Alomar (1989). A modified system for naming of biotypes is proposed. PMID- 8676748 TI - Sensitization to acid induced by sodium ions in Escherichia coli: dependence of (p)ppGpp and cAMP and suppression of the relA-associated defect by mutations in envZ. AB - NaCl-induced acid sensitivity is not a response to high osmotic pressure but is triggered by a high internal sodium ion concentration, evidenced by the finding that conditions which enhance Na+ influx or reduce Na+ efflux, led to increased internal Na+ and allowed induction at lower external sodium ion concentrations and that induction could occur with no osmotic upshock. NaCl-induced acid sensitivity was not observed in Escherichia coli strain MC4100 and its relA lesion was investigated as a possible cause. Transformation of this strain and two other relA mutants to relA+ allowed sensitization by NaCl and whereas strain CF1648 (relA+) was sensitized, its relA deletion derivative was not. Additionally, transduction of two relA+ strains to relA produced derivatives which were not sensitized by salt. Although MC4100 was not sensitized by NaCl, envZ derivatives of it were sensitized. Lesions in fur and tonB did not prevent sensitization by NaCl, although extent of sensitization was slightly increased by fur and considerably increased by tonB. Acetate strongly inhibited sensitization, which was also subject to glucose repression, reversible by cAMP. The possibility was discussed that (p)ppGpp and cAMP both positively affect transcription of the genes encoding the acid sensitization components; in accord with this, high concentrations of cAMP suppressed the effect of the relA lesion of sensitization. Salt-induced organisms are more sensitive to acid damage to DNA, to acid inhibition of enzyme synthesis and DNA transfer and slightly less able to repair acid-damaged transforming DNA. PMID- 8676750 TI - Computer simulation of factors involved in the down-regulation of hormonal effects. AB - Down-regulation of hormonal effects is in the presented simulation related to the number of functional receptors and quantity of available hormonal stimulation. The former is in the model substituted with the quantity of stimulation able to produce a full down-regulation (Hs100) of target cells. The halftime (t1/2) of the hormonal effect recovery means the interval before the second hormonal stimulation can elicit half of the initial hormonal effect. Recovered hormonal effects are calculated after periods of two, three, four and five t1/2. The interval among hormonal stimulations varied from 1/2 to 5/2 of t1/2. Shorter than t1/2 intervals showed profound down-regulation even at weak hormonal stimulations (> 20% of Hs100). Stable levels of hormonal effects after frequent hormonal stimulations are found only in cases of very weak stimulations (< 10% of Hs100). Intervals equalling t1/2 among weak stimulations (< 20% Hs100) produced stable hormonal effects. Further prolongation among repeated stimulations improved stability of hormonal effects and even strong stimulations (> 60% of Hs100) were followed with only temporary profound down-regulation. Hormone-binding receptors unable to activate target cells are in the model described as defective. Probability for the target cell to be stimulated is in the model defined as P. Relative quantity of hormonal stimulation per target cell needed to achieve certain P is calculated for cells bearing different proportions of defective receptors. Activation following weak hormone stimulations is highly probable (> 90%) for cells bearing less than 30% of defective receptors. With the proportion of defective receptors over 60%, the activation probability after weak hormone stimulations is reduced (< 66%). Down-regulation can be considered as a modulator of hormonal effects. In prediabetic patients, intense stimulation of pancreatic insulin secretion by frequent or increased ingestion of carbohydrates might lead to sustained hyperinsulinemia. A substantial portion of the target tissue would become down-regulated with increased number of defective insulin receptors. Poor glucose utilization in the down-regulated tissue with resultant hyperglycemia would further stimulate insulin secretion until failure. Reduced tissue transportability of large hormone molecules, such as hGH, or proinsulin, can make their effects more pronounced in the perivascular space. Circulating hormone binding proteins or the basal membrane thickening in small vessels can further decrease the hormonal effects on more remote cells. Physical activity in IDDM patients increases insulin effect. Possible explanation is that increased muscle perfusion is making more insulin available to the less down-regulated skeletal muscle cells. PMID- 8676749 TI - Lipopolysaccharide-, granulocyte-monocyte colony stimulating factor and pentoxifylline-mediated effects on formyl-methionyl-leucine-phenylalanine stimulated neutrophil respiratory burst in the elderly. AB - The impairment of superoxide anion (O2-) generation by aged polymorphonuclear cells (PMN) stimulated with formyl-methionyl-leucine-phenylalanine (FMLP) has been reported. In this work the effect of lipopolysaccharide (LPS), granulocyte macrophage colony stimulating factor (GM-CSF) and pentoxifylline (POF) pretreatment on FMLP-triggered neutrophil oxidative metabolism in a group of healthy elderly individuals, was investigated. Results provide evidence that LPS and/or GM-CSF priming was able to enhance O2- production in old PMN, even if values were still lower than those observed in similarly-treated young cells. Moreover, even if the lag period was unaffected by inflammatory mediator treatment, the priming gave rise to a significant increase of maximum O2- release rate. On the contrary, POF pretreatment led to a significant decrease of oxidative responsiveness in either unprimed or primed PMN suspensions. These findings suggest the occurrence of different mechanisms in the imbalance of FMLP activated neutrophil oxidative responsiveness during senescence. This may be of paramount significance for explaining the augmented frequency of severe infectious diseases with advancing age. PMID- 8676751 TI - The diseases of Alzheimer and Pick from the viewpoint of prevention. AB - Alzheimer disease, Pick disease and senile dementia are all characterized by similar morphological changes, both macroscopic and microscopic, and similar psychiatric symptoms. All three should, therefore, be viewed as aspects of one disease, which is termed Alzheimer-type dementia. Nothing contradicts the view that immune complexes take part in the etiology of Alzheimer-type dementia. There are various types of immune complexes and so their points of action in the organism may vary. There might be two main means of preventing Alzheimer-type dementia: the first could be named the serological (basic) and the second relying on pharmacotherapy (additional). Pharmacological prevention of disease might be aided by the use of parasympathomimetic drugs, e.g. pilocarpine. PMID- 8676752 TI - Pros and cons in the search for extraterrestrial intelligence. AB - I propose a new term, 'galactic organism with distinct intelligence', for the extraterrestrial forms, with which humans can make contact. This is because, among the three existing terms: (a) 'the search for extraterrestrial intelligence' 'excludes biology and is inelegant'; (b) 'extraterrestrial' does not distinguish between the micro-organisms and highly-evolved intelligent life forms; and (c) 'unidentified flying object' projects a sense of mysticism. On the presence of galactic organisms with distinct intelligence, scientists belong to three camps. Astronomers, physicists and some biochemists belong to the believers group. Evolutionists are in the doubters category. The third camp is represented by the 'uncommitted'. Approaches for contacting galactic organisms with distinct intelligence would take three steps. These are: (a) radioastronomical observations in the galaxy and interstellar space for the presence of organic matter; (b) initiating radio contact and listening to any transmitted message, as set out by the search for extraterrestrial intelligence program, and (c) landing instruments and humans in the galaxy. PMID- 8676753 TI - The omnipotent platelet. AB - This information was derived from the increase in platelets of patients following fractures and/or bone surgery and in conjunction with a vast amount of published literature. The increase in numbers of platelets reflects the extent of bone involvement, especially noted in the hip, knee, post-coronary artery bypass graft, and multiple fractures. The role of the platelet in any and all tissues, i.e. soft tissue or bone, whether beneficial or detrimental, is multifunctional. The platelet responds to all physiologic and pathologic states and, if tissue involved is sufficient, the role of the platelet becomes obvious. PMID- 8676754 TI - Up-regulation of intracellular signalling pathways may play a central pathogenic role in hypertension, atherogenesis, insulin resistance, and cancer promotion- the 'PKC syndrome'. AB - The modern diet is greatly different from that of our paleolithic forebears' in a number of respects. There is reason to believe that many of these dietary shifts can up-regulate intracellular signalling pathways mediated by free intracellular calcium and protein kinase C, particularly in vascular smooth muscle cells; this disorder of intracellular regulation is given the name 'PKC syndrome'. PKC syndrome may entail either a constitutive activation of these pathways, or a sensitization to activation by various agonists. The modern dietary perturbations which tend to induce PKC syndrome may include increased dietary fat and sodium, and decreased intakes of omega-3 fats, potassium, calcium, magnesium and chromium. Insulin resistance may be both a cause and effect of PKC syndrome, and weight reduction and aerobic training should act to combat this disorder. PKC syndrome sensitizes vascular smooth muscle cells to both vasoconstrictors and growth factors, and thus promotes both hypertension and atherogenesis. In platelets, it induces hyperaggregability, while in the microvasculature it may be a mediator of diabetic microangiopathy. In vascular endothelium, intimal macrophages, and hepatocytes, increased protein kinase C activity can be expected to increase cardiovascular risk. Up-regulation of protein kinase C in stem cells may also play a role in the promotion of 'Western' fat-related cancers. Practical guidelines for combatting PKC syndrome are suggested. PMID- 8676755 TI - Lewy body diseases: possible new directions in prophylaxis and therapy. AB - No therapy exists for the Lewy body diseases, which are an important cause of dementia. We regard Lewy body diseases and Parkinson disease as components of a spectrum of disorders having a degree of Alzheimer disease neuropathology. Immunologic features of Alzheimer disease and Parkinson disease suggest the involvement of similar phenomena in Lewy body diseases pathogenesis. Based on the efficacy of anti-inflammatory medication in arresting the progression of Alzheimer disease and the presence of common immunologic features in Alzheimer disease and Parkinson disease, a case is made for therapeutic intervention at the immune system level. Anti-inflammatory medications appear to be an appropriate therapeutic approach to Lewy body diseases. PMID- 8676756 TI - Prion function and dysfunction: a structure-based scenario. AB - Prion diseases are transmissible, neurodegenerative disorders associated with as yet incompletely defined isoforms of a cellular protein termed prion protein (PrP). We have now identified in PrP structural information compatible with nucleotide- and nucleic acid-binding. As such, PrP contains a putative nicotinamide adenine dinucleotide (NADH)-binding site. Moreover, the PrP octarepeats reveal homology to the nucleic acid-binding and strand-annealing octarepeats of mammalian heterogeneous ribonucleoprotein (RNP) A1. Therefore, PrP may have NADH-dependent oxidoreductase activity as well as A1-like functions such as nucleic acid annealing and splicing. Moreover, we propose that infectious prions are propagated through a dynamic molecular symbiosis between a ribozyme like nucleic acid and a conformational isomer of the RNP-like prion protein. Thus, our model has important implications for the understanding and treatment of prion diseases. PMID- 8676757 TI - Cancer: a response to prolonged tissue necrosis. AB - Various observations about cancers do not support the prevailing view that cancer is caused by genetic mutations. Some of these discrepancies are discussed and and a new theory of the nature of cancer is presented--namely, that cancer is a response to prolonged tissue necrosis. This leads to several predictions about carcinogens and possible cancer therapies. PMID- 8676758 TI - If Schizophrenia is enantiomorphism, is light the morphogen? AB - Schizophrenia remains an enigmatic condition. It would appear that both genetic and environmental influences are relevant to the aetiopathogenesis of the disorder. Although a great amount of research has been carried out concerning the condition, the results have often lead to further questions and attempts to more closely delineate the object of study have lead to the originally observed findings becoming tenuous. One way to objectively view some aspects of this large body of work is to consider the condition as a cerebral situs inversus, as data from various lines of reasoning have suggested an inversion of the situation seen in normal controls. The hypothesis presented here draws on existing biological evidence to argue the likely role of light as a relevant, stimulatory variable which may interact with asymmetrical cerebral maturation in the establishment of functional laterality. PMID- 8676759 TI - The role of central nervous system endothelial cell activation in the pathogenesis of hepatic encephalopathy. AB - I propose that central nervous system endothelial cells are directly or indirectly responsible for the brain pathology in hepatic encephalopathy, and that this damage to the central nervous system is mediated by specific cytokines and nitric oxide which activate endothelial cells and thereby alter their cell functions. Liver diseases are conditions characterized by high circulating levels of cytokines, namely interleukin-1, interleukin-6 and tumor necrosis factor. Interactions between these cytokines and central nervous system endothelial cells may trigger a cascade of events including enhanced blood-brain barrier permeability, brain edema, astrocyte alterations and gliosis. Cytokine-induced production of nitrogen reactive molecules by endothelial cells themselves may also lead to further cellular damage and neuronal dysfunction. This hypothesis may explain several characteristics of hepatic encephalopathy including reversibility, disease progression and clinical features. It also suggests potential ways of intervention. PMID- 8676760 TI - The role of the nucleus in organogenesis: Part 1. AB - Organogenesis is the result of cell allocation followed by cell differentiation, and the processes involved are still to be elucidated. Present-day teaching suggests that the cytoplasmic membrane, the extracellular matrix and the cytoskeleton, in combination, are responsible, but the literature also suggests that other factors must be working as well. Because organogenesis is under strict genetic control, the controlling mechanism must reside in the nucleus and when the biology of the embryonic stem cell's nucleus was looked into, some interesting features emerged. One noteworthy feature was that the cytoplasm formed an incomplete ring around the nucleus so that part of the nuclear envelope was bare of cytoplasm, and in the aggregates of stem cells which made up an organ rudiment, the bare margins were in intimate contact. Another noteworthy feature was that the cytoplasm of the embryonic cells then underwent dissolution prior to differentiation, and the specialized cytoplasm arose progressively from the bare nuclei. The argument is put that, when embryonic stem cells join to form an organ rudiment, the bare margins of the nuclei of adjoining cells make intimate contact, allowing the correct spatial orientation of the cells to be achieved by means of positional cues in the nuclei. The cytoplasm of the embryonic cells then undergoes dissolution and the specialized cytoplasm of the differentiated cells is constructed by the denuded nuclei. PMID- 8676761 TI - The role of the nucleus in organogenesis: Part 2. AB - In a previous paper, it was proposed that the spatial orientation of stem cells was dependent on nucleus/nucleus contact. This proposition is discussed in more detail here. The correct spatial orientation of the cells making up the organs of the adult demands a molecular plan of some type to be encoded in the DNA, and it is suggested that the plan is encoded in the nontranscribed DNA. This DNA is present in the form of loops and folds, giving rise to a spatial array of enormous complexity, and the general belief is that the spatial array is dependent on sequence-specific proteins which firmly bind to the DNA. It is proposed that the binding proteins can also join the DNA of two adjacent stem cell nuclei once nucleus/nucleus contact has been made, and in this way determine the spatial orientation of the future specialized cells. There is enough information encoded in the spatial arrays to correctly position the myriad of cells that make up the adult organism. If cell alignment is carried out by nuclear union, then the development of the neuron can be better understood. It is suggested that malignancy may be due to a fault in either the nontranscribed DNA responsible for spatial orientation or in the sequence-specific binding proteins. PMID- 8676762 TI - Glutamine deficiency as a cause of human immunodeficiency virus wasting. AB - Tissue wasting often occurs during human immunodeficiency virus infection and acquired immune deficiency syndrome. While weight-loss in the human immunodeficiency virus-infected individual can be seen as an isolated symptom, catabolism during acquired immune deficiency syndrome is usually associated with complications such as diarrhea, malabsorption, fever and secondary infection. Glutamine is an amino acid central to many important metabolic pathways and recent findings suggest that glutamine depletion may explain the progression of tissue wasting during human immunodeficiency virus infection. PMID- 8676763 TI - Einstein's medical friends and their influence on his life. AB - Albert Einstein had at least six medical friends who influenced his thoughts. In each period (Munich, Switzerland, Berlin and Princeton) of his life, one could identify the medically qualified individuals with whom Einstein was in close contact. These include Max Talmey, Heinrich Zangger, George Nicolai, Hans Muhsam, Janos Plesch and Gustav Bucky. They probably enriched Einstein's life and thoughts significantly by being mentors, confidants, intellectual sparring partners and research collaborators to him. With Muhsam, Einstein published a paper in a German medical journal. In collaboration with Bucky, he also received a US patent for a light-intensity self-adjusting camera in 1936. PMID- 8676764 TI - Nutritional modulation of the final outcome of hepatotoxic injury by energy substrates: an hypothesis for the mechanism. AB - Survival after hepatocellular injury and necrosis may depend on the ability of the remaining hepatocytes to divide and restore an adequate population of functioning cells. Although adequate nutritional support is necessary for liver regeneration after severe liver damage, much is yet to be discovered concerning which nutritional factors are critical for liver regeneration. Clinically, nutritional substances are administered only from the energy aspect, without regard to whether or how these substrates may facilitate or impede liver tissue repair processes. Glucose is used as principal source of energy in liver damage because of accompanying marked hypoglycemia. But the contribution of glucose to compensatory liver regeneration and/or survival is unclear. This paper advances the hypotheses that: (1) glucose increases the toxicity of centrilobular hepatotoxicants by inhibiting hepatic cell division and tissue repair allowing unrestrained progression of injury; (2) fatty acids facilitate hepatic-cell division permitting hepatolobular restoration to occur thus preventing death from even a lethal dose. If hepatic tissue repair can be stimulated by some therapeutically compatible mechanism, then it might be possible to prevent death from even massive hepatocellular injury. In addition to nutritional manipulation, it should be possible to exploit molecular mechanisms that regulate organized cell division (tissue repair) to increase survival rates of patients suffering from fulminant hepatic failure. These findings have significant impact on tissue repair in a variety of other organs and tissues, particularly in diabetes-like conditions. PMID- 8676765 TI - Dietary shifts may explain the incidence of periodontitis in industrialized countries. AB - A new hypothesis for the etiology of periodontal disease is presented. We suggest that the formation of calcifying dental plaque, together with an established gingival sulcus, leads to circumstances which favor the growth of pathogenic microbes associated with the destruction of the periodontium. We assume that, in ancient humans, this problem was avoided by the nonexistence of sulci around the teeth. Such a situation may have resulted from the usage of a hard and gritty diet which caused occlusal attrition compensated by tooth eruption. Unfortunately, in modern humans, sulcus formation is normal. However, only a part of the population in industrialized countries has hard, calcifying dental plaque any more. Soft plaque may be associated with the lower calcium content of the modern diet. The impetus behind the introduction of this alternative hypothesis now is our fear that routine treatment of this disease by antibiotics will lead into an insoluble dilemma. PMID- 8676766 TI - Pulse wave numerical analysis. AB - The general deterioration of the arterial system is well recognized but not easily measured. Leg pulse waves, generated by the electric impedance plethysmograph, would seem to be a promising method. This study is a mathematical analysis of these pulse waves from the legs. The data were taken from a previous study by the same authors. That study analyzed the pulse waves using a frequency analysis (Fourier) and a lumped component model of the circulatory system. Blood pressure became clinically very meaningful when a number could be assigned to it. This study is being done to determine if a numerical value could be assigned to different types of pulse waves. If this can be done it would furnish a new tool for analyzing the peripheral circulation and peripheral atherosclerosis. This would offer another method for analyzing therapeutic endeavors that affect the circulatory system. These pulse waves were from a rather homogeneous group of generally healthy white males. The subjects were arranged according to age: ages 5-11, ages 19-24, 36-45, ages 55-62, and ages 74-91. This present analysis involves an advanced mathematical analysis done by a computer. The first graph (4a)--sine amplitude vs age--showed a sloping line which intersects the abscissa at about age 100. The second graph (4b)--notch (of the downstroke of the pulse wave) vs age--showed a sloping line intersecting the age line at about age 100. Thus, these calculations suggest that the untreated circulatory system is programmed to have a functional death at about age 100. The two methods used, one involving mathematical calculations and one involving graphic measurements, showed that a number can be put on the pulse wave. The higher the number, theoretically the better the circulation. Then if a treatment scheme can substantially raise the patient's pulse wave number, it might be expected to increase the longevity of their circulatory system. PMID- 8676768 TI - Boron levels in man: preliminary evidence of genetic regulation and some implications for human biology. AB - Boron is a ubiquitous constituent of man's external environment. Levels of the element in human blood reflect both acute and chronic exposure, usually as dietary intake (food and drinking water). There is an absolute requirement for boron in vascular plants but evidence for biological essentiality in animals (including man) is limited. A high body burden of the element may be harmful, especially to young animals (including human neonates). Information on boron deficiency is scanty. It has been proposed that boron contributes to living systems by acting indirectly as a proton donor and that it exerts a particular influence on cell membrane structure and function. The present study examines the variation in blood levels within and between human sibships and provides some support for the possibility that boron metabolism is subject to genetic regulation. PMID- 8676767 TI - Evaluation of various aspects of paediatric malignancies in Turkey and Turkey's status in health statistics. AB - Geographic differences in childhood cancer occurrence have been of great interest and have contributed to the current notion that most cancer cases are caused by environmental and cultural factors. The toxins, some of which are encountered by the general population, such as commonly used drugs, household products, solvents, pesticides, and insecticides, have been implicated as carcinogens and are factors that may add to the childhood cancer incidence in Turkey. Lack of information relevant to the disease, low family income, low educational status of parents, cessation of therapy, uncertainty about the child's future, fear for the child's survival, anxiety over the treatment and its effect as well as some cultural and traditional factors, are the basic individual characteristics of the population that interfere with the successful treatment of children with cancer in Turkey. Because the child with cancer is under enormous physical and emotional stress, appropriate psychosocial resources for the patient and family are important for optimal therapy. Community resources, healthcare services, income maintenance, medical insurance, financial assistance for treatment expenditures for the families who have children with cancer are extremely limited. These parameters are the unanswered needs which cancer patients and families face in our society. Despite impressive improvements, major problems remain to be solved. PMID- 8676769 TI - Origin of blood-group antigens: a self-declaration mechanism in somatic cell society. AB - Blood-group antigens have been developed as a self-declaration mechanism in higher organisms, since blood cells carry different DNA from that of germ-line cells, and their selfishness must be strictly limited. If not, symbiosis between somatic DNA and germ-line DNA cannot be maintained since blood cells can express autonomy programmed within themselves. For the sake of maintenance of symbiosis, this self-declaration is not limited to blood cells and all somatic cells need a self-plural declaration mechanism such as blood-group antigens. Differentiation and development including induction and inhibition also depend on the self declaration--recognition mechanism. PMID- 8676770 TI - How does zinc modify the common cold? Clinical observations and implications regarding mechanisms of action. AB - Clinical studies have shown that ionic zinc (Zn2+) dissolved in the mouth shortened manifestations of the common cold significantly, by an unknown mechanism. The observed immediate effect on symptoms is consonant with osmotic transport of Zn2+, placing a temporary chemical clamp on critical nerves. It is proposed that transient elevation of Zn2+ concentration in and around the nasal cavity facilitates Zn2+ complexation with known intercellular adhesion molecule binding sites on rhinovirus surfaces which prevents rhinovirus binding to cells and interrupts infection. The crystallographically determined surface of rhinovirus-14 has been found to contain binding sites for at least 360 Zn2+. Such binding of Zn2+ would be stabilized by numerous histidine, methionine, tyrosine and carboxyl/carboxylate groups known to line the HRV-14 surface canyons. The resulting blockage of HRV docking with intercellular adhesion molecule binding sites is proposed to be responsible for the observed reduction of the duration of colds by statistically significant and clinically meaningful times. PMID- 8676771 TI - Use of unrefrigerated fresh whole blood in massive transfusion. AB - OBJECTIVE: To establish the efficacy of transfusion of fresh unrefrigerated whole blood in surgical patients with ongoing massive bleeding despite adequate blood component replacement therapy and adequate surgical haemostasis. DESIGN: A retrospective review of patients who received fresh unrefrigerated whole-blood transfusions, noting blood usage and outcome. SETTING: A tertiary care teaching hospital with a major cardiac surgical and trauma service. PATIENTS: All patients (n=11) receiving fresh unrefrigerated whole-blood transfusions from March 1992 to February 1995. RESULTS: Mean blood usage in the 24 hours before the decision to transfuse fresh unrefrigerated whole blood was 16.5 units of packed cells (range, 6-27), 17.1 units of platelets (8-32), 14.5 units of fresh frozen plasma (6-26) and 13.5 units of cryoprecipitate (4-36). After the transfusion of fresh whole blood there was an immediate and substantial reduction in the rate and volume of blood loss in all patients. This was sustained in seven patients, who had a successful outcome; the other four patients died within 24 hours from recurrent uncontrollable haemorrhage. The reduction in blood usage in the 24 hours after the transfusion of fresh whole blood was statistically significant in the surviving patients but not in the patients who died. None of the surviving patients showed evidence of viral seroconversion six months after the transfusion. CONCLUSIONS: Our study provides preliminary evidence that there is a role for transfusion of fresh unrefrigerated whole blood in surgical patients with unresponsive life-threatening haemorrhage. PMID- 8676772 TI - Screening recommendations in general practice: a survey of graduates from different medical schools. AB - OBJECTIVE: To examine the influence of sociodemographic background, medical school background, general practice characteristics and attitudes towards preventive medicine on the screening recommendations of New South Wales (NSW) general practitioners (GPs). METHODS: From the NSW Medical Board Register, a sample was obtained of all GPs who graduated between 1983 and 1987 from the University of Newcastle and a random 1-in-3 sample of GPs from the Universities of Sydney and NSW. Two questionnaires were mailed consecutively. PARTICIPANTS: 363 GPs (56% response rate) who completed questionnaires suitable for analysis. MAIN OUTCOME MEASURE: A composite screening score for assessing agreement with standard screening guidelines. The score was derived by allocating points to the screening intervals that GPs recommended for 13 screening tests. A score of 39 indicated maximum agreement with guidelines. RESULTS: 87% of GPs reported being aware of standard screening guidelines. For most screening tests, there was a discrepancy between GPs' recommendations and those of the guidelines. Composite screening scores ranged from 8-38. There were significantly higher screening scores for graduates of Newcastle versus Sydney and NSW university medical schools combined (adjusted mean, 28.0 versus 25.9; P=0.0436), group versus solo GPs (adjusted mean, 26.3 versus 25.6; P=0.0092) and GPs in rural versus urban locations (adjusted mean, 27.9 versus 25.6; P=0.0049). CONCLUSIONS: GPs' recommendations for screening are not always consistent with standard guidelines, despite an awareness of them. Research is needed into the variation with which different screening tests are ordered. PMID- 8676773 TI - The reliability and validity of work measurement in Australian general practice consultations. AB - OBJECTIVES: To examine the reliability of relative work value assessment in general practice consultations and to determine whether different methods of assessing work produce consistent rankings. DESIGN: Cross-sectional observational assessment of general practice consulations. SETTING: General practices in Victoria between October 1991 and October 1992. PARTICIPANTS: 686 patients attending one of 58 general practitioners (GPs) drawn from a random, stratified sample. METHODS: Each participating GP had one day of consultations videotaped. They rated the work value of each consultation by using a magnitude estimation scale relative to a reference vignette. Three GP observers independently applied the same scale to the videotaped consultations. After three months, the observers applied a second measurement of work value, a compensation scale (also relative to the reference vignette), to the videotaped consultations. Duration of consultation was the third rating method. MAIN OUTCOME MEASURES: The reliability of work value assessment for each scale. Consultation rank order correlation coefficients among all rating methods. RESULTS: Observer reliability was high for both scales. Practising GPs showed lower levels of reliability in assessing the work value of their consultations. Strong positive correlations were found for consultation rankings among the observer scales and duration of the consultation. The duration of the consultation emerged as an important predictor of consultation work value. CONCLUSIONS: Scaling methods appear to be of little value to the practising GP in reliably assessing the relative work value of their consultations; training in the use of these scales may improve their reliability. However, the duration of consultation may be a reasonable proxy for relative work value assessment in general practice consultations. PMID- 8676774 TI - A cluster of murine typhus cases in Western Australia. AB - Measures to control rodents have resulted in a decreased incidence of murine typhus, but it is also likely that it is being underdiagnosed because many medical practitioners do not include it in their differential diagnosis of pyrexia of unknown origin. Four recent cases are described, and historical aspects of this disease in Australia are presented. PMID- 8676775 TI - Iodine deficiency: a global problem. AB - The United Nations and other international organisations, in cooperation with national governments, aim to eliminate this major cause of fetal brain damage by the year 2000. PMID- 8676776 TI - What's new in clinical transfusion practice. AB - Although the Australian blood supply is among the safest in the world, homologous transfusion is not risk-free. In some circumstances, alternatives are available or being developed. Clinicians need to be aware of the risks, benefits and options in transfusion therapy and to fully inform patients of these. PMID- 8676777 TI - Managing HIV. Part 6: People living with HIV. 6.4 Medically acquired HIV infection. AB - Often an underlying disorder (such as haemophilia) creates special management issues for people with medically acquired HIV. Although the risk of infection through donated biological materials is now slight, an unknown number of undiagnosed cases remain in the community. PMID- 8676778 TI - Managing HIV. Part 6: People living with HIV. 6.5 HIV and injecting drug use. AB - Injecting drug use can not only lead to HIV infection via the sharing of injecting equipment, it can also complicate the course and management of infection. PMID- 8676779 TI - Managing HIV. Part 6: People living with HIV. 6.6 HIV and isolated Aboriginal communities. AB - Aboriginal communities and their health services should prepare together and in advance for caring for an HIV-infected person. Good social support will be the keystone to successful clinical management. Health care workers must look to Aboriginal people for the lead in developing appropriate responses. PMID- 8676780 TI - Managing HIV. Part 6: People living with HIV. 6.7 Travellers with HIV. AB - Many HIV-infected people travel abroad, and although most can travel in relative safety there are a range of issues and risks to be considered by their medical advisers. PMID- 8676781 TI - Contact dermatitis and occupational skin disease. PMID- 8676782 TI - Is a syringe exchange feasible in a prison setting? PMID- 8676783 TI - Polyvalent vaccines and the National Immunisation Schedule. PMID- 8676784 TI - The health of Australia's mothers and babies. PMID- 8676785 TI - Continuity of care by a midwife team versus routine care during pregnancy and birth: a randomised trial. PMID- 8676786 TI - Cellulitis caused by a multidrug-resistant group A streptococcus. PMID- 8676787 TI - Hypoallergenic products. PMID- 8676788 TI - Toxic little black pills. PMID- 8676789 TI - The decline in hospital autopsy rates. PMID- 8676790 TI - Compliance with medication: some things change little. PMID- 8676791 TI - Epilepsy and art. PMID- 8676792 TI - Tradition of professional courtesies. PMID- 8676793 TI - Valuing medical work. PMID- 8676794 TI - The quality (of) use of medicines. PMID- 8676795 TI - Fighting a rearguard action in the massively transfused patient. PMID- 8676796 TI - Nutrition and Metabolism in Renal Disease. Proceedings of the 7th International Conference on Renal Nutrition and Metabolism. Stockholm, Sweden, May 29-June 1, 1994. PMID- 8676797 TI - Recombinant human erythropoietin improves enzyme activity in erythrocytes of predialysis uremics. AB - The influence of r-HuEPO on the activity of erythrocyte transketolase (ETKA), glutathione reductase (GSH) and glutamic-pyruvic transaminase (EGPT) was determined by spectrophotometry. 150 IU/kg BW/week of r-HuEPO was given i.v. during 2 months to 12 predialyzed uremics (PDU). Twenty healthy volunteers (HV) served as controls. GSH and EGPT activity were expressed as a coefficient. ETKA in HV = 2.39 +/- 0.10 and PDU = 1.53 +/- 0.10 mumol/ml/min differed significantly (p < 0.001). GSH in HV = 1.20 +/- 0.09 and PDU = 1.25 +/- 0.07, EGPT in HV = 1.20 +/- 0.10 and PDU = 1.38 +/- 0.11 differed significantly (p < 0.01 and p < 0.001, respectively). After 2 months of r-HuEPO treatment, ETKA, GSH and EGPT rose significantly (p < 0.01). Thus, r-HuEPO increases the activity of enzymes related with the content of vitamins B1, B2 and B6 in uremics. PMID- 8676799 TI - Folic acid treatment of hyperhomocysteinemia in dialysis patients. AB - We measured fasting total plasma homocysteine (Hcy) in 10 chronic hemodialysis (HD) and 10 chronic peritoneal dialysis (PD) patients. Mean (+/- SEM) Hcy was 55.7 +/- 10.1 and 50.5 +/- 14.3 mumol/l, respectively (normal range 6-19 mumol/l). Hemodialysis treatment lowered Hcy by about 30%. Daytime Hcy concentrations were stable in the PD patients. Six weeks of treatment with folic acid (FA) significantly lowered Hcy in HD and PD patients to 24.0 +/- 1.8 and 21.0 +/- 3.6 mumol/l, respectively. After withdrawal, Hcy rose slowly, in parallel with the gradually decreasing plasma FA concentrations, which were greatly elevated during treatment. Chronic treatment with FA of another group of patients showed a similar effect on Hcy. Preliminary results of oral methionine loading in chronic dialysis patients were compatible with delayed homocysteine metabolism via the transsulfuration pathway. Further studies on the optimal treatment of hyperhomocysteinemia in chronic dialysis patients are needed. PMID- 8676798 TI - Long-term folic acid (but not pyridoxine) supplementation lowers elevated plasma homocysteine level in chronic renal failure. AB - Moderate hyperhomocysteinemia, a risk factor for premature atherosclerosis, is present in chronic uremic patients. We prospectively evaluated the effects of sequential supplementation with pyridoxine (70 mg/day) and folic acid (10 mg/day) for two 3-month periods in 37 nondialyzed patients (29 males) with creatinine clearance (CCr) ranging from 10 to 80 ml/min, whose plasma vitamin B12 and folate level was in the normal range. Mean (+/- SD) baseline plasma total homocysteine (Hcy) was 14.9 +/- 5.2, 16.5 +/- 5.1 and 26.1 +/- 12.1 mumol/l (upper limit in 45 healthy controls 14.1 mumol/l) in patients with CCr 40-80, 20-40 and < 20 ml/min, respectively. Following pyridoxine Hcy did not significantly decrease whereas following folic acid Hcy decreased significantly to 9.9 +/- 2.9 (-33% vs. baseline), 10.3 +/- 3.4 (-37%) and 15.4 +/- 5.5 (-40%), respectively (Student's paired t test, p < 0.001) in the 3 groups. We conclude that folate (but not pyridoxine) pharmacologic supplementation is effective in lowering elevated plasma Hcy in chronic renal failure patients, thus suggesting that enhancing the Hcy remethylation pathway may overcome hyperhomocysteinemia in such patients. In view of the potential atherogenic effects of hyperhomocysteinemia, long-term folate supplementation should be considered in uremic patients. PMID- 8676800 TI - Neurotransmitter and monoaminergic amino acid precursor levels in rat brain: effects of chronic renal failure and of malnutrition. AB - Effects of chronic renal failure on brain neurotransmitters (dopamine, norepinephrine, serotonin and histamine) and on monoaminergic amino acid precursors (tyrosine, phenylalanine and histidine) were investigated. To eliminate the consequences of uremia-induced restriction of food intake, rats with malnutrition (pair-fed animals) were also studied and both were compared with control rats fed ad libitum. Malnutrition of a moderate degree (food intake 84% of controls) had no effect on amino acid concentrations in plasma and brain or on neurotransmitter levels in brain. Concerning plasma amino acids in chronic renal failure a lowered tyrosine level was found resulting in a diminished tyr/phe ratio. In brain tissue, the tyr/phe ratio was found to be normal, because brain tyrosine levels in chronic renal failure were similar to controls. Histidine, which was normal in plasma at this degree of chronic renal failure, was found to be significantly enhanced in brain in uremia. Also the neurotransmitters studied were found to be elevated in brain of chronic uremia, depending on the stage of renal insufficiency. PMID- 8676801 TI - Calcium alpha-ketoglutarate administration to malnourished hemodialysis patients improves plasma arginine concentrations. AB - Calcium alpha-ketoglutarate administration to 24 malnourished hemodialysis patients for 1 year leads to a significant increase in plasma concentrations of L arginine from 53.6 +/- 18.3 (compared to a healthy control group: 87.5 +/- 27.3) to 71.1 +/- 15.9 mumol/l (p < 0.05). Furthermore, concentrations in plasma of proline and histidine, precursors of glutamate biosynthesis, are increased; inorganic phosphate and urea are significantly decreased in hemodialysis patients after 1 year of calcium alpha-ketoglutarate administration. PMID- 8676802 TI - Effectiveness of dietary protein augmentation associated with angiotensin converting enzyme inhibition in the management of the nephrotic syndrome. AB - To determine whether the increase in proteinuria resulting from high dietary protein intake could be prevented by angiotensin-converting enzyme inhibition (ACEI), we performed paired studies on 8 nephrotic patients with normal GFR. They were fed sequential diets with a protein content of 0.8 (LPD) and 1.6 g/kg BW (HPD) each for 8 weeks. Patients on HPD received enalapril (ENAL) 10 mg/day. Despite the significant difference in protein intake, urinary protein excretion, at the end of the two dietary periods, was not statistically different. However, total serum protein and serum albumin increased significantly with HPD + ENAL treatment. The capability of ACEI to prevent the increase in proteinuria induced by HPD may be due to changes in glomerular hemodynamics, possibly mediated by changes in the activity of angiotensin II. Our study indicates that protein metabolism in nephrotic patients is better maintained with HPD + ENAL than with LPD alone. PMID- 8676803 TI - Insulin-like growth factor I in the kidney. AB - Insulin-like growth factor I (IGF-I) is synthesized in renal glomeruli and distal tubules. The rather high serum IGF-I levels (20-40 nM) result mainly from synthesis in the liver. In the circulation > or = 99% of IGF-I is bound in binding protein complexes. IGF-I can act in the kidney by autocrine and paracrine as well as endocrine modes. IGF-I raises GFR through reducing arteriolar resistance and increasing LpA. The peptide also increases the tubule transport of phosphate both in vitro and in vivo. IGF-I has been associated with the initiation of hypertrophy in models of compensatory renal growth and may contribute to the accumulation of extracellular matrix proteins in the nephron in chronic renal diseases. In the nephrotic syndrome, IGF-I is ultrafiltered into tubule fluid in association with IGF-binding protein-2 and activates apical proximal tubule cell receptors. PMID- 8676804 TI - Classification of lipid disorders in chronic hemodialyzed patients. AB - The aim of our study was to introduce the classification given by the European Atherosclerosis Society (A B C D E groups) for monitoring lipid disorders in chronic renal failure patients during the first year of dialysis therapy (DT). Studies were carried out in 41 chronically uremic patients (19 F, 22 M). Before the start of DT, and then every 2 months, following parameters were determined in the serum: total cholesterol, HDL-cholesterol and triglycerides. Moreover, electrophoresis of serum lipoproteins were also performed. At the start of the DT 63% of chronically uremic patients had normal values of basic lipid parameters, but this number decreased to only 29% after the first year of DT. We conclude that the modified A B C D E classification of lipid disorders in hemodialyzed patients is more convenient than the classic Fredrickson one used before. PMID- 8676805 TI - Insulin-like growth factor 1 resistance in chronic renal failure. AB - Renal failure is characterized by endocrine and metabolic disorders, some of them being described as a state of resistance to growth hormone (GH) and/or insulin like growth factor (IGF) 1. There is evidence for a reduced metabolic action of IGF-1 (formerly somatomedin C) in hemodialysis and kidney transplant children and in adults undergoing hemodialysis. Since the development of recombinant human (rh) IGF-1, despite strong metabolic actions, some experimental studies suggest a decrease in metabolic effects of rhIGF-1 in chronic renal failure (CRF). Preliminary reports in adult dialysis patients also stressed the possibility of a resistance to rhIGF-1 metabolic actions. The perturbed IGF-binding protein system in CRF may play an important role in modifying storage and IGF-I delivery to tissues. Also, by analogy with insulin, receptor and postreceptor defects may be involved in this condition, as suggested by rhIGF-1 resistance with aging or in obese Zucker rats. However, rhIGF-1 remains a potent anabolic factor in uremia. Further studies will therefore be necessary to clarify this IGF-1 resistance state. Such knowledge might allow physicians to reduce the amount of rhIGF-1 administered to the patients and improve the anabolic actions of rhIGF-1 during acute and chronic renal failure. PMID- 8676806 TI - Primary and secondary results of the modification of diet in renal disease study. AB - The modification of diet in renal disease (MDRD) study was a prospective, randomized, multicenter trial in 840 patients with chronic renal disease of diverse etiology. Patients in study A (585) had a GFR of 25-55 ml/min at baseline and patients in study B (255) had a GFR of 13-24 ml/min. After randomization to different diet and blood pressure groups the mean follow-up was 2.2 years. The results of the blood pressure and dietary interventions on GFR decline with time are summarized. PMID- 8676807 TI - Effects of low-protein diet supplemented with ketoacids on plasma lipids in adult chronic renal failure. AB - We designed a short-term randomized controlled study in 12 adult patients with chronic renal failure to assess the metabolic effects of a low-protein diet (LPD) supplemented or not with ketoacids (Cetolog, Clintec Corp., France). Dietary survey included a monthly 3-day food record and a 24-hour urinary urea measurement. After a baseline period (1.11 g protein, 31.7 kcal/kg BW/day), patients reduced their protein intake (PI) to 0.71 g/kg BW/day. Energy intake (EI) was kept constant (31.4 kcal/kg BW/day) during the 3-month period. Baseline plasma lipids did not show overt hyperlipemia. After reducing PI, a significant increase in apolipoprotein AI and the Apo-AI/Apo-B ratio was observed. Plasma Lp(a) levels were elevated at baseline and did not change during the 3-month LPD period. There was no difference between groups receiving ketoacids or not. Thus, in adult chronic renal failure, under a sufficient EI, reducing PI by 40% had a beneficial effect on plasma lipid profile. This improvement in lipid profile might reduce the high cardiovascular risk in these patients. PMID- 8676808 TI - Effects of lipids on the pathogenesis of progressive renal failure: role of 3 hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in the prevention of glomerulosclerosis. AB - Increasing experimental evidence suggests that lipids might be important modulators in progressive glomerulosclerosis. The inhibitors of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase have demonstrated beneficial effects in different models of progressive renal failure. Monocyte infiltration, mesangial cell proliferation and mesangial matrix expansion have been shown to be early events in the process of glomerulosclerosis that can be lessened by HMG-CoA reductase inhibition. Recent experimental data suggest that these agents may also have glomerular protective effects independent of a reduction in circulating lipids. In vitro, lovastatin has been shown to downregulate mesangial cell production of monocyte chemoattractant protein-1 and colony-stimulating factor. In addition, HMG-CoA reductase inhibitors can directly reduce mesangial cell proliferation. These effects appear related to the ability of this class of agents to inhibit mesangial cell formation of intermediates of cholesterol formation, the nonsterol isoprenoids. Although low density lipoprotein cholesterol can induce mesangial cells to increase synthesis of matrix proteins, e.g., type-IV collagen, we have shown that lovastatin does not directly influence mesangial cell type-IV collagen metabolism. Thus, prevention of mesangial matrix expansion in vivo with type-IV collagen by HMG-CoA reductase inhibitors could be related to an indirect mechanism related to inhibition of monocyte influx into the glomerulus. Alternatively, a direct effect of these agents, through their cholesterol-lowering capabilities, could play a role in reducing matrix expansion. PMID- 8676809 TI - Protein turnover in the hypertrophying kidney. AB - To establish whether altered proteolysis contributes to the increase in protein content in hypertrophying kidneys, we studied protein turnover in proximal renal tubules isolated from rats with three forms of renal hypertrophy, diabetes mellitus (DM), ammonium chloride-induced acidosis and compensatory renal growth (CRG). We found that in DM and in chronic acidosis the normal balance in protein turnover is altered due to attenuated proteolysis and accelerated protein synthesis. Together this favors an increase in kidney protein content. In contrast, in CRG, the increase in protein content is entirely due to increased protein synthesis. Thus, the changes in protein turnover leading to the net gain in kidney protein content in renal hypertrophy depends on the cause of hypertrophy. PMID- 8676811 TI - Lipoprotein(a) in chronic renal disease. AB - Atherosclerotic vascular disease is a major cause of morbidity and mortality in patients with chronic renal disease and in renal transplant recipients. Epidemiological studies have shown that a high lipoprotein(a) [Lp(a)] concentration in the general population is an independent risk factor for the development of atherosclerotic complications, such as coronary heart disease. Interestingly, plasma levels of Lp(a) have often been reported to be elevated in chronic renal disease. Recent studies have found no difference in the isoform distribution of apo(a) between healthy subjects and patients with renal disease, suggesting that factors other than genetic differences are involved in the high levels of Lp(a) reported in chronic renal disease. In particular, patients with major losses of protein in urine and/or dialysate, such as nephrotic patients and those treated with continuous ambulatory peritoneal dialysis, have been reported to have elevated plasma Lp(a) levels. The results regarding plasma Lp(a) levels in hemodialysis patients are conflicting, although recent evidence suggests that serum albumin levels are of importance for the prevailing Lp(a) levels. In renal transplant recipients conflicting data regarding plasma Lp(a) levels have also been reported, a finding that may be attributable to posttransplant urinary protein losses and/or different immunosuppressive regimens. The importance of Lp(a) as a risk factor for atherosclerotic disease in patients with chronic renal failure remains to established, and prospective evaluations of the role of Lp(a) are necessary. PMID- 8676810 TI - Impaired proteolytic activity as a potential cause of progressive renal disease. AB - Renal hypertrophy (an increase in cellular protein content and cellularity as well as an accumulation of extracellular matrix) is due to the imbalance between protein synthesis and degradation. Proteolytic activity in the kidney plays an important role in maintaining this balance. Impaired renal proteolytic activity caused by such factors as high protein intake, metabolic acidosis, angiotensin II and transforming growth factor-beta 1 in vivo and in vitro may result in decreased protein degradation and subsequent induction of cellular hypertrophy, even in the absence of increased protein synthesis. PMID- 8676812 TI - Protein restriction influences glomerular matrix turnover and tubular hypertrophy by modulation of renal proteinase activities. AB - Following renal ablation, there is marked compensatory renal growth, which is associated with alterations in the activities of renal proteinases. In the present study, rats underwent 5/6 nephrectomy (5/6-NX). Sixteen weeks after surgery, glomeruli and tubules were isolated and proteinase activities were determined using fluorogenic peptidyl substrates. Following 5/6-NX, there was considerable compensatory renal growth resulting in a final weight of 1,923 +/- 46 mg for the remnant kidney as compared to 1,402 +/- 63 mg for the left kidney of SHAM animals. This hypertrophic response was associated with lower activities of tubular cysteine proteinases (cathepsin L & B: -43%; cathepsin B: -61%; cathepsin H: -53%). Significantly reduced activities were also observed for glomerular collagenase (20.2 +/- 6.2 vs. 53.4 +/- 5.7 mU/micrograms DNA) and gelatinase (24.1 +/- 5.0 vs. 130.8 +/- 8.4 mU/micrograms DNA) activities. Protein restriction (5 vs. 20% casein) considerably attenuated compensatory renal growth after surgical ablation (790 +/- 45 vs. 1,923 +/- 46 mg) and partially prevented the fall in tubular cathepsin activities. In terms of glomerular enzymes, protein restriction caused a significant increase in the activity of gelatinase from 24.1 +/- 5.0 to 66.7 +/- 9.2 mU/micrograms DNA, while collagenase remained unchanged. From these data, we conclude that compensatory renal growth is strongly influenced by the amount of protein ingested. It appears that this effect is mediated by modulation of renal proteinase activities. PMID- 8676813 TI - Influence of nitric oxide on renal function in toxic acute renal failure in the rat. AB - Besides other mechanisms, nitric oxide (NO) plays a major role in maintaining the high renal blood flow (RBF) and is also involved in the regulation of glomerular hemodynamics and contractility of mesangial cells. We examined the hypothesis that L-arginine-derived NO exerts beneficial effects in toxic acute renal failure (ARF) in the rat. To induce ARF uranyl nitrate (UN) was given intravenously as a bolus injection (25 mg/kg over 5 min) following a basal period. After the initiation phase of ARF (3 h) saline in the control group (C) and drugs in the experimental groups (I-III, each n = 8) were administered for 60 min. Group I: Arg (= L-arginine, 300 mg/kg), group II: MeArg (= N-methyl-L-arginine, 30 mg/kg), group III: Arg + MeArg (300 mg/kg, 30 mg/kg respectively). The experiments were continued for additional 60 min following the infusion period. Glomerular filtration rate (GFR, inulin clearance) was reduced 3 h after UN to about 50% of normal values in group I-III and control group. After infusion of Arg GFR had significantly improved, but remained unchanged after MeArg in relation to control. One hour after the infusion period these effects were even more pronounced. We conclude that NO exerts beneficial effects on renal function in this animal model of ARF. These results underline the regulatory role of the L arginine/NO pathway for renal function not only under basal conditions but also in ARF. PMID- 8676814 TI - Dietary salt, intracellular ion homeostasis and hypertension secondary to early stage kidney disease. AB - Abnormal salt metabolism plays a central role in the pathogenesis of hypertension caused by early-stage renal disease. The mechanisms by which alterations in salt balance and the vasoconstrictor state are related are unclear. We studied the effects of three different salt diets (3, 6-9 and 12 g sodium chloride) on cellular ion homeostasis in platelets in 20 patients with renal hypertension. Compared to normal subjects, patients with renal hypertension had raised cytosolic sodium and calcium concentrations. The platelet sodium pump activity was significantly depressed and calcium ATPase activity increased. These abnormalities of cellular ion metabolism were aggravated by salt overload. On the other hand, dietary salt restriction tended to normalise these parameters. The data presented indicate that a circulating inhibitor of the sodium pump plays a central role in the pathogenesis of salt-induced renal hypertension and that the final common pathway of hypertension secondary to early-stage parenchymal renal disease is an elevation of resting cytosolic calcium followed by an elevation of peripheral vascular resistance. PMID- 8676815 TI - Effects of parathyroid hormone on renal tubular proteinases. AB - Parathyroid hormone (PTH) has been implicated to exert detrimental effects on remnant nephrons in chronic renal failure. The present investigation addressed the influence of PTH on the proteolytic capacity of isolated proximal tubules both from normal (SHAM) and partially nephrectomized rats (5/6-NX). Proteolytic activities were measured either against azocasein (pH 5.4) or with specific fluorogenic peptidyl substrates for individual cysteine proteinases. Azocaseinolytic activity was enhanced 6 weeks after 5/6-NX in tubules (SHAM 19.0 +/- 1.0 vs. 5/6-NX 24.4 +/- 1.5 U/mg protein), while thereafter activities declined progressively with time (5/6-NX 16 weeks: 12.9 +/- 1.2 U/mg protein). This loss in proteolytic activity could almost completely be prevented by parathyroidectomy (PTX) (5/6-NX + PTX 16 weeks: 18.6 +/- 1.1 U/mg protein). By contrast, severe hyperparathyroidism (induced by a low calcium/high phosphorus diet fed for 6 weeks) in 5/6-NX animals resulted in a significant decline in proteolytic activities in remnant tubules (5/6-NX 24.4 +/- 1.5 vs. 5/6-NX+diet 16.4 +/- 1.9 U/mg protein). When specific activities of tubular cathepsins were measured in healthy rats who had received exogenous PTH, each individual cysteine proteinase (cathepsin L: -42%; cathepsin B: -27%; cathepsin H: -51%) was suppressed. This effect of PTH could readily be abolished by the simultaneous administration of verapamil. These results suggest that chronic PTH excess exerts a suppressive effect on tubular proteinase activities both in normal and partially nephrectomized rats. This PTH effect seems to be mediated by an increase of cytosolic calcium. PMID- 8676816 TI - Hyperparathyroidism: is it really the major factor affecting glucose tolerance in uremia? AB - The effects of secondary hyperparathyroidism (sHPTH) on immunoreactive insulin (IRI) release and glucose (G) tolerance were studied in two groups of dialysis patients with normal (NPTH, n = 9) or elevated PTH levels (HPTH, n = 8), 27 +/- 24 and 660 +/- 440 pg/ml, respectively. The patients received an intravenous glucose tolerance test (IVGTT) using 0.33 g/kg of glucose solution. G, IRI and C peptide (C-p) levels were determined calculating the G constant decay (K) and the relative incremental areas for each study. Regardless of PTH levels, all patients showed an impaired glucose tolerance (GT). IRI secretion and K values were not significantly different between the two groups. However, a significantly lower K value with a reduced (although not significant) early and late IRI secretion was found in the subgroup of patients with more severe. sHPTH (PTH: 560-1,500 pg/ml, n = 5) as compared to patients with moderate sHPTH (PTH: 87-341 pg/ml, n = 4) or normal (5-32 pg/ml, n = 8) PTH levels. No relationship was found between PTH and G, IRI or C-p levels. Our results point to a threshold limit for PTH's inhibitory effect on IRI secretion and suggest that other factors, known to affect IRI secretion and GT besides PTH levels, may modulate the role played by excess PTH levels on carbohydrate metabolism of dialysis patients. PMID- 8676817 TI - Morphometry of uremic rat growth plate. AB - Growth retardation is a common manifestation of chronic renal failure in children. To gain insight into the alterations of bone growth plate of chronic uremia, a morphometric study of tibia proximal growth plate was performed in 5/6 nephrectomized rats (NX, n = 4) and sham animals (SHAM, n = 4). Toluidine blue stained sagittal sections (5-6 microns) from ethanol-fixed and methylmethacrylate embedded tibias were analyzed. Widths (X +/- SEM) of growth plate (GPW), proliferative (PZW) and hypertrophic zones (HZW) were calculated. Results were as follows: [table: see text] Growth plate modifications in uremia are rather due to alterations in the hypertrophic than proliferative zone. This is consistent with an abnormal metabolism of condrocytes as shown by a lower mean area of extracellular matrix (EMA) per cell in the hypertrophic zone of the NX rats (0.23 vs. 0.58 microns 2). PMID- 8676818 TI - Long-term treatment with calcium-alpha-ketoglutarate corrects secondary hyperparathyroidism. AB - Calcium-alpha-ketoglutarate (Ca-ket) is known as a highly effective phosphate (P) binder in hemodialysis (HD) patients. In addition, alpha-ketoglutarate has been shown to improve metabolic alterations. We investigated the effect of long-term P binding therapy with Ca-ket to determine whether P accumulation is the main reason of secondary hyperparathyroidism (HPT) in HD patients or not. Ca-ket was prescribed to 14 HD patients as a soluble preparation in a mean dosage of 4.5 g/day (0.975 g elemental Ca) for a period of 36 months. Serum P continuously dropped from prestudy 2.6 +/- 0.1 (mean +/- SEM) to 1.9 +/- 0.07 mmol/l (p < 0.001), whereas serum Ca increased from 2.2 +/- 0.1 to 2.47 +/- 0.08 mmol/l (p < 0.05). Thus, Ca/P ratio in serum converted significantly from 0.91 +/- 0.02 (prestudy) to 1.28 +/- 0.01 (p < 0.001). Intact parathyroid hormone (iPTH) continuously normalized in all patients from 29 +/- 5 to 8 +/- 2 pmol/l (p < 0.001). The present data show that long-term treatment with Ca-ket normalizes secondary HPT by simultaneously P binding and correcting Ca/P ratio in serum without vitamin D treatment. PMID- 8676819 TI - Prevalence of hyperlipidemia in a cohort of CAPD patients. Italian Cooperative Peritoneal Dialysis Study Group (ICPDSG). AB - An association between hyperlipidemia and cardiovascular disease is well described in the literature. We conducted an observational study in order to evaluate the lipid profile, the prevalence of hyperlipidemia and its relationship with age, sex, duration of CAPD, peritoneal glucose load (PGL), serum albumin (ALB), serum glucose (GLU), and BMI in a large cohort of uremics undergoing long term treatment with CAPD. 457 nondiabetic patients (245 males, 212 females; mean age 63.8 +/- 11.9 years; mean duration of CAPD: 41.8 +/- 26.9 months) treated during 1992 in 25 centers participating in the Italian Cooperative Peritoneal Dialysis Study Group (ICPDSG) were studied. The serum lipid parameters evaluated were triglycerides (TG), total cholesterol (CHO), HDL-cholesterol (HDL). Indications given in the New England Journal of Medicine, SI Unit Conversion Guide, 1992, were adopted for normal ranges. In the whole population the evaluation of lipid parameters showed: TG 227.4 +/- 123.3 mg/dl, CHO 232.8 +/- 56.0 mg/dl, HDL 40.7 +/- 12.0 mg/dl. No differences were found between the two sexes with regard to age, BMI, duration of CAPD, distribution of renal diseases, TG, ALB, and GLU; whereas CHO and HDL were significantly lower in males than in females (CHO: 222.2 +/- 53.5 vs. 245.0 +/- 56.5 mg/dl, p < 0.001; HDL: 39.3 +/- 11.4 vs. 42.6 +/- 12.6 mg/dl, p < 0.05). The prevalence of hypercholesterolemia was significantly lower in males than in females (19.7 vs. 35.4%; p < 0.001). The multiple regression analysis indicated that TG were directly correlated to PGL (p < 0.05), and HDL was inversely correlated with TG (p < 0.001). The coexistence of the two variables (TG and HDL) may increase the risk of cardiovascular events. Further strategies should therefore be developed to select and manage CAPD patients to reduce the incidence of hyperlipidemia. PMID- 8676820 TI - Lipoprotein(a) in patients with the nephrotic syndrome: influence of immunosuppression and proteinuria. AB - Lipoprotein(a) [Lp(a)] is a plasma lipoprotein whose structure and composition closely resemble that of low-density lipoproteins, but contains an additional protein called apolipoprotein(a) [apo(a)]. Factors which modulate plasma Lp(a) concentrations are poorly understood. The influence of nephrotic syndrome on Lp(a) levels was investigated in 103 patients with nephrotic syndrome: 72 with primary kidney disease and 31 with diabetic nephropathy. Nephrotic patients had significantly higher Lp(a) levels (mean 63 +/- 7 mg/dl; median 42 mg/dl) compared with controls (mean 22 +/- 2 mg/dl; median 8 mg/dl). Fifty-seven percent of the patients and 22% of the controls had values greater than 30 mg/dl. Within all apo(a) isoform classes, higher concentrations of Lp(a) were seen in the nephrotic patients compared with controls. In 17 patients with primary kidney disease remission of the nephrotic syndrome was induced by immunosuppressive treatment and Lp(a) concentration dropped in parallel with the reduction of proteinuria (pretreatment mean, 98 +/- 9 mg/dl vs. remission mean, 25 +/- 5 mg/dl). In 9 patients where multiple measurements were done, multiple regression analysis showed a strong relation of Lp(a) with the amount of proteinuria (p < 0.01). We conclude that most patients with the nephrotic syndrome have Lp(a) concentrations which are substantially elevated compared with control subjects of the same apo(a) isoform. Because Lp(a) concentrations are substantially reduced when remission of the nephrotic syndrome is induced by immunosuppressive drugs, it is likely that nephrotic syndrome directly results in elevation of Lp(a). The high levels of Lp(a) in nephrotic syndrome could potentially cause glomerular injury as well as increase the risk of atherosclerosis and thrombotic events associated with this disorder. PMID- 8676821 TI - Effect of plasma oncotic pressure on apolipoprotein levels in rats with Heymann nephritis. AB - The nephrotic syndrome is characterized by reduced plasma albumin and colloid osmotic pressure (pi). Infusion of dextran or albumin reduces lipid levels suggesting that reduced plasma pi plays a role in causing hyperlipidemia in the nephrotic syndrome. To determine whether apolipoprotein (Apo) levels were affected by pi, passive Heymann nephritis (HN) was created in 20 rats. Hyperoncotic (25%) human albumin or ficoll was infused continuously into each of 5 HN rats adjusted to maintain a plasma pi above 20 mm Hg. Either saline or a mixture of amino acids calculated to approximate those released from catabolized human albumin were infused into 5 HN as controls. Urinary rat albumin loss was not different between the 4 groups of HN. Plasma apo A-I, B and E were all increased significantly in saline and amino acid infused HN, but apo A-IV was decreased. Infusion of either albumin or ficoll normalized apo A-I, and apo E levels in HN even though proteinuria continued unabated. In contrast, apo B remained significantly elevated in HN infused with albumin, but was reduced to normal by ficoll. Fifteen non-nephrotic control animals were studied in 3 groups of 5 animals each; one receiving human albumin, one ficoll, both adjusted to increase plasma pi to supranormal levels, and a 3rd group received saline. In contrast to HN, plasma apo A-I, E, and B levels were unaffected by albumin or ficoll infusion in control animals. Ficoll caused a significant reduction in apo A-IV in both HN and control animals to subnormal levels, but albumin infusion was without effect. Reduced plasma pi, but not reduced plasma albumin is necessary for increased apo A-I, and E levels in the nephrotic syndrome. When plasma pi is normal extensive proteinuria does not increase plasma apo A-I or E levels. Factors other than an albumin concentration or pi, such as persistent urinary protein loss, play a role in establishing increased apo B containing lipoproteins in the nephrotic syndrome. Ficoll may cause changes in plasma lipoprotein levels by means other than its ability to increase plasma pi. PMID- 8676822 TI - Cholesterol metabolism in glomerular cells: effect of lipoproteins from nephrotic patients. AB - Although hyperlipidemia is a well recognized complication of the nephrotic syndrome, the precise metabolism of human lipoproteins by human glomerular cells and the effects of abnormalities in lipid and protein composition on this process have not been defined. This study examined the effects of apoB-100 containing low density-lipoprotein (LDL) and apo B,E, containing intermediate-density lipoprotein (IDL), isolated from patients with the nephrotic syndrome (n = 6), on intracellular sterol synthesis and cholesterol esterification by human glomerular epithelial and mesangial cells. For comparison studies, human skin fibroblasts and Hep G2 cells were used. In the patients, serum LDL cholesterol level was increased threefold and IDL tenfold as compared to healthy subjects. LDL of nephrotic patients showed no differences in lipid/protein composition as compared to control LDL but IDL contained 58% more cholesterol than IDL from healthy controls. Therefore, nephrotic and control LDL showed identical inhibition of intracellular sterol synthesis and similar cholesteryl ester formation in all the four cell types. In contrast, cholesterol-rich IDL of nephrotic patients suppressed intracellular sterol synthesis more effectively than control IDL. The cholesterol esterification rate of IDL from patients was enhanced three fold on average as compared to control IDL. The various cell types differed in their rate of LDL esterification. The data indicate that the enhanced inhibition of intracellular sterol synthesis and cholesterol esterification by apo E-containing cholesterol-ester-rich IDL, which accumulate in nephrotic patients, may render these lipoproteins possible candidates for glomerular lipid deposition and progressive renal injury. PMID- 8676823 TI - Role of atherogenic lipoproteins in cytokine-mediated renovascular injury. AB - Recent advances have clarified many basic cellular and molecular mechanisms associated with glomerular injury. We propose that atherogenic lipoproteins (e.g., native LDL and its more atherogenic oxidized variants) play a central role as biological modifiers in monocyte- and cytoregulatory peptide-induced glomerulosclerosis. Following lipoprotein activation of mesangial and other intrinsic glomerular cells, monocytes adhere, transmigrate, differentiate, and proliferate within the glomerular mesangium. These events are mediated by increased expression of adhesion molecules (ICAM-1, VCAM-1, etc.) and specific monocyte chemoattractants (M-CSF, MCP-1, etc.). Furthermore, atherogenic lipoprotein can activate mesangial cells to express additional proinflammatory cytokines (TNF-alpha, TGF-beta, etc.) that culminate in the elaborated expression of extracellular matrix proteins and irreversible injury. These results support a distinct pathobiological role for atherogenic lipoproteins in the initiation and progression of cytokine-mediated renal injury. PMID- 8676825 TI - How is lean body mass conserved with the very-low protein diet regimen? AB - Eight CRF patients (GFR = 18.8 +/- 2.7 ml/min) underwent a crossover comparison of a very-low-protein diet (VLPD) providing 0.28 g protein and 35 kcal/kg/day, plus an isomolar mixture of ketoacids (KA) or essential amino acids (EAA). During each dietary period, a 5-day nitrogen balance (BN) was performed and whole-body protein turnover (WBPT) was measured during fasting and feeding using intravenous [1-13C]leucine and intragastric [5,5,5-2H3]leucine. Although the VLPD/KA regimen contained 15% less nitrogen, BN was neutral and did not differ between the regimens. Similarly, rates of WBPT did not differ between the KA or EAA regimens, and neutral BN was achieved by a marked suppression of amino acid oxidation and postprandial inhibition of protein degradation (PD). Participants were then discharged on the VLPD/KA regimen and monitored as outpatients for > or = 1 year. Repeat BN was neutral and rates of WBPT did not differ from baseline values. Thus, the adaptive responses to dietary protein restriction are sustained during long-term therapy. PMID- 8676824 TI - Low-density lipoprotein suppresses cathepsins B and L activity in rat mesangial cells. AB - Disturbances of lipid metabolism are considered to play a pathogenetic role in glomerulosclerosis. Since intraglomerular have been proposed to be involved in the pathogenesis of the glomerulosclerosis, we have investigated the influence of LDL on the activity of the cellular proteases. Cathepsins B and L were measured with the aid of fluorometry, and 7-amido-4-methylocoumarin derivates were used as substrates; Z-Arg-Arg-AMC for cathepsin B, Z-Phe-Arg-AMC for cathepsins B and L together. Rat mesangial cells cultured 24 h in medium supplemented with LDL revealed inhibition of cathepsin B activity at concentrations of 250 micrograms LDL/ml medium, lower LDL concentrations were without apparent effect. Since the glomerular accumulation of structural and nonstructural proteins plays an important role in glomerulosclerosis, we conclude that the augmented proteolytic activity of mesangial cells might be one of the pathways located by which hyperlipidemia causes an increased susceptibility to glomerular damage. PMID- 8676826 TI - Muscle protein turnover in chronic renal failure patients with metabolic acidosis or normal acid-base balance. AB - It is currently unknown if metabolic acidosis has any effect on muscle protein metabolism in patients with chronic renal failure (CRF). To address this question, muscle protein turnover was studied in patients with CRF and controls in the postabsorptive state by using the forearm perfusion method together with the 3H-phenylalanine kinetics. Nine patients were acidotic ([HCO-3]a = 20 +/- 0.5 mEq/l) whereas 4 patients had a normal acid-base balance ([HCO-3]a = 25 +/- 0.3 mEq/l). In patients with metabolic acidosis the rates of phenylalanine appearance and disposal from the forearm were increased as compared to controls. Phenylalanine net balance, i.e. net proteolysis, was only slightly higher than in controls. In patients under a normal acid-base balance both rates of appearance and disposal of phenylalanine as well as phenylalanine net balance were similar to controls. These preliminary data suggest that metabolic acidosis can enhance the rate of muscle protein degradation in patients with CRF. PMID- 8676827 TI - Metabolic acidosis stimulates protein metabolism in uremia. AB - It is well established that chronic renal failure is associated with loss of lean body mass. Possible explanations for protein losses include a limited ability to reduce essential amino acid oxidation and protein degradation when dietary protein is low. Alternatively, uremia could directly stimulate protein catabolism. In rats, we have uncovered evidence that metabolic acidosis not only blunts the responses to a low-protein diet but also stimulates the degradation of muscle protein. We find that the ATP-ubiquitin-proteasome-dependent pathway causing muscle protein degradation is activated by acidosis. Glucocorticoids are required but are not sufficient to elicit this catabolic response. PMID- 8676828 TI - Influence of acid loading, extracellular pH and uremia on intracellular pH in muscle. AB - Our previous work has shown that chronic metabolic acidosis can induce changes in protein and amino acid metabolism in muscle. The relationship of these metabolic responses to changes in muscle pH is unknown. To examine the role that acute acidosis might have on intracellular pH in rats, we evaluated the influence an acute infusion of HCl had on intracellular pH using 31P-NMR. Male rats fed 22% protein and weighing between 150 and 170 g were infused with 150 mM HCl (4 mmol/kg) over a 2- or 4-hour period. Baseline blood pH was 7.36 and dropped to 7.04 at the end of the infusion. Despite this, no changes in intracellular pH were seen. In contrast, we found that chronic acid loading (4 mmol NH4Cl/100 g/day for 5 days) produces a small change in muscle pH (0.05 pH units, p < 0.05). Chronic uremia did not change resting muscle pH despite a decrease in extracellular pH to 7.23 even though metabolic changes are well documented. CONCLUSIONS: (1) An acute acid load does not alter intracellular pH while chronic metabolic acidosis does reduce intracellular pH. (2) The lack of an acute change in intracellular pH suggests that intracellular buffering capacity changes over time. PMID- 8676829 TI - Acidosis and glucocorticoids induce branched-chain amino acid catabolism. AB - Chronic renal failure (CRF) is frequently complicated by malnutrition and wasting. The loss of lean body mass in CRF is the result of accelerated protein and amino acid degradation. Both appear to occur via acidosis-induced, glucocorticoid-dependent processes. In skeletal muscle, acidosis stimulates the activity of the rate-limiting enzyme in branched-chain amino acid metabolism, branched-brain ketoacid dehydrogenase (BCKAD). The activation of BCKAD in acidosis is likely to be glucocorticoid-dependent. PMID- 8676830 TI - Necessary but not sufficient: the role of glucocorticoids in the acidosis-induced increase in levels of mRNAs encoding proteins of the ATP-dependent proteolytic pathway in rat muscle. AB - Muscle protein degradation is accelerated by the acidosis associated with chronic renal failure. In isolated muscles from acidotic rats, a cytosolic, ATP-dependent proteolytic pathway is stimulated with a concurrent increase in the abundance of mRNAs encoding ubiquitin and subunits of the 26S proteasome complex associated with this degradative pathway. Adrenalectomy (ADX) prevents the acidosis-induced increase in muscle protein degradation unless high physiologic doses of glucocorticoids are administered to acidotic, adrenalectomized rats. We have examined the roles that acidosis and glucocorticoids have in the increase in mRNAs encoding proteins of the ATP-dependent-ubiquitin-proteasome proteolytic pathway in ADX rats. We found that ubiquitin and proteasome C2 and C9 subunit mRNA levels are increased in the white fiber, extensor digitorus longus (EDL) and mixed fiber, gastrocnemius muscles from acidotic ADX rats that received dexamethasone whereas acidosis alone or dexamethasone alone failed to increase these mRNAs. In contrast, acidosis plus dexamethasone decreased the total RNA content in both muscles. These data suggest that in muscle, the response to acidosis involves the specific activation of the ATP-ubiquitin-proteasome proteolytic pathway. Moreover, glucocorticoids are required but not directly responsible for the acidosis-induced increase in the mRNAs encoding proteins of this degradative pathway. PMID- 8676831 TI - Body fluid overload and bioelectrical impedance analysis in renal patients. AB - Using a new bivariate vectorial approach to the standard bioimpedance analysis (tetrapolar, 50-kHz frequency), we evaluated the performance of a graphical method for the identification of patients with fluid overload. Two hundred and seventeen adult Caucasian subjects were divided into four classification groups: 86 healthy control subjects, 55 patients with mild-to-terminal chronic renal failure in conservative treatment (15% with apparent edema), 36 patients with idiopathic nephrotic proteinuria (58% with apparent edema), and 40 obese subjects. We found a bioimpedance threshold for apparent edema on the lower pole of the sex-specific 75% tolerance ellipse (bivariate tolerance interval) of the healthy population. This innovative graphical method allows identification, monitoring and therapy planning of patients with fluid overload using direct bioimpedance measurements without any assumption on body composition. PMID- 8676832 TI - Assessment of protein intake in children with chronic renal insufficiency. AB - Daily nitrogen intake was estimated in 19 children, aged (mean +/- SD) 9.9 +/- 5.0 (range: 1-19) years with chronic renal insufficiency (creatinine clearance 47.1 +/- 19.3 ml/min/1.73 m2, range: 11-75) by 31 three-day prospective dietary records (NIDR) and simultaneous 24-hour urine urea excretion (NIUE). Daily nitrogen intake was 11.05 +/- 3.9 g by NIDR and 8.52 +/- 3.3 g by NIUE, and a significant correlation (r = 0.61; p = 0.0003) existed between both methods of measurement. However, the difference in nitrogen intake estimated from dietary records and from 24-hour urine collection (NIDR-NIUE) was 2.5 +/- 3.3 g, greater than the mean estimated nitrogen intake calculated from both methods, (NIDR + NIUE)/2, 95% limits of agreement being +9.1 to -4.1. Thus, NIDR and NIUE values show a good correlation in children with chronic renal insufficiency, although both methods may provide quite a different estimation in a given child. PMID- 8676834 TI - Continuous enteral feeding in uremic rats. AB - Because of constant uremia-induced anorexia, food restriction of normal rats is generally used to study the consequences of uremia. The effects of a normal food supply in uremic rats has never been tested, since no author has succeeded in providing normal intakes. Uremic rats either fed ad lib (U rats, n = 12) or force fed through a gastric catheter (UF rats, n = 10), and sham-operated rats (C rats, n = 10) were compared from days 7 to 21 after surgery. U rats had lower food intake (13.8 vs. 17 g/day), weight gain (5.16 vs. 6.23 g/day), length gain (4 vs. 5 mm/day), nitrogen balance (228 vs. 279 mg/day) and muscle fractional protein synthesis rate (9.5 vs. 10.6%) measured in vivo by 3H-phenylalanine injection (p < 0.05 for all). All parameters were restored to normal values in UF rats, possibly due to correction of underhydration in addition to undernutrition. Such continuous enteral feeding may provide a model for normal nutritional supply in uremia. PMID- 8676833 TI - Analysis of growth in five-sixths-nephrectomized rats. AB - The present study was designed in an attempt to better define the pattern of growth in five-sixths-nephrectomized rats. Male Sprague-Dawley rats underwent two stage (days 0 and 7) five-sixths nephrectomy (NX, n = 16) or sham surgery (SHAM, n = 9). At the time of sacrifice (day 21), renal failure (CRF) of NX rats was confirmed by elevated (p < or = 0.0001) serum concentrations (X +/- SEM) of urea nitrogen (SUN) (56 +/- 5 vs. 20 +/- 1 mg/dl) and creatinine (0.7 +/- 0.04 vs. 0.4 +/- 0.02 mg/dl) and reduced SUN (0.13 +/- 0.02 vs. 0.44 +/- 0.05 ml/min/100 g) and creatinine clearances (0.23 +/- 0.02 vs. 0.58 +/- 0.05 ml/min/100 g). As shown by lower cumulative gains of weight (41 +/- 6 vs. 74 +/- 4 g) and length (5.0 +/- 0.4 vs. 6.8 +/- 0.3 cm), NX rats grew subnormally. Detailed analysis of growth data revealed: (1) In spite of being identically matched in weight and length on day 0, at day 7, NX rats already weighed less than SHAM animals (147.1 +/- 2.3 vs. 153.4 +/- 1.9 g, p = 0.03). (2) From day 7 on, daily gain of weight was lower in the NX group only on days 8 (-6.08 +/- 0.52 vs. -1.60 +/- 0.69 g/100 g body weight) and 9 (-0.41 +/- 1.73 vs. 5.18 +/- 0.63 g/100 g body weight). (3) Following the early post-second-nephrectomy period, two subgroups of NX rats were clearly differentiated according to whether or not their daily growth rate was lower than that of SHAM animals. Maintained subnormal growth rate was observed in rats with severe CRF (SUN 73 +/- 5 mg/dl, range 54-90) but not in rats having milder uremia (42 +/- 3 mg/dl, range 31-51). Thus, growth in five-sixths nephrectomized rats should be reported based on daily weight increments (g/100 g body weight). Subnormal growth can be attributed to CRF provided SUN is at least 3 times as high as normal while growth impairment of rats with less marked reduction of renal function is likely related to transient acute renal failure and postsurgical catabolic state. PMID- 8676836 TI - Biomodulation of the toxic and nutritional effects of small bowel bacterial overgrowth in end-stage kidney disease using freeze-dried Lactobacillus acidophilus. AB - Small bowel bacterial overgrowth (SBBO), well known to occur in end-stage kidney failure, is responsible for producing uremic toxins and contributing to the patient's decreased nutritional well-being. In this study, 8 hemodialysis patients were treated with a course of oral Lactobacillus acidophilus (LBA) in an attempt to alter this SBBO. LBA treatment was effective in lowering 2 compounds generated in vivo. Serum dimethylamine (DMA) levels dropped from 224 +/- 47 to 154 +/- 47 micrograms/dl at the end of LBA treatment (p < 0.001). Nitrosodimethylamine, a carcinogen, levels also decreased significantly from 178 +/- 67 (untreated) to 83 +/- 49 ng/kg (after LBA treatment). Patients nutritional status, assessed as serum albumin, body weight, caloric intake, midarm muscle area (MAMA) and appetite improved modestly, but not significantly. LBA changed small bowel pathobiology by modifying metabolic actions of SBBO, reducing in vivo generation of toxins and carcinogens and promoting nutrition with no adverse side effects. PMID- 8676835 TI - Why are lipids not predictive of cardiovascular death in the dialysis patient? AB - The rate of cardiovascular death, and specifically of cardiac death, in dialysis patient is excessive and comparable to that in the high-risk group of survivors of myocardial infarction. Yet, in patients on dialysis total cholesterol, LDL cholesterol, apolipoprotein B and other indicators of coronary risk--with the exception of lipoprotein(a)--are consistently higher in survivors than in those dying from cardiovascular causes, but at least in diabetic patients on dialysis, an extremely high-risk population, lipids are predictive of cardiac death. Malnutrition as a confounding factor might explain the inverse relation between lipid indicators and cardiac death in nondiabetic patients. Indirect arguments can be marshalled that malnutrition increases cardiac death as a consequence of low L-arginine levels and the ensuing diminished synthesis of NO. PMID- 8676837 TI - Is peritoneal permeability an adverse risk factor for malnutrition in CAPD patients? AB - In light of the correlation between the dialysate to plasma ratio of creatinine (D/P Cr), peritoneal (PD) protein loss and hypoalbuminaemia, peritoneal permeability has been implicated as a risk factor for malnutrition in CAPD patients. However, serum albumin is also affected by hydration which is itself influenced by peritoneal permeability. In a cross-sectional study of 147 CAPD patients we investigated the relationship between peritoneal permeability, PD protein loss and nutritional state. Stepwise regression analysis revealed D/P Cr to be the only significant predictor of serum albumin independent of PD protein loss. No significant relationship was demonstrated between D/P Cr, body fat, lean muscle mass and dietary protein intake. Increased peritoneal permeability does not cause hypoalbuminaemia as a consequence of increased PD protein loss, and does not adversely affect somatic fat and protein status. PMID- 8676838 TI - Diagnostic testing for the evaluation of headaches. AB - Headaches are one of the most common symptoms that neurologists evaluate. Although most are caused by primary disorders, the list differential diagnoses is one of the longest in all of medicine, with over 300 different types and causes. The cause or type of most headaches can be determined by a careful history supplemented by a general and neurologic examination. Reasons for obtaining neuroimaging include medical indications as well as anxiety of patients and families and medico-legal concerns. In the era of managed care, concerns over deselection and negative capitation may dissuade the physician from ordering even a medically indicated scan. The yield of neuroimaging in the evaluation of patients with headache and a normal neurologic examination is quite low. Combining the results of multiple studies performed since 1977 for a total of 3026 scans reveals the overall percentages of various pathologies as: brain tumors, 0.8%; arteriovenous malformations, 0.2%; hydrocephalus, 0.3%; aneurysm, 0.1%; subdural hematoma, 0.2%; and strokes, including chronic ischemic processes, 1.2%. EEG is not useful in the routine evaluation of patients with headache. Similarly, the yield of neuroimaging in the evaluation of migraine is quite low. Combining the results of multiple studies performed since 1976 for a total of 1440 scans of patients with various types of migraine, the overall percentages of various pathologies are: brain tumor, 0.3%; arteriovenous malformation, 0.07%; and saccular aneurysm, 0.07%. WMA have been reported on MRI studies of patients with all types of migraine, with a range from 12% to 46%. The cause of WMA in migraine is not certain. Cerebral atrophy has been variable reported as more frequent and no more frequent in migraineurs compared with controls. The "first or worst" headache has a long list of possible causes and always includes the possibility of acute subarachnoid hemorrhage. Headaches--especially the sentinel type caused by SAH--often are misdiagnosed. The probability of detecting an aneurysmal hemorrhage of CT scans performed at various intervals after the ictus is: day 0.95%; day 3, 74%; 1 week, 50%; 2 weeks, 30%; and 3 weeks, almost nil. The location of a ruptured saccular aneurysm often is suggested by the predominant site of the SAH. The probability of detecting xanthochromia with spectrophotometry in the CSF at various times after a subarachnoid hemorrhage is: 12 hours, 100%; 1 week, 100%; 2 weeks, 100%; 3 weeks, more than 70%; and 4 weeks, more than 40%. The management of thunderclap headaches with normal CT scan and CSF examinations is controversial. Most patients have a benign course but an unruptured saccular aneurysm occasionally may be responsible for the headache. MR angiography may be a reasonable test to obtain instead of a cerebral arteriogram in many of these cases. About 30% to 90% of patients have headaches of various types and causes after mild head injury. Although most headaches are relatively benign, perhaps 1% to 3% of these patients have life-threatening pathology, including subdural and epidural hematomas, that are detected on CT and MRI scans. Headaches caused by subdural hematomas can be nonspecific. When new-onset headaches begin in patients over the age of 50 years, the physician always should consider whether it may be a secondary headache disorder requiring specific diagnostic testing and treatment. Up to 15% of patients 65 years and over who present to neurologists with new-onset headaches may have serious pathology such as stroke, TA, neoplasm, and subdural hematoma. Headaches are the most common symptom of TA, reported by 60% to 90%. The only over the temple. The diagnosis of TA is based on a high index of clinical suspicion that usually but not always is confirmed by laboratory testing. The erythrocyte sedimentation rate can be normal in 10% to 36% of patients with TA. A superficial temporal artery biopsy can give a false-negative result in 5% to 44% of patients. PMID- 8676839 TI - Diagnostic tests for the evaluation of back and neck pain. AB - The number of available diagnostic tests for patients with back and neck pain has grown dramatically over the past two decades, and their cost has increased as well. The impact of managed care and an increased understanding of the natural history of these conditions have led to close evaluation of the sensitivity and specificity of these tests and their effect on patient outcomes. Advanced anatomic and physiologic tests within the first month should be reserved for patients with red flags for serious pathologic conditions on clinical examination. Specific criteria are being developed for each electrodiagnostic and imaging test in the evaluation of the patient whose symptoms do not resolve within 1 month. Guidelines for the testing of patients with chronic back and neck pain have yet to be developed. Stronger emphasis on psychosocial issues and the assurance that pathologic progression has not been missed without the use of repetitive testing form the mainstay of diagnostic protocols in this population. PMID- 8676840 TI - Laboratory testing in peripheral nerve disease. AB - Selecting appropriate laboratory tests in diagnosing peripheral neuropathies is important because it increases the yield of correct diagnoses and is cost effective. A large number of tests are available. This article provides a guide to selecting appropriate tests and reviews the clinical situations that suggest specific tests. Electrodiagnostic testing is valuable in almost all patients with peripheral neuropathy. Quantitative sensory testing adds additional information and is especially useful in patients with small fiber neuropathy. On occasion, routine blood tests may discover metabolic disorders causing a patient's neurologic disorder. A number of antibody assays for neuropathies are available commercially, with the most useful being anti-MAG, anti-GM1, anti-GQ1b, anti-Hu, and anticalcium channel antibodies, but only in very select situations and not as "screening studies". The role of cutaneous nerve and skin biopsies in selected disorders is discussed. PMID- 8676841 TI - Diagnosis in neuromuscular diseases. AB - The diagnosis of neuromuscular diseases can be challenging and successful in the majority of patients, due to advancements in electrophysiology, muscle and nerve biopsy immunohistochemistry, and cytogenetics. This article reviews diverse topics, highlighting these recent achievements, with an emphasis on how they affect the clinical and laboratory diagnosis of specific neuromuscular disorders. PMID- 8676842 TI - Diagnostic testing in movement disorders. AB - The diagnosis of movement disorders is essentially clinical. Work-up depends on patient age, part of the body affected, drug response, and presence of other systemic or neurologic symptoms and signs. Typical Parkinson's disease, essential tremor, and tics need only minimal work-up if any. Brain magnetic resonance imaging/computed tomography, positron emission tomography and single photon emission computed tomography, and DNA studies are promising diagnostic tools. Exclusion of Wilson's disease and neuroacanthocytosis is emphasized in children and young adults with movement disorders. PMID- 8676843 TI - Diagnostic testing. Sleep disorders. AB - Sleep/wake complaints are very prevalent and may be associated with severe personal distress, with personal and societal socioeconomic consequences. A through clinical evaluation, coupled with judicious use of laboratory studies, usually reveals a specific and treatable underlying condition. PMID- 8676844 TI - Diagnostic tests in neuro-ophthalmology. AB - This article reviews the diagnostic testing used in the evaluation of several common neuro-ophthalmologic entities including optic nerve disease, pseudotumor cerebri, anisocoria, ptosis, and ocular motor palsies. Emphasis is placed on these bedside tests that help to establish the diagnosis of these common clinical problems. The utility of the cocaine and Tensilon (edrophonium chloride) tests as well as the role of neuroimaging in these conditions are reviewed. PMID- 8676845 TI - Diagnostic reasoning in neurology. AB - Studies examining physicians' clinical decisions have demonstrated considerable variation in decisions and practices and identified numerous challenges to effective, efficient, and accurate decision making. Although use of the decision aids and tools described in this article may help overcome many of these challenges, greater self-awareness of the diagnostic reasoning process and the factors influencing decisions also should help improve clinical decisions and reduce variation, irrespective of the use of these tools. Continued research into the determinants and nature of the diagnostic reasoning process will provide additional insights that can be used to develop and apply improved decision aids and corrective procedures to overcome persistent problems. PMID- 8676846 TI - Medicolegal aspects of neurodiagnostic tests. AB - Legal issues that may arise in neurodiagnostic testing are reviewed briefly. This article focuses on applications of medical malpractice law with respect to negligence in selection, conduct, and interpretation of tests. The impact of the doctrine of informed consent is considered both in the context of malpractice law and human subjects research. The article concludes with a short exposition on enterprise liability and diagnostic tests, indicating the ways in which the growing role of corporations in medical practice may prompt changes in how claims for test-related medical injuries are processed. This article aims to convey an appreciation of how the law attempts to reduce test-related harms by imposing liability on individuals and organizations. PMID- 8676847 TI - The diagnosis of multiple sclerosis. AB - The process of diagnosing multiple sclerosis (MS) is much like that of analyzing evidence in a courtroom; they both rely on reason, judgement, and experience, rather than on any formal set of diagnostic criteria. The history, physical examination, and laboratory tests all have limitations and pitfalls that make MS one of the most difficult diseases to diagnose. PMID- 8676848 TI - Diagnostic testing and dementia. AB - The prevalence of dementia is expected to increase markedly as our population ages. Although only a minority of cases currently are found to have treatable causes, the personal and financial costs of misdiagnosis are great. Furthermore, progress in developing effective therapy hinges on accurate diagnosis. This article reviews the current state of diagnostic testing in the diagnosis of dementia. PMID- 8676850 TI - Neurotology. AB - As in most areas of clinical medicine, the history often is the key to determining the diagnosis in patients presenting with neurotologic symptoms. The most common cause of vertigo--benign positional vertigo--can be diagnosed at the bedside based on the characteristic history and the finding of fatigable positional nystagmus on the Dix-Hallpike positional test. Furthermore, it can be cured with a simple positioning maneuver. Quantitative auditory and vestibular function tests are important for documenting the site and severity of deficit in patients with chronic neurotologic symptoms. Only a few presentations (listed in section on acute vertigo) require immediate neuroimaging. PMID- 8676849 TI - Diagnostic testing of seizure disorders. AB - Although a thorough history and physical examination remain the basis for the evaluation of patients with a possible seizure disorder, electroencephalography (EEG) is a necessary extension of the neurologic examination. Most patients also require a magnetic resonance imaging (MRI) scan to identify a potentially epileptogenic lesion. This article reviews the technical considerations, common findings, and potential pitfalls related to the use of EEG and MRI. Adjunctive test such as ambulatory EEG, video/EEG, positron emission tomography, single photon emission computed tomography, and serum evaluation also are discussed for use in specific circumstances. PMID- 8676851 TI - Blastomycosis--Wisconsin, 1986-1995. AB - Blastomycosis is a disease of humans and animals caused by inhalation of airborne spores from Blastomyces dermatitidis, a dimorphic fungus found in soil. The spectrum of clinical manifestations of blastomycosis includes acute pulmonary disease, subacute and chronic pulmonary disease (most common presentations), and disseminated extrapulmonary disease (cutaneous manifestations are most common, followed by involvement of the bone, the genitourinary tract, and central nervous system). Although the disease is not nationally notifiable, it was designated a reportable condition in Wisconsin in 1984 following two large outbreaks. This report summarizes information about cases of blastomycosis reported in Wisconsin during 1986-1995 and highlights the importance of surveillance for blastomycosis in areas with endemic disease. PMID- 8676852 TI - Measles pneumonitis following measles-mumps-rubella vaccination of a patient with HIV infection, 1993. AB - The Advisory Committee on Immunization Practices (ACIP) recommends measles-mumps rubella vaccine (MMR) for all persons asymptomatically infected with human immunodeficiency virus (HIV) and recommends that MMR be considered for all symptomatic HIV-infected persons who would otherwise be eligible for measles vaccine, because measles virus infection can cause severe illness and death in such persons. Serious or unusual adverse events in HIV-infected persons after receiving MMR have not been reported previously. This report summarizes the investigation of a case of progressive vaccine-associated measles pneumonitis in a person with acquired immunodeficiency syndrome and provides interim recommendations for the use of measles-containing vaccine among HIV-infected persons. PMID- 8676853 TI - Biopsy-confirmed hypersensitivity pneumonitis in automobile production workers exposed to metalworking fluids--Michigan, 1994-1995. AB - In 1994, union and management officials and local physicians in southeastern Michigan noted the occurrence among automobile production workers of respiratory illness consistent with hypersensitivity pneumonitis (HP). Local and national health authorities reviewed medical records, and in June 1994, individual employees and the union requested that CDC's National Institute for Occupational Safety and Health (NIOSH) evaluate potential occupational exposures associated with these illnesses. This report summarizes preliminary findings of the evaluation, including detailed information about one HP case and a summary description of the six biopsy-confirmed cases among automobile production workers from three different plants (plants A, B, and C) in southeastern Michigan; all six workers had jobs that entailed frequent exposure to metalworking fluids (MWFs). The findings suggest the need for further evaluation of a possible association of occupational exposure to MWFs with HP. PMID- 8676854 TI - Update: outbreaks of Cyclospora cayetanensis infection--United States and Canada, 1996. AB - Since May 1996, CDC has received reports of clusters and sporadic cases of infection with the parasite Cyclospora cayetanensis that occurred in May and June in the United States and Canada. This report describes preliminary findings of an investigation by the New Jersey Department of Health and Senior Services (NJDHSS) and updates the findings of other ongoing investigations. PMID- 8676855 TI - Requirement for two conserved cysteine residues in the Ada protein of Escherichia coli for transactivation of the ada promoter. AB - Cysteine residue 69 of the Escherichia coli Ada transcription factor, which accepts a methyl group from methylphosphotriester in methylated DNA, was substituted by each of 19 other amino acids. Only the mutant Ada (C69H), carrying a histidine substitution of Cys69, exhibited a limited degree of transactivating potential for the ada promoter in E. coli cells although the mutant protein was completely devoid of methylphosphotriester-DNA methyltransferase activity. Using a multicopy plasmid system for the expression of Ada protein, we have shown that Ada C69H has a transactivating capacity equivalent to that of wild-type Ada protein in the absence of an alkylating agent. This indicates that the zinc binding capacity of histidine at residue 69 is likely to be sufficient for Ada to recognize and bind to the ada promoter. Furthermore, transactivation of the ada promoter by Ada C69H was enhanced up to 6-fold by treatment with methylating agents. An additional substitution was made with alanine in Ada C69H, replacing Cys321, the site for acceptance of a methyl group from O6-methylguanine and O4 methylthymine residues in DNA, with alanine. This renders the protein completely inactive as a methyltransferase but this derivative is constitutively active as a transactivator for the ada promoter. Therefore, acquisition of a methyl group at Cys321 apparently enhances the transactivating capacity of Ada protein on the ada promoter. We propose that the transcription-regulating function of Ada protein is under dual control by methylation of cysteine residues at positions 69 and 321; the former enhances DNA binding, while the latter enhances the transactivating capacity of the protein. PMID- 8676856 TI - Characterization and subcellular localization of a small GTP-binding protein (Ara 4) from Arabidopsis: conditional expression under control of the promoter of the gene for heat-shock protein HSP81-1. AB - Small GTP-binding proteins belonging to the rab/YPT family play key roles at various steps in intracellular transport pathways in yeast and mammalian cells. Many members of rab/YPT family have been isolated from plants to date. However, detailed information about the localization and function of the gene products remains limited, even though intracellular transport is likely to be involved in important phenomena such as cell elongation, transport of storage proteins, determination and maintenance of cell polarity and intercellular signal transduction. We have attempted to establish transgenic Arabidopsis plants that overexpress ARA-4, a rab/YPT homologue in order to analyze the function and the localization of the gene product. For overexpression and also for regulation of the expression of this gene, the promoter of the gene for HSP81-1 was employed to drive the transcription of ARA-4 in transgenic plants. The response of the introduced genes to heat shock was analyzed. Upon heat-shock treatment, the ARA-4 gene was efficiently transcribed and translated. The induction of ARA-4 by heat shock was transient, and at least two distinct forms of this protein were found in membrane and cytosolic fractions from transgenic plants. Prolonged incubation after heat shock reduced the amount of the cytosolic form of the induced protein, and the cytosolic form of the protein thus probably represents the unprocessed precursor. Using transgenic plants, we determined the subcellular localization of the product of ARA-4. The protein was predominantly localized on Golgi-derived vesicles, Golgi cisternae and the trans-Golgi network. PMID- 8676857 TI - A genetic analysis of bx bxd cis double mutants in the Drosophila Ultrabithorax gene. AB - The Ultrabithorax (Ubx) gene of Drosophila melanogaster includes two functionally distinguishable regions. One is the Ubx transcription unit, which gives rise by alternative splicing to a family of morphogenetic Ubx proteins (UBX). The other is its upstream bithoraxoid (bxd) region. On the basis of genetic and molecular studies, it is generally assumed that the Ubx transcription unit contains internal positively acting cis-regulatory elements controlling UBX expression in the T3a compartment of the body of Drosophila, while the bxd region contains positive cis-regulatory elements controlling UBX expression in the T3p and A1a compartments. We have performed a genetic analysis of bx bxd cis double mutant chromosomes containing one mutation (bx alleles) affecting the Ubx unit, and a second (bxd alleles) affecting the bxd region of the Ubx gene. Our study of different bx bxd/bx combinations shows that bxd alleles partially rescue the adult mutant phenotypes of bx alleles, which suggests that the bxd region contains a negative cis-regulatory element involved in the control of the activity of the Ubx gene in the T3a compartment. PMID- 8676858 TI - Self-incompatibility (S) alleles of the Rosaceae encode members of a distinct class of the T2/S ribonuclease superfamily. AB - Stylar ribonucleases (RNases) are associated with gametophytic self incompatibility in two plant families, the Solanaceae and the Rosaceae. The self incompatibility-associated RNases (S-RNases) of both the Solanaceae and the Rosaceae were recently reported to belong to the T2 RNase gene family, based on the presence of two well-conserved sequence motifs. Here, the cloning and characterization of S-RNase genes from two species of Rosaceae, apple (Malus x domestica) and Japanese pear (Pyrus serotina) is described and these sequences are compared with those of other T2-type RNases. The S-RNases of apple specifically accumulated in styles following maturation of the flower bud. Two cDNA clones for S-RNases from apple, and PCR clones encoding a further two apple S-RNases as well as two Japanese pear S-RNases were isolated and sequenced. The deduced amino acid sequences of the rosaceous S-RNases contained two conserved regions characteristic of the T2/S-type RNases. The sequences showed a high degree of diversity, with similarities ranging from 60.4% to 69.2%. Interestingly, some interspecific sequence similarities were higher than those within a species, possibly indicating that diversification of S-RNase alleles predated speciation in the Rosaceae. A phylogenetic tree of members of the T2/S RNase superfamily in plants was obtained. The rosaceous S-RNases formed a new lineage in the tree that was distinct from those of the solanaceous S-RNases and the S-like RNases. The findings suggested that self-incompatibility mechanisms in Rosaceae and Solanaceae are similar but arose independently in the course of evolution. PMID- 8676859 TI - Construction of Hermes shuttle vectors: a versatile system useful for genetic complementation of transformable and non-transformable Neisseria mutants. AB - A versatile shuttle system has been developed for genetic complementation with cloned genes of transformable and non-transformable Neisseria mutants. By random insertion of a selectable marker into the conjugative Neisseria plasmid ptetM25.2, a site within this plasmid was identified that is compatible with plasmid replication and with conjugative transfer of plasmid. Regions flanking the permissive insertion site of ptetM25.2 were cloned in Escherichia coli and served as a basis for the construction of the Hermes vectors. Hermes vectors are composed of an E. coli replicon that does not support autonomous replication in Neisseria, e.g. ColE1, p15A, or ori(fd), fused with a shuttle consisting of a selectable marker and a multiple cloning site flanked by the integration region of ptetM25.2. Complementation of a non-transformable Neisseria strain involves a three-step process: (i) insertion of the desired gene into a +Hermes vector; (ii) transformation of Hermes into a Neisseria strain containing ptetM25.2 to create a hybrid ptetM25.2 via gene replacement by the Hermes shuttle cassette; and (iii) conjugative transfer of the hybrid ptetM25.2 into the final Neisseria recipient. Several applications for the genetic manipulation of pathogenic Neisseriae are described. PMID- 8676860 TI - recB recJ mutants of Salmonella typhimurium are deficient in transductional recombination, DNA repair and plasmid maintenance. AB - recB recJ mutants of Salmonella typhimurium are deficient in transduction of chromosomal markers and ColE1-derived plasmids, and also in the maintenance of ColE1 and F plasmids. Plasmid instability is less severe in recD recJ strains; ColE1 plasmid DNA preparations from these strains show an increased yield of high molecular weight (HMW) linear multimers and a concomitant reduction in plasmid monomers compared to the wild type. Plasmids remain unstable in recA recD recJ mutants; since these do not produce HMW linear concatemers, we propose that a decrease in monomer production leads to plasmid instability. recB recJ strains also display decreased viability, a component of which may be related to their deficiency in DNA repair. In contrast to their severe defects in recombination, DNA repair and plasmid maintenance, recB recJ mutants of S. typhimurium behave similarly to the wild type in the segregation of chromosome duplications. The latter observation suggests that neither RecBCD nor RecJ functions are required for chromosomal recombination events that do not involve the use of free ends as recombination substrates. PMID- 8676861 TI - Cis-elements important for the expression of the ADP-glucose pyrophosphorylase small-subunit are located both upstream and downstream from its structural gene. AB - ADP-glucose pyrophosphorylase (AGP) is a key regulatory enzyme in the biosynthesis of starch in higher plants. Previous studies have suggested that, unlike other plants that display tissue-specific AGP genes, potato expresses the same AGP small-subunit gene (sAGP) in multiple tissues. This view was confirmed by the spatial patterns of expression of the sAGP gene in transgenic potato plants observed when a promoter-dependent-beta-glucuronidase (beta-GUS) system was used. sAGP-beta-GUS chimeric gene fusions were expressed at high levels in tubers and in many other starch-containing cells throughout the plant. Deletional analysis of the 5'-upstream region of sAGP revealed that the observed spatial patterns of expression were due to different regions of the promoter of sAGP functioning in combination to confer cell- and organ-specific patterns of expression. Depending on the tissue examined, the patterns of reporter-gene expression were enhanced, suppressed, or altered when the 3'-nopaline-synthase terminator was replaced by the 3'-flanking sequence of sAGP. The observed cellular expression patterns of sAGP only partially overlap with the reported expression patterns of the major large-subunit gene (lAGP) in leaves. Since AGP is a heterotetrameric enzyme, composed of two sAGP and two lAGP subunits, this difference in the cellular expression patterns as well as quantitative differences in expression of the two AGP genes may account for the observed post transcriptional regulation, i.e., relatively high levels of transcript but low levels of sAGP subunit in leaves. PMID- 8676862 TI - Co-induction of DNA relaxation and synthesis of DnaK and GroEL proteins in Escherichia coli by expression of LetD (CcdB) protein, an inhibitor of DNA gyrase encoded by the F factor. AB - We examined the influence of overexpression of LetD (CcdB) protein, an inhibitor of DNA gyrase encoded by the F factor of Escherichia coli, on DNA supercoiling and induction of heat shock proteins. Cells were transformed with a plasmid carrying the structural gene for LetD protein under control of the tac promoter, and LetD protein was induced by adding isopropyl beta-D-thiogalactopyranoside (IPTG) to the culture medium. Analysis by agarose gel electrophoresis in the presence of chloroquine revealed relaxation of plasmid DNA in cells depending on the concentration of IPTG employed for induction. Protein pulse-labeling experiments with [35S]methionine and cysteine revealed that synthesis of DnaK and GroEL proteins was also induced by IPTG, and concentrations necessary for DNA relaxation and induction of the heat shock proteins were much the same. Expression of mutant LetD protein lacking two amino acid residues at the C terminus induced neither DNA relaxation nor the synthesis of DnaK and GroEL proteins. Induction of wild-type LetD protein but not mutant LetD protein markedly enhanced synthesis of sigma32. We interpret these results to mean that DNA relaxation in cells caused by the expression of LetD protein induces heat shock proteins via increased synthesis of sigma32. PMID- 8676864 TI - Allele-specific suppression of a Saccharomyces cerevisiae prp20 mutation by overexpression of a nuclear serine/threonine protein kinase. AB - The yeast PRP20 protein is homologous to the RCC1 protein of higher eukaryotes and is required for mRNA export and maintenance of nuclear structure. RCC1/PRP20 act as guanine nucleotide exchange factors for the nuclear Ras-like Ran/GSP1 proteins. In a search for prp20-10 allele-specific high-copy-number suppressors, the KSP1 locus, encoding a serine/threonine protein kinase was isolated. Ksp1p is a nuclear protein that is not essential for vegetative growth of yeast. Inactivation of the kinase activity by a mutation affecting the catalytic center of the Ksp1p eliminated the suppressing activity. Based on the isolation of a protein kinase as a high-copy-number suppressor, the phosphorylation of Prp20p was examined. In vivo labeling experiments showed that Prp20p is a phosphoprotein; however, deletion of the KSP1 kinase did not affect Prp20p phosphorylation. PMID- 8676865 TI - RNA facilitates RecA-mediated DNA pairing and strand transfer between molecules bearing limited regions of homology. AB - The RecA protein of Escherichia coli catalyzes homologous pairing and strand exchange between a wide range of molecules showing nucleotide sequence complementarity, including a linear duplex and a single-stranded DNA molecule. We demonstrate that RecA can promote formation of joint molecules when the duplex contains an RNA/DNA hairpin and a single-stranded circle serves as the pairing partner. A chimeric RNA/DNA hairpin can be used to form stable joint molecules with as little as 15 bases of shared homology as long as the RNA stretch contains complementarity to the circle. The joint molecule bears some resemblance to a triple helical structure composed of RNA residues surrounded by two DNA strands which are in a parallel orientation. Evidence is presented that supports the notion that short stretches of RNA can be used in homologous pairing reactions at lengths below that required for DNA-DNA heteroduplex formation. PMID- 8676866 TI - Molecular characterization of the lysosomal acid phosphatase from Drosophila melanogaster. AB - In Drosophila, unlike humans, the lysosomal acid phosphatase (Acph-1) is a non essential enzyme. It is also one of the most rapidly evolving gene-enzyme systems in the genus. In order to determine which parts of the enzyme are conserved and which parts are apparently under little functional constraint, we cloned the gene from Drosophila melanogaster via a chromosomal walk. Fragments from the gene were used to recover an apparently full-length cDNA. The cDNA was sub-cloned into a Drosophila transformation vector where it was under the control of the 5' promoter sequence of the hsp-70 gene. Three independent transformants were obtained; in each, Acph-1 expression from the cDNA was constitutive and not dependent on heat shock, as determined by densitometric analyses of the allozymic forms of the enzyme. The pattern of expression indicates the hsp-70 and endogenous Acph-1 promoters act together in some, but not all, tissues. The sequence of the cDNA was determined using deletions made with exonuclease III, and primers deduced from the cDNA sequence were used to sequence the genomic clone. Five introns were found, and putative 5' upstream regulatory sequences were identified. Amino acid sequence comparisons have revealed several highly conserved motifs between Drosophila Acph-1 and vertebrate lysosomal and prostatic acid phosphatases. PMID- 8676863 TI - Characterization of a sex-influenced modifier of gene expression and suppressor of position-effect variegation in Drosophila. AB - Modifier of white (Mow), a dominant transacting gene, has been identified through a mutagenic screen for second-site loci that alter the level of expression of the white eye color locus. Mow reduces the expression of white in most developmental stages, but enhances its expression in the pupal stage, the time at which the major contribution to the adult phenotype is made. Tests with an Alcohol dehydrogenase promoter-white reporter and a series of white truncation constructs have shown that Mow fails to affect the reporter; cis-regulatory mutations of white also show no response, suggesting a requirement for white regulatory domains for interaction with Mow. A quantitative analysis of steady-state transcript levels reveals that the white mRNA level decreases in the presence of one dose of Mow in larvae and adults, but the reduction is greater in females than males. Two other functionally related genes, brown and scarlet, also exhibit a similar sexually dimorphic alteration in expression, mediated by Mow. In the mid-pupal stage, by contrast, the level of white and brown mRNA is increased by Mow. In addition, Mow acts as a weak suppressor of position effect variegation (PEV). These observations suggest a connection between dosage modulation of gene expression and suppression of position-effect variegation. PMID- 8676867 TI - The transcriptional activator Opaque-2 controls the expression of a cytosolic form of pyruvate orthophosphate dikinase-1 in maize endosperms. AB - The maize Opaque-2 (O2) protein is a transcription factor of the basic/leucine zipper class, involved in the regulation of endosperm proteins including the 22kDa alpha-zein storage proteins and b32 protein. In this study we have focussed our attention on the relationship between O2 and the cyPPDK1 gene, which encodes a cytoplasmic pyruvate orthophosphate dikinase (PPDK) isoform. The results of this study showed that PPDK activity is detectable in wild-type maize endosperms, while in o2 mutant endosperms, the levels of PPDK protein, mRNA and enzymatic activity are reduced, indicating that O2 is involved in the regulation of cyPPDK1 in this tissue. By employing transient expression experiments in tobacco mesophyll protoplasts, we have demonstrated that the O2 protein can activate expression of a chloramphenicol acetyl transferase reporter gene placed under the control of the cyPPDK1 promoter. An in vitro binding assay and DNaseI footprint analysis demonstrated that a specific sequence in the cyPPDK1 promoter can be recognized and protected by maize O2 protein. The regulation by the O2 locus of cyPPDK1 reported here, and control of alpha-zein synthesis by O2 suggest that the O2 protein may play a more general role in maize endosperm development than previously thought. PMID- 8676868 TI - Complementation of an Arabidopsis thaliana biotin auxotroph with an Escherichia coli biotin biosynthetic gene. AB - The Arabidopsis thaliana biotin auxotroph biol was rendered prototrophic by transformation with a chimeric transgene containing the Escherichia coli bio A gene driven by a constitutive promoter. The bio A gene encodes the biotin biosynthetic enzyme 7, 8-diaminopelargonic acid aminotransferase. Unlike the untransformed control plants, transgenic plants expressing the bacterial transgene synthesized biotin and grew to maturity without biotin-deficiency symptoms. These findings demonstrate that bio1/bio1 mutant plants are defective in the gene encoding 7,8-diaminopelargonic acid aminotransferase. PMID- 8676869 TI - Identification and isolation of the FEEBLY gene from tomato by transposon tagging. AB - The Ac/Ds transposon system from maize was used for insertional mutagenesis in tomato. Marker genes were employed for the selection of plants carrying a total of 471 unique Ds elements. Three mutants were obtained with Ds insertions closely linked to recessive mutations: feebly (fb), yellow jim (yj) and dopey (dp). The fb seedlings produced high anthocyanin levels, developed into small fragile plants, and were insensitive to the herbicide phosphinothricin. The yj plants had yellow leaves as a result of reduced levels of chlorophyll. The dp mutants completely or partially lacked inflorescences. The fb and yj loci were genetically linked to the Ds donor site on chromosome 3. Reactivation of the Ds element in the fb mutants by crosses with an Ac-containing line resulted in restoration of the wild-type phenotypes. Plant DNA fragments flanking both sides of the Ds element in the fb mutant were isolated by the inverse polymerase chain reaction. Molecular analysis showed that phenotypic reversions of fb were correlated with excisions of Ds. DNA sequence analysis of Fb reversion alleles showed the characteristic Ds footprints. Northern and cDNA sequence analysis indicated that transcription of the FEEBLY (FB) gene was impeded by the insertion of Ds in an intron. Comparison of the predicted amino acid sequence of the FB protein with other database sequences indicated that FB is a novel gene. PMID- 8676870 TI - Isolation, characterization and transposition of an (IS2)2 intermediate. AB - We have isolated and characterized a dimer derivative of the extensively studied Escherichia coli insertion sequence IS2. The dimer structure--called (IS2)2- consists of two IS2 elements arranged as a direct repeat, separated by 1 bp. The junction between the (IS2)2 dimer and target sequences is located at various positions in independent isolates; however, one position was preferred. The transposition of (IS2)2 into a target plasmid resulted in cointegrate-type structures. The transposition frequency of the (IS2)2 dimer itself was significantly higher than that of the isogenic monomer IS2 insertion. The poor stability and high activity of (IS2)2 indicates that this is an active transposition intermediate. The mode of transposition of (IS2)2 is analogous to the joined dimer model described in the case of (IS21)2 and (IS30)2. PMID- 8676871 TI - Cytochrome P450 gene clusters in Drosophila melanogaster. AB - Twelve cytochrome P450 cDNA fragments were cloned from Drosophila melanogaster by reverse transcriptase/PCR (RT/PCR) using degenerate oligonucleotide primers. The corresponding genes belong to several subfamilies of the CYP4 and CYP9 P450 families. Only two of these genes, Cyp4dl and Cyp4d2, have previously been described. In situ hybridization of each of the cDNA fragments showed two clusters of genes; one near the tip of the X chromosome and the other on the left arm of chromosome 2. Interestingly the latter cluster comprises widely divergent genes belonging both to the CYP9 and CYP4 families and also to the CYP6 family (Cyp6a2). Putative allelic variants of several of the genes were found in different insecticide-resistant and -susceptible strains (Hikone R, Haag 79 and Oregon R). The identification of these genes and alleles will allow us to clarify the involvement of P450s in xenobiotic metabolism and will facilitate a genetic analysis of P450 functions in insects. PMID- 8676872 TI - Genetic and physical mapping in Brassica diploid species of a gene cluster defined in Arabidopsis thaliana. AB - We report the genetic and physical analysis by pulse field gel electrophoresis (PFGE) in three Brassica diploid genomes for a cluster of five genes characterized in a selected segment of 15 kb on chromosome 3 of Arabidopsis thaliana, encoding a Bradyrhizobium CycJ homologue (At1), a rat p67 translation factor homologue (At2), an Em-like (early methionine) protein (At3), chlorophyll synthase (At4) and a yeast Sac1 homologue (A5). The Arabidopsis gene array was found to be conserved on a single linkage group in each of the Brassica genomes. However, partial complexes were found to be duplicated in other chromosome segments on the same or other linkage groups. Some of the At genes, which could not be genetically mapped because of lack of polymorphism, were assigned to their respective linkage groups by physical mapping. The presence of multiple copies of the A. thaliana gene cluster in the three Brassica genomes further establishes their complex nature, which results from extensive duplication and chromosomal rearrangement. In general, genetic distances between the At genes agreed with values expected for the physical distances determined in Brassica. PMID- 8676873 TI - Regulation of the operon responsible for broad-spectrum mercury resistance in Streptomyces lividans 1326. AB - The broad-spectrum mercury resistance of Streptomyces lividans 1326 is mediated by six open reading frames (orf). These are arranged in two divergently transcribed operons. The orfs mer A (mercuric reductase) and mer B (organolyase) form one of the two operons. These genes and their regulation were further studied by deletion analysis and transcriptional fusion to the reporter gene xylE in the plasmid pXE4. An increase in XylE activity in response to the presence of mercuric ions was observed. The function of ORF2 (MerT) and ORF3 (MerP) as mercury-specific transport proteins, previously postulated based on the structural features of the predicted proteins, was confirmed. Transcription of the mer genes starts within the intercistronic region and two divergent promoters were identified by S1 nuclease mapping. Expression of the genes was negatively regulated by the product of orf1, now called merR. The repressor function was confirmed by gel retardation assays. MerR, produced in Escherichia coli, bound to two sites (operators) in the fragment containing the promoter region between merA and merR. Addition of mercuric ions and phenylmercuric acetate prevented the binding of MerR. PMID- 8676874 TI - Molecular analysis of irradiation-induced and spontaneous deletion mutants at a disease resistance locus in Lactuca sativa. AB - The major cluster of disease resistance genes in lettuce (Lactuca sativa) contains at least nine downy mildew resistance genes (Dm) spanning a genetic distance of 20cM and a physical distance of at least 6 Mb. Nine molecular markers that were genetically tightly linked to Dm3 were used to analyze nine independent deletion mutants and construct a map of the region surrounding Dm3. This analysis identified a linear order of deletion breakpoints and markers along the chromosome. There was no evidence for chromosomal rearrangements associated with the deletions. The region is not highly recombinagenic and the deletion breakpoints provided greater genetic resolution than meiotic recombinants. The region contains a mixture of high-and low-copy number sequences; no single-copy sequences were detected. Three markers hybridized to low-copy-number families of sequences that are duplicated predominantly close to Dm3. This was not true for sequences related to the triose-phosphate isomerase gene; these had been shown previously to be linked to Dm3, as well as to two independent clusters of Dm genes, and elsewhere in the genome. Two spontaneous mutants of Dm3 were identified; several markers flanking Dm3 are absent in one of these two mutants. The stability of the Dm3 region was also studied by analyzing the genotypes of diverse related cultivars. The 1.5 Mb region surrounding Dm3 has remained stable through many generations of breeding with and without selection for Dm3 activity. PMID- 8676875 TI - Conservation of the organization of the mitochondrial nad3 and rps12 genes in evolutionarily distant angiosperms. AB - The organization of the genes nad3 and rps12 has been investigated in the mitochondrial genome of two dicotyledonous plants - Helianthus and Magnolia - and one monocotyledonous plant (Allium). These plants all contain a complete rps12 gene downstream of the nad3 gene. This arrangement is thus highly conserved within angiosperms. The two genes are co-transcribed and the transcript is modified at several positions by RNA editing of the C to U-type, thus confirming that both genes encode functional proteins. Some 26, 35 and 27 editing events have been identified in the PCR-derived nad3-rps12 cDNA population from sunflower, Magnolia and onion, respectively. Editing of the nad3-rps12 transcript is thus more extensive in Magnolia than in the other angiosperms so far investigated and radically changes the genomically encoded polypeptide sequence. A novel species-specific codon modification was observed in Magnolia. Several homologous sites show differences in editing pattern among plant species. A C-to U alteration is also found in the non-coding region separating the nad3 and rps12 genes in sunflower. The PCR-derived cDNA populations from the nad3-rps12 loci analysed were found to be differently edited. In addition the plant species show marked variations in the completeness of RNA editing, with only the Magnolia nad3 mRNA being edited fully. PMID- 8676876 TI - Mutants in position 69 of the Trp repressor of Escherichia coli K12 with altered DNA-binding specificity. AB - Structural analysis by X-ray crystallography has indicated that direct contact occurs between Arg69, the second residue of the first helix of the helix turnhelix (HTH) motif of the Trp repressor, and guanine in position 9 of the alpha-centred consensus trp operator. We therefore replaced residue 69 of the Trp repressor with Gly, Ile, Leu or Gln and tested the resultant repressor mutants for their binding to synthetic symmetrical alpha- or beta-centred trp operator variants, in vivo and in vitro. We present genetic and biochemical evidence that Ile in position 69 of the Trp repressor interacts specifically with thymine in position 9 of the alpha-centred trp operator. There are also interactions with other bases in positions 8 and 9 of the alpha-centred trp operator. In vitro, the Trp repressor of mutant RI69 binds to the consensus alpha-centred trp operator and a similar trp operator variant that carries a T in position 9. In vivo analysis of the interactions of Trp repressor mutant RI69 with symmetrical variants of the beta-centred trp operator shows a change in the specificity of binding to a beta-centred symmetrical trp operator variant with a gua-nine to thymine substitution in position 5, which corresponds to position 9 of the alpha centred trp operator. PMID- 8676877 TI - Identification of ovarian enhancer-binding factors which bind to ovarian enhancer 1 of the Drosophila genes yp1 and yp2. AB - It has been reported that three different DNA regions-the fat body enhancer and ovarian enhancers 1 and 2-direct the tissue-specific expression of yp1 and yp2 in Drosophila melanogaster. In the present study, we identified ovarian enhancer 1 specific binding proteins. Electrophoretic mobility shift assay revealed that these proteins are present in the adult ovary, but not in adult testis or fat body. Southwestern blot analysis showed that about 130 kDa and 40 kDa proteins, designated OEF1 and OEF2, respectively, from ovarian nuclear or crude extracts bind specifically to the ovarian enhancer 1. The two proteins were partially purified by streptavidin/agarose-DNA affinity chromatography, and their binding activity was confirmed by electrophoretic mobility shift assay. These ovarian enhancer factors may play an important role in the regulation of transcription of yp1 and yp2 in the ovary. PMID- 8676878 TI - Effect of mutY and mutM/fpg-1 mutations on starvation-associated mutation in Escherichia coli: implications for the role of 7,8-dihydro-8-oxoguanine. AB - MutY specifies a DNA glycosylase that removes adenines unnaturally paired with various bases including oxidized derivatives of guanine, such as 7,8-dihydro-8 oxoguanine (8-oxoG). The rate of mutation in starved Escherichia coli cells is markedly raised in mutY mutants defective in this glycosylase. As predicted, the mutations produced include G to T transversions. Bacteria carrying mutM or fpg-1 mutations (defective in Fapy glycosylase, which removes oxidized guanine residues such as 8-oxoG) show little or no enhancement of mutation under starvation conditions. When present together with mutY, however, mutM clearly further enhances the rate of mutation in starved cells. Plasmids resulting in overproduction of MutY or Fapy glycosylases reduce the rate of mutation in starved cells. We conclude that, in non-growing bacteria, oxidized guanine residues, including 8-oxoG, constitute an important component of spontaneous mutation. Addition of catalase to the plates did not reduce the mutant yield, indicating that extracellular hydrogen peroxide is not involved in the production of the premutational damage. Singlet oxygen, known to give rise to 8-oxoG, may be the ultimate oxidative species. PMID- 8676879 TI - Interaction of Saccharomyces cerevisiae Pho2 with Pho4 increases the accessibility of the activation domain of Pho4. AB - In Saccharomyces cerevisiae, expression of acid phosphatase, encoded by the PHO5 gene, requires two positive regulatory factors, Pho4 and Pho2 (also called Bas2 or Grf10). Using GAL4-PHO4 fusions, we demonstrate that a functional interaction between these two proteins is necessary for transcriptional activation to occur. This functional interaction between Pho4 and Pho2 is independent of the presence of the negative regulatory factor, Pho80, which also interacts with Pho4. Interestingly, truncations of Pho4 missing amino acids 252-265, which encompass the basic region of the basic helix-loop-helix (bHLH) DNA binding motif, exhibit high transcriptional activation that is independent of the Pho2 molecule. Single amino acid mutations of highly conserved residues within this area all display this Pho2-independent phenotype. A region near the C-terminus of Pho2 appears to be critical for this interaction with Pho4. A model to account for the requirement for Pho2 in Pho4-dependent transcriptional activation is proposed. PMID- 8676881 TI - Selectable marker recycling in the chloroplast. AB - The bacterial gene aadA is an important and widely used selectable marker for manipulation of the chloroplast genome through biolistic transformation. Because no other such marker is available, two strategies for recycling of the aadA cassette have been developed. One utilizes homologous recombination between two direct repeats flanking the aadA cassette to allow its loss under non-selective growth conditions. A second strategy is to perform co-transformation with a plasmid containing a modified, non-essential chloroplast gene and another plasmid in which the aadA cassette disrupts a chloroplast gene known to be essential for survival. Under selective growth conditions the first mutation can be transferred to all chloroplast DNA copies whereas the aadA insertion remains heteroplasmic. Loss of the selectable marker can be achieved subsequently by growing the cells on non-selective media. In both cases it is possible to reuse the aadA cassette for the stepwise disruption or mutagenesis of any gene in the same strain. PMID- 8676880 TI - Transgenic Arabidopsis tester lines with dominant marker genes. AB - The map positions of a set of eight T-DNA insertions in the Arabidopsis genome have been determined by using closely linked visible markers. The insertions are dispersed over four of the five chromosomes. Each T-DNA insert contains one or more of the chimeric marker genes neomycin phosphotransferase (neo), hygromycin phosphotransferase (hpt), phosphinothricin acetyltransferase (bar), beta glucuronidase (gusA) and indole-3-acetamide hydrolase (iaaH). The neo, hpt and bar marker genes are dominant in a selective germination assay or when used as DNA markers in a polymerase chain reaction. These dominant markers will allow recombinants to be discerned in a germinating F2 population, one generation earlier than with a conventional recessive marker. The transgenic marker lines will speed up and simplify the isolation of recombinants in small genetic intervals, a rate-limiting step in positional cloning strategies. The transgenic lines containing the hpt marker will also be of interest for the isolation of deletion mutants at the T-DNA integration sites. PMID- 8676883 TI - Colicin M is inactivated during import by its immunity protein. AB - Colicin M (Cma) displays a unique activity that interferes with murein and O antigen biosynthesis through inhibition of lipid-carrier regeneration. Immunity is conferred by a specific immunity protein (Cmi) that inhibits the action of colicin M in the periplasm. The subcellular location of Cmi was determined by constructing hybrid proteins between Cmi and the TEM-beta-lactamase (BlaM), which confers resistance to ampicillin only when it is translocated across the cytoplasmic membrane with the aid of Cmi. The smallest Cmi'-BlaM hybrid that conferred resistance to 50 micrograms/ml ampicillin contained 19 amino acid residues of Cmi; cells expressing Cmi'-BlaM with only five N-terminal Cmi residues were ampicillin sensitive. These results support a model in which the hydrophobic sequence of Cmi comprising residues 3-23 serves to translocate residues 24-117 of Cmi into the periplasm and anchors Cmi to the cytoplasmic membrane. Residues 8-23 are integrated in the cytoplasmic membrane and are not involved in Cma recognition. This model was further tested by replacing residues 1-23 of Cmi by the hydrophobic amino acid sequence 1-42 of the penicillin binding protein 3 (PBP3). In vivo, PBP3'-'Cmi was as active as Cmi, demonstrating that translocation and anchoring of Cmi is not sequence-specific. Substitution of the 23 N-terminal residues of Cmi by the cleavable signal peptide of BlaM resulted in an active BlaM'-'Cmi hybrid protein. The immunity conferred by BlaM'-'Cmi was high, but not as high as that associated with Cmi and PBP3'-'Cmi, demonstrating that soluble Cmi lacking its membrane anchor is still active, but immobilization in the cytoplasmic membrane, the target site of Cma, increases its efficiency. Cmi delta 1-23 remained in the cytoplasm and conferred no immunity. We propose that the immunity protein inactivates colicin M in the periplasm before Cma can reach its target in the cytoplasmic membrane. PMID- 8676882 TI - A newly identified Minute locus, M(2)32D, encodes the ribosomal protein L9 in Drosophila melanogaster. AB - A gene encoding a ubiquitously expressed mRNA in Drosophila melanogaster was isolated and identified as the gene for ribosomal protein L9 (rpL9) by its extensive sequence homology to the corresponding gene from rat. The rpL9 gene is localized in polytene region 32D where two independent P element insertions flanking the locus are available. Remobilization of either P element generated lines with a typical Minute phenotype, e.g. thin and short bristles, prolonged development, and female semisterility in heterozygotes as well as homozygous lethality. All these characteristics can be rescued when a 3.9 kb restriction fragment containing the rpL9 gene is reintroduced by P element-mediated germline transformation. This result confirms that M(2)32D codes for ribosomal protein L9. PMID- 8676884 TI - The effect of orientation within a chimeric peptide on the immunogenicity of Chlamydia trachomatis epitopes. AB - Peptides representing the Chlamydia trachomatis major outer membrane protein variable domains (VD) 1 and 4 of serovars C and E, respectively, have been shown to elicit a neutralizing antibody response in mice. To assess whether the position within a chimeric peptide influences the immunogenicity of the epitopes, two constructs, VD 1-4 and VD 4-1, were made in which the position of the VD relative to the amino and carboxy terminals were rotated. C57BL/10 mice were immunized with 100 micrograms of peptide in complete Freund's adjuvant (FA) on day 0, followed by an immunization with peptide (100 micrograms) in complete FA on day 14. By day 21 the immunodominant epitope in both chimeras as measured by ELISA was the one located at the carboxy terminus. A pepscan of the VD 1-4 antisera revealed a main peak in VD 4 which had been previously identified by neutralizing MAbs. The VD 4-1 antisera gave a peak in the VD 1 region which did not correspond to regions previously mapped with neutralizing MAbs. The VD 1-4 antisera but not the VD 4-1 antisera was able to neutralize in vitro serovar E. In summary, the position of these chlamydial epitopes within a chimeric peptide greatly influenced the resulting immune response. PMID- 8676885 TI - Target cell-induced perforin mRNA turnover in NK3.3 cells is mediated by multiple elements within the mRNA coding region. AB - We have previously shown that in cytolytic cells exposed to sensitive targets the mRNA of the cytolytic protein perforin undergoes rapid downregulation. We now demonstrate that perforin message undergoes accelerated turnover in NK3.3 cells exposed to sensitive TC. This inducible mRNA decay phenomenon is specific for cytolytic protein messages, as levels of the constitutive message beta-actin are unchanged. This TC-induced perforin mRNA turnover cannot be attributed to a blockage of RNA synthesis, or to a rapid half-life (t 1/2). To determine the region(s) within the perforin transcript responsible for governing this TC mediated turnover event, various segments of the perforin cDNA were cloned and inserted into the 3' UTR of rabbit beta globin (RG). Constructs containing perforin coding region cDNA, but not 3' UTR cDNA, mediated TC-induced mRNA turnover. These data indicate that multiple elements governing perforin mRNA stability reside within the coding region, a novel type of mRNA regulation not previously described. PMID- 8676886 TI - Functional effects of domain deletions in a multidomain serine protease, C1r. AB - The C1r subcomponent of the first component of complement is a complex, multidomain glycoprotein containing five regulatory or binding modules in addition to the serine protease domain. To reveal the functional role of the N terminal regulatory domains, two deletion mutants of C1r were constructed. One mutant comprises the N-terminal half of domain I joined to the second half of the highly homologous domain III, resulting in one chimeric domain in the N-terminal region, instead of domains I-III. In the second mutant most of the N-terminal portion of domain I was deleted. Both deletion mutants were expressed in the baculovirus-insect cell expression system with yields typical of wild type C1r. Both mutants maintained the ability of the wild type C1r to dimerize. The folding and secretion of the recombinant proteins was not affected by these deletions, and C1-inhibitor binding was not impaired. The stability of the zymogen was significantly decreased however, indicating that the N-terminal region of the C1r molecule contains essential elements involved in the control of activation of the serine protease module. Tetramer formation with C1s in the presence of Ca2+ was abolished by both deletions. We suggest that the first domain of C1r is essential for tetramer formation, since the deletion of domain I from C1r impairs this interaction. PMID- 8676887 TI - Generation of a variant of human interleukin-4 by alternative splicing. AB - A second species of interleukin-4 (IL-4) mRNA was identified using both a reverse transcription-polymerase chain reaction and an RNase protection assay. This novel IL-4 mRNA was 48 base pairs smaller than IL-4 mRNA, which is the size of IL-4 exon 2. Sequence data of cloned cDNA demonstrated that this variant contained IL 4 exons 1,3 and 4, with exon 1 spliced directly to exon 3 in an open reading frame. The entire protein encoding region of this variant, named IL-4 delta 2, was identical to IL-4 except for the omission of exon 2. IL-4 delta 2 mRNA was detected in all human peripheral blood mononuclear cells tested and in purified CD3+ T cells. Amounts of both IL-4 and IL-4 delta 2 mRNAs increased upon T cell activation, although IL-4 mRNA increased to a greater extent than IL-4 delta 2 mRNA did. Human IL-3, IL-5, IL-13, and granulocyte macrophage-colony stimulating factor did not use alternative splicing to delete exon 2. We speculate that IL-4 delta 2 may regulate IL-4 function. PMID- 8676888 TI - The MHC class II-associated invariant chain-derived peptide clip binds to the peptide-binding groove of class II molecules. AB - Major Histocompatibility Complex (MHC) class II proteins bind to peptides derived from processed foreign antigens, and display them on the cell surface of antigen presenting cells for recognition by CD4+ regulatory T lymphocytes. Prior to their binding to antigenic peptides in endosomal compartments, class II molecules are associated with a nested set of peptides CLIP derived from amino acids 80 to 107 of the invariant chain (Ii). Currently the interaction between the CLIP peptide and class II molecules is not clear. Using an FITC-labeled CLIP peptide and soluble empty class II molecules synthesized in insect cells, we have investigated the direct binding of the CLIP peptide to class II molecules, and the influence of localized polymorphic residues in the peptide-binding groove on the binding. We found that the human class II HLA-DR1 molecule contains a single binding site for the CLIP peptide as well as the antigenic peptide MP19-31, as analysed by Scatchard analysis. Further studies also showed that occupancy of the peptide-binding groove by antigenic peptides inhibited the binding of CLIP to DR1 molecules and vice versa. Most importantly, the polymorphic residues beta 85 and 86, which define the major peptide-binding pocket, strikingly influence the CLIP DR1 interaction, as assayed by the SDS-stability of class II-peptide complexes and the affinity of class II-peptide interactions. These data indicate that the peptide-binding pocket and thus the peptide-binding groove of the class II molecule are directly involved in the association with the CLIP peptide. PMID- 8676889 TI - Calreticulin is transcriptionally upregulated by heat shock, calcium and heavy metals. AB - Calreticulin is a new human rheumatic disease-associated autoantigen that plays a multifaceted role in cell biology. In earlier studies, this protein was shown to share an intimate relationship with the Ro/SS-A autoantigen complex, although the nature of this association continues to be debated. Since modulation of the Ro/SS A autoantigen in epidermal keratinocytes has been implicated in the pathogenesis of subacute cutaneous lupus erythematosus and neonatal lupus erythematosus, we have begun to examine the transcriptional regulation of calreticulin. A 504 bp calreticulin promoter fragment was subcloned into a reporter gene plasmid containing firefly luciferase. Calcium ionophore, heat shock, and heavy metals such as zinc and cadmium were consistently found to increase calreticulin transcriptional activities in A431 cells (a human epidermoid squamous carcinoma cell line) under transient transfection conditions. These studies suggest that (a) calreticulin is regulated at the transcriptional level, and (b) calreticulin, like some other LE-related autoantigens, appears to function as a heat shock/stress-response gene. PMID- 8676890 TI - Processing of DR1-restricted determinants from the fusion protein of measles virus following two distinct pathways. AB - A panel of human T cell clones specific for measles virus was characterized and among them fusion protein-specific, DR1-and DP-restricted T cell clones were selected to study the processing and presentation of determinants borne by a viral membrane protein. Using two independent methods to assess the activation of T cells when they encounter antigen-presenting cells, proliferation assay and Ca2+ flux measure by flow cytometry, we show that determinants from the fusion protein of measles virus presented to two DR1-restricted T cell clones have strikingly different processing requirements. While treatment with chloroquine, leupeptin and brefeldin A of antigen-presenting cells infected with the measles virus inhibits presentation of the first determinant, presentation of the second is prevented only by leupeptin but not by chloroquine and brefeldin A. The major histocompatibility complex deletion mutant cell line T2 was transfected with DR alpha and DR1 beta genes to be tested as antigen-presenting cells with the measles virus-specific T cell clones. DR1-transfected T2 cells infected with the measles virus presented the fusion protein determinant whose processing was sensitive to chloroquine and brefeldin A but failed to display insensitivity to these two drugs, further indicating that the two determinants are generated following two distinct pathways. The first is likely to be independent of the expression of the class II major histocompatibility complex-like molecule DM, whereas the other requires it. In conclusion, determinants on the same polypeptide can have profoundly dissimilar processing requirements. Due to transport to successive compartments with different processing capabilities, more determinants are successfully released from antigens and/or captured by class II major histocompatibility complex molecules, thereby increasing the repertoire of determinants displayed by class II major histocompatibility complex molecules. PMID- 8676891 TI - Reduction in IgE binding to allergen variants generated by site-directed mutagenesis: contribution of disulfide bonds to the antigenic structure of the major house dust mite allergen Der p 2. AB - Site-directed mutagenesis was used to investigate the contribution of disulfide bonds to the antigenic structure of Der p 2. Single amino acid variants were generated at cysteine residues, preventing the formation of disulfide bonds at positions 21-27, 73-78, and 8-119. The variants were tested for binding to murine monoclonal antibodies (mAb) and human IgE antibodies (Ab) in an inhibition enzyme immunoassay. Removal of the disulfide linking the amino-carboxy termini (C8-C119) had no effect on mAb binding, however, IgE Ab binding was reduced by up to 10 fold. The other two disulfides form small loops and disruption of these bonds gave different binding patterns. The variant lacking the C21-C27 bond showed up to a 40-fold reduction in antibody binding, while the variant lacking the C73-C78 bond showed more than a 100-fold reduction in IgE Ab binding and failed to bind 3 of 4 mAb. Intradermal skin testing with the C73-C78 variant supported the in vitro findings; the variant was 10 to 100-fold less reactive than rDer p 2. These two bonds thus make markedly different contributions to stabilizing the antigenic determinants of Der p 2. The results suggest that the C73-C78 bond plays a critical role in stabilizing the antigenic structure of this major mite allergen. PMID- 8676892 TI - Coordinate regulation of HLA class II genes: a novel DNA binding complex. AB - We have characterized a nuclear protein complex from B lymphoblastoid cell lines that binds to HLA class II promoters as detected by electrophoretic gel mobility shift assays (EMSA). This complex (C1) binds to three independent sites in the proximal DRA promoter which have not been identified previously as cis-acting elements. C1 is very abundant in Burkitt's lymphoma cell lines, but less abundant in "normal" B lymphoblastoid cell lines. The binding specificity of the C1 complex was analysed using competition experiments and chemical footprinting methods. Complexes with specificity similar to C1 also bind the DPA and DQA promoters. Though mutation of the sequences in the DRA promoter that severely reduced binding of the C1 complex had no effect on the ability of the DRA fragment to drive transcription of the reporter gene in transient expression or in vitro transcription assays, this conservation of binding sites among all class II promoters tested suggests functional relevance in transcription. In addition, complexes similar to C1 were observed in nuclear extracts from all cell lines examined, but minor differences in mobility appeared to correlate with class II expression. Thus, the C1 complex may act as a trans-acting factor in MHC class II expression. PMID- 8676893 TI - Common IgE-epitopes of recombinant Phl p I, the major timothy grass pollen allergen and natural group I grass pollen isoallergens. AB - Grass pollen allergens are potent elicitors of Type I allergy. More than 95% of grass pollen allergic patients display IgE-cross-reactivity to group I grass pollen allergens of different grass species. A cDNA coding for the major timothy grass pollen allergen, Phl p I, was isolated previously. To investigate the presence of common IgE-epitopes among naturally occurring group I grass pollen isoallergens, Phl p I was expressed in Escherichia coli and used for IgE absorption experiments. Recombinant Phl p I was able to inhibit IgE-binding to most of group I isoallergens from seven grass species as identified by two dimensional electrophoresis. When tested in competitive ELISA experiments, recombinant Phl p I bound a high percentage of grass pollen specific IgE. The results indicate that recombinant Phl p I shares many of the IgE-epitopes with natural group I grass pollen allergens and hence may represent a useful tool for specific diagnosis and therapy of grass pollen allergy. PMID- 8676894 TI - The human lambda immunoglobulin enhancer is controlled by both positive elements and developmentally regulated negative elements. AB - We have recently reported the localization of the first transcriptional enhancer in the human lambda (lambda) immunoglobulin light chain locus. Enhancer activity was contained on a 1.2 kb SstI fragment, with partial activity retained on a core 111 bp PstI-SstI fragment. This enhancer is located 11.7 kb downstream of C lambda 7, the most 3' lambda constant region gene. Using a chloramphenicol acetyl transferase (CAT) assay system, we have now determined the boundaries of the complete enhancer and find it is two- to four-fold as active as the core fragment in both pre-B and B cell lines. Interestingly, a larger fragment, containing the complete enhancer as well as 5' and 3' flanking sequences has four- to eight-fold reduced activity when tested in pre-B cell lines, but full activity in B cell lines. This suggests the presence of developmentally regulated negative elements flanking the human lambda enhancer which prevent or reduce its activity at a developmentally incorrect time. By using in vivo footprinting we have begun to examine the protein interactions within this enhancer in a more physiologically relevant manner and have identified motifs which are shared with the murine lambda enhancers, as well as motifs unique to the human lambda enhancer. PMID- 8676895 TI - Recombinant human Fab antibody fragments to HIV-1 Rev and Tat regulatory proteins: direct selection from a combinatorial phage display library. AB - A human Fab phage display library has been produced from peripheral blood lymphocytes of an individual who was asymptomatic after 10 years of infection with human immunodeficiency virus type-1 (HIV-1). The library was panned against the HIV-1 Rev and Tat regulatory proteins and several clones, producing Fab binding to these proteins, were isolated (3 to Rev and 4 to Tat) with binding constants varying from 10(-6)M to 10(-8)M. DNA sequencing demonstrated two unique anti-Rev Fab clones, but the four anti-Tat Fab comprised only two unique IgG1 heavy chain Fd fragments, illustrating redundancy of light chains. Peptide mapping of the epitopes recognized by these Fab indicated that three of the anti Tat Fab were directed to the functional domain between amino acid residues 22-33 of the Tat molecule, and that binding was inhibited by reduction of this cysteine rich region with dithiothreitol. The anti-Rev Fab were directed to sites adjacent to the Rev basic nucleolar localization sequence (residues 52-64) and to the Rev activation domain (residues 75-88). Binding constants were of a similar order to that of an anti-Rev single-chain Fv fragment (SFv) used successfully for intracellular immunization, and as such intracellular effects with the human anti Tat and anti-Rev Fab are not precluded. These newly described human antibody fragments to HIV-1 regulatory proteins may be critical moieties for gene therapeutic protocols, to control HIV-1 replication in human cells. PMID- 8676896 TI - Purification, characterization and molecular cloning of Cha o 1, a major allergen of Chamaecyparis obtusa (Japanese cypress) pollen. AB - Pollen of Chamaecyparis obtusa (Japanese cypress) is one of the causes of allergic pollinosis in Japan. A major allergen of the pollen designated Cha o 1, was purified by two-step ion exchange chromatography. Cha o 1 was separated into four components with molecular masses of 48.5 kDa and 52.0 kDa, each with pIs of 6.77 and 6.82. The 23-residue N-terminal sequence of Cha o 1 was determined and shown to have high identity with that of Cry j 1, a major allergen of Cryptomeria japonica pollen. cDNA coding for Cha o 1 was cloned by hybridization screening using Cry j 1 cDNA as a probe. One of the cDNA clones, pCHA-1 was sequenced and found to code for a putative 21-residue signal peptide and a 354-residue native protein with a derived molecular mass of 38.1 kDa. The deduced amino acid sequence of Cha o 1 showed 79-80% identity with those of Cry j 1. These findings were consistent with observations of a close crossreaction between the two allergens. Homology analyses revealed that Cha o 1 had 46-49% identity with Amb a 1 families and Amb a 2, the major allergens of short ragweed. Cry j 1 has pectate lyase enzyme activity, suggesting that Cha o 1 may have the same enzyme activity as Cry j 1. PMID- 8676897 TI - The regulation of GM-CSF is dependent on a complex interplay of multiple nuclear proteins. AB - GM-CSF is an important mediator of hematopoiesis and its dysregulation may play a role in neoplastic and inflammatory conditions. Previous studies have demonstrated that GM-CSF production depends upon the accumulation of specific mRNA, which occurs by transcriptional and post-transcriptional mechanisms. In order to dissect the cis-acting sequences responsible for its regulation, we performed an extensive mutagenesis study spanning 54 nucleotides 5' of the GM-CSF coding region. Our analysis suggests that the previously-described functional elements of the GM-CSF promoter, kappa B and a repetitive CATTT/A motif, the former co-exists with an overlapping 9 nucleotide site which silences promoter activity, and the CATTT/A complex binds multiple polypeptides which differentially contribute to basal and inducible promoter activity. These two sites interact to provide tissue-appropriate and stimulus-specific promoter function. Using DNA-protein cross-linking and co-transfection studies, we demonstrate that the c-rel-related proteins p65 and p50 bind to the GM-CSF promoter and that p65 binding is primarily responsible for the enhancing effects at this site. In addition, we show that the GM-CSF kappa B decanucleotide is inadequate to provide full binding affinity; mutation of nucleotides flanking this site affect promoter function by altering NF-kappa B binding affinity. Together these results suggest that the transcriptional response of GM-CSF is dependent on a complex interplay of multiple DNA binding proteins. PMID- 8676898 TI - Functional and modelling studies of the binding of human monoclonal anti-DNA antibodies to DNA. AB - The relationships between the antigen-binding specificities of four human monoclonal anti-DNA antibodies and the structural aspects of the combining sites of two of these were examined. Competition ELISAs were used to examine the reactivities of two IgM MAbs (WRI-176 and RT-79) and two IgG mAbs (D5 and B3) to a wide range of polynucleotides. The mAbs WRI-176 and RT-79 were found to bind predominantly ssDNA, with a preference for poly (dT), whilst D5 and B3 bound components of both ss- and dsDNA, and Z-DNA. The mAb B3 also exhibited a preference for A(T) rich nucleotides. Computer models were generated for the Fv regions of WRI-176 and B3. Models for RT-79 and D5 were not generated as the structure of the long CDR-H3 loops in these mAbs could not be predicted. The B3 combining site contains a groove flanked by three arginines at positions CDR-L1 27A, CDR-L2-54 and CDR-H2-53. Using interactive molecular graphics, B-DNA was docked into the B3 antigen combining site along the plane of the VH/VL interface, whilst Z-DNA was best-fitted at approximately 90 degrees to this direction. The models provide a hypothesis to explain the ability of a single autoantibody to bind two different antigens. In addition, aspects of the base specificity of B3 may be explained. The model of the WRI-176 Fv region revealed a relatively flat surface, on which a large number of hydrophobic and aromatic residues were present. Trp-H52, in particular, is prominent on the surface. This may participate in ssDNA binding through base stacking interactions. The models allow identification of potential targets for site-directed mutagenesis. PMID- 8676899 TI - Influence of benzylisothiocyanate and 13-cis-retinoic acid on micronucleus formation induced by benzo[a]pyrene. AB - The purpose of this study was to investigate the influence of benzylisothiocyanate (BIT) and 13-cis-retinoic acid (RA) upon the genotoxic potential of benzo[a]pyrene (BaP) to induce micronucleus formation in the bone marrow of mice. Eighty-two male mice were divided into 10 groups. One group served as a negative control (olive oil intubation). Four groups received an oral intubation of various concentrations of BIT (15 to 120 mg/kg) and i.p. injections of BaP (185 mg/kg). Another four groups were treated identically, but received RA (20 to 150 mg/kg) in place of BIT. Finally, one group received only i.p. injection of BaP (185 mg/kg). The results showed that both BIT and RA significantly reduced the frequency of micronucleus formation in the bone marrow of the BaP treated animals. BIT was found to be effective at all the tested concentrations. RA was effective only at three of the four tested concentrations (40, 75 and 150 mg/kg). These findings indicate that both BIT and RA may reduce the genotoxic effects of benzo[a]pyrene in the mice under the test conditions utilized. PMID- 8676900 TI - Radioresistant DNA synthesis in fibroblast cell lines derived from LEC strain rats. AB - Immortalized cell lines from LEC strain (LEC) rats by SV40 large T antigen were more sensitive to X-irradiation than the cell lines from WKAH strain (WKAH) rats. The dose-response curves for inhibition of DNA synthesis in WKAH-derived cells showed a steep decline at low doses and a shallow decline at high doses. On the contrary, the dose-response curves for LEC-derived cell lines showed no steep component; they were almost identical to the shallow component of the curves for WKAH-derived cells. PMID- 8676901 TI - Inhibitory effect of folinic acid on radiation-induced micronuclei and chromosomal aberrations in V79 cells. AB - Folinic acid (FA), clinically called leucovorin, has been widely used as a nutrient supplement in dietary intake and is capable of inhibiting cytotoxicity and chromosomal damage induced by chemicals. However, data on its antigenotoxic effect on radiation-induced chromosomal damage are limited. The present study was, therefore, performed to investigate the effect of FA on radiation-induced (X rays and UV radiation) micronuclei (MN) and structural chromosomal aberrations (SCA) concurrently in V79 Chinese hamster lung cells. Exponentially growing cells were exposed to five doses of X-rays (1-12 Gy) and UV radiation (50-800 microJ x 10(2)/cm2) and post-treated with 5 or 50 micrograms FA/ml of culture medium for 16 h. The slides were analyzed for the presence of MN and SCA using standard procedures. The results showed that X-ray treatment alone produced dose-related cytotoxicity as measured by nuclear division index (NDI) and mitotic index (MI). X-rays produced a clear dose-related clastogenicity as measured by percent of micronucleated binucleated cells (MNBN) (5-79%) and percent of aberrant cells (11 92%). FA at 5 micrograms/ml slightly decreased X-ray induced chromosomal damage in both assays; however, the inhibition was significant (12-46% of MNBN, 14-48% in aberrant cells) only when X-ray-treated cultures were post-treated with 50 micrograms FA/ml. Post-treatment of FA had no effect on X-ray induced cytotoxicity as measured by NDI and MI. A similar a dose-related increase in % MNBN (0.5-10.3%) and percent aberrant cells (6-35%) was produced by UV radiation treatment alone. There were significant percentages of MNBN and aberrant cell inhibitions at both 5 and 50 micrograms/ml in both assays. As in the case of X ray-treated cells, there was a clear dose-related cytotoxicity in UV-treated cells alone. No reduction in NDI or MI was found when UV-exposed cells were post treated with 5 or 50 micrograms of FA. These data demonstrate the beneficial effect of FA in decreasing radiation-induced chromosomal damage. PMID- 8676902 TI - Frameshift mutagenesis by 9-aminoacridine: antimutagenic effects of adenosine compounds. AB - It has been shown that frameshift mutagenesis by 9-aminoacridine (9AA) in Salmonella typhimurium is significantly inhibited if glucose is present while cells are being treated in liquid defined medium. We suggested that this effect might be a result of glucose-provoked alterations of cAMP levels within the cell. We therefore sought to investigate the effects of exogenous cAMP on mutagenesis by 9-aminoacridine in both Salmonella typhimurium and Escherichia coli. Contrary to expectation, we found that frameshift mutagenesis was significantly depressed when high concentrations of cAMP were added to the defined medium during liquid treatment with 9AA. Other adenosine 5'-phosphates such as adenosine 5' triphosphate (ATP), adenosine 5'-diphosphate (ADP) and adenosine 5'-monophosphate (AMP) added to the liquid medium during 9AA treatment also substantially decreased the reversion rate to prototrophy in both S. typhimurium and E. coli, as did adenosine itself. Further experiments showed that neither influx nor efflux of 9-aminoacridine molecules were greatly affected by adenosine compounds, and that although cAMP and adenosine exerted similar antimutagenic effects on 9AA treated stationary phase cells, their effects on log phase cells were quite different. The antimutagenic effect of a representative adenosine compound (ATP) was found to persist for some time after stationary phase cells had been washed, with maximal mutability being regained only after about 3 h. PMID- 8676903 TI - In vitro induction of micronuclei and chromosome aberrations by quinolones: possible mechanisms. AB - The bacterial gyrase inhibitors, ciprofloxacin and PD 124816, were tested for clastogenic and aneugenic activity in V79 Chinese hamster lung cells in vitro. Cells were exposed for 3 h, washed free of drug, and subcultured for assessment of various endpoints. For structural chromosomal aberration (SCA) analysis, cells were incubated for 18 h, and treated with Colcemid for 2 h before harvest. For micronucleus (MN) analysis, treated cells were incubated with cytochalasin B (CYB) for 16 h. Aneugenicity was assessed by utilizing antikinetochore antibody to detect kinetochore-containing (K +) MN. Both quinolones induced significant increases in SCAs and MN, indicating clastogenic activity. With both compounds, however, the MN response was apparent at lower doses, and remained much higher throughout the dose range than the SCA response. The induced MN were predominantly K --, indicating that aneugenicity was not playing a major role in their induction. A possible explanation for the chromosome effects is that cross reactivity of the gyrase inhibitors with mammalian topoisomerase II interferes with the separation of chromatids at anaphase leading to chromosome breaks and MN. Quinolones are known to inhibit resolution of the normally transient topoisomerase II-DNA cleavable complex, which may result in chromosome stickness. Thus, SCAs detected in metaphase cells may be attributed to quinolone-induced inhibition of topoisomerase II prior to mitosis while MN arise in binucleated cells as a result of this effect which interferes with chromatid separation during anaphase. PMID- 8676904 TI - IPCS harmonization of methods for the prediction and quantification of human carcinogenic/mutagenic hazard, and for indicating the probable mechanism of action of carcinogens. AB - A flow chart is presented as a recommended sequence of tests to predict the carcinogenic hazard, and to predict and quantify the mutagenic hazard to germ cells of chemicals to humans. Ten associated principles of testing for these endpoints are also suggested. These recommendations are the result of a meeting convened under the auspices of the International Programme on Chemical Safety (IPCS), as part of their project on 'Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals'. The meeting was held at Carshalton, Surrey, from 13-17 February 1995. PMID- 8676905 TI - Selecting chemicals and assays for assessing mammalian germ cell mutagenicity. PMID- 8676906 TI - Comparison of the duration of spermatogenesis between male rodents and humans. PMID- 8676907 TI - Detection of aneuploidy in human and rodent sperm using FISH and applications of sperm assays of genetic damage in heritable risk evaluation. AB - Efficient molecular methods are being developed for detecting various types of cytogenetic genetic damage in sperm, especially numerical aneuploidy for chromosomes involved in trisomies that survive at birth. These methods provide new approaches for identifying potentially detrimental environmental exposures, genetic predisposition, chromosomal rearrangements, and physiologic factors which may increase a man's risk of fathering a genetically defective offspring. Corollary methods are also being developed for detecting sperm aneuploidy in laboratory rodents and these will be used to make inter-species comparisons of mutagen sensitivities and for investigating mechanisms of induction and persistence of aneuploidy. Validated assays for detecting genetic alterations in human and rodent sperm (of which sperm aneuploidy is a first example) permit comparisons of somatic and germinal response to mutagens within individuals, comparisons of human and rodent germinal sensitivity to mutagens, and can be applied in an extended parallelogram model to sperm for assessing heritable risk resulting from paternal mutagen exposures. PMID- 8676908 TI - The rodent bone marrow micronucleus assay: contrast between its sensitivity to human carcinogens and its insensitivity to NTP rodent carcinogens. AB - The rodent bone marrow micronucleus (MN) assay occupies a critical position in the accompanying schemes to detect potential human carcinogens and germ cell mutagens (Shelby, 1996; Ashby et al., 1996: for reviews of the MN assay see Heddle et al., 1983; Schlegel and MacGregor, 1984; CSGMT, 1990; Mavournin et al., 1990; Tinwell, 1990; Gatehouse, 1994; Asanami et al., 1995). The intention of this article is to note two perceptional problems currently associated with the MN assay. The first concerns how it should be used--as a screening assay, or as a means to evaluate the genetic toxicity in vivo of genotoxins defined in vitro. The second relates to its sensitivity to the rodent carcinogens defined by the US National Toxicology Program (NTP). PMID- 8676909 TI - The micronucleus test and NTP rodent carcinogens: not so many false negatives. AB - In the study by Shelby et al. (1993) on 49 chemicals, the results of the micronucleus (MN) test in mouse bone marrow were compared with the results of the 2 year rodent carcinogenicity assays. Seven of the 25 rodent carcinogens were considered positive in the MN test, 5 following a protocol in which chemicals were given in three daily doses, and a further 2 when the chemical was administered only once. This low rate of positive results has led to disappointment in the MN test as a screen for carcinogens, but a careful examination of the data and of its analysis by Shelby et al. (1993) shows that many of the negative results are appropriate because: of the 18 carcinogens that were negative in the MN test, 1 has been retested and found to be non carcinogenic, 9 were non-genotoxic and at least 2 were site-of-contact carcinogens not expected to be detected in the bone marrow. Two others were clearly positive in the MN test in other labs. Thus, the MN test 'missed' not 18 carcinogens, but 4 genotoxic carcinogens. The significance of these 4 needs further assessment, since three were liver specific carcinogens and the fourth was a very weak inducer of hemangiosarcomas in female mice only. Overall, the results of Shelby et al. (1993) do not cast such a shadow on the micronucleus test as many feared, and must be examined in the context of all the information available on each chemical. As Ashby and Tinwell emphasize in the accompanying article and in Tinwell and Ashby (1994), the data show that the MN test is capable of identifying human carcinogens and rodent germ cell mutagens, and remains a useful part of genotoxicity evaluation of chemicals. PMID- 8676910 TI - The micronucleus test: its value as a predictor of rodent carcinogens versus its value in risk assessment. PMID- 8676911 TI - Activities of the rodent carcinogens thioacetamide and acetamide in the mouse bone marrow micronucleus assay. AB - Thioacetamide is confirmed as active in the mouse bone marrow micronucleus assay, following single oral administration to both sexes of two different strains of mice (C57BL/6, BALB/c) in five separate experiments. Acetamide is shown to be consistently and clearly negative as a micronucleus-inducing agent in mouse bone marrow in four repeated assays using different sexes of two strains of mice (C57BL/6, CBA). The present findings support the adequacy of the limited micronucleus test protocol (male animals, two sampling times) for the efficient detection of genotoxic rodent carcinogens in this assay. PMID- 8676912 TI - UV- and gamma-irradiation-induced DNA single-strand breaks and their repair in human blood granulocytes and lymphocytes. AB - Ionizing irradiation and UV-irradiation cause DNA damage. Ionizing irradiation induces single-strand breaks, much less abundantly double-strand breaks, alkali labile sites, and various oxidized purines and pyrimidines. UV-irradiation, on the other hand, causes cyclobutane pyrimidine dimers, (6-4) photoproducts, and various monomeric base damages. The deposition of energy in DNA may result directly in single-strand breaks (predominant form after ionizing radiation), or the strand breaks may be generated during the repair process (predominant form after UV-irradiation). We investigated the formation and repair of DNA single strand breaks in human blood granulocytes and lymphocytes by the single-cell gel electrophoresis or comet assay. The induction and repair of DNA lesions by gamma irradiation was comparable in human blood granulocytes and lymphocytes. The finding is consistent with the expression of the pertinent base excision repair proteins in these cells. In contrast to gamma-irradiation, fewer single-strand breaks were observed immediately after UV-irradiation; the maximum number of breaks were seen when the cells were incubated for 30-60 min. After an incubation period of 150 min, a significant reduction of single-strand breaks was noted. It is conceivable that the first 30-60 min represented a period during which the incision-excision phase of nucleotide excision repair (NER) predominated. After that, strand joining was dominant, evidently representing the synthesis and ligation phase of NER. These results indicate that the approx. 30 different polypeptides required for complete NER are functional in these mature blood cells. This is the first demonstration of the expression of global NER in human granulocytes. PMID- 8676914 TI - Concentration-dependent mutational hotspots induced by the antineoplastic drug chloroethyl-cyclohexyl-nitroso-urea in mammalian cells. PMID- 8676913 TI - Molecular analysis of mutations induced by ethylating N-nitroso compounds in the lacI gene of Escherichia coli. AB - We have investigated the mutational specificities of two ethylating agents, N nitroso-N,N-diethylamine (NDEA) and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) in the NC+ domain of the lacI gene in Escherichia coli. G:C-->A:T transitions predominated in each of the two spectra, but its importance varies. While 95% of mutations induced by ENNG are G:C-->A:T transition, they account for only 61% of the total events following NDEA treatment. A:T-->G:C transitions are more often recovered following treatment with NDEA than with ENNG. Deletions, duplications, and frameshifts were also recovered after treatment with NDEA, but not ENNG. Mutations obtained in this study are also compared with those induced by corresponding methylating agents. The 5' flanking base appears to affect the distribution of the G:C-->A:T events. G:C-->A:T transition appears more likely to be recovered at 5'-PuG-3' sites. NDEA, however, induced a significant number of G:C-->A:T changes at 5-PuC-3' sites (51%). The possible reasons for these site specificities are discussed. Although these alkylating agents most likely induce the bulk of their mutation via common mutagenic intermediates, each agent does induce a characteristic spectrum in which specific sites are enhanced or reduced. PMID- 8676915 TI - 'External' proofreading of DNA replication errors and mammalian autonomous 3'- >5'exonucleases. AB - Mammalian nuclear DNA polymerases alpha and beta are known to be devoid of the editing 3'-->5' exonucleolytic activity. The base substitutions misinserted by these polymerases could be eliminated with two kinds of an 'external' proofreading carried out (1) by the 3'-->5' exonuclease function intrinsic to DNA polymerases delta and epsilon or/and (2) by the autonomous 3'-->5' exonucleases non-associated covalently with DNA polymerases. DNA polymerases delta and epsilon can be separated from autonomous 3'-->5' exonucleases by means of sedimentation. Ultracentrifugation of the nuclear extracts and cytosols from normal and regenerating rat liver as well as from total embryos has shown the bulk of the cellular 3'-->5' exonucleolytic activity is due to autonomous nucleases. Moreover, the level of such a specific activity correlates with the replicative status of the organs from adult animals: spleen > regenerating liver > normal liver > cardiac muscle > brain, maximum difference being an order of magnitude. In addition, autonomous exonucleases were shown to be the constituents of the multienzyme forms of DNA polymerases alpha and beta. Hence, autonomous 3'-->5' exonucleases seem to be the principal participants in an 'external' proofreading. PMID- 8676916 TI - Cell cycle phase duration in bone marrow cells from malnourished rats during suckling. AB - The generation time and duration of the different phases of the cell cycle were estimated in cultured bone marrow cells from malnourished and well-nourished rats during the lactation period by the percentage labeled mitosis (PLM) technique after a short pulse treatment with tritiated thymidine. The PLM were obtained in sequential analysis after every 3 h from removing labeled thymidine to 27 h of incubation. Results have shown a longer cell cycle time in cells from malnourished rats. The G1 + 1/2M phases are sensitive to experimental severe protein malnutrition (PCM), while S and G2 + 1/2 M phases did not show any differences in duration between malnourished and well-nourished rats. PMID- 8676917 TI - p53 accumulates in micronuclei after treatment with a DNA breaking chemical, methylnitrosourea, and with the spindle poison, vinblastine. AB - Micronuclei (MN) induced by N-methyl-N-nitrosourea (MNU) or vinblastine in cultured mammalian cells were analyzed for the accumulation of p53 by immunocytochemical staining with a p53 monoclonal antibody. Our data showed that MN induced by both agents were p53-negative at early post-treatment times, but became positive at late times. Assuming that most MNU-induced micronuclei reflect DNA damage, and most vinblastine-induced micronuclei reflect damage to the mitotic apparatus, we conclude that p53 accumulation in micronuclei is not triggered by DNA damage per se but instead probably stems from DNA degradation occurring during ageing of micronuclei. PMID- 8676918 TI - Micronucleus frequencies in urothelial cells of catheterized patients with chronic bladder inflammation. AB - Epidemiological studies suggest an association between chronic inflammation and increased risk for cancer, although the mechanism underlying this relationship is unresolved. In the present study, we test the hypothesis that DNA damage is induced in the epithelium of tissues during such inflammation by products of activated inflammatory cells. Individuals on long-term indwelling urinary catheterization were used as a study population. These individuals have chronic bladder inflammation and, as a population, an increased risk for bladder cancer. Urine of 29 patients and 26 age-matched non-catheterized controls was collected and micronucleus (MN) frequencies were determined in exfoliated urothelial cells in the urinary sediments. The urine from the catheterized group had large numbers of white blood cells (mean count, 26.6 +/- 3.6 cells per high-power field), indicating the presence of a chronic bladder infection and an inflammatory reaction. In contrast, white blood cells were not present in urine from individuals in the control group. There was no significant difference in MN frequencies in the 2 groups (mean frequencies, controls: 0.098 +/- 0.030%; catheterized: 0.140 +/- 0.025%, p = 0.13). These data imply that chromosomal damage does not always occur during chronic inflammation. Although the reasons for this observation are yet to be determined, possible explanations include the pathophysiology of the inflammatory reaction and the influence of vitamins, non steroidal anti-inflammatory drugs and the catheter itself in protection against inflammatory cell-mediated DNA damage. PMID- 8676919 TI - Spontaneous mutants recovered from liver and germ cell tissue of low copy number lacI transgenic rats. AB - The finding of a large discordance between animal species in their response to a carcinogenic challenge, has led to the realization that the useful extrapolation of animal test data to humans requires a better understanding of animal interspecies differences. With the development of transgenic shuttle vector based animal systems we are now able to study mutation of the same genetic target in both mice and rats. We have begun to analyze mutants recovered from rat lines carrying low copy numbers of the same lambda/lacI constructs carried by the Big Blue mouse. A large database on mutations in lacI transgenic mice is already available for comparison. The data indicate that the differences between the mutations recovered from rat liver and germ cell tissues are similar to those recovered from transgenic mice, but when compared with a large database of mutations available for mice, some site-to-site differences may exist. This study represents the first interspecies look into the molecular nature of mutations in the lacI transgenic rodents. PMID- 8676920 TI - Characterization of the GADD45 response to ionizing radiation in WI-L2-NS cells, a p53 mutant cell line. AB - We have previously reported that WI-L2-NS, a human lymphoblastoid cell line, has very high basal levels of GADD45 mRNA and protein in spite of a p53 mutation at amino acid 237. Regardless of the amount of Gadd45 in this cell line, no growth suppression activity was detected. We report here that in WI-L2-NS, the mutated p53 protein adopts predominantly a wild type (wt) conformation and binds to the p53 binding site in the GADD45 third intron. In this cell line, the already high levels of mutated p53 protein can be induced further by ionizing radiation (IR) but the response of the p53 downstream effector genes is altered. Induction of GADD45 and CIP1/WAF1 is reduced compared to p53 wt cell lines but is still substantially higher than the average fold induction obtained from 39 p53 mutant cell lines. Induction of the MDM2 gene was not detected in WI-L2-NS following IR. The induction pattern of the three p53 effector genes by the alkylating agent methylmethane sulfonate (MMS) was also attenuated in WI-L2-NS cells. In TK6 cells, a WI-L2-NS sister cell line having a p53 wt genotype, the induction of the p53 downstream effectors is normal, i.e. induced, both at the protein and the mRNA levels. These results indicate that the DNA binding activity of the mutated p53 protein in WI-L2-NS might be responsible, at least in part, for the high basal levels of GADD45 but can not mediate the full induction of the p53 downstream effector genes. The reason(s) for the inability of Gadd45 to suppress growth in this cell line remains however unknown. PMID- 8676921 TI - Characterization of an apparent hotspot for spontaneous mutation in exon 5 of the Chinese hamster APRT gene. AB - We describe an apparent hotspot for spontaneous deletions and base substitution mutations at a TTC trinucleotide direct repeat/MboII restriction site in exon 5 of the Chinese hamster APRT gene, in a region with the potential to form a relatively stable, quasipalindromic, stem-loop structure. The recurrent 3 bp TTC deletions observed at this site, which account for approx. 20% of the characterized spontaneous APRT deletions in hemizygous CHO cell lines, represent the only spontaneous deletion events that have been recovered more than once at this locus. A total of 11 independently derived, spontaneous CHO cell APRT mutants with identical 3 bp TTC deletions at this exon 5 MboII site, plus another five mutants that have single base substitutions at this site have been identified among spontaneous mutant collections in several different laboratories. Intriguingly, each of the frequently deleted or mutated bases at this exon 5 deletion hotspot site would correspond to one of the unpaired bases within a single-stranded 'loop' region of a stable, quasipalindromic, stem-loop structure that can be formed by intrastrand pairing of inverted repeats in this portion of the APRT gene sequence. An identical TTC trinucleotide direct repeat sequence at the same site in exon 5 of the human APRT gene also appears to be a hotspot for spontaneous deletion. PMID- 8676922 TI - A selectable system for mutation detection in the Big Blue lacI transgenic mouse system: what happens to the mutational spectra over time. AB - Transgenic animals offer a powerful tool to study the mechanisms of spontaneous and induced mutagenesis in vivo. Herein we used a test version of a growth selectable assay to obtain spontaneous mutants in a lacI target transgene recovered from lacI transgenic B6C3F1 mice (Big Blue). This selection system may have certain advantages relative to the more established plaque screening system for mutation detection because: (1) the plating density of the phage is up to 60 times higher in the selectable assay, reducing the number of plates needed to be screened for a comparable amount of mutants; and (2) the mutant frequency obtained from the selectable assay is higher compared to the plaque assay, possibly due to a higher sensitivity for weaker mutants. However, the longer incubation time of the growth selectable assay might allow E. coli host derived mutants to appear. To address this issue, we investigated the sequence changes in the amino-terminal domain of the lacI gene of 405 mutants derived from the liver, spleen, brain, germ cells and skin of five untreated 6-week-old mice. The mutant colonies were isolated after 60, 84, 108 and 150 h of incubation under growth selectable conditions. Tissue-specific differences in the mutational pattern obtained after 60 and 84 h disappear after a longer time of incubation, possibly due to an increasing contribution of E. coli derived mutants. The evolving selectable systems offer the potential to increase screening efficiency, but the results suggest caution in interpreting data from this system because repair by E. coli of DNA lesions or mismatched heteroduplexes either originating in mouse in vivo or produced by ex vivo manipulation as well as de novo mutations in E. coli might contribute significantly to the observed mutational spectra at each timepoint. PMID- 8676923 TI - Mutational spectra induced under distinct excision repair conditions by the 3 methylating agents N-methyl-N-nitrosourea, N-methyl-N'-nitro-N-nitrosoguanidine and N-nitrosodimethylamine in postmeiotic male germ cells of Drosophila. AB - This paper describes the analysis of mutations induced at the vermilion locus in postmeiotic male germ cell stages of Drosophila exposed to 3 different N-methyl-N nitroso compounds: N-methyl-N-nitrosourea (MNU); N-methyl-N'-nitro-N nitrosoguanidine (MNNG); and N-nitrosodimethylamine (DMN). With MNU and DMN, the impact of DNA nucleotide excision repair (NER) on the spectra of mutations was studied. Mutants were isolated from F1 (mutations fixed before the first mitotic replication after fertilization) and F2 (mutations fixed following one or more mitotic replications; mosaics in F1) generations. The vermilion system enables the analysis of both intra- and inter-locus DNA changes for which several techniques have been adapted: (1) amplification of the vermilion gene by PCR, cloning of the fragment and sequence analysis of ssDNA; (2) Southern blot hybridization; and (3) cytological analysis of polytene chromosomes. In total, 49 MNU (26 from the exr+ genotype and 23 from the exr- genotype), 47 DMN (28 from the exr+ genotype and 19 from the exr- genotype) and 16 MNNG-induced mutations were characterized. The F1 spectra of all 3 agents contained base-pair changes and deletions (intra- and multi-locus) in a ratio of roughly 1 to 1, indicating a significant contribution of nitrogen DNA adducts to the spectra. In all F2 spectra the levels of base-pair changes were significantly higher compared to those in the F1 spectra, a finding also made for methyl methanesulfonate-induced mutations in earlier studies. There is an increase of mutations of, especially, the transversion types of mutations under exr- conditions in comparison to the exr+ situation. The induced transversions, clearly present in all spectra (exr+ and exr-), are presumably caused by N-methyl DNA adducts, which upon release from the DNA backbone lead to apurinic sites in a time-related process. Regarding the occurrence of transitions, it turned out for all 3 mutagens that the AT-->GC type strongly dominated the GC-->AT transitions. This suggest that O6-methylguanine is efficiently repaired, in contrast to O4-methylthymine. Based on the data obtained in the vermilion system with ENU, we propose, in addition, that the Drosophila alkyltransferase system repairs O6-methylguanine more efficiently than O6 ethylguanine. PMID- 8676924 TI - Catalytic activity of poly(ADP-ribose) polymerase is necessary for repair of N methylpurines in nontranscribed, but not in transcribed, nuclear DNA sequences. AB - The role of poly(ADP-ribose) polymerase (PADPRP) in nuclear DNA repair and other nuclear processes has been intensely studied and debated for decades. Recent studies have begun to shed new light on these arguments with firm experimental data for its role, primarily, as a remodeler of chromatin structure. Those studies imply that PADPRP plays an indirect role in DNA repair, serving to expose DNA to repair enzymes through chromatin remodeling. Only DNA that is tightly packaged would require PADPRP activity for its repair; while DNA in an open conformation would be accessible to DNA repair enzymes and not require PADPRP activity. The purpose of the current studies was to address the above hypothesis directly. Using quantitative Southern blot analysis, we studied repair in transcribed and nontranscribed nuclear DNA sequences in ADPRT 351 cells 95% deficient in PADPRP activity. Cells were exposed to methylnitrosourea (MNU) for 1 h and allowed to repair for 8 or 24 h. Densitometric scans of autoradiographs revealed that, when compared to their parental V79 cell line, ADPRT 351 cells 95% deficient in PADPRP activity were equally as efficient in repair of N methylpurines in the transcribed sequence containing the dihydrofolate reductase gene. However, the ADPRT 351 cells were deficient in the ability to repair these lesions in the nontranscribed sequence containing the IgE gene compared to repair of the same sequence in the parental V79 cells. Nucleoid sedimentation assays demonstrated that the ADPRT 351 cells are deficient in repair across the entire genome when compared to the parental V79 cells. These studies indicate that PADPRP activity is not required for repair of N-methylpurines in transcribed nuclear DNA sequences but is necessary for the repair of these lesions in nontranscribed nuclear DNA sequences as well as across the entire genome since the DNA in a given cell is predominantly nontranscribed. PMID- 8676925 TI - Induction of E. coli oh8Gua endonuclease by oxidative stress: its significance in aerobic life. AB - The induction of 8-hydroxyguanine (oh8Gua) endonuclease, a DNA repair enzyme for an oxidatively modified guanine, oh8Gua was studied in various growth conditions in Escherichia coli (AB1157). Anaerobically grown E. coli were found to have a very low activity of this enzyme while aerobically grown cells showed activity about 20 times that of the anaerobic level. Under the same condition, superoxide dismutase (SOD) showed about 6-fold increase in activity. A shift in growth conditions from anaerobic to aerobic resulted in rapid induction of this enzyme, and this induction was blocked (but not completely) by chloramphenicol. It is indicated that molecular oxygen is an effective stimulator to the induction of this enzyme and its induction depends partly on protein synthesis. Superoxide producing compounds such as paraquat and menadione also increased the activity of endonuclease as well as SOD, but H2O2 showed no effect. Thus, superoxides are also implied as a stimulator. In contrast, hyperoxia induced only SOD not the endonuclease. This induction of the endonuclease by hyperoxia was only observed in a SOD-deficient strain (QC774). The aerobic activity of the endonuclease in QC774 was the same as that of wild types (AB1157, GC4468). It is implied that the responsiveness of oh8Gua endonuclease to superoxides is less sensitive than that of SOD. The endonuclease was also induced by a temperature shift from 30 to 43 degrees C and treatment with nalidixic acid. Among the stimuli used, molecular oxygen seems to be most effective for its induction. The inducible nature of this enzyme will serve as an important mechanism for the protection of oxidative DNA damage in the aerobic environment. PMID- 8676926 TI - Heat-shock enhanced reactivation of a UV-damaged reporter gene in human cells involves the transcription coupled DNA repair pathway. AB - A recombinant nonreplicating human adenovirus type 5, Ad5HCMVsp1lacZ, expressing the lacZ gene under control of the human cytomegalovirus immediate early promoter, was used to assess the effect of heat-shock (HS) on DNA repair of a UV damaged reporter gene. Host cell reactivation (HCR) of beta-galactosidase (beta gal) activity for UV-irradiated Ad5HCMVsp1lacZ was used as an indicator of DNA repair in the transcribed strand of an active gene. Repair was examined in heat shock (HS) pretreated and mock-treated normal fibroblasts, normal lung epithelial cells, xeroderma pigmentosum group A, C, D and G fibroblasts (XP-A, XP-C, XP-D and XP-G), Cockayne's syndrome group A fibroblasts (CS-A), SV40-transformed normal fibroblasts (GM637f) and 5 tumour cell lines (SKOV-3, HeLa, HT29, SCC-25 and U20S). HS enhanced reactivation (HSER) of the reporter gene was detected in normal cells, HT29 tumour cells and XP-C fibroblasts. HSER was reduced or absent in all other XP, CS and tumour cell lines tested. HSER in normal and XP-C cell lines, but not CS-A, XP-A, XP-D or XP-G cells, suggests that HS treatment can enhance the repair of UV-damaged DNA through an enhancement of transcription coupled repair (TCR) or a mechanism which involves the TCR pathway. Since this response was absent in the SV40-transformed fibroblast cell line and 4 of 5 tumour cell lines examined, HSER of beta-gal activity for UV-irradiated Ad5HCMVsp1lacZ also requires some cellular function(s) affected by transformation. PMID- 8676927 TI - Conference report: 10th International Congress of Radiation Research, Wurzburg, Germany, August 27-September 1, 1995. PMID- 8676928 TI - Evidence that mammalian cells possess homologous recombinational repair pathways. PMID- 8676929 TI - The comet assay: mechanisms and technical considerations. AB - The comet assay is frequently used to measure DNA damage in individual cells. In order to better understand the mechanisms behind the technique, we have studied the behaviour of DNA under different electrophoresis conditions in mammalian cells exposed to gamma radiation. The comet tails obtained after neutral electrophoresis seem to consist of DNA loops which are attached to structures in the nucleus, since the DNA cannot move in the second direction after two dimensional electrophoresis. When the DNA is labelled by a short pulse, microautoradiography reveals that all label appear in the head of the comets when neutral electrophoresis is applied. After chase incubation, the label moves out into the tails. This gives further support to the view that the DNA loops are fixed to some structure in the nucleus where also the DNA synthesis takes place. Under alkaline electrophoresis conditions, however, the entire comet tails move in the new electrophoresis direction. Thus, it appears that the alkaline comet tails consist of free DNA fragments. Further, the effects of alkaline concentration and sodium chloride during unwinding and electrophoresis are discussed. Throughout the study, a protocol for drying and fixation of the comets has been used. PMID- 8676930 TI - Purification and characterization of Drosophila melanogaster photolyase. AB - Animal-type photolyases have very limited sequence homology to microbial-type photolyases. We wanted to find out whether the two types of enzymes have different or similar biochemical and photochemical properties. In particular, the chromophore/cofactor composition of animal photolyases is of special interest since the presence and nature of a second chromophore in these enzymes are not known in contrast to the microbial photolyases which contain FAD cofactor, and folate or deazaflavin as second chromophores. We overproduced the Drosophila melanogaster photolyase in Escherichia coli using the cloned gene. The enzyme contains FAD and folate and thus belongs in the folate class of enzymes but with an action spectrum peak at 420 nm. PMID- 8676931 TI - A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. Canadian HIV Trials Network Protocol 010 Study Group. AB - BACKGROUND: Bacteremia with the Mycobacterium avium complex is common in patients with the acquired immunodeficiency syndrome (AIDS), but the most effective treatment for this infection remains unclear. METHODS: We randomly assigned 229 patients with AIDS and M. avium complex bacteremia to receive either rifampin (600 mg daily), ethambutol (approximately 15 mg per kilogram of body weight daily), clofazimine (100 mg daily), and ciprofloxacin (750 mg twice daily) (the four-drug group) or rifabutin (600 mg daily), ethambutol (as above), and clarithromycin (1000 mg twice daily) (the three-drug group). In the three-drug group the dose of rifabutin was reduced by half after 125 patients were randomized, because 24 of 63 patients had uveitis. RESULTS: Among 187 patients who could be evaluated, blood cultures became negative more often in the three drug group than in the four-drug group (69 percent vs. 29 percent, P<0.001). Among patients treated for at least four weeks, the bacteremia resolved more frequently in the three-drug group (78 percent vs. 40 percent, P<0.001). In the three-drug group, bacteremia resolved more often with the 600-mg dose of rifabutin than with the 300-mg dose (P=0.025), but the latter regimen was more effective than the four-drug regimen (P<0.05). The median survival was 8.6 months in the three-drug group and 5.2 months in the four-drug group (P = 0.001). The median Karnofsky performance score was higher in the three-drug group than in the four-drug group from week 2 to week 16 (P<0.05). Mild uveitis developed in 3 of the 53 patients receiving the 300-mg dose of rifabutin, an incidence about one quarter that observed with the 600-mg dose (P<0.001). CONCLUSIONS: In patients with AIDS and M. avium complex bacteremia, treatment with the three-drug regimen of rifabutin, ethambutol, and clarithromycin leads to resolution of the bacteremia more frequently and more rapidly than treatment with rifampin, ethambutol, clofazimine, and ciprofloxacin, and survival rates are better. PMID- 8676932 TI - Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. California Collaborative Treatment Group. AB - BACKGROUND: Azithromycin is active in treating Mycobacterium avium complex disease, but it has not been evaluated as primary prophylaxis in patients with human immunodeficiency virus (HIV) infection. Because the drug is concentrated in macrophages and has a long half-life in tissue, there is a rationale for once weekly dosing. METHODS: We compared three prophylactic regimens in a multicenter, double-blind, randomized trial involving 693 HIV-infected patients with fewer than 100 CD4 cells per cubic millimeter. The patients were assigned to receive rifabutin (300 mg daily), azithromycin (1200 mg weekly), or both drugs. They were monitored monthly with blood cultures for M. avium complex. RESULTS: In an intention-to-treat analysis, the incidence of disseminated M. avium complex infection at one year was 15.3 percent with rifabutin, 7.6 percent with azithromycin, and 2.8 percent with both drugs. The risk of the infection in the azithromycin group was half that in the rifabutin group (hazard ratio, 0.53; P = 0.008). The risk was even lower when two-drug prophylaxis was compared with rifabutin alone (hazard ratio, 0.28; P<0.001) or azithromycin alone (hazard ratio, 0.53; P = 0.03). Among the patients in whom azithromycin prophylaxis was not successful, 11 percent of M. avium complex isolates were resistant to azithromycin. Dose-limiting toxic effects were more common with the two-drug combination than with azithromycin alone (hazard ratio, 1.67; P=0.03). Survival was similar in all three groups. CONCLUSIONS: For protection against disseminated M. avium complex infection, once-weekly azithromycin is more effective than daily rifabutin and infrequently selects for resistant isolates. Rifabutin plus azithromycin is even more effective but is not as well tolerated. PMID- 8676933 TI - Images in clinical medicine. Cauliflower ear. PMID- 8676935 TI - Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 24-1996. A 54-year-old woman with infiltrative lung disease and mild dyspnea. PMID- 8676934 TI - Prosthetic heart valves. PMID- 8676936 TI - For-profit health plans. PMID- 8676937 TI - For-profit health plans. PMID- 8676938 TI - For-profit health plans. PMID- 8676939 TI - For-profit health plans. PMID- 8676940 TI - For-profit health plans. PMID- 8676941 TI - For-profit health plans. PMID- 8676942 TI - For-profit health plans. PMID- 8676944 TI - For-profit health plans. PMID- 8676943 TI - For-profit health plans. PMID- 8676945 TI - For-profit health plans. PMID- 8676946 TI - For-profit health plans. PMID- 8676947 TI - For-profit health plans. PMID- 8676948 TI - Not-for-profit health plans. PMID- 8676949 TI - Not-for-profit health plans. PMID- 8676951 TI - Not-for-profit health plans. PMID- 8676950 TI - Not-for-profit health plans. PMID- 8676952 TI - Columbia/HCA and the resurgence of the for-profit hospital business. (2) PMID- 8676953 TI - Images in clinical medicine. Endoscopic palliation of malignant dysphagia. PMID- 8676954 TI - Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 25-1996. A 38-year-old man with fever, cough, and a pleural effusion. PMID- 8676955 TI - Physician-assisted suicide. PMID- 8676956 TI - Physician-assisted suicide. PMID- 8676957 TI - Physician-assisted suicide. PMID- 8676958 TI - Physician-assisted suicide. PMID- 8676959 TI - Assessment of quality of life. PMID- 8676960 TI - Assessment of quality of life. PMID- 8676961 TI - Assessment of quality of life. PMID- 8676962 TI - Long-term outcome of hepatitis C infection after liver transplantation. PMID- 8676963 TI - Long-term outcome of hepatitis C infection after liver transplantation. PMID- 8676965 TI - Sertraline and hyponatremia. PMID- 8676964 TI - Antibodies against recombinant human erythropoietin in a patient with erythropoietin-resistant anemia. PMID- 8676966 TI - Earnings of male and female physicians. PMID- 8676967 TI - Earnings of male and female physicians. PMID- 8676968 TI - [Prescribing antibiotics in children with exacerbations of airway symptoms?]. PMID- 8676969 TI - [Calcium antagonists: safe or unsafe?]. PMID- 8676970 TI - [Bacteriuria caused by bladder catheters; value of various preventive measures]. PMID- 8676971 TI - [Changed diagnosis and treatment of hepatocellular carcinoma]. PMID- 8676972 TI - [Creutzfeldt-Jakob disease: diagnosis in 10 patients]. AB - OBJECTIVE: To describe experiences with the diagnosis of Creutzfeldt-Jakob disease (CJD). SETTING: Department of Neurology, Academic Medical Center, Amsterdam, the Netherlands. DESIGN: Descriptive. METHODS: By retrospective analysis of patient files and follow-up data case histories were studied of ten patients diagnosed since 1980 as having CJD. RESULTS: Follow-up of two patients (who recovered) led to rejection of the diagnosis of CJD. Symptoms and results of ancillary investigations of the remaining eight patients were similar to those in large patient series from the literature. CONCLUSIONS: On the basis of our experience and data from the literature we conclude that a classification can be made of three degrees of probability of the diagnosis CJD: possible (rapidly progressive dementia with or without myoclonus); probable (if the clinical syndrome is accompanied by triphasic complexes in the EEG and/or hyperintense basal ganglia or (parts of) the cerebral cortex on T2-weighted MRI images); and certain (vacuolisation, neuronal loss and gliosis on neuropathological examination). PMID- 8676973 TI - [Zidovudine-resistant HIV strains in intravenous drug users and homosexual men in Amsterdam]. AB - OBJECTIVE: To investigate the spread of HIV strains resistant to antiviral drugs prescribed in the Netherlands. DESIGN: Descriptive. SETTING: Amsterdam. METHOD: In several cohorts of homosexual men and intravenous drug users being followed in Amsterdam, in cases of newly acquired HIV infections in the period 1992-1995 HIV RNA was isolated from serum. The nucleic acid sequence encoding the first 250 amino acids of the HIV reverse transcriptase was determined in order to detect mutations conferring resistance to reverse transcriptase inhibitors. RESULTS: Among participants of the Amsterdam cohort studies, 12 new HIV infections of homosexual men and 23 of IV drug users were observed. In the group of homosexual men the first infection by a zidovudine-resistant HIV was observed in 1995. In the group of IV drug users the first infection by a zidovudine-resistant strain was noticed in 1993 with two more infections in 1995. The mutations regarded positions 41, 67, 70 and 215 of the HIV reverse transcriptase. No HIV strains resistant to didanosine, deoxycytidine, lamuvidine or nevirapine were found in untreated persons with an acute infection. CONCLUSION: As zidovudine is a vital part of the latest and most efficacious combination therapies of HIV infection, testing for zidovudine-resistance prior to treatment is recommended. PMID- 8676975 TI - [An infant with a fatal cerebral hemorrhage due to vitamin K deficiency]. AB - A 7-week old, male infant died from an intracerebral haemorrhage due to vitamin K deficiency. He had been exclusively breast-fed. Directly after birth no vitamin K was administered. From day 10 a daily dose of 25 microgram vitamin K was given orally. At post mortem a mild cholestasis was found which may have been an additional factor contributing to late vitamin K deficiency. PMID- 8676974 TI - [Prevalence of hemorrhages due to vitamin K deficiency in The Netherlands, 1992 1994]. AB - OBJECTIVE: To determine the prevalence of vitamin K deficiency bleeding in the Netherlands, in order to evaluate the efficacy of recommendations on vitamin K prophylaxis. DESIGN: Descriptive. SETTING: University Hospital Nijmegen, the Netherlands. METHODS: Active surveillance of vitamin K deficiency bleeding (VKDB) by the Dutch Paediatric Surveillance Unit from October 1, 1992 to December 31, 1994. RESULTS: Of the 19 reported cases 5 could be validated as late vitamin K deficiency bleeding: 2 idiopathic cases, and 3 secondary cases due to liver disorders. One case had intracranial bleeding and died. None of the cases had received exactly the recommended prophylaxis. The incidence of late VKDB was calculated to be 1.1/100,000 live births. Before vitamin K prophylaxis was recommended the incidence was estimated to be 7/100,000. CONCLUSION: The present Dutch recommendations for prevention of vitamin K deficiency bleeding-1 mg vitamin K at birth and thereafter for breastfed infants daily 25 micrograms from 2 to 13 weeks-appear effective. PMID- 8676976 TI - [History of healing; the introduction of insulin and the treatment of diabetes mellitus in The Netherlands (1923-1940)]. PMID- 8676977 TI - [Screening for familial hypercholesterolemia]. PMID- 8676978 TI - [Total mesorectal excision: a new standard for the surgical treatment of rectal carcinoma]. PMID- 8676979 TI - [Total mesorectal excision: a new standard for the surgical treatment of rectal carcinoma]. PMID- 8676981 TI - [3 children with velocardiofacial (Shprintzen) syndrome]. PMID- 8676980 TI - [Total mesorectal excision: a new standard for the surgical treatment of rectal carcinoma. ColoRectal Cancer Group]. PMID- 8676982 TI - [Socioeconomic variations in the survival of cancer patients]. PMID- 8676983 TI - [Pseudoxanthoma elasticum; etiology, diagnosis and therapy]. PMID- 8676984 TI - [The calcium hypothesis of brain aging]. AB - The "calcium hypothesis of brain aging" assumes that a small increase in free intra-cellular calcium concentration ([Ca2+]i) over years or decades finally leads to brain lesions similar to the short [Ca2+]i overload following one acute event (e.g., stroke). Recent data are reviewed that disprove the hypothesis in this rather simple form. Studies on brain cells of experimental animals as well as on animal and human blood cells suggest that [Ca2+]i is reduced rather than elevated in brain aging. However, probably as compensation, aging seems to lead to enhanced sensitivity of the brain (or of calcium-dependent mechanisms in the brain) to changes in [Ca2+]i. Under normal conditions, both alterations seem to compensate each other. However, under situations of additional stress leading to elevated [Ca2+]i (hypoxia, hypoglycemia), aged brain cells might be more vulnerable because of a reduced ability to down-regulate [Ca2+]i. In contrast to these typical changes in the aging, very little evidence exists that [Ca2+]i is also changed in Alzheimer's disease. On the other hand, recent evidence suggests that the modulation of [Ca2+]i by beta-amyloid is specifically altered in this disease, but the pathogenetic significance of this observation is not yet finally understood. PMID- 8676985 TI - [Huntington chorea. Molecular genetic principles, mutation detection and predictive diagnosis]. AB - Predictive genetic testing offers the opportunity for persons at risk to obtain information about their carrier status concerning Huntington's disease (HD). HD is associated with the expansion of a (CAG) repeat in the gene IT15. HD chromosomes contain about 40-75 repeat units, whereas normal chromosomes show a range between 11 and 33 repeats. The HD repeat is highly unstable during transmission, involving both increases and decreases in size with the largest expansions occurring in male meioses. The number of (CAG) copies is inversely correlated with the onset age of the disorder. Investigation of sporadic cases revealed that new mutations for HD are more frequent than estimated. Analysis of the repeat length allows direct DNA diagnosis of affected individuals and asymptomatic persons at risk. From 1989 to March 1993 in our institute predictive testing by indirect DNA methods was requested by 108 persons at risk. After cloning of the HD gene in 1993, direct testing was requested by 113 persons at risk between April 1993 and April 1994 in Gottingen. In about 400 patients differential diagnosis was performed with the direct method. In approximately 82% of the patients the expanded (CAG) repeat was found, and the HD diagnosis could be confirmed. PMID- 8676986 TI - [Genetic counseling in psychiatric diseases]. AB - We review current knowledge and application of genetic counselling for psychiatric disorders. Empirical data for genetic counselling exist for affective disorder, schizophrenia, Alzheimer's and Huntington's disease. In Huntington's chorea and partly in Alzheimer's disease molecular genetic methodology may be applied, whereas for affective disorder and schizophrenia only empirical risk figures are available. We describe the principles of genetic counselling and their application in the respective diseases. Problems of presymptomatic testing are particularly outlined. In addition, teratogenic aspects of therapy with psychopharmacological agents during pregnancy are discussed. PMID- 8676987 TI - [Do alcohol or drug abuse induce schizophrenia?]. AB - The high comorbidity of schizophrenia and substance abuse raises the question of a causal relationship between the two disorders. Clarifying the temporal sequence of their onsets can shed light on this issue. For this purpose, onset and course of schizophrenic symptoms and of alcohol and drug abuse were retrospectively investigated within the ABC Schizophrenia Study in a representative first-episode sample of 232 schizophrenic patients. The rates of alcohol abuse (24%) and of drug abuse (14%) were twice the rates compared to the general population but schizophrenic patients seemed to have started substance abuse later than the control group. Male sex and early symptom onset were major risk factors. At all important landmarks during the early course of schizophrenia, drug-abusers were younger than alcohol-abusers who were younger than non-abusers. Alcohol abuse usually started during the prodromal phase, i.e., after the first sign of schizophrenia but before the first positive symptom. Drug abuse emerged before the first symptom in one third, simultaneously with it in another third, and during the prodromal phase in the last third of patients. Drug abuse significantly preceded the psychotic phase. The hypothesis that substance abuse causes schizophrenia thus is not generally supported. Findings on symptomatology illustrate the problems substance-abusing schizophrenics pose from early on with dissocial behaviors and preoccupation with magical ideas but without a specific positive or negative subsyndrome. PMID- 8676988 TI - [Quantitative magnetic resonance tomography and the severity of deficits in dementia of the Alzheimer type]. AB - The aim of the present study was to investigate the severity of dementia of the Alzheimer type (DAT) with respect to morphological changes revealed by quantitative magnetic resonance imaging (MRI). Seventeen patients with DAT (NINCDS-ADRDA guidelines) and 10 healthy elderly controls were included. The severity of dementia was evaluated on the Mini Mental State Examination (MMSE), the Global Deterioration Scale (GDS) and the Brief Cognitive Rating Scale (BCRS). Three-dimensional MRI sequences were acquired using a 1.5-T Siemens Magnetom. Whole-brain volume and the volume of the amygdala-hippocampus complex (AHC) were assessed using the newly developed software NMRWin. This software provides a semi automated measure of the whole brain volume, while measurement of substructures requires manual guidance. In addition, the ventricle-brain ratio (VBR) was assessed. All morphometric parameters differed significantly between the two groups. AHC volumes discriminated best between them with only a small overlap. These findings were confirmed when only the data of the mildly demented patients were included in the analysis. The degree of AHC atrophy exceeded that of generalized cerebral atrophy. The severity of dementia as indicated by the MMSE, GDS and BCRS scores was correlated significantly with the volumes of the AHC bilaterally, but not with whole-brain volume or with VBR. These results underline the importance of the mesial temporal substructures in the etiology and progression of DAT and indicate that the volume of the AHC can be monitored by MRI and may be used to follow up the disease process. PMID- 8676989 TI - [Volumetric brain changes and quantitative EEG in normal aging and Alzheimer's dementia]. AB - We studied (1) the differences of volumetric estimates of brain atrophy in normal ageing and Alzheimer's disease (AD); (2) the correlation of these estimates with age and cognitive performance; (3) the differences between absolute EEG power between ageing and AD; (4) the correlation between EEG power and age or cognitive performance; and (5) the correlation between volumetric and EEG data. 84 patients with a clinical diagnosis of AD and 45 age-approximated non-demented controls between 48 and 91 years of age were examined. For statistical comparisons the volumetric estimates of intracranial cerebrospinal fluid (csf) spaces were converted into percentages of total intracranial volume. The EEG was recorded from 17 locations at resting conditions, eyes closed, according to the 10/20 system. Logtransformed absolute band powers were compared between the AD and control groups and correlated with clinical and volumetric findings. The total intracranial csf-space, both lateral ventricles, the third ventricle, anterior, lateral and posterior fissures were significantly larger in AD than in non demented controls. In normal ageing the csf-volumes were significantly correlated with age, whereas age and cognitive performance were differentially correlated with these variables in AD. In AD, the absolute delta or theta power was significantly higher in all locations, whereas alpha power was lower than in normal controls. These differences were significantly correlated with cognitive performance. There were no significant correlations between the csf-volumes and EEG-power in AD and the control group with one exception: we found a significant inverse correlation between the volumes of the anterior and posterior fissure and the alpha-1 and alpha-2 power independent of electrode location in AD. We conclude that the morphological and EEG-changes in AD are largely independent and suggest that the functional relationship between alpha-power and anterior or posterior fissure volume needs further examination. PMID- 8676990 TI - [Therapy of post-stroke depression with fluoxetine. A pilot project]. AB - Depression is a common but often unrecognized complication after cerebrovascular stroke. Tricyclic antidepressants (TCA) have been found to be effective in poststroke depression, but side effects such as orthostatic hypotension, arrhythmia limit their wider use. In this pilot study the effects of treatment with the specific serotonin reuptake inhibitor (SSRI) fluoxetine (20 mg) in 10 severely depressed patients (HAM-D score between 27 and 35) after cerebrovascular stroke were investigated. Four patients dropped out of the study prematurely because of worsening of their condition (n = 4) and one patient discontinued the study because of transfer to a nursing home. After 3 weeks of fluoxetine treatment there was a significant amelioration in all the measured scores (HAM-D, Beck, CGI and Barthel: P < 0.05). At the end of the study one patient with recurrent cerebrovascular lesions still had an HAM-D score of 25, but the other four patients had HAM-D scores between 6 and 11. The physical rehabilitation scores measured with the Barthel Index showed negative correlations with the HAM D, Beck and CGI scores for most items; this has to be interpreted with caution considering the number of patients involved in this investigation. The authors suggest that future double blind trials are warranted to test the efficacy of fluoxetin therapy for poststroke depression. Methodological problems in connection with pharmacological trials in these severely ill patients are discussed. PMID- 8676991 TI - [Dementia-paranoid syndrome as the initial manifestation of AIDS. Case report and diagnostic overview]. AB - A 33-year-old HIV-1-positive man developed dementia and a paranoid symptomatology with auditory hallucinations as the first manifestation of AIDS. The immunodeficiency syndrome is currently represented only by the immunohistochemical findings (CD4 216/microliters; CD4/CD8 ratio 0.12); no other manifestations of the disease are present. According to the literature about 15% of patients suffering from AIDS are likely to develop dementia during the course of the disease, usually after preceding opportunistic infections, severe systemic illness, or neoplasm. The manifestation of the disease solely by dementia is a rare phenomenon and represents, particularly if the incident of infection is cryptic, a diagnostic challenge. PMID- 8676992 TI - [Acute organic psychosis after malaria tropica]. AB - Neuropsychiatric complications in the course of plasmodium falciparum infection are usually summarized as cerebral malaria. Heterogeneous clinical symptoms, different courses and inconstant parasitemia, however, suggest different pathogenic mechanisms. We report a case of an acute symptomatic psychosis occurring two weeks after successful therapy of a primary manifestation of plasmodium falciparum infection. The diagnosis of meningoencephalitis was based on lymphocytic pleocytosis of cerebrospinal fluid and hyperintense lesions in cranial magnetic resonance imaging. Due to the lack of plasmodium falciparum parasitemia and of serological evidence of viral infection a final diagnosis was not possible. Considering the pertinent literature, an immune-mediated complication of plasmodium falciparum infection (acute disseminated encephalomyelitis, ADEM) appears to be more probable than a direct viral or plasmodium CNS infection. We propose to reverse the term cerebral malaria for the cases with direct pathogenic influence of plasmodium falciparum, and to distinguish it from cases with possible immune-mediated pathogenesis. PMID- 8676993 TI - [New therapeutic possibilities with low-affinity NMDA receptor antagonists]. AB - Glutamate receptor antagonists with selective action at the N-methyl-D-aspartate (NMDA) receptor are promising agents for the neuroprotective and symptomatic pharmacotherapy of various neuropsychiatric disorders. Although NMDA receptor antagonists of the phencyclidine (PCP) type are precluded from clinical use because of their psychotomimetic properties, amantadine and memantine have been administered to human patients with idiopathic Parkinson's disease and spasticity for many years without serious adverse effects. The mechanisms underlying these differences in psychotogenicity of different NMDA receptor antagonist are currently being discussed. Different affinity to the PCP binding site of the NMDA receptor, region-specific pharmacology, as well as different binding profiles to neurotransmitter receptors other than the NMDA type glutamate receptor, most likely play a role in determining whether an NMDA receptor antagonist drug will be tolerated clinically or not. PMID- 8676994 TI - [From degeneration to anticipation. Systematic and historical scientific aspects of the genetics of neuropsychiatric diseases]. PMID- 8676995 TI - [Proceedings of the German Society of Psychiatry, Psychotherapy and Neurology]. PMID- 8676996 TI - [German Society of Psychiatry, Psychotherapy and Neurology. Brief update (status: 31 December 1995)]. PMID- 8676997 TI - [Clinical application of functional mapping; the present state of the art and its future prospects: (series 5) functional mapping of the human thalamus]. PMID- 8676998 TI - [Profound hypothermia and circulatory arrest in cerebral aneurysm surgery]. PMID- 8676999 TI - [BA top aneurysm]. PMID- 8677000 TI - [Cranio-orbital zygomatic extradural approach for cavernous sinus or Meckel's cave tumors]. AB - Direct surgery to cavernous sinus (CS) lesions has become one of the optimal treatments based on advancement in microsurgical anatomy and imaging modality, and the progress of microsurgical techniques. We have removed the CS or Meckel's cave tumors extradurally when they do not extend intradurally, using modified Al Mefty's cranio-orbital zygomatic craniotomy. Three CS tumors; trigeminal neurofibroma, squamous cell carcinoma and chondrosarcoma, and a Meckel's cave meningioma were reported. Total removal was achieved in all but one (case 4). Postoperative complications were permanent ophthalmoplegia in one, transient ophthalmoplegia in one, subcutaneous CSF accumulation in two and trigeminal dysfunction in one. The extradural approach can be the first choice of methods for total removal of tumors when they are confined to the CS or Meckel's cave. PMID- 8677001 TI - [Radiosurgery of cavernous sinus meningiomas with gamma-knife]. AB - The treatment results of cavernous sinus meningioma with gamma-radiosurgery are reported. There were 18 cases of cavernous sinus meningioma, including 2 males and 16 females, whose age ranged from 39 to 63 with an average of 51.0 years. As prior treatments, operative tumor resection or biopsy had been carried out in 14 cases, and the pathology was verified. The other 4 cases were diagnosed clinically with radiological studies. The mean tumor diameter was 28.3mm (17.7 35.0) during the radiosurgery. The maximum dose ranged from 22 to 36Gy (mean 28.0Gy), with the marginal tumor dose ranging from 11 to 18Gy (mean 13.9Gy). Irradiation to the near-by optic nerves was less than 10Gy. Follow-up period ranged from 12 to 50 months with a mean of 25.5 months. MRI showed a minor tumor shrinkage in 9 (50.0%) and no obvious change in 8 (44.4%), and tumor progression in 1 (5.6%), which required a 2nd radiosurgery. Neurologically facial pain and facial dysesthesia were well improved (7/13). However the ophthalmoparesis was usually unchanged and only 1 out of 11 (9.1%) improved after radiosurgery. Deterioration of neurological signs was rare. Symptomatic edema presenting neurological signs was not seen. In conclusion, radiosurgery with a gamma-knife is one of the useful alternatives to operative intervention in the treatment of cavernous sinus meningiomas, not only for tumor control, but also for relief from the symptoms. PMID- 8677002 TI - [Long-term evaluation of radiographic changes following cervical anterior fusion with hydroxyapatite ceramic spacer]. AB - Cervical anterior fusion with iliac bone crest has become a popular surgical technique for cervical spondylotic disease. Since about 10 years ago, we have substituted hydroxyapatite ceramic spacer for autologous graft because of postoperative painful hip syndrome. Fourteen patients who underwent cervical anterior fusion with ceramic spacer were evaluated by plain radiographs for over eight years postoperatively. In six among the fourteen patients plain films demonstrated minimal stenosis of intervertebral disc height, of which the ratio ranged from 15% to 28% (mean 22%). The increase in mobility of the adjacent segment after fusion was noted in ten of the fourteen patients, although the ratio ranged only between 12% and 24% (mean 18%). In none of all the patients did dynamic plain films show cervical instability such as slippage and swan neck deformity. It seems that anterior fusion with ceramic spacer is a useful and safe method for a cervical spondylotic disease. PMID- 8677003 TI - [Changes in red blood cell aggregation rate after aneurysmal subarachnoid hemorrhage]. AB - Red blood cell (RBC) aggregability is one of the important factors determining blood viscosity in the microcirculation. The RBC aggregation rate was monitored in 38 patients who underwent early aneurysmal clipping surgery after subarachnoid hemorrhage (SAH). The intravascular factors (hematocrit, serum albumin, alpha 2 macroglobulin, fibrinogen, IgG) that influence RBC aggregation were also examined. The RBC aggregation rate increased on days 5-7 but decreased significantly as a result of hypervolemic hemodilution therapy (H-H therapy). The hematocrit level was also reduced by H-H therapy. The serum albumin concentration decreased and the serum alpha 2-macroglobulin concentration increased significantly on days 5-7. After H-H therapy, the serum albumin concentration increased and the serum alpha 2-macroglobulin concentration decreased significantly. Serum IgG and plasma fibrinogen concentrations did not change significantly. It is known that albumin decreases and alpha 2-macroglobulin increases RBC aggregability. It has become apparent that serum albumin and alpha 2-macroglobulin play important roles in the determination of RBC aggregability after SAH. We conclude that the improvement in RBC aggregability induced by H-H therapy is effective for reversing progressive neurological deterioration due to cerebral vasospasm. PMID- 8677004 TI - [A case of occult AVM diagnosed 17 years after subdural hematoma in the neonatal period]. AB - There have been few reports on cerebral arteriovenous malformation (AVM) of newborns. We present here an interesting case of occult AVM diagnosed 17 years after an episode of acute subdural hematoma in the neonatal period. The cause of subdural hematoma had remained unclear and the patient had suffered from an intractable epilepsy of 17 years duration. Seizures were mainly characterized by drop attacks and included other seizure types such as complex partial seizure and generalized tonic clonic seizure. The symptoms had gradually become worse and the intervals between the occurrences of symptoms had become shorter. An interictal scalp EEG showed a focal spike in the left temporoparietal lobe. CT and MRI of that region demonstrated a porencephalic cyst which was supposed to have resulted from an old hematoma. There were no vascular abnormalities in angiography. Temporoparietal craniotomy and a corticogram were performed. The cortex with a focus was resected and the disappearance of a focal spike in the corticogram was confirmed during operation. Microscopically the cortex included AVM with gliosis. The initial postoperative course was good and seizures disappeared immediately after the operation. However, the symptoms of drop attacks observed before operation began to occur again 3 months later. The fact of postoperative recurrence suggests that the long history of the patient's seizures originating from AVM may have produced secondary epileptic foci. PMID- 8677005 TI - [A case of primary intracranial malignant fibrous histiocytoma associated with peritumoral hemorrhage]. AB - Malignant fibrous histiocytoma (MFH) is common among the soft-tissue sarcoma and especially occurs in the retroperitoneum and the four extremities. However primary intracranial MFH is an extremely rare occurrence. A case with primary intracranial MFH associated with peritumoral hemorrhage is reported. A 81-year old woman was admitted to our department with impaired consciousness and left hemiparesis. On admission, she was drowsy. Computed tomography (CT) scans revealed a low density mass lesion of 4.5 x 3.5 x 6.0cm in diameter, which was surrounded by a high density area suggesting hematoma, in the right frontal lobe adjacent to the falx cerebri. The low density mass was homogeneously enhanced by contrast medium. Magnetic resonance imaging revealed that the mass was hypointense on T1 weighted image and hyperintense on T2 weighted image. After administration of Gd-DTPA, the mass was homogeneously enhanced and the falx cerebri was also enhanced at the site of attachment. Right carotid angiogram showed a tumor stain fed by the anterior cerebral artery. On operation, bleeding was encountered between the tumor and the falx cerebri on opening the dura mater. Hematoma existed between the tumor and the normal cerebral parenchyma. The tumor was sharply demarcated and didn't invade the normal cerebral parenchyma or the falx cerebri, so we considered that the tumor originated from the meninges. Histologically, pleomorphic spindle cells in atypical storiform pattern were observed. Multinucleated giant cells were also seen. This case suggested to us that primary intracranial MFH may be associated with intracranial hemorrhage. PMID- 8677006 TI - [Huge skull base neurofibroma: case report]. AB - A case of a huge skull base neurofibroma completely resected by a combined subtemporal-infratemporal and basal subfrontal approach is reported. A 32-year old female complained of left facial paresthesia and deformity since several months before. Neurological examination revealed hypesthesia in the distribution of the left trigeminal nerve second branch. CT and MRI images showed a huge tumor in the infratemporal fossa, parapharyngeal space and middle fossa extending into the cavernous sinus, compressing the left temporal lobe and distorting the left hypothalamus and the brain stem. The patient tolerated trial balloon occlusion of the left internal carotid artery for 45 minutes. Transmaxillary biopsy revealed the tumor to be a neurofibroma. Through a combined basal subfrontal and a subtemporal-infratemporal approach in two staged operations, total tumor resection was performed. This tumor originated at the second branch of the trigeminal nerve. We recommend these combined approaches and two staged operations for such a huge skull base tumor as presented in this case. PMID- 8677007 TI - [A case of thoracic meningioma presenting paraplegia at 4.5 years after removal of a falx meningioma]. AB - A case of a thoracic meningioma presenting paraplegia 4.5 years after removal of a falx meningioma is reported. A 73-year-old woman, complaining of diplopia, was admitted to our department. Neurological examination revealed right abducens palsy. CT demonstrated a well-enhanced right frontal mass beneath the falx. The mass was totally removed under right frontal craniotomy. Its histology was transitional meningioma with rich fibroblasts. 4.5 years after craniotomy, she complained of progressing gait disturbance and nocturnal leg pain. Neurological examination revealed paraplegia, complete loss of leg sensation, loss of patellar and ankle reflex, bilateral positive Babinski reflex and urinary disturbance. Rectal function and anal reflex were preserved. Thoracic MRI demonstrated an intradural extramedullary mass which was well enhanced with Gd-DTPA at Th6-7. Under laminectomy, the mass was totally removed. Its histology was transitional meningioma with rich psammoma bodies and whirl formations. 4 months after removal, her palsy and sensory loss were almost completely recovered. We were able to find 15 cases of combined intracranial and spinal meningiomas in the literature. A young woman of neurofibromatosis suffered from tentorial, intraventricular and C1-2 meningiomas. Of 15 cases without neurofibromatosis including our case, 4 cases were of young boys and 11 cases were of women. Their initial symptoms originated from intracranial meningiomas in 8 cases. Multiple intracranial meningiomas were revealed in only 4 cases. In 9 cases, one case presented a combination of one intracranial meningioma and one spinal meningioma. Histology of intracranial meningioma was almost the same that of spinal meningioma in almost half of the 10 cases. These findings suggest the multi sentricity theory of multiple meningiomas originating in other neuroaxial compartments. Severe spinal dysfunction was recovered after removal in our case. Rectal function and anal reflex were preserved. These anorectal findings suggest that spinal dysfunction is either complete or incomplete. Motor evoked potentials are hopeful tools which can select reversible spinal motor dysfunctions. PMID- 8677008 TI - [Bilateral chronic subdural hematomas presented with subarachnoid hemorrhage: report of two cases]. AB - Computed tomography (CT) findings of chronic subdural hematomas are usually diagnostic, unless hematomas are isodense and bilateral. The authors report two cases of bilateral chronic subdural hematomas, in which CT scans on admission were both misdiagnosed as delayed subarachnoid hemorrhage (SAH). The first case was a 43-year-old woman who suffered from a sudden onset of headache and nausea. She had no past history of head injury. CT scans on admission did not clearly reveal the Sylvian fissures and the mesencephalic cistern, without any mass effects. A lumbar puncture demonstrated xanthochromic cerebrospinal fluid (CSF), which was considered to be responsible for her headache. Cerebral angiography performed on day 4 failed to demonstrate any cerebral vascular disorders. Follow up CT scans on day 7 demonstrated a high density lesion in the left subdural space. Magnetic resonance images (MRIs) confirmed a diagnosis of bilateral chronic subdural hematomas. Removal of the hematomas cleared all signs and symptoms smoothly. The second case was a 44-year-old man who was referred from another hospital because of xanthochromic CSF found by lumbar puncture. He began to suffer headache and be subject to vomiting 6 weeks earlier and these symptoms were still present on the day of admission. CT scans did not clearly show the cerebral cisterns without mass effects. Because the second lumbar puncture showed xanthochromic CSF again, SAH from aneurysm was suspected. However, emergency cerebral angiography failed to demonstrate cerebral aneurysms. MRI performed two days later demonstrated bilateral chronic subdural hematomas. Following surgery, the patient improved immediately and was discharged from hospital without any complications. In both cases, a retrospective study of the angiograms revealed the evidence of bilateral avascular areas over the convexities in the venous phase. The reason why these subdural hematomas were missed at the time of angiography was due to too much attention being paid to the arterial phase in an effort aimed only at identifying cerebral aneurysms. There are no reports of chronic subdural hematoma which demonstrated sudden onset of headache associated with xanthochromic CSF. PMID- 8677009 TI - Differential pattern of c-fos mRNA in rat brain following central and systemic administration of interleukin-1-beta: implications for mechanism of action. AB - Interleukin-1-beta (IL-1 beta) is a potent activator of the hypothalamic pituitary-adrenal (HPA) axis, resulting in the release of corticosteroids from the adrenal glands. This effect is evident after both central and peripheral administration, and controversy surrounds the mechanism(s) by which systemic administration of this peptide, which should not cross the blood-brain barrier, may activate the HPA axis. In the present study, IL-1 beta was administered systemically (5 micrograms/kg i.p.) or centrally (100 ng i.c.v.) to male rats. Both routes of administration of IL-1 beta resulted in significant and comparable activation of the HPA axis, as assessed by analysis of plasma conrticosterone. In addition, both routes of administration of IL-1 beta resulted in c-fos mRNA induction in specific regions, as determined by in situ hybridization. These included the meninges, cerebral vasculature, choroid plexus and circumventricular organs. Semiquantitative analysis revealed that both routes of administration resulted in significant and comparable induction of c-fos mRNA in the paraventricular nucleus of the hypothalamus, as compared with control animals. In contrast, in the nucleus tractus solitarius (NTS) and central nucleus of the amygdala (CeA), levels of c-fos mRNA were 3-4 times higher in animals treated intraperitoneally compared with intracerebroventricularly. A similar differential activation of c-fos mRNA was observed in the lateral divisions of the parabrachial nucleus (PBN) and bed nucleus of the stria terminalis (BNST). These data indicate that following systemic administration, IL-1 beta may activate specific brain areas through mechanisms distinct from those involved following central administration. The differential magnitude of the c-fos mRNA response in the NTS, PBN, CeA and BNST is consistent with vagal activation. Physiologically, these results suggest that IL-1 beta may have differential central effects depending on its source or point of entry to the brain. PMID- 8677010 TI - Involvement of central histamine in the early phase of ACTH and corticosterone responses to endotoxin in rats. AB - The involvement of histaminergic transmission in the rapid and sustained plasma ACTH and corticosterone (CORT) responses induced in conscious rats by intra arterial infusions of 25 micrograms.kg-1 Escherichia coli lipopolysaccharide (LPS) was investigated. LPS challenge produced a rapid and transient increase (+ 62%) in the amount of histamine (HA) in the median eminence 15 min after LPS administration, which contrasted with constant concentrations of plasma HA throughout the entire study (up to 480 min). Blockade of histaminergic receptors by intra-arterial pretreatment with H1 or H2 antagonists (mepyramine, 1 mg/rat, and cimetidine, 2 mg/rat), administered separately, did not affect either ACTH or CORT responses to LPS. Pretreatment with the same doses of the two antagonists in combination very significantly but transiently impaired the earliest phase (30 min) of the ACTH and CORT responses, without any apparent effect on the late phase of these responses. Pretreatment of the animals with an H3-receptor agonist (R alpha-methylhistamine dihydrochloride, 1 mg/rat) similarly blunted the early corticotropic responses to LPS, and also slightly depressed the long-lasting CORT response. These findings support the view that activated central HA transmission may be a key intermediate mechanism triggering the CRH41-ACTH-CORT responses to LPS, in addition to the previously demonstrated activating role of catecholaminergic afferences to the CRH41 neurons during this early complex phase of corticotropic response to LPS. PMID- 8677011 TI - Interleukin 6 modulates interleukin-1-and stress-induced activation of the hypothalamic-pituitary-adrenal axis in male rats. AB - This study examined the interaction between interleukin 6 (IL-6) and IL-1 and between IL-6 and stress on the activation of the hypothalamic-pituitary-adrenal (HPA) axis. Coadministration of IL-6 (100 ng/rat) with IL-1 (20 or 100 mg/ rat) resulted in synergistic stimulation of the HPA axis, as determined by increased plasma levels of ACTH and corticosterone (CORT) which were greater in rats that received both cytokines than in rats receiving either cytokine alone. Concomitant administration of IL-6 (100 ng/rat) with exposure to a novelty stressor also synergistically stimulated the activation of the HPA axis, as IL-6-treated rats subjected to novelty stress had greater increases in plasma levels of ACTH and CORT than vehicle-treated rats exposed to novelty stress or rats receiving IL-6 alone. However, concomitant administration of IL-6 (100 ng/rat) did not significantly affect restraint stress induced elevation of plasma levels of ACTH and CORT, although IL-6 tended to prolong restraint stress induced elevation of plasma levels of CORT. These findings indicate a modulatory role for IL-6 stimulated HPA axis activity in response to IL-1 or a novelty psychological stressor, but not for restraint stress. PMID- 8677012 TI - Endocrine effects of recombinant interleukin 6 in man. AB - In a phase II study, 5 male patients with a good performance status, who had metastatic renal cell carcinoma, received interleukin 6 (IL-6) to evaluate a possible antitumor effect of the cytokine. This offered the opportunity to investigate endocrine effects of IL-6 in man. The patients were studied the day before (day-1), and on days +1 and +21 of the IL-6 therapy (150 micrograms administered subcutaneously every day at 09.00 h). Blood was sampled at 09.00, 11.00, 13.00, 16.00, and 20.00 h. Compared with day -1, on days +1 and +21 serum levels of IL-6 were substantially elevated between 11.00 and 20.00 h. IL-6 significantly decreased serum thyrotropin (TSH) levels on day +1 (p < 0.05). The decrease was even more pronounced on day +21 when TSH concentrations were persistently below the respective values of day +1, suggesting, in addition to the acute action of IL-6, an effect developing with repeated IL-6 administrations. Total serum T3 and T4 levels were significantly lower on day +21 than on days -1 and +1. In contrast, free T3 and free T4 values did not differ among days -1, +1 and +21. Acutely, IL-6 had no effect on serum luteinizing hormone (LH) concentrations. However, on day +21, averaged serum LH levels (between 11.00 and 20.00 h) were significantly higher (8.4 +/- 1.1 IU/l) than on days -1 (6.5 +/- 0.2 IU/l) and +1 (6.4 +/- 0.4 IU/l). Average serum testosterone levels were slightly but not significantly enhanced on day +21. IL-6 did not influence follicle-stimulating hormone, growth hormone, or prolactin levels, neither acutely nor after 3 weeks of daily administration. The data indicate a modulating effect of IL-6 on secretory activity of different endocrine axes in man. PMID- 8677014 TI - Cellular trafficking of exogenous growth hormone in dwarf rat pituitary. AB - In order to determine the processing of growth hormone (GH) by its pituitary target cells, male rats were injected intracardially with 125I-bGH and their pituitaries removed at specific time intervals (2-120 min). Autoradiographic analysis performed at the electron-microscopic level showed that only three cell populations specifically took up 125I-bGH: somatotropes, lactotropes and gonadotropes. Specificity was demonstrated by concomitant injection with an excess of unlabeled bGH. A time course study indicated that eight compartments had distinct labeling patterns. The plasma membrane was highly labeled after as little as 2 min, and showed biphasic labeling 2 and 60 min after injection. The secretory granules of the somatotropes were more intensely labeled than those of the other cell populations. The rough endoplasmic reticulum was more intensely labeled in the gonadotropes. The Golgi apparatus was specifically labeled only in the gonadotropes. The mitochondria showed the highest degree of labeling at 15 and 120 min after injection. The lysosome compartment showed triphasic labeling, with maxima at 2, 30 and 120 min after injection. The labeling of the nuclear membrane showed a biphasic pattern, firstly at 15 min, then at 120 min after injection, except in the gonadotropes, and the labeling in the nuclear matrix showed similar biphasic pattern and maxima. These results show that GH is specifically taken up in the anterior pituitary by the somatotropes, lactotropes and gonadotropes, where, after binding to the plasma membrane, it is internalized into several cellular compartments, including the nucleus. The differences in cellular localization and processing between these cell types may reflect different paracrine and autocrine roles for GH. PMID- 8677013 TI - Arachidonic acid-induced hormone release in somatotropes: involvement of calcium. AB - Arachidonic acid (AA) has been implicated in signaling actions in several cell types including endocrine cells. In the present study, we investigated the effect of exogenous AA on GH release from dispersed pituitary cells and tried to elucidate the mechanism involved in this process. We show that AA stimulates GH release in a dose- and extracellular calcium-dependent manner. The effects of AA on cytosolic calcium concentration ([Ca2+]i) were studied using dual-emission microspectrofluorimetry in identified somatotropes. AA (1 microM) induced an increase in intracellular calcium concentration ([Ca2+]i) by stimulating Ca2+ influx through dihydropyridine-sensitive, voltage-dependent calcium channels. In these cells, the effects of AA were only reduced by the inhibition of protein kinase C (PKC) activity, suggesting that the fatty acid may act by both PKC dependent and PKC-independent pathways. In order to determine whether AA metabolites were involved in the effects attributed to AA, and, if so, which ones, we inhibited the three arachidonate metabolic pathways: cyclo-oxygenase by indomethacin (50 microM), lipoxygenase by nordihydroguaiaretic acid (NGDA, 50 microM), and epoxygenase by 5,8,11, 14-eicosatetraynoic acid (ETYA, 10 microM). NGDA and ETYA reduced the effects of AA on GH release (50 and 74%, respectively) and inhibited the [Ca2+]i response, whereas indomethacin slightly potentiated both AA-induced GH release and [Ca2+]i increase. As these results suggested that lipoxygenase metabolites may be responsible for AA-induced Ca2+ influx and GH release, we tested the effects of 5-, 12- and 15-hydroperoxyeicosatetraenoic acids (5-, 12- and 15-HpETE) on [Ca2+]i and GH release. They all stimulated calcium influx and GH release in a dose-dependent manner, 12-HpETE being more potent than 5- and 15-HpETE. We conclude that lipoxygenase metabolites of arachidonic acid, particularly 12-HpETE, may be involved in the GH secretion mechanism, probably by facilitating Ca2+ influx via L-type Ca2+ channels. PMID- 8677015 TI - Effects of selective serotonin and dopamine agonists on plasma levels of glucose, insulin and glucagon in the rat. AB - Male Sprague-Dawley rats were given one of the 5-HT receptor agonists 8-OH-DPAT (0.5-2.0 mg kg-1), TFMPP (0.125-2.0 mg kg-1), DOI (0.125-2.0 mg kg-1), and m-CPBG (1.25-20.0 mg kg-1), selective for 5-HT1A, 5-HT1B, 5-HT2 and the 5-HT3 receptors, respectively, or one of the DA receptor agonists bromocriptine (2.0-32.0 mg kg 1), quinpirole (0.5-8.0 mg kg-1) and 7-OH-DPAT (0.2-3.2 mg kg-1), selective for DA D2, DA D2/D3 and DA D3 receptors, respectively. An additional group of animals was given buspirone (2.0-8.0 mg kg-1) a 5-HT1A receptor agonist and DA D2 receptor antagonist. Separate groups of rats were given both the 5-HT1A receptor antagonist pindolol and 8-OH-DPAT or both the DA D2/D3 receptor antagonist raclopride and 7-OH-DPAT. Blood samples were collected 30 min (in some cases 120 min) after drug administration and assayed for insulin, glucagon and glucose levels. The 5-HT1A receptor agonist 8-OH-DPAT produced a statistically significant decrease in plasma insulin levels and an increase in glucose, whereas glucagon levels were unaffected. The only effect observed after buspirone treatment was a small increase in plasma glucose levels. No significant effects on plasma insulin, glucagon or glucose were seen after treatment with the 5-HT1B, 5-HT2 or 5-HT3 agonists. The DA D3 receptor agonist 7-OH-DPAT produced a decrease in plasma insulin (3.2 mg kg-1, 120 min) and an increase in glucose levels. Administration of the DA D2/D3 receptor agonist quinpirole resulted only in increased plasma glucose, whereas the DA D2 receptor agonist bromocriptine had no effect. In support of a separate mediation of glucose secretion by 5-HT1A and DA D3 receptors, the effects of 8-OH-DPAT on glucose levels were antagonized by ( )pindolol pretreatment, and the 7-OH-DPAT-induced effects on glucose levels were antagonized by raclopride pretreatment. It is concluded that plasma glucose levels are under separate serotonergic and dopaminergic control, exerted via 5 HT1A and DA D3 receptors, respectively. PMID- 8677016 TI - alpha-2-Adrenergic activation of proopiomelanocortin-containing neurons in the arcuate nucleus causes opioid-mediated hypotension and bradycardia. AB - Treatment of rats for 4 days with alpha-methyldopa, 200 mg/kg/day i.p., increases steady state levels of proopiomelanocortin (POMC) mRNA in the mediobasal hypothalamus, as measured by DNA excess solution hybridization. The increase is prevented by parallel treatment with yohimbine, 2 mg/kg/day i.p., but not by naltrexone, 2 mg/kg/day i.p. Treatment with the peripheral vasodilator hydralazine, 2 mg/kg/day, does not affect POMC mRNA levels. In situ hybridization histochemistry with a cRNA probe for POMC indicates that POMC-containing cells are located within the confines of the arcuate nucleus both in control and in alpha-methyldopa-treated rats, and confirms the increase in POMC mRNA in the latter. Microinjection of 2 micrograms of alpha-methylnorepinephrine unilaterally into the arcuate nucleus of urethane-anesthetized rats causes hypotension and bradycardia, which can be inhibited by 200 ng of yohimbine microinjected into the same site, or by 100 ng l-naloxone microinjected into the ipsilateral nucleus tractus solitarii, but not into the arcuate nucleus. These findings are interpreted to indicate that activation of alpha 2-adrenergic receptors located on POMC-containing neurons in the arcuate nucleus causes beta-endorphin release and stimulation of opiate receptors in the NTS, which results in hypotension and bradycardia, and that this mechanism contributes to the hypotensive action of alpha-methyldopa. PMID- 8677017 TI - Testicular injection of 5,6-dihydroxytryptamine or vasectomy interferes with the local stimulatory effect of oxytocin on testicular steroidogenesis in immature rats. AB - Previous studies indicated that in immature rats testicular administration of oxytocin stimulates testicular steroidogenesis. In the present study, testicular treatment with oxytocin (50 ng) was combined with pharmacological or surgical denervation of the testis in hemigonadectomized immature rats. For denervation 5,6-dihydroxytryptamine (160 micrograms/testis), a substance that destroys serotoninergic neuronal elements, was injected intratesticularly or vasectomy was performed, which also includes transection of the inferior testicular nerve. In 9 day-old animals both vasectomy and pretreatment of the testis with 5,6 dihydroxytryptamine prevented the oxytocin-induced rise in serum testosterone concentration. In addition, intratesticular injection of oxytocin combined with vasectomy resulted in a significant increase in in vitro basal testosterone secretion of the testis. A similar effect was not observed in the 5,6 dihydroxytryptamine-pretreated group receiving oxytocin. The results indicate that testicular innervation is involved in the control of local peptide effects, and data further suggest a differential role of these neural elements in intratesticular regulatory processes. PMID- 8677018 TI - Inhibitory effect of baclofen on lordosis in female and male rats with dorsal raphe nucleus lesion or septal cut. AB - The inhibitory effect of baclofen, a GABAB receptor agonist, on lordosis was examined in female and male rats with dorsal raphe nucleus lesions (DRL) or cut of the septal fibers (ARD). Both female and male DRL and ARD rats showed higher lordosis quotients (LQ) than corresponding controls without brain surgery. This indicates that the dorsal raphe nucleus and the septum exert lordosis-inhibiting influences in female and male rats. After treatment with 10 mg/kg baclofen, the mean LQs in female control and female ARD groups were significantly lower than those of vehicle-treated control and ARD females. In DRL females, however, LQs did not decrease, even after the injection of baclofen. In males, baclofen also diminished lordosis in ARD rats, but not in DRL rats. These results suggest that the GABAB receptor system plays an inhibitory role in regulating lordosis behavior not only in female but also in male rats. Furthermore, the function of the GABA neurons depends on the inhibitory mechanism of the dorsal raphe nucleus in the regulation of female sexual behavior. PMID- 8677019 TI - Differential regulation of basal and kindling-induced TRH mRNA expression by thyroid hormone in the hypothalamic and limbic structures. AB - It has previously been demonstrated that thyrotropin-releasing hormone (TRH) mRNA expression is dramatically increased in limbic structures including dentate gyrus granular layer, and pyriform, entorhinal and perirhinal cortices following amygdala kindling. Since thyroid hormone regulates TRH mRNA in the paraventricular nucleus of the hypothalamus (PVN), we investigated whether basal or kindling-induced TRH mRNA expression in limbic regions is also regulated by thyroid hormone. Hypo- and hyperthyroidism was induced by treating rats with 0.05% 6-n-propyl-2-thiouracil (PTU) (equivalent to approximately 30 mg/kg/day) or 0.9 microM 3,5,3'-triiodo-L-thyronine (T3) (equivalent to approximately 50 micrograms/kg/day), respectively, in their drinking water for 10 days before kindling and throughout the kindling procedure. Rats were sacrificed 4 h after their first stage 5 seizure. None of the thyroid hormone manipulations altered kindling development, or behavioral and electrographic after-discharge seizure durations. Pituitary TSH beta mRNA levels were significantly increased by PTU and suppressed by T3, but unaffected by kindling. In addition, in situ hybridization showed that PTU administration increased and T3 administration decreased TRH mRNA levels in the PVN, consistent with thyroid hormone's negative feedback effects. At the same time, kindling had no effect on TRH mRNA in the PVN. In contrast, kindling dramatically increased TRH mRNA in the dentate gyrus granular layer, and pyriform, entorhinal and perirhinal cortices, but thyroid hormone manipulations did not affect either basal or kindling-induced TRH mRNA expression in limbic structures. These findings demonstrate that TRH mRNA expression is differentially regulated in the hypothalamic PVN and limbic structures. PMID- 8677020 TI - Early predictors of cerebral visual impairment in infants with cystic leukomalacia. AB - A longitudinal prospective follow-up study looking at the correlation between haemorrhagic-ischaemic lesions on neonatal cranial ultrasound (US) and the development of cerebral visual impairment (CVI) in infancy resulted in the detection of nine infants with severe visual impairment, which was not due to opthalmological abnormalities. Extensive cystic leukomalacia proved to be highly predictive of CVI, as well as of severe mental and motor deficit in these nine infants. The present report outlines the results of different examinations (acuity card procedure [ACP], visual evoked potential [VEPs], magnetic resonance imaging [MRI]) performed during the first 18 months, to find out which combination of examinations would be the most predictive of CVI at an early stage. The results indicated that infants with a gestational age of 35 weeks or more, who sustained extensive cystic leukomalacia during the neonatal period, and were subsequently not fixating at the acuity cards at term and at three months of age, invariably developed CVI. VEPs were also severely abnormal in the infants with the worst visual outcome, but were not providing a more reliable prognosis. Also, a good correlation between MRI-abnormalities of the optic radiations and/or the visual cortex and CVI was found, but MRI was usually performed beyond the age of 12 months. PMID- 8677021 TI - Evaluation of congenital dysautonomia other than Riley-Day syndrome. AB - We report on four children, from different families, who suffer from a congenital autonomic disorder, presumably inherited. Three of them have a sensory neuropathy but do not fit any described hereditary sensory and autonomic neuropathy. All four were examined along with some of their immediate family members. We assessed the cardiovagal, sympathetic adrenergic and sympathetic cholinergic functions with a battery of non-invasive tests. Results demonstrated that sudomotor and cardiovascular orthostatic regulation exhibited the greatest abnormalities, pointing to a predominant impairment of sympathetic components, both cholinergic and adrenergic. The overall examination showed a heterogeneous group of congenital dysautonomia, exclusive of Riley-Day or other recognized hereditary sensory and autonomic neuropathies. We emphasize the importance of studying whole family groups to diagnose subclinical impairment and to provide correct genetic counselling. PMID- 8677022 TI - Childhood onset of Friedreich ataxia: a clinical and genetic study of 36 cases. AB - The onset of Friedreich ataxia (FA) was before 10 years of age in 36 out of 95 personally observed patients. We studied the clinical and laboratory findings of these childhood onset patients. Mean onset age +/- SD was 6.3 +/- 2.4 years. Gait and stance ataxia and lower limb areflexia were constant, dysmetria, dysarthria, Babinski sign, pes cavus, scoliosis and decreased vibration sense were present in the majority of patients. Higher occurrence of diabetes in childhood onset cases (25%) was the only statistical difference in comparison with later onset patients. Mean onset age of diabetes was 21.1 +/- 6.9 years and all patients required insulin. ECG was abnormal in 72% of the patients and echocardiographic evidence of hypertrophic cardiomyopathy was found in 43%. Linkage analysis, performed in 10 families, showed no recombination between the polymorphic markers of the 9q13-21.1 region and the disease locus with a peak lod score of 4.21 at a recombination fraction = 0.00. PMID- 8677023 TI - Neurosensory hearing loss in secondary adhalinopathy. AB - We report mild-to-moderate neurosensory hearing loss and severe childhood autosomal recessive muscular dystrophy with adhalin-deficiency in two siblings from a Bulgarian sibship of Turkish origin. Microsatellite analysis excluded linkage to the adhalin gene, mutations of which cause limb girdle muscular dystrophy (LGMD) 2D, but was compatible with linkage to the gene locus of LGMD 2C on chromosome 13q12. Compound heterozygosity of the affected siblings was detected in this chromosomal region. A severe autosomal recessive form of neurosensory deafness has been linked to the same region (locus NSRD1) which is now contained in a 7 Mb YAC contig. Using polymorphic markers and STS PCR primers mapping in this contig, we did not find evidence for major rearrangements in the suspected region. These preliminary findings are not in favor of, but do not completely exclude a contiguous gene syndrome in these cases. Therefore, we consider a potential role of the putative 13q12 gene product and/or adhalin in neurosensory hearing. PMID- 8677024 TI - Differentiation of rare leukodystrophies by post-mortem morphological and biochemical studies: female adrenoleukodystrophy-like disease and late-onset Krabbe disease. AB - Two 6-year-old patients with clinical signs of leukodystrophy had no nosological diagnoses in vivo. Neuropathological studies revealed scavenger cells to be clustered in perivascular regions of the demyelinated brains. Histochemical and ultrastructural details of the non-metachromatic storage macrophages suggested lipid storage and prompted a biochemical analysis of cerebral tissue. The detection of increased amounts of very long chain fatty acids in the cholesterol ester fraction from formalin tissue in one patient was consistent with a diagnosis of an adrenoleukodystrophy-like condition, while the marked reduction in beta-galactocerebrosidase activity in a frozen brain sample of the second patient indicate Krabbe disease. The diagnostic potential of post-mortem studies in rare leukodystrophies is addressed. PMID- 8677025 TI - Successful treatment of transverse myelitis in a child with systemic lupus erythematosus. AB - We describe a 13-year-old female patient with systemic lupus erythematosus (SLE) who presented with acute transverse myelitis (ATM) in the course of SLE. IgG and IgM anticardiolipin antibodies (aCL) were positive at moderate titers. Magnetic resonance imaging (MRI) of the thoracic spine demonstrated decreased signal intensity and diffuse edema of the spinal cord from T2 to T6 on T1-weighted images. Dramatic clinical improvement of the neurologic impairment was noted a few days after high dose intravenous (IV) methylprednisolone (MP) and cyclophosphamide (Cy). Herein we further emphasize the benefit of IV MP and Cy in ATM and the relationship between ATM and antiphospholipid antibodies (aPLA) in SLE. PMID- 8677026 TI - Evaluation of surgically formed collateral circulation in moyamoya disease with 3D-CT angiography: comparison with MR angiography and X-ray angiography. AB - Three patients with moyamoya disease who had undergone bypass surgery at which bilateral encephaloduro-arterio-synangiosis (EDAS) anastomoses were created were studied with three-dimensional spiral CT angiography (3D-CTA). In one patient, magnetic resonance angiography (MRA) clearly visualized the bilateral EDAS, and 3D-CTA also visualized these anastomoses in detail with extreme clarity. In the other two patients, MRA did not clearly demonstrate the right EDAS anastomosis, but 3D-CTA visualized both side surgical collaterals clearly. External carotid angiography confirmed these findings. 3D-CTA might have great value in the evaluation of surgical bypass patency and, in following the disease progression. PMID- 8677028 TI - Arthrogryposis multiplex congenita and bilateral parietal polymicrogyria in association with the intrauterine death of a twin. AB - A case of neurogenic arthrogryposis multiplex congenita (AMC) with associated neuronal migration abnormalities is described. A child with neurogenic AMC and developmental delay presented with late onset of seizures. The first trimester of the mother's pregnancy was marked by an episode of gastro-enteritis and the intrauterine death of a twin fetus. Computer tomography (CT) and magnetic resonance (MR) imaging demonstrated abnormal neuronal migration consisting of bilateral parietal polymicrogyria, and an isolated grey matter heterotopia. PMID- 8677027 TI - Unilateral cerebellar aplasia. AB - We describe three children with unilateral cerebellar aplasia (UCA). Deliveries at term and neonatal periods were uneventful. Pregnancy was normal in one and complicated by mild bleeding (in second and fourth month respectively) in two instances. Presenting signs were delayed motor development with marked contralateral torticollis (n = 1), hemiplegia (n = 1) and unusual head nodding (n = 1). Neuroradiological investigations revealed complete aplasia (n = 1) and subtotal aplasia (n = 2) of one cerebellar hemisphere with only a residual wing like structure below the tentorium. There was contralateral underdevelopment of the brainstem. The infant with hemiplegic cerebral palsy had an additional supratentorial periventricular parenchymal defect, contralateral to the cerebellar hypoplasia. In view of literature reports, describing similar neuroradiological or neuropathological findings in asymptomatic individuals, it is doubtful whether UCA is responsible for our patient's problems. In our cases UCA has presumably resulted from a prenatal destructive lesion, possibly an infarct, but the timing and exact nature are unknown. PMID- 8677029 TI - Clinical spectrum and diagnostic criteria of infantile spinal muscular atrophy: further delineation on the basis of SMN gene deletion findings. AB - With the evidence of deletions in the region responsible for autosomal recessive spinal muscular atrophy (SMA) on chromosome 5, it is now possible to further clarify the clinical and diagnostic findings in proximal SMA. Homozygous deletions of the survival motor neuron (SMN) gene can be detected in about 95% of patients with early onset SMA. In a series of more than 200 patients, we tested 31 patients with atypical features of SMA who fulfilled at least one exclusion criterion according to the diagnostic criteria of the International SMA Consortium for the presence of SMN gene deletions. The patients were subdivided into two groups: 1. Seven index patients being not deleted for the SMN gene who belonged to a well-defined SMA plus variant that has already been shown to be unlinked with chromosome 5q markers: diaphragmatic SMA, SMA plus olivopontocerebellar hypoplasia, SMA with congenital arthrogryposis and bone fractures. 2. Twenty-four patients with clinical signs of SMA and neurogenic findings in EMG/muscle biopsy who had unusual features or other organ involvement. In order to structure this heterogeneous group, each patient was assigned to a subgroup according to the leading atypical feature. In 5 out of 8 unrelated patients with a history of preterm birth and/or perinatal asphyxia leading to a picture of severe SMA in combination with respiratory distress and/or cerebral palsy, no deletion of the SMN gene could be detected. There were five unrelated patients with extended central nervous system involvement (cerebral atrophy, EEG abnormalities, pyramidal tract signs, evidence of cerebellar involvement). Most of these patients (4/5) proved to belong to SMA 5q on the basis of SMN gene deletion findings. The same applied to a group of three patients with classical SMA in association with congenital malformations (mainly heart defect). A fourth group of three patients was characterized mainly by an unusual improvement of the condition; in these patients no SMN gene deletions were present. In three index patients a more complex syndrome of the CNS and other organs was suggested, but the detection of SMN gene deletions in two of them made a coincidence of features more likely. In addition, SMN gene deletions were found in two patients with evidence of congenital fibre type dysproportion in one and extremely raised CK activity ( > 10fold) in the other. While the confirmation of SMN gene deletions is very useful in cases with diagnostic doubts, caution is required when offering prenatal prediction with regard to SMA 5q in families with atypical features. There is strong evidence that there are clinical entities resembling SMA which most likely have another pathogenetic background. PMID- 8677030 TI - Examining the role of vigabatrin. PMID- 8677031 TI - Treatment with antiepileptic drugs: possible neuroprotective effects. AB - Findings from studies involving both rat models of epilepsy and humans with temporal lobe epilepsy suggest that epileptic seizures may induce hippocampal neuronal damage. This damage appears to be progressive over time and has been shown to be associated with memory impairment. Vigabatrin has been shown to protect against hippocampal neuronal cell death in experimental models of epilepsy. Because of the protection it provides against neuronal loss and functional impairment, vigabatrin may be a useful component of antiepileptic polytherapy. PMID- 8677032 TI - Newer antiepileptic drugs as monotherapy: data on vigabatrin. AB - Studies examining the use of vigabatrin as monotherapy for the treatment of epilepsy are relatively scarce, and of the few that have been reported, only two were of sufficient size to provide definitive data. In both trials, vigabatrin was compared with carbamazepine for efficacy and safety. In one of these studies, carbamasepine was found to be more effective than vigabatrin in reducing seizure frequency, and the two were found to be comparably efficacious in the other study. What differed significantly, however, was vigabatrin's favorable safety profile. Vigabatrin appears to be a reasonable choice for single-drug therapy in the treatment of certain types of seizures. In other patients, it remains useful as an adjunct to other antiepileptic drugs. PMID- 8677033 TI - Cognitive effects of vigabatrin: a review. AB - Studies were reviewed in which patients who received vigabatrin underwent cognitive testing. The overall results were categorized into five areas of cognitive function: reception, attention, intellectual function, memory, and psychomotor function. Overall, the studies showed either no detrimental effects or, in some cases, slightly improved function. It is speculated that a relationship exists between GABA and the results of these studies because vigabatrin enhances the GABAergic mechanism in the CNS. PMID- 8677035 TI - [Long term central venous catheterization revisited]. AB - The authors describe their experience about long-term VAD (Venous Access Devices) placement and in particular of placement techniques types of catheters, complications, and risk and benefit. 243 placements of VAD in 112 males and 131 females mainly affected by leukemia or breast cancer have been analyzed. 145 Leonard, 54 Groshong and 44 Hickman type silicon catheters have been implanted. The preferred access vein was the right internal jugular vein in 75% of patients and the right subclavian vein in the remained. The results show implant success in 98.7% of the patients. Complications have been rare and not serious and they have been divided into: 1) complications due to venipuncture, 2) complications during implant, 3) complications during the staying of catheter, 4) complications during the removal. The authors underline the advantages of puncture access through the right internal jugular vein in comparison with access through the right subclavian vein. Groshong type catheter is better than Leonard and Hickman. Very few infections have been noticed and patients seem to accept more willingly percutaneous placement than surgical one. PMID- 8677034 TI - Haemodynamic and haemoximetric aspects of experimental orthotopic liver transplantation: comparison between two different doses of propofol. AB - OBJECTIVE: Evaluation of haemodynamic and gas exchange modifications using propofolnitrous oxide anaesthesia after ketamine induction during experimental orthotopic liver transplantation (OLT). DESIGN: Measurements of haemodynamic and haemoximetric effects of two anaesthesiological conditions, differing each other for the different dose of propofol, performed in an experimental model characterized by temporary anhepatism followed by revascularization. SETTING: Surgical experimental laboratory of the University Hospital of Florence. ANIMALS: Thirty experimental OLT on female pigs (weight 30 +/- 2 kg) were performed. MEASUREMENTS AND MAIN RESULTS: The following haemodynamic: HR, MAP, MPAP, PCWP, CI, SI, RVSWI, LVSWI, SVR, PVR, RPP and gas-exchange parameters: PaCO2, etCO2, D(aA)CO2, PaO2/PAO2, VD/VTphys, HB, PaO2, SaO2, DO2, O2ER, VO2, SvO2, VO2/DO2 relationship were evaluated. Anaesthesia was induced by ketamine and maintained by N2O and propofol infusion using 0.28 mg x kg(-1)x min(-1) (Group 1) and 0.19mg x kg(-1) x min(-1) (Group 2). During the anhepatic phase we used cavalportal jugular by-pass (CPJ). Haemodynamic preoperative data confirmed the absence of any myocardial depressant effect at the lower dose of propofol. During the most critical stages of surgery a progressive decrease of CI associated with low values of PCWP was observed. The decrease of etCO2 during the anhepatic phase is due to the VD/VT increase following CI reduction and CO2 production decrease. VO2 decreased significantly during the anhepatic phase and successively increased during the reperfusion phase whereas CI remained low, during both surgical phases. These results demonstrated that VO2 was largely independent from DO2 because cellular O2ER gradually increased as DO2 remained constantly low, thus indicating a good cellular metabolism reuptake. The decrease of SVO2 is related to the decrease of CI and to the increase of VO2 and O2ER. CONCLUSION: The VO2/DO2 relationship showed a complete O2 supply-non-dependency suggesting an adequate cellular metabolism maintenance during the anhepatic and postanhepatic phases. According to these results, the authors suggest that propofol, within the two different anaesthesiological protocols at two different doses, surely favoured a good cellular perfusion also under low cardiac output conditions, undoubtedly contributing to the realization of stress-resistant conditions and influencing a good recovery and postoperative outcome. PMID- 8677036 TI - [High-dose vecuronium in "open-eye" emergency surgery]. AB - BACKGROUND: Succinylcholine is contraindicated in "open eye" surgery because it raises intraocular pressure. High dose vecuronium reduces onset time for orothracheal intubation. The objective of the study was to evaluate clinical efficacy of high dose vecuronium (0.2 and 0.3 mg/kg) and its effects on intraocular pressure for its use in "open eye" emergency surgery. DESIGN: Randomized, prospective, clinical trial. SETTING: Eye clinic of University of Florence. PATIENTS: 40 patients scheduled for vitrectomy, excluding any drug action on IOP, subdivided into two groups: the first (20 patients) had 0.2 mg/kg vecuronium at the induction of anaesthesia, the second (20 patients) 0.3 mg/kg. ANAESTHESIA: Premedication: atropine 0.01 mg/kg. Preinduction: fentanyl 3 micrograms/kg. Induction: thiopentone 4 mg/kg+ after 1 minute) vecuronium. Orotracheal intubation after 90". MEASURES: IOP was obtained by applanation tonometry in three time: T0 = preinduction; T1 = 50" after thiopentone; T2 = 50" after vecuronium. Systodiatolic pressure was obtained at the same time. Neuromuscular function was evaluated by vocals cord relaxation and by clinical evaluation of response to ulnar nerve stimulation (by train of four). STATISTIC: "t"-Student. MAIN RESULTS AND CONCLUSIONS: No modification of IOP and systodiastolic pressure was caused by administration of vecuronium; no statistic differences are between T1 and T2 values. All patients were intubated after 90" vecuronium administration; the vocal cord relaxation was maxima in all the patients. High dose vecuronium seems to be useful in "open eye" emergency surgery when succinylcholine is contraindicated. PMID- 8677037 TI - [Clinico-instrumental assessment of swallowing in head injury rehabilitation]. AB - During the phase of clinical and neurological stability following head injury, the recommencement of oral nutrition indicates not only the recovery of normal physiological function but is also closely correlated to the overall rehabilitation process and therefore represents a complex source of valuable stimuli in the context of a therapeutic and rehabilitation programme of the cognitive functions themselves. Before any attempt of oral feeding it is important to make a full clinical and instrumental evaluation of the swallowing process in order to diagnose any dysphagic problems and to assess the correct feeding method for the patient so as to avoid the severe sequelae caused by the penetration of food into the air paths. PMID- 8677038 TI - [A new instrument for neuromuscular transmission monitoring: the accelerometer Tofguard. Comparative study of isometric force transduction in the assessment of pipecuronium dose-response relationship]. AB - Pipecuronium effective doses 50,90,95 (ED50, ED90, ED95) have been obtained with the cumulative dosage method studying the influences of two different anesthetic techniques (TIVA vs isoflurane), of the patients age, of two different monitoring techniques, force transduction vs accelerometry, both evaluated by T1/TC ratio, ratio between Ist muscular response following the muscle relaxant and the values obtained before its injection, and TOFR, ratio between 4th and Ist response of every train. 33 patients, 55 years average age, 66 kgs average weight, ASA 1&2, scheduled for elective operations were anesthetized with propofol-fentanyl-N2O; tracheas were intubate under topical analgesia; maintenance of anesthesia included propofol and fentanyl or isoflurane 1 MAC. Neuromuscular monitoring included the simultaneous measurement of force of thumb adduction (FT 10 Grass) and its acceleration (Tofguard); neuromuscular blockade was evaluated by T1/TC and TOFR. Pipecuronium was administered in small decreasing boluses until 95% of T1/TC depression. Under force monitoring, ED50, ED90, ED95 values were 19, 28, 33 micrograms/kg respectively with T1/TC, being slightly lower with TOF stimulation (15, 24, 26 micrograms/kg); ED's were not influenced by anesthesia and were inversely related to age. Under accelerometry, EDs were always lower (16,27 e 27 micrograms/kg) under T1/TC, while with tof their values were similar to those derived from force measurements. ED's values obtained with T1/TC, either with force than accelerometry, while accelerometry was more sensitive than force for all ED's. EDs values, both under T1/TC than TOF, either with force transduction than accelerometry, resulted highly correlated each other, indicating a substantial agreement between the two mechanical methods of monitoring. It is concluded that the new instrument Tofguard offers the same reliability than force transduction, with the advantages of being smaller, portable and able to calculate directly the depth of neuromuscular blockade. PMID- 8677039 TI - [A proposed classification of inguinocrural hernias. The classification of hernias in the inguinal and crural regions in the adult as a function of their surgical therapy]. AB - Surgery for the treatment of inguinal and femoral hernias has recent years acquired numerous increasingly modern, innovative techniques. This has been possible thanks modern, innovative techniques. This has been possible thanks to the introduction of prosthetic material which is better tolerated by the tissues and to the utilization of new ways of approach. A new method of hernia classification, no longer based on anatomical criteria but on a broader evaluation which takes multiple aspects into account, is now needed to decide on valid criteria for choice of operation, at the same time expressing themselves in a common language which will allow the results to the verified. PMID- 8677040 TI - [CT-guided FNA in the diagnosis of lung opacities. Our experience]. AB - Between January 1989 and December 1994 we accomplished 130 CT-guided transthoracic fine needle aspirations (FNA) in 120 patients. Ten patients underwent a second FNA because of the negativity and doubts of the first. Diagnosis was targeted in 114 (95%) patients and 89% showed cytological evidence of malignancy. FNA-CT guided is reliable in the diagnosis of lung cancer, but less accurate in excluding diagnosis of malignancy. In our experience FNA had an accuracy with regard to lung cancer, of 92%. Sensitivity and specificity were respectively 93.8% and 100%. There were 6 false negative and 9 very negative. All patients should have bronchoscopy rather than FNA as the initial diagnostic procedure and perform it only in the absence of endobronchial lesions and malignant cells obtained with cytologic sputum or fiber bronchoscopy. In our experience 91 patients have lung cancer and thoracotomy was performed in 21% with confirm of diagnosis. FNA offers several advantages over other diagnostic procedures used in the evaluation of patients with intra-thoracic nodules and masses. The uses of small needles (20-22 gauge) and CT-guide has practically eliminated the risk of major haemorrhage. Deep and superficial lesions of the lung may be approached safely with FNA-CT guided and complications are no fatalities. Pneumothorax occurred in our experience in 5 cases and no occurred a chest drainage. PMID- 8677041 TI - [Stomach cancer in the elderly patient]. AB - Gastric cancer is a typical disease of old age, in fact about one half of the patients affect by it are aged over 65. Elderly patients imply a problematical choice of surgical treatment due to the general and specific risk and to life expectancy. In order to evaluate the specific features of gastric cancer in aged people and to share their experience in choosing the surgical treatment, a series of 50 patients with gastric cancer selected on the age > or = 75 years and observed from 1970 to 1993, was reviewed by the authors. Some features have been settled such as sex ratio approaching the unity, a prevalence of tumors located in the distal third of the stomach, the higher incidence of intestinal type and a wide incidence of intestinal type and a wide incidence of patients in III or IV stage. No surgical procedure was undertaken in eleven patients. The remaining 39 patients (78%) underwent a surgical procedure. In 22 patients (56.4) a resection was performed: 17 (77.3%) underwent a subtotal gastric resection, 11 curative and 6 palliative, and 5 (22.7%) a total gastrectomy out of necessity for tumor localization. In 17 patients (43.6%) a bypass procedure was carried out, while in 7 (17.9%) the surgical procedure was a simple laparatomy. Postoperative morbidity incidence was 17.9%, mortality rate 10.2%. Actuarial 5 years survival rate for curative resection was 41.5%. Median survival time was 13 months for patients who underwent a palliative resection and 6 months after bypass procedures. The data suggest that subtotal gastrectomy, also as palliative procedure, fits better to geriatric patients' requirements and is able to offer a satisfactory quality of life, to prevent cancer complications and to determine a longer survival. PMID- 8677042 TI - [The choice of the intervention in the surgical treatment of nontoxic diffuse multinodular goiter]. AB - The choice between sub-total (STT) and total (TT) thyroidectomy in surgical management of multinodular goitre should be based on the disease pathophysiology and the critical review of short and long-term results of these treatments. In order to make a comparative evaluation the authors carried out a retrospective analysis on a series of patients operated from 1970 to 1993 and on the results of a 16.3 years mean follow-up. Of 551 patients operated on the thyroid gland, 389 (70.6%) affected by multinodular goitre were considered. 340 were female and 49 male (39 years medium age). 341 (87.6%) underwent STT and 48 (12.4%) TT. Post operative opotherapy was adjusted according to hormonal assays. Post-operative vocal cord motility and calcemia were assessed. A routine endocrinological follow up protocol has been carried out on all patients since 1980. Transitory vocal cord palsy and hypocalcemia were significantly more frequent in TT, while permanent damage was not. Of 40 TT (complete 5 years mean follow-up, 97.5% of the patients reached euthyroidism with replacement therapy. Of 189 STT (complete 16.3 years mean follow-up), 61.4% of the patients received opotherapy. A recurrent goitre was ascertained in 39.1% of the total (73.3% in the patients not receiving opotherapy) and operated in 16.2% of the cases. According to the authors their results support the choice of TT as it matches the rationale of surgical treatment of multinodular non-toxic goitre based on the pathophysiology of the disease. Moreover it allows easy achievement of euthyroidism avoiding goitre relapse and subsequently re-operation, with an incidence of permanent recurrent nerve palsy and hypoparathyroidism not significantly different from that after STT. PMID- 8677043 TI - [Bilateral breast carcinoma. 12 years' experience]. AB - In order to assess bilateral breast carcinoma (BBC) clinical findings, 19 BBC cases were enrolled in succession (1982-1993). Of these, 7 (1.6%) had synchronous breast carcinomas and 12 (2.7%) had metachronous breast carcinomas. The occurrence of BBC was of 4.3% of women with breast cancer. The median age of the patients was 63.7 years for synchronous cancers and 53.5% for metachronous. Synchronous carcinomas were found symmetrically located in 42.5% of cases and metachronous in 58.3%. The most frequent location was in the upper outer quadrant (UOQ): 50% in synchronous and 37.5% in metachronous. T1 was detected in 71 and 66% of cases in the second tumor, synchronous and metachronous respectively, and in 28 and 25% of cases in the first tumor, always synchronous and metachronous. The 71.4% of synchronous carcinomas and the 83.3% of metachronous carcinomas were represented by invasive ductal carcinoma (IDC). Between the first and the second metachronous carcinoma the free time interval ranged from 11 to 144 months (mean, 67 months). All the patients were treated by surgery and adjuvant therapy (RT, CT, HT) according to stage, to menopausal status and to receptor status. In synchronous carcinomas only 1 recurrence was recorded, while in metachronous carcinomas the recurrences were 5. The 5-year actuarial survival was of 100% in synchronous carcinomas and of 33% in metachronous carcinomas independently of stage, while the 5-year actuarial survival after the metachronous tumor was of 50%, if the free time interval was less than 3 years, and of 75%, if more. PMID- 8677044 TI - [Our experience of 350 endoscopic polypectomies of the colon]. AB - The authors report their experience of the endoscopic removal of 350 polyps of the colon. Vegetating lesions of doubtful endoscopic appearance and nature were excluded from this study. Indications regarding intestinal cleaning and the most appropriate pharmacological preparation are given on the basis of personal experience. No patient had to be hospitalised and the colon was fully explored in all cases; the cecum was reached in 85% of cases. The maximum limit of endoscopic removal was 5 cm due to the greater risk of complications and presence of cancer on polyps. A total of up to 8 polyps were removed in a single session in cases of multiple polyposis. From 1986 to 1992 350 polypectomies were performed in 177 patients, of which 301 were adenoma (85.9%) and 49 mixed (14.1%). Adenomas were 80.5% tubular, 13.6% tubulo-villous and 4.3% villous. Cancer was found on polyps in 5 cases (1.6%). 146 polyps were found in the rectum (41.8%), 84 in the sigma (24%), 76 in the descending (21.7%), 21 in the transverse (6%), and 23 in the right colon (6.5%). Patients were aged between 3 and 81 years, and the most frequently affected age bracket was between 40-70 years. Follow-up consisted in checks at 6, 12 and 24 months in cases of adenoma and quarterly checks during the first year in the event of carcinoma in situ. The decision to use a diathermic loop or hot biopsy was made in relation to lesion size, reserving the former for polyps with diameters of over 8 mm. All polyps under 5 cm were removed and subjected to histological tests. No cases of early or late complications were reported in the 350 polypectomies performed. The authors indicate the criteria of choice which led to surgical resection of the first instance. In the event of in situ carcinoma, endoscopic removal is considered sufficient provided that it is radical. The following must be evaluated in the case of invasive carcinoma: tumor size, the degree of differentiation, lymphatic or vascular invasion and generic or specific risk factors linked to the individual patient. PMID- 8677045 TI - [Benign schwannoma of the celiac tripod simulating a pancreatic neoplasm]. AB - The authors present a rare case of benign retroperitoneal schwannoma; initially diagnosed as a neoplasm of the pancreas. A comprehensive review of the literature is employed to focus on the main problems involved in the management of this disease: difficulty in formulating a diagnosis, due to the non-specific nature of clinical manifestations; and difficulty in formulating a prognosis, because of the lack of criteria available for distinguishing benign from malignant forms. PMID- 8677046 TI - [The selection of patients who are candidates for lung transplantation]. AB - From January 1991 to September 1993 we evaluated 49 patients (27 males and 22 females--mean age 42 years) with chronic respiratory failure as possible candidates for lung transplantation. 27 patients had idiopathic pulmonary fibrosis, 9 emphysema, 4 bronchiectasis, 3 cystic fibrosis, 3 primary pulmonary hypertension and 1 respectively lymphangiomatosis, thromboembolism and vanishing lung. 16 patients were considered suitable for single or double lung transplantation. 4 patients died waiting, 4 underwent single lung transplantation and 8 are still on the waiting list. The mean survival of patients in the waiting list was 145 days (52 for patients with idiopathic pulmonary fibrosis), ranging between 35 and 398 days. PMID- 8677047 TI - [A carcinoid with cecal localization. Apropos a case]. AB - An observed case of carcinoid tumor of the large-bowel in a 68-year-old woman leads to an analysis of the clinical-diagnostic and therapeutic aspects of this rare gastrointestinal tumour. Carcinoid tumour represents 0.8-1.5% of malignant digestive tumours, in 6% of cases it is localized in large-bowel and in 2-3% in cecal-bowel. In our experience there is no specific symptoms and diagnosis was based on postoperative histopathologic analysis. Right hemicolectomy with lymphadenectomy performed and the operative specimen included a 7 cm diameter tumour, which had narrowed the lumen by 80% and infiltrated ileocecal valve. Carcinoid tumour presents considerable problems of diagnosis because symptoms are aspecific. Diagnosis is possible only in patients with high urinary levels of 5 HIAA, in presence of carcinoid syndrome and by endoscopic biopsy when tumour infiltrated gastrointestinal mucosa. False negative cases are frequent in small carcinoids ( < 2 cm) because the tumour tissues are covered by integral mucosa. C.T., ultrasonography and angiography play a primary role in the diagnosis of this tumour but octreotide scintigraphy is very important for tumour and metastases localization in consequence of its ability to demonstrate somatostatin receptor positive tumours. Radical surgery is the only treatment in very little carcinoids to prevent metastases risk. Determinant risk factors are: primary size, localization, serosal penetration. In patients with any of these risk factors, resection with regional lymphadenectomy is recommended. Other prognostic factors include histologic differentiation, the presence of macroscopic residual disease after initial surgery and level of 5-HIAA in urine. We think that neither adjuvant chemotherapy, or radiotherapy may play a significant role in this neoplasm. Many authors report considerable unsuccessful with this treatment and it is used mainly for palliation. At present, the medical treatment of inoperable gastrointestinal carcinoid consist in association with interferon alpha and octreotide. During this treatment the size of the tumour is stable: reduction of symptoms and 5-HIAA urinary levels are noted. PMID- 8677048 TI - [Angiolipoma of the cecum]. AB - The paper reports a case of angiolipoma localised on the ileocecal valve. No cases of intestinal angiolipoma have been reported in the literature. The authors analyse the anatomopathological diagnostic criteria used, together with the clinical characteristics of a pathology which, even when examined macroscopically, resembles a malignant neoplasia of the colon. The authors conclude by underlining the importance of histological diagnosis for a correct surgical choice. PMID- 8677049 TI - [Choledochal calculosis due to a suture thread]. AB - The authors recently observed a patient suffering from recurrent choledochal, postcholecystectomy calculosis caused by suture thread. Given the relative rarity of this pathology, the difficulty of preoperative diagnosis and the possible confusion with other anatomoclinical syndromes, they take this opportunity to make a number of diagnostic and therapeutic comments in the light of the latest literature on this subject. PMID- 8677050 TI - [Biliary ileus. A report of 2 cases]. AB - The authors starting from two observed cases of gallstone ileus, describe of these, the pathogenesis, the diagnostic difficulty, and they express their opinion with regard to surgical treatment to execute, related to the data reported by the authors and from their own experience. PMID- 8677051 TI - [Giant fibroadenoma of the breast. Its clinical picture and differential diagnosis. A report of a clinical case]. AB - An 18-year-old girl came to our Institute with a large tumefaction at the right breast, that during the last year had risen slowly but continuously. She underwent some clinical and instrumental exams that allow us to diagnose a giant adenofibroma or cystosarcoma phyllodes without excluding either of them. Then she undergoes a subcutaneous mastectomy with an application of a prosthesis. From the histologic point of view it is a giant adenofibroma. Giant adenofibroma is a rare breast pathology, always benign. Nowadays we have some difficulties distinguishing it from cystosarcoma phyllodes, which has both a benign and malignant form. It is important to distinguish the two pathologies before operation as they have a different therapeutic approach and a different follow up. Cystosarcoma phyllodes can in fact relapse and when malignant can cause metastasis. PMID- 8677052 TI - [Urachal cyst. A case report and review of the literature]. AB - The pathology of urachal disease is rarely seen. This article refers to a case of urachal cyst in a twenty-five-year-old male. In order to discuss the pathogenic, clinical and therapeutic aspects of this rare pathology, it is necessary to carry out a complete revision of the literature. Diagnosis is helped by ultrasound and CT scan of the lower abdomen, while fistulography is necessary when there is cutaneous drainage. The treatment consists of surgical approach which includes complete en-bloc excision of the cyst together with possible urachal residue. Such treatment is indispensable in order to avoid acute infection and/or malignant degeneration, frequent complications which are very serious. PMID- 8677053 TI - [Hemorrhoidectomy by a modified Lentini method. The authors' own caseload]. AB - Haemorrhoidectomy by high-frequency electric bistoury was introduced by Prof. Lentini: this technique is based on the capacity of this electric bistoury to make an effective coagulation avoiding ligatures. The authors describe a new technique by the same electric bistoury introducing principles of the French school and discuss the results of their experience. PMID- 8677054 TI - Nutrition recommendations update: dietary fats and children. PMID- 8677055 TI - Report of the Dietary Guidelines Advisory Committee Dietary Guidelines for Americans, 1995. PMID- 8677056 TI - Distress over fetal distress. PMID- 8677057 TI - Fetal transfusion therapy. AB - Rapid advances are occurring in the diagnosis and treatment of the fetus with a red blood cell or platelet cytopenia. Noninvasive methods of monitoring the alloimmunized pregnancy, invasive methods such as amniocentesis and cordocentesis, and intrauterine transfusion therapy of both red cells and platelets, are being further refined to allow the prompt recognition and treatment of fetal cytopenias. Specialized centers have now accrued a large experience in the management of the fetus severely affected by alloimmunization. Advances in ultrasound, blood banking techniques, and genetic engineering technology have spurred the most recent advances. The indications for diagnosis, timing and frequency of invasive procedures for treatment, and technical considerations regarding preparation of blood products and volume of transfusion, are outlined in this review. Polymerase chain reaction (PCR) determination of fetal Rh(D) genotype by chorionic villus sampling or amniocentesis in the first or second trimesters is a recent clinically useful advance. The advent of hematopoietic stem cell transplantation and the potential for gene therapy are exciting advances in the treatment and prevention of hematopoietic diseases, including, but not limited, to the fetal cytopenias. PMID- 8677058 TI - Surgical treatment of vulvar lichen sclerosus: a review. AB - Surgical therapy of lichen sclerosus of the vulva consists of three main operations: vulvectomy (with or without a skin graft), cryosurgery, and laser ablation. It is indicated in two conditions, either when malignant transformation is present or is likely to occur, or when medical treatment has failed. The overall risk for malignant transformation of vulvar lichen sclerosus is low, ranging between 0 and 9 percent. However, specific histological criteria, such as mixed dystrophy, have recently been associated with higher malignancy rates. Vulvectomy is indicated only when these criteria are met. Both skinning and simple vulvectomies are associated with recurrence rates as high as 50 percent. However, better sexual function and cosmetic results have been reported in the former, especially with concomitant split skin grafting. Cryosurgery also has high recurrence rates, although short-term results are favorable. Although only small series have been reported, laser therapy seems to carry better long-term results than other modes of treatment. Convalescence is complete within 6 weeks posttreatment, and remission rates are as high as 85 percent at 3 years of follow up. The high recurrence rate of all surgical modalities makes surgical treatment suitable only for patients who failed to respond to multiple medical treatments such as topical high potent steroid ointments, testosterone, and retinoids. PMID- 8677059 TI - Differential diagnosis and management of very low second trimester maternal serum unconjugated estriol levels, with special emphasis on the diagnosis of X-linked ichthyosis. AB - Incorporation of maternal serum unconjugated estriol into the calculation of risk may increase the yield of serum screening performed during pregnancy for detection of fetal chromosomal and structural anomalies. The differential diagnosis of very low and undetectable levels of unconjugated estriol in maternal serum is discussed, with special emphasis on the prenatal diagnosis of X-linked ichthyosis. The prenatal detection of these findings dictates skilled genetic counseling, targeted sonographic evaluation and examination of fetal karyotype and fetal cDNA for Xp 22.32 with amniotic fluid levels of cortisol, STS, and ASC. PMID- 8677060 TI - The preterm prediction study: fetal fibronectin testing and spontaneous preterm birth. NICHD Maternal Fetal Medicine Units Network. AB - OBJECTIVE: To evaluate the presence of fetal fibronectin in the cervix and vagina as a screening test for spontaneous preterm birth. METHODS: Two thousand nine hundred twenty-nine women at ten centers were routinely screened every 2 weeks from 22-24 to 30 weeks for cervical and vaginal fetal fibronectin. A positive test was defined as a value equal to or greater than 50 ng/mL. The relation between a positive test at four gestational ages and spontaneous preterm birth at various intervals after the test was determined. RESULTS: In each testing period, 3-4% of the fetal fibronectin tests were positive. The correlation between cervical and vaginal fetal fibronectin at the same visit was always approximately 0.7 (P < .001), and that between cervical or vaginal fetal fibronectin in consecutive visits was between 0.17 and 0.25 (P < .001). The sensitivity of fetal fibronectin at 22-24 weeks to predict spontaneous preterm birth at less than 28 weeks was 0.63, and the relative risk for a positive versus negative test was 59. The specificity was always 96-98%, whereas the positive predictive value rose from 13% to 36% as the upper limit of the definition of preterm birth was increased from less than 28 to less than 37 weeks. The relative risk for spontaneous preterm birth after a positive fetal fibronectin test compared with a negative fetal fibronectin test varied substantially by testing period and by the definition of spontaneous preterm birth, but always remained greater than 4 and statistically significant. CONCLUSION: A positive cervical or vaginal fetal fibronectin test at 22-24 weeks predicted more than half of the spontaneous preterm births at less than 28 weeks (sensitivity 0.63). As the definition of spontaneous preterm birth was extended to include later gestational ages or when the fetal fibronectin test was performed later in pregnancy, the level of association between a positive fetal fibronectin test and spontaneous preterm birth, while remaining highly significant, tended to decrease. Although fetal fibronectin is an excellent test for predicting spontaneous preterm birth, we present no evidence that the use of this test will result in a reduction in spontaneous preterm birth. PMID- 8677061 TI - Prediction of spontaneous preterm birth by fetal fibronectin and uterine activity. AB - OBJECTIVE: To evaluate the usefulness of fetal fibronectin and home uterine contraction assessment in predicting preterm birth (before 34 weeks) in at-risk asymptomatic women. METHODS: One hundred fifty women were enrolled prospectively; five were lost to follow-up, leaving 145 women available for analysis. Because patients with preterm labor before 34 weeks' gestation most commonly develop this problem after 28 weeks, the period of 26-28 weeks' gestation was selected prospectively as the first window for prediction and study analysis. Eighty-five of 145 asymptomatic women at high risk for preterm birth had both home uterine contraction assessment of 2 hours per day and one or more cervical sampling(s) for fetal fibronectin measurement at 26-28 weeks. A positive home uterine contraction assessment was defined as contractions exceeding two per hour averaged over the 2-week study interval. Positive fetal fibronectin was defined as greater than 50 ng/mL. RESULTS: Fourteen of the 85 women (16.5%) delivered before 34 weeks. Home uterine contraction assessment alone had a sensitivity, specificity, positive predictive value, and negative predictive value for preterm birth of 64, 85, 45, and 92%, respectively; fetal fibronectin alone was associated with values of 43, 89, 43, and 89%, respectively. A positive home uterine contraction assessment was associated with a relative risk (RR) for preterm birth of 5.9% (95% confidence interval [CI] 2.4-14.2), whereas a positive fetal fibronectin demonstrated an RR of 3.8 (95% CI 1.5-9.4). When both assessments were positive, all patients delivered before 34 weeks and there was an RR of 27.0 (95% CI 8.7-84.1) compared with those with both tests being negative. Only two patients with both tests negative delivered before 34 weeks (negative predictive value 96%). CONCLUSION: Both the home uterine contraction assessment and fetal fibronectin accurately predicted preterm birth before 34 weeks. When both tests were combined, the predictive ability improved substantially. PMID- 8677062 TI - The preterm prediction study: fetal fibronectin, bacterial vaginosis, and peripartum infection. NICHD Maternal Fetal Medicine Units Network. AB - OBJECTIVE: To determine the relation between vaginal and upper genital tract infection and cervical-vaginal fetal fibronectin levels. METHODS: We screened 2899 women at ten centers every 2 weeks from 23-24 to 30 weeks' gestation for cervical and vaginal fetal fibronectin. A positive test was defined as a level of at least 50 ng/mL. The relation between a positive test and bacterial vaginosis at 23-24 weeks and clinical or histologic chorioamnionitis at delivery plus neonatal sepsis was determined. RESULTS: Fetal fibronectin was present in 4.0% of cervical and/or vaginal samples at 23-24 weeks and was nearly twice as common in women with bacterial vaginosis. Adjusting for the presence of bacterial vaginosis, race, and parity, women positive for fetal fibronectin were much more likely to have clinical chorioamnionitis (mean +/- standard deviation gestational age 30.6 +/- 4.1 weeks), with an odds ratio of 16.4 and 95% confidence interval of 7.1-37.8, and neonatal sepsis (6.3 and 2.0-20.0, respectively), than those who were fetal fibronectin-negative. A positive cervical fetal fibronectin test was a better predictor of clinical chorioamnionitis and neonatal sepsis than was a vaginal test or a combination of vaginal and cervical tests. Among 40 women who delivered before 32 weeks and had placental histology available for evaluation, ten had a positive cervical and/or vaginal fetal fibronectin test before delivery; all ten had histologic evidence of chorioamnionitis, compared with only 13 of 30 women (43%) who were fetal fibronectin-negative (P = .02). CONCLUSION: Women with bacterial vaginosis were more likely to have a positive fetal fibronectin test than uninfected women. Women with a positive fetal fibronectin test who delivered before 32 weeks' gestation all had evidence of histologic chorioamnionitis. Women positive for fetal fibronectin also had a 16-fold increase in clinical chorioamnionitis and a sixfold increase in neonatal sepsis. There is strong evidence that upper genital tract infection and cervical and/or vaginal fetal fibronectin are closely linked. PMID- 8677063 TI - Microalbumin as a marker of premature delivery. AB - OBJECTIVE: To determine if microalbumin excretion can predict the development of premature delivery. METHODS: The possibility of predicting, early in pregnancy, the development of a preterm delivery using urinary albumin was investigated in 1422 nulliparous women recruited prospectively. A first morning urine sample was collected at three occasions during pregnancy (8-14, 15-24, 25-34 weeks' gestation) for the determination of urinary albumin excretion. RESULTS: No significant correlation was found between gestational age and urinary albumin (absolute concentration, albumin-creatinine ratio, or relative clearance of albumin) at either visit (r ranging from -0.043 to 0.036; P > .1). The incidence of preterm birth was similar for the first and fourth quartiles of the urinary albumin-creatine ratio for the second visit (5.8 and 5.7%, respectively). CONCLUSION: Urinary albumin is not a useful marker of preterm birth in a low-risk general population. PMID- 8677064 TI - Effect of external peer review on cesarean delivery rates: a statewide program. AB - OBJECTIVE: To assess the effectiveness of a joint-specialty society and health department statewide peer-review program to reduce cesarean rates. METHODS: Forty five of the 165 hospitals with active delivery services were reviewed between 1989 and 1993. Differences in total and repeat cesarean rates and vaginal birth after cesarean (VBAC) rates were compared by hospital review status using Student t tests and linear regression for the years before and after completion of the program. RESULTS: Reviewed hospitals reduced their total cesarean rate by 3% and repeat cesarean rate by 0.7%, and increased their VBAC rate by 14.6% compared with nonreviewed hospitals, for which the respective reduction in rates was 1%, 0.6%, and 12.7%. Statistically, there was no difference between reviewed and nonreviewed hospitals in terms of rate changes. CONCLUSION: This joint-specialty society and health department peer review had no apparent impact on cesarean rates. PMID- 8677065 TI - Births to teenagers: trends and obstetric outcomes. AB - OBJECTIVE: To compare the trends and obstetric outcomes of pregnancy in teenage women with those of adult women. METHODS: We analyzed a 19-year (1975-1993) computerized perinatal data base with data on 69,096 births collected prospectively from a single inner-city tertiary medical center. RESULTS: Of all the births, 1875, (2.7%) were to teenagers 12-15 years old and 17,359 (25.3%) were to teenagers 16-19 years old. Over the study period, the number and proportion of births to teenagers of both age groups declined (P < .001 in both cases). The proportions of teenagers 12-15 and 16-19 years old were highest among blacks (4.1% and 28.1%, respectively), followed by Hispanics (2.4%, 24.7%) and whites (1.6%, 23.1%). More than 95% of teenagers had no private health insurance coverage (staff), significantly higher than the 81.6% of mothers aged 20 years or older (P < .001). More than 8.1% of teenagers 12-15 years old had two or fewer prenatal care visits, significantly higher than 6.8% for teenagers 16-19 years old and 7.1% for adults (P < .001). The average gestational age and birth weight were significantly lower for teenagers 12-15 years old compared with those 16-19 years old and adults. Patients 16-19 years of age had longer gestational age and higher birth weight than the adults. The proportion of primary cesarean deliveries among teenagers 12-15 years old was 11.6%, significantly higher than 9.4% for those 16-19 years old and 10.2% for adults (P < .001). CONCLUSION: On average, females 16-19 years old had better obstetric outcomes than adults, whereas obstetric outcomes for those 12-15 years old were worse than for adults. Therefore, all teenagers should not be grouped together when their obstetric outcomes are compared with those of adults. PMID- 8677066 TI - Racial-ethnic differences in prenatal diagnostic test use and outcomes: preferences, socioeconomics, or patient knowledge? AB - OBJECTIVE: To determine whether use of chorionic villus sampling and amniocentesis varies by racial-ethnic group and, if so, whether this variation is reflected in the prevalence of Down syndrome-affected births to women age 35 and older, the ages at which prenatal diagnosis is offered currently. METHODS: Medical charts of 238 women 35 years of age and older presenting for care at the University of California at San Francisco by 20 gestational weeks in 1993 and 1994 were reviewed to assess prenatal diagnostic test use. The prevalence of Down syndrome-affected births in California during 1983-1991 was obtained from the Birth Defects Monitoring Program. RESULTS: Latinas and African-American women were much less likely to undergo prenatal diagnosis than were whites and Asians. Odds ratio (OR) and 95% confidence intervals (CI), with white women serving as the reference group, were as follows: Asians 1.16 (0.57-2.36), Latinas 0.19 (0.08 0.43), and African-Americans 0.19 (0.04-0.49). Trends persisted, at diminished magnitude, after adjustment for socioeconomic characteristics: OR for Asians 1.77 (0.78-3.98) Latinas 0.28 (0.09-0.83) , and African-Americans 0.33 (0.10-1.10). Non-white women age 35 and older were significantly more likely than white women to give birth to a Down syndrome-affected infant: risk ratios for Asians 1.81 (1.61-2.03), Latinas 3.00 (2.74-3.28), and African-Americans 1.86 (1.63-2.11). CONCLUSION: Racial-ethnic differences exist in prenatal diagnostic test use and associated outcomes in women aged 35 and older. Socioeconomic factors are partially responsible; patient education and preferences may play a role. PMID- 8677067 TI - Randomized trial of antenatal dexamethasone in surfactant-treated infants delivered before 30 weeks' gestation. AB - OBJECTIVE: To determine if an additive effect exists between antenatal corticosteroid administration and postnatal surfactant therapy in the prevention of respiratory distress syndrome (RDS) in preterm infants. METHODS: A randomized, double-blind trial was conducted from April 1990 to June 1994, in which dexamethasone (5 mg every 12 hours for a total of four doses) or saline was given to women at risk for delivery at 24-29 weeks' gestation. At birth, prophylactic surfactant was administered to all study infants. Main outcome measures were RDS occurrence and severity. Secondary clinical end points included bronchopulmonary dysplasia, pneumothorax, patent ductus arteriosus, necrotizing enterocolitis, retinopathy, intraventricular hemorrhage, and death. RESULTS: Seventy-five of the 124 randomized subjects delivered 96 infants within the studied gestational age range (dexamethasone, n = 54; placebo, n = 42). Similar maternal demographics and obstetric complications were noted between study groups. A greater population of infants were delivered from multi-fetal gestations in the dexamethasone cohort (26 of 54 versus 12 of 42 newborns; P = .05). There were no significant differences in the occurrence or severity of RDS between the dexamethasone and placebo infants (none or mild, 67 versus 67%; moderate, 24 versus 26%; severe, 9 versus 7%, respectively), or differences in any of the secondary clinical outcomes. The study size was sufficient to exclude a 50% reduction in RDS incidence as a consequence of dexamethasone exposure. An analysis restricted to singletons (dexamethasone, n = 28; placebo, n = 30) revealed similar overall occurrence of intraventricular hemorrhage (12 of 28 versus ten of 30; P = .63), but significantly fewer grade 3 and 4 intraventricular hemorrhages in dexamethasone-exposed neonates (two of 12 versus six of ten; P = .048). CONCLUSION: Antenatal dexamethasone does not appear to decrease the incidence or severity of RDS in surfactant-treated infants delivered at 24-29 weeks' gestation, but may be associated with reduced severity of intraventricular hemorrhages in surfactant-treated singletons in this gestational age range. PMID- 8677068 TI - Prevention of early-onset group B streptococcal disease: another look at single dose penicillin at birth. AB - OBJECTIVE: To determine the effect of single-dose penicillin given at birth on the rate of early-onset group B streptococcal (GBS) invasive disease in an inner city population. METHODS: Laboratory-based surveillance of GBS disease from 1972 1994 at Parkland Memorial Hospital and Children's Medical Center in Dallas, Texas, was reviewed retrospectively. All infants born at Parkland Memorial Hospital from January 1, 1972 to December 31, 1994, or a total of 259,049 live births, were included. Early-onset (within 3 days) GBS disease rates were compared for each of five observation groups to determine the efficacy of a single dose of aqueous penicillin G 50,000 U for infants weighing 2,000 g or more and 25,000 U for those weighing less than 2,000 g) administered intramuscularly within 1 hour of delivery for prevention of GBS disease. RESULTS: The rates of early-onset GBS disease were compared in five observation groups: A) pre-study, January 1, 1972 to December 3, 1977--no GBS prophylaxis; B) prospective, controlled intervention study, December 4, 1977 to May 31, 1981, including infants who received a single dose of penicillin at birth (group B1) and those who did not (group B2); C) universal penicillin prophylaxis, June 1, 1981 to October 31, 1986; and D) no routine penicillin prophylaxis, November 1, 1986 to December 31, 1994. The incidence of early-onset GBS disease in the penicillin groups (B1, C) was significantly lower than that in the untreated groups (A, B2, D): 0.25 and 0.63 per 1,000 versus 1.59, 1.19, and 1.95 per 1,000, respectively (P < or = .03). The incidence of late-onset GBS disease was unaffected by penicillin prophylaxis, and there was no increase in the incidence of disease caused by penicillin-resistant pathogens or associated mortality in penicillin treated infants; 2.2 and 2.1 per 1,000 versus 1.6 and 3.3 per 1,000 for disease; 1.0 and 0.5 per 1,000 versus 0.4 and 0.3 per 1,000 for deaths. CONCLUSION: Universal administration of single-dose penicillin at birth is a safe and effective intervention for the prevention of early-onset GBS disease. PMID- 8677069 TI - Normal values for amniotic fluid index during uncomplicated twin pregnancy. AB - OBJECTIVE: To establish the gestational age trends of amniotic fluid index (AFI) in uncomplicated twin pregnancies. METHODS: Amniotic fluid index was measured in uncomplicated twin pregnancies seen between 1985 and 1993 and meeting the following criteria: 1) no maternal medical or obstetric complications, 2) normal growth of both twins by serial ultrasound, and 3) normal amniotic fluid volume by ultrasound. Amniotic fluid index was measured by adding the deepest vertical pockets in four quadrants, defined by the umbilicus and linea nigra. The relation between gestational age and AFI was evaluated using linear regression analysis. RESULTS: Two hundred eighty-two sets of twins were considered uncomplicated; 1101 AFI measurements were performed on these pregnancies between 25.5 and 40.5 weeks' gestation. Percentile values for AFI were determined according to gestational age. The regression equation relating the median AFI to gestational age was: AFI = 19.4 - 0.12 x gestational age (P = .03). The R2 value was 0.04. CONCLUSION: Gestational age trends in normative AFI measurements for twin pregnancies have been established. Their use will facilitate a more reproducible, quantitative diagnosis of oligohydramnios in twins, compared with subjective, qualitative approaches to amniotic fluid volume assessment. PMID- 8677070 TI - Maternal cigarette smoking and placenta previa. AB - OBJECTIVE: To identify the relationship between maternal cigarette smoking and ultrasound-confirmed placenta previa. METHODS: A matched case-control design was used. Cases were drawn from the New England Medical Center and Cambridge Hospital from July 1992 through March 1994. Each case was delivered by cesarean after 24 weeks' gestation and had an antenatal ultrasound examination confirming placenta previa. Matched controls were obtained by requesting records on the first three deliveries by the referring provider the same month as the index case. Data on potential risk factors were drawn from the records of the initial prenatal visit, before previa was diagnosed. The data were analyzed with conditional logistic regression. RESULTS: Thirty-two cases of ultrasound-documented placenta previa were identified. A number of potential confounders were associated with previa: age (odds ratio [OR] 1.15, 95% confidence interval [CI] 1.05-1.26), gravidity (OR 1.4, 95% CI 1.1-1.7), parity (OR 1.4, 95% CI 1.1-1.9), prior spontaneous abortion (OR 3.1, 95% CI 1.3-7.4), prior elective abortion (OR 3.0, 95% CI 1.2-7.6), and prior cesarean delivery (OR 3.5, 95% CI 1.3-9.9). The crude OR for current smoking was 3.0 (95% CI 1.1-8.6). The OR for smoking ranged from 2.6-4.4, despite controlling for confounders. CONCLUSION: Current cigarette smoking is associated with a 2.6-4.4-fold increased risk of placenta previa. PMID- 8677071 TI - The effect of capitated and fee-for-service remuneration on physician decision making in gynecology. AB - OBJECTIVE: To evaluate the variations in physician behavior leading to performance of gynecologic surgical procedures related to fee-for-service and capitation reimbursement systems. METHODS: This study compared the physician practice utilization of surgical services for fee-for-service and capitated contract reimbursement systems within a gynecology clinic. Attending gynecologists were reimbursed on a fee-for-service basis for all surgical services performed during a 6-month interval; subsequently, the same physicians were reimbursed on a capitated basis for 6 months and received a fixed payment for the clinical and surgical services provided. RESULTS: Three thousand seven hundred eighty consecutive outpatient gynecology visits were evaluated at the university gynecology clinic during 1994. We found a 15% overall decrease in the number of surgical procedures that were performed during the capitated reimbursement period compared with the fee-for-service time interval. The procedure most responsible for the reduction of surgical services was elective sterilization by laparoscopy, which underwent a statistically significant decrease (P < .01). CONCLUSION: The remuneration system in our review seemed to affect physician decision making for only the most elective procedures, whereas physicians maintained similar practice patterns for more severe conditions. Fee for-service seems to encourage, whereas capitation seems to discourage, gynecologist from performing elective procedures. PMID- 8677072 TI - The effect of vesical volume on Valsalva leak-point pressures in women with genuine stress urinary incontinence. AB - OBJECTIVE: To determine the effect of increasing vesical volume on the Valsalva leak-point pressure, examine the relationship between leakage at a given volume and clinical incontinence severity, and evaluate the relationships between leakage at a given volume and other measures of urethral resistance. METHODS: One hundred twenty women with genuine stress urinary incontinence (GSI) underwent serial Valsalva leak-point pressure determinations at vesical volumes of 100, 200, and 300 mL, and at maximum cystometric capacity. Urinary diary data, quantitative pad testing, and passive and dynamic urethral profilometry were also performed. RESULTS: Thirty-three women had leakage starting at a vesical volume of 100 mL, 18 at 200 mL, and 19 at 300 mL, and 17 had leakage only at maximum cystometric capacity. The mean first positive Valsalva leak-point pressures were significantly higher than Valsalva leak-point pressures at maximum capacity in all groups: in women who began to leak at 100 mL, 57 versus 36 cm H2O (P < .001); at 200 mL, 59 versus 45 cm H2O (P < .001); and at 300mL, 61 versus 47 cm H2O (P = .01). Women who had leakage at lower vesical volumes had worse measures of clinical incontinence severity and lower maximum urethral closure pressure less than or equal to 20 cm H2O) and pure intrinsic sphincteric deficiency (low urethral pressure and the lack of urethral hypermobility), but the specificities were 63 and 50%, respectively. CONCLUSIONS: Women with GSI are more likely to leak during Valsalva with increasing vesical volume. Valsalva leak-point pressures decrease significantly with bladder filling. The volume at which leakage occurs correlates inversely with clinical severity and directly with maximum urethral closure pressure. A negative Valsalva leak-point pressure at 300 mL excludes the presence of low urethral pressure and pure intrinsic sphincteric deficiency; however, the specificity and positive predictive value are inadequate for making a clinical diagnosis of either condition. PMID- 8677073 TI - Urinary incontinence in older women: who is at risk? Study of Osteoporotic Fractures Research Group. AB - OBJECTIVE: To estimate the prevalence of and identify factors associated with urinary incontinence in older women. METHODS: A cross-sectional study involved 7949 community-dwelling women, with a mean (+/- standard deviation) age of 76.9 +/- 5.0 years, recruited from population-based listings to participate in the Study of Osteoporotic Fractures. The prevalence and severity of urinary incontinence during the previous 12 months were assessed by questionnaire. Factors potentially associated with urinary incontinence were assessed by questionnaire, interview, and physical examination. Multivariate logistic regression analysis was used to determine the independent associations between these factors and the primary outcome of daily incontinence. RESULTS: Forty-one percent (3285) of the women reported urinary incontinence, with 14% (1130) reporting daily incontinence. In multivariate analysis, the prevalence of daily urinary incontinence increased significantly with age (odds ratio [OR] 1.3 per 5 years, 95% confidence interval [CI] 1.2-1.5), prior hysterectomy (OR 1.4, 95% CI 1.1-1.6), higher body mass index (OR 1.6 per 5 units, 95% CI 1.4-1.7), history of stroke (OR 1.9, 95% CI 1.3-2.7), diabetes (OR 1.7, 95% CI 1.2-2.4), chronic obstructive pulmonary disease (OR 1.7, 95% CI 1.1-1.9), and poor overall health (OR 1.6, 95% CI 1.3-2.1). Faster gait speed (OR 0.8 per 0.2 units, 95% CI 0.6 1.0) was associated with decreased incontinence. CONCLUSION: Urinary incontinence is a common problem in older women, more common than most chronic medical conditions. Of the associated factors that are preventable or modifiable, obesity and hysterectomy may have the greatest impact on the prevalence of daily incontinence. PMID- 8677074 TI - Relationship between sonographic endometrial thickness and progestin-induced withdrawal bleeding. AB - OBJECTIVE: To determine whether the response to the progestin challenge test can be predicted from the endometrial thickness measured sonographically. METHODS: Progestin challenge tests were performed on 44 women with secondary amenorrhea, each of whom also had her endometrial thickness measured by transvaginal ultrasonography and her serum estradiol (E2) levels determined. The relationships between the response to the challenge test, endometrial thickness, and serum E2 levels were studied, as well as whether the presence or absence of withdrawal bleeding could be predicted from the endometrial thickness and serum E2 levels. RESULTS: The endometrium was significantly thicker in 32 women who had withdrawal bleeding (10.3 +/-4.1 mm) than in the 12 who did not bleed (5.0 +/- 1.3 mm) (P < .001). The serum E2 level was also significantly higher in the positive group: 45.3 +/- 19.4 versus 18.6 +/- 8.0 pg/mL (P < .001). Endometrial thickness of 6.0 mm or more predicted the occurrence of withdrawal bleeding with an accuracy of 95.5%. Endometrial thickness was superior to the serum E2 level in predicting withdrawal bleeding. CONCLUSION: Progestin-induced withdrawal bleeding can be predicted from the endometrial thickness measured sonographically. PMID- 8677075 TI - Cervical dilation from multiple laminaria tents used for abortion. AB - OBJECTIVE: To quantify the cervical dilation achieved from multiple medium-thick laminaria tents used for 16-26 hours in single applications before abortion. METHODS: In a practice setting, cervical dilation was studied from all abortions done at greater than 8 weeks in which one or more medium-thick laminaria tents were used in a single application for 16-26 hours. Multiple regression analysis was used to quantify results. RESULTS: There was a positive linear regression of dilation against weeks of gestation for all numbers of tents. The more tents, the greater the dilation; the more weeks, the greater the dilation. CONCLUSION: Approximate cervical circumferential dilation from medium-thick laminaria tents under the constraints listed is provided by the formula: Pratt dilation = 12.36 + (2.35 x tents) + (1.79 x weeks). PMID- 8677076 TI - Laboratory evaluation of acute upper genital tract infection. AB - OBJECTIVE: To evaluate the diagnostic test characteristics of common tests used to diagnose upper genital tract infection. METHODS: Subjects included women who either met the Centers for Disease Control and Prevention's minimal criteria for acute pelvic inflammatory disease or who had other signs of upper genital tract infection (i.e., atypical pelvic pain, abnormal uterine bleeding, or cervicitis). The subjects were evaluated with a baseline interview, comprehensive laboratory testing, and either an endometrial biopsy or laparoscopy for definitive diagnosis of upper genital tract infection. Patients were considered positive for upper genital tract infection if they had any of the following findings: 1) histologic evidence of acute endometriosis or salpingitis, 2) laparoscopic visualization of purulent exudate in the pelvis without another source, or 3) positive testing for Neisseria gonorrhoeae or Chlamydia trachomatis from the endometrium, fallopian tubes, or pelvis. RESULTS: One hundred twenty women with adequate endometrial samples were evaluated between August 1993 and September 1995. The median age of the study population was 24 years: 38% were white, 52% were smokers, 81% were insured by Medicaid or were uninsured, and 67% were single. Sensitivities for elevated white blood cell count (WBC), erythrocyte sedimentation rate, C-reactive protein, and increased vaginal white blood cells are 57, 70, 71, and 78%, respectively. If any one test is abnormal, the sensitivity is 100% and specificity is 18%. If all four tests are abnormal, sensitivity is 29% and specificity is 95%. CONCLUSION: Testing for increased vaginal white blood cells was found to be the most sensitive laboratory indicator for upper genital tract infection, whereas serum WBC was the most specific. No one diagnostic laboratory test is pathognomonic for upper genital tract infection. Combinations of positive tests can improve diagnostic specificity and positive predictive value, but with a diminution of sensitivity and negative predictive value. Combinations of negative tests can reliably exclude upper genital tract infection. PMID- 8677077 TI - Laparotomy to complete staging of presumed early ovarian cancer. AB - OBJECTIVE: To assess the findings and complications of laparotomies for completely staging presumed early-stage ovarian cancer in patients who initial surgery was inadequate. METHODS: Records of 45 patients surgically restaged at our institution, after having been incompletely staged elsewhere, were reviewed for original operative reports, pathologic diagnoses, restaging procedures, operative results, and perioperative complications. RESULTS: Initial clinical staging was IA, 28; IB, three; IC, 12; IIA, one; IIB, one. Histologic distribution was as follows: invasive epithelial, 19 (42%); borderline epithelial, 16 (36%); germ cell tumor, seven (16%) had their disease reclassified to a more advanced stage. Of patients with borderline ovarian tumors, two, initially staged as IA, were restaged to IB and IC, and one was restaged from IIB to IIIA. Three patients with invasive epithelial adenocarcinoma were reclassified to a higher stage: one, with a presumed stage IC, poorly differentiated adenocarcinoma, to IIIB; one, with a stage IC, grade 2 mucinous cystadenocarcinoma, to IIIA; and a third, with a IIA, poorly differentiated adenocarcinoma, to IIIC. A patient with granulosa cell tumor, initially stages as IC, was restaged to IIB. Fifteen patients (33%) had complications after restaging surgery. Seven (16%) patients undergoing restaging laparotomy for presumed early ovarian cancer were reclassified to a higher stage, resulting in alteration of treatment for only on patient. In 18 patients with invasive cancer, the second operation confirmed the presence of low-risk stage IA/B disease, allowing adjuvant chemotherapy to be withheld. CONCLUSION: Although restaging laparotomies provide important prognostic information with minimal morbidity, they provide little benefit to those patients already requiring chemotherapy based on the original operative findings. PMID- 8677078 TI - Parametrial involvement, regardless of nodal status: a poor prognostic factor for cervical cancer. AB - OBJECTIVE: To evaluate the effect of resection of central disease when the parametria are involved by tumor in high-risk stage I cervical cancer patients. METHODS: Thirty-two patients with high-risk stage I cervical cancer who underwent radical hysterectomy and had pathologic findings of positive lymph nodes (N = 13), positive parametria (N = 7), or both (N = 12) were identified retrospectively. The effects of various histopathologic findings on disease-free interval and survival were evaluated, including the effect of resection of central disease with and without positive nodal disease. Kaplan-Meier survival curves were compared with the log-rang test. Multivariate analyses using a stepwise regression model were performed. RESULTS: Compared with other histologies, adenocarcinoma was associated with a significantly shorter disease free interval (P = .037). Among patients with parametrial involvement lymph node status did not affect disease-free interval or survival. However, when patients with positive lymph nodes were examined, the additional finding of parametrial positivity significantly worsened both disease-free interval (P = .039) and survival (P = .036). When the 19 patients with positive parametria, regardless of lymph node status, were compared with those with positive lymph nodes alone, the former group had a significantly shorter disease-free interval (P = .038). The tumor recurred in 12 of these 19 patients; all cases involved the pelvis, with a median time to recurrence of 15 months. Multivariate analysis showed that adenocarcinoma histology (P = .038) and parametrial involvement (P = .043) were independent, poor prognostic indicators for disease-free interval. CONCLUSION: Involvement of the parametria, regardless of lymph node status, and adenocarcinoma histology confer a poor prognosis in high-risk patients undergoing radical hysterectomy. Caution should be used when contemplating resection of bulky tumors as part of primary therapy if the parametria appear to be involved by tumor. PMID- 8677079 TI - Ifosfamide treatment of recurrent or metastatic endometrial stromal sarcomas previously unexposed to chemotherapy: a study of the Gynecologic Oncology Group. AB - OBJECTIVE: To determine the effectiveness and toxicity of ifosfamide chemotherapy in women with metastatic or recurrent endometrial stromal sarcomas unexposed to other chemotherapy. METHODS: In a prospective, multi-institutional phase II study conducted by the Gynecology Oncology Group, the starting dose of ifosfamide was 1.5 g/m2 given daily intravenously (i.v.) for 5 days (reduced to 1.2 g/m2 daily in patients who had previously received radiotherapy). Mesna (2 mercaptoethane sodium sulfonate) was given i.v. immediately and at 4 and 8 hours after the administration of ifosfamide. Each dose of mesna was 20% of the total daily dose of ifosfamide. Patients were treated every 3 weeks if blood counts permitted. Therapy was discontinued if there was progression of the cancer or unacceptable toxicity. RESULTS: Twenty-two patients were entered into this study. One was excluded from analysis because of the wrong histologic type, leaving 21 evaluable for response and toxicity. Gynecologic Oncology Group grade 3 or 4 granulocytopenia occurred in four patients (19%), and one patient each experienced Gynecologic Oncology Group grade 4 anemia and genitourinary toxicity. Three patients experienced complete tumor responses and four had partial responses, for an overall response rate of 33.3%. CONCLUSION: Ifosfamide is active in the therapy of women with chemotherapy-naive metastatic or recurrent endometrial stromal sarcomas. PMID- 8677080 TI - Tumor angiogenesis as a predictor of recurrence in stage Ib squamous cell carcinoma of the cervix. AB - OBJECTIVE: To explore the possibility of using histologic microvessel count of sections from the tumor to predict recurrence of stage Ib squamous cell carcinoma of the cervix. METHODS: Tumor sections from 22 patients (11 patients free of disease after 3 years and 11 patients with recurrence) were stained histoimmunochemically for factor VIII-related antigens. Vessel counting in the most active area of angiogenesis was performed by two pathologists on a x 200 microscopic field (0.739 mm2) without knowledge of the patient's' outcome. To predict recurrence, vessel count was compared with age, tumor size, tumor grade, lymph-vascular invasion, duration of follow-up, and type of therapy. RESULTS: Only high microvessel count (mean 19.9, range 7-43, versus mean 30.1, range 17 78; P < .05) and tumor size (mean 2.84 cm, range 1-4.2, versus mean 4.11 cm, range 2.2-6; P < .05) were independent factors predicting recurrence. CONCLUSION: High microvessel count in tumors may be used to predict recurrence in stage Ib squamous cell carcinoma of the cervix. PMID- 8677081 TI - Analysis of the retinoblastoma gene in human endometrial carcinoma. AB - OBJECTIVE: To examine the Rb gene that controls the cell cycle in human endometrial carcinoma. METHODS: Six endometrial carcinoma cell lines (Ishikawa, Hec1-A, Hec1-B, KLE, RL95-2, and AN3 CA) and 48 human endometrial carcinoma tissues were studied by Southern blotting, Northern blotting, polymerase chain reaction (PCR), and DNA sequencing. RESULTS: Southern blotting analysis did not reveal any abnormalities at the DNA level in the endometrial carcinoma cell lines. Size and quantity of Rb transcripts also appeared normal in these cell lines, as evidenced by Northern blotting and reverse transcription-PCR. Sequence analysis of Rb cDNA revealed that the Ishikawa cell line had an abnormality. In human endometrial carcinoma, 20 of 48 cases (42%) were informative and only two cases of 20 (10%) showed loss of heterozygosity at the Rb locus. CONCLUSION: An Rb gene abnormality was found in some human endometrial carcinomas. Therefore, our results suggest that Rb gene abnormalities may be involved in some human endometrial carcinogenesis. PMID- 8677082 TI - Determinants of gestational weight gain outside the recommended ranges among black and white women. AB - OBJECTIVES: To identify factors influencing risk of gaining outside the Institute of Medicine recommendations for pregnancy weight gain, and to determine whether these factors differ by race. METHODS: Multivariate methods were used to identify risk factors for under- and over-gain among 2617 black and 1253 white women delivering at the Johns Hopkins Hospital during 1987-1989. RESULTS: Only 28.2% of black women and 32.5% of white women gained the recommended amounts of weight during pregnancy. Maternal pre-pregnancy body mass index (BMI), height, parity, education, smoking, hypertension, duration of pregnancy, and fetal sex influenced risk for under-gain or over-gain. Black women were 1.51 (95% confidence interval [CI] 1.23-1.85) times more likely to under-gain, but 0.89 (95% CI 0.74-1.08) times less likely to over-gain than white women. No interactions were found between any factor examined and BMI or race. CONCLUSION: Only about one-third of women are gaining the recommended amounts of weight during pregnancy. Black women are at increased risk for gaining less weight than recommended, and selected maternal characteristics associated with race do not explain this difference. Further, risk factors for under-or over-gain do not differ between black and white women. PMID- 8677083 TI - A randomized controlled trial of membrane stripping at term to promote labor. AB - OBJECTIVE: To determine the effectiveness of membrane stripping at term to promote the onset of labor. METHODS: One hundred twenty gravidas at 38 weeks' gestation, who were attending an antenatal clinic and planned to deliver at Maharaj Nakorn Chiang Mai University Hospital in northern Thailand, were assigned randomly to one of two groups. One group had weekly pelvic examinations only, and the other also had membrane stripping, beginning at 38 weeks' gestation and continuing until the onset of labor or until 42 completed weeks' gestation. Outcome measures included the proportion of patients who delivered with 7 days after the first examination, Bishop scores among those who did not deliver, days from the first examination to delivery, incidence of postterm pregnancy, and maternal and fetal complication. RESULTS: Twenty-five of 61 patients (41%) assigned to membrane stripping delivered within 1 week, compared with 12 of 59 controls (20.3%), a statistically significant difference (P = .014). There was also a statistically significant difference (P = .013, Mann-Whitney U test) in the Bishop scores among those who did not deliver within 1 week (4 +/- 2.5 versus 2.6 +/- 1.7 in the study and control groups, respectively). A significant difference was also observed with respect to the mean number of days to delivery (8.8 +/- 6.7 versus 13.6 +/- 7.5, respectively; P < .001). The incidence of postterm pregnancy was one of 61 (1.6%) and three of 59 (5.1%) in the stripping and control groups, respectively. No significant differences were observed in maternal and fetal complications. CONCLUSION: Membrane stripping is safe and effective in promoting the onset of labor at term. PMID- 8677084 TI - The epidemiology of placental features: associations with gestational age and neonatal outcome. AB - OBJECTIVE: To investigate the epidemiologic and pathogenetic significance of placental features and neonatal outcome in a high-risk population. METHODS: One pathologist examined 1252 placentas from clinically selected at-risk singleton pregnancies. Placental pathology features were analyzed relative to gestational age and status of the newborn, including fetal growth restriction (FGR), low 1 minute Apgar score, infection, liver disorder, anomalies, and death in the immediate postnatal period. RESULTS: The most frequent placental pathologic features were ischemic change, meconium staining, and chorioamnionitis. Only 8% of placentas were considered normal. The number of features per placenta increased with gestational age. Among preterm infants, chorioamnionitis occurred most frequently with low 1-minute Apgar score (40%), clinically apparent infection (43%), liver disorder (43%), and anomalies (42%), compared with healthy newborns (15%). Chorioamnionitis at term was most frequent among infants with low 1-minute Apgar score (26%), infection (30%), and liver disorder (23%), compared with healthy newborns (16%). Meconium and ischemic changes were most frequent in placentas from healthy newborns, compared with affected newborns, regardless of gestational age. Multivariable analyses revealed an independent association between chorioamnionitis and low 1-minute Apgar score (P < .05), and both chorioamnionitis and villitis were associated with newborn infection (P < .05). CONCLUSION: The frequency of many major pathologic placental features, especially ischemic changes and meconium, in the absence of immediately detectable abnormality is relatively high. Thus, continued follow-up is needed to determine their long-term clinical significance. In addition, associations of ischemic changes and infarction with FGR in term infants suggest that need for comprehensive investigations of the effects of histopathologically apparent low placental blood flow. PMID- 8677085 TI - Bacteremia shortly after placental separation during cesarean delivery. AB - OBJECTIVE: To assess frequency, risk factors, and microbiology of bacteremia within 15 minutes of placental separation during cesarean delivery. METHODS: Ninety-three women undergoing cesarean delivery after a minimum of 4 hours of labor or ruptured membranes were compared with 26 women not in labor undergoing cesarean. Blood cultures for aerobic and anaerobic bacteria were obtained within 15 minutes of delivery of the placenta and before prophylactic antibiotic administration. Chorioamnionic membranes were also cultured. Demographic, labor, delivery, and postpartum characteristics were abstracted from the medical record. RESULTS: Bacteremia was detected in 13 (11%) of 119 women. Bacteremia occurred in 13 (14%) of 93 women after labor or rupture of membranes compared with zero of 26 women not in labor (P = .02). Isolates included group B streptococcus (n = 5), Gardnerella vaginalis (n = 5), Streptococcus pneumoniae (n = 1), Peptostreptococcus sp (n = 1), and mixed flora of Prevotella bivia, G vaginalis, and viridans streptococci (n = 1). Bacteremia was associated with earlier median gestational age, lower median birth weight, and a positive chorioamnionic membrane culture. After adjustment for gestational age, intrauterine monitoring was also significantly associated with bacteremia. CONCLUSION: Bacteremia was common after labor in this population, especially in preterm deliveries and those with positive chorioamnionic-placental culture. Many of the isolates are capable of causing endocarditis. Appraisal of the risk of bacteremia and the risk of bacterial endocarditis should be made in individual patients to assess the need for antibiotic prophylaxis. PMID- 8677086 TI - A new procedure for removal of a "lost" intrauterine device. AB - OBJECTIVE: To evaluate the efficacy of removal of a "lost" intrauterine device (IUD) with the use of a cylindrical brush. METHODS: Women aged 25-43 years with so-called "lost" IUD, in whom the string was indiscernible, were enrolled in the study. During gynecologic examination, a cylindrical brush was rotated in the cervical canal until the device was extracted by a rotating motion. No antibiotics were used after removal of the IUD with the cylindrical brush. RESULTS: Twenty-seven women whose IUD could not be removed from the uterine cavity because of an indiscernible string were referred for a trial of IUD removal. All patients had used a plastic, copper-releasing IUD. Before admission, they had undergone an attempt at IUD removal by their physician using either a hook or clamp. In 24 patients who were referred to our center, the IUD was removed by using a cylindrical brush to view the string. The IUD was removed by hysteroscopy in three cases, in two of which no string was found. CONCLUSION: A cylindrical brush can be used safely as an adjunct to remove an IUD and is a simple method that may be performed before another invasive procedure is attempted. PMID- 8677087 TI - Treatment of vulvar varicosities by injection-compression sclerotherapy and a pelvic supporter. AB - Injection of vulvar varicosities with a 1% solution of sodium tetradecyl sulfate and subsequent compression therapy with a pelvic supporter was used to treat five women with symptoms of vaginal pressure, swelling, and pain. Three patients were premenstrual, and the two others were approximately 8 weeks post-vaginal delivery. Physical examination was performed in the upright as well as the dorsal lithotomy positions, and injection was given in the supine position. All patients noticed marked improvement in symptoms after treatment. We conclude that this technique has potential as a simple, effective way to treat symptomatic vulvar varicosities. PMID- 8677088 TI - Pharmacologic treatment of psychiatric disease in pregnancy and lactation: fetal and neonatal effects. AB - OBJECTIVE: To review published data pertaining to safety of psychoactive drugs used to treat psychiatric disorders during pregnancy and lactation. DATA SOURCES: A computerized search of articles published through July 1995 was performed on the MEDLINE data base. Additional sources were identified through cross referencing. METHODS OF STUDY SELECTION: All identified references were reviewed with particular attention given to study design. DATA EXTRACTION AND SYNTHESIS: Each reference was reviewed to determine the safety of psychoactive agents to treat depression, bipolar disease, schizophrenia, and anxiety during pregnancy and lactation. Prospective or large retrospective studies were given more importance than case reports. CONCLUSION: Psychoactive medications may be used during pregnancy. Because data on safety are largely retrospective, treatment decisions must be weighed carefully. PMID- 8677089 TI - Eschew obfuscation. PMID- 8677090 TI - Learning from the community about barriers to health care. PMID- 8677091 TI - Intentional delivery versus expectant management with preterm ruptured membranes at 30-34 weeks' gestation. PMID- 8677092 TI - The effect of manual removal of the placenta on post-cesarean endometritis. PMID- 8677093 TI - Acute myocardial infarction in pregnancy with subsequent medical and surgical management. AB - BACKGROUND: Myocardial infarction is a rare event in pregnancy that requires medical stabilization with possible surgical interventions. CASE: A 37-year-old woman developed an anterior wall myocardial infarction secondary to severe coronary artery disease during the early third trimester of pregnancy. The patient was managed with multiple modalities to stabilize her condition and prolong the gestation. The salient point in the management included: defibrillation and pharmacologic agents, intra-aortic balloon pump, coronary artery bypass graft surgery using a cardiopulmonary bypass pump while maintaining continuous fetal heart rate monitoring, and delivery of the neonate at term. CONCLUSION: Aggressive management of this patient allowed continuation of pregnancy with good outcome for mother and neonate. PMID- 8677094 TI - Cocaine-associated rhabdomyolysis causing renal failure in pregnancy. AB - BACKGROUND: Cocaine use is known to have multisystemic effects. Recently, acute renal failure as a result of rhabdomyolysis has been described as a complication of cocaine use. During pregnancy, cocaine is associated with abruptio placentae. A patient presenting with both complications is described. CASE: A 25-year-old multiparous woman at 34 weeks' gestation developed abruptio placentae approximately 18 hours after using cocaine alkaloid. Six hours later, a cesarean delivery was performed after she presented with vaginal bleeding and fetal bradycardia. Oliguria was present from admission and persisted despite aggressive fluid hydration, dopamine infusion, and intravenous administration of furosemide. Serum creatinine phosphokinase and urine myoglobin were both elevated at 558 IU/L and 432 ng/mL. Hemodialysis was required for presumed cortical necrosis. CONCLUSION: Rhabdomyolysis, as indicated by elevated creatinine phosphokinase and the presence of myoglobin in the urine, suggests that nephrotoxicity from myoglobinuria may contribute to acute renal failure in cases of cocaine mediated abruptio placentae. PMID- 8677095 TI - Endoscopic management of biliary disease during pregnancy. AB - BACKGROUND: The transient but substantial alterations in the biliary system during pregnancy increase the risk of cholecystitis, choledocholithiasis, and pancreatitis. Traditionally, these disorders are managed conservatively or with operative cholecystectomy. Recent advances in fiber-optic technology allow endoscopy to be used as a safe, effective, and definitive treatment alternative for pancreaticobiliary disease in pregnancy. CASES: Three gravid women with cholelithiasis, acute cholecystitis, and/or gallstone pancreatitis were treated endoscopically with stone extraction and experienced rapid resolution of symptoms and successful pregnancy outcomes. CONCLUSION: Aggressive endoscopic intervention for biliary disorders in pregnancy appears to decrease morbidity, mortality, and costs. Endoscopy offers a safer, more effective treatment alternative to prolonged medical management and traditional surgical intervention during pregnancy. Because biliary abnormalities resolve rapidly in the postpartum period, it is unlikely these women will need subsequent treatment. PMID- 8677096 TI - Pregnancy in patients with preexisting transverse myelitis. AB - BACKGROUND: Although several cases of pregnancies of traumatic spinal cord injury patients have been reported, to our knowledge, only one case has been reported detailing the perinatal outcome in a patient with preexisting transverse myelitis. CASE: The prenatal course and pregnancy outcome in two patients with preexisting transverse myelitis is presented. The major complications encountered were urinary tract infections and mobility problems. CONCLUSION: Patients with preexisting transverse myelitis can have successful pregnancies with term vaginal deliveries. Prevention of potential complications, such as anemia, preterm labor and delivery, decubitus ulcers, and autonomic dysreflexia can be achieved with coordinated multidisciplinary management. PMID- 8677097 TI - Erythropoietin treatment of erythropoietin-deficient anemia without renal disease during pregnancy. AB - BACKGROUND: The use of recombinant human erythropoietin in pregnancy has been described in patients with renal impairment. We present a patient with a hypoproliferative anemia with low serum erythropoietin levels and no renal disease or other known cause for this type of anemia, who was treated with recombinant human erythropoietin. CASE: A 29-year-old white woman who became pregnant after leuprolide acetate and menopausal gonadotropin therapy developed a moderate anemia (hemoglobin 8.5 g/dL) in early pregnancy. The only important laboratory findings were a hypoproliferative marrow and a low serum erythropoietin level. She was treated successfully with injections of recombinant human erythropoietin. Her pregnancy was otherwise uncomplicated and her pre delivery hemoglobin level was 12 g/dL. CONCLUSION: Hypoproliferative anemia in pregnancy with low erythropoietin levels and no renal disease can be treated successfully with recombinant human erythropoietin. PMID- 8677099 TI - Uterine rupture as a cause of shoulder dystocia. AB - BACKGROUND: Shoulder dystocia and uterine rupture are complications that rarely are related. CASE: A 34-year-old white woman, gravida 4, para 2, therapeutic abortion 1, was admitted for labor induction. Fetal heart rate monitoring was normal until full dilation, when bradycardia developed and persisted. With the use of forceps, the vertex was delivered. Head retraction signaled the possibility of shoulder dystocia. Attempts at vaginal delivery failed, necessitating abdominal delivery. The fetal body was found anterior to the already contracted, anterolaterally ruptured uterus. An abdominally assisted vaginal delivery was accomplished. CONCLUSION: Uterine rupture may be an unsuspected cause of shoulder dystocia. PMID- 8677098 TI - Treatment of essential thrombocythemia during pregnancy with interferon-alpha. AB - BACKGROUND: Only a few cases of essential thrombocythemia in pregnant women have been reported, and the management of this myeloproliferative disorder during pregnancy remains uncertain. We report a successful pregnancy in a patient who had essential thrombocythemia and who was treated with interferon-alpha, and we review the literature for the outcome of similar patients. CASE: A 32-year-old woman, gravida 4, para 3, aborta 0, presented at 18 weeks' gestation with two episodes of amaurosis fugax and an elevated platelet count of 2300 x 10(9)/L. The initiation of interferon-alpha led to a progressive fall of the platelet level, with no occurrence of thrombotic or hemorrhagic manifestations. Serial ultrasound examinations revealed normal fetal and placental development. The patient was delivered of a male infant at 37 weeks. Both child and placenta were normal on examination. CONCLUSION: Our case and the current available data suggest that interferon-alpha may be the best therapeutic option for pregnant patients with essential thrombocythemia in whom myelosuppression is required. PMID- 8677100 TI - Bilateral radial nerve palsies from use of the standard birthing bar. AB - BACKGROUND: Serious injury can result from improper use of the birthing bar. CASE: A 31-year-old woman delivered a neonate using a birthing bar for her entire second stage of labor. Shortly after delivery, she experienced bilateral upper extremity weakness from compression of the radial nerve. She was treated with physical therapy and electromuscle stimulation and regained functional use of her upper extremities within 3 months. One year after delivery, the patient continued to display bilaterally only 80% muscle strength in her radial-innervated musculature. CONCLUSION: Improper use of the birthing bar during labor can cause serious and permanent injury to the radial nerve. Care should be taken when instructing patients on how to use the birthing bar to avoid this complication. PMID- 8677101 TI - Hysterotomy to effect vaginal delivery with mentum anterior head entrapment. AB - BACKGROUND: Entrapment of the aftercoming head after mentum anterior rotation is a life-threatening complication of vaginal breech delivery. Few options exist when rotation and flexion from this position cannot be performed successfully either transabdominally or with vaginal maneuvers. CASE: A term primigravida presented with a singleton breech in advanced labor. The fetal torso and arms delivered vaginally, but the aftercoming head became extended and was entrapped in a mentum anterior position. The fetal head could not be rotated and flexed, either vaginally or transabdominally with suprapubic pressure. Laparotomy and hysterotomy were performed, and vaginal delivery of a live fetus was accomplished after rotation and flexion of the fetal head through this incision. CONCLUSION: Hysterotomy is a safe and effective maneuver for delivery of the entrapped fetal head with mentum anterior rotation after standard procedures have failed. PMID- 8677102 TI - Monomicrobial necrotizing fasciitis complicating pregnancy and puerperium. AB - BACKGROUND: Necrotizing fasciitis is an uncommon, rapidly progressive, life threatening infection involving the subcutaneous tissue and fascia. Usually, it is a synergistic polymicrobic infection that occurs in patients with coexisting factors predisposing them to bacterial inoculation and the spread of infection. CASES: We report a monomicrobial variant of necrotizing fasciitis affecting three otherwise healthy pregnant or postpartum women. The necrotizing fasciitis involved either the lower extremity or the abdominal wall. The causative bacteria were Streptococcus pyogenes (two cases) and Staphylococcus aureus (one). All patients presented with an acute fulminant infection, including one woman who died from overwhelming sepsis. CONCLUSION: These cases raise a question about the possible role of increased bacterial virulence and the immunologic changes of pregnancy as potential predisposing factors in the development of necrotizing fasciitis. PMID- 8677103 TI - Magnetic resonance imaging of peripartum rupture of the symphysis pubis. AB - BACKGROUND: Peripartum pubic symphyseal rupture is diagnosed on clinical grounds. Although the diagnosis may be supported by radiography, which shows diastasis of the pubic rami, magnetic resonance imaging (MRI) can visualize the nature of the soft tissue injury. CASE: Two puerperas thought clinically to have pubic symphyseal rupture were imaged with MRI. In addition to diastasis of the pubic rami, clefts were seen within the symphyseal cartilage, extending the entire breadth of the joint. The clefts were filled with fluid or hemorrhage, seen in T1 and T2-weighted images. The fluid was encapsulated within the joint by the surrounding ligaments. Four control normal puerperas, who had vaginal deliveries but were asymptomatic, showed none of the aforementioned findings. CONCLUSION: MRI can visualize the soft tissue injury seen in pubic symphyseal rupture and may be used to confirm the clinical diagnosis. PMID- 8677104 TI - Persistence of partial molar placenta and severe preeclampsia after selective termination in a twin pregnancy. AB - BACKGROUND: Triploid molar pregnancies are usually managed by evacuation of the uterine contents. CASE: A 25-year-old woman had a clomiphene citrate-induced twin pregnancy. Ultrasound scan at 13 weeks revealed one anomalous twin. Cytogenetic analysis revealed a karyotype of 69, XXY and a normal other twin. In an attempt to salvage the normal fetus, selective termination was successfully performed at 15 weeks by intracardiac potassium chloride injection. However, the placenta continued to grow and severe preeclampsia developed at 19 weeks, requiring pregnancy termination. CONCLUSION: Selective termination of a triploid twin does not guarantee resolution of molar growth and sequelae of the mole; severe preeclampsia can still develop. PMID- 8677106 TI - Tachycardia as the sole fetal heart rate abnormality after funipuncture. AB - BACKGROUND: Fetal bradycardia is a common complication of funipuncture. We present a case of fetal exsanguination in which fetal tachycardia was the sole fetal heart rate abnormality. CASE: Funipuncture was performed at 32 weeks' gestation for evaluation of Rh isoimmunization. A persistent fetal tachycardia ensued and, although there was no immediate ultrasound evidence of bleeding, repeat ultrasonography revealed active bleeding at the puncture site. A neonate with an initial hematocrit of 42% was delivered by cesarean. Despite aggressive replacement of blood products, a repeat hematocrit was only 35% and a severe, persistent coagulopathy ensued. The newborn died 18 hours after delivery. Autopsy findings were consistent with neonatal coagulopathy. CONCLUSION: Although fetal bleeding is usually a common, relatively benign complication of funipuncture, streaming may not always be detected on ultrasonographic examination. Our case demonstrates that fetal tachycardia may be the only sign of fetal hemorrhage. PMID- 8677105 TI - Recurrent cervical pregnancy after assisted reproduction by intrafallopian transfer. AB - BACKGROUND: Cervical pregnancy is an uncommon, yet potentially catastrophic form of ectopic pregnancy. Early diagnosis and intervention are important in avoiding short-term and long-term morbidity. Although transcervical embryo transfer is thought to increase the incidence of this phenomenon in patients undergoing in vitro fertilization, its occurrence after intrafallopian transfer is rarely seen. CASE: A 43-year-old nulliparous white female with a history of unexplained infertility experienced recurrent cervical pregnancy after two consecutive gamete/zygote intrafallopian transfer cycles. Abnormally rising beta-hCG levels combined with transvaginal sonography helped establish the diagnosis in each case. Intramuscular (IM) methotrexate combined with intra-amniotic potassium chloride successfully treated this condition initially, and IM methotrexate alone was sufficient for successful treatment in the second case. CONCLUSION: Cervical pregnancy may occur with assisted reproductive techniques involving intrafallopian transfer. Early diagnosis may be important for successful treatment of cervical pregnancy with conservative measures. Even in the case of recurrence, prompt intervention may allow for preservation of a patient's future fertility potential. PMID- 8677107 TI - Direct fetal therapy for hydrops secondary to congenital atrioventricular heart block. AB - BACKGROUND: The outcome for the fetus with hydrops fetalis secondary to complete congenital heart block is almost uniformly poor. Transplacental fetal therapy with inotropic drugs may be unreliable in the hydropic fetus. We describe our experience of direct fetal therapy with digoxin and furosemide in three cases. CASES: In the first two cases, fetal hydrops secondary to congenital heart block was detected at 33 and 31 weeks. Direct fetal therapy with digoxin and furosemide was given and the mothers received digoxin concurrently. The neonates were born normally at 35 weeks and 33 weeks; one required ventricular pacing, but both are currently alive and well. In the third case, fetal hydrops was detected at 24 weeks, when furosemide was used alone for direct fetal therapy. The mother developed chorioamnionitis at 29 weeks and was delivered by cesarean; the infant died of cardiac failure after 48 hours. CONCLUSION: Initial direct fetal therapy with digoxin and furosemide followed by transplacental treatment with digoxin and direct fetal therapy with diuretics might improve the perinatal salvage of hydropic fetuses with congenital heart block. Treatment must be individualized because development of infection and preterm labor might defeat the objective. PMID- 8677108 TI - Successful treatment of recurrent non-immune hydrops secondary to fetal hyperthyroidism. AB - BACKGROUND: Non-immune fetal hydrops is a heterogeneous disorder with a mortality rate of 50-98%. Resolution of non-immune fetal hydrops is rare but has been reported to occur spontaneously or after targeted therapeutic measures. CASE: A euthyroid gravida with Graves disease presented with a history of three prior perinatal deaths between 26 and 28 weeks' gestation, all associated with fetal hydrops. In the current pregnancy, the fetus developed hydrops at 24 weeks' gestation. Fetal hyperthyroidism, with high-output cardiac failure, was diagnosed with fetal blood sampling. After maternal therapy with propylthiouracil, resolution of the non-immune hydrops were documented and a healthy neonate subsequently delivered to term. The neonate developed transient hyperthyroidism after delivery, which required treatment for 10 weeks. CONCLUSION: Non-immune hydrops occurring as a result of fetal hyperthyroidism with high output cardiac failure is treatable with propylthiouracil. PMID- 8677109 TI - Omphalocele and pericardial effusion: possible sonographic markers for the pentalogy of Cantrell or its variants. AB - BACKGROUND: The pentalogy of Cantrell consists of defects involving the diaphragm, abdominal wall, pericardium heart, and lower sternum. CASES: We report three cases of the pentalogy of Cantrell (variant form), involving an omphalocele complicated by an anterior diaphragmatic hernia. In two cases, a pericardial effusion was noted at antenatal scanning; the case without a pericardial effusion had an intact diaphragmatic pericardium at surgical repair. CONCLUSION: The presence of a pericardial effusion in association with an omphalocele should prompt a detailed search for other features of the pentalogy of Cantrell or its variants. PMID- 8677110 TI - Familial recurrence of pulmonary sequestration. AB - BACKGROUND: Pulmonary sequestration is not believed to be familial. We report two male infants with this anomaly who were born to the same parents. CASES: The prenatal diagnosis of pulmonary sequestration was made in a woman's two consecutive pregnancies by demonstrating systemic arterial supply to an echogenic mass located in the left lower lung of each fetus. Postnatal radiographic evaluation confirmed the prenatal diagnoses. CONCLUSION: Recurrent pulmonary sequestration in two male offspring from the same parents raises the possibility of a genetic predisposition for this condition. PMID- 8677111 TI - Prenatal diagnosis of intracranial lipoma associated with agenesis of the corpus callosum. AB - BACKGROUND: Lipoma of the corpus callosum is a congenital malformation present in 1:1700 individuals. Only three cases of prenatal sonographic diagnosis have been described. CASES: Two cases of prenatal sonographic diagnosis of intracranial lipoma are described. The first case was visible at 26 weeks' gestation and was associated with partial agenesis of the corpus callosum, a characteristic midline gyral pattern, and fetal colpocephaly. The second case was an isolated lipoma diagnosed at 37 weeks. In both cases transvaginal scanning and color Doppler studies were useful adjuncts in making the diagnosis. CONCLUSION: Prenatal sonographic diagnosis of intracranial lipoma associated with agenesis of the corpus callosum is possible as early as 26 weeks' gestation. Because prognosis depends on associated anomalies, a detailed examination of fetal intracranial anatomy and a complete anatomic survey should be performed. Awareness of this lesion can be expected to increase its detection on prenatal sonography. PMID- 8677112 TI - Perinatal management of a lingual teratoma. AB - BACKGROUND: Teratomas of the head and neck are rare and occur almost exclusively in neonates. Prenatal diagnosis of these tumors allows for a carefully planned delivery that maintains an open airway and potentially improves perinatal outcome. We report the perinatal management of a huge intrapharyngeal and intra oral teratoma that had a broad connection to the base of the tongue. CASE: An anterior neck mass (5 x 5 cm) in an otherwise normal-appearing fetus was detected at 19 weeks' gestation. The mass increased in size over the next 10 weeks to 8 x 6.8 x 4.3 cm. Marked fetal head deflexion was noted along with concomitant hydramnios. The mother had spontaneous rupture of membranes with preterm labor at 29 weeks' gestation. A 1860-g male neonate was delivered by classical cesarean delivery. A tracheostomy was performed in the delivery room for ventilation after the upper airway could not be accessed by bronchoscopy. Histologic examination after surgical excision confirmed a congenital teratoma with immature neuroectodermal tissue and alpha-fetoprotein-bearing endodermal sinus tumor components with exclusively polyvesicular vitelline characteristics. The origin of the pharyngeal mass was the base of the tongue. CONCLUSION: The prenatal diagnosis of a pharyngeal teratoma should prompt a careful delivery plan to optimize perinatal outcome. PMID- 8677113 TI - Spontaneous intrauterine linear skull fracture: a rare complication of spontaneous vaginal delivery. AB - BACKGROUND: Fetal skull fracture has been reported in conjunction with difficult delivery or extrinsic trauma. CASE: We report a case of linear, undisplaced, nondepressed skull fracture occurring in a 3540-g male infant born at 37 weeks and 4 days' gestation. Linear skull fracture occurred despite an uncomplicated spontaneous vaginal delivery in the absence of extrinsic trauma or cephalopelvic disproportion. Subsequent clinical follow-up 6 years later revealed normal neurological development without evidence of epileptiform activity or focal neurologic deficit. CONCLUSION: Linear skull fracture in association with uncomplicated, spontaneous vaginal delivery is distinctly rare, in contrast to focal, congenital molding depressions of the skull. This case demonstrates that normal spontaneous vaginal delivery without instrumentation or obvious complication can involve sufficient trauma to result in a linear skull fracture. The precise etiology of these fractures requires further study. PMID- 8677114 TI - Monosomy 7 syndrome associated with congenital adrenal hypoplasia and male pseudohermaphroditism. AB - BACKGROUND: Bone marrow monosomy 7 is an uncommon disorder of the pluripotent stem cells that leads to frequent childhood infections and leukemia. Primary adrenal hypoplasia occurs very rarely and is incompatible with life. Male pseudohermaphroditism results from inadequate androgen secretion or inappropriate androgen action. We report a case of monosomy 7, adrenal hypoplasia, and male pseudohermaphroditism. CASE: An infant was born with sexual ambiguity and bilateral inguinal masses. Bone marrow karyotype was 45, XY,-7. Serum testosterone level was low normal. The infant died on the fourth day of life. Autopsy revealed severely hypoplastic adrenal glands, inguinal testes, and a vaginal pouch. CONCLUSION: Monosomy 7 and male sexual ambiguity are reported in association with primary adrenal hypoplasia of the cytomegalic (X-linked) type. PMID- 8677115 TI - Non-mosaic trisomy 16 in a third-trimester fetus. AB - BACKGROUND: Trisomy 16 in the most common trisomy first-trimester spontaneous abortions, suggesting a high rate of non-disjunction of this chromosome. Deoxyribonucleic acid studies in aborted conceptuses with trisomy 16 have demonstrated a maternal origin in all cases. There have been cases of confined placental mosaicism, fetal mosaicism, and partial trisomy involving chromosome 16 reported in term fetuses. However, to our knowledge, there have been no previous reports of a near-term fetus with full trisomy 16 since the advent of modern chromosomal banding techniques. CASE: A 25-year-old Filipino woman underwent obstetric sonographic evaluation at 32 weeks' gestation; results were remarkable for oligohydramnios, severe growth restriction, and multiple dysmorphic features. Percutaneous umbilical blood sampling was performed for rapid karyotyping, viral serology, and blood profiles. The fetal karyotype was 47, XY+16; the remainder of the laboratory analysis was unremarkable. The patient went into spontaneous labor at 35 weeks' gestation and delivered a stillborn female fetus (birth weight 783 g). Chromosomes from skin, brain, and chorionic villi were examined and all demonstrated trisomy 16 (47, XX,+16). Deoxyribonucleic acid primers for known polymorphic regions of chromosome 16 were used and determined the origin of the extra chromosome to be non-disjunction during paternal meiosis. CONCLUSION: Previously, full trisomy 16 has been thought to be incompatible with fetal survival past the early second trimester. This case also contrasts with previously reported experience with trisomy 16 in that parental origin studies determined that the extra chromosome 16 originated from the father, suggesting that paternal derivation of the additional chromosome may play a role in the ultimate phenotypic expression. PMID- 8677116 TI - Possible association between the Norplant contraceptive system and thrombotic thrombocytopenic purpura. AB - BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare, potentially fatal disease of uncertain etiology. Early diagnosis and treatment are essential to patient survival. The ]purpose of this report is to describe three patients with levonorgestrel implants (Norplant system) who developed TTP. CASES: A 24 year-old woman with levonorgestrel implants in place for 7 months was admitted to our hospital for treatment of TTP. Clinical symptoms included easy bruising, menorrhagia, headaches, and fever; laboratory evaluation revealed thrombocytopenia (18 x 10(9)/L) and microangiopathic hemolytic anemia. She was treated with plasmapheresis, and the implants were removed. Through the Freedom of Information Act, we reviewed all adverse events associated with Norplant use reported to the Food and Drug Administration (FDA) as of the end of 1992. Two additional cases were identified. CONCLUSIONS: Although a causal relationship between progestogen-only contraceptives and TTP is not established by the data presented, these three cases may represent an increased incidence of TTP in women using levonorgestrel implants. Patients who receive Norplant should be advised to seek medical attention if symptoms appear. Physicians and other health care providers should be aware of the possible association between use of the Norplant system and TTP and are urged to report similar cases to the FDA. PMID- 8677117 TI - Laser treatment of recurrent vulvar angiokeratoma associated with Noonan syndrome. AB - BACKGROUND: Vulvar angiokeratoma is often confused with other, more common perineal lesions. Chronically elevated venous pressures may contribute to this rare disorder. Laser treatment may lend palliation for several years. CASE: A woman with the characteristic cardiac abnormalities of Noonan syndrome initially responded to Argon laser treatment of vulvar angiokeratoma. Excessive recurrent disease was treated satisfactorily with the Nd:YAG laser. CONCLUSION: Recurrent vulvar angiokeratoma in Noonan syndrome supports the premise that increased persistent central venous pressure may be involved in the disease process. PMID- 8677118 TI - Tissue expansion vaginoplasty for treatment of congenital vaginal agenesis. AB - BACKGROUND: A patient with congenital vaginal agenesis was unsuccessful in the use of dilation to create a vaginal orifice and rejected the option of a buttock graft. CASE: Two tissue expanders were introduced beneath the labia majora bilaterally and slowly expanded over 4 weeks. Redundant labial tissue was advanced as a bipedicle flap to line the neovagina created intraoperatively. Postoperative stent placement and dilation resulted in a vaginal canal lined by full-thickness mucosa exceeding 8 cm in depth. CONCLUSION: A modified method of tissue expansion vaginoplasty using a bipedicle flap is an option for the surgical creation of a vaginal orifice. PMID- 8677119 TI - Vaginal vault evisceration after total laparoscopic hysterectomy. AB - BACKGROUND: Vaginal vault rupture with intestinal herniation, although rare, is a recognized postoperative complication of vaginal and abdominal hysterectomies. The incidence after laparoscopic hysterectomy is unknown. CASES: Three women, ages 40-43 years, presented to the emergency room with bleeding and pain 2-5 months after total laparoscopic hysterectomy. The small bowel was visible through the introitus or protruding into the vagina. Inspection of the bowel revealed no evidence of trauma. Two vaginal cuff repairs were completed transvaginally and one laparoscopically, all with interrupted sutures of no. 0 polydioxanone or polyglactin. In follow-up period of 12-17 months, the patients were doing well. CONCLUSION: Total laparoscopic hysterectomy may be associated with an increased risk of vaginal vault evisceration. Because laparoscopy increasingly is used to replace abdominal hysterectomy, it is important to be aware of this complication and its management. PMID- 8677120 TI - Testosterone-producing solitary ovarian cyst with luteinized stromal-cell hyperplasia. AB - BACKGROUND: Hormone production is a characteristic associated with the presence of solid tumors in the ovary. We present a case of a solitary ovarian cyst producing large amounts of testosterone and presenting with rapid onset of hirsutism. CASE: A woman presented approximately 6 months postpartum with irregular menses and rapid onset of hirsutism. Laboratory and radiologic evaluation indicated an ovarian cyst as the source. On removal, the cyst was found to have high amounts of testosterone in its fluid and the surrounding stroma had nests of luteinized cells. CONCLUSION: The chronic anovulation in the postpartum period may have prolonged the lifespan of the luteinized stromal cells, resulting in high levels of circulating testosterone and causing rapid progression of hirsutism. PMID- 8677121 TI - Giant ovarian leiomyoma as a rare cause of acute abdomen and hydronephrosis. AB - BACKGROUND: Leiomyoma of the ovary is rare, usually small, and rarely induces serious symptoms. CASE: We report a case of a leiomyoma of the ovary that weighed 11.65 kg and led to acute abdomen and bilateral hydronephrosis. To our knowledge, this complication has not been described previously. Transabdominal sonography and computed tomography scan did not identify tumor type or origin. We performed a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Abdominal symptoms and defects in urinary function disappeared completely after surgery. CONCLUSION: In very few cases, benign leiomyoma of the ovary may cause giant pelvic masses and peritoneal irritation. PMID- 8677122 TI - Ovarian lipoma of teratomatous origin. AB - BACKGROUND: Lipomatous tumors of ovarian origin are rare and may arise from overgrowth of metaplastic fat cells in the stroma. CASE: A 5-cm, circumscribed, grossly yellow tumor was an incidental finding at the time of hysterectomy for endometrial cancer. The ovarian tumor was composed almost exclusively of benign adipocytes. Small collections of benign sweat glands were present at the periphery of the tumor. CONCLUSION: This predominantly lipomatous ovarian tumor likely represents a fat-rich solid teratoma. PMID- 8677123 TI - Castleman disease presenting as a pelvic mass. AB - BACKGROUND: To our knowledge, giant lymph node hyperplasia (Castleman disease) may present as a pelvic mass on magnetic resonance imaging (MRI). CASE: A postmenopausal woman with rapidly enlarging leiomyoma uteri was found to have a suspicious left adnexal mass mimicking an ovarian neoplasm on preoperative MRI. At laparotomy, the suspected uterus and normal ovaries were extirpated. In addition, a firm, 4 x 8-cm solid mass within the sigmoid colon mesentery was found and resected. The final histologic diagnosis was Castleman disease. CONCLUSION: Entities such as Castleman disease should be considered when assessing a pelvic mass. Characterization of the origin of pelvic masses can often be difficult, despite sophisticated diagnostic imaging studies such as MRI. PMID- 8677124 TI - Vesicular neonatal rash at the site of vacuum application. PMID- 8677125 TI - Two successful vaginal deliveries in a heart transplant recipient. PMID- 8677126 TI - Pelvic mass in a patient with Behcet's disease. PMID- 8677127 TI - Spontaneous perforation of a degenerative nongestational uterine leiomyoma. PMID- 8677128 TI - Pasteurella multocida tubo-ovarian abscess in a virgin. PMID- 8677129 TI - Antibiotics at the time of induced abortion: the case for universal prophylaxis based on a meta-analysis. AB - OBJECTIVE: To determine the efficacy of periabortal antibiotics in preventing postabortal upper genital tract infection using data from published trials. DATA SOURCES: We performed a literature search of all studies published from January 1966 to September 1, 1994, using MEDLINE, and we manually searched bibliographies of published articles. MEDLINE search terms included: abortion, infection, prophylaxis, antibiotics, pelvic inflammatory disease (PID), and suction curettage. METHODS OF STUDY SELECTION: Randomized, controlled trials comparing antibiotics with placebo in women undergoing suction curettage abortion before 16 weeks' gestation were identified. TABULATION, INTEGRATION, AND RESULTS: Data were extracted independently by two reviewers, one of whom was blinded to journal, year of publication, authors, and institution. Data from 12 studies were combined using meta-analytic techniques based on a fixed-effects model. The overall summary relative risk (RR) estimate for developing postabortal upper genital tract infection in women receiving antibiotic therapy compared with those receiving placebo was 0.58 (95% confidence interval [CI] 0.47-0.71). Of high-risk women, those with a history of PID had a summary RR estimate of 0.56 (95% CI 0.37 0.84); women with a positive chlamydia culture at abortion had a summary RR estimate of 0.38 (95% CI 0.15-0.92). Of low-risk women, those with no reported history of PID had a summary RR estimate of 0.65 (95% CI 0.47-0.90); in women with a negative chlamydia culture, the summary RR estimate was 0.63 (95% CI 0.42 0.97). The lowest summary RR estimate was among women drawn from populations with a low incidence (5-6%) of postabortal infection (summary RR estimate 0.22, 95% CI 0.11-0.42). The overall 42% decreased risk of infection in women given periabortal antibiotics is similar to the risk reduction demonstrable when only studies published before 1985 are combined (summary RR estimate 0.63, 95% CI 0.44 0.89). CONCLUSION: Our meta-analysis revealed a substantial protective effect of antibiotics in all subgroups of women undergoing therapeutic abortion, even women in low-risk groups. No more placebo-controlled trials should be performed, because women assigned to placebo are exposed to preventable risk. Routine use of periabortal antibiotics in the United States may prevent up to half of all cases of postabortal infections. PMID- 8677130 TI - The effect of routine early amniotomy on spontaneous labor: a meta-analysis. AB - OBJECTIVE: To obtain estimates of the effects of amniotomy on the risk of cesarean delivery and on other indicators of maternal and neonatal morbidity (Apgar score less than 7 at 5 minutes, admission to neonatal intensive care unit [NICU]). DATA SOURCES: Published studies were identified through manual and computerized searches using Medline and the Cochrane Collaboration Pregnancy and Childbirth Database. METHODS OF STUDY SELECTION: Our search identified ten trials, all published in peer-reviewed journals. Trials were assigned a methodological quality score based on a standardized rating system. Three trials were excluded from the analysis for methodological limitations. TABULATION, INTEGRATION, AND RESULTS: Data were abstracted by two trained reviewers. Typical odds ratios (OR) were calculated. Amniotomy was associated with a reduction in labor duration varying from 0.8-2.3 hours. There was a nonstatistically significant increase in the risk of cesarean delivery; OR 1.2, 95% confidence interval (CI) 0.9-1.6. The risk of a 5-minute Apgar score less than 7 was reduced in association with early amniotomy (OR 0.5, 95% CI 0.3-0.9). Groups were similar with respect to other indicators of neonatal status (arterial cord pH, NICU admissions). CONCLUSION: Routine early amniotomy is associated with both benefits and risks. Benefits include a reduction in labor duration and a possible reduction in abnormal 5-minute Apgar scores. This meta-analysis provides no support for the hypothesis that routine early amniotomy reduces the risk of cesarean delivery. An association between early amniotomy and cesarean delivery for fetal distress was noted in one large trial, suggesting that amniotomy should be reserved for patients with abnormal labor progress. PMID- 8677131 TI - A review of the clinical effects of phytoestrogens. AB - OBJECTIVE: To review the sources, metabolism, potencies, and clinical effects of phytoestrogens on humans. DATA SOURCES: The MEDLINE data base for the years 1980 1995 and reference lists of published articles were searched for relevant English language articles concerning phytoestrogens, soy products, and diets with high phytoestrogen content. METHODS OF STUDY SELECTION: We identified 861 articles as being relevant. Human cell line studies, human epidemiologic studies (case control or cohort), randomized trials, and review articles were included. Animal studies regarding phytoestrogens were included when no human data were available concerning an important clinical area. TABULATION, INTEGRATION, AND RESULTS: Included were studies containing information considered pertinent to clinical practice in the areas of growth and development, menopause, cancer, and cardiovascular disease. When findings varied, those presented in this study reflect consensus. All studies concurred that phytoestrogens are biologically active in humans or animals. These compounds inhibit the growth of different cancer cell lines in cell culture and animal models. Human epidemiologic evidence supports the hypothesis that phytoestrogens inhibit cancer formation and growth in humans. Foods containing phytoestrogens reduce cholesterol levels in humans, and cell line, animal, and human data show benefit in treating osteoporosis. CONCLUSION: This review suggests that phytoestrogens are among the dietary factors affording protection against cancer and heart disease in vegetarians. With this epidemiologic and cell line evidence, intervention studies are now an appropriate consideration to assess the clinical effects of phytoestrogens because of the potentially important health benefits associated with the consumption of foods containing these compounds. PMID- 8677132 TI - Population dynamics of Theileria sergenti in persistently infected cattle and vector ticks analysed by a polymerase chain reaction. AB - Theileria sergenti Shintoku stock consists of 2 parasite populations bearing 2 allelic forms of p33/32, an immunodominant piroplasm surface protein. Parasite population changes during parasite passages among cattle and tick vectors, and during persistent infection in individual calves were analysed by using allele specific polymerase chain reaction (PCR). The parasite DNAs were prepared from piroplasms from calves which had been infected with Shintoku stock by inoculation of sporozoite stabilates or parasitized erythrocytes, and from sporozoite stabilates which had been prepared from Shintoku stock-infected ticks. Changes in a dominant parasite population were demonstrated during transmission from calves to vector ticks and from infected ticks to calves. Parasite population changes were also apparent during persistent infection in cattle over several months, and this change is thought to occur under host immune pressure. The results of this study indicate that expression of diverse forms of p33/32 may play a role in parasite persistence within mammalian hosts and its transmission from tick vector. PMID- 8677134 TI - Contractile protein system in the asexual stages of the malaria parasite Plasmodium falciparum. AB - F-actin was detected in asexual-stage Plasmodium falciparum parasites by fluorescence microscopy of blood films stained with fluorescent phalloidin derivatives. F-actin was present at all stages of development and appeared diffusely distributed in trophic parasites, but merozoites stained strongly at the poles and peripheries. No filament bundles could be discerned. A similar distribution was obtained by immunofluorescence with 2 polyclonal anti-actin antibodies, one of which was directed against a peptide sequence present only in parasite actin (as inferred from the DNA sequence of the gene). A monoclonal anti actin antibody stained very mature or rupturing schizonts but not immature parasites. Myosin was identified in immunoblots of parasite protein extracts by several monoclonal anti-skeletal muscle myosin antibodies, as well as by a polyclonal antiserum directed against a consensus conserved myosin sequence (IQ motif). The identity of the polypeptides recognised by these antibodies was confirmed by overlaying blots with biotinylated F-actin. The antiserum and one of the monoclonal antibodies were used in immunofluorescence studies and were found to stain all blood-stage parasites, with maximal intensity towards the poles of merozoites. Our results are consistent with the presence of an actomyosin motor system in the blood-stage malaria parasite. PMID- 8677133 TI - Plasmodium falciparum lacks sialidase and trans-sialidase activity. AB - Sialic acid on the red cell surface plays a major role in invasion by the malaria parasite Plasmodium falciparum. The NeuAc(alpha 2,3) Gal motif on the O-linked tetrasaccharides of the red cell glycophorins is a recognition site for the parasite erythrocyte-binding antigen (EBA-175). Consequently, the interaction of P. falciparum and the red cell might share homology with that of the influenza virus. The cellular interactions of P. falciparum were examined for their sensitivity to 4-guanidino-2,3-didehydro-D-N-acetyl neuraminic acid (4-guanidino Neu5Ac2en), a potent inhibitor of influenza virus sialidase. Parasite invasion and subsequent development was unaffected by the sialidase inhibitor. The inhibitor did not affect rosette formation of parasite-infected erythrocytes with uninfected cells nor their cytoadherence to C32 melanoma cells. Furthermore, we were unable to confirm the presence of a previously reported parasite sialidase using sensitive fluorometric or haemagglutination assays, neither was any malarial trans-sialidase identified. We conclude that P. falciparum possesses neither sialidase nor trans-sialidase activity and that an inhibitor of influenza virus sialidase has no effect on important cellular interactions of this parasite. PMID- 8677135 TI - Paramyosin isoforms of Schistosoma mansoni are phosphorylated and localized in a large variety of muscle types. AB - Paramyosin, although a widely distributed muscle component among invertebrates, has hitherto not clearly been shown to occur in the muscles of schistosomes. Instead, it has been reported to occur in the tegument. In the present study, a specific antibody reacting with each of 10 isoforms of paramyosin was used for light microscopical immunolocalization in sections of Schistosoma mansoni. Specimens were fixed by a new method to immobilize antigens with uranyl acetate trehalose-methanol. In cercariae, schistosomula, and adults, the circular and longitudinal muscles of the body wall, the dorsoventral muscles and those surrounding the gut and the pharynx as well as the fast moving cross-striated muscles of the tail of cercariae intensely reacted with the antibody. However, neither immunohistologically nor on Western blots of isolated tegument, were indications found for the presence of paramyosin in the tegument. In vivo phosphorylation and binding of anti-phospho-tyrosine and anti-phospho-serine antibodies show phosphorylation of paramyosin which probably is responsible for the generation of the isoforms. PMID- 8677136 TI - Analysis of lectin- and snail plasma-binding glycopeptides associated with the tegumental surface of the primary sporocysts of Schistosoma mansoni. AB - Carbohydrates associated with the tegumental surface of Schistosoma mansoni primary sporocyst may serve as potential receptors for mediating recognition by the internal defence system of the molluscan host, Biomphalaria glabrata. Therefore, a combination of SDS-PAGE and lectin probe analyses were carried out on biotin-labelled tegumental glycopeptides as a first step to defining the carbohydrates expressed at the sporocyst surface. The majority of surface polypeptides, ranging in relative molecular masses from 27 to 113 kDa, reacted with horseradish peroxidase-labelled Canavalia ensiformis (Con A), Erythrina corallodendron (ECA), Glycine max (SBA) and Triticum vulgaris (WGA) lectins indicating that most, if not all, tegumental proteins are glycosylated. However, differences in the binding of some lectins to individual glycopeptides suggest a degree of heterogeneity in the structure/composition of sugar moieties comprising these surface glycoconjugates. This notion is supported by the finding that the fucose-specific Tetragonolobus purpureas (TPA) lectin only reacted with approximately 50% of glycopeptides identified at the tegumental surface. Experiments employing biotin-labelled plasma (cell-free haemolymph) from S. mansoni-susceptible and -resistant B. glabrata snails as probes, further demonstrated that many of the identified surface glycoproteins also serve as plasma-binding sites for both snail strains. Binding interactions between plasma and sporocyst surface glycoproteins appeared to be, at least in part, mediated by carbohydrates since periodate treatment of sporocyst proteins or pre-incubation of plasma with the glycoproteins, fetuin or mucin, resulted in a decrease in plasma reactivity to blotted larval proteins. PMID- 8677137 TI - Trypanosoma brucei s.l: evolution, linkage and the clonality debate. AB - The Index of Association (IA) has been proposed by Maynard Smith et al. (1993) as a general method for characterizing the population structures of microorganisms as either: clonal, epidemic, cryptic species or panmictic. With reference to the current debate surrounding the mode of reproduction in parasitic protozoa, this study explores (i) the suitability and limitations of the IA for characterizing populations of Trypanosoma brucei s.l., and (ii) the idea that the significance of genetic differences between populations may be better understood if the evolution, spread and temporal stability of certain parasite genotypes are also considered. Four populations of T. brucei from Cote d'Ivoire, Uganda and Zambia are analysed using the IA and a complementary test for linkage disequilibrium, test f of Tibayrenc, Kjellberg & Ayala (1990). The two populations from Uganda are characterized as epidemic, while the others appear more or less clonal; the merits of the two methods are compared. The implications of the various population classifications are discussed with reference to genotype longevity in each region; the evolution and biomedical consequences of the genetic non homogeneity of T. brucei are reviewed. PMID- 8677138 TI - Intestinal parasite burden in five troops of olive baboons (Papio cynocephalus anubis) in Gombe Stream National Park, Tanzania. AB - A cross-sectional parasitological study of a population of wild olive baboons (Papio cynocephalus anubis), consisting of 5 troops, was conducted in Gombe Stream National Park. Baboons were individually recognizable. Information on age, sex, troop membership, reproductive status, social rank and life-history of each individual baboon could be related to parasite infection. Seven helminth taxa and 2 protozoan taxa were found. All baboons were parasitized by at least 1 taxon. Distributions of helminths were aggregated among hosts. There were significant differences among troops in the prevalence of all but 2 of the recorded helminths. Age had a significant impact on the prevalence and intensity of Strongyloides sp. No significant effect of sex on the prevalence of infection could be detected. There was some indication that female reproductive status was related to Trichuris egg output. In contrast to a previous study, no significant correlations between parasite infection and social rank could be found. Troop membership constituted the predominant factor contributing to heterogeneity of prevalence of infection. This suggests that spatial location and/or genetics may be important in determining levels of parasite infection. PMID- 8677139 TI - In vitro polarization of carp leucocytes in response to the blood fluke Sanguinicola inermis Plehn, 1905 (Trematoda: Sanguinicolidae). AB - An in vitro assay was used to determine the effects of Sanguinicola inermis adults and cercariae on the polarization responses of pronephric leucocytes of carp. Leucocytes were isolated and exposed to live adult flukes or cercariae for up to 48 h. Differences in polarization responses were related to the presence of the parasite, the presence or absence of carp serum and the time of incubation. The mean proportions of cells exhibiting polarization in unstimulated controls ranged from 5 to 30% over the experimental period. Within 15 min of exposure to adults or cercariae, significant increases in mean polarization responses were observed of up to 75% and levels remained higher than control values for over 24 h. Overall, the presence of normal carp serum, either untreated or heat inactivated, did not enhance the polarization responses of leucocytes incubated with only cercariae or adults. However, between 0.25 and 3 h, the presence of carp serum with cercariae significantly enhanced polarization responses when compared with cells incubated with cercariae alone. PMID- 8677141 TI - Fast spin-echo MR imaging of the pediatric brain. AB - On a 1.5-T MR unit conventional spin-echo (CSE) and fast spin-echo (FSE) images were obtained in 70 consecutive children ranging from 4 days to 13 years in age. They suffered from developmental retardation, neurodegenerative, ischemic or inflammatory diseases. In our prospective study artifacts, lesion conspicuity and general impression were compared between double-echo (proton density- and T2 weighted) CSE and single-echo (T2-weighted) FSE images. Phase artifacts from flowing blood were seen rarely on the FSE images, while motion artifacts appeared more frequently. Assessment of myelination in 43 children with unfinished myelination revealed no difference between FSE and CSE. The lesion conspicuity in 20 children with focal abnormalities compared favorably between FSE and CSE. There was no diagnostically relevant difference between FSE and CSE, although in FSE spin density images were missing. FSE sequences can be used in MR imaging of the pediatric brain without disadvantage and with a time reduction of 67-75%. PMID- 8677140 TI - Orbital sonography in children. AB - Orbital sonography with color-flow Doppler imaging is a relatively new technology with significant application in the pediatric patient. This review stresses the primary indications for pediatric ophthalmic ultrasound and also discusses those instances where the use of ultrasound supplements other imaging studies. PMID- 8677142 TI - Lumbar spinal cord motion measurement with phase-contrast MR imaging in normal children and in children with spinal lipomas. AB - We assessed the normal movement of the lumbar spinal cord using phase-contrast MR imaging, and also the movement of the spinal cord in patients with spinal lipoma pre- and postoperatively. Phase-contrast MR imaging proved to be a valuable tool in this context. PMID- 8677143 TI - Presacral myelolipoma: sonographic appearance. AB - We describe an uncommon case of presacral myelolipoma in a 11/2-year-old boy, causing urinary retention and constipation. The sonographic appearance of the mass mimics a "pseudoprostatic enlargement". PMID- 8677144 TI - Hypomelanosis of Ito associated with neuroblastoma. AB - We report a patient with hypomelanosis of Ito associated with neuroblastoma. Though not previously reported, the association is plausible since both conditions are forms of "neurocristopathy". PMID- 8677145 TI - Henoch-Schonlein purpura with intracerebral hemorrhage: case report. AB - We report the case of a 5-year-old patient with Henoch-Schonlein purpura (HSP) who had a large intracerebral hematoma (ICH) in the left parietal area. HSP complicated by ICH is rare, with only three cases reported in the literature. Conservative treatment with steroid therapy in this patient was successful and no further major neurologic sequelae occurred. PMID- 8677146 TI - Diffuse pneumocephalus due to meningitis: CT findings. AB - Diffuse pneumocephalus due to infection by gas forming organisms is very unusual. We report computed tomography (CT) findings of such a case in an infant with Clostridium meningitis. PMID- 8677147 TI - MRI examination and monitoring of pediatric patients under sedation. AB - From April 1992 to May 1994, 780 patients aged from 1 day to 8 years were examined. Sedation of these patients was conducted by giving chlorprothixene orally and, in some cases, chloral hydrate had to be added. The patients were monitored with a pulse oxymeter. Investigations could begin after 50 -120 min. In 710 patients (91%) the first attempt to perform the examination was successful; 70 patients required one or two further attempts. Only two of the 780 patients (0.5%) showed evidence of respiratory depression. The total number of pediatric MRI examinations performed in 1 year is almost 1000. In the hands of an experienced pediatric radiologist these examinations can be performed entirely without anesthesia. PMID- 8677148 TI - Regional cerebral blood flow estimates in newborn lamb using amplitude-mode color Doppler ultrasound. AB - PURPOSE: To establish the feasibility of determining changes in regional cerebral blood flow using amplitude-mode color Doppler ultrasound in the newborn lamb. METHODS: Regional cerebral blood flow was modified by intrastriatal injection of N -methyl-D-aspartic acid (NMDA) in two newborn lambs and compared with that in a control animal receiving only intrastriatal saline. Serial color Doppler ultrasound energy images were obtained in coronal projection at the level of the foramen of Monro, before and at 20, 40, and 60 min after NMDA or saline injection using a 7.0-MHz linear transducer. Real-time images were obtained and transferred onto a computer workstation. Regions of interest were drawn over each striatum and cerebral hemisphere and were analyzed for mean pixel intensity (MPI) at each interval. Paired regional cerebral blood flow (r-CBF) determinations (radiolabeled microsphere technique) were also obtained in every animal. MPI and r-CBF for each anatomic region were compared using linear regression. RESULTS: Mean color pixel intensities increased significantly in the ipsilateral basal ganglia and cerebral hemisphere (p < 0.0001) in both animals injected with NMDA, but not in the animal injected with normal saline (p < 0.63). A strong and significant linear correlation was found between MPI and r-CBF for striatum (r = 0.89, p < 0.0001) and cerebral hemisphere (r = 0.85, p < 0.0001). CONCLUSIONS: Amplitude-mode color Doppler ultrasound shows potential for technically simple determination of serial changes in regional cerebral blood flow in infants. PMID- 8677149 TI - Magnetic resonance imaging of knee injuries in children. AB - The purpose of this study was to evaluate the significance of meniscal appearances and determine the frequency of abnormalities seen on magnetic resonance (MR) imaging in children with knee injuries. We reviewed 78 consecutive MR imaging studies of 74 children aged 5-16 years with unfused epiphyses. Menisci were evaluated using conventional grading techniques. We used chi2 to compare the frequencies of medial and lateral meniscus and anterior cruciate ligament (ACL) tears with each other and with published data for children. Similarly, we compared the proportions of tears of these structures with published data. Arthroscopy results from 26 children were used to calculate sensitivity and specificity of MR imaging for meniscal tears, which were 100% (8/8) and 89% (16/18), respectively. The majority of studies (82%) had grade I or II signal intensity in one or both menisci. Arthroscopy results available in 33% of this group revealed normal menisci. Tears of the medial and lateral menisci were significantly more common than of the ACL. Injuries of the ACL were seen significantly less frequently than previously reported. Grade I or II meniscal signal intensity in children with knee injuries is consistent with a normal meniscus. Tears of the menisci are more common than ACL tears. MR imaging in this context appears reliable. PMID- 8677151 TI - Ultrasound contribution in the analysis of the newborn and infant normal and clubfoot: a preliminary study. AB - The aim of this study was to evaluate the potential use of ultrasound in the preoperative assessment of clubfoot and follow-up growth. We first studied 50 normal newborns and infants (aged 1 day to 1 year). The normal values established were reliable, dynamic and reproducible measurements allowing the assessment of osteo-articular relationships and cartilage morphology. Ultrasound appears to be more useful than radiography because it allows delineation of cartilaginous structures (which are not visible on conventional radiographs) and dynamic study of foot positions, and has no danger from radiation. A future paper will contain preliminary results of cases of clubfoot studied by ultrasound. PMID- 8677150 TI - The value of sonography in the detection of osteomyelitis. AB - PURPOSE: A retrospective study was carried out in order to determine the role of sonography in establishing the diagnosis in extremity osteomyelitis. MATERIALS AND METHODS: The imaging documents of 24 infants and children aged from 2 weeks to 13 years with osteomyelitis (acute 21, chronic 3) were reviewed. Sonograms and conventional radiographs were available in all patients. Additional skeletal scintigraphy had been performed in 13 patients and MRI in only 3. Special emphasis was put on the different ultrasound findings and their onset in the course of disease. RESULTS: Intra-articular fluid collections (in 15 cases) and/or subperiosteal abscess formation (in 12) were the most frequent early sonographic findings, and preceded any radiographic changes by several days in 11 of these cases. Together with positive clinical signs of inflammation, they were usually sufficient to establish the correct diagnosis. In selected cases, fluid or abscess puncture for immediate microscopic and later bacteriological studies was carried out under sonographic control. In addition, sonography was also able to detect superficial cortical erosion and even an intramedullary focus in a very young patient. CONCLUSION: Ultrasonography is a very helpful tool for establishing the correct diagnosis in osteomyelitis and reducing the frequency of additional imaging studies. PMID- 8677152 TI - Neonatal osteofibrous dysplasia: report of two cases. AB - Skeletal neoplasms of the newborn and neonatal period are infrequently encountered and often misdiagnosed. Osteofibrous dysplasia is a tumor of childhood that may be seen in the newborn. Because of its unique natural history, with and without surgical treatment, and the similarity in radiographic appearance of this tumor to other lesions, a high index of suspicion must be maintained when a tibial lesion is encountered in the newborn. We present two additional cases of neonatal osteofibrous dysplasia and discuss the differential diagnostic considerations. PMID- 8677153 TI - [Bone marrow transplantation in children]. AB - The most frequent indications for bone marrow transplantation and complications of this method of treatment are reviewed. The results are compared with results of conventional therapy. Attention is focused on increasing possibilities of autologous transplantations in children having no HLA-compatible siblings. PMID- 8677154 TI - [Blood antioxidant defense in children with malignant disease. I. Plasma antioxidant activity and level of ceruloplasmin and transferrin]. AB - In this study we examined selected elements of the antioxidant defence system in the plasma of children with the most common solid tumors (nephroblastoma, neuroblastoma, rhabdomyosarcoma, osteosarcoma). We observed a significant increase of plasma antioxidant activity (AOA) in the majority of the examined children. This factor changed during clinical treatment, i.e. induction of chemotherapy, surgery and/or radiotherapy and during maintenance chemotherapy. We conclude that the elevated plasma antioxidant activity in children with malignancy may be due to the higher concentration of ceruloplasmin in affected children than in their healthy counterparts. PMID- 8677155 TI - [Defense system antioxidants in blood of children with neoplasms. II. Antioxidant enzymes and lipid peroxidation in erythrocytes]. AB - The aim of the work was to investigate selected parameters of antioxidant defence in red blood cells of children suffering from various types of solid tumors. In patients with these tumors, glutathione reductase and glutathione S-transferase activities were found to be reduced in comparison to healthy children. PMID- 8677156 TI - [Nephrotoxicity evaluation of cytostatic agents in children with acute lymphoblastic leukemia]. AB - Urinary excretion of the markers of tubular nephrotoxicity, total NAG and isoenzymes A and B and B-2-M, were evaluated in urine of 21 children with acute lymphoblastic leukaemia after the first injection of cytostatic administrated according to the BFM scheme: VCR + Rub, L-aspa, CY, Ara-C. Every administrated drug caused temporary elevation in urinary excretion of total NAG and isoenzyme B and B-2-M. GFR was unchanged. These results point to nephrotoxicity of cytostatics. Peak total NAG, isoenzyme B and B-2-M excretion was observed on the third day after L-aspa and Ara-C injection. PMID- 8677157 TI - [Strumectomy in children and adolescents--personal studies with 12,000 operations]. AB - At the Surgery Clinic of the Endocrinology Institute in Lodz we operated 12 344 patients between 1974 and 1992 because of various types of goitre. Among these there were 295 children and adolescents, 2.4%- aged between 9-18 years: 268 girls (90.8%) and 27 boys (9.2%). The goitre was 9.9 times more frequent in girls than in boys. In adults the ratio was 8:1. PMID- 8677158 TI - [Estimation of effectiveness of antiemetic treatment with Zofran given in one dose to children with neoplasms]. AB - Clinical studies of antiemetic treatment with Zofran in children suffering from neoplastic diseases are presented. The studies were carried out in 33 children aged 3 months to 17 years treated in 1993. The majority of the patients were treated for ALL (20), Hodgkins disease (3), nephroblastoma (3), non-Hodgkin lymphoma (2), solid tumors (5). Two-hundred thirty-eight cycles of chemotherapy with cystostatics having varied emetic effects were carried out in these children. Zofran was given in one dose, one hour before chemotherapy in a dose of 4 or 8 mg. The intensity of vomiting was assessed according to the WHO 5-grade scale. O to 1 grade of vomiting was observed in 84.4%, 2nd grade in 15.2%. There were no cases of 3rd or 4th grade vomiting. No side-effects of the medication were observed in the studied group. It was found that Zofran is an effective and well-tolerated antiemetic medication in children on chemotherapy. PMID- 8677159 TI - [Preliminary evaluation of individualized use of large doses of methotrexate for treatment of osteosarcoma in children and adolescents]. AB - To improve the final treatment results in children with osteosarcoma, we applied after French DD-11 protocol HD MTX increasing with the younger age of patients, modified next on the basis of maximal serum drug concentrations (Cmax) as feed back dosing. Toxic side effects were analysed according to WHO grading correlated with MTX elimination. We administered 39 HD MTX courses in 13 patients with osteosarcoma: aged 7-20 yrs (median 12 yrs). We performed 301 measurements of MTX concentration using the method of fluorescence polarisation. Therapeutic Cmax of 1000 microM/L and higher were obtained in 20 courses, the mean of lower values was 770 microM/L. We modified the next MTX doses in 23.7% of courses. Drug elimination was good in the majority of cases: in 34 of 39 courses at 24 hrs, in 36 of 39 at 48 hrs. Nevertheless, III and IV degree toxic side-effects accompanied about half of the courses and could not be predicted by MTX serum level measurements. HD MTX therapy with monitoring MTX serum levels proved feasible with acceptable toxicity. Therapeutic MTX levels were obtained in about 60% of cycles in patients with a favourable course of the disease in comparison with 25% in patients with an unfavorable course but the beneficial effect of age tailored MTX and feed-back dosing on the treatment results will be possible to assess in the next 3 years. PMID- 8677160 TI - [Role of chemotherapy in treatment of osteosarcoma]. AB - The paper is dedicated to various forms of chemotherapy used in osteosarcoma from the very beginning in '70-ties, when only one drug treatment was applied through the following 20 years full of assays and clinical trials, which finally proved the necessity of multidrug chemotherapy in all cases of osteosarcoma. The introduction of crucial neoadjuvant chemotherapy with exemplary Rosen programme T 10 which enabled the progress of conservative limb-salvage surgery and experience with this programme of many national groups are discussed. PMID- 8677161 TI - [Prognostic factors in neuroblastoma in children]. AB - The paper presents the review of prognostic factors which were investigated from the first interests of neuroblastoma, as a model for cancer biology in pediatric oncology. The authors on the basis of other authors experiences and on the own observations, as well stress the importance of basic sciences from the field of molecular biology, cytogenetics and biochemistry, leading to better understanding of the nature of neuroblastoma and to introduction of rational treatment. The stratification of neuroblastoma patients according to the known prognostic variables influenced favourably treatment results. PMID- 8677162 TI - [Chemotherapy with combined treatment of malignant germ cell tumors in children]. AB - Significant improvement in the prognosis of malignant germ cell tumors in children is related to the introduction of multi-drug chemotherapy based on cisplatin. The most effective combinations of drugs are BEP and BVP; in advanced tumors they make it possible to employ radical surgical procedures. PMID- 8677163 TI - [Modern therapy of osteogenic sarcoma in children. Our experience in limb salvage surgery]. AB - The author presents the contemporary multimodality treatment in osteosarcoma in children and adolescents, taking into account salvage surgery and less mutilating surgery. Between 1962 and 1994, 158 osteosarcoma and 105 Ewing's sarcoma patients were treated in The Research Institute of Mother and Child. In these population 60 less mutilating operations were done. The comprehensive therapy influenced positively the results causing the increase of cure rate from 4.5% to 75% in osteosarcoma and from 4.3% to 41.3% in Ewing's sarcoma patients. PMID- 8677164 TI - [An isolated parathyroid adenoma]. AB - The paper presents a 14-year-old girl with an isolated parathyroid adenoma which was manifested by arthralgia, decreased muscle strength and gait disturbances. Hyperparathyroidism resulting from parathyroid adenoma was diagnosed on the basis of the characteristic X-ray picture and biochemical findings. Surgical treatment led to a subsidence of symptoms and a gradual improvement of the bone lesions as visualized by X-ray. The authors stress the rare incidence of parathyroid adenoma in such young patient. PMID- 8677165 TI - [Clear cell carcinoma of the kidney in an 8-year-old boy]. AB - The case of clear cell carcinoma of the kidney in an 8-year-old boy is presented. The boy initially presented with hematuria and diagnosis of tumor of the right kidney was based upon IVP. Chemotherapy was started due to suspicion of Wilms' tumor (vincristine and actinomycin), and subsequently the child underwent surgery. Microscopic examination revealed the presence of clear cell carcinoma of the kidney. Chemotherapy was continued after surgery and radiation therapy was applied to the tumor bed. Presently, after 17 years follow-up the patient remains with no evidence of disease. PMID- 8677166 TI - [Malignant neuroectodermal tumor of the arm in a 15-year-old girl successfully treated with chemo- and radiotherapy]. AB - In a 15-year-old girl with right upper arm tumor diagnosed at first as neuroblastoma, the second histopathological examination revealed PNET. In spite of the advanced stage of disease (IIIrd or IVth) surgical excision was not performed but chemotherapy (8 courses of VADRAC and 8 courses of VP16 + CDDP) and radiotherapy (40 Gy) was administered. After 4 initial cycles all symptoms of the disease disappeared. The child remains in CCR for 60 months, including 40 months of therapy. PMID- 8677167 TI - [Multidrug chemotherapy in a 8-year old child with advanced olfactory neuroblastoma]. AB - Successful treatment of olfactory neuroblastoma is more often described in less advanced tumors and mostly in adults. Fewer presentations concern successful chemotherapy in advanced stages of the disease. PMID- 8677168 TI - [Intrapericardial teratoma in a 3-month-old infant]. AB - A 3-month-old infant with extensive intrapericardial teratoma compressing and dislocating the great vessels and the heart underwent successful surgery despite severe intraoperative circulatory disturbances. PMID- 8677169 TI - Efficacy and safety of continuous albuterol nebulization in children with severe status asthmaticus. AB - We prospectively examined the efficacy and safety of continuous albuterol nebulization (CAN) therapy for children diagnosed with impending respiratory failure and status asthmaticus. Serum creatine phosphokinase (CPK) levels were measured, and other factors associated with cardiotoxicity were monitored. Seventeen patients (20 months to 17 years old) were enrolled in the study. No chest pain, arrhythmias, or signs of clinical deterioration occurred in any patient receiving CAN. No study subject required therapy with isoproterenol or mechanical ventilation. An elevation of total serum CPK was found in three patients; however, only one of these patients had an elevated (positive) CPK-MB isoenzyme fraction. We feel that CAN is safe for use in children diagnosed with status asthmaticus. Monitoring of serum CPK enzymes during CAN therapy is warranted until further studies have determined the significance of elevated CPK MB isoenzymes in otherwise asymptomatic children treated for severe status asthmaticus. PMID- 8677170 TI - Technical skills experiences in pediatric emergency medicine fellowship programs. AB - Guidelines for Pediatric Emergency Medicine (PEM) fellowship programs were published by the Curriculum Subcommittee, Section of Emergency Medicine, American Academy of Pediatrics in February 1993. The guideline listed 120 technical skills that the subcommittee felt all fellows should be able to perform at the completion of their training. The purpose of this study was to measure the experience of PEM fellows in performing skills recommended by the subcommittee and to determine if documentation lists were being maintained. A written survey was mailed to 63 graduating fellows in May 1993, requesting information on the number of times procedure skills were performed. Limited experience was defined as having performed a procedure five or less times. Thirty-two surveys (51%) were returned. Eleven fellows (34%) stated they maintained a procedure documentation list. Of 117 skills analyzed, the majority of fellows had limited experience in 49 procedures and zero experience in 22 procedures. The majority of fellows had limited experience in 12 of 20 life- or limb-saving procedures and zero experience in five. Large emergency department volumes did not influence number of procedure completions. Our data indicate that graduating PEM fellows have limited experience in performing many common as well as several life- and limb saving skills. Documentation lists of technical skills are not being maintained by most fellows. PMID- 8677171 TI - Child life programs in the pediatric emergency department. AB - Child life (CL) programs have long been utilized in the inpatient setting to help in relieving the stress and anxiety associated with hospitalization. The objective of this study was to determine the current availability of such programs in pediatric emergency departments (ED) and what interventions were provided in one ED with a CL program. We conducted a telephone survey of EDs in 44 large children's hospitals in the United States as to their use of child life specialists (CLS). Also, a retrospective review was performed of the CL intervention in one large pediatric ED over a two-year period. Only 6/44 EDs (14%) had at least one full-time CLS, with three of those having two full-time workers. In these EDs the CLS prepared children for painful or anxiety-provoking procedures and provided developmentally appropriate activities in the ED. Another 6/44 (14%) had CL services available by consult. There were no CLS available in 32/44 (72%) EDs, where nursing staff prepared children for painful procedures. EDs with a higher census were more likely to have a full-time CLS (P = 0.02). Hospitals with certified pediatric trauma centers were less likely to have any CL services available in the ED (P = 0.04). A review of the records of the ED at Arkansas Children's Hospital revealed that 32% of patient contacts by the CLS were for invasive procedure teaching and support. Another 22% of interventions were for developmental stimulation. Family support (21.5%) and therapeutic intervention (17.5%) were the next most common contacts. Admission teaching accounted for 4%, while preoperative teaching and support accounted for only 3% of the total. There were more patient contacts made by the worker on evening shift. CL programs, while common in the inpatient setting, are currently underutilized in most pediatric EDs. CLS can provide a variety of services in the pediatric ED. PMID- 8677172 TI - Acute periorbital swelling: evaluation of management protocol. AB - OBJECTIVE: Reporting and evaluating a general pediatric unit experience with a simplified protocol based on clinical signs stated on admission used to classify cases of periorbital cellulitis in potential high- and low-risk complication groups. POPULATION: All children under the age of 14 years with acute periorbital swelling not resulting from an immediate direct trauma to the eye and the orbit, referred to the emergency department between December 1, 1986, and December 31, 1992. METHOD: A high-risk case was defined by: age under two months, meningeal or focal neurologic signs, vision loss, limitation of eye movement, eye malformation or operation in the vicinity, and clinically toxic child on admission. Absence of these elements defined the low-risk case. Initial antibiotic management was the same in both groups, but work-up was different according to the classification of the case. RESULTS: Thirty-four patients were included in the study. Only one (six months old) had a positive blood culture with Haemophilus influenzae found in the low-risk group (16 patients), and no serious complication was encountered. In the high-risk group (18 patients), five had positive cerebrospinal fluid and/or blood culture, two had subperiosteal abscesses, and three had intracranial abscesses. In the whole series, "toxicity" was significantly associated with either positive cerebrospinal fluid or blood culture. Fifty percent of positive cultures were due to H. influenzae. CONCLUSION: The protocol is considered practical, safe, and represents a suitable triage tool particularly if the high-risk age was raised to 12 months. There is no necessity to perform lumbar puncture in the low-risk group. PMID- 8677173 TI - Orthopaedic trauma in children less than three years old: the orthopaedist's and pediatrician's problem. AB - A retrospective study of children under three years old with orthopaedic trauma (fractures and soft-tissue injuries of the extremities) from a selected five-year period (1987-1991) was performed in Pirogov Emergency Medical Institute in Sofia, Bulgaria. This study confirmed that these kinds of injuries have an excellent prognosis owing to the specific features of the growing skeleton; however, this excellent prognosis in small children is not guaranteed unless pediatricians, orthopaedists, and parents collaborate closely. Particularly, pediatricians in primary care settings play an especially important role in this respect. Pediatricians need an exact approach and protocol. PMID- 8677174 TI - Pediatric and neonatal critical care transport: a comparison of therapeutic interventions. AB - OBJECTIVE: To compare the therapeutic interventions provided to newborn and pediatric patients by a dedicated combined neonatal pediatric critical care transport team. METHOD: From November 1987 through December 1989 we prospectively compared the number of therapeutic interventions performed by the critical care transport team on newborns and pediatric patients. The transport team (critical care physician [PL3 or greater], pediatric respiratory therapist, critical care nurse), recorded all therapeutic interventions, including both procedural and pharmacologic, for 213 newborn and 149 pediatric consecutive transports. Data were analyzed by analysis of variance or chi 2 statistic. RESULTS: All patients were admitted to either the pediatric or the neonatal intensive care unit, and over 80% of both age groups received assisted ventilation. Newborns commonly suffered from respiratory diseases (159/213), while pediatric patients suffered from respiratory (52/149), central nervous system (28/149), and traumatic conditions (37/149). Airway maintenance procedural interventions (intubation, ventilation) were the commonest in both groups, although more frequent in neonates. Neonates received antibiotics and morphine (P < 0.05) while pediatric patients received anticonvulsants and respiratory drugs (P < 0.05) more frequently. Newborns received significantly more interventions than pediatric patients (average 3.56 vs 2.93, P < 0.05). Newborns also received significantly more procedural interventions (2.06 vs 1.36, P = < 0.05) including intubation (34.7% vs 15.4%, P < 0.05) and the initiation of mechanical ventilation (38% vs 22%, P < 0.05). CONCLUSION: Overall, newborns received more interventions, including intubation, and ventilation from the transport team than did pediatric patients. Our data suggest that combined pediatric neonatal transport teams should be prepared to intervene in a wide range of conditions from preterm respiratory distress to the multiply traumatized adolescent. PMID- 8677175 TI - Pediatric emergency department utilization habits: a consumer survey. AB - The objective of this study was to identify pediatric emergency department (PED) utilization patterns to develop areas for future educational interventions. To this end a verbally administered questionnaire by a single interviewer was given over 17 days between February 8, 1993, through April 7, 1993, at a PED of an urban university hospital. Participating were 300 families (convenience sample) who were interviewed at varying times of the day and night. They represented about 20% of PED visits during the survey days. Each parent was surveyed about his/her child's health. Parents were also asked to indicate on a linear scale how sick they believed their child was. The mean patient age was 3.8 +/- 4.3 years; 81% were African-American, 15% were Caucasian, and 2% were Hispanic; 65% had medical assistance (MED), 21% had commercial insurance (COM), and 4% had both. Ten percent either had no insurance or their insurance status was unknown. Thirty four percent of patients utilized a community clinic for primary health care, 32% identified a private physician, and 28% used the hospital's pediatric clinic. The most commonly stated reasons for coming to the PED differed between the MED and COM groups; 14% of the MED group was referred compared to 59% of the COM group (P = 0.002, chi 2), 24% of the MED group came because their primary care provider's office was closed compared to 3% of the COM group (P < 0.01, chi 2). Seventy-one percent of COM group called their primary care provider before coming to the PED compared to 27% of MED group (P < 0.001, chi 2). Analysis of parental rating of their child's illness severity on a linear (10-point) scale showed a mean of 5.7 +/- 2.5. The COM group had lower triage scores (indicating greater severity of illness) than the MED group: 50% COM patients were scored < or = 2.5 compared to 30% of MED patients (P < 0.01, chi 2). We found a significant difference in the PED utilization habits of patients on medical assistance compared to those with commercial insurance, and we plan to develop educational materials to meet the needs of our patients, many of whom utilize the PED for nonurgent illnesses. PMID- 8677176 TI - Conscious sedation for pediatric orthopaedic emergencies. AB - The objective of this study was to assess complications and risk factors among children undergoing conscious sedation (CS) with fentanyl (F) and midazolam (M) for reduction of fractures and dislocations. A 22-month retrospective review was made of an urban pediatric emergency department's records after implementing a CS protocol for the administration of F/M. Data collection was facilitated by standard CS forms, and data were analyzed using descriptive statistics, chi 2 analysis, Fisher's exact test, t test, odds ratio, and logistic regression. A total of 339 children (65% boys), mean age of 8.4 years, were enrolled in the study. The mean time to sedation was 11.3 +/- 6.2 minutes and to discharge was 92 +/- 36.3 minutes. The mean total doses of M and F were 0.17 +/- 0.08 mg/kg and 1.5 +/- 0.8 micrograms/kg, respectively. An alteration in respiratory status occurred in 37 (11.0%) patients: 28 (8.3%) had oxygen saturation < 90%; 16 (4.7%) received oxygen; 12 (3.6%) were given verbal breathing reminders, eight (2.4%) received airway positioning maneuvers, and 2 (0.6%) received naloxone. Four patients (1.2%) vomited. None required assisted ventilation, intubation, or admission resulting from complications of CS. Characteristics associated with the respiratory events included female sex (odds ratio = 2.2) and deep sedation (odds ratio = 2.7). We conclude that complications associated with F/M administered by protocol were few, minor, and easily managed. Patients who are female or who enter a state of deep sedation may be at modestly increased risk for alterations in respiratory status. Careful attention to monitoring vital functions on all patients is necessary to provide safe CS. PMID- 8677177 TI - Toxicology screening in adolescent trauma. AB - We sought to define the prevalence of positive drug screens in adolescent victims of major trauma. The records of 125 consecutive adolescent patients presenting with major trauma to an inner-city trauma center during the last nine months of 1990 were reviewed. Eighty-five (68%) received urine toxicology screens for alcohol and illicit drugs. Twenty-one (25%) of screened patients had a positive urine drug screen. The most commonly detected drugs were alcohol, cocaine, and opiates. Gender, race, mechanism of injury, mental status at presentation, injury severity score, and revised trauma score were not associated with a positive drug screen. We conclude that: 1) 25% of screened adolescent victims of major trauma seen at an inner-city trauma center had positive urine toxicology screens for alcohol or illicit drugs. 2) As none of the study variables was associated with a positive drug screen, selective drug screening cannot be supported. PMID- 8677178 TI - Traumatic rupture of an unsuspected mesenteric cyst: an uncommon cause of an acute surgical abdomen following a minor fall. PMID- 8677179 TI - Intraperitoneal rupture of an infected urachal cyst: a rare cause of peritonitis in children. AB - Intraperitoneal rupture of an infected urachal cyst is a rare cause of peritonitis in children, and has previously been reported in four children. We report this condition in a 34-month-old toddler who presented with a two-week history of abdominal pain and four days of infraumbilical swelling and erythema. Abdominal ultrasonography (US) and computerized tomography (CT) scan with contrast were helpful in the preoperative evaluation, showing an inflammatory process involving the anterior abdominal wall. The child was treated with intravenous antibiotics, and the infected urachal cyst, other parts of the urachal remnant, and a small portion of the dome of the bladder were excised. The postoperative hospital course was uncomplicated. Because of its rarity and variable manifestations, prompt diagnosis depends on maintaining a high index of suspicion. This diagnosis should be entertained in children with peritonitis in association with umbilical and midline abdominal abnormalities. PMID- 8677180 TI - Noninvasive nasal mask positive pressure ventilation in a pediatric patient with acute hypoxic respiratory failure. PMID- 8677181 TI - The emergency management of hyperglycemic-hyperosmolar nonketotic coma in the pediatric patient. AB - We recommend consideration of HHNK in comatose pediatric patients and advocate the prompt institution of fluid therapy. Insulin is not required during the initial course of treatment and potentially can have adverse effects. Compared to adults, pediatric patients appear to be at a greater risk of developing potentially fatal cerebral during the course of treatment. In order to prevent complications associated with the rapid decrease in serum tonicity the initial management should consist of fluid therapy directed toward repleting the intravascular volume, correcting electrolyte abnormalities, and slowly returning serum tonicity to normal. PMID- 8677182 TI - Case records of the Medical College of Virginia: a 10-year-old girl presenting with an acute onset of abdominal pain. PMID- 8677183 TI - Child abuse among friends and acquaintances. PMID- 8677184 TI - Pediatric emergency medicine: legal briefs. PMID- 8677185 TI - Latex allergy in pediatric emergency department personnel. AB - Allergy to natural latex proteins has been recently recognized as a dangerous entity among health care professionals. Cutaneous symptoms related to latex glove use vary from the redness and scaling of contact dermatitis to urticaria. In addition, anaphylactic reactions have been reported. We report the spectrum of reactions to latex glove use in 93 members of our emergency department (ED) staff during a one-month study period. In addition, we attempt to correlate these symptoms with serologic evidence of atopy and latex allergy. Eighty-four of these subjects underwent total serum immunoglobulin E and latex-specific radioallergosorbent test (RAST) testing. Fifty-four percent of subjects reported symptoms relating to latex glove use, categorized as either contact dermatitis (48.4%) or urticaria (5.4%). Of the urticaria group, two subjects reported additional symptoms related to latex glove use such as rhinitis, conjunctivitis, or sneezing. All three groups of subjects (asymptomatic, contact dermatitis, and urticaria) were alike with respect to age, sex, and race. The urticaria group reported a higher incidence of environmental allergies (chi 2, P = 0.02). Serum total immunoglobulin E levels and latex-specific RAST results did not differ among the three groups. The one subject with a positive latex-specific RAST reported urticarial and nasoocular symptoms when exposed to latex gloves. Seventeen percent of symptomatic subjects reported decreased use of latex gloves because of these symptoms. It was concluded that many members of our pediatric ED staff exhibit a sensitivity to latex antigens. Clinical symptoms, rather than serologic testing, must be used to identify latex-sensitive individuals in this setting. Recommendations are offered to assist in the identification and management of hospital personnel who exhibit allergy to latex-containing products. PMID- 8677186 TI - Treating complications of circumcision. PMID- 8677187 TI - Diarrhea, fever, and anorexia for one week in an infant. PMID- 8677188 TI - Prehospital management of asthmatic children. PMID- 8677189 TI - [Effect of spa therapy on the endocrine system. I. Stress reaction hormones]. AB - The present study aimed to assess a.) the influence of spa treatment in Wysowa on the circadian rhythm of plasma concentration of ACTH, cortisol, growth hormone and prolactin, and b.) the influence of kind of pathology on the hormonal profile of the above mentioned hormones. Four groups of patients were examined. The first one comprised 48 patients with essential hypertension, the second one--47 patients with inflammatory renal disease with normal excretory renal function, the third one--39 patients with gastrointestinal diseases and cholelithiasis and the fourth one--41 patients with neurovegetative neurosis. The hormonal parameters were assessed during a clinical check-up, and after 4 and 20 days of spa therapy in Wysowa respectively. In all examined groups spa treatment was accompanied by a significant increase of serum concentrations of all examined hormones. Spa treatment did not influence the circadian rhythm of ACTH, cortisol, growth hormone and prolactin plasma concentration in all examined groups of patients. CONCLUSION: spa therapy shows a marked influence on secretion of "stress" hormones, but does not influence the circadian rhythm of plasma concentration of these compounds. PMID- 8677190 TI - [The influence of spa therapy on the endocrine system. II. Erythropoietin]. AB - The stimulatory effect of spa therapy on erythropoiesis is well documented. The present study aimed to elucidate the pathogenesis of this effect. The influence of spa therapy on plasma erythropoietin and erythropoiesis was studied in four groups of patients: 35 patients with essential hypertension, 35 patients with inflammatory renal diseases at a stabilized stage and normal excretory renal function. 25 patients with gastrointestinal pathology or cholelithiasis and 33 patients with neurovegetative neurosis. Spa therapy for 20 days in Wysowa was accompanied by a significant increase of plasma erythropoietin, iron, ferritin and saturation of transferrin with iron and by an increase of blood haemoglobin and haematocrit value. These alterations were especially marked in patients with essential hypertension. CONCLUSIONS: 1. Spa therapy exerts a stimulatory effect on erythropoiesis caused, among other factors, by increased erythropoietin secretion and iron mobilization. 2. This stimulatory effect is especially marked in patients with essential hypertension. PMID- 8677191 TI - [Microproteinuria and circadian rhythm of blood pressure in patients with arterial hypertension]. AB - Microproteinuria is a recognized sign of early nephropathy in the course of arterial hypertension. There is few data concerning the excretion of proteins other than albumin in this group of patients. The aim of the study was to examine circadian rhythm of alfa-l-microglobulin (AlMG), albumin (ALB), immunoglobulin G (IgG) excretion and N-acetyl-beta-glukosaminidase (beta NAG)-activity, then to compare the results with the results of 24 hour ambulatory monitoring of arterial blood pressure in patients with arterial hypertension. The study comprised 28 patients. The control group included 27 healthy volunteers. Albumin concentration was determined by Beckman ICS2 nephelometer, using Beckman and Dako reagents. Blood pressure and ECG were monitored by analysis with ABP-system (AMP-USA). In patients with arterial hypertension significantly higher levels of ALB, AlMG, IgG and increased beta NAG activity were observed in morning urine samples. Despite hypotensive treatment blood pressure values were slightly, though significantly higher than in the control group. Among patients in the study circadian BP rhythm was disturbed. The results obtained suggest that in this group of patients subclinical nephropathy develops involving renal glomeruli and proximal tubules- probably resulting from vascular and humoral disorders, with accompanied hypertension. PMID- 8677192 TI - [Secretion of atrial natriuretic peptide in patients with active renal stone disease]. AB - The role of the atrial natriuretic peptide (ANP) in Na and water metabolism is well recognized. Much less known is the physiological importance of ANP in the metabolism of other electrolytes e.g. calcium and magnesium, which are presumably involved in the pathogenesis of active renal stone disease (ARSD). The present study aimed to assess the potential role of ANP in the pathogenesis of ARSD. Two groups of subjects were examined. The first one comprised 30 patients with ARSD (diagnosed according to Smith's criteria) while the second one consisted of 21 healthy subjects. Both groups were studied under bed rest (BR) and water immersion (IW) conditions. The examined groups were not different by age, sex, serum electrolyte profile (Na, Ca, Mg) and urinary excretion of Na, Ca, Mg and oxalic acid. Patients with ARSD showed significantly higher basal level of ANP and a significantly higher response of ANP secretion to IW as normals. In spite of this abnormality, patients with ARSD showed a similar increase in water, Na, Ca, Mg and oxalic acid excretion stimulated by IW as compared with normals. In contrast to healthy subjects, patients with ARSD showed no significant correlation between serum ANP levels and urinary excretion of Na, Ca and Mg. In addition, only patients with ARSD showed a significant positive correlation between serum ANP and urinary excretion of oxalic acid during WI. Results obtained in this study suggest, that ANP may be involved in the pathogenesis of ARSD. PMID- 8677194 TI - [Evaluation of skeletal muscle function during calcitriol treatment in patients dialyzed for uremia]. AB - The purpose of the present study is to investigate whether Rocaltrol therapy in uremic patients undergoing dialysis treatment can improve muscle function. In 8 uramic patients (2--on CAPD, 6-on HD treatment) calcitriol (Rocaltrol, Roche) was given in the dosis at 1 mcg/day during 15 months. At the beginning of therapy and every month the following parameters were determined in serum: creatinine (Cr), calcium (Ca), phosphate (PO4) and parathyroid hormone (PTH). At the beginning and at the end of treatment the quantitative electromyography (EMG) was performed. We observed a slight increase of serum Cr during 15 months of treatment in 4 patients. Serum Ca, PO4 and PTH did not changed significantly. The EMG revealed abnormal polyphasic motor nerve unit potentials of brief durations, decrease in the amplitude and fibrillations potentials. The EMG findings did not change after Rocaltrol therapy, but all patients on physical examinations exhibited disappearance of clinical manifestations of uremic myopathy. In conclusion, our findings suggest that vit. D deficiency is one of the causes of uremic myopathy and a careful treatment with Rocaltrol can diminish muscle weakness in uremic patients. PMID- 8677193 TI - [Analysis of angiotensin converting enzyme (ACE) polymorphism in patients with myocardial infarction in the Polish population]. AB - Analysis is presented of polymorphism of gene specifying angiotensin converting enzyme in Polish population and its comparison with results obtained for control group. Insertion/deletion polymorphism was detected by polymerase chain reaction. Frequencies of I/D alleles in control group were similar to those reported in French population but different frequencies were observed in patients with myocardial infarction. PMID- 8677195 TI - [Low molecular weight heparin (Fraxiparine) as adjunctive therapy with thrombolysis for acute myocardial infarction: a pilot study with a one year follow up]. AB - In 53 patients with recent (< 6 hrs) acute myocardial infarction a study was undertaken to evaluate the safety of conjunctive therapy with streptokinase (1.5 mln U), aspirin (150 mg) and low molecular weight heparin (Fraxiparine). Patients were treated with Fraxiparine 250 U anti-Xa IC/kg/24 hrs iv for 2 days (with bolus 12.5 U anti-Xa IC/kg), and 125 U anti-Xa IC/kg twice a day sc for 5 subsequent days. Clinical course in one-year observation was compared regarding the time the therapy was initiated. In the group undergoing therapy 3-6 hrs after the infarct had occurred 4 (7.5%) patients died (2 during hospitalization, 2 after discharge). In 31 patients treated within 3 hrs of the myocardial infarction there were fewer cases of recurrent myocardial infarction, unstable angina or congestive heart failure necessitating rehospitalization their (9.1%) than in 22 patients included in the treatment regimen between 3 rd and 6th h of the infarction (27.3%). Earlier thrombolysis was also connected with higher left ventricular ejection fraction (55 +/- 8% vs 49 +/- 10%) and more frequent peak CK MB values 12 hrs after thrombolysis (81% and 68% of patients respectively). Neither symptomatic deep vein thrombosis nor pulmonary embolism was detected. The left ventricular thrombosis was diagnosed by echocardiography in 4 of 20 patients (20%) with the first anterior myocardial infarction. There was neither bleeding requiring blood transfusion nor cerebrovascular stroke. The treatment with Fraxiparine did not induce the prolongation of APTT values. Conjunctive thrombolytic therapy with low molecular weight heparin was safe and followed by a favorable outcome of the acute myocardial infarction, especially if instituted within the first 3 hrs after the onset of infarction. PMID- 8677197 TI - [Multiple myeloma--the biology of malignant plasma cells]. PMID- 8677196 TI - [Endocarditis lenta--a problematic disease]. AB - 4 endocarditis lenta cases with negative blood cultures are reported: 3 patients with risk heart lesions and 1 subject with no predisposing cardiac condition. The mean age of the patients was 53.7 years. Based on the cases reported the following items are discussed: evolution of the clinical syndrome, diagnostic difficulties, problem of negative blood cultures, therapeutic procedure. PMID- 8677198 TI - [Involvement of the larynx during the course of plasmocytoma]. AB - A case is reported of 63 year old male with disseminated multiple myeloma treated for more than 2.5 year with chemotherapy and radiotherapy. After partial remission lasting for 8 months secondary myeloma infiltration closing nearly the whole hypoglottical part of the larynx and upper part of the trachea developed. Surgical excision of the infiltration was technically impossible to perform. An intensive cytostatic treatment was ineffective but radiotherapy seemed to give some results. Patient suddenly died during morning toilet. PMID- 8677199 TI - [ICAM-3, the role and significance of leukocyte interactions]. PMID- 8677200 TI - [Professor Igor S. Glasunov awarded the honorary medal of the Polish Society of Internal Medicine]. PMID- 8677201 TI - [Professors Antoni Dziatdowiak and Andrzej Nowak: honorary members of the Calisien Medical Society]. PMID- 8677202 TI - [Monitoring of plasma digoxin. If, when, how? Consensus of the Clinical Pharmacology Committee of Experimental Therapy at the Polish Academy of Education]. PMID- 8677203 TI - [Evaluation of lipoprotein (a) and fibrinogen levels in men after premature myocardial infarction and in their sons]. AB - Lipoprotein (a) and fibrinogen admittedly are independent risk factors of coronary heart disease. Since Lp (a) has been shown to inhibit plasminogen binding to endothelial cells and to fibrin monomers, this led to the speculation that high Lp (a) levels in plasma could interfere with fibrinolysis. Therefore the aim of our work was to estimate the lipoprotein (a) and fibrinogen levels and to find correlation between lipoprotein (a) and fibrinogen levels at the men after a myocardial infarction and also at their sons. We examined 33 men of age 31-57 after a myocardial infarction and their 18 sons 4-14 years old. The control group consisted of 40 men of age 18-57 and their 19 sons 5-14 years old. The Lp (a) was determined with electroimmunodiffusion method and fibrinogen by Clauss method. The fibrinogen level in the examined group was found to be statistically significantly higher (338 mg/dl) than in the control group (313 mg/dl). There was no correlation between Lp(a) and fibrinogen concentration. In the group of sons of patients mean fibrinogen and Lp (a) levels were similar to those of the control group. However there was a negative correlation between the fibrinogen and the triglycerides concentration in sons of patients but not in the control group. The results seem to confirm the significance of fibrinogen as a risk factor for the development of the coronary heart disease. PMID- 8677204 TI - [Effect of positive pressure respiration on diurnal catecholamine excretion by patients with obstructive sleep apnea]. AB - The aim of the study was to investigate effects of CPAP treatment on diurnal catecholamine excretion in urine in patients with obstructive sleep apnea (OSA). 12 males with severe OSA (mean AHI = 63) were measured in 3 separate 8 hour samples by fluorimetric method. NA levels were higher in OSA patients in all urine samples than in obese, mildly hypertensive males (control group = C). In C group patients NA levels were significantly lower at night than during the day contrary to OSA patients in whom NA levels dropped insignificantly during sleep. In OSA patients NA levels during sleep correlated with severity of apneas (r = 0.42) and night hypoxaemia (r = -0.46). CPAP treatment resulted in significant fall in NA levels during sleep (p < 0.01). A levels did not change after CPAP treatment. We conclude that abnormally high NA level during sleep in OSA patients may be related to sleep fragmentation and hypoxia. CPAP treatment restores normal circadian rhythm of NA excretion. PMID- 8677205 TI - [Plasma renin activity, aldosterone and adrenergic activity in patients with hypertension and in normotensives with a family history of hypertension]. AB - The aim of the study was to analyse plasma renin activity (PRA), aldosterone (Ald) and catecholamines at rest, after psychological stress and physical exercise in patients with essential hypertension (EH) and normotensive persons with (FH +) and without (FH-) family history of hypertension. MATERIALS AND METHODS: 100 men, aged 18-35 years, were investigated: 36 in EH, 32 in FH + and 32 in FH- groups. PRA, Ald and plasma level of adrenaline (A), noradrenaline (NA) and dopamine (D) were estimated at rest, after 30' of stress (Kraepelins test) and at the end and 30, after submaximal ergometric exercise. RESULTS: The groups did not differ in respect to PRA and Ald in all periods of study as well as to A and NA at rest and during stress. A in EH and FH + as well as NA in FH + were significantly higher than FH- at the end and 30 after exercise. D in EH was higher (p < 0.05) than in both normotensive groups and at rest and stress than FH during exercise and recovery. There were also some correlations between PRA, Ald and catecholamines. In FH + and FH- but not in EH group PRA and Ald positively correlated at rest (r = 0.588 and 0.612) and during stress (r = 0.626 and 0.477). On the contrary in EH as well as FH + groups PRA positively correlated with A (r = 0.385 and 0.368) and NA (r = 0.370 and 0.386) at rest. In addition PRA correlated positively with A during stress (r = 0.368) as well as with NA during recovery (r = 0.313) in FH + groups. Ald correlated with D positively in FH + (r + 0.380) and negatively (r = 0.304) in FH- at rest, whereas Ald was positively correlated with A in EH (r = 0.511) as well as in FH + (r = 0.354) during exercise. CONCLUSIONS: Hypertension and family history of it changes adrenergic reactivity and influences the relationship between plasma renin activity, aldosterone, and catecholamines. PMID- 8677206 TI - [Prolactin secretion in diabetic nephropathy of patients with diabetes mellitus type I (IDDM)]. AB - Disturbances of prolactin secretion occur both in the chronic renal failure and in diabetes mellitus. The study aimed to investigate if the diabetic nephropathy as a cause of chronic renal failure disturbs prolactin secretion. The study was conducted in 5 groups of patients: group I-12 patients with IDDM without diabetic nephropathy; group II-12 patients with IDDM with diabetic nephropathy treated conservatively; group III-16 patients with chronic renal failure of non-diabetic origin; group IV-12 patients with IDDM with end stage renal failure in the course of diabetic nephropathy treated with haemodialysis; group V-16 patients with end stage renal failure of non diabetic origin treated with haemodialysis. 12 healthy subjects served as the control group. In all investigated groups as well as in the control group the TRH test was performed. The mean serum prolactin concentration was estimated in the investigated groups just before the intravenous TRH injection and then after 15, 30, 45, 60 and 120 minutes. The mean area over the basic value (AOBV) of prolactin was also assessed. The patients with IDDM without diabetic nephropathy did not differ from healthy subjects both in the basic and TRH induced prolactin secretion. Basic and TRH induced prolactin secretion in patients with diabetic nephropathy both conservatively treated and treated with haemodialysis were lower than in patients with the same stage of chronic renal failure of non-diabetic origin. PMID- 8677207 TI - [Analysis of risk factors for coronary disease in women with their first acute myocardial infarction]. AB - Based on the analysis of the results of the investigation performed in 92 women hospitalized between 1989 and 1992 with the first acute myocardial infarction (AMI), frequency of coronary artery disease (CAD) risk factors was assessed with attention to the patient's age. It was proved that in women under 44 yrs the most common factors are: cigarette smoking, family history of CAD or myocardial infarction (MI), decreased levels of HDL-cholesterol and hypertriglyceridemia. In older age there are: hypercholesterolemia, decreased levels of HDL-cholesterol, hypertriglyceridemia, arterial hypertension, obesity and diabetes mellitus. Furthermore, some differences in the frequency of CAD risk factors between the both sexes were noted. In women under 44 yrs cigarette smoking, significant family history, decreased levels of HDL-cholesterol and hypertriglyceridemia occurred more often than in men. In women above 56 yrs we found significantly higher levels of total cholesterol and triglycerides, lower levels of HDL cholesterol, higher frequency of hypertension, diabetes and obesity, compared to men. PMID- 8677208 TI - [Hypertensive crisis in a female patient on a prolonged hemodialysis program treated with erythropoietin for nephrogenic anemia]. PMID- 8677209 TI - [Hemangioblastoma of the breast]. PMID- 8677210 TI - [Diurnal blood pressure rhythm in patients with hypertension]. PMID- 8677211 TI - [Arterial hypertension induced by erythropoietin]. PMID- 8677212 TI - [Genetic aspects of atopic diseases]. PMID- 8677213 TI - Summary of the DSM-IV mood disorders field trial and issue overview. AB - The DSM-IV Mood Disorders Field Trial addressed several issues concerning the relationship among major depression, dysthymia, recurrent brief depression, minor depression, and depressive personality disorder. The Mood Disorders Field Trial is a naturalistic, multisite study that investigated the diagnostic criteria for dysthymia, the reliability and validity of longitudinal course modifiers, the nosology of minor and recurrent brief depression, and the relationship between depressive personality disorder and dysthymia. Research on the nosology of chronic depressive disorders will, it is hoped, contribute to a better understanding of pathophysiology, etiology, and treatment. This article presents findings from the Field Trial as well as brief reviews of the other nine articles in this issue. PMID- 8677214 TI - Chronic mood disorder and depressive personality. AB - This article considers the relationship between chronic mood disorders and depressive personality from several perspectives. A historical overview of various theoretical, descriptive, and empirically based typologies is provided as well as a review of the relevant classifications from the psychiatric nomenclatures. The defining features of the different conceptions of chronic depression and depressive personality then are considered within the framework of dimensional models of personality, including the dimensions of positive and negative affectivity, and the five-factor model. It is proposed that these dimensional models may provide a useful integrating framework for future work in this area. PMID- 8677215 TI - Pharmacotherapy for chronic depression. AB - There is now strong evidence from controlled studies that antidepressant medication, including SSRIs, tricyclic antidepressants, and MAOIs, is effective in treating both the depressive symptomatology and social dysfunction of many patients with chronic depression. Encouraging data from a controlled long-term trial in progress indicate that desipramine is effective in sustaining recovery during maintenance treatment. Future studies are needed to better understand the optimal duration of treatment, the efficacy of augmentation strategies, and the efficacy of combined treatment with psychotherapy and pharmacotherapy in chronic depression. PMID- 8677216 TI - Psychotherapy for dysthymic disorder. AB - The psychotherapy of dysthymic disorder has received too little serious attention and funding. Impressive advances in the pharmacotherapy of dysthymic disorder should not obscure the need for psychosocial treatment for the high proportion of patients who do not respond to medication. Despite the dearth of psychotherapy outcome studies in this area, such data that do exist suggest that relatively brief, focal, antidepressant psychotherapies may successfully treat many patients with lifelong mood disorders. Maintenance therapy probably is indicated to ensure the persistence of treatment gains. PMID- 8677217 TI - Combined medication and psychotherapy in the treatment of chronic mood disorders. AB - This article discusses the use of combined treatments for patients with chronic mood disorders. Although very little research concerning the efficacy of combined treatments for patients with chronic depression exists, clinical experience and limited available research suggest that combined treatment may be the most effective treatment option available for this population. The use of combination treatment involving pharmacotherapy, individual psychotherapy, and marital/family therapy is recommended to address the complex biopsychosocial issues involved in chronic mood disorders. Other theoretical and pragmatic issues concerning the delivery of combined treatment also are discussed. PMID- 8677218 TI - Nosology of chronic mood disorders. AB - In attempting to assess the complex relationship of chronic depression with other conditions to which it may be a predisposition, an accompaniment, or a consequence of, a few concluding caveats may be useful. It must be recognized that chronic depression has a wide variety of different presentations and causes. Current definitions of major depressive disorder and dysthymic disorder may create a misleading distinction of what may be two aspects of the overall course of a depressive disorder. Furthermore, much of what is considered to be comorbidity of other disorders with chronic depression actually may be a complex syndrome with a common pathogenesis. PMID- 8677219 TI - Symptomatology in dysthymic and major depressive disorder. AB - The lists of associated symptoms included in the DSM-III, DSM-III-R, and DSM-IV criteria for dysthymic disorder have been criticized for lacking content and discriminant validity. The literature on the content and discriminant validity of dysthymic symptoms was reviewed and relevant data from the DSM-IV Mood Disorders Field Trial were presented. These data indicate that cognitive and social motivational symptoms are much more characteristic of dysthymic disorder than are vegetative and psychomotor symptoms. In addition, subjects with major depressive disorder exhibit higher rates of most depressive symptoms than do subjects with dysthymic disorder, but there is little evidence of qualitative distinctions in symptomatology between these conditions. Finally, after taking course and exclusion criteria into account, variations in the symptom criteria do not have a major effect on case definition. PMID- 8677220 TI - Differential diagnosis of chronic depressive disorders. AB - This article has traced the development of the diagnostic nomenclature for the chronic affective disorders during the past four decades. Much has been accomplished. In fact, our current differential diagnostic capabilities have surpassed our knowledge of how to treat the chronic depressions. It is hoped that in the next decade there will be notable increases in the treatment efficacy literature of the chronic mild depressions. Next, we suggest that practitioners assist academic investigators in determining the best way to treat the chronic depressions. To realize this goal, clinicians must begin to view themselves as part-time researchers. Several technological procedures have been described to facilitate this undertaking. We suggest that the assumption of such a research practitioner role will, in the long run, improve the quality of patient care. PMID- 8677221 TI - Reliability of diagnosis in mood disorders. AB - The reliability of diagnosing mood disorders is reviewed for previous and current versions of the American Psychiatric Association's DMS. Reliability is shown to improve with the increasing specificity of diagnostic criteria. The new specifiers for the course of major depression in relation to dysthymia also are shown to be reliable. PMID- 8677222 TI - Recovery, chronicity, and levels of psychopathology in major depression. AB - Major depression is a chronic and recurrent disorder for many people who are afflicted by it. There is a wealth of literature addressing the course of this disorder with follow-up times varying from several months to several decades, which gives a remarkably consistent picture in treated and untreated populations. Fortunately, most people who develop major depression recover from their initial episode; unfortunately, a significant minority do not recover fully and a near majority develop additional episodes. This article examines a selected group of studies that have examined the course of depression, with a focus on a large naturalistic longitudinal prospective study of affective disorders--the NIMH Collaborative Depression Study. PMID- 8677223 TI - [The role of the HTLV-I virus in transformation of T lymphocytes]. AB - HTLV-I virus is as etiological agent of adult T-cell leukemia (ATL). The virus encodes Tax regulatory protein, which induces malignant transformation of the T lymphocytes. Tax increases the expression of cell protooncogenes as well as lymphokines, among others IL-2 and its receptor. This protein induces autocrine proliferation of T lymphocytes, which is probably the main cause of their transformation. Tax represses the human beta-polymerase gene enzyme involved in host cell DNA repair, and then irreversible damage is effected in the T lymphocyte genome. Moreover, this regulatory protein cooperates with Rex phosphoprotein, stabilizing cell mRNA, which originate as the result of Tax protein activity. The regulatory proteins of HTLV-I virus influence the transcription of some cell genes and their products and in this way induce malignant transformation. PMID- 8677224 TI - [Essential properties of the group O virus with direct medical importance]. PMID- 8677225 TI - [Quantitative analysis of oxidative base damage in DNA]. AB - Oxidative DNA damage produced by free radicals has been implicated to play a role in mutagenesis, carcinogenesis and aging. There is, therefore, increasing interest in the development of accurate assays for measuring DNA base damage. Such assays should help to define the biological consequences of oxidative DNA modifications and to identify enzymatic repair pathways. The present article describes the potential usefulness of different technique for chemical characterization and quantitation of oxidative modifications in DNA. PMID- 8677226 TI - [Imidazol receptor agonists--new possibilities for treating hypertension]. AB - Adrenergic alpha 2-receptors mediate important regulatory functions in both the brain and the periphery. Activation of these receptors lowers blood pressure through a decrease in sympathetic and vasomotor nerve activity. Agonists of the alpha 2-adrenoceptors are often used in the treatment of arterial hypertension. As recently discovered, their chemical structure includes so called "imidazoline ring" and compounds with such chemical structure bind to nonadrenergic sites known as imidazoline receptors. These receptors are localized in midportions of the brain but they are also present in other organs such as lungs, heart, adrenal medulla, liver and kidneys. Their selective activation lowers blood pressure without inducing sedation typical for alpha 2-agonists. Several substances binding with high selectivity to imidazoline receptors have recently been synthesized. Some of them as rilmenidine and moxonidine have successfully been introduced to the treatment of arterial hypertension in humans. PMID- 8677227 TI - [A free radical mechanism for inhibition of arteriosclerosis development with calcium antagonists]. AB - Work presents current views on involvement of free radicals in inhibition of development of arteriosclerosis by calcium antagonist (ACa). The importance of other substances, which interferes with calcium ions can contribute to the inhibition of arteriosclerosis development. PMID- 8677228 TI - [Heparin--new perspectives on its antiinflammatory action]. AB - Heparine is used as a therapeutic anticoagulant. Research carried out in the last years showed in both in vivo and in vitro experiments (also in men), that this is a pleiotropic substance with many diverse activities. Immunoregulatory properties of heparine, including immunosuppressive and most of all anti-proliferative lead to create the theory of its possible use in several chronic inflammatory processes. First experiments seem to justify this opinion. PMID- 8677230 TI - Yet another treatise on managed care. PMID- 8677229 TI - [Uremic autonomic neuropathy--pathogenesis, diagnostic methods]. AB - Autonomic impairment is associated with poor prognosis in many diseases. The pathogenesis of the uremic autonomic neuropathy has not been convincingly established, so the article reviews available information on factors involved in its development, furthermore the authors put forward their own hypothetical scheme of the pathogenesis. The last section outlines the methods most commonly used for its diagnosis and finally the authors discuss symptoms suggestive of this neuropathy in clinical setting. PMID- 8677231 TI - To pauperize or empower: public health nursing at the turn of the 20th and 21st centuries. AB - From its inception, public health nursing has provided health care and teaching to all people including those who are disadvantaged and impoverished. Based on the work and beliefs of Florence Nightingale and Lillian Wald, public health nurses developed positive relationships with people which resulted in healthier environments and lifestyles among diverse families and communities. And, despite societal concern that nursing care for the poor would pauperize them, it did not. It empowered them. A review of concepts of poverty and comparisons of issues and circumstances at the turn of the 20th and 21st centuries underscores the values inherent in these early initiatives and their continuing relevance to public health nursing practice that can empower, rather than pauperize, those who are disadvantaged or living in poverty. PMID- 8677232 TI - Focus groups: collecting aggregate-level data to understand community health phenomena. AB - Focus-group method is an apt strategy for studying community health phenomena at the aggregate level. Not only can its use facilitate the inclusion of segments of the population who have been underserved by previous research, but it can generate a depth of understanding about public health problems, community strengths, and potential interventions that have local meaning and utility. Advantages and potential uses of focus groups are explored, as well as purposes and processes of focus-group interviewing, strategies for analysis, methodological limitations, and implications for practice and policy. The author presents investigatory examples to illustrate how focus-group method expands on the possibilities of individual interviewing to explore community interpretations and understand the health needs and experiences of an aggregate. PMID- 8677233 TI - The partnership model: working with individuals, families, and communities toward a new vision of health. AB - Increasingly, health professionals must learn to work in new partnership relationships with clients and community to promote health effectively. A partnership requires a transformation of the professional role from chief actor to partner, and the client role from passive recipient to partner. A partnership approach has particular merit in a reformed health care system that increasingly emphasizes active involvement and self-care actions of individuals and families to maintain health and prevent disease. A partnership approach is also important to professionals working with underserved, vulnerable, and/or minority populations. For too long professionals and policymakers have relegated these groups to passive roles in health decision making and action. This article will provide a description of the partnership process as it has been developed and implemented by nurse practitioners in an urban Hispanic community with emphasis on a community partnership. A partnership model is described and compared to the more traditional professional model. A definition and essential criteria for partnership are presented. Finally, a specific example of how the partnership process was implemented at the community level is discussed. PMID- 8677234 TI - ACTION: application and extension of the GENESIS community analysis model. AB - GENESIS (General Ethnographic and Nursing Evaluation Studies In the State) is a tested and proven community analysis strategy that integrates ethnographic and epidemiologic data to arrive at a comprehensive, holistic description of the health of a community and its residents. Communities analyzed in most project GENESIS studies have been rural or semirural. ACTION (Assessing Communities Together in the Identification Of Needs) is an extension of the GENESIS community analysis model that was developed to meet the unique needs of community-level research and analysis in an urban, multicultural setting. Significant differences in the context in which the ACTION projects took place necessitated extensions in specific components of the GENESIS model. Application of the GENESIS model by the ACTION team is described. Based on the experiences with ACTION, recommendations are offered for future urban, multicultural community analysis projects. PMID- 8677235 TI - Nursing diagnoses and home care nursing utilization. AB - The purpose of this study was to identify, from routinely collected health care record data, patient characteristics that describe home care clients' health care needs and explain variation in home health care utilization. Retrospective data were obtained from a total of 317 home health care patient records from one home health care agency. Outcome variables of care included number of visits and hours of care. Predictor variables included nursing diagnoses, medical diagnoses, and patient demographic variables. Nursing diagnoses were classified by the Omaha System. Nursing diagnoses explained a significant amount of variance over and above the demographic and medical diagnosis variables in both the number of nursing visits and hours of nursing care. The results of this study suggest that data related to nursing diagnoses are a valuable source of information when examining home health care nursing resource use. PMID- 8677236 TI - Evaluation of an interagency home visiting program to reduce postneonatal mortality in disadvantaged communities. AB - This paper describes an interagency home visiting program, Resources, Education and Care in the Home (REACH), designed to reduce preventable causes of morbidity among normal, socioeconomically disadvantaged infants at risk for adverse outcomes due to social factors. Home nursing visits by a trained nurse-community worker team were made throughout the first year of life to 1,269 infants from predominantly African American families. Results demonstrate that repeated home visits with ongoing infant health monitoring plus individualized and culturally sensitive teaching helped mothers maintain good health practices and identify illnesses early. Infants' outcomes during the neonatal period and at 12 months showed consistent, though statistically nonsignificant, positive effects on physical health. The postneonatal mortality rate among REACH infants was 4.7 deaths per 1000 live births in communities where rates for nonparticipants ranged from 5.2 to 10.9 per 100. The evaluation demonstrates a need in this population for more intensive services with greater continuity of care. Specific areas where more education is needed include home safety, skin care, and early identification and treatment of upper respiratory infections. Infants from communities with high infant mortality rates present numerous preventable morbidities requiring interventions, even when they are not considered medically high-risk at birth. PMID- 8677237 TI - Effectiveness of counseling in the health promotion of HIV-positive clients in the community. AB - The purpose of this study was to examine the effects of a nurse's counseling intervention on high-risk sexual behaviors of HIV-positive patients and to explore the relationship of gender, race, age, and education to high-risk sexual behaviors. A convenience sample of 20 adults who were newly diagnosed with HIV and were being treated at an inner-city out-patient clinic was used. Subjects were administered a questionnaire to determine their precounseling AIDS knowledge and precounseling sexual behaviors. A registered nurse then counseled them about safe-sex practices. After 2-3 months the questionnaire was readministered to determine the effects of counseling on AIDS knowledge and high-risk sexual behaviors. Although statistical analysis indicated a significant main effect for change in high-risk sexual behaviors after counseling, there were no significant relationships among change and the individual demographic variables of age, gender, race, and education. Pretest knowledge was not found to influence pretest behavior, nor was posttest knowledge found to affect posttest behavior. Paired t tests indicated a significant change in high-risk sexual behavior scores after counseling but no significant change in knowledge scores. PMID- 8677238 TI - Latino women and AIDS risk. AB - This study describes risk behaviors among Puerto Rican women and identifies variables related to high-risk behavior, including sociodemographic status, knowledge about HIV and AIDS, religiosity, acculturation, and attitudes toward contraceptive use and homosexuality. Puerto Rican women (N = 121) were recruited through a community-based organization in Philadelphia. Respondents were an average of 30 years old; 21% were married and not separated, 79% were either single (50.9%), separated (14.3%), divorced (11.6%), or widowed (1.8%); 69% had 1 3 children. Most women (74%) were at moderate to high risk for AIDS. Results from logistic regression with a single independent variable yielded no statistical significance for the following variables: income, number of children, religiosity, Rosenberg Self-Esteem Scale, AIDS knowledge, homophobia, Symptom Checklist-90-R, and Population Policy Questionnaire items. When the three acculturation variables consisting of a language score, an activity score, and a preference score were examined, however, the language score was highly statistically significant, with a p value of 0.0001. Its positive logistic regression coefficient indicates that AIDS risk increases as preference for English increases. Further research is needed of Latino women that studies other Latino subgroups, given that HIV prevalence varies across subgroups. PMID- 8677239 TI - Female adolescent contraceptive use or nonuse at first and most recent coitus. AB - The purpose of this study was to determine factors that differentiate contraceptive use behaviors of sexually active adolescent women. A sample of 159 subjects, recruited from three publicly supported family planning clinics, were classified according to nonuse, inconsistent, or consistent use of contraceptives at first and most recent coitus. The Health Promotion Model provided the organizing framework for this study. Factors entered into the discriminate functions included self-image, problem solving, health-promoting behavior, race, age at first coitus, previous pregnancy, contraceptive history, chronological age, family structure and size, mother's education, and Medicaid status. Three group multivariate discriminate analysis resulted in two significant functions that explained 38.7% of the variance in contraceptive behavior. The three groups of adolescents were discriminated by age at first coitus, history of previous pregnancy, health-promoting behavior, self-image, problem-solving skill, chronological age, family size, and race. In particular, the findings suggest public health nurses and other health care providers can reduce unintended pregnancy through interventions that address the alterable factors. PMID- 8677240 TI - Molecular genetics and cytogenetics of Ewing's sarcoma. PMID- 8677242 TI - The art of renewal. PMID- 8677241 TI - Overview of the newer antibiotics. PMID- 8677243 TI - Diabetes mellitus--update of mortality experience among insured lives. PMID- 8677245 TI - Preferred risk underwriting: what are the choices? PMID- 8677244 TI - Underwriting the young. PMID- 8677246 TI - Diabetes mellitus--current clinical aspects. PMID- 8677247 TI - HIV/AIDS report. PMID- 8677248 TI - Major depressive disorder. PMID- 8677249 TI - High tibia osteotomy and other challenges. PMID- 8677250 TI - Genetic testing--improving health; calculating risk. PMID- 8677251 TI - Athlete's heart vs. cardiomyopathy: bigger isn't always better. PMID- 8677252 TI - The impact of genetic developments on breast cancer. PMID- 8677254 TI - Psychiatric disability claims. PMID- 8677253 TI - Beyond medicine: the doctor as a member of the corporate business team. PMID- 8677255 TI - Underwriting the elderly life insurance applicant. PMID- 8677256 TI - Managed care: managed change. PMID- 8677257 TI - Remarkable preservation of biomolecules in ancient radish seeds. AB - Desiccated seeds from a 6th century AD storage vessel recovered from Qasr Ibrim, Egypt, were examined for the presence of lipids and nucleic acids. A remarkable degree of lipid preservation was discovered, the fatty acid and sterol profiles being very similar to those of modern radish seeds. The only significant differences were hydrolysis of triacylglycerols and depletion of the polyunsaturated fatty acids (C18:2 and C18:3). The delta 13 C values of the principal fatty acids were in the range -25.4 to -29.2/1000, which is congruent with modern radish (C3 seeds) taking account of isotopic shifts caused by recent changes in atmospheric CO2. Deoxyribonucleosides and nucleic acid bases were detected by direct chemical analysis, and polymerase chain reactions gave products with sequences comparable to those from modern radish. The degree of lipid preservation, which was much greater than that reported for other archaeological remains, suggests that the microenvironment within desiccated seeds retards biomolecular decay. The results illustrate the utility of combined lipid-nucleic acid analysis in chemotaxonomic and genotypic studies of archaeobotanical remains. PMID- 8677258 TI - 470 million years of conservation of microsatellite loci among fish species. AB - Primers for 18 microsatellite loci originally isolated from whiting (Merlangius merlangus, n = 6), stickleback (Gasterosteus aculeatus, n = 5) and cod (Gadus morhua, n = 7) were tested across a panel of diverse fish species, representing the three principal superclasses and most principal superorders of fish, to examine conservation of microsatellite regions across distantly related taxa. Three methods were used. First, amplified fragments were analysed by Southern blotting using the relevant microsatellite motif probes. A total of 17 of the tested primer pairs gave a product in the expected size range in at least four of 11 tested species. Second, for two study loci the amplified polymerase chain reaction products were cloned and sequenced in five fish species to reveal a high level of conservation of the flanking and microsatellite sequences. Finally, the 17 loci successfully amplified in non-source species were tested for polymorphism in groups of unrelated individuals from nine species, in several cases revealing extensive polymorphism. Levels of polymorphism were generally high in species from which the loci were derived or among closely related species. The conservation of flanking sequences for particular microsatellite motifs over the span of fish evolution represented in the test species (470 million years) far exceeds that hitherto reported and lends support to the suggestion (derived from studies of whales and marine turtles) that the rate of base substitution in nuclear and mitochondrial sequences is lower in aquatic than terrestrial organisms. A further explanation could be that these sequences, although generally considered neutral, may play an important role in eukaryotic genomes, and may be under strong selective constraints. The study suggests that heterologous primers will be a ready source of polymorphic markers among fish species, but also indicates that caution should be used in cross-species comparisons of variability. PMID- 8677259 TI - Colour vision as an adaptation to frugivory in primates. AB - Most mammals possess two classes of cone, sensitive to short and to long wavelengths of light, but Old World primates (Catarrhini) have distinct medium and long wavelength sensitive classes. The sensitivities of these cones photopigments are alike in all catarrhines with peaks at about 440 nm ('blue'), 533 nm ('green') and 565 nm ('red'). One possible reason for the evolution and conservatism of catarrhine trichromacy is that colour vision is a specialization for finding food. A model of retinal coding of natural spectra, based on discrimination thresholds, is used to examine the usefulness of dichromatic and trichromatic vision for finding fruit, and for identifying fruit and leaves by colour. For identification tasks the dichromat's eye is almost as good as a trichromat's, but the trichromat has an advantage for detecting fruit against a background of leaves. PMID- 8677260 TI - Neural competition and statistical mechanics. AB - Computational models of activity-dependent competitive neural plasticity typically impose competition in networks in which plasticity is accommodated by permitting changes in the efficacies of synapses in an anatomically fixed network. This is despite the fact that much evidence suggests that neurons compete for neurotrophins, during both target innervation and activity-dependent synaptic re-arrangement, which influence the sprouting and retraction of axonal processes. We therefore present a new approach to the computational modelling of competitive neural plasticity which permits neurons to compete explicitly for neurotrophins. This competition is associated with the sprouting and retraction of axonal processes. Because there is much uncertainty regarding the basic mechanisms, we adopt the powerful machinery of statistical mechanics to avoid the need to address these issues. We show that such an approach can readily account for a wide range of plasticity phenomena in a range of systems, including the results of various pharmacological manipulations. PMID- 8677261 TI - Orientation discrimination is impaired in the absence of the striate cortical contribution to human vision. AB - We have examined visual discrimination of orientation for bars and edges presented to the 'blind' hemifield of a patient, GY, who has an extensive lesion involving the left striate and prestriate cortex. The patient's residual vision in response to transient light stimulation of his 'blind' hemifield has been well characterized, and it provides discrimination on the basis of differences in target velocity, flicker frequency or colour. We now show that using his residual vision, GY can identify accurately the orientation of a flickering bar, although his performance is sub-normal for bars shorter than 10 deg. He is, however, unable to identify the orientation of a one-dimensional grating presented within a circular aperture, and is unable to detect a grating structure formed by equiluminant coloured bars or by alternating, equiluminant flickering and steady bars. We also show that he has poor orientation discrimination for edges formed by colour contrast, by contrast between moving stimuli or by flicker contrast. We conclude that in the absence of the striate cortical input, the residual mechanisms which provide discriminations for colour, flicker or movement are not well organized for the detection and discrimination of stimulus orientation. We discuss the physiological mechanisms responsible for the various aspects of GY's residual vision. PMID- 8677262 TI - Growth hormone increases predation exposure of rainbow trout. AB - The energetic state of an animal strongly influences decisions that balances feeding against predation risk. Growth hormone increases the metabolic demands, which should elevate the feeding motivation of an animal. This, in turn, may increase the willingness to risk exposure to predators during feeding. To test this hypothesis, we studied the effect of growth hormone on the behavioural response of rainbow trout (Oncorhynchus mykiss) to simulated attacks from a model heron. After attacks, growth hormone treated trout foraged closer to the water surface, resumed feeding earlier, and ate more food than did control trout. Such behaviour should increase the susceptibility to aerial predation. Thus, predation may select against high endogenous growth hormone secretion in wild fish. Furthermore, genetic manipulations to increase growth hormone levels, intended to improve growth performance in aquaculture, may result in individuals with substantially altered behavioural patterns. In light of the increasing potential for interactions between farmed and wild fish, growth hormone transgenic fish may pose a threat to wild fish populations. PMID- 8677263 TI - A mathematical model for collagen fibre formation during foetal and adult dermal wound healing. AB - Adult dermal wounds, in contrast to foetal wounds, heal with the formation of scar tissue. A crucial factor in determining the nature of the healed tissue is the ratio of collagen 1 to collagen 3, which regulates the diameter of collagen fibres. We develop a mathematical model which focuses on the stimulus for collagen synthesis due to the secretion of the different isoforms of the regulatory chemical transforming growth factor beta. Numerical simulations of the model lead to a value of this ratio consistent with that of healthy tissue for the foetus but corresponding to scarring in adult wound healing. We investigate the effect of topical application of TGF beta isoforms during healing and determine the key parameters which control the difference between adult and foetal repair. PMID- 8677264 TI - Intestinal absorption of water-soluble vitamins. AB - Vitamin utility is a scientific/medical topic that appears to be pursued as ardently by the lay public as by scientists and medical practitioners. A group of epidemiologists evaluates the effects on health of vitamin intake in the natural diet and by supplementation. The role in ocular disease, cancer of the breast or colon, and cardiovascular disease are a few of the concerns. The results and recommendations concerning dietary vitamin intake will likely continue to change. However, the processes by which dietary vitamins are delivered from intestinal chyme to the blood are more certain. The concept of homeostasis might apply to various of the vitamins as it does to minerals, water, etc. This review will discuss some common methods used to study vitamin absorption and the proposed mechanisms of absorption, and will conclude with a section about dietary regulation. PMID- 8677265 TI - Expression of thrombospondin-1 in cancer: a role in tumor progression. AB - Thrombospondin-1 (TSP-1), a trimeric high molecular weight glycoprotein, is one of the major secreted proteins of human platelets and an extracellular matrix component of a variety of cells including vascular endothelial cells and tumor cells. TSP-1 has been shown to be highly expressed in human malignant tissues and present in higher than normal levels in the plasma of cancer patients. TSP-1 has also been shown to promote hematogenous tumor spread, tumor cell adhesion and invasion, and angiogenesis. Overall these studies provide compelling evidence for the conclusion that TSP-1 plays an important role in tumor progression. PMID- 8677266 TI - The nature of the scrapie agent: the virus theory. AB - All spongiform encephalopathies (SEs) are slow virus-transmissible infectious disorders of the brain. Tubulofilamentous particles/scrapie-associated fibrils (SAF) are ultrastructural markers, while protease-resistant protein (PrP) is a protein marker. The PrP molecules aggregate to form SAF, which occurs as an internal part of the tubulofilamentous particle termed nemavirus (NVP). Each NVP consists of three layers: (i) an outer protein coat, (ii) an intermediate ssDNA layer, and (iii) inner PrP/SAF. A chronological study of scrapie-infected hamster brain revealed that NVP and SAF are seen 10 days postinoculation from the inoculated right side of the brain and from 18 days postinoculation from both sides of the brain. The existence of at least 20 stable strains of SEs implies that a nucleic acid molecule serves as the information molecule. This is incompatible with the hypothesis that PrP by itself or a specific point mutation is the agent. It appears that an "accessory protein" coded by the ssDNA of the nemavirus interacts with normal PrPc molecules, resulting in their conversion to PrPsc/SAF. The pathogenesis process in infected animals with increasing incubation periods reveals that larger amounts of normal PrP molecules are modified to form SAF. This interferes with the normal supply of PrP to cell membranes, which become disrupted and eventually fragment, resulting in the vacuoles typical of those found in the SEs. PMID- 8677267 TI - Autoimmune disease of the kidney: an update. PMID- 8677268 TI - Effects of antidotes to cocaine on the deregulation of the baroreflex by the alkaloid. AB - Cocaine exerts in the rat an inhibitory effect on the baroreflex induced by bilateral clamping of the carotid arteries. The present series of experiments were designed to test the effectiveness of cocaine antidotes on this deregulation of the baroreflex. Sprague-Dawley rats were fitted under pentobarbital anesthesia with a catheter in the caudal artery, and their carotid arteries were exposed. The pressure signal from the caudal artery was treated on line by a microcomputer for continuous display of blood pressure and heart rate measurements. The animals were administered intraperitoneally either 50 mg cocaine or an equal volume of saline. Five minutes later, they were administered either saline or proven antidotes to cocaine (diltiazem, nicardipine, enzyme converting inhibitor [ECI], enalaprilat associated with diazepam). After 2 min, stimulation of the baroreceptor was performed by bilateral clamping of the two carotids for a period of 2 min. The measures of the maximal variation in systolic pressure before and after clamping indicated a significant difference between saline and cocaine treated animals (P < 0.05), with the former displaying a much greater increment in blood pressure after clamping. The cocaine-treated animals, administered diltiazem, nicardipine, and ECI associated with diazepam, presented after clamping of the carotid arteries a normal baroreflex with increments in blood pressure not significantly different from those occurring in the animals receiving saline, but significantly different from those administered cocaine only (P < 0.05). Baroreflex deregulation by cocaine may also be restored by an angiotensin II receptor antagonist. The possible role of this peptide in mediating in part baroreflex activity is discussed. PMID- 8677269 TI - Effect of estrogen on hyperprolactinemia-induced glucose intolerance in SHN mice. AB - The effects of prolactin (PRL) on circulating levels of glucose and insulin, and of estradiol on hyperprolactinemia-induced glucose intolerance of tissues were studied in pituitary-grafted SHN mice (PG mice) and sham-operated controls. Pituitary grafting (PG) decreased blood glucose levels in male mice at 1 and 3 months after the operation but did not alter those in females. PG had little effect on serum insulin levels in males, but increased those in females. In female mice at 2 months after PG, blood glucose levels were significantly higher at 1, 2, and 4 hr after glucose load when compared with those in controls. In contrast, there was no significant difference in blood glucose levels after glucose load between male PG and control mice. The rate at which blood glucose levels decreased was slower in female PG mice than in controls during the 30 min after insulin injection, whereas there was no difference in the rate after insulin injection between male PG and control mice. In ovariectomized (Ovx) mice, no significant difference was found in the blood glucose levels after a glucose load between PG and control groups at 2 months after PG. In Ovx mice treated daily with estrogen, however, a PG-dependent high level of blood glucose was observed after glucose load. These results suggest that hyperprolactinemia decreases glucose tolerance via an increase in insulin resistance in female SHN mice and that estrogen is essential to the expression of the PRL effect. PMID- 8677270 TI - The role of stressor intensity in influencing the course of heart disease in cardiomyopathic hamsters. AB - Our earlier work showed that stress had progressively more serious consequences in a hamster model of congestive heart failure as the magnitude of heart failure worsened. Based on that study, we hypothesized that the intensity of the stressor used might play an important part in determining this outcome as well as in influencing coronary reactivity to arginine vasopressin (AVP). Cardiomyopathic (2.5, 6.5, and 10 months) hamsters (CMHs) were stressed with a 2-hr period of supine immobilization for five consecutive days. Stressor intensity was increased by exposing the hamsters to progressively longer periods at 4 degrees C: the low stress group was never put in the cold; the moderate stress group was exposed to cold for 1 hr, and the high stress group for 2 hr. CMHs were anesthetized and sacrificed 5 days after stress, and their hearts were perfused using a modified Langendorff system. Maximum +/- dP/dt, developed pressure, ventricular relaxation time, (T), and coronary vascular resistance (CVR) were recorded, and CVR was also measured following coronary infusion of AVP. Stressor intensity had no effect on cardiac mechanics in 2.5-month CMHs. In 6.5-month CMHs, only the high-intensity stressor impaired ventricular mechanics (decreased maximum +/- dP/dt and developed pressure, increased T; P < 0.05), while low and moderate stress produced no effects. In 10-month CMHs, stress at all intensities exacerbated ventricular dysfunction (decreased maximum +/- dP/dt and developed pressure; P < 0.05). These results support our first hypothesis that stressor intensity interacts multiplicatively with severity of the underlying disease to influence the course of heart failure. However, our second hypothesis was not supported, because stress-regardless of intensity-affected reactivity of the coronary vasculature to AVP only in 2.5-month CMHs. A further test of the relation of stressor intensity and coronary vascular reactivity requires study of additional groups of CMHs during the period of their disease characterized by coronary vasospasm. PMID- 8677271 TI - pHi in piglet cerebral microvascular endothelial cells: recovery from an acid load. AB - Cerebral microvascular endothelial cells form a barrier between the blood and brain, which is critical for normal neuronal functions. These endothelial cells can be challenged by metabolic and respiratory acidosis, especially in newborn babies. We investigated mechanism(s) by which cerebral endothelial cells recover intracellular pH (pHi) when challenged with an intracellular acid load. pHi in piglet cerebral microvascular endothelial cells in primary culture was monitored using the pH-sensitive fluorescent dye BCECF (2',7'-bis-2-carboxyethyl-5(6) carboxy-fluorescein acetoxymethyl ester), with dual wavelength fluorescence spectroscopy. Endothelial cells attached to coverslips and continuously superfused with HCO3-/CO2 containing medium (25 mM HCO3-, 5% CO2; pH 7.40) have a steady state of pHi of 7.18 +/- 0.02. Under basal conditions, amiloride (100 microMol) and H2DIDS (0.5 mM) decreased pHi 0.12 +/- 0.01 and 0.05 +/- 0.01 pH units, respectively. Removal of external Na+ lowered pHi 0.18 +/- 0.02pH units, while Cl- free medium decreased pHi 0.16 +/- 0.03pH units. These data suggest the presence of an amiloride-sensitive Na+-H+ exchanger and a Na+-dependent HCO3- -Cl anion exchanger in endothelial cells. Propionate and high PCO2 cause rapid intracellular acidification at constant pH. The cells recover to control pHi over 10 min. Recovery from propionate was largely inhibited by amiloride, slightly inhibited by H2DIDS, and completely prevented by the combination. pHi recovery during elevated PCO2 was blocked by amiloride, H2DIDS, or Na+-free media. These results indicate that recovery from intracellular acidosis can involve amiloride sensitive Na+-H+ exchange and a Na+-dependent HCO3-/Cl- anion exchange. Relative contributions of pumps and their independence appears to depend on the nature of the acid load. PMID- 8677272 TI - Nitric oxide attenuates the renal hemodynamic responses to increased peripheral and renal sympathetic nerve activity. AB - The role of nitric oxide (NO) in renal function was evaluated under conditions of elevated peripheral and renal sympathetic nerve activity (RSNA), achieved by bilateral carotid occlusion (CO) in anesthetized dogs. Renal function was monitored during CO with the NO system intact and with it blocked by the administration of L-NAME. With NO intact, CO increased arterial pressure and heart rate. With renal perfusion pressure held constant, CO also significantly decreased renal blood flow (RBF) and glomerular filtration rate (GFR) by 46% and 43%, respectively. CO, after L-NAME administration, resulted in a significantly exaggerated renal vasoconstriction. RBF and GFR decreased by 82% and 80%, respectively. Changes in water and sodium excretion were not different between the NO-intact and NO-blocked states during CO. These studies were also performed with the converting enzyme inhibitor, Captopril. The exaggerated renal hemodynamic responses to CO with NO synthesis inhibition were identical with or without Captopril. These findings indicate that under conditions of elevated peripheral and RSNA, NO plays an important role in modulating renal hemodynamics, but not sodium excretion. This effect does not appear to involve angiotensin II. PMID- 8677273 TI - Diminished mammary gland lymphocyte functions parallel shifts in trafficking patterns during the postpartum period. AB - Once activated, lymphocytes can regulate both specific and nonspecific immune responses. Alterations in lymphocyte function may increase the host's vulnerability to bacterial infections such as mastitis. Susceptibility to mastitis as well as diminished leukocyte functional capabilities have been shown to be influenced by lactational stage. Therefore, the present study characterized the phenotypes and functions of several bovine lymphoid populations at two points in the lactational cycle. Mononuclear cells were isolated from peripheral blood, supramammary lymph nodes, and mammary parenchyma of mid-lactating and postpartum dairy cows. The phenotypic composition, proliferative ability, cytokine secretion, and cytotoxic activity of isolated leukocytes were assessed with respect to lactational stage and tissue source. Lower percentages of T lymphocytes were consistent with diminished mitogen-stimulated proliferation and spontaneous cytotoxic activity by lymphocytes isolated from postpartum compared with mid-lactating animals. Stimulation with interleukin-2 did not enhance the cytotoxic activity or proliferative ability of lymphocytes isolated postpartum to similar levels observed for those isolated from mid-lactating animals. These data indicate that certain diminished lymphocyte functions observed during the postpartum period may result from shifts in leukocyte trafficking patterns. PMID- 8677274 TI - Murine red blood cell fragility is not affected by either vitamin E depletion or supplementation. AB - Male ICR mice were Pair-fed semipurified diets containing 0, 55 (control), and 500 IU/kg of vitamin E. Plasma and hepatic concentrations of vitamin E were determined and found to parallel the vitamin E levels in the diet. Even though plasma vitamin E levels were virtually zero in mice fed the depleted vitamin E diet for up to 304 days, there was no statistical difference in the red blood cell fragility between these animals and controls, as determined by a hypoosmotic fragility test. The diet with enriched vitamin E concentrations also did not affect the fragility of the red blood cell (RBC). Even after 300 days of zero dietary vitamin E, mice appeared healthy, demonstrating neither neurologic dysfunction nor failure to thrive. The data indicates that mice, unlike several other species, are more resistant to vitamin E depletion and may have other mechanisms to compensate for loss of this important antioxidant. PMID- 8677275 TI - Cardiac hypertrophy in copper-deficient rats is not attenuated by angiotensin II receptor antagonist L-158,809. AB - We tested the hypothesis that cardiac hypertrophy which accompanies copper (Cu) deficiency was mediated by angiotensin II (Ang II). Thirty 17-day-old male Holtzman rats were offered a semipurified low-Cu diet (0.45 mg Cu/kg) for 39 days. Fifteen controls (Cu adequate) were given supplemental Cu (20 microgram/ml) in their drinking water, the other 15 (Cu deficient) were given deionized water. Five from each dietary treatment group were chronically infused by using osmotic pumps for 4 weeks with the Ang II receptor antagonist L-158,809, and five from each group were infused with propylene glycol vehicle. Five from each group were not implanted. Blood pressure (BP) changes to injection of Ang II, phenylephrine, and acetylcholine were monitored in cannulated rats. Cu-deficient rats had higher heart weight, left ventricular (LV)/body weight (BW), right ventricular (RV)/BW, lower mean BP, and coronary vascular resistance (CVR) than Cu-adequate rats. L 158-809 did not alter Cu levels or RV/BW in either dietary group, but did lower LV/BW, CVR, and mean BP in both dietary groups. Since Ang II blockage lowered HW/BW and LV/BW in both groups, the stimulus for cardiac hypertrophy in Cu deficient rats remains unknown. PMID- 8677276 TI - Intertester reliability of a modified version of McKenzie's lateral shift assessments obtained on patients with low back pain. AB - BACKGROUND AND PURPOSE: McKenzie described a two-step process for assessing patients with low back pain for a lateral shift. The purpose of this study was to determine whether reliable judgments about lateral shifts could be obtained. SUBJECTS: Forty-nine patients with low back pain were each examined separately by two randomly paired physical therapists. METHODS: Assessments of the presence and direction of lateral shifts (step 1) were obtained by use of a simple instrument. The relevance of the lateral shifts to the patients' pain complaints (step 1) also was assessed by use of the side-glide test sequence. RESULTS: Generalized kappa coefficients were calculated to determine reliability. The kappa value for the two-step process of lateral shift assessment was .16. The percentage of agreement was 47%. CONCLUSION AND DISCUSSION: Each step in this two-step process was examined separately for possible sources of error. The kappa value for determinations of the presence and direction of lateral shifts was .00, indicating very poor reliability. The kappa value for the determination of the presence of a positive side-glide test sequence was .74, indicating high reliability. The role of lateral shift assessment in the McKenzie system should be reconsidered, given the strong research evidence for poor reliability of determinations of the presence and direction of lateral shifts. PMID- 8677277 TI - Content validity of the Harris Infant Neuromotor Test. AB - BACKGROUND AND PURPOSE: The purpose of this study was to assess the content validity of the Harris Infant Neuromotor Test (HINT), a new screening tool designed to detect early signs of cognitive and neuromotor delays in infants with known risk factors. SUBJECTS: A multidisciplinary panel of 26 international experts, including researchers and clinicians in physical therapy, occupational therapy, developmental pediatrics, child neurology, and psychology, was selected to assess, review, and suggest modifications to the HINT. METHODS: A validity questionnaire that was keyed to the three parts of the HINT (background information, parent questionnaire, and infant assessment) and to individual items within each part was mailed to the selected content experts. Data were analyzed using descriptive statistics. RESULTS: Twenty experts completed the validity questionnaires, and the remaining 6 experts provided written comments. The experts generally agreed that the items on the initial development edition of the HINT were clearly worded and free of cultural bias. Based on written feedback, additional background information items were added, a fifth question was added to the parent questionnaire portion, and 20 of the 22 infant assessment items were modified. CONCLUSION AND DISCUSSION: After receiving questionnaire responses and written comments from a panel of 26 experts, the original version of the HINT was modified and printed as development edition 2 in November 1993. This revised edition is currently being used to examine the reliability and validity of the HINT in assessing infants at risk. PMID- 8677279 TI - Structure and function of the abdominal muscles in primigravid subjects during pregnancy and the immediate postbirth period. AB - BACKGROUND AND PURPOSE: The purpose of this study was to investigate the abdominal muscle structural adaptations and functional capabilities during pregnancy and the postbirth period. SUBJECTS: Six primigravid subjects, aged 28 to 33 years, participated in nine test sessions from 14 weeks of gestation to 8 weeks postbirth. METHODS: At each test session, three-dimensional photography of abdominal skin markers was used to determine the gross morphology of a representative abdominal muscle, the rectus abdominis muscle. The functional capability of the abdominal muscle group was assessed on the ability of the muscle group to stabilize the pelvis against resistance. RESULTS: Increases were found in rectus abdominis muscle separation width, length, and angles of insertion as pregnancy progressed. Reversal in rectus abdominis muscle separation was found by 4 weeks postbirth. The ability to stabilize the pelvis against resistance was shown to be decreased as pregnancy progressed and remained compromised postbirth. Decrements in abdominal muscle function paralleled in time the structural adaptations as pregnancy progressed. Continued functional deficits were found in parallel with incomplete resolution of structural adaptations postbirth. CONCLUSION AND DISCUSSION: Abdominal muscle function is affected by structural adaptations that occur during pregnancy. Because our results showed that the ability to stabilize the pelvis against resistance is decreased during pregnancy and at least 8 weeks postbirth, abdominal muscle exercises should be chosen with care. [Gilleard WL, Brown JMM. Structure and function of the abdominal muscles in primigravid subjects during pregnancy and the immediate postbirth period. PMID- 8677278 TI - Phonophoretic delivery of 10% hydrocortisone through the epidermis of humans as determined by serum cortisol concentrations. AB - BACKGROUND AND PURPOSE: The purpose of this investigation was to determine whether application of hydrocortisone phonophoresis enhances transcutaneous delivery of topically applied hydrocortisone in humans, as determined by blood cortisol levels. SUBJECTS: The subjects were 16 men and women, between the ages of 18 and 33 years (X = 25, SD = 2.74), without symptoms of any ongoing inflammatory condition. METHODS: A gel coupling medium containing 10% hydrocortisone acetate was used. Ultrasound was delivered over a 50-cm2 area for 5 minutes at an intensity of 1.0 W/cm2 and a frequency of 1.0 MHz. Each subject received a control treatment (ultrasound alone) and an experimental treatment (hydrocortisone phonophoresis) on the volar aspect of the forearm 1 week apart. Blood was drawn, under both control and experimental conditions, from a cubital vein just proximal to the treatment site prior to each treatment and 0,5, and 15 minutes posttreatment. Serum cortisol concentrations were measured using a fluorescence polarization immunoassay. RESULTS: No rise in serum cortisol concentrations following hydrocortisone phonophoresis was detected. CONCLUSION AND DISCUSSION: These findings suggest that there was no penetration of hydrocortisone through the epidermis and into the underlying vasculature. Clinical implications regarding hydrocortisone levels within the subcutaneous tissues are discussed, and further research is suggested. PMID- 8677280 TI - Temporal stability of gait in Parkinson's disease. AB - BACKGROUND AND PURPOSE. Evaluation of physical therapy for gait disorders in patients with Parkinson's disease (PD) requires an under-standing of how the patients' medication cycle affects function. Four experiments were conducted to investigate stability of gait variables. METHODS AND RESULTS. In experiment 1, 15 subjects with idiopathic PD and 15 subjects without PD performed two sets of gait trials spaced 30 minutes apart, with the initial trial conducted with the subjects at a peak dose of medication. Strong correlations, as determined by intraclass correlation coefficients (ICC[2,1]), occurred between repeat measures of speed (ICC = .92), cadence (ICC = .92), stride length (ICC = .94), and time spent in double support (DS) (ICC = .93). In experiment 2, 16 subjects with PD were tested at the same time on two consecutive days. There was good repeatability for speed (ICC = .88), cadence (ICC = .85), stride length (ICC = .84), and DS (ICC = .80). When we assessed the repeatability of measurements taken at peak dose and at end of dose, there were low correlations for speed (ICC = -.54), cadence (ICC = -.07), stride length (ICC = -.35), and DS (ICC = -.38). In a final experiment on 16 subjects with PD, we used time-series analysis to examine the stability of measurements taken every 15 minutes for 2 1/2 hours. Slopes of regression models, standard deviations, and residual autocorrelations were negligible, indicating that the measurements were stable. CONCLUSION AND DISCUSSION. The parkinsonian gait pattern is reproducible across either brief time intervals or 24 hours when peak medication prevails. At the end of dose, however, marked changes in gait occur, apparently related to depletion of medication. PMID- 8677281 TI - Evaluating scientific merit. PMID- 8677282 TI - Pointillism and science. PMID- 8677283 TI - Researching the health effects of victimization: the next generation. PMID- 8677284 TI - Long-term psychological effects of natural disasters. AB - Relationships between self-reported psychological distress (Symptom Checklist) and experience with two earthquakes are presented for a group of male factor workers (N = 772) from Naples, Italy, participating in the 1987 follow-up of the Olivetti Heart Study. Although all were exposed to the 1980 earthquake that racked southern Italy, only men residing in the Naples suburb of Pozzuoli experienced the continuing swarm of earthquakes ("bradyseism") of 1983-1984, allowing for the observation of a "natural experiment" of sorts. Levels of psychological distress were found to be higher 7 years after the first earthquake for those men who reported damage from that earthquake. Overall, findings were similar for those who were evacuated, or suffered financial loss from the 1983 1984 bradyseism earthquakes. Stratification by 1980 earthquake damage revealed that 1983-1984 evacuation or financial loss was associated with increased distress reporting only for those men who had not reported damage from the 1980 earthquake. Overall, however, distress scores tended to be higher for men evacuated in 1983-1984 if they had also reported damage from the prior earthquake (only the F ratio for anxiety reached criterion for statistical significance). These findings suggest that the psychological consequences of earthquake exposure are long lasting and seem to be related to the consequences of the earthquake in terms of damage/loss. PMID- 8677285 TI - Relationships between circulating catecholamines and low frequency heart period variability as indices of cardiac sympathetic activity during mental stress. AB - Heart rate increases during psychological stress are the product of cardiac sympathetic activation and parasympathetic withdrawal. Levels of plasma epinephrine (E) and norepinephrine (NE) have a long history as indicators of cardiac adrenergic activity and, accordingly, generally increase in response to psychological challenge. Recently, several investigators have suggested that indices derived from power spectral analysis of heart period variability (HPV) also may provide estimates of cardiac sympathetic nervous system activity. These indices include power in the low frequency band (0.04-0.15 Hz, LF), and the ratio of low to high frequency (0.15-0.50 Hz, HF) power (LF/HF). The relationship between spectral and neurohumoral indices during psychological stress has not been investigated. This issue was addressed by studying spectrally defined measures of HPV and levels of plasma E and NE in 34 normal subjects who participated in a study of responsiveness to a psychologically challenging arithmetic task. Heart rate (HR), LF and HF power, the LF/HF ratio, and blood pressure were measured during the 5-minute baseline and 5-minute task periods. Integrated samples of forearm venous blood were collected for both periods. E and NE were analyzed by high performance liquid chromatography. The task produced significant increases in HR, systolic and diastolic pressures, and NE. Of the 12 Pearson correlation coefficients used to examine the relationships between power spectral measures and catecholamines for the baseline, task, and delta values, none achieved statistical significance, suggesting little relationship between neurohumoral and spectral estimates of cardiac sympathetic activity. We conclude that under conditions of psychological stress, LF power provides no useful information about cardiac sympathetic activity, both because power in this frequency band falls whereas HR rises and because there is no relationship between LF power and plasma NE. PMID- 8677286 TI - Effect of slowed respiration on cardiac parasympathetic response to threat. AB - The present study was designed to examine the effect of voluntarily slowed respiration on the cardiac parasympathetic response to a threat: the anticipation of an electric shock. Thirty healthy college students were randomly assigned to the slow, fast, and nonpaced breathing groups (10 subjects each). Subjects in the slow and fast paced breathing groups regulated their breathing rate to 8 and 30 cpm, respectively, and those in the nonpaced breathing group breathed spontaneously. Immediately after the period of paced or nonpaced breathing for 5 minutes, the subjects were exposed for 2 minutes to the anticipation of an electric shock during breathing paced at 15 cpm. The amplitude of the high frequency (HF) component of the heart rate variability, an index of cardiac parasympathetic tone, significantly decreased during the threat in the fast and nonpaced breathing groups, whereas it was unchanged in the slow paced breathing group. No significant difference was observed among the three groups in the amplitude of respiration during the threat. Results suggest that a slowed respiration decreases the cardiac parasympathetic withdrawal response to the threat. This study provides a rationale for the therapeutic uses of the slowed respiration maneuver in attenuating the cardiac autonomic responses in patients with anxiety disorder. PMID- 8677287 TI - A controlled comparison of multiple chemical sensitivities and chronic fatigue syndrome. AB - The present study had two objectives: 1) to determine the characteristics that differentiated subjects with multiple chemical sensitivities (MCS), chemical sensitivities (CS), and chronic fatigue syndrome (CFS); and 2) to evaluate the psychiatric and neuropsychological complaints of these groups relative to normal controls. A cross-sectional comparison was made of the following groups matched for age, sex, and education: 1) patients whose sensitivities to multiple low level chemical exposures began with a defined exposure (MCS; N = 23); 2) patients with sensitivities to multiple chemicals without a clear date of onset (CS; N = 13); 3) patients meeting CDC criteria for Chronic Fatigue Syndrome (CFS; N = 18); and 4) normal controls (N = 18). Subjects with sensitivities to chemicals (MCS and CS) reported significantly more lifestyle changes due to chemical sensitivities and significantly more chemical substances that made them ill compared with chronic fatigue and normal controls. MCS, CS, and CFS patients had significantly higher rates of current psychiatric disorders than normal controls and reported significantly more physical symptoms with no medical explanation. Seventy-four percent of MCS and 61% of CFS did not qualify for any current Axis I psychiatric diagnosis. Chemically sensitive subjects without a defined date of onset (CS) had the highest rate of Axis I psychiatric disorders (69%). On the MMPI-2, 44% of MCS, 42% of CS, 53% of CFS, and none of the controls achieved clinically significant elevations on scales associated with somatoform disorders. With the exception of one complex test of visual memory, no significant differences were noted among the groups on tests of neuropsychological function. Standardized measures of psychiatric and neuropsychological function did not differentiate subjects with sensitivities to chemicals from those with chronic fatigue. Subjects with sensitivities to chemicals and no clear date of onset had the highest rate of psychiatric morbidity. Standardized neuropsychological tests did not substantiate the cognitive impairment reported symptomatically. Cognitive deficits may become apparent under controlled exposure conditions. PMID- 8677288 TI - Sexual and physical abuse history in gastroenterology practice: how types of abuse impact health status. AB - OBJECTIVE: There is an increasing amount of literature pointing to a relationship between sexual and/or physical abuse history and poor health status, although few studies provide evidence concerning which aspects of abuse may impact on health. In female patients with gastrointestinal (GI) disorders, the present study examined the effects on health status of: 1) history of sexual abuse and physical abuse, 2) invasiveness or seriousness of sexual abuse and physical abuse, and 3) age at first sexual and physical abuse. METHOD: The sample included 239 female patients from a referral gastroenterology clinic who were interviewed to assess sexual and physical abuse history. RESULTS: We found the following: 1) 66.5% of patients experienced some type of sexual and/or physical abuse; 2) women with sexual abuse history had more pain, non-GI somatic symptoms, bed disability days, lifetime surgeries, psychological distress, and functional disability compared to those without sexual abuse; 3) women with physical abuse also had worse health outcome on most health status indicators; 4) rape (intercourse) and life threatening physical abuse seem to have worse health effects than less serious physical violence, and sexual abuse involving attempts and touch; and 5) those with first abuse in childhood did not appear to differ on health from those whose first abuse was as adults. CONCLUSIONS: The authors conclude that asking about abuse should be integrated into history taking within referral-based gastroenterology practices. PMID- 8677289 TI - Assessing somatization disorder in the chronic fatigue syndrome. AB - This study was conducted to examine the rates of somatization disorder (SD) in the chronic fatigue syndrome (CFS) relative to other fatiguing illness groups. It further addressed the arbitrary nature of the judgments made in assigning psychiatric vs. physical etiology to symptoms in controversial illnesses such as CFS. Patients with CFS (N = 42), multiple sclerosis (MS) (N = 18), and depression (N = 21) were compared with healthy individuals (N = 32) on a structured psychiatric interview. The SD section of the Diagnostic Interview Schedule (DIS) III-R was reanalyzed using different criteria sets to diagnose SD. All subjects received a thorough medical history, physical examination, and DIS interview. CFS patients received diagnostic laboratory testing to rule out other causes of fatigue. This study revealed that changing the attribution of SD symptoms from psychiatric to physical dramatically affected the rates of diagnosing SD in the CFS group. Both the CFS and depressed subjects endorsed a higher percentage of SD symptoms than either the MS or healthy groups, but very few met the strict DSM III-R criteria for SD. The present study illustrates that the terminology used to interpret the symptoms (ie, psychiatric or physical) will determine which category CFS falls into. The diagnosis of SD is of limited use in populations in which the etiology of the illness has not been established. PMID- 8677290 TI - Studies of the mortality of atomic bomb survivors. Report 12, Part I. Cancer: 1950-1990. AB - This continues the series of periodic general reports on cancer mortality in the cohort of A-bomb survivors followed by the Radiation Effects Research Foundation. The follow-up is extended by the 5 years 1986-1990, and analysis includes an additional 10,500 survivors with recently estimated radiation doses. Together these extensions add about 550,000 person-years of follow-up. The cohort analyzed consists of 86,572 subjects, of which about 60% have dose estimates of at least 0.005 Sv. During 1950-1990 there have been 3086 and 4741 cancer deaths for the less than and greater than 0.005 Sv groups, respectively. It is estimated that among these there have been approximately 420 excess cancer deaths during 1950 1990, of which about 85 were due to leukemia. For cancers other than leukemia (solid cancers), about 25% of the excess deaths in 1950-1990 occurred during the last 5 years; for those exposed as children this figure is nearly 50%. For leukemia only about 3% of the excess deaths in 1950-1990 occurred in the last 5 years. Whereas most of the excess for leukemia occurred in the first 15 years after exposure, for solid cancers the pattern of excess risk is apparently more like a life-long elevation of the natural age-specific cancer risk. Taking advantage of the lengthening follow-up, increased attention is given to clarifying temporal patterns of the excess cancer risk. Emphasis is placed on describing these patterns in terms of absolute excess risk, as well as relative risk. For example: (a) although it is becoming clearer that the excess relative risk for those exposed as children has declined over the follow-up, the excess absolute risk has increased rapidly with time; and (b) although the excess relative risk at a given age depends substantially on sex and age at exposure, the age-specific excess absolute risk depends little on these factors. The primary estimates of excess risk are now given as specific to sex and age at exposure, and these include projections of dose-specific lifetime risks for this cohort. The excess lifetime risk per sievert for solid cancers for those exposed at age 30 is estimated at 0.10 and 0.14 for males and females, respectively. Those exposed at age 50 have about one-third these risks. Projection of lifetime risks for those exposed at age 10 is more uncertain. Under a reasonable set of assumptions, estimates for this group range from about 1.0-1.8 times the estimates for those exposed at age 30. The excess life-time risk for leukemia at 1 Sv for those exposed at either 10 or 30 years is estimated as about 0.015 and 0.008 for males and females, respectively. Those exposed at age 50 have about two thirds that risk. Excess risks for solid cancer appear quite linear up to about 3 Sv, but for leukemia apparent nonlinearity in dose results in risks at 0.1 Sv estimated at about 1/20 of those for 1.0 Sv. Site-specific risk estimates are given, but it is urged that great care be taken in interpreting these, because most of their variation can be explained simply by imprecision in the estimates. PMID- 8677291 TI - Modifying effect in vivo of interferon alpha on induction and repair of lesions of DNA of lymphoid cells of gamma-irradiated mice. AB - The induction of structural lesions and repair in DNA of lymphoid cells from the peripheral blood, spleen and thymus of mice treated with natural mouse interferon alpha (IFN-alpha) 24 and 48 h prior to gamma irradiation were studied using the comet assay and apurinic-apyrimidinic (AP) site radiolabeling. It was demonstrated that the radiation-induced damage assessed by the comet assay in the DNA of peripheral blood lymphocytes (PBLs), splenocytes and thymocytes of mice treated with IFN-alpha before irradiation was considerably less and was repaired more easily in the postirradiation period than that in untreated mice. The DNA of PBLs and splenocytes from interferon-treated mice showed a decrease in the spontaneously occurring and radiation-induced AP sites, as determined immediately and 90 min after irradiation, compared to the level of AP sites in the DNA of untreated mice. The results lead us to assume that IFN-alpha activates the DNA repair systems in the cells of lymphoid tissue. PMID- 8677292 TI - Angiotensin II receptor antagonists in the prevention of radiation nephropathy. AB - Angiotensin-converting enzyme (ACE) inhibitors can be used to prevent the development of radiation nephropathy. Current studies were designed to determine whether blocking the angiotensin II (AII) receptor, rather than preventing the creation of AII, would be effective in the prophylaxis of radiation nephropathy. Rats received 17 Gy total-body irradiation (TBI) in six fractions followed by syngeneic bone marrow transplantation (BMT). Prior to TBI the rats were randomized to groups receiving an ACE inhibitor (captopril), an AII type 1 (AT1) receptor antagonist (L-158,809) or no treatment. Renal function was assessed over 40 weeks, and a subset of animals were sacrificed for histopathology at 33 weeks. Renal function deteriorated progressively in animals receiving TBI alone, leading to renal failure by 34 weeks. Renal function was significantly better in animals receiving either captopril or L-158,809, and none of these animals had progressed to renal failure by 43 weeks. Analysis of both renal function and histopathology shows that the AII receptor antagonist is more effective than the ACE inhibitor in the prophylaxis of BMT nephropathy. This indicates that a reduction of activation of the AT1 receptor by AII, by itself, is sufficient for the prophylaxis of radiation nephropathy. PMID- 8677293 TI - Effect of ionizing radiation on in vivo striatal release of dopamine in the rat. AB - The time-course effect of ionizing radiation on the levels of basal and KCl stimulated striatal release of dopamine (DA) was examined in vivo using microdialysis techniques. The basal level of extracellular DA in sham-irradiated controls was 0.172 +/- 0.042 pmol/sample (n = 9), and it increased 7.1-fold after the stimulation by 30 mM KCl (20microliters). However, the release of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), two metabolites of DA, was reduced significantly by 30 mM KCl (P < 0.05). In the presence of 10 microM forskolin, an activator of adenylate cyclase, a second stimulation by 30 mM KCl increased the release of DA 6.9-fold. Radiation exposure, at a dose of 10 Gy at 10 Gy/min, had no significant effect on the levels of either basal or KCl stimulated release of DA or on the release of DOPAC and HVA. Striatal DA release increased in response to two consecutive challenges of KCl. However, the release of DA in response to the second challenge of KCl was significantly smaller than that after the first challenge (543 +/- 110% compared to 794 +/- 164%, P < 0.05; Student's paired t test). Pretreatment with 10 muM forskolin, which by itself had no significant effect on the level of basal release of DA, prevented the decreased response of DA to the second challenge of KCl. Our results suggest that radiation exposure at the dose we used has no significant effect on the level of the basal release of DA or the release of DA stimulated by 30mM KCl in the rat striatum, and that a reduced release of DA in response to repeated KCl stimulation might involve the cAMP effector system. PMID- 8677294 TI - Comments on "Radiation-induced apoptosis in HL60 cells: oxygen effect, relationship between apoptosis and loss of clonogenicity, and dependence of time to apoptosis on radiation dose" by Hopcia et al. (Radiat. Res. 145, 315-323, 1996) PMID- 8677295 TI - Incidence of salivary gland tumors among atomic bomb survivors, 1950-1987. Evaluation of radiation-related risk. AB - A wide-ranging search for benign and malignant tumors of the major and minor salivary glands among members of the Life Span Study sample of the Radiation Effects Research Foundation identified 41 malignant and 94 benign incident tumors, including 14 malignant and 12 benign tumors of the minor salivary gland, plus 10 major gland tumors of unknown behavior. Dose-response analyses found statistically significant increases in risk with increasing A-bomb dose for both cancer and benign tumors. Estimated relative risks at 1 Sv weighted tissue kerma (RR1Sv, with 90% confidence interval in parentheses) were 4.5 (2.5-8.5) for cancer and 1.7 (1.1-2.7) for benign tumors. When analyzed by histological subtype within these two broad groups, it appeared that most of the dose response for malignant tumors was provided by an exceptionally strong dose response for mucoepidermoid carcinoma [11 exposed cases with dose estimates, RR1Sv = 9.3 (3.5 30.6)], and most or all of that for benign tumors corresponded to Warthin's tumor [12 cases, RR1Sv = 4.1 (1.6-11.3)]. There was a marginal dose response for malignant tumors other than mucoepidermoid carcinoma [RR1Sv = 2.4 (0.99-5.7)] but no significant trend for benign tumors other than Warthin's tumor [RR1Sv = 1.3 (0.9-2.2)]. Re-examination of the original data from published studies of other irradiated populations may shed new light on the remarkable type specificity of the salivary tumor dose response observed in the present study. PMID- 8677296 TI - Risk of lung cancer mortality after exposure to radon decay products in the Beaverlodge cohort based on revised exposure estimates. AB - Exposures to radon decay products have been re-estimated for 65 men who died of lung cancer between 1950 and 1980, and 126 matched controls selected from the Beaverlodge cohort of 8,487 workers at the Beaverlodge mine in Northern Saskatchewan. The revised exposure estimates were based on a more thorough review of individual employment records for the study subjects than originally conducted, together with historic data from area-specific measurements of exposure rates in the mine. The revised cumulative exposures are approximately 60% higher than the original exposure estimates, which were based on mine-wide averages for those exposures incurred prior to 1967, and which used geometric rather than arithmetic means for area exposure rates. Despite the increase in estimated exposures using the revised estimates, the excess relative risk per 100 working level months has increased from 2.70 to 3.25, most likely due to a substantial reduction in random exposure measurement error. The new data show similar modifying effects of risk by time since exposure and age at risk as other studies of underground miners, but provide no evidence of an inverse exposure rate effect, in contrast to a strong effect seen in the analyses based on the original exposure estimates. PMID- 8677297 TI - Somatic cell mutations at the glycophorin A locus in erythrocytes of atomic bomb survivors: implications for radiation carcinogenesis. AB - To clarify the relationship between somatic cell mutations and radiation exposure, the frequency of hemizygous mutant erythrocytes at the glycophorin A (GPA) locus was measured by flow cytometry for 1,226 heterozygous atomic bomb (A bomb) survivors in Hiroshima and Nagasaki. For statistical analysis, both GPA mutant frequency and radiation dose were log-transformed to normalize skewed distributions of these variables. The GPA mutant frequency increased slightly but significantly with age at testing and with the number of cigarettes smoked. Also, mutant frequency was significantly higher in males than in females even with adjustment for smoking and was higher in Hiroshima than in Nagasaki. These characteristics of background GPA mutant frequency are qualitatively similar to those of background solid cancer incidence or mortality obtained from previous epidemiological studies of survivors. An analysis of the mutant frequency dose response using a descriptive model showed that the doubling dose is about 1.20 Sv [95% confidence interval (CI): 0.95-1.56], whereas the minimum dose for detecting a significant increase in mutant frequency is about 0.24 Sv (95% CI: 0.041-0.51). No significant effects of sex, city or age at the time of exposure on the dose response were detected. Interestingly, the doubling dose of the GPA mutant frequency was similar to that of solid cancer incidence in A-bomb survivors. This observation is in line with the hypothesis that radiation-induced somatic cell mutations are the major cause of excess cancer risk after radiation exposure. Furthermore, the dose response was significantly higher in persons previously or subsequently diagnosed with cancer than in cancer-free individuals. This may suggest an earlier onset of cancer due to elevated mutant frequency or a higher radiation sensitivity in the cancer group, although the possibility of dosimetry errors should be considered. The findings obtained in the present study suggest that the GPA mutant frequency may reflect the cancer risk among people exposed to radiation. PMID- 8677298 TI - A new model describing the curves for repair of both DNA double-strand breaks and chromosome damage. AB - A review of reports dealing with fittings of the data for repair of DNA double strand breaks (DSBs) and excess chromosome fragments (ECFs) shows that several models are used to fit the repair curves. Since DSBs and ECFs are correlated, it is worth developing a model describing both phenomena. The curve-fitting models used most extensively, the two repair half-times model for DSBs and the monoexponential plus residual model for ECFs, appear to be too inflexible to describe the repair curves for both DSBs and ECFs. We have therefore developed a new concept based on a variable repair half-time. According to this concept, the repair curve is continuously bending and dependent on time and probably reflects a continuous spectrum of damage repairability. The fits of the curves for DSB repair to the variable repair half-time and the variable repair half-time plus residual models were compared to those obtained with the two half-times plus residual and two half-times models. Similarly, the fits of the curves for ECF repair to the variable repair half-time and variable half-time plus residual models were compared to that obtained with the monoexponential plus residual model. The quality of fit and the dependence of adjustable parameters on the portion of the curve fitted were used as comparison criteria. We found that: (a) It is useful to postulate the existence of a residual term for unrepairable lesions, regardless of the model adopted. (b) With the two cell lines tested (a normal and a hypersensitive one), data for both DSBs and ECFs are best fitted to the variable repair half-time plus residual model, whatever the repair time range. PMID- 8677299 TI - Fibroblast radiosensitivity in vitro and lung fibrosis in vivo: comparison between a fibrosis-prone and fibrosis-resistant mouse strain. AB - Radiation-induced pneumonitis and fibrosis in the lung after treatment to the thoracic cavity for malignant disease currently limit the maximum tolerated dose to that region. It has been suggested that heterogeneity in susceptibility to radiation-induced fibrosis exists in the population, implying that the lung tolerance dose is defined by a sensitive subset of the patient population. Studies of radiotherapy patients have indicated that the survival at 2 Gy (SF2) of cultured skin fibroblasts correlates with the incidence and severity of postirradiation damage in a number of tissues, suggesting that this assay may be a useful predictor of late tissue effects. The goal of the studies presented here was to determine if the radiosensitivity of fibroblasts in vitro isolated from mouse lungs was correlated with the severity of radiation-induced fibrosis in the lungs of two inbred strains of mice previously shown to differ markedly in their susceptibility to radiation-induced lung fibrosis: the C3Hf/Kam strain, classified as fibrosis-resistant, and the C57BL/6J strain, classified as fibrosis prone. Quantitative measurements of lung fibrosis after irradiation were compared to SF2 values for fibroblasts of skin and lung cultured from each strain. Lung fibrosis was quantified, using computerized image analysis, as the percentage of fibrosis on Masson's Trichrome-stained lung sections from both strains after single doses of radiation to the thorax. For the measurements of SF2, fibroblasts plated at the second passage and grown to confluence were given single doses of radiation ranging from 0 to 6 Gy. Survival curves were constructed and SF2 values obtained from a linear-quadratic fit to the data. The radiosensitivity of fibroblasts from the lung and skin of SCID mice was determined and served as a positive control. The percentage of radiation-induced lung fibrosis was significantly different between the two strains, 5.1% and 0.2% in the C57 strain and C3H strain, respectively. Follow-up of long-term survivors (two mice) from the C3H strain did not change this conclusion. However, the lung fibroblast SF2 for the C57BL/6J strain (fibrosis-prone), 0.50 +/- 0.03, was not statistically different from the C3Hf/Kam strain (fibrosis-resistant), 0.55 +/- 0.07. These data indicate that in vitro radiosensitivity of lung fibroblasts as assayed by survival at 2 Gy does not correlate with the development of lung fibrosis in this mouse model. The SF2 for lung fibroblasts from SCID mice was 0.10. Similar SF2 values were obtained for both the C3Hf/Kam mouse lung and skin fibroblasts, 0.55 and 0.56, respectively, and C57BL/6J mouse lung and skin fibroblasts, 0.50 and 0.52, respectively, indicating that the radiosensitivity of fibroblasts isolated from lung and skin within a strain is the same. PMID- 8677300 TI - Evidence for two patterns of inheritance of sensitivity to induction of lung fibrosis in mice by radiation, one of which involves two genes. AB - We showed previously that autosomal recessive determinants control the development of pulmonary fibrosis in mice during the early and late phases after irradiation. The extent of fibrosis was inversely correlated with the intrinsic lung activity of both plasminogen activator (PLA) and angiotensin-converting enzyme (ACE). To test these observations further, two groups of mice were given a dose of 15 Gy to the thorax: offspring of a backcross between C57L/J ("fibrosing mice") and the F1 of CBA/J ("non-fibrosing in the early phase") x C57L/J, and additional F1 individuals of CBA/J x C57L/J. Mice were euthanized upon developing a substantial respiratory deficiency (50% reduction in carbon monoxide uptake) during the early phase (14-25 weeks postirradiation). Seventeen mice from the backcross were heavily fibrosed, 38 were classed as intermediate, and 15 contained no fibrosis. No evidence of sex linkage was seen. These data strongly support our earlier conclusions and suggest that two autosomal genes which function additively determine the extent of the principal type of fibrosis in these strains. As no indication of a bimodal distribution of lung PLA or ACE activity was obtained, it is unlikely that one of the genes controls the level of either enzyme. The F1 mice unexpectedly showed small amounts of an unusual type of fibrosis which was not associated with hyaline material or fibrin deposits, in contrast to all previous reports of fibrosis during the early phase in mice. Similar, fibrin-free fibrosis was found during the early phase in mast cell deficient WBB6F1/J mice (and their normal siblings). In the F1 mice this unusual fibrosis appears to be regulated independently by two additional genes, one of which is sex-linked. PMID- 8677302 TI - The influence of sex on life shortening and tumor induction in CBA/Cne mice exposed to X rays or fission neutrons. AB - An experimental study of male and female CBA/Cne mice was set up at Casaccia primarily to investigate the influence of sex on long-term survival and tumor induction after exposure to high- and low-LET radiation. Mice were whole-body irradiated at 3 months of age with fission-neutron doses of 0.1, 0.2, 0.4, 0.8, 1.2 and 1.8 Gy at the RSV-TAPIRO reactor (mean neutron energy 0.4 MeV, in terms of kerma, y(D) = 51.5 keV/micron), or with 250 kVp X-ray doses of 1, 3, 5 and 7 Gy. Control and irradiated animals were then followed for their entire life span. As a general finding, male CBA/Cne mice appear more susceptible to tumorigenesis than females. In particular, the incidences of induced acute myeloid leukemia and malignant lymphomas are significant only in male mice. Benign and malignant solid tumors of many types are observed in mice of both sexes, the most frequent being in the lung, liver and ovary. However, evidence for a radiation response is limited to the case of Harderian gland neoplasms. In addition, a comparison of the observed frequency of all irradiated compared to unirradiated animals bearing solid tumors shows that the total tumor occurrence is not altered markedly by radiation exposure. A decrease in survival time is observed for both sexes and radiation types and correlates well with increasing dose. Moreover, both sex and radiation quality appear to influence the life shortening. A similar dose dependence of survival time is found when tumor-free animals alone are considered, suggesting a non-specific component of life-shortening. PMID- 8677301 TI - The biological effectiveness of radon-progeny alpha particles. V. Comparison of oncogenic transformation by accelerator-produced monoenergetic alpha particles and by polyenergetic alpha particles from radon progeny. AB - Generation of estimates of risk caused by exposure to radon in the home, either from miner data or from A-bomb data, requires several scaling factors such as for dose, dose rate and radiation quality, and possible synergisms. Such scaling factors are best developed from laboratory-based studies. Two possible sources of alpha particles for such studies are (1) a polyenergetic spectrum, generated directly by radon and its progeny, or (2) a series of monoenergetic alpha particles. We compare here the results of oncogenic transformation from studies using both systems. At the Columbia University Radiological Research Accelerator Facility (RARAF), C3H 10T1/2 cells were irradiated with alpha particles of various energies, with defined LETs from 70 to 200 keV/mum. At Pacific Northwest Laboratory, cells from the same stock were exposed to alpha particles from radon gas and its progeny, which were in equilibrium with the culture medium. There was good agreement between the results of oncogenic transformation experiments using the two different exposure systems. Apart from the experimental transformation frequencies themselves, such a comparison requires (1) reliable dosimetry at both facilities and (2) estimated LET distributions for the polyenergetic alpha particle irradiator. Thus this good agreement gives some confirmation to the technique which is used to fold together oncogenic transformation rates from monoenergetic alpha particles to yield a predicted rate for a spectrum of alpha particles. PMID- 8677303 TI - The response of mouse lymphosarcoma cells to continuous gamma irradiation. AB - Long-lasting survival of LS/BL tumor cells under continuous exposure in vivo to 60Co irradiation at an exposure rate of 10 cGy/h was observed. While LS/BL tumor cells tolerated the irradiation for more than 150 weeks, the number of hematopoietic stem cells decreased to less than 1% of control values within 7 days of irradiation. The liver colony method was used to develop sublines from nonirradiated and continuously (110 weeks) irradiated LS/BL cells for the analysis of karyotypes of the resulting clones of lymphosarcoma cells. The appearance of new structural abnormalities t(12:9) in one of the sublines tested correlated with its faster host killing when compared to the parent line. PMID- 8677304 TI - Effects of X irradiation on metabolism of proteoglycans. AB - The effects of X irradiation on matrix formation by growth-plate and articular chondrocytes, as reflected by metabolism of proteoglycans and type II collagen, were examined in a rabbit chondrocyte culture system. Irradiation with 1 to 10 Gy selectively inhibited synthesis of proteoglycans (incorporation of [35S]sulfate) depending on the stage of differentiation of the irradiated cells; however, synthesis of type II collagen was not affected. Irradiation of an immature culture, in which chondrocytes had just reached confluence, suppressed incorporation of [35S]sulfate into the glycosaminoglycan, 10 Gy inducing approximately 45-50% inhibition. In contrast, the irradiation of mature cultures, in which chondrocytes had already secreted extensive cartilage matrix, did not affect the rate of synthesis of proteoglycans (incorporation of [35S]sulfate). We also found that here irradiation stimulated the degradation of proteoglycans, but with the effect differing in growth-plate chondrocytes and articular chondrocytes. In growth-plate chondrocytes, cleavage from a site close to the G1 globular domain induced by 10 Gy enhanced the release of 35S-labeled proteoglycans into the medium, whereas in articular chondrocytes, irradiation had only marginal effects on the release of 35S-labeled proteoglycans. Our results show that irradiation with 1-10 Gy impaired proteoglycan metabolism in cartilage, with differing effects according to the stage of cell differentiation and the type of chondrocyte. PMID- 8677305 TI - CT of the pediatric gastrointestinal tract. AB - Despite the fact that children are not small adults, some children will invariably be evaluated with adult imaging protocols. As CT gains popularity in the evaluation of the adult gastrointestinal (GI) tract, there will undoubtedly be some spillover into the pediatric age group. This pictorial essay reviews the CT appearance of some common pediatric GI disorders as common diseases may present uncommonly, both clinically and radiographically. PMID- 8677306 TI - Imaging of gastrointestinal malignancy in childhood. AB - Gastrointestinal malignancies in children are a rare and diverse group of neoplasms. Presenting signs and symptoms are nonspecific, but age at presentation and the presence of an elevated serum alpha-fetoprotein can provide helpful clues in tailoring a differential diagnosis. The role of imaging is to localize and characterize the tumor and define resectability. Plain films, ultrasound, and CT scans are the primary modalities employed, with MR imaging utilized in equivocal cases. PMID- 8677307 TI - Intussusception. Issues and controversies related to diagnosis and reduction. AB - Diagnosis and management of intussusception remain controversial. The authors discuss the evolution of changes and advances in practice and procedures. They advocate sonographic diagnosis and air enema reduction; the abdominal radiograph is reserved for children with clinical evidence of peritonitis and suspected perforation, if clinical findings are unusual, or if the sonographic examination is equivocal. PMID- 8677308 TI - Imaging in liver transplantation. AB - Thoughtfully planned and skillfully executed diagnostic and interventional imaging is indispensible in preoperative assessment of the pediatric liver transplant candidate and for the detection and management of the myriad postoperative complications that may affect the liver recipient. PMID- 8677309 TI - The gastrointestinal manifestations of pediatric AIDS. AB - The manifestations of AIDS in the gastrointestinal tract in children are mainly secondary to opportunistic infections and AIDS-related neoplasms. This article reviews the radiologic and pathologic findings seen throughout the gastrointestinal tract and within the abdomen in children afflicted with AIDS. Although many radiologic findings are not specific for a particular infection or neoplasm, the radiologist can narrow the differential diagnosis with a good knowledge of the imaging findings and pathologies specific for children with AIDS. PMID- 8677310 TI - Ultrasonography of the acute pediatric abdomen. AB - In this article I have attempted to illustrate just how potentially useful the current ultrasound examination can be in the evaluation of the acute pediatric abdomen. It must be understood, however, that not all radiologists agree on the merits of ultrasound in the evaluation of the gastrointestinal tract, and in practice the choice will reflect the radiologist's experience and expertise as well as the confidence level of the referring physician. Proficiency in pediatric ultrasonography is not gained overnight and cannot be attained by those who only occasionally perform such examinations. Certainly, unskilled use of ultrasound quickly leads to disasters and to profound mistrust by referring clinicians. Nevertheless, in experienced hands ultrasonography can provide valuable information, much of which cannot be obtained by any other imaging modality, and thus will change forever the radiologist's role in the work-up of the acute pediatric abdomen. PMID- 8677311 TI - CT scan of bowel trauma in the pediatric patient. AB - In the CT evaluation of children with blunt abdominal trauma, bowel injury may represent the most problematic condition that the radiologist encounters. In cases where there is a large, unexplained pneumoperitoneum or extravasation of oral contrast, the diagnosis is straightforward. Significant, potentially life threatening injuries, however, may be manifest only by focal bowel wall thickening and peritoneal fluid accumulation. Meticulous attention to detail with regard to scanning, administration of contrast, and review of the images along with the recognition of patterns and sites of more common injuries can improve the sensitivity of the radiologist in the detection of bowel trauma. PMID- 8677312 TI - Emergency gastrointestinal radiology of the newborn. AB - Imaging plays a major role in most neonatal gastrointestinal emergencies. The role may vary from helping to establish a diagnosis, to the evaluation of associated abnormalities, to surgical planning, or to therapy for some conditions like meconium ileus or meconium plug syndrome. Plain radiographs and bowel contrast examinations serve as primary imaging modalities with ultrasound, CT scan, and MR imaging playing roles in more complex cases. PMID- 8677313 TI - Pediatric gastrointestinal nuclear imaging. AB - Scintigraphy is an excellent choice for physiologic imaging of the GI tract in pediatric patients. In many instances it provides adequate anatomic information and additional functional data with lower radiation exposure to the patient than possible with fluoroscopic evaluation (GER and gastric emptying), with invasive cholangiography (neonatal jaundice), or with angiography (GI bleeding studies). In other instances, scintigraphy provides complimentary information that, when combined with other imaging modalities, leads to a definitive diagnosis. PMID- 8677314 TI - CT scan of mesentery-omentum peritoneum. AB - The peritoneal cavity and its specialized folds, the mesentery and omentum, are often involved in infectious, neoplastic, and traumatic conditions. Abnormalities in the development of these structures may also result in pathologic conditions. CT scans are often the modality of choice for evaluation of many of these entities. The following discussion reviews the normal anatomy and the CT features of disease processes that involve the peritoneal cavity, mesentery, and omentum in children. Identification and characterization of these pathologic conditions depend on knowledge of the normal appearance of the peritoneal cavity and its specialized folds and familiarity with the anatomic pathways for spread of disease. PMID- 8677315 TI - Inflammatory bowel disease in children. AB - Pediatric inflammatory bowel disease is a complex area of pediatric gastrointestinal imaging. Multiple causative factors are discussed with emphasis upon disorders without known or presumed infectious etiology. Conditions discussed include Henoch-Schonlein purpura, Kawasaki disease, Behcet's disease, Crohn's disease, and ulcerative colitis with their respective clinical and radiological findings, differential diagnosis features, plus pertinent extraintestinal manifestations of inflammatory bowel disease. PMID- 8677316 TI - Interventional procedures in the gastrointestinal tract in children. AB - Significant growth and innovation in interventional procedures involving the gastrointestinal tract has occurred over the last 15 years. The authors discuss historical background, procedural planning, sedation, and monitoring during the procedure, technique, postprocedural care, and potential procedural complications in the pediatric population. PMID- 8677317 TI - [Cost-benefit analysis in radiology]. PMID- 8677318 TI - [Diagnostic radiology in the cost development spectrum in medicine]. AB - Health care costs have risen considerably since 1970 in all industrialized countries. This has several causes: changes in demographic structure, the large number of physicians, increased personnel needs resulting from generous vacation and special leave privileges, wage increases and--last but not least--medical progress. Advances in medical technology are often regarded as one of the main reasons for spiraling costs in health care. Careful analyses reveal, however, that the high costs of imaging services are due to conventional radiography rather than to high-technology (CT, MR) imaging. The legitimate demands for cost reduction have to be met with improved cost efficiency while optimal quality standards must also be maintained. Relevant suggestions, such as generally accepted examination strategies, should be realized with the help of the scientific societies. PMID- 8677319 TI - [Effectiveness and cost effectiveness of innovative medical techniques in public health]. AB - Electromedical technology and systems are an integral part of health services and contribute to their costs. Despite the sometimes high capital costs, they have proved to be effective and efficient for health services. Technological assessment with respect to benefit and cost aspects has been well and systematically evaluated, but requires much work in detail. In many cases less sophisticated procedures are sufficiently effective for a reliable evaluation. Corresponding results that show the cost-saving potential of advanced technology for radiology are reported. PMID- 8677320 TI - [Cui bono? Comments on cost-benefit analysis in ultrasound diagnosis]. AB - Despite the low costs of a single examination, the overall expenses for ultrasonography are exceptionally high (1.4 billion DM in 1993), not counting the costs of further examinations because of unclear findings. The advantages of sonography are that it is harmless and yields diagnostically important results. Its clinical benefit is beyond doubt in the case of acute clinical symptoms, but unclear for staging and followup of malignant tumors. It has been shown to be efficient in screening for renal and prostatic cancer. Here, the costs for sonographic screening appear to be potentially outweighed by the reduction in treatment expenses. However, the cost of sonographic examinations can sometimes be avoided: sonography should not be used if there is no clear indication or if the examiner is not really qualified or the equipment is insufficient. There is a conflict of interest when the referring physician performs to sonography himself, leading to unnecessary examinations. To limit costs it would be potentially helpful if sonographic examinations are only performed when the indications are valid. The education of the examining physicians must be improved, better equipment must be used, scanners can be shared, and patients can be referred to colleagues who are more experienced in sonography. The currently reformed reimbursement scheme is of little value because it does not permit a qualified, thorough, cost-efficient examination. PMID- 8677321 TI - [Cost benefit considerations in modern diagnostic sectional imaging exemplified by upper abdominal organs]. AB - Demands for increased productivity despite cuts in financial resources have renewed the discussion of cost effectiveness in medical care. Unfortunately, there is a lack of reliable data for evaluating the cost effectiveness of diagnostic procedures. The present article discusses various aspects of this topic and presents examples from the diagnostic evaluation of the upper abdomen. It is argued that modern imaging procedures have in the past helped to reduce costs and that they can become cost effective when they replace established combinations of diagnostic procedures. The present discussion is severely hampered by the fact that there are no generally accepted standards for evaluating diagnostic strategies and that there are no well-founded studies of the cost effectiveness of the strategies used in abdominal diagnosis. Cost effectiveness will in the future become an additional criterion for assessing the quality of medical care. PMID- 8677322 TI - [Cost-benefit analysis in mammography screening]. AB - The Swedish Mammography-Screening trials have shown a long-term reduction in the mortality rate in women aged between 50-69 of up to 30%. The lower reduction in mortality observed in women aged 40-49 was not statistically significant. Long term observation over 20 years) has shown that a radiation dose of 2.4 mGy for a 2-view-mammography per breast does not lead to an increase in occurrence of breast cancers. The advantage of screening with regard to a reduction in death rate, frequent use of breast cancerving therapy and the reduction by half in the average size of the tumor compared to control groups results in: A recommendation for quality controlled screening in Germany from the age of 50 to 70. The possible advantage for younger women must be examined in further trials. Screening in the form of a de-centralized check-up system is to be carried out by practising doctors in co-operation with hospitals which will be responsible for double findings, assessment of difficult cases and continuous cost evaluation. Quality assurance centres, reference and training centres are required. The mammography in curative check-ups will also benefit from a screening programme. PMID- 8677323 TI - [Digital radiography. Cost-benefit analysis]. AB - Due to its high dynamic range and contrast discernibility, digital radiography offers substantial advantages compared with conventional film-screen systems. Moreover, further advantages can be assumed for radiation protection. Digital radiography also allows conventional image data to be included in PACS (Picture Archiving Communication System). These well-known advantages are faced with legal questions which are not yet settled. Cost effectiveness in using systems of digital radiography and PACS are also under discussion. By means of examining economic efficiency and cost analysis of digital radiography systems, economic effectiveness was assessed. This was also compared with conventional alternatives. As a result, it may be assumed that amortization is reached in three to four years. Based on lower costs for films, digital systems are more cost effective than conventional systems after this period. PMID- 8677324 TI - [Cost and effectiveness of different strategies in diagnosis of osteoporosis]. AB - Osteoporosis represents one of the most common disorders in Germany. Because of the general aging of the population and due to several secular trends (less exercise, nutritional deficits, higher standard of living) the prevalence of osteoporosis will increase substantially. Therefore, it is important to develop preventive strategies and analyze them according to both medical and economical criteria. During the last couple of years substantial progress has been made both in the area of diagnostic approaches as well as treatment modalities. Thus, from a medical point of view important conditions for a positive assessment of the cost-benefit-ratio of diagnostic approaches in osteoporosis are now fulfilled. Currently, a strategy for selective screening of well-defined high risk groups appears to be most appropriate. These include 1. women with subnormal hormonal status provided that other risk factors are present, 2. patients with low-trauma fractures, 3. patients under prolonged steroid therapy, and 4. patients with secondary osteoporosis due to other causes. International studies have demonstrated that even more far-reaching preventive strategies can be conceived that could be both medically and economically effective. Currently, however, data for a detailed cost-benefit-analysis are lacking or based on outdated diagnostic equipment or treatment agents. New Studies on this topic are critically needed to evaluate preventive strategies, specifically for Germany. PMID- 8677325 TI - [Electron beam tomography in cost effective diagnosis of coronary heart disease]. AB - BACKGROUND: Electron beam CT (EBCT) can acquire rapid, multiple thin-section tomograms of the beating heart in synchrony with the electrocardiogram and quantity coronary calcification without intravenous contrast. Coronary calcification is an active process exclusively associated with atherosclerotic plaque formation and regulated in a manner similar to the calcification of bone. Clinical studies have demonstrated that EBCT coronary calcification (1) follows a pattern similar to the epidemiology of coronary artery disease (CAD), (2) has a high sensitivity (90-95%) for coronary plaque and significant angiographic coronary stenoses, and (3) has the potential to assess the prognosis of patients with coronary atherosclerotic disease. Coronary calcium area or "score" correlates best with overall plaque burden within the coronary system. However, coronary calcium is of limited value in distinguishing coronary stenosis on a segment-by-segment basis. EBCT AND CAD: Due to spiraling health care costs, there is a need for cost-efficient strategies in the diagnosis and stratification of patients with known or suspected CAD. There are two major patient groups in which EBCT calcium scanning has a potential for cost-efficient application: (1) in asymptomatic, high-risk patients, identification of significant plaque burden may direct judicious use of long-term drug therapy or further investigation to those individuals most likely to benefit from an aggressive risk factor modification and medical program; (2) in patients with chest pain syndromes but no prior CAD, EBCT calcium scanning compares favorably with conventional diagnostic methods. In particular, using receiver operating characteristic analysis, the sensitivity and specificity of an EBCT calcium score of 80 in detecting obstructive CAD are both about 85%. Using a theoretical model, EBCT calcium scanning was found to be the most cost-effective approach to diagnosis in populations with a low-to-moderate likelihood of obstructive CAD when compared with treadmill exercise, stress thallium, and stress echocardiography. CONCLUSIONS: EBCT calcium scanning is not a substitute for coronary angiography, but it has clear advantages over other more traditional diagnostic methods for CAD. In particular, it can be performed conveniently and inexpensively in most patients. Additionally, the site and extent of calcification are intimately related to the atherosclerotic plaque burden. The analyses presented suggest that it may also provide a cost-effective clinical alternative in specific subsets of the population. PMID- 8677326 TI - [Positron emission tomography. Cost-benefit considerations]. AB - To date, positron emission tomography (PET) is the most powerful tool for the non invasive study of biochemical processes. Besides its usefulness for basic research PET has been proven to be superior to conventional diagnostic methods in several clinical indications. However, the introduction of PET into clinical practice has been hindered considerably by its costs. Several American studies lend support to the hypothesis that PET may be more cost-effective than the conventional diagnostic work-up-at least for some of its clinical indications. In Germany, however, this hypothesis has still not been verified. PMID- 8677327 TI - [Gamma knife versus stereotactic linear accelerator. Utilization, clinical results and cost-benefit relations]. AB - INTRODUCTION: The principles of radiosurgery were developed in 1951 by Leksell. Their technical realization led to the development of the gamma knife and stereotactically modified linear accelerator. METHODS: In addition to the gamma knife, we present the different principles of convergent beam irradiation (radiosurgery with linear accelerator), the further development to fractionated stereotactic conformal radiotherapy, and the necessary quality-assurance steps. RESULTS: The greatest uncertainties in the precision of radiosurgery result from medical imaging (CT 0.7 x 0.7 x 1 mm; DSA 1-5 mm; MR angiography < 2 mm). The focusing accuracy of the gamma knife (+/- 0.3 mm) can also be achieved today by linear accelerators using a stereotactic floorstand. For the same indication and the same dosage for the target volume, there are no clinical differences between the gamma knife and the linear accelerator (AVM: 80% complete obliteration; metastases: 85% local tumor control; AN: 90% tumor control). However, there are greater differences in costs. There is no constellation where the gamma knife is just as expensive or more cost-effective than the linear accelerator treatment. The most cost-effective solution is modification of an available linear accelerator, resulting in treatment costs per patient of 9,201.25 DM (50 patients/year). CONCLUSION: There seem to be no methodological, physical, clinical or cost reasons for using a gamma knife, especially because the trend is going towards fractionated conformation radiotherapy instead of the application of high single doses. PMID- 8677328 TI - [Primary non-Hodgkin's lymphoma of the skull in an 11-year-old girl. Follow-up and review of the literature]. AB - The authors present a rare case of solitary non-Hodgkin lymphoma (NHL) in the skull of an 11-year-old girl. The clinical, radiological and histological findings as well as a review of the literature are included in this report. The morphological features of intra- and extracerebral tumor masses and the change in tumor extension due to chemotherapy and radiation therapy were evaluated with magnetic resonance imaging. Although rare, NHL should be considered in the differential diagnosis of skull tumors in children. PMID- 8677329 TI - [A method of computer-assisted, 3-dimensional subtraction angiography using spiral roentgen computerized tomography]. AB - The objective of this study was to develop a method for 3D subtraction CT angiography and to optimize the visualization after semi-automatic segmentation. Ten patients with aneurysms of the abdominal aorta were examined using spiral CT. To reconstruct the vessels, as well as adjacent organs such as the liver and kidneys, one image data volume was acquired before and after injection of the contrast agent. The CT scans were obtained with a Siemens Somatom Plus 4. To improve the results of automatic segmentation, as well as visualization by maximum intensity projection (i.e. removal of bony structures), subtraction of both image volumes is necessary. However, small translation shifts disturb the subtraction process and produce artificial contours. To calculate the disparities along the three coordinate axes of two corresponding image volumes, a cepstrum filter is applied to a pair of image volumes. After detection of the disparities, which manifest as bright spots, the real shift of the two subsignals can be calculated. Translation of the corresponding image volume pairs to their correct positions improves the subtraction process. In all cases the size of the aneurysm and the abdominal organs could be better segmented and visualized. Application of the cepstrum filter and subtraction of the image volumes before and after contrast medium injection completely removes the bony structures in the image data and results in superior visualization results. PMID- 8677330 TI - [Spiral CT for detection of heart valve disease with complex postoperative changes]. PMID- 8677331 TI - [Use of an image serve for external communication in a radiologic department]. AB - In radiology picture information is increasingly acquired digitally. Image postprocessing is sometimes carried out via the picture archiving and communication system (PACS). In this paper we present a strategy for the simple implementation of an external picture communication system. METHODS: Image transfer for the entire radiology department is carried out through a single image server, which physically and logically separates the PACS from the external network. The server is organized as an image mailbox system. For each user the images can be transferred to their respective mailbox from the radiology department. However, direct access to the image archive is prevented by the system. RESULTS: Because the networks are separate, a high degree of access security is guaranteed. New users can easily be added to the server without additional configuration of the PACS. System usage has received wide acceptance within the department and with external users. CONCLUSIONS: The integration of an image server into a PACS has proved to be non-problematic. The concept allows for more effective information sharing in the field of teleradiology. PMID- 8677332 TI - [Psychobiology of motivation and organization of psychological aspects from the viewpoint of a hierarchical model]. AB - Expressly leaving aside the classical Freudian theory of instinctual drives, itself largely based on obsolete biological models, and drawing on Lichtenberg's theory of motivation, Gedo outlines a five-stage motivation model encompassing both pre-programmed biological patterns and those acquired via learning and experience. With reference to brief examples from clinical practice the author describes how human behaviour can derive from various motives, thus making it essential to go beyond Freud's theory of libido. To do justice to the complexity of the phenomenon, he introduces a hierarchical schema taking account of the interaction between various motivations, the ways in which they may conflict and ultimately the ways in which they may best be reconciled. PMID- 8677333 TI - [Values and moral attitudes]. PMID- 8677334 TI - [Fear of repetition. Comments on the process of working through in psychoanalysis]. PMID- 8677335 TI - A scientific approach to technology, culture and training of physicians, continuing education. PMID- 8677336 TI - Tumors of cerebral hemispheres. AB - Pediatric brain tumors are substantially represented by neuroepithelial neoplasms. If intraventricular tumors are excluded, diagnostic imaging can be referred to 3 main types: gliomas, neuronal and mixed tumors, embryonal tumors. Following a short review of the various neuroimaging procedures, CT and MRI findings of most common pediatric hemispheric neoplasms, are described. Neuroradiologic findings supply a satisfactory "characterization" of the neoplasm. They are at times so specific as to achieve a univocal diagnostic hypothesis. More frequently, only a likely histologic hypothesis is achieved based on the combination of neuroimaging and clinical findings. Finally, the role of diagnostic imaging is underlined, being important in the definition of the relationships between hemispheric tumors with some "critical" areas, because of "functional" relevance, and in the identification of the site and pattern of infiltration which impact on prognosis and treatment. PMID- 8677337 TI - Intraventricular supratentorial tumors in children. AB - Overall, intraventricular supratentorial tumors are rare in childhood. Classification can be based on the separation of lesions originating in intraventricular structures, such as choroid plexuses, from glial neoplasms of the ventricular wall which tend to infiltrate the ventricular cavities. Aim of the present study is to review the most common neoplasms of this region in childhood. Choroid plexus tumors (papillomas and carcinomas) and subependymal giant cell astrocytomas are dealt with, while for the other neoplasms which are rarer or more typic of other age ranges, specific reports should be consulted. Choroid plexus papillomas affect infants and are the most frequent oncological type among congenital tumors. The malignant variant (grade III-IV) is represented by the less frequent the neoplasms. The malignant variant (grade III-IV) is represented by the less frequent choroid plexus carcinoma which is markedly invasive with respect to adjacent nervous structures and has a high tendency to form metastases even at onset. Anaplastic papillomas are intermediate forms whose correct histopathology is still debated. Most frequent glial tumors are subependymal giant-cell astrocytomas. They are benign tumors (grade I) typically albeit not constantly associated to tuberous sclerosis. In this case the differentiation from subependymal nodules plays a major role. Contrast enhanced CT is fundamental in this assessment. Anaplastic variants, though rare, are well known. PMID- 8677338 TI - Neoplasms of the optic-chiasmatic region. AB - Diagnosis of neoplasms of the optic-chiasmatic region is facilitated by assessment of onset symptoms. They represent the basis for a specific radiologic study, allowing a differential diagnosis between radiologically similar forms. An easy approach to these neoplasms is to separate malignant lesions from non neoplastic space-occupying lesions. Diagnostic imaging of neoplasms of the optic chiasmatic region is based on MRI, occasionally combined with CT. Because of its peculiar embryology, the region is the site of numerous neoformations. However, differential diagnosis is ready in most cases. To plan the most suitable surgical management, the relations of the lesions with adjacent anatomical structures should be carefully assessed. More complex syndromes (gliomas in NF1, infundibulopeduncular histiocytosis in eosinophilic granulomatosis, etc.) should also be considered. PMID- 8677339 TI - Neuroradiology in pediatric neuro-oncology: intracranial supratentorial tumors. PMID- 8677340 TI - Neoplasms of the basal ganglia. AB - Neoplasms of the basal ganglia are deep-seated and this markedly impacts on therapy, especially with respect to the surgical approach. However, neoplasms purely involving the basal ganglia are rare: more frequently, basal ganglia are secondarily involved by tumors originating in the cerebral hemispheres, the ventricles and the pineal or suprasellar regions. Following an anatomical and epidemiologic overview, most frequent CT and MR imaging findings of pediatric neoplasms of basal ganglia are described. PMID- 8677342 TI - Intracranial supratentorial tumors: classification, clinical findings, surgical management. AB - Pediatric supratentorial tumors represent about 50% of all intracranial neoplasms. The most frequent tumors of the cerebral hemispheres are gliomas that arise from astrocytes, oligodendrocytes or ependymal cells. The incidence of the different histologic types is difficult to be established as many tumors have a mixed cellularity, thus classification is based on the prevalent oncotype or the most malignant component. Choroid plexus papillomas and ependymomas are the most common ventricular neoplasms. However, subependymal giant cell astrocytomas, subependymomas, teratomas are also observed. The parasellar region is a frequent site of pediatric tumors as craniopharyngiomas, optic pathway gliomas and germinomas. Pinealomas are less common. Signs and symptoms related to increased intracranial pressure are often reported and vary according to the patient's age. Macrocrania and a bulging fontanel can be observed in infants and toddlers, whereas headache, papilledema and vomiting are present in the older children. A tumor hindering CSF circulation may cause hydrocephalus. Focal signs include epilepsy and neurological deficits characteristic of tumor location. Total removal of the tumor is the ideal surgical therapy. When eloquent areas are involved, partial exeresis is indicated. Radiotherapy is usually administered to malignant tumors even if in younger children its use in markedly limited by the possible severe side-effects on the developing brain. Chemotherapy seems effective in some brain neoplasms, however most suitable drugs and dose need to be established. It may represent an alternative to radiotherapy in children less than three years of age. PMID- 8677341 TI - Tumors of the pineal region. AB - The role played by neuroradiologic examinations in the diagnosis of neoformations of the pineal region is considered. Results of reports of literature are compared with the personal experience (40 patients) to draw possible significant conclusions for the diagnosis of the oncological type. First, intrinsic pineal lesions should be separated from those of adjacent structures. Reliable discriminating parameters useful in the differential diagnosis are represented by sex and age. Diagnosis based on biochemistry with markers was shown not to be univocal. A further separation can be based on CT and MRI findings. In particular, teratomas appear as solid tumors with calcification and fat. The latter is depicted on MRI even if minimal. To the contrary, germinomas do not contain fat and are markedly enhancing. Microcysts seem to be more common in tumors originating from parenchymal pineal cells. A reliable differential diagnosis is however possible only for small-sized lesions where identification of the anatomical structure of origin is easier. PMID- 8677343 TI - [Gene therapy of respiratory diseases: a new era?]. PMID- 8677344 TI - [Evaluation of the quality of life in chronic respiratory diseases]. PMID- 8677345 TI - [To speak plainly: BC, BPCO, BPCONA? Or BOT?]. PMID- 8677346 TI - [Sarcoidosis: immunopathology and criteria of biological activity]. AB - In France, sarcoidosis is the most frequent interstitial lung disease of unknown origin. Its prevalence is about 9.5 in 100 000. Almost 30% of the patients require corticosteroid treatment. Although the aetiology remains unknown, detailed concepts of the immunopathogenesis have been suggested. Employing the technique of bronchoalveolar lavage, some immunopathogenic mechanisms have been elucidated and the hypothesis that an unknown causative agent stimulates T lymphocytes and macrophages by physiological mechanisms has emerged. The activity of these cells maintains the inflammation and is the target of the corticosteroid therapy. By new serologic parameters it is possible to gauge this activity and to document the therapeutic effect. PMID- 8677347 TI - [CYFRA 21-1 and bronchial cancer]. AB - CYFRA is a new marker which measures a fragment of cytokeratin 19 in the serum by an immune radiometric method. The test is based on the preservation of the cytokeratin expression on the epithelial cells during the course of malignant transformation. In immuno-histochemistry the antibodies which selectively recognise cytokeratin react with all histological types of bronchial cancer. The presence of cytokeratin in the serum of patients suffering from cancer would be linked to their liberation during the course of cellular death. The threshold of specificity for CYFRA 21-1 is 3.3.3.6 ng/ml in a population suffering from benign respiratory diseases. The study performed in bronchial cancer produced the following conclusions: the marker is, above all, useful for epidermoid cancer; it is more discriminating than other markers to separate bronchial cancers and non malignant respiratory disease. An elevated level of CYFRA 21-1 is predictive of advanced disease but does not permit any prediction as to inoperability. In 65% of cases, variations of CYFRA 21-1 are concordant with the stage of the disease during chemotherapy. Finally, elevated levels of CYFRA 21-1 predict a poor prognosis independent of the state of the disease. PMID- 8677348 TI - [Bibliometry of biomedical periodicals]. AB - Bibliometry or the science citation index is a quantitative evaluation of periodical literature, biomedical or others. It depends above all on an analysis of citations which allows for a calculation of different indices characterising and classifying journals (number of articles published, frequency of citation, impact, topicality...). The applications of bibliometry are varied from the administration of library collections to the appreciation of the significance of a review in its own speciality area. By extension the bibliometry index are sometimes used to evaluate the importance of a discipline in the literature, the place of a nation within a discipline, the significance of certain opinions or the quality of research. The intrinsic limits of bibliometry are such that this last application should be handled with caution. In effect, various biases can mechanically affect the value of different indices and particularly the fact that an article appearing in a prestigious review should not prejudge its quality such as the relevance of the question posed, the validity of the methodology employed or the accuracy of the results. For this, the study of citations is insufficient and some qualitative or semi-quantitative criteria bearing on the contents of the article should be used (critical reading, gate analysis, etc.) This general review has, as its aim, to expose both the definitions and limits of bibliometry illustrating them with some information calculated from the principal respiratory journals. PMID- 8677349 TI - [Deleterious effects of mechanical ventilation on the lower lung]. AB - Mechanical ventilation may have adverse effects on the lung. The appearance of extra-alveolar air, either as a pneumothorax or as subcutaneous emphysema along with other manifestations, is a complication of barotrauma which has been known for a long time. Recent experimental studies have clearly shown that mechanical ventilation can also lead to alterations in the blood gas barrier. Mechanical ventilation with high inflation pressure and elevated tidal volumes induces pulmonary oedema; the genesis of which results principally from anomalies of alveolar capillary permeability. These anomalies are made as a result of pulmonary distension and not as a result of elevated pressures in the airways, thus justifying the term "volume traumatism". The existence of previous acute pulmonary injury considerably worsens the deleterious pulmonary effect of mechanical ventilation. Although the direct clinical implications of these experimental studies are difficult to confirm, these latter have nevertheless lead to profound changes in ventilatory strategy during the course of acute pulmonary disease such as the adult respiratory distress syndrome. PMID- 8677350 TI - [Single-lung transplant in chronic obstructive disease]. AB - The feasibility and the good immediate acceptability of unilateral lung transplants in the patients with obstructive respiratory problems have recently been demonstrated and since the initial reports, some hundreds of lung transplants have been performed in various parts of the world for this indication. Nevertheless, few results of respiratory function are currently available in the medium term. We report these in a series of 20 patients with severe obstruction who were given single lung transplants. The actual probability of survival for 1 and 2 years was 75 and 70% respectively with 4 peri-operative deaths and 2 later deaths. In the 16 survivors of more than 6 months, in relation to the pre-operative values, a significant improvement was observed 3 months after the graft in the FEV1 which rose from 17 +/- 6 to 53 +/- 13% of the predicted values. The PaO2 rose from 52 +/- 10 to 81 +/- 3 mmHg. The distance covered on the six minute walking test went from 99 +/- 84 m before the graft to 587 +/- 147 m 6 months after the operation. In addition to the improved distance, the lung function was stable in a group of patients as the months went by, although there was a fall in the respiratory function in others with the appearance of the syndrome of bronchiolitis obliterans or in 2 patients with bronchial complications. The four patients with severe deterioration in the graft function were re-transplanted with a good clinical result in three of them, the fourth dying in the immediate post-operative period. We conclude that single lung transplant represents an effective treatment both in the short and medium term in patients with chronic airflow obstruction. PMID- 8677351 TI - [Gene therapy: technics, strategy and application]. AB - The concept of gene therapy extends to all treatments involving modification of cellular genetics. This approach has numerous applications such as the treatment of genetic disorders, cancer and viral diseases. The first of these implies the introduction of a normal gene to replace the function of the defective gene. In the other two, several strategies may lead to a therapeutic effect. The transfer of genes is equally applicable in any disease where the expression of the gene in the particular tissue is more effective than systemic or local treatment with the corresponding protein (for example Dopamine or Tyrosine hydroxylase for Parkinson's Disease). According to its application and to the strategy chosen, therapeutic gene may be transferred, in vitro or in vivo, with the aid of plasmid vectors or recombinant viruses. These vectors may contain targeting systems and/or regulation of the specific expression of the target cell. Some encouraging results have been obtained for different applications in animals and there are numerous clinical studies currently in progress. PMID- 8677352 TI - [Endoscopic treatment of post-intubation tracheal stenosis. Apropos of 58 cases]. AB - Over a period of 6 years, 58 patients aged between 55 +/- 16 years have been treated for post-intubation tracheal stenosis (STPI). These patients were characterised by their frequency of an underlying respiratory or cardiac failure, a duration of intubation which was sometimes short and a delay between the extubation and the detection of stenosis which was les than one month in about one half of the cases. Thirty of the 58 patients presented with respiratory distress on admission. All the stenoses were treated initially by mechanical dilatation using a rigid bronchoscope. Radial incisions using an Nd-Yag laser were performed when necessary to facilitate the dilatation. The great majority of stenoses which were not fitted up with a tracheal endoprosthesis (EPT) at the first attempt recurred, leading to repeated therapeutic bronchoscopies (221 sessions in all). Fitting an EPT (Dumon prosthesis) was necessary in 35 cases on 12 occasions at the first attempt with the first bronchoscopy, and 23 times following a recurrence. Amongst the recurring stenoses a stabilisation was obtained at the price of repeated dilatations (4.3 sessions on average in only nine patients). Seven patients finally had a surgical resection and anastamosis of the trachea, of whom four had a transitory instillation of an EPT for the stenosis. The removal of the EPT was later attempted in 11 patients. Four did not present with any symptomatic recurrence. The secondary migration of the EPT is in practice one of the main inconveniences of the silicon prosthesis (8 cases now experienced). Our approach, which used to favour the mechanical dilatation has lead to a relatively high number of failures and thus to repeated bronchoscopies. This has lead us to re-define our therapeutic approach. The current schema which we propose is in the course of being validated in which we use EPT and surgical repair of the trachea more often. Only short stenoses (less than 1 cm) with a diaphragm are treated by dilatation and laser. The others are fitted initially with an EPT. The final management is guided by the progress in the stenosis, the tolerance of the endoprosthesis and the operability of the patients. PMID- 8677353 TI - [Palliative percutaneous treatment under x-ray computed tomographic control of inoperable pulmonary aspergilloma. Apropos of 30 cases]. AB - The authors report 30 cases of the percutaneous treatment of symptomatic pulmonary aspergilloma by injection of amphotericine paste in patients who were not considered to be operable. The treated aspergillomas had developed as a sequel to bacilliary infection and pulmonary fibrosis. Surgery was contraindicated in these patients on account of severe respiratory failure. The authors specify the technique for the preparation of the paste and for the type of percutaneous injection, the aim being to obtain complete filling of the cavity and creating an anaerobic environment for the aspergillus. The contribution of this technique for the non-surgical treatment of patients appears interesting but should be carried on a larger series to identify the exact indications and the interaction with other new treatments which have just appeared. PMID- 8677354 TI - [Basal cell (basaloid) carcinoma of the bronchi]. AB - Basal cell carcinomas (BCC) have been described in various locations such as skin, anal canal, tongue, larynx and recently the lungs. These tumors seem to have a poor prognosis. A series of 115 surgically resected lung tumors, previously classified as poorly or undifferentiated carcinoma was retrospectively reviewed. From those 37 cases were reclassified as BCC and were compared in terms of clinical features and survival with 40 cases reclassified as poorly differentiated squamous cell carcinoma (PDSC) of the lung. There was no difference between the groups with respect to age, clinical presentation, pattern of relapse and cause of death. Median and overall survival were different between the 2 groups, especially for stage I and II patients: 5 years actuarial survival in BCC was 15% and in PDSC 47% p = 0.009). There was also a difference in survival when we studied the patients alive 4 weeks after surgery (p = 0.04). This subset of non small cell lung cancer (NSCLC) has a worse prognosis than other NSCLC. PMID- 8677355 TI - [Definitive results of a phase I study of a chemotherapy regimen using cisplatin and paclitaxel for non-small cell bronchial cancer]. AB - A phase I trial has been performed in patients with advanced non-small lung cancer without prior chemotherapy in order to determine the optimal administration schedule of a combination of high dose cisplatin and paclitaxel (Taxol). Those drugs have been evaluated at respective dosages of 100-120 mg/m2 and of 135-170-200 mg/m2, the later being given over a 3-hour infusion. Seventeen patients have been treated in 4 different steps, without occurrence of an acute limiting toxicity, neither hematological, neither of another type. No major acute hypersensitivity reaction has been observed but three cases of potential cardiac toxicity including one death were documented. The regime appeared to be active with an objective response rate of 47% (8/17) but a severe polyneuropathy occurred lately, avoiding further treatment administration in the majority of responders (5/7). In conclusion, the combination can only be recommended for short treatment. PMID- 8677356 TI - [Impact on the quality of life of respiratory symptoms and airway obstruction in an agricultural population]. AB - Respiratory diseases are known to have consequences on health status. The objective of this study was to assess the quality of life of subjects with obstructive respiratory disorders coming for preventive medicine examinations. We conducted a study on a sample of adults living in agricultural areas (n = 1,235). We used two questionnaires: a respiratory questionnaire and the Nottingham Health Profile (NHP), which is a questionnaire designed to capture self-reported morbidity. It has been recently validated in french. Each subject performed a pulmonary function test on a portable spirometer to separate lung function obstructive abnormalities. Statistical analysis was realized by non parametric test. The number of positive responses (which shows bad health status) and the scores of the six dimensions are higher in females than males. According to sex and smoking habits, cough and chronic bronchitis are responsible for bad scores of health profile (for the total number of positive responses and the scores of each dimension). In case of airway obstruction, there is no major consequences on health profile. Subjective health measurements are interesting tools in subjects with non-chronic diseases. They can be associated with medical questionnaires because they give complementary inquiries. PMID- 8677357 TI - [Plastic bronchitis]. AB - We report a case of plastic bronchitis occurring in a 58 year-old man free from underlying pulmonary disease. Relief of symptoms was observed under steroid therapy (1 mg/kg), but relapse occurred as treatment being tapered. Such evolution is in accordance with recent published data. PMID- 8677358 TI - [Intrathoracic cavernous hemangioma. Apropos of a case]. AB - A cavernous haemangioma of the mediastinum is a rare benign vascular tumour. Generally it is totally asymptomatic and the diagnosis is most often made in a child or young adult. The treatment is surgical. We report a case in a 60 year old man who was a smoker. PMID- 8677359 TI - [Endo- and exo-bronchial schwannoma treated by resection-anastomosis of the left bronchial stump]. AB - Bronchial schwannomas are rare tumours. We report a case of an endo and exobronchial schwannoma which presented with dyspnoea and left pulmonary atelectasis. This was treated by complete resection of the tumour with a resection and anastomosis of the left bronchial stump flush with the lobar bifurcation. This tumour is most often benign and a conservative approach should be taken each time that this is permissible anatomically. PMID- 8677360 TI - [Lung disease induced by isotretinoin]. AB - A young man without any past history of note had taken isotretinoin for disfiguring acne before the summer season. He presented with a severe bilateral pneumonia, associated with dyspnoea two months after the start of treatment. On the pulmonary radiography there was a bilateral ground glass appearance which was worse on the right. The elevated level of eosinophils (54% in 564,000 cells/ml) in the alveolar lavage lead to a diagnosis of allergic pneumonia. The rapidly favourable outcome following the cessation of the medication and with the addition of corticosteroids seemed to us a supplementary argument in favour of a diagnosis of eosinophilic pneumonia, due to isotretinoin which seemed the primary initiating factor. PMID- 8677362 TI - [Construction of a light-weight molded nasal mask for assisted nasal ventilation]. PMID- 8677361 TI - [Purulent pleurisy due to Salmonella typhi associated with a splenic abscess]. AB - We report a case of 25 year old man who presented with a febrile illness and bilateral lower chest pain a pain in the left hypochondrium with fever and weight loss; investigations revealed a left sided empyema. The cause of the empyema was confirmed following the isolation in the pleural pus of Salmonella typhi. There was also a mass in the left hypochondrium which was shown on ultrasound to be a splenic abscess. After antibiotic therapy with Cotrimoxazole, repeated pleural aspirates and physiotherapy, there was a satisfactory outcome and the pleural effusion dried up and there was a significant reduction in the volume of the splenic abscess. In the light of their observations, the authors report the rare presentation of empyemas due to Salmonella typhi, the late presentation during the course of the third septenaire and the often favourable outcome under general antibiotic therapy associated with pleural aspirates to evacuate the pus and respiratory physiotherapy. PMID- 8677363 TI - [Transtracheal oxygen therapy]. PMID- 8677364 TI - [Exogenous surfactants in neonatology]. PMID- 8677365 TI - [Treatment of purulent pleurisy in a surgical setting]. PMID- 8677366 TI - [Malignant otitis externa: apropos of 19 cases]. AB - In the Anglo-Saxon literature, necrotizing otitis in the diabetic patient, known as malignant otitis externa (MOE), represents a specific and in many ways serious entity. We report on our personal experience with 19 cases of MOE with hospitalization and a 9-year follow-up. Our diagnostic criteria are as follows: all our patients are diabetic (with diabetes revealed twice by the MOE). Otalgia is a predominant feature of the clinical picture, with facial palsy being recorded in practically all our patients. A pyocyanic germ was responsible in 16 cases. The use of CT instead of Tc99 scintigraphy enabled the assessment of the extent of the complaint. Surgical treatment (mastoidectomy), recommended for our first patients, is now considered pointless due to its lack of efficacy against an already extensive process, and with the arrival on the market of new families of ATB's, in particular the quinolones. It would appear that this general treatment, combined with local treatment, provides a better control of the evolution of the MOE, which nonetheless carries a high mortality rate estimated at 18%. On the basis of this series, we present the data in the literature, recalling the diagnostic criteria, the value of skull base imaging and the criteria of recovery. PMID- 8677367 TI - Stapedial reflex and radionuclide investigation of submandibular salivary glands in Bell's palsy. AB - We compared the prognostic value of the stapedial reflex and the results of submandibular salivary gland scintigraphy in 14 cases of Bell's Palsy. PMID- 8677368 TI - [Parapharyngeal tumors: apropos of 14 cases]. AB - The author reports on fourteen parapharyngeal tumours, of which 7 are of parotidean salivary origin. The other etiologies, in particular 1 chemodectoma and 1 aneurysm of the internal carotid artery, justify a systematic arteriography with a CT scan. In surgery, 9 operations were performed via the purely cervical approach, and 5 via a combined cervical and transvelar approach. The endobuccal vault is limited and dangerous. PMID- 8677369 TI - [Laryngeal papillomatosis in children: therapeutic problems apropos of 39 cases at the Lome University Hospital Center]. AB - The retrospective study about 39 cases of laryngeal papillomatosis emphasizes the management difficulties due to slenderness of therapeutical resources, delayed consultations because of health under education of the community and patients' discouragement during treatment of such a relapsing disease. Consequently, tracheostomy was needed immediately (25.64%), breaking of the voice (48.72%) was noted as well as school backwardness. The use of laser and interferon in laryngeal papillomatosis treatment is for the future in Togo. PMID- 8677370 TI - Dominant symphalangism and conductive hearing loss. AB - Dominant symphalangism in three generations is presented in this paper. Conductive hearing loss of a 14 year old male patient with proximal symphalangism was due to fixation of the stapes. PMID- 8677371 TI - [Nasal localization of a cicatricial pemphigoid: apropos of a case]. AB - The authors reports the case of a 34 years old patient with a cicatricial pemphigoid whose diagnosis was made on a nasal symptomatology, isolated, persistent and with an increasing aggravation over the five last years. This auto immune bullous disease is quite unusual and has got the trend of a synechia characteristic. The mucous membrane O.R.L. attacks are scarce not to say exceptional in their nasal aspect. The treatment based on Disulone has quickly allowed a progress over a trouble caused by the lesions but had to be interrupted for problems of tolerance. PMID- 8677372 TI - [Choristoma of the gastric mucosa: report of a case]. AB - Choristomas are tumor like masses consisting of tissues that are histologically normals but in abnormal location. These are rare in oral cavity and occur generally in tongue. There are seven categories of choristomas on the basis of types of tissues recognized. The presenting case in a gastric mucosal choristoma type, and the treatment was surgical excision. No recurrence of the mass was revealed. Special care should be taken with lingual thyroid choristoma, because 86% of the cases is the only functional thyroide tissue in the body. PMID- 8677373 TI - [Apropos of an uncommon disease of the larynx: pyolaryngocele]. AB - The laryngopyocele is a rare complication of laryngocele. About one case of laryngopyocele and review of literature, the authors recall the main characteristics of this affection. Its clinical picture is often alarming. The CT scan, not often made emmergenceley, give a characteristic image. The treatment is mainly surgical but also endoscopic, then facilitated by the use of laser. The fact of thinking to this diagnosis toward a laryngeal dyspnea with fever permit sometimes to avoid tracheotomy then usually made emmergencely. PMID- 8677374 TI - [External injuries of the larynx in the adult: apropos of a case]. AB - Reporting one case of negliged laryngeal traumatism, the authors expose their laryngeal injuries attitude. They detail admitted classification and propose a management which is based on initial respiratory functions. In view of the case, as extreme situation, laryngeal subtotal surgery was the better management, because of association with polytraumatism, which not permitted earlier treatment. PMID- 8677375 TI - Technique and results in total reconstruction of the posterior canal wall using costal cartilage. AB - Middle ear reconstruction using the closed technique for the purpose of rehabilitating radical cavities includes all the surgical steps necessary to perform a combined approach tympanoplasty, both with respect to eradication of the disease and to reconstruction. The only point of difference is the total reconstruction of the posterior wall, which moreover constitutes the essential step. At present we perform posterior wall reconstruction by means of a coastal cartilage allograft, inserted into two grooves in the bone and firmly stabilized by fibrin glue. The operation, in 90% of cases, is performed in more than one stage. PMID- 8677376 TI - Tympanoplasty using autologous crushed cartilage. AB - The effect of crushing was evaluated in three kinds of human cartilages. Tragal cartilage was most regularly crushed and conchal cartilage was not suitable for crushing because of easy fragmentation. In clinical application crushed cartilages were grafted in 53 cases of tympanoplasty for various purposes. i.e., they were used as a reinforcement of the ear drum, a material for attic reconstruction, protector of the prosthesis, etc. The role of crushing and uses of crushed cartilages are discussed. PMID- 8677377 TI - Improvement of the surgical technique of anterior tympanoplasty in cholesteatoma. AB - Technical improvements in anterior tympanotomy with a transmastoid approach in cholesteatoma surgery are reported. Mastoidectomy must be extended to the root of the zygoma and the space anterior to the malleus head must be opened. For this purpose, the visual axis must coincide with the external meatal axis. In this head position, complete removal of the anterior attic bony plate becomes possible only through the transmastoid approach, without touching the ossicular chain. In the case of the pyramidal type bony plate with a normal ossicular chain, the incudo-malleal joint is temporary subluxated, as this is more convenient for access and removal of pathology than incudostapedial joint subluxation. Our clinical results on postoperative hearing showed no damage to the inner ear by the improved technique. PMID- 8677378 TI - The precision level of the objective hearing tests. AB - A comparative study was performed with 51 patients, using the stapedial reflex (ART), early auditory brain-stem responses (ABR), later auditory evoked potentials (SN10) and the audiogram, to assess the value of objective tests in the evaluation of the auditory level. The ABR and the SN10 are valid to determine the level of hearing. The ART s of limited value. PMID- 8677379 TI - Therapeutic effect of hyperbaric oxygenation in acute acoustic trauma. AB - Retrospectively 78 patients with uni- or bilateral acute acoustic trauma (AAT) were evaluated to assess the therapeutic effect of hyperbaric oxygenation (HBO). All subjects received saline or dextran (Rheomacodrex) infusions with Ginkgo extracts (Tebonin) and prednisone. Thirty six patients underwent additional hyperbaric oxygenation at a pressure of 2 atmospheres absolute for 60 minutes once daily. Both treatment groups were comparable as far as age, gender, initial hearing loss and prednisone dose are concerned. The delay of therapy onset was 15 hours in both groups and treatment was started within 72 hours in all cases. Control audiometry was performed after 6.5 days, when the HBO group had had 5 exposures to hyperbaric oxygenation. The average hearing gain in the group without HBO was 74.3 dB and in the group treated additionally with HBO 121.3 dB (P < 0.004). It is concluded, that hyperbaric oxygenation significantly improves hearing recovery after AAT. Therefore acute acoustic trauma with significant hearing threshold depression remains an otological emergency. Minimal therapy involving waiting for spontaneous recovery, which is mostly incomplete leaving a residual C5 or C6 and handicapping tinnitus, is not the treatment of choice. Randomized prospective clinical trials with a larger patient series are needed and further experimental studies are required to understand the physiological mechanisms of HBO responsible for the clinical success in AAT. PMID- 8677380 TI - [Vaccination and immunologic diseases]. PMID- 8677381 TI - [Immunologic studies in the differential diagnosis of infectious endocarditis and septicemia without endocardiac lesion]. AB - Differential diagnosis between infective endocarditis and septicemia without endocarditis remains a crucial clinical difficulty. Value of immunological data during those pathologies has been evaluated in a 2 year prospective study. Sixty one patients, admitted in an internal medicine and infectious diseases unit for a documented infectious disease, were included. They were separated in three groups: group I (n = 21): demonstrated infective endocarditis; group II (n = 19): septicemia without endocarditis and group III (n = 21): non septicemic well defined infectious disease. Following parameters were studied: immune circulating complexes, C reactive protein, erythrocyte sedimentation rate, fibrinogen, rheumatoid factor, antinuclear antibodies, Treponema pallidum serodiagnostic and cryoglobulinemia. There were no differences between the three studied groups. In particular, immune circulating complexes were present in respectively 67%, 58% and 62% of the patients of the three groups. So, presence or absence of immunologic abnormalities does not provide help for diagnosis of endocarditis in a febrile patient. PMID- 8677382 TI - [Pneumocystis carinii pneumonia in AIDS: retrospective analysis of 80 documented cases (1985-1993)]. AB - Eighty initial episodes of HIV-associated Pneumocystis carinii pneumonia (PCP) diagnosed at Bordeaux hospital between 1985 and 1993 are reported (57 were men and 23 women). PCP revealed HIV infection in 29 patients (36%). Others cases were patients with poor medical follow up (10%), with a CD4+ lymphocyte count above 200/mm3 at last follow-up (9%), non compliant with PCP prophylaxis (9%), or using aerolized pentamidine (AP+) (20%). The main clinical symptoms were fever (90%), dyspnea (68%), non productive (63%) and productive (17%) cough. Radiographic infiltrates were purely interstitial (59%), acinar and interstitial (25%), purely acinar (5%) and absent (11%). Thirty-eight percent of AP+ had upper lobe preferential involvement and 13% a pleural effusion. In all cases, Pneumocystis carinii was detected in bronchoalveolar lavage. Extrapulmonary localizations of pneumocystosis were noticed (eye, liver, spleen, ascitis) in two AP+. Mean CD4+ count was 54/mm3 in patients not having received aerolized pentamidine (AP-) and 22/mm3 in AP+. P24 antigenemia was positive in 53% (AP-) and 88% (AP+). PaO2 LDH and albuminemia were similar in both groups. Antimicrobial therapy (Cotrimoxazole in 91% of the cases) was combined with corticosteroids in 45% and mechanic ventilation in 19%. After 30 days of follow-up, 17 deaths were observed (21%) and 14 attributed to PCP: mortality was worse in AP+ (31%) than in AP- (19%). The main conclusions of our study are the followings: HIV related PCP is still in 1995 frequent and severe; atypical features should not rule out diagnosis; preventive measures are neither sufficient nor efficient. PCP remains in 1995 a priority in HIV related public health and therapeutical research. PMID- 8677383 TI - [Homocysteine: relations to ischemic cardiovascular diseases]. AB - Homocysteine, a sulfur-containing amino acid, is an intermediate metabolite of methionine. Patients with homocystinuria and severe hyperhomocysteinemia develop premature arteriosclerosis and arterial thrombotic events, and venous thromboembolism. Studies suggest that moderate hyperhomocysteinemia can be considered as an independent risk factor in the development of premature cardiovascular disease. In vitro, homocysteine has toxic effects on endothelial cells. Homocysteine can promote lipid peroxidation and damage vascular endothelial cells. Moreover, homocysteine interferes with the natural anticoagulant system and the fibrinolytic system. Homocysteinemia should be known in patients with premature vascular diseases, especially in subjects with no risk factors. Folic acid, vitamin B6 can lower homocysteine levels. PMID- 8677384 TI - [The heart and antiphospholipid antibodies. Personal experience and review of the literature]. AB - Since the recognition of the antiphospholipid syndrome, a great number of cardiac manifestations have been reported in association with these antibodies: valvular disease, coronary artery disease, cardiomyopathy and intracardiac thrombosis. However this association raises numerous questions related to the pathogenic role of antiphospholipids, their prognostic significance and their frequency in a non selected population with a definite cardiac manifestation. In view of the literature and our personal experience, it seems necessary to distinguish two kinds of situations. During systemic lupus and primary antiphospholipid syndrome (which must be systematically looked for in patients with history of thrombo embolic disease), antiphospholipids antibodies certainly play a role in the occurrence of cardiac manifestations, but the precise place of thrombosis has to be best defined along with immunologic/inflammatory mechanisms. On the other hand, in a non-selected population, antiphospholipids antibodies may just be the consequence of the cardiac lesion and do not seem to have prognostic implications. This distinction, actually hypothetical, should be supported on the basis of distinct specificities of antiphospholipids antibodies and especially their dependence on beta 2-glycoprotein I, which would help to distinguish the harmful antibodies from those which probably just appear as an epiphenomenon. PMID- 8677385 TI - [Uterine localization of periarteritis nodosa disclosed by fever of long duration]. AB - We report the case of an 81 year-old woman admitted because of declining general health, fever and elevated sedimentation rate. Identification of a pelvic mass on the computed tomographic scan led to perform hysterectomy with a working diagnosis of ovarian malignancy. Histological examination revealed typical lesions of polyarteritis nodosa of uterus and fallopian tube vessels. Diffuse process of the vasculitis was suggested by persistence of fever and elevated erythrocyte sedimentation rate after hysterectomy. Treatment consisting of high dose corticosteroids and pulses of cyclophosphamide resulted in prompt clinical and biological improvement. We discuss the incidence, the clinical features and the localized or diffuse nature of genital involvement in polyarteritis nodosa and other vasculitis. PMID- 8677386 TI - [Stunned myocardium or hibernating myocardium? Apropos of a case]. AB - The authors relate a case report of unstable angina pectoris accompanied by a well-documented stunned myocardium phenomenon. Stunned and hibernating myocardium resulting from an acute or chronic coronary ischaemia on the myocardium are notions which widely govern revascularisation indications, especially after a myocardial infarction. At present, their detection is based on isotopic methods and stress echocardiography. PMID- 8677387 TI - [Digital necrosis associated with fenoxazoline poisoning. Apropos of a case and review of the literature]. AB - We report the case of a 53 year-old woman with paroxystic hypertension and digital ischemia. The only triggering factor was chronic intoxication by a nasal vasoconstrictor:fenoxazoline. The worsening of the lesions required amputation of the third phalanx of the 3rd and 5th finger and the pulp of the 4th finger of the left hand. The review of literature exhibits association between fenoxazoline intoxication and paroxystic hypertension, myocardial ischemia or stroke, but association between fenoxazoline intoxication and digital ischemia has never been reported. We emphasize the extreme caution necessary with the prescription and the chronic consumption of this kind of drug. PMID- 8677388 TI - [Buerger's disease disclosed by a perforation in the digestive system. Apropos of a case and review of the literature]. AB - A 27 year-old man who underwent an intestinal segmental resection for small bowel perforation was hospitalized for chronic abdominal pain with weight loss. Coeliac and mesenteric stenosis was diagnosed and laparotomy was performed. Histologic findings were consistent with Buerger's disease. One month later, he developed intermittent claudication of the left leg, and 8 years later amputation of a toe was performed. Since 1956, 25 cases of abdominal Buerger's disease has been reported in the literature. In eight cases, intestinal involvement inaugurated the disease. The clinical presentation can be various: chronic abdominal pain, mesenteric infartus, occlusion, perforation. Small bowel, colon and rectum can be concerned. The literature points out a mortality rate of 25% in intestinal Buerger's disease, contrasting with a mortality rate of 4% in peripheral forms of the disease. Although rare, intestinal form of Buerger's disease should be diagnosed early, because of its high mortality rate. Doppler of mesenteric arteries may contribute to the early diagnosis. PMID- 8677389 TI - [Prostacyclin in the treatment of hemolytic-uremic syndrome: apropos of a case]. AB - A 52 year-old man was hospitalised for acute renal failure with thrombocytopenia and hemolytic anemia without oliguria. A haemolytic-uremic syndrome was diagnosed and prostacyclin infusion was started. Twenty-four hours later, the renal function improved as well as thrombocytopenia and anemia. Recovery occurred after 11 days of treatment. Haemolytic-uremic syndrome treatment is not well codified: plasmaphoresis, fresh frozen plasma, transfusions showed inconstant efficiency and data about prostacycline treatment are rare and often contradictory. Multicentric studies must be started in order to determine the precise benefit of this treatment. PMID- 8677390 TI - [Synthetic progestational hormones in the treatment of neoplastic cachexia]. AB - Cachexia frequently occurs in cancer patients. Indeed, this syndrome affects about 50% of hospitalized patients. This clinical entity may be described by different characteristics: appetite and weight loss, several metabolic abnormalities, possible influence of cytokines, poor prognosis. During the last decade, several papers have shown the beneficial activity of medroxyprogesterone acetate (MPA) and megestrol acetate (MA) in cancer cachexia. Seven randomized trials emphasized their activity on patients weight and appetite. Megestrol acetate doses in those trials are different: from 160 mg/24 h to 1600 mg/24 h; this drug is similar to MPA in terms of clinical and pharmacological properties. Iatrogenic toxicity due to MA and MPA is mild, but numerous questions still subsist: optimal date of introduction during the course of the disease, posology, treatment duration and its impact on quality of life of cancer patients. PMID- 8677391 TI - [Primary biliary cirrhosis with systemic symptoms or Still's disease with hepatic fibrosis?]. PMID- 8677392 TI - [A case of pseudomembranous colitis]. PMID- 8677393 TI - [Pseudophlebitis disclosing nodular and focal myositis]. PMID- 8677394 TI - [Post-partum cerebral thrombophlebitis disclosing congenital protein C deficiency]. PMID- 8677395 TI - [Prolonged fever following treatment with acenocoumarol]. PMID- 8677396 TI - Decision and detection limits for linear homoscedastic assays. AB - This paper focuses on the effect of estimating the calibration parameters on the decision and detection limits for linear homoscedastic assays. Assay decision and detection limits are defined. For linear homoscedastic assays expressions for these limits are derived when the calibration parameters are known and unknown. These expressions, together with others previously reported in the literature, are used to calculate limits for a particular example of a cyclic AMP assay. The various methods of computing decision and detection limits are compared in a simulation study. The results demonstrate the importance of taking into consideration the variation in the estimators of the calibration parameters. PMID- 8677397 TI - A comparison of methods for correlated ordinal measures with ophthalmic applications. AB - For many clinical trials and epidemiologic investigations in the field of ophthalmology, paired ordinal data are often collected through the detailed grading of retinal photographs. One method for analysis of these data is the extension of the generalized estimating equation (GEE) methodology to multinomial data with cumulative link functions. Prior to the development of this advanced technique, however, ophthalmologists developed a method of combining the ordinal responses of both eyes of a patient into a single person-level response on a new ordinal scale. A relationship between the regression coefficients of these two methods is derived as a function of the correlation between eyes. We investigate the applicability of this result and the relationship of the standard errors in simulation experiments and in an example from the Wisconsin Epidemiologic Study of Diabetic Retinopathy. PMID- 8677398 TI - Multi-state models and diabetic retinopathy. AB - This paper discusses the application of a multi-state model to diabetic retinopathy under the assumption that a continuous time Markov process determines the transition times between disease stages. The multi-state model consists of three transient states that represent the early stages of retinopathy, and one final absorbing state that represent the irreversible stage of retinopathy. By using a model with covariables, we explore the effects of factors that influence the onset, progression, and regression of diabetic retinopathy among subjects with insulin-dependent diabetes mellitus. We can also introduce time-dependent covariables in the model by assuming that the covariables remain constant between two observations. We can also obtain survival-type curves from each stage of the disease and for any combination of patient risk factors. PMID- 8677399 TI - Methods for bounding the marginal survival distribution. AB - For time to event data with many potential failure types, one cannot uniquely determine the distribution of time to a specific event type, or marginal survival distribution, in the case where event types are mutually exclusive. In this paper we discuss several methods for estimating functions that bound the non identifiable marginal survival distribution in the competing risks problem. We compute and compare bounds for data simulated from two bivariate survival distributions. Results show that the methods provide a suitable estimate of the marginal survival probability when one has specified dependence correctly. Data from a large clinical trial for breast cancer illustrate the methods. PMID- 8677400 TI - Construction, validation and updating of a prognostic model for kidney graft survival. AB - The construction, validation and updating of a prognostic model for kidney graft survival is reported using data from the Eurotransplant database. First, a model is constructed for data from transplantations in the period 1984 to 1987. The model is later updated for the 1988 1990 data. The first data set was randomly split into a training set (two-thirds of the data) and a validation set (one third). To prevent overfitting empirical Bayes estimation of the transplantation centre effect was employed. After that, the validation set was used for fine tuning by shrinkage. For updating with the 1988 1990 data parametric models were used after suitable transformation of the time axis; it appeared that survival had slightly improved. This necessitated a correction of the parameters in the exponential model. Correctness of the model was checked by extension to a Weibull model. The lack of fit was statistically significant, but practically ignorable. Recommendations are made to place less emphasis on the selection of variables and cut-off points, and more emphasis on the fine-tuning of the prognostic model by means of low-dimensional parametric models in independent data sets. PMID- 8677401 TI - Self-modelling with random shift and scale parameters and a free-knot spline shape function. AB - The shape invariant model is a semi-parametric approach to estimating a functional relationship from clustered data (multiple observations on each of a number of individuals). The common response curve shape over individuals is estimated by adjusting for individual scaling differences while pooling shape information. In practice, the common response curve is restricted to some flexible family of functions. This paper introduces the use of a free-knot spline shape function and reduces the number of parameters in the shape invariant model by assuming a random distribution on the parameters that control the individual scaling of the shape function. New graphical diagnostics are presented, parameter identifiability and estimation are discussed, and an example is presented. PMID- 8677402 TI - Residual plots for the censored data linear regression model. AB - To be consistent, censored data linear regression estimators typically require a correctly specified linear regression function and independent and identically distributed errors. For uncensored data one can assess these model assumptions informally by examining plots of the residuals against the independent variables or fitted values. In this paper I propose plots for censored data analogous to these uncensored data residual plots. One can use such plots in the same way as their uncensored data counterparts for checking model assumptions; if the model assumptions are correct, then the plots should exhibit a random scatter. I show that the proposed plots are useful in selecting a linear regression model for the Stanford heart transplant data. PMID- 8677403 TI - Sample size determination in stratified trials to establish the equivalence of two treatments. AB - When designing a trial to establish that a new treatment is as effective as a standard one, the conventional test procedure and sample size based on a null hypothesis of no difference between two treatments is inappropriate. Several authors have investigated test statistics and corresponding sample sizes based on the null hypothesis that the standard treatment is more effective than the new by at least some specific value for a single 2 x 2 table. This paper considers a trial that involves several 2 x 2 tables and presents an approximate formula for the sample size required to obtain a given power of a one-tailed score test for a null hypothesis of a specific common non-zero difference between two treatments across strata. I show that the sample size for a trial based on an unstratified test is always larger than that based on a stratified test when the design is balanced. PMID- 8677404 TI - Notes on conditional confidence limits under inverse sampling. AB - When the number of subjects in a two-by-two table is small or moderate, we may commonly use the exact conditional distribution with all marginals fixed to derive the conditional confidence limits on the underlying parameter. Under inverse sampling, in which we continue to sample subjects until we obtain exactly a pre-determined number of subjects failing into a specific category, this paper notes that derivation of a confidence interval, which has the coverage probability equal to or larger than a nominal 1-alpha confidence level, for relative risk and relative difference in cohort studies is straightforward. This paper further finds that, when the underlying disease is rare, we can similarly apply an inverse sampling to produce an approximate 1-alpha conditional confidence limits on attributable risk in case-control studies as well. When the number of subjects is small and the test statistic derived on the basis of large sample theory is not strictly adequate for use, this paper also presents an exact hypothesis testing procedure for the above parameters in the corresponding study designs. PMID- 8677405 TI - [Vaginal sacral-spinal fixation or Richter's procedure. Experience of a surgical team with 54 cases]. AB - Vaginal sacro-spino-fixation or Richter's procedure is valuable for the treatment of posthysterectomy vaginal prolapse. Although technically difficult, this procedure is associated with minimal trauma and is effective in correcting pelvic static disorders. There seem to be few complications. Results are very promising. The functional and anatomic improvements induced by the operation persist over the long term. Although the main indication is treatment of prolapse of the vaginal vault, Richter's procedure is also useful for the prevention of prolapse. Based on the experience acquired by a surgical team, the technique, indications, complications, and results of Richter's procedure are discussed. PMID- 8677406 TI - [Granulomatous mastitis]. AB - Six cases of granulomatous mastitis are reported. Based on a review of the relevant literature, the clinical features, etiology, and management of this pathologic entity are discussed. The definition of granulomatous mastitis is given and the characteristics that distinguish this condition from other inflammatory breast diseases are pointed out. PMID- 8677408 TI - [Struma ovarii. A case report]. AB - Struma ovarii is a rare ovarian tumor composed entirely or in part of thyroid tissue. Pathogenesis is unclear. Diagnosis rests on the histologic study. A case is reported. Specific features of struma ovarii are discussed based on a review of the literature. The treatment is surgical and the outcome generally favorable. PMID- 8677407 TI - [Pregnancy after transposition and repositioning of the ovaries in a patient with clear-cell adenocarcinoma]. AB - A young woman with a history of in utero exposure to distilbestrol was diagnosed with vaginal clear-cell adenocarcinoma. Management consisted of limited excision of the tumor followed by brachytherapy after transposition of the ovaries. The patient had a successful pregnancy after reimplantation of the ovaries in their normal position and right adnexectomy for Chlamydia infection. The child was delivered by cesarean section. This is probably the first case with a pregnancy after repositioning of the ovaries in Europe and perhaps even in the world. PMID- 8677409 TI - [Struma ovarii. Three malignant cases and one benign case]. AB - Four cases of struma ovarii were seen among 308 ovarian tumors removed surgically at the Salah Azaiz Institute, Tunis, Tunisia, between 1980 and 1989. This yields an occurrence rate of 1.3%, which is comparable to previously publishes rates (0.3% to 2%). One of the four tumors was malignant. Malignant transformation of struma ovarii is very rare (5% to 10%). The histologic diagnosis of malignancy is difficult, particularly in well-differentiated follicular forms. The prognosis is relatively favorable even in patients with metastases. Based on their personal experience and on a review of the literature, the authors discuss the diagnosis, management, and outcome of struma ovarii, in particular with malignant transformation. PMID- 8677410 TI - [Reflections on compliance in menopause hormone replacement therapy]. AB - Compliance with hormone replacement therapy (HRT) in postmenopausal women is discussed. Although accurate quantitative evaluation is difficult, estimates in French women are provided. Thirty percent of postmenopausal women are under HRT, but data are lacking on the age groups in which HRT is most prevalent. Given the benefits of HRT in terms of public health, physicians should make every effort to educate their patients, in particular regarding differences between oral contraception and HRT. Other targets for HRT education include general practitioners, health insurance agencies, and the media. Better information provided by physicians and drug companies would allow to increase the use of HRT. PMID- 8677411 TI - [Current indications for medical treatment of ectopic pregnancy]. AB - Today, the early diagnosis of ectopic pregnancy (EP) is made possible by the assay of plasmatic hCG and the improvement of trans-vaginal sonography. These different tests lead to diagnose the EP before the ruptured stage. Therefore, the medical treatment is today a logical alternative to the surgical one. The medical treatment is mainly based upon the use of methotrexate (MTX). The logical indications for EP medical treatment are: early EP without peritoneum effusion, with hCG < or = 5000 mUI/ml, without embryonic cardiac activity at sonography. The medical therapy by intramuscular injection of MTX at 1 mg/kg gives a success rate of 91.8% similar to the success rate of intra tubal injection of MTX under sonographic control. PMID- 8677412 TI - [Parental alcoholism, fetal alcohol syndrome. Conference of the Institute of Scientific Research on Beverages]. PMID- 8677413 TI - [Concerning the article: Simultaneous intrauterine and extrauterine pregnancy in the presence of an inert intrauterine device]. PMID- 8677415 TI - The use of aminoglycosides in neutropenic patients. AB - Aminoglycoside antibiotics are widely used for the empirical treatment of febrile neutropenic patients. They are administered in combination with beta-lactam antibiotics and sometimes with glycopeptide antibiotics. This review sets out to determine which patient populations are most likely to benefit from the administration of aminoglycoside antibiotics. In addition, the efficacy and safety of aminoglycoside antibiotics administered in a single daily dose are discussed in the light of a recent trial. PMID- 8677414 TI - [Aminoglycosides in the treatment of infectious endocarditis]. AB - The role of aminoglycosides in the treatment of infective endocarditis is well established. The combination of a beta-lactam with an aminoglycoside shortens the treatment of endocarditis due to penicillin-sensitive streptococci (MIC < or = 0.1 micrograms/mL) when compared to beta-lactams alone. Patients at higher risk (e.g. with prosthetic valves, clinical duration of symptoms > 3 months) should be treated with penicillin for 4 weeks in combination with an aminoglycoside for 2 weeks. Once-daily dosing (ODD) of aminoglycosides can be recommended in penicillin-sensitive streptococcal endocarditis. The treatment of endocarditis due to streptococci relatively and/or highly resistant to penicillin requires combined treatment with penicillin plus an aminoglycoside for a longer duration. At present ODD of aminoglycosides cannot be recommended. Enterococcal endocarditis requires combined treatment for 4 to 6 weeks. Based upon experimental data, ODD of aminoglycosides appears to be markedly inferior to q 8 h dosing. Enterococcal isolates should be screened for high-level resistance to streptomycin and gentamicin. Gentamicin is the preferred agent if susceptibility testing is not performed. Aminoglycosides are administered during the initial 3 to 5 days of treatment for staphylococcal endocarditis on native valves in order to shorten the duration of bacteremia. For staphylococcal prosthetic valve endocarditis, aminoglycosides are administered for the initial 2 weeks of treatment. However, there are no reliable clinical data for methicillin susceptible isolates to support this recommendation. In prosthetic valve endocarditis due to coagulase-negative staphylococci combination with an aminoglycoside appears to suppress the emergence of rifampin-resistant variants during treatment. There are no data on ODD of aminoglycosides in staphylococcal endocarditis. Right-sided staphylococcal endocarditis due to methicillin susceptible staphylococci is adequately treated with a two-week course of a beta lactam plus an aminoglycoside. This short regimen can be recommended for low risk patients, e.g. those without significant heart failure and vegetations < 2 cm3 and with an aminoglycoside-susceptible isolate. PMID- 8677416 TI - [Treatment of severe infections: should one always administer an aminoglycoside?]. AB - Until recently, aminoglycoside antibiotics were the cornerstone for the treatment of severe infections. The rationale for using combination therapy containing beta lactams and aminoglycosides was not only to broaden the antimicrobial spectrum but also to achieve enhanced bacterial killing by synergism and to prevent the emergence of antibiotic resistance. However, with the advent of new potent broad spectrum and highly bactericidal antibiotics, the necessity of combining beta lactams with aminoglycosides should be reassessed. This review questions the use of aminoglycosides in three severe infections frequently observed in intensive care units, nosocomial pneumonia, nosocomial sepsis and severe diffuse peritonitis. A review of the literature suggests that the addition of an aminoglycoside to a broad-spectrum beta-lactam does not improve the outcome in nosocomial pneumonia and severe diffuse peritonitis. However, the lack of large prospective studies in severe sepsis or septic shock makes it impossible to draw any conclusion about the addition of an aminoglycoside, and the administration of these agents must be decided on an individual basis. PMID- 8677417 TI - [Aminoglycosides in pediatrics]. AB - The aminoglycosides continue to be needed in hospital pediatrics. Their advantage is high predictability of both efficacy and toxicity. This review focuses on the background to the aminoglycosides and defines their present role in antibiotic therapy of pediatric patients. Both the beneficial and unfavourable characteristics of these antimicrobial agents are discussed. The clinical uses of aminoglycoside antibiotics and their possible modes of administration are also commented on. The author attempts to compare the currently available aminoglycosides gentamicin, tobramycin, amikacin and netilmicin in the light of their antibacterial activity in vitro, their clinical efficacy, and their ototoxic and nephrotoxic potential. For the future it is important not to lose sight of these backup drugs where appropriately and safely used. A possible renaissance of the aminoglycosides would require either a molecular miracle (new aminoglycosides with decreased toxicity and an increased spectrum of activity) or a bacterial revolt (rapid emergence of resistance of many gram-negative enteric bacilli to other antibiotic classes). PMID- 8677418 TI - [Dosing aminoglycosides once a day]. AB - In the past few decades aminoglycosides have usually been administered as multiple daily dosing regimens. However, animal experiments have shown that nephrotoxicity can be reduced if, with the same total daily dose, the dosing interval is spread out. Further, several in-vitro and in-vivo studies suggest that once-daily dosing may be more effective. In 24 randomized, clinical trials, once- vs. multiple daily dosing regimens of amikacin, netilmicin and gentamicin have been compared in a total of 3181 patients. An analysis of these studies revealed significant advantages in favour of once-daily dosing for both clinical efficacy (89.5% vs. 84.7%, p < 0.001) and bacteriological efficacy (88.6% vs. 83.4%, p < 0.01). In addition, improved but not statistically significant results were obtained with once-daily dosing with regard to nephrotoxicity (4.5% for once daily vs. 5.5% for multiple daily dosing) and ototoxicity (4.2% vs. 5.8%). Furthermore, once-daily dosing is cheaper, as less infusions are required and the expense of monitoring serum levels can be reduced. In conclusion, amikacin, netilmicin and gentamicin can be administered once a day. PMID- 8677419 TI - [The role of aminoglycosides in HIV-infected patients]. AB - The frequency of serious infections due to Pseudomonas aeruginosa is increasing among patients with advanced HIV infection; most of the cases are community acquired. Early diagnosis and adequate treatment--usually with the combination of an anti-pseudomonas beta-lactam antibiotic and an aminoglycoside--have a crucial bearing on prognosis. The good in vitro activity of aminoglycosides against mycobacteria contrasts with the need for intravenous administration and toxicity. In patients with Mycobacterium avium complex infection, amikacin should be given only in the event of difficulty with an oral regimen and only on a temporary basis. Similar rules apply to the treatment of multiresistant tuberculosis with streptomycin or amikacin. Paromomycin is not absorbed by the gastrointestinal tract when taken orally, constitutes the treatment of choice against cryptosporidiosis and serves as an alternative against Entamoeba histolytica and Giardia lamblia. Topical treatment with paromomycin ointment can be used in cutaneous leishmaniasis. PMID- 8677420 TI - Use of aminoglycosides: the Swiss consensus. Swiss Society of Infectious Diseases. PMID- 8677421 TI - [The use of aminoglycosides in Swiss university hospitals]. AB - BACKGROUND AND OBJECTIVES: In 1990, the Commission for Anti-infectious Agents of the Swiss Society for Infectious Diseases decided to monitor trends in hospital consumption of antibiotics to understand better and rationalize their use. This article describes and analyzes the evolution in the use of aminoglycosides in Swiss university hospitals. METHODS: Annual consumption figures for four aminoglycosides were provided by pharmacists of participating hospitals for the period 1990-1993. RESULTS: Between 1990 and 1993, the overall consumption of oral and intravenous (i.v.) antibiotics increased by 22% and 38% respectively. On average, 38% of hospitalized patients were receiving antibiotics in 1993 (0.38 daily defined doses [DDD]/day). Aminoglycosides represented 11.3% of all i.v. antibiotics in 1990. There were wide differences between hospitals (range: 7.9 to 36.3% DDD per 1000 days). The four-year trend showed relative stability of use in four hospitals and wide variations in two. Overall, gentamycin remains the most commonly used aminoglycoside while amikacin is less used and retains its role of second line drug. CONCLUSION: The analysis of hospital consumption of aminoglycosides in Swiss university hospitals shows that the trend in use is not identical in all hospitals and that there are wide differences between hospitals (some hospitals use five times more than others). Although the reasons for these differences remain unclear, this monitoring system provides the data needed to formulate and evaluate recommendations designed to rationalize the use of aminoglycosides. PMID- 8677422 TI - [Mouse hepatitis virus]. AB - Mouse hepatitis virus (MHV), the coronavirus of the mouse (mus musculus), is one of the most important viral pathogens in contemporary laboratory mouse colonies. It is a highly mutable virus consisting of numerous antigenically distinct serotypes with different pathology. These can be divided according to their tissue tropism into respiratory and enterotropic strains. The course of an MHV infection is dependent on virus strain and host factors. Generally MHV causes an acute, self limiting infection which is inapparent in adult mice. Neonates are highly susceptible to disease and show high mortality. In an enzootically infected colony however, they are protected by maternally derived passive immunity. MHV's importance in biomedical research on one hand stems from its potential as an interfering agent, mainly in the field of immunology. On the other hand MHV serves as a model for coronaviruses of other species including man in studies on virus replication and tissue tropism. Since MHV infections are usually subclinical, detection depends on serological screening of colonies using Enzyme-linked immunosorbent assay (ELISA) or immunofluorescence. MHV is controlled by culling and rederivation of the affected colony using hysterectomy or embryo transfer or by elimination by cessation of breeding. PMID- 8677423 TI - [A case of acute disseminated pneumomycosis in a cow]. AB - The case of a five year old Swiss Braunvieh cow suffering from an acute disseminated mycotic pneumonia caused by an Aspergillus fumigatus infection is presented. The animal had calved one month previously and was admitted to the clinic because of recurrent fever. Clinical findings included a reduced general condition, a rectal temperature of 40.6 degrees C, an increased respiratory rate, coughing and serous nasal discharge. On auscultation increased bronchovesicular sounds and moist rales could be heard. Radiographs of the thorax showed a diffuse interstitial nodular pattern throughout the lung. The cow had to be slaughtered in spite of intensive therapy. Necropsy showed multiple nodules measuring up to 4 mm in diameter covering the entire surface of the lungs. Histology revealed an acute disseminated necrotising bronchopneumonia containing numerous branched, septate fungal hyphae identified as Aspergillus fumigatus. A primary aerogenous infection caused by inhalation of spores originating from mouldy hay or soil was suspected. PMID- 8677425 TI - Efficacy of maduramicin against turkey coccidiosis in battery: a clinical and pathological study. AB - Two groups of 24 three-day-old turkeys each were inoculated with Eimeria meleagrimitis sporulated oocytes and fed a diet containing respectively 5 and 6 ppm of maduramicin ammonium. Clinical signs, mortality rates, weight gain, intestinal lesions and replication of the parasite were compared to the data obtained from a group of infected, untreated birds kept in the same experimental conditions over a period of 17 days. The treated birds showed better performances and less severe intestinal damages; the replication and the development of the parasite in the intestinal mucosa were impaired and delayed by the drug. All the data were dose dependent. PMID- 8677424 TI - [Cryptosporidiosis of calves as a serious farm problem]. AB - Repeated outbreaks of cryptosporidiosis in three to fourteen days old calves on a dairy farm gave rise to a detailed description of the induced therapeutic, epidemiological and prophylactic measures. In farms with ongoing problems of diarrhea in calves, its etiology should be cleared. For cryptosporidiosis, which can not be cured by a conventional symptomatic treatment, only Lasalocid-Na is available. In Switzerland the ionophoric polyether antibiotic Lasalocid-Na is available as a food additive (Bovatec, 15% Lasalocid-Na, Hoffmann-La Roche AG). After the establishment of a diagnosis it must be administered as follows: 2 x 6 mg/kg BW, i.e. 2 x 40 mg Bovatec/kg BW, daily for three days. The recommended dose has to be respected because of a very high risk of intoxication. Moreover, on contaminated farms strict measures of hygiene, disinfection and cleaning have to be respected. Calving cows have to be kept separated during the calving period and the newborn calves must be separated from the adult cattle unit. PMID- 8677426 TI - [What is your diagnosis? Which treatments do you suggest? Dysecdysis in a boa constrictor]. PMID- 8677427 TI - Mercury in human hair and relation to fish consumption in Bangladesh. AB - Human scalp hair mercury concentrations were determined in 219 hair samples from male individuals from different regions of Bangladesh. Total hair mercury concentrations were very low with a mean value of 0.44 +/- 0.19 micrograms Hg/g (range 0.02-0.95) for a moderately elevated fish consumption averaging 2.1 kg/month (range 1.4-2.6). A highly significant positive correlation (r = 0.88, P < 0.001) was found between fish consumption and hair mercury concentration. Neither age, region nor occupation had any influence on the hair mercury content. Our results in agreement with literature values, are described by equation (X = 183Y + 0.16) linking calculated daily methylmercury intake (X, mg) and hair total mercury level (Y, micrograms/g). Low concentrations in hair were linked to extremely low levels of daily mercury intake, the determining factor being remarkably low mercury levels in Bangladesh fish. PMID- 8677428 TI - Levels of DDT residues in human milk of Venezuelan women from various rural populations. AB - The levels of DDT residues were studied in 145 breast milk samples 25 days postpartum from women living in various rural populations where DDT has been used in farming activities and to interrupt malaria transmission. All participants showed quantifiable milk levels of DDT residues in the range from 5.1 to 68.3 micrograms/l and their levels significantly increased (P < 0.05) with maternal age. The determination of DDT residues (as DDE) in human milk was performed after a saponification process by gas chromatography with electron-capture detection. Confirmatory analysis was achieved using high-performance liquid chromatography with a diode array detection. PMID- 8677429 TI - Serum selenium levels during normal pregnancy in healthy Spanish women. AB - In this study, we determined selenium concentrations in serum samples of healthy women (146 pregnant and 74 nonpregnant) living in the Mediterranean area of the coast of Granada (southeast Spain). The subjects were distributed in two groups: group A (pregnant women), divided into three categories according to the trimester of pregnancy, and group B (nonpregnant women). No significant differences were observed in the selenium levels either among pregnant women according to the trimester of pregnancy or in the group of nonpregnant women. No other significant differences were determined as regards the age of pregnant women (P > 0.05). Serum selenium levels are slightly lower during pregnancy. Considering that serum selenium levels affect the body selenium status, the concentrations determined establish the non-existence of selenium problems in the daily dietary intake with respect to maternal and fetal necessities during pregnancy. PMID- 8677430 TI - Association of cadmium with human breast cancer. AB - The carcinogenic potential of cadmium might be affected by several factors such as smoking, hormones and presence of other metals, such as selenium and zinc. Cadmium was analyzed in breast-fat tissue of 43 breast cancer patients and 32 healthy control subjects. Patients were thoroughly characterized according to such variables as stage of cancer, smoking habits, and number of children. Correlation of cadmium levels with these variables, with hormone receptors, and with previously reported selenium and zinc were all analyzed. The mean cadmium concentration found in breast cancer patients (20.4 +/- 17.5 micrograms/g) did not differ significantly from that of the healthy controls (31.7 +/- 39.4 micrograms/g). However, unexpectedly high concentrations of cadmium (3.2-86.9 vs. 0.1-160.4 micrograms/g) were found in breast samples, which may indicate that cadmium binding proteins exist in human breast tissue. Correlation of cadmium with smoking rate of cancer patients was positive (Rs = 0.0505, p < 0.05). Correlation of cadmium with estrogen receptors in breast cancer was suggestive (Rs = 0.309, 28 cases, P = 0.06). No correlation was found with other trace elements such as selenium, zinc and copper. These results seem neither to prove nor to disprove the role of cadmium in breast cancer initiation, promotion or progression. PMID- 8677431 TI - A cautionary tale. PMID- 8677432 TI - HIV quasispecies and resampling. PMID- 8677433 TI - Gene therapy chronology. PMID- 8677434 TI - Creationists evolve new strategy. PMID- 8677435 TI - Teams tackle protein prediction. PMID- 8677436 TI - New methods for expanding the chromosomal paint kit. PMID- 8677437 TI - New mammal data challenge evolutionary pulse theory. PMID- 8677438 TI - Hormone mimicry. PMID- 8677439 TI - Spinal cord regeneration. PMID- 8677440 TI - Clinical Applications of Alkylating Agents. Proceedings of a Cleveland Clinic Foundation CME program. January 12-13, 1996. PMID- 8677441 TI - Ifosfamide-based combination chemotherapy in advanced non-small cell lung cancer: two phase I studies. AB - Two studies were performed to determine the maximum tolerated dose (MTD) of paclitaxel and vinorelbine, respectively, in combination with a fixed dose of ifosfamide in previously untreated patients with stage IIIB or IV non-small cell lung cancer. Response rate and survival were also assessed. Both regimens were given with mesna and granulocyte colony-stimulating factor support. The maximum tolerated dose of paclitaxel in combination with 1.6 g/m2/d X 3 ifosfamide was 300 mg/m2, and the recommended dose for phase II study is 250 mg/m2. Among 31 patients treated with ifosfamide/paclitaxel, there were seven partial responses; additionally, 10 patients had either minor regression or stable disease. The maximum tolerated dose of vinorelbine in combination with 1.6 g/m2/d X 3 ifosfamide was 35 mg/m2/d X 3, and the recommended dose for phase II study is 30 mg/m2/d X 3. Among 42 patients treated with ifosfamide/vinorelbine, responses have been encouraging, and final analysis is pending. The dose-limiting toxicity for both regimens was neutropenia. These findings indicate that ifosfamide containing combination chemotherapy regimens have activity in advanced non-small cell lung cancer and are well tolerated when administered with granulocyte colony stimulating factor. PMID- 8677442 TI - Ifosfamide in the treatment of soft tissue sarcomas. AB - Ifosfamide is one of the three most active agents in the treatment of soft tissue sarcomas. Ifosfamide-induced urothelial toxicity has been adequately controlled with the use of hydration and the uroprotective agent mesna. This is a review of pilot and phase I and II studies of ifosfamide as a single agent and randomized trials of combination chemotherapy regimens incorporating ifosfamide in the treatment of soft tissue sarcomas. Issues of schedule and dose of ifosfamide will be addressed as well. PMID- 8677443 TI - Ifosfamide in the treatment of small cell lung cancer. AB - Ifosfamide as a single agent has produced overall response rates greater than 5O% in the treatment of small cell lung cancer (SCLC). Etoposide/ifosfamide/cisplatin (VIP) has produced overall response rates of 74% to 100% with complete response rates of 27% to 64% in SCLC patients. In a Hoosier Oncology Group randomized study involving extensive-disease SCLC patients, VIP was superior to etoposide/cisplatin with regard to median time to progression (6.6 v 5.8 months), median survival times (9.1 v 7.3 months), and 2- and 3-year survival rates (13% v 5% and 5% v 0%, respectively). In limited-disease SCLC, ifosfamide/carboplatin/etoposide (ICE) achieved overall response rates of 76% to 94%, median durations of survival ranging from 14 to 19 months, and 2-year survival rates of 24% to 37%; in extensive disease, overall response rates ranged from 72% to 100%, median durations of survival ranged from 9 to 14 months, and 2 year survival rates ranged from 14% to 22%. The use of high-dose ICE plus epirubicin and peripheral blood stem cell support appears promising in the treatment of limited-disease SCLC. PMID- 8677444 TI - High-dose ifosfamide in the treatment of sarcomas of soft tissues and bone. AB - Ifosfamide is an alkylating agent with clinical activity in the treatment of sarcomas, and data support a dose-response relationship in this disease. Attaining a clinical response can be a significant end point in sarcomas because such a response may allow function-sparing surgery or improved surgical resection of bulky primary tumors. Studies have shown that higher response rates can be obtained in sarcomas using dose-intensified chemotherapy than with conventional dose chemotherapy. Although the early data using high-dose ifosfamide in the treatment of sarcomas are promising, the median durations of response have been less than 1 year. The continuing advances in supportive care technology will facilitate the ability to conduct large-scale trials in sarcomas using dose intensified chemotherapy. The aim of these trials should be to optimize the dosing and antineoplastic efficacy of ifosfamide as a single agent and in combination regimens. PMID- 8677445 TI - Ifosfamide in the treatment of non-Hodgkin's lymphoma. AB - Ifosfamide has been used extensively for the treatment of patients with non Hodgkin's lymphoma (NHL). This review is limited to published series in which 30 or more evaluable patients were treated in a prospective, uniform fashion either with ifosfamide alone or in combination with other chemotherapeutic agents. Studies in which ifosfamide was used solely as part of a high-dose chemotherapy preparative regimen with autologous hematopoietic progenitor cell transplantation are not included. Three different applications of ifosfamide are addressed: (1) ifosfamide as a single agent and in combination chemotherapy for patients with previously treated NHL, (2) ifosfamide in combination chemotherapy for patients with newly diagnosed, aggressive NHL; and (3) ifosfamide in combination chemotherapy as consolidation for patients with aggressive NHL in first complete remission. PMID- 8677446 TI - Dose-intensive ifosfamide for the treatment of non-Hodgkin's lymphoma. AB - Patients with non-Hodgkin's lymphoma (NHL) who either fail to achieve or relapse following an initial complete remission have a poor prognosis with conventional salvage chemotherapy. Patients with chemotherapy-sensitive NHL have a 45% chance of long-term disease-free survival with high-dose chemotherapy and autologous bone marrow transplantation (ABMT). Patients with chemotherapy-resistant NHL have a significantly reduced chance of long-term disease-free survival. Ifosfamide, a synthetic analogue of cyclophosphamide, has been evaluated in a few small trials of high-dose chemotherapy and ABMT in lymphoma. Because of their clinical synergy, ifosfamide has been combined with carboplatin and etoposide (ICE) and given with ABMT in several phase I/II dose-escalating studies. Maximum tolerated doses of the ICE regimen in these trials are 16 to 20.1 g/m2 ifosfamide, 1.8 g/m2 carboplatin, and 1.2 to 3.0 g/m2 etoposide. Renal, central nervous system, and cardiac toxicities have precluded further dose escalation. Sequential dosing protocols, administration of high-dose chemotherapy with peripheral blood progenitor cell support, and other approaches, possibly combining current treatment options, may be necessary to further improve the long-term survival of patients with relapsed NHL. PMID- 8677447 TI - Ifosfamide in the treatment of breast cancer. AB - Ifosfamide is an alkylating agent that has demonstrated efficacy in the treatment of several malignancies. Preclinical data also support non-cross-reactivity between cyclophosphamide and ifosfamide in several cell lines. These data suggest that ifosfamide may be highly effective in the salvage setting for breast cancer patients who have received previous treatment with cyclophosphamide. Unfortunately, the available data on ifosfamide use in advanced disease are derived from poorly designed studies that evaluated various patient populations and dosing schedules. This review examines the efficacy of ifosfamide in salvage therapy for breast cancer and emphasizes the need to determine the optimal dosing schedule for ifosfamide used as a single agent or in combination chemotherapy for advanced breast cancer. PMID- 8677448 TI - Analysis of dose-response relationships in the setting of high-dose ifosfamide, carboplatin, and etoposide and autologous hematopoietic stem cell transplantation: implications for the treatment of patients with advanced breast cancer. AB - Dose intensity appears to play a role in the treatment of breast cancer. Although many reports have been published regarding dose intensity using nonmyeloablative doses, little data have been presented in the setting of high-dose chemotherapy and autologous hematopoietic stem cell transplantation. The results of a retrospective review of a phase I/II trial evaluating the effect of escalating doses of ifosfamide/carboplatin/etoposide on survival of patients with locally advanced and metastatic breast cancer are discussed here. Patients were divided by ifosfamide dose: low dose (6,000 to 14,400 mg/m2) and high dose (17,100 to 24,000 mg/m2). Three-year event-free survival was no different between the two dose groups in patients with locally advanced disease (71% [low] v 56% [high]). In patients with metastatic disease, however, although the difference did not meet statistical significance, there did appear to be a trend toward improved survival with increased dose intensity (8% [low] v 25% [high]). Our results show that dose intensity may be important in inflammatory and metastatic breast cancer. This trend was seen in both anthracycline-responsive and -refractory patients. While further study of dose intensity in this setting is warranted, dose-intensive high-dose therapy with autologous hematopoietic stem cell transplantation can be considered for patients with advanced breast cancer. PMID- 8677449 TI - Ifosfamide in the treatment of ovarian cancer. AB - Ifosfamide has been assessed in the treatment of ovarian cancer for more than two decades. The drug possesses well-documented but modest activity (10% to 15% range) in women with platinum/alkylating agent-resistant ovarian cancer. A potentially important ongoing clinical trial is attempting to define the level of activity of ifosfamide administered in the salvage setting to patients with advanced ovarian cancer who have been previously treated with a platinum drug plus paclitaxel but not an alkylating agent. PMID- 8677450 TI - Ifosfamide in the treatment of bladder cancer. AB - Although chemotherapy for advanced bladder cancer has historically been based on cisplatin-based combination regimens, the limitations of these regimens both in terms of efficacy and toxicity are now widely appreciated. In response to these limitations, other single agents have been studied, and a number have demonstrated significant activity, including ifosfamide. Older single-agent phase II trials of ifosfamide in previously untreated patients suggested a response rate as high as 40%, including objective responses in nontransitional histologies. More recently, the Eastern Cooperative Oncology Group has defined the response rate for ifosfamide in patients with one prior chemotherapy regimen to be 20%, with central nervous system toxicity, nephrotoxicity, and myelosuppression as the dose-limiting toxicities. Phase II trials of ifosfamide in combination with vinblastine and gallium nitrate have been completed, while others, including trials with paclitaxel alone or paclitaxel plus cisplatin, are ongoing. The precise role of ifosfamide in the therapy of advanced bladder cancer is in the process of being defined. However, the frequency of occult or clinically evident renal insufficiency in this patient population may limit ifosfamide's role in this disease. PMID- 8677451 TI - The role of ifosfamide and systemic therapy in the management of carcinoma of the cervix. AB - Nineteen single agents have activity in patients with advanced or recurrent carcinoma of the cervix. The agents that have attracted the greatest attention, however, are the platinum compounds and ifosfamide. Although most phase II trials combining these agents demonstrate activity but not relative merit, a recent phase III randomized trial shows that ifosfamide/cisplatin yields a superior response rate than cisplatin alone (33% v 19%, respectively). An ongoing randomized study is evaluating cisplatin/ifosfamide with or without bleomycin on the basis of a number of phase II reports suggesting a high order of activity for the three-drug combination. Randomized trials in less advanced disease demonstrate superior response rate, progression-free interval, and overall survival for concomitant chemoradiation in patients with stage IIIB to IVA disease. Regimens with demonstrated efficacy in this setting include hydroxyurea plus radiation and cisplatin/5-fluorouracil plus radiation. Of two randomized trials of cisplatin/ifosfamide/bleomycin followed by radiation versus radiation alone, the one completed study shows no overall advantage for the combined approach but does suggest an improved 32-month survival in patients with stage IIIB disease. The other trial is ongoing, with an early observation of a superior response rate with the combined approach. Current recommendations are to use ifosfamide/cisplatin as the treatment of choice for advanced or recurrent disease and concomitant chemoradiation with either hydroxyurea or cisplatin/5 fluorouracil for stage IIIB to IVA disease. PMID- 8677452 TI - Ifosfamide in the treatment of germ cell tumors. AB - Ifosfamide is currently the third most active agent in the treatment of germ cell cancer, behind cisplatin and etoposide. Ifosfamide has single-agent activity comparable to etoposide in very poor-prognosis, cisplatin-refractory disease. In the salvage setting, ifosfamide-based combination chemotherapy can be expected to achieve disease-free status in approximately 50% of cisplatin-sensitive testicular cancer patients, although half of these patients will eventually relapse. As first-line therapy in previously untreated poor-risk patients, ifosfamide-based chemotherapy is therapeutically equivalent to standard therapy but associated with increased toxicity, especially myelosuppression. The role of high-dose ifosfamide in dose-intensive carboplatin/etoposide regimens for the treatment of recurrent disease is unknown and awaits clarification in future research. Current research with this drug continues primarily in the realm of refining ifosfamide-based salvage therapy. PMID- 8677453 TI - Ifosfamide in non-small cell lung cancer. AB - Ifosfamide is an analogue of cyclophosphamide that is active against a variety of solid tumors, including non-small cell lung cancer. In preclinical studies, ifosfamide had yielded an average response rate of 20% to 25% and a median length of survival of 4 to 5 months. With the introduction of mesna, hematologic toxicity is the major toxicity associated with ifosfamide use. Response is not affected by the schedule of drug administration, nor is the response rate compromised by oral delivery of ifosfamide. Neurotoxicity is greater with oral administration, however. Ifosfamide has been used in combination with many different agents, including cisplatin and etoposide and newer drugs like vinorelbine and paclitaxel. The results of the combination studies indicate improved response rates. However, results of randomized phase II trials suggest there may be no survival benefit with the addition of ifosfamide to establish drug combinations. Further study of ifosfamide in combination with newer drugs is appropriate. PMID- 8677454 TI - Ifosfamide, carboplatin, etoposide, and paclitaxel chemotherapy: a dose escalation study. AB - Ifosfamide, carboplatin, cisplatin, etoposide, and paclitaxel are chemotherapeutic agents active in treating many malignant diseases. The ICE combination (ifosfamide/carboplatin [or cisplatin]/etoposide) has been studied in breast cancer, small cell and non-small cell lung cancer, testicular cancer, lymphoma, and other malignancies with promising results. We conducted a dose escalation study of paclitaxel in combination with ICE (ICE-T) to evaluate the toxicity and define the maximum tolerated dose of paclitaxel. To date, 24 patients have been treated with ICE-T. Patients had to have no or minimal prior chemotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate bone marrow, liver, and kidney function. The doses of ICE were as follows: ifosfamide 1.25 g/m2/d days 1 to 3, carboplatin 300 mg/m2 day 1, and etoposide 80 mg/m2/d days 1 to 3. Paclitaxel was given at a dose of 120 mg/m2 to five patients, 135 mg/m2 to five patients, 150 mg/m2 to three patients, and 175 mg/m2 to 11 patients. All patients received granulocyte colony-stimulating factor support. The most common side effect was neutropenia. Grade 4 neutropenia and thrombocytopenia occurred during 34% and 20% of 94 cycles, respectively, with leukopenic fever occurring during 14% of cycles. No treatment-related death or sepsis occurred due to brief nadir durations of 3.5 days for neutropenia and thrombocytopenia. Other toxicities were mostly mild to moderate and did not require dose modification, although alopecia was universal. Nine patients (100%) with metastatic breast cancer and four (67%) with soft tissue sarcoma have attained documented objective responses with four complete remissions (one breast cancer and three sarcoma patients). The maximum tolerated dose of paclitaxel has not yet been defined, and the study is ongoing. In conclusion, this pilot study showed that ICE-T is safe and tolerable. The response to ICE-T is encouraging and warrants further study with this regimen. PMID- 8677455 TI - Phase I trial of dose-escalated paclitaxel and carboplatin in combination with ifosfamide and filgrastim: preliminary results. AB - The purpose of this phase I study is to determine the maximally tolerated doses of paclitaxel and carboplatin (dosed by area under the concentration-time curve) when given at specified times in combination with 6 g/m2 ifosfamide (3 g/m2 at 8 AM on days 1 and 2) with mesna and 5 microg/kg/d filgrastim (from day 4 until the absolute neutrophil count is > 10,000/microL) every 21 days for six cycles. Twelve patients have been treated thus far, 10 of whom are currently eligible for toxicity and response analyses: three each at dose levels 1 and 2, and four at dose level 3. Hematologic toxicity has been the only grade 4 toxicity noted. Only one episode of neutropenic fever occurred in the 43 cycles delivered to date, and only one patient experienced an ifosfamide-related change in mental status. Two patients have developed reversible renal tubular acidosis. No other significant neurologic or renal toxicities have been noted. Patient disease distribution is three non-small cell lung cancer, two breast cancer, two adenocarcinomas of unknown primary site, one prostate cancer, one angioimmunoblastic lymphadenopathy, and one mesothelioma. The median age is 48 years (age range, 34 to 75 years), and median prior chemotherapy treatments was zero. One patient on dose level 1 required a dose delay on cycle 6 because of inadequate hematologic recoveries and one patient required a 50% reduction of the ifosfamide dose during cycle 4 due to mental status change. No patients receiving dose level 2 required dose reductions or delays. One patient at dose level 2 was removed from study due to deterioration of performance status and subsequently died. At dose level 3 dose delays have been required in six of 15 cycles, but no dose reductions have been necessary. Four patients have achieved a complete response (40%) and six a partial response (60%), for a total response rate of 100%. At the completed dose levels, this regimen appears to be tolerable and active with minimal nonhematologic toxicities. PMID- 8677456 TI - Ongoing clinical studies of ifosfamide for pediatric cancer in the United States. AB - This article gives highlights of ongoing pediatric solid tumor and leukemia trials in the United States that use ifosfamide in combination with mesna. These trials are being carried out both by large cooperative groups and single institutions. Some role for ifosfamide with mesna in the front-line treatment of sarcomas is assured. Neurotoxicity, nephrotoxicity, and other unusual toxicities are discussed. PMID- 8677457 TI - Oral administration of mesna with ifosfamide. AB - Mesna can be given orally to simplify outpatient ifosfamide therapy. Oral administration of mesna solution or tablets has been approved in Canada, Denmark, Germany, Italy, The Netherlands, and the United Kingdom, and programs for registration are ongoing in other European countries and in the United States. This review summarizes dosing schedules and the incidence of hematuria in 47 clinical studies, in which oral mesna was given to at least 1,986 patients who received more than 6,475 courses of ifosfamide. Various doses and schedules of oral mesna, usually in combination with intravenously injected mesna, provided effective uroprotection for a wide range of ifosfamide regimens. PMID- 8677458 TI - Continuous subcutaneous administration of mesna to prevent ifosfamide-induced hemorrhagic cystitis. AB - Hemorrhagic cystitis is a major potential toxicity of ifosfamide that can be prevented by administering mesna along with the cytotoxic agent. Mesna is generally administered by the intravenous route, although experience with oral delivery of the drug has increased. The continuous subcutaneous administration of mesna has the advantage of not requiring intravenous access. In addition, subcutaneous delivery of the neutralizing agent will not be associated with the risk of inadequate urinary mesna concentrations, such as in a patient taking oral mesna who experiences severe ifosfamide-induced emesis and is unable to absorb the drug. Limited clinical experience with continuous subcutaneous mesna administration suggests it is a safe, practical, and economic method of drug delivery that permits ifosfamide to be administered successfully in the outpatient setting. PMID- 8677459 TI - [Egas Moniz (1874-1955)]. PMID- 8677460 TI - [Radiologic diagnosis of infectious spondylitis]. PMID- 8677462 TI - [Andersson lesion (spondylodiscitis in Bechterew disease)]. PMID- 8677461 TI - [A radiologically unclassifiable pancreatic tumor: pseudotumorous nodular lymphoplasmacellular pancreatitis. A special form of retroperitoneal fibrosis?]. PMID- 8677463 TI - [Retrobulbar pleomorphic adenoma]. PMID- 8677464 TI - [1995 literature review: ultrasound and roentgen diagnosis of gallbladder, bile ducts and pancreas]. PMID- 8677465 TI - A cost-to-benefit analysis of blood products used during the initiation of an orthotopic liver transplantation programme. AB - Orthotopic transplantation is the treatment of choice for selected patients with end-stage post-necrotic and cholestatic liver diseases. These individuals typically have disturbed haemostasis, which reflects both impaired hepatic synthesis of clotting factors and disseminated intravascular coagulation compounded by large-volume transfusions of blood products occasionally required during surgery. The latter contribute significantly to the cost of this procedure, but may approximate the cumulative consumption of that required for the support of patients in liver failure. Perspective is provided by prospective analysis of data from the first 10 patients in the current programme. There were striking, if transient, intra-operative changes in standard laboratory parameters of coagulation and fibrinolysis; all patients were readily controlled with replacement therapy administered according to serial haemostatic measurements combined with clinical judgement. In most patients these values had stabilised within 24 hours of surgery. Those with post-necrotic liver cirrhosis had the most marked degrees of hepatic dysfunction, reflected in more profound haemostatic disturbances; these patients required the largest amounts of blood products. Inclusive median costs for the first year were estimated at R35,000 and for the first 5 years at R60,000, with 80% of the patients expected to be alive between 5 and 10 years later and enjoying an excellent quality of life. These figures contrast with those estimated for optimal medical and non-transplant surgical management following variceal bleeding as a major complication of liver disease (R30,000 for the first year and R70,000 at 3 years). In addition, the latter patients would usually be unable to work and have a poor quality of life with minimal likelihood of survival beyond this point. We conclude that with a multidisciplinary approach in an academic centre, surgical replacement of the irreversibly damaged liver in properly selected patients is no more expensive and has a better outcome than acceptable alternative approaches. PMID- 8677466 TI - Omentopexy for the difficult perigraft lymphocele after renal transplantation. AB - Between January 1977 and October 1992, 6 patients who had undergone renal transplantation presented with a symptomatic lymphocele that failed to resolve after conventional therapy and eventually required surgical intervention. This complication developed between 7 and 36 months postoperatively. Patients presented with local discomfort combined with deteriorating graft function caused by ureteric obstruction. The lymphoceles recurred after aspiration or external drainage and resolved after omentopexy. We conclude that omentopexy is a satisfactory procedure for the treatment of lymphoceles which fail to resolve after aspiration or external drainage. PMID- 8677467 TI - Carcinoma of the gallbladder--a possible regional predisposition in the western Cape and northern Cape. AB - An analysis of 19 patients with confirmed carcinoma of the gallbladder who were treated over a period of 68 months emphasised known clinical features of the disease, i.e. nonspecific symptomatology, late presentation and poor prognosis. Comparison with 883 patients undergoing surgery for benign calculous biliary tract disease during the same period identified a more advanced mean age (67.0 v. 55.3 years), larger mean maximum stone diameter (20.3 v. 11.9 mm) and a higher proportion of patients resident in the Cape interior and west coast region (57.8% v. 11.8%) as features associated with carcinoma of the gallbladder. Further investigation of the regional predisposition suggested by this study may identify new factors linked to the development of gallbladder cancer. PMID- 8677468 TI - Acute appendicitis among black South Africans. AB - Acute appendicitis has become the commonest nontrauma-related abdominal surgical emergency at Cecilia Makiwane Hospital. The records of 122 patients undergoing appendicectomy were reviewed. Attention is drawn to late presentation and the high complication rare encountered. Mortality rate (0.8%) and overall diagnostic accuracy (85%) were acceptable. The need for adequate patient education is stressed as a possible measure to reduce high morbidity associated with late presentation. PMID- 8677469 TI - An unusual cause of back pain in a patient with an abdominal aortic aneurysm. A case report. AB - A case of a 50-year-old man with chronic back pain, an abdominal aortic aneurysm and bony erosion of the lumbar spine due to a chondrosarcoma is reported. This report shows that the lumbar erosion seen in association with an aneurysm is unlikely to be a result of pressure erosion of the spine by the aneurysm, and that an extensive metastatic and septic work-up is required in such patients. PMID- 8677470 TI - The role of thrombolysis in the management of acute arterial occlusions of the lower limb. PMID- 8677471 TI - [The tensor fascia lata myocutaneous flap in reconstruction of inguinal skin defects after radical lymphadenectomy]. AB - The tensor fascia lata (TFL) myocutaneous transposition flap was used for reconstruction of large groin defects in 11 consecutive patients who had had radical inguinal or ilio-inguinal block dissection as palliation for advanced secondary nodal cancer. Good groin coverage was achieved in all cases with lower than expected operative morbidity. Excellent palliation was also achieved in 72% of patients. PMID- 8677472 TI - Patch-grafting for regional femoral bone loss in cementless revision hip arthroplasty. AB - The authors reviewed 33 revision hip arthroplasties using the long-stemmed porous coated anatomic (PCA) prosthesis that required adjuvant patch-grafting for proximal defects of the femur. All hips were revised for aseptic loosening. The mean follow-up period was 3.7 years (2.0-5.8 years). The hips were clinically evaluated by means of the Harris Hip Score: 26 (79%) were found to be good or excellent, 3 (9%) fair and 4 (12%) poor. Graft incorporation occurred in 31/33 cases (94%). Proximal stress protection bone resorption was not seen, although cancellisation of the calcar was noted in 20/33 (60%) hips. Serial radiological review demonstrated some degree of subsidence of the femoral stem in 20/33 (60%) hips. The authors conclude that patch-grafting of the proximal femur at revision surgery incorporates and is not inhibited by the presence of a rigid long-stemmed implant. PMID- 8677474 TI - Use of a jejunal island flap for repair of a large duodenal defect after resection of a malignant duodenocolic fistula. PMID- 8677473 TI - Postlaryngectomy voice restoration--a 2-year review. AB - We present a 2-year (1991/92) review of tracheo-oesophageal speech following total laryngectomy with tracheo-oesophageal fistula formation and subsequent use of a voicing prosthesis. Thirty-five primary fistulas and four secondary fistulas were created. Initially, 86% of patients obtained daily use of intelligible, fluent voice with few extraneous stomal sounds. Over a 2-3-month period following surgery, approximately one-third of these lost their fistula speech. The reasons for this were mainly related to psychological and socio-economic factors. Patient selection, surgical technique and postoperative management are described. Although a successful outcome requires a consolidated team approach, primary health care workers also need to know about postlaryngectomy prosthetic (fistula) speech and its management. PMID- 8677475 TI - Schistosomiasis of the gallbladder. PMID- 8677476 TI - Neurosurgical training. PMID- 8677477 TI - All it takes is a few minutes. PMID- 8677478 TI - Have neurosurgeons lost their chance to operate on spine problems? PMID- 8677480 TI - Update: the new ventriculoperitoneal shunt at The Institute of Neurology of Mexico. PMID- 8677479 TI - Pediatric lumbar disc surgery: 20 patients under 15 years of age. AB - BACKGROUND: Patients in their first or second decades of life who present with back pain without sciatica or painless scoliosis have been found to have a central lumbar disc protrusion. This study was elected to determine the difference between pediatric and adult disc symptomatology, surgical findings, and the results of surgery. METHODS: Review of office and Children's Hospital records from 1958 through 1995 yielded a total of 60 patients under the age of 20 years who had lumbar discectomy by the author. Twenty were under the age of 15. This group is reported herein. All but 3 have been followed for up to 20 years. RESULTS The youngest was a boy 10 years and 8 months at operation. Only 20% complained initially of sciatic pain; 60% had it by the time of surgery; 20% never had it. The offending disc was at L5-S1 in 75%. The disc protrusion was central in 75%; no disc had ruptured. The posterior spinal ligament had ossified in the protruded position in 40%. Computed tomography (CT) scans were particularly useful. Significant antecedent trauma was present in 45%. Sixty percent were males. There was a family history of disc disease in 60%. The whereabouts of 3 of the 20 patients is unknown; their operations were 20-36 years ago. CONCLUSIONS: Lumbar disc disease in the first 2 decades may be missed because of the absence of sciatica. Once diagnosed, conservative therapy for as long as 2 years has failed. Lumbar discectomy in children under 15 years was safe in all cases and known to be successful in 88%. PMID- 8677481 TI - Health care concerns worldwide. PMID- 8677482 TI - Invasion of a peritoneal catheter into the inferior vena cava: report of a unique case. AB - A case is reported in which the peritoneal catheter of a ventriculoperitoneal shunt was found to have eroded into the inferior vena cava. It was working well, draining CSF, even through oriented against the flow of blood. PMID- 8677483 TI - How would you treat this patient? Dysembryoplastic neuroepithelial tumor. PMID- 8677484 TI - Asymptomatic large pituitary adenomas discovered at autopsy. AB - BACKGROUND: Pituitary adenomas over 1 inch (2.5 cm) in diameter might seem to warrant surgical intervention by virtue of their inevitable compression and distortion of surrounding neural tissues. METHODS: We report three pituitary adenomas over 1 inch in diameter, causing gross distortion of the optic nerves, chiasm, and tracts, as well as surrounding brain structures. All three tumors were asymptomatic and were discovered incidentally at autopsy in patients 65, 79, and 101 years of age. RESULTS: Tumor diameters were 2.5, 4.0, and 2.5 cm, respectively. Histologically, all were chromophobe adenomas, free of either hemorrhage or necrosis. In the absence of hormonal secretion or pituitary apoplexy, symptom-free giant adenomas of the pituitary are compatible with a long life. CONCLUSIONS: We conclude that the need for surgical intervention in pituitary adenomata should be determined by considerations other than mere tumor presence and size. PMID- 8677485 TI - A case of central pontine myelinolysis after surgical removal of a pituitary tumor. AB - CASE REPORT: We have experienced a case in which surgical removal of a pituitary tumor from a male patient was followed by the occurrence of hyponatremia, which in turn was later associated with central pontine myelinolysis (CPM). A 4 X 3 X 3 cm pituitary tumor with hypothalamic extension was removed via a transsphenoidal approach. The post-operative course was uneventful until severe hyponatremia developed. To avoid drastic correction of electrolyte levels, reestablishment of normal serum levels was spread over 1 week. Following this, however, various neurologic symptoms such as pseudobulbar palsy, quadriplegia, extrapyramidal symptoms, and mental symptoms appeared. The case was diagnosed as CPM and extrapontine myelinolysis (EPM) on the basis of the clinical course and symptoms, and high-dosage steroid therapy was commenced. RESULTS: There was consequent gradual improvement in symptoms. One month later, MRI revealed typical demyelination lesions in the central pons and striatum. Abnormal electrolyte conditions easily occur in pituitary tumors associated with hypothalamic extension in an altered hormone environment. It is known that CPM and EPM result from drastic correction of hyponatremia. CONCLUSIONS: The frequent measurement of electrolytes and cautious correction of sodium imbalance are important for the prevention of CPM and EPM in the postoperative management of patients who undergo surgery for a pituitary tumor and whose high-dosage steroid therapy are effective. PMID- 8677486 TI - Primary Ki-1-positive T-cell lymphoma of the brain--an aggressive subtype of lymphoma: case report and review of the literature. AB - BACKGROUND: By detection of the Ki-1 antigen, Stein (1985) defined a new entity of anaplastic large cell lymphoma [24]. Apart from our case, only four further cases of Ki-1 positive primary central nervous system lymphoma (PCNSL) have been reported in the literature to date. CASE REPORT: A 63-year-old man presented with two frontal and parietal mass lesions and one ring lesion on computed tomography scan. Clinically, no evidence of brain metastases or abscesses could be found. Immunohistochemical investigations of biopsy specimens revealed a large cell anaplastic T-cell lymphoma positive to Ki-1 antigen. In spite of all therapeutic efforts, the patient died less than 3 months after the onset of symptoms. DISCUSSION: In all cases the clinical course was very rapid, suggesting that Ki-1 positive PCNSL might form an aggressive subtype of lymphomas. Since the radiologic appearance was atypical and clinical diagnosis was not possible, diagnostic biopsy for immunohistochemical diagnosis should be performed. PMID- 8677487 TI - Extradural extension of glioblastoma multiforme into the oral cavity: case report. AB - A rare case of glioblastoma multiforme with oral extension is presented in a 41 year-old female. She underwent two surgical treatments and both radiotherapy and chemotherapy for the right temporoparietal glioblastoma multiforme. A follow-up computed tomographic scan and magnetic resonance imaging demonstrated destruction of the temporal base and extradural extension of the tumor into the orbital, nasal, and oral cavities. This is the first report of the oral extension of glioblastoma multiforme. The mechanism for the extradural extension is discussed. PMID- 8677488 TI - Neurosurgery of the peripheral nervous system--Part I: basic anatomic concepts. PMID- 8677489 TI - Cerebral aneurysm in the HIV patient: a report of six cases. AB - BACKGROUND: In view of the almost certain mortality of the acquired immune deficiency syndrome (AIDS) patient, controversy may arise as to how to treat those individuals with concomitant aneurysmal disease. METHODS: We conducted a retrospective case review of six patients seen in a 1-year period, who had a history of either being positive for human immunodeficiency virus (HIV) or prior opportunistic pneumonias and who, therefore, by Centers for Disease Control definition, have frank AIDS. The patients, who were in otherwise stable health, presented with subarachnoid hemorrhage from angiographically demonstrated ruptured berry aneurysms. RESULTS: There was no increased incidence of postoperative infections and the quality of life of the surviving five patients was quite good. CONCLUSIONS: In a patient in stable health, the diagnosis of HIV infection should not necessarily preclude the established regimen for the treatment of aneurysmal disease. PMID- 8677490 TI - Spontaneous dissecting aneurysm of the anterior cerebral artery: report of two cases. AB - BACKGROUND: Dissecting aneurysms of the vertebrobasilar artery have been increasingly reported. However, those of the anterior circulation are still rare lesions. Those confined to the anterior cerebral artery are extremely rare and their clinical features are not well known. CASE REPORT: Two cases of spontaneous dissecting aneurysm of the anterior cerebral artery are described. Both patients are middle-aged males and presented with ischemic attacks, although they were lacking any factors correlated to atherosclerosis. Definite diagnosis was made by angiography, which demonstrated characteristics of dissecting aneurysm, such as "double lumen" and "string sign." Serial angiography was performed and revealed dynamic changes during the time course. Nonsurgical therapy was utilized and both patients achieved good recovery. CONCLUSION: Most of the dissecting aneurysms confined to the anterior cerebral artery present with ischemic attacks. Although their etiology remains uncertain, such aneurysms may be a potent cause of occlusive diseases of the anterior cerebral artery, especially in relatively young males lacking any factors correlated to atherosclerosis. PMID- 8677491 TI - Treatment of ruptured cerebral aneurysm in moyamoya disease. AB - BACKGROUND: Direct surgical intervention to treat ruptured cerebral aneurysms in patients with moyamoya disease has rarely been attempted and few of these patients have demonstrated full recovery following treatment. METHODS: To clarify the particular operative problems encountered in performing aneurysmal surgery in patients with moyamoya disease, we present two cases and review 10 cases in the literature. RESULTS: The first patient had a newly formed internal carotid artery aneurysm, which enlarged within a period of approximately 2 years. The second patient had multiple basilar artery aneurysms. Both patients had their aneurysms successfully clipped and were discharged without any neurologic deficits. CONCLUSIONS: Aneurysmal surgery in moyamoya disease presents three problems unlike those encountered in uncomplicated aneurysmal surgery: (1) the ordinary approach is prohibited by the presence of moyamoya vessels, (2) careful consideration is required to preserve collateral circulation, and (3) acute surgery is necessary to prevent cerebral vasospasm due to massive subarachnoid hemorrhage. PMID- 8677492 TI - Acute focal cerebral ischemia in rats studied by diffusion-weighted magnetic resonance imaging--an experimental study. AB - BACKGROUND: Temporary occlusion of the cerebral artery is occasionally repeated during neurosurgical operations, but the safety of such a procedure remains to be studied further. METHOD: We studied early changes and reversibility of focal cerebral ischemia and the cumulative effects of repeated ischemic insults in rats using magnetic resonance imaging (MRI). RESULTS: Diffusion-weighted magnetic resonance images (DWI) and determination of signal intensity ratio (SIR) proved to be a valuable measure of studying early changes and reversibility of transient focal cerebral ischemia and cumulative adverse effects of repeated ischemic insults. DWIs showed marked intensity changes shortly after focal cerebral ischemia, while T2-weighted images failed to show hyperintensities until 2.5 hours after the onset of permanent ischemia. The critical period of ischemia in this model was 60 minutes. However, 20 minutes ischemia, when repeated twice with 60 minutes reperfusion in between, showed irreversible damage. CONCLUSION: Repeated insults of focal regional cerebral ischemia may cause irreversible tissue damage even if each ischemic period is less than the critical one. PMID- 8677493 TI - Brain tissue oxygen pressure, carbon dioxide pressure, and pH during hypothermic circulatory arrest. AB - BACKGROUND: This study evaluated brain tissue oxygen pressure (PO2), carbon dioxide pressure (PCO2), and pH in a patient during hypothermic circulatory arrest. METHODS: A combined PO2, PCO2, and pH sensor was placed in cortex tissue. Brain temperature was then decreased to 17 degrees C followed by circulatory arrest for 44 minutes during an endarterectomy of the M1 segment of the middle cerebral artery. RESULTS: Brain tissue PO2 increased during brain cooling from 10 mmHg-30 mmHg and decreased to zero following exsanguination. During circulatory arrest, tissue PCO2 increased to >200 mmHg and pH decreased to 6.0. Tissue PCO2 and pH recovered during circulatory rewarming but the increase in PO2 was delayed. Tissue parameters continued to improve during 2 days of postsurgical monitoring and were correlated with neurologic recovery. CONCLUSIONS: These results show that brain tissue PO2, PCO2, and pH measures indicate the severity of ischemia during hypothermic cardiac arrest and recovery in the postoperative period. PMID- 8677494 TI - Sensitive carotid sinus. AB - In 1968, a head-injured male, age 20, suffered four cardiac arrests in rapid succession after undergoing the performance of a cerebral arteriogram by the injection of radiopaque material into the common carotid artery in the neck. Several attempts at injection were required before a clear flow was obtained. It was assumed that these several needle stabs in the vicinity of the carotid sinus caused damage to this critical area, resulting in the cardiac arrests. After a precarious few hours, he made a successful recovery and was known to be alive and working 28 years later. PMID- 8677495 TI - Selective angiography of the vertebral artery in the rabbit: technical note. AB - BACKGROUND: Selective angiography of the vertebral arteries has not been performed in rabbit models. We used a tracker-10 microcatheter for selective vertebral artery angiography. METHODS: Five Japanese male rabbits weighing 2.0 to 2.5 kg were used. The right femoral artery was identified and an 18-gauge Teflon catheter was introduced into the iliac artery. A Tracker-10 microcatheter was introduced through the 18-gauge Teflon catheter into the right vertebral artery under fluoroscopic guidance. RESULTS: Selective angiograms of the right vertebral artery were obtained using a bolus injection of 0.1 mL of iopamidol in all five rabbits. CONCLUSIONS: Selective vertebral artery angiograms could be obtained via the transfemoral route with the use of Tracker-10, and intraarterial selective administration of vasodilators will be achieved using our technique. PMID- 8677497 TI - Recurrent disc vs. scar? PMID- 8677496 TI - The safety and efficacy of chronically implanted subdural electrodes: a prospective study. AB - BACKGROUND: The popularity of subdural electrodes for the presurgical evaluation of patients with intractable seizures is increasing. However, few reports have prospectively dealt with their efficacy and safety. METHODS: We conducted a 5 year prospective study of patients evaluated by the California Comprehensive Epilepsy Program, who subsequently underwent subdural electrode implantation at one of two institutions. Efficacy was examined by ultimate outcome with regards to postsurgery resection seizure frequency. Fifty-five patients underwent 58 implant procedures and postresection outcomes were available in 47 patients. Safety was defined by the incidence of expected and unexpected complications, and neuropathologic examination of tissue specimens. RESULTS: The most common expected adverse effects during implant were fever < or = 102 degrees (41%), cerebrospinal fluid leakage (19%), headache (15%), and nausea (4%). There were no infections. Unexpected adverse events included fever > 102 degrees F (5%), migraine (5%), iatrogenic electrode dysfunction (5%), and temporalis muscle fibrosis (5%). The incidence of pathologic findings suggestive of foreign body reaction was 10%. There were no permanent sequelae. Surgical outcomes were excellent in all (> or = 75% seizure reduction) with 50% seizure free regardless of the focus. CONCLUSIONS: Subdural electrodes are a safe, easy, and efficacious tool for evaluating seizure foci prior to resective surgery. They should no longer be considered investigational devices. PMID- 8677498 TI - Localization of the central sulcus. PMID- 8677499 TI - [The development of metastases and their classification]. AB - PURPOSE: The process of metastasis has been elucidated by thorough morphological studies on resection specimens and new findings in the field of molecular biology in recent years. The successful surgical removal of distant metastases lead to the necessity of a detailed and precise classification system of distant metastases. PATIENTS AND METHODS: The new molecular findings as well as data obtained from morphological studies and the results of a international field study on behalf of the UICC lead to the proposed system presented here as a new classification system for metastases. RESULTS: A general classification of distant metastases of any primary tumor should separate 5 different categories: M1 for non-regional lymph node metastases only, M2 for liver metastases only, M3 for lung metastases only, M4 for bone metastases only and M5 for metastases in 2 or more of these organs or others. In case of liver metastases of colorectal carcinoma, 2 different classifications were proposed; a clinical classification based on locoregional tumor status, number of liver metastases and involved lobes and a post-surgical classification depending on locoregional tumor status and size of metastases removed surgically and assessed by the pathologist. CONCLUSION: More detailed knowledge of the metastatic process and success in surgical treatment makes a detailed and exact classification system for distant metastases essential. This should be used as a fundamental base for future therapeutical and prognostic studies. PMID- 8677500 TI - [Abdominal irradiation in seminomas: improvement in its planning with MRT]. AB - BACKGROUND: Standard therapy for early stages of seminomas is the irradiation of the para-aortal and paracaval lymphatic vessels. PATIENTS AND METHOD: Prior to radiotherapy coronal T1-weighted MRI of the abdomen was performed including imaging of target volume and critical organs. The position and course of the large abdominal vessels are projected on simulator radiographs of the abdomen. The target volume is enclosed by blocks, which are individual formed with a 2 cm margin along the vessels. RESULTS: An irregular course of the vessels in 34% of the patients resulted in modifications of the radiation field compared with standard fields. Thus more than 10% of the volume of the left kidney could be taken out of field in 25% of the patients. Simultaneously fields were enlarged on contralateral side to make sure that the paracaval lymphatic drainage was enclosed. CONCLUSIONS: MRI-assisted planning of radiotherapy allows a more individualized treatment by visualization of the big abdominal vessels guiding the para-aortal lymphatics. The target volume is surely enclosed, healthy organs are optimal spared. PMID- 8677501 TI - Late local recurrence after radiotherapy for tongue and early glottic carcinoma. AB - BACKGROUND/AIM: Late local recurrence after radiotherapy for tongue and early glottic carcinoma is rarely discussed. In the head and neck cancer, approximately 90% of local recurrence occurred within 2 years after radiotherapy. However, we found that late local recurrence after radiotherapy for glottic cancer was not rare. Our aim was to evaluate the late local recurrence after radiotherapy for early glottic and tongue cancer. PATIENTS AND METHODS: From 1967 through 1982, 633 patients with tongue carcinoma and 330 patients with early (T1T2N0) glottic carcinomas were treated at the Department of Radiology, Osaka University Hospital. Of these 821 patients, 329 patients with tongue carcinoma and 221 patients with early glottic carcinoma survived at 5 years after radiotherapy without local recurrence. For tongue carcinoma, patients were divided by T category. For early glottic carcinoma, patients were divided by the tumor response at 40 Gy. RESULTS: Late local recurrence occurred in 23 of 329 patients (7%) with tongue carcinoma, and in 9 of 221 (4%) with early glottic carcinoma. For tongue carcinoma, late recurrence occurred in 19 of 249 patients (8%) in stage I and II, and 4 of 80 patients (5%) in stage III and IV. For glottic carcinoma, late recurrence occurred in 8 of 137 patients (6%) with tumor clearance at 40 Gy and 1 of 63 patients (2%) with tumor persistence at 40 Gy. The incidence of double cancer was also evaluated. Of 329 5-year survivors with tongue carcinoma, 39 patients (12%) had another malignancy, and 26 patients of 221 5-year survivors with early glottic carcinoma (12%) had also another malignancy. Of 39 double primaries of tongue carcinoma, 10 patients (26%) had head and neck malignancies, and none of 26 double primaries of early glottic carcinoma. CONCLUSION: Late local recurrence was not rare in tongue and early glottic cancer. Poor prognostic group showed lower incidence of late recurrence than good prognostic group. This result suggests that secondary tumor at the same site of primary tumor is late local recurrence. PMID- 8677502 TI - [The survival rate of patients with a differentiated thyroid carcinoma without primary percutaneous irradiation of the neck area]. AB - PURPOSE: Results of survival rates in differentiated thyroid carcinoma and comparison with a review of literature are given. PATIENTS AND METHODS: Four hundred and sixty-four patients with differentiated cancer of the thyroid (354 female, 110 male, range: 6 to 84 years, median: 46.8 years; 275 patients with papillary and 190 with follicular cancer) were analyzed retrospectively. All patients were treated with ablative doses of radioiodine after thyroidectomy including compartment oriented lymphadenectomy in 27 patients. All patients passed an individual systematic follow-up according to risk: "low risk" pT < or = 3NxM0 vs. "high risk" pT4 and/or M1. Early postoperative radiation was not included even in patients with local invasion (pT4). RESULTS: The corrected 5- and 10-year survival rates for papillary cancer are 0.91 and 0.91, for follicular cancer 0.94 and 0.78 respectively [correction of 0.94 bzw. 0.78] (p = 0.55), age ( < or = 40 years 0.96 and 0.96, > 40 years 0.90 and 0.80; p = 0.008), gender (female 0.93 and 0.92, male 0.90 and 0.70; p = 0.06) and invasion/distant metastases (pT4 and/or M1 0.83 and 0.71, other 0.97 and 0.97; p = 0.0001). CONCLUSION: A systematic follow-up with an individually adapted standardized scheme is associated with high survival rates in patients with differentiated cancer of the thyroid. Early diagnosis of recurrences, locoregional lymph node and distant metastases with early surgical treatment including compartment oriented lymphadenectomy and radioiodine therapy yield high survival even without external radiation. PMID- 8677503 TI - An automated fast MR-imaging method for localized measurements of dose distributions using NMR-Fricke gel dosimetry. Evaluation of influences on the measurement accuracy. AB - PURPOSE: The calculation of radiation absorbed dose using a chemical dosimeter and NMR-imaging techniques provides non-invasive 3D dosimetry. The main problems with this new method are measurement accuracy and diffusion effects. These involve influences on chemical preparations, correct data acquisition (evaluation of the T1 values) and a lack of methods for reducing diffusion effects. The aim of this study was to develop a computer assisted localized dosimetry method using fast and quantitative NMR-imaging techniques in order to reduce diffusion effects and to determine the accuracy of this new approach. We show successful localized dosimetry experiments and present a new method for the calculation of the diffusion coefficient. MATERIAL AND METHODS: The dosimeter gel contained a modified Fricke solution and was stabilized with gelatin. Several compositions of dosimeter gels and different conditions were investigated in order to optimize the treatment. IR-Snapshot-Flash has been used to determine the T1-values. The diffusion coefficient of the bound ferric ions was estimated by taking advantage of the short acquisition times of this fast NMR-imaging technique. RESULTS: Dependencies of the dosimeter system were investigated. The calculated error limits for evaluation of the measurement accuracy are in the range of 10 to 20%. The accurate localized determination of the T1-values and the diffusion has considerable influence on the measurement. Fast and quantitative NMR-imaging methods for accurate T1-calculations like IR-Snapshot-Flash reduce this effect. CONCLUSION: Our results show the advantage of the use of fast MR-imaging techniques for NMR Fricke dosimetry. The diffusion effects are reduced effectively, so even details can be imaged. We also developed a new method for the calculation of the diffusion coefficient, which can be used for paramagnetic ions in any aqueous solution. PMID- 8677504 TI - [The demonstration of heritable lethal mutations in the progeny of x-ray irradiated CHO cells by micronucleus count in clone cells]. AB - PURPOSE: Low doses of ionizing radiation reduce the growth rates of clones following irradiation of the progenitor cells. Such reductions of clone growth have been proven by means of measurements of clone size distributions. The medians of such distributions can be used to quantify the radiation damage. Prolongations of generation times and cell death as result of heritable lethal mutations have been discussed as causes for the reduction of clone growth. MATERIAL AND METHODS: The cell number of a clone of hypotetraploid CHO-cells was compared to the frequency of micronucleated binucleated cells in the same clone using the cytokinesis-block-micronucleus method. The dose dependent reduction of clone sizes is measured by the difference of the medians (after log transformation) of the clone size distributions. RESULTS: At cytochalasin-B concentrations of 1 microgram/ml and after an incubation time of 16 h a yield of binucleated cells of about 50% was obtained. Median clone size differences as a measure of clonal radiation damage increased linearly with incubation times of 76, 100, 124, and 240 h following irradiation with 3, 5, 7, and 12 Gy. The frequency of binucleated clone cells with micronuclei strongly increased with decreasing clone size by a factor up to 20 following irradiation with 3, 5, and 7 Gy. The frequency of micronucleated binucleated clone cells was found to be independent of incubation time after irradiation. CONCLUSION: Radiation induced clone size reductions result from cell losses caused by intraclonal expression of micronuclei which have its origin in heritable lethal mutations. Measurements of clone size distributions can be done automatically. They can serve as predictive test for determination of median cell loss rates of surviving cell clones. PMID- 8677505 TI - Geometrical considerations in dose volume analysis in intracavitary treatment. AB - PURPOSE: The present work was aimed at to study the relationship between the volume enclosed by reference isodose surface and various geometrical parameters of the intracavitary applicator in treatment of carcinoma of cervix. MATERIAL AND METHODS: Pearshape volume of the reference isodose derived from the Total Reference Air Kerma (TRAK) and the product of its dimensions, height H, width W and thickness T which is dependent on the applicator geometry, were estimated for 100 intracavitary applications treated by Selectron LDR machine. Orthogonal radiographs taken for each patient were used for measurement of actual geometric dimensions of the applicator and carrying out the dosimetry on TP-11 treatment planning system. The dimensions H, W and T of reference isodose surface (60 Gy) were also noted. RESULTS: Ratio of the product HWT and the pearshape volume was found mainly to be a function of colpostat separation and not of other geometrical parameters like maximum vertical and anterio-posterior dimension of the applicator. The ratio remained almost constant for a particular combination of uterine tandem and colpostat. Variation in the ratios were attributed to the non-standard geometry. CONCLUSION: The ratio of the volume of reference isodose surface to the product of its dimensions in the applicator depends upon the colpostat separation. PMID- 8677506 TI - [Radiotherapy in advanced osseous destruction in chronic myeloid leukemia. A case report]. AB - PURPOSE: Chronic myelocytic leukemia is a disease of myeloproliferative disorder. In chronic myelocytic leukemia occasionally myelosarcomas occur as defined tumors which can cause localized symptoms. We report a case of successful palliative radiotherapy. PATIENT AND METHODS: A 44-year-old patient with total destruction of the left humerus caused by myelosarcoma of the bone in chronic myelocytic leukemia was treated with percutaneous megavoltage radiotherapy, the total applied dose was 40 Gy. After radiotherapy the patient was free of pain. The tumorous swelling of soft tissue subsided completely, there was total formation of callus in the affected humerus and the patient could be mobilized. CONCLUSIONS: This case report confirms the high effectiveness of palliative radiotherapy even in advanced cases of myelosarcomas which has been described in literature. PMID- 8677508 TI - [Adjuvant chemotherapy improves survival in head and neck carcinomas. On the article by T. G. Wendt: Strahlenther. Onkol. 171 (1995), 715-20, Literatur kommentiert]. PMID- 8677507 TI - [The remineralization of the vertebral metastases of breast carcinoma after radiotherapy]. AB - BACKGROUND: The early detection of effects caused by radiotherapy on bone mineralisation has influence on clinical treatment. Usually the follow-up is done by conventional X-rays, presenting a loss of calcification of at least 30%. Quantitative CT-measurements are much more sensitive. PATIENTS AND METHODS: In a prospective study we evaluated the CT-scans of 14 patients with multiple vertebral metastases of mamma carcinoma. Our patients underwent SEQCT (one 10 mm slice in each affected vertebral body, 80 kV, 250 mAs) before and immediately after radiation therapy (total dose 30 Gy to 36 Gy) followed by further examinations 6 weeks and 3 months later. RESULTS: While there is no significant change in increased BMD (bone mineral density) of osteosclerotic and decreased BMD of osteolytic metastases just after therapy, the following examinations present an increase of BMD in osteolytic metastases 6 weeks after therapy more distinct 3 months after. Osteosclerotic metastases show a decline in bone density. In mixed metastases is no significant change while normal bone lying in the irradiation field demineralizes. Additive chemotherapy is very important especially for mineralisation of lytic metastases. Referring to mixed metastasis in one vertebral body we suggest a separate evaluation of the left and right side. CONCLUSION: Mineralizing effects of radiation therapy depend on the characteristics of the metastases. Supported by QCT histopathological change can be documented and exactly demonstrated to the clinician. PMID- 8677509 TI - [Tumorectomy plus irradiation in ductal in-situ carcinoma]. PMID- 8677510 TI - [A randomized comparison of adjuvant radiation therapy alone with sequential chemo-/radiotherapy in the treatment of resected non-small-cell bronchial carcinoma (NSCLC)]. PMID- 8677511 TI - [Palliative chemotherapy for metastatic soft-tissue sarcoma in adulthood--the results of a European study of the EORTC. European Organization for Research and Treatment of Cancer]. PMID- 8677512 TI - Review of the Wisconsin DHSS report on health concerns attributed to reformulated gasoline use in southeastern Wisconsin. PMID- 8677513 TI - Comparative short-term health responses to sulfur dioxide exposure and other common stresses in a panel of asthmatics. AB - We studied 14 unmedicated sulfur dioxide (SO2)-sensitive asthmatics to test the hypothesis that SO2 exacerbates asthma more than other everyday respiratory stressors. In Phase I, subjects underwent controlled exposures to 0.0, 0.5, and 1.0 ppm SO2 with light, medium, and heavy exercise (average ventilation 30, 36, and 43 l/min, respectively). Lung function, symptoms of asthma, and psychophysical (stamina) changes were measured. Function, symptom, and stamina responses correlated modestly. Increasing SO2 had stronger unfavorable effects than increasing exercise. In Phase II, subjects performed eight different physical tasks in SO2-free ambient air while symptoms and stamina were measured. Fast stair-climbing evoked symptoms similar to the effects of 0.5 ppm SO2/light exercise, while stamina reduction was comparable to 0.5 ppm SO2/heavy exercise. In Phase III, subjects recorded time-activity patterns, symptoms, and stamina during randomly selected intervals on a typical weekday and weekend day. Most reported activities were sedentary. Infrequent, strenuous Phase III exercise increased symptoms more than did 0.5 ppm SO2/light exercise, but with less effect on stamina. We conclude that for typical mild asthmatics, ten-minute SO2 exposures at concentrations > 0.5 ppm and ventilation > 30 l/min can cause short term asthma manifestations more intense than those usually experienced from everyday stresses without SO2 exposure. PMID- 8677514 TI - Respiratory peripheral sensory irritation and hypersensitivity studies with glutaraldehyde vapor. AB - Overexposure to glutaraldehyde (GA) vapor (CAS No. 111-30-8) is known to cause peripheral sensory irritant effects in humans. Respiratory sensory irritation was investigated in male ND4 Swiss Webster mice to quantify the effect, and also as a preliminary to a study of the respiratory sensitizing potential of GA. For the irritation study, groups of four mice were exposed to seven different GA vapor concentrations in the range of 1.6 to 36.7 ppm, while respiratory rate (RR) was measured by plethysmography. Concentration-related decreases in RR were measured, with a maximum decrease at 3 to 20 min, which was sustained, indicating an absence of desensitization. The 50% decrease in RR (RD50) was calculated to be 13.9 ppm, which accords with the known sensory irritancy of GA and other aliphatic aldehydes. In a separate study, the respiratory sensitizing potential of GA vapor was studied in male Hartley guinea pigs, who were exposed for one hour per day for five consecutive days to an inducing GA vapor concentration of 13.9 ppm. Subsequent challenge exposures to 4.4 ppm at 14, 21, and 35 days after the final induction exposure did not produce any evidence of respiratory sensitization. The above findings confirm that GA vapor is a moderately potent peripheral sensory irritant, and does not produce respiratory sensitization in the guinea pig at the concentrations tested. PMID- 8677515 TI - Tamoxifen--breast cancer preventive or human carcinogen? AB - Much has been written on both sides of the debate over the safety of tamoxifen. This paper discusses the toxicity of this chemical and the latest findings supporting the end of tamoxifen trials. PMID- 8677516 TI - An approach for incorporating tissue composition data into physiologically based pharmacokinetic models. AB - The objective of this study was to develop an approach for incorporating tissue composition data into physiologically based pharmacokinetic (PBPK) models in order to facilitate "built-in" calculation of tissue: air partition coefficients (PCs) of volatile organic chemicals. The approach involved characterizing tissue compartments within PBPK models as a mixture of neutral lipids, phospholipids, and water (instead of using the conventional description of them as "empty" boxes). This approach enabled automated calculation of the tissue solubility of chemicals from n-octanol and water solubility data, since these data approximate those of solubility in tissue lipids and water. Tissue solubility was divided by the saturable vapor concentration at 37 degrees C to estimate the tissue: air PCs within PBPK models, according to the method of Poulin and Krishnan (1995c). The highest and lowest lipid and water levels for human muscle, liver, and adipose tissues were obtained from the literature and incorporated within the tissue composition-based PBPK model to calculate the tissue: air PCs of dichloromethane (DCM) and simulate the pharmacokinetics of DCM in humans. The PC values predicted for human tissues were comparable to those estimated using rat tissues in cases where the relative levels of lipids and water were comparable in both species. These results suggest that the default assumption of using rat tissue: air PCs in human PBPK models may be acceptable for certain tissues (liver, adipose tissues), but questionable for others (e.g., muscle). The PBPK modeling exercise indicated that the interindividual differences in tissue dose arising from variations of tissue: air PCs may not be reflected sufficiently by venous blood concentrations. Overall, the present approach of incorporating tissue composition data into PBPK models would not only enhance the biological basis of these models but also provide a means of evaluating the impact of interindividual and interspecies differences in tissue composition on the tissue dose surrogates used in PBPK based risk assessments. PMID- 8677517 TI - Toxicological investigations in the semiconductor industry: IV. Studies on the subchronic oral toxicity and genotoxicity of vacuum pump oils contaminated by waste products from aluminum plasma etching processes. AB - Dry etching processes in semiconductor manufacturing use ionized gases in closed reactors at pressures below 1 torr. Vacuum pump systems that service the reaction chambers are potential sources of exposure to complex mixtures of inorganic and organic compounds. These mixtures consist of unused process gases and process by products that condense and accumulate in the vacuum pump oils. To evaluate potential hazards of dry etch vacuum equipment, a contaminated vacuum pump oil sample from a BCl3/Cl2 etching process was analyzed. The waste oil was administered by gavage for 14 or 28 days to male and female Wistar rats. Neither death nor behavioral changes occurred after subchronic treatment or during a 14 day posttreatment period. Only slight effects on body weights, clinical chemistry, and hematology data were seen in the exposed animals, although the livers of all waste oil-exposed rats of both sexes showed remarkable hypertrophic degenerations. Genotoxicological investigations were performed through the Ames assay (Salmonella assay) and the Micronucleus assay. The contaminated oil sample caused clear genotoxic effects in both test systems. PMID- 8677518 TI - Rapid assay of cytotoxicity using Tetramitus flagellates. AB - A simple test for measuring cytotoxic agents has been developed using the flagellate phenotype of Tetramitus rostratus. The test measures dose-dependent inhibition of cell division by individual agents such as 4-nitroquinoline-N-oxide and other mutagens. Dose-response data are given also for mixtures including coal tar pitch condensate, centrifuged particles obtained from tap water, and water concentrates prepared with XAD-2 resin. Because Tetramitus flagellates have a gullet and are particle-feeders, the assay allows for cytotoxic measurements of whole particles without prior extraction or solvent substitution procedures. The cytotoxic activities observed may reflect genotoxic activity, since all chemicals that produced a positive response are genotoxic in other test systems. PMID- 8677519 TI - Fertility and family planning in Vietnam: evidence from the 1994 Inter-censal Demographic Survey. AB - Results from the 1994 Vietnam Inter-censal Demographic Survey reveal substantial change over recent years in reproductive behavior and attitudes. Fertility has continued to decline to a level not far above a total fertility rate of three children per woman. Compared with the late 1980s, contraceptive knowledge has broadened and contraceptive prevalence has increased, reaching a level of 65 percent of currently married women of reproductive age. The dominance of the IUD among modern methods has been reduced somewhat. Stated family-size preferences have shifted noticeably downward. Recently married women indicate that they want only 2.3 children, on average, suggesting that fertility will continue to fall in coming years. These findings suggest that Vietnam is in the midst of a transition that will lead to low levels of fertility in the near future. PMID- 8677520 TI - Childlessness, subfertility, and infertility in Tanzania. AB - This study examines the trends and variations in childlessness, subfertility, and infertility in Tanzania according to data from the 1973 National Demographic Survey and the 1991-92 Demographic and Health Survey. Between the surveys, the proportion of women older than 30 who were childless was found to have declined more than 60 percent, and the proportion with an open birth interval extending for longer than five years was reduced by 40 to 50 percent in each standard five year age group from 20 to 39. Within Tanzania, both childlessness and infertility are higher among urban than rural residents, and a substantial range prevails across eight rural zones. Finally, evidence suggests that the decline in impaired fertility has been followed by an increase in the total fertility rate. The difficulties of implementing population policies that aim simultaneously to control population growth and to improve women's health are discussed. PMID- 8677521 TI - Issues in measuring maternal morbidity: lessons from the Philippines Safe Motherhood Survey Project. AB - This report explores the limitations of survey research for obtaining population based data to define the magnitude of maternal morbidity in settings that lack a well-developed infrastructure to support women's health requirements. The experience gained in the Philippines Safe Motherhood Survey Project is described. The drawbacks and benefits of the preliminary validation and qualitative phase of research conducted to develop the questionnaire are presented. The survey results indicate that interview-based diagnosis, although it implies the commitment of considerable resources, may be the only way to obtain an idea of the prevalence of some kinds of maternal morbidity in a given population, information necessary to the improvement of obstetric care and women's overall health status. PMID- 8677522 TI - Detecting induced abortions from reports of pregnancy terminations in DHS calendar data. AB - This study considers whether pregnancy terminations reported in Demographic and Health Survey (DHS) calendar data can be classified accurately as having been spontaneous or induced based upon other information collected in the survey interview. A classification scheme is proposed that is an adaptation of the method developed by the World Health Organization for categorizing cases in which women admitted to hospitals experienced complications of pregnancy termination. The scheme is evaluated using data from the 1993 Turkey DHS. Evaluation results indicate that the method identifies true cases of induced abortion accurately, but tends to classify a relatively large number of reported spontaneous terminations as induced abortions. However, when it is corrected for likely respondent misreporting of induced abortions as spontaneous terminations, both the sensitivity and specificity of the method appear to be acceptable. PMID- 8677523 TI - Comparing the Peru service availability module and situation analysis. AB - This report reviews the experience of the World Fertility Surveys and the Demographic and Health Surveys (DHS) in collecting community-level data on family planning. It assesses the validity of the community data for Peru that were collected via a service availability module, much like that which is used for the DHS, through a comparison with data from the Situation Analysis. The analysis indicates that the knowledgeable informant, the main source of information about family planning in each community for the service availability module, may not be an accurate source of data. Information about the availability of family planning services is more reliable when it is obtained by means of visits to service sites. However, given cost considerations, sampling problems, and analysis issues, routine linkage of Situation Analyses to household surveys such as the DHS is not recommended at this time. PMID- 8677524 TI - Development of near-field optic/atomic force microscope for biological materials in aqueous solutions. AB - This paper reports improvements of optical fiber cantilevers and the scanning near-field optical microscopy imaging of biological materials in liquid. In our scanning near-field optical/atomic-force microscope (SNOAM), the scanning of an optical fiber cantilever over the specimen was controlled by dynamic mode AFM to reduce damage to the probe and soft specimens. The typical resonant frequency of the optical fiber cantilever was 19.5 kHz, while it was 23.0 kHz in air. The Q factor of the cantilever depended on the vibration amplitude and was typically 260-600 in air and 40-240 in water. The relationship between the vibration amplitude and the average sample-probe separation indicated that the cantilever worked in the non-contact mode in water, while it worked in the cyclic-contact mode in air. Cultured cells in aqueous solutions were visualized by the SNOAM, indicating that the SNOAM is suitable to observe soft specimens. PMID- 8677525 TI - Detection of fluorescence in situ hybridization on human metaphase chromosomes by near-field scanning optical microscopy. AB - Fluorescence in situ hybridization signals on human metaphase chromosomes are detected by a near-field scanning optical microscope. This makes it possible to localize and identify several fluorescently labeled genomic DNA fragments on a single chromosome with a resolution superior to traditional fluorescence microscopy. Several nucleic acid probes have been used. The hybridization signals are well resolved in the near-field fluorescence images, and the exact location of the probes can be correlated to the topography as it is afforded by the shear force feedback. PMID- 8677526 TI - The discrimination of IgM and IgG type antibodies and Fab' and F(ab)2 antibody fragments on an industrial substrate using scanning force microscopy. AB - We have previously employed scanning force microscopy (SFM) to study antibody antigen molecular interactions on microtiter wells used for enzyme linked immunosorbant assays (ELISA). Here we demonstrate the ability of SFM to image and discriminate different types of antibody and antibody fragments bound to an ELISA well surface. The samples studied include a type IgG antibody with a proportion of bound IgM and two-dimensional films of whole IgG antibody, and Fab' and F(ab)2 antibody fragments. Molecular resolution is achieved in each case despite the size of substrate features exceeding most of the molecular dimensions observed. Analysis of the data shows that the SFM overestimates molecular dimensions by an approximately constant amount, which is proposed to principally result from the effects of a finite probe size and not from deformation of the molecular species due to the imaging forces employed. PMID- 8677527 TI - A characterisation of dark-field imaging of colloidal gold labels in a scanning transmission X-ray microscope. AB - While X-ray microscopes provide images of biological specimens for which the contrast is mainly due to the difference in the absorption of carbon and oxygen when X-rays transmitted through the specimen are detected, signals other than absorption can also be used to form images. Using the Stony Brook scanning transmission X-ray microscope at the National Synchrotron Light Source, high angle dark-field images have been formed of cells labelled with colloidal gold, with and without silver enhancement. The high density of the colloidal gold particles, or the silver particles seeded by the gold, leads to a large scattering signal, and the fact that the particle diameters are comparable to the width of the microscope point spread function results in good localisation of the label with high contrast. The dark-field images can have a greater signal to noise ratio than bright-field images acquired with the same incident X-ray dose. The theory of dark-and bright-field imaging is reviewed. Theoretical calculations of scattering from gold and silver particles are presented and good agreement is found between these and experimental dark-field images of 30 nm diameter gold particles. The signal to noise ratios of experimental bright-and dark-field images are measured and found to be in agreement with theory. Images are presented of cells labelled by immunolabelling and in situ hybridisation. PMID- 8677528 TI - Epidemiology of urinary symptoms in the geriatric population. AB - As the US population ages, there is a growing need for information about the urologic health problems facing older adults. In conjunction with findings from clinical studies and basic research on biological mechanisms, the epidemiologic approach offers insights on the prevalence, etiology, and impact of these geriatric conditions. This information can provide the basis for planning health care services and intervention programs. The authors discuss trends associated with population aging and the challenges posed by the epidemiologic study of older adults. Also reviewed are current findings on the prevalence, incidence, and correlates of urinary incontinence and other common urologic symptoms. PMID- 8677529 TI - Interpreting the effect of common medical conditions on voiding dysfunction in the elderly. AB - Medical conditions often have an important causal role in urinary incontinence in the elderly. Aside from causing functional impairments, such diseases directly may involve the genitourinary system--particularly its neurologic control- resulting in specific lower urinary tract pathophysiology. Knowledge of the specific effects that medical conditions may have on the genitourinary system and continence can assist the urologic specialist in determining the often complex cause(s) of UI in older persons. PMID- 8677530 TI - Intracavernous pharmacotherapy: treatment for the aging erectile response. AB - Fueled by serendipity, observation, and direct scientific investigations over the last 15 years the normal mechanisms of erection, and the pathophysiology of erectile dysfunction have been revealed. The demonstrations that vasoactive injections could produce penile erection without benefit of psychic or tactile stimuli revolutionized the diagnosis and treatment of erectile dysfunction by providing a direct test of end organ integrity or deficiency. This article reviews the clinical pharmacology of vasoactive corporal agents and outlines what has been surmised about the aging erectile response. PMID- 8677531 TI - Psychosocial issues in geriatric urology: problems in treatment and treatment seeking. AB - Psychological and social issues are important in geriatric urology because they affect not only the patient's ability and willingness to seek out therapy, but also their ability to benefit from it. Many older adults with problems of bladder control, such as frequency, urgency, nocturia, and incontinence are deterred from seeking treatment by factors such as social disapproval and belief that bladder symptoms are normal or untreatable. Many older adults who present for treatment experience limitations of mental status or functional ability that merit attention because they can interfere with learning, motivation, and cooperation needed for successful treatment. Strategies are described that help to address these psychosocial issues and needs in older patients. PMID- 8677532 TI - Urologic care in long-term facilities. AB - The urologic care of the institutionalized elderly is confounded by the high prevalence of comorbid conditions. There is also a challenge to provide cost effective care to this group that requires a disproportionate share of health care resources. Bacteriuria, hematuria, and problems of urine control and drainage provide unique clinical conditions that must be dealt with. PMID- 8677533 TI - Cryosurgery of the prostate: techniques and pitfalls. AB - The preliminary data on prostate cryosurgery encompass reports only on local recurrence rates. The procedure is too new to report any survival figures. For localized organ-confined disease, the initial reports at 1 year of positive biopsies following cryosurgery range from 8% to 33%. With clinical stage C disease, a review of the literature also shows a range of 16% to 33% for local recurrence at one year. The largest series of patients treated after failure from radiation therapy is from the M.D. Anderson Cancer Center, which reports a positive biopsy rate of 29% at 6 months. Reports of major complications have included a 2% to 5% incidence of rectourethral fistulas, a 7% to 15% incidence of urinary retention requiring a secondary TURP or prolonged catheter drainage, 2% to 7% incidence of stress incontinence, and a 50% to 80% incidence of impotence. While these overall results may not be optimal to many, they do give us optimism. It is important to recognize that knowledge of the cryosurgical technique is evolving rapidly, and present modifications are not reflected yet in our results. Because hypothermia is a modality proven to cause lethal injury to cancer cells, it would be unfortunate if clinicians dismissed this modality without rigorous review of the surgical technique. The detailed methodology described in this article expedites the learning curve of practicing cryosurgeons and helps to standardize the way cryosurgery is performed. PMID- 8677534 TI - Anesthetic considerations in the geriatric patient. AB - As the population ages the incidence of many urologic diseases increases. The elderly patient often is afflicted with many other concomitant diseases in addition to the general deterioration in their overall health status that occurs as a part of the normal aging process. With new advances in technology, many less invasive techniques have become available to treat many of these conditions, thus making many more elderly patients candidates for surgery. In the geriatric population the anesthetic consideration for surgery is as important as the surgical consideration and good communication between the patient, the family, the urologist and the anesthesiologist can make the entire surgical experience a successful one and achieve the desired outcome. PMID- 8677535 TI - Perioperative care in the elderly urologic patient. AB - This article summarizes the preoperative evaluation and postoperative care recommended for elderly patients undergoing urologic procedures. Most of the common issues faced during the perioperative period are discussed, but many other topics require reference to other sources or consultation with specialists. A thorough preoperative evaluation is needed, and meticulous attention to postoperative care is mandatory. The most important common problem is assessment of cardiovascular risk in patients and a general approach is suggested by the authors. Surgical risk in elderly patients is increased, but most of this excess risk is because of associated comorbid conditions. Effective pre- and postoperative assessment and care can minimize this risk and maximize the chances of a successful outcome. PMID- 8677536 TI - Bacteriuria and urinary infections in the elderly. AB - Aging is associated with a decreased physiological functioning, reflecting the body's progressive inability to maintain homeostasis as age increases. The physiologic dysfunctions experienced in response to the aging process increase the individual's susceptibility to infection. Many elderly subjects are hospitalized for the care and treatment of functional disabilities; thus, an increased exposure to possible uropathogens (many with antimicrobial resistance) often results in infection. Additionally, indwelling catheters and other attending procedures may provide a microenvironment conducive to infection. In catheterized patients, the drainage bag often is infected with polymicrobes, which enhances the transference of antimicrobial genetic information. Postmenopause reflects a decrease in circulating estrogen, and a relational decrease in lactobacilli colonization with a lower vaginal pH. Consequently, vaginal colonization with possible uropathogenic and gastrointestinal bacteria increases, which partially may account for the generally higher incidence of bacteriuria in elderly women as opposed to elderly men. Urinary infections in the elderly more commonly are asymptomatic. Treatment for asymptomatic bacteriuria is not justified and will often present opportunities for the infecting organism to acquire antimicrobial resistance. Only symptomatic bacteriuria presenting adverse conditions in the host should be treated. Antimicrobial selection for the treatment of complicating symptomatic urinary infections in elderly subjects is complicated by the many physiological and environmental conditions associated with older age patients. Unfortunately, data confirming the efficacy and safety of antimicrobial agents for the treatment of symptomatic infections in the elderly presently are insufficient. PMID- 8677537 TI - Geriatric incontinence. AB - Regardless of age, mobility, mentation, or institutionalization, incontinence is never normal. By attenuating physiologic reserve, aging increases the likelihood of becoming incontinent in the setting of additional physiologic, pharmacologic, or pathologic insults. Because many of these problems lie outside the urinary tract, so too must the diagnostic and therapeutic focus. Such a strategy, however, coupled with a multifactorial, creative, persistent, and optimistic approach, increases the chances of a successful outcome and generally rewards patient and physician alike. PMID- 8677538 TI - Prostatism: benign prostatic hyperplasia. AB - This article is devoted to the most common cause of outlet obstruction in the male geriatric population, benign prostate hyperplasia (BPH). The prevalence, pathophysiology, and natural history of BPH is discussed, along with the work-up and indications for medical or surgical intervention. The authors also focus on medical and surgical options now available for management of BPH. PMID- 8677539 TI - Management of prostate and bladder cancer in the elderly. AB - The management of prostate and bladder cancer in the elderly will increasingly require clinicians to judge the impact on comorbidity and toxicity of the proposed therapy in order to make sound management decisions. As PSA-based screening has rapidly increased, physicians are increasingly challenged to decide the upper age limits for such screening and therapy. Bladder cancer management in the elderly differs little from that offered to the younger patient and the new therapeutic developments may improve the risk-to-benefit ratio of treating advanced disease. It is clear that as the US population ages, management of prostate and bladder cancer will become an increasingly common dilemma for the urologic practitioner. PMID- 8677540 TI - Sexuality in the elderly. AB - Sexuality and aging are not incompatible terms. However, sexual issues are often ignored in older adults. Impacts of altered physiology and pathologic changes, such as cardiovascular disease are discussed in this article. What is clear is that many older adults are interested in remaining sexually active throughout the years. PMID- 8677541 TI - [The use of antimicrobial preparations in preventing infectious wound complications after an operation on the kidney and upper urinary tract]. AB - Pre-, intra- and postoperative use of wide-spectrum antibiotics alone appeared insufficient to prevent postoperative infectious inflammation. Antiseptic chlorhexidine (0.02% solution) does not eradicate the infection focus either. Cleansing of the wound is effective provided antibacterial treatment of the operative wound is combined with intraoperative application of local long-acting antimicrobial plates gentacicol and solution of antiseptic sodium hypochlorite. The above approach results in a 3.5 times reduction in the number of infectious postoperative complications in patients operated on the kidney and upper urethra. PMID- 8677542 TI - [The reaction of the kidneys and acid-base and osmotic homeostasis to moderate physical exertion in patients with chronic pyelonephritis in the pre-azotemia period]. AB - Bicycle ergometry (BE) up to submaximal heart rate provoked moderate metabolic acidosis in 52 patients with chronic pyelonephritis (CP) in preuremic stage. Similar changes in acid-base balance following BE were noted in 14 patients with chronic glomerulonephritis (CGN). BE in CP promoted the reduction in diuresis and fraction water excretion, elevation of creatinine concentration in the urine and its concentration index in the absence of alterations in sodium and osmotic homeostasis. In CGN BE induced similar changes but an insignificant decrease in diuresis and a significant rise in serum sodium concentrations, osmolality of the urine, osmotic concentration index, absolute reabsorption of osmotically free water, fall in excreted sodium fraction. It is suggested that the above differences in the response to exercise test in CP and CGN may relate to tubulointerstitial nature of CP. PMID- 8677543 TI - [Inferior venacavography in a kidney tumor]. AB - Indications to inferior cavography were detailed after examination and treatment of 745 patients with renal carcinoma (vena cava inferior was involved in 108 of them). Tumor invasion of the renal vein on the right and left, right kidney tumor T3 may displace and press vena cava inferior. Metastases to the lymph nodes increased the aortocaval space. PMID- 8677544 TI - [The late results of organ-preserving operations in acute hemorrhages in patients with bladder cancer]. AB - Surgical aid in acute hemorrhage due to cancer of the urinary bladder was rendered within 1986-1994 to 65 patients (53 males and 12 females) aged 30-50, 51 60, 61-70 and over 70 years (10, 11, 24 and 20 cases, respectively). The majority had the disease stage T2 and T3. In 42 (64.6%) patients with profuse hematuria complicated by bladder tamponade an urgent resection was performed: segmental in 22, hemiresection in 8, open bladder electroexcision of the tumor in 10 patients. 2 patients had sigmoid cancer with bladder involvement managed by subtotal resection of the bladder and resection of the sigmoid colon. Nephro- or cystostomy was performed because of grave condition (purulent pyelonephritis, azotemia) in 23 patients (35.4%). Total postoperative lethal outcomes made up 33.3% (14 patients): 6 patients died early after surgery, 8 patients 6 months to 8 years later. 27 patients (64.3%) are alive. Of them 10 are 5-8-year survivors. These patients had cancer stage T2 and T3 with tumor location on the lateral wall. In three 4-year survivors there were tumor recurrences 2 and 3 years after surgery which were treated by transurethral resection and electroexcision on the open bladder. Long-term outcomes of urgent surgery show that different kinds of resection of the bladder may be effective in the treatment of acute hemorrhages from bladder tumors. PMID- 8677545 TI - [The international system of overall scoring assessment of the symptoms and quality of life of patients with benign prostatic hyperplasia]. AB - The paper presents the International system of overall score estimation of symptoms and life quality for patients with benign prostatic hyperplasia and reviews the results of this system application for objective diagnosis and evaluation of the efficacy of the treatment (chemotherapy, transurethral resection, transvesicular adenomectomy, transrectal hyperthermia, YAG-Nd laser prostatectomy) in 250 patients with benign prostatic hyperplasia. The fault of the system is the absence of specific recommendations for rating objective test results. The authors propose their variant of estimation of prostatic volume, maximal urination rate, residual urine. PMID- 8677546 TI - [The complications of transurethral resection of the bladder for tumor]. AB - Transurethral resection (TUR) is now widely used in combined treatment of urinary bladder cancer, but the procedure may be compromised if applied without evaluation of infiltration and malignancy degree and metastases responsible for frequent recurrences. The aim of this study was design of effective measures to prevent TUR complications. For 8 years the surgeons from the Moscow Medical Academy urological clinic made 824 TURs for bladder tumors in 322 patients (mean age 57.5 years, 72.6% of males, 27.4% of females). At the stage T3-4 TUR was conducted in contraindications to cystectomy or absence of distant metastases. The following intra- or postoperative complications were observed: hemorrhages (4.6%), intraperitoneal perforations (0.3%), extraperitoneal perforations (0.9%), vesicoureteral reflux (2.8%), enuresis (1.2%). The emergence and severity of the complications were dependent on the bladder tumor stage and degree of infiltration of the muscular layer. Positive TUR results are more feasible in more strict approach to the indications for surgery, adequate surgical skills and technique, high-quality anesthesia, early arrest of hemorrhage, low pressure of the washing liquid in the course of operation. PMID- 8677547 TI - [The use of BCG vaccine for preventing recurrences of superficial bladder cancer]. AB - Responses to immunoprophylaxis of superficial bladder cancer in 94 post transurethral resection patients were analyzed. Once-a-week intravesicular instillations of BCG vaccine in a dose 100 mg diluted in 50 ml of physiological solution were initiated 30 days after transurethral resection. The main course of therapy comprised 8 instillations made outpatiently. Subsequently the patients underwent a maintenance immunoprophylactic course once a month in the same dose (100 mg) for a year since transurethral resection. 3 years after therapy gave rise to the tumor recurrences in 12 (12.8%) out of 94 patients contrary to 37 (43.0%) patients out of 86 patients. BCG is able to prevent recurrences of superficial bladder cancer subjected to transurethral resection in the majority of patients. PMID- 8677548 TI - [The chemotherapy of nonseminomatous testicular tumors]. AB - 236 patients with nonseminomatous germ cell tumors have been treated for the last decade with VAB-6 combination and 188 ones with etoposide-containing regimens BEP and EP. Complete remissions were achieved in 97(41%) VAB-6 treated patients, 72(31%) patients were currently alive without evidence of the disease for 76 months of follow-up. Patients on BEP-EP presented better outcomes: 130(69%) of 188 patients achieved a complete remission and 119(63%) of them were free of symptoms within 47 months of follow-up. In spite of more pronounced toxicity, mainly myelosuppression, etoposide-containing combinations are more efficient than VAB-6 and should be considered as an induction chemotherapy in patients with nonseminomatous germ cell tumors. PMID- 8677549 TI - [The transurethral microwave thermotherapy of benign prostatic hyperplasia]. AB - Treatment outcomes are available for 502 patients with benign prostatic hyperplasia exposed to transurethral microwaves (TUMW) on Prostatron unit. Of the patients whose age ranged from 55 to 84, 328 had stage I disease, the rest stage II. 32 patients had previously undergone cystostomy. Acute urine retention was registered in 67 patients on day 1-4 after microwave therapy because of edema of the tumor. To remove the urine, cystostoma and catheter were placed in 18 and 49 patients, respectively. In half a year a positive effect occurred in 80% of cases. As microwave therapy relieves symptoms, increases the quality of life, improves urine flow and reduces the tumor size it can be recommended for the treatment of benign hyperplasia of the prostate. PMID- 8677551 TI - [The potentials of the Reflexotest computer diagnostic system with patients suffering from kidney failure]. AB - Computer diagnostic system (CDS) Reflexotest based on the Nakatani method with the use of IBM PC/AT personal computer noticeably facilitates data accumulation and processing. It is a new non-invasive and simple electrophysiological method providing information on the status of autonomic nervous system which is indirectly indicative of functional capacity of different organs and systems. CDS efficacy is illustrated on 12 cases with chronic renal insufficiency (4 patients in compensation, 8 in terminal stages) who demonstrated low mean potential of biologically active points (BAP) and unbalance of potentials specific for different meridians. In patients with positive treatment effects there was a tendency to better BAP parameters. Deterioration of clinical condition was also reflected by BAP evidence. CDS Reflexotest is recommended for practice as a promising adjuvant diagnostic method. PMID- 8677550 TI - [A clinico-morphological analysis of the efficacy of therapy in chronic glomerulonephritis using prednisone, a cytostatic, an anticoagulant and an antiaggregant]. AB - Four-component therapy (chlorbutin 0.2 mg, prednisone [correction of prednisolone] 60 mg, curantyl 400 mg/day per os, i.v. heparin 10,000 U twice a day) was given for 9-36 months to 76 patients with chronic glomerulonephritis (CGN). A statistically significant lowering of proteinuria was achieved irrespective of CGN clinicomorphological variant. As indicated by remission frequency and normalization of urinary osmotic concentration, efficacy of the above treatment is related to a clinical CGN type. Because clinical and morphological CGN types are correlated, the disease morphology and treatment effect are associated. The treatment proved effective in nephrotic mesangioproliferative, mesangiocapillary glomerulonephritis, focal-segmental glomerular sclerosis, active nephritic mesangiocapillary glomerulonephritis and inactive nephritic mesangioproliferative and mesangiocapillary glomerulonephritis. Nephrotic-hypertonic focal-segmental glomerulosclerosis and mesangiocapillary glomerulonephritis were resistant to therapy. PMID- 8677552 TI - [The serological diagnosis of hemorrhagic fever with renal syndrome]. AB - Early serological diagnosis of hemorrhagic fever with renal syndrome (HFRS) in 45 patients did not affect survival and policy of hemodialysis. However, the number of procedures, invasive in particular, to verify the diagnosis was much less. Perfection of HFRS early diagnosis promotes optimization of the disease detection. PMID- 8677554 TI - [The basic mechanisms of microcirculatory disorders before and during operations in children with developmental defects of the kidneys and urinary tract]. AB - The authors studied biomicroscopic picture of microcirculation in the vessels of bulbar conjunctiva, renal hemodynamics, blood cell metabolism in 50 patients aged 3-12 with renal and ureteral defects. By morphology of the kidneys assessed at aortography, computer renangiography and other tests 2 groups of children were identified: bilateral congenital urological disorder combined with severe advanced dysplasia of the renal tissue and the ureter, low renal function (group 1); light or moderate disorder of renal function, minimal dysplasia of the renal tissue. In children with renal and urinary defects with renal dysfunction there was systemic abnormal microcirculation (group 1) characterized by severe capillarotrophic insufficiency in the form of unusual winding of all the microvessels, formation of vascular loops and balls, narrowing of capillary lumen, etc. in the presence of acute arteriolar spasm and rheological alterations in microvessels. In addition to functional changes in arteriolar tone, mechanisms of microcirculatory disturbances in children with congenital surgical disorders of the kidneys and urinary tracts involve membrane-destructive processes. Changes in phospholipids level and their spectrum in plasma and red cell membranes, a rise in the activity of phospholipase A and C in the serum and red cell membranes exhibit close correlation with microhemodynamic impairment. Instructions are provided for conduction of preoperative preparation and multicomponent anaesthesia with allowances for principal mechanisms of microcirculatory disorders in children with severe congenital renal and urinary affections. PMID- 8677553 TI - [The variants and potentials of reconstructive surgery of the penile skin]. AB - The authors have operated 24 patients to repair total and subtotal defects of penile integuments due to oleogranuloma. They have performed a total of 13 transplantations of axial island cellolocutaneous inguinal flaps basing on the external pudendal, superficial epigastric or superficial circumflex iliac arteries; 3 transplantations of free axial inguinal grafts; 2 transplantations of free axial grafts from the forearm on the radial artery. Microvascular anastomoses with the recipient zone vessels were formed. 8 two-stage Reich operations were conducted. Postoperative dynamic monitoring (skin thermometry, oxygen polarography, Doppler ultrasound scanning of the vessels) of the graft has found more favourable vascular reactions in the axial flaps vs. scrotal ones. Effective contralateral grafting was performed in a patient with the transplant necrosis on the superficial epigastric artery. PMID- 8677555 TI - [Endoscopic ureterocutaneostomy]. AB - The authors have developed and used in 16 patients an endoscopic technique of continuous drainage of the upper urinary tracts by means of ureterocutaneostomy and assisting retroperitoneoscopy. The most reliable cutaneous fistula not inclined to scarring or narrowing can be established of small triangular skin flap from the wound margin sutured into the 2-3 cm longitudinal incision of the ureteral stump (stump ureterotomy). Such fistula may even heal without further internal drainage. In a short ureteral stump skin anastomosis may be formed in the depth of the wound with the use of longer cutaneous graft. PMID- 8677556 TI - [Polyps of the urethra and bladder in children]. PMID- 8677557 TI - [A gunshot wound of the penis and scrotum]. PMID- 8677558 TI - [Cavernous hemangioma of the penis]. PMID- 8677559 TI - [Laser technology in prostatic surgery]. PMID- 8677560 TI - [Laparoscopic nephrectomy in a patient with a parenchymatous form of nephrogenic hypertension]. AB - The years following the first laparoscopic nephrectomy in man performed in 1990 were evidencing wide spread of transabdominal laparoscopic approach in operative interventions on the kidney, adrenals, ureter, urinary bladder, in iliac lymphadenectomy for prostatic and bladder cancer, in the treatment of varicocele, etc. Since 1993 we have made 4 nephrectomies using laparoscopic approach. The first operation in a 18-year-old male with parenchymatous hypertension lasted 7 hours, the following operations took from 2 hours 47 min to 1 hour 30 min. No complications occurred. Postoperative stay in hospital was, on the average, 7.2 days. The laparoscopic approach in urology and surgical nephrology of adults and children needs detailed studies, specification of indications and contraindications prior to its introduction into wide practice. PMID- 8677561 TI - Speckle analysis using signal to noise ratios based on fractional order moments. AB - The SNR (signal-to-noise ratio) of the echo envelope image is a monotonically increasing function of scatterer number density. Various SNRs, like amplitude SNR and intensity SNR, can be used to quantify the scatterer density. The problem of using a SNR based on higher order moments like the intensity SNR is that they require large sample sizes to obtain estimates with high confidence (the variance of the estimate becomes large for higher moments). In this paper, we consider SNRs based on fractional order moments (moments of order less than 1), and obtain mathematical analyses of their properties using the K distribution, which has been shown to be a good model for the density function of backscatter echo envelope signal. Statistics of SNRs based on fractional moment are derived and appear to be more robust and useful than the amplitude and intensity SNRs previously studied. The SNRs based on fractional order moments have greater dynamic range and the sample size requirements are smaller than those for integral order moment SNRs, like amplitude SNR or intensity SNR. Thus, SNRs based on fractional order moments could be used to better quantify the variations in scatterer density which can be used for tissue classification problems. PMID- 8677562 TI - A method for estimating an overlying layer correction in quantitative ultrasound imaging. AB - A new method is tested to compensate for attenuation losses through the intervening layers in quantitative ultrasound imaging. The method subtracts the echo signal power spectrum acquired from a uniform region beneath the overlying layers from the signal power spectrum obtained from a reference phantom using the same instrumentation system settings. Changes in spectral components with frequency are then used to estimate the attenuation of the overlying layers. Several phantoms were used to test the method, among which was a phantom having three windows, one with no overlying layers and the other two with fat and muscle mimicking layers of different degrees of irregularity. Attenuation losses through the windows were compensated for using the technique, producing backscatter estimator images of a simulated tumor inside the phantom. After applying the method, consistent results for the backscatter estimator of the tumor, as well as the backscatter coefficient of the background material, were obtained from the various windows. PMID- 8677563 TI - Multiple resolution Bayesian segmentation of ultrasound images. AB - We propose a novel method for obtaining the maximum a posteriori (MAP) probabilistic segmentation of speckle-laden ultrasound images. Our technique is multiple-resolution based, and relies on the conversion of speckle images with Rayleigh statistics to subsampled images with Gaussian statistics. This conversion reduces computation time, as well as allowing accurate parameter estimation for a probabilistic segmentation algorithm. Results appear to provide improvements over previous techniques in terms of low-contrast detail and accuracy. PMID- 8677564 TI - Primary nephrectomy for Wilms' tumor: approach of the National Wilms' Tumor Study Group. PMID- 8677565 TI - Preoperative chemotherapy in management of Wilms' tumor. PMID- 8677566 TI - A comparative analysis of prostate-specific antigen gene sequence in benign and malignant prostate tissue. AB - OBJECTIVES: Different molecular forms of prostate-specific antigen (PSA) appear to be expressed by benign prostatic hyperplasia (BPH) compared with prostate cancer. These differences are not well understood and may arise from aberrant RNA splicing, altered protein glycosylation, or variant PSA complexing to macroglobulins. To our knowledge, a direct comparison of PSA mRNA sequences in BPH versus prostate cancer to account for these differences has not been reported. The purpose of this study was to compare the complete PSA mRNA gene sequences in benign and malignant prostate tissue to determine whether altered PSA phenotypes are a result of gene mutations and to compare the published PSA sequences. METHODS: Total RNA was extracted from 17 prostate specimens from 8 patients, including matched benign and malignant prostate tissue in 6 patients. The samples were subjected to reverse transcriptase-polymerase chain reaction (RT PCR) of the PSA coding sequence and part of the 3' untranslated region. Directed DNA sequencing was performed on these fragments. RESULTS: The benign and malignant prostate tissue cDNA sequence data of both strands were aligned and a computer analysis revealed 100% match with no evidence of mutation in prostate cancer compared to normal tissue. Sequence analysis did not reveal point mutations or aberrant splicing in any of the samples, including the matched malignant and nonmalignant tissues. Comparison with published sequences revealed infrequent and inconsistent sequence differences. CONCLUSIONS: These findings suggest that the PSA gene expressed in malignant prostate tissue is the wild type. PSA structural alterations previously reported in the literature may occur through post-transitional mechanisms. A detailed understanding of the possible differences in the PSA gene sequence is essential as we develop newer techniques that utilize RT-PCR to perform molecular diagnosis and staging of prostate cancer. PMID- 8677567 TI - Retroperitoneoscopy: a laparoscopic approach for adrenal and renal surgery. AB - OBJECTIVES: Retroperitoneoscopy has gained acceptance for urologic surgery. We assessed the safety and efficacy of this procedure for renal and adrenal surgery. METHODS: Since December 1994, 20 patients (18 to 75 years old) have undergone laparoscopic adrenalectomy and nephrectomy, including simple nephrectomy in 8, partial nephrectomy in 1, radical nephrectomy in 2, tumorectomy with cyst excision in 1, and adrenalectomy in 8. The retroperitoneal space was created by blunt dissection with the index finger, completed by insufflation, without balloon dissection. RESULTS: Average kidney size was 65 m (range 50 to 108), and average adrenal tumor size was 31 mm (range 20 to 40). The average operating time was 127 minutes (range 60 to 180) for nephrectomy and 84 minutes (range 45 to 140) for adrenalectomy. The average hospital stay was 3 days (range 1 to 7) for nephrectomy and 2.4 days (range 1 to 4) for adrenalectomy. Average blood loss was 65 mL for both nephrectomy and adrenalectomy. Conversion from the laparoscopic procedure to open surgery was never required. Peritoneal effraction and ureteral injury occurred in only 4 patients and 1 patient, respectively. CONCLUSIONS: The laparoscopic retroperitoneal approach is safe and effective for simple renal nephrectomy and for excision of small adrenal tumors. Perioperative morbidity and hospital stay are reduced. PMID- 8677568 TI - Cadaveric kidney transplantation under prophylactic polyclonal antibody immunosuppression with anti-lymphoblast globulin versus anti-thymocyte globulin. AB - OBJECTIVES: This retrospective study was undertaken to evaluate and compare the clinical and immunologic outcomes following prophylactic induction treatment with Minnesota anti-lymphoblast globulin (MALG) and Upjohn anti-thymocyte globulin (ATGAM) in cadaver renal transplantation. METHODS: From 1990 to 1994, 63 patients with renal transplants from cadavers received MALG and 77 patients received ATGAM for induction treatment. Most pretransplant parameters were equivalent in both groups. There was no significant difference in the total dose and mean duration of MALG/ATGAM administration. The post-transplant outcome in these groups was compared. RESULTS: There was no difference between the MALG and ATGAM groups with respect to the overall number of rejection episodes, median days to rejection, or the number of steroid-resistant rejection episodes. However, MALG-treated patients experienced a greater number of rejections in the first 60 days postoperatively (P = 0.06). There was no difference in the nadir serum creatinine level in the first 20 postoperative days in the two groups; however, it took fewer days to reach the nadir in the ATGAM group (P = 0.03). The incidence of delayed graft function was higher in the MALG group than in the ATGAM group (38% versus 31%) but not statistically significant. Graft survival at 12 and 24 months was comparable in both groups. However, patient survival was superior at 12 and 24 months in ATGAM-treated transplant recipients (P = 0.03). The mean serum creatinine at 6, 12, and 24 months was similar in both the MALG and ATGAM groups. The mean fall and recovery of CD3, CD4, and CD8 T-lymphocyte subsets while on MALG/ATGAM were similar in both groups. The incidence of infectious complications was greater in the MALG group. CONCLUSIONS: MALG and ATGAM have comparable clinical immunosuppressive effects. Patients receiving ATGAM experienced fewer rejections in the first 2 months, fewer infections, and better survival. PMID- 8677569 TI - Simultaneous radical nephrectomy and repair of abdominal aortic aneurysm. AB - OBJECTIVES: The combination of abdominal aortic aneurysm repair with other intra abdominal surgery is controversial. Most studies have shown that a variety of procedures can be performed at the same time as an aneurysm repair with little change in mortality or complication rates. We conducted a retrospective study to determine if aneurysm repair could be safely and effectively combined with radical nephrectomy. METHODS: We studied 10 patients who underwent combined abdominal aortic aneurysm repair and radical nephrectomy during a 4-year period. Results from this group were compared to a separate control group of 10 patients who underwent radical nephrectomy alone and another of 12 patients underwent abdominal aortic aneurysm repair alone, during the same time period. RESULTS: The overall mortality was 10% and significant complications occurred in an additional 10% of patients. Minor, self-limiting complications occurred in 30% of patients. There were no aortic graft infections that occurred in the entire series of patients at 18 months of mean follow-up. There were no remarkable differences in the entire series of patients and the combined values in a separate group of control patients who had undergone either procedure alone. CONCLUSIONS: Simultaneous radical nephrectomy for presumed renal cell carcinoma can be safely combined with repair of abdominal aortic aneurysm in selected patients. PMID- 8677570 TI - Long-term follow-up of endoscopically treated upper urinary tract transitional cell carcinoma. AB - OBJECTIVES: This report focuses on the long-term follow-up of patients with endoscopically treated upper tract transitional cell carcinoma (TCC) to determine the effectiveness of endoscopic therapy. METHODS: From May 1983 to April 1994, 44 patients with TCC of the upper urinary tract underwent conservative endourologic treatment with either electrocautery fulguration or neodymium:yttrium-aluminum garnet laser at our institution. The mean follow-up period was 5 years (range, 3 months to 11 years). RESULTS: Renal pelvic tumor sizes ranged from 0.4 to 4.0 cm (mean, 1.5) and ureteral tumors from 0.2 to 1.0 cm (mean, 0.5). The majority of tumors were of pathologic grade 3 or less, and all were Stage T2 or less. Seventeen of 44 patients (38.6%) had local tumor recurrence (mean time to recurrence, 12.8 months; range 1.5 to 64). Mean recurrence time was 7.3 months for renal pelvic tumors and 17.8 months for ureteral tumors. Nineteen of 44 patients (43.2%) developed bladder tumors. The overall 5-year disease-free rate was 57%. No recurrent tumor was shown to have increased in grade, and one recurrent tumor was proved to have progressed in stage. Six patients (14%) ultimately required a nephroureterectomy for recurrence. There were no major complications as a result of endoscopic therapy. Six patients (14%) died of the effects of metastatic TCC, 5 of whom had known muscle invasive bladder TCC. CONCLUSIONS: Endourologic techniques and the conservative treatment of upper urinary tract TCC is an evolving field and can be safely and effectively used as a first-line treatment for upper tract TCC in selected patients. PMID- 8677571 TI - Complications of radical cystectomy: impact of the timing of perioperative chemotherapy. AB - OBJECTIVES: To evaluate the impact of timing of perioperative chemotherapy on morbidity of radical cystectomy in patients with bladder cancer. METHODS: We compared the complications in patients randomized to neoadjuvant (n = 53) or adjuvant (n = 49) MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) chemotherapy. RESULTS: In the 95 patients who underwent cystectomy, there were no significant differences in treatment compliance, surgical parameters, or postoperative recovery between the two groups. In patients who received neoadjuvant chemotherapy, there were more complications, and there was one perioperative death; however, these differences were not significant. The neoadjuvant group took longer to complete therapy (P < 0.001). Nine patients (3 neoadjuvant, 6 adjuvant) did not undergo cystectomy on time. CONCLUSIONS: Cystectomy following neoadjuvant MVAC chemotherapy is feasible. We were unable to demonstrate any difference between neoadjuvant and adjuvant chemotherapy in mortality, morbidity, or postoperative clinical course. PMID- 8677572 TI - Bladder calcifications after photodynamic therapy: analysis of a rare complication. AB - OBJECTIVES: We analyzed bladder calcifications occurring after photodynamic therapy administered for the treatment of superficial bladder cancer, a finding not previously reported after this treatment. METHODS: Bladder biopsies from 20 patients undergoing photodynamic therapy were evaluated. Bladder calcifications were identified in 2 patients and analyzed for composition. RESULTS: One patient had diffuse microcrystalline deposition in two biopsies composed of calcium oxalate monohydrate A. A second patient had a focal stone at a healing biopsy site composed of monoclinic calcium hydrogen phosphate dihydrate (brushite) (66%), calcium oxalate (25%), hydroxyapatite (6%), and protein (3%). CONCLUSIONS: Rare calcium oxalate and brushite calcifications were identified after photodynamic therapy and presumed to occur because of tissue injury associated with treatment. PMID- 8677573 TI - Etiology of voiding dysfunction in men less than 50 years of age. AB - OBJECTIVES: Chronic lower urinary tract symptoms in young men are often attributed to misdiagnosed chronic nonbacterial prostatitis. The purpose of this study was to analyze etiology of chronic voiding dysfunction in men less than 50 years of age. METHODS: The videourodynamic studies of 137 men 50 years of age or less with chronic voiding dysfunction, performed between January 1990 and October 1995, were retrospectively analyzed. RESULTS: The distribution of urodynamic abnormalities included 74 (54%) patients with primary vesical neck obstruction, 33 (24%) with obstruction localized to membranous urethra (pseudodyssnergia), 23 (17%) with impaired bladder contractility, and the remaining 7 (5%) with an acontractile bladder. Detrusor instability was present in 67 men (49%). CONCLUSIONS: Voiding dysfunction among young men is common and is often misdiagnosed. Videourodynamic evaluation is very useful in establishing the correct diagnosis and ultimately in delivery of appropriate therapy. PMID- 8677574 TI - An observational urodynamic evaluation of men with lower urinary tract symptoms treated with doxazosin. AB - OBJECTIVES: To assess the urodynamic changes in men with lower urinary tract symptoms (LUTS) suggestive of bladder outlet obstruction treated with doxazosin and to correlate these changes with voiding symptoms. METHODS: Fifty patients with LUTS were treated with doxazosin at a dose of 4 mg/day for 3 months. All men were initially evaluated by International Prostate Symptom Score (I-PSS) questionnaires, measurements of urinary flow rate, and complex urodynamic study. Those patients completing the 3-month study underwent repeat testing. RESULTS: Forty-four (88%) men underwent initial and follow-up urodynamic evaluation. The mean I-PSS improved from 20.6 to 10.5 (P < 0.001), mean peak urinary flow rate increased for 11.7 to 13.2 cc/s (P = 0.20), mean detrusor pressure at peak flow decreased from 9 3.6 to 83.0 cm H20 (P = 0.15), and mean cystometric bladder capacity increased from 266 to 304 cc (P = 0.07). Using the Abrams-Griffiths nomogram and number, more than 58% of patients remained obstructed after treatment with doxazosin for 3 months. Men with and without objective evidence of bladder outlet obstruction at the outset of the study had similar improvement in voiding symptoms. Most patients elected to continue treatment with doxazosin at the completion of the study (41/44, 93%). CONCLUSIONS: The majority of patients had objective evidence of persistent bladder outlet obstruction after treatment with doxazosin for 3 months despite significant benefit. The results of complex urodynamic evaluation did not predict treatment response in men with LUTS suggestive of bladder outlet obstruction. Urodynamic study does not appear to be helpful in the evaluation of patients with uncomplicated LUTS prior to treatment with doxazosin. PMID- 8677575 TI - Optical characterization and coagulation performance of side-emitting fiber delivery systems for laser therapy of benign prostatic hyperplasia: a comparative study. AB - OBJECTIVES: Currently, various side-emitting optical fibers with different tip geometry are used transurethrally to deliver laser radiation for treatment of benign prostatic hyperplasia (BPH). Since fiber tip design could profoundly affect the size and profile of the emitted laser beam, and consequently the tissue response and the extent of tissue coagulation, we evaluted commercially available fibers in regard to their optical characteristics and their ability to coagulate tissue in a controlled experimental setting. METHODS: Thirteen fibers manufactured by different companies and clinically used at the present time were tested using a surgical neodymium: yttrium-aluminum-garnet laser. The profile of the laser beam delivered via each fiber was imaged on a CCD camera at various distances and evaluated by means of a laser beam analyzer. Beam divergence angle was then calculated for each tip. Tissue coagulation effects were assessed by irradiating samples of beef muscle immersed in water at 37 degrees C. The fiber tip was kept 2.5 mm away from the tissue and irrigation was maintained at flow rate of 350 to 400 cc/min during irradation. Laser powers of 20, 40, and 60 W were used for 180, 90, and 60 seconds, respectively, delivering a total energy of 3600 J. RESULTS: The results of the optical evaluation divided the fibers into two major groups: broad beam with large divergence angle and narrow beam with small divergence angle. Statistical analysis of the data (using analysis of variance) showed that volumes of coagulated tissue were significantly larger for broad beam fibers than for narrow beam fibers (1.15 +/- 0.32 versus 0.89 +/- 0.34 cm 3; P < 0.05). Also, significantly larger volumes were obtained for 20 W when compared with 60 W (1.08 +/- 0.43 versus 0.88 +/- 0.27 cm 3; P < 0.05). CONCLUSIONS: The laser power density delivered by individual fibers to the prostate tissue may vary significantly, thus greatly affecting the extent of tissue coagulation. Therefore, irradiation parameters must be optimized for each fiber type. PMID- 8677576 TI - Antibiotic prophylaxis for patients undergoing transurethral resection of the prostate. AB - OBJECTIVES: To evaluate the prevention of urinary tract infections (UTIs) after transurethral resection of the prostate (TURP) in a prospective randomized study using a quinolone antibiotic (fleroxacin) to compare the efficacy of: (1) a single oral dose, (2) a single intravenous (IV) dose, and (3) an extended regimen consisting of an initial IV dose followed by oral therapy until removal of the urinary catheter, but for less than 6 days. METHODS: We excluded from study patients who received antimicrobial agents within 48 hours of surgery. Single dose prophylaxis consisted of 400 mg of fleroxacin given either orally or intravenously. The extended regimen consisted of an initial 400 mg IV dose followed by 400 mg oral each day (patients older than 75 years, or with a creatinine clearance less than 40 mL/min, received 200 mg/day). UTI was defined as clinical evidence of infection plus the presence of more than 10 white blood cells (WBC)/mm3 in any urine specimen plus the presence of more than 10(4) cfu/mL in midstream urine specimens or more than 10(2) cfu/mL in catheter specimens. RESULTS: Prior to TURP, 30% (25/84) of the patients had a urethral catheter in situ and 12% (3/25) of these patients had bacteriuria. Only 1 patient developed a UTI and that was 22 days after a TURP (intergroup comparisons, Fisher's exact test greater than 0.05). There were no instances of urosepsis. CONCLUSIONS: A single oral dose of a fluoroquinolone agent provided optimum prophylaxis for patients undergoing TURP. PMID- 8677577 TI - Reassessment of nonplanimetric transrectal ultrasound prostate volume estimates. AB - OBJECTIVES: To assess the accuracy and reproducibility of nonplanimetric transrectal ultrasound (TRUS) volume estimates because inaccurate volume estimates may potentially undermine the value of serum prostate-specific antigen density (PSAD) in early prostate cancer detection. METHODS: We prospectively evaluated 535 consecutive male patients with two consecutive volume determinations performed by the same ultrasonographer at the time of the same visit. RESULTS: Pearson correlation coefficients between two consecutive gland volume estimates ranged from 0.82 to 0.85 depending on the formula used; however, these correlation coefficients corresponded to an average 25% difference between the first and second gland volume estimates. CONCLUSIONS: Although two consecutive nonplanimetric TRUS volume estimates show statistically good correlation, clinically up to a 25% volume difference should be expected between two such volume estimates. In consequence, nonplanimetric TRUS volume estimates should be interpreted with caution, especially when used for PSAD calculation, in the early detection of prostate cancer. PMID- 8677578 TI - Serum prostate-specific antigen and digital rectal examination for early detection of prostate cancer in a national community-based program. The Prostate Cancer Education Council. AB - OBJECTIVES: This study analyzed methods of prostate cancer early detection in community settings throughout the United States against standards and findings of earlier studies conducted at academic medical centers. METHODS: The study was conducted at 148 clinical centers during Prostate Cancer Awareness Week in September 1993 and continued through June 1994. A total of 31,953 eligible subjects were tested by both digital rectal examination (DRE) and prostate specific antigen (PSA). PSA was tested with the Abbott IMx PSA assay and reported by Roche Biomedical, Inc. RESULTS: The study confirmed that elevated PSA levels (greater than 4.0 ng/mL) aid in the detection of organ-confined prostate cancer when used in conjunction with the DRE. Reflecting more conservative biopsy decision-making practices, study results nonetheless are comparable to earlier reports. Among 1307 subjects who underwent biopsy, 322 cancers were detected. The cancer detection rate was 3.6% for PSA, 3.0% for DRE, and 4.7% if either test result was positive. The positive predictive value (PPV) for elevated PSA levels (greater than 4.0 ng/mL) was 3l.6%, significantly better (P < 0.0001) than the PPV for abnormal DRE results (25.5%). Nearly 90% (88.9%) of staged cancers were diagnosed as localized. Elevated PSA levels detected more localized cancers (76 of 105 [72.4%]) than the DRE (72 of 105 [68.6%]). Of localized tumors, 33 (31.4%) were missed by DRE and detected solely by PSA, and 29 (27.6%) were missed by PSA and detected solely by DRE. The combined use of the two methods detected 33 additional localized tumors. CONCLUSIONS: Community practice throughout the United States demonstrates that PSA and DRE are consistently effective and efficient in the early detection of prostate cancer. PMID- 8677579 TI - Induction androgen deprivation plus prostatectomy for stage T3 disease: failure to achieve prostate-specific antigen-based freedom from disease status in a phase II trial. AB - OBJECTIVES: There is interest in treating prostate cancer with induction androgen deprivation prior to radical prostatectomy. Data on long-term prostate-specific antigen (PSA)-based survival analyses among patients treated with neoadjuvant hormonal therapy (NHT) and prostatectomy are limited. In 1991 we instituted a pilot study for T3 disease based on endorectal coil magnetic resonance imaging (eMRI), mandatory negative laparoscopic nodal dissection prior to hormonal manipulation, and prostatectomy followed by pathologic and PSA-based outcome determinations. METHODS: Of 26 patients, 21 had negative laparoscopic lymphadenectomy followed by 4 months of NHT (leuprolide +/- flutamide) prior to radical prostatectomy. eMRI was performed at the time of diagnosis and following hormonal treatment. Serum PSA was determined at 3-month intervals. Prostatectomy specimens were evaluated by 3-mm whole-mount step sections. RESULTS: Prior to prostatectomy, biochemical response was documented in all patients and downsizing was observed by eMRI in 57%. Pathologic downstaging to a lower stage (T2c or lower) was achieved in 48%. However, the actuarial 3-year freedom from biochemical relapse rate was only 24%. CONCLUSIONS: Using laparoscopy to exclude node-positive patients and 4 months of NHT appears to result in pathologic and initial biochemical evidence of regression. These factors have not translated into improved freedom from biochemical relapse among patients with Stage T3 disease treated with NHT and prostatectomy. Recent data strongly suggest a beneficial effect in patients with clinical T2 disease treated with NHT and radical prostatectomy. The NGT and radical prostatectomy approach appeared to offer no clear advantage when compared with PSA-based benchmarks achieved with conformal irradiation or NHT followed by external beam treatment among patients with clinical T3 disease. PMID- 8677580 TI - Detection of residual prostate cancer after radical prostatectomy with the Abbott IMx PSA assay. AB - OBJECTIVES: This analysis was performed to define the level of serum prostate specific antigen (PSA) measured with the Abbott IMx assay that indicates residual or progressive prostate cancer after radical retropubic prostatectomy (RRP). METHODS: Since March 1992, we have used the Abbott IMx assay to determine PSA levels. Between March 1992 and June 1994, 102 of those patients having RRPs were found to have pathologic Stage C prostate cancer. Fifty-one of these patients had at least one serum PSA measurement of 0.1 ng/mL or greater. Eight patients were excluded from the analysis because they received postoperative radiotherapy that might have influenced subsequent PSA levels. The remaining 43 patients are the subjects of this analysis and were evaluated to determine the "clinical threshold" or minimal serum PSA level after RRP indicative of progressive disease. Patients were followed for 6 to 36 months (median 23 months) from the date of the RRP. Failure was defined as a subsequent increase of PSA to greater than 0.3 ng/mL. Freedom from failure was determined using the Kaplan-Meier product limit method. RESULTS: Of the patients with at least one postoperative serum PSA level of 0.1 ng/mL, the subsequent freedom from failure was 80% at 23 months as compared with 13% in patients with at least one postoperative PSA level of 0.2 ng/mL (P = 0.003). CONCLUSIONS: Following RRP for pathologic Stage C prostate cancer, a solitary PSA level of 0.1 ng/mL (measured with the IMx assay) was followed by a progressive rise in PSA levels in only a minority of patients within the first 2 years after surgery. In contrast, the majority of patients with a postoperative PSA level of 0.2 ng/mL subsequently had progressively rising PSA levels. This indicates that a serum PSA level of 0.2 ng/mL is reflective of residual prostate cancer. PMID- 8677581 TI - Low-dose cyproterone acetate plus mini-dose diethylstilbestrol--a protocol for reversible medical castration. AB - OBJECTIVES: To determine whether a low dose of cyproterone acetate (CPA) (50 mg twice a day) with minidose diethylstilbesterol (DES) is efficacious in rapidly reducing and maintaining serum testosterone at less than 10% of pretreatment level and whether the effect is reversible upon cessation of therapy. METHODS: Data were collected prospectively on 62 subjects, aged 50 to 90 years (mean 69) with histologically confirmed prostate cancer and normal serum testosterone levels. Treatment was initiated with CPA 50 mg twice a day plus DES 0.11 mg once a day, both administered orally, and continued or 6 months unless discontinued for reasons unrelated to the study. Subsequent management was at the discretion of the investigator/managing physician. Treatment was discontinued with determination of at least one follow-up testosterone level in 28 patients. RESULTS: Mean pretreatment testosterone level was 13.8 nmol/L (range 4.5 to 46.6, median 14.0, 95% confidence interval [CI] 12.0 to 15.0). Testosterone dropped to a mean of 0.6 nmol/L (range 0.1 to 2.2, median 0.5, 95% CI 0.4 to 0.6) by first follow-up (usually 1 month) in all patients (P <0.001) and remained at this level as long as treatment continued. Testosterone normalized in all subjects whose treatment was discontinued. Side effects were minimal. CONCLUSIONS: An oral dosage of CPA of 50 mg twice a day in combination with a mini-dose of DES results in rapid and reversible reduction in serum testosterone to castrate levels. This regimen minimizes morbidity and monetary costs of therapy and allows the implementation of novel treatment approaches such as intermittent or neoadjuvant withdrawal therapy. PMID- 8677582 TI - Comparison of fascial and vaginal wall slings in the management of intrinsic sphincter deficiency. AB - OBJECTIVES: To compare safety and efficacy of fascial versus vaginal wall slings in the management of women with intrinsic sphincter deficiency (ISD). METHODS: The hospital and office records of 79 consecutive women with ISD were retrospectively analyzed from January 1991 to September 1995. There were 43 fascial slings (group A) and 36 vaginal wall slings (group B). Parameter of evaluation included efficacy based on postoperative presence of stress or urge incontinence and number of pads used, complications, and miscellaneous factors, including length of catheterization time, length of hospitalization, quantity of analgesics used, and loss of work days. RESULTS: Baseline clinical and urodynamic data were the same for both groups. Pad use decreased from 6.9 to 0.6 for group A and from 5.7 to 0.3 for group B. Persistent stress and urge incontinence was present in 5% and 16% of group A patients and in 3% and 11% of group B patients, respectively. Group A (89%) and group B (94%) patients were either very satisfied or satisfied with their surgical outcome. The operative time, hospital days, and days lost from work for group B patients (42.3 +/- 13.4 minutes, 1.4 +/- 0.9 days, 18.4 +/- 3.2 days, respectively) were significantly lower than for group A patients (84.2 +/- 17.8 minutes, 3.7 +/- 1.9 days, 28.4 +/- 7.8 days, respectively). CONCLUSIONS: Both fascial and vaginal wall slings are effective in treating women with ISD. However, the use of vaginal wall slings resulted in significantly shorter hospital stay, decreased catheterization time, decreased use of analgesics, and decreased loss of days of work compared with fascial slings. Therefore, the vaginal wall sling should be the preferred surgical method of treating sphincter deficiency. PMID- 8677583 TI - Urethral obstruction after anti-incontinence surgery in women: evaluation, methodology, and surgical results. AB - OBJECTIVES: To evaluate a group of women with voiding dysfunction and a low maximum flow rate (MFR) (less than or equal to 12 mL/s) after surgery for stress urinary incontinence (SUI); to establish diagnostic parameters indicating obstruction in an attempt to determine treatment selection; and to evaluate preliminary surgical results. METHODS: Eighteen women who underwent anti incontinence surgery for SUI were diagnosed as having infravesical obstruction (IO). Thirteen women (group A [72%]) presented with clinically predominant symptoms of urgency, frequency, intermittency, and a variable vesical residual volume (RV), and five (group B [28%]) had as their most significant symptoms a high vesical RV and urinary tract infection that had been managed with intermittent catheterization (IC). The diagnosis of IO, suspected after clinical history, was established after physical examination and cystoscopic, cystographic and urodynamic investigations. RESULTS: Bladder instability was demonstrated in 6 group A patients (46%) and 1 group B patient (20%) (P = NS). Mean MFRs were 8.07 and 7.2 mL/s, respectively, in both groups (P = NS). Mean maximal voiding pressures (MVPs) were 20.23 and 5 cm H20, and mean RVs were 57.46 and 174 mL, respectively; both differences were statistically very significant (P <0.01 and P <0.001, respectively). High to normal MVPs occurred in 2 patients overall (11%). Bladder neck overcorrection, midurethral distortion, and postsurgical cystocele were demonstrated in both groups in 11 (85%), 0, and 2 (15%) patients in group A and 3 (60%), 2 (40%), and 3 (60%) patients in group B, respectively (P = NS). Patients in group A were treated surgically with cystourethrolysis and a repeated, less obstructive anti-incontinence operation. In group B 2 women (40%) had a similar surgical procedure; 1 (20%) underwent isolated urethrolysis; and 2 (40%) are currently maintained with IC. CONCLUSIONS: Among these 18 patients with voiding dysfunction after anti-incontinence surgery, a primary diagnosis of IO was established clinically. Only patients with a low MFR were selected for this study. Cytographic and endoscopic investigation as well as the presence of postsurgical cystocele assisted in establishing the diagnosis. The success rate with urethrolysis and resuspension was 60% for the 13 women with predominantly urgency, frequency, and the highest MVPs (20.23 +/- 9.67 cm H20 [group A) and 33% for the 5 women with urinary retention presenting the lowest MVPs (5.00 +/- 7.07 cm H20 [group A]) and 33% for the 5 women with urinary retention presenting the lowest MVPs (5.00 +/- 7.07 cm H20 [group B]). An added resuspension procedure is probably unnecessary in the latter group of patients and requires careful individual selection in the former group. PMID- 8677584 TI - Long-term experience with the double-cuff AMS 800 artificial urinary sphincter. AB - OBJECTIVES: To assess the efficacy and safety of the double-cuff artificial urinary sphincter over a long-term period. METHODS: Ninety-five patients charts were reviewed from December 1986 to November 1995. Data on the degree of urinary incontinence and complications were compiled and tabulated. RESULTS: There were 10 cuff erosions (10.5%) and one infection (1.1%) requiring removal of the double cuff system, with one death from unrelated causes. Two patients in the erosion group had a double-cuff system reinserted at a later date. Eighty-six patients have a double-cuff system, with 97.6% remaining dry. CONCLUSIONS: A tandemly placed double-cuff artificial urinary sphincter is safe and effective in the treatment of severe postprostatectomy urinary incontinence. PMID- 8677585 TI - Latex allergen levels of injectable collagen stored in syringes with rubber plungers. AB - OBJECTIVES: To assess the latex allergen content of glutaraldehyde cross-linked injectable bovine collagen stored in rubber plunger syringes. METHODS: Extracts of syringe plungers and collagen solutions before and after storage in syringes with natural rubber latex plungers were tested for latex protein allergens. Thirty-nine patients known to be allergic to latex underwent skin prick testing with extracts of the latex plungers, collagen solutions before and after storage in syringes, standard latex skin test reagents, four extracts from commercially available gloves, and positive (histamine) and negative (diluent) control solutions. Thirty-one control patients not known to be latex allergic were similarly tested. RESULTS: No latex proteins were detected using in vitro immunochemical techniques. Only 1 of 39 (2.5%) latex allergic patients reacted to the syringe extract and the collagen stored in the syringe. No reactions were recorded to collagen that no contact with latex. CONCLUSIONS: The level of latex antigens in injectable collagen is very low. The low prevalence of skin test reactivity in these highly latex allergic individuals suggests that type 1 hypersensitivity reactions as a result of latex contamination would be unlikely. PMID- 8677586 TI - Slow injection of prostaglandin E1 decreases associated penile pain. AB - OBJECTIVES: A randomized, double-blind study to determine whether speed of intracavernous injection of prostaglandin E1 (PGE1) is associated with pain. METHODS: On two separate occasions, using two different speeds of injection (5 versus 60 seconds), 11 subjects received the same dose of PGE1 that they used at home. The presence, duration, and intensity of pain were recorded. RESULTS: We found that fast penile injection of PGE1 was associated with a greater intensity of pain (P = 0.04). CONCLUSIONS: Slow injection of PGE1 is less often associated with penile pain, the most common adverse effect of this treatment. PMID- 8677587 TI - Laparoscopic creation of a continent cecal tube for antegrade colonic irrigation. AB - OBJECTIVES; The antegrade continence enema (ACE) procedure has been used for the treatment of overflow fecal incontinence or constipation inpatients with spina bifida. The procedure requires an appendiceal reimplantation into the cecum with creation of a continent abdominal stoma for antegrade colonic washout. To preserve the appendix for potential use in urinary diversion, we developed two surgical techniques for tubularizing an antimesenteric cecal segment to use in place of the appendix. METHODS: The surgery was performed in 6 dogs. The first two procedures used an open surgical technique through a 10-cm midline laparotomy. The cecum was isolated, and a small cecotomy was made. A 10F red rubber catheter was introduced into the cecotomy, and a 4-cm length of cecum was tubularized along its antimesenteric border with a gastrointestinal anastomosis stapler over the catheter. A nipple was created at the base of the tube to enhance continence, and the tubular segment was brought through the lower abdominal wall to create a catheterizable stoma. After our success, four subsequent procedures were performed laparoscopically to create the same tubularized cecal segment. A 4-cm antimesenteric tubularized cecal segment with sufficient lumen to accommodate a 10F to 12F catheter was constructed using a laparoscopic gastrointestinal anastomosis stapler. Rather than creating a nipple at the base of the tubular segment, continence of the stoma was achieved by tunneling the cecal tube through a 2-cm lower quadrant subcutaneous tunnel. A flush stoma was then created and secured to the skin. RESULTS: Stoma viability was grossly confirmed in all 6 dogs during the postoperative period, with no incidence of bowel obstruction. Slight fecal leakage through the stoma was observed in 1 dog with a laparotomy but not in those with laparoscopy. Catheterization was easily performed in all dogs with a 10F red rubber catheter during the postoperative period. The dogs were killed on postoperative day 10, and gross anatomic and histologic examination of the cecal segment confirmed luminal patency and viability. CONCLUSIONS: Open and laparoscopic continent cecostomies were successfully constructed in a canine model and are likely to be applicable to humans with neuropathic constipation. PMID- 8677588 TI - Urethroscopy in small neonates with posterior urethral valves and ureteroscopy in children with ureteral calculi. AB - OBJECTIVES: To describe our recent experience using a 6.9F cytoscope in the fulguration of posterior urethral valves (PUVs) in premature neonates and distal ureteroscopy with stone extraction in children. METHODS: Fulguration of PUVs was performed in 3 premature neonates born at 34 to 36 weeks' gestation with weights of 2480 to 2900 g. The PUVs were fulgurated during a single endoscopic procedure using a 6.9F cystoscope and a 3F bugbie electrode. In addition, 11 children (8 girls, 3 boys; mean age, 11.1 years; range 5 to 16) with symptomatic calculi underwent 15 distal ureteroscopic procedures using the 6.9F cystoscope. RESULTS: In the neonates with fulguration of PUVs, vesicostomy, the only reasonable alternative, was avoided, and each infant now voids with an excellent stream 3 to 16 months later, without evidence of stricture or residual valves. In the children with distal ureteroscopy, the ureteral calculi were retrieved using a 3F four-wire stone basket. With one exception, distal ureteroscopy was performed without dilation of the ureteral orifice. Extracorporeal shock-wave lithotripsy (ESWL) was not recommended because of stone position and difficult radiographic visualization. Nine children were rendered stone free with one procedure. Two procedures were required in 1 child and three in another. In both cases, ureteral edema was present, and the stone was embedded in the ureteral wall. One child underwent separate procedures for bilateral calculi. In all cases general anesthesia was used, with a mean duration of 63 minutes (range 28 to 96). Temporary ureteral stenting was performed in 10 (93%) patients, and 9 (81%) were discharged home on the same day or the next morning. A mean follow-up period of 8.5 months (range, 0.5 to 22) has failed to show any problems related to ureteral stricture or injury. CONCLUSIONS: Endoscopic fulguration of PUVs is now possible in small neonates and is minimally invasive compared with vesicostomy. Distal ureteroscopy with stone retrieval should be considered in children, especially those with calculi that are not suitable for ESWL. PMID- 8677589 TI - The Giuliani muscle splitting and nerve-sparing anterolateral transabdominal approach to the kidney. AB - We report on an anterolateral transabdominal approach to the kidney, which is appropriate when vascular control is important (such as, radical nephrectomy, traumatic renal injury, and difficult nephrectomy). The technique splits muscles and spares nerves and that allows good exposure both downward as far as the aortic bifurcation and upward as far as the diaphragm. This approach has been used in 42 patients during the last 20 months (mean follow-up, 6.5). In all these patients the active control of the abdominal wall muscles has been completely preserved, while, during the period from 1974 to 1994, about half of 434 patients who underwent the same approach, but with muscle and nerve transection, showed abdominal wall relaxation. PMID- 8677590 TI - Balloon-wire retrieval of a migrated urethral stent in the early postoperative period. AB - We report on a new endoscopic approach to the removal of a migrated urethral stent following hypospadias repair. A flexible balloon-tipped guide wire allows the effective cystoscopic retrieval of a urethral stent, suggesting potential applications to the removal of other foreign bodies in the urinary tract. PMID- 8677591 TI - The scrotal hitch for hemostasis and edema prevention in scrotal surgery. AB - Postoperative hematoma, edema, and echymosis are the most common complications in scrotal surgery. Without proper hemostasis intraoperatively or appropriate scrotal compression postoperatively, significant morbidity, including re exploration and prolonged convalescence, can occur. The scrotal hitch provides hemostasis, minimizes edema and hematomas, and reaffirms other clinicians' findings. PMID- 8677592 TI - Urinary calculus in pregnancy. PMID- 8677593 TI - Bellini duct (collecting duct) carcinoma of the kidney. AB - Bellini duct (collecting duct) carcinoma of the kidney is a rare entity often misinterpreted as renal or transitional cell carcinoma on histologic examination. Immunohistochemical identification of specific antigens is needed for the differential diagnoses. We describe a case of Bellini duct carcinoma that arose from the collecting ducts of Bellini and was treated with aggressive surgery and interferon-based immunochemotherapy. PMID- 8677594 TI - Ureteral pseudodiverticulosis: the case for the retrograde urogram. AB - Ureteral pseudodiverticula are small outpouchings along the length of the ureter diagnosed primarily by the retrograde urogram. They are associated with hematuria and urinary tract infections, although it is now known whether they cause these associated symptoms or are a result of them. Herein we report 2 cases that highlight the characteristic clinical correlates of ureteral pseudodiverticulosis and review the pertinent literature. PMID- 8677595 TI - Bladder wall fibrosis following intravesical mitomycin treatment for superficial bladder cancer. AB - Mitomycin is used extensively for the prevention of recurrence of superficial bladder cancer. Most treatment regimens of mitomycin are long term, since this seems more effective in preventing recurrence. During treatment some patients develop cystitis of variable severity, which may lead to mucosal ulcerations and cessation of treatment. We report a case in which long-term treatment with mitomycin, following a single episode of transitional cell bladder cancer, has led to bladder fibrosis and loss of its function, without evidence of tumor recurrence. PMID- 8677596 TI - Continent reconstruction of detrusor hyperreflexia by sacral bladder denervation combined with continent vesicostomy. AB - We describe a two-stage surgical procedure for complex hyperreflexic detrusor dysfunction refractory to conservative therapy. First, ventral and dorsal sacral rhizotomies (S2 to S4/5) are performed to restore vesical storage function and abolish autonomic dysreflexia. Then, after an interval of several weeks to allow for detrusor relaxation, continent vesicostomy is performed for suprapubic clean intermittent catheterization. The procedure is effective both objectively and subjectively, is only moderately invasive, and requires neither sophisticated nor expensive medical equipment. PMID- 8677597 TI - Penile edema and meatal ulceration after intravesical instillation with bacillus Calmette-Guerin. AB - Bacillus Calmette-Guerin (BCG) bladder instillation is an accepted treatment modality in the management of superficial transitional cell carcinoma but is associated with frequent side effects. A report of intravesical BCG-induced penile edema and meatal ulceration that occurred in 2 patients is presented. During induction therapy, both patients complained of progressive penile edema. In 1 patient the edema appeared after the second instillation and in the other after the fourth instillation. Edema was associated with ensuing meatal ulceration and enlarged inguinal lymph nodes. BCG instillation was aborted, and oral antituberculous treatment was initiated. There was no report of external spillage during the administration of BCG or of genital or urethral trauma during catheterization. Patients were treated at different clinics but with BCG of the same strain and batch. Symptoms continued for 6 weeks until they abated. Both patients were managed with oral antituberculous drugs for a period of 3 months. Adverse effects of BCG intravesical administration affect several organs in the genitourinary system. The penis and urethra may also be involved, presenting as penile edema and meatal ulceration. Physicians who administer BCG must be familiar with the possible complications and their appropriate management. PMID- 8677598 TI - Gangrene of the perineum. AB - Fournier's gangrene, an anaerobic necrotizing cellulitis of the infradiaphragmatic soft tissues, is a serious pathologic entity with an unpredictable course. From 1978 to 1991, a total of 24 men (mean age, 57 years; range 27 to 90) were treated for this entity at our institution. Diagnosis prompted immediate institution of multimodal treatment combining triple antibiotics, surgical dissection, debridement, and repeated surgical drainage. Fecal diversion (16 patients), hyperbaric oxygenation, and standard intensive care procedures were widely indicated and performed quasi-systematically. The mean interval between initial symptoms and diagnosis was 7.4 days. Lesions were limited to the perineum in 11 patients but extended to the abdomen, thighs, or loins in the remaining 13. The pathogens were identified in 19 patients, and hemoculture results were positive in 5. A coloproctologic origin was identified in 12 patients and a urogenital origin in 4. In 2 patients, perineal gangrene occurred postoperatively, and no etiology was determined for 6. Six patients died, and 18 patients recovered, without any sequelae. The prognosis is better when the patient is young (less than 60 years old), has clinically localized disease, without systemic involvement, and sterile hemocultures and is managed with colostomy. A thorough workup is mandatory to determine the etiology (locoregional lesion, malignancy, hemopathy, arteritis). PMID- 8677599 TI - Persistence of injectable collagen in human urethra: case report. AB - A polypoid lesion was found near the bladder neck during cystoscopy in a woman with urinary incontinence who had undergone periurethral collagen (Contigen) injections 3 years before. She had previously received radiation therapy in addition to a radical vulvectomy for vaginal cancer. On transurethral resection of the lesion, particles of unresorbed collagen material extruded from the capsulated suburothelial space. Histologic evaluation verified the material as the foreign collagen. The persistence of glutaraldehyde cross-linked collagen in our patient was much longer than previously reported and may have been due to effects of previous radiation treatment. PMID- 8677600 TI - Ultrasonic estimation of bladder weight as a measure of bladder hypertrophy in men with infravesical obstruction: a preliminary report. AB - The aim of the present study was to evaluate the usefulness of ultrasonic estimation of bladder weight as a measure of bladder hypertrophy using transabdominal ultrasonography in men with infravesical obstruction. Ultrasonically estimated bladder weight (UEBW) was calculated from the thickness of the bladder wall measured ultrasonically and the intravesical volume at the ultrasonic measurement, assuming a spheric bladder. There was a statistically significant correlation (r = 0.970, P <0.001) between the actual bladder weight of cadaver bladders and the UEBW. The UEBW did not change with bladder filling. The UEBW in the obstructed group (group O, 49.7 +/- 19.5 g, mean +/- SD) was significantly greater than that in the normal control group (group NC, 25.6 +/- 5.7 g; P <0.001) or the nonobstructed group (group NO, 28.4 +/- 4.2 g; P <0.001). The greatest UEBW was 34.8 g in group NC and 35.2 g in group NO, whereas 94% (45 of 48) of group O had a UEBW greater than 35.0 g. In all 5 patients with benign prostatic hyperplasia (BPH), the increased UEBW decreased to a normal control level at 3 months after treatment of BPH. This new noninvasive method may be useful in investigation of bladder hypertrophy. PMID- 8677601 TI - Molecular staging of genitourinary malignancies. PMID- 8677602 TI - Seromuscular colocystoplasty lined with urothelium. PMID- 8677603 TI - Evaluation of SEF14 fimbrial dot blot and flagellar western blot tests as indicators of Salmonella enteritidis infection in chickens. AB - The serological responses to Salmonella enteritidis flagella (H: g,m) and its fimbrial antigen SEF14 were evaluated as indicators of infection in chickens and to confirm serological results obtained by an ELISA using S enteritidis lipopolysaccharide (LPS) (O: 9,12) as the detecting antigen. The SEF14 antigen and flagella were extracted from S enteritidis and transferred to nitrocellulose paper for use in Western and dot blot tests. Antisera to 19 salmonella serotypes including S enteritidis were raised in rabbits and their cross reactivity to the flagellar and SEF14 antigens was evaluated. Cross reactivity with the SEF14 antigen was found in one antiserum, raised against S blegdam, and to flagella in eight of 19 antisera raised against various salmonella serotypes, most of which shared the flagellar factors g or m with S enteritidis. The intensity of cross reaction to flagella was strongest in S derby and S blegdam antisera. Antisera raised in chickens against S typhimurium and S panama did not cross react in either test, and neither did pooled sera from eight-week-old salmonella-free, broiler breeder parent chickens. Field sera from two commercial flocks with no history of salmonella infection were negative when tested by the LPS ELISA. These sera were also negative when tested by the flagellar and SEF14 blots. S enteritidis infection in a commercial laying flock was detected initially when the sera were tested by the LPS ELISA and confirmed in individual and pooled sera by the SEF14 and flagellar tests. S enteritidis PT4 was isolated from this flock post mortem. PMID- 8677604 TI - Comparisons of intravaginal and intrauterine insemination of bitches with fresh or frozen semen. AB - To compare the importance of the route of insemination when using fresh or frozen semen, six groups of five bitches were inseminated either into the uterus (groups 4, 5 and 6) or the vagina (groups 1, 2 and 3) with fresh (groups 1 and 4) or frozen semen (groups 2, 3, 5 and 6). The fresh semen was collected when needed from the same dog. The frozen semen used in groups 2 and 5 was obtained from seven dogs on the same day, and pooled and processed simultaneously so that the groups were inseminated with exactly the same semen. The frozen semen used in groups 3 and 6 was obtained from different dogs and processed independently to evaluate not only the effect of the route of insemination but also the potential effect of the dog. The mean concentration of the fresh semen was 310 x 10(6) spermatozoa/ml, its motility was greater than 80 per cent and the percentage of normal live spermatozoa was 80 to 92 per cent. The mean spermatozoal concentration of the frozen semen was 200 x 10(6) spermatozoa/ml, its motility was greater than 60 per cent and the percentage of normal live spermatozoa was 80 per cent. In all the groups there were fewer than 15 per cent abnormal spermatozoa. The animals inseminated with fresh semen received significantly more spermatozoa than the others. The bitches were inseminated twice, three and five days after the estimated peak of luteinising hormone, with a total volume of 5 ml for the vaginal inseminations and 2 ml for the intrauterine inseminations. Sixty per cent of the bitches inseminated with frozen semen and 100 per cent of the bitches inseminated with fresh semen became pregnant, irrespective of the insemination technique used. PMID- 8677605 TI - Sensitivity of strains of Serpulina hyodysenteriae isolated in Hungary to chemotherapeutic drugs. AB - The sensitivity of 332 strains of Serpulina hyodysenteriae isolated in Hungary between 1978 and 1992 was tested against seven chemotherapeutic drugs frequently used for the treatment of swine dysentery, and the changes in the patterns of resistance were also monitored. All the strains remained sensitive to carbadox, with minimum inhibitory concentrations (MIC) of only 0.05 to 0.40 microgram/ml at present. The susceptibility of the strains to dimetridazole has gradually decreased, but about half of the strains are still sensitive, with large numbers of "moderately sensitive' strains; the MIC values varied within wide limits (0.1 to 50 micrograms/ml). Most of the strains were resistant to tylosin, with MIC values from 0.1 to 100 micrograms/ml. The number of strains resistant to lincomycin has gradually increased, but about half of the strains remain sensitive; the MIC values ranged from 0.2 to 100 micrograms/ml. Recently, tiamulin has proved the most effective antibiotic, but some resistant strains have already emerged (MIC values 0.05 to 50 micrograms/ml). Monensin was good for the prevention of swine dysentery, but resistance may evolve quickly; the MIC values ranged from 0.4 to 25 micrograms/ml. For sedecamycin, the MIC values (6.25 to 100 micrograms/ml) were much higher than expected. PMID- 8677606 TI - Absence of detectable infectivity in trachea of BSE-affected cattle. PMID- 8677608 TI - Obstipation following ovariohysterectomy in a cat. PMID- 8677607 TI - Encephalitis and mass mortality of farmed salmon smolts in an isolated sea bay in Ireland. PMID- 8677609 TI - Primary bronchiolo-alveolar adenocarcinoma in a bull. PMID- 8677610 TI - Classical transmissible gastroenteritis returns. PMID- 8677611 TI - Circovirus-like particles in the bursae of young racing pigeons. PMID- 8677612 TI - Rabies policy. PMID- 8677613 TI - Hyperammonaemia in Irish wolfhounds. PMID- 8677614 TI - NOAH and the Internet. PMID- 8677615 TI - Udder oedema in ewes. PMID- 8677616 TI - Veterinary treatment of reptiles. PMID- 8677617 TI - BSE in Great Britain: consistency of the neurohistopathological findings in two random annual samples of clinically suspect cases. AB - Two annual, random samples of clinically suspect cases of bovine spongiform encephalopathy (BSE) were taken in 1992-93 (year 1, 1500 cases) and 1993-94 (year 2, 1000 cases). From each sample, 100 positive cases were examined in detail to establish the severity of the vacuolation in 17 specific neuroanatomical locations. The resultant 'lesion profiles' were compared with the profile obtained from a similar sample of BSE-affected cattle from early in the epidemic (1987-89); the comparison showed that the distribution and severity of vacuolation in BSE has remained unchanged. The cases not confirmed as BSE on histological examination (172 in year 1 and 162 in year 2) were examined for evidence of any alternative neurohistological diagnosis. As in previous studies, the majority of these cases showed no significant lesions (61.6 and 61.7 per cent). The remainder consisted of bilateral focal spongiosis of unknown significance (26.7 and 21.0 per cent), inflammatory conditions (8.1 and 11.1 per cent) and a small number of cases with tumours, cerebrocortical necrosis or idiopathic brainstem neuronal chromatolysis. No evidence was found of any cases of BSE with an atypical distribution of lesions. These findings support the theory that the BSE epidemic is sustained by a single, stable strain of the BSE agent, and confirm that the existing statutory diagnostic criteria continue to be appropriate. PMID- 8677618 TI - A survey of the presence of a new infectious bronchitis virus designated 4/91 (793B). AB - On the basis of virus isolation and the demonstration of specific neutralising antibody in sera, infectious bronchitis virus (IBV) 4/91 (commonly called 793B) has been shown to be present in broiler, breeder and layer flocks of chickens in many parts of western Europe and also in Thailand and Mexico. These flocks had all been vaccinated against infectious bronchitis and the need for improved methods to control this new virus, still prevalent at least four years after it was first isolated, is discussed. PMID- 8677619 TI - Disposition of antimony after the administration of N-methylglucamine antimoniate to dogs. AB - A study was carried out in dogs to define the pharmacokinetic profile of antimony and to define a better therapeutic protocol for the treatment of canine leishmaniasis. Six healthy beagle dogs received 100 mg/kg of N-methylglucamine antimoniate containing 27.2 per cent of antimony intravenously, intramuscularly and subcutaneously. After intravenous administration the plasma concentration of antimony decreased rapidly and after 240 minutes it was lower than the ED50 values suggested for Leishmania donovani. The pharmacokinetic parameters and bioavailability of antimony were calculated after each route of administration in each dog. The curves of plasma concentrations vs time were best described by a triexponential open model with a mean (sd) half life t1/2 alpha of 9.4 (4.4) min, a t1/2 beta of 45.3 (4.5) min and a t1/2 gamma of 618.0 (93.5) min. The mean volume of distribution at steady state was 0.25 (0.03) litres/kg and the total body clearance was 0.25 (0.04) litres/h/kg. The peak plasma concentration (Cmax) after intramuscular administration was 27.2 (3.1) micrograms/ml, and after subcutaneous administration it was 25.5 (4.5) micrograms/ml; they were reached after 73.6 (11.9) min and 85.6 (11.3) min, respectively. The bioavailabilities after intramuscular and subcutaneous administration were 91.7 (7.1) and 92.2 (7.1) per cent, respectively. More than 80 per cent of the antimony was excreted in the urine in the first nine hours. PMID- 8677620 TI - Tissue culture-propagated orf virus vaccine protects lambs from orf virus challenge. AB - Twenty, eight-day-old specific pathogen-free (SPF) lambs were vaccinated by a single scarification approximately 4 cm in length on the inner right thigh with a double-pronged applicator. The titre of live virus in the vaccine was 10(7.2) TCID50/ml and the estimated dose per lamb was 0.04 ml. Three months and six months later 10 of the vaccinated lambs and five age-matched unvaccinated control specific pathogen free lambs were challenged by a single scarification with virulent virus on the inner left thigh in the same way. After the vaccination all 20 lambs developed lesions characteristic of orf virus infection that had largely resolved four weeks later, when they all had reciprocal ELISA antibody titres > or = 3200 that persisted in all but one of them until they were challenged. After the challenge, the development of lesions in the vaccinated and unvaccinated sheep was compared daily for four weeks by means of a clinical scoring system. Both groups of vaccinated lambs had significantly lower (P < 0.01) total clinical scores after challenge at three months and six months than the unvaccinated lambs. PMID- 8677621 TI - Peste des petits ruminants in goats in India. PMID- 8677622 TI - Prunus padus (bird cherry) poisoning in cattle. PMID- 8677623 TI - Wildlife rehabilitation. PMID- 8677624 TI - Wildlife rehabilitation. PMID- 8677626 TI - Bovine embryo transfer. PMID- 8677625 TI - Bovine embryo transfer. PMID- 8677627 TI - Exocrine pancreatic insufficiency. PMID- 8677628 TI - Illegal poisoning. PMID- 8677629 TI - Live animal exports. PMID- 8677630 TI - Society of Greyhound Veterinarians. PMID- 8677631 TI - Characterization of natural killer cytotoxic factor (NKCF) from canine NK cells. AB - We investigated the presence of canine natural killer cytotoxic factor (NKCF). Canine natural killer (NK) cell-mediated cytotoxicity measured by 51chromium (51Cr) release assay was found to be highest in the T-cell population, which was fractionated into the 35-40% Percoll fraction by discontinuous gradient centrifugation. The cytotoxicity of NKCF in the culture supernatant showed a similar tendency to NK activity. Release of NKCF was rapid after contact with target cells, and reached a plateau in 60 min. The cytotoxicity of NKCF could be detected within at least 15 min in coculture with CL-1 target cells, reaching a plateau in 60 min. We also characterized canine NKCF and found it to be a protein, which was stable against both heat and cold treatment. These findings suggest that canine NK cells release NKCF immediately after recognition and binding to the target cell, and that NKCF plays an important role in canine NK mediated cytotoxicity. PMID- 8677632 TI - Effect of porcine circovirus infection on porcine alveolar macrophage function. AB - The effect of porcine circovirus (PCV) infection of porcine alveolar macrophage cultures on some of the functional properties of these cells are reported. PCV infection of alveolar macrophages did not effect their ability to phagocytose and kill complement-coated yeast cells or the expression of Fc or complement receptors. A transient increase in major histocompatibility complex (MHC) class I expression in PCV-infected cells were observed 4 days after infection and a decrease in the number of cells expressing MHC class II antigens was observed 8 days after infection. Infection of alveolar macrophages with PCV also resulted in a transient decrease in their ability to act as accessory cells in mitogen induced lymphocyte proliferation of monocyte-depleted porcine peripheral blood mononuclear cells. PMID- 8677633 TI - Effect of dietary restriction on cell-mediated immune responses in cattle infected with Mycobacterium bovis. AB - Nine M. bovis-infected cattle on a diet deficient in both protein and energy for 133 days lost approximately 17% of their original body weight. However, dietary restriction did not result in any significant reduction in skin sensitivity to PPD, in vitro production of IFN-gamma or lymphocyte blastogenesis. The number of circulating BoCD4+ cells and B cells were similar in both the malnourished and the control cattle. However, significantly lower numbers (P < 0.01) of circulating BoCD2+ cells, BoCD8+ cells, WC1+ gamma delta T cells and ACT2+ cells were found in the malnourished cattle. With the exception of inorganic phosphate, the changes in plasma biochemical parameters were unremarkable. PMID- 8677634 TI - Enhanced proliferation of CD4+ T cells induced by dendritic cells following antigen uptake in the presence of specific antibody. AB - Afferent lymph dendritic cells bear an Fc gamma receptor which binds antigen/antibody complexes thereby enhancing uptake of antigen. In this report, we have addressed the question of whether the enhanced uptake of antigen results in augmented antigen presentation and T cell proliferation in in vitro secondary responses in sheep. Inclusion of affinity-purified IgG anti-ovalbumin antibody in cultures of afferent lymph dendritic cells, purified CD4+ T cells, and substimulating amounts of ovalbumin resulted in a five- to 169-fold enhancement of T cell proliferation. This effect was antigen-specific as replacement of the anti-ovalbumin antibody with an IgG anti-human serum albumin specific antibody did not cause enhanced T cell responses. The antigen-specific augmentation required intact antibody Fc portions as F(ab')2 fragments of the anti-ovalbumin antibodies were ineffective. The enhanced antigen presentation was found to be maximal with immune complexes in moderate antibody excess (three- to 30-fold), but still occurred at antibody/antigen ratios of 300. The augmented responses were inhibitable with anti-MHC Class II specific antibodies, indicating that at least some of the antigen taken in via Fc gamma receptors entered a Class II processing pathway. The results thus show that antigen uptake via Fc gamma receptors on dendritic cells results in functional augmentation of antigen presentation and T cell proliferation. PMID- 8677635 TI - Increased intestinal TNF-alpha, IL-1 beta and IL-6 expression in ovine paratuberculosis. AB - Mycobacterium avium subspecies paratuberculosis is an intracellular parasite of intestinal macrophages and causes a chronic granulomatous enteritis in sheep and other ruminants (paratuberculosis or Johne's disease). Macrophages can be produced a variety of immunoregulatory cytokines that may influence mycobacterial killing and produce disordered inflammation within the gut. In this study, messenger RNA (mRNA) was extracted from intestinal tissue from control and multibacillary diseased sheep and profiles for the cytokines tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), IL-6, transforming growth factor-beta1 (TGF-beta1) and granulocyte-macrophage colony stimulating factor (GM-CSF) were semi-quantified using reverse transcriptase polymerase chain reactions (RT-PCR). Infected intestinal tissues had significantly increased mRNA for TNF-alpha, IL-1beta and IL-6 but TGF-beta1 and GM-CSF mRNA levels were significantly different from controls. Supernatants from in vitro intestinal cultures were assayed for TNF-alpha activity using the PK(15)-1512 cytotoxicity bioassay and levels were significantly raised in diseased samples. TNF-alpha was not detected in any serum samples. Further analysis on intestinal tissues from sheep with the different, paucibacillary, form of the disease showed significant elevation of TNF-alpha mRNA but not other cytokines tested. Increased pro inflammatory cytokine expression in the intestine coincident with a failed or misdirected immune response may contribute to the pathogenesis of paratuberculosis and the persistence of a chronic inflammatory state. PMID- 8677636 TI - Changes in airway inflammatory cell populations in standardbred racehorses after interferon-alpha administration. AB - Natural human interferon-alpha (nHuIFN alpha) was administered to actively training Standardbred racehorses with inflammatory airway disease (IAD). Inflammatory airway disease was characterized by poor exercise performance and inflammation and exudate in the upper and lower airway. Placebo, 50, 150, or 450 units(U) of nHuIFN alpha was administered orally for 5 consecutive days to eight horses per treatment group in a double-blind, randomized block design. Response to nHuIFN alpha was monitored by semiquantitative endoscopic examination score and cytologic examination of bronchoalveolar lavage fluid (BALF) performed at baseline (Day 1), Day 8 and Day 15 after initiation of nHuIFN alpha administration. Neutrophil, macrophage, lymphocyte, and nucleated cell counts in BALF were lower (P < 0.05), compared with BALF cell counts in placebo-treated horses 8 days after administration of 50 U and 150 U nHuIFN alpha, and 15 days after administration of 50 U nHuIFN alpha. Neutrophil, lymphocyte and nucleated cell counts were lower than cell counts from placebo-treated horses, 8 days following administration of 450 U nHuIFN alpha. The proportion CD4-, CD5-, and CD8-positive lymphocytes in BALF was not affected by administration of nHuIFN alpha. Oral administration of low-dose nHuIFN alpha reduced inflammation of the lowest respiratory tract in Standardbred racehorses with IAD. PMID- 8677637 TI - Macrophage function in deer. AB - Macrophage inflammatory and immune functions were characterised in red deer (cervus elaphus), for use as a model for natural infection with bovine tuberculosis. Highly enriched populations of deer macrophages were obtained from 14 day cultures of plastic-adherent peripheral blood mononuclear cells. Cervine macrophages produced superoxide anion in response to respiratory burst stimuli (serum-opsonised zymosan and phorbol myristic acetate), but nitric oxide production could not be detected under the conditions tested. The lysosomal enzymes acid phosphatase and lysozyme were detected at the intercellular and extracellular level. Stimulation with bacterial lipopolysaccharide extract (Escherichia coli LPS) enhanced the production of superoxide and acid phosphatase with a peak increase in activity observed after 2h. Production of interleukin 1 (IL-1) and tumour necrosis factor (TNF), determined using cytokine-sensitive cell lines and mRNA analysis (Northern blotting), indicated maximal secretion of both cytokines after 24 h stimulation with LPS, preceded by a peak in message accumulation at 2-6 h post-stimulation. Cervine macrophages stimulated proliferative responses in T cell-enriched lymphocyte populations derived from the peripheral blood of autologous animals that had been primed to mycobacterial antigens (Mycobacterium bovis Bacille Calmette-Guerin, BCG). Macrophages were able to stimulate responses after pulsing with particulate (BCG) or soluble (purified protein derivative) mycobacterial antigens. These results indicate that macrophage inflammatory and immune responses in red deer are similar to those in other mammalian species, and that macrophages may play an important role in resistance to mycobacterial infection. PMID- 8677638 TI - Characterization of extrathymic T cells of chickens. AB - The function of CD4+ T cells in antibody production was examined by using T cell subset-depleted chickens. CD4- and CD8-depleted chickens, established by the combination of thymectomy and injection of T cell subset-specific monoclonal antibodies, were immunized with sheep red blood cells (SRBC). Titers of anti-SRBC antibody produced in CD4-depleted chickens were lower than those in control chickens, while no difference in the antibody production was observed between CD8 depleted and control chickens. In chickens depleted of both CD4+ and CD8+ T cells, the recovery of T cells in the periphery was demonstrated starting 3 weeks after T cell depletion. Those T cells recovered in the periphery predominantly expressed CD4 molecules. Although low titers of antibody against SRBC were detected in chickens depleted of both CD4+ and CD8+ T cells, an increase of anti SRBC antibody production was coincidentally observed with the recovery of CD4+ T cells in the periphery. These results suggest that CD4+ T cells could differentiate in extrathymic environments in chickens, and have a helper function in antibody production similar to that of intrathymic T cells. These extrathymic T cells, however, showed a lower proliferative response to concanavalin A than intrathymic T cells, suggesting that these extrathymic T cells may have some properties distinct from intrathymic T cells. PMID- 8677639 TI - [The problems and ways to improve therapeutic care in the Armed Forces]. PMID- 8677640 TI - [To do all for the recovery of the health of border guards. Interview by G. Piskunov]. PMID- 8677641 TI - [Modern gunshot trauma]. PMID- 8677642 TI - [Experience with the use of cerebrospinal anesthesia in a garrison hospital]. PMID- 8677643 TI - [Optimization of the etiological diagnosis and adequate antibacterial therapy in acute disseminated pneumonias]. AB - Analysing literature data and results of the own studies, the authors note, that etiological spectrum of the modern acute widespread pneumonias have modified essentially. The origin of the given pneumonias is determined today by the next pneumotropicous infections: Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella spp. In this connection prescribing of the modern generation of macrolides to the patients with pulmonary inflammation have been proved to be correct, because they are more effective against these infectious agents. PMID- 8677644 TI - [The efficacy of the synthetic prostaglandin Cytotec in preventing and treating symptomatic gastropathy]. PMID- 8677645 TI - [The use of Betadine in surgery]. PMID- 8677646 TI - [The characteristics of the work of epidemiological health institutions (subdivisions) under emergency situations]. PMID- 8677647 TI - [Current problems in the medical support for strategic-mission rocket troops]. PMID- 8677648 TI - [Acute viral hepatitides]. AB - The article describes the characteristics of the acute virus hepatitis A, B, C, D, E, F, G. The clinic aspects of the asymptomatic, cholestatic and fulminant forms of the disease have been examined. Have been reported in detail on diseases being a part of the group of atypical forms, about the preventive measures of the acute viral hepatic diseases. PMID- 8677649 TI - [Ecological approaches in assessing the health status of adolescents (2)]. PMID- 8677650 TI - [Current aspects of the noise problem in aviation medicine]. AB - The authors discuss the problem of improvement the noise factor prevention in aviation medicine. The analysis of the real acoustic load on aviation engineer specialists, performing maintenance of the modern military aircraft have been given. The authors show the importance of the approach to the aviation noise as an ecological significant factor, that means taking into account the acoustic load during work time as well as during rest-sleep periods. The authors suggested the advanced complex of the preventive measures for the purpose of optimization of the noise exposure on the aviation specialists. PMID- 8677651 TI - [100 years guarding the health of the border guards]. PMID- 8677652 TI - [The academic methodological and scientific work of the Department of Surgery of the Military Medical Faculty in the Russian Medical Academy of Postgraduate Education (on the 15th anniversary of the formation of the department)]. PMID- 8677653 TI - [The 15th anniversary of the Department of Therapy of the Military Medical Faculty in the Russian Medical Academy of Postgraduate Education]. PMID- 8677654 TI - [A prominent Soviet hygienist (on the centenary of the birth of F. G. Krotkov)]. PMID- 8677655 TI - [The organizational and methodological aspects of medical expertise work in the new Regulations on military medical expertise]. AB - In Regulations about military medical examination the medical essence of fitness categories for the military service in peace and wartime, which were determined by Russian Federation law, have been worked out. The Regulations determine the most important legal norms of organization and conducting of military medical examination. List of diseases--the main functional part of Regulations--contains 89 articles (in previous--116) and 4 columns, which envisage the requirements to health state of the different categories of citizens. The article' names in List of diseases and there sequence are been adapted at most to International Disease Classification. PMID- 8677656 TI - [100 years of roentgen rays. The contribution of Austrian scientists to discovery and applications]. AB - In January 1896 experiments were made around the world with cathode-tubes to test Rontgen's paper "a new kind of rays". Mostly hands without pathological variations were X-rayed. At the same time in Vienna the clinical applications of X-rays were investigated. Two patients were successfully operated on after X-ray examination. Remarkable for that time was an X-ray of an arteriogram of the arm of a dead person. It was made on 17th January 1896. The experiments with Lenard's cathode-tube were important for the discovery of X-rays. His experimentation was the inspiration for Rontgen's discovery of X-rays. PMID- 8677657 TI - [Evaluation of a new method for determining glycated hemoglobin with monoclonal antibodies (DCA 2000)]. AB - HPLC (High Performance Liquid Chromatography) is commonly regarded as the reference method for HbAlc measurements. However, HPLC requires a relatively large technical staff, expensive laboratory equipment and is rather time consuming. The mobile DCA 2000 instrument determines HbAlc in only 9 minutes, using only one microliter of capillary blood. It uses an immunoassay based on the inhibition of latex agglutination and a monoclonal antibody specific for the glycated N-terminal end of the beta-chain of haemoglobin. In order to determine the reliability of this new method for clinical practice we compared HbAlc measurements on DCA 2000 with HPLC values. A correlation analysis in 283 diabetic patients showed a highly significant correlation between the two methods (r = 0.96; p < 0.0001). In 215 samples (75.7%) the value measured by means of DCA 2000 was lower than the reference value (mean deviation: 0.6% HbAlc), in 58 samples (20.8%) it was higher (mean deviation: 0.39%). In 10 samples the values were identical. The maximum deviations were plus 1.6% and minus 1.3% HbAlc. DCA 2000 is easy to handle and gives rapid and reliable information on long-term metabolic control. Hence, it could be very useful for clinical practice and outpatient departments. PMID- 8677658 TI - [Decrease of thrombocyte volume after several days infusion of highly substituted medium molecular weight hydroxyethyl starch (HAES 200/0.62)]. AB - Dextrans are known to inhibit platelet aggregation. However, conflicting results have been reported with hydroxyethyl starch (HES), usually administered as a single dose. To clarify this, we studied the effects of HES on platelet number, aggregation and volume during the course of long-term hemodilution therapy. Twelve patients with disturbances of cerebrovascular perfusion were randomized and divided into two groups of 6 patients each. One group was treated with 10% HES 200/0.62, the other with 6% HES 200/0.62. The patients in group 1 received a loading dose of 500 ml, followed by 500 ml daily for 10 days. Group 2 patients were infused a loading dose of 500 ml, followed by 1000 ml on days 1 to 4 and 500 ml on days 5 to 10. 10% HES had a larger volume effect. The hematocrit was lowered by 19.0%, whereas 6% HES caused a decrease of only 15.6%. 10% HES lowered the platelet number significantly (p < 0.05) by 5.8%, 6% HES did not lower the platelet number significantly. Platelet volume decreased significantly during therapy (p < 0.05) in both groups. 10% HES reduced the platelet volume by 13.9%, the reduction with 6% HES was 9.0%. Under therapy with 10% HES, platelet aggregation declined slightly, but significantly (p < 0.05), whilst no effect was seen with 6% HES. During long-term hemodilution therapy with HES, the initial decrease in platelet number, which is due to dilution, is quickly compensated. The continuous decline in mean platelet volume during therapy is probably due to colloid-osmotic shrinkage. Since there is a positive correlation between platelet size and function, the slight inhibition of platelet aggregation caused by 10% HES is possibly due to the observed decline in platelet volume. PMID- 8677660 TI - [Intraventricular morphine administration as a treatment possibility for patients with intractable pain]. AB - The treatment of intractable pain, especially in cancer patients, often sets problems to patient and therapist. While epidural and intrathecal spinal administration of opiates is a routine treatment in pain with a sub-diaphragmatic topography it is almost ineffective in cervicocephalic or thoracic cancer. An alternative here is the administration of morphine into the lateral or third ventricle by a catheter-reservoir system. We report on our experience in the treatment of twenty patients, mostly suffering from cancer (18 cases), from 1990 to 1993. It is shown to be an effective, non-destructive method with minimal side effects in the treatment of nociceptive pain. Analgesia takes effect within a few minutes and the necessary doses are low. Our results agree with those of other authors describing good to excellent results in 95% of patients with somatogenic pain. However, no or only minimal effect is achieved in the treatment of neurogenic pain by intracerebroventricular morphine therapy. PMID- 8677659 TI - [Mucormycosis--a rare complication in patients with diabetes mellitus]. AB - Mucormycosis usually occurs in immunocompromised patients or in patients with diabetes mellitus. Pathogens are moulds of the mucorales species. The diagnosis is made by histological examination of biopsies. A 39 year-old patient with insulin-dependent diabetes mellitus was admitted with a tentative diagnosis of a tumour of the maxilla. After diagnosis of hyphae of the mucorales species, the patient's diabetes was stabilised and he was treated over 17 weeks with amphotericin B (40 mg per day) and made a good recovery. A 58 year-old insulin dependent patient with ethmoidali and sphenoidali sinusitis did not respond to antibiotic therapy. Mucormycosis was diagnosed by means of biopsy. Although treatment with amphotericin B was started, the patient died after 3 weeks due to multiple organ failure. PMID- 8677661 TI - Intensive care management of acute pancreatitis: recognition of patients at high risk of developing severe or fatal complications. AB - The clinical spectrum of acute pancreatitis ranges from mild, self-limiting disease of fulminant illness that may rapidly lead to multiple organ failure and death. To identify factors associated with a subsequent severe course and/or high mortality we investigated retrospectively 91 patients admitted to the medical intensive care unit (ICU) with acute pancreatitis during a 2 year period. 67% of the attacks were mild (< or = 1 complication). The overall mortality rate was 9%, whereby 3% of patients with alcoholic and 13% with biliary pancreatitis died. 75% of the patients in the group with a fatal outcome were aged over sixty and 30% in the group with a mild course (p < 0.05). Females with pancreatitis of biliary origin had a mild course in 57% and a severe (> or = 2 complications) or fatal outcome in 43%. In males with alcohol abuse we observed a mild form of pancreatitis in 79% and a severe or fatal course in 21%. The delay between onset of abdominal pain and commencement of treatment in hospital was greater than 12 hours in 70% of all patients studied and there was no association with severity and development of subsequent complications. The median of the acute physiology and chronic health evaluation scoring system (APACHE-III) on the day of admission was 19 in patients with mild disease, which was significantly lower than in patients with severe (40) or fatal acute pancreatitis (53) (p < 0.0001). Serial APACHE-III measurements over 5 days after admission provided further differentiation between mild and severe or fatal cases (p < 0.0001), but no significant difference was observed between survivors with severe course and fatal outcome. In addition, RANSON scores were calculated for comparison with APACHE-III at admission and after 48 hours: concerning the recognition between mild and severe/fatal pancreatitis both scoring systems exhibited similar significant differences on day 1 and day 2. The RANSON scoring system provided further a significant differentiation between survivors with a severe course of pancreatitis when compared to deaths on day 2, whereas the APACHE-III scoring system did not. Advanced age, female sex, biliary obstruction and elevated RANSON and APACHE-III scores are risk factors for an increased rate of life-threatening complications in acute pancreatitis. The daily assessment of such scoring systems may allow the recognition of such patients and may be helpful in the routine clinical management and monitoring of acute pancreatitis. PMID- 8677662 TI - [Dilatation treatment of achalasia as initial therapy. Results of a prospective study]. AB - From 1972 to 1991 primary dilatation therapy was investigated in a prospective study in 77 patients suffering from achalasia of the gastroesophageal sphincter. The patients were followed up continuously and the median follow-up period was ten years. 70% of patients were symptom-free after dilatation therapy at the time of the last follow-up examination, whereby 50% were cured of symptoms after a single dilatation. 27% required surgery after unsuccessful dilatation therapy. The probability of avoiding operation after dilatation therapy within 15 years of diagnosis of achalasia was 73%. The clinical symptomatology at diagnosis graded according to a scheme from I to IV, was significantly worse in patients requiring an operation (Wilcoxon test, p < 0.0005). The data of esophageal manometry were of no prognostic relevance. PMID- 8677663 TI - [Local vascular complications after iatrogenic femoral artery puncture]. AB - Over a period of 5 years 81 vascular complications after 15,460 catheterizations of the femoral artery for diagnostic (n = 11,883) or therapeutic (n = 3577) procedures were registered. The following complications were observed in declining frequency: 1. False aneurysm (n = 65), 2. arterial occlusion (dissection, embolia, thrombosis) (n = 8), 3. vascular lesion causing profuse bleeding (n = 7), 4. AV-fistula (n = 1). The total complication rate was 0.52%. The complication rate was significantly higher in therapeutical procedures (1,03%) than in diagnostic investigations (0.37%). Pseudoaneurysms were complicated by thrombosis of the femoral vein (n = 3), lymphatic fistula (n = 3) and deep wound infection (n = 9); secondary complication rate 18.5%. Risk factors for local vascular complications are old age, female gender, high grade arteriosclerosis at the puncture site, overweight, manifest arterial hypertension and medication with cumarin, acetylsalicylic acid or heparin. Further complicating factors are connected with technical risks such as duration of the procedure. French size of the catheter, the catheter sheath and multiple punctures. Vascular repair was performed by simple angiography in most cases, but in 14.8% more extensive surgical procedures were required. In patients with signs of occlusive vascular disease the external iliac artery was replaced by a PTFE vascular access graft in 4 cases and an arterioplasty of the deep femoral artery was performed in 2 patients. 36% of the operations were undertaken as emergencies. Reintervention was necessary for a postoperative bleeding complication in 1 case (surgical complication rate 1.2%). A female patient suffering from aortic valve stenosis died during emergency operation due to massive retroperitoneal hemorrhage after cardiac catheterization (mortality rate 1.2%). Over a median follow-up period of 37 months no late complications of the intervention were recorded, nor recurrences of peripheral arterial occlusive disease. PMID- 8677664 TI - [Catheter ablation of accessory atrioventricular conduction pathways in all locations--consecutive results of a new curative therapy of paroxysmal supraventricular tachycardia]. AB - Accessory atrioventricular pathways are a frequent cause of paroxysmal supraventricular tachycardias. This study analyses our results with a recently developed therapeutic approach-radiofrequency (RF) catheter ablation. This was applied in 150 consecutive patients (97 men, 53 women, mean age 42 +/- 15 years) with a total of 159 accessory pathways in all locations. All but 4 patients were symptomatic, with a spectrum ranging from palpitations (146 patients), syncope (39 patients) to aborted sudden death (2 patients). Prior to ablation, 115 patients had received long-term treatment with up to 4 antiarrhythmic drugs unsuccessfully. The mean number of applied current pulses was 12 +/- 14, and the mean cumulative procedure duration was 256 +/- 243 minutes, with a cumulative fluoroscopy time of 49 +/- 72 minutes. Patients with left-sided pathways were approached via the retrograde aortic approach in 88/90 cases. One-hundred fifteen patients were treated in a single session, repeat sessions were required in the remaining 35 patients. The predominant sites of interruption of right-sided and left-sided accessory pathways were their atrial and ventricular insertion, respectively. Long-term cure was achieved in 141 patients (94%), non-life threatening complications were observed in 3 patients (2%). These results compare well with published studies on large patient collectives and demonstrate that RF catheter ablation, which is highly cost effective, is the therapy of choice to cure symptomatic patients with accessory atrioventricular pathways in all locations. PMID- 8677665 TI - [Acute pulmonary histoplasmosis with liver and lung involvement outside the endemic area--differential diagnosis]. AB - A case of acute pulmonary histoplasmosis in a non-endemic setting is described. A 36 year-old male patient was admitted because of fever attacks, weakness and dyspnea on exertion. The chest X-ray revealed bilateral patchy and nodular consolidations and bilateral enlargement of the hilar lymph nodes. On computed tomography of the abdomen the spleen was enlarged with a longitudinal diameter of 12.7 cm. Respiratory insufficiency was demonstrated by an arterial oxygen tension (PaO2) of 7.71 kPa at rest. Pathological values of liver function tests were indicative of liver involvement. A transbronchial lung biopsy was performed. Histologic examination of the biopsy specimen revealed scattered small nonnecrotizing granulomas with epithelioid cells and multinucleated giant cells. Precipitating antibodies to Histoplasma capsulatum were detected by immunodiffusion in bronchoalveolar lavage fluid and blood, IgG antibodies to Histoplasma capsulatum yeast antigens were revealed by enzyme immunoassay. The histoplasmin skin test was negative. The pneumonitis, lymph node and spleen enlargement and the pathological liver function tests resolved within one month without treatment. The PaO2 returned to normal within one week. PMID- 8677666 TI - [Can the two "cultural phenomena" information and creativeness be integrated? A comment on the newly published book "Information and creation: integrating the 'two cultures'" German A. Golitsyn, Vladimir M. Petrow.--Basel, Boston; Birkhauser, Berlin 1995]. PMID- 8677667 TI - [Symptoms, diagnosis and therapy of post-traumatic stress disorder]. AB - More and more studies have been carried out on Posttraumatic Stress Disorder (PTSD) in recent years which deal with classification, epidemiology, etiology and therapy. The problems in classifying PTSD result from the differences in the duration and in the subjective assessment of the disorder. Empirical research on psychotherapeutic intervention is still scarce. The article reviews and compares the therapeutic approaches described in the literature. In view of their theoretical foundation and the results of empirical research, interventions based on behavioral therapy have the strongest chance of being effective. PMID- 8677668 TI - [Depressive symptoms and syndromes in adolescents]. AB - The present study examined the frequency of self-reported depressive symptoms in high school students aged 11 to 19 years using the Revised Ontario Child Health Study Scales. A high percentage of subjects occasionally experienced some types of depressive symptoms in the last six months. Three levels of diagnostic certainty were generated by varying the severity of depressive symptoms. The frequency of depression for the 'low diagnostic certainty' was 51.6%, the "medium diagnostic certainty' 5.6%, and for the 'high diagnostic certainty' 0%. Depressive symptoms correlated significantly with doctor's visit and life events. The implication of the results for clinical practice and research was discussed. PMID- 8677669 TI - [Subjective perception of social support in the population]. AB - The ISEL scale (Interpersonal Support Evaluation List) has been developed to assess social support. Despite good reliability and validity of the original scale the German version has been rately applied. Thus, perceived social support as measured by the ISEL scale was studied in a general population sample of Tyrol/Austria (n = 216). The reliability of the German ISEL version is as high as the original version. Our results showed that sociodemographic variables significantly influence scale scores: Males and rural subjects indicated more tangible support than females and urban subjects, respectively. Elder people (50 70 years) reported the lowest scale scores, except in tangible support. With the exception of tangible support, significant socioeconomic status differences were found in all dimensions of social support. However, the middle classes showed less social support than upper and lower class subjects. Income only increased tangible support, as higher educational degrees did with self-esteem support. Marital status showed no influence on scale scores, whereas unemployment decreased tangible and belonging support. Our results can be used as preliminary German language norm data for evaluating social support in epidemiological and clinical studies. PMID- 8677670 TI - [Dyssocial identity disorder (double identity) in psychopathology and poetry]. AB - Identity dissociation signifies: there seem to exist two identities in one personality that take turns-apparently without knowing about each other. Descriptions of this rare state are often spectacular. As scientifically proven they depend on culturally specific conditions and iatrogeneous influences. The disorder is to be analysed in this article for the case of both psychiatry and every-day-life-experiences in a matter-of-fact way. The first description of the phenomenon is not found in psychiatric literature but in poetry. The novellas of E.T.A. Hoffmann contain at least eight descriptions of 'double life'. The 'Fraulein von Scuderi' (1820) seems to be the most interesting of these and is therefore focused on in this article. E.T.A. Hoffmann himself was at the same time well respected jurist and significant artist of great versatility: poet as well as musician, composer, painter. Hoffmann's artistic and his civic life stood in sharp contrast, which gives reason to use of the term 'double life'. PMID- 8677671 TI - [Individual therapy goals: on outcome documentation of inpatient psychotherapy from the patient and therapist viewpoint]. AB - The results of a study evaluation in practicability of two newly developed documentation forms are presented. Examined are 82 inpatient treatment episodes in an already published clinical concept with different treatment settings. Parallel versions of the forms were completed by patients and therapists. The 'Erge-Doku-A-Form' allows for the naming of up to five therapy goals determined at the beginning of therapy and evaluated in relation to their achieved quality at the end of therapy. The 'Erge-Doku-B-Form' describes a variety of problem areas as well as questions related to medication and changes induced by therapy. Surprising there were a high number of 230 Individual Therapy Goals (ITG) by patients and 262 ITG by therapists which could be arranged into 89 content categories and 5 main categories. Outcome measurement shows different results. There was a significant relationship between the 'well-being', the impression of 'satisfying treatment' at the end of the inpatient period and 'success in the main ITG'. The documentation forms presented here allow an outcome-measurement depending on differential indications. PMID- 8677672 TI - [Mental health--personality--existentialism. An empirical contribution from the existential analytic viewpoint]. AB - For the purposes of a survey of the correlation between psychic health-personhood existentiality 211 predominantly higher qualified and in elevated professional positions working adults at the age of 18 to 70 years (43,6% male, 56,4% female) were examined with the Trierer-Personlichkeitsfragebogen (TPF-Becker, 1989) and the Existenz-Skala (Langle & Orgler, 1991). The results show, that existentiality was found to be a correlative for psychic health to a medium extent in several subscales of the TPF; personhood correlates with psychic health only in the dimension self-transcendence, but not in the dimension self-distance. PMID- 8677673 TI - [Psychosomatic medicine between explanation and understanding]. AB - Explanatory and hermeneutic concepts in psychosomatic medicine are frequently discussed in a controversial manner. Inherent in an explanatory concept is a patient ideally visualized as a separated object, hereby trying to imitate principles in physics, which have dominated this discipline during the 19th century. However with the development of the quantum theory it became obvious that the observer cannot be separated from the object of his observation. The limitation of historical causation became clear and circular relationships at different levels for instance at the cellular level or at the sociological level were taken into account. The human being seen as an open system with selforganizing potentiality can now be described with semiotic terms at all the different organizational levels. Th.v. Uexkull has described this in his 'Situationskreis'-model. A case presentation is given to illustrate these more theoretical remarks. PMID- 8677674 TI - [The chemical structure of the peripheral autonomic (visceral) reflex]. AB - The article reviews the information available at present on the chemical mediators transmitting excitation in each link of the autonomous reflex are: sensory, inserted and effector. It describes the modern views on the functional structure of these links. On the basis of microelectrode analysis, histochemistry and, in particular, of immunochemistry, detailed analysis is provided of the new concepts of the mediators of the interneuronal and autonomous neuroeffector transmission by classical transmitters, and by the peptide component including P substance, calcitonin-gene-related peptide, VIP, DIN, ANK, etc. Neuropeptide get the key role information of the functional specificity of neurons. Peptides may be secreted and stored together with various neuromediators in presynaptic structures of various links of the reflex are. Special attention is given to the para-, prevertebral and intramural ganglia, which are interpreted as the lowest centres of autonomous periphery having significant integrative abilities. The immunohistochemical studies are reliably indicating that the main ganglionic neurons, the same as the nerve fibres entering the nodes are chemically coded in relation to contents of the transmitting molecules. PMID- 8677675 TI - [The plasticity of systemic brain mechanisms]. AB - Mechanisms of plasticity of the main components (dominant motivation and reinforcement) of systemic behavioural act organisation are considered. It is shown that dominant motivation changes different properties of brain neurones including their specific sensitivity to neuromediators and neuropeptides. Reinforcement in its turn modifies the properties of brain neurones which take part in dominant motivation. The foregoing reinforcement influences the modification of genetic apparatus of neurones involved in dominant motivation and, as a consequence, they begin to express specific information molecules under the influence of dominant motivation in the subsequent formation of the corresponding drive. The information molecules organise a corresponding behaviour. Plasticity properties of brain neurones are mostly revealed in conflict situations leading to emotional stress. Reorganisation of chemical integration of limbic-reticular neurones takes place under emotional stress. Oligopeptides play the leading role in these processes. It is shown that oligopeptides are able to compensate the functions of damaged limbic-reticular brain structures. PMID- 8677676 TI - [The participation of the respiration in the rhythmic interactions in the body]. AB - The review of the modern notions about the rhythmic interaction of the respiration, cardiovascular system and CNS is produced in this article. The own data of the authors dedicated to individual, sex and age manifestations of this interaction during the voluntary control of respiration are used. The possible mechanisms of the connection of respiratory rhythms with rhythmic processes of cardiovascular system and CNS are discussed. PMID- 8677677 TI - [The role of mediator-metabolic factors in the development of brain edema swelling]. AB - In modern conception on the mechanisms of a brain edema-swelling formation and a role of various tissue factors in these processes are examined in the issue. Particular attention is paid to analysis of nervous mediator and metabolic changes with a brain edema-swelling. Conceptional models of this reaction development are also presented. PMID- 8677679 TI - [Laparoscopic surgery 1996]. PMID- 8677678 TI - [Food-acquisition and avoidance behaviors: the role of immunomodulators in their systemic organization]. AB - The experimental data concerning some aspects of neuroimmunology were analysed. The problems of likeness between immune and nervous systems (origin, functions, common substances, etc.) and particularly the participation of immunomodulators in the mechanisms of neural memory are under discussion. It was shown that administration of immunomodulator neurotropin (NSP) results in more steady consolidation and retention of feeding and avoidance behavior, and some neurophysiological mechanisms of that phenomena were revealed. Among them were the reorganization of neuronal interspike patterns in cortex and hippocampus; increasing the levels of vegetative (heart rate, respiration) and behavior parameters of learning during conditioning. Whole this complex of changes was retrieved during intersignal periods. The results suggest that one of the mechanisms of immunomodulators action on the learning and memory is the activation of reverberation processes in brain. PMID- 8677680 TI - [Biomechanical heart and cardiovascular support]. AB - A surgical association between skeletal muscle and heart muscle dates back to experiments at the beginning of this century. Initially, the use of skeletal muscles aimed at plastic reconstructions of myocardial defects and enhancement of myocardial blood flow. The application of the contractile force of the skeletal muscle failed because of skeletal muscle fatigue. In the late sixties, investigations in muscle physiology demonstrated the "functional plasticity" of muscle tissue: Chronic electrical stimulation induces a transformational process of the cellular organelles, the metabolism, the fiber proteins and the calcium regulatory systems which results in "fatigue resistance" of the muscle. This was is a prerequisite for the application of skeletal muscles for continuous support of the circulation. Biomechanical support of the heart and the circulation is experimentally performed as skeletal muscle ventricles, chronic extraaortic counterpulsation and ventricular and atrial cardiomyoplasty. The electrical stimulation is performed with "burst" impulses, in order to increase the force and the length of contraction. The first clinical application of ventricular cardiomyoplasty is attributed to the French surgeon Alain Carpentier. Clinical investigations show that cardiomyoplasty results in an impressive symptomatic improvement of the patients clinical condition with only moderate changes of objective hemodynamic parameters. Further research will investigate the clinical applicability of the other, thus far only experimental techniques of biomechanical support. The introduction of cardiomyoplasty has induced great scientific interest in all forms of skeletal muscle circulatory support. Close collaboration between basic researchers and clinical investigators is of utmost importance for further developments in this field. The combined international research effort can be expected to yield considerable progress within the forthcoming years. PMID- 8677681 TI - [Laparoscopic therapy of choledocholithiasis]. AB - The introduction of laparoscopic cholecystectomy has led to controversial discussions about the proceeding in case of coincident common bile duct stones. In our unit choledocholithiasis has been treated laparoscopically since November 1991. Basic requirement has been a routine intraoperative cholangiography. 67 patients with common bile duct stones were treated until January 1995. All patients underwent a follow up and the results were compared to other concepts. In 40 cases common bile duct stones were eliminated via cystic duct and in 27 cases by choledochotomy. The choledochus was drained routinely for postoperative x-ray control. In 9 cases we found residual concrements: 7 patients required postoperative endoscopic papillotomy and in 2 cases the calculi where eliminated with a dormia basket introduced via drainage tube. In one case surgical management was changed to laparotomy. Postoperative complications occurred in 8 cases. One patient suffering from bacterial peritonitis underwent laparotomy on the 9th postoperative day; one with bleeding from the cystic artery was treated by relaparoscopy. One patient developed a liver abscess and two patients a bilioma requiring ultrasound guided drainage. A superficial wound infection in one patient and a biliary leakage after removal of the drainage in two patients healed spontaneously. Due to an intact papilla with less stress to the patient, as well as a complication rate comparable with other published therapeutic concepts, this strategy can be recommended as a valuable alternative procedure. PMID- 8677682 TI - [Therapy splitting: are intra-operative cholangiography and surgical bile duct revision still indicated?]. AB - The role of therapeutic splitting in cases of cholecystolithiasis and choledocholithiasis has to be reviewed since laparoscopic bile duct exploration might be an alternative. To assess the need of the new approach we evaluated our results of the therapeutic splitting. Between 1988-1992 a cholecystectomy was performed in 577 cases either as an open (n = 274) or laparoscopic (n = 277) procedure. Pre- or postoperative endoscopic retrograde cholangiopancreatography (ERC/P) was performed if the clinical presentation, laboratory findings or ultrasound showed signs of choledocholithiasis. In the laparoscopic cases no intraoperative cholangiography was carried out. The patient follow-up was evaluated by a questionnaire. 128 patients were suggested to have a common bile duct (CBD) stone and had a preoperative ERC/P. In 68 cases stones were extracted. After cholecystectomy 19 ERC/P's were performed. In 4 patients residual stones after preoperative ERC/P were detected. So far occult stones were found in 5 cases. Intraoperative cholangiography was performed additionally in the patients with open cholecystectomy n = 207?, of whom two demonstrated choledocholithiasis. Endoscopic clearance of the common bile duct was achieved in all patients. Minor complications occurred after ERC/P in 1.5%. Within a median follow-up time of 48 months patients with endoscopic papillotomy did not develop further CBD stones or a cholangitis. The therapeutical splitting facilitates in all patients with cholecysto- or choledocholithiasis a successful clearance of the CBD. Intraoperative cholangiography is not necessary according to our experience. With an experienced endoscopic team the therapeutic splitting should be the preferred treatment modality compared to the laparoscopic bile duct exploration, which will probably lead to a high complication rate if performed outside specialized centers. PMID- 8677684 TI - [Differential concept on use of laparoscopic anti-reflux operations]. AB - The introduction of laparoscopic technique in antireflux surgery has created hope for an improvement in patient outcome. Initial experience with minimally invasive procedures show that the application in antireflux surgery depends more on a differentiated indication for operation and an operative procedure designed to remove or compensate the underlying pathophysiologic functional defect. The method of access is of lesser priority. The promising results of this series may encourage continuation of the demonstrated protocol and operative technique. PMID- 8677683 TI - [Surgical correction of bile duct injuries after laparoscopic cholecystectomy]. AB - The rate of iatrogenic bile duct lesions has raised up to 3.5% after the introduction of laparoscopic cholecystectomy. Lesions that can not be managed endoscopically require surgical intervention. In this study 12 patients that presented with iatrogenic bile duct lesions following laparoscopic cholecystectomy and underwent reconstructive surgery at our institution are included. In nine patients a hepaticojejunostomy was performed, whereas two patients underwent end-to-end anastomosis. In one patient the lesion was oversewn. There were no complications postoperatively. After a median follow-up of 24,5 months (SD +/- 8 months) all patients are without symptoms. However, in two patients a postoperative endoscopic stenting for 4 months was necessary for bouginage. Reconstructive surgery, mainly hepaticojejunostomy in bile duct lesions is a safe and efficacious treatment of endoscopic treatment failure. PMID- 8677685 TI - [Laparoscopic cardiomyotomy in achalasia]. AB - Surgical therapy of choice for achalasia is cardiomyotomy. Alternative procedure is the endoscopic pneumatic dilatation. Compared with the conventional operation, the laparoscopic approach promised to have advantages concerning postoperative convalescence. Between May 94 and October 95 four patients with achalasia underwent a laparoscopic cardiomyotomy. In all patients endoscopic therapy was tried. With the minimal invasive approach a myotomy of the esophagus was only shortly extended on the stomach. All patients had an endoscopic control of extension of the myotomy and intact mucosa during the operation. An antireflux procedure was not performed. Operation time came to 60 to 130 minutes. All patients immediately could swallow without problems and were discharged between day 2 and 8 postoperatively. During the follow-up (up to 18 months) all patients were free of dysphagia and regurgitation. The dynamic x-ray of the esophagus showed a free passage into the stomach. Only one patient claimed mild symptoms of reflux. Cardiomyotomy can very well be performed laparoscopically, leads to good functional results and shows the expected advantages for patients concerning postoperative convalescence. The need for an antireflux procedure is discussed controversially in the literature. It might be unnecessary if the myotomy is only shortly extended to the stomach. PMID- 8677686 TI - [Laparoscopic repair of ventral abdominal wall hernias]. AB - The surgical treatment of incisional hernias is still an unsolved problem despite of a considerable number of conventional methods. Nearly all methods induce some tension on the fascial skeleton resulting in a high recurrence rate. The damaged fascial skeleton can be bridged and reinforced by laparoscopic technique. The implantation of alloplastic well-tolerated meshes fulfills the principles of hernia surgery: fascial stabilisation and integrity of the muscle wall. PMID- 8677687 TI - [Laparoscopic hernioplasty (TAPP)--complications and recurrences in 900 operations]. AB - A prospective study of 900 patients with inguinal hernia who underwent transabdominal preperitoneal laparoscopic hernia repair (TAPP) was performed. The median operation time was 50 minutes (range 20-155); overall 44 complications (4.8%) were recorded. 8 patients (0.9%) required reoperation, in 6 cases because of postoperative bleeding or haematoma formation respectively, in one case because of testicular tenderness and in one case because of a mesh infection. Now, with the maximum follow-up of 26 months, 12 recurrences have been noted, giving a 1.33% recurrence rate. Return to work was 21 days (range 4-47 days). One year postoperatively about 83% of patients were without any complaints. A strict correlation between the complication and recurrence rate and the learning curve was found. It is concluded, that laparoscopic hernia repair (TAPP) is a safe and effective procedure. Complications and hernia recurrences diminish with experience. PMID- 8677688 TI - [Laparoscopic abdomino-perineal rectum excision]. AB - In the department of surgery at the Medical University of Luebeck 10 laparoscopic abdomino-perineal rectum resections were performed within 2 years. Using 3-4 working trocars the intraabdominal dissection of the rectum and sigmoid colon, complete lymphadenectomy with radicular dissection of the inferior mesenteric artery and vein, and dissection of the mesocolon and colon were accomplished. Following a conventional perineal excision the specimen was delivered through the perineal wound. The procedure is finished by establishing a conventional colostomy using the upper left trocar incision. The operation times ranged from 4 to 7.5 hours. The patients--51 to 82 years old--left hospital within 2 weeks after operation. 18 months after operation all patients operated with curative intention were still alive and tumor free except one patient, who died after a heart attack without any recurrent tumor. Two smaller, local stoma complications and one venous bleeding occurred postoperatively. There was no conversion to open surgery caused by intraoperative complications. The abdomino-perineal resection seems to be an ideal indication for laparoscopic surgery, because of its completely intraabdominal preparation, the excellent laparoscopic view into the small pelvis, the oncologic lymphadenectomy and the unproblematic delivery of the specimen. PMID- 8677689 TI - [Torsion of the gallbladder--a rare cause of acute cholecystitis]. AB - Torsion of the gallbladder with onset of gangrene is a rare condition which is generally due to an abnormal anatomical variation: loss of the fixation of the organ to the inferior margin of the liver with the presence of a long mesocyst. This case shows that ultrasound is able to make the right diagnosis which was so often confirmed not before laparotomy. In the future lethality should be reduced by early operation. PMID- 8677690 TI - [Minor abdominal trauma by laparoscopic surgery? Comparison of adhesion formation and intestinal motility after laparoscopic and conventional operations in the dog]. AB - Early postoperative intestinal motility after conventional and laparoscopic cholecystectomy was registered in dogs (n = 10) by implanted serosal electrodes to compare the abdominal trauma. In addition postoperative adhesions after laparoscopic and conventional resection of the cecum were measured in dogs (n = 14). A significantly shortened postoperative atony occurred after laparoscopic cholecystectomy compared with the conventional operations. Laparoscopic operations caused significantly less adhesions. After conventional operations extensive adhesions to the abdominal wall and interenteric adhesions were found. The shortened postoperative atony and the reduced adhesions document the minor abdominal trauma of laparoscopic surgery. PMID- 8677691 TI - [On the 50th anniversary of the death of Erwin Payr (1871-1946)]. AB - Erwin Payr was a man with a profound knowledge and extraordinary surgical skill, a brilliant teacher and a very loyal personality. By these attributes he became one of the most famous surgeons of this century. During his whole life he admired his academic teacher Nicoladoni who promoted him in any way. Owing to his powerful scientific activity, particularly in experimental research, Payr became soon a known scientist among his surgical colleagues all over the world. His great desire to become Professor of surgery was realized with the appointments to the chair of the Greifswald university and 3 years later of the Konigsberg university. Payr's special personality became apparent with the chairmanship of the large department of surgery of the Leipzig university. During more than 25 years he took care of innumerable patients and educated many disciples who became later famous academic teachers by themselves. His scientific publications represented a special achievement. As head of an important and worldwide accepted surgical school, Erwin Payr has given his profound experiences to the following generations. PMID- 8677692 TI - [Report on the 83rd annual meeting of the Society of Middle Rhine Surgeons 28-30 September 1995 in Mainz]. PMID- 8677693 TI - [Therapy of morbid obesity--is the surgeon consulted?]. AB - The surgical treatment of morbid obesity overlooks now more than 25 years beginning with the jejunocolostomy reaching to the vertical banded gastroplasty in any of the various modifications. Despite effective weight loss there are some dangerous complications, even in the long-term run. Though the surgical therapy of extreme obesity should be carried out restrictively and only in the correct indication according to the rules of the bariatric society or the National Consensus Conference. PMID- 8677694 TI - [Regulation of food intake]. AB - Food intake results in distention of the stomach with subsequent activation of afferent vagal fibers via gastric stretch receptors. The afferent vagal fibers transmit the information about the volume of a meal to the regulatory center in the hypothalamus. Apart from this neurally mediated pathway there is most likely a hormonally mediated regulatory loop which is activated by the chemical constituents of a meal. Neural and hormonal factors activate inhibitory neurotransmitters in the hypothalamus which signal termination of food intake. The exact nature of the peripherally activated hormonal signal and the interaction between the various stimulatory and inhibitory hypothalamic neurotransmitters are as yet largely unknown. PMID- 8677695 TI - [Conservative therapy of obesity]. AB - The essentials of conservative treatment of obesity are supervision by a physician, psychological advice, nutritional information and physical activity. A very successful therapy of massively obese is induced by modified fasting. Drugs should be used only as an adjunct to the diet and should be prescribed only for a limited time period. PMID- 8677696 TI - [10 years experience with vertical banded gastroplasty for operative therapy of morbid obesity]. AB - Since 1985 vertical banded gastroplasty has been performed in a consecutive series of 300 morbid obese patients. Two years after operation the average weight loss was 46 kg or 67% of the initial overweight. There was one postoperative and one late death. The reintervention rate was 2% per year for the first 5 years. In the treatment of morbid obesity vertical banded gastroplasty is an effective procedure, rapid and simple to perform and without irreversible changes of the digestive tract. PMID- 8677697 TI - [Initial outcome of vertical gastroplasty in treatment of morbid obesity]. AB - The VBG enables a significant weight loss from an initial weight of 138.9 kg (mean value, n = 387) to 87.3 kg after 36 months. BMI is reduced from 48.9 to 30.8 kg/m2. Even the pathological metabolic disorders are improved like the rate of metabolic syndrome (8.4% to 2.2%). The postoperative complication rate is low with a letality of 0.26% or a thrombosis rate of 1,03%. The relative high rate of patients with ineffective weight loss (30-40%) should not lead to the consequence to stop the procedure, but to improve the pre-operative screening. PMID- 8677698 TI - [Results of revision and new operation in arteriovenous shunt complications]. AB - Over a 10 years period 260 arterio-venous fistulas have been performed and followed up. The Brescia-Ciminoshunt was the most frequent type (n = 174). This type of fistula has been performed in about 85.2% of all cases as primary operation method. In secondary formations the saphena-interposition was used most frequently (49.4% of all cases). A shunt revision should be performed in cases of immediate thrombosis although a shorter life time of revisioned shunts compared with new formations is known. The new formation of a shunt should be considered if terminal thrombotic changes have been detected as well as in cases of shunt infection or shunt insufficiency. PMID- 8677699 TI - [Reconstruction of isolated lower leg arteriovenous occlusions in the critical foot ischemia stage--assessment of current status]. AB - Between May 1, 1986 and November 1, 1994 94 distal reconstructions were performed in diabetics with isolated tibioperoneal vessel occlusive disease. Mostly the below knee popliteal artery was used as inflow site and most grafts were anastomosed distally to a malleolar artery. Autologous vein was implanted throughout. Mortality at 30 days was 1.06%. Primary and secondary cumulative patency rates were 78% and 82% at 1 year, 65% and 78% at 5 years. Limb salvage rates were 76% at 1 year and 72% at 5 years. Major amputations became inevitable in 12 cases of uncontrollable foot infections despite patent grafts. This is probably due to the diabetic immunopathy. The experience we have gained suggests that distal bypasses in patients with peripheral vascular occlusive disease and critical foot ischemia are excellently suited to attain limb salvage. PMID- 8677700 TI - [Foot salvage in diabetic gangrene]. AB - In 35 patients with diabetic gangrene, amputation above the ankle (n = 18) or below the ankle (n = 17) was planned by nonspecialised general surgical departments or practicing surgeons. Prior to the operation, these patients presented to a specialised diabetic foot clinic; their clinical courses were analysed retrospectively. RESULTS: in 14 cases, peripheral arterial occlusive disease (PAOD) stage IV was the underlying cause, which was treated by bypass surgery in 10 cases and by angioplasty in 1 case. In 2 cases, bypass-operation was impossible due to anatomic conditions, and in 1 case it failed (all 3 cases were amputated below knee). In 21 patients, neuropathic infection was the underlying cause (without PAOD), which was unrecognized. In 13/21 cases osteomyelitis, and in 7/21 cases Charcot-foot was present. Treatment consisted of drainage, pressure relief, antibiotics, and minor amputations (3 toes, 3 midfoot). CONCLUSION: in our retrospective analysis, 83% of major amputations that had been considered by non-specialised surgeons, could be prevented by a combined medical and vascular surgical approach. 79% of the minor amputations that had been considered, proved to be unnecessary. Thus, salvage of the gangrenosis diabetic foot is possible in the majority of cases, provided suitable vascular surgery and infection containment. The traditional high amputation rate in diabetic patients seems to be unfounded. PMID- 8677701 TI - [Long-term results of surgical and conservative treatment of ruptures of the long biceps tendon]. AB - INTRODUCTION: The therapeutic concept for rupture of the long biceps tendon continues to be controversially discussed. Various operative procedures compete with mostly unstructured conservative ones. QUESTION INVESTIGATED: a) Is operative therapy of the long biceps tendon rupture superior to the conservative treatment? b) For which group of patients should the operative or the conservative therapy be recommended? PATIENTS AND METHOD: The value of operative versus conservative therapy was examined based on a collective of 43 ruptures (39 patients), 31 operatively and twelve conservatively treated. The investigation comprised the following: 1) the subjective evaluation of the long-term result by the patient, 2) a thorough clinical examination including the function of the shoulder and the elbow joint and 3) an isokinetic force and endurance test on Cybex II. The results of the follow-up were evaluated by a score. RESULTS: It was found that very good but also poor results can be achieved with both operative and conservative therapy, the good results distinctly predominating in the operated collective. Statistically significant differences could not be detected because of the small number of cases and the relatively large variation range. Good results after conservative therapy require a differentiated rehabilitation program corresponding to the normal course followed after operative treatment. CONCLUSION: Since results tended to be better for the operated collective in our study, we recommend a surgical procedure for active younger patients. It seems to be of decisive importance to perform the operation as early as possible and to achieve optimal tension of the muscle by refixation of the tendon. PMID- 8677702 TI - [Atypical initial manifestation of Takayasu arteritis]. AB - Primary clinical manifestations in patients with Takayasu arteritis are mostly unspecific signs of inflammation. First involved are the main brachiocephalic arteries and the aorta. Later the disease becomes symptomatic through organ ischemia. Often a renal hypertension appears due to an arteritic stenosis of the renal artery. Here we present a patient suffering from Takayasu arteritis. The disease first appeared with renal hypertension and an encephalopathy. The hypertension was induced by compression of the right renal artery which in turn was caused by an aortic aneurysm. The aneurysm had been resected and the aorta was reconstructed by aorto-aortal prosthetic interposition and implantation of the renal arteries. The postoperative course was uneventful. PMID- 8677703 TI - [Acute rupture of an aneurysm of the popliteal artery: case report]. AB - A case of acute rupture of an atherosclerotic popliteal aneurysm is reported. The popliteal aneurysm was partially resected and revascularisation of the leg was successfully performed by implantation of an e-PTFE-prosthesis. The postoperative course was uneventful and the patient remained asymptomatic two years later. The peculiarities of the diagnosis and the surgical treatment of the acute rupture of a popliteal aneurysm are reported. We think that in the management of the popliteal aneurysm a prophylactic surgical repair is the treatment of choice. PMID- 8677704 TI - [Cholecystoduodenal fistula with subsequent gallstone ileus: case report of an unusual course]. AB - Gallstone ileus is a rare complication of cholecystolithiasis with a high mortality because of the advanced age of the patients and the often delayed diagnosis. Signs of a cholecystoduodenal fistula are often absent in conventional ultrasonic and radiological methods. Treatment options are: 1. Enterolithotomy, 2. One stage procedure or 3. Two stage procedure consisting of enterolithotomy and the surgery of the biliary tract. In the case of our patient we performed a conventional cholecystectomy and the closure of the cholecystoduodenal fistula, which was found accidentally. When the gallstone ileus appeared 6 days later the enterolithotomy was performed. Thus in case of accidentally found cholecystoduodenal fistula an exploration of the abdominal cavity and the small intestine to find the gallstone should be performed on principle. Gallstones with a diameter of more than 2-3 cm should be removed by enterolithotomy to prevent the gallstone ileus. PMID- 8677705 TI - [Bradykinin antagonism in ischemia and reperfusion of the pancreas]. AB - INTRODUCTION: Acute pancreatitis is characterized by two different courses of the disease, edematous and hemorrhagic-necrotizing pancreatitis. The pathogenesis and causes for the progression of pancreatitis are unknown. Ischemia/reperfusion with formation of oxygen free radicals, activation of leukocytes and consecutive failure of the microcirculation has gained attention as a causative factor. Furthermore, the degree of microcirculatory injury correlates with the severity of pancreatitis. The aim of the study was to investigate the influence of long term reperfusion after ischemia of the pancreas for 2 hours on morphological changes and enzyme release of the pancreas in rats. Since the characteristic features of postischemic pancreatic reperfusion injury are kinin-mediated we employed the bradykinin B2-receptor antagonist HOE 140 to inhibit the progression of postischemic changes of the pancreas. METHODS: Under ether anesthesia Sprague Dawley rats (n = 28) were laparotomized, the 4 supplying arteries of the pancreas were isolated (gastroduodenal artery, left gastric artery, splenic artery and caudal pancreaticoduodenal artery) and occluded with microvascular clips for 2 hours. At the end of ischemia the abdomen was closed and the animals were allowed to awake. 15 minutes before end of ischemia an osmotic minipump filled with NaCl (ischemia group NaCl), phosphate buffer (ischemia group phosphate buffer) or HOE 140 dissolved in phosphate buffer (ischemia group HOE 140) was placed intraperitoneally. Control animals underwent sham operation without vessel occlusion; the osmotic minipump was filled with 0.9 % NaCl. Five days after ischemia the animals were sacrificed for histology. Amylase concentration and peripheral leukocyte count were determined at baseline and daily after operation. RESULTS: After ischemia of 2 hours during reperfusion of 5 days all 14 animals developed histopathological changes as seen in hemorrhagic-necrotizing pancreatitis with a mortality rate of 50 %. These morphological changes were associated with a significant increase (p < 0.05) of pancreas amylase concentration from 1850 +/- 149 U/L before ischemia to a maximum of 3934 +/- 435 U/L at 1st postoperative day and decreased to 1518 +/- 399 U/L at 4th postoperative day. Leukocyte count increased significantly (p < 0.05) from 10 x 10(12)/L to 31 x 10(12)/L. In control animals as well as in animals receiving HOE 140, morphological and enzyme changes typical for acute pancreatitis were absent, leukocyte count increased only slightly. CONCLUSION: Ischemia of the pancreas of 2 hours with ensuing reperfusion of 5 days induces morphological and biochemical changes as observed in hemorrhagic-necrotizing pancreatitis. Organ dysfunction after ischemia/ reperfusion can be effectively inhibited by administration of the bradykinin-antagonist HOE 140. PMID- 8677706 TI - [In memory of Carl Thiersch--on the 100th anniversary of his death]. AB - Carl Thiersch is one of the great surgeons of the 19th century. His life, full of work and success was a fortune for surgery. At the occasion of Carl Thiersch's centenary of death a review of his life and an appreciation of his scientific work are presented. His childhood in a family of scientists with an early start of his studies and the different periods of education are described. The influence of his tutor Stromeyer became early visible. The work at the department of pathology of the Munich University was for Thiersch not only a short temporary event but a time of profound scientific activity. The fundamental anatomical research work later on had a high importance for the scientific investigations of Carl Thiersch. The important scientific results achieved during his time at Erlangen and Leipzig University are presented. They were highlights in surgery making the ingenious surgeon well known all over the world. Carl Thiersch was an investigator rich of ideas. He was also a teacher with a phenomenal knowledge and a great expert in anatomical dissecting at operation. Finally he was a charming man with goodness, sensitiveness, modesty and honesty. Carl Thiersch will serve also further generations of surgeons as a noble preceptor. PMID- 8677707 TI - [The outstanding Russian neurologist M. N. Lapinskii]. PMID- 8677708 TI - [The nociceptive flexor reflex: a method for studying the brain mechanisms of pain control]. PMID- 8677709 TI - [Clinical angioneurology on the border of the centuries]. AB - The peculiarities of the investigation of cerebrovascular diseases in Institute of Neurology of Rus. Acad. Med. Sci. for the last 50 years on the background of world achievements in this field are outlined. The very term "angioneurology" arose in the process of researches development in Institute of Neurology. The thesis was postulated that the achievements in development of clinical angioneurology were mainly determined as well as will be determined in future by the progress in fundamental investigations in medicine, biology and neurosciences. PMID- 8677710 TI - [The concept of reification in psychiatry and sociology]. PMID- 8677711 TI - [The pathophysiological mechanisms of disorders of cerebral circulation and the new directions in their prevention and treatment]. AB - The contribution of Laboratory of Nervous System's Experimental Pathology (Institute of Neurology of Russian Academy of Medical Sciences) to cerebrovascular circulation investigations is described. The following questions were considered: cerebral circulation in cerebrovascular disturbances, collateral circulation in the "turned off" state of different brain arteries, and immunological brain alterations as the result of brain organic diseases. Results of the investigation of the damaging effect of acute increase in arterial pressure as well as individual sensitivity to brain ischemia and to drug administration were presented. The particular importance of researches of blood circulation biomechanics as well as of factors of its normalization were also emphasized. PMID- 8677712 TI - [Angioneurosurgery at the Institute of Neurology of the Russian Academy of Medical Sciences]. AB - The Angioneurosurgery Clinic exists in Institute of Neurology of Rus. Acad. Med. Sci. for 30 years (from 1965). The main scientific approaches have been formed here in these years. Some of investigations meet the requirements in general neurology in the field of clinical neurology: surgery in head main arteries pathology; surgical intervention in hemorrhage insults resulting from hypertension, atherosclerosis as well as from aneurysm rupture; the treatment of extrapyramidal diseases (stereotaxic and functional neurosurgery; surgical methods of control and therapy of operative complications; combined treatment of neuroectodermal brain tumors. PMID- 8677713 TI - [Multiple sclerosis and amyotrophic lateral sclerosis. The development of concepts of their etiology and pathogenesis]. AB - The analysis of the results of investigations concerning etiology and pathogenesis of multiple sclerosis and amyotrophic lateral sclerosis performed in Institute of Neurology of Rus. Acad. Med. Sci. There were three main periods of the researches determined mainly by theoretical achievements. For the last years the standards of such investigations have approached fundamental levels and corresponded to the trends of world science. PMID- 8677714 TI - [The clinical and molecular genetic aspects of the study of hereditary diseases of the nervous system]. AB - The results of 30-year work of Neurogenetic Department (Institute of Neurology, Russian Academy of Medical Sciences) are summarized in this article. The main conceptions of pathogenesis of extrapyramidal degenerations elaborated in this department were presented. The possibilities of application of molecular genetic approaches in neurogenetics including in search for more effective pathogenetic methods of inherited diseases treatment were demonstrated. PMID- 8677715 TI - [The development of the science of neural resuscitation]. AB - The complex approach to both restoration and maintenance of vital functions in patients with severe nervous system diseases is described in this article. The respiratory reanimation is thought to be the main problem of neuroreanimatology. The long-term experience of the Institute of Neurology of Rus. Acad. Med. Sci. in this field is presented. It was concerned with the arbitrary respiratory control disorders, automatic respiratory regulation disturbances, the damages of peripheral centers associated with respiratory function. PMID- 8677716 TI - [The molecular genetic approach to the study of dominant spinocerebellar ataxias]. AB - At least 5 different genes of autosomal dominant spinocerebellar ataxias (SCA) were revealed recently. Their discovery permitted to elaborate the most perfect classification of this heterogeneous group of diseases. In two forms of ataxias (SCA1 and SCA3) the mutations consist in the expansion of CAG-trinucleotides repetitions. The Russian population of patients with dominant SCA (13 families) was examined for the first time in terms of the evaluation of mutant gene carriers of SCA1 and SCA3. SCA1 was diagnosed in 5 families on the molecular level. The cerebellar ataxia, dysarthria as well as pyramidal symptoms comprised the basis of SCA1 clinical pattern. There were no SCA3 cases at DNA-testing. The perspectives of DNA-diagnosis of inherited ataxias were considered. PMID- 8677717 TI - [Progressive aphasia without dementia--the onset of an atrophic process of the brain]. AB - Three cases of progressive aphasia were analyzed. Moderate motor aphasia without any cognitive disturbances was observed at an early stage of the disease. Subsequently gradual development of severe motor aphasia, agraphia, alexia, as well as of speech comprehension disorder, intellectual retardation, aspontaneity, and apraxia was observed in such patients. Computer tomography revealed brain fronto-temporal local atrophy which was growing progressively as far as the disease developed. Any cerebrovascular diseases were absent. The conclusion was made that progressive isolated aphasia was the debut of cerebral cortex atrophy. PMID- 8677718 TI - [Pathology of the hemostatic system in the acute period of an ischemic stroke and the possibilities for its therapeutic correction]. AB - The indices of blood haemostasis adequately reflecting the state of coagulative, fibrinolytic, anticoagulative and platelet aggregation systems were examined in 150 patients with acute ischemic stroke. The four haemostasiological syndromes such as hyperaggregation, hypercoagulation, depressed fibrinolysis, hypercoagulation and three types of thrombophilias were distinguished and described in detail. The special features of coagulopathic disorders depending on etiology, severity and stroke onset period were characterized. The authors developed some recommendations on selective medical correction of haemostatic disorders in acute period of brain infarction. PMID- 8677719 TI - [The achievements of the Institute of Neurology of the Russian Academy of Medical Sciences over 50 years]. AB - The historical review of the main research fields of Institute of Neurology of Rus. Acad. Med. Sci. from 1945 to nowadays is presented, some of them are: the investigations of both traumatic and infectious damages to nervous system, cerebrovascular pathology (angioneurology), neurogenetics, neuroreanimatology and neurosurgery (angioneurosurgery, in particular). The peculiarities of the development of approaches mentioned above as well as of corresponding problems are described in the review. PMID- 8677720 TI - [A disorder of serotonin metabolism in patients in the acute period of nontraumatic intracranial hemorrhages]. AB - The indices of serotonin metabolism in cerebrospinal fluid (CSF) and blood were studied in 43 patients with nontraumatic intracerebral hemorrhage in the interval from 1 - 2 to 28 days after the onset of the disease. The considerable increase of tryptophan, serotonin and its main metabolite 5-hydroxyindoleacetic acid (5 HAA) in CSF and blood was found. The relationship between liquor and blood serum serotonin levels, hemorrhage focus size, severity and outcome of disease was also observed. There were no significant differences between serotonin, 5-HAA, free and bound serotonin levels in patients with the break of blood into different part of liquor space. The possible mechanisms of alteration of serotonin metabolism in patients with intracerebral hemorrhage were discussed. PMID- 8677721 TI - [Psychogenic manias (A clinico-catamnestic study)]. AB - 25 patients (18 women, 7 men) which had at the age of 18 - 61 reactive manias were examined. The patients were followed up from 3 to 12 years. The two types of reactive manias were recognized. The first type of mania was presented by the patients with "true" manic reactions, the second one consisted of the individuals with manic phases evoked by psychogenic factors. The first type reactions were caused by severe psychic traumas important for individuals. Such reactions had the tendency to the formation of postreactive development. Manic symptoms were combined with psychopathic manifestations. The gradual reduction of affective disorders was observed in such patients while psychogenic complex remained essential. The second type reactions developed as a response to events not so objectively important including relatively pathogenic ones. In such cases the clinical pattern was comparable with the pattern of "simple" mania. Affective disorders during psychogenic complex reduction revealed the signs of autochthonous dynamics. The outcomes of psychogenias of the second type may be either the full restoration of premorbid psychic functions or the development of steady hyperthymic pseudopsychopathic states which are typical for residual schizophrenia. PMID- 8677722 TI - [The action of high-intensity light on catecholamine excretion in depressive patients]. AB - The action of bright light (2600-2800 lux) on the catecholamine (CA) excretion was analyzed in patients with anxious (11) and melancholic (12) depressions resultant from manic-depressive psychosis and schizophrenia. The melancholic depressed patients were characterized by decreased noradrenaline (NA) and increased adrenaline (A) levels; in anxious depression NA and A were increased. The light therapy resulted in decrease of A level but NA level remained invariable in melancholic depression. Meanwhile the tendency to normalization of excretion of both CA was observed in anxious patients after light therapy. The contrary alterations in A/NA ratio as well as its considerable individual fluctuations were observed after light therapy. The A/NA ratio after light therapy depended mainly upon the initial A/NA ratio (the higher or lower ratio compared to control value). PMID- 8677723 TI - [A trial of the use of nifedipine for preventing relapses in affective and schizoaffective psychoses]. AB - Nifedipine was applied for the secondary prophylaxis of affective phasic disorders. 21 patients with both affective and schizoaffective psychoses were treated with nifedipine for 1-3 years (mostly for 2 years) in a dose of 20-60 mg daily (usually 30-40 mg). The clear prophylactic effect of nifedipine was observed in 76.2% of cases. The duration of affective phases reduced by 44.8% while their frequency decreased by 40.4% as compared with the control group. The positive therapeutic effect was more pronounced for manic disorders (the transition of the disturbances to subclinical, ambulant level). The preventive effect of the drug was more clear in affective than in schizoaffective psychoses (91.7% and 55.6%, respectively) as well as it was more expressed in bipolar (84.6%) than in monopolar (62.5%) patients. The low frequency (23.8%) of side effects occurred to be the positive characteristics of nifedipine treatment especially in long-term therapy. PMID- 8677724 TI - [The effect of electrotranquilization on the hormonal indices of alcoholic patients]. AB - The correlation between clinical signs of alcoholism dynamics and hormonal status indices was analysed in 26 patients during medical electrotranquilization sessions. Electrotranquilization (ET) was carried out by "Lenar" (Russia) apparatus. There were estimated the concentrations of the following hormones: adrenocorticotropic hormone, hydrocortisone, prolactin, follicle stimulating, luteinizing hormones, estriol, testosterone, somatotropic, thyrotropic hormones, triiodothyronine, tyrosine and insulin. The inverse correlation was observed between the estriol, testosterone and tyrosine levels on the one hand and the clinical signs of the reaction to alcohol administration on the other hand. So far as the disease severity strengthened, both the elevation of estriol and the decrease of testosterone levels were observed. The prolactin concentration correlated directly with meta-alcoholic clinical signs gravity. This confirmed the prolactin role both in postalcoholic haemostasis restoration and in pathogenesis of meta-alcoholic clinical signs. In alcoholic patients the ET normalized the serum prolactin level as well as promoted the trend to normalization of estriol and testosterone levels. PMID- 8677725 TI - [Magnetic resonance tomography of the brain in a lesion of the trigeminal system]. AB - 26 patients with trigeminal disorders were examined in terms of magnetic resonance tomography. It was established that the trigeminal disorders occurred to be secondary and symptomatic in all patients. They were caused by various cranial and cerebral pathology mainly by voluminous changes of basal localization. The results of investigation testified that the magnetic resonance tomography application in atypical course of trigeminal pathology was quite useful to avoid different diagnostic mistakes and to create the most effective treatment strategy. PMID- 8677726 TI - [The search for a mutation in the gene coding the beta-amyloid protein precursor gene in patients with Alzheimer-type dementias]. AB - Missence mutation in codon 717 of the amyloid precursor protein (APP) gene that codes for the precursor to the beta-protein found in the amyloid deposits of Alzheimer disease was recently shown to be segregated with this disease in some kindreds. The following study aimed to determine the frequency of the codon 717 mutation in familial and "sporadic" cases of dementia of the Alzheimer type has been performed in Russian patients. 62 patients with senile dementia and the Alzheimer disease with early and late onset and 43 normal controls were tested for this mutation. None of them were positive. Thus this mutation is considered to be rare in studied population though in some cases it may be the cause of the disease. PMID- 8677727 TI - [Additional approaches to the classification of the type and degree of disorders in the tonus of the craniocerebral vessels]. PMID- 8677728 TI - [The training of neurologists in the USA]. PMID- 8677729 TI - [The gifts of the clinical power of observation]. PMID- 8677730 TI - [The ambulatory rehabilitation of patients with the sequelae of a stroke: a differential approach]. PMID- 8677732 TI - [Experience with the accreditation of the neurological and neurosurgical services of Saint Petersburg during the transition of public health to the principles of medical insurance]. PMID- 8677731 TI - [The pathogenetic therapy of Raynaud's syndrome]. PMID- 8677733 TI - [A comparative study of the efficacy of normovolemic hemodilution and traditional therapy in treating ischemic stroke]. PMID- 8677734 TI - [Blood filterability and its correction with naftidrofuril in patients with cerebrovascular diseases]. PMID- 8677735 TI - Molecular Biology of Hematopoiesis. Proceedings of the 9th symposium. Genoa, Italy, June 23-27, 1995. PMID- 8677736 TI - T cells, graft-versus-host disease and graft-versus-leukemia: innovative approaches for blood and marrow transplantation. AB - Allogeneic bone marrow transplantation is most commonly used as treatment for leukemia. Allotransplantation is associated with several interrelated immunologic processes, graft rejection, graft-versus-host disease (GvHD) and graft versus leukemia (GvL). Graft rejection can be overcome by intensive pretransplant immunosuppressive therapy. Following transplantation, immunoreconstitution must occur from donor-derived progenitors and GvHD may occur from reactivity of donor derived immunocompetent cells against host tissues. In a related, but distinct process, donor immunocompetent cells may react against the recipient leukemia and recent data confirm that this GvL effect plays a critical role in preventing posttransplant relapse. This report summarizes present data regarding the mechanism of these processes. A major challenge is to separate the beneficial GvL effect from GvHD, the major complication of allogeneic marrow transplantation. We summarize data regarding innovative approaches to modify the composition of the transplanted marrow to optimize clinical outcome as well as use of donor lymphocyte infusions as a means to induce posttransplant GvL. PMID- 8677737 TI - Combined use of growth factors to stimulate the proliferation of hematopoietic progenitor cells after autologous bone marrow transplantation for lymphoma patients. AB - We studied the kinetic response and concentration of bone marrow (BM) progenitor cells of patients with lymphoid malignancies submitted to autologous bone marrow transplantation (ABMT), treated with a granulocyte-colony-stimulating factor (G CSF)/interleukin-3 (IL-3) combination. The results were compared with those of lymphoma patients receiving the same pretransplant conditioning regimen followed by G-CSF alone. Recombinant human (rh)G-CSF was administered as a single subcutaneous (s.c.) injection at the dose of 5 micrograms/kg/day from day + 1 after reinfusion of autologous stem cells, while rhIL-3 was added from day +6 at the dose of 10 micrograms/kg/day s.c. (overlapping schedule). In both groups (i.e. G-CSF- and G-CSF/IL-3-treated patients), cytokine administration was discontinued when the absolute neutrophil count was > 0.5 x 10(9)/l of peripheral blood for 3 consecutive days. Following treatment with the CSF combination, the percentage of marrow CFU-GM and erythroid progenitors (BFU-E) in the S phase of the cell cycle increased from 9.3 +/- 2 to 33.3 +/- 12% and from 14.6 +/- 3 to 35 +/- 6%, respectively (p < 0.05). The number of actively cycling megakaryocyte progenitors (CFU-MK and BFU-MK) also increased. Conversely, G-CSF augmented the proliferative rate of CFU-GM (22.6 +/- 6% compared to a baseline value of 11.5 +/ 3%; p < 0.05) but not of BFU-E, CFU-MK or BFU-MK, and the increase in S-phase CFU-GM was significantly lower than that observed in the posttreatment samples of patients receiving IL-3 in addition to G-CSF. The absolute number of both CFU-GM and BFU-E/ml of BM was significantly augmented after treatment with G-CSF/IL-3 but not G-CSF alone. Similarly, administration of the cytokine combination resulted in a higher number of CD34+ cells and their concentration was significantly greater than that observed in the posttreatment samples of G-CSF patients. We also investigated the responsiveness to CSFs, in vitro, of highly enriched CD34+ cells, collected after priming with G-CSF in vivo (i.e. after 5 days of G-CSF administration). Our results demonstrated that pretreatment with G CSF modified the response of BM cells to subsequent stimulation with additional CSFs. When the hematological reconstitution of patients treated with G-CSF/ IL-3 was compared to that of individuals receiving G-CSF alone, the addition of IL-3 resulted in a significant improvement in granulocyte and platelet recovery, a lower transfusion requirement and shorted hospitalization. In conclusion, our results indicate that in vivo administration of two cytokines increases the proliferative our results indicate that in vivo administration of two cytokines increase the proliferative our results rate and concentration of BM progenitor cells better than G-CSF alone and support a role for growth factor combinations for accelerating hematopoietic recovery after high-dose chemotherapy. PMID- 8677738 TI - Density separation and cryopreservation of umbilical cord blood cells: evaluation of recovery in short-and long-term cultures. AB - The clonogenic capacity of human umbilical cord blood (UCB) has been evaluated in several studies, which have shown high numbers of primitive hematopoietic progenitor cells. Recently, UCB progenitor cells were demonstrated to possess significant advantages over bone marrow (BM) in terms of proliferative capacity and immunologic reactivity. Therefore, UCB has been considered an attractive source of hematopoietic stem cells for both research and clinical applications. Previous reports have documented a significant loss of progenitor cells by any manipulation other than cryopreservation. We have evaluated the feasibility of fractionating and cryopreserving UCB samples with minimal loss of progenitor cells. We compared separation over three different densities of Percoll (1.069, 1.077 and 1.084 g/ml), sedimentation over poligeline (Emagel), and sedimentation over poligeline followed by separation over Ficoll/Hypaque (F/H). Separated samples (n = 25) were analyzed for recovery of CD34+ cells and progenitor cells (CFU-GEMM, BFU-E, CFU-GM). Separation by sedimentation over poligeline followed by F/H allowed the highest depletion of RBCs (hematocrit of the final cellular suspension 0.4 +/- 0.1%), while maintaining a high recovery of CD34+ cells (85.3%) and total recovery of CFU-GEMM, BFU-E and CFU-GM. After cryopreservation, recovery of clonogenic progenitors was 82% for CFU-GEMM, 94% for BFU-E, 82% for CFU-GM and 90% for colony-forming units after 5 weeks of longterm culture. Moreover, the presence of Stem cell factor significantly increased CFU-GEMM (14 +/- 4 vs. 49 +/- 5, p < or = 0.0005) and CFU-GM (112 +/- 18 vs. 178 +/- 19, p < or = 0.025), but not B FU-E (42 +/- 7 vs. 53 +/- 7, p < or = 0.375) growth. In conclusion, RBC depletion of UCB can be accomplished with minimal loss of committed and primitive hematopoietic progenitors. This procedure may have important implications in the large-scale banking of UCB and in ex vivo expansion/gene therapy protocols. PMID- 8677739 TI - Peripheral blood pressure cells transplants across a major histocompatibility barrier in rabbits: positive effects of a higher number of precursor cells? AB - Peripheral blood precursor cells (PBPCs) are used with increasing frequency for hematopoietic transplants and have more or less replaced autologous bone marrow transplants. First clinical and experimental reports document the feasibility of PBPCs as a source for allogeneic transplants. Few data exist on the optimal procedure and the ideal number of cells for the transplant. We have previously shown in rabbits that PBPCs can be used for transplants even across a major histocompatibility barrier. We used this model to test whether the number of transplanted precursor cells would influence graft outcome. Adult outbred Red Burgundy rabbits were used as donors, New Zealand White rabbits of the opposite sex as recipients. One individual donor was taken for one individual recipient. Conditioning consisted of single-dose total body irradiation of 10 Gy followed by a short course of cyclosporine to enhance engraftment. Donor animals were treated with recombinant human granulocyte-colony-stimulating factor, 10 micrograms/kg subcutaneously daily from day -2 until day +9. PBPCs were obtained from the artery of the donor animal by repetitive centrifugation of 2 x 40 ml heparinized blood on each day of donation, i.e. days 0, +2, +3, +6, +8, and +10 and infused without further manipulation. Eight animals underwent transplantation. Seven took the grafts, six died of graft-versus-host disease and pneumonia between days 12 and 55 (median survival of all animals: 34 days). One animal was still alive after 120 days. Transplanted nucleated cells varied from 7.3 to 15.4 x 10(8)/ kg (median 9.2 x 10(8)/kg) and CFU-GM from 12.3 to 176.8 x 10(4)/kg (median 42 x 10(4)/kg). Survival tended to increase with more CFU-GM) r = 0.716, p = 0.0704). These data confirm that allogeneic PBPCs can engraft across a major histocompatibility barrier and suggest that a higher number of CFU-GM might be advantageous. PMID- 8677740 TI - Molecular findings and classification of malignant lymphomas. AB - We review the problem of lymphoma classification in the light of the Revised European-American Lymphoma (REAL) scheme, recently proposed by the International Lymphoma Study Group (ILSG). The REAL classification is a list of clinicopathologic entities, all well known from the literature, upon which the ILSG members agreed. Although it contains nothing new, for the first time all the elements, including immunophenotype and molecular data, which characterise a given lymphoma entity are considered. This approach corresponds to the need for objective criteria integrating the often puzzling morphologic findings. Furthermore, better knowledge of the molecular events which contribute to tumour development and progression if of paramount importance for the development of more specific and successful therapies. Some relevant molecular findings included in the classification and additional data obtained by the ILSG members following its publication are discussed. PMID- 8677741 TI - Role of anthracyclines in the treatment of adult acute lymphoblastic leukemia. AB - In acute myelogenous leukemia, early treatment is usually attempted with the so called 3+7 regimen, employing daunorubicin (DNR) or idarubicin (IDR) for 3 consecutive days. In acute lymphoblastic leukemia (ALL), the role of agreement regarding ANT dosage and schedule, preferable compound, and indications for remission induction and consolidation treatment phases. Here we review the role of these drugs in adult ALL. The results indicate that ANTs may offer the best survival chance when used at full dosage during induction and early consolidation treatment. IDR may be a better choice that DNR or doxorubicin, and CD10+ t(9;22)/bcr- ALL may have an excellent prognosis following an early dose intensive ANT consolidation program. PMID- 8677742 TI - AIDS-related non-Hodgkin's lymphomas: molecular genetics, viral infection and cytokine deregulation. AB - AIDS-related non-Hodgkin's lymphomas (AIDS-NHLs) are almost invariably derived from B cells and are grouped into three distinct histologic categories, including small-non-cleaved-cell lymphoma (SNCCL), diffuse large-cell lymphoma (DLCL), and anaplastic large-cell lymphoma (ALCL). In addition, AIDS-NHLs presenting solely as a body cavity effusion are thought to be a peculiar clinicopathologic entity and are defined as body-cavity-based lymphoma (BCBL). At the biologic level, AIDS related lymphomagenesis is characterized by activation of proto-oncogenes, inactivation of tumor suppressor genes, viral infection of the tumor clone, and deregulated cytokine production. Distinct AIDS-NHL types associate with specific molecular pathways. The first pathogenetic pathway clusters with AIDS-SNCCL, and is characterized by a relatively mild degree of host immunodeficiency. AIDS-SNCCL consistently associates with c-myc rearrangements and p53 inactivation in 100 and 60% of cases, respectively, whereas infection by Epstein-Barr virus (EBV) is restricted to 30% of the cases. Production of high levels of interleukin-10 is an additional peculiar feature of EBV-positive AIDS-SNCCL. The second pathogenetic pathway associates with AIDS-DLCL, which is usually accompanied by marked host immunodeficiency. AIDS-DLCL is characterized by EBV infection in the large majority of cases and by the mutually exclusive presence of bcl-6 rearrangements and c-myc translocations in 40% of the cases. A third pathway characterizes AIDS BCBL, which associates in virtually all cases with infection by EBV and with the presence of DNA sequences of the recently identified Kaposi sarcoma herpesvirus in the apparent absence of other known genetic lesions. Finally, the pathogenetic features of AIDS-ALCL are still under investigation. PMID- 8677743 TI - Anti-HIV viral interference induced by retroviral vectors expressing a nonproducer HIV-1 variant. AB - A Hut-78 cell clone (F12) harboring a nonproducer human immunodeficiency virus (HIV-1) variant shows complete resistance to HIV-1 or HIV-2 superinfection. The F12-HIV provirus produces an altered HIV-1 protein pattern and cannot generate even immature viral particles. We demonstrated that HeLa CD4+ cells transfected with the F12-HIV genome resist HIV superinfection through a CD4-independent mechanism. As F12-HIV appears to be a useful system to induce anti-HIV intracellular immunization, we constructed various retroviral vectors containing the F12-HIV genome, modified by elimination of the F12 3'LTR and part of its nef gene, inserted 'antisense' with respect to the Moloney murine leukemia virus 5' LTR. Here we show that recombinant retroviral particles carrying the N2/F12-HIV nef- (as) construct can stably transduce both CEMss human cells and primary human peripheral blood lymphocytes, inducing the expression of the F12-HIV genome. These results could open the way to an anti-AIDS gene therapy strategy based on F12-HIV-induced intracellular immunization. PMID- 8677744 TI - Suppression of hematopoietic support function is associated with overexpression of interleukin-4 and transforming growth factor-beta 1 in LP-BM5 murine-leukemia virus-infected stromal cell lines. AB - Murine acquired immunodeficiency syndrome (MAIDS) induced by defective LP-BM5 murine leukemia virus (MuLV) is a disease with many similarities to human AIDS. Our previous studies demonstrated that the depressed hematopoiesis observed in LP BM5-infected marrow cultures could be attributed to a defective hematopoietic stroma. We report now the generation of permanent stroma cell lines from noninfected and LP-BM5-infected marrow cultures. Retrovirus infection was confirmed by the polymerase chain reaction for detecting viral genome expression of the p12 envelope glycoprotein. The ability of these cell lines to support in vitro hematopoiesis was evaluated. The results demonstrated that when cocultured with normal or infected nonadherent mononuclear cells, noninfected cell lines efficiently supported the production of hematopoietic progenitors, whereas in virus-infected progenitors was suppressed. Expression of cytokine genes in stromal cell lines was also examined. All cell lines expressed equivalent levels of transcripts for interleukin (IL)-1 beta, IL-2, IL-3, IL-6, IL-7, IL-10, interferon, tumor necrosis factor-alpha and stem cell factor. However, infection was associated with higher expression of IL-4 and transforming growth factor-beta 1. These findings demonstrate that infected stomal cell lines generate a defective hematopoietic microenvironment to produce altered cytokine expression and faulty hematopoiesis. Further characterization of these defective cell lines should assist elucidation of the mechanism(s) whereby retroviruses alter hematopoiesis ultimately leading to the generation of immunodeficiency. PMID- 8677745 TI - Simulation of hematopoiesis: implications for the gene therapy of lysosomal enzyme disorders. AB - Although the hematopoietic stem cell is an attractive target for gene transfer, little is known about its biology in vivo in large animals (including humans). We have studied the in vivo behavior of hematopoietic stem cells in glucose-6 phosphate dehydrogenase heterozygous (female Safari) cats, and demonstrated that clonal instability persists for up to 4.5 years after autologous marrow transplantation. This contrasts with the 2-6 months of clonal disequilibrium reported in comparable murine studies. Our data also suggest that hematopoietic stem cells do not self-renew more than once every 3 weeks. These data may have relevance for strategies to optimize gene therapy in large animals and, by extension, in humans. PMID- 8677746 TI - Expression and signal transduction of the FLT3 tyrosine kinase receptor. AB - FLT3 is a receptor tyrosine kinase of 130-55 kDa expressed on normal bone marrow stem and early progenitor cells and on leukemic blasts from patients with acute leukemias. The FLT3 ligand, FL, is a new cytokine which acts on hematopoietic progenitors in synergy with other cytokines. FLT3 transduces FL-mediated signal through interaction with a number of cytoplasmic substrates. PMID- 8677747 TI - JAK2 is constitutively associated with c-Kit and is phosphorylated in response to stem cell factor. AB - Stem cell factor (SCF) interacts with the receptor tyrosine kinase c-Kit and has potent effects on hematopoiesis. We have examined the role of JAK2 in the SCF signal transduction pathway. JAK2 and c-Kit were constitutively associated, and treatment with SCF resulted in rapid and transient tyrosine phosphorylation of JAK2. Incubation of cells with JAK2 antisense oligonucleotides resulted in significant decreases in SCF-induced proliferation. These data suggest that JAK2 plays a role in SCF-induced proliferation. PMID- 8677748 TI - Erythroid-specific activation of the distal (testis) promoter of GATA1 during differentiation of purified normal murine hematopoietic stem cells. AB - To understand the molecular mechanisms of erythroid differentiation, we analyzed by semiquantitative RT-PCR the expression of the transcription factor GATA1, the erythropoietin receptor (EpoR), and erythroid (beta-globin) differentiation markers in purified hematopoietic stem cells (HSCs) after in-vitro-induced differentiation. Whether GATA1 transcription was from the proximal (with respect to the AUG, also known as erythroid) or the distal (also known as testis) promoter was analyzed as well. Low-density marrow cells which bind to wheat germ agglutinin, but not to the antibody 15.1.1, and which either do or do not retain the dye rhodamine-123 (Rho-bright and Rho-dull, respectively), were purified. Rho dull, but not Rho-bright cells permanently reconstitute lymphomyelopoiesis in W/Wv and severe-combined-immunodeficiency mice and, therefore, contain HSCs. Both Rho-dull and Rho-bright cells give rise to progenitor and differentiated cells (peak values at days 15 and 5, respectively) in liquid culture. Multilineage, erythroid-restricted or myeloid-restricted differentiation is observed when the cultures are stimulated with stem cell factor (SCF) + interleukin (IL)-3, SCF + IL-3 + Epo, or SCF + IL-3 + granulocyte-colony-stimulating factor, respectively. Rho-dull cells have barely detectable reconstitution potential at day 5 of culture. None of the genes examined were expressed in purified Rho-bright or Rho dull cells. The only exception was GATA1 which was expressed at maximal levels in Rho-bright cells at the onset of culture. Rho-dull cells did not express GATA1 before day 3 of culture (maximal expression at days 10-15). Activation of GATA1 and EpoR was observed in all growth of mRNA for the two genes expressed by the cells. In contrast, beta-globin mRNA was detected only in the presence of Epo. The transcription of GATA1 was exclusively from the proximal promoter in the absence of Epo but both proximal and distal transcripts were observed in its presence. Maximum transcription from the distal promoter (approximately equal to 0.2% of total GATA1 mRNA) coincided with maximal globin mRNA levels (day 5 or day 15 for Rho-bright and Rho-dull cells, respectively). These results indicate that GATA1 is activated at the transition point between HSCs and pluripotent progenitor cells and erythroid-specific GATA1 regulation involves activation of the distal GATA1 promoter. PMID- 8677749 TI - Proto-oncogene products Vav and c-Cbl are involved in the signal transduction through Grb2/Ash in hematopoietic cells. AB - Grb2/Ash is composed of one SH2 and two SH3 domains and functions as an adapter linking tyrosine kinase receptors and Ras in fibroblasts. We have investigated the nature of proteins interacting with Grb2/Ash in hematopoietic cells. The product of the vav proto-oncogene (Vav) is expressed exclusively in hematopoietic cells and has guanine nucleotide exchange activity. Here we report that granulocyte/macrophage-colony- stimulating factor (GM-CSF), interleukin-3, and erythropoietin (Epo) induce rapid and transient tyrosine phosphorylation of Vav and that Vav is constitutively associated with the SH3 domain of Grb2/Ash in a human leukemia cell line UT-7. These data implicate Vav in a signaling pathway leading to activation of Ras or Ras-related proteins in hematopoietic cells. Furthermore, we have shown that the proto-oncogene c-cbl product (c-Cbl) is also tyrosine-phosphorylated by stimulation with GM-CSF or Epo and is constitutively associated with the SH3 domain of Grb2/Ash in UT-7. However, we could not find the homologous regions with guanine nucleotide exchange factors or GTPase activating proteins in the c-cbl gene. Therefore, Grb2/Ash might also transduce a signal that is different from the signal leading to the small-G protein regulation. PMID- 8677750 TI - Adhesion of human hematopoietic progenitor cells to bone-marrow-derived stromal cells is enhanced by antibodies to CD44. AB - It has been suggested that CD44 mediates adhesive interactions between hematopoietic progenitor cells and the stromal microenvironment. Ligands of CD44 include several extracellular matrix components, such as hyaluronic acid and fibronectin. Antibodies against CD44 have been shown to induce homotypic T cell aggregation, and to stimulate T and natural killer cell activity. We hypothesized that CD44 could similarly amplify interactions between blast-colony-forming cells and bone marrow stromal cells (BMSCs). Indeed, we have previously found that the anti-CD44 antibody NKI-P2 enhanced VLA-4-dependent interactions. Here, we studied an additional panel of nineteen anti-CD44 antibodies from the 5th Workshop on Leukocyte Differentiation antigens, to find out whether amplification was associated with a particular CD44 epitope. None of these antibodies showed inhibitory activity, whereas nine significantly increased the number of blast colonies more than 2-fold. Seven of these recognized epitope 1, and two epitope 2. More than 4-fold enhancement was only observed with epitope 1 antibodies: 4.C3 (4.4-fold), 212.3 (6.3-fold), L178 (9.1-fold), and NIH44-1 (9.2-fold). Our data suggest that primarily epitope 1 is associated with enhancement of colony formation. Furthermore, the findings support a role for CD44 as an amplifier in progenitor-BMSC interactions. PMID- 8677751 TI - GATA transcription factors negatively regulate erythropoietin gene expression. AB - We examined regulation of the human erythropoietin (Epo) gene through the GATA sequence in the Epo promoter, and demonstrated that Hep3B and HepG2 cells express human GATA-2 (hGATA-2) mRNA and protein. Nuclear extracts of QT6 cells transfected with hGATA-1, -2 or -3 transcription factors revealed specific binding to the GATA element in the human Epo gene promoter by gel mobility shift assay. Transient transfection of Hep3B cells with hGATA-1, -2 or -3 demonstrated that each of these transcription factors significantly decreased the level of expression of Epo mRNA as assessed by a competitive polymerase chain reaction. Furthermore, transient transfection of Hep3B cells with hGATA-1, -2 and -3 and and Epo reporter gene construct showed significant inhibition of the Epo promoter. We conclude that the hGATA-1, -2 and -3 transcription factors specifically bind to the GATA element in the human Epo gene promoter and negatively regulate Epo gene expression. PMID- 8677752 TI - Stem cell factor as a survival and growth factor in human normal and malignant hematopoiesis. AB - Stem cell factor (SCF) is an essential hematopoietic cytokine that interacts with other cytokines to preserve the viability of hematopoietic stem and progenitor cells, to influence their entry into the cell cycle and to facilitate their proliferation and differentiation. SCF on its own cannot drive noncycling hematopoietic progenitor cells into the cell cycle but does prevent their apoptotic death. SCF when combined with other cytokines increases the cloning efficacy of hematopoietic progenitor cells from all lineages. SCF also stimulates the growth of CD34+ leukemic progenitor cells from most patients with acute myeloid leukemia (AML). The mRNA expression of the SCF receptor c-kit has been shown to be significantly increased in all fresh AML blast cells compared with normal controls (healthy volunteers), in particular CD34+ cells. Two inhibitory cytokines, transforming growth factor-beta and interleukin-4, decreased c-kit expression, whereas tumor necrosis factor-alpha increased c-kit expression, but chemotherapeutic drugs showed no effect on c-kit expression, but chemotherapeutic drugs showed no effect on c-kit expression in AML cells. Apoptosis has been shown to be directly related to a high complete remission rate in AML patients following induction therapy. Since SCF has been shown to stimulate the proliferation of mainly CD34+ AML cells, we have investigated whether the poor response of patients with CD34+ myeloid leukemia cells to chemotherapy could be due to SCF-induced resistance to apoptosis. The effect of SCF on the apoptosis induced by chemotherapeutic drugs commonly used in the treatment of AML - cytarabine, daunorubicin and carboplatin - was examined in human CD34+ myeloid leukemia cells in serum-free cultures. SCF significantly reduced the induced apoptosis by more than 50% in all CD34+ human leukemia cells treated by any of the three chemotherapeutic drugs. Antibodies blocking c-kit reversed the significant inhibitory effect of SCF on chemotherapy-induced apoptosis, confirming the role of SCF in the resistance to chemotherapy-induced apoptosis in CD34+ human leukemia. These results suggest that the poor response of patients with CD34+ leukemia cells could be at least partially due to less chemotherapy induced apoptosis resulting from protection by SCF as an adjuvant mechanism for drug resistance in myeloid leukemia. We conclude that an antisense strategy to block c-kit expression in AML blast cells may prove valuable for decreasing the chemoresistance of AML patients. The abrogation of leukemic resistance to apoptotic death through anti-SCF/c-pit expression combined with chemotherapy offers potential for designing novel therapeutic approaches for refractory AML patients. PMID- 8677753 TI - Development and evolutionary aspects of thymic T cell education to neuroendocrine self. AB - Thymic epithelial cells, including nurse cells (TECs/TNCs), from various species synthesize neuroendocrine-related precursors belonging to neurohypophysial, tachykinin and insulin hormone families. The thymic repertoire of neuroendocrine related polypeptides illustrates at the molecular level the paradoxical role of the thymus in both T cell positive and negative selection. On the one hand, these precursors are a source of signals which interact with neuroendocrine-type receptors expressed by target pre-T cells according to the cryptocrine type of cell-to-cell signaling. On the other hand, the same precursors constitute a source of self-antigens which are presented to pre-T cells by the thymic major histocompatibility complex system. Basically, the model of thymic T cell education to neuroendocrine self was established by the identification in TECs/TNCs of immunoreactive (ir) oxytocin as the self-antigen of the neurohypophysial family. Nevertheless, through the expression in TECs/TNCs of ir neurokinin A and ir-insulin-like growth factor-II, the model also applies to the tachykinin and insulin hormone families. PMID- 8677754 TI - Interleukin-1, -6 and tumor necrosis factor-alpha release is down-regulated in whole blood from septic patients. AB - Proinflammatory cytokines are important mediators during endotoxemia. In experimental models, injection of lipopolysaccharide (LPS) activates macrophages leading to excessive secretion of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL-6; infusion of high dose of these mediators results in organ failure and death. Natural infection may be different, because it persists over days or even weeks, with repeated endotoxin challenge to macrophages. Little is known about the capacity of peripheral blood mononuclear cells (PBMCs) to release proinflammatory cytokines under these conditions. Therefore, as an ex vivo model of sepsis, the expression of proinflammatory cytokines after stimulation of whole blood with LPS was studied. A high LPS dose (1 microgram/ml) maximally increased TNF-alpha, IL-1 beta and IL-6 secretion in controls, but a marked depression was observed in septic patients (p < 0.01; 15 patients with severe sepsis versus 20 control patients without infection). This reduction persisted for up to 10 days after diagnosis of sepsis. The release of TNF-alpha, IL-1 beta and IL-6 was markedly decreased in the septic group even when a lower and physiologically more relevant LPS concentration (1 ng/ml) was used. IL-1 beta mRNA was similar to controls, but a down-regulation was observed in TNF-alpha and IL-6 transcript levels in PBMCs from the blood of septic patients. This was at least in part due to a marked reduction in TNF and IL-6 mRNA half-life. These results indicate that different mechanisms down-regulate proinflammatory cytokine release in the whole blood of septic patients. Although excessive secretion is known to be deleterious, low concentrations of these cytokines are involved in regulating essential cellular and humoral immune functions. Thus, the reduced capacity to express and release adequate amounts of proinflammatory cytokines after exposure to endotoxin, as observed in whole-blood PBMCs from septic patients, may contribute to the development of immunodeficiency. PMID- 8677755 TI - Role of bone marrow stromal cells in irradiation leukemogenesis. AB - The role of bone marrow stromal cells of the hematopoietic microenvironment in ionizing-irradiation leukemogenesis is a focus of current investigation. Evidence from recent in vitro and in vivo experiments suggests that damage by slowly proliferating cells of the hematopoietic microenvironment contributes to the sustained survival of irradiation-damaged hematopoietic progenitor cells/stem cells and can contribute to the selection and proliferation of a malignant clone. The molecular mechanism of the interaction of irradiated stromal cells with attached hematopoietic cells has been difficult to evaluate. Irradiated bone marrow stromal cell line D2XRII demonstrated altered patterns of fibronectin splicing and increased expression of several transcriptional splice variants of macrophage-colony-stimulating factor. Differential display has revealed specific radiation-induced gene transcripts which persist after irradiation of stromal cells in vitro or in vivo. In recent experiments, we demonstrated that irradiation of mouse bone marrow stromal cell line D2XRII induces release of significant levels of transforming growth factor (TGF)-beta into the tissue culture medium despite the lack of a detectable increase in TGF-beta mRNA. Since TGF-beta is known to induce reactive oxygen species (ROS), we tested how a target hematopoietic cell line, responsive to ROS by up-regulation of a transgene for an antioxidant protein, responded to cocultivation with irradiated bone marrow stromal cells. Bone marrow stromal cell line GPIa/GBL, derived from long-term bone marrow culture of a C57BL/6J-GPIa mouse, was irradiated in vitro and then cocultured with the interleukin (IL)-3-dependent hematopoietic progenitor cell line 32D cl 3, or with each of several subclonal lines expressing a transgene for human manganese superoxide dismutase (MnSOD). Cobblestone island formation, as a measure of adherence and proliferation by 32D-MnSOD clones in the presence or absence of IL-3, was increased with irradiated compared to control GPIa cells. Furthermore, using a fluorescent dye which detects ROS, hematopoietic cells cocultivated with irradiated stromal cells demonstrated higher levels of intracellular ROS than cells cocultivated and forming cobblestone islands on nonirradiated stromal cells. Since ROS are known to induce mutations in hot spots in the p53 gene, it appears worthwhile to investigate a potential mechanism for irradiated stromal cell induction of hematopoietic stem cell transformation through ROS-induced mutations. The present cell culture and molecular biology techniques provide new methods to analyze the effects of irradiated stromal cells on closely attached hematopoietic stem cells during irradiation leukemogenesis. PMID- 8677756 TI - Defective natural killer cell activity in B-cell chronic lymphocytic leukaemia is associated with impaired release of natural killer cytotoxic factor(s) but not of tumour necrosis factor-alpha. AB - The mechanisms accounting for the impaired natural killer cell activity (NKa) in B-cell chronic lymphocytic leukaemia (B-CLL) were investigated in 34 B-CLL patients. We found that patients with B-CLL have indeed very low NKa which may be increased in the presence of recombinant human interferon-alpha or recombinant human interleukin-2. Patients had also very low mitogen-induced cellular cytotoxicity. Their absolute numbers of peripheral blood CD16+, CD57+, CD3+, and CD8+ cells were significantly increased. Patients' NK cells had a normal tumour cell binding capacity but failed to release sufficient amounts of soluble cytolytic molecules upon stimulation with K562 cells or activation with phytohaemagglutinin (PHA). However, B-CLL NK cells released tumour necrosis factor-alpha (TNF-alpha) following stimulation with PHA. We concluded that defective NKa in B-CLL patients is probably the result of an impairment in the production and/or release of soluble cytolytic mediators, but not of TNF-alpha by NK cells. Further studies on the production and release of other cytolytic molecules, such as perforin and granzymes, as well as studies on the possible inability of NK cells to activate the apoptotic mechanisms in the target cells are in progress in our laboratory. PMID- 8677757 TI - Prognostic relevance of lipoprotein cholesterol levels in acute lymphocytic and nonlymphocytic leukemia. AB - We studied serum lipid and lipoprotein changes before and after induction treatment in 25 acute nonlymphocytic leukemia (ANLL) and in 18 acute lymphocytic leukemia (ALL) patients in order to investigate their relationship with disease activity and their prognostic relevance. ANLL at diagnosis is associated with significantly low levels of all lipid parameters, the same applies to ALL patients apart from plasma triglycerides and very-low-density-lipoprotein cholesterol (VLDL-C) which are significantly higher than in the normal population. In ANLL responders, after effective chemotherapy, a significant increase of total cholesterol, low-density-lipoprotein cholesterol (LDL-C) and apolipoprotein B levels, without changes of high-density-lipoprotein cholesterol (HDL-C) values, is observed. A further decrease of total cholesterol and LDL-C was found in nonresponders and in ANLL responders treated with granulocyte macrophage colony-stimulating factor (GM-CSF), known for its cholesterol-lowering action; in fact after the completion of GM-CSF therapy, these parameters returned progressively toward normal values. In ALL responders an increase of total cholesterol, HDL-C and apolipoprotein A1 with a simultaneous decrease of triglycerides and VLDL-C is evident; no variation was found in the nonresponder group. These results suggest a close correlation between serum lipids and acute leukemia: total cholesterol and LDL-C in ANLL, and HDL-C and VLDL-C in ALL may be considered reliable markers of complete remission and may be useful in the follow up of leukemic patients. PMID- 8677758 TI - Red blood cells expressing fetal antigens: their presence in adults with certain forms of anemia. AB - Using the IgG fraction of an antiserum against cord red blood cell (RBC) membranes (F-IgG), antigenic properties of RBC of newborns (n = 24) and patients suffering from anemia (n = 46) [either due to beta-thalassemia intermedia (n = 37) or hemorrhage (n = 9)] as compared to those of normal adults (n = 18) were examined with fluorescence microscopy, flow cytometry and radioimmunoassays (RIA). With fluorescence microscopy and flow cytometry 1.01 +/- 0.31 and 0.82 +/- 0.28% (mean +/- SD), respectively, of cord RBC and 0.79 +/- 0.31 and 0.53 +/- 0.28% of RBC from anemic patients reacted with F-IgG. RBC of normal adults showed virtually no F-IgG reactivity. In anemic patients there was a good correlation between the percent of F-IgG-reactive cells and the percent of reticulocytes, although the former were only two thirds of the latter; the ratio of F-IgG reactive cells to reticulocytes was higher in posthemorrhagic anemia than in thalassemia. Moreover, double stainings revealed that the majority of F-IgG reactive RBC were at the reticulocyte stage (80%), and coexpressed transferrin receptor (96%). Furthermore, the F-IgG-positive RBC correlated inversely with Hb levels. When RIA was employed, F-IgG binding to RBC of anemic patients and newborns was similar and considerably and significantly higher than that to RBC from healthy adults. The results demonstrate the reappearance in certain forms of anemia of F-IgG-reactive RBC, which are likely to represent a subpopulation of reticulocytes. PMID- 8677759 TI - Evaluation of cytosine arabinoside, carboplatin and etoposide chemotherapy in the treatment of relapsing and refractory non-Hodgkin's lymphoma. AB - Twenty-eight patients (14 with relapsing and 14 with refractory non-Hodgkin's lymphoma; NHL) were treated with a combination of CACE chemotherapy (cytosine arabinoside, carboplatin, and etoposide) and recombinant granulocyte colony stimulating factor (G-CSF) to investigate the efficacy and adverse effects of this regimen. Twenty-eight NHL patients (16 men and 12 women, median age 52 years) received intravenous infusions of cytosine arabinoside (100 mg/m2) on days 1-7, carboplatin (250 mg/m2) on day 1, and etoposide (70 mg/m2) on days 1-3, as well as the subcutaneous administration of G-CSF (2 micrograms/kg) beginning on day 9. Eleven of 28 (39.3%) patients achieved complete remission (CR) and 10 patients (35.7%) partial remission (PR). Therefore, a total response rate of 75% was achieved. Nine patients with relapsing disease and 2 with refractory NHL achieved CR. Of the 28 patients 51.5% were alive at 3 years, while the 3-year survival rate for those who achieved CR was 87.5%. The 50% disease-free survival duration was 20.8 months. Adverse effects included leukopenia (2 x 10(9)/l) in 4 patients (14.2%) and thrombocytopenia (50 x 10(9)/l) in 18 patients (64.3%). Although the efficacy of the CACE regimen was demonstrated for treatment of relapsing NHL, the efficacy of CACE was not satisfactory for the treatment of refractory NHL. Further study is required to determine the value of the CACE regimen as therapy for the refractory NHL. PMID- 8677760 TI - Immunoglobulin gene rearrangement in T-cell-rich reactive pleural effusion of a patient with B-cell chronic lymphocytic leukemia. AB - Pleural effusion in chronic lymphocytic leukemia (CLL) is a relatively rare phenomenon. We report a case of a pleural effusion associated with B-cell CLL but with predominantly reactive T lymphocytes in the effusion. A cell surface phenotype study showed that T lymphocytes predominated in the pleural effusion, although B lymphocytes were predominant in the peripheral blood. Genotypic analysis of the cells in the peripheral blood, bone marrow, lymph node, and pleural effusion showed the same rearrangement pattern of the immunoglobulin heavy chain genes consistent with a B-lymphocytic neoplasm (CLL). A pleural biopsy demonstrated diffuse infiltration of lymphoid cells. Most of the cells demonstrated T cell markers, although some cells revealed B cell markers by immunologic staining. These results suggested that the pleural involvement by B CLL may have caused a reactive T-lymphocyte proliferation in the pleura and pleural effusion. To our knowledge, this is the first published case indicating that genotypic analysis of immunoglobulin heavy chain gene rearrangement may be useful in the diagnosis of a pleural effusion associated with B-cell CLL. PMID- 8677761 TI - Anaplastic large cell Ki-1 lymphoma: primary bone presentation in an elderly man. AB - Ki-1 anaplastic large cell lymphoma (Ki-1 ALCL) is a recently recognized entity. Primary presentation in the bone is very rare. Very few cases of primary bone presentation have been reported. All previous reported patients were children and young adults, usually with multiple bone involvement. We report a case of a 60 year old man who presented with extensive mixed blastic and lytic lesions in one tibia, simulating osteogenic sarcoma radiographically, with regional lymphadenopathy. Further studies showed this tumor to be a B cell Ki-1 ALCL. Tumor cells stained positive for Ki-1 antigen (CD30), leukocyte common antigen (CD45), vimentin, and L26 (CD20), negative for cytokeratin, S100, Leu M1 (CD15). The patient was treated with combination chemotherapy and local radiation, with an excellent initial response. PMID- 8677762 TI - Oncocytic nonsecretory multiple myeloma. A clinicopathologic study of a case and review of the literature. AB - We report on a morphologic variant of multiple myeloma, identified in a 39-year old man, with osteolytic lesions in two ribs and three lumbar vertebrae. Serum electrophoresis was normal and immunofixation of serum and urine was negative. Histologic examination of a resected rib revealed a homogeneous population of neoplastic plasma cells with granular and eosinophilic cytoplasm. Immunohistochemical stains showed monoclonality for lambda light chain and negativity for all heavy chains. At the ultrastructural level, the cytoplasm of the neoplastic plasma cells was almost totally occupied by round and elongated mitochondria, pushing the rough endoplasmic reticulum to the periphery. To the best of our knowledge, only two similar cases have been reported in the literature so far. The usefulness of obtaining a clinicopathologic correlation for the behaviour of this extremely rare variant of multiple myeloma is discussed. PMID- 8677763 TI - A plea for more inter-departmental collaboration between university departments in obstetrics and gynecology. PMID- 8677764 TI - A study of monoamine oxidase activity in fetal membranes. AB - OBJECTIVE: To study the role of decidual monoamine oxidase (MAO)-A and -B activities before delivery, the relationship between MAO activity in fetal membranes and catecholamine (CA) concentration in amniotic fluid (AF) was determined. METHODS: Fetal membranes and AF were obtained at the time of elective Cesarean section (CS group, n = 11) and Cesarean section due to fetal distress without labor pains (FD group, n = 5). MAO-A and -B activities were radiometrically measured using 14C-5-hydroxytriptamine for MAO-A substrate and 14C-benzylamine for MAO-B substrate. CA concentrations in AF were measured by high performance liquid chromatograph with an electro-chemical detector. RESULTS: Both MAO-A and -B activities in decidua obtained from CS were significantly lower than those obtained from FD. Both norepinephrine (NE) and epinephrine (EP) concentrations were significantly lower in the CS group than the FD group. A significant positive correlation between decidual MAO-A activity and NE concentration in AF was observed. No significant correlation was observed between MAO-B activity and the concentration of NE in AF. There was no correlation between EP concentrations and MAO activities. CONCLUSION: These results suggest that CA concentration in AF may be related to the activity of MAO in fetal membranes, determined by certain physiological processes during pregnancy. It has been suggested that metabolism of monoamines in fetal membranes also plays an important role in reducing monoamine influx into maternal myometrium from the AF. PMID- 8677765 TI - Plasma platelet aggregating factor and platelet aggregation studies in pre eclampsia. AB - OBJECTIVE: A plasma platelet aggregation factor (PAF) has been implicated in the pathogenesis of platelet activation in thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Similar mechanism may be operative in pre eclampsia. METHODS: Coagulation profile and detailed in vitro platelet aggregation with various agonists were studied. PAF was demonstrated by spontaneous aggregation of normal platelets with test plasma. Non-parametric Wilcoxon's rank sum test and Krauskal Wally's one way analysis of variance were applied. RESULT: Twenty-two pre-eclamptic patients and 20 normal pregnant controls were studied. Anti-thrombin III levels were within normal range and fibrin degradation products were only border line raised ( > 10 < 40 micrograms/ml) in 14 (65.4%) patients. In vitro platelet aggregation was abnormal in 17 (77.2%) patients. PAF was demonstrable in 10 of 22 (45.5%) patients. CONCLUSION: Platelet aggregation studies indicated the presence of both activated (hyperaggregable) as well as exhausted (hypoaggregable) platelets in circulation. PAF demonstrable in 45.4% pre-eclampsia patients would suggest its role in the pathogenetic mechanism of platelet activation in this disease. PMID- 8677766 TI - Effects of endothelin-1 and the ETA receptor antagonist BQ-123 on resistance arteries from normal pregnant and preeclamptic women. AB - OBJECTIVE: To compare the effect of endothelin on isolated resistance arteries from different vascular beds in normal and preeclamptic women before and after pretreatment with the ETA receptor antagonist BQ-123. MATERIALS AND METHODS: Resistance arteries from myometrial and omental biopsies obtained at cesarean section of normal pregnant and preeclamptic women were dissected and mounted in organ baths for recording of isometric tension. The contractile response to endothelin-1 in presence and absence of BQ-123 was recorded. RESULTS: Endothelin 1 induced similar concentration-dependent contractions in all arteries investigated. In women with preeclampsia the contractile response induced by endothelin-1 was significantly higher in omental as compared to myometrial vessels. Pretreatment with BQ-123 significantly shifted the concentration response curve to the right but only reduced the maximum contractile response in omental vessels. CONCLUSION: Endothelin-1 is a potent constrictor of resistance arteries from different vascular beds in normal pregnancy and preeclampsia. The contractile effect is at least in part mediated by ETA receptors, since it was significantly reduced after pretreatment with BQ-123. In preeclamptic but not in normal pregnant women the response to endothelin-1 was reduced in myometrial as compared to omental arteries, possibly secondary to receptor down regulation. PMID- 8677767 TI - Pregnancy related changes in some cardiovascular risk factors. AB - BACKGROUND: Certain risk factors for development of ischemic heart disease are influenced by pregnancy related changes of female sex hormone levels. METHODS: As a part of the cardiovascular risk factor studies in Finnmark county, Norway, 1974 75 and 1977-78, cross-sectional clinical and non-fasting laboratory data were obtained prior to conception (n = 463), during pregnancy (n = 335), and following delivery (n = 451). RESULTS: Compared with prepregnancy values, total cholesterol was on average 7% lower in the first trimester (p < 0.001), and 30% higher at the end of gestation (p < 0.001). High density lipoprotein cholesterol was 38% higher at mid-pregnancy (p < 0.001), but only 14% higher in the last trimester (p < 0.01). Serum triglycerides were 18% lower in the first (p < 0.001) and 123% higher in the third trimester (p < 0.001). Blood glucose was 5% lower than baseline in mid-pregnancy (p < 0.001). Except for the second trimester, when only 27% of women smoked, more than 40% of the women examined were smokers. Postpartum values were similar to prepregnancy levels, except serum triglycerides which remained 35% higher (p < 0.001) and blood glucose (p < 0.05). CONCLUSIONS: The major serum lipid fractions, and blood glucose, were significantly different during pregnancy and postpartum, which may influence the risk of cardiovascular disease development in women. PMID- 8677768 TI - A comparative study of obstetric outcome of patients with pregnancy induced hypertension: economic considerations. AB - BACKGROUND: Hypertension in pregnancy is associated with increased maternal and fetal morbidity and mortality. The aim of this prospective study was to evaluate the obstetric outcome of patients with pregnancy induced hypertension (PIH) that delivered at the Maternity Hospital Kuwait within a period of six months and evaluate the economic implications of present management strategies. METHODS: This was a comparative study with age and parity, as matching variables, in 224 pregnant hypertensive women and 224 normotensive controls. RESULTS: During the study period, the incidence of PIH was 4.9 percent. They were more associated with diabetes mellitus and multiple pregnancy than controls (p < 0.02). About 43 percent of the hypertensive parturients used antihypertensive therapy. More of them had induction of labor (p < 0.001), preterm delivery (p < 0.0002) and cesarean section (p < 0.001), and babies with low birthweight (p < 0.01). In the linear regression analysis, hypertension in pregnancy gave rise to more hospitalisation, intrauterine growth retardation and operative deliveries than the normotensive controls. The perinatal mortality was higher (p < 0.001). CONCLUSION: Despite the economic expenditure of about five times more for hypertensive women in pregnancy than in controls, both obstetric and neonatal outcome, are still significantly worse in the former. This study therefore advocates more research into the prevention, prediction and management, including neonatal care, of hypertensive disorders of pregnancy. PMID- 8677769 TI - Maternal and perinatal implications of the use of human recombinant erythropoietin. AB - BACKGROUND: The use of human recombinant erythropoietin (rHuEPO) in pregnant patients has been limited by the fear of eventual maternal and fetal repercussions (either direct or indirect). METHODS: The authors present their experience with the use of rHuEPO during pregnancy, with two pregnant women with kidney transplants and in three others with chronic renal insufficiency (one with diabetic nephropathy, another dialysis dependent), all with hematocrit below 30% and adequate iron reserves. RESULTS: Three of the patients had needed blood transfusions before beginning therapy, and another needed transfusion after significant metrorrhagia. The length of the treatment varied between 2 and 23 weeks and the hematocrit at delivery varied between 26% and 36%. Secondary effects (appearance or worsening of hypertension and seizures) were nil. There was one fetal death at 23 weeks of pregnancy (following an abruptio placenta), two neonates weighing between the 5th and the 10th percentiles, and three needing phototherapy (1 to 2 days). One year after birth, all showed a normal ponderal and neurologic development. CONCLUSIONS: Among the cases presented, no maternal and perinatal complications attributable to rHuEPO were registered. It is important that institutions report their experiences with the use of rHuEPO, given its restrictive indications and the limited experience of each institution. PMID- 8677770 TI - Cytogenetic evaluation of cystic hygroma associated with hydrops fetalis, oligohydramnios or intrauterine fetal death: the roles of amniocentesis, postmortem chorionic villus sampling and cystic hygroma paracentesis. AB - BACKGROUND: Pregnancies complicated by fetal cystic hygroma in the second and third trimesters are often associated with hydrops fetalis, oligohydramnios or intrauterine fetal death which may make genetic assessment more difficult. We investigated the roles of amniocentesis, postmortem chorionic villus sampling and cystic hygroma paracentesis in cytogenetic evaluation of cystic hygroma under such circumstances. METHODS: Thirty-five fetuses of cystic hygroma associated with hydrops fetalis, oligohydrammos, or intrauterine fetal death were studied. All fetuses were delivered at Mackay Memorial Hospital, Taipei, Taiwan between January, 1987 and July, 1995. Data collected included maternal age, prenatal sonograms, gestational age at diagnosis, fetal karyotypes and diagnostic procedures. RESULTS: Of 35 fetuses, all had hydrops fetalis, 19 had suffered IUFD at the time of diagnosis, and 10 had severe oligohydramnios. Cytogenetic studies were performed via amniocentesis, postmortem chorionic villus sampling, or cystic hygroma paracentesis. Successful karyotyping was achieved in 32 fetuses and the karyotype of 45,X was found in 24 fetuses. In cases with IUFD, successful karyotyping rates on cells from amniotic fluid, chorionic villi and cystic hygroma fluid were 88.9% (8 of 9), 69.2% (9 of 13) and 20% (1 of 5), respectively, whereas, in cases with living hydropic fetuses, successful karyotyping was achieved in 12 of 12 amniotic fluid and 5 of 5 cystic hygroma fluid samples. CONCLUSIONS: Amniocentesis is a better method for cytogenetic evaluation of fetal cystic hygroma associated with intrauterine fetal death than postmortem chorionic villus sampling and cystic hygroma paracentesis. However, in the case with a living hydropic fetus and oligohydramnios, cystic hygroma paracentesis appears to be a practical alternative for cytogenetic assessment. PMID- 8677771 TI - The effects of parity on birthweight using successive pregnancies. AB - OBJECTIVE: Accurate assessment of the difference in birthweight between first and second live-births to the same woman having excluded the effects of physiological factors known to affect birthweight. DESIGN: Retrospective longitudinal observational study. SETTING: Three large obstetric units in the East Midlands of the United Kingdom. SUBJECTS AND METHODS: Women in whom data were recorded for their first two pregnancies on the UK East Midlands Obstetric database which resulted in the delivery of a liveborn, singleton and congenitally normal baby. Six thousand five hundred and thirty such cases were identified, of which 3457 had complete datasets and delivered both babies at term (259 to 300 days). An analysis was performed of changes between the paired pregnancies of physiological factors known to affect birthweight. Regression analyses were used to enable prediction of the second birthweight with the knowledge of the first birthweight. RESULTS: The mean crude birthweight difference between first and second pregnancies was an increase of 138 g. Significant differences between the paired pregnancies were found in maternal booking visit weight, blood pressure, maternal age and gestation at delivery. Independent factors affecting difference in birthweight were gestation at delivery, maternal booking weight and baby's sex. Regression towards the mean was demonstrated which meant that a woman delivering a first baby weighing more than 3720 g could expect a lighter baby for her second delivery provided that all other factors remained constant. CONCLUSIONS: In general terms a woman is more likely to deliver a heavier baby in her second pregnancy than in her first pregnancy. However, maternal physiological factors differ in the two pregnancies and these differences have additional effects on birthweight. The effects of both these observations are tempered by regression towards the mean which has a profound influence in predicting the likely change in birthweight between first and second pregnancies. Clinical decisions should not be based on the assumption that a second baby will inevitably be heavier than the first baby. PMID- 8677772 TI - A placebo-controlled trial of oral ergometrine to reduce postpartum hemorrhage. AB - BACKGROUND: Active management with oral ergometrine 0.4 mg was compared with expectant management for the control of blood loss in the third stage of labor in women at low risk of postpartum hemorrhage (PPH). METHODS: A three-arms randomized trial in which 0.4 mg ergometrine (2 tablets of 0.2 mg) was set off against placebo, both groups allowing comparison with a standard oxytocin regimen of 5 IU. Women at low risk for PPH. Of 367 parturients, 146 were randomised to ergometrine 0.4 mg, 143 to placebo and 78 to intramuscular oxytocin in a 2:2:1 design. RESULTS: Compared with placebo, ergometrine reduced blood loss with 5% ( 5%; Confidence interval: -20% to +13%). Oxytocin reduced blood loss with 9% (-9%; Confidence interval: -26% to +12%) versus placebo. CONCLUSION: Oral ergometrine has too little effect on blood loss after childbirth in order to be a good alternative to parenteral prophylactic management. PMID- 8677773 TI - Surgical management of tubal infertility. A regional study. AB - OBJECTIVE: To investigate an unselected group of patients in a regional area undergoing tubal surgery for infertility and to identify those women who would benefit from surgery and those who should be referred directly to in vitro fertilization (IVF). DESIGN: A retrospective study based on medical records and questionnaires. SETTING: The Departments of Obstetrics and Gynecology, Gentofte. Glostrup and Herlev Hospitals, University of Copenhagen, Denmark. SUBJECTS: Two hundred and thirty-six women with primary or secondary infertility undergoing tubal surgery or adhesiolysis during a five year period from 1985 to 1989 with a follow-up period of minimum of 24 months. RESULTS: Ninety-four women (40%) became pregnant at least once and accounted for the total number of 144 pregnancies. One hundred and forty-two patients (60%) did not become pregnant. The delivery rate was 25%, and 37 women (16%) had at least one ectopic pregnancy. There were no significant differences in the delivery rates of the operations in between, but the risk of ectopic pregnancy was significantly lower after adhesiolysis only than after tubal surgery (p < 0.05). The initial laparoscopic findings could not be used to predict the probability of intrauterine pregnancy. CONCLUSION: There is still a place for surgical treatment of tubal infertility, but the risk of ectopic pregnancy should be taken into account before a decision concening line of treatment is made. PMID- 8677774 TI - How should we investigate women with postmenopausal bleeding? AB - OBJECTIVE: To evaluate the optimum method(s) of investigating women with postmenopausal bleeding. DESIGN: Prospective study of 76 postmenopausal women. SETTING: Teaching Hospital. Interventions. All women had pipelle endometrial biopsy in outpatient clinic. Prior to inpatient hysteroscopy and uterine curettage, each woman had pelvic ultrasonography to measure the endometrial thickness and to exclude ovarian pathology. RESULTS: Pipelle biopsy was successful in 70% of cases and has a sensitivity of 70%. Hysteroscopy has superior diagnostic capabilities allowing direct visualisation of the endometrial cavity with directed biopsies. Endometrial thickness of > 5 mm used as an indicator of endometrial pathology compared to uterine curettage has a sensitivity of 83%, a specificity of 77%, and a positive predictive value of 54%. Ultrasound also detected five ovarian tumors, two of which were malignant and three missed by pelvic examination alone. CONCLUSIONS: We recommend the routine use of pelvic ultrasonography in all women with postmenopausal bleeding as it is an invaluable diagnostic tool in excluding ovarian pathology. In addition, sampling of the endometrial cavity, preferably with outpatient hysteroscopy, is mandatory for histological diagnosis. Overall, the combination of ultrasound and outpatient endometrial sampling would spare hospital admission for at least 60% of women with postmenopausal bleeding. PMID- 8677775 TI - Outcome of short stay surgery in conventional gynecological operations. AB - BACKGROUND: To find out the suitability of increasingly common short stay surgery in major conventional gynecological operations. METHODS: A retrospective study of sixty-six patients who underwent major conventional gynecological operations on a short stay basis between January 1990 and December 1992, in a private hospital, at Turku, Finland, were enrolled to the study. The length of the operation, the time of hospitalization, the duration of the sick leave and possible complications were retrospectively studied. The postoperative long-term outcome and the satisfaction of the patients with short stay surgery was evaluated with a questionnaire. RESULTS: The patients were hospitalized for mean 2.6 days. There were no peroperative complications but four patients (6%) needed rehospitalization because of postoperative problems. Five minor complications (two wound infections and three urinary tract infections) were treated in outpatients after discharge. All patients were satisfied with the short stay surgery. The day of discharge was considered suitable by 80% of the patients and most of the patients (97%) would also recommend similar treatment to their acquaintances. CONCLUSION: These results suggest that short stay surgery in major gynecological operations can be considered as an alternative to conventional hospitalization. PMID- 8677776 TI - Age of sexual debut related to life-style and reproductive health factors in a group of Swedish teenage girls. AB - AIM: To compare life-style and reproductive health care factors in girls with a coitus debut < 15 years of age and girls with a later debut. METHODS: Girls resident in the municipality of Karlstad, Sweden, starting their upper secondary school education were invited to attend the teenage clinic during two years (five visits). Gynecological examinations were performed and questions were asked about possible symptoms, sexual activity, contraception and sexually transmitted diseases. RESULTS: Ninety-eight girls accepted the invitation to participate and 88 girls completed all visits (mean age on admission 16 years). Median age for coitarche was 16 years. A sexual debut < 15 years was reported by 17 girls (19.3%), 54 (61.4%) had their debut > or = 15 years and 17 girls (19.3%) had not had their sexual debut on completion of this study. Girls with an early sexual debut had a greater number of sexually transmitted diseases (p < 0.05) and more cervical atypias (p < 0.05), and more often had a menarcheal age < 13 years (p < 0.05), > two brothers and/or sisters (p < 0.01), were more often not living with their parents (p < 0.01) and reported a greater number of life-time partners (p < 0.06) than the remainder, Girls with a sexual debut < 15 years started drinking alcohol earlier than others (p < 0.01). There was a greater proportion of smokers among girls with an early sex debut compared to the remainder (p < 0.05). CONCLUSIONS: Early sexual debut is associated with an earlier menarche and a more premature adult life-style and is an important indicator for continued risk behavior regarding reproductive health. PMID- 8677777 TI - Sexual risk behavior and history of sexually transmitted diseases in relation to casual travel sex during different types of journeys. AB - OBJECTIVES: The study investigated if women with experience of casual travel sex, with a previously unknown man abroad, on different types of journeys (charter, vagabond, business and education trips), differ with regard to sexual risk behavior and history of sexually transmitted diseases (STDs). STUDY DESIGN: The study population consisted of 996 women. Of these, 27.7% admitted that they had had casual sex during journeys. The remaining women were used as a comparison group. History of STDs and sexual risk behaviors were investigated. RESULTS: The frequency of women who had more than ten lifetime sexual partners were greatly increased in all groups, as compared to the controls. A history of gonorrhea was most frequent among the charter travellers. A history of genital chlamydial infection was most common among the vagabond travellers. The lowest frequencies of a history of STDs was observed in women engaging in casual sex on 'business' journeys and they had significantly less often a history of STDs as compared to the charter travellers. A high frequency of STDs were seen in women who had experience of casual sex on different types of journeys. CONCLUSION: Women on business trips, although they had a similar sexual risk behaviour as the other groups of travellers, had less often a history of STDs. PMID- 8677779 TI - Prenatal diagnosis of epignathus causing acute polyhydramnios. PMID- 8677780 TI - A congenital lethal form of hypophosphatasia: histologic and ultrastructural study. PMID- 8677778 TI - Isolated rectal lesions during parturition. PMID- 8677781 TI - Endometrioma of the vagina in menopause. PMID- 8677783 TI - Urinary pregnanetriol-3-glucuronide in children: age-related change and application to the management of 21-hydroxylase deficiency. AB - Urinary concentrations of pregnanetriol-3-glucuronide (PT-3-G) were determined in 485 normal Japanese subjects (277 males and 208 females), aged 5 days to 20 years, using an enzyme-linked immunosorbent assay (ELISA). The usefulness of urinary PT-3-G concentrations before giving the morning dose of medications in monitoring the adequacy of glucocorticoid treatment was assessed in eight patients with 21-hydroxylase deficiency (21-OHD). The ratio of PT-3-G to excreted creatinine (PT-3-G/Cre ratio) increased significantly during the first month and did not change from age 1 month to 1 year of life. The ratio decreased to a nadir at age 3 or 4 years followed by continuous, significant increase until late adolescence. In the subjects treated with corticosteroids for 21-OHD, PT-3-G/Cre ratios at the 50th percentile or below suggested a risk of excessive treatment, as judged by the patients' growth. Measurement of the PT-3-G/Cre ratio enabled recognition of corticosteroid overtreatment, which was not demonstrated by determining the serum concentrations of 17 alpha-hydroxyprogesterone (17-OHP). On the other hand, ratios at the upper 95-99% tolerance limits seemed to be required for optimal control. The present study revealed the normal age-related changes in urinary excretion of PT-3-G and showed it to be a reliable marker for evaluating glucocorticoid treatment in young children with 21-OHD. PMID- 8677782 TI - Primary endometrioid carcinoma of the fallopian tube. PMID- 8677784 TI - Magnetic resonance imaging of clival marrow in patients with anorexia nervosa. AB - Hematological abnormalities, commonly associated with anorexia nervosa (AN) patients, are thought to be the results of serous atrophy in the bone marrow. Magnetic resonance imaging (MRI) has been utilized to ascertain T1 and T2 prolongation of marrow intensity in the lumbar spine, pelvis and proximal femora. The results correlate well with the severity of hematological abnormalities, and body mass index. More importantly, the propensity for peripheral marrow involvement of T2 prolongation contrasts with the axial involvement in other marrow disorders. MRI undertaken in patients with AN to exclude hypothalamic tumor showed that the clival marrow was equivalent to the peripheral marrow. The signal pattern of clival marrow on sagittal T1 weighted MR images was evaluated in four teenage female patients with AN complicated by hematological abnormalities. Although the clival marrow intensity should be uniformly high in teenagers, three patients, two with pancytopenia and one with leukopenia and anemia, exhibited homogeneous low intensity. One patient who had leukopenia only and the highest body mass index, showed inhomogeneous low intensity. The signal changes returned to normal in all patients but one, who died before examination after 6-11 months, at which time the others had almost recovered their original weight and normal hemogram. T1 prolongation in the clival marrow represents bone marrow dysfunction and the inhomogeneity of the signal change may imply relative preservation of hematopoiesis and body fat composition. Lack of knowledge of this phenomenon may lead to diagnostic confusion with other marrow disorders on cranial MRI. PMID- 8677785 TI - Serum cortisol and prolactin levels in childhood paroxysmal disorders. AB - Postictal serum prolactin and cortisol levels were measured in 37 children having either epilepsy, febrile seizure or syncopal attack and in 37 normal controls. Blood samples were obtained within 1.5 h following the seizure episode. All serum levels were compared between each group and the control groups. Significantly higher (P < 0.005) prolactin levels (56.64 +/- 34.78 ng/mL) were found in the epileptic group, compared to the levels in children with febrile seizures (21.72 +/- 12.92 ng/mL), syncope attacks (13.88 +/- 5.27 ng/mL) and the control group (14.32 +/- 5.05 ng/mL). In contrast, serum cortisol levels were non-specifically elevated in children with epilepsy, febrile seizures and syncopal attacks. Cortisol secretion appears to be non-specifically elevated in all stressful events. Elevated prolactin levels may be helpful in differentiating epilepsy from febrile seizures and syncope. PMID- 8677786 TI - Immunogenicity of the whole antigen and glycoprotein I of varicella-zoster virus (VZV) and the VZV skin test antigen. AB - Specific cellular immunity against the whole antigen and glycoprotein I (gp I) of varicella-zoster virus (VZV) and the skin test antigen were determined for 13 healthy immune adults to compare the immunogenicity of these antigens using a lymphoproliferative assay. The stimulation index values (mean +/- s.d.) were 16.4 +/- 11.2 against the whole VZV antigen, 4.2 +/- 2.9 against the VZV skin test antigen and 1.1 +/- 0.5 against gp I. The immunogenicity of the skin test antigen, which mainly contains gp III and gp IV, appears to be more favorable than that of gp I alone, but to be weaker than that of the whole VZV antigen. PMID- 8677787 TI - IgG subclasses in children with recurrent respiratory tract infections in an allergy practice. AB - Isolated or combined deficiencies of immunoglobulin G (IgG) subclasses have been recognized in children with recurrent infections. In our allergy practice, there are a subset of children with recurrent respiratory tract infections. To investigate the presence of immunoglobulin G subclass deficiency (IgGSD), 60 children with atopy and 14 children without atopy suffering from recurrent respiratory tract infections were studied in an attempt to determine whether atopy is associated with a certain IgG subclass pattern. Ten atopic children were found to have isolated or combined IgG subclass deficiencies: one with IgG1, two with IgG2, four with IgG3 and three children had IgG2-IgG3. Neither IgG subclass concentration nor the frequency of children with high or low IgG subclasses showed any difference between atopic and non-atopic groups. Except for a week correlation with IgG3, no correlation existed between IgE and other IgG subclasses. It was concluded that childhood respiratory diseases complicated by recurrent respiratory tract infections may be associated with IgG subclass deficiencies. Although there have been reports noting some IgG subclass patterns in atopic disorders, in the present study, no distinctive feature between atopics and non-atopics with respect to IgG subclass concentrations and patterns was observed. PMID- 8677788 TI - Outbreak of acute glomerulonephritis in children: observed association with the T1 subtype of group A streptococcal infection in northern Kyushu, Japan. AB - Group A streptococcal infection is associated with the occurrence of acute glomerulonephritis (AGN) and rheumatic fever (RF). A surveillance study in the Saga area, in northern Kyushu, Japan, showed a small variation in the reported number of group A streptococcal infections in the period 1988-94. However, of the AGN cases reported in this period, more than half were observed in 1992. In order to examine whether some change had occurred in the serotype distribution of Streptococcus pyogenes during the period, patients in the Saga area diagnosed as having group A streptococcal infection and patients with AGN or RF were analyzed. Serological T-typing of S. pyogenes was carried out for patients with group A streptococcal infections, and the association between the occurrence of AGN or RF and the distribution of each different T subtype was analyzed. M-typing of S. pyogenes was also carried out and the correlation between T and M types was examined. From 1988 to 1994, the annual number of patients with group A streptococcal infections in the Saga area showed a small variation, range 65-100 patients/year. Of the 42 patients with AGN and three with RF observed in this period, 27 with AGN (64%) and one with RF (33.3%) were detected in 1992. Only the T1 subtype increased in 1992; the other T subtypes showed little variation in incidence. The number of patients with the T1 subtype was significantly correlated with the occurrence of AGN by regression analysis (P < 0.01). Of the 170 subjects tested for both T and M subtypes, 44 of the 45 T1-typed subjects had the M1 protein. Our epidemiological study suggested that the T1 subtype of streptococcal infection was associated with an outbreak of AGN in 1992 in the Saga area. PMID- 8677789 TI - Interleukin 8 and granulocyte elastase alpha 1 proteinase inhibitor complex in the tracheobronchial aspirate of infants with chronic lung disease following inter-uterine infection. AB - In order to elucidate the role of interleukin 8 (IL-8) in the development of chronic lung disease (CLD) of neonates with intra-uterine infection, serial and simultaneous measurements of the concentration of IL-8 and granulocyte elastase alpha 1 proteinase inhibitor complex (E-alpha 1 PI) in the tracheobronchial aspirate of low birth weight infants were conducted. Infants with a high serum IgM level at birth, and who subsequently developed CLD, showed significantly high concentrations of IL-8 and E-alpha 1 PI in the first 48 h. It seemed that IL-8 stimulated neutrophils to release neutrophil enzymes which, in turn, caused the lung tissue injury, resulting in the development of CLD following intra-uterine infection. PMID- 8677790 TI - Long-term ventilator-assisted children in Japan: a national survey. AB - Owing to improved technology and care for patients who need mechanical ventilation, the quality of life as well as the prognosis for long-term ventilator-assisted patients has improved significantly in recent years. However, the increased number of these patients has raised economic, ethical and medical problems. In order to assess the magnitude of these problems, we conducted the first nationwide survey on the status of long-term ventilator-assisted children in Japan. Questionnaires were mailed to 2524 pediatric departments at hospitals in Japan with more than 100 beds. At the time of the survey, 282 hospitals had 567 patients who had been ventilated for more than a month. Among these patients, 434 were younger than 20 years and had been ventilated for more than 3 months. The most common basic disorders were: various myopathies (n = 65), hypoxic ischemic encephalopathy (n = 60), spinal muscular atrophy type 1 (Werdnig Hoffmann disease, n = 55), chronic lung disorders of prematurity (n = 21), Ondine's curse (n = 22), drowning (n = 17) and congenital heart diseases (n = 16). Of these 434 patients, only 61 were ventilated at home. Although home care was considered suitable for chronic ventilator patients by many pediatricians who responded to the survey, its realization has been hampered by the lack of a system and regulations to support it. The fact that many pediatricians in Japan have actively prolonged the life of Werdnig-Hoffmann patients, from whom aggressive life saving measures have been withheld in most Western countries, has raised ethical as well as medical issues. PMID- 8677791 TI - The safety of a nitric oxide inhalation system using a conventional infant respirator. AB - Attention is becoming increasingly focused on inhalation of nitric oxide (NO) as a selective pulmonary vasodilator. Its metabolite nitrogen dioxide (NO2), however, is a toxic molecule. The purpose of the present study was to evaluate the safety of a NO inhalation system using a conventional infant respirator from the viewpoint of NO2 production. The NO inhalation system consisted of a standard neonatal ventilator, a neonatal circuit and a test lung. The NO concentration was increased from 0 up to 19 ppm. At each level of NO, the oxygen (O2) concentration was changed from 21 to 100%. The NO and NO2 concentrations were measured with a chemiluminescence analyzer using a molybdenum converter. The NO2 concentration was increased when either the O2 or the NO concentration was increased. The maximum concentration of NO2 was 0.10 +/- 0.02 ppm when the concentrations of NO and O2 were 19 ppm and 100% respectively. The NO inhalation system, using a conventional infant respirator, can be used safely when monitoring NO and NO2 concentrations. PMID- 8677792 TI - Evaluation of the peripheral circulatory status of the neonate during homeothermal adjustment by plethysmo-time-interval. AB - The plethysmo-time-interval (PTI) is the time interval between the beginning of the QRS complex on an ECG and the upstroke of the pulse wave on a plethysmogram, as measured by pulse oximetry. In the present study, we investigated homeothermal acclimatization to the extra-uterine environment in human neonates using the Coretemp thermometer and a pulse oximeter. Temperature was measured at three sites: the central deep temperature (CDT) on the upper sternum, the peripheral deep temperature (PDT) on the flat part of the left sole of the foot and the surface temperature (ST) at the side of the abdomen. After delivery, CDT and ST were higher than PDT. The difference between CDT and PDT was large at first, but gradually decreased. PDT, initially in the range of 32.4 +/- 0.28 degrees C, reached a stable value (34.4 +/- 0.41 degrees C) at 2.5 h after delivery. PTI was prolonged in parallel with PDT. The difference between CDT and PDT probably reflected the contraction of skin vessels, particularly the arterioles, which occurs as a body defense mechanism against heat loss. As PTI was prolonged in parallel with PDT, we demonstrated objectively that this catch-up phenomenon of PDT after delivery was affected by the increase in skin blood flow as a result of dilatation of peripheral arterioles. It was concluded that PTI can be used to evaluate the peripheral circulatory status of the neonate, even during homeothermal adjustment after birth, by applying a new principle of pulse oximetry that is widely used in neonatal intensive care units. PMID- 8677793 TI - Change of immunological parameters in the clinical course of a myasthenia gravis patient with chronic graft-versus-host disease. AB - The change in immunological parameters was studied during the clinical course of a myasthenia gravis (MG) patient with chronic graft-versus-host disease (GVHD), which developed after bone marrow transplantation from an HLA-identical donor. Anti-acetylcholine receptor antibody gradually decreased in the patient treated with immunosuppressive agents, but was not detected in the donor. Lymphocyte numbers were low just before the onset of MG, increased abruptly within several days and then gradually decreased with treatment. The percentage of CD3+ and CD19+ lymphocytes was higher at onset than before, the percentage of CD4+ cells was higher at onset and gradually decreased with treatment, while CD8+ cells showed the lowest level just before onset and gradually increased during the clinical course. CD4+/CD45RA- cells also showed the highest levels at onset and a gradual decrease with treatment. Cellular, as well as humoral immune responses, might be associated with the pathogenesis of MG with chronic GVHD. PMID- 8677794 TI - Hepatitis B virus-associated nephropathy: 17 year progression from onset to end stage renal failure. AB - Hepatitis B virus-associated nephropathy (HB nephropathy) was first described in 1971. There have been few reports on the long-term prognosis in children with HB nephropathy. A case is reported here of a child who presented with symptoms of acute glomerulonephritis at 12 years of age and progressed to end-stage renal failure 17 years after the clinical onset, in spite of the seroconversion of HB virus by formation of HBe antibody. PMID- 8677795 TI - Successful percutaneous closure of a coronary artery fistula with a detachable balloon. AB - Percutaneous transcatheter closure technique of a coronary artery fistula with a detachable balloon was performed for a 14 year old male student. Complete closure of the fistula without any complications was confirmed by angiography after the procedure. When the patient underwent a second angiography 6 months after the closure, it was confirmed that the position of the balloon had not changed, that the interruption of the flow of the fistula had been maintained and that the diameter of the left coronary artery and the fistula were reduced. Percutaneous closure technique using a detachable balloon may become the primary treatment for a coronary artery fistula in place of surgical ligation. PMID- 8677796 TI - Gigantic aneurysm in the thoraco-abdominal aorta of an infant. AB - We report the case of a boy with a gigantic aneurysm in the thoraco-abdominal region which was detected by a chest X-ray taken prior to surgical correction of ptosis of the eyelids at 11 months of age. At 18 months, he successfully underwent aneurysm exclusion and bypass grafting. A biopsy from the thoracic aorta revealed medial degeneration with conspicuous smooth muscle cell involvement. Laboratory examination showed altered elastase activity in the granulocytes and whole blood. The present case may represent a unique form of aneurysm in infancy. PMID- 8677797 TI - A case of dysembryoplastic neuroepithelial tumor of the parietal lobe with characteristic magnetic resonance imaging. AB - The case of a 4 year old boy with a dysembryoplastic neuroepithelial tumor (DNT) of the left parietal lobe is reported. The DNT was located mainly in the cortex and showed no mass effect on magnetic resonance imaging (MRI). T1-weighted images of the DNT showed the characteristic findings of lesion hypointensity, but with a well preserved gyrus-like configuration. This lesion was isointense to the normal cortex on proton density imaging and hyperintense on T2-weighted imaging. The characteristic features on T1-weighted and proton density imaging in this patient were useful in differentiating DNT from other types of tumors. Histologic findings in DNTs, which include the presence of both glial and neuronal cells without atypia and no definite transitional zone between the adjacent disorganized cortical cell layers, suggest that DNT is not a true neoplasm but rather a dysplastic lesion. It is clinically important to differentiate this tumor both from other benign tumors and malignant tumors which have different prognoses and therapies. The distinctive MRI findings, as well as the histologic features of DNT, support the diagnosis in the clinical setting. PMID- 8677798 TI - Focal nodular hyperplasia in an adolescent with glycogen storage disease type I with mesocaval shunt operation in childhood: a case report and review of the literature. AB - As patients with glycogen storage disease type I survive longer, cases with hepatic tumor have been increasingly documented. A 16 year old boy with glycogen storage disease type I was evaluated for multiple liver tumors. He was diagnosed on clinical features at 9 months of age and underwent a mesocaval shunt operation at 5 years of age. The biopsy of one of the masses showed focal nodular hyperplasia. This is uncommon in patients with glycogen storage disease type I, compared to those with adenoma or malignant hepatic tumor. The association of a portacaval shunt with focal nodular hyperplasia is significant compared to other tumors. An environment of high estrogen concentration or sex hormone binding globulin accompanied by shunt operation may cause focal nodular hyperplasia to develop in the liver of patients with glycogen storage disease type I. PMID- 8677799 TI - Current status and future prospects of human gene therapy. AB - Gene therapy is defined as the treatment of diseases by the transfer of genes into patients. Clinical trials of gene therapy became feasible as a result of the development of retroviral mediated gene transfer techniques. The first trial was begun in September 1990 at the National Institutes of Health when a four year old girl was treated for adenosine deaminase deficiency. Currently, more than 500 patients are being treated by this innovative therapeutic strategy. In the present review article, the basic concepts and present status of human gene therapy are summarized. PMID- 8677800 TI - Adenovirus vector technology: an efficient method for constructing recombinant adenovirus and on/off switching of gene expression. AB - An efficient method of constructing recombinant adenoviruses (Ad) has been established. The expression unit to be introduced into recombinant Ad was first inserted into the unique SwaI site of the full-length Ad genome cloned in a cassette cosmid. The cassette bearing the expression unit was then cotransfected to 293 cells together with the Ad DNA-terminal protein complex digested at several sites with EcoT22I. The use of the parent Ad DNA-terminal protein complex instead of the deproteinized Ad genome DNA allowed very efficient recovery of the desired recombinant Ad, and the restriction digestion drastically reduced regeneration of the parent virus. This method may facilitate the application of recombinant Ad and should be useful for further improvement of Ad vectors. Also a recombinant adenovirus expressing Cre recombinase derived from bacteriophage P1 was constructed. To assay the Cre activity in mammalian cells, another recombinant Ad bearing an on/off switching reporter unit, where a LacZ-expression unit can be activated by the Cre-mediated excisional deletion of an interposed stuffer DNA, was also constructed. Co-infection experiments together with the Cre expressing and the reporter recombinant Ad showed that the Cre-mediated switching of gene expression was detected in nearly 100% of cultured CV1 cells. These results suggest that the recombinant Ad efficiently expressed functional Cre and offers a basis for establishing a powerful on/off switching strategy of gene expression in cultured mammalian cells and presumably in future gene therapy. PMID- 8677801 TI - Gene therapy for ornithine transcarbamylase deficiency. AB - Ornithine transcarbamylase (OTC) deficiency in humans is the most common and severe inborn error of the urea cycle. Despite therapeutic advances, OTC deficiency remains without adequate treatment, hence mortality rates are high. In the two available strains of OTC-deficient murine models, spf and spfash, researchers have tried to make genetic corrections by introducing the OTC gene. Transient but complete recovery of OTC was obtained in adult spfash mice and in OTC-deficient human primary hepatocytes, using a recombinant adenoviral vector. These experiments represent a first step in the development of human gene therapy for OTC deficiency and other hepatic enzyme deficiencies. PMID- 8677802 TI - Gene therapy for metachromatic leukodystrophy. AB - Metachromatic leukodystrophy (MLD) is an inherited metabolic disease which is characterized by a deficiency of arylsulfatase A (ASA). This deficiency causes progressive accumulation of cerebroside sulfate in oligodendrocytes (OL) in the brain, resulting in dysmyelination. Approaches being developed by the authors to treating MLD are based on direct delivery of ASA genes into the brain. In the present report, it has been shown that the recombinant adenovirus (Adex1SRLacZ) was able to transduce the OL very efficiently. Moreover, primary fibroblasts from MLD patients were exposed to recombinant adenovirus expressing the ASA gene (Adex1SRASA) and the cells expressed the transgene. The influence of overexpression of ASA on the activity of other sulfatases was also tested in fibroblasts from patients with MLD using a retrovirus vector (MFG-ASA). It was demonstrated that the overexpression of ASA reduces the activity of various sulfatases by a small amount but does not induce an accumulation of glycosaminoglycan. These results indicate that the influence of ASA overexpression on other sulfatases is different from that of the N acetygalactosamine-4-sulfatase overexpression in a previous report. It was concluded that the correction of ASA deficiency by a recombinant adenovirus that potentially could be used to transfer the gene to the brain, and gene therapy for MLD based on gene transfer of the ASA gene to mutant cells will be feasible because the overexpression of ASA in cells does not lead to profound deficiency of other sulfatases or result in a new phenotype. PMID- 8677803 TI - Adolescents' perceived risk and personal experience with natural disasters: an evaluation of cognitive heuristics. AB - Elevated risk judgments for negative life events have been linked to personal experience with events. We tested the hypothesis that cognitive heuristics are the underlying cognitive mechanism for this relation. The availability (i.e., memory for incidents) and simulation (i.e., imagery) heuristics were evaluated as possible mediators for the relation between personal experience and risk estimates for fatal weather events. Adolescents who had experienced weather disasters estimated their personal risk for weather events. Support was obtained for the simulation heuristic (imagery) as a mediator for the relation. Availability for lightning disaster experience was also found to be a mediator for the relation between personal lightning disaster experience and risk estimate for future events. The implications for risk perception research are discussed. PMID- 8677804 TI - Left and right visual field advantages are a function of scotopic and photopic retinal adaptation, respectively, in simple reaction time to near-threshold targets. AB - Modulation of stimulus luminance in a tachistoscopic face discrimination task has been found to significantly invert visual hemifield advantage in reaction time (RT) (Sergent, 1982a, Sergent, 1982b). However, there is no more physiological rationale for that than for a similar effect, say, of retinal adaptation, and it is even conceivable that the latter may have confounded the former in past experiments. The experiments reported here were therefore designed to tease out the relative contributions of stimulus luminance and of background illumination (i.e., retinal adaptation) in a simple RT task. Two equally difficult conditions of dim targets were set up, one with light-adapted subjects and one with dark adapted subjects. Similarly, two equally difficult conditions of bright targets were set up with light and dark-adapted subjects. It was found that dim targets (near detection threshold) yielded a significant right visual field RT advantage in light-adapted subjects and that dim targets (equally near detection threshold) yielded a significant left visual field RT advantage in dark-adapted subjects. Future experiments will determine whether cone-mediated RT to detection is left hemisphere dominant and whether rod-mediated RT to detection is right hemisphere dominant. PMID- 8677805 TI - Inattention and the perception of visual feature conjunctions. AB - Visual processing of objects in the absence of focused attention appears to be limited. We varied the degree of attention, or visual processing, that observers paid to objects using an instruction set manipulation. In 2 experiments, subjects performed tasks that required superficial or detailed visual analysis of the objects involved. In subsequent recognition tests, information about conjunctions of shape and internal color/texture pattern was limited when only superficial visual analysis was required to encode the object. This implies that the degree of visual processing, during object encoding affects the likelihood that feature conjunctions are incorporated into the visual representation of these objects. PMID- 8677806 TI - Viability of resource theories in explaining time-sharing performance. AB - The primary objective of the present research was to test for performance tradeoff induced by priority instructions with the purportedly unbiased optimum maximum method. In experiment 1, performance tradeoff was observed when the tracking task was optimized but not when the Sternberg memory task was optimized. It was hypothesized that the tracking task was protected by peripheral vision when subjects focused on the optimized memory task. The second experiment tested the generality of the results with additional variations of the task pairs selected to represent different degrees of shared resources. The extent of performance tradeoff and time-sharing efficiency varied systematically with the extent of predicted resource overlap between the time-shared tasks. The observed performance tradeoff was strongly indicative of subjects' voluntary allocation control. Further, subjective ratings suggested that such control was effortful. These results were supportive of multiple resource theories and the viability of resource explanation of task interference. PMID- 8677807 TI - Absorbed dose in AgBr in direct film for photon energies ( < 150 keV): relation to optical density. Theoretical calculation and experimental evaluation. AB - In the radiological process it is necessary to develop tools so as to explore how X-rays can be used in the most effective way. Evaluation of models to derive measures of image quality and risk-related parameters is one possibility of getting such a tool. Modelling the image receptor, an important part of the imaging chain, is then required. The aim of this work was to find convenient and accurate ways of describing the blackening of direct dental films by X-rays. Since the beginning of the 20th century, the relation between optical density and photon interactions in the silver bromide in X-ray films has been investigated by many authors. The first attempts used simple quantum theories with no consideration of underlying physical interaction processes. The theories were gradually made more realistic by the introduction of dosimetric concepts and cavity theory. A review of cavity theories for calculating the mean absorbed dose in the AgBr grains of the film emulsion is given in this work. The cavity theories of GREENING (15) and SPIERS-CHARLTON (37) were selected for calculating the mean absorbed dose in the AgBr grains relative to the air collision kerma (Kc,air) of the incident photons of Ultra-speed and Ektaspeed (intraoral) films using up-to-date values of interaction coefficients. GREENING'S theory is a multi grain theory and the results depend on the relative amounts of silver bromide and gelatine in the emulsion layer. In the single grain theory of SPIERS-CHARLTON, the shape and size of the silver bromide grain are important. Calculations of absorbed dose in the silver bromide were compared with measurements of optical densities in Ultra-speed and Ektaspeed films for a broad range (25-145 kV) of X ray energy. The calculated absorbed dose values were appropriately averaged over the complete photon energy spectrum, which was determined experimentally using a Compton spectrometer. For the whole range of tube potentials used, the measured optical densities of the films were found to be proportional to the mean absorbed dose in the AgBr grains calculated according to GREENING'S theory. They were also found to be proportional to the collision kerma in silver bromide (Kc,AgBr) indicating proportionality between Kc,AgBr and the mean absorbed dose in silver bromide. While GREENING'S theory shows that the quotient of the mean absorbed dose in silver bromide and Kc,AgBr varies with photon energy, this is not apparent when averaged over the broad (diagnostic) X-ray energy spectra used here. Alternatively, proportionality between Kc,AgBr and the mean absorbed dose in silver bromide can be interpreted as resulting from a combination of the SPIERS-CHARLTON theory, valid at low photon energies ( < 30 keV) and GREENING'S theory, which is strictly valid at energies above 50 keV. This study shows that the blackening of non-screen films can be related directly to the energy absorbed in the AgBr grains of the emulsion layer and that, for the purpose of modelling the imaging chain in intraoral radiography, film response can be represented by Kc,AgBr (at the position of the film) independent of photon energy. The importance of taking the complete X-ray energy spectrum into full account in deriving Kc,AgBr is clearly demonstrated, showing that the concept of effective energy must be used with care. PMID- 8677808 TI - [Urology specialization. Part I. Current status and perspectives]. AB - At present the only official way for training and obtention of a degree of specialist in Urology is through the Resident In-house Physician (MIR) program. Although in general terms, the MIR program offers the best way to train specialists, we believe a review and self-evaluation of this system aimed both to elucidate the existing problems and to improve the programme would be useful and necessary. Three different questionnaires were prepared and sent to the Heads of Training Services, to the Residents in all the Urology Services where certified training is being given, or has been given over a five-year period, and to a random sample of Heads of Services who have no Residents appointed. The objective was to get to know the state of opinion on the specialization system, the attitude with regard to other possibilities, as well as to shape a resident's profile, make an evaluation of the professional and working environment, and obtain a general objectivization of the Spanish hospitals. Although the level of response was not consistent in all three groups, it was sufficient to be able to state that the system is considered good and the training correct. However, not all centres fulfill the requirements to have a Teaching Service. Training is not as consistent as it should be in a MIR-type system. PMID- 8677809 TI - [Urology specialization. Part II. Survey of the heads of teaching services]. AB - The Heads of the Teaching Services have in their hands a large share of responsibility for the training of specialists. Therefore, they are the group with greater power to decide and give their opinion on this question. A large majority (77%) responded to the survey conducted. The questions covered 213 of the 252 residents preparing their specialty at the time in Spain. From their answers it can be deduced that a Teaching Service attends 30-35 beds (although there are exceptions) with 8-10 attached physicians, 5 residents on average. They are well equipped (although marked differences can be noted), they mainly do calls in their specialty and most of the services have been training residents for more than eight years. The Heads of the Teaching Services believe the MIR programme is the best way to prepare the degree, although an important portion postulates it should not be the only one. PMID- 8677810 TI - [Urology specialization. Part III. Opinion of resident internal physicians]. AB - At present the only official way for the training and obtention of a degree of specialist in Urology is through the Resident In-house Physician (MIR) program. With the passing of time both the rights and the wrongs of the training program under consideration come to light. From the former we try to obtain the maximum yield and with the latter we attempt to improve them or withdraw them if obsolete. The purpose of this survey was to evaluate from the Urology resident in house physicians point of view, their training term. To that end, we have chosen the MIR examination of groups for the years between 1988 and 1992, both inclusive, a population that amounts to 252 subjects. There has been three releases of the questionnaire to all Teaching Hospitals within the national geography but only 81 (32.1%) resident physicians have answered it. The extensive questionnaire was divided in 6 sections: demographics, personal evaluation of the hospital staff and service, health care activities (admittance schedule, out patient surgery, operating theatre and emergencies), non-health care activities (publications, attendance to congresses, etc...), evaluation of the MIR system, and professional aspirations. PMID- 8677811 TI - [Urology specialization. Part IV. Survey of the heads of non-teaching services]. AB - Presentation of the results obtained from the answers to the survey sent to the Heads of Urology Services with no certification for teaching the specialty. Information relative to Service possibilities, training aspects and evaluation of the current specialization system is requested. Also, an evaluation is made of the suitability of the number of specialists per year and their training level. Finally, they are also asked for an evaluation of assistants in urology. PMID- 8677812 TI - [PSA levels and its relationship with digital examination, age, and score of prostatic symptoms]. AB - Between November 1992 and March 1993 our Service conducted a campaign for early detection of prostate disease among the male population of Vigo. The study focused in the relationship of PSA with the age, rectal examination and prostate symptomatology score. In view of the results obtained it has been concluded that PSA levels increase gradually as a function of age, volume and prostate symptomatology score. PMID- 8677813 TI - [Eosinophilic cystitis: a single anatomopathologic entity and three different presentation forms. Proposed classification]. AB - The present work was intended to be a revision of our series of Eosinophilic Cystitis and we have found that, from one single anatomicopathological picture three different clinical pictures emerge with different treatments and prognosis. Group I is constituted by young people and children with a profuse background of atopy and parasitosis, which develop mictional syndrome and haematuria and show good response to steroids. Group II includes middle-aged women, with development of chronic recurrent cystopaty and a poor response to treatment. Group III comprises elderly patients with a history of vesical injury or chronic vesical irritation, with no separate clinical signs and symptoms and requiring no treatment. PMID- 8677814 TI - [Assessment of double-J ureteral catheters at a lithotripsy unit: our experience]. AB - The present study evaluated a total of 350 patients who underwent placement of double-J catheters as a result of their lithiasic condition. The work includes a review of the patients' urological background, indication for the double-J placement, tolerance to catheter, time of permanence, reason for withdrawal, presence of encrustations in the catheter and relationship between all these parameters. A significant increase of adverse symptoms was observed when permanence of the double-J catheter lasted longer than 6 weeks. Likewise, there was a significant increase in the number of encrustations in catheters retained longer than 6 weeks, as well as when the lithiasic mass was meaningful and urine cultures were positive. The authors consider that double-J catheters effectively prevent the complications of the lithiasic condition but an excessively long permanence, more than 6 weeks, increases occurrence of side-effects significantly. PMID- 8677815 TI - [PSA and hormone-refractory period in prostatic cancer]. AB - Study of the characteristics of the hormone-refractory period in 32 patients with disseminated prostate cancer who had achieved a complete response to total androgen suppression, appreciating in all of them a subclinical or asymptomatic stage and a clinical or symptomatic one. The subclinical stage was characterized by raised PSA levels and ranged between 3-35 months; at 12 months 59% of patients had advanced to the symptomatic stage, while at 24 months this percentage is 84%. The clinical stage extends from appearance of symptoms to the patient's death, ranging from 3 to 32 months; at 12 months 41% has died; and 91% at 2 years. PMID- 8677816 TI - [Congenital prepubic sinus]. AB - Presentation of one case of Urethral Duplicity of the Blind Epispadias variant, also known as Congenital Prepubic Sinus. This form of accessory urethra is a congenital malformation which consists in a pseudofistular passage which starts at the proximity of the bladder's anterior side-though uncommunicated with it-and spreads to the skin of the pubic area where it ends. No other malformative condition was found in the comprehensive study conducted, and only the existence of repeat episodes of mucopurulent drainage material advised its removal. This manoeuvre was followed by a complete cure and, after more than two years follow up, the patient remains asymptomatic. PMID- 8677817 TI - [Leydig cell tumor in the adult]. AB - Presentation of 3 cases of Leydig's cells tumour in the adult seen in our hospital over the last 10 years. They account for 3% of all testicular tumours, 20 to 25% of them appearing during the pre-puberty period. Although an isolated testicular nodule is the most frequent symptom, gynaecomastia can be found in about 30% of adult patients, as it happened in 2 of our patients. Even though no malignant case has been described in children, up to 10% of cases in adults have metastasis, this being the only demonstration of malignant behaviour in these tumours, so radical orchiectomy is the choice therapy. Certain histological and hormonal parameters may be suggestive of the aggressive behaviour of this neoplasia which, however, we have not found in our series of all whom presented a good evolution after surgery. The most common diagnostic and therapeutic approaches, based on the different characteristic of the tumour, are reviewed. PMID- 8677818 TI - [Evolutive orchiepididymitis or ischemic testis?: that is the question]. AB - We report a case of deferred acute scrotum in a young teenager. Even though initially the aetiological diagnosis seemed clear (partially treated epididymo orchitis), glandular viability remained uncertain due to ultrasound findings and the time elapsed since initial diagnosis. Colour Doppler Ultrasound is examined as the most useful ancillary method in differential diagnosis in this setting, as well as the different ultrasound findings in subsequent stages of spermatic cord torsion and epididymo-orchitis. Possible testicular ischaemia in this clinical setting is emphasized, explaining its pathophysiology. PMID- 8677819 TI - [Epididymal leiomyoma. Report of 2 cases]. AB - At present, the paratesticular tumors are not frequent, but when they appear, the most common location is on spermatic cord and epididymis. Within the epididymal tumors the most frequent (75%) are benign tumors, been the second one the leiomyoma after the adenomatoid tumor. We want to show two clinical cases about epididymal leiomyoma in patients who had different ages. We achieve the definitive diagnostic after the tumor removed by histological analysis. We also checked the medical literature. PMID- 8677820 TI - [Prostatic abscess: diagnosis and treatment]. AB - Prostatic abscesses are an infrequent pathology, probably due to a better and early management of prostatic infections. Predisposing factors in this pathology are diabetes mellitus, urethral catheterism or manipulation, and immunodepressed states like AIDS. Nowadays, ultrasonography is an excellent diagnostic method of this pathology, and serves as a guidance of directed drainage. We present five cases in which the size of the abscess was determining in relation to the therapeutic attitude. Abscesses of less than 2 cm, measured by transrectal ultrasonography, can be evacuated by directed puncture, followed by antibiotic treatment. When the diameter of the abscess is greater than 2 cm, we realize a perineal drainage with a catheter placed with transrectal ultrasonography. Currently, TUR and other methods seems to be overcome. PMID- 8677821 TI - [Number of authors in Actas Urologicas Espanolas]. AB - OBJECTIVE: To study the number of authors of papers published in Actas Urologicas Espanolas, and to assess the consequences on multiple authorship of the restriction to 6 of the number of authors for paper, established in the instructions for authors since January 1995. METHODS: The authors and papers appearing on sections "Originals". "Reviews" and "Case reports" from 1992 to 1995, were counted. RESULTS: Five hundred and forty eight papers were reviewed. The mean (+/- standard deviation) number of authors (6.1 +/- 2; 95% IC = 5.9-6.3) didn't show a statistically significant change between the 4 studied years (ANOVA, F = 1.42; p = 0.23). Fifty percent of the Originals and Reviews and 36% of Case reports had more than 6 authors and these proportions didn't change significantly between years (chi 2 = 3.48; p = 0.32), even considering that more than one third of papers published in 1995 were accepted that year. CONCLUSIONS: A great number of authors should modify their habits of co-authorship on papers submitted to Actas Urologicas Espanolas, in order to fulfill the new instructions for authors. PMID- 8677822 TI - [Focal infarction of the testis]. PMID- 8677823 TI - [Treatment of infiltrating transitional carcinoma of the bladder with partial cystectomy]. PMID- 8677824 TI - [P53 protein gene. Review of the literature and assessment of the prognostic impact of its mutations in bladder tumors]. AB - The p53 protein, of the core protein group, was initially considered an oncogene but it was later noted to be included in the group of tumour-suppressive genes, the function of which seems to be focused in the control of cell growth, regulation of DNA transcription, and inhibition of certain oncogenes. A mutant protein variety has been observed with longer than normal mean life and altered function, so that it is not effective for the inhibitory control of cell growth. Mutations of that protein's gene, located in the short arm of chromosome 17, have been discovered in a large variety of tumours in humans, and in the urogenital region they have been consistently seen in both vesical and prostate tumours. The objective of the study was to confirm the need of this gene mutation, so that the vesical transitional cell tumour develops an infiltrant nature. The presence of mutations in this gene's exons 5 and 8 in infiltrant transitional cell tumours (28.5% cases) was demonstrated using as controls either surface transitional cell tumours, non-transitional tumours and healthy vesical tissue obtained together with the tumour specimen in each surgical procedure. The methods used were PCR (polymerase chain reaction) and the identification of the mutated specimen through TGGE (temperature gradient electrophoresis). The absence of mutations in the control strips together with the observation of mutations in the specimens from infiltrant tumours confirms the above hypothesis. PMID- 8677825 TI - SORT: a validation study with stroke patients. Salford Objective Recognition Test. AB - The Salford Objective Recognition Test (SORT) was developed as a measure of recognition memory suitable for use with elderly people as it requires a shorter administration time than Warrington's Recognition Memory Test. Normative data for the SORT were collected from 50 normal elderly people living in the community. Fifty stroke patients were assessed on the SORT and other tests of psychological functioning. The words and faces subtests were found to correlate well with other measures of memory. The SORT was found to be uninfluenced by the effects of sex and time since onset of stroke, but was affected by language difficulties and perception problems. The split-half reliability of the test was found to be good as alternative versions of the subtests correlated well with each other. PMID- 8677826 TI - Informant ratings of cognitive decline of elderly people: relationship to longitudinal change on cognitive tests. AB - Formal assessment of cognitive decline with cognitive tests can be difficult, requiring either two measurement points or a comparison of 'hold' with 'don't hold' tests. Informant-based assessment provides an alternative approach because informants can adopt a longitudinal perspective and directly rate cognitive change. A study was carried out to assess the validity of informant ratings collected by means of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). A community sample of 500 subjects aged 74 or over underwent four cognitive tests on two occasions 3 1/2 years apart. On the second occasion, informants filled out the IQCODE. Subjects rated as having moderate or severe decline were found to have greater change on the cognitive tests. These findings support the validity of informant ratings of cognitive decline. PMID- 8677827 TI - Prevention of hepatitis A virus infection. AB - Hepatitis A virus infection is major cause of acute hepatitis in the United States, accounting for approximately 75,000 cases of clinical illness each year. These infections occur among persons in every age group and are associated with a variety of exposures related to fecal-oral transmission. Recently, the U.S. Food and Drug Administration approved licensure of two inactivated hepatitis A vaccines. Both vaccines are highly immunogenic and have been licensed in pediatric and adult formulations. The prevention of hepatitis A virus infection is directly related to many aspects of family practice, and family physicians may see patients in a variety of settings that warrant administration of hepatitis A vaccine. Groups for whom vaccination is currently recommended include international travelers, children in communities with high rates of hepatitis A virus infection, men who have sex with men, Illicit drug users, patients with chronic liver disease and persons with clotting factor disorders. PMID- 8677828 TI - Evaluation of women with hirsutism. AB - Hirsutism is a common disorder of androgen activity that manifests in women as excessive growth of terminal hairs in androgen-dependent regions of the body. In most women with hirsutism, the condition is idiopathic or caused by polycystic ovary syndrome. However, a thorough evaluation is necessary to exclude more serious causes of hirsutism, such as adrenal or ovarian neoplasm. In most patients, an appropriate history and physical examination and minimal laboratory evaluation suffice. However, signs of virilization demand more extensive diagnostic evaluation. PMID- 8677829 TI - Rotator cuff disorders. AB - The supraspinatus, infraspinatus, teres minor and subscapularis muscles form a musculotendinous rotator cuff that provides dynamic stability to the shoulder joint. Symptoms of rotator cuff injury include limitation of motion, weakness and pain that often radiates down the upper arm and is present at night. Examination may reveal deltoid and rotator cuff atrophy, tenderness, limited passive range of motion and weakness on abduction and external rotation. Radiographs may show degenerative changes of the acromion or acromioclavicular joint, cysts, sclerosis and spurs of the greater tuberosity, and calcific deposits within the supraspinatus tendon. In most patients with subacromial impingement, conservative management, including physical therapy, nonsteroidal anti-inflammatory drugs and subacromial injections, is successful. Failure of conservative therapy after six to 12 weeks merits further evaluation with magnetic resonance imaging or arthrography, and consideration of surgery. PMID- 8677830 TI - Practical nutrition for the healthy term infant. AB - Breast milk is universally recommended as the preferred source of infant nutrition, in part because of its superior nutrient and immunologic properties. Successful breast feeding requires nursing on demand, prevention of sore nipples and convenient access to medical advice. For mothers relying on bottle feeding, cow's-milk-based formula is the preferred choice. Because soy-based formulas are lactose-free, they may be tolerated by infants who are allergic to cow's-milk protein. Protein hydrolysate formulas should be used only in infants who cannot tolerate cow's-milk-based or soy-based formulas. Low-Iron formulas and whole cow's milk should not be used during the first year. Breast-fed infants rarely require vitamin supplementation. Fluoride supplementation is no longer recommended for infants less than six months of age. PMID- 8677831 TI - Initial stabilization and medical management of acute spinal cord injury. AB - Despite intensive preventive efforts, acute spinal cord injury remains a significant public health problem. The pathophysiology of this type of injury involves both the primary, or initial, mechanical injury and secondary injury mechanisms such as ischemia, lipid peroxidation and intracellular calcium influx. Initial management includes immobilization of the injured spine, maintenance of the airway, systemic oxygen delivery and treatment of neurogenic shock. All patients with acute spinal cord injury should receive an intravenous bolus of methylprednisolone, 30 mg per kg, within eight hours of injury, followed by an infusion of 5.4 mg per kg per hour for 23 hours. Transfer to a regional acute spinal cord injury unit for definitive management should be accomplished as soon as the patient's condition is stabilized. PMID- 8677832 TI - The MILD interview: evaluating complaints of memory loss. AB - Patients complaining of memory loss present a complex diagnostic challenge to the physician. The physician must evaluate the patient's mood disturbance, medical condition, lifestyle and drug use as potential contributors to memory loss. An interview strategy focused on these factors may help the physician identify patients who simply need information and reassurance, patients who may benefit from new or revised treatment plans and patients who should undergo more comprehensive assessment. PMID- 8677833 TI - Use of the Mogen clamp for neonatal circumcision. AB - Most newborn circumcisions performed in the United States are done with either a Gomco clamp or a Plastibell device. The Mogen clamp, devised by a jewish mohel, provides a quick and simple surgical alternative. The foreskin is freed from the glans by blunt dissection, but no dorsal slit is made. A dorsal hemostat is placed, and traction is applied to bring the foreskin forward. Placement of the Mogen clamp follows the angle of the corona to avoid removing excess skin ventrally and to obtain a superior cosmetic result. The clamp crushes the foreskin along a line that is 1 mm wide, and the foreskin is excised distal to the clamp. After removal of the clamp, the glans is liberated by pulling the crush line apart. The procedure usually takes three to four minutes and is virtually bloodless. PMID- 8677834 TI - An update on vaccine safety. AB - Vaccination has dramatically reduced the number of annual cases of pertussis, diphtheria, measles and congenital rubella syndrome. Although side effects of immunizations can occur, serious adverse events are rare for all vaccines commonly used in the United States. Infantile spasms and sudden infant death syndrome are not associated with childhood vaccines. Compared with whole-cell pertussis vaccine, acellular pertussis vaccines are significantly less likely to produce moderate reactions such as fever, fussiness, pain, drowsiness, anorexia and local redness or swelling. Despite the documented safety and efficacy of childhood vaccines, concerns about vaccine safety increase when diseases such as measles, pertussis and rubella are no longer common. Parents need to be reminded that their child is susceptible to these diseases, that these diseases are preventable by reasonably safe and effective immunizations and that their child needs a series of vaccines at regular intervals by the age of two years. Since 1994, all physicians have been required by law to use the Vaccine information Statements for measles-mumps-rubella vaccine, diphtheria and tetanus toxoids and pertussis vaccine, poliovirus vaccines and tetanus and diphtheria toxoids for adults. PMID- 8677835 TI - Guillain-Barre syndrome: a team approach to diagnosis and treatment. AB - Guillain-Barre syndrome is the most frequently acquired demyelinating peripheral polyneuropathy. In approximately two-thirds of cases, Guillain-Barre syndrome is preceded by a viral respiratory or gastrointestinal infection. The mechanism of injury is unclear but is believed to be immunologic. The cardinal clinical feature is symmetric and rapidly progressive weakness. Aspiration and respiratory failure are the major concerns. Sensory symptoms, such as paresthesias, are common. The most severe stage of the disease is reached two to four weeks after onset. Dysautonomia has replaced respiratory failure as the most common cause of death. Recovery is variable: 50 percent of patients recover completely, about 35 percent experience permanent neurologic sequelae, and 15 percent are significantly and permanently damaged. About 10 percent relapse before complete recovery, and 2 to 5 percent experience recurrence after full recovery. Laboratory confirmation of Guillain-Barre syndrome includes the typical cerebrospinal fluid cytoalbumin dissociation (elevated protein without white blood cells). Treatment is primarily symptomatic and preventive. Convalescent patients require intensive inpatient physical and occupational therapy to improve strength and prevent disabling contractures. PMID- 8677836 TI - Diagnostic imaging in the evaluation of blunt abdominal trauma. AB - Blunt abdominal trauma is a common cause of death and nonfatal injury. Diagnostic imaging may provide useful information in hemodynamically stable patients. In addition, patients who are comatose may benefit from imaging when intra-abdominal findings would change the course of clinical management. Computed tomographic scanning of the abdomen usually provides accurate information and may allow the physician to determine whether observation or surgery is warranted. PMID- 8677837 TI - Intussusception. AB - Intussusception is the invagination of one bowel segment into another. It is an emergent condition that most commonly affects infants between five and nine months of age, but it can also occur in other age groups. The etiology is usually idiopathic in infants five to nine months of age; neonates, older children and adults more commonly have lead points such as a Meckel's diverticulum or a neoplasm. Early diagnosis is essential to avoid treatment delays, which can increase morbidity and mortality. It has been reported that patients with intussusception present with abdominal pain, vomiting and bloody stools, but this classic triad is often absent. More commonly, lethargy and irritability are the presenting signs. A rectal examination, with testing for occult blood, is an important part of the evaluation and is frequently positive. Barium enema is the gold standard for diagnosis and also has therapeutic potential for reducing the intussusception. Ultrasound is an accurate, low-risk screening tool when performed and interpreted by an experienced ultrasonographer. Surgical reduction is performed if nonoperative reduction is contraindicated or unsuccessful, or if a lead point is suspected. PMID- 8677838 TI - Common oral conditions. AB - Although some oral lesions, such as torus palatinus, are normal variants, and others, such as benign migratory glossitis, are self-limited, several common oral conditions require prompt diagnosis and treatment to reduce the potential for serious complications. Treatment of dental and periodontal abscesses may include incision and drainage, antibiotic therapy, pain control and dental extraction. Treatment of sialolithiasis (blockage of the salivary gland ducts) may require application of moist heat, antibiotics and surgical removal of impacted stones. Hyperkeratosis, a white patch on the oral mucosa that does not rub off or bleed (as does the white patch of candidiasis) commonly occurs in persons who use smokeless tobacco products. The lesion may require biopsy if it still persists two to four weeks after discontinuation of the tobacco product. Squamous cell carcinoma, which accounts for 95 percent of all oral cancers and is most commonly associated with alcohol and tobacco use, is usually asymptomatic until the late stage of the disease. Suspicious lesions should be biopasied to confirm the diagnosis. PMID- 8677839 TI - Exertional collapse and sudden death associated with sickle cell trait. AB - Although rare, exertional collapse and sudden death are the most serious potential complications of sickle cell trait. Studies suggest that this condition may occur in susceptible persons when poor physical conditioning, dehydration, heat stress or hypoxic states precipitate sickling of the abnormal erythrocytes. Sickling leads to endothelial damage, which can cause vasoconstriction, disseminated intravascular coagulation and local tissue damage. Cardiac effects include acute ischemia and arrhythmias. Muscle damage results in acute compartment syndromes and release of myoglobin into the circulation. Acute renal failure is possible. Diagnosis is based on a high index of suspicion, and characteristic presentation and laboratory findings, including myoglobinuria, hyperkalemia, hypocalcemia, hyperphosphatemia and elevated creatine kinase levels. The differential diagnosis includes pulmonary embolism, acute cardiac events, anaphylaxis and heat stroke. Management is based on stabilization, rehydration, and the treatment and prevention of complications. PMID- 8677840 TI - Management of heart failure. AB - Heart failure is associated with high rates of morbidity and mortality. Because heart failure is difficult to diagnose accurately on the basis of the history and physical examination alone, It is vital that clinical evaluation such as echocardiography be used to confirm the diagnosis. In addition, it is important to identify etiologic or predisposing factors that may be reversible. Angiotensin converting enzyme inhibitors should be considered in all patients with a diagnosis of left ventricular systolic dysfunction, unless contraindications exist. Diuretics and digoxin are helpful in specific circumstances. Comorbid factors such as excessive alcohol intake and coronary artery insufficiency should be addressed. Patient and family education and cooperation with medical regimens can reduce morbidity and mortality. PMID- 8677841 TI - Alpha blockers: a reassessment of their role in therapy. AB - Intended for the treatment of hypertension, alpha blockers offer advantages in treating patients who also have other risk factors for coronary artery disease. Alpha blockers lower blood pressure by decreasing vascular resistance and are effective for the treatment of mild to moderate hypertension. In addition, alpha blockers have beneficial effects on lipid levels; they increase high-density lipoprotein levels and decrease total cholesterol, low-density lipoprotein and triglyceride levels. Alpha blockers do not induce glucose intolerance or hyperinsulinemia. Although they appear to decrease left ventricular mass, the clinical significance of this action is unknown. Alpha blockers are also effective for improving the symptoms of benign prostatic hypertrophy, although surgery is recommended for patients with severe symptoms. PMID- 8677842 TI - Ways to access FDA information. PMID- 8677843 TI - American academy of Pediatrics addresses meningococcal disease prevention and control strategies. PMID- 8677844 TI - ACOG releases report on gynecologic ultrasonography. PMID- 8677845 TI - American Thoracic Society issues a new position statement on smoking and health. PMID- 8677846 TI - Ritonavir for advanced HIV infection. PMID- 8677847 TI - First HIV antigen screening test. PMID- 8677848 TI - Nutrition. Recommended core educational guidelines for family practice residents. American Academy of Family Physicians. PMID- 8677849 TI - Antimicrobials in children and the problem of drug resistance. PMID- 8677850 TI - Thyrotoxic periodic paralysis. PMID- 8677851 TI - Treatment vs. nontreatment of asymptomatic genital warts. PMID- 8677853 TI - Support group for patients with androgen insensitivity. PMID- 8677852 TI - Delayed microsurgical repair of avulsion injury. PMID- 8677854 TI - Public health policies for HIV/AIDS prevention. PMID- 8677855 TI - Sexual abstinence for prevention of Chlamydia trachomatis infection. PMID- 8677856 TI - Care of diabetic foot lesions. PMID- 8677857 TI - Care of diabetic foot lesions. PMID- 8677858 TI - Digital dilatation for relief of proctalgia fugax. PMID- 8677859 TI - Links between hypertension and myocardial infarction. AB - The mechanisms through which hypertension contributes to the occurrence of myocardial infarction should be discussed from two points of view: (1) common risk factors for the two diseases, such as genetic risk, insulin resistance, sympathetic hyperactivity, and vasoactive substances such as angiotensin K, and (2) linking factors that are induced by hypertension and contribute to the development of atherosclerosis and myocardial infarction, such as atherosclerosis and left ventricular hypertrophy. Mechanical stress on blood vessels because of high blood pressure is an especially important factor in endothelial dysfunction, the progression of atherosclerosis, and plaque rupture. This article concentrates on these factors from the perspective of their relationship with the renin angiotensin system, because recent multicenter trials have demonstrated that angiotensin-converting enzyme inhibitors are effective for preventing recurrence of myocardial infarction. PMID- 8677860 TI - Implications of the links between hypertension and myocardial infarction for choice of drug therapy in patients with hypertension. AB - Meta-analyses of major outcome trials have demonstrated that the benefits of antihypertensive treatment for reduction of the incidence of stroke are entirely consistent with the benefits predicted from epidemiologic data; however, there remains a shortfall in the expected reduction of the incidence of coronary heart disease. Several explanations have been proffered to account for this shortfall, including the potential deleterious metabolic effects of long-term antihypertensive treatment; this has led to the speculation that antihypertensive agents with beneficial ancillary properties might confer additional significant advantage. However, with the exception of the angiotensin-converting enzyme inhibitors, few of these agents have translated into clinical benefit for humans. In addition, sound reasons exist to justify a focus on maintaining and improving the "quality" of blood pressure control. Current evidence suggests that optimal benefit is likely to result from the use of pharmacologic strategies that lower blood pressure consistently over a 24-hour period while at the same time maintaining the "normal" circadian pattern of blood pressure. This result will only be achieved with drugs and drug regimens that genuinely offer long duration of action with the additional potential benefit of maintaining a significant blood pressure lowering effect beyond the end of the dosage interval. This factor is particularly important because many patients with hypertension demonstrate poor adherence to prescribed dosage regimens. PMID- 8677861 TI - The role of neurohormonal activation in chronic heart failure and postmyocardial infarction. AB - Chronic heart failure is a disabling and lethal disorder with high incidence and prevalence in Western societies. Treatment with angiotensin-converting enzyme (ACE) inhibitors and heart transplantations diminish both mortality and morbidity, although both still remain high. Increased understanding of some of the pathophysiologic mechanisms involved in the development of left ventricular dysfunction and the transition from asymptomatic systolic dysfunction to symptomatic heart failure has opened gates to new dimensions for the treatment of this disorder. The initial event in the pathophysiologic process is damage to the myocardium, most frequently a myocardial infarction. Almost simultaneously, activation of different neurohormonal systems occurs. The renin-angiotensin system and sympathetic nervous system are activated. Increased concentrations of hormones with counteractive activity have also been found, such as ANP and BNP. Interestingly, prolonged neurohormonal activation seems to occur only in patients with large infarcts or in patients with poor systolic function of the left ventricle. Moreover, available data from an echocardiographic study indicates that in patients with high concentrations of neurohormones in plasma a week after their infarction, left ventricular dilatation and systolic dysfunction of the left ventricle are highly likely to develop during long-term follow-up. Several studies have showed that ACE inhibitors are efficacious in chronic heart failure and among patients with reduced ejection fraction after myocardial infarction. What these patients have in common is prolonged neurohormonal activation, which theoretically may be harmful to myocardial cell structure and function. ACE inhibitors reduce the breakdown of angiotensin I to angiotensin II and increase the concentration of circulating bradykinins and prostaglandins. Further modulation of neurohormonal activity might be beneficial. Therefore, future treatment of chronic heart failure or asymptomatic left ventricular dysfunction might include beta-adrenergic blockers, neutral endopeptidase inhibitors, ANP, BNP, angiotensin II receptor antagonists, and modulators of sympathetic activity. PMID- 8677862 TI - Angiotensin-converting enzyme inhibition after myocardial infarction: the Trandolapril Cardiac Evaluation Study. AB - To study the importance of giving an angiotensin-converting enzyme (ACE) inhibitor to patients with reduced systolic function after an infarction, the Trandodolapril Cardiac Evaluation study was designed to include the majority of patients with echocardiographic signs of left ventricular dysfunction among consecutively screened patients with infarctions. A total of 2606 consecutive patients with left ventricular systolic dysfunction corresponding to an ejection fraction < or = 35% were identified. Of these patients, 1749 (67%) were randomly assigned to receive oral trandolapril or placebo beginning on day 3 to 7 after the infarction. The follow-up period was 2 to 4 years. Trandolapril reduced all cause mortality, with a relative risk reduction associated with trandolapril treatment of 0.78 (p = 0.0013). Benefit was seen within 1 month of treatment. Trandolapril also reduced cardiovascular death (relative risk 0.75, p = 0.001), sudden death (relative risk 0.76, p = 0.03), and progression to severe/ resistant heart failure (relative risk 0.71, p = 0.003). Recurrent myocardial infarction (fatal or nonfatal) was not significantly reduced (relative risk 0.86, p = 0.29). More than 80% of patients in both treatment groups reached the target dose of 4 mg trandolapril or placebo at the end of dose titration. Nearly half of the patients in both treatment groups discontinued taking study medication before death or trial closure. The need for open-label ACE inhibition was the reason for discontinuation for 48 and 75 patients in the trandolapril and placebo groups, respectively. In conclusion, long-term treatment with trandolapril in patients with reduced left ventricular function shortly after myocardial infarction significantly reduced mortality and morbidity. Most patients received the target dose of 4 mg trandolapril daily. The benefit observed is likely to reflect the benefit in clinical practice because the majority of eligible patients were randomized and the difference in patients leaving the trial to receive open-label ACE inhibition was moderate. PMID- 8677863 TI - Who should be treated with angiotensin-converting enzyme inhibitors after myocardial infarction? AB - Angiotensin-converting enzyme (ACE) inhibitors are now established drugs in the treatment of hypertension and heart failure. However, their use in patients after a myocardial infarction has occurred remains controversial. The major clinical question regarding ACE inhibitors is whether they should be given to all patients immediately after thrombolysis or whether their use should be restricted to a particular subgroup. This question has now been addressed in several large-scale trials of mortality after myocardial infarction, and no important new information seems likely to emerge on the issue. Clinicians must therefore decide what their practice will be on the basis of data that are currently available. The authors of the recently published Gruppo italiano per lo Studio delta Sopravvlvenza nell' infarcto Miocardico (GISSI-3) and Fourth International Study of Infarct Survival (ISIS-4) mega-trials advocate a policy of widespread and early use of ACE inhibitors in all patients after myocardial infarction occurs. However, the small mortality benefit observed from use of ACE inhibitors in these studies lacks certainly and may prove difficult to reproduce in the general population of patients who have had an infarct outside the setting of a trial. Although patients were essentially not selected apart from the exclusion of those with marked hypotension, the low 6-month and 1-year mortality figures indicate "selection" compared with the typical population of patients who have had a myocardial infarction. Furthermore, a significant long-term mortality benefit was not observed with the short-term (4- to 6-week) use of ACE inhibitors in these trials. In contrast, in the Survival and Ventricular Enlargement (SAVE), Acute Infarction Ramipril Efficacy (AIRE), and Trandopril Cardiac Evaluation (TRACE) trials, where evidence of impairment of ventricular function was used to select patients, both a marked and certain benefit regarding mortality was apparent from long-term prescription of these drugs. Importantly, the marked benefit observed in these selected patients may have been "diluted out" in the larger scale trials of unselected patients where the majority may have gained little and some may have been harmed by treatment or its withdrawal. In most of the large mortality trials the rationale for use of ACE inhibitors after myocardial infarction was stated to be their likely beneficial effect on "remodeling" of the heart after "Infarct expansion." Because adverse remodeling occurs in only a proportion of patients after a heart attack, the benefits of ACE inhibitor therapy might be predicted to be largely limited to this group, which would favor a selective policy. However, strong claims have been made that ACE inhibitors have other important actions, including prevention of myocardial infarction. If this is confirmed in a number of ongoing large-scale trials. then an even ore widespread use of these agents can be expected. PMID- 8677865 TI - Usefulness of beta-blocker therapy in patients with non-insulin-dependent diabetes mellitus and coronary artery disease. Bezafibrate Infarction Prevention (BIP) Study Group. AB - The benefit of beta-blocker therapy in patients after myocardial infarction is well established. The use of beta blockers in the high-risk subgroup of patients with combined diabetes mellitus (DM) and coronary artery disease (CAD) remains controversial. From a database of 14,417 patients with chronic CAD who had been screened for participation in the Bezafibrate Infarction Prevention (BIP) study, 2,723 (19%) had non-insulin-dependent DM. Baseline characteristics and 3-year mortality were analyzed in patients with DM receiving (n = 911; 33%) and not receiving (n = 1,812; 67%) beta blockers. Total mortality during a 3-year follow up was 7.8% in those receiving beta blockers compared with 14.0% in those who were not (a 44% reduction). A reduction in cardiac mortality of 42% between the 2 groups was also noted. Three-year survival curves showed significant differences in mortality with increasing divergence (p = 0.0001). After multiple adjustment, multivariate analysis identified beta-blocker therapy as a significant independent contributor to improved survival (relative risk = 0.58; 90% confidence interval 0.46 to 0.74). Within the diabetic population, the main benefit associated with beta-blocker therapy was observed in older patients, in those with a history of myocardial infarction, those with limited functional capacity, and those at lower risk. Thus, therapy with beta blockers appears to be associated with improved long-term survival in the high-risk subpopulation of patients with DM and CAD. PMID- 8677864 TI - Relation of patient characteristics to cardiac ischemia during daily life activity (an Asymptomatic Cardiac Ischemia Pilot Data Bank Study). AB - Cardiac ischemia during daily life activities, detected by ambulatory electrocardiographic (AECG) monitoring has been associated with increased risk for adverse outcomes. Because daily life ischemia is usually asymptomatic, prevalence and descriptive data of patients with asymptomatic cardiac ischemia (ACI) are not well defined. Accordingly, patients screened for the Asymptomatic Cardiac Ischemia Pilot (ACIP) trial by 48-hour AECG monitoring were investigated to identify factors associated with ACI. A total of 1,820 patients with ischemia on a screening stress test and/or known or suspected coronary artery disease underwent AECG monitoring. Their mean age was 61 years, range 33 to 89; 83% were men and 81% were white. On AECG monitoring, ACI occurred in 897 patients (49%). There was a modest trend (p = 0.04) between increasing age and ACI prevalence. Increased risk for ACI was observed in patients reporting angina 6 weeks before screening (odds ratio 1.38, 99% confidence interval 1.08 to 1.77, p = 0.0008). There was a positive association between increases in heart rate during daily life and ACI prevalence (p < 0.0001). No daily, monthly, or seasonal variation in ACI prevalence was found, although ACI was more prevalent in northern than southern sites. In this group of clinically stable patients, selected on the basis of high risk for coronary artery disease, the prevalence of ACI was higher than expected from previous reports. Several readily available clinical characteristics (i.e., advanced age, recent angina, increased heart rate change with daily activity) were associated with significantly increased probability of ACI. PMID- 8677866 TI - Cost and therapeutic modification of intracoronary ultrasound-assisted coronary angioplasty. AB - Intracoronary ultrasound is used to define plaque morphology and quantitative characteristics before and after coronary angioplasty. The cost of the technique was defined in 87 patients who underwent elective, noncomplex procedures: group A was composed of 37 patients without intracoronary ultrasound, who served as a control group; group B comprised 23 patients who had only postcoronary angioplasty ultrasound; and group C was 27 patients who had pre-and postangioplasty ultrasound. Economic analysis was done for the hospital ("bottom up" methodology of equipment, supplies, support personnel, post-PTCA room) and physician costs (using resource-based relative value scale). The cost in the cardiac catheterization laboratory was: group A = $3,679 +/- $688; group B = $4,650 +/- $457; and group C = $5,301 +/- $835, p < 0.0001. The postprocedure cost for all groups was similar. The total cost was: group A = $5,326 +/- $1,135; group B = $6,815 +/- $1,276; and group C = $7,240 +/- $1,494, p < 0.0001. Intracoronary ultrasound modified the coronary angioplasty procedure in 36% of patients. Precoronary angioplasty intracoronary ultrasound defined the luminal diameter, precluding the use of additional balloons, and thus decreased the cost approximately $650. Use of ultrasound after the procedure increases the cost approximately $200 as a result of performing additional interventions. For intracoronary ultrasound to be economically viable, the change in angioplasty technique will need to be accompanied by improved clinical outcome. PMID- 8677867 TI - Linear and nonlinear dynamics of heart rate variability after acute myocardial infarction with normal and reduced left ventricular ejection fraction. AB - We analyzed heart rate variability (HRV) in 2 groups of patients after acute myocardial infarction with normal and reduced ejection fraction (EF) by considering both the power of the 2 major harmonic components at low and high frequency and 2 indexes of nonlinear dynamics, namely the 1/f slope and the correlation dimension D2. HRV of patients with a reduced EF was characterized by a diminished RR variance as well as a different distribution of the residual power in all frequency ranges, with lower values of the low-frequency component expressed in both absolute and normalized units, and of the low- to high frequency ratio. In these patients we also observed a steeper slope of the negative regression line between power and frequency in the very low frequency range. The presence of a smaller fractal dimension was suggested by a lower D2. Thus, in patients after acute myocardial infarction with a reduced EF, the reduction in HRV is associated with a different distribution of the residual power in the entire frequency range, which suggests a diminished responsiveness of sinus node to neural modulatory inputs. PMID- 8677868 TI - Utility of the 12-lead electrocardiogram in identifying underlying coronary artery disease in patients with depressed left ventricular systolic function. AB - We assessed the utility of the 12-lead electrocardiogram (ECG) in identifying severe coronary artery disease (CAD) in patients with depressed left ventricular (LV) systolic function. In 336 patients referred for cardiac catheterization with LV ejection fractions < 0.50, we compared the 12-lead ECG of those with and without CAD by multivariate analysis. The sensitivities, specificities, and positive and negative predictive values of all dichotomous electrocardiographic variables for identifying the presence of severe CAD were determined. In comparison to subjects with CAD, those without disease were more likely to exhibit left-axis deviation (p = 0.01), left bundle branch block (p < 0.001), or LV hypertrophy (p < 0.001), and less likely to exhibit pathologic inferior Q waves (p < 0.001). The presence of anterior or any Q waves was similar between the groups. The presence of any diagnostic Q wave had a positive predictive value of 92%, sensitivity of 57%, and specificity of 80% for identifying severe CAD. In patients with LV systolic dysfunction, the 12-lead ECG is insensitive and nonspecific for identifying those with concomitant severe CAD. PMID- 8677869 TI - Comparison of impedance cardiography with thermodilution and direct Fick methods for noninvasive measurement of stroke volume and cardiac output during incremental exercise in patients with ischemic cardiomyopathy. AB - In the last decade, an inexpensive and simple noninvasive method (i.e., transthoracic electrical bioimpedance cardiography, has been tested in healthy subjects and patients with various heart disease for measuring stroke volume and cardiac output at rest and/or during exercise. However, the results are still controversial, especially when measurements are obtained during exercise and data on reproducibility during exercise are lacking. Twenty-five consecutive patients (20 men and 5 women, mean age 48 +/- 9 years) in sinus rhythm with documented coronary artery disease and a previous myocardial infarct were studied. Patients were divided into 2 groups. Group A had ischemic cardiomyopathy, characterized by left ventricular (LV) enlargement and LV ejection fraction depression (35 +/- 8%). Group B had normal LV dimensions and ejection fraction (62 +/- 9%). After a familiarization study, all patients underwent an exercise test with gas exchange analysis and hemodynamic measurements. Stroke volume and cardiac output were simultaneously obtained at rest and at the end of each work rate stage with 3 methods: impedance, thermodilution, and direct Fick. Group A reached a lower peak oxygen uptake (56%), peak work load (60%), and peak systolic blood pressure (69%) than group B. Cardiac output and stroke volume were significantly greater at submaximal and peak exercise in group B than in group A (p < 0.0001). There were no significant differences in stroke volume and cardiac output in the 3 techniques at any matched work rate. There was no significant difference between measurements obtained by 2 experienced observers or between those obtained on 2 exercise tests performed on 2 different days. These results demonstrate that impedance cardiography is a noninvasive, simple, accurate, and reproducible method of measurement of cardiac output and stroke volume over a wide range of workloads. PMID- 8677871 TI - Electrophysiologic evaluation of sinus node function and atrioventricular conduction in patients with prolonged ventricular asystole during obstructive sleep apnea. AB - In 15 patients with ventricular asystole of 8.5 +/- 3.5 seconds (range 5.0 to 16.8) occurring exclusively during obstructive sleep apnea, electrophysiologic study of sinus node function and atrioventricular conduction before and after administration of intravenous atropine (0.02 mg/kg) was performed. Electrophysiologic parameters of sinus node function were normal in 12 of 15 patients (80%) and atrioventricular (AV) nodal function was normal in 7 patients (47%). Almost all abnormal findings of sinus node function and AV nodal function were reversible by administration of atropine. The HisPurkinje system function was normal in 6 patients (40%). Prolonged HV intervals (57 to 73 ms) were found in 9 patients (60%). Intra- or infra-His block was not observed in any patient. In summary, electrophysiologic parameters of sinus node function and AV conduction were normal or only slightly abnormal in all 15 study patients, which suggests that prolonged ventricular asystole during obstructive sleep apnea is not due to fixed or anatomic disease of the sinus node or the AV conduction system. PMID- 8677870 TI - Comparison of subgroups assigned to medical regimens used to suppress cardiac ischemia (the Asymptomatic Cardiac Ischemia Pilot [ACIP] Study). AB - This report focuses on the subset of 235 patients from the Asymptomatic Cardiac Ischemia Pilot (ACIP) study receiving randomly assigned medical therapy to treat angina and suppress ischemia detected on ambulatory electrocardiography: 121 patients received the sequence of atenolol and nifedipine, and 114 diltiazem and isosorbide dinitrate. After 12 weeks of therapy, the primary end point (absence of ambulatory electrocardiographic (ECG) ischemia and no clinical events) was reached in 47% of atenolol/nifedipine- versus 31% of diltiazem/isosorbide dinitrate-treated patients (adjusted p = 0.03). A trend to increased exercise time to ST depression was seen in the atenolol and nifedipine versus diltiazem and isosorbide dinitrate regimens (median treadmill duration 5.8 vs 4.8 minutes; p = 0.04). However, when adjusted for baseline imbalances in ambulatory ECG ischemia, the 2 medical combinations were similar in suppression of ambulatory ECG ischemia. In both medication regimens, an association between mean heart rate and ischemia on ambulatory electrocardiography after 12 weeks of treatment was observed so that patients on either regimen with a mean heart rate > 80 beats/min had ischemia detectable almost twice as often as those with a mean heart rate < 70 beats/min (p < 0.001). PMID- 8677872 TI - Deletion polymorphism of the angiotensin-converting enzyme gene is independently associated with left ventricular mass and geometric remodeling in systemic hypertension. AB - An insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with myocardial infarction, cardiomyopathy, and left ventricular (LV) hypertrophy. LV mass and geometry are related to cardiovascular morbidity and mortality. Two-dimensional directed M-mode echocardiograms and 24 hour ambulatory blood pressure monitoring were performed in 67 hypertensive subjects. Echocardiographic measurements were assessed in blinded fashion. LV mass index and relative wall thickness were calculated. ACE genotypes were determined by polymerase chain reaction amplification of deoxyribonucleic acid prepared from leukocytes, using primers that encompass the polymorphic segment. Systolic ambulatory blood pressure was higher in subjects with the II genotype. All other patient characteristics were similar across genotype groups. After adjustment for other covariables, the DD and ID genotypes were associated with significantly higher LV mass index than was the II genotype. Adjusted relative wall thickness was also higher in subjects with the DD genotype than in subjects with the ID and II genotypes. On multiple regression analysis, systolic ambulatory blood pressure, gender, body mass index, and the ACE genotype were each independently related to LV mass index (R2 = 0.53). Systolic ambulatory blood pressure, race, and ACE genotype were each independently related to relative wall thickness (R2 = 0.34). The ACE genotype explained an additional 3% and 4% of the variations of LV mass index and relative wall thickness, respectively. In conclusion, ACE polymorphism accounted for a small but statistically significant proportion of the variation in LV mass and geometry in our hypertensive subjects. PMID- 8677873 TI - Detection and significance of a discrete very low frequency rhythm in RR interval variability in chronic congestive heart failure. AB - Although in advanced chronic congestive heart failure (CHF) very low frequency (< 0.04 Hz, VLF) oscillations are prominent, the clinical importance and the physiologic basis of these rhythms have not been elucidated. To investigate the physiologic determinants of the VLF rhythms in RR interval variability, we studied 36 patients with stable, moderate to severe CHF (33 men, age: 58 +/- 8 years, ejection fraction 25 +/- 10%, peak oxygen consumption 18.1 +/- 4.6 ml/kg/min) and 12 age- and sex-matched controls using autoregressive spectral analysis of RR interval, blood pressure, and respiratory signals during controlled conditions. We quantified low frequency (LF) (0.04 to 0.15 Hz), high frequency (HF) (0.15 to 0.40 Hz), VLF, and total power (0 to 0.5 Hz), and calculated the coherence between systolic blood pressure and RR interval variability within each band. Peripheral chemosensitivity was assessed by the ventilatory response to hypoxia using transient inhalation of pure nitrogen. The influence of transient inactivation of peripheral chemoreceptors on the VLF rhythm was investigated by exposing 6 patients to hyperoxic (60% oxygen) conditions for 20 minutes. Twenty-three patients (64%) with CHF, but no controls, had a discrete VLF rhythm (0.019 +/- 0.008 Hz) in RR variability. The presence of VLF rhythm was not related to any difference in clinical parameters (etiology, New York Heart Association class, ejection fraction, oxygen uptake) but rather to a different pattern in RR interval and blood pressure variability: lower LF power (2.8 +/- 1.6 ms2 natural logarithm [ln]) compared either to patients without VLF (4.0 +/- 1.3 ms2 ln) or to controls (5.9 +/- 0.7 ms2 ln), higher percentage of power within VLF band (86.3 +/- 8.3% vs 77.5 +/- 7.9% and 61.5 +/- 14.1%) and a markedly impaired coherence between RR interval and systolic blood pressure variability within the LF band (0.26 +/- 0.10 vs 0.42 +/- 0.18 and 0.63 +/- 0.15, in patients with vs without VLF peak and controls, respectively). Patients with VLF had significantly increased hypoxic chemosensitivity, and hyperoxic conditions were able to decrease VLF power and abolish the VLF rhythm in 5 of 6 patients with CHF. Discrete VLF oscillations in RR variability are common in patients with advanced CHF and appear to be related to severely impaired autonomic regulation and suppression of baroreceptor function, with enhancement of hypoxic chemosensitivity. We hypothesize that this rhythm represents an enhanced chemoreflex harmonic oscillation in CHF patients, which may have application for arrhythmogenesis. PMID- 8677874 TI - Value of the cardiovascular physical examination for detecting valvular heart disease in asymptomatic subjects. AB - To determine the accuracy of the cardiovascular physical examination for the diagnosis of asymptomatic valvular heart disease (VHD), we prospectively studied 143 subjects, 68 apparent normal subjects and 75 patients with diseases known to produce VHD. All subjects underwent a complete physical examination with dynamic cardiac auscultation by a physician blinded to clinical data and compared with the results of transesophageal color Doppler echocardiography (TEE). By TEE, 33 subjects (23%), and by physical examination, 25 subjects (17%) had at least 1 form of VHD. Despite a high frequency of mild valve abnormalities and a 31% prevalence of functional murmurs, the physical examination showed a sensitivity of 70%, a specificity of 98% (confidence interval = 0.51 to 0.84, and 0.94 to 0.99, respectively), and a positive and negative predictive value of 92% for the diagnosis of VHD. Only 2 of the 10 patients with VHD by TEE, but not by physical examination, had clinically important VHD. We conclude that the physical examination is a sensitive and highly specific method of screening for VHD in subjects without cardiac symptoms. Therefore, its use should be encouraged rather than the routine application of echocardiography. PMID- 8677875 TI - Aortic valve regurgitation after surgical versus percutaneous balloon valvotomy for congenital aortic valve stenosis. AB - To compare characteristics of aortic regurgitation (AR), the results of 213 procedures (110 balloon aortic valvotomies [BAV] and 103 surgical aortic valvotomies [SAV]) for treatment of congenital aortic valve stenosis were reviewed. These procedures were performed in 187 patients from June 1981 to September 1993. Echocardiograms recorded immediately before, within 6 months afterward, and at latest follow-up were compared. Color Doppler was used to assess the degree of AR and was quantified as the ratio of the regurgitant jet width to valve annulus, the jet width ratio. Whereas BAV patients were older (median age 5.7 years vs 3 months; p = 0.0001), there was no significant difference in median follow-up interval (3.1 years [range 0.5 to 7.2] for BAV vs 3.6 years [range 0.6 to 10.4] for SAV; p = 0.44). The mean balloon-to-annulus ratio for BAV was 0.99 +/- 0.09. An open valvotomy was performed in 83% of surgical cases. Acute systolic gradient reduction and subsequent increase at late follow-up was similar for both groups. Acutely, the mean jet width ratio increased similarly (p = 0.84) for BAV (+9 +/- 15%; p = 0.0001) and SAV (+9 +/- 12%; p = 0.0003) and was not related to age at procedure. At late follow-up, mean jet width ratio further increased significantly in both groups, although there was no difference (p = 0.17) in amount of progression (BAV +10 +/- 12%; p = 0.0001, SAV +15 +/- 13%; p = 0.0002). Thus, BAV and SAV produce AR of similar severity with similar rates of progression. PMID- 8677876 TI - Biopsy-induced flail tricuspid leaflet and tricuspid regurgitation following orthotopic cardiac transplantation. AB - Damage to the tricuspid valve apparatus has been described after endomyocardial biopsy and may be associated with hemodynamically significant tricuspid regurgitation (TR). This study was performed to determine the prevalence of TR and flail tricuspid leaflet in cardiac transplant recipients and to evaluate the use of a 45 cm sheath placed directly in the right ventricle during endomyocardial biopsy to reduce the incidence of these complications. Echocardiograms and right heart catheterization data of 72 orthotopic cardiac transplant recipients were assessed for the presence of flail tricuspid leaflet, TR, and right-sided cardiac dysfunction 29 +/- 20 months (mean +/- SD) after transplantation. Moderate or severe TR was present in 23 patients (32%). Ten patients (14%) had flail tricuspid leaflet, with 7 of these having severe TR. Right atrial pressure (10 +/- 5 vs 6 +/- 5 mm Hg, p < 0.05) was higher, cardiac index (2.0 +/- 0.2 vs 2.5 +/- 0.7 L/min/m2, p < 0.05) was lower, and right-sided cardiac dimensions were greater in patients with flail leaflets than in those without flail leaflets. Both the prevalence of flail tricuspid leaflet (41% to 6%, p < 0.0001) and mean grade of TR (2 to 1, p < 0.0001) were reduced after the use of a 45 cm sheath. We conclude that TR secondary to biopsy-induced damage to the valve apparatus occurs in cardiac transplant recipients and is associated with signs of early right-sided heart failure. Use of a 45 cm sheath during endomyocardial biopsy reduces the prevalence of flail tricuspid leaflet and the severity of TR. PMID- 8677877 TI - Automatic backscatter analysis of regional left ventricular systolic function using color kinesis. AB - Assessment of regional wall motion by 2-dimensional echocardiography can be performed by either semiquantitative wall motion scoring or by quantitative analysis. The former is subjective and requires expertise. Quantitative methods are too time-consuming for routine use in a busy clinical laboratory. Color kinesis is a new algorithm utilizing acoustic backscatter analysis. It provides a color encoded map of endocardial motion in real time. In each frame a new color layer is added; the thickness of the color beam represents endocardial motion during that frame. The end-systolic image has multiple color layers, representing regional and temporal heterogeneity of segmental motion. The purpose of this study was to validate the use of color kinesis for semiquantitative analysis of regional left ventricular systolic function and quantitatively in measurement of endocardial excursion. Semiquantitative wall motion scoring was performed in 18 patients using both 2-dimensional echo and color kinesis. Scoring was identical in 74% of segments; there was 84% agreement in definition of normal vs. abnormal. There was less interobserver variability in wall motion scoring using color kinesis. Endocardial excursion was quantified in 21 patients. 70% of the imaged segments were suitable for analysis. Correlation between 2-dimensional echocardiographic measurements and color kinesis was excellent, r = 0.87. The mean difference in excursion as measured by the 2 methods was -0.05 +/- 2.0 mm. In conclusion, color kinesis is a useful method for assessing regional contraction by displaying a color map of systolic endocardial excursion. This algorithm may improve the confidence and accuracy of assessment of segmental ventricular function by echocardiographic methods. PMID- 8677878 TI - Epinephrine-induced changes in serum potassium and cardiac repolarization and effects of pretreatment with propranolol and diltiazem. AB - Although increases in serum epinephrine are known to cause hypokalemia, the epinephrine dosages and concentrations at which this effect occurs, and the electrocardiographic consequences, have not been evaluated. Because epinephrine infusion is now being used to provoke arrhythmias in some patients, we have determined the physiologic effects of a range of dosages of epinephrine. The effects of pretreatment with propranolol and diltiazem on these indexes of epinephrine effect were also evaluated. Epinephrine dose ranging started at 10 ng/kg/min, with doubling of the dose every 10 minutes until a predetermined end point was reached. At the end of each dosage level, serum electrolytes, catecholamines, and an electrocardiogram were recorded. Whereas even the lowest dosage of epinephrine significantly increased heart rate, serum glucose levels increased and serum potassium decreased only when dosages of 160 to 320 ng/kg/min were administered. Plasma concentrations of epinephrine at these dosages were mean +/- SD 1,328 +/- 902 pg/ml, comparable to those observed in these subjects during maximal exercise (1,003 +/- 527 pg/ml). The major electrocardiographic effect of epinephrine infusion was a dose-related increase in QTc, but pretreatment with propranolol blunted this effect and tended to shorten QTc. At an epinephrine dose of 40 ng/kg/min, QTc prolongation persisted and was inhibited by diltiazem. These data suggest that the major electrocardiographic effect of epinephrine infusion is mediated by increased calcium current. At dosages > 80 ng/kg/min, plasma epinephrine concentrations are comparable to those observed with severe stress, and hypokalemia is common. The use of epinephrine as an electrophysiologic provoker at dosages > 80 ng/kg/min results in both a direct effect, as well as an indirect effect due to hypokalemia. PMID- 8677879 TI - Acute effects of ethanol ingestion on signal-averaged electrocardiograms. PMID- 8677880 TI - Selective radiofrequency ablation of the "slow" atrioventricular nodal pathway for control of the ventricular response to atrial fibrillation. AB - In summary, this study reports 2 important findings: (1) AV nodal modification using the conservative protocol we describe reduces long-term success for ventricular rate control during atrial fibrillation but eliminates the incidence of permanent AV block; (2) directed lesions that eliminate clinical AV nodal reentry slow ventricular response to acute atrial fibrillation but are not sufficient to control ventricular response of chronic atrial fibrillation. Further refinement of these techniques may allow an optimal balance between rate control and avoidance of permanent pacing. PMID- 8677881 TI - Observations on carotid sinus hypersensitivity from direct intraneural recordings of sympathetic nerve traffic. AB - In summary, we studied 4 patients with mixed-type CS hypersensitivity. We demonstrated that CS massage rapidly inhibits sympathetic nerve activity and decreases heart rate. Arterial pressure starts to decline abruptly with complete sympathetic withdrawal, but the nadir is delayed, suggesting that arterial dilation is not instantaneous. Arterial pressure rebounds slowly, suggesting a latency between the neural reflex and vascular compliance. Pacing had little effect on preventing hypotension in these patients. Our data support the concept that sympathetic withdrawal is responsible for the vasodilatory component seen with CS syncope. PMID- 8677882 TI - Triple atrioventricular nodal pathways can be masked. AB - In summary, CL modulates the dispersion in refractoriness of triple nodal pathways by causing greater changes in refractoriness in the slower pathways and thus determines the feasibility of manifestation. PMID- 8677883 TI - Transient complete atrioventricular block during radiofrequency ablation of slow pathway for atrioventricular nodal reentrant tachycardia. PMID- 8677884 TI - Percutaneous radiofrequency valvotomy using a standard 5Fr electrode catheter for pulmonary atresia in neonates. AB - Radiofrequency energy applications with a standard 5Fr 3 mm tip electrode catheter facilitated opening of the pulmonary valve in neonates with pulmonary atresia. Shortening of the catheter tip electrode would probably improve efficiency. PMID- 8677885 TI - Catecholamine-induced ductus arteriosus constriction in children. AB - Our data suggest that the vascular smooth muscle of the PDA remains capable of constriction beyond a patient's infancy, at least at the pulmonary end. In some cases of PDA, catecholamines may induce late closure. PMID- 8677886 TI - Comparison of occurrence of genetic syndromes in ventricular septal defect with pulmonic stenosis (classic tetralogy of Fallot) versus ventricular septal defect with pulmonic atresia. AB - Our results confirm that classic TF can be associated with many genetic conditions, but most patients are nonsyndromic. In contrast, children with TF-PA have a high incidence of genetic syndromes, particularly those related to CATCH22 syndrome. PMID- 8677887 TI - Long-term changes in left ventricular performance following mitral valve replacement for pure rheumatic mitral regurgitation. AB - Our data indicate that MVR, with or without chordal preservation, for pure severe MR in symptomatic younger rheumatic patients with a good preoperative ejection fraction results in normalization of LV size and performance by 1 year. Normalization of LV performance was only achieved at 1 year after surgery, and it is therefore essential to extend the assessment of LV function to at least 1 year postoperatively. PMID- 8677888 TI - Risk factors for new atherothrombotic brain infarction in 664 older men and 1,488 older women. AB - The relation between obesity and new ABI is also unclear. The Framingham Study found that relative weight was not a risk factor for new ABI in older men but was a weak risk factor for new ABI in older women. Barrett-Connor and Khaw found no association between body mass index and new ABI in older men or women. The present study showed that obesity was not a risk factor for new ABI in older men. Obesity was a risk factor for new ABI in older women by univariate analysis but not by multivariate analysis. However, because obesity is associated with other risk factors for ABI and new coronary events, we would try to lower weight in obese older men and women. PMID- 8677889 TI - Safety of medically supervised exercise in a cardiac rehabilitation center. AB - Medically supervised exercise continues to have a low major cardiovascular complication rate. Direct gym supervision by a physician does not appear necessary for safety. The currently proposed cardiac rehabilitation risk stratification criteria do not appear to identify patients at risk for these major complications. The safety of exercise programs with less supervision and electrocardiographic telemetry monitoring is unknown. PMID- 8677890 TI - Accessory hepatic vein to pulmonary venous atrium as a cause of cyanosis after the Fontan operation. AB - The presence of an accessory hepatic vein to the pulmonary venous atrium should be considered in the setting of progressive cyanosis following the Fontan procedure. An inferior vena caval angiogram with "levo-phase" should demonstrate it. Surgical intervention or transcatheter occlusion should lead to prompt resolution of cyanosis. PMID- 8677891 TI - Prognosis of patients with coronary artery disease on treatment with calcium channel antagonists. Introduction. PMID- 8677892 TI - Verapamil and angiotensin-converting enzyme inhibitors in patients with coronary artery disease and reduced left ventricular ejection fraction. AB - Verapamil is effective as antianginal medication but contraindicated in patients with congestive heart failure. Angiotensin-converting enzyme (ACE) inhibitors improve survival in patients with congestive heart failure but have limited effect on patients with angina pectoris. No studies have been published on the combined treatment with verapamil and ACE inhibitors in patients with stable angina pectoris and left ventricular dysfunction. We performed an open study in 14 patients with angina pectoris and ejection fraction < 40%. The patients received verapamil 180 mg and trandolapril 2 mg twice daily for 3 months. We found a significant increase in ejection fraction from 28 +/- 6 to 35 +/- 11 (p < 0.03), wall motion index from 1.0 +/- 0.3 to 1.2 +/- 0.3 (p < 0.03), exercise duration from 6.9 +/- 2.5 to 7.7 +/- 2.9 minutes (p < 0.01), and ratio of exercise to rest rate-pressure product from 2.2 +/- 0.4 to 2.5 +/- 0.6 (p < 0.02). Use of nitroglycerin and number of angina pectoris attacks were both significantly reduced after 3 months of treatment. These findings support the hypothesis that the combination of verapamil and trandolapril is useful in patients with attenuated left ventricular function and angina pectoris. PMID- 8677893 TI - Prognosis of patients with unstable angina or acute myocardial infarction treated with calcium channel antagonists. AB - The safety of calcium channel antagonists has become a controversial issue among cardiologists. Thus, the role of calcium antagonists in the treatment of myocardial infarction is reviewed, and the differences among the 3 classes of calcium channel antagonists, phenylalkylamines, dihydropyridines, and benzothiazepines, are discussed. PMID- 8677894 TI - Use of calcium channel antagonists in myocardial revascularization procedures. AB - Calcium channel antagonists possess a number of properties that may be beneficial after revascularization procedures. Therefore, we present an overview of the use of these drugs after percutaneous intervention in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT), and compare the results in CAVEAT with those in published randomized trials. Also reviewed are the use of calcium channel antagonists to control perioperative hypertension, reduce myocardial necrosis, and prevent arrhythmias during cardiopulmonary bypass. PMID- 8677895 TI - What does it mean to improve prognosis of patients with coronary artery disease? AB - When improvement in prognosis of patients with coronary artery disease is the goal, the physician must be knowledgeable about the patient-related factors and the fact that therapies influence prognosis in such patients. Further, the clinician must be very specific in choice of therapeutic agents directed toward improvement of prognosis, and this process must include prescriptions of appropriate formulation and dosage. PMID- 8677896 TI - Anti-ischemic intervention as prognosis improvement in patients with coronary artery disease, with special focus on verapamil. AB - Angina pectoris is a significant risk predictor in patients with atherosclerotic heart disease. The major complications are myocardial infarction, heart failure, and arrhythmias. Plaque rupture turns stable angina pectoris into acute coronary syndrome by provoking platelet aggregation and thereby thrombus formation. Verapamil significantly inhibits platelet aggregation and thrombus formation, which may be one of several reasons for the protective effect of verapamil on reinfarction in patients recovering from myocardial infarction. Ischemia may lead to left ventricular dilation and diastolic dysfunction, and thereby heart failure. In postinfarction patients intervention with verapamil significantly reduced the use of diuretics compared with placebo, indicating that anti-ischemic intervention may prevent heart failure. Ventricular arrhythmias are significantly associated with arrhythmic as well as non-arrhythmic death. The lack of preferential association of ventricular arrhythmias with arrhythmic death rather than nonarrhythmic death may imply that arrhythmias are provoked by ischemia. Antiarrhythmic intervention in postinfarction patients significantly increases death and arrhythmic events compared with placebo, especially in patients with residual ischemia. This may be due to a significant slowing of conduction during ischemia in patients treated with antiarrhythmic agents. In animal studies anti ischemic agents prevent or suppress ventricular arrhythmias during ischemia, whereas traditional antiarrhythmic drugs have no effect or even worsen the arrhythmias, especially during episodes with elevated sympathetic activity. Verapamil significantly reduces plasma norepinephrine levels and the norepinephrine release during ischemia, whereby ventricular arrhythmias may be prevented. Also, supraventricular arrhythmias are significantly associated with myocardial ischemia and are prevented by verapamil. In patients with atherosclerotic heart diseases, angina pectoris is a significant risk predictor, but anti-ischemic intervention should be considered even in patients in whom the major problem is heart failure or arrhythmias. PMID- 8677897 TI - Prognosis of patients with stable angina pectoris on antianginal drug therapy. AB - Antianginal drug treatment reduces symptoms and ischemia but may also influence the prognosis of patients with stable angina pectoris. The Atenolol Silent Ischemia Study (ASIST) compared atenolol and placebo treatment (about 140 patient years on each) in patients with mainly silent ischemia and found less aggravation of angina and a tendency toward fewer cardiac complications with atenolol treatment. The Total Ischaemic Burden European Trial (TIBET) compared slow release nifedipine, atenolol, or the combination (about 450 patient-years on each) and found no significant differences with regard to cardiac complications, a nonsignificant trend toward better prognosis on combined treatment, and more side effects on nifedipine alone compared with the other treatments. The Angina Prognosis Study in Stockholm (APSIS) compared metoprolol and verapamil (about 1,400 patient-years on each) and found similar effects on cardiovascular endpoints, tolerability, and psychosocial variables with the 2 treatments. Hypothesis-generating subgroup analyses in APSIS suggest that treatment effects may differ in hypertensive and diabetic subgroups. Beneficial effects in primary and secondary prevention, together with data from ASIST, suggest that beta 1 blockade influences prognosis favorably. The safety of short-acting nifedipine in ischemic heart disease is questioned, but TIBET data suggest that slow release nifedipine may be safe. Verapamil has beneficial effects after myocardial infarction (Danish Verapamil Infarction Trial II) and shows similar efficacy as metoprolol in the APSIS study. The paucity of placebo data (antianginal treatment cannot be withheld during long periods of time in symptomatic patients) precludes firm conclusions regarding effects of drug treatment on prognosis. It is argued that patients with stable angina pectoris do well on medical treatment, and that beta 1 blockers, verapamil, and, possibly, slow-release nifedipine may influence their prognosis favorably. PMID- 8677898 TI - The impact of regulations, tradition, and experimental design on clinical cancer trials: report and recommendations resulting from Washington Cancer Trials Conference. PMID- 8677899 TI - Adjuvant radiotherapy for breast carcinoma in men: a 20-year clinical experience. AB - Breast cancer in men is a rare malignancy. Current knowledge about its natural history and diagnostic and therapeutic management relies on reviews and few retrospective studies. From 1972 to 1993, 21 men were irradiated for operable primary (n = 17) or recurrent (n = 4) breast cancers at our institution. The mean age at initial diagnosis was 60 years (45-79 years). Tumor distribution by stage was: stage I (two), stage II (seven), stage III (six), stage IV (two), and unknown in four cases. Patients received radiotherapy to the chest-wall and ipsilateral lymph nodes (17) and to the axilla (seven). Additionally hormones (two) and chemotherapy (four) were applied in some cases. Follow-up ranged from 24 to 190 months (median, 53 months). At last follow-up (November 1994), nine patients were alive and eight without disease. The median overall survival of the whole group was 69 months (mean, 106 months). The 3-year (70%), 5-year (59%) and 10-year survival rates (46%) were consistent with literature data. Overall, relapse- and disease-free survival rates were better in patients with stage I/II than in those with stage III/IV disease. Univariate analysis revealed more favorable results for patients with negative axillary nodes, patients younger than 60 years, those with centrally localized tumors, and patients with a diagnostic delay of < 3 months, but the differences were not statistically significant. Six patients relapsed who had not received initial adjuvant radiotherapy to the site of their relapse. At last follow-up, 13 patients had distant metastases, and 12 of them are dead of the metastatic disease, which developed less frequently in stage I/II than in stage III/IV disease. Postoperative adjuvant radiotherapy is an essential part of the overall treatment strategy of advanced node-negative and node-positive cancer of the breast in men. PMID- 8677900 TI - Prognostic factors of locoregionally recurrent nasopharyngeal carcinoma--a retrospective review of 182 cases. AB - Locoregional relapse is the major cause of failure of nasopharyngeal carcinoma (NPC) after radical radiation therapy. The prognosis of such patients is dismal, and the factors related to the outcome are not well identified. Between January 1983 and December 1989, 1,168 new patients with biopsy-proven NPC were seen at this hospital. Eight hundred and eighty-three of these patients were treated uniformly with radical external irradiation and intracavitary treatment with or without chemotherapy. The clinical courses, retreatment outcomes, and prognostic factors for locoregional relapse and subsequent distant metastasis were analyzed. During the follow-up period of 3-10 years or until death, 182 patients (20.6%) developed locoregional relapses without distant metastasis initially. T stage and age were significant prognostic factors for locoregional recurrence. In contrast, histopathologic subtype, N stage, sex, and systemic chemotherapy were not. There were 36 patients (19.8%) who developed subsequent distant metastasis with or without retreatment. The median time from locoregional relapses to distant metastasis was 6 months in this study, and bone was the most frequent and the earliest site of distant metastasis. The N stage at diagnosis, the initial disease-free interval, the presence of neck nodal disease at relapse, and age were the significant factors for predicting the subsequent distant metastasis in locoregionally recurrent NPC patients. We recommend that additional systemic chemotherapy should be considered for retreatment of locoregional relapsed NPC, not only for enhancement of local control but also for eradicating microscopic metastasis as anticipated. PMID- 8677902 TI - Sweet syndrome in a patient with osteosarcoma. AB - Neutrophilic dermatosis (Sweet syndrome) is a rare condition characterized by painful indurated cutaneous plaques infiltrated with mature neutrophils and may be accompanied by fever, granulocytosis, arthritis, and conjunctivitis. It is associated with various malignant and preneoplastic states, the most common being leukemia and myeloproliferative disorders. Its association with solid tumors is infrequent. The case described here represents, to our knowledge, the first report of Sweet syndrome in a patient with osteogenic sarcoma, a primary tumor of bone arising from mesenchymal cells. PMID- 8677901 TI - M-CAVI, a neoadjuvant carboplatin-based regimen for the treatment of T2-4N0M0 carcinoma of the bladder. AB - Carboplatin, methotrexate, and vinblastine (M-CAVI) is an active and well tolerated regimen for bladder cancer patients ineligible for cisplatin-based regimens. We treated 47 T2-4 N0 M0 bladder cancer patients with M-CAVI in a neoadjuvant phase II trial. These 47 patients are evaluable for clinical response and toxicity. Clinical overall response rate was 34%, for a 95% confidence interval (CI95%) of 21-49%. Pathological response was seen in 40% of the patients (CI95%, 26-56%) with a 26.5% rate of pathological complete response (CI95%, 15 42%). Factors associated with the achievement of a response to therapy were the initial TNM stage (pT3a or lower, greater than pT3a, p = 0.001) and a Karnofsky score greater or equal than 90%, which was marginally significant (p = 0.08). With a median follow-up of 14 months, the disease-specific actuarial survival at 2 years is 42%. No patient has relapsed beyond 21 months of follow-up in a disease-free status. Toxic effects have been moderate. In conclusion, M-CAVI is an active and well-tolerated regimen that should be compared in terms of response rate and survival with a cisplatin-based regimen for invasive bladder cancer. PMID- 8677903 TI - Late onset of isolated central nervous system metastasis of liposarcoma--a case report. AB - Metastatic soft-tissue sarcoma of the central nervous system (CNS) is exceedingly rare. We report a case of a 56-year-old male treated for a right lower extremity liposarcoma at the age of 30 years, whose first recurrence was an intracerebral metastasis occurring 26 years after resection of the primary tumor. Initial treatment of the metastasis with surgical resection and adjuvant radiotherapy was followed rapidly by CNS recurrence in 3 months. Further debulking and interstitial brachytherapy were unsuccessful in controlling disease progression. Clinical presentation and treatment of brain metastases in soft-tissue sarcoma are discussed. PMID- 8677904 TI - Neoadjuvant chemotherapy with cisplatin-vindesine-5-fluorouracil and folinic acid for locally advanced head and neck carcinoma. AB - The aim of this study was to establish the feasibility, evaluate the response rate, and assess the impact on local control and survival in locally advanced (bulky nodal) squamous cell carcinoma of the head and neck (SCCHN) patients treated with neoadjuvant chemotherapy consisting of cisplatin followed by continuous infusion of vindesine and fluorouracil with intermittent i.v. folinic acid. Eligibility criteria included histologically proven SCCHN, previously untreated locally advanced stage III-IV with measurable or evaluable disease, no distant metastases, an Eastern Cooperative Oncology Group (ECOG) performance status of less than 2, patient age of at least 18 years, and adequate bone marrow, hepatic, and renal functions. The protocol consisted of three cycles (day 1, day 21, day 42) of Cisplatin (CDDP) 100 mg/m2/day i.v. on day 1 immediately followed by 4 days (96 h) of continuous infusion of vindesine 0.8 mg/m2/day and 5 fluorouracil (5-FU) 600-700 mg/m2/day with folinic acid 150 mg/m2 i.v. every 6 h x 16 doses before locoregional treatment with radiotherapy preceded by radical surgery when appropriate. Twenty-nine patients were enrolled in this study, and 28 were evaluable for activity; an objective response rate of 55% (four complete responses, 12 partial responses) was achieved. Leukopenia and mucositis were the most frequent and severe toxicities. The addition of vindesine did not improve the activity of the CDDP-FU-folinic acid combination, but this may be partly because of the particularly poor prognosis of the present patient population, with 75% of stage IV bulky nodal disease (N2c-N3). PMID- 8677905 TI - Malignant melanoma of the head and neck. Clinical and immunological considerations. AB - Prolonged exposure to sun for long periods during most of the year has led to an increase in the frequency of malignant melanoma in Israel, especially for head and neck (H&N) melanoma. H & N melanoma is found in males more than in females and diagnosed when already locally advanced. The disease-free interval between treatment of the primary lesion and recurrence of the disease correlated with the patient's age and the depth of invasion according to Breslow. A higher recurrence rate correlated with male gender, location in the scalp, and the stage of the disease. Metastatic disease involved the lungs, liver, and brain and responded poorly to systemic therapy. Improved survival was related to female gender, early stage of the disease, low Breslow thickness, and location of the primary lesion elsewhere than the scalp. Immunologically, we found that the titers of antimelanoma antibodies in patients with metastatic disease originating in the area of the head and neck were higher than the titer in disease-free H & N melanoma patients (p = 0.05). Moreover, patients with metastatic H & N melanoma had a higher titer of antityrosinase antibodies compared with healthy subjects. These two types of antibodies might be used as markers for disease progression in H & N melanoma. The more aggressive character of H & N melanoma was not reflected by different titers of antimelanoma antibodies nor by antityrosinase antibodies in patients with H & N versus non-H & N melanoma. PMID- 8677906 TI - Phase II evaluation of ifosfamide/mesna in metastatic prostate cancer. A Southwest Oncology Group study. AB - The combination of ifosfamide and mesna was evaluated in a phase II trial in the treatment of metastatic prostate cancer. Two separate groups of patients were to be evaluated: patients with no prior hormonal therapy and hormonally refractory patients. Patients were treated with ifosfamide 1.5 g/M2, and mesna at 30% of the ifosfamide dose was administered immediately before and 4 and 8 h after ifosfamide treatment. Both drugs were given i.v. daily for 5 days every 21 days. Response was assessed every 6 weeks. Of 29 eligible and evaluable patients with hormonally refractory disease, there were two partial responders for a response rate of 7% (95% confidence interval, of 0.1-23%). Of nine eligible patients with no prior hormone treatment, there was one partial response, for a response rate of 11% (95% confidence interval, 0.3-48%). Unfortunately, the target accrual goal for this arm of the study was never achieved. The most common toxicities were myelosuppression and neurologic toxicity. These drugs do not warrant further evaluation in the disease. PMID- 8677907 TI - Toxicity and therapeutic response to chemotherapy in patients aged 70 years or older with advanced cancer. AB - To evaluate the impact of chemotherapy in terms of feasibility and activity in elderly patients, we treated 120 patients aged 70 years or older with advanced cancer in six major organ sites (breast, colorectum, lung, stomach, ovary, and head and neck). Furthermore, we compared the results in this age group with those in 120 patients with similar clinical features receiving the same chemotherapeutic combinations but whose age was under 70. Our results show that chemotherapeutic regimens routinely used in younger patients yield the same benefits and levels of toxicity in older patients. In none of the different organ sites, in fact, did we observe a higher incidence or severity of side effects, nor were there differences in response rate and survival. In conclusion, elderly cancer patients who are not suffering from medical complications, which are generally increased in aged patients (e.g., cardiovascular, pulmonary, renal, or neurological diseases), can be considered candidates for full doses of chemotherapy, like their younger counterparts. PMID- 8677908 TI - Treatment of olfactory neuroblastoma. A report of 11 cases. AB - Eleven olfactory neuroblastomas treated at Helsinki University Central Hospital between 1970 and 1991 were reviewed retrospectively. The distribution of the patients was according to Morita's staging (modified Kadish's classification) as follows: one stage A, one stage B and nine stage C. Tumor resections were performed in all cases, and five were considered radical. All patients received radiotherapy: total doses ranged from 42 to 70 Gy. At least a short treatment response was achievable in all cases. Chemotherapy was given to two patients: one remission was obtained by methotrexate with leucovorin rescue and doxorubicin for residual disease after radiotherapy. Distant metastases were observed in three cases, two in the lungs and one intraperitoneally. After a median follow-up of 63 (range, 6-140) months, five patients are alive and well, two patients have died with no evidence of disease; two patients who received only 42 and 50 Gy in 5 and 6 weeks have died of local recurrences and two of distant metastases. None of the patients with advanced (stage B or C) disease who received radical radiotherapy ( > or = 60 Gy given in 6 to 9 weeks) developed local recurrence. The increasing incidence of distant metastasis justifies an intensification of initial treatment, especially in state C disease. PMID- 8677909 TI - A phase II study of ifosfamide in recurrent squamous cell carcinoma of the head and neck. AB - Chemotherapy has not significantly altered the overall survival of patients with recurrent squamous cell carcinoma of the head and neck; therefore, the development of new agents is essential. The purpose of the current phase II study was to define the efficacy of ifosfamide in the treatment of recurrent squamous cell carcinoma of the head and neck. All patients were required to have squamous cell carcinoma of the head and neck that had recurred following surgery or radiotherapy or both. Patients may have received prior chemotherapy. Patients were initially treated with ifosfamide 2 g/m2/day for 4 days (dose level 0). Dose level-1 was 2 g/m2/day for 3 days, and dose level-2 was 2 g/m2/day for 2 days. All patients received mesna 400 mg/m2/day prior to and 1,200 mg/m2/day as a continuous infusion after ifosfamide. Thirty-eight patients were enrolled in the study. Five patients were inevaluable for toxicity or response. Overall, the regimen was well tolerated, with grade 4 granulocytopenia the only significant toxicity occurring in 16 patients. Overall, eight of 31 evaluable patients (25.8%) had a major response. Only one of the 10 patients (10%) with prior chemotherapy responded, but seven of the 21 patients (33.3%) with no prior chemotherapy had major responses. Ifosfamide is an active agent in recurrent squamous cell carcinoma of the head and neck. Further studies of ifosfamide in combination with other agents, particularly as induction therapy in patients with locally advanced disease, are warranted. PMID- 8677910 TI - A combination of vinblastine and doxorubicin with interferon alpha. AB - Advanced renal cell carcinoma still has poor overall treatment results, whatever chemotherapy is used. We treated 11 patients with advanced renal cell carcinoma with vinblastine (4 mg/m2) and doxorubicin (12 mg/m2) weekly, combined with recombinant IFN-alpha 2a given 3 x 10(6) IU s.c. three times per week during the first week, and 9 x 10(6) IU three times per week during the second week, and then on an ongoing basis 18 x 10(6) IU three times per week from the third week. The treatment of all patients had to be interrupted after 6 to 9 weeks because of leukopenia. Median survival was 6 months, and two partial responses were observed. We conclude that this regimen proved to be excessively toxic and failed to show significant advances compared with two-drug combination. PMID- 8677911 TI - A phase II study of cisplatin/ifosfamide in recurrent/metastatic undifferentiated nasopharyngeal carcinoma among young blacks in southern Africa. AB - Recurrent/metastatic, undifferentiated nasopharyngeal carcinoma (UDNPC) is known to be chemosensitive but has rarely been studied in Phase II methodology. No studies concerning its chemoresponsiveness among southern Africans have been demonstrated to date. From 1990 through 1994, 18 African patients from the Johannesburg metropolitan area with recurrent (following radiotherapy failure) or primarily metastatic (bone) UDNPC were treated with ifosfamide (3 g/m), mesna, and cisplatin (50 mg/m) for 2 days. Three patients (15%) attained complete remission and eight (44%) partial remission, yielding an overall response rate of 59%. Median response duration was 28 weeks. Two patients (11%) had stable disease with symptomatic improvement and five (30%) progressed on therapy. Treatment was generally well tolerated but there was one treatment-related death (neutropenic sepsis). The combination of ifosfamide/cisplatin appears to be promising in UDNPC commonly seen in young patients in southern Africa. However, the duration of response still tends to be brief. PMID- 8677912 TI - Radiation therapy of metastatic pheochromocytoma: case report and review of the literature. AB - Malignant pheochromocytomas are rare tumors, which are considered radioresistant on the basis of little information. We report a patient, with cranial nerve deficits from a pheochromocytoma metastatic to the parasellar region, who promptly responded to radiation therapy (2,500 cGy) with reversal of neurologic deficit. The disease recurred 2 years later and again promptly responded upon treatment to 2,000 cGy. Hepatic metastases were controlled for over 1 year with 3,240 cGy. The radiotherapy of pheochromocytoma and chemodectoma is reviewed, and the similarities between the two kinds of tumor are discussed. We speculate that a higher initial radiation dose might have resulted in a more sustained remission in our patient and recommend doses of 4,000-5,000 cGy if they can be safely administered, in 4-5 weeks for pheochromocytomas. PMID- 8677913 TI - Assessing quality of life in patients with cancer: a comparison of a visual analogue and a categorical model. AB - A simple instrument for self-assessment of quality of life (QL) in patients with cancer was elaborated using a linear analogue scale (LAS). The instrument was based on five questions, exploring different functional areas; the same questions were also addressed in a parallel format, where problems were seen from an opposite point of view (positive/negative). The LAS was given to 222 patients, for a total of 372 tests collected. Internal consistency was satisfactory (Cronbach's alpha = 0.75); QL score was significantly correlated to parameters of disease. Concordance between scales, as judged by comparison of parallel formats, was statistically significant but poor. A questionnaire was then elaborated with similar items, based on a categorical scale. A direct comparison between LAS and our questionnaire was made on a group of 41 patients. Internal consistency was poor for the LAS (alpha = 0.58) and good for the questionnaire (alpha = 0.93); Spearman's rank correlation coefficients were disappointing for the LAS and good for the questionnaire; the questionnaire was judged reliable in 82.9% of cases, the LAS in 29.3% only; the questionnaire score, and not the LAS score, was significantly correlated with PS and disease status. In conclusion, many patients appeared unable to correctly interpret the visual-analogue scale; the categorical scale was more immediate and correctly understood by the large majority of patients; the correlation between score and important parameters of QL was maintained, and internal consistency was excellent, indicating a satisfactory reliability of this instrument. PMID- 8677914 TI - A phase II trail of aminothiadiazole in patients with mixed mesodermal tumors of the uterine corpus: a Gynecologic Oncology Group study. AB - Aminothiadiazole (NSC 4728) is an analog of the thiadiazoles, a group of drugs that stimulated interest because they do not cause significant myelosuppression and have a unique ability to increase uric acid production unrelated to tissue damage. Previous articles have reported results in ovarian cancer, squamous cell cervical cancer, nonsquamous cell cervical cancer, and endometrial cancer. The Gynecologic Oncology Group chose to study aminothiadiazole in patients with mixed mesodermal tumors of the uterus refractory to prior chemotherapy. Twenty-two patients were entered into this study. Eligibility required that patients had histologically confirmed measurable malignancy. All patients received a starting dose of aminothiadiazole of 125 mg/m2 intravenously (30-45 min infusion) repeated at weekly intervals. All patients also took allopurinol, 300 mg orally per day, to prevent hyperuricemia. Subsequent therapy was not given unless the white blood cell count was > 3,000/microliters and platelets were > 100,000/microliters prior to treatment. One patient (5%) in this study had a partial response, which lasted only 1.2 months. The site of this response was a mesenteric mass. Most patients in this study had no toxicity whatsoever, and no life-threatening toxicity was seen. There were no complete responses. Aminothiadiazole in this dose schedule appears to have no utility in previously treated patients with mixed mesodermal tumors of the uterus. PMID- 8677915 TI - Simultaneous radiochemotherapy for recurrent and metastatic breast carcinoma: evaluation of two treatment concepts. AB - Patients with locally recurrent and metastatic breast carcinoma require effective palliation of pain and complicating cutaneous, soft tissue, and lymph node metastases. Since October 1989, 48 consecutive patients with recurrent breast carcinoma after mastectomy and no further surgical option were entered in a phase I-II study comparing two radiochemotherapy (RCT) regimens. Treatment-related toxicity was analyzed in 48 patients together with short- and long-term efficacy in 44 patients who had a minimum follow-up of at least 1 year. Since October 1989, group A (28 patients) received 60 Gy "split-course" radiotherapy (RT) over 10 weeks with two breaks of 2 weeks each after the second and fourth week of RT. Simultaneous 5-fluorouracil, methotrexate, and cyclophosphamide (CMF) was given during RT. From October 1991 to April 1993, group B (20 patients) received 54-60 Gy "conventional" RT over 6 weeks. Simultaneous 5-fluorouracil/mitomycin C was applied in the first and fifth week. Overall response [complete response (CR) + partial response (PR)] was 82% in group A (CR, 21%). Five of 28 patients developed grade 3-4 toxicity (EORTC/RTOG/WHO). Overall response rate in group B was 87% (CR, 19%). In this group, 6 of 20 patients experienced grade 3-4 toxicities. In both groups, the rate of local response was remarkably lower in patients with distant metastases and a short relapse interval < 2 years. Although both regimens achieved a similar local response rate, group B patients experienced a higher toxicity rate than did group A patients, but the treatment duration was considerably shorter. The local tumor response was greatly influenced by the extent of systemic disease. PMID- 8677916 TI - Prognostic factors of colorectal cancer. Results of multivariate analysis of curative resection cases with or without adjuvant chemotherapy. AB - One thousand two hundred fifty-four cases (610 colonic and 644 rectal cancers resected during 2 years from 1984 and followed up for more than 5 years) were entered from 140 institutions in Japan and analyzed by means of Cox's proportional hazards model. The analyzed pathologic variables were the size and depth of invasion, Dukes' stage, venous invasion, lymphatic permeation, and other clinical features, such as the sex and age of the patient and location of the tumor. The extent of dissection, serum carcinoembryonic antigen (CEA) level, and the presence or absence of adjuvant chemotherapy were also analyzed. Adjuvant chemotherapy consisted of three arms for both colonic and rectal cancers. For colonic cancer, arm I was a combination of i.p. (intraportal) and i.v. mitomycin C (MMC) + p.o. 5-fluorouracil (5-FU); arm II was i.v. MMC + p.o. 5-FU; and arm III was surgery only. For rectal cancer, arm IV was a combination of i.a. (inferior mesenteric artery) and i.v. MMC + p.o. 5-FU; arm V was i.v. MMC + p.o. 5-FU; and arm VI was surgery only. As for the factors affecting the disease-free survival of the patient, multivariate analysis disclosed nodal involvement, venous invasion, an elevated CEA level, and the lower part of the rectum. The effect of adjuvant chemotherapy on the patient's survival was proven for rectal cancer but not for colonic cancer. We conclude that these factors should be considered in setting the stage of tumor pre- and postoperatively. PMID- 8677917 TI - Positron emission tomography in the pretreatment evaluation and follow-up of non small cell lung cancer patients treated with radiotherapy: preliminary findings. AB - The purpose of this study was to prospectively evaluate positron emission tomography (PET) for delineating lung cancers preradiotherapy and to assess PET's ability to distinguish residual tumor from scarring following radiotherapy. Between April 1991 and October 1992, 20 patients underwent 18fluoro-2 deoxyglucose (18FDG) PET scanning of the chest prior to radiotherapy for lung cancer. Tumor volumes on chest x-ray (CXR) and computerized tomography (CT) scan were correlated with abnormalities on PET scans. Follow-up PET studies were compared to postradiotherapy chest x-ray and/or CT scans, and correlated with clinical outcome. Six of seven well-demarcated tumors showed increased uptake of 18FDG correlating with the CT/CXR tumor volume. Twelve poorly demarcated tumors demonstrated increased 18FDG uptake. In seven of 12, the CT/CXR abnormality correlated with changes on PET scan. In three of 12, CT/CXR abnormalities were larger than on PET, whereas in two of 12, abnormalities on PET extended outside the region of CT/CXR changes. The 13th patient in the poorly demarcated category had diffuse carcinoma in situ at the surgical margin that demonstrates increased 18FDG uptake, but was not visible by CT/CXR. Of 12 patients with follow-up studies, all had changes on CXR and/or CT that made it difficult to assess response. Four of 12 had a complete response by PET; all remain locally controlled. The remaining eight patients had either a partial response (n = 6) or no response (n = 2) by PET. Four of these eight patients remain alive and well 11 24 months after therapy. 18FDG PET may be useful for delineation of lung cancer volumes that are poorly defined by CXR and/or CT scan. The value of PET in differentiating tumor from fibrosis after radiotherapy for lung cancer remains to be established. PMID- 8677918 TI - The group sequential triangular test for phase II cancer clinical trials. AB - In cancer, phase II clinical trials are usually noncomparative. Their purpose is to determine whether a new chemotherapy is effective enough to warrant further evaluation in phase III. Therefore, in order to meet ethical requirements, decision-making methods must allow for early termination when inefficacy (or efficacy) is clear. We previously extended the Triangular Test, a group sequential method initially proposed for phase III trials, to phase II trials and demonstrated its advantages (i.e., type I error rate alpha and power close to the nominal values, reduction of the sample size) over other methods. The aim of this paper is to present the Triangular Test from a practical standpoint that will facilitate its application to phase II clinical trials in oncology. After summarizing the minimal theoretical knowledge required to use the method appropriately, we discuss its use in the design and analysis of a phase II cancer trial. PMID- 8677919 TI - Stevens-Johnson syndrome resulting from whole-brain irradiation and phenytoin. PMID- 8677920 TI - Biliary stents in the treatment of malignant ductal obstruction. PMID- 8677921 TI - Nonulcer dyspepsia: great expectations? PMID- 8677922 TI - American College of Gastroenterology: a pyramid of strength for the practitioner, educator, and clinical investigator. PMID- 8677923 TI - Evaluation of hypotheses on pathogenesis of alcoholic pancreatitis. PMID- 8677924 TI - Duodenogastric reflux: an update. AB - Although the role of duodenogastric reflux in the pathogenesis of reflux gastritis is firmly established, for other foregut diseases, such as chronic gastritis, esophagitis, functional dyspepsia, peptic ulcer, and malignancy, it remains controversial and only speculative. The aim of this paper is to review merits and flaws of the methods currently used for the detection of duodenogastric reflux, with emphasis on the newly developed method for 24-h bilirubin detection in the gastric and esophageal content, by a fiberoptic small size probe (Bilitec 2000), and to summarize recent advances in understanding the role of duodenogastric reflux in foregut disorders, in an attempt to identify topics for future research. PMID- 8677925 TI - Wallstents versus plastic stents in malignant biliary obstruction: effects of stent patency of the first and second stent on patient compliance and survival. AB - OBJECTIVES: In prospective trials in patients with malignant biliary obstruction, it has been reported that Wallstents prolong stent patency, but this does not translate into a significant survival benefit. Compared with prospective trials, however, survival may be different in clinical practice because of differences in patient compliance. We report on a retrospective, long term analysis comparing Wallstents versus plastic stents. METHODS: Plastic endoprostheses (70 patients) and endoscopic Wallstents (95 patients) were placed in 165 consecutive patients with irresectable, malignant biliary obstruction in a first (1990-91) and second (1992-93) time period. Stent occlusion was treated by plastic stent placement. RESULTS: Patient characteristics were quite comparable in both stent groups. Initial placement of a Wallstent resulted in an increase of median stent patency of the first (10 vs 4 months, p < 0.001) and second (8 vs 3 months, p < 0.05) stent, a decrease of additional endoscopic procedures (20 vs 58%, p < 0.005), an increase of patient compliance reflected by a decrease of patients dying with untreated stent occlusion (9 vs 30%, p < 0.001), and an increase of survival time (6.5 vs 4 months, p < 0.05). CONCLUSIONS: Initial placement of a Wallstent results in an increase of stent patency of the first and second stent. Duration of stent patency appears to have a determinant effect on patient compliance. Increased stent patency and patient compliance seem to improve survival in clinical practice. PMID- 8677926 TI - Drug treatment of functional dyspepsia: a systematic analysis of trial methodology with recommendations for design of future trials. AB - OBJECTIVES: To evaluate drug treatment of functional dyspepsia (including Helicobacter pylori) and provide guidelines for future trials based on a critical systematic overview of published studies. METHODS: Data sources were a Medline search for articles published in English going back to 1966 and a manual search of four GI journals going back to 1980. Original randomized, double-blind, placebo-controlled trials were selected that enrolled at least 20 patients. Using a standardized, pretested data extraction form, studies were evaluated independently by two observers for study design, outcome measures, and results. RESULTS: Fifty two eligible studies were evaluated. Many studies suffered from important weaknesses in study design and execution. Only five studies used previously validated outcome measures. CONCLUSIONS: Because of suboptimal design and/or unclear presentation of the data, none of the trials provided unequivocal evidence that there is efficacious therapy for the treatment of functional dyspepsia. PMID- 8677927 TI - Improved computer analysis of solid phase gastric emptying scans. AB - OBJECTIVES: The solid phase gastric emptying scan (GES) is used to confirm the clinical impression of abnormal gastric emptying. There is variability in the interpretation of GES. Determination of initial lag phase of the GES and the emptying half-time (t1/2) is generally performed by curve inspection and thus may suffer from lack of objectivity. The purpose of this study was to develop a physiological model for interpretation of the GES using nonlinear curve fitting. This model resulted in computer-generated best fits for lag time and t1/2, which were analyzed in a group of patients with suspected gastroparesis. METHODS: All gastric emptying scans performed at our institution over a 3.5-yr period were studied. Raw data from these studies were analyzed by nonlinear curve fitting. Using the equation: If (x < xo, plateau, plateau * exp( - K * (x - xo))) data were best fit to a function describing a lag followed by a log linear decay. This model generated four parameters; lag, K, t1/2, and T50%. Forty patients with less than 50% emptying at 1 h (group II) were compared with 31 patients with normal emptying (group I). RESULTS: The nonlinear model resulted in better curve fitting (higher r2) in 59 of 71 studies (81%) when compared with a monoexponential decay after a lag of 0 min. Mean lag for patients in group I was 8.5 +/- 1.2 min and was 25.9 +/- 3.1 min in group II (p < 0.0005). Mean t1/2 was 31.7 +/- 1.8 min in group I and 69.7 +/- 5.0 min in group II (p < 0.007). By adding 2 SD to lag and t1/2 in group I, normal values for these parameters were 21.9 and 52.2 min, respectively. Eleven patients in group II had a prolonged lag alone, 13 had a prolonged t1/2, and 13 had prolongation of both parameters. CONCLUSIONS: A new physiological model for the interpretation of GES is presented. Individual patients with delayed gastric emptying may have increased lag times, a decreased rate of antral emptying, or both abnormalities. PMID- 8677928 TI - Predictive value of esophageal manometry and gastroesophageal pH monitoring for responsiveness of reflux disease to medical therapy in children. AB - OBJECTIVES: The aim of the study was to evaluate, in 42 children with gastroesophageal reflux disease, the predictive value of both esophageal manometry and gastroesophageal intraluminal pH on the responsiveness of the disease to medical therapy. METHODS: Motility of lower esophageal sphincter and esophageal body was carried out through a perfused pediatric sleeve-probe; prolonged recording of the sphincteric profile was evaluated at the occurrence of reflux episodes as detected by an esophageal electrode; intraluminal pH of the esophagus and stomach was also measured for 24-h through portable equipment. Children were treated for 8 wk with cisapride and ranitidine and were classified as healed or refractory after endoscopy and clinical evaluation. RESULTS: Twenty one children healed, and 21 were refractory. Compared with healed patients, refractory patients showed, at basal evaluation, an increased esophageal acid exposure (p < 0.05), a reduced basal sphincteric pressure and peristalsis amplitude (p < 0.01), an increased rate of sphincteric pressure drifts (p < 0.01), and a higher rate of transient lower esophageal sphincter relaxations (p < 0.01). The following parameters contributed significantly (p < 0.01) to a multivariate discriminant analysis: peristalsis amplitude, basal sphincter pressure, rate of transient relaxations of the sphincter, and rate of sphincteric pressure drifts. A correct classification of virtually all cases (97.62%) was reached. CONCLUSIONS: Motor dysfunctions of both lower esophageal sphincter and esophageal body are the major factors predicting refractoriness of reflux disease in children to a standard medical treatment. Of the two main mechanisms of reflux, i.e., transient lower esophageal sphincter relaxation and lower esophageal sphincter pressure drift, the latter had the highest predictive value for the refractoriness of reflux disease. PMID- 8677929 TI - Treatment of proctalgia fugax with salbutamol inhalation. AB - OBJECTIVES: Although no generally effective treatment for proctalgia fugax is known, inhalation of salbutamol has been reported to shorten pain attacks in isolated cases. METHODS: We conducted a randomized, double-blind, placebo controlled, crossover trial of inhaled salbutamol in 18 patients with proctalgia fugax. The clinical effect was evaluated by recording the duration of severe pain and discomfort during acute attacks. In addition, anorectal motility recordings were analyzed for possible changes in anal resting tone, sphincter relaxation during rectal distension and in rectal compliance prior to and following administration of the two test substances. RESULTS: Sixteen patients completed all investigations. Compared to placebo, salbutamol inhalation shortened the duration of severe pain (p = 0.019). The effect was most marked in patients having prolonged attacks. In the asymptomatic state, neither salbutamol nor placebo led to a significant change in anal resting pressure, anal relaxation during rectal distension, or rectal compliance. Salbutamol also did not alter the threshold for rectal sensation. CONCLUSIONS: Salbutamol inhalation shortens attacks of severe pain in patients with proctalgia fugax. The mechanism of this effect remains unexplained. PMID- 8677930 TI - Noninvasive detection of Helicobacter pylori infection in clinical practice: the 13C urea breath test. AB - OBJECTIVES: To validate the 13C urea breath test for the detection of Helicobacter pylori infection both before and after treatment. METHODS: 13C urea breath tests with 125-mg and 250-mg doses were carried out on each of 60 infected and 60 noninfected subjects. Results were compared with histological examination of gastric biopsies to establish detection limits. The best cut-off point was used in a clinical trial of the efficacy of the breath test in duodenal ulcer patients before and after antimicrobial therapy. The incremental increase (percentage, delta over baseline in U of delta/mil) in respiratory 13CO2 abundance was associated with histological evidence of H.pylori. Outpatient, tertiary care medical center, and secondary and primary care facilities were included. One hundred twenty healthy asymptomatic subjects and 465 patients with duodenal ulcer disease were studied. The test kit assessed repeatability of breath sample collection and storage and stability of stored samples. Test performance was analyzed by comparison of 125-mg and 250-mg 13C urea with measurements at 30 and 40 min postdose. The test was used to diagnose active H.pylori infection and gauge success of antimicrobial therapy. RESULTS: The test kit results were highly reproducible. The cut-off values were higher with 250-mg compared with 125-mg doses of 13C urea and 40 min compared with 30 min. Using a 125-mg 13C urea and test detection limit of 2.4% at 30 min, the accuracy was 94.8 (95% confidence interval = 92-97%) before antimicrobial therapy and 95.4% (95% confidence interval = 91-98%) after. An increase of 2.4% in the abundance of breath 13CO2 measured 30 min after a 125-mg dose of 13C urea reliably indicated the presence of active H.pylori infection either before or after antimicrobial therapy. The 13C urea breath test provides a simple and reliable and noninvasive method of assessing H.pylori status. PMID- 8677931 TI - Omeprazole coupled with two antibiotics for Helicobacter pylori eradication and prevention of ulcer recurrence. AB - BACKGROUND: Numerous therapeutic trials aimed at eradicating Helicobacter pylori (HP) from the gastric mucosa and preventing ulcer recurrence have been carried out; however, an optimal treatment has not yet been established with carefully controlled randomized studies. OBJECTIVE: The aim of our study was to evaluate the efficacy of an association of omeprazole (OM) coupled with two antibiotics in the eradication of HP and prevention of duodenal ulcer (DU) recurrence. METHODS: One hundred and eighty three patients with active DU were randomized under double blind conditions to receive either OM 20 mg for 4 wk plus amoxycillin 3 g daily and metronidazole 1 g daily during the 2nd and 3rd wk (91 patients, group A) or OM 20 mg for 4 wk plus matching placebo (92 patients, group B). Endoscopy was performed before and at the end of the 4-wk treatment as well as 2, 6, and 12 months later. Biopsies were taken from the duodenum, antrum, and gastric body at each endoscopic examination for HP histological detection and for evaluation of inflammatory changes according to the Sydney system. RESULTS: After 4 wk, 84/86 patients (98%) of group A and 80/86 (93%) of group B were healed of their ulcers. The percentage of eradication was 90% in group A and 1% in group B. During a 12 month follow-up, DU relapsed in 4/63 (6%, including two of three reinfected cases) HP-eradicated group A patients, 4/8 (50%) HP-noneradicated group A patients, and 52/65 (80%) persistently HP-positive group B patients. Rapid, complete, and persistent suppression of gastroduodenitis activity and gastric surface epithelium lesions was observed in most HP-eradicated group A patients, whereas a transient decrease of bacterial colonization and inflammatory scores in the antrum and a transient worsening of corpus gastritis were found in group B patients. CONCLUSIONS: The combined therapy with amoxycillin, metronidazole, and omeprazole is highly effective in both HP eradication and prevention of duodenal ulcer recurrence. PMID- 8677932 TI - Hemostasis with endoscopic hemoclipping for severe gastrointestinal bleeding in critically ill patients. AB - OBJECTIVES: The fact that endoscopic hemostasis is difficult to achieve and that the rebleeding rate is high in critically ill patients with gastrointestinal bleeding has often been reported. The purpose of this study was to examine the efficacy of endoscopic hemoclipping for gastrointestinal bleeding from ulcers and gastrointestinal lesions associated with critical illnesses. METHODS: Critically ill patients who were treated in a university hospital were studied prospectively. For patients with predefined clinically significant gastrointestinal bleeding, an established protocol of endoscopic hemoclipping (including indications and procedures) was used. RESULTS: Ten of 885 patients were treated according to this protocol. All suffered circulatory collapse, and respiratory management required intubation. The initial rate of hemostasis was 100%, and no rebleeding was observed. The APACHE III scores at 24 h after hemostasis were reduced, relative to the time of bleeding (p < 0.01). CONCLUSION: Endoscopic hemoclipping is useful in achieving hemostasis in critically ill patients with severe gastrointestinal bleeding. PMID- 8677933 TI - Endoscopic cecal perforation: mechanisms of injury. AB - OBJECTIVE: Most endoscopic perforations of the colon occur in the rectosigmoid area and are thought to be secondary to direct injury from the endoscopic instrument. The aim of this study was to describe the mechanisms of injury and clinical outcome of endoscopic perforation involving the cecum. METHODS: Retrospective review of 6684 consecutive colonoscopic procedures performed at a university hospital over a 7-yr period. RESULTS: Colonoscopy was complicated by perforation in 0.22%. Five of the 15 perforations occurred in the cecum. The mean age of these five patients was 79.6 +/- 17.7 yr (mean +/- SD). Indications for the procedure were bleeding (n = 4) and suspected obstructing cecal mass (n = 1). Abnormal endoscopic findings included diverticulosis, vascular malformations, cecal ulcer/inflammation, mass, and polyps. Perforation was directly attributable to an ancillary procedure (three routine biopsies, one electrocautery) in the cecal area in four patients, and cecal pathology (inflammation, ulceration) was a contributing risk factor in three patients. Mortality was 80%. In contrast, a noncecal perforation usually occurred at the sigmoid region and was associated with technical difficulties, e.g., inability to traverse a stricture or reach the cecum. CONCLUSIONS: Routine forceps biopsy (without electrocautery) is an under recognized cause of cecal perforation. Ancillary endoscopic interventions in the cecal region should be minimized in elderly patients with evidence of cecal inflammation. Pneumatic injury may be an additional risk factor for cecal perforation in patients with a colonic stricture or a tortuous colon. PMID- 8677934 TI - Lymphocytic and collagenous colitis: an immunohistochemical study. AB - OBJECTIVES: An increase of intraepithelial lymphocytes (IEL) is commonly found in lymphocytic colitis (LC) and collagenous colitis (CC), and has also been observed in the colonic mucosa of some patients with celiac disease or celiac-like disease. Thus, a similar mechanism could play a role in these apparently different entities. The aim of this work was to determine the phenotype of IEL and of lamina propria lymphocytes in the setting of LC and CC. METHODS: Biopsies were taken from all segments of the large bowel and from the ileon of eight patients with CC, four patients with LC, and 10 controls. An immunohistochemical study using monoclonal antibodies directed against IEL, T-cells, helper T-cells, suppressor/cytotoxic T-cells, HLA DR antigens, T-cell-bearing T-cell receptor (TcR) alpha beta, and TcR gamma delta was carried out. RESULTS: There was an increased in mean numbers of IELs in both LC and CC, with significantly more CD 8 IELs than CD 4 IELs. Most IELs were bearing TcR alpha beta; TcR gamma delta bearing cells were not increased in CC or LC. CD 4+ helper T-cells predominated in the lamina propria. Epithelial cells of colonic mucosa abnormally expressed HLA DR antigens. There were no significant differences between findings in LC and CC. CONCLUSION: This study suggests that the immune abnormalities are similar in LC and CC and that a MHC-restricted immune mechanism could be involved in both diseases. Evidence for this includes: 1) the accumulation of CD 4+ T-cells within the lamina propria, 2) epithelial damage closely related to the increase of CD 8 TcR alpha beta IELs, and 3) abnormal class II MHC molecule expression on epithelial cells of colonic mucosa. Furthermore, the results suggest that the putative immune mechanisms underlying LC or CC are probably different from those that are incriminated in celiac disease. PMID- 8677935 TI - Gastric polyps: relationship of size and histology to cancer risk. AB - OBJECTIVES: Management of gastric polyps based on polyp size (< or > 2 cm), and histology obtained from forceps biopsy sampling is controversial. To illuminate this subject, the 4-yr experience with endoscopic management of gastric epithelial polyps at a university hospital and a Veterans Administration medical center was reviewed with histopathologic correlation. METHODS: A computer data base was used to recall the endoscopic diagnosis of "gastric polyp." Endoscopy reports, video, and still photography were reviewed for data on polyp appearance, size, location, and management. These data had been entered prospectively as required by the Computer-Based Management System. Histopathology was reviewed by a second, blinded, pathologist. Gastric polyps of epithelial origin, at least 0.5 cm in diameter, and not associated with polyposis syndromes, were included. RESULTS: Thirty-five gastric polyps in 23 patients met inclusion criteria. Snare polypectomy was ultimately performed on 26, and complete resection with forceps biopsy alone on 9. On histopathology 31 polyps were hyperplastic and 4 were adenomas. Six hyperplastic polyps contained focal dysplasia. Among these, carcinoma in situ was identified in three, all <2.0 cm. Furthermore, forceps biopsy in two of these did not reveal the dysplastic components. One adenomatous polyp also contained carcinoma, also <2.0 cm. CONCLUSIONS: These data emphasize that management based on polyp size or histology obtained from forceps biopsy sampling may be faulty. We recommend that gastric polyps >0.5 cm be removed in toto. PMID- 8677936 TI - Celiac disease and pregnancy outcome. AB - OBJECTIVES: This study investigated the effect of gluten-free diet on pregnancy outcome and lactation in 125 women affected with celiac disease. METHODS: The study has been designed as a case-control study and a before-after study. RESULTS: In the case-control study, comparison of 94 untreated with 31 treated celiac women indicated that the relative risk of abortion was 8.90 times higher (95% confidence limits: 1.19/66.3), the relative risk of low birth weight baby was 5.84 times higher (90% confidence limits: 1.07/31.9), and duration of breast feeding was 2.54 times shorter (p < 0.001) in untreated mothers. Abortion, low birth weight of baby, and duration of breast feeding did not significantly relate to the severity of celiac disease among untreated women. In the before-after study, 12 pregnant celiac women in either treated or untreated condition were compared. Results indicated that the gluten-free diet reduced the relative risk of abortion by 9.18 times (95% confidence limits: 1.05/79.9), reduced the number of low birth weight babies from 29.4% down to zero (p < 0.05), and increased duration of breast feeding 2.38 times (p < 0.10). Both case-control and before after studies indicated that threatened abortion and premature delivery did not significantly relate to treatment of celiac disease. CONCLUSIONS: The high incidence of abortion, of low birth weight babies, and of short breast-feeding periods is effectively corrected by gluten-free diet in women with celiac disease. PMID- 8677937 TI - MALTectomy (appendectomy/tonsillectomy) does not influence the occurrence or mode of presentation of adult celiac disease. AB - OBJECTIVE: Recent reports suggest that appendectomy may protect against the development of ulcerative colitis. Depletion of mucosal helper T-cells is the suggested mechanism. Because mucosal T-cell activity has an even more critical role in the pathogenesis of celiac disease, our objective was to determine whether the development or mode of presentation of this disorder is influenced by appendectomy and/or tonsillectomy. METHODS: One hundred fifty consecutive adult celiac patients were compared with 138 consecutive patients examined at orthopedic clinics. One hundred twenty consecutive patients with ulcerative colitis from the same ethnogeographic population were included as positive disease control. RESULTS: Contrary to the previous findings in ulcerative colitis, which were again confirmed in this study, appendectomy and/or tonsillectomy did not influence the occurrence of celiac disease. In addition, presenting features, predefined in the study protocol, did not differ significantly in the appendectomy and nonappendectomy celiac patients. CONCLUSION: Resection of mucosa-associated lymphoid tissue (MALT) does not influence the occurrence or the mode of presentation of adult celiac disease. Therefore, in this classical example of a T-cell-mediated disorder, the hypothesis that surgical depletion of mucosal T-cells has a protective effect or influences the clinical manifestations cannot be supported. PMID- 8677938 TI - Early changes of body composition in asymptomatic celiac disease patients. AB - BACKGROUND/AIM: This is a study of patients with asymptomatic celiac disease. The aims of this study were: 1) To evaluate the nutritional status of asymptomatic patients with newly diagnosed celiac disease, and 2) to compare these findings with those of untreated/symptomatic and treated patients. MATERIAL: We examined 41 patients with celiac disease divided into three groups: a) 8 asymptomatic (diagnosed in a study of first-degree relatives of probands), b) 20 untreated/symptomatic patients, and c) 13 treated patients. Nutrition of patients from groups A and B was assessed at the time of diagnosis. METHODS: Nutritional status was evaluated by: 1) body composition (fat and lean mass) by dual energy x ray absorptiometry (DEXA), and 2) anthropometric measurements. RESULTS: Compared with sex and age matched controls (n = 153), asymptomatic patients presented a moderate but significant reduction of the fat compartment (-29%; p < 0.001), but not of the lean-tissue mass (p = NS). Untreated/symptomatic patients showed a more severe depletion of fat (-46%; p < 0.001) and lean mass (-9.0%; p < 0.05) compared with healthy controls. Although fat mass of treated patients was significantly reduced with respect to controls (-24%; p < 0.003), lean mass was not affected. The anthropometric measurements of fat showed a significant correlation with the evaluation by DEXA (multiple regression analysis r = 0.918). CONCLUSION: Asymptomatic patients in our study with an unequivocal diagnosis of celiac disease established by mucosal biopsy exhibited a modified body composition. PMID- 8677939 TI - Treatment of refractory distal ulcerative colitis with short chain fatty acid enemas. AB - OBJECTIVES: To determine the efficacy and safety of short chain fatty acids (SCFA) in the treatment of refractory distal ulcerative colitis (UC). METHODS: Ten patients with distal UC who had failed to respond to rectal and oral therapy with 5-ASA and corticosteroids were treated with twice daily enemas containing sodium acetate 60 mM, sodium propionate 30 mM, and sodium butyrate 40 mM titrated to a pH of 7. Patients were assessed clinically (rectal bleeding, tenesmus, bowel motions), endoscopically, and histologically before and after 6 wk of therapy. In addition, patients gave a self-assessment of the efficacy of treatment. RESULTS: Five of the 10 patients responded clinically, and four of these had a clinical remission as reflected by a decrease in degree of bleeding (2.2 vs. 1.2, p < 0.05) and tenesmus (1.6 vs. 0.3, p < 0.05) and by global self-assessment. Endoscopic improvement occurred in five (6.78 +/- 0.83 vs. 4.44 +/- 2.7, p < 0.05). Histologically, no improvement was noted. No side effects were noted, and no patient's condition deteriorated. CONCLUSIONS: In this open-labeled study in patients with highly refractory distal UC, 50% had an overall clinical and endoscopic response. Forty percent of the patients assessed the treatment to be superior to previous treatments and expressed a desire to continue. This trial confirms other studies as to the efficacy of this treatment and further confirms the need for controlled trials of this promising therapy. PMID- 8677940 TI - Prevalence of associated infections in community-acquired spontaneous bacterial peritonitis. AB - OBJECTIVES: The frequency with which other infections occur in association with spontaneous bacterial peritonitis is not known, but has implications for both pathogenesis and management. Spontaneous bacterial peritonitis that occurs in hospitalized patients is mainly a nosocomial infection, the study of which must take into account multiple confounding factors. We conducted a prospective study to compare the clinical features and the frequency of associated infections in patients with community-acquired spontaneous bacterial peritonitis to those of cirrhotic patients with ascites but without spontaneous bacterial peritonitis. Previous studies of spontaneous bacterial peritonitis have not found an infection consistently present at some other site, but those studies did not separate community-acquired from hospital-acquired spontaneous bacterial peritonitis. METHODS: Over a 5-yr study period, 176 cirrhotic patients with ascites were enrolled and were followed. There were 68 patients who had 83 admissions with spontaneous bacterial peritonitis and 108 patients with 124 admissions without spontaneous bacterial peritonitis. Of the 68 patients with spontaneous bacterial peritonitis, 56 had single episodes of peritonitis and 12 had 27 episodes of recurrent bacterial peritonitis. All episodes of spontaneous bacterial peritonitis were diagnosed within 24 h of admission. All subjects had cultures of ascitic fluid, blood, and urine. RESULTS: Patients with spontaneous bacterial peritonitis were more often symptomatic than the nonspontaneous bacterial peritonitis patients. Ascites cultures were positive in 63 (76%) episodes of spontaneous bacterial peritonitis. The frequency of bacteremia in the spontaneous bacterial peritonitis group was significantly higher than that of the nonspontaneous bacterial peritonitis (56.6% vs. 4.8%, p < 0.0001). Bacteriuria occurred in 51 episodes of spontaneous bacterial peritonitis compared with only nine in nonspontaneous bacterial peritonitis patients (61.4% vs. 7.3%, p < 0.0001). Bacteriuria was observed even more often in recurrent bacterial peritonitis patients than in single episode bacterial peritonitis patients (77.8% vs. 53.6%, p < 0.0001). Most patients with bacteriuria had no urinary tract symptoms. There was no significant difference between the frequency of pneumonia in spontaneous bacterial peritonitis patients compared with nonspontaneous bacterial peritonitis patients (8.4% vs. 10.5%, p = 0.17). CONCLUSIONS: Asymptomatic bacteriuria occurs often in association with community-acquired spontaneous bacterial peritonitis. PMID- 8677941 TI - Effect of daily administration period of natural alpha-interferon in patients with chronic hepatitis C. AB - OBJECTIVE: A randomized, controlled trial was performed to study the effect of the period of daily administration of interferon therapy in patients with chronic hepatitis C. PATIENTS AND METHODS: Sixty-three patients were administered a total dose of 480 MU of natural alpha-interferon, 6 MU each day. In 32 cases, interferon was given daily for 2 wk, followed by intermittent administration (three times a week) for 22 wk. The other 31 patients received daily administration for 8 wk, followed by intermittent administration (twice a week) for 12 wk. The responses were based on the normalization of ALT and the clearance of hepatitis C virus. RESULTS: Although ALT normalized in 37 patients during the administration of interferon, it relapsed after the end of interferon therapy in 20 patients. The other 17 patients achieved sustained normalization of ALT and clearance of hepatitis C virus RNA. Responses did not differ according to the administration period of interferon. CONCLUSIONS: Prolonged daily administration did not improve the responses to interferon therapy when the total dose was the same. PMID- 8677942 TI - Activation of the tumor necrosis factor-alpha system in the liver in chronic hepatitis B virus infection. AB - To determine the status of the tumor necrosis factor-alpha (TNFalpha) system in the liver in chronic hepatitis B virus (HBV) infection, hepatic expression of TNFalpha, its two receptors (TNFR-A, TNFR-B), HLA class I antigens (HLA-I), and HBV core antigen (HBcAg) were studied by immunohistochemistry in 24 patients with chronic HBV infection. TNFalpha was detected exclusively in the infiltrating mononuclear cells (MNC) in 19 of 24 patients. The expression of TNFalpha in infiltrating MNC correlated with serum markers of HBV replication and liver histology. TNFR were detected in hepatocytes, sinusoidal cells, and infiltrating MNC. The expression of TNFR correlated with liver histology (p < 0.01) but had no bearing on viral replication. There was a parallel expression of TNFalpha and TNFR (p < 0.01). Hepatocytic expression of HLA-I was increased, and this was related to liver histology but not with TNF alpha nor TNFR. These data indicate that the TNFalpha system is activated in the liver in chronic HBV infection. PMID- 8677943 TI - Characteristics of hepatocellular carcinoma associated with extrahepatic primary malignancies in southern Japan. AB - OBJECTIVES: This study was conducted to clarify the characteristics of patients with extrahepatic primary cancers (EHPC) associated with hepatocellular carcinoma (HCC), as well as to investigate the influence of EHPC on both patient survival and disease-free survival after hepatic resection. METHODS: Forty-one of 463 patients who underwent hepatic resection were included. The clinicopathological factors, including survival, were compared between patients with and without EHPC. We also compared the same factors among the prehepatectomy, synchronous, and posthepatectomy groups. Different types of extrahepatic cancers were also investigated in detail. RESULTS: Gastric and colorectal cancers were the most common EHPC. No definite relationship was observed between HCC and other specific cancers such as B-cell lymphoproliferative disorders. There also were no differences in either the liver function tests, alpha-fetoprotein, or prognostic pathological indicators such as portal vein invasion and intrahepatic metastases. In addition, we found no difference in patient survival between the patients with and without EHPC. However, disease-free survival rates in patients with EHPC were significantly higher than in those without EHPC. Patients in the prehepatectomy group were older than those in the synchronous and posthepatectomy groups, and no positive hepatitis B surface antigen was found in the prehepatectomy group. Patient survival was significantly higher in the posthepatectomy group than in the prehepatectomy group; however, no significant difference in disease-free survival was found among the three groups. Only one patient died of EHPC. CONCLUSIONS: No specific clinicopathological factors were observed in patients with HCC associated with EHPC. Furthermore, EHPC had no adverse effect on either patient survival or disease-free survival after hepatic resection. The predominant cancer was gastric cancer, whereas the most frequent cause of death was HCC itself. Therefore, a strict follow-up of HCC--as well as screening for the most common cancers, such as gastric cancers in southern Japan--should be required for patients with HCC associated with EHPC. PMID- 8677944 TI - Increased prevalence of aortic calcification in chronic pancreatitis. AB - OBJECTIVES: The seemingly frequent radiological observation of aortic calcification in patients with chronic pancreatitis seen in our clinic prompted us to assess the prevalence of this lesion in this disease. METHODS: Fifty-seven consecutive patients with chronic pancreatitis (52 male, five female; mean age 44.2 yr, range 26-59 yr), and 66 healthy controls, matched for sex and age, were studied. Of the 66 controls, 40 were both smokers and drinkers, as were most of the patients. The presence of aortic calcification was determined by performing anteroposterior and lateral radiograms of the prelumbar region. RESULTS: Radiological evidence of aortic calcification was found in 35 of the 57 patients with chronic pancreatitis (61.4%) and in 12 of the 40 smoker control (30.0%) (p < 0.005); none of the nonsmoker controls had aortic calcification. The increased frequency was more pronounced among the patients under 50 yr of age (40.0% vs. 0% and 70.4% vs. 35.3% in the 30-39 and 40-49 yr age groups, respectively). No significant differences in serum levels of cholesterol and triglycerides, blood pressure, alcohol, and smoking habits were observed between chronic pancreatitis patients with aortic calcification and those without, or between patients with aortic calcification and controls. CONCLUSIONS: The results indicate that patients with chronic pancreatitis have a significantly higher prevalence of aortic calcification than controls. The reason for the increased prevalence of this advanced atherosclerotic lesion is nuclear. PMID- 8677945 TI - Predicting the presence of choledocholithiasis in patients with symptomatic cholelithiasis. AB - OBJECTIVES: Accurate preoperative prediction of choledocholithiasis is essential in order to minimize patient risk and curtail health care expenditures. This study was designed to identify independent risk factors for choledocholithiasis in patients who had undergone cholecystectomy for symptomatic cholelithiasis and to develop a predictive model based on those factors. METHODS: The charts of 1264 consecutive patients who had undergone cholecystectomy at one of three North Carolina hospitals between January 1, 1989 and December 31, 1991 were reviewed; 465 of these patients had confirmed presence or absence of choledocholithiasis by cholangiography and/or common bile duct exploration and were eligible for analysis. Candidate predictor variables included age and maximum preoperative values for each of the following: temperature, alkaline phosphatase, bilirubin, AST, amylase, white blood cell count, and common bile duct diameter. Model development and validation were conducted using standard data-splitting (60% "training," 40% "test") and logistic regression techniques. RESULTS: Choledocholithiasis was confirmed in 115 (25%) of the 465 eligible patients. Univariate analysis identified bilirubin, common bile duct diameter, AST, temperature, alkaline phosphatase, and age as predictors. Multivariable analysis subsequently identified bilirubin, common bile duct diameter, AST, alkaline phosphatase, and age as independent predictors of choledocholithiasis. A final model containing these variables (except age, whose contribution to the model was small) accurately predicted choledocholithiasis (c-index = 0.76). CONCLUSIONS: Accurate estimates of choledocholithiasis risk can be made using maximum preoperative bilirubin, common bile duct diameter, AST, and alkaline phosphatase values. Use of the model may help physicians select those patients with symptomatic cholelithiasis who would most likely benefit from further investigation to exclude choledocholithiasis. PMID- 8677946 TI - Use of endosonographic evaluation of colorectal tumor depth in determining the appropriateness of endoscopic mucosal resection. AB - OBJECTIVES: To determine the efficacy with which endoscopic ultrasonography (EUS) is able to differentiate between mucosal and submucosal invasion for application of endoscopic resection. METHODS: We prospectively analyzed 60 patients who were diagnosed with early cancer by conventional EUS with regard to the accuracy of mucosal neoplasia as a function of gender, age, location, size, endoscopic configuration, histological diagnosis, and method of resection. RESULTS: Forty lesions interpreted as mucosal by EUS were shown histologically to include 32 lesions in the mucosa and eight in the submucosa or deeper, whereas 20 tumors interpreted as invasive cancer included six lesions in the mucosa and 14 in the submucosa or deeper. The accuracy of mucosal neoplasia (AMN) detection was 77% (true-positive and true-negative mucosal neoplasias divided by all lesions). Assessment of pure cancers without adenomatous components produced a significantly lower AMN (59%, p = 0.03) than the assessment of pure adenomas (95%) or cancers in adenomas (87%). However, there were no significant differences in the EUS assessment of intramucosal neoplasia as a function of sex, age, endoscopic configuration, size, location, or treatment. CONCLUSIONS: We conclude that conventional EUS interpretation alone cannot determine the appropriate treatment for early colorectal cancer. PMID- 8677947 TI - Utility of endoscopic ultrasonography with color Doppler function for the diagnosis of islet cell tumor. AB - OBJECTIVE: To evaluate the efficacy of endoscopic ultrasonography with color Doppler function for the diagnosis of islet cell tumor. METHODS: Endoscopic ultrasonography was compared with other modalities such as ultrasonography, computed tomography, and angiography in the evaluation of seven patients with islet cell tumor and 28 patients with duct cell cancer. RESULTS: In cases of islet cell tumor, the tumor detection rates by ultrasonography and endoscopic ultrasonography were 86% and 100%, respectively. Color signals were detected in 14% and 100% of the cases of islet cell tumor by ultrasonography and endoscopic ultrasonography, respectively. The pattern of color signals obtained was rich and abundant, showing pulsatile and/or continuous wave patterns. Angiography and computed tomography showed hypervascularity. However, in cases of duct cell cancer, the tumor detection rates by ultrasonography and endoscopic ultrasonography were 96% and 100%, respectively, whereas color signals were detected in 78% with both ultrasonography and endoscopic ultrasonography. The image of blood flow, which was connected to surrounding vessels, showed a linear pattern and few blood flow signals. In these cases, angiography and computed tomography demonstrated encasement of the artery or portal vein without hypervascularity. CONCLUSIONS: Endoscopic ultrasonography was usefull for the localization and differential diagnosis of islet cell tumor because of its excellent ability to visualize small lesions and tumor vascularity simultaneously. PMID- 8677948 TI - Budd-Chiari syndrome attributed to protein C deficiency. AB - The protein C anticoagulant pathway is an important downregulating mechanism of the blood coagulation cascade. We report a 47-yr-old male with Budd-Chiari syndrome and occlusion of the inferior vena cava. His plasma protein C antigen level was decreased to 42%, and its activity was 34%. Other coagulable factors were normal. Protein C deficiency should be considered a possible etiological factor of the Budd-Chiari syndrome. PMID- 8677949 TI - Blue rubber bleb nevus syndrome. AB - A 26-yr-old man was admitted with malaise and melena. During the physical examination, six hemangiomas were spotted on the skin, and laboratory evaluations proved the existence of severe iron deficiency anemia (Hb 2.9 g/dl). Upper endoscopy and small bowel follow-through revealed no pathology. Colonoscopy documented the presence of a blue-red cavernous hemangioma, 1 cm in diameter, at the splenic flexura. The skin and colonic lesions were typical; thus, blue-rubber bleb-nevus syndrome was diagnosed. The patient was given blood transfusions followed by oral iron supplementation. He refused further evaluation or surgery and is still fine after a follow-up period of 6 months. Here, we present a discussion of this case, together with a detailed review of the literature. PMID- 8677950 TI - Extreme hyperbilirubinemia associated with the use of anabolic steroids, health/nutritional supplements, and ethanol: response to ursodeoxycholic acid treatment. PMID- 8677951 TI - Perihepatic abscess formation in diabetes: a complication of silent gallstones. AB - Perforation of the gallbladder is a serious complication of acute cholecystitis, with significant morbidity and mortality rates. We present the case of a diabetic adult in whom the usual signs and symptoms of acute cholecystitis were obscured. A high index of suspicion at the time of admission prompted emergent evaluation. Computerized axial tomography revealed a large perihepatic abscess extending from a perforated gallbladder. Fourteen hundred milliliters of malodorous brown fluid were drained by ultrasound-guided percutaneous aspiration from the collection. Early clinical suspicion combined with conservative surgical management may prevent serious morbidity and/or mortality in diabetic patients with complicated cholecystitis. PMID- 8677952 TI - Toothpick perforation of the intestine diagnosed by a small bowel series. AB - We report the case of a 50-yr-old man who unknowingly swallowed a double-pointed toothpick that ultimately perforated the distal small bowel over a period of several weeks. Appendicitis and ileitis were sequentially considered as diagnosis. A foreign body was diagnosed on a second small bowel series and removed. It has been noted that, because toothpicks are not radiopaque, radiographic studies are not useful in the diagnostic workup. In the case reported, the toothpick was seen on the contrast radiograph of the small bowel and the correct diagnosis ultimately made. PMID- 8677953 TI - Small cell carcinoma of gallbladder: report of two cases. AB - Extrapulmonary small cell carcinoma has been reported from multiple sites, including the gallbladder. Small cell carcinoma of the gallbladder is a very rare tumor, found usually in elderly women and associated with cholelithiasis. It carries a grave prognosis, metastasizing early and causing death shortly after diagnosis. Treatment of metastatic disease with two different chemotherapeutic regimens has been shown to improve survival. To the best of our knowledge, this tumor has not been previously reported in a black individual, or in any subject less than 49 yr or more than 79 yr old. We report two cases: one is the first black and youngest reported case. The second is the oldest person reported with this rare malignancy. Radiological studies such as ultrasound and CT scan were useful in evaluating tumor spread and follow-up. PMID- 8677954 TI - Primary jejunal malignant mixed tumor in a patient with von Recklinghausen neurofibromatosis. AB - A rare case of primary jejunal malignant mixed tumor arising in a 49-64-old Japanese male with von Recklinghausen's disease is reported. The patient, who had a past history of partial gastrectomy due to duodenal ulcer, was admitted with a complaint of epigastric pain. Upper gastrointestinal examinations showed a huge polypoid tumor located in the efferent loop of the gastrojejunostomy site. Because the tumor was strongly suggestive of leiomyosarcoma on histological examination of biopsy specimens, laparotomy was performed. The resected tumor measuring 10 X 7 X 7 cm was composed of adenocarcinoma admixed with various sarcomatous components, including rhabdomyosarcoma, osteosarcoma, and other sarcomas. Immunohistochemical analysis also supported this diagnosis. The features of this tumor closely resembled malignant mixed mullerian tumor of heterologous type that develops in female genital organs. It is well known that patients with von Recklinghausen neurofibromatosis have an increased incidence of mesenchymal tumors and malignant neoplasias, and therefore, it seems that there is a possible relationship between the histogenesis of this peculiar tumor and the genetic abnormality in this patient. PMID- 8677955 TI - Variant of intraductal carcinoma (with scant mucin production) is of main pancreatic duct origin: a clinicopathological study of four patients. AB - OBJECTIVES: To investigate the histopathological and immunohistochemical features of intraductal "nodular" tumor located in the main pancreatic duct. METHODS: Four cases were studied, and the results were compared with those in 10 cases of common ductal adenocarcinomas of the pancreas. RESULTS: The intraductal nodular carcinoma were large, more than 3 cm in diameter (range, 3-7 cm), lacked macroscopic mucin production, and presented a papillotubular adenocarcinoma. These tumors showed minimal invasion into the periductal tissue, duodenum, and choledochus. Immunohistochemically, the tumor cells were negative for anti-CEA and faintly positive for anti-CA19-9, in all except one tumor, whereas the common ductal adenocarcinomas were clearly positive for both. The postoperative course was favorable, and all three living patients remained healthy for more than 4 yr. CONCLUSION: These tumors may be variants of intraductal tumors with a more favorable prognosis. PMID- 8677956 TI - Adenomatous polyposis coli presenting as adenocarcinoma of the appendix. PMID- 8677957 TI - The sign of Leser-Trelat associated with esophageal carcinoma. AB - A 79-year-old woman was admitted to our hospital with complaints of dysphagia and multiple verrucous papules that had developed over the previous year. The diagnosis of esophageal carcinoma was based on upper gastrointestinal radiography and endoscopic examination with biopsy. The clinical syndrome was consistent with the sign of Leser-Trelat associated with esophageal carcinoma. Although radiation therapy and chemotherapy were undertaken, the patient died 8 months later because of the sign of Leser-Trelat in association with squamous cell esophageal carcinoma. PMID- 8677958 TI - Eosinophilic gastroenteritis presenting as a giant gastric ulcer. AB - We describe a 43-yr-old female with a giant gastric ulcer, refractory to medical treatment, that ultimately proved to be due to the mural form of eosinophilic gastroenteritis. The patient presented with a 6-month history of abdominal pain, diarrhea, and weight loss. Endoscopy showed a giant gastric ulcer, and biopsies revealed only chronic active ulcerative inflammation. The ulcer progressed on omeprazole therapy; therefore, a distal antrectomy with gastrojejunal anastomosis and bilateral vagotomy was performed. Pathology of the surgical specimen demonstrated the mural form of eosinophilic gastritis. To the best of our knowledge, this case is the first to demonstrate that refractory giant gastric ulcers may be a manifestation of the mural form of eosinophilic gastroenteritis. PMID- 8677959 TI - Acute cholecystitis and cholangitis caused by Echinococcus granulosus. AB - We report for the first time in the recent North American literature, the case of a patient with rupture of a hepatic hydatid cyst into the gallbladder, with subsequent obstruction of the cystic duct by a daughter cyst acting as a ball valve and causing acute acalculous cholecystitis. PMID- 8677960 TI - Primary gastroduodenal tuberculous infection presenting as pyloric outlet obstruction. AB - Gastroduodenal tuberculosis occurs in underdeveloped areas and, although rarely, also in western countries, affecting mainly immigrants, immunodepressed, or low socioeconomic classes. We report a case of gastroduodenal tuberculosis presenting as pyloric outlet obstruction. We describe the clinical features and the diagnostic approach to the patient, emphasizing the role played by surgery in the diagnosis and treatment of the established complication. Developments are needed in the diagnostic area (video-laparoscopy, polymerase chain reaction of mycobacterial DNA) and in the mini-invasive treatment of obstructive complications (endoscopic balloon dilatation, video-laparoscopic surgery). PMID- 8677961 TI - Duodenal obstruction by multiple percutaneous endoscopic gastrostomy tube inner bumpers. PMID- 8677962 TI - Solitary fibrous tumor of the mesentery. AB - We report a solitary fibrous tumor of the abdominal cavityt that presented as a encapsulated mass attached to the mesentery in a 33-yr-old man. Histologically, the lesion showed a disorganized arrangement of spindle cells in a collagenous background and prominent vascular channels of varying size. Tumor cells showed immunohistochemical reactivity for vimentin only. Cytokeratins and CD34 were negative. This report further extends the anatomic range of solitary fibrous tumor, a neoplasm that must be included in the differential diagnosis of well defined abdominal masses. The behavior of this mesenteric solitary fibrous tumor has been benign. PMID- 8677963 TI - Gastric lipoma with severe hemorrhage. PMID- 8677964 TI - Sonography useful after TIPS. PMID- 8677965 TI - Re: ACG's guideline on reflux disease. PMID- 8677966 TI - Response to Dr. Dantas: occasional dysphagia for solid foods. PMID- 8677967 TI - The use of azithromycin in short-term low-dose triple therapies for Helicobacter pylori infection. PMID- 8677968 TI - Successful combination endoscopic therapy for duodenal Dieulafoy's lesion. PMID- 8677969 TI - Folliculitis and mesalamine. PMID- 8677970 TI - Meglumine antimoniate-induced pancreatitis. PMID- 8677971 TI - Re: life-threatening severe immune thrombocytopenia after alpha-interferon therapy for chronic hepatitis C infection. PMID- 8677972 TI - Pitfalls of bile duct stone removal after balloon sphincter dilation. PMID- 8677973 TI - Cryptogenic fibrosing alveolitis predating ulcerative colitis. PMID- 8677975 TI - Is the incidence of gastric cancer still in decline? PMID- 8677974 TI - The effect of seasons on variceal bleeding in patients with cirrhosis. PMID- 8677976 TI - Gastroscopy and insertion of a jejunal feeding tube via a PEG stoma with 5-mm neonatal endoscope (Olympus GIF N30) PMID- 8677977 TI - Esophageal tuberculosis. PMID- 8677978 TI - Failure to detect HTLV-I proviral DNA in the liver of a patient with primary biliary cirrhosis and HTLV-I-associated myelopathy. PMID- 8677979 TI - The inhibitory effects of dai-chai-hu-tang (dai-saiko-to) extract on supersaturated bile formation in cholesterol gallstone disease. PMID- 8677980 TI - Liver biopsy complications and routine ultrasound. PMID- 8677981 TI - The clinical significance of hepatitis B mutations. PMID- 8677982 TI - When a doctor is a patient. PMID- 8677983 TI - Prevention of biliary stent clogging: a clinical review. AB - Endoscopic stenting is a well established treatment for obstructive jaundice. The major complication of the technique is late stent blockage, which results from bacterial biofilm and sludge deposition. Numerous approaches to overcoming this problem have been proposed. Large diameter stents can provide longer patency, but they do not prevent blockage indefinitely. Although many plastics have been investigated for resistance to biofilm adherence, there is no convincing evidence that any material prevents clogging in vivo. Changes in stent design and placement techniques to prevent bacterial colonization may provide more lasting effects. Long term antibiotic prophylaxis offers an intriguing possibility for prolonging stent patency. However, its efficacy remains uncertain, and more studies are required to assess timing, dosage, and the optimal spectrum of antibacterial coverage. Metal stent designs now permit delivery of larger diameters; these must be improved to prevent tumor ingrowth and to allow subsequent stent removal. In summary, our understanding of the behavior of bacterial biofilm and its role in stent blockage has improved, but we are still searching for methods to maintain stent function indefinitely. PMID- 8677984 TI - Radiation proctitis: a review. AB - Radiation therapy of cancers in the pelvic region may lead to radiation proctitis. Radiation injury to the rectal wall eventually causes connective tissue fibrosis and obliterative endarteritis with subsequent local tissue ischemia. Patients with radiation proctitis may be minimally ill and heal spontaneously. However, symptoms of proctitis may persist, and the disease progresses to chronic bleeding and/or stricture and fistula formation. Medical therapy is often unsuccessful, and surgery is eventually required. Because of numerous postoperative complications and no guarantee of success, surgery should only be done as a last resort. PMID- 8677985 TI - Frequency and clinical profile of precore and surface hepatitis B mutants in Asian-Indian patients with chronic liver disease. AB - BACKGROUND: Infection due to hepatitis B virus (HBV) could be due to wild or mutant (precore or surface) viruses. The prevalence and clinical profile of different viral forms in patients with chronic liver disease has not been established. METHODS: One hundred and twenty patients with histologically proven HBV-related chronic liver disease were studied. Patients with dual infection with HCV/HDV/HIV, past history of interferon therapy, or autoimmune hepatitis were excluded. Eighteen (15.5%) patients had the precore mutation (HBsAg +ve, HBeAg ve/anti-HBe +ve, HBV DNA +ve), and 13 (10.8%) had the surface gene mutations (HBsAg -ve, HBeAg -ve, IgG anti-HBc, and HBV DNA +ve). The remaining 89 (74.2%) patients were infected with wild type HBV. The course of all patients with mutant forms and 41 of those with the wild type form was followed for a mean (+/- SD) of 4.4 +/- 2.4 yr. RESULTS: Compared with wild-type-infected patients, those with surface mutation were younger (39.9 +/- 14 vs. 30.1 +/- 12.4 yr, p < 0.05). Patients with precore mutations had a shorter illness than those with surface mutant (p < 0.01) and wild forms (p < 0.05). Histologically, patients with precore type had more active liver disease than wild type (39% vs. 15%, p < 0.05). Patients with precore mutations were always symptomatic, often presenting with ascites (67%) and jaundice (55%). Patients with surface mutant forms often presented with quiescent cirrhosis (77%) or cirrhosis with hepatoma (15%). CONCLUSIONS: One-fourth of HBV-related chronic liver disease in Asian Indians is attributable to mutant HBV forms. The presence of variant viruses alters the natural history of the disease, with the precore variance having a more aggressive course and the surface mutant, a more quiescent but unfavorable course, compared with the wild type. PMID- 8677986 TI - Percutaneous biopsy in diffuse liver disease: increasing diagnostic yield and decreasing complication rate by routine ultrasound assessment of puncture site. AB - OBJECTIVE: To evaluate the usefulness of routine ultrasound assessment of puncture site before performing percutaneous biopsy in diffuse liver disease. Seven hundred fifty-three consecutive patients were studied retrospectively. METHODS: Serial scanning of the last intercostal spaces allowed us to establish the most suitable access to the thicker liver parenchyma (assessing the most favorable angulation of the needle too), avoiding the puncture of adjacent organs; no more than 1 min was necessary for such a determination. RESULTS: In 99.4% of patients, a definitive or indicative pathological diagnosis of chronic liver disease was obtained. Only one hemorrhagic complication (0.13%) occurred, requiring no surgical treatment or blood transfusion. Three cases of vasovagal reaction occurred (0.40%): two of these recovered spontaneously, while the other one needed i.v. administration of atropine. Mortality was 0 in our series. CONCLUSIONS: Routine ultrasound of the puncture site is a quick method of assessment, allowing one to increase the diagnostic yield of percutaneous liver biopsy and to maintain low complication rates for such a procedure. PMID- 8677987 TI - Allelic variation in the cagA gene of Helicobacter pylori obtained from Korea compared to the United States. AB - OBJECTIVE: Helicobacter pylori is an important factor in the development of duodenal ulcer disease and has been implicated in the pathogenesis of gastric adenocarcinoma. It has been suggested that the cagA gene is a marker for more virulent strains of H. pylori. METHODS: We determined the prevalence of the cagA gene in 60 clinical isolates [34 from gastric carcinoma patients (CA), 26 from duodenal ulcer patients (DU)] from Korea, a country with a high incidence and mortality from gastric cancer. Genomic DNA was polymerase chain reaction amplified by using two different primer sets for the cagA gene. The first cagA primer set amplifies a 297-bp product from the midregion of the cagA gene. The second primer set, which was previously established in a patient population from the Houston area (21 DU patients, 20 from individuals with asymptomatic gastritis) amplified a 1.4-kb region further downstream in the cagA gene. RESULTS: The expected 297 bp polymerase chain reaction amplicon for cagA was identified in 59/60 (98.3%) H. pylori isolates from Korea (33/34 CA, 26/26 DU), and in 36/41 (88%) isolates from the Houston area (20/21 DU, 16/20 asymptomatic gastritis) (NS). Using the second cagA primer set, the expected 1.4-kb product was found in only 1/60 (1.7%) H. pylori isolates from Korea (1/34 CA, 0/26 DU), and in 36/41 (88%) of isolates from the Houston area (20/21 DU, 16/20 GST) (p < 0.001). Western blot analysis showed that all Korean H. pylori isolates expressed cagA. CONCLUSIONS: The high prevalence of the cagA gene in H. pylori isolates from Korean patients with gastric adenocarcinoma or duodenal ulcers indicates that the cagA gene is common in H. pylori strains, and therefore, is not reliable as a single marker for the discrimination of H. pylori strains with respect to a specific disease. Our data further suggest that allelic variations in the genome of H. pylori strains may exist and that distinct H. pylori populations may circulate in different geographic regions. PMID- 8677988 TI - Selective endoscopic retrograde cholangiography and preoperative bile duct stone removal in patients scheduled for laparoscopic cholecystectomy: a prospective study. AB - OBJECTIVES: Laparoscopic cholecystectomy (LC) has become the treatment of choice for patients with symptomatic cholelithiasis. About 10% of patients with symptomatic gallstones may bear associated common bile duct (CBD) stones. The preferred approach to these patients is the removal of CBD stones by endoscopic retrograde cholangiography (ERCP) before LC. However, ERCP before LC should be performed only in patients with suspected choledocholithiasis. The aims of this study were to: 1) generate an efficacious predictive model for selecting patients with suspected choledocholithiasis to submit to preoperative ERCP, and 2) test the safety of the endoscopic/laparoscopic procedure. METHODS: Historical, biochemical, and ultrasonographic data were collected prospectively. Receiver operating characteristics curve analysis was adopted for determining optimal biochemical and ultrasonographic cut-off values. Multivariate analysis using logistic regression with generation of the best model identifying independent predictors of CBD stones was also employed. RESULTS: The optimal model predicted a 95% probability of CBD stones in a patient who presented with elevated ALP (over 300 IU/L) and ALT (over 40 IU/L) levels and CBD dilation > 8 mm at ultrasonography. Endoscopic removal of CBD stones was achieved in 95% of patients, with minimal morbidity and no mortality. CONCLUSIONS: The identified independent predictors of CBD stones are highly efficient selectors of patients with choledocholithiasis. Moreover, endoscopic removal of CBD stones before LC is a safe and efficacious procedure. PMID- 8677989 TI - Feasibility of high-volume screening sigmoidoscopy using a flexible fiberoptic endoscope and a disposable sheath system. AB - OBJECTIVES: Sigmoidoscopy is an effective screening test for colorectal cancer but has yet to have a major impact on mortality because, in part, of inadequate utilization by physicians. To address concerns of inefficient use of time and resources, we examined the feasibility of high volume, single-day flexible sigmoidoscopy (FS) screening sessions using an innovative fiberoptic sigmoidoscope with a disposable sheath system. METHODS: All City of Boston employees over the age of 50 yr (n = 6137) were invited by mail to undergo a screening FS at Boston City Hospital (BCH). Respondents (n = 564) were contacted by phone by the program coordinator on receipt of a prepaid postcard and were scheduled (n = 227) consecutively into 15-min slots on 1 of 6 1/2-day (3-h) weekend sessions. Preregistration was completed at BCH during the week before each session and included enrollment, completion of a brief risk questionnaire, documentation of informed consent, and bowel prep instructions. Procedures were performed by three physician endoscopists rotating among four endoscopy rooms per session. Each room was staffed with a nurse to aid in patient care and a technician to set up equipment. RESULTS: A total of 198 of the 227 (87%) scheduled patients underwent screening FS during the three sessions. Physicians performed a mean of 3.5 procedures per room per hour, or 4.7 procedures per hour overall, with a mean depth of scope insertion of 51 +/- 10 cm and a mean procedure time of 4.7 +/- 3.3 min. Equipment set-up time and patient turnaround time averaged 4.6 +/- 1.7 min and 11.0 +/- 6.0 min, respectively. Polyps were detected in 29 (14.6%) patients, and a Dukes' A cancer was detected in one (0.5%). The only complication was a cardiac arrhythmia. A crude estimate of direct costs approximated $ 75 per examination. CONCLUSION: High volume, single day FS using the fiberoptic sigmoidoscope with a disposable sheath system offers an effective strategy for enhancing physicians compliance, and possibly patient compliance, with screening sigmoidoscopy through more efficient use of time and resources. PMID- 8677990 TI - A comparison of mesalamine suspension enema and oral sulfasalazine for treatment of active distal ulcerative colitis in adults. AB - OBJECTIVES: To compare the efficacy and safety of mesalamine (5-ASA) suspension enema versus oral sulfasalazine (SAS) in patients with active mild to moderate distal ulcerative colitis. METHODS: Thirty-seven patients were randomly assigned to treatment with either rectal mesalamine, 4 g at night, (n = 19) or oral sulfasalazine, 1 g four times a day, (n = 18) in a 6-wk, double-blind, double dummy, parallel-group, multicenter study. Patients known to be refractory to SAS or 5-ASA preparations were excluded. Efficacy was assessed by a physician-rated Disease Activity Index (DAI), which included symptom evaluations and sigmoidoscopic findings, by physician-rated Clinical Global Improvement (CGI) scores, and by Patient Global Improvement (PGI) scores. Safety was assessed by adverse event reports, clinical laboratory tests, and physical examination. Results. Mean DAI scores indicated significant improvement from baseline in both treatment groups. CGI scores indicated that 94% of the 5-ASA patients were either "Very Much Improved" or "Much Improved" at wk 6 versus 77% of the SAS patients. PGI ratings showed more improvement in the 5-ASA treatment group than in the SAS group at wk 2 (p = 0.02) and at wk 4 (p = 0.04). Adverse events, primarily headache and nausea, occurred significantly more frequently (p = 0.02) in the SAS than in the 5-ASA group (83 vs 42%). Three patients were withdrawn from SAS treatment because of adverse events. CONCLUSIONS: Rectally administered 5-ASA is as effective as oral SAS in treatment of active distal ulcerative colitis but is associated with fewer and milder adverse events. Patients treated with 5-ASA reported improvement earlier than those treated with SAS. PMID- 8677991 TI - A prospective endoscopic evaluation of the causes of upper GI hemorrhage in alcoholics: a focus on alcoholic gastropathy. AB - OBJECTIVE: To determine prospectively the causes of upper GI hemorrhage (UGIH) in alcoholics, focusing on the prevalence of alcoholic gastropathy, and to compare the etiology of bleeding in patients who drink alcohol to that of nondrinkers. METHODS: From August 1, 1990 through September 9, 1994, all patients evaluated by the gastroenterology consultative service at a large inner-city hospital presenting with UGIH were prospectively identified. Patients had to have a subnormal hematocrit on or within 12 h of admission or a fall of at least 5 points from a previous baseline determination to be included. Upper GI endoscopy was performed in all patients within 48 h of admission. Alcohol use was quantitated as chronic (80 g or more per day for at least 1 month), binge, occasional, or none. RESULTS: Over the 4-yr study period, 727 patients met the inclusion criteria, and of these, 212 (29%) were classified as chronic alcohol users. Overall, peptic ulcer disease was the most common cause of bleeding (60%). Gastropathy (diffuse subepithelial hemorrhage) was considered etiological in only 32 patients (4%). The most common causes of gastropathy were portal hypertension in 22 patients and nonsteroidal anti-inflammatory drug use in five. Only three patients were identified in whom alcoholic gastropathy was considered etiological; in these patients, bleeding was mild and self-limited. When the causes of bleeding were compared between drinkers and nondrinkers, drinkers were more likely to bleed from varices (p = 0.024) or other portal hypertension related causes (p < 0.01), whereas peptic ulcer was more common in nondrinkers compared with chronic users (67 vs 53%; p < 0.01). Esophagitis (p = 0.95) and Mallory-Weiss tear (p = 0.15) prevalences were not significantly different between the two groups. CONCLUSION: In the actively drinking patient, the most common causes of UGIH are peptic ulcer and disorders related to portal hypertension. Alcoholic gastropathy appears to be a rare and previously overemphasized cause of bleeding. PMID- 8677992 TI - Does routine abdominal ultrasound enhance diagnostic accuracy in irritable bowel syndrome? AB - OBJECTIVE: The current recommendation that irritable bowel syndrome (IBS) should be diagnosed positively using minimum investigation raises the possibility that some disorders, particularly gynecological, may be overlooked. Transabdominal ultrasound is now sufficiently sophisticated to allow assessment of all abdominal viscera for associated pathology, and this study was designed to evaluate its role in the diagnosis of IBS. METHODS: An ultrasound scan was performed in 125 patients (100 females, 25 males) for whom a confident diagnosis of IBS had been made. RESULTS: No serious intra-abdominal pathology was encountered, but 20% of females and 8% of males had an ultrasound abnormality. None of these abnormalities resulted in any additional therapeutic measures. A hepatobiliary abnormality was found in similar proportions of males and females (10 vs 8%). Gallstones were most common (5 vs 4%), but in no individual were they considered to entirely account for the presenting symptoms. Eight percent of the women were found to have a pelvic abnormality, but it was not regarded as serious in any of them. CONCLUSIONS: This study confirms that a positive approach to diagnosing IBS is a safe policy. Furthermore, routine ultrasound scanning in IBS is unnecessary and could be counter-productive by detecting many minor abnormalities, which can pose further therapeutic dilemmas. PMID- 8677993 TI - Gastric emptying and dyspeptic symptoms in patients with gastroesophageal reflux. AB - OBJECTIVES: To clarify 1) whether gastric emptying of a mixed meal is delayed in patients with gastroesophageal reflux and 2) the relationship between dyspeptic symptoms and delayed gastric emptying in refluxers. METHODS: Gastric emptying of a solid meal was studied by ultrasound in 25 patients with pathological esophageal acid exposure. Gastric emptying was then assessed in relation to upper digestive endoscopy, esophageal manometry, 24-h pH monitoring and quantification of symptoms of reflux- and dysmotility-like dyspepsia. RESULTS: Fifteen of 25 refluxers had esophagitis, and 15 were "dyspeptic". Refluxers exhibited a significant delay in gastric emptying compared with controls [307.6 (21.0) vs. 209 (10.4) min, p < 0.001). Patients with delayed emptying had low LES pressure [11.9 (2.1) vs. 18.6 (2.1) mm Hg, p < 0.05]. There was no correlation between delayed emptying and either pH monitoring or presence of esophagitis. There were no differences in any of the pH monitoring parameters between refluxers with and without coexisting dysmotility-like symptoms. CONCLUSIONS: Gastric emptying of a solid meal is markedly delayed in patients with gastroesophageal reflux. However, no direct causal link was found between delayed emptying and reflux. Our data suggest the presence of a motility disorder in gastroesophageal reflux which is not confined to the esophagogastric junction. PMID- 8677994 TI - Cyclosporine and 6-mercaptopurine for active, refractory Crohn's colitis in children. AB - OBJECTIVES: This prospective, open trial of treatment was conducted to determine whether cyclosporine A (CSA) is effective in inducing remission in children with severe, active Crohn's colitis refractory to other medical treatment and if remission may be maintained by 6-mercaptopurine (6-MP) and 5-aminosalicylic acid (5-ASA) after discontinuing CSA. METHODS: Ten children (five males, five females), ages 1.2-16 yr (mean 11), all had failed to respond to 4 wk of treatment with i.v. methylprednisolone and total parenteral nutrition/elemental diet; three were already receiving 6-mercaptopurine. CSA was initially given as a twice daily i.v. dosage and was switched to oral CSA when a clinical response was observed. At the same time, corticosteroids were switched to the oral route and tapered over the next 3 months. Patients were grouped by treatment outcome. "Responders" were those who achieved remission with i.v. CSA therapy, "relapsers" were those who achieved remission with i.v. CSA but relapsed later, and nonresponders had not achieved remission after 4 wk of i.v. CSA. Responders were given 6-MP with intent to discontinue CSA after 6 months and maintain remission by 6-MP and 5-ASA. RESULTS: There were seven responders to CSA. For all patients, the Pediatric Crohn's Disease Activity Index (PCDAI) (score range 0-100) had a mean value of 55 (range 40-65) just before treatment; PCDAI improved to a mean of 19 (range 5-42.5) after 2 wk of CSA therapy. Four of the seven responders discontinued CSA after 6 months and remain well on 6-MP and 5ASA alone for 22, 13, 8, and 3 months. One patient had massive GI bleeding (from active Crohn's colitis), which stopped within 48 h of CSA treatment. There were three relapsers (at 2-6 months of CSA), and three were nonresponders. Three patients who were already receiving 6-MP before CSA therapy either did not respond to CSA or relapsed while receiving it. The six nonresponders and relapsers required surgical resection. Transient side effects included hypertension responding to nifedipine in one child and hirsutism and tremors in another. CONCLUSIONS: We conclude that CSA offers a good remission rate for children with severe Crohn's colitis failing other medical treatment, although relapse was common especially if the child was already on 6-MP. In addition, CSA may offer "temporizing" therapy in severe, active Crohn's colitis; this may allow surgery to be performed electively, with time for psychosocial and nutritional preparation before surgery. PMID- 8677995 TI - Single dose-inactivated hepatitis A vaccination schedule for susceptible youngsters. AB - OBJECTIVE: To investigate the feasibility of a single-dose primary hepatitis A vaccination for young travelers. METHODS: One hundred and nineteen susceptible youngsters, 9-18 yr old, received a dose of 720 ELISA units of the inactivated hepatitis A vaccine at month 0, and then a booster at month 6. RESULTS: Antibodies to hepatitis A virus (anti-HAV) seroconversion ( > or = 20 mIU/ml) in these vaccinees was 91% (106/117) on day 15, and reached 99% (118/119) 1 month after the single-dose vaccination. At month 6 before the booster, 97% (110/113) of the vaccinees still had detectable anti-HAV. All vaccinees (113/113) had measurable titers of anti-HAV 1 month after booster vaccination, and were still seropositive (68/68) at month 12. The anti-HAV response was found to be slower in vaccinees positive for hepatitis B surface antigen (11/16, 68.8%), compared with noncarrier vaccinees (95/101, 94.1%; p < 0.01) 15 days after the priming dose. After initial vaccination, the geometric mean titers of anti-HAV among vaccine responders were 220, 255, 117, 3308, and 1094 mIU/ml at day 15 and months 1, 6, 7, and 12, respectively. CONCLUSION: These results suggest that a single dose of hepatitis A vaccine could be a good alternative to immune serum globulin administration for immunoprophylaxis in young healthy travelers. PMID- 8677996 TI - Muscle cramps in patients with cirrhosis. AB - OBJECTIVE: To determine the prevalence of muscle cramps in subjects with chronic liver disease and to identify factors associated with their development. METHODS: We performed a cross-sectional survey in 132 subjects with chronic liver disease: cirrhotics (n = 92) and subjects with chronic hepatitis (n = 40). In addition, to control for diuretic use, patients with congestive heart failure (n = 40) were included as a comparison group. RESULTS: The prevalence of chronic muscle cramps was significantly greater in cirrhotics compared with patients with chronic hepatitis [48/92 (52%) vs 3/40 (7.5%), respectively, p < 0.0001] and compared with subjects with congestive heart failure [8/40 (20%), p < 0.001]. Factors, including age, gender, alcoholic liver disease, electrolytes, and diuretic use were similar among cirrhotics with and without cramps. Significantly higher total bilirubin and lower albumin levels were noted in cirrhotics with and without cramps, respectively; however, there was no significant difference in Child's A or B classification. CONCLUSIONS: There is an increased prevalence of chronic muscle cramps in subjects with cirrhosis that appears to be independent of the etiology of cirrhosis, diuretic consumption, serum electrolyte alterations, or differences in Child's classification. These results suggest that cramps in these patients are related specifically to the development of cirrhosis, and worsening liver function may be a risk factor for the development of cramps. PMID- 8677997 TI - Relationship between hepatic iron deposits and response to interferon in chronic hepatitis C. AB - OBJECTIVES: The response to interferon in chronic hepatitis C is believed to be affected by hepatic iron content. We histopathologically examined liver biopsy specimens from patients with chronic hepatitis C to determine whether the presence or absence of hepatic iron deposits correlated with the response to interferon. METHODS: Sixty-three patients with hepatitis C treated with interferon-alpha were examined. Liver biopsy specimens obtained just before treatment were sliced and stained with Perls' Prussian blue. Twenty patients had complete responses, 24 patients had transient responses, and 19 patients had no response. RESULTS: Iron deposits stained by Prussian blue were seen in hepatocytes, sinusoidal cells, and portal mesenchymal cells. The degree of hepatocytic and sinusoidal iron deposits did not correlate with the response to interferon. However, the degree of portal iron deposits did correlate with hepatic inflammation activity (tau = 0.55, p < 0.001) and the severity of liver fibrosis (tau = 0.60, p < 0.001), and it correlated negatively to the response to interferon (tau = -0.49, p < 0.001). CONCLUSIONS: The results suggest that portal iron deposits are a factor in the response to interferon. The presence of portal iron deposits seems to be related to a poor response. PMID- 8677998 TI - Interferon therapy for chronic hepatitis C in habitual drinkers: comparison with chronic hepatitis C in infrequent drinkers. AB - OBJECTIVE: To assess the efficacy of interferon therapy for chronic hepatitis C among habitual drinkers. METHODS: Ninety-five hepatitis C virus ribonucleic acid positive patients with chronic hepatitis were treated with four standardized regiments of interferon. Patients were divided into four groups based on the degree of daily alcohol consumption and duration of abstinence before treatment: 47 infrequent drinkers, 12 moderate drinkers who had consumed more than 23 gm but less than 69 gm of ethanol daily but stopped drinking for 39 +/- 18 months before therapy, 19 heavy drinkers I who had consumed more than 69 gm of ethanol daily but stopped drinking for 38 +/- 37 months before treatment, and 17 heavy drinkers II who consumed more than 69 gm ethanol daily soon before treatment. RESULTS: The rate of responders; in whom serum ALT levels remained normal for 6 months after the end of treatment, was in a decreasing order of: infrequent drinkers (36.2%), moderate drinkers (33.3%), heavy drinkers I (26.3%), and heavy drinkers II (5.9%) (p < 0.05, infrequent drinkers vs heavy drinkers II). The negative rate of serum hepatitis C virus ribonucleic acid 6 months after the end of treatment was in a similar order (27.7%, 25.0%, 15.8%, and 0%, respectively) (p < 0.05, infrequent drinkers vs heavy drinkers II). CONCLUSION: Heavy drinking will reduce the efficacy of interferon therapy for chronic hepatitis C, and the adverse effect of drinking on efficacy might be reversed, partly, by abstinence for a long period before treatment. PMID- 8677999 TI - Determination of serum des-gamma-carboxy prothrombin levels in patients with small-sized hepatocellular carcinoma: comparison of the conventional enzyme immunoassay and two modified methods. AB - OBJECTIVES: Currently available enzyme immunoassays for des-gamma-carboxy prothrombin (DCP) are not sensitive enough to detect hepatocellular carcinoma (HCC) at an early stage. Therefore, the objectives of this study were to enhance the sensitivity of the currently available enzyme immunoassay (EIA) for DCP and to assess the diagnostic values of the new methods compared with those of alpha fetoprotein (AFP) in patients with small-sized HCC. METHODS: Coded serum samples obtained from a total of 128 patients with chronic liver diseases, including 27 patients with small-sized HCC, were analyzed. DCP levels were determined in three different ways: 1) conventional EIA, 2) the overnight method, similar to the conventional EIA but the first reaction (immunoreaction of DCP with the monoclonal antibody) was proceeded overnight, and 3) the avidin-biotin complex (ABC) method. RESULTS: In 27 patients with HCC ( < or = 3 cm in diameter), the rates of abnormal values obtained by the conventional, the overnight, and the ABC methods were 14.8, 25.9, and 29.6%, respectively. The overnight and the ABC methods comparably increased the sensitivity, whereas the ABC method gave the highest false-positive value in patients with chronic liver diseases (cirrhosis and chronic hepatitis) without HCC. The negative predictive value was 84.9% when AFP and the overnight DCP assays were combined, whereas the true positive rate by the combination assay of the ABC method for DCP and AFP (cut-off level at 200 ng/ml) was 33.3%. CONCLUSIONS: Two modifications of the conventional EIA for DCP comparably increased the sensitivity, but the overnight method may be of more practical value in terms of specificity and ease. The rate of detection of small sized HCC by tumor markers alone, however, is not satisfactory even when the modified DCP and AFP measurements are combined. PMID- 8678000 TI - A retrospective analysis of the effect of contrast-enhanced CT on the outcome of acute pancreatitis. AB - OBJECTIVES: Contrast CT is widely used to assess the severity of acute pancreatitis. Recently, studies in rats have shown that the administration of i.v. contrast material worsens the outcome of experimental acute pancreatitis. The aim of the current study was to determine if an effect of the administration of i.v. contrast could be identified in clinical acute pancreatitis. METHODS: Charts from the University of Kentucky Hospital from 1992 with an ICD-9 code of acute pancreatitis were reviewed. APACHE II scores at diagnosis of pancreatitis were calculated for all patients. The duration of clinical pancreatitis was determined from the date of onset of pain to the date of resolution of pain and resumption of oral nutrition. Contrast CT and noncontrast groups were compared using a Mann-Whitney rank sum test. RESULTS: There was no significant difference in the original APACHE II scores between the two groups. The contrast CT group had a mean duration of clinical pancreatitis of 10.8 days versus 6.2 days for the non-CT group (p = 0.004). CONCLUSIONS: This retrospective study supports the conclusions of recent animal studies that suggest that i.v. contrast might worsen or prolong attacks of acute pancreatitis. PMID- 8678001 TI - Single application extracorporeal shock wave lithotripsy is the first choice for patients with pancreatic duct stones. AB - OBJECTIVES: We performed extracorporeal shock wave lithotripsy (ESWL) as the treatment of first choice on 32 chronic pancreatitis patients with main pancreatic duct (MPD) stones prospectively to establish more convenient and safer treatment. METHODS: All patients were treated in a prone position, and shock waves were discharged from the ventral side. ESWL was performed once or twice a week, and no other treatments before ESWL had been applied. RESULTS: Disintegration of all MPD stones to 3 mm or less in diameter could be achieved in all treated patients. Complete clearance of the stones was obtained in 24 patients (75%) without the necessity of endoscopic extraction of fragments. Reduction of MPD diameters after ESWL was statistically significant (p < 0.01). Epigastric and/or back pain complaints before ESWL were completely alleviated in 79% (periods of follow-up: 16-63 months, mean 44), and the pancreatic exocrine function also improved in 61%. No severe complications occurred in any of the patients. CONCLUSIONS: ESWL, which is comparatively easy to perform, is a safe and efficient approach that changes endoscopy's status as an indispensable pretreatment. Therefore, ESWL can be recommended as the first choice treatment for patients with chronic pancreatitis accompanied by MPD stones that should be tried before consideration of either surgical or endoscopic procedures. PMID- 8678002 TI - Low H. pylori reinfection rate after triple therapy in Chilean duodenal ulcer patients. AB - OBJECTIVES: We studied prospectively in a single-blind controlled manner the efficacy of 4-wk triple-antibiotic therapy, with amoxicillin (500 mg p.o., t.i.d.), metronidazole (250 mg p.o., t.i.d.), and bismuth subsalicylate tablets (524 mg p.o., q.i.d.), plus omeprazole (20 mg p.o., q.d.) and compared it with omeprazole (id) in the treatment of duodenal ulcer (DU) patients colonized with Helicobacter pylori. METHODS: One hundred DU patients were entered prospectively over a 12-month period. Fifty-seven of them received triple therapy plus omeprazole and 43 received omeprazole alone. Clinical, endoscopic, and bacteriological evaluations were performed on admission and at 28 days, 4, 8, and 12 months after treatment. RESULTS: After 4-wk treatment (day 28), the ulcer healing rate was high, but there was no significant difference between rates in the triple therapy and omeprazole groups (99% vs. 91%). In contrast, the long term DU recurrence rate after 12-month follow-up was significantly lower (p > 0.01) for triple therapy (3/57, 5%), compared with omeprazole (34/43, 79%). The difference (higher relapse rate for omeprazole-treated patients) was significant (p < 0.001) by the second evaluation, 4 months after treatment. The eradication rate of H. pylori was also significantly higher among DU patients treated with triple therapy (p < 0.001) during all prospective evaluations, grand mean, 82% (range 82-87%), compared with the omeprazole-treated group, in which there were no cases in which H. pylori was eradicated. Follow-up revealed that 2/47 H. pylori-eradicated patients became reinfected after 1 yr, giving a reinfection rate of 4.2 patient/yr. CONCLUSIONS: Four-week triple-antibiotic therapy plus omeprazole constitutes an adequate alternative for treatment of Chilean DU patients. PMID- 8678003 TI - The effects of Helicobacter pylori colonization on gastric function and the incidence of portal hypertensive gastropathy in patients with cirrhosis of the liver. AB - OBJECTIVES: To investigate the prevalence of Helicobacter pylori infection in 50 cirrhotic patients with biopsy-proven cirrhosis with and without portal hypertensive gastropathy and to study whether or not the effects of H. pylori colonization of the stomach on gastric acid and pepsin secretion, serum gastrin and pepsinogen I levels, gastric mucus, and gastric emptying contributed to the development of portal hypertensive gastropathy in cirrhotics. METHODS: All patients underwent an upper GI endoscopy followed by determination of basal and pentagastrin and insulin-stimulated gastric acid and pepsin secretion and serum gastrin and pepsinogen I levels. The gastric biopsies were stained to detect H. pylori infection, portal hypertensive gastropathy, and gastritis. The amount of gastric mucus was estimated by a microanalytical technique. The rate of gastric emptying was assessed by the radionuclide method using a semi-solid meal. RESULTS: Thirty-three (66%) patients had endoscopic evidence of portal hypertensive gastropathy, 10 with the severe (20%) and 23 with mild form (46%). Twenty (40%) patients had histological evidence of H. pylori infection. Eleven out of 33 (33%) patients with endoscopic portal hypertensive gastropathy had microscopic evidence of H. pylori infection. Eighteen out of 20 (90%) patients with chronic active gastritis had concomitant H. pylori colonization. In contrast, the gastric mucosa was histologically normal in 21 of the 30 patients (70%) not infected with H. pylori. Marked hypochlorhydria and reduced pepsin secretion associated with a tendency to hypergastrinemia were observed in cirrhotic patients colonized with H. pylori compared with those without. However, there was no significant difference in serum pepsinogen I concentrations, the ratio of polymeric to degraded gastric mucus, or the rate of gastric emptying between cirrhotics with and without H. pylori colonization of the stomach. Furthermore, these parameters were not significantly different in patients with portal hypertensive gastropathy with and without H. pylori infection. CONCLUSION: These observations suggest that H. pylori infection is unlikely to be involved in the pathogenesis of portal hypertensive gastropathy. PMID- 8678004 TI - Gastric mucosal hepatocyte growth factor in Helicobacter pylori gastritis and peptic ulcer disease. AB - OBJECTIVES: Hepatocyte growth factor (HGF) is increasingly recognized for its role in a variety of hepatic and systemic diseases. Its relationship to gastritis has not been studied. We aimed at measuring gastric mucosal HGF levels in the presence or absence of Helicobacter pylori gastritis, in peptic ulcers, and in response to H. pylori eradication. METHODS: Fifty one patients were studied. Patients were not entered if they had liver disease, malignancy, or any systemic illness. HGF was measured in gastric antral incubates using an enzyme-linked immunosorbent assay. Assessments were repeated 6 wk after a 2-wk course of anti H. pylori triple therapy in 12 patients. Code numbers were used for blinding. RESULTS: The median gastric mucosal HGF level was 36 ng/gm/tissue in patients with H. pylori gastritis (n = 33) compared with 19 ng/gm in 18 negative controls (p = 0.0024), 18 ng/gm after the eradication of H. pylori (p = 0.021), 23 ng/gm in all patients with ulcers (n = 10), and 26 ng/gm/tissue in H. pylori-positive ulcers (n = 7). CONCLUSIONS: Gastric mucosal HGF levels were elevated in H. pylori gastritis and reduced by its eradication. These results are relevant to our understanding of the increased gastric cell proliferation in patients with H. pylori-related gastritis. PMID- 8678005 TI - Assessment of arterial invasion in pancreatic cancer using color Doppler ultrasonography. AB - OBJECTIVE: We report the first study on the value of color Doppler ultrasonography (CDUS) in assessing arterial invasion of pancreatic cancer. METHODS: The relationships between tumors and surrounding major splanchnic arteries (celiac, superior mesenteric, common hepatic, splenic, and gastroduodenal arteries) were preoperatively evaluated with CDUS in 33 consecutive patients with pancreatic cancer. When a tumor partially or completely surrounded the artery, the invasion was diagnosed as positive. Imaging results were then compared with angiographic, surgical, and histopathological findings. RESULTS: In 22 nonsurgical patients, the correspondence rate of CDUS with angiography for the presence of invasion, absence of invasion, and overall was 78%, 95%, and 88%, respectively. In 11 surgical patients, a sensitivity of 60%, specificity of 93%, and accuracy of 87% for detection of arterial invasion were obtained in comparing CDUS with surgical and histopathological findings. There was no significant difference between the accuracy of CDUS and that of CT, or that of angiography. However, the accuracy of CDUS was higher than that of CT (72%) and equal to that of angiography (91%). CONCLUSION: Color Doppler ultrasonography is useful for detecting arterial invasion in pancreatic cancer. It may make angiography unnecessary, especially with advanced tumors, if thorough evaluation for the large artery invasion is performed initially. PMID- 8678006 TI - Serum interleukin-6 levels reflect disease status of gastric cancer. AB - OBJECTIVES: Interleukin-6 (IL-6) has been shown to be associated with cancer development. However, its role in gastric cancer patients has never been investigated. Our intent was to investigate this role. METHODS: Using enzyme linked immunosorbent assay, we determined the IL-6 levels in sera of patients with gastric cancer (n = 218), benign gastric lesions (n = 9), and hepatitis B (n = 9), and in normal subjects (n = 85). C-reactive protein (CRP) levels and Helicobacter pylori antibodies were simultaneously determined in 150 and 133 gastric cancer patients, respectively. Serial serum IL-6 levels were also measured in 14 gastric cancer patients. Six gastric cancer cell lines were examined for IL-6 secretion. For comparison, serum carcinoembryonic antigen levels in all gastric cancer patients were also determined. RESULTS: Mean IL-6 levels were significantly higher in patients with gastric cancer (10.0 +/- 9.5 pg/ml) than in patients with benign gastric lesions (2.6 +/- 0.5 pg/ml), in hepatitis B carriers (2.8 +/- 0.9 pg/ml), and in normal subjects (2.5 +/- 0.3 pg/ml). Gastric cancer patients with IL-6 > 10 pg/ml increased in a stage-related manner (p = 0.0001). Serum IL-6 levels increased when four patients had recurrence, whereas IL-6 levels decreased in 10 patients with a disease-free status after gastric resection. Serum IL-6 levels correlated moderately with serum CRP levels (r = 0.5, p < 0.01), but not with H. pylori antibody titers (p = 0.23). Serum IL-6 levels correlated with survival, but not as an independent prognostic indicator. Conversely, patients with CEA > 5 ng/ml increased in a stage-related manner, but this is not an effective reflection of disease progression. Five of six gastric cancer cell lines secrete IL-6. CONCLUSIONS: Serum IL-6 levels correlate with disease status of gastric cancer and may be used as a new tumor marker for monitoring treatment and response of gastric cancer patients. PMID- 8678007 TI - Reversible esophageal motility disorder in a patient with sarcoidosis. AB - We report the case of a patient who presented with new onset of dysphagia for solids and liquids. Her condition was subsequently diagnosed as sarcoidosis on the basis of granulomatous inflammation in tissue obtained from transbronchial fine needle aspiration, noncaseating granulomas in a full-thickness lip biopsy, mild uveitis on slit lamp examination, and serum angiotensin-converting enzyme activity of 120 U/L. Esophageal manometry revealed a nonspecific esophageal motility disorder with 60% nontransmitted contractions and a lower esophageal sphincter that failed to relax with wet swallows. The patient was treated with 40 mg prednisone per day, and within 2 wk her dysphagia had markedly improved. Prednisone was continued with a slow taper, and after 1 month ber dysphagia had resolved and her esophageal manometry was normal. To our knowledge, this is the first case of sarcoidosis presenting with dysphagia and documented esophageal dysmotility in which symptoms and manometric abnormalities normalized after therapy with systemic corticosteroids. PMID- 8678008 TI - End stage liver disease in a 13-year old secondary to hepatitis C and hemochromatosis. AB - Hepatic parenchymal iron deposition is a well-known complication of chronic hepatic inflammatory states. This can make the differential between chronic hepatitis and hereditary hemochromatosis difficult, however. The case of a 13-yr old male with chronic hepatitis C and hereditary hemochromatosis resulting in end stage liver disease and the need for orthotopic liver transplantation is described. There has been no previously described case of the coexistence of these two diseases in a pediatric patient, resulting in end stage liver disease. The progression to cirrhosis in a patient of this age suggests a more rapid progression of the combined diseases than with either disease alone. PMID- 8678009 TI - Neurological complications of celiac disease: a rare but continuing problem. AB - Neurological complications are a recognized but unusual manifestation of celiac disease. We present here our experiences with four current cases. Age of patients at presentation with neurological signs varied from 7 to 67 yr. In one patient, the neurological disability developed before the diagnosis of celiac disease, whereas, in the other three, it occurred from months to 16 yr after the diagnosis had been established. One patient died of rapidly progressive neuromyopathy. The other three patients had combinations of cerebellar and posterior and lateral column abnormalities. All four patients developed neurological complications despite a strict gluten-free diet. In three of four patients, there was no improvement in duodenal histology on this diet. Treatment with vitamin B12, folic acid, or vitamin D failed to reverse the changes. No other nutritional deficiencies were found. Vitamin E levels were normal in two of three patients. One patient had no response to treatment with immunosuppressive drugs. The mechanisms responsible for these neurological complications are poorly understood, although patients whose duodenal histology fails to improve on a gluten-free diet may be at greater risk. There have been no real advances in the understanding of this condition since the original description nearly 30 yr ago. PMID- 8678010 TI - Acute hepatitis associated with the use of a Chinese herbal product, ma-huang. AB - Herbal medicines are widely perceived by the public as being healthful and innocuous. A number of herbal medicines have now been linked with hepatotoxicity. We report a case of acute hepatitis associated with the use of ma-huang, a herbal product derived from plants of the Ephedra species, which is advertised as being useful for causing weight loss and enhancing energy levels. Given the lack of reports in the literature of hepatotoxicity with ma-huang and ephedrine, we speculate that the ma-huang product our patient took contained some other ingredient or contaminant or was misidentified. Our report and others in the literature, which we review, indicate that the clinician should consider herbal medicines as a possible cause of unexplained liver injury. PMID- 8678011 TI - Massive rectal bleeding from colonic tuberculosis. AB - We describe a patient with massive rectal bleeding from colonic tuberculosis. This is an uncommon presentation of gastrointestinal tuberculosis with fewer than 20 cases reported in the medical literature. The incidence of tuberculosis has been increasing during the last decade. The resurgence of tuberculosis (secondary to increased immigration, more patients on immunosuppressive therapy, and the AIDS epidemic) mandates that the clinician be aware of the wide spectrum of presentation of intestinal tuberculosis. Endoscopy is the preferred method used to diagnose colonic tuberculosis. PMID- 8678012 TI - Rapidly progressive portal hypertension 23 years after post-traumatic arterioportal fistula of the liver. AB - Intrahepatic arterioportal fistulas may occur after blunt abdominal trauma and lead to severe portal hypertension, which can be prevented by early diagnosis and treatment. The diagnostic workup of an asymptomatic young male with elevated transaminases revealed an arterioportal fistula secondary to a traumatic liver rupture during childhood, 23 yr earlier. Three years after initial diagnosis, the patient presented with gastrointestinal hemorrhage. Progression of portal hypertension had resulted in esophageal varices and ascites. After ligation of the right hepatic artery, the esophageal varices and ascites disappeared. Twelve months after surgery, the patient is asymptomatic without any signs of liver decompensation or recurrence of gastrointestinal hemorrhage. Our case demonstrates that rapid progression of portal hypertension with severe complication can occur in patients with arterioportal fistula after a long lasting asymptomatic course of 23 yr. Simultaneous chronic hepatitis C may have a contributory role. PMID- 8678013 TI - Exposure to domestic cats: risk factor for Pasteurella multocida peritonitis in liver cirrhosis? AB - Pasteurella multocida is most commonly associated with acute skin and soft tissue infections following an animal bite or scratch. Peritonitis caused by P. multocida in patients with cirrhosis is rarely reported. We present a case of spontaneous bacterial peritonitis with P. multocida in a patient with cirrhosis, squamous cell cancer of the head and neck, and nontraumatic domestic cat exposure. Nasopharyngeal colonization with P. multocida, with subsequent transient bacteremia and seeding of the peritoneum in immunocompromised (particularly cirrhotic) cat-owners, could play an important pathogenetic role in the development of spontaneous bacterial peritonitis. A review of the literature showed that in nine of 13 patients with cirrhosis and P. multocida peritonitis, exposure to domestic animals was reported. The mortality rate is high in this setting, even with prompt antibiotic treatment. Preventive strategies for immuno compromised patients should include minimization of animal contact, especially cats, which have a high carriage rate (70-90%) of P. multocida. PMID- 8678014 TI - Small bowel intussusception and brown bowel syndrome in association with severe malnutrition. AB - Brown bowel syndrome is a rare condition characterized by deposition of lipofuscin in the smooth muscle cells of the gastrointestinal tract. The number of reported cases is small, but all are associated with malabsorptive states. Despite these small numbers, there is considerable evidence that vitamin E deficiency is important etiologically. We report here the case of a severely malnourished [body mass index 11.7 kg/m (2): normal range 20-25 kg/m (2)] 31-yr old black male with a longstanding history of alcohol abuse, who was on anti tuberculosis therapy. The patient presented with an acute abdomen and was found, at operation, to have a mid-ileal intussusception. Histological examination of the resected specimen demonstrated lipofuscin accumulation consistent with brown bowel syndrome, but no tumor. Subsequent investigations revealed no significant quantities of vitamin E in the blood and pancreatic steatorrhea. However, deficiency of other fat-soluble (vitamin A and D) and water-soluble vitamins (vitamin C and thiamine) also were detected. This report supports the association of brown bowel syndrome with vitamin E deficiency but cannot exclude the compounding effects of protein calorie malnutrition, multiple vitamin deficiencies, and chronic alcohol toxicity. PMID- 8678015 TI - Albendazole-induced pseudomembranous colitis. AB - We report a patient with AIDS and intestinal microsporidiosis. While undergoing treatment with albendazole, he developed worsening diarrhea with abdominal pain and fever. The diagnosis of pseudomembranous colitis was made by flexible sigmoidoscopy and a positive stool specimen for Clostridium difficile toxin. The patient's symptoms resolved with oral vancomycin and his stool C. difficile toxin became negative. Albendazole is an antibiotic that is chemically related to metronidazole. Although a few case reports link metronidazole with the development of pseudomembranous colitis, albendazole has not been associated with the development of this condition. The spectrum of antimicrobial activity of albendazole and its efficacy in the treatment of intestinal microsporidiosis are reviewed. Pathogenic mechanisms for the development of pseudomembranous colitis and the epidemiology of this condition in patients with AIDS are discussed. PMID- 8678016 TI - Rupture of the spleen as the initial manifestation of Wilson's disease. PMID- 8678017 TI - Drug-induced vanishing bile duct syndrome: response to ursodiol. PMID- 8678018 TI - Factitious gastrointestinal bleeding: a case of autophlebotomy and ingestion. PMID- 8678019 TI - An unusual association: celiac disease and Becker muscular dystrophy. AB - A history of poor growth in early childhood associated with persistent diarrhea and iron deficiency anemia led to a diagnosis of celiac disease in a 9-yr-old boy hospitalized for acute rhabdomyolysis. Elevated serum creatine kinase levels had been documented over the previous years, and Becker's muscular dystrophy was diagnosed by immunostaining of dystrophin and DNA analysis. PMID- 8678020 TI - Intrapericardial rupture of amebic liver abscess managed with percutaneous drainage of liver abscess alone. PMID- 8678021 TI - Fistula between duodenum and portal vein caused by peptic ulcer disease and complicated by hemorrhage and portal vein thrombosis. AB - We document a patient with a penetrating peptic ulcer of the first part of the duodenum, that extended into the main portal vein forming a fistula. This is the first reported case of a duodenoportal fistula secondary to peptic ulcer disease. The fistula was complicated by massive gastrointestinal hemorrhage, extra- and intrahepatic portal vein thrombosis, hepatic parenchymal infarction, and intrahepatic portal vein foreign body granulomas containing vegetable matter. PMID- 8678022 TI - Crohn's disease complicating male genitourinary tract without overlying cutaneous involvement. PMID- 8678023 TI - Chemotherapy in stage II/Duke's B2 colon cancer: tolerable but necessary? PMID- 8678024 TI - Magnetic resonance cholangiography: requiem for routine diagnostic ERCP? PMID- 8678025 TI - Helicobacter pylori, dyspepsia, and urea breath tests. PMID- 8678026 TI - Internal stents and postsurgical bile leaks. PMID- 8678027 TI - The black esophagus. PMID- 8678028 TI - Antituberculous drugs and hepatotoxicity. PMID- 8678029 TI - Re: Bernstein et al: surveillance colonoscopy in ulcerative colitis. PMID- 8678030 TI - Re: Duodenal ulcer treatment for Helicobacter pylori. PMID- 8678031 TI - Helicobacter pylori, intestinal metaplasia, and gastric cancer: histopathological point of view. PMID- 8678032 TI - Endotoxin in Aeromonas sobria infection: speculative pathogenesis and treatment strategies in advanced liver disease with soft-tissue infection. PMID- 8678033 TI - Infections in the cirrhotic patient. PMID- 8678034 TI - Acetaminophen overdose: need to consider intravenous preparation of N acetylcysteine in the United States. PMID- 8678035 TI - p53 mutation in hepatocellular carcinoma and chronic liver disease. PMID- 8678036 TI - Bacillus subtilis as a cause of cholangitis in polycystic kidney and liver disease. PMID- 8678037 TI - Membranous obstruction of the inferior vena cava: common entity in the developing world. PMID- 8678038 TI - Hepatitis B virus and hepatitis C virus infections in Turkish patients with hepatocellular carcinoma. PMID- 8678039 TI - Increased prevalence of diabetes mellitus in patients with chronic hepatitis C virus infection. PMID- 8678040 TI - In situ detection of Epstein-Barr virus in the gastric glands with intestinal metaplasia. PMID- 8678041 TI - Sudden infant death syndrome and local meteorologic temperature in North Carolina. AB - The association between meteorologic temperature and sudden infant death syndrome was investigated in the 1982-1983 North Carolina birth cohort. Maximum daily temperatures recorded at weather stations in the subject's county of residence for each day of the first year of life were entered into hazards models as time dependent covariates. Risk ratios for a maximum temperature of < or = 53 degrees F (12 degrees C) 5 days before the event compared with a maximum temperature of > 53 degrees F were 2.3 (95% confidence interval 1.6-3.3) for blacks and 1.5(95% confidence interval 1.0-2.1) for whites. Similar results were found for minimum daily temperature. The analysis controlled for season of birth, sex, maternal age, maternal education, parity, and birth weight. PMID- 8678042 TI - Comparison of weight- and height-based indices for assessing the risk of death in severely malnourished children. AB - To compare the effectiveness of treating malnourished children in different centers, the authors believe there is a need to have a simple method of adjusting mortality rates so that differences in the nutritional status of the children are taken into account. The authors compared different anthropometric indices based on weight and height to predict the risk of death among severely malnourished children. Anthropometric data from 1,047 children who survived were compared with those of 147 children who died during treatment in therapeutic feeding centers set up in African countries in 1993. The optimal ratio of weight to height determined by logistic regression was weight (kg)/height (m)1.74 (95% confidence interval of beta estimate 1.65-1.84). The receiver operating curves (sensitivity vs. specificity) showed that the body mass index (weight (kg)/height (m)2), optimal ratio of weight to height, and weight/height index expressed as the percentage of the median of the National Center for Health Statistics' standard were equivalent and superior to the weight/height index expressed as the z score of the National Center for Health Statistics' standard to predict death. As the optimal ratio of weight to height is easier to calculate than the weight/height index expressed as the percentage of the median or z score and does not depend upon either standards or tables, the optimal ratio of weight to height could be conveniently used to adjust mortality rates for nutritional status in therapeutic feeding centers. PMID- 8678043 TI - Nutrition and subsequent hip fracture risk among a national cohort of white women. AB - This study investigated three aspects of general nutritional status (dietary intake, biochemical markers, and anthropometric measurements) in relation to subsequent hip fracture risk by using prospective data from the First National Health and Nutrition Examination Survey (NHANES I) epidemiologic follow-up studies. A cohort of 2,513 white women 45 years and over who participated in the NHANES I survey in 1971-1975 were subsequently followed in the three follow-up studies in 1982-1984, 1986, and 1987, respectively. Multiple nutritional variables were measured at baseline, and 130 incident hip fractures were identified by hospital records or by death certificates during the follow-up period. Cox regression analyses showed that baseline dietary energy intake; serum albumin; and weight, body mass index, skinfold, and arm muscle area were significantly and inversely related to subsequent hip fracture risk (relative risks for a 1-standard deviation increment in these variables ranged from 0.68 to 0.83). The authors suggest that poor nutritional status, evident in inadequate dietary intake, reduced serum albumin, and decreased body mass and soft tissues, increases the risk for subsequent hip fracture. The study also showed that age and previous fracture history were significant risk factors; however, self reported physical activity, parity, and alcohol use were not significantly related to subsequent hip fracture. PMID- 8678044 TI - Successful aging: predictors and associated activities. AB - Six-year predictors of successful aging were analyzed for 356 Alameda County Study men and women aged 65-95 years measured prospectively in 1984 and followed to 1990. Successful aging was defined as needing no assistance nor having difficulty on any of 13 activity/mobility measures plus little or no difficulty on five physical performance measures. After adjusting for baseline successful aging, sex, and age, the authors found that 1984 predictors of 1990 successful aging included income above the lowest quintile (odds ratio (OR) = 2.01, 95% confidence interval (CI) 0.99-4.11), > or = 12 years of education (OR = 1.67, 95% CI 0.98-2.84), white ethnicity (OR = 2.12, 95% CI 0.93-4.86), diabetes (OR = 0.10, 95% CI 0.01-0.79), chronic obstructive pulmonary disease (OR = 0.41, 95% CI 0.17-0.97), arthritis (OR = 0.43, 95% CI 0.26-0.71), and hearing problems (OR = 0.48, 95% CI 0.25-0.89). Adjusting for all variables, the authors found that behavioral and psychosocial predictors included the absence of depression (OR = 1.94, 95% CI 1.10-3.42), having close personal contacts (OR = 1.82, 95% CI 1.05 3.18), and often walks for exercise (OR = 1.77, 95% CI 1.00-3.12). Cross sectional comparisons at follow-up revealed significantly higher community involvement, physical activity, and mental health for those aging successfully. PMID- 8678045 TI - Circulating anti-Helicobacter pylori immunoglobulin A antibodies and low serum pepsinogen I level are associated with increased risk of gastric cancer. AB - Helicobacter pylori infection has been suggested to be associated with an increased risk of gastric cancer, and low levels of serum pepsinogen I (PG I) have been linked to atrophic gastritis, which is a risk factor for gastric cancer. In Finland, 39,268 persons from 25 cohorts participated during 1968-1972 in a health examination survey and were followed for up to 13 years. A nested case-control study was performed on 84 stomach cancer patients identified from the Finnish Cancer Registry and 146 controls matched for age, sex, and municipality. Serum samples drawn at the baseline study were analyzed. An elevated level of serum anti-H. pylori immunoglobulin A (IgA) antibodies (a titer > or = 70) and a low serum PG I level ( < 49 micrograms/liter) were associated with an increased risk of gastric cancer. The odds ratios were 2.52 (95% confidence interval (CI) 1.14-5.57) for high IgA and 2.68 (95% CI 1.35-5.30) for low PG I. For high immunoglobulin G (IgG) ( > or = 700), the odds ratio was only 1.50 (95% CI 0.70-3.22). When both high IgA and low PG I were present, the odds ratio was 5.96 (95% CI 2.02-17.57). The association of H. pylori infection with cancer became stronger with longer follow-up times, whereas that of low PG I was strongest at shorter follow-up times. Our findings support the hypothesis that H. pylori infection is a prevalent and potentially preventable cause of gastric cancer. They stress the value of IgA antibody determinations and provide new evidence for a pathogenesis leading from prolonged infection through atrophic gastritis to gastric cancer. PMID- 8678046 TI - Leukemia following occupational exposure to 60-Hz electric and magnetic fields among Ontario electric utility workers. AB - In a nested case-control study of 1,484 cancer cases and 2,179 matched controls from a cohort of 31,543 Ontario Hydro male employees, the authors evaluated associations of cancer risk with electric field exposure and reevaluated the previously reported findings for magnetic fields. Pensioners were followed from January 1, 1970, and active workers (including those who left the corporation) from January 1, 1973, with both groups followed through December 31, 1988. Exposures to electric and magnetic fields and to potential occupational confounders were estimated through job exposure matrices. Odds ratios were elevated for hematopoietic malignancies with cumulative electric field exposure. After adjustment, the odds ratio for leukemia in the upper tertile was 4.45 (95% confidence interval (CI) 1.01-19.7). Odds ratios were also elevated for acute nonlymphoid leukemia, acute myeloid leukemia, and chronic lymphoid leukemia. For cumulative magnetic field exposure, there were similar elevations that fell with adjustment. Evaluation of the combined effect of electric and magnetic fields for leukemia showed significant elevations of risk for high exposure to both, with a dose-response relation for increasing exposure to electric fields and an inconsistent effect for magnetic fields. There was some evidence of a nonsignificant association for brain cancer and benign brain tumors with magnetic fields. For lung cancer, the odds ratio for high exposure to electric and magnetic fields was 1.84 (95% CI 0.69-4.94). PMID- 8678047 TI - Oral contraceptive use and risk of breast cancer in middle-aged women. AB - The authors used data from a population-based, case-control study of breast cancer conducted among women residing in King County, Washington State, who were 50-64 years of age in 1988-1990, to examine the relation of oral contraceptive use to the risk of breast cancer. There were no clear differences between cases and controls with respect to the total duration of oral contraceptive use, time since last use, or age at first or last use. While a small increase in risk was noted in women who had first used oral contraceptives within 20 years of the interview reference date, within that period there was no trend in risk observed with decreasing amounts of time since the last use of these agents. Overall, this study supports the absence of any strong association between oral contraceptive use and breast cancer risk during middle age in the cohort of women who first used these drugs. PMID- 8678048 TI - Intake of vitamins A, C, and E and postmenopausal breast cancer. The Iowa Women's Health Study. AB - The association between dietary antioxidant vitamin intake and the risk of breast cancer was examined in a prospective study of 34,387 postmenopausal women in Iowa. Intakes of vitamins A, C, and E and of retinol and carotenoids were assessed in 1986 by mailed semiquantitative food frequency questionnaire. Through December 31, 1992, 879 incident breast cancer cases occurred in this cohort. There was little suggestion that breast cancer risk was associated with differences in intake of these vitamins. For example, from the lowest to highest total vitamin A intake categorized by quintiles, the age-adjusted relative risks of breast cancer were 1.0, 0.95, 1.17, 1.20, and 0.90 (p trend = 0.92). Similarly unremarkable relative risk patterns were seen for the intakes of vitamins C and E and of retinol and carotenoids. These findings were not altered after adjustment for breast cancer risk factors or in analyses confined to women who reported no supplemental vitamin intake. Exclusion of cases that occurred in the first 2 years of follow-up, under the assumption that women may have increased intake of these vitamins in response to preclinical symptoms of breast cancer, did not suggest an inverse association of these vitamins with the risk of breast cancer. Women who reported consuming at least 500 mg/day of supplemental vitamin C had a relative risk of breast cancer of 0.79 compared with women who did not take supplemental vitamin C, and women who reported consuming more than 10,000 IU/day of vitamin A had a corresponding relative risk of 0.73. However, these relative risks were not statistically significant. These results provide little evidence that intake of these vitamins is associated with breast cancer risk. PMID- 8678049 TI - Tea consumption and cancer incidence in a prospective cohort study of postmenopausal women. AB - Tea has consistently been shown to inhibit the occurrence of tumors in experimental animals. The evidence for such a beneficial effect in humans, however, is limited. The authors examined the association between non-herbal tea consumption and cancer incidence in a prospective cohort study of 35,369 postmenopausal Iowa women. In this cohort, information on the frequency of tea drinking and other dietary and lifestyle factors was collected by mailed survey in 1986. After 8 years of follow-up, 2,936 incident non-skin cancer cases were ascertained in this cohort through the State Health Registry of Iowa. Proportional hazards regressions were used to derive adjusted relative risks and 95% confidence intervals for the association between tea consumption and cancer incidence. After controlling for confounding factors, the authors found that regular tea consumption was related to a slight, but not statistically significant, reduced incidence of all cancers combined. Inverse associations with increasing frequency of tea drinking were seen for cancers of the digestive tract (p for trend, 0.04) and the urinary tract (p for trend, 0.02). For women who reported drinking > or = 2 cups (474 ml) of tea per day, compared with those who never or occasionally drank tea, the relative risk for digestive tract cancers was 0.68 (95% confidence interval (CI) 0.47-0.98) and for urinary tract cancers, 0.40 (95% CI 0.16-0.98). Similar inverse associations were seen for specific digestive and urinary tract cancers, although site-specific analyses were not statistically significant. No appreciable association of tea drinking was found with melanoma, non-Hodgkin's lymphoma, or cancers of the pancreas, lung, breast, uterine corpus, or ovary. This study suggests that tea, one of the most popular beverages consumed worldwide, may protect against some cancers in postmenopausal women. PMID- 8678050 TI - Cigarette smoking and Warthin's tumor. AB - The etiology of Warthin's tumor, a benign parotid gland tumor, is unknown. Recent evidence suggests a possible relation with cigarette smoking as well as increasing incidence. We reviewed the medical record of subjects with a major salivary gland tumor newly diagnosed in Jefferson County, Alabama, from 1968 to 1989, and identified 149 Warthin's tumors. The 533 cases with other major salivary gland tumors were used as controls. The analysis showed that 96% of Warthin's tumors occurred in whites. The relative incidence of Warthin's tumor among smokers versus nonsmokers was 7.6 for men (95 percent confidence interval 3.2-18.3; p < 0.001) and 17.4 for women (95 percent confidence interval 6.5-54.7; p < 0.001). Smokers of both sexes with Warthin's tumor smoked more heavily than did those with other salivary gland tumors (p < 0.001). From 1968 through 1988, Warthin's tumors steadily increased in number and as a proportion of salivary gland tumors (males, p = 0.003; females, p = 0.008). We also observed a significant increase in the incidence rate for Warthin's tumor (p = 0.041) but not for other salivary gland tumors. We conclude that Warthin's tumor is strongly associated with cigarette smoking and that the incidence rate is increasing. The disease is rare in blacks. PMID- 8678051 TI - Mortality of Kauai residents in the 12-month period following Hurricane Iniki. AB - On September 11, 1992, Hurricane Iniki struck Kauai leaving all residents without electricity and telephone services and damaging 70% of the homes. This study examined the hypothesis that Hurricane Iniki increased the mortality of Kauai residents by comparing mortality data for the 5 years preceding Hurricane Iniki with mortality data for the 12 months immediately following. Although the overall mortality rate was increased in the post-Iniki period, the only significant increase was in the rate of diabetes mellitus-related deaths (relative risk = 2.61, 95% confidence interval 1.44-4.74). Hurricane Iniki did not appear to significantly increase the risk of dying of Kauai residents in the 12 months immediately following the disaster. PMID- 8678052 TI - Optimizing power in allocating resources to exposure assessment in an epidemiologic study. AB - We consider an epidemiologic study with a fixed budget, in which resources may be put into increasing sample size or into improving accuracy of exposure assessments. To maximize study power (efficiency), improving accuracy is preferable if and only if the proportional increase in the square of the validity coefficient is more than the proportional increase in total study costs per subject that is required to achieve it. (The validity coefficient is the correlation between the true exposure and the approximate assessment in the study base.) This is most likely to be so if the cost of exposure measurement remains a small proportion of the overall costs per subject. The design with maximum power will not generally have minimum bias in measure of effect, so that alternative optimality criteria are required if this bias is important. PMID- 8678053 TI - Re: "The frequency of idiopathic Parkinson's disease by age, ethnic group, and sex in northern Manhattan, 1988-1993". PMID- 8678054 TI - 1996 Spring Clinical Nephrology Meeting. Abstracts. PMID- 8678055 TI - Malignant vascular disease of the kidney: nature of the lesions, mediators of disease progression, and the case for bilateral nephrectomy. AB - A case of thrombotic microangiopathy presenting as a hemolytic uremic syndrome complicated by untreatable hypertension and ultimately requiring bilateral nephrectomy is discussed. Severe hypertension and renal failure may complicate the course of vascular diseases of the kidney, including thrombotic microangiopathy, chronic hypertension, and scleroderma. Toxins, pressure stress, and immune material may trigger the initial injury to vascular endothelium. The malignant course of these renal vascular diseases seems linked to the severity of vascular injury. Endothelial injury manifests with swelling and detachment of endothelial cells from the basement membrane, expansion of the subendothelial space, and newly formed basement membrane-like material. In arterioles, endothelial injury precedes myointimal swelling and proliferation, leading to vascular lumina narrowing or obliteration and secondary glomerular ischemia, with glomerular tuft collapse and garland-like wrinkling and thickening of the capillary wall. Endothelial cell injury is very likely the common determinant of a cascade of events that lead to irreversible renal failure. When the initial insult (toxins, mechanical stress, antibodies) is promptly removed, lesions are self-limiting and the patient usually recovers. However, a severe insult persisting for some time can lead to chronic and irreversible vascular lesions that, through renal ischemia, trigger maximal activation of the renin angiotensin system with a brisk elevation in arterial blood pressure that may combine to further vascular injury and renal ischemia. Moreover, enhanced shear stress in the severely narrowed microcirculation, through abnormal von Willebrand factor processing, can also favor endothelial injury and platelet aggregation, which may further worsen the vascular lesions and sustain the microangiopathic process. Plasma manipulation, arteriolar vasodilators, and angiotensin-converting enzyme inhibitors normally control the vicious circle, but in few severe cases bilateral nephrectomy remains the last chance to save the patient's life. PMID- 8678056 TI - High binding of immunoglobulin M kappa rheumatoid factor from type II cryoglobulins to cellular fibronectin: a mechanism for induction of in situ immune complex glomerulonephritis? AB - In our previous experimental work we suggested that the frequent nephritogenicity of type II cryoglobulins could depend on a particular affinity of the immunoglobulin (Ig) M kappa rheumatoid factor (RF) component for mesangial matrix. Since cellular fibronectin (cFN) in the human kidney is mainly represented in glomerular mesangium, we studied the binding capacity to cFN of IgM kappa RFs from type II cryoglobulins compared with other different monoclonal and polyclonal IgM and IgM RFs. We purified 13 IGM kappa from human IgM kappa/IgG cryoglobulins, eight monoclonal IgM from patients with Waldenstrom's macroglobulinemia, nine polyclonal IgM from normal donors, and eight polyclonal IgM RFs from patients with rheumatoid arthritis. Purified IgM were used at the same concentration in enzyme-linked immunosorbent assay (ELISA) on cFN-coated plates. All the cryoglobulin IgM showed high specific binding to cFN while IgM from Waldenstrom's macroglobulinemia, normal IgM, and polyclonal IgM RFs had low or absent binding. These data were confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis of cFN followed by Western blot analysis with purified IgM. The IgM kappa binding to cFN persisted using IgM kappa monomers, and was inhibited by cFN but not by plasma FN in a specific inhibition test. Further enzyme-linked immunosorbent assay studies showed that cryoglobulin IgM kappa RFs are still able to bind IgG in a dose-dependent manner once linked to solid-phase cFN. The data suggest that the affinity of cryoglobulin IgM kappa RFs for immobilized cFN could be involved in the particular high nephritogenicity of type II cryoglobulins and might lead to in situ immune complex formation. PMID- 8678057 TI - Childhood steroid-sensitive nephrotic syndrome: does the histology matter? AB - Renal biopsy specimens from 51 children with steroid-sensitive nephrotic syndrome who were following a frequently relapsing or steroid-dependent course were reviewed by two histopathologists. In all cases the biopsy was performed prior to the commencement of an 8-week course of cyclophosphamide. The clinical courses of these patients both prebiopsy and for a minimum of 2 years after completion of cyclophosphamide therapy were analyzed using retrospective case note analyses. The distribution of histologic diagnoses differed significantly from that reported by the International Study of Kidney Disease in Children in their study of children who underwent biopsy at the time of presentation, there being an excess of focal segmental glomerulosclerosis and mild mesangial hypercellularity in this series. The prebiopsy clinical course did not predict for histologic diagnosis, and there was no correlation between prebiopsy course or histology and postcyclophosphamide course. The findings of this study support the clinical impression that steroid sensitivity rather than histology is the major determinant of prognosis in childhood nephrotic syndrome and that frequency of relapse alone is not an indication for biopsy. PMID- 8678058 TI - Angiotensin-converting enzyme inhibition in nondiabetic progressive renal insufficiency: a controlled double-blind trial. AB - Angiotensin-converting enzyme inhibitors delay progression of renal disease in different animal models of nephropathy. We tested this treatment modality in 70 hypertensive patients with severe renal disease of various etiologies. We report a double-blind study of the effect of 5 mg enalapril once daily compared with placebo in patients with nondiabetic severe chronic renal impairment (plasma creatinine 2.8 to 6.8 mg/dL; mean creatinine clearance 15 mL/min/1.73 m2) followed for up to 2 years. Efficacy parameters were the slopes of 51Cr-EDTA clearance, reciprocal of plasma creatinine, creatinine clearance, and the effect on urinary protein excretion. Thirty-one patients completed 2 years of treatment (12 in the enalapril group and 19 in the placebo group). Two patients died from nonrenal causes (one patient each in the enalapril and placebo groups), 16 patients commenced dialysis (seven in the enalapril group and nine in the placebo group), and eight patients were discontinued due to adverse events (five in the enalapril group and three in the placebo group). Eleven patients were discontinued because they were noncompliant, uncooperative, or moved (nine in the enalapril group and two in the placebo group). Two enalapril-treated patients were dropped from the study due to protocol deviations. Importantly, the statistical approach in this study evaluated all patients, regardless of the duration of treatment. A mixed-effects linear model and intention to treat analysis, taking into account the number of observations per patient, indicated that enalapril significantly reduced the rate of deterioration of renal disease: glomerular filtration rate (P = 0.038), reciprocal of plasma creatinine (P = 0.017), or creatinine clearance (P = 0.031). The renal protective effects of enalapril were shown to be in addition to its antihypertensive effect when blood pressure was held constant. Proteinuria was reduced by enalapril (P = 0.007) and was slightly increased in the placebo-treated patients (P = 0.051). The difference between these two groups was highly significant (P = 0.002). In conclusion, enalapril retarded the progression of chronic renal failure, as assessed by changes in glomerular filtration rate, creatinine clearance, and 1/plasma creatinine, and reduced proteinuria in patients with nondiabetic severe chronic renal insufficiency. PMID- 8678059 TI - Comparative analysis of percutaneous transluminal angioplasty and operation for renal revascularization. AB - Contemporary patients requiring renal revascularization often have diffuse atherosclerosis, and increasingly undergo intervention for salvage of renal function rather than control of hypertension alone. Risk-benefit analyses and outcome data are difficult to obtain, since few reports have analyzed a modern, unselected series of consecutive patients subjected to renal revascularization by surgical as well as interventional techniques. We reviewed our 5-year experience with 76 consecutive renal revascularizations in 63 patients. Indications for intervention were hypertension and renal salvage, 60 percent (n = 38); hypertension, 24 percent (n = 15); renal salvage, 9.5 percent (n = 6); and other, 6.5 percent (n = 4). Ninety-four percent (n = 59) of patients had atherosclerotic occlusive disease of the renal arteries. Percutaneous transluminal angioplasty (PTA) was initially performed on 18 renal arteries in 16 patients, of whom 56 percent (n = 9) subsequently required surgical reconstruction. Fifty-eight surgical reconstructions were performed in 56 patients and consisted of aortorenal bypass (n = 27), aortorenal endarterectomy (n = 18), and extra anatomic bypass (n = 13). Concomitant aortic replacement was required in 57 percent (n = 32) of patients. Preoperative risk factors and operative indications did not differ between the PTA and surgical reconstruction groups. Morbidity and mortality rates associated with PTA were 33 percent and 4.8 percent, respectively, while for surgical treatment the morbidity rate was 7 percent and the mortality rate 5.3 percent (P = NS). Functional improvement was achieved in 74 percent of surgically treated patients compared with 22 percent of PTA-treated patients (P < 0.01). Actuarial renal artery primary patency at 48 months was 81 percent for the surgery group and 17 percent for the PTA group (P < 0.01). Aortorenal bypass, endarterectomy, and extra-anatomic bypass were equally efficacious (P > 0.05). The results of surgical reconstruction are excellent, offering more durable patency and functional improvement than PTA, without increased risk. The operation should be tailored to fit the individual patient's disease, since the results of endarterectomy and bypass procedures are equivalent. PMID- 8678061 TI - Effect of access recirculation on the modeled urea distribution volume. AB - The effect of vascular access recirculation (AR) on the modeled urea distribution volume (V) is not straightforward. When blood is sampled properly so that it is not admixed with recirculated blood, AR will cause an unexplained increase in V in cases in which AR is present throughout the dialysis session (when AR is limited to the terminal portion of a dialysis session it will cause little or no change in the modeled V). On the other hand, when blood is sampled from the arterial line after simply stopping the pump, postdialysis blood urea nitrogen (BUN) represents arterial line BUN and does not always reflect the BUN in the patient's blood. Under these conditions, when AR is present throughout the dialysis session the modeled V usually shows an unexplained decrease, but V may be unchanged, depending on the urea reduction ratio (URR). We performed a mathematical analysis to predict when V would be decreased and when it would be unchanged when the postdialysis BUN is contaminated with admixed blood. The analysis revealed that when AR is present uniformly throughout the dialysis session, the modeled V should be underestimated when the URR is < or = O.70. When the URR is greater than 0.70, even severe degrees of AR may not be reflected by a change in V. When AR is limited to the terminal part of the dialysis session or when AR increases during the dialysis session, and when V is based on admixed postdialysis blood, underestimation of V will occur in almost all circumstances. In a cross-sectional comparison of modeled to anthropometric volume ratios in eight patients with severe AR and in 11 controls, and in sequential modeling studies in a single patient in whom severe AR developed gradually over time, the volume ratio was low in most, but not all instances when modeled V was based on an admixed postdialysis BUN sample. PMID- 8678060 TI - Accurate measurement of impaired glomerular filtration using single-dose oral cimetidine. AB - To improve the validity of a timed creatinine clearance as a measure of glomerular filtration rate (GFR), we investigated whether a single 800-mg dose of oral cimetidine was sufficient to inhibit tubular secretion of creatinine (TScr). Forty-five 3-hour timed creatinine clearances (Clcr) with single 800-mg dose oral cimetidine (TCC) in 17 renal transplant recipients with marked renal function impairment (creatinine 2.0 to 7.1 mg/dL) were compared with simultaneous [125I] iothalamate GFR (Cliothal). For comparison, 13 timed Clcr without cimetidine (TC), and 36 24-hour Clcr were performed. The TCC was the most accurate: the ratio (mean +/- SD) of TCC:Cliothal was 1.12 +/- 0.02, compared with 1.33 +/- 0.08 for Clcr:Cliothal and 1.53 +/- 1.02 for TC:Cliothal. The difference between Cliothal and TCC was small over the range of GFRs tested (mean +/- 2 SD), 0.9 +/- 2.5 mL/min/1.73 m2. The intraclass correlation (R) for within-subject reproducibility of the TCC in five subjects was 0.8 (95 percent CI; 0.5, 0.9), and in 11 subjects who had at least three GFR determinations over 24 weeks, the TCC was as responsive to change in GFR as Cliothal. There was an inverse relationship between fractional excretion of cimetidine and GFR (r2 = -0.70), suggesting increased tubular secretion of cimetidine with decreasing GFR. In conclusion, a single 800-mg oral dose of cimetidine was effective in inhibiting TScr such that the TCC was an accurate, reproducible, and responsive test of GFR. PMID- 8678062 TI - Regional hemodialysis anticoagulation: hypertonic tri-sodium citrate or anticoagulant citrate dextrose-A. AB - Regional citrate anticoagulation should be a simple process of substituting hypertonic (1.6 mol/L) citrate for heparin and adjusting the infusion to obtain an arterial activated clotting time of 150 to 200 seconds. Serious, documented complications of citrate anticoagulation involve citrate intoxication during isolated ultrafiltration; hyperaluminemia, hyperammonemia, and hypernatremia during sorbent dialysis; and profound alkalosis, paresthesias, arrhythmia, and cardiac arrest during bicarbonate dialysis. We suspected that some of these complications could be avoided by using anticoagulant citrate dextrose-A (ACD) rather than hypertonic tri-sodium citrate (TSC) as the anticoagulant. In a cross over study with random assignment order eight adults underwent mid-week dialyses with ACD (0.113 mol/L citrate) and TSC (1.6 mol/L citrate) regional citrate anticoagulation. Predialysis to postdialysis changes in Na (mEq/L), Ca (mg/dL), ionized Ca (mg/dL), pH, and HCO3 (mEq/L) are listed below. [Table in journal] Using continuous blood flow and avoiding isolated ultrafiltration and sorbent dialysis should prevent the delivery system complications of regional citrate anticoagulation. During this evaluation isotonic and hypertonic citrate resulted in similar serum sodium changes, and standard dialysate effectively reversed the citrate/calcium interaction of both hypertonic and isotonic citrate infusions to restore homeostasis without a separate calcium infusion. The combination of TSC and bicarbonate dialysate does produce a profound metabolic alkalosis, which is lessened by using ACD. In general, regional citrate anticoagulation is simplified by using standard dialysate with a hypertonic rather than an isotonic citrate infusion, and dangerous complications are further evaded by adjusting the dialysate bicarbonate to 25 to 30 mmol/L or substituting a mixture of citric acid and TSC (ACD) for TSC. PMID- 8678063 TI - Reducing symptoms during hemodialysis by continuously monitoring the hematocrit. AB - Previous studies have demonstrated that patients on hemodialysis develop intradialytic symptoms when the blood volume decreases to a critical level. Using a continuous monitor (CRIT-LINE; In-Line Diagnostics, Riverdale, UT) to determine the instantaneous hematocrit and blood volume, we observed that certain intradialytic symptoms occurred at a patient-specific hematocrit. In the present study, we exploited this hematocrit threshold concept to decrease the occurrence of lightheadedness, cramping, and nausea, regardless of blood pressure changes. In the first phase of the study, hematocrit threshold was established in six hypotension-prone patients. Five patients entered into the second phase in which ultrafiltration rates were increased 25 percent above prescribed values at the beginning of the experimental sessions. Subsequently during the experimental sessions, ultrafiltration rates were manipulated to maintain the instantaneous hematocrit value 2 units below the established hematocrit threshold. Sessions without ultrafiltration rate adjustments based on hematocrit served as controls. There were no differences between experimental (n = 27) and control (n = 28) sessions with respect to treatment time (230 minutes v 229 minutes), fluid volume removed (3,351 mL v 3,383 mL), and maximum percentage change in systemic blood pressure (-26 percent v -24 percent). However, there were less symptoms during the experimental sessions (26 percent v 57 percent; P = 0.038). These data suggest that a twofold reduction in intradialytic symptoms can be achieved using continuous hematocrit monitoring without altering treatment times or volume removed in hypotension-prone patients. PMID- 8678064 TI - Differences between employed and nonemployed dialysis patients. AB - Three hundred fifty-nine chronic dialysis patients (85 employed and 274 nonemployed) were surveyed to identify/verify those characteristics which differentiate between employed versus nonemployed status. Education emerged as a significant correlate of employment, as noted by previous investigators, whereas, unlike previous research, neither mode of dialysis, length of time on dialysis, number of comorbid conditions, nor cause of renal failure (eg, diabetes) were associated with employment status. Measures of functional status (MOS SF-20 and Karnofsky) were positively associated with employment. Furthermore, patients' perceptions that their health limited the type and amount of work that they could do were negatively associated with employment. In addition, using a series of de novo items, we found subjects' beliefs about dialysis patients' ability to work to be a "self-fulfilling prophecy" with regard to employment status. That is, patients who themselves believed that dialysis patients should work and had this notion reinforced by significant others were more likely to be employed. Interestingly, 21 percent of unemployed patients reported that they were both able to work and wanted to return to work. Because it is consistently reported that only a small percentage of dialysis patients are employed, targeting the patients who are both willing and able to work for vocational rehabilitation might significantly increase the numbers of employed dialysis patients. PMID- 8678065 TI - A prospective comparison of bicarbonate dialysis, hemodiafiltration, and acetate free biofiltration in the elderly. AB - Hemodiafiltration (HDF) and more recently acetate-free biofiltration (AFB) have shown good blood purification and cardiovascular stability in young and middle aged hemodialysis patients. It is not clear if this is also valid for elderly patients. Twelve patients aged more than 70 years (mean age +/- SD, 76 +/- 4 years) on regular dialysis for at least 5 months were treated with bicarbonate dialysis (BD), HDF, or AFB in a randomized sequence and prospectively followed for 6 months (72 dialysis sessions/patient) for each procedure. The dialysis solution (containing bicarbonate), blood flow rate, and dialysate flow rate were the same with all the methods. During HDF and AFB solutions containing bicarbonate at a concentration of 27 to 30 mEq/L and 145 mEq/L, respectively, were infused postdilution at a rate of 66 +/- 7 mL/min and 2.81 +/- 0.12 L/hr, respectively. During the period of observation we evaluated the number of intradialytic hypotensions, the episodes of nausea, vomiting, headache (dialysis intolerance), body weight, the interdialysis weight gain, the duration of the dialysis session, the number of hospitalizations/patient, and the length of hospitalization/patient. At the end of each observation period we determined: Kt/V, protein catabolic rate, acid base balance, serum creatinine, serum calcium, serum phosphorus, alkaline phosphatases, and serum intact parathyroid hormone. After the switch from BD to either HDF or AFB, the results have shown a significant reduction of dialysis hypotension episodes (18 percent on BD, 14 percent on HDF, and 13 percent on AFB; BD v HDF, P = 0.001; BD v AFB, P = 0.0001; and HDF v AFB, P = NS) and of dialysis intolerance (3.3 percent on BD, 1.3 percent on HDF, and 1.1 percent on AFB; BD v HDF, P = 0.021; BD v AFB, P = 0.019; and HDF v AFB, P = NS). Kt/V improved significantly after the switch from BD to either HDF or AFB (1.17 +/- 0.06 on BD, 1.32 +/- 0.12 on HDF, and 1.32 +/- 0.13 on AFB; BD v HDF, P = 0.021; BD v AFB, P = 0.003; HDF v AFB, P = NS). Protein catabolic rate also improved in HDF and AFB compared with BD (0.90 +/- 0.12 on BD, 1.03 +/- 0.15 on HDF, and 1.04 +/- 0.14 on AFB; BD v HDF, P = 0.001; BD v AFB, P = 0.009; and HDF v AFB, P = NS). AFB showed a better correction of acidosis compared either with BD or HDF (serum bicarbonate, 20.3 +/- 1.1 mEq/L on BD, 20.8 +/- 2.2 mEqL on HDF, and 22.2 +/- 2.4 mEq/L on AFB; BD v HDF, P = NS; BD v AFB, P = 0.01; and HDF v AFB, P = 0.030). The other parameters observed did not differ. In conclusion HDF and AFB show a better dialysis efficiency and a better hemodynamic tolerance compared with BD. This fact is associated with an improvement in protein intake as assessed by kinetic criteria. Acetate-free biofiltration has the further advantage of a better control of the acid-base balance compared with BD and HDF. HDF and AFB are useful dialytic options to traditional BD hemodialysis even in patients older than 70 years. PMID- 8678066 TI - Controlled study on the improvement of quality of life in elderly hemodialysis patients after correcting end-stage renal disease-related anemia with erythropoietin. AB - Despite the long experience in erythropoietin (EPO) treatment in end-stage renal disease (ESRD)-related anemia, controversy remains as to whether EPO treatment of anemia can improve the quality of life (QL) in elderly ESRD patients, as it does in younger ones. We conducted a prospective study of 57 stable patients on hemodialysis who started on EPO treatment. A control group of 29 hemodialysis patients not requiring EPO was simultaneously studied. Diabetic patients and patients with severe comorbidity were excluded. Quality of life was assessed at baseline before EPO treatment and after 3 and 6 months of follow-up, using the Karnofsky scale (KS) and the Sickness Impact Profile (SIP) questionnaire. A high KS score and a low SIP score indicate better QL. Erythropoietin patients were stratified into two age groups: <60 years (n = 34) and > or = 60 years (n = 23). In the EPO group mean hematocrit values improved from 21 percent at baseline to 29 percent at the sixth month; mean KS scores increased from 68 +/- 1.8 to 81 +/- 1.5 (P < 0.0001) and the mean global score of SIP decreased from 19.8 +/- 1.6 to 13.5 +/- 1.2 (P < 0.0001). No significant changes were observed in the control group. Elderly patients in the EPO group showed improved KS scores, from 61 +/- 1.5 to 75 +/- 2.5 (P < 0.0001), and the global score of SIP decreased from 27.7 +/- 2.1 to 20 +/- 1.8 (P < 0.001). Younger patients had improvement of their KS scores, from 73 +/- 2.5 to 85 +/- 1.5 (P < 0.0001), and the global score of SIP decreased from 14.5 +/- 1.9 to 9.1 +/- 1.2 (P < 0.001). No relationship was found between age groups and improvement in QL indicator scores. On regression analysis, a poor basal QL score was related to higher QL improvement under EPO treatment, and final hematocrit was positively related to global SIP improvement. Treatment of ESRD-related anemia with EPO significantly improved the QL of hemodialysis patients. Quality of life in elderly patients improved as much as in younger patients, thereby fully justifying the use of EPO for the elderly. PMID- 8678067 TI - An economic evaluation of hospital-based hemodialysis and home-based peritoneal dialysis for pediatric patients. AB - The purpose of this study was to assess the relative health system cost of pediatric ambulatory hospital-based hemodialysis and home-based peritoneal dialysis, including both continuous ambulatory peritoneal dialysis and continuous cycling peritoneal dialysis when either treatment is equally appropriate. A cost analysis was performed from the viewpoint of the "study hospital" and service providers (physicians) using treatment protocols, based on current clinical practice, which incorporate procedures to establish dialysis access sites, ongoing dialysis maintenance, and possible complications. Cost estimates used information from the period between April 1, 1993, to March 31, 1994, including fully allocated inpatient and outpatient costs. A sensitivity analysis was conducted to analyze the effect of complications on treatment costs. Total annual costs (in 1994 Canadian dollars, $1.00 CDN approximately $0.75. US) of a typical and uncomplicated continuous ambulatory peritoneal dialysis, continuous cycling peritoneal dialysis, and hemodialysis patient were $47,569, $48,658, and $76,023, respectively. Differences in cost between peritoneal dialysis and hemodialysis patients were due to hemodialysis maintenance costs, which were attributed to larger physician fees (25.8 percent), greater direct treatment costs incurred by the study hospital (14.2 percent), and higher overhead costs (60.0 percent). The expected total cost of hemodialysis complicated by an arteriovenous fistula clot and central venous line blockages, or peritoneal dialysis complicated by hernia repair and peritonitis was $78,568 and $50,438 for hemodialysis and peritoneal dialysis, respectively. For the range of complication probabilities considered, expected total costs were always lower with peritoneal dialysis than with hemodialysis. The cost analysis demonstrates that peritoneal dialysis is less costly than hemodialysis for pediatric patients. Such analyses are but one component of the treatment decision, and as such, should not be viewed as the sole means to yield a treatment decision, but rather as a device for systematically evaluating the alternative treatment options. PMID- 8678068 TI - Comparison of methods for measuring albumin in peritoneal dialysis and hemodialysis patients. AB - Serum albumin levels have been used extensively as an indicator of morbidity in patients with end-stage renal disease. Recent evidence suggests that albumin levels vary considerably in hemodialysis patients depending on the laboratory method used, but formulas for comparing albumin values by different methods have not been developed. We prospectively evaluated the effects of measuring albumin by three different methods on paired plasma and serum from 23 patients on continuous ambulatory peritoneal dialysis (CAPD) and 53 patients on chronic maintenance hemodialysis. Plasma and serum gave virtually identical results independent of method used. In CAPD patients, bromcresol green and nephelometry gave nearly identical albumin measurements through the entire range of plasma levels. In contrast, bromcresol purple gave values that were 9.9 percent +/- 1.3 percent lower (P < 0.05). Hemodialysis patients showed a similar pattern with close agreement between bromcresol green and nephelometry, but bromcresol purple gave lower albumin levels by 19.1 percent +/- 1.2 percent (P < 0.05). The discrepancy in albumin in CAPD patients was significantly less than in the hemodialysis patients (P < 0.05), suggesting that there were fewer interfering substances in the blood of CAPD patients than in hemodialysis patients. Linear regression analysis was used to develop simple formulas for comparing albumin values obtained by the different methods in CAPD and hemodialysis patients. These studies show that values for albumin in blood vary significantly by method of analysis in CAPD and hemodialysis patients. By the use of these formulas, it becomes possible to compare albumin values between centers using different methods for the purpose of quality management. PMID- 8678069 TI - Recurrent Goodpasture's disease. AB - Goodpasture's disease is usually a monophasic illness that can be successfully treated in a large proportion of patients. Recurrent disease is rare. We report a case of Goodpasture's disease in which recurrent pulmonary hemorrhage and glomerulonephritis were observed over 12 years. Antiglomerular basement membrane autoantibody was monitored throughout this period, and we demonstrate the close association of antibody levels with disease recurrence. PMID- 8678070 TI - Renal oncocytomatosis. AB - Renal oncocytoma is an uncommon benign renal neoplasm of unknown etiology. Bilateral, multicentric renal oncocytomas are rare and diffuse renal oncocytomas are even rarer. We report a patient with incidentally detected marked bilateral nephromegaly due to innumerable oncocytomas. The term "oncocytomatosis" should be strictly applied to cases in which oncocytomas diffusely infiltrate the kidneys. PMID- 8678071 TI - Pan-nephritis (glomerulonephritis, arteriolitis, and tubulointerstitial nephritis) associated with predominant mesangial C1q deposition and hypocomplementemia: a variant type of C1q nephropathy? AB - A 35-year-old man showed acute nephritic syndrome manifested as proteinuria, hematuria, and hypocomplementemia after upper respiratory infection. A renal biopsy showed mild to moderate mesangial proliferative glomerulonephritis with an accumulation of mononuclear cells in the capillary loop and with the deposition of C1q (graded as 3+), immunoglobulin (Ig) G, C3 (2+), IgA, IgM, and fibrinogen (weak to 1+), and mononuclear cell infiltration of the glomerular hilus, arterioles, and proximal tubules, which was a peculiar form of renal lesion. The mesangial deposition of C1q has been well documented in lupus nephritis, membranoproliferative glomerulonephritis, and endocapillary glomerulonephritis. The clinical signs and laboratory data in our patient ruled out these diseases. Although an immunofluorescence study showed these similarities to Clq nephropathy, the histopathological features of the peculiar arteriolitis and tubulointerstitial nephritis and laboratory findings of hypocomplementemia, as well as the good response to oral steroid therapy, differed from typical C1q nephropathy. The current patient appears to be a very rare phenotype of nephritis, being the only 1 case in almost 2,800 renal biopsies. PMID- 8678072 TI - A family with two sisters with collagenofibrotic glomerulonephropathy. AB - Collagenofibrotic glomerulonephropathy is a recently recognized disease entity. Although an autosomal recessive inheritance pattern has been suggested for this condition, there are few reports of familial cases. Only four pairs of child siblings, with histological confirmation of the glomerular lesions, have been reported. The current report describes a family including two sisters with histological evidence of collagenofibrotic glomerulonephropathy. Serum concentrations of the procollagen III peptide were elevated in the affected sisters, whereas their parents and other siblings demonstrated neither proteinuria nor increased blood levels of the procollagen III peptide. Our findings support an autosomal recessive pattern of inheritance for this type of glomerulonephropathy. They also suggest that the serum concentration of the procollagen III peptide is a useful marker for collagenofibrotic glomerulonephropathy. PMID- 8678073 TI - Candida infection of the arteriovenous fistula used for hemodialysis. AB - Arteriovenous fistula infection is an exceedingly rare manifestation of Candida infection, with only one case previously reported in the English literature. This report describes three cases of Candida arteriovenous fistula infection seen in a prospective study and reviews the previously reported case. All cases involved the polytetrafluoroethylene graft. The presentations can be either acute or subacute in onset, with drainage at the fistula site as the most common sign. The diagnosis of Candida arteriovenous fistula infection relies on the isolation of the organism from an intraoperative culture of the fistula. Candida was isolated from blood in three of four cases, and wound drainage in two of three cases. Antifungal therapy should be given, but complete removal of the arteriovenous fistula may be necessary for long-term cure. PMID- 8678074 TI - Post-renal transplantation hyponatremia. PMID- 8678075 TI - Recovery of gastrointestinal function after renal transplantation in patients with sclerosing peritonitis secondary to continuous ambulatory peritoneal dialysis. PMID- 8678076 TI - Learner-centered strategies in clerkship education. PMID- 8678077 TI - Aspirin use and fecal occult blood testing. PMID- 8678078 TI - Asymptomatic chronic gastrointestinal blood loss in patients taking aspirin or warfarin for cardiovascular disease. AB - OBJECTIVE: To determine whether low-dose aspirin or warfarin induces fecal occult blood loss. PATIENTS AND METHODS: A prospective, cross-over study, of 100 participants over 40 years of age in 1 of 3 groups, taking: (1) no aspirin or warfarin, (2) daily aspirin (either 81 or 325 mg), or (3) warfarin, but no aspirin. Stool samples were collected and analyzed for the presence of occult blood using HemoQuant and Hemoccult II. After collection of baseline samples, patients initially taking no aspirin (group 1) were asked to take regular aspirin (325 mg daily) for 2 months. Patients initially taking aspirin 81 mg daily (group 2) were switched to 325 mg daily for 2 months, and vice versa. RESULTS: Patients taking no aspirin had mean fecal blood of 0.68 +/- 0.05 mg hemoglobin/g stool, which increased to 1.41 +/- 0.36 mg/g after taking 325 mg of aspirin daily (P = 0.02). In contrast, patients in group 2, taking 81 mg and 325 mg of aspirin, had mean fecal blood of 0.82 +/- 0.08 mg/g (P = 0.57) and 1.04 +/- 0.23 mg/g (P = 0.13), respectively (comparisons with patients taking no aspirin). The mean blood loss in patients taking warfarin was 0.51 +/- 0.04 mg/g (P = 0.55), and fecal blood was not related to the degree of anticoagulation. There was no increase over normal in the rate of Hemoccult II-positive stool tests with aspirin or warfarin therapy. CONCLUSION: Aspirin, but not warfarin, caused a small but clinically insignificant increase in occult fecal blood. The small blood loss in patients taking aspirin or warfarin is unlikely to interfere with fecal occult blood test. Therefore, positive fecal occult blood tests, in patients taking either low-dose aspirin or warfarin, should be managed in the same fashion as patients not taking these medications. PMID- 8678079 TI - Inadequate treatment with HMG-CoA reductase inhibitors by health care providers. AB - PURPOSE: To determine if patients treated with HMG-CoA reductase inhibitors have their LDL cholesterol levels at or below the levels recommended by the National Cholesterol Education Program (NCEP) and if patients on these medications are monitored for potential toxicity. PATIENTS AND METHODS: Ninety patients from the VA Medical Center in San Francisco were randomly selected in this retrospective analysis. All patients were taking a HMG-CoA reductase inhibitor as monotherapy for treatment of high blood cholesterol for a minimum of 1 year. Medical charts and laboratory and pharmacy computer databases were utilized to gather information regarding the patients' medical history, treatment history, relevant laboratory tests, and medication refill profile. RESULTS: The majority of patients, 73%, were secondary prevention patients. Only 33% of the 90 subjects met the LDL cholesterol goal recommended by the NCEP. For the secondary prevention patients, only 24% met goal LDL. Even when the stringency of the NCEP guidelines was reduced by 20% (goal LDL < 120 mg/dL), 50% of the secondary prevention patients were still inadequately treated. Only 2 of the 90 patients were on maximal dosage regimens. Sixty-seven percent of patients had annual lipid panels and 49% had annual liver panels. Forty-five percent of patients followed by nonphysicians met goal LDL while only 29% and 31% of patients followed by attending physicians and residents/fellows met goal LDL, respectively. In addition, patients followed by nonphysicians were monitored more closely for efficacy and toxicity of the medications. CONCLUSIONS: Based on the current NCEP recommendations, patients on monotherapy with HMG-CoA reductase inhibitors are often inadequately treated. Only 33% of the patients evaluated at our institution were at or below the NCEP recommended LDL cholesterol levels and less than half of the patients were adequately monitored for hepatotoxicity. PMID- 8678080 TI - Safety of dapsone as Pneumocystis carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with allergy to trimethoprim/sulfamethoxazole. AB - OBJECTIVE: To assess the safety of dapsone prophylaxis of Pneumocystis carinii pneumonia (PCP) in patients with prior intolerance to trimethoprim/sulfamethoxazole (TMP/SMX). METHODS: We conducted a retrospective study in the categorical human immunodeficiency virus out-patient program of a university hospital. Patients who had filled prescriptions for dapsone at our pharmacy between January 1991 and April 1994 were evaluated and 75 patients were found eligible for analysis. RESULTS: The overall incidence of adverse events (AE) in our study cohort was 39%. The most common AEs were anemia (23%) and rash (16%). However, after critical evaluation of each case, only 3 cases of anemia (4%) and 2 cases of rash (3%) were judged to be "likely related" to dapsone. Only 5/75 patients (7%) developed the same intolerance to dapsone as previously experienced on TMP/SMX, and none of these cases was viewed as "likely related" to dapsone. A dapsone regimen of 100 mg qd and a prior episode of PCP were associated with a higher incidence of AEs. Eight cases of PCP occurred in spite of dapsone prophylaxis for an incidence of 7 cases per 1,000 patient-months. Seven of the cases of PCP occurred in patients who were receiving secondary prophylaxis. CONCLUSIONS: Given the low incidence of AEs judged to be "likely related" to dapsone, this drug is a reasonable choice for PCP prophylaxis in patients with prior AEs to TMP/SMX. PMID- 8678081 TI - The changing face of candidemia: emergence of non-Candida albicans species and antifungal resistance. AB - OBJECTIVES: To assess the changing epidemiology of candidemia in the 1990s, to evaluate the clinical implications for the presence of non-Candida albicans in blood, and to evaluate the presence of antifungal resistance in relation to prior antifungal administration. DESIGN: Multicenter prospective observational study of patients with positive blood cultures for Candida species or Torulopsis glabrata. SETTING: Four tertiary care medical centers. RESULTS: Four hundred twenty-seven consecutive patients were enrolled. The frequency of candidemia due to non-C. albicans species significantly increased in each hospital throughout the 3.5-year study period (P = 0.01). Thirteen percent of candidemias occurred in patients who were already receiving systemic antifungal agents. Candidemias developing while receiving antifungal therapy were more likely caused by non-C. albicans species than by C. albicans species (P = 0.0005). C. parapsilosis and C. krusei were more commonly seen with prior fluconazole therapy, whereas T. glabrata was more commonly seen with prior amphotericin B therapy. Candida species isolated during episodes of breakthrough candidemia exhibited a significantly higher MIC to the antifungal agent being administered (P < 0.001). CONCLUSION: In this large scale study, the non-C. albicans species, especially T. glabrata, emerged as important and frequent pathogens causing fungemia. This finding has major clinical implications given the higher complication and mortality rate associated with the non-C. albicans species. The change in the pattern of candidemia might be partly attributed to the increase in number of immunocompromised hosts and the widespread use of prophylactic or empiric antifungal therapy. This is an ominous sign given the in vitro resistance of the non-C. albicans species to currently available antifungal agents. PMID- 8678082 TI - Prophylactic antibiotics for the prevention of early infection in multiple myeloma. AB - PURPOSE: Patients with multiple myeloma are at increased risk for bacterial infection. During the first 2 months of initial chemotherapy the rate of infection is twice that experienced during the remainder of the disease course. As many as one-third of these early infections are fatal, and many more prevent adequate administration of chemotherapy. This study was designed to determine whether the morbidity and mortality of early infection can be prevented by prophylactic administration of trimethoprim-sulfamethoxazole (TMP-SMX). PATIENTS AND METHODS: Eligible patients about to begin chemotherapy for multiple myeloma were randomly assigned to prophylaxis for 2 months or to no prophylaxis (control). Antibiotic prophylaxis consisted of TMP-SMX 160/800 mg orally every 12 hours administered for the first 2 months of initial chemotherapy. All patients were observed for infection for 3 months after the start of chemotherapy. RESULTS: Of 57 patients entered into the study, 54 were evaluable, representing 13.1 patient-years of observation. The 28 TMP-SMX patients and 26 control patients were comparable in terms of chemotherapy regimen, age, gender, stage, and bone marrow function. Bacterial infection during the 3-month study period occurred in 11 control patients but in only 2 patients assigned TMP-SMX (P = 0.004). Eight severe infections occurred in controls compared with 1 in a TMP-SMX patient (P = 0.010) leading to 4 and 1 infection deaths, respectively (P = not significant). Severe infections included 5 pneumonias (3 with sepsis), 2 urinary tract infections with complicating pneumonia or sepsis, 1 diverticulitis with perforation, and 1 staphylococcal scalded skin syndrome. None of the 4 nonbacterial infections was severe. The rate of bacterial infection was 2.43 per patient-year for controls and 0.29 per patient-year for the TMP-SMX group (P = 0.001). Toxicity (skin rash 6 patients, nausea 1 patient) was not life threatening but required discontinuation of TMP-SMX in 25% of patients. CONCLUSION: Administering TMP-SMX for the first 2 months of initial chemotherapy is effective, inexpensive prophylaxis for early bacterial infection in multiple myeloma. PMID- 8678083 TI - Modification of the diagnostic criteria proposed by the Duke Endocarditis Service to permit improved diagnosis of Q fever endocarditis. AB - BACKGROUND: Q fever endocarditis is a life-threatening disease for which the diagnosis is usually based on serology. The major microbiologic criterion for the diagnosis of infectious endocarditis (two separate positive blood cultures) cannot be achieved in most routine laboratories because of the biohazard associated with the culture of Coxiella burnetii, the etiological agent of Q fever. PURPOSE: Recently, new criteria for the diagnosis of infectious endocarditis have been proposed, and in this study we attempted to assess the suitability of these criteria specifically for the diagnosis of Q fever endocarditis. PATIENTS AND METHODS: To achieve this aim, we first selected from our series 20 recent cases in whom endocarditis had been confirmed following valvular pathological examination, and for whom microbiological evidence for the involvement of C burnetii was available. Then, we applied the criteria proposed by the Duke Endocarditis Service (ie, C burnetii positive serology being considered a minor criterion) to this cohort of patients but excluding pathological findings. Although the Duke Endocarditis Service criteria confirmed diagnosis in 16 of the patients, 4 were misclassified as "possible" cases (20%). However, when the Q fever serological results (using an 1/800 antiphase I immunoglobulin G cut off) and single blood culture results were changed from minor to major diagnostic criteria, endocarditis was confirmed in them all. A second time, prospectively, we applied the Duke Endocarditis Service criteria to a further 5 patients affected with Q fever endocarditis. Strict application of these criteria resulted in 1 of the 5 being misdiagnosed. Applying the suggested modification for C burnetii results, all 5 were confirmed as having infectious endocarditis. CONCLUSION: We propose that the modifications discussed in this study be applied to the Duke Endocarditis Service criteria in order that the diagnosis of C burnetii induced endocarditis is improved. PMID- 8678084 TI - Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome. AB - PURPOSE: To evaluate the aerobic power (as maximum volume of oxygen consumed [VO2 max]) of women with chronic fatigue syndrome (CFS). PATIENTS AND METHODS: Twenty one women with CFS and 22 sedentary healthy controls (CON) were studied at the CFS Cooperative Research Center Exercise Laboratory at the VA Medical Center, East Orange, New Jersey. Performance was measured on an incremental treadmill protocol walking to exhaustion. Expired gases were analyzed by a metabolic system, heart rate was recorded continuously, and ratings of perceived exertion (RPE) were taken at each workload. The groups were divided into those who achieved VO2 max (CFS-MAX and CON-MAX) and those who stopped at a submaximal level (CFS-NOMAX and CON-NOMAX) by using standard criteria. RESULTS: Seventeen CON and 10 CFS subjects achieved VO2 max. The VO2 max (mL/kg/min) of the CFS-MAX (28.1 +/- 5.1) was lower than that of the CON-MAX (32.1 +/- 4.3, P = 0.05). The CFS-MAX achieved 98 +/- 11% of predicted VO2 max. The CFS group had a higher RPE at the same absolute workloads as controls (P < 0.01) but not the same relative workloads. CONCLUSION: Compared with normal controls, women with CFS have an aerobic power indicating a low normal fitness level with no indication of cardiopulmonary abnormality. Our CFS group could withstand a maximal treadmill exercise test without a major exacerbation in either fatigue or other symptoms of their illness. PMID- 8678085 TI - Resting electrocardiographic abnormalities as predictors of coronary events and total mortality among elderly men. AB - PURPOSE: To examine the prognostic significance of electrocardiographic (ECG) abnormalities among the elderly. MATERIALS AND METHODS: The Finnish cohorts of the Seven Countries Study involved 697 men aged 65 to 84 years at baseline in 1984. A 5-year follow-up was made from 1984 to 1989. Fatal myocardial infarction, nonfatal myocardial infarction, and all-cause mortality were outcome measures. RESULTS: Seventy-four fatal myocardial infarctions (MI), 101 fatal or nonfatal Mis, and 207 deaths occurred. When electrocardiographic changes were analyzed one by one, men with Q waves (n = 98), high-amplitude R waves (n = 112), depressed ST interval (n = 122) or T-wave changes (n = 263) had significantly (P < 0.05) higher risk of coronary events and all-cause mortality than men without these changes. Additionally, men with atrial fibrillation (n = 49) had significantly higher risk of death. Highest risk was observed among men with Q waves together with ST- or T-wave changes. Men with both ST depression and T flattening/inversions without Q waves had also increased risk, whereas this was not true for men with Q waves without concomitant ST- or T-wave changes. CONCLUSION: Electrocardiographic abnormalities suggestive of coronary heart disease are associated with a high risk for coronary events and total mortality among elderly men. Among the elderly, a reliable history of coronary heart disease may not be easily achievable, thus the ECG could potentially be used as an indicator of symptomless or atypical heart disease. PMID- 8678087 TI - The basis of current and future therapy for inflammatory bowel disease. AB - The majority of patients with IBD can be managed with currently available therapy, but the currently available agents do not seem to alter the natural history of the disease. An explosion of information about the immune system and the mediators of inflammation has now generated a host of new strategies that will likely benefit patients with IBD as well as patients with other chronic inflammatory and autoimmune disorders. Molecules of the immune system are being harnessed to treat disorders of the immune system. Some of these new concepts and therapies have been discussed here. Some are already in clinical trials, others have yet to be tried. As more specific immune modulators are tested in patients, it is likely that some will be effective in Crohn's disease but not ulcerative colitis and vice versa, due to, and revealing, the differences in the pathogenesis of these two diseases. The hope is that the application of these new modalities will alter the natural history of these diseases to the benefit of our patients. PMID- 8678086 TI - Is syncope a risk factor for poor outcomes? Comparison of patients with and without syncope. AB - OBJECTIVE: To determine whether syncope, independent of underlying comorbidities, is associated with increased mortality or other cardiovascular outcomes. PATIENTS AND METHODS: A prospective cohort study of patients with syncope and a group of patients without syncope matched with respect to age, gender, site of care (inpatient/ outpatient) and a cardiac disease index at an urban university medical center. Overall mortality, cardiac mortality, cardiovascular outcomes, and occurrence of syncope within 1 year of study enrollment were compared between the groups with Kaplan-Meier rates and Mantel-Cox statistics. RESULTS: The characteristics of 470 patients with syncope and the matched patients without syncope were similar except that the patients without syncope had more cardiac diseases than those with syncope (P = 0.002). Patients with and without syncope had similar rates of 1-year overall mortality (9% versus 11%, P = 0.29) and cardiac mortality (3% versus 6%, P = 0.08). In multivariate analyses, syncope was not a significant predictor of overall or cardiac mortality, but male gender, age > 55 years, and congestive heart failure were. One-year rates for other cardiovascular outcomes (myocardial infarction, congestive heart failure, cardiac arrest with survival, and cerebrovascular events) in patients with syncope were similar to those in patients without syncope (P > or = 0.2 for all comparisons). Patients with syncope had a 20.2% recurrence rate in 1 year as compared with a 2.1% rate for new syncope in patients without prior syncope (P < 0.00001). CONCLUSIONS: Syncope itself is not a risk factor for increased overall and cardiac mortality or cardiovascular events. Underlying heart diseases are risk factors for mortality regardless of whether the patient has syncope or not. The major focus of the evaluation of patients with syncope should be to identify and treat underlying heart diseases. PMID- 8678088 TI - Pyoderma gangrenosum and subcorneal pustular dermatosis: clues to underlying immunoglobulin A myeloma. PMID- 8678090 TI - G-CSF and exacerbation of rheumatoid arthritis. PMID- 8678089 TI - Tamoxifen for the prevention of breast cancer. PMID- 8678091 TI - Impact of Changing Bacterial Epidemiology in Treating Moderate-to-Severe Infection. Symposium. PMID- 8678092 TI - Susceptibility of bacterial isolates to beta-lactam antibiotics from U.S. clinical trials over a 5-year period. AB - Results are reported for agar dilution susceptibility testing of 3,075 isolates of aerobic bacteria collected from >200 U.S. institutions, located in 30 different states. These isolates were collected from 1987 through 1991 from patients who participated in cefepime clinical trials. Cefepime susceptibility was compared with ceftazidime, cefotaxime, ceftriaxone, cefoperazone, and imipenem. To avoid duplication of strains, only initial isolates were included. Cefepime minimum inhibitory concentration (MIC90) values for Enterobacteriaceae were < or = 0.5 microg/mL, except for two species, Citrobacter freundii and Providencia stuartii, with MIC90 values of 2 and 1, respectively. The MIC90 values of the other cephalosporins were higher, especially for Enterobacter aerogenes and C. freundii. The MIC90 values of cefepime for methicillin susceptible Staphylococcus aureus (4 microg/mL) and Pseudomonas aeruginosa (8 microg/mL) were similar to those of cefotaxime for S. aureus (4 microg/mL), and to ceftazidime for P. aeruginosa (8 microg/mL). Streptococcus pneumoniae was similar in susceptibility to cefotaxime at 0.06 microg/mL. The activity of cefepime against a diverse group of gram-positive and gram-negative (1987-1991) bacteria isolates demonstrates the excellent activity of cefepime compared to third-generation cephalosporins and imipenem, particularly among C. freundii and E. aerogenes isolates, which were often resistant to other cephalosporins. PMID- 8678093 TI - Comparative susceptibilities of Klebsiella species, Enterobacter species, and Pseudomonas aeruginosa to 11 antimicrobial agents in a tertiary-care university hospital. AB - The in vitro activity of cefepime was compared versus that of 10 antimicrobial agents commonly used in the treatment of serious infections caused by common aerobic gram-negative bacteria: aztreonam, cefoperazone, ceftazidime, ceftriaxone, ciprofloxacin, gentamicin, imipenem, piperacillin, ticarcillin clavulanic acid, and tobramycin. We tested 30 clinical isolates representing a cross section of Klebsiella and Enterobacter species and Pseudomonas aeruginosa collected at our tertiary-care university hospital. The most potent beta-lactams were imipenem and cefepime, which demonstrated significant activity against the majority of strains in all 3 genera of bacteria tested, as did ciprofloxacin and tobramycin. Ceftazidime was active against Pseudomonas aeruginosa but was less potent against Klebsiella and Enterobacter spp. Cefoperazone and ceftriaxone were less active than ceftazidime against Pseudomonas aeruginosa. Cefepime was found to be highly active against many resistant organisms that traditionally have been difficult to treat. PMID- 8678094 TI - Comparative activity of eight antimicrobial agents against clinical bacterial isolates from the United States, measured by two methods. AB - In a surveillance study conducted during 1992-1993 at 83 medical institutions of different types and sizes (e.g., laboratories, community hospitals, teaching hospitals) and from different geographical areas of the United States, clinical bacterial isolates were tested for their susceptibility to eight comparative antimicrobial agents (cefepime, ceftazidime, cefotaxime, ceftriaxone, ciprofloxacin, gentamicin, imipenem, and piperacillin). A total of 12,574 isolates were tested by either the Etest method (AB Biodisk) or a microdilution method (MicroScan) in the participating laboratories; 11.8% of these isolates were subsequently retested for quality assurance purposes by both methods in a central laboratory. The results obtained in the central laboratory were essentially the same as the results obtained in the participating laboratories. This article presents data for gram-negative and gram-positive isolates other than Streptococcus pneumoniae, the results of which have been previously published. Antimicrobial susceptibility results obtained with the two different minimum inhibitory concentration (MIC) methods--MicroScan and Etest--showed that most isolates of Enterobacteriaceae were susceptible to cefepime, exceeding the activity of ceftazidime, ceftriaxone, and cefotaxime, principally because of the greater activity of cefepime against the species that produce Bush group 1 beta lactamases (predominantly Enterobacter cloacae, Enterobacter aerogenes, and Citrobacter freundii). In addition, the activity of cefepime against Pseudomonas aeruginosa isolates was essentially equivalent to that of ceftazidime and greater than that of third-generation cephalosporins. Most methicillin-susceptible Staphylococcus aureus were susceptible to all the cephalosporins, whereas methicillin-resistant S. aureus and enterococci were resistant. Overall, the most active antimicrobials in this study were imipenem, ciprofloxacin, and cefepime, but the activity of all the antimicrobials varied with different species. Categorically, the results from the microdilution and Etest methods were equivalent. PMID- 8678095 TI - Impact of changing pathogens and antimicrobial susceptibility patterns in the treatment of serious infections in hospitalized patients. AB - The selection of drug-resistant pathogens in hospitalized patients with serious infections such as pneumonia, urinary tract infections (UTI), skin and skin structure infections, and primary or secondary bacteremia has generally been ascribed to the widespread use of antimicrobial agents. Issues of concern regarding gram-negative bacilli include the expression of extended spectrum beta lactamase-producing Escherichia coli and Klebsiella pneumonias and constitutive resistance in some Enterobacteriaceae caused by Bush group 1 beta-lactamases. Current concerns with gram-positive pathogens are increasing multidrug resistance in methicillin-resistant Staphylococcus aureus, enterococci, and coagulase negative staphylococci, and increasing incidence of penicillin-resistant Streptococcus pneumoniae. Contemporary treatment strategies for pneumonia in hospitalized patients mandate early empiric therapy for the most likely gram positive and gram-negative pathogens. Newer beta-lactams, such as fourth generation cephalosporins, may be useful in the treatment of pneumonia, including those cases associated with bacteremia. Combination beta-lactam/beta-lactamase inhibitor drugs, an aminoglycoside co-drug, or a carbapenem may also be indicated. The initial treatment of UTI in the hospital setting also may be empirically treated with the newer cephalosporins, combination broad-spectrum penicillins plus an aminoglycoside, a quinolone, or a carbapenem. Current problems in treating UTI include the emergence of extended spectrum beta lactamase-producing Escherichia coli, the tendency of fluoroquinolones both to select for resistant strains of major UTI pathogens and to induce cross resistance among different drug classes, and beta-lactam and vancomycin resistance of enterococci and coagulase-negative staphylococci. Treatment of skin and skin-structure infections is complicated by the coexistence of gram-positive and gram-negative infections, which may be drug resistant. Both fourth-generation beta-lactams and carbapenems may have in vitro activity against these pathogens; however, where these drugs--with their increased spectra and lower affinity for beta-lactamases and less susceptibility to beta-lactamase hydrolysis--fit into the therapeutic armamentarium remains to be determined. Initial clinical studies appear to be promising, nonetheless. The ability of both nosocomial and community acquired pathogens to develop resistance to powerful broad-spectrum agents presents a great challenge for prescribing patterns and in the development of new drugs to be relatively resistant to inactivation. PMID- 8678096 TI - The pharmacokinetic profile of a new generation of parenteral cephalosporin. AB - Cefepime, a fourth-generation cephalosporin with activity against both gram negative and gram-positive organisms, has been investigated in healthy subjects and in special patient populations, including the elderly and those whose ability to eliminate drugs may be compromised. This review of seven pharmacokinetic studies indicates that the pharmacokinetic disposition of cefepime, administered either intravenously or intramuscularly, is similar to that of other cephalosporins with regard to dose linearity, renal excretion, and low serum protein binding. The elimination half-life of intravenous cefepime has been found to be approximately 2 hours, and peak serum concentrations approach 82 microg/mL for a 1-g dose and 164 microg/mL for a 2-g dose. Total body clearance is approximately 120 mL/min, independent of dose, and >80% of the drug is excreted unchanged by the kidneys. Dosage adjustment is warranted for patients with renal insufficiency but not hepatic dysfunction. The pharmacokinetic disposition of cefepime is altered in the elderly but not enough to necessitate additional dosage adjustment. Tissue penetration studies indicate similarity to other cephalosporins with low protein binding. PMID- 8678097 TI - Bacteriologic and clinical applications of a new extended-spectrum parenteral cephalosporin. AB - Although third-generation cephalosporins have been considered the backbone of antibiotic therapy for the treatment of many kinds of serious infections, including those in hospitalized patients, lack of activity against some important pathogens still exists among currently available drugs. In addition, increasing accounts of antibiotic resistance, particularly in the hospital environment, are of deep concern and have thus led to the need for the development of newer antimicrobial agents. Cefepime is a now parenteral cephalosporin with an extended spectrum of antibacterial activity that includes both aerobic gram-negative and gram-positive bacteria. It is also active against many gram-negative organisms resistant to ceftriaxone and cefotaxime, as well as many strains of Enterobacter and Citrobacter resistant to ceftazidime. Cefepime appears to be less likely to select out resistant organisms, and it may be less likely to change hospital flora than currently available antimicrobials. Cefepime has been shown to be very well tolerated and effective in the treatment of a variety of infections including moderate-to-severe pneumonia (including cases associated with concurrent bacteremia), complicated and uncomplicated urinary tract infections (also including cases associated with concurrent bacteremia), and skin and skin structure infections. Clinical response rates are > or = 75% for most infections and have been comparable to ceftazidime in comparative trials. In addition, pretreatment susceptibility testing indicates that >94% of organisms isolated in patients enrolled in clinical trials were susceptible to cefepime. PMID- 8678098 TI - Clinical applications of a new parenteral antibiotic in the treatment of severe bacterial infections. AB - Cephalosporins are one of the mainstays of antibiotic therapy, and third generation cephalosporins are first-line agents for the treatment of many types of serious infections, including those of nosocomial origin. Gaps in activity of currently available third-generation cephalosporins such as cefotaxime, cefoperazone, ceftriaxone, and ceftazidime, and increasing reports of gram negative bacilli resistance to some of these agents, especially Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterobacter spp., make it necessary to investigate new compounds. Cefepime, a fourth-generation cephalosporin with a wide range of activity against gram-positive and gram-negative bacteria, including multi-resistant strains of Enterobacteriaceae, was evaluated in comparison with ceftazidime for the treatment of serious infections in hospitalized patients. Ceftazidime is a commonly prescribed third-generation cephalosporin used for empiric treatment of serious infections such as pneumonia, urinary tract infection, and skin and skin-structure infection. This investigation was an open, randomized comparative study involving 882 patients in North America. Cefepime 2 g every 12 hours demonstrated similar efficacy to that of ceftazidime 2 g every 8 hours for the treatment of pneumonia and urinary tract infection (including cases associated with concurrent bacteremia), and skin and skin-structure infections. The bacteriologic responses were generally >85%. The most common pathogens isolated were Escherichia coll, Streptococcus pneumoniae, P. aeruginosa, K. pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Streptococcus, group B. Overall, approximately 94% of pathogens isolated in pretreatment cultures were susceptible to cefepime and ceftazidime. Cefepime and ceftazidime were well tolerated; only 3% of patients in each group discontinued therapy because of an adverse event. The most common adverse events were headache, diarrhea, nausea, vomiting, pruritus, and rash. The results of this study indicate that cefepime is a promising, effective, and safe single-agent therapy for serious infections in hospitalized patients. PMID- 8678099 TI - A new therapeutic option for the treatment of pneumonia. AB - Patients with bacterial pneumonia often are treated empirically with parenteral broad-spectrum antimicrobials intended to cover potential gram-negative and gram positive pathogens. However, beta-lactamase-mediated resistance has developed to many of these antimicrobials, particularly third-generation cephalosporins, and has led to the development of fourth-generation agents that are relatively beta lactamase stable. The purpose of these studies was to compare the efficacy and safety of the fourth-generation agent, cefepime, with that of the third generation agent, ceftazidime, in the treatment of hospitalized patients with moderate-to-severe bacterial pneumonia. A total of 336 (97 evaluable) patients were enrolled in an open-label study, and 99 (23 evaluable) patients were enrolled in a blinded study of patients with lower respiratory tract infections (LRTI) including pneumonia. Patients were randomized to receive either cefepime 1 g every 12 hours or ceftazidime 1 g every 8 hours given as an intravenous infusion over 30 minutes. Efficacy analysis included the evaluable patients while the safety analysis included all patients. The results in the open-label study were as follows: In patients with pneumonia, clinical response was satisfactory in 58 (85%) of 68 patients in the cefepime group and 21 (72%) of 29 patients in the ceftazidime group. Bacteriologic eradication occurred for 75 (93%) of 81 pathogens and 30 (94%) of 32 pathogens isolated from the 68 cefepime-treated patients and 29 ceftazidime-treated patients, respectively. The results in the blinded study were as follows: In patients with pneumonia, clinical response was satisfactory in 12 (80%) of 15 cefepime patients and in 7 (88%) of 8 ceftazidime patients, and the bacteriologic eradication rates were 85% (17/20 pathogens) and 73% (8/11 pathogens) isolated from the 15 cefepime-treated patients and the eight ceftazidime-treated patients, respectively. Among the most frequent adverse events in both groups were nausea, diarrhea, vomiting, and abdominal pain. Similar adverse events were noted in the 99 patients in the blinded study. These studies indicate that the efficacy and safety of cefepime administered at 1 g twice daily is comparable to that of ceftazidime administered at 1 g three times daily for treatment of hospitalized patients with pneumonia caused by susceptible pathogens. PMID- 8678100 TI - Safety of cefepime: a new extended-spectrum parenteral cephalosporin. AB - The purpose of this study was to compare the safety profile of cefepime, a new extended-spectrum, fourth-generation cephalosporin used to treat mild-to-severe bacterial infections, with that of ceftazidime. A total of 2,032 patients enrolled in North American and European cefepime trials were analyzed. The study population spanned adolescence to the elderly (15-100 years); the median age was 62 years. Cefepime was compared with ceftazidime (1,456 patients), a third generation cephalosporin. Cefepime dosing was 1-4 g/day (0.5-2.0 g twice daily) for adults; ceftazidime dosing was 1-6 g/day (0.5 g every 12 hours to 2.0 g every 8 hours). A limited number of cefepime-treated patients received 2 g every 8 hours. The median length of dosing for both cefepime and ceftazidime was 7 days. In randomized trials in which cefepime (2,032 patients) was compared with ceftazidime (1,456 patients), analysis of comparative data indicated that adverse events of probable or unknown relation to study drugs were observed in 13.8% of cefepime patients and 15.6% of ceftazidime patients. The most commonly observed adverse event for cefepime was headache (2.4%), followed by nausea (1.8%), rash (1.8%), and diarrhea (1.7%). For ceftazidime, the most commonly observed adverse event was diarrhea (3.2%), followed by headache (2.5%), nausea (2.1%), rash (1.9%), and constipation (1.5%). The incidence of positive Coombs' test was higher in high-dose cefepime recipients than in ceftazidime recipients (14.5% vs 8.7%; p = 0.043), although there was no evidence of hemolysis in either treatment group. Coadministration of analgesics, diuretics, and anticoagulants did not increase incidence of adverse events associated with study-drug therapy. Adverse renal and hematologic events, as well as anaphylaxis and death, were rare in both groups. In the comparative trials with cefepime, anaphylaxis was reported in no patients receiving cefepime and in one patient receiving ceftazidime. None of the three seizures reported in patients receiving cefepime and one of six seizures in patients receiving ceftazidime were of probable or possible relationship to the study drugs. None of the 12 cases of gastrointestinal hemorrhage reported in cefepime patients or five cases reported in ceftazidime patients were judged to be related to treatment drug. Tolerance for intravenous administration in both treatment groups was similar. Cefepime did not effect any significant or unusual allergic, hematologic, gastrointestinal, neurologic, or renal toxicity when administered to patients with mild-to-severe infections, including those receiving concomitant medications. The safety profile of cefepime is excellent and comparable to that of ceftazidime and those reported for other cephalosporins. PMID- 8678101 TI - Treatment of urinary tract infections: selecting an appropriate broad-spectrum antibiotic for nosocomial infections. AB - Clinical and in vitro data indicate that cefepime, a fourth-generation cephalosporin, may be a valuable addition in the treatment of serious infections. In this study, hospitalized patients with complicated and uncomplicated urinary tract infection (UTI), for which parenteral therapy was appropriate, were enrolled in a 2:1 ratio open, randomized trial comparing the efficacy and safety of cefepime and ceftazidime. A total of 180 patients, including 6 with concurrent bacteremia, were evaluated for their response to cefepime (n = 118) or ceftazidime (n = 62), both of which were administered by intravenous infusion or intramuscular injection in doses of 500 mg every 12 hours. In cases of complicated UTI, cefepime produced a satisfactory clinical response in 83 of 93 (89%) patients and eradicated 83 of 98 (85%) pathogens. A satisfactory clinical response to ceftazidime was experienced by 43 of 50 (86%) patients; and in 39 of 50 (78%) cases pathogens were eradicated. In uncomplicated cases, the clinical response and bacterial eradication rates for cefepime were 23 of 25 (92%) and 22 of 26 (85%), respectively, and for ceftazidime 12 of 12 (100%) and 11 of 12 (92%). Of the 6 patients with concomitant bacteremia, 5 received cefepime and 1, ceftazidime. The infecting organisms, Escherichia coli and Proteus mirabilis, were eradicated in all cases, although one cefepime-treated patient had an unsatisfactory clinical response. The most common adverse events in both groups were headache, diarrhea, and vomiting; most events were unrelated to therapy. Adverse events forced only a 2% withdrawal of patients in either group. There was local tolerance to both agents, and abnormalities in laboratory values were judged to be clinically insignificant. The results of this study indicate that cefepime can be used safely and successfully to treat both complicated and uncomplicated nosocomial infection of the urinary tract, including cases associated with concurrent bacteremia. Moreover, its safety profile appears comparable to those of other cephalosporins, and local tolerance is similar to that of ceftazidime. No patient in either group required discontinuation of therapy because of local intolerance at the infusion or injection site. PMID- 8678102 TI - Clinical experience with single agent and combination regimens in the management of infection in the febrile neutropenic patient. AB - Choice of antibiotic therapy for the management of infection in the neutropenic patient continues to challenge the clinician. The shift toward gram-positive organisms and the continuing need to provide gram-negative coverage demands the use of an agent or agents that provide coverage for the spectrum of potential infecting organisms. Cefepime is an extended-spectrum fourth-generation cephalosporin that has good activity against gram-positive and gram-negative organisms; in addition, it resists degradation by Bush group 1 beta-lactamases. These properties make this agent a promising candidate for empiric therapy with febrile neutropenic patients. Data presented in this article are from febrile neutropenic cancer patients enrolled into two randomized, prospective, nonblinded comparative U.S. clinical trials. Patients were randomized to receive cefepime (2 g thrice daily) or a comparator regimen of either ceftazidime (2 g thrice daily) or piperacillin + gentamicin (3 g every 4 hours + 1.5 mg/kg every 8 hours). When indicated, vancomycin was added to the regimen. A total of 109 febrile episodes were treated with cefepime and 107 episodes were treated with the comparator regimens. Neutropenia (< or = 500 PMNs/mm3) persisted for > or = 10 days in >40% of episodes and severe neutropenia (< or = 100 PMNs/mm3) in >25%. More than 40% of the total number of episodes were documented bacterial infections. These characteristics did not differ among treatment groups. Duration of therapy was similar in both groups (median: cefepime, 9 days; comparators, 11 days). In >40% of episodes, patients received study therapy without addition of other antibacterials (cefepime, 46%; comparators, 41%). Vancomycin was added in almost half of all the episodes (cefepime, 45%; comparators, 53%). Patients became afebrile by the fourth day of study therapy in approximately 60% of episodes (cefepime, 58%; comparators, 60%). In approximately 75% of the episodes, patients had a satisfactory response at the end of therapy (cefepime, 74%; comparators, 76%); and following approximately 90% of episodes, patients survived for >30 days (cefepime, 90%; comparators, 92%). Eradication rates were similar for all pathogens for cefepime and comparator agents. There were similar numbers of superinfecting organisms in each treatment arm; most involved gram-positive organisms. These multiple measures of efficacy suggest that initial empiric cefepime monotherapy is comparable to the pooled experience with standard therapies and that antibacterial modifications occur with similar frequency for cefepime compared with standard empiric regimens. PMID- 8678103 TI - Current and future management of serious skin and skin-structure infections. AB - The purpose of this study was to compare in a randomized, open-label clinical study, the efficacy and safety of cefepime (1 g every 12 hours) with that of ceftazidime (1 g every 8 hours) in patients with serious skin and skin-structure infections. Of 298 patients enrolled in the study, 130 with serious skin and skin structure infections were evaluable. Demographics and underlying medical conditions were comparable in both groups. The most common infections were cellulitis, abscesses, ulcers, and postoperative wound infections. The most common pathogens isolated were Staphylococcus aureus, group A streptococci, Enterobacteriaceae, and Pseudomonas aeruginosa. Duration of therapy in the 93 patients treated with cefepime was 3-18 days and in the 37 ceftazidime-treated patients was 4-16 days. Pathogen bacteriologic response rates were high: 92% (124 of 135) of pathogens were eradicated by cefepime and 95% (55 of 58) by ceftazidime. Clinical response rates were satisfactory in 88% (82 of 93) of cefepime-treated patients and in 89% (33 of 37) of ceftazidime-treated patients. Adverse events occurred with similar frequency in both groups. Events probably related to study drugs affected 3% (6 of 198) of patients treated with cefepime and 4% (4 of 100) of ceftazidime-treated patients. Cefepime, a new parenteral cephalosporin administered every 12 hours, is an extremely well tolerated and effective alternative to ceftazidime given every 8 hours for the treatment of serious skin and skin-structure infections. PMID- 8678104 TI - Reliable computer-assisted classification of the EEG: EEG variants in index cases and their first degree relatives. AB - A method which optimizes on global properties of sample recordings is proposed for the definition of and the discrimination between electroencephalogram (EEG) classes. The sample was drawn from students at the University of Heidelberg from 1974 to 1978 and consists of 15 healthy index cases clinically ascertained as belonging to the low voltage EEG group. In addition, the three clinically defined groups: diffuse beta (18 index cases), borderline alpha (12 index cases) and monomorphous alpha (18 index cases) have been included in the study, as well as the first degree relatives of the index cases, thus providing a clinical classification into four groups. The proposed method provides an automatic and reliable classification algorithm using discriminant and cluster analysis. The relation between such an automatized classification and clinical classification schemes is investigated. In particular, the inheritance of the low voltage EEG, the question on sex differences and the question of a simple Mendelian mechanism had been examined. The method of random splittings had been applied for discriminant and cluster analysis. Our findings can be summarized as follows: (1) except for the monomorphous alpha EEG group, the clinical classification shows rather marginal separation (discriminating performance 60% to 75%), while a new and more reliable grouping scheme improves the discriminating performance up to 87% to 91%. The latter scheme leads to the concept of personal channel pattern (PCP) and was compared to the clinical classification scheme by means of contingency tables; (2) only a weak correlation between the clinically and PCP based groups could be found (Cramer Index: 0.27). Accordingly, we continued to investigate the extent to which the proposed EEG classification scheme can nevertheless explain the genetic mechanisms apparently involved in the low voltage EEG. We thus considered the role of sex differences manifest in our proposed new grouping scheme; (3) males occurred more frequently in the new group 3 and females more frequently in the new group 1. In this regard, a much better correlation of the new groups between mothers and children than between fathers and children was observed; and (4) with help of our new PCP scheme, we have been able to reproduce a simple two gene Mendelian scheme to explain inheritance of the clinical low voltage EEG group. In this PCP-based scheme, the low voltage property does not occur when dominance of a certain gene (called gene A) is absent. PMID- 8678106 TI - Ultraviolet light-related neural tube defects? PMID- 8678105 TI - Positive association between a DNA sequence variant in the serotonin 2A receptor gene and schizophrenia. AB - Sixty-two patients with schizophrenia and 96 normal controls were investigated for genetic association with restriction fragment length polymorphisms (RFLPs) in the serotonin receptor genes. A positive association between the serotonin 2A receptor gene (HTR2A) and schizophrenia was found, but not between schizophrenia and the serotonin 1A receptor gene. The positive association we report here would suggest that the DNA region with susceptibility to schizophrenia lies in the HTR2A on the long arm of chromosomes 13. PMID- 8678107 TI - Assessing risk for the Tourette spectrum of disorders among first-degree relatives of probands with Tourette syndrome. AB - Previous studies have indicated that genetic investigations of Tourette syndrome (TS) should focus on a phenotype that includes not only TS, but chronic tics (CT) and obsessive-compulsive disorder (OCD) as well. These studies have shown that sex may play a role in determining which of the disorders in the TS spectrum is expressed in a susceptible individual. Female relatives of TS probands far more often express OCD, while male relatives more often express TS or CT. Data from the Yale Family Study of TS were used to model risk to first-degree relatives of probands with TS for a variety of TS disease phenotypes. Risk to relatives was modeled using multivariate Cox regression analysis, a method appropriate for assessing risk when there is correlation among disease onsets. This is the first known application of this method to family data. The study identified two proband characteristics that increase the risk for disease onset among both male and female relatives for all TS spectrum disorders, lending credence to the hypothesis that TS spectrum disorders share a common etiology. These were a relatively younger age-at-onset, and no experience of simple motor tics. The predictive ability of two additional factors varied by both sex and disease phenotype. These characteristics, i.e., proband onset with compulsive tics, and proband onset with range, appear to increase risk primarily in female relatives, and for the OCD part of the spectrum. PMID- 8678108 TI - Male-to-male transmission in extended pedigrees with multiple cases of autism. AB - Despite strong genetic influences in autism, the true mode of inheritance remains unknown. Sex differences in autism have been described in both singleton and multiplex families [Lord et al., 1982; Volkmar et al., 1993; McLennan et al., 1993; Lord, 1992]: Boys outnumber girls by 3 or 4 to 1, and so a sex-linked mode of transmission must also be considered. The key characteristic of X-linkage is that all sons of affected men are unaffected (no male-to-male transmission). In the present study, which is part of an ongoing linkage project in autism, we describe 77 multiplex autism families, 11 of who are affected cousin or half sibling families. By using these families, it is possible to trace the path of genetic transmission and observe whether the hypothesis of X-linkage is tenable. Of 11 extended pedigrees from 77 multiplex families, six show male-to-male transmission; in these families, X-linkage can be excluded as the genetic basis for their autism. The data from the other five families are compatible with either an autosomal or an X-linked mode of transmission. The key point to emerge, then, is that autism cannot be exclusively an X-linked disorder; there must be an autosomal mode of transmission at least in some families. Thus we must consider the alternative hypotheses that autism is either entirely autosomal, or it is genetically heterogeneous, involving at least one autosomal locus with genderspecific expression, as well as a possible locus on the X-chromosome. PMID- 8678109 TI - Retroviruses and schizophrenia revisited. AB - Both genetic and environmental factors appear to contribute to the causation of schizophrenia. Evidence indicating that fetal development is disrupted in schizophrenia and the finding of an excess of winter births among schizophrenic patients have led to continued speculation that an intrauterine viral infection may cause developmental lesions, genetic mutations, or persistent infections that lead to schizophrenia. Certain unique characteristics of the retroviruses render them plausible as candidate "schizoviruses" and the involvement of an endogenous retrovirus would be compatible with some of the puzzling epidemiological findings in schizophrenia. Reverse transcriptase (RT) is a retrovirally encoded enzyme essential for retroviral integration into host DNA. While attempts to detect retroviral infections by measuring RT activity in the peripheral lymphocytes and serum of schizophrenic patients have been unsuccessful, such negative findings may simply mean that the virus is not active in peripheral lymphocytes. A more sensitive and comprehensive approach to detect a retrovirus is to search the genomes of schizophrenic patients directly for the presence of retroviral DNA sequences encoding RT and one possible approach is described. PMID- 8678110 TI - Increased expression of aphidicolin-induced common fragile sites in Tourette syndrome: the key to understand the genetics of comorbid phenotypes? AB - In a comparison of 80 common aphidicolin-induced fragile sites (FS) between 26 DSM-IV Tourette syndrome (TS) and 24 control individuals, the mean of the summed break frequencies following mild aphidicolin pretreatment was significantly higher in TS individuals than in controls (P < 0.001). Other breakpoints encountered during this study, i.e., random breaks, breaks corresponding to rare FS, and breakpoints recorded by others but not listed as common FS according to the Chromosome Coordinating Meeting [1992] were listed as category II breakpoints. By using the most significantly different mean FS breakage figures between TS and control individuals, further stepwise discriminant analysis allowed identification of TS individuals from only a few sites in both the common FS and category II breakpoint groups. Future research needs to focus on confirmation of altered common fragile site expression in association with behavioral variation, whether expression of certain discriminatory sites concurs with specific comorbid disorder expression; the nature of the molecular alterations at these FS and the implications of a genomic instability phenotype for the mapping of a primary TS gene or genes. PMID- 8678111 TI - Common subtypes of idiopathic generalized epilepsies: lack of linkage to D20S19 close to candidate loci (EBN1, EEGV1) on chromosome 20. AB - Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). A trait locus (EBN1) for a rare subtype of IGEs, the benign neonatal familial convulsions, and a susceptibility gene (EEGV1) for the common human low-voltage electroencephalogram have been mapped close together with D20S19 to the chromosomal region 20q13.2. Both loci are potential candidates for the susceptibility to IGE spectra with age-related onset beyond the neonatal period. The present study tested the hypothesis that a putative susceptibility locus linked to D20S19 predisposes to spectra of IGEs with age-related onset from childhood to adolescence. Linkage analyses were conducted in 60 families ascertained through IGE patients with juvenile myoclonic epilepsy, juvenile absence epilepsy or childhood absence epilepsy. Our results provide evidence against linkage of a putative susceptibility gene for four hierarchically broadened IGE spectra with D20S19 assuming tentative single-locus genetic models. The extent of an "exclusion region" (lod scores below-2) varied from 0.5 cM up to 22 cM on either side of D20S19 depending on the trait assumed. These results are contrary to the expectation that a susceptibility gene in vicinity to D20S19 confers a common major gene effect to the expression of IGE spectra with age related onset from childhood to adolescence. PMID- 8678112 TI - A combined analysis of D22S278 marker alleles in affected sib-pairs: support for a susceptibility locus for schizophrenia at chromosome 22q12. Schizophrenia Collaborative Linkage Group (Chromosome 22). AB - Several groups have reported weak evidence for linkage between schizophrenia and genetic markers located on chromosome 22q using the lod score method of analysis. However these findings involved different genetic markers and methods of analysis, and so were not directly comparable. To resolve this issue we have performed a combined analysis of genotypic data from the marker D22S278 in multiply affected schizophrenic families derived from 11 independent research groups worldwide. This marker was chosen because it showed maximum evidence for linkage in three independent datasets (Vallada et al., Am J Med Genet 60:139-146, 1995; Polymeropoulos et al., Neuropsychiatr Genet 54:93-99, 1994; Lasseter et al., Am J Med Genet, 60:172-173, 1995. Using the affected sib-pair method as implemented by the program ESPA, the combined dataset showed 252 alleles shared compared with 188 alleles not share (chi-square 9.31, 1df, P = 0.001) where parental genotype data was completely known. When sib-pairs for whom parental data was assigned according to probability were included the number of alleles shared was 514.1 compared with 437.8 not shared (chi-square 6.12, 1df, P = 0.006). Similar results were obtained when a likelihood ratio method for sib-pair analysis was used. These results indicate that may be a susceptibility locus for schizophrenia at 22q12. PMID- 8678113 TI - Familial risk of psychosis as a function of putative organic etiology in psychotic probands: evaluation of a population-based sample. AB - It is unresolved what, if any, characteristics should be used as a basis for assigning psychotic probands to different liability classes in high density family studies seeking to detect possible genetic linkage. Justification for any such assignments should ideally ensue from empirical evaluation of unselected samples. It has been suggested that the genetic liability of probands with an "organic" psychosis is lower than that found in "primary" cases. Should such cases be assigned differential liabilities in linkage analyses as one way of modeling etiologic heterogeneity? Utilizing data from a population-based family study conducted in County Roscommon in Western Ireland, we examined risk in the relatives of psychotic probands as a function of clinician ratings reflecting the probability that the proband's illness was organic. Contrary to expectation, risk was not significantly lower in relatives of probands whose illness was rated as organic by experienced clinicians. Attempts to identify possible phenocopies of psychosis with a lower familial liability in this treated epidemiologic sample were unsuccessful. PMID- 8678114 TI - Location of the handedness gene on the X and Y chromosomes. AB - Accumulated data from five handedness surveys show that concordance for sex is slightly but reliably higher among siblings of the same handedness than among those of opposite handedness. This is consistent with Crow's theory that the genetic locus for handedness is in an X-Y homologous region of the sex chromosomes. The small size of the effect is predicted from genetic models in which there is a substantial random component underlying phenotypic left handedness. The findings are relevant to the putative role of cerebral asymmetry in the aetiology of psychosis. PMID- 8678115 TI - Psychiatric symptoms and CAG expansion in Huntington's disease. AB - The mutation responsible for Huntington's disease (HD) is an elongated CAG repeat in the coding region of the IT15 gene. A PCR-based test with high sensitivity and accuracy is now available to identify asymptomatic gene carriers and patients. An inverse correlation between CAG copy number and age at disease onset has been found in a large number of affected individuals. The influence of the CAG repeat expansion on other phenotypic manifestations, especially specific psychiatric symptoms has not been studied intensively. In order to elucidate this situation we investigated the relation between CAG copy number and distinct psychiatric phenotypes found in 79 HD-patients. None of the four differentiated categories (personality change, psychosis, depression, and nonspecific alterations) showed significant differences in respect to size of the CAG expansion. In addition, no influence of individual sex on psychiatric presentation could be found. On the other hand in patients with personality changes maternal transmission was significantly more frequent compared with all other groups. Therefore we suggest that clinical severity of psychiatric features in HD is not directly dependent on the size of the dynamic mutation involved. The complex pathogenetic mechanisms leading to psychiatric alterations are still unknown and thus genotyping does not provide information about expected psychiatric symptoms in HD gene carriers. PMID- 8678116 TI - Systematic chromosome examination of two families with schizophrenia and two families with manic depressive illness. AB - Systematic and detailed chromosome analysis, combined with a semistructured interview, was performed in 2 families with schizophrenia and in 2 families with manic depressive illness. Prometaphase technique did not reveal any subtle structural chromosome abnormalities. However, in standard techniques, gain and loss of sex chromosomes were observed. This occurred in patients at a younger age than in unaffected persons. This gives rise to the suspicion that sex chromosome aneuploidy may somehow be related to the development of psychosis. But since the data set is small, especially with respect to schizophrenia, further studies are needed to elucidate this observation. In one family, cosegregation of the disease locus with a marker on chromosome 21 was seen. Therefore, further research should determine if chromosome 21 contains a gene for manic depressive illness. PMID- 8678117 TI - Dopamine D3 receptor gene: organization, transcript variants, and polymorphism associated with schizophrenia. AB - DNA fragments from a genomic library were used to establish the partial structure of the human dopamine D3 receptor gene (DRD3). Its coding sequence contains 6 exons and stretches over 40,000 base pairs. The complete DRD3 transcript and three shorter variants, in which the second and/or third exon are deleted, were detected in similar proportions in brains from four controls and three psychiatric patients. The Msp I polymorphism was localized in the fifth intron of the gene, 40,000 base pairs downstream the Bal I polymorphism and a PCR-based method was developed for genotyping this polymorphism. The distribution of the Msp I and Bal I genotypes were not independent in 297 individuals (chi 2 = 10.5, df = 4, P = 0.03), but only a weak association was found between allele 1 of the Bal I polymorphism and allele 2 of the Msp I polymorphism (chi 2 = 3.99, df = 1, P = 0.04). The previously reported association between homozygosity at both alleles of the Bal I polymorphism and schizophrenia was presently maintained in an extended sample, comprising 119 DSM-III-R chronic schizophrenics and 85 controls (chi 2 = 5.3, df = 1, P = 0.02) and found more important in mal than in females. The presence of the Bal I allele 2 is associated with an early age at onset, particularly in males (df = 35, t value = 2.6, P = 0.014). In the same sample, allelic frequencies, genotype counts, and proportion of homozygotes for the Msp I polymorphism did not differ between schizophrenics and controls (chi 2 = 0.06, df = 1, P = 0.80, chi 2 = 0.22, df = 1, P = 0.90 and chi 2 = 0.16, df = 1, P = 0.69, respectively). The large distance of the Msp I polymorphism from the Bal I polymorphism and its localization in the 3' part of the gene may explain the discrepant results obtained with the two polymorphisms. PMID- 8678118 TI - Segregation analysis of alcoholism in high density families: a replication. AB - We have previously reported segregation analysis of alcoholism in 35 multigenerational families, each ascertained through a pair of male alcoholics by using the mixed model implemented by POINTER. This analysis suggested that liability to alcoholism was, in part, controlled by a major effect with or without additional multifactorial effects. The hypothesis that the major effect was explained by a single genetic locus with strictly mendelian transmission was rejected. The purpose of the present analysis was to use the regressive model implemented by the REGD program from the Statistical Analysis for Genetic Epidemiology computer package (S.A.G.E.) to confirm by replication that a major effect was present in these 35 families. Evidence for the major effect found in Pointer was replicated in the present analysis by using S.A.G.E. Also, we found strong evidence for parental effects that were independent of the major locus transmission from ancestral relatives to children. Mendelian transmission of this major effect was rejected when models incorporated parental effects. When the major effect was calculated adjusting for parental phenotypes, the relative risk of affection for children was about twice as high with affected parents vs. unaffected parents. PMID- 8678119 TI - Facial emotion identification in males with fragile X syndrome. AB - Fifteen postpubertal males with fragile X syndrome (FRA(X)) and 15 non-FRA(X) males matched on IQ and age were assessed for their ability to identify the facially expressed emotions of happiness, sadness, anger, fear, disgust, and surprise. Emotions of happiness and sadness were the easiest to identify for both groups of participants. Regardless of etiology, individuals with higher IQ scores performed better at this task than did individuals with lower IQ scores. Results were consistent with findings in females having the fragile X mutation. The current study supported the notion that FRA(X) individuals are sensitive to facial emotion cues presented by others. This finding is discussed in the context of autism and gaze aversion. PMID- 8678120 TI - Genotype-to-phenotype analysis: search for clinical characteristics of a missense change in the GABAA-beta 1 receptor gene. AB - Genotype-to-phenotype analysis reverses the classical approach to genetic disease in which an unknown genotype is sought for a known phenotype. This paper provides an example of genotype-to-phenotype analysis for the possible psychiatric effects of a missense mutation (H396Q) at a highly conserved residue of the beta 1 subunit gene of the gamma aminobutyric acid type A receptor. DNA samples from 1,507 Caucasians of Western European descent were screened, and 10 heterozygotes for H396Q were identified. These individuals were matched to homozygous normal individuals by age, gender, and length of available medical records. The complete medical records of these 20 individuals were reviewed blindly by two psychiatrists (D.C.S., L.L.H.) to assess psychiatric symptomatology, with an emphasis on anxiety and related disorders. However, no association was found between this missense change at a conserved amino acid and a dominant neuropsychiatric disease phenotype. Thus, this missense change may be neutral or only mildly deleterious, may only cause recessive disease in rare individuals, or may interact epistatically with some other gene(s). PMID- 8678121 TI - Direct detection of expanded trinucleotide repeats using PCR and DNA hybridization techniques. AB - Recently, unstable trinucleotide repeats have been shown to be the etiologic factor in seven neuropsychiatric diseases, and they may play a similar role in other genetic disorders which exhibit genetic anticipation. We have tested one polymerase chain reaction (PCR)-based and two hybridization-based methods for direct detection of unstable DNA expansion in genomic DNA. This technique employs a single primer (asymmetric) PCR using total genomic DNA as a template to efficiently screen for the presence of large trinucleotide repeat expansions. High-stringency Southern blot hybridization with a PCR-generated trinucleotide repeat probe allowed detection of the DNA fragment containing the expansion. Analysis of myotonic dystrophy patients containing different degrees of (CTG)n expansion demonstrated the identification of the site of trinucleotide instability in some affected individuals without any prior information regarding genetic map location. The same probe was used for fluorescent in situ hybridization and several regions of (CTG)n/(CAG)n repeats in the human genome were detected, including the myotonic dystrophy locus on chromosome 19q. Although limited at present to large trinucleotide repeat expansions, these strategies can be applied to directly clone genes involved in disorders caused by large expansions of unstable DNA. PMID- 8678122 TI - Segregation analysis of Alzheimer pedigrees: rare Mendelian dominant mutation(s) explain a minority of early-onset cases. French Alzheimer Collaborative Group. AB - Segregation analysis of Alzheimer disease (AD) in 92 families ascertained through early-onset ( < or = age 60 years) AD (EOAD) probands has been carried out, allowing for a mixture in AD inheritance among probands. The goal was to quantify the proportion of probands that could be explained by autosomal inheritance of a rare disease allele "a" at a Mendelian dominant gene (MDG). Our data provide strong evidence for a mixture of two distributions; AD transmission is fully explained by MDG inheritance in < 20% of probands. Male and female age-of-onset distributions are significantly different for "AA" but not for "aA" subjects. For "aA" subjects the estimated penetrance value was close to 1 by age 60. For "AA" subjects, it reaches, by age 90, 10% (males) and 30% (females). We show a clear cutoff in the posterior probability of being an MDG case. PMID- 8678123 TI - Mutational analysis of the human MAOA gene. AB - The monoamine oxidases (MAO-A and MAO-B) are the enzymes primarily responsible for the degradation of amine neurotransmitters, such as dopamine, norepinephrine, and serotonin. Wide variations in activity of these isozymes have been reported in control humans. The MAOA and MAOB genes are located next to each other in the p11.3-11.4 region of the human X chromosome. Our recent documentation of an MAO-A deficiency state, apparently associated with impulsive aggressive behavior in males, has focused attention of genetic variations in the MAOA gene. In the present study variations in the coding sequence of the MAOA gene were evaluated by RT-PCR, SSCP, and sequencing a mRNA or genomic DNA in 40 control males with > 100-fold variations of MAO-A activity, as measured in cultured skin fibroblasts. Remarkable conservation of the coding sequence was found with only 5 polymorphisms observed. All but one of these were in the third codon position and thus did not alter the deduced amino acid sequence. The one amino acid alteration observed, lys --> arg, was neutral and should not affect the structure of the protein. This study demonstrates high conservation of coding sequence in the human MAOA gene in control males, and provides primer sets which can be used to search genomic DNA for mutations in this gene in males with neuropsychiatric conditions. PMID- 8678124 TI - Relationship between T2-weighted hyperintensities (unidentified bright objects) and lower IQs in children with neurofibromatosis-1. AB - To address the controversy regarding the relationship between cognitive impairment (lowering of IQ) and magnetic resonance imaging (MRI) characteristics (T2-weighted hyperintensities or unidentified bright objects [UBOs]) in children with neurofibromatosis-1 (NF-1), we used a pairwise NF-1/ sibling design; we set out to predict the lowering of IQ in each child with NF-1 as a discrepancy from the IQ of an unaffected sibling (D-SIQ). Our multiple regression model included the age of the child with NF-1, familial or sporadic nature of the NF-1, number of locations in the child's brain occupied by T2-weighted hyperintensities (UBOs), and the volumetric percentage of brain tissue occupied by T2-weighted hyperintensities (UBOs). Only the number of locations occupied by UBOs accounted for IQ lowering (D-SIQ) in children with NF-1 (42% of the variance in D-SIQ). This is the first report to confirm that a continuum of lowered IQs in NF-1 affected children exists in relation to the distribution of UBOs (range 0-7), not just presence (vs. absence) of any UBOs. PMID- 8678125 TI - Use, don't lose, the wind. Presidential address. 62nd annual meeting of the Pacific Coast Obstetrical and Gynecological Society. PMID- 8678126 TI - Office hysteroscopy versus transvaginal ultrasonography in the evaluation of patients with excessive uterine bleeding. AB - OBJECTIVE: Our purpose was to compare office hysteroscopy with transvaginal ultrasonography for diagnosing intrauterine pathologic disorders in patients with excessive uterine bleeding, with specimens obtained from either hysterectomy or operative hysteroscopy used to represent the true diagnosis. STUDY DESIGN: A total of 149 patients underwent office hysteroscopy between July 1993 and December 1994. They were evaluated for complaints of menorrhagia, metrorrhagia, or postmenopausal bleeding. Data encompassing patient age, gravidity, parity, indication, ultrasonographic and hysteroscopic findings, comfort level, time required, and complications were gathered by resident physicians. Most hysteroscopic examinations were preceded by transvaginal ultrasonography. All patients received premedication with 600 mg of ibuprofen and a paracervical block with 1% lidocaine without epinephrine. Sixty-five patients underwent operative hysteroscopy or hysterectomy later. The pathologic diagnoses of these specimens were compared with hysteroscopic and ultrasonographic findings, and the sensitivity and specificity of each test were calculated. RESULTS: Hysteroscopy was 79% sensitive and 93% specific in diagnosing intracavitary pathologic disorders, whereas transvaginal ultrasonography was only 54% sensitive and 90% specific. One hundred forty-one patients were comfortable during the procedure, and inspection of the uterine cavity was considered adequate in 136. The majority of procedures were completed in <10 minutes. Twenty-six patients underwent operative hysteroscopy and another 39 underwent hysterectomy. No patient who underwent operative hysteroscopy has had a recurrence of abnormal bleeding over a 12- to 30-month follow-up. CONCLUSION: Office hysteroscopy is a rapid, safe, well tolerated, and highly accurate means of diagnosing the cause of excessive uterine bleeding. It permits patient and physician to discuss more treatment options before surgery, including outpatient operative hysteroscopic procedures. This means savings in time and in drug, procedure, professional, and hospital costs. PMID- 8678127 TI - Reliability of multimodal evaluation of abnormal screening mammogram results. AB - OBJECTIVE: Our purpose was to evaluate the effectiveness and reliability of the multimodal evaluation of suspicious or equivocal screening mammogram results by use of ancillary imaging studies and needle biopsies. STUDY DESIGN: This article reports on the experience of the Breast Evaluation Center at Long Beach Memorial Medical Center between 1989 and 1993 where 43,125 screening mammograms were performed. RESULTS: A total of 2866 patients were called back for additional evaluation, which consisted of magnification views and ultrasonography. Since 1990 fine-needle biopsies have been done on selected patients and since 1992 core biopsies have been available. Needle localization excisional biopsies were performed on 344 patients, and 158 cancers were diagnosed. This represents a 46% positive predictive value. Careful follow-up was obtained on the patients seen in 1990 to attempt to determine whether any cancers developed within a year of the time the patients with abnormal screening mammogram results had been evaluated with imaging modalities but no tissue diagnosis made. One cancer may have been missed. The cost savings of this protocol are also examined. CONCLUSION: Multimodal evaluation of patients with suspicious screening mammogram results appears to be a cost effective approach with adequate sensitivity and specificity. PMID- 8678128 TI - Phase II study of high-dose cisplatin, etoposide, and cyclophosphamide for refractory ovarian cancer. AB - OBJECTIVES: A phase II trial of high-dose cyclophosphamide, etoposide, and cisplatin was done. STUDY DESIGN: Forty-eight patients with progressive or persistent disease and previous cisplatin-based chemotherapy and no paclitaxel therapy were entered for treatment on the basis of two cycles of cyclophosphamide (4500 mg/m2), etoposide (750 mg/m2), and cisplatin (120 mg/m2). RESULT: Seventy four cycles were delivered. Six patients died during treatment (12.5%). Of 28 with measurable disease, there was a 25% response rate and 32% had stable disease. Median time to recurrence and survival were significantly different for minimal versus bulky disease (p = 0.0089, p = 0.0008, log rank) and for platinum sensitive versus platinum-resistant disease (p = 0.18, p = 0.0012, log-rank). The number of prior regimens was not correlated with time to progression or survival. CONCLUSION: This study shows little advantage for high-dose protocols except for patients with a response to platinating agents and minimal residual disease. PMID- 8678129 TI - Conservative management of options for patients with dysplasia involving endocervical margins of cervical cone biopsy specimens. AB - OBJECTIVE: Our purpose was to study the feasibility of conservatively managing selected cases of dysplasia involving endocervical cone margins. STUDY DESIGN: A retrospective review of patients conservatively managed after being found to have squamous cell dysplasia involving the endocervical margins of their cervical cone biopsy specimens. In phase I patients who had cold-knife conization with positive endocervical margins underwent repeat Papanicolaou smears and colposcopy, with biopsies and endocervical curettage as indicated. Those found free of disease were followed up with frequent Papanicolaou smears. In phase II patients with dysplasia to the endocervical resection edges on loop electrical excision procedure biopsy specimens were followed up with frequent cytologic studies. RESULTS: In phase I, 31 patients with positive endocervical margins on cold-knife conization and no evidence of dysplasia on reevaluation were followed up for 1 to 18 years. Dysplasia was detected in one patient during cytologic surveillance. In phase II, 11 patients were followed up for 12 to 31 months; only one patient has dysplasia. CONCLUSION: Selected patients with squamous cell dysplasia at endocervical cone biopsy margins may avoid additional surgery. PMID- 8678130 TI - Simplified surgical revision of the vulvar vestibule for vulvar vestibulitis. AB - OBJECTIVE: The prototype of surgical treatment for vulvar vestibulitis has been the Woodruff vulvoplasty. A simpler surgery could be less morbid, technically easier, and equally effective. STUDY DESIGN: Twelve patients underwent vestibular revision, nine with local anesthesia. They were followed up for between 6 months and 6 years. Outcome was judged by ease of healing and relief of tenderness. This was a feasibility study. RESULTS: Ten of 12 patients had complete resolution of vestibulitis. Two others had improvement. Other causes of dyspareunia remain in 2 subjects. Issues of patient histories, postoperative healing, and functional outcome are reported. CONCLUSION: A simple surgery seems well suited to this problem. Additional causes of dyspareunia need to be recognized preoperatively and clarified. Development of granulation tissue in areas of wound separation can create sites of continued pain. Postoperatively, reflex vaginismus should be expected and needs therapy to complement the surgical treatment. PMID- 8678131 TI - Effects of estrogen and progestin on aortic size and compliance in postmenopausal women. AB - OBJECTIVE: Our purpose was to determine whether sex steroids alter aortic size and compliance in postmenopausal women. STUDY DESIGN: Twenty-six postmenopausal women were randomized to receive either conjugated estrogens 0.625 mg per day (group 1) or conjugated estrogens 0.625 mg per day and medroxyprogesterone 2.5 mg per day (group 2). Aortic cross-sectional area was measured by magnetic resonance imaging before and after 3 months of hormone therapy. RESULTS: Estradiol levels increased in both group 1 and group 2 (p < 0.0001). Ascending aortic cross sectional area increased from 439 +/- 7 mm2 to 466 +/- 7 mm2 in group 1 (p < 0.008) but was unchanged in group 2. Within the range of aortic pressures studied, no change in aortic compliance could be detected. CONCLUSION: Estrogen therapy in postmenopausal women was associated with an increase in aortic size; but this effect was not detectable with the addition of progestin. The potential antagonistic effect of progestin on estrogen-induced aortic enlargement suggests that the favorable cardiovascular effects of postmenopausal estrogen therapy cannot be automatically extended to the combination estrogen-progestin. PMID- 8678132 TI - Gestational diabetes: a triage model of care for rural perinatal providers. AB - OBJECTIVE: Our purpose was to develop a protocol for surveillance, diagnosis, and management of diet-controlled gestational diabetes for rural care providers. STUDY DESIGN: Protocols for medical, nutritional, educational, and psychosocial education and treatment were developed. Data were collected on maternal-fetal outcome, birth weight, and provider time specific for diabetes. A diabetes educator, registered dietitian, and social worker provided protocol training on site to rural providers. A control group had multidisciplinary care according to California Diabetes and Pregnancy Program protocols. RESULTS: No significant difference in outcome between 39 protocol patients and 48 controls was noted except in time spent for diabetes care. The pilot providers averaged 4.3 hours and control providers 5.6 hours. CONCLUSIONS: With appropriate protocols, rural providers can successfully treat diet-controlled gestational diabetes without a multidisciplinary team. This could extend the outreach of California Diabetes and Pregnancy Programs and potentially reduce costs. PMID- 8678133 TI - Fetal and maternal endocrine responses to experimental intrauterine infection in rhesus monkeys. AB - OBJECTIVE: Our purpose was to describe the temporal and quantitative relationships among intrauterine infection, fetal-placental steroid biosynthesis, and preterm labor in a nonhuman primate model. STUDY DESIGN: On approximately day 130 of gestation (term 167 days) chronically instrumented rhesus monkeys (Macaca mulatta) were infected with 10(6) colony-forming units of group B streptococci either by intraamniotic (n = 4) or choriodecidual (n = 2) inoculation. As controls, four additionally chronically instrumented noninfected monkeys were followed up to spontaneous parturition. Amniotic fluid and maternal and fetal arterial blood were serially sampled in all monkeys (both before and after infection) for progesterone, estrone, estradiol, dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and cortisol by specific radioimmunoassays, and uterine activity was continuously recorded. RESULTS: Spontaneous parturition was preceded by gradual and significant increases in the plasma concentrations of fetal dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione and fetal and maternal levels of estrone, estradiol, and progesterone but not by changes in cortisol. In contrast, infection associated parturition (either intraamniotic or choriodecidual) was characterized by abrupt increases in fetal dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, progesterone, and cortisol but not by increases in maternal or fetal estrone or estradiol. Infection-associated steroid changes occurred concurrently with or after increases in uterine activity. CONCLUSION: Infection-associated preterm parturition is associated with dramatic increases in fetal adrenal steroid biosynthesis but not by corresponding increases in placental estrogen biosynthesis. This suggests that fetal stress in accompanied by placental dysfunction and that infection-associated parturition is not dependent on the increased estrogen biosynthesis observed in spontaneous parturition. PMID- 8678134 TI - The effect of thigh-length support stockings on the hemodynamic response to ambulation in pregnancy. AB - OBJECTIVE: Our purpose was to determine the effect of thigh-length support stockings on hemodynamic response when pregnant subjects change from the sitting to the lateral recumbent position and then after standing with ambulation. STUDY DESIGN: Eighteen subjects in the late second and early third trimester of pregnancy acted as their own controls. The cardiovascular status of the subjects was assessed by a noninvasive technique--thoracic electrical bioimpedance before and after wearing support stockings for 1 week. Urine catecholamines were measured in 13 patients before and after wearing support stocking to assess the release of catecholamines. Samples were collected after the subjects had been in the lateral recumbent position 40 minutes and again 40 minutes later after standing with ambulation. RESULTS: Heart rate and mean arterial blood pressure decreased significantly when subjects changed from the sitting to the lateral recumbent position and then increased with ambulation. Wearing compression stockings significantly increased mean arterial pressure and afterload in all three positions. Position change from lateral recumbent to standing and ambulation marginally increased urinary dopamine levels (p = 0.097) and significantly increased norepinephrine levels (p = 0.006). CONCLUSIONS: There are significant hemodynamic changes in pregnant subjects when they change from the sitting position to the lateral recumbent position and then change to standing with ambulation. Support stocking have a significant mechanical effect: they significantly increase afterload and systemic vascular resistance by preventing pooling of blood in the lower extremities. There may also be a biochemical effect that results in less catecholamine release. These results suggest that compression stockings could play an important role in supporting the circulation during ambulation. PMID- 8678135 TI - Head entrapment and neonatal outcome by mode of delivery in breech deliveries from 28 to 36 weeks of gestation. AB - OBJECTIVES: We attempted to determine whether there are differences in the incidence of head entrapment and adverse neonatal outcome by mode of delivery in breech deliveries from 28 to 36 weeks of gestation. STUDY DESIGN: Computerized data and charts of 321 viable consecutive singleton breech deliveries from 28 to 36 weeks' gestation were reviewed. Statistical methods used included chi2, logistic regression, and analysis of variance. RESULTS: Head entrapment occurred in 4 of 52 (7.7%) neonates delivered vaginally and 14 of 269 (5.2%) neonates delivered by cesarean section (p = 0.48). There were no statistically significant associations between head entrapment and adverse neonatal outcomes. CONCLUSIONS: There was no significant difference in the incidence of head entrapment by mode of delivery for breech infants at 28 to 36 weeks' gestation, nor was there an association with adverse neonatal outcomes after entrapment. PMID- 8678136 TI - Physician attitudes toward human immunodeficiency virus testing in pregnancy. AB - OBJECTIVE: Our purpose was to determine physician attitudes regarding voluntary versus mandatory status of human immunodeficiency virus testing in pregnant women. STUDY DESIGN: A questionnaire was sent to a sampling of the membership in District IX of The American College of Obstetricians and Gynecologists. Members were queried about experience with pregnant patients who were human immunodeficiency virus positive. Practice characteristics were sampled, as were experiences with antiviral agents in pregnant women. RESULTS: Physician attitudes were influenced by their type of medical practice environment. Bioethical considerations were further influenced by data reflecting zidovudine use in pregnant women. Two thirds of respondents favored mandatory human immunodeficiency virus testing of all pregnant patients. More than 90% favored public health reporting of all human immunodeficiency virus-positive patients. One quarter of respondents were not current on California human immunodeficiency virus codes. A persistent percentage do not offer human immunodeficiency virus counseling or testing. CONCLUSION: Considerable physician support exists for mandating human immunodeficiency virus testing in all pregnant patients as the primary means of decreasing maternal-fetal human immunodeficiency virus transmission and the considerable resulting costs. PMID- 8678137 TI - Microendoscopic surgery: a comparison of four microendoscopes and a review of the literature. AB - OBJECTIVE: Our purpose was to compare four microendoscopes to evaluate their clinical and cost effectiveness. STUDY DESIGN: The experience of 27 patients scheduled for diagnostic or minor operative procedures is reported. All patients had microendoscopic laparoscopy performed using the Medical Dynamics optical catheter (Englewood, Col.), the Origin Pixie microendoscope (Menlo Park, Calif.), the Imagyn Microlap (Laguna Niquel, Calif.), or the Karl Storz microendoscope (Culver City, Calif.). A 5 mm conventional laparoscope was used when visualization was inadequate. RESULTS: Thirteen patients had tubal sterilization. Fourteen patients had diagnostic laparoscopy. For 22 patients the microendoscopes were adequate. The remaining 5 patients required the use of a 5 mm laparoscope to complete the procedure. Among the microendoscopes, the Imagyn Microlap was considered to have the best combination of field of vision, clinical adaptability, ease of operation, mode of sterilization, and operating cost. The 5 mm endoscope provided the best visualization at the lowest overall cost. CONCLUSION: Microendoscopes are adequate for diagnostic and minor operative procedures. The 5 mm endoscope is the most clinically cost effective. PMID- 8678138 TI - Laparoscopic radical hysterectomy (type III) with aortic and pelvic lymphadenectomy. AB - OBJECTIVE: The purpose of this study was to incorporate a wide range of operative laparoscopic techniques to complete a type III radical hysterectomy with aortic and pelvic lymphadenectomy. STUDY DESIGN: A type III radical hysterectomy with bilateral aortic and pelvic lymph node dissection was separated into eight component parts: (1) right and left aortic lymphadenectomy, (2) right and left pelvic lymphadenectomy, (3) development of the paravesical and pararectal spaces, (4) ureteral dissection, (5) ligation and dissection of the uterine artery, (6) development of the vesicouterine and rectovaginal spaces, (7) resection of the parametria, and (8) resection of the upper vagina. The adequacy of the component parts was determined and documented on video. RESULTS: Complete aortic and pelvic lymphadenectomy and a type III radical hysterectomy were performed by operative laparoscopy. Argon beam coagulation and countertraction facilitated pelvic and aortic lymph node dissection, including removal of nodal tissue lateral to the iliac vessels. Ureteral dissection with resection of the cervicovesical fascia ("the tunnel") was completed with right-angle dissectors, vascular clips, and argon-beam coagulation. Resection of the cardinal and ureterosacral ligaments was successful by use of Endo-GIA stapling instruments (United States Surgical Corporation, Norwalk, Ct.). CONCLUSION: A complete pelvic and aortic lymphadenectomy and type III radical hysterectomy were performed laparoscopically. This approach could potentially decrease morbidity historically associated with radical hysterectomy and lymphadenectomy performed either abdominally or vaginally. Only prospective randomized trails will allow for the evaluation of potential benefits associated with this surgical technique. PMID- 8678139 TI - Lumbosacral plexopathy after gynecologic surgery: case report and review of the literature. AB - Very unusual lumbosacral plexopathy, symptoms appearing after an uncomplicated abdominal hysterectomy prompted a review of the literature. The patient's symptoms spanned the somatic and autonomic systems and ranged from T-11 to S-4; a cause that would explain these is perplexing. Pelvic neuroanatomy and plexopathy symptoms are presented. Etiologies of neurologic symptoms are discussed and preventive strategies are explored. PMID- 8678140 TI - The effect of peritoneal fluid from patients with endometriosis on human sperm function in vitro. AB - OBJECTIVE: Our purpose was to evaluate the effect of peritoneal fluid from women with endometriosis on sperm motility and function in an in vitro model. STUDY DESIGN: Peritoneal fluid was collected at laparoscopy from patients with and without endometriosis. Human donor sperm was diluted with this fluid, and its effect on sperm function and motility was measured was measured with the zona free hamster egg sperm penetration assay and computer-assisted semen analysis. RESULTS: The mean number of eggs penetrated by the sperm mixed with peritoneal fluid from patients with endometriosis was significantly fewer than the number penetrated by the sperm mixed with fluid from control patients (22.9 +/- 5.31 vs 44.4 +/- 4.96, p < 0.01, Student t test, n = 20). When evaluated by computer assisted semen analysis, sperm mixed with peritoneal fluid from patients with endometriosis showed a significant decrease in mean swimming velocity compared with sperm mixed with peritoneal fluid from control patients (54.0 +/- 1.77 vs 59.2 +/- 1.05, p = 0.02, Student t test, n = 20). A significant increase in the fraction of sperm swimming at slower velocities was also found. A trend toward a positive correlation between eggs penetrated and sperm velocity was seen, but statistical significance was not achieved (correlation coefficient 0.4392, p = 0.053, n = 20). CONCLUSION: These data suggest that substances found in the peritoneal fluid of patients with endometriosis could contribute to infertility through impairment of both sperm function and motion kinematics. PMID- 8678141 TI - Depth of endometrial penetration in adenomyosis helps determine outcome of rollerball ablation. AB - OBJECTIVE: Our purpose was to determine whether the depth of endometrial penetration into the myometrium correlates with outcome of rollerball endometrial ablation. STUDY DESIGN: Fifty consecutive patients with hysteroscopically normal appearing cavities (without gross polyps or submucous fibroids) had endometrial ablations for menorrhagia and were subsequently studied for > or = 3.5 years. A posterior myometrial biopsy to determine the amount of endometrial penetration was performed and correlated with outcome. RESULTS: Patients with deep endometrial penetration into the myometrium (deep adenomyosis) had poor outcomes after ablation. Those with no or minimal endometrial penetration (superficial adenomyosis) had good results with few exceptions. CONCLUSION: A myometrial biopsy specimen at the time of operative hysteroscopy can diagnose adenomyosis and help predict outcome after rollerball endometrial ablation. Superficial adenomyosis can be treated definitively with ablation. Deep adenomyosis responds poorly to ablation. Hysterectomy should be considered when myometrial biopsy, preoperative ultrasonography, or magnetic resonance imaging demonstrates deep adenomyosis. PMID- 8678142 TI - Cost and quality-of-life analyses of surgery for early endometrial cancer: laparotomy versus laparoscopy. AB - OBJECTIVE: The purpose of this study was to determine whether the cost or quality of life associated with surgical treatment of presumed early-stage endometrial cancer differed on the basis of the surgical approach. STUDY DESIGN: A retrospective analysis was performed on a consecutive series of women with presumed early-stage endometrial cancer treated at the Women's Cancer Center of Northern California. The senior author was the surgeon, cosurgeon, or assistant on all cases. The women comprise two groups with different surgical approaches. The first group of 17 women underwent exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and aortic lymphadenectomy. The second group of 13 women underwent the same surgery by laparoscopy. The two groups were compared with a two-tailed Student t test. Variables analyzed included age, height, weight, Quetelet index, and predisposing medical problems. Lymph node counts were compiled. Hospital costs were broken down into four cost categories: (1) operating room, (2) hospital bed, (3) pharmacy, and (4) anesthesia. A two-tailed Student t test was also used in this analysis. Issues examined regarding quality of life included (1) average hospital stay, (2) complications, and (3) time to return to normal activity. RESULTS: The patient population differed significantly (p < 0.05) with regard to weight and Quetelet index. The laparotomy group required significantly longer hospitalization than the laparoscopy group (6.3 vs 2.4 days, p < 0.001), resulting in higher overall hospital costs ($19,158 vs $13,988, p < 0.05). Similarly, patients undergoing laparotomy took longer to return to normal activity (5.3 weeks vs 2.4 weeks, p < 0.0001). CONCLUSION: Laparoscopic management of endometrial cancer may result in significant cost savings and improved quality of life as demonstrated by shortened hospital stays and an earlier return to normal activity. PMID- 8678143 TI - Droperidol and diphenhydramine in the management of hyperemesis gravidarum. AB - OBJECTIVE: Hyperemesis gravidarum is a common pregnancy complication requiring hospitalization. Continuous droperidol infusion and bolus intravenous diphenhydramine were instituted as treatment. We compared the number and length of hospitalizations for hyperemesis gravidarum, readmissions for this diagnosis, and pregnancy outcome in patients receiving this treatment protocol with a historic group of patients receiving other forms of parenteral therapy for hyperemesis gravidarum. STUDY DESIGN: All patients hospitalized with a diagnosis of hyperemesis gravidarum between January 1992 and January 1994 were offered the droperidol-diphenhydramine protocol. These patients were compared with patients admitted between January 1990 and January 1992 with a diagnosis of hyperemesis gravidarum but who were not treated with droperidol at any time or with diphenhydramine as primary therapy for the control of severe nausea and vomiting. Data regarding the number and length of hospitalizations and readmissions for hyperemesis gravidarum were compared, as were maternal and perinatal outcomes. RESULTS: Patients treated with the droperidol-diphenhydramine protocol had significantly shorter hospitalizations (3.1 +/- 1.9 vs 3.8 +/- 2.4 days, p = 0.028), fewer days per pregnancy hospitalized for hyperemesis (3.5 +/- 2.3 days vs 4.8 +/- 4.3 days, p = 0.018), and fewer readmissions with this diagnosis (15.0% vs 31.5%, p = 0.015). There were no significant differences in maternal or perinatal outcomes. CONCLUSION: Droperidol and diphenhydramine infusion is a beneficial, cost-effective therapy for the treatment of hyperemesis gravidarum. PMID- 8678145 TI - A knee in the back and a little balsam of Peru. Presidential address. 63rd annual meeting of the Central Association of Obstetricians and Gynecologists. PMID- 8678144 TI - Umbilical cord blood acid-base state: what is normal? AB - OBJECTIVE: Umbilical cord blood gases and acid-base data from vigorous neonates were examined to determine normal values and ranges. STUDY DESIGN: The University of California, San Francisco, Perinatal Data Base was used to retrieve information from deliveries between 1977 and 1993. Newborns with 5-minute Apgar scores > or = 7 were selected because it is generally accepted that a vigorous newborn has not had substantial intrapartum asphyxia lasting until delivery. RESULTS: Full blood gas and obstetric data were available for 16,060 newborns. Of these, 15,073 (94%) had a 5-minute Apgar score > or = 7. The median umbilical artery values, with 2.5th percentile values in parenthesis, were pH 7.26 (7.10), PCO2 52 mm Hg (74), base excess -4 mEq x L(-1) (-11), and PO2 177 mm Hg (6). Although the distributions were skewed, the mean +/- 2 SDs were similar to these values. Data for these babies were further analyzed by method of delivery, gestational age, presentation, and presence of thick meconium. Although the means were significantly different in all groups, the differences between groups were relatively small. CONCLUSION: A wide range of acid-base values were found in babies with normal Apgar scores, defining the "physiologic acidemia" of the normal vigorous newborn. PMID- 8678146 TI - Hepatic imaging in HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count). AB - OBJECTIVES: Our objective was to describe the hepatic imaging findings in selected patients with HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) and to correlate these findings with the severity of concurrent clinical and laboratory abnormalities. STUDY DESIGN: Patients with laboratory criteria for HELLP syndrome with complaints of severe right upper quadrant abdominal pain in association with either shoulder pain, neck pain, or relapsing hypotension underwent imaging of the liver. Clinical and laboratory parameters were then correlated with the hepatic imaging findings. RESULTS: Thirty-four patients were evaluated in this study. Computed tomographic scanning of the liver was used for 33 patients. Additional imaging evaluations included magnetic resonance imaging for 4 patients and ultrasonographic evaluation of the liver for 5 patients. In 15 cases (45%) the computed tomographic results were abnormal. The most frequent abnormal hepatic imaging findings were subcapsular hematoma (n = 13) and intraparenchymal hemorrhage (n = 6). There was no statistically significant correlation between the presence of an abnormal hepatic imaging finding and the severity of liver function test abnormalities. However, the severity of thrombocytopenia did correlate with hepatic imaging findings (p = 0.04). In particular, an abnormal hepatic imaging finding was noted for 10 of 13 patients (77%) with a platelet count of < or = 20 x 10(9)/L (p = 0.012). CONCLUSIONS: Abnormalities in liver function test results do not accurately reflect the presence of abnormal hepatic imaging findings in HELLP syndrome. Patients with HELLP syndrome having complaints of right upper quadrant pain and neck pain, shoulder pain, or relapsing hypotension should undergo imaging of the liver. PMID- 8678147 TI - The use of power Doppler and color power angiography in fetal imaging. AB - OBJECTIVE: The potential usefulness of a new color Doppler ultrasonography technique called color power angiography in imaging fetal anatomy is presented. STUDY DESIGN: An ultrasonography system set on color power angiography was used to image fetal anatomy. Perfusion of normal organs was compared, with several fetuses demonstrating pathologic disorders of these organ systems. Color power angiography was compared with standard color Doppler imaging. RESULTS: We were able to demonstrate detailed imaging of the fetal vasculature in the lung, kidney, and brain. Abnormal lung and renal anatomy could be visualized by the distinctive perfusion "footprint." Fetal movement compromised the ability of color power angiography to visualize these structures but could be overcome by judicious use of the cineloop and persistence functions. Color power angiography was found to be more sensitive to low-flow states than was Doppler imaging. CONCLUSION: Color power angiography, which is more sensitive to low-flow states than color Doppler imaging is, may be useful in the imaging of normal and abnormal fetal anatomic structures. PMID- 8678148 TI - The significance of ultrasonographically diagnosed fetal wrist position anomalies. AB - OBJECTIVE: Our purpose was to determine the clinical significance of ultrasonographically diagnosed fetal wrist position anomalies. STUDY DESIGN: The relationship of the fetal hand to the forearm was prospectively evaluated in all second- and third-trimester scans over a 5-year period. If an abnormal wrist position was detected, a targeted scan, including echocardiography, was performed. The outcomes of abnormal pregnancies were obtained. RESULTS: An abnormal relationship of the hand to the forearm was found in 22 fetuses in 27,467 scans. Nine had a normal karyotype, and 13 had an abnormal karyotype. Among the nine with normal chromosomes, three had evidence of a movement disorder. Three with normal karyotypes are alive; two of these are the only normally functioning survivors. They had no other major anomalies and were shown prenatally to have normal movement of the limbs. CONCLUSIONS: An abnormal fetal wrist position is associated with a high incidence of karyotype and movement abnormalities. PMID- 8678149 TI - Single-dose methotrexate for the treatment of ectopic pregnancy: Northwestern Memorial Hospital three-year experience. AB - OBJECTIVE: Our purpose was to evaluate the effectiveness of single-dose intramuscular methotrexate in the treatment of ectopic pregnancies by physicians in the Department of Obstetrics and Gynecology of Northwestern Memorial Hospital and to compare the results with those of previously published studies. STUDY DESIGN: A retrospective chart review was performed of 50 patients with ectopic pregnancies treated with single-dose methotrexate according to the protocol of Stovall et al. from January 1992 to February 1995. RESULTS: The mean pretreatment level of beta-human chorionic gonadotropin was 1896.4 +/- 2399 mlU/ml. Only 32 women (64%) were successfully treated with a single dose of methotrexate. An additional 7 women required a second or third injection. The combined success rate for medical management of ectopic pregnancy with one to three doses of methotrexate was 78% (39 women). Pretreatment beta-human chorionic gonadotropin levels were significantly lower in women who responded to single-dose therapy than in those who required either two or three doses or who had failure of medical management (p = 0.0011). The mean time to resolution of beta-human chorionic gonadotropin was 26.5 +/- 17 days. Higher pretreatment levels correlated with longer resolution time (r = 0.83, p < 0.001). Eleven women (22%) with failure of medical management required surgery. CONCLUSIONS: In our series single-dose methotrexate was only 64% successful. Women with a pretreatment beta human chorionic gonadotropin level >5000 mlU/ml had a greater probability of requiring either surgical intervention or multiple doses of methotrexate. The potential for emergency surgery remains an important risk. PMID- 8678150 TI - Prenatal paternity testing with deoxyribonucleic acid techniques. AB - OBJECTIVES: Our purpose was to determine the feasibility and optimal techniques for prenatal paternity testing. STUDY DESIGN: Since January 1989 we have offered prenatal paternity testing by deoxyribonucleic acid testing. We analyzed the ability to complete the testing and the time required to complete the testing and developed polymerase chain reaction-based tests to speed test results. RESULTS: Before April 1990 only five of nine cases could be completed. Since that time 28 consecutive cases were successfully completed before delivery. Introduction of polymerase chain reaction-based testing has allowed us to perform testing on uncultured chorionic villi and to derive results within 3 weeks. CONCLUSION: Analysis of uncultured chorionic villi allows prenatal paternity testing to be completed within the first trimester of pregnancy. Prenatal paternity testing can also be performed on cultured amniocytes and chorionic villi. PMID- 8678151 TI - Inflammatory cytokine (interleukins 1, 6 and 8 and tumor necrosis factor-alpha) release from cultured human fetal membranes in response to endotoxic lipopolysaccharide mirrors amniotic fluid concentrations. AB - OBJECTIVE: This study was conducted to quantitate and compare the amount of cytokines released from human fetal membranes in response to treatment with bacterial lipopolysaccharide and to compare this with amniotic fluid levels. STUDY DESIGN: Amniochorionic membranes were collected from women undergoing elective repeat cesarean section and showing no signs of infection- or pregnancy related complications. Membranes were maintained in an organ explant system and stimulated with bacterial lipopolysaccharide for 24 hours. Media samples were collected and stored at -20 degrees C until cytokine levels were assayed by enzyme-linked immunosorbent assay. RESULTS: Enzyme-linked immunosorbent assay results demonstrated that lipopolysaccharide stimulated production of interleukins 1, 6 and 8 and tumor necrosis factor-alpha by the fetal membranes in comparison with the control cultures. A greater release of interleukin-6 and interleukin-8 compared with interleukin-1 and tumor necrosis factor-alpha was noticed. The relationships between cytokine concentrations observed in culture mirror those seen in amniotic fluid. CONCLUSION: Amniochorionic membranes can respond to an infectious process with increased secretion of interleukins 1, 6 and 8 and tumor necrosis factor-alpha. Cytokines produced from both amnion and chorion (interleukin-6 and interleukin-8) are released in greater quantities than those cytokines produced from chorion or amnion alone (interleukin-1 and tumor necrosis factor-alpha). These studies support a major role for amnion in infection-induced preterm labor. PMID- 8678152 TI - Anterior vaginal wall culdeplasty at vaginal hysterectomy to prevent posthysterectomy anterior vaginal wall prolapse. AB - OBJECTIVE: The purpose of our study was to evaluate a surgical technique we have developed that, when used at vaginal hysterectomy, helps prevent posthysterectomy anterior vaginal segment (wall) prolapse. STUDY DESIGN: This modified surgical procedure was used in 966 consecutive vaginal hysterectomies performed from January 1989 through December 1994. Patients returned at 1, 3, and 12 months and annually thereafter for follow-up. The longest follow-up period to date is 5.5 years. RESULTS: Of the 925 patients in our study followed up for > or = 1 year, 908 (98.1%) retained excellent anterior vaginal support. Symptomatic anterior vaginal segment prolapse occurred in 12 patients (1.3%), and asymptomatic prolapse, with the anterior vaginal wall descending less than halfway from the ischial spines to the hymen, occurred in 5 (0.5%). None of the 42 patients followed up for <1 year has had evidence of prolapse. CONCLUSION: This procedure is an acceptable method to help prevent posthysterectomy anterior vaginal segment prolapse. PMID- 8678153 TI - Trauma in pregnancy: the role of interpersonal violence. AB - OBJECTIVE: Our purpose was to determine what role interpersonal violence as intentional injury plays in the pregnant trauma victim. STUDY DESIGN: We performed a retrospective review of medical records. RESULTS: During a 9-year period in a single university medical and trauma center, 203 pregnant women were treated for a physically traumatic event. Sixty-four women (31.5%) were victims of intentional injury, in most cases by the husband or boyfriend. Although the mean Injury Severity Score was higher in women with fetal death than in women with successful pregnancy outcomes (7.25 vs 1.74, respectively; p < 0.01), 5 of the 8 women with fetal losses incurred these despite an apparent absence of physical injury (maternal Injury Severity Score = 0). CONCLUSIONS: Interpersonal violence during pregnancy is a frequent and increasingly common cause of maternal injury. The inconsistent relationship between Injury Severity Score and serious fetal injury or death is underscored by the loss of 5 fetuses despite an Injury Severity Score of 0. PMID- 8678154 TI - Angiogenesis factor in endometrial carcinoma: a new prognostic indicator? AB - OBJECTIVE: Tumor angiogenesis is believed to be a prognostic indicator associated with tumor growth and metastasis. Studies of angiogenesis in breast, prostate, and lung cancer, as well as melanoma, have shown that neovascularization correlates with the likelihood of metastasis and recurrences. The purpose of this study was to evaluate microvessel density as a prognostic factor in endometrial cancer. METHODS: Between 1980 and 1991 the tumor registry identified 25 patients with a diagnosis of recurrent endometrial cancer. These patients were matched with 25 patients with nonrecurrent disease for age, stage, grade, and treatment. The histologic slides of the 50 patients were reviewed. The paraffin blocks were obtained, and the area of the deepest myometrial invasion was selected for staining. The microvessels within the invasive cancer were highlighted by means of immunocytochemical staining to detect factor VIII-related antigen. Microvessels were counted by two investigators who were blinded to the patients' clinical status. Survival data were analyzed with Kaplan-Meier survival curves. RESULTS: Microvessel count was related to likelihood of recurrence, although this trend did not reach statistical significance. Patients with tumors of low capillary density had a mean survival time of 123 months. Patients with tumors of high capillary density had a mean survival time of 75 months (p = 0.02). Among patients with recurrent disease, those with a low capillary count survived a mean of 64 months. Patients with recurrent disease with tumors of high capillary density survived a mean of 45 months (p = 0.002). CONCLUSION: Angiogenesis factor correlates with survival in endometrial carcinoma. PMID- 8678156 TI - Etiology and outcome of extremely low-birth-weight infants. AB - OBJECTIVE: Our purpose was to determine whether the reason for delivery of extremely low-birth-weight infants influenced the immediate neonatal outcome. STUDY DESIGN: At a regional perinatal center a retrospective analysis of 111 neonates with birth weights between 500 and 800 gm and their respective mothers was performed. The mother-infant pairs were grouped according to the reason for delivery. Group 1 included those with idiopathic preterm labor. Group 2 included mothers with preterm rupture of membranes. Group 3 included those delivered for maternal or fetal indications. Group 4 included all multiple gestations. Maternal, intrapartum, and neonatal outcome variables were then evaluated for statistical significance by analysis of variance and chi2 methods and a p value of 0.05. RESULTS: The neonatal outcome variables (survival and incidence of major intraventricular hemorrhage, hyaline membrane disease, and fetal sepsis) were not found to be significantly different among the four groups tested. CONCLUSION: The reason for the delivery of extremely low-birth-weight infants does not have an impact on the immediate neonatal outcome in these neonates. PMID- 8678155 TI - The preterm prediction study: a clinical risk assessment system. AB - OBJECTIVE: Our aims were to develop a risk assessment system for the prediction of spontaneous preterm delivery using clinical information available at 23 to 24 weeks' gestation and to determine the predictive value of such a system. STUDY DESIGN: A total of 2929 women were evaluated between 23 and 24 weeks' gestation at 10 centers. Demographic factors, socioeconomic status, home and work environment, drug and alcohol use, and medical history were evaluated. Information regarding symptoms, cultures, and treatments in the current pregnancy were ascertained. Anthropomorphic and cervical examinations were performed. Univariate analysis and multivariate logistic regression were performed in a random selection, constituting 85% of the study population. The derived risk assessment system was applied to the remaining 15% of the population to evaluate its validity. RESULTS: A total of 10.4% of women were delivered of preterm infants. The multivariate models for spontaneous preterm delivery were highly associated with spontaneous preterm delivery (p < 0.0001). A low body mass index (<19.8) and increasing Bishop scores were significantly associated with spontaneous preterm delivery in nulliparous and multiparous women. Black race, poor social environment, and work during pregnancy were associated with increased risk for nulliparous women. Prior obstetric outcome overshadowed socioeconomic risk factors in multiparous women with a twofold increase in the odds of spontaneous preterm delivery for each prior spontaneous preterm delivery. Current pregnancy symptoms, including vaginal bleeding, symptomatic contractions within 2 weeks, and acute or chronic lung disease were variably associated with spontaneous preterm delivery in nulliparous and multiparous women. When the system was applied to the remainder of the population, women defined to be at high risk for spontaneous preterm delivery (> or = 20% risk) carried a 3.8-fold (nulliparous women) and 3.3-fold (multiparous women) higher risk of spontaneous preterm delivery than those predicted to be at low risk. However, the risk assessment system identified a minority of women who had spontaneous preterm deliveries. The sensitivities were 24.2% and 18.2% and positive predictive values were 28.6% and 33.3%, respectively, for nulliparous and multiparous women. CONCLUSIONS: Although it is possible to develop a graded risk assessment system that includes factors that are highly associated with spontaneous preterm delivery in nulliparous and multiparous women, such a system does not identify most women who subsequently have a spontaneous preterm delivery. This system has investigational value as the basis for evaluating new technologies designed to identify at-risk subpopulations. PMID- 8678157 TI - The economic cost of the medical-legal tort system. AB - OBJECTIVE: Our goal was to evaluate the financial expenditures of the medical legal tort system on the single largest medical campus in the United States. STUDY DESIGN: The true financial expenditures directed to the medical-legal system were determined and related to the total revenue and expenses of the Detroit Medical Center. All costs were determined, including malpractice premiums, paid claims information, accrual expense information, and risk management administrative expenses for the fiscal years 1992, 1993, and 1994. RESULTS: The total medical-legal expenses for the years 1992, 1993, and 1994 were $73,732,000, $70,490,000, and $79,043,000, respectively. The claims paid to plaintiffs were 35.9%, 28.1%, and 28.1% for the same years. CONCLUSION: The medical-legal system process in the United States is very long and fraught with many inequities and inefficiencies. It was found that approximately 12% of the medical-legal expenditures of the Detroit Medical Center go to the individual alleged victim after defense and plaintiff attorney fees and costs and administrative costs. The failure of the American health care system could be in jeopardy if the nation's leaders do not reform the process to provide a more cost effective system. PMID- 8678158 TI - Randomized, double-blind trial of prostaglandin E2 intravaginal gel versus low dose oxytocin for cervical ripening before induction of labor. AB - OBJECTIVE: Our purpose was to compare two methods of preinduction cervical ripening in a randomized, double-blind clinical trial. STUDY DESIGN: Two intravaginal, 4 mg prostaglandin E2 gel applications administered 4 hours apart were compared with 10 hours of low-dose oxytocin (2 mU/min) in 200 patients undergoing preinduction cervical ripening. RESULTS: There were no differences in parity, initial Bishop scores, estimated gestational ages, indications for induction, or birth weights. Prostaglandin E2 gel was significantly better (p < 0.0001) at achieving a change in the Bishop score of 3 or more. The number of successful inductions was significantly greater (p < 0.0003) and the mean time to active labor was significantly shorter (p < 0.0002) in the prostaglandin E2 group than in the oxytocin group. More multiple-day inductions (p < 0.01) occurred in the oxytocin group, and fewer discharged patients who did not deliver infants (p < 0.03) were seen in the prostaglandin E2 gel group. There were no differences between patient groups in the cesarean section rate, meconium staining, hyperstimulation, and Apgar scores. CONCLUSION: Two 4 mg doses of prostaglandin E2 intravaginal gel applied 4 hours apart are superior to low-dose oxytocin in producing cervical ripening and preparing for successful induction. PMID- 8678159 TI - Treatment of low-risk metastatic gestational trophoblastic tumors with single agent chemotherapy. AB - OBJECTIVE: Our purpose was to evaluate the efficacy and toxicity of single-agent chemotherapy and to identify risk factors associated with chemotherapy resistance in the treatment of low-risk metastatic gestational trophoblastic tumors. STUDY DESIGN: We reviewed the records of all patients with gestational trophoblastic tumors treated with single-agent chemotherapy at the John I. Brewer Trophoblastic Disease Center of Northwestern University between 1962 and 1992. A total of 92 patients with low-risk metastatic gestational trophoblastic tumors by National Cancer Institute criteria were identified. Patients received methotrexate (n = 61), actinomycin D (n = 4), alternating methotrexate and actinomycin D (n = 5), or hysterectomy with methotrexate (n = 20) or actinomycin D (n = 2). RESULTS: All 92 patients with low-risk metastatic gestational trophoblastic tumors were cured. Primary remission was achieved with initial single-agent therapy in 62 patients (67.4%). A second sequential single agent was used because of drug resistance in 20 patients (21.7%) or drug toxicity in 10 patients (10.9%). Only one patient (1%) needed multiagent chemotherapy to be cured. Adjuvant hysterectomy was performed in 22 patients (23.9%). Surgery was not required to remove resistant tumor foci. Chemotherapy toxicity, most commonly stomatitis, occurred in 36 patients (39.1%), but none of these effects was life threatening. Large vaginal metastasis was the only identifiable factor significantly associated with failure of initial single-agent chemotherapy (p = 0.03). CONCLUSION: In this large series of patients with low-risk metastatic gestational trophoblastic tumors, sequential single-agent chemotherapy with methotrexate and actinomycin D provided safe and extremely effective treatment. PMID- 8678160 TI - Integration of genetics and ultrasonography in prenatal diagnosis: just looking is not enough. AB - OBJECTIVE: There has been a gradual shift of the focus of prenatal diagnosis from genetics to ultrasonography. We assessed our primary genetics approach to determine what would be missed without the genetics component. STUDY DESIGN: We evaluated referral indications for patients with normal and abnormal prenatal findings from Jan. 1, 1990, to March 31, 1995, and categorized them according to type of fetal anomalies and genetic abnormalities found. Discordance among initial indication, identified risk factors, and observed abnormalities was assessed. RESULTS: The proportion of patients referred for very-high-risk indications increased over time; 13.5% of all patients (1992 of 14,725) had abnormalities. Abnormal outcomes were categorized as 26% chromosomal, 58% ultrasonographic dysmorphologic features, 11% biochemical or deoxyribonucleic acid disorders, 5% infectious, and 11% other. Of the cases of ultrasonographic dysmorphism (exclusive of the aneuploidies), 3.5% were ultimately determined to be syndromic and 2.5% to be discrepant, that is, having a different abnormality than the referred diagnosis. Including the whole spectrum of disorders seen, half of the abnormalities would not be detectable with even high-quality ultrasonography. CONCLUSION: A large number of abnormal findings were not consistent with initial indication for referral. Correct diagnosis depended on increased acuity provided by genetic pedigree analysis and recognition of syndromes. Diligence in the search for associated anomalies, aneuploidy, pedigree analysis, and syndromic abnormalities remain critical components in the differential diagnosis. The elucidation of unexpected findings suggests the advantages of early counseling and a genetics-based approach combined with tertiary rather than primary ultrasonography with counseling only when anomalies are detected. PMID- 8678161 TI - Intrapartum factors in early-onset group B streptococcal sepsis in term neonates: a case-control study. AB - OBJECTIVE: A case-control study was used to (1) examine the intrapartum characteristics of term neonates with early-onset group B streptococcal sepsis and (2) determine what percentage of patients meet The American College of Obstetricians and Gynecologists guideline for intrapartum administration of antibiotics. STUDY DESIGN: Twenty-one women delivered of term neonates who contracted early-onset group B streptococcal sepsis were matched with 63 mothers who were colonized with group B streptococci. The women were matched for race, age, parity, and gestational age. A Student t test and chi2 analysis were performed. Significance was defined as p < 0.05. RESULTS: The attack rate was 2.1 instances of sepsis per 1000 live births. For both groups, the maternal demographics and the actual birth weights were similar. Case mothers compared with controls had longer labor (11.4 +/- 6.9 vs 5.8 +/- 4.3 hours, p < 0.0001), had longer time elapsed between rupture of membranes and delivery (10.3 +/- 6.4 vs 3.2 +/- 3.6 hours, p < 0.0001); required oxytocin more often (76% vs 32%, p < 0.001); required more pelvic examinations (6 or more; 71% vs 46%, p < 0.05); and had a significantly higher cesarean section rate (33% vs 3%; p < 0.001). Only 10% (2 of 21) of case mothers met The American College of Obstetricians and Gynecologists guideline for chemoprophylaxis. CONCLUSION: The American College of Obstetricians and Gynecologists guideline for chemoprophylaxis identifies only 10% of women whose term newborns contract early-onset group B streptococcal sepsis. PMID- 8678162 TI - Screening should not be compared with diagnosis. PMID- 8678163 TI - CITROG (Committee on In-Training Examination for Residents in Obstetrics and Gynecology) examination remediation indicator: the next steps. PMID- 8678164 TI - The CHUMS (Collaborative Home Uterine Monitoring Study) clinical trial--what does it really say? PMID- 8678165 TI - Further insights into autoimmune thrombocytopenia in pregnancy. PMID- 8678166 TI - Hepatocyte growth factor and placental development. PMID- 8678167 TI - Relationships of age and axis I diagnoses in victims of completed suicide: a psychological autopsy study. AB - OBJECTIVE: Psychiatric illness is a potent risk factor for suicide, rates of which differ markedly with age. The purpose of this study was to examine whether the psychiatric diagnoses of suicide victims vary predictably with age. METHOD: DSM-III-R axis I diagnoses of 141 persons aged 21 to 92 years who had completed suicide were established by the psychological autopsy method. Multiple logistic regression analyses were used to determine whether age, gender, or their interaction predicted the presence of specific disorders. RESULTS: One or more axis I conditions were diagnosable in 90.1% of the suicide victims. Substance use disorders were most frequent, followed by mood disorders and primary psychotic illness. Younger age at death was a significant predictor of substance abuse or dependence and primary psychoses, while older age predicted major mood disorders. Comorbidity of substance use and mood disorders was common. Among victims with substance abuse or dependence, older age at death predicted major depression; among victims with mood disorders, younger age at death predicted comorbid substance abuse or dependence. CONCLUSIONS: The distribution of psychiatric illnesses in suicide victims differs across the life course. Age-related patterns of addictive and psychotic disorders echo their prevalence in the general population. In contrast, the relationship between age and mood disorders among suicide victims is distinctly different from that of the general population. These findings suggest that risk for suicide increases with age in individuals with major affective illness. Depressed elderly men are particular targets for suicide prevention strategies. PMID- 8678168 TI - Prevalence and comorbidity of mental disorders in persons making serious suicide attempts: a case-control study. AB - OBJECTIVE: The aim of this study was to compare the prevalence and comorbidity patterns of psychiatric disorders in subjects making medically serious suicide attempts and in comparison subjects. METHOD: The association between mental disorders and the risk of a suicide attempt was examined in 302 consecutive individuals who made serious suicide attempts and 1,028 randomly selected comparison subjects. Each subject completed a semistructured interview, and a significant other underwent a parallel interview; best-estimate DSM-III-R diagnoses were then generated. RESULTS: Of those who made serious suicide attempts, 90.1% had a mental disorder at the time of the attempt. Multiple logistic regression showed that those who made suicide attempts had high rates of mood disorders (odds ratio = 33.4, 95% confidence interval = 21.9-1.2); substance use disorders (odds ratio = 2.6, 95% confidence interval = 1.6-4.3); conduct disorder or antisocial personality disorder (odds ratio = 3.7, 95% confidence interval = 2.1-6.5); and nonaffective psychosis (odds ratio = 16.8, 95% confidence interval = 2.7-105.8). The relationship between psychiatric morbidity and suicide risk varied with age and gender. The incidence of comorbidity was high: 56.6% of those who made serious suicide attempts had two or more disorders. The risk of a suicide attempt increased with increasing psychiatric morbidity: subjects with two or more disorders had odds of serious suicide attempts that were 89.7 times the odds of those with no psychiatric disorder. CONCLUSIONS: Individuals who made serious suicide attempts had high rates of mental disorders and of comorbid disorders. Subjects with high levels of psychiatric comorbidity had markedly high risks of serious suicide attempts. PMID- 8678169 TI - Suicidal feelings in a population sample of nondemented 85-year-olds. AB - OBJECTIVE: The authors studied the 1-month frequency of suicidal feelings among very old people. METHOD: A population sample (N = 345) of nondemented 85-year olds in Gothenburg, Sweden, were examined by a psychiatrist. Suicidal feelings were rated by the system of Paykel et al. Mental disorders were diagnosed according to DSM-III-R. RESULTS: Of the mentally healthy subjects (N = 225), 4.0% had thought during the last month that life was not worth living, 4.0% had had death wishes, and 0.9% had thought of taking their own lives. None had seriously considered suicide. The figures were higher among subjects with mental disorders (N = 120); 29.2% had thought that life was not worth living, 27.5% had had death wishes, 9.2% had thought about taking their lives, and 1.7% had seriously considered suicide. Among the subjects with mental disorders, including depression, suicidal feelings were associated with greater use of anxiolytics but not of antidepressants. Women who felt that life was not worth living had a higher 3-year mortality rate than did women without these feelings (43.2% versus 14.2%). This finding was independent of concomitant physical and mental disorders. CONCLUSIONS: Mild suicidal feelings are common in elderly subjects with metal disorders but infrequent in the mentally healthy. The substantially higher mortality rate in women who felt that life was not worth living, compared to women who did not, suggests these feelings must be taken seriously. Because of the high suicide rate in the elderly, there is a need for better diagnosis and treatment of mental disorders in this age group. PMID- 8678170 TI - Gender, type of treatment, dysfunctional attitudes, social support, life events, and depressive symptoms over naturalistic follow-up. AB - OBJECTIVE: The present study investigated gender differences in depressive symptoms during a naturalistic follow-up for outpatients with major depressive disorder in the National Institute of Mental Health Treatment of Depression Collaborative Research Program. Specifically, the study investigated whether gender interacted with type of treatment received, dysfunctional attitudes, life events, or social support to predict severity of depressive symptoms. In addition, aspects of these psychosocial factors (need for approval, interpersonal life events, and close friendships), hypothesized to be more salient for women, were examined to determine if they had a differential impact on level of depressive symptoms in men and women. METHOD: Assessments conducted 6, 12, and 18 months after treatment included measures of depressive symptoms, dysfunctional attitudes, current life events, and social support. Data were available for 188 subjects (134 women and 54 men). Regression analyses were conducted to examine whether gender as a main effect, or interacting with dysfunctional attitudes, life events, social support, or subtypes of these variables, predicted cross sectional or longitudinal measures of depressive symptoms during follow-up. RESULTS: A consistent finding of the study was that over the 18 months of this naturalistic follow-up, there were no main effects for gender or any significant interactions involving gender and any of the variables of interest. The study demonstrated that life events and social support were related to severity of depressive symptoms for both genders. CONCLUSIONS: Despite differential prevalence rates of major depression for men and women, findings do not support a different process in outcome of illness for men and women. PMID- 8678171 TI - Winter seasonal affective disorder: a follow-up study of the first 59 patients of the National Institute of Mental Health Seasonal Studies Program. AB - OBJECTIVE: The purpose of this study was to characterize the long-term course of patients with seasonal affective disorder. METHOD: The first 59 patients with winter seasonal affective disorder who had entered winter protocols were retrospectively followed up after a mean interval of 8.8 years. Detailed life charts were constructed through use of a semistructured interview and collateral records. RESULTS: The disorder of 25 patients (42%) remained purely seasonal, with regular recurrences of winter depression and no depression or treatment through any summer. The course of illness was complicated by varying degrees of nonseasonal depression in 26 patients (44%). The disorders of eight patients (14%) had fully remitted. Certain features of the group with complicated seasonal affective disorder suggested that they were more severely ill. Twenty-four patients (41%) continued to use light treatment regularly throughout the follow up period. Light treatment was preferred to medication for winter recurrences, although antidepressants had been used in the winter by most (63%) of the patients who still used lights at follow-up. CONCLUSIONS: The pattern of winter depressions and summer remissions remained fairly persistent over time in this group of patients. The temporal distribution of depressive episodes both within and across individual patients was consistent with the results of several recent follow-up studies of seasonal affective disorder, providing support for the predictive and construct validity of the Rosenthal et al. diagnosis of winter seasonal affective disorder. Light treatment, while remaining a safe and satisfactory treatment for many, may be insufficient for more severely ill patients. The appearance of nonseasonal depressions in patients with winter seasonal affective disorder may be associated with greater severity of illness and less responsiveness to light treatment. PMID- 8678172 TI - cAMP-dependent protein kinase activity in major depression. AB - OBJECTIVE: The author's intent was to evaluate the activity of the beta adrenoceptor-linked, cAMP-dependent protein kinase (protein kinase A) in patients with major depression compared with a group of nondepressed volunteer subjects. METHOD: Skin fibroblast samples were obtained by 2-mm punch biopsy from 12 patients (11 were women) who had major depression diagnosed according to the Structured Clinical Interview for DSM-III-R and from 10 nondepressed volunteers (seven were women). Fibroblasts were cultured in Dulbecco's modified Eagle medium. Baseline and cAMP-stimulated activities of protein kinase A were determined in both particulate and supernatant fractions (900g). Linkage of the finding to beta adrenergic receptor function was evaluated by determination of protein kinase A activity after incubation of the confluent cultures for 30 minutes with 10 microM isoproterenol. RESULTS: There were significant differences between groups in the baseline and cAMP-stimulated phosphorylation in the supernatant fraction. Moreover, the attenuated protein kinase A response was accompanied by a blunted isoproterenol response. CONCLUSIONS: Patients with depression exhibit significantly less activity of beta-adrenoceptor-linked protein kinase A than do normal subjects. The reductions in protein kinase A activity support the significance of beta-receptor-mediated events in depression. PMID- 8678173 TI - Stigma, depression, and somatization in South India. AB - OBJECTIVE: The relationships of stigma to both depression and somatization were studied in psychiatric patients in South India to test the hypothesis that stigma is positively related to depressive symptoms and negatively related to somatoform symptoms. METHOD: Illness experience, symptom prominence, and indicators of stigma for 80 psychiatric outpatients were addressed with the Explanatory Model Interview Catalogue. Stigma scores and ratings of symptom prominence were derived. The Structured Clinical Interview for DSM-III-R and the Hamilton Depression Rating Scale were administered to assess psychiatric diagnoses and symptoms of depression. Clinical narratives were analyzed to clarify the nature of relationships between stigma and symptom prominence. RESULTS: The mean stigma scores were 18.2 (SD = 13.0) for patients with somatoform disorders only, 36.0 (SD = 19.0) for patients with depressive disorders only, and 26.8 (SD = 16.0) for those with mixed depressive and somatoform disorders. The stigma scores were positively related to depressive symptoms, as indicated by Hamilton scale scores and prominence ratings for depressive symptoms, but stigma was inversely related to somatoform symptoms, as indicated by ratings of symptom prominence. Although both depressive and somatic symptoms were distressing, qualitative analysis clarified meanings of perceived stigma, showing that depressive symptoms, unlike somatic symptoms, were construed as socially disadvantageous. CONCLUSIONS: The tendency to perceive and report distress in psychological or somatic terms is influenced by various social and cultural factors, including the degree of stigma associated with particular symptoms. This study with the Explanatory Model Interview Catalogue demonstrates how quantitative and qualitative methods can be effectively combined to examine key issues in cultural psychiatry. PMID- 8678174 TI - Psychological symptoms, somatic symptoms, and psychiatric disorder in chronic fatigue and chronic fatigue syndrome: a prospective study in the primary care setting. AB - OBJECTIVE: This study assessed relationships among psychological symptoms, past and current psychiatric disorder, functional impairment, somatic symptoms, chronic fatigue, and chronic fatigue syndrome. METHOD: A prospective cohort study was followed by a nested case-control study. The subjects, aged 18-45 years, had been in primary care for either clinical viral infections or a range of other problems. Questionnaire measures of fatigue and psychological symptoms were completed by 1,985 subjects 6 months later; 214 subjects with chronic fatigue were then compared with 214 matched subjects without fatigue. Assessments were made with questionnaires, interviews, and medical records of fatigue, somatic symptoms, psychiatric disorder, and functional impairment. RESULTS: Subjects with chronic fatigue were at greater risk than those without chronic fatigue for current psychiatric disorder assessed by standardized interview (60% versus 19%) or by questionnaire (71% versus 31%). Chronic fatigue subjects were more likely to have received psychotropic medication or experienced psychiatric disorder in the past. There was a trend for previous psychiatric disorder to be associated with comorbid rather than noncomorbid chronic fatigue. Most subjects with chronic fatigue syndrome also had current psychiatric disorder when assessed by interview (75%) or questionnaire (78%). Both the prevalence and incidence of chronic fatigue syndrome were associated with measures of previous psychiatric disorder. The number of symptoms suggested as characteristics of chronic fatigue syndrome was closely related to the total number of somatic symptoms and to measures of psychiatric disorder. Only postexertion malaise, muscle weakness, and myalgia were significantly more likely to be observed in chronic fatigue syndrome than in chronic fatigue. CONCLUSIONS: Most subjects with chronic fatigue or chronic fatigue syndrome in primary care also meet criteria for a current psychiatric disorder. Both chronic fatigue and chronic fatigue syndrome are associated with previous psychiatric disorder, partly explained by high rates of current psychiatric disorder. The symptoms thought to represent a specific process in chronic fatigue syndrome may be related to the joint experience of somatic and psychological distress. PMID- 8678175 TI - Family history of panic disorder and hypersensitivity to CO2 in patients with panic disorder. AB - OBJECTIVE: The authors investigated the relationships between hypersensitivity to CO2 and familial-genetic risk for panic disorder in patients with panic disorder. METHOD: Morbidity risks for panic disorder were calculated for families of 203 patients with panic disorder, each of whom was challenged with 35% CO2. RESULTS: Patients who reacted with a positive response to the 35% CO2 challenge showed a genetic risk for panic disorder (morbidity risk = 14.4%) that was significantly higher than that for patients who did not react (morbidity risk = 3.9%). CONCLUSIONS: These findings support the idea that hypersensitivity to CO2 might be associated with a subtype of panic disorder specifically related to a greater familial loading. PMID- 8678176 TI - Day hospital/crisis respite care versus inpatient care, Part I: Clinical outcomes. AB - OBJECTIVE: The authors investigated the clinical feasibility and the outcome for patients of a program designed as an alternative to acute hospitalization. METHOD: This was a random-design study comparing a conventional inpatient program for urban, poor, severely ill voluntary patients who usually require hospitalization to an alternative experimental program consisting of a day hospital linked to a crisis residence. Patients were assessed with standardized measures of symptoms, functioning, social adjustment, quality of life, and satisfaction with clinical services upon admission to the study, at discharge from the index admission, and at follow-ups 2, 5, and 10 months after discharge. RESULTS: One hundred ninety-seven patients were enrolled in the 2-year research program and followed for 10 months. Of the voluntary patients who would have been admitted to the hospital, 83% were appropriate for the experimental program. The clinical, functional, social adjustment, quality of life, and satisfaction outcome measures were not statistically different for the patients in the two treatment conditions; however, there was a slightly more positive effect of the experimental program on measures of symptoms, overall functioning, and social functioning. CONCLUSIONS: The experimental condition, a combined day hospital/crisis respite community residence, seems to have had the same treatment effectiveness as acute hospital care for urban, poor, acutely ill voluntary patients with severe mental illness. PMID- 8678177 TI - Day hospital/crisis respite care versus inpatient care, Part II: Service utilization and costs. AB - OBJECTIVE: The authors compared service utilization and costs for acutely ill psychiatric patients treated in a day hospital/crisis respite program or in a hospital inpatient program. METHOD: The patients (N = 197) were randomly assigned to one of the two programs and followed for 10 months after discharge. Both programs were provided by a community mental health center (CMHC) in a poor urban community. Data were collected for developing service utilization profiles and estimates of per-unit costs of the inpatient, day hospital, and outpatient services provided by the CMHC. RESULTS: On average, the day hospital/crisis respite program cost less than inpatient hospitalization. The average saving per patient was +7,100, or roughly 20% of the total direct costs. There were no significant differences between programs in service utilization or costs during the follow-up phase. Cost savings accrued in the index episode because per-unit costs were lower for day hospital/crisis respite and the average stay was shorter. Significant differences in cost were found among patient groups with psychosis, affective disorders, and dual diagnoses; psychotic patients had the highest costs in both programs. The two programs had roughly equal direct service staff and capital costs but significantly different operating costs (day hospital/crisis respite operating costs were 51% of inpatient hospital costs). CONCLUSIONS: The programs were equally effective, but day hospital/crisis respite treatment was less expensive for some patients. Potential cost savings are higher for nonpsychotic patients. Cost differences between the programs are driven by the hospital's relatively higher overhead costs. The roughly equal expenditures for direct service staff costs in the two programs may be an important clue for understanding why these programs provided equally effective acute care. PMID- 8678178 TI - Interpersonal relatedness and paranoid schizophrenia. AB - A 33-year-old man presented with a 10-year history of psychosis and an imaginary companion; he carried a past diagnosis of chronic schizophrenia. He responded quickly to neuroleptic and was noted to be an easily engageable person. It is argued that despite his first-rank Schneiderian symptoms, the patient may not best be conceptualized as having schizophrenia. Specific treatment recommendations are made, predicated on this man's developmental history, his attachment and separation behavior, and his response to a structured social milieu. PMID- 8678179 TI - Images in psychiatry. New York State Psychiatric Institute. PMID- 8678180 TI - Gender differences in personality disorders in psychiatrically hospitalized adolescents. AB - OBJECTIVE: The authors examined gender differences in DSM-III-R personality disorders in adolescent psychiatric inpatients. METHODS: Structured diagnostic interviews were reliably performed with a series of 138 consecutively admitted adolescent inpatients. To reduce variability due to heterogeneity of axis I diagnoses, a subgroup of 87 patients with major depression was retested for gender differences. RESULTS: Females were significantly more likely than males to meet the criteria for borderline personality disorder. Narcissistic personality disorder was diagnosed only in males. A similar pattern was observed in the subgroup of patients with major depression. CONCLUSIONS: The findings suggest potentially important gender differences in personality disorders in adolescent inpatients. PMID- 8678181 TI - Lack of association between polymorphisms in the 5-HT2A receptor gene and the antipsychotic response to clozapine. AB - OBJECTIVE: The authors' goal was to determine whether either of two 5-HT2A receptor polymorphisms, 102-T/C and 452-His/Tyr, are associated with clozapine response. METHOD: Brief Psychiatric Rating Scale (BPRS) ratings were obtained in 70 patients with schizophrenia or schizoaffective disorder to determine their response to clozapine compared with a typical neuroleptic. Patients were genotyped with the polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: Neither 102-T/C nor 452-His/Tyr was associated with clozapine response. There were no significant differences in BPRS scores among patients with different 5-HT2A genotypes at week 10 of clozapine administration. CONCLUSIONS: Allelic variation in the 5-HT2A gene is not associated with individual differences in clozapine response. PMID- 8678182 TI - Efficacy of enhanced outreach counseling to reenroll high-risk drug users 1 year after discharge from treatment. AB - OBJECTIVE: Because discharged methadone maintenance patients represent a population at particularly high public health risk, the authors studied such patients 1 year after their discharge from a methadone program. METHOD: The locations of 94 of 110 discharged patients were successfully determined 1 year after discharge. Nine (10%) of these patients had died, 37 (39%) were already reenrolled in treatment, and 7 (7%) did not require treatment. The 41 remaining subjects were randomly assigned to either the enhanced outreach counseling condition (N = 27) or a standard referral condition (N = 14). RESULTS: Within 2 weeks following this intervention, 17 (63%) of the 27 patients in the enhanced outreach counseling program and one (7%) of the 14 patients not in the program had reenrolled in treatment. CONCLUSIONS: These data suggest that enhanced outreach counseling may be an effective outreach strategy as well as a risk reduction for discharged methadone maintenance patients. PMID- 8678183 TI - Pilot study of explicit grading criteria in the American Board of Psychiatry and Neurology. Part II. Examination. AB - OBJECTIVE: The purpose of this study was to identify specific competencies that differentiated passing from failing performance on the American Board of Psychiatry and Neurology Part II oral board certification examination. METHOD: A total of 363 candidates were rated in 18 areas of competence defined by behavioral criteria. Data were analyzed to determine which areas best discriminated between passing and failing candidates. RESULTS: In both parts of the examination, the ability to develop a comprehensive treatment plan was most influential. After that, specific interview and observational skills discriminated best. Failing candidates had most difficulty detecting and following informational and affective cues in their interview of a patient and presenting a biopsychosocial formulation and comprehensive treatment plan. CONCLUSIONS: Specific candidate competencies related to passing and failing performances can be identified and assessed by a rating scale of observable behaviors on the board certification examination in psychiatry. PMID- 8678184 TI - Malingering versus factitious disorder. PMID- 8678185 TI - Haloperidol dosing strategies. PMID- 8678186 TI - Haloperidol dosing strategies. PMID- 8678187 TI - Anxiety sensitivity. PMID- 8678188 TI - Effectiveness of the light visor. PMID- 8678189 TI - Dexamethasone for depression. PMID- 8678190 TI - Dexamethasone for depression. PMID- 8678191 TI - Sex is complex. PMID- 8678192 TI - Images in neuroscience. Neuroimaging, XI. PET and pharmacodynamics. PMID- 8678193 TI - Androgens, brain, and behavior. AB - OBJECTIVES: This article defines androgens (and anabolic steroids), describes their mechanisms of action, and summarizes their behavioral effects and relevance in animals and humans. METHOD: A MEDLINE-derived review of the literature on androgens and behavior was performed; pivotal earlier publications were also obtained and included in the review. RESULTS: In animals, the effects of androgens on brain structure and function are well-established and profound, with behavioral implications extending far beyond reproduction. Androgens play a prominent role in the organization or programming of brain circuits, which are subsequently activated by gonadal steroids. In humans, roles for androgens have been described, albeit inconsistently, in the regulation of sexuality, aggression, cognition, emotion, and personality. The relevance of androgens for psychiatry is further suggested by gender-related differences in pharmacokinetics/pharmacodynamics and in the prevalence, course, and treatment response characteristics of several psychiatric disorders. Direct psychoactive effects of exogenously administered androgens have been described for many years, most recently in reports of the psychotoxic effects of anabolic steroids. CONCLUSIONS: Data from both animals and humans suggest that the biological and behavioral responses to androgens are context-dependent. PMID- 8678194 TI - Resistance to antidepressant medications and short-term clinical response to ECT. AB - OBJECTIVE: Traditionally, it has been widely assumed that the likelihood of response to ECT is independent of the adequacy of previous treatment with antidepressant medications. However, recent research has raised the possibility that medication-resistant patients with depression have a poorer clinical ECT outcome than patients who have not failed previous adequate medication trials. METHOD: Medication resistance of 100 patients with primary, unipolar, nonpsychotic major depression was evaluated during the index episode with the Antidepressant Treatment History Form. Patients were recruited and treated with ECT at three sites; standardized ECT and clinical assessment procedures were used. Clinical outcome was assessed immediately and 1 week after completion of the ECT course. RESULTS: Patients who previously had failed one or more adequate antidepressant medication trials were less likely to respond to subsequent ECT than patients not known to be medication resistant. This finding held within each study site, whether clinical response was assessed categorically or in terms of the magnitude of symptomatic improvement and after the authors accounted for other potential predictors of clinical outcome. Resistance to heterocyclic antidepressants predicted poorer outcome after ECT, while resistance to selective serotonin reuptake inhibitors and monoamine oxidase inhibitors did not show significant predictive relations. CONCLUSIONS: While a substantial percentage of medication-resistant patients respond to ECT, clinical outcome in this group is inferior to that of patients without established medication resistance. The predictive power of medication resistance is generalizable across diverse clinical settings, particularly for heterocyclic antidepressants, which perhaps suggests an overlap in the mechanisms of actions of ECT and this medication class. PMID- 8678195 TI - Lithium use and discontinuation in a health maintenance organization. AB - OBJECTIVE: For decades, lithium has been prescribed to treat bipolar disorder. Its efficacy has been documented by clinical trials and by data from specialized clinics. An issue of considerable interest is the use of lithium in managed care systems. This project examined the use of lithium and its continuity of use by enrollees of a health maintenance organization (HMO). METHOD: In a 6-year longitudinal cohort study, 1,594 lithium users aged 15 years and older who were enrolled in an HMO were followed from 1986-1991. Data were obtained from automated databases and from medical record review of a random 5% subsample of the group (N = 74). RESULTS: Bipolar disorder was the most frequent morbidity treated. Eighty-four percent (N = 62 or 74) received services from a psychiatrist. Annual prevalence of lithium use increased over the 6-year period from 1.4 to 2.3 persons per thousand HMO members. Duration of use varied widely with some long-term but many short-term users. Discontinuation of treatment was associated with evaluated rates of psychiatric hospitalization and use of psychiatric emergency services. Lithium users were much more likely to receive a variety of other psychotropic drugs than nonusers of the same sex and age. CONCLUSIONS: Lithium use in this population was more often sporadic than continuous. Discontinuation of lithium was associated with psychiatric hospitalization. If lithium is to be a cost-effective treatment for bipolar disorder, managed care systems will need to improve adherence to drug treatment regimens. PMID- 8678196 TI - Operative complications and quality improvement. PMID- 8678197 TI - Timeliness and use of antibiotic prophylaxis in selected inpatient surgical procedures. The Antibiotic Prophylaxis Study Group. AB - BACKGROUND: Twenty-five percent of all nosocomial infections are wound infections. Professional guidelines support the timely use of preoperative prophylaxis for prevention of postoperative wound infections. Barriers exist in implementing this practice. IPRO, the New York State peer review organization, as part of the Health Care Financing Administration's Health Care Quality Improvement Program, sought to determine the proportion of patients receiving timely antibiotic prophylaxis for aortic grafts, hip replacements and colon resections in 44 hospitals in New York State. METHODS: IPRO conducted a retrospective medical record review of 44 hospitals through out New York State stratified for teaching, nonteaching status. A sample was drawn of 2651 patients, 2256 from Medicare and 395 from Medicaid, undergoing either abdominal aortic aneurysm repair, partial or total hip replacement or large bowel resection. The study determined the proportion of patients who had documentation of receiving antibiotics and those who received antibiotics timely, that is less than or equal to 2 hours preoperatively. RESULTS: Eighty-six percent of patients had documentation of receiving an antibiotic. Forty-six percent of aneurysm repairs and 60% of hip replacements had evidence of receiving timely antibiotic prophylaxis, that is within 2 hours prior to surgery. For colon resections, 73% of cases had either oral prophylaxis or timely parenteral therapy. An increased proportion of patients had received parenteral antibiotics prematurely as the surgical start time occurred later in the day. A total of 44 different antibiotics were recorded for prophylaxis. CONCLUSIONS: Antibiotic prophylaxis was performed in 81% to 94% of cases, however, anywhere from 27% to 54% of all cases did not receive antibiotics in a timely fashion. By delegating implementation of ordered antibiotic prophylaxis to the anesthesia team, timing may be improved and the incidence of postoperative wound infections may decrease. PMID- 8678198 TI - Endoscopic management of benign and malignant biliary strictures. AB - BACKGROUND: It is now possible to manage most extrahepatic bile duct strictures, benign or malignant, using endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic dilatation and stenting. METHODS: Over a 5-year period we treated 218 patients with strictures of extrahepatic bile ducts. Eighty-six patients had benign biliary stricture. Endoscopic treatment was performed in 67 (78%) of these patients. Open surgical biliary drainage was preferred in 12 patients (14%), and 7 patients (8%) were managed conservatively without stenting or surgery. One hundred and thirty-two patients had malignant biliary stricture. One hundred and one patients (77%) underwent endoscopic stent placement. Thirty-one patients (23%) underwent surgery for potential curative resection after diagnostic ERCP. The average life span in the malignant stricture group was 5 months (range 0.1 to 25 months) after the initial endoscopic procedure. RESULTS: Altogether 313 endoscopic procedures in 218 patients were performed for benign and malignant bile duct strictures. Complications included hemorrhage in 8 (3%), pancreatitis in 10 (3%), and suspected retroperitoneal perforation in 2 (0.6%). There were no ERCP related deaths; one patient died of uncontrolled bleeding from transhepatic stenting. In benign strictures, there has been no recurrence of strictures after the last stent removal with a mean followup of 21 months (range 0.1 to 31 months). All complications were successfully treated conservatively. CONCLUSIONS: Endoscopic management of benign and malignant biliary stricture is possible with minimal morbidity and mortality and should be considered an acceptable option to surgical management. PMID- 8678199 TI - Indications for the choledochoscopic removal of intrahepatic stones based on the biliary anatomy. AB - BACKGROUND: Choledochoscopic treatment has been used primarily to remove intrahepatic stones. However, failure in removing such stones can occasionally occur, resulting in the need for additional surgery. The aim of this study was to clarify the clinical indications and limitations of choledocoscopic treatment for the removal of intrahepatic stones. METHODS: A review of the records of 86 patients treated for intrahepatic stones between April 1974 and December 1993 formed the basis of this study. These patients were evaluated based on their bile duct findings (no strictures, mild strictures, or severe strictures), the site of the stones (left hepatic lobe, right hepatic lobe, and the bilateral lobes), and the presence of variations in the posterior segmental bile-duct drainage. RESULTS: Complete removal of stones was achieved in 59 patients (69%). Further, choledochoscopic removal was mainly successful in patients with no strictures or, to a lesser degree, with mild strictures; whereas stone removal was impossible in all patients (19) with severe strictures (P < 0.0001). As for the site of the stones, no statistical differences were seen among the three groups. Regarding the presence of drainage variations of the segmental bile duct, removal of the stones was more difficult in patients with variations than in those without variations (P < 0.01). With respect to long-term clinical outcomes, of the 59 successful patients, only 2 (3%) developed recurring stones. CONCLUSION: Based on these findings, choledochoscopic treatment should be indicated for patients who have no, or only mild, bile-duct strictures and who mainifest normal segmental bile-duct drainage. PMID- 8678200 TI - Pancreatitis associated with neuroendocrine (islet cell) tumors of the pancreas. AB - BACKGROUND: The association of pancreatitis with neuroendocrine tumors of the pancreas is uncommon, whereas its association with exocrine pancreatic cancer is well recognized. Since the latter, but not the islet cell tumor, is thought to originate within the ductal system, it is not surprising that pancreatitis is less likely to result from the islet cell tumor. The senior author has recently noted that the first recognizable indication of an islet cell carcinoma may be one or more discrete attacks of acute pancreatitis. METHODS AND RESULTS: Acute pancreatitis, resulting from an islet cell tumor, has been observed in five patients, in one of whom it had become chronic. In four of the patients, the tumor was malignant. A review of the English language literature reveals 14 such patients with pancreatitis, and 2 others have been noted in other languages (a total of 21 patients). The tumor was malignant in 15 of the 21 patients (71%). Although the development of pancreatitis was found to result from the obstruction of the duct in most patients, at least three seemed unrelated. In 12 of 21 cases (57%), an acute attack of pancreatitis, usually recurrent, was the initial syndrome, in contradistinction to pancreatitis resulting from exocrine tumors, which has usually been chronic in nature. CONCLUSION: Pancreatitis, particularly acute pancreatitis, may result from an islet cell tumor. Although unusual, its occurrence may be the first signal of the presence of the tumor. In our experience, obstruction of the pancreatic duct by the islet cell carcinoma appears to be the important etiologic factor. PMID- 8678201 TI - Pain relapses in the first 10 years of chronic pancreatitis. AB - PURPOSE: To evaluate whether the annual number of pain relapses of chronic pancreatitis correlated with sex, type of pancreatitis, drinking and smoking, presence of intraductal calcifications, pancreaticojejunostomy, and length of follow-up in the first 10 years of follow-up. METHODS: The authors analyzed 205 nonobstructive chronic pancreatitis cases with at least a 10 year follow-up, for a total of 2,034 person/year observations. Data were recorded on the daily number of cigarettes smoked and grams of alcohol drunk, as well as the presence of intraductal calcifications, and performance of pancreaticojejunostomy. RESULTS: The model for multivariate autoregressive repeated measures analysis indicated that drinking (P < 0.0001), smoking (P < 0.0001), calcifications (P < 0.0001), pancreaticojejunostomy (P < 0.0011), and length of follow-up (P < 0.0001) all correlated significantly with annual number of pain relapses. Pancreaticojejunostomy is probably very effective in reducing pain both physically, by removing the largest intraductal calcifications and obstructions through drainage of Wirsung's duct, and psychologically, by inducing patients to cut down their postsurgical alcohol intake. CONCLUSIONS: Regardless of surgical treatment, patients should be advised to reduce both their alcohol intake and cigarette smoking. PMID- 8678202 TI - The value of clinical judgment in the diagnosis of nosocomial pneumonia. AB - BACKGROUND: Nosocomial pneumonia presents a diagnostic and therapeutic challenge in the care of critically ill patients. The present study was designed to determine as closely as possible the occurrence of nosocomial pneumonia in surgical intensive care unit (ICU) patients using clinical, radiographic, and bacteriological parameters in a prospective concurrent fashion. METHODS: This clinical study enrolled all surgical, trauma, and neurosurgical patients admitted to a surgical ICU over a 13-month period. Routine surveillance was used to identify those patients suspected of developing nosocomial pneumonia. Numerous clinical parameters concerning ventilatory support, acute lung injury, organ dysfunction, nutrition, and length of stays were used to identify factors disposing to development of pneumonia. Univariate and multivariate analyses were used for this purpose. Patients thought to have pneumonia were then followed concurrently to determine, as closely as possible, whether pneumonia was present by serial examination of clinical, bacteriologic, and radiographic data. Those "validated" by this process were then compared to those "nonvalidated" to see if any distinction could be made. RESULTS: Of the 352 patients enrolled, 46 (13%) were initially labeled as having developed nosocomial pneumonia when compared to the 306 patients without pneumonia. Univariate analysis demonstrated a greater need for intubation and mechanical ventilation, longer mechanical ventilation, more acute lung injury, longer ICU and hospital stays, poorer nutrition, and higher mortality (17% versus 5%, P < 0.01). Multivariate analysis demonstrated only length of ICU stay and length of intubation/mechanical ventilation as longer in the pneumonia group. On further concurrent review, 23 of 46 patients were validated as having pneumonia while the rest were felt not to have pneumonia. When the two groups were compared, only asymmetric and segmental radiographic infiltrates distinguished validated from nonvalidated pneumonia patients and all other clinical parameters, including mortality and length of stay, were similar. CONCLUSION: Nosocomial pneumonia was initially suspected in 13% of this ICU population. Numerous clinical parameters clearly distinguished these pneumonia patients from others and they suffered a substantially higher mortality. However, within this pneumonia group, only half of the patients could be validated as truly having pneumonia using available clinical parameters. Nevertheless, those validated were indistinguishable in their clinical behavior from those who were not. This calls into question the need for elaborate and sometimes expensive investigations for diagnosis of nosocomial pneumonia. PMID- 8678203 TI - Use of growth hormone for postoperative respiratory failure. AB - BACKGROUND: The authors examined the efficacy of human growth hormone (HGH) in patients dependent on mechanical ventilation who were being weaned from the respirator. METHODS: A total of 53 patients were chosen by the primary surgical team in consultation with the critical care service to undergo HGH therapy. These patients had been receiving standard ICU support and had failed standard ventilator weaning protocols. As such, they were treated with HGH in an attempt to increase respiratory muscle strength and facilitate weaning from mechanical ventilation. RESULTS: General demographic information was recorded. Patients suffered from a high incidence of co-morbid conditions and infectious complications. The average duration of HGH therapy was 38 days, and 81% of the previously unweanable patients were eventually weaned from mechanical ventilation with an overall survival of 76%. Mortality as predicted by APACHE II Scores was significantly less than actual mortality (24% actual mortality vs. 42% predicted mortality, P < 0.05). CONCLUSIONS: This phase I study presents clinical evidence supporting the safety and efficacy of HGH in promoting respiratory independence in a selected group of surgical ICU patients. Randomized, blinded, controlled trials now seem warranted. PMID- 8678204 TI - Mediastinal tracheostomy. AB - BACKGROUND: Advanced carcinoma of the lower neck with direct extension to the superior mediastinum is a major therapeutic challenge. Complete removal of the tumors requires a radical operation in order to remove the larynx, portions of trachea and esophagus, and to construct a tracheostomy stoma with intrathoracic trachea. METHODS: We present our experience and technique for removal of difficult tumors in this region and construction of mediastinal tracheostomy. A technique for reconstruction of a very short segment of distal trachea is also proposed. Twelve mediastinal tracheostomies were performed; all except 3 patients underwent total laryngopharyngectomy and resection of tumor with gastric pullup. RESULTS: There were 2 operative deaths, 1 from tracheoinnominate artery fistula and the other from cerebral infarction. Complications included pharyngeal fistula (2 patients), respiratory failure (1), and osteomyelitis of sternum (1). Postoperative survival was disease-dependent. All patients who survived the operation achieved good airway patency and relief of dysphagia. CONCLUSIONS: The method of airway reconstruction by mediastinal tracheostomy is an advance in surgical treatment of malignancies in the cervicothoracic region. By careful selection of patients, successful operation resulted in good palliation and sometimes cure with acceptable quality of life. PMID- 8678205 TI - Low-dose enteral feeding is beneficial during total parenteral nutrition. AB - BACKGROUND: Enteral support is the preferred feeding route for stressed patients due in part to the provision of gut-specific fuels. In those patients who must be maintained parenterally, small amounts of enteral stimulation might blunt gut atrophy and lead to improvement in host defense mechanisms decreasing macromolecular and/or bacterial translocation (BT). METHODS: Forty-eight rats were infused with TPN for 9 days, and were randomized to receive 0%, 6%, 12%, or 25% of their calories as partial enteral nutrition (PEN) in an isocaloric, isonitrogenous fashion. Twenty-four hours before harvest animals were gavaged with lactulose and urinary excretion quantified. At harvest, mesenteric lymph nodes were cultured to assess BT and intestinal histology determined. RESULTS: Provision of as little as 25% of total calories PEN improved nitrogen balance and reduced BT, in a dose dependent fashion. It did not alter TPN-associated increased macromolecular lactulose permeability (4.4% +/- 1.0%). CONCLUSION: Concurrent small amounts of PEN, aimed to support the gut's metabolic needs, are beneficial during periods of prolonged TPN. PMID- 8678206 TI - Distal splenorenal shunt versus 10-mm low-diameter mesocaval shunt for variceal hemorrhage. AB - BACKGROUND: Portal hypertension surgery remains a good therapeutic choice for well selected patients with variceal bleeding. The distal splenorenal shunt (DSRS) has shown good long-term results and low-diameter shunts have emerged as an alternate choice. METHODS: A prospective, controlled and not randomized study was designed to compare the DSRS (23 patients) and the low-diameter 10 mm ring reinforced PTFE mesocaval shunt (LDMCS) (22 patients) in low-risk electively operated patients (Child-Pugh A-B). The operation was selected according to the anatomical status of the veins. RESULTS: Both groups were comparable. No differences were observed regarding rebleeding, operative mortality and survival. Significative differences were observed regarding encephalopathy and shunt thrombosis (higher in the LDMCS). Postoperative angiography showed better maintenance of portal blood flow in the DSRS group. CONCLUSIONS: Both operations are adequate alternatives for the elective treatment of portal hypertension in low-risk patients. However, the DSRS has more advantages than the LDMCS. PMID- 8678207 TI - Gastrointestinal myoelectric activity during endotoxemia. AB - BACKGROUND: Gastrointestinal myoelectric activity during postoperative ileus has been well characterized. However, the common clinical scenario of ileus occurring during and after episodes of sepsis is not well understood. The aim of our study was to determine the effects of a single, sublethal dose of endotoxin on canine gastrointestinal myoelectric activity. METHODS: Eight dogs underwent placement of serosal electrodes on the stomach and small intestine and insertion of a jejunal cannula. After the animals recovered, electrical activity and jejunal mucosal blood flow were determined during fasting and with feeding. Following completion of these baseline studies dogs were given a single, sublethal dose of Escherichia coli lipopolysaccharide (200 g/kg) intravenously, and the studies were repeated daily for 3 consecutive days. RESULTS: Endotoxin resulted in an absence of the interdigestive migrating myoelectric complex for 2 days, a decrease in duodenal and jejunal action potentials during fasting and with feeding, but no decreases in jejunal mucosal blood flow. The gastrointestinal myoelectrical patterns returned to those found in health on postendotoxin day 3. CONCLUSIONS: A single, sublethal dose of endotoxin results in a temporary disruption of gastrointestinal myoelectric activity similar to that seen during postoperative ileus. The etiology of this "adynamic" ileus is unknown but does not appear to be secondary to intestinal ischemia. PMID- 8678208 TI - Laparoscopic truncal vagotomy and gastroenterostomy for pyloric stenosis. AB - BACKGROUND: Gastric outlet obstruction secondary to chronic duodenal ulceration is an indication for surgery as conservative management with balloon dilatation frequently fails. The standard operation is truncal vagotomy and a drainage procedure. However, development of minimally invasive surgery has revolutionized the surgical approach to this clinical problem. METHODS: Twelve male patients with pyloric stenosis secondary to duodenal ulceration underwent laparoscopic truncal vagotomy and gastrojejunostomy. The perioperative and long term outcome of this group of patients were analyzed. RESULTS: The median operating time was 210 (range 180 to 240) minutes. Median postoperative stay was 6 (range 4 to 41) days. Conversion to laparotomy was necessary in one patient. Delayed gastric emptying occurred in two patients but resolved on conservative measures. At a median postoperative followup of 6 (range 1 to 12) months all patients had a good symptomatic outcome (Visick grades I or II). CONCLUSIONS: Laparoscopic truncal vagotomy and gastrojejunostomy is a feasible technique. Intermediate followup shows good symptomatic results when used for pyloric stenosis. PMID- 8678209 TI - The art of mentoring. AB - While the golden era of mentoring may have been the age of apprentice ships in medicine, the birth of the clinical clerkship in the late 1800s provided the structure for the relationship between faculty and medical student. The last few decades, however, have seen a dramatic change in the availability of faculty to mentor students in clinical teaching settings despite a 600% increase in the number of clinical full-time medical school faculty. This work explores some of the reasons for this deterioration in mentoring and looks at the role of the mentor in professional development, specifically in the area of medical education. Recommendations for implementing structured mentoring programs within a department of surgery are provided. The article concludes with discussion of individual characteristics of the effective mentor in surgical education. PMID- 8678210 TI - The learning needs of first-year surgical residents in the intensive care unit. AB - BACKGROUND: Residents are more likely to learn from educational experiences when properly prepared from the start of instruction and expectations are clear and consistent. The purpose of this study was to examine what first year residents need to know and be able to perform before starting their rotation in the intensive care unit (ICU). METHODS: The sample included surgical faculty, first through fifth year general surgery residents, and ICU nurses. A survey was developed that listed 110 knowledge and skill items felt to be possible prerequisite learning objectives. Respondents were asked to evaluate the required level of knowledge or skill on a 5-point Likert-type scale. RESULTS: Items were divided into knowledge or skill categories and then ranked in descending order by their mean ratings. Four knowledge and 10 skill items were ranked highly by all 3 groups of respondents. Kruskall-Wallis analyses found 58 items with statistically significant differences in mean ratings between groups of respondents. CONCLUSION: With this information a self assessment tool was developed to determine the level of performance on these identified learning objectives. A course of instruction can now be developed to assist residents in meeting these objectives before they assume patient care responsibilities in the ICU. PMID- 8678211 TI - Teaching effectiveness of surgeons. AB - BACKGROUND: Evaluation of clinical teaching is essential for feedback to teachers, and for reliable and valid data for the purpose of promotion and tenure. METHODS: The teaching effectiveness of 43 surgeons was evaluated continuously over a 9-year period. Stability of Teaching Effectiveness Scores (TES) over the 9-year period, correlation with age, and the changes after academic promotion were analyzed. RESULTS: A total of 3,750 evaluations were completed. The average of 10 evaluations per surgeon per year gave an intraclass correlation of 0.65. The mean TES did not show any significant change over the 9 years. The majority of the "good" and "average" surgeons maintained their TES ratings, and most of the "poor" group improved their TES. The age of the surgeon was not a factor. Most surgeons had a decrease in their TES after academic promotion. CONCLUSIONS: A reliable system of teaching evaluation was achieved. Teaching scores were stable over time for good and average teachers, whereas the poor teachers tended to improve their scores. PMID- 8678212 TI - Pharmacodynamics of antimicrobial therapy in surgery. AB - INTRODUCTION: "Pharmacodynamics" refers to the relationship of drug concentrations in serum or tissues to effects on biologic systems. Concepts used to describe antimicrobial pharmacodynamics include the minimal inhibitory concentration (MIC), the minimal bactericidal concentration (MBC), and serum bactericidal titers (SBT), as well as post-antibiotic effect. METHODS: Pertinent published literature was identified through a MEDLINE search. RESULTS: Aminoglycosides have a concentration-dependent effect on bacteria killing and possess a relatively long postantibiotic effect. Given these characteristics, single-daily dosing, where the total daily dose with a traditional aminoglycoside regimen is given as one dose, may be more efficacious compared with more frequent dosing. For beta-lactam antimicrobials, bacterial killing is related to the duration of time that the free drug concentration exceeds the bacterial MIC. Beta lactam antimicrobials have been shown to have no, or a short postantibiotic effect. Beta-lactam antimicrobials may be more effective when administered as continuous intravenous infusions. CONCLUSIONS: Pharmacodynamic variation may result from differences in drug sensitivity among individuals and the nature of the interaction between antimicrobials and microorganisms. Proper use of pharmacokinetic and pharmacodynamic principles can result in more effective and less toxic antimicrobial regimens. PMID- 8678213 TI - [Allelic loss on chromosome 11q13 in male breast cancer]. PMID- 8678214 TI - [A Mediterranean model of bioethics?]. PMID- 8678215 TI - [Emotion and subjectivity]. PMID- 8678216 TI - [Ovariectomy in a perimenopausal woman]. PMID- 8678217 TI - [Centenary of the discovery of x-rays]. PMID- 8678218 TI - [A centenary of x-rays]. PMID- 8678219 TI - [Goya, a cyclothymic genius]. PMID- 8678220 TI - [Dental implants]. PMID- 8678221 TI - [Variability factors in pharmacotherapy (from the easily foreseeable to the usually not thought about)]. PMID- 8678222 TI - [Maternal placenta]. PMID- 8678223 TI - Missing O-rings and volatile agents. PMID- 8678224 TI - Use of a modified Magill's forceps to place a flexible laryngeal mask. PMID- 8678225 TI - Neonatal resuscitation and the laryngeal mask. PMID- 8678226 TI - Propofol-induced bronchodilation in status asthmaticus? PMID- 8678227 TI - Co-sedation in the critically ill. PMID- 8678228 TI - Local anaesthesia and venous cannulation. PMID- 8678229 TI - Local anaesthesia and venous cannulation. PMID- 8678230 TI - Suxamethonium-related hyperkalaemic cardiac arrest in intensive care. PMID- 8678231 TI - Rocuronium in the myasthenic patient. PMID- 8678232 TI - Postoperative nausea and vomiting--the importance of power. PMID- 8678233 TI - Pulse oximetry during cardiopulmonary resuscitation. PMID- 8678234 TI - Modified Macintosh laryngoscope blade and the real McCoy. PMID- 8678235 TI - Anaesthetic assistants during electroconvulsive therapy. PMID- 8678236 TI - The treatment of postoperative shivering. PMID- 8678237 TI - Is the microlaryngeal tube the right solution? PMID- 8678238 TI - Misplacement of a mini-tracheostomy. PMID- 8678239 TI - Fatal subclavian artery haemorrhage. PMID- 8678240 TI - Computerised discharge letters from the intensive care unit. PMID- 8678241 TI - No blood or blood products. PMID- 8678242 TI - Clonidine--an adjunct in isoflurane-N20/02-relaxant anaesthesia. PMID- 8678244 TI - The fetus comes of age. PMID- 8678243 TI - Pregnancy-induced hypertension or a normal variant? PMID- 8678245 TI - Interobserver variation in the chest radiograph component of the lung injury score. AB - The lung injury score is a semi-quantitative system used in the definition and grading of the acute respiratory distress syndrome. It is composed of two, three or four equally weighted components. One component is derived from the chest radiograph, which may contribute up to 50% of the total score. A score of 1 is awarded for each quadrant on the chest radiograph which contains alveolar consolidation. We examined the interobserver variation between two anaesthetists, two radiologists and two critical care physicians who scored blindly 100 chest radiographs from patients with adult respiratory distress syndrome. There was very good agreement between the two radiologists in the total scores (kappa 0.97) and in individual scores in each of the 4 quadrants (kappa 0.97-1.0). The agreement between anaesthetists and radiologists was only fair for the total score (kappa 0.37-0.42), but moderate to good for individual quadrant scores (kappa 0.43-0.73). The agreement between the two anaesthetists was moderate for individual quadrant scores (kappa 0.44-0.60), but only fair for total score (kappa 0.34). There was poor agreement between the two critical care physicians for total score (kappa 0.05) and for individual quadrant scores (kappa 0.04 0.20). Agreement between the physicians and other observers was poor to fair for the total score (kappa 0.12-0.32) and poor to moderate for the individual quadrant scores (kappa 0.15-0.63). Both anaesthetists and physician 2 underestimated the overall chest scores (median scores 2, 3 and 1 respectively) in comparison to the radiologists (median scores 3.5). Physician 1 significantly overscored (median score 4). The chest radiograph component of the lung injury score can be consistently assessed by radiologists, but significant variations may be introduced when assessed by other clinicians. This has significant implications for the use of the lung injury score in studies of adult respiratory distress syndrome and other studies which incorporate radiographic appearances in the definition. PMID- 8678246 TI - Effects of magnesium sulphate on suxamethonium-induced complications during rapid sequence induction of anaesthesia. AB - Twenty patients were studied in a double-blind manner to investigate whether magnesium sulphate, when given during a rapid-sequence induction of anaesthesia, lessens the side effects caused by suxamethonium. Patients were randomly allocated to two groups; equal volumes of either magnesium sulphate (40 mg.kg-1) or saline were given during rapid-sequence induction of anaesthesia, after thiopentone but before the administration of suxamethonium (1.5 mg.kg-1). The changes in the serum potassium concentration, the degree of muscle fasciculations and the presence of postoperative myalgia were recorded. The mean serum potassium concentration increased by 0.08 mmol.l-1 in the magnesium group and by 0.1 mmol.l 1 in the control group at 2 min after injection of suxamethonium; in neither group was there a significant increase from baseline values. The systolic blood pressure and heart rate increased in both groups after tracheal intubation. The incidence of fasciculations was significantly lower in the magnesium group. Magnesium did not clinically prolong muscle relaxation. There was no difference between the groups in the incidence of myalgia after surgery (one patient in each group). Since no significant increase in the serum potassium concentration was demonstrated, no assessment could be made of the effect of magnesium sulphate on the serum potassium concentration after administration of suxamethonium. PMID- 8678247 TI - Assessment of recovery following day-case arthroscopy. A comparison between propofol and isoflurane-based anaesthesia. AB - Fifty healthy patients, aged 15-45 years, undergoing day-case arthroscopy, participated in a study to assess aspects of recovery and mood. Psychomotor tests, including the p-deletion test and the Trieger dot test, were performed pre operatively and mood was measured using the mood adjective checklist. Anaesthesia in all patients was induced with propofol and a laryngeal mask airway was inserted immediately. All patients received alfentanil as the intra-operative analgesic. The patients were randomly allocated to receive one of two different regimens for maintenance of anaesthesia: propofol group--maintenance with an infusion of propofol 10 mg.kg-1.h-1 for 15 min followed by 6 mg.kg-1.h-1 and nitrous oxide and oxygen (bolus doses of propofol were given if anaesthesia was deemed to be light); isoflurane group--maintenance with isoflurane (inspired concentration 0.5-2.0%) in nitrous oxide and oxygen. Postoperatively, psychomotor tests were repeated every 30 min and mood was measured after 2 h and 24 h. Psychomotor recovery was quicker in the isoflurane group than the propofol group and had returned to baseline values in the isoflurane group by 60 min. The time to discharge was similar in both groups as was the incidence of side effects. There was no difference in mood scores between the groups either at the time of discharge or at 24 h. We conclude that psychomotor recovery is somewhat quicker when isoflurane-based anaesthesia is used for day-case arthroscopy, but other factors, including time to awakening, mood and time to discharge are similar for both techniques. PMID- 8678248 TI - A comparison of the stress response to laryngoscopy. The Macintosh versus the McCoy blade. AB - The cardiovascular changes and catecholamine concentrations were compared in 20 patients before and after laryngoscopy with either the Macintosh or the McCoy laryngoscope blades. Following induction with fentanyl and thiopentone and muscle relaxation with vecuronium the vocal cords were visualised for 10 s with either the Macintosh or McCoy blade, chosen at random. Heart rate, arterial blood pressure and plasma noradrenaline and adrenaline concentrations were measured before, and at, laryngoscopy, and 1, 3 and 5 min later. There was a significant increase in both heart rate (33%) and arterial blood pressure (27%) after laryngoscopy using the Macintosh blade (p < 0.01). Use of the McCoy blade did not result in any significant change in either heart rate or arterial blood pressure. There was a slight increase (p > 0.05) in plasma noradrenaline concentrations using the Macintosh blade which persisted for 5 min after laryngoscopy. This was not observed with the McCoy blade. There was no change in plasma adrenaline concentrations with either blade during the 5 min after laryngoscopy when compared to the values before laryngoscopy. It is concluded that the stress response to laryngoscopy is less marked with the use of the McCoy blade and is probably due to a reduction in the force necessary to obtain a clear view of the larynx. PMID- 8678249 TI - The influence of isoflurane on a continuous infusion of mivacurium. AB - Sixty surgical patients were studied to evaluate the neuromuscular effects of mivacurium 0.15 mg.kg-1 (2 x ED95) for tracheal intubation. After intubation the patients were randomly allocated to receive alfentanil with either propofol (starting with 9 mg.kg-1 h-1, reducing to 6 mg.kg-1 h-1 after 20 min) or isoflurane (0.5% end-tidal). In addition, all the patients were given a continuous infusion of mivacurium 10 micrograms.kg-1 min-1 after tracheal intubation which was adjusted to maintain 90% depression of T1. Following mivacurium 0.15 mg.kg-1 T1 decreased below 25% in all but four patients. Mean (SD) percentage maximum block attained was 92.9% (12.5) after 309 (89)s. Tracheal intubation was completed 232 (155) s after administration of the relaxant and intubating conditions were graded as 'excellent' or 'good' in 56 patients. Although the mean (SD) mivacurium infusion rate for maintaining T1 at 10% was higher in the propofol group, 4.8 (2.1) compared with 4.4 (2.0) micrograms.kg-1 min-1 in the isoflurane group, this was not significantly different (p > 0.05). The mean (SD) recovery index was prolonged in the isoflurane patients, 757 (508)s, compared to those receiving propofol, 466 (219)s (p < 0.05). PMID- 8678250 TI - Comparative study of limited intentional normovolaemic haemodilution in patients with left main coronary artery stenosis. AB - Intentional normovolaemic haemodilution is a blood saving technique which can be performed when major blood loss is expected. Severe coronary artery disease and particularly left main stenosis are considered a contraindication for intentional normovolaemic haemodilution. The effects and complications of limited intentional normovolaemic haemodilution in patients with left main coronary artery stenosis scheduled for coronary artery bypass grafting were evaluated. Patients were randomly allocated to two groups: group A (n = 15) underwent limited intentional normovolaemic haemodilution to a haematocrit of 34%; group B (n = 15), no intentional normovolaemic haemodilution was performed. In both groups succinyl linked gelatin was used to maintain normovolaemia. Haemodynamic parameters were kept as constant as possible. In group A, a mean (SD) volume of 785 (250) ml of blood was withdrawn [range 500-1200 ml]. ST segment changes occurred on the ECG in three patients in each group. There were no statistically significant differences for frequency, maximum deflection and duration of ST-segment changes. Limited intentional normovolaemic haemodilution can be performed safely in patients with left main coronary artery stenosis. In this study it was not associated with increased frequency, severity or duration of ST-segment changes, or with arrhythmias or haemodynamic instability. PMID- 8678251 TI - The effect of the anticoagulation regimen on endothelial-related coagulation in cardiac surgery patients. AB - Heparin is still the most commonly used anticoagulant in cardiac surgery necessitating cardiopulmonary bypass. In recent years, endothelial-related coagulation (e.g. thrombomodulin/protein C-system) has enlarged our knowledge of the regulation of haemostasis. In a controlled randomised study, the influence of different regimens of anticoagulation on the thrombomodulin/protein C-system was studied. Sixty patients undergoing elective coronary artery bypass grafting were randomly allocated into four groups (n = 15) to receive: 300 IU.kg-1 of heparin before bypass; 600 IU.kg-1 of heparin; 300 IU.kg-1 of heparin as bolus followed by a continuous infusion of 10 000 IU.h-1 until the end of bypass; or 600 IU.kg-1 of heparin plus 'high dose' aprotinin (2 million IU of aprotinin before bypass, 500 000 IU.h-1 until the end of the operation and 2 million IU added to the bypass pump prime). Grouping was blinded for the surgeon and the anaesthetist. Plasma concentrations of thrombomodulin, protein C and (free) protein S as well as thrombin/antithrombin III were measured by enzyme-linked-immunosorbent assays after induction of anaesthesia, during and after bypass, at the end of surgery, 5 h after bypass, and on the first postoperative day. Activated clotting time was significantly longer during bypass in group 2 (566 (60)s) and group 4 (655 (59)s), whereas standard coagulation parameters showed no differences between the four groups. Blood loss and use of homologous blood and blood products were highest in groups 2 and 3. Thrombomodulin plasma levels were similar (and normal) at baseline (< 40 ng.l-1), decreased during bypass and reached baseline values postoperatively without showing significant group differences. Protein C did not show any differences among the groups within the investigation period. 'Free' protein S plasma levels were most reduced in group 1 (from 68 (8)% to 48 (9)% after bypass). Thrombin/antithrombin III plasma concentrations increased most in groups 1 (to 69 (14) micrograms.l-1 after bypass) and 2 (to 48 (7) micrograms.l-1 after bypass), whereas they remained significantly lower in groups 3 and 4. The thrombomodulin/protein C-system was not significantly influenced by the regimen of anticoagulation. Administration of 'high-dose' heparin was associated with the highest blood loss, which could not be related to endothelial-associated coagulation. PMID- 8678252 TI - The effect of a cervical collar on the tidal volume of anaesthetised adult patients. AB - Semi-rigid cervical collars may be used to assist the stabilisation of the cervical spine during transport in patients suffering from major trauma. We have attempted to evaluate the effect of one such collar on airway patency in the presence of depressed airway reflexes. Thirty-eight patients undergoing anaesthesia via face mask with spontaneous ventilation were studied. Tidal volume was measured with the airway in three different positions, both with and without a collar. The collar made no statistically significant difference to tidal volume in any position. Changing support of the airway increased tidal volume both with and without the collar. Patients fitted with an incorrectly sized collar may develop upper airway obstruction in the presence of impaired consciousness. Experience should be gained in the correct fitting of semi-rigid collars. PMID- 8678253 TI - Lessons from in vitro testing of spinal needles. AB - In vitro testing of spinal needles is intended to identify a best buy, but such tests are not necessarily good indicators of clinical performance and some bench tests appear to conflict with mock clinical assessments. Discrepancies can be explained by examining the role of the hub. The Visual Probability Test, which assesses the needle as a complete unit, would appear to be more useful than the more complex measurements of shaft flow. Not all needle manufacturers use the same gauge, creating confusion when comparisons are made. Packaging frequently fails to give adequate information. Changes in hub design could permit earlier identification of dural puncture. PMID- 8678254 TI - Early proponents of cardiac massage. AB - Open-chest cardiac massage in humans to treat chloroform syncope was first performed by Niehans in Berne and Langenbuch in Berlin in the late 1880s. Closed chest cardiac massage in humans was advocated by Koenig and Maass in Gottingen in the last two decades of the 19th century. The closed technique was used in Central Europe for several decades to treat chloroform syncope. PMID- 8678255 TI - The supine hypotensive syndrome. 1960. PMID- 8678256 TI - Severe hyperventilation and respiratory alkalosis during pressure-support ventilation: report of a hazard. AB - A 53-year-old woman with a flaccid quadriparesis developed severe hyperventilation and respiratory alkalosis during pressure-support ventilation. A gas leak in the ventilator system caused a loss of positive end-expiratory pressure and autocycling of the ventilator. Large ventilator breaths were then delivered because a high level of pressure support was set in a patient with low respiratory impedance. The complication is rare and its occurrence requires a combination of patient and equipment factors. Awareness of the responsible factors will promote detection and prevention of the hazard. PMID- 8678257 TI - Anaesthesia in a child with Patau's syndrome. AB - A 5-year-old girl who had Patau's syndrome associated with double outlet right ventricle and pulmonary stenosis required general anaesthesia for the formation of a modified Blalock-Taussig shunt. PMID- 8678258 TI - Patients' attitudes to rectal drug administration. AB - One hundred adult patients attending for day case surgery were surveyed by anonymous questionnaire in order to determine their attitudes to rectal drug administration. Fifty four patients did not want an analgesic drug (diclofenac sodium) administered rectally whilst under anaesthesia, all preferring to take it orally if available. Ninety eight patients thought that drugs administered per rectum should always be discussed with them beforehand and a few had very strong feelings about this route of administration. We suggest that prescribers of rectal diclofenac should always discuss it with patients pre-operatively. Whilst many are happy to have suppositories, some young patients are sensitive about this and prefer to take such medication by mouth. PMID- 8678259 TI - Postoperative laryngeal competence. The laryngeal mask airway and tracheal tube compared. AB - We investigated the incidence of postoperative laryngeal incompetence in 40 patients undergoing lower limb arthroplasty. Patients were randomly allocated to one of two groups using a standardised general anaesthetic/muscle relaxant technique; in group A the patients' lungs were ventilated via a laryngeal mask airway and in group B via a tracheal tube. Following recovery from general anaesthesia, at a time when patients were considered safe for discharge back to the general ward, they were asked to swallow 20 ml of barium, and an immediate portable chest X ray was taken. The X rays were examined for evidence of tracheopulmonary aspiration. Contrary to previous studies the incidence of aspiration was low, occurring in only one patient. This aspiration was, however, clinically silent. The exact mechanism of this apparent laryngeal incompetence, which occurred in a patient from the tracheal tube group, is unclear. Due to the relatively small numbers of patients studied no conclusions can be drawn about the relative benefits of the use of the laryngeal mask airway with regard to postoperative laryngeal competence. PMID- 8678260 TI - Comparison of the reinforced laryngeal mask airway and tracheal intubation for nasal surgery. AB - Airway maintenance and protection during anaesthesia and recovery provided by the reinforced laryngeal mask airway was compared with the sequential use of a tracheal tube followed by the Guedel airway in 66 patients having anaesthesia for nasal surgery. One patient was withdrawn from the laryngeal mask group because the airway was difficult to position. All patients had an oropharyngeal pack inserted and Moffett's solution instilled into the nasal cavities. At the end of surgery the nasal cavities were packed. During operation airway maintenance was good and airway protection was equally effective in both groups. Contamination of the lower airway occurred in only five patients. During recovery from anaesthesia the laryngeal mask and Guedel airway were well tolerated by most patients, but only the mask laryngeal provided an unobstructed airway in all patients. The laryngeal mask protects the larynx from contamination during and after operation until the return of the patient's own protective reflexes. PMID- 8678261 TI - Metoclopramide and prochlorperazine do not decrease propofol hypnotic requirements. AB - One hundred patients scheduled for minor surgery were given either saline, metoclopramide 0.1 mg.kg-1 or 0.2 mg.kg-1, or prochlorperazine 0.1 mg.kg-1 or 0.2 mg.kg-1 before induction of anaesthesia with a fixed rate infusion of propofol. Neither metoclopramide nor prochlorperazine reduced the induction dose of propofol. The possibility that these agents increased the induction dose could not be excluded. PMID- 8678262 TI - The anaesthetic management of Caesarean section for placenta praevia: a questionnaire survey. AB - The purpose of this study was to determine current UK anaesthetic practice regarding the use of regional anaesthesia in the management of patients with placenta praevia presenting for Caesarean section. We asked the members of the Obstetric Anaesthetists Association to complete a postal questionnaire in which a range of clinical situations involving varying degrees of placenta praevia were presented. In each case respondents were asked whether they would be willing to use regional anaesthesia. A wide variety of clinical practice was demonstrated. Anaesthetists with two or more obstetric sessions were more willing to use regional anaesthesia for Caesarean section in the presence of placenta praevia in both elective and emergency situations associated with haemorrhage. PMID- 8678263 TI - Bilateral paravertebral analgesia for major abdominal vascular surgery: a preliminary report. AB - Paravertebral analgesia is highly effective in blocking unilateral afferent input from the trunk, but its bilateral use does not appear to have been described. Eight patients undergoing major abdominal vascular surgery had pre-operative bilateral paravertebral catheters inserted. A dose of 25 ml of bupivacaine 0.5% divided between the two catheters provided the basis of an effective intra operative analgesic regimen which was continued postoperatively by infusion of bupivacaine for 4 days. Diclofenac and morphine completed a balanced analgesic regimen which was started pre-operatively and continued for 5 and 3 days respectively. Cardiovascular stability was notable throughout surgery, even with aortic clamping and all patients were extubated at the end of surgery. Good quality analgesia was obtained as assessed by low postoperative pain scores at rest and on movement. Three patients were not admitted to the intensive care unit, where mean stays for the group was 10 h (range 0-24 h) and mean hospital stay was 10 days (range 7-14). There were no additional demands made on the nursing staff and no postoperative pain-related complications occurred. We conclude that bilateral paravertebral analgesia, as part of a balanced analgesic technique, is an alternative method of providing effective afferent blockage for major abdominal surgery. PMID- 8678264 TI - An evaluation of two concentrations of hyaluronidase for supplementation of peribulbar anaesthesia. AB - We studied the effect of the addition of hyaluronidase to a mixture of lignocaine 2% and bupivacaine 0.75% for peribulbar anaesthesia in 60 patients presenting for elective intra-ocular surgery. Using a randomised, double-blind design, patients were allocated to one of three groups: no hyaluronidase (group A) (n = 20); hyaluronidase 50 iu.ml-1 (group B) (n = 20); hyaluronidase 150 iu.ml-1 (group C) (n = 20). The speed of onset of the block, the presence of akinesia, analgesia and the need for supplementary injections were assessed. The addition of 150 iu.ml-1 of hyaluronidase resulted in a mean (SEM) time to akinesia of 9.2 (0.9) min compared to 10.9 (0.9) min in the control group and 10.7 (1.1) min in those receiving the lower dose. Fewer patients in group C required a further injection (20%) than those in groups A (40%) or B (45%). None of the findings were statistically significant. Hyaluronidase was not associated with any complications. PMID- 8678265 TI - [Awareness during general anesthesia. Definition, incidence, clinical relevance, causes, avoidance and medicolegal aspects]. AB - The possibility that a patient during general anaesthesia is aware of the operation going on and aware of severe pain that might be remembered postoperatively must be very alarming to patients and anaesthetists alike. Furthermore, there is experimental evidence showing that conscious recall of intraoperative events is only the tip of an iceberg; it seems very probable that there is even a higher incidence of unconscious perception during general anaesthesia. Therefore, the following stages of intraoperative awareness must be distinguished: (1) conscious awareness with explicit recall and with severe pain; (2) conscious awareness with explicit recall but no complaints of pains; (3) conscious awareness without explicit recall and possible implicit recall; (4) subconscious awareness without explicit recall and possible implicit recall; (5) no awareness. The incidence of conscious awareness with explicit recall and severe pain has been estimated at less frequent than 1/3000 general anaesthetics. Conscious awareness with explicit recall but no complaints of pain has been reported in the literature with an incidence of 05-2%. With 7-72%, conscious awareness without explicit recall and possible implicit recall shows a very wide range of variation and its occurrence probably depends on the anaesthetic drugs used. Subconscious awareness with possible implicit recall has an incidence of up to 80%, but there are many methodological problems in demonstrating implicit memory of intraoperative events. Reports of intraoperative awareness do not come exclusively from cardiac surgery and obstetrics, but also from all other operative specialties. Postoperatively, patients who experience intraoperative awareness may develop a so-called post-traumatic stress syndrome. Symptoms involve re-experiencing the event awake or in dreams, sleep disturbances, depression, avoidance of stimuli associated with the event. The probability of the development of the post-traumatic stress syndrome seems to coincide with the experience of severe pain. When a patient complains of intraoperative awareness postoperatively the anaesthesiologist should discuss the event frankly with the patient. When the symptoms of the post-traumatic stress syndrome persist a psychotherapy should follow. Causes for intraoperative awareness may be: equipment failure, too-light anaesthesia, e.g. for a caesarean section or for emergency surgery in severely injured or polytraumatized patients, during cardiac surgery, bronchoscopy of difficult intubation. There is interindividual variability in anaesthetic effect; for example, chronic drug or alcohol abuse or overweight may make increased anaesthetic doses necessary. They are at risk for intraoperative awareness. Some general anaesthetics or anaesthetic procedures, e.g. the combination of a relaxant and N2O, opioid mono-anaesthetics, or opioids combined with benzodiazepines, seem to involve a higher risk of intraoperative awareness than do volatile anaesthetics. The bases of litigation are medical malpractice, breach of contract by the anaesthesiologist or lack of informed consent from the patient. Therefore, patients who are at risk of intraoperative awareness should be given detailed information on this special risk before the operation. PMID- 8678266 TI - [The effect of propofol on vomiting after strabismus surgery in children]. AB - Strabismus surgery in children is associated with a high incidence of postoperative nausea and vomiting (PONV). METHODS. Ninety ASA class I and II children aged 6 to 16 years and scheduled for strabismus surgery were randomly assigned to one of the following groups: Group 1 (n=30):thiopentone 4-6 mg/kg i.v., halothane 0.8-1.5%, N2O--O2 2:1, no opioids, droperidol 75 micrograms/kg i.v.; Group 2 (n=30):propofol 2-3 mg/kg i.v., propofol 6-9 mg/kg.h, alfentanil 30 micrgrams/kg.h, N2O-O2 2:1, no antiemetics; Group 3 (n=30):similar to group 2, but ventilation with air and O2 2:1. All patients were mechanically ventilated during anaesthesia and gastric contents were aspirated. Recovery scores were calculated for 2 h, emetic scores for 24 h postoperatively. PMID- 8678267 TI - [A new two-chamber model for examination and demonstration of transdural fluid leakage after spinal anesthesia]. AB - Various in vitro models have been introduced for comparative examinations of post dural-puncture trauma and measurement of liquor leakage through puncture sites. These models allow simulation of subarachnoid, but not of peridural, pressure. A new two-chamber-model realizes the simulation of both subarachnoid and peridural pressure and allows observation of in vitro punctures with video-documentation. Frame grabbing and (computer-aided) image analysis show new aspects of spinal puncture effects. Therefore, post-dural-puncture trauma and retraction can be objectively visualized by this method, which has not previously been demonstrated. METHODS: Two-chamber-model consists of two short aluminium cylinders. Native human dura patches (8X8 mm) from fresh cadavers are put (correctly oriented) between two special polyamide seals. Mounted between the upper and lower cylinder, these seals stretch the dura patch, which remains flexible and even in all directions. After filling of the lower (subarachnoid) and upper (peridural) chamber with Ringer lactate solution, positive or negative physiological pressure can be adjusted by way of two (Ringer lactate solution filled) infusion lines in each chamber. Puncturing is performed at an angle of 57 degrees to the dura. The model allows examination with epi-illumination and transmitted (polarized) light. In vitro punctures are observed through an inverted camera lens with an CCD-Hi8 video camera (Canon UC1HI) looking into the peridural chamber and documented by means of an S-VHS video recorder (Panasonic NV-FS200EG). After true-colour frame grabbing by a video digitizer (Fast Screen Machine II), single video frames can be optimized and analysed with a 486-66 MHz computer and conventional software (Corel Draw 3.0, Photostyler 1.1a, DDL Aequitas 1.00b). Punctures demonstrated in this paper have been done under simulation of a transdural gradient of 20 cm water similar to the situation of a recumbent patient (15 cm water in the subarachnoid and -5 cm water in the peridural chamber). The punctures were followed by short-time observation for up to 10 minutes. RESULTS: By making it possible to obtains a picture of the puncture site at 20-ms intervals (because of the PAL norm of 50 half-frames/s), video-documentation has become accepted as superior to conventional photography. When the Ringer lactate solution in the subarachnoid chamber is stained with methylene blue, transdural leakage can easily be observed. The result of this documentation technique demonstrate that not dural puncture can be atraumatic, when a 29-G Quincke needle is used. Calculation on the difference between a digitized video frame before and after the puncture clearly illustrates the dural trauma. Owing to their non-cutting tip, as expected, pencil-point needles leave diffuse changes across the dura patch, whereas a more local trauma was observed after puncturing with cutting-tip needles. The same computer calculation between two video frames allows examination of post-puncture-dural retraction of the puncture site. In this connection, we found that relevant dural retraction is a phenomenon limited to the first minute after puncture. Thin spinal needles with so-called modern tips (e.g. Whitacre, Atraucan) can minimize the post-dural puncture trauma, whereas thicker, conventional, spinal needles (Quincke) leave considerable dural defects. CONCLUSIONS: The two-chamber-model presented allows easy simulation of physiological subarachnoid and peridural pressure. The Ringer lactate solution in the subarachnoid chamber corresponds to the liquor, whereas that in the peridural chamber corresponds to the intercellular (peridural) space. The tension of the dural patch between the polyamide seals is similar to the situation in an anotomical model observed by spinaloscopy (in an earlier study). With the video documentation and computer-aided analysis technique introduced, dural trauma and retraction of the puncture site can be examined and demo PMID- 8678268 TI - [Fructose vs. glucose in total parenteral nutrition in critically ill patients]. AB - Parenteral nutrition required following surgery or injury should not only meet post-aggression caloric requirements but also match the specific metabolic needs so as not to worsen the metabolic disruptions already present in this situation. The primary objective of parenteral nutrition is body protein maintenance or restoration by reduction of protein catabolism or promotion of protein synthesis or both. Whether all parenteral energy donors, ie., glucose, fructose, other polyols, and lipid emulsions, are equally capable of achieving this objective continues to be a controversial issue. The objective of the present study was to answer the following questions: (1) Do glucose and fructose differ in their effects on the metabolic changes seen following surgery or injury, the changes in glucose metabolism in particular? (2) Can the observation of poorer glucose utilization in the presence of lipids be confirmed in ICU patients? PATIENTS, MATERIALS AND METHODS: A prospective, randomized clinical trial has been conducted in 20 aseptic surgical ICU patients to generate an objective database along these lines by performing a detailed analysis of the metabolic responses to different parenteral nutrition protocols. The effects of a glucose solution+lipid emulsion regimen vs fructose solution+lipid emulsion regimen on a number of carbohydrate and lipid metabolism variables were evaluated for an isocaloric (carbohydrates: 0.25 g/kg body weight/h; lipids: 0.166g/kg body weight/h) and isonitrogenous (amino acids: 0.0625 g/kg body weight/h) total nutrient supply over a 10-h study period. RESULTS: A significantly smaller rise in blood glucose concentrations (increase from baseline: glucose+lipids P<0.001 vs fructose+lipids n.s.) suggested that fructose had a small effect, if any at all, on glucose metabolism. Serum insulin activity showed significant differences as a function of carbohydrate regimen, i.e. infusion of fructose instead of glucose produced a less pronounced increase in insulin activity (increase from baseline: glucose+lipids P<0.001 vs fructose+lipids P<0.01). Impairment of glucose utilization by concomitant administration of lipids was observed neither in patients who first received glucose nor in those who first received fructose. CONCLUSIONS: As demonstrated, parenteral fructose, unlike parenteral glucose, has a significantly less adverse impact than glucose on the glucose balance, which is disrupted initially in the post-aggression state. In addition, the less pronounced increase in insulin activity during fructose infusion than during glucose infusion can be assumed to facilitate mobilization of endogenous lipid stores and lipid oxidation. Earlier workers pointed out that any rise in free fatty acid and ketone body concentrations in the serum produces inhibition of muscular glucose uptake and oxidation, and of glycolysis. These findings were recorded in a rat model and could not be confirmed in our post-aggression state patients receiving lipid doses commensurate with the usual clinical infusion rates. The serious complications that can result from hereditary fructose intolerance are completely avoidable if a careful patient history is taken before the first parenteral use of fructose. If the patient or family members and close friends, are simply asked whether he/she can tolerate fruit and sweet dishes, hereditary fructose intolerance can be ruled out beyond all reasonable doubt. Only in the extremely rare situations in which it is not possible to question either the patient or any significant other, a test dose will have to be administered to exclude fructose intolerance. The benefits of fructose-specific metabolic effects reported in the literature and corroborated by the results of out own study suggest that fructose is an important nutrient that contributes to metabolic stabilization, especially in the post-aggression phase and in septic patients. Hyperglycaemic states are largely prevented and fewer patients require ex PMID- 8678269 TI - [Inadvertant suture fixation of a Swan-Ganz catheter to the pulmonary artery following heart surgery]. AB - We report a patient undergoing redo cardiac surgery for combined replacement of the aortic and mitral valves. During the course of the operation, a Swan-Ganz catheter - positioned preoperatively - was accidentally fixed to the wall of the pulmonary artery. As this did not interfere with cardiac output measurement or the pulmonary artery pressure wave form, the fixation was not noticed until an attempt was made to remove the catheter. Fluoroscopy revealed both the catheter's immobility and the location of the suture fixation. The patient required a sternotomy to remove the catheter. In order to avoid this complication, the indications for pulmonary artery catheters during cardiac surgery should be carefully considered. If catheters are inserted, their mobility should by all means be ensured before the chest is closed. PMID- 8678270 TI - [Loss of brain stem auditory evoked potential waves I and II during controlled hypotension]. AB - For surgical removal of a malignant choroid melanoma, it is necessary to reduce systolic blood pressure to around 50-60 mmHg in order to prevent choroidal haemorrhages. However, blood pressure reduction is associated with the risk of cerebral ischaemia. We report a patient with a malignant choroid melanoma in whom waves I and II of the brainstem auditory evoked potentials (BAEP) disappeared during surgery under controlled arterial hypotension and hypothermia (31.1 degrees C). The waves could be recorded again immediately after the mean arterial pressure was increased from 48 to 77 mmHg. The oesophageal temperature had dropped by 0.3 degrees C at this time. The 2-channel electroencephalogram (EEG) showed no irregularities during this time period. A bilateral, reversible, apparently blood-pressure-dependent loss of waves I and II during arterial hypotension despite a normal EEG has to our knowledge not been previously described in the literature. The isolated loss of waves I and II with maintenance of waves III, IV, and V is unusual. The literature contains reports of acoustic neurinoma patients in whom only wave V could be recorded. This is regarded as an indication of continued impulse conduction despite the loss of waves I to IV. Others have observed a patient with temporary and reversible loss of BAEP wave I due to vasospasm of the internal auditory artery that apparently occurred during or shortly after manipulation of the internal auditory meatus. Assuming anatomic peculiarities in the blood supply to the generators of the BAEP waves, a stenosis of the basilar artery could be considered as the cause of the bilateral reversible loss of waves I and II. Another potential source could be induced hypothermia, but this does not seem very likely because the patient's temperature was 0.3 degrees C lower at the return of the waves than at their loss. PMID- 8678271 TI - [An atraumatic needle for continuous epidural and plexus anesthesia]. AB - The needle type introduced by Edward Tuphy for continuous spinal anaesthesia in 1944 is still used as the standard instrument for epidural anaesthesia up to the present day. Puncture of the dura and severance of the epidural catheter are the typical, though fare, complications of this procedure, giving rise to most of the actions brought for damage suffered during obstetric anaesthesia. The cerebral spinal fluid loss caused by thick needles can have serious consequences, including subdural and intracranial haematoma, cranial nerve pareses, labyrinthine hearing impairments and pneumocephalus. Special Sprotte needle for catheter introduction. In spinal anaesthesia and lumbar puncture the Sprotte needle has proven a very suitable instrument for the CSF loss syndrome and, to a large degree, post-spinal headaches. To adapt the atraumatic properties of this needle point for epidural anaesthesia the needle has been equipped with a plastic ramp to direct catheter insertion, and the opening geometry has been slightly modified for epidural application (see Fig. 1). The lateral catheter channel projects into the base of the needle point, which is thus shortened, and the edges of the needle opening are rounded so that the catheters cannot be severed. This needle bears the type designated "Special Sprotte needle" (EP no. 271715, USP no. 4842585). Needle diameter and application fields. The 1.1-mm (19.5 G) needle with 23-G catheter was introduced for epidural anaesthesia and continuous plexus anaesthesia at the Wurzburg University Hospital and has proven itself in routine clinical practice. A 20-G version is being tested with a 25-G catheter for continuous spinal anaesthesia at several centers in USA, because finer spinal catheters are not permitted there by the FDA. For continuous spinal anaesthesia this needle has been available without the modified opening geometry since 1989 in sizes 22 G and 24 G and is wide by used in Europe. CSE technique with special and standard Sprotte needles. Spinal analgesia or anaesthesia) can be performed with the special needle and 123-mm-long 27 G or 29 G standard Sprotte needles before placement of the peridural catheter. PMID- 8678272 TI - [Mixtures of infusion solutions and drugs. Compatibility and incompatibility]. PMID- 8678273 TI - [Clinical aspects of acute lung failure in adults (ARDS)]. AB - Acute respiratory distress syndrome (ARDS) is rare but beset with a high mortality rate. In recent years, however, a trend towards higher survival rates has been observed. High inspiratory oxygen concentrations, large tidal volumes, and high peak inspiratory airway pressures applied during mechanical ventilation have been identified as harmful to the lung and can contribute to the progression of ARDS. This had led to reconsideration of the sequelae of ventilatory therapy. Mechanical ventilation and other adjunctive strategies in ARDS have changed from the conventional approach aiming at normalisation of physiological ventilatory parameters to an elaborated approach that intends to protect the ventilated lung, prevent oxygen toxicity, recruit the infiltrated atelectatic and consolidated lung and reduce the anatomical and alveolar dead space. This new approach consists of various forms of pressure-controlled mechanical ventilation with PEEP and permissive hypercapnia, body position changes, and inhalation of nitric oxide. Should these procedures fail to improve impaired gas exchange, extracorporeal membrane oxygenation is an additional therapeutic option. None of these therapeutic procedures, however, has been tested against traditional standard treatment in a classical randomised controlled trial. The following review focuses on the latest insights into the pathophysiology, diagnosis, and treatment of ARDS. PMID- 8678274 TI - [Artificial respiration with technical aids already 5000 years ago?]. AB - Performed at the end of the mummification process, the "mouth-opening" ritual was a ceremony for the spiritual resurrection of the dead Pharaoh. The techniques used are astonishingly similar to modern emergency-room procedures. For example, the mouth-opening device was made of meteoric iron. In the Egypt of that time, the use of iron was very unusual and the higher levels of nickel in meteoric iron contributed to the stability of the instrument. There are other signs of medically sound methods in the mouth-opening ritual. Symbolically, the mummy's teeth were extracted, the eyes opened with a special device, and gold capsules inserted, perhaps in the sense of a breathing tube. There is a possibility that this ritual contains a forgotten synopsis of knowledge gained empirically in connection with the Egyptian cult of royal resurrection. PMID- 8678275 TI - [Sevoflurane or halothane in inhalational anesthesia induction in childhood. Anesthesia quality and fluoride level]. AB - Due to its low blood:gas partition coefficient (0.69) and its neutral odor, sevoflurane (S) is suitable for inhalational induction of anaesthesia. At the moment halothane (H) is preferentially used for this purpose due to its non irritating odor and the smoothness of anaesthetic action. However, experience is limited with the use of S in children, and concern exists about potential renal toxicity of its metabolite, i.e. fluoride. Therefore, we compared S and H in an open, randomized phase III trial. MATERIAL AND METHODS: With approval of the ethics committee and written informed parental consent, 40 children (age 1-10, mean 5.3 years, ASA class I and II) had anaesthesia induced without premedication (fresh gas flow 6 l/min, N2O/O2 = 65/35). Concentration of volatile anaesthetics was increased every 3-5 breaths (S: 0.8...3.2 vol%, H: 0.4...1.6 Vol%). The ciliary reflex was tested until it disappeared. Airway reflexes and excitation were quantified using a score. Upon venipuncture, relaxation and intubation, anaesthesia was maintained with S (Fi: 2.4 vol%) or H (Fi: 1.2 vol%) in N2O/O2 (3 l/min, etCO2 35-38 mm HG). Alfentanil was supplemented in repeated doses of 20 micrograms/kg. ECG, NIBP, SpO2, Fi and Fet of CO2 and volatile anaesthetics were continuously recorded. At the end of surgery anaesthetics were terminated abruptly and fresh gas flow was increased to 6 l/min O2. Time to the first purposeful movement was registered. Serum fluoride levels were determined immediately after venipuncture, at the end of surgery and 70 min later. Time to possible discharge from the PACU was quantified using a modified Aldrete score. Data were analysed with descriptive methods, Student's t-test or non-parametric tests as appropriate. RESULTS: Groups did not differ with respect to age, weight, sex, or type of surgery. Total dose of anaesthetics was 1.60 MACxh for S and 1.77 MACxh for H (p = 0.68). Table 6 shows the essential data. Mean arterial blood pressures and heart rate remained within +/- 20% of age-related normal values (Table 7). Mean serum fluoride level was 23.1 +/- 1.2 mumol/l at the end of surgery and decreased to 18.6 +/- 0.970 min later (Fig. 3). CONCLUSIONS: Sevoflurane is an alternative to halothane in pediatric inhalational anaesthesia, with a comparable, low incidence of airway irritation and smoothness of induction. Because of the significantly faster induction and recovery it seems superior to halothane. With the fluoride levels measured, an impairment of renal function is unlikely. PMID- 8678276 TI - [Serum fluoride concentrations and exocrine kidney function with sevoflurane and enflurane. An open, randomized, comparative phase III study of patients with healthy kidneys]. AB - Sevoflurane is a "new" volatile inhaled anaesthetic. Owing to its lower blood-gas solubility coefficient, emergence from anaesthesia is faster with sevoflurane than with isoflurane, enflurane, or halothane. Sevoflurane undergoes metabolic biodegradation, releasing inorganic fluoride ions that could produce nephrotoxicity. In this study, we compared serum inorganic fluoride concentrations (IFCs) in patients receiving either sevoflurane or enflurane. Furthermore, indices of renal function were evaluated until the 3rd postoperative day. METHODS: Thirty patients with no history of renal or hepatic disease and with an anticipated duration of anaesthesia of at least 3 h were studied in an open, prospective, randomised clinical trial. Anaesthesia was induced with fentanyl, thiopentone, and vecuronium for facilitating endotracheal intubation. Anaesthesia was maintained with sevoflurane or enflurane, 60% nitrous oxide in oxygen, and additional doses of fentanyl. Blood samples for serum IFCs were obtained preoperatively and 2 and, if possible, 4 and 6 h after starting sevoflurane or enflurane, at the end of anaesthesia, and 1, 2, 4, 8, 12, 24, 48 and 72 h post-anaesthesia. Fluoride analysis was performed using an ion-selective electrode. Indices of renal function (serum sodium, osmolality, creatinine, urea, and uric acid, urine specific gravity, osmolality, and pH) were evaluated preoperatively, at the end of anaesthesia, and 24, 48, and 72 h post-anaesthesia. RESULTS: The duration of anaesthetic exposure was approximately 1.65 MAC-h for both inhaled anaesthetics. Peak serum IFCs were higher with sevoflurane (34.5 mumol/l) than with enflurane (19.4 mumol/l). Fluoride levels decreased more rapidly with sevoflurane: 24 h post-anaesthesia there was no difference between sevoflurane and enflurane (Fig. 1). The area under the curve (AUC) was greater with sevoflurane (688 mumol/l.h) than with enflurane (591 mumol/l.h). For both groups correlation coefficients were higher for MAC-h and AUC than for MAC-h and peak serum IFC (Figs. 2 and 3). Indices of renal function did not change in either group. DISCUSSION: In our study 1.69 MAC-h sevoflurane produced peak serum IFCs of 34.5 mumol/l. This is in accordance with the investigation of Frink et al. [4], who reported approximately 30 mumol/l after 1.4 MAC-h sevoflurane. Peak serum IFCs with sevoflurane were twice those with enflurane. Within the first 24 h post-anaesthesia, fluoride levels decreased more rapidly after sevoflurane. AUC may be more important than peak serum IFC in evaluating patients who are at risk for renal concentrating defects. In our study there was no evidence of renal dysfunction in either group. PMID- 8678277 TI - [Desflurane and isoflurane. A comparison of recovery and circulatory parameters in surgical interventions]. AB - OBJECTIVES: The new volatile anaesthetic desflurane is characterized by very low blood-gas and tissue-blood partition coefficients, so that rapid induction of anaesthesia and shorter recovery times can be expected. The aim of this investigation was to compare the effects of desflurane and isoflurane on haemodynamics and recovery time when used as part of a balanced anaesthesia technique for elective surgery. METHODS: Fifty patients (18 years and older, ASA status I-III) scheduled for elective surgery (no laparoscopies) of at least 60 min duration were included in this open, randomised, phase-III clinical trial. After oral premedication with midazolam 7.5 mg 45 min before transfer to theatre, anaesthesia was induced with fentanyl 0.1 mg and thiopental 5 mg/kg; succinylcholine or vecuronium facilitated intubation. Desflurane and isoflurane, respectively, were used for maintenance of anaesthesia, both in 50% N2O, with the inspired concentration adapted to the degree of stimulation. All patients were ventilated in a semi-closed system; muscle relaxation was achieved with vecuronium. The electrocardiogram, heart rate (HR), and direct arterial blood pressure (BP) were recorded continuously and anaesthetic gas detection was performed by an infrared absorption technique. With termination of surgery the volatile anaesthetic was discontinued and the following emergence times recorded: spontaneous ventilation (VT > 300 ml), extubation, eye opening, correctly answering the date of birth, arrival in and possible discharge from the post anaesthesia care unit (PACU). RESULTS: In all, 49 patients were studied at random (desflurane n = 24, isoflurane n = 25). Data of demographics and anaesthetic technique were comparable in both groups (Tables 2 and 3). Anaesthetic elimination (expressed as FA/FAO) was significantly more rapid in the desflurane group 3 min after termination of anaesthesia (Fig. 1). Comparing the emergence times, there was no significant difference between desflurane and isoflurane: in both groups patients opened their eyes 12 min (median time) after termination of the operation (Table 4). Haemodynamics (HR, systolic and diastolic BP) were comparable at intubation, skin incision, end of surgery, extubation, and in the PACU (Fig. 2a, b). In 2 patients a rapid increase in the inspired concentration of desflurane during induction of anaesthesia produced a profound sympathoadrenergic reaction with an excessive increase in BP and HR. Similar reactions in other patients did not occur when the inspired concentration of desflurance was slowly increased. CONCLUSIONS: Despite the physicochemical properties of the new agent, emergence times were similar for desflurane and isoflurane in our study. These results, which are in contrast to those of some other authors, are most probably due to the study design, which included the use of premedicants (midazolam) and a low dose of fentanyl. The reported sympatho adrenergic reactions after rapid changes in the inspired concentration of desflurane during induction of anaesthesia have been observed by others as well. It seems that this initial cardiovascular stimulation can be avoided by slow increases in desflurane concentration. In summary, desflurane compares to isoflurane in balanced anaesthesia for general surgical procedures with regard to haemodynamics, while the time to awakening is not necessarely reduced. PMID- 8678278 TI - [Neuromuscular blockade after atracurium and alcuronium with propofol and thiopental]. AB - Does propofol or thiopentone enhance the effect of nondepolarizing muscle relaxants? We evaluated the effects of propofol and thiopentone on the pharmacodynamics of atracurium and alcuronium in 43 surgical patients (ASA I and II) under general anaesthesia. METHODS: The patients were randomized into five groups, A-E. Anaesthesia was induced in all patients with fentanyl 4 micrograms/kg i.v. Patients in groups A and C patients received thiopentone 7 mg/kg i.v., and relaxation was achieved with alcuronium 0.25 mg/kg (group A) and atracurium 0.5 mg/kg (group C). Electromyography (train of four, TOF) was used to determine the time of onset of relaxation (AZ) and the maximum degree of blockade (T%). The recovery times to 25%, 50% and 75% of baseline muscle strength were recorded. Additionally, the TOF ratio T4:T1 was calculated, indicating the probable end of relaxation at a ratio of 0.7. At the beginning of the recovery phase (T1 = 15%) propofol 1% 3 mg/kg was given, and the effect on the TOF was measured. Patients in groups B and D patients received total intravenous anaesthesia (TIVA) with propofol 1% 6-12 mg/kg per hour continuously after induction with 3 mg/kg. The action profile of alcuronium 0.25 mg/kg (group B) and atracurium 0.5 mg/kg (group D) were recorded. Group E patients received thiopentone (10 mg/kg per hour) under the use of atracurium 0.5 mg/kg. Ventilation was performed with 30%/70% oxygen and N2O. The results were analyzed for significance using the Mann-Whitney U-test (P = 0.019). RESULTS: A slight difference in AZ was noted for alcuronium under the use of TIVA between propofol and thiopentone: 13 min and 5 min, respectively. Otherwise, the pharmacodynamics (T% and recovery of neuromuscular function) of the two relaxants exhibited no major differences related to thiopentone, propofol or their combination. The TOF was not influenced under additional propofol application. Noteworthy were the wide distribution of the time course of action (up to 3 h) and the magnitude of T% depression under alcuronium. CONCLUSION: Propofol and thiopentone have no potentiating influence on the time course of action and the magnitude of relaxation with alcuronium and atracurium. Pharmacodynamics of nondepolarizing muscle relaxants do not seem to be influenced by these two hypnotics. PMID- 8678280 TI - [Percutaneous puncture technique for portofemorosubclavicular venovenous bypass in orthotopic liver transplantation]. AB - Portofemoro-axillary bypass systems are commonly used to treat adverse haemodynamic effects during the anhepatic phase of orthotopic liver transplantation (OLT). However, low shunt flows may reduce the efficacy of these bypass systems. In order to improve veno-venous bypass management, a percutaneous cannulation technique (PCT) was used to insert large-bore catheters (21 F) into the left femoral and subclavian veins. This study prospectively addresses the complications of the PCT in 195 adult patients undergoing 203 OLTs. METHODS: The left femoral and subclavian veins were cannulated preoperatively with 21 F single lumen catheters (DLP, Grand Rapids, MN, USA) using a Seldinger technique. Intra operatively, the centrifugal pump (Biopump, Biomedicus, Minnesota, USA) and the portal part of the bypass were connected with the femoral and subclavian catheters. Coagulation profiles, shunt flows, haemodynamic parameters, and complications during OLT associated with the bypass system were recorded. RESULTS: Percutaneous cannulation of the left subclavian and femoral veins was successful in 198 (97.6%) patients. Mean portofemoro-subclavian shuntflow was 4.3 (SD 1.3 l min-1). Although cardiac index (shunt 3.91 [SD 1.1] vs pre-shunt 4.42 [SD 1.0] l min-1 m-2, P < 0.05) and oxygen delivery (shunt 496 [SD 111] vs. pre shunt 562 [SD 153] ml ml-1.m-2, P < 0.05) were not maintained at pre-shunt levels, renal perfusion pressure stayed above 50 mm Hg during the anhepatic phase. Two intra-operative air embolism (0.98%) and one myocardial infarction (0.49%) at the beginning of the anhepatic phase were observed. There were no bleeding complications. CONCLUSIONS: The portofemoro-subclavian bypass can be performed by percutaneous cannulation without additional complications in patients undergoing OLT. Although haemorrhagic complications following central venous catheterisation are reported to occur in patients with haemostatic defects, none of them was observed in this study. Two events of air embolism and one cardiac arrest could not be related to the PCT. In conclusion, femoro subclavian percutaneous cannulation is a simple, rapid, and safe alternative to commonly used veno-venous bypass systems. PMID- 8678279 TI - [Combined "3-in-1"/sciatic nerve block. Block effectiveness, serum level and side effects using 700 mg mepivacaine 1% without and with adrenaline and prilocaine 1%]. AB - A high dose of local anaesthetic is necessary for the combined "3-in-1"/sciatic nerve block. Prilocaine is recommended for its low toxicity. However, in some patients prilocaine results in pronounced methaemoglobin formation due to toludine. Little has been known hitherto about the use of high-dose mepivacaine for the combined 3-1/sciatic nerve block. This study was undertaken to compare the use of 700 mg mepivacaine 1% and of 700 mg prilocaine 1%. METHODS: The study was approved by the ethics committee of our hospital. Once their informed consent had been obtained in writing 3 x 20 patients (ASA 1-2) undergoing planned surgery on the foot or ankle joint were enrolled in the study. The patients were randomized to the following three groups on a double-blind basis: group 1,700 mg mepivacaine without epinephrine; group 2,700 mg mepivacaine with 0.2 mg epinephrine (1:350,000); group 3,700 mg prilocaine 1%. Arterial blood samples for determination of local anaesthetic serum levels were collected over a 120-min period. We determined methaemoglobin and oxygen saturation before and 120 min after the blockade and continued these measurements for 6 h in group 3. At 15-min intervals, all patients were questioned about early signs of toxicity. The perioperative monitoring including blood pressure, ECG and pulse oximetry. Data were analysed using ANOVA and Student's t-test, P < 0.05 considered statistically significant. RESULTS: The blocking efficacy did not differ among the groups (groups 1, 2, 3:90%, 95%, 90%). The maximum mepivacaine serum level in group 1 was 3.91 micrograms/ml +/- 0.95 and 2.94 micrograms/ml +/- 0.58 in group 2 (Fig. 2). Over the entire observation period the addition of epinephrine resulted in a significant reduction of the serum level (between 60.3% at t = 15 min and 19.7% at t = 120 min). In the prilocaine group the maximum serum level was 2.07 micrograms/ml +/- 0.56, significantly less than in either mepivacaine group. No patient showed signs or symptoms of local anaesthetic toxicity. In the prilocaine group there was wide variation in methaemoglobin formation among the patient, with a median of 10.1% (Fig. 3, Table 3). Three patients showed a maximum methaemoglobinemia between 16% and 17%. Five patients were still cyanotic after 6 h when they were transferred to the ward. The fractional SaO2 values amounted to 88% (median) with a minimum of 80.3%. CONCLUSION: Both mepivacaine 1% and prilocaine 1% are appropriate local anaesthetics for the combined 3-in-1/sciatic nerve block at a dose of 700 mg. There was no difference in the blocking efficacy. No patient showed clinical signs or symptoms of a local anaesthetic toxicity. Following prilocaine we are sometimes faced with high methaemoglobinemia, which may necessitate prolonged monitoring. PMID- 8678281 TI - [Acute spinal subdural hematoma after attempted spinal anesthesia]. AB - This is a report of a case of a subdural haematoma with resulting paraplegia after attempted spinal anaesthesia. Epidural and subdural haematomas are rare complications after central neural blockade. The complication described here was the result of an unsuccessful attempt to puncture the spinal channel. The patient was a 72-year-old woman with a fracture of the left femoral neck, which it was intended to stabilize operatively. Findings that made lumbar spinal puncture difficult were severe overweight, and lordosis and scoliosis of the lumbar spine resulting from degenerative changes. Spinal anaesthesia was suggested because the patient had eaten shortly before and because she suffered from asthma. From the aspect of haemostasis no contraindications were present, and the anaesthesist was experienced in spinal anaesthesia even under difficult anatomical conditions. Several unsuccessful attempts were made to puncture the lumbar spinal channel while the patient was lying on her right side. It was also impossible to reach the spinal channel from a median or left paramedian approach. We used atraumatic pencil-point needles (Sprotte gauge 24, 90 mm). No blood was aspirated during any of the attempts. The surgical intervention was finally performed under a general anaesthetic in view of the urgency. No significant complications occurred during the operation, and no neurological abnormalities were observed immediately after or in the next 8 h after the operation. At 12 h after the operation a paraparesis was found caudal to L3. After this had been verified by radiological and neurological tests, neurosurgical decompression was carried out as quickly as possible. During the operation a distinct subdural haematoma without any detectable source of bleeding was discovered. Even after surgical revision and evacuation of the remaining haematoma it was not possible to reverse the paraplegia, in spite of rehabilitation measures. Despite a certain fragility of the vessel and pretreatment with pentoxifylline and thromboembolic prophylaxis with low-molecular heparin starting postoperatively, it must be assumed that a vessel accompanying one of the spinal nerves was punctured, possibly, the radiculomedullary vessel of Adamkiewicz. A similar case was published in 1988 by Parker. In the present case it must be assumed that the vessel was punctured during a paramedian approach in the area of the foramen intervertebrale, as the spinal channel was definitely not entered. Although this is an extremely rare complication, we conclude that close neurological controls are essential at least during the first 24 h after surgery, even after an unsuccessful attempt at central neural blockade. PMID- 8678282 TI - [The Bullard laryngoscope. An aid in unforseen difficult intubation]. AB - The standard procedure when difficulties are anticipated with intubation, e.g. following the clinical classification as per Mallampati, is the fibreoptic bronchoscopic method applied while the patient is awake. In the case of unexpected difficulties encountered during intubation while the patient is anaesthetized, a scenario that cannot be absolutely ruled out, e.g. in an emergency resection when there is no longer a simple method of returning the patient to the waking condition, and when problems are accentuated by seriously hampered mask respiration, aspiration risk, danger of hypoxia, and visual obstruction by secretions and blood, the fibrebronchoscope is no longer the instrument of choice. A larynx mask or a combination tube is probably a better option. Our experience has shown that the Bullard laryngoscope (BL) can help to improve the situation because, while it has similar advantages to the flexible bronchoscope, it can be operated almost exactly as quickly as a Macintosh intubation spatula. In contrast to the bronchoscope, fibreoptic orientation under impeded visual conditions caused by secretions and blood is, in our experience, much easier. The BL is routinely deployed, as an alternative to the Macintosh instrument, for practice purposes by all our colleagues in the department. It has proved to be remarkably effective: to date it has led to the target quickly and without complications in every case. As examples three case histories selected from a series of cases in which the BL was used have been highlighted. PMID- 8678283 TI - [Effectiveness of preclinical emergency management. Fiction or fact?]. AB - The current increase in the cost of health care must be considered as a severe threat to the prehospital emergency services system. Two examples have been selected--the patient with polytrauma and the patient in cardiac arrest--to demonstrate the dilemma between a need for objective data and the requirements of emergency patients. Study results obtained in trauma patients indicating that total prehospital time, including scene time, is correlated to patient outcome have led to the conclusion that at the scene treatment by emergency physicians may be dispensable. It has, however also been demonstrated that the time required for medical treatment at the scene is equivalent to 20% of the total scene time, thus representing only a fraction of the total prehospital time. Correlating the total prehospital time or scene time to outcome therefore appears absurd. The treatment principle of aggressive shock treatment in polytrauma needs critical reevaluation on the basis of results obtained by recent preclinical studies in patients with penetrating torso injuries. Small volume resuscitation could not be demonstrated to improve outcome in polytrauma patients, although a slight improvement in patients with brain injury may be assumed. Endotracheal intubation and early artificial ventilation are proven therapeutic principles in polytraumatized patients. Unfortunately, for ethical reasons randomised carefully controlled comparative studies can not be performed in polytrauma patients unless the patient is fully conscious. The importance of endotracheal intubation and artificial ventilation in unconscious trauma patients becomes apparent under conditions of anaesthesia where the application of the endotracheal tube averts regurgitation, aspiration and concomitant morbidity and mortality. The common causes of cardiovascular collapse and their pathomechanisms, as well as the mechanisms of cardiopulmonary resuscitation, have been widely investigated. Nevertheless, various aspects of their application are still controversial. The most recent study results have recommended initial ventilation prior to thoracic compression. New methods of assisting mechanical cardiopulmonary resuscitation, such as ACD CPR or vest CPR, have shown promising results in animal experiments. However, the importance of results obtained by preclinical randomised controlled investigations in humans need to be confirmed by further studies as to outcome. The efficacy of defibrillation in cases of ventricular fibrillation has been clearly demonstrated, particularly with a view to the interval between ventricular fibrillation and defibrillation. It has further been demonstrated that basic cardiopulmonary resuscitation preserves ventricular fibrillation and thus improves the chance of survival. The present generation of defibrillators has been further improved, particularly by the introduction of biphasic defibrillator wave forms, which may reduce the required energy, as well as possible complications, while offering an increase in the efficacy of defibrillation and a reduction in defibrillator size. Scientific emergency medicine is responsible not only for the development and validation of new methods and concepts, but in particular for their application under quality control conditions. Politicians require an improvement in the quality of the validation of emergency measures, although the instruments available for the investigation of these measures are known to be obsolete (experimental models, experimental design). Additionally, the financial support of research in emergency medicine suffers from being accourded low priority by public research funds such as the German Research Fund. However, in view of the rapid application of experimental results to daily practice it should be emphasized that patients also support research in emergency medicine via their direct financial contributions to the health insurance companies. PMID- 8678284 TI - [Patient-controlled analgesia with clonidine and piritramide]. AB - Following parenteral administration, clonidine has analgesic effects at both cerebral and spinal levels. Patient-controlled analgesia (PCA) makes it possible to determine equipotent dosages of analgesics by relating analgesic consumption per time to the levels of analgesia obtained in comparable patient populations. Therefore, we studied the equipotency ratios of clonidine and piritramide and the incidence of undesired side effects in the treatment of postoperative pain in patients undergoing maxillo-facial surgery. METHODS: After approval of the local ethics committee and informed consent 40 patients (age > 18 year, ASA I-III) were studied. Following randomization, the patients each received a PCA device containing either clonidine (bolus 30 micrograms), or piritramide (bolus 1.5 mg) for treatment of postoperative pain (lockout interval 5 min in both groups). During the postoperative period, pain was determined using a visual analogue scale, while analgesic consumption, sedation, haemodynamic parameters, respiration rate, and the occurrence of undesired side effects were documented additionally. RESULTS: The groups had comparable distributions of biometric data, duration of anaesthesia, and ASA classification. Pain level decreased significantly (P < 0.0001) in both groups during the first 2 h of PCA. Mean arterial pressure and heart rate were lower (P < 0.05) in the clonidine group 4 and 6 h after PCA onset, while the degree of sedation after 2 (P < 0.01) and 6 (P < 0.05) h was higher than in the piritramide group. Nausea and vomiting were more frequent (P < 0.05) in the piritramide group. Both groups showed a wide interpatient variation in analgesic requirement. The equipotency ratio clonidine/piritramid was 1:63.7. CONCLUSION: Intravenous clonidine is a potent analgesic and is suitable or the treatment of postoperative pain following maxillo-facial surgery. The analgesic potency of 150 micrograms clonidine i.v. was equivalent to that of 9.56 mg piritramide i.v. Nausea and vomiting occurred more rarely in the clonidine group, while deeper sedation was observed more frequently than in the piritramide group. Owing to the wide interindividual variation of analgesic consumption, clonidine dosages have to be adjusted to the actual requirements. PMID- 8678285 TI - [Comments on the contribution by K. Sterzik et al. The effect of different anesthesia procedures on hormone regulation in the woman]. PMID- 8678286 TI - [Ambivalence to prolonging life from the medical ethics viewpoint]. PMID- 8678287 TI - Models of gel electrophoresis. PMID- 8678288 TI - Large-scale production of palindrome DNA fragments. AB - Our structural studies of nucleosomes necessitated the production of over 100 mg of a 146-bp perfect palindrome DNA for use in the reconstitution of perfectly symmetrical nucleosome core particles for detailed X-ray crystallographic analysis. The propagation of palindromic DNA DNA sequences by bacterial culture is hindered by the instability of these sequences during bacterial replication and recombination. While the loss of some palindrome sequences can be eliminated by the use of sbcB or sbcC mutants of Escherichia coli, not all palindrome containing plasmids are faithfully maintained by these strains. The production of large quantities of palindrome DNA that involves production of plasmid containing multiple copies of the repeating unit of the palindrome which are isolated by restriction digestion and ligated in vitro to form the palindrome DNA. The procedure has resulted in the production of over 20 mg of a 146-bp DNA fragment in 2 weeks. PMID- 8678289 TI - Detection of arginine-ADP-ribosylated protein using recombinant ADP ribosylarginine hydrolase. AB - We made use of ADP-ribosylarginine hydrolase to detect arginine-ADP- ribosylated proteins. The hydrolase was expressed in Escherichia coli as a protein fused with glutathione S-transferase (GST). The fusion protein GST-ADP-ribosylarginine hydrolase catalyzed the hydrolysis of alpha-ADP-ribosylarginine to produce ADP ribose and arginine. Casein ADP-ribosylated with [32P]NAD and chicken heterophil arginine-specific ADP-ribosyltransferase served as a substrate for the recombinant ADP-ribosylarginine hydrolase and the released ADP-ribose was determined. Protein ADP-ribosylated by cholera toxin could serve as substrate of the hydrolase but protein ADP-ribosylated by pertussis toxin, diphtheria toxin, or C(3) enzyme of Clostridium botulinum could not. The hydrolase did not release the radioactivity incorporated into isolated rat liver nuclei incubated with [(32)P]NAD or in bovine brain cytosol incubated with [(32)P]ADP-ribose. In homogenate of mouse heart which contained arginine-specific ADP ribosyltransferase, labeling of a 55-kDa protein by incubation with [(32)P]NAD was removed by ADP-ribosylarginine hydrolase treatment; hence, the specific hydrolysis of ADP-ribose-arginine bond by GST-ADP-ribosylarginine hydrolase can be used to detect the arginine-ADP-ribosylated proteins in crude preparations. Arginine--ADP-ribosylated proteins in crude preparations. Arginine-ADP ribosylated proteins in mouse spleen lymphocytes were identified using this method. PMID- 8678290 TI - Studies on the rate and control of antibody oxidation by periodate. AB - The oxidation of antibody carbohydrate residues by periodate is a common approach for the site-specific immobilization or modification of antibodies for use in various bioanalytical methods. This study examined the time dependence of this oxidation process under a variety of pH, temperature, and concentration conditions. Polyclonal rabbit immunoglobulin G (IgG)was used as the model system for these studies. Flow-injection analysis and a hydrazide label (Lucifer yellow CH) were used to monitor the progress of the oxidation reaction. It was found that the number of oxidized sites that were available for labeling could be varied between one and eight groups per antibody by adjusting the time, pH, periodate concentration, or reaction temperature. In each case, most of these groups were produced during the first 30-60 min of the reaction. A comparison was made between these results and those of previous studies that have examined the effects of periodate treatment on amino acid residues and antibody activity. From this work, general guidelines were developed for the control and optimization of antibody oxidation for use with assays that require either high or low levels of antibody modification. PMID- 8678291 TI - New methods using polyvinylidene difluoride membranes to detect enzymes involved in glycosphingolipid metabolism. AB - Two new methods are described using polyvinylidene difluoride (PVDF) membranes to detect enzymes involved in glycosphingolipid metabolism. One is the detection of enzymes on a PVDF membrane to which glycosphingolipids have been transferred from an HPTLC-plate by TLC blotting. The glycosphingolipids on the membrane were incubated with an enzyme preparation, and the resulting product was detected by immunostaining with a monoclonal antibody directed to the product. IV(3)NeuAc(alpha)Lc(4)Cer that had been transferred to a PVDF membrane was incubated with Clostridium perfringens sialidase. Lc(3)Cer then was transferred to the membrane, and the whole incubated with bovine milk beta1-4 galactosyltransferase, after which the product, nLc(4)Cer, was detected by immunostaining with the monoclonal antibody H11 that recognizes the GAl(beta)1 4GlcNAc(beta)1-3Gal structure of neolactoseries glycosphingolipids. This method detects glycosphingolipid-metabolizing enzymes that produce the same epitope. The second method is the detection of enzymes located on a polyacrylamide gel. A sialidase preparation from C. perfringens was subjected to native polyacrylamide electrophoresis then transferred to a PVDF membrane impregnated with IV(3)NeuAc(alpha)nLc(4)Cer as the enzyme substrate. The membrane then was incubated, and the resulting product, nLc(4)Cer, detected by immunostaining with the monoclonal antibody H11. The area stained shows the location of the sialidase on the polyacrylamide gel. The method is effective for determining the apparent molecular weight(s) of the enzyme(s) in the crude enzyme preparation. This was demonstrated by using crude sialidase preparation from C. perfringens. PMID- 8678292 TI - Design and synthesis of fluorescence energy transfer dye-labeled primers and their application for DNA sequencing and analysis. AB - We have designed and synthesized fluorescent oligonucleotide primers having improved fluorescence and electrophoretic properties by exploiting the concept of resonance fluorescence energy transfer (ET). These primers carry a fluorescein derivative at the 5' end as a common fluorescence donor and other fluorescein and rhodamine derivatives attached to a modified thymidine within the primer sequence as acceptors. These primers all have strong absorption at a common excitation wavelength (448 nm) and fluorescence emission maxima of 525, 555, and 605 nm. The fluorescence emission intensity of the ET primers increases as the spacing between the donor and acceptors is increased, and of the spacings studied the strongest fluorescence was observed when the number of nucleotides between the donor and acceptors is 10. The electrophoretic mobilities of the primers were also found to be a function of the spacing between the donor and the acceptors, and mobilities of the single base extension DNA fragments generated with primers (F10F, F10J, F10T, and F10R) is 2- to 14-fold greater than that of the corresponding primers labeled with only one dye. The increased fluorescence intensity of the ET primers and the substantially similar mobilities of the DNA fragments generated with the four ET primers allow four-color DNA sequencing on a capillary electrophoresis DNA sequencer using a single laser line at 488 nm for excitation and without applying mobility shift adjustments. With single-stranded M13mp18 DNA as the template, a typical run with the ET primers on a commercial sequencer provided DNA sequences with 99-100% accuracy in the first 500 bases using 8-fold less DNA template than that typically required using T7 DNA polymerase. PMID- 8678293 TI - Quantitation of platelet-activating factor in biological samples using liquid chromatography/mass spectrometry with column-switching technique. AB - A procedure is described for the fully automated quantitative determination of platelet-activating factor (PAF) using liquid chromatography/fast atom bombardment mass spectrometry (LC/FAB-MS) with two types of column-switching techniques. Various parameters in LC/FAB-MS were optimized, and the use of a microbore column allowed highly selective detection of PAF. A column-switching system was incorporated to minimize band broadening and to increase the permissible injection volume. Analysis of authentic PAF indicated that the limit of quantitation was at the low picogram level (about 50 pg/ml). Another system using both a strong cation-exchange column and an ODS column in tandem was developed for the analysis of PAF in blood samples. These methods were validated with standard samples and applied to the determination of PAF in human polymorphonuclear neutrophils stimulated by addition of a calcium ionophore and in human blood. PMID- 8678294 TI - High-performance liquid chromatographic analysis of biological and chemical heme polymerization. AB - Free hematin can be converted to a stable polymer both chemically, by heating hematin in acid suspensions, or biologically, in the food vacuoles of malaria. A high-performance liquid chromatographic assay has been developed which can separate and quantitate both free hematin and the polymer (beta-hematin), based on the differential solubility of the two compounds. Ion-pair reverse-phase chromatography, utilizing tetramethylammonium chloride and heptane sulfonate as the ion-pair agents in the presence of 40% acetonitrile, was performed on a polymeric-resin-based column with a phenyl bonded phase. Initiating the runs at pH 2.5 led to elution only of the free hematin, and a subsequent shift to pH 12.0 converted the beta-hematin back to hematin which then eluted separately. The method was found to have a linear range of detection from 78 pmol to 20 nmol injected hematin and intra- and interday variations of 9.71 and 12.46%, respectively. The assay was used to study several basic aspects of heme polymerization in vitro, including effects of hematin and beta-hematin concentration on the rate of polymerization. PMID- 8678295 TI - Quantification of 5-fluorouracil incorporation into RNA of human and murine tumors as measured with a sensitive gas chromatography-mass spectrometry assay. AB - 5-Fluorouracil (5FU) can exert its cytotoxic activity by either inhibition of thymidylate synthase or incorporation into RNA. The extent and importance of the latter in tumors of patients are not clear, due to the lack of sensitive and reproducible methods. RNA from 5FU-treated human WiDr colon tumor cells was isolated and [(14)CL]5FU incorporation into RNA was measured by traditional scintillation counting while that of nonradiolabeled 5FU was measured with the present, new method. For the latter purpose, isolated RNA was incubated with RNase, alkaline phosphatase, and uridine phosphorylase, resulting in a complete degradation of RNA, nucleotides, and nucleoside to 5FU. 5FU was then measured with gas chromatography coupled to mass spectrometry. For both methods RNA incorporation was 0.4 pmol/h/micrograms RNA at 25 microM 5FU while a similar time (up to 4 h) and concentration dependence (25 to 50 microM) were found. Reproducibility of the assay was more than 95%. In a murine colon tumor 5FU incorporation into RNA reached a peak of 10 pmol/micron RNA at 2 h after administration of the the maximum tolerated dose of 80 mg5FU/kg, which was retained until at least 72 h at 2.5 pmol/micron. In tumors from patients treated with 500 mg5FU/m(2) incorporation into RNA after 24 h amounted to 1.0-1.5 pmol/micrograms RNA. In conclusion, a novel approach, combining different sensitive and reproducible techniques, was established to measure 5FU incorporation into RNA in clinical tumor specimens enabling determination of its clinical relevance. PMID- 8678296 TI - Chloroplast biogenesis 72: a [4-vinyl]chlorophyllide a reductase assay using divinyl chlorophyllide a as an exogenous substrate. AB - [4-Vinyl]Chlorophyllide alpha reductase (4VCR) catalyzes the conversion of 2,4 divinyl chlorophyllide alpha (DV Chlide alpha) to 2-vinyl,4-ethyl chlorophyllide alpha (MV Chlide alpha) via an NAPDH- dependent reaction. MV Childe alpha is the immediate precursor of monovinyl chlorophyll alpha in plants. In etiolated cucumber (Cucumis sativus L.) cotyledons, 4VCR is a plastidic membrane-bound enzyme. Further research on this enzyme required the development of an assay that utilizes DV Childe alpha as an exogenous substrate. Such an assay is now described. It involves conversion of exogenous DV Chlide alpha to MV Chlide alpha at high rates by etioplast membranes of cucumber, corn (Zea mays L.), and barley (Hordum vulgare L.). 4VCR exhibits high activity between 30 and 40C and in the pH range of 6.3 to 7.0. Activity is quasilinear for the first 60 s of incubation. PMID- 8678297 TI - Stable and general-purpose chemiluminescent detection system for horseradish peroxidase employing a thiazole compound enhancer and some additives. AB - A stable and highly sensitive chemiluminescent detection system for horseradish peroxidase (HRP)/luminol/hydrogen peroxide using a newly designed thiazole compound enhancer has been established. Some additives for the chemiluminescent reaction were explored to overcome some defects of the reaction such as rapid decay and high background of light emission. Recrystallization of luminol and the addition of several detergents into the reacting solution were effective to increase specific light emissions. The addition of skim milk into the reacting solution reduced the background. Consequently, skim milk combined with a detergent increased the signal to noise ratio about 20 times compared with the reactions in the absence of both additives. The optimal concentration of enhancer and the addition of egg albumin stabilized the emission. In the new method, 6x 10(-18) mol of HRP was detectable. This would be the most sensitive enhanced chemiluminescent detection system for HRP. Furthermore, we could detect picogram per milliliter (10(-17) mol) concentrations of a trace component in biological materials such as endothelin-1 by employing this reaction. PMID- 8678298 TI - Organic acid production by Aspergillus niger in recycling culture analyzed by capillary electrophoresis. AB - Wild-type Aspergillus niger N402 and glucoamylase++ overproducing transformant A. niger N402[pAB6-10]B1 have grown in maltodextrin- and xylose-limited recycling culture at pH 4.5 on mineral medium. The only products formed were organic acids and proteins, among which glucoamylase. The production of organic acids by the fungus has been analyzed qualitatively and quantitatively using capillary electrophoresis. The only organic acids produced in these cultures were substantial amounts of citric acid. This is the first demonstration of abundant oxalic acid production and a very low citric acid production by submerged cultures of A. niger. In the maltodextrin-limited culture the oxalic acid production rate increased during the first 80 h of cultivation and decreased after that time. In xylose-limited recycling culture the oxalic acid production rate always increased in time and highest values were found in the last samples taken from the culture after about 140 h of cultivation. Oxalic acid production rates were highest by the wild-type strain grown on xylose as carbon source, i.e., when the lowest glucoamylase production rates were observed. A clear negative correlation was found between the oxalic acid production rate and the respiration quotient (RQ). An increase in the oxygen consumption rate, due to the production of strongly oxidized oxalic acid, caused the RQ to be lowest at those stages of recycling cultivation when highest oxalic acid production rates were observed. PMID- 8678299 TI - Purification of synthetic peptide libraries by affinity chromatography using the avidin-biotin system. AB - The specific interaction between biotin and avidin was exploited in the affinity purification of solid-phase synthesized peptide libraries. During peptide library synthesis, by means of the single-resin method in which coupling on variable positions is carried out using an equimolar mixture of amino acids, biotin was used to cap the unreacted amino groups remaining after coupling of the equimolar amino acid mixture. The following synthesis and deprotection procedures were performed as usual in tert,-butyloxycarbonyl chemistry. The purification of the peptide mixture containing N-biotinylated sequences was performed by affinity chromatography on an avidin-agarose column. The unwanted terminated sequences were retained in the avidin column while the purified peptide mixture was eluted as indicated by reverse-phase HPLC and MS analysis monitoring. The avidin column was regenerated and the biotinylated sequences were released under reversible denaturing conditions. The usefulness of biotinylation for peptide library purification is demonstrated here for the first time for a peptide mixture containing by-products that cannot be separated from the mixture by classical HPLC purification. This purification technique could be applied to all syntheses, presenting difficult reacting steps. PMID- 8678300 TI - Improved radiolabeled substrates for soluble epoxide hydrolase. AB - Two rapid assays for the soluble epoxide hydrolase (sEH) are described. First, a sensitive radiometric assay based on thin-layer chromatography of [(14)C]-cis 9,10-epoxystearic acid and its corresponding diol ((14)C]-9,10-dihydroxystearic acid) is described. The cis fatty acid oxide exhibits higher specific activity of hydration with sEH from mouse, rat, human, and potato compared to trans-stilbene oxide (TSO). The K(m) and V(max) obtained for [(14)C]-cis-9,10-epoxystearic acid with mouse sEH are 11.0 microM and 3460 nmol/min/mg protein, respectively. [(14)C]-cis-9,10- Epoxystearic acid might more closely mimic the structures of natural substrates for sEH. Second, [2-(3)H]-trans-1,3-diphenyl-propene oxide ([(3)H]-tDPPO) and [2-(3)H]-cis-1,3-diphenylpropene oxide ([(3)H]-cDPPO) were synthesized and rapid radiometric assays for epoxide hydrolases (EHs) were developed by differential partitioning of the epoxide into iso-octane and its corresponding diol into aqueous phase containing methanol. It was shown that sEHs from mouse, rat, human, and potato rapidly hydrolyze [(3)H]-tDPPO and in comparison to TSO have 20-,49-,28-, and 7-fold higher rates, respectively. Mouse sEH hydrates [(3)H]-tDPPO at 26,200 nmol/min/mg protein, and a K(m)p4 of 2.80 microM is observed. PMID- 8678301 TI - Isolation of unstable myosins and the analysis of light chains by capillary electrophoresis. AB - A rapid method for the isolation of unstable fish myosins by Sepharose Q ion exchange chromatography is described which yields a pure protein essentially free of contamination or breakdown products in less than 6 h. A protocol was developed for determining the molar ratios of myosin light chains (LC) by capillary electrophoresis. The method is quantitative, rapid (<20 min), highly reproducible (<2.1% variation in relative peak migration time), and only uses Femtomole quantities of protein. It was able to separate myosin light chains which could previously only be resolved by 2-D sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Capillary electrophoresis in the presence of SDS gave similar apparent relative molecular masses (M(r)) for most proteins, but an anomalously high M(r) for myosin light chain 3(LC3), as has been reported previously for SDS-PAGE methods. PMID- 8678302 TI - A method for the purification of oligonucleotides containing strong intra- or intermolecular interactions by reversed-phase high-performance liquid chromatography. AB - Synthetic oligodeoxyribonucleotides containing a high guanine content have a tendency to form intra- or intermolecular complexes in solution make HPLC purification difficult or sometimes impossible. We have developed a simple method that has enabled us to purify a series of highly guanine-rich and self complementary oligonucleotides by HPLC on a reverse-phase PRP-1 column. Although others have shown that this type of oligonucleotide can be purified on an ion exchange column by adding formamide to the mobile phase, the resulting resolution is poor and the formamide must subsequently be removed from the purified product. We find that simply having 20% formamide in the loading buffer is sufficient to remove the interfering interactions. This small amount of formamide passes quickly through the reverse-phase column, far removed the peak position of the oligonucleotides. Quantities of up to 35 ODs have been satisfactorily purified with recoveries of 95% or better. This procedure was particularly suitable for purification of oligonucleotides containing base-labile modifications, such as acetylaminofluorene-modified oligonucleotides,since other denaturing HPLC purification methods usually employ strong alkaline conditions or high temperatures that might result in damage to the adduct. PMID- 8678303 TI - Kinetics of protein-protein interactions at the surface of an optical biosensor. AB - Methods based on the use of optical biosensors have recently become available to provide a convenient means of determining the rate and equilibrium constants for bimolecular interactions between immobilized ligands and soluble ligate molecules. However, the association data that these methods provide are not always accurately described by the expected pseudo-first-order reaction mechanism, particularly when the ligand is immobilized on a dextran matrix. We show that a better description of the association data, especially at higher ligate concentrations, is achieved with a double exponential function, indicating that at least two rate-limiting processes are involved. Various models are considered in order to explain these observations: the presence of two (or more) distinct populations of immobilized ligand; a change, possibly conformational, in the immobilized ligand before or after ligate binding; or the hindrance of ligate binding to immobilized ligand. We suggest that steric hindrance caused by ligate binding to the dextran-coated sensor surface seems the most likely explanation for the observed biphasic association kinetics and that the faster initial phase should be used in oder to determine association constants that can be compared to those in solution. PMID- 8678304 TI - Analysis of oxidative phosphorylation complexes in cultured human fibroblasts and amniocytes by blue-native-electrophoresis using mitoplasts isolated with the help of digitonin. AB - The electrophoretic method of Schagger and von Jagow (Anal. Biochem. 199, 233-231 (1991) was adapted to allow analysis of enzymes of the respiratory chain and the ATP-synthase in cultured human skin fibroblasts and amniocytes. The cells were fractionated with digitonin and mitoplasts were isolated and used for electrophoresis. The purification of mitoplasts and the resolution by electrophoresis of the oxidative phosphorylation complexes were optimal when 0.8 1.6 mg of digitonin/mg protein was used. Intact complexes I, III, IV, and V were clearly separated by blue native-polyacrylamide gel electrophoresis (PAGE) in the first dimension and their individual subunits by tricine-sodium dodecyl sulfate PAGE in the second dimension. Approximately 10(6) fibroblasts or amniocytes (0.4 0.6 mg protein) were sufficient for complete analysis of the oxidative phosphorylation complexes using detection by staining and by Western blotting. Comparable resolution was obtained with other cell types. Studies of fibroblasts from patients with cytochrome c oxidase deficiency demonstrated the usefulness of the method for diagnosis of mitochondrial disorders. PMID- 8678305 TI - Separation of mono- and divinyl chlorophyll species by high-performance liquid chromatography using an octadecyl polyvinyl alcohol polymer column. AB - Most of the chlorophylls and their related compounds from nonesterified chlorophyllide to esterified pheophytin were separated by high- performance liquid chromatography using a wide pore, C(18) polyvinyl alcohol polymer column with an elution using a binary gradient starting from a buffered mobile phase. The high selectivity of this system enabled not only the separation of common chlorophyll species but also the resolution of structurally similar compounds such as mono- and divinyl chlorophyllide and pheophorbide species which usually coelute on monomeric bonded phases. The method is successfully applied to analyses of the pigments extracted from green and etiolated tissues of higher plants and photosynthetic bacterial cells. PMID- 8678306 TI - Quantitative determination of effective nibbling activities contaminating restriction endonuclease preparations. AB - A simple and sensitive procedure with which to detect residual exonucleolytic nibbling activities contaminating restriction endonuclease preparations is described. The procedure uses the kyosei-plasmid, pKF4, which confers kanamycin resistance and enforces streptomycin sensitivity encoded by the trp promoter/operator-driven rpsL+amber(PO(trp)-rpsL+4(am)) gene onto Escherichia coli streptomycin-resistant, amber-suppressive, trp repressor-negative strains such as TH5. When TH5 cells transformed by pKF4 were selected on agar medium containing kanamycin plus streptomycin, the efficiency of transformation plating was substantially lower than that on agar containing kanamycin alone. However, when pKF4 DNA was digested by restriction enzymes that cut once per molecule within PO(trp)-rpsL+4(am) and relegated, the plating efficiency increased depending on the degree of contamination of exonucleolytic nibbling activities in the enzyme preparations, due to deletion mutation at the ligand junction. Plating efficiency was converted to "effective nibbling activity" corresponding to Bal31 nuclease-equivalent units. Using this procedure, effective nibbling activities were detected in 17 of 34 commercial samples of restriction enzymes tested. The method is simple and more sensitive than the procedures used by the commercial suppliers and it is applicable to the quality control testing of more than 100 restriction enzymes. PMID- 8678307 TI - A continuous spectrophotometric method for determining the monophenolase and diphenolase activities of apple polyphenol oxidase. AB - A continuous spectrophotometric method for the determination of the monophenolase and diphenolase activities of apple polyphenol oxidase is described. The method is based on the coupling reaction between 3-methyl-2-benzothiazolinone hydrazone (MBTH) and the quinone product of the oxidation of p-hydroxyphenyl propionic acid and 3,4-dihydroxyphenyl propionic acid in the presence of polyphenol oxidase. The lambda(max) and molar absorptivity (epsilon) for the MBTH-quinone adduct have been calculated. The presence of MBTH in the reaction medium decreases the lag period during the expression of monophenolase activity. The high value of V(mas) suggests the existence of a high catalytic constant. This, together with the value of epsilon for the MBTH-quinone adduct, makes this method more sensitive than other continuous methods. PMID- 8678308 TI - Fluorescence energy-transfer cyanine heterodimers with high affinity for double stranded DNA. I. Synthesis and spectroscopic properties. AB - We have designed, synthesized, and characterized fluorescent cyanine heterodimers that exploit resonance energy transfer to achieve strong emission above 650 nm with 488-nm excitation. Thiazole orange serves as the common fluorescence donor in these dyes and thiazole-indolenine, thiazole blue, or symmetric thiazole blue as acceptors. The donor and acceptor chromophores are linked by a polymethylene linker containing quaternary amino groups. These heterodimers have a high affinity for double-stranded DNA (dsDNA). The donor emission in the dsDNA-bound dyes is quenched by over 85%. The affinity for dsDNA and the quenching of donor fluorescence were optimized by varying the length of the linker between the donor and acceptor. Complexes of dsDNA fragments with such optimized dyes dissociated very slowly (t(0.5) > 300 min) during agarose gel electrophoresis. PMID- 8678309 TI - Fluorescence energy-transfer cyanine heterodimers with high affinity for double stranded DNA. II. Applications to multiplex restriction fragment sizing. AB - Energy-transfer cyanine dyes, a thiazsole orange-thiazole-indolenine (butylTOTIN) and a thiazole orange-thiazole blue heterodimer (pentylTOTAB), form high-affinity complexes with double-stranded (ds)DNA with donor fluorescence (lambdaF(max)527 nm) quenched >90% and with acceptor fluorescence emission above 650 nm (S. C. Benson, Z. Zeng, and A. N. Glaser (1995) Anal. Biochem. 231, 247-255). After separation by agarose gel electrophoresis, bands of precomplexed dsDNA-dye restriction fragments containing 10 pg of dsDNA are readily detected with a laser excited confocal-fluorescence gel scanner (R. A. Mathies et al. (1994) Rev. Sci. Instrum. 65, 807-812) following donor excitation at 488 nm (argon ion laser) or direct acceptor excitation at 647 nm (krypton ion laser). Accurate two-color multiplex sizing of restriction fragments is obtained with 488-nm excitation with dsDNA fragments precomplexed with thiazole orange dimer (TOTO) as unknowns (detected at 500-565 nm, green channel) and dsDNA fragments stained with the energy-transfer cyanine dyes (detected at 645-750 nm, red channel) as internal standards. There is negligible cross talk of fluorescence between the red and green channels and no significant dye migration in mixtures of prelabeled standard and unknown fragments. PMID- 8678310 TI - Detection of the amine acceptor protein substrates of transglutaminase with 5 (biotinamido) pentylamine. PMID- 8678312 TI - Spectrophotometric assay for porcine liver esterase activity. PMID- 8678311 TI - Influence of DNA sequence and methylation status on bisulfite conversion of cytosine residues. PMID- 8678313 TI - A plasmid purification scheme for characterization of small fragments cloned into vectors. PMID- 8678314 TI - Amino and carboxyl terminal modifications to facilitate the production and purification of a G protein-coupled receptor. PMID- 8678315 TI - Quantitation of short- and medium-chain acylcarnitines in plasma by radioisotopic exchange/high-performance liquid chromatography. AB - A method for the quantitation of short- and medium-chain acylcarnitines in plasma and its clinical application are described. The method is based on enzymatic exchange of L-[3H]carnitine into the acylcarnitine pool, subsequent separation of labeled acylcarnitines by high-performance liquid chromatography, and quantitation of the radioactivity by a beta flowthrough detector. Since only acylcarnitines are detected, no sample cleanup procedure is required. Isotopic equilibrium, a prerequisite for accurate quantitation, was reached in plasma after 1 h of incubation for all acylcarnitines except isovalerylcarnitine which required a longer incubation time. No significant hydrolysis of acylcarnitines occurred during the incubation. Linearity was demonstrated after adding increasing amounts of individual acylcarnitines to plasma. The method is highly sensitive requiring no L-carnitine administration to the patient and differentiates short-chain acylcarnitine isomers. It is suitable for the detection of a number of inborn errors of organic acid and fatty acid metabolism. PMID- 8678316 TI - Protein production in three different expression vectors from a single polymerase chain reaction product. PMID- 8678317 TI - Obelin mRNA--a new tool for studies of translation in cell-free systems. AB - Obelin mRNA obtained in vitro with the aid of SP6 RNA polymerase was translated in a wheat germ cell-free system. Only the polypeptide with a molecular mass of about 20 kDa was synthesized. The activation of apoobelin with a synthetic coelenterazine revealed a luminescence activity initiated by calcium. The specific activity was 3.6 +/- 0.4 x 10(15)photons per mg of the in vitro synthesized obelin (k=6.9s(-1)). The luminescence of the obelin was in a good correlation with the protein concentration calculated by the incorporation of [14C]Leu. The determination of the amount of de novo synthesized obelin based on measurement of its luminescence is one-thousand times more sensitive than the approach based on the incorporation of labeled amino acid. Thus, obelin mRNA has some advantages for evaluating the efficiency of cell-free translation when compared with standard methods. PMID- 8678318 TI - Downward blotting of proteins in a model based on apolipoprotein(a) phenotyping. AB - Standard immunoblotting ("Western blot") involves electrotransfer of proteins from a separation gel (usually acrylamide) onto a membrane. Recently, a downward capillary method with increased hybridization efficiency was developed for DNA and RNA. The present work assessed the applicability of this method to proteins in a model based on human apolipoprotein(a)[apo(a)] isoforms which consist of a single, >200-kDa polypeptide chain varying in size with a repeat sequence. After reduction treatment and sodium dodecyl sulfate-agarose gel electrophoresis, serum proteins were transferred from the gel by upward or downward (Turboblotter) capillary action onto nitrocellulose membranes in Tris-buffered saline, pH 7.5, at room temperature. Increased detectability of apo(a) isoforms was achieved by substituting comparatively high molar concentrations of protein A for true second antibody. With downward capillary transfer and short 37 degrees C incubations, the apo(a) phenotyping could be completed in about 26 h and required less than 8 h effective processing time. The downward transfer was about twice as fast (complete within 1 h) as the upward version and with this speed it offers a good alternative to electroblotting as well. PMID- 8678319 TI - Irreversible, oriented immobilization of antibodies to cobalt-iminodiacetate resin for use as immunoaffinity media. AB - A method for the construction of antibody affinity columns has been developed which utilizes the innate affinity of antibodies for metal. Antibodies that are reversibly bound to a cobalt-iminodiacetate resin are attached in an "exchange inert" fashion when the cobalt is oxidized from the 2+ to 3+ state. Antibodies bound in this fashion are not removed by metal chelating reagents, high salt, detergents, or chaotropic agents. Only reagents which reduce the metal are capable of removing the antibody. Since the metal binding site in antibodies is in the C-terminus of the heavy chain, antibodies bound to the resin are oriented with the combining site directed away from the resin thus allowing maximal antigen binding. The oxidation conditions used are mild and do not subject the antibody to harsh immobilization chemistry. This technique may be used to construct affinity media using multiple subclasses of antibodies since the metal binding site is conserved. This immobilization strategy may be a general technique for the oriented immobilization of antibody to surfaces. PMID- 8678320 TI - Lysine-directed radioiodination of proteins with a cyanuric chloride derivative of aminofluorescein. AB - Protein radioiodination via iodo-5-([4,6-dichlorotria- zin-2 yl]amino)fluorescein(DTAF), a cyanuric chloride derivative of aminofluorescein, was characterized. Commercially available DTAF was iodinated by the Iodogen reaction and then conjugated to IgC antibodies in a 4-h incubation in borate buffer, pH 9.0. With low amounts of protein, 10 micron, molar ratios of iodine:IgC of nearly 1:1 were obtained. With 25 micron protein, which was used routinely, 15-20% efficiency of (125)I incorporation was obtained. Polylysine was labeled efficiently, and labeling was inhibited by ethanolamine, which is consistent with previous data indicating that conjugation is to amino in the protein. A low level of aggregates, primarily dimers, was generated. This procedure is a simple, inexpensive method to test the advantage of lysine directed protein iodination, with proteins for which oxidative iodination is unsuitable. Abs labeled with DTAF retained strong antigen-binding activity, and, in the case of one Ab, were much more active than the chloramine T-labeled Ab. Catabolic products of iodo-DTAF conjugates, produced after internalization and degradation of Ab bound to the cell surface, were retained within some but not all human carcinoma cell lines. PMID- 8678321 TI - Purification and analysis of synthetic, triple-helical "minicollagens" by reversed-phase high-performance liquid chromatography. AB - To better study collagen-mediated cellular and enzymatic activities, a generally applicable solid-phase methodology has been developed by which aligned triple helical peptides (designated THPs or "minicollagens") ranging from 79 to 124 residues can be assembled. Reversed-phase HPLC is typically the purification method of choice following chemical synthesis of small proteins of this size, as well as one of the analytical techniques used to verify product purity. We have thus compared the effects of different stationary phases (C18, C4, or diphenyl), organic modifiers (acetonitrile or isopropanol), support pore sizes (120 angstroms, 300 angstroms, or nonporous), and counterions for the reversed-phase HPLC analysis of THPs. Large pore C18 or C4 reversed-phase HPLC gave broad peaks, resulting in poor resolution of the desired THP from synthetic impurities. Broad peaks were presumably due to conformational instability of THPs to reversed-phase conditions and subsequent slow cis-trans isomerization of the peptide bonds. Peak sharpness was improved greatly by use large-pore diphenyl reversed-phase HPCL. We found that THPs can be best resolved from synthetic impurities by diphenyl or non porous C18 reversed-phase HPLC using water-acetonitrile gradients. These results most likely reflect conditions which maintain the native conformation of collagen like triple-helices. PMID- 8678322 TI - Separation of amino acid enantiomers by micellar electrokinetic capillary chromatography using synthetic chiral surfactants. AB - A synthetic chiral surfactant was employed for the enantioselective micellar electrokinetic capillary chromatographic (MECC) separation of amino acid enantiomers derivatized with 6-aminoquinoyl-N-hydroxysuccinimidyl carbamate (AQC). The effect of surfactant concentration and buffer pH on resolution was studied, and the optimized conditions were used to evaluate the method in terms of sensitivity, reproducibility, and linearity. Resolution and alpha values for 12 ACQ-derivatized amino acids are reported. The ability to perform both achiral and chiral separations simultaneously is illustrated in a separation of a mixture of six amino acid enantiomeric pairs, all with baseline resolution. The direct reversal of enantiomer migration order, useful in quantitation and chiral identification, is also shown. Comparisons with other N-protected amino acid derivatives are made in terms of resolution and sensitivity, and the advantages of this chiral MECC technique used in conjunction with the inherent advantages of the AQC derivatizing reagent are discussed. PMID- 8678323 TI - On-column reduction of catecholamine quinones in stainless steel columns during liquid chromatography. AB - The chromatographic behavior of quinones derived from the oxidation of dopamine and N-acetyldopamine has been studied using liquid chromatography (LC) with both a diode array detector and an electrochemical detector that has parallel dual working electrodes. When stainless steel columns are used, an anodic peak for the oxidation of the catecholamine is observed at the same retention time as a cathodic peak for the reduction of the catecholamine quinone. In addition, the anodic peak exhibits a tail that extends to a second anodic peak for the catecholamine. The latter peak occurs at the normal retention time of the catecholamine. The origin of this phenomenon has been studied and metallic iron in the stainless steel components of the LC system has been found to reduce the quinones to their corresponding catecholamines. The simultaneous appearance of a cathodic peak for the reduction of catecholamine quinone and an anodic peak for the oxidation of the corresponding catecholamine occurs when metallic iron in the exit frit reduces some of the quinones as the latter exits the column. This phenomenon is designated as the "concurrent anodic-cathodic response." It is also observed for quinones of of 3,4-dihydroxybenzoic acid and probably occurs with o- or p-quinones of other dihydroxyphenyl compounds. The use of nonferrous components in LC systems is recommended to eliminate possible on-column reduction of quinones. PMID- 8678324 TI - Polypeptide amino acid composition and isoelectric point. II. Comparison between experiment and theory. AB - Experimental isoelectric points and amino acid compositional data for 58 proteins were compiled and organized. The experimental isoelectric points correlated well with the acidic to basic amino acid molar ratio. This agreement proved the usefulness of a recently presented analytical expression correlating explicitly protein isoelectric point to acid-base composition. Regressed acidic and basic dissociation constants were determined to be pK(alpha) = 4.9 and pK(beta) = 10.0, in fair agreement with the expected values of pK(alpha) = 4.2 and pK(beta) = 11.2. Theoretical isoelectric points determined by a more complete computational procedure were on the average in as good an agreement with the experimental values as those calculated via the theoretical approximation using the regressed dissociation constants. Thus, the analytical approximation is a powerful tool for the convenient and accurate calculation of protein isoelectric point from the amino acid composition. PMID- 8678325 TI - Determination of local refractive index for protein and virus crystals in solution by Mach-Zehnder interferometry. AB - To establish the importance of, and quantitatively evaluate, the macromolecular concentration gradients in the neighborhood of growing protein, virus, and nucleic acid crystals, a convenient, accurate, and nonintrusive method has been devised. This approach should prove particularly relevant in the rigorous comparison of crystals grown in a conventional laboratory setting with those grown in a microgravity environment. The method is based on precise determination of the local refractive index using Mach-Zehnder interferometry. Presented here are data for five protein and three virus systems. From data for these and other systems, optical monitoring experiments to measure local growth conditions and growth kinetics in liquid-liquid diffusion, batch, and vapor diffusion crystal growth experiments can be designed. PMID- 8678326 TI - Glycosylphosphatidylinositol-alkaline phosphatase from calf intestine as substrate for glycosylphosphatidylinositol-specific phospholipases--microassay using hydrophobic chromatography in pipet tips. AB - An electrophoretically homogeneous glycosylphosphatidylinositol- alkaline phosphatase fraction from calf intestine, obtained by hydrophobic chromatography, was used as "enzyme-labeled" substrate for testing phospholipase activity. The reaction products were separated by (i) hydrophobic chromatography in pipet tips and (ii) Triton X-114 phase partitioning. The chromatographic method presented permits high test frequencies, does not need temperature-controlled sample handling, and is only slightly disturbed by detergents, organic solvents, and proteins. The method was used to characterize phosphatidylinositol- specific phospholipase C from Bacillus cereus and phospholipase D from calf serum. Measurement of substrate hydrolysis by phospholipases is apparently linear to enzyme concentration and time. Relative activity of both enzymes is maximum at pH 6.5, corresponding to the optimal pH range found with other glycosylphosphatidylinositol substrates and phosphatidylinositol-specific phospholipases of other sources. Maximum activity of phospholipase C was found at 0.03% Triton X-100, 0.01% Brij 35, and 0.2% n-octylglucoside. The activity is not affected by Ca(2+), NaHCO(3), o-phenanthroline, or EDTA, increasingly inhibited by MgCl(2), MnCl(2), and ZnCl(2), and slightly activated by Na+ and K+. Calf serum phospholipase D shows maximum activity at 0.05% Triton X-100, 0.02% Brij 35, and 0.4% n-octylglucoside. The apparent Km values for phospholipase C (12.25 micron) and phospholipase D (4.94 micron) found with glycosylphosphatidylinositol alkaline phosphatase are compared with values published for other glycosylphosphatidylinositol substrates. PMID- 8678327 TI - Prevalence and correlates of symptomatic peripheral atherosclerosis in individuals with coronary heart disease and cholesterol levels less than 240 mg/dL: baseline results from the Cholesterol and Recurrent Events (CARE) Study. AB - PURPOSE: To determine the prevalence and correlates of symptomatic peripheral atherosclerosis in individuals with a history of myocardial infarction (MI) and cholesterol levels lower than 240 mg/dL. MATERIALS AND METHODS: A cross-sectional analysis was conducted at baseline of 4159 participants in the Cholesterol and Recurrent Events (CARE) Study. Symptomatic diffuse atherosclerosis was defined as a history of MI plus lower extremity or cerebrovascular atherosclerosis or claudication by Rose questionnaire. RESULTS: The prevalence of symptomatic diffuse atherosclerosis was 12.9%; 353 participants (8.5%) had lower extremity disease and 219 (5.3%) had cerebrovascular disease. After controlling for other variables, diffuse atherosclerosis was associated with age (Odds Ratio [OR] = 1.44 per ten-year increase), systolic blood pressure (OR = 1.13 per 10 mm Hg increase), a history of multiple myocardial infarctions (OR = 1.76), diabetes (OR = 1.76), hypertension (OR = 1.38), reduced exercise performance (OR = 1.55), current smoking status (OR = 2.87), and lower alcohol intake (OR = 0.97 per drink per week). There was no association with race, gender, or lipid levels. CONCLUSIONS: The presence of clinically evident diffuse atherosclerosis is common and is associated with several modifiable risk factors. Early identification of these individuals could affect treatment and clinical outcomes. PMID- 8678328 TI - Evaluation of the coagulation and fibrinolytic systems in men with intermittent claudication. AB - The authors evaluated elements of the coagulation and fibrinolytic systems in 18 male patients with intermittent claudication vs 19 men matched for risk factors who served as controls. Prothrombin time and activated partial thromboplastin time did not significantly differ in the patients and the controls. The plasminogen level in the two groups was not significantly different. The level of lipoprotein(a) was significantly higher in the patients than in the controls. The levels of antigen and the activity of protein C did not differ significantly between the two groups. The thrombomodulin level was significantly higher in the patients than in the controls. There were no significant differences between the two groups in the levels of alpha 2-macroglobulin, C1-inactivator, or antithrombin III. The levels of fibrinogen and alpha 1-antitrypsin were significantly higher in the patients vs the controls. Significantly lower levels of alpha 2-plasmin inhibitor and higher levels of alpha 2-plasmin inhibitor/plasmin complex and thrombin/antithrombin III complex were found in the patients vs the controls. These findings suggest that the levels of thrombin/antithrombin III complex, alpha 2-plasmin inhibitor/plasmin complex, and thrombomodulin may perhaps serve as indicators for injury to the peripheral endothelium and that the coagulation and fibrinolytic systems may be activated in patients with intermittent claudication. PMID- 8678329 TI - Effects of a single heparin bolus on neointimal growth after arterial injury in intact rabbits. AB - Heparinization is a routine procedure during angioplasty; however, its consequences on the late vascular response to a severe injury are unclear. The authors' objective was to explore the effect of a single heparin bolus at the time of a severe vascular injury on late intimal proliferation and neointimal thickening. The iliac artery of 57 normolipemic rabbits was overdistended with a balloon catheter. Heparin (250 IU/kg i.v.) was given to 29 rabbits ten minutes before angioplasty, whereas 28 rabbits served as untreated controls. Neointimal thickening was prominent at fourteen days after injury and reached near-maximal values at day 28. The intimal/medial area ratio was reduced by an average 28.3% with heparin (at day 28: 2.19 +/- 0.51 vs 1.57 +/- 0.59, control vs heparin, P = 0.02). Neointimal cells stained positively for HHF-35 antibody, directed against smooth muscle cell antigens. Neointimal proliferation, quantified through the number of cell nuclei peroxidase-stained for PCNA/cyclin antigen, was significantly decreased by 43% and 49% with heparin, respectively, at days 7 and 14 after injury. These data suggest that early exposure even to low doses of heparin accounts for much of its inhibitory effect in vascular response to injury; such an effect might prove important in interpreting results of human trials of interventions against restenosis. PMID- 8678330 TI - Effects of verapamil and magnesium sulfate on electrophysiologic changes during acute myocardial ischemia and following reperfusion in dogs: comparative effects of administration by intravenous and coronary sinus retroperfusion routes. AB - The authors evaluated the effects of verapamil (Ve) and magnesium sulfate (Mg) on the electrophysiologic changes induced in dogs during acute myocardial ischemia and following reperfusion. The effects of their intravenous (i.v.) administration and administration by coronary sinus retroperfusion (CSR) were also compared. Sixty-five dogs were divided into five groups: Ve-i.v.: 9 dogs, 0.1 mg/kg; Ve-CS: 9 dogs, 0.05 mg/kg; Mg-i.v.: 12 dogs, 20 mg/kg; Mg-CS: 11 dogs, 10 mg/kg, control: 24 dogs. The left anterior descending coronary artery was ligated for ten minutes, then quickly reopened. The changes in ventricular effective refractory period (ERP) and intramyocardial conduction time (ICT) were determined during ischemia and following reperfusion. The authors observed a shortening of the ERP and a prolongation of the ICT in the control group versus an attenuation of those effects in all other groups. The ERP was shortened to a lesser extent in the Mg-i.v. group than in the Ve-i.v. group. Drug administration by CSR inhibited the changes in ERP and ICT to a greater extent than i.v. administration, even though the dose given by CSR was one-half the i.v. dose. Ventricular fibrillation (Vf) occurred in 12 of 24 dogs (50%) in the control group during ischemia, and in 5 of 12 dogs (41.7%) following reperfusion. Vf occurred during ischemia and following reperfusion, respectively, in 22.2% and 0% in the Ve-i.v. and Ve-CS groups, in 25% and 22.2% in the Mg-i.v. group, and in 9.1% and 10% in the Mg-CS group. Thus, verapamil and magnesium sulfate inhibited the electrophysiologic changes and prevented ventricular arrhythmias during myocardial ischemia and following reperfusion. Administering the antiarrhythmic agent by coronary sinus retroperfusion may be useful for treating patients with acute myocardial infarction with intractable arrhythmias, according to these experimental results. PMID- 8678331 TI - Peripheral neuropathy associated with ischemic vascular disease of the lower limbs. AB - This paper deals with the possible identification of somatic and autonomic nerve damage in patients with peripheral obliterative arterial disease (POAD) at different stages of the disease, with a well-reproducible technique like electroneurographic evaluation of nerve conduction. In 64 patients with intermittent claudication, 19 patients with pain at rest, and 7 patients with trophic ulcers, electroneurographic evaluation of motor (tibial and peroneal) and sensory (superficial peroneal and sural) nerve conduction was performed. The median nerve (motor and sensory) was used as control. A severe impairment of sural and superficial peroneal nerve velocities was evident in many claudicant patients and in all patients with pain at rest and trophic ulcers, with a progression in the conduction abnormalities in advanced stages of the disease. Motor nerve conduction showed only minor reductions in patients with claudication and pain at rest, although some of them did show very poor velocity values. In 21 patients with intermittent claudication and sensory nerve abnormalities, the autonomic fibers activity, evaluated by the skin sympathetic response (SSR) test, was significantly depressed, thus suggesting an involvement of the local autonomic system in the ischemic disease. A correlation exists between the severity of the somatic nerve damage and the stage of the vascular insufficiency. However, in the group of claudicant patients, the evidence of similar ischemic threshold (claudication distance) may be associated with a marked difference in the amount of somatic nerve damage. The somatic and autonomic nerve alterations may play a relevant role in the progression of the disease toward critical limb ischemia. PMID- 8678332 TI - Serial changes in blood pressure and neurohormone levels after the onset of lacunar stroke. AB - To assess serial changes in blood pressure and its circadian variation following a lacunar stroke, the authors studied 7 patients who developed a single lacunar infarction in either the internal capsule or the corona radiata. Blood pressure and pulse rate were monitored noninvasively for twenty-four hours by an ambulatory blood pressure monitoring device in the acute, subacute, and chronic phases of the strokes. In the acute and chronic phases, the authors also measured urinary excretion of catecholamines every 6 hr, and serum cortisol concentration at 9:00, 17:00, and 21:00 hr. The patients were free from antihypertensive agents during the study. The twenty-four-hour averages of both systolic and diastolic blood pressure in the chronic phase were lower than those in the acute phase (P < 0.05). A nighttime fall in blood pressure was observed in the subacute and chronic phases (P < 0.05), but not in the acute phase. Urinary excretion of epinephrine at night in the acute phase was significantly higher than that in the chronic phase (P < 0.05). Serum levels of cortisol at 17:00 and 21:00 hr in the acute phase also exceeded those in the chronic phase (P < 0.05 and P < 0.01, respectively). The authors conclude that an increased secretion of epinephrine and cortisol might, at least in part, contribute to a high blood pressure and a lack of circadian variation in blood pressure in the acute phase of lacunar stroke. PMID- 8678333 TI - Use of color Doppler imaging in assessment of preoperative and postoperative flow characteristics of internal thoracic artery in myocardial revascularization. AB - Between January 1993 and February 1993, the left internal thoracic arteries of 40 consecutive patients scheduled for aortocoronary bypass operation were examined by transthoracic B-mode imaging. Perioperative measurements correlated well with preoperative noninvasive measurements (r = 0.914). In the postoperative period, B mode images could not be obtained in 17 (44.7%) of 38 patients. Adequate Doppler spectra of the internal thoracic artery were obtained in all patients preoperatively and in 36 (94.7%) of 38 patients postoperatively. Preoperatively a triphasic wave form was obtained with a large systolic peak followed by small reversed and diastolic components in all patients. Postoperatively this triphasic wave form had been converted into a combined systolic-diastolic wave form. In all patients peak systolic velocity of the internal thoracic artery decreased (96.4 +/- 15.3 vs 64.2 +/- 18.9 cm/sec., P < 0.05), and peak diastolic velocity increased (21.7 +/- 8.8 vs 28.3 +/- 11.2 cm/sec., P < 0.05) significantly in the postoperative period as compared with the preoperative values. A slight decrease in peak systolic and diastolic velocities was detected at twelve months postoperatively. This study indicates that transthoracic B-mode imaging and Doppler spectrum analysis are reliable techniques in the preoperative and postoperative assessment of the internal thoracic artery in myocardial revascularization. PMID- 8678334 TI - Successful application of hypothermia combined with intra-aortic balloon pump support to low-cardiac-output state after open heart surgery. AB - The authors report a successful application of hypothermia, along with intra aortic balloon pump (IABP) support, to postcardiotomy ventricular failure. Surface-cooling hypothermia was applied in 8 patients after open heart surgery. The original cardiac procedure consisted of 3 aortocoronary bypass graftings (ACBGs), 2 aortic valve replacements (AVRs), 1 repair for left ventricular (LV) rupture after mitral valve replacement (MVR), 1 MVR + ACBG, and 1 MVR + AVR + tricuspid valve annuloplasty (TAP). Their ages ranged from fifty-two to sixty eight years with a mean of sixty-one years. Hemodynamic criteria for induction of hypothermia included cardiac index (CI) less than 2.0 L/min/m2 with left atrial pressure greater than 18 mmHg despite the use of IABP and maximum pharmacologic support. Blood temperature was maintained at around 33 degrees C. By six hours after induction of hypothermia the tissue oxygen consumption decreased significantly with no hemodynamic deterioration as compared with that before cooling. The duration of hypothermia ranged from thirty-six to one hundred fifty nine hours with a mean of seventy-eight hours. All 8 patients finally discontinued IABP support with a mean driving time of one hundred thirty-two hours. Five of them were ultimately discharged from the hospital and returned to their previous life-style. The authors believe that, from the perspective of monetary and personal resources, the use of hypothermia with IABP support could be a therapeutic option for patients with postcardiotomy ventricular failure. PMID- 8678335 TI - Hydatid disease presenting as cardiac tamponade. A case history. AB - Although hydatid disease has been reported in almost all human tissues, cardiac involvement is uncommon. The authors report a case of cardiac hydatid disease presenting with cardiac tamponade. The diagnostic value of transthoracic and transesophageal echocardiography, computed tomography, and angiography in hydatid heart disease is also discussed. PMID- 8678336 TI - Bilateral internal carotid artery disease secondary to cervical radiation. A case report. AB - A patient with radiation-induced bilateral carotid artery disease is presented. A fifty-six-year-old man was admitted to hospital for evaluation of recurrent transient ischemic attacks. He had received cervical radiation for pharyngeal squamous cell carcinoma five years earlier. The radiation was directed at the cervical fields bilaterally and the anterior cervical field using x-rays for a total of 120 Gy. Computed tomography of the brain obtained at admission revealed a low-density area in the right parietal lobe. Carotid arteriograms revealed a completely occluded right internal carotid artery and a severely narrowed left internal carotid artery. There was good collateral supply from the posterior communicating arteries to the internal carotid arteries, bilaterally. The patient was medically treated with anticoagulant and antiplatelet therapy and has been free of subsequent cerebral ischemic attacks. PMID- 8678337 TI - Unusual right coronary artery runoff with right and left main coronary artery aneurysm. A case report. AB - A rare case of unusual right coronary artery runoff with right and left main coronary artery aneurysm is presented. The discussion is mainly from the etiologic point of view. PMID- 8678338 TI - Single coronary artery from the right sinus of Valsalva, associated with absence of left anterior descending and an ostium-secundum-type atrial septal defect: a rare combination. A case report. AB - A case of single coronary artery from the sinus of Valsalva, with an anomalous origin of the left circumflex coronary artery from the just proximal portion of the right coronary artery, absence of the left anterior descending, and an ostium secundum-type atrial septal defect is presented. This combination seems to be very rare. PMID- 8678339 TI - Unusual appearance of intracranial fibromuscular dysplasia. A case report. AB - Fibromuscular dysplasia (FMD) of intracranial arteries is seen rarely and usually limited to the intrapetrosal internal carotid artery or carotid siphon. The authors report a case with recurrent subarachnoid hemorrhage diagnosed angiographically as FMD with extensive involvement of intracranial arteries. Angiography showed large fusiform dilatations and multiple aneurysms along the left intracranial internal carotid artery into its major branches, middle cerebral and posterior communicating arteries, and tip of the basilar and posterior cerebral arteries. Such an angiographic appearance has not been previously reported. Radiologic findings are demonstrated and possible pathophysiologic mechanisms are discussed. PMID- 8678340 TI - Case report CA: cleft lip and palate with bilateral crossbites. PMID- 8678341 TI - Case report SS: A patient with temporomandibular joint disorders. PMID- 8678342 TI - Tomographic assessment of temporomandibular joints in patients with malocclusion. AB - There is a paucity of information on the morphological assessment of the temporomandibular joint in relation to varying skeletal and dental relationships. The purpose of this study was to evaluate the morphologic relationship of the condyle and fossa in patients with different malocclusions and skeletal relationships. Pretreatment records of 232 orthodontic patients, 95 males and 137 females, of Caucasian descent and ranging in age from 9 years 4 months to 42 years 6 months, were examined. Records included dental casts, lateral cephalometric radiographs, hand-wrist radiographs, and corrected tomograms of right and left TM joints. Nonconcentricity and mild asymmetry of the condyle fossa relationship were commonly observed. The left condyle was found to be more anteriorly positioned than the right, with the mean percentage of joint space being 6.93% on the left side and -1.24% on the right. Skeletal and dental Class III patients demonstrated significantly more anteriorly positioned condyles (P < 0.05). There were no significant differences in condylar position between Class I and Class II groups based on ANB or Angle's classification. Further, no significant difference in condylar position was observed between groups based on overbite or crossbite. PMID- 8678343 TI - Adding value to case reports. PMID- 8678344 TI - Digital imaging of cephalometric radiography, Part 1: Advantages and limitations of digital imaging. AB - Digital imaging has several potential advantages over traditional cephalometry. These include storage, transmission, and enhancement of images, reduced exposure to radiation for patients, and the possibility of automated cephalometric analysis. This paper outlines some of these advantages, discusses the limitations of digital imaging and suggests possible future developments. PMID- 8678345 TI - Digital imaging of cephalometric radiographs, Part 2: Image quality. AB - The aim of this study was to compare the diagnostic quality of conventional cephalometric radiographs with that of digital image counterparts. The random error associated with angular and linear measurements recorded on the digital images was greater than on the conventional radiographs. In addition, there was a systematic error producing statistically significant differences in the majority of angular and linear measurements between the digital images and the conventional radiographs. The errors that occurred with some measurements were of sufficient magnitude to be of clinical significance, particularly in a cephalometric situation where a high degree of accuracy is required. It is therefore suggested that, for digital imaging of cephalometric radiographs, a pixel matrix larger than 512 x 512 with more than 64 gray levels is required to maintain the diagnostic quality of the original radiograph. PMID- 8678346 TI - Effect of head orientation on posterior anterior cephalometric landmark identification. AB - This study examined the effect of head rotation about the vertical and transverse axes on posterior anterior cephalometric landmarks. Radiographs were taken on 25 skulls, first in a normal position, then in four positions each rotated 5 degrees from normal. The identification errors of 52 bilateral and midline landmarks were determined in the horizontal and vertical dimensions. The landmark identification errors for each of the five orientations were compared and those landmarks affected by 5 degrees rotation were identified. Landmarks with significantly larger identification error in a rotated position were: nasal cavity, mandible/occiput, foramen rotundum and orbitale. Best fit vertical and horizontal reference lines were determined, and the effect of head rotation on the choice of best fit reference lines was assessed. Rotation about the transverse axis did not affect the relationship of landmarks to the best vertical or horizontal lines. Rotation about the vertical axis did not affect the relationship of landmarks to the best horizontal line but did affect their relationship to the best vertical line. PMID- 8678347 TI - Effects of fluoride application on shear bond strength of orthodontic brackets. AB - The purpose of this study was to determine the shear bond strength and debonding failure modes of orthodontic brackets bonded to teeth that have been treated with various fluoride concentrations. Thirty-six recently extracted human premolars were divided into three groups: prophylaxis with pumice only, prophylaxis using a 13,500 ppm fluoridated pumice, and prophylaxis with pumice followed by application of a 2500 ppm fluoridated paste. The teeth were etched with a 37% phosphoric acid gel, then bonded with a metal orthodontic bracket. The teeth were mounted in phenolic rings and stored in de-ionized water at 37 degrees C for 72 hours. A Zwick Universal Testing Machine was used to determine shear bond strengths. The residual adhesive on the enamel surface was estimated using the Adhesive Remnant Index. Analysis of variance was used to compare the various groups, and significance was predetermined at p < or = 0.5. The results indicate that there were no significant differences in bond strengths between the treated and untreated teeth (p = .233). The Chi Square test evaluating the residual adhesive on the enamel surfaces also showed no significant differences (p =.456). In conclusion, the use of fluoridated prophylactic pastes with varying fluoride concentrations does not significantly affect shear bond strength or bond failure location. PMID- 8678348 TI - RVG-S, VIXA, and Ektaspeed film in detection of proximal enamel defects under orthodontic bands. AB - An in vitro investigation was carried out to compare CCD-based intraoral radiographic systems with E-speed film for the detection of proximal enamel defects beneath orthodontic bands, with and without added niobium filtration to attenuate the x-ray beam. Twenty caries-free extracted teeth were randomly divided into five groups. Fifteen of 30 contacting proximal surfaces remained lesion free; the other 15 received a small, medium large mechanically induced enamel defect. Images were made with and without the addition of 30 microns niobium filtration, and with and without orthodontic bands. Six dentists were viewers. Receiver operating characteristic (ROC) curves were developed for each modality under each test situation. The area under the curve (Az) was used as an index of diagnostic accuracy, and the critical ratio was used for statistical comparisons. In the absence of orthodontic bands, the Az values for E-speed film and for nonenhanced RVG-S were greater than for all other modalities tested, indicating that they have the greatest diagnostic accuracy. With orthodontic bands, the RVG-S with steep gradient enhancement (X-function) had a higher Az value than all other modalities. Addition of niobium had no significant effect on defect detection. CCD-based devices hold no diagnostic advantage over conventional film for detecting changes in the density of enamel not covered by orthodontic bands. Contrast enhancement of digital images (RVG-S X-function) holds promise for the detection of such changes beneath orthodontic bands. PMID- 8678349 TI - Stability of the palatal rugae as landmarks for analysis of dental casts in extraction and nonextraction cases. AB - To determine whether the positions of the palatal rugae were affected by orthodontic therapy, pre- and posttreatment maxillary dental casts of 57 adult patients treated in the graduate orthodontic clinic at the University of North Carolina were evaluated. The orthodontic extraction group (n = 27) was composed of patients whose treatment included the extraction of two maxillary premolars. The remaining patients (n = 30) had been treated without extractions. Transverse changes observed over time were significantly different from zero only for the medial points of the first rugae in the nonextraction group and for the lateral points of the first rugae in the extraction group. None of the changes observed in the transverse measures were statistically different between the two groups. In the extraction group, there were significant anteroposterior changes in the right lateral points between the first and second rugae and between the second and third rugae, and in the right medial points between the second and third rugae. There were no statistically significant anteroposterior changes observed in the nonextraction group over time. When the two groups were compared, the average distance between the lateral first and second right rugae, and the average distance between the lateral second and third right rugae were significantly different. The medial and lateral points of the third rugae appear to be stable landmarks for the construction of anatomic reference pints in longitudinal cast analysis. PMID- 8678350 TI - Alternative donor site for alveolar bone grafting in adults with cleft lip and palate. AB - Grafting of the alveolar ridge with autogenous bone is an integral stage of contemporary management of complete cleft lip and palate cases. Alveolar bone grafting restores continuity of the dental arch, closes oronasal fistulae, supports the alar base, and facilitates spontaneous eruption of permanent teeth adjacent to the cleft. However, timing of the graft and the selection of materials have been topics of much debate in the literature. This article discusses an alternative donor site in cases where rehabilitation has passed the recommended time. Harvesting bone from the third molar regions allows not only the removal of impacted third molars during the same surgical procedure, but also eliminates the morbidity associated with additional surgical sites such as the ilium or mandibular symphysis. This report should not be interpreted as a recommendation for the use of this alternative site in cases where grafting is carried out within the optimal time period, which is usually in the mixed dentition stage. However, when grafting is necessary in young adults suffering from complete cleft lip and palate, the third molar region may provide another acceptable donor site. PMID- 8678351 TI - In-situ forces in the human posterior cruciate ligament in response to posterior tibial loading. AB - Although some investigators have referred to the human posterior cruciate ligament (PCL) as the center of the knee, it has received less attention than the more frequently injured anterior cruciate ligament (ACL) and medial collateral ligament (MCL). Therefore, our understanding of the function of the PCL is limited. Our laboratory has developed a method of measuring the in-situ forces in a ligament without contacting that ligament by using a universal force-moment sensor (UFS). In this study, we attached a UFS to the tibia and measured in-situ forces of the human PCL as a function of knee flexion in response to tibial loading. At a 50-N posterior tibial load, the force in the PCL increased from 25 +/- 11 N (mean +/- SD) at 30 degrees of knee flexion to 48 +/- 12 N at 90 degrees of knee flexion. At 100 N, the corresponding increases were to 50 +/- 17 N and 95 +/- 17 N, respectively. Of note, at 30 degrees knee flexion, approximately 45% of the resistance to posterior tibial loading was caused by contact between the tibia and the femoral condyles, whereas, at 90 degrees of knee flexion, no resistance was caused by such contact. For direction of the in-situ force, the elevation angle from the tibial plateau was greater at 30 degrees of knee flexion than at 90 degrees of knee flexion. The data gathered on the magnitude and direction of the in-situ force of the PCL should help in our understanding of the dependence of knee flexion angle of the forces within the PCL. PMID- 8678352 TI - Segmental inertial parameters of the human trunk as determined from computed tomography. AB - This study used computed tomography (CT) imaging to determine in vivo mass, center of mass (CM), and moments of inertia (Icm) about the CM of discrete segments of the human torso. Four subjects, two males and two females, underwent serial transverse CT scans that were collected at 1-cm intervals for the full length of the trunk. The pixel intensity values of transverse images were correlated to tissue densities, thereby allowing trunk section mass properties to be calculated. The percentage of body mass observed by vertebral levels ranged from 1.1% at T1 to 2.6% at L5. The masses of the upper, middle, and lower trunk segments as percentages of body mass were estimated to be 18.5, 12.2, and 10.7%, respectively. The whole trunk mass was estimated to comprise 41.6% of the total body mass. Transverse vertebral CM values were found to lie anterior to their respective vertebral centroids by up to 5.0 cm in the lower thoracic region. For the upper, middle, and lower trunk segments, the average CM positions were found to be 25.9, 62.5, and 86.9% of the distance from the superior to inferior ends of the trunk. The upper and middle trunk CMs corresponded to approximately 4.0 cm anterior to T7/T8 vertebral centroid levels and 1.0 cm anterior to L3/L4 vertebral centroid levels, respectively. For the whole trunk, the CM was 52.7% of the distance from the xiphoid process and approximately 2.0 cm anterior to L1/L2 vertebral centroid levels. Variations in CM and Icm values were observed between subject, but these were within the range of previous reports of body segment parameters. Differences from previous studies were attributable to variations in boundary definitions, measurement techniques, population groups, and body states (live versus cadaver) examined. The disparity between previous findings and findings of this study emphasizes the need to better define the segmental properties of the trunk so that improved biomechanical representation of the body can be achieved. PMID- 8678353 TI - A nonlinear model for myogenic regulation of blood flow to bone: equilibrium states and stability characteristics. AB - A simple compartmental model for myogenic regulation of interstitial pressure in bone is developed, and the interaction between changes in interstitial pressure and changes in arterial and venous resistance is studied. The arterial resistance is modeled by a myogenic model that depends on transmural pressure, and the venous resistance is modeled by using a vascular waterfall. Two series capacitances model blood storage in the vascular system and interstitial fluid storage in the extravascular space. The static results mimic the observed effect that vasodilators work less well in bone than do vasoconstrictors. The static results also show that the model gives constant flow rates over a limited range of arterial pressure. The dynamic model shows unstable behavior at small values of bony capacitance and at high enough myogenic gain. At low myogenic gain, only a single equilibrium state is present, but a high enough myogenic gain, two new equilibrium states appear. At additional increases in gain, one of the two new states merges with and then separates from the original state, and the original state becomes a saddle point. The appearance of the new states and the transition of the original state to a saddle point do not depend on the bony capacitance, and these results are relevant to general fluid compartments. Numerical integration of the rate equations confirms the stability calculations and shows limit cycling behavior in several situations. The relevance of this model to circulation in bone and to other compartments is discussed. PMID- 8678355 TI - Damped oscillation analysis of natural and artificial periodontal membranes. AB - The mechanical mobility of human teeth was studied by using a wave data treatment system with an accelerometer attached to a personal computer. The healthy teeth in different generations of men and women, who ranged in age from their teens to their forties, showed similar damped oscillation patterns. The spring constant and coefficient of viscous damping were estimated by using a viscoelastic model of damped oscillation with 1 degree of freedom. The coefficient of viscous damping increased dramatically with increases in the damping factor, whereas the spring constant scarcely varied. Silicone membranes were used as model periodontal membranes. The coefficient of viscous damping decreased with increases in silicone membrane thickness. Collagen membranes, which are expected to function as artificial periodontal membranes, were adhered to the model tooth by drying collagen gel and fixed with apatite-collagen composites. The collagen membranes showed damped oscillation wave patterns similar to those of human periodontal membranes. PMID- 8678354 TI - The electrical and dielectric properties of human bone tissue and their relationship with density and bone mineral content. AB - In this study, we examined the electrical properties of wet human cortical and cancellous bone tissue from distal tibia and their relationship to the wet, dry, and ash tissue densities. The resistivity and specific capacitance of both cortical and cancellous bone were determined for different frequencies and directions (orientation). The wet, dry, and ash tissue densities of the bone samples were measured, and the ash content was determined. Correlation and regression analysis was used to examine the possible relationships among the electrical properties and the tissue densities for cancellous and cortical bone specimens separately as well as for all of the bone specimens combined. Highly significant positive correlations (p < 0.001) were found between the wet density of bone and the dry and ash densities. The specific capacitance of the cancellous bone specimens in all three orthogonal directions showed significant (p < 0.01) positive correlations with the wet, dry, and ash densities. In general, the specific capacitance depended more on density for all bone specimens, and only a weak relationship was found between the resistivity of human cortical bone and density. PMID- 8678356 TI - A model for cochlear outer hair cell deformations in micropipette aspiration experiments: an analytical solution. AB - We propose a mathematical model to describe the deformations of the cochlear outer hair cell (OHC) in the micropipette aspiration experiments. The bending effect is considered, and the OHC is treated as a cylindrical shell. The pipette effect is modeled by two-dimensional normal loading. Considering the OHC wall as an infinitely long cylinder, we obtain solution in terms of Fourier series with respect to the circumferential coordinate, where coefficients are expressed by closed formulae. We keep leading terms in fourier series and derive a closed formula for the length of tongue of the aspirated cell surface in terms of pipette pressure, cell geometry, and elastic moduli. To demonstrate application of the theory, we use data recently reported from the micropipette aspiration experiments and obtain an estimate of the elastic shear modulus for the OHC lateral wall. PMID- 8678357 TI - The identification of nonlinear biological systems: Volterra kernel approaches. AB - Representation, identification, and modeling are investigated for nonlinear biomedical systems. We begin by considering the conditions under which a nonlinear system can be represented or accurately approximated by a Volterra series (or functional expansion). Next, we examine system identification through estimating the kernels in a Volterra functional expansion approximation for the system. A recent kernel estimation technique that has proved to be effective in a number of biomedical applications is investigated as to running time and demonstrated on both clean and noisy data records, then it is used to illustrate identification of cascades of alternating dynamic linear and static nonlinear systems, both single-input single-output and multivariable cascades. During the presentation, we critically examine some interesting biological applications of kernel estimation techniques. PMID- 8678358 TI - Fractal character of the electrocardiogram: distinguishing heart-failure and normal patients. AB - Statistical analysis of the sequence of heartbeats can provide information about the state of health of the heart. We used a variety of statistical measures to identify the form of the point process that describes the human heartbeat. These measures are based on both interevent intervals and counts, and include the interevent-interval histogram, interval-based periodogram, rescaled range analysis, the event-number histogram, Fano-factor, Allan Factor, and generalized rate-based periodogram. All of these measures have been applied to data from both normal and heart-failure patients, and various surrogate versions thereof. The results show that almost all of the interevent-interval and the long-term counting statistics differ in statistically significant ways for the two classes of data. Several measures reveal 1/f-type fluctuations (long-duration power-law correlation). The analysis that we have conducted suggests the use of a conveniently calculated, quantitative index, based on the Allan factor, that indicates whether a particular patient does or does not suffer from heart failure. The Allan factor turns out to be particularly useful because it is easily calculated and is jointly responsive to both short-term and long-term characteristics of the heartbeat time series. A phase-space reconstruction based on the generalized heart rate is used to obtain a putative attractor's capacity dimension. Though the dependence of this dimension on the embedding dimension is consistent with that of a low-dimensional dynamical system (with a larger apparent dimension for normal subjects), surrogate-data analysis shows that identical behavior emerges from temporal correlation in a stochastic process. We present simulated results for a purely stochastic integrate-and-fire model, comprising a fractal-Gaussian-noise kernel, in which the sequence of heartbeats is determined by level crossings of fractional Brownian motion. This model characterizes the statistical behavior of the human electrocardiogram remarkably well, properly accounting for the behavior of all of the measures studied, over all time scales. PMID- 8678359 TI - Dynamic model of oxygen transport for transcutaneous PO2 analysis. AB - A dynamic model of oxygen transport through the outer skin layers and a polarographic sensor was developed for the analysis of transcutaneous oxygen tension (tcPO2). It provides a basis for quantifying the factors that determine the relationship between tcPO2 and arterial oxygen tension (PaO2). Model simulations show the importance of stratum papillare metabolic oxygen consumption; the oxygen permeability of the skin relative to that of the sensor membrane and electrolyte; and temperature and the oxyhemoglobin dissociation curve. These simulations were consistent with experimental data obtained by using microcathode transcutaneous oxygen sensors, which were placed on the skin of 10 healthy adults. Furthermore, the model indicates that accurate evaluation of arterial oxygen tension by using transcutaneous measurements requires continuous estimation of skin perfusion. On the basis of tcPO2 measurements made during arterial occlusion, simulations indicate that quantitative evaluation of the metabolic oxygen consumption of the viable skin tissues is possible only when the oxygen permeabilities of the skin and sensor are known. PMID- 8678361 TI - Estimation of turbulent shear stress in free jets: application to valvular regurgitation. AB - In an attempt to better assess the severity of valvular regurgitation, an in vitro experiment has been conducted to estimate turbulent shear stress levels within free jets issuing from different orifice shapes and sizes by means of hot wire anemometry. On the basis of the measured mean velocities and the jet profiles, the distributions of the normalized kinematic turbulent shear stress (uv/Um2) were estimated for different jets by using an equation available for self-preserving circular jet. The results indicate that the equation can estimate the distributions of uv/Um2 independent of the orifice shape and Reynolds number of the jet. For the range of Reynolds numbers considered, the estimation of maximum turbulent shear stress inferred from these distributions suggests that the critical shear stress level of approximately 200 N/m2, corresponding to destruction of blood cells, is exceeded for typical blood flow velocity of 5 m/s at the valvular lesion. PMID- 8678360 TI - A preliminary physiologically based pharmacokinetic model for naphthalene and naphthalene oxide in mice and rats. AB - Naphthalene is a toxicant with unusual species and tissue specificity that has been the subject of in vitro studies. We describe a preliminary physiologically based pharmacokinetic (PBPK) model for naphthalene constructed solely from in vitro data for comparison to animal data without the use of adjustable parameters. The prototypical PBPK model containing five lumped tissue compartments was developed to describe the uptake and metabolism of naphthalene by mice and rats dosed intraperitoneally (i.p.) and orally (po). The model incorporates circulation and biotransformation of the semistable reactive intermediate, naphthalene oxide, as well as the parent compound naphthalene. Circulation is included because the toxic action of naphthalene has been proposed to be caused by the formation of a reactive metabolite in one organ (liver) and its circulation to another organ (lung) being adversely affected by the metabolite. The model allows conversion of naphthalene oxide into dihydrodiol, glutathione (GSH) conjugates, 1-naphthol (non-enzymatically) and covalently bound adducts with proteins. Model simulations are compared with previously reported in vivo measurements of glutathione depletion, mercapturic acid formation, and covalently bound protein formation. The mouse model predicts accurately the amount of mercapturates excreted, the effect of various pretreatments, and the extent of covalent binding in the lung and liver resulting from ip administration, including the sharp increase in binding between 200 and 400 mg/kg. PMID- 8678362 TI - Optimal placement of impedance epigastrography electrodes. AB - Impedance electrogastrography (IE) is a noninvasive method to assess gastric contractile activity. This indirect method uses a four-terminal impedance measuring method to determine impedance variations of the gastric region of the torso. These variations can be related to changes in the stomach shape and, therefore, to gastric contractions. Because the impedance variations are very small, the placement of the measuring electrodes on the skin is critical. In this study, a three-dimensional resistor model consisting of 4,466 resistors was used to simulate the human torso. The model was implemented on a personal computer, and the experimentally obtained optimal electrode locations were found to be superior to the commonly used ones. Measurements of volunteers confirmed these findings. PMID- 8678364 TI - Serpentine thrombus traversing the foramen ovale: paradoxical embolism shown by transesophageal echocardiography. PMID- 8678363 TI - Physicians' attitudes about the care of patients in the persistent vegetative state: a national survey. AB - OBJECTIVE: To study the attitudes and beliefs of physicians who have experience caring for patients in the persistent vegetative state (PVS). DESIGN: Mailed questionnaire survey. PARTICIPANTS: 500 physicians, 250 from the American Academy of Neurology and 250 from the American Medical Directors Association. MEASUREMENTS: Physicians' beliefs about diagnosis of the PVS, patient awareness and suffering, treatment withdrawal, appropriate use of health maintenance and life-prolonging therapies, organ donation, lethal injection, and the treatment they would want if they were in the PVS. RESULTS: 68% of surveyed neurologists and 60% of medical directors responded. Thirteen percent of responders believe that patients in the PVS have awareness and experience hunger and thirst; 30% believe they experience pain. Fewer than 9% believe that respiratory failure, cardiogenic shock, acute renal failure, or cancer should be aggressively treated. Eighty-nine percent believe that it is ethical to withdraw artificial hydration and nutrition. Almost two thirds of responders believe that it would be ethical to use the vital organs of patients in the PVS for transplantation, and 20% believe that it would be ethical to hasten the patient's death by lethal injection. CONCLUSIONS: When evaluating the appropriateness of treatments for patients in the PVS, neurologists and medical directors largely concur. Most physicians in both groups believe that patients in the PVS would be better off dead; that it is not necessary to provide aggressive therapeutic interventions; and that all therapeutic interventions, including artificial nutrition and hydration, can be withheld in certain circumstances. The areas of consensus are remarkable and suggest that an ethical standard that physicians believe should be followed when caring for these patients may be emerging. PMID- 8678365 TI - Management of an outbreak of tuberculosis in a small community. AB - OBJECTIVE: To investigate an outbreak of tuberculosis, determine the number of active cases and infections, and examine efforts to control the spread of disease. SETTING: A small town in Maine, in which no cases of tuberculosis had been reported in the previous 3 years. DESIGN: Epidemiologic investigation of an outbreak of tuberculosis infection and disease. MEASUREMENTS: A patient with an active case of tuberculosis was defined as a resident of the town or the surrounding area or an employee of the local shipyard who had a culture of sputum or tissue that was positive for Mycobacterium tuberculosis between June 1989 and May 1992. A case of tuberculous infection was defined as a positive tuberculin skin test result in a person with no previous positive test result. RESULTS: 21 active cases of tuberculosis occurred among shipyard workers and persons residing in the affected community between 1989 and 1992. One patient was the source of the outbreak; 8 months lapsed between the onset of this patient's illness and appropriate diagnosis and treatment. The M. tuberculosis strains isolated from this patient and from six other patients belonged to phage type I, auxiliary 14. All isolates were susceptible to drug treatment. Of 9898 persons who were tested, 697 (7%) were newly infected. Because isoniazid prophylaxis was not routinely offered to infected persons older than 35 years of age, only 341 (49%) infected persons completed isoniazid prophylaxis. CONCLUSIONS: Many secondary cases of tuberculosis occurred throughout this small Maine community because of delayed diagnosis and treatment of the source patient, delayed outbreak investigation, and failure to promote isoniazid prophylaxis to all persons infected during the outbreak. Aggressive efforts to identify persons with new infection are of limited value in controlling tuberculosis unless they are accompanied by an equally aggressive use of isoniazid prophylaxis. PMID- 8678366 TI - Prostate cancer: emerging concepts. Part I. AB - OBJECTIVE: To review important topics related to prostate cancer that have arisen since this subject was last covered in Annals in 1993. The review consists of two parts, Part I describes advances in prostate-specific antigen (PSA) interpretation (including PSA density and velocity, age-specific reference ranges, "free" and "bound" PSA ratios, the utility of PSA in defining the pathologic extent of prostate cancer, and the use of these concepts in helping define appropriate treatment strategies), the management of patients with organ confined prostate cancer, and pathologic interpretation of prostatectomy specimens. STUDY SELECTION: Randomized studies identified through a MEDLINE search (1992 to 1996); large, single-institution conferences and consortiums; and studies presented at regional, national, and international symposia. DATA SYNTHESIS: Both qualitative and quantitative data are reported. Most of the data presented in part I concern advances in the interpretation of PSA results and characterization of the pathologic findings of prostatectomy specimens. Studies show that almost 50% of patients with clinically organ-confined prostate cancer have disease that is beyond the confines of the prostatic capsule. The chances of developing clinical (radiographic) and biochemical failure (that is, elevation of PSA levels) are 3% and 6%, respectively, for pathologically organ-confined cancer and 10% and 26%, respectively, for non-specimen-confined prostate cancer. Actual progression-free survival rates 10 years after radical prostatectomy are 70% for patients with organ-confined cancer and 39% for patients with cancer that has spread through the capsule. CONCLUSIONS: Prostate cancer is being detected with increasing frequency, and many patients with this condition are receiving such treatments as radical prostatectomy and radiation therapy. Although refinements in PSA-based testing have contributed substantially to the increased detection rate of prostate cancer, the incidence of disease was increasing dramatically even before the detection of PSA was possible. Yet, despite earlier detection, the optimal therapy for the early form of the disease remains enigmatic. Further studies and longer follow-up of patients who participated in completed studies are needed to better define the outcomes of prostate cancer therapies and to help determine the importance of the therapies. Increased research efforts are necessary to help elucidate the reasons for the great increase in the incidence of the disease; such efforts should help define strategies to ultimately prevent prostate cancer. PMID- 8678367 TI - Advances in the management of AIDS-related cytomegalovirus retinitis. AB - Cytomegalovirus (CMV) retinitis, a common complication of the acquired immunodeficiency syndrome (AIDS), is increasing in frequency as patients infected with the human immunodeficiency virus (HIV) live longer. In recent years, the lifetime risk for CMV disease in HIV-infected persons has increased from 24.9% to 44.9%. Cytomegalovirus retinitis is usually diagnosed clinically: Almost all patients are CMV seropositive and have CD4+ counts less than 50 cells/mm3. Specific diagnostic tests that use antigen detection or quantitation of circulating nucleic acid to detect CMV are being developed, but they have not been validated for routine clinical use. Such tests would help predict disease, diagnose acute retinitis, and monitor therapy. Therapy with systemic agents, including intravenous ganciclovir, intravenous foscarnet, and intravenous cidofovir, is effective. However, it is cumbersome, costly, and associated with considerable toxicity, therapy encouraging investigation of other therapeutic approaches. Intravitreous injections with antiviral agents are effective, but the short half-life of available agents makes these injections inconvenient. Intraocular implants that slowly release ganciclovir have been effective for both acute therapy and long-term maintenance, but they need to be directly compared with intravenous and oral regimens to determine which regimen will optimally maximize convenience, preserve vision, and improve survival. Cytomegalovirus retinitis could be prevented by improved antiretroviral therapies or by immune based therapies that would prolong the time during which patients remain immunocompetent. Once patients become immunologically susceptible to CMV end organ disease (when their CD4+ counts decrease to < 50 cells/ mm3), specific chemotherapy with oral ganciclovir is promising, but the cost, inconvenience, toxicity, and conflicting reports of efficacy associated with this strategy mean that it needs careful assessment before it can be considered standard treatment. Management of CMV retinitis is on the verge of major changes. In the next few years, improvements in diagnostic, therapeutic, and preventive tools should reduce morbidity and mortality from this disease. PMID- 8678368 TI - Whose death is it, anyway? AB - As medicine has increasingly gained the power to prolong life in the face of devastating illness, patients have increasingly become concerned about maintaining some control over how and when death arrives. Competent patients have the legal right to refuse treatment, but critically ill patients are frequently unable to participate in decision making. Advance directives were designed to help patients establish the level of care they would receive if they were to be rendered incompetent; yet, as the case discussed in this essay shows, even a valid advance directive does not guarantee that unwanted medical interventions will not be forced on us. The problem of physicians ignoring their patients' wishes goes beyond issues of communication and reflects an ongoing ambivalence about power and control in the physician-patient relationship. Unfortunately, many physicians find it easier to define success in terms of life and death than to try to determine what sort of existence is meaningful to an individual patient. PMID- 8678369 TI - Zinc: the biology and therapeutics of an ion. PMID- 8678370 TI - Treatment of cytomegalovirus retinitis in patients with AIDS. PMID- 8678371 TI - Clinical incoherence about persons: the problem of the persistent vegetative state. PMID- 8678372 TI - A letter from a patient's daughter. PMID- 8678373 TI - Adult group B streptococcal disease. PMID- 8678374 TI - Alopecia associated with fluconazole therapy. PMID- 8678375 TI - Alopecia associated with fluconazole therapy. PMID- 8678376 TI - Liver cirrhosis and circadian rhythm. PMID- 8678377 TI - Diagnosing vascular causes of renal failure. PMID- 8678378 TI - Quantitation of hepatitis C virus RNA. PMID- 8678379 TI - Tuberculous abscess of the prostate in AIDS. PMID- 8678380 TI - Thrombocytopenia and leukopenia associated with itraconazole. PMID- 8678381 TI - Principles of economic analysis of health care technology. PMID- 8678382 TI - Thrombocytosis associated with low-molecular-weight heparin. PMID- 8678383 TI - Performance of U.S. and international medical graduates on the 1995 internal medicine in-training examination. PMID- 8678384 TI - Zinc gluconate lozenges for treating the common cold. A randomized, double-blind, placebo-controlled study. AB - BACKGROUND: The common cold is one of the most frequent human illnesses and is responsible for substantial morbidity and economic loss. No consistently effective therapy for the common cold has been well documented, but evidence suggests that several possible mechanisms may make zinc an effective treatment. OBJECTIVE: To test the efficacy of zinc gluconate lozenges in reducing the duration of symptoms caused by the common cold. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Outpatient department of a large tertiary care center. PATIENTS: 100 employees of the Cleveland Clinic who developed symptoms of the common cold within 24 hours before enrollment. INTERVENTION: Patients in the zinc group (n = 50) received lozenges (one lozenge every 2 hours while awake) containing 13.3 mg of zinc from zinc gluconate as long as they had cold symptoms. Patients in the placebo group (n = 50) received similarly administered lozenges that contained 5% calcium lactate pentahydrate instead of zinc gluconate. MAIN OUTCOME MEASURES: Subjective daily symptom scores for cough, headache, hoarseness, muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, sneezing, and fever (assessed by oral temperature). RESULTS: The time to complete resolution of symptoms was significantly shorter in the zinc group than in the placebo group (median, 4.4 days compared with 7.6 days; P < 0.001). The zinc group had significantly fewer days with coughing (median, 2.0 days compared with 4.5 days; P = 0.04), headache (2.0 days and 3.0 days; P = 0.02), hoarseness (2.0 days and 3.0 days; P = 0.02), nasal congestion (4.0 days and 6.0 days; P = 0.002), nasal drainage (4.0 days and 7.0 days; P < 0.001), and sore throat (1.0 day and 3.0 days; P < 0.001). The groups did not differ significantly in the resolution of fever, muscle ache, scratchy throat, or sneezing. More patients in the zinc group than in the placebo group had side effects (90% compared with 62%; P < 0.001), nausea (20% compared with 4%; P = 0.02), and bad-taste reactions (80% compared with 30%; P < 0.001), CONCLUSION: Zinc gluconate in the form and dosage studied significantly reduced the duration of symptoms of the common cold. The mechanism of action of this substance in treating the common cold remains unknown. Individual patients must decide whether the possible beneficial effects of zinc gluconate on cold symptoms outweigh the possible adverse effects. PMID- 8678385 TI - Effectiveness and safety of intranasal ipratropium bromide in common colds. A randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: To determine the tolerability and clinical effectiveness of intranasal ipratropium bromide for the treatment of symptoms of common colds. DESIGN: Multicenter, double-blind, randomized trial. SETTING: 3 university student health services. PATIENTS: 411 previously healthy persons 14 to 56 years of age who had cold symptoms that had lasted for no more than 36 hours, rhinorrhea subjectively judged to be of at least moderate severity, and documented nasal discharge of at least 1.5 g over a 1-hour observation period. INTERVENTION: Either 1) ipratropium bromide nasal spray 0.06% in buffered salt solution, two 42-micrograms sprays per nostril administered by metered pump spray; 2) control nasal spray, which consisted of buffered salt solution; or 3) no treatment. Treatments were self administered three or four times daily during waking hours for 4 days. After receiving their morning dose, patients stayed at the study center for 6 hours on study day 1 and 3 hours on study day 2; symptom severity was recorded and nasal mucus discharges were collected and weighed hourly during these periods. RESULTS: Ipratropium recipients had 26% less nasal discharge than controls (P = 0.0024) and 34% less nasal discharge than untreated patients (P = 0.0001). Severity of rhinorrhea as judged subjectively was reduced in ipratropium recipients by 31% compared with controls and by 78% compared with untreated patients (P = 0.0001 for both comparisons). In addition to being associated with reductions in daily assessments of the severity of rhinorrhea (P < or = 0.003), ipratropium was associated with reduced sneezing on study days 2 (20% difference; P = 0.03) and 4 (30% difference; P = 0.02) but not with reduced nasal congestion compared with the control spray. Ipratropium was generally well tolerated but was associated with higher rates of blood-tinged mucus (16.8% in the ipratropium group compared with 3.6% in the control group; P = 0.01) and nasal dryness (11.7% in the ipratropium group compared with 3.6% in the control group; P = 0.021) than the control spray. Patient assessments of the overall effectiveness of treatment were more favorable for ipratropium than for the control spray (P < or = 0.026) or for no treatment (P < or = 0.002) on each day of inquiry (study days 1, 2, and 5). CONCLUSIONS: Intranasal ipratropium bromide provides specific relief of rhinorrhea and sneezing associated with common colds. PMID- 8678386 TI - Treatment of cytomegalovirus retinitis with intravitreous cidofovir in patients with AIDS. A preliminary report. AB - BACKGROUND: Cytomegalovirus retinitis remains a major cause of illness in patients with the acquired immunodeficiency syndrome (AIDS), and existing therapies for this condition are relatively ineffective and toxic. OBJECTIVE: To evaluate the efficacy of intravitreous cidofovir injections alone for initial and maintenance therapy for cytomegalovirus retinitis. DESIGN: Prospective, nonrandomized, consecutive case series. SETTING: University ophthalmology referral clinic. PATIENTS: 22 patients with AIDS and cytomegalovirus retinitis. In 15 of 32 affected eyes, intravitreous cidofovir was administered as the initial treatment for cytomegalovirus retinitis (group A); 17 eyes had previously been treated with intravenous therapy (group B). INTERVENTION: All eyes were intravitreously injected with 20 micrograms of cidofovir at 5- to 6-week intervals. No patient in either group received systemic anticytomegalovirus therapy at any time during the study period. MEASUREMENTS: Healing of retinitis was defined as resolution of retinal opacification and cessation of border progression. Progression, the primary end point, was defined as 750 microns of border progression or development of a new lesion. RESULTS: The mean duration of follow-up was 15.3 weeks (range, 5 to 44 weeks). Of the eyes with active retinitis, 100% (95% CI, 87% to 100%) healed in response to the initial injection. In two eyes (6%; CI, 0% to 15%), two episodes of retinitis progression occurred (one in each eye). Both of these eyes were in a patient with clinically resistant retinitis. In 3% of eyes (CI, 0% to 9%), the retina became detached. Mild iritis developed after 14% of the injections that had been preceded by prophylaxis with oral probenecid. Irreversible, visually significant hypotonia developed in one eye. CONCLUSION: Treatment and subsequent maintenance of cytomegalovirus retinitis with 20 micrograms of intravitreously injected cidofovir, given at 5- to 6-week intervals, is safe and highly effective. PMID- 8678387 TI - Clinical and epidemiologic features of primary HIV infection. AB - BACKGROUND: The acute clinical events surrounding the acquisition of human immunodeficiency virus (HIV) have not been well characterized. OBJECTIVE: To further define the clinical and epidemiologic presentation of primary HIV infection. DESIGN: Descriptive cohort study. SETTING: University research clinic. PATIENTS: 46 adults (43 men and 3 women) with primary HIV infection who enrolled in the study a median of 51 days after HIV seroconversion. MEASUREMENTS: Documentation of recent HIV seroconversion. Standardized collection of demographic characteristics and sexual contact history, results of tests for HIV RNA, HIV culture, and T-cell subsets. RESULTS: 41 of 46 patients (89%) developed an acute retroviral syndrome. Primary HIV infection was infrequently diagnosed at the initial medical encounter, even in persons enrolled in routine HIV screening programs. Median numbers of sexual partners 6 months and 1 month before acquisition of HIV were three and one, respectively; 21 patients (46%) reported having had only one partner in the month before seroconversion. Of the 12 patients who could identify the precise date of and activity leading to seroconversion, 4 reported having only oral-genital contact. CONCLUSIONS: Primary HIV infection causes a recognizable clinical syndrome that is often underdiagnosed, even in persons enrolled in a program of routine surveillance for HIV infection. Frequency of sexual contact and overall numbers of sexual partners in this group of homosexual men who acquired HIV were markedly lower than those seen a decade ago. Acquisition of HIV does occur, even in persons with relatively few sexual partners. Increased attention to oral-genital contact as a means of acquiring HIV appears to be warranted. PMID- 8678388 TI - Reduced response to activated protein C is associated with increased risk for cerebrovascular disease. AB - BACKGROUND: Resistance to activated protein C (APC), which results from various factors, including a mutation in the gene for coagulant factor V, has been associated with increased risk for venous thrombosis. However, its relation to arterial disease is still not well defined. OBJECTIVE: To investigate the association of both response to APC and the factor V Leiden mutation with arterial disease. DESIGN: Population-based case-control study. SETTING: A district of Rotterdam, the Netherlands. PARTICIPANTS: 115 patients with a history of myocardial infarction; 112 patients with a history of stroke, transient ischemic attack, or both; and 222 age-matched controls without arterial disease chosen from among 7983 persons in the Rotterdam Study cohort. Patients using anticoagulant drugs were excluded. MEASUREMENTS: Response to APC was determined in double-centrifuged platelet-poor plasma. Patients were genotyped for the Arg 506 to Gln mutation in the gene for coagulant factor V. RESULTS: The prevalence of cerebrovascular disease increased gradually and corresponded to a decreasing response to APC (odds ratio per 1-unit decrease of response to APC, 1.43 [95% CI, 1.12 to 1.81], adjusted for age and sex). Adjustment for the factor V mutation did not change the findings. We found no association between response to APC and myocardial infarction or between factor V mutation and cerebrovascular disease or myocardial infarction. CONCLUSIONS: Low response to APC is associated with an increased risk for cerebrovascular disease but not with an increased risk for myocardial infarction, independent of the factor V Leiden mutation. The association between the factor V Leiden mutation and cerebrovascular disease or myocardial infarction remains to be determined. PMID- 8678389 TI - Safety and immunogenicity of a candidate HIV-1 vaccine in healthy adults: recombinant glycoprotein (rgp) 120. A randomized, double-blind trial. NIAID AIDS Vaccine Evaluation Group. AB - OBJECTIVE: To evaluate the safety and immunogenicity of recombinant glycoprotein (rgp) 120, a candidate vaccine for the human immunodeficiency virus (HIV), formulated with a novel adjuvant, MF59, with or without a biological response modifier, MTP-PE. DESIGN: Multicenter, double-blind, randomized trial. SETTING: University medical centers. PARTICIPANTS: 49 healthy, HIV-seronegative volunteers 18 to 60 years of age who were at low risk for HIV type 1 (HIV-1) infection. INTERVENTIONS: In part A of the study, 32 participants were randomly assigned to receive either 15 micrograms of rgp 120 in MF59, 15 micrograms of rgp 120 in MF59 plus 50 micrograms of MTP-PE, 50 micrograms of rgp 120 in MF59, or 50 micrograms of rgp 120 in MF59 plus 50 micrograms of MTP-PE. Participants were vaccinated at 0, 1, 6, and 12 to 18 months. In part B, 17 participants were randomly assigned to receive five monthly injections of either 50 micrograms of rgp 120 in MF59 or MF59 alone followed by a booster injection at 12 to 18 months. MAIN OUTCOME MEASURES: Local and systemic reactions; laboratory measures of hepatic, renal, immunologic, and bone marrow toxicity; and HIV-specific serologic and cell mediated immune responses. RESULTS: 13 patients in part A received 50-micrograms doses of rgp 120; type-specific neutralizing antibody responses against the SF-2 strain of HIV-1 (HIV-1/SF-2) were induced in all 13. Nine of the 13 had crossreactive neutralizing activity against the MN strain of HIV-1 (HIV-1/MN), and 2 had crossreactive neutralizing activity against the IIIB strain of HIV-1 (HIV-1/IIIB). Twelve patients had typespecific fusion inhibition activity; only 1 had crossreactive fusion inhibition activity against HIV-1/MN. The monthly vaccination schedule used in part B resulted in decreased antibody titers, indicating that a rest period in the schedule is necessary for maximal immunogenicity. Lymphoproliferative responses against gp120 were induced in all vaccine recipients. The stimulation index to gp120 was persistently greater than 15 for 6 months after the last booster vaccination was given. CD8+ cytotoxic T lymphocyte activity was detected in 1 of the 11 participants tested. Vaccine that contained MTP-PE caused a greater number of moderate or severe local and systemic reactions (of 16 participants, 4 had local reactions and 13 had systemic reactions) than did vaccine formulated with MF59 alone (of 16 participants, 7 had local reactions [P < 0.01] and 0 had systemic reactions [P < 0.001]). CONCLUSIONS: The SF-2 rgp120 vaccine is safe and immunogenic. Three vaccinations with rgp120 in MF59 can induce type-specific and crossreactive neutralizing antibody against B-subtype laboratory strains of HIV-1. Human immunodeficiency virus-specific lymphoproliferative responses were induced in all vaccinated participants, and CD8+ cytotoxic T-lymphocyte activity was shown in one participant. A trend toward the augmentation of lymphoproliferative and humoral responses by MTP-PE was seen in the participants receiving 15 micrograms of rgp120. However, MTP-PE caused a statistically significant increase in the incidence of local and systemic side effects, which was felt to outweigh the small increase in immunogenicity provided by this biological response modifier in an otherwise well-tolerated vaccine. PMID- 8678390 TI - Self-assessment of tuberculin skin test reactions by New York City firefighters: reliability and cost-effectiveness in an occupational health care setting. AB - OBJECTIVE: To determine whether self-assessment of purified protein derivative of tuberculin (PPD) skin test reactions, done using a simple two-choice approach, is an effective screening method for tuberculosis. DESIGN: Double-blind comparison between self-assessments and trained professional readings of PPD skin test reactions, done 72 hours after test administration. SETTING: The New York City Fire Department's Bureau of Health Services. PARTICIPANTS: 2011 New York City firefighters and fire officers were given PPD skin tests during a mandatory retraining course. Thirty-seven persons were excluded because of a history of a positive PPD skin test result or a bacille Calmette-Guerin vaccination. All others agreed to participate in testing and self-assessment done using simple written instructions. Self-assessment results were submitted just before trained professional readings were done. MEASUREMENTS: Self-assessments and trained professional readings of PPD skin test reactions. RESULTS: 1833 participants (91%) interpreted their test reactions as flat. Of these interpretations, 1824 (99.5%) matched the professional reading and 9 (0.5%) did not. One hundred seventy-eight participants (9%) interpreted their test reactions as not flat; 136 of these interpretations (76.4%) matched the professional reading and 42 (23.6%) did not (kappa = 0.828; lower 95% confidence limit = 0.790). The predictive value of a negative self-assessment reading was 99.5%, and the specificity was 97.7%. CONCLUSION: In this occupational health care setting, we follow (and recommend to others with similar populations) a tuberculin screening program based on self assessment. Repeated tests with follow-up are required for all persons who do not report their results. All persons with self-assessments of "not flat" should return for readings by trained professionals, counseling, and treatment. PMID- 8678391 TI - Factors associated with do-not-resuscitate orders: patients' preferences, prognoses, and physicians' judgments. SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment. AB - BACKGROUND: Medical treatment decisions should be based on the preferences of informed patients or their proxies and on the expected outcomes of treatment. Because seriously ill patients are at risk for cardiac arrest, examination of do not-resuscitate (DNR) practices affecting them provides useful insights into the associations between various factors and medical decision making. OBJECTIVE: To examine the association between patients' preferences for resuscitation (along with other patient and physician characteristics) and the frequency and timing of DNR orders. DESIGN: Prospective cohort study. SETTING: 5 teaching hospitals. PATIENTS: 6802 seriously ill hospitalized patients enrolled in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment (SUPPORT) between 1989 and 1994. MEASUREMENTS: Patients and their surrogates were interviewed about patients' cardiopulmonary resuscitation preferences, medical records were reviewed to determine disease severity, and a multivariable regression model was constructed to predict the time to the first DNR order. RESULTS: The patients' preference for cardiopulmonary resuscitation was the most important predictor of the timing of DNR orders, but only 52% of patients who preferred not to be resuscitated actually had DNR orders written. The probability of surviving for 2 months was the next most important predictor of the timing of DNR orders. Although DNR orders were not linearly related to the probability of surviving for 2 months, they were written earlier and more frequently for patients with a 50% or lower probability of surviving for 2 months. Orders were written more quickly for patients older than 75 years of age, regardless of prognosis. After adjustment for these and other influential patient characteristics, the use and timing of DNR orders varied significantly among physician specialties and among hospitals. CONCLUSIONS: Patients' preferences and short-term prognoses are associated with the timing of DNR orders. However, the substantial variation seen among hospital sites and among physician specialties suggests that there is room for improvement. In this study, DNR orders were written earlier for patients older than 75 years of age, regardless of prognosis. This finding suggests that physicians may be using age in a way that is inconsistent with the reported association between age and survival. The process for making decisions about DNR orders needs to be improved if such orders are to routinely and accurately reflect patients' preferences and probable outcomes. PMID- 8678392 TI - Splenectomy done during hematologic remission to prevent relapse in patients with thrombotic thrombocytopenic purpura. AB - OBJECTIVE: To assess whether splenectomy done during hematologic remission reduces the relapse rate in patients with relapsing thrombotic thrombocytopenic purpura. DESIGN: Consecutive case series. SETTING: Tertiary care teaching hospital. PATIENTS: 6 consecutive patients seen during a 10-year period who had had one or more relapses of thrombotic thrombocytopenic purpura. INTERVENTIONS: All patients had elective splenectomy while in hematologic remission and were followed after surgery for as long as 8.0 years. MEASUREMENTS: Attack rates (events per year) were calculated for each patient from time of presentation to time of splenectomy and from time of splenectomy to January 1996. RESULTS: A total of 26 episodes of thrombotic thrombocytopenic purpura occurred over 22.3 patient-years before splenectomy. After splenectomy, 3 acute episodes occurred over 22.7 patient-years. The attack rate (+/-1 SD) decreased from 2.3 +/- 2.0 events per year to 0.1 +/- 0.1 events per year. CONCLUSION: In patients who have had one or more relapses of thrombotic thrombocytopenic purpura, splenectomy done during hematologic remission reduces the frequency of acute relapse and the resulting need for medical therapy. PMID- 8678393 TI - Formation of antibodies to factor VIII in patients with hemophilia A who are treated with interferon for chronic hepatitis C. AB - OBJECTIVE: To evaluate the risk for development of antibodies to factor VIII (factor VIII inhibitors) during and after interferon therapy in patients with hemophilia A and chronic hepatitis C infection. DESIGN: Patients were divided into two treatment groups and an untreated control group. Test results from the two treatment groups were compared with those from the control group. SETTING: 3 clinical centers in the Netherlands. PATIENTS: 35 men with hemophilia A who had acquired hepatitis C through the use of plasma-derived clotting factor concentrates. MEASUREMENTS: Patients were tested for factor VIII inhibitors before the start of interferon therapy and every 6 months thereafter. RESULTS: 21 patients with hemophilia A received interferon therapy for chronic hepatitis C infection for a mean of 19.5 months (range, 0.5 to 36 months). In 2 patients, inhibitors were detected on one occasion (maximum titer, 1.2 Bethesda units/mL) during interferon therapy. In 3 patients who were known to have had inhibitors before interferon therapy, no anamnestic reaction was seen during treatment. In 3 of 14 untreated controls who were followed for a mean of 28 months (range, 18 to 40 months), inhibitors were detected on one occasion (maximum titer, 2.3 Bethesda units/mL). CONCLUSION: Long-term interferon therapy in patients with hemophilia did not increase the risk for development of factor VIII inhibitors. PMID- 8678394 TI - The urinary metanephrine-to-creatinine ratio for the diagnosis of pheochromocytoma. AB - OBJECTIVE: To compare the operating characteristics of two tests for diagnosing pheochromocytoma: 1) measurement of the ratio between urinary metanephrine and creatinine levels and 2) measurement of urinary metanephrine levels alone. A second objective was to ascertain the reasons for false-positive test results. DESIGN: Cross-sectional study. SETTING: Hypertension referral center. PATIENTS: 1013 patients referred for hypertension and tested for pheochromocytoma. MEASUREMENTS: 24-hour urinary levels of metanephrine (measured using liquid chromatography) and creatinine. The presence of pheochromocytoma was confirmed at surgery. In patients with positive test results, the absence of pheochromocytoma was documented by negative results of retests and imaging procedures. RESULTS: Of 58 patients with increased metanephrine levels or increased metanephrine-to creatinine ratios, 20 had pheochromocytoma and 38 did not. Of the 38 patients without pheochromocytoma, 15 had high metanephrine levels but normal metanephrine to-creatinine ratios. The respective operating characteristics of measurement of urinary metanephrine levels and measurement of the metanephrine-to-creatinine ratio were as follows: sensitivity, 95% and 100%; specificity, 98% and 98%; positive predictive value, 46% and 47%; and negative predictive value, 100% and 100%. In 13 of the 23 patients who had a high metanephrine-to-creatinine ratio, various acute events may have caused hypersecretion of catecholamines. CONCLUSIONS: Measurement of the metanephrine-to-creatinine ratio is a sensitive and specific test for pheochromocytoma. However, acute events may increase urinary metanephrine excretion to the level that occurs with tumors. PMID- 8678395 TI - Diabetic and hypertensive heart disease. AB - OBJECTIVE: To review the literature on the cardiac effects of diabetes mellitus and hypertension. DATA SOURCES: A MEDLINE search of English-language articles published between 1980 and January 1996 was done using the terms diabetes mellitus, hypertension or blood pressure, and heart. References cited in identified articles were also reviewed. STUDY SELECTION: Selected studies were divided into those addressing coronary artery disease or myocardial ischemia and those addressing nonischemic cardiomyopathy and its sequelae. Preference was given to articles about the cardiac complications of both diabetes mellitus and hypertension. RESULTS: Patients with diabetes and hypertension have a higher incidence of coronary artery disease than do patients with diabetes or hypertension alone. The former patients also show impaired systolic and diastolic function and have more severe left ventricular hypertrophy as documented by echocardiography and at autopsy. The structural myocardial damage seen in these patients has been attributed primarily to hypertension; the myocellular dysfunction has been attributed primarily to diabetes. In diabetic hypertensive patients with cardiomyopathy, coronary artery disease as well as structural and functional cardiac abnormalities are more pronounced than would be expected from either diabetes or hypertension alone. CONCLUSIONS: Considerable evidence from both experimental animal models and humans points to hypertension as a critically important factor in the pathogenesis of severe heart disease in persons with diabetes. The pathogenetic sequelae of diabetes and hypertension are devastating to the heart and often lead to premature congestive heart failure, sudden cardiac death, and acute myocardial infarction. Strict control of arterial pressure and glycemia may prevent or even ameliorate heart disease in patients with hypertension and diabetes. PMID- 8678396 TI - Atrial fibrillation: restoration and maintenance of sinus rhythm and indications for anticoagulation therapy. AB - PURPOSE: To review the efficacy and safety of electrical and pharmacologic conversion of atrial fibrillation, strategies for maintenance of sinus rhythm, and the importance of antithrombotic therapy. DATA SOURCES: English-language trials were identified from the MEDLINE database through 1995, bibliographic references, Current Contents, textbooks, and recent abstracts. STUDY SELECTION: Randomized trials (including abstracts) were selected. Cohort studies were used if randomized trials were not available. DATA EXTRACTION: Study design and data were extracted from clinical trials. Statistical analysis of combined data was not appropriate, given the marked variations in study designs and study populations. DATA SYNTHESIS: Cardioversion restores sinus rhythm in more than 80% of patients. In atrial fibrillation of recent onset, pharmacologic regiments have a success rate of 40% to 90%. Sinus rhythm at 1 year is maintained in 30% of patients without antiarrhythmic therapy but in 50% of patients with such therapy. The efficacy and safety of antiarrhythmic drugs relative to one another are not established because trials done to date have been small and cases vary. Successful cardioversion and maintenance of sinus rhythm are most predictable when the duration of atrial fibrillation is brief. Warfarin reduces the incidence of ischemic strokes and emboli in patients with nonvalvular atrial fibrillation from 4.5% to 1.4% per year. Aspirin (325 mg/d) appears to be equally effective in patients younger than 75 years of age who do not have hypertension or a history of thromboembolism or recent heart failure. Although warfarin is more effective than aspirin in preventing embolic strokes in patients older than 75 years of age, it may increase the incidence of hemorrhagic stroke and result in a similar rate of disabling stroke. CONCLUSION: Cardioversion remains the preferred method with which to re-establish sinus rhythm. Long-term antiarrhythmic therapy is warranted only if recurrences or initial clinical instability are seen; pro arrhythmic concerns and potential side effects should guide drug selection. Antithrombotic therapy is indicated for all patients older than 60 years of age and in all patients younger than 60 years of age who have clinical evidence of a primary cardiac disorder. PMID- 8678398 TI - Plasma or urinary metanephrines for the diagnosis of pheochromocytoma? That is the question. PMID- 8678397 TI - Heterosexual transmission of HIV in Haiti. AB - BACKGROUND: Despite the importance of human immunodeficiency virus (HIV) transmission through heterosexual contact, the incidence of HIV infection in heterosexual cohorts has not been well studied, particularly in the developing world. OBJECTIVE: To 1) determine the incidence of HIV infection in discordant heterosexual couples (couples in which one partner had HIV infection and the other did not) in Haiti and 2) assess risk factors for and methods of preventing HIV infection. DESIGN: Prospective study. SETTING: National Institute for Laboratory Research, Portau-Prince, Haiti. PARTICIPANTS: 475 HIV-infected patients and their noninfected regular sex partners. MEASUREMENTS: Patients and their partners were evaluated at 3- to 6-month intervals for HIV infection, sexually transmitted diseases, and sexual practices. The efficacy of counseling and provision of free condoms was also evaluated. RESULTS: Among the 177 couples who remained sexually active during the prospective study period, 20 seroconversions to HIV positivity occurred, for an incidence rate of 5.4 per 100 person-years (95% CI, 5.16 to 5.64 per 100 person-years). Thirty-eight couples (21.5%) discontinued sexual activity during the study. Only 1 seroconversion occurred among the 42 sexually active couples (23.7% of the 177 sexually active couples) who always used condoms. In contrast, the incidence in sexually active couples who infrequently used or did not use condoms was 6.8 per 100 person-years (CI, 6.49 to 7.14 per 100 person-years). Transmission of HIV was associated with genital ulcer disease, syphilis, and vaginal or penile discharge in the HIV negative partner and with syphilis in the HIV-infected partner. CONCLUSION: Counseling and the provision of free condoms contributed to the institution of safe sex practices or abstinence in 45% of discordant heterosexual couples. However, 55% of couples reported that they continued to have unprotected sex, resulting in an incidence of HIV infection of 6.8 per 100 person-years. PMID- 8678399 TI - Medical savings accounts. American College of Physicians. AB - This position paper examines medical savings accounts (MSAs) as a supplemental mechanism for financing health care services. Although federal legislation to encourage MSAs did not pass in 1995 and is not likely to pass in 1996, MSAs will continue to be seriously considered by public policymakers. Individual retirement accounts accumulate funds for retirement; MSAs could be used to accumulate funds for health care expenditures. Changes in the federal tax code would be required to permit tax-deductible contributions and tax-free earnings to individual MSAs. To be withdrawn without penalty, funds from an MSA could only be used to pay for approved medical or health insurance expenses. Each person would own and control his or her account, regardless of changes in employment. Coupled with high deductible health insurance, MSAs could empower cost-conscious patients in health care decision making, increasing competitive pressure to reduce health care costs. Administrative costs and paperwork associated with health insurance might also be reduced, and some people who currently do not have health insurance might be able to obtain some financial protection. Medical savings accounts may not help unemployed persons or low- and middle-income persons who cannot afford to contribute to such accounts. These accounts may result in reduced health insurance protection and greater out-of-pocket expenses for those most in need of health care. Problems of adverse risk selection could arise if healthy persons choose insurance options involving MSAs; this choice would cause premiums to increase for persons who desire traditional health insurance. PMID- 8678400 TI - The longest house call. PMID- 8678401 TI - Extrahepatic manifestations of hepatitis C virus infection. PMID- 8678402 TI - Extrahepatic manifestations of hepatitis C virus infection. PMID- 8678403 TI - Extrahepatic manifestations of hepatitis of C virus infection. PMID- 8678404 TI - Extrahepatic manifestations of hepatitis C virus infection. PMID- 8678405 TI - Extrahepatic manifestations of hepatitis C virus infection. PMID- 8678406 TI - Extrahepatic manifestations of hepatitis of C virus infection. PMID- 8678407 TI - Diuretics and sudden cardiac death. PMID- 8678408 TI - Diuretics and sudden cardiac death. PMID- 8678409 TI - Diuretics and sudden cardiac death. PMID- 8678410 TI - Diuretics and sudden cardiac death. PMID- 8678411 TI - Diuretics and sudden cardiac death. PMID- 8678412 TI - Diuretics and sudden cardiac death. PMID- 8678413 TI - Beta-blockers and sudden cardiac death. PMID- 8678414 TI - Relapsing group B streptococcal infection. PMID- 8678415 TI - "Sucking with vampires". The medicine of unreason. PMID- 8678416 TI - Antiscience trends in the rise of the "alternative medicine" movement. PMID- 8678417 TI - Constructivism in psychotherapy. Truth and consequences. PMID- 8678418 TI - Freudian suspicion versus suspicion of Freud. PMID- 8678419 TI - Use of plant viruses for delivery of vaccine epitopes. PMID- 8678420 TI - Expression of cholera toxin subunits in plants. PMID- 8678421 TI - Bioproduction of human enzymes in transgenic tobacco. AB - Transgenic plants have significant potential in the bioproduction of complex human therapeutic proteins due to ease of genetic manipulation, lack of potential contamination with human pathogens, conservation of eukaryotic cell machinery mediating protein modification, and low cost of biomass production. Tobacco has been used as our initial transgenic system because Agrobacterium-mediated transformation is highly efficient, prolific seed production greatly facilitates biomass scale-up, and development of new "health-positive" uses for tobacco has significant regional support. We have targeted bioproduction of complex recombinant human proteins with commercial potential as human pharmaceuticals. Human protein C (hPC), a highly processed serum protease of the coagulation/anticoagulation cascade, was produced at low levels in transgenic tobacco leaves. Analogous to its processing in mammalian systems, tobacco synthesized hPC appears to undergo multiple proteolytic cleavages, disulfide bond formation, and N-linked glycosylation. Although tobacco-derived hPC has not yet been tested for all posttranslational modifications or for enzymatic (anticlotting) activity, these results are promising and suggest considerable conservation of protein processing machinery between plants and animals. CropTech researchers have also produced the human lysosomal enzyme glucocerebrosidase (hGC) in transgenic tobacco. This glycoprotein has significant commercial potential as replacement therapy in patients with Gaucher's disease. Regular intravenous administration of modified glucocerebrosidase, derived from human placentae or CHO cells, has proven highly effective in reducing disease manifestations in patients with Gaucher's disease. However, the enzyme is expensive (dubbed the "world's most expensive drug" by the media), making it a dramatic model for evaluating the potential of plants to provide a safe, low-cost source of bioactive human enzymes. Transgenic tobacco plants were generated that contained the human glucocerebrosidase cDNA under the control of an inducible plant promoter. hGC expression was demonstrated in plant extracts by enzyme activity assay and immunologic cross-reactivity with anti-hGC antibodies. Tobacco synthesized hGC comigrates with human placental-derived hGC during electrophoretic separations, is glycosylated, and, most significantly, is enzymatically active. Although expression levels vary depending on transformant and induction protocol, hGC production of > 1 mg/g fresh weight of leaf tissue has been attained in crude extracts. Our studies provide strong support for the utilization of tobacco for high-level production of active hGC for purification and eventual therapeutic use at potentially much reduced costs. Furthermore, this technology should be directly adaptable to the production of a variety of other complex human proteins of biologic and pharmaceutical interest. PMID- 8678422 TI - Antibody production and engineering in plants. AB - Plants have always been important in the pharmaceutical industry, and plant biotechnology now offers new applications. The use of heterologous expression systems for production of recombinant proteins including antibodies is no longer novel. Attention has now turned towards the end-user, and specifically to engineering the antibody to precise requirements. In expanding the choice of production systems, plants offer unique alternatives for antibody users not only in the bulk production of antibody molecules but also in the ability to assemble full-length and complex, multimeric antibodies. Although the initial investment of time and effort is substantial compared to that of other expression systems, antibody production on an agricultural scale can be envisioned, and the economy of this approach opens many new areas for potential antibody applications in addition to their traditional research and pharmaceutical uses. PMID- 8678423 TI - Long-term follow-up of tracheoesophageal puncture results. AB - Since its introduction by Blom and Singer in 1980, tracheoesophageal puncture with a voice prosthesis has become the most frequently recommended choice for speech rehabilitation of total laryngectomies. Many studies have reviewed the initial speech acquisition success rates following tracheoesophageal puncture; however, long-term follow-up in these initial successes has been lacking. In addition, factors predictive of long-term success with tracheoesophageal speech have not been defined. Over a 10-year period, we retrospectively reviewed all total laryngectomy patients, including those who have undergone primary or secondary tracheoesophageal puncture, at the University of Illinois Hospital and Clinics and the Westside Veterans Administration Hospitals. Survival in the total laryngectomy cohort of 202 patients ranged from 35% to 50%. Forty of these patients underwent tracheoesophageal puncture, in whom survival was 75%. Short term success with tracheoesophageal speech was approximately 70% for our patients, while long-term success was achieved in 66%. Despite low socioeconomic status and relatively high alcoholism rates, successful maintenance of tracheoesophageal speech was achieved in the majority of cases. Tracheoesophageal speech should therefore be considered as a primary method of vocal rehabilitation in all patients undergoing total laryngectomy. PMID- 8678424 TI - Acoustic measurement of subglottic stenosis. AB - A device that determines cross-sectional area (CSA) of the airway by acoustic reflections (Hood, Inc) was used to measure subglottic area. Airway models were made from Plexiglas rings with known internal dimensions similar to clinically encountered stenoses of various lengths and diameters. Acoustic measurements of airway area were made and compared to actual CSA. There is a strong correlation between CSA measured acoustically and the actual area of simulated stenoses. However, when the CSA of the stenosis was < 0.64 cm2, the signal was impaired, resulting in overestimation of the stenotic CSA. In simulated stenoses with a CSA of < 0.38 cm2, acoustic measurement of the CSA beyond the stenotic segment was unreliable. Determination of the origin of stenosis was accurate with this method. The CSA of cadaver airways was also measured acoustically. The CSA 2.0 cm below the glottis of normal airways in males ranged from 1.28 to 2.74 cm2 and in females 0.87 to 1.43 cm2, with means of 2.16 and 1.09 cm2. It appears that acoustic measurement of CSA of subglottic stenosis is a feasible clinical technique that yields dimensions of the airway in situations in which direct measurements are impossible. It was suggested that this technique be used for assessment of subglottic stenosis and evaluation of the efficacy of treatment of subglottic stenosis. PMID- 8678425 TI - Nd:YAG laser treatment for laryngeal and hypopharyngeal hemangiomas: a new technique. AB - The treatment of laryngeal and hypopharyngeal hemangiomas is indicated when they are symptomatic, causing dysphagia, recurrent bleeding, or airway obstruction. These tumors are found in the glottis, supraglottic larynx, and hypopharynx. Histologically, they are considered as mixed or cavernous-type hemangiomas. By utilizing a glass slide to compress the lesion, its thickness and blood flow are reduced. The tumor can then be laser-photocoagulated with less energy, with the glass slide used as a laser platform. These conditions optimize the benefits of laser ablation while minimizing the adverse heat sink effects to the surrounding healthy tissue. We present three patients with hemangiomas of the larynx and hypopharynx who were treated with this technique. The details of the technique in each case will be presented with the objective of improving the care of these unusual and challenging tumors. PMID- 8678426 TI - Evaluation and management of hemoptysis in infants and children. A report of nine cases. AB - Hemoptysis is an occasional complication of adult pulmonary disease and is rare in children. The most common causes in adults are infection, bronchiectasis, pulmonary neoplasm, cystic fibrosis, pulmonary infarct, and trauma; in children the most common causes are infection and congenital abnormalities of the cardiopulmonary vasculature. Nine cases of hemoptysis in seven infants and two children will be presented. Two cases were fatal, thus illustrating the importance of rapid and definitive therapy early in the course. One of the fatal cases is the first case report in the otolaryngological literature of fatal hemoptysis in the newborn as a result of vascular anomalies associated with an absent left pulmonary artery. Eight cases of various causes, including small vessel vascular abnormality, trauma, recurrent pulmonary infection, and laryngotracheal papilloma, are discussed. The literature is reviewed, embryology is discussed, and a mechanism of death is theorized for the patient with the congenital vessel anomaly. Management considerations for hemoptysis in infants and children are discussed. PMID- 8678427 TI - Repeatedly successful closure of the larynx for the treatment of chronic aspiration with the use of botulinum toxin A. AB - Botulinum toxin A was used preoperatively to temporarily paralyze the intrinsic laryngeal muscles to hinder movements during the healing period after operation. In addition, toxin was injected into the cricopharyngeal muscle to allow a better passive drainage of the saliva into the esophagus. We treated six patients. Three suffered from chronic aspiration problems after multiple lower cranial nerve lesions, and three patients were apallic (after stroke and major brain injury). Two weeks before scheduled operation, we injected the toxin into the posterior cricoarytenoid muscles, the aryepiglottic muscles, and the vocalis muscle on both sides, as well as the cricopharyngeal muscle. The amount of injected toxin varied between 1.0 and 1.4 mL, equal to 200 to 280 units of botulinum toxin A (Dysport). After a complete palsy of these muscles (controlled by direct electromyography), a closure of the larynx was performed. After laminotomy and exposure of the intralaryngeal structures, the false vocal cords were mobilized and adapted with sutures. Because involuntary movements of the intralaryngeal musculature were absent, primary healing without complications occurred in all cases. Aspiration and related complications disappeared in all patients. In addition, the intensity of patient care could be considerably reduced. Preoperative use of botulinum toxin A allows sufficient laryngeal closure. This procedure is especially useful in the treatment of children and young adults, preserving the ability of later speech rehabilitation because of the return of voluntary movements of the intrinsic laryngeal muscles 6 months after the injection. Furthermore, this technique, as minimal surgical intervention, can be performed in high-risk patients. PMID- 8678428 TI - Immunohistochemical characterization of benign laryngeal lesions. AB - It has been proposed that laryngeal nodules and polyps represent injury to the basement membrane zone of the vocal fold. Repeated trauma from shearing forces produced by excessive or abusive phonation leads to basement membrane zone disruption and thickening. This thickening, along with poorly understood vascular changes, creates the characteristic clinical appearance of the vocal nodule or polyp. As such, to better understand vocal fold nodules it is imperative to characterize the extracellular matrix in this area of injury. Secondary to the small size and relatively acellular nature of these lesions, hematoxylin and eosin (H & E) preparations of histologic material are unsatisfying. A previous study examined this area with immunohistochemical techniques to better characterize its contents. The report, however, contained little information with regard to the clinical appearance of the lesions prior to excision. Therefore, we were prompted to review histologic material from 31 patients who underwent microsurgical excision of 41 benign lesions, vocal nodules (4), polyps (19), polypoid corditis (4), and cysts (14) with immunohistochemical techniques to characterize the patterns of fibronectin and collagen type IV within these lesions. Normal human vocal folds were stained for control. All material was correlated with the H & E preparations and the clinical diagnosis. Collagen type IV and fibronectin appeared present in relatively abnormal patterns in the areas adjacent to the lesion. This study validates earlier results. In addition, correlation with clinical data allows association of immunohistochemical staining patterns with clinical diagnosis. PMID- 8678429 TI - Acute airway obstruction in the hospitalized infant: four hard lessons in the distal trachea. AB - Acute obstructing lesions of the distal (lower) trachea present a unique challenge to the pediatric otolaryngologist. The small caliber of the airway and tenuous medical status of such patients test the ingenuity of the surgeon and the limits of instrumentation. This report presents the operative findings and management of four hospitalized infants with worsening respiratory distress. Difficulties encountered in maintaining airway control while diagnosing and correcting these lesions are described. PMID- 8678430 TI - Omohyoid muscle transposition for the treatment of bowed vocal fold. AB - Imperfect glottal closure is usually the most important factor causing dysphonia in patients with bowing of the vocal folds. We have performed laryngeal framework surgery, which allows the medialization of the vocal folds from the outside without creating any scar tissue on them. Over the past 6 years, however, we encountered three cases with marked bowing of the vocal folds that could not be cured by laryngeal framework surgery alone. We used an open laryngeal procedure in these cases, even though such procedures had been considered contraindicated in the treatment of hoarseness. After performing a laryngofissure, we made a small pocket beneath the vocal fold mucosa at the anterior commissure. The superiorly based omohyoid muscle flap was then transposed into the mucosal pocket and sutured to the vocal process. This procedure should be considered an option in treating highly bowed vocal folds. PMID- 8678431 TI - Management of subglottic foreign bodies. AB - Foreign body aspiration is not an infrequent encounter in the practice of otolaryngology and requires immediate attention. The vast majority of foreign body aspirations occur in children less than 3 years of age, and the actual event of aspiration is frequently not witnessed. Although inhaled foreign bodies most often lodge in the bronchi, laryngotracheal foreign bodies also occur and are potentially more dangerous. Specifically, subglottic foreign bodies present unique clinical challenges. The diagnosis of subglottic foreign bodies is often difficult and they are commonly confused with other causes of upper airway obstruction. We present our experience with the diagnosis and management of seven patients with subglottic foreign bodies, who presented with an abnormal airway and whose problems were initially misdiagnosed. The radiographic and clinical features are discussed with a review of our surgical management. PMID- 8678432 TI - Videoendoscopic analysis of laryngeal function during laughter. AB - Although commonly encountered in all human cultures, laughter remains poorly understood. In order to examine laryngeal function during laughter, telescopic and fiberscopic videolaryngoscopy was performed on five subjects, who laughed in the different vowels, at various frequencies, and in several voice qualities. During laughter, the vocal folds were found consistently to undergo rhythmic abduction and adduction. At the end of these specific phonation tasks, all subjects were able to gain voluntary control of paramedian vocal fold positioning. This study defined laryngeal function during laughter. These results have important clinical implications. Voluntary vocal fold positioning has important applications in speech therapy for dysphonias, such as vocal fold nodules, in which the primary cause is vocal fold hyperadduction. Patients suffering from these hyperadductive dysphonias may be able to utilize laughter to correct them. PMID- 8678433 TI - Nitrergic innervation of the rat larynx measured by nitric oxide synthase immunohistochemistry and NADPH-diaphorase histochemistry. AB - We evaluated the involvement of nitric oxide (NO) in the laryngeal innervation of rats using NADPH-diaphorase (NADPH-d) histochemistry and neuronal nitric oxide synthase (nNOS) immunohistochemistry. The findings obtained by NADPH-d histochemistry were identical with those obtained by nNOS immunohistochemistry, indicating that NADPH-d is nNOS in the laryngeal innervation system. We found NADPH-d-positive nerve fibers in every region of the larynx. In the epithelia of the mucosa, a small number of NADPH-d-positive nerve fibers were detected. The plexus of NADPH-d-positive nerve fibers was commonly found in the lamina propria, and some of these fibers were clearly associated with blood vessels. We also noted NADPH-d-positive nerve fibers in the region of laryngeal glands. Some of these fibers appeared to terminate in the glandular cells. We found NADPH-d positive nerve fibers with varicosities in the intrinsic laryngeal muscle and free-ending nerve fibers on the muscle fiber. Motor end plate-like structures were positive for NADPH-d histochemistry. The NADPH-d-positive nerve fibers appeared to terminate at motor end plate-like structures in two of nine rats examined. A cluster of NADPH-d-positive neurons were occasionally present in the lamina propria of the laryngeal mucosa, in the connective tissue between the thyroid cartilage and intrinsic laryngeal muscle, and in the connective tissue near the cricoarytenoid joint. The present findings suggest that NO participates in the autonomic, sensory, and motor innervation of the larynx. PMID- 8678434 TI - Pediatric tracheobronchial foreign bodies: historical review from the Johns Hopkins Hospital. AB - We investigated changing trends in pediatric tracheobronchial foreign body removal and resident experience from 1939 to 1991. We retrieved the records of 234 cases of tracheobronchial foreign body removal at Johns Hopkins. The mean number of cases per year was 5.9. The most common foreign bodies removed were peanuts, accounting for 38.9%. The average yearly incidence of pediatric tracheobronchial foreign bodies remained relatively constant during the period studied. Our data suggested little change in outcome or complications with the advent of optical telescopes in the mid-1970s, despite their great value in improved visualization. Resident experience and training were evaluated by the number of cases attended by each resident during his or her training. The number varied from 1 to 8 cases, not including experience acquired at our sister institutions. Although complete data could not be obtained in many of the older medical records, our review suggests that despite the advantage offered by the optical forceps technology, proper training and experience in traditional rigid endoscopic techniques is still crucial to optimize outcome and minimize the risk of complications in pediatric tracheobronchial foreign body removal. Chevalier Jackson's recommendation that residency training include an animal laboratory course in foreign body removal still applies. PMID- 8678435 TI - Adenovirus-mediated gene therapy for head and neck squamous cell carcinomas. AB - Advanced head and neck squamous cell carcinomas (HNSCCs) have a poor prognosis despite aggressive multimodal therapy. The goal of our study was to test the feasibility of gene transduction as a novel therapy for head and neck cancer. Three human HNSCC cell lines were transduced in vitro with a replication deficient recombinant adenovirus containing the lacZ marker gene (Ad2/CMV beta gal). Gene transduction efficiency was dependent on multiplicity of infection, duration of exposure to the virus, and viral concentration. Next, the HEp-2 cell line was transduced with an adenoviral vector (Ad.RSVtk) containing the herpes simplex virus thymidine kinase (HSVtk) gene, which, when expressed, sensitizes transduced cells to ganciclovir (GCV). Subsequent administration of GCV resulted in complete tumor cell killing. These results suggest that adenovirus-mediated transfer of HSVtk and administration of GCV has potential as a new therapy for HNSCC. PMID- 8678436 TI - Onlay bone augmentation with an osteoinductive implant. AB - The repair of contour defects of craniofacial bone can be accomplished by several methods, including autogenous bone grafts, demineralized bone, and alloplastic materials. The objective of this study was to assess a biodegradable, xenogeneic, osteoinductive implant for craniofacial onlay bone augmentation. Twelve New Zealand White rabbits each had craniofacial onlays consisting of three experimental materials: 1) autograft; 2) allogeneic, demineralized block implant; and 3) partially purified osteoinductive protein (osteogenin) with allogeneic collagen and 50:50 poly (DL-lactide-co-glycolide). Implants with host bone were recovered after 20 weeks and assessed by histomorphometric methods. There was no evidence of adverse local reaction to the three treatments. No significant difference in bone replacement or bone density resulting from each of the implant types was demonstrated. In conclusion, the osteoinductive implants were well tolerated, and over the 20-week period they appeared to maintain their contour as onlays. PMID- 8678437 TI - Magnetic resonance imaging of an inhaled peanut. PMID- 8678438 TI - Laryngeal lymphoma derived from mucosa-associated lymphoid tissue. AB - Extranodal lymphomas account for as many as 40% of non-Hodgkin's lymphomas, and most arise in the gastrointestinal tract, but other mucosal organs may be involved, especially the upper aerodigestive tract. Low-grade B-cell lymphomas arising in the gastrointestinal tract and other mucosae have been found to recapitulate the structure and cytologic features of mucosa-associated lymphoid tissue (MALT). Histologically low-grade MALT lymphomas are characterized by centrocyte-like B-cells with a phenotype similar to that of so-called marginal zone B-cells. Tumors evolving from MALT are generally rare among lymphomas of the upper aerodigestive tract, but a few cases of laryngeal lymphomas derived from MALT have been reported. Primary MALT lymphoma of the larynx should always be considered in tumors with histopathologic features of low-grade B-cell lymphoma, or so-called pseudolymphoma. PMID- 8678439 TI - A case of prostatic cancer metastatic to the orbit and ethmoid sinus. PMID- 8678440 TI - Papillary neoplasms (Heffner's tumors) of the endolymphatic sac. PMID- 8678441 TI - Surgical implications of tumour immunology. AB - The presence of immune infiltration of tumour deposits and the existence of effective in vitro anti-tumour immune responses would suggest the possibility of therapeutic manipulation against tumour cells. However, clinical immunotherapy has shown little promise as a cancer treatment. Numerous explanations for this inefficacy have been proposed, one of which involves the elaboration of immunosuppressive moieties from tumour cells. The results of studies presented below show that serum from patients with gastrointestinal and other tumours have immunosuppressive influences on normal lymphocytes. The degree of this in vitro inhibition is related to tumour 'bulk' and may reflect a systemic immunosuppressive influence of the tumour. Isolation and culture of lymphocytes from gastrointestinal tumour deposits demonstrated that these immune cells are functionally inert, suggesting the existence of an immunosuppressive tumour microenvironment. The isolation and partial purification of an immunosuppressive moiety from conditioned culture medium of a variety of human tumour cell lines further supports the hypothesis of tumour-mediated immunosuppression. A number of protein tumour cell products have been described with potent immunosuppressive properties. These include transforming growth factor-beta, interleukin-10, and the retroviral envelope protein p15E. The surgical implications of the proposed tumour-host immune relationship includes the hypothesis that clinically apparent disease may not be amenable to immune attack owing to tumour-mediated immune suppression. The use of immunostimulatory strategies as adjuvant perioperative therapy would seem a more effective environment for the activation of antitumour immune responses in the surgical patient. PMID- 8678442 TI - Minimum standards for the management of cleft lip and palate: efforts to close the audit loop. Royal College of Surgeons of England. AB - Intercentre audit in the late 1980s revealed poorer outcomes for facial growth for British patients with cleft lip and palate than equivalent patients in northern Europe. A subsequent survey of the surgical practices in England and Wales, under the auspices of the Surgical Audit and Epidemiology Unit, revealed the widespread involvement of low-volume operators in cleft care, a tendency for low-volume operators to have an incomplete network of associated professionals, and non-standardised record keeping protocols. Recommendations for minimum standards of care for children born with cleft lip and palate were produced by a multidisciplinary steering group. A further investigation is planned to determine their validity and to provide a baseline for future audit cycles. PMID- 8678443 TI - Laparoscopic orchidopexy: one-stage alternative for non-palpable testes. AB - Laparoscopy was utilised in the evaluation of 24 non-palpable undescended testes in 19 children. The procedure was accurate in all patients while ultrasound (US) and magnetic resonance imaging (MRI) failed to localise the testes in most cases. At the same time laparoscopic orchidopexy was performed on 15 testes (62.5%). The remaining testes were either absent or atrophic, in which case they were excised. There were no complications from these procedures and the hospital stay was short. Paediatric laparoscopy is safe and effective in the definitive management of non-palpable undescended testes. PMID- 8678444 TI - Corrosive injuries of the oesophagus and stomach: experience in management at a regional paediatric centre. AB - In a 21-year period between June 1974 and May 1995, eight children required surgery for the treatment of complications after ingestion of corrosive substances. There were six oesophageal injuries due to alkali ingestion and two gastric injuries secondary to acid ingestion. Of those ingesting alkali, diagnosis of stricture was made at a mean of 28 days and all children underwent endoscopic dilatation with a mean of six treatments (range 2-13). Two children subsequently required oesophageal replacement and colonic interposition. One of the children ingesting acid presented as an emergency with peritonitis and required laparotomy at which partial gastrectomy and pyloroplasty were performed. The second child presented 3 weeks after ingestion with a gastric stricture and required gastrostomy. All children are currently alive and well and are asymptomatic. The details of management are discussed, together with a review of the literature. PMID- 8678445 TI - Palliation of carcinoma of the oesophagus with brachytherapy and the Didcott dilator. AB - Forty-one patients with oesophageal cancer who developed strictures after high dose rate intraluminal brachytherapy were dilated using a slow continuous dilator (Didcott dilator). After dilatation, all patients were evaluated monthly for relief of dysphagia. At the end of the 1st month, 41 patients were evaluable: 28 had no dysphagia while 13 had improvement; at the end of the 2nd month, 40 were evaluable, 26 had no dysphagia while 14 had improvement; at the end of the 3rd month, 34 patients were evaluable, 24 had no dysphagia while 10 had improved. Three patients developed worsening of dysphagia owing to tumour recurrence among 32 patients who were evaluable at the end of the 4th month. Five patients developed worsening of dysphagia among the 26 patients who were evaluable at the 5th month due to tumour. These patients were dilated with the Didcott dilator and were treated with further brachytherapy. At the end of the 6th month, 14 patients were evaluable; seven had no dysphagia, while seven had improvement over their presenting dysphagia scores. Slow continuous dilatation using the Didcott dilator is very effective in the dilatation of strictures after high dose rate intraluminal brachytherapy. Dilatation is prolonged and sustained and a single dilatation is usually enough to maintain patency. PMID- 8678446 TI - Total hip replacement: the way forward. PMID- 8678447 TI - Pathophysiology of the fundic enterochromaffin-like (ECL) cell and gastric carcinoid tumours. AB - The genesis of human gastric carcinoma is ill understood but is invariably related to achlorhydria. Gastrin secretion is negatively regulated by luminal acid and hypergastrinaemia is thus associated with low acid states which may be natural (atrophic gastritis) or owing to acid inhibitory therapy. Apart from its acid secretory activity, gastrin is trophic to the mucosa, via stimulation of the fundic enterochromaffin-like (ECL) cells to secrete histamine. In conditions of elevated gastrin levels, ECL cell hyperplasia and even neoplasia have been noted. The relationship between low acid, hypergastrinaemia, ECL cell hyperplasia, and neoplasia may be of relevance since ECL cells secrete histamine and TGF alpha which are both recognised mitogens. We studied the rodent mastomys, which spontaneously develop gastric carcinoid tumours, which can be generated in 4 months under conditions of drug-induced acid inhibition and inhibited by octreotide administration. A pure (90-95%) cell preparation was used to evaluate ECL cell physiology and trophic regulation. A gastrin/CCKB receptor responsible for histamine secretion and DNA synthesis was identified, cloned and sequenced. Octreotide lowers plasma gastrin levels, decreases ECL cell neoplasia and, in vitro, inhibits ECL cell DNA synthesis. H1 receptor antagonists inhibited DNA synthesis in vitro and ECL neoplasia in vivo without altering gastrin levels. Hypergastrinaemia increased TGF alpha/EGF receptor and TGF alpha production and TGF alpha massively stimulated ECL cell DNA synthesis. Since ECL cells produce both histamine and TGF alpha and regulate parietal cells which produce TGF alpha, it is possible that achlorhydria-generated ECL cell dysfunction may play an initiative role in the pathobiology of gastric adenocarcinoma. The long-term clinical consequences of drug-induced sustained acid inhibition are worthy of further consideration. PMID- 8678448 TI - Colour flow duplex in the assessment of recurrent varicose veins. AB - Recurrent varicose veins represent a common clinical problem. They require accurate assessment of all sites of reflux before surgery to ensure the correct surgical approach and reduce further recurrences. We report our experience of colour flow duplex in 190 legs with recurrent disease with reference to the pattern of reflux seen. We found that multiple sites of reflux were common, and that neovascularity and calf-perforators were most frequently seen. Our observations compare favourably with previously published data. Despite the reported greater accuracy of phlebography for detection of incompetent perforators, its invasive nature and potential contrast reactions have prompted us to use colour flow duplex routinely for the assessment of recurrent varicose veins. PMID- 8678449 TI - Problematic renal calculi presenting during pregnancy. AB - Urinary tract calculi presenting during pregnancy are rare, with less than 0.1% of pregnancies being associated with stones, the vast majority being asymptomatic and a chance finding. We outline six cases treated over an 8-year period. They presented with combinations of pain, sepsis and obstruction. Intervention was required in four cases: insertion of antegrade nephrostomy, double-J stent, Dormia basket stone extraction, open pyelolithotomy and induction of labour. In each case the pregnancy had a successful outcome. Renal colic can precipitate premature labour. Delayed diagnosis and intervention can result in permanent renal impairment. Ionising radiation and anaesthetic agents may be harmful during pregnancy. The problem is rarely encountered and we therefore present information on the relative risks in each trimester of exposure to the mother and fetus and present a clinical algorithm for the management of these patients. PMID- 8678450 TI - Iatrogenic accessory nerve injury. AB - Accessory nerve injury produces considerable disability. The nerve is most frequently damaged as a complication of radical neck dissection, cervical lymph node biopsy and other surgical procedures. The problem is frequently compounded by a failure to recognise the error immediately after surgery when surgical repair has the greatest chance of success. We present cases which outline the risk of accessory nerve injury, the spectrum of clinical presentations and the problems produced by a failure to recognise the deficit. Regional anatomy, consequences of nerve damage and management options are discussed. Diagnostic biopsy of neck nodes should not be undertaken as a primary investigation and, when indicated, surgery in this region should be performed by suitably trained staff under well-defined conditions. Awareness of iatrogenic injury and its consequences would avoid delays in diagnosis and treatment. PMID- 8678451 TI - Endoscopic stapling diverticulotomy of pharyngeal pouch. AB - Endoscopic diverticulotomy (Dohlman's procedure) is a well-established and effective alternative to external diverticulectomy in the treatment of pharyngeal pouch. The division of the common septum between the pouch and the oesophagus is usually performed either with electrocautery or with a laser. We describe a new technique of endoscopic diverticulotomy using a linear cutter stapling gun. This technique has the advantages of being quick and bloodless, avoiding the need for a nasogastric tube, permitting oral intake as early as the first postoperative day and allowing early discharge from hospital. It also has the theoretical advantage over the electrocautery or the laser technique of reducing the risk of fistula formation, mediastinitis and thermal injury to the recurrent laryngeal nerve. PMID- 8678452 TI - An audit of one surgeon's experience of oral squamous cell carcinoma using a computerized malignancy database. PMID- 8678453 TI - The treacherous fibroadenoma: a 'mighty mouse'. PMID- 8678455 TI - Vascular trauma in civilian practice. PMID- 8678454 TI - Colorectal cancer: surgical prophylaxis and chemoprevention. PMID- 8678456 TI - A regional study of thyroidectomy: surgical pathology suggests scope to improve quality and reduce cost. PMID- 8678457 TI - Parotid duct stenosis: interventional radiology to the rescue. PMID- 8678459 TI - Blood transfusion requirements in femoral neck fractures. PMID- 8678458 TI - Randomized comparison of silicone versus Teflon cannulas for peripheral intravenous nutrition. PMID- 8678460 TI - Trephine colostomy: a warning. PMID- 8678461 TI - Acute scybalous colonic obstruction and perforation. PMID- 8678462 TI - Tension-free mesh hernia repair: review of 1098 cases using local anaesthesia in a day unit. PMID- 8678463 TI - Parastomal hernia. AB - Parastomal herniation is a common complication after stoma formation. The incidence can be reduced by using an extraperitoneal technique, limiting the size of the trephine to 1.5-2.0 cm or by strengthening with a mesh. If an intraperitoneal technique is used the intestine should be brought out through the rectus muscle. Generally, the symptoms are easily controlled with a support belt. Various techniques have been advocated for surgical repair. Fascial repair alone should no longer be performed owing to an unacceptably high recurrence rate, but should be combined with a prosthetic mesh. Relocation of the stoma should be performed for primary repairs. PMID- 8678464 TI - Colonic mucus, smoking and ulcerative colitis. AB - Human colonic mucosal protection is not fully understood but may in part rely on a layer of mucus gel adherent to the mucosa. Ulcerative colitis may occur if mucosal protection breaks down. Two studies are presented, both of which relate to the aetiology of ulcerative colitis. First, a layer of adherent mucus gel was demonstrated by a simple, reliable method. Measurements of mucus layer thickness were made in freshly resected colonic specimens and shown to increase from a mean of 107 microns on the right colon to 155 microns in the rectum. In ulcerative colitis the layer is significantly thinner or absent, whereas in Crohn's disease the colonic mucus layer is significantly thicker. Second, the relationship between smoking and colitis is explored by a double-blind, randomised and placebo controlled trial of transdermal nicotine in active disease. Significant clinical benefit was seen, indicating nicotine may be both useful therapeutically and the component of tobacco smoke that acts to protect against colitis. Since smoking and nicotine have actions on mucosae and mucus in other organs, it is argued that there is a mucus deficiency in ulcerative colitis that smoking acts to reverse. PMID- 8678465 TI - Xenotransplantation: benefits, risks and regulation. PMID- 8678466 TI - The immune response in small bowel transplantation. AB - The immunological problems of small bowel transplantation have not yet been overcome. Frequent severe rejection episodes are common in clinical practice, and GVHD may emerge as a significant complication once rejection is more effectively controlled. Both are caused by the large number of lymphocytes in the graft. There is extensive exchange migration of lymphocytes between graft and host even in the absence of rejection, and persisting donor cells in the host may carry the propensity for GVHD. Various techniques including analysis of host peripheral blood samples are being developed to enable earlier and easier diagnosis of rejection, which should facilitate early treatment and reduce infective complications. The balance between rejection and GVHD can be manipulated experimentally, and clinical trials are under way to determine whether such techniques can improve the outcome for human transplant recipients. PMID- 8678467 TI - Body composition: overview of methods and future directions of research. AB - A short overview is given on the most important analytical body composition methods. Principles of the methods and advantages and limitations of the methods are discussed also in relation to other fields of research such as energy metabolism. Attention is given to some new developments in body composition research such as chemical multiple-compartment models, computerized tomography or nuclear magnetic resonance imaging (tissue level), and multifrequency bioelectrical impedance. Possible future directions of body composition research in the light of these new developments are discussed. PMID- 8678468 TI - Selected vitamins and trace elements in blood of vegetarians. AB - Selected vitamin (A, C, E, beta-carotene) and trace element (selenium, zinc, copper) levels were estimated in the blood of 67 vegetarian nonsmokers aged 34-60 years. The average period of lacto- or lacto-ovovegetarianism was 6.2 years. The results were compared with those of 75 nonvegetarians of the same age and living in the same region. Vegetarians had significantly higher plasma levels of essential antioxidants: vitamin C, beta-carotene, and vitamin A. A significantly higher molar ratio vitamin E/cholesterol indicates a more effective protection especially of low-density lipoproteins against peroxidation. Oxidation of low density lipoproteins represents one of the key factors in the pathogenesis of atherosclerosis. The molar ratio vitamin E/total lipids was significantly higher in plasma of vegetarians, demonstrating a more effective protection of polyunsaturated fatty acids against peroxidation. Vegetarians had significantly higher plasma levels of selenium and similar levels of zinc and copper when compared to nonvegetarians. These trace elements are important for the activity of antioxidant enzymes. The results document a beneficial effect of vegetarian nutritional habits on antioxidative parameters and thus on the reduction of cardiovascular diseases and cancer risk. Reactive products of oxygen metabolism and subsequent toxic products of lipid peroxidation play an important role in the etiology of these diseases. PMID- 8678469 TI - Assessment of nutritional risk in the elderly. AB - To enhance physicians' awareness of nutritional problems in the elderly, a nutritional risk assessment scale was developed and validated. 126 patients (mean age 82.0 +/- 6.7, range 65-96 years) admitted from home to a geriatric hospital were enrolled in the study. After informed consent was obtained, they underwent a comprehensive geriatric assessment of physical, emotional, and cognitive functions, overall functional capacity, and social situation. The nutritional status was assessed by the nutritional risk assessment scale. This scale consists of items relating to gastrointestinal disorders, chronic diseases with pain, immobility, alterations in body weight, appetite, difficulties in eating, cognitive or emotional problems, medication, smoking and drinking habits, and social situation. The maximum score which indicates a high risk is 12. The scores from the nutritional risk assessment scale were compared with a physician's clinical judgement (patients being graded as "obese', "well-nourished', "undernourished') as the "gold standard' and with body mass index, other anthropometric findings, and serum albumin and prealbumin levels. The nutritional risk assessment scale was reliable (inter- and intrarater) and showed construct and concurrent validity. There was a significant correlation with clinical judgement (p < 0.01) and other parameters of nutritional status (p < 0.05). The scores of undernourished patients (n = 37; 5.35 +/- 1.60, range 3-8) were significantly different (p < 0.05) from those who were classified as well nourished (n = 63; 2.66 +/- 1.59, range 0-7) or obese (n = 26; 2.73 +/- 1.76, range 0-7). When implemented as part of a comprehensive geriatric assessment, this questionnaire can be completed within 5-10 min. The nutritional risk assessment scale is simple and reliable and helps in the identification of elderly patients at risk of poor nutrition. PMID- 8678470 TI - Protein metabolism in cirrhotic rats: effect of dietary restriction. AB - This paper evaluates the role of decreased food intake in protein metabolism in cirrhotic animals by comparing the changes with those observed in pair-fed controls. Rats were injected with [14C]leucine and then divided into 3 groups. Liver cirrhosis was induced in 1 group of rats by repeated intragastric administration of CCl4 in oil over a period of 8 weeks. Control animals were gavaged with oil and either pair-fed or given access to food ad libitum. Three days after the last intragastric dose, rats were injected with [3H]leucine and sacrificed 20 min later. The daily food intake of CCl4 rats declined to 60% of that of the ad libitum controls. Both the pair-fed control group and the cirrhotic group showed decreased body weight gain, and a decline in muscle and intestinal protein degradation. The pair-fed and the cirrhotic groups differed from one another in many metabolic abnormalities. In the cirrhotic group we observed higher levels of serine, asparagine, proline, methionine, tyrosine, phenylalanine, ornithine and histidine, and lower levels of valine, isoleucine and arginine. In these animals higher relative (per kilogram body weight) weights and protein content of the spleen, kidneys and heart were observed. Additionally higher liver weight despite lower protein concentration, as well as lower liver protein degradation and lower skeletal muscle protein synthesis were found. PMID- 8678471 TI - Fluorometric riboflavin titration in plasma by riboflavin-binding apoprotein as a method for vitamin B2 status assessment. AB - A method for plasma riboflavin determination by riboflavin-binding apoprotein titration has been proposed for vitamin B2 status evaluation. The method is based on the formation of riboflavin-apoprotein complex accompanied by full loss of fluorescence peculiar to free riboflavin. The data obtained have demonstrated a correlation with indicators of the vitamin B2 status such as urinary excretion, erythrocyte content, and stimulation of the glutathione reductase activity by flavin adenine dinucleotide. Levels > 6 ng/ml blood plasma may be considered to be a criterion for normal vitamin B2 supply. PMID- 8678472 TI - Effect of phytic acid and microbial phytase on Cd accumulation, Zn status, and apparent absorption of Ca, P, Mg, Fe, Zn, Cu, and Mn in growing rats. AB - Three groups of individually housed albino rats (n = 6, initial average weight = 47 g) were fed diets based on egg white and cornstarch (basal diet 8 g Ca, 5.2 g P, 0.76 g Mg, 100 mg Zn, 100 mg Fe, 50 mg Mn, 7 mg Cu, and 5 mg Cd per kilogram diet) over a 4-week period. Group I (controls) was fed the basal diet free of phytic acid (PA) and microbial phytase. In groups II and III cornstarch was replaced by 0.5% PA from NaPA (molar PA/Zn ratio approximately 5). In group III, 2,000 U of microbial phytase from Aspergillus niger per kilogram diet was added. Live weight gain, zinc status (zinc in plasma, femur, liver, and testes; activity of the plasma alkaline phosphatase), and apparent absorption of zinc, iron, copper, and manganese remained unchanged by the different dietary treatments. The apparent phosphorus absorption was highest in the phytase group. PA decreased and microbial phytase improved the apparent absorption of calcium and magnesium. Liver cadmium concentration, total liver and kidney cadmium content, as well as fractional liver and kidney cadmium accumulation in rats fed the diet containing PA were significantly higher than those in the controls. Phytase supplementation lowered liver and kidney cadmium accumulation. Differences in calcium and magnesium bioavailability due to PA and microbial phytase may be one factor in the alteration of tissue cadmium accumulation. PMID- 8678473 TI - Eating behavior and energy and nutrient intake in overweight/obese and normal weight Spanish elderly. AB - Dietary patterns were studied in 122 Spanish elderly people divided into two groups: overweight/obese subjects (O) (BMI > or = 25 kg/m2), and normal-weight subjects (NW) (BMI < 25). O subjects ate less fruit and more meat than NW subjects. No differences were found between NW and O subjects with respect to energy intake, but O elderly obtained more of their energy from proteins and less from carbohydrates. Further, O subjects showed a higher cholesterol intake per MJ than NW subjects. The existence of the dietary imbalances seen in the diet of the O elderly may damage their health. PMID- 8678474 TI - Limitations of thermophilic anaerobic wastewater treatment and the consequences for process design. AB - Thermophilic anaerobic digestion offers an attractive alternative for the treatment of medium- and high-strength wastewaters. However, literature reports reveal that thermophilic wastewater treatment systems are often more sensitive to environmental changes than the well-defined high-rate reactors at the mesophilic temperature range. Also, in many cases a poorer effluent quality is experienced while the carry over of suspended solids in the effluent is relatively high. In this paper recent achievements are discussed regarding the process stability of thermophilic anaerobic wastewater treatment systems. Laboratory experiments reveal a relatively low sensitivity to temperature changes if high-rate reactors with immobilized biomass are used. Other results show that if a staged process is applied, thermophilic reactors can be operated for prolonged periods of time under extreme loading conditions (80-100 kg chemical oxygen demand.m-3.day-1), while the concentrations of volatile fatty acids in the effluent remain at a low level. PMID- 8678475 TI - Simulation of constituent processes of anaerobic degradation of organic matter by the "methane" model. AB - The model of anaerobic digestion described earlier by the authors was used for analysis of the different phases of the process. It was shown that at the glucose conversion a coexistence of hydrogen-producing acidogenic bacteria and hydrogen utilizing non-methanogenic bacteria causes a hydrogen partial pressure decrease at an increase of solids retention time (i), the intensity of the negative feed back effect in sulfate-reduction through hydrogen sulfide formation is regulated by the pH level during an oscillation dynamics in acetate/sulfate system (ii), under the toxicity influence the processes of methanogenesis and acetogenesis together with hydrolysis may be rate-limiting steps in the anaerobic system with particulate substrate degradation (iii). PMID- 8678476 TI - Inactivation of virus during anaerobic digestion of manure in laboratory scale biogas reactors. AB - Reduction of porcine parvovirus, bovine enterovirus and faecal enterococci were measured in biogas reactors continuously run on manure and manure supplemented with household waste at 35 degrees C and 55 degrees C and in batch test run at 70 degrees C. The aim of the experiments was to study the sanitation effect of anaerobic digestion and to evaluate the use of faecal enterococci as an indicator of sanitation. Parallel studies on the reduction of virus and faecal enterococci were done in physiological saline solution. Heat inactivation was found to be an important factor in thermophilic biogas plants and the overall dominant factor at 70 degrees C. However, other environmental factors with a substantial virucidal and bactericidal effect were involved in inactivation. The death rates for faecal enterococci were generally higher than for porcine parvovirus and lower than for bovine enterovirus. For faecal enterococci, a logarithmic reduction of 4 (corresponding to the recommended minimum guaranteed retention time) was obtained after 300 hours at 35 degrees C and after 1-2 hours at 55 degrees C. In continuously-fed reactors, a high reduction rate was initially seen for the virus tested, followed by a reduction in the rate. For porcine parvovirus, a minimum guaranteed retention time of 11-12 hours is necessary at 55 degrees C in the initial phase (0-4 hours) and 54 hours hereafter (4-48 h). Correspondingly, for bovine enterovirus a MGRT of 23 hours was necessary at 35 degrees C and < 0.5 hours at 55 degrees C. The data indicate that faecal enterococci measurements give a good indication of inactivation of enterovirus and other more heat sensitive virus, especially under thermophilic conditions. Parvovirus is very suitable for comparative investigations on inactivation in the temperature range of 50-80 degrees C, due to the extreme thermal resistance of this virus. However, in stipulating sanitation demands for biogas reactors it seems more reasonable to use less resistant virus, such as a reovirus or picornavirus, which better represents the pathogenic animal virus. PMID- 8678477 TI - Combined removal of nitrate and carbon in granular sludge: substrate competition and activities. AB - Granular sludge from an upflow anaerobic sludge blanket reactor treating synthetic waste water containing a mixture of volatile fatty acids and nitrate showed a removal efficiency of nearly 100% for both nitrogen and carbon. This activity was achieved by a combined process of denitrification and methanogenesis under conditions of surplus carbon. Under batch conditions the two processes proceeded clearly separated in time with first denitrification dominating and excluding methanogenesis. However, as soon as nitrate was depleted, methane production was initiated, showing that the inhibition of methanogenesis by nitrate was reversible. Of the volatile fatty acids supplied to the reactor, i.e. acetate, propionate, and butyrate, the denitrifying population clearly preferred butyrate and propionate even though acetate could also be metabolized. Consequently, growth of syntrophic volatile fatty acid degraders was suppressed by the denitrifiers in cases of low C:N ratios in the medium, leaving acetate as the major substrate for methanogenesis. PMID- 8678478 TI - The influence of anaerobic pretreatment on the nitrogen removal from biosynthetic pharmaceutical wastewaters. AB - The C:N ratio of the pharmaceutical wastewaters is usually suitable for a combination of the anaerobic pretreatment with the high COD removal and aerobic posttreatment with the efficient biological N removal. This kind of anaerobic aerobic process was tested in semipilot scale by using a UASB reactor and an activated sludge system with a predenitrification (total volume 100 l). It was found that at a total HRT of 2.3 days an average of 97.5% of COD and 73.5% of total N was removed. The UASB reactor was operated at 30 degrees C with a volumetric loading rate of 8.7 kg.m-3.d-1, the efficiency of COD removal was 92.2%. The processes, which take part in the biological removal of nitrogen, especially the nitrification, were running with lower rates than usually observed in aerobic treatment systems. PMID- 8678479 TI - Post-treatments of anaerobic effluents. AB - Post-treatments are necessary if anaerobic effluents need to be discharged into surface waters, because anaerobic digestion alone is not able to produce effluents that can meet the discharge standards applied in most industrialized countries, particularly for suspended solids, particulate COD, nitrogen, phosphorus and sulphides. This paper has the aim to present some results obtained in the recent years in our laboratory, where different comprehensive processes that include anaerobic digestion have been studied. Discussion will regard: 1) the ANANOX (ANaerobic-ANoxic-OXic) process for the treatment of municipal wastewater; 2) a process studied for the biological removal of C, N and P from piggery wastewater that has a hybrid anaerobic/anoxic reactor as the first treatment step; 3) the use of a Sequencing Batch Reactor for the post-treatment of digested cheese whey mixed with cheese factory cleaning waters. PMID- 8678480 TI - Introduction of a de novo bioremediation activity into anaerobic granular sludge using the dechlorinating bacterium DCB-2. AB - The strictly anaerobic, pentachlorophenol (PCP) degrading bacterium DCB-2 was immobilized in an Upflow Anaerobic Sludge Blanket (UASB) reactor containing sterile granules. PCP and lactate were fed to the reactor and the concentration of chlorophenols in the effluent were monitored for 641 days. PCP was found to be degraded and transformed into 3,4,5-trichlorophenol in the reactor where DCB-2 introduced PPCP was still transformed to 3,4,5-trichlorophenol when the hydraulic retention time was decreased to six hours which was much lower than the generation time of DCB-2 insuring no free living cells in the reactor. This indicated that DCB-2 was immobilized in the granular layer. A control reactor that contained only sterile granules did not dechlorinate PCP indicating that the performance in the inoculated reactor was only due to the introduced bacteria. Immobilization of DCB-2 in the granules was further demonstrated by adding an antibody raised against DCB-2 to sliced granules. Bacteria thus visualized formed a net structure inside the granules. No DCB-2 bacteria could be found in granules from the control reactor. When lactate was omitted from the influent, the reactor still dechlorinated PCP in accordance with our findings that lactate was not used by DCB-2. This suggested that the reducing equivalents for reductive dechlorination were derived from the granules themselves. The reactor performance was 120 mumol.l reactor-1.day-1, comparable to the best described performance of a UASB-reactor and to aerobic reactors. Our study demonstrates that granules can be constructed which possess specific abilities such as a dechlorinating activity and at the same time be high performing. This result have implications for eco engineering of granules for anaerobic treatment of contaminated waters. PMID- 8678481 TI - Anaerobic degradation of xenobiotics by organisms from municipal solid waste under landfilling conditions. AB - The potential for biological transformation of 23 xenobiotic compounds by microorganisms in municipal solid waste (MSW) samples from a laboratory scale landfill reactor was studied. In addition the influence of these xenobiotic compounds on methanogenesis was investigated. All R11, 1,1 dichloroethylene, 2,4,6 trichlorophenol, dimethyl phthalate, phenol, benzoate and phthalic acid added were completely transformed during the period of incubation ( > 100 days). Parts of the initially added perchloroethylene, trichloroethylene, R12, R114, diethyl phthalate, dibutyl phthalate and benzylbutyl phthalate were transformed. Methanogenesis from acetate was completely inhibited in the presence of 2,5 dichlorophenol, whereas 2,4,6 trichlorophenol and R11 showed an initial inhibition, whenafter methane formation recovered. No transformation or effect on the anaerobic microflora occurred for R13, R22, R114, 3 chlorobenzoate, 2,4,6 trichlorobenzoate, bis(2 ethyl)hexyl phthalate, diisodecyl phthalate and dinonyl phthalate. The results indicate a limited potential for degradation, of the compounds tested, by microorganisms developing in a methanogenic landfill environment as compared with other anaerobic habitats such as sewage digestor sludge and sediments. PMID- 8678482 TI - Methanogenesis at low temperatures by microflora of tundra wetland soil. AB - Active methanogenesis from organic matter contained in soil samples from tundra wetland occurred even at 6 degrees C. Methane was the only end product in balanced microbial community with H2/CO2 as a substrate, besides acetate was produced as an intermediate at temperatures below 10 degrees C. The activity of different microbial groups of methanogenic community in the temperature range of 6-28 degrees C was investigated using 5% of tundra soil as inoculum. Anaerobic microflora of tundra wetland fermented different organic compounds with formation of hydrogen, volatile fatty acids (VFA) and alcohols. Methane was produced at the second step. Homoacetogenic and methanogenic bacteria competed for such substrates as hydrogen, formate, carbon monoxide and methanol. Acetogens out competed methanogens in an excess of substrate and low density of microbial population. Kinetic analysis of the results confirmed the prevalence of hydrogen acetogenesis on methanogenesis. Pure culture of acetogenic bacteria was isolated at 6 degrees C. Dilution of tundra soil and supply with the excess of substrate disbalanced the methanoigenic microbial community. It resulted in accumulation of acetate and other VFA. In balanced microbial community obviously autotrophic methanogens keep hydrogen concentration below a threshold for syntrophic degradation of VFA. Accumulation of acetate- and H2/CO2-utilising methanogens should be very important in methanogenic microbial community operating at low temperatures. PMID- 8678483 TI - Observation of baker's yeast strains used in biotransformation by atomic force microscopy. AB - Different strains of baker's yeast (Saccharomyces cerevisiae) were imaged with an atomic force microscope (AFM). The images of uncoated and nonfixed samples were reproducible with high-constrast and nanometer-resolution. Molecules from the polysaccharide surface of the cell wall were pictured and the distance of atoms was measured. The preparation of samples was easy, suggesting that AFM is a useful tool in this type of analyses. PMID- 8678484 TI - The immobilized porcine pancreatic exopeptidases and its application in casein hydrolysates debittering. AB - The practical application of exopeptidase has been limited by the high cost of the enzymes resulting from the low content of individual exopeptidase in the raw material. This can be overcome by the use of a combination of all the exopeptidases in the same enzyme source, as well as the use of the enzyme immobilization technology. A porcine pancreatic exopeptidase mixture was prepared by the ammonium sulfate precipitation at 35% saturation of the autolyzed pancreatic juice. The enzyme preparation was immobilized on thin shrimp chitin film by crosslinking with glutaraldehyde. The immobilized porcine pancreatic exopeptidases (IPPE) was effective in releasing the free amino acids from peptides. Of these amino acids, the concentrations of arginine, lysine, histidine, tyrosine, phenylalanine, leucine, and glutamine were increased much more than those of other amino acids. This indicated that both the porcine pancreatic exopeptidases preparation and the IPPE contained carboxypeptidase A, B, and aminopeptidase. The IPPE was also efficient in the decrease of the hydrophobicity of protein hydrolysates demonstrated by hydrophobic chromatographic analysis. This led to the application of the immobilized exopeptidases in protein hydrolysate debittering. The IPPE was able to remove the bitterness of the tryptic/chymotryptic casein hydrolysates. PMID- 8678485 TI - Selectivity of methyl-fructoside synthesis with beta-fructofuranosidase. AB - Enzyme synthesis of methyl fructoside was studied using beta-fructofuranosidase from Sacharomyces cerevisiae and sucrose and methanol as substrates. Taking into account the inhibition and deactivation effects of methanol on the enzyme, a system with 4.9M (20%, v/v) methanol was selected. At this alcohol level, 35% of sucrose is converted to fructoside at low or high substrate concentrations. The effect of enzyme concentration, pH, and temperature on both the synthesis and the hydrolysis of the fructoside was investigated. It was found that if the reaction proceeds at pH 6.0, 4 degree C and/or 0.014 mg/mL (3 U/mL) of beta fructofuranosidase at varying sucrose concentrations, methyl fructoside may be obtained with a minimum loss of the fructoside at the end of the reaction. PMID- 8678486 TI - Performance of a magnetically stabilized bed reactor with immobilized yeast cells. AB - This paper is focused on the possibility to apply the magnetic stabilization technique in bioprocessing. The feasibility of a continuous ethanol fermentation process with immobilized Saccharomyces cerevisiae cells in a magnetically stabilized bed (MSB) was demonstrated. The fermentation processes were carried out in an external magnetic field, transverse to the fluid flow. The flexibility to change the bed expansion owing to the independent change of the fluid flow and the field intensity (the "magnetization FIRST" mode) permitted the creation of fixed beds with different particle arrangements, which affected the bed porosity, the effective fluid-particle contact area, and the mass transfer processes on the particle-fluid interface. As a result, higher ethanol concentration, ethanol production, and glucose uptake rates than in conventional packed bed reactor were reached. PMID- 8678487 TI - [Familial cancer and oncogenic factors]. AB - The recent remarkable progress in molecular biology has revealed that various kinds of genetic alteration occur in cancers. Recently, many genes that cause hereditary cancer have been identified. For example, hMSH2 and hMLH1, which are known as DNA mismatch repair genes have been found to cause HNPCC (hereditary non poliposis colorectal cancer). Mutation of RET oncogene has been recognized in the families of MEN (multiple endocrine neoplasia) type II. Mutations of the tumor suppressor genes are the most common changes in the genes of familial cancer. BRCA1 and BRCA2 are tumor suppressor genes that have recently been identified as familial breast and ovarian cancer, familial breast cancer genes. This paper reviewed the hereditary cancer families in which genetic alterations have been revealed and the recent progress in mapping and cloning of familial breast cancer candidate genes which have not been identified. PMID- 8678488 TI - [Why is prostate cancer important in clinical field, now?]. PMID- 8678489 TI - [Etiology of prostate cancer and significance of screening for early prostate cancer]. AB - The incidence and mortality rate of prostate cancer in Japan are lower than in Western countries. Though studies of migrating populations would suggest that dietary or environmental factors may influence the etiology of the disease. The Westernized lifestyle after the Second World War may have influenced the increasing incidence of this disease in Japan. The screening by prostate specific antigen (PSA) on an asymptomatic healthy population can detect early prostate cancer. It is expected that the mortality may be decreased through such a system. However, some scientists hesitate to perform an aggressive program of early detection because of the possibility of latent cancer detection, the difficulty of distinguishing between clinically important and unimportant cancer, a high false positive rate to detect early stage cancer, and the lack of well-executed randomized prospective studies. Current clinical studies of the prostate cancer have demonstrated that the unimportant cancer detection rate by PSA was less than 10%. When a 4.0 ng/ml PSA cut-off value is applied for early detection, the false positive rate is approximately 80%. It is important to make subjects examined by the screening program aware of its the meaning. However, there is not a complete and cost-effective diagnostic modality to detect early prostate cancer. Moreover, it is confirmed that radical prostatectomy improves survival, but it has not been confirmed to improve the mortality based on population. We propose that well executed randomized studies by the end point of the survival, cancer death rate, cost effective, QOL and etc. are urgently needed. PMID- 8678490 TI - [Recent improvements and results of radical prostatectomy]. AB - In Japan, the proportion of patients with localized prostate cancer treated by radical prostatectomy is increasing rapidly. The recent improvements and treatment results of radical prostatectomy were reviewed. As for the qualifications of patient candidates for radical surgery, including patient age, various clinical and pathological findings to predict tumor extent and disease free outcome (clinical stage, serum prostate specific antigen, PSA density, number of positive biopsies, histological grade, etc) must be kept somewhat tidy. Recently, there has been increased interest in the application of preoperative hormone treatment for localized tumor group in order to improve radicality and survival. Several studies reported the results of neoadjuvant endocrine therapy. As for stage C tumors, the proportion of patients with capsular invasion, positive surgical margin, invasion of seminal vesicle and positive node metastasis are 67-86%, 39-64%, 32-47% and 38-50%, respectively. Prospective randomized studies should provide conclusive information on the potential benefits of this treatment modality. The new anatomical approach to radical retropubic prostatectomy with its nerve-sparing option assures preservation of erection. This procedure achieves excellent cancer control for patients with a definite organ-confined tumor, but it is difficult to diagnose a specimen confined tumor preoperatively. There is limited information on cancer control with the nerve-sparing option. More time is needed to obtain information on the long-term outcome after radical prostatectomy. PMID- 8678491 TI - [Progress of endocrine therapy for prostate cancer and results]. AB - We studied clinical results for newly diagnosed prostate cancer patients treated with first-line endocrine therapy during 1980-1989 (Nagasaki and Gunma Group Study). Of the 670 patients, 429 and 90 were given estrogens and chlormadinone acetate (CMA) with or without castration, respectively. LHRH agonists were administered to 136 patients and castration was done only in 15 patients. Estrogens were more often administered to patients with less differentiated and high-stage cases, whereas CMA was frequently used for those with more clearly differentiated and low stage. The cause-specific survival rate at 5 years for stage D patients was 45.8%. In a multivariate analysis of 5 possible prognostic factors (age, clinical stage, histological grade, estrogens and castration), stage and grade were found to have a significant effect on the cause-specific survival. However, estrogens and castration were not important factors. The results of total androgen blockade (TAB) done in Europe and the USA were discussed. PMID- 8678492 TI - [Treatment for hormone-refractory or relapsing prostatic cancer]. AB - Androgen ablative treatments for advanced prostatic cancer have achieved great progress with new concepts of therapy in the last decade such as chemical castration with LH-RH analogue and total androgen ablation. However, in treatment for hormone-refractory or relapsing prostatic cancer it remains controversial whether cytotoxic chemotherapy is acceptable or palliative, and whether there is an alternative treatment for this incurable disease. The current status of cytotoxic chemotherapy for advanced prostatic cancer patients in Nara Medical University since 1980 is reported in this paper with the some review of recent advances in hormone-independent prostatic cancer treatment. The overall objective response rate of CDDP-based multi-drug regimens including CDDP monotherapy was 49.6% (CR 0% + PR 49.6%). Response rate of primary chemotherapy group constituted with untreated patient was 67.2%, against 23.9% in the hormone refractory or relapse group. Five-year survival rate was 61.1% in the primary chemotherapy group, 35.5% in the hormone refractory group and 40.6% in the relapse group. Basically, there was no significant difference in response rates and survival rates among the groups of CDDP monotherapy, CDDP+bleomycin+vinblastine, CDDP+cyclophosphamide+adriamycin or CDDP+etoposide. The different response rates among the regimens seemed mainly to depend on the population of refractory or relapsing cases in each group. The important problems remaining unsolved in the research of chemotherapy for prostatic cancer are that there is no effective breakthrough agent and the lack of the harmonization in response criteria. The new agents are under development based on the cellular biology of hormone refractory prostatic cancer, and there is a bright future in the treatment of this intractable disease. PMID- 8678493 TI - [QOL assessment in the treatment of prostate cancer]. AB - It has been stressed that evaluation of QOL is an essential part of a clinical trial. We started a prospective randomized trial for advanced prostate cancer comparing various types of endocrine therapies which included QOL study in 1992. The QOL was evaluated before, one month after, three months after, and 12 months after the start of therapy. An EO-RTC questionnaire system was translated into Japanese and its reproducibility was assessed before the study. Eighty-four patients who were registered to the trial replied before the start of therapy. Endocrine therapies showed good effects on patients' QOL, especially in the domains of disease-related symptoms, physical feelings, mental distress and social life, which were improved significantly three months after the start of therapy. Sex life was seen to deteriorate from the therapies. In conclusion, the results of our QOL study reflected well the effects of endocrine therapy, and are expected to provide useful information for evaluation of the different effects of each treatment group. PMID- 8678494 TI - [Evaluation of chemotherapy for stage IV non-small cell lung cancer employing a regression tree type method for quality-adjusted survival analysis to determine prognostic factors]. AB - To evaluate the effect of chemotherapy on QOL, the survival period was categorized by 3 intervals: one in the hospital for chemotherapy (TOX), on an outpatient basis (TWiST Time without Symptom and Toxicity), and in the hospital for conservative therapy (REL). Coefficients showing the QOL level were expressed as ut, uw and ur. If uw was 1 and ut and ur were plotted at less than 1, ut TOX+uwTWiST+urREL could be a quality-adjusted value relative to TWiST (Q-TWiST). One hundred five patients with stage IV non-small cell lung cancer were included. Sixty-five were given chemotherapy, and the other 40 were not. The observation period was 2 years. Q-TWiST values for age, sex, PS, histology and chemotherapy were calculated. Their quantification was performed employing a regression tree type method. Chemotherapy contributed to Q-TWiST when ut approached 1 i.e., no side effect was supposed). When ut was less than 0.5, PS and sex had an appreciable role. PMID- 8678495 TI - [Chemo-endocrine therapy including mitomycin C and medroxyprogesterone acetate in doxorubicin-refractory advanced breast cancer]. AB - In the management of doxorubicin (ADR)-refractory advanced breast cancer, combination chemotherapies including mitomycin C (MMC) have been widely acknowledged to have definitive therapeutic effects. A randomized comparative study was performed estimating the efficacy and toxicity of MMV chemotherapy (MMC+methotrexate+vincristine), MMVM (MMV+medroxyprogesterone acetate (MPA), and MMVP (MMV+predo-nisolone (P). A total of 108 patients with advanced breast cancer resistant to ADR or relapsed after response were randomized, and 102 were evaluable. Response rates of 9.5% (2/21) in MMV, 37.5% (15/40) in MMVM, and 29.2% (12/41) in MMVP were obtained; with a significant difference between MMV and MMVM (p = 0.021). The time to progression of patients treated with MMVM and MMVP was shown to be longer than MMV patients. Thrombocytopenia was less appeared by adding MPA, making the dose escalation of MMV agents. It was concluded also from reviewing the references that MMVM is an effective 2nd-line therapy of advanced breast cancer after ADR treatment. PMID- 8678496 TI - [Effectiveness of combination hormonal therapies in advanced or recurrent breast cancer--a randomized trial of tamoxifen (TAM), medroxyprogesterone acetate (MPA), their simultaneous combination, and an alternating sequential combination of TAM plus MPA]. AB - The effects of tamoxifen (TAM), medroxyprogesterone acetate (MPA), their simultaneous combination or an alternating sequential combination of TAM plus MPA (TAM-MPA), was evaluated in 52 patients with advanced or recurrent breast cancer in a randomized controlled trial. The response rates of TAM, MPA, TAM & MPA, and TAM-MPA were 13.3%, 36.4%, 7.1% and 25.0%, respectively. All four therapies showed a higher response rate in the patients with soft tissues or with no previous therapy. However, there were no significant differences between the patient's characteristics and response rate among these four therapies. The differences in the frequency of adverse effects among these therapies were not significant, and there were no severe adverse effects with any therapy. In the cross-over trial of TAM and MPA, although 15.4% of patients who failed to show a response to TAM showed an objective response to MPA, no response to TAM was seen in the patients who had failed to show a response to MPA. In conclusion, TAM & MPA was not more effective than TAM or MPA, and TAM-MPA was not more effective than MPA. Adverse effects were not increased with TAM & MPA or TAM-MPA. MPA was useful as a second-line therapy after TAM. PMID- 8678497 TI - [Efficacy of intra-arterial chemotherapy with reservoir for patients with unresectable hepatocellular carcinoma]. AB - Long-term results of intra-arterial chemotherapy using a reservoir (IA) for patients with unresectable hepatocellular carcinoma (HCC) were investigated. Ninety-nine patients with unresectable HCC who were treated in our department during the past 7 years were enrolled in this study. Thirty-four out of the 99 patients were treated by IA with a conventional reservoir (SR group), and 21 by IA with a double-lumen reservoir (DR group) by which IA with occlusion of hepatic arterial flow would be possible. The other 44 patients were treated by transcatheter arterial embolization (TAE group). Cumulative 1-and 2-year survival rates were 54.2 and 21.7% in DR group, respectively, and 50.8 and 35.2% in TAE group, respectively. The results of these two groups were statistically equivalent, and were more favorable than those of the SR group. Cumulative patency rate of reservoirs was maintained at 93.7% after one year and at 61.8% after two years. No difference was recognized in this rate according to the type of reservoir. We concluded that IA with a double-lumen reservoir should be taken into consideration as one of the strategies for treatment of unresectable HCC. However, maintenance of catheter-patency would be necessary for satisfactory outcome. PMID- 8678498 TI - [Evaluation of chemotherapy in the treatment of advanced colorectal cancer--pilot study of 5-FU by biochemical modulation]. AB - We undertook a randomized trial in patients with advanced colorectal cancer, comparing 5-fluorouracil and leucovorin versus combination of these agents with additional cisplatin. Between July 1991 and October 1994, 21 patients with advanced measurable colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either 5-FU (500-750 mg/body) and LV (30 mg/body) for 5 days, or the combination of 5-FU and LV in the same daily dose plus cisplatin (10 mg/body). The overall responses were 30% and 36.3% for the 5 FU/LV and the 5-FU/LV/CDDP treatment arms, respectively. The three-drug combination appeared superior to 5-FU/LV for response duration. A comparative analysis of the toxicities experienced by the patients in the two treatment groups showed a comparable rate, although moderate leukocytopenia was prolonged in one patient treated with 5-FU/LV for 5 days. We conclude that the 5-FU/LV/CDDP treatment arm is an effective therapy for advanced colorectal cancer, but further attempts should be made to increase response rate, prolong response duration and assure effective therapy. PMID- 8678499 TI - [A course of pirarubicin vesical irrigation at thirty mg effectively prevents post-TUR recurrence of superficial bladder cancer]. AB - In order to study its safety and anti-cancer dose-effectiveness in the prevention of cancer recurrence, two groups of patients having superficial bladder cancer (TUR-Bt) had their bladder intravesically irrigated post-surgically with 20 or 30 mg aliquots of (2''R)-4'-0-tetrahydropyranyl-adriamycin (THP). A total of 74 patients with bladder cancer were entered in the study. Four cases proved ineligible, and 30 could not complete the planned treatment. THP vesical irrigation of 14-17 sessions was regarded as a condition for eligibility: Clinical evaluation was feasible with 19 patients of 20 mg and 21 of 30 mg THP. Non-recurrence rates at 1, 2, 3 and 4 years were 89.5, 53.3, and 26.6%, respectively, for the 20 mg group, and 95.2, 84.3, 75.9 and 75.9%, respectively, for the 30 mg THP group. The incidence of side effects appeared slightly greater in the 30 mg THP group than in the 20 mg group, and there were no systemic adverse reactions. Topical reaction of cystitis was noted to be as low as 12.5%. Thus, THP vesical irrigations at 30 mg were found tolerable and effective for the prevention of local recurrence following TUR-Bt. PMID- 8678500 TI - [In vitro chemosensitivity test for seven undifferentiated thyroid carcinoma cell lines using MTT assay]. AB - In the current study, we ran a chemosensity test on 7 human undifferentiated carcinoma cell lines against 10 anticancer compounds using MTT assay. Efficacy was estimated by comparing fifty percent inhibitory concentration (IC50) with the peak plasma concentration. The results showed that the 7 cell lines could be divided into two groups which had different (high or low) chemosensitivity, and that in the high sensitivity group, ACD, VCR, and etoposide were indicated as useful drugs. Our results suggest that it may be impossible to rescue all undifferentiated carcinoma patients by chemotherapy alone because the tumor may consist of 2 clones which have a different chemosensitivity. PMID- 8678501 TI - [Study on clinical effect of a continuous intravenous infusion of azasetron against nausea and vomiting induced by anticancer drugs including CDDP]. AB - Azasetron, a selective 5-HT3 receptor antagonist, has been previously shown to be highly effective in the prophylaxis of nausea and vomiting induced by anticancer drugs and is widely used in the clinical setting in Japan. In order to improve the antiemetic effect of azasetron, we designed a continuous intravenous infusion method of this drug and compared the antiemetic effect of this method with that of standard bolus intravenous injection on nausea and vomiting associated with anticancer drugs including 75 mg/m2 cisplatin (CDDP). A continuous group is intravenous bolus injection of 2.5 mg azasetron followed by 7.5 mg continuous intravenous infusion for 24 hrs, and a bolus group is intravenous bolus injection of 10 mg azasetron. The inhibitory effect on nausea of the continuous group was significantly superior to those of the bolus group on day 3 and 4 (p < 0.05) and inhibitory effect on vomiting of the continuous group was significantly superior to those of bolus group on day 2 (p < 0.05). No adverse effects were observed in either group of this study. From these data, continuous intravenous infusion of azasetron was considered to be highly effective in prophylaxis of nausea and vomiting induced by anticancer drugs. PMID- 8678502 TI - [A case of hepatocellular carcinoma responding to oral administration of 5' DFUR]. AB - A 65-year-old female patient with liver cirrhosis complicated with hepatocellular carcinoma (HCC) was treated with oral administration of 5'-DFUR (600 mg/day). The titer of serum alpha-fetoprotein gradually decreased, and reduction of the hepatic tumor size was observed by abdominal computed tomography (CT) following 5'-DFUR treatment. HCC was obviously diminished since the start of 5'-DFUR administration and almost disappeared in fifteen months. This case suggests the treatment with 5'-DFUR for hepatocellular carcinoma is completely effective. PMID- 8678503 TI - [A case report of small cell carcinoma of the esophagus with remarkable response to neoadjuvant chemotherapy]. AB - A 61-year-old male consulted our hospital with complaints of pain in swallowing. The X-ray Barium studies and upper gastrointestinal (UGI) scope revealed an irregular ulcerated lesion in the middle portion of the esophagus. He was diagnosed as having small cell carcinoma of the esophagus by means of biopsy specimens. Three courses of combined chemotherapy with CDDP, etoposide and 5-FU were used before operation. Following the chemotherapy, according to the UGI scope findings, the tumor of the esophagus disappeared. An esophagectomy through a thoracolaparotomy was performed. The chemotherapy resulted in a Grade 2 response, as ascertained by means of pathological findings for the resected specimen. After an additional course of chemotherapy, the patient was discharged from the hospital. Although we performed the curative resection for this patient, extensive recurrences and distant metastasis to the mediastinal lymph nodes and lung were found in less than a year. It is said that this tumor has a poor prognosis, and the one-year survival rate is about 10% following the treatment. It is necessary to combine surgery with effective chemotherapy and irradiation to obtain a good prognosis after resection of small cell carcinoma of the esophagus. PMID- 8678504 TI - [A case of advanced gastric cancer responding to chemotherapy and radiotherapy]. AB - A thirty three-year-old male complaining of vomiting was diagnosed as having type 3 advanced gastric cancer of upper stomach and multiple liver metastasis, and had undergone total gastrectomy. The conclusive stage was P2H2n4se stage IVb. Intraoperatively, ethanol injection was performed for the liver metastasis under ultrasonography, and CDDP 100 mg was injected into the intra-abdominal cavity. Postoperative adjuvant therapy was added using oral fluorouracil and OK-432. Then we utilized FP chemotherapy (consisting of 5-FU and cisplatin) and radiotherapy for the bone metastasis. The patient survived 4 years and 4 months with good quality of life. PMID- 8678505 TI - [A case of acute myelocytic leukemia in relapse controlled by continuous home administration of Ara-C]. AB - A 50-year-old male with acute myelocytic leukemia (AML) achieved complete remission after combination chemotherapy. However, the AML recurred after six months. He did not respond to various treatments and his condition deteriorated after chemotherapy. After we attempted continuous administration of cytosine arabinoside (Ara-C), the number of leukemic cells was controlled for nine months. During this period, he could stay and receive treatment with Ara-C at home. In this case, the continuous administration of Ara-C at home was truly effective not only to control the number of leukemic cells but also to improve the quality of life. PMID- 8678506 TI - [Alternating chemotherapy with cyclophosphamide, adriamycin, vincristine and prednisolone (CHOP); etoposide, procarbazine, vindesine and prednisolone (EPVP) as a treatment for advanced-stage Hodgkin's disease]. PMID- 8678507 TI - [Impact of rapid advancement of international standardization on technical requirements for new drug registration]. AB - Internationalization of new drug research and development is rapidly progressing. When mutual international acceptance of clinical trial data is realized, scientifically superior data will eradicate and replace all not so scientific data. This means that healthy competition would benefit the data of clinical trials. The same is true of anti-tumor drugs. Some Japan originated antitumor drugs were developed in foreign countries prior to domestic clinical development. In future, geographic centralization of clinical trials in areas which can conduct scientifically more consistent trials is expected. There are only a limited number of institutes which can conduct high-quality clinical trials of antitumor drugs, so they want Japan, a potential country, to come to other areas to produce high-quality clinical trial data. The resolution of a number of daily stumbling blocks such as informing the patient that he or she is suffering from cancer is a prerequisite for conducting high-quality clinical trials. But every effort must be made so that it will not be said: "Data produced overseas are better. There is no need for Japan to use its knowledge and effort in the field of clinical development." PMID- 8678508 TI - [Advances in the treatment of colorectal cancer]. AB - Colorectal cancer is one of the most serious diseases of our time. Recent progress in its treatment is reviewed in this paper. There are many approaches for treating colorectal cancer; extended surgery to function-preserving surgery. The aim of surgical treatment is to excise the tumor completely, so extended surgery has been performed for curative resection of colorectal cancer. However, the quality of life (QOL) of the patients has been extremely impaired. In recent years, surgical treatments for avoiding colostomy, and urinary and sexual difficulties have been widely carried out, and QOL of the patients could be maintained in the postoperative period. Stage-oriented therapy is accepted as the concept of surgical treatment of colorectal cancer. For further improving the clinical results of colorectal cancer, we advocated "type-oriented therapy" which is based on the biological characteristics of colorectal cancer, by determining i.e., p53 abnormalities of cancer cells, serum p53 antibodies, micrometastasis in the bone marrow and/or sensitivity to anticancer drugs. PMID- 8678509 TI - [Prognostic factors of colorectal cancer concerning metastases]. AB - Four prognostics factors were investigated for colorectal cancer metastases. 1) There were statistically more venous invasions using Victoria blue elastic staining in patients with liver or lymph node metastasis than in those without metastasis. 2) The immunohistochemical expression rate of c-erbB-2 in liver metastasis cases was 27%, which was significantly higher than 3% in no metastasis cases. 3) Sialyl Lewis x (SLex) is related with cell adhesion. SLex positive rates in vessel invasion cancer cells were 71.4% with metastasis and 31.0% without metastasis. 4) Matrilysin is one of MMPs and it was significantly increased with Dukes stage by fluorescence intensity. PMID- 8678510 TI - [Recent advance in chemotherapy for advanced colorectal cancer]. AB - Chemotherapy for advanced colorectal cancer is reviewed stressing the historical development of combination chemotherapy and the application of a new idea called biochemical modulation based upon a preclinical biochemical and molecular pharmacological rationale. While 5-fluorouracil (5-FU) is a key drug for more than three decades, many a combination chemotherapy with 5-FU and other drugs such as methyl-CCNU, vincristine, streptozocin, mitomycin C and so on has been studied extensively only to show no significant improvement compared with monotherapy with 5-FU. Recently, the mechanisms of 5-FU action have been recognized more in detail biochemically, and it enabled us to try the drug in a more optimal way. For example, bolus i.v. infusion of 5-FU can produce a response rate of around 10% to 15% at most for advanced colorectal cancer. On the other hand, a more continuous mode of i.v. infusion, typically known as protracted i.v. infusion lasting up to 6 weeks or more, can produce the response rate of up to 40%. The difference underlying the mechanisms of action in these typical two administrative methods is that the main target can be RNA-directed cytotoxicity in the bolus type infusion and it can be shifted toward DNA-directed cytotoxicity in the continuous type infusion through the inhibition of thymidylate synthase (TS) enzyme activity which is relevant to DNA de novo synthesis. More importantly, investigations using clinical materials imply that DNA-directed cytotoxicity may be more relevant in a clinical setting, showing consistent findings between bench-top experiments and the clinical outcome. Given a precise knowledge about the mechanisms of 5-FU action, we could have developed a new type combination chemotherapy called biochemical modulation which manipulates non cytotoxic agents or cytotoxic agents in non-cytotoxic level as modulators enhancing cytotoxicity of 5-FU biochemically. Among modulators, leucovorin (LV) has been shown to have a pivotal role in this field. Although no optimal combination dose schedule of LV is well known, randomized studies have shown improved activity of 5-FU modulation by LV over 5-FU alone for advanced colorectal cancer doubled the response rate by monotherapy (20-25%) vs 10-15%). New drugs are also promising with the response rate of 25% approximately obtained with a new camptothecin derivative CPT-11, and a pure TS inhibitor, Tomudex in phase II trials. It is also necessary to explore the clinical activity of the combination of low-dose cisplatin and 5-FU, chronotherapy, new dihydropyrimidine dehydrogenase inhibitors and new TS inhibitors. We are facing a new era with a new treatment concept of biochemical modulation or an understanding of optimal administrative methods with the key drug, 5-FU. Obviously, we still seek new agents or new laboratory rationales which enable us to extend the survival of patients with advanced colorectal cancer. PMID- 8678511 TI - [Diagnosis and targeting therapy of colorectal cancer using antibody]. AB - Application of monoclonal antibody for diagnosis and therapy of colorectal cancer was reviewed. The history and present status of radioimmunoimaging of cancer were presented. Immuno-guided surgery using radiolabeled antibody and hand-aided detector during surgery is a promising approach for complete excision of cancerous region. Also, a new antibody labeling method using a micro-magnet instead of radioisotopes may lead to a new era in immunodiagnosis of cancer. Finally, immunotargeting chemotherapy using antibody-anticancer drug conjugates was reviewed. A new type of immunoconjugate composed of human/mouse chimeric antibody and Neocarzinostatin seems to be one of the most promising drug formulas for immunotargeting chemotherapy. PMID- 8678512 TI - [Progress of adjuvant chemotherapy in colon cancer]. AB - There have been no life-prolonging effects of surgical adjuvant chemotherapy with 5-FU alone or in combination with chemotherapeutic drugs, so surgical resection has been considered a standard therapy for colorectal cancer. Recently, clinical trials of modulation therapy with 5-FU and leucovorin showed higher efficacies in advanced colorectal cancer, and significant prolongations of survival time and disease-free interval were reported in a randomized trial of 5-FU and leucovorin for postoperative adjuvant therapy of resected colon cancer. Moreover, in a scientifically well controlled randomized study with 5-FU and levamisole, the significance of this regimen for Dukes C colon cancer has been shown for standard adjuvant chemotherapy. PMID- 8678513 TI - [Radiotherapy combined with daily administration of low dose cisplatin for head and neck cancer]. AB - Radiotherapy combined with daily administration of low-dose cisplatin (CDDP) was applied to 12 cases with head and neck cancer. They consisted of 12 carcinomas, occurring in the epipharynx (3 cases), mesopharynx (3), oral cavity (1), larynx (3) and parasinuses (2). The total response rate (CR + PR) was 83.3%. There was a remarkable effect in reducing tumor size, particularly on patients with laryngeal or epipharyngeal carcinoma. Severe mucositis with ulcers as a side effect was seen in eight cases after the irradiation of 20 to 30 Gy. Six of them tolerated a full dose of irradiation, but CDDP administration was stopped except in one case. To continue the CDDP administration in cases having irradiation of over 40 Gy, it is necessary to reduce the frequency of CDDP administration and/or to give post irradiative hydration with 500 ml saline. When this combination therapy is used as a preoperative treatment, daily administration should be continued. Incidence of nausea or vomiting was not so frequent and they could be easily controlled by a serotonin-antagonist. Leukopenia was not severe. PMID- 8678514 TI - [Administration and dosage of fluorouracil (5-FU) continuous i.v. infusion in patients with non-curative resected/non-resected gastric cancer]. AB - This study was conducted to establish the optimum postoperative adjuvant chemotherapy with 5-FU in patients with gastric cancer. Seventy gastric cancer patients were treated after surgery with one of the following regimens; 5-FU 10 mg/kg/24 hrs c.i.v. x 24 days (arm A, n = 25); 5-FU 20 mg/kg/24 hrs c.i.v. x 4 days/w x 3 courses (arm B, n = 16); 5-FU 30 mg/kg/24 hrs c.i.v. x 2 days/w x 4 courses (arm C, n = 25). Blood 5-FU concentration, adverse effects and prognosis in each arm were compared. Changes in blood 5-FU concentrations were dose related. The three-year survival rates in arms A, B and C were 15.0, 13.5 and 0.0%, respectively; they tended to be greater in arms A and B, but differences were not statistically significant. The most frequent adverse effects of the treatments were gastrointestinal, such as stomatitis. The incidence of reactions tended to be low in arm C, i.e., high-dose intermittent administration. Arm B (4 days-on, 3 days-off) was modified to 4 days-on, 6 days-off (arm B'), because severe stomatitis developed. The severity and incidence of stomatitis were reduced in the modified arm B group. We believe that intensive postoperative adjuvant chemotherapy for patients with gastric cancer should be designed using the arm B' approach. PMID- 8678515 TI - [Changes in folate levels after cisplatin treatment of gastric cancer]. AB - Currently, biochemical modulation for 5-fluorouracil (5-FU) by cisplatin (CDDP) is one of the most successful forms of chemotherapy for gastric cancer. Although the mechanism of this modulation is thought to increase intracellular folate levels, it is still unknown how much CDDP is needed to elevate folate levels. The purpose of this study is to determine the appropriate volume of CDDP as a modulator for 5-FU. Either 5, 20, 100 mg/body of CDDP was administered intravenously to advanced gastric cancer patients just before operation. Four hrs later, the stomach was resected and folate levels were measured in the tumor and normal mucosa by thymidylate synthase binding assay. The results showed folate elevation only after administration of 100 mg/body of CDDP, both in the tumor and mucosa (p < 0.01). In conclusion, if CDDP is infused as a bolus, a relatively large amount is needed to modulate the intratumor folate level. PMID- 8678516 TI - [Effect of leucovorin and 5-FU for advanced colorectal cancer patients]. AB - In 17 cases of advanced colorectal carcinoma with accessible metastatic lesions, a low dose of leucovorin (LV, 30 mg/body) + 5-fluorouracil (5-FU 500 - 750 mg/body) was administered intravenously as a bolus injection, or by injection into the hepatic artery from a reservoir. Two of the 12 patients (16.7%) who received intravenous injection, and one of the five cases who received intra hepatic artery injection showed partial response (PR). The side effect of this treatment was mild, and the performance status of the patients was excellent. This article deals with 3 PR cases. Case 1 had a bipulmonary multiple metastasis. When LV + 5-FU was administered intravenously, a reduction rate of 87% was obtained, and the patient survived for 27 more months. Case 2 had paraaortic lymph node metastasis. When LV + 5-FU was administered intravenously, a reduction rate of 59% was obtained, but the patient died after 9 months. Case 3 had a multiple liver metastasis. LV + 5-FU was administered intravenously in the liver, and a reduction rate of 69% was achieved. The patient survived for 30 months from the administration. LV + 5-FU is an effective treatment for advanced colorectal cancer. In the future, more research should be conducted to study the amount and method of administration, and combined treatment, to increase the response rate and to extend the period of good health. PMID- 8678517 TI - [Successful treatment of clear cell adenocarcinoma of the ovary (OCCA) with a combination of CPT-11 and mitomycin C]. AB - Among advanced ovarian cancer, OCCA has worse prognosis compared with serous cystadenocarcinoma because of its poor sensitivity to CDDP-based chemotherapy (CTX). Indeed, there has ever been no one patient with pure OCCA showing an appreciable response to CTX. OCCA has recently been increasing in prevalence and has occupied approximately 20-25% of all ovarian cancer. Thus, there is an urgent need to find effective regimens. Based on the results of chemosensitivity tests previously performed both in vitro and in vivo, we designed a combination of CPT (140 mg/m2, i.v.-infused over 4 hours on day 1, 15, and 29) and MMC (7 mg/m2, i.p. injection through a reservoir on day 1, 15, and 29). The course was repeated every 4 weeks. To date 10 pts were entered The median age was 53 (41-69). Among total 25 courses, grade 3 diarrhea was observed in 3 courses. Other toxic signs were acceptable. The responses by tumor size were 2 CR for disease < or = 2 cm in diameter, and 2 CR, 2 PR, 2 NC, and 2 PD for > 2 cm. Six responders showed a significantly longer survival compared with 4 non-responders (p < 0.0396 for Log rank test). Thus, the present protocol is the first to demonstrate a significant activity for pure OCCA. PMID- 8678518 TI - [A device for rapid elevation of plasma methotrexate (MTX) concentration and its maintenance in high-dose MTX therapy]. AB - For 5 osteosarcomas and one synovial sarcoma, 24 courses of high-dose methotrexate (MTX) therapy were performed. At MTX doses of 300 mg/kg with several infusion patterns, the plasma MTX concentrations were measured by fluorescence polarization immunoassay. In the various types of infusions, five hours oblique and five hours bolus infusions were well maintained at 1,000 micromol/l for several hours. In particular, five hours bolus infusion of MTX needed only 20 minutes to reach 822 micromol/l and maintained 1,000 micromol/l during almost the entire infusion period. Optimization of chemotherapy for sarcomas by MTX requires individual adaptation of the infusion pattern. PMID- 8678519 TI - [Experimental studies on intravesical instillation of SM-5887, a novel anthracycline derivative for treatment of bladder carcinoma]. AB - SM-5887 is a novel anthracycline derivative. Experimental studies of its intravesical chemotherapy were carried out to elucidate its histopathological effect on the normal bladder mucosa and the pharmacokinetics in Beagle dogs. Forty mg (4,000 micrograms/ml), 60 mg (6,000 micrograms/ml) and 80 mg (8,000 micrograms/ml) of SM-5887 dissolved in 10 ml of physiological saline were instilled into the empty bladders of dogs with bilateral cutaneous ureterostomy, respectively. SM-5887 instilled intravesically scarcely passed into the blood. In only one dog of five instilled with 80 mg of SM-5887 intravesically, the serum level of 0.0248 micrograms/ml was detected 2 hours after instillation, but all the others were below the detection limit (0.020 micrograms/ml). Excretion of SM 5887 into the urine was also low. The highest urinary excretion was observed 6 hours after instillation of 80 mg of SM-5887, yet the concentrations of SM-5887 and its metabolites in the urine were extremely low. The urinary concentrations of SM-5887 and its active metabolite, 13-OH derivative, were 0.029 micrograms/ml and 0.131 micrograms/ml, respectively. Other metabolites were not detected. The distribution of SM-5887 in the bladder mucosa and muscular layer was almost equal, but the concentration of its active metabolite, 13-OH derivative, was 5 to 10 times higher in the bladder mucosa than in the bladder muscular layer. The distributions of SM-5887 in the organs other than the bladder, that is, the cortex and medulla of kidney, heart, lung, liver, and spleen, were very low, and those of a 13-OH active metabolite were even lower. In addition, SM-5887 barely affected the normal bladder mucosa. In dogs instilled with 80 mg of SM-5887, no histological change was observed in the bladder mucosa and submucosal layer even after 6-hour retention at the highest concentration of 8,000 micrograms/ml. PMID- 8678521 TI - [Clinical evaluation of TPA-assay kit using monoclonal antibodies]. AB - The clinical utility of a newly-developed radioimmunometric assay kit for tissue polypeptide antigen (TPA) was evaluated focusing on the serum diagnosis of gastrointestinal cancers. Serum TPA concentrations of normal subjects, patients with various benign and gastrointestinal malignant diseases were measured using this kit. From the TPA concentrations of normal subjects, the cut-off value was determined to be 70 U/l, which was 40 U lower than the previous kit. It showed a fairly high false positive rate in patients with liver dysfunction, so care should be taken in evaluating patients with liver disorders. It showed high positive rates in patients with wide range of gastrointestinal cancers, confirming the wide-range usefulness of this assay. Cancer patients with advanced stages and recurrences showed a higher positive rate and also higher serum TPA concentrations than in the early stages, indicating that this TPA assay is especially useful in the evaluation of therapeutic effects and in the detection of recurrent diseases. PMID- 8678520 TI - [Evaluation of subrenal capsule assay (SRC) for clinical cancers]. AB - For clinical cancers of esophagus (10 cases), stomach (7), colon and rectum (11) and breast (5), subrenal capsule assays (SRC) were performed using normal or AF nude mice. The sensitivity of anticancer drugs (UFT, CDDP) was evaluated by both the change in graft size under the renal capsule and the histological findings of these grafts. SRC was found to be a very reliable testing method for cancer of esophagus, colon and rectum because these grafts possessed remarkable viability. Evaluability of these two cancers was very high (approximately 80%). Sensitivity of UFT was 29% (2/7) for esophageal cancer, 50% (5/10) against colon and rectal cancer, and that of CDDP was 40% (2/5) and 17% (1/6), respectively. Evaluability of gastric and breast cancers was very low because of the poor growth of the grafts irrespective of the immunity of host animals. It was discussed why the evaluation rate depended on the type of cancer. These results suggest that indications for SRC are restricted, but that for colon and rectal or esophageal cancer SRC is a reliable testing method for anticancer drugs in clinical use. PMID- 8678522 TI - [A case of breast cancer with metastasis of multiple organs showing marked efficacy of medroxyprogesterone acetate (MPA)]. AB - The patient, a 55-year-old female, was diagnosed as having right breast cancer (T1aN2M1, Stage IV) with metastasis of multiple organs (lung, pleura, bone, mediastinal and unilateral axillary lymph nodes) when she underwent tumorectomy. Postoperative adjuvant therapy was performed using oral administration of MPA (800 mg/day). After 3 months of this treatment, metastatic lesions in the lung and pleura had disappeared. After 37 months, complete remission (CR) was evaluated in the multiple lesions of bone metastasis. She achieved a complete remission (CR) by this treatment lymph nodes metastasis in both mediastinum after 24 months and unilateral axillae after 15 months. Complete response time was 38 months in both lung and pleura, 15 months in bone metastasis, 15 months in mediastinal lymph nodes, 24 months in unilateral ones. Normalization of tumor markers was acquired after 7 months of this hormonal therapy. This CR condition continues at present without severe complications. PMID- 8678523 TI - [A case of advanced gastric cancer with lung and liver metastasis treated by CDDP and 5-FU]. AB - A 62-year-old man suffering from advanced gastric cancer with multiple lung and liver metastasis was treated with FP (CDDP . 5-FU) therapy. As a result, lung metastasis disappeared completely and liver metastasis was significantly reduced in size (93%). Then, total gastrectomy, splenectomy and micro-wave-coagulation of the liver tumors were performed. Therefore, it can be said that FP therapy is an effective neoadjuvant chemotherapy. PMID- 8678524 TI - [A case of hepatocellular carcinoma with reduction of primary tumor and disappearance of multiple lung metastasis]. AB - A 62-year-old male patient was admitted for spontaneous rupture of hepatocellular carcinoma. He also had multiple lung metastases and liver dysfunction. So neither operation nor trans-arterial embolization could be performed. He had been administered UFT (400 mg/day) orally every day. After 5 months of daily administration, there was complete disappearance of multiple lung metastasis and reduction of the primary tumor. This case suggests that UFT is effective for some advanced hepatocellular carcinoma with extrahepatic metastasis. PMID- 8678525 TI - [High-dose chemotherapy rescued with peripheral blood stem cell transplantation for high-risk patients with breast cancer]. PMID- 8678526 TI - [Detection of platinum concentration in mice on administrated cisplatin--compared total reflection X-ray fluorescence spectrometry (TRXRF) with atomic absorption spectrometry (AAS)]. PMID- 8678527 TI - [Prognostic factors in malignant gliomas]. AB - The most important prognostic factor in malignant gliomas is histopathological diagnosis of the tumor. The survival of patients with anaplastic astrocytoma is much longer than that of patients with glioblastoma. The median survival of the former has been improved up to almost 4 years by the recent progress of multidisciplinary treatment, whereas that of the latter has still remained in less than 1.5 years. Other important factors proved to be associated with survival of patients with malignant gliomas are the age of patients, Karnofsky performance status on admission, surgery, radiotherapy and chemotherapy. There is substantial evidence suggesting an association between younger patient age and longer survival in adults with supratentorial anaplastic astrocytoma as well as glioblastoma. It is also consistent with evidence that the patients with better performance status on admission live longer after treatment. Gross total resection of supratentorial anaplastic astrocytoma is directly associated with longer and better survival when compared to subtotal or partial resection. For glioblastoma, however, gross total resection has not been proved to have a significant survival advantage over subtotal or partial removal. Radiotherapy has been proved to be associated with longer survival of patients with supratentorial anaplastic astrocytoma and glioblastoma. Chemotherapy has not proved effective in prolonging the survival of patients with glioblastoma. Multidrug chemotherapy with CCNU, procarbazine and vincristine has proved to have significant survival advantage over BCNU alone, suggesting chemotherapy is also a prognostic factor in patients with anaplastic astrocytoma. PMID- 8678528 TI - [Pregnancy outcome in long-term survivors with adult acute leukemia, malignant lymphoma and breast cancer]. AB - By means of a mail questionnaire, we evaluated the influence of treatment for acute leukemia on offspring of long-term survivors and determined whether pregnancy in patients (or spouses) induced relapse of acute leukemia. In 322 replies from the 445 institutions where a questionnaire was sent, there were 1,136 adult long-term survivors. We analyzed 43 adults who had become pregnant or a father after postremission therapy. The mean age at leukemia onset was 26.4 and 21.6 years for males and females, respectively. Forty-six normal children (26 boys and 20 girls) were born to long-term survivors including 7 pairs of siblings and a pair of twin sisters. There were no malformed babies. The average duration until delivery was 79 months after diagnosis and 49 months after the final postremission therapy. Four of 38 parents of live offspring died (3 relapse, 1 other disease), and the other 34 parents of live offspring were in complete remission at the point of this survey. The literature since 1986 (except case report) was reviewed for the current situation of pregnancy outcome in long-term survivors after chemotherapy for adult acute leukemia, malignant lymphoma and breast cancer. PMID- 8678529 TI - [Pathomorphologic characteristics and differential diagnosis of small hepatocellular carcinoma]. AB - Recent advances in various diagnostic imagings have made possible early diagnosis of hepatocellular carcinoma (HCC). Grossly, small HCCs of the early stage up to around 1.5 cm in diameter are vaguely demarcated from surrounding liver tissue. Such minute tumors are classified as small HCC with indistinct margins. Histologically, these tumors consist of uniform distribution of well differentiated cancerous tissues, which are characterized by increased cell density with increased nuclear/cytoplasmic ratio, irregular thin-trabecular pattern with occasional pseudoglandular structure, and frequent fatty and/or clear cell change. In all small HCCs with indistinct margins, varying numbers of portal tracts are contained within the cancerous tissues. None of them represents invasion of the portal vein or intrahepatic metastasis. Thus, small HCC with indistinct margins is considered to be HCC of the earliest stage that can be clinically detected at this moment. Along with the increase of resected small HCCs, hyperplastic lesions such as adenomatous hyperplasia (AH) and atypical AH, which are difficult to differentiate from well-differentiated HCC have also been found. Atypical AH is considered a borderline malignancy. Some focal nodular hyperplasias and liver cell adenomas are also difficult to differentiate from well-differentiated HCC. It should be recalled that some metastatic tumors such as carcinoid tumor, renal cell carcinoma and hepatoid adenocarcinoma also resemble HCC. PMID- 8678530 TI - [Percutaneous ethanol injection therapy for small hepatocellular carcinoma]. AB - Hepatocellular carcinoma is different from other solid tumors. Because of concomitant cirrhosis or multiple lesions, most hepatocellular carcinoma is unresectable. Still worse, hepatocellular carcinoma frequently recurs after surgical resection; the 5-year cumulative recurrence rate is 70-90% even after curative hepatectomy. The situation is similar in small hepatocellular carcinoma 2 cm or less in diameter. Thus, non-surgical treatment plays an important role. At present, we think that percutaneous ethanol injection therapy (PEIT) is best for the treatment of hepatocellular carcinoma because of its local curativity, minimal adverse effect on liver function, and the easy feasibility of repeated treatment for recurrence. We have recently treated about 85% of hepatocellular carcinoma cases by PEIT and have achieved satisfactory long-term results. Here we describe our results in PEIT for small hepatocellular carcinoma. By the end of December 1995, we performed PEIT on 410 patients with hepatocellular carcinoma. Among them, 140 patients were diagnosed as having small hepatocellular carcinoma 2 cm or less in diameter. The 1-, 3-, 5-, 7-, and 10-year survival rates of the 140 patients were 93%, 73%, 55%, 51%, and 32%, respectively. Furthermore, in 83 patients who had a single, small hepatocellular carcinoma 2 cm or less in diameter, the 1-, 3-, 5-, 7-, and 10-year survival rates were 92%, 82%, 72%, 66%, and 66%, respectively. Thus PEIT achieved satisfactory long-term survival rates in the treatment of small hepatocellular carcinoma. PMID- 8678531 TI - [Chemoembolization therapy in small hepatocellular carcinoma]. AB - As chemoembolotherapy (TAE) for relatively small hepatocellular carcinoma (HCC) including small HCC of less than 2 cm in diameter, which is restricted to a sub subsegment, subsegment or segment of the liver, segmental Lp-TAE using Lipiodol (Lp) mixed with an anticancer agent, which includes subsegmental and sub-sub segmental therapy, not restricted to the tumor-bearing segment, is expected to move to the forefront of HCC treatments and also causes fewer complications and less strain to the patient. Of the 15 cases that underwent surgery following segmental Lp-TAE, complete necrosis was found histopathologically in more than 80% of the main tumor, satellite nodules in the embolized region and areas of capsular invasion. Its therapeutic efficacy for 51 cases with tumors smaller than 3 cm was comparable to that of surgery. PMID- 8678532 TI - [Surgical treatment of small hepatocellular carcinoma]. AB - Two hundred thirty-five patients with small hepato-cellular carcinomas (HCCs) (mixed hepatocellular and cholangiocellular carcinoma included) measuring no more than 3 cm in diameter treated by surgical resection between 1980 and 1990 were reviewed retrospectively. Ninety-nine percent of the patients also had chronic hepatitis and 73% were diagnosed histologically as having liver cirrhosis. The operative and hospital mortality rates were 0.4% and 1.3%, respectively. The number of tumors, intrahepatic metastasis and vascular invasion were significant prognostic factors. Overall the 1-,3-and 5-year survival rates (operative deaths included) were 93.2%, 72. 7%, and 49.7%, and those of 144 patients treated in the late 80s (1986-1990) were 93.6%, 76.3%, and 52. 1%, respectively. These results were appreciably better than those for percutaneous ethanol injection therapy (PEIT) and transcatheter arterial embolization therapy (TAE) reported previously. In particular, the survival of the patient with single tumor demonstrated a clear advantage of surgery. The selection of treatment modalities is discussed, and our present standard strategy for surgical treatment is described. PMID- 8678533 TI - [Current status of treatment for small hepatocellular carcinoma]. AB - In recent years ethanol injection therapy (PEI) and transcatheter hepatic arterial embolization (TAE) have come to be widely used in the treatment of small hepatocellular carcinoma, and the introduction of microwave coagulation therapy (MCT) more recently has made it possible to perform a variety of non-surgical treatments even in cases in which surgical resection has been indicated until now. There have also been reports based on survival rates that results comparable to those obtained by surgical resection can be achieved with non-surgical methods. The main issue is whether PEI or resection should be selected to treat small hepatocellular carcinomas. However, the recurrence rate after PEI is higher than after surgical resection, and according to our results, in patients with solitary lesions, especially when the tumor diameter is 2 cm or less, the level of malignancy in many cases is also low biologically, and postoperative survival rates (recurrence-free survival rates) are favorable [5 years : 85.0% (64.3%); 10 years: 67.9% (42.2%)]. After thoroughly evaluating liver function in these cases, while surgical resection should be considered first, it is also important to use a combination of various treatment methods rather than always resort to a single method. PMID- 8678534 TI - [Clinical significance of soluble interleukin-2 receptor levels in the cerebrospinal fluid in patients with adult T-cell leukemia complicated with meningeal infiltration]. AB - We measured soluble interleukin-2 receptor (sIL-2R) levels in the cerebrospinal fluid (CSF) of patients with hematological malignancies especially, adult T-cell leukemia (ATL) and non-Hodgkin's lymphoma (NHL) with or without meningeal infiltration. CSF levels of sIL-2R were significantly higher in patients with ATL and NHL with meningeal infiltration than in patients with both diseases without meningeal infiltration. The sIL-2R levels in CSF were elevated in 4/4 ATL patients (100%) and 3/13 NHL patients (23%) with meningeal infiltration. CSF levels of sIL-2R from ATL patients with meningeal infiltration had a tendency to elevate in correlation with numbers of mononuclear cells and lactic dehydrogenase (LDH) in CSF. However, these had no correlation with serum levels of sIL-2R. Therefore, sIL-2 levels in CSF may be useful in the diagnosis of meningeal infiltration in patients with ATL, are probably specific markers for meningeal infiltration of ATL. PMID- 8678535 TI - [A randomized controlled study of maintenance therapy with (2"R)-4'-O tetrahydropyranyladriamycin for advanced and recurrent breast cancer. Clinical Study Group of THP for Breast Cancer in Japan]. AB - We conducted a randomized controlled study to evaluate the clinical usefulness of (2"R) -4'-O-Tetrahydropyranyladriamycin (THP)-based combination therapy subsequent to induction therapy which was consisted with THP, 5'-DFUR, and CPA in the treatment of advanced or recurrent breast cancer. In maintenance therapy, Arm C received CPA and TAM, and Arm T received these two drugs plus THP. Survival time of 50% for all cases in which maintenance therapy was conducted was 26.9 months in Arm T and 20.9 months in Arm C, showing no significant difference by the log-rank test (p = 0.64). Survival time in all cases in which therapy had been completed was 54.6 months in Arm T and 28.1 months in Arm C, showing a significant difference by the log-rank test (p = 0.03) although the number of cases was few. A few cases showed a decrease in total leukocyte count to below 2,000/mm3 at the time of induction therapy, but this was transient in all cases. No significant difference in count was noted between two arms at the time of maintenance therapy. However, many cases in Arm T showed decreased total leukocyte count and hemoglobin content, and thrombocytopenia. These results suggest that combination therapy including THP conducted as maintenance therapy after induction is useful in the prolongation of survival time in patients with advanced or recurrent breast cancer. PMID- 8678537 TI - [Prolongation of survival and antitumor activity of antitumor drugs in murine cancer cachexia model]. AB - We examined the activity of UFT, ADM and MMC, which are used for colon tumors, in terms of their prolongation of the survival period, growth inhibition of the primary tumor and improvement of cachexia in murine cancer cachexia model. The mean survival period of Colon 26, mouse adenocarcinoma bearing mice was 25.0 +/- 4.9 days. The maximal ILS value of the UFT administered group was 103.2%, against 7.2 and 26.0%, respectively, ADM and MMC maximal ILS value. For therapeutic activity of hypercalcemia, UFT was superior to other drugs, although all drugs showed equivalent tumor growth inhibitory activity. These findings indicate that UFT can prolong the survival period due to improvement of cancer cachexia. Therefore, we measured plasma interleukin-6 (IL-6) and found that UFT administration lowered the plasma IL-6 level more than other drugs. Moreover, the prostaglandin E2 (PGE2) level in the tumor was significantly decreased only by UFT-administration. Since PGE2 has been shown to enhance IL-6 production from Colon 26 in vitro, it was speculated that UFT improve cachexia and prolongs life by decreased IL-6 resulting from decreased PGE2. PMID- 8678538 TI - [Effect of preoperative oral 5-fluorouracil on cell cycle of advanced cervical squamous cell carcinoma]. AB - Using flow cytometry, we examined the correlations between the tumor stage and the cell cycle in subjects with advanced cervical squamous cell carcinoma as well as between the changes of cell cycle caused by 5-FU and their prognoses. Before 5 FU treatment, 75.9 +/- 9.6% of the patients were at G1 phase, 16.8 +/- 3.9% at S and 7.3 +/- 4.5% at G2/M. The change of cell cycle was not accompanied by the progression of tumor stage. Sixteen patients received oral 5-FU (300 mg/day) for at least 2 weeks before operation. In the patients at stage I, the cell cycle was not changed even after 5-FU treatment. They have been cancer-free for 3 postoperative years. While early recurrence was found in 4 of 5 cases at stage II or III showing progression at G1, all 6 cases who had regressed or remained unchanged at G1 were free from recurrence (p = 0.0152). These results suggested that the cell cycle is not necessarily correlated with the progression of tumor stage in patients with this kind of carcinoma, and that the change of cell cycle due to preoperative oral 5-FU could be a predictive indicator for their prognoses. Especially for those with poor prognoses who had shown progression at G1, more potent adjuvant chemotherapy should be planned. PMID- 8678536 TI - [Correlation between an enzyme (glutathione S-transferase-pi) and effects of chemotherapy (cisplatin + etoposide)]. AB - OBJECTIVES: We studied the correlation between cisplatin and etoposide chemotherapy and GST-pi staining in patients with untreated primary non-small cell lung cancer. METHODS: Of patients diagnosed as having primary lung cancer, 27 patients (26 men, 1 woman; median age 74.9 years) with stage III b or over were studied. Histological types included squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. A course of treatment consisted of cisplatin 100 mg/m2/day x one day and etoposide 100 mg/m2/day x 3 days during 28 days. After 2 courses of treatment, the therapeutic effects were judged and examined in relation to immunostaining levels obtained with anti-GST-pi antibody. RESULTS: Of patients with PR (14), 11 showed GST-pi (-) staining. CONCLUSION: There is a correlation between GST-pi staining and the effects of cisplatin and etoposide chemotherapy. PMID- 8678540 TI - [Relationship of intracellular concentration and duration of contamination of pirarubicin and adriamycin in human bladder cancer cell lines and human bladder normal mucosa cell line]. AB - To establish a method for reasonable clinical use of adriamycin (ADM) and pirarubicin (THP) in the intravesical chemotherapy for superficial bladder cancer, intracellular concentrations of these drugs were examined in culture cell lines (T-24, T-24/ADM and FHS736b1) with variable durations of contamination. The intracellular concentration of THP showed a plateau at 15-30 min. contamination in T-24, and in T-24/ADM, and showed the time dependence of contamination in FHS736b1, human normal bladder mucosa cell line. The intracellular concentration of ADM showed the time dependence of contamination in T-24, T-24/ADM and FHS736b1. And these concentrations of THP were 20 times higher than those of ADM. In conclusion, it seems better that THP was retained for 5-15 min. in the bladder in the intravesical chemotherapy, from the point of view of drug efficacy and preventing side effects. And it seems good that ADM was retained for more than 30 min. in the case with drug sensitive tumors. PMID- 8678539 TI - [Efficacy of granisetron rescue therapy for nausea and vomiting induced by cancer chemotherapies in urogenital malignant tumor]. AB - In this study, the usefulness of granisetron rescue therapy for nausea and vomiting induced by cancer chemotherapies, including CDDP, was examined. Granisetron was given to twenty patients with urogenital malignant tumor by iv infusion for thirty minutes after the onset of nausea or vomiting. Nausea disappeared in 15 out of 20 patients (75%), 8 of whom (40%) experienced its disappearance while the granisetron was being administered. Vomiting was perfectly controlled in 5 out of 20 patients (25%) for 24 hours after the granisetron administration. No adverse event seemingly due to granisetron was observed. The result of this study confirmed the speedy effect granisetron on nausea induced by cancer chemotherapy including CDDP, but it stopped short of demonstrating sufficient efficacy for vomiting. Prophylactic use, therefore, seems more desirable in view of the patient's QOL, when a highly emetogenic anti tumor drug, such as CDDP, is used. PMID- 8678541 TI - [A case of hepatocellular carcinoma responding to oral administration of UFT]. AB - A 77-year-old male with liver cirrhosis was admitted to our hospital for further examination and treatment of liver tumor. A tumor, which was in the S5 of liver and 7.2 cm in diameter, was revealed by ultrasonography, CT scan and MRI. The titers of serum AFP and PIVKA-II were 600 ng/ml and 3.5 AU/ml, respectively. According to the findings of imaging diagnosis and laboratory data, the patient was diagnosed as having hepatocellular carcinoma. He was treated by the oral administration of UFT (300 mg/day). Ultrasonically guided aspiration biopsy of the tumor and CT scan, which were performed ten and fourteen months after the beginning of administration of UFT, respectively, revealed the necrosis of the tumor. Twelve months later, the tumor size reduced to 1.4 cm in diameter, and the titer of PIVKA-II was reduced to the normal range. This case shows the clinical effectiveness of oral administration of UFT. PMID- 8678542 TI - [A case of advanced gastric cancer with liver metastasis with no recurrence and long survival]. AB - A 61-year-old male was admitted after detecting gastric lesion by gastrography in a medical health examination. The patient was diagnosed as Borrmann 2 advanced gastric cancer with remarkable intraperitoneal lymph node metastasis and liver tumor of lateral segment. Relative non-curative gastrectomy was performed with combined partial hepatectomy. The liver tumor measured 1.5 x 1.5 cm and was intraoperatively diagnosed as metastasis of gastric cancer. Mitomycin C 26 mg was given intravenously on the day of operation and 5-fluorouracil (5-FU) 150 mg/day orally since postoperative 14th day as adjuvant chemotherapy. The administration of 5-FU was continued for 5 years. As a result of such combination therapy, the patient still has had no recurrence 8 years following operation. PMID- 8678544 TI - [Combined chemotherapy with MMC, ADM, CDDP, etoposide (VP-16) and 5'-DFUR, (MACVD therapy) as a second-line chemotherapy for metastatic gastric cancer: three cases]. AB - Three patients with chemotherapeutically pretreated metastatic gastric cancer were given MAC-VD therapy combining MMC, ADM, CDDP, Etoposide (VP-16) and 5' DFUR. All were evaluable for their responses. Patients ranged in age from 49 to 61 years. Performance status scale (P.S.) grade 0 was two cases; and P.S. grade 1 was one case. The overall response rate, CR+PR, was 0+2/3 (66.7%). The response rate in the primary lesions was 0%, against 66.7% (2/3) in the liver, 100% (1/1) in the spleen, 100% (1/1) in the lung, and 0% in the abdominal lymph node metastasis. The chief manifestations of toxicity were hematologic, such as leukocytopenia, anemia and thrombocytopenia in 100% of the cases. Non-hematologic toxicity was seen in alopecia in 66.7%, diarrhea in 33.3%, fever in 33.3%, and pigmentation in 33.3%. Severe toxicity was not observed. From these data, the administration of MAC-VD therapy was considered tolerable and these data suggested that this therapy could be given as a second-line chemotherapy when initial treatment failed to obtain a response after a partial response. PMID- 8678543 TI - [A case of early gastric cancer transformed from adenoma by chemotherapy and radiotherapy]. AB - A 69-year-old male had a gastric adenoma at the greater curvature of the antrum. At the same time, malignant lymphoma of the liver and several bones were disclosed, but these tumors had become remarkably smaller after chemotherapy, radiotherapy and transcatheter hepatic arterial chemoembolization. Five and one half years later, however, the gastric adenoma had developed into gastric cancer that invaded submucosal layer. It is suspected that some chemotherapeutic agents and radiation were associated with malignant transformation of gastric adenoma. PMID- 8678545 TI - [Successful neoadjuvant chemotherapy in a patient with advanced gastric cancer with periaortic lymph node metastasis]. AB - We described a case of advanced gastric cancer accompanied by metastasis to the periaortic lymph node. Two cycles of the neoadjuvant chemotherapy consisting of 5 FU and low-dose CDDP (FP therapy) were given. 5-FU (800mg/body/day) was administered as a continuous intravenous infusion for five days, and CDDP (10mg/body/day) was given as an intravenous infusion for an hour on days 1-5. The FP therapy resulted in a significant effect in the metastatic periaortic lymph node. Then, total gastrectomy with combined resection of spleen was done. Histological examination of the resected specimen revealed the histological effect showing Grade 3 in the primary site and Grade 2 in the periaortic lymph node. The patient is alive with no evidence of recurrence 13 months after operation. Thus, FP therapy is thought to be effective against advanced gastric cancer. PMID- 8678546 TI - [A case of nonresectable advanced gastric cancer responding to combined chemotherapy with 5'-DFUR, CDDP, and MMC]. AB - A 39-year-old man was referred for epigastric fullness and a mass in the umbilical region. A giant mass was palpated in the epigastric region, while a mass 1 cm in diameter with a hemorrhagic tendency was felt in the umbilical region. Fluoroscopy of the upper gastrointestinal tract and gastroscopy revealed a Borrmann 3 tumor in the upper part of the gastric corpus. The tumor was found by CT scanning to be growing clearly across the wall of the stomach, and the invasion to the transverse colon was suspected by the enema. The tumor was unresectable because of the extensive tumor invasion of the abdominal wall. Therefore, the patient received 2 courses of combined chemotherapy with 5'-DFUR, CDDP, and MMC. As a result, the tumor in the epigastric region was reduced dramatically, and it became unpalpable 6 months after treatment. At the same time, the tumor in the umbilical region disappeared. Both CT scanning and upper gastrointestinal radiography disclosed tumor reduction, and sufficient oral ingestion became possible. The administration of 5'-DFUR has since been continued as maintenance therapy. Aside from transient anorexia and slight leukopenia, the patient developed no symptoms during the treatment period. At present. 2 years and 9 months after starting chemotherapy, the patient is in good health. PMID- 8678547 TI - [A lower-leg ulcer during hydroxyurea therapy for essential thrombocythemia]. AB - A skin ulcer of the lateral malleous developed in a 61-year-old man receiving hydroxyurea for essential thrombocythemia. In the past, skin ulcers have been reported in patients with chronic myeloproliferative diseases, including essential thrombocythemia, who had been treated with hydroxyurea. In the current case, vasculitis or thrombi in vessels of the biopsied specimen of the lower leg were not observed, and the patient required skin-graft operation. Accordingly, we concluded that the skin ulcer might be due to the administration of hydroxyurea. Thus, the dose of hydroxyurea was decreased. PMID- 8678548 TI - [Chemotherapy for advanced urothelial cancer patients with a combination of low dose consecutive cisplatin and etoposide]. PMID- 8678549 TI - [The results of chemosensitivity test for clear cell adenocarcinoma of the ovary]. PMID- 8678550 TI - [Prognostic factors in squamous cell carcinoma of the head and neck]. AB - The clinical and histological factors predicting survival of patients with head and neck cancer were discussed. Recent reports with multivariate analysis focusing on clinical prognostic factors revealed that staging of nodal metastases is most significant. Number and size of metastatic nodes can be evaluated as factors to predict the outcome of advanced cancer. The number of positive nodes over 4 may be associated with poor prognosis. A scoring system of histological grading has been developed at this primary site. The mode of invasion or depth of invasion of cancer may predict the metastases to regional nodes. The research on molecular pathology is ongoing in head and neck cancer. No independent prognostic factor is yet available in clinical practice. PMID- 8678551 TI - [Correlation between intratumor DNA ploidy distribution pattern and prognosis by tumor stage in colorectal carcinomas]. AB - Curatively resected specimens of 124 cases of colorectal carcinoma, and 6 cases of colorectal carcinoma showing hematogenous metastasis were used in this study. Each carcinoma was cut out in stepwise section through the entire tumor. DNA ploidy for each section was determined by flow cytometry, and the intratumor DNA ploidy distribution pattern was decided, and divided into 5 types (Type A-E). These 5 types were broadly divided into 2 types; predominantly diploidy type (Type A, C) and predominantly aneuploidy type (Type B, D, E). A statistically significant difference was seen in the 5-year survival between 25 cases of the predominantly diploidy type (100%) and 99 cases of the predominantly aneuploidy type (76.7%). However, there was no statistically significant difference in survival between these 2 types in any Dukes stage. The intratumor DNA ploidy distribution pattern in 6 cases of colorectal carcinoma showing hematogenous metastasis comprised 3 cases of Type E, 2 Type D and 1 Type B. And that of 8 cases of curatively resected colorectal carcinoma showing hematogenous metastasis postoperatively comprised 5 cases of Type D, 2 Type E and 1 Type B. Thus, a close correlation between the aneuploidy predominant type, especially Type D as well as Type E, and hematogenous metastasis, was suggested. PMID- 8678552 TI - [Flow cytometric DNA analysis of malignant potential in colorectal cancer]. AB - Significance of flow cytometric DNA analysis for assessing malignant potential and survival of colorectal cancer was investigated using paraffin-embedded materials from 163 patients who underwent resection of curability A from 1971 to 1985, excluding intramucosal carcinoma. DNA diploid was confirmed in 46% (75 cases) of the patients and DNA aneuploid in 54% (88 cases). No significant correlation was seen between DNA ploidy and clinicopathological factors, such as tumor location, macroscopic type, histological type, depth of invasion, lymph node metastasis and stage. Cumulative survival rates after curable resection of colorectal cancer were significantly lower in patients with DNA aneuploid tumor than those with DNA diploid tumor. Furthermore, in patients in stage of II and III, survival rates were lower in DNA aneuploid patients than DNA diploid patients, respectively. A multivariate analysis of survival data using Cox's proportional hazard model showed that DNA ploidy was the significant discriminating factor on survival in stage II and III cancer. In conclusion, nuclear DNA ploidy in patients with stage II and III colorectal cancer undergoing curable resection may represent malignant potential and may be an independent prognostic factor. PMID- 8678554 TI - [Correlation between intratumor DNA ploidy distribution pattern and clinicopathologic variables in large-bowel carcinoma]. AB - Surgically resected specimens of 139 cases of large-bowel carcinoma were analysed in this study. Each carcinoma was cut out in stepwise section through the whole tumor, and flow cytometric DNA measurement was performed for each section. The intratumor DNA ploidy distribution pattern decided in this way was classified into 5 types (Type A-E). The 139 cases of carcinoma comprised 19 cases of Type A, 27 Type B, 11 Type C, 37 Type D and 45 Type E. The intratumor DNA ploidy distribution pattern showed a statistically significant correlation to tumor size, gross type, depth of invasion, growth pattern at the tumor margin, venous permeation of visceral wall, DNA Index and Dukes stage. Among these 5 types of carcinoma, carcinoma showing Type E was seen most frequently, even in the earlier stage, and found most frequently among the cases showing invasive growth pattern at the tumor margin, positive venous permeation in the visceral wall and DNA Index of more than 1.7. Therefore, the intratumor DNA ploidy distribution pattern seemed to reflect the degree of tumor malignancy as well as that of tumor advancement. Moreover, Type E pattern of carcinoma appeared to reveal the highest grade of malignancy, and early detection of this type seemed to be necessary in order to improve survival after surgery. PMID- 8678553 TI - [DNA index as a significant prognostic indicator of colorectal cancer]. AB - To investigate the prognostic significance of DNA ploidy pattern and DNA index (DI), DNA contents were measured by flow cytometer in 412 patients with colorectal cancer and correlation between their prognoses and DNA contents were analyzed on the same clinical stage. There were significant differences in the survival rate and the incidence of tumor recurrence between diploid and aneuploid tumors, especially the poor survival rate and frequent tumor recurrence in the aneuploid tumor with DI above 1.5. Cox's multiple regression proportional hazard model was used to investigate the prognostic value of DNA ploidy pattern, DI and clinicopathological findings. From these analyses, DI 1.5 was found to be the most significant prognostic factor. These results suggest that flow cytometrically evaluated DI values have a relevant independent power for predicting the clinical outcome of colorectal cancer patients. PMID- 8678555 TI - [Flow cytometric analysis of the DNA content of resected non-small cell lung cancer with reference to long-term follow-up]. AB - We measured the cellular DNA content of paraffin-embedded tumor specimens by flow cytometry from 340 cases of resected non-small cell lung cancer, and investigated the correlation of DNA content and prognosis of these cases with long-term follow up. These 340 cases were divided into some populations according to pathological stage, histologic type, surgical curativity and N factor, and we compared the prognosis of DNA diploidy cases and DNA aneuploidy cases in each population. DNA aneuploidy cases had a significantly less favorable prognosis than DNA diploidy cases in population of stage I adenocarcinoma, stage IIIA non-small cell lung cancer and N2 cases among stage IIIA non-small cell lung cancer, all after curative operation. But in other populations, there was no significant difference in prognosis between DNA diploidy cases and DNA aneuploidy cases. In conclusion, DNA ploidy pattern is a prognostic factor for survival in patients with stage I adenocarcinoma and N2 cases of stage IIIA non-small cell lung cancer. PMID- 8678556 TI - [DNA ploidy pattern in resected human hepatocellular carcinomas from the view point of biological malignant potential]. AB - Nuclear DNA ploidy analysis was studied in patients with hepatocellular carcinoma (HCC) who underwent hepatic resections. These patients were classified three groups according to the following prescriptions. Group A (n = 100) was a group of patients of which excluded ones treated by absolute non-curative resection, Group B (n = 43) was patients who underwent absolute curative resection or relative curative resection, and Group C (n = 81) was patients whose tumor sizes were more than 2 cm in Group A. Aneuploid pattern was found in 59 cases (59.0%) in Group A, 22 cases (51.2%) in Group B and 54 cases (66.7%) in Group C. The rate of aneuploid pattern was significantly higher in patients with carcinomas more than 2 cm in diameter, fc-inf positive growth, Stage III + IV and PCNA LI > or = 40% in Group A, those with carcinomas more than 2 cm in diameter, fc-inf positive growth, im-positive and Stage III + IV in Group B, and those with PCNA LI > or = 40% in Group C. The postoperative prognoses of patients with aneuploid pattern in Group A and Group C were significantly poorer than those of the diploid one in cumulative survival rates and survival rates after recurrence. Patients with aneuploid pattern in Group B had a poorer prognosis than those with diploid one in cumulative survival rates and disease-free survival rates. These results suggest that nuclear DNA ploidy analysis was a useful marker of biological malignant potential in resected human HCCs. PMID- 8678557 TI - [Comparative study of mRNA expression of E-cadherin and collagenase IV in early and advanced cancers]. AB - During the process of invasion, tumor cells must detach from the primary neoplasm and degrade host stroma. E-cadherin is responsible for the cell-cell adhesion and collagenase IV is the one of the matrix metalloproteinases. We determined whether the levels of mRNA for E-cadherin and collagenase IV were differently expressed within 12 cases of early and 13 cases of advanced gastric cancers using a rapid calorimetric in situ hybridization assay for mRNA. In 6 of 12 early cancers, we found a decreased expression of E-cadherin mRNA in the invasion edge compared to the main tumor. In advanced gastric cancers, 3 out of 13 cancers also exhibited this finding. Higher expression of the collagenase IV at the invasion edge of the tumor compared to the main tumor was observed in half of the early and advanced gastric cancer cases. Inverse expression levels of E-cadherin and collagenase IV mRNA were observed in 6 of 12 early cancers. However, only one of 13 advanced cancer cases expressed the same finding. PMID- 8678558 TI - [Correlation between expression of RB protein and prognosis of gastric cancer]. AB - In this study, the expression of retinoblastoma (RB) protein was investigated immunohistochemically in 94 patients with gastric cancer. Overexpression of RB was detected in 48 tumors (51.1%). There was no significant association among the expression of RB, histologic type, lymph node metastasis, and liver metastasis. However, a significant difference was noted with respect to depth of invasion and peritoneal metastases. Among 94 patients, peritoneal metastases were observed in 11 patients. RB expression was detected in only two of these cases with peritoneal metastases, which was significantly less than those without peritoneal metastases. In relation to prognosis, patients with RB-positive tumors had a significantly better prognosis than those with RB-negative tumors. In conclusion, this study suggested that expression of RB has a prognostic value in gastric cancer. PMID- 8678559 TI - [Association between p53 expression and chemosensitivity in advanced and recurrent gastric cancer]. AB - Fifteen cases with very advanced and recurrent gastric carcinoma were treated by 5-FU plus cisplatin. Among them, 6 cases were responder (CR + PR) and 9 cases were nonresponder (NC). In order to select the responder, p53 protein status in the tissue obtained by endoscopical biopsy before chemotherapy was studied. The immunohistochemical method was by the avidin-biotin complex method using anti-p53 protein monoclonal antibody. One CR case showed negative p53 staining and 2 of 5 cases of PR cases exhibited positive p53 staining. The staining of all 9 NC cases was positive. Significantly high p53 protein overexpression in the nonresponder cases was indicated. In conclusion, our result suggested that the immunohistochemical method detecting p53 protein in the biopsy specimen may be useful to predict the effect by chemotherapy. PMID- 8678560 TI - [K-ras gene mutations in adenomas from familial adenomatous polyposis]. AB - A 18-year-old woman underwent total colectomy for familial adenomatous polyposis. In order to clarify the significance of K-ras mutations in early colorectal carcinogenesis, K-ras mutations were analyzed in multiple adenomas by PCR-SSCP method. A total of 256 adenomas were found throughout the entire colon and rectum, and the distribution was a sparse type. The correlation between K-ras gene and clinicopathological factors was examined in 90 adenomas. There was no correlation among K-ras mutations and anatomical distribution, or morphological classification, but K-ras mutation was more frequent in severe compared with slight atypia. We investigated the correlation between the size of adenoma in the horizontal and vertical directions and K-ras mutation. K-ras mutation was more frequent in the horizontal size greater than 6 mm in diameter, and also more frequent in vertical size greater than 20 mm in height. It was concluded that the adenomas detecting K-ras mutations might have proliferating potential, and would be applied to determine polypectomy. PMID- 8678561 TI - [The results of p53 immunostaining in colorectal adenomas, early cancers, advanced cancers and their hepatic metastasis]. AB - Overexpression of the p53 protein was analyzed in colorectal adenomas, early cancers, advanced cancers and their hepatic metastasis by immunostaining using monoclonal antibody (DO-7). Positive staining for p53 was detected in 8 (22.9%) of 35 adenomas, 19 (82.6%) of 22 early cancers, and 59 (63.2%) of 95 advanced cancers. In adenomas, p53 immunoreactivity for severe dysplasia was higher than that for mild or moderate dysplasia (3/9.33.3% vs 2/16.12.5% or 3/10.33.3%), we found almost the same p53 immunoreactivity both in early cancers in adenoma (7/8.87.5%) and "de novo" cancers without an adenoma component (12/14. 85.7%). In 95 of advanced cancers, we found p53 positive cells in 33 (76.7%) of 43 cases with hepatic metastasis, against 26 (50.0%) of 52 cases without hepatic metastasis and surviving more than 5 years from the colorectal cancer resection. The former group had a significantly higher incidence of p53 overexpression (p < 0.05). In the 33 above mentioned cases, both primary and liver metastatic lesions were p53 positive, and the others were negative in both of them. In this series, it was suggested that p53 had important roles in the colorectal adenoma-carcinoma sequence from adenoma to advanced cancer and its metastatic potential, as well as in "de nove" carcinoma. PMID- 8678562 TI - [Analysis of genetic changes in progression of colorectal cancer]. AB - To investigate whether genetic changes of the p53 gene and genetic defects in DNA mismatch repair systems are involved in progression of colorectal carcinomas (CRCs), we examined loss of heterozygosity (LOH) on 17p and mutations in exon 5 through 8 of the p53 gene as well as replication errors (RER) at four microsatellite loci in DNAs from 108 CRCs at all clinical stages (20 Dukes A, 40 Dukes b, 48 Dukes C). We observed that LOH on 17p and/or p53 mutation were detected in 93% of Dukes A carcinomas and in 84% of Dukes C carcinomas, suggesting that the p53 gene is mutated and/or deleted before carcinoma has been produced. RER-positive phenotype was observed in approximately 30% of CRCs, irrespective of clinical stage. These results suggest that genetic instability is likely to play an important role in development of a subpopulation of sporadic CRCs, but not in progression of CRCs. In addition, we found no significant association between genetic alterations and progression of CRCs. We consider that genetic defects in DNA-mismatch repair pathway do not necessarily promote genomic instability at the p53 sequences in CRCs. PMID- 8678563 TI - [Expression of CD44 variant isoforms in human primary colon carcinomas and metastasis]. AB - The CD44 is a cell adhesion molecule that is present as numerous isoforms created by mRNA alternative splicing. A variety of human carcinomas display the overexpression of CD44 variant isoforms. To identify the relationship between the expression of CD44 variant isoforms and the metastatic potential of colon carcinomas, we performed a polymerase chain reaction analysis following reverse transcriptase treatment for CD44 expression in fresh surgical specimens obtained from 25 colon carcinomas and corresponding normal colonic mucosa. The CD44H, a common type of the CD44 isoform, was amplified from all carcinomas and normal tissues, whereas a splice variant form corresponding to CD44E was expressed in 19 out of 23 colon carcinomas (83%) and 7 out of 19 normal mucosa specimens (37%), suggesting that the CD44E expression was predominantly observed in colon carcinomas compared to normal tissues (p < 0.05). The multivariant form of CD44 was identified in 10 out of 23 carcinomas (44%) and 5 out of 19 normal samples (26%). The CD44E/CD44H (E/H) ratio was significantly higher in colon carcinomas than in normal mucosa (p < 0.01). However, neither the E/H ratio nor CD44 multivariant expression correlated with the clinicopathological features. These results suggest that CD44E expression and high E/H ratio are commonly observed in colon carcinomas and that the expression of the CD44 multivariants is not associated with clinicopathological parameters. PMID- 8678564 TI - [Occurrence of numerical aberrations of chromosomes in metachronous liver metastases of colorectal cancers]. AB - To investigate the change of numerical aberrations of chromosome 17 or 18 during progression of Colorectal carcinoma, we applied FISH, using chromosome specific probes, to 3 colorectal primary carcinomas and a total of 4 metachronous metastatic lesions in the liver. We also investigated the relationship between the DNA content of whole nucleus and the number of chromosome 17 by multiparametric analysis using autostage cytofluorometry. When compared with the results for primary lesions, in 4 metastatic lesions, the population of tetrasomy 17 cells increased in 2 lesions, and that of monosomy 18 cells increased in 1 lesion. The nuclear DNA contents histograms for disomy 17 and aneusomy 17 cells analyzed individually for 3 primary and 4 metastatic lesions, showed almost no appreciable difference of peak DNA values. These results indicate that the numerical aberrations of chromosome 17 and 18 accumulate during the progression of colorectal carcinomas, and that the subpopulation of aneusomy 17 consist mainly of those cells that involve the numerical aberrations in a few chromosomes. PMID- 8678565 TI - [Clonal analysis of hepatocellular carcinoma]. AB - We investigated the cell clonality of 12 cases of female solitary hepatocellular carcinoma (HCC) that were associated with hepatitis virus infection. The clonal origin of HCC could be assessed by the method based on restriction fragment length polymorphism (RFLP) of X-chromosome-linked androgen receptor gene (AR) and phosphoglycerate kinase (PGK) gene, taking advantage of random inactivation of one of two X-chromosomes by methylation in females. We extracted DNA samples from both fresh and paraffin-embedded specimens of the same lesion as a source of DNA sample for polymerase chain reaction (PCR). Consequently, it was possible to use methylation-sensitive restriction enzymes and PCR to study differential methylation patterns among alleles of these genes for both DNA samples. The RFLPs of AR gene and PGK gene were found in eight of 12 cases and five of 12 cases, respectively. There were two cases which had no RFLPs in either AR gene or PGK gene. All cases of HCC which had RFLP in either AR gene or PGK gene demonstrated monoclonal origin of the tumor regardless of their histologic patterns. PMID- 8678566 TI - Livedoid vasculitis. Response to low-dose danazol. PMID- 8678567 TI - The role of the part-time physician-teacher in dermatology. AB - As we approach the 21st century, specialty training programs in dermatology are feeling increasing pressures that have begun to erode clinical teaching. Full time faculty members are being asked to spend more time in patient care to support an increasing portion of their income or are spending more time to develop laboratory data and write grant applications to survive in a brutally competitive academic world. Other faculty members are leaving academic medicine for private practice having decided that the risk-reward ratio is no longer acceptable. In California, the state government has implemented a plan that decreases specialty residency positions and their funding in favor of primary care positions. Third-party payers are becoming more restrictive in paying for inpatient and outpatient dermatologic services. Dermatologic inpatient services in some university teaching programs have been eliminated. Third-party payers are also balking at subsidizing teaching and research activities at teaching hospitals. PMID- 8678568 TI - Effects of isotretinoin on bone mineralization during routine therapy with isotretinoin for acne vulgaris. AB - OBJECTIVE: To examine the effects of isotretinoin on bone mineralization and other markers of calcium homeostasis in individuals receiving isotretinoin for routine therapy for severe acne vulgaris. DESIGN: Cohort study. SETTING: An academic medical center. PATIENTS: Twenty individuals receiving isotretinoin for severe acne vulgaris. INTERVENTION: None. MAIN OUTCOME MEASURE: The primary outcome was the change in bone mineralization as measured by dual-energy x-ray absorptiometry of the lumbar spine and hip before and after isotretinoin therapy. Additional measurements included serum osteocalcin, calcium, 25-dihydroxyvitamin D, 1,25-dihydroxyvitamin D, and intact parathyroid hormone and urine hydroxyproline or calcium. RESULTS: No changes were noted in bone mineralization of the lumbar spine or hip. Furthermore, no alterations were noted in serum measurements of osteocalcin, calcium, 25-dihydroxyvitamin D, intact parathyroid hormone, or urine measurements of hydroxyproline or calcium. A statistically significant change was noted in 1,25-dihydroxyvitamin D when serum from before and after isotretinoin therapy was compared. CONCLUSION: The use of isotretinoin for 20 weeks for the treatment of severe acne vulgaris does not appear to have any substantial adverse effect on bone mineralization. PMID- 8678569 TI - Acne therapy. Medication use and sources of care in office-based practice. AB - BACKGROUND AND DESIGN: This study quantifies visits to office-based physicians for the treatment of acne from 1980 through 1991 and describes treatments prescribed. Data were collected from the National Ambulatory Medical Care Survey, a multistage probability survey conducted in 1980, 1981, 1985, 1989, 1990, and 1991, and were used to estimate visits with specific characteristics. Of 276 689 visits sampled in these surveys, 3075 included a diagnosis of acne and 2678 were principally for acne. RESULTS: Visits for acne as a primary complaint decreased from 7.5 million per year in 1980 and 1981 to 5.4 million per year in 1989 to 1991. The proportion of visits to physicians other than dermatologists increased 2.1-fold from 1980 and 1981 to 1989 through 1991. Differences in the rate of prescribing oral antibiotics between dermatologists and nondermatologists narrowed from 1980 to 1991. Of drugs available throughout the study, topical tretinoin had the greatest increase in usage. Oral isotretinoin was more often prescribed at visits for men than for women. The proportion of acne visits at which isotretinoin was prescribed was comparable for dermatologists and nondermatologists. CONCLUSIONS: Acne remains one of the most frequent reasons for visiting dermatologists. By 1991, nondermatologists provided 23% of care for this disease. From 1980 to 1991, the pattern of prescribing medications for acne by dermatologists and nondermatologists became more alike. Demand for dermatologists' services for acne treatment is decreasing. PMID- 8678570 TI - Treatment of cutaneous leishmaniasis with itraconazole. Randomized double-blind study. AB - OBJECTIVE: To compare the efficacy of itraconazole with placebo in the treatment of cutaneous leishmaniasis caused by Leishmania major. DESIGN: Double-blind placebo-controlled study. SETTING: Patients were selected from volunteers wit cutaneous leishmaniasis who lived in a hyperendemic area. PATIENTS: One hundred forty patients were randomly selected for this double-blind study. Exclusion criteria were pregnancy, gestation, age younger than 12 years, and duration of disease of more than 4 months. INTERVENTION: Each patient received itraconazole (7 mg/kg per day) or placebo for a 3-week period. The patients were kept under observation for an additional 30-day period. OUTCOME. The study was completed as planned in 131 patients. RESULTS: Complete healing occurred in 59% of the itraconazole group in comparison with 44.3% of the patients who were treated with placebo capsules. No difference was found between the 2 groups with respect to adverse effects. CONCLUSIONS: Although itraconazole has the advantage of being an oral agent that is used in the treatment of cutaneous leishmaniasis, the low response rate in patients receiving itraconazole indicates that itraconazole cannot be used as the single agent in the treatment of patients with cutaneous leishmaniasis caused by L. major. PMID- 8678571 TI - Progressive osseous heteroplasia. AB - BACKGROUND: Primary heterotopic ossification beginning in childhood is quite rare but occurs in several well-described conditions, such as Albright hereditary osteodystrophy, fibrodysplasia ossificans progressiva, and platelike osteoma cutis. Recently, a new disorder called progressive osseous heteroplasia (POH) has been described in the orthopedic literature. Primary cutaneous calcification and ossification beginning in infancy are presenting signs of this progressive and potentially debilitating disorder. OBSERVATIONS: We describe 2 children with POH who were recently seen at Children's Hospital of Wisconsin. Both children were female and developed cutaneous calcification and ossification within the first 6 months of life. Both girls had progression of the lesions to involve ossification of the deeper tissues. No abnormalities in calcium, phosphorus, vitamin D, or parathyroid hormone levels were identified in these patients. No associated anomalies were detected. Biopsy results from the lesions showed calcinosis cutis superficially, with both endochondral and intramembranous bone formation in the deeper tissues. CONCLUSIONS: Progressive osseous heteroplasia must now be included in the differential diagnosis of primary cutaneous ossification beginning in childhood. Because the first clinical manifestations of POH appear in the skin. It is important for dermatologists to be aware of this newly described condition. PMID- 8678572 TI - Olmsted syndrome. Case report and identification of a keratin abnormality. AB - BACKGROUND: Olmsted syndrome is a rare disorder characterized by a mutilating palmoplantar keratoderma and periorificial keratotic plaques. It begins in early childhood and is complicated by the development of painful flexion contractures, constrictions, and autoamputations of the digits. Only 11 cases of Olmsted syndrome have been reported to date. However, no biochemical abnormalities in the skin were reported in any of these cases. OBSERVATIONS: We report the 12th case of Olmsted syndrome. In addition, we describe a keratin abnormality found in a skin specimen obtained from our patient. The specimen showed a suprabasilar staining pattern with AE1, an antibody that shows only basilar staining in normal skin. CONCLUSION: We report the 12th case of Olmsted syndrome, review the literature, and describe a keratin abnormality that was found in our patient's skin specimen. PMID- 8678573 TI - Expression of interleukin-4 in scleroderma skin specimens and scleroderma fibroblast cultures. Potential role in fibrosis. AB - BACKGROUND: Scleroderma (systemic sclerosis) is a fibrotic disease characterized by an uncontrolled tissular accumulation of collagen. Several cytokines have been implicated in the fibroblast activation leading to fibrosis. For instance, we have previously demonstrated that interleukin-4 (IL-4) is a potent activator of collagen synthesis in fibroblast cultures. In this study, using immunocytochemical methods and in situ hybridization, we investigated the expression of IL-4 in normal and scleroderma skin and fibroblast cultures. OBSERVATIONS: Immunocytochemical studies with anti-IL-4 antibody were performed on biopsy specimens from 9 patients with normal skin and 11 patients with scleroderma. The label was intense or strong in 8 of the 11 scleroderma skin specimens, whereas it was negative or faint in 8 of the 9 normal skin specimens (P < .01). In situ hybridization demonstrated a significant increase of the number of IL-4 messenger RNA grains in scleroderma skin compared with normal skin (3.1 +/- 1.5 [mean +/- SD] vs 0.8 +/- 0.7; P < .001). A strongly positive labeling with the anti-IL-4 antibody was found in the 4 scleroderma fibroblast cultures, whereas it was negative in the 5 fibroblast control cultures (P < .05). CONCLUSIONS: Our results demonstrate that IL-4 is strongly expressed in the dermis of a large majority of patients with scleroderma and might be synthesized by scleroderma fibroblasts. We suggest that IL-4 is one of the cytokines implicated in the early steps of the fibrotic process. PMID- 8678574 TI - A factual, not arbitrary, basis for choice of resection margins in melanoma. AB - Try as some might, it has proved exceedingly difficult to dispel the notion that primary melanoma should be treated by arbitrarily wide resection margins. There was never any substantive scientific foundation for the traditional 5-cm margin, but for much of this century it nevertheless found favor in medical folklore. Current opinions concerning melanoma management in the dermatologic literature, while careful to point out the limitations of supportive data, have continued the tradition of offering arbitrary guidelines for resection margins. The last 2 decades have witnessed the acquisition of sufficient experimental evidence to warrant further scrutiny of the practice. PMID- 8678576 TI - Is it reasonable for a dermatologist to treat acne? PMID- 8678575 TI - Skin and bones. AB - Through the examples above, we can begin to see how rare diseases may shed light not only on more common conditions but also on each other. Disorders such as FOP, POH, MAS, and AHO provide a fertile molecular neighborhood for investigating a disease such as POH. Will POH be linked to the G proteins, c-fos, the BMPs, the BMP receptors, or perhaps an as yet undiscovered gene? For the moment, there are few answers, but there are at least some tantalizing questions to ponder and investigate. We all look forward to the day when our knowledge of, and treatment for, diseases like POH will be more than just skin and bones. PMID- 8678577 TI - Widespread papules and nodules in a Ugandan man with acquired immunodeficiency syndrome. African blastomycosis. PMID- 8678578 TI - A nodule on the lip. Nodular secondary syphilis. PMID- 8678579 TI - Cutaneous lesions provide a clue to mysterious pulmonary process. Pulmonary and cutaneous North American blastomycosis infection. PMID- 8678580 TI - Extensive inguinal lymphadenitis. Ecthyma with inguinal lymphadenitis. PMID- 8678581 TI - Are neutrophilic dermatoses during granulocytopenia really neutrophilic? PMID- 8678582 TI - Whole-body positron emission tomography: an accurate staging modality for metastatic melanoma. PMID- 8678584 TI - Calciphylaxis without renal failure. PMID- 8678583 TI - Human papillomavirus in nonmelanoma skin cancer? The phylogenetic tree of the papillomavirus family is not yet complete. PMID- 8678585 TI - Raynaud's phenomenon secondary to weever fish stings. PMID- 8678586 TI - Pulsed dye laser-resistant port-wine stains. PMID- 8678587 TI - Absence of human T-cell lymphotropic virus genomic determinants in canine mycosis fungoides. PMID- 8678588 TI - Value of fine-needle aspiration in infectious cellulitis. PMID- 8678589 TI - Occurrence of alopecia areata in a patient receiving systemic cyclosporine A. PMID- 8678590 TI - Idiopathic lenticular mucocutaneous pigmentation or Laugier-Hunziker syndrome with atypical features. PMID- 8678591 TI - The development of green vision in association with terbinafine therapy. PMID- 8678592 TI - Cutaneous findings in Gulf War veterans. PMID- 8678593 TI - [Intermittent testicular torsion]. AB - OBJECTIVES: The present study focuses attention on intermittent testicular torsion, a well-differentiated but underdiagnosed entity. METHODS: Four cases of intermittent testicular torsion are described. The presence of recurrent acute testicular pain that remits spontaneously or following self-manipulation and the horizontal of the testis (bell clapper) are sufficient to make the diagnosis. RESULTS: All four cases underwent bilateral orchipexy with excellent results. At years' follow-up all patients remain asymptomatic. CONCLUSIONS: Intermittent testicular torsion must be considered appropriately since these patients comprise the largest group at high risk for developing acute testicular torsion. Bilateral orchidopexy will ensure the viability of the testis with 100% good results. PMID- 8678594 TI - [Neoplasms of the tunica of the testis. Report of 5 cases (3 mesothelial tumors and 2 fibrous pseudo-tumors)]. AB - OBJECTIVES: The problems arising from tumors of the tunica vaginalis testis are reviewed and the differential diagnosis of this uncommon tumor type is discussed. MATERIAL AND METHODS: Five cases of benign tumor of the tunica vaginalis testis that had been incidentally discovered during hydrocelectomy are described. The patients were evaluated two and five years postoperatively, with no evidence of recurrence or presence of tumor at other sites of the serosa. RESULTS: The tumors did not compromise the gonad and were treated by simple excision of the hydrocele sac. CONCLUSIONS: The association of this condition with hydroceles is underscored. The true incidence of exposure to asbestos in the pathogenesis of this tumor type cannot be elucidated from the cases described herein or those in the literature. PMID- 8678595 TI - [Renal adenocarcinoma with venous tumor extension to the right atrium: diagnostic and therapeutic considerations]. AB - OBJECTIVES: We report our experience in two cases of renal adenocarcinoma with tumor thrombus extending into the right atrium. The literature is reviewed and the diagnostic aspects, surgical techniques, complications, mortality and aspects of retroperitoneal collateral venous blood supply are discussed. METHODS: The clinical records of both patients are reviewed, with special reference to the diagnostic approach and the surgical technique utilized. RESULTS: The cephalad portion of the thrombus in the right atrium was accurately defined by MRI. Both patients underwent radical nephrectomy and infrahepatic inferior cavectomy, with cardiopulmonary bypass without cardiocirculatory arrest. CONCLUSIONS: MRI was the method that best defined the cephalad portion of the tumor thrombus extending into the right atrium. The bypass technique utilized allowed complete removal of the thrombus without intraoperative complications. PMID- 8678596 TI - [Urothelial tumors of the upper urinary tract: epidemiologic study, diagnostic assessment, and treatment]. AB - OBJECTIVES: The result of an epidemiological study and evaluation of diagnosis and treatment of transitional cell tumors of the upper urinary tract are presented. MATERIAL AND METHODS: A retrospective study was conducted on 34 patients with transitional cell tumor of the upper urinary tract. RESULTS: The most common symptom was intermittent hematuria. Smoking was found to be the most important risk factor and 41.7% of the cases previously had a bladder cancer. IVP was the diagnostic technique most commonly utilized (61.7%). Nephroureterectomy was performed in 58.8% of the cases. Six cases had recurrence of the upper urinary tract tumor. There were 9 deaths (26.5%). CONCLUSIONS: The epidemiological data are similar to those of larger series. The tumors appear to develop in the presence of generalized urothelial disease. The low incidence of recurrence in the ipsilateral ureteral meatus indicates that resection of the distal ureter may not be required in patients at high risk. PMID- 8678597 TI - [Reliability of the estimate of post-voiding bladder volume with ultrasound. Comparison of 2 ultrasonography methods]. AB - OBJECTIVES: To determine the reliability of the postvoiding volume measurement of two US methods. METHODS: A comparative study of transabdominal and portable ultrasound (Bladderscan model) in the selected and non-selected modes was conducted in 96 patients (54 males, 42 females; mean age 59.92 yrs). RESULTS: Conventional US had the lowest failure rate (26.99%). The failure rate was 41.66% for the selected mode and 57.77% for the non-selected mode. The main failure of transabdominal ultrasound was a defect failure. The non-selected mode had a defect and excess failure. The selected mode had a defect failure. There was and inverse relationship between the residual volume and the failure rate of the non selected mode of the Bladderscan model. The failure rate was higher for males vs females in the non-selected mode. The possible sources of failure are analyzed. CONCLUSION: Conventional transabdominal ultrasound is currently the most reliable ultrasound method. PMID- 8678598 TI - [Non-coordinated voiding syndrome: classification and urodynamic characterization]. AB - OBJECTIVES: To determine the urodynamic characteristics of uncoordinated voiding. METHODS: Fifty consecutive patients with a diagnosis of uncoordinated voiding were studied; 82% were females and 18% were males; mean age 11.9 years (range 5 to 34 yrs). All patients had a complete urodynamic study including patient history, neurological evaluation, uroflowmetry, cystometry and detrusor pressure/voiding flow. The perineal electromyographic (EMG) activity was recorded throughout the study using surface electrodes. To rule out neurogenic detrusor sphincter dyssynergy, periurethral sphincter EMG using concentric nail-electrodes was performed in selected cases (20% of the patients). Based on our urodynamic findings, three subtypes of uncoordinated voiding can be distinguished: Type A: micturition is achieved through detrusor involuntary contraction. Type B: micturition is achieved through detrusor voluntary contraction. Type C: micturition is achieved through abdominal straining. RESULTS/CONCLUSIONS: The most important urodynamic findings in uncoordinated voiding, independently of Q max, were the absence of relaxation and increased perineal EMG activity during uroflowmetry. The detrusor pressure/voiding flow test was essential in the classification of uncoordinated voiding. In our series, 58% of the patients were type A, 28% type B and 14% type C. PMID- 8678599 TI - [Changes in physical characteristics of endourologic catheters caused by shock waves]. AB - OBJECTIVE: To analyze the shock wave effects on double-J stent. METHODS: Retention strength modifications induced by shock waves were analyzed: a) 60 double-J stents obtained from patients were compared (20 had not been treated by ESWL; 20 had been treated by piezoelectric-ESWL and 20 by electrohydraulic-ESWL; b) the effects of piezoelectric-ESWL were determined in vitro using 36 stress tested double-J stent segments (Urosoft, C-Flex and silicone) vs. a control group. RESULTS: The retention strength of the stents from ESWL-treated patients, especially those that had been submitted to piezoelectric-ESWL, was lower than in stents from patients that had not undergone ESWL (p < 0.05). The foregoing has been corroborated by the in vitro findings. The impact frequency causing maximum damage is specific for each material. Microphotographic studies revealed fracture lines on the surfaces of the ESWL-treated stents (Urosoft and C-Flex). CONCLUSIONS: The foregoing findings may explain the high incidence of double-J stent migration observed in ESWL-treated patients. PMID- 8678600 TI - [Percutaneous treatment of Fraley syndrome]. AB - OBJECTIVE: A case of upper calyx obstruction of the left kidney from an artery encroaching on the infundibulum is described. Treatment was by percutaneous insertion of a prosthesis. The results show the usefulness of the percutaneous approach in the treatment of this condition. METHODS: A Palmaz prosthesis was inserted into the obstructed infundibulum through a nephrostomy. Intravenous urography was performed immediately postoperatively and at 3, 6 and 12 months. RESULTS: No complications were observed postoperatively. At one-year follow-up the patient is asymptomatic and the urographic controls show improvement. CONCLUSIONS: Percutaneous insertion of a prosthesis in the treatment of infundibular stenosis had achieved good results in the case described herein, although a larger series and long-term follow-up are required to determine the usefulness of this approach. PMID- 8678601 TI - [Bladder leiomyosarcoma. Report of 2 cases]. AB - OBJECTIVES: The difficulties encountered in making the differential diagnosis and the highly malignant nature of leiomyosarcoma of the bladder, an uncommon tumor type, have prompted us to report on these two cases. MATERIAL AND METHODS: Two cases of leiomyosarcoma of the bladder are described: a 64-year-old female that was treated sequentially by TUR and chemotherapy and died of metastatic disease after 14 months, and an 81-year-old male with metastasis at the time of diagnosis. The literature is reviewed and the clinical pathological immunohistochemical features and treatment are discussed. CONCLUSIONS: The differential diagnosis of this tumor type is complex and requires immunohistochemical data. The diagnosis of leiomyosarcoma is confirmed by the expression of myogenic antigens. Historically, patient survival has been poor and management has been based upon information obtained from a relatively small number of cases with diverse treatment regimens. Because the efficacy of chemotherapy and radiotherapy remains unclear, the treatment of choice is by radical cystectomy or partial cystectomy when tumor location and size permit. PMID- 8678602 TI - [Urinary fistula. Its surgical treatment. Report of 16 cases]. AB - OBJECTIVES: To report our experience in the surgical treatment of urinary fistulas. METHOD: The clinical records of the patients seen during the period 1988-1991 were reviewed. RESULTS: Sixteen cases of urinary fistulas were found; most of these had been caused during a gynecological procedure. All cases were treated by surgery, which achieved a satisfactory result in 100% of the cases. CONCLUSIONS: Abdominal hysterectomy was the most frequent cause of urinary fistula. The most common was vesico-vaginal fistula, predominantly located in the upper portion of the trigone. The surgical technique most commonly utilized was transvesical fistulectomy. PMID- 8678603 TI - [Pararenal pseudocyst as unusual cause of obstruction in a patient with solitary kidney]. AB - OBJECTIVE: An uncommon case of left pararenal pseudocyst associated with anuria in a patient with a hypoplastic contralateral kidney is described. METHODS: The etiopathological aspects and the good correlation between the preoperative findings and the information provided by the imaging techniques are analyzed. CONCLUSIONS: Ultrasound is essential in determining the structural characteristics, anatomical relationships and for adequate management of this uncommon condition. PMID- 8678604 TI - [Candidiasis of the upper urinary tract. Report of a case]. AB - OBJECTIVE: We report a case of candidiasis of the upper urinary tract that presented as acute renal failure associated with septic syndrome. The patient initially required hemodialysis. Right hydronephrosis and perirenal collection were observed on ultrasound examination. METHODS: A percutaneous nephrostomy was performed. Nephrostomy urine cytology and cultures were positive for Candida tropicalis. An anterograde pyelography showed a 'fungus ball' in the urinary tract. RESULTS: Therapy with oral fluconazole and percutaneous amphotericin B achieved excellent results. CONCLUSIONS: Candidiasic urinary infection of the upper urinary tract often produces obstructive uropathy requiring percutaneous nephrostomy, which can also be used to instill amphotericin B. Combination therapy with amphotericin B and fluconazole can achieve excellent results. PMID- 8678605 TI - [Retroperitoneal fibrosis without dilatation of the upper urinary tract and non obstructive anuria]. AB - OBJECTIVE: An unusual case of retroperitoneal fibrosis with non-obstructive anuria is described and the therapeutic alternatives are discussed. METHODS/ RESULTS: Repeated obstruction of the double-J ureteral catheter and intense lumbar pain did not permit endourological management and surgery was required. Excellent results were achieved and the patient is asymptomatic 12 months postoperatively. CONCLUSIONS: Conservative endourological management and corticosteroids may not always be feasible. The anuria without dilation in the case described is not unlike other reported cases considered as reflex anuria whose mechanism remains unknown. PMID- 8678606 TI - [Testicular infarction as a cause of benign intrascrotal tumor]. AB - OBJECTIVES: We report on a patient with an increase in testicular size that had been initially diagnosed as neoplasm. METHODS: The ultrasound and histological findings, the atypical clinical features and possible causes are analyzed. RESULTS: Segmental infarction with diffuse testicular atrophy. CONCLUSION: Infarction of testis may atypically present as a testicular mass that may lead us to suspect a testicular neoplasm since the age of presentation of both types of lesions are similar. PMID- 8678607 TI - [Complications of immunotherapy with BCG. Report of a case with retractile bladder]. AB - OBJECTIVES: We report a case of contracted bladder following BCG immunotherapy to prevent recurrence of a superficial bladder carcinoma. Other possible complications and their prevention are also discussed. METHODS: The patient had extreme contracted bladder and marked bilateral ureterohydronephrosis that required cystectomy and bladder substitution. The histopathological examination revealed detrusor muscle fibrosis without inflammation. RESULTS: Surgery achieved good results and the patient is disease-free 5 months postoperatively. CONCLUSIONS: The major complication that must be avoided is absorption following traumatic catheterization. Recognizing the early symptoms, particularly cystitis, together with adequate and early treatment of the localized effects can significantly reduce the incidence of severe toxicity. PMID- 8678608 TI - Percutaneous ureterolitholapaxy: the best bet to clear large bulk impacted upper ureteral calculi. AB - OBJECTIVES: The outcome of treating impacted upper ureteral calculi by extra corporeal shock wave lithotripsy was less satisfactory than antegrade litholapaxy in our earlier experience. During a four year period (October 1988 to September 1992) 86 reno-ureteral units with impacted upper ureteral calculi were treated by percutaneous litholapaxy. We review our methods and results of this accumulated experience. METHODS: Moderate to severe proximal hydronephrosis on excretory urography or ultrasound was taken as evidence of impaction. Antegrade extraction was performed in a single stage, except in patients who presented with anuria, severe azotemia and urosepsis where the system was decompressed by initial nephrostomy drainage. RESULTS: 86 impacted upper ureteral calculi in 80 patients were treated by the percutaneous antegrade approach. Eleven were in a solitary functioning unit; 33% presented with moderate to severe renal failure. The average stone size was 256 sq mm. Associated renal calculous disease was present in 22 ipsilateral and 28 contralateral units. Total clearance was achieved in 74 units (86%) by antegrade litholapaxy alone. Adjunct ESWL (5) and ureteroscopy (4) rendered 96% of the units free; 3 units with recurrent calculi were salvaged by ESWL (2) and ureterolithotomy (1). Complications encountered in 17 (20%) patients were fewer in 13 (16%), ureteric perforation in 7 (9%), hematuria in 6 (7%) and ureteric stricture 1 (1%). Hospital stay was 5 days in uncomplicated cases; prolongation of stay (average 8.8 days) was necessitated in staged procedures (sepsis, renal failure), treatment of the contralateral unit or due to postoperative morbidity. The majority of the stones (80%) were of the calcium oxalate monohydrate variety. CONCLUSION: It is concluded that failing a retrograde manipulation, percutaneous ureterolitholapaxy offers the best bet to clear large bulk impacted upper ureteral calculi. PMID- 8678609 TI - Chemoembolization for hepatocellular carcinoma. What, when, and for whom? PMID- 8678610 TI - Management of secondary peritonitis. AB - OBJECTIVE: The authors review current definition, classification, scoring, microbiology, inflammatory response, and goals of management of secondary peritonitis. SUMMARY BACKGROUND DATA: Despite improved diagnostic modalities, potent antibiotics, modern intensive care, and aggressive surgical treatment, up to one third of patients still die of severe secondary peritonitis. Against the background of current understanding of the local and systemic inflammatory response associated with peritonitis, there is growing controversy concerning the optimal antibiotic and operative therapy, intensified by lack of properly conducted randomized studies. In this overview the authors attempt to outline controversies, suggest a practical clinical approach, and highlight issues necessitating further research. METHODS: The authors review the literature and report their experience. RESULTS: The emerging concepts concerning antibiotic treatment suggest that less-in terms of the number of drugs and the duration of treatment-is better. The classical single operation for peritonitis, which obliterates the source of infection and purges the peritoneal cavity, may be inadequate for severe forms of peritonitis; for the latter, more aggressive surgical techniques are necessary to decompress increased intra-abdominal pressure and prevent or treat persistent and recurrent infection. The widespread acceptance of the more aggressive and demanding surgical methods has been hampered by the lack of randomized trials and reportedly high associated morbidity rates. CONCLUSIONS: Sepsis represents the host's systemic inflammatory response to bacterial peritonitis. To improve results, both the initiator and the biologic consequences of the peritoneal infective-inflammatory process should be addressed. The initiator may be better controlled in severe forms of peritonitis by aggressive surgical methods, whereas the search for methods to abort its systemic consequences is continuing. PMID- 8678611 TI - A prospective randomized trial comparing R1 subtotal gastrectomy with R3 total gastrectomy for antral cancer. PMID- 8678612 TI - Preoperative chemoradiotherapy for rectal cancer. PMID- 8678613 TI - Laparoscopic splenectomy in patients with hematologic diseases. AB - OBJECTIVE: The authors review their initial experience with laparoscopic splenectomy in patients with hematologic diseases. Efficacy, morbidity, and mortality of the technique are presented, and other patient recovery parameters are discussed. SUMMARY BACKGROUND DATA: Laparoscopic splenectomy is performed infrequently and data regarding its safety and efficacy are scarce. Factors such as a high level of technical difficulty, the potential for sudden, severe hemorrhage, and slow accrual of operative experience due to a relatively limited number of procedures are responsible. The potential patient benefits from the development of a minimally invasive form of splenectomy are significant. METHODS: Clinical follow-up, a prospective longitudinal database, and review of medical records were analyzed for all patients referred for elective splenectomy for hematologic disease from March 1992 to March 1995. RESULTS: Laparoscopic splenectomy was attempted in 43 patients and successfully completed in 35 (81%). Therapeutic platelet response to splenectomy occurred in 82% of patients with immune thrombocytopenic purpura and hematocrit level increased in 60% of patients with autoimmune hemolytic anemia undergoing successful laparoscopic splenectomy. The morbidity rate was 11.6% (5 of 43 patients), and the mortality rate was 4.7% (2 of 43 patients). Return of gastrointestinal function occurred in patients 23.1 hours after laparoscopic splenectomy and 76 hours after conversion to open splenectomy (p < 0.05). Mean length of stay was 2.7 days after laparoscopic splenectomy and 6.8 days after conversion to open splenectomy (p < 0.05). CONCLUSION: Laparoscopic splenectomy may be performed with efficacy, morbidity, and mortality rates comparable to those of open splenectomy for hematologic diseases, and it appears to retain other patient benefits of laparoscopic surgery. PMID- 8678614 TI - Accurate localization and surgical management of active lower gastrointestinal hemorrhage with technetium-labeled erythrocyte scintigraphy. AB - OBJECTIVE: There is disagreement over the reliability of technetium Tc 99m (99mTc)-labeled erythrocyte scintigraphy in the localization of active lower gastrointestinal hemorrhage. A previous study at The New York Hospital-Cornell Medical Center that showed a superior sensitivity for localization of scintigraphy versus angiography in surgical patients led the authors to emphasize scintigraphy as the diagnostic test of first choice in the clinical diagnostic algorithm. The authors hypothesized that tagged erythrocyte scintigraphy can be used accurately as the primary diagnostic modality in localizing acute bleeding and guiding surgical intervention. METHODS: The authors conducted a 5-year, retrospective analysis of 224 inpatients who underwent scintigraphic imaging for diagnosis and localization of active lower gastrointestinal bleeding. Using scintigraphy as the primary diagnostic test, with colonoscopy, upper endoscopy, and angiography as adjunctive studies, 99mTc-labeled erythrocyte scans were performed at the clinician's discretion and were reviewed again for study purposes by two nuclear radiologists who were blinded to clinical outcome. Adjunctive diagnostic tests also were ordered for clinical indications. RESULTS: Using delayed periodic scintigraphic imaging, results of 115 scans (51.3%) demonstrated bleeding, with 96 scans (42.9%) localizing to a specific anatomic site. Patients with positive scans were five times more likely to require surgery (p < 0.005) than patients with negative scans, and surgical patients were twice as likely to localize by scintigraphy (p < 0.0001). Fifty patients (22.3%) required surgical intervention to control hemorrhage and had a bleeding site confirmed by both clinical and pathologic examinations. Forty-eight of those patients (96%) had a bleeding site determined preoperatively. For 37 patients with bleeding sites localized preoperatively by scintigraphy, 36 (97.3%) had correct localization based on surgical pathology. Only one patient required a subtotal colectomy solely because of nonlocalized bleeding. No patient bled postoperatively, and there was no mortality in either operated or nonoperated patients. The mean volume of transfused erythrocytes was similar in both scan localized and nonlocalized surgical patients. CONCLUSION: When performed correctly and interpreted conservatively, scintigraphy is a useful and safe means of guiding segmental resection, and should be the primary tool used in the diagnosis of patients with active lower gastrointestinal bleeding. PMID- 8678615 TI - Total gastrectomy. Updated operative mortality and long-term survival with particular reference to patients older than 70 years of age. AB - OBJECTIVE: The authors conducted a study of patients who underwent total gastrectomy for gastric malignancy to elucidate contributing factors that lead to successful management of this disease in geriatric patients. SUMMARY BACKGROUND DATA: The average mortality rate for patients undergoing stomach surgery due to carcinoma is 7.8% according to the literature overview, still relatively high. Even higher mortality rates are observed for geriatric patients after a total gastrectomy. Because of epidemiologic changes, a total gastrectomy is required with growing frequency in these high-risk patients. METHODS: The study involved 380 patients with a gastric malignancy. Risks and benefits of a total gastrectomy with radical lymphadenectomy at an advanced age were analyzed retrospectively in 163 patients older than 70 years of age. The results achieved in these patients were compared with those observed in 217 younger patients. RESULTS: The 30-day mortality and morbidity rates for the elderly patients were 3% and 33.7%, respectively; for the younger patients, they were 0.46% and 21.2%, respectively. A statistically significant correlation was found between the presence of risk factors, the occurrence of complications, and the mortality rate. No difference was seen between the two age groups when risk factors were absent. The 5-year survival rate was 30%, with no difference between young and elderly patients. CONCLUSIONS: The data prove that a total gastrectomy with a radical lymphadenectomy can be carried out safely in older patients, with long-term results comparable to those achieved in younger patients. PMID- 8678616 TI - Is preoperative hepatic arterial chemoembolization safe and effective for hepatocellular carcinoma? AB - OBJECTIVE: The value of preoperative transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) has not been duly appreciated. The authors assessed the advantages and disadvantages of preoperative TACE by reviewing their experience with the procedure. METHODS: A total of 140 patients who underwent hepatectomy for HCC were entered into the study (105 received preoperative TACE and 35 did not). The authors investigated the reduction of tumor size and the complications after TACE, as well as the relationship between the interval from TACE to resection and the occurrence of complications. They compared postoperative morbidity and mortality between the TACE and non-TACE groups. They also compared survival and disease-free survival between the two groups, as well as between subgroups, defined by the extent of tumor necrosis achieved with TACE. RESULTS: A distinct reduction of tumor size was observed in approximately half of the TACE group. However, there were 68 appreciable complications of TACE in 56 patients (53.3%), and the interval between TACE and resection was significantly prolonged in the patients with complications. The postoperative morbidity and mortality rates of the TACE group were not different from those of the non-TACE group. Preoperative TACE did not improve the survival or disease-free survival of the whole patient group after hepatectomy. In addition, the survival and disease-free survival rates of the three TACE subgroups were not different from those of the non-TACE group. CONCLUSIONS: Preoperative TACE should only be performed to reduce tumor bulk in patients with HCC with borderline resectability. In such patients, increased tumor resectability appears to improve the survival rate. Preoperative TACE does not promote tumor recurrence. PMID- 8678617 TI - Proximal gastric vagotomy. Comparison between open and laparoscopic methods in the canine model. AB - OBJECTIVE: The authors compared open and laparoscopic proximal gastric vagotomies for efficacy of acid reduction and preservation of gastric emptying. SUMMARY BACKGROUND DATA: Laparoscopic methods have been used to perform vagotomy in patients with duodenal ulcer; however, no direct comparisons are available of laparoscopic and open surgical procedures regarding acid reduction and gastric emptying. METHODS: Thirty-one consecutive dogs were randomized to open proximal gastric vagotomy (OPGV; n = 11), laparoscopic anterior seromyotomy and posterior truncal vagotomy (ASPTV; n = 10), or laparoscopic proximal gastric vagotomy (LPGV; n = 10). Intraoperative endoscopic Congo red testing assured complete vagotomy. Basal acid output (BAO) and maximal acid output (MAO) during pentagastrin and insulin-induced hypoglycemia were measured with marker dilution techniques, and gastric emptying was assessed with radionuclide-labelled solid and liquid markers before and 5 weeks after operation. RESULTS: Operative time (mean +/- standard error of the mean) for OPGV was shorter compared with ASPTV and LPGV (86 +/- 7 minutes vs. 124 +/- 7 minutes and 115 +/- 7 minutes; p < 0.002). Postoperative BAO did not decrease in any group. Open proximal gastric vagotomy and LPGV, but not ASPTV, decreased MAO (p < 0.05); (after pentagastrin, OPGV from 26.4 +/- 1.7 mEq/hour to 11.3 +/- 0.1 mEq/hour, LPGV from 21.4 +/- 1.0 mEq/hour to 6.4 +/- 0.5 mEq/hour; after insulin-induced hypoglycemia, OPGV from 9.9 +/- 0.5 mEq/hour to 2.2 +/- 0.3 mEq/hour, LPGV from 7.9 +/- 0.5 mEq/hour to 1.9 +/- 0.4 mEq/hour). Gastric emptying of liquids and solids, as quantitated by the time for one half of the marker to empty (T 1/2) and the shape of the emptying curve, were similar before and after all three surgical procedures. CONCLUSIONS: Laparoscopic proximal gastric vagotomy was comparable to OPGV in decreasing stimulated gastric acid production without significantly altering gastric emptying. Anterior seromyotomy and posterior truncal vagotomy was less effective in decreasing MAO and required more operative time. Laparoscopic proximal gastric vagotomy has the potential to become accepted therapy for patients with duodenal ulcer managed presently with OPGV. PMID- 8678618 TI - Dysphagia after laparoscopic antireflux surgery. The impact of operative technique. AB - BACKGROUND: Concerns about laparoscopic antireflux surgery include the frequent appearance of troublesome postoperative dysphagia. This study reviews the frequency of early (less than 6 weeks) and persistent (greater than 6 weeks) solid food dysphagia in patients undergoing Toupet, Rosetti-Nissen, or Nissen fundoplications. METHODS: One hundred eighty-four consecutive patients with normal esophageal peristalsis undergoing laparoscopic antireflux surgery were prospectively studied. Before operation, all patients had endoscopy, 24-hour pH study, and an esophageal motility study. The choice of operation was dependent on anatomy and surgeon preference. Before discharge, all patients were given instructions on a soft diet. Postoperative symptoms were scored by the patients as absent, mild, moderate, or severe 4 weeks and 12 weeks after operation. The option of esophageal dilation was offered to patients with moderate to severe persistent solid food dysphagia. RESULTS: New onset moderate to severe dysphagia to solid foods was present in 30 (54%), 8 (17%), and 13 (16%) patients undergoing Rosetti-Nissen, Nissen, and Toupet fundoplications, respectively, in the first month after operation (p < 0.001). Moderate to severe dysphagia persisted at 3 months in six (11%), one (2%), and two (2%) patients undergoing laparoscopic Rosetti-Hell, Nissen, and Toupet fundoplications, respectively (p < 0.05). Esophageal dilatation was performed in five (4%), zero, and one (1%) patients undergoing laparoscopic Rosetti-Nissen, Nissen, and Toupet fundoplications, respectively (p < 0.05). There was no additional morbidity related to division of short gastric vessels in patients undergoing Nissen fundoplication. CONCLUSIONS: Laparoscopic Rosetti-Nissen fundoplication is associated with a higher rate of early and persistent postoperative dysphagia than either laparoscopic Nissen fundoplication or Toupet fundoplication. Consideration of complete fundus mobilization should be a part of all laparoscopic antireflux procedures. PMID- 8678619 TI - Randomized comparison of straight and colonic J pouch anastomosis after low anterior resection. AB - OBJECTIVE: The authors compared clinical bowel function and complications of a low anterior resection with either a straight or colonic J pouch anastomosis. SUMMARY BACKGROUND DATA: Urgency and frequent bowel movements after rectal resection with a low anastomosis have been related to the loss of rectal reservoir function. Reconstruction with a colonic J pouch possibly can obviate some of this dysfunction. Earlier reports have been favorable, but they must be verified in randomized trials. METHOD: One hundred patients with rectal cancer in whom a sphincter-saving procedure was appropriate were randomized to reconstruction with either a straight or a colonic J pouch anastomosis. RESULTS: The incidence of symptomatic anastomotic leakage was lower in the pouch group (2% vs. 15%, p = 0.03). Eighty-nine patients could be evaluated after 1 year. The pouch patients had significantly fewer bowel movements per 24 hours, and less nocturnal evacuations, urgency, and incontinence. Overall well-being owing to the bowel function was rated significantly higher by the pouch patients. CONCLUSION: Reconstruction with a colonic J pouch was associated with a lower incidence of anastomotic leakage and better clinical bowel function when compared with the traditional straight anastomosis. Functional superiority was especially evident during the first 2 months. PMID- 8678620 TI - Barrett's esophagus with high-grade dysplasia. An indication for prophylactic esophagectomy. AB - OBJECTIVE: The authors review the results and outcomes of esophagectomy (prophylactic esophagectomy) for patients with Barrett's esophagus and high-grade epithelial dysplasia (HGD). SUMMARY BACKGROUND DATA: The role of prophylactic esophagectomy for Barrett's esophagus with HGD is controversial, with some authors recommending surgery and others favoring endoscopic surveillance until biopsy diagnosis of carcinoma is made. METHODS: Between 1982 and 1994, 30 consecutive patients with HGD underwent esophagectomy and had the pre- and postoperative pathology reviewed at our institution. The medical records were reviewed to determine patient characteristics, preoperative endoscopic data, surgical approach, operative morbidity and mortality, length of hospitalization, and treatment outcome. Patients were divided into two groups based on whether invasive adenocarcinoma was found in the resection specimen (group 1) or not (group 2). RESULTS: The duration of reflux symptoms was 22 +/- 14 years for group 1 and 9 +/- 11 years for group 2 (p = 0.05). There was one operative death (3.3%) and six complications (20%). In 13 patients (43%, group 1), invasive adenocarcinoma was found in the resected esophagus. The American Joint Committee on Cancer stage for these patients was stage I (8 patients), stage II (2 patients), and stage III (3 patients). One stage I patient died of adenocarcinoma (72 months) in an incompletely excised HGD segment. Other stage I and II patients are alive without adenocarcinoma with an 18-and 63-month mean follow-up, respectively. Outcome for stage III patients was one operative death, one noncancer death (6 months), and one patient with metastatic adenocarcinoma (26 months). For group 2 (57%), there were no adenocarcinoma deaths (40 months). CONCLUSIONS: High-grade epithelial dysplasia is an indication for esophagectomy because of the prevalence of occult adenocarcinoma (43%). Esophagectomy can be performed safely, and survival in patients with completely resected Barrett's esophagus and early-stage adenocarcinoma is excellent. PMID- 8678622 TI - The retained surgical sponge. AB - OBJECTIVE: A review was performed to investigate the frequency of occurrence and outcome of patients who have retained surgical sponges. METHODS: Closed case records from the files of the Medical Professional Mutual Insurance Company (ProMutual, Boston, MA) involving a claim of retained surgical sponges were reviewed for a 7-year period. RESULTS: Retained sponges occurred in 40 patients, comprising 48% of all closed claims for retained foreign bodies. A falsely correct sponge count after an abdominal procedure was documented in 76% of these claims. Ten percent of claims involved vaginal deliveries and minor non-body cavity procedures, for which no sponge count was performed. Total indemnity payments were $2,072,319, and defense costs were $572,079. In three cases, the surgeon was deemed responsible by the court despite the nursing staff's admitting liability and evidence presented that the surgeon complied completely with the standard of care. A wide range of indemnity payments was made despite a remarkable similarity of outcome in the patients studied. CONCLUSIONS: Despite the rarity of the reporting of a retained surgical sponge, this occurrence appears to be encountered more commonly than generally is appreciated. Operating teams should ensure that sponges be counted for all vaginal and any incisional procedures at risk for retaining a sponge. In addition, the surgeon should not unquestioningly accept correct count reports, but should develop the habit of performing a brief but thorough routine postprocedure wound/body cavity exploration before wound closure. The strikingly similar outcome for most patients would argue for a standardized indemnity payment being made without the need for adversarial legal procedures. PMID- 8678621 TI - Spontaneous hepatic hemorrhage associated with pregnancy. Treatment by hepatic arterial interruption. AB - OBJECTIVE: The authors determined the effectiveness of hepatic arterial interruption in treating patients with spontaneous hepatic hemorrhage associated with pregnancy. BACKGROUND DATA: This rare syndrome frequently is seen with eclampsia/preeclampsia and is associated with high maternal mortality. The recommended treatment has been the use of local hemostatic measures. METHODS: The authors reviewed their experience managing eight patients by hepatic arterial interruption. RESULTS: Operative hepatic artery ligation was the initial method of controlling hepatic hemorrhage in three patients. One patient recovered, a hepatic sequestrum developed in one, and one patient died. Three patients survived after hepatic arterial embolization, but a sequestrum developed in one. Two patients died when hepatic arterial interruption was used after failed local hemostatic measures. CONCLUSIONS: The authors believe that hepatic arterial interruption is the preferred treatment for spontaneous hepatic hemorrhage associated with pregnancy. If the diagnosis is made at the time of cesarean section delivery, operative hepatic arterial ligation is indicated. If the diagnosis is made postpartum, percutaneous angiographic embolization should be performed. PMID- 8678623 TI - A prospective study of laparoscopic spinal fusion. Technique and operative complications. AB - OBJECTIVE: The authors hypothesized that anterior transperitoneal laparoscopic interbody fusion was feasible and safe. SUMMARY BACKGROUND DATA: Low back pain associated with degenerative disc disease is optimally treated with distraction of the disc space and permanent fusion of the adjacent vertebral bodies. Exposure usually is obtained by a posterior muscle-splitting incision. Although the posterior approach is effective, the procedure results in significant debility secondary to the muscle splitting incision, a 4- to 6-day inpatient hospital stay, and the loss of employment for 3 to 6 months after the procedure. METHODS: Twenty consecutive patients with discogenic back pain were prospectively treated with laparoscopic anterior lumbar instrumentation and fusion. The anterior L5-S1 or L4-L5 disc spaces were exposed laparoscopically. Distraction of the disc space and fixation were achieved by insertion of a threaded titanium cage packed with cancellous bone. RESULTS: Three technical complications occurred all in the first four patients and required two conversions to open transperitoneal fusion. Hospital stay for the patients treated by laparoscopic instrumentation and fusion averaged 1.7 days. Twelve of 20 patients reported excellent pain relief and returned to work in 3 to 8 weeks. No motion was identified in the 16 patients who obtained flexion extension radiographs at 6 months. CONCLUSIONS: Laparoscopic transperitoneal anterior lumbar instrumentation and fusion is safe, and the early results are encouraging. PMID- 8678624 TI - CD14 expression in injured patients correlates with outcome. AB - OBJECTIVE: The authors determined the correlation between monocyte CD14 expression and outcome in severely injured patients. SUMMARY BACKGROUND DATA: Human leukocyte antigen-DR (HLA-DR) expression CD14 positive monocytes correlates with the development of major infection and subsequent death in severely injured patients. Recent studies show that CD14 is not only a marker for mature monocytes, but also is an important endotoxin/lipopolysaccharide receptor. METHODS: Flow cytometry data obtained by dual staining techniques (CD14 and HLA DR) of monocytes in 213 severely injured patients were analyzed over a 30-day period. Outcome criteria included survival and the development of both major and minor infections. RESULTS: The percentage of cells expressing CD14 (%CD14) correlated with clinical outcome, reaching significance (p < 0.05) between noninfected survivors (n = 74) and nonsurvivors (n = 21) at days 3, 7, 11, 17, 24, and 30. At days 3, 7, and 17, the %CD14 also was different between noninfected and infected survivors. After 7 days, differences were only seen between survivors and nonsurvivors (p < 0.05). The mean fluorescence intensity (MC CD14) in monocytes of all patients was significantly reduced at day 3 compared with day 1 and remained low for 30 days (p < 0.05). The nonsurvivor group had consistently low MC CD14 values, which were significant at day 5 (p < 0.05). CONCLUSIONS: In addition to HLA-DR expression, CD14 expression on monocytes is an indicator of clinical outcome after injury and could represent a more precise target for treatment. PMID- 8678625 TI - Lactic acidosis during sepsis is related to increased pyruvate production, not deficits in tissue oxygen availability. AB - OBJECTIVE: The purpose of this study was to quantitate the derangements in intermediary carbohydrate metabolism and oxygen use in severely septic patients in comparison with healthy volunteers. SUMMARY BACKGROUND DATA: It commonly has been assumed that the development of lactic acidosis during sepsis results from a deficit in tissue oxygen availability. Dichloroacetate (DCA), which is known to increase pyruvate oxidation but only when tissue oxygen is available, provides a means to assess the role of hypoxia in lactate production. METHODS: Stable isotope tracer methodology and indirect calorimetry was used to determine the rates of intermediary carbohydrate metabolism and oxygen use in five severely septic patients with lactic acidosis and six healthy volunteers before and after administration of DCA. RESULTS: Oxygen consumption and the rates of glucose and pyruvate production and oxidation were substantially greater (p < 0.05) in the septic patient compared with healthy volunteers. Administration of DCA resulted in a further increase in oxygen consumption and the percentage of glucose and pyruvate directed toward oxidation. Dichloroacetate also decreased glucose and pyruvate production, with a corresponding decrease in plasma lactate concentration. CONCLUSIONS: These findings clearly indicate that the accumulation of lactate during sepsis is not the result of limitations in tissue oxygenation, but is a sequelae to the markedly increased rate of pyruvate production. Furthermore, the substantially higher rate of pyruvate oxidation in the septic patients refutes the notion of a sepsis-induced impairment in pyruvate dehydrogenase activity. PMID- 8678626 TI - Transplantation as a primary treatment for hypoplastic left heart syndrome: intermediate-term results. AB - BACKGROUND: Hypoplastic left heart syndrome is a lethal malformation. For the last 10 years, orthotopic cardiac transplantation has been our preferred treatment for infants with hypoplastic left heart syndrome. METHODS: One hundred seventy-six infants with hypoplastic left heart syndrome were entered into a cardiac transplant protocol between November 1985 and November 1995. Interventional procedures to stent the ductus arteriosus or enlarge the interatrial communication were performed in 8 and 35 patients, respectively. Thirty-four patients (19%) died during the waiting period, and 142 infants underwent cardiac transplantation. Age at cardiac transplantation ranged from 1.5 hours to 6 months (median, 29 days). The majority of grafts were oversized, and the median graft ischemic time was 273 minutes (range, 60 to 576 minutes). The implantation procedure used a period of hypothermic circulatory arrest ranging from 23 to 110 minutes (median, 53 minutes). Repair of other significant defects included interrupted aortic arch and total or partial anomalous pulmonary venous connection. RESULTS: There were 13 early and 22 late deaths. Patient actuarial survival at 1 month and at 1, 5 and 7 years was 91%, 84%, 76%, and 70% respectively. Half of the late deaths were due to rejection. Severe graft vasculopathy was confirmed in 8 patients. Retransplantation was performed in 5 patients for graft vasculopathy 4 and rejection 1. Lymphoblastic leukemia developed in 1 patient 3 years after cardiac transplantation. CONCLUSIONS: Cardiac transplantation can be performed in infants with hypoplastic left heart syndrome with good operative and intermediate-term results. Improved survival can be achieved with increased donor availability, better management of rejection, and control of graft vasculopathy. PMID- 8678627 TI - Autotransfused shed mediastinal blood has normal erythrocyte survival. AB - BACKGROUND: Autotransfusion of shed mediastinal blood may reduce the need for homologous blood transfusions in cardiac surgery. In an earlier study we have shown that the red blood cells (RBCs) of shed mediastinal blood have a normal membrane stability (osmotic fragility) compared with circulating RBCs after coronary artery bypass grafting and better than stored RBCs. This indicates that RBCs in shed mediastinal blood are not damaged further during salvage. It remains to be determined how autotransfusion affects the survival of RBCs from shed mediastinal blood. METHODS: We performed a prospective, randomized, and controlled study involving 26 patients having elective, uncomplicated coronary artery bypass grafting. Dual-isotope labeling technique (chromium 51 and technetium 99m) was used to investigate the 24-hour survival of RBCs from shed mediastinal blood and RBCs from circulating blood, and to estimate the mean survival time of RBCs. RESULTS: There was no significant difference between the 24-hour survival of shed mediastinal RBCs and circulating RBCs. The estimated mean cell lifespan was 20.5 days (range, 11.6 to 29.0 days) for shed mediastinal RBCs and 22.7 days (range, 14.4 to 36.2 days) for circulating RBCs. CONCLUSIONS: The survival of RBCs from shed mediastinal blood after autotransfusion is comparable with the survival of RBCs in the patients' circulating blood. PMID- 8678628 TI - Impact of transfusion of mediastinal shed blood on serum levels of cardiac enzymes. AB - BACKGROUND: Infusion of shed mediastinal blood using an autotransfusion system is a widely applied technique of blood conservation in cardiac surgery. Serial determinations of serum creatine kinase (CK), its MB isoenzyme (CK-MB), and lactate hydrogenase (LDH) levels have been used to monitor perioperative myocardial injury. We investigated the impact of postoperative autotransfused blood infusion on serum levels of these enzymes. METHODS: We performed a retrospective analysis of postoperative serum CK, CK-MB, and LDH levels of 300 patients who had elective uncomplicated aortocoronary bypass grafting. Shed mediastinal blood samples from 26 patients were analyzed for CK, CK-MB (enzymatic activity and mass), and LDH levels before infusion. RESULTS: High postoperative serum levels of CK and LDH were observed after infusion of autotransfused blood. Shed mediastinal blood contained extremely high levels of these enzymes, particularly from patients who had internal mammary artery dissection. There was a strong correlation (r = 0.96) between measured CK-MB enzyme activities and those calculated from the CK-MB mass units. CONCLUSIONS: Infusion of autotransfused blood containing high concentrations of CK and LDH results in elevated serum levels of these enzymes. Hemolysis, frequently present in shed blood, does not interfere with the routine biochemical assays for CK and CK-MB enzyme activities. Caution should be taken when postoperative cardiac enzyme levels are used to determine myocardial injury after aortocoronary bypass grafting if autotransfusion is used as a method of blood conservation. PMID- 8678629 TI - Influence of age on cerebral recovery after deep hypothermic circulatory arrest in piglets. AB - BACKGROUND: In the first weeks of life there are important maturational changes in the central nervous system in many species in energy metabolism, synapse number, and concentration of neuronal excitatory receptors. METHODS: Four groups of 10 piglets (aged 1, 2, 4, and 10 weeks) underwent 1 hour of deep hypothermic circulatory arrest at 15 degrees C, with cooling and rewarming on cardiopulmonary bypass. Cerebral blood flow and metabolic rate measurements and electroencephalographic recordings were obtained from 5 animals per group. The remaining animals underwent cerebral magnetic resonance spectroscopy. RESULTS: Preoperative cerebral blood flow and glucose consumption were higher at 4 and 10 weeks than at 1 and 2 weeks. Cerebral adenosine triphosphate content decreased more rapidly during deep hypothermic circulatory arrest at 4 and 10 weeks. Phosphocreatine recovery was greater at 30 minutes of reperfusion at 10 weeks compared with 1 week. Recovery of cerebral phosphocreatine/ adenosine triphosphate ratio and intracellular pH was remarkably uniform at all ages. Latency to recovery of electroencephalographic activity decreased with increasing age (p = 0.04). CONCLUSIONS: Differences in acute recovery of brain energy metabolism and electroencephalogram after cardiopulmonary bypass and 1 hour of deep hypothermic circulatory arrest in piglets between 1 and 10 weeks of age are small. Further studies are required to correlate these acute findings with subsequent neurologic outcome. PMID- 8678630 TI - Correction of truncus arteriosus with autologous arterial flap in neonates and small infants. AB - BACKGROUND: This study describes the results of techniques using the autologous truncal wall and part of the pulmonary artery for correction in anticipation of the growth of the pulmonary tract in patients with truncus arteriosus. METHODS: Seven consecutive patients with truncus arteriosus were reviewed. The posterior wall of the pulmonary tract was obtained by anastomosing the lower edge of the truncal arteriotomy to the upper corner of the ventriculotomy from the truncus in types I and II. Anterior translocation of the pulmonary artery was performed in a type III. A pericardial patch with or without a monocusp was placed to complete the right ventricular outflow tract. RESULTS: There were two hospital deaths, one of which was unrelated to a cardiac problem. Postoperative right-to-left ventricular peak pressure ratio was less than 0.55. There was one left pulmonary stenosis due to monocusp adherence in the late postoperative period. The sizes of the pulmonary tract at anastomosis were between 107% and 166% of the normal value between 7 months and 3.8 years of follow-up. CONCLUSIONS: The use of autologous arterial wall instead of a conduit is recommended for the repair of truncus arteriosus to expect growth of the pulmonary tract. PMID- 8678631 TI - Normothermic versus hypothermic cardiopulmonary bypass: do changes in coagulation differ? AB - BACKGROUND: The differences between hypothermic and normothermic cardiopulmonary bypass (CPB) on platelet function and endothelial-related coagulation (eg, the thrombomodulin/protein C/protein S system) should be investigated. METHODS: According to a randomized sequence, 30 patients undergoing aortocoronary bypass grafting underwent either hypothermic (rectal temperature, 27 degrees C to 28 degrees C, n = 15) or normothermic CPB (rectal temperature, more than 35 degrees C, n = 15). Arterial blood samples were taken after induction of anesthesia (baseline values), before, during, and immediately after CPB, 5 hours after CPB, and on the morning of the first postoperative day. Circulating thrombomodulin, (free) protein S, protein C, and thrombin/antithrombin III complex were measured from these samples. Platelet function was assessed by aggregometry (turbidometric technique) induced by adenosine diphosphate (2 mumol/L), collagen (4 micrograms/L), and epinephrine (25 mumol/L). RESULTS: Hypothermic patients showed a significantly higher blood loss and need for homologous blood than the normothermic patients. Thrombomodulin plasma level increased more in the hypothermic (from 28 +/- 5 ng/mL to 60 +/- 10 ng/mL) than in the normothermic group (from 28 +/- 7 ng/mL to 41 ng/mL); p < 0.05). Both protein C and (free) protein S were reduced significantly in the hypothermic (protein C, from 88% +/- 25% to 60% +/- 11%; protein S, from 71% +/- 10% to 40% +/- 8%) than in the normothermic patients. Platelet aggregation was significantly more decreased in the hypothermic (adenosine diphosphate, maximum decrease by -43% relative to baseline) than in the normothermic patients (adenosine diphosphate, maximum decrease by -22% relative to baseline). In the hypothermic CPB group, platelet aggregation had recovered incompletely, whereas in the normothermic patients platelet aggregation even slightly exceeded baseline values. CONCLUSIONS: Hypothermic CPB resulted in more pronounced alterations of platelet aggregation and endothelial-related coagulation than normothermic CPB. Plasma levels of soluble thrombomodulin were more increased in hypothermic than in normothermic CPB indicating more extensive endothelial damage or activation associated with hypothermic CPB. PMID- 8678632 TI - Absent pulmonary valve syndrome: surgical treatment and considerations. AB - BACKGROUND: The operative management of absent pulmonary valve syndrome remains controversial regarding the need for pulmonary valve implantation and remodeling of pulmonary arteries. Moreover, symptomatic infants are considered to have a poor prognosis. This retrospective report summarizes the experience of a single institution. METHODS: Between May 1977 and May 1995, 37 consecutive patients underwent repair of absent pulmonary valve syndrome. Patients were divided into two groups according to age at operation: group A (10 infants less than 1 year old) and group B (27 patients older than 1 year). Mean age at operation was 5 +/- 4 months in group A and 72 +/- 42 months in group B. Initially, repair consisted of ventricular septal defect closure and relief of right ventricular outflow tract obstruction combined with pulmonary valve implantation. More recently, the concept of treatment has evolved with pulmonary arterioplasty without pulmonary valve insertion, except in patients with elevated pulmonary artery pressure. RESULTS: Of the 37 patients, 34 had successful repair. The overall in-hospital mortality rate was 8% (two deaths in group A and one in group B). No hemodynamic data were correlated with operative death. Death was associated with longer extracorporeal circulation time (p = 0.005) and longer aortic cross-clamping time (p = 0.019). In fact, these were clearly related to more complex anatomy (p = 0.001): multiple ventricular septal defects in 1, left pulmonary artery arising from the ductus in another, and left pulmonary artery arising from the aorta in the remainder. Follow-up was available in 22 of the 34 survivors. Mean follow-up time was 30 +/- 47 months in group A and 38 +/- 33 months in group B. All but 1 had no restriction of exercise, and most of them had pulmonary incompetence of Doppler echocardiography. One developed severe exercise intolerance because of pulmonary valve stenosis (xenograft), leading to uneventful reoperation 123 months after initial repair. One infant died suddenly of complete atrioventricular block 3 months after repair. The late mortality rate was 5%. CONCLUSIONS: Surgical treatment of absent pulmonary valve syndrome should include pulmonary arterioplasty to reduce bronchial obstruction, with no need for pulmonary valve insertion. This procedure is feasible and is recommended especially in markedly symptomatic infants. PMID- 8678633 TI - Cardiac surgical conditions induced by beta-blockade: effect on myocardial fluid balance. AB - BACKGROUND: Both crystalloid and blood cardioplegia result in cardiac dysfunction associated with myocardial edema. This edema is partially due to the lack of myocardial contraction during cardioplegia, which stops myocardial lymph flow. As an alternative, acceptable surgical conditions have been created in patients undergoing coronary artery bypass operations with esmolol-induced minimal myocardial contraction. We hypothesized that minimal myocardial contraction during circulatory support using either standard cardiopulmonary bypass (CPB) or a biventricular assist device would prevent myocardial edema by maintaining cardiac lymphatic function and thus prevent cardiac dysfunction. METHODS: We placed 6 dogs on CPB and 6 dogs on a biventricular assist device and serially measured myocardial lymph flow rate and myocardial water content in both groups and preload recruitable stroke work only in the CPB dogs. In all dogs we minimized heart rate with esmolol for 1 hour during total circulatory support. RESULTS: Although myocardial lymph flow remained at baseline level during CPB and increased during biventricular assistance, myocardial water accumulation still occurred during circulatory support. However, as edema resolved rapidly after separation from circulatory support, myocardial water content was only slightly increased after CPB and biventricular assistance, and preload recruitable stroke work was normal. CONCLUSIONS: Our data suggest that minimal myocardial contraction during both CPB and biventricular assistance supports myocardial lymphatic function, resulting in minimal myocardial edema formation associated with normal left ventricular performance after circulatory support. The concept of minimal myocardial contraction may be a useful alternative for myocardial protection, especially in high-risk patients with compromised left ventricular function. PMID- 8678634 TI - Partial atrioventricular canal with congestive heart failure in the first year of life: surgical options. AB - BACKGROUND: An important subgroup of patients with partial atrioventricular canal require an operation in the first year of life because of refractory congestive heart failure. METHODS: From June 1982 to April 1995, of 128 patients with partial atrioventricular canal, 35 patients (27%) underwent surgical treatment at less than 1 year of life. Associated cardiac anomalies were present in 22 patients. Only 7 patients (20%) had Down's syndrome. Five patients with left ventricular hypoplasia underwent aortic coarctectomy (3 patients) or Norwood operation (2 patients). The other 30 patients underwent anatomic repair in 24 cases and aortic coarctectomy in 6. The surgical results of patients submitted for anatomic repair were retrospectively correlated with the echocardiographic mitral valve diameter. RESULTS: There were 7 deaths (29%) after anatomic repair, 2 (22%) after aortic coarctectomy, and 2 (100%) after Norwood operation. Infants with a mitral valve diameter less than 2.5 x 10-2 m/m2 died at repair. In a mean follow-up of 73.5 months there were five secondary mitral valve plasties and three repairs after aortic coarctectomy. CONCLUSIONS: Among patients with partial atrioventricular canal, there is an important subgroup with clinical signs of heart failure in the first year of life. Left-sided obstructive lesions and complex mitral valve anomalies seem to play a fundamental role in the clinical evolution and prognosis of these patients. The echocardiographic mitral valve diameter may be useful for determining the correct surgical indication. PMID- 8678635 TI - Long-term follow-up of autologous pericardial valved conduits. AB - BACKGROUND: The aim of this study was to evaluate the long-term results of the use of an autologous pericardial valved conduit in the outflow tract of the venous ventricle in congenital heart malformations. METHODS: Fifty-one patients were followed up for a period of 12 to 120 months; 30 for more than 36 months and 13 for more than 72 months. All were evaluated clinically and by two-dimensional and Doppler echocardiography. Eight patients were recatheterized. Postoperative evaluation included serial measurement of pressure gradients and the conduit's diameter at the proximal, valvular, and distal levels. Reoperation because of stenosis was indicated when the gradient across the right ventricular outflow was greater than 50 mm Hg. The reoperation rate in relation with postoperative time, diameter of the autologous pericardial valved conduit at the time of implantation, and malformation was statistically analyzed. RESULTS: In 27 patients the conduit increased its diameter 1 to 7 mm. In 20 patients the diameter remained unchanged, whereas a reduction was noted in 4. Conduit survival free of reoperation for the whole group was 89.9% at 5 years. Conduit survival free of reoperation was 100% at 5 and 7 years for conduits larger than 16 mm at the time of implantation. It was 95% (standard deviation = 4.8%) at 5 years and 72.3% at 7 years for those 16 mm or less. For patients operated after January 1, 1986 (technical modification), conduit survival free of reoperation was 95.4% at 7 years postoperatively. CONCLUSIONS: These results compare favorably with those of other available conduits. PMID- 8678636 TI - Internal thoracic artery for coronary artery grafting in octogenarians. AB - BACKGROUND: Use of the left internal thoracic artery as a bypass graft has been shown to result in better long-term patency and improved survival. In elderly patients, the internal thoracic artery has been used less often for coronary artery bypass grafts because of the belief that greater morbidity and mortality are associated with this procedure. This study was undertaken to test this premise in the octogenarian population. METHODS: Over an 8-year period, 474 consecutive patients 80 years of age and greater had coronary artery bypass grafting. The left internal thoracic artery was used in 188 patients (39.7%) (group 1) and saphenous vein grafts only (group 2), in 286 (60.3%). The mean age was 82.6 years (range, 80 to 95 years). There were 312 men (65.8%) and 162 women (34.2%). RESULTS: Use of the internal thoracic artery as a graft has risen steadily each year, as has the number of patients who are octogenarians. The hospital mortality rate was 7.8%. Patients in group 1 had a mortality rate of 9.0% and patients in group 2, a mortality rate of 7.0%. The mortality rate among survivors at 1 year was 6.7%. Long-term survival was significantly greater in group 1. CONCLUSIONS: On the basis of this study, we conclude that the internal thoracic artery is the bypass graft of choice, especially in regard to long-term mortality, and should not be denied to this high-risk group. PMID- 8678637 TI - Spontaneous acquisition of discontinuous pulmonary arteries. AB - BACKGROUND: Discontinuous pulmonary arteries have been considered a rare complication of systemic-to-pulmonary shunt operations. We report a series of children who spontaneously acquired pulmonary artery discontinuity. METHODS: All children from 1989 through 1995 with congenital pulmonary atresia were reviewed. RESULTS: Pulmonary artery discontinuity developed in 29% (15 patients), none related to shunt operation. In 6 of 15 patients, the neonatal angiogram showed a pattern that seemed to predict subsequent discontinuity; in 9 of 15, pulmonary arteriography was normal at birth. Two clinical patterns were identified: an early rapid acquisition of discontinuity within hours to days, and a delayed, more subtle development that occurred over months. Eight of 15 have died. Pathologic studies in 6 children showed ductal tissue extending along and into the pulmonary artery wall as well as intimal hypertrophic reaction and maladaptive remodeling. CONCLUSIONS: Children with congenital pulmonary atresia may experience spontaneous acquisition of pulmonary artery discontinuity. Ductal tissue is responsible for local pulmonary artery distortion and discontinuity; this may be exacerbated by previous prostaglandin E1 administration. Clinical algorithms are suggested for patients with pulmonary atresia. PMID- 8678638 TI - Calcification of bovine pericardium: glutaraldehyde versus No-React biomodification. AB - BACKGROUND: Calcific degeneration is the most frequent cause of clinical dysfunction of glutaraldehyde (GA)-pretreated bioprosthetic heart valves. The No React (NR) process has been shown to be a promising anticalcification treatment. In this comparative study, our objective was to delineate the advantages of the NR treatment over GA. METHODS: Bovine pericardial strips pretreated with GA and NR were individually incubated in calcium phosphate solution for 21 days at 37 degrees C. The pretreated bovine pericardium then was implanted subcutaneously in rats and retrieved at 14, 21, and 35 days after-implantation. Mineral and morphologic analyses were performed on each specimen. RESULTS: The NR-treated pericardium revealed significantly reduced in vitro calcification compared with the GA-treated tissue (mean tissue calcium content 1.3 +/- 0.2 versus 5.9 +/- 0.7 micrograms/mg; p < 0.001). Mineral analysis showed progressive calcification of the GA-pretreated pericardium over the period of implantation (calcium content increasing from 49.6 +/- 9.6 micrograms/mg after 2 weeks to 134.3 +/- 9.1 micrograms/mg at 5 weeks after-implantation). The NR-treated implants had calcified significantly less (p < 0.05) at each corresponding interval. Moreover, morphologic examinations demonstrated a protracted inflammatory response in the form of giant cell and mononuclear cell infiltration associated with intrinsic collagen disruption in the GA-treated tissue; the NR-treated pericardium maintained morphologic integrity with a mild inflammatory response. CONCLUSIONS: The NR biochemical process appears not only to attenuate pericardial calcification, but also to abort the host's destructive inflammatory response to the xenograft. PMID- 8678639 TI - Right anterolateral thoracotomy for repair of atrial septal defect. AB - BACKGROUND: To procure a cosmetic incision in female patients, we performed operation on atrial septal defects through a right anterolateral thoracotomy. METHODS: From 1984 to 1994, 80 female patients with a mean age of 24 +/- 13 years (ranging from 12 to 62 years) underwent right anterolateral thoracotomy for atrial septal defect repairs. Defects repaired included 62 ostium secundum, 12 sinus venosus, 2 low septal defect, and 4 ostium primum. The right iliac external artery was systematically used for arterial cannulation, through a cosmetic incision. Repairs were always performed under fibrillation, except in the 4 ostium primum defects, for which cardioplegia was used. RESULTS: There was no operative or late mortality, and no morbidity directly related to the thoracotomy approach. CONCLUSIONS: The right thoracotomy incision appears to be a safe and effective alternative to median sternotomy for repair of atrial septal defects. PMID- 8678640 TI - Results of represervation of the chordae tendineae during redo mitral valve replacement. AB - BACKGROUND: Previous studies have shown that preservation of the chordae tendineae improves early and late postoperative left ventricular function after mitral valve replacement. This report describes the results of represervation of the chordae tendineae during redo mitral valve replacement in patients who had their chordae tendineae preserved during their initial operation. METHODS: Fifty four patients undergoing reoperative mitral valve replacement with preservation of their chordal annular attachments (chordae group) were compared with 187 patients who had redo mitral valve replacement without preservation of the chordae (nonchordae group). The interval between the initial operation and the reoperation was 8.7 +/- 4.4 years in the chordae group and 8.6 +/- 4.9 years in the nonchordae group (p = 0.315). Seventy-three patients underwent aortic valve replacement during their redo mitral valve replacement compared with 168 patients who had mitral valve replacement alone. There were 15 patients who had their chordal attachments represerved during redo double-valve replacement. RESULTS: In the chordae group, intraoperative assessment revealed excellent chordal connection between the preserved papillary muscles and the mitral annulus in all patients. One patient had adhesions between the preserved chordae and the stent of the tissue valve. The chordal attachments were preserved during insertion of the second valve in all patients. The incidence of low output syndrome and operative mortality in the chordae group was 16.7% and 7.4%, respectively. In the nonchordae group, the incidence of low output syndrome was 27.3% (p = 0.112 compared with the chordae group) and the operative mortality was 13.4% (p = 0.236 compared with the chordae group). In patients with double-valve replacement, represervation of the chordae was associated with a reduction in low output syndrome (0% versus 24%; p = 0.034) and mortality (6.7% versus 15.5%; p = 0.374). CONCLUSIONS: Preservation of the chordal attachments between the papillary muscles and the mitral annulus can be accomplished during reoperative mitral valve replacement. Represervation of the chordae tendineae may reduce postoperative low output syndrome, especially in high-risk patients undergoing redo double-valve replacement. PMID- 8678641 TI - Impact of left ventricular dysfunction on cytokines, hemodynamics, and outcome in bypass grafting. AB - BACKGROUND: Although patients with reduced left ventricular ejection fraction undergoing cardiac operation experience a higher rate of perioperative complications, the contribution of proinflammatory cytokines released during extracorporeal circulation is not well defined. METHODS: We compared arterial and mixed venous levels of interleukin-6, tumor necrosis factor-alpha, soluble interleukin-2 receptor, and interleukin-2 at 10 points in time (24 hours before until 48 hours after extracorporeal circulation) in 21 patients with an ejection fraction of less than 0.45 (study group) to 15 patients with an ejection fraction of more than 0.55 (control group) undergoing elective coronary artery bypass grafting. The study and control group differed with regard to left ventricular ejection fraction (0.37 +/- 0.05 versus 0.66 +/- 0.11, p < 0.05) and reperfusion time (35 +/- 42 minutes versus 18 +/- 4 minutes, p = 0.07), but not age, sex, vessel involvement, number of grafts performed, cross-clamp time, extracorporeal circulation time, core temperature, and duration of ventilation. RESULTS: Six patients in the study group required mechanical support and 1 died. There were no complications in the control group. In the study group, there were higher preoperative interleukin-2 and tumor necrosis factor-alpha levels and a higher maximum cytokine response to extracorporeal circulation for interleukin-2, soluble interleukin-2 receptor, interleukin-6, and tumor necrosis factor-alpha (all p < 0.05). Interleukin-6 correlated with duration of extracorporeal circulation, dose of norepinephrine and epinephrine support, pulmonary capillary wedge pressure, mean pulmonary arterial pressure, right atrial pressure, heart rate, cardiac index, and inversely with systemic vascular resistance. Interleukin 6 was highest in patients with complications. Arterial and venous cytokine levels correlated closely. CONCLUSIONS: Preoperative left ventricular dysfunction is associated with a higher degree of proinflammatory cytokine release during elective coronary artery bypass grafting. This response is associated with impaired hemodynamics and a higher incidence of perioperative complications. PMID- 8678643 TI - "Classic" repair of congenitally corrected transposition and ventricular septal defect. AB - BACKGROUND: This study examined the results of "classic" repair of congenitally corrected transposition of the great arteries and ventricular septal defect. METHODS: From 1974 to 1994, 52 patients underwent a classic complete repair of lesions associated with congenitally corrected transposition. They were divided into two groups: ventricular septal defect plus left ventricular outflow tract obstruction (group I, 37 patients) and isolated ventricular septal defect (group II, 15 patients). Tricuspid plasty or replacement was performed primarily in 1 patient of group I (3%) and in 8 patients of group II (53%). RESULTS: The overall operative mortality was 15% (8/52 patients), and the incidence of postoperative atrioventricular block was 27% (14/52 patients). Eight patients died secondarily, 5 of heart failure. Survival rates were 83% +/- 6% at 1 year and 55% +/- 14% at 10 years for group I and 86% +/- 9% at 1 year and 71% +/- 12% at 10 years for group II (not significant). Redo tricuspid plasty or replacement was performed in 12 patients. CONCLUSIONS: Results of classic complete repair of lesions associated with congenitally corrected transposition are not satisfactory in our experience because (1) the operative mortality and the incidences of tricuspid valve replacement and atrioventricular block are high and (2) secondary heart failure is frequent. However, a retrospective review of morphologic findings shows that "anatomic" complete repairs would not have been feasible in 6 of our patients. PMID- 8678642 TI - Moderate hypothermia reduces cardiopulmonary bypass-induced impairment of cerebrovascular responses to platelet products. AB - BACKGROUND: The purpose of this study was to determine whether cerebral cortical microvascular responses to platelet-derived vasoactive substances are altered after normothermic cardiopulmonary bypass (CPB), and whether these alterations are modified by moderate hypothermia. METHODS: Pigs were placed on normothermic CPB (37 degrees C) for 2 hours and then perfused off CPB with normothermic blood for either 15 minutes (n = 8) or 60 minutes (n = 6). Another group was placed on moderately hypothermic CPB (25 degrees C) for 2 hours and then perfused off CPB at 37 degrees C for 15 minutes (n = 6). Alphastat pH management was used. In vitro responses of isolated cortical cerebral arterioles (90 to 170 microns internal diameter) to platelet-derived vasoactive substances were examined in a pressurized no-flow state with videomicroscopy. Microvessels from noninstrumented pigs (n = 14) were used as controls for in vitro studies. RESULTS: Cerebrovascular resistance and internal carotid artery blood flow were similar 15 minutes after CPB in both normothermic and hypothermic groups. However, relaxations of microvessels to adenosine 5' diphosphate or serotonin were reduced in vessels from both groups. One hour of after CPB cerebral perfusion did not change this pattern of altered vascular reactivity. Hypothermia caused a partial but significant reduction in impairment of responses to adenosine 5' diphosphate and serotonin. Microvascular relaxation to the endothelium-independent agent sodium nitroprusside and contraction to a thromboxane A2 analog were similar in all experimental groups, suggesting normal vascular smooth muscle responsiveness. CONCLUSIONS: This study demonstrates that normothermic extracorporeal circulation reduces endothelium-dependent relaxation responses to products of platelet activation in the cerebral microcirculation. Moderate hypothermia attenuates the CPB-induced impairment of endothelium-dependent relaxation, but has no effect on baseline cerebral blood flow after rewarming. PMID- 8678644 TI - Effect of aminoguanidine and cyclosporine on lung allograft rejection. AB - BACKGROUND: Aminoguanidine, a nitric oxide synthase inhibitor, has been shown to reduce the inflammatory allogeneic response. Here we used it in combination with cyclosporine to evaluate its effect on a clinically relevant immunosuppressive protocol. METHODS: Orthotopic left lung transplantation was performed in 120 rats, of which 24 were syngeneic Lewis to Lewis controls, and allogeneic transplantations were performed across major histoincompatibility barriers (ACI to Lewis). We studied synchronous histologic changes accompanying cytokines and nitric oxide synthase messenger RNA by reverse transcriptase polymerase chain reaction in the grafted lungs. Nitrate/nitrite, oxidized degradation products of nitric oxide, were measured in the whole blood, as were concentrations of cyclosporine. Lung tissue was immunohistochemically stained for nitric oxide synthase protein. Rats receiving allografts were either untreated (24) or received low-dose cyclosporine (232 +/- 105 ng/mL blood by high-performance liquid chromatography), high-dose cyclosporine (2,046 +/- 664 ng/mL), aminoguanidine alone (800 mg. kg-1. day-1 intraperitoneally), or aminoguanidine plus low-dose cyclosporine. RESULTS: The results suggest that aminoguanidine combined with low doses of cyclosporine can reduce the allogeneic response across major histoincompatibilities in rodent lung transplantation. Its biologic effect may not exclusively depend on the inhibition of nitric oxide synthase and may, by other means, reduce proinflammatory cytokines. CONCLUSIONS: Aminoguanidine may be an effective adjuvant to conventional immunosuppression. PMID- 8678645 TI - Role of video-assisted thoracic surgery in the treatment of pulmonary metastases: results of a prospective trial. AB - BACKGROUND: A retrospective review revealed a 42% error rate between computed tomographic scan reports and thoracotomy findings; therefore, a prospective study was designed to compare the value of computed tomographic scans, video-assisted thoracoscopic exploration, and open thoracotomy in the management of pulmonary metastases. METHODS: Eligibility included any patient with only one or two ipsilateral pulmonary metastases identified on computed tomographic scan who was being considered for surgical resection. Initially video-assisted thoracic surgery was performed and all lesions identified were resected. A thoracotomy adequate for complete lung palpation was then carried out and any additional lesions found were removed. RESULTS: Eighteen patients of a planned 50 were treated before closure of the study. Four patients (22%) had no additional lesions found at thoracotomy. The primary sites of tumor were colon (10), breast (3), and one patient each skin (squamous), cervix, kidney, melanoma, and sarcoma. Four patients (22%) did have additional lesions at thoracotomy, which were benign. In the remaining 10 patients (56%) additional malignant lesions were found at thoracotomy after video-assisted thoracoscopic exploration. After 18 patients were entered, analysis of the early results disclosed a 56% failure rate of a computed tomographic scan and video-assisted thoracic surgery to detect all lesions. Being within the 95% confidence interval (32% to 78%), the study was abandoned. CONCLUSIONS: We conclude that video-assisted thoracic surgery should be used only as a diagnostic tool in managing lung metastasis. A thoracotomy is required to achieve complete resection, which is the major survival prognosticator for satisfactory long-term results. PMID- 8678646 TI - Open drainage of massive tuberculous empyema with progressive reexpansion of the lung: an old concept revisited. AB - BACKGROUND: This study examined the results of open drainage of massive tuberculous empyema. METHODS: During a 7-year period 47 patients with primary mixed chronic tuberculous empyema with near or total lung collapse were treated. The initial procedure was chest tube suction drainage, which permitted evaluation of the pleural cavity and the lung parenchyma despite minimal if any reexpansion of the lung. All patients were treated with antibiotics and multidrug regimens of antituberculosis agents. A pleurocutaneous window was established by removing sections of two ribs one intercostal space above the base of the pleural cavity. Irrigation was performed daily with dilute povidone iodine solution. RESULTS: Twenty-eight patients achieved complete reexpansion of the lung after 4 to 30 months of drainage and are cured. Eleven are in various stages of reexpansion and probably will be cured. Eight patients did not achieve reexpansion. Criteria were established retrospectively on an ongoing basis that indicate when pulmonary reexpansion is possible. CONCLUSIONS: These totally collapsed "entrapped" lungs expanded to fill the entire pleural space despite the presence of bronchopleural fistulas and an "open" pleura. Reexpansion was progressive, gradual, and dependent on improved compliance, clearing of bronchial inflammation and obstruction, and pleural cleansing. Criteria are established that identify those patients in whom complete reexpansion may take place and the disease may be cured. PMID- 8678647 TI - Mechanisms of right ventricular dysfunction after pulmonary resection. AB - BACKGROUND: Significant right ventricular (RV) dysfunction as measured by increased end-diastolic volume and reduced ejection fraction has been documented in the postoperative period after pulmonary resection. We hypothesized that changes in RV contractile state or afterload may contribute to this RV pump dysfunction. METHODS: In part one of the study, RV preload was altered on postoperative day 2 (n = 6) by rapid infusion of Hespan to a total of 250, 500, and 1,000 mL. The relationship between RV stroke work and end-diastolic volume was plotted using linear regression. This preload recruitable stroke work relation had been previously validated as a load-insensitive index of RV contractility. The slopes of the preoperative relation (n = 35) and postoperative relation were compared. In part two of the study, RV afterload was reduced by continuous infusion of prostaglandin E1 (n = 6) through postoperative day 2 and RV pump function was assessed. RESULTS: Comparison of the slopes of the preload recruitable stroke work relation plotted preoperatively and on postoperative day 2 revealed no significant difference, indicating no change in RV contractile state. Infusion of prostaglandin E1 in the postoperative period (n = 6) significantly reduced pulmonary vascular resistance (3.67 +/- 0.19 versus baseline 5.72 +/- 0.19 dyne . s . cm-5/ m2; p < 0.05). However, RV ejection fraction remained significantly reduced (0.34 +/- 0.01 versus baseline 0.42 +/- 0.01; p < 0.05) and end-diastolic volume significantly increased (105 +/- 5 versus baseline 93 +/- 2 mL/m2; p < 0.05). Heart rate was increased compared with baseline throughout the postoperative period. CONCLUSIONS: The present study suggests that RV dysfunction after pulmonary resection is not caused by primary alterations in contractility or immediate changes in afterload. Better control of heart rate with minimal effect on inotropy may enhance RV pump function. PMID- 8678648 TI - Integrated cardioplegia allows complex valve repairs in all patients. AB - BACKGROUND: Traditionally, most surgeons have taken adversarial positions with respect to whether cardioplegia should be given warm or cold, antegrade or retrograde, continuous or intermittent. Because each method has weaknesses, myocardial protection is compromised when only one method is employed. It is our contention that an "integrated" approach that combines all of the aforementioned principles will improve myocardial protection, allowing the time needed for complex valve repairs. METHODS: Thirty-four patients (25 undergoing complex mitral valve repairs and 9 undergoing Ross procedures) have undergone complex valve repair since we began using an integrated cardioplegic strategy that incorporates all of the techniques mentioned above and is based on the following principles: (1) Cardioplegia is infused antegrade and retrograde, warm and cold. (2) Surgical precision is optimized by a dry, bloodless field using cold intermittent arrest to limit ischemia when visualization is needed. (3) Continuous blood cardioplegia is used when visualization is not problematic, thereby avoiding unnecessary ischemia. RESULTS: Average age was 46 +/- 4 years (range, 9 to 79 years), and 9 patients (26%) were having reoperations. All mitral patients had severe mitral regurgitation, 52% (13/25) had a preoperative ejection fraction less than 0.40, and 40% (10/25) had pulmonary artery pressures greater than 60 mm Hg. In the Ross patients 33% (3/9) had an ejection fraction less than 0.40, including 2 patients who concomitantly underwent complex mitral valve repair. Despite cross-clamp times of 187 +/- 12 minutes (range, 138 to 267 minutes) in the Ross group and 139 +/- 8 minutes (range, 92 to 218 minutes) in the complex mitral valve repair group with a predicted mortality (Parsonnet) of approximately 10%, no patients died, only 5 (15%) required inotropes, none required intraaortic balloon pumping, only 1 (3%) required antiarrhythmics, and the average postoperative hospital stay was 8 days in the mitral repair group and 5 days in the Ross group. CONCLUSIONS: We believe an integrated approach incorporating the strategies of warm and cold blood cardioplegia, antegrade and retrograde delivery, and continuous and intermittent infusion affords better myocardial protection, avoids unnecessary ischemia, facilitates technical ease of operation, and results in a more stable postoperative course. Integrating these modalities into a comprehensive strategy (instead of relying on one) maximizes each method's strength while minimizing weaknesses, thereby allowing surgeons to perform complex valve repairs safely in all patients. PMID- 8678649 TI - Delay of adenosine triphosphate depletion and hypoxanthine formation in rabbit lung after death. AB - BACKGROUND: If lungs could be retrieved for transplantation from non-heart beating cadavers, the shortage of donors might be significantly alleviated. METHODS: Adenosine triphosphate (ATP) and hypoxanthine levels were measured postmortem in rabbit lungs comparing deflation (group 1), ventilation with room air (group 2), inflation with room air (group 3), ventilation with oxygen (group 4), ventilation with cooled air (group 5), deflation plus cadaver cooling (group 6), and cooling by pulmonary arterial flush (group 7). RESULTS: The level of ATP dropped to 25.9% and HYP increased elevenfold at 30 minutes in group 1 but remained constant during 24 hours in group 7. The ATP catabolism beyond 2 hours postmortem appeared less in group 2 compared with group 3 (3.58 +/- 1.24 versus 0.39 +/- 0.08 mumol/g dry weight for ATP and 3.03 +/- 0.49 versus 7.64 +/- 0.94 mumol/g dry weight for hypoxanthine at 24 hours, respectively; p < 0.05). Cadaver cooling significantly slowed ATP catabolism. Changes in ATP level were similar in groups 2, 4, and 5. CONCLUSIONS: These data suggest that in the non-heart-beating cadaver (1) cooling, ventilation, and inflation can delay ATP catabolism; (2) postmortem ventilation but not inflation for more than 2 hours will inhibit further ATP breakdown; (3) ventilation with either oxygen or cooled air is not more beneficial than room air ventilation; and (4) cold flush more than cadaver cooling will prevent ATP depletion. PMID- 8678650 TI - One hundred consecutive thymectomies for myasthenia gravis. AB - BACKGROUND: Between June 1997 and November 1993, 100 consecutive thymectomies for myasthenia gravis were performed at University of North Carolina Hospitals in Chapel Hill. METHODS: A consistent, planned protocol involving preoperative, intraoperative, and postoperative care was followed. All thymectomies were performed through a median sternotomy with removal of all visible thymus and perithymic fat in the anterior mediastinum. RESULTS: There was no perioperative mortality or longterm morbidity. Mean postoperative hospital stay was 6.3 days (range, 3 to 18 days). Ninety-six percent of the patients were extubated the day of the operation, and all patients were extubated within 24 hours. Mean postoperative intensive care unit stay was 1.2 days (range, 1 to 4 days). After a mean follow-up of 65 months (range, 1 to 199 months), 78% of all patients are improved by at least one modified Osserman classification when their current status is compared with their worst preoperative disease severity. In fact, 69% of patients with mild disease preoperatively (class I, II, or III maximal severity) are in pharmacologic remission (asymptomatic without regular medication), whereas 29% of patients with severe disease (class IV or V) are in remission (p = 0.0001). CONCLUSIONS: Our programmatic approach to thymectomy through a sternotomy has shown minimal morbidity and mortality. It is beneficial to myasthenics at both ends of the age and severity spectrum. PMID- 8678651 TI - Distribution of distant metastases from newly diagnosed non-small cell lung cancer. AB - BACKGROUND: The purpose of our study was to determine the incidence and locations of M1 disease at presentation in patients with non-small cell lung cancer to help design appropriate preoperative imaging algorithms. METHODS: All patients with non-small cell lung cancer seen between 1991 and 1993 were identified, and records were reviewed. For patients with M1 disease, the sites of distant metastases and the methods of diagnosis were recorded. RESULTS: Of 348 patients identified, 276 (79%) had M0 disease and 72 (21%) had M1 disease. In 40 of 72 patients (56%), M1 disease was detected via chest or abdominal computed tomography (CT). Brain, bone, liver, and adrenal glands were the most common sites of metastatic disease, in decreasing order. Brain metastases often occurred as an isolated finding, although isolated liver metastases were uncommon. CONCLUSIONS: M1 disease was common at presentation, and was often detectable via chest CT. The incremental yield of abdominal CT over chest CT was very small, and therefore abdominal CT is not an effective method of screening for metastases if chest CT has been performed. PMID- 8678652 TI - Morbidity and mortality after thoracoscopic pneumonoplasty. AB - BACKGROUND: Both video-assisted thoracic surgery and open pneumonoplasty procedures have been used to achieve lung reduction in emphysema patients. METHODS: The surgical and hospital course of 339 patients with a mean forced expiratory volume in 1 second of 750 mL and a mean ratio of forced expiratory volume in 1 second to forced vital capacity of 35% undergoing video-assisted thoracic surgical laser pneumonoplasty was analyzed. RESULTS: The incidence of myocardial infarctions was 0.9% and the hospital mortality rate was 4.1%. CONCLUSIONS: Factors leading to increased morbidity and mortality were advanced age (65 years and greater, especially greater than 75 years), sex (men greater than women), carbon dioxide retention in the resting state (especially an arterial carbon dioxide tension greater than 55 mm Hg), forced expiratory volume in 1 second less than 700 mL for men and 500 mL for women, maximum voluntary ventilation less than 25% predicted, and a ratio of residual volume/total lung capacity greater than 60%. PMID- 8678653 TI - Late conduit occlusion after modified Fontan procedure with classic Glenn shunt. AB - A number of patients with complex congenital heart disease who were initially palliated with a classic Glenn shunt subsequently underwent modified Fontan procedures. This report discusses the operative management of complete occlusion of right atrial-to-right ventricular conduits in patients with patent classic Glenn shunts. The literature is reviewed regarding similar patients, and alternative treatment strategies are discussed. PMID- 8678654 TI - Fringed valve prosthesis for aortic root abscess. AB - Two patients with aortic root abscess were successfully treated with a fringed valve prosthesis, in which a fringe material was secured to the sewing cuff of a bileaflet prosthetic valve using a 4-0 running suture. This fringed valve technique provides dual security for annular attachment of the prosthesis without coronary reimplantation. Good late outcome suggests it would be a useful alternative for aortic root abscess. PMID- 8678655 TI - Coronary-pulmonary steal syndrome. AB - The development of an internal thoracic artery-pulmonary artery fistula after operation is a rare entity of no clear etiology. We report a patient who underwent coronary bypass reoperation, presented 3 years later with angina on exertion, and upon investigation was found to have an internal thoracic artery pulmonary artery fistula. This patient was managed conservatively. PMID- 8678656 TI - Venous cannula obstruction by Swan-Ganz catheter during cardiopulmonary bypass. AB - During a routine coronary revascularization procedure in a 51-year-old man, venous return was suddenly interrupted. The venous cannula was rapidly removed, revealing the pulmonary artery catheter wrapped around it. The catheter also had entered the lumen of the cannula, and the inflated balloon completely obstructed the venous return. The prompt removal and reinsertion of the venous cannula resulted in uneventful recovery of the patient. PMID- 8678657 TI - Biventricular assist for severe acute rheumatic pancarditis. AB - Severe heart failure in acute rheumatic myocarditis is rare. It may be rapidly reversible with treatment, so maximal medical treatment and, if necessary, mechanical support should be given before heart transplantation is considered. PMID- 8678658 TI - Long tracheobronchial and esophageal rupture after blunt chest trauma: injury by airway bursting. AB - Tracheobronchial rupture can be associated with blunt thoracic trauma. An important factor in the physiopathology of these lesions is reflex closure of the glottis, which can be related to closed chest trauma. We report a case of nonpenetrating thoracic trauma that caused a long membranous tracheal rupture from the subcricoid area to the main carina, extending to both main bronchi. In addition, a complex esophageal rupture occurred due to the great energy liberated by the airway rupture acting as a real tracheal burst. Both lesions were diagnosed by flexible bronchoscopy. The postoperative period was without serious complications. PMID- 8678659 TI - Giant aneurysm of main pulmonary artery. AB - Aneurysm of the main pulmonary artery is an extremely rare entity. The first successful repair of an aneurysm of the main pulmonary artery was reported in 1971. Since then, surgical correction of the aneurysm of main pulmonary artery has been undertaken in only 6 cases. A thorough survey of the literature, including autopsy cases, medical cases, and surgical cases, shows the aneurysm in the present case to be one of the largest. PMID- 8678660 TI - Leiomyosarcoma of the superior vena cava. AB - Leiomyosarcoma of the superior vena cava is exceptional. A case in a 52-year-old man is described. A treatment by means of neoadjuvant chemotherapy, operation, and adjuvant radiotherapy was performed. This aggressive treatment has permitted the patient to obtain a relatively long survival with a good quality of life. PMID- 8678661 TI - Giant bronchogenic cyst presenting as a lobar emphysema in a newborn. AB - Bronchogenic cysts are relatively uncommon congenital lesions. Because of the variability in clinical presentation and the shortcomings of diagnostic procedures, bronchogenic cysts present a diagnostic problem. This report describes a giant bronchogenic cyst that presented as a lobar emphysema in a newborn. PMID- 8678662 TI - Irreversible tetraplegia after tracheal resection. AB - The case of a 21-year-old woman without previous cervical pathology in whom irreversible tetraplegia developed after operation for tracheal stenosis is reported. After tracheal resection the neck was kept in extreme flexion and after extubation she was moved to a sitting position. The different causal agents that could produce the neurologic damage remain unclear, although we think that the combination of relative arterial hypotension secondary to the sitting position and disturbed autorregulation, caused by extreme neck flexion, could result in ischemic spinal cord injury. PMID- 8678663 TI - Intracoronary thrombolysis in the treatment of graft closure immediately after CABG. AB - A patient with a hypercoagulable state underwent coronary artery bypass grafting and was recovering uneventfully until diffuse electrocardiographic changes and cardiogenic shock developed within hours of the operation. Because of severe hemodynamic compromise on high-dose inotropic drugs and intraaortic balloon pump support, she was taken to the catheterization laboratory, where the patient was discovered to have thrombotic occlusion of all grafts, including the left internal mammary artery to the left anterior descending artery. Multiple graft percutaneous transluminal coronary angioplasty and thrombolysis with urokinase successfully opened the grafts, without bleeding complication. Anastomoses were all free of significant anatomic lesion. She has remained free of cardiac symptoms for 3.5 years after operation. PMID- 8678664 TI - Bronchoesophagopleural fistula after photodynamic therapy for malignant mesothelioma. AB - A 66-year-old woman presented with a bronchoesophagopleural fistula 10 weeks after thoracic photodynamic therapy for malignant mesothelioma. This is the third reported case of an esophagopleural fistula developing subsequent to photodynamic therapy for mesothelioma. We review the literature on this topic and report our successful management of this complication. PMID- 8678665 TI - Successful reconstruction of a complex traumatic carinal disruption. AB - Complex traumatic tracheobronchial disruption often results in mortality or prolonged morbidity. This case report highlights a successful strategy for diagnosis and management of an unusually extensive carinal disruption in a patient with multiple trauma. PMID- 8678666 TI - Trachea-innominate artery fistula and concomitant critical cerebrovascular disease. AB - To avoid the laborious task of investigating the cerebrovascular circulation in the midst of a trachea-innominate artery fistula, we strongly recommend preoperative cerebrovascular investigations in all patients about to undergo mediastinal tracheostomy. Paramount to this dictum remains the possibility of asymptomatic cerebrovascular disease. Inadequate preoperative cerebrovascular assessment may result in, as described in this report, the possibility of significant postoperative neurologic morbidity or mortality. Angiography should assist the surgeon in deciding which method of cerebral arterial reconstruction is best suited to the individual circumstance. We recommend the avoidance of innominate artery reconstruction even with the interposition of autologous tissues, as the operative field remains grossly infected. PMID- 8678667 TI - Pericardial patch augmentation of right atrioventricular valve in atrioventricular canal. AB - Untreated pericardial patch was successfully used to augment tissue-deficient bridging leaflets of the right atrioventricular valve in a patient after previous repair of complete common atrioventricular canal. Medium-term echocardiographic follow-up showed excellent tricuspid valve function with trivial central regurgitation. PMID- 8678668 TI - Selective management of embolized intracardiac missiles. AB - Intracardiac projectiles are occasionally found in stable patients who have sustained penetrating trauma. These missiles may arise from embolization from a peripheral injury site. We describe 3 patients with embolized intracardiac projectiles. The diagnosis was suggested by the presence of a foreign body within the cardiac silhouette on chest roentgenograms and was confirmed using fluoroscopy, echocardiography, or computed tomography. The management of embolized intracardiac missiles should be individualized to each patient. All of our patients had fixed intracavitary right-sided missiles and were successfully managed expectantly. PMID- 8678669 TI - Coronary ostial reconstruction. PMID- 8678670 TI - Heart-lung transplantation in situs inversus. AB - Reconstruction was accomplished in a 2 heart-lung recipients with situs inversus resulting in a left-sided systemic venous atrium. We created a large common atrium that was closed on the left side, leaving an atrial cuff on the inferior right quadrant. To this we anastomosed the donor right atrium, which had been opened laterally between the cavae. This resulted in some clockwise rotation of the ventricles and anterior positioning of the apex. The right pulmonary veins passed superior to the atrial anastomosis and posterior to the donor right atrium. Cardiopulmonary function was excellent in both cases. PMID- 8678671 TI - Transthoracic intraaortic balloon pump: a simplified technique. AB - A technique of transthoracic intraaortic balloon pump insertion and a clinical experience with 14 patients is reported. The technique of transthoracic intraaortic balloon pump insertion can be done in a rapid and atraumatic fashion. A short prosthetic graft is used, and intraaortic balloon pump removal does not require resternotomy. The technique is a safe alternative in postcardiotomy failure patients with inadequate peripheral arterial access. PMID- 8678672 TI - Lung preservation: the importance of endothelial and alveolar type II cell integrity. AB - The practice of lung transplantation is constrained by a shortage of suitable donor organs. Furthermore, even "optimal" donor lung grafts are at risk of significant dysfunction perioperatively. Significant insights into the cellular and molecular mechanisms of pulmonary ischemia-reperfusion injury have occurred since the publication of previous reviews on lung preservation 3 to 4 years ago. Recent evidence indicates that the endothelium plays an essential role in regulating the dynamic interaction between pulmonary vasodilatation and vasoconstriction and is a major target during lung injury. In addition, the composition, function, and metabolism of pulmonary surfactant produced by alveolar type II cells are increasingly being recognized as important factors in pulmonary ischemia-reperfusion injury. We hypothesize that reperfusion after a period of pulmonary ischemia results in significant endothelial and alveolar type II cell dysfunction and that an important strategy in lung preservation is to preserve the integrity of these cells in the face of this injury. Given the persistent shortage of lungs available for transplantation, laboratory studies need to focus also on the "rescue" of compromised donor lungs that would have been previously regarded as unsuitable. Importantly, innovative work from the laboratory needs to be translated into clinical practice via prospective, randomized trials to ensure that the prevalence of postoperative lung graft dysfunction is reduced and the shortage of lung grafts for transplantation is alleviated. PMID- 8678674 TI - Barrett's esophagus. PMID- 8678673 TI - Myocardial protection with potassium-channel openers is as effective as St. Thomas' solution in the rabbit heart. AB - BACKGROUND: Previous work from our laboratory has demonstrated the advantage of adenosine triphosphate-sensitive potassium-channel openers as cardioplegic agents when compared with hyperkalemic (20 mmol/L KCl) Krebs-Henseleit solution. However, Krebs-Henseleit with 20 mmol/L KCl is not an ideal hyperkalemic cardioplegia. Therefore, we investigated the hypothesis that hyperpolarized arrest with pinacidil and aprikalim could provide equal or superior myocardial protection to hyperkalemic arrest with the widely accepted St. Thomas' solution. METHODS: Myocardial protection was compared in the blood-perfused isolated parabiotic rabbit heart Langendorff model. Twenty-four hearts were protected with a 50-mL infusion of cardioplegia for a 30-minute global normothermic ischemic period followed by 30 minutes of reperfusion. Systolic function (percent recovery of developed pressure) and the diastolic properties of the left ventricle were measured. Coronary blood flow was measured throughout each experiment. RESULTS: The percent recovery of developed pressure (mean +/- standard error of the mean) for St. Thomas' solution, pinacidil, and aprikalim was 53.1% +/- 5.4%, 64.0% +/- 3.0%, and 62.4% +/- 3.2%, respectively. The time (minutes) until mechanical and electrical arrest was significantly longer in the pinacidil (4.82 +/- 0.10 and 12.06 +/- 1.07) and aprikalim (3.33 +/- 0.28 and 11.12 +/- 0.94) groups when compared with the St. Thomas group (1.84 +/- 0.74, and 3.17 +/- 1.44). Coronary blood flow upon reperfusion was significantly greater in the pinacidil (16.4 +/- 2.1 mL/min) and aprikalim (19.4 +/- 2.8 mL/min) groups compared with the St. Thomas' solution group (8.0 +/- 1.0 mL/min), and this returned to baseline after 15 minutes of reperfusion. CONCLUSIONS: Myocardial protection with pinacidil and aprikalim is comparable with that of St. Thomas' solution in the blood-perfused isolated rabbit heart despite prolonged mechanical and electrical activity during ischemia. PMID- 8678675 TI - Management of cold agglutinemia with intermittent warm blood cardioplegia and normothermia. PMID- 8678676 TI - Comparative study of biological glues. PMID- 8678677 TI - Central venous pressure/pulmonary capillary wedge pressure ratio. PMID- 8678678 TI - Locating the embedded anterior descending coronary artery: follow-up comment. PMID- 8678679 TI - Double-loop sternal wiring technique. PMID- 8678680 TI - Technique for measuring a reduction in systolic average transmural pressure. PMID- 8678681 TI - Esophageal resection for recurrent achalasia. PMID- 8678682 TI - Transmyocardial laser revascularization and coronary artery bypass grafting without cardiopulmonary bypass. PMID- 8678683 TI - Prosthetic valve endocarditis caused by Staphylococcus capitis. PMID- 8678684 TI - The Spanish Monostrut Study Group: a ten-year experience with 8,599 implants. AB - BACKGROUND: The Monostrut valve is a pyrolytic carbon, tilting-disc prosthesis with no welds. After the first implantation in Spain in May 1983, the Spanish Monostrut Study Group was established to evaluate prospectively the performance of the valve using uniform protocols. METHODS: During a 10-year period, 8,599 Monostrut valves were implanted in 7,317 patients in 22 centers. Mean age was 53.3 +/- 11 years. Of the total group, 3,229 underwent aortic valve replacement, 2,806 had mitral valve replacement, and 1,282 had double valve replacement. Follow-up was 96% complete, with a mean period of 4.3 years and a total of 29,155 patient-years. RESULTS: The operative mortality rate was 7.2%. The 10-year probability of freedom from valve-related complications and linearized rates (event/100 patient-years in parentheses) were as follows: structural deterioration, 100% (0); nonstructural dysfunction, 96% +/- 0.5% (0.51); thromboembolism, 82.9% +/- 1.5% (1.32); anticoagulant-related hemorrhage, 87.6% +/- 1.4% (0.98); and prosthetic valve endocarditis, 96.1% +/- 0.5% (0.48). There were five obstructive valve thromboses (0.017/100 patient-years). Actuarial freedom from reoperation was 95% +/- 0.5% at 10 years. Actuarial freedom from all valve-related morbidity was 70.2% +/- 1.6%; freedom from all valve-related morbidity and mortality (including operative and sudden deaths) was 62.6% +/- 2% (70.1% +/- 2% for aortic valve replacement, 56.9% +/- 2% for mitral valve replacement, and 59.8% +/- 3% for double valve replacement; p < 0.0001). Clinically, 5,988 patients (94%) are in New York Heart Association class I-II. CONCLUSIONS: The Monostrut valve has shown no structural failures and a low rate of valve-related complications over a 10-year period in a large patient population. PMID- 8678685 TI - Long-term results of operation for paravalvular abscess. AB - BACKGROUND: Operation for infective endocarditis with paravalvular abscess is reportedly associated with high mortality and morbidity rates. In an attempt to improve surgical outcome, an approach of radical resection of the abscess and inflamed tissues and reconstruction of the heart with either fresh or glutaraldehyde-fixed bovine pericardium was adopted by two surgeons at our institution. METHODS: From 1979 to 1995, 70 consecutive patients with active infective endocarditis and paravalvular abscess underwent operation. Their mean age was 49 years (range, 16 to 75 years), and 50 patients (71%) were men. Thirty four patients had native and 36 had prosthetic valve endocarditis (8 had had composite replacement of the aortic valve and ascending aorta). Most patients (78%) were in New York Heart Association functional class IV. The principal indication for operation was cardiogenic or septic shock in 11 patients, or one or more of the following: persistent sepsis despite adequate antibiotic therapy in 36, congestive heart failure in 31, and recurrent emboli in 16. Staphylococci were responsible for the infection in 37 patients (53%). The abscess was in the mitral annulus in 11 patients, in the aortic root in 44, and in the aortic root and at least one other annulus in 15. After wide resection of the abscess, we reconstructed the heart and annuli with autologous or bovine pericardium. Mechanical heart valves were implanted in 36 patients, bioprostheses in 30, and aortic homografts in 2; valve repair was possible in 2. Sixteen patients required composite replacement of the ascending aorta and aortic valve. RESULTS: There were 9 operative deaths (13%). Infections caused by staphylococci and infections in multiple annuli were associated with increased operative mortality rates. Only 1 patient had persistent infection and required reoperation. The mean follow-up was 56 +/- 40 months. There were 12 late deaths, mostly cardiac. The actuarial survival including operative deaths was 64% +/- 8% at 8 years. In 8 patients, recurrent infective endocarditis developed 10 to 102 months after operation. The freedom from recurrent endocarditis was 76% +/- 10% at 8 years. CONCLUSIONS: This experience indicates that radical resection of the abscess and reconstruction of the heart with pericardium yield an excellent chance of eradicating the infection in patients with infective endocarditis and paravalvular abscess. The type of valve implanted may not be as important as radical resection of the abscess. These patients appear to have a greater than average risk of recurrent endocarditis. PMID- 8678686 TI - Non-heart-beating donors: a model of thoracic allograft injury. AB - 4ACKGROUND. Non-heart-beating donors (NHBDs) have been proposed for the critical shortage of donors for cardiac and pulmonary transplantation. We determined the effects of prearrest hypoxia and postarrest warm ischemia on cardiac and pulmonary allografts procured from NHBDs undergoing hypoxic arrest. METHODS. Rabbit hearts and lungs were procured from separate donors and placed on isolated blood perfusion circuits. Controls were excised and perfused without ischemia. Heart from NHBDs underwent either prearrest hypoxic perfusion alone or consecutive periods of prearrest hypoxic perfusion and 20 minutes of postarrest warm ischemia. A third group of hearts underwent 30 minutes of warm, global ischemia alone. Two groups of pulmonary allografts were studied using similar hypoxic perfusion/20-minute ischemia and 30-minute ischemia donors. RESULTS. Prearrest hypoxic perfusion clearly causes significant dysfunction of cardiac allografts from NHBDs compared with nonischemic controls. Prearrest hypoxic perfusion combined with postarrest ischemia results in an additive degree of dysfunction more severe than a similar period of warm ischemia alone. Both groups of experimental lungs displayed function similar to that of nonischemic controls in terms of pulmonary hemodynamics, airway resistance, and oxygenation potential. CONCLUSIONS. We conclude that prearrest hypoxic perfusion significantly contributes to the dysfunction of NHBD cardiac allografts. Pulmonary allografts may be more amenable to procurement of NHBDs. PMID- 8678687 TI - Bilateral internal mammary artery grafting in women: a 21-year experience. AB - BACKGROUND: Coronary artery bypass grafting traditionally has carried a higher mortality rate in women than in men. It remains the leading cause of death in women despite major advances in diagnosis and treatment over the past 2 decades. METHODS: A retrospective analysis was conducted to identify risk factors that adversely influence hospital mortality, morbidity, and long-term clinical results in women undergoing bilateral internal mammary artery grafting. From January 1972 through October 1994, 327 consecutive women received bilateral internal mammary artery grafts and supplemental vein grafts. Patient age ranged from 32 to 84 years (mean, 65.7 years). There were 262 patients (80.1%) with three-vessel disease; 71 (21.7%) had substantial (> 50%) stenosis of the left main coronary artery, 65 (19.9%) had a moderately reduced (0.30 to 0.50) ejection fraction, and 11 (3.4%) had a severely reduced (< 0.30) ejection fraction. Preoperatively, 316 patients (96.6%) were in New York Heart Association class III or IV. RESULTS: There were 1,016 coronary artery grafts (mean, 3.1 per patient). The overall hospital mortality rate was 3.4% (11 of 327). Postoperative complications included myocardial infarction in 18 patients (5.5%), stroke in 5 (1.5%), pulmonary insufficiency in 11 (3.4%), reoperation for bleeding in 7 (2.1%), and sternal infection in 8 (2.4%). Independent predictors of operative death were postoperative cardiac arrest (p < 0.001), use of intraaortic balloon pump (p < 0.001), and reoperation for bleeding (p < 0.050). Follow-up was completed on 316 hospital survivors (100%) and ranged from 6 months to 21 years (mean, 5.1 years). Actuarial survival (mean +/- standard error of the mean) was 90.5% +/- 1.9% at 5 years and 65.6% +/- 6.1% at 10 years. At follow-up, 252 patients (94.0%) were asymptomatic in New York Heart Association class I, and 12 (4.5%) were in class II. CONCLUSIONS: This longitudinal study demonstrates that bilateral internal mammary artery grafting, though technically demanding, can be achieved in women with low hospital mortality and morbidity rates. Patients experienced reduced late cardiac events, excellent functional improvement, and enhanced long-term survival. PMID- 8678688 TI - Surgical management of hypoplastic left heart syndrome. AB - BACKGROUND: The treatment of infants with hypoplastic left heart syndrome has been challenging and controversial. METHODS: To assess the operative management and intermediate-term outcome, we retrospectively analyzed our surgical experience with 50 newborns with hypoplastic left heart syndrome operated on between January 1989 and June 1995. RESULTS: Surgical palliation with a first stage Norwood operation was offered to 28 patients. The remaining 22 infants were initially listed for heart transplantation, and 15 underwent the operation. Ten of the 15 recipients are alive, and all are in New York Heart Association class I. Seven infants underwent a Norwood procedure after being on the list for transplantation for 12 to 42 days. A total of 34 patients underwent Norwood procedures with one operation aborted because of inoperable anatomy. Two infants who survived the first-stage Norwood operation underwent subsequent heart transplantation and are currently doing well. The 1-year mortality rate for heart transplantation was 18% (3/17) versus 50% (17/34) for the Norwood procedure. Risk factors for early mortality after a Norwood procedure include longer circulatory arrest time (> 50 minutes), preoperative acidosis (pH < 7.20), larger systemic pulmonary artery shunt (> or = 4 mm), diminutive ascending aorta (< or = 2.0 mm), and anatomic subtype of aortic and mitral atresia. The 1-year survival rate for the Norwood procedure improved from 36% for the patients operated on during 1989 through 1992 to 75% during 1993 to mid-1995 (p = 0.005). Of the 17 survivors of a first-stage Norwood operation, 10 have undergone the second stage (bidirectional Glenn procedure), and 7 have completed a Fontan procedure. Heart transplantation results have also improved, with no deaths since 1992. CONCLUSIONS: Both the Norwood procedure and heart transplantation have encouraging early to intermediate results in infants with hypoplastic left heart syndrome. Hypoplastic left heart syndrome should be managed selectively on the basis of cardiac morphology, donor availability, and family wishes. Development of a flexible program involving the use of both procedures may aid in the successful management of infants with hypoplastic left heart syndrome. PMID- 8678689 TI - Effect of triiodothyronine on graft function in a model of heart transplantation. AB - BACKGROUND: Brain death is associated with neuroendocrine changes that result in impaired metabolism, reduced myocardial energy stores, and deteriorating cardiac function. As a result of these changes, a substantial number of normal human hearts are not considered suitable for transplantation. In the hope of preventing these complications and stabilizing the condition of cardiac donors, we compared the function of transplanted hearts from brain-dead rats that received triiodothyronine (T3) (n = 6) with that of hearts from a group that received a placebo (n = 5). METHODS: This experiment was designed to be both blinded and randomized. Brain death was achieved by bilateral carotid ligation and inflation of an intracranial balloon. Triiodothyronine or placebo was administered in a blinded, randomized fashion. The brain-dead donors were then supported with conventional techniques for 2 hours after which time heterotopic transplantation was performed using hypothermic preservation and a working heart model. Hemodynamics of the transplanted hearts were assessed 48 hours postoperatively. RESULTS: The hearts from donors that had been pretreated with T3 were found to have a significantly higher (p < 0.005) peak left ventricular pressure than the hearts from the placebo-treated group (137 +/- 17 mm Hg versus 115 +/- 15 mm Hg). Left ventricular end-diastolic pressure was significantly lower (p < 0.01) in the T3-treated group (5.2 +/- 2.2 mm Hg) compared with the placebo-treated group (6.9 +/- 0.5 mm Hg). There was also a significantly higher (p = 0.03) maximal first derivative of left ventricular pressure in the T3-treated group compared with the placebo-treated group (4,876 +/- 1,348 mm Hg/s versus 3,344 +/- 1,016 mm Hg/s). Finally, the cardiac output in the group given T3 was 93 +/- 16 mL/min compared with 61 +/- 22 mL/min in the group given the placebo (p < 0.01). CONCLUSIONS: Hearts from brain-dead rats that had received T3 before transplantation showed improved postoperative function. The experimental design of predonation brain death, cold immersion storage, and transplantation in a working heart model should make these data more relevant clinically than those previously reported. PMID- 8678690 TI - Inotropes in the hypoplastic left heart syndrome: effects in an animal model. AB - BACKGROUND: Despite substantial changes in the surgical treatment of children born with the hypoplastic left heart syndrome, overall mortality remains high. Although further improvements in outcomes appear to depend on more effective perioperative care, few experimental data exist to guide appropriate pharmacologic therapy in these infants. Because different inotropic agents may have different effects on the ratio of pulmonary to systemic flow (Qp/Qs), we hypothesize that they may not be equally effective at increasing oxygen delivery. METHODS: In neonatal piglets (n = 6; 3.5 to 6.5 kg), we placed an innominate artery-to-pulmonary artery shunt, created an atrial septal defect, and then occluded right ventricular outflow. We examined the effects of a number of commonly used inotropic agents, administering high and low concentrations of dopamine (5 and 15 micrograms.kg-1 .min-1), dobutamine (5 and 15 micrograms.kg 1.min-1), and epinephrine (0.05 and 0.1 microgram /min). RESULTS: Dobutamine at 15 micrograms.kg-1.min-1 increased the Qp/Qs ratio from 1.03 +/- 0.6 at baseline to 2.52 +/- 0.55 (p < 0.05) and decreased oxygen delivery from 50 +/- 4.3 to 36 +/- 1.7 mL/min (p < 0.1). The arterial-venous oxygen difference increased as oxygen delivery went down, going from 44% +/- 1% to 48% +/- 2% (p < 0.1). Epinephrine at 0.1 microgram.kg-1.min-1 decreased the Qp/Qs ratio from 1.23 +/- 0.21 to 0.82 +/- 0.08 (p < 0.05) and increased oxygen delivery from 40 +/- 9.7 to 56 +/- 1.7 mL/min (p < 0.05). Systemic venous oxygen saturation increased from 36% +/- 4.8% to 50% +/- 8.6% (p < 0.05). Although dopamine decreased the Qp/Qs ratio and increased oxygen delivery, these changes were not statistically significant. CONCLUSIONS: Dopamine, dobutamine, and epinephrine all increased cardiac output but had substantially different effects on the Qp/Qs ratio and on oxygen delivery, possibly due to differential effects on systemic and pulmonary vascular resistances. This suggests that inotropic agents may not be equally beneficial in the clinical setting. Systemic venous oxygen saturation and the arteriovenous oxygen difference may help determine if a given inotrope improves oxygen delivery. PMID- 8678691 TI - Salvage of ischemic myocardium with simplified and even delayed coronary sinus retroperfusion. AB - BACKGROUND: Despite the proven efficacy of pressure-controlled intermittent coronary sinus obstruction (PICSO) and synchronized retrograde perfusion (SRP) in salvaging ischemic myocardium, wide application of these coronary sinus (CS) retroperfusion techniques has been limited by concerns about their safety and complexity and in particular the need for repeated occlusion of the CS with a balloon. To address these concerns a simplified retroperfusion technique (SR) was developed that continuously infuses superior vena caval blood at 7 mL/min into the CS catheter without balloon occlusion. METHODS: Thirty pigs underwent 90 minutes of ischemia imposed by snaring the two largest diagonal branches of the left anterior descending artery and were randomized to one of five treatment groups: One group received no retroperfusion (control). Three groups had immediate (Im) institution of PICSO, SRP, or SR. In a final group, an initial 60 minutes of ischemia was followed by 30 minutes of delayed SR with superior vena caval blood. All animals were then placed on cardiopulmonary bypass and, after a 60-minute cardioplegic arrest, the coronary artery obstructions were removed, to simulate surgical revascularization. This was followed by 3 hours of reperfusion. The area of myocardium at risk and the area of infarction were determined by methylene blue and triphenyltetrazolium chloride staining with planimetric quantification. RESULTS: Results are reported as mean +/- standard deviation. The area of the left ventricle at risk for infarction was similar in all the treatment groups and represented 22.3% +/- 4.1% of the left ventricular mass. The area of infarction after 3 hours of reperfusion was 48.5% +/- 11.0% for the control group, 26.8% +/- 7.3% for Im-PICSO, 24.9% +/- 4.8% for Im-SRP, 22.4% +/- 6.6% for Im-SR, and 27.7% +/- 7.2% for delayed SR (p < 0.01 for each group versus control). The mean CS pressure (in mm Hg) during treatment was 6.3 +/- 1.7 for the control group, 25.7 +/- 4.5 for Im-PICSO, 22.8 +/- 3.7 for Im-SRP, 5.0 +/- 1.5 for Im-SR, and 6.3 +/- 2.1 for delayed SR (p < 0.01 for Im-PICSO and Im-SRP versus control). CONCLUSIONS: The simplified retroperfusion technique is as effective as PICSO and SRP in salvaging ischemic myocardium, but is considerably simpler. The simplified retroperfusion technique is inherently safer because of the lower CS pressures imposed by low flows and the lack of CS balloon obstruction. The efficacy of delayed SR has profound implications on possible mechanisms of ischemic myocardial salvage. Further investigation is warranted. PMID- 8678692 TI - Twelve-hour canine heart preservation with a simple, portable hypothermic organ perfusion device. AB - BACKGROUND: Cardiac transplantation is limited to an ischemic time of around 6 hours by available preservation solution and technique. Complex organ preservation devices have been developed that extend this time to 24 hours or more, but are clinically impractical. This study evaluates a portable oxygen driven organ perfusion device weighing approximately 13.5 kg. METHODS: Organs are perfused with the University of Wisconsin solution at low perfusion pressure using less than 400 L of oxygen per 12 hours. Left ventricular parameters were measured in anesthetized adult beagles to establish control values (n = 5). Hearts were procured after cardioplegia with 4 degrees C University of Wisconsin solution, weighed, then stored for 12 hours in University of Wisconsin solution at 4 degrees C. Hearts were perfused (n = 3) or nonperfused (n = 2) during storage. Organ temperature, partial pressure of oxygen in the aorta and right atrium, perfusion pressure, and aortic flow were recorded hourly in perfused hearts. After 12 hours, hearts were transplanted into littermates and left ventricular parameters measured after stabilization off bypass. RESULTS: Organ weight for both groups was unchanged. Nonperfused hearts required both pump and pharmacologic support with significantly depressed left ventricular function. Perfused hearts needed minimal pharmacologic support, with left ventricular end diastolic pressure, cardiac output, and rate of change of left ventricular pressure showing no statistical difference from control. CONCLUSIONS: These findings confirm the potential for extended metabolic support for ischemia intolerant organs in a small, lightweight, easily portable preservation system. PMID- 8678694 TI - [The centenary of radiology]. PMID- 8678693 TI - Early clinical results of retrograde cerebral perfusion for aortic arch operations in Japan. AB - BACKGROUND: In Japan, retrograde cerebral perfusion (RCP) has been used for protection of the brain since 1986. The techniques vary by institution, and thus the optimum perfusion conditions have not yet been established. METHODS: A survey of 49 institutions was performed to investigate the early results of RCP in Japan. There were 228 patients collected, 46 (20.2%) of whom sustained brain complications. Twenty-seven patients had permanent and 19, temporary neurologic dysfunction. There were 31 early deaths (13.6%) and an additional 14 hospital deaths (6.1%). Significant predictors of brain complications and mortality were evaluated by univariate analysis and multivariate analysis using stepwise logistic regression. RESULTS: By multivariate analysis, preoperative cardiac arrest (odds ratio 8.901, p = 0.0004) and RCP duration longer than 60 minutes (odds ratio 3.234, p = 0.0352) were significant predictors of permanent neurologic dysfunction. Preoperative hemodynamic compromise (odds ratio 6.150, p = 0.0070), presence of preoperative neurologic symptoms (odds ratio 7.155, p = 0.0283), and left thoracotomy (odds ratio 2.37, p = 0.0335) were significant predictors of early death. Duration of RCP was the single RCP-related factor predictive of a brain complication (odds ratio 1.025 per minute, p < 0.0001). The incidence of permanent neurologic dysfunction was less than 10% when the RCP time was shorter than 60 minutes but increased abruptly when the RCP time exceeded 100 minutes, and it remained approximately 15% between 60 and 99 minutes. CONCLUSIONS: Less than 60 minutes of RCP can be tolerated with minimal risk of brain complication. Retrograde cerebral perfusion is one method of cerebral protection during circulatory arrest. This method is not the complete answer for brain protection, but, given specific guidelines, it may help prolong the safe time of circulatory arrest. PMID- 8678695 TI - [Differences between the effects of indorenate and other 5-HT1A agonists on the rabbit aorta]. AB - The aim of this study was to determine if like buspirone, ipsapirone and 8 hydroxy-2(di-N-propylamino)tetralin (8-OH-DPAT), the alpha 1-adrenoceptors are involved in the responses elicited by indorenate in rabbit aorta. Exception made of ipsapirone, all the 5-HT1A agonists above mentioned contracted aortic rings. The contraction elicited by buspirone and 8-OH-DPAT was blocked with prazosin (alpha 1-adrenergic antagonist), whereas the effect of indorenate was unaffected with this blocker but it was inhibited with ritanserin (5-HT2 antagonist). On the other hand, buspirone, ipsapirone and 8-OH-DPAT but not indorenate relaxed arteries precontracted with methoxamine (alpha 1-adrenergic agonist) and none of the agonists relaxed preparations precontracted with acetylcholine or KCl. The results indicate that buspirone and 8-OH-DPAT are partial alpha 1-adrenoceptor agonists since they elicited contractions which are blocked with prazosin and relaxed only rings precontracted with methoxamine. Ipsapirone behaved as an alpha 1-adrenoceptor antagonist since it showed the relaxant but not the contractile effect. Finally, we found no evidence that indorenate has afinity for alpha 1 adrenoceptors. Contraction elicited by this agonist seems to be mediated by 5-HT2 receptors, inasmuch it was blocked with ritanserin. PMID- 8678696 TI - [The action of intravenous flecainide in experimental ventricular arrhythmias]. AB - Experimental ventricular tachycardias were provoked in dog hearts with minute crystals of aconitine introduced into the periphery of an infarcted area, produced by intramural injection of 1-1.5 ml of phenol near the apex of left ventricle. The response of these tachycardias (VT) to flecainide was studied. Leads II, aVL, intraventricular right and left unipolar records, as well as one on the superior vena cava (SVC) were registered under control conditions, with VT and after the injection of this antiarrhythmic agent. This injection was infused into SVC over 15-20 minutes. Records were obtained with constant intervals, waiting for the recovery of sinus rhythm (SR) and the posterior reappearance of ventricular tachycardia. The experiments were performed 6 to 8 hs with continuous infusion of Hartmann' solutions. Throughout these periods, the variations of systemic systolic pressure were registered. Of the 22 dogs receiving 4 mg/kg of flecainide, transient SR was observed in 12 (55%), while in 4 (18%) this medication had no effect. Heart block presented in 2 animals and a fall of arterial pressure in 4. Of another 25 dogs receiving 2.5 mg/kg of flecainide, similar to clinical doses, transient SR appeared in 11 (44%), while in 3 (12%) SR was not observed. In other 2 groups, each of 15 dogs, the repeated antiarrhythmic action of flecainide was present in 33% with 4 mg/kg and in 20% with 2.5 mg/kg. This medication had no effect in 20% of the former and in 40% of the latter. However the low dose did not produce undesirable effects. Furthermore these differences were no significant statistically. Flecainide is effective in certain experimental ventricular tachycardias probably related to sodium-dependent potentials. PMID- 8678697 TI - [Coronary endovascular prostheses (stents) in the treatment of imminent or acute occlusion as a complication of coronary angioplasty]. AB - Acute coronary occlusion as a consequence of dissection or thrombosis occurs in 2 to 11% of patients treated with percutaneous transluminal coronary angioplasty (PTCA), and continues to be the principal cause of early morbidity and mortality. In this study the experience of one center is presented with the application of two types of stents, Wiktor (Medtronic Inc.) or Gianturco-Roubin (Cook Inc.) for bailout of acute or threatening coronary occlusion that persisted after treatment with prolonged balloon inflation. All patients received a complete anticoagulation scheme with heparin, dextran, dipyridamole, aspirin and coumadin. From January to November 1993, 26 patients with 27 prosthesis were included. There were 21 men and 5 women with mean age of 58 years (range 36 to 73). The indications for stenting were: total occlusion in five (19%) threatening occlusion in 13 (50%) and severe persistent dissection in eight (31%). Initial implantation success was 93% (25/27). Procedure related clinical complications were death in one patient, bypass surgery in two (8%) and myocardial infarction in four (15%). Acute stent thrombosis occurred in three cases and subacute in one (11 and 4% respectively). Three patients, had non-fatal bleeding complications. Final clinical success without myocardial infarction, bypass surgery or death was 77%. In conclusion, coronary stenting for bailout of acute or threatening coronary occlusion after PTCA is a good alternative to emergency surgery. New antithrombotic strategies and better anticoagulation schemes may improve further this procedure. PMID- 8678698 TI - [Usefulness of the measurement of the left-ventricular isometric relaxation time by echo-Doppler during the administration of dipyridamole or dobutamine as a method of inducing myocardial ischemia]. AB - Myocardial isquemia prolongs ventricular relaxation. The purpose of this study was to assess the isovolumetric relaxation time of the left ventricle (IVRT) as a parameter of global ventricular relaxation, during the administration of Dipyridamol or Dobutamine intravenously. We studied 58 patients with ischemic heart disease uncovered by the administration of pharmacological agents. They were divided in two groups: 22 patients in the group of Dipyridamole, which was administered intravenously at a dose of 0.84 mg/kg during 10 minutes and 36 patients in the group of Dobutamine administered at a dose of 5, 10, 20, 30 and 40 mcg/kg/min in stepping fashion every three minutes. Coronariography was performed in all patients. The measurements of the maximal velocities of the E and A waves, as well as the deceleration time of the E wave and the pressure half time of the mitral flow did not show significant changes in both groups. If the study was positive by criterion of alteration of the wall motion, the IVRT corrected from the heart rate (IVRT/C) had an increase in 54% (p < 0.01) with respect to baseline values in the same patient in the Dipyridamole group and in the Dobutamine group the increment of the IVRT/C was 26% (p < 0.20). The sensibility (Sen), specificity (Sp) and positive predictive value (PPV) of the IVRT/C increments in detecting proximal significant obstruction of the left anterior descending coronary artery of trivascular disease in the Dipyridamole group was of 50%, 100% and 100% respectively. In the Dobutamine group the Sen was of 74%, the Sp of 60% and the PPV of 89%. Nor Dipyridamol neither Dobutamine produced a significant prolongation of IVRT/C when alterations of wall motion were absent or when the existing alterations were not exacerbated. On the basis of these results we concluded that the measurement of the IVRT/C in studies of myocardial ischemia with pharmacological provocative maneuvers is an additional useful parameter together with segmental alterations of wall motion to differentiate positive from negative studies. PMID- 8678699 TI - [Genetic and environmental factors in essential arterial hypertension in an urban population of Cuba]. AB - The present trial has been conducted in order to determine familia aggregation and the relationship between high blood pressure, inheritance and environmental factors. We studied 108 subjects (36 high blood pressure patients, 36 controls and 36 first degree relatives) ranging in age from 21 to 55 years. This case control study was undertaken to determine risk factors. Multivariance analysis with logistic regression was carried out. Our results showed hereditary factors in 73.8% of the cases. Being the main gene autosomal recessive. Thus the main factor for high pressure is hereditary predisposition. Others factor are, body mass index and the coefficient waist-hip. We found no correlation with serum lipids. PMID- 8678701 TI - [Diastolic dysfunction as a cause of heart failure in the hypertensive patient]. AB - Hypertensive cardiomyopathies can be divided into 4 ascending categories according to the pathophysiologic and clinical impact of hypertension on the heart: Grade I. This category is characterized by LV diastolic dysfunction with no associated LV hypertrophy. Grade II. Patients at this stage present LV diastolic dysfunction with echocardiographic LV hypertrophy. Exercise capacity in terms of maximal oxygen consumption may be normal (Grade IIA) o impaired (Grade IIB). Grade III. This stage is distinguished by the presence of congestive heart failure (severe dyspnea and X-ray pulmonary edema with normal EF (> or = 50%). Patients having LV mass/volume ratio > 1.8 with little or no myocardial ischemia are classified as IIIA, as compared with IIIB patients having LV mass/volume ratio < 1.8 and significant myocardial ischemia. Clinically, these two subgroups can be distinguished as follows: the presence of a fourth sound and the absence of cardiomegaly for classification as IIIA, and a third sound plus cardiomegaly for classification as IIIB. Grade IV. Here the profile is one of dilated cardiomyopathy, LV hypertrophy and impaired EF (< 50%). The 5-year mortality rate is higher for Grade IV patients than for Grade III patients, although the morbility rate is similar in both. PMID- 8678700 TI - [The antihypertensive effect of lisinopril in a single daily dosage. A study of arterial pressure with ambulatory monitoring]. AB - We studied 25 patients with hypertension documented through ambulatory blood pressure monitoring (ABPM) to know the antihypertensive effect of Lisinopril and its action throughout the day. ABPM was done in all patients after two weeks of washout (phase 1). Then patients took 20 mg daily of Lisinopril during four weeks and after that ABPM was repeated (phase 2). Finally, those patients who persisted with high blood pressure received 40 mg daily of Lisinopril during four more weeks and again ABPM was repeated (phase 3). We found statistic difference in the systolic and diastolic blood pressure among the three phases. During the first phase there were 17 patients (68%) with high blood pressure and this number decreased to 8 (32%) in the second one and to 7 (28%) in the third phase. The results show that Lisinopril has satisfactory antihypertensive effect in about 40% of patients. Nevertheless 20% of the case remained with high blood pressure despite treatment with 40 mg of Lisinopril. On the other hand, both, systolic and diastolic blood pressure decreased satisfactory during the night with the dosage received in the morning. We concluded that Lisinopril has moderate effect when it is given as monotherapy and, it has satisfactory effect all over the day. PMID- 8678702 TI - [Arterial embolism. The detection of the central emboligenic source by transthoracic echocardiography. A study of 38 cases]. AB - 38 cases with systemic embolism were studied with transthoracic echocardiography. Patients with previous history of neurologic manifestations or intermittent claudication were excluded. Only patients with good quality echocardiographic studies were included. The goals of the study were: to diagnose intracardiac masses responsible for the embolic episode and to evaluate the study as a guide for medical or surgical therapy in this group of patients in order to prevent new embolic events. In 9 patients an intracardiac mass was identified as responsible for the embolic event, 5 cases located in the left atrium, 2 cases of left ventricular thrombus, 1 case of left atrial myxoma and 1 case of marantic endocarditis. The later two were resected surgically and 3 cases of rheumatic mitral valve disease and 1 case of left ventricular aneurism were corrected surgically. It is concluded that transthoracic echocardiography is a valuable study in this patients not only as a diagnostic tool but as a guide to surgical and medical management. PMID- 8678703 TI - [Ischemic cardiopathy in women: the role of estrogens in the coronary vascular wall and in syndrome X]. PMID- 8678704 TI - [The history of angiocardiopneumography. Its beginnings]. PMID- 8678705 TI - Detours on the road to autonomy. A critique of the New York State do-not resuscitate law. PMID- 8678706 TI - The Physicians' Desk Reference. Problems and possible improvements. AB - The Physicians' Desk Reference (PDR) is a widely used source of drug information by American physicians and patients, but as we shall discuss, it suffers from numerous shortcomings. The PDR is a collection of written and pictorial information that is provided and paid for by pharmaceutical manufacturers. The written material for a given drug is a compilation of data and recommendations that are identical to those in the drug's package insert. The wording and directives that are included in these package inserts (and thus in the PDR) represent information that the pharmaceutical companies are permitted to present following discussion and approval by the Food and Drug Administration (FDA), Rockville, Md. The PDR is thus a negotiated effort of commercial enterprises and governmental regulators. PMID- 8678707 TI - Thrombosis in ischemic heart disease. AB - Thrombus formation on a fissured or disrupted atherosclerotic plaque is the main pathogenetic mechanism for the acute coronary syndromes of myocardial infarction and unstable angina. Myocardial infarction results from an acute total occlusion of the artery, while unstable angina is secondary in most cases to mural thrombus formation. Thrombus formation has also been implicated in chronic atherosclerotic disease progression and in restenosis following coronary angioplasty. Therapeutic measures to treat thrombus rely on the ability of drugs to either prevent thrombus extension, dissolve its fibrin component, or prevent further platelet aggregation. Other measures rely on the ability of intracoronary techniques to open coronary arteries. The primary prevention of intracoronary thrombus formation is evolving. Measures to stabilize plaques or to reduce hypercoagulability are being tested or have been tested in recent trials. PMID- 8678708 TI - Osteoporosis. Frequency, consequences, and risk factors. AB - More than half of all women and about one third of men will experience osteoporotic fractures during their lives. Although no symptoms occur prior to fracture, bone mineral density and other risk factors can be used to identify high-risk patients, and because effective interventions exist, many of these fractures are now preventable. The proportion of people who are affected, the mortality and morbidity resulting from osteoporotic fractures, and the major known risk factors are discussed. Greater attention should be given to measuring bone mineral density and identifying other risk factors to quantitate the degree of fracture risk among patients (with or without a history of previous fractures), because the consequences of fractures often are severe, and no symptoms other than fractures are associated with disease progression. PMID- 8678709 TI - What role do patients wish to play in treatment decision making? AB - BACKGROUND: Although current ideology suggests patients should be active participants in decision making about their care, the literature suggests that patients wish to be informed but not involved. OBJECTIVE: To test the hypothesis that most patients want their physicians to take the responsibility for problem solving (PS, identifying the one right answer), but that many want to be involved in decision-making (DM, selecting the most desired bundle of outcomes) tasks. METHODS: Survey responses from 300 patients undergoing angiogram at a Toronto, Ontario, hospital were analyzed (response rate, 72%). Survey items included scales to measure desire for information and participation, including Autonomy Preference Index, the Krantz Health Opinion Survey, and the Deber-Kraetschmer Problem-Solving Decision-Making Scale measured on a scale from, 1 (doctor only) to 5 (patient only). RESULTS: Patients had a relatively high desire for information. On the Problem-Solving Decision-Making Scale, they overwhelmingly wished the PS tasks to be performed by or shared with the physician (98.4% of the 12 PS scores are between 1 and 3), but wanted to be involved in DM (78% of the 6 DM scores are between 3 and 5). Preference for handing over control to the physician was significantly greater for the vignette involving potential mortality (chest pain) than for the vignettes involving mainly morbidity (urinary problems) or quality of life (fertility). CONCLUSIONS: Although patients do not wish to be involved in PS tasks, few wish to hand over DM control to their physician. These findings suggest 2 major roles for clinicians--assisting patients in PS to structure choices and supporting them in making often difficult decisions. PMID- 8678710 TI - Antinuclear antibody testing. A study of clinical utility. AB - OBJECTIVE: To determine the clinical utility of the antinuclear antibody (ANA) test as ordered in a large teaching hospital. METHODS: Retrospective chart review in a 400-bed teaching hospital that provides care for hospital-based and community-based practices. PATIENTS: A consecutive sample of 1010 patients (including inpatients and outpatients) for whom ANA testing was ordered over 10 months; all patients with positive ANA test results and an equal number of randomly selected patients with negative test results were included. Clinical utility of the ANA in the identification of rheumatic disease was determined by its estimated sensitivity, specificity, and positive and negative predictive values. RESULTS: Of 1010 ANA test results reviewed, 153 were positive. The group with positive ANA test results included more patients aged 65 years or older than the group with negative ANA test results (30% vs 15%, P < .003). The diagnosis of systemic lupus erythematosus (SLE) was established in 17 patients, all of whom had positive ANA test results. Other rheumatic diseases were found in an additional 22 patients. The estimated sensitivity and specificity of the ANA test for SLE were 100% and 86%, respectively. For other rheumatic diseases, sensitivity and specificity were 42% and 85%, respectively. The positive predictive value of the ANA test was 11% for SLE and 11% for other rheumatic diseases. Specificity and positive predictive value for ANA testing in the elderly patients were lower than among younger patients. CONCLUSIONS: The sensitivity of the ANA test for SLE was high, but overall the positive predictive value was low for SLE or other rheumatic diseases. Sensitivity was low for ANA testing among patients with non-SLE rheumatic disease. More selective test ordering might improve the clinical utility of this test. Clinicians ordering the ANA test should be aware of the test's low-positive predictive value in settings with a low prevalence of rheumatic disease, particularly among older patients. PMID- 8678711 TI - Recurrent pneumococcal bacteremia. A warning of immunodeficiency. AB - BACKGROUND: Recurrent pneumococcal infections are known to occur occasionally in patients with profound immune defects. We performed a case-control analysis of recurrent pneumococcal bacteremias). PATIENTS AND METHODS: The 547 episodes of Streptococcus pneumoniae bacteremia detected from January 1, 1985, to December 31, 1994, were reviewed. We selected all cases with more than 1 episode separated by 30 days or more ("cases") and compared each of them with 2 controls (patients with single episodes of pneumococcal bacteremia). RESULTS: Fifteen patients (2.8%) had 31 episodes of pneumococcal bacteremia. Except for multiple myeloma (P < .02), the underlying disease was remarkably similar among patients with single and recurrent episodes of pneumococcal bacteremia. However, among patients positive for human immunodeficiency virus infection, those who had recurrences were at a more advanced stage of their disease than those who did not. The presence of an ultimately fatal underlying condition was more frequent in case patients (P < .001). Overall, 47% of the patients with recurrences died during their second episode of pneumococcal bacteremia. CONCLUSIONS: Our data suggest that recurrence is more than anecdotal in patients with bacteremic infections caused by S pneumoniae (2.8%). We believe that recurrence is a warning sign of immunodeficiency. Patients with multiple myeloma, human immunodeficiency virus infection, solid organ tumors, and chronic liver disease with bacteremic pneumococcal infections should be offered antipneumococcal vaccine and other potentially preventive measures, despite doubts about their efficacy. This is justified by the high mortality rate associated with recurrent episodes (47%). PMID- 8678712 TI - New York State primary care physicians' attitudes to community pharmacists' clinical services. AB - BACKGROUND: Recent changes in education law and regulations governing the practice of pharmacy in New York State have extended the clinical responsibilities of pharmacists. There is limited information in the United States about physicians' opinions of these potential activities by pharmacists. OBJECTIVE: To determine the attitudes of New York State primary care physicians, who practice in a community setting, of community pharmacists as providers of these services, as well as further extended services. METHODS: Questionnaires were mailed to a randomly selected sample of 1400 board-certified internists and family practitioners chosen from New York State counties with populations of less than 251,000. Questions were structured to determine perceptions toward specific extended roles, pharmacists' dispensing of particular drugs without a prescription, the current role of pharmacists, and the relationship between the professions. RESULTS: There were 630 (47.4%) responses, of which 594 (44.7%) were analyzed. Most physicians (93%) agreed that pharmacists should report adverse drug reactions and advise them on cost-effective prescribing (75.6%). Few (23%) believed that pharmacists should initiate a community pharmacy and therapeutics committee. Most responders (64%) agreed that pharmacists could provide, without a prescription, a 3-day course of a vaginal cream containing 2% butoconazole for vaginal candidiasis in nonpregnant women and a rectal suppository containing steroids for hemorrhoid sufferers (61%). However, few (5%) agreed with dispensing antibiotics for sore throats or a 4- to 6-week supply of ranitidine for nightly "point" abdominal tenderness that is relieved by food (5%). Most physicians agreed that pharmacists should provide their patients with information concerning the drug's dose and administration (92%), possible adverse drug reactions (89%), and possible food and drug interactions (97%). Few believed that pharmacists should provide screening services for their patients. CONCLUSIONS: This survey suggests that most physicians support the current patient-counseling activities of community pharmacists. However, there was little support for limited prescribing by pharmacists, even within specific protocols. Increased information to patients was deemed desirable, but few physicians believed that pharmacists should provide health screening services. PMID- 8678713 TI - Development and implementation of cost-effective guidelines in the laboratory investigation of diarrhea in a community hospital. AB - BACKGROUND: Fecal cultures are often inappropriately requested in the investigation of diarrhea. OBJECTIVES: To develop and determine the efficacy of practice guidelines for the ordering and processing of stool cultures that are submitted for the diagnosis of community-acquired diarrhea. METHODS: The results of stool cultures that were submitted to the microbiology laboratory of a tertiary care nonteaching community hospital were retrospectively reviewed. Following the implementation of guidelines, the efficacy was evaluated by comparison of fecal culture results in a prospective manner. RESULTS: Analysis of results of stool cultures that were obtained from 3072 patients during a 3-year period revealed that (1) the sensitivity (40%) and predictive value (20%) of finding neutrophils in smear preparations were too low to be clinically useful, (2) routine cultures from patients with nosocomial diarrhea were uniformly negative, and (3) multiple specimens from a patient rarely provided additional information. Based on these findings, new guidelines were developed and implemented with the cooperation of clinical staff. Three-month follow-up results showed that the total number of specimens, the number of specimens from patients with nosocomial diarrhea, and multiple specimens declined by 37.7%, 70.6%, and 50%, respectively. However, the isolation rate of pathogens increased from 11.7% to 18.7%. CONCLUSIONS: The application of practice guidelines that include elimination of smear examination of rectal swabs, exclusion of routine cultures from patients with nosocomial diarrhea, and rejection of repeated cultures can result in significant cost saving without adversely affecting patient care. PMID- 8678714 TI - Prevalence and pathogenicity of Clostridium difficile in hospitalized patients. A French multicenter study. AB - BACKGROUND: Although Clostridium difficile is the main agent responsible for nosocomial diarrhea in adults, its prevalence in stool cultures sent to hospital microbiology laboratories is not clearly established. OBJECTIVES: To determine the prevalence of C difficile in inpatient stools sent to hospital microbiology laboratories and to assess the relationship between serotypes and toxigenicity of the strains isolated and the clinical data. METHODS: From January 18, 1993, to July 31, 1993, the presence of C difficile was systematically investigated in a case-control study on 3921 stool samples sent for stool culture to 11 French hospital microbiology laboratories. The prevalence of C difficile in this population (cases) was compared with that of a group of 229 random hospital controls matched for age, department, and length of stay (controls). Stool culture from controls was requested by the laboratory although not prescribed by the clinical staff. Serotype and toxigenesis of the strains isolated were compared. RESULTS: The overall prevalence of C difficile in the cases was twice the prevalence in the controls (9.7% vs 4.8%; P < .001) and was approximately 4 times as high in diarrheal stools (ie, soft or liquid) as in normally formed stools from controls (11.5% vs 3.3%; P < .001). The strains isolated from diarrheal stools were more frequently toxigenic than those isolated from normally formed stools. Serogroup D was never toxigenic, and its proportion was statistically greater in the controls than in the cases (45% vs 18%; chi 2 = 5.2; P < .05). Conversely, serogroup C was isolated only from the cases. Clostridium difficile was mainly found in older patients ( > 65 years), suffering from a severe disabling disease, who had been treated with antibiotics and hospitalized for more than 1 week in long-stay wards or in intensive care. CONCLUSIONS: This multicenter period prevalence study clearly supports the hypothesis of a common role of C difficile in infectious diarrhea in hospitalized patients. Disease associated with C difficile should therefore be systematically evaluated in diarrheal stools from inpatients. PMID- 8678715 TI - Bloodstream infections with vancomycin-resistant enterococci. AB - OBJECTIVES: To describe the population in whom bloodstream infections with vancomycin-resistant enterococci occur and the clinical and microbiologic features of infection. METHODS: From June 1, 1991, to January 31, 1994, 73 patients with bloodstream infections with vancomycin-resistant enterococci were identified by retrospective review of hospital charts and microbiology records. RESULTS: Fifty-two (73%) of 71 patients with evaluable data were hospitalized in an intensive care, unit, the adult oncology unit, or the acquired immunodeficiency syndrome unit. Before the development of the bloodstream infection with vancomycin-resistant enterococci, patients were hospitalized and received antibiotics for a median of 26 and 25.5 days, respectively. A hematologic malignancy, respiratory failure, or renal failure requiring dialysis was present in 59 patients (83%). Acute Physiology and Chronic Health Evaluation II scores of the patients ranged from 6 to 35 (median, 17). Forty-five (63%) of the patients died. Compared with 37 patients who had only a single positive blood culture, the 34 patients with 2 or more blood cultures positive for vancomycin resistant enterococci more often were neutropenic or had acquired immunodeficiency syndrome (74% vs 35%; P = .002). CONCLUSIONS: Bloodstream infections with vancomycin-resistant enterococci predominantly affect severely ill patients who have received extensive antibiotic treatment during a prolonged hospitalization. Immunocompromised patients are more likely to have a persistent blood-stream infection with vancomycin-resistant enterococci. PMID- 8678716 TI - Multiple myeloma in patients younger than 30 years. Report of 10 cases and review of the literature. AB - OBJECTIVES: To analyze the presenting clinical and laboratory features and the outcome in a series of 10 patients younger than 30 years with multiple myeloma (MM) and to compare the findings with those reported in the literature. METHODS: The records of all patients younger than 30 years with MM who were seen at the Mayo Clinic, Rochester, Minn, between January 1, 1956, and December 31, 1992, were reviewed. RESULTS: The frequency of MM in patients younger than 30 years who were seen at the Mayo Clinic was 0.3%. The clinical and laboratory features were typical of MM in 7 of the 10 patients. Two patients with no increase in bone marrow plasma cells had extensive extramedullary involvement, along with multiple skeletal lesions and the presence of an M protein in the serum and urine samples. One patient had multiple lytic lesions and 10% bone marrow plasma cells with no M component until 6 years after diagnosis, when a sacral plasmacytoma developed and an IgA-kappa protein became apparent. Four patients had initial extramedullary involvement, 3 had renal insufficiency, and 2 had hypercalcemia. Osteolytic lesions were initially found in 6 patients. The M protein was light chain only in 5 patients and IgD in 2. Five patients responded to the initial conventional therapy, and 2 patients with primary resistant disease achieved long-lasting responses with high-dose therapy. The median duration of survival of the patients was 87 months. The proportion of patients who were predicted to be alive at 5 and 10 years was 69% and 31%, respectively. CONCLUSIONS: In very young patients with MM, the presenting findings and the response to conventional therapy are similar to those in patients of all ages who have MM. However, a high proportion of patients had light-chain and IgD myeloma, and 2 patients with primary resistant disease achieved long-lasting responses with high-dose therapy. The survival of our patients was considerably longer than that of patients of all ages with MM. PMID- 8678717 TI - Pneumococcal pyomyositis. Case report, review of the literature, and comparison with classic pyomyositis caused by other bacteria. AB - Pyomyositis is caused by staphylococci in 70% to 90% of patients. We report a case of pneumococcal pyomyositis (PP), review the 11 cases previously published, and compare the features of pneumococcal pyomyositis with those of classic (nonpneumococcal) pyomyositis. Several clinical characteristics have been identified that are notably different in both groups. Psoas muscle involvement was observed in two thirds of the patients with PP, and a source for the infection was identified in half of the patients. Patients with PP were older than those with classic pyomyositis. Men were affected less often than women with PP, but the opposite was the rule in classic pyomyositis. The systemic response to the infection was more prominent in patients infected with pneumococci than from other causes. Most patients with PP were successfully treated with antibiotics and drainage. Secondary meningitis was observed in 3 patients with psoas muscle abscess caused by pneumococci. Mortality is low in pyomyositis regardless of the causative pathogen. PMID- 8678718 TI - Bleeding tendency and patient interview: usefulness for surgery screening. PMID- 8678719 TI - Neutropenia and iatrogenic neutrophil dysfunction in human immunodeficiency virus infection and acquired immunodeficiency syndrome. PMID- 8678720 TI - Lowering cholesterol and lowering costs. PMID- 8678721 TI - Pathogenesis of diabetic vasculopathy: role of glycosylated hemoglobin. PMID- 8678722 TI - [Recent advances in combined therapy with surgery for pancreatic cancer]. PMID- 8678723 TI - Surgical excision of adrenal masses; a ten-year experience. AB - We reviewed the records of 13 patients with adrenal masses operated on over a ten year period to clarify clinical characteristics of adrenal tumors. Tumors were found incidentally in seven of nine patients with primary adrenal tumors (78%); however, three of these seven patients (43%) proved to have shown symptoms related to adrenal hyperfunction when re-evaluated. Other adrenal tumors (metastatic in three patients and inflammatory in one) were found without any symptoms referable to the tumors. In nine of 13 patients (69%), tumors were discovered by computerized tomography (CT). All patients with primary tumors have been gotten free of disease postoperatively. In contrast, although all three patients with metastatic adrenal tumors underwent resection of all known disease tissue, they died of the recurrence of malignancies within 10 months. This study suggests that a number of functional adrenal tumors are possibly left undiagnosed until found incidentally, and that CT is the most powerful tool to detect adrenal tumors. Our data did not support surgical intervention in cases of metastatic adrenal tumors. PMID- 8678725 TI - Noticeable hyperbilirubinemia following major hepatectomy in patients with biliary tract carcinoma. AB - Serum bilirubin concentrations were examined in patients who received hepatectomy for biliary tract carcinoma. They were divided into two groups according to the presence or absence of preoperative obstructive jaundice (POJ): the POJ group (n = 14) and non-POJ group (n = 10). The POJ group underwent percutaneous transhepatic drainage to delineate jaundice before definitive surgery. Total bilirubin concentration in the POJ group had increased at 1, 3, 5, 7 and 14 days after operation compared to the non-POJ group; the direct bilirubin level had increased at 1, 3, 5 and 7 days, and the indirect bilirubin level had increased at 1 and 3 days. Liver functional data before and 14 days after the operation were similar for the two groups. The incidence of cholangitis was higher in the POJ group than in the non-POJ group. Blood loss was greater in the POJ group than in the non-POJ group. The morbidity rate in the POJ group was higher than that in the non-POJ group. These results suggest that characteristic hyperbilirubinemia developed after major hepatectomy in patients with biliary tract carcinoma, and the bilirubin response is evoked by underlying preoperative biliary passing disturbance. PMID- 8678724 TI - Cell proliferation and differentiation of cultured chondrocytes isolated from growth plate cartilage of rat rib. AB - The present study was undertaken to investigate the relationship among cell morphology, proliferation, and maturation of chondrocytes in primary cultures. Chondrocytes were isolated from the growth cartilages of the rat ribs and cultured for 6 days. In situ DNA cytofluorometry using an inverted epi illumination cytofluorometer (Nikon P1-I) and 3H-thymidine autoradiography were carried out for the correlated analysis of cell morphology and proliferation. Cytoskeletal staining with fluorescent phalloidin and 35S-sulphate autoradiography were also performed. In addition, in situ hybridization to c-myc mRNA was carried out using DNA probe. According to the results obtained, the cultured chondrocytes were composed of mixed populations of large, polygonal cells and of small, round cells. The round cells showed a significantly higher 35S uptake than the polygonal cells. The cytoskeletal staining clearly revealed stress fibers in the cytoplasm of the polygonal cells, whereas only a fine filamentous structure was shown in the cytoplasm of the round cells. In situ DNA cytofluorometry clearly demonstrated that cell proliferative activity was high in the polygonal cells and low in the round cells. In addition, 3H-thymidine autoradiography with cumulative labeling method revealed that the polygonal cells were changing into the small, round cells. C-myc mRNA signals were detected in the cytoplasm of over a half of the round cells, whereas no evidence of c-myc expression were found in the polygonal cells. From these results, it appears that as the shape of the cultured chondrocytes shifts from polygonal to round, the cell proliferative activity decreases in association with cell differentiation. It was also suggested that c-myc mRNA is amplified in the well differentiated round chondrocytes, and not in the proliferative polygonal cells. PMID- 8678726 TI - Wrap-around neurorrhaphy: an improved method of repair for disparate nerve stumps. AB - We report a new method of nerve Reconstruction, wrap-around neurorrhaphy, in which the funicular suture site is wrapped with the epineurium of the larger stump. The specific applications of this procedure in brachial plexus reconstruction are described and the clinical results presented. The method was applied in intercostal nerve transfer to the musculocutaneous nerve in 21 patients and in 12 patients with axillary nerve injury who underwent reconstruction with autografts using wrap-around neurorrhaphy. Rigid fixation of the neurorrhaphy site could be obtained using this method, and the clinical results were satisfactory. PMID- 8678727 TI - [Brain hypothermia for brain protection]. PMID- 8678728 TI - [A report on pancreas-preserving operation and complications relating pancreatorrhea in total gastrectomy]. AB - During the period from 1986 to 1993, a total gastrectomy was performed in 174 patients with gastric malignancy in Uwajima City Hospital. Among these patients, 160 patients required lymph node dissection around the splenic artery, 109 (68.1%) of whom received pancreas-preserving operation and 51 distal pancreatectomy. Although in the former group only 3 patients (2.8%) had complications relating to pancreatorrhea, 14 patients (27.5%) suffered this complication in the latter group. On the other hand, only about 11.5% were histologically proved to have metastatic involvement in the lymph nodes around the splenic artery. These findings suggest that pancreas-preserving operation should be positively evaluated in lymph node dissection around the splenic artery. PMID- 8678729 TI - [Application of molecular biology for treatment of digestive carcinomas]. PMID- 8678730 TI - Malignant lymphoma arising in the duodenum combined with gastric lymphoma and early gastric cancer: a case report. AB - We report here a 65-year old man with primary duodenal malignant lymphoma combined with gastric lymphoma and early gastric cancer. Malignant lymphoma in the bulbus of the duodenum was suspected of by endoscopic biopsy during follow up of duodenal ulcer. Preoperative examination revealed an extension of malignant lymphoma from the bulbus to the stomach in combination with early gastric cancer. We performed a pancreaticoduodenectomy because the tumor invaded to the second portion of the duodenum. The postoperative course was uneventful and he received adjuvant chemotherapy following surgery. To our knowledge, this case is the first report of primary duodenal malignant lymphoma combined with gastric lymphoma and early gastric cancer. PMID- 8678731 TI - [A case of gastric cancer developed in the gastric tube 11 years after subtotal esophagectomy for esophageal cancer]. AB - A case of adenocarcinoma developed in the reconstructed gastric tube after esophagectomy was reported. The patient was 66 years old man and he had received subtotal esophagectomy for the carcinoma of the esophagus 11 years previously. The follow-up examination of upper GI series revealed an ulcerative lesion in the lower part of the gastric tube and endoscopic biopsy showed adenocarcinoma. The partial resection of the lower gastric tube with mediansternotomy was performed because of limiting the invasion of the carcinoma. Pathological examination showed that poorly differentiated adenocarcinoma with signet ring cells had invaded muscularis propria. The postoperative course was uneventful and he is well without any recurrence 6 months after the operation. A double carcinoma, such as esophageal cancer concomitant gastric cancer is not rare, but a carcinoma of the gastric tube which was substituted for the esophagus is rare. Recently, the incidence of carcinoma of the gastric tube is increasing due to the increasingly long-term survival rate of patients who had esophageal carcinoma. In order to ensure the early detection of a second carcinoma which can minimalize damage from curative resections, follow up examinations should be conducted with the utmost diligence. PMID- 8678732 TI - [Pulmonary arteriovenous fistula. A rare cause of dyspnea and cyanosis in an adult]. AB - The authors report the case of a pulmonary arteriovenous fistula presenting with dyspnoea and cyanosis in a young adult. The malformation was situated on the proximal pulmonary vessels and was cured by surgical correction. The diagnostic value of the clinical signs and complementary investigations of this rare conditions, often detected during adulthood, is discussed. The functional tolerance of the condition is often variable. Oxygen desaturation of arterial blood indicates a right-to-left shunt. Pulmonary angiography enables visualisation of the lesions and guides surgical management. The prevalence of complications of this condition is not well known, but the potential severity is an argument for therapeutic intervention. Embolisation techniques are developing but there is a risk of a systemic embolism. Surgery is the reference for the treatment of proximal fistulae, its curative effect being immediate and definitive. PMID- 8678733 TI - [Unexpected sudden cardiac death. An evaluation of 1000 autopsies]. AB - The aim of this study was to search for a cardiac cause of death after an otherwise negative medico-legal autopsy in 1,000 adults under 65 years of age with no previous history, who suffered a sudden death. Four hundred and seven coronary causes were established with 152 negative autopsies and 441 other cardiac lesions. These 441 cases comprised 193 cardiomyopathies, 106 His bundle lesions, 50 partial forms of Uhl's anomaly (or arrhythmogenic right ventricular dysplasia), 14 isolated mitral valve prolapses, 22 chronic valvular lesions, 8 myocarditis, 16 pulmonary embolisms, 11 chronic cor pulmonale, 11 aortic dissections and 10 atrophic fibrous plaques of the left ventricle, sequellae of thoracic trauma. His bundle lesions (isolated and associated) were observed 299 times out of 1,000 cases and mitral valve prolapse 125 times. Age and gender, circumstances of sudden death, the weight of the heart, are reported for each group of conditions. The frequency of associations, especially of His bundle lesions, suggests that they may have a potentialising effect on the genesis of the fatal arrhythmia. PMID- 8678734 TI - [Surgery FOR annulo-dystrophic disease of the ascending aorta. Apropos of 203 cases]. AB - From April 73 to June 94, 203 patients (167 men, 36 women) aged from 10 to 74 years (mean 44.8 +/- 15) underwent ascending aortic replacement with a composite graft for: dystrophic aneurysm (AN) (130 cases, 64.5%), chronic dissection (CD) (35 cases, 17.2%), type A acute dissection (AD) (38 cases, 19%). Forty-six patients (22.6%) suffered from Marfan syndrome (24 AN, 13 AD, 9 CD). Thirty patients (14.7%) had undergone a previous cardiac or aortic operation. The ascending aortic replacement was extended to the transverse arch in 28 patients (14%). A mechanical valve was used in 193 cases (95%). The technique of coronary reattachment has varied with time and according to the aortic lesions. The classic "Bentall" technique was used in 87 patients (43%), the "button" technique in 74 (36%), the "Cabrol" technique in 26 (13%) and a "mixed" technique in 16 cases (8%). The hospital mortality rate was 7.3% (15/203) (AN: 2.3%, CD: 11.4%, AD: 21%). The only predictors of hospital death were emergency AD (p < 0.03) and arch replacement (p < 0.02). Mean follow-up was 46 +/- 10 months (2-246). The overall long-term survival rate was (Kaplan Meier) 89 +/- 6% at 1 year, 77.9% at 5 years, 67.7 +/- 12% at 10 years and 61.3% +/- 15% at 12 years. The 10 years survival rate is significantly higher in patients with AN (77.8 +/- 11%) than in those with AD (61.6 +/- 17%) (Log.rank: p < 0.01). The late survival rate is also significantly higher after the "button" or Bentall reimplantation that after the "Cabrol" or "mixed" methods (90 +/- 5% in the "button" group and 88.7 +/- 6%, 83.8 +/- 9% and 76.6 +/- 12% in the "Bentall" group vs 80 +/- 18%, 63 +/- 21% and 58 +/- 35% in the "Cabrol" group at 1, 5 and 8 years, respectively). In conclusion, ascending aortic replacement with a composite graft is a safe procedure especially when performed electively in patients with dystrophic aneurysm or Marfan syndrome. The technique of coronary reimplantation has a significant on the long-term results. PMID- 8678735 TI - [Does gender affect long-term results of coronary angioplasty in patients with multivessel disease?]. AB - Multivessel coronary angioplasty, defined as angioplasty of 2 or 3 main coronary vessels performed during the same procedure, was performed in 203 selected patients between 1981 and 1986. The results in men (n = 159, group I) were compared with those in women (n = 44, group II). The angiographic appearances were comparable in the two groups, but the women were older, more often hypertensive and diabetic, and more symptomatic than the men (82% vs 57% in grades 3 or 4 of the Canadian Cardiovascular Society (CCS) Classification; p < 0.009). Complete revascularisation with angioplasty of all stenoses > 50% was attempted during the same session. The primary success rate per lesion was comparable in the two groups (90% in men, 93% in women; NS), as was the number of segments successfully dilated per patient (2.2 +/- 0.7 in group I and 2.2 +/- 0.8 group II; NS). Angioplasty was complicated by myocardial infarction and/or emergency coronary bypass surgery in 11 men and 2 women (NS). Clinical follow-up was obtained for an average of 71 +/- 22 months in the men and 70 +/- 22 months in the women in 96% of cases. The global seven year survival rate without recurrent infarction or cardiovascular death was 81% in men and 83% in women (NS). The number of repeat revascularisation procedures was comparable in the two groups (46% in women and 43% in men; NS) as was the number and duration of hospital admissions during follow-up (8.4 +/- 12.3 days in the women and 6.7 +/- 8.4 days in the men; NS). The functional status at the end of follow-up was the same in the two groups with 84% of men and 81% of women being asymptomatic or grade 1 of the CCS classification. The authors conclude that the long-term results of multivessel angioplasty are good and comparable in men and women. This revascularisation procedure should be considered as an alternative to surgery in women and men. PMID- 8678736 TI - [Long-term effects of prescription drugs in 174 patients treated for myocardial infarction, followed up from 4 to 5 years (the DEVENIR study)]. AB - The aim of this study was to document changes in drug prescription after myocardial infarction. One hundred and seventy four men with typical myocardial infarction recensed by the Toulouse MONICA centre between 1989 and 1990 were followed up for 4.5 years. A copy of their drug prescription was obtained during the acute phase of infarction, at the time of discharge from hospital or clinic, after 6 months, and finally, after 4.5 years after infarction. During the acute phase, the majority of patients received nitrate derivatives, platelet antiaggregants, calcium antagonists, betablockers and antiarrhythmics. Between hospital discharge and the sixth month, the prescription of lipid lowering drugs quadrupled (from 8 to 33%; p < 0.00001) and those of platelet anti-aggregants decreased (from 82 to 70%; p < 0.01). The prescriptions of other drugs remained relatively stable. Between the 6th month and the 4th year of follow-up the only prescription to increase significantly was that of ACE inhibitors (from 14 to 23%; p < 0.03). The other prescriptions were maintained: platelet anti-aggregants (70% at 6 months vs 75% at 4.5 years), nitrate derivatives (59 vs 51%), betablockers (51 vs 52%), calcium antagonists (51 vs 48%), lipid lowering drugs (33 vs 42%), diuretics (3 vs 6%) and inotropic agents (2 vs 2%). Overall analysis showed an increase in the prescriptions of lipid-lowering agents (p < 0.00001) and ACE inhibitors (p < 0.002). On the other hand, the prescriptions of calcium antagonists and nitrate derivatives tended to decrease. These results show that the treatment of patients with coronary artery disease is based on drugs of proven efficacy, reflecting the impact of large scale therapeutic trials on everyday medical practice. PMID- 8678738 TI - [Contribution of multiplane transesophageal echocardiography in the study of mitral valve prostheses]. AB - Many reports have confirmed the value of transoesophageal echocardiography in the diagnosis of mechanical mitral valve prosthesis dysfunction: new biplane and multiplane probes seem to provide additional information in the assessment of cardiac disease. The aim of this study was to quantify the additional value of these new probes in the assessment of mitral valve prostheses. Seventy-five mitral valve prostheses were assessed with the multiplane probe, 45 normal bileaflet prostheses, 17 with regurgitant dysfunction and 12 with non obstructive thrombi and/or strands, and one with a blocked leaflet. In order to compare the respective values of monoplane, biplane and multiplane probes, the recordings were performed at 0 degrees, 90 degrees and from 0 degrees to 180 degrees in continuous sweep mode through the scanning plane. Globally, with the monoplane assessment, it was only possible to visualise both leaflets simultaneously in 13% of cases. The majority of prostheses was correctly analysed between 60 and 100 degrees. This was of paramount importance for the diagnosis of blockage of one leaflet. With respect to para-prosthetic valve regurgitation, the transverse view allowed visualisation of the lateral and paraseptal annular regions. The addition of a longitudinal view allowed visualisation of anterior and posterior regurgitant jets: the supplementary views provided by the multiplane probe allowed detection of small regurgitant jets in the diagonal planes between the longitudinal and transverse views. The multiplane probe offers the possibility of identifying the precise origin of the jet and helps quantification and peroperative localisation of its position. Small, non-obstructive thrombi and strands are better seen using a multiplane probe, especially when of small size. Therefore, multiplane transoesophageal echocardiography improves the assessment of mitral valve prostheses, the majority of diagnoses being, however, accessible with biplane probes. PMID- 8678737 TI - [Orthotopic cardiac transplantation with caval anastomosis: a comparative randomized study with standard procedure in 81 cases]. AB - Complete resection of the right atrium with conservation of a strip of left atrium around the 4 pulmonary veins followed by direct anastomosis on the vena cava has recently been proposed as an alternative to the standard orthotopic cardiac transplantation described by Shumway and Lower. In order to determine whether this "anatomical" transplantation should now be considered to be the procedure of choice, a prospective randomised study was undertaken in 1991 including 78 patients undergoing 81 cardiac transplantations by one of the two techniques: gr. I: classical transplantation (n = 40), gr. II: "anatomical" transplantation (n = 41). The groups were comparable in age, sex, weight, nature of the underlying cardiac disease and clinical status at the time of transplantation. Similarly, the parameters of the donors were comparable with respect to age, sex, weight and dosage of inotropic drugs at the time of explantation. All patients came of cardiopulmonary bypass with comparable ischaemia time of the graft (gr. I: 136 +/- 46 min; gr. II: 138 +/- 51 min). Immediate return to sinus rhythm occurred in 20 cases in gr. I and 36 cases in gr. II. Atrial arrhythmia persisted in 5 cases in gr. I but in no cases of gr. II. These differences were very significant (p < 0.001). There were 13 early deaths in gr. I and 8 in gr. II. Doppler echocardiography was performed two to three months after transplantation. The right atrial surface was significantly decreased in gr. II (18 +/- 4.7 cm2) compared with gr. I (24 +/- 7 cm2): the same difference was observed for the left atrium (gr. I: 24 +/- 4.5 cm2; gr. II: 20 +/ 5 cm2), p = 0.001. Tricuspid regurgitation was observed in 82% of patients in gr. I compared with 57% in gr. II (p < 0.005). Exercise stress tests during the same period showed no difference in peak oxygen consumption between the groups. Holter ECG monitoring led to permanent pacing in 2 patients of gr. I (5%). The technical simplicity and reduction of postoperative morbidity, especially with respect to arrhythmias, suggest an advantage with the "anatomical" technique considering the lack of surgical complications. PMID- 8678739 TI - [Early detection of cardiotoxicity of anthracyclines. Value of isotopic method]. AB - Anthracyclines are antitumoral agents whose therapeutic efficacy is limited by dose-dependent cardiotoxicity. Thirty-one adult patients treated with long-term anthracycline were included in a prospective study to evaluate the ejection fraction and certain parameters of left ventricular diastoclic function by radionuclide angiography, and the left ventricular phase by Fourier's method. Scintigraphic acquisitions were obtained before starting and four weeks after ending chemotherapy. A significant decrease in the maximal velocity of early diastolic filling (2.84 +/- 0.57 to 2.49 +/- 0.45 VTD/s; p < 0.01), the ejection fraction also fell from 57.6% +/- 4.7% to 53.8% +/- 4.6% (p < 0.01). No significant changes in early diastolic filling time or analysis of left ventricular phase with respect to standard deviation (p > 0.05) were observed. In addition, the change in maximal velocity of early diastolic filling did not correlate with the reduction in ejection fraction. Therefore, left ventricular diastolic dysfunction is probably an early marker for anthracycline cardiotoxicity, the sensitivity of which is close to that of the ejection fraction in the detection of infraclinical cardiotoxicity. PMID- 8678740 TI - [Value of human cardiac troponin I determination in the diagnosis of acute myocardial infarction]. AB - Immunoenzymatic assay (IEMA) of human cardiac Troponin I (TnI c) was used in patients admitted to the coronary care unit with acute myocardial infarction (AMI). TnI c was detected in all patients with AMI. The detection of TnI c was earlier after the onset of pain (4.5 +/- 2.3 hours) than that of CKMB activity (6.3 +/- 3.6 hours), p = 0.003. The kinetics of TnI c are usually monophasic and parallel to that of CKMB activity. The peak value occurs 12.2 +/- 4.6 hours and 15.8 +/- 9.0 hours after the onset of pain in patients treated by thrombolysis. The TnI c disappears from the plasma between 5 and 9 days after the onset of pain, later than CKMB activity (p = 0.0001). In 49 patients admitted for AMI treated by thrombolysis, the comparative sensitivities of TnI c (threshold: 0.1 ng/ml) and of CKMB activity (threshold: 15 IU/l; CK > or = 100 Ul/l) were, at the first sampling on admission, 61% and 22% respectively (p = 0.0002) (average interval from onset of pain to first blood sampling: 3.4 +/- 1.3 hours). TnI c was not detected in the plasma of 145 normal subjects nor in any of the 6 patients with severe muscular trauma or rhabdomyolosis (specificity: 100%). This IEMA is a specific and a sensitive method of diagnosing acute and subacute myocardial infarction. It is ideal for the detection of myocardial necrosis in complex clinical situations when the usual enzymatic markers may be ineffective. PMID- 8678741 TI - [Value and limits of exercise radionuclide ventriculography in chronic aortic insufficiency. Apropos of 47 operated cases]. AB - The role of exercise radionuclide angiography in the therapeutic strategy of chronic aortic insufficiency remains controversial. In order to assess the value of this technique, 47 patients with pure chronic aortic insufficiency were evaluated before and one year after valve replacement. The preoperative EF decreases or does not increase on exercise (51.9% vs 48 +/- 10%; p < 0.001) in the majority of patients (78%), whereas, after surgery, the EF tends to increase on exercise (55 +/- 11% vs 57 +/- 11%; NS). Despite optimal surgical correction, 16 of the surviving 46 patients still had left ventricular dysfunction at one year after surgery. The preoperative parameters correlating with this dysfunction were, in order, resting radionuclide EF (r = 0.65; p = 0.0001) and the echocardiographic parameters: left ventricular endosystolic dimension, fractional shortening, and the radius/thickness ratio. The preoperative exercise radionuclide parameters did not correlate with postoperative left ventricular dysfunction. In patients without postoperative left ventricular dysfunction, the EF increased on exercise, contrary to the other group. The exercise EF remains valuable for retrospective evaluation of surgical benefit. The exercise radionuclide EF does not reflect myocardial contractile reserve alone but also the conditions of left ventricular load. This study confirms the superiority of the resting radionuclide EF and echocardiographic parameters over exercise radionuclide EF for the prediction of postoperative left ventricular dysfunction. PMID- 8678742 TI - [Thrombolytic therapy in arterial disorders other than myocardial infarction]. AB - Thrombolytic therapy is used in many cardiovascular diseases other than myocardial infarction and pulmonary embolism. In unstable angina, the results of trials have rather been disappointing. In prosthetic valve thrombosis, the role of thrombolytic therapy is increasing. In peripheral arterial thrombosis, intravenous thrombolysis was practically abandonned and local administration has been tried but no systematic attitude can be deduced. In cerebral arterial thrombosis intravenous alteplase thrombolytic treatment is effective and relatively safe in a well defined subgroup of stroke patients with moderate to severe neurologic deficit and without extended infarct signs on the initial CT scan. PMID- 8678743 TI - [Cocaine and the heart: a clinical reality]. AB - Cocaine is a drug which has been relatively little used in France until recently but its abuse seems to be on the increase with nearly 1% of 20 year-old-men admitting to having taken it more than 10 times in 1993. The cardiovascular manifestations of cocaine consumption should be known to all cardiological emergency units because of their prevalence and severity. Acute toxicological expertise and retrospective analysis allows formal diagnosis. PMID- 8678744 TI - [A rare cause of pure isolated chronic aortic insufficiency: congenital quadricuspid aortic valve. Apropos of 2 cases]. AB - The authors report two new cases of congenital quadricuspid aortic valve complicated by pure, severe, chronic, aortic regurgitation. This abnormality was diagnosed fortuitously at transoesophageal echocardiography in one case and at aortography in the other, and confirmed at surgery. This congenital abnormality was associated with superior displacement of the left coronary ostium. PMID- 8678745 TI - [Coxiella burnetti endocarditis on bioprosthesis. Apropos of a case]. AB - A patient with two bioprostheses was admitted to hospital with pyrexia and a small vegetation on the aortic bioprosthesis visible only on transoesophageal echocardiography without aortic incompetence. Blood cultures were negative. Serology to Coxiella burnetti was positive at high dilution and confirmed the diagnosis of infectious endocarditis. Medical therapy with doxycycline and chloroquine was instaured without surgery. A Coxiella burnetti infection should be systematically searched for in all cases of endocarditis with negative blood cultures. The features of this infection, particularly the aetiological circumstances, diagnosis, history and treatment are reviewed. PMID- 8678746 TI - [Left atrial free floating thrombus without mitral valve disease. Review of the literature apropos of a case]. AB - Free ball thrombi of the left atrium are usually observed with mitral valve disease. The authors report the unusual case of this condition without mitral valve disease. A number of classical echocardiographic criteria suggested the precise nature of this left atrial mass before surgical excision. The diagnosis of a free ball thrombus of the left atrium should lead to urgent surgery because of the high risk of haemodynamic and embolic complications. PMID- 8678747 TI - [Management of refractory unstable angina in 1996]. PMID- 8678748 TI - [Treatment of refractory unstable angina by transluminal coronary angioplasty]. AB - The aim of this retrospective study was to assess the value of percutaneous transluminal coronary angioplasty (PTCA) in unstable angina refractory to maximal medical therapy. The results of this procedure in these patients were compared with the results in unstable angina controlled by medication before angioplasty. Between january 1987 and january 1993, 30 patients underwent emergency PTCA for refractory unstable angina (group I). The clinical and angiographic features were compared with these of 30 patients with medically controlled unstable angina, paired for age and dilated artery (group II). The left ventricular ejection fraction was compared in the two groups (58 and 57%). The morphology of the coronary lesions according to the Ambrose classification, TIMI grading, number of lesions, degree of stenosis and severity of coronary calcification were comparable in the two groups. However, in group I, there was a significantly higher number of filling defects (30% compared with 10%, p = 0.05) and a greater number of per-PTCA complications, especially acute occlusions (23 compared with 13%, NS) with 3 deaths and 2 myocardial infarctions (compared with 1 death and 2 myocardial infarctions in group II). At long term, the restenosis, myocardial infarction and secondary death rates were comparable in the two groups with an average follow-up of 27 +/- 18 months. The poor prognosis of refractory unstable angina is therefore related to morbidity in the hospital period. These results confirm the physiopathological importance of the thrombotic process in unstable angina; the presence of "filling defect" is a poor prognostic factor associated with resistance to medical therapy. Coronary angioplasty is a valuable technique in this context but carries a higher risk of acute complications which can be reduced by an optimal platelet antiaggregant and anticoagulant therapy and in future by the use of new antithrombotic agents. PMID- 8678749 TI - [Mortality and morbidity in the acute phase of myocardial infarction. Comparison of 3 patient cohorts admitted to hospital over 10 years]. AB - The management of acute myocardial infarction has been transformed over the last thirty years by a number of therapeutic innovations. The authors decide to compare the outcomes of three cohorts of unselected patients admitted to hospital at 10 year intervals, to evaluate the impact of these innovations on morbidity and mortality. Six hundred and sixty one patient admitted to the Coronary Care Unit for acute myocardial infarction were included: Group I comprised 223 patients admitted consecutively during the period 1972-1973; Group II comprised 243 patients admitted between 1982-1983 and Group III comprised 195 patients admitted between 1992-1993. The average age was comparable, about 65 years, in the 3 groups, although there were gender differences. Taking into consideration earlier hospital admission, the in-hospital mortality decreased from 25% in Group I to 21.8% in Group II and to 15.4% in Group III (p < 0.05 between the first 2 groups and the third group). This decrease in mortality is even greater in anterior wall infarction and is observed in all ages. Similarly to selected patients in large scale randomised clinical trials, the ordinary "run of the mill" patient has also benefited from therapeutic innovations over the last ten years. PMID- 8678750 TI - [Detection of multivessel lesions after myocardial infarction. Improvement of the predictive value of early exercise stress test by discriminant analysis]. AB - The aim of this study was to assess, by a discriminant analysis, the different parameters of exercise stress testing associated with multivessel disease after uncomplicated myocardial infarction and to determine whether their combination improved the diagnostic value of ST depression alone, the usual diagnostic criterion. One hundred and seventeen out of 240 consecutive pts admitted for acute myocardial infarction between october 1992 and may 1994 underwent early exercise stress testing and coronary angiography 8.5 +/- 3 days and 13 +/- 8 days respectively after infarction. The population was divided into two groups: a "study" group (pts recruited between october 1992 and october 1993) for whom a diagnostic equation had been established based on a discriminant analysis, and "a control" group (pts recruited between november 1993 and may 1994) allowing validation of the diagnostic equation. Of the 9 clinical and 14 exercise stress test variables, only 3 remained statistically significant after discriminant analysis in this study group: the number of METS achieved (p < 0.0005), maximal ST depression in V5 (p < 0.005) and maximal heart rate (p < 0.01). Using these three parameters, a discriminating equation was established in the study group and then validated in the control group. Using this equation, the percentage of pts correctly identified as having multivessel disease was 75% in the study group and 79% in the control group, whereas ST depression, the most commonly used criterion, only classified 68% of the study group and 60% of the control group correctly. This study confirmed the good tolerance of early maximal exercise stress testing after uncomplicated myo-cardial infarction. The combination of three easily discernable parameters improved the diagnostic performance of the stress test in identifying multivessel disease after myocardial infarction. PMID- 8678751 TI - [Return to work following myocardial infarction. Medical and socio-professional factors]. AB - The aim of this study was to assess the influence of medical and socioprofessional factors on return to work after myocardial infarction. The authors studied a continuous series of 174 patients with an average age of 51.3 years, all of whom were active before their illness. The average follow-up period was 33 months. One hundred and thirty of the patients (75%) returned to work. The only clinical factors predictive of not returning to work were older age short exercise time and fall in blood pressure on exercise. On the other hand, nearly all socioprofessional factors, social class, type of occupation, size of company, length of employment in their company, physical stresses related to their occupation, were related to return to work. The average time before returning to work was 5.5 +/- 1 month. Though certain immediate criteria of severity of infarction such as previous myocardial infarction or anterior wall infarction were related to a more delayed return to work. The cardiac status evaluated by complementary investigations (left ventricular ejection fraction, exercise testing and Holter monitoring) was not related to the time before return to work. Of the socioprofessional factors, only difficulties related to the patients' work (modification or change of job) were associated with a more delayed return to work. Forty-four patients (33.8%) returned to work after a change in working hours (28 patients), the tasks involved (20 patients) or position (7 patients). Only the lower socioprofessional classes, independent workers and extremes of age could benefit from these measures. PMID- 8678752 TI - [Coronary artery disease in patients with aortic abdominal aneurysm. Apropos of a consecutive series of 172 cases]. AB - Coronary artery disease is common in patients with abdominal aortic aneurysms (AAA). It is responsible for half the operative deaths explaining the necessity of diagnosing asymptomatic coronary patients. Between 1980 and 1993, 172 patients aged 47 to 92 years (average 69 years) were operated for AAA. Fifty-four of them (31%) were known to have coronary artery disease; 30 preoperative coronary angiograms and 16 prophylactic coronary revascularisation procedures were performed before operating the AAA. In cases with ruptured AAA (42 cases) the operative mortality was 31% (13 patients) compared with 6% (8 patients) in those without rupture (130 cases). Myocardial disease was responsible for 25% of all deaths (2 out of 8) and for 40% of deaths (2 out of 5) in the subgroup of 54 coronary patients. The majority of non-lethal cardiac complications also occurred in this subgroup. On the other hand, no deaths were observed in the group of 16 patients who underwent myocardial revascularisation beforehand. Follow-up of the 151 patients discharged from hospital was complete (100%). With an average follow up period of 3.5 years (range 5 months to 13 years), 39 secondary deaths have been observed (26%) including 6 (15%) of cardiac causes. In addition, 3 patients in the coronary subgroup and 1 patient from the non-coronary group underwent myocardial revascularisation after surgical cure of their AAA. Coronary artery disease may be totally asymptomatic and severe lesions go unrecognised; the main problem is therefore to detect silent myocardial ischaemia in the absence of totally reliable non-invasive techniques, in order to perform preventive coronary revascularisation in high risk patients before their surgery. Coronary angiography is essential in all documented cases of severe coronary artery disease; exercise testing and thallium scintigraphy should be proposed in cases with clinical or electrocardiographic presumption of angina. However, systematic investigation is not required in the absence of suggestive symptoms. PMID- 8678753 TI - [Video-surgery for pericardial effusion. Technique and results]. AB - Videosurgery is a relatively non-invasive method of draining the pericardium by the creation of a pleuropericardial window. It provides an excellent view of the thoracic cavity and allows selection of pericardial and pleural, pulmonary or mediastinal biopsy sites. The authors report their preliminary results with this technique. Between May 1994 and May 1995, 22 patients with pericardial effusions were operated by videosurgery at the Pitie Hospital. None of the patients had clinical signs of tamponade. The technique consists in introducing, through 2 or 3 thoracic incisions of 15 mm, trocarts allowing passage of an endoscopic camera and different surgical instruments. Access to the thoracic cavity enabled assessment of the pleura, evacuation of pleural effusions (n = 8) and biopsy of pleural nodules (n = 2). One pulmonary biopsy was performed. Opening the pericardium enabled evacuation of pericardial effusions averaging 622 ml. Pericardial biopsies showed appearances suggesting tuberculosis (n = 2), lupic vasculitis (n = 1) and post-radiation pericarditis (n = 1). In other cases, a histologic diagnosis of non-specific pericarditis was made. A biopsy of a pleural nodule showed undifferentiated carcinoma in one case. A pulmonary biopsy revealed the presence of relatively undifferentiated carcinoma. There were no complications related to the technique. There was one recurrence of pericardial effusion at one month in a patient with carcinoma of the lung who had previously had subxiphoid drainage. There were no cases of secondary pericardial constriction. Therefore, videosurgery is a relatively non-invasive and effective technique of pericardial drainage and biopsy. When there is no emergency, it is probably the method of choice in the treatment and diagnosis of pericardial effusions. PMID- 8678754 TI - [Cardiac retransplantation (42 cases in 38 patients). Indications and outcome]. AB - In order to determine the results of cardiac retransplantation 38 cases were reviewed (42 transplantations; 4 patients underwent 3 transplantations). Clinical indications included acute rejection and infection before and after retransplantation: the explanted heart was sent for anatomopathological study. The indications were dominated by coronary artery disease of the graft (26 cases) with an average of 45.3 months between the two transplantations and a long-term survival comparable to that of primotransplantation. Conversely, in the other indications of retransplantation, the delay was much shorter (less than 12 days in half the cases) and the results were poor (9 deaths out of 12 cases). Therefore, coronary disease of the graft would seem to be the only justified indication for retransplantation at it associates stable haemodynamic conditions and therapeutic impregnation comparable to the primotransplantation. PMID- 8678755 TI - [Heart rate response to ventricular stimulation]. AB - Analysis of heart rate variability (HRV) by Holter monitoring is the method of choice for assessing the cardiac autonomic regulation. Rapid ventricular stimulation also provokes changes in the autonomic nervous system tone. The aim of this study was to compare time and frequency domain analysis of HRV (Elatec version 3.02) with variations of HR observed after incremental ventricular stimulation to 200/min in 130 patients. In 80 patients, ventricular stimulation provoked an initial acceleration in HR followed by a slowing with a variation of over 10%. In the other 50 patients, these variations were not observed. Holter analysis of HRV showed concordance between the two methods. In time domain analysis, the standard deviation of normal R-R intervals, the coefficient of variability [(CV = SD/mean RR) and percentage of adjacent RR intervals with a difference of more than 50 msec (pNN 50) were significantly reduced in the abnormal group, the respective values in the normal and abnormal groups being: SD 122 vs 72 msec; CV 15 versus 9% and pNN50 9 versus 5%)]. In frequency domain analysis, there was a reduction of low and high frequency spectra and of the ratio of low/high frequencies in abnormal subjects. The authors conclude that the disappearance of HR changes after ventricular stimulation is correlated to the absence of HRV on Holter recording. This simple test may be performed systematically during electrophysiological investigations. The measurements are reproductible and the results are not affected by arrhythmias or technical problems of quality recording by the Holter method which may affect analysis of HRV. PMID- 8678756 TI - [Role of power and temperature monitoring in radiofrequency ablation]. AB - Variations of temperature, impedance and power and the relationship between these three factors were studied in 20 patients during 351 applications of radiofrequency energy delivered by a generator with a regulated output power. The applications were divided into 3 groups according to the maximal temperature attained: group I (< 50 degrees C; n = 112), group II (50-60 degrees C; n = 100), and group III (60-70 degrees C; n = 139). Analysis of the total duration of time of applications (average +/- standard deviation) showed: the duration (seconds) was 23.9 +/- 11.9 seconds for group I, 36.1 +/- 18.7 seconds for group II and 45 +/- 23.6 seconds for group III. The time to attain maximal temperature was 6.8 +/ 9.6 seconds in group I, 11.7 +/- 12.7 in group II and 10 +/- 10.4 seconds in group III. The impedance remained under 200 omega in all applications, the target temperature being set at 70 degrees C. Analysis of the first three seconds of application: correlations coefficients between temperature and impedance were 0.08 (p < 0.001) in group I and -0.23 (p < 0.0001) in groups II and III. These coefficients were recalculated with respect to the average power delivered during the applications: < 40 watts (n = 79), r = -0.33; < 30 watts (n = 55), r = -0.41; < 20 watts (n = 33), r = 0.49 and < 10 watts (n = 15), r = -0.7 (p < 0.0001). The authors conclude that radiofrequency generators with thermal regulation allow early interruption of ineffective applications of radiofrequency and avoid increases in impedance. The poor correlations observed between increase in temperature (measured at the tip of the catheter) and the fall in impedance (related to tissue heating) for the first 3 groups, show that temperature alone is not a good indicator of contact. The improvement of the correlations for decreasing output power applications indicates better thermal transfer between the electrode and endocardium. Therefore a low power delivered in the first seconds at > 50 degrees C is to be interpreted as a marker of the quality of contact and a predictive factor of efficacy. PMID- 8678757 TI - [Mitral valve repair by transfer of the posterior tricuspid leaflet and its chordae]. AB - Mitral valve repair was performed in six patients by transferring the posterior tricuspid leaflet with its sub-valvular apparatus onto the mitral valve. This new technique considers the tricuspid valve as the patients own tissue bank where the posterior leaflet and eventually the adjacent part of the anterior leaflet is used as a "donor" valve, based on the knowledge that the right atrio-ventricular valve can be efficiently repaired with a very low risk of significant dysfunction. The mitral repair consists of incorporating the tricuspid autograft by securing the tricuspid papillary muscle to the mitral papillary muscle and by suturing the leaflet tissue where required. A mitral annuloplasty ring reinforces the repair. The tricuspid valve is subsequently repaired by annular plication and leaflet suture. A tricuspid ring is necessary to maintain efficient remodeling. The six patients ages ranged from 20 to 70 years. A etiology, was rheumatic in the first case and degenerative in the following. In three cases, sterilised endocarditis was responsible for ruptured chordae and leaflet destruction. The mitral insufficiency was located in a commissural area in 4 cases, and was due to a widespread posterior prolapse in 2. Post-operative control transesophageal echocardiography confirmed the excellent results of the repair and proved that, in selected cases, the tricuspid leaflet inserted onto the mitral apparatus is very efficient in correcting mitral insufficiency, without causing significant tricuspid impairment. With a 3 to 7 month follow-up, the results are stable. PMID- 8678758 TI - [Contact dermatitis following cardiac pacemaker implantation]. AB - The authors report a case illustrating the causality between the appearance of contact eczema and the implantation of a cardiac pacemaker. To the authors' knowledge, only 11 cases of eczema secondary to the implantation of a pacemaker have been previously reported, all in dermatological journals. In 60% of caes, the lesions were observed over the pacemaker implantation and the appearance of the rash varied from 2 days to 24 months. The causal allergens were mainly the metallic and plastic components. The physiopathological mechanisms, though not completely understood, are related to cellular immunity and therefore, to delayed hypersensitivity reactions. From the therapeutic point of view, locak steroid applications to limited excema lesions have been suggested but recurrence is common. The only effective treatment is removal of the allergen. PMID- 8678759 TI - [Primary liposarcoma of the left ventricle. Apropos of a case and review of the literature]. AB - Primary malignant myocardial tumours are rare and essentially sarcomas. The authors report a case of primary left ventricular liposarcoma which is the 18th reported case. The presenting signs were of cardiac failure. Metastases are common by the time of diagnosis. Surgical ablation, though rarely complete because of its myocardial localisation, is justified for precise histological diagnosis. The prognosis of these lesions is poor. Complementary treatment is rarely used. However, it should be proposed as surgery alone has been shown to have limited curative applications. PMID- 8678760 TI - [Non bacterial thrombotic endocarditis (marantic endocarditis). Apropos of a case and value of transoesophageal echocardiography]. AB - Marantic or non-bacterial thrombotic endocarditis is a common complication of terminal malignancy, usually discovered at autopsy. The authors report a case of marantic endocarditis as a presenting sign of pancreatic carcinoma in which the diagnosis was made ante-mortem by transoesophageal echocardiography. PMID- 8678761 TI - [Emergency angioplasty for total thrombosis of the left main coronary artery. Apropos of a case]. AB - Complete thrombosis of the left main coronary artery is a rare angiographic finding and usually gives rise to cardiogenic shock during unstable angina or myocardial infarction. The prognosis of this condition is very dependent on the collateral coronary circulation and the myocardial protection seems to depend on the rapidity of revascularisation. Two therapeutic approaches may be envisaged; emergency coronary bypass grafting or percutaneous angioplasty, the natural history being particularly disastrous. The authors report the case of a 42-year old patient with complete occlusion of the left main stem responsible for unstable angina and acute pulmonary oedema. The outcome with angioplasty in the acute phase associated with surgical revascularisation four days later, was good. PMID- 8678762 TI - [Apropos of a case of malignant cardiac lymphoma in HIV infection]. PMID- 8678763 TI - Financial morbidity. Recognition and treatment of the "rich-boy syndrome". PMID- 8678764 TI - The use of duplex ultrasonography in penetrating neck trauma. AB - OBJECTIVE: To compare intraoperative findings and/or angiography with color-flow duplex scan. DESIGN: This prospective double-blind study was performed on all stable patients with zone 1, 2, or 3 penetrating neck trauma. Results of angiographic or intraoperative findings were compared with the results of duplex ultrasonographic scans. MAIN OUTCOME MEASURES: Fifty-five patients were studied over a 2-year period in which the distribution of injuries included 23 stab wounds (42%), 30 gunshot wounds (54%), and 2 motor vehicular lacerations (4%). There were 42 patients (76%) with normal ultrasonographic results and 13 patients (24%) with abnormal ultrasonographic results. The true-negative rate was 100%; however, there were 2 false positives resulting in 100% sensitivity and 85% specificity. CONCLUSIONS: Duplex ultrasonography provides an excellent diagnostic modality with cost-saving, patient-friendly characteristics and a low rate of morbidity. It should be instituted as the primary diagnostic procedure of choice for penetrating neck trauma. PMID- 8678765 TI - Cost-effectiveness of prophylactic anticoagulation prolonged after hospital discharge following general surgery. AB - OBJECTIVE: To evaluate the net clinical benefit and the economic burden of prophylactic anticoagulation prolonged after hospital discharge following general surgery. DESIGN: A cost-effective analysis representing the risks of developing symptomatic venous thromboembolism beyond the hospital stay, the risks of major bleeding, and the efficacy of treatment. Data were drawn from the literature. SUBJECTS: A hypothetical cohort of 10,000 patients discharged from the hospital after general surgery (gastrointestinal, gynecologic, urologic, or vascular surgery). INTERVENTIONS: We compared 2 strategies: (1) prolonged self administered prophylactic low-dose low-molecular-weight heparin during 4 weeks after discharge from the hospital and (2) anticoagulant therapy with heparin started immediately after the first clinically overt venous thromboembolism. MAIN OUTCOME MEASURES: The number of venous thromboembolisms prevented, the number of major bleeding events induced, and the average direct costs. RESULTS: Prophylactic low-molecular-weight heparin was an effective therapy. Depending on the rate of venous thromboembolism (0.06% to 0.18% per week), this strategy prevented 19 to 58 venous thromboembolisms for a cohort of 10,000 patients treated, more than the number of anticoagulation-related complications (n = 10). Its marginal costs, however, exceeded $2.5 million (US dollars) for 10,000 patients. As the weekly rate of venous thromboembolism increased, prophylactic low-molecular-weight heparin became more cost-effective, with a marginal cost effectiveness ratio per venous thromboembolism prevented ranging from $135,903 (rate of venous thromboembolism, 0.06% per week) to 45,353 (rate of venous thromboembolism, 0.18% per week). CONCLUSION: Although prolonged prophylactic anticoagulation after hospital discharge for general surgery is effective in preventing venous thromboembolism, we believe that its marginal costs are too high to recommend its indiscriminate use. PMID- 8678766 TI - Adrenal lesions in a large kindred with multiple endocrine neoplasia type 1. AB - OBJECTIVE: To review the prevalence and natural history of adrenal lesions occurring in patients from a single kindred with multiple endocrine neoplasia type 1 (MEN-1). DESIGN: Case series. SETTING: Tertiary referral center. PATIENTS: Medical records of 33 patients from the Tasman 1 MEN-1 kindred who had undergone abdominal computed tomographic (CT) scanning were reviewed. In 30 patients, the results of abdominal ultrasonographic examinations were available for correlation with CT scan. Computed tomographic and ultrasound scans of 18 patients were reviewed by a radiologist blinded to the patients' clinical details. Three patients underwent adrenalectomy, and the histopathologic material was reviewed. MAIN OUTCOME MEASURES: Computed tomographic and ultrasound scans. RESULTS: Adrenal lesions were detected in 12 patients (36%) by CT scan examination. Ultrasound imaged 58% of these lesions. Pancreatic lesions were present in all cases of adrenal disease. Follow-up was available for 8 patients with adrenal disease. Over 5.5 years, 6 patients (75%) had stable disease, 1 patient had an adrenal lesion that enlarged by 5 mm, and 1 patient had a lesion that enlarged by 50 mm. Adrenal histopathologic material was available in 3 patients. Macronodular cortical hyperplasia was present in 2 patients and a cortical adenoma present in 1 patient. Another kindred had bilateral macronodular cortical hyperplasia at autopsy. CONCLUSIONS: Adrenal lesions are common in MEN-1 and occur in association with pancreatic disease. Abdominal CT scan is more sensitive than ultrasonographic examination in detecting adrenal disease. Primary hypersecretory syndromes of the adrenal glands appear to be rare, and the majority of lesions follow an indolent clinical course. PMID- 8678767 TI - The role of whole-body positron emission tomography with [18F]fluorodeoxyglucose in identifying operable colorectal cancer metastases to the liver. AB - OBJECTIVE: To compare the accuracy of whole-body position emission tomography (PET)using [18F]fluorodeoxyglucose (FDG) with conventional radiological imaging techniques in identifying operable colorectal cancer metastases to the liver. DESIGN: A double-blind comparative study of FDG-PET as the criterion standard vs conventional radiological imaging methods as the criterion standard, in staging of recurrent colorectal cancer. SETTING: Institutional practice in a tertiary referral center. PATIENTS: Thirty-four consecutive patients with suspected colorectal cancer metastases recruited for the study between May 1993 and October 1994. INTERVENTIONS: Conventional radiological methods of cancer staging included abdominal computed tomography (CT) (n = 34), chest x-rays (n = 15), and chest CT (n = 19) to evaluate extrahepatic disease. Twenty-seven patients were subsequently considered to have apparently isolated cancer metastases to the liver. Anatomical resectability was assessed by magnetic resonance imaging (n = 24) or CT angiography (n = 3) in all study patients. The FDG-PET studies (n = 34) were performed within 8 weeks of conventional radiological imaging. MAIN OUTCOME MEASURES: Malignancy of suspected lesions detected by means of FDG-PET and conventional radiological imaging was confirmed by histopathologic examination of resected specimens and percutaneous biopsy specimens and by serial CT scans demonstrating progression of disease. RESULTS: Unsuspected extrahepatic malignant disease that was missed by conventional radiological imaging was detected by FDG PET in 11 patients (32%). The PET-detected extrahepatic malignant disease included retroperitoneal nodal metastases (n = 6), pulmonary metastases (n = 3), and locoregional cancer recurrences (n = 2). The additional information afforded by PET consequently had an influence on the clinical management in 10 patients (29%). CONCLUSIONS: The FDG-PET method enabled selection of patients with apparently curable colorectal cancer metastases to the liver for hepatic resection. PMID- 8678769 TI - Use of transrectal ultrasonography to select type of surgery for villous tumors in the lower two thirds of the rectum. AB - OBJECTIVE: To determine the accuracy of transrectal ultrasonographic (TRUS) staging of rectal villous tumors when used to select a surgical procedure. DESIGN: Case series. SETTING: College hospital, Hyogo, Japan. PATIENTS: From 1988 to 1995, 24 patients were treated for villous tumors after diagnosis by TRUS, and were followed up for 0.5 to 7.5 years. MAIN OUTCOME MEASURES: Ultrasonographic tumor stage (u-T), pathologic tumor stage (p-T), biopsy findings, and surgical procedures were studied. RESULTS: Overall, 71% of the tumors were accurately staged by TRUS. However, 4 u-T1 and 3 u-T2 tumors were overstaged, with pathological examination showing 2 adenomas and 5 p-Tis tumors. Three of these 7 patients were overtreated surgically. The results of a biopsy predicted adenoma in 2 of the u-T1 tumors and 2 of the u-T2 tumors that were overstaged by TRUS. Pathological examination revealed that an enlarged lymphoid follicle in the mucosa had deformed the thin muscle layer of the rectal wall and abolished its continuity on TRUS imaging. The weakness of TRUS would seem to be in the accuracy of p-Tis staging. CONCLUSIONS: Transrectal ultrasonography had the advantage of predicting malignant infiltration in rectal villous tumors. The surgeon should know the limitations of TRUS diagnosis to select the most appropriate operation for each patient. PMID- 8678768 TI - Adenocarcinoma in the distal esophagus with and without Barrett esophagus. Differences in symptoms and survival rates. AB - OBJECTIVE: To evaluate differences in clinical appearance and survival rates in patients operated on for adenocarcinoma in the distal esophagus with and without Barrett epithelium. DESIGN: Prospective clinical study. SETTING: University hospital, Sweden. PATIENTS: Fifty-four patients with adenocarcinoma in the distal esophagus with (n = 17) or without (n = 37) Barrett epithelium. INTERVENTION: Esophagectomy or total gastrectomy. MAIN OUTCOME MEASURES: Preoperative symptoms, endoscopic results, and histological findings; postoperative morbidity, mortality, and survival rates. RESULTS: The main indication for the endoscopic examination that revealed tumor in the group with Barrett esophagus was reflex related symptoms in 6 patients (routine Barrett examination, n = 4; symptoms of reflux, n = 2), symptoms related to upper gastrointestinal tract bleeding in 6, and malignant symptoms in 5 (dysphagia, n = 4; weight loss, n = 1). In contrast, most patients in the cardia cancer group were admitted because of malignant symptoms (dysphagia, n = 26; epigastric pain, n = 9; and anemia, n = 2). Ten of 17 patients in the Barrett esophagus cancer group had tumors limited to the mucosa and submucosa only. In 1 patient the tumor grew into the muscular layer but not through it. In the remaining 6 patients the tumor did grow through the muscular layer and lymph node metastases were found. Wall penetration was found in 30 patients and metastases to lymph nodes in 29 patients in the cardia cancer group. The hospital mortality rate was 0 of 17 patients in the Barrett cancer group and 2 of 37 patients in the cardia cancer group. In the patients operated on for adenocarcinoma in the distal esophagus, a better long-term survival rate was seen in those with Barrett epithelium (50%) than in those without this metaplasia (10%) (log rank P = .005; X2 = 7.80). CONCLUSIONS: Concomitant Barrett epithelium improved the prognosis for patients with adenocarcinoma in the distal esophagus. Probably the reason for this was a higher rate of early-stage disease, because symptoms of gastroesophageal reflux and other benign disorders, not dysphagia, were most common in patients with adenocarcinoma without Barrett epithelium in the distal esophagus. PMID- 8678770 TI - Immunomodulatory effects of ornithine alpha-ketoglutarate in rats with burn injuries. AB - OBJECTIVE: To investigate the influence of enterally administered ornithine alpha ketoglutarate (OKG) on muscular amino acid content, eicosanoid release, and polymorphonuclear leukocyte responsiveness after induction of burn injury in rats. DESIGN: Experimental trial. MATERIALS AND METHODS: Four groups of rats were considered: (1) healthy rats that received a standard diet supplemented with 5 g/kg per day of OKG; (2) rats with burn injuries that received the same nutrition as group 1; (3) healthy rats that received standard diet supplemented with glycine in an isonitrogenous amount relative to OKG; and (4) rats with burn injuries that received the same nutrition as group 3. The thymus and 1 skeletal muscle were weighed. The oxidative metabolism of pleural polymorphonuclear leukocytes was measured by means of superoxide generation (O2-) and the chemiluminescent response to opsonized zymosan. Prostaglandin E2 and 6-keto prostaglandin F1 alpha were measured in the supernatants of pleural and peritoneal cells. RESULTS: The weights of the thymus and the muscle from healthy rats were similar. Those of rats from group 4 were significantly lower (P < .05), whereas those of rats from group 2 were not. Metabolism of OKG led to enhanced amounts of arginine and glutamine in skeletal muscle. The metabolic bursts of polymorphonuclear leukocytes from healthy rats were similar. Those of glycine treated rats with burn injuries were significantly depressed (P < .05), whereas those of the OKG-treated group were not. Pleural and peritoneal cells from the rats with burn injuries that received OKG generated significantly more prostaglandins (P < .01) than did cells from the other groups of rats. CONCLUSION: Ornithine alpha-ketoglutarate administered to rats with burn injuries displays immunomodulatory properties that can enhance host-defense mechanisms in animals that are affected by a severe injury. PMID- 8678771 TI - Recurrent secondary hyperparathyroidism. An argument for total parathyroidectomy. AB - OBJECTIVE: To define better the incidence and causes of recurrent secondary hyperparathyroidism. DESIGN: Review of total parathyroidectomy with autotransplantation in uremic patients and literature review. SETTING: Two teaching hospitals. PATIENTS: Nine patients treated for secondary hyperparathyroidism between 1982 and 1993 by a single surgeon. INTERVENTIONS: Total parathyroidectomy with autotransplantation into the sternocleidomastoid muscle. Recurrence was treated, if necessary, with a graft reduction procedure. MAIN OUTCOME MEASURES: The symptomatic and biochemical response to initial therapy, morbidity, and mortality, as well as the development of recurrent hypercalcemia. RESULTS: All patients were normocalcemic after their initial surgery. One patient died postoperatively (mortality, 11%). Three (38%) of the remaining patients developed recurrent hypercalcemia, 2 (25%) requiring reoperation. Of the 2 patients who underwent surgery for recurrence, 1 had an adenoma in the implant and the other had graft hyperplasia. CONCLUSIONS: Recurrence rates after total parathyroidectomy with autotransplantation are substantial and, given the pathophysiology of secondary hyperparathyroidism, unavoidable in patients with uncorrected renal failure. An argument is made for performing total parathyroidectomy alone in patients with secondary hyperparathyroidism who will not undergo renal transplantation in the near future. PMID- 8678772 TI - Preload assessment in trauma patients during large-volume shock resuscitation. AB - OBJECTIVES: To evaluate the utility of the right ventricular end-diastolic volume index (RVEDVI) as a method of preload assessment in trauma patients during large volume shock resuscitation, and to compare the RVEDVI with the pulmonary artery occlusion pressure (PAOP) as a predictor of preload in this patient population. DESIGN: Retrospective study of a consecutive series of 46 trauma patients, admitted between June 1, 1992, and June 1, 1993, who received a volumetric oximetry pulmonary artery catheter and greater than 10 L of fluid in 24 hours. SETTINGS: University level 1 trauma center. MAIN OUTCOME MEASURES: Correlations of the RVEDVI and PAOP with the cardiac index (CI) during the defined study period. RESULTS: Three hundred fourteen measurements of the RVEDVI, PAOP, CI, and other hemodynamic variables were evaluated. Patients received a mean +/- SD of 22.1 +/- 13.3 L of blood and fluid during the 24 hours. The RVEDVI correlated better (P < .001) with the CI (r = 0.39) than did the PAOP (R = 0.05). Furthermore, there was a better correlation (P < .04) between the RVEDVI and CI when the RVEDVI was 130 mL/m2 or less (r = 0.54) than when it was greater than 130 mL/m2 (r = 0.30). CONCLUSIONS: The RVEDVI is a better predictor of preload than the PAOP in trauma patients during large-volume shock resuscitation. When the RVEDVI is 130 mL/m2 or less, volume administration will likely increase the CI. PMID- 8678773 TI - Noninvasive physiologic monitoring of high-risk surgical patients. AB - OBJECTIVES: To study the feasibility of multicomponent noninvasive monitoring, consisting of a new bioimpedance method for estimating cardiac output together with routine pulse oximetry and transcutaneous oximetry, and to compare physiologic data obtained noninvasively with hemodynamic and oxygen transport data obtained by standard invasive pulmonary artery thermodilution catheter to evaluate circulatory function in high-risk surgical patients. DESIGN: Prospective descriptive analysis of the time course of physiologic patterns in surgical patients. SETTING: University-run county hospital. PATIENTS: Seventy-one consecutively monitored, high-risk critically ill surgical patients in their perioperative period. OUTCOME MEASURES: Simultaneous measurements by invasive and noninvasive methods to describe and compare the temporal physiologic patterns of survivors and nonsurvivors. RESULTS: The new impedance cardiac output estimations closely approximated those of the thermodilution method (r = 0.82, P < .001). Episodes of hypotension, tachycardia, low cardiac index, arterial hemoglobin desaturation, low transcutaneous oximetry, reduced oxygen delivery, and low oxygen consumption occurred with both groups but were more pronounced in the nonsurvivors than in the survivors. Noninvasive monitoring provided information similar to that of the thermodilution method. Both approaches indicated low flow and poor tissue perfusion (oxygenation) that was worse in the nonsurvivors. CONCLUSIONS: The multicomponent noninvasive monitoring provides continuous online, real-time displays of physiologic data that allow immediate recognition of circulatory dysfunction as well as the means to titrate therapy to appropriate predetermined therapeutic goals. The noninvasive systems are easy to apply, safe, inexpensive, reasonably accurate, and cost-effective. PMID- 8678774 TI - Measurement of oxygen free radicals in a rabbit shock lung model. Effect of superoxide dismutase and retinol. AB - OBJECTIVES: To develop an isolated rabbit lung model in which oxygen free radical activity could be measured and to examine the effects on the model of oxygen free radical scavengers. DESIGN: Prospective, randomized study. SETTING: A clinical and basic research facility attached to a teaching hospital. PARTICIPANTS: Twenty five New Zealand white rabbits weighing 3.5 to 4.5 kg. INTERVENTIONS: The mechanism of lung injury by oleic acid or by phorbol myristate acetate (20 ng/mL) plus polymorphonuclear neutrophils (PMA-PMN) in an ex vivo rabbit shock lung model may be the production of oxygen free radicals. Using a standard heart-lung preparation from these rabbits, baseline mean pulmonary artery pressure was maintained at 15 mm Hg and the mean airway pressure at 10 mm Hg. Experimental perfusates were infused over 30 minutes, followed by Krebs-Henseleit solution, pH 7.4. Dimethyl pyrroline oxide trapped oxygen free radicals, levels of which were measured by electron paramagnetic resonance spectroscopy. Lung injury was assessed by light and scanning electron microscopy and by lung weight. RESULTS: A 5-fold increase in pulmonary artery pressure (P < .001) and a nearly 3-fold increase in mean airway pressure (P < .001) were observed in both the oleic acid and PMA-PMN models. Superoxide dismutase (20,000 U/kg), but not retinol palmitate (2000 U), prevented lung injury, the increases in pulmonary artery pressure and mean airway pressure, and the increase in oxygen free radicals in the PMA-PMN model. There were no increases in oxygen free radicals in the control, oleic acid, or PMA-PMN/superoxide dismutase groups (n = 5 in each group). Maximum mean +/- SD increases in oxygen free radicals were 112 +/- 22 nmol/L in the PMA-PMN group (P < .003, n = 5) and 108 +/- nmol/L in the PMA-PMN/retinol group (P < .003, n = 5). CONCLUSIONS: The mechanism of lung injury in the PMA-PMN model is an increase in oxygen free radicals, because superoxide dismutase prevents both the rise in oxygen free radicals and lung injury. Administration of retinol does not prevent lung injury. Oleic acid produces injury not by an increase in oxygen free radicals but rather by another, unknown mechanism. PMID- 8678775 TI - A cost-effectiveness evaluation of 3 antimicrobial regimens for the prevention of infective complications after abdominal surgery. AB - OBJECTIVE: To measure the cost and effectiveness of 3 established antimicrobial regimens for the prevention of infective complications after abdominal surgery. DESIGN: A prospective randomized trial was performed involving a total of 1070 patients undergoing abdominal surgery. SETTING AND PATIENTS: All patients having upper gastrointestinal tract, colorectal, appendiceal, or biliary surgery at a major teaching hospital in Melbourne, Australia, were considered for entry into the study. INTERVENTIONS: Patients were randomized prior to surgery to receive a single dose of cefotaxime sodium (1 g), ticarcillin plus clavulanic acid (3.1 g), or ceftriaxone sodium, (1 g). All drugs were given intravenously at the start of anesthesia. MAIN OUTCOME MEASURES: Rates of major wound infections, minor wound infections, other wound problems, and other infective complications. The acquisition and administrative costs of the drugs used and the costs of the infective complications were measured. RESULTS: A Total of 1070 patients were entered into the study. Major wound infections occurred in 21 patients (2.0%). Twenty-five patients (2.3%) developed a minor wound infection. Other infective complications developed in 107 patients. There were significantly fewer minor wound infections in the ceftriaxone-treated group as compared with the other 2 groups. There was no differences in the frequency of major wound infections, other wound problems, or other infective complications. The acquisition costs of cefotaxime and ticarcillin plus clavulanic acid were less than those of ceftriaxone. The estimated cost of treating the infective complications in the group of patients who received ticarcillin plus clavulanic acid ($128,039) was greater than the cost associated with the groups being treated with cefotaxime ($91,243) or ceftriaxone ($96,095). CONCLUSIONS: The study indicates that each of the 3 regimens was associated with highly satisfactory control of postoperative infective complications after abdominal surgery. On the basis of the estimated costs of infective complications, cefotaxime and ceftriaxone appear equally effective for the prevention of infective complications after abdominal surgery. Acquisition costs for cefotaxime were lower and it is recommended as the preferred agent on this basis. PMID- 8678776 TI - Summary of the 5th European Congress of Surgery and the 10th meeting of the Spanish Society of Surgeons. PMID- 8678777 TI - Feasibility and safety of 1-day postoperative hospitalization for carotid endarterectomy. AB - OBJECTIVE: To determine whether 1-day postoperative hospitalization after carotid endarterectomy is safe and the degree to which this can be achieved. DESIGN: Consecutive sample series of all carotid endarterectomies performed by a single surgical group. SETTING: A single tertiary-care hospital. PATIENTS: All who underwent carotid endarterectomy. Patients with procedures combined with coronary revascularization and patients undergoing the first part of a staged bilateral carotid endarterectomy performed in 1 hospitalization were excluded. INTERVENTION: In December 1993, a fast-track protocol was initiated, aiming for a 1-day stay after carotid endarterectomy without admission to an intensive care unit (ICU). Before this date, postoperative care included obligatory monitoring for at least 1 night in an ICU. MAIN OUTCOME MEASURES: Length of stay, admission to and stay in the ICU, complications, and hospital readmission rate. RESULTS: Over a 21-month period, 152 patients had 163 carotid endarterectomies. Of these, 124 were elective and 39 urgent (patients with a critical stenosis). Indications were stroke (n = 14 [8.6%]), transient ischemic attack (n = 50 [30.7%]), amaurosis fugax (n = 36 [22.1%]), and asymptomatic stenosis (n = 63 [38.7%]). General anesthesia was used for 159 procedures, cervical block for 4. Mean operation time was 2.6 hours. Postoperative stay was 1 day for 82 procedures (50%), 2 days for 49 procedures (30%), 3 days for 12 procedures (7%), and longer for 20 procedures (12%). In the last half of the study, 61% of patients (50/82) were discharged on postoperative day 1 and 87% (71/82) by postoperative day 2. One hundred three patients went to a surgical floor postoperatively. Overall, 60 patients went to the ICU, but only 18 (22%) of the last 82 procedures required ICU admission. The total stay averaged 3.8 days. Twenty-one patients (13%) experienced complications, including 3 deaths within 30 days and 5 neurological deficits. There were 14 early readmissions, but none was attributable to discharge on the first or second postoperative day. CONCLUSIONS: Early discharge home after carotid endarterectomy is safe and efficacious, and obligatory admission to an ICU is not necessary. At least 60% of patients who undergo carotid endarterectomy can have a postoperative stay of 1 day, and more than 80% can be discharged by postoperative day 2. A short postoperative stay is not associated with a significant risk of readmission for complications. PMID- 8678778 TI - Effect of hyperbaric oxygen on neutrophil concentration and pulmonary sequestration in reperfusion injury. AB - OBJECTIVE: To evaluate the effect of hyperbaric oxygen (HBO) on muscle flap arterial neutrophil concentration and pulmonary neutrophil sequestration following ischemia-reperfusion injury in a rat gracilis muscle microcirculation model. DESIGN: Prospective randomized experimental trials. SETTING: Laboratory. MATERIALS: Male Wistar rats weighing 150 to 300 g. INTERVENTIONS: Gracilis muscle flaps were raised on isolated vascular pedicles. Three groups were evaluated: (1) sham (flap raised, 4-hour observation, no ischemia, no HBO), (2) ischemia control (4-hour flap is ischemia, no HBO); and (3) ischemia (4-hour flap is ischemia) plus HBO (last 90 minutes of ischemia, 100% oxygen, 2.5 atm absolute). MAIN OUTCOME MEASURES: Flap pedicle arterial leukocyte and neutrophil concentrations were assessed at 5 and 90 minutes of reperfusion in the 3 groups. Pulmonary neutrophil sequestration was measured in a blinded fashion, using histologic examination and myeloperoxidase assay in the 3 groups at 5 and 90 minutes of reperfusion. RESULTS: Ischemia produced an increase in pedicle arterial leukocyte and neutrophil concentrations in blood flowing to the gracilis muscle flap; administration of HBO significantly reduced concentration to sham levels (P < .05). There were no significant differences in pulmonary neutrophil sequestration among the experimental groups. CONCLUSIONS: In this rat gracilis muscle microcirculation model, the increase in pedicle arterial leukocyte and neutrophil concentrations following ischemia-reperfusion injury was significantly reduced to sham levels by HBO treatment. This observed reduction was not attributable to HBO induced pulmonary sequestration, which did not significantly change with HBO administration. Further investigation is required to elucidate the mechanisms of action of HBO in ameliorating ischemia-reperfusion injury in this model. PMID- 8678779 TI - Long-term peritoneal dialysis before transplantation and intra-abdominal infection after simultaneous pancreas-kidney transplantations. AB - OBJECTIVE: To investigate whether long-term peritoneal dialysis before transplantation entails a higher risk than hemodialysis for intra-abdominal infection after bladder-drained simultaneous pancreas-kidney transplantations. DESIGN: Large single-center case-control study. SETTING: A large university hospital (referral center). PATIENTS: In all, 189 bladder-drained simultaneous pancreas-kidney transplantations were done from January 1, 1986, to December 31, 1994: before transplantations were performed, 32 recipients (17%) were undergoing peritoneal dialysis, 71 recipients (38%) were undergoing hemodialysis, and 86 recipients (46) were not undergoing dialysis. MAIN OUTCOME MEASURES: The intra abdominal infection rate after transplantation and the rate of graft loss due to infection. RESULTS: Intra-abdominal infections developed in 33 recipients (18%) after transplantation. Graft and patient survival rates were significantly lower for recipients with vs without an infection (P < .001 for both). Both the dialysis mode and dialysis dependence did not affect the infection rate: of the 33 recipients with an infection, 7 (21%) were undergoing peritoneal dialysis, 15 (46%) were undergoing hemodialysis, and 11 (33%) were not undergoing dialysis before transplantation (P = .3). The rate of graft loss due to infection was not significantly different for recipients who were undergoing peritoneal dialysis vs hemodialysis (P = .1). However, it was higher for recipients who were undergoing dialysis (peritoneal dialysis and hemodialysis) vs those patients who were not undergoing dialysis (P = .04). CONCLUSIONS: Candidates for simultaneous pancreas kidney transplantation should undergo the transplantation preemptively (ie, before they become dependent on dialysis) because the rate of graft loss due to infection was higher for recipients who were undergoing dialysis (irrespective of the dialysis mode). If dialysis cannot be avoided, the choice of peritoneal dialysis vs hemodialysis can be individualized, since these dialysis modes do not have significantly different rates of infection or of graft loss due to infection. PMID- 8678780 TI - Effects of nitric oxide donor SIN-1 on oxygen availability and regional blood flow during endotoxic shock. AB - BACKGROUND: An excessive release of nitric oxide (NO) has been incriminated in the circulatory disturbances of septic shock. OBJECTIVE: To study the effects of an NO donor, 3-morpholinosydnonimine (SIN-1), an oxygen availability and regional blood flow during endotoxic shock to see if a beneficial effect of NO synthase inhibitors in septic shock could be conclusively demonstrated. MATERIALS AND METHODS: In 14 anesthetized and mechanically ventilated dogs, global invasive hemodynamic monitoring was completed and ultrasonic flow probes were placed around the superior mesenteric, left renal, and left femoral arteries for simultaneous measurements of regional blood flow. All dogs received Escherichia coli endotoxin, 2 mg/kg. A control group (n = 7) was administered saline at 20 mL/kg per hour, and a SIN-1 group (n = 7) was given a combination of saline with SIN-1 at successive doses of 1, 2, and 4 micrograms/kg per minute. RESULTS: Neither systemic nor pulmonary arterial pressures were influenced by SIN-1. Cardiac index, stroke index, and left ventricular stroke work index did increase at low to moderate doses of SIN-1 but tended to decrease at the highest dose. Systemic and pulmonary vascular resistances decreased. Fractional blood flow increased in the mesenteric bed at all doses used, was not influenced in the renal bed, but decreased in the femoral bed at the highest dose. Oxygen-derived variables were similar in the 2 groups. Blood lactate and plasma concentrations of tumor necrosis factor were not significantly influenced. At the end of the SIN 1 infusion, the administration of 5 mg/kg of methylene blue increased arterial pressure, pulmonary arterial pressure, and systemic and pulmonary vascular resistances but decreased cardiac index and regional blood flow. CONCLUSIONS: The administration of low to moderate doses of the NO donor SIN-1 can significantly increase cardiac index and superior mesenteric blood flow without deleterious effects on arterial pressure in this model of endotoxic shock. These findings support the hypothesis that NO is essential to maintain organ blood flow even during endotoxic shock. PMID- 8678781 TI - Moderation of anal sphincter tone with nitric oxide agonists and antagonists. AB - OBJECTIVE: To test the thesis that agonists and antagonists of nitric oxide, when applied topically to the anal and rectal mucosa, could moderate rectal pressure. BACKGROUND: In vitro studies of muscle strips have suggested that tension of the internal anal sphincter is controlled by nitric oxide. METHODS: Gently restrained, unanesthetized rats were used. The experimental drug in a volume of 0.1 mL was introduced into the rectal lumen with a fine syringe. Thereafter a soft catheter-tipped balloon was inserted and inflated with 1 mL of water, and, after 1 minute when the reflex muscle spasm had abated, pressure was measured with a strain gauge transducer. The catheter was reinserted at 10- to 30-minute intervals for pressure measurements. RESULTS: Tumor necrosis factor alpha led to a dose-dependent reduction in pressure, reaching a nadir at 30 minutes and returning toward baseline at 60 minutes. At a concentration of 0.1 microgram per 0.1 mL of saline, pressure fell from 63 to 47 mm Hg, while pressure fell from 72 to 23 mm Hg at 10 micrograms. The precursor of nitric oxide, L-arginine, in concentrations of 0.01 mg but not 0.0001 mg, also led to declines in sphincter pressure (P < .05). The higher concentrations appeared to cause a more rapid fall in pressure; however, in all cases the nadir was reached at 30 minutes. Sphincter pressure remained low at 60 minutes but could be restored to baseline 30 minutes after the topical application of 1 mg of the L-arginine antagonist, N-omega-nitro L-arginine methyl ester (L-NAME) but not with saline. In animals treated with L arginine mixed in a water-soluble jelly, sphincter pressure continued to fall during the 60 minutes of monitoring. At a concentration of 1 mg, pressure fell from 56 +/- 3 to 33 +/- 2 (mean +/- SEM) mm Hg (P < .05); at 10 mg, pressure fell from 63 +/- 4 to 36 +/- 3 mm Hg (P < .05). When L-NAME was admixed with L arginine in the water-soluble jelly, there was no fall in pressure during the 60 minute observation period. CONCLUSION: These data indicate that the action of agonists and antagonists of nitric oxide synthesis carries across the anorectal mucosa and rapidly modifies sphincter tone. PMID- 8678782 TI - Functional contribution of preoperative portal vein occlusion to hepatectomy. With special reference to hepatic energy charge and DNA synthesis after hepatectomy in rats. AB - OBJECTIVE: To examine possible functional contributions of preoperative portal branch ligation before hepatectomy (PBL-Hx). DESIGN: Rats were randomly divided into 3 groups. In the PBL-Hx group, the portal branch supplying the left lateral and median lobes of the liver was ligated and the corresponding lobes (48% of the whole liver) were excised 2 days later. In the sham groups (one 68% Hx; the other 47% [hereafter, sham-67% Hx, and sham-47% Hx]), originally ligated lobes and left lateral and caudate lobes, similar to the excised liver volume in the PBL-Hx group, respectively, were excised 2 days after sham operation without PBL. MAIN OUTCOME MEASURES: Hepatic adenine nucleotides and energy charge, which are essential for vital function of hepatocytes, and liver regeneration were assessed by the DNA synthesis rate and weight before Hx and on days 1, 2, 3, and 7 after Hx. RESULTS: The remaining liver weight was restored similarly in the PBL-Hx and sham-47% Hx groups and more rapidly than in the sham-68% Hx group. Further enhancement of DNA synthesis did not occur after Hx in the PBL-Hx group, and hepatic energy charge did not decrease. In contrast, hepatic DNA synthesis was significantly activated depending on the excised liver volume in both the sham-Hx groups and was accompanied by corresponding decreases in hepatic energy charge. CONCLUSION: Preoperative PBL has a functional advantage because the recovery of the remaining liver volume is not impaired and hepatic energy charge is preserved with no further enhancement of DNA synthesis after Hx. PMID- 8678783 TI - Acute appendicitis following abdominal trauma. AB - Acute appendicitis (AA) is generally considered to be a consequence of lumenal obstruction and inflammation of the appendix. At the beginning of the 20th century, trauma was considered to be one of the possible causes of AA but this relationship has not been examined much since then. Our experience with three cases of AA following blunt abdominal trauma led to an extensive review of the world literature on the subject. We believe that abdominal trauma might be causative of AA. The potential for this hazardous and easily missed diagnostic entity should be appreciated in cases of blunt abdominal trauma both for sound clinical decision making and for its potential medical and legal implications. PMID- 8678784 TI - Operative injury to the hepatic artery. PMID- 8678785 TI - The new era in breast cancer. PMID- 8678786 TI - Connexin genes and cell growth control. PMID- 8678787 TI - Disruption of polarized function in hepatocytes. PMID- 8678788 TI - Cytokines in human lung fibrosis. AB - Fibrosis is a pathological process characterized by the replacement of normal tissue by mesenchymal cells and the extracellular matrix produced by these cells. The sequence of events leading to fibrosis of an organ involves the subsequent processes of injury with inflammation and disruption of the normal tissue architecture, followed by tissue repair with accumulation of mesenchymal cells in the area of derangement. The same sequence of events occurs in wound healing with normal granulation tissue and scar formation, but, while normal scar formation is very localized and transient, in contrast, in fibrosis, the repair process is exaggerated and usually widespread and can be chronic. Inflammatory cells (mainly mononuclear phagocytes), platelets, endothelial cells, and type II pneumocytes play a direct and indirect role in tissue injury and repair. The evaluation of three human fibrotic lung diseases, two diffuse [idiopathic pulmonary fibrosis (IPF), and the adult respiratory distress syndrome (ARDS)], and one focal (tumor stroma in lung cancer), has shown that several cytokines participate to the local injury and inflammatory reaction [interleukin-1 (IL-1), interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha)], while other cytokines are involved in tissue repair and fibrosis [platelet derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-beta), and basic-fibroblast growth factor (b-FGF)]. A better understanding of the cytokines and cytokine networks involved in lung fibrosis leads to the possibility of new therapeutic approaches. PMID- 8678789 TI - The glio-vascular toxicity of m-dinitrobenzene and related agents: modulation of toxicity by neuronal activation. PMID- 8678790 TI - Mechanistical studies of the inhibition of intercellular communication by organochlorine compounds. AB - Many hydrocarbons are environmental pollutants that, due to their lipophilicity and chemical stability, accumulate in biological systems including milk and body fat. A number of investigations have demonstrated that many organochlorine compounds can act as tumour promoters in vivo and inhibit gap junctional intercellular communication between cells in culture. In the present study we have investigated the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), different polychlorinated biphenyls, chlorinated paraffins and the pesticide endosulfan. Using techniques of scrape loading dye/transfer and Western blot analysis the function, expression and phosphorylation of different connexins in vitro and in vivo were studied. The results show a good correlation between the ability to act as a tumour promoter and to interfere with gap junctional intercellular communication. All tested compounds inhibited the intercellular communication in a liver derived cell line (IAR 20). However, the results show that the time to inhibition varies between the different agents. Endosulfan and chlorinated paraffins inhibit the communication within one hour, whereas dioxin like substances need to expose the cells for 48 hours before the communication is affected. PMID- 8678791 TI - Halogenated organic compounds and the human immune system: preliminary report on a study in hobby fishermen. PMID- 8678792 TI - Biotransformation and renal processing of nephrotoxic agents. AB - Nephrotoxicity is often observed as an endpoint in animal toxicity studies. In recent years, the mechanisms of biotransformation, which often provide the basis for renal toxicity, have been elucidated for a variety of compounds. These studies showed that nephrotoxicity of chemicals is either due to accumulation of certain metabolites in the kidney and further bioactivation or due to intrarenal bioactivation of the parent xenobiotic. Both types of mechanisms will be discussed using two relevant samples. The polychlorinated olefin hexachlorobutadiene and other haloolefins cause necrosis of the S-3 segment of the proximal tubules; their nephrotoxicity is dependent on bioactivation reactions. In the liver, hexachlorobutadiene is transformed by conjugation with glutathione to (S-pentachlorobutadienyl)glutathione. This S-conjugate is processed by the enzymes of mercapturic acid formation to give N-acetyl-(S pentachlorobutadienyl)-L-cysteine, which is accumulated in the proximal tubule cells and deacetylated there to give (S-pentachlorobutadienyl)-L-cysteine. Further bioactivation is catalyzed by renal cysteine conjugate beta-lyase. Both the renal accumulation by the organic anion transporter and the topographical distribution of cysteine conjugate beta-lyase along the nephron are major determinants of organ and cell selectivity. Vinylidene chloride (VDC) is nephrotoxic in mice after inhalation, but not after oral or intraperitoneal administration. The nephrotoxicity of VDC is due to the selective expression of an androgen-dependent cytochrome P450 in the proximal tubules of male mice. This enzyme oxidizes VDC to an electrophile and is not present in female mice, but can be induced be androgen treatment. The observation of nephrotoxicity of VDC after inhalation only is due to the high blood flow to the kidney and thus high concentrations of VDC delivered to the kidney after inhalation. After oral or intraperitoneal application, hepatic first-pass metabolism efficiently reduces the amount of VDC delivered to the kidney. The results demonstrated here demonstrate that prior to in vitro nephrotoxicity screening, toxicokinetics and biotransformation pathways for a chemical have to be elucidated and metabolites have to be included into the testing regimen. PMID- 8678793 TI - Methods for studying renal toxicity. PMID- 8678794 TI - Site specific drug and xenobiotic induced renal toxicity. PMID- 8678795 TI - Mobilizers of stored cadmium. PMID- 8678796 TI - Chemical, pharmacological, toxicological and therapeutic advances of deferiprone (L1) and other iron and aluminium chelators. PMID- 8678797 TI - Risk assessment for the harmful effects of UVB radiation on the immunological resistance to infectious diseases. AB - Risk assessment comprises four steps: hazard identification, dose-response assessment, exposure assessment, and risk characterization. According this scheme, we have analysed the effects of UVB radiation on basal immune functions in rats and man, and the immunological resistance to infectious diseases in rats. Non-threshold mathematical methods were used in order to estimate the risk for the human population after increased exposure to UVB radiation. These data demonstrate that UVB radiation, at doses relevant to outdoors exposure, may affect the immunological resistance to infectious diseases in human individuals. This study may also provide a basis for a strategy to assess the risk of adverse effects of exposure to immunotoxic agents. PMID- 8678798 TI - Free radicals in toxicology: redox cycling and NAD(P)H:quinone oxidoreductase. PMID- 8678799 TI - Cytotoxic impact of DNA single vs double strand breaks in oxidatively injured cells. AB - Hydrogen peroxide is a potent inducer of DNA single strand breaks (SSBs) in cultured mammalian cells. These lesions, however, are efficiently repaired and do not appear to mediate the cytotoxic response. This inference is based on the observations that a) inhibiting the rate of SSB-removal does not result in an increased cytotoxicity; b) using different experimental conditions it is possible to dissociate the formation of DNA SSBs from the cytotoxic response; c) the induction/loss of the oxidant-resistant phenotype in cell variants characterized by different levels of resistance to the lethal effect of the oxidant does not correlate with resistance to DNA SSB-induction; d) a much larger accumulation of DNA SSBs can be observed following treatment with H2O2 at 4 degrees C, as compared to 37 degrees C, although the opposite is true in terms of cytotoxicity. In the presence of micromolar levels of L-Histidine, H2O2 also induces DNA double strand breaks (DSBs), a type of lesion which we suggest may mediate the lethal event. This conclusion finds experimental support in the following observations: a) DNA DSBs are generated at survival-range concentrations, and a linear correlation exists between the level of this lesion and cytotoxicity; b) this correlation curve overlaps with the curves generated under similar experimental conditions using different cell lines with different sensitivity to the oxidant alone, or different clones derived from the same cell line, some of which showed a high degree of resistance to H2O2. Finally, the formation of DNA DSBs appears to enhance both apoptotic and necrotic cell death. PMID- 8678800 TI - Mineral fiber-induced oxidative stress in phagocytes. PMID- 8678801 TI - Chemical methods for assessing systemic exposure to dietary heterocyclic amines in man. AB - A significant proportion of the mutagenic material present in cooked beef is accounted for by 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2 amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) which are formed during the cooking of meat. N-hydroxylation catalyzed by CYP1A2 is the major pathway of metbolism of MeIQx and PhIP and is solely responsible for the generation of mutagenic species. Assays for MeIQx and PhIP in foods and body fluids were developed utilising gas chromatography/mass spectrometry with stable isotope labelled analogues as internal standards. Studies using these assays have demonstrated that both MeIQx and PhIP are well absorbed and extensively metabolised following ingestion of amine-containing beef by humans. Studies in which furafylline, a potent and selective inhibitor of human CYP1A2, was administered before ingestion of beef revealed that more than 90% of MeIQx and 70% of PhIP are N-hydroxylated in vivo, probably pre-systemically in the liver. The results demonstrate that unchanged MeIQx and PhIP in urine are accurate and sensitive measures of systemic exposure to the amines. PMID- 8678802 TI - Immunological methods for dosimetry of heterocyclic amines. PMID- 8678803 TI - Formation and processing of reactive metabolites of the heterocyclic amines. PMID- 8678805 TI - Sentinel screening for human immunotoxicity. PMID- 8678804 TI - Enzymic and interindividual differences in the human metabolism of heterocyclic amines. AB - Heterocyclic amines (HAs) present in cooked meat (PhIP and MeIQx) are activated only by CYP1A2 in the liver of most species, including man. This enzyme exhibits marked interindividual differences in its expression, due to induction and possibly also genetically. The absence of CYP1A2 appears to protect from HA-(PhIP and MeIQx) induced cancer, as exemplified by results in the cynomolgus monkey. Differences in the potency of these HAs are not due to differences in the kinetics of their activation. The catalytic efficiency of CYP1A2 towards HAs and their oxidative fate varies amongst species, in both cases increasing the susceptibility of humans compared to that of the rat. Interindividual and inter organ differences in the further metabolism of N-hydroxy-HAs appear to be important determinants of cancer susceptibility, as does the glutathione S transferase catalysed detoxication of esters of N-hydroxy-PhIP. There is a need for an effective means of quantifying the in vivo activation of HAs in man to enable the possible risk posed by these compounds to be assessed effectively. PMID- 8678806 TI - The Gerhard Zbinden Memorial Lecture. Alteration of cell signalling in chemical toxicity. PMID- 8678807 TI - Extrapolation of heterocyclic amine carcinogenesis data from rodents and nonhuman primates to humans. AB - Twenty different heterocyclic amines have been isolated and identified from cooked foods especially beef, fish, pork and fowl. Other HCAs have also been isolated but their structure remains to be elucidated and new HCAs are likely to be identified in the future. The HCAs are highly mutagenic and all ten HCAs that have been tested for carcinogenic activity, produce tumors in mice and rats. For humans the average daily intake of HCAs is in quantities of 10-20 mg/person/day. The HCAs are procarcinogens and are activated by the cytochrome P450 system especially CYP 1A2. Rodents, monkeys and humans have the capacity to activate HCAs. Studies using hepatic microsomes demonstrated that humans have a greater capacity to activate the majority of HCAs tested than rodents or cynomolgus monkeys. Three HCAs are currently under evaluation in nonhuman primates for carcinogenic activity and one, IQ, is highly carcinogenic inducing primary hepatocellular carcinomas in the majority of cynomolgus monkeys treated. Epidemiological studies, although not definitive, are supportive of an association of HCAs intake to the etiology of human cancer. Risk assessments from animal data show a risk of HCAs to humans in the range of 10(-3) to 10(-4) which is an order of magnitude greater than compounds currently regulated by the U.S. Food and Drug Administration or the Environmental Protection Agency. Taken together evidence from mutagenicity data, activation by various species including humans, carcinogenicity in animals, human consumption data, epidemiological studies and risk assessment, supports the conclusion that HCAs are probable human carcinogens. PMID- 8678808 TI - Antibodies proposed as therapeutic agents. PMID- 8678809 TI - Unanticipated human toxicology of recombinant proteins. AB - Recombinant human proteins play already an important role in therapy, e.g. erythropoietin and colony stimulating factors, while several promising candidates such IL-6, IL-12, thrombopoietin and others are in clinical development. Since the recombinant proteins are copies of endogenous proteins, it was assumed that they would be well tolerated. While this assumption is correct for some, other proteins proved to be a highly toxic. Therefore, preclinical safety assessment of these proteins is necessary. Based on the experience with several proteins, some guidance for the safety assessment can be given. Furthermore, data are presented demonstrating that preclinical toxicity studies have a predictive value for man. Limitations of the classical approach of safety tests and new concepts are discussed. PMID- 8678810 TI - Impact of environmental pollution on respiratory sensitization and asthma. PMID- 8678811 TI - The mechanism of action of tetanus and botulinum neurotoxins. PMID- 8678812 TI - Specific factors leading to interindividual variability in response to occupational toxicants. PMID- 8678813 TI - Genetic predisposition in occupational toxicology. PMID- 8678814 TI - Individual susceptibility to occupational toxicants: practical consequences for risk management. PMID- 8678816 TI - Interdisciplinary "case studies" and training experts for primary prevention of environmentally-born health hazard. PMID- 8678815 TI - Persistent organic pollutants--the state of contamination of ambient air in central Europe. Possible sources and effects. PMID- 8678817 TI - Plants and animals as biomonitors of heavy metal level in the aquatic ecosystem of the river Danube. PMID- 8678818 TI - Ataxonomic assessment of phytoplankton integrity by means of flow cytometry. AB - Flow cytometry, a method well established in medicine and biotechnology, can also make an important contribution to (applied) limnological as well as ecotoxicological studies on phytoplankton. Flow cytometry can, for instance, contribute to the ataxonomic structural and functional assessment of phytoplankton. This approach may serve as a supplement to the well-established taxonomic evaluation by means of various microscope techniques. We present some examples for such ataxonomic phytoplankton evaluation. These examples include phytoplankton of eutrophicated and acidified water bodies as well as slowly flowing rivers. Phytoplankters may be differentiated by their pigment contents into carotinoid-rich ones (such as Chrysophyceae, Bacillariophyceae, and Dinophyceae) and carotinoid-poor ones (such as Euglenophyceae and Chlorophyceae). As a useful biomass parameter of phytoplankton algae we tested successfully protein staining by fluorescein isothiocyanate. We discuss the advantage of this approach as compared with results obtained by Coulter counter or by biomass calculations from microscope analyses. Up to now, evaluation of the biological quality of pelagic water bodies is still laborious and time consuming because of the microscopical examination of planktic communities usually practiced. As a possible improvement we present a structural ataxonomic approach for assessing the integrity of individual phytoplankters (on the basis of physiological parameters) as well as of the phytoplankton communities that is based on annual means of biomass spectra. Flow cytometry can provide considerable relief. PMID- 8678819 TI - Identification of the highly polymorphic S-mephenytoin hydroxylase in humans. PMID- 8678820 TI - Introduction to functional teratology. PMID- 8678821 TI - The neurobehavioural toxicology and teratology of lead. AB - When comparing neurobehavioural observations from occupational lead-exposure of adults on the one hand, and environmental lead exposure of children on the other, it appears that the developing relative to the mature brain is more at risk. Neurobehavioural toxicity in occupational lead-exposure has typically not been observed at blood lead-concentrations (PbBs) below 400 micrograms/l, whereas ih environmentally exposed children such deficit has been reported to occur down to PbB of 100-150 micrograms/l and, perhaps, even below this range. Both cross sectional and prospective studies have arrived at similar conclusions in this respect. The preferred endpoint in most such studies has been the IQ-measure, which has good psychometric qualities, is sufficiently well standardized to be comparable across studies, and exhibits attractive simplicity for the regulator in a public health context. At the same time, however, this IQ-focus has also interfered with systematic efforts to identify more specific lead-induced functional deficits by means of more detailed neurobehavioural analyses (Bellinger 1995). Metanalyses on both cross sectional and prospective studies in lead-exposed children have concluded that a typical doubling of PbB from 100 to 200 micrograms/l is associated with an average IQ-loss of 1-3 points (Pocock et al. 1994; WHO 1995), and no threshold has as yet been identified. Since, however, cause-effect contingencies necessarily remain doubtful in epidemiological studies if the observed effects are as subtle as these, experimental studies in animals have become helpful in supporting the causative role of lead to produce neurobehavioural deficit at steady-state PbB down to about 150 to 200 micrograms/l. Such deficit has been demonstrated by means of a variety of learning/memory models with positive and negative reinforcement contingencies in the rat--and in primates as well. It has also been shown in such studies that neurobehavioural deficit subsequent to early developmental exposure extends long into adulthood after cessation of exposure at weaning. It, therefore, appears that the neurobehavioural teratology of lead has more convincingly been demonstrated in animal models than in human exposure conditions, so far. A coherent theory to explain the particular vulnerability to lead of the developing brain is still lacking. Recent data do suggest, however, that Pb-induced disruption of calcium homeostasis in the immature brain might interfere with normal brain development. PMID- 8678822 TI - Teratogenic effects of alcohol: current status of animal research and in vitro models. PMID- 8678823 TI - Developmental neurotoxicology in the neonate--effects of pesticides and polychlorinated organic substances. PMID- 8678824 TI - Drug treatment in the perinatal period and the risk of functional teratogenicity. PMID- 8678825 TI - The effects on mammals of pre- and postnatal environmental exposure to PCBS. The Dutch Collaborative PCB/Dioxin Study. PMID- 8678826 TI - The regulation mechanism of c-jun and junB by human papillomavirus type 16 E5 oncoprotein. AB - In this study, we show that HPV-16 E5 induced anchorage-independent growth in immortalized human epidermal keratinocytes and that HPV-16 E5 in human keratinocytes had higher expression of c-jun and junB; also, we investigated the role of transcriptional initiation pathways in the expression elevation. In addition, Ras-dependent pathway, as well as PKC-dependent pathway, leads to HPV 16 E5-induced c-jun gene expression. PMID- 8678827 TI - Expression of V-SRC and chromosome analysis of a newly established cell line from rat sarcoma induced by an avian retroviral strain. AB - In the newly established rat sarcoma cell line LSR-SF (SR) expression of pp60v src was detected. Karyotype analyses revealed various chromosome aberrations during prolonged passaging of the tumor cells in vitro. Polyploidy was found to be a characteristic feature of the line studied. A large metacentric chromosome persistently present in the cells was accepted as a line marker. PMID- 8678828 TI - Natural scrapie in a closed flock of Cheviot sheep occurs only in specific PrP genotypes. AB - Natural scrapie in a closed flock of South Country Cheviot sheep has resulted in 45 deaths between 1986 and 1995. Of these cases, 35 sheep have been analysed for disease-linked PrP gene polymorphisms and all encode valine at codon 136 on at least one allele with 77% homozygous (VV136) and 23% valine/alanine heterozygotes (VA136). Mean survival time was 907 and 1482 days for VV136 and VA136 scrapie affected animals respectively. VV136 animals were all at great risk of disease if allowed to live long enough. However scrapie occurred only in a specific subgroup of VA136 sheep, survival advantage depending on VA136 animals being heterozygous for other polymorphisms at codons 154 or 171. The flock history has been recorded in great detail since its foundation in 1960 however there was no strong evidence for simple maternal or paternal transmission of disease other than inheritance of PrP genotype. PMID- 8678829 TI - Nucleotide sequence of the genome of a citrus isolate of olive latent virus 1. AB - The 3699 nt genome of olive latent virus 1 (OLV-1), described years ago from Southern Italy as a putative sobemovirus, was completely sequenced. OLV-1 genomic RNA was not polyadenylated and had a structure virtually identical to that of species of the Necrovirus rather than the Sobemovirus genus. Five open reading frames (ORFs) were identified, of which the 5'-proximal encoded a 23K protein and ended with an amber codon whose readthrough could yield a putative 82K product. This polypeptide had extensive sequence similarity with polymerases of serotypes A and D of tobacco necrosis necrovirus (TNV-A and TNV-D) and species of the family Tombusviridae and related genera (Dianthovirus and Machlomovirus). Two small ORFs followed, which encoded polypeptides of 8K and 6K, respectively. The 6K product had extensive homology with the comparable 6K protein of TNV-A and was also related to the 11K protein of shallot latent carlavirus, one of the "triple block" polypeptides involved in cell-to-cell virus movement. The 3'-proximal ORF was in the same position as the coat protein (CP) cistron of necroviruses and encoded a 30K product related to CP of both TNV-A and -D. Computer-assisted comparative analysis of structural and non-structural proteins of OLV-1, TNV-A and TNV-D disclosed on overall distant relationship between OLV-1 and TNV-D. OLV 1 genome appeared homologous to that of TNV-A, but differences from TNV-A were the absence of the small ORF downstream of the CP cistron and in the low degree of sequence identity in CP (39% aa identity). OLV-1 is serologically distantly related to TNV-A and even more distantly related to TNV-D. We propose that OLV-1 is a necrovirus species in its own right. PMID- 8678830 TI - Identification of a novel splice acceptor in the HIV-1 genome: independent expression of the cytoplasmic tail of the envelope protein. AB - Multiple splicing sites exist in the RNA genome of the human immunodeficiency virus type 1 (HIV-1). In a screen for subgenomic forms of the HIV-1 genome that could be transferred to fresh cells by virus infection, we identified a novel spliced variant of HIV-1 RNA that uses a hitherto unknown splice acceptor site within the envelope (Env) gene. We demonstrate that this splice acceptor is infrequently used in HIV-infected T cells. Interestingly, an AUG initiator codon is created at this splice junction which has the potential to direct the synthesis of the cytoplasmic tail of the Env gp41 protein. Transient transfection experiments with the new cDNA cloned in an expression vector demonstrated efficient utilization of this start codon and the C-terminus of the Env open reading frame. Independent expression of the 152 amino acid long, intracellular Env domain provides novel regulatory mechanisms for modulating viral infectivity and perhaps pathogenicity. PMID- 8678831 TI - Anti-EBNA1/anti-EBNA2 ratio decreases significantly in patients with progression of HIV infection. AB - Reactivation of EBV infection is common in immunocompromised individuals. We determined specific antibodies to EBV-encoded nuclear antigens (EBNA)1 and 2 in 102 sera of HIV-infected individuals. Anti-EBNA1/anti-EBNA2 ratio (E1/E2) is less than 1 in chronic infection and exceeds 1 in healthy EBV-positive carriers. 52% of cases had E1/E2 < 1. E1/E2 decreased remarkably during the progression of HIV infection. Detectable HIV-Antigen, decline of CD4+ cell count and CD4+/CD8+ ratio were correlated with an increasing prevalence of E1/E2 below 1. We conclude that determination of E1/E2 is useful in immunocompromised patients. PMID- 8678832 TI - Characterization of Toronto virus capsid protein expressed in baculovirus. AB - Toronto virus (TV), previously called "minireovirus", a human calicivirus classified as genogroup 2 and phylogenetic type P2-A, was originally described in association with diarrhea in children. The second open reading frame, encoding the capsid protein of TV24, was expressed in a baculovirus recombinant. The recombinant baculovirus produced a protein (rTV) with an apparent molecular mass of 58 kDa that self-assembled into virus-like particles approximately 30 nm in diameter with a density of 1.29 g/ml. Antigenic and immunogenic characteristics of these particles were determined by protein immunoblot, immunoprecipitation, and enzyme immunoassay. Seroconversion to the rTV protein was detected in 6 of 8 (75%) patients from a recent outbreak of gastroenteritis associated with a virus of similar phylogenetic type. These results confirm and extend the previous reports of the expression of the Norwalk and Mexico virus capsid proteins. PMID- 8678833 TI - Polymerase chain reaction detection of the hemagglutinin gene from an attenuated measles vaccine strain in the peripheral mononuclear cells of children with autoimmune hepatitis. AB - We examined the measles H gene using reverse transcriptase-polymerase chain reaction in peripheral mononuclear cells obtained from 4 pediatric and 2 adult patients with autoimmune hepatitis and 12 healthy children who had been infected with measles or vaccinated with an attenuated measles vaccine in the past. All patients were positive for the presence of the gene. Only one healthy control, who had been vaccinated two weeks before the study, was positive, while the other 11 controls were negative for the presence of the gene. The restriction enzyme patterns of the products in the pediatric patients were different from those observed in adults. The sequences of amplified products from pediatric patients coincided with the vaccine strain, whereas those from adults were different from the vaccine strain. The sequence of those from one of two adult patients was similar to those of the isolates in 1990 and later. Our results demonstrated that children with autoimmune hepatitis can have persistence of the vaccine strain in vivo for many years after vaccination. PMID- 8678834 TI - Complete nucleotide sequence and synthesis of infectious in vitro transcripts from a full-length cDNA clone of a rakkyo strain of tobacco mosaic virus. AB - The complete nucleotide sequence of the genome of a rakkyo strain of tobacco mosaic virus (TMV-R), which exhibits distinct host range differences from the common strain of TMV, was determined. The overall nucleotide sequence homology with TMV-U1 (a common strain of TMV) is 94.2%. The amino acid sequence homologies of the four encoded proteins (180K, 130K, 30K, coat protein) are from 95.9% to 98.0% compared with TMV-U1. To facilitate the analysis of the novel host range of TMV-R, a full-length clone of the genome containing a bacteriophage T7 RNA polymerase promoter was assembled from two cDNA clones and designated pRF3. In vitro transcripts derived from pRF3 were highly infectious. The infections of RF3, wild-type TMV-R, and U3/12-4 (derived from pU3/12-4, an infectious clone of TMV-U1) were compared on Nicotiana tabacum cv. Bright Yellow (BY) plants. No systemic mosaic symptoms were observed on plants inoculated with RF3 and TMV-R, while BY plants inoculated with U3/12-4 developed distinct mosaic symptoms on the upper leaves 8-9 days post-inoculation. The green fluorescent protein (GFP) gene was introduced into pRF3 and pU3/12-4 by replacing the coat protein gene to get two GFP expressing chimeric virus clones: pR-GFP or pU1-GFP. Transcripts from pU1 GFP produced strong fluorescence when inoculated onto BY leaves, while those from pR-GFP produced only very faint fluorescence. PMID- 8678835 TI - Intratypic genome variability of echovirus type 30 in part of the VP4/VP2 coding region. AB - The genetic relationship of 33 echovirus type 30 (E30) isolates associated with three different outbreaks of meningitis in Norway and one outbreak in USA was assessed using direct sequencing of amplicons derived from a region covering part of the capsid proteins VP4 and VP2. The E30 sequences were compared to each other, and to other enteroviruses. Less sequence variation was observed between the isolates from a single outbreak (2-3%) than between groups of isolates from different outbreaks (4-9%). All observed nucleotide substitutions were amino acid silent. Homology between enteroviruses obtained from GenEMBL and the nucleotide consensus sequence generated from the E30 isolates varied between 44.8% (coxsackievirus A24) and 72.6% (coxsackievirus A9). Comparing the E30 sequences in this part of the genome with other enteroviruses, E30 clearly belongs to the coxsackie B-like virus group. PMID- 8678836 TI - Ebola virus infection in guinea pigs: presumable role of granulomatous inflammation in pathogenesis. AB - An approach combining virology with light and electron microscopy was used to study the organs of guinea pigs during nine serial passages of Ebola virus, strain Zaire. It was observed that the wild type of Ebola virus causes severe granulomatous inflammation in the liver and reproduces in the cells of the mononuclear phagocyte system (MPS). Based on morphological characterization, two types of virus-cell interactions were demonstrated. The obtained data evidenced for heterogeneity of the population of wild type of Ebola virus. The virus accumulated in the liver of the infected animals, and the lesions became more pronounced with passage. Degenerative changes appeared, and their severity was increased with passage in the other organs as well. The set of target cells diversified and, as a result, not only the MPS cells, but also hepatocytes, spongiocytes, endotheliocytes and fibroblasts became involved in the reproduction of Ebola virus. The possible role of granulomatous inflammation in the development of the adaptive mechanism of Ebola virus to guinea pigs is discussed. PMID- 8678837 TI - A variant of MDCK cell line which restricted growth of influenza viruses mainly through suppression of viral primary transcription. AB - By serial subculture of MDCK cells which survived high multiplicity infections with AWBY-140, a weakly cytolytic mutant of influenza virus A/WSN (H1N1), we established a variant cell line (MDCK-L cells) that was uniquely resistant to infection with influenza A and B viruses, yielding 3 to 4 orders lower amount of progeny virus compared with MDCK cells. Competitive polymerase chain reaction revealed that the amount of primary transcript produced in MDCK-L cells infected with 10 PFU/cell of influenza virus A/Aichi was suppressed to 1/100 of that in MDCK cells similarly infected, although the amount of virus adsorbed to MDCK-L cells was 1/4 of MDCK cells. Even when MDCLK-L cells were infected with 40 PFU/cell of Aichi to overcome the lower amount of internalized virus in those cells, the results were the same. The synthesis of v-, c- and mRNAs, as well as proteins of infected A/Aichi was below detectable level in MDCK-L cells, in contrast with MDCK cells, where they were clearly demonstrable by ribonuclease protection assay or polyacrylamide gel electrophoresis. PMID- 8678838 TI - Sequence of the 3'-terminal region of a Zimbabwe isolate of cowpea aphid-borne mosaic virus (CABMV). AB - The 3'-terminal 1221 nucleotides of a Zimbabwe isolate of cowpea aphid-borne mosaic potyvirus (CABMV) genome have been sequenced. The sequence comprises an open reading frame (ORF) of 990 nucleotides and a 3' non-coding-region of 231 nucleotides followed by a poly-A. The ORF has high similarity to NIb and coat proteins (CP) of potyviruses. A potential CP Q/S cleavage site was identified, yielding a CP of 30.5 kDa containing 275 amino acids. The CABMV sequence is closely related to that of South African passiflora virus (SAPV) which should therefore be regarded as a strain of CABMV. PMID- 8678839 TI - Virus and virus-like particles observed in the intestinal contents of the possum, Trichosurus vulpecula. AB - Intestinal contents derived from the Australian brush-tailed possum, Trichosurus vulpecula, were examined by negative stain electron microscopy for the presence of viruses. Out of 100 samples, 23 contained at least one type of vertebrate virus or virus-like particle. Adenovirus was identified in six samples, herpesvirus in two samples, coronavirus in four samples, and coronavirus-like particles in 14 samples. To date no viruses of the brush-tailed possum have been isolated in tissue culture but these results indicate that this species is probably host to several viral species. PMID- 8678840 TI - Inactivation of hepatitis C virus cDNA transgene by hypermethylation in transgenic mice. AB - Transgenic mice were produced by microinjection of a partial hepatitis C virus (HCV) genome sequence including the structural protein region, under the control of the albumin promoter and enhancer into fertilized eggs of C57BL/6 and BDF1 mice. Three founders carrying at least five copies of the transgene but not expressing HCV-specific RNA were generated. Methylation analysis indicated that the transgene was extensively methylated. Mapping of methylated cytosine residues of the transgenic mouse DNA showed that all C residues of a particular part of the HCV genome but not all the CpG island like sequences were methylated. Transiently expressed HCV cDNA in COS7 cells and the active endogenous albumin gene were not methylated. Furthermore, 5-azacytidine, a potent demethylating agent, induced HCV gene expression in a line of these transgenic mice. These results suggest that methylation of HCV cDNA is a cause of its inactive expression in transgenic mice, and that this phenomenon may occur in other stable systems for expression of the HCV genome. PMID- 8678841 TI - Genetic and phylogenetic analyses of hantaviral sequences amplified from archival tissues of deer mice (Peromyscus maniculatus nubiterrae) captured in the eastern United States. AB - The S and M segments of a hantavirus, enzymatically amplified from tissues of Cloudland deer mice (Peromyscus maniculatus nubiterrae) captured during 1985 in West Virginia, diverged from strains of Four Corners virus from the southwestern United States by more than 16% and 6% at the nucleotide and amino acid levels, respectively. Phylogenetic analysis suggested that this virus strain (designated Monongahela) forms a possible evolutionary link between the Four Corners and New York hantaviruses. PMID- 8678842 TI - Famous institutions in virology. The Department of Microbiology, Australian National University and the Laboratory of Cell Biology, National Institute of Allergy and Infectious Diseases. PMID- 8678843 TI - Experimental determination of the effective point of measurement of a parallel plate ionisation chamber. AB - The effective point of measurement (EPM) of a Kemp-Barber parallel plate ionisation chamber exposed to cobalt-60 has been determined experimentally. The variation of the EPM as a function of plate separation and the build-up cap thickness has also been studied. In general, for a constant size of build-up cap, the EPM moves downstream from the inner front wall towards the back wall of the chamber as the plate separation decreases. For parallel plate chambers, conventional theoretical analyses suggest that the EPM is the inner front wall and that it shifts towards the geometric centre of the chamber as the plate separation increases. The experimentally determined variation of the EPM, which appears to contradict these conclusions, suggests that the distribution of ionisation within a parallel plate chamber is not adequately accounted for in present theoretical descriptions. Such considerations may also affect other experimental determinations of the EPM for cylindrical chambers, as many are based on a comparison using parallel plate ionisation chambers with an assumed EPM on the inner front wall. PMID- 8678844 TI - Potential ocular hazard from a surgical light source. AB - A surgical light source has been examined to determine the potential for retinal damage to staff in the operating theatre. It has been shown that under certain circumstances the light source examined can give an irradiance at the cornea which is well in excess of accepted safety standards. Calculation using data on the retinal irradiance required to produce retinal damage indicates that for an accidental exposure at a distance of 500 mm there is a significant possibility of retinal damage. At closer distances the probability of retinal damage is even higher. It is possible that other surgical light sources produce a similar degree of hazard and hospitals should establish suitable safety measures where necessary. PMID- 8678845 TI - Monitoring surface shape variations on the human body. AB - Monitoring changes on the surface of the human body can be difficult due to the very unstable nature of skin. Stable control points between epochs are difficult to establish. This paper examines previous attempts to monitor the human surface. An algorithm is presented which is capable of matching two models of the one area on the human body which have been gathered at different epochs. No control points are required to exist on the human surface, or between epochs. Further, the algorithm is expanded to include surface differencing capabilities. This allows surfaces which have changed shape between epochs to be matched and the differences identified. PMID- 8678846 TI - The inferior boundary condition of a continuous cantilever beam model of the human spine. AB - The continuous cantilever beam model of the human spine usually assumes that the beam tangent at the inferior end of the structure is exactly perpendicular to the surface in which it is built into. The model used in this paper allows for realistic imperfections in the beam so that a small non-zero rotation is allowed at its inferior end. Such a model is used to investigate the lateral deformation of the muscle-relaxed spine as it supports asymmetrical loads in the frontal plane. By comparing the model deformations with previously published results, it was easily seen how such imperfections can effect the solution quantitatively. This was found to be especially true when the model was used to estimate the gross flexural rigidity of the spine in the frontal plane. It could also explain why some spines are more prone to lateral curvature and instability than others. Considering the importance of such a parameter when used in the continuous model, an investigation into the true nature of the inferior model boundary condition could be warranted. PMID- 8678848 TI - Statistics for publication. PMID- 8678847 TI - A variational approach to the problem of optimizing the radiation dose distribution in tumours. AB - This paper presents a precise mathematical formulation of a biological criterion by which the radiation dose distribution in tumours homogeneous or heterogeneous in cell density and radiosensitivity can be optimized. The criterion is formulated as search for a dose distribution that would minimize the mean dose delivered to the tumour under the constraint that the tumour control probability reaches a given desired value. Using a method from the calculus of variations it has been proven that a homogeneous dose distribution is the solution in case of tumours homogeneous in radiosensitivity independent of their cell spatial density status. Thus the usual requirement for homogeneous dose distribution in case of homogeneous tumours is proven if the leading clinical criterion is the described one. The formula for the dose distribution in case of tumours heterogeneous in cell radiosensitivity is given too. PMID- 8678849 TI - Primary repair for colonic gunshot wounds. AB - BACKGROUND: Penetrating injuries of the colon have been managed traditionally by diverting colostomy. Recently, a trend towards primary repair has been observed, particularly for knife injuries. The purpose of this study is to evaluate the safety of primary repair for colonic gunshot wounds in the presence of certain clinical risk factors. METHODS: A retrospective analysis of 223 patients with colonic bullet injuries in a period of 3 years (1990-93) was performed. RESULTS: Of 223 patients with colonic trauma, 168 were primarily repaired (group A) and 55 underwent a colostomy (group B). Intra-abdominal septic complications occurred in 5.9% of group A patients and 10.9% of group B patients (P > 0.05, NS). These patients were, furthermore, stratified according to well-known risk factors for the development of complications, namely, site of injury, presence of shock on admission, degree of faecal contamination and number of associated injuries. We were unable to find any statistically significant differences in intra-abdominal septic complication rates between patients treated with primary repair and patients treated with colostomy. CONCLUSIONS: Primary repair seems to be a safe therapeutic option for gunshot wounds of the colon. Even in the presence of the above-mentioned risk factors, colostomy may be avoided in most cases as primary repair does not appear to be associated with higher complication rates. PMID- 8678850 TI - Colorectal injury: where do we stand with repair? AB - BACKGROUND: The chief danger of colonic injury is sepsis resulting from faecal spill. Primary repair is now well established in the USA, particularly injuries, in up to 81% of patients. However, in Australia, highly destructive blunt trauma forms a larger proportion of injuries, and the purpose of this study was to determine if there are any contrasts in the management of these patients. METHOD: A retrospective survey was undertaken over the past 20 years of all of the patients with full-thickness colorectal injuries presenting at the three major hospitals which receive multi-trauma patients in Brisbane. RESULTS: Of 112 patients 114 sustained full-thickness colorectal injuries. Forty patients had penetrating injuries, 41 had blunt injuries and 33 had iatrogenic injuries. Primary repair or resection and anastomosis was performed in 39% of patients with colonic injuries and the leak rate was 8%. Exteriorized repairs had a 67% leak rate. A colostomy was used in 58% of patients. The mortality for penetrating injuries was zero. The mortality for blunt colonic injuries was 17% and for iatrogenic injuries was 7%, but for blunt rectal injuries was 50%. The overall mortality was 10%. Colostomy closure had a 20% morbidity but no mortality. CONCLUSIONS: In the absence of shock, associated injuries, or gross faecal soiling primary repair or resection with anastomosis may be considered. For blunt injury, colostomy is still usually indicated, often with resection. For iatrogenic injury, when seen early, primary repair can be performed. We do not recommend exteriorized repair. Extraperitoneal rectal injuries require proximal colostomy and distal washout, with drainage where appropriate. Blunt devitalizing injury is relatively more common in Australia than in the USA, and therefore there is less indication here for primary repair. Colostomy remains an important consideration in operative management. PMID- 8678851 TI - Stimulated gracilis neosphincter: a new procedure for anal incontinence. AB - BACKGROUND: The gracilis muscle has been used previously to construct an anal neosphincter, but this was not successful since a short-lived muscle contraction was insufficient to restore continence. Recently, a procedure was described in which conversion to a fatigue-resistant muscle was achieved by chronic low frequency electrical stimulation, and the resultant ability to sustain a constant contraction was associated with improved continence. Our initial results with this procedure, using a standardized operation and treatment protocol in 12 consecutive patients, is reported. METHODS: Seven women (mean age 50 years, range 22-71 years) had faecal incontinence, and five patients (F:M, 3:2; aged 53-72 years) underwent reconstruction after abdominoperineal excision of the rectum for cancer. A detailed questionnaire including continence score was completed pre operatively. Eight patients have been assessed after ileostomy closure at a mean time of 10 months. RESULTS: Slow-twitch muscle conversion was achieved in each case and all patients have a functional neosphincter. Mean continence score was 6.8 (range 4-12), and seven patients were continent. There was significant improvement in continence in the non-cancer group (p = 0.03). Mean pre-operative resting anal pressure, functional neosphincter pressure (NPfunc), and maximal neosphincter pressure (NP(max)) were 36, 102 and 207 cmH2O, respectively. There was a significant improvement in pressure comparing NPfunc (P = 0.03) and NP(max) (P = 0.03) with pre-operative pressure. Complications included deep vein thrombosis, pulmonary embolism, saphenous nerve injury, leg wound haematoma, and late pacemaker infection. CONCLUSION: The stimulated gracilis neosphincter achieves satisfactory continence in a majority of patients. PMID- 8678852 TI - Completion total thyroidectomy in the management of differentiated thyroid carcinoma. AB - BACKGROUND: Completion thyroidectomy is the removal of any thyroid tissue that remains after a less than total thyroidectomy. This procedure has been commonly performed when the final histopathology of the excised ipsilateral thyroid lobe reveals papillary or follicular carcinoma of the thyroid. Complete thyroidectomy carries little morbidity if performed by experienced surgeons using a lateral approach. The purpose of this study is to reinforce the usefulness of a lateral approach. METHODS: A retrospective analysis over a 5 year period at the Department of Endocrine Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS) yielded 19 patients who underwent completion thyroidectomy. This group represents 23% of 82 patients who underwent total thyroidectomy for differentiated thyroid cancer (DTC) during that period. The residual thyroid tissue was excised through a lateral approach and could be resected safely, preserving the recurrent laryngeal nerve (RLN) and the parathyroid glands. RESULTS: A lateral approach dissection could be performed with ease in a virgin area. Excision of residual thyroid tissue could be performed safely even in cases with prior partial lobectomy or bilateral subtotal resection. Tumour was found in 52% of the re-operative specimens: in three out of four of those after a previous partial lobectomy, in six out of 12 of those after a total lobectomy, and in one out of three of those after a prior bilateral (although incomplete) thyroid resection. Postoperative complications included transient RLN palsy (n = 2) and transient hypoparathyroidism (n = 4). CONCLUSIONS: Completion thyroidectomy using a lateral approach is safe in re-operative thyroid surgery. PMID- 8678853 TI - Early discharge after open appendicectomy. AB - BACKGROUND: There is increasing pressure on surgeons to minimize the time patients stay in hospital, and there is therefore a need to establish guidelines for reasonable lengths of stay for common operations. This study was conducted to test the feasibility and safety of early discharge after open appendicectomy. In addition, this study was performed to provide standards for open appendicectomy against which the results of laparoscopic appendicectomy can be compared. METHODS: A prospective study of all patients having open appendicectomy for suspected acute appendicitis at Liverpool Hospital, Sydney during a 4 month period was undertaken. An early discharge programme was established, with the aim of discharging patients within 48 h of operation in uncomplicated cases. Discharge was allowed when the patient was eating, walking, and had passed flatus. Follow up was with the consultant surgeon at 1 week postoperatively, and with a community nurse at 2 weeks. Multivariate linear regression, using the number of postoperative hours to discharge as the outcome, was used to analyse the data for the following four factors: age, gender, incision type, and pathology. RESULTS: One hundred and sixteen consecutive patients were enrolled in the study. The median postoperative stay for all patients was 46 h. Perforation of the appendix, use of a midline laparotomy for appendicectomy, and age significantly prolonged hospital stay, but gender had no effect. The main complication was wound infection, which was seen in 7.5% of patients. No patient had a problem directly related to early discharge. A community nurse saw 81% of patients 2 weeks after discharge. Over three-quarters of the patients seen had returned to full normal activities by 2 weeks, including work or school. Eighty eight per cent of patients considered the timing of their discharge "good' or "excellent'. CONCLUSIONS: Discharge at 2 days after open appendicectomy is both feasible and safe for patients having an unperforated appendix removed through a right iliac fossa incision. Passage of stool is not required prior to discharge. Early discharge is well accepted by patients and may result in financial savings for hospitals where payment is according to Diagnosis-Related Groups. On the basis of the results of the six randomized controlled trials comparing laparoscopic and conventional open appendicectomy published to date, and on the results of this study, the authors conclude that laparoscopic appendicectomy should not yet be considered the "procedure of choice', and surgeons are justified in performing appendicectomy by either method. PMID- 8678854 TI - A decade of gastroschisis in the era of antenatal ultrasound. AB - BACKGROUND: Gastroschisis is an uncommon condition in which viscera protrude at the base of the umbilical cord. To investigate the possible relationships between antenatal ultrasound findings, patient demographics, smoking, alcohol consumption and this condition, 21 causes are reviewed. METHODS: The medical records and antenatal ultrasounds of 21 children diagnosed with gastroschisis at the Adelaide Children's Hospital between 1 January 1985 and 31 December 1992 were reviewed. RESULTS: Antenatal ultrasound was employed in 15 cases, and the diagnosis was accurately made in 13 (86.7%) of these. There were 17 live births, two elective terminations and two pre-term abortions. Seven of the 21 cases had associated anomalies. The anomalies included five atresias, a ventricular septal defect (VSD), and a dislocated gall-bladder. Postoperative complications (which included one death) occurred in seven of the 17 patients. Bowel dilatation or thickening was first detected on five ultrasound examinations performed before 21 weeks' gestation, and four ultrasounds after 21 weeks. The nine cases with bowel changes on ultrasound were associated with a high atresia rate and a longer hospital stay, but not with an increased complication rate. Maternal race, parity, and alcohol consumption were not associated with increased risk of fetal gastroschisis. All mothers were under 27 years of age. There were nine mothers who smoked during pregnancy and a disproportionate number of mothers who lived outside the metropolitan area with gastroschisis-affected offspring. CONCLUSIONS: Bowel changes seen on antenatal ultrasound increase the chances of intestinal atresia and longer hospitalization. Smoking during pregnancy may be associated with an increased risk of gastroschisis. PMID- 8678855 TI - White blood cell counts in patients undergoing abdominal surgery. AB - BACKGROUND: The role of pre-operative white blood cell counts (WBCC) in patients with an acute abdomen is contentious. METHODS: This study documents the association between pre-operative WBCC and the extent of intraperitoneal inflammation at the time of surgery in a heterogeneous group of 1166 patients undergoing abdominal surgery. RESULTS: WBCC failed to adequately discriminate between groups of patients with varying degrees of intraperitoneal inflammation. For example, only 31% (37/118) of the patients with either free pus or an abscess within the peritoneal cavity had a WBCC > 15.0 x 10(9)/L. CONCLUSIONS: There is a need to replace the WBCC with more powerful predictors of inflammation within the peritoneal cavity. PMID- 8678856 TI - The role of omental transfer in Buerger's disease: New Delhi's experience. AB - BACKGROUND: Buerger's disease is a specific, idiopathic, recurrent, segmental, inflammatory, obliterative vascular disease involving medium-sized arteries and veins of the limbs. We performed omental transfer on a group of patients with Buerger's disease that had previously undergone lumbar sympathectomy and the results are described. METHODS: Between January 1988 and December 1993, 100 cases of peripheral vascular disease (PVD) diagnosed as Buerger's Disease were subjected to femoral angiography. Fifty cases of angiographic intermediate/distal type blocks underwent omental transposition. RESULTS: Of 50 patients subjected to omental transfer all had intermittent claudication, 40 had rest pain of whom 36 had non-healing ulcers, 8 had gangrene and 32 had bilateral lower limb involvement. Fifteen patients underwent bilateral omental transfer and posterior tibial artery biopsy was performed in 40. All patients showed improved skin temperature, rest pain decreased in 36 and claudication distance increased in 48. Ulcers healed in 32 of 36 patients and the line of demarcation receded in six of eight patients with gangrene. CONCLUSIONS: Omental transfer improved skin and muscle microcirculation and forestalled the need for amputation by providing symptomatic relief and clinically arresting the progress of Buerger's disease. Omental transfer should be considered seriously as an alternative to other modalities of therapy to delay the ischaemic complications of Buerger's disease. PMID- 8678857 TI - 48th annual scientific meeting of the Urological Society of Australasia. Auckland, New Zealand, 12-17 March 1995. PMID- 8678858 TI - Invagination stripping of the long and short saphenous vein using the PIN stripper. AB - The technique of invagination stripping (IS) of the long saphenous vein (LSV) and short saphenous vein (SSV) using the PIN stripper (PS) is described. One hundred consecutive legs with long saphenous incompetence have been treated with IS of the LSV from the groin to just below the knee using the PS. In 28 of these legs associated short saphenous incompetence was treated with IS of the SSV from the popliteal fossa to just below half-way in the calf. It was found that technically the PS is easy to use. It passes from the groin to just below the knee in the LSV without difficulty. The blunt, slightly bent tip manoeuvres past tributaries and valves with ease. Similarly, the PS passes easily down the SSV to a point just past half-way down the calf. The exit of the stripper tip is much easier than with conventional strippers; there is less tissue trauma and a smaller scar. Inversion stripping is associated with much less tissue trauma, bruising and postoperative pain, and earlier mobilization. The technique appears to have eliminated trauma to the saphenous and sural nerves. This technique will facilitate the use of "day only surgery' for varicose veins and can be performed under femoral nerve block and local anaesthesia. PMID- 8678859 TI - The orthopaedic lever: a simple method to reduce unstable posteriorly displaced or angulated proximal femoral fractures. AB - The satisfactory management of unstable posteriorly displaced or angulated proximal femoral fractures is an orthopaedic challenge. In these fractures, significant displacement of bony fragments is often associated with comminution and soft-tissue stripping. Unsatisfactory fixation may lead to serious complications such as refracture with failure of the fixation device. Accurate reduction, reconstruction and fixation of these fractures are demanding in both strength and technique of the surgeon. The orthopaedic lever providing means for pre-operative reduction that will maintain the reduced position while fixation is achieved is described. PMID- 8678860 TI - Laparoscopic extraperitoneal lumbar sympathectomy: technique and early results. AB - A new technique of balloon-assisted laparoscopic lumbar sympathectomy is described and the results of the initial three cases are described. The procedure is technically straightforward and was accomplished without any complications. It should be compared with other techniques of lumbar sympathectomy in comparative trials; however, this early experience is most encouraging. PMID- 8678861 TI - Frederic Wood Jones: the missing manuscript. PMID- 8678862 TI - Prognostic factors and the curability of breast cancer. PMID- 8678863 TI - Laparoscopic excision of distal pancreas including insulinoma. AB - A case of sporadic occult insulinoma treated by laparoscopic distal pancreatectomy using a laparoscopic ultrasound probe to facilitate localization of the insulinoma and a laparoscopic surgical stapler to transect the pancreas is presented. This is believed to be the first case description of a laparoscopic pancreatic resection. PMID- 8678864 TI - Choledocholithiasis in anomalous biliary system. AB - Although congenital biliary abnormalities are common, preduodenal portal vein is very rare, not to mention preduodenal common bile duct (CBD) which has not been described before in the literature. A case with both anomalies complicated by biliary tract stones is reported. A brief review of embryonic development is also presented to explain the unusual biliary anatomy of this patient. PMID- 8678865 TI - Hereditary presacral teratoma. AB - A case of hereditary presacral teratoma involving father and daughter is described. The use of magnetic resonance imaging in the diagnosis of this condition is illustrated and a review of the literature of this unusual condition is presented. PMID- 8678866 TI - Immature mediastinal teratoma in a 2 1/2 year old Chinese girl. AB - Teratoma is a rare tumour in children accounting for about 3% of all childhood malignancy. A case of immature mediastinal teratoma in a young Chinese girl is reported. PMID- 8678867 TI - Congenital bulbar urethral strictures occurring in three brothers. AB - Three brothers with identical congenital bulbar urethral strictures are presented. These rare lesions are distinct from posterior urethral valves although the exact embryological origin is uncertain. The current literature is also reviewed. PMID- 8678868 TI - Selecting advanced trainees: can we do it better? PMID- 8678869 TI - Trainee selection for general surgery. PMID- 8678870 TI - First aid in the air. AB - BACKGROUND: First aid is commonly required during commercial aircraft flights, especially during international flights. An intimidating and sometimes threatening array of in-flight medical emergencies challenge the doctor, flight attendants and other passengers in such medical emergencies. Cramped conditions, difficulties of access to the victim, lack of privacy, cultural and language differences and noise and vibration all compound to increase the difficulties of the normal first aid drills which are required in the management of in-cabin emergencies. Doctors who fly as passengers are liable to be called upon to render first aid in the air. We provide an analysis of the types of medical emergencies encountered during commercial air travel. METHODS: We have reviewed all consecutive in-flight medical incident reports for QANTAS international flights for 1993. All incidents requiring the attention of a doctor were included. RESULTS: A total of 454 significant medical incidents occurred. These included, in rank order, syncope (35%), angina and cardiac emergencies (23%), gastrointestinal conditions (13%), respiratory tract infections and asthma (9%) and anxiety and panic reactions warranting medical intervention (5%). CONCLUSIONS: Syncope, the management of gastrointestinal symptoms and problems of angina comprise over half (58%) of the presenting symptoms which confront a fellow traveller who may coincidentally be a medical practitioner. Problems of anxiety, sleeplessness, airport bustle, immobility, barotrauma, alcohol abuse and mild hypoxia are discussed in the context of precipitating factors which may trigger an in-flight emergency. Psychological problems are very common and challenge the first aider, whether or not he or she is medically trained. We emphasize the necessity for doctors and nurses to be trained in first aid, as a distinct profession in its own right and a series of drills and skills which are distinctive from those of surgery-based health care. The 5% annual increase in air-passenger traffic, predicted for the next two decades, highlights the importance of special training for "first aid in the air'. PMID- 8678871 TI - Paediatric renal trauma: caution with conservative management of major injuries. AB - BACKGROUND: The kidney is the most frequently injured abdominal organ in children and controversy surrounds some aspects of management. This study looks at the experience of our institution and reviews the literature towards developing an optimal strategy for managing this common childhood injury. METHODS: One hundred and forty-two cases of paediatric renal trauma are reported from a catchment population of approximately 240,000 children < 14 years of age over a 12 year period. Injuries were classified into four groups: groups 1 and 2 were regarded as minor injuries (85%) and group 3 and 4 injuries were those with extravasation of urine or pedicle injury (15%). RESULTS: The male:female ratio was 2:1 with an average age of 8.5 years. Major renal injuries frequently required large amounts of resuscitation fluid. Associated injuries were present in 41% of all cases with an average of two injuries each. With one exception in each case, the development of complications and the need for early surgery were confined to major injuries. There were no long-term complications. The renal loss rate was 2.1%. CONCLUSIONS: Renal injuries can be usefully classified into major or minor by determining whether extravasation of urine or pedicle injury is present. Minor injuries should be managed conservatively. Major injuries causing ongoing haemorrhage require urgent surgery. Other major injuries should be imaged regularly and patients with more severe urinomas benefit from early elective surgery at 2-5 days. In cases where extravasation of urine has not shown clear evidence of settling by 5 days' elective surgery probably results in less morbidity and fewer complications than protracted conservative treatment. PMID- 8678872 TI - A prospective audit of selective cholangiography for laparoscopic cholecystectomy. AB - BACKGROUND: With the introduction of laparoscopic cholecystectomy (LC) there has been a reduction in the use of operative cholangiography. The practice of selective cholangiography (SC), where the common bile duct (CBD) is imaged only in those patients where the surgeon believes there is a significant risk of CBD stones has contributed to this reduction. Selective cholangiography has been criticized by advocates of routine cholangiography who argue that there will be more CBD stones missed and more CBD injuries. METHODS: This prospective study reports the outcome in a series of 457 patients who had LC performed between 1990 and 1992 where cholangiography was used according to a strict protocol relying on clinical history, CBD size and pre-operative liver function tests. There were no CBD injuries. Twenty-nine patients (6.4%) had CBD stones. RESULTS: Follow up by structured questionnaire at 12-24 months detected 6 patients (1.3%) with CBD stones. Three of these 6 patients had cholangiograms. Of the 3 patients with missed stones and no X-ray, 2 were protocol breaches and only 1 patient from 307 (0.3%) with no indication for SC was subsequently found to have a CBD stone. CONCLUSION: We believe that this study validates a policy of SC. PMID- 8678873 TI - A survival regression analysis of prognostic factors in colorectal cancer. AB - BACKGROUND: Many prognostic factors of colorectal cancer are known but their actual clinical validity is still uncertain. The aim of the present study was to verify, on the basis of our experience, the prognostic validy of variables for survival by using survival regression analysis. METHODS: From January 1978 to December 1986 the prognostic factors for 192 patients were analysed. These patients had undergone surgical resection for colorectal cancer. The follow up was completed in every patient by the end of December 1992, with a median follow up of 10 years (range 6-14 years). The prognostic factors considered in the statistical analysis were age, sex, size of tumour, site, grade, direct spread, node involvement and stage (according to Astler-Coller and pTNM). RESULTS: Of the prognostic factors, sex was the only one not to show any prognostic significance. In the survival regression analysis we have used an accelerated failure time model (equivalent to the Cox proportional hazard model); age, grade and stage were significant covariables. CONCLUSIONS: Although clinical pathological staging (pTNM) appears as a pre-eminent prognostic factor, and as our analysis shows, it needs a further variable (grading), which has been shown to affect the prognosis in a significant way. PMID- 8678874 TI - Immediate breast reconstruction in Chinese women using the transverse rectus abdominis myocutaneous (TRAM) flap. AB - BACKGROUND: Total mastectomy remains the mainstay of operative treatment for breast cancer mainly because it is preferred by surgeons. The techniques and benefits of reconstructing the amputated breast have been well documented in the medical literature but there have been very few reports on this issue in Chinese women. Immediate breast reconstruction using the transverse rectus abdominis myocutaneous (TRAM) flap in Chinese women suffering from early breast cancer who require mastectomy is summarized. METHODS: Since September 1991, the option of immediate breast reconstruction was offered to all patients less than 60 years of age suffering from early cancer (Tis, T1 or T2) who were not suitable for breast conserving treatment or who preferred to have a mastectomy. The single-pedicled TRAM flap was used. RESULTS: From September 1991 to September 1994, 27 reconstructions were performed. Partial flap loss occurred in four patients (15%), fat necrosis in three patients (11%) and abdominal bulging in one patient (4%). Operations performed by two teams simultaneously reduced operating time by 1.5 h without increasing the risk of complications. Twenty-one patients (78%) were satisfied or very satisfied with the outcome of reconstruction. CONCLUSIONS: The TRAM flap is a satisfactory method of breast reconstruction in Chinese women. A two-team approach can be employed safely to shorten operative time. Overall patient satisfaction was high. PMID- 8678875 TI - Modification of growth of desmoid tumours in tissue culture by anti-oestrogenic substances: a preliminary report. AB - BACKGROUND: Tamoxifen and toremifene have been used in patients with advanced desmoid tumours with response rates of 51%. METHODS: We developed an experimental model of desmoid tumour cells in tissue culture to study their effect. Four cell lines were established in tissue culture. All native and corresponding cultured tumours were oestrogen receptor negative. Tumour 1 was from a 22 year old with familial adenomatous polyposis (FAP) and recurrent abdominal wall desmoid tumours. She remains disease free on tamoxifen 4 years following surgery. Both her mother and sister also have shown regression of their FAP-associated desmoid tumours at the menopause and on tamoxifen, respectively. We assessed the effect of tamoxifen on desmoid tumours in tissue culture at 780 ng/mL. The results were assessed by cell density counting. RESULTS: Tumours 1 and 2 have responded with an approximately. 50% reduction in growth to tamoxifen at 780 ng/mL. CONCLUSIONS: This apparent growth inhibitory effect of tamoxifen on two desmoid tumour cell lines appears to be independent of oestrogen and correlates with the in vivo effect of tamoxifen on three desmoid tumours in an FAP family. PMID- 8678876 TI - TGF-alpha immunoreactivity in laryngeal carcinoma: lack of prognostic value and correlation to EGF-receptor expression. AB - BACKGROUND: Transforming growth factor alpha (TGF-alpha) is a polypeptide that is structurally similar to epidermal growth factor (EGF) that binds to the epidermal growth factor receptor (EGFR) and has been implicated in the development of several types of human tumours. METHODS: The expression of TGF-alpha is examined in laryngeal squamous cell carcinoma (SCC) (n = 24) and non-neoplastic polyps (n = 7) using streptavidin-biotin immunohistochemistry and a monoclonal antibody to the TGF-alpha protein. These cases had been previously characterized for EGFR immunoreactivity. The carcinomas were classified as well differentiated (n = 2), moderately differentiated (n = 16) and poorly differentiated (n = 6). Tissues from metastatic tumour deposits in lymph nodes (n = 5) were also studied. RESULTS: TGF-alpha overexpression was defined as intense immunoreactivity in more than two-thirds of tumour cells immunostained for TGF-alpha and was present in the majority of the SCC cases (n = 15; 63%) and metastatic tumour deposits (n = 4; 80%). In contrast, although some of the vocal cord polyps showed weak (n = 2) to moderate (n = 5) immunostaining, none had evidence of strong TGF-alpha immunoreactivity. The differences in TGF-alpha immunoreactivity were significant between primary laryngeal SCC and vocal cord polyps (P = 0.013; chi 2 test with continuity correction), and between metastatic laryngeal SCC and vocal cord polyps (P = 0.023; chi 2 test with continuity correction). There was no significant difference in TGF-alpha expression between the different grades of carcinomas (P = 0.92, chi 2 test) or between non-metastatic and metastatic carcinomas (P = 0.82; chi 2 test with continuity correction). No significant correlation was found between TGF-alpha expression and patient survival or tumour recurrence (r = 0.077, r2 = 0.006, P = 0.75; simple regression analysis), or between TGF-alpha expression and EGFR immunoreactivity (r = 0.325, r2 = 0.106, P = 0.0851). CONCLUSIONS: In conclusion, increased TGF-alpha immunoreactivity is present in most cases of laryngeal SCC with no specific relationship to tumour grade, suggesting that it may be important in the development of laryngeal carcinomas but not in its progression. No significant correlation was found between TGF-alpha and EGFR expression in laryngeal tumours and TGF-alpha immunoreactivity is of no prognostic value. PMID- 8678878 TI - Becoming an orthopaedic surgeon: background of trainees and their opinions of selection criteria for orthopaedic training. AB - A questionnaire survey of registrars in training in Australia in orthopaedic surgery was used to profile successful applicants and to ascertain what entry criteria they considered appropriate for the Orthopaedic Training Scheme. Typically, trainees were male, average age 31 years, married with children, born in Australia, privately educated and from a traditional family background. Respondents believe that referees' reports, performance as a resident and a registrar, and experience as a non-accredited registrar are the most appropriate selection criteria. Trainees held the opinion that too much emphasis may currently be placed on the support of influential surgeons and hospitals, and too little emphasis on medical school performance and surgical expertise. Academic achievement was considered to be of little relevance. The implications of these findings are discussed. PMID- 8678877 TI - Bone replacement in head and neck surgery: a biocompatible alternative. AB - BACKGROUND: Defects in the skull have presented difficult reconstructive problems. Recently glass-ionomer cement and preformed. implants have been used to repair bony defects in the skull base and in cranio-facial surgery. Three patients are reported to illustrate possible applications for this new material. METHODS: Ionocap cement and Ionoroc-skull standardized implants have been used. The cement is available as a two component blister pack. When mixed and blended a gel is produced which can be worked for approximately 5 min before hardening. It can then be contoured and drilled to the required shape. The resultant material is biocompatible and biostable, is non-toxic and permanently bonds to bone with no increase in temperature or shrinkage. RESULTS: The material has been used to fill the temporal defect left by transplantation of the temporalis muscle for oral reconstruction, the anterior and lateral walls of the maxilla and following craniofacial resection, the posterior wall of the frontal sinus and anterior skull base. CONCLUSIONS: Three patients with different reconstructive problems have been presented to illustrate the use of an alloplastic material that has a tensile strength similar to bone and firmly adheres to it. The material was found to be safe and easy to use. All three patients have now been followed for 12 months with no adverse affects. PMID- 8678879 TI - Interactive urology: an evaluation. AB - BACKGROUND: Interactive Urology is a multimedia software program that has been written to provide computer-assisted interaction for medical students at the University of Sydney during their surgical term in urology. An evaluation sought to establish how the software will be used by medical students in the learning context and to explore the efficacy of the software in the transfer of content as well as problem-solving skills. METHODS: Interactional analysis during student computer sessions and pre- and post-testing included a total of 80 medical students to evaluate Interactive Urology. RESULTS: The software package appeared to promote higher-order thinking skills with brainstorming activities occupying about half the time available. utilizing pre- and post-testing, Interactive Urology was found to be efficacious in the transfer of content and problem solving skills. It was also found to be as effective as text in transferring content and problem-solving skills. The sequence of text and computer assisted learning (CAL) did not alter learning efficacy. CONCLUSION: It was concluded from the present study that Interactive Urology is an effective and valuable learning resource for medical students. PMID- 8678880 TI - The aetiology, investigation and management of surgical disorders of the thyroid gland. AB - There have been many recent advances in our understanding of thyroid disease, including thyroid physiology, the molecular biology of thyroid neoplasms, guidelines for the management of surgical thyroid disease and the operative approach to thyroidectomy. The control of thyroid growth and function is better understood now that the thyroid stimulating hormone (TSH) receptor has been characterized as a G-protein coupled transmembrane receptor. The peripheral action of thyroid hormones is also better understood in terms of their interaction with nuclear thyroid hormone receptors. An adenoma-carcinoma sequence for the development of thyroid neoplasms has been proposed based on the characterization of a number of proto-oncogenes and tumour suppressor genes, and different pathways for the development of papillary and follicular thyroid carcinoma have been demonstrated. Fine needle biopsy has become, over the past few years, the principal diagnostic technique for evaluation of thyroid nodules, and has resulted in a significant reduction in the need for surgery for benign thyroid nodules. The approach to the management of thyroid carcinoma can now be based on comprehensive scoring systems for assigning patients to a particular risk group, the most recent of which is the MACIS system based on distant metastases (M), age (A), completeness of resection (C), invasion (I) and size (S). The capsular technique of thyroidectomy as described has now been shown to be the best method to preserve parathyroid blood supply, protect the recurrent laryngeal nerve and minimize the complications of thyroid surgery. PMID- 8678881 TI - Patterns of injury from major trauma in Victoria. PMID- 8678882 TI - Inflammatory pseudotumour of the spleen. AB - Inflammatory pseudotumours are benign tumour-like masses of unknown aetiology that show microscopically a range of inflammatory and reactive responses and are of importance because they may be mistakenly identified as neoplasms. This case report describes a 15 year old girl with a cystic inflammatory pseudotumour of the spleen in whom a partial splenectomy was performed with a satisfactory outcome. PMID- 8678883 TI - Delayed rupture of the spleen 5 1/2 years after conservative management of traumatic splenic injury. AB - A patient in whom spontaneous rupture of the spleen occurred 5 1/2 years following conservative management of splenic trauma is reported. The problem of late splenic rupture following splenic conservation therapy is discussed. PMID- 8678884 TI - Video assisted thoracoscopic staple resection of a giant bulla. AB - Video assisted thoracoscopic surgery (VATS) for spontaneous pneumothorax has been well described. However, there are few reports on the use of this technique on giant bullae. We report a 49 year old man with a symptomatic giant bulla who underwent a successful thoracoscopic staple resection. His chest drains were removed on the second postoperative day and he was discharged on the third postoperative day with virtually no discomfort. We conclude that thoracoscopic staple resection of a giant bulla is feasible technically and is an attractive alternative to the conventional open technique. PMID- 8678885 TI - Acute aortic dissection as a complication of coronary artery surgery. AB - Acute dissection of the ascending aorta is a rare, potentially fatal complication of cardiac surgery. During surgery patients with long-standing hypertension and atheromatous arterial disease require careful handling and cannulation of the aorta and aggressive intra-operative and postoperative management of aortic pressure. We present the successful treatment of a patient with acute aortic dissection following elective coronary artery surgery. PMID- 8678886 TI - Peri-colic diverticular mass of the sigmoid colon presenting in A strangulated inguinal hernia. PMID- 8678887 TI - [Sonography in veterinary medicine]. PMID- 8678888 TI - [Sonographic possibilities in emergency medicine]. AB - Sonography can help to find quickly the correct diagnosis of emergency cases. More than a few ml's of fluid can easily be detected in the thoracic and abdominal cavity. Cells in this fluid are visible as fine dots. In this paper, diseases of the diaphragm, the spleen and the urogenital system, that can be diagnosed or excluded echotomographically with high security, are discussed. For the examination of the stomach, the intestines and the pancreas, sonography is an important time-saving supplementation to radiology. Therefore contrast media can often be avoided. Necessary punctures and biopsies can be performed sonographically aimed with a minimum of risk. PMID- 8678889 TI - [The importance of sonography in orthopedics for dogs]. AB - For the ultrasonographic examination of the musculoskeletal system in dogs a 7,5 MHz linear scanner is used best, in some cases with a standoff pad. Radiography is the technique of choice to detect bone abnormalities. For certain circumstances the sonography can be used to give additional information (e.g. surrounding tissue with osteomyelitis or bone tumors). For the diagnostic of joint diseases ultrasonography is an excellent completion for the radiographic examination. Joint effusion and thickened capsule can be detected. Defects of articular cartilage like osteochondrosis dissecans in the knee or shoulder joint can be well seen. Instabilities of the joint can be identified with a dynamic examination. For evaluating the soft tissue areas ultrasonography is the optimal imaging procedure. Tears of muscles or tendons (e.g. achilles or biceps tendon), partial or complete ones, are seen in the sonographic examination. The process of healing with consolidation of the tendon can be controlled and documented. The tendon of the biceps brachii muscle is often affected in the soft tissue area of the shoulder. Luxation of the tendon, old injuries with scar formation, free dissections in the biceps tendon sheath and a tendovaginitis can be seen. Abscesses, foreign bodies, hematomas and soft tissue tumors in the musculoskeletal system can be well presented in the echotomogram. A tumor in the region of the brachial plexus can be detected directly with ultrasound. PMID- 8678890 TI - [Ultrasonic studies in reptiles]. AB - Ultrasonography in reptiles is a safe, noninvasive repeatable diagnostic imagine method. Size, volume and inner structure of organs can easily be determined. Based on 460 ultrasonographic examinations in 8 species of terrapins, 12 species of snakes and 22 species of lizard normal appearance of heart, gonads, fat bodies, kidneys, bladder and gastrointestinal tract are described. Pathological findings are explained in details using examples. PMID- 8678891 TI - [The use of sonography in the andrologic diagnosis in bulls, pathologic changes and false artifacts]. AB - The real-time ultrasonography is a tool for producing additional information to the clinical andrological examination in bulls. To find out the significance and the limits of this techniques these experiments have been carried out. In the testicles of slaughtered bulls artefacts were produced by injecting either crystalline, metallic or aqueous solutions respectively. The effect of metallic or crystalline solutions are good to be seen whereas water or gas are giving not so clear echograms. In the second part of the experiment 100 pairs of testicles where examined and compared to in situ examinations and histological preparations. In 95 cases of the examined animals pathological findings became evident both by sonographic examination and histologically, alterations that must be at least regarded as suspicious with respect to bulls to be used for reproduction. PMID- 8678892 TI - Quantification of endogenous carcinogens. The ethylene oxide paradox. AB - Although ethylene oxide is a proven genotoxic carcinogen in experimental animals, its human carcinogenicity is still being debated. Alkylations (hydroxyethylation) of DNA and proteins by ethylene oxide are well established. Ethylene oxide is metabolically formed from ethylene, which is a natural body constituent. Thus, endogenous sources of ethylene/ethylene oxide contribute to background alkylations of physiological macromolecules. There are now experimentally well established data sets on the background hydroxyethylations of the N-terminal valine of hemoglobin and of the 7-N position of guanine in DNA, in laboratory animals as well as in humans: A review of these data leads to the conclusion that these background levels display remarkable consistency between the different species studied and, as far as DNA adducts are concerned, also between different tissues. From the existing database it can be deduced that in rats a hemoglobin alkylation, equivalent to the level of normal background, would be caused by repetitive external atmospheric exposures to ethylene oxide (6 hr/day, 5 days/week for several weeks) of about 30 ppb. On the contrary, in the same species, a DNA alkylation, equivalent to the level of normal background, would be caused by similar repetitive exposures to ethylene oxide at about 1-2 ppm. This paradox is unresolved. It points, however, to the biological importance of endogenous DNA alkylations and questions current regulatory procedures of assessing the risk of minute doses of exogenous carcinogens. PMID- 8678893 TI - The gelatinase inhibitory activity of tetracyclines and chemically modified tetracycline analogues as measured by a novel microtiter assay for inhibitors. AB - A quantitative nonisotopic solution assay for gelatinases and inhibitors was developed using biotinylated gelatin as enzyme substrate. In this assay, residual biotinylated substrate is sandwiched between avidin-coated plates and streptavidin-peroxidase and is quantified by the peroxidase reaction. This assay was useful for measuring gelatinase activities and defining the activities of gelatinase inhibitors. When 23 tetracycline analogues were compared, significant differences in gelatinase B inhibition were found between various compounds. 4 epioxytetracycline base, 4-epichlortetracycline, meclocyclinesulfosalicylate, and unmodified metacycline and minocycline proved to be the most potent gelatinase B (EC 3.4.24.35) inhibitors. The gelatinase B inhibitory activity of tetracyclines was clearly dissociated from their antimicrobial activity. The effect of high molecular-weight inhibitors, such as monoclonal antibodies, was also demonstrable in the microtiter plate assay. In view of the pathophysiological function of gelatinases, the definition of gelatinase inhibitors with known efficacy, safety, and side effects is crucial for the treatment of diseases such as rheumatoid arthritis and multiple sclerosis. Particular tetracyclines fulfil these criteria and the described assay is useful for defining other gelatinase-inhibiting lead compounds. PMID- 8678894 TI - Specific targeting of a lipophilic prodrug of iododeoxyuridine to parenchymal liver cells using lactosylated reconstituted high density lipoprotein particles. AB - We recently reported the conversion of the water-soluble antiviral drug iododeoxyuridine (IDU) into the lipophilic prodrug dioleoyl-iododeoxyuridine (IDU Ol2). The prodrug was incorporated into reconstituted high-density lipoprotein (NeoHDL) particles with physical and biological properties similar to those of native HDL. We also found, in initial experiments, that lactosylation of the prodrug-loaded NeoHDL increases its liver uptake. Because this offers the attractive perspective of using these particles for the delivery of drugs to the liver, we now analyze the characteristics and biological fate of lactosylated IDU Ol2-loaded NeoHDL. The particles (containing approximately 25 prodrug molecules) have the same size and charge as native HDL, indicating that lactosylation does not cause aggregation or oxidative modification. At 10 min after intravenous injection of lactosylated [3H]IDU-Ol2-loaded NeoHDL into rats, only 13.5 +/- 2.8% of the dose was left in plasma and 75.9 +/- 2.4% of the dose was recovered in the liver. The relative specific uptake by the liver was 1-2 orders of magnitude higher than that of any other tissue. The hepatic uptake of lactosylated [3H]IDU Ol2-loaded NeoHDL was much higher than that of free [3H]IDU ( < 20% of the dose). Both parenchymal liver cells and Kupffer cells express galactose-specific receptors. By isolating liver cells after injection of the prodrug-loaded particles, it was established that hepatic uptake occurred mainly (for 84.4 +/- 3.8%) in parenchymal liver cells. Preinjection with asialofetuin substantially reduced the liver uptake of lactosylated [3H]IDU-Ol2-loaded NeoHDL, which points to uptake by the asialoglycoprotein receptor. Subcellular fractionation of the liver indicated that lactosylated [3H]IDU-Ol2-loaded NeoHDL does not merely associate to cells, but is internalized and delivered to the lysosomes. In conclusion, we show that IDU can be specifically targeted to the parenchymal liver cell. Conversion of the water-soluble parent drug into a lipophilic prodrug that is incorporated into a lactosylated reconstituted HDL particle, is an approach that may also be used to deliver other water-soluble drugs to the parenchymal liver cells. This may lead to more effective therapy for liver diseases such as hepatitis B. PMID- 8678895 TI - CV-11974, the active metabolite of TCV-116 (Candesarten), inhibits the synergistic or additive effect of different growth factors on angiotensin II induced proliferation of vascular smooth muscle cells. AB - Many previous studies have demonstrated that angiotensin II (AII) type I (ATI) receptor antagonists remarkably reduced intimal lesions in rats following balloon injury. Using vascular smooth muscle cells (VSMC) in culture, we tested the hypothesis that other classical growth factors may enhance AII effects on VSMC growth, and ATI receptor antagonists may inhibit these effects. AII, platelet derived growth factor-BB (PDGF-BB), and epidermal growth factor (EGF) caused a 3426 +/- 262%, 277 +/- 69%, and 1568 +/- 62% increase in [3H]thymidine incorporation in VSMC (mean +/- SD, n = 3), respectively. The exposure of the cells to AII in combination with PDGF-BB or EGF resulted in an approximately 2 fold or 1.5-fold elevation of the AII-dependent effect, respectively. 2-ethoxy-1 [[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimi dazole-7- carboxylic acid (CV-11974), the active metabolite of the specific nonpeptide AT1 receptor antagonist (+/-)-1-cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5 yl)biphenyl-4-yl]methyl]-1H-benzimi dazole- 7-carboxylate (TCV-116, Candesartan), suppressed the effect of AII down to basal values, as well as reducing the synergistic effect of PDGF or the additive effect of EGF on AII-induced [3H]thymidine incorporation. AII and PDGF-BB per se induced 57 +/- 19 and 70 +/- 14% increase in VSMC number. Combination of both agonists resulted in a 2-fold increase of the AII effect on cell number. Again, CV-11974 blocked the effect of AII, as well as the additive effect of PDGF-BB on cell number. From these findings, it may be concluded that AT1 receptor antagonists may reduce or prevent the development of intimal lesions following vascular injury through inhibition of direct and indirect growth-promoting effects of AII in VSMC. PMID- 8678896 TI - Expression of the low-density lipoprotein receptor, HMG-CoA reductase, and multidrug resistance (Mdr1) genes in colorectal carcinomas. AB - Some malignant cells have elevated uptake of plasma low-density lipoprotein (LDL). We determined the expressions in colorectal cancers of the LDL receptor gene, of the gene for the rate-limiting enzyme in cholesterol synthesis, 3 hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and of the multidrug resistance gene (mdr1) by quantitative RNA-RNA solution hybridisation. LDL receptor RNA levels in tumor tissue exceeded those in normal mucosa in 20 of 23 patients (2-11-fold higher in 17 of 23 patients), with a mean +/- SD of 7.8 +/- 5.8 copies/cell in tumor tissue vs 3.5 +/- 2.5 in normal mucosa (P = 0.002). The HMG-CoA reductase gene was similarly expressed in tumor and normal tissue, with means and SD of 2.0 +/- 1.3 copies/cell versus 2.2 +/- 1.9 (pi = 21). Mdr1 RNA was undetectable ( < 0.15 copies/cell) in 5 of 20 tumors, with a mean +/- SD of 1.0 +/- 1.1 copies/cell vs 1.6 +/- 1.7 in normal mucosa. Expression of all three genes was, in most cases, higher in normal liver than in liver metastasis of colorectal carcinomas or normal colon mucosa. The results may form the basis for using LDL as a drug carrier for treatment of colorectal carcinomas, and may indicate that drug resistance in these tumors is not due to overexpression of the mdr1 gene. PMID- 8678897 TI - Anti-proliferative activity and target cell catabolism of the vitamin D analog 1 alpha,24(S)-(OH)2D2 in normal and immortalized human epidermal cells. AB - Vitamin D analogs represent valuable new agents for the suppression of proliferation of a variety of cell types, including those of the skin. One such analog is the vitamin D2 metabolite, 1 alpha,24(S)-dihydroxyvitamin D2, which binds strongly to the vitamin D receptor and induces vitamin D-dependent gene expression in vitro. In the work described here, we studied the anti proliferative activity and target cell metabolism of 1 alpha,24(S) dihydroxyvitamin D2 in cells of human epidermal origin. We found this analog to be equally potent in its anti-proliferative effect to the hormone 1 alpha,25 dihydroxyvitamin D3. Furthermore, 1 alpha,24(S)-dihydroxyvitamin D2 was metabolized by the human keratinocyte cell line HPK1A-ras at a slower rate than either 1 alpha,25-dihydroxyvitamin D3 or calcipotriol, a drug used effectively in the treatment of psoriasis. We characterized the metabolic products of 1 alpha,24(S)-dihydroxyvitamin D2 as a mixture of side-chain truncated and hydroxylated products. The main product was identified by GC-MS and NMR techniques as 1 alpha,24(S),26-trihydroxyvitamin D2. The biological activity of this main product was determined in a vitamin D-dependent, growth-hormone reporter gene expression system to be lower than that of the parent molecule. We conclude from these data that 1 alpha,24(S)-dihydroxyvitamin D2 is a valuable new anti-proliferative agent with a slower rate of catabolism by cells of epidermal origin. Preliminary evidence suggests that the parent molecule, and not its products, is responsible for this biological activity in vitro. PMID- 8678899 TI - 4-Chloro-m-cresol: a specific tool to distinguish between malignant hyperthermia susceptible and normal muscle. AB - Single-channel recordings have indicated that ryanodine receptor (RyR1) mutation Arg615Cys of porcine malignant hyperthermia-susceptible (MHS) muscle is not directly associated with the enhanced caffeine sensitivity of MH(S) muscle [1]. In the present study, the effect of a novel activator of RyR1, 4-chlorom-cresol (4-CmC), was investigated on high-affinity [3H]ryanodine binding to porcine skeletal sarcoplasmic reticulum. The 4-CmC affinity of [3H]ryanodine binding to MHS vesicles was 2-fold higher compared to that in normal tissue. This enhanced affinity was confirmed when the effect of 4-CmC on [3H]ryanodine binding to the isolated CHAPS-solubilized MHS RyR1 was investigated. 4-CmC is, therefore, suggested to be a potent tool to distinguish between Ca2+ release from MHS and normal muscle. PMID- 8678898 TI - Nitrosyl cyanide, a putative metabolic oxidation product of the alcohol-deterrent agent cyanamide. AB - When incubated with catalase/glucose-glucose oxidase, 13C-labeled cyanamide gave rise not only to 13C-labeled cyanide, but also to 13C-labeled CO2. Moreover, a time-dependent formation of nitrite was observed when cyanamide was oxidized in this system. These results suggested that the initial product of cyanamide oxidation, viz. N-hydroxycyanamide, was being further oxidized by catalase/H2O2 to nitrosyl cyanide (O = N-C = N). Theoretically, nitrosyl cyanide can hydrolyze to the four end-products detected in the oxidative metabolism of cyanamide in vitro, viz. nitroxyl, cyanide, nitrite, and CO2. Accordingly, both unlabeled and 13C-labeled nitrosyl cyanide were synthesized by the low temperature (-40 to -50 degrees) nitrosylation of K-(18-crown-6)cyanide with nitrosyl tetrafluoroborate. The product, a faint blue liquid at this temperature, was transferred as a gas to phosphate-buffered solution, pH 7.4, where it was solvolyzed. Analysis of the headspace by gas chromatography showed the presence of N2O, the dimerization/dehydration product of nitroxyl, while cyanide was detected in the aqueous solution, as measured colorimetrically. [13C]CO2 was analyzed by GC/MS. An oxidative biotransformation pathway for cyanamide that accounts for all the products detected and involving both N-hydroxycyanamide and nitrosyl cyanide as tandem intermediates is proposed. PMID- 8678900 TI - Ebselen-binding equilibria between plasma and target proteins. AB - The antiinflammatory drug ebselen (2-phenyl-1,2-benzisoselenazo-3(2H)-one) is known to bind covalently to thiols to form seleno disulfides that, directly or indirectly, are responsible for its pharmacological effects. Due to its reactive thiol group and high plasma concentration, albumin is a preferred target of ebselen, which it binds covalently. Ebselen should not, then, be available for intracellular actions at other target proteins. We have addressed this question, and show by difference spectroscopy that the interaction of ebselen with albumin occurs stoichiometrically under ring opening, but is readily reversible in the presence of glutathione. With intact human polymorphonuclear leukocytes (PMN), a similar stoichiometric reaction with distinct spectral features was observed with ebselen that was completely abolished by pretreatment of PMN with N ethylmaleimide, but not by selective depletion of cellular glutathione. Human platelets, again, exhibited different spectral changes upon addition of ebselen. In agreement with results reported in the literature, we show that 14C-ebselen is in dynamic equilibrium with all accessible thiol groups and, hence, despite mostly being bound covalently to albumin, it will exchange rapidly with other target proteins in PMN or platelets. PMID- 8678901 TI - Enhancement of ricin toxin A chain immunotoxin activity: synthesis, ionophoretic ability, and in vitro activity of monensin derivatives. AB - Site-selective toxin delivery was achieved by coupling monoclonal antibody to the A chain subunit of ricin (RTA-IT). The cell-killing potency of RTA-IT can be drastically increased in vitro by using ionophores such as monensin. To reduce the intrinsic toxicity of monensin and to enhance its in vitro and in vivo activity, we synthesized 7 derivatives characterized by different lipophilicities. These derivatives were also analyzed for ionophoretic activity on intact cells, toxicity, and RTA-IT-enhancing activity. Two different RTA-IT were assayed on a human leukemia cell line. A correlation between lipophilicity, ionophoretic activity, and RTA-IT enhancement was observed. The compounds with the highest polar charge showed low intrinsic toxicity, revealed moderate ionophoretic activity, and were able to enhance RTA-IT only at high concentrations, whereas more lipophilic compounds (with a C28 tail or a phenyl group) showed significant ionophoretic activity and good enhancing properties. PMID- 8678902 TI - Ca2+ entry induced by calcium influx factor and its regulation by protein kinase C in rabbit neutrophils. AB - Extracellular application of acid extract from platelet-activating factor- or thapsigargin-treated rabbit neutrophils induced a rise of cytosolic free calcium concentration ([Ca2+]i) in neutrophils and adrenal chromaffin cells suspended in Ca(2+)-containing, but not in Ca(2+)-deficient, medium. The ability of the extract to selectively induce Ca2+ entry was also confirmed by the increase in 45Ca2+ uptake and failure to stimulate Ca2+ release in digitonin-permeabilized neutrophils. 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibited the extract induced [Ca2+]i rise in a staurosporine (ST)-sensitive fashion, neither of which had any effect on its production. SK&F 96365 and econazole also reduced extract induced Ca2+ entry. These results suggest that a Ca2+ entry-inducible substrate (calcium influx factor) is extracted from Ca2+ store-depleted neutrophils, and that its action may be regulated by protein kinase C and certain pharmacological agents. PMID- 8678903 TI - Evidence of a direct action of taurine and calcium on biological membranes. A combined study of 31P-nuclear magnetic resonance and electron spin resonance. AB - To determine the actions of taurine and calcium on biological membranes, the effects of these compounds on the mobility of phospholipids of resealed and sonicated ghosts of human erythrocytes were investigated, using 31P-NMR spectroscopy. In addition, the effects of taurine and calcium on lipid fluidity were investigated by ESR spectroscopy, using a spin-labeling method with 5-doxyl stearic acid. The mobility of the membranes decreased following treatment with 10 mM taurine, but coadministration of 2.5 mM calcium blocked this effect. The fluidity of the membranes was not changed following treatment with 10 mM taurine, but decreased following coadministration of 2.5 mM calcium. These actions of taurine and calcium on the dynamics of biological membranes might explain, in part, the observation that most of the pharmacological effects of taurine on mammalian organs occur in the presence of calcium ions. PMID- 8678904 TI - Increased DT-diaphorase expression and cross-resistance to mitomycin C in a series of cisplatin-resistant human ovarian cancer cell lines. AB - In a series of ovarian carcinoma cell lines selected in vitro for resistance to cisplatin by continuous exposure to increasing drug concentrations, the level of resistance is proportional to the expression of gamma-glutamylcysteine synthetase (gamma-GCS). To determine if other detoxicating genes are coordinately expressed, we measured the activity of DT-diaphorase and cytochrome P450 reductase. The specific activity of DT-diaphorase, but not that of cytochrome P450 reductase, increased with increasing resistance to cisplatin. Steady-state mRNA levels for DT-diaphorase correlated with enzyme activity and hence with cisplatin resistance. Since the activity of DT-diaphorase has been associated with sensitivity to quinones, we studied the cytotoxicity of mitomycin C under oxic conditions. Unexpectedly, resistance to mitomycin C increased proportionally with that to cisplatin (r = 0.997). Pretreatment with buthionine sulfoximine, which inhibits glutathione (GSH) synthesis, failed to sensitize either the sensitive or the resistant lines to mitomycin C. Thus, the basis for collateral resistance to mitomycin C in the cisplatin-resistant lines under oxic conditions is unrelated to overproduction of GSH. Under hypoxia, the toxicity of mitomycin C to the most sensitive (A2780) cell line was unchanged. However, the most resistant (C200) line was 2-fold more resistant to mitomycin C under hypoxic conditions. The coordinate overexpression of DT-diaphorase and gamma-GCS in the resistant cell lines is thus associated with hypoxic cell resistance, and supports the involvement of shared mechanisms of gene regulation in the observed resistant phenotype. PMID- 8678905 TI - Inhibition of [3H]dopamine uptake into striatal synaptosomes by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. AB - Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) may be endogenous neurotoxins causing nigral cell death in Parkinson's disease. These compounds inhibit mitochondrial function but, like MPP+, require accumulation in dopaminergic neurones via the dopamine reuptake system to exert toxicity. We, now, examine the substrate affinity of 14 neutral and quaternary isoquinoline derivatives (7 isoquinolines, 2 dihydroisoquinolines and 5 1,2,3,4 tetrahydroisoquinolines) for the dopamine reuptake system by their ability to inhibit the uptake of [3H]dopamine into rat striatal synaptosomes. Ten isoquinoline derivatives and MPP+ inhibited [3H]dopamine uptake in a concentration-dependent manner. Only 5 isoquinoline derivatives produced 50% inhibition of [3H]dopamine uptake (IC50 = 8.0-50.0 microM), none of which were as potent as MPP+ (IC50 = 0.33 microM). These findings suggest that isoquinoline derivatives are moderate to poor substrates for the dopamine reuptake system and that high concentrations of, or prolonged exposure to, isoquinoline derivatives may be necessary to cause neurodegeneration. PMID- 8678906 TI - Differential effects of tenidap on the zymosan- and lipopolysaccharide-induced expression of mRNA for proinflammatory cytokines in macrophages. AB - Tenidap is a novel antirheumatic drug that combines cyclooxygenase inhibition with cytokine modulating qualities. We demonstrate here that tenidap inhibits the zymosan-induced expression of both interleukin 1 and tumor necrosis factor alpha in macrophages, at the mRNA and protein levels. The concentration-dependence of the tenidap-induced inhibition of the expression of mRNA for these proinflammatory cytokines agrees with that of its inhibitory effects on zymosan induced arachidonate mobilization and changes in phosphoprotein pattern. The effects of tenidap on the lipopolysaccharide-induced expression of these cytokines are more complex. Tenidap inhibits the induction of interleukin 1 by lipopolysaccharide or bacteria, but less potently than the interleukin 1-response induced by zymosan. In contrast, the drug markedly potentiates the lipopolysaccharide-induced expression of tumor necrosis factor alpha at both the mRNA and protein levels. The latter effect is demonstrated to be due to cyclooxygenase inhibition and is reversed by prostaglandin E2. PMID- 8678907 TI - Interaction of glutathione transferase P1-1 with captan and captafol. AB - Glutathione transferase (GST, EC 2.5.1.18) P1-1 was strongly inhibited by captan and captafol in a time- and concentration-dependent manner. The IC50 values for captan and captafol were 5.8 microM and 1.5 microM, respectively. Time-course inactivation of GSTP1-1 by two pesticides was prevented by 3 microM of hexyl glutathione, but not by methylglutathione. The fact that the inactivated enzyme recovered all the 5,5'-dithiobis(2-nitrobenzoic acid) titrable thiol groups, with concomitant recovery of all its original activity after treatment with 100 microM dithiothreitol, suggested that captan and captafol were able to induce the formation of disulfide bonds. That the inactivation of GSTP1-1 by captan and captafol involves the formation of disulfide bonds between the four cysteinil groups of the enzymes was confirmed by the SDS-PAGE experiments on nondenaturant conditions. In fact, on SDS-PAGE, GSTP1-1 as well as the cys47ala, cys101ala, and cys47ala/cys101ala GSTP1-1 mutants treated with captan and captafol showed several extra bands, with apparent molecular masses higher and lower than the molecular mass of native GSTP1-1 (23.5 kDa), indicating that both intra- and inter-subunit disulfide bonds were formed. These extra bands returned to the native 23.5 kDa band with concomitant restoration of activity when treated with dithiothreitol. PMID- 8678908 TI - Simultaneous measurement of Ca2+ transients and changes in the cell volume and microviscosity of the plasma membrane in smooth muscle cells. Evaluation of the effect of formoterol. AB - The effects of the beta 2-adrenoceptor agonist formoterol (50 nM) on the angiotensin II (20 nM)-induced Ca2+ response and changes in the cell volume and microviscosity of the plasma membrane of vascular smooth muscle cells were studied. Applied as a model substance for the stimulation of the phosphoinositide phospholipase C pathway, angiotensin II has been used to simulate the bronchospasm of smooth muscle in asthma. Our results demonstrated that angiotensin II-induced smooth muscle contraction primarily involves an InsP3 mediated release of Ca2+ from intracellular stores and, to a minor extent, an enhanced influx of Ca2+ through the plasma membrane. Both the Ca2+ response and the contractile reaction were strongly antagonized by pretreatment of the cells with 50 nM formoterol. The protective effect of formoterol on smooth muscle contractions is proposed to be mainly related to a direct stimulation of beta 2 adrenoceptor-coupled cAMP generation. Moreover, it is predicted that the interaction between the beta 2-adrenoceptor glycoprotein and adenylate cyclase will be enhanced following a formoterol-associated decrease in the microviscosity of the plasma membrane. PMID- 8678910 TI - Cellular distribution and cellular reactivity of platinum (II) complexes. AB - We have investigated whether or not the cellular content of reactive platinum, aside from total cellular and DNA-bound platinum, is a measure of the growth inhibitory potential of a given platinum complex. Human MCF-7 breast cancer cells, after treatment with cisplatin [cis-diamminedichloroplatinum(II)] and several 1,2-diphenylethylenediamineplatinum(II) complexes at a fixed dose of 3 microM, were analyzed for their contents of platinum in total cells, isolated nuclei, chromosomal DNA, and the cellular pool of reactive platinum, and compared with ED50-values. Platinum was measured by atomic absorption. Reactive platinum was identified after its reaction with calf thymus DNA that had been added to the cells before their lysis. The amounts of platinum binding to chromosomal DNA were related to previously established ED50-values, and such a correlation could not be found for platinum in total cells, nuclei, and, especially, reactive platinum. The observed differences in the platinum contents of DNA were referred to variations in the rate of adduct formation rather than repair because two representative platinum complexes were indistinguishable by their effects on the chloramphenicol acetyltransferase (EC 2.3.1.28) transfection system. One of the other platinum complexes accumulated, showing an increased growth inhibition in support of this interpretation with regard to the other platinum complexes. During prolonged treatment of MCF-7 cells with the platinum(II) complexes, pools of reactive platinum were found to persist even after drug depletion in the culture medium. This suggested a hitherto unrecognized cellular storage and availability of reactive platinum. PMID- 8678909 TI - The 2,2'-bipyridyl-6-carbothioamide copper (II) complex differs from the iron (II) complex in its biochemical effects in tumor cells, suggesting possible differences in the mechanism leading to cytotoxicity. AB - 2,2'-bipyridyl-6-carbothioamide (BPYTA) is an antitumor agent with chelating properties. It has previously been shown that the R2 subunit of ribonucleotide reductase (RR) is its major cellular target, but RR inhibition is observed only in the presence of ferrous iron (BPYTA-Fe, molar ratio 2:1). Because the copper (II) complex of BPYTA (BPYTA-Cu, molar ratio 1:1)) has in vitro antitumor activity comparable to that of BPYTA-Fe, we studied the mechanism of action of this new metal complex. Spectorphotometric and HPLC studies demonstrated that, at pH 7.5, BPYTA-Cu is stable at molar ratio 2:1 and copper is in its favored oxidized form [BPYTA-Cu(II)]. Electron paramagnetic resonance (EPR) studies with mouse recombinant R2 demonstrated that BPYTA-Cu destroys the R2 tyrosyl radical at the same concentration at which BPYTA-Fe does (78% vs 73% destruction at 200 microM, with 5 min of contact), but R2 inhibition is not time-dependent. Studies of the metabolism of [14C] cytidine suggest that the cytotoxic activity of BPYTA Cu can be explained in terms of RR inhibition. However, the significant inhibition of RNA synthesis and the lack of cross-resistance to BPYTA-Cu of cell lines resistant to other RR inhibitors suggest that BPYTA-Cu may have more than one cellular target. Moreover, cell proliferation studies suggest that, unlike BPYTA-Fe, BPYTA-Cu displays its activity immediately after contact with the target cells. Our study demonstrates that significant differences in the biochemical effects of BPYTA and, perhaps, also its mechanism of action are due solely to the bonded transition metalloelement. This might also be the case with other chelators that demonstrate cytotoxic activity following metalloelement chelation. PMID- 8678911 TI - Metabolite complex formation of orphenadrine with cytochrome P450. Involvement of CYP2C11 and CYP3A isozymes. AB - Expression and inhibition of cytochrome P450 (CYP) isozymes capable of forming an orphenadrine metabolite complex were studied in microsomes of untreated and inducer-treated male and female rats. High levels of complex-forming isozymes were found in microsomes of untreated male as compared to female rats. Treatment of male rats with several P450 inducers did not considerably increase the extent of in vitro complex formation. In female rats, however, phenobarbital or dexamethasone treatments led to pronounced induction. The isozyme specificity of complex formation was investigated by several approaches including: 1. inhibition by orphenadrine of isozyme-specific P450 activities, such as hydroxylation of testosterone, O-dealkylation of pentoxy-and ethoxyresorufin and complex formation with triacetyloleandomycin (TAO), 2. inhibition of orphenadrine complex formation by metyrapone, TAO, and cimetidine, and 3. correlation of complex levels with immunochemically, enzymatically, or spectroscopically determined amounts of P450 isozymes. Our data suggest that CYP2C11, a CYP3A isozyme and an unidentified P450 species are involved in complex formation with orphenadrine, but exclude the involvement of CYP1A1/2 and CYP2B1/2. The capability of CYP2C11 to form a metabolite complex with orphenadrine is strongly suggested for the following reasons: 1. Efficient inhibition of testosterone 2 alpha- and 16 alpha hydroxylation by complex formation with orphenadrine in microsomes of untreated male rats, 2. high expression of orphenadrine-complexing isozymes in untreated male compared to female rats, 3. specific inhibition of in vitro complex formation by cimetidine, 4. suppression of complex-forming isozymes by 3 methylcholanthrene and beta-naphthoflavone, and 5. concomitant induction of complex-forming isozymes, immunodetectable CYP2C11, and testosterone 2 alpha hydroxylase by stanozolol. That at least one, but not all, CYP3A isozymes is involved in complex formation is concluded from inhibition experiments with TAO that show that orphenadrine complexation can be significantly inhibited in microsomes of dexamethasone-treated, but not in microsomes of untreated rats. Furthermore, complex formation with TAO is not inhibited by orphenadrine in microsomes of phenobarbital (PB)-treated rats. In PB-treated female rats, a further unidentified complex-forming isozyme can be detected that is not inhibited by complex formation with TAO. PMID- 8678912 TI - First-pass elimination of a peptidomimetic thrombin inhibitor is due to carrier mediated uptake by the liver. Interaction with bile acid transport systems. AB - CRC 220 (4-methoxy-2, 3, 6-trimethylphenylsulfonyl-L-aspartyl-D-4 amidinophenylalanyl -piperidide) is a competitive peptide-based trombin inhibitor with high affinity to human alpha-thrombin (Ki 2.5 nM). The amphiphilic compound exhibits virtually no systemic bioavailability despite proteolytic stability and proven enteral absorption. After intravenous application (V. jejunalis) in rats CRC 220 is almost completely excreted into bile. Simultaneous administration of bile acids considerably decreases this first-pass elimination. CRC 220 is extensively taken up in isolated rat hepatocytes by a saturable carrier-mediated transport with Km 23.7 microM and Vmax 775 pmol x mg-1 x min-1. A large part of this transport is energy-dependent. At temperatures above 20 degrees C, the uptake is accelerated exponentially. The activation energy amounts to 82 kj/mol. A minor portion of CRC 220 uptake occurs by physical diffusion with a permeability coefficient of 7.83 x 10(-7) cm/sec at 12 degrees C. Sodium ions energize CRC 220 uptake. Replacement of sodium by choline or lithium decreases the transport rate of 23-40%. In addition, a negative membrane potential facilitates the uptake. CRC 220 transport is only observed in hepatocytes: it is absent in BHK, FAO, HepG2, HPCT 1E3, and HPCT 1E3-TC cells. In the presence of 4 amidinophenylalanine derivatives, CRC 220 uptake is considerably decreased. Inhibition also occurs with bile acids and bromosulfophthalein, but less with bumetanide. Because CRC 220 inhibits bile acid uptake into hepatocytes and vice versa, the results suggest that the first-pass elimination of this amphiphilic thrombin inhibitor is due to an active carrier-mediated transport process in the basolateral plasma membrane of rat hepatocytes, and that this transport occurs via a bile acid transport system. PMID- 8678913 TI - Hemoglobin affects lipid peroxidation and prostaglandin E2 formation in rat corticocerebral tissues in vitro. AB - Variations of lipid peroxidation and arachidonic acid (AA) metabolism products were found when experimental subarachnoid hemorrhage or ischemia and reperfusion were performed in an animal brain model. In a previous study, we showed that hemoglobin (Hb) produces prostaglandins when incubated in AA. To elucidate how Hb affects lipid peroxidation and AA metabolism in the CNS, we measured lipid hydroperoxides (LOOH), PGE2 and thiobarbituric acid reactant substances (TBARS) in corticocerebral homogenates and slices of rats (normal rats) after incubation with different concentrations (10(-9) to 10(-5) M) of Hb. In addition, brain cortices of indomethacin-treated (40 mg/Kg) rats (IN-treated rat) were incubated in the presence of 10(-5) M indomethacin (IN) to exclude the interference of prostaglandin enzyme synthetase. Hb was able to affect LOOH, PGE2, and TBARS production in both normal and IN-treated rat brain cortex homogenates and slices. In all cases, we found an increase in prostaglandin when 10(-8) M Hb was used, whereas no effect was noticed with 10(-9) M. On the other hand, with higher Hb concentrations (10(-6)-10(-5) M), the LOOH and PGE2 values did not reach statistical significance, and TBARS significantly increased. In all cases, when 10(-4) M scavenger or metal-chelating compounds were added to an incubation mixture with 10(-8) M Hb, PGE2 formation was inhibited, whereas no variation occurred when 10(-4) M IN was further added to IN-treated rat corticocerebral homogenate or slices. We hypothesize that in in vivo experimental neuropathologies, Hb must attain the 10(-8) M concentration in the reaction cellular microenvironment to stimulate PGE2 production, and that an evaluable part of this PGE2 production may be directly ascribable to the iron-heme oxy redoxy activity of Hb. PMID- 8678914 TI - High density lipoproteins and coronary heart disease. AB - An inverse relationship between the concentration of high density lipoprotein (HDL) cholesterol and the development of coronary heart disease (CHD) is well established. It is unclear from the human studies whether this relationship reflects an ability of HDLs to protect against coronary disease or whether a low HDL in coronary patients is simply an epiphenomenon. Recent studies of transgenic mice, however, indicate that HDLs are directly antiatherogenic. The mechanism of the protection is unknown but may relate both to an involvement of HDLs in plasma cholesterol transport and to a range of non-lipid transport functions of HDLs. It is also unclear from human studies whether specific HDL subpopulations have differing abilities to protect against CHD, although such specificity is suggested from studies of transgenic mice. There is circumstantial evidence that elevating the concentration of HDL cholesterol in human subjects translates into a reduced coronary risk, although it should be stressed that there are still no reports of studies designed specifically to address this issue. PMID- 8678915 TI - Two novel partial deletions of LDL-receptor gene in Italian patients with familial hypercholesterolemia (FH Siracusa and FH Reggio Emilia). AB - In the present study we report two novel partial deletions of the LDL-R gene. The first (FH Siracusa), found in an FH-heterozygote, consists of a 20 kb deletion spanning from the 5' flanking region to the intron 2 of the LDL-receptor gene. The elimination of the promoter and the first two exons prevents the transcription of the deleted allele, as shown by Northern blot analysis of LDL-R mRNA isolated from the proband's fibroblasts. The second deletion (FH Reggio Emilia), which eliminates 11 nucleotides of exon 10, was also found in an FH heterozygote. The characterization of this deletion was made possible by a combination of techniques such as single strand conformation polymorphism (SSCP) analysis, direct sequence of exon 10 and cloning of the normal and deleted exon 10 from the proband's DNA. The 11 nt deletion occurs in a region of exon 10 which contains three triplets (CTG) and two four-nucleotides (CTGG) direct repeats. This structural feature might render this region more susceptible to a slipped mispairing during DNA duplication. Since this deletion causes a shift of the BamHI site at the 5' end of exon 10, a method has been devised for its rapid screening which is based on the PCR amplification of exon 10 followed by BamHI digestion. FH Reggio Emilia deletion produces a shift in the reading frame downstream from Lys458, leading to a sequence of 51 novel amino acids before the occurrence of a premature stop codon (truncated receptor). However, since RT-PCR failed to demonstrate the presence of the mutant LDL-R mRNA in proband fibroblasts, it is likely that the amount of truncated receptor produced in these cells is negligible. PMID- 8678916 TI - Tyrosine kinase is involved in angiotensin II-stimulated phospholipase D activation in aortic smooth muscle cells: function of Ca2+ influx. AB - In the present study, we examined the effect of angiotensin II (Ang II) on phosphatidylcholine-hydrolyzing phospholipase D activity in subcultured rat aortic smooth muscle cells (SMC). Ang II dose-dependently stimulated the formation of choline and inositol phosphates. The effect of Ang II on the formation of inositol phosphates (EC50 was 0.249 +/- 0.091 nM) was more potent than that on the formation of choline (EC50 was 2.39 +/- 1.29 nM). A combination of Ang II and 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C, additively stimulated the formation of choline. Staurosporine, an inhibitor of protein kinases, inhibited the TPA-induced formation of choline, but had little effect on the Ang II-induced choline formation. Ang II stimulated Ca2+ influx from extracellular space time- and dose-dependently. The depletion of extracellular Ca2+ by (ethylenebis(oxyethylenenitrilo)) tetraacetic acid (EGTA) significantly reduced the Ang II-induced formation of choline. Genistein and tyrphostin, protein tyrosine kinase inhibitors, significantly suppressed the Ang II-induced Ca2+ influx. Genistein and tyrphostin also suppressed the Ang II induced formation of choline. These results suggest that Ang II stimulates phosphatidylcholine-hydrolyzing phospholipase D due to Ca2+ influx from the extracellular space in rat aortic SMC, and that protein tyrosine kinase is involved in the Ang II-induced Ca2+ influx, resulting in the promotion of phosphatidylcholine hydrolysis. PMID- 8678917 TI - Inhibition of the protective effect of estrogen by progesterone in experimental atherosclerosis. AB - The aim of the present study was to determine the effect of progesterone on the action of estrogen in the development of atherosclerosis. A total of 48 female New Zealand white (NZW) rabbits were ovariectomized. The animals were separated into 6 groups of 8 animals each and received subsequently a 0.5% cholesterol diet for 12 weeks. During this cholesterol feeding period, either estradiol (1 mg/kg body weight (BW)/week), progesterone (25 mg/kg BW/week), or combined estradiol/progesterone (in above dosages) was administered intramuscularly in each group (n = 8 each) of ovariectomized rabbits. One additional group of 8 animals received a combined estrogen/ progesterone regimen, but with progesterone at one third of the above mentioned dosage. In another 8 rabbits, progesterone was reduced to one ninth of the maximum dosage above, whereas estrogen was kept the same, at 1 mg/kg BW/week. Eight ovariectomized animals served as the control group and received no hormone treatment. After 12 weeks, the animals were sacrificed and the proximal aortic arch was removed for further histological examination. An inhibitory effect of estrogen of intimal thickening was found, in comparison to the control group (intimal area: 0.7 +/- 0.5 mm2 vs. 3.7 +/- 2.5 mm2, P < 0.01), whereas progesterone alone did not show a significant effect on intimal plaque size (intimal area: 4.0 +/- 2.3 mm2). In combination with progesterone (high dose), estrogen was not able to reduce intimal atherosclerosis (intimal area: 3.4 +/- 2.4 mm2). However, the beneficial effect of estrogen was not affected by progesterone, when this was reduced respectively to one third (intimal area: 0.8 +/- 0.7 mm2), or to one ninth of the highest dosage (intimal area: 0.6 +/- 0.4 mm2). Interestingly, these differences in atherosclerotic plaque development were observed without significant changes in plasma cholesterol concentrations by the administered hormones. In conclusion, progesterone was dose-dependently able to completely inhibit the beneficial effect of estrogen in experimental atherosclerosis, suggesting that progesterone exerts a direct inhibitory effect on the athero-protective action of estrogen. In the context of recently published data, the present work confirms the importance of the 'non-lipid-mediated', anti-atherosclerotic effect of estrogen, probably due to an interaction with six hormone receptors in vascular smooth muscle cells (VSMC). PMID- 8678918 TI - Apolipoprotein E polymorphism influence on lipids, apolipoproteins and Lp(a) in a Spanish population underexpressing apo E4. AB - The apolipoprotein E (apo E) polymorphism in a Spanish working population of Tenerife (Canary Islands, Spain) was analyzed. The distribution of apo E alleles (epsilon 3, 0.850; epsilon 2, 0.075; epsilon 4, 0.075) and phenotypes (E3/3, 72.6%; E3/4, 13%; E3/2, 11.5%; E4/4, 0.8%; E2/2, 1.5%; E4/2, 0.5%) was significantly different from those of a combined Caucasian population owing to a lower frequency of apo E4. We have also investigated the effect of apo E polymorphism on serum levels of cholesterol, LDL-cholesterol, HDL-cholesterol, Lp(a) and apolipoproteins A-I, B and E. The average effect of E4 (in whole sample and men only, respectively) was to raise serum levels of total cholesterol (by 4.1 mg/dl and 8.3 mg/dl), LDL-cholesterol (by 6.5 mg/dl and 9 mg/dl), and apo B (5.3 mg/dl and 4.5 mg/dl). The average effect of E2 was to lower serum levels of total cholesterol (by 14.8 mg/dl mg/dl and 8.3 mg/dl), LDL-cholesterol (by 20.2 mg/dl and 15.5 mg/dl) and apo B (11.5 mg/dl and 6.5 mg/dl), and to raise apo E (1.14 mg/dl and 3.4 mg/dl and 3.4 mg/dl). We found significantly higher serum triglyceride levels in individuals carrying E4, but no differences were found in serum HDL-cholesterol, apo A-I or Lp(a) by alleles. Data confirm previous reports about an underexpression of apo E4 in societies living in Southern Europe, and its repercussion in a more beneficial lipid profile and relatively low cardiovascular mortality rate in the Mediterranean region. PMID- 8678919 TI - Effects of saturated, mono-, and polyunsaturated fatty acids on the secretion of apo B containing lipoproteins by Caco-2 cells. AB - We studied the effects of addition of physiological concentrations (0.5 mM) of fatty acids i.e., palmitic (16:0), stearic (18:0), oleic (18:1) and linoleic acid (18:2) on lipoprotein secretion by polarized Caco-2 cells. With saturated fatty acids, secreted lipoproteins were at IDL/LDL density, 1.009 < d < 1.068 g/ml. The numbers of secreted lipoproteins, expressed as secreted apolipoprotein (apo) B, were comparable to control without fatty acid (palmitic acid, 551 +/- 185; stearic acid, 629 +/- 304 and control, 504 +/- 176 ng apo B/4.7 cm2 filter). With unsaturated fatty acids, apo B containing lipoproteins were secreted at chylomicron/VLDL density (d < 1.006 g/ml). Oleic acid caused a two-fold higher secretion of apo B than control (1058 +/- 87 vs. 504 +/- 176 ng/4.7 cm2 filter, P < 0.001). The increase in apo B secretion was attributed to a specific increase in apo B-48. Unsaturated fatty acid caused a two-fold higher secretion of triglyceride than saturated fatty acids but incorporation of newly synthesized lipid into the secreted lipoproteins, measured by incorporation of a fatty acid marker, was 10- to 20-fold higher, indicating preferential translocation of unsaturated triglycerides into lipoproteins. Mixtures rich in either polyunsaturated, monounsaturated, or saturated fatty acids, resembling nutritional fat and oils, were capable of a two-fold stimulation of secretion of apo B containing triglyceride-rich lipoproteins. The triglyceride/apo B ratio in the basolateral medium was higher with the monounsaturated 'olive oil' mixture (12 250 +/- 2000 mol/mol) than with the polyunsaturated 'corn oil' mixture (7830 +/- 2480 mol/mol) and incorporation of newly synthesized lipid into the secreted lipoproteins was 1.5-fold higher as well. In conclusion, unsaturated fatty acids were most potent in stimulating the secretion of apo B by specifically increasing apo B-48 secretion. Unsaturated triglycerides, that contain mainly oleic acid, were more efficiently incorporated into lipoproteins than saturated triglycerides, suggesting preferential translocation by microsomal triglyceride transfer protein. PMID- 8678920 TI - Desialylated LDL uptake in human and mouse macrophages can be mediated by a lectin receptor. AB - We have compared the uptake of desialylated low density lipoprotein (LDL) with other modified forms of LDL in mouse peritoneal macrophages and PMA-activated human U937 monocytes. Neuraminidase-treated LDL (NT-LDL) caused significant cholesterol ester accumulation in both cell types, although the efficiency relative to loading with acetylated LDL (AcLDL) was markedly different, suggesting a very different complement of receptors in the cells. We therefore determined the effect of PMA-activation on lipoprotein receptor expression in U937 cells and found that while scavenger receptor concentration was elevated after PMA-activation, there was no significant change in the expression of the LDL receptor. Receptor specificity of NT-LDL uptake was examined by competition experiments using the degradation assay. This showed that 125I-labelled NT-LDL uptake in U937 cells could largely be accounted for by the persistent expression of the LDL receptor in these cells. In contrast, in mouse peritoneal macrophages where LDL receptor expression is very low, 125I-labelled NT-LDL degradation was also effectively competed by asialofetuin. Surprisingly, 125I-labelled NT-LDL degradation was also effectively competed by AcLDL. Measurement of sialic acid content of AcLDL showed that approximately 14% of the LDL sialic acid, equivalent to 2 to 3 residues per particle, was lost during acetylation of LDL with acetic anhydride. Thus competition between 125I-labelled NT-LDL and AcLDL could be due to lectin receptor binding rather than competition for scavenger receptor binding. PMID- 8678921 TI - Evidence for more extensive deposits of epitopes of oxidized low density lipoprotein in aortas of young people with elevated serum thiocyanate levels. PDAY Research Group. AB - Elevated levels of low density lipoprotein (LDL) and smoking have long been recognized as risk factors for atherosclerosis and coronary heart disease (CHD). However, the mechanisms by which these factors contribute to the disease have not been fully elucidated. It has been postulated from in vitro studies using serum and LDL from smokers that smoking increases the oxidation of LDL, which in turn contributes to atherogenesis. We know of no direct evidence linking oxidized LDL (oxLDL) in human arteries to increased atherosclerosis in individuals who show elevated serum thiocyanate levels (HST) as an indicator of recent smoking. We have studied arterial samples from smokers micromorphometrically and found that 'smokers' have a greater area in which oxLDL can be identified in the early stages of the disease than do "nonsmokers', i.e., individuals with low serum thiocyanate levels (LST). This study demonstrates a positive correlation between the extent of oxLDL in the fatty streaks as well as the fatty plaques of standardized core sample areas of the thoracic and abdominal aortas of a sample group of young people, aged 15-34, who have evidence of recent smoking based on their postmortem serum thiocyanate levels. PMID- 8678922 TI - Effect of testosterone replacement therapy on lipids and lipoproteins in hypogonadal and elderly men. AB - We investigated the effects of long-term testosterone replacement in hypogonadal and elderly men on lipids and lipoproteins. Twenty-two men with initial serum testosterone concentrations below 3.5 ng/ml took part in the study: 11 with hypopituitarism (1st group) and 11 otherwise healthy elderly men with low testosterone levels (2nd group). Testosterone deficiency was replaced by intramuscular injections of testosterone enanthate 200 mg every second week. Plasma levels of sex hormones, gonadotropins, SHBG, lipids and lipoproteins were determined before the treatment and after 3, 6 and 12 months of treatment. During the treatment serum testosterone and estradiol increased significantly, reaching normal levels. This was associated with a decrease in total cholesterol (from 225 +/- 16.9 mg/dl to 202 +/- 13.6 mg/dl after 6 months and 198 +/- 12.8 mg/dl after 1 year of testosterone administration, P < 0.0001 in men with hypoandrogenism associated with aging and from 255 +/- 12.1 mg/dl to 214 +/- 10.6 mg/dl after 6 months and 206 +/- 9 mg/dl after 1 year of treatment, P < 0.0001 in men with hypopituitarism) and LDL-cholesterol concentrations (from 139 +/- 12.5 mg/dl to 126 +/- 10.7 mg/dl after 6 months and 118 +/- 9.8 mg/dl after 1 year of testosterone administration, P < 0.0001 in men with hypoandrogenism associated with aging and from 178 +/- 10.3 mg/dl to 149 +/- 10.2 mg/dl after 6 months and 140 +/- 7.3 mg/dl after 1 year of treatment, P < 0.001 in men with hypopituitarism). However, no significant decrease in HDL-cholesterol levels or HDL2- and HDL3-cholesterol subfractions was observed. The effects of testosterone replacement therapy on lipids and lipoproteins were similar in both groups with different aetiology of hypogonadism. No side effects on the prostate were observed. The results of this study indicate that testosterone replacement therapy in hypogonadal and elderly men may have a beneficial effect on lipid metabolism through decreasing total cholesterol and atherogenic fraction of LDL cholesterol without significant alterations in HDL-cholesterol levels or its subfractions HDL2-C and HDL3-C. PMID- 8678923 TI - Effects of inflation pressure of balloon catheter on vascular injuries and subsequent development of intimal hyperplasia in rabbit aorta. AB - Balloon catheter de-endothelialization is the most popular means of arterial injury in experimental animals and has been used as the model system to investigate atherogenesis and restenosis after percutaneous transluminal coronary angioplasty (PTCA). The aim of this study was to examine the relationship between balloon inflation pressure and vascular damage and also subsequent intimal hyperplasia. Retrograde pullback balloon injury of rabbit aortas was made at three different balloon pressures (1.5, 1.75, and 2.0 atm). The medial injuries, such as necrosis of smooth muscle cells and disruption of elastic lamina, were occasionally found in the injured segment of the aorta by balloon catheter at 1.75 atm and more frequently at 2.0 atm. No prominent medial injury was observed in the aortic segment to balloon catheter injury at 1.5 atm; Intimal hyperplasia developed in each animal and increased with time, 2, 4, and 8 weeks after injury. The intimal hyperplasia followed by balloon injury at 1.75 and 2.0 atm was more prominent than that at 1.5 atm, however, the development of the intimal hyperplasia was not parallel to the degree of inflation pressure. On the other hand, decrease of DNA content of the media and reduction of norepinephrine induced vasoconstriction were observed in a pressure-dependent manner after balloon injury. These findings indicate that intimal hyperplasia is not proportionally correlated to the severity of the vascular injury. The control of inflation pressure is very important in order to examine vascular injuries, subsequent intimal hyperplasia and vasomotor responses in animal models of balloon catheter injury. PMID- 8678924 TI - Lipoperoxidative injury to macrophages by oxidatively modified low density lipoprotein may play an important role in foam cell formation. AB - Both oxidatively and malondialdehyde modified low density lipoprotein (Ox-LDL and MDA-LDL) could be recognized by the scavenger receptor and induce intracellular cholesteryl ester accumulation of macrophage. The cholesteryl ester accumulation caused by MDA-LDL could be largely cleared by high density lipoprotein (HDL3), but that caused by Ox-LDL could not be. Further studies showed that Ox-LDL and MDA-LDL all could decrease the binding capacity of HDL3 and increase intracellular thiobarbituric acid reactive substances (TBARS). When macrophages were first cultured with MDA-LDL and then in medium without LDL, the decreased binding capacity of HDL3 was somewhat recovered and the intracellular TBARS did not increase any more. However, if macrophages were first cultured with Ox-LDL, the binding capacity of H DL3 continued to decrease and intracellular TBARS continued to increase. There was a negative correlation (r = -0.81, P < 0.01) between the decreased binding capacity of HDL3 and the increased intracellular TBARS caused by Ox-LDL. These results imply that lipid peroxidative injury to macrophages caused by Ox-LDL play an important role in foam cell formation. PMID- 8678926 TI - In vitro lipolysis of human VLDL: effect of different VLDL compositions in normolipidemia, familial combined hyperlipidemia and familial hypertriglyceridemia. AB - Suboptimal lipolysis of very low density lipoproteins (VLDL) due to reduced substrate affinity for lipoprotein lipase (LPL) may contribute to the accumulation of apolipoprotein (apo) B in familial combined hyperlipidemia (FCH) or the characteristic increase in triglyceride-rich lipoproteins in familial hypertriglyceridemia (FHTG). To investigate this hypothesis in detail, the VLDL composition and substrate affinity for lipoprotein lipase was determined in 22 normolipidemic controls, 16 FCH probands, and 12 FHTG subjects. VLDL from FCH subjects were enriched in cholesterol and phospholipid. VLDL from FHTG subjects were enriched in triglycerides, cholesterol and phospholipid. Potential apolipoprotein regulators of LPL activity including apo C-II, apo C-III and apo E were not significantly different between FCH and controls when expressed per VLDL apo B. High apo C-III concentrations were present in FHTG-VLDL, and the apo C III/E-ratio was significantly higher than in FCH- and control-VLDL. An increase of C-III-0, the desialylated isoform, was observed in FHTG-VLDL. The kinetic indicators for in vitro triglyceride hydrolysis by LPL, KM and VMAX, were not significantly different between the groups. KM values measured in vitro were remarkably and consistently high (1.54 mmol VLDL-TG/I), predicting saturation of LPL when VLDL-TG levels exceed 5.5 mmol/l (2 times KM + 2S.D.). In conclusion, VLDL from individuals with FCH or FHTG are normal substrate for lipoprotein lipase in spite of significant differences in lipid and apolipoprotein composition. The high apo C-III content of FHTG-VLDL supports a role in the expression of hypertriglyceridemia. PMID- 8678925 TI - Study of causes underlying the low atherosclerotic response to dietary hypercholesterolemia in a selected strain of rabbits. AB - We have recently characterized a strain of rabbits that shows a low atherosclerotic response (LAR) to dietary hypercholesterolemia in contrast to the usual high atherosclerotic response (HAR) of rabbits [1]. Presently, we have focused on three well established and important stages of atherogenesis, i.e., monocyte adhesion to endothelium, cell mediated peroxidative modification of lipoproteins and induction of a receptor that recognizes modified low density lipoprotein (LDL). The results obtained show that (1) beta-very low density lipoprotein (beta-VLDL) from LAR and HAR rabbits enhanced monocyte adhesion to endothelial cells to the same extent; (2) Cell mediated peroxidation of LDL and beta-VLDL, tested by loss of alpha-tocopherol and formation of thiobarbituric acid reacting substances (TBARS), was compared using macrophages, fibroblasts and smooth muscle cells (SMC) of LAR and HAR rabbits and no significant differences were found; (3) Induction of scavenger receptor by phorbol ester (phorbol 12 myristate 13-acetate (PMA)) and platelet-derived growth factor-BB (PDGF-BB) was determined in SMC or fibroblasts from LAR and HAR rabbits using 1,1'-dioctadecyl 3,3,3',3'-tetramethylindocarbocyanine perchlorate-acetylated LDL (DiL-acLDL). We found a significantly higher uptake of DiI-acLDL in SMC and fibroblasts derived from HAR rabbits as compared with cells from LAR rabbits. Similar results were also obtained with [125I]-acLDL in fibroblasts from LAR and HAR rabbits with respect to cellular lipoprotein degradation after PMA pretreatment. Even though the attenuated atherosclerotic response to hypercholesterolemia of LAR rabbits may have multiple underlying causes, the most prominent so far is an apparent difference in inducibility of scavenger receptor in SMC and fibroblasts. PMID- 8678927 TI - The influence of age and relative weight on the presentation of familial combined hyperlipidemia in childhood. AB - BACKGROUND: Familial combined hyperlipidemia (FCHL) has been described as the leading cause of familial hyperlipidemia. FCHL is dominantly inherited, occurs in at least 1% of the population, and is responsible for about 10% of premature coronary artery disease (CAD). OBJECTIVE: Because FCHL in childhood is not well characterized, we evaluated the interrelationships among age, percentage of ideal body weight (%IBW) and plasma lipoprotein levels in FCHL children (age 2-18 years), exploring the possibility that obesity and age may influence the presentation of FCHL in childhood. METHODS: One hundred and eighty-nine children with FCHL were studied. Significant correlations within this group were further evaluated by examining a subset of 36 FCHL children, each of whom had an unaffected sibling who could serve as a control for comparison. RESULTS: When the full group was divided into those with TG levels > 90% and those with TG levels < 90%, the correlation with %IBW was stronger in the former (r = 0.45, P < 0.005) as compared with the latter (r = 0.25, P = 0.05). Within the subset of 36 FCHL children and their 36 unaffected siblings (controls), age and sex distributions were similar. Percentage IBW (mean +/- S.D.) (117.3 +/- 29.1 for FCHL and 111.2 +/- 19.4 for controls) was similar and in the overweight range. FCHL children had significantly higher levels of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B) and triglyceride (TG) levels compared with controls (P < 0.0005 for all comparisons). Of several significant correlations observed in the full group (n = 189), only the correlations of %IBW with plasma TG levels (r = 0.45, P = 0.006), and of age with plasma TG levels (r = 0.48, P = 0.003) persisted with a similar degree of magnitude in the subset of 36 FCHL children. No correlation was significant in the controls. By Fisher's Z test, the correlation between %IBW and TG in the FCHL children was significantly different from controls. CONCLUSIONS: These results suggest that TG levels in FCHL children, but not in their unaffected siblings, and sensitive to the presence of obesity, implying an interaction between obesity and the underlying condition, in addition, the association between age and TG level in FCHL children suggests a gradual expression of the hyperlipidermia (i.e. TG) during childhood. PMID- 8678928 TI - Induction of heat shock protein in monocytic cells by oxidized low density lipoprotein. AB - The atherosclerotic lesion may be characterized as a chronic inflammatory process, and oxidized LDL is believed to be a key event in the development of atherosclerosis, though the mechanisms by which oxidized LDL exerts its proatherogenic properties are largely unknown. Heat shock proteins (hsp) are a group of proteins with a highly conserved structure and of these, hsp60 has been suggested to play a role in autoimmunity due to T lymphocyte crossreactivity between bacterial and human hsp60. The present study was designed to investigate the effects of oxidized LDL on the expression of hsp60 using the monocytic cell lines U937 and HL60 as models. The expression of hsp60 was determined by using monoclonal antibodies to hsp60 in FACScan, Western blot, and a sandwich ELISA. The results show that hsp60 is induced in both cell types after 2 h exposure to oxidized LDL, with a maximal effect at 20 micrograms/ml for U937 cells and 5 micrograms/ml for HL60 cells. A close to 3-fold increase in the expression of hsp60 was seen after culturing oxidized LDL (20 micrograms/ml) treated U937 cells for a period of 24 h. Interleukin 1-beta had similar effects on hsp60 expression to oxidized LDL. The results indicate that expression of hsp60 by monocytes in the vascular wall may be enhanced by oxidized LDL. It is thus possible that the chronic inflammatory process characterizing atherosclerosis is perpetuated by autoreactive T cells, which recognize hsp60 expressed by monocytes, induced by oxidized LDL. PMID- 8678931 TI - An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. AB - BACKGROUND: To avert major hemorrhage, physicians need to know the lowest intensity of anticoagulation that is effective in preventing stroke in patients with atrial fibrillation. Since the low rate of stroke has made it difficult to perform prospective studies to resolve this issue, we conducted a case-control study. METHODS: We studied 74 consecutive patients with atrial fibrillation who were admitted to our hospital from 1989 through 1994 after having an ischemic stroke while taking warfarin. For each patient with stroke, three controls with nonrheumatic atrial fibrillation who were treated as outpatients were randomly selected from the 1994 registry of the anticoagulant-therapy unit (222 controls). We used the international normalized ratio (INR) to measure the intensity of anticoagulation. For the patients with stroke, we used INR at admission; for the controls, we selected the INR that was measured closest to the month and day of the matched case patient's hospital admission. RESULTS: The risk of stroke rose steeply at INRs below 2.0. At an INR of 1.7, the adjusted odds ratio for stroke, as compared with the risk at an INR of 2.0, was 2.0 (95 percent confidence interval, 1.6 to 2.4); at an INR of 1.5, it was 3.3 (95 percent confidence interval, 2.4 to 4.6); and at an INR of 1.3, it was 6.0 (95 percent confidence interval, 3.6 to 9.8). Other independent risk factors were previous stroke (odds ratio, 10.4; 95 percent confidence interval, 4.4 to 24.5), diabetes mellitus (odds ratio, 2.95; 95 percent confidence interval, 1.3 to 6.5), hypertension (odds ratio, 2.5; 95 percent confidence interval, 1.1 to 5.7), and current smoking (odds ratio, 5.7; 95 percent confidence interval, 1.4 to 24.0). CONCLUSIONS: Among patients with atrial fibrillation, anticoagulant prophylaxis is effective at INRs of 2.0 or greater. Since previous studies have indicated that the risk of hemorrhage rises rapidly at INRs greater than 4.0 to 5.0, tight control of anticoagulant therapy to maintain the INR between 2.0 and 3.0 is a better strategy than targeting lower, less effective levels of anticoagulation. PMID- 8678932 TI - Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva. AB - BACKGROUND: Fibrodysplasia ossificans progressiva is a heritable disorder of connective tissue characterized by congenital malformation of the great toes and postnatal formation of ectopic bone. Although the disorder was first described more than 300 years ago, the genetic defect and pathophysiology remain unknown. Bone morphogenetic proteins are potent bone-inducing morphogens that participate in the developmental organization of the skeleton, and increased production of one or more of these proteins has been proposed as the cause of fibrodysplasia ossificans progressiva. METHODS: We studied lymphoblastoid cell lines established from peripheral-blood mononuclear cells of patients with fibrodysplasia ossificans progressiva and fibroblast-like cell lines derived from lesional and nonlesional tissue. We used Northern blot analysis and ribonuclease protection assays to measure the expression of messenger RNA (mRNA) of bone morphogenetic proteins 1 to 7 and immunohistochemical analysis to examine protein expression. RESULTS: Among the bone morphogenetic proteins and mRNAs examined, only bone morphogenetic protein 4 and its mRNA were present in increased levels in cells derived from an early fibroproliferative lesion in a patient with fibrodysplasia ossificans progressiva. Bone morphogenetic protein 4 mRNA was expressed in lymphoblastoid cell lines from 26 of 32 patients with fibrodysplasia ossificans progressiva but from only 1 of 12 normal subjects (P<0.001). Bone morphogenetic protein 4 and its mRNA were detected in the lymphoblastoid cell lines from a man with fibrodysplasia ossificans progressiva and his three affected children (two girls and a boy), but not from the children's unaffected mother. No other bone morphogenetic proteins were detected. CONCLUSIONS: Overexpression of a potent bone-inducing morphogen (bone morphogenetic protein 4) in lymphocytes is associated with the disabling ectopic osteogenesis of fibrodysplasia ossificans progressiva. PMID- 8678934 TI - Effect of theophylline on sleep-disordered breathing in heart failure. AB - BACKGROUND: Theophylline has been used to treat central apnea associated with Cheyne-Stokes respiration (periodic breathing). We studied the effect of short term oral theophylline therapy on periodic breathing associated with stable heart failure due to systolic dysfunction. METHODS: Fifteen men with compensated heart failure (left ventricular ejection fraction, 45 percent or less) participated in the study. Their base-line polysomnograms showed periodic breathing, with more than 10 episodes of apnea and hypopnea per hour. In a double-blind crossover study, the patients received theophylline or placebo orally twice daily for five days, with one week of washout between the two periods. RESULTS: After five days of treatment, the mean (+/-SD) plasma theophylline concentration was 11 +/- 2 microgram per milliliter. Theophylline therapy resulted in significant decreases in the number of episodes of apnea and hypopnea per hour (18 +/- 17, vs. 37 +/- 23 with placebo and 47 +/- 21 at base line; P<0.001), the number of episodes of central apnea per hour (6 +/- 14, vs. 26 +/- 21 and 26 +/- 20, respectively; P<0.001), and the percentage of total sleep time during which the arterial oxyhemoglobin saturation was less than 90 percent (6 +/- 11 percent, vs., 23 +/- 37 and 14 +/- 14 percent, respectively; P<0.04). There were no significant differences in the characteristics of sleep, the frequency of ventricular arrhythmias, daytime arterial-blood gas values, or the left ventricular ejection fraction during the base-line, placebo, and theophylline phases of the study. CONCLUSIONS: In patients with stable heart failure, oral theophylline therapy reduced the number of episodes of apnea and hypopnea and the duration of arterial oxyhemoglobin desaturation during sleep. PMID- 8678935 TI - Liver disease in pregnancy. PMID- 8678937 TI - Treatment of benign prostatic hyperplasia. PMID- 8678938 TI - The Scylla and Charybdis of oral anticoagulant treatment. PMID- 8678939 TI - Invasive group A streptococcal infections. PMID- 8678940 TI - Fibrodysplasia ossificans progressiva -- lessons from rare maladies. PMID- 8678943 TI - Gip-2 codon 179 oncogene mutations: absent in adrenal cortical tumors. AB - The role of G protein mutations in the pathogenesis of adrenal cortex neoplasms is controversial. Two published studies disagree on the existence of a cysteine or histidine for arginine substitution at position 179 (R179C/H) of the GTP binding region of the alpha chain of an inhibitory G protein (Gi2alpha) in these tumors. Prior studies using detection by mutation-specific oligonucleotide hybridization showed either 3 of 11 or 0 of 56 tumors harbored mutations. To resolve this discrepancy and ascertain the importance of the R179C/H Gi2alpha mutation in the development of adrenal cortex tumors, we screened tumors from 29 patients (24 with adenoma, 5 with carcinoma) using a more sensitive assay employing polymerase chain reaction (PCR) and examination for restriction fragment length polymorphisms (RFLP). Detection of the potential R179C/H mutation by this technique was possible because the wild-type coding sequence includes the BSTU-1 restriction endonuclease recognition site CGCG, whereas the mutated gene does not. Results showed complete digestion of the amplified DNA samples from all 29 patients and the negative control DNA by BSTU-1, indicating that all tumor samples exhibited only the wild-type sequence. Direct sequencing of PCR product from four tumor samples confirmed the presence of only the wild-type sequence. The 0 of 29 rate of R179C/H mutations we found in Gi2alpha is different than the 3 of 11 positive rate (p < 0.05, Fishers' exact) previously reported but agrees with the report showing 0 of 56 mutations. We conclude a mutation at position 179 of Gi2alpha is not important in the pathogenesis of most adrenal cortical tumors. PMID- 8678944 TI - Epidermal growth factor receptor status in hyperparathyroidism: immunocytochemical and In situ hybridization study. AB - The epidermal growth factor receptor (EGFr) family has been increasingly recognized as an important component in the control of normal cell proliferation and the pathogenesis of cancer. We have studied EGFr expression in 104 cases of hyperparathyroidism by immunocytochemistry (ICC) and by in situ hybridization (ISH). Using two different monoclonal antibodies, ICC for EGFr was performed on 66 cryostat sections and 38 wax-embedded parathyroid glands. ISH was performed on 49 of these glands using a cocktail of three anti-sense probes to EGFr mRNA and a nonspecific control probe to human HPV-18 virus. Breast and prostate tumors were employed as positive controls for both ICC and ISH. Controls demonstrated positive EGFr staining. None of the 104 parathyroid glands showed any ICC positivity. ISH displayed positive staining for EGFr mRNA in five of six carcinomas and eight of nine nonrenal hyperplastic glands. Only 3 of 15 adenomas and 3 of 19 renal hyperplastic glands showed positive staining. This difference was statistically significant between adenoma and carcinoma (p < 0.05) and between adenoma and nonrenal hyperplasia (p < 0.01) (Tukey's multiple comparison test). This study demonstrates that EGFr mRNA is present in parathyroid tumors. Expression in carcinoma and nonrenal hyperplasia is significantly different from adenoma and renal hyperplastic glands. In contrast, ICC failed to demonstrate EGFr protein expression. These findings suggest that either receptor numbers are too low to detect by ICC or there is a failure of mRNA translation. More studies are needed to establish whether the EGFr plays a role in the development of parathyroid cancer or hyperplasia. PMID- 8678945 TI - Clonal analysis of nodular parathyroid hyperplasia in renal hyperparathyroidism. AB - Although it is well known that chronic renal failure induces parathyroid hyperplasia, the pathogenesis and development of this parathyroid lesion in this disease are poorly understood. Histopathologically, there is progression from diffuse to nodular hyperplasia, and each nodule consists of a single cell type with aggressive proliferative potential. Pathophysiologic and clinical investigations have suggested that neoplastic tumors may emerge from nodular hyperplasia. In this study the clonality of parathyroid tissue in nodular and diffuse hyperplasia in renal hyperparathyroidism was analyzed by a method based on restriction fragment length polymorphism of the X chromosome-linked phosphoglycerokinase gene and on random inactivation of the gene by methylation. DNA of peripheral lymphocytes was screened in 43 women undergoing parathyroidectomy for advanced renal hyperparathyroidism, and 10 of these patients appeared to be heterozygous. Fourteen specimens from these patients were available for clonal analysis. The analysis showed that all four specimens of diffuse hyperplasia were polyclonal, whereas all seven specimens from nodules in nodular hyperplasia and all three samples representing parathyroid tissue removed from forearm because of graft-dependent recurrence were revealed to be monoclonal. It is likely that the clonal origin of each nodule is independent. These results suggest that in renal hyperparathyroidism parathyroid glands initially grow diffusely and polyclonally, and then the cells in the nodules are later transformed monoclonally and proliferate aggressively. From the present study it can be concluded that nodular hyperplasia represents monoclonal parathyroid neoplasia, which might explain why patients with nodular hyperplasia in renal hyperparathyroidism are refractory to medical treatment, requiring parathyroidectomy. To prevent recurrences, nodular hyperplastic tissue should not be left at surgery. PMID- 8678946 TI - Prediction of bone mass in renal hyperparathyroidism by newly developed bone metabolic markers: evaluation of serum levels of carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen and carboxy-terminal propeptide of type I procollagen. AB - Serum levels of the carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP) and the carboxy-terminal propeptide of type I procollagen (PICP) were measured in 95 patients with renal hyperparathyroidism who had undergone a total parathyroidectomy and autotransplantation of a small portion of the resected gland. The results were compared with the serum levels of other bone metabolic markers and bone mineral densities in the distal radius (R-BMD) and lumbar vertebrae (L-BMD), which were measured by dual energy x-ray absorptiometry and converted to the percentage of the mean value of sex- and age-matched healthy controls. The preoperative mean values of ICTP and PICP were 142.4 ng/ml and 187.8 ng/ml, respectively. Although the serum levels of PICP levels exceeded the normal range in 42.1% of the patients, those of ICTP exceeded it in all of them. The serum levels of ICTP correlated positively not only with those of tartrate resistant acid phosphatase (TRACP), total alkaline phosphatase (ALP), and osteocalcin but also negatively with the values of %R-BMD and %L-BMD and seemed to manifest specifically the disturbance of bone metabolism. On the other hand, the serum levels of PICP correlated with those of ALP and TRACP but not with values of %BMDs. After surgery, the serum levels of ICTP decreased gradually, but those of PICP increased immediately up to peak values at 7 days and then decreased gradually after 14 days, reaching the normal range at 3 months. These changes in the bone metabolic markers seemed to reflect the change in bone metabolism that was converting from bone resorption to bone formation. The percent change in the PICP/ICTP ratio at 7 days correlated significantly with the percent change in R-BMD at 12 months, and it was suggested that postoperative bone gain might be predicted using a combination of postoperative changes in PICP and ICTP. PMID- 8678947 TI - Laparoscopic adrenalectomy. AB - Using the transperitoneal, laparoscopic approach, we performed 67 successful adrenalectomies between June 1993 and July 1995 at Greenslopes Hospital, Brisbane. There were 30 women and 37 men. Syndromes of primary adrenal hormone overproduction--primary aldosteronism (n = 52), pheochromocytoma (n = 6), and hypercortisolism (n = 1)--were present in 59 patients and apparently nonfunctioning adrenal tumors (of which one was malignant) in 8 patients. There was a significant difference in the time of operation between patients weighing < 80 kg and those weighing > 80 kg. Operations on males were slower than those on females, possibly explained by males being significantly heavier. Left-sided tumors outnumbered right-sided tumors; removal of right-sided adrenals took, on average, longer, but this difference was not significant. PMID- 8678948 TI - Laparoscopic approach to pheochromocytoma: hemodynamic changes and catecholamine secretion. AB - This study compares the outcome of laparoscopic adrenalectomy (LpA) in 23 patients using CO2 insufflation with the outcome of this procedure in another 8 patients with pheochromocytoma (7 unilateral, 1 bilateral) using helium for pneumoperitoneum. The adrenal lesions in the first group included nonfunctional adenoma (n = 3), aldosterone adenoma (n = 11), Cushing's adenoma (n = 6), and Cushing's disease (n = 3). The latter patients were compared with a third group of 8 patients with pheochromocytoma undergoing conventional transabdominal adrenalectomy (CTA). With both procedures, intraoperative changes in plasma catecholamine levels were studied during pheochromocytoma removal and the changes correlated with intraoperative cardiovascular derangements. LpA was successfully performed in 95% of patients with adrenal lesions and in 100% of patients with pheochromocytoma. There was no significant difference in laparoscopic adrenalectomy for pheochromocytoma compared to that for other adrenal lesions in terms of operative time, blood loss, hospital stay, analgesic requirements, and return to normal activity. The outcome was less favorable in pheochromocytoma patients undergoing CTA. The largest increase of catecholamine levels in pheochromocytoma patients occurred during tumor manipulation with both LpA (17.4 fold for epinephrine and 8.6-fold for norepinephrine) and CTA (34.2-fold for epinephrine and 13.7-fold for norepinephrine), but cardiovascular instability was associated only with CTA. LpA may become the technique of choice for surgical removal of adrenal lesions and may also become the preferred method for removing pheochromocytoma. PMID- 8678949 TI - Posterior retroperitoneoscopy as a new minimally invasive approach for adrenalectomy: results of 30 adrenalectomies in 27 patients. AB - Posterior retroperitoneoscopic adrenalectomy is a new minimally invasive method. It represents an alternative to conventional open procedures and laparoscopic techniques. Between July 1994 and November 1995 a total of 30 retroperitoneoscopic adrenalectomies were performed on 27 patients. In 24 patients, unilateral tumors were seen (size 1-7 cm): seven Cushing adenomas, five Conn adenomas, seven pheochromocytomas, four hormonally inactive tumors, one cyst. Three patients suffered from Cushing syndrome with bilateral adrenal gland hyperplasias (two inoperable pituitary gland tumors, one bronchial carcinoid with ACTH secretion). The operations were carried out in prone position. After balloon dilatation of the retroperitoneum and creation of a pneumoperitoneum the preparation of the adrenal gland was performed via three trocar sites positioned below the 12th rib. Twenty-five adrenalectomies were completed endoscopically, and five times (among four patients) conversion to the conventional posterior technique was necessary. The average operating time of complete endoscopic adrenalectomies was 124 minutes (45-225 minutes); blood loss was 10 to 120 ml. With minimal need for postoperative analgesia (average dosage 7.9 mg of piritramide), mobilization and adequate food uptake were possible on the day of operation. The posterior retroperitoneoscopic adrenalectomy is a relatively fast, safe method, with the advantages of the posterior open approach and minimally invasive surgery. It therefore represents an important addition to adrenal gland surgery. PMID- 8678950 TI - Role and operative risk of bilateral adrenalectomy in hypercortisolism. AB - Transsphenoidal pituitary surgery has radically modified the management of pituitary-dependent hypercortisolism (Cushing's disease). Bilateral adrenalectomy may, however, represent the ultimate treatment in some cases of hypercortisolism. In the present study we report our experience of bilateral adrenalectomy in 82 patients operated on during the last 15 years. The causes of hypercortisolism were Cushing's disease (n = 78), ectopic ACTH syndrome (n = 3), and primary adrenocortical nodular dysplasia (Carney-Meador syndrome) (n = 1). Before operation 37% of the patients had severe symptoms of hypercortisolism. A bilateral posterior approach was undertaken in 58 patients, whereas 18 patients had an anterior transabdominal approach and 6 patients a laparoscopic approach. There were two operative deaths (2.4%). Postoperative complications occurred mostly in cases of advanced disease and were observed in 14 patients (17%), among whom 4 had severe complications. At long-term follow-up, one recurrence of hypercortisolism and 12 Nelson syndromes (15%) were observed. In conclusion, bilateral adrenalectomy carries an acceptable operative risk, and we recommend bilateral adrenalectomy rather than long-term suppressive therapy in patients requiring prompt and definitive control of their hypercortisolism or after pituitary surgery failure. PMID- 8678951 TI - Adrenalectomy for treatment of Cushing syndrome: results in 122 patients and long term follow-up studies. AB - Patients with Cushing syndrome (n = 122) who underwent adrenalectomy from 1957 through 1993 were reviewed for survival and complications. Of the 122 patients, 70 had adrenocortical adenoma, 30 Cushing's disease, 6 primary pigmented nodular adrenocortical disease (PPNAD), 7 other types of primary nodular hyperplasia, 5 adrenocortical carcinoma, and 4 ectopic ACTH syndrome. Sixty-five patients with adrenocortical adenoma are alive, and the survival rate was equal to the age matched control population, when patients who died of the postoperative complication were excluded. Of the patients with Cushing's disease, 20 are alive; and 10 of 16 patients (63%) who were followed-up and evaluated had skin pigmentation. Four of sixteen patients (25%) developed Nelson's syndrome. Four PPNAD patients and five with other types of nodular hyperplasia are alive. Most of these patients underwent bilateral total adrenalectomy, but some patients remitted after unilateral adrenalectomy. All of five adrenocortical carcinoma patients and four with ectopic ACTH syndrome died within 2 years after operation. The prognosis for patients with adrenocortical adenoma after unilateral adrenalectomy is excellent, though it is important to avoid operative complications. The rapid cure of signs and symptoms of glucocorticoid excess after total adrenalectomy is ensured, and prognosis is satisfactory under careful glucocorticoid replacement, making total adrenalectomy an alternative treatment for Cushing's disease. PMID- 8678953 TI - Surgical treatment of Graves' disease in patients younger than 18 years. AB - Eighty-two children and adolescents (18 males, 64 females; median age 14 years) surgically treated for Graves' disease at a single institution between 1979 and 1993 were retrospectively reviewed. Most of the patients (74%) coming to thyroidectomy had been treated medically for a period ranging from 2 to 80 (median 15) months. Bilateral subtotal thyroid resection was the most frequently performed procedure (86%). Postoperatively, no permanent recurrent laryngeal nerve palsy or permanent hypocalcemia occurred. Operative mortality was zero. With a median follow-up of 8.3 years, recurrent hyperthyroidism occurred in five patients (6%), one of whom required reoperation. Most children and adolescents with Graves' disease can be rendered euthyroid by nonsurgical treatment options. However, prolonged and ineffective medical treatment should be avoided in these patients who are in the formative years of their lives. Surgical treatment, when indicated and employed, offers young patients with Graves' disease a safe, rapid, definitive, cost-effective treatment with a high success rate. PMID- 8678952 TI - Adrenaloma: a call for more aggressive management. AB - We review our experience from the surgical management of 57 patients (24 males, 33 females) with a mean age of 48.5 years who underwent adrenalectomy because of the computed tomography (CT) finding of a "nonfunctioning" adrenal tumor (adrenaloma). We found that CT consistently underestimated the real histologic size of the adrenal tumor (p = 0.001). Of the 57 resected tumors, 23 were cortical adenomas, 7 myelolipomas, 8 adrenal cysts, 11 nodular hyperplasias, 2 primary adenocarcinomas, 2 metastatic carcinomas, and 4 pheochromocytomas. The mean diameter was 5.89 cm and the mean weight 114.07 g. The mean diameter of the resected primary adenocarcinomas was 3.0 cm and 4.5 cm, respectively. The operative mortality was zero and the perioperative morbidity minimal. The mean operating time was 137 minutes (range 60-240 minutes). The posterior approach had the shortest operating time and the laparoscopic approach the shortest hospital stay and the least postoperative need for narcotics. During the 6.2 years mean follow-up period, five patients with preoperative hypertension remained normotensive, and both patients with the resected primary adenocarcinomas are alive without recurrence. We suggest a more liberal surgical approach to patients with adrenalomas because: (1) even small tumors can be malignant or potentially lethal (e.g., pheochromocytomas); (2) some tumors that appear to be nonfunctioning may in reality be functioning; and (3) other nonfunctioning tumors may, with time (and without prior notice), function. The low risk of adrenalectomy especially via the laparoscopic approach can provide an early definitive diagnosis and treatment, avoiding the cost of repeated CT scans and other studies as suggested by the currently prevailing conservative management of these tumors. PMID- 8678954 TI - Preoperative change of thyroid stimulating hormone receptor antibody level: possible marker for predicting recurrent hyperthyroidism in patients with Graves' disease after subtotal thyroidectomy. AB - To make the surgical treatment for Graves' disease more ideal, it is important to elucidate factors related to postoperative thyroid dysfunction in addition to thyroid remnant. Because TSH receptor antibody (TRAb) is thought to be one of the essential causes of Graves' disease, we investigated whether preoperative changes in serum TRAb levels are related to postoperative recurrent hyperthyroidism. Between 1987 and 1992 a total of 1520 patients with Graves' disease were treated by subtotal thyroidectomy. Of these patients 335 visited Ito Hospital with no history of drug treatment of their disease and were treated surgically after several courses of antithyroid drug (ATD) therapy. There were 68 males and 267 females with a mean age of 25.8 years. The mean follow-up period was 48 months (range 12-84 months). Factors analyzed by univariate and multivariate analysis were as follows: age, sex, duration of ATD treatment, weight of resected thyroid, weight of thyroid remnant, preoperative titer of MCHA, TRAb at the time of initial examination (TRAb1), TRAb at the time of surgery (TRAb2), and DeltaTRAb, the difference between TRAb1 and TRAb2 (DeltaTRAb = TRAb1 - TRAb2). The chi square test was used for univariate analysis and a logistic model for multivariate analysis. Of this group, 119 patients were euthyroid (35.5%), 50 were hyperthyroid (14.9%), and 166 were hypothyroid (49.3%). Significant factors related to recurrent hyperthyroidism were weight of thyroid remnant and DeltaTRAb in both univariate and multivariate analyses. DeltaTRAb is a possible new marker for predicting postoperative recurrent hyperthyroidism. If the preoperative TRAb level is not improved by ATDs in patients with Graves' disease, the thyroid remnant should be made smaller. PMID- 8678956 TI - Prophylactic surgery for multiple endocrine neoplasia type IIa after genetic diagnosis: is parathyroid transplantation indicated? AB - Identification of germline mutations in the RET proto-oncogene predisposing to multiple endocrine neoplasia type IIa (MEN-IIa) has allowed a DNA-based approach to diagnosis and treatment by prophylactic thyroidectomy in children testing genetically positive. Although total thyroidectomy is the accepted operation for C cell disease, the necessity of routine total parathyroidectomy and autotransplantation as previously described in these asymptomatic children is questionable, particularly given the low occurrence of hyperparathyroidism in MEN IIa (10-20%). Thirty-six children (ages 1 month to 12 years) from four MEN-IIa kindreds at risk for disease underwent genetic testing. Mutational analysis was done using a highly sensitive PCR-based denaturing gradient gel electrophoresis technique. Parathyroid or serum calcium concentrations were determined preoperatively. Of the 36 children at risk, 18 were found to have a MEN-IIa mutation; 11 have undergone prophylactic thyroidectomy at ages ranging from 2 to 12 years (mean 7.5 years). In each case, there was no biochemical evidence of hypercalcemia preoperatively, and all parathyroid glands were identified and were found to be grossly normal at exploration. Glands were carefully dissected and left in situ. Postoperatively, 10 of the 11 children maintained normocalcemia, allowing discharge within 24 to 36 hours. Resected thyroid glands contained C cell hyperplasia in nine, medullary carcinoma in one, and normal histology in one. We conclude that an alternative to routine parathyroidectomy may be desirable for prophylactic treatment of MEN-IIa. In situ parathyroid preservation can be safely achieved without compromising the completeness of the thyroid resection. This conservative approach obviates the potential morbidity associated with total parathyroidectomy and autotransplantation. PMID- 8678955 TI - Primary hyperparathyroidism in multiple endocrine neoplasia type IIa: retrospective French multicentric study. Groupe d'Etude des Tumeurs a Calcitonine (GETC, French Calcitonin Tumors Study Group), French Association of Endocrine Surgeons. AB - Primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia (MEN) type IIa is rare, occurring in 20% to 30% of the patients. The aim of this study was to evaluate clinical findings, surgical therapy, and outcome for 56 patients affected by PHPT among 249 MEN-IIa patients collected from 84 families assembled by the Groupe d'Etude des Tumeurs a Calcitonine (GETC, French Calcitonin Tumors Study Group). This retrospective study was based on cases registered by the GETC (20 participating centers) from 1969 to 1994. Characteristics of PHPT in 56 patients (31 women, 25 men) with MEN-IIa were reviewed. All but two underwent cervicotomy. The median age at diagnosis was 37.6 years. PHPT was found concomitantly with medullary thyroid carcinoma (MTC) or pheochromocytoma in 43 patients (77%). PHPT was asymptomatic in 68% of the patients. Serum calcium levels ranged from 2.20 to 3.70 mmol/L (median 2.82 mmol/L; normal 2. 10-2.60 mmol/L). The number of parathyroid glands removed at surgery was 0 (n = 2), 1 (n = 24), 2 (n = 5), > 2 (n = 12), 4 (n = 11). Pathology (initial surgery) consisted of 24 adenomas, 4 double adenomas, and 25 hyperplasia. Cure after initial surgery was obtained in 89%, including a 22% incidence of hypoparathyroidism. There were 6 cases (11%) with persistent PHPT. With a mean follow-up of 6.4 years, five patients (9%) had recurrent PHPT. The results indicate that MEN-IIa-related PHPT is generally associated with mild, often asymptomatic hypercalcemia. Despite recurrences encountered 5 to 15 years after the first cervicotomy, resection of only macroscopically enlarged glands generally appears sufficient. Subtotal or total parathyroidectomy with autotransplantation is associated with a high rate of hypoparathyroidism. PMID- 8678958 TI - Parathyroid incidentalomas in normocalcemic patients during thyroid surgery. AB - The aim of this study was to compare the clinical, biochemical, and pathologic findings of normocalcemic patients with macroscopically enlarged parathyroid tissue identified at thyroid surgery with those of patients treated surgically for preoperatively proved primary hyperparathyroidism (PHPT). The records of 28 patients with incidental parathyroid enlargement and 533 patients with PHPT were reviewed to compare age, sex, serum calcium and phosphate, intact parathyroid hormone (iPTH), parathyroid weight, number of diseased glands, cell and histologic types, PTH content, and cure rate. Incidentally found lesions were lighter and developed in younger patients. Biochemistry and pathology found them to be less hyperfunctioning. Sex, number of diseased glands per patient, and cell type were not different. PTH content was low in the incidental lesions. Incidentally discovered enlarged parathyroid glands are mildly hyperfunctioning at the time of discovery. They may represent an early stage of lesion responsible for overt PHPT. In the absence of knowledge concerning their significance and evolution, we recommend that enlarged parathyroids found during the course of a thyroid operation be removed. PMID- 8678957 TI - Effect of growth factors on growth of bovine parathyroid cells in serum-free medium. AB - Published work has suggested a possible role of the epidermal growth factor receptor (EGFr) in parathyroid disease. Bovine parathyroid cells (BPCs) are frequently used as a tissue model for studying parathyroid disorders. We have studied the effect of the EGFr ligands EGF and transforming growth factor alpha (TGFalpha), alone and with insulin-like growth factors IGF-I and IGF-II on BPC growth. Experiments were run in triplicate and repeated three times. Cell numbers were assessed on day 5 by colorimetric MTT assay as well as by tritiated thymidine uptake. Results show that TGFalpha alone (p < 0.05) and IGF-I and IGF II alone (p < 0.05) significantly stimulated growth over controls (t-test). Furthermore, the combination of TGFalpha with IGF-I and IGF-II exhibited significant enhancement above that seen with IGF-I and IGF-II alone (p < 0.01). EGF did not stimulate growth over controls. EGFr may be expressed in BPCs, but TGFalpha exhibits a more potent growth stimulus than EGF. Addition of IGF-I or IGF-II to the growth medium further enhances this effect. PMID- 8678959 TI - Values of ultrasonography, sestamibi scintigraphy, and intraoperative measurement of 1-84 PTH for unilateral neck exploration of primary hyperparathyroidism. AB - Unilateral neck exploration (UNE) is a controversial approach to the treatment of primary hyperparathyroidism (PHP), and most surgeons favor bilateral neck exploration. The aim of this study was to assess the value of ultrasonography, sestamibi scintigraphy, and intraoperative measurement of urinary cyclic AMP (UcAMP) or 1-84 PTH in 200 patients undergoing unilateral neck exploration under local anesthesia. Conditions for UNE were (1) a presumed solitary adenoma detected by ultrasonography, (2) no thyroid disease, and (3) no family history of PHP or multiple endocrine neoplasia. Patient's consent was obtained for conversion to bilateral exploration according to surgical and biologic findings. Sensitivity of ultrasonography was 92.5%. Sestamibi scintigraphy, performed in 70 patients, was less sensitive than ultrasonography (80%). Persistent PHP was accurately detected by intraoperative measurement of UcAMP or 1-84 PTH in all cases. At follow-up, 96.0% of the patients were cured either after unilateral neck exploration only (90.5%), or after conversion into bilateral exploration. Ultrasonography and intraoperative measurement of 1-84 PTH allow unilateral neck exploration with excellent results in a selected group of patients with PHP. PMID- 8678960 TI - Two-dimensional proton magnetic resonance spectroscopy for tissue characterization of thyroid neoplasms. AB - We have previously demonstrated that one dimensional (1D) proton (1H) magnetic resonance spectroscopy (MRS) can distinguish normal thyroid tissue from thyroid carcinoma using a spectral ratio of peak intensity at 1.7 ppm/0.9 ppm. Two dimensional (2D) 1H-MRS allows identification of specific molecules that have overlapping peaks in the 1D-MR spectrum. Specimens from 93 consecutive thyroid nodules were examined using 2D 1H-MRS on a Bruker AM-360 wide-bore spectrometer. There was a progressive increase in lipid cross peaks assigned to di /triglycerides when comparing colloid/hyperplastic nodules to follicular adenoma, and adenoma to carcinoma. A specific cross peak attributable to cholesterol/cholesteryl esters was commonly seen in carcinomas. In contrast, two unassigned cross peaks unique to the thyroid were more prevalent in benign lesions. There was an overall increase in cross peaks attributable to cell surface fucosylation in carcinoma when compared to benign lesions, although the fucose spectral pattern was not specific for cancer. On this basis, a spectral ratio of peak intensity at 2.05 ppm/0.9 ppm more clearly distinguished benign follicular adenoma from carcinoma. 2D 1H-MRS thus identifies chemical changes that allow more specific tissue characterization of thyroid neoplasms. PMID- 8678961 TI - Thyroid cancer detected by ultrasound-guided fine-needle aspiration biopsy. AB - A greater percentage of thyroid cancers can be detected by ultrasound-guided fine needle aspiration biopsy (UG-FNAB) than by ordinary FNAB. A group of 678 patients were selected sequentially as having been diagnosed with benign nodules by the conventional FNAB method. We reexamined these patients by UG-FNAB and investigated the types of thyroid cancer that were missed by the conventional FNAB. Of the 678 patients diagnosed with benign nodules (using conventional FNAB), 571 (84.2%) demonstrated the same diagnosis when UG-FNAB was used. The remaining 107 patients (15.8%) studied were suspected of having a malignancy after UG-FNAB had been performed. Surgical specimen histology proved thyroid cancer in 99 of the 107 patients: 93 had papillary carcinoma, 4 had follicular carcinoma, 1 had medullary carcinoma and 1 had anaplastic carcinoma. Two drawbacks were noted when conventional FNAB was used: (1) cancer lesions difficult to palpate (n = 55) (e.g., small cancers with or without benign lesions or cancers associated with Hashimoto's thyroiditis or Graves' disease); and (2) palpable cancers with insufficient cell material for analysis (n = 44) (e.g., cystic carcinoma and cancers with calcified lesions. UG-FNAB is a powerful technique for detecting microcancers, cystic carcinomas, cancers associated with benign nodules, Hashimoto's thyroiditis, or coarse calcifications. PMID- 8678962 TI - Improved survival of patients with papillary thyroid cancer after surgical microdissection. AB - A total of 195 patients had surgery for papillary thyroid cancer. The mean age at operation was 50 years. A microdissection technique was used for total thyroidectomy and lymph node clearance. Postoperative radioiodine tests showed no uptake or an uptake close to the background activity in 77% of the examined patients. By counting the lymph nodes removed at surgery we were able to check on the quality of the lymph node dissection. Men had a higher incidence (70%) of lymph node metastases than women (45%). Only 4% of the patients had radioiodine ablation of the thyroid remnant. The median follow-up time was 13 years. None of the patients below 45 years of age at surgery died of thyroid cancer. In the older age group eight patients died of thyroid cancer at a mean age of 75 years. Five of those who died of a thyroid carcinoma had distant metastases at diagnosis. Among patients with resectable disease, three (1.6%) died of thyroid cancer, all of whom had lived for more than 17 years after surgery. Hence longer follow-up is needed before we know the final mortality in our series. The results suggest that surgical technique and strategy can positively influence the survival of patients with papillary thyroid cancer. PMID- 8678963 TI - Incidence of regional recurrence guiding radicality in differentiated thyroid carcinoma. AB - Total thyroidectomy has become the routine procedure for treatment of differentiated thyroid carcinoma. However, the necessity of unilateral or bilateral neck dissection is far less standardized. Our usual procedure has been to perform a routine neck dissection in T4 tumors and in all other tumor stages only in the presence of positive diagnostic or intraoperative findings. The results concerning regional tumor recurrence in cervical lymph nodes subsequent to thyroidectomy are studied and discussed. Between April 1986 and December 1992 a group of 252 patients were operated on for differentiated thyroid carcinoma (DTC) (176 papillary, 76 follicular). Postoperative treatment included radioiodine therapy as a rule in all patients more than stage T1, and follow-up encompassed thyroglobulin measurements, cervical ultrasonography, and radioiodine scintigraphy. After a mean follow-up of 6.9 years, 77 (31%) of the patients underwent reoperation because of regional tumor recurrence [46 of 176 (26%) papillary, 31 of 76 (41%) follicular]. In papillary thyroid cancer a significant difference could be demonstrated between patients with thyroidectomy only versus thyroidectomy plus neck dissection in all tumor stages (T2, 13 of 29 (45%) versus 1 of 34 (3%); T3, 10 of 13 (77%) versus 4 of 11 (36%); T4, 6 of 8 (75%) versus 6 of 18 (33%) (p < 0.0001). Similar results could be achieved for follicular thyroid cancer, showing statistical significance with regard to operative procedure (p < 0.009). Our experience demonstrates a positive correlation of regional tumor recurrence with increasing tumor stage for both histologic tumor types. The high rate of regional recurrence justifies a more radical approach, including neck dissection at the initial operation. The impact on survival, however, must be proved by further evaluation. PMID- 8678964 TI - Epidemiologic and clinical evaluation of thyroid cancer in children from the Gomel region (Belarus). AB - This study reviews the epidemiology of thyroid cancer during childhood from the environs of Gomel in Belarus and the clinical data of 64 children aged 4 to 16 years from this area who had been diagnosed with differentiated thyroid carcinoma following the nuclear accident of Chernobyl. One case of thyroid cancer in children (aged < 15 years at diagnosis) was observed during the period 1981-1985 (rate = 0.5; expressed as annual averages per million children under age 15 years in the region of Gomel and period identified) before the Chernobyl accident. Twenty-one cases of thyroid cancer in children were observed during 1986-1990 (rate = 10.5) and 143 (rate 97) during 1991-1994 after the Chernobyl accident. During the first 7 months of 1995, there were 33 more cases of thyroid cancer observed in children. Three children with thyroid cancer were born since 1986 in the Gomel region. A total of 64 children aged 4 to 16 years from this area who had been diagnosed with differentiated thyroid carcinoma had been reviewed by us during the period May to November 1994. The female/male ratio was 1.4:1.0. At the time of the first diagnosis the mean age of the children was 9.4 +/- 2.8 years, and at the time of the accident their mean age was 3.8 +/- 2.4 years. More than 90% of the patients were less than 6 years of age and 3 were still in utero at the time of the accident. The period of latency between the accident and the first diagnosis was 5.6 +/- 1.5 years. Their ages at the time of the first diagnosis and their ages at the time of the accident were significantly correlated (p = 0.001); there was no significant correlation between the age of each child at the time of the accident and the latent period before the onset of carcinoma. The aggressiveness of the tumor, evaluated on the basis of T stage, lymph node status, and lung metastases, did not correlate with age at the time of the first diagnosis or with the age at the time of the accident. The susceptibility of the thyroid to the carcinogenetic effects of radiation, particularly during the first years of life (< 5 years) has clearly been demonstrated. However, there appears to be no correlation between the aggressiveness of the tumor and the age of the patients. PMID- 8678966 TI - Islet cell carcinoma of the pancreas. AB - Islet cell carcinoma (ICC) of the pancreas is a rare, indolent malignancy associated with higher resectability rate and better survival than ductal carcinoma. This retrospective study presents results of surgical treatment from a single institution. From 1985 through 1993 a total of 64 patients (36 men, 28 women) were surgically treated for ICC. Ages ranged from 22 to 80 years (median 55 years) with a median postoperative follow-up of 39 months (range 10-97 months). Of the 64 patients, 30 (47%) had functioning and 34 (53%) nonfunctioning tumors. Gastrinoma (n = 11) followed by glucagonoma (n = 6) and insulinoma (n = 4) were the most common functioning tumors. In the patients undergoing a laboratory study, 67% of the nonfunctioning tumors had elevated peptide hormone levels. Potentially curative resections were performed in 17 patients (26%), palliative procedures in 35 (55%), and exploratory laparotomy alone in 12 (19%). One patient (2%) died within 30 days after operation. Symptomatic improvement was achieved in 96% of patients with a mean duration of 22 months. Three- and five year survivals were 66% and 49%, respectively. In patients with curative resection, the disease-free survival at 3 years was 53% (95% CI: 32-86%). The presence of diffuse hepatic metastases was a predictor of poor survival at 3 years (74% versus 58%;p = 0.05); there was no statistically significant difference in survival between functioning and nonfunctioning groups (p > 0.1). Although curative resection for ICC is rare, meaningful palliation can be achieved in most patients with rare mortality and acceptable morbidity. PMID- 8678965 TI - Surgery for asymptomatic pancreatic lesion in multiple endocrine neoplasia type I. AB - Patients with multiple endocrine neoplasia (MEN) type I underwent pancreatic surgery at presymptomatic (n = 8, mean age 33 years) or symptomatic (n = 12, mean age 51 years) stages of pancreatic endocrine involvement with the principal aim to evaluate postoperative morbidity, survival, and malignant potential of the pancreatic lesion. Radiologic signs of malignancy were not identified in any patient prior to exploration. All patients displayed multiple tumors with generally complex immunoreactivity. Normal postoperative pancreatic tumor markers were recorded in five of the asymptomatic patients, which became abnormal in three of them at a mean of 3 years after surgery. All patients remained without symptoms for a mean of 6 years after operation. In four symptomatic individuals (33%) metastases were identified at exploration, and two died with tumor; 83% of symptomatic patients displayed persistent or recurrent endocrine morbidity from the pancreatic lesion. Recognizing lead time bias, this limited and uncontrolled patient comparison suggests that exploration at the symptomatic stage of pancreatic involvement in MEN-I patients is unsatisfactory. Rather than to obtain biochemical cure, surgery in asymptomatic patients might be regarded as a means of cancer prevention. The malignancy of the pancreatic lesion may be preceded by several decades of biochemical abnormality. Extensive screening for this lesion allows diagnosis during adolescence and the timely application of primary exploration. Active management of individuals with repeated biochemical analyses followed by selective reintervention could enable satisfactorily maintained pancreatic functions and substantial duration of cancer prevention. PMID- 8678967 TI - Operative experience of U.S. general surgery residents with diseases of the adrenal glands, endocrine pancreas, and other less common endocrine organs. AB - The aim of this study was to determine if the experience of general surgery residents is adequate and effective. The Resident Statistic Summaries (Report C) of the Residence Review Committee (Surgery) for eight academic years from 1986 to 1994 were analyzed. The main outcome measurements were total number of residents and programs, average number of operations performed, maximum number of operations performed, standard deviation, and the most common number of operations performed. For adrenalectomy, the average per resident was 0.98. The maximum range was from 7 to 15. The standard deviations ranged from 1.12 to 2.00. For pancreatic endocrine operations the average per resident was 0.15 with maximums of 3 to 10. For other endocrine procedures (nonthyroid and nonparathyroid) the average per resident was 0.14, with the maximums ranging from 7 to 19. The most common number of any of these procedures performed by U.S. graduates was 0. The number of adrenal, endocrine pancreas, and other less common endocrine procedures available for graduates of U.S. residency training programs is limited. As a consequence, most U.S. resident graduates have little or no experience with any of these procedures. Our findings suggest a strong need for fellowship training for any surgeon hoping to develop expertise in the management of these unusual and infrequent endocrine surgical diseases. PMID- 8678968 TI - Survival of patients with disseminated midgut carcinoid tumors after aggressive tumor reduction. AB - Sixty-four consecutive patients with disseminated midgut carcinoids were treated during an 8-year period according to a single clinical protocol aimed at aggressive tumor reduction by surgery alone or with subsequent hepatic artery embolization. All patients had markedly elevated urinary 5-hydroxyindoleacetic acid (5-HIAA) levels (581 +/- 79 micromol/24 h) and hormonal symptoms. Fourteen patients (22%) reached anatomic and biochemical cure by surgery alone. At follow up, the mean 5-HIAA levels were still normal after 69.0 +/- 6. 2 months; two patients had died from unrelated causes. With the introduction of somatostatin receptor scintigraphy, subclinical disease was diagnosed in 7 of these 14 patients. Forty patients with bilobar hepatic disease underwent embolization in combination with octreotide. In this group, 5-HIAA levels were still reduced by 55% after 71 +/- 11 months of follow-up, and the 5-year survival was 56%, estimated from the total death hazard function. After embolization, two subgroups could be identified with marked differences in their long-term response to treatment. Ten patients were not embolized owing to complicating diseases. The 5 year survival for the entire series was 58%. A significantly increased risk of cardiovascular deaths was seen, which underlines the importance of total survival analysis in a disease with multiple hormonal effects. It is concluded that an active surgical approach must be recommended to patients with the midgut carcinoid syndrome. In patients with bilobar hepatic disease, embolization combined with octreotide treatment markedly reduced the 5-HIAA excretion and suggested a prolonged 5-year survival. PMID- 8678969 TI - Progression of metastases and symptom improvement from laparotomy in midgut carcinoid tumors. AB - A total of 121 consecutive patients with midgut carcinoid tumors underwent regular clinical control and 158 laparotomies for abdominal symptoms with 1 to 11 years (mean 5.2 years) of follow-up. Metastases were present in 93% of the patients at study inclusion and developed at initially uninvolved sites with an overall probability of 0.38. Patients without initial tumor spread developed mesenteric or liver metastases with the probability of 0.25 (mean delay 12 years), whereas those with mesenteric metastases exhibited a probability 0.56 to develop liver metastases (mean delay 6.1 years). Spread to extraabdominal sites in patients with mesenteric and liver metastases exhibited a probability of 0.22 (mean delay 4.3 years), and this spread was especially frequent (probability 0.60) in patients with only liver metastases at inclusion. Patients without the carcinoid syndrome (52%) mainly suffered from more or less episodic abdominal pain, nausea, and diarrhea. Marked mesenteric fibrosis detected at surgery (n = 59) generally was accompanied by symptoms of abdominal pain and weight loss, and it often required urgent intervention due to intestinal obstruction or ischemia. Complete or partial symptom alleviation was accomplished in 82% of the operated patients, and generally was most auspicious after primary acute or subacute procedures (n = 54). The complete or partial symptom improvements after surgery lasted for mean 5.3 years and tended to be longer after elective (n = 50) than acute operations. The findings substantiate encouraging results of laparotomy in a compromised cohort of patients with midgut carcinoid tumors. Because the patients also displayed a generally slow progression of metastases, liberal indications for laparotomy should prevail in symptomatic and possibly also asymptomatic individuals with midgut carcinoid tumors. PMID- 8678970 TI - Metastatic endocrine tumors: medical treatment, surgical resection, or liver transplantation. AB - We reviewed our experience with 34 patients with metastatic endocrine tumors (METs) who were treated by different modalities. Eight patients were treated by chemotherapy or chemoembolization because of stable disease or surgical contraindications. Seventeen patients underwent curative or cytoreductive surgical resection. Nine patients received grafts based on the following criteria: no extrahepatic spread on imaging workup and nonresectable symptomatic metastatic disease. Of the eight medically treated patients, the five patients with initial stable clinical condition are alive 32 to 56 months after referral. Of the 17 patients treated by liver resection, 13 are alive 6 to 108 months after surgery, and 7 are disease-free. After curative resection, the 5-year actuarial survival and disease-free survival rates were 62% and 52%, respectively. Of the nine grafted patients, three patients grafted for carcinoid tumor are alive at 15, 24, and 62 months, one of whom has a late recurrence. Our results indicate that therapeutic indications for METs should be based on age, clinical symptoms, histologic type, and tumor extension: Patients with stable MET may benefit from surgical restraint; liver resection in patients with aggressive MET may provide good long-term palliation and possibly cure one-third of the patients; liver transplantation should be restricted to young patients with nonresectable carcinoid MET but remains a high-risk operation because of previous surgery and chemoembolization. PMID- 8678971 TI - Clinical spectrum and outcome of functional extraadrenal paraganglioma. AB - Functioning extraadrenal paragangliomas represent more than 10% of all pheochromocytomas, occur at diverse anatomic locations, and are said to have a higher malignancy rate than intraadrenal pheochromocytomas. Sixty-six patients had surgery for catecholamine-producing paragangliomas between 1952 and 1992. Median follow-up was 8.8 years. Median age was 40 years (11-67 years); the male/female ratio was 29:37. Familial disease occurred in 9 patients (13.6%), and 10 patients (15.2%) also developed adrenal pheochromocytoma. Solitary paragangliomas occurred in 52 patients: 46 abdominal, 4 thoracic, and 2 head and neck. Fifty-three tumors developed in 14 patients with multiple paragangliomas: 38 abdominal and 15 thoracic. Of 28 patients with solitary tumors undergoing localization studies over the past 10 years accurate localization was achieved in 27. There was one operative death; 15 patients had persistent disease; and 50 were cured postoperatively. Of those cured, nine developed recurrence, disease free survival being 86%, 80%, and 80% at 5, 10, and 20 years. Metastatic disease was found in 14 patients (21%), 7 of whom have died. An additional 10 patients (15%) had locally invasive disease, of whom 4 have died. Cause-specific survivals at 5, 10, and 20 years were 90%, 83%, and 72%. Risk factors for death from pheochromocytoma were tumor size > 5 cm (p = 0.0002), metastatic disease (p = 0.001), and tumor invasion (p = 0.0023). Cause-specific survival for patients with tumors > 5 cm was 59% at 15 years compared to 100% among patients with tumors 5 cm and the occurrence of invasive or metastatic disease are strong predictors of outcome. Most tumors are abdominal, and imaging is highly successful for localization. PMID- 8678972 TI - Pheochromocytomas: tendency to degenerate and cause paroxysmal hypertension. AB - Eighty-four patients with pheochromocytoma underwent surgery during the 13-year period from 1981 to 1994. These patients were divided into three groups according to the degree of parenchymal degeneration, which was estimated by preoperative dynamic computed tomography (CT) scans and resected specimens: solid group, cystic group, and highly cystic group. The relation between the degree of parenchymal degeneration and the clinical variety, size of the tumor, predominant plasma catecholamine, and type of blood pressure disturbance was analyzed. There were 39 cases of solid pheochromocytoma, 37 cases of cystic tumor, and 8 cases of highly cystic pheochromocytoma. The maximal mean diameters for each group were as follows: 5.1 +/- 2.3, 6.8 +/- 3.0, and 7.9 +/- 3.2 cm, respectively. Of the tumors < 3 cm in diameter, 84% were solid; when the tumors were >/= 6 cm in diameter, approximately 50% were cystic and 20% highly cystic. Of the adrenal pheochromocytomas, 60% were degenerated; 79% of the extraadrenal tumors were solid. Of the epinephrine-secreting tumors, 70% were degenerated, and 55% of the norepinephrine-secreting tumors were solid. The clinical pattern of hypertension was related to the degree of degeneration: In the paroxysmal hypertension group 87% of the tumors were degenerated, and in the sustained hypertension group 69% were solid. We therefore believe that parenchymal degeneration of pheochromocytoma is highly correlated with the tumor diameter, location of the tumor, secreted catecholamine, and clinical pattern of hypertension. PMID- 8678973 TI - Parathyroid tissue in normocalcemic and hypercalcemic primary hyperparathyroidism recruited by health screening. AB - Parathyroid tissue from 57 women (mean age 65.5 years) with sporadic primary hyperparathyroidism (HPT) was analyzed mainly to clarify its characteristics versus tissue from those with normocalcemia. Patients were recruited by population-based health screening of menopausal women. Analysis of three or four total serum calcium values showed normocalcemia in 16 patients (mean 2.53 mmol/L); 20 and 21 of the women were consistently (mean 2.82 mmol/L) or intermittently (mean 2.59 mmol/L) hypercalcemic, respectively. Parathyroid operation demonstrated a single adenoma in 81% of the individuals, and these lesions were most prevalent and commonly dominated by oxyphil parathyroid cells in the persistently hypercalcemic patients. Chief cell hyperplasia (two or three abnormal glands) of the nodular type was found more often in the normocalcemic patients. Total glandular weight was the smallest (mean 270 mg) among the normocalcemic women and contributed to delicate decisions with regard to the extent of resection. Immunostaining of cryosections with a monoclonal antibody recognizing a putative Ca2+ sensor demonstrated variably heterogeneous down regulation of the recognized glycoprotein in the pathologic parathyroid glands from all the individuals. Dose-response relations for PTH release and the cytoplasmic Ca2+ concentration ([Ca2+]i) were determined in Ca2+ 0.5-3.0 mmol/L by examining dispersed cells with radioimmunoassay and microfluorometry after fura-2 loading, respectively. ED50 for PTH release and [Ca2+]i and the [Ca2+]i concentrations at Ca2+ 3.0 mmol/L were the least deranged in cells from pathologic glands of the normocalcemic patients. The findings substantiate that the abnormal parathyroid tissue of normocalcemic HPT principally is characterized by the same, albeit less extensive, morphologic and functional derangements, which consistently have been demonstrated in patients with HPT accompanied by hypercalcemia and detected clinically. PMID- 8678974 TI - Enzymatic properties of transplanted glomerulosa cells. AB - There are several theories about the physiologic regeneration of adrenals and maintenance of physiologic steroid secretion after subtotal loss of adrenal cortical cells. According to the cell migration theory, adrenocytes from the zona glomerulosa migrate centripetally toward the medulla. This theory is opposed by the zonal theory according to which each zone resplenishes its cells independently. What these theories have in common is that they are based on data from the intact adrenal gland. We transplanted purified glomerulosa cells under the kidney's capsule of Lewis rats. The tissue was removed 30, 60, 90, and 150 days after transplantation to investigate the presence of two specific enzymes that are responsible for the secretion of aldosterone and corticosterone. Cytochrome p-450as is specific for glomerulosa cells producing aldosterone, and cytochrome p-45011beta is specific for fasciculata cells producing corticosterone. After sequencing the genetic code of these enzymes it became possible to demonstrate expression of the enzymes by in situ hybridization. The transplanted glomerulosa cells turned their enzymatic property to fasciculata cells expressing cytochrome p-45011beta. Our results suggest that glomerulosa cells are able to take over the physiologic function of a whole adrenal cortex in the absence of fasciculata cells, and that they are sufficient to maintain the function of the adrenal cortex. PMID- 8678976 TI - Comparative mapping on the mouse X chromosome defines a myotubular myopathy equivalent region. AB - The gene for X-linked myotubular myopathy (MTM1) has been localized to a 300-kb critical region in human Xq28 between IDS and GABRA3. As part of an effort to clone this gene, we developed a YAC contig on the mouse X Chromosome (Chr) which includes loci homologous to those within the human MTM1 critical region. The murine contig consists of 18 YACs and spans 2.5-3.0 Mb. We have aligned the human and murine physical maps by isolating conserved mouse genomic fragments, including CpG islands and trapped exons. We believe that the simultaneous isolation of genes from both mouse and human and continued comparative mapping will prove helpful in the eventual identification of MTM1 and other genes in the region. PMID- 8678977 TI - Identification and genetic mapping of random amplified polymorphic DNA (RAPD) markers to the sheep genome. AB - The random amplified polymorphic DNA (RAPD) assay utilizes the polymerase chain reaction (PCR) and short primers of arbitrary nucleotide sequence to amplify DNA. In this study, the RAPD assay was used to identify and map polymorphic markers in the AgResearch International Mapping Flock (IMF) sheep pedigrees. Sires and dams of eight of the full-sib IMF pedigrees were screened with 131 different 10-mer oligonucleotide primers. An average of 85 RAPD polymorphisms was identified between each parental pair, and 53 markers were contributed to the AgResearch IMF collaboration. Forty-five of the RAPD markers were mapped in the AgResearch IMF genetic linkage map, and at least one marker was located on 17 of the 26 autosomes and both sex chromosomes. Three lines of evidence were used to check for the homology of scored polymorphisms in different pedigrees, pedigree evaluation, segregation analysis, and Southern blot analysis. These results demonstrate that the RAPD assay is a powerful approach for identifying polymorphisms that can be used as markers for constructing a sheep genetic linkage map. PMID- 8678978 TI - Genetic mapping and embryonic expression of a novel, maternally transcribed gene Mem3. AB - To study the molecular function of genes expressed during preimplantation development, we isolated a novel maternal transcript SSEC (Stage Specific Embryonic cDNA)-26 from a partial subtraction library of mouse unfertilized eggs and preimplantation embryos. The SSEC-26 transcript is abundant in the unfertilized egg and also actively transcribed from the newly formed zygotic genome. On the basis of its expression in eggs and embryos, this new mouse gene is named Mem (maternal-embryonic) 3. The genomic locus of Mem3 has been mapped to Chromosome (Chr) 8 near the D8Mit78 marker and the glutaryl CoA dehydrogenase (Gcdh) locus. The deduced amino acid sequence of MEM3 resembles that of the yeast VPS (Vacuolar Protein Sorting) 35 in two separate domains. A cDNA sequence of the potential human homolog of Mem3 has been assembled with partial clones from the EST database and assigned to human Chr 16. PMID- 8678979 TI - Mapping the homolog of the human Rb1 gene to chromosome 14 of higher primates. AB - The Rb1 gene has been implicated with retinoblastoma and is located on human Chromosome (Chr) 13q14.2. A unique sequence human Rb1 cosmid DNA probe has been used to localize this region on apes' Chr 14 by the FISH technique. The conservation of the Rb1 gene in higher primates at the corresponding equivalent chromosome locus (14q14) of the human may serve as a phylogenetic marker to further trace the evolutionary pathway of human descent. PMID- 8678980 TI - Organization and chromosomal localization of a B1-like containing repeat of Microtus subarvalis. AB - A repetitive DNA sequence, MS2, was isolated from EcoRI-digested genomic DNA of the vole, Microtus subarvalis. The fragment was cloned and sequenced. Sequence analysis of this 1194-bp fragment revealed a 156-bp region demonstrating a 55% homology with the mouse B1 repeat. The remaining MS2 sequence shows no significant homology with other known GenBank sequences. The results of in situ hybridization of MS2 on vole metaphase chromosomes indicate the fragment is confined to heterochromatin blocks of the sex chromosomes in all but one species (M. arvalis). Distribution of MS2 sequences provides evidence for heterogeneity of the giant heterochromatin blocks of the XY Chromosomes (Chrs) in voles, for the unique cluster-like localization of MS2 within these blocks. PMID- 8678981 TI - Composite exon structure of an unusual Ig lambda-like gene located at human 22q11 position. AB - The surrogate light chain, composed of the VpreB and the lambda-like proteins, plays a critical role in controlling the early stages of B lymphocyte development. The lambda-like locus, located on the q11. 2-q11.3 region of human Chromosome (Chr) 22, contains three genes (14.1 Flambda-1, and 16.1) among which only the 14.1 is functional. This gene contains three exons, whereas the others lack exon 1. We have isolated in fetal liver a transcript of the Flambda-1 gene that contains the exon 3 sequence and a long non-Ig related sequence upstream. We show that this sequence resulted from the splicing of three new exons located telomeric to the Flambda-1 gene, highly homologous to beta-glucuronidase exon 11 (Chr 7), to the ABR exon 8 (Chr 17), and to an Expressed Sequence Tag (EST), respectively. We also show that this chimeric transcript is expressed in cells or tissues from various origins. This composite gene structure appears to be a new example of human genome flexibility, which can be explained by mechanisms such as exon shuffling and which results in the emergence of new transcription units inserted in regions involved in translocations. PMID- 8678982 TI - PCR-analyzed microsatellites for the inbred mouse strain 129/Sv, the strain most commonly used in gene knockout technology. PMID- 8678983 TI - Identification of an S19 pseudogene lying close to the Xist sequence in the mouse. PMID- 8678984 TI - Molecular analysis of an isoYq chromosome in a sterile male mouse. PMID- 8678985 TI - A high-resolution linkage map of the tight skin 2 (Tsk2) locus: a mouse model for scleroderma (SSc) and other cutaneous fibrotic diseases. PMID- 8678986 TI - Production of pig-mink cell hybrids with single pig chromosomes 2, 5, 12, or t(1,13). PMID- 8678987 TI - A high-density molecular genetic map around the weaver locus. PMID- 8678988 TI - Genetic and physical mapping of the murine Sox1 gene. PMID- 8678989 TI - Mapping of the mouse Bcl6 gene to chromosome 16. PMID- 8678990 TI - Genetic mapping of farnesyltransferase alpha(Fnta) to mouse chromosome 8. PMID- 8678991 TI - Dlgh1, a mouse homolog of the drosophila discs-large gene, is located on chromosome 16. PMID- 8678992 TI - Assignment of the mouse sterol carrier protein gene (Scp2) to chromosome 4. PMID- 8678993 TI - Structure and localization of the thrombin receptor gene on mouse chromosome 13. PMID- 8678994 TI - Localization of gene encoding the thyroid stimulating hormone receptor (Tshr) on mouse chromosome 12. PMID- 8678995 TI - A linkage map of porcine chromosome 7 composed of 19 short tandem repeat polymorphisms. PMID- 8678996 TI - The localization of the von Willebrand factor gene on cattle, sheep and goat chromosomes illustrates karyotype evolution in mammals. PMID- 8678997 TI - Physical mapping of connexin 32 (GJB1) and 43 (GJA1) genes to bovine chromosomes Xq22 and 9q15/16 by fluorescence in situ hybridization. PMID- 8678998 TI - The bovine butyrophilin encoding gene (BTN) maps to chromosome 23. PMID- 8678999 TI - Isolation and chromosomal location of mE4, a novel murine gene of the immunoglobulin superfamily. PMID- 8679000 TI - Riz maps to distal chromosome 4 near genes involved in tumorigenesis and nerve degeneration. PMID- 8679003 TI - Isolation of a mouse homolog of the human DAZ (Deleted in Azoospermia) gene. PMID- 8679004 TI - Linkage mapping of the rat Tp53 gene on chromosome 10. PMID- 8679006 TI - Localization of the rat stimulatory G-protein alpha subunit (GNPAS) gene to rat chromosome 3 by linkage analysis. PMID- 8679008 TI - Medical education about alcohol: review of its role and effectiveness. AB - Many reports have described inadequate responses by doctors to problems associated with alcohol misuse. Low levels of medical knowledge and inappropriate attitudes continue to be documented in the alcohol area. However, in recent years, greater emphasis has been placed on the need to improve doctors' skills in relation to alcohol problem detection and intervention. Experiential teaching approaches have been recommended and strategies which incorporate feedback methods offer considerable promise. In the United Kingdom and Canada, there has been no centrally funded approach to improve alcohol medical education. In contrast, federally funded initiatives in the United States of America and Australia have been associated with impressive increases in alcohol-related teaching hours and elective opportunities. Despite the substantial effort invested in achieving these curriculum gains, there is a dearth of research demonstrating impacts on medical behaviours or evaluating the cost-effectiveness of different educational strategies. Evidence from trials in smoking cessation training indicate that well-designed programmes can alter doctor behaviours in relation to substance abuse. If the alcohol medical education field is to progress, there is an urgent need for the development and evaluation of programmes which are better designed and are more informed by theory. PMID- 8679007 TI - Localization of rat Pgy3 (mdr2) to the same region as Pgy2 (mdr1b) at 4q11-12. PMID- 8679009 TI - Effects of alcohol and liver cirrhosis on the GH-IGF-I axis. AB - Decreased serum insulin-like growth factor (IGF-I) levels have been shown in malnutrition and liver diseases. To analyse which of them is the main cause of GH IGF-I axis alterations, serum levels of growth hormone (GH), growth-hormone releasing factor (GHRH), IGF-I and its binding protein IGFBP-3 were measured in 85 hospitalized alcoholics (51 without cirrhosis, 15 with compensated cirrhosis and 19 with cirrhosis with ascites) and in 25 healthy controls. Liver function tests and objective nutritional assessment were also performed. Serum IGF-I and IGFBP-3 levels were lower in alcoholics, particularly in those with liver cirrhosis. Serum GH was raised in cirrhotics with ascites but GHRH levels were not significantly altered. Although these patients were frequently malnourished there was no relationship between data derived from GH-IGF-I axis and nutritional parameters. However, there was a significant positive correlation between serum GH concentrations and impaired liver function and a significant negative correlation between serum IGF-I and IGFBP-3 and impaired liver function. This suggests that, in this population, serum IGF-I and IGFBP-3 levels reflect liver dysfunction rather than malnutrition. PMID- 8679010 TI - Alcohol and road traffic accidents. AB - Twenty per cent of a prospective representative sample of subjects suffering road accident injury were classified as 'problem drinkers'. A third had blood alcohol levels > 80 mg/dl at admission. There were few changes in alcohol consumption or drinking in relation to driving at 1 year follow-up. No specialist help was offered during initial or follow-up hospital care. PMID- 8679011 TI - Teenage drinking: a 4-year comparative study. AB - Two adolescent drinking surveys carried out within 4 years in the same region of the UK were compared on three aspects of drinking behaviour. The results showed that there was a higher proportion of non-drinkers in 1992 as compared with 1988 for males aged 11-15 and females aged 11-13; more 11-13 year-old females in 1992 reported their home as the location of their first alcoholic drink without their parents; and younger boys were less likely, in 1992, to report ever being drunk. The relative increase in the proportion of non-drinking adolescents is in line with similar recent trends in national sample surveys of young adults. PMID- 8679012 TI - Acetaldehyde involvement in ethanol-induced potentiation of rat hepatocyte damage due to the carcinogen 1,2-dibromoethane. AB - Previous experiments with hepatocytes isolated from ethanol-treated rats showed that alcohol potentiates the toxic action of 1,2-dibromoethane (DBE) by inhibiting its metabolism via glutathione-S-transferase. The aim of this study was to investigate whether acetaldehyde, the main product of ethanol metabolism, may be responsible for such inactivation. By pretreatment with 4-methylpyrazole, an inhibitor of acetaldehyde formation, the ethanol inactivation of glutathione transferase was actually prevented. As a consequence of this protective action, 4 methylpyrazole also prevented the high basal lipid peroxidation and the potentiated DBE toxicity observed in hepatocytes from ethanol-dosed animals. Finally, the inactivation of glutathione-S-transferase by concentrations of acetaldehyde likely to occur in the ethanol-intoxicated animal was confirmed in an in vitro model by direct aldehyde addition to hepatocyte suspensions. PMID- 8679013 TI - Influence of ethanol administration on the activity and compartmentation of rat liver monoamine oxidases. AB - Single-dose ethanol administration to rats caused inhibition of liver mitochondrial monoamine oxidases (MAO) A and B, and an increase in susceptibility of MAO A (but not MAO B) to limited proteolysis. Chronic ethanol feeding resulted in a less distinct alteration in catalytic activity and susceptibility to proteolysis of mitochondrial MAO, but increased the amount of soluble MAO. The sensitivity of membrane-bound MAO to inhibitors (imipramine and chlorpromazine), action of which depends on their lipophilicity and/or hydrophobicity, remained unchanged, compared with controls. Increased amounts of soluble MAO seen after chronic ethanol feeding probably reflect an impairment of insertion of newly synthesized enzyme molecules into the outer mitochondrial membrane, rather than solubilization of MAO from it. PMID- 8679014 TI - Intermittent ethanol exposure of adult rats: hippocampal cell loss after one month of treatment. AB - The effects of intermittent intraperitoneal ethanol exposure (3 g/kg body weight twice daily) on hippocampal cells of adult rats were examined after a 1-month exposure period. Continuous oral exposure to ethanol in the drinking water (20%) over the same time period was used for comparison. Pyramidal cells from the CA3 region and granule cells from the dentate gyrus were also qualitatively assessed using electron microscopy. One month of intermittent, peaking, exposure induced a significant loss of CA2-CA3 pyramidal cells and an increase in the number of lipofuscin granules in the remaining cells. A significant reduction in thickness of the dentate gyrus granule cell layer was also seen in the same animals. No significant reduction in pyramidal cell number or granule cell layer thickness was seen in continuously orally exposed animals in spite of a higher total ethanol intake. These studies thus demonstrate the harmful effect of intermittent high ethanol peaks and repeated withdrawal phases on hippocampal cells of the mammalian brain and emphasize the importance of considering the differential effects of different ethanol exposure patterns when assessing ethanol-induced cellular damage. PMID- 8679015 TI - Parental history of alcoholism: a risk factor for alcohol-related peripheral neuropathies. AB - The aim of this study was to identify the risk factors of alcohol-related peripheral neuropathies. A case-control study was performed to compare two groups of alcoholic patients, one with peripheral neuropathy and the other without, but with alcohol-related cirrhosis, pancreatitis or cardiomyopathy. Ninety patients were recruited in four in-patient units of a French hospital: 32 patients had a peripheral neuropathy and 58 patients did not. Univariate analysis showed no differences between the two groups for sex, age, body mass index and duration of the alcoholic disease. Peripheral neuropathies were associated with a higher frequency of parental history of alcoholism, severity of alcohol dependence, heavier alcohol consumption and more alcohol-related somatic diseases. Multivariate analysis showed a strong relationship between a parental history of alcoholism and the presence of a neuropathy, when the severity of the alcoholic disease was taken into account (adjusted OR = 6.8, IC95% [2.2-21.6], P < 0.001). The hypothesis that neuropathy may be a marker of an inherited susceptibility to alcoholism is discussed. PMID- 8679016 TI - The pharmacological treatment of alcoholism: from basic science to clinical medicine. AB - Recent advances in the understanding of the neurobiological basis of alcohol dependence have led to the development of pharmacological agents for the treatment of drinking problems. However, alcoholism is a complex disease with psychological and social dimensions in addition to medical problems. This implies that, in this domain, pharmacotherapy must be integrated in a general strategy of treatment and directed to specific aspects of management of the disease, such as treatment or prevention of the withdrawal syndrome or prevention of relapse after detoxification. Whereas the treatment of the withdrawal syndrome with pharmacological agents such as the benzodiazepines is now an established practice, the use of drugs for other dimensions of the disease is more controversial. However, the pharmacological approach aimed towards prevention of relapse appears promising, by means of classical medications such as disulfiram or new drugs (e.g. opiate antagonists and acamprosate). The clinical evaluation of such medications requires guidelines that will permit extrapolation of the results of the trials to situations that are commonly faced by practitioners. PMID- 8679017 TI - Detoxification: the use of benzodiazepines. AB - The use of benzodiazepines in the management of alcohol withdrawal in chemically dependent alcoholics is reviewed. Benzodiazepines are safer than earlier sedative drugs used for this purpose, such as barbiturates, chloral hydrate and paraldehyde. Differences in efficacy between individual benzodiazepines are slight, but benefits and disadvantages of longer acting (diazepam and chlordiazepoxide) drugs and shorter acting (lorazepam and oxazepam) are compared. Long-term outcome is commented on. PMID- 8679005 TI - Interpreting cDNA sequences: some insights from studies on translation. AB - This review discusses some rules for assessing the completeness of a cDNA sequence and identifying the start site for translation. Features commonly invoked-such as an ATG codon in a favorable context for initiation, or the presence of an upstream in-frame terminator codon, or the prediction of a signal peptide-like sequence at the amino terminus-have some validity; but examples drawn from the literature illustrate limitations to each of these criteria. The best advice is to inspect a cDNA sequence not only for these positive features but also for the absence of certain negative indicators. Three specific warning signs are discussed and documented: (i) The presence of numerous ATG codons upstream from the presumptive start site for translation often indicates an aberration (sometimes a retained intron) at the 5' end of the cDNA. (ii) Even one strong, upstream, out-of-frame ATG codon poses a problem if the reading frame set by the upstream ATG overlaps the presumptive start of the major open reading frame. Many cDNAs that display this arrangement turn out to be incomplete; that is, the out-of-frame ATG codon is within, rather than upstream from, the protein coding domain. (iii) A very weak context at the putative start site for translation often means that the cDNA lacks the authentic initiator codon. In addition to presenting some criteria that may aid in recognizing incomplete cDNA sequences, the review includes some advice for using in vitro translation systems for the expression of cDNAs. Some unresolved questions about translational regulation are discussed by way of illustrating the importance of verifying mRNA structures before making deductions about translation. PMID- 8679018 TI - The management of alcohol withdrawal using chlormethiazole. AB - Chlormethiazole is an extremely useful and flexible drug for use in the management of acute alcohol withdrawal. It is not a treatment for alcohol abuse and should not be used in this patient group, other than in the withdrawal period, and then for less than 10 days. It is extremely safe when used correctly by practitioners familiar with its properties. Problems can arise, however, if used by practitioners unaware of its limitations and the precautions needed for safe prescribing. PMID- 8679019 TI - How to get the best out of antabuse. AB - In the field of alcoholism treatment, disulfiram or calcium carbimide is one part of the treatment package and these deterrent drugs have to be combined with counselling and support to be effective. Besides adequate dosage and formulation of substance, the Antabuse tablet has to be taken under supervision by a therapist to strengthen compliance and motivate the patient to continue long-term treatment. Disulfiram metabolism is very complex and although new metabolites have been identified, clinically useful and practical determination of active substances for routine use has not been developed. In clinical situations, the disulfiram-ethanol reaction (DER) is still of major importance to demonstrate the effectiveness of the drug. This reaction was originally used to induce aversive conditioning. In the course of time, emphasis has focused more on sobriety and the DER has been used as a positive reinforcement during treatment. Antabuse therapy is remarkably free of serious side-effects. The latency time from start of treatment to the manifestation of adverse drug reactions differs according to organ. Hepatotoxicity has special interest in women with nickel dermatitis. PMID- 8679020 TI - Acamprosate as an aid in the treatment of alcoholism. AB - Acamprostate is a gamma-aminobutyric acid (GABA) analogue for which evidence is accumulating of a clinically useful benefit when used as an adjunct for conventional treatments to prevent relapse in alcohol dependence. This paper reviews published randomized controlled studies involving 1304 patients. To date no abstinence syndrome associated with acamprostate has been identified nor serious adverse effects. It is not effective in all patients, and the characteristics of the individuals most likely to respond and the treatment setting and modalities in which it is likely to be most helpful, have yet to be specified. PMID- 8679021 TI - Medical management of alcohol dependence: clinical use and limitations of naltrexone treatment. AB - Historically, pharmacological and psychosocial treatments for alcohol dependence have demonstrated only modest effectiveness in reducing alcohol drinking. However, the recent US Food and Drug Administration approval of naltrexone for the treatment of alcohol dependence offers a new, safe and effective medication to reduce relapse following alcohol detoxification. This paper reviews the various psychosocial and pharmacological treatments currently available and the effectiveness of these treatments. This paper also reviews preclinical research which demonstrates the involvement of the opioid system in the reinforcing effects of alcohol. This research led to clinical trials on the use of the opioid antagonist, naltrexone, to reduce alcohol's pleasurable effects and enhance the effectiveness of psychosocial therapy. In two randomized clinical trials, naltrexone treatment reduced rates of alcohol relapse, number of drinking days and alcohol craving. The clinical efficacy of all pharmacological treatments for substance abuse are limited by compliance with taking the medication. Also, pharmacological treatment does not address the psychosocial complications which often result from chronic alcohol dependence. Therefore, the integration of medications such as naltrexone and psychosocial therapies may offer the best treatment. The further development and investigation of new pharmacological agents will enable matching of patient populations with specific treatments, offering more successful treatment outcomes. PMID- 8679022 TI - Second-line and 'alternative' treatments for alcohol withdrawal: alpha-agonists, beta-blockers, anticonvulsants, acupuncture and neuro-electric therapy. AB - Drugs which reduce autonomic overactivity but have no sedative effects can be useful in alcohol withdrawal, either as the sole pharmacological intervention or in conjunction with sedative drugs. They may reduce sedative requirements, but their lack of anticonvulsant and anti-delirium effect can be a disadvantage. Beta blockers are more effective than alpha-2 agonists. Non-sedative anticonvulsants are of questionable value. Acupuncture and neuro-electric therapy, though often popular with patients and therapists, appear to be no more than impressive placebos in this context. Non-specific treatment effects can be very prominent in withdrawal. Support, information, reassurance and good nursing can reduce the need for specific pharmacological or psychological interventions. PMID- 8679023 TI - Isometry testing for anterior cruciate ligament reconstruction revisited. AB - The purpose of this study was to determine the effect, if any, that varying the distal testing position (tibial level) has on isometry data produced with a common anatomic proximal testing position at the native anterior cruciate ligament (ACL) origin. During ACL reconstruction in 25 knees, in vivo isometry measurements were recorded using two different isometry testing methods, which differed in the tibial level of the distal fixation testing point. Method 1 tested distally at a point 13 cm peripheral to the native ACL insertion on a vector in line with the tibial tunnel. Method 2 tested distally at a point central in the native ACL insertion at the level of the intercondylar floor. All tibial tunnels were standardized with similar sagittal tunnel-plateau angles and similar tunnel lengths. The proximal testing point was standardized at a point that was anatomically located at or near the central ACL origin 7 mm anterior to "over the top" in all knees. Using these methods, length changes between the proximal and distal testing points were recorded in each knee with each testing method, with the knee ranged from 70 degrees of flexion to full extension and from 70 degrees to 140 degrees of flexion. From these data, a total excursion from 0 degree to 140 degrees of flexion was calculated. A nonanatomic distal testing point (Method 1) produced a 6 mm +/- 1 mm total excursion, whereas anatomic testing points (Method 2) in the same knees produced a 1 mm +/- 1 mm total excursion. From these data, the authors conclude that the tibial level of the distal isometry testing point has a significant effect on the resultant isometry measurement such that anatomic testing points are most isometric. Isometers that produce data between nonanatomic testing points should not be used to position tunnels for ACL reconstruction and should not be used to assume the elongation forces an ACL substitute will see when fixed at different points. Conversely, the clinical relevance of this study is that both anatomic graft position and anatomic graft fixation position are important and, when achieved, should result in minimal graft elongation with early postoperative range of motion, leading to a more stable long-term result. PMID- 8679024 TI - Comparison of intraarticular bupivacaine with the addition of morphine or fentanyl for analgesia after arthroscopic surgery. AB - A randomized study on 30 patients undergoing knee arthroscopy was performed. Group I (n = 15) received 50 mg of 0.25% bupivacaine and 1 mg of morphine, and group II (n = 15) received 50 mg of 0.25% bupivacaine and 100 micrograms of fentanyl. The visual analogue scale was recorded at intervals of 1, 2, 3, 4, 6, 12, 24, and 48 hours after the operation. Supplementary analgesia requirements were also recorded. In group I, pain scores were lower than group II (P < .05) during the 1st, 2nd, 3rd, 12th, 24th, and 48th hours. The duration of analgesia on group I was significantly longer than group II. The combination of intraarticular morphine and bupivacaine has a longer analgesic duration and effect than a combination of fentanyl and bupivacaine. PMID- 8679025 TI - Arthroscopy of symptomatic total knee replacements. AB - Between December 1983 and August 1992, 21 knees in 19 patients with symptomatic total knee replacements were arthroscopically diagnosed. The average time between total knee replacement and arthroscopy was 20 months (ranging from 4 to 84 months). All patients were primary total knee replacements. Metal bars, 5 and 8 mm in diameter and 40 cm in length, were made for arthroscopic treatment of fibroarthrosis. Thirteen knees of 11 patients with a diagnosis of arthrofibrosis had an average improvement of 42 degrees arc of motion 1 year after arthroscopic surgery. Three knees with an average of 15 degrees increase of motion were determined to be failures. Another two patients had arthroscopic resection of fibrous bands with complete relief of patella pain. Among six patients who had revision of total knee replacements after arthroscopic diagnosis, four had wear in the metal backed patella components, and two had wear in the tibial insert and loosening of cementless patella component. An early diagnosis of implant failure under arthroscopic control was made, which easily allowed revision of the metal backed patellar button before the development of metallosis and massive osteolysis caused by the marked wear of polyethylene. With the use of our specially made metal bars for treating arthrofibrosis, we could release the adhesion more easily and avoid damage of valuable arthroscopic instruments. PMID- 8679026 TI - Costs analysis of successful rotator cuff repair surgery: an outcome study. Comparison of gatekeeper system in surgical patients. AB - In an effort to determine the cost effectiveness of rotator cuff repair surgery in workers' compensation patients, a financial analysis of 50 consecutive patients with a "successful" result was performed. Treatment costs were analyzed from the date of initial injury through all evaluations, diagnostic studies, surgical reconstruction, physical therapy and work hardening. Additionally, all workers' compensation payments and the cost of settlement was analyzed. The average cost of medical care was $50,302.25 per patient. The average time to return to unrestricted duty from the date of injury was 11 months. However, patients referred to a specialist immediately following the diagnosis of a rotator cuff tear had total costs that averaged $25,870.64 and returned to work an average of 7 months postoperatively. Patients managed via a "gatekeeper" system averaged $100,280.10 in total costs and the average return to work was 18 months. These differences in cost and return to work were both statistically significant, P < .05. In conclusion, immediate referral of rotator cuff tears for specialized care results in decreased cost and earlier return to work. PMID- 8679027 TI - Periarticular heterotopic ossification: a complication of arthroscopic anterior cruciate ligament reconstruction using a two-incision technique. AB - Extra-articular heterotopic bone formation was recognized as a postoperative complication of arthroscopic anterior cruciate ligament reconstructions in four knees around the femoral drill hole. Although laxity of the reconstructed anterior cruciate ligament was not observed in these patients, local pain, swelling, and deformity at the site of heterotopic ossification required surgical intervention. The ectopic bone can be successfully excised with restoration of function. The incidence rate of this complication is less than 1%. PMID- 8679028 TI - Arthroscopy for limitation of motion of the elbow. AB - Twenty-five patients with limitation of motion of the elbow joint caused by the intraarticular pathologies were treated with the following arthroscopic procedures: removal of loose bodies, excision of osteophytes, anterior capsular release, abrasion arthroplasty, and partial excision of the radial head. The extension of the elbow improved by 7 degrees, from a preoperative average of 21 degrees to a postoperative average of 14 degrees. The flexion of the elbow improved by 17 degrees, from a preoperative average of 113 degrees to a postoperative average of 130 degrees. The total range of motion improved by 24 degrees, from a preoperative average of 92 degrees to a postoperative average of 116 degrees. The average score of the Elbow Rating Scale of Morrey improved from a preoperative value of 2.8 to a postoperative value of 4.6. Twenty-three patients (92%) were satisfied with their results. Arthroscopy of the elbow is an effective diagnostic and therapeutic procedure for the limitation of motion caused by the intraarticular problems with minimal morbidity and rapid functional recovery. PMID- 8679029 TI - Radiographic sizing for meniscal transplantation. AB - Allograft or synthetic meniscal replacement has the potential to delay the arthritic sequelae of the meniscectomized knee. Meniscal implants must, however, be side and size specific. A cadaveric study was performed in which medial and lateral menisci were painted with a radiopaque tantalum powder-cyanoacrylic mixture. Radiographs of this preparation demonstrated reproducible relationships between each meniscus and established bony landmarks. When corrected for magnification, meniscal size could be derived from plain films. Meniscal width equaled the distance (coronal) from the peak of the tibial eminence to the periphery of the tibial metaphysis on anteroposterior films. Meniscal length was measured from lateral radiographs. Medial meniscal length was 80%, and lateral meniscal length was 70% of the measured sagittal length of the tibial plateau. Measurement error averaged 7.8% by these parameters. PMID- 8679030 TI - Positioning of the tibial tunnel for anterior cruciate ligament reconstruction. AB - Two mechanisms of unintentional anterior tibial tunnel axis shift can occur despite accurate placement of the guide wire within the proximal tibia. The first results from using a short-block reamer head joined to a shaft of smaller diameter. If the tibial tunnel is drilled obliquely, it is possible for the reamer head to displace anteriorly in the knee joint before completion of the posterior portion of the tibial tunnel. The second mechanism of anterior shift involves using two sequential drills to create the tibial tunnel. To delineate the causes of this unwanted shift, cadaveric studies and special roentgenographic studies were undertaken. Results demonstrated that the shift is related directly to the presence of high-density bone in the tibial plateau. In an effort to minimize this effect, various drill designs were tested, and it was determined that a drill-head length of 25 mm was most effective at reducing the shift without sacrificing the freedom of movement necessary to obtain precise endosteal placement of the femoral tunnel. Along with these experimental studies, a retrospective 7-year review of anterior cruciate ligament (ACL) reconstruction failures was performed to assess the clinical significance of inadvertent anterior positioning of the tibial tunnel. PMID- 8679031 TI - Arthroscopic shoulder surgery with three different laser systems: an evaluation of laser applications. AB - Twelve cadaveric shoulder arthroscopies were performed to evaluate the use of lasers as an adjunctive tool in arthroscopic shoulder surgery. The three most common lasers historically used in orthopedic surgery were examined: Holmium:YAG, Neodymium:YAG, and the CO2. The following parameters were evaluated for each laser system: (1) ease of use of the laser system and handpiece; (2) ability to excise and trim bursae, synovium, ligament, tendon, bone, and articular cartilage; and (3) ability to contract ligaments and capsule by heat transfer. None of these lasers efficiently cut bone, whereas all three systems readily debrided the soft tissues around the shoulder. The free-beam Ho:YAG and CO2 systems heat contracted soft tissues with more control than the contact Nd:YAG. The fiberoptic delivery system of the Neodymium:YAG and Holmium:YAG laser performed well in the saline arthroscopy, and the CO2 delivery system was cumbersome. Overall, the CO2 system removed tissue better than the others, but its difficult use favored the Holmium laser as the best overall current laser system for shoulder arthroscopy. PMID- 8679032 TI - Incidence of deep vein thrombosis after arthroscopic knee surgery: a prospective study. AB - Deep vein thrombosis (DVT) with subsequent pulmonary emboli (PE) is the most life threatening complication of knee arthroscopy. Although the incidence of clinically diagnosed DVT after arthroscopy is low, clinical examination is less sensitive and specific than other diagnostic modalities for the detection of venous clot. This study used compression ultrasound to prospectively evaluate patients before and after arthroscopic surgery for the presence of DVT. Preoperatively, patients were screened for DVT risk factors. Eighty-five patients completed the study. Three asymptomatic "silent" DVTs were identified, for an incidence of 3.5%. There was no statistically significant difference between those with and without risk factors for the development of DVT. PMID- 8679033 TI - Arthroscopic-assisted reduction of distal radius fractures. AB - The outcomes of seven patients with severe comminuted intraarticular fractures of the distal radius treated by arthroscopic reduction and percutaneous external fixation (ARPEF) were retrospectively reviewed. All of the fractures were classified as C3 types using the AO classification scheme. Outcomes were evaluated using the Gartland and Werley functional criteria, an objective wrist examination, a radiographic analysis, and a self-assessment outcome form at an average follow-up of 27 months (range, 12 to 45 months). All patients were free of pain and had returned to their prior occupations. No patient had articular incongruency of greater than 1 mm, and there was no evidence of radiocarpal degenerative change. Active range of motion and maximal grip strength averaged 92% and 98%, respectively, of the uninjured wrist. The technique of arthroscope assisted reduction and percutaneous external fixation yielded excellent results in a small group of patients, with minimal complications. PMID- 8679034 TI - Aspects of coracoacromial ligament anatomy of interest to the arthroscopic surgeon. AB - Examination was performed on 100 cadaveric specimens to demonstrate the anatomy of the coracoacromial (C-A) ligament. In a substantial number (34 specimens), the bipartite nature of the ligament and the breadth of its insertions were considerably more pronounced than usually perceived through the arthroscope. Supplementing the cadaveric material, 300 dry bone scapulae were examined from museum specimens of older persons. These demonstrated various degrees of transformation of the C-A ligament into bone (enthesopathy) at its acromial insertion. Variations in the patterns of these enthesopathic transformations corresponded to variations in the patterns seen in the cadaveric material. This variability is of practical importance in a variety of operative procedures. Additionally, the relationship between the acromial insertion of the C-A ligament and the overlying deltoid muscle was examined. An understanding of this relationship is crucial in avoiding complications when operating in this area. PMID- 8679035 TI - Redislocation with a bony bankart lesion after arthroscopic Bankart repair. AB - This case report presents a traumatic dislocation after an arthroscopic Bankart repair in which the repair site was intact and failure occurred through a new bony interval. The new bony Bankart lesion was identified 3 years after the initial arthroscopic repair. This highlights the issue of whether a traumatic redislocation after a surgical repair for recurrent shoulder instability represents a failure of repair or a reinjury. PMID- 8679036 TI - Popliteal artery injury complicating arthroscopic meniscectomy. AB - We describe two patients who sustained serious vascular complications following arthroscopic lateral meniscectomy. Such injuries are rarely encountered or reported in the literature and, as such, the potential catastrophic sequelae of this particular complication of arthroscopy may be underestimated. Investigation of suspected popliteal artery injuries is outlined and the need for a high index of suspicion and early referral to a vascular surgeon is stressed. PMID- 8679037 TI - Suprascapular nerve entrapment by ganglion cysts: a report of six cases with arthroscopic findings and review of the literature. AB - Suprascapular nerve entrapment by a ganglion cyst can produce pain and shoulder dysfunction. We report six cases with the associated arthroscopic intraarticular findings of a posterior capsulolabral injury (only the second such description) and review the literature. Based on the current literature and our experience, we document our treatment algorithm for suprascapular nerve entrapment secondary to a ganglion cyst. We believe it is necessary to evaluate and treat the intraarticular pathology as well as the ganglion cyst/nerve entrapment to successfully manage these patients. PMID- 8679038 TI - An intermeniscal fibrous band in a recreational runner. AB - An intermeniscal fibrous band was found to produce anterior knee pain in a recreational runner. Arthroscopic resection of the band eliminated the symptoms of pain with running. A literature review found no prior reports of this entity. The differential of plica syndrome and Hoffa's disease was reviewed. PMID- 8679039 TI - A ring-shaped lateral meniscus. AB - Ring-shaped lateral meniscus has not previously been reported. We report a case of ring-shaped lateral meniscus with ruptured anterior cruciate ligament. PMID- 8679040 TI - Bilateral hypoplastic lateral meniscus. AB - Among other anomalies of the menisci, a hypoplastic medial meniscus is extremely rare, with only four cases being described in the English literature. We were unable to find a description of this anomaly in the lateral knee compartment. A case report of a young patient with an arthroscopic diagnosis of bilateral hypoplastic lateral menisci is presented. We believe the arthroscopist should be familiar with this rare entity, even though it might be an incidental finding. PMID- 8679041 TI - Endoscopic therapy in epicondylitis radialis humeri. AB - After making an exact diagnostic verification of tennis elbow and after intensive conservative treatment has been used without any signs of improvement, the Hohmann operative procedure involving the incision of the proximal extensor tendon has distinct advantages as far as the pathophysiological aspects are concerned. This operative treatment can be safely carried out using endoscopy. A normal 30 degrees endoscope, nonelectrolyte fluid, an exploratory probe, and an electrotome are necessary. The procedure is described in detail. PMID- 8679042 TI - Patellar tendon graft harvesting using horizontal incisions for anterior cruciate ligament reconstruction. AB - Autograft endoscopic anterior cruciate ligament (ACL) reconstruction traditionally has been performed via standard arthroscopy portals and a single longitudinal anterior incision. This vertical incision is used for harvesting the central third of the patellar tendon with patellar and tibial bone blocks. From 1992 to 1995, more than 400 cases have been done with a new technique of graft procurement. This new method employs two transverse incisions that are more cosmetic and are less likely to become a source of pain or flexion limitation. PMID- 8679043 TI - [The high risk cardiac patient in anesthesia]. AB - As a result of more offensive therapeutic measures and the given abilities of modern medicine and the increasing number of geriatric patients who are characterized by multimorbidity, more perioperative complications, in particular those of cardiac origin, can be expected. As in any other medical discipline, the safety of anaesthesiological care of the patient very much depends on the individual professional qualification and competence of the physician. For the field of anaesthesiology it can be concluded that it is necessary to tackle the specific problems of this risk group in order to reduce the rate of complications to a minimum. In line with a number of studies showing equal manifestation of cardiac risk factors during the pre-, intra- and postoperative periods, we should concentrate on the consistent use of all preventive and therapeutic measures available during these three periods. Besides evaluation of the cardiac risk factors and planning of the intra- and postoperative management, premedication is of particular importance in the preoperative period. To avoid sympathicoadrenergic contraregulations, benzodiazepines are particularly recommended because of their anxiolytic and sedative effects. The selection of a special anaesthetic method suitable for the patient with high cardiac risk should be influenced not only by anaesthesiological aspects but also by the complex effects of anaesthetic drugs on the determinants of the myocardial oxygen balance. In this connection, an increased sympathicoadrenergic tonus is of particular importance, i.e. extreme changes in blood pressure or heart rate- compared to preanaesthetic values--and an increase in diastolic wall tension should be avoided. An anaesthetic regime comprising gentle general anaesthesia combined with epidural block and small doses of opioids or local anaesthetics meets these requirements, as does a combination of opioids with low doses of volatile anaesthetics or intravenous hypnotics. The quality of perioperative management is also strongly determined by careful haemodynamic monitoring and early correction of circulatory disturbances. Since cardiac patients remain at risk up to three days after surgery, a level of haemodynamic monitoring appropriate to the level of cardiac risk must be maintained. Three main symptoms- increasing oxygen uptake (as a product of pain or shivering), hypoventilation and hypoxaemia--should be avoided in the postoperative period. Therefore, respiratory insufficiency should be diagnosed without fail by respiratory monitoring. If required, artificial ventilation must be continued, with particular attention being given to circulatory effects during artificial ventilation and weaning from the ventilator. PMID- 8679044 TI - [Muscle relaxation with atracurium in myasthenia gravis]. AB - This report concerns a narcosis in a 42-year-old female patient suffering from myasthenia gravis in a state of clinical remission after thymectomia. Six months after thymectomia relaxometric control (Datex AMG) was performed while the patient underwent major colorectal surgery. We found a persisting sensitivity to relaxants during isoflurane anaesthesia supplemented with fentanyl. During 270 minutes of anaesthesia we needed only 25 mg atracurium (0.4 mg/kg bodyweight) only 57% of a theoretical normal dose. This is the result of a continuing muscular weakness in asymptomatic patients suffering from clinically reliable myasthenia gravis. Therefore, a reduced demand for muscle relaxants can be expected in these patients. PMID- 8679045 TI - [Postoperative vomiting after pars plana vitrectomy]. AB - In the present investigation we compared two different techniques of anaesthesia- total intravenous anaesthesia (TIVA) versus balanced anaesthesia--with and without antiemetic prophylaxis, with regard to postoperative nausea, strangling irritation and vomiting and their influence upon postoperative complications (intraocular bleedings) and postoperative intraocular pressure after pars plana vitrectomia. For this investigation four groups were formed. The anaesthesias were carried out as orotracheal intubational anaesthesia following two standard techniques, which only differ in the choice of the narcotics. Half the patients in each group were treated with an antiemetic prophylaxis of 2.5 mg DHBP. With regard to the occurrence of postoperative nausea and vomiting, the TIVA-groups proved to be better than those with balanced anaesthesia (16% to 43.5%; p < 0.05): DHBP in both methods led to a reduction of postoperative vomiting and nausea, but the differences showed not to be significant (p > 0.05). Best results were achieved with a combination of TIVA (propofol, alfentanil, atracurium, air/O2) and DHBP (4.7%). The total rate of postoperative complications in form of intraocular bleedings amounted to 8.6%. The appearance of complications increased when postoperative nausea and vomiting or increased intraocular pressure were observed (16.6% to 6.3%; 21.2% to 6.1%). Intraocular pressure, measured for four hours postoperatively, was significantly lower in the TIVA-groups than in the balanced anaesthesia-groups (15.5 +/- 7.7 mmHg to 18.3 +/- 8.2 mmHg). Therefore, we conclude that TIVA with propofol appears to be especially suitable for intraocular surgery. PMID- 8679046 TI - [Thyrotoxic crisis--a difficult diagnosis in a polytrauma patient--a case report]. AB - It is reported on a multiple injured female patient with severe head injury showing confusion, hyperthermia and tachycardia. These symptoms were relatively late recognized as typical signs of 'thyreotoxic crisis'. Based on this case report the authors want to remind on this disease as a possible complication of surgical and anaesthesiological interventions and they give information how to diagnose this relatively seldom occurring disease in multiple injured intensive care patient. PMID- 8679047 TI - Nutrition and wound healing: an overview. AB - Nutrients play a vital role in wound healing, helping to facilitate wound healing, maintain immune competence and decrease risk of infection. The basis of a well-balanced nutrition intake consists of carbohydrate and glucose, protein, fat, vitamins and minerals. Knowing what nutrients are necessary for a patient's recovery is not enough; knowing how to implement nutritional therapy to positively influence the outcome of the patient is also important for the caregiver. Methods of nutritional support include the oral diet, oral supplements, tube feeding and parenteral feeding. Assessing a patient's nutritional needs and implementing a realistic plan of care to provide these needs is crucial for wound healing. PMID- 8679048 TI - Differences in coping strategies among community-residing older adults with functional urinary continence, dysfunctional urinary continence and actual urinary incontinence. AB - With a prevalence of urinary incontinence in the community of approximately 30 percent for older adults, and mixed findings on the relationship between psychosocial effects and bladder patterns, it is important to understand the effective (functional) and ineffective (dysfunctional) coping mechanisms older adults use to confront incontinence. This study examined 117 participants who were mentally competent, able to communicate in English, not confined to bed, and residing in the community. Ages ranged from 58 to 93 years with a mean of 75.6. Participants were distributed into three groups: dysfunctional continence (28.2%), functional continence (32.5%) and urinary incontinence (39.2%). A self reporting, 4-point, Likert-like scale was used to determine coping methods. The functional continence group varied significantly from the dysfunctional continence and actual incontinence groups. Chi-square analysis indicated significant differences between the two groups in four items regarding the use of fluid restriction, management of odor, attitude, and the influence of age. There were significant differences in coping scores and gender, with women scoring higher. Finally, 73 to 85 percent of the dysfunctional continence and actual incontinence groups never talked to any healthcare provider about their urinary concerns. These high percentages emphasize that nurses must actively seek ways to open communication and discuss sensitive topics with older clients. PMID- 8679049 TI - Standardizing skin care across settings. AB - While healthcare providers are struggling to provide optimum patient care and health outcomes in a cost efficient manner, patients are demanding assurance that the care they receive offers the best chance for health improvement. The way to achieve the most effective and efficient treatments is through knowledge of current research and treatment options and standardized care. Resources are the AHCPR's Clinical Practice Guidelines on urinary incontinence and pressure ulcers in adults. Kaiser Permanente's Northern California Region created a Task Force to demonstrate nursing's contribution to positive patient outcomes, investigate and capture opportunities to participate in an interdisciplinary approach to measuring the effectiveness of patient care, and focus efforts on measurement, improvement, research, and development. Part of this effort was the conductance of a study which demonstrated that the absorbent product with the least expensive purchase price that had traditionally been used for incontinent patients was the most expensive product to use. The results of that study have been used, not only to improve purchase decisions, but also to teach nurses how theory, research, and practice are related to issues that concern caring for their patients. PMID- 8679050 TI - Perineal dermatitis risk factors: clinical validation of a conceptual framework. AB - As part of a larger study previously published in December of 1994, the question was asked whether commonly used pressure ulcer assessment tools (the Braden and Medley) were applicable to a broader definition of "skin risk assessment" and altered skin integrity related to perineal dermatitis (PD), and, if so, which risk factors were actually related to PD. The three site randomized clinical trial compared the use of diapers and underpads for 166 adult patients hospitalized on medical and surgical floors who were incontinent of urine and/or feces. Variables related to skin breakdown were the number of incontinence episodes, fecal incontinence, poor skin condition, pain, poor oxygenation, fevers, and mobility problems. Results also suggest that older patients may not have the sensory perception to experience discomfort in the same intensity as younger patients. Based on the findings of this study, pressure ulcer risk assessment tools are not good risk assessment tools for PD. The previously published conceptual framework for PD was modified and validated to form a basis for preventive measures. PMID- 8679051 TI - Pressure and shear: the pros and cons of "gentle therapeutic movement", and product testing. PMID- 8679052 TI - Synthesis and biological evaluation of a series of tyrphostins containing nitrothiophene moieties as possible epidermal growth factor receptor tyrosine kinase inhibitors. AB - A series of 36 nitrothiophene tyrphostins were synthesized, 32 of which were novel structures. Their ability to inhibit the epidermal growth factor (EGF) receptor tyrosine kinase was assessed in a cell-free assay. Compounds containing a dinitrile, 2-aminoethene-1, 1-dinitrile or a thioamide group were good inhibitors of the receptor tyrosine kinase. Although anti-proliferative and cytotoxic activity was seen, no evidence of inhibition of EGF receptor autophosphorylation in intact cells was observed. The compounds showed no preferential inhibition of EGF-dependent proliferation of fibroblasts transfected with the EGF receptor. Furthermore, in a panel of squamous cell carcinoma cell lines with varying levels of EGF receptor expression, there was no selective cell kill of lines with the highest EGF receptor expression. The 2-nitro-5-substituted thiophenes and the 2-nitro-3-substituted-thiophenes showed reduction potentials falling within the range likely to be reduced by cellular reducing agents, while the 2-nitro-4-substituted-thiophenes and 4-nitro-2-substituted-thiophenes did not. Compounds from the 2-nitro-5-substituted-thiophene series were shown to induce DNA damage, while no evidence of DNA damage was demonstrated with compounds from the 2-nitro-4-substituted-thiophene series. The 2-nitro-5 substituted-thiophene compound 4 showed significant tumour-type selectivity in the US National Cancer Institute human tumour cell line panel. The leukaemia cell lines were particularly sensitive to the compound, as were the majority of the colon cancer, melanoma and breast cancer cell lines, while the central nervous system-derived lines and the non-small cell lung cancer lines were particularly resistant. Further work is required to determine the precise mechanisms involved in these effects. PMID- 8679053 TI - Bis-naphthalimides 3: synthesis and antitumor activity of N,N'-bis[2-(1,8 naphthalimido)-ethyl] alkanediamines. AB - The bis-naphthalimides are a new class of antitumor agent. Previously, we have described initial synthetic series which established that two naphthalimide chromophores joined by polyamine linkers can produce agents with antitumor activity. We now extend these studies to describe the synthesis of a N,N'-bis[1,8 naphthalimido)-ethyl]alkanediamine series and examine the alkyl linker and chromophore substitution requirements for optimal antitumor activity. As a result, a bis-naphthal-imidoethyl derivative with no chromophore substitution and a NH-(CH2)3-NH bridge was identified. This agent (LU 79553) had both potent cellular cytotoxicity (IC50 = 0.014 microM) and was curative against MX-1 tumors grown in athymic mice. It has now been selected for clinical development. PMID- 8679054 TI - Synthesis of a series of cytotoxic 2-acyl-1,2-dihydroellipticines which inhibit topoisomerase II. AB - An array of novel 2-acyl-1,2-dihydroellipticines was prepared and evaluated for in vitro cytotoxicity in a variety of human cancer cell lines. The ellipticine analogs were also tested for inhibition of topoisomerase II in both decatenation and cleavable complex formation assays. Some of the new ellipticine derivatives were prepared by acylation of ellipticine with acid chlorides in tetrahydrofuran, followed by reduction of the intermediate 2-acylellipticinium ions with sodium cyanoborohydride. Others were synthesized by acylation of ellipticine with p nitrophenyl chloroformate, reduction of the 2-acylellipticinium ion with sodium cyanoborohydride, and displacement of the p-nitrophenoxide anion with a variety of oxygen and nitrogen nucleophiles. The cytotoxicities of the new 2-acyl-1,2 dihydroellipticines varied widely, and correlated well with their topoisomerase II inhibitory activities. PMID- 8679055 TI - Design, synthesis and topoisomerase II inhibition activity of 4' demethylepipodophyllotoxin-lexitropsin conjugates. AB - The design and synthesis of 4'-demethylepipodophyllotoxin-lexitropsin conjugates capable of inhibiting the actions of topoisomerase II are described. Siteselective topoisomerase II cleavage was observed in the presence of the new inhibitors, as determined by DNA sequencing. Additional topoisomerase II cleavage sites were observed with the new compounds that seem to be characteristic of the minor groove-binding lexitropsin moieties. Compound 17, having three pyrrole units in its binding moiety, exhibited distinct topoisomerase-mediated sites of cleavage at positions 4258, 4257, 4255 and 4247 of the pBR322 DNA fragment. These results demonstrate that conjugation with minor groove-binding moieties can alter or increase the number of topoisomerase II-induced cleavable sites and contribute to our understanding of the cytostatic activity of these compounds against KB cancer cell lines. PMID- 8679056 TI - Pyrimido [4,5,6-kl] acridines, a new class of potential anticancer agents. Synthesis and biological evaluation. AB - A series of 3-(aminoalkyl)-2,7-dihydro-6-nitropyrimido [4,5,6-kl] acridin-2-ones 3, strictly related to the pyrazoloacridines 1, have been synthesized. Thus, the reaction of the suitable 1-(aminoalkyl)amino-9, 10-dihydro-9-imino-4 nitroacridine 2 with ethyl chloroformate afforded the pyrimidoacridines 3a-f. By hydrolysis in hydrobromic acid of the 10-methoxy derivatives 3d-f, the 10-hydroxy derivatives 3g-i were obtained. The pyrimidoacridines 3a-i were tested in vitro for their cytotoxic activity against L1210 murine leukemia and HT29 human colon adenocarcinoma cell lines, showing significant potency of growth inhibition. Different DNA-binding assays as well as attempts to correlate cytotoxicity and DNA affinity have been carried out. PMID- 8679057 TI - Effect of tacrine on behavioral symptoms in Alzheimer's disease: an open-label study. AB - We conducted an open-label study designed to assess the effects of tacrine on behavioral changes in patients with Alzheimer's disease (AD). Twenty-eight subjects completed a baseline evaluation and at least one assessment during treatment. Behavioral symptoms and cognitive function were assessed with the Neuropsychiatric Inventory (NPI) and Mini-Mental State Examination (MMSE), respectively. The mean NPI score at the maximum individual dose of tacrine attained was markedly decreased (behavior improved, compared to baseline). Symptoms of anxiety, apathy, hallucinations, aberrant motor behaviors, and disinhibition were most responsive. Subject stratification by dementia severity revealed a substantially reduced mean NPI score only in the group with moderate dementia, independent of cognitive response. Over half of the subjects with cognitive improvement had a marked reduction in behavioral symptoms, particularly apathetic behaviors. These data suggest that tacrine may be beneficial for selected behavioral symptoms in AD patients, particularly at higher doses and in those with moderate cognitive deficits. PMID- 8679058 TI - Usefulness of the SF-36 Health Survey in measuring health outcomes in the depressed elderly. AB - Longitudinal data from a clinical trial were analyzed to evaluate the usefulness of the SF-36 Health Survey in estimating the impact of depression and changes in severity over time on the functional health and well-being of 532 patients, 60 to 86 years of age, who met DSM-III-R criteria for major depressive disorder. The Hamilton Depression Rating Scale, the Clinician's Global Impression of Severity and Improvement, and the Geriatric Depression Scale were used to define clinical severity and changes in severity over a 6-week period. Answers to SF-36 questions tended to be complete and to satisfy assumptions underlying methods of scale construction and scoring. As hypothesized, the SF-36 Mental Health Scale and Mental Component Summary measure, shown in previous studies to be most valid in measuring differences in mental health, exhibited the strongest associations with severity of depression in cross-sectional analyses and were most responsive to changes in severity in longitudinal comparisons. We conclude that the SF-36 Health Survey is useful for estimating the burden of depression and in monitoring changes in functional health and well-being over time among the depressed elderly. PMID- 8679059 TI - Rate of progression in familial Alzheimer's disease. AB - The clinical course of early-onset, dominantly inherited, familial Alzheimer's disease (FAD) was contrasted with late-onset, sporadic Alzheimer's disease (AD). Eight FAD and 23 sporadic AD patients were followed over a mean of 63 months from estimated disease onset. The two groups did not differ notably in duration of symptoms from onset, global disease severity, or degree of cognitive deficits on initial evaluation. The Kaplan-Meier lifetable method was used to assess time from estimated disease onset to dependence in self-care, institutionalization, and death. A greater percentage of FAD patients became dependent in self-care and died earlier than did sporadic AD patients. The lifetable results suggest that FAD may have a more rapid course than dose late-onset sporadic AD. PMID- 8679060 TI - Late-onset Huntington's disease: a geriatric psychiatry perspective. AB - Late-onset Huntington's disease is more common than has been generally appreciated and is associated with a wide range of psychiatric symptoms and syndromes. Geriatric psychiatrists have an important role to play in establishing the diagnosis and providing guidance to elderly patients and their families as they struggle with difficult management decisions. An illustrative case report and selective literature review are presented that highlight the genetic and clinical aspects of the condition. PMID- 8679061 TI - Longitudinal changes in cognitive functioning in adult day care participants. AB - This study examines longitudinal changes in cognitive functioning over the course of 2 years in participants of adult day cae programs. Cognitive measures included the Brief Cognitive Rating Scale (BCRS) and the Mini-Mental State Examination (MMSE). Longitudinal data were available for five measurement points over 2 years for 82 participants (22 males and 60 females). Overall, results from this study suggest that there were significant cognitive declines on BCRS and MMSE, even after only 1 or 2 years in the study. The rates of impairment over the 2 years for BCRS and MMSE were highly correlated. Within each measure, the individual rates of decline were very heterogenous and were influenced by the presence, type, and prognosis of dementia. Participants with multi-infarct dementia had greater cognitive decline than did those with other types of dementias. Initial cognitive functioning and physician's prognosis of dementia trajectory were also significant predictors of change over time. Results suggest a floor effect in the BCRS. PMID- 8679062 TI - Cardinal features of cognitive dysfunction in Alzheimer's disease: a factor analytic study of the Alzheimer's Disease Assessment Scale. AB - Factor analysis methodology applied to Alzheimer's Disease Assessment Scale (ADAS) subtest profiles for patients in two large-scale clinical trials of the antidementia drug tacrine yielded three oblique factors interpreted as dysfunctions in memory, language, and praxis. The factor structures confirmed reliable assessment of primary dimensions of cognitive impairment in Alzheimer's disease that the original authors of the ADAS proposed to measure and that correspond well to that of the only previously reported factor analysis of the ADAS-COG. The presence of a strong general factor, supported by stable correlations among the oblique primary factors, justifies the recommendation to continue reliance on the ADAS-COG total score as a primary outcome measure in clinical trials, whereas the factor scores are recommended for evaluation of differential treatment effects on more specific aspects of the general cognitive decline. The stability of correlations across time appears to satisfy a primary requirement for application of repeated measures ANOVA to ADAS-COG total score and factor scores in longitudinal clinical trials. PMID- 8679063 TI - Multimodal evoked potentials in Alzheimer's disease and Binswanger's disease. AB - Somatosensory evoked potentials (SEPs), brainstem auditory evoked potentials (BAEPs), visual evoked potentials (VEPs), and auditory event-related potentials (ERPs) were studied in 15 patients with Alzheimer's disease (AD), eight patients with Binswanger's disease (BD), and 15 normal subjects. Patients with BD showed significant prolongation of the interpeak latency between N13 and N20 (N13-N20) and N20-P40 of SEPs as compared with the normal controls, whereas patients with AD only demonstrated significant prolongation of N20-P40. The interpeak latency between waves I and V of BAEPs in patients with both AD and BD was significantly longer than that of controls. There were no significant differences in P100 latency of VEPs among these three groups. Both groups with dementia showed significant prolongation of N200 and P300 latencies of ERPs compared with normal controls. In addition, patients with AD showed significant prolongation of P200 latency. We conclude that these two dementing diseases have different electrophysiologic features that may be related to their underlying pathogenetic mechanisms. Furthermore, the measurement of multimodal evoked potentials may be helpful in the differential diagnosis of AD and BD. PMID- 8679064 TI - Differential dose delivery for cancers of the head and neck. AB - A technique was developed for the treatment of head and neck cancers that employs differential dose delivery to primary and nodal areas while simultaneously correcting the dose delivered through various thickness of tissue in the field(s). Our technique modulates the intensity of the static lateral fields in three dimensions utilizing data acquired from a pre-treatment CT scan. This technique has been used to treat patients with various cancers of the head and neck. All patients tolerated treatment well with no observed increase in acute normal tissue reactions. PMID- 8679065 TI - Criteria for the evaluation of treatment planning systems. AB - Radiation treatment planning systems (RTPS) are evolving on a rapid and continual basis. After the evaluation of several commercial systems, we have developed a list of features we consider desirable in a product. The goal in the compilation of these criteria was a comprehensive worksheet which categorized the characteristics of RTPS into hardware (computer and peripheral devices), 2-D planning tools, 3-D planning tools, irregular field planning tools, and brachytherapy planning. With these distinctions, one can evaluate a system conforming to the specific planning needs, e.g., conformal therapy, dynamic therapy capabilities, or optimized remote afterloading brachytherapy, of a department. The rationales of the special requirements are provided for justification. PMID- 8679066 TI - Spatial information on dose distribution using multisectional dose-volume histograms. AB - Dose-volume histograms are useful tools to summarize the information on the dose profiles resulting within a target volume. However, the spatial relationships of the hot and the cold spots are blunted in the dose-volume histograms. This study tries to circumvent this problem using multisectional dose-volume histograms and highlight the utility of these in the optimization of a radiation therapy plan. PMID- 8679067 TI - A simple backup for a radiosurgery treatment planning system. AB - To calculate the dose distribution and the number of monitor unit (MU) per arc, all radiosurgery systems utilize some sort of computer. These computers are, of course, subject to equipment malfunction such as problems with the magnetic tape drive, keyboard, mouse, etc. Since most radiosurgery procedures are quite invasive and time consuming, it is important to have a reliable and reasonably accurate backup system for planning the treatment. This paper will show that a simple PC based system, along with a digitizer, may be used as a backup for a commercial, VAX based radiosurgery system. A complete radiosurgery planning procedure was carried out on a head phantom with a target imbedded inside. The treatment planning and verification using the PC based system is also compared with that using the VAX based system. PMID- 8679068 TI - Clinical implications of collimator exchange effect, relative collimator and phantom scatter. AB - It is well established that the beam fluence on the central axis for rectangular or blocked fields is not always the same as that of its collimator equivalent square field. Many centers still determine monitor unit settings using a single output factor based on the collimator equivalent square field size because they feel the small errors introduced by this approach do not justify the extra data and effort required to correctly determine the monitor unit settings. Analyzing clinical monitor unit determinations for 6 and 15 MV photon irradiation. it is shown that failure to account for these discrepancies in central axis beam fluence may introduce 2.5-3% error in clinical situations. While the error is generally small, it must be eliminated if we intend to reach the commonly stated goal of 5% overall uncertainty in dose determination. PMID- 8679069 TI - Electron-photon field matching in the treatment of paranasal sinus tumors: a case report. AB - The treatment planning of paranasal sinus tumors is technically demanding due to the compact anatomy of the region and the close proximity of critical structures. In the majority of cases, conventional approaches utilizing 2 or 3 photon fields are adequate. However, in patients with locally advanced disease, these standard techniques may result in the unnecessary treatment of surrounding structures. We present here a case in which, because of the complex tumor geometry, conventional techniques would result in treating through both orbits. A novel treatment approach has been devised in which opposed lateral photon fields are matched to an anterior electron field (both in depth and in profile) to provide a uniform dose distribution to the target volume, while minimizing the dose to certain critical structures. The treatment design, in particular the methodology of electron-photon field matching as well as the specification of tissue compensation and customized blocking, is discussed. PMID- 8679070 TI - Treatment planning for parotid sparing in the patient requiring bilateral neck irradiation. AB - The use of three dimensional (3-D) planning techniques for treatment of head and neck cancers has primarily been used in cases which require only unilateral neck irradiation. However, tumors that require bilateral neck irradiation are commonly managed with parallel opposed treatment portals. A common morbidity associated with this standard form of treatment is xerostomia. In an effort to reduce the incidence of this debilitating side effect, a protocol has been developed which attempts to balance effective tumor control with preservation of salivary flow. Key to this protocol is the use of 3-D treatment planning. The close proximity of the targeted tissues to critical structures and the related dose requirements and/or restrictions of these tissues often require the treatment planner to utilize "non-standard" approaches to achieve the unique dose distributions necessary to meet protocol eligibility. This may include treatment planning options such as non-coplanar, non-axial beams; and modulation of beam intensity. PMID- 8679071 TI - [Karyological studies on the fruit of Gardenia jasminoides Ellis]. AB - This paper reports the karyological studies on the fruit of Gardenia jasminoides and G. jasminoides var. grandiflora. The chromosome numbers are 2n = 22 and the places of centromere are metacentric and submedian. The fruit of G. jarminoides is more primary than Gardenia jarminoidce var. grandiflora in karyotype. PMID- 8679072 TI - [Quantitative determination of ursolic acid in folium Ilicis cornutae (gouguye) gathered in different and periods]. AB - The content of ursolic acid in Folium Ilicis Cornutae (Gouguye) gathered in different periods from Yongfeng county of Jiangxi province was determined by TLCS method. The result shows that the content appears to be low in samples gathered in April, but about the same in samples of February, June, August, October and December. PMID- 8679073 TI - [Effect of different processing methods on 5 kinds of chemical compounds in Trachycarpus fortunei H. Wendl]. AB - The contents of p-hydroxybenzoic acid, protocatechuic acid, protocatechuic aldehyde, (+)catechin and gallic acid in Trachycarpus fortunei were defermined by HPLC. The relationship between processing methods and changes of content is discussed. PMID- 8679074 TI - [Betaine in differently processed root of Achyranthes bidentata Bl]. AB - The contents of betaine in differently processed root of Achyranthes bidentata were determined to be 0.930%-1.029% by reineckate precipitation and UV-visible spectrophotometry. The average recovery and relative standard deviation were 99.2% and 6.2%, respectively. PMID- 8679075 TI - [Technological studies of effects of inclusion on pericarpium Citri reticulatae volatile oil-beta-cyclodextrin]. AB - The effects of inclusion on Pericarpium Citri Reticulatae volatile oil-beta cyclodextrin were studied by comparing four methods saturation, grinding, liquid to liquid and liquid to gas. The utilization ratio of oil, the ratio of oil in inclusion complex and the recovery of inclusion complex were used as the criteria in evaluating the inclusion effectiveness. The results showed that the saturation method was the best. PMID- 8679076 TI - [Quantitative determination of magnolol and honokiol in baoji pill by HPLC]. AB - A HPLC method for the determination of magnolol and honokiol in Baoji Pill has been established. The method can be used to control the quality of Boji Pill. PMID- 8679077 TI - [High pressure liquid chromatographic determination of baicalin in lung-cleaning and diarrhoea-relieving infusion]. AB - The baicalin in the compound recipe of traditional Chinese medicine Lung-cleaning and Diarrhoea-relieving Infusion was determined by reverse phase high pressure liquid chromatographic method. Methanol-water-tetrahydrofuran (200: 300: 50) was used as the mobile phase at ODS C-18 column with ultraviolet detection. The result showed that baicalin was separated well from other components. External standard method was used for quantitative determination. The recovery rate was 101.4% and RSD 0.83%. PMID- 8679078 TI - [Chemical components of Codonopsis pilosula (Franch.) Nannf. var. volubilis (Nannf.) L.T. Shen]. AB - Ten compounds were isolated from Codono psis pilosula var. volubilis. Six of them were characterized as friedelin, taraxerol, alpha-spinasterol, alpha-spinasterol beta-D-glucopyranoside, n-butyl-alpha-D-fructofuranoside and n-butyl-beta-D fructopyranoside. PMID- 8679080 TI - [Determination of di-alpha-phosphatidylcholine in the seeds of Astragalus chinensis L. by TLC-scanning]. AB - PC (di-alpha-phosphatidylcholine) contents in the seeds of Astragalus chinensis were determined by TLC-scanning. These data can be used to study the phospholipids in Astragalus chinensis and evaluate its quality. This method is simple, sensitive and has better reproducibility, higher recoveries and steadiness in operation. PMID- 8679079 TI - [Chemical constituents of Clematis intricata Bunge]. AB - Five compounds were isolated from the aerial part of Clematis intricata for the first time. On the basis of spectral data (UV, IR, MS, 1HNMR and 13CNMR), they were identified as scopoletin, caffeic acid, inositol, 1-tria-contanol and beta sitosterol. PMID- 8679081 TI - [Micellar solubilized spectrophotometric determination of trace Mn2+ in rhizoma Zedoariae, fruit Amomi and herba Epimedii]. AB - A green quaternary complex of manganese with o-phenanthroline (Phen), cetyltrimethylammoniun bromide (CTMAB) and chromazurol S (CAS) has been studied in the pH range of 10.10-10.80, with maximum absorption at 612nm and molar absorptivity being 8.79 x 10(4) L.mol-1.cm-1. Beer's law is obeyed in the range of 0-16 micrograms/25ml for manganese. The molar ratio for Mn-Phen-CTMAB-CAS in the complex is established to be 1:1:4:2. The influence of foreign ions and their elimination have also been studied. PMID- 8679083 TI - [Influence of Cinnamomum migao H.W.Li oil on hemodynamic action in anesthetized cats]. AB - Cinnamomum migao oil (CV-3) 0.2ml.kg-1 was intraduodenum given to anesthetized open-chest cats. Ninety minutes after treatment with the oil, the SAP and DAP were slowly reduced to 15.2% and 14.2%, respectively. At the sametime, the HR was slowed down and CO decreased. The left ventricular pressure (LVP), the left ventricular end diastolic pressure (LVEDP), dp/dtmax and Vmax were remarkably reduced respectively. The LVP-(dp/dtmax)P-1 loop was narrowed. Isosorbide dinitrate showed similar effects to CV-3. PMID- 8679082 TI - [Comparative study on pharmacological effects of various species of Pueraria]. AB - Through comparative studies on the acute toxicity of four species of Pueraria, it was found that the toxicity of P. peduncularis was the highest, followed by P. lobata and P. omeiensis, and that of P. thomsonii was the lowest. The inhibitory effects of P. lobata, P. omeiensis and puerarin on the fever induced by 2,4 dinitrophenol in rats were very fast and significant, maintaining for about 8 hours, while the effect of P. thomsonii is relatively weak. As for influence upon the degrees of myocardiac ischemia induced by pituitrin, P. omeiensis appeared to be the most potent, and P. thomsonii the least one, while P. lobata and puerarin were intermediate between the above two. Summarily, the antipyretic and anti myocardiac ischemia effects of P. lobata and P. omeiensis are stronger than those of P. thomsonii, and puerarin is one of their effective components. PMID- 8679084 TI - [Changes of intestinal flora in senile mouse models and the antagonistic activity of the root of Astragalus membraceus (Fisch) Bge]. AB - Inhaled by mice, ozone induced stronger free radical reaction in the organism and led to a series of changes similar to senility. In this way the senility mouse models were established to observe the changes of intestinal flora in senile mice. The senile mice were given the root of Astrogolus membraceus decoction orally. The results showed that the imbalance of intestinal flora in these mice was recovered. PMID- 8679085 TI - [Effect of radix Ginseng-faeces Trogopterori combination on pharmacodynamics and effective chemical composition of radix Ginseng]. AB - The experiments have shown that there is incompatibility on anti-stress because the action of Radix Ginseng alone is stronger than that of Radix Ginseng and Faeces Trogopterori combined, but there is little incompatibility on non-specific immune function when both are used. The analysis of chemical composition of Radix Ginseng has indicated that the acquired rate of total saponin from the semifinished products and Rg1 of Radix Ginseng is markedly increased when the two drugs are decocted together. The results suggest that the traditional theory is limited in holding that Radix ginseng and Faeces Trogopterori are incompatible with each other. PMID- 8679086 TI - [Textual study and resource investigation on traditional Chinese drugs duhuo, jiuyanduhuo and qianghuo]. AB - By means of Bencaological study on traditional Chinese drugs Duhuo, Jiuyanduhuo and Qianghuo, it has been found out that the Duhuo recorded in earlier Bencao works should be Qianghuo, and Duhuo was first used medically in the South-North Dynasty period, whereas Jiuy-anduhuo's medical use started in the Ming Dynasty. Resources of the three drugs were investigated and their main species were found out. PMID- 8679087 TI - [Tissue culture and rapid propagation of Pinellia ternata (Thunb) Breit]. AB - In this papar, selection of the explaints and morphogenesis of the plantlet involved in the tissue culture of Pinellia ternata have been investigated, the effect of different combinations of growth-regulating substances on the morphogenesis has been studied, and the result of the establishment of clonal rapid propagation system and the transplanting of test-tube Pinellia seedlings has also been reported. PMID- 8679088 TI - [Protein analysis of 6 crude drugs and their processed products by polyacrylamide gel electrophoresis technique]. AB - In this paper, the proteins in 6 crude drugs (Prunus persica; P. armeniaca; Dolichos lablab; Strychnos nux-vomica; Mylabris phalerata; Whitmania pigra) and their processed products were analysed by polyacrylamide gel electrophoresis technique, and the effect of different processing methods on the quantity and kind of protein was explored. Protein electrophorograms of 20 samples are drawn. PMID- 8679089 TI - [Analytical study on drug-processing of the root of Glycyrrhiza uralensis Fisch. by HPLC]. AB - This paper presents a study on the drug-processing of the root of Glycyrrhiza uralensis. A HPLC method for the determination of glycyrrhizic acid in Glycyrrhiza uralensis and its processed products has been established. The method is simple, specific and accurate. The recovery is 99.97% and the relative standard deviation is 0.9%. PMID- 8679090 TI - [Percutaneous absorption of venenum bufonis in vitro]. AB - V-C horizontal diffusion cell and HPLC determination have been used to study the effect of 1,2-propanediol and azone on the percutaneous absorption Venenum Bufonis. The contents of resibufogenin have been determined through mouse skin in vitro by HPLC. The results indicate that the contents get increased when 1,2 propanediol is added and that azone can shorten the lag time of percutaneous absorption of resibufogenin through mouse skin in vitro. PMID- 8679091 TI - [Quantitative analysis of gamma-schizandrin in manganbao granules, a complex prescription of Chinese medicine]. AB - This paper deals with a HPLC method for determining the content of gamma schizandrin in Manganbao granules. Samples are extracted with haxane, re dissolved in MeOH, chromatographed on HPLC (Column, Spheri-5 RP-18, 220 mm x 4. 6mm, mobile phase, 75% MeOH) and the main components can be easily isolated. Six samples were analyzed by calibration curve method. The results have shown that the quantitative analysis of gamma-schizandrin conducted in this way is convenient, fast and highly reproducible. PMID- 8679092 TI - [Colorimetric method for the determination of carboxymethyl pachyman]. AB - Carboxymethyl pachyman gives a red color when treated with phenol and concentrated sulfuric acid. The reaction is sensitive and the color is stable. Based on this reaction, a colorimetric method has been developed to analyse carboxymethyl pachyman, and some factors that affect the determination were discussed. PMID- 8679093 TI - [Chemical components of decoction of radix Paeoniae and radix Glycyrrhizae]. AB - Eleven compounds were isolated from the water extract of the decoction of Radix Paeoniae and Radix Glycyrrhizae, namely benzoic acid, formononetin, isoliguiritigenin, liquiritigenin, 4',7-dihydroxyflavone, formononetin-7 glucoside, liquiritin, gallic acid, paeoniflorin, isoliquiritin and glycyrrhizin acid. PMID- 8679094 TI - [Chemical constituents of Hemsleya pengxianensis W.J. Chang]. AB - Six compounds were isolated from the tubers of Hemsleya pengxianensis and identified as chikuset-susaponin IV a, hemslosides Ma1, G1, H1, dihydrocucurbitacin F-25-O-acetate and dihydrocucurbitacin F on the basis of chemical and physical properties and spectral data. They were all isolated from this plant for the first time. PMID- 8679095 TI - [Antiviral activity of tannin from the pericarp of Punica granatum L. against genital Herpes virus in vitro]. AB - Based on cell culture techniques this study has demonstrated that tannin from the pericarp of Punica granatum is an effective component against genital herpes virus (HSV-2). The tannin not only inhibits HSV-2 replication, but also shows stronger effects of killing virus and blocking its absorption to cells. PMID- 8679096 TI - [Effects of Astragalus polysaccharides and ginsenosides of Ginseng stems and leaves on lymphocytes membrane fluidity and lipid peroxidation in traumatized mice]. AB - From days 0 to 3 posttrauma, daily administration of Astragalus polysaccharides (250mg/kg,ip) and ginsenosides of ginseng stems and leaves (50mg/kg,sc) can elevate significantly the lymphocytes membrane fluidity of plasmalemma, mitochondria and microsome from spleen,thymus and mesenteric lymph nodes in traumatized mice, reduce lipid peroxide levels, and increase superoxide dismutase activities in serum and lymphocytes from traumatized mice. PMID- 8679098 TI - [Improving effect of rhizoma Gastrodiae on learning and memory of senile rats]. AB - After giving Rhizoma Gastrodiae to aging rats continuously for 3 months, the process of their learning and memory was observed through step-down test and the content of lipid peroxides (LPO) was determined. It has been found out that Rhizoma Gastrodiae can effectively improve the ability of learning and memmory of these rats and reduce the content of LPO. The result may indicate that it is by clearing away the free-radicals that Rhizoma Gastrodiae improves the brain function. PMID- 8679097 TI - [Effect of puerarin on cerebral blood flow in dogs]. AB - The hemodynamics of left intra- and extracranial arteries was determined by a pulsatile Doppler flowmeter and a transcranial Doppler system simultaneously in anesthetized dogs. Low doses of puerarin (50mg/kg, iv) did not alter the cerebral perfusion pressure, but reduced the flow velocities of both middle cerebral artery and anterior cerebral artery. The globle cerebral blood flow was enhanced due to dilatation of the intracranial arteries. PMID- 8679099 TI - [Uses of analytic type countercurrent chromatography]. PMID- 8679100 TI - Remote controlled high dose rate brachytherapy. PMID- 8679101 TI - Stem cells from bone marrow, umbilical cord blood and peripheral blood for clinical application: current status and future application. AB - Bone marrow transplantation (BMT) has progressed rapidly during the past two decades to that of a treatment of choice as a therapeutically effective modality for the treatment of selected patients with malignant disease and non-malignant hematological disorders. However, its use is limited by availability of human leukocyte antigens (HLA)-matched donor cells, engraftment and graft-versus-host disease (GVHD). Prevention of GVHD, improvement in the speed and quality of marrow reconstitution, and screening of new immunomodulating agents which improve engraftment and augment hemopoiesis are intense areas of investigation. To this end there has clearly been progress in purification and characterization of human stem cells from different tissue sources. Discussed in this review are: (a) stem cell purification, characterization and ex vivo expansion; (b) bone marrow stem cell transplantation; (c) cord blood stem cell transplantation; (d) peripheral blood stem cell transplantation; (e) fetal liver stem cell transplantation; (f) in utero stem cell transplantation; and (g) evaluation of the capacity of stem cells to serve as targets for gene therapy. PMID- 8679102 TI - Status of new anthrapyrazole and pyrazoloacridine derivatives. PMID- 8679103 TI - Ribonucleotide reductase inhibitors: new strategies for cancer chemotherapy. PMID- 8679104 TI - Protein purification in the nineties. PMID- 8679105 TI - Restricted integration into genomic DNA following transfection of Chinese-hamster ovary cells with N-acetylgalactosamine-4-sulphatase cDNA. AB - The effect of using different conditions of electroporation for introducing the gene coding for human N-acetylgalactosamine-4-sulphatase into Chinese-hamster ovary (CHO) cells has been studied in an effort to increase the yield of recombinant protein. In each case the range of enzyme activities in the medium of transfected cells proved to be similar, with genetic analysis of a higher producer revealing only one gene copy integrated. Hence, allowing for position effects, the number of gene copies stably integrated into the CHO genome of all transfectants presumably was low, potentially a single copy in each. This inability to allow high-copy-number integration may suggest a constraint on the levels of this protein which can be tolerated by the cell. PMID- 8679106 TI - Use of nuclease enzyme in the purification of VAQTA, a hepatitis A vaccine. AB - The development of the purification process for VAQTA, which results in a highly purified inactivated hepatitis A vaccine, was driven by modifications in the cell culture and harvest methods which permit hepatitis A virus propagation to support large-scale manufacture. The starting material for the purification was initially a concentrated cell pellet scraped from roller bottles. However, when the cell culture method was scaled up to use high-surface-area Nunc cell factories or Costar cubes, the early steps in the process had to be modified to handle large volumes of dilute lysate. Membrane concentration was used at first, and a highly purified vaccine was prepared, but virus-poly(nucleic acid) complexes were formed, which reduced the yields in later processing steps. The introduction of a nuclease digestion immediately after harvest followed by capture chromatography on an anion-exchange column eliminated the formation of these complexes and resulted in more consistent performance and higher yields of downstream operations. PMID- 8679107 TI - Polylysine enhances cationic liposome-mediated transfection of the hepatoblastoma cell line Hep G2. AB - Plasmid DNA condensed by polylysine enhanced cationic-liposome-mediated transfection of Hep G2 cells. The luciferase expression plasmid pCMVL was complexed with the polycation poly-L-lysine and mixed with liposomes that contained a 1:1 molar ratio of the cationic lipid 1,2-dioleoyloxy-3-trimethyl ammoniumpropane, with the neutral phospholipid 1,2-di-(cis-9-octadecenoyl)-sn glycero-3-phosphoethanolamine. Polylysine enhanced cationic-liposome-mediated transfection of the hepatoblastoma cell line Hep G2 9-fold compared with pCMVL complexed alone with liposomes. The ratio of cationic to anionic charge of the polylysine-pCMVL complexes, and the quantity of cationic liposomes, are important determinants for optimal transfection of Hep G2 cells. PMID- 8679108 TI - Immobilization of L-asparaginase into a biocompatible poly(ethylene glycol) albumin hydrogel: I: Preparation and in vitro characterization. AB - The feasibility of the immobilization of Escherichia coli L-asparaginase into a hydrogel matrix made of poly-(ethylene glycol) (PEG) and BSA was demonstrated. After immobilization a 200-fold increase in the Km value was observed. The use of an L-aspartic acid analogue, carbobenzoxy-L-aspartic acid and surface modification by methoxy-PEG of molecular mass 5 kDa cause a only a slight gain in affinity of the enzyme for its natural substrate. The immobilized L-asparaginase has an optimal activity over a larger range of pH than the native enzyme, owing to the effect of the matrix. At a physiological pH of 7.3, the immobilized enzyme retained 90% of its activity compared with only 43% for the native form. The immobilized enzyme retained a high proportion of its initial activity, more than 90% after 50 days of incubation at 37 degrees C, even in the presence of its substrate. This may be compared with a half-life of 2 days observed for native enzyme incubated under the same conditions. These results suggest that the BSA PEG matrix can be very useful for enzyme immobilization and, taking into account the good biocompatibility of the matrix, one can expect that this matrix will provide a functional bioreactor for use in vivo. PMID- 8679109 TI - Effect of monoclonal antibodies in preventing carboxypeptidase A aggregation. AB - With an increase in temperature, carboxypeptidase A shows a decrease in solubility that is accompanied by loss of enzymic activity and conformational changes leading to its aggregation. In the present study we investigated the suppression of enzyme aggregation via its interaction with two monoclonal antibodies raised against the native protein. The protein aggregation process was monitored by ELISA measurements and determination of residual enzymic activity. As previously found, selected monoclonal antibodies which do not inhibit the biological activity of the antigen and bind with a similar affinity constant to their epitopes on the molecule exhibit a chaperone-like activity in the refolding of their antigen. These antibodies have an inhibitory effect on the aggregation of the enzyme which seems to be related to the location of the antigenic site recognized by each antibody. Identifying the aggregating epitopes' as sequences that are related to the sites where protein aggregation is initiated and preparing monoclonal antibodies against these regions may facilitate the understanding and prevention of protein-aggregation processes. PMID- 8679110 TI - Purification and characterization of a novel esterase induced by growth of Aspergillus niger on sugar-beet pulp. AB - An inducible esterase has been isolated from a liquid culture of Aspergillus niger grown on sugar-beet pulp. The enzyme was active on methyl esters of cinnamic acids, caffeic > p-coumaric > ferulic, and is therefore termed a cinnamoyl esterase. The enzyme was not active on methyl sinapinate, a good substrate for ferulic acid esterase III, which was purified previously from A. niger [Faulds and Williamson (1994) Microbiology 140, 779-787]. With methyl caffeate as substrate the enzyme had temperature and pH optima of 50 degrees C and 6.0 respectively, and a specific activity of 96.9 units per mg of protein. The purified protein (native molecular mass 145 000 Da) gave a single heavily stained band on SDS/PAGE, suggesting the protein was a dimer, and seemed to be heavily glycosylated. Isoelectric focusing gave a single band corresponding to a pl of 4.80. The pure enzyme was free of other carbohydrase activities. The activity of the pure enzyme was inhibited by more than 99% after treatment with the serine-specific protease inhibitor aminoethylbenzenesulphonylfluoride (1 mM) for 12 h. The enzyme was capable of releasing ferulic acid from sugar beet pulp. PMID- 8679111 TI - Release of ferulic acid from sugar-beet pulp by using arabinanase, arabinofuranosidase and an esterase from Aspergillus niger. AB - Aspergillus niger cinnamoyl esterase (CinnAE) is shown to be active towards a wide range of feruloylated oligosaccharides derived from sugar-beet pulp (SBP). The esterase hydrolysed ferulic acid ester-linked to either C-2 of arabinose or C 6 of galactose residues, and demonstrated the highest activity towards the feruloylated arabinose trisaccharide. However, CinnAE was able to release only 0.88% of total alkali-extractable ferulic acid from SBP in 24 h when acting alone. To determine whether cell-wall-degrading enzymes could increase the release of ferulic acid by CinnAE, SBP was incubated with various carbohydrases [cellulase, polygalacturonase, endo-arabinanase, alpha-L-arabinofuranosidase, endo-(1,4-beta-D-galactanase, beta-D-galactosidase]. These were added alone and in pairs, both in the presence and absence of CinnAE. We showed that all the carbohydrases tested were free of esterase activity. When individual carbohydrases were incubated with SBP, whether in the presence or absence of CinnAE, less than 1% of the feruloyl groups were released. When incubated with a mixture of endo-arabinanase and alpha-L-arabinofuranosidase, the esterase was able to release 14 times more of the alkali-extractable ferulic acid present in the whole pulp as free acid than CinnAE alone. Ferulic acid is linked either to L arabinose or D-galactose in SBP, but no corresponding increase in ferulic acid release was detected when SBP was incubated with CinnAE plus endo-(1,4)-beta-D galactanase and beta-D-galactosidase (both from A. niger). Hence feruloylated arabinans in SBP are readily available for hydrolysis by arabinan-degrading enzymes, whereas feruloylated galactans are not available for hydrolysis by galactan-degrading enzymes. PMID- 8679112 TI - The use of chitosan to increase the stability of calcium alginate beads with entrapped yeast cells. AB - A method was developed for increasing the stability of calcium alginate beads with entrapped Saccharomyces cerevisiae cells. Polyelectrolyte complexes were used as surface-coating materials by dropping alginate into chitosan. The coacervation agent sodium triphosphate was needed for the formation of the polyelectrolyte complexes. Gel beads maintained their rigidity during ethanol production and were chemically stable in phosphate buffer. No differences in ethanol production were found between S. cerevisiae immobilized in calcium alginate and in calcium alginate coated with polyelectrolyte complexes. The maximum productivity by immobilized S. cerevisiae cells was 74.1 g of ethanol/h per g of gel beads obtained at pH 4.8-6.0 and at 30 degrees C. PMID- 8679113 TI - Expression of acylphosphatase in Saccharomyces cerevisiae enhances ethanol fermentation rate. AB - Previous experiments in vitro have demonstrated the ability of acylphosphatase to increase the rate of glucose fermentation in yeast. To evaluate the possibility of increasing fermentation in vivo also, a chemically synthesized DNA sequence coding for human muscle acylphosphatase was expressed at high level in Saccharomyces cerevisiae. Ethanol production was measured in these engineered strains in comparison with a control. Acylphosphatase expression strongly increased the rate of ethanol production both in aerobic and anaerobic culture. This finding may be potentially important for the development of more efficient industrial fermentation processes. PMID- 8679114 TI - Atopic allergy and other hypersensitivities editorial overview: technological advances and new insights into pathogenesis prelude novel therapeutic strategies. PMID- 8679115 TI - Recombinant allergens for diagnosis and therapy of allergic diseases. AB - A considerable number of cDNAs coding for allergens have been isolated and expressed. Structural and immunological similarities between recombinant allergens and natural allergens indicate that a sufficient panel of recombinant allergens can be produced for diagnosis and therapy of allergic diseases. Recent studies document the successful in vitro and in vivo determination of a patient's allergen profile (allergogram) with recombinant allergens and encourage the use of recombinant allergens for specific therapy. PMID- 8679116 TI - Peptide modulation of allergen-specific immune responses. AB - In vitro peptide stimulation of allergen-reactive T-helper type 1 and type 0 cells, in the absence of costimulatory signals, induces anergy that is accompanied by the modulation of cell surface phenotype and changes in cytokine production. In experimental animal models, the administration of allergen-derived peptides may result in the downregulation of cytokine and antibody production, which is preceded by transient activation of CD4+ T cells, without the induction of effector immunity. Preliminary results of clinical trials using allergen derived peptides for desensitization are becoming available and should provide some insight into the efficacy of peptide therapy in man. PMID- 8679117 TI - Role and modulation of T-cell cytokines in allergy. AB - Allergic sensitization and the development of effector functions are controlled by IL-4-secreting and IL-5-secreting type 2 T cells. Recent studies have provided new insights into the events triggering the development of type 1 and type 2 T cells, the discrimination of type 1 and type 2 effector T cells from various T cell subsets, and the improvement of established and new therapeutic strategies, which are aimed at modulating such T-cell functions in the allergic patient. PMID- 8679118 TI - Antagonizing the differentiation and functions of human T helper type 2 cells. AB - Allergen-specific T cells from atopic patients generally belong to the T-helper type 2 subset. IL-4 and IL-13 produced by these cells induce IgE synthesis by B cells and play a major role in allergic disease mediated by IgE. Recent advances in our understanding of the differentiation and IgE-inducing activities of T helper type 2 cells suggest that targeting allergen-specific T cells may provide a novel way to intervene in allergy. PMID- 8679119 TI - Anti-IgE therapy. AB - Controlling the IgE response at either the synthesis level or the effector phase should have a profound impact on the allergic cascade. For more than a decade, researchers have focused on ways of interfering with the binding of IgE to its high-affinity receptor on proinflammatory cells. Several approaches have also been taken to antagonize the complex interplay of cytokines and cell-associated molecules (CD40, CD23) that are implicated in IgE synthesis. Recently, anti-IgE antibodies have been developed that are potent IgE antagonists. These antibodies are currently under clinical investigation as potential therapeutics for allergic disease. PMID- 8679120 TI - Autoimmunity. PMID- 8679121 TI - Genetics of autoimmune disease. AB - In the past year, the major advances in understanding the genetics of autoimmune disease in both man and mouse have been made as a result of using the positional cloning approach. Construction of congenic mouse strains, and, in humans, the exploitation of linkage disequilibrium between very closely linked markers and disease-predisposing loci, is enabling fine mapping of these loci. PMID- 8679122 TI - The Th1/Th2 balance in autoimmunity. AB - The study of autoimmune disease in the context of T-helper type 1 (Th1) and T helper type 2 (Th2) CD4+ T-cell responses demonstrates that the relative contribution of either T-cell type to the development of a particular autoimmune response can influence whether or not this response leads to clinical disease. Moreover, this influence can be quite different depending on whether the particular disease process is cell mediated or antibody mediated. Recent studies have demonstrated that the development of Th1 and Th2 responses may be significantly influenced by the costimulatory molecules recognized by responding CD4 T cells, and by other undefined factors in the genetic background. It has also been demonstrated that autoreactive Th2 CD4+ cells can regulate the activity of disease-causing Th1 CD4+ T cells in vivo. Control of autoimmune disease may thus be achieved by procedures that regulate the relative contribution of Th1/Th2 CD4 T cells to an autoimmune response. PMID- 8679123 TI - Transgenic/knockout mice--tools to study autoimmunity. AB - Transgenic and knockout mice have been valuable tools for clarifying the roles of individual cell types and effector molecules in the pathogenesis of autoimmunity. During the past year, new strains have been added to the large array of transgenic mice, with broad or tissue-specific expression of transgene products. These laboratory models, as well as knockout mice lacking genes for a particular molecule, have greatly enhanced our understanding of autoimmune disease. PMID- 8679124 TI - The regulation of self-reactive B cells. AB - Self-reactive B cells are eliminated in a series of checkpoints that are triggered by antigen binding. Recent reports have shown that in addition to the processes of elimination at the immature B-cell stage, B-cell anergy and regulation of T-cell help, self-reactive cells are also controlled by follicular competition, Fas-mediated elimination by T cells and censoring in the germinal centres. Each checkpoint operates at a threshold that reflects the need to maintain immune diversity at the same time as suppressing autoimmune disease. Analysis of the motheaten mutation has given a direct demonstration of how such thresholds can be modulated by genetic effects. PMID- 8679125 TI - Natural autoantibodies. AB - Autoantibodies of the IgM, IgG and IgA classes, reactive with a variety of serum proteins, cell surface structures and intracellular structures, are 'naturally' found in all normal individuals. Present in human cord blood and in 'antigen free' mice, their variable-region repertoire is selected by antigenic structures in the body and remains conserved throughout life. Encoded by germline genes with no, or few, mutations, natural autoantibodies are characteristically 'multireactive' and do not undergo affinity maturation in normal individuals. Natural autoantibodies may participate in a variety of physiological activities, from immune regulation, homeostasis and repertoire selection, to resistance to infections, transport and functional modulation of biologically active molecules. PMID- 8679126 TI - Ribonucleoprotein complexes as autoantigens. AB - Many intracellular proteins and nucleic acids, that are involved in important biosynthetic pathways, are targeted by autoantibodies occurring spontaneously in the sera of patients with systemic autoimmune diseases. Frequently, the autoantigens are assembled into multicomponent complexes containing both nucleic acid(s) and proteins. Recently, progress has been made in the study of autoantigenic ribonucleoprotein complexes, the most important of which are spliceosomal ribonucleoproteins, nucleolar ribonucleoproteins, Ro/La ribonucleoproteins and complexes of aminoacyl-tRNA synthetase and tRNA. In addition to new structural and functional information, important results have been obtained on epitope spreading, as well as on a potential role for apoptosis during the development of an autoimmune response against these complexes. PMID- 8679127 TI - Glutamic acid decarboxylase and other autoantigens in IDDM. AB - Autoantigens in insulin-dependent diabetes serve as diagnostic markers and as potential therapeutic immunomodulators. Recent studies have focused particularly on two well studied molecules, glutamic acid decarboxylase and insulin, as well as several new antigens that have been recently identified, recognized by antibody and/or cell-mediated immune responses in diabetic patients. Temporal aspects of antigen exposure, antigen processing of specific peptide antigens, and the interplay between specific antigens, MHC genetics, and host T-cell responses remain to be explored. PMID- 8679128 TI - Metal ion induced autoimmunity. AB - Metal-induced autoimmunity is a well established but poorly understood phenomenon. Recent work has begun to elucidate the molecular interactions of metal ions with immune cells and self-proteins. Metal-induced presentation of cryptic self-peptides emerges as a possible mechanism for activation of 'metal specific' T cells, challenging the hypothesis of a random polyclonal activation of T and B cells by metals. A preferential T-helper cell type 2 response is involved in metal ion induced systemic autoimmune disease. PMID- 8679129 TI - Apoptosis in brain-specific autoimmune disease. AB - Recent neuropathological studies of experimental autoimmune encephalomyelitis have focused attention on the high number of cells in the lesions that show typical morphological features of apoptosis. Surprisingly, it has turned out that the vast majority of apoptotic cells are T lymphocytes and that they actually represent the antigen-specific T-cell population responsible for the induction of the disease. Taken together, these data suggest that clearance of autoimmune inflammation in the nervous system is accomplished by the destruction of the antigen-specific T-cell population within the lesions. This may explain the low level of central nervous system specific T-cell memory formation, as well as previously unexplained phenomena of 'epitope spreading', in autoimmune inflammation of the nervous system. PMID- 8679131 TI - Atopic allergy and other hypersensitivities. PMID- 8679130 TI - Bullous skin diseases. AB - Fundamental advances in the fields of molecular biology and immunology have facilitated investigation of the autoimmune blistering disorders. Recently, the use of human autoantibodies has helped to identify biologically important adhesion molecules of the skin, and the pathogenic mechanisms involved in bullous skin diseases are now being precisely defined. PMID- 8679132 TI - Autoimmunity. PMID- 8679133 TI - [Traffic accidents in alcoholic intoxication]. AB - A study of group comprising all road accidents caused by drivers of private cars who were under the influence of alcohol (BAC > = 0.3 g/kg; X = 1.56 +/- 0.62 g/kg) that occurred in a defined area over the span of one calendar year (n = 625) was compared with a randomly selected control group of 718 road accidents in which the drivers had not been under the influence of alcohol. The drivers in the study group were marginally younger than the ones in the control group. However, there was no evidence of an alcohol related increase in the risk of an accident associated with younger age. The sex ratio in the study group corresponded to that, generally found amongst people driving under the influence of alcohol. In the study group there was no evidence of a restricted manner and extent of car use, based on the distances between the sites of the accidents and the offenders' homes. However, the proportion of accidents occurring out of towns was greater in the study group. Alcohol associated accidents occurred more frequently in the evenings and at night, which reflects habitual drinking patterns. Therefore these accidents occurred mainly in darkness and twilight. Surprisingly, unfavorable weather conditions such as rain or ice did not lead to an increase in accidents due to alcohol. In fact, in the study group, proportionally fewer accidents occurred on icy roads. Both injury to persons and damage to property were more severe in the study group. While no relationship between accident severity and blood alcohol concentration could be proven within the study group, the risk of death or severe injury was 3 to 4 times greater in this group than in the control group. PMID- 8679134 TI - [Reliability of back-calculation of blood alcohol concentration to the time of infraction]. AB - In order to be able to give an accurate legal judgement of a drink driving offense, the BAC at the time of the offense has to be determined. The calculation which may be necessary is based on the time of blood sampling and on the time of the offense. The authors examined records of 854 blood samples taken in the years 1979 and 1989 with regards to the times recorded. Blood sampling recorded on the hour or on the half hour could be found four times more frequently than would have been statistically expected. Blood sampling recorded to the nearest five or ten minutes were documented three times as often as those ending on the exact minute. Times of the offense were recorded at least ten times as often to the nearest five minutes. The rounding up of times could cause discrepancies of more than 0.01% when calculating the BAC at the time of offense. PMID- 8679136 TI - [Changes in the spectrum of alcohol-induced traffic accidents in relation to blood alcohol level]. AB - A retrospective study was undertaken to determine whether the degree of alcohol intoxication has an effect on the driving performance with regards to both the quantity and quality. A total of 625 accidents caused by drivers who were under the influence of alcohol were reviewed. They were divided into three groups according to the blood alcohol concentration (BAC):0.30 - 1.09 g/kg, 1.10 - 1.99 g/kg and > 2.00 g/kg. In order to exclude the influence of factors unrelated to alcohol, the groups were matched for age, sex, location of accident and the light and road conditions. This resulted in a total of 85 accidents in each group. The accidents were classified with reference to the "Register of causes of accidents" used in road accident statistics. The three groups differed significantly in their causes of accidents (p < 0.025), although those due to speeding dominated in each group. In the group with low BAC, the next most common accidents were the ones caused by failure to give way. In the group with medium BAC, rear-end collisions and accidents occurring during low speed manoeuvres were the second most common. In the group with highest BAC, the next most common causes of accidents were the leaving of the correct traffic lane unassociated with speeding. PMID- 8679135 TI - [Use of the ADH/REA method (Abbott Tdx-REA) in forensic blood alcohol determination]. AB - The ethanol determination using the ADH/REA method (Abbott TDx-REA) is based on the principle of radiative energy attenuation (REA) applying the classic ADH method. However, instead of measuring the extinction of the reaction product NADH, a chromogen formed by a coupled diaphorase reaction is measured. Serum, whole blood and urine are used for ethanol determination without prior treatment. The following analytical procedures such as sampling, addition of reagents and measuring are automated. Sample solutions of 100 to 200 microliters should be used. Daily calibration of the apparatus is recommended. Both precision and reproducibility meet the requirements of BAC-assays in forensic specimens. The results obtained by using gas chromatography and ADH/REA method show an excellent correlation (factor r = 0.9977). The ADH/REA method has proved to be a reliable assay procedure in routine determination of the BAC in forensic samples. PMID- 8679137 TI - [Alcohol and aggression--violence prone drivers preventing passing maneuvers]. AB - 1. The regulation that currently applies to driving bans is not an "ineffective weapon". The span of sanction of 1 to 3 months is sufficient. Anything in addition to that will be covered by the safety aspects of the section 69, 69 a StGB. 2. In cases of violence in traffic there is no deficit in sanctions with regards to the instruments e. g. section 240, 315 b and 315 c StGB. 3. The assessing of the drivers fitness requires more than the driving ban, the withdrawal of the driving license and the psychological retraining of drivers. It also requires an expert assessment of the officially authorized assessment office. PMID- 8679139 TI - Relationship between variations in pathogenicity and lag phase at 37 degrees C of Listeria monocytogenes previously stored at 4 degrees C. AB - Three haemolytic, pathogenic strains of Listeria monocytogenes (a reference strain, a food-derived strain and a human strain) were held at 4 degrees C for 4 weeks in phosphate-buffered saline pH 5.5 or 7.0, with and without 0.2% potassium sorbate or 0.3% sodium acetate. The number of viable cells did not change significantly during this storage. Pathogenicity of non-growing L. monocytogenes cells for 14-d-old chick embryos was determined before and after storage. Storage at 4 degrees C resulted in decreased pathogenicity, but effects were strain-, pH and substrate-dependent. After 4 weeks storage at 4 degrees C non-growing bacterial cells were transferred to Brain Heart Infusion broth and growth characteristics were determined during incubation at 37 degrees C. Strains that showed decreased pathogenicity had significantly longer lag phases at 37 degrees C than strains that maintained pathogenicity. It is concluded that decreased pathogenicity of L. monocytogenes stored without growth at 4 degrees C for 4 weeks and subsequent long lag phase at 37 degrees C are correlated. PMID- 8679140 TI - Reduction of Saccharomyces cell adhesion by liquid mechanical vibration. AB - The effect of liquid mechanical vibration on the adhesion of Saccharomyces cerevisiae cells to the internal glass surface of a pipette was studied using a 25 Hz vibration source. The maximum vibration amplitude was 1.06 mm (peak to peak) along the pipette direction. Relative movements between the pipette and yeast suspension in it were produced by vibration and reduced the cell adhesion. The reduction in adhesion was affected by both vibration amplitude and suspension pH. Analysis showed that in routine cell counts, cell adhesion to the pipette wall was a significant error source. The construction of a vibration device for routine cell count work appears feasible. PMID- 8679138 TI - Detection by polymerase chain reaction of Clostridium perfringens producing epsilon toxin in faeces and in gastrointestinal contents of goats. AB - A polymerase chain reaction (PCR) was used to identify the gene-encoding epsilon toxin production in Clostridium perfringens types B and D in faeces and in gastrointestinal contents of goats. The samples were cultured in thioglycollate broth and centrifuged. The upper layer of the pellet was used as a template for PCR, obviating the need for DNA extraction. This technique specifically differentiated Cl. perfringens types B and D from Cl. perfringens types A and C and from Escherichia coli. When used to identify Cl. perfringens type D in samples artificially spiked with the micro-organism, the PCR detected as few as 1.4 x 10(2) cfu g-1 of sample. Gastrointestinal contents and faeces were collected from 20 goats at slaughter and processed by PCR. Several positive results were obtained from the first five goats that were slaughtered and sampled a few days after their arrival at the abattoir, but only a few samples gave positive results during the following weeks, after the goats had been fed a concentrated ration containing monensin. A possible role of this drug in control of enterotoxaemia is suggested. PMID- 8679141 TI - Transfer of conjugative plasmid pAM beta 1 from Lactococcus lactis to mouse intestinal bacteria. AB - Conjugal transfer of plasmid pAM beta 1 from Lactococcus lactis to intestinal bacteria of BALB/c mice was studied. Plasmid transfer was observed to Enterococcus faecalis in vitro by a filter mating method with transfer frequencies of 2.3 x 10-3 and with lower frequencies to other species. In vivo, using gastric intubation with the pAM beta 1-bearing Lactococcus lactis as donor and Ent. faecalis as recipient, a few transconjugants were detected from faecal Ent. faecalis. However, when these mice were given erythromycin through drinking water, a large number of conjugated Ent. faecalis were detected in faeces. Plasmid transfer to Ent. faecalis occurred at high frequency, 1.2 x 10-3, in mice whose anus was artificially closed after gastric intubation with pAM beta 1 bearing Lactococcus lactis. These results demonstrate clearly that pAM beta 1 transfer occurs between Gram-positive bacteria in the gut of mice harbouring many species of bacteria. PMID- 8679142 TI - Anomalous but helpful findings from the BBL Crystal ID kit with Haemophilus spp. AB - Fourteen strains of Haemophilus (12 H. influenzae, 1 H. parainfluenzae and 1 H. aphrophilus) were processed in BBL Crystal ID Enteric/Nonfermenter, API 20E and API 20NE kits, to determine whether the BBL kit misidentifies, as API kits may do, Haemophilus spp. as Pasteurella spp. The 13 H. influenzae and H. parainfluenzae strains produced uninterpretable colour reactions in the Crystal kit, thus signalling that an inappropriate species had been tested. On the other hand, the API kits (especially 20NE) often confidently "identified' Haemophilus spp. as Pasteurella spp., giving no warning that this was a misidentification. PMID- 8679144 TI - Repetitive element sequence-based PCR for species and strain discrimination in the genus Listeria. AB - Repetitive element sequence-based PCR (rep-PCR) was used to generate DNA fingerprints for Listeria spp. Two primer sets (REP 1R-I REP 2-I and ERIC 1R ERIC 2) used in respectively REP- and ERIC-PCR revealed that bacteria of the genus Listeria possess short repetitive extragenic palindromic elements and enterobacterial repetitive intergenic consensus sequences. Specific band profiles obtained by ERIC-PCR enabled the identification of Listeria species. With both REP- and ERIC-PCR the L. monocytogenes serotypes 1/2a, 1/2b, 1/2c, 3b and 4b could be clearly distinguished from each other. Within the serotype 1/2a, REP-PCR showed a higher discriminative potential than ERIC-PCR and a comparable discriminative potential as RAPD combining 3-4 primers. PMID- 8679143 TI - Pretreatment to reduce somatic Salmonella phage interference with FRNA coliphage assays : successful use in a one-year survey of vulnerable groundwaters. AB - Somatic salmonella (SS) phages were commonly found in higher numbers than F specific RNA (FRNA) coliphages in a multi-site survey of contamination-vulnerable groundwaters. The relative abundance of SS phages required that a pretreatment procedure be implemented to reduce the SS phage content of samples before FRNA coliphage assay with Salmonella typhimurium WG49. Pretreatment involved selective SS phage removal by Salm. typhimurium WG45 cells. This pretreatment proved effective in producing interference-free samples throughout the one-year survey period and in seeded evaluation, was shown not to affect the detection of representative FRNA coliphage MS2. During the survey, 30 groundwater sites located in the continental United States, Puerto Rico and the Virgin Islands were examined for FRNA coliphages and SS phages at monthly intervals. FRNA coliphages were detected at six of the 30 sites and in 33 of 329 monthly samples. SS phages were also detected at six sites and in 28 of 329 monthly samples. Five of the phage-positive sites were positive for both phage groups. At those five sites, 58 monthly samples were collected during the survey period. Those 58 samples yielded an average FRNA coliphage concentration of 140 pfu per 100 l of groundwater as compared to an average SS phage concentration of 565 pfu per 100 l of groundwater. Twenty of the 58 samples were positive for both the FRNA coliphages and SS phages. In those samples, FRNA coliphages were more abundant in five samples; SS phages were more abundant in 15 samples. Because these results demonstrate that SS phage levels may often exceed FRNA coliphage levels in environmental waters, it is clear that SS phage removal procedures will greatly enhance the effectiveness of the WG49-based FRNA coliphage assay. PMID- 8679145 TI - Effectiveness of a steam-vacuum sanitizer for reducing Escherichia coli O157:H7 inoculated to beef carcass surface tissue. AB - A steam-vacuum sanitizer reduced aerobic plate counts associated with bovine faecal contamination from 5.5 log10 cfu cm-2 to 3.0 +/- 0.21 log10 cfu cm-2 on beef carcass short plates. The same beef carcass short plates inoculated with 7.6 +/- 0.09 log10 cfu cm-2 Escherichia coli O157:H7 in faeces, yielded an average residual level of E. coli O157:H7 of 2.1 +/- 0.21 log10 cfu cm-2, after steam vacuum treatments. This study demonstrates the effectiveness of a steam-vacuum sanitizer for removing E. coli O157:H7 from beef carcasses. PMID- 8679146 TI - A selective medium for the isolation of Arcobacter from meats. AB - A method, including enrichment in Arcobacter Selective Broth (ASB) and isolation on semisolid Arcobacter Selective Medium (ASM) under aerobic conditions at 24 degrees C, is described for the isolation of Arcobacter from retail meat products. Selective agents used in ASB and ASM were cefoperazone, trimethoprim, piperacillin and cycloheximide. Arcobacters were isolated from 53 (24.1%) of 220 poultry meat products and also, at lower incidence from samples of beef and pork. The isolates were identified as A. butzleri or A. butzleri-like and belonged to a wide variety of serotypes and biotypes. PMID- 8679147 TI - Reduction of Brochothrix thermosphacta on beef surfaces following immobilization of nisin in calcium alginate gels. AB - Lean and adipose beef carcass tissues inoculated with Brochothrix thermosphacta (BT) (approx. 4.50 log10 cfu cm-2) were left untreated (U) or treated with 100 micrograms ml-1 nisin (N), calcium alginate (A) or 100 micrograms ml-1 nisin immobilized in a calcium alginate gel (AN). Tissue samples were refrigerated after treatments and bacterial populations and nisin activity were determined at 0, 1, 2 and 7 d. U, A and N treatments of lean and adipose tissues did not suppress bacterial growth ( > 6 log10 cfu cm-2 by day 7) while treatments of lean and adipose tissues with AN suppressed bacteria ( > 2.42 log10 cfu cm-2 by day 7). Bacteriocin titres from both tissues were higher in AN vs N samples after the 7 d incubation. This study demonstrates that immobilization of nisin in a gel may be a more effective delivery system of a bacteriocin to the carcass surface than direct application. PMID- 8679148 TI - The potential uses of high-dose-rate brachytherapy in patients with head and neck cancer. AB - Brachytherapy has proven to be an extremely valuable method of treatment for head and neck cancer. The data supporting its application, however, is based on continuous low-dose-rate brachytherapy. To benefit from improved radiation protection, outpatient treatments, and increased patient tolerance of treatment set-up over that encountered in conventional low-dose-rate manually afterloaded brachytherapy, we implemented a high-dose-rate remote afterloading approach in selected patients with head and neck cancers. This treatment was utilized in two different roles in managing 29 patients. In its first role, it was used as the sole treatment in 13 patients with T1-2 N0 malignancies. A total of ten treatments of 450-500 cGy each were delivered twice a day with a minimum of 5-6 h between treatments. With a median follow-up of 9 months, only 1 patient failed locally. In a second role, brachytherapy was applied in a post-operative adjuvant setting following wide local excision of tumors in patients who presented with recurrent disease (12 cases) or a second primary in the head and neck (4 cases). All patients had previously received external irradiation to the head and neck. Due to this previous course of irradiation, only eight treatments of 300 cGy each were delivered, for a total of 2400 cGy over a period of 4 days. However, with a follow-up of 2-16 months, only 3 patients remain disease-free. PMID- 8679149 TI - Comparison of preoperative computed tomographic findings with postoperative histopathological findings in laryngeal cancers. AB - In this study of 22 patients with laryngeal cancer, computed tomographic (CT) scans in the axial plane were compared with histopathological sections prepared in the same plane. The value of the preoperative CT for evaluating tumor invasion, location and size was then investigated. Findings demonstrated that CT was most sensitive in determining tumor invasion to the paralaryngeal and preepiglottic spaces, anterior and posterior commissures and subglottis. In contrast, CT was less sensitive in determining actual tumor invasion to the laryngeal cartilages, extralaryngeal tissues and metastases to cervical lymph nodes. PMID- 8679150 TI - Light and transmission electron microscopic studies following frontal sinus obliteration with ionomer cement in cats. AB - Osteoplastic frontal sinus surgery in combination with sinus obliteration can be performed for various indications, including chronic sinusitis, frontal sinus trauma and removal of osteomas. In an experimental study using cats, the mucous lining of the frontal sinus was removed, the nasofrontal duct sealed with semifluid ionomer cement and the cavity filled with Ionogran, a solid and porous bone substitute based on ionomer cement. Histological investigations up to 1 year after surgery showed increasing sinus obliteration by regenerating bone, starting from the sinus wall, and formation of connective tissue between the cement grains. There was no evidence for mucosal regeneration. Electron microscopic examination of the interface between the cement and connective tissue revealed mesenchymal cells, collagen fibers and areas of mineralization in close contact with the implant material. Newly formed connective tissue matrix in intimate contact with the cement was a good indication for biocompatibility of the material and is a possible explanation for the implant's solid adhesion to bone. The present findings indicate that Ionogran is a suitable alloplastic material for experimental frontal sinus obliteration in cats. PMID- 8679151 TI - A new biochemical assay in the diagnostic management of nasal cerebrospinal fluid leakage. AB - A new method for the detection of cerebrospinal fluid (CSF) leakage is described, and is a refinement of the method originally reported by Oberascher and Arrer in 1986. Immuno-electrophoretic measurements are performed in a two-buffer system, making the test easier to do and providing qualitatively better images. Genetic variants of transferrin (which has a general population incidence of 2-4%) can be discriminated from false-positive test results in affected families. The test described is recommended as the method of choice for initial screening of suspected CSF leakage. PMID- 8679152 TI - A modified technetium-99m isotope test to measure nasal mucociliary transport: comparison with the saccharine-dye test. AB - In this study two indirect mucociliary transport tests were compared. Nine subjects underwent duplicate saccharine-dye tests and duplicate modified technetium-99m (99mTc) tests, in which the radioactive 99mTc was nebulized in the nostril by means of a pump spray. The efficacy of mucociliary transport was deduced from the transport time of saccharine, dye and 99mTc. Transport rate also provided additional information in the 99mTc test. Transport rate correlated best in the repeated tests (r = 0.46), but was not significant (P = 0.21). Use of a pump spray for the 99mTc test instead of placement of a single droplet on the nasal mucosa makes the test easier to perform. PMID- 8679153 TI - A comparison of transcranial magnetic stimulation with electroneuronography as a predictive test in patients with Bell's palsy. AB - The aim of this study was to examine the neuronographic findings of electrical and transcranial magnetic stimulation of the facial nerve and to compare their ability to predict clinical recovery from idiopathic facial nerve palsy (Bell's palsy). Eighty-six patients were examined clinically and neurophysiologically immediately on presentation to Tampere University Hospital. Electroneuronography (ENoG) and transcranial magnetic stimulation (TMS) were performed 1-6 times for each patient. The time interval between each examination varied from 2 to 7 days. Seventy-eight patients were followed for a median period of 13 months after the onset of palsy. Facial nerve function was graded according to the House-Brackmann grading system. Relative amplitude differences of ENoG and TMS during the acute phase were then correlated with clinical outcome. Statistical analysis of the results showed that a TMS response elicitable during the first 5 days of the palsy was correlatable with a good prognosis. ENoG results correlated with clinical outcome at a later time from onset of symptoms. TMS was well tolerated and no adverse effects were seen. These results indicate that TMS is a useful method for the early prediction of outcome in patients with Bell's palsy. PMID- 8679154 TI - The rheological characteristics of nasal mucus in patients with rhinitis. AB - In this paper we have analyzed the physical properties of nasal mucus from 120 outpatients with rhinitis. We focused on the most relevant rheological features: viscosity, elasticity, adhesiveness, as well as ability to be spun ("spinability") or poured ("pourability"). A double-capillary type viscometer was used to measure viscosity and elasticity and the platinum ring method to measure adhesiveness. "Spinability" was measured with an automatic apparatus (Filancemetre Sefam) and "pourability" was determined by describing flow under gravity. Efficacy of nasal clearance was analyzed by measuring mucociliary transport time with an inert tracer using vegetal charcoal powder. Results showed that impaired nasal mucosal function in patients with rhinitis could be determined by studying rheological features in addition to measuring mucociliary activity. Information provided proved invaluable when considering possible treatment with agents affecting kinesis of nasal mucus. PMID- 8679155 TI - DNA index, cellular proliferative activity and nucleolar organizer regions in cancers of the larynx. AB - The DNA index, expression of cell-cycle-related proteins--proliferating cell nuclear antigen (PCNA, cyclin) and Ki-67--and the content of silver-binding nucleolar organizer regions (AgNORs) were evaluated in 30 unselected consecutive primary squamous cell carcinomas of the larynx. Results were compared and subsequently related to histological grading, lymph node status, pT category, and pathological stage. DNA content was non-diploid in 9 cases (30%). Mean AgNOR counts per tumor ranged from 2.52 to 8.76. PCNA and Ki-67 expressions were similar in 10 cases (33%). In the remaining cases, PCNA-positive cells usually outnumbered Ki-67-positive cells. No significant correlation was found among DNA index, PCNA and Ki-67 expressions, and AgNOR counts. Although there was a positive trend when Ki-67 was compared with histological grading, findings were not statistically significant. In contrast, a significant correlation was found between DNA index and lymph node status (P = 0.035), with a higher incidence of neck node metastases in non-diploid tumors. These data suggest that tumor ploidy can be correlated with lymph node spread in laryngeal squamous cell carcinoma and might be used as an additional prognostic factor when planning treatment. PMID- 8679156 TI - Immunohistochemical examination of 11 cell lines derived from human head and neck squamous cell carcinomas, their recurrences or metastases. AB - Since in vitro derived tumor cell lines usually correspond to their tumors of origin, a potential biological difference between a primary tumor and its derivative metastases and recurrent tumors should be reflected in established tumor cell lines. The aim of this study was to determine useful cellular markers in permanent tumor cell lines of head and neck squamous cell carcinomas (SCC) and to evaluate a possible relationship between these markers and the origin of selected cell lines. The cell lines, established in the laboratory of T. Carey at the University of Michigan (UM) (Ann Arbor, Mich., USA), were derived from primary tumor and its metastases (UM-SCC 10A, 10B), primary tumor and its recurrent tumors (UM-SCC 14A, 14B, 14C) and single tumors (UM-SCC 11B, 17A, 22B). An additional tumor cell line (HLac 79) was isolated by H.-P. Zenner (Tubingen, Germany) and a clone (8029 NA) with its cisplatin-resistant subline (8029 DDP4) was established in our laboratory. As markers we chose three groups known to be related to growth behavior and/or tumor differentiation: cytoskeletal proteins, oncogene products and membrane-associated antigens. These markers were detected by immunohistochemical methods using commercially available monoclonal antibodies. The "metastatic" and "recurrent" cell lines showed changes in comparison to the corresponding "parental" lines, which could be associated with a higher degree of de-differentiation, such as the occurrence of vimentin and neuroectodermal proteins, loss of HLA-ABC or HLA-DR and increased expression of epidermal growth factor receptor. The expression of cytokeratins was more stable and dissociation of the classical cytokeratin pairs was observed only in a few cases. Oncogene products were practically identical in cell lines from parental and recurrent or metastatic tumors. These data serve not only as a basis for further experiments with these cell lines but also provide information about the biological significance of various markers in newly established cell lines from primary tumors. PMID- 8679157 TI - Immunohistochemical demonstration of c-myc oncogene product in middle ear cholesteatoma. AB - Cholesteatoma epithelium is characterized by a dysregulation with a hyperproliferative growth and altered differentiation. In a variety of cells c myc oncogene was found to be highly linked to the control of growth and differentiation. Expression of c-myc was studied in cholesteatoma epithelium using a monoclonal antibody directed against the 67 kDa c-myc protein product and the alkaline phosphatase-antialkaline phosphatase method. For quantitative analysis a computer-linked analyzing system was used. In contrast to normal skin, keratinocytes of basal and suprabasal layers showed nuclear staining in cholesteatoma epithelium. The extent of nuclear staining of epithelial cells in the cholesteatomas studied was significantly increased. Concurrent cytoplasmic staining was observed in both skin and cholesteatoma, but with a stronger reactivity in the latter. These findings suggest participation of the c-myc oncogene in cholesteatoma epithelium. PMID- 8679158 TI - Inverted ductal papilloma of minor salivary gland origin: morphological aspects and cytokeratin expression. AB - Ultrastructural features and cytokeratin expression of inverted ductal papillomas of minor salivary gland origin were studied. Under the electron microscope, an increased number of desmosomes and mucus-like granules in some cells were the most striking features. Immunohistochemical study revealed that tumor cells displayed strongly positive reactions with cytokeratins 13 and 14, and less strong reactions with cytokeratins 7, 8, 18 and 5D3. These results support the hypothesis that an inverted ductal papilloma can be derived from the proximal portion of a salivary gland excretory duct. PMID- 8679159 TI - Trace elements in chronic sinusitis. AB - Trace elements are indispensable for life and play an important role in the immunological system. Since it is believed that serum trace element values decrease in chronic infections, 43 patients with chronic sinusitis were evaluated for Zn, Mg and Cu levels. While all trace elements were found to be within normal ranges, Cu values were found to be significantly lower than in a control group of 20 age- and sex-matched volunteers. The reasons for this are unclear in the present study. PMID- 8679160 TI - Primary non-Hodgkin's lymphoma of the temporal bone. AB - A rare case of primary non-Hodgkin's lymphoma in the mastoid cells of a 2-year old boy is presented and the available literature reviewed. PMID- 8679162 TI - The possible roles of hormones and enzymes in the production of the acute attack in Meniere's disease. PMID- 8679161 TI - A petrous bone destructive acoustic neurinoma: a tumor of far-lateral origin? AB - We report a case of an acoustic neurinoma that recurred more than 11 years after "total" tumor removal through the posterior cranial fossa. Recurrent tumor had obliterated the petrous bone, filled the middle ear, and was visible grossly at the external auditory meatus. The unique behavior of this tumor implied that the site of origin was within the labyrinth, beyond the fundus of the internal auditory canal and far lateral to the usual site of acoustic neurinoma origin. We offer an hypothesis as to why these tumors occasionally recur, even after clinical "total" removal. PMID- 8679163 TI - [Epidemiology of invasive infections with Haemophilus influenzae type b in the world and in Italy]. AB - The incidence of Haemophilus influenzae type b (Hib) disease in the 0-5 years age group has been studied in many countries. In the United States, before the introduction of mass vaccination, the incidence of invasive Hib disease ranged from 7 per 100,000 in the 4-5 years age group to 452 pert 100,000 in the 6-11 months age group. In Europe, the incidence of this disease has been estimated to range from 21 to 60 per 100,000 per year in the 0-5 years age group. Hib infection is mainly transmitted by the respiratory route. Risk factors of the disease include: attending a day-care center, a high number of household members, low socio-economic level, age less than two years, and belonging to certain ethnic groups. Accurate estimates of the incidence of invasive Hib disease do not exist in Italy. Among the 15,601 children participating in the "Progetto Pertosse", a clinical trial for the evaluation of antipertussis vaccines, there occurred six cases of Hib meningitis, one of Hib sepsis, and one of Hib cellulitis. These episodes yield an incidence density of 28.7 per 100,000 person years in the 2-30 month age group. Incidence data will also need to be collected for children in the 30 months-5 years age group before attempting a cost-benefit analysis with the aim of planning a mass vaccination. PMID- 8679164 TI - [Vaccinal coverage for measles and pertussis: a study in 7 regions of Italy]. AB - During the year 1993 a series of surveys aimed to estimate the immunization coverage against measles and pertussis have been carried out in seven Italian regions and two large towns (Milan and Naples). Mothers of children aged between 12 and 23 months, randomly selected from the list of newborns, by using the EPI cluster sampling, have been interviewed in order to determine the reasons for absent or incomplete vaccinations. The observed coverage for pertussis ranges between 8% in the Molise region and 71% in the town of Milan; coverage for measles ranges between 9% in the town of Naples and 52% in the region Lombardy. The most commonly reported reason for not-vaccinating for pertussis has been the negative advise given by the caring physician. Immunization against measles has often not been administered because of relative contraindications and the negative advise by the physicians. The coverage for the two non-compulsory vaccinations are low compared to compulsory vaccinations and to the immunization level reported for most European countries, pointing out that further health education is needed for improving the up-take of such voluntary vaccinations. PMID- 8679165 TI - Hepatitis B vaccination in young nurses of a general hospital. AB - Several reports have clearly demonstrated that intradermal way of administration of hepatitis B vaccine represent a valid alternative to the intramuscular route, producing an high percentage of seroconversion. The characteristics of the intradermal way, short time of immunization and lower cost, have induced us to conduct a clinical trial among 116 healthcare workers in a hospital setting, which represent an high risk group especially at their first admission to the hospital. 99 selected participants (average age 22 years, range 17-27) received, after screening for HBV markers, 5 mcg of vaccine intradermally on the volar surface of the forearm, according to the schedule 0, 15, 30 and 45 days. Serum samples were collected after one month from the last inoculation of vaccine. The percentage of seroconversions obtained was significantly high (93.9%) confirming that intradermal vaccination with hepatitis B vaccine may be appropriate in providing a rapid protection for certain population subgroups. PMID- 8679166 TI - [Epidemiology of breast carcinoma]. AB - With the aim of strengthening epidemiological knowledge on breast cancer, the authors analyze the geographical and temporal distribution of mortality and incidence of the neoplasy in Italy and other countries in the world; attention is focused on recent years and on the influence that the year of birth, the period and age of death have on Italian mortality trend. Analysis of the latest available data confirm the great variability in distribution of breast cancer in different countries of the world, with greater frequency in economically advanced western countries, urbanized and industrilized areas, white women and in higher socio-economic classes. The incidence of breast cancer in the world shows a continuous increases which is more evident and rapid in the countries and among the ethnic groups that were until now in lower risk categories. In Italy, during the period between 1950-88, there is a steady increase in the mortality rate, more evident in the first 20 years. The cumulative rates 25-49 years and 50-75 years demonstrates that the essential contribution to the trends is due to the mortality of elderly women. It is plausible that this trend is influenced by the increased survival, although a different cohort effect due to the exposure to different risk factors is possible. The cohort analysis of mortality shows a sharp cohort effect: the mortality increases in an evident way for all cohorts until those born in 1925, afterwhich we find a tendency towards reduction. The identification of specific reasons that are the basis of the observations can contribute to the knowledge of breast cancer eziology. PMID- 8679168 TI - [Functioning of the sterilization equipment used in the surgical departments of a Roman hospital]. AB - The Authors describe the results of a surveillance program on the efficacy of autoclaves used in the surgical wards of a large hospital in Rome. Data show that only 2.8% of the tests performed with UNI methodology was unfavourable, while the percentage rise to 12.5% for autoclaves following the "flash cicle". In conclusion, the Authors suggest to expand the routine surveillance to all autoclaves of the hospital and to use the "flash cicle" only for the emergency. PMID- 8679167 TI - [Epidemiological analysis of nosocomial infections at the "Arcispedale St. Anna" in Ferrara between 1989 and 1991]. AB - The Authors describe the results of an epidemiology project on nosocomial infection performed from 1989 through 1991 at the "Arcispedale S. Anna", Ferrara, Italy. Data are considered from 4.183 patients who were hospitalized for surgical treatment and intensive care: 301 patients (7.2%) developed 402 episodes of infection, namely 1.34 infections per patient. 8.2% of the patients who underwent surgery had at least one infection, while 3.9% of the those who did not have surgery showed at least one infection. The majority of infections came out higher among those submitted (11.4%) than among those not submitted (4.4%) to antibiotic prophylaxis. Infections were caused by both Gram+ and Gram- bacteria, and often the infections were polimicrobial. PMID- 8679169 TI - [Environmental hygiene characteristics of gymnasia in the city of Pescara]. AB - The Authors carried out a survey in 25 gyms in the city of Pescara during the period May-July '93 to evaluate their building characteristics, management and organization and to assess microclimate and microbial contamination of the indoor environment. Most of the gyms were not in conformity with the current regulatory issues and because of the lack of basic requirements, e.g. climatisation, the microclimate, expressed as comfort indexes, was by far inadequate. The microbiological findings clearly demonstrated poor hygienic conditions particularly in dressing-rooms and toilets. The Authors, given the inadequacy of most of the gyms examined, point out the need of specific mandatory regulations to assure acceptable levels of indoor climate, hygiene and safety. PMID- 8679170 TI - [Nematodes in drinking water: analysis of an Italian case]. AB - The paper describes an infestation by nematodes in a municipal drinking water plant in Eastern Italy. The procedures for detecting the public health significance of these presences and the measures for avoiding risks for population are reported. Furthermore the preliminary results of the analyses of water from a pilot plant carrying a Diatomeaceus Hearth Filtration are reported. PMID- 8679171 TI - [Relationships between the National Health Service and universities as regulated by the legislative decree of 30 December 1992, No. 502 and its successive modifications and integrations]. AB - The mutual relationship between the Schools of Medicine and the Italian National Health Service are discussed according to the commitment following the implementation of the new Health Service reorganization. The organization of teaching hospitals and the curricula for health professionals are considered in order to highlight their possible impact on the new organization. New opportunities seem to arise for the medical schools to improve the level of quality of their performance according to the aims and objectives of the National health plan for the years 1994-1996. Three topics are discussed in depth (i) the improvement of skills for health managers, (ii) the role of health service research in planning and evaluating the way health care is delivered with particular attention payed to the impact of DRGs as system of payment recently introduced for financing hospitals and community services. Finally it seems reasonable to expect a rise of quality in teaching programs and the development of newly designed ones for continuous training according to the needs of the health care system. PMID- 8679172 TI - [General practice and preventive activities in a Local Health Unit in Lazio]. AB - The Authors describe the results of a survey addressed to evaluate GP's opinions and behaviours regarding prevention. The GP's report they offer health informations about cardiovascular diseases and diabetes very often (score 3.6 and 3.4) and junior doctors (under 45 year) satisfy this request significantly more than senior doctors (p = 0.0057). The GP's consider their clinics the best place were to carry out health promotion activities (score: 3.8) and 85% of them would like to have a health promotion centre within their District (in italian: Local Health Unit), mainly to increase the coordination of GP's activities. PMID- 8679173 TI - [Incidence of Haemophilus influenzae type b meningitis in Italy. Preliminary results]. AB - The Authors describe the survey's results aimed at quantifying the Haemophilus influenzae type b meningitis incidence rate in Italy. The survey collected all the cases of 1994 notified per region to the Ministry of Health; furthermore, regional incidence rates are compared and integrated with other data obteined from local ad hoc studies. The results obtained show a high incidence in the age group 0-2 years and a large discrepancy in the incidence rate between regions (from 0.0 to 16.8 cases per 100,000); furthermore, in the same age group, for a large amount of meningitis cases (18% of the total) the aetiological diagnosis was not successful; this phaenomenon is certainly one of the causes for the underestimation of the disease. The integration with data collected in longitudinal studies, increases largely the regional incidence rate, showing the highest rate in the Lazio Region (18.5 cases per 100,000). The Authors conclude by stressing the need to increase the cooperation between the Regional Health Authorities and the Ministry of Health, in order to obtain more reliable figures of the national incidence rates. PMID- 8679174 TI - [Use of the economic evaluation in the comparison of different vaccination programs against Haemophilus influenzae type b disease]. AB - Although economic evaluation offers a relevant contribution to the health policy's choices, only few studies appeared so far on its application to the field of vaccinations. The present study compares several hypotheses of vaccination strategies in order to evaluate the opportunity to introduce a vaccination program against Haemophilus influenzae b infection. The vaccination strategies are evaluated in terms of costbenefits, cost-effectiveness and cost utility. The results show that the highest benefits could be obtained performing mass vaccination in the age-group 0-5 years. Actually this hypothesis, compared to other, offers the best compliance and externalities; furthermore it has the highest ethical value. PMID- 8679175 TI - [Notes on cases of meningitis admitted to the Ospedale Cotugno of Naples in the period 1987-91]. AB - The notification of the cases of meningitis admitted to the Hospital Cotugno of Naples in the period 1987-91 were analyzed by a retrospective study: aim of the study was to outline the epidemiological trend of meningitis and to evaluate the quality of the data around the change of the reporting system, which took place in 1991. We examined 566 clinical charts, selecting only the cases whose agents were identified. Our data agree with the national and international literature, with the exception that the majority of cases were produced by S. pneumoniae. Moreover, the data about tuberculous meningitis still show that the highest incidence occur in youth, while other Authors noticed a trend toward older ages. Further studies are in progress to improve the knowledge of tuberculous meningitis in our Country. PMID- 8679176 TI - [Hepatitis C in Italy in 1992: analysis of individual reports]. AB - The Authors examined the individual reporting forms of Hepatitis C infections received by the Communicable Diseases Reporting Centre of the Ministry of Health during the year 1992. Thanks to the adoption of a point estimator, 1448 cases of viral hepatitis C have been sorted out. The incidence rate of Hepatitis C has been, on the whole, 2.8 per 100,000, 3.9 for males and 1.9 for females. The highest incidence by age was observed at 20-29 y, and also among women aged 60-69 y. Moreover, the incidence was higher in the low socio-economic classes. Analyzing the data by geographical area, the highest incidence (11.8 per 100,000) was observed in the Basilicata Region, and the County of Potenza, in that Region, reached up 16.7 per 100,000. PMID- 8679177 TI - [AIDS-related knowledge and sex behavior: a review of Italian studies of young people]. AB - To plan further AIDS health promotion programmes information is needed about knowledge and attitudes relating to HIV infection among the general public. This article reviews the results of Italian studies conducted from 1990 to 1994 on young's knowledge and behaviour related to HIV infection. Eighteen studies were identified. The results show a good level of knowledge of the means of transmitting the virus, but suggest that the information does not necessarily involve a change in attitude and behaviour. PMID- 8679178 TI - [Distribution of blood lead level in a general population]. AB - The goal of this study was to evaluate the distribution of blood lead level (B.L.L.) in a general adult population aged between 20 and 79 years non professionally exposed to lead, and to verify the influence on B.L.L. of demographic variables (i.e. sex and age), behavioural habits (i.e. alcohol consumption and cigarette smoking), and anthropometric variables (i.e. body mass index--BMI). We studied the distribution of B.L.L. by explorative analysis method (E.D.A.), which showed that data did not follow a Gaussian distribution. Distribution fit to normality was determined by Shapiro-Wilk test, that identified the natural logarithm of B.L.L. as the best transformation in order to normalize the parameter. According to literature data, sex appears one of the most important variable in determining B.L.L. In both sexes we found a direct relation between B.L.L. and age. Alcohol consumption emerged as the third most important variable that influences B.L.L. BMI and cigarette smoking do not influence data distribution. PMID- 8679179 TI - [Foodborne diseases: a survey on working methods used by 6 Public Health Services in the Lombardy Region. 1. Outbreaks]. AB - Since foodborne diseases, especially those caused by bacteria, have become an increasingly important public health problem, the Authors conducted a survey in order to evaluate the organization of, and the intervention carried out by, six Public Health Services in the Lombardia region, after reports of foodborne diseases outbreaks. Lack of correct methodology was detected, not to mention the usual omission of epidemic curves and attack rates. Besides, too many microbiological tests were made and it took too much time to take care of and to report the outbreaks to Regional and National Health Authorities. Forty-one outbreaks were examined: 415 cases occurred (AR: 28.7%), most of which home-made food-related. In 25 outbreaks the suspected food vehicles were eggs or fish, but only 5 of them were confirmed by laboratory tests. Salmonella enterica, either serovar Eenteritidis or group D, appeared responsible for 26 of the outbreaks [corrected]. PMID- 8679180 TI - [Research and sanitary significance of the presence of heavy metals in cow's milk produced in the Province of Rome]. AB - The presence of Lead, Mercury, Cadmium and Chromium has been estimated in the cow's milk produced in the Rome County. The results show the presence of the metals in cow's milk in different concentrations (5.6-102 micrograms/kg for Pb; 0.9-38 micrograms/kg for Hg: 2.3-53 micrograms/kg for Cr; only one sample positive at 0.77 microgram/kg for Cd). The sanitary evaluation of the data was based on the amounts of metals theorically assumed with milk, and compared with the "tolerable" values as suggested by International Organizations. PMID- 8679181 TI - [Dental health and the state of oral hygiene in an elderly population in Rome]. AB - The purpose of this study was to investigate dental conditions and oral hygiene in a population of 369 elderly people residing in Rome--293 females and 76 males- aged between 60 and 99 years (mean 81.9 +/- 8.1). The sample was interviewed following a dental examination. Clinical tests revealed that 40% were totally edentulous, whereas subjects with natural teeth had a mean of 11.4, teeth, of which 1.5 were decayed. Oral hygiene habits were investigated by means of questions on use of dental tools (toothbrush, mouth-wash, dental floss), which were not much used. Moreover, many elderly people reported they had not been to the dentist's recently (86.2% during the last year) because they did not feel it necessary. From this study a rather low level of oral health has emerged, along with a limited knowledge of prevention for dental and periodontal diseases. These results show the need of dental treatment and prevention for the elderly population. PMID- 8679182 TI - One-step cloning of murine Fab gene fragments independent of IgH isotype for phage display libraries. PMID- 8679183 TI - Sensitive, nonradioactive differential display method using chemiluminescent detection. PMID- 8679185 TI - Generation of a combination of mutations by use of multiple mutagenic oligonucleotides. PMID- 8679184 TI - Guanidine-HCl extraction of proteins expressed in Escherichia coli using polycistronic operons based on the pUR expression vectors. PMID- 8679186 TI - Identification and cloning of integration site of DNA by PCR. PMID- 8679187 TI - PCR-mediated synthesis of exogenous competitors for quantitative RT-PCR. PMID- 8679188 TI - Rapid and gentle method for the isolation of DNA from nuclear polyhedrosis viruses. PMID- 8679189 TI - Long primers for RAPD mapping and finger-printing of grape and pear. PMID- 8679190 TI - Method for preparing YAC sublibraries in a plasmid vector. PMID- 8679191 TI - SDS-polyacrylamide gel electrophoretic analysis of proteins in the presence of guanidinium hydrochloride. PMID- 8679192 TI - Environmentally benign staining procedure for electrophoresis gels using Coomassie Brilliant Blue. PMID- 8679193 TI - Rapid Coomassie blue staining and destaining of polyacrylamide gels. PMID- 8679194 TI - Fabrication of a high-capacity rack for microcentrifuge tubes. PMID- 8679196 TI - Recovering DNA from agarose gels with pumice. PMID- 8679195 TI - Modified microassay for serum nitrite and nitrate. PMID- 8679197 TI - Immunofluorescent artifacts due to the pH of antifading mounting media. PMID- 8679198 TI - Three methods for identification of true positive cloned cDNA fragment in differential display. PMID- 8679199 TI - Internet on-ramp. Searching the Internet. PMID- 8679200 TI - Subtractive hybridization strategy using paramagnetic oligo(dT) beads and PCR. AB - Subtractive hybridization has been widely used for the identification of differentially expressed genes. Here we describe a simple, sensitive strategy of subtractive hybridization that involves binding the driver poly(A)+ RNA pool to paramagnetic Dynabeads Oligo (dT)25. After hybridization with target cDNA, the molecules common to both pools are removed. The subtracted cDNA is then amplified with PCR and used for library screening. Using this method, we have identified four cDNA clones that represent developmentally regulated transcripts in the central nervous system of the tobacco hornworm Manduca sexta. All four transcripts are of low abundance, comprising only 0.001%-0.5% of the poly(A)+ RNA pool. PMID- 8679201 TI - Multiplex-PCR-based single-strand conformation polymorphism protocol for simultaneous analysis of up to five fragments of the low-density-lipoprotein receptor gene. AB - Single-strand conformation polymorphism has become a screening method for the detection of mutations in different genes. For analysis of the promotor region and the coding sequence of the low-density-lipoprotein receptor gene by standard protocols, 21 radiolabeled PCRs and electrophoreses have to be performed. To accelerate this procedure, we developed a nonradioactive multiplex approach of the single-strand conformation polymorphism analysis. Multiplex PCRs were established, each resulting in the amplification of 4 or 5 fragments of this gene. The heat-denatured, single-stranded multiplex-PCR products were electrophoresed, blotted on a nylon membrane and visualized using a chemiluminescence detection system. The simultaneously amplified fragments were clearly resolved by their different mobility on the gel. Comparing the pattern of bands of each separately amplified PCR product and the multiplex-PCR products allowed identification of each band as one exon, part of an exon or the promotor region of the gene. To determine the sensitivity of this method, the low-density lipoprotein receptor gene of 11 patients with 11 different mutations was analyzed. All mutations could be identified in the multiplex reactions. We conclude that a multiplex-PCR-based, single-strand conformation polymorphism protocol is much faster but equally sensitive compared to standard protocols. PMID- 8679202 TI - Nonradioactive characterization of low-level heteroplasmic mitochondrial DNA mutations by SSCP-PCR enrichment. AB - Mitochondrial DNA (mtDNA) mutations have been implicated in an increasing number of human diseases. Many of these mutations are heteroplasmic and are only present at low levels in readily accessible human tissue such as blood. The technique of single-stranded conformational polymorphism (SSCP) allows the detection of mtDNA variants from peripheral blood, but characterization of these variants by automated sequencing is hampered by the low level of heteroplasmy. We have therefore developed a technique for the enrichment of mtDNA mutations that allows reliable sequence data to be obtained even if the variant mtDNA represents only 1% of the total mtDNA. The procedure involves the excision, purification and subsequent PCR amplification of selected DNA fragments from SSCP gels. The techniques can be applied to other heterogeneous mutations such as mosaic mutations in skin biopsies or somatic oncogene mutations in tumor tissue. PMID- 8679203 TI - Simple procedure for creation of in-frame deletion mutations throughout an open reading frame. AB - A general method is presented for randomly mutagenizing open reading frames (ORF) to generate in-frame deletions and insertions. The protocol requires expression of the ORF of interest as a hybrid ORF-beta-galactosidase fusion protein. This allows colorimetric screening for beta-galactosidase activity during subsequent mutagenesis steps. Consequently, proteins with no suitable phenotypic selection or screening properties can be readily screened for mutations that disrupt and subsequently restore the reading frame of the hybrid protein. In addition, this system provides gene expression for subsequent biochemical analysis of the mutant proteins. The bovine papillomavirus type 1 (BPV-1) EI ORF has been mutagenized using this method as an example. PMID- 8679204 TI - Optimization of competitor poly(dI-dC).poly(dI-dC) levels is advised in DNA protein interaction studies involving enriched nuclear proteins. AB - Procedures used for investigating DNA-protein interactions, such as the electrophoretic mobility shift assay (EMSA) or DNasel footprinting, require that exogenous nucleic acids (or synthetic equivalents) be added to the reaction mixture to prevent or reduce the nonspecific interaction of nuclear proteins with the labeled probe of choice, especially when proteins are obtained from crude nuclear extracts. One of the most potent, and likely the most widely used, non specific competitor is the synthetic polymer poly(dI-dC).poly(dI-dC). Its addition to the reaction mixture prior to crude nuclear proteins has unquestionably proven very efficient in reducing nonspecific interactions by facilitating detection of the complexes of interest. However, in certain instances, the use of crude extracts alone does not provide adequate answers and the need to further enrich such extracts becomes absolutely necessary. In this study, we provide evidence that amounts of poly(dI-dC).poly(dI-dC) well below those currently described in the literature substantially impair, or even totally prevent, the detection of specific DNA-protein complexes in EMSA when enriched, gel-fractionated or commercially purified nuclear proteins are used, therefore indicating the need to precisely optimize the amount of such a competitor in DNA protein interaction studies. PMID- 8679205 TI - Consecutive cycles of precise, unidirectional 14-bp deletions using a BseRI/BsgI trimming plasmid. AB - A straightforward method for generating precise, consecutive, unidirectional 14 bp deletions into cloned DNA, adopted from the trimming principle developed by Szybalski and his colleagues, is presented. The method utilizes pTRIM14, a plasmid constructed with the class-IIS restriction enzyme recognition sites for BseRI and BsgI arranged in the form of a cassette, just upstream from the cloned DNA. Class-IIS restriction enzymes cleave DNA downstream of their recognition sites. pTRIM14, containing the cloned DNA, is processed through a trimming cycle that involves sequential restriction digestions with BsgI and then BseRI, followed by treatment with Mung Bean nuclease and then with ligase. One trimming cycle results in a net 14-bp deletion. We demonstrate precise, consecutive deletions at very high efficiency. PMID- 8679206 TI - Identification of biotinylated molecules using a baculovirus-expressed luciferase streptavidin fusion protein. AB - A genetic fusion between streptavidin of Streptomyces avidinii and luciferase of Pyrophorus plagiophthalamus was constructed. The fusion protein was produced in the Sf9 insect cell line using the baculovirus expression vector system (BEVS). Sodium dodecyl sulfate polyacrylamide gel electrophoresis of the proteins from cells infected with the recombinant virus, VL1393-LucGR-StreptAv, revealed that the fusion protein migrated with an apparent molecular weight of 75 kDa. Light emission measurements showed that the infected cells produced about 255 mg of the chimeric protein per liter of cell culture (127.5 micrograms/1 x 10(6) cells). Precipitation of the LucGR-StreptAv fusion protein with biotinylated acrylic beads as well as immunoblot analyses using biotinylated immunoglobulins indicated that both fusion moieties of the chimeric protein product were functional with respect to their physical and enzymatic activities. PMID- 8679207 TI - Generation of high-titer defective HSV-1 vectors using an IE 2 deletion mutant and quantitative study of expression in cultured cortical cells. AB - Vectors based on herpes simplex virus type 1 (HSV-1) show promise for gene transfer into mammalian cells because of their wide host range, efficient infection and ability to deliver genes to nondividing cells. Defective HSV-1 vectors, or amplicons, are plasmid vectors which are unable to propagate on their own but contain specific HSV-1 sequences that, in the presence of helper virus, support DNA replication and subsequent packaging into virus particles. We compared three replication-incompetent HSV-1 mutants (KOS strain 5dl1.2, strain 17 D30EBA, KOS strain d120) as the helper virus for packaging the prototype defective HSV-1 vector, pHSVlac, which uses the HSV-1 immediate-early (1E) 4/5 promoter to regulate expression of the Escherichia coli lacZ gene. Use of 5dl1.2, which contains a deletion in the IE 2 gene, consistently produced virus stocks that contained a high level of vector, undetectable levels of wild-type HSV-1 and a ratio of vector to helper greater than 1. Virus stocks prepared using 5dl1.2 were superior to those prepared using helper viruses that harbor a deletion in the IE 3 gene, either D30EBA or dl20, and supported more efficient gene transfer than possible with previously published procedures. Lactate dehydrogenase efflux assays in rat cortical cultures showed that 5dl1.2 was no more cytotoxic than either D30EBA or dl20, despite the expression of more viral genes. Rat cortical cultures infected with pHSVlac packaged with either 5dl1.2 or D30EBA were used to quantify the stability of vector expression. Our results show a decrease in the number of cells with detectable levels of beta-galactosidase to 30% of peak levels after one week, irrespective of the helper virus used. However, simultaneous superinfection with 5dl1.2, but not with either D30EBA or dl20, produced a transient increase in the number of cells expressing beta galactosidase. Superinfection with 5dl1.2 at 9 days after gene transfer increased the number of cells expressing detectable beta-galactosidase back to peak levels, most probably because of reactivation of the IE 4/5 promoter in pHSVlac. These results thus provide the first quantitative demonstration of long-term persistence of defective HSV-1 vectors in neurons. PMID- 8679208 TI - Quantitative RT-PCR on CYP1A1 heterogeneous nuclear RNA: a surrogate for the in vitro transcription run-on assay. AB - A quantitative reverse transcription polymerase chain reaction (RT-PCR) assay was developed to amplify a region of the CYP1A1 heterogeneous nuclear RNA (hnRNA) transcript encompassing the first intron-exon boundary. The RT-PCR protocol uses a CYP1A1 recombinant RNA internal standard identical to the target hnRNA except for an engineered unique internal restriction site. Its inclusion enables normalization between reactions and a measurement of the absolute number of target hnRNA transcripts. Specificity for the hnRNA was achieved by using intron directed primers in both the RT and the PCR. Nuclear run-on assays and the hnRNA RT-PCR assay detected an equivalent increase in transcription of Cyp1a-1 in cultured murine Hepa 1c1c7 cells following exposure to 2,3,7,8-tetrachlorodibenzo p-dioxin (TCDD). The RT-PCR assay also revealed TCDD-dependent transcriptional activation of the Cyp1a-1 gene in murine skin, a tissue unsuited to the nuclear run-on assay because of inherent difficulties associated with the isolation of nuclei. These examples demonstrate that the hnRNA RT-PCR assay is a facile surrogate for the nuclear run-on assay. Moreover, the sensitivity and design characteristics of the RT-PCR assay suggest the potential for its broad application in general transcriptional research. PMID- 8679209 TI - High and low annealing temperatures increase both specificity and yield in touchdown and stepdown PCR. AB - Touchdown (TD) PCR represents a versatile one-step procedure for optimizing PCRs even if the degree of primer-template complementarity is not fully known. The protocol relies on incremental annealing temperature decreases in progressive cycles designed to bracket the melting temperature (Tm) of the reaction. Here we investigate the characteristics of TD PCR that serve to minimize the need to optimize annealing temperature or buffer conditions and yet produce single strong target amplicons. We demonstrate that priming initiates above the optimum annealing temperature; this helps to ensure a competitive advantage for the target amplicon. On the other hand, as the cycling program progresses, annealing temperatures well below the Tm can serve to significantly increase yields in reactions that would otherwise be marginal due to suboptimal buffer composition and yet do not promote spurious amplification. Modified forms of TD PCR, termed stepdown PCR, consisting of fewer but steeper incremental declines in annealing temperature, are also shown to be effective and can simplify thermal cycler programming. PMID- 8679210 TI - PCR with random primers to obtain sequence from yeast artificial chromosome insert ends or plasmids. AB - A technique that can be used to isolate vector/insert junctions from clones in vectors, such as yeast artificial chromosomes and P1s, and to sequence plasmid inserts more rapidly has been developed. A vector primer is combined with single, randomly chosen oligonucleotides in PCRs, to create pools of products. With 12-24 random primers used in separate reactions, a given insert junction can frequently be isolated. For plasmid inserts, multiple products are created that can be sequenced from their random-primed ends to provide internal coverage for a clone. It is often possible to sequence a significant portion of an insert with one set of reactions. The speed and simplicity of the method in each case and its use of existing techniques and reagents make it appealing. PMID- 8679211 TI - Preparation of pure plasmid or cosmid DNA using single-strand affinity matrix and gel-filtration spin columns. AB - A rapid method has been developed for ultrapure plasmid or cosmid DNA isolation from ten-mL to several hundred-mL cultures of Escherichia coli (midi to maxi prep). A cleared lysate is prepared by alkaline lysis, followed by a quick alcohol precipitation step. Denatured bacterial DNA and RNA having at least 20 nucleotides of single-stranded regions are removed from the supercoiled plasmid by binding strongly to the single-strand affinity matrix (SSAMTM). Plasmid DNA is then effectively purified on a gel-filtration spin column to remove SSAM, proteins, small RNA and salts. This method produces consistent yields of high quality plasmids that are suitable for use in many molecular biology applications. In addition, recombinant cosmids of approximately 46 kb can be purified intact, free of chromosomal DNA. PMID- 8679212 TI - Approach to an organo-typical environment for cultured cells and tissues. AB - If cells or tissues are taken out of an organ and put in culture, normally they lose morphological, physiological and biochemical features. This dedifferentiation process starts during the isolation procedure and continues during the whole culture period. It is caused by the stagnant liquid condition and the inadequate anchorage of cells at the bottom of tissue culture plasticware. The use of filters as basement membrane substitutes and the coating of cultureware with extracellular matrix proteins improve the environmental factors for cultured cells but do not consider the paracrine influence of cytokines or the nutritional needs of individual cell types. To limit cellular dedifferentiation in culture, we constructed a new system, which adapts, as far as possible, cell and tissue cultures to an organo-typical environment. The system is based on a compatible cell carrier arrangement, which allows individual selection of supports for optimal cell anchorage and differentiation. The cell carriers are placed in a newly constructed container, which is permanently perfused with fresh culture medium. The system runs outside an incubator with simple laboratory tools; only a peristaltic pump, a warming table and pH stabilized media are necessary. Without any subculturing, acute and chronic influences of drugs or the quality of medical implantation grafts can be studied over months. PMID- 8679213 TI - Repair of naphthalene-injured microdissected airways in vitro. AB - Nonciliated bronchiolar epithelial (Clara) cells, as both the primary target for metabolically activated pulmonary toxicants and the progenitor cell for repair after bronchiolar injury, are critical for distal airway epithelial function and regeneration. Previously, we described a model system whereby differentiated Clara cells can be maintained in culture using explants of microdissected distal airways. The purpose of this study is to establish whether distal airway explants can be used to study bronchiolar epithelial repair in vitro. Lungs from adult mice treated with naphthalene, a metabolically activated Clara cell cytotoxicant, or vehicle were inflated with agarose and distal airways were microdissected. Distal airway explants were cultured for up to 7 days in serum-free medium. Clara cells in explants from naphthalene-treated mice exhibited the characteristic cytotoxic responses previously reported in vivo when maintained in vitro: cell swelling, formation of cytoplasmic vacuoles, and exfoliation of injured cells into the airway lumen 1 to 2 days after injury (DAI). Epithelial cells squamated to cover the injured area 2 to 4 DAI. At 7 DAI, the epithelium generally consisted of cuboidal cells. Proliferating cells and marker proteins for differentiated Clara cells (Clara cell 10 kD secretory protein, or CC10, and cytochrome P450 monooxygenase isozyme 2B, or CYP2B) were detected immunochemically and their pattern of distribution during the injury and repair response in vitro paralleled the pattern of cell regeneration seen previously in vivo. We conclude that Clara cells in explants from defined regions of murine tracheobronchial airways can be used to study the early phases of the repair response to naphthalene injury, including differentiation and proliferation, in vitro. PMID- 8679214 TI - Hyperoxia induces platelet activation and lung sequestration: an event dependent on tumor necrosis factor-alpha and CD11a. AB - Mice were exposed to pure oxygen for various times to explore the pulmonary platelet trapping associated with alveolar damage, its mechanism, and its role in the lesions. Platelet sequestration, evaluated by electron microscopy and by injection of radiolabeled platelets, was detectable after 72 h and reached a maximum after 96 h of exposure (i.e., shortly before death). Circulating platelets (analyzed by Facscan) showed some increase in the expression of CD11a and CD62, but little change in CD31 and CD61. Both platelet activation and lung sequestration were dependent on TNF-alpha, since antibody against TNF-alpha reduced the expression of CD11a on circulating platelets and their sequestration in the lung. Lung platelet sequestration was also decreased by anti-CD11a MoAb. Northern blot analysis of lung mRNA isolated at 96 h of oxygen exposure revealed a 7-fold increase in CD54 (intercellular adhesion molecule-1 [ICAM-1]) and a 2.5 fold increase in TNF-alpha mRNAs respectively. These results demonstrate that the platelet pulmonary trapping induced by hyperoxia is dependent upon TNF-alpha and the CD11a-CD54 adhesion molecules. However, platelet trapping does not appear to play an important pathogenic role in acute oxygen injury, since treatments that decrease trapping (anti-TNF-alpha, anti-CD11a, or antibody-induced thrombocytopenia) did not markedly attenuate the alveolar damage. PMID- 8679215 TI - Surfactant associated protein-A inhibits human lymphocyte proliferation and IL-2 production. AB - The hyporesponsive state of lung-derived mononuclear leukocytes has been, in part, attributed to the effects of the lipid rather than the protein components of pulmonary surfactant. In the present study, however, the results suggest that purified preparations of pulmonary surfactant-associated protein A (SP-A) suppress both phytohemagglutinin (PHA, 1 microgram/ml)- and anti-CD-3 (1 to 10 ng/ml) activated proliferation of human peripheral blood and tonsillar mononuclear cells in a dose-dependent manner at concentrations as low as 50 pM (6.25 micrograms/ml) when added at the initiation of cultures. Addition of SP-A to PHA-stimulated peripheral blood mononuclear cells (PBMC) as late as 24 to 36 h after PHA was also capable of suppressing [3H]thymidine incorporation measured at 72 h. In contrast, concanavalin A (Con A; 2 micrograms/ml)-stimulated PBMC proliferation was slightly augmented by the addition of SP-A. Analysis of the supernatants of PHA-stimulated cultures treated with SP-A revealed that accompanying the inhibition of proliferation was a corresponding decline in measurable interleukin-2 (IL-2) concentrations, from 154 pg/ml for the PHA treated cells to 57.8, 28.4, 5.2, and less than 2 pg/ml of IL-2 when SP-A was added at 6.25, 12.5, 25, and 50 micrograms/ml, respectively. We suggest that the action of SP-A on PHA-stimulated human PBMC may involve the blocking of a costimulatory signal crucial for in vitro T-cell activation. PMID- 8679216 TI - Developmental expression patterns of CFTR in ferret tracheal surface airway and submucosal gland epithelia. AB - Submucosal glands are a major site of cystic fibrosis transmembrane conductance regulator (CFTR) expression in the human airway and may play an important role in the pathogenesis of cystic fibrosis. In humans, strategies for gene targeting to submucosal glands will likely be dependent on in utero gene transfer to submucosal gland progenitors because of the inaccessibility of these regions from the fully developed airway. However, little is known about the ontogeny of CFTR gene expression in developing submucosal glands and the potential functional role(s) CFTR may have during gland development. To this end, we describe the partial cloning of the ferret CFTR cDNA which was used for in situ mRNA localization studies in developing ferret trachea. The ferret animal model is attractive for studies pertaining to the development of tracheal submucosal glands because postnatal tracheal development in this species mirrors in utero gland development in humans. Sequence analysis of the first nucleotide binding domain (NBD1) from ferret CFTR revealed a striking homology to the human gene at both the DNA (94.4%) and amino acid level (97%). Interestingly, this high level of amino acid homology extends to a group of mammalian species (ferret, human, sheep, and bovine) which have similar lung morphologies with respect to the presence of surface airway goblet cells and submucosal glands. In contrast, mouse and rat airways which are quite divergent from those of ferret, human, sheep, and bovine species with respect to secretory cell types in the airway and abundance of submucosal glands, demonstrate significantly less homology (80%) with respect to CFTR amino acid sequence in the NBD1 domain. Given that traditional phylogenetic classification of these species does not mirror the evolutionary conservation of CFTR, such findings would suggest that certain aspects of lung morphology may be reflected in the evolutionary conservation of CFTR NBD1 amino acid sequences. CFTR in situ hybridization studies in ferret trachea demonstrate a developmental increase (3-4 fold) in CFTR mRNA expression within the surface airway epithelium between -2 day to 5 wk which mirrors an increase in ciliogenesis over this time frame. Additionally, all stages of gland development including the most primordial gland-forming buds could be seen to contain infrequent cells which highly express CFTR at a level that remained constant throughout development. Such findings suggest that differentiation of gland progenitor cells to CFTR-expressing submucosal gland cells occurs very early within submucosal gland development and morphogenesis. PMID- 8679217 TI - Pseudomonas aeruginosa and epithelial permeability: role of virulence factors elastase and exotoxin A. AB - Lung injury in bacterial infection is a multifactorial phenomenon that involves bacterial metabolites and host factors. Primary isolates of type II pneumocytes and established cultures of Madin-Darby canine kidney (MDCK) cells were used to study effects of Pseudomonas aeruginosa exoproducts on epithelial paracellular permeability. The results indicate that elastase (PE) and exotoxin A (Exo A) have different, but complementary, actions that diminish epithelial barrier function. We measured transepithelial electrical resistance (TER) and permeability coefficient for mannitol (Pm) across cell monolayers plated on tissue culture membranes. Application of 100 ng/ml of Exo A to the basal side decreased TER from 1,405 +/- 106 to 462 +/- 50 ohm (omega) and increased Pm for mannitol 6-fold in 16 h (P < 0.05). Application of Exo A to the apical side did not affect either TER or Pm. In contrast, PE (6.5 U/ml) applied either apically or basolaterally reduced TER to 353 +/- 66 omega and increased Pm by 10-fold within 90 min (P < 0.05). The increase in permeability correlated with the number of bacteria that traversed the epithelial monolayers. Fluorescent staining and western immunoblot analysis of toxin-treated cells showed that two tight junctional proteins, ZO-1 and ZO-2, were depleted in monolayers treated with enzymatically active PE. The junctional proteins decreased in cells treated overnight with Exo A but were not depleted. Neither agent diminished cell viability as measured by trypan blue staining or release of radioactivity from 51 Cr-labeled cells. Elastase from P. aeruginosa thus seems to increase alveolar epithelial permeability by damaging tight junction-associated proteins. Exo A, through its effect on protein synthesis, may render the cells unable to restore the junctional proteins and thus the functional junctions. PMID- 8679219 TI - Phenotypic analysis of airway eosinophils and lymphocytes in a Th-2-driven murine model of pulmonary inflammation. AB - In order to investigate whether the pulmonary response to helminth antigens mimics that seen in allergic inflammation of the airways, we have examined the phenotypic characteristics of lymphocytes and eosinophils recruited to the airways following Nippostrongylus brasiliensis (N.b.) infection. Specifically, the cellular response was divided into an early and a late phase. During the early response there was a small but significant increase in neutrophil numbers recovered by bronchoalveolar lavage (BAL). Phenotypic analysis of BAL leukocytes revealed an early rise in the percentage of BAL lymphocytes expressing the naive T cell markers CD45RB and L-selectin, and the activation marker IL-2R. In addition, during the early response, there was an increased percentage of lymphocytes expressing the gamma delta TCR, but not the alpha beta TCR. In contrast, the late response was marked by a much larger accumulation, in the lungs and BAL, of memory CD4+ T lymphocytes and an influx of small, hypodense eosinophils which produced LTB4 and LTC4 on stimulation with calcium ionophore. At this time there was a substantial increase in the number of T lymphocytes and eosinophils expressing ICAM-1 and the integrins VLA-4 and LFA-1, implicating these adhesion molecules in inflammatory cell recruitment to the airways. We conclude that the pattern and phenotypic characteristics of the cellular recruitment seen following N.b. infection resemble those seen in early- and late phase allergic inflammation of the airways in asthma, and therefore N.b. may be used to model these aspects of the disease. PMID- 8679218 TI - Apoptosis is observed in mesothelial cells after exposure to crocidolite asbestos. AB - Asbestos causes protracted, dose-dependent increases in steady-state mRNA levels of the proto-oncogenes c-fos and c-jun, and AP-1 DNA-binding activity in normal rat pleural mesothelial (RPM) cells (1). To determine the phenotypic end points of overexpression of these early response genes by asbestos, both cell proliferation and apoptosis were examined in confluent RPM cells exposed to a range of concentrations (1.25 to 10 micrograms/cm2 dish) of crocidolite asbestos for 24 and 48 h. Quantitation of RPM cells pulsed with 5-bromo-2'-deoxyuridine revealed that asbestos caused dose-dependent decreases in cells undergoing DNA synthesis. Decreases in cell proliferation were accompanied by dose-related increases in apoptosis using (1) terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (i.e., ApopTag technique), (2) 4',6 diamidino-2-phenylindole cell staining, and (3) fluorescent-activated cell sorter after incorporation of propidium iodide. Less striking but significant dose related increases in apoptosis were observed in RPM cells exposed to H2O2 (300 microM), and no apoptosis was seen after exposure of cells to high concentrations (10 micrograms/cm2 dish) of glass beads. Our results are unique in that they demonstrate that asbestos induces apoptosis in mesothelial cells at concentrations eliciting increased expression of the proto-oncogenes c-fos and c jun. PMID- 8679220 TI - TNF alpha is important in human lung allergic reactions. AB - Tumor necrosis factor alpha (TNF alpha) is a potentially important cytokine in allergic respiratory reactions since it is released by mast cells and eosinophils, and it can promote mediator and cytokine release, adhesion molecule expression, and granulocyte migration. Therefore, we induced an IgE-mediated response in human lung samples and studied: (1) whether TNF alpha was produced in sufficient quantities to promote granulocyte migration; and (2) which cells expressed mRNA for TNF alpha using in situ hybridization. Lung fragments (from thoracotomy) were treated for 30 min with either anti-IgE, 1:100 dilution, or buffer (control). Anti-IgE treatment of 16 lungs resulted in greater than 4-fold increase in histamine release and the significant production of chemotactic activity. The chemotactic activity generated induced dose-responsive neutrophil and eosinophil migration through naked filters and endothelial and pulmonary epithelial monolayers. Fourteen of 16 samples had a significant increase in TNF alpha subsequent to anti-IgE treatment (P < 0.05). Anti-TNF alpha antibody (4 micrograms/ml) inhibited about 25% of the neutrophil chemotactic activity in supernatants from anti-IgE treated lungs. TNF alpha at a concentration measured after anti-IgE treatment of lung samples (50 pg/ml) induced neutrophil transendothelial migration. Finally, we found that anti-IgE treatment led to an increase in TNF alpha mRNA-positive cells by in situ hybridization (1.6/ mm2 experimental versus 0.5/mm2 control), some of which were eosinophils. Thus, human lung IgE-mediated responses in vitro results in: (1) release of TNF alpha in amounts sufficient to effect a biologic response, granulocyte chemotaxis: and (2) upregulation of mRNA for TNF alpha in eosinophils and other cells. These findings suggest that TNF alpha is an important effector molecule in the pathogenesis of allergic respiratory reactions. PMID- 8679221 TI - Overexpression of Bcl-2 and mutations in p53 and K-ras in resected human non small cell lung cancers. AB - We investigated expression of Bcl-2, mutations in p53, and K-ras oncogene in 51 resected human non-small cell lung cancers. The studies were designed to test for the possibility of cooperativity between these oncogenes and p53 in the pathogenesis of lung cancer. An inverse relationship was found between expression of Bcl-2 and mutant p53 by immunohistochemistry (P < 0.01; Fisher exact test), suggesting that either Bcl-2 overexpression or mutations in p53 may fulfill a critical function in the pathogenesis of human non-small cell lung cancers. Tumors that harbored K-ras codon 12 mutations seldom had p53 mutations or overexpressed Bcl-2. Statistical analysis of these data showed that mutations in p53 and K-ras or overexpression of Bcl-2 and mutations in K-ras occurred at a frequency that could be explained only by chance [P > 0.1 in each case (Fisher exact tests)]. This suggests that cooperativity between mutant K-ras and mutant p53 or mutant K-ras and overexpressed Bcl-2 is not a common mechanism in the pathogenesis of human non-small cell lung cancers. PMID- 8679222 TI - Activation of the TNF alpha-p55 receptor induces myocyte proliferation and modulates agonist-evoked calcium transients in cultured human tracheal smooth muscle cells. AB - Evidence suggests that cytokines may modulate smooth muscle cell function in a variety of inflammatory diseases. In the present study, we characterized the specific receptor subtypes that mediate tumor necrosis factor alpha (TNF alpha) effects on myocyte proliferation and on agonist-induced calcium transients in cultured human tracheal smooth muscle cells (TSMC). Pretreatment of human TSMC with TNF alpha potentiated cytosolic calcium [(Ca2+)i] transients evoked by carbachol. In a similar manner, selective TNF alpha-p55 receptor agonists such as htr-9, an activating monoclonal antibody, or a recombinant TNF-p55 (rTNF-p55), which specifically activates the TNF alpha-p55 receptor but not the TNF alpha-p75 receptor, also augmented [Ca2+]i transients evoked by carbachol. In parallel experiments, TNF alpha, rTNF alpha-p55, and htr-9 induced human TSMC proliferation as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Interestingly, activation of the TNF alpha-p75 receptor with a selective agonist, recombinant TNF alpha-p75 (rTNF alpha-p75), or inhibition of the TNF alpha-p75 receptor with utr-1, an inhibitory anti-TNF alpha p75 receptor antibody, had no effect on TNF alpha-augmented calcium transients or on myocyte growth. To further confirm the receptor specificity of these findings, immunocytochemical studies were performed using receptor-specific antibodies. These studies demonstrated marked cell-surface expression of the TNF alpha-p55 receptor compared with expression of the TNF alpha-p75 receptor on human TSMC. Taken together, our results suggest that TNF alpha modulates agonist-induced calcium transients and induces human TSMC proliferation by specific activation of the TNF alpha-p55 receptor. Further studies addressing the cellular and molecular mechanisms regulating cytokine modulation of airway smooth muscle function may provide new insight into mechanisms that induce airway hyperresponsiveness in asthma. PMID- 8679223 TI - Apoptosis in human alveolar macrophages is induced by endotoxin and is modulated by cytokines. AB - A central factor in the pathogenesis of inflammatory and fibrotic lung disease (adult respiratory distress syndrome, sarcoidosis, idiopathic pulmonary fibrosis) is the locally elevated number of alveolar macrophages (AM). An elevation in the production rate of AM, chemoattraction and differentiation of monocytes, or a diminution in the death rate might be underlying mechanisms. The aim of the present study was to investigate the modulatory role of endotoxin and cytokines on the death rate of human AM. Lipopolysaccharide (LPS) treatment resulted in a 4 fold increase (7.6 to 30.2%) of AM death. AM death was apoptotic as assessed by in situ DNA end labeling (ISDE), transmission electron microscopy, DNA gel electrophoresis, fluorometry of fragmented DNA, and an ELISA specific for histone associated DNA fragments. Among the different bacterial cell wall components tested, LPS was the only inducer of apoptosis in human AM. None of the tested cytokines (interleukin-1 beta [IL-1 beta], IL-4, IL-6, IL-10, tumor necrosis factor-alpha [TNF-alpha], transforming growth factor-beta 2 [TGF-beta 2], interferon-gamma [IFN-gamma], macrophage colony-stimulating factor [M-CSF], granulocyte colony-stimulating factor [G-CSF], and granulocyte-macrophage colony stimulating factor [GM-CSF]) was capable of enhancing the spontaneous rate of apoptosis. However, LPS-induced apoptosis was significantly enhanced by the macrophage-activating cytokine IFN-gamma, and reduced by the macrophage deactivating cytokines IL-4, IL-10, and TGF-beta. PMID- 8679224 TI - In vivo expression of intercellular adhesion molecule 1 in type II pneumocytes during hyperoxia. AB - Cell-to-cell communication is often disrupted when tissue damage occurs, triggering new signals to cope with the injury. The expression of intercellular adhesion molecule (ICAM-1), a protein involved in the migration, binding, and activation of leukocytes, is markedly increased in mouse lungs damaged by acute hyperoxic exposure. Type I alveolar epithelial cells are sensitive to hyperoxic lung injury, and must be removed from the air spaces following their destruction. In contrast, type II pneumocytes are relatively resistant to hyperoxia and may have a role in the removal process. Two reports demonstrate increased ICAM-1 in alveoli after hyperoxia (Welty et al., 1993, AJRCMB 9:393-400; and Kang et al., 1993, AJRCMB 9:350-355), but the cellular site(s) of ICAM-1 synthesis were not determined. We hypothesized that during in vivo exposure to 100% oxygen (O2), type II pneumocytes synthesize and secrete ICAM-1, an important step in attracting inflammatory cells to the site of injury. Adult mice were exposed to 100% O2 for up to 72 h. To determine whether type II cells express ICAM-1, tissue sections were studied by electron microscopy single-label in situ hybridization or light microscopy dual-label in situ hybridization, using radiolabeled and nonradiolabeled probes. In the lungs of unexposed animals, ICAM-1 mRNA was detected in many cells-including type I pneumocytes-but not in type II cells. After hyperoxia, ICAM-1 transcripts were detected in bona fide, surfactant protein C mRNA-containing, type II alveolar epithelial cells. This observation suggests that type II cells play an important and previously unrecognized role in pulmonary inflammation from O2 toxicity and emphasizes the importance of type II pneumocytes in alveolar repair after injury. PMID- 8679225 TI - Differential expression of the urokinase receptor in fibroblasts from normal and fibrotic human lungs. AB - Binding of urokinase-type plasminogen activator (uPA) to a specific receptor (uPAR) on human lung fibroblasts enables it to regulate cellular proteolysis and remodeling of the extracellular matrix. Binding studies with radiolabeled uPA indicated that both normal and fibrotic lung fibroblasts express the receptor, but cells from fibrotic tissues bound significantly more uPA (P < 0.001). Phorbol myristate acetate, lipopolysaccharide, transforming growth factor-beta (TGF beta), and tumor necrosis factor-alpha (TNF-alpha) increased uPA binding and plasminogen activation at the cell surface, with a greater maximal effect on fibrotic than on normal fibroblasts. Excess unlabeled uPA, specific antibody, or antisense oligonucleotides inhibited uPA binding. Ribonuclease (RNase) protection assays showed higher levels of uPAR messenger ribonuleic acid (mRNA) in each of the five fibrotic cell lines than in normal fibroblasts. uPA was mitogenic for normal as well as fibrotic fibroblasts, indicating that receptor binding concurrently localizes cellular proteolytic activity and stimulates mitogenesis. Morphometry and immunohistochemical analysis showed that uPAR, as well as uPA, was increased in fibroblasts in fibrotic lung tissue. Increased expression of uPAR by fibrotic lung fibroblasts and enhanced urokinase binding induced by proinflammatory cytokines suggest a novel mechanism by which fibroblast-mediated matrix remodeling and proliferation may be regulated in interstitial lung diseases. PMID- 8679226 TI - Inhibition of the transcription factors NF-kappa B and AP-1 underlies loss of cytokine gene expression in rat alveolar macrophages treated with a diffusible product from the spores of Aspergillus fumigatus. AB - The spores of Aspergillus fumigatus have a survival advantage over other respirable fungal spores in the lung, leading to a number of lung diseases associated with this fungus. We have hypothesized that a component on the spore surface can inhibit the activation of alveolar macrophages, known to play an essential role in immune regulation in the lung. A diffusible product from the spores of A. fumigatus (AfD) inhibited the production of tumor necrosis factor alpha (TNF alpha) protein by alveolar macrophages in an enzyme-linked immunosorbent assay. Using a semiquantitative reverse transcription-polymerase chain reaction, we also demonstrated a potent inhibitory effect of AfD on the production of proinflammatory cytokine transcripts in rat alveolar macrophages. The inhibition occurred at the level of transcription, with AfD inhibiting the synthesis of TNF alpha-and interleukin 6 (IL-6)-specific mRNA transcripts. No effect was seen on the synthesis of interleukin 1 beta (IL-1 beta) cytokine transcripts or on the expression of the housekeeping gene beta-actin. Furthermore, AfD specifically inhibited the activation of nuclear transcription factors NF-kappa B and AP-1, both of which are required for the coordinate upregulation of transcription of the proinflammatory cytokines TNF alpha, IL-1 beta, and IL-6. We conclude that AfD can inhibit normal alveolar macrophage responses by selectively inhibiting the production of key inflammatory cytokines, and that the mechanism of inhibition is primarily at the level of transcriptional activation. PMID- 8679227 TI - Heme oxygenase-1: function, regulation, and implication of a novel stress inducible protein in oxidant-induced lung injury. AB - Accumulating evidence suggests that oxidative stress plays a central role in the pathogenesis of many pulmonary diseases including adult respiratory distress syndrome, emphysema, asthma, bronchopulmonary dysplasia, and interstitial pulmonary fibrosis. The morbidity and mortality of these diseases remain high even with optimal medical management. In our attempts to devise new therapies for these disorders, it is crucial to improve our understanding of the basic mechanism(s) of oxidant-induced lung injury. A major line of investigation seeks to characterize the cellular and molecular responses of the lung to oxidant insults. Much progress has been made in our understanding of the role of the "classic" antioxidant enzymes (e.g., superoxide dismutase, catalase, glutathione peroxidase) in mediating the lung's resistance against oxidant lung injury. However, it is becoming clear that other oxidant-induced gene products may also play vital roles in the lung's adaptive and/or protective response to oxidative stress. One such stress-response protein is heme oxygenase-1, HO-1. Since the identification of HO-1 in 1968, many of the studies involving this enzyme were understandably focused on the regulation and function of HO-1 in heme metabolism. This emphasis is self-evident as HO-1 catalyzes the first and rate-limiting step in heme degradation. Interestingly, however, evidence accumulated over the past 25 years demonstrates that HO-1 is induced not only by the substrate heme but also by a variety of non-heme inducers such as heavy metals, endotoxin, heat shock, inflammatory cytokines, and prostaglandins. The chemical diversity of HO-1 inducers led to the speculation that HO-1, besides its role in heme degradation, may also play a vital function in maintaining cellular homeostasis. Further support for this hypothesis was provided by Tyrrell and colleagues who showed in 1989 that HO-1 is also highly induced by a variety of agents causing oxidative stress. Subsequently, many investigators have focused their attention on the function and regulation of HO-1 in various in vitro and in vivo models of oxidant mediated cellular and tissue injury. The magnitude of HO-1 induction after oxidative stress and the wide distribution of this enzyme in systemic tissues coupled with the intriguing biological activities of the catalytic byproducts, carbon monoxide, iron, and bilirubin, makes HO-1 a highly attractive and interesting candidate stress-response protein which may play key role(s) in mediating protection against oxidant-mediated lung injury. This review will focus on the current understanding of the physiological significance of HO-1 induction and the molecular regulation of HO-1 gene expression in response to oxidative stress. We hope that this discussion will stimulate interest and investigations into a field which is still largely uncharted in the pulmonary research community. PMID- 8679228 TI - Glucocorticoid effects in an endotoxin-induced rat pulmonary inflammation model: differential effects on neutrophil influx, integrin expression, and inflammatory mediators. AB - To understand the basis for the refractory nature of acute respiratory distress syndrome (ARDS) to glucocorticoids, the effects of dexamethasone pretreatment (DEX, 2 mg/kg, intraperitoneally) on the kinetics of airway tumor necrosis factor alpha (TNF alpha) and macrophage inflammatory protein 2 (MIP-2) production, and polymorphonuclear leukocyte (PMN) influx after intratracheal lipopolysaccharide (LPS) (1 mg/kg) in rats were investigated. In the absence of exogenous glucocorticoids, TNF alpha and MIP-2 levels in bronchoalveolar lavage (BAL) fluid peaked at 21 and 300 ng, respectively, by 3 h. DEX pretreatment resulted in a 74% reduction in BAL TNF alpha, yet MIP-2 accumulation was unchanged. In addition, DEX reduced PMN influx at 5 h by 58.4% to 4.1 +/- 0.7 x 10(6) PMN (n = 5). DEX, however, did not mitigate the 3-fold increase in total BAL protein observed at 5 h, attributable to albumin influx. The effects of subacute DEX treatment (3.8 mg/kg per day, for 3 days) on cell-surface expression of the adhesion molecules CD11a, CD11b, and L-selectin were determined by flow cytometric analysis of peripheral blood and autologous BAL PMN. Compared with peripheral blood PMN, exudative PMN had 4-fold greater CD11b expression, no change in CD11a, and loss of L-selectin immunoreactivity 5 h after LPS challenge. The upregulation of CD11b on exudative PMN was insensitive to DEX pretreatment, which, together with a failure to suppress MIP-2 levels, provides a possible explanation for the lack of efficacy of steroids in the management of ARDS. PMID- 8679229 TI - Left ventricular volume determination using Albunex. AB - The aim of this study was to assess the ability of intravenous injection of Albunex to improve left ventricular volume determination in patients with various cardiac diseases. It is conceivable that the intravenous injection of microbubbles could improve echocardiographic left ventricular border delineation leading to improved interobserver variability. Echocardiograms were obtained during simultaneous intravenous injection of 0.08 and 0.12 ml/kg Albunex (four chamber view). Within 6 hours after the recording of the contrast echocardiograms routine left heart angiography was performed. Volumes were measured using the slice method in native and contrast echocardiograms as well as in the angiograms by two independent investigators. The mean differences of angiographic-native echocardiographic and angiographic-contrast echocardiographic volumes (ml) as well as the calculated ejection fraction and their confidence intervals were tabulated and significance was anticipated if the confidence interval did not include zero. Significant changes to angiographic values could be observed concerning end-diastolic, echocardiographic, and contrast echocardiographic volumes at end diastole and end systole, while ejection fractions were similar. Differences between observers were significantly smaller in the contrast echocardiographic images than in the native echocardiographic images. Albunex led to a significantly decreased interobserver variability. PMID- 8679230 TI - Intraaortic mass after repair of an aortic dissection. AB - After graft repair of an ascending aortic aneurysm, a patient was seen by us with a chest x-ray film indicating a retained foreign body. Mediastinal exploration had been unrevealing. Transesophageal echocardiography demonstrated the nature and exact location of the foreign body and therefore was instrumental in directing its retrieval. PMID- 8679231 TI - Valvulitis involving a bioprosthetic valve in a patient with systemic lupus erythematosus. AB - A 37-year-old man with systemic lupus erythematosus, who underwent an aortic valve replacement with a Carpentier-Edwards porcine valve for severe aortic insufficiency, was admitted to the hospital with pulmonary edema. Transesophageal echocardiography revealed severe aortic insufficiency arising from partial dehiscence of the valve sewing ring, as well as centrally from the valve cusp. In addition, marked thickening of the mitral valve was observed with severe eccentric regurgitation. At surgery, valvulitis of the native mitral and bioprosthetic aortic valves was demonstrated, with a perforation of the porcine valve cusp. After replacement of both valves, the patient had a stormy postoperative course with recurrent communications between the left ventricle and atrium requiring multiple surgeries and eventually died. This case illustrates the severity of valvulopathy and ensuing complications that can affect patients with systemic lupus erythematosus and demonstrates that the valvulopathy can affect bioprosthetic valves, a finding that has significant implications as to the type of valve replacement in these patients. PMID- 8679232 TI - Cardiac tamponade: an unusual complication of pericardial cyst. AB - Pericardial cysts are not common and rarely cause symptoms. We report a unique case of a 15-year-old male patient with cardiac tamponade clinically diagnosed who was referred for echocardiography. Transthoracic echocardiography revealed, in addition to a large pericardial effusion associated with echocardiographic signs of cardiac tamponade, an 8 x 5 cm echofree image suggesting a pericardial cyst adjacent to the right atrium. Immediately after pericardiocentesis, yielding a serosanguinous liquid, the patient showed striking clinical improvement and echocardiography demonstrated minimal pericardial effusion with persistence of the cystic image. At surgery a pericardial cyst containing a sanguinous fluid was found and the pathologic findings were consistent with hematic pericardial cyst. Thus echocardiography played a fundamental role for the diagnosis and treatment of the rare complication of a pericardial cyst documented in this patient. PMID- 8679233 TI - The role of automatic endocardial edge detection in the evaluation of left ventricular diastolic function in children. AB - Forty-nine normal children underwent echocardiography to study the role of automatic border detection (ABD) in diastolic evaluation by (1) determining the relationship of diastolic ABD indexes to heart rate and traditional diastolic indexes and (2) establishing inter-observer variability. ABD diastolic indexes were less associated with heart rate than were M-mode and Doppler diastolic indexes. ABD left ventricular peak filling rate correlated with Doppler mitral E wave peak velocity. Interobserver variability for ABD indexes ranged from 4% to 24%. We then compared the ability of ABD left ventricular filling rate to M-mode and Doppler indexes to detect diastolic dysfunction in a test group of 20 children with diastolic disease. ABD left ventricular peak filling rate had the highest sensitivity of all indexes (90%). Thus ABD left ventricular peak filling rate is an accurate index of diastolic function that is readily usable by almost all clinical laboratories. PMID- 8679234 TI - Safety and feasibility of dobutamine-atropine stress echocardiography in patients with ischemic left ventricular dysfunction. AB - The aim of this study was to analyze whether left ventricular dysfunction affects the safety and feasibility of high-dose dobutamine-atropine stress echocardiography. We examined the results of the test in 318 consecutive patients who were referred for high-dose dobutamine-atropine stress echocardiography and also underwent diagnostic cardiac catheterization. Forty-four patients had a left ventricular ejection fraction of 25% or less (mean, 21%; range, 15% to 25%). In the entire group of 318 patients, no serious complications (death, myocardial infarction, or ventricular fibrillation) occurred. The overall feasibility of completing the test was excellent (97%). A trial fibrillation occurred in four patients, nonsustained ventricular tachycardia in 12, and sustained ventricular tachycardia in one. A decrease in systolic blood pressure of greater than 40 mm Hg or a peak systolic pressure of less than 80 mm Hg was present in eight cases. In the group with an ejection fraction of 25% or less, there was a higher rate of significant tachyarrhythmias (14% versus 5%; p = 0.03), whereas the feasibility of the test was slightly lower (89%; p < 0.01), but no difference for hypotension was found. By multivariate analysis, a history of tachyarrhythmias was the only predictor of stress-induced arrhythmias. Advanced left ventricular dysfunction does not represent a contraindication for dobutamine-atropine stress testing. PMID- 8679235 TI - Comparison of adenosine echocardiography, with and without isometric handgrip, to exercise echocardiography in the detection of ischemia in patients with coronary artery disease. AB - This study was undertaken to evaluate whether adenosine echocardiography is comparable to exercise echocardiography in the detection of ischemia in patients with suspected coronary artery disease and to assess whether the addition of handgrip exercise to adenosine enhances the induction of ischemia in these patients. Accordingly, 67 patients with suspected or known coronary artery disease referred for exercise testing underwent adenosine, adenosine with handgrip, and post-treadmill exercise echocardiography. A maximal adenosine infusion dose of 170 micrograms/kg/min was used. Images at baseline and during each of the three stress modalities were digitized in a quad-screen format, randomized, and blinded as to the stage and mode of intervention for nonbiased interpretation. An ischemic response was defined as a new or worsening wall motion abnormality. Ischemia was detected by exercise echocardiography (n = 20) more often than by adenosine echocardiography alone (n = 11; p = 0.039) but similarly to adenosine plus handgrip (n = 16; difference not significant). Exact agreement in individual response between exercise adenosine echocardiography was seen in 51 (80%) of 64 patients and increased to 88% between exercise and adenosine plus handgrip. In the patients who underwent angiography (n = 45), the sensitivity for coronary artery disease (n = 33) was 87% for adenosine, 91% for adenosine plus handgrip, and 93% for exercise echocardiography. The respective sensitivities decreased to 64%, 81%, and 89% in patients without previous myocardial infarction. Specificity was 91% for adenosine with or without handgrip and 82% for exercise echocardiography. Image quality during adenosine with and without handgrip was superior to that during exercise (p < 0.01). Thus in patients with coronary artery disease able to exercise, exercise echocardiography induces ischemia more frequently than does adenosine echocardiography alone. The addition of handgrip exercise to adenosine infusion enhances the detection of ischemia without reducing specificity or image quality and is recommended when adenosine echocardiography is used as a pharmacologic stress test. PMID- 8679236 TI - The effect of aortic outflow on the quantification of mitral regurgitation by the flow convergence method. AB - The effect of aortic outflow on the quantification of mitral regurgitation by the flow convergence method was investigated by both in vitro experiments and computational simulations. Digital analysis of the color Doppler M-mode images was compared with results obtained with laser Doppler anemometry, an engineering gold standard, and three-dimensional computational simulations. Regurgitant orifices of 3.2 and 6.4 mm in diameter were used with instantaneous aortic flow rates from 0 to 500 ml/sec, corresponding to net cardiac outputs of 0 to 5 L/min. In the absence of aortic outflow, a clear plateau was observed in plots of the calculated flow rate as a function of the distance from the orifice, indicating that there was a zone in which the hemispheric assumption was valid. As the aortic outflow was increased, the length of this plateau region decreased and then disappeared at high aortic flow rates. Farther from the orifice, beyond the plateau zone, the flow rate was overestimated and this overestimation increased with increasing aortic flow rate. Results showed excellent agreement between in vitro experiments and computational stimulations. This study demonstrated that aortic outflow has a dramatic effect on the flow convergence region and therefore must be considered in flow rate calculations. PMID- 8679237 TI - Visualization and identification of the left common carotid and left subclavian arteries: a transesophageal echocardiographic approach. PMID- 8679238 TI - Left atrial spontaneous echo contrast: its prevalence and importance in patients undergoing transesophageal echocardiography and particularly those with a cerebrovascular embolic event. PMID- 8679239 TI - Transesophageal echocardiographic evaluation of the morphologic and hemodynamic cardiac changes during ventricular fibrillation. AB - To analyze cardiac motion during ventricular fibrillation (VF), we used transesophageal echocardiography to study nine male subjects, aged 44 +/- 7 years, affected by heart disease who have poor left ventricular function, during implantation of an Implantable Cardioverter Defibrillator, when VF is induced several times to determine the defibrillation threshold. Wall and valvular motion, transmitral and transaortic blood flow, and blood echoreflectivity were evaluated in all patients. Moreover, in basal conditions, during VF, 1 and 5 minutes after restoration of basal rhythm, we calculated the left ventricular end diastolic volume (EDLVV) and area (EDLVA), the left ventricular end-systolic volume and area, the ejection fraction, and the fractional area change with a four-chamber echocardiographic view. At the onset of VF, the myocardium and valves exhibited a chaotic motion. About 10 seconds later the oscillatory movement of the heart walls became more ample and regular; the mitral valve showed a cyclic closure and opening with a forward flow, and the aortic valve exhibited similar behavior, although at a lower intensity. A spontaneous echo contrast appeared inside the atrial and ventricular cavities, gradually becoming an incrt homogeneous mass that was completely flushed away with the restoration of the basal rhythm. When VF started, EDLVV (286 +/- 98 ml) and EDLVA (50 +/- 16.5 cm2) decreased abruptly (EDLVV = 182 +/- 65 ml, p < 0.02; EDLVA = 38 +/- 9.2 cm2,p < 0.05); so did ejection fraction (31.8% +/- 15% versus 11% +/- 5%; p < 0.003) and fractional area change (25.8% +/- 6.5% versus 7% +/- 3.4%; p < 0.001). When the basal rhythm was restored, the heart extended again and EDLVV, EDLVA, ejection fraction, and fractional area change after 1 and 5 minutes were similar to those calculated before induction of VF. This behavior was observed during both the first and last induced VF. Thus during VF, great variations of heart morphology and dynamics, as well as blood echoreflectivity, occur; the heart seems to make attempts to organize its dynamics during the arrhythmia. Repeated episodes of VF and defibrillation with low energies do not seem to worsen left ventricular dynamics even in impaired hearts. PMID- 8679241 TI - Effect of left and right lateral decubitus positions on Doppler mitral flow patterns in patients with severe congestive heart failure. AB - Patients with severe congestive heart failure (SCHF) complain of increasing dyspnea when adopting left lateral decubitus (LLD) position that improves when turning over to the right lateral decubitus (RLD) position (trepopnea). We hypothesize that this clinical sign is due to changes in left ventricular (LV) preload and such changes would modify mitral flow. This study analyzes the effect of RLD and LLD positions on LV filling pattern assessed by Doppler echocardiography in patients with SCHF. Seventeen men and seven women (aged 56.22 +/- 18.52 years) with SCHF in New York Heart Association functional class III-IV and nine normal control subjects (eight men and one woman aged 56.96 +/- 18.14 years) were studied. We analyzed early (E) and late (A) LV filling velocities, E/A ratios, deceleration time, mitral time-velocity integral in each decubitus position, and the differences between them. Patients with SCHF have smaller mitral time-velocity integral, shorter deceleration time, greater E velocity and E/A ratio, and lower A velocity in LLD position than do normal control subjects. On assuming RLD position, patients with SCHF show decreases in E velocity and E/A ratio and lengthening of the deceleration time, suggesting a decrease in LV preload on changing position. This pathophysiologic mechanism may explain why patients with SCHF willingly adopt RLD position. PMID- 8679240 TI - Transesophageal echocardiographic diagnosis of thoracic aortic dissection with the completely thrombosed false lumen: differentiation from true aortic aneurysm with mural thrombus. AB - The conventional criteria of aortic dissection with a completely thrombosed false lumen by transesophageal echocardiography is separation of the intima from the layer of thrombus; however, it is not always easy to distinguish from true aortic aneurysm with mural thrombus. Thus we proposed a new transesophageal echocardiographic diagnostic criteria. Seventeen operative patients with suspected subacute or chronic thoracic aortic dissection in whom it was difficult to exclude true aortic aneurysm with mural thrombus underwent transesophageal echocardiography. In thoracic aortic dissection with in completely thrombosed false lumen, the inner lesion surface composed of intima may be smooth and crescent-shaped thrombus may appear inside the wall surface. Therefore our criteria were on the basis of any two of the following: (1) high-echogenic lesion surface, suggesting intima, over the thrombus, (2) smooth lesion surface, and (3) crescent-shaped thrombus. Imaging data were referenced to intraoperative findings. According to the present criteria only two out of 17 patients were misdiagnosed, whereas according to the conventional criteria six patients were misdiagnosed. The sensitivity was significantly higher than when the conventional criteria were used (90% versus 40%; p < 0.05), whereas the specificity was similar. We conclude that the present transesophageal echocardiographic criteria for detection of thoracic aortic dissection with a completely thrombosed false lumen is clinically useful. PMID- 8679242 TI - On-line echocardiographic assessment of hemodynamic indexes by an adaptive Doppler analysis algorithm and signal/noise ratio calculation. AB - Assessment of cardiac diseases commonly involves the use of spectral Doppler echocardiography. Its use, however, often requires manual digitization of various transvalvular flow profiles. A new approach has been developed for on-line analysis of Doppler data, which involves thresholding based on the signal/noise ratio, calculating instantaneous values, and plotting on the spectral display in real time. We examined the reliability of this new method in 32 patients with 59 various flow jets by comparing it with the data derived by manual analysis. Correlations between the algorithm analysis and manual analysis for peak velocity, peak gradient, velocity-time integral, and acceleration time were excellent. These indexes were obtained with the algorithm in a shorter time and with better reproducibility than with manual analysis. Thus this new adaptive Doppler analysis algorithm yields reliable on-line quantification of valuable hemodynamic variables and represents an advance in quantitative echocardiography. PMID- 8679243 TI - Three-dimensional echocardiography of a flail tricuspid valve. AB - A 71-year-old man with an old myocardial infarction and blunt chest trauma 2 years previously came to our hospital with increasing dyspnea. Three-dimensional echocardiography was performed and a ruptured papillary muscle with flail anterior tricuspid valve was demonstrated from a surgical perspective (electronic atriotomy). These findings were confirmed during open-heart surgery with close similarity. PMID- 8679244 TI - Cardiac fibroma mimicking apical hypertrophic cardiomyopathy: a case report and differential diagnosis. AB - A 55-year-old man was seen with palpitations, dyspnea, syncope, and a large apical left ventricular mass. A diagnosis of apical hypertrophic cardiomyopathy had been made by cardiac catheterization 10 years previously. Transthoracic echocardiography performed during the current evaluation, however, was suggestive of a primary cardiac tumor. At operation, a large fibroma was excised. Knowledge of the echocardiographic appearance of apical left ventricular abnormalities can be helpful in determining the most appropriate choice of therapy. PMID- 8679245 TI - Acidic and basic fibroblast growth factors have comparable effects on the haemostatic function of vascular endothelium. AB - Acidic and basic fibroblast growth factor (aFGF and bFGF respectively) are closely related mitogens (55% homology) of the heparin binding growth factor family. Reports of the relative potency of these growth factors and the ability of heparin to potentiate the activity of bFGF are conflicting. We have examined the effect of heparin and human recombinant aFGF and bFGF on basal and thrombin challenged release of metabolites from cultured human umbilical vein endothelial cells (HUVEC). Culture supernatant was assayed for thrombospondin, prostacyclin and PAI-1 and cell lysates were analysed for t-PA. aFGF and bFGF were equipotent in regulating ther release of all metabolites studied, except thrombin stimulated release of PGI2 where bFGF was more potent than aFGF in the absence of heparin. Heparin potentiated the mitogenic and metabolic effects of both bFGF and aFGF. However, heparin was not essential for the expression of the biological activity of FGF. PMID- 8679246 TI - Basic fibroblast growth factor alterations during development of monocrotaline induced pulmonary hypertension in rats. AB - The chemical signaling pathways which orchestrate lung cell responses in hypertensive pulmonary vascular disease are poorly understood. The present study examined temporal alterations in lung basic Fibroblast Growth Factor (bFGF) in a well characterized rat model of monocrotaline (MCT)-induced pulmonary hypertension. By immunohistochemical analysis, there were progressive increases in bFGF in airway, vascular and gas exchange regions of MCT-treated rat lungs. Increases in bFGF preceded the onset of right ventricular hypertrophy at day 21 after MCT administration. Enhanced bFGF immunostaining was observed as early as day 4 in focal areas of the parenchyma, and by day 14 there was enhanced bFGF staining in alveolar macrophages, neutrophils and alveolar septa, which persisted through day 21. In conducting airways, there was elevated bFGF immunostaining in the smooth muscle cell (SMC) layer by days 4 and 7 and in the ciliated epithelium and its basement membrane at days 14 and 21. Cells morphologically similar to Clara cells in the luminal surfaces of bronchioles stained intensely on days 14 and 21. In the nucleus and cytoplasm of medial SMCs within pulmonary arteries, there was a progressive increase in bFGF staining starting at day 4. Lung bFGF mRNA was increased slightly at days 1, 4 and 7, while lung bFGF protein, as judged by western blot analysis, was increased at days 14 and 21 compared to controls. The present results, considered in teh light of teh documented roles of bFGF in vascular cell migration, growth and synthesis of extracellular matrix components, suggest that bFGF may contribute to the structural remodeling processes underlying the development of chronic pulmonary hypertension in MCT treated rats. PMID- 8679247 TI - Initial characterization of mitogenic activity of ovine corpora lutea from early pregnancy. AB - To characterize angiogenic factors produced by ovine corpora lutea (CL) during early pregnancy, two experiments were performed. In Experiment 1, luteal explants from days 12, 18, 24, and 30 (n=4 ewes/day) after mating were incubated in serum free medium for 6 h. Luteal-conditioned media (LCM) were evaluated for their ability to stimulate proliferation of endothelial and 3T3 cells, as well as migration of endothelial cells. Pools of the LCM (one pool/day) then were characterized biochemically. In Experiment 2, two pools of LCM from days 24 of pregnancy were evaluated for their effects on endothelial cell, 3T3 cell, and ovine luteal cell proliferation. These pools of LCM then were concentrated by ultrafiltration and subjected to heparin-agarose affinity chromatography with salt gradient (0-4 M NaCl in buffer) elution, and fractions were evaluated for mitogenic activity for endothelial and 3T3 cells. The resulting five peaks of mitogenic activity from heparin-agarose chromatography were characterized biochemically. The five peaks of mitogenic activity were further purified by using chromatography, then were concentrated and subjected to SDS-PAGE and Western analysis for FGF-2. Ovine CL from each day of early pregnancy secreted mitogens (P<0.05) for endothelial (285 +/- 8% of unconditioned media controls) and 3T3 (142 +/- 7%) cells as well as factors which stimulated migration of endothelial cell (153 +/- 8% of controls). LCM pool from day 24 of pregnancy also stimulated (P<0.05) proliferation of ovine luteal cells in a dose-dependent manner. In Experiment 1, mitogenic activity for endothelial cells was greater than 100 kDa, heat-labile, trypsin-sensitive and bound to DEAE-Sephacel and heparin-agarose columns, but not to a CM-Sepharose column. Antibody against FGF-1 did not affect mitogenic activity of LCM for endothelial and 3T3 cells, whereas treatment with FGF-2 antibody decreased (P<0.05) mitogenic activity of LCM for both endothelial and 3T3 cells. In Experiment 2, heparin-agarose affinity chromatography resolved five peaks of mitogenic activity: a non-heparin-binding peak that was specific for 3T3 cells, three heparin-binding peaks that were specific for endothelial cells, and one heparin-binding peak that was specific for 3T3 cells. In Experiment 2, heparin-, heat-, or trypsin-treatment and immunoneutralization with FGF-1 or FGF-2 antibodies influenced mitogenic activity of all of the peaks. Whereas SDS-PAGE demonstrated several bands of protein within each peak, Western analysis was unable to detect the presence of FGF-2 in any of the heparin-binding peaks. These data demonstrate that ovine CL from early pregnancy produce mitogenic factors that can be resolved into 5 separate peaks of activity with differing affinities for heparin. These data also indicate that the endothelial mitogens produced by CL of early pregnancy are immunologically related to, but biochemically distinct from FGF-2. Mitogens for endothelial and other cells likely play a role in regulation of luteal function during early pregnancy in sheep. PMID- 8679248 TI - MIP-1 alpha increases the self-renewal capacity of the hemopoietic spleen-colony forming cells following hydroxyurea treatment in vivo. AB - In this report, the effect of macrophage inflammatory protein (MIP-1alpha) on the self-renewal, in vivo, of haemopoietic spleen colony-forming units (CFU-S) following cytotoxic damage, has been investigated. CFU-S recovery following injection of hydroxyurea, HU (1 g/kg at 0 and 7 hers) with or without MIP-1alpha intervention was measured over the following 5 days. In addition to the initial protection conferred by MIP-1alpha, the CFU-S population recovered about 1.7 times faster than in the unprotected controls. Direct measurement of the self renewal capacity of the CFU-S population was made at 2 days after HU + MIP-1alpha treatment by measuring the number of CFU-S/spleen colony in a secondary transplant assay. CFU-S following HU treatment alone generated 60 CFU-S/colony. Additional MIP-1alpha treatment increased this to 90 CFU-S/colony. It is concluded that MIP-1alpha modifies the generation age structure of a regenerating CFU-S population such that recovery is initiated from the more primitive cells of the population's age spectrum and that this observation should extend the range of cytotoxic agents from which MIP-1alpha can give protection. PMID- 8679249 TI - Monocyte chemotactic protein-1 (MCP-1) mRNA is down-regulated in human dermal fibroblasts by dexamethasone: differential regulation by TGF-beta. AB - Macrophages are a source of cytokines driving repair. Wound macrophages are derived from circulating monocytes. Monocyte chemotactic protein-1 (MCP-1) is a potent specific monocyte chemoattractant. Treatment of serum stimulated dermal fibroblasts with dexamethasone led to a dose dependent down-regulation of MCP-1 mRNA levels. Such an anti-inflammatory effect may partially explain the negative influence of glucocorticoid treatment on wound repair. Topical or parenteral of fibroblasts cultured in serum free media with TGF-beta increased MCP-1 mRNA levels. TGF-beta treatment of fibroblasts cultured in serum also partially overcame the dexamethasone mediated decrease in MCP-1 mRNA levels. In glucocorticoid treated animals TGF-beta may stimulate repair by an indirect pro inflammatory action following transcriptional up-regulation of MCP-1. PMID- 8679250 TI - Involvement of loop 2 of platelet-derived growth factor-AA and -BB in receptor binding. AB - Platelet-derived growth factor (PDGF) is a disulfide-bonded antiparallel dimer of A- and B-polypeptide chains. Each subunit contains two loops (loops 1 and 3) which point in the same direction, and which are located close to a region (loop 2) from the other subunit of the dimer. Previous studies have shown that epitopes in loops 1 and 3 are important for binding to PDGF alpha- and beta-receptors. The aim of the present investigation was to determine the importance of loop 2 for receptor interactions. PDGF A- and B-chain cDNA:s were mutated in the loop 2 regions and transfected into COS cells. Analyses of conditioned media of such cell cultures revealed that PDGF B-chain mutated in the loop 2 region lost its ability to compete with 125I-PDGF for binding to PDGF beta-receptors, but retained 2-5% of its binding of alpha-receptors. The A-chain binds only to alpha receptors; 2-5% of this binding was also retained after mutation of the loop 2 region. In conclusion, the loop 2 region of PDGF is important for receptor binding, but appears to be more important for binding to the PDGF beta-receptors than to the alpha-receptors. PMID- 8679251 TI - TGF beta promotes the basal phenotype of epidermal keratinocytes: transcriptional induction of K#5 and K#14 keratin genes. AB - TGFbeta is an important regulator of epidermal keratinocyte function because it suppresses cell proliferation, while it induces synthesis of extracellular matrix proteins and their cells surface receptors. To examine whether TGFbeta affects synthesis of intracellular proteins as well, specifically the transcription of keratin genes, we transfected a series of DNA constructs that contain keratin gene promoters into human epidermal keratinocytes. The transfected cells were grown in the presence and absence of TGFbeta. We found that TGFbeta specifically induces transcription controlled by the promoters of K#5 and K#14 keratin genes, markers of basal cells. No other keratin gene promoters were induced. The effect of TGFbeta is concentration-dependent, can be demonstrated in HeLa cells, does not depend on keratinocyte growth conditions and can be elicited by both TGFbeta1 and TGFbeta2. We conclude that TGFbeta promotes the basal cell phenotype in stratified epithelia such as the epidermis. PMID- 8679252 TI - Growth/differentiation factor-10: a new member of the transforming growth factor beta superfamily related to bone morphogenetic protein-3. AB - We have identified a new member of the transforming growth factor-beta (TGF-beta) superfamily, growth/differentiation factor-10 (GDF-10), which is highly related to bone morphogenetic protein-3 (BMP-3). The nucleotide sequence of GDF-10 encodes a predicted protein of 476 amino acids with a molecular weight of approximately 52,000. The GDF-10 polypeptide contains a potential signal sequence for secretion, a putative RXXR proteolytic processing site, and a carboxy terminal domain with considerable homology to other known members of the TGF-beta superfamily. In the mature carboxy-terminal domain GDF-10 is more homologous to BMP-3 (83% amino acid sequence identity) than to any other previously identified TGF-beta family member. GDF-10 also shows significant homology to BMP-3 (approximately 30% amino acid sequence identity) in the pro- region of the molecule. Based on these sequence comparisons, GDF-10 and BMP-3 define a new subgroup within the larger TGF-beta superfamily. By Northern analysis, GDF-10 mRNA was detected primarily in murine uterus, adipose tissue, and brain and to a lesser extent in liver and spleen. In addition, GDF-10 mRNA was present in both neonatal and adult bone samples, with higher levels being detected in calvaria than in long bone. These results suggest that GDF10 may play multiple roles in regulating cell differentiation events, including those involved in skeletal morphogenesis. Gdf10 was mapped to the proximal region of mouse chromosome 14 close to a region known to contain a spontaneous recessive mutation that is associated with a craniofacial defect. PMID- 8679253 TI - 4th Scandinavian Symposium on Radiolabeled Monoclonal Antibodies in Diagnosis and Therapy of Cancer. Lillehammer, Norway, January 15-17, 1995. PMID- 8679254 TI - Twenty years with monoclonal antibodies: State of the art--Where do we go? AB - In this review, we have selected some parameters with the potential to improve the efficacy of RIL and RIT. Focus has partially been on the behaviour of radiolabelled antibodies in vivo in relation to properties and amounts of both target antigen and the antibodies used. If, out of the 28 factors listed in Table 1, some should be given preference in future work, it is our opinion that after the initial saturation of the tumour site a rapid decrease in redundant antibody is of significant importance. Furthermore, quantitative aspects of both antigens and antibodies should be more carefully evaluated when possible. By combining several of the listed approaches toward increasing efficiency, a more extensive use of RIL and RIT could be expected in the future. PMID- 8679256 TI - Penetration and binding of monoclonal antibody in human osteosarcoma multicell spheroids. Comparison of confocal laser scanning microscopy and autoradiography. AB - Penetration and binding of monoclonal antibody (MAb) in multicell osteosarcoma spheroids have been studied by autoradiography and confocal laser scanning microscopy (CLSM). Optical sectioning of the 3-dimensional spheroids was performed by CLSM. Owing to attenuation of fluorescence intensity, FITC-labelled MAb could not be detected at depths greater than 60 microm within the spheroids. The antibody uptake seen in autoradiographs and CLSM images 60 microm within the spheroids were essentially identical. MAb had reached all parts of the spheroids within 6 h. Quantitative measurements of the fluorescence intensity of FITC labelled MAb seen in confocal images and measurements of MAb bound per cell using flow cytometry, showed that maximum uptake was reached after 6 h. The possibility to perform both quantitative and qualitative measurements makes CLSM a promising method for studying antibody uptake in thick tissue samples. PMID- 8679257 TI - Secondary antibodies as tools to improve tumor to non tumor ratio at radioimmunolocalisation and radioimmunotherapy. AB - One way of selectively improving the efficiency of radioimmunolocalization and radioimmunotherapy is to eliminate redundant, circulating, non-targeting radiolabeled antibodies after saturation of the target sites. Secondary antibodies of different types have been proposed as clearing agents for such purposes. The conceptually different approaches of the 'secondary antibody' strategy including its advantages and limitations are discussed. This mini-review also presents a model describing the kinetics of the components (the antigen, the primary and secondary antibodies) and approaches required to improve the efficacy of both radioimmunolocalization and radioimmunotherapy. PMID- 8679255 TI - In vivo modulators of antibody kinetics. AB - The aim of the present study was to summarize the effect of in vivo modulation of antibody kinetics and to present new data on the in vivo effect of the cell membrane active detergent Tween 80 and the cytokine interleukin-2 (IL-2) on the accumulation and clearance of a radioactive antibody. Mice bearing Lewis lung carcinoma xenografts and rats bearing DMBA-induced mammary carcinomas were studied after injecting I-125 labeled IgG1 monoclonal antibody (3c4c7g6) raised against a tyrosine kinase receptor protein Tie. Expression of Tie is known to be abundant in vascular endothelia and possibly related to malignant angiogenesis. Tween 80 was administered intratumorally (0.04% of tumor volume), whereas IL-2 was administered intraperitoneally. In the Lewis lung tumor model, the absolute tumor uptake varied between 2 and 5% ID/g, and maximum uptake was achieved after 24 h with Tween, and after 48 h without Tween. Tween manipulation did not increase the uptake in any normal organ, but it enhanced antibody clearance from the blood. In the DMBA rat model, IL-2 had no effect on blood clearance, but enhanced the uptake of Tie antibody into the tumor from 2.5-0.9 to 4.5-0.4% ID/g at 48 h. These data indicate that antibody biodistribution and pharmacokinetics can be modulated by a surface detergent and a cytokine, giving decreased exposure to critical organs, and increased uptake into the tumor. This type of manipulation provides an opportunity to optimize radioimmunotherapy. PMID- 8679258 TI - Generation of human monoclonal antibodies against ganglioside antigens and their applications in the diagnosis and therapy of cancer. AB - Different approaches to generating human monoclonal antibodies (MAbs) against tumor-associated ganglioside antigens have been carried out in several laboratories. A specific goal addressed by our laboratory is to produce human MAbs to several ganglioside antigens of relevance as therapeutic targets, such as the GM2, GD2, GD3 and GM3 gangliosides in melanoma. In vitro immunization of human B lymphocytes from normal donors was performed using liposomes containing gangliosides as the immunizing antigen combined with either complete tetanus toxoid or a synthetic peptide corresponding to a T helper epitope to stimulate in vitro immunization. Specific human anti-ganglioside antibodies were obtained, indicating that the antibody response found in vitro was antigen-driven. To overcome the widely reported problems concerning stability of immunoglobulin production by the antibody-secreting cell lines, a method of positive selection using GM3-coated magnetic beads has been developed in order to rescue unstable clones. Development of new methods to reproducibly generate ganglioside-specific human MAbs will amplify the possibilities for diagnostic and therapeutic applications. PMID- 8679260 TI - A putative mechanism for the non-specific uptake of intact radiolabelled monoclonal antibodies in the testes and prostate. AB - Non-specific testicular accumulation of radiolabelled intact anti-CEA monoclonal antibody (MAb), (A431/26, Behringwerke AG) was observed in 11 out of 12 patients with the testes and prostate included in the examination field at radioimmunoscintigraphy (RIS). Previous studies have shown that placental alkaline phosphatase (PLAP) serves as an Fc-receptor, mediating IgG transport through the placenta. A closely related protein, the germ cell alkaline phosphatase (GCAP), is expressed in the testes. The testicular uptake of IgG is observed only when intact but not fragmented MAbs are used, indicating involvement of Fc-receptors. MDCK cells (dog kidney cell line) transfected with the plasmid pSVT7 containing the GCAP gene were shown to acquire the capacity to both express membrane bound GCAP and to bind IgG on the cell surface. This might indicate that GCAP is responsible for the non-specific accumulation of intact MAb in the testes and prostate often observed when intact murine MAbs are used for radioimmunolocalization (RIL). PMID- 8679259 TI - Abundant tyrosine residues in the antigen binding site in anti-osteosarcoma monoclonal antibodies TP-1 and TP-3: Application to radiolabeling. AB - The variable (V) genes of TP-1 and TP-3 MAbs have been cloned and sequenced. Because of the potential use of these antibodies in the diagnosis and treatment of osteosarcoma, it is important to determine the presence and position of amino acid residues that may react with radiolabeling within the V domains. In this article, location of the tyrosine residues is determined using the knowledge of immunoglobulin structures in general. The TP-1V domains have a total of 19 tyrosines, whereas TP-3V domains have 18, with approximately half of these located within complementarity determining regions (CDRs). Thus, if equal reactivity of all tyrosines is assumed, smaller fragments of MAbs have a high probability of being radiolabeled at one of these sites with possible resultant loss of antigen binding. PMID- 8679261 TI - Extracorporeal immunoadsorption from whole blood based on the avidin-biotin concept. Evaluation of a new method. AB - This study of 36 rats with rat colon adenocarcinoma transplants was carried out to investigate the efficacy of a new method of whole blood immunoadsorption (WBIA) in removing biotinylated monoclonal antibodies (MAbs) directly from unseparated blood, in order to increase 'the tumor/normal-tissue uptake ratio', as compared with extracorporeal immunoadsorption (ECIA) of antibodies from plasma. Compared with the ECIA system, the overall volume of the WBIA system (comprising only a pump, an adsorption column, a drop-chamber and tubings) was less (3.6 vs. 6.2 ml), and procedure duration 2 h less. The 17 rats undergoing the WBIA procedure, started 12 h after i.v. injection of 4.0-4.5 MBq 125I-BR96 biotin, manifested neither hemolysis nor any other complication; no signs of organ edema were found at dissection; whole body and blood radioactivity values were reduced by 51% and 89.5%, respectively. The WBIA method was as effective as ECIA, but technically simpler, safer and more reliable. PMID- 8679262 TI - Immunoscintigraphy: Importance for researchers and patients. AB - One of the subtle differences between the cancer cell surface and the normal cell is exploited by immunoscintigraphy. The clinical role and some technical aspects of imaging cancer with radiolabelled antibodies are reviewed. 99mTc is the best radiolabel for immunoscintigraphy. Specificity is added to the general sensitivity of nuclear medicine techniques by this approach to imaging cancer. PMID- 8679263 TI - Breast cancer 99mTc SM3 radioimmunoscintigraphy. AB - 99mTc SM3 radioimmunoscintigraphy is combined with kinetic analysis and probability mapping using a change detection algorithm to investigate axillary node involvement before primary surgery in patients with breast cancer. Whereas planar imaging was unsuccessful, axillary node involvement was correctly determined in 11 out of 13 patients 6 out of 7 true negatives and 5 out of 6 true positives down to 0.35 grams. A prospective study is underway. PMID- 8679264 TI - Parameters influencing volume and activity quantitation in SPECT. AB - Several factors influence the accuracy to which information on the in vivo activity concentration can be obtained from SPECT images. The accuracy in image contrast and the quantitation of volume and activity has here been examined for a SPECT system aimed for absorbed dose determinations in systemic radiation therapy. The influence of source dimensions, object contrast, noise level, energy window width and the reconstruction filter was examined. All the investigated parameters affected the recoveries. Volumes of above 20 cm3 could be quantified to within +/- 20%, for object contrasts of above 96%, and within +/- 40% for object contrasts above 81%, providing limited levels of noise. Both the image contrast and the volume quantification is expected to be improved in situations with low object contrasts, if accurate correction for scattered photons can be developed. Obtained limitations in the quantitation of activity with the present method should be reduced by development of a more accurate background subtraction technique. PMID- 8679265 TI - Targeting disseminated melanoma with radiolabelled methylene blue: Comparative bio-distribution studies in man and animals. AB - Targeted radiotherapy for pigmented melanoma with 3,7-(dimethylamino) phenazathionium chloride [methylene blue (MTB)] labelled with Astatine-211 (211At; alpha-particle emitter) proved to be very effective in animal model systems. Since the results justified an introduction of the treatment to the clinic, the aim of the bio-distribution studies using [123I]-MTB and [131I]-MTB in patients was to confirm selectiveness of radiolabelled MTB uptake in melanoma lesions. The investigations were carried out using planar and SPECT (single photon emission computed tomography) gamma-cameras. A stable uptake of radioiodinated MTB was found in pigmented melanomas in man, with tumour/surrounding tissue and tumour/blood ratios amounting to 9 at 19 h after a single i.v. injection. A time-dependent kinetics of radioiodinated MTB distribution was similar to that observed in human melanoma-bearing athymic mice. Blood radioactivity decreased by about 90% during the first 2.5 min after i.v. injection of the compound (T1/2biol = 0.58 min). Its retention time in various organs was either the same or very similar to that characteristic of the blood. A rapid uptake of radioiodinated MTB in the liver and kidneys confirmed the importance of these organs in excreting the compound: 25-30% of the radioactivity administered was expelled with urine over the first 24 h after the injection. There was no obvious retention of radioiodinated MTB in the brain over the observation period and in the eyes for at least the first 14 h. PMID- 8679266 TI - Radioimmunotherapy of solid cancers: A review. AB - Depending on radionuclide characteristics, radioimmunotherapy (RIT) relies on radioactivity to destroy cells distant from immunotargeted cells. Therefore, even heterogeneous tumors (for antigen recognition) can be treated, because not all cells have to be targeted. Substantial complete response rates have been reported in patients with non-Hodgkin's lymphoma. Much more modest results have been reported for patients with bulky solid tumors, e.g. adenocarcinomas. The radiation doses delivered by targeting antibodies are generally too low to achieve major therapeutic responses. Dose escalation is limited by myelotoxicity, and higher doses need to be delivered to neoplasms less radiosensitive than lymphomas. Various trials for both systemic and regional RIT have been reported on. Intraperitoneal administration has been applied for colorectal and ovarian carcinomas. Our own results indicate that, e.g., intraperitoneal pseudomyxoma can be treated with RIT. Myelotoxicity can be reduced by anti-antibody-enhancement, 2 and 3-step strategies, bispecific monoclonal antibodies (MAbs), and extracorporeal immunoadsorption. The radionuclide has to be selected properly for each purpose; it can be a beta-emitter, e.g. I-131, Y-90, Re-188, Re-186, Lu-177 or Sm-153, an alpha-emitter At-211 or Bi-212 or an Auger-emitter, e.g. I-125, I 123. One major problem with RIT, besides slow penetration rate into tumor tissue and low tumor-to-normal tissue ratio, is the HAMA response, which can be partly avoided by the use of humanized MAbs and immunosuppression. However, RIT will be, because of all the recent developments, an important form of cancer management. PMID- 8679268 TI - A Monte-Carlo program converting activity distributions to absorbed dose distributions in a radionuclide treatment planning system. AB - In systemic radiation therapy, the absorbed dose distribution must be calculated from the individual activity distribution. A computer code has been developed for the conversion of an arbitrary activity distribution to a 3-D absorbed dose distribution. The activity distribution can be described either analytically or as a voxel based distribution, which comes from a SPECT acquisition. Decay points are sampled according to the activity map, and particles (photons and electrons) from the decay are followed through the tissue until they either escape the patient or drop below a cut off energy. To verify the calculated results, the mathematically defined MIRD phantom and unity density spheres have been included in the code. Also other published dosimetry data were used for verification. Absorbed fractions and S-values were calculated. A comparison with simulated data from the code with MIRD data shows good agreement. The S values are within 10-20% of published MIRD S values for most organs. Absorbed fractions for photons and electrons in spheres (masses between 1 g and 200 kg) are within 10-15% of those published. Radial absorbed dose distributions in a necrotic tumor show good agreement with published data. The application of the code in a radionuclide therapy dose planning system, based on quantitative SPECT, is discussed. PMID- 8679267 TI - Double-tracer dosimetry of organs in assessment of bone marrow involvement by two monoclonal antibodies. AB - Five patients with ductal breast cancer were studied using simultaneous administration of 99Tcm-labelled BW250/183 and 131I-labelled B72.3 monoclonal antibodies (MAbs). The distribution and dosimetry of these tracers were evaluated using the information from simultaneous anterior and posterior whole body scintigrams, together with 99Tcm and 131I standard activity sources, recorded on an average of 1, 4, 24, 90 and 224 h after injection. A method to eliminate 131I Scatter on 99Tcm-channel was developed. The geometric means of conjugate views and region-of-interest analysis were used to determine organ uptakes, mean residence times and absorbed radiation dose estimates of organs induced by the tracers. Organ uptakes (% of injected activity/ml) varied from 6.2 x 10(-3 /red marrow to 3.1 X 10(-2)/liver for 99Tcm-MAb and from 3.1 x 10(-2)/red marrow to 1.8 x 10(-1)/liver for 131I-MAb, one hour after injection. Calculated average residence times of organs for 99Tcm-labelled BW250/183 were in the range of physical mean-life of 99Tcm and from 71 to 95 h for 131I-B72.3 respectively. The average total absorbed dose from 99Tcm-MAb to the bone marrow was 0.01 and to the spleen 0.14 mGy/MBq and from 131I-MAb the corresponding values were 0.48 and 10.76 mGy/MBq. This double-tracer technique provides information from two antibodies having different kinetic behaviour and may facilitate in distinguishing various antigens in targeting and control MAb applications. PMID- 8679269 TI - Radioimmunotherapy with alpha-particle emitting radioimmunoconjugates. AB - Radionuclides which decay by the emission of alpha-particles are attractive for certain radioimmunotherapeutic applications. These include the treatment of lymphomas, compartmentally spread malignancies such as ovarian cancer and neoplastic meningitis, and micrometastatic disease. Two alpha-emitting radionuclides of interest for this purpose are 212Bi (60.6 min half life) and 211At (7.2 hr half life). Compared with the beta-emitters commonly used for radiotherapy, the alpha-particles of 212Bi and 211At are of higher energy, much shorter range (less than 100 microm), and considerably higher linear energy transfer. Preliminary results obtained in a variety of in vitro systems and in vivo models have documented the exquisite toxicity of alpha-particles and have established a basis for initiating radiotherapy trials in humans with monoclonal antibodies labeled with alpha-emitting radionuclides. PMID- 8679271 TI - Radiolabeled monoclonal antibodies in diagnosis and therapy of cancer. Summary and perspectives. AB - The papers of the 4th Scandinavian Symposium on Radiolabeled Monoclonal Antibodies in Diagnosis and Therapy of Cancer are summarised. Particular emphasis is placed on quantitation, dosimetry and radionuclide therapy. Some biological aspects of radionuclide therapy are indicated. PMID- 8679270 TI - Targeted radiotherapy of osteosarcoma using 153 Sm-EDTMP. A new promising approach. AB - We report a case where targeted radionuclide therapy using 153Sm-EDTMP gave substantial palliative effect. A 35-year-old male with a primary osteosarcoma located in the first lumbar vertebra relapsed with progressive back pain after conventional treatment modalities had failed. He became bedridden, and developed paraparesis and impaired bladder function. On a diagnostic bone-scan intense radioactivity was localized in the tumor. He therefore was given 153Sm-EDTMP treatment twice, 8 weeks apart, 35 and 32 MBq/kg body weight respectively. After a few days the pain was significantly relieved and by the second radionuclide treatment the pareses subsided. For six months he was able to be up and about without any neurological signs or detectable metastases. Eventually, however, he experienced increasing local pain, developed paraparesis, was re-operated but died 4 months later. The dramatic transient improvement observed in this case warrants further exploration using 153Sm-EDTMP as a boost technique, supplementary to conventional external radiotherapy. PMID- 8679272 TI - [Relationship between the structure--modified N- and C- termini and the biological activity of TNF alpha molecule]. AB - In order to elucidate the relationship between N-, C-termini of TNF alpha and it's biological activity, a TNF alpha derivative 10 (TNF alpha D10) was prepared by changing amino acid at the N-terminus positions Ser(4), Ser(5), Asp(10) and C terminus position Leu(157) to N-terminus Cys(4), Thr(5), Arg(10) and C-terminus Phe(157) with PCR site-directed mutagenesis. The results showed that the expression level of this mutein has not altered but its cytotoxic activity increased. This might result from trimer formation of TNF alpha D10 by changing N terminal Ser(4) residue to Cys. HPLC showed that the molecular weight of TNF alpha D10 was 17kD, 35kD, 55kD respectively. In addition, we also found that the stability of TNF alpha D10 was less than that of TNF alpha when to be stored at 20 degrees C for two months. It might be caused by changing Leu(157) to Phe(157). PMID- 8679273 TI - [The analysis of GPI in chimeric mice of ES cells (MESPU 13)]. AB - To estimate the differential potentiality of ES (Embryonic Stem) cell line MESPU 13, the heart, liver, spleen, lung, kidney, pancreas, gonad, muscle and blood of 19 chimeric mice were analyzed for GPI (Glucose Phosphate Isomeras) marker, in these studies, type A band from the ES cells, appeared parallel to the coat color chimerism of the mice. When coat color chimerism is below 40%, type A band was not seen except in the kidney of a few mice. Type A band was detected in nearly all the organs and tissues, when coat color chimerism was over 85%, indicated the ES cell has a fairly high potential to differentiate into cells of endoderm, mesoderm and ectoderm. In addition, only type A band was observed in the muscles of 6 mice which coat color chimerism is over 85%, the results indicated that these muscles were differentiated only from ES cells. PMID- 8679275 TI - [Surgery of the hypopharynx after radiotherapy]. AB - Changes in surgical procedures for hypopharynx cancer after definitive radiotherapy are important since the use of pedicled myocutanous flaps and free digestive transplants. Postoperative course is improved and salvage surgery more frequent. From 1970 to 1990, 160 hypopharyngeal carcinomas were operated on after radiotherapy, 103 due to failures or complications after definitive irradiation and 57 metachronous cancers. During this period, the rate of lethal postoperative complications decreased from 25% to 8%. Crude survival rates are 51% at 1 year, 22% at 3 years and 15% at 5 years. Poor prognostic features are local extension, positive margins and extracapsular nodal spread. Postoperative deaths and failures in primary or neck account for 60% of the causes of death. Results of salvage surgery are unsatisfactory: the choice of definitive radiotherapy with surgery in reserve must be restricted to selected cases. PMID- 8679274 TI - [Prevention of second primary cancer with vitamin supplementation in patients treated for head and neck cancers]. AB - Second primary cancers often occur in head and neck cancer patients successfully treated by radiation therapy. Experimental and epidemiological data suggest that these second primaries might be prevented by antioxidant vitamins, in particular beta-carotene and alpha-tocopherol. A randomized double-blind clinical trial is being conducted in Canada to determine whether vitamin supplementation with beta carotene (30 mg/d) and alpha-tocopherol (400 IU/d) reduces the incidence of second primaries in head and neck cancer patients treated by radiation therapy. PMID- 8679276 TI - [Surgery of the oropharynx after radiotherapy]. AB - Over 40 years after the first commando procedures performed by M Dargent, surgical techniques such as mandibulotomy and myocutaneous flaps yield important changes in oropharyngeal surgery after definitive radiotherapy. Wide resections and simultaneous neck dissection are possible with good functional results. From 1970 to 1990, 250 patients with a carcinoma of the oropharynx were operated on after radiotherapy, 163 because of failure or complication of irradiation, 87 for a metachronous carcinoma occurred in an previously irradiated field. The postoperative mortality rate was 6%. The risk of carotid blow-up did not increase with the extension of the resection. Survival rates at 1, 3 and 5 years are 55%, 22%, 16% in salvage surgery and 69%, 36% and 24% in patients with metachronous cancer. Postoperative complications and failures in the primary and/or the neck account for 60% of causes of death. These results suggest that prior surgery of deeply ulcerative carcinoma of the oropharynx followed by radiotherapy is a better strategy than definitive radiotherapy with salvage surgery in reserve. PMID- 8679278 TI - [Restoration of the mandible after trans-mandibular approach of invasive tumors of the oropharynx (43 cases)]. AB - Preservation of the mandible is often possible in surgery of invasive malignant tumors of the oropharynx. From 1983 to 1993, we operated 158 T3 of the oropharynx: 73% with mandibulectomy and 27% with osteotomy (43 cases). Now, the osteotomy of the mandible is performed in more than 90% of the patients. The osteosynthesis needs two titanium plates; the pharyngoplasty is made with a pectoralis major myocutaneous flap. Followup: 36 cases of 43 gave satisfactory results. The osteotomy complication rate was 5 (12%): 5 osteitis (2 after radiotherapy). PMID- 8679277 TI - [Value of anti-Epstein-Barr antibody detection in the diagnosis and management of undifferentiated carcinoma of the nasopharynx]. AB - The Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC). Serological studies have shown that the clinical onset of NPC is preceded by the appearance of a high antibody titer of IgA to viral capsid antigens and early antigens. The titers increase with the total tumor burden and the antibodies decline with the response to therapy. In patients with confirmed clinical remission elevation of IgA serological titers is highly significant for prediction of relapse. This demonstrates the usefulness of EBV serology for the clinical management of NPC patients. PMID- 8679279 TI - [Hypothyroidism following radiosurgical treatment of cancers of the hypopharynx]. AB - In a series of 224 patients treated between 1980 and 1992 for hypopharyngeal carcinoma by surgery and post postoperative radiotherapy we found an overall 54% incidence of elevated TSH levels. Decreased FT4 levels were associated in about one-third of the patients. When thyroidectomy was performed, 71% of the patients developed thyroid dysfunction. Most TSH abnormalities (45%) occurred within two years of treatment. Nevertheless, long-term followup is indicated since those complications may be delayed. Hormonal replacement therapy is recommended for patients with elevated TSH. PMID- 8679280 TI - [Value of the combination of external radiotherapy and curietherapy in carcinoma of the velo-tonsillar region. Statistical study of a series of 361 patients]. AB - From 1977 to 1991, we treated 361 carcinomas of the velotonsillar region, either by brachytherapy alone (18 cases), or by an association of external radiotherapy and brachytherapy (343 patients). The latter was performed using a special technique with iridium wires in plastic tubes with afterloading. The primary was the tonsil in 128 patients, the soft palate in 134 patients. We numbered also 9 posterior pillars, 63 anterior pillars and 27 velotonsillar sulcus. According to the UICC staging system (28), we classified the patients in 90 T1, 141 T2, 119 T3, 2 T4, 9 Tx with 230 N0, 93 N1, 9 N2, 20 N3 and 9 Nx. The results at 5 and 10 years show respectively: local control (LC) 80% and 75%, locoregional control 75% and 70%, global survival 53% and 28%, specific survival 63% and 52%. The univariate study shows at 5 years a better local control for T1-T2 (87%) than for T3 (67%) with p = 0.00004. The locoregional control is better for N0 (80%) than for N+ (66%) with p = 0.002, this is the same for global survival (59% versus 42%, p = 0.002). The two groups were individualised according to the primary. Inside each of these groups, the prognosis is identical for different localisations, which allows to put them together. We can therefore distinguish a group A which includes the tonsil, the soft palate and posterior pillar. This group has a better prognosis (controls and survivals) than group B (anterior pillar and velotonsillar sulcus) (p < 0.002). The tumours extended to the mobile tongue, the base of the tongue or the velotonsillar sulcus have a poorer prognosis than those without propagation or with an upwards propagation (p < 0.002). The statistical study of radiobiological factors that can influence the tissular repair shows that there are less recurrences if the duration of treatment is inferior to 55 days and if the interval between external irradiation and brachytherapy is inferior to 20 days. A sufficient safety margin seems also necessary for a good local control. The dose rate within the limits used does not seem to influence the local control and the total dose delivered to the tumour, but this is not surprising since the highest doses are given to the tumours with the smallest regression during external irradiation. The multivariate study for local control shows that the most significant factors are the T, the tumoral localisation and the total duration of treatment. For complications (classified in 4 stages), the dose rate is the most significant factor. PMID- 8679282 TI - [Radiotherapy and curietherapy of squamous cell carcinoma of the posterior pharyngeal wall (excluding the nasopharynx)]. AB - From 1986 to 1992, 55 cases of PPWC were treated with a conservative intent at the Regional Cancer Center (Rennes, France) and Saint-Yves Center (Vannes, France): 16 oropharyngeal posterior wall carcinoma (OP) and 39 hypopharyngeal posterior wall (HP); the mean age of the population was 60.3 years (31-81 years). A previous and simultaneous head and neck cancer was noted in 15 and 13% of cases respectively. Half of the cases (55%) were T1 T2 tumors and 82% were N0 N1. Except for three patients treated by curietherapy (5%), all patients were treated by radiotherapy (RT) alone (75%) or associated with curietherapy (7%) or partial pharyngectomy (13%). 15% received neoadjuvant chemotherapy, mainly for T3 tumors. With a followup of 4-88 months (mean: 23 months) 38% of patients are still alive; 8% of loco-regionally controlled patients died of second cancer or intercurrent disease. The tumor control was 67%. The nodes control was 90%. During the course of the disease, 19% of patients had metastases. The complete response at the end of treatment was 78%. Among these patients, 54% remained definitively free of disease. There is no difference between OP and HP. The analysis of survival curves showed the following points: significant difference between T1 T2, and T2 T3 (P < 0.05), N0 N1 and N2 N3 (P < 0.03), well differentiated histology or not (P < 0.02), RT alone or associated with curietherapy or surgery (P < 0.03) even for limited tumors T1 T2 N0 N1 (P < 0.03). There was no significant difference between group treated or not by chemotherapy even for T3 tumors. These findings do not differ if we consider either OP or HP. We conclude that OP and HP have the same prognostic factors and must be considered as the same clinical entity. For limited tumors T1 T2 N0 N1, patients managed by radiotherapy associated with complementary local treatment (conservative surgery or curietherapy) do better than patients treated by RT alone (plateau 80% at 18 months+vs plateau 25% at 12 months +). For these limited tumors, our recommendation is to treat patients by external RT (50 Gy) and curietherapy boost (20 Gy) rather than by conservative surgery and external RT (70 Gy). These two treatments have the same efficacity but the first one is expected to diminish late complications of RT. Neo adjuvant chemotherapy does not seen to improve survival even for advanced tumors. Generally speaking these results remain poor for locally advanced desease and for undifferentiated tumors. These patients need a new therapeutic approach (concomittant radio-chemotherapy, hyper or hypofonctionnated RT). PMID- 8679281 TI - [Place of iridium 192 implantation in irradiation of T1-T2 squamous cell carcinoma of the velopharyngeal arch]. AB - We have reviewed the results of 165 T1 and T2 squamous cell carcinomas of the faucial arch treated by definitive irradiation including or not iridium 192 brachytherapy to ascertain whether a significant relationship exists between iridium implantation, local control, complications and survival. From March 1971 to November 1990, 58 T1 and 107 T2 (NO: 107/165; N1: 30/165; N2: 9/165; N3: 19/165) biopsy proven squamous cell carcinomas of the tonsillar region (104/165) and the soft palate and uvula (61/165) were treated in the Henri Mondor Hospital by definitive irradiation with curative intent. From 1971 to 1981 (period 1), only guide gutter technique was available, so that implants were reserved for small tumors: patients were either managed by definitive telecobaltherapy to tumor site and neck node areas (group I; n = 48; mean dose: 70 Gy; confidence interval: +/- 5.5, 5 fractions of 1.8 Gy per week) or by exclusive iridium implant (group 2; n = 11; all T1NO; 64 Gy +/- 4.8) or by a combination of external beam radiation therapy to tumor site and neck nodes areas and iridium implant (group 3; n = 40). In 1981 (period 2), a new plastic tube technique, which enables implantation of larger areas, was introduced and all patients (group 4; n = 66) were then managed by external radiation therapy (group 3 + 4: 47 Gy +/- 4.3) followed by an iridium implant (31 Gy +/- 10.5). Clinically positive neck nodes either received additional external dose with electrons or were excised. Overall 5-year survival (Kaplan Meier) was 23%, 50.5%, and 60% in groups 1, 2 and 3 + 4, respectively (p < 0.001, log rank). Five-year local control was 58%, 100%, and 91%, respectively (p < 0.001). Five-year necrosis rate was 10%, 25% and 30%, respectively (NS). Comparison of results between the two periods of the study (group 1 + 2 + 3 vs group 4) shows that these two groups are statistically comparable according to site and size of tumor and N status and that both local control (77% vs 94% at 5 years; p < 0.01) and disease free survival (56% vs 71%; p = 0.03) were improved after 1980, while there was a trend to an increase in overall survival (42% vs 53% at 5 years; p = 0.08); nodal control (86% vs 95% at 5 years) and necrosis rate (11% vs 20% at 5 years) were not modified. Multivariate analysis showed that both local control (p < 0.0001) and overall survival (p < 0.0001) were improved when tumor was implanted. We recommend then to treat T1 and T2 squamous cell carcinomas of the faucial arch by external radiation therapy to tumor site and neck areas (45 Gy/25 fractions/5 weeks) followed by a 30 Gy iridium implant and, for patients with clinically positive nodes, either a further 25-30 Gy electron beam irradiation to the nodes or neck node dissection. PMID- 8679283 TI - [Apropos of a recent trip to Quebec]. PMID- 8679285 TI - New insights into the role of host cell proteins in antiviral vaccine protection. PMID- 8679284 TI - [Incidence and risk factors of second primary cancers in patients treated for primary pharyngeal cancer]. AB - About 13% of patients treated for a pharyngeal cancer suffer from a second primary cancer. Excessive consumptions of tobacco and/or alcohol are recognized as risk factors of second primary cancers in these patients. Epidemiologic studies suggest that antioxidant vitamins could have a protective effect on the occurrence of second primary cancers; however, this hypothesis should be confirmed by randomized clinical trials. A better knowledge of the risk factors of second primary cancers in patients with a pharyngeal cancer could help reducing the occurrence of second primary cancers and improving the follow-up of these patients. PMID- 8679286 TI - HLA class II on HIV particles is functional in superantigen presentation to human T cells: implications for HIV pathogenesis. AB - The mechanisms of immune suppression by the human immunodeficiency virus, HIV-1, are more complex than simple helper T cell deletion via infection and viral induced lysis. Since the recent description of cellular proteins associated with HIV suggests that these proteins may be active in viral pathogenesis, the nature of HLA class II gene product carried on HIV, one of the most abundant of the human components carried with the virus, was examined. HIV bearing HLA-DR was shown to act with bacterial superantigen, staphylococcal enterotoxin A (SEA), to stimulate highly purified human T lymphocytes. T cell stimulation by wild-type HIV was shown by both induction of proliferation and by production of the cytokine interleukin 2 (IL-2). In contrast, HIV produced from mutant cells lacking class II genes were unable to cooperate with SEA to activate T cells. Neither whole HIV nor several proteins purified from HIV (gp120, gp41, p24, p7, and p6) exhibited superantigen-like activity in this system. HLA-DR-bearing HIV could, in the continued presence of SEA, induce T cell apoptosis, as detected by nuclear fragmentation and morphological criteria. These data indicate that human cellular proteins associated with HIV may be biologically active, and these proteins should be considered in mechanisms of viral pathogenicity and immunogenicity. PMID- 8679287 TI - Aspects of molecular interaction between HIV p17 and human gamma interferon. AB - We describe the specific interaction between high-purity recombinant human immunodeficiency virus (HIV) type 1 p17 and human gamma interferon (hIFN-gamma) proteins. This interaction was found to be dose dependent and to involve conformational epitopes on both sides. Specificity was confirmed by competition ELISA, using monoclonal antibodies (MAbs) to hIFN-gamma as specific reagents. By competition experiments we also identified the epitope(s) on the hIFN-gamma molecule involved in p17 binding, very close to the receptor binding site. The kinetic constants were determined by surface plasmon resonance (SPR) analysis. The affinity constant (KA) of the complex was 2.78 x 10(8) M-1, that is, the ratio between a low dissociation rate constant (Koff)(1 x 10(-5)sec-1) and a high association rate constant (Kon) (3 x 10(3) M-1sec-1). However, p17 did not displace the binding of hIFN-gamma to its cellular receptor, nor did it interfere with the capability of the lymphokine to induce de novo expression of HLA-DR antigens on human monocytic cells or to inhibit the proliferation of tumor cells. PMID- 8679288 TI - A resting cell assay for improved detection of antibody-mediated neutralization of HIV type 1 primary isolates. AB - The sensitivity with which antibody-mediated neutralization is detected in vitro is dependent on the virus, the antibody, the target cells, and the culture conditions used in the assay. Using activated and transformed target cells, the ability of various culture-adapted and primary strains of HIV-1 to be neutralized by different polyclonal and monoclonal antibody preparations has been thoroughly studied. However, the vast majority of HIV-1-susceptible CD4+ cells in vivo are not activated or transformed, but are quiescent. Because resting lymphocytes can be infected with HIV-1, we initiated studies to determine (1) if the use of resting lymphocytes as target cells would result in a neutralization assay with increased sensitivity, (2) if the degree of target cell activation had a measurable effect on the sensitivity with which antibody-mediated neutralization could be detected, and (3) whether, using a more sensitive assay, neutralizing antibodies in patients' sera might be detectable that had been below the threshold of detection when using "conventional" assays. The experiments described in the studies below reveal that an inverse relationship exists between the level of target cell activation and the sensitivity with which neutralization can be detected. Moreover, using an assay in which unstimulated peripheral blood mononuclear cells serve as target cells, experiments show that antibody-mediated neutralization of primary and prototype laboratory isolates of HIV-1 can be detected with 10- to 100-fold greater sensitivity than when stimulated peripheral blood mononuclear cells are used as target cells. With this resting cell assay, neutralizing activity can be detected in the sera of HIV-positive subjects that, by previously used "conventional" neutralization assays, was undetectable. PMID- 8679289 TI - Genetically engineered HIV type 1 peptides as tools for the determination of anti V3 loop antibody titers in sera from HIV type 1-infected patients. AB - Recombinant peptides from Escherichia coli encoding the principal neutralizing domain (PND) and surrounding sequences of gp120 of human immunodeficiency virus type 1 (HIV-1) with a C-terminal polyhistidine tag were expressed and purified on Ni(2+)-nitrilotriacetate agarose. High yields of more than 99% pure protein were obtained. Their serological reactivity with anti-HIV-positive and -negative human sera was compared to chemically synthesized V3 loop peptides. Overall the genetic PND peptides of the HIV-1MN isolate showed higher and broader reactivity patterns (84%) with HIV-positive sera from German patients than the chemically synthesized peptides (74%). By their higher reactivity and easy way of production and purification, recombinant peptides seem to be highly preferable for the determination of antibody titers to the PND of HIV-infected patients. PMID- 8679290 TI - Redefinition of tropism of common macrophage-tropic human immunodeficiency virus type 1. AB - Previous studies have suggested that the abilities of human immunodeficiency virus type 1 (HIV-1) to infect primary macrophages and transformed T cell lines are mutually exclusive and define an important biological distinction among HIV-1 strains. In a survey of eight macrophage-tropic HIV-1 strains and nine T cell lines, all frequently used in studies of tropism, we have found that six virus strains replicate in one or more T cell lines and that four T cell lines are highly susceptible to macrophage-tropic HIV-1. Passage through T cell lines did not affect the tropism or the env V3 sequence of monocytotropic HIV-1 strains. We conclude that HIV-1 replication in transformed T cells and primary macrophages are not mutually exclusive, and that as such, these definitions of tropism per se are not generally useful markers for other biological properties of HIV-1. PMID- 8679291 TI - Temporal relationship between elongation of the HIV type 1 glycoprotein 120 V2 domain and the conversion toward a syncytium-inducing phenotype. AB - The second and third variable domains (V2 and V3) of the human immunodeficiency virus type 1 (HIV-1) gp120 envelope molecule have been shown to be determinants of syncytium-inducing (SI) capacity. Previously we have reported evidence that increased length of the V2 domain and duplication or relocation of potential N linked glycosylation sites in V2 might be used as prognostic markers for evolution toward an SI phenotype. Here, we used a PCR assay that discriminates a 6-nucleotide difference in the length of the V2 domain, with a sensitivity of 1 elongated V2 domain when present in a background of 125 to 625 short V2 domains. Analysis of DNA isolated directly from PBMCs from 11 HIV-1-infected individuals prior to SI phenotype conversion revealed, however, that the usefulness of this PCR for V2 length polymorphism as predictive marker for SI phenotype evolution is limited. The strong association as observed in our previous study between elongation of the V2 domain and an SI phenotype prompted us to expand our first analysis. An extremely significant correlation was observed between V2 length and virus phenotype for samples obtained at about the moment of SI conversion, but not for samples obtained 3 to 35 months after SI phenotype conversion, suggesting that changes in V2 may be only transiently required to allow SI phenotype evolution. This possibly only transient nature of V2 elongation may explain the discrepancy between results by our group and others. PMID- 8679292 TI - Safety and immunogenicity of a recombinant HIV type 1 glycoprotein 160 boosted by a V3 synthetic peptide in HIV-negative volunteers. AB - The safety and the immunogenicity of a recombinant hybrid envelope glycoprotein MN/LAI (rgp160) followed by booster injections of a V3 (MN) linear peptide were evaluated in HIV-negative adults at low risk for HIV infection. Volunteers received either rgp160 in alum at 0, 1, and 6 months (group A), rgp160 at 0 and 1 months followed by V3 at 3 and 6 months formulated in alum (group B), or in Freund's incomplete adjuvant (FIA) (group C). Local and systemic reactions were mild to moderate and resolved within the first 72 hr after immunization. No significant biological changes (routine tests and autoantibodies) were observed. One month after the last injection in either group, neutralizing antibodies (NAs) against the HIV-1 MN isolate were detected in 4 of 5 (A), 7 of 10 (B), and 10 of 10 (C) subjects with significantly higher geometric mean titers in the latter group. Four of nine sera with the highest NA titers against MN weakly cross neutralized the HIV-1 SF2 isolate; none had NA against the HIV-1 LAI strain or against a North American primary isolate. Specific lymphocyte T cell proliferation to rgp160 was detected in 92% of the subjects after the second injection of rgp160 and in 80% of them 12 months after the first injection. A weak and short-lived envelope-specific CD(4+)-mediated cytotoxic lymphocyte activity was detected at certain time points in few subjects. This prime-boost vaccine approach using rgp160 followed by a V3 peptide was safe in humans, and was able to elicit high levels of neutralizing antibodies and a strong and persistent T cell lymphoproliferative response to rgp160 and to V3. However, the neutralization response was restricted to the homologous HIV-1 strain and little env-specific cytotoxic activity was induced. PMID- 8679293 TI - Replication of HIV type 1 in rabbit cell lines is not limited by deficiencies in tat, rev, or long terminal repeat function. AB - HIV-1 infection has been documented in rabbits, but infection proceeds slowly in this species. Human and rabbit cell lines were compared in order to identify barriers to efficient HIV-1 infection of rabbit cells. A direct comparison of human and rabbit CD4 as receptor for HIV-1 indicated that the rabbit CD4 homolog did not function well even when expressed by human cells. Examination of viral RNA production indicated that the major HIV transcripts were produced in HIV infected rabbit cells, but were present at levels significantly lower than those found for human cells. Ability of HIV-1 LTRs to direct protein expression in human and rabbit cells was compared using gene constructs with the chloramphenicol acetyltransferase (cat) gene flanked by HIV-1 LTRs. Chloramphenicol acetyltransferase protein expression was equivalent in rabbit and human cell lines transfected with the HIV-1/CAT constructs and cotransfections with the HIV-1 tat gene led to similar increases in CAT expression. Subsequent transfections with an infectious molecular HIV clone yielded approximately equal levels of HIV protein expression in rabbit and human cell lines, suggesting that major barriers to virus production in rabbit lines exist at steps prior to transcription of the viral genome. Because HTLV-I replicates with high efficiency in rabbit cells, a chimeric virus clone was constructed consisting of the 5' portion of HIV-1 through the nef coding sequence followed by the 3' HTLV-I LTR. Transfection of most rabbit cell lines with the chimera produced levels of p24gag protein higher than those transfected with the parent HIV-1 clone. By contrast, the unmodified HIV clone replicated more efficiently in all human cell lines tested. PMID- 8679295 TI - Similar patterns of simian immunodeficiency virus env sequences are found in the blood and lymphoid tissues of chronically infected macaques. AB - Two cynomolgus macaques were infected with a genetically complex challenge stock of simian immunodeficiency virus (SIVmac251-32H). One animal developed SIV induced disease and was sacrificed at 16 months postinfection. The second remained healthy until it too was sacrificed at 20 months postinfection. The polymerase chain reaction (PCR) was used to amplify env gp120-coding sequences from provirus present in samples of blood, spleen, and inguinal lymph node taken from both animals on the day of sacrifice. The proviral burden present in each of the tissue samples was also determined using a quantitative PCR assay. The proviral burdens in the blood, spleen, and inguinal lymph node of the healthy animal (I225) were similar. This was not the case for animal I227, in which the burden in the inguinal lymph node was much higher than for blood or spleen. Phenogram analysis of the hypervariable V1 region of env revealed that the diversity of nucleotide sequences recovered from each tissue of both macaques were similar and overlapping. Some selected amino acid differences were observed that were specific for a tissue or one of the macaques. However, the results do not suggest that the overall evolution of env in provirus populations recovered from lymphoid tissues is distinct from that recovered from the blood. PMID- 8679294 TI - Bidirectional enhancing activities between human T cell leukemia-lymphoma virus type I and human cytomegalovirus in human term syncytiotrophoblast cells cultured in vitro. AB - The syncytiotrophoblast layer of the human placenta has an important role in limiting transplacental viral spread from mother to fetus. Human cytomegalovirus (HCMV) is capable of establishing a latent infection in syncytiotrophoblast cells, with restriction of gene expression to immediate-early and early proteins. We analyzed the extent of replication of human T cell leukemia-lymphoma virus type I (HTLV-I) in human term syncytiotrophoblasts infected with HTLV-I alone or coinfected with HTLV-I and HCMV. Although syncytiotrophoblasts could be infected with cell-free HTLV-I, no viral protein expression was found in the singly infected cells. On the contrary, coinfection of the cells with HTLV-I and HCMV resulted in simultaneous replication of both viruses. Bidirectional enhancing activities between HTLV-I and HCMV were mediated primarily by the Tax and immediate-early proteins, respectively. The stimulatory effect of HTLV-I Tax on HCMV replication appeared to be mediated partly by tumor necrosis factor beta and transforming growth factor beta-1. We observed formation of pseudotypes with HTLV I nucleocapsids within HCMV envelopes, whereas HCMV was not pseudotyped by HTLV-I envelopes in dually infected syncytiotrophoblast cells. Our data suggest that in vivo dual infection of syncytiotrophoblast cells with HTLV-I and HCMV may facilitate the transplacental transmission of both viruses. PMID- 8679296 TI - Effects of total lymphoid irradiation on SIV-infected macaques. AB - The identification of antiretroviral drugs that prevent, or delay for extended periods, progression of HIV-related disease has been of limited success. Because the number of HIV-infected people continues to increase, other therapeutic approaches must be tested. Using simian immunodeficiency virus (SIV)-infected macaques in a feasibility study, total lymphoid irradiation (TLI) was administered in fractionated doses to the supradiaphragmatic and then the infradiaphragmatic lymph nodes until a cumulative dose of 34.2 Gy was achieved in each field. During treatment and for more than 1 year of follow-up, the effects of TLI on various virological, hematological, and immunological parameters were evaluated and compared to those of similarly treated, uninfected macaques. Despite sustained low numbers of CD4+ lymphocytes (< 100/microliters blood) during treatment, TLI was well tolerated, did not result in intercurrent infections, and more importantly, induced a transient decrease in viral burden and did not exacerbate disease. Remarkably, this lack of disease progression and apparent containment of SIV replication were maintained despite persistent failure of PBMCs to respond to mitogen stimulation. Because SIV (and HIV) requires activated lymphocytes to replicate, failure of PBMCs to respond fully to stimuli may have contributed to restricting virus replication. This idea was supported by in vitro experiments in which infection of PBMCs before TLI produced higher levels of cell-free SIV than those obtained during or after TLI. Last, repopulation of peripheral blood and lymph nodes with lymphocytes paralleled that observed in uninfected control animals. The results indicate that (1) immunosuppression alone is not sufficient to induce progression to AIDS, (2) SIV infection does not undermine the ability of the immune system to regenerate new cells during the clinically latent phase, and (3) further evaluation of TLI or other immunosuppressive regimens as potential therapies for HIV disease is warranted. PMID- 8679297 TI - HTLV type I isolated from a Pygmy in Cameroon is related to but distinct from the known central African type. PMID- 8679298 TI - The phylogenetic relationship of HTLV type I from non-Mashhadi Iranians to that from Mashhadi Jews. PMID- 8679299 TI - Completion of nucleotide sequences of non-syncytium-inducing and syncytium inducing HIV type 1 variants isolated from the same patient. PMID- 8679300 TI - Sequence analysis of the V1/V2 and V3 domains in an HIV-seronegative AIDS patient. PMID- 8679301 TI - HIV type 1 V3 sequences and the development of dementia during AIDS. AB - The most frequent neurological complication of AIDS is a dementia-like syndrome. Power and collaborators (J Virol 1994; 68:4643-4649) have reported an association between the clinical signs of AIDS dementia and the amino acid composition of two positions (305 and 329) within the V3 region of HIV-1 strains amplified from brain tissue. Similarly, we analyzed position 305 in the V3 region of HIV-1 present in the brain or cerebrospinal fluid of 25 nondemented subjects at different clinical stages of HIV-1 infection. Our results are, however, at variance with the findings presented by Power and colleagues. Histidine, found to be common among sequences derived from demented patients, was also present in the majority (16 of 25) of nondemented patients analyzed by us. In the hands of Power and colleagues, sequences derived from nondemented patients contained proline at position 305. None of our patients had proline in this position. We also asked the question whether the presence of a specific amino acid at position 305 of the V3 loop is linked to an increased capacity of HIV-1 isolates to infect primary microglial cells, the major target cell for HIV-1 infection in the brain. Primary HIV-1 isolates derived from blood and cerebrospinal fluid of five patients, two asymptomatic and three AIDS patients, were used to infect microglia cell cultures. Infection was monitored by syncytium formation and by p24 antigen release in the culture supernatant. All but one of the paired blood/CSF isolates replicated in human brain cultures. Replication occurred independently from the amino acid present at position 305 of the V3 region of the viral envelope. Our results indicate that the majority of HIV-1 isolates, even derived during the asymptomatic stage, have the capacity to infect microglial cells. The relevance of viral envelope sequences in determining tropism for microglial cells and development of neurological symptoms remains an open question. PMID- 8679302 TI - Sequence analysis of the V3 loop in brain and spleen of patients with HIV encephalitis. AB - Infection with a particularly neurovirulent strain of HIV has been hypothesized to explain why only a subset of patients develops HIV encephalitis. We studied the third hypervariable region (V3) of multiple clones from both brains and spleens of three patients who died with HIV encephalitis, to see if there was a molecular signature associated with neurological disease. Clones from the spleen and brain of individual patients showed significant nucleic acid homology and had envelope sequences characteristic of macrophage-tropic viruses. No brain-specific unique sequences were observed, suggesting that while CNS virus is macrophage tropic there is no evidence in the V3 envelope region studied to suggest a specific neurotropic variant. PMID- 8679303 TI - Interaction of human immunodeficiency virus type 1 envelope glycoprotein gp120 with a galactoglycerolipid associated with human sperm. AB - The expression of a molecule recognized by anti-galactosyl ceramide antibodies (MAb) O1 on the surface membrane of human spermatozoa was investigated by biochemical and immunochemical methods. Indirect immunofluorescence shows that this molecule is preferentially localized on the middle piece of the sperm tail. Immuno-thin-layer chromatography has identified it as a glycolipid related but not identical to galactosylceramide. Consistent with a structure similar to galactosylceramide, the sperm glycolipid is capable of binding gp120. An improved ELISA has been utilized to demonstrate the specificity of binding of the antibodies and gp120 to the isolated lipid fraction. Identity of the binding site of the two ligands to the glycolipid is suggested by competition assays. On the basis of preliminary biochemical analysis this glycolipid was tentatively classified as a galactosylalkylacylglycerolipid (GalAAG), the nonsulfated form of the seminolipid, a glycolipid known to be present in the testis and germ cells of mammals. These data indicate that human sperm express a glycolipid similar in structure to the receptor for HIV described on the CD4- neural and colonic epithelial cell lines, and moreover suggest that this glycolipid could also function as HIV receptor and possibly be implicated in its transmission. PMID- 8679304 TI - Epitope specificity of anti-HIV antibodies in human and murine autoimmune diseases. AB - This article reports the HIV epitope specificity of antibodies present in the sera of HIV-negative patients with autoimmune diseases. Recombinant gp120 and a panel of synthetic peptides derived from the amino acid consensus sequences of either related (gp120, gp41, and p24) or unrelated (Mage-1, necdin, heat shock protein [65 kDa], and amyloid) HIV proteins were tested by a specific ELISA. The first set of experiments performed on four patients with Sjogren's syndrome (SjS) and four patients with systemic lupus erythematosus (SLE) revealed a significant anti-gp120 antibody reactivity in autoimmune patients when compared to healthy HIV-negative controls. Moreover, such binding could be almost completely inhibited by preincubation with free gp120. A significant anti-p24 reactivity was observed in 18 of 29 sera from SjS patients and in 13 of 25 sera from SLE patients, while anti-gp41 was observed only in 3 of 14 SjS and in 2 of 20 SLE affected patients. Similar analyses were performed in the murine model of autoimmunity, showing that sera from MRL/lpr mice were able to bind all HIV related peptides in an age-dependent manner. The analysis of a panel of HIV unrelated peptides showed that SLE as well as MRL/lpr sera bind both HIV-related and unrelated peptides, while SjS sera failed to do so, revealing the polyclonal nature of the SLE and MRL/lpr repertoire and the oligoclonal reactivity of SjS sera. This is also supported by inhibition experiments, which showed that SLE, but not SjS, sera competitively inhibited the binding to HIV gp120 peptide of sera from autoimmune MRL/lpr mice. These results indicate that an overlapping polyclonal repertoire is present in both SLE and MRL/lpr sera, while the oligoclonal specificity of SjS antibodies may be related to a specific, nonpolyclonal, activation against putative retroviral antigens. PMID- 8679305 TI - Delayed virus-specific CD8+ cytotoxic T lymphocyte activity in an HIV-infected individual with high CD4+ cell counts: correlations with various parameters of disease progression. AB - This 4-year longitudinal study monitored the temporal association between the HIV specific cytotoxic T lymphocyte (CTL) response and the control viremia in an individual infected with human immunodeficiency virus type (HIV-1). At the beginning of the study, this asymptomatic individual with a high CD4+ cell count showed no HIV-specific cytotoxic activity after polyclonal in vitro restimulation with autologous PHA-blasts, unlike most HIV-seropositive individuals. Anti-HIV CTLs were detected only in the last year of the study, both after in vitro restimulation and directly ex vivo. This was correlated with the inversion of the CD4+/CD8+ ratio, essentially due to increased numbers of CD8+CD28- T lymphocytes. The HIV-specific cytolytic activity was mediated by this CD28+CD28- subpopulation. The amount of HIV-1 provirus in peripheral blood mononuclear cells (PBMCs) did not change during the study, but the HIV RNA in plasma increased and virus was isolated from PBMCs only at the time when HIV-specific CTL activity was detected. This suggests overall that the HIV-1 replication was low in this individual, with a transient increase that could have reached the threshold for CTL reactivation, and was perhaps controlled thereby. PMID- 8679306 TI - Drug combinations and effect parameters of zidovudine, stavudine, and nevirapine in standardized drug-sensitive and resistant HIV type 1 strains. AB - Reference strains of HIV-1 from the NIH AIDS Research and Reference Reagent Program, including wild-type IIIB, G762-3, and AZT resistant with RT 215T-->Y (G910-11/AZT); 67D-->N, 70K-->R, 215T-->F, 219K-->Q (G691-2/AZT); as well as nevirapine (NEV) resistant with 181Y-->C (N119/NEV); and 103K-->N, 181Y-->C (A17/NEV), were subjected to quantitative parametric efficacy analysis using AZT, stavudine (D4T), and nevirapine (NEV) singly or in combinations in MT4 or MT2 cells. The median-effect principle and combination index (CI) method of Chou Talalay (see Ref. 26) have been used, which take into account both the potency (Dm value or EC50) and the shape of the dose-effect curve (m value). Under standardized assay conditions, G910-11 and G691-2 strains showed 600- and 7800 fold resistance to AZT, and N119 and A17 strains showed 3600- and 1000-fold resistance to NEV at the EC50 level, respectively. AZT-resistant strains exhibited slight cross-resistance to D4T. Computerized analysis indicates that IIIB gave sigmoidal dose-effect curves (m = 2.8, 3.4, and 3.1 for AZT, D4T, and NEV, respectively) whereas drug-resistant strains showed negative sigmoidicity toward the corresponding AZT or NEV, with m = 0.27-0.73. Therefore, the degrees of drug resistance are drastically different at classic EC50 and at therapeutically more relevant EC95 levels (ranging from severalfold to several log orders). Combinations of AZT+NEV and AZT+NEV+D4T showed synergism against IIIB, G762-3 (wild type) and A17/NEV, G910-11/AZT strains. D4T+NEV and AZT+D4T showed nearly additive or moderate antagonism. Synergism or additive effect leads to a favorable dose-reduction index (DRI). The present study on RT inhibitors provides quantitative assessment of the combinations of AZT, NEV, and D4T against HIV infections involving drug-sensitive and drug-resistant HIVs. PMID- 8679307 TI - B cell epitopes of HIV type 1 p24 capsid protein: a reassessment. AB - The objective of the present study was to identify p24 antigenic domains recognized during natural human immunodeficiency virus type 1 (HIV-1) infection, the determination of the major epitopes of p24 having significant applications for both the improvement of diagnostic approaches and the development of vaccines. Reactivity of 20 HIV-1-infected patients and 8 HIV-1-negative patients was analyzed using an enzyme-linked immunosorbent assay (ELISA) developed with 45 overlapping synthetic pentadecapeptides, spanning amino acids 133 to 363 of HIV-1 p55gag precursor. Two peptides covering aa 178-192 and 288-302 of p55 were recognized by 40 and 45% of HIV-1 antibody-positive human samples, respectively. A peptide covering aa 272-322 of p55 was synthesized and recognized by most human sera in indirect ELISA. However, inhibition assays indicated that this sequence does not contain all of the immunodominant domains of p24 since it was not sufficient to block binding of human sera to whole p24. A three-dimensional model of p24 derived from the Mengovirus VP2 suggests that the two distant sequences recognized by human sera containing antibodies to HIV-1 could possibly be a part of a conformational epitope built up by two loops corresponding to aa 183-186 and 289-292. PMID- 8679308 TI - Cyclic AMP-mediated growth arrest is associated with increased expression of human T cell leukemia virus type I structural and transforming genes. AB - The effect of increased intracellular cyclic AMP levels on gene expression of the human T cell leukemia virus type I (HTLV-I) provirus was examined. Induction of infected cells to produce elevated levels of cyclic AMP was associated with specific increases in viral surface antigen expression, protein synthesis, p24 release into the supernatant, and RNA levels. The patterns of HTLV-I proviral gene expression observed support results from transfection experiments regarding the function of Tax, Rex, and cyclic AMP in HTLV-I gene regulation. As evidenced by thymidine incorporation, treatment of the infected cells to produce cyclic AMP caused reversible growth arrest. The data indicate that HTLV-I RNA and protein synthesis can proceed at an elevated level in the absence of cell growth. Sustained increases in the intracellular level of cyclic AMP may represent a method for enriching cell cultures in HTLV-I proteins. PMID- 8679309 TI - Negative regulation of gene expression from the HTLV type II long terminal repeat by Rex: functional and structural dissociation from positive posttranscriptional regulation. AB - Regulation of human T cell leukemia virus type II (HTLV-II) gene expression by Rex is mediated by cis-acting elements in the 5' viral long terminal repeat (LTR). Rex acts posttranscriptionally to enhance cytoplasmic accumulation of incompletely spliced viral mRNAs encoding structural proteins. We report a distinct negative regulatory function mediated by Rex affecting expression from the viral 5' LTR. Using both LTR-driven CAT reporters and a full-length HTLV-II proviral construct, we demonstrate that Rex decreases total cellular levels of LTR-containing mRNA in a dose-dependent manner. Negative regulation is an independent function as demonstrated by structural and functional dissociation from Rex positive posttranscriptional regulation. This negative regulatory action was dependent on nuclear localization sequences, but did not require the previously defined Rex-responsive element (RxRE). Negative regulation was observed in T cell lines but not in B cell lines, suggesting the involvement of cell type-specific factors distinct from those involved in posttranscriptional regulation. An internal deletion mutant of Rex removing aa 38-80 retained the ability to repress, but did not posttranscriptionally increase expression, while negative regulation requires a previously uncharacterized carboxy-terminal region (aa 154-170). These findings suggest that Rex may serve two simultaneous functions: to decrease overall levels of transcribed viral mRNA, and to facilitate nuclear to cytoplasmic export of mRNAs encoding structural proteins. The negative regulatory function of Rex may play a role in viral latency. PMID- 8679310 TI - Temporal lobe electroencephalogram power modifications during olfactory stimulation in HIV-infected patients. AB - Evidence derived from studies concerning brain metabolism and brain electrical activity suggests that temporal lobe functioning is impaired in the course of HIV infection. To test the hypothesis of temporal lobe dysfunction in HIV infection, we utilized computerized electroencephalogram (EEG) analysis to evaluate temporal lobe EEG power modifications induced by olfactory stimulation in 10 HIV-infected patients as compared with 10 seronegative control subjects. Our findings show that HIV-infected patients respond to olfactory stimulation with an increase in temporal lobe slow electrical activity (theta EEG power), whereas control subjects show a decrease in the same activity. The theta EEG power increase during olfactory stimulation in HIV-infected patients can be interpreted as a paradoxical response of the deep temporal regions to specific procedures, supporting the hypothesis of temporal lobe dysfunction in HIV infection. PMID- 8679311 TI - Complete DNA sequence of the gene encoding the external glycoprotein (gp120) from a Cuban HIV type 1 isolate. PMID- 8679312 TI - Sequences and phylogenetic analysis of the nef gene from Thai subjects harboring subtype E HIV-1. PMID- 8679313 TI - Diversity of HIV type 1 envelope V3 loop region in saliva. PMID- 8679314 TI - [Present strategy and future perspective of therapy in Parkinson's disease]. PMID- 8679315 TI - [Stimulus effect of submaximal trains of impulses on nerves]. AB - Although the occurrence of rate-dependent conduction block upon exposure to supramaximal stimuli is a well-known phenomenon, changes in the stimulus effect of submaximal trains of impulses on nerves remain unknown. To investigate changes in the stimulus effect, we evaluated median nerve action potentials using various frequencies of impulse trains. The subjects were 12 healthy controls and 9 patients with diabetic polyneuropathy. A tungsten microelectrode was inserted into the median nerve trunk at the elbow. Weak stimuli that produced 10 microV compound nerve action potentials were repeated. Each value recorded is the average of 20 trials. Repetition of 1- to 5-Hz stimuli yielded the same average wave, but above 7-Hz, the stimuli produced a diminution in amplitude and slight prolongation of the latency of each peak. This was most prominent with 50-Hz or 100-Hz repeated stimuli. The potentials changed amplitude with a waxing and waning pattern, and gradually stabilized at a lower level. The averaged wave corresponded to the record of reduced stimuli at 0.6 mA, maximally. Paired stimuli at an interval of less than 5 msec were equivalent to a relative refractory period, whereas at an interval of 4-18 msec they were equivalent to a supernormal period, and at 12-90 msec, to a subnormal period. The 'jumping' (unexpected shortening of the latency of a potential in response to increased stimulus intensity) of a single nerve unit was provoked or released corresponding to these periods. No differences were found between healthy individuals and patients with diabetic polyneuropathy. As a consequence of electrogenic Na+/K+ pumping, a three-Na+ ion efflux occurred instead of a two-K+ ion influx. Thus, repeated high-frequency impulses induced membrane hyperpolarization that reduced the stimulus effect on nerves. With trains of impulses at a frequency of 100-Hz, which corresponds to a stimulus every 10 msec, the second response was greater than the first, reflecting the supernormal period, but impulse trains provoked hyperpolarization, as mentioned above, and reduced the amplitude of nerve action potentials. The results of this study show that the stimulus effect on nerves decreased at submaximal stimuli greater than 7-Hz, which reduced the amplitude of compound nerve action potentials. Therefore, averaging should be done at a stimulus frequency below 6-Hz. PMID- 8679316 TI - [The relationship between visual agnosia and visual pathway for perception]. AB - We report a patient with a unique visual agnosia, who was thought to have lost visual functions except for the primary visual function. The patient was a 71 year-old woman with progressive memory loss and cerebro-cortical atrophy in MRI; her clinical diagnosis was senile dementia of Alzheimer's type. A battery of tests to detect higher visual dysfunctions was performed. First of all, we presented small dots and lines in front of the patient; the patient was able to recognize them. When a triangle, a tetragon, a cube, pieces of paper of different colors and lines of different length were presented, she was unable to recognize those objects. When pictures of her family members or filled circles of different size including small dots and lines were presented, the patient could only detect those small dots and any of lines; she could not recognize the members of her family. The cerebral blood flow was severely reduced in the occipital lobe except for the striate cortex. These data suggested that the visual function of striate cortex was preserved in this patient; the disturbance of higher visual functions was thought to be caused by the dysfunction of extra striate cortex. PMID- 8679317 TI - [Analysis of the proliferative potential of meningiomas with MIB-1 monoclonal antibodies]. AB - Tumor recurrence was observed in 12 (11.3%) out of 106 cases of intracranial meningioma followed for more than 5 years. Proliferative potential was evaluated immunohistochemically with MIB-1 monoclonal antibodies in 37 cases of non recurrent meningioma and 12 cases (21 samples) of recurrent meningioma. The proliferating cell index (PCI) was much higher in the non-recurrent meningiomas than the recurrent meningiomas (10.6 +/- 7.7 [mean +/- SD] versus 1.9 +/- 1.5). Most recurrent meningiomas had high PCI values, greater than 3%. High PCI values of more than 5% were found in 13 (62%) of the 21 samples of recurrent meningioma. However, only 4 of the 37 cases of nonrecurrent meningioma had high PCI values with MIB-1 of more than 3%. The 12 cases of recurrent meningioma were classified into 3 groups: 6 cases in which both the initial and recurrent meningiomas were benign (Group I), 5 cases in which the meningioma at the time of the initial operation was benign, but the recurrent meningioma was malignant (Group II), and one case in which malignant meningioma was diagnosed at the time of the initial operation (Group III). The PCI values with MIB-1 in most of the recurrent meningiomas were higher at the time of recurrence than at the time of the initial operation. Malignant meningiomas, such as anaplastic and atypical meningioma, and some meningotheliomatous meningiomas among the benign meningiomas recurred and had higher PCI with MIB-1 values than other meningiomas. It is concluded that PCI with MIB-1 is important as a predictive factor for the recurrence of meningiomas. Meningiomas having a PCI value with MIB-1 of more than 3% in particular should be followed carefully. PMID- 8679318 TI - [Functional imaging of the sensorimotor cortex using an ultra-fast MR imaging method]. AB - The aim of this study was to assess changes in brain activity during a motor task and variable sensory stimulation using echo planar imaging, which represents the fastest clinically usefull imaging technique available. MATERIALS AND METHODS: The subjects of this study were 11 healthy-volunteers, 4 males and 11 females, with an average of 26.4 years. The subjects were instructed to tap the fingers of one hand as the motor task. Compressed air was applied 5 times a second as "simple" sensory stimulation. Simple figures were drawn on the subjects palm as "complex" sensory stimulation. In all cases, functional imaging was performed by T2*-weighted echo planar imaging (TE = 53 msec, TR = 3000 msec, flip angle = 90 degrees, matrix 64 x 64, FOV = 205 mm, slice thickness = 8 mm) alternately at rest and during the task (intervals: 30 sec). A total of 60 images was collected in 3 minutes. Images obtained by subtracting images at rest and during the task were analyzed. RESULTS AND DISCUSSION: Almost all subjects showed a transient signal increase in the contralateral paracentral region during simple sensory stimulation. Continuous signal increases in the contra- and/or ipsi-lateral para central region were observed during complex sensory stimulation. Some exhibited signal increases in the parietal or frontal association cortex, but they disappeared when subject's attention was distracted during stimulation. All subjects displayed signal increases in the contralateral para-central region during the motor task. Some of them exhibited signal increases in the medial frontal area (supplementary motor area) and ipsilateral para-central region. These results suggest that the signal increases of functional MRI reflect not only simple reactions to stimulation but higher cerebral function as well. PMID- 8679319 TI - [Etiology and pathogenesis of parkinson's disease]. PMID- 8679320 TI - [Hypothalamic-adenohypophysial function of corticotropin releasing hormone (CRH) ACTH system in hypoxic coma]. AB - To evaluate the hypothalamic-adenohypophysial function of corticotropin releasing hormone (CRH)-ACTH system in severe hypoxic coma, basal serum values of ACTH and cortisol was measured, and insulin-tolerance test (ITT) and CRH stimulation test was performed in 15 cases. They were divided into two groups according to their prognosis: brain death (group A, 7 cases) and persistent vegetative state (group B, 8 cases). Basal values were within normal range in most cases apart from those measured in few days after the brain death, however, stimulation tests were negative in many cases. In group A, basal values in impending stage were significantly higher han those after the brain death (p < 0.05), however, both stimulation tests were negative regardless of the stage. In group B, basal values in acute stage, which was measured within a week after the hypoxia, were slightly higher (without significance) than those in chronic stage, which was measured more than a months after the hypoxia. CRH test and ITT were positive in 0/4 and 2/5 in acute stage, and in 4/8 and 3/8 in chronic stage, respectively. In early stage of group A, the impending stage, showed slightly higher basal values than those in acute stage of group B (without significance). ITT was negative in the former whereas positive in some cases (2/5) of the latter, however, CRH test was negative in both groups. These results suggest that endocrinological evaluation of the hypothalamic-adenohypophysial function may help to predict outcome in early stage of hypoxic coma. PMID- 8679321 TI - [Indication of early surgery in elderly patients with ruptured intracranial aneurysms--the comparison between surgical and conservative therapy]. AB - The purpose of this study was to investigate the indication of direct early surgery for elderly cases aged over 70 years with ruptured intracranial aneurysms. The result of early surgical treatment in 39 elderly cases was analyzed and was compared with that of conservative treatment in 39 elderly patients. According to the multiple logistic analysis, surgery was only significant factor influenced the outcome, however, Hunt & Kosnik grade (HKG), activity of daily life (ADL) before subarachnoid hemorrhage (SAH) and past history were related to the outcome. The outcome in the direct early surgical group statistically correlated (p < 0.05) with preoperative HKG, although the outcome in the conservative group did not correlate with HKG. The outcome in conservative group was miserable because of rerupture or poor preoperative neurological grade. The indication of direct early surgery for elderly cases with ruptured intracranial aneurysms should be considered as follows, HKG 1 to 3, ADL before SAH 1, no or minor past history and age under 84 since most elderly patient was 84 in our series. Direct early surgery in elderly patients seems to improve the outcome under these indications. PMID- 8679322 TI - [A case showing recurrence of myelopathy and optic nerve disturbance accompanied by pusturosis palmaris et plantaris and positive anticardiolipin antibody]. AB - The patient is a 62-year-old woman who was admitted to our hospital with chief complaints of paresthesia in the four extremities and the trunk and gait disturbance in February 1993. Habitual abortions and left retrobulbar optic neuritis were present in the past history. She had been suffering from pusturosis palmaris et plantaris for 10 years. On admission, weakness of the distal muscles in the right upper extremity and severe disturbance of the deep sensations in the bilateral lower extremities and the right upper extremity were present. With the progress of the neurological symptoms, pusturosis palmaris et plantaris progressed. After the admission, the neurological symptoms became better by the administration of corticosteroid hormone medicine. After that, myelopathy and left optic nerve disturbance relapsed and IgG anti-cardiolipin antibody in the serum was present. The neurological symptom, pusturosis palmaris et plantaris and positive IgG anti-cardiolipin antibody in the serum may be caused by immunological mechanism. Anti-phospholipid antibodies such as IgG anti cardiolipin antibody in the serum should be examined in patients with clinical multiple sclerosis like our case. PMID- 8679323 TI - [An autopsy case of "diffuse neurofibrillary tangles with calcification", multiple infarctions and hyaline arteriosclerosis]. AB - "Diffuse neurofibrillary tangles with calcification (DNTC)" is a slowly progressive form of presenile dementia characterized by localized temporal atrophy, pronounced calcareous deposits and numerous neurofibrillary tangles (NFTs) without senile plaques. We report a 70-year-old woman with DNTC, multiple infarctions and hyaline arteriosclerosis. This case was clinically characterized by persistent delusional ideas and personality changes. Intellectual deterioration was mild, and no focal manifestations were noted. Neuropathologically, numerous NFTs were seen distributed primarily in the hippocampal region, and massive calcareous deposits were observed in the cerebrum, basal ganglia and cerebellum. There were no senile plaques. Although the findings in this case were compatible with a diagnosis of DNTC, certain additional findings were also noted. The first was the presence of multiple infarctions in the basal ganglia and hyaline arteriosclerosis. Although these lesions may have been induced by hypertension, our review of previous reports of DNTC revealed a high incidence of arteriosclerosis. The second was the absence of lobar atrophy, which may have been due to the cerebral edema caused by the subdural hemorrhage or related to the relatively short duration of the illness. The dilatation of the temporal horn of the lateral ventricle and prominent NFTs in the hippocampal region indicate the initial occurrence of the disease in this region. PMID- 8679324 TI - [Isolated angiitis of the central nervous system presenting as subcortical hemorrhage--a case report of benign type]. AB - A 47-year-old woman had an episode of severe headache for a few days. She suddenly experienced right leg weakness and sensory loss. A CT scan revealed subcortical hematoma at the left parietal lobe on admission. Cerebral angiography showed multiple vascular irregularities such as segmentally narrow or sausage like dialatated areas. Her laboratory studies were entirely normal including antinuclear antibody and coagulation tests. The diagnosis of isolated angiitis of the CNS was made and she responded well to the low dose corticosteroid therapy. Repeated cerebral angiography two months after the onset demonstrated most of the areas of segmental irregularity had improved with a few unchanged areas. Some cerebral angiitis do exist that respond well to corticosteroid therapy, therefore, early diagnosis and treatment are suggested in cases of angiitis. PMID- 8679325 TI - [A 32-year-old man who developed a posterior fossa mass 12 years after the radiation therapy for cerebellar arteriovenous malformation]. AB - We report a 32-year-old man who developed cerebellar ataxia and a posterior fossa mass 12 years after the radiation therapy for a cerebellar arteriovenous malformation (AVM). The patient was well until 19 years of the age when he had an acute onset of vertigo and vomiting. A spinal tap was performed and the CSF was bloody. He was admitted to another hospital where an arteriovenous malformation was found in the cerebellum by angiography. Four years after the onset, he developed tingling sensation in the distribution of the second division of the right trigeminal nerve. He was admitted to the neurosurgery service of our hospital where the cerebellar AVM was confirmed. He was transferred to University of California where Bragg peak stereotaxic radiotherapy was successfully performed; this utilizes high energy alpha-ray produced by a cyclotron. Three years after the radiotherapy, marked reduction in the size of the AVM was confirmed by angiography. Twelve years after the onset of his initial symptom, he noted unsteadiness of gait. He was readmitted to our neurosurgery service where obstructive hydrocephalus was found. He was treated by ventriculoperitoneal shunting and placement of a Ommaya reservoir. After these therapy, he noted marked improvement in his gait and ataxia. However, in 1993, his unsteadiness of gait recurred, and he was again admitted to our neurosurgery service on June 20, 1993. On admission, T1-weighted MRI revealed a slightly low signal intensity mass lesion in the right cerebellar hemisphere compressing the brain stem; a spotty high signal intensity lesion and another small low intensity lesion were seen within the mass. Vertebro-basilar angiograms revealed upward displacement of the superior cerebellar arteries. No arteriovenous nidus was visualized. On July, 3rd, the cyst was surgically drained and the Ommaya reservoir was removed. Post operative course was uneventful, however, he developed head tremor after the surgery. Neurologic examination on July 20, 1993 revealed an alert and well oriented man in no acute distress. General physical examination was unremarkable. Neurologic examination revealed no dementia; higher cerebral functions appeared intact. The optic discs were flat, and visual fields were intact. Ocular movements were full but convergence was restricted. Horizontal gaze nystagmus was noted more in the right lateral gaze. Pupils were intact. Facial sensation and facial muscles were intact. Hearing was normal. His voice was of nasal quality. Pharyngeal reflex was diminished. The tongue showed deviation to the left without atrophy. Head tremor at 5 c/s was noted. He was able to stand with support but was unable to walk. No muscle atrophy or weakness was noted. The finger-to-nose and the heel-to-knee tests showed dysmetria and decomposition more on the right. Rapid alternating movements were ataxic on the right. Muscle tone was diminished on the right. Muscle stretch reflexes were normally elicited and were symmetric. The plantar response was flexor bilaterally. Sensation was intact. On July 21, a posterior fossa exploration was performed. After the surgery, he was treated with 30 mg/day of alotinolol which showed no effect on his head tremor. He was then treated with gradually increasing doses of clonazepam; when he received 8 mg/day of clonazepam, his tremor showed marked improvement. He was discussed in a neurologic CPC on the nature of the posterior fossa lesion and his tremor. Opinions were divided between delayed radiation necrosis and a radiation-induced brain tumor. The chief discussant arrived at the conclusion that the patient had delayed radiation necrosis compressing the brain stem and cerebellar hemispheres. Regarding the nature of his tremor, he thought that his head tremor was of cerebellar type of postural tremor. Histologic examination of the biopsied specimen revealed accumulation of relatively fresh blood constituents in the deep area of the cerebellum forming a mass. Most of the PMID- 8679326 TI - [Gene hunting of facioscapulohumeral muscular dystrophy]. PMID- 8679327 TI - [Gene hunting for Fukuyama type congenital muscular dystrophy]. PMID- 8679328 TI - [How was the gene for dentatorubral-pallidoluysian atrophy discovered?]. PMID- 8679329 TI - [Gene hunting for Machado-Joseph disease]. PMID- 8679330 TI - [Huntington's disease gene: molecular genetics and molecular biology]. PMID- 8679331 TI - [MR diffusion-weighted imaging of cerebral infarction]. AB - MR diffusion-weighted imaging was performed to investigate changes in water diffusion in patients with cerebral infarction, and diffusion-weighted images (DWI) were compared with T2-weighted images (T2WI). Acute and subacute infarcts were seen as areas of high intensity on DWI and showed lower apparent diffusion coefficients (ADCs), while chronic infarcts showed a relative increase in ADCs. The relative ADC increased progressively over time, becoming renormalized at 3 to 4 weeks, and was elevated in the chronic state. On DWI, infarcts as small as 5 to 6 mm in diameter and lesions adjacent to the ventricular or subarachnoid space could be readily identified. DWI was useful for distinguishing acute lesions from chronic lesions in patients with multiple cerebral infarction, and provided valuable pathophysiologic information on the course of ischemic stroke evolution. PMID- 8679332 TI - [Gamma knife treatment of AVM of the basal ganglia and thalamus]. AB - Arteriovenous malformatios (AVMs) in the basal ganglia (BG) and thalamus (Thal) are difficult to treat by microsurgery or intravascular embolization alone, and the role of stereotactic gamma radiosurgery (gamma knife) of these AVMs is discussed. We have treated 324 cases of AVM with gamma knife since May 1991, and in 71 of these cases (19%) the AVM was in the BG or Thal. The results of gamma radiosurgery on AVMs of the BG and Thal were compared with the results of treating AVMs at other intracranial locations by gamma radiosurgery. The nidi were small (mean diameter: 16.4 mm), and they were treated with a mean maximum dose of 36.4 Gy and marginal dose of 19.9 Gy. The results were evaluated angiographically in 39 (55%) of the 71 cases, with a mean follow-up period of 23 months. The complete obliteration rate of AVMs in the BG and Thal 1 and 2 years after treatment was 54.3% and 92.0%, respectively, and the rate at the other locations was 42.9% and 76.0%, respectively. Adverse effects of this treatment in the AVM cases overall were rebleeding from the nidus in 5 cases (1.5%) and radiation necrosis in 4 cases (1.2%). In conclusion, AVMs of the BG and Thal were effectively and safely treated with the gamma knife, and stereotactic radiosurgery is a definitive alternative treatment for deep seated AVMs. PMID- 8679333 TI - [Contingent negative variations associated with vocalization in humans]. AB - We investigated the late negative components of the contingent negative variations (CNVs) in the verbalization task. Six subjects were instructed to perform three different motor tasks, jaw opening, vocalization of a meaningless sound and that of a word, in response to a sound stimulus following a visual warning stimulus with interstimulus interval of 4.0 sec. The electroencephalograms (EEGs) were recorded from the midline-central (Cz), left and right temporal areas (T3 and T4) and frontal areas (F7 and F8). EEGs were averaged 16 times using the visual stimulus pulse as a trigger to obtain the CNVs in each motor task. There was no significant difference between the tasks of the jaw opening and vocalization of the sound in the CNV amplitudes at bilateral electrodes. However, the amplitudes of the CNVs at the left frontal and temporal areas were significantly larger in the case of vocalization of the word than in that of jaw opening (p < 0.05). On the other hand, there was no significant difference between these two tasks in the CNV amplitudes at the right frontal and temporal areas. Our results suggested that the CNVs generated over the left hemisphere might reflect the brain activities involved in language production. PMID- 8679335 TI - [Complex visual hallucinations in the hemianopic field following an ischemic lesion of the occipitotemporal base--confirmation of the lesion by MRI and speculations on the pathophysiology]. AB - We report a patient who presented with complex visual hallucinations in the right hemianopic field following an infarction in the left occipitotemporal base. A 73 year-old right-handed woman developed right homonymous hemianopia. A week after its onset, she noticed a strange man with glasses, or a man wearing a gray hat and a black coat standing in the defective visual field. Such visual images later included a nurse, a large hand extending from the right side to the center, and many pieces of cloth descending from the roof. Most of these objects were unfamiliar to her, but may have been related to previous experiences. Her hallucinations were usually black and white singular and motionless, and sometimes consisted of multiple identical replications of objects. All of the hallucinations vanished when the patient tried looking directly at them. An EEG failed to showed any epileptic discharges. T1-weighted MRI with gadolinium-DTPA performed nine days after the onset revealed a localized high-signal-intensity region suggesting an infarction around the left collateral sulcus that included part of the lingual gyrus and the fusiform gyrus. 123I-IMP SPECT showed hypoperfusion of the left occipitotemporal base. The hallucinations gradually resolved a month after the onset, but the right homonymous hemianopia persisted. The enhanced lesion on T1-weighted images was no longer visible on MRI performed a month after the onset but, remained high-intensity on the T2-weighted images. There have been reports of complex visual hallucinations in hemianopic fields, but there have been only a few reports in which the responsible lesion was discussed on the basis of the CT and MRI findings. The findings in our patient suggest that lesions of the occipitotemporal base are one of the possible causes of this symptom. Taken together with earlier reports, not only pure release phenomena but irritative phenomena in the association visual cortex may be involved in the complex visual hallucinations in the hemianopic field, as Lance and Kolmel suspected. PMID- 8679334 TI - [Expression of fibroblast growth factor receptors (FGFRs) mRNA in human astrocytomas]. AB - Although fibroblast growth factor receptor (FGFR) 4 has been reported not to be expressed in normal human astrocytes, we have demonstrated expression of FGFR-1, 3, and -4 in six human glioblastoma cell lines (SNB19, T98G, UW18, D54 MG, U251MG, and U373MG) by RT-PCR Southern blot analysis. All six lines exhibited predominantly beta-type (with only two extracellular Ig-like domains) FGFR-1 expression. In contrast, FGFR-2 expression was only detected in the UW18 cell line. This evidence support our previous observation that malignant progression in astrocytomas is associated with a shift in FGFR-1 mRNA splicing from the alpha type (with three extracellular Ig-like domains) to the beta-type with concomitant loss of FGFR-2 expression. It also demonstrates the unique finding that FGFR-4 induction in astrocytomas is associated with transformation. In addition to these cell lines, expression of FGFRs was analyzed in normal human brain tissue and in human astrocytoma tissue samples corresponding to different grades of malignancy. FGFR-4 mRNA was undetectable in normal adult white matter, the site of origin of astrocytomas, while astrocytomas of all grades exhibited significant expression of FGFR-4 mRNA as determined by RT-PCR Southern blot analysis. The proportion of FGFR-4 mRNA did not appear to change in relation to the malignant progression of the astrocytomas. This suggests that induction of FGFR-4 expression in astrocytes represents an early event in their malignant transformation. Induction of FGFR-4 in malignant astrocytomas is consistent with previous reports demonstrating that expression of aFGF, which activates FGFR-4, increases in astrocytomas. The simultaneous induction of FGFR-4 and aFGF may establish a potential autocrine pathway that endows astrocytoma cells with a selective growth advantage. Interestingly, very high expression of FGFR-4 mRNA was found in human fetal brain tissue. The above findings suggest that the malignant transformation of astrocytes may involve the activation of a fetal growth promoting pathway. PMID- 8679336 TI - [A 65-year-old man with Parkinsonism, gaze palsy, and dementia]. AB - We report a 65-year-old man with parkinsonism, supranuclear gaze palsy, and dementia. The patient was well until 58 years of the age (1984) when he noted an onset of tremor in his right hand. He visited our neurology service two years after the onset; neurologic examination at that time revealed moderate restriction in down ward gaze, horizontal gaze nystagmus in left and right gaze, stooped posture with loss of arm swing when he walked, slight rigidity in the neck and the right upper and lower extremities, and resting tremor in his right hand and foot; mentation was intact. He was treated with 600 mg of levodopa with carbidopa; his tremor partially improved. He received left Vim thalamotomy on March 14 of 1987. His tremor disappeared after the thalamotomy. Post-operative course was complicated by transient clouding of consciousness due to subdural hematoma which developed after the surgery. Six months after the surgery, he noted increase in the unsteadiness of gait; he also experienced urinary incontinence once in a while, and he became mentally dull. In November of 1988, he had episodes of stiffening of his body. Although his spontaneous speech was very much reduced, he repeatedly hummed a same tune; no one could make him stop humming. In June of 1989, he was totally unable to move his eyes in the vertical direction. He was hospitalized to another hospital in May of 1990 where he died six month after admission because of pneumonia. The clinical course of this patient was characterized by the onset with parkinsonian resting tremor, and supranuclear gaze palsy and dementia in the later course. The patient was discussed in a neurological CPC and the chief discussant arrived at the conclusion that the patient had an overlap syndrome of progressive supranuclear palsy (PSP) and diffuse Lewy body disease. Majority of the participants thought that the patient had progressive supranuclear palsy, but many of them had an impression that parkinsonian tremor responding to levodopa as the initial symptom for PSP is rather unusual. Postmortem examination revealed severe loss of neurons in the substantia nigra, the globus pallidus, and the subthalamic nucleus with reactive gliosis; formy spheroids were seen in the substantia nigra, however, no Lewy bodies or neurofibrillary tangles were observed. Moderate neuronal loss was also seen in the dentate nucleus of the cerebellum. In addition, the precentral gyrus showed moderate neuronal loss, astrocytosis, and spongy change in the second layer; ballooned neurons were seen in the third and the fifth layers. Histologic characteristics were consistent with the pathologic diagnosis of corticobasal degeneration. PMID- 8679337 TI - [Median clefts of the hand. Classification and therapeutic indications apropos of 29 cases]. AB - Based on a series of 29 patients with median clefts of the hand (29 hands), the authors define the place of this malformation, its various clinical features and the therapeutic indications. The series consists of 13 boys and 7 girls, 9 bilateral cases and 11 unilateral cases. Involvement of the feet was observed in 9 cases. Several children also presented other malformations. 16 children were operated (22 hands). Two types of technique were used: simple closure of the cleft (Barsky's operation) and transposition of the index finger according to the Snow-Littler or Miura-Komada techniques. All operated patients were reviewed with a follow-up of more than one year and the results were assessed in terms of three criteria: overall use of the hand, thumb-index finger pinch grip, aesthetic appearance. The authors propose a new classification of median clefts of the hand based on examination of this series of 20 children: simple clefts with more or less complete absence of the middle finger, complex clefts with syndactyly (especially I and II), transverse bone polydactyly, extensive clefts with severe aplasia of the radial segment of the hand. Clinical and radiological examination confirm the experimental studies by Ogino. Barsky's operation gives satisfactory results in simple forms with parallel fingers. Translocation of the index finger to the base of the 3rd metacarpal is necessary in the presence of divergent fingers and syndactyly. Median clefts of the hand are very distinct from median aplasia, which is always unilateral, with no familial nature and no involvement of the feet and which can be classified together with brachysyndactyly. Each case must be studied before deciding treatment, as functional adaptation is always remarkable. The least favourable surgical results are observed in forms with abnormal position of the index finger (malrotation syndactyly). Lastly, the Snow Littler operation is not devoid of complications. PMID- 8679338 TI - [Surgical treatment of camptodactyly]. AB - Almost all anatomical structures of the hand have been held responsible for non traumatic, non-paralytic flexion deformity of the proximal interphalangeal joint. Together with Millesi and Flatt, we define camptodactyly as a disorder of flexor extensor equilibrium in the PIP. This definition determined our therapeutic approach. 59 patients with one or several fingers affected by camptodactyly were followed between 1975 and 1989. In 3 cases, the anomaly was associated with another malformation of the hand and 56 cases, it was isolated. 11 children did not receive any active treatment, but were followed and manipulated. 17 (27 fingers) were treated by static or dynamic splints. 31 (43 fingers) were operated according to the following technique: total anterior tenoarthrolysis leading to recession of the flexor apparatus and lengthening of the skin on the palmar surface of the first phalanx by a rotation flap. This operation was preceded and followed by application of a dynamic extension splint onto the operated finger. Of the 20 fingers treated by manipulations and reviewed, 11 had improved, 7 were stable and 2 had deteriorated. Of the 24 fingers treated by splints and reviewed, 14 had improved, 5 were stable and 5 had deteriorated. Of the 30 fingers operated and reviewed, 30 had improved, 7 were stable and 2 had deteriorated. Although recent anatomical studies tend to indicate that anomalies of the lumbrical muscles are frequent in operated camptodactyly, these studies do not take into account the numerous anomalies of these muscles observed in the general population. The therapeutic conclusion resulting from these studies are also unconvincing. The technique which we propose cannot be applied to every case. The milder forms only require orthopaedic treatment. C camptodactyly in adolescents or adults with joint blocking are only slightly improved by surgery and only require corrective osteotomy. In all other cases, especially in young children, anterior tenoarthrolysis of the finger with cutaneous elongation allows reduction or correction of the deformity. PMID- 8679339 TI - [Surgical treatment of duplication of the thumb. Apropos of 106 cases]. AB - The surgical treatment of thumb duplication remains difficult, the sequelae usually observed are aesthetic (ungual dystrophy, hypoplastic pulp, clinodactyly) or functional (joint stiffness or instability). In order to clarify our therapeutic approach, we classify duplications into two types: proximal duplications (Wassel stage IV, V and VI) and distal duplications (Wassel stage I, II and III). Our experience is based on 106 cases operated over the last 15 years (1977). Our indications and operative techniques have progressed since 1988, in particular, we no longer perform Bilhaut-Cloquet operation, and prefer to perform the first operation before the age of one year. Resection of the hypoplastic supernumerary thumb. Preservation of the pulp skin to reconstitute the paronychium and pulp of the remaining thumb. Resection of supplementary joint facets. Meticulous repair of the capsulo-ligamentus apparatus by means of a capsulo-periosteal flap taken from the "sacrificed" thumb. Tendinous reequilibration and reinsertion of thenar muscles. We do not perform systematic subcapital osteotomy. When necessary, this procedure is performed during a complementary operation at the age of 2 to 3 years. Since the introduction of these technical modifications, our functional and aesthetic results have improved. Temporary overcorrection of the pulp is necessary. Parents must be advised that this deliberately hypertrophic appearance becomes normal with growth. PMID- 8679340 TI - [Fibrolipoma of the median nerve. Review of 10 surgically treated cases with a mean recall of 8 years]. AB - Lipofibromatous hamartoma of the median nerve and its branches is rare, but is the most frequent lesion associated with digital hypertrophy in the upper limb. We present a pediatric series of 8 patients, two of whom had bilateral involvement. Digital enlargement or true macrodactyly was the presenting complaint. Fatty infiltration of the palm was a constant finding and is considered very suggestive of lipofibromatous hamartoma of the median nerve, as confirmed by MRI in cases of uncertain diagnosis. No causal link between the nerve hamartoma and the enlargement of soft tissues in the territory of the nerve has yet been proven; it appears to be a regional disease related to unknown development factors, and other congenital anomalies may be associated in the same territory. Treatment was mostly symptomatic, with carpal tunnel release and superficial removal of epineural proliferation; no interfascicular dissection was performed and we never made any attempt to completely resect the lipofibromatous constituents; no median nerve resection was performed. Debulking of the palm and enlarged digits was associated with nerve decompression, but true macrodactyly required a separate operative procedure and is not the subject of this study. Mean follow-up is 8 years and 5 operated lipofibromas have been reviewed after 13 years. Two-point discrimination was often abnormal, but sensory impairment was stabilized, as well as soft tissue enlargement. However no objective argument can currently support more radical nerve surgery, and the superiority of nerve resection on the course of digital hypertrophy has not been proven. PMID- 8679342 TI - Impact factors in anaesthesia journals. PMID- 8679341 TI - [Anesthesia for hand surgery in patients with bullous epidermolysis]. AB - Epidermolysis bullosa is a rare genetic disease, characterized by the formation of bullae in the skin and squamous epithelium following minimal trauma. The majority of surgical indications specific to this disease concern autosomal recessive dystrophic epidermolysis bullosa (RDEB). Hand surgery is one of the fields of surgery involved. The cicatricial course of the lesions results in retraction and pseudosyndactylization of the fingers, sometimes leading to complete destruction of the hand. Since 1988, we have treated 23 patients, including 11 children under the age of 8 years and weighing less than 20 kg. 185 procedures were performed by two anaesthetists, using regional plexus blocks in 157 cases and general anaesthesia in only 28 cases. This series is comparable in number, to that reported by the London team, which prefers general anaesthesia. Regional anaesthesia has been previously used, but only following general anaesthetic induction. Our approach, based on the experience of a hand surgery center, is in marked opposition with this standard paediatric approach. Regional anaesthetic techniques, particularly in the upper limb, present many advantages in addition to their feasibility in small children: efficacy, simplicity, postoperative analgesia, and outpatient comfort. In the context of the specificities and difficulties encountered in the management of these patients suffering from epidermolysis bullosa, the authors demonstrate the value of first line regional anaesthesia, even in very young children (less than 3 years). The presence of a parent in the operating room is a valuable aid, which is still insufficiently used, but which should be used with conviction for the benefit of all concerned. PMID- 8679343 TI - Airway management in cleft lip and palate surgery. PMID- 8679344 TI - Difficult laryngoscopy in cleft lip and palate surgery. AB - We studied prospectively 800 paediatric patients undergoing repair of cleft lip and palate to determine the predictors of difficult laryngoscopy. The incidence of difficult laryngoscopy (Cormack and Lehane grade III and IV) was 2.95% in patients with unilateral cleft lip, 45.76% in bilateral cleft lip and 34.61% in patients with retrognathia. Tracheal intubation was successful in 99% of patients in whom laryngoscopy was difficult. There was a significant association between age and laryngoscopic view (P < 0.01). PMID- 8679345 TI - Volumetric analysis of aeration in the lungs during general anaesthesia. AB - Spiral computed tomography (CT) allows volumetric analysis of formation of atelectasis and aeration of the lungs during anaesthesia. We studied 26 premedicated patients undergoing elective surgery allocated to group 1 (conscious, spontaneous breathing, investigating inspiration and expiration), group 2 (general anaesthesia with mechanical ventilation, investigating inspiration and expiration) or group 3 (general anaesthesia with mechanical ventilation, investigating changes over time). Using spiral CT, the lungs were studied either before or during general anaesthesia. CT scans were grouped into the following areas: overaeration, normal aeration, reduced aeration, poor aeration and atelectasis. The mechanism of atelectasis appeared to be both gravitational forces and a diaphragm-related force that acts regionally in caudal lung regions. Mean atelectasis formation and poorly aerated regions comprised approximately 4% of the total lung volume between the diaphragm and carina, giving a mean value of 16-20% of the normal aerated lung tissue being either collapsed or poorly aerated. The vertical ventilation distribution was more even during anaesthesia than in the awake state. PMID- 8679346 TI - Sevoflurane-nitrous oxide or halothane-nitrous oxide for paediatric bronchoscopy and gastroscopy. AB - We have studied 120 infants and children, in three age groups (3-11 months, 1-5 yr and 6-15 yr), to compare anaesthesia with sevoflurane or halothane for bronchoscopy or gastroscopy, or both. Premedication or i.v. anaesthetic agents were not used. Patients were allocated randomly to receive either 7% sevoflurane or 3% halothane in 66% nitrous oxide in oxygen for induction of anaesthesia. The same inspired mixture was continued during bronchoscopy while the concentration of the inhalation agent was reduced by 50% during gastroscopy. Induction times were shorter for infants than for children and shorter for sevoflurane than for halothane. Cardiac arrhythmias were significantly more frequent during halothane than during sevoflurane anaesthesia. Physiological and psychomotor recovery were more rapid after sevoflurane than after halothane. At 24-h follow-up, children who received sevoflurane had significantly less nausea and vomiting. We conclude that sevoflurane was superior to halothane for paediatric bronchoscopy and gastroscopy. PMID- 8679348 TI - Effects of surgical skin incision on respiration in patients anaesthetized with enflurane. AB - We measured ventilation in 12 subjects anaesthetized with enflurane (end-tidal concentration 1.25-1.45%) and nitrous oxide to assess the effect of surgical stimulation on ventilation in humans. Tidal volume and respiratory timing were measured by pneumotachograph before and just after a standardized surgical skin incision. Surgical stimulation increased ventilation by increasing tidal volume, which increased progressively over the first five breaths after incision. The first breath after the stimulus was prolonged, but the timing of the subsequent breaths returned rapidly to the duration observed before incision. Ventilation increased from median 3.6 (quartiles 2.9, 4.3) to 5.4 (3.8, 7.0) litre min-1 (P < 0.01). The increased tidal volume was not associated consistently with shortening of inspiratory duration. PMID- 8679347 TI - Cricoid pressure applied after placement of the laryngeal mask prevents gastric insufflation but inhibits ventilation. AB - We studied 50 patients, in a blind, crossover study, to assess if cricoid pressure applied after placement of the laryngeal mask prevented gastric insufflation without affecting ventilation. After induction of anaesthesia and neuromuscular block, a laryngeal mask was inserted and confirmed to be placed correctly. The lungs were ventilated with a maximum inflation pressure of 15 cm H2O. In the first 25 patients, expiratory volumes were measured with and without cricoid pressure (30 N). On both occasions, a free hand was placed under the patient's neck. In the next 25 patients, the effect of cricoid pressure on ventilation without support of the neck was also studied. The effect of cricoid pressure with support of the neck on gastric insufflation was then assessed using a stethoscope in all 50 patients, while the lungs were ventilated with a maximum inflation pressure of 30 cm H2O. At the end of the study, the position of the mask was re-assessed. Cricoid pressure significantly decreased mean expiratory volume (P << 0.001). This inhibitory effect was significantly greater when the pressure was applied without support of the neck (P << 0.001). Cricoid pressure significantly reduced the incidence of gastric insufflation (12 patients vs one patient; P << 0.001; 95% CI for difference 10.5-33.5%). In no patient was the mask dislodged after these procedures. Thus, although cricoid pressure applied after insertion of the laryngeal mask prevented gastric insufflation, it also decreased ventilation. The inhibitory effect of cricoid pressure on ventilation without support of the neck was greater than cricoid pressure with support of the neck. PMID- 8679349 TI - Efficiency of a circle system for short surgical cases: comparison of desflurane with isoflurane. AB - Patients undergoing short surgical procedures but requiring ventilation of the lungs were allocated randomly to receive either desflurane or isoflurane by circle absorption system, initially at a high fresh gas flow. The inspired and expired concentrations of the volatile agent were measured and the fresh gas flows reduced to low flow (500 ml min-1 total when FE/FI = 0.8), as measured on a multigas analyser. In patients receiving desflurane (n = 32), the median time at which flows were reduced was 5 min (interquartile range (IQR) 1 min) while with isoflurane (n = 32), the median time was 19 (IQR 12) min. After the reduction in flow, expired concentrations of volatile agent decreased in both groups. In the isoflurane group the concentration continued to decrease during anaesthesia. In the desflurane group the initial decrease was followed by a slow recovery. We conclude that the circle system can be used efficiently for short anaesthetics using desflurane. PMID- 8679350 TI - Oxygen consumption and delivery relationship in brain-dead organ donors. AB - The oxygen delivery (DO2) and consumption (VO2) relationship in brain-dead organ donors is unknown. Therefore, in a prospective study, we determined the DO2/VO2 relationship in 21 consecutive brain-dead patients. Patients were allocated to one of two groups, according to plasma lactate concentration: normal (group NL, n = 11) or high (> 2.5 mmol litre-1) (group HL, n = 10). VO2 was measured independently, using indirect calorimetry, under control conditions, during low DO2 challenge with PEEP administration, and high DO2 challenge with inflation of medical antishock trousers and volume expansion or blood transfusion, as required. Under control conditions, there were no significant differences between groups NL and HL in haemodynamic or oxygenation variables, both groups having a low VO2 (mean 114 (SD 21) ml min-1 m-2). In group HL there was a different DO2/VO2 relationship pattern, with a dependent VO2 only. The mean slope of the DO2/VO2 relationship was significantly higher in group HL than in group NL (0.12 (0.09) vs 0.04 (0.07), P < 0.05). We conclude that brain death was associated with a low VO2, and patients in group HL exhibited DO2/VO2 dependency which was not observed in patients in group NL. PMID- 8679351 TI - Sepsis-induced vasoparalysis does not involve the cerebral vasculature: indirect evidence from autoregulation and carbon dioxide reactivity studies. AB - We have studied cerebral autoregulation and vasoreactivity to carbon dioxide in 10 patients with the sepsis syndrome receiving intensive therapy. All patients were sedated with infusions of midazolam and fentanyl, and their lungs were ventilated mechanically with oxygen-air to maintain normoxia and normocapnia. Inotropic support and antibiotics were administered as necessary. During a period of constant level of sedation and stable haemodynamics, cerebral autoregulation was tested by increasing mean arterial pressure (MAP) by 23 (SD 2) mm Hg from baseline with an infusion of phenylephrine and simultaneously recording middle cerebral artery blood flow velocity (vmca) using transcranial Doppler ultrasonography. Carbon dioxide reactivity was tested by varying PaCO2 between 3.0 and 7.0 kPa and simultaneously recording vmca. There was no significant change in vmca (57 (22) and 59 (23) cm s-1) during the increase in MAP (75 (11) to 98 (10) mm Hg). The mean index of autoregulation (IOR) was 0.92 (SEM 0.03), which was not significantly different from 1, indicating near perfect autoregulation. Although absolute carbon dioxide reactivity was lower than reported previously in awake subjects, relative carbon dioxide reactivity was within normal limits for all patients (11.6 (SEM 0.8) cm s-1 and 20.3 (3) % kPa 1, respectively). We conclude that cerebral carbon dioxide reactivity and pressure autoregulation remained intact in patients with the sepsis syndrome, providing indirect evidence that at least in the early stages of the syndrome, the widespread sepsis-induced vasoparalysis does not involve the cerebral vasculature. PMID- 8679352 TI - Remifentanil reduces auditory and somatosensory evoked responses during isoflurane anaesthesia in a dose-dependent manner. AB - We studied 60 patients during stable isoflurane anaesthesia (0.4 MAC) after premedication with temazepam. Patients were allocated randomly to one of three dose regimens of remifentanil: 1 microgram kg-1 i.v. over 1 min and an infusion of 0.2 microgram kg-1 min-1 (low dose); 2.5 micrograms kg-1 and 0.5 microgram kg 1 min-1 (medium dose); and 5 micrograms kg-1 and 1 microgram kg-1 min-1 (high dose). The auditory (AER) and median nerve somatosensory (SER) responses were elicited throughout, and recorded before and after tracheal intubation, and surgical incision, together with systolic and diastolic arterial pressure and heart rate. Venous blood concentrations of remifentanil were measured at the above times. After administration of remifentanil, Pa and Nb amplitudes of the AER increased at the low dose, remained constant at the medium dose and decreased at the high dose. This dose-related effect was linear and significant (P = 0.012, P = 0.05). Pa amplitude correlated inversely with remifentanil blood concentrations before and after intubation and incision (P = 0.002, P < 0.001, P < 0.001 and P < 0.001). In the SER, P15-N20 amplitudes decreased after administration of remifentanil (P < 0.001), whereas P25-N35 and N35-P45 amplitudes increased at all dose concentrations (P < 0.001 and P < 0.001). After intubation, P15-N20 and N35-P45 amplitudes increased at the low dose, did not change at the medium dose and decreased at the high dose (P = 0.001, P = 0.027). After remifentanil, systolic and diastolic arterial pressure and heart rate decreased in a linearly dose-related manner (P = 0.033, P < 0.001, P < 0.001). At all doses the three variables increased after intubation (P = 0.001, P < 0.001, P < 0.01), and systolic and diastolic arterial pressure increased after incision (P = 0.027, P = 0.039). PMID- 8679353 TI - Effect of the addition of alfentanil to lignocaine during axillary brachial plexus anaesthesia. AB - Peripheral administration of opioids has been suggested as a means of improving regional block. We studied 60 patients receiving axillary brachial plexus anaesthesia, allocated randomly to receive either normal saline 10 ml or normal saline 10 ml with alfentanil 10 micrograms/kg body weight through an axillary cannula. All patients received 1.5% lignocaine at a dose of 7 mg/kg body weight with adrenaline 1 in 200,000. The incidence of satisfactory block was similar in both groups. Although the percentage of patients with complete anaesthesia in the median nerve distribution was greater in the alfentanil group, there was no significant difference in any other distribution. The time to return of sensation and motor function was prolonged significantly in the alfentanil group (P < 0.05). After return of normal sensation, there was no significant difference between groups in postoperative analgesia. In a second part of the study, there was no significant increase in plasma concentrations of alfentanil in 10 patients given lignocaine and alfentanil, as outlined above. These observations suggest that alfentanil may have a peripheral local anaesthetic action. PMID- 8679354 TI - Analgesic and anti-inflammatory effects of lignocaine-prilocaine (EMLA) cream in human burn injury. AB - Pain relief may be improved by reducing sensitization of nociceptive pathways caused by tissue injury. Such a reduction depends mainly on inhibition of local inflammatory changes and the relation between duration of nociceptive block and nociceptive input. In this study we examined if prolonged topical treatment with local anaesthetics could reduce late hyperalgesia and local inflammation after burn injury in healthy volunteers. The effects of EMLA treatment for 8 h after burn on hyperalgesia, inflammation and wound healing were compared with the contralateral placebo-treated leg for 48 h after bilateral burn injuries (15 x 25 mm, 49 degrees C for 5 min) in a double-blind, randomized study in 12 healthy volunteers. Wound healing was studied 1 and 2 weeks after injury. Neither mechanical nor thermal primary hyperalgesia were affected significantly by prolonged EMLA treatment. Secondary hyperalgesia and skin erythema were also not changed. Seven of 12 placebo-treated legs developed blisters, in contrast with four of 12 EMLA-treated legs. Wound healing showed no apparent differences. Our data suggest that prolonged, topical treatment with local anaesthetics did not reduce local inflammation and late hyperalgesia. PMID- 8679355 TI - Continuous extrapleural paravertebral infusion of bupivacaine for post thoracotomy analgesia in young infants. AB - We have studied the efficacy of a continuous paravertebral infusion of bupivacaine for the management of post-thoracotomy pain in 20 infants with a median age of 5.3 weeks (range 2 days to 20 weeks). Immediately before chest closure, 0.25% bupivacaine 1.25 mg kg-1 was injected into an extrapleural paravertebral catheter, inserted under direct vision. A continuous infusion of 0.25% bupivacaine 0.5 mg kg-1 h-1 was commenced 1 h later and terminated after 24 h. We found that extrapleural paravertebral catheter placement under direct vision was easy in neonates and infants. The technique provided effective postoperative pain relief in 18 (90%) patients and the failure in two (10%) infants was attributed to catheter block. Mean maximum serum concentrations of bupivacaine after the loading dose and during infusion were 1.03 (SD 0.56) and 2.00 (0.63) microgram ml-1, respectively. There were no major complications relating to the technique and we conclude that extrapleural paravertebral block is a simple and effective method for post-thoracotomy analgesia in young infants. PMID- 8679356 TI - Surgical pain is followed not only by spinal sensitization but also by supraspinal antinociception. AB - Nociception can produce segmental spinal sensitization or descending supraspinal antinociception. We assessed both types of sensory change after surgery during isoflurane-nitrous oxide anaesthesia with or without fentanyl before nociception. Patients undergoing back surgery received fentanyl 3 micrograms kg-1 (n = 15) or placebo (n = 15) before anaesthesia in a prospective, randomized, blinded study. Sensation, pain detection and tolerance thresholds to electrical stimulation were measured before operation at the arm, incision and herniated disc dermatomes (HDD) and 1, 2, 4, 6, 24 h and 5 days after operation, together with pain scores and patient-controlled morphine consumption (duration 24 h). For segmental effects, thresholds were normalized to the thresholds at a distant dermatome (arm). Raw pain thresholds were increased after operation (fentanyl > placebo) and were maximal at 4 h (pain tolerance in HDD: fentanyl +5.2 mA (+62.7%), placebo, +3.8 mA (+44.2%); P < 0.05 vs baseline for both). Normalized sensation thresholds decreased for placebo only (HDD/4 h: placebo, -1.8 (-44.8%), P < 0.05; fentanyl, +0.1 (+5.5%) ns). All changes returned to baseline by 24 h except for the placebo group normalized HDD sensation (d5: placebo, -2.4 (-59.7)%, P < 0.05; fentanyl -0.1 (-5.5%) ns). Pain scores and morphine consumption were similar. The study demonstrated both supraspinal analgesia and spinal sensitization after surgery. Fentanyl administration before operation augmented the former while decreasing the latter, and hence sensitization, especially if neuropathic, may particularly benefit from pre-emptive analgesia. PMID- 8679357 TI - Haemostatic changes caused by i.v. regional anaesthesia with lignocaine. AB - The various components of i.v. regional anaesthesia (IVRA), that is ischaemia, tourniquet compression and the presence of high concentrations of local anaesthetics in the blood vessels of the extremity, may affect haemostatic mechanisms. We performed a cross-over study in 10 healthy male volunteers to examine the role of lignocaine in IVRA on several haemostatic variables, and those indicating fibrinolysis and platelet function in particular. Venous blood samples were obtained from the test arm and the opposite arm before IVRA, at the time of tourniquet cuff deflation and 30 min thereafter. Metal needle punctures were used, and for the sample from the test arm at the time of cuff deflation, cuff pressure was reduced from 300 mm Hg to individual mean arterial pressure. The IVRA technique included exsanguination by arm elevation and axillary artery compression, inflation of the tourniquet cuff for 20 min and deflation of the cuff in one step (after obtaining the venous sample). Each subject received, in random order, either 0.5% lignocaine 3 mg kg-1 or the corresponding volume of saline i.v. All fibrinolysis markers, that is, D-dimer, tissue plasminogen activator antigen (t-PA antigen), tissue plasminogen activator activity (t-PA activity), plasminogen activator inhibitor activity (PAI) and protein C indicated enhanced fibrinolysis by IVRA, but only t-PA antigen and PAI showed greater changes in the lignocaine compared with the saline group in the exposed arm at the time of cuff deflation. Platelet function tests (ADP-induced platelet aggregation, beta-thromboglobulin and thrombelastogram (TEG)) indicated no differences between the lignocaine and saline groups. Although IVRA appeared to induce some platelet dysfunction, there was a small increase in TEG amplitude indicative of improved fibrin-platelet interaction in the lignocaine-exposed arm at the time of cuff deflation. We conclude that the presence of high i.v. lignocaine concentrations (median 144.4 micrograms ml-1 in cubital veins at the end of the tourniquet time) potentiated ischaemia-induced fibrinolysis activation during IVRA. Concomitant platelet dysfunction was not aggravated by lignocaine. PMID- 8679358 TI - Effect of systemic N-methyl-D-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia in humans. AB - Ketamine reduces nociception by binding noncompetitively to the N-methyl-D aspartate (NMDA) receptor, activation of which increases spinal hypersensitivity. We studied 19 healthy, unmedicated male volunteers, aged 20-31 yr. Burn injuries were produced on the medial surface of the dominant calf with a 25 x 50 mm rectangular thermode. On 3 separate days, at least 1 week apart, subjects received a bolus of either ketamine 0.15 mg kg-1, ketamine 0.30 mg kg-1 or placebo, delivered by a mechanical infusion pump over 15 min. The bolus was followed by continuous infusion of ketamine 0.15 mg kg-1 h-1, ketamine 0.30 mg kg 1 h-1 or placebo, respectively, for 135 min. Ketamine reduced the magnitude of both primary and secondary hyperalgesia, and also pain evoked by prolonged noxious heat stimulation, in a dose-dependent manner. In contrast, ketamine did not alter phasic heat pain perception (perception of transient, painful, thermal stimuli) in undamaged skin. The analgesic effects of ketamine in the burn injury model are in agreement with results from experimental studies, and can be distinguished from those of local anaesthetics and opioids. Side effects caused by continuous infusion of ketamine 0.15 and 0.30 mg kg-1 h-1 were frequent but clinically acceptable. PMID- 8679359 TI - Combination of ondansetron and dexamethasone in the prophylaxis of postoperative nausea and vomiting. AB - We studied 100 ASA I-II females undergoing general anaesthesia for major gynaecological surgery, in a prospective, double-blind, placebo-controlled, randomized study. Patients received one of four regimens for the prevention of postoperative nausea and vomiting (PONV): ondansetron 4 mg (n = 25), dexamethasone 8 mg (n = 25), ondansetron with dexamethasone (4 mg and 8 mg, respectively, n = 25) or placebo (saline, n = 25) There were no differences in background factors or factors related to operation and anaesthesia, morphine consumption, pain or side effects between groups. The incidence of nausea and emetic episodes in the ondansetron with dexamethasone group was lower than in the placebo (P < 0.01), ondansetron (P < 0.05) and dexamethasone (P = 0.057) groups. There were no differences between ondansetron and dexamethasone, and both were more effective than placebo (P < 0.05 and P < 0.01, respectively). Dexamethasone appeared to be preferable in preventing nausea than emetic episodes. Fewer patients in the ondansetron with dexamethasone group needed antimetic rescue (P < 0.01 vs placebo and P < 0.05 vs ondansetron). We conclude that prophylactic administration of combined ondansetron and dexamethasone is effective in preventing PONV. PMID- 8679360 TI - Differential effects of desflurane and halothane on peripheral airway smooth muscle. AB - Volatile anaesthetics have been shown to have direct relaxant effects on airway smooth muscle. We have examined the effects of 0.9, 1.9, and 2.8 dog MAC of desflurane and halothane on isolated proximal and distal canine airways precontracted with acetylcholine. The proximal and distal airway smooth muscle relaxed with increasing concentration of each anaesthetic in a dose-related manner. Desflurane had a greater relaxant effect than halothane on the proximal airway only at 2.8 MAC. Desflurane relaxed the distal airway to a greater extent than halothane at 1.9 and 2.8 MAC. The distal airway smooth muscle was more sensitive to volatile anaesthetics than the proximal airway smooth muscle with either halothane or desflurane at all concentrations tested. This effect may be a result of differences in cartilage content, myosin content, epithelium-dependent effects, receptor density, myofilament sensitivity to Ca2+, sarcoplasmic reticulum Ca2+ control, or ionic fluxes in the proximal airway compared with the distal airway. The increased sensitivity of airway smooth muscle to desflurane compared with halothane is not known but may be related to possible differences in the effects of Ca2+ homeostasis. PMID- 8679361 TI - Halothane and potassium channels in airway smooth muscle. AB - Earlier studies have suggested that halothane may relax smooth muscle in part by opening adenosine triphosphate-sensitive potassium (KATP) channels. We tested this hypothesis in vitro by examining the interaction of halothane with glibenclamide, a KATP channel blocker, and YM934, a KATP channel opener, in strips of canine tracheal smooth muscles mounted in an organ bath system. To examine the specificity of any effects of halothane on the KATP channel, we assessed the interaction of halothane with tetraethylammonium (TEA), an antagonist of the large-conductance, calcium-activated potassium channel. Experiments were conducted with drugs added before exposure to increasing concentrations of acetylcholine (ACh), and with drugs added after stable increases in force produced by ACh were achieved (ACh precontraction). Exposure to halothane 0.62 mmol litre-1 (equivalent to approximately 2 MAC) increased significantly the ED50 for ACh-induced contractions (by 0.24 (SEM 0.07) mumol litre-1). TEA 1 mmol litre-1 but not glibenclamide 10 mumol litre-1 significantly augmented this increase in ED50 (by an additional 0.17 (0.06) mumol litre-1). In strips precontracted with ACh, TEA, but not glibenclamide, potentiated concentration-dependent relaxation induced by halothane. Incubation with YM934 0.32 mumol litre-1 increased significantly the ED50 for ACh-induced contractions (from 0.12 (0.02) to 0.55 (0.11) mumol litre-1), an increase not affected by exposure to halothane 0.72 mmol litre-1. When added to strips precontracted with approximately ACh 0.3 mumol litre-1, YM934 produced concentration-dependent relaxation; halothane had little effect on this relaxation. These results do not support the hypothesis that halothane relaxes canine tracheal smooth muscle in part by opening KATP channels. PMID- 8679362 TI - Recovery of respiratory ciliary function after depression by inhalation anaesthetic agents: an in vitro study using nasal turbinate explants. AB - We have developed a human tissue preparation suitable for measurement of cilia beat frequency derived from nasal turbinates. Cilia beat frequency of turbinate explants from 11 patients did not change significantly over a 10-day observation period while maintained in an incubator, with mean cilia beat frequency of 13.1 (SEM 0.3) Hz to 14.4 (0.2) Hz (ANOVA for repeated measures, P = 0.168). We have used this preparation to investigate recovery of ciliary function after depression by inhalation anaesthetic agents. Eight or nine turbinate explants were exposed to three times the minimum alveolar concentration (MAC) of halothane, enflurane or isoflurane for a period of 1 h and thereafter to a period of air washout. After exposure to the inhalation agent there was a significant reduction in cilia beat frequency with all three agents: halothane 14.3 (0.4) Hz to 9.5 (0.3) Hz; enflurane 13.7 (0.6) Hz to 10.5 (0.5) Hz;isoflurane 15.9 (0.6) Hz to 10.6 (0.3) Hz. Cilia beat frequency returned to values after air washout that were not significantly different from baseline after 90 min of washout of halothane and 60 min of washout of enflurane and isoflurane (repeated measures ANOVA, unpaired t test; P = 0.01 at 60 min and P = 0.31 at 90 min washout for halothane; P = 0.83 at 60 min washout for enflurane; P = 0.26 at 60 min washout for isoflurane). PMID- 8679363 TI - Effect of halothane on myocardial reoxygenation injury in the isolated rat heart. AB - Several studies have reported a protective effect of halothane on myocardial injury in an ischaemia-reperfusion situation. It is unclear if the protection is a result of the haemodynamic effects of halothane or if halothane has a specific action on ischaemia or reperfusion pathomechanisms. To examine this question, we have used an isolated rat heart model where heart rate (300 beat min-1), ventricular volume and coronary flow are constant. Left ventricular developed pressure (LVDP) and release of creatine kinase (CK) were measured as variables of myocardial performance and cellular injury, respectively. Five control hearts were subjected to 35 min of low-flow (2 ml min-1) anoxic and substrate-free perfusion and were then perfused for 1 h with the oxygenated buffer. In the treatment groups, halothane 0.4 mmol litre-1 was added during the first 30 min of anoxic perfusion (n = 5) or during the first 30 min of reoxygenation (n = 5). In five additional hearts, the effect of halothane 0.4 mmol litre-1 was tested under normoxic conditions. Mean basal CK release was 0.29 (SEM 0.13) iu g-1 min-1 and LVDP was 105.5 (4.0) mm Hg. Under normoxic conditions, halothane reduced LVDP to 52.0 (2.6) mm Hg. In control hearts, the major cell injury occurred at the onset of reoxygenation (CK release increased to 149.1 (9.1) iu g-1 min-1) and functional recovery after 1 h of reoxygenation was poor (control LVDP, 14.2(2.)% of baseline). Halothane during anoxia attenuated myocardial injury only moderately (CK release 50.2(5.7) iu g-1 min-1) and LVDP recovered to 30.8(3.0)% (each P < 0.05 vs control). When halothane was administered at reoxygenation, CK release was reduced to 10.1 (0.9) iu g-1 min-1 and LVDP recovered to 69.4(4.9)% (each P < .05 vs control). We conclude that halothane not only attenuated ischaemic injury but had a specific protective action against reoxygenation injury. PMID- 8679364 TI - Occupational x-ray exposure of anaesthetists. AB - Lithium fluoride thermoluminescent dosimeter chips were used to measure the radiation dose received by anaesthetists caused by the use of image intensification during a typical 4-week period in an orthopaedic theatre. These were used to estimate an annual dose, for comparison with dose limits, to ascertain if anaesthetists should be included in personnel monitoring services. Doses proved to be below detectable limits; hence anaesthetists are at minimal risk from occupational exposure to radiation. The orthopaedic theatre is believed to use more x-rays than other theatres, so exposure elsewhere should also be undetectable. PMID- 8679365 TI - Total i.v. anaesthesia for transcranial magnetic evoked potential spinal cord monitoring. AB - Continuous intraoperative monitoring of transcranial magnetic motor evoked potentials (TcMMEP) can warn the surgeon of motor tract damage more effectively than somatosensory evoked potentials. As a non-invasive technique it is especially useful during post-traumatic internal fixation and is applicable whatever the level of the spinal cord at risk. Inhalation and many i.v. anaesthetics block the single pulse TcMMEP but a total i.v. anaesthetic regimen based on methohexitone, alfentanil and ketamine was effective in seven patients undergoing post-traumatic internal fixation. Consistent TcMMEP of 100-1000 mcV were obtained in all patients, with a latency change of only 2 ms above preoperative values. Good cardiovascular stability was maintained during operation. PMID- 8679366 TI - Spinal clonidine produces less urinary retention than spinal morphine. AB - We have conducted a double-blind, randomized study in two groups of 20 patients each, undergoing hip surgery during spinal anaesthesia, to compare the incidence of urinary retention after spinal morphine or clonidine. Patients received 0.5% spinal bupivacaine 15 mg combined with either clonidine 75 micrograms or morphine 0.2 mg. After operation, patients were examined for micturition, bladder distension, or both; when they failed to void, they received naloxone 0.2 mg, and if bladder distension persisted, a catheter was inserted. At 12 h, all patients in the morphine group but only five in the clonidine group had bladder distension, and at 24 h this was present in seven and one patient in the morphine and clonidine groups, respectively (P < 0.001). Naloxone was given in 16 and one, and a catheter was placed in one and six patients in the morphine and clonidine groups, respectively (P < 0.001). We conclude that spinal clonidine impaired bladder function to a lesser extent than morphine. PMID- 8679367 TI - Removal of the laryngeal mask airway in children: anaesthetized compared with awake. AB - We studied 60 children, aged 12 months to 8 yr, undergoing plastic surgery under general anaesthesia supplemented by regional anaesthesia. Patients were allocated randomly to have the laryngeal mask airway removed either on awakening or while anaesthetized. Subsequent observation of respiratory factors and oxygen saturation showed a significant difference between the groups for coughing (P < 0.001), with a greater incidence (17 of 33) in the awake group compared with those from whom the laryngeal mask airway was removed while anaesthetized (two of 27). There were no differences in the incidences of laryngospasm, desaturation (< 95%) and excess salivation between the groups. Removed of the laryngeal mask airway during deep anaesthesia reduced coughing in the immediate postoperative period. PMID- 8679368 TI - Fracture of the cricoid cartilage after Sellick's manoeuvre. AB - We report a case of fracture of the cricoid cartilage associated with cricoid pressure during rapid sequence tracheal intubation in a patient with status asthmaticus. This patient had a history of laryngeal trauma 48 yr previously. Fracture of the cricoid cartilage has not been reported previously after cricoid pressure. PMID- 8679369 TI - Balloon mitral valve dilatation as an aid to weaning from ventilatory support in patients with intractable pulmonary oedema caused by severe mitral stenosis. AB - Intractable pulmonary oedema in patients undergoing mechanical ventilation must be investigated as older patients with severe mitral stenosis can be rescued by balloon dilatation of the mitral valve, thus enabling elective cardiac surgery at reduced risk. We describe two such cases and discuss the role of transoesophageal echocardiography in the intensive care unit in the diagnosis and management of these patients. PMID- 8679370 TI - Suxamethonium and auditory evoked potentials. PMID- 8679371 TI - Extradural clonidine for postoperative pain relief. PMID- 8679372 TI - Aprotinin during liver transplantation. PMID- 8679373 TI - Aortic stent surgery. PMID- 8679374 TI - Suxamethonium in children. PMID- 8679375 TI - Suxamethonium in children. PMID- 8679376 TI - Isolated forearm technique. PMID- 8679377 TI - CSF progesterone concentrations in pregnancy. PMID- 8679378 TI - Extradural analgesia in the first stage of labour. PMID- 8679379 TI - Extradurals and infection. PMID- 8679380 TI - Cervical haematoma and airway obstruction. PMID- 8679382 TI - European Association of Cardiothoracic Anaesthesiologists 11th annual meeting. Leuven, Belgium, 22-25 May 1996. Abstracts. PMID- 8679381 TI - Management of pre-eclampsia. PMID- 8679383 TI - European Society of Anaesthesiologists annual congress. London, 1-5 June 1996. Abstracts. PMID- 8679384 TI - [Incorrect use of language in medical literature]. PMID- 8679385 TI - [Surgical treatment of acquired laryngotracheal stenosis in children]. AB - Severe laryngotracheal stenosis in children is a problem of increasing incidence following the widespread adoption of prolonged endotracheal intubation for respiratory support. A variety of methods have been developed to solve the problem of extensive tracheal stenosis. Seven patients from 9 months to 14 years were treated from December 1992 to November 1994 with posterior cricoid split and hyoid bone graft. Stenting was performed in all cases with a Montgomery Silastic laryngeal stent during three weeks. All patients have been extubated. PMID- 8679386 TI - [Rectocolonic plasty using mechanical stapler as a surgical solution in complications of megacolon]. AB - Hirschsprung's disease surgically treated with Duhamel's technique in which no mechanical suture has been used, usually presents, as main complication, cronic constipation, due to fecalomas in the rectal pouch. In our experience (30 cases plus four patients sent to our hospital for reintervention), this complication is not present when mechanical suture is introduced to the Duhamel's Technique. This allows us to assure that perineal rectocoloplasty, with auto-suture material is a precise optional treatment, with excellent results and allows the chance of not going through laparotomy in those cases that require reintervention. PMID- 8679387 TI - [Neonatal treatment of Hirschsprung disease using the Duhamel-Martin technique]. AB - The definitive surgical treatment in the first months of life without colostomy are essential principles at present in the management of Hirschsprung's disease. The appearing of little size stapling devices like EndoGIA, from the development of laparoscopic surgery, make possible the application of the classical surgicall procedures on early age patients. The experience in five patients operated under two months of life with the Duhamel-Martin procedure is reported. Only in one case previous colostomy was performed for one episode of enterocolitis at age of fifthteen days. The stapling of both pouches was performed with EndoGIA. The agartglionic pouch was closed with TA Roticulator. That provides a reduction in the high of the aganglionic pouch at minimum. Follow-up varied from 3 months to 2 years, without any complication. PMID- 8679388 TI - [Intra-abdominal infections caused by Eikenella corrodens in children]. AB - Eikenella corrodens is a fastidious, facultative anaerobe, not a strict anaerobe, gram-negative bacillus, that was placed in the Brucelaceae family. The difficulties in its isolation delayed its recognition as a human pathogen. The course of disease is usually indolent, and abscess formation is almost universally seen. To date, 30 reported cases describing E corrodens infections of the abdominal cavity have been published and only 17 in children. We reviewed the bacteriology laboratory records for a period of 5 years. This organism was cultured from 5 children, aged 1 to 7 years who had peritonitis secondary to perforated appendicitis. The organism was obteined at the original operation and/or from postoperative intra-abdominal abscesses. Two children required surgical drainage of the abscess and one was treated by means of percutaneous drainage. All patients fully recovered. PMID- 8679389 TI - [Retrospective analysis of 80 cases of neonatal necrotizing enterocolitis]. AB - We present the cases of necrotizing enterocolitis (NEC) treated in our hospital between 1980 and 1994, in order to analyze the risk factors that appear in the disease. We elaborate treatment and follow-up protocols. Prematurity, low birth weight and perinatal stress have a significant influence in NEC. Hemodinamic inestability, bloody stools, abdominal distension with decrease gastric outlet, along with significant radiological evidence in 90 percent of the cases, should rise suspition of NEC. We find fundamental the prevention of the disease in premature newborns with risk factors. Mean gestational age was 33 weeks. Prematurity was found in 87.5 percent of the patients, with a mean birth weight of 1683 g. Symptoms appeared at the age of 14 days. 32 percent of the cases were operated, 13 cases (16%) presenting with pneumoperitoneum, and a Mortality rate 15 percent. We treated 15 patients with colonic stenosis by resection and end-to end anastomosis, with 6 percent mortality global mortality rate for NEC has been 28 percent. PMID- 8679390 TI - [Problems associated with nephrectomy of transplanted kidneys]. AB - Graft survival is not indefinite and a proportion of the failures must be removed. This study pretend to know the fate of failed renal transplant (RT) in the child, indication for transplant nephrectomy (TN) and morbidity involved. 96 RT were performed between 1985 and september 1994, during this time 31 grafts were lost: 71% immunologic causes, 13% relapse of original disease and 16% other reasons. Mean patient age and weight were 9 years and 27.3 kg, respectively. TN was performed in 28 (29%) and the most common indication was symptomatic rejection after withdrawal of immunosuppression (35.7%). Postoperative complications were diverse, including wound hematoma (13.6%), major hemorrhage (7%), fluid and electrolyte disorders (45.5) and 1 patient died (4.5%). Re surgical approach was necessary in the 2 patients with major hemorrhage and 50% of the patients were in need of dialysis in the early postoperative. In this paper we appreciated that child with failed renal allograft could need TX in 90% of the cases, mainly because of symptomatic rejection. Furthermore, this procedure is more risky than simple native nephrectomy. PMID- 8679391 TI - [Wilms' tumors with intra-cava infiltration]. AB - Since Gross established the basic rules for nephrectomy in Wilms' tumour (WT) in 1953, the management of nephroblastoma has been more straightforward; however, some cases with intravascular involvement, currently detected by ultrasound (US), may represent a daunting challenge for the surgeon. Inferior vena cava with tumour thrombus induced by WT can be asymptomatic, and if undetected, contribute to poorer prognosis for two main reasons: possible neoplastic cells inside the thrombus and higher morbidity risk of surgery. From 1979 to 1993, 81 WT were studied by routine US. Intracaval thrombosis was diagnosed in four (5%), in one of which the thrombus extended to the right atrium. In our experience, the surgical strategy in each of the four cases (100% survival), depended on the length of the thrombus and whether or not it infiltrated the vena cava wall. If the thrombus can be easily removed: complete resection. However in cases of atrial thrombus and more particularly if the thrombus involves the intima, we suggest the thrombus not be touched since the problem may be solved by preoperative and postoperative chemotherapy. Thus, the favourable prognosis would be maintained and superfluous risky surgery avoided. PMID- 8679392 TI - [Treatment of ureterocele by endoscopic puncture]. AB - Ureterocele is a congenital cystic dilatation of the intravesical segment of the ureter. As a consequence, the proximal ureter and renal pelvis become dilated and that results in renal-parenchymal pathological involvement. Management of this anomaly is still controversial. Among the therapeutical options there is a place for endoscopic punction. Our experience with 11 patients undergoing this treatment modality is reported. In all these cases endoscopic punction was the initial treatment. In 7 patients this technique was all that was needed. The technique of intravesical punction is described and its results are specified. PMID- 8679394 TI - [Changes in traditional techniques in anterior hypospadias]. AB - After confirming that the Magpi and Mathieu techniques are not sufficient for the adequate treatment of 100% of the anterior forms of hypospadias and observing that they often cause defects in the appearance of the meatus, 23 patients were selected and treated with traditional urethroplasties modified by the pyramid technique (King), the Barcat technique, or both, with satisfactory results in all cases. These techniques which are easy to perform, effectively contribute to improving the final appearance of the penis, do not involve major operating time, and present a lower incidence of complications than the traditional techniques. PMID- 8679393 TI - [Our experience in endoscopic teflon treatment in vesicoureteral reflux in children]. AB - We report our experience with the endoscopic treatment of vesicoureteral reflux by submucosal injection of Teflon (STING) in children. Since December of 1992, 45 children and a total of 67 ureters were treated. The overall success rate was 90% after one injection and 95% after two injections. The success rate was better in primary reflux with 95%, 87.5% in duplicated ureters and 75% in secondary reflux after one injection. Actually we treat the reflux grade II and III with STING when it doesn't improve after one year with medical treatment. PMID- 8679395 TI - [Bilateral multilobular cystic adenomatoid malformation]. AB - We reported a case of bilateral and multilobar Congenital Cystic Adenomatoid Malformation (C.C.A.M.) in a four months old child with good clinical results after resections of the lesions. This is a relatively rare form of pulmonary illness. The final prognosis, in those patients, depends on the type of malformation, the presence or absence of fetal hydrops and on the degree of affected lung. There have been reported a few cases of multiple affectation. We will consider the physiopathological aspects of the case, late clinical presentation and treatment and the positive surgical response based in the findings of the functional and anatomic imagen studys. PMID- 8679396 TI - [Epidermoid cysts of the spermatic cord]. AB - We report two cases of epidermoid cyst of the spermatic cord in infants 14 months and 2 1/2 years old, respectively. The initial diagnosis in one patient was funicular hydrocele and paratesticular mass no transilluminable in the other case. The treatment was the local excision of tumor and the diagnostic was histological in both patients. Postoperative course was excellent in both, the first after fistullization and surgical treatment. Must be explored the transillumination of the mass which would have led us to think other of the diagnoses different from that of the cord hydrocele before the operation, since it would have given negative. During the operation, must be assured that the cystic anomaly is limited to spermatic cord, to evite fistulization in the postoperative course. PMID- 8679397 TI - [Current therapy of esophageal varices]. PMID- 8679398 TI - [Assessment of various immunologic parameters in silicone implant carriers]. AB - The Authors evaluated some immunological parameters in women carrying silicone gel-filled breast implants for over one year. Peripheral blood samples from 22 patients were examined in order to assess both the antigenic pattern of lymphocyte subpopulations by cytofluorimetric analysis, and the cell proliferation of PHA-stimulated lymphocytes by the uptake of tritiated thymidine. These tests were performed at the time of the sample withdrawal and after in vitro reexposure to silicone extract for 48-72h. Changes in lymphocyte subpopulations and functional response were observed when patients were divided into groups according to the type of surgery, i.e. breast augmentation or reconstruction, or to the degree of periprosthetic capsular contracture. These results suggest the possibility of an interaction between silicone and the immune system, which cannot be disregarded for the explanation of the silicone related complications. PMID- 8679399 TI - [Primary choledocholithiasis after side-to-side choledochojejunostomy]. AB - Primary choledocholithiasis represents a quite unusual sequela of biliary tract surgery. Primary stones originate in the common bile duct and are soft, smooth, with a yellowish or brown-reddish colour, reproducing the shape of the duct in which arise. The Authors report a review of the cases observed in the division of General and Vascular Surgery-Department of Surgery and Surgical Emergencies of the University of Perugia. From January 1988 to December 1993, 577 laparotomic biliary tract operations were performed, and in 8 cases a re-operation was needed. Among the latter, particularly interesting were 2 cases of primary choledocholithiasis occurred in two patients with bilio-digestive anastomosis previously performed, i.e. two side-to-side Roux-en-Y or Braun loop choledochojejunostomies, respectively. Therefore, primary lithiasis following a choledochojejunostomy occurred when the bilio-digestive anastomoses were performed with the indication of a curative re-operation on the biliary tract. On the contrary, most choledochojejunostomies are performed as a palliative procedure in patients presenting a low survival rate not allowing to develop a Sump Syndrome and a consequent choledocholithiasis, which are long-term complications. PMID- 8679400 TI - [Renal microcarcinomas: a particular clinical entity]. AB - According to the possibility of an early diagnosis, related to diagnostic imaging and predictive indexes such as DNA and vascular permeability, in the presence of a low grade-low stage tumor, and with the support of the Literature, the Authors hypothesize an increasing applicability of conservative surgery in the management of small renal carcinomas. PMID- 8679401 TI - [Poland syndrome. Problems of reconstructive and aesthetic surgery--a clinical case]. AB - The Authors report a case of Poland's syndrome formerly undergone reconstructive surgery with unsatisfactory results. Therefore, a new surgical reconstructive strategy having aesthetic purposes is illustrated. PMID- 8679402 TI - [Spontaneous retroperitoneal hematoma from ileopsoas muscle bleeding. A case report]. AB - The Authors report a case of spontaneous retroperitoneal hematoma due to iliopsoas muscle bleeding. The different causes responsible of such hematomas are taken into account as well as clinical, therapeutical and pathophysiologic aspects connected with the spontaneous bleeding of the iliopsoas muscle. As in the case observed, the Authors suggest that often a careful wait-and-see approach represents the most appropriate therapeutical choice. PMID- 8679403 TI - [Septic ascites: a rare post-operative complication]. AB - Spontaneous bacterial peritonitis in patients with chronic hepatitis represents a very controversial matter in terms of frequency, pathology and treatment. This unusual complication mainly due to decreased immunological defences and ascitic fluid opsonic activity is not accepted by all the Authors as a rare event. However, there is agreement as far as management is concerned: cultural examination of the ascitic fluid and the relative antibiogram are the best tools in guiding the approach to an adequate antibiotic therapy. PMID- 8679404 TI - [Local anesthesia in breast augmentation]. AB - The Authors report their experience in the application of local anesthesia during breast prosthesis implantation. PMID- 8679406 TI - [Renal cell carcinoma. Significance of prognostic factors & current treatment]. AB - The Authors carried out a literature review on prognostic factors and current management of renal cell carcinoma. A significant factor influencing survival appears to be the extension of the primary tumor (T). The finding of no nodal involvement is not always a favourable prognostic factor if the tumor is no more confined. A perfect knowledge of the prognostic factors may be useful to identify those patients who need post-operative chemotherapy. Surgery is still the treatment of choice for renal cell carcinoma. Extensive lymphadenectomy does not influence long-term survival, nevertheless since there is no additional mortality or morbidity, it is considered useful for a correct staging and a better evaluation of long-term prognosis. PMID- 8679405 TI - [Advanced gastric cancer in the elderly. Oncologic evaluation & considerations of operative technique]. AB - The Authors reviewed their series of 28 consecutive elderly patients operated on for gastric cancer in the Division of General and Oncological Surgery--Department of Surgery and Surgical Emergencies of the University of Perugia from January 1993 to December 1994. Thirteen subtotal gastrectomies associated with resection of the nearby organs in 5 cases, six total gastrectomies, two gastrojejunal bypass, and seven atypical resections of the middle third of the stomach were performed. The Authors focus their attention on this atypical technique pointing out the advantages compared to other procedures as well as criteria for patients selection. Gastric resection of the middle third seems a worthwhile procedure for well selected elderly patients, resulting in a good quality of life with low morbidity and mortality. PMID- 8679407 TI - [Therapeutic strategies in the treatment of esophageal cancer: our experience]. AB - Esophageal cancer has a poor prognosis. The Authors in reviewing esophageal carcinogenis stress the importance of an early diagnosis to improve surgical results and compare their experience with those of other Authors. PMID- 8679408 TI - [Hemorrhage caused by rupture into the duodenum of aneurysm of a branch of the pancreaticoduodenal artery (posterior superior or retroduodenal pancreaticoduodenal artery)]. AB - A case of serious haemorragic shock caused by the rupture into the duodenum of a septic aneurysm of the pancreatic-duodenal artery is reported. The diagnostic difficulties and the need to carry on "blind" laparotomies, in these cases, are underlined. PMID- 8679409 TI - [Cystic dilatation of the common bile duct]. AB - The Authors report a case of cystic dilatation of the common bile duct and a review of the Literature. The lesion is a congenital malformation of infancy or childhood, being rare in adult life. The main symptoms are biliary colic with jaundice and fever. Modern techniques such as abdominal ultrasonography, CT, ERCP, PTC generally provide to achieve preoperative diagnosis. When radical surgery is possible the complete excision of the cyst is the management of choice. The case reported is classified as type 1 of Todani's classification. Surgical management consisted in a complete excision of the cyst. Bile flow was re-established by hepaticojejunostomy. PMID- 8679410 TI - [Bednar's syndrome: a case report]. AB - The case of a tumor of Bednar, which is a rather rare form (less than 5% of cases) of dermatofibrosarcoma protuberans presenting similar biologic behavior, is reported. Therefore, the same curative procedures including a radical surgical approach and the application of the Limberg flap were adopted. PMID- 8679411 TI - [Complications of the laparoscopic access]. AB - The Authors analysed the complications observed during 156 laparoscopic accesses. In 38 cases following the classic closed technique, two pneumoderma, one pneumoscrotum, one pneumoepiploon and two laparoceles were observed in the umbilical area. In 30 patients the laparascopic access was performed according to the open technique, registering a significant loss of gas during the operation though not compromising it in 4 patients, and two infections of the umbilical incision. In 88 cases the modified closed technique was used and only one infection in the umbilical trocar insertion area was observed. After discussing the incidence, the etiopathogenesis, the diagnosis and the treatment of complications related to the laparoscopic access, the Authors emphasize the fact that in patients with surgical scars near the naval or patients who have already undergone laparascopy, or those with a positive history of affections causing abdominal adherence, the laparoscopic access must be performed using the open technique. PMID- 8679412 TI - [Late radiation-induced injuries: breast carcinoma in post-actinic ulceration of the thoracic-breast region with infected osteoradionecrosis. A case report]. AB - Severe skin reactions are commonly observed after breast irradiation. Chronic ulcerations, soft tissue damage and osteonecrosis are well-known though relatively rare long-term radiation-induced injuries. The ever-present possibility of recurrence or persistence of the primary malignant neoplasm within the irradiated tissue must be always suspected and adequately established by multiple biopsies before planning an eventual resective and or reconstructive strategy. In the present report a neoplastic recurrence arised from an extensive radiation-induced ulceration along the parasternal area with chest wall osteonecrosis complicated by infection in a 42 y.o. woman, who had received postoperative roentgen therapy a long time before for breast carcinoma and thyroid cancer, is described. Radiation-induced injuries and therapeutical options are discussed in relation to the site of the lesion and to the complexity of the single case. In conclusion, when recurrent malignancy is present, although the long-term prognosis may be poor, the quality of life of many patients undoubtedly may be improved by a multidisciplinary approach involving oncologysts, as well as general, thoracic and plastic surgeons. PMID- 8679413 TI - [Cholecystectomy and colorectal cancer: a retrospective study of a sample of 285 operated patients]. AB - A review of 285 patients operated for colo-rectal cancer in order to evaluate cholecystectomy rate in their pathologic history is reported. A surprisingly high rate (9.47%) was registered also when compared with Literature data. Although not definitely conclusive for a positive correlation between cholecystectomy and colo rectal cancer, the Authors believe that this study identifies a subgroup of patients potentially at risk for colo-rectal cancer. In these subjects a prophylactic, periodic colonoscopy could be useful. PMID- 8679414 TI - [Total thyroidectomy with preservation of the parathyroid glands]. AB - The operative treatment of thyroid pathology has to be distinguished for benign and malignant pathology. The major complications associated with thyroid surgery are injury to the recurrent laryngeal nerve and hypoparathyroidism. Postoperative hypoparathyroidism is rarely the result of inadvertent removal of all parathyroid glands but, non commonly, is due to disruption of their blood supply. Postoperative hypoparathyroidism results in patients with symptomatic hypocalcemia, transitory and permanent hypoparathyroidism. Subtotal thyroidectomy is used for the treatment of benign thyroid pathology while tumors are treated by total thyroidectomy with neck dissection. PMID- 8679415 TI - [Gastroesophageal reflux. Conventional surgery versus laparoscopic treatment: manometric-pH metric evaluation after 4 months]. PMID- 8679416 TI - [Atraumatic skin closure with Fasterzip]. AB - The Authors report their experience of skin closure using a new device, a surgical "zipper", without applying any sort of sutures. The application of this device, the functional and aesthetic advantages and the results obtained are described. PMID- 8679417 TI - Exclusively aortic cold flushing for liver procurement from hemodynamically stable donors. An experimental study in the pig. AB - Liver cooling before grafting is usually achieved by aortic plus portal flushing; exclusively aortic flushing is reserved to hemodynamically unstable or non heart beating donors. We have compared the effects of "aortic plus portal" (8 cases) and "aortic" (8 cases) cold flushing on the early function of pig liver grafts from hemodynamically stable donors. The time for liver removal (mean +/- standard deviation) was 30.4 +/- 7.1 min. in the "aortic plus portal" and 19.7 +/- 3.3 min. in the "aortic" group (p < 0.01). All the recipients survived for at least 72 hrs; only those of the "aortic plus portal" group showed some degree of primary liver dysfunction; recipient serum aspartate transaminase (AST) was significantly higher in the "aortic plus portal" than the "aortic" group. Since aortic flushing allowed for shorter operation times and was better tolerated than and at least as effective as aortic plus portal flushing, it can be proposed for routine liver procurement even from hemodynamically stable donors. PMID- 8679418 TI - [Caroli's disease: 2 case reports and review of the literature]. AB - The most appropriate management of Caroli's disease is still controversial: in fact many surgical modalities have been proposed for patients exhibiting cholangitis or intrahepatic lithiasis, but these approaches have been seldom performed on asymptomatic or oligosymptomatic patients. However, this figure, due to the surgical risk related with a bilio-enteric anastomosis or with an hepatic resection, should be always compared with the possible development of a cholangiocarcinoma within the enlarged biliary tree (7%), as clearly shown in the 2 cases herein reported. PMID- 8679419 TI - [Abdominal vascular and biliary pathology: timing of the combined treatment]. AB - The Authors, after an accurate review of the Literature, report their experience in the combined management of aorto-iliac and biliary lesions. Surgical priorities are well specified in order to reduce the possibility of bacterial contamination of the vascular prosthesis. PMID- 8679420 TI - [A case of myofibroblastoma]. AB - The Authors report a case of myofibroblastoma, a rare primitive mesenchymal tumor of the lymph node. Differential diagnosis with Kaposi sarcoma, neurilemmoma and metastatic neoplasm is discussed. PMID- 8679421 TI - [Use of endoscopic ultrasonography in the staging of esophageal tumors]. AB - Endoscopic Ultrasound (EUS) was performed in 15 patients with esophageal and cardial carcinoma with the aim to evaluate intramural or extraesophageal invasion and regional lymph node metastases. In 10 patients the Authors correctly evaluated the tumoral depth invasion. In 5 patients mediastinal lymph node metastases were observed. It is concluded that EUS is a useful diagnostic method in the staging of esophageal carcinoma. PMID- 8679422 TI - [Gasless laparoscopic cholecystectomy using retractor of the abdominal wall]. AB - The Authors present a new gasless laparoscopic cholecystectomy method using an abdominal wall elevator with subcutaneous traction ("laparotenser"). Fifty patients between May 1994 and March 1995 were operated by videolaparoscopy using this new gasless method. Twenty of them were operated with Nagai's method while the laparotenser was used in the remaining thirty. The results obtained are similar to those using pneumoperitoneum. It has been observed a global reduction of costs, less postoperative pain, no influence in cardiovascular and metabolic indexes. No complications were reported during the postoperative period but two cases of conversion to laparotomy not related to the method used were needed. Laparoscopic cholecystectomy without pneumoperitoneum using the subcutaneous elevator of the abdominal wall ("laparotenser") has demonstrated that it's possible to operate in a working space similar to that created by the pneumoperitoneum. After an initial period of distrust towards the laparoscopic methods without pneumoperitoneum it has been accepted that gasless methods multiply the indications to minimally invasive surgery in patients with cardiorespiratory problems considered no ideal candidates to laparoscopic cholecystectomy with pneumoperitoneum. PMID- 8679423 TI - [Use of prostheses in the treatment of large laparoceles]. AB - The Authors report a series of 18 cases of large laparoceles treated with the use of Dacron prosthesis which was installed according to Rives' technique. They observed 0% of recurrence, 1 case (5%) of mortality for pulmonary embolism, 3 cases (16%) of pulmonary embolism and 1 case (5%) of surgical wound infection. PMID- 8679424 TI - [Polyethylene glycol versus sodium phosphate: comparison of 2 preparations for colonoscopy]. AB - The intention of this study is to compare the efficacy and tolerability of an electrolytic solution containing polyethylene glycol (PEG) with a saline solution containing sodium phosphate in the preparation of colon for an endoscopic examination. 80 patients were subdivided at random into two groups: Group 1; PEG 4 liters - Group 2; sodium phosphate 3 packets plus one microenema. The efficacy of the two preparations was decided on the basis of: presence or absence of liquid/solid faecal residues observed by the endoscopist during the exploration of the large intestine, and classified as follows: perfect, good, mediocre and bad. Acceptability was established on the basis of patient tolerability in completing or not the preparation as well as presence of any side effect. The PEG solution was observed to be more efficient than sodium phosphate solution while both preparations had comparable tolerability. The cost of the PEG preparation was higher compared to the sodium phosphate preparation. PMID- 8679425 TI - [Physiopathology and clinical aspects of renovascular hypertension]. PMID- 8679426 TI - Current controversies in laparoscopic colorectal surgery. PMID- 8679427 TI - [Technique of vascular reconstructive bench surgery in pancreas transplantation]. AB - Vascular reconstructive bench surgery has become a basic step in pancreas transplantation, in order to prevent vascular thrombosis. The Authors describe their experience, also reporting literature results. PMID- 8679428 TI - [Esophagectomy without thoracotomy: indications and our experience]. AB - In this paper the Authors report their experience of Orringer operation in 12 patients with oesophageal cancer observed from 1978 to 1992, and stress the possibility to extend the indications to Akijama oesophagectomy without thoracotomy for the treatment of malignant tumors of the entire oesophagus. PMID- 8679429 TI - [Conservative surgery in the environment of a screening program for breast carcinoma: evaluation of the results in terms of local recurrence]. AB - This report evaluates the results of conservative surgery plus radiotherapy (QUART) in a group of 123 patients from the screening programme of the District Health Board USSL 41 in Brescia, Italy (over 250 tumours diagnosed in two screening rounds, between 1987 and 1993). To date no recurrence of neoplasms in the operated breast have been diagnosed in either of the two QUART groups (64 patients from the first round, average follow-up 28 months, median 66 months; 59 patients from the second round, average follow-up 28 months, median 30 months). A new carcinoma in the contralateral breast occurred in 3 patients (2 from the first and 1 from the second round), while in 3 cases there was a recurrence in another site (2 from the first and 1 from the second round). These results confirm both the proven effectiveness of conservative treatment in the local control of breast tumours, and the importance of the correct choice of conservative treatment in optimising aesthetic and therapeutic results. PMID- 8679431 TI - Itch mediators. PMID- 8679430 TI - Some neurophysiological aspects of itch. PMID- 8679433 TI - The measurement of scratching. PMID- 8679432 TI - Measurement of itch. AB - Measurement in its broadest sense can be defined as the assignment of numerals to objects or events according to rules. The rules settle the scale level, which in turn determines the mathematical and statistical operations permissible when handling the data. Itch is a subjective symptom that can be assessed only by the subject himself. No animal models are established for the investigation of itch. In contrast to pain research, a field with many similarities, rather few scientific attempts have been made to develop and evaluate methods for the quantitative analysis of itch. However, several investigators have recently addressed the challenge of itch measurement in both experimental and clinical situations. This is important, as valid quantitative techniques for the assessment of itch are of considerable value for studying the mechanisms of pruritus, and for the evaluation of antipruritic therapies. PMID- 8679434 TI - Investigation of the pruritic patient in daily practice. PMID- 8679435 TI - Uremic pruritus. PMID- 8679436 TI - The pruritus of cholestasis. AB - The pruritus of cholestasis is a difficult clinical problem to manage. The pathogenesis of this symptom is unknown. All conventional therapies have been unsuccessful in isolating a particular group of substances that could be implicated as direct or indirect causative agents. It should be emphasized that nonspecific treatment modalities that lower the plasma concentrations of a variety of substances (such as cholestyramine, colestipol, charcoal hemoperfusion, plasmapheresis, partial external diversion of bile, and drugs that induce hepatic enzymes), can potentially ameliorate the pruritus of cholestasis by lowering the circulating levels of an undefined pruritogen or a factor responsible for inducing the primary mechanism of the pruritus. The encouraging results reported by the use of antibiotic therapy for this condition merits investigation. Increased opioidergic neurotransmission is part of the syndrome of cholestasis and it contributes, at least in part, to the pruritus associated with it. Opiate antagonists seem to be an effective alternative therapy for some patients. Recent preliminary reports suggest that other neurotransmitter systems, eg, serotoninergic, may be involved in the pruritus of cholestasis. The need for quantitation of scratching activity cannot be over emphasized. The use of quantitative methodology offers the opportunity to facilitate the study of scratching behavior that is a biological phenomenon secondary to liver disease. PMID- 8679437 TI - Aquagenic pruritus. PMID- 8679438 TI - Pruritus in the elderly. PMID- 8679439 TI - Treatment of itch. PMID- 8679440 TI - The itchy scalp and other pruritic curiosities. PMID- 8679441 TI - Deficient DNA repair capacity, a predisposing factor in breast cancer. AB - Women with breast cancer and a family history of breast cancer and some with sporadic breast cancer are deficient in the repair of radiation-induced DNA damage compared with normal donors with no family history of breast cancer. DNA repair was measured indirectly by quantifying chromatid breaks in phytohaemagglutinin (PHA)-stimulated blood lymphocytes after either X-irradiation or UV-C exposure, with or without post treatment with the DNA repair inhibitor, 1 beta-D-arabinofuranosylcytosine (ara-C). We have correlated chromatid breaks with unrepaired DNA strand breaks using responses to X-irradiation of cells from xeroderma pigmentosum patients with well-characterised DNA repair defects or responses of repair-deficient mutant Chinese hamster ovary (CHO) cells with or without transfected human DNA repair genes. Deficient DNA repair appears to be a predisposing factor in familial breast cancer and in some sporadic breast cancers. PMID- 8679442 TI - Expression of NM23 in human melanoma progression and metastasis. AB - NM23 is a putative metastasis-suppressor gene for some human cancers. Here we have studied NM23 expression during melanoma progression using Northern blotting and immunocytochemistry. There was no significant difference in the average amounts of NM23 mRNA between cell lines derived from metastatic and primary melanomas. The level of NM23 mRNA was also determined for three pairs of poorly metastatic parental (P) and their highly metastatic variant (M) cell lines; the ratios for M/P were 1.2, 0.98 and 0.80. Next we used immunocytochemistry to study NM23 protein in normal skin, benign naevi and primary and metastatic melanomas. Melanocytes in all normal skin and benign samples were positive for NM23; however most primary melanomas (7/11) were not stained by the antibody. All metastatic melanoma samples (5/5) were positively stained. Findings were similar with an antiserum reactive with both forms of NM23 (H1 and H2), and with an antibody specific for NM23-H1. No relationship was apparent between NM23 immunoreactivity in primary tumours and their aggressiveness or prognosis. Hence, in contrast to the situation described for murine melanoma, the amount of NM23 mRNA or protein in human melanoma did not correlate inversely with metastasis. PMID- 8679443 TI - Loss of heterozygosity on chromosome 5q in ovarian cancer is frequently accompanied by TP53 mutation and identifies a tumour suppressor gene locus at 5q13.1-21. AB - Forty-nine ovarian tumours were examined for loss of heterozygosity (LOH) on chromosome 5 using eight microsatellite markers spanning both arms, including one at the APC locus. LOH on 5q was a frequent event, detectable in 23 of 49 (47%) tumours, whereas 5p LOH was detected in only 1 of 22 tumours (5%). Six tumours showed partial LOH on 5q, enabling the candidate region to be localised to a 22 cM region proximal to APC, flanked by D5S424 and D5S644. An association was found between 5q LOH and TP53 mutation, with 18 of 23 (78%) tumours with LOH on 5q also harbouring a TP53 mutation. LOH on 5q was observed in 6 of 18 (33%) stage I tumours, suggesting that it may be an early event in the molecular pathogenesis of certain ovarian carcinomas. PMID- 8679444 TI - p16 mutations/deletions are not frequent events in prostate cancer. AB - Cyclin-dependent kinase-4 inhibitor gene (p16INK4) has recently been mapped to chromosome 9p21. Homozygous deletions of this gene have been found at high frequency in cell lines derived from different types of tumours. These findings suggested therefore, that p16INK4 is a tumour-suppressor gene involved in a wide variety of human cancers. To investigate the frequency of p16INK mutations/deletions in prostate cancer, we screened 20 primary prostate tumours and four established cell lines by polymerase chain reaction (PCR) and single strand conformation polymorphism (SSCP) analysis for exon 1 and exon 2. In contrast to most previous reports, no homozygous deletions were found in prostate cancer cell lines, but one cell line (DU145) has revealed to a mutation at codon 76. Only two SSCP shifts were detected in primary tumours: one of them corresponds to a mutation at codon 55 and the other one probably corresponds to a polymorphism. These data suggest that mutation of the p16INK4 gene is not a frequent genetic alteration implicated in prostate cancer development. PMID- 8679445 TI - Heterogeneity in renal cell carcinoma and its impact no prognosis--a flow cytometric study. AB - In the process of tumour progression genetic instability is the basis for the evolution of tumour cell clones with various genotypic and phenotypic characteristics causing heterogeneity. Renal cell carcinoma has a long prediagnostic growth period, which increases the probability of clonal evolution. We have studied 200 consecutive renal cell carcinomas, addressing the interrelationship between intratumour heterogeneity and clinicopathological factors. DNA ploidy patterns were analysed in multiple samples from each tumour using flow cytometry and compared with clinical stage, tumour invasion, metastatic rate and survival. Eighty-five of 192 evaluable tumours (44%) were homogeneous concerning DNA ploidy (62% diploid, 38% aneuploid). Among 107 heterogeneous tumours a majority (79%) contained aneuploid as well as diploid cell clones. Homogeneously diploid tumours had a lower incidence of local tumour spread compared with tumours with aneuploid cell clones (P < or = 0.001), but the frequency of distant metastasis at time of diagnosis was similar. The presence of aneuploidy in at least one sample from a tumour was a significant adverse prognostic factor (P < 0.001), whereas the degree of heterogeneity had no influence on survival. The frequent heterogeneity demonstrated indicates that multiple samples must be investigated to evaluate properly the malignant character of renal cell carcinoma. PMID- 8679446 TI - Do positive resection margins after ablative surgery for head and neck cancer adversely affect prognosis? A study of 352 patients with recurrent carcinoma following radiotherapy treated by salvage surgery. AB - It is generally accepted by surgeons that failure to eradicate malignant disease at the primary site has an adverse effect on survival. The present study investigates 352 patients with squamous carcinoma of the head and neck treated by primary radical radiotherapy and who subsequently underwent surgical ablation for a recurrent carcinoma. A total of 303 (86%) patients had a negative resection margin and 49 (14%) had a positive resection margin. Oral carcinoma was 1.7 times more likely to be associated with a positive margin than other tumours (P = 0.0292). Actuarial calculations demonstrated that 47% of patients with negative margins and 66% of patients with positive margins developed a primary site recurrence (P = 0.0286). Neck node recurrence occurred in 10% of those patients with negative margins and 12% of patients with positive margins. Patients with positive margins had a significantly poorer survival than those with negative margins (P = 0.022). Multivariate analysis failed to confirm any independent adverse effect from a positive margin. The 5 year tumour-specific survival of patients with a positive margin was poorer by 12% than for those patients with a negative margin. The pattern of failure differed between the two groups, with patients having positive margins tending to die of local recurrence. PMID- 8679448 TI - Immunochemical vs guaiac faecal occult blood tests in a population-based screening programme for colorectal cancer. AB - Two faecal occult blood tests (FOBTs), Hemoccult II (guaiac based) and Hemeselect (immunochemical) were compared in a population screening for colorectal cancer on 24 282 subjects aged 40-70. Hemeselect was interpreted according to a lower (+ and +/-) and a higher (+) positivity threshold. A total of 8008 compliers were enrolled in the study. Positivity rates: Hemoccult = 6.0%, Hemeselect (+ and +/) = 8.2%, Hemeselect (+) = 3.1%. Among FOBT-positive subject complying with the diagnostic work-up, 22 had colorectal cancer (17 Hemeselect-positive (+), four Hemeselect-borderline (+/-), 15 Hemoccult-positive) and 166 subjects had adenomas (62 Hemeselect(+), 56 Hemeselect-borderline (+/-), 79 Hemoccult-positive) were detected. The positive predictive values (PPVs) for cancer were as follows: Hemoccult = 3.7%, Hemeselect (+ and +/-) = 3.8%, Hemeselect (+) = 8.4%. The PPVs for adenoma(s) were: Hemoccult = 19.7%, Hemeselect (+ and +/-) = 21.4%, Hemeselect (+) = 30.5%. The specificity for cancer was: Hemoccult = 94.1%, Hemeselect (+ +/-) = 92%, Hemeselect (+) = 97.1%. Ratios between detection rates of each test and expected incidence of colorectal cancer suggest that Hemoccult anticipates cancer diagnosis by approximately 2 years on average whereas the mean diagnostic anticipation of Hemeselect ranges between 2.5 and 3.2 years. Hemeselect is superior to Hemoccult as it is at least as effective but more efficient and acceptable than guaiac testing. Further evaluation of Hemeselect cost-effectiveness and sensitivity is needed in order to assess the optimal threshold of positivity and screening frequency. PMID- 8679447 TI - Glycolipids of human primary testicular germ cell tumours. AB - The glycolipid content of human non-seminomatous germ cell tumour cell lines correlates with their differentiation lineage. To analyse whether this reflects the situation in primary tumours, we studied five embryonal carcinomas, five yolk sac tumours and nine (mixed) non-seminomas, using thin-layer chromatography and carbohydrate immunostaining. We also analysed the glycolipid content of 19 seminomas to reveal their relationship with non-seminomas. Lactosylceramide (CDH) was detected in all embryonal carcinomas, but in fewer than half of the seminomas. Seminomas and embryonal carcinomas contained globoseries glycolipids, including globotriosylceramide (Gb3), globoside (Gb4), galactosy globoside (Gb5) and sialy1 galactosyl globoside (GL7). The lacto-series glycolipid Le(x) was found in all embryonal carcinomas, but only in one seminoma. Gangliosides GD3 and GT3 were detected in many seminomas, but rarely in embryonal carcinomas. Yolk sac tumours displayed a heterogeneous glycolipid profile. Compared with seminomas and pure embryonal carcinomas, differentiated non-seminomas had reduced levels of globo-series glycolipids, especially Gb3 and Gb5, whereas CDH, Le(x), GD3 and GT3 were found in the majority of cases. Thus, the glycolipid content of non-seminoma cell lines reflects the situation in primary tumours. Globo-series glycolipids are similarly expressed in seminomas and embryonal carcinomas. The expression of Gb3 and Gb5 is reduced in non-seminomas upon differentiation. Le(x) expression in non-seminomas, including embryonal carcinomas, allows discrimination from seminomas. Expression of gangliosides in seminomas might indicate their maturation from ganglioside-negative precursor cells. Reprogramming of these precursors would result in the formation of Le(x)-expressing embryonal carcinomas. PMID- 8679450 TI - Patterns of childhood cancer among siblings. AB - The National Registry of Childhood Tumours contains over 51000 records of children born in Great Britain who developed cancer under the age of 15 years. Patterns of childhood cancer among families containing more than one child with cancer have been studied. A total of 225 "sib pair' families have been ascertained from interviews with parents of affected children, from hospital and general practitioner records and from manual and computer searches of names and addresses of patients. A number of special groups have been identified, including those with a known genetic aetiology such as retinoblastoma, twins and families with three or more affected children. A further 148 families not in any of the above groups contain two children with cancer: in 46 families the children had tumours of the same type, most commonly leukaemia. Some of the families are examples of the Li-Fraumeni syndrome; some are associated with other conditions, including Down's syndrome. There is clearly a genetic element in the aetiology of cancer in some families discussed here; shared exposure to environmental causes may account for others and some will be simply due to chance. PMID- 8679449 TI - Calcium, phosphorus, vitamin D, dairy products and colorectal carcinogenesis: a French case--control study. AB - A protective effect of calcium against colorectal cancer has been described in Anglo-Saxon but not in Latin communities, and no such effect has been observed regarding adenomas. We investigated the relationship between calcium, dairy products and the adenoma-carcinoma sequence in a French region by comparing small adenoma ( < 10 mm, n = 154), large adenoma (n = 208) and polyp-free (n = 426) subjects, and cancer cases (n = 171) with population controls (n = 309). There was no protective effect of calcium against colorectal tumours except for low fat calcium and large adenomas in men (OR for highest quintile = 0.3, P for trend = 0.06). There was even a trend towards an increased risk of cancer with dairy calcium in men and non-dairy calcium in women. Vitamin D was inversely related to the risk of small adenomas in women (OR for highest quintile = 0.4, P for trend = 0.04). Regarding dairy products, only consumption of yoghurt displayed an inverse relationship with risk of large adenomas, in both men and women. These data failed to demonstrate a protective effect of calcium against colorectal carcinogenesis. They suggest that the type of dairy product might be the important factor with regard to prevention of colorectal tumours. PMID- 8679451 TI - Fat, fish, fish oil and cancer. AB - There is an ecological association between total and animal fat consumption and colorectal and breast cancer risk. Mortality data for breast and colorectal cancer for 24 European countries correlated, as expected, with the consumption of animal, but not vegetable, fat. There was an inverse correlation with fish and fish oil consumption, when expressed as a proportion of total or animal fat, and this correlation was significant for both male and female colorectal cancer and for female breast cancer, whether the intakes were in the current time period, or 10 years or 23 years before cancer mortality. These effects were only seen in countries with a high ( > 85 g caput-1 day-1) animal fat intake. This evidence suggests that fish oil consumption is associated with protection against the promotional effects of animal fat in colorectal and breast carcinogenesis. PMID- 8679452 TI - Nicotinamide pharmacokinetics in humans: effect of gastric acid inhibition, comparison of rectal vs oral administration and the use of saliva for drug monitoring. AB - The effect of inhibiting gastric acid secretion on nicotinamide pharmacokinetics was studied in five volunteers with the intent of reducing the large variations observed previously in the time to and magnitude of peak plasma concentrations. Plasma levels were determined using a standard high-performance liquid chromatography (HPLC) method after an oral dose of 3 g of nicotinamide either alone or preceded by pretreatment with omeprazole. Suppression of gastric acid production had no significant effect on the rate of uptake or on the peak levels achieved. To bypass gastric acidity, the rectal route was also assessed using a suppository in four volunteers and one patient undergoing radiotherapy. Absorption was slow and variable and much lower plasma levels were observed than after oral dosing. Thus, no improvement in the pharmacokinetics of nicotinamide was observed using either of these two approaches. Parallel estimations were made using a novel and non-invasive method for monitoring nicotinamide pharmacokinetics in saliva. A large and variable fraction of the total amount of nicotinamide-related material in saliva was found to be nicotinic acid, a metabolite not normally found in human plasma. This conversion was inhibited by the use of a chlorhexidine mouthwash, indicating that the oral flora was responsible for its production. The time to peak levels of nicotinamide or of nicotinamide plus nicotinic acid in saliva correlated well with that in plasma. However, peak concentrations for nicotinamide alone were significantly lower than in plasma, and very variable, whereas for nicotinamide plus nicotinic acid saliva levels were 20-30% higher, but more consistent. Although there are some practical difficulties in quantitatively handling saliva, the method is very useful for monitoring nicotinamide pharmacokinetics and for assessment of compliance with nicotinamide treatment. PMID- 8679453 TI - Apoptosis and necrosis induced with light and 5-aminolaevulinic acid-derived protoporphyrin IX. AB - The mode of cell death induced by photodynamic treatment (PDT) was studied in two cell lines cultured in monolayer, V79 Chinese hamster fibroblasts and WiDr human colon adenocarcinoma cells. The cells were incubated with 5-aminolaevulinic acid (5-ALA) as a precursor for the endogenously synthesised protoporphyrin IX, which was activated by light. Free DNA ends, owing to internucleosomal DNA cleavage in apoptotic cells, were stained specifically with a fluorescent dye in the terminal deoxynucleotidyl transferase (TdT) assay. The free DNA ends were measured by flow cytometry and the fractions of apoptotic cells determined. Total cell death was measured in a cell survival assay to determine the necrotic fraction after subtraction of the apoptotic fraction. V79 cells did undergo apoptosis while WiDr cells were killed only through necrosis. With time, the apoptotic fraction of V79 cells increased until a maximum was reached about 3-4 h after ALA-PDT treatment. For increasing ALA-PDT doses, a maximal apoptotic fraction 75-85% of the cells was measured at about 85% of total cell death. The flow cytometric assay of apoptosis was confirmed by the typical ladder of oligonucleosomal DNA fragments obtained from agarose gel electrophoresis, by fluorescence micrographs visualising the induced free DNA ends and by electron micrographs showing the typical morphology of apoptotic cells. PMID- 8679455 TI - DNA double-strand break rejoining rates, inherent radiation sensitivity and human tumour response to radiotherapy. AB - The relationship between DNA double-strand break rejoining rates, inherent radiation sensitivity and tumour response to radiation therapy was determined for a group of 25 squamous cell carcinoma (SCC) and eight sarcoma (SAR) tumours. DNA double-strand break frequencies were measured by neutral filter elution in first passage following explant tumour samples after in vitro exposure to 100 Gy of 60Co gamma-rays. There was no significant difference between SCC and SAR tumour cells in their sensitivity to break induction, but in a 1 h time period SAR tumour cells rejoined significantly fewer breaks than SCC tumour cells, consistent with the greater sensitivity of SAR and suggesting that differences in rates of break rejoining account for the different distributions of radiosensitivities seen when different tumour types are compared. The percentage of breaks rejoined in 1 h in these tumour samples correlated well with D(o) and with the beta component of the survival curve, measured in vitro by clonogenic assay in tumour cell lines established from the tumour samples, but not with SF2 or the alpha component of the survival curve. The rates of DNA double-strand break rejoining therefore appear to influence the exponential portion of survival curves and probably the interactions between breaks. The percentage of breaks rejoined in 1 h was higher in SCC tumours that subsequently failed radiotherapy and, although the differences were not significant, they suggest that rates of break rejoining are an important component of tumour response to radiation therapy. PMID- 8679454 TI - Strong and prolonged induction of c-jun and c-fos proto-oncogenes by photodynamic therapy. AB - Photodynamic therapy (PDT) is currently under investigation in phase II and III clinical studies for the treatment of tumours in superficial localisations. Thus far, the underlying mechanisms of PDT regarding cellular responses and gene regulation are poorly understood. Photochemically generated singlet oxygen (1O2) is mainly responsible for cytotoxicity induced by PDT. If targeted cells are not disintegrated, photo-oxidative stress leads to transcription and translation of various stress response and cytokine genes. Tumour necrosis factor (TNF) alpha, interleukin (IL) 1 and IL-6 are strongly induced by photodynamic treatment, supporting inflammatory action and immunological anti-tumour responses. To investigate the first steps of gene activation, this study focused on the proto oncogenes c-jun and c-fos, both coding for the transcription factor activator protein 1 (AP-1), which was found to mediate IL-6 gene expression. We here determine the effects of photodynamic treatment on transcriptional regulation and DNA binding of transcription factor AP-1 in order to understand the modulation of subsequent regulatory steps. Photodynamic treatment of epithelial HeLa cells was performed by incubation with Photofrin and illumination with 630 nm laser light in vitro. Expression of the c-jun and c-fos genes was determined by way of Northern blot analysis, and DNA-binding activity of the transcription factor AP-1 was evaluated by electrophoretic mobility shift assay (EMSA). Photofrin-mediated photosensitisation of HeLa cells resulted in a rapid and dose-dependent induction of both genes but preferential expression of c-jun. Compared with the transient expression of c-jun and c-fos by phorbol ester stimulation, photodynamic treatment led to a prolonged activation pattern of both immediate early genes. Furthermore, mRNA stability studies revealed an increased half-life of c-jun and c-fos transcripts resulting from photosensitisation. Although mRNA accumulation after PDT was stronger and more prolonged compared with phorbol ester stimulation, with regard to AP-1 DNA-binding activity, phorbol ester was more efficient. Surprisingly, in addition to the activation of AP-1 DNA-binding via PDT, photodynamic treatment can decrease AP-1 DNA-binding of other strong inducers, such as the protein kinase C-mediated pathway of phorbol esters and the antioxidant pyrrolidine dithiocarbamate (PDTC). This study demonstrates a strong induction of c-jun and c-fos expression by PDT, with prolonged kinetics and mRNA stabilisation as compared with activation by phorbol esters. Interestingly, this observation is not coincident with an overinduction of AP-1 DNA-binding, hence suggesting that post-translational modifications are dominant regulatory mechanisms after PDT that tightly control AP-1 activity in the nucleus thus limiting the risk of deregulated oncogene expression. PMID- 8679456 TI - An improved method of encapsulation of doxorubicin in liposomes: pharmacological, toxicological and therapeutic evaluation. AB - We describe here an improved method of encapsulating doxorubicin in liposomes using phosphatidylcholine, cholesterol and synthetic tetramyristoyl cardiolipin. With this new composition of lipids the entrapment of doxorubicin was found to be > 90%. Cytotoxicity studies using vincristine-resistant HL-60/VCR leukaemia cells showed that liposome-encapsulated doxorubicin reverses multidrug resistance 5 fold compared with conventional doxorubicin and at levels equivalent to that obtained using liposomes with natural cardiolipin. In normal mice, liposome encapsulated doxorubicin was much less toxic than the conventional drug. A dose of 25 mg kg-1 i.v. of conventional doxorubicin produced 100% mortality in mice by day 14, whereas liposomal doxorubicin exhibited only 10% mortality by day 60. Liposomal doxorubicin demonstrated enhanced anti-tumour activity against murine ascitic L1210 leukaemia compared with conventional doxorubicin. At a dose of 15 mg kg-1, liposomal doxorubicin increased the median life span with 12 of 18 long term (60 days) survivors compared with only 3 of 18 with conventional drug. Mice injected i.v. with liposomal doxorubicin had plasma levels 44-fold higher than conventional doxorubicin, producing significantly higher (P < 0.02) area under the plasma concentration curve. An altered tissue distribution was also observed with liposomal doxorubicin; cardiac tissue demonstrating at least 2-fold lower levels with liposomal doxorubicin probably accounting for its lower toxicity. This altered pharmacokinetics of liposome-encapsulated doxorubicin, providing enhanced therapeutic advantage and the ability to modulate multidrug resistance, could be useful in a clinical setting. PMID- 8679457 TI - Photodynamic therapy on the normal rabbit larynx with phthalocyanine and 5 aminolaevulinic acid induced protoporphyrin IX photosensitisation. AB - Photodynamic therapy (PDT) is a promising technique for the treatment of small tumours in organs where it is essential to minimise damage to immediately adjacent normal tissue as PDT damage to many tissues heals by regeneration rather than scarring. As preservation of function is one of the main aims of treating laryngeal tumours, this project studied the effects of PDT on the normal rabbit larynx with two photosensitisers, endogenous protoporphyrin IX (PPIX) induced by the administration of 5-aminolaevulinic acid (ALA) and disulphonated aluminium phthalocyanine (AIS2Pc). The main aims of the study were to examine the distribution of protoporphyrin IX and AIS2Pc by fluorescence microscopy in the different regions of the larnyx and to assess the nature and subsequent healing of PDT damage. Peak levels of PPIX were found 0.5-4 h after administration of ALA (depending on dose) with highest levels in the epithelium of the mucosa. With 100 mg kg-1, PDT necrosis was limited to the mucosa, whereas with 200 mg kg-1 necrosis extended to the muscle. With 1 mg kg-1 AIS2Pc, 1 h after administration, the drug was mainly in the submucosa and muscle, whereas after 24 h, it was predominantly in the mucosa. PDT at 1 h caused deep necrosis whereas at 24 h it was limited to the mucosa. All mucosal necrosis healed by regeneration whereas deeper effects left some fibrosis. No damage to cartilage was seen in any of the animals studied. The results of this study have shown that both photosensitisers are suitable for treating mucosal lesions of the larynx, but that for both it is important to optimise the drug dose and time interval between drug and light to avoid unacceptable changes in normal areas. PMID- 8679458 TI - An analysis of surveillance for stage I combined teratoma--seminoma of the testis. AB - We analysed 973 patients with stage I testicular tumours presenting between 1983 and 1994. The median ages at presentation for non-seminomatous germ cell tumour (teratoma) were 27 years, seminoma 36 years and combined tumour 33 years. These differences were statistically significant (Mann-Whitney P < 0.05), suggesting that combined tumours may have a separate natural history. We, therefore, analysed all stage I patients managed with surveillance (530 in total) post orchidectomy. The actuarial 5 year relapse-free survival and anatomical patterns of relapse were identical for non-seminomatous germ cell tumour (NSGCT) and combined tumour and both were statistically distinct from seminoma (P = 0.01, log rank test, chi-square test P = 0.001). The association of seminoma within a histologically confirmed NSGCT has no influence on the clinical outcome. PMID- 8679460 TI - p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer. AB - Expression of both P-glycoprotein (P-gp) and mutant p53 have recently been reported to be associated with poor prognosis of breast cancer. The expression of P-gp is associated in vitro and in vivo with cross-resistance to several anti cancer drugs. p53 plays a regulatory role in apoptosis, and mutant p53 has been suggested to be involved in drug resistance. Interestingly, in vitro experiments have shown that mutant p53 can activate the promoter of the MDR1 gene, which encodes P-gp. We investigated whether p53 and P-gp are simultaneously expressed in primary breast cancer cells and analysed the impact of the co-expression on patients prognosis. Immunohistochemistry was used to investigate P-gp expression (JSB-1, C219) and nuclear p53 accumulation (DO-7) in 20 operable chemotherapy untreated and 30 locally advanced breast cancers undergoing neoadjuvant chemotherapy with doxorubicin and cyclophosphamide. Double immunostaining showed that P-gp expression and nuclear p53 accumulation often occur concomitantly in the same tumour cells. A correlation between p53 and P-gp expression was found in all 50 breast cancers (P = 0.003; Fisher's exact test). P-gp expression, nuclear p53 accumulation, and co-expression of p53 and P-gp were more frequently observed in locally advanced breast cancers than in operable breast cancers (P = 0.0004, P = 0.048; P = 0.002 respectively. Fisher's exact test). Co-expression of p53 and P gp was the strongest prognostic factor for shorter survival by multivariate analysis (P = 0.004) in the group of locally advanced breast cancers (univariate analysis: P = 0.0007). Only 3 out of 13 samples sequentially taken before and after chemotherapy displayed a change in P-gp or p53 staining. In conclusion, nuclear p53 accumulation is often associated with P-gp expression in primary breast cancer, and simultaneous expression of p53 and P-gp is associated with shorter survival in locally advanced breast cancer patients. Co-expression of P gp and mutant p53 belong to a series of molecular events resulting in a more aggressive phenotype, drug resistance and poor prognosis. PMID- 8679459 TI - The effect of combined expression of interleukin 2 and interleukin 4 on the tumorigenicity and treatment of B16F10 melanoma. AB - The recent use of interleukin 2 (IL-2) and interleukin 4 (IL-4) single cytokine modified tumour cells in rodent models has demonstrated a potential use of these cytokines to produce autologous cancer cell vaccines. Here we compare the potential therapeutic benefit of transduction with IL-2 or IL-4 alone, and combined IL-2 + IL-4 in B16F10 cells, a murine malignant melanoma of poor immunogenicity. Transduction of B16F10 cells (MHC class I and II negative) to express either IL-2 or IL-4 alone delays the formation of tumours, IL-4 being more effective than IL-2. However, combined expression of IL-2 + IL-4 reduces tumorigenicity more than either cytokine alone. The eventual formation of tumours may result from loss of gene expression, and preliminary results suggest methylation of the retroviral long terminal repeat (LTR), rather than loss of the transduced DNA sequences. Histological examination of tumours expressing either IL-2 or IL-4 alone shows a non-specific inflammatory reaction with an increased tissue infiltrate of immune effectors (monocytes/macrophages, lymphocytes, granulocytes) localised around the tumour. In comparison, when cells expressing combined IL-2 + IL-4 were injected there were more granulocytes present, and perhaps more importantly, these were mainly localised within the tumour. The benefit of combined IL-2 + IL-4 expression results from a local rather than systemic effect as the growth of tumours from cells expressing IL-2 or IL-4 alone injected at distant sites was comparable with a single inoculation of cells expressing either cytokine alone. However, when cells expressing single cytokines IL-2 or IL-4 were mixed and injected at the same site, in comparison with the clonal population of cells expressing combined IL-2 + IL-4, tumour growth was characteristic of IL-4 alone rather than IL-2 + IL-4. Treatment of established tumours with a single injection of lethally irradiated tumour cells expressing IL 2 + IL-4 was sufficient to either reject tumours, or at least delay further tumour development. Furthermore, treatment stimulated an initial non-specific immune reaction that lead to a systemic immunity. Lethally irradiated wild-type cells were also successful in treating some established tumours, although this did not induce any systemic immunity. However, although successful in treatment studies, neither wild-type nor combined IL-2 + IL-4 expressing cells were able to vaccinate animals against a subsequent challenge with live wild-type tumour. These results indicate a potential therapeutic benefit with the use of combination IL-2 + IL-4 transduction of autologous cancer cells. PMID- 8679461 TI - Endothelial Tie growth factor receptor provides antigenic marker for assessment of breast cancer angiogenesis. AB - Breast cancer prognosis has previously been linked to the degree of tumour vascularisation. In order to establish additional markers for tumour angiogenesis, we have used monoclonal antibodies against the endothelial Tie receptor tyrosine kinase to study the degree of vascularisation of breast carcinomas and the regulation of Tie expression in the vascular endothelial cells. Antibodies were used for Tie detection and the results were correlated with other prognostic markers. Of four monoclonal antibodies directed against different epitopes of the Tie extracellular domain, two reacted against Tie in unfixed histopathological sections of breast carcinomas. One of these antibodies (clone 7e8) was specific for the endothelial cells whereas the other (clone 10f11) also reacted with basement membranes and occasional carcinoma cells. When Tie expression was studied with the antibody clone 7e8, all 27 carcinomas, two in situ carcinomas, samples of histologically normal breast tissue (n = 16) or normal skin or lymph node tissue (n = 5) showed staining. Microvessel counts were higher in carcinomas (median 14; range 3-27) than in fibrodenomas (median 10; range 5-18) or histologically normal breast tissue (median 7; range 3-15, P = 0.0006). A similar result was obtained using antibodies against the CD31 (PECAM) antigen. Microvessel counts in 7e8 staining were not significantly associated with primary tumour size, axillary nodal status, histological grade or staining for oestrogen receptor, progesterone receptor, Ki-67 proliferation marker or p53 oncoprotein. PMID- 8679462 TI - Drug sensitivity testing for clinical samples from oesophageal cancer using adhesive tumour cell culture system. AB - A total of 83 specimens of surgically resected tumours from 78 patients with oesophageal cancer were assayed for drug sensitivity using an adhesive tumour cell culture system (LifeTrac CSA assay). Seventyone of 83 specimens had a sufficient number of cells to permit growth in culture and 57 of 71 (80%) were evaluable for drug response. Cells (3 x 10(3) ml-1 well-1) were cultured for 14 days and exposed to drugs on days 3-8. Growing cells were confirmed as cancer cells by immunohistochemical staining. IC90 values against several anti-cancer drugs were determined and population distributions of IC90 for each drug served as the basis for judging sensitivity. The 10th percentiles of IC90 (microgram ml 1) for CDDP, 5-FU, DOX, CPM, MTX, VP16, IFOS, VDS, BLM and CDDP + 5-FU were 0.3, 0.16, 0.005, 0.9, 0.006, 0.09, 0.8, 0.006, 0.04 and 0.15 + 0.09 respectively. The population distribution of IC90 against each drug showed a specific pattern that was very similar among histopathological gradings and stages of the disease. This system appeared to be a clinically applicable drug sensitivity test for human oesophageal cancer. PMID- 8679463 TI - Expression of Bcl-2 in node-negative breast cancer is associated with various prognostic factors, but does not predict response to one course of perioperative chemotherapy. AB - The aim of this study was to assess relationships between Bcl-2 expression, response to chemotherapy and a number of pathological and biological tumour parameters in premenopausal, lymph node-negative breast cancer patients. Expression of Bcl-2 was determined using immunohistochemistry on paraffin embedded sections in a series of 441 premenopausal, lymph node-negative breast cancers of patients randomised to receive perioperative chemotherapy (5 fluorouracil, doxorubicin, cyclophosphamide) or no perioperative chemotherapy. Immunohistochemistry of Bcl-2 was evaluated by scoring both staining intensity (0 3) and number of positive cells (0-2). Using these scores tumours were grouped into categories 0-6. It was found that 9.2% of the tumours were completely negative (0), 17.2% weakly (1 + 2), 41.6% moderately (3 + 4) and 31.9% strongly positive (5 + 6) for Bcl-2. A positive correlation was found between high Bcl-2 expression and oestrogen (P < 0.001) and progesterone receptor positivity (P < 0.001) and low tumour grade (P < 0.001), whereas high Bcl-2 expression was negatively correlated with p53 (P < 0.001) and c-erb-B-2 positively (P < 0.001), high Ki-67 index (P < 0.001), mitotic index (P < 0.001) and large tumour size (P = 0.006). Patients with tumours expressing high levels of Bcl-2 (overall score 3 6) had a significantly better disease-free (P = 0.004) and overall (P = 0.009) survival. However, in a multivariate model this association no longer remained significant. There was a trend for an effect of adjuvant chemotherapy on disease free survival both for patients with Bcl-2-positive (HR-0.61, 95% CI 0.35-1.06, P = 0.07) and negative (HR = 0.55, 95% CI 0.27-1.12, P = 0.09) breast tumours at a median follow-up of 49 months. The level of Bcl-2 expression does not seem to predict response to perioperative chemotherapy in premenopausal, lymph node negative breast cancer patients. High levels of Bcl-2 are preferentially expressed in well-differentiated tumours and are associated with favourable prognosis. However, Bcl-2 expression is not an independent prognostic factor in this patient series. PMID- 8679464 TI - Lack of prognostic significance of epidermal growth factor receptor and the oncoprotein p185HER-2 in patients with systemically untreated non-small-cell lung cancer: an immunohistochemical study on cryosections. AB - The prognostic role of the epidermal growth factor receptor (EGFR) and the related receptor p185HER-2 in lung cancer is as yet undefined. We investigated the immunohistochemical expression of EGFR (monoclonal antibody R1; Amersham) and p185HER-2 (polyclonal antibody A485; Dako) in cryosections. A total of 186 unselected and systemically untreated patients with non-small-cell lung cancer (NSCLC) diagnosed and treated at Odense University Hospital, Denmark, were included. Median follow-up period was 66 months. EGFR and p185HER-2 was highly expressed in 55% and 26% of cases respectively. Expression of EGFR was independent of p185HER-2 expression. The expression of EGFR was higher in squamous cell carcinomas whereas the level of p185HER-2 staining was higher in adenocarcinomas. Expression of either or both receptors was not correlated with age, histological grading, stage and prognosis. We conclude that immunohistochemical detection of these growth factor receptors failed to demonstrate a prognostic significance in patients operated on for NSCLC. PMID- 8679467 TI - British Association for Cancer Research 37th annual meeting, European Association for Cancer Research 14th meeting, and Association of Cancer Physicians 11th annual meeting. Edinburgh, 31 March-3 April 1996. Abstracts. PMID- 8679465 TI - Epidermal growth factor receptor expression in pancreatic lesions induced in the rat by azaserine. AB - In the present study, the expression of the epidermal growth factor receptor (EGFR) was investigated in putative preneoplastic and neoplastic acinar cell lesions induced in the rat pancreas by azaserine, using Northern blotting, in situ hybridisation (ISH) and immunohistochemistry. EGFR protein levels were decreased in putative preneoplastic eosinophilic acinar cell lesions (atypical acinar cell nodules, AACN) in comparison with normal acinar cells of the pancreas. However, EGFR mRNA expression correlated positively with the volume of AACN in pancreatic homogenates and ISH showed equal or stronger EGFR mRNA expression in AACN than in the surrounding normal acinar cells. Neither EGFR protein nor EGFR mRNA was detected in more advanced lesions such as acinar adenocarcinomas (in situ). Moreover, EGFR protein expression showed an inverse relationship with the mitotic rate of the acinar cells. These findings suggest that down-regulation of EGFR at the protein level may abrogate negative constraints on cell growth, which may stimulate the development of putative preneoplastic AACN to more advanced lesions and, ultimately, acinar adenocarcinomas. PMID- 8679468 TI - Human rights can mean better health. PMID- 8679466 TI - K-ras mutations and HLA-DR expression in large bowel adenomas. AB - A total of 72 sporadic colorectal adenomas in 56 patients were studied for the presence of point mutations in codons 12 and 13 of the K-ras gene and for HLA-DR antigen expression related to clinicopathological variables. Forty K-ras mutations in 39 adenomas were found (54%): 31 (77%) in codon 12 and nine (23%) in codon 13. There was a strong relationship between the incidence of K-ras mutations and adenoma type, degree of dysplasia and sex. The highest frequency of K-ras mutations was seen in large adenomas of the villous type with high-grade dysplasia. Fourteen out of 15 adenomas obtained from 14 women above 65 years of age carried mutations. HLA-DR positivity was found in 38% of the adenomas, large tumours and those with high-grade dysplasia having the strongest staining. Coexpression of K-ras mutations and HLA-DR was found significantly more frequently in large and highly dysplastic adenomas, although two-way analysis of variance showing size and grade of dysplasia to be the most important variable. None of the adenomas with low-grade dysplasia showed both K-ras mutation and HLA DR positivity (P = 0.004). K-ras mutation is recognised as an early event in colorectal carcinogenesis. The mutation might give rise to peptides that may be presented on the tumour cell surface by class II molecules, and thereby induce immune responses against neoplastic cells. PMID- 8679469 TI - Prison pregnancies. PMID- 8679470 TI - No nursing shortage, say employers. PMID- 8679471 TI - Training which saves lives. PMID- 8679472 TI - World AIDS Day. Crisis of silence. PMID- 8679473 TI - Clinical supervision: doing it for themselves. PMID- 8679474 TI - Listening to children. PMID- 8679475 TI - Setting up a helpline on heart disease. AB - This article describes how the first nurse-led national telephone helpline for the prevention of coronary heart disease (CHD) was set up and presents the results after the first year of operation. The free service was well received. Most callers were seeking advice on CHD prevention for the first time and traditional risk factors and general healthy lifestyle advice remained major areas of concern. PMID- 8679476 TI - Bionursing: carpal tunnel syndrome. AB - In this case, the nurse/midwife was quick to recognise the significance of the hand pain Lynn developed. She was aware of the risk of CTS in pregnancy. The nurse used her knowledge of the condition to probe for additional details and to test for clinical signs of the condition. This allowed for an early diagnosis and appropriate treatment. PMID- 8679478 TI - Testing the need for a follow-up visit after child day surgery. AB - Day surgery for children is becomingly increasing common because of the advantages to children and their families, and the reduction in costs. However, community follow-up of children appears to be sporadic. The author conducted a survey of parents, day surgery nurses and community nurses to determine if a follow-up visit was necessary after day surgery for insertion of grommets. Just over three quarters of parents (77 per cent) said they could have coped without the visit, a view echoed by both groups of nurses. Furthermore, 54 per cent of parents felt the visit was not absolutely necessary. This leads to the conclusion that provision of this service needs reviewing. PMID- 8679477 TI - Mental health teams in the community. AB - This article describes how one community psychiatric nursing service established a forum to clarify the roles and professional boundaries for nurses working within a multidisciplinary team. The author describes the initiative within the context of the wider issues surrounding mental health care in the community. PMID- 8679479 TI - Self image: no smoke without fire. PMID- 8679480 TI - Healthy debate: nurses valued! PMID- 8679481 TI - One minute wisdom. Dual role as wife and nurse when her husband became critically ill. PMID- 8679483 TI - Private health care: safeguarding standards. PMID- 8679482 TI - Courses conflict and control. PMID- 8679484 TI - Drug advice: trouble on the superhighway. PMID- 8679485 TI - Practice tips: talking sex. PMID- 8679486 TI - Lifesaver: paediatric CPR (continuing education credit). PMID- 8679488 TI - [Possibilities for gentle care within the framework of conventional intensive care medicine]. PMID- 8679487 TI - Making decisions. PMID- 8679490 TI - [A student project--planning, organization and execution of continuing education in prevention of pneumonia]. PMID- 8679489 TI - [A special hospital stay--the Spina bifida week at the pediatric hospital Auf der Bult]. PMID- 8679491 TI - [Care of a child with Lyell syndrome caused by drugs]. PMID- 8679492 TI - [The new nursing insurance--chances and perspectives]. PMID- 8679493 TI - [Chances and perspectives in nursing insurance]. PMID- 8679494 TI - [Health expenses can be deducted for income tax purposes]. PMID- 8679495 TI - [Toxic and less toxic plants. 22]. PMID- 8679496 TI - [Cooking in the pediatric department]. PMID- 8679497 TI - [Pediatric oncologic nursing and home nursing in Oxford]. PMID- 8679498 TI - Assessment of autonomic function using complex demodulation and posture entrainment techniques: an application to normal subjects and diabetic patients. AB - The assessment of autonomic nervous systems (sympathetic and parasympathetic) using the method of complex demodulation and posture entrainment are presented. The heart rate variability signals were derived from the ECG of normal subjects and diabetic patients in both supine and standing positions. The method of complex demodulation is employed on the heart rate variability data for both groups. Two significant bands in the heart rate variability spectrum were investigated by this technique. The amplitude of the high frequency band (0.181 0.4 Hz) showed the parasympathetic changes in normal subjects and, to a lesser extent, in the diabetic patients. The amplitude of the low frequency band (0.03 0.15 Hz) showed the influence of sympathetic changes in both groups. The complex demodulation method indicated the effect of high frequency and low frequency bands on both divisions of autonomic function in regulating the heart rate variability in both normal subjects and diabetic patients. In the supine position, the parasympathetic and sympathetic were balanced. On standing (posture entrainment), the high frequency band showed a decrease in amplitude due to decreased parasympathetic activity, while the low frequency band showed an increase in amplitude, which indicated an increase in sympathetic activity. These patterns were repeated in both normal subjects and diabetic patients. It seems that the use of posture entrainment combined with the complex demodulation method is significant to characterize, assess and quantify the autonomic function in health and disease. PMID- 8679499 TI - Difference of EEG spectral powers observed between binocular rivalry and binocular fusion. AB - Spontaneous EEGs were measured at 12 electrode positions over the entire head when subjects perceived alternately one of two stimuli, that were given separately to the left and right eyes, in binocular rivalry. Upward and downward triangles of the same size were used as the two stimuli. The EEGs when subjects perceived a fused image in binocular fusion by receiving the same stimuli, i.e. upward or downward triangles, to the left and right eyes, under the same experimental conditions to binocular rivalry, were also measured for comparison. The difference of the EEG spectral powers obtained under the two states of binocular rivalry and binocular fusion was analyzed in the theta (4-7 Hz), alpha (8-13 Hz) and beta (16-24 Hz) bands. A significant difference in the power was obtained in the alpha band, although the physical parameters of the stimuli, i.e. the shape, luminance, size and contrast, given to both eyes in the states of rivalry and fusion were identical. A large difference of the alpha power was observed at the occipital, parietal and posterior temporal regions. PMID- 8679500 TI - Estimation of the position and orientation of the kinematic axis of the temporomandibular joint. AB - The kinematic axis refers to a theoretical intercondylar axis of the temporomandibular joint, which translates on a curved surface during all sagittal movements. In normal joints, the translation of this rotational axis is nearly reciprocal. Its estimation is arrived at in two steps: (i) axis points are estimated in several sagittal planes, using data of sagittal mandibular movements, and (ii) an axis is then fitted to them. Neither of them, however, takes into consideration any geometric constraints on the trajectories of the kinematic axis. To correct this theoretical inconsistency, this paper presents a technique capable of directly exploring the position and orientation of the axis. During exploration, the axis is evaluated by the extent of its motion range, which is approximated from trajectile data obtained at several points on the axis. The validity of this technique was verified, through experiments employing data of actual mandibular movements. PMID- 8679501 TI - Measurement of visco-elastic properties of muscles around the ankle during standing. AB - The aim of this study was to determine elastic and viscous coefficients of muscles around the ankle during standing, and to investigate whether these coefficients depended on the balance task. By means of a servo-controlled platform, angle disturbances of the ankle were imposed upon a standing subject under three conditions: (a) standing on both legs with eyes open, (b) standing on both legs with eyes closed and (c) standing on one leg with eyes open. Visco elastic properties of muscles around the right ankle of seven subjects were estimated using data for ankle moment and angle. Mean elastic coefficients changed from 151 to 220 Nm/rad and mean viscous coefficients changed from 15 to 49 Nms/rad. Both of them tended to increase as the balance task became more demanding, i.e. in the order (a), (b) and (c). PMID- 8679502 TI - A compartmental brain model for chemical transport and CO2 controlled blood flow. AB - A compartmental transport model is developed, capable of predicting the evolution of CO2, HCO-3 and H+ in the cerebrovascular system. In the model, the transport of these components is simulated at a subset of three compartments: cerebrospinal fluid (CSF), capillary-choroid plexus and brain tissue, belonging to a seven compartmental assembly representing the entire brain. The remaining ones are; artery, vein, venous sinus and jugular bulb. The model accounts for advection associated with non-steady perfusion fluxes across semi-previous boundaries. Pressures, associated with perfusion, are solved in the seven-compartment model. The three-compartment transport model also takes into account changes in compartmental volume due to displacement of its boundaries, diffusion through boundaries and rate of generation of substances by chemical reactions. A first order reaction rate is assumed in the CSF compartment. A parameter estimation method is then developed to assess boundary diffusivities from time-averaged observed values of perfusion pressure, tension of carbon dioxide, pH values, and concentration of free hydrogen and bicarbonate ions. An equation of state describing the regulation of flow from arteries to capillaries, as a function of CO2 tension in the CSF, is then suggested. Upon solving all coupled mass balance equations, and for a pre-evaluated perfusion pressure in the artery and capillary compartments, one can estimate the change in arteries to capillaries conductance at every time step. Boundary diffusivities between the capillary, cerebrospinal fluid and brain tissue compartments, were estimated. A sensitivity analysis proves the consistency between model predictions and available clinical observations, this, in terms of the influence of the parameter associated with CO2 metabolic rate on CO2 tension. It was shown that decrease of this tension caused an abrupt pressure fall at the first instant which later increased to an asymptotic value. This, however, was not evident in the capillaries at which pressure slightly falls and then remains constant. PMID- 8679503 TI - The methodology for studying coordinated calcium concentration changes in a pancreatic beta cell line. AB - Intracellular calcium concentration was imaged in beta Tc cells with the aid of Fluo-3 indicator and the Meridian ACAS 570 interactive laser cytometry. This cell line does not respond by an elevation in [Ca2+]in to increase in extracellular [glucose], but does respond to 10 microM forskolin. It was found that forskolin increases the mean [Ca2+]in and produces calcium spikes. Time series analysis was performed on individual pixels. Autocorrelation revealed that forskolin induces oscillation in [Ca2+]in. Cross-correlation analysis showed that all the intracellular pixels along the line scan are highly correlated, indicating that the increase in [Ca2+]in encompasses the entire cell. PMID- 8679504 TI - Phosphate load as the evolutionary driving force for the development of a high filtration rate based excretory organ: a hypothesis. AB - It is proposed that the nutritional load of phosphate is the primary factor that led to the development of an excretory organ that is based on a high filtration rate of the extracellular fluid. This hypothesis is based on the following arguments: 1) phosphate and potassium impose the highest average nutritional load rates defined as the ratio between the average ion content in foods that satisfies the energy demands of the body per unit time and the respective ionic plasma concentration. Due to the much higher intracellular than extracellular potassium concentration it is argued that a secretory based excretory organ would be more useful for disposal of potassium. 2) Magnesium and calcium nutritional load rates are lower than that of phosphate; in addition the disposal of magnesium should have been dealt with preferably by secretion due to its slightly higher intracellular concentration. The nutritional load rate of calcium is tempered by the inherently low absorption capacity of the intestinal mucosa. 3) In aglomerular teleost fishes the phosphate plasma concentration is significantly elevated vis a vis the mammals and other marine fishes, in comparison to only slight differences in calcium, magnesium and potassium levels. It is suggested that the seemingly peculiar and costly way in which sodium excretion is accomplished in the kidney represents the outcome of the solution to the phosphate nutritional load. PMID- 8679505 TI - Energy requirements of the fat sand rat (Psammomys obesus) when consuming the saltbush, Atriplex halimus: a review. AB - The fat sand rat (Psammomys obesus; Gerbillinae), a diurnal gerbillid rodent, is herbivorous and able to thrive while consuming only the saltbush Atriplex halimus (Chenopodiaceae), a plant relatively low in energy content and high in ash and water. Before consuming A. halimus leaves, fat sand rats scraped off the outer layer with their teeth. This removed much of the electrolytes but increased gross energy and organic matter content of the leaves by only about 3.1%. Basal metabolic rate of fat sand rats was 168 kJ.kg-0.75.d-1, 57 to 60% of that expected for a eutherian mammal of its body size, and average daily metabolic rate was 499 kJ.kg-0.75.d-1, 88% of that expected for a rodent of its body mass. Field metabolic rate was 565 kJ.kg-0.75.d-1 in summer and 680 kJ.kg-0.75.d-1 in winter. The rate of energy expenditure during summer was 60% of that expected for a herbivore and 83% of that expected for a desert eutherian mammal of its body mass. The difference in rate of energy expenditure between winter and summer was taken as thermoregulatory costs. Fat sand rats appear to be well adapted to high air temperatures but less so to low air temperatures. The efficiency of utilization of energy of A. halimus for maintenance was only 0.32 and for growth only 0.30 and their respective heat increments of feeding were 0.68 and 0.70. This low utilization of feed plus its low energy yield and high water content forced fat sand rats to consume large quantities of forage for maintenance. In spite of this, there are several advantages for consuming mainly this diet, namely: (1) it provides a more stable diet throughout the year than do seeds; (2) fat sand rats have no competition for this food resource from other rodents; and (3) fat sand rat burrows are at the base of the plants and therefore they expend minimal energy for foraging. PMID- 8679506 TI - Mechanical and metabolic performance of the rat heart: effects of combined stress of heat acclimation and swimming training. AB - Although the individual effects of heat acclimation and swimming exercise on cardiovascular reserve and efficiency have been studied, the relative and cumulative effects of these interventions have not. Myocardial developed force, coronary flow (CF), and oxygen consumption during baseline conditions and during pacing-induced tachycardia were therefore studied in isolated perfused hearts from four groups of rats: normothermic sedentary (C), heat acclimated sedentary (AC), normothermic swimmers (CS), and heat acclimated swimmers (ACS). Normothermic temperature was 24 degrees C. Heat acclimation was attained by continuous exposure to 34 degrees C for one and two months. Swimmers had two daily 75 minute sessions for five days a week with water temperatures of 33-35 degrees C and 36-38 degrees C for CS and ACS rats, respectively. After one month AC animals showed a remarkable decrease in O2 consumption. In contrast, ACS increased both O2 consumption and the maximal isometric force generated. After two months, O2 consumption of AC rats continued to be low. The heart failed to restitute the force developed at high pacing frequency. In these rats CF was remarkably low and remained unchanged with increased pacing. In contrast ACS maintained the ability to develop force at all pacing rates at a level similar to that of the normothermic C and ACS rat hearts, but at high oxygen cost. The data suggest that the AC heart is more efficient but cannot meet demands at high pacing rates. In contrast, swimming in the heat improved performance of ACS temporarily, without decreasing the metabolic rate. PMID- 8679507 TI - Multimodality (auditory, visual and somatosensory) evoked potentials in the sand rat, Psammomys obesus. AB - Multimodality (auditory, visual and somatosensory) evoked potentials were recorded in the sand rat (Psammomys obesus) and compared to those obtained in albino rats, under almost identical conditions. Clear responses could be obtained from each species. The evoked potentials from the sand rat were qualitatively similar in waveform, latency and amplitude to those recorded in albino rats. Since there is a strain of sand rat which develops diabetes when on standard chow and since the sand rat has adapted to the desert environment, further study should involve evoked potential recordings in sand rats during hyper- and hypothermia and in diabetic sand rats. PMID- 8679508 TI - Mechanism of heat acclimation induced bradycardia in the sand rat. AB - The effect of heat acclimation on chronotropic response of the heart under normothermic and hyperthermic conditions was studied in the sand rat, Psammomys obesus, a diurnal desert species. All animals were acclimated at 34 degrees C for 0, 5, 14, 30 or 60 days; heat stress was achieved by exposure at 38 degrees C. Continuous measurements of heart rate (HR) were carried out on conscious animals, using chronic subcutaneous electrodes. Atropine (0.1 mg/100 g) and propranolol (1 mg/100 g) were administered to evaluate the para-sympathetic (V) and sympathetic (S) influences on HR. Intrinsic HR (HRi) was measured following administration of both drugs simultaneously. P. obesus developed bradycardia from day 5 of the acclimation. This bradycardia was induced solely by decreased HRi, overriding partial vagal withdrawal. During hyperthermia apparent thermal insensitivity of HR was observed. This was attained by partial sympathetic withdrawal compensating for the increase in HRi due to body temperature rise. It can be concluded that in P. obesus, heat acclimation induced bradycardia is attained by intrinsic changes in the pacing cells. It also emerges that the hyperthermic response is independent of and is not affected by heat acclimation. PMID- 8679509 TI - Distribution of atrial natriuretic peptides in the sand rat (Psammomys obesus) in comparison to that in the rat. AB - Atrial natriuretic peptides (ANP) are a family of humoral compounds involved in water and salt homeostasis. Immunoreactive ANP (IR-ANP) was determined in the plasma and tissues of the rat and the sand rat (Psammomys obesus) using sensitive and specific radioimmunoassay. IR-ANP from the rat and the sand rat elute at identical retention times from reverse phase HPLC indicating that the same chemical entity is present in both species. IR-ANP highest levels were found, in both species, in the heart but it was also present in the adrenal gland, lung, kidney, liver, plasma and several loci in the central nervous system. The IR-ANP levels in the heart, adrenal gland, kidney, liver, cerebellum and cerebral cortex were lower in the sand rat compared to the rat. The plasma IR-ANP level of the diabetes-resistant sand rat was further decreased to about 10% of the level in the diabetes-resistant sand rat. PMID- 8679510 TI - The fat sand rat: a quintessential desert rodent. PMID- 8679511 TI - The efficiency of sand rat metabolism is responsible for development of obesity and diabetes. AB - Two separate lines--diabetic and partially diabetes-resistant--have been isolated from the sand rat (Psammomys obesus), each with different growth characteristics in response to diets of varying digestible caloric densities (high energy, HE, 2.93 kcal/g, or low energy, LE, 2.38 kcal/g). Over a two week period all animals consumed similar quantities (c. 125 g) irrespective of the diet consumed. Weight gains were as follows: diabetic line on HE diet - 59.7 g, on LE - 46.2 g; non diabetic animals from the diabetes-resistant line on HE - 44 g. Only animals from the diabetic line, fed the HE diet, developed hyperinsulinemia, obesity and diabetes. The energy cost of weight gain for the diabetic line fed either HE or LE diets was 6.0 - 6.3 kcal/g whereas for the diabetes-resistant line on the HE diet, the cost of growth was 50% higher at 9.3 kcal/g. These differences could be due either to alterations in the content of tissue laid down or to differences in energy expenditure. It has already been established that diet-induced obesity and diabetes develop in the diabetic line with features typical of insulin resistance in the metabolism of the pancreas, liver and peripheral tissues. Some of the animals of the diabetes-resistant line may also develop diabetes over a long time period and go through a phase of transient hyperinsulinemia-normoglycemia. This may represent an intermediate stage in the development of the diabetic syndrome and serve as a model of type 2 diabetes in man. PMID- 8679512 TI - Effect of miglitol and acarbose on starch digestion, daily plasma glucose profiles and cataract formation. AB - The effect of two alpha - glucosidase inhibitors, acarbose and miglitol, on postprandial glucose levels following wheat and potato starch loading was evaluated in sand rats with resultant dramatically reduced postprandial glucose levels. The inhibitory effect on starch digestion was dose concentration dependent. Eighty-six and 72% inhibition was reached with 1 mg of miglitol and acarbose, respectively. Daily plasma glucose profiles and cataract formation were determined following long-term feeding with a diet containing acarbose and miglitol. Both drugs led to a significant reduction in glucose levels, acarbose being more potent, possibly via inhibition and delay of carbohydrate digestion. Acarbose caused a marked decrease in cataract incidence; the mechanism for this effect requires more elucidation. Since acarbose delayed and possibly prevented cataract formation in sand rats, we support the concept of its use as an adjuvant in the treatment of diabetic patients. PMID- 8679513 TI - Psammomys obesus of the Jerusalem colony: a model for nutritionally induced, non insulin-dependent diabetes. PMID- 8679514 TI - Neurons and glial cells of the enteric nervous system: studies in tissue culture. AB - The enteric nervous system (ENS) has been recognized as the main component in regulating the function of the digestive tract and as a model for studying neuronal physiology and pharmacology. Most of the present knowledge on the ENS was derived from in vitro studies on freshly isolated plexuses. In 1978 the first study on cultured myenteric neurons was published and since then there has been a growing interest in this method. Several different culture preparations have been introduced, including the recent development of cultures from adult guinea-pigs and humans. This review summarizes the findings which have been made using cultured enteric neurons and glia. The main topics that are described are the role of the extracellular matrix and of hormones on neuronal growth, neuron-glia interactions, release of neuropeptides and their actions on neurons and co transmission between neurons. PMID- 8679515 TI - The hemispheric distribution of Torpedo nicotinic receptors expressed in Xenopus oocytes. AB - The physical and the functional distribution of Torpedo nicotinic-cholinergic receptors expressed in Xenopus oocytes was assayed. Physical hemispheric receptor distribution was tested by binding of 125[I]-bungarotoxin. The density of the expressed nicotinic receptors was equal on both hemispheres (ratio animal/vegetal = 1.1 +/- 0.2). Functional distribution was tested either by whole hemispheric response assay or by monitoring responses from small areas on the two hemispheres. While the first method yielded results that suggested uniform receptor density distribution, the second method indicated two-fold higher responsiveness on the animal hemisphere, when compared with the vegetal hemisphere. Direct comparison on oocytes of the same donors did not reveal significant differences between the two assays. We did see, however, a high variability among the different donors (animal/vegetal activity ratio range 0.5 4.7). Overall, in 35 experiments in 18 donors, the animal/vegetal ratio of hemispheric responsiveness was 1.4. The possible source of this high variability may have been the large excess of bungarotoxin-binding sites over the number of active channels. We have also tested hemispheric responsiveness ratio with different concentrations of acetylcholine. When acetylcholine concentration was below 10 microM, the animal/ vegetal ratio was significantly lower than 1.0. Similar results were obtained with nicotinic receptors expressed after injection of RNA transcribed in vitro from cloned mouse nicotinic receptor subunits. These results imply that hemispheric membrane heterogeneity may affect receptor and/or channel activities to yield polarized channel activity despite nearly homogeneous receptor distribution. PMID- 8679516 TI - Effect of oxidative stress on avian erythrocytes. AB - Avian erythrocytes differ from mammalian erythrocytes in being nucleated and oval. In the circulation, chicken cells survive for only 35 days, compared to 120 days for human cells. In humans, red cell oxidation processes, involving methemoglobin formation, have been correlated with cellular aging. This study compared oxidative resistance of two avian red cells (chicken and ostrich) to that of discoid enucleated human cells. Reduced glutathione levels (GSH) and methemoglobin were higher in chicken and ostrich cells than in human cells. SOD levels were higher in human cells. Diamide exposure diminished intracellular GSH levels in all species, with the greatest effect on human cells. Regeneration potential was high for all cells. Ostrich cells were more sensitive to hydrogen peroxide when hemoglobin oxidation was involved; BHP exposure affected GSH depletion and methemoglobin production in ostrich cells more than in the others. Lipid peroxidation was found to be highest in the human cells. Chicken cells were only slightly more resistant than human cells. Our data suggest that the extensive, complex oxidation by BHP cannot represent in vivo aging processes. In addition, the milder, selective oxidation by diamide affects human cells (endowed with long life span) more than avian cells. It is concluded that in vitro oxidation by diamide and BHP cannot be correlated with red cell survival. PMID- 8679517 TI - Models of glycerol-induced acute renal failure in rats. AB - Acute renal failure (ARF) following rhabdomyolysis is not uncommon in man. The popular model for ARF formation following rhabdomyolysis in experimental animals is glycerol injection into the leg muscle following a 24 hour period of water deprivation. A large percentage of patients developing ARF following rhabdomyolysis do not suffer from such long periods of water deprivation. On the contrary, fluid loss in patients developing ARF is relatively fast and is the result of excessive sweating or hemorrhage. Since it is known that the hydration state of the body during rhabdomyolysis considerably affects the development of ARF, it seems that the popular model of glycerol injection following a prolonged period of water deprivation in experimental animals is, to a certain extent, deficient. The aim of the present study was to examine two models of ARF formation in the rat following glycerol injection and acute diminution of the body's water content: 1) by sucrose injection (200 mg/100 g), 2) by hemorrhage (0.7 ml/100 g). A number of differences were found between the various models of ARF formation by glycerol. The differences are mainly expressed in the urine volume three hours after the glycerol injection. In the sucrose and hemorrhage groups a decrease of 29% and 66% (p < 0.001) in urine volume was found at the end of the experiment. In contradistinction, in the group that underwent water deprivation for a period of 24 hours prior to the glycerol injection, an increase of 46% (p < 0.001) in the urine volume was observed at the end of the experiment. Differences were also found in potassium uptake and in the extent of the decrease in renal cortex blood flow as measured by the laser Doppler flowmetry technique. From this study it may be concluded that glycerol injection to the rat leg muscle results in ARF in all three methods of decreasing the body's fluid content. It is possible that the models of sucrose injection or hemorrhage prior to glycerol injection are better suited for reflecting the hydration condition of humans suffering from rhabdomyolysis than 24 hours of water deprivation prior to this injection. PMID- 8679518 TI - Positive inotropic effect in the heart produced by acetylcholine. AB - The effect of acetylcholine on cardiac muscle contractility and hemodynamics was investigated in human atrial strips and in isolated working rat heart. Activation of the muscarinic receptor in the heart muscle is generally known to result in negative chronotropic and inotropic effects. In our study, positive inotropic effects of acetylcholine (ACh) were observed in both human right atrial strips and in the working rat heart. Exposure of the human right atrial strips to ACh (10(-7)-10(-4) M) produced a dose dependent tri-phasic (positive-negative positive) inotropic effect in approximately 40% of the strips. In muscle strips that exhibited only a negative inotropic effect, a positive response was observed following washout of ACh. Both positive and negative effects were antagonized by atropine. Exposure of the paced working rat heart to ACh (10(-7) - 10(-5) M) resulted in a dose dependent decrease in mean coronary flow followed by depression in cardiac function. When the heart was initially treated with the vasodilator adenosine (2 x 10(-6) M), exposure to ACh (10(-7) - 10(-5) M) had no effect on coronary flow and produced a dose dependent augmentation of all cardiodynamic indices: left ventricular pressure, isovolumic pressure, cardiac output, maximal aortic flow and stroke work. This positive response was antagonized by atropine. Exposure of the rat ventricular strips increased the formation of [3H]phosphoinositide breakdown products (e.g. inositol phosphates IP, IP2, IP3). These observations demonstrate that cholinergic muscarinic stimulation may produce positive inotropic effects in both human and rat cardiac muscle. Furthermore, our results suggest that IP3 may be a mediator in this process. PMID- 8679519 TI - Vitamin E reduces bleomycin-induced lung fibrosis in mice: biochemical and morphological studies. AB - Bleomycin is a widely used antineoplastic drug which produces dose- and time dependent interstitial pulmonary fibrosis in humans. The mechanism of bleomycin induced lung injury is not well understood. However, current data show that bleomycin can generate reactive oxygen species such as superoxide and hydroxyl radicals. The antioxidant role of vitamin E in biological systems is well known. We investigated the effect of vitamin E on bleomycin-induced lung fibrosis in mice biochemically and histologically. Animals were divided into four groups: control, saline + vitamin E (S/Vit E), bleomycin + saline (Bleo/S) and bleomycin + vitamin E (Bleo/Vit E). Bleomycin was administered subcutaneously at a dose of 10 mg/kg in Bleo/S and Bleo/Vit E groups, and vitamin E was administered intraperitoneally at a dose of 15 mg/animal in S/Vit E and Bleo/Vit E groups twice weekly for 4 weeks. The control group received saline. As a marker of collagen amount or fibrosis in lung tissue, hydroxyproline and soluble protein content were measured and hydroxyproline/soluble protein ratio per gram wet lung tissue was calculated. For hydroxyproline and protein determinations, and histologic examination of lung tissue, 6 mice from the control and S/Vit E groups and 7 mice from the Bleo/S and Bleo/Vit E groups were killed at at 4, 6 and 8 weeks after administration of bleomycin. The mean hydroxyproline/soluble protein ratio of the Bleo/Vit E group was significantly lower than that of the Bleo/S group and significantly higher than those of the control and S/Vit E groups at 6 and 8 weeks (p < 0.05). Parallel with the biochemical findings, the grade of the histological lesions in the Bleo/Vit E group was lower than that in the Bleo/S group, but higher than those of the S/Vit E and control groups (p < 0.05). These results suggest that a high dose of vitamin E considerably reduces the fibrotic effect of bleomycin on lung tissue in mice. PMID- 8679520 TI - A mechanism for hydroxylation by tyrosine hydroxylase based on partitioning of substituted phenylalanines. AB - The iron-containing enzyme tyrosine hydroxylase catalyzes the hydroxylation of tyrosine to dihydroxyphenylalanine. A series of 4-X-substituted (X = H, F, Br, Cl, CH3, or CH3O) phenylalanines have been characterized as substrates to gain insight into the mechanism of hydroxylation. Multiple hydroxylated products were formed in most cases. As the size of the substituent at the 4-position increased, the site of hydroxylation switched from the 4- to the 3-position of the aromatic ring. The total amount of product formed with each amino acid showed a very good correlation with the sigma parameter of the substituent, with rho values of -4.3 +/- 0.7 or -5.6 +/- 0.8 when tetrahydrobiopterin or 6-methyltetrahydropterin, respectively, was used as cosubstrate. These values are consistent with a highly electron deficient transition state for hydroxylation. Oxygen addition at the 4 position resulted in either elimination of the substituent to form tyrosine or an NIH shift to form the respective 3-X-tyrosine. The relative amount of the product due to an NIH shift decreased in the order Br > CH3 > Cl >> F approximately CH3O approximately 0. A chemical mechanism for hydroxylation by tyrosine hydroxylase is presented to account for product formation from the various 4-substituted phenylalanines. PMID- 8679521 TI - Mechanism of NO-induced oxidation of myoglobin and hemoglobin. AB - Nitric oxide (NO) has been implicated as mediator in a variety of physiological functions, including neurotransmission, platelet aggregation, macrophage function, and vasodilation. The consumption of NO by extracellular hemoglobin and subsequent vasoconstriction have been suggested to be the cause of the mild hypertensive events reported during in vivo trials of hemoglobin-based O2 carriers. The depletion of NO from endothelial cells is most likely due to the oxidative reaction of NO with oxyhemoglobin in arterioles and surrounding tissue. In order to determine the mechanism of this key reaction, we have measured the kinetics of NO-induced oxidation of a variety of different recombinant sperm whale myoglobins (Mb) and human hemoglobins (Hb). The observed rates depend linearly on [NO] but show no dependence on [O2]. The bimolecular rate constants for NO-induced oxidation of MbO2 and HbO2 are large (k.ox,NO = 30-50 microM-1 s-1 for the wild-type proteins) and similar to those for simple nitric oxide binding to deoxygenated Mb and Hb. Both reversible NO binding and NO-induced oxidation occur in two steps: (1) bimolecular entry of nitric oxide into the distal portion of the heme pocket and (2) rapid reaction of noncovalently bound nitric oxide with the iron atom to produce Fe(2+)-N=O or with Fe(2+)-O-O delta- to produce Fe(3+)-OH2 and nitrate. Both the oxidation and binding rate constants for sperm whale Mb were increased when His(E7) was replaced by aliphatic residues. These mutants lack polar interactions in the distal pocket which normally hinder NO entry into the protein. Decreasing the volume of the distal pocket by replacing Leu(B10) and Val(E11) with aromatic amino acids markedly inhibits NO-induced oxidation of MbO2. The latter results provide a protein engineering strategy for reducing hypertensive events caused by extracellular hemoglobin-based O2 carriers. This approach has been explored by examining the effects of Phe(B10) and Phe(E11) substitutions on the rates of NO-induced oxidation of the alpha and beta subunits in recombinant human hemoglobin. PMID- 8679522 TI - Conversion of the spin state of the manganese complex in photosystem II induced by near-infrared light. AB - The manganese complex (Mn4) which is responsible for water oxidation in photosystem II is EPR detectable in the S2 state, one of the five redox states of the enzyme cycle. The S2 state is observable at 10 K either as a multiline signal (spin 1/2) or as a signal at g = 4.1 (spin 3/2 or spin 5/2). It is shown here that at around 150 K the state responsible for the multiline signal is converted to that responsible for the g = 4.1 signal upon the absorption of infrared light. This conversion is fully reversible at 200 K. The action spectrum of this conversion has its maximum at 820 nm (12 200 cm-1) and is similar to the intervalence charge transfer band in di-mu-oxo-(MnIIIMnIV) model systems. It is suggested that the conversion of the multiline signal to the g = 4.1 signal results from absorption of infrared light by the Mn cluster itself, resulting in electron transfer from MnIII to MnIV. The g = 4.1 signal is thus proposed to arise from a state which differs from that which gives rise to the multiline signal only in terms of this change in its valence distribution. The near infrared light effect was observed in the S2 state of Sr(2+)-reconstituted photosystem II and in Ca(2+)-depleted, EGTA (or citrate-)-treated photosystem II but not in ammonia-treated photosystem II. Earlier results in the literature which showed that the g = 4.1 state was preferentially formed by illumination at 130 K are reinterpreted as being the result of two photochemical events: the first being photosynthetic charge separation resulting in an S2 state which gives rise to the multiline signal and the second being the conversion of this state to the g = 4.1 state due to the simultaneous and inadvertent presence of 820 nm light in the broad-band illumination given. There is therefore no reason to consider the state responsible for the g = 4.1 signal as a precursor of that which gives rise to the multiline signal. PMID- 8679523 TI - Inhibition of IMPDH by mycophenolic acid: dissection of forward and reverse pathways using capillary electrophoresis. AB - The objective of this work was to contribute to the understanding of mechanisms for IMPDH inhibition. We over-expressed hamster type II IMPDH in Escherichia coli, purified the protein to apparent homogeneity, and used capillary electrophoresis to quantify enzyme turnover events accompanying inhibition by mycophenolic acid (MPA). We dissected two convergent pathways leading to MPA inhibition; a rapid "forward" pathway beginning with substrates and linked to enzyme catalysis, and a slower "reverse" pathway apparently not involving catalysis. MPA-inhibition occurred rapidly in the forward direction by interrupting the enzyme turnover cycle, after IMP and NAD+ binding, after hydride transfer, and after NADH release. Slow inhibition, without substrate turnover, was achieved by incubating free enzyme with excess XMP and MPA. We propose that mycophenolic acid inhibits IMPDH by trapping a transient covalent product of the hydride transfer reaction (IMPDH approximately XMP*) before a final hydrolysis step that precedes XMP and enzyme release in the forward reaction pathway. Understanding the ligand occupancy of the protein has also proven important for producing homogeneous, chemically defined complexes for structural studies. IMPDH samples inhibited by MPA in the forward and reverse pathways yielded similar, high-quality crystals that are currently undergoing X-ray diffraction analyses. PMID- 8679524 TI - Molecular identification of I1PP2A, a novel potent heat-stable inhibitor protein of protein phosphatase 2A. AB - The amino acid sequences of two tryptic peptides derived from purified preparations of I1PP2A indicated that this potent heat-stable protein inhibitor of protein phosphatase 2A (PP2A) may be equivalent to putative histocompatibility leukocyte antigens class II-associated protein I (PHAP-I). Experiments using purified preparations of recombinant human PHAP-I confirmed that this protein inhibited PP2A. Half-maximal inhibition of the phosphatase occurred at about 4 nM PHAP-I, similar to the half-maximal inhibition obtained with purified preparations of bovine kidney I1PP2A. In addition, PHAP-I did not affect the activities of protein phosphatase 1, 2B, and 2C in a manner analogous to that of I1PP2A. Together, the results establish the identity of I1PP2A on a firm basis. PMID- 8679525 TI - Structural properties of UMP-kinase from Escherichia coli: modulation of protein solubility by pH and UTP. AB - UMP-kinase from Escherichia coli, unlike the analogous enzyme from eukaryotic organisms, is an oligomeric protein subjected to complex regulatory mechanisms in which UTP and GTP act as allosteric effectors. While the enzyme has an unusually low solubility at neutral pH (< or = 0.1 mg of protein/ mL), its solubility increases markedly above pH 8 and below pH 4. Furthermore, the solubility of the bacterial UMP-kinase at neutral pH is greatly enhanced in the presence of Mg-free UTP. Thermal denaturation experiments have demonstrated that UTP also increases the stability of the protein. Fourier-transform infrared spectroscopy and circular dichroism show that the secondary structure of the protein is the same at neutral and at alkaline pH. These data indicate that variations in enzyme solubility must be related to subtle changes in the tertiary and/or quaternary structure which modulate the exposure of hydrophobic surfaces in the protein molecule. A variant of UMP-kinase, obtained by site-directed mutagenesis (Asp159Asn), which is similar to the wild-type enzyme in its stability and kinetic properties, has a much increased water solubility (> 5 mg protein/mL) even at neutral pH. This suggests that salt bridges may be involved in the equilibrium between the soluble and aggregated forms of the wild-type enzyme, and that conformational changes induced upon binding of UTP increase the protein solubility by disrupting these salt bridges. PMID- 8679526 TI - Crystal structures of Escherichia coli dihydrofolate reductase complexed with 5 formyltetrahydrofolate (folinic acid) in two space groups: evidence for enolization of pteridine O4. AB - The crystal structure of Escherichia coli dihydrofolate reductase (ecDHFR, EC 1.5.1.3) as a binary complex with folinic acid (5-formyl-5,6,7,8 tetrahydrofolate; also called leucovorin or citrovorum factor) has been solved in two space groups, P6(1) and P6(5), with, respectively, two molecules and one molecule per asymmetric unit. The crystal structures have been refined to an R factor of 14.2% at resolutions of 2.0 and 1.9 A. The P6(1) structure is isomorphous with several previously reported ecDHFR binary complexes [Bolin, J.T., Filman, D.J., Matthews, D.A., Hamlin, R.C., & Kraut, J. (1982) J. Biol. Chem. 257, 13650-13662; Reyes, V.M., Sawaya, M.R., Brown, K.A., & Kraut, J. (1995) Biochemistry 34, 2710-2723]; enzyme and ligand conformations are very similar to the P6(1) 5,10-dideazatetrahydrofolate complex. While the two enzyme subdomains of the P6(1) structure are nearly in the closed conformation, exemplified by the methotrexate P6(1) binary complex, in the P6(5) structure they are in an intermediate conformation, halfway between the closed and the fully open conformation of the apoenzyme [Bystroff, C., Oatley, S.J., & Kraut, J. (1990) Biochemistry 29, 3263-3277]. Thus crystal packing strongly influences this aspect of the enzyme structure. In contrast to the P6(1) structure, in which the Met-20 loop (residues 9-23) is turned away from the substrate binding pocket, in the P6(5) structure the Met-20 loop blocks the pocket and protrudes into the cofactor binding site. In this respect, the P6(5) structure is unique. Additionally, positioning of a Ca2+ ion (a component of the crystallization medium) is different in the two crystal packings: in the P6(1) structure it lies at the boundary between the two molecules of the asymmetric unit, while in P6(5) it coordinates two water molecules, the hydroxyl group of an ethanol molecule, and the backbone carbonyl oxygens of Glu-17, Asn-18, and Met-20. The Ca2+ ion thus stabilizes a single turn of 3(10) helix (residues 16-18 in the Met-20 loop), a second unique feature of the P6(5) crystal structure. The disposition of the N5 formyl group in these structures indicates formation, at least half of the time, of an intramolecular hydrogen bond between the formyl oxygen and O4 of the tetrahydropterin ring. This observation is consistent with the existence of an enol-keto equilibrium in which the enolic tautomer is favored when a hydrogen bond acceptor is present between O4 and N5. Such would be the case whenever a water molecule occupies that site as part of a hypothetical proton-relay mechanism. Two arginine side chains, Arg-52 in the P6(5) structure and Arg-44 in molecule A of the P6(1) structure, are turned away drastically from the ligand (p aminobenzoyl)glutamic acid moiety as compared with previously reported DHFR binary complex structures. As in the ecDHFR dideazatetrahydrofolate complex, in both the P6(1) and P6(5) structures a water molecule bridges pteridine O4 and Trp 22(N epsilon 1) with ideal geometry for hydrogen bonding, perhaps contributing to the slow release of 5,6,7,8-tetrahydrofolate from the enzyme-product complex. When either the P6(1) or the P6(5) structures are superimposed with the NADPH holoenzyme [Sawaya, M. R. (1994) Ph.D. Dissertation, University of California, San Diego], we find that the distances between the nicotinamide C4 and pteridine C6 and C7 are very short, 2.1 and 1.7 A in the P6(1) case and 2.0 and 1.4 A in the P6(5) case, perhaps in part explaining the more rapid release of tetrahydrofolate from the enzyme-product complex when NADPH is bound. PMID- 8679527 TI - Solution structure of reduced plastocyanin from the blue-green alga Anabaena variabilis. AB - The three-dimensional solution structure of plastocyanin from Anabaena variabilis (A.v.PCu) has been determined by nuclear magnetic resonance spectroscopy. Sixty structures were calculated by distance geometry from 1141 distance restraints and 46 dihedral angle restraints. The distance geometry structures were optimized by simulated annealing and restrained energy minimization. The average rms deviation from the mean structure for the 20 structures with the lowest total energy is 1.25 A for the backbone atoms and 1.75 A for all heavy atoms. Overall, the global tertiary fold of A.v.PCu resembles those of other plastocyanins which have been structurally characterized by X-ray diffraction and NMR methods. This holds even though A.v.PCu is longer than any other known plastocyanins, contains far less invariant amino acid residues, and has an overall charge that differs considerably from those of other plastocyanins (+1 vs -9 +/- 1 at pH > or = 7). The most striking feature of the A.v. PCu structure is the absence of the beta turn, formed at the remote site by residues (58)-(61) in most higher plant plastocyanins. The displacement caused by the absence of this turn is compensated for by an extension of the small helix [from Ala53(51) to Ser60(58) in A.v.PCu] found in other plastocyanins. Moreover, the extra residues of A.v.PCu from Pro77 to Asp79 form an appended loop. These two features allow A.v.PCu to retain almost the same global fold as observed in other plastocyanins. From a comparison with the structures of other plastocyanins it is concluded that the lack of negatively charged residues at the remote site, rather than the specific structure of A.v.PCu, is the main reason for the failure of the remote site of this plastocyanin to function as a significant electron transfer site. PMID- 8679528 TI - Crystal structure of the hypoxanthine-guanine-xanthine phosphoribosyltransferase from the protozoan parasite Tritrichomonas foetus. AB - The crystal structure of the hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRTase) from Tritrichomonas foetus has been determined and refined against X-ray data to 1.9 A resolution. T. foetus HGXPRTase crystallizes as an asymmetric dimer, with GMP bound to only one of the two molecules that form the asymmetric unit. Each molecule of HGXPRTase is formed by two lobes joined by a short "hinge" region, and the GMP binds in a cavity between the two lobes. A comparison of the two molecules in the asymmetric unit shows that the hinge region is flexible and that ligand binding affects the relative positions of the two lobes. The binding of GMP brings the two lobes closer together, rotating one lobe by about 5 degrees relative to the other. T. foetus appears to depend on HGXPRTase for its supply of GMP, making this enzyme a target for antiparasite drug design. A comparison of the structures of T. foetus HGXPRTase and human HGPRTase reveals that, while these enzymes retain a similar polypeptide fold, there are substantial differences between the active sites of these two homologs. These differences suggest that it will be possible to find compounds that selectively inhibit the parasite enzyme. PMID- 8679529 TI - DNA polymerase beta: pre-steady-state kinetic analysis and roles of arginine-283 in catalysis and fidelity. AB - DNA polymerase beta (pol beta) is the smallest and least complex DNA polymerase. The structure of the enzyme is well understood, but little is known about its catalytic properties, particularly processivity and fidelity. Pre-steady-state analysis of the incorporation of a single nucleotide into a short 25/45 oligonucleotide primer-template by pol beta was used to define the kinetic parameters of the polymerase. In addition, nucleotide analogs and site-specific mutants, along with structural analyses, were used to probe the structure function relationship of pol beta. Several significant findings have been obtained: (i) The catalysis by pol beta is processive and displays an initial burst under pre-steady-state conditions, but the processivity is poor compared to other polymerases. (ii) The fidelity of pol beta is also low relative to other polymerases. (iii) Under pre-steady-state conditions the chemical step appears to be only partially rate-limiting on the basis of the low thio effect (4.3), defined as kpol(dNTP)/kpol(dNTP alpha S). The thio effect increases to 9 for incorporation of an incorrect nucleotide. These results are consistent with the existence of a substrate-induced conformational change that is also partially rate-limiting. (iv) A comparison between the two-dimensional NMR spectra of the wild-type and mutant enzymes indicates that the mutations at position 283 did not significantly perturb the structure of the enzyme. The conformational stability of the mutants is also unperturbed. Thus, R283 is not important to the overall structure of the enzyme. (v) The results of kinetic analyses of R283A and R283K mutants indicate that the hydrogen bond between R283 of pol beta and the template is important for catalysis. Both R283A and R283K mutants displayed decreases in catalytic efficiency by a factor of ca. 200 relative to wild-type pol beta. The mutants are also less faithful by a factor of 2-4, in terms of the T-G mispair vs the T-A correct pair. The perturbation, however, could occur at both the implied conformational step and the chemical step, since the thio effects of the mutants for both correct and incorrect nucleotides are similar to those of WT pol beta. PMID- 8679530 TI - Electron paramagnetic resonance imaging of rat heart with nitroxide and polynitroxyl-albumin. AB - Electron paramagnetic resonance (EPR) imaging utilizing stable nitroxyl radicals is a promising technique for measuring free radical distribution, metabolism, and tissue oxygenation in organs and tissues [Kuppusamy, P., Chzhan, M., Vij, K., Shteynbuk, M., Lefer, D. J., Giannella, E., & Zweier, J. L. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 3388-3392]. However, the technique has been limited by the rapid reduction of nitroxide in vivo to its hydroxylamine derivative, a diamagnetic, EPR-inactive species. In this report a novel, polynitroxylated derivative of human serum albumin is shown to be capable of reoxidizing the hydroxylamine back to nitroxide in vivo. Polynitroxyl-albumin (PNA) is shown to be effective in maintaining the signal intensity of the nitroxide 4-hydroxy 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL or TPL) in the ischemic isolated rat heart, allowing the acquisition of high-resolution three-dimensional (3D) EPR images of the heart throughout a prolonged 2.5 h period of global cardiac ischemia. In serial transverse sections of the 3D image, TPL intensity maps of the heart showed cardiac structure with submillimeter resolution. TPL intensities in coronary arteries and myocardium showed that nitroxide concentration decreases with increasing distance from large blood vessels. These results demonstrate that EPR imaging in vivo is possible using nitroxides in conjunction with PNA. In addition to its utility in the emerging technology of EPR imaging, the greatly prolonged half-life of TPL observed in the presence of PNA may facilitate the therapeutic application of nitroxides in a variety of disease processes. PMID- 8679531 TI - Equilibrium and transient state spectrophotometric studies of the mechanism of reduction of the flavoprotein domain of P450BM-3. AB - The flavoprotein domain of P450BM-3 (BMR), which is functionally analogous to eukaryotic NADPH-P450 oxidoreductases, contains both FAD and FMN. When BMR is titrated with NADPH or sodium dithionite under anaerobic conditions, addition of 2 electron equivalents per mole of BMR results in the reduction of the high potential flavin (FMN) without the accumulation of semiquinone intermediates. Additional sodium dithionite first produces some neutral, blue flavin semiquinone radical and, finally, fully reduced FADH2. During reduction with NADPH, an absorbance increase characteristic of the formation of a flavin-pyridine nucleotide charge-transfer complex was observed only during the addition of the second mole of NADPH per mole of BMR. On the basis of these results, we conclude that the midpoint reduction potential for the FMN semiquinone/FMNH2 couple is more positive than that for FMN/FMN semiquinone. The kinetics of reduction of BMR with NADPH were studied by stopped-flow spectrophotometry. With a 1:1 ratio of NADPH to BMR, the absorbance changes can be fit to five consecutive first order reactions with rate constants of 350 s-1, 130 s-1, 27 s-1, 2.3 s-1, and 0.05 s-1. These reactions are most probably the following: (a) complex formation between BMR and NADPH; (b) reduction of FAD with formation of the NADP(+)-FADH- charge transfer complex; (c) transfer of the first electron from FADH- to FMN to form an anionic, red FMN semiquinone leaving the FAD as the neutral, blue semiquinone. Precise identification of intermediates beyond this point is difficult. In the presence of a 10-fold molar excess of NADPH, the absorbance changes and rate constants are somewhat different due to the formation of several additional reduced species of BMR. The rate of the first step increases, confirming that this is the formation of the NADPH-BMR complex. Our results indicate that the kinetic and thermodynamic control of the flavins in BMR is significantly different from that in microsomal P450 reductase. The low potential of the anionic FMN semiquinone can be utilized to reduce the P450 heme. When the anionic semiquinone becomes protonated, its potential becomes more positive and it is readily reduced to FMNH2, which is not capable of reducing P450. PMID- 8679532 TI - Sterol biosynthesis: strong inhibition of maize delta 5,7-sterol delta 7 reductase by novel 6-aza-B-homosteroids and other analogs of a presumptive carbocationic intermediate of the reduction reaction. AB - A series of mono- and diazasteroids have been synthesized as analogs of a predicted carbocationic intermediate of delta 5,7-sterol delta 7-reductase (delta 7-SR). 6-Aza-B-homo-5 alpha-cholest-7-en-3 beta-ol (4), a novel compound whose synthesis is described for the first time, and 6,7-diaza-5 alpha-cholest-8(14)-en 3 beta-ol (6) were shown to be very powerful inhibitors of delta 7-SR in a preparation isolated from maize (Zea mays) (K(i),app = 50-70 nM, Ki,app/Km,app = 1.0 x 10(-4) to 1.3 x 10(-4). The data are consistent with a carbonium ion mechanism for the reduction; compounds 4 and 6 probably act as reaction intermediate analogs. Compound 4, in contrast to compound 6, displayed in the same microsomal preparation more than 50-fold selectivity for inhibition of the delta 7-SR versus delta 8-delta 7-sterol isomerase, cycloeucalenol isomerase, and delta 8,14-sterol delta 14-reductase, the mechanism of these four enzymes involving presumptive cationic intermediates centered respectively at C7, C8, C9, and C14. These observations highlight the paramount importance of the location of the positively charged nitrogen atom(s) in the B-ring structure for selectivity among these enzymes involving structurally close cationic reaction intermediates. Efficient in vivo inhibition of sterol biosynthesis in bramble cell suspension cultures by a low concentration of compound 4 was demonstrated and confirmed the in vitro properties of this derivative.) PMID- 8679533 TI - Looking for residues involved in the muscle acylphosphatase catalytic mechanism and structural stabilization: role of Asn41, Thr42, and Thr46. AB - Asn41, Thr42, and Thr46 are invariant residues in both muscle and erythrocyte acylphosphatases isolated so far. Horse muscle acylphosphatase solution structure suggests their close spatial relationship to Arg23, the main substrate binding site. The catalytic and structural role of such residues, as well as their influence on muscle acylphosphatase stability, was investigated by preparing several gene mutants (Thr42Ala, Thr46Ala, Asn41Ala, Asn41Ser, and Asn41Gln) by oligonucleotide-directed mutagenesis. The mutated genes were cloned and expressed in Escherichia coli, and the mutant enzymes were purified by affinity chromatography and investigated as compared to the wild-type enzyme. The specific activity and substrate affinity of Thr42 and Thr46 mutants were not significantly affected. On the contrary, Asn41 mutants showed a residual negligible activity (about 0.05-0.15% as compared to wild-type enzyme), though maintaining an unchanged binding capability of both substrate and inorganic phosphate, an enzyme competitive inhibitor. According to the 1H nuclear magnetic resonance spectroscopy and circular dichroism results, all mutants elicited well constrained native-like secondary and tertiary structures. Thermodynamic parameters, as calculated from circular dichroism data, demonstrated a significantly decreased stability of the Thr42 mutant under increasing temperatures and urea concentrations. The reported results strongly support a direct participation of Asn41 to the enzyme catalytic mechanism, indicating that Asn41 mutants may well represent a useful tool for the investigation of the enzyme physiological function by the negative dominant approach. PMID- 8679535 TI - The hydrophobic nature of residue-5 of human protein C is a major determinant of its functional interactions with acidic phospholipid vesicles. AB - We have previously proposed that a cluster of surface-exposed hydrophobic amino acids, viz., F4, L5, and L8, present at the amino-terminus of the Ca(2+)-bound form of gamma-carboxyglutamic acid domain (GD) of human protein C (PC), contributes a substantial portion of the total functional binding energy of PC and its activated form, APC, to acidic phospholipid (PL) vesicles. A deeper understanding of the importance of the hydrophobic nature of sequence position 5, and the particular relevance of leucine at that location, was sought by examination of the properties of a series of mutant proteins containing A5, V5, I5, and W5 as replacements for L5 in recombinant (r)-PC and APC. The Ca(2+)- and PL-dependent plasma-based anticoagulant activities of [L5A]r-APC, [L5V]r-APC, [L5I]r-APC, and [L5W]r-APC were determined to be approximately 28%, 51%, 98%, and 105%, respectively, of that of wild-type r-APC. A similar trend in activities of the mutant enzymes was observed in in vitro factor V/Va and factor VIII/VIIIa inactivation assays. Apparently normal Ca(2+)-dependent conformations were adopted by each of the mutant proteins, but the Ca(2+)-bound form of [L5A]r-PC was relatively the most defective of the mutants in its binding to PL. These results confirm the importance of the hydrophobic character at sequence position 5 as critical to the functional binding of PC to PL. PMID- 8679534 TI - Transition-state structures for the native dual-specific phosphatase VHR and D92N and S131A mutants. Contributions to the driving force for catalysis. AB - Isotope effects have been measured for the reaction of the human dual-specific phosphatase VHR with p-nitrophenyl phosphate (pNPP). Isotope effects in the nonbridge oxygen atoms, in the bridge oxygen atom, and in the nitrogen atom were measured by the competitive method using an isotope ratio mass spectrometer. These are isotope effects on V/K, and give information on the chemical step of phosphoryl transfer from substrate to the enzymatic nucleophile Cys-124. With native VHR, 18(V/K)nonbridge = 1.0003 +/- 0.0003, 18(V/K)bridge = 1.0118 +/- 0.0020, and 15(V/K) = 0.9999 +/- 0.0004. The values are similar to the intrinsic isotope effects for the uncatalyzed reaction, indicating that the chemical step is rate-limiting with the pNPP substrate. The transition-state structure resembles that for the uncatalyzed reaction and those previously found for the protein-tyrosine phosphatases YOP51 and PTP1, and is highly dissociative with P-O bond cleavage and protonation of the leaving group by the general acid Asp-92 both well advanced. The D92N mutant exhibits a transition state similar to that of the uncatalyzed reaction of the pNPP dianion, dissociative and with the leaving group departing as the nitrophenolate anion. The S131A mutation causes an increase in the pKa of the nucleophilic Cys, but the isotope effect data are unchanged from those for the native enzyme, indicating no effects of this increase in nucleophilicity on transition-state structure. The double mutant D92N/S131A manifests both the increase in pKa of the nucleophilic Cys and the loss of general acid assistance to the leaving group. In the absence of the general acid, the change in nucleophile pKa results in an increase in 18(V/K)nonbridge from 1.0019 (with D92N) to 1.0031 (with D92N/S131A), indicating loss of P-O nonbridge bond order in the transition state. It is concluded that this is more likely caused by electrostatic effects rather than resulting from increased nucleophile-phosphorus bonding in a less dissociative transition state, although the latter explanation cannot be excluded on the basis of the present data. Electrostatic effects between the thiolate anion nucleophile and the phosphoryl group may be an important part of the driving force for catalysis in this family of enzymes. PMID- 8679536 TI - Effect of soluble tissue factor on the kinetic mechanism of factor VIIa: enhancement of p-guanidinobenzoate substrate hydrolysis. AB - The mechanism by which the protein cofactor, tissue factor, enhances the activity of its cognate serine protease, coagulation factor VIIa (FVIIa), has been studied using the fluorogenic ester substrate 4-methylumbelliferyl p'-guanidinobenzoate (MUGB). Kinetic data were collected at pH 8.4 and pH 7.6 in the presence and absence of soluble tissue factor (sTF; recombinant human tissue factor containing only the extracellular domain). Pre-steady-state techniques allowed the determination of the individual rate constants for acylation (k2) and deacylation (k3) of the sTF.FVIIa complex as well as the dissociation constant for the noncovalent Michaelis complex with MUGB. Alternative methods were required for determination of these parameters for free FVIIa due to extremely slow hydrolysis of MUGB in the absence of sTF. Under all experimental conditions, deacylation was found to be rate-limiting. The major effect of sTF was to raise the affinity of FVIIa for MUGB (31-fold at pH 8.4 and 36-fold at pH 7.6); only minor changes in k2 and k3 were observed. Thus, we conclude that for the ester substrate MUGB, sTF exerts greater allosteric effects on substrate binding than on the later steps involved in the catalytic pathway. PMID- 8679537 TI - Mechanism of hydrogen cyanide binding to myoglobin. AB - Cyanide binding to myoglobin is much slower than that of other ferric and ferrous ligands, suggesting rate limitation by bond formation and disruption within the distal pocket. This interpretation is supported by two key experimental observations. First, His64(E7) to Gly and Ala mutations, which open a direct channel from the solvent to the iron atom, and Phe46(CD4) to Leu, Ile, and Val mutations, which increase the mobility of the distal histidine, have little effect on the association rate constant for cyanide binding. In contrast, these mutations cause 100-1000-fold increases in the rate constant for azide binding, showing convincingly that the binding of this ligand is limited by the rate of its movement into the protein. Second, the rate constant for cyanide dissociation is unaffected by changing the size of the residue at position 64(E7) in the series Gly, Val, Leu, Ile, Phe, whereas there is a 2000-fold decrease in the rate of azide dissociation in going from Gly64 to Phe64 metmyoglobin. The major determinants of the cyanide affinity are the ease of water displacement from the ferric iron atom in metmyoglobin, the acid dissociation constant of HCN inside the protein (K*a), and steric hindrance and electrostatic interactions at the sixth coordination position. Direct hydrogen bonding to the distal histidine does not appear to play an important role in stabilizing bound cyanide. Instead, the general polarity of the distal pocket and its effect on K*a are the key factors regulating cyanide affinity under physiological conditions. PMID- 8679538 TI - Characterization of the P2' and P3' specificities of thrombin using fluorescence quenched substrates and mapping of the subsites by mutagenesis. AB - The importance of substrate residues P2' and P3' on thrombin catalysis has been investigated by comparing the hydrolysis of a series of fluorescence-quenched substrates. Each consisted of a 10-residue peptide, carrying a 2-aminobenzoyl (Abz) group at the N-terminus, and a penultimate 2,4-dinitrophenyl (Dnp) derivatized lysine. Cleavage of such a peptide relieves the intramolecularly quenched fluorescence, allowing determination of the kinetic parameters. The nature of the P2' residue was found to have a major influence on the rate of cleavage: the Kcat/Km value for the hydrolysis of the Arg-Ser bond in Abz-Val-Gly Pro-Arg-Ser-Phe-Leu-Leu-Lys(Dnp)-Asp-OH was nearly 3 orders of magnitude higher than that for the hydrolysis of the same substrate with aspartate instead of phenylalanine at the P2' position. Comparatively, the P3' side chain was less important: the kcat/Km value for the substrate with the least effective residue (aspartate) was only 33 times lower than that of the substrate with the most favorable amino acid (lysine). The role of thrombin residues Arg35, Lys36, Glu39 and Lys60f in the putative P2' and P3' binding sites was also examined. Replacement of Lys60f by glutamine improved the rate of cleavage for peptides with P2' lysine or leucine. Compared with thrombin, mutants E39K and E39Q hydrolyzed faster substrates with an acidic residue in P2' or P3', but slightly slower those with a lysine at either position. Mutations R35Q and K36Q only improved the hydrolysis of substrates with an acidic P2' residue. Overall, thrombin prefers bulky hydrophobic side chains in subsite S2' and positively charged residues in S3', whereas acidic residues are markedly antagonistic to both subsites. PMID- 8679539 TI - Native complex formation between apolipoprotein E isoforms and the Alzheimer's disease peptide A beta. AB - To explore whether the genetic linkage between apolipoprotein E (ApoE) alleles and susceptibility to Alzheimer's disease might be attributable to a direct molecular interaction between ApoE and the amyloid peptide A beta, we have produced ApoE variants in Escherichia coli and studied their interactions with A beta under native conditions. When incubated with A beta at 20-40 microM concentrations, all three isoforms of ApoE (2, 3, and 4) readily form complexes with A beta which can be isolated by gel filtration in native buffer. Freshly mixed ApoE and A beta generate a complex that co-migrates in gel filtration with the main A280 peak, which migrates identically to the ApoE tetramer alone. After several hours incubation, an additional, high molecular weight, soluble aggregate appears which also contains both ApoE and A beta. Neither ApoE nor A beta incubated by themselves produces high molecular weight aggregates under these conditions. Incubation of A beta with control proteins bovine serum albumin and immunoglobulin generates negligable binding in the gel filtration assay. Similar results were obtained whether A beta (1-40) or A beta (1-42) was used, and plasma derived ApoE gave similar results to E. coli-produced material. The data are consistent with a role for ApoE-A beta interactions in modulating the development of AD. Since no major differences were observed in the behavior of the three ApoE isotypes, however, the molecular basis of the genetic trend between ApoE alleles and AD cannot be attributed to specific activity differences between the molecular forms of ApoE characterized in this study. PMID- 8679540 TI - Studies on the hydrolytic properties of (serine) carboxypeptidase Y. AB - The activity of serine carboxypeptidases is dependent on a catalytic triad, an oxyanion hole, and a binding site equivalent to those found in the serine endopeptidases. The action of carboxypeptidase Y on substrates containing amino acids, alcohols, and amines as leaving groups is described. It is demonstrated that the features common to serine endopeptidases and carboxypeptidases are sufficient for hydrolysis of ester bonds. However, rapid hydrolysis of amide bonds is dependent on interactions between the C-terminal carboxylate group of the substrate and the C-terminal recognition site of the enzyme. Furthermore, on the basis of the pH dependencies of wild-type and mutant enzyme, combined with the ability of the enzyme to utilize binding energy to promote catalysis, alternative models for the high activity of carboxypeptidase Y at low pH are discussed. They describe how the catalytically essential histidine is maintained in its active deprotonated state through perturbation of its pKa value in the enzyme-substrate complex. PMID- 8679541 TI - Activation of the multicatalytic endopeptidase by oxidants. Effects on enzyme structure. AB - It is well established that the functional properties of proteins can be compromised by oxidative damage and, in vivo, proteins modified by oxidants are rapidly degraded. It was hypothesized that oxidants may also affect the ability of proteases to hydrolyze peptides and proteins. We therefore examined the effect of oxidants on the endopeptidase activities of the 650 kDa 20S proteasome or multicatalytic endopeptidase (MCP), which is thought to play a central role in nonlysosomal protein breakdown. Treatment of the MCP with the oxidant system, FeSO4-EDTA-ascorbate, stimulated the peptidase activities of the MCP while H2O2 treatment showed little or no stimulation. However, treatment of the MCP with FeSO4-EDTA-ascorbate or H2O2 stimulated proteinase activity by 480% and 730%, respectively. An endogenous activator of the MCP, PA28, stimulated the acidic, basic, and hydrophobic peptidase activities of the MCP, but had no effect on proteolytic activity. Treatment of PA28 with oxidants in the presence of MCP or alone did not greatly affect PA28's ability to activate the peptidase activities of the MCP. Using nondenaturing polyacrylamide gel electrophoresis, structural alterations in the enzyme which may be responsible for the activation of peptidase and protease activities following exposure to oxidants were investigated. Treatment of the MCP with reagents that activate proteolysis, including H2O2, as well as the serine protease inhibitor 3,4-dichloroisocoumarin and the cysteine protease inhibitor p-(chloromercuri) benzenesulfonic acid, all caused dissociation of the 650 kDa MCP. However, exposure to FeSO4-EDTA-ascorbate resulted in little or no dissociation of the complex. The MCP complex dissociated by p-(chloromercuri) benzenesulfonic acid could be reassociated upon treatment with the reducing agent dithiothreitol, but dithiothreitol failed to completely reassociate 3,4-dichloroisocoumarin- or H2O2 treated MCP. Therefore, chemical modification of the MCP can cause activation with varying degrees of complex dissociation. These results suggest that metabolites, such as reactive oxygen species, in addition to endogenous proteins, such as PA28, are capable of modulating MCP activity. PMID- 8679542 TI - Covalent reinforcement of a fragile region in the dimeric enzyme thymidylate synthase stabilizes the protein against chaotrope-induced unfolding. AB - Urea and guanidinium chloride induced unfolding of thymidylate synthase, a dimeric enzyme, and engineered interface mutants have been monitored by circular dichroism, fluorescence, and size-exclusion chromatography. Equilibrium unfolding studies show biphasic transitions, with a plateau between 3.5 and 5 M urea, when monitored by far-UV CD and fluorescence energy transfer employing an (aminoethylamino) naphthalenesulfonyl (AEDANS) label at the active site residue, Cys198. AEDANS was also specifically incorporated at position Cys155 in the mutant protein T155C. Direct excitation of this extrinsic fluorophore in the wild type protein (labeled at Cys198) and mutant T155C (labeled at Cys155) showed remarkable differences in the unfolding profiles. C155 AEDANS has a transition centered at 3.5 M urea, which is in contrast to Cys 198 AEDANS (5.5 M urea). Unfolding studies monitored by following intrinsic fluorescence of Trp residues which are located in a small structural domain suggest that this region of the protein is intrinsically fragile. The stable equilibrium intermediate is identified to be an ensemble of partially unfolded aggregated species by gel filtration studies. The chaotrope-induced denaturation of TS appears to proceed through a partially unfolded intermediate that is stabilized by aggregation. Dissociation and loss of structure occur concomitantly at high denaturant concentrations. Introduction of two symmetrically positioned disulfide bridges across the dimer interface in the triple mutant T155C/E188C/C244T (TSMox) stabilized the protein against denaturant-induced unfolding. Aggregate formation was completely abolished in the mutant TSMox, which also enhanced the overall structural stability of the protein. Structural reinforcement of the fragile interface in thymidylate synthase results in dramatic stabilization toward chaotrope-induced unfolding. PMID- 8679544 TI - The pyrrole locus is the major orienting factor in ryanodine binding. AB - Ryanodine, a natural product, is a complex modulator of a class of intracellular Ca2+ release channels commonly called the ryanodine receptors. Ryanodine analogs can cause the channel to persist in long-lived, subconductance states or, at high ligand concentrations, in closed, nonconducting states. In this paper, we further explore the relationship between structure and ryanodine binding to striated muscle. Ryanodine, 3-epiryanodine, and 10-ryanodine are three structural isomers of ryanodine. The dissociation constants of these compounds were measured using rabbit skeletal muscle ryanodine receptors. Placing the pyrrole carbonyl group at the 3-epi- and 10-positions of ryanodol largely restores the large loss of binding energy observed when ryanodine is hydrolyzed to ryanodol. Comparative molecular field analysis successfully predicts the enhanced binding and indicates that the pyrrole group controls the orientation of ligand binding. We propose that the ryanoids are reorientated in the binding site of the ryanodine receptors such that the pyrrole always occupies the same subsite. By applying this model, the binding constants of other ryanoids are predicted. PMID- 8679543 TI - Selective regulation of RNK-16 cell matrix metalloproteinases by the EP4 subtype of prostaglandin E2 receptor. AB - Cell surface expression of multiple structurally and functionally distinct prostaglandin E2 (PGE2) receptors (Rs), designated the EP1, EP2, EP3, and EP4 Rs, is a principal determinant of the diverse cellular effects of PGE2. The RNK-16 line of rat large granular lymphocytes, which has served as a model for natural killer cells, coexpresses a mean of 1092 EP3 Rs and EP4 Rs per cell with a mean Kd of 2.7 nM. The presence of the EP3 and EP4 Rs and the absence of the EP1 and EP2 Rs were revealed by inhibition of [3H]PGE2 binding by the EP3/EP1R agonist sulprostone, the EP3/EP2/EP4R agonist M&B 28767, and the EP2/EP4/EP3R agonist misoprostol but not by the EP1R antagonist SC-19220 or the EP2R agonist butaprost. Functional EP4 R expression was confirmed by finding that PGE2 and misoprostol, but not butaprost or sulprostone, evoked increases in the intracellular concentration of cyclic AMP ([cAMP]) in RNK-16 cells. Matrix metalloproteinase (MMP)-1 and -3 were identified by zymography and Western blots as the principal MMPs secreted by RNK-16 cells. Secretion of both MMPs by RNK-16 cells attained a maximal level after 24 h of incubation and was enhanced significantly by 10(-9) to 10(-7) M PGE2, 10(-6) M misoprostol, and 10(-4) M dibutyryl cyclic AMP, but not by the EP3R agonist sulprostone. Thus, the effect of PGE2 on RNK-16 cell MMP secretion is mediated by an EP4 R-dependent mechanism involving increases in [cAMP]i. The migration of RNK-16 cells across micropore filters, without or with a layer of Matrigel, was stimulated chemokinetically by PGE2 and misoprostol. PGE2-elicited chemokinesis of RNK-16 cells across a Matrigel model basement membrane, but not across a microfilter alone, was suppressed by the GM 6001 inhibitor of MMP activities. Stimulation of MMP activities in RNK-16 cells by the EP4R thus facilitates migration of the NK cells across vascular basement membranes. PMID- 8679545 TI - Serum albumin is a significant intermediate in cholesterol transfer between cells and lipoproteins. AB - The function of albumin in the movement of cholesterol into and out of non cholesterol-loaded fibroblasts has been investigated. Cholesterol efflux from cholesterol labeled normal human skin fibroblasts to fatty acid-free human serum albumin (HSA) is biphasic with a rapid first phase that plateaus at about 15 min followed by a nearly linear phase up to 90 min, the longest incubation in this study. Saturation of efflux is observed at about 10 mg of albumin/mL. Efflux is specific to albumin since other molecules, such as ovalbumin or gelatin, do not induce efflux. The ability of HSA to induce cellular cholesterol efflux is low compared to reconstituted discoidal lipoprotein A-I (LpA-I). HSA at 2 mg/mL produces a rate of cholesterol efflux similar to that of LpA-I at 45 micrograms of protein/mL; however, these concentrations are within the physiological range for both HSA and apolipoprotein A-I (apoA-I). The efflux to the medium containing both LpA-I and HSA is greater than that to each of them alone but does not show complete additivity, indicating a competition between HSA and LpA-I. The HSA mediated cholesterol movement is bidirectional as demonstrated by the transfer of cholesterol from HSA-(3H)- cholesterol complexes to fibroblasts; moreover, the HSA-mediated transfer is much faster than that from cholesterol-containing LpA-I (0.8 versus 0.2 pmol (micrograms of cell protein)-1 (90 min)-1. However, the presence of either low-density lipoprotein (LDL) or LpA-I in the incubation medium significantly inhibits the transfer of cholesterol from HSA-(3H) cholesterol complexes to fibroblasts, thus allowing the bidirectional transfer of cholesterol between HSA and cells to possibly operate as a net efflux. In conclusion, albumin plays a significant role in cholesterol transfer between cells and lipoproteins. PMID- 8679546 TI - Hemoglobin oxidation products extract phospholipids from the membrane of human erythrocytes. AB - Hydrogen peroxide oxidation of human erythrocytes induces a transfer of phospholipid from the membrane into the cytosol [Brunauer, L.S., Moxness, M.S., & Huestis, W.H. (1994) Biochemistry 33, 4527-4532]. The current study examines the mechanism of lipid reorganization in oxidized cells. Exogenous phosphatidylserine was introduced into the inner monolayer of erythrocytes, and its distribution was monitored by microscopy and radioisotopic labeling. Pretreatment of cells with carbon monoxide prevented both hemoglobin oxidation and the transfer of phosphatidyserine into the cytosolic compartment. The roles of the various hemoglobin oxidation products in lipid extraction were investigated using selective oxidants. Nitrite treatment of intact cells produced almost complete conversion to methemoglobin, but no detectable lipid extraction. Treatments designed to produce the green hemoglobin derivatives, sulfhemoglobin and choleglobin, resulted in cytosolic extraction of phosphatidylserine. Ion exchange and size exclusion chromatography of oxidized cytosolic components revealed a lipid-hemoglobin complex. The interaction between lipid and hemoglobin oxidation products was verified in a model system. Purified hemoglobin, enriched in sulfhemoglobin and choleglobin by treatment with H2O2, H2S, or ascorbate, extracted phospholipid from small unilamellar phospholipid vesicles. Electron paramagnetic resonance studies demonstrated that hemoglobin oxidation products also adsorb fatty acids from solution. This newly described activity of hemoglobin may play a role in the clearance of oxidatively damaged and senescent cells from circulation. PMID- 8679547 TI - Evidence for electron transfer from the nitrogenase iron protein to the molybdenum-iron protein without MgATP hydrolysis: characterization of a tight protein-protein complex. AB - MgA TP hydrolysis has been proposed to be absolutely required for electron transfer from the nitrogenase iron (Fe) protein to the molybdenum-iron (MoFe) protein. This work presents evidence for primary electron transfer from the Azotobacter vinelandii nitrogenase Fe protein to the MoFe protein in the absence of MgATP hydrolysis. Deletion of an amino acid (Leu 127) in a signal transduction pathway in the Fe protein resulted in an Fe protein conformation resembling the MgATP-bound state. This altered Fe protein (L127delta) was found to bind to the MoFe protein in the absence of MgATP, forming a tight protein complex. Both steady state and stopped-flow transient kinetic measurements suggest that two L127delta Fe proteins bind to one MoFe protein with an extremely high affinity. From pre-steady state kinetic determinations of the rate of complex dissociation, the affinity was found to be at least 350 times tighter than that of the wild type A. vinelandii nitrogenase complex and at least 20 times tighter than that of the heterologous Clostridium pasteurianum Fe protein-A. vinelandii MoFe protein complex. The L127delta Fe protein-MoFe protein complex was isolated by gel filtration liquid chromatography. Scanning densitometry of an SDS gel of the complex isolated from the gel filtration column revealed a stoichiometry of 1.7 L 127 delta Fe proteins bound per MoFe protein. The L 127 delta Fe protein was found to transfer a single electron from its [4Fe-4S] cluster to the MoFe protein at a rate of 0.2s-1. This compares with the MgATP dependent electron transfer rate of 140 s-1 observed for transfer of an electron from the wild-type Fe protein to the MoFe protein. No substrate reduction (H+ or C2H2) was detected when wild-type MoFe protein was complemented with L 127 delta Fe protein. The MgATP-independent electron transfer from the L 127 delta Fe protein to the MoFe protein required active MoFe protein and was not inhibited by MgADP. EPR spectroscopy of the complex was employed to confirm the electron transfer reaction. These results show that Fe protein in a conformation resembling the MgATP-bound state can transfer at least one electron to the MoFe protein without the need for MgATP hydrolysis. PMID- 8679548 TI - Role of lipid hydroperoxides in the activation of 15-lipoxygenase. AB - We have used stopped-flow rapid reaction methods, employing both fluorescence and absorbance monitoring, together with HPLC analysis of the products to study the activation of soybean 15-lipoxygenase by 13(S)-hydroperoxy-9, 11(E,Z) octadecadienoic acid (13-HPOD). When lipoxygenase is mixed with an equimolar concentration of 13-HPOD, the enzyme undergoes a rapid change in fluorescence. The rate of the change of fluorescence is dependent on the concentration of the 13-HPOD (k = 6.7 x 10(6) M-1 s-1) and is accompanied by activation of the enzyme. The fluorescence change is not accompanied by any change in the UV absorbance of the 13-HPOD, suggesting no loss of the conjugated diene during enzyme activation, and HPLC analysis of the products of the reaction confirms that the 13-HPOD can be recovered unchanged following this reaction. In the presence of an inhibitor (BWA4C, a hydroxamate inhibitor) that reduces the active-site iron, the 13-HPOD and the inhibitor are destroyed in a peroxidase-like reaction. On the basis of these observations we propose that 13-HPOD binds to the enzyme and facilitates activation of the enzyme, possibly through the formation of a protein radical, and that the 13-HPOD is not changed chemically in this process. PMID- 8679549 TI - Expression in yeast and purification of functional macrophage nitric oxide synthase. Evidence for cysteine-194 as iron proximal ligand. AB - Mouse macrophage NO-synthase (mNOS) was expressed in a unique yeast-based system by using a three-step procedure which allows yeast growth and NOS expression to be uncoupled. Despite cytotoxic effects related to mNOS expression, levels of catalytically active enzyme up to 0.5 mg of protein per 5 L of culture was obtained after purification. Its electrophoretic, spectroscopic [lambda max = 446 nm for its Fe(II)-CO complex], and catalytic properties were similar to those previously reported for mNOS purified from macrophages. Recombinant mNOS catalyzed the NADPH-dependent oxidation of L-arginine to citrulline (Km = 7 +/- 3 microM) as well as the reduction of cytochrome C by NADPH [Km = 34 +/- 8 microM and Vm = 25 +/- 5 mumol min-1 (mg of protein-1)]. Two mutants of mNOS in which Cys 194 was replaced with either serine or histidine were constructed and expressed in the same yeast strain at a level higher than that of the wild type protein, as they appear less toxic for the host. Both mutants exhibited electrophoretic properties and activities toward cytochrome C reduction identical to those of wild type NOS. However, they were unable to catalyze the oxidation of L-arginine to citrulline and did not appear to bind heme (no appearance of peaks around 400 and 446 nm for the resting enzyme and its CO complex, respectively, in visible spectroscopy). These data provide the first experimental evidence in favor of previous suggestions that Cys 194 was the proximal iron ligand of mouse mNOS. PMID- 8679550 TI - Reversible phosphorylation as a controlling factor for sustaining calcium oscillations in HeLa cells: Involvement of calmodulin-dependent kinase II and a calyculin A-inhibitable phosphatase. AB - The role of reversible phosphorylation in histamine-induced Ca2+ oscillations in HeLa cells has been investigated by using various activators and inhibitors of protein kinases and phosphatases. Electroporation was employed to introduce impermeable materials into single cells, which proved to be a useful and convenient tool. Of the kinases examined, cAMP-dependent kinase, protein kinase C, and calmodulin-dependent kinase II (CaMK II), only CaMK II was essential. When added during oscillations, both W-7, a calmodulin antagonist, and KN-62, a specific CaMK II inhibitor, caused one large Ca2+ spike before halting the process. Introduction of the Ca2+/calmodulin-independent catalytic domain of CaMK II into the cells forestalled their response to histamine. These results show that intracellular Ca2+ cannot oscillate when CaMK II is locked in either the inactive or the stimulated state. External Ca2+ electroporated into cells preloaded with the catalytic domains was quickly removed (but not when the cells were pretreated with the endoplasmic reticulum Ca(2+)-ATPase inhibitor, tapsigargin), indicating that the ATP-driven Ca2+ pump was somehow activated by CaMK II. Protein phosphatase inhibitors calyculin A and okadaic acid abolished ongoing oscillations and, when added at low concentrations, prolonged the interspike interval. Immunoprecipitation experiments with 32P(i)-labeled cells provided the first evidence that inositol 1,4,5-trisphosphate receptor (IP3R) was phosphorylated by CaMK II in vivo. The extent of phosphorylation was increased in the presence of histamine, significantly enhanced by calyculin A, and greatly reduced by W-7. Our observations are consistent with the concept that repetitive phosphorylation-dephosphorylation cycles regulating IP3R and Ca2+ pumps are a controlling factor for sustained Ca2+ oscillations in HeLa, and possibly other, cells. PMID- 8679551 TI - Role of the Dictyostelium 30 kDa protein in actin bundle formation. AB - We have studied the formation of bundles in mixtures of actin with the Dictyostelium 30 kDa actin-bundling protein as a function of 30 kDa protein concentration, actin concentration, and filament length. The presence of the 30 kDa protein promotes formation of filament bundles at actin concentrations and filament lengths that are not spontaneously aligned into liquid crystalline domains in the absence of the 30 kDa protein. Bundle formation in the presence of the 30 kDa protein was observed over a broad range of actin filament lengths and concentrations. Bundling was filament length dependent, and short filaments were more efficiently bundled. Bundles formed at actin concentrations as low as 2 microM. The volume fraction of the bundled portion and concentrations of actin and the 30 kDa protein in the bundled portion were measured using a sedimentation assay. Bundles have concentrations of actin and 30 kDa protein that are 10-20 and 5-20 times, respectively, greater than that of the bulk solution. Computer modeling reveals that bundling of actin by a bundling protein increases both the mean length and the polydispersity of the length distribution, factors which lower the actin concentration required for spontaneous alignment within the bundle. We propose that entropy-driven spontaneous ordering may contribute to bundle formation in two ways. Bundling of actin creates longer aggregates with a more polydisperse length distribution in which actin aligns spontaneously within the bundle at very low concentrations. In addition, bundling creates locally high concentrations of actin within these aggregates that will spontaneously align, providing an additional driving force for bundle ordering. PMID- 8679552 TI - Determining the secondary structure and orientation of EmrE, a multi-drug transporter, indicates a transmembrane four-helix bundle. AB - EmrE is a member of a newly emerging family of MiniTEXANS, a family of multi-drug antiporters from bacteria characterized by their small size of roughly 100 amino acids. In this report we have obtained transmission FTIR spectra of EmrE in CHCl3:MeOH, DMPC vesicles, and Escherichia coli lipid vesicles. Secondary structure analysis has shown that both in DMPC vesicles and in CHCl3: MeOH the protein adopts a highly helical secondary structure that correlates remarkably well with that predicted by hydropathy analysis. The protein was shown to be resistant to amide proton H/D exchange, providing evidence that most of the protein is embedded in the lipid bilayer. Polarized ATR-FTIR spectra of the protein in DMPC vesicles have shown that the helices are oriented with an average tilt angle of 27 degrees from the bilayer normal. The protein was found to be less oriented in E. coli lipid vesicles, most likely as a result of the poor orientation of the bilayer lipids themselves. Thus, the protein is identified as a transmembrane four-helix bundle providing valuable structural data for this family of multi-drug transporters. The results set the stage for further studies aimed at deriving a detailed model for this protein. PMID- 8679553 TI - Conformation of manganese(II)-nucleotide complexes bound to rabbit muscle creatine kinase: 13C NMR measurements using [2-13C]ATP and [2-13C]ADP. AB - Conformations of cation-nucleotide complexes bound to rabbit muscle creatine kinase were investigated by measuring paramagnetic effects on 13C spin relaxation in E.Mn[2-13C]ATP and E.Mn[2-13C]ADP at three different frequencies, viz., 50, 75, and 125 MHz, and as a function of temperature in the range of 7-35 degrees C (at 75 MHz). Arrhenius plots of the temperature dependencies of relaxation rates show a positive slope with low activation energies of 1.3 +/- 0.2 kcal/mol and 2.0 +/- 0.2 kcal/mol for E.Mn ATP and E.MnADP, respectively. The relaxation rates of both complexes show strong frequency dependence, indicating that these rates are not exchange limited. Analysis of the data yields Mn(II)-2C distances of 10.0 +/- 0.5 A for E.MnATP and 8.6 +/- 0.5 A for E.MnADP. These data were interpreted, along with previously published information, on the location of the cation with respect to the phosphate chain [Jarori, G. K., Ray, B.D., & Nageswara Rao, B. D. (1985) Biochemistry 24, 3487-3494], and on the adenosine conformation [Murali, N., Jarori, G. K., & Nageswara Rao, B. D. (1993) Biochemistry 32, 12941-12948] in these complexes. The Mn(II)-2C distances depend on the orientation of the phosphate chain relative to the adenosine moiety. Conformational searches were performed by varying the two torsion angles, phi 1 (C4'-C5'-O5'-P alpha), and phi 2 (C5'-O5'-P alpha-O alpha beta), along with CHARMm energy computations, in order to determine acceptable conformations compatible with the distances determined. The significant difference in the Mn(II)-2C distances in E.MnATP and E.MnADP is indicative of the structural alterations occurring at the active site as the enzyme turns over. PMID- 8679554 TI - Photoaffinity labeling with UMP of lysine 992 of carbamyl phosphate synthetase from Escherichia coli allows identification of the binding site for the pyrimidine inhibitor. AB - UMP is a highly specific reagent for photoaffinity labeling of the allosteric inhibitor site of carbamyl phosphate synthetase (CPS) from Escherichia coli and has been found to be photoincorporated in the COOH-terminal domain of the large subunit [Rubio et al. (1991) Biochemistry 30, 1068-1075]. In the present work we identify lysine 992 as the residue that is covalently attached to UMP. This identification is based on two lines of evidence. First, [14C]UMP is found to be incorporated between residues 939 and 1006, as shown by peptide mapping and by mass estimates of [14C]UMP-peptides generated by chemical and enzymatic cleavage of CPS. Secondly, we have purified two radioactive peptides derived exclusively from those enzyme molecules (approximately 5% of the total enzyme) that had incorporated [14C]-UMP. Edman analyses show the sequences of the labeled peptides (989)LVNXVHEGRPHIQD and (989)LVNXVHE to be overlapping. Since neither a phenylthiohydantoin (Pth) derivative (in cycle 4) nor any radioactivity is released from the membrane during sequencing, we can conclude that Lys992 and [14C]-UMP form a covalent adduct that remains bound to the membrane. Formation of this adduct agrees with all of the evidence and with the finding that UMP labeling prevents trypsin cleavage at Lys992. Lysine 992 is invariant in those CPSs that are inhibited by UMP, and is located 30 residues upstream of the site whose phosphorylation in hamster CAD reduces inhibition of CAD by UTP. Multiple sequence alignment of the residues surrounding Lys992 of the E. coli enzyme and the corresponding residues of the yeast and animal enzymes supports the existence of a uridine nucleotide binding fold in this region of the protein. We conclude that sequence changes in the binding fold provide a structural basis for the different regulatory properties found among CPSs I, II, and III. PMID- 8679555 TI - Significance of the O-helix residues of Escherichia coli DNA polymerase I in DNA synthesis: dynamics of the dNTP binding pocket. AB - In order to identify functionally important residues in the O and O1 helices of Escherichia coli DNA polymerase I, we mutated 9 residues of this region to alanine. The alanine substitutions result in moderate to severe effects on the polymerase activity of the individual mutant enzymes. Severe loss of activity is associated with R754A, K758A, F762A, and Y766A. However, the loss of polymerase activity with different template primers exhibited a rather unique pattern implying differential participation of the individual residue in the synthesis directed by poly(rA), poly(dA), and poly(dC) templates. The ability of all mutants to form E-DNA binary complex was found to be unaffected with the exception of Y766A and F771A, where significant reduction in the cross-linking of both the template and the primer strand was noted. Most interestingly, the catalytic activity of all inactive mutant enzymes, with the exception of K758A, could be restored by substituting Mn2+ in place of Mg2+ as a divalent cation. Based on these results and associated changes in the kinetic parameters and other properties of the individual mutant enzyme, we conclude the following: (a) Tyr 766 and Phe 771 are either involved in the binding of template-primer or are in the vicinity of the DNA binding track. (b) Residues Arg 754, Lys 758, Phe 762, and Tyr 766 appear to be required for the binding of Mg.dTTP, while only Arg 754 and Lys 758 are utilized in the polymerization of Mn.dTTP. (c) In the polymerization of dGTP, only Lys 758 appears essential regardless of the type of divalent cation. (d) Phe 762 participates only in the binding of Mg.dTTP. Finally, (e) based on the analysis of the time course of nucleotide incorporation, processivity, and pyrophosphorolysis reaction, we suggest that Lys 758 is probably involved in a conformational change of the ternary complexes preceding and following the chemical step. In summary, our results suggest that the formation of the dNTP binding pocket is a dynamic process which requires the participation of different residues depending on the type of dNTP and the divalent cation. PMID- 8679556 TI - RecA-catalyzed, sequence-specific alkylation of DNA by cross-linking oligonucleotides. Effects of length and nonhomologous base substitutions. AB - Oligodeoxyribonucleotides (ODNs) bearing the reactive nitrogen mustard chlorambucil have been used as sequence-directed affinity labeling reagents to investigate the length and homology requirements for RecA-catalyzed alkylation of double-stranded DNA. The cross-linkage reaction, which takes place at the N-7 position of a targeted complementary strand guanine following strand exchange, was highly sequence specific with both a 272 bp DNA fragment and a linearized plasmid. Alkylation required the ODN to be at least 26 nucleotides long and to possess homology to the target in the vicinity of the modification site. The extent of alkylation was improved by using longer ODNs, with a 50-mer giving over 50% reaction. Mismatches inhibited alkylation when they perturbed the structure of the strand exchange product near the targeted guanine. Longer heterology also inhibited alkylation when it prevented strand exchange. Our inability to detect cross-linkage in stable synaptic complexes unable to undergo complete strand exchange is best explained by a model for homologous alignment in which the presynaptic filament approaches from the minor groove of the duplex. Since the N 7 position of guanine is in the major groove, it is inaccessible to the tethered chlorambucil group of the ODN during the search for homology. The reaction specificity of chlorambucil-bearing ODNs suggests that they may have general use as recombinase-mediated DNA targeting agents. PMID- 8679557 TI - Formation of the amino acid-DNA complexes by hexavalent and trivalent chromium in vitro: importance of trivalent chromium and the phosphate group. AB - We have recently shown that a substantial fraction of all Cr-DNA adducts in chromate-exposed cells are represented by ternary complexes involving amino acids or glutathione bridged by Cr-(III) to DNA. The tridentate amino acids such as cysteine, glutamic acid, and histidine were predominantly found cross-linked to DNA. The mechanism by which Cr can cross-link these amino acids to DNA has been modeled by reacting DNA and trivalent and hexavalent chromium with cysteine and histidine. The formation of a Cr(III)-amino acid binary complex was required before Cr(III) reacted with DNA to yield a ternary complex. Cr(III)-pretreated DNA did not bind cysteine or histidine even after prolonged incubations. Reduction of Cr(VI) in the presence of DNA gave rise to an extensive cross linking of cysteine and histidine. Addition of DNA to Cr(VI) mixtures at the start of reduction or after the reduction was complete had little effect on the level of ternary complexes indicating that Cr(III)-amino acid binary complexes were DNA-attacking species. In order to identify DNA groups involved in the ternary complex formation, pre-formed Cr(III)-histidine complexes were reacted with nucleosides and nucleotide monophosphates followed by separation and analysis of the products. The incubation of the Cr(III)-histidine complexes with nucleotide monophosphates but not with nucleosides gave rise to ternary complexes that contained both histidine and Cr, showing the primary importance of the phosphate group in this reaction. All four DNA nucleotides were capable of the ternary complex formation with Cr(III) and histidine. No apparent base preference in the amino acid cross-linking was also found in the reaction of Cr(III)/cysteine and Cr(VI)/cysteine mixtures with oligonucleotides of base specific composition. PMID- 8679558 TI - Is the strong actinomycin D binding of d(5'CGTCGACG3') the consequence of end stacking? AB - It has been reported that ACTD binds strongly and cooperatively to a non-GC containing self-complementary octamer d(CGTCGACG) with a 2:1 drug to duplex ratio (Synder et al., 1989). If one views the classic intercalative preference of ACTD for the 5'GpC3' sequence to be the drug favoring the 3'-side of dG, the possibility exists that the drug molecules may in fact stack on the G.C base pairs at both ends of this oligomeric duplex. To investigate this possibility, d(CGTCGACG) and several related oligomers resulting from replacing the terminal base(s) or appending with dT and/or dA are used in a comparative study employing equilibrium titration, thermal denaturation, kinetic, and various spectral measurements. Absorbance titrations at 20 degrees C confirm the strong and highly cooperative nature of ACTD binding to this octamer. The stoichiometric association constants for the binding of the first and second drugs were found to be 1 x 10(5) and 3.2 x 10(7) M-1, respectively. The base replacements of dG and dC at the respective ends resulted in a much weaker ACTD binding affinity, the loss of binding cooperativity, and much faster association and dissociation kinetics. These are consistent with the inability of the drug to stack on the 3' side of dG due to base replacements. Appending the end(s) with dA and/or dT resulted in some diminution of binding affinity and cooperativity, appearance of slower association kinetic components, and unusually strong 7-amino-ACTD fluorescence enhancement for oligomers with dA or dT attached to dG at the 3' terminal. To further support our postulate, studies were also made with d(CGACGTCG), which is related to the parent octamer by inverting the A.T pairs. It was found that, despite the altered internal sequence, this oligomer exhibits cooperative ACTD binding and kinetic characteristics very similar to those of the parent octamer, consistent with its ability to end-stack on the 3'-side of dG. PMID- 8679559 TI - Guanidine hydrochloride unfolding of peptide helices: separation of denaturant and salt effects. AB - To provide a model for understanding the unfolding of proteins by the chemical denaturant guanidine hydrochloride, we have measured helix unfolding for homologous series of peptides with the repeating sequence Ala-Glu-Ala-Ala-Lys-Ala and chain lengths from 7 to 50 residues. The free energy for helix unfolding varies as a function of guanidinium chloride (GdmCl) for all the peptides. The slope of the linear plot of the free energy of helix formation as a function of the molar concentration of GdmCl, termed the m-value, was found to be strongly dependent on the total ionic strength of the solution. A comparison of the m value for urea denaturation of the same series of peptides [Scholtz, J. M., Barrick, D., York, E. J., Stewart, J. M., & Baldwin, R. L. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 185-189] reveals that, under many conditions, GdmCl is roughly twice as effective as a denaturant than urea on a molar basis, in agreement with many studies on proteins. However, when the ionic strength of aqueous GdmCl is controlled with additional NaCl, it is possible to separate the observed m-value for GdmCl solutions into two components: one that is identical to that found for urea and a second which depends only on the molar concentration of the chloride anion. Therefore, for these peptides, an equimolar mixture of urea and NaCl is nearly as effective as GdmCl in unfolding the helical conformation. PMID- 8679560 TI - A mechanism for reducing entropic cost of induced fit in protein--RNA recognition. AB - Induced fit has been postulated to be an important component of ligand interactions with proteins, including protein-DNA interactions. We imagined that the entropic cost of induced fit might be highly dependent on the local protein sequence context around critical contact residues. To investigate this question, we analyzed the basis for active or inactive phenotypes found in a library of combinatorial sequence variants of a surface-located helix-loop peptide which is essential for the anticodon-binding activity of a class I tRNA synthetase. Molecular dynamics simulations of the domain encompassing the helix-loop peptide of the active variants consistently demonstrated fixation of the local motion of five critical (for function) residues which are highly mobile in inactive variants. Additional experiments with other rationally chosen mutants extended the correlation between phenotype and motion of these vital residues. We propose that the need for fixation of local motion is an important constraint on sequences of surface peptides which form parts of RNA-binding sites. The fixation of motion of critical residues in the unbound protein can significantly reduce the entropic cost of complex formation by induced fit. PMID- 8679561 TI - Structure of 4-chlorobenzoyl coenzyme A dehalogenase determined to 1.8 A resolution: an enzyme catalyst generated via adaptive mutation. AB - Here we describe the three-dimensional structure of 4-chlorobenzoyl-CoA dehalogenase from Pseudomonas sp. strain CBS-3. This enzyme catalyzes the hydrolysis of 4-chlorobenzoyl-CoA to 4-hydroxybenzoyl-CoA. The molecular structure of the enzyme/4-hydroxybenzoyl-CoA complex was solved by the techniques of multiple isomorphous replacement, solvent flattening, and molecular averaging. Least-squares refinement of the protein model reduced the crystallographic R factor to 18.8% for all measured X-ray data from 30 to 1.8 A resolution. The crystallographic investigation of this dehalogenase revealed that the enzyme is a trimer. Each subunit of the trimer folds into two distinct motifs. The larger, N terminal domain is characterized by 10 strands of beta-pleated sheet that form two distinct layers which lie nearly perpendicular to one another. These layers of beta-sheet are flanked on either side by alpha-helices. The C-terminal domain extends away from the body of the molecule and is composed of three amphiphilic alpha-helices. This smaller domain is primarily involved in trimerization. The two domains of the subunit are linked together by a cation, most likely a calcium ion. The 4-hydroxybenzoyl-CoA molecule adopts a curved conformation within the active site such that the 4-hydroxybenzoyl and the adenosine moieties are buried while the pantothenate and pyrophosphate groups of the coenzyme are more solvent exposed. From the three-dimensional structure it is clear that Asp 145 provides the side-chain carboxylate group that adds to form the Meisenheimer intermediate and His 90 serves as the general base in the subsequent hydrolysis step. Many of the structural principles derived from this investigation may be directly applicable to other related enzymes such as crotonase. PMID- 8679562 TI - Crystal structures of an NH2-terminal fragment of T4 DNA polymerase and its complexes with single-stranded DNA and with divalent metal ions. AB - We report the crystal structure of an NH2-terminal 388-residue fragment of T4 DNA polymerase (protein N388) refined at 2.2 A resolution. This fragment contains both the 3'-5' exonuclease active site and part of the autologous mRNA binding site (J. D. Karam, personal communication). The structure of a complex between the apoprotein N388 and a substrate, p(dT)3, has been refined at 2.5 A resolution to a crystallographic R-factor of 18.7%. Two divalent metal ion cofactors, Zn(II) and Mn(II), have been located in crystals of protein N388 which had been soaked in solutions containing Zn(II), Mn(II), or both. The structure of the 3'-5' exonuclease domain of protein N388 closely resembles the corresponding region in the Klenow fragment despite minimal sequence identity. The side chains of four carboxylate residues that serve as ligands for the two metal ions required for catalysis are located in geometrically equivalent positions in both proteins with a rms deviation of 0.87 A. There are two main differences between the 3'-5' exonuclease active site regions of the two proteins: (I) the OH of Tyr-497 in the Klenow fragment interacts with the scissile phosphate in the active site whereas the OH of the equivalent tyrosine (Tyr-320) in protein N388 points away from the active center; (II) different residues form of the binding pocket for the 3' terminal bases of the substrate. In the protein N388 complex the 3'-terminal base of p(dT)3 is rotated approximately 60 degrees relative to the position that the corresponding base occupies in the p(dT)3 complex with the Klenow fragment. Finally, a separate domain (residues 1-96) of protein N388 may be involved in mRNA binding that results in translational regulation of T4 DNA polymerase (Pavlov & Karam, 1994). PMID- 8679563 TI - Electron transfer from copper to heme within the methylamine dehydrogenase- amicyanin--cytochrome c-551i complex. AB - Methylamine dehydrogenase (MADH), amicyanin, and cytochrome c-551i are soluble redox proteins that form a complex in solution [Chen, L., Durley, R., Mathews, F. S., & Davidson, V. L. (1994) Science 264, 86-90] which is required for the physiologic electron transfer from the tryptophan tryptophylquinone cofactor of MADH to heme via the copper center of amicyanin. The electron transfer reaction from copper to heme within the protein complex has been characterized by transient kinetic and thermodynamic analysis. The rate of this electron transfer reaction is 87 s-1 at 30 degrees C, and it varied with temperature. The reaction exhibited a reorganizational energy (lambda) of 1.1 eV and an electronic coupling (H(AB)) of 0.3 cm-1. The results of these analyses also predict an electron transfer distance, depending upon the value of beta which is used, of 13-24 A. The larger value approximates the direct copper to heme distance observed in the crystal structure of the complex. The most efficient pathways for electron transfer were predicted from the crystal structure using the Greenpath program, and these predictions were correlated with the results of the solution studies of the electron transfer reaction. It is concluded that electron transfer is, in fact, rate limiting for the observed electron transfer reaction in solution and that the two redox centers are strongly coupled, given the distance which separates them. PMID- 8679564 TI - Structure of chimeric duplex junctions: solution conformation of the retroviral Okazaki-like fragment r(ccca)d(AATGA).d(TCATTTGGG) from Moloney murine leukemia virus. AB - We have determined the solution structure of the synthetic chimeric duplex r(ccca)d(AATGA).d(TCATTTGGG) by two-dimensional NMR, distance geometry, restrained molecular dynamics, and full relaxation matrix simulation of the two dimensional nuclear Overhauser effect spectra at various mixing times. The chimeric strand of this duplex consists of the last four residues of the tRNA(Pro) primer for (-) strand DNA synthesis of Moloney murine leukemia virus and the first five residues of the (-) strand DNA produced by extending this primer; the complementary DNA strand corresponds to the (+) strand product from this template. The hybrid section of this chimeric duplex assumes a structure similar to that found for pure hybrid duplexes of mixed sequence, while the DNA section assumes a conformation closer to B-form DNA. There is significant distortion of the duplex at the hybrid-DNA junction which is manifested in marked changes in the helical parameters buckle, roll, and tip, changes in glycosidic torsion angles, and changes in the backbone torsion angles delta, epsilon, and zeta. The sugar conformations also undergo large changes, from heteromerous puckers in the hybrid section to a more B-form in the DNA section. Furthermore, the intrastrand phosphate separation in the chimeric strand is more typical of A form duplexes in the RNA section but more like B-form duplexes in the DNA section. In the DNA section the minor groove width changes gradually from B-form at the periphery and approaches hybrid-like dimensions closer to the junction. The structural discontinuities act synergistically to produce a bend of 18 +/- 3 degrees at the junction. The global structure of this sequence is similar to that previously found in the chemically analogous Okazaki fragment r(gcg)d(TATACCC).d(GGGTATACGC) in solution. Such structure homology suggests a possible link between structure and function with respect to the recognition and cleavage of the junction RNA residues in both retroviral chimeras and Okazaki fragments during reverse transcription and normal DNA replication. PMID- 8679565 TI - Synthesis and characterization of a caged receptor ligand suitable for chemical kinetic investigations of the glycine receptor in the 3-microseconds time domain. AB - Here we report the development and characterization of a new photolabile protecting group for the carboxyl group of neurotransmitters, 2-methoxy-5 nitrophenyl. The synthesis and characterization of a photolabile derivative of beta-alanine, caged beta-alanine, are described. beta-Alanine can activate the glycine receptor, a major inhibitory receptor in the mammalian central nervous system; the 2-methoxy-5-nitrophenyl derivative of beta-alanine combined with a laser-pulse photolysis method makes it possible to investigate the chemical kinetic mechanism of the receptor in the 3-microseconds time domain. The derivative is photolyzed by a laser pulse to release free beta-alanine within 3 microseconds and with a product quantum yield of 0.2. In aqueous solution in the dark and at neutral pH, the compound is more stable, by a factor of approximately of 25, than the analogous derivative of glycine [Ramesh, D., Wieboldt, R., Niu, L., Carpenter, B. K., & Hess, G. P. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 11074-11078]. 2-Methoxy-5-nitrophenyl-beta-alanine hydrolyzes in aqueous solution at neutral pH with a t1/2 of approximately 1.5 h. Neither the 2-methoxy-5 nitrophenyl-beta-alanine nor the 2-methoxy-5-nitrophenol photolysis side product activates, inhibits, or potentiates the response of glycine receptors in rat hippocampal neurons to glycine. Photolysis of 2-methoxy-5-nitrophenyl-beta alanine by irradiation with a 600-ns laser pulse at 333 nm releases beta-alanine, which then activates glycine receptor-channels on neurons equilibrated with the caged compound, as detected by whole-cell current recording. Compared with the analogous derivative of glycine, in terms of quantum yield, photolysis rate, and stability, this new compound is not only a better candidate for use in chemical kinetic investigations of the glycine receptor, but can also be used in determining the location of glycine receptors in neuronal cells. PMID- 8679566 TI - Activation of ribulose-1,5-biphosphate carboxylase/oxygenase (Rubisco) involves Rubisco activase Trp16. AB - The role of the N-terminal region of tobacco Rubisco activase in ATP hydrolysis and ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) activation was examined by construction of mutant proteins. Deletion of the first 50 amino acids of Rubisco activase almost completely eliminated the ability to activate Rubisco, without changing the ATP-hydrolyzing and self-associating properties of the enzyme. Thus, the N-terminus of Rubisco activase is distinct from the ATP hydrolyzing domain and is required for Rubisco activation. Directed mutagenesis of the species-invariant tryptophan residue at position 16 inhibited Rubisco activation but not the binding or hydrolysis of ATP. The ability to activate Rubisco was less severely inhibited when Trp was replaced by a Tyr or Phe than by an Ala or Cys, indicating that an aromatic residue at position 16 and particularly a Trp is required for proper activation of Rubisco. Fluorescence quenching of the 7-nitrobenz-2-oxa-1,3-diazole-modified W16C mutant upon addition of nucleotide suggested that position 16 becomes more solvent accessible in response to nucleotide binding. However, changes in the intrinsic fluorescence of truncated and Trp16 mutants upon addition of ATP were similar to those of the wild type, evidence that Trp16 is not the residue reporting the conformational change that accompanies subunit association. PMID- 8679567 TI - Potency and selectivity of the cathepsin L propeptide as an inhibitor of cysteine proteases. AB - The cathepsin L propeptide (phcl-2) was expressed in Saccharomyces cerevisiae using a human procathepsin L/alpha-factor fusion construct containing a stop codon at position -1 (the C-terminal amino acid of the proregion). Since the yield after purification was very low, the cathepsin L propeptide was also obtained by an alternate procedure through controlled processing of an inactive mutant of procathepsin L (Cys25Ser/Thrl10Ala) expressed in Pichia pastoris, by small amounts of cathepsin L. The peptide resulting from the cleavage of the proenzyme (phcl-1) was then purified by HPLC. The purified propeptides were characterized by N-terminal sequencing and mass spectrometry and correspond to incomplete forms of the proregion (87 and 81 aa for phcl-1 and phcl-2 respectively, compared to 96 aa for the complete cathepsin L propeptide). The two peptides were found to be potent and selective inhibitors of cathepsin L at pH 5.5, with Ki values of 0.088 nM for phcl-1 and 0.66 nM for phcl-2. The Ki for inhibition of cathepsin S was much higher (44.6 nM with phcl-1), and no inhibition of cathepsin B or papain could be detected at up to 1 microM of the propeptide. The inhibitory activity was also found to be strongly pH-dependent. Two synthetic peptides of 75 and 44 aa corresponding to N-terminal truncated versions of the propeptide were also prepared by solid phase synthesis and displayed Ki values of 11 nM and 2900 nM, respectively, against cathepsin L. The data obtained for the 4 propeptide derivatives of various lengths indicate that the first 20 residues in the N-terminal region of the propeptide are more important for inhibition than the C-terminal region which contributes little to the overall inhibitory activity. PMID- 8679568 TI - Wild type and mutant human heart (R)-3-hydroxybutyrate dehydrogenase expressed in insect cells. AB - (R)-3-Hydroxybutyrate dehydrogenase (BDH) is a lipid-requiring mitochondrial enzyme with a specific requirement of phosphatidylcholine (PC) for function. PC is an allosteric activator that enhances NAD(H) binding to BDH. The enzyme serves as a paradigm to study specific lipid-protein interactions in membranes. Analysis of the primary sequence of BDH, as determined by molecular cloning, predicts that lipid binding and substrate specificity are contributed by the C-terminal third of the protein [Marks, A. R., McIntyre, J. O., Duncan, T. M., Erdjument-Bromage, H., Tempst, P., & Fleischer, S. (1992) J. Biol. Chem. 267, 15459-15463]. The mature form of human heart BDH has now been expressed in catalytically active form in insect cells (Sf9, Spodoptera frugiperda) transfected with BDH-cDNA in baculovirus. Endogenous PC in the insect cells fulfills the lipid requirement for the expressed BDH since enzymatic activity is lost upon digestion with phospholipase A2 and restored selectively by reconstitution with PC vesicles. The K(m)s for NAD+ and (R)-3-hydroxybutyrate (R-HOB) of expressed BDH are similar to those for bovine heart or rat liver BDH in mitochondria. Replacing Cys242 (the only cysteine in the C-terminal domain) with serine by site-directed mutagenesis resulted in a 10-fold increase in K(m) for R-HOB with no change in the K(m) for NAD+, indicating a role for Cys242 in substrate binding. Carboxypeptidase cleavage studies had indicated a requirement of the C-terminal for catalysis and a role in lipid binding [Adami, P., Duncan, T. M., McIntyre, J. O., Carter, C. E., Fu, C., Melin, M., Latruffe, N., & Fleischer, S. (1993) Biochem J. 292, 863 872]. We now show that deletion of twelve C-terminal amino acids to form a truncated BDH mutant results in loss of enzymic function. The expression in Sf 9 cells of the constitutively active full-length mature form of human heart BDH and the first expression and characterization of BDH mutants validate this system for structure-function studies of BDH. PMID- 8679569 TI - Substitution of cadmium for zinc in farnesyl:protein transferase alters its substrate specificity. AB - Ras proteins are mutationally activated in a variety of human cancers. Since farnesylation of Ras proteins is required for expression of their oncogenic potential, the enzyme responsible for this reaction, farnesyl:protein transferase (FPT), has become a major target for anticancer drug development. FPT is a zinc metalloenzyme, and the zinc is essential for its catalytic activity. To begin to elucidate the role of zinc in catalysis, we initiated metal substitution studies. Of all metals tested, only cadmium was able to functionally substitute for zinc, reconstituting enzymatic activity with native substrates (H-Ras and farnesyl diphosphate) to about 50% of that of the zinc-containing enzyme. Several important differences were observed between cadmium-substituted FPT (Cd-FPT) and zinc-containing FPT (Zn-FPT). Cd-FPT not only uses H-ras with its native CaaX motif (Ras-CVLS) as a substrate but also can farnesylate H-ras in which the CaaX motif is altered to contain a C-terminal leucine residue (Ras-CVLL). Similarly, Cd-FPT can farnesylate leucine-terminated peptides. Leucine-terminated proteins and peptides are usually substrates for the related enzyme geranylgeranyl:protein transferase type I. Farnesylation of Ras-CVLS and Ras-CVLL by Cd-FPT exhibited similar sensitivity to the FPT inhibitor SCH 44342 and to the peptide inhibitor CAIM. However, unlike Zn-FPT, Cd-FPT is also potently inhibited by the leucine terminated peptide CAIL. These results indicate that the metal ion content of FPT strongly influences its protein substrate specificity. PMID- 8679570 TI - Chaotropic agents and increased matrix volume enhance binding of mitochondrial cyclophilin to the inner mitochondrial membrane and sensitize the mitochondrial permeability transition to [Ca2+]. AB - Binding of mitochondrial cyclophilin (CyP) to the inner mitochondrial membrane is induced by treatment of mitochondria with thiol reagents or oxidative stress and correlates with a sensitization to [Ca2+] of the cyclosporin A-sensitive mitochondrial permeability transition pore (MTP) [Connern, C. P., & Halestrap, A. P. (1994) Biochem. J. 303, 321-324]. Here we show that detection of the bound CyP by Western blotting is greatly enhanced by fixing the CyP to the blotting membrane with glutaraldehyde. CyP binding was only observed when mitochondria were incubated and then frozen in KSCN medium before preparation of the membrane fraction, but not when KCl medium was used. However, incubation of mitochondria (energized or deenergized) in KCl medium followed by KSCN addition immediately prior to freezing did allow CyP binding to be detected. The action of KSCN could be mimicked by guanidinium chloride, implying that the chaotropic action of these agents stabilized the bound complex. The sensitivity to [Ca2+] of the MTP in deenergized mitochondria was greatly enhanced in KSCN medium as compared to KCl medium. Binding of CyP to the mitochondrial membrane was increased by treatment with tert-butylhydroperoxide, phenylarsine oxide, and diamide and by hypoosmotic KCl medium. These conditions all increased the sensitivity of the MTP to [Ca2+]. Conditions known to increase the mitochondrial NADH/NAD+ ratio decreased CyP binding. In contrast, the effects of mitochondrial membrane potential, matrix pH, and adenine nucleotide translocase conformation on the sensitivity of the MTP to [Ca2+] were not associated with a change in CyP binding. Our data imply that there may be two independent mechanisms of altering the Ca2+ sensitivity of the MTP, one brought about by CyP binding which is stabilized by chaotropic agents and another involving additional regulatory sites on the pore complex. PMID- 8679571 TI - Effects of mutagenesis of aspartic acid residues in the putative phosphoribosyl diphosphate binding site of Escherichia coli phosphoribosyl diphosphate synthetase on metal ion specificity and ribose 5-phosphate binding. AB - The three conserved aspartic acid residues of the 5-phospho-D-ribosyl alpha-1 diphosphate binding site (213-GRDCVLVDDMIDTGGT-228) of Escherichia coli phosphoribosyl diphosphate synthetase were studied by analysis of the mutant enzymes D220E, D220F, D221A, D224A, and D224S. The mutant enzymes showed an increase in KM for ribose 5-phosphate in the presence of at least one of the divalent metal ions Mg2+, Mn2+, Co2+, or Cd2+, with the most dramatic changes revealed by the D220E and D220F enzymes in the presence of Co2+ and the D221A enzyme in the presence of Mn2+ or Co2+. The D220F and D221A enzymes both showed large decreases in Vapp in the presence of the various divalent metal ions, except for the D221A enzyme in the presence of Co2+. Vapp of the D220E enzyme was similar to that of the wild-type enzyme in the presence of Mg2+, Mn2+, or Cd2+, whereas the Vapp was increased in the presence of Co2+. Vapp values of the D224A and D224S enzymes were lowered to 10-15-fold and 3-4-fold in the presence of Mg2+ or Mn2+, respectively, whereas Vapp was similar to that of the wild-type and KM for Rib-5-P was increased 4-fold in the presence of Cd2+. The changes in KM for ribose 5-phosphate and Vapp of the mutant enzymes were dependent on the metal ion present, suggesting a function of the investigated aspartic acid residues both in the binding of ribose 5-phosphate, possibly via a divalent metal ion, and in the interaction with a divalent metal ion during catalysis. PMID- 8679572 TI - Transition-state theory and secondary forces in antigen--antibody complexes. AB - Secondary forces, defined as those interactions between the antigen (epitope including the surrounding environment) and areas immediately adjacent to the antibody active site, were investigated using monofluorescein-derivatized synthetic peptides of varying electrostatic properties. Secondary forces were quantitated by measuring the unimolecular rate constants at two different temperatures using the high-affinity anti-fluorescein monoclonal antibody 4-4-20 complexed with fluorescein-derivatized synthetic peptides. Unimolecular rate constants were correlated with transition-state theory to explain secondary effects. An acidic peptide produced a large temperature-dependent effect upon binding including a significant enthalpic factor (+33.28 kcal/mol) relative to the binding of fluorescein ligand (+23.96 kcal/mol). Binding of a basic peptide produced both a relatively smaller temperature effect and enthalpy factor than fluorescein ligand. The antibody-ligand binding results were interpreted invoking the concepts of thermally averaged metatypic (liganded) states of the antibody as well as potential biochemical interactions between the antigen and accessible surface regions of the antibody's complementarity determining regions. PMID- 8679573 TI - Dynamic features of prothrombin interaction with phospholipid vesicles of different size and composition: implications for protein--membrane contact. AB - The dynamics of prothrombin interaction with membrane vesicles of different size and composition was investigated to ascertain the impact of membrane surface characteristics and particle size on this interaction. Dissociation rates were highly sensitive to membrane composition and varied from about 20/s for membranes of 10% PS to 0.1/s for membranes of 50% PS. Overall affinity also varied by more than two orders of magnitude. Very small differences between prothrombin binding to SUV versus LUV were found. Association with large unilamellar vesicles (LUV of 115 nm diameter) was about 4-fold slower, when expressed on the basis of binding sites, than association with small unilamellar vesicles (SUV, 30 nm diameter) of the same composition. Both reactions proceeded at less than 25% of the collisional limit so that the differences were largely due to intrinsic binding properties. Vesicles of 325 nm diameter showed even slower association velocities. Dissociation rates from LUV were about 2-fold slower than from SUV. Again, these differences arose primarily from intrinsic binding properties. Dissociation conformed to a single first order reaction over a wide range of protein occupancy on the membrane. At very high packing density, the dissociation rate increased by about 2-fold. At equilibrium, prothrombin preferred binding to SUV over LUV by about 2-fold. This very small difference, despite substantial differences in phospholipid headgroup packing and hydrocarbon exposure, appeared inconsistent with an important role for protein insertion into the hydrocarbon region of the membrane. However, prothrombin-membrane interaction may arise from a series of interaction forces that have compensating features at equilibrium. The small differences in prothrombin binding to SUV versus LUV, together with differences in the number of protein binding sites per vesicle, were important to identify mechanisms of substrate delivery to the active site of the prothrombinase enzyme [Lu, Y., & Nelsestuen, G. L. (1996) Biochemistry 35, 8201 8209]. PMID- 8679574 TI - The prothrombinase reaction: "mechanism switching" between Michaelis-Menten and non-Michaelis-Menten behaviors. AB - Kinetic properties of prothrombinase were investigated as a function of composition and structure of the membrane component. The kinetic properties were quite diverse, giving linear or nonlinear Eadie-Hofstee plots and substrate concentrations at half-maximum velocity ([S]0.5) that varied from 5 to more than 200 nM. This reaction might be described as a "catalytic system" in order to distinguish it from standard models that have been developed to describe the kinetics of soluble enzymes. The latter do not anticipate a key feature of prothrombinase and probably other membrane-bound enzymes, which is the presence of reaction steps that do not contain an enzyme (E) term. At least four kinetic mechanisms can arise from a logical series of steps that may occur during the prothrombinase reaction. All of these mechanisms appeared to contribute to reaction properties under some conditions. In some cases, one mechanism dominated at low substrate concentration and another at high substrate concentration. This change in the course of a titration was referred to as "mechanism switching". Only membranes of low phosphatidylserine (PS) content displayed Michaelis-Menten behavior. Transfer of substrate from the membrane surface to the enzyme was not important so that the enzyme was involved in capture of substrate directly from solution. As PS content increased, transfer of substrate from the membrane surface to the enzyme occurred. In these cases, multiple mechanisms contributed to the reaction so that K(M) and apparent K(M), properties that describe an enzyme active site, were not appropriate, even when Eadie-Hofstee plots were linear. At high PS content, the enzyme captured every substrate molecule that became bound to the same vesicle. Reaction velocity was governed entirely by protein-membrane binding rather than by enzyme properties. Eadie-Hofstee plots were often nonlinear and/or V(max) was less than kcat[E1]. A small impact from collision-limited kinetics was also detected. Small unilamellar vesicles (SUV, 30 nm diameter) gave higher [S]0.5 values than large unilamellar vesicles (LUV, 100 nm diameter) of the same phospholipid composition. There appeared to be two bases for this behavior. First, LUV may provide a better relationship between the phospholipid surface and the enzyme, giving a better substrate binding site. Second, for membranes containing high PS, the number of substrate binding sites per vesicle contributed to the enhanced function of LUV. These studies showed that mechanism-switching was important to prothrombinase reaction in vitro and suggest that various mechanisms, generated by the nature of the membrane, may be an important regulator for prothrombinase behavior in vivo. PMID- 8679575 TI - Importance of cis-proline 22 in the membrane-binding conformation of bovine prothrombin. AB - Upon addition of calcium to the metal-free protein, bovine prothrombin displays a conformational change with behavior of a classic trans- to cis-proline isomerization. The change is accompanied by a decrease of the intrinsic protein fluorescence and is essential to creating the membrane-binding conformation of prothrombin. This study showed that an identical conformational change was displayed by a peptide corresponding to residues 1-45 of prothrombin. This peptide contains a single tryptophan that underwent extensive quenching upon calcium addition. The kinetics were slow (t1/2 = 2.7 min at 24 degrees C) and displayed an activation energy of 24 kcal/mol. These properties overlapped precisely with the behavior of bovine prothrombin fragment 1 (residues 1-156). Consistent with studies on prothrombin and other vitamin K-dependent proteins that have been modified or truncated, the 1-45 peptide required about 10-fold higher calcium to elicit these behaviors than did fragment 1. The conformational change was necessary for membrane binding by the 1-45 peptide. The only proline in this sequence is at position 22. This proline is of the trans configuration in a crystallized form of calcium-bovine prothrombin fragment 1 [Soriano-Garcia, M., et al. (1992) Biochemistry 31, 2554]. Unless the protein conformational change is based on another behavior, this study showed that biochemical properties of the protein are inconsistent with structure solutions. Further studies are needed to reconcile structure/function in membrane association. Proline 22 in bovine prothrombin may constitute a useful biochemical marker for the membrane-binding conformation of a vitamin K-dependent protein. PMID- 8679576 TI - Human pro-tumor necrosis factor is a homotrimer. AB - The structure of human transmembrane pro-TNF-alpha was studied both in intact cell systems and in an in vitro translation system. In intact cell systems (LPS induced THP-1 and TNF cDNA-transfected COS-7), a trimer of pro-TNF was detected after chemical cross-linking based on its molecular weight in Western blotting analysis. The trimer was shown to be a TNF-specific protein and could be partially cleaved to 26-kDa pro-TNF monomers by cleaving the cross-linkers. The trimeric structure was assembled intracellularly, because it could be detected in both the in vitro microsomal translation system and in THP-1 cells coincident with the appearance of pro-TNF in the cell lysate, prior to secretion of mature TNF. To further analyze the relationship between the trimeric structure and the biological activity of pro-TNF, we characterized several noncleavable pro-TNF deletion mutants. We observed a correlation between expression of TNF cytotoxicity in a juxtacrine fashion and detection of trimer. Thus, human pro-TNF alpha, like the secreted mature TNF-alpha, has trimeric structure which is assembled intracellularly before transport to the cell surface and is apparently required for mediating its biologic activity. PMID- 8679577 TI - Length of the linking domain of human pro-tumor necrosis factor determines the cleavage processing. AB - Several studies have indicated that only one cleavage site (Ala-1/Val+1) is involved in the release of mature TNF from human pro-TNF, whereas others have suggested that the linking sequence (residues -20 to -1) may be important. We previously demonstrated that a pro-TNF deletion mutant, delta -20- -1, was able to form a trimeric structure and mediate TNF cytotoxicity in a juxtacrine fashion without releasing mature TNF. We constructed seven mutants with smaller deletions within this region. Three 15-residue deletion mutants, delta -20- -6, delta -15- 1 and delta -20- -16, -10- -1, were noncleavable, although able to form a trimer and to mediate cytotoxicity through cell-to-cell contact. Three five- or ten residue deletion mutants, delta -20- -16, delta -10- -1, and delta -5-, -1, behaved like the wild-type TNF; all formed a trimer and released mature TNF. These results suggested that in pro-TNF (1) the number of residues between the base of the trimer and the plasma membrane determines accessibility of the cleavage site to the pro-TNF processing enzyme(s) since small deletions did not block cleavage whereas large ones did regardless of the presence of the native cleavage site (-1/+1), (2) the native cleavage site is not sufficient for releasing mature TNF because mutant delta -20- -6, in which the native cleavage site was intact, was noncleavable, and (3) alternative cleavage site(s) may exist since mutants delta -10- -1 and delta -5- -1, which lack the native cleavage site, were cleavable. PMID- 8679578 TI - Isolation of the human gamma-carboxylase and a gamma-carboxylase-associated protein from factor IX-expressing mammalian cells. AB - A model system for the analysis of intracellular events governing the modification of individual vitamin K-dependent (VKD) proteins by the carboxylase has been developed using recombinant VKD protein-transfected cell lines. When untransfected 293 cells were analyzed by in vitro carboxylation followed by SDS PAGE, endogenous VKD proteins were not detected. With 293 cells stably transfected with recombinant native factor IX, most (> 95%) of the carboxylase was in complex with the factor IX, as assayed by adsorption of carboxylase activity to immobilized anti-factor IX antibody. In contrast, with 293 cells stably-transfected with recombinant factor IX deleted in the propeptide sequence (amino acids -18 to -4, delta pro factor IX), no association of factor IX with the carboxylase was observed. This observation was used to specifically isolate and identify the human carboxylase, and carboxylase-associated protein. When the carboxylase was purified from solubilized microsomes from either native factor IX, or delta pro factor IX, stably-transfected 293 cells, a single 98 kDa band was specifically obtained from native factor IX microsomes, but not from delta pro factor IX microsomes. This band was subsequently shown by Western and microsequencing analysis to comprise both the carboxylase and carboxylase associated protein. This isolation, which represents the first isolation to near homogeneity of both the human carboxylase and the carboxylase from cell lines, will be valuable in isolating enzymatically active recombinant carboxylase, which has been refractile to other purification attempts. This system was also used to show that the human carboxylase in 293 cells is capable of binding and modifying two different liver-derived proteins. Protein C-producing 293 cells were generated from the same 293 progenitor cell line used to created the factor IX expressing cells. With both factor IX- and protein C-transfected 293 cells, the secreted proteins were almost completely carboxylated, and in microsomes from each cell line the carboxylase was found in near quantitative complex with the two different VKD proteins. Thus the carboxylase modifies both VKD proteins. The approach described here for the analysis of the carboxylase from recombinant VKD protein-transfected cell lines should provide an important new system for studying protein carboxylation and VKD protein-carboxylase interaction. PMID- 8679579 TI - Purification and mass spectrometric analysis of ADP-ribosylation factor proteins from Xenopus egg cytosol. AB - The GTP analog GTP gamma S potently inhibits nuclear envelope assembly in cell free Xenopus egg extracts. GTP gamma S does not affect vesicle binding to chromatin but blocks vesicle fusion. Fusion inhibition by GTP gamma S is mediated by a soluble factor, initially named GSF (GTP gamma S-dependent soluble factor). We previously showed that vesicles pretreated with GTP gamma S plus recombinant mammalian ARF1 were inhibited for fusion, suggesting that "GSF activity" was due to the ARF (ADP-ribosylation factor) family of small GTP-binding proteins. To ask if any soluble proteins other than ARF also inhibited vesicle fusion in the pretreatment assay, we purified GSF activity from Xenopus egg cytosol. At all steps in the purification, fractions containing ARF, but no other fractions, showed GSF activity. The purified GSF was identified as Xenopus ARF by immunoblotting and peptide sequence analysis. Reverse phase HPLC and mass spectrometry revealed that GSF contained at least three distinct ARF proteins, all of which copurified through three chromatography steps. The most abundant isoform was identified as ARF1 (62% of the total GSF), because its experimentally determined mass of 20 791 Da matched within experimental error that predicted by the sequence of the Xenopus ARF1 cDNA, which is reported here. The second-most abundant isoform (25% of GSF activity) was identified as ARF3. We concluded that ARF is most likely the only soluble protein that inhibits nuclear vesicle fusion after pretreatment with GTP gamma S. PMID- 8679581 TI - The role of zinc and the reactivity of cysteines in Escherichia coli primase. AB - Primase is the zinc metalloenzyme responsible for synthesizing RNA primers for use during DNA synthesis. To establish whether the zinc played a catalytic or structural role, the zinc was removed and the activity of the apoprimase determined. The zinc was removed with p-(hydroxymercuri)-benzenesulfonate (PMPS), which covalently reacts with cysteine sulfhydryls, EDTA was added to chelate the zinc, DTT was added to remove the PMPS from the apoprimase, and then the apoprimase was separated from the small molecules. The resulting apoprimase was fully active, indicating that the zinc played a structural role but not one involved in thermodynamic folding/unfolding. PMPS and 5,5'-dithiobis(2 nitrobenzoic acid) (DTNB) cysteine reactivities indicated that the cysteines fell into three categories: one or two were fast-reacting, three were zinc-ligating, and two or three were slow or nonreacting. The major distinction between apoprimase and natural primase was that apoprimase became inactivated during storage at 4 degrees C for 10 days. Storage-induced inactivation correlated with disulfide bond formation and could be reversed by incubation with a mild reducing agent. Apoprimase oxidation also prevented zinc reconstitution which was only achieved with freshly-reduced enzyme, indicating that the zinc-ligating cysteines participated in the inactivating disulfide bonds. The conclusion was that, in natural primase, the zinc prevented disulfide bond formation which, in turn, prevented inactivation. The zinc reconstitution studies identified a strong and a weak zinc binding site. Zinc could be prevented from binding to the weak site by the presence of magnesium, indicating that the weak site may be the catalytic magnesium site in which two of the seven cysteines were located. PMID- 8679580 TI - The synthetic/editing active site of an aminoacyl-tRNA synthetase: evidence for binding of thiols in the editing subsite. AB - The active site of methionyl-tRNA synthetase (MetRS) possesses two functions: synthetic, which provides Met-tRNA for protein synthesis, and editing, which rejects inadvertently misactivated homocysteine. During editing, the side chain SH group of homocysteine reacts with its activated carboxyl group forming a cyclic thioester, homocysteine thiolactone. As shown here, the side chain -SH and the activated carboxyl groups do not need to be present on the same molecule for the editing to occur. Thioester formation occurs when a thiol and activated methionine, in the form of Met-tRNA, are incubated with MetRS. Depending on the structure of thiols, methionine thioesters may undergo secondary acyl transfer reactions to cis amino, hydroxy, or carboxyl groups which yield methionine dipeptides, esters, or anhydrides, respectively. At saturating thiol concentrations, formation of some thiol derivatives of methionine is as fast as formation of homocysteine thiolactone. Thiol specificity of the reaction and noncompetitive inhibition by the cognate methionine, as well as structure function studies of active site MetRS mutants, all indicate that there is a specific -SH binding subsite, distinct from the methionine binding subsite, in the synthetic/editing active site of MetRS. PMID- 8679582 TI - The mammalian DNA polymerase delta--proliferating cell nuclear antigen--template primer complex: molecular characterization by direct binding. AB - Three direct assays, polyacrylamide gel electrophoresis-band mobility shift, agarose gel electrophoresis-band mobility shift, and nitrocellulose filter binding, were established to study complexes formed among mammalian DNA polymerase delta (pol delta), proliferating cell nuclear antigen (PCNA), and synthetic oligonucleotide template-primers. In all contexts, complex formation requires simultaneous presence of pol delta, PCNA, and template-primer. Moreover, we showed in one such assay that the complex formed contains each molecular component. Nuclease protection experiments demonstrate that complex formation protects template from degradation by DNase I. The mass determined for the pol delta.PCNA.template-primer complex was about 267 kDa, consistent with the participation of one molecule of pol delta, two or three molecules of PCNA and one molecule of template-primer. PCNA alone behaved as a trimer (mass determined to be about 87 kDa). Complex could be manipulated enzymologically. Measurement of off rates demonstrates directly that PCNA stabilizes the pol delta.template primer complex. PMID- 8679583 TI - A eukaryotic translation initiation factor 2-associated 67 kDa glycoprotein partially reverses protein synthesis inhibition by activated double-stranded RNA dependent protein kinase in intact cells. AB - A eukaryotic translation initiation factor 2 (eIF-2)-associated 67 kDa glycoprotein (p67) protects the eIF-2 alpha-subunit from inhibitory phosphorylation by eIF-2 kinases, and this promotes protein synthesis in the presence of active eIF-2 alpha kinases in vitro [Ray, M. K., et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 539-543]. We have now examined the effect of overexpression of this cellular eIF-2 kinase inhibitor in an in vivo system using transiently transfected COS-l cells. In this system, coexpression of genes that inhibit PKR activity restores translation of plasmid-derived mRNA. We now report the following. (1) Transient transfection of COS-1 cells with a p67 expression vector increased p67 synthesis by 20-fold over endogenous levels in the isolated subpopulation of transfected cells. (2) Cotransfection of p67 cDNA increased translation of plasmid-derived mRNAs. (3) Overexpression of p67 reduced phosphorylation of coexpressed eIF-2 alpha. (4) p67 synthesis was inhibited by cotransfection with an eIF-2 alpha mutant S51D, a mutant that mimics phosphorylated eIF-2 alpha, indicating that p67 cannot bypass translational inhibition mediated by phosphorylation of the eIF-2 alpha-subunit. These results show that the cellular protein p67 can reverse PKR-mediated translational inhibition in intact cells. PMID- 8679584 TI - Identification of functional positive and negative thyroid hormone-responsive elements in the rat apolipoprotein AI promoter. AB - Transcription of the antiatherogenic protein apolipoprotein AI is regulated by the thyroid hormone, L-triiodothyronine. Transient transfection and electrophoretic mobility shift assays were used to identify the cis-acting elements involved. In transient transfection assays, hormone bound to either thyroid hormone receptor alpha or beta exerts a positive effect through a thyroid hormone response element, site A (-208 to -193). In the absence of site A, liganded receptor alpha or beta have a negative effect on promoter activity. This negative effect is mediated by a 40 bp fragment spanning nucleotides -46 to -7. Closer examination of this region of the gene shows there to be a negative thyroid hormone response element at position -25 to -20 which is fused to the 3' end of the TATA element. Electrophoretic mobility shift assays show that bacterially expressed chicken or rat thyroid hormone receptor alpha 1 binds to site A, either as a homodimer or as a heterodimer with the human 9-cis-retinoic acid receptor alpha. In contrast, the negative thyroid hormone responsive element binds chicken thyroid hormone receptor alpha exclusively as a monomer. Site directed mutagenesis of the negative thyroid hormone response element abolished the inhibitory effects of the hormone and increased basal promoter activity by up to 40-fold. These data suggest that functional positive and negative thyroid hormone response elements coexist within the rat apolipoprotein AI promoter and both elements contribute to the control of apolipoprotein AI gene expression. PMID- 8679585 TI - Control of cell membrane ecto-ATPase by oligomerization state: intermolecular cross-linking modulates ATPase activity. AB - The extracellular ATPase (ecto-ATPase) is a divalent cation-dependent nucleoside triphosphatase with an unusually high specific activity. Monoclonal antibodies, described previously [Stout, J. G., Strobel, R. S., & Kirley, T. L. (1995) J. Biol. Chem. 270, 11845-11850], and newly generated polyclonal antibodies, both raised against the chicken gizzard ecto-ATPase, were evaluated for their ability to cross-react with mammalian ecto-ATPases and were used as specific immunochemical probes to identify non-cross-linked and cross-linked ecto-ATPase. Unlike previous results obtained with the rabbit skeletal muscle ecto-ATPase enzyme, cross-linking the chicken gizzard smooth muscle ecto-ATPase with 3,3' dithiobis(sulfosuccinimidylpropionate) (DTSSP) and dithiobis(succinimidylpropionate) (DSP) increased the activity of the enzyme which corresponded to an increase in a approximately 130 kDa immunoreactive band, proposed to be a ecto-ATPase homodimer, and a concomitant decrease in a approximately 66 kDa immunoreactive band, the ecto-ATPase monomer. Ecto-ATPase was immunochemically identified in chicken, rat, mouse, rabbit, and pig. Interestingly, under nonreducing conditions, the ecto-ATPase activity in rat and pig (unlike chicken and rabbit) was evident on Western blots as an immunoreactive band at approximately 200 kDa, proposed to be an intermolecularly disulfide linked ecto-ATPase homotrimer. Nonreducing Western blot analysis of various rat tissues with three different monoclonal antibodies that recognize the 66 kDa chicken gizzard ecto-ATPase monomer strengthened the hypothesis that this 200 kDa band indeed represents the trimeric ecto-ATPase. After reduction, ecto-ATPase monomers were found to be approximately 66 kDa in all species examined. The differences in ecto-ATPase quaternary structure stability may account for the observed species differences in ecto-ATPase enzymatic properties. Intermolecular disulfide bonds appear to be one of the species-specific ways to stabilize the native, active ecto-ATPase quaternary structure (the homotrimer). Based on the data obtained, as well as previous data from this and other laboratories, a hypothesis was developed to explain the modulation of ecto-ATPase activity by a variety of agents, including detergents, chemical cross-linkers, lectins, antibodies, and small molecule inhibitors. It is proposed that agents and conditions stabilizing ecto-ATPase oligomers stimulate enzyme activity, whereas agents and conditions destabilizing ecto-ATPase homooligomers would inhibit the ecto-ATPase. PMID- 8679586 TI - Evidence that casein kinase 2 phosphorylates hepatic microsomal calcium-binding proteins 1 and 2 but not 3. AB - We have extensively purified three of the hepatic microsomal intralumenal Ca2+ binding proteins, CBP1, CBP2, and CBP3, which were originally described by Van et al. [(1989) J. Biol. Chem. 264, 17494-17501]. These apparently homogeneous preparations showed only single 45Ca2+ binding bands. On the basis of the peptide sequence, CBP2 was found to be highly homologous with the previously described protein ERp72. Similarly, CBP3 was identical to calreticulin and CBP1 had some homology to calmodulin. Contrary to the report of Van et al. (1989), we found that CBP2 had little thiol:protein disulfide oxidoreductase activity. Of the three purified preparations, only CBP2 exhibited apparent intrinsic protein kinase activity. This activity was found to be due to contamination of the CBP2 preparation by an extremely low concentration of tightly bound casein kinase 2 (CK2). In line with this observation, the phosphorylation was inhibited by heparin, removed by antibody to CK2, and stimulated by spermine. Furthermore, CBP2 was readily phosphorylated in vitro by added CK2 but only slowly phosphorylated by several other protein kinases. Thus, the persistence of CK2 in a highly purified preparation of CBP2 along with several other lines of evidence presented in this study might suggest that the protein CBP2 is a physiologically relevant substrate for CK2. Furthermore, these data suggest that CK2 might be localized in the lumen of the endoplasmic reticulum and that the phosphorylation of CBP2 in the lumen may play a role in the chaperone activity attributed to this protein. PMID- 8679587 TI - The fourth EF-hand of calmodulin and its helix-loop-helix components: impact on calcium binding and enzyme activation. AB - CaM (4 cTnC) is a calmodulin--cardiac troponin C chimeric protein containing the first, second, and third calcium-binding EF-hands of calmodulin (CaM) and the fourth EF-hand of cardiac troponin C (cTnC) [George, S.E., Su, Z., Fan, D., & Means, A.R. (1993) J. Biol. Chem. 268, 25213-25220]. CaM (4 cTnC) showed 2-fold enhanced carboxy-terminal Ca2+ affinity relative to CaM and also exhibited impaired activation of the CaM-regulated enzymes smooth muscle myosin light chain kinase (smMLCK), neuronal nitric oxide synthase (nNOS), and phosphodiesterase (PDE). To investigate the molecular basis for these effects, we constructed (1) additional chimeras, replacing most of CaM helix 7, Ca2+-binding loop 4, and helix 8 with the corresponding helices and loops of cTnC; and (2) point mutants in the fourth EF-hand of CaM. Replacement of CaM's fourth loop with the corresponding loop of cTnC enhanced Ca2+ affinity by over 3-fold through an increase in the Ca2+ on rate and also reduced cooperativity of Ca2+ binding. In contrast, substitution of CaM helix 7 or 8 modestly decreased Ca2+ affinity by increasing the Ca2+ off rate, without impairment of cooperativity. All three of the helix and loop chimeras fully activated PDE, with minor shifts in Kact. CaM (helix 7 cTnC) showed a significantly impaired ability to activate smMLCK and nNOS, whereas the other two chimeras retained about 80% of the maximal smMLCK and nNOS activation observed with CaM. PMID- 8679588 TI - Evidence for the distinct vanadyl(+4)-dependent activating system for manifesting insulin-like effects. AB - Both exogenously added vanadate (oxidation state +5) and vanadyl (oxidation state +4) mimic the rapid responses of insulin through alternative signaling pathways, not involving insulin receptor activation [reviewed in Shechter et al. (1995) Mol. Cell. Biochem. 153, 39-47]. Vanadium exhibits complex chemistry, fluctuating between vanadate(+5) and vanadyl(+4), according to the prevailing conditions. Using several experimental approaches, we report here on a distinct vanadate(+5) independent, vanadyl(+4)-dependent activating pathway. The key components of this pathway are membrane protein phosphotyrosine phosphatases (PTPases) and a cytosolic (nonreceptor) protein-tyrosine kinase (CytPTK). We further suggest that vanadate(+5) is not reduced rapidly to vanadyl(+4) inside the cell, and entered vanadyl sulfate(+4) is capable of undergoing spontaneous oxidation to vanadate(+5) in vivo. Finally, we show that the promotion and full expression of a downstream bioeffect such as lipogenesis requires both activation of CytPTK and prolonged stability of vanadyl(+4) against oxidation. PMID- 8679590 TI - Crystal structure of ribonuclease T1 carboxymethylated at Glu58 in complex with 2'-GMP. AB - The carboxymethylation of RNase T1 at the gamma-carboxyl group of Glu58 leads to a complete loss of the enzymatic activity while it retains substrate-binding ability. Accompanying the carboxymethylation, RNase T1 undergoes a remarkable thermal stabilization of 9 degrees C in the melting temperature (Tm). In order to clarify the inactivation and stabilization mechanisms of RNase T1 by carboxymethylation, the crystal structure of carboxymethylated RNase T1 (CM-RNase T1) complexed with 2'-GMP was determined at 1.8 A resolution. The structure, including 79 water molecules and two Na+, was refined to an R factor of 0.194 with 10 354 reflections > 1 sigma (F). The carboxyl group of CM-Glu58, which locates in the active site, occupies almost the same position as the phosphate group of 2'-GMP in the crystal structure of intact RNase T1.2'-GMP complex. Therefore, the phosphate group of 2'-GMP cannot locate in the active site but protrudes toward the solvent. This forces 2'-GMP to adopt an anti form, which contrasts with the syn form in the crystal of the intact RNase T1.2'-GMP complex. The inaccessibility of the phosphate group to the active site can account for the lack of the enzymatic activity in CM-RNase T1. One of the carboxyl oxygen atoms of CM-Glu58 forms two hydrogen bonds with the side-chains of Tyr38 and His40. These hydrogen bonds are considered to mainly contribute to the higher thermal stability of CM-RNase T1. Another carboxyl oxygen atoms of CM-Glu58 is situated nearby His40 and Arg77. This may provide additional electrostatic stabilization. PMID- 8679589 TI - Crystallographic complexes of glucoamylase with maltooligosaccharide analogs: relationship of stereochemical distortions at the nonreducing end to the catalytic mechanism. AB - Crystal structures at pH 4 of complexes of glucoamylase from Aspergillus awamori var. X100 with the pseudotetrasaccharides D-gluco-dihydroacarbose and acarbose have been refined to R-factors of 0.147 and 0.131 against data to 1.7- and 2.0-A resolution, respectively. The two inhibitors bind in nearly identical manners, each exhibiting a dual binding mode with respect to the location of the last sugar residues. The reduced affinity of D-gluco-dihydroacarbose (K1 = 10(-8) M) relative to acarbose (K1 = 10(-12) M) may stem in part from the weakening of hydrogen bonds of the catalytic water (Wat 500) to the enzyme. Steric contacts between the nonreducing end of D-gluco-dihydroacarbose and the catalytic water perturb Wat 500 from its site of optimal hydrogen bonding to the active site. Interactions within the active site displace the 6-hydroxymethyl group of the nonreducing end of both acarbose and D-gluco-dihydroacarbose toward a more axial position. In the case of D-gluco-dihydroacarbose the shift in the position of the 6-hydroxymethyl group occurs with a 12 degrees change in two dihedral angles of the glucopyranose ring toward a half-chair conformation. The observed conformational distortion of the first residue of D-gluco-dihydroacarbose is consistent with the generation of a glucopyranosyl cation in the transition state. Comparable distortions of stereochemistry in model compounds require approximately 2 kcal/mol, not more than 25% of the energy necessary to form the half-chair conformation in glucose. The magnitude of stereochemical distortion observed in the active site of glucoamylase suggests that favorable electrostatic interactions between the putative glucopyranosyl cation intermediate and the active site must be more important in stabilizing the transition state than mechanical distortion of the substrate. PMID- 8679591 TI - Conformational constraints on the headgroup and sn-2 chain of bilayer DMPC from NMR dipolar couplings. AB - This paper presents new NMR constraints on the conformation of the headgroup, glycerol backbone, and sn-2 chain of 1,2-dimyristoyl-sn-glycero-3 phosphatidylcholine (DMPC) in the liquid-crystalline bilayer. Using two dimensional 13C-1H chemical shift correlation spectroscopy, we find significant dipolar couplings between the carboxyl carbon CO2 and the headgroup protons. This indicates that a conformation in which the DMPC headgroup and the beginning of the sn-2 chain bend toward each other is significantly populated in the fluid bilayer. The predominance of this headgroup orientation can be further confirmed by 31P-13C dipolar couplings from the literature, which constrain the glycerol G2 G3 torsion angle to be close to trans, excluding a significant presence of one of the two conformations found in the DMPC crystal. Combining and reexamining 20 known NMR couplings for the glycerol backbone and its adjacent segments of L alpha-DMPC, we find that several torsion angles and bond orientations in the core of the DMPC molecule are constrained severely and must differ from those in the crystal structure. We propose a consistent molecular model for phosphocholine lipids in the liquid-crystalline phase, with a rigid backbone in the core of the molecule, a bent-back headgroup, and increasing mobility toward the ends of the acyl chains and the headgroup. PMID- 8679592 TI - On the reactivity and ionization of the active site cysteine residues of Escherichia coli thioredoxin. AB - Within various proteins of the thioredoxin family, the stability of the disulfide bond formed reversibly between the two active site cysteine residues, one accessible and one buried, varies widely and is directly correlated with the pKa value of the accessible cysteine thiol group. If applicable to thioredoxin, its stable disulfide bond would imply that its accessible thiol group should have a high pKa value, whereas it has long been considered to be about 6.7, largely on the basis of the pH dependence of its reactivity. Such kinetic data are shown to be inconsistent with known pKa values in this case; the rate constants may reflect effects in the transition state for the reaction, which is catalyzed by thioredoxin, rather than the protein itself. Ionization of the thioredoxin thiol groups was measured indirectly by the pH dependence of the equilibrium constant for their reaction with glutathione and directly by detection of the thiolate anion by its UV absorbance. Both observations indicated that both cysteine thiol groups of thioredoxin ionize with apparent pKa values in the region of 9-10 and that their ionization is not linked strongly to that of any other groups. This conclusion is not incompatible with the other data available and would make thioredoxin consistent with the relationship between thiol group ionization and disulfide stability observed in other members of the thioredoxin family. PMID- 8679593 TI - Helical and reverse turn changes in the BR->N transition of bacteriorhodopsin. AB - Fourier transform infrared deconvoluted spectra of bacteriorhodopsin and the N intermediate were compared with the N/BR infrared difference spectrum. In the amide I, clear changes in the bands at 1666 cm-1, assigned to alpha II helices, 1659 cm-1, assigned to alpha I and alpha II helices, and 1652 cm-1, assigned to both alpha I helices and unordered structures, were found. These changes could arise from conversion of some alpha II and alpha I helices. Variations in the bands at 1692 and 1683 cm-1, corresponding to reverse turns, were also detected. The side chains of Tyr (band at 1517 cm-1) and Phe (band at 1498 cm-1) were found to change in going from BR to N. In the carboxylate region, no band was detected at 1737 cm-1 in the deconvoluted spectra that could correspond to the peak observed in the difference spectrum. It is argued that resolution-enhancement methods used along with difference spectra provide more detailed insights into the conformational changes occurring between photocycle intermediates. PMID- 8679594 TI - Shift of the special pair redox potential: electrostatic energy computations of mutants of the reaction center from Rhodobacter sphaeroides. AB - Shifts of the special pair redox potential of the photosynthetic reaction center of Rhodobacter sphaeroides are considered for several point mutations [Lin. X., Murchison, H. A., Nagarijan, V., Parson, W. W., Allen, J. P., & Williams, J. C. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 10265-10269] in the neighborhood of the special pair. The shifts are calculated from electrostatic energies by solving Poisson's equation for energy-minimized structures of the reaction center. Different conditions for the evaluation of the electrostatic energy are probed. To test the influence of the hydrogen bonding at the acetyl groups of the special pair, the orientation and torsion potential of the acetyl groups are varied. The calculated shifts of the midpoint potential of double and triple mutants can approximately be obtained from the corresponding shifts of the single point mutations. The calculated shifts agree with the measured values for all single and double mutants considered. However, a clear decision between different acetyl group conformations was only possible for the mutants HF(L168) and HF(L168) + LH(L131) where the calculated shifts of the redox potential agree with experiments only if the acetyl oxygen atom at DM points toward the Mg2+ ion of DL. This is corroborated by computations of the interaction energy of the acetyl group at DM, which adopts a lower value in the wild-type reaction center if its oxygen atom is bonded to the Mg2+ ion of DL. PMID- 8679595 TI - Spectroscopic states of the CO oxidation/CO2 reduction active site of carbon monoxide dehydrogenase and mechanistic implications. AB - CO dehydrogenases catalyze the reversible oxidation of CO to CO2, at an active site (called the C-cluster) composed of an Fe4S4 cube with what appears to be a 5 coordinate Fe (called FCII), linked to a Ni (Hu, Z., Spangler, N. J., Anderson, M. E., Xia, J., Ludden, P. W., Lindahl, P. A., & Munck, E. (1996) J. Am. Chem. Soc. 118, 830-845). During catalysis, electrons are transferred from the C cluster to an [Fe4S4]2+/1+ electron-transfer cluster called the B-cluster. An S = 1/2 form of the C-cluster (called Cred1) converts to another S = 1/2 form (called Cred2) upon reduction with CO, at a rate well within the turnover frequency of the enzyme (Kumar, M., Lu, W.-P., Liu, L., & Ragsdale, S. W. (1993) J. Am. Chem. Soc. 115, 11646-11647). This suggests that the conversion is part of the catalytic mechanism. Dithionite is reported in this paper to effect this conversion as well, but at a much slower rate (kso = 5.3 x 10(-2) M-1 s-1 for dithionite vs 4.4 x 10(6) M-1 s-1 for CO). By contrast, dithionite reduces the oxidized B-cluster much faster, possibly within the turnover frequency of the enzyme. Dithionite apparently effects the Cred1/Cred2 conversion directly, rather than through an intermediate. The conversion rate varies with dithionite concentration. The Cred1/Cred2 conversion occurs at least 10(2) times faster in the presence of CO2 than in its absence. CO2 alters the g values of the gav = 1.82 signal, indicating that CO2 binds to a C-cluster-sensitive site at mild potentials. CN- inhibits CO oxidation by binding to FCII (Hu et al., 1996), and CO, CO2 in the presence of dithionite, or CS2 in dithionite accelerate CN- dissociation from this site (Anderson, M. E., & Lindahl, P. A. (1994) Biochemistry 33, 8702-8711). The effect of CO, CO2, and CS2 on CN- dissociation suggested that these molecules bind at a site (called the modulator) other than that to which CN- binds. The effects of CO2, CS2, CO, and dithionite on the Cred1/Cred2 conversion rate followed a similar pattern, suggesting that this rate is also influenced by modulator binding. Some batches of enzyme cannot convert to the Cred2 form using dithionite, but pretreatment with CO or CO2/dithionite effectively "cures" such batches of this disability. The results presented suggest that the Ni of the C-cluster is the modulator and the substrate binding site for CO/CO2. The inhibitor CS2 in the presence of dithionite also accelerates the decline of Cred1, leading first to an EPR-silent state of the C-cluster, and eventually to a state yielding an EPR signal with gav = 1.66. CS2 binding thus shares some resemblance to CO2 binding. Approximately 90% of the absorbance changes at 420 nm that occur when oxidized CODHCt is reduced by dithionite occur within 2 min at 10 degrees C. This absorbance change occurs in concert with the gav = 1.94 signal development. The remaining 10% of the A420 changes occur over the course of approximately 50 min, apparently coincident with the Cred1/Cred2 conversion. One possibility is that the conversion involves reduction of an (unidentified) Fe-S cluster. A three-state model of catalysis is proposed in which Cred1 binds and oxidizes CO, Cred2 is two electrons more reduced than Cred1 and is the state that binds and reduces CO2, and Cint is a one-electron-reduced state that is proposed to exist because of constraints imposed by the nature of the CO/CO2 reaction and the properties of the clusters involved in catalysis. PMID- 8679596 TI - Inactivation of ribonucleotide reductase by (E)-2'-fluoromethylene-2' deoxycytidine 5'-diphosphate: a paradigm for nucleotide mechanism-based inhibitors. AB - Ribonucleotide reductase (RDPR) from Escherichia coli catalyzes the conversion of nucleotides to deoxynucleotides and is composed of two homodimeric subunits: R1 and R2. (E)- and (Z)-2'-fluoromethylene-2'-deoxycytidine 5'-diphosphate (FMCDP) are time dependent inactivators of this protein, with approximately 1.5 equiv being sufficient for complete loss of catalytic activity. Inactivation results from loss of the essential tyrosyl radical on R2 and alkylation of R1. Studies using electron spin resonance spectroscopy reveal that tyrosyl radical loss is accompanied by formation of a new, substrate-based radical. Experiments using [6' 14C]-(E)-FMCDP and [5-3H]-(E)-FMCDP reveal that alkylation of R1 is accompanied by release of 0.5 equiv of cytosine and 1.4 equiv of fluoride ion. When R1 is denatured subsequent to inactivation, approximately 1 equiv of label per R1 is observed only in studies carried out with [14C]FMCDP. Under these same conditions with [3H]FMCDP, 1.5 equiv of radiolabel is detected as cytosine. Inactivation of R1 thus results from alkylation by the sugar moiety of FMCDP. While studies to isolate the alkylated amino acid on R1 were unsuccessful, studies using a variety of site-directed mutants of R1 (C462S, C225S, C754/759S, C439S, and E441Q) indicate that E441 or possibly C439 is the modified residue. Inactivation is accompanied by rapid formation of a new chromophore with a lambda max at 334 nm. Dithiothreitol does not protect the enzyme against inactivation by FMCDP, although it does prevent chromophore formation. Two possible mechanisms are proposed to accommodate these experimental observations. PMID- 8679597 TI - Tryptophan luminescence as a probe of enzyme conformation along the O acetylserine sulfhydrylase reaction pathway. AB - O-Acetylserine sulfhydrylase A (OASS-A) is a pyridoxal 5'-phosphate- (PLP-) dependent enzyme that catalyzes the last step in the synthesis of L-cysteine, the beta-replacement of acetate in O-acetyl-L-serine (OAS) by sulfide. The phosphorescence properties of the two tryptophans of wild-type OASS-A, W51 and W162, and of W162 in the W51Y mutant protein have been characterized over the temperature range 170-273 K. In glasses at 170 K, the apoenzyme exhibits a phosphorescence spectrum which is the superposition of two spectra with well resolved 0,0 vibronic bands centered at 405 and 410 nm, the blue lambda max suggesting that one of the two Trp residues in OASS-A is in a polar pocket, while the other is in a relatively hydrophobic pocket. The presence of PLP in the OASS A holoenzyme reduces the intrinsic fluorescence by 40-45%, but the spectrum is unaltered except for the appearance of the internal Schiff base ketoenamine fluorescence band centered at 484 nm. The phosphorescence is strongly quenched by PLP, with about 70% reduction in intensity and lifetime. Further, the phosphorescence spectrum of the holoprotein exhibits a single and narrow 0,0 vibronic band centered at 405 nm and a broad band in the 450-550-nm range resulting from delayed fluorescence of the ketoenamine tautomer of the internal Schiff base, sensitized by triplet-singlet energy transfer from tryptophan to the ketoenamine tautomer of PLP. Comparison with data obtained for the W51Y mutant strongly suggests that the 405-nm phosphorescence band derives from W162, and that W51 in the wild type is entirely quenched either by singlet or triplet energy transfer to PLP or by some local group in the protein. From the rate of energy transfer, the separation between W162 and PLP is estimated to be about 25 A. Substrates other than OAS affect only the intensity of the coenzyme fluorescence band (484 nm) and the intensity of delayed fluorescence relative to that of phosphorescence, effects that are attributable to changes in fluorescence quantum yield of the ketoenamine chromophore. Addition of OAS, on the other hand, leads to a splitting of the 0,0 vibronic band in the phosphorescence spectrum of W162, yielding poorly resolved peaks at 406 and 408.5 nm, indicating thereby a change in the environment of the tryptophan residue and therefore in the conformation of the macromolecule as the internal Schiff base is converted to the alpha-aminoacrylate Schiff base. In buffer at 273 K, both the fluorescence and phosphorescence spectra relax to longer wavelengths and the phosphorescence lifetime is reduced to a few milliseconds, all indications that W162 is in a flexible region of the macromolecule, probably in close proximity to the aqueous interface. The phosphorescence lifetime in fluid medium reveals conformational heterogeneity in OASS-A and unveils important structure modulating effects of cofactor, substrates, and pH. Binding of PLP to the apoprotein increases the rigidity of the polypeptide in the region of W162 (in agreement with the greater thermal stability of the holoprotein), while OAS and L-serine have an opposite effect. Increasing the pH from 6.5 to 9 results in a 1.7-fold increase in tau av and a change in the relative amplitudes of the two lifetime components. Since the phosphorescence originates from a single tryptophan residue, the two tau components reflect distinct conformations of the subunit. In this case the conformational equilibrium (slow on the phosphorescence time scale) is governed by one or more groups in the protein with a pK around 8. PMID- 8679598 TI - Biosynthesis of the unusual amino acid (4R)-4-[(E)-2-butenyl]-4-methyl-L threonine of cyclosporin A: enzymatic analysis of the reaction sequence including identification of the methylation precursor in a polyketide pathway. AB - 3(R)-Hydroxy-4(R)-methyl-6(E)-octenoic acid, the C9-backbone of the unusual amino acid (4R)-4-[(E)-2-butenyl]-4-methyl-L-threonine (Bmt), is biosynthesized as a coenzyme A thioester from acetyl-CoA, malonyl-CoA, NADPH, and S adenosylmethionine via a polyketide pathway. Here we present detailed enzymatic studies about the basic assembly process. After attachment of the activated building units to Bmt polyketide synthase the intermediates remained enzyme-bound throughout the cycle. Premature cutoff of biosynthesis led to the release of the intermediates from the enzyme, either as coenzyme A thioesters or, in the case of reactive C8-intermediates, as lactones. Enzyme-bound 3-oxo-4-hexenoic acid, the condensation product of the second elongation cycle, could be identified as the exclusive substrate for the introduction of the methyl group. Part of the biosynthesis including the first elongation cycle, the second condensation reaction, and the methylation step was shown to follow a processive mechanism. All activated intermediates of this processive part could be introduced into the correct pathway at the respective steps, whereas 2-methyl-3-oxo-4-hexenoyl-CoA and all following methylated intermediates were not able to enter the cycle any more. Obviously, the region of Bmt polyketide synthase responsible for this latter part of the biosynthetic pathway is inaccessible for externally supplied coenzyme A thioesters. Butyryl-CoA was recognized by Bmt polyketide synthase with an efficiency comparable to that of crotonyl-CoA and processed to 3-hydroxy-4 methyloctanoyl-CoA, the saturated analog of the natural basic assembly product, indicating a relaxed specificity of Bmt polyketide synthase with respect to the starter unit. PMID- 8679599 TI - Direct measurement of excitation transfer in the protein complex of bacterial luciferase hydroxyflavin and the associated yellow fluorescence proteins from Vibrio fischeri Y1. AB - Time-resolved fluorescence was used to directly measure the energy transfer rate constant in the protein-protein complex involved in the yellow bioluminescence of Vibrio fischeri, strain Y1. In this reaction the putative donor is the fluorescent transient intermediate, luciferase hydroxyflavin, which exhibits a major fluorescence lifetime of the bound flavin of 10 ns. On addition of the acceptor, the V. fischeri yellow fluorescence protein containing either FMN or riboflavin as ligand, a rapid decay time, 0.25 ns, becomes predominant. The same results are observed using rec-luciferase from Photobacterium leiognathi to produce the donor. Because of favorable spectral separation in this system, this rapid decay rate of 4 ns-1, can be directly equated to the energy transfer rate. This rate is ten times higher than the rate previously observed in the Photobacterium luciferase hydroxyflavin-lumazine protein, donor-acceptor system, derived from emission anisotropy measurements. This ten-times ratio is close to the ratio of spectral overlaps of the donor fluorescence with the acceptor absorption, between these two systems, so it is concluded that the topology of the protein complexes in both cases, must be very similar. Energy transfer is also monitored by the loss of steady-state fluorescence intensity at 460 nm of the donor, on addition of the acceptor protein. A fluorescence titration indicates that luciferase hydroxyflavin and the yellow protein complex with a 1:1 stoichiometry with a Kd of 0.7 microM (0 degree C). These parameters account for the bioluminescence spectral shifting effects observed in these reactions. PMID- 8679600 TI - Estimation of the distance change between cysteine-457 and the nucleotide binding site when sodium pump changes conformation from E1 to E2 by fluorescence energy transfer measurements. AB - The first indication of the size of a conformational change implicated in ion transport by sodium pump has been obtained by measuring the change in efficiency of fluorescence energy transfer between two specific locations on the alpha subunit. The donor (5'-(iodoacetamido)fluorescein) attaches covalently to cysteine-457, and the acceptor (2'(or 3')-O-(trinitrophenyl)adenosine 5' triphosphate) binds reversibly to the active site. The acceptor binds nearly 2 orders of magnitude tighter to the Na+ than to the K+ conformation of the enzyme and quenches donor fluorescence more efficiently in the Na+ than in the K+ conformation. The estimated distance between donor and acceptor, assuming random orientation of their emission and absorption dipoles, increases 2.9 +/- 0.6 A when the enzyme changes from the Na+ to the K+ conformation. Stopped-flow measurements of the change in fluorescence energy transfer efficiency with time when the doubly-labeled pump is mixed with Na+ or K+ demonstrate that the donor/acceptor pair reports the change between the E1 and E2 conformations of unphosphorylated enzyme. The observed first-order rate constant for the change in energy transfer efficiency depends sigmoidally on [K+] and inversely on [Na+], and both rate and amplitude data for the change in energy transfer efficiency can be fit with the same values of the rate and ion-dissociation constants as published data for the conformational change between E1 and E2 obtained by singly labeling the enzyme with fluorophores that report changes in protein microenvironment. The prerequisite for successfully measuring the distance change and equating the protein rearrangement with a step in the catalysis-transport cycle is that the donor by itself does not report the conformational change. PMID- 8679601 TI - Simultaneous detection of multiple nucleic acid targets in a homogeneous format. AB - The acridinium ester 4-(2-succinimidyloxycarbonylethyl)phenyl-10-methylacridinium 9-carboxylate trifluoromethane sulfonate (AE), which reacts rapidly with alkaline hydrogen peroxide to produce light, has been used as a detection label in a number of assay procedures, including nucleic acid probe-based systems [Nelson et al. (1995) in Nonisotopic Probing, Blotting and Sequencing (Kricka, L. J., Ed.) pp 391-428, Academic Press, Inc., San Diego, CA]. We have synthesized a number of derivatives of this AE and characterized their chemiluminescent properties. These derivatives display significant differences in the kinetics of the chemiluminescence reaction as well as optimal pH for light production. These differences allow two or more derivatives to be simultaneously detected and quantitated in a single reaction vessel. Several of these derivatives have been covalently linked to nucleic acid probe molecules and have been further characterized in regard to chemiluminescence properties as well as hydrolysis of the ester bond in both single- and double-stranded conformations. On the basis of these properties, homogeneous assay formats utilizing DNA probes labeled with various AE derivatives were developed. Simultaneous detection and quantitation of Chlamydia trachomatis and Neisseria gonorrhoeae, the gag and pol regions of HIV, and wild-type and mutant HIV sequences was achieved with high sensitivity and discrimination. PMID- 8679602 TI - Base-catalysis of imino proton exchange in DNA: effects of catalyst upon DNA structure and dynamics. AB - Characterization of the kinetics and energetics of base-pair opening in nucleic acids relies upon measurements of the rates of exchange of imino protons with water protons at high concentrations of the exchange catalyst. Under these conditions, the exchange catalyst may affect structural or dynamic properties of the nucleic acid molecule and thus, limit the significance of the exchange data. To address this problem, we have used NMR spectroscopy to characterize the effects of a catalyst of imino proton exchange, namely, ammonia upon the structure and dynamics of the self-complementary DNA dodecamer [d(CGCAGATCTGCG)]2. The changes in structure were monitored in proton NOESY and DQF-COSY experiments and in phosphorus spectra at 15 degrees C and at ammonia concentrations ranging from 0.002 to 0.5 M. The results indicate that ammonia induces subtle changes in the solution conformation of the dodecamer, but the overall structure is maintained close to the B-type DNA structure. However, the relaxation rates (i.e., transverse, longitudinal, and cross-relaxation rates) of several non-exchangeable protons were found to increase by approximately 50% upon changing ammonia concentration from 0.002 to 0.5 M. The increases were comparable for all protons investigated suggesting that they originate from an ammonia induced increase in the overall correlation time of the DNA dodecamer. Numerical analysis revealed that the catalyst-induced enhancements in proton relaxation can alter significantly the calculated values of the exchange rates of imino protons, especially those obtained from measurements of the line widths of these proton resonances. PMID- 8679603 TI - Transbilayer transport of ions and lipids coupled with mastoparan X translocation. AB - The transbilayer movement of ions and lipids induced by mastoparan X, a peptidic toxin from Vespa xanthoptera, was investigated by use of lipid vesicles as a model membrane system. Negatively charged phosphatidylglycerol remarkably enhanced the peptide-lipid interactions. Mastoparan X induced the ion flow by forming a short-lived, multimeric pore in the lipid bilayer, as determined from the leakage of an anionic dye, calcein, from the liposomes. The pore formation was coupled with the translocation of the peptide into the inner leaflet. The latter was detected by three experiments using fluorescence techniques [Matsuzaki, K., Murase, O., Fujii, N., & Miyajima, K. (1995) Biochemistry 34, 6521-6526; Matsuzaki, K., Murase, O., & Miyajima, K. (1995) Biochemistry 34, 12553-12559]. The lipid flip flop was monitored on the basis of the chemical quenching of 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-labeled lipids by sodium dithionite. Mastoparan X triggered the rapid flip-flop of both negatively charged and zwitterionic lipids in coupling with the pore formation and the peptide translocation. A novel model of the mastoparan-lipid interactions was proposed to explain these observations. PMID- 8679604 TI - Folding nuclei of the scFv fragment of an antibody. AB - The folding kinetics of the variable domains of the phosphorylcholine-binding antibody McPC603, combined into a scFv fragment [VH-(Gly4Ser)3-VL], were investigated by the use of fluorescence spectroscopy, nuclear magnetic resonance (NMR), and mass spectrometry (MS). All three methods gave evidence for the occurrence of a major kinetic intermediate during the refolding of the denatured, oxidized scFv fragment. This intermediate is formed within the first 30 s of folding and comprises exchange-protected amide protons of hydrophobic and aromatic amino acids, most of which are localized within the inner beta-sheet of the V(L) domain. In the subsequent slow step, most of the amide protons become protected with rate constants that are very similar for residues of both domains. These data are in agreement with the MS results, which indicate a cooperative folding event from the intermediate to the native state of the scFv fragment. PMID- 8679605 TI - Human 25-hydroxyvitamin D3-24-hydroxylase, a multicatalytic enzyme. AB - Human 25-hydroxyvitamin D-24-hydroxylase has been expressed in Spodoptera frugiperda (Sf21) insect cells using the previously cloned cDNA in baculovirus (AcNPV-P450cc24). The activity of recombinant h-P450cc24 required adrenodoxin, adrenodoxin reductase, and NADPH. Incubation of this reconstituted system with 25 OH-[26,27-(3)H]D3 substrate produced several metabolites that were resolved on a normal-phase cyano HPLC system. These products exactly comigrated with authentic standards for 24-oxo-25-OH-D3, 23(S),25-(OH)2D3, 24(R),25-(OH)2D3, and 24-oxo 23(S),25-(OH)2D3. The soluble proteins from Sf21 cells infected with wild-type baculovirus produced neither 24,25-(OH)2D3 nor any of the other 25-OH-D3 metabolites. The products were isolated and subjected to a normal-phase amino HPLC for further separation, purification, and characterization. Comigration on two HPLC systems, periodate cleavage reactions, and NaBH4 reduction established clearly the identity of these metabolites. Incubation of recombinant h-P450cc24 with 25-OH-[3 alpha-3H]D3 led to the isolation of an additional product that comigrated with 24,25,26,27-tetranor-23-OH-D3. Treatment of putative 24,25,26,27 tetranor-23-OH-[3 alpha-3H]D3 with acetic anhydride changed its migration on amino HPLC to a less polar position, indicating acetylation of a hydroxyl group(s). These data demonstrate conclusively that h-P450cc24 is a multicatalytic enzyme catalyzing most, if not all, of the reactions in the C-24/C-23 pathway of 25-OH-D3 metabolism. It is likely that this enzyme by itself converts 25-OH-D3 and 1,25-(OH)2D3 to one of its final excretion products. PMID- 8679606 TI - Isoprenylation/methylation of proteins enhances membrane association by a hydrophobic mechanism. PMID- 8679607 TI - Calcium modulation of bovine photoreceptor guanylate cyclase. AB - Bovine photoreceptor guanylate cyclase (ROS-GC) consists of a single transmembrane polypeptide chain with extracellular and intracellular domains. In contrast to non-photoreceptor guanylate cyclases (GCs) which are activated by hormone peptides, ROS-GC is modulated in low Ca2+ by calmodulin-like Ca(2+) binding proteins termed GCAPs (guanylate cyclase-activating proteins). In this communication we show that, like the native system, ROS-GC expressed in COS cells is activated 4-6-fold by recombinant GCAP1 at 10 nM Ca2+ and that the reconstituted system is inhibited at physiological levels of Ca2+ (1 microM). A mutant ROS-GC in which the extracellular domain was deleted was stimulated by GCAP1 indistinguishable from native ROS-GC indicating that this domain is not involved in Ca2+ modulation. Deletion of the intracellular kinase-like domain diminished the stimulation by GCAP1, indicating that this domain is at least in part involved in Ca2+ modulation. Replacement of the catalytic domain in a non photoreceptor GC by the catalytic domain of ROS-GC yielded a chimeric GC that was sensitive to ANF/ATP and to a lesser extent to GCAP1. The results establish that GCAP1 acts at an intracellular domain, suggesting a mechanism of photoreceptor GC stimulation fundamentally distinct from hormone peptide stimulation of other cyclase receptors. PMID- 8679608 TI - Mitochondrial ADP/ATP carrier can be reversibly converted into a large channel by Ca2+. AB - Single-channel current measurements of excised patches with reconstituted purified mitochondrial ADP/ATP carrier (AAC) indicates the presence of a large low cation selective (PK+/PCl- = 4.3 +/- 0.6) channel. The channel conductance has multiple sublevels and varies from 300 to 600 pS. It has low probability of current fluctuations at Vhold up to 80-100 mV of both signs and is reversibly gated at Vhold > 150 mV. The opening of the channel is Ca(2+)-dependent (1 mM Ca2+) and can be reversibly closed on removal of Ca2+. It is strongly pH dependent and closes completely at pHex 5.2. The AAC-specific inhibitor bongkrekate inhibits the channel partially and completely in combination with ADP, whereas carboxyatractylate did not affect the conductance. The effects of these AAC-specific ligands prove that the channel activity belongs to AAC. The AAC-linked conductance can clearly be differentiated from the porin channel, rarely detected in our preparations. The properties of the AAC-linked channel coincide with the mitochondrial permeability transition pore (MTP), which is also affected by the AAC ligands [Hunter, D. R., & Haworth, R. A. (1979) Arch. Biochem. Biophys. 195, 453-459] and resembles the mitochondrial "multiconductance channel" [Kinnally, K. W., Campo, M. L., & Tedeschi, H. T. (1989) J. Bioenerg. Biomembr. 21, 497-506] or "megachannel" [Petronilli, V., Szabo, I., & Zoratti, M. (1989) FEBS Lett. 259, 137-143]. Therefore we conclude that the AAC, when converted into a large unselective channel, is a key component in the MTP and thus is involved in the ischemia-reperfusion damage and cytosolic Ca2+ oscillations. The channel opening in AAC is proposed to be caused by binding of Ca2+ to the cardiolipin, tightly bound to AAC, thus releasing positive charges within the AAC which open the gate. PMID- 8679609 TI - RNA hydration: a detailed look. AB - The crystal structure of the RNA duplex [r(CCCCGGGG)]2 has been refined to 1.46 A resolution with room temperature synchrotron diffraction data. This represents the highest resolution reported to date for an all-RNA oligonucleotide and is well beyond the best resolution ever achieved with an A-form DNA duplex. The analysis of the ordered hydration around the octamer duplex reveals conserved regular arrangements of water molecules in both grooves. In the major groove, all located first shell water molecules can be fitted into a pattern that is repeated through all eight base pairs, involves half the phosphate oxygens, and joins the two strands. In the minor groove, roughly across its narrowest dimension, tandem water molecules link the 2'-hydroxyl groups of adjacent nucleotides in base-pair steps in a similarly regular fashion. The structure provides evidence for an important role of the 2'-hydroxyl groups in the thermodynamic stabilization of RNA, beyond their known functions of locking the sugar pucker and mediating 3' - > 5' intrastrand O2'...O4' hydrogen bonds. The ribose 2'-hydroxyls lay the foundation for the enthalpic stability of the RNA relative to the DNA duplex, both as a scaffold for the water network in the minor groove and through their extensive individual hydration. PMID- 8679610 TI - Mechanism of heparin activation of antithrombin. Evidence for reactive center loop preinsertion with expulsion upon heparin binding. AB - A heparin-induced conformational change is required to convert antithrombin from a slow to a fast inhibitor of factor Xa. It has been proposed [van Boeckel et al. (1994) Nat. Struct. Biol. 1, 423-425] that the reactive center residue P14 is inserted into beta-sheet A in native antithrombin and is displaced from the beta sheet by heparin binding, thereby altering the conformation of the reactive center and making it a better target for factor Xa binding. To test this hypothesis, we have characterized a P14 serine --> tryptophan antithrombin variant. From changes in tryptophan fluorescence upon heparin binding, increased affinity for heparin, and partial activation of the variant against factor Xa, we conclude that the proposed mechanism of heparin activation is correct with respect to loop expulsion and that it may consequently be possible to create more highly activated antithrombin variants through suitable hinge region substitutions. PMID- 8679611 TI - A resonance Raman study of the C=N configurations of octopus rhodopsin, bathorhodopsin, and isorhodopsin. AB - The resonance Raman spectra of octopus rhodopsin, bathorhodopsin, and isorhodopsin at 120 K have been obtained as well as those of pigments regenerated with isotopically labeled retinals near the C14-C15 bond. Deuteration of the Schiff base nitrogen induces relatively large changes in the C-C stretch region between 1100 and 1300 cm-1, including a large frequency shift of the C14-C15 stretch mode located at 1206-1227 cm-1 in the three octopus species, as revealed by the Raman spectra of their 14,15-(13)C2 derivatives. Such results are different compared to those of the bovine pigments, in which no significant frequency shift of the C14-C15 stretch mode was observed upon Schiff base N deuteration. In an earlier Raman study of a Schiff base model compound which contained only one single bond adjacent to two double bonds, we have found that the stretch mode of this C-C single bond at 1232 cm-1 shifts up by 15 cm-1 and its intensity is also greatly reduced upon Schiff base N deuteration when the C=N configuration is anti [Deng et al., (1994) J. Phys. Chem. 98, 4776-4779]. The same study has also shown that when the C=N configuration is syn, the C-C stretch mode should be at about 1150 cm-1. Since the C14-C15 stretch mode frequency is relatively high in the spectra of octopus rhodopsin and bathorhodopsin (> 1200 cm 1) and since the normal mode pattern near the Schiff base is similar to the model, we suggest that the C=N configuration in these two species is anti. The different responses of the C14-C15 stretch mode to the Schiff base nitrogen deuteration in bovine and octopus pigments are due to the fact that the coupled C14-C15 stretch and the C12-C13 stretch motions in the model compound or in bovine rhodopsin are altered in octopus rhodopsin so that the stretch motion of the C14-15 bond is more localized, similar to the C-C stretch motion in the small Schiff base model compound. In clear contrast with the bovine rhodopsin Raman spectrum, which is very similar to that for the 11-cis-retinal Schiff base, the drastically different octopus rhodopsin spectrum indicates large protein perturbations on the C11=C12-C13 moiety, either by steric or by electrostatic interactions. Further studies are required to determine if such spectral differences indicate a difference of the energy conversion mechanism in the primary photochemical event of these two pigments. PMID- 8679612 TI - Selenite incubated with NADPH and mammalian thioredoxin reductase yields selenide, which inhibits lipoxygenase and changes the electron spin resonance spectrum of the active site iron. AB - Selenite and selenodiglutathione (GS-Se-SG) efficiently inhibited 5-lipoxygenase activity in sonicates of human monoclonal B-lymphocytes. The apparent IC50 of GS Se-SG was 0.5 microM. The inhibitory effect of these compounds was observed within 10 min of incubation. In order to elucidate if the mechanism of inhibition by these compounds was result of direct interference with lipoxygenase or indirectly mediated by cellular factors, pure 15-lipoxygenase from soybeans was used as a model system for enzyme assays and electron spin resonance (ESR) measurements. Incubation of 15-lipoxygenase with a mixture of human placenta thioredoxin reductase (TR) or calf-thymus TR, selenite, and NADPH blocked the activity of the enzyme. Neither TR and NADPH nor selenite inhibited soybean lipoxygenase when incubated separately. These results suggest that selenite must be reduced to selenide in order to inhibit 5- and 15-lipoxygenase activities. Preincubation anaerobically of 15-lipoxygenase with chemically generated selenide (6 microM) resulted in a strong inhibition of activity, in assays with arachidonic acid in the presence of oxygen. In contrast, selenide exposed to air prior to preincubation did not inhibit the enzyme. Since selenide is known to be efficiently oxidized by oxygen and to form elemental selenium the results evidence that selenide was the inhibitor of lipoxygenase activity in the anaerobic preincubations. After incubation with TR, NADPH, and selenite or with chemically generated selenide, the ESR spectrum of 15-lipoxygenase changed: the dominant axial component with a peak at g = 6.1 decreased, and a rhombic form with a feature at g = 4.28 grew. The results suggest that selenide produced by the reduction of selenite reduces the active site iron to the ESR invisible state and changes the ligation geometry of the oxidized form. PMID- 8679613 TI - Transforming growth factor beta 1: three-dimensional structure in solution and comparison with the X-ray structure of transforming growth factor beta 2. AB - The three-dimensional solution structure of human transforming growth factor beta 1 (TGF-beta 1) has been determined using multinuclear magnetic resonance spectroscopy and a hybrid distance geometry/ simulated annealing algorithm. It represents one of the first examples of a mammalian protein structure that has been solved by isotopic labeling of the protein in a eukaryotic cell line and multinuclear NMR spectroscopy. The solution structure of the 25 kDa disulfide linked TGF-beta 1 homodimer was calculated from over 3200 distance and dihedral angle restraints. The final ensemble of 33 accepted structures had no NOE or dihedral angle violations greater than 0.30 A and 5.0 degrees, respectively. The RMSD of backbone atoms for the ensemble of 33 structures relative to their mean structure was 1.1 A when all residues were used in the alignment and 0.7 A when loop regions were omitted. The solution structure of TGF-beta 1 follows two independently determined crystal structures of TGF-beta 2 (Daopin et al., 1992, 1993; Schlunegger & Grutter, 1992, 1993), providing the first opportunity to examine structural differences between the two isoforms at the molecular level. Although the structures are very similar, with an RMSD in backbone atom positions of 1.4 A when loop regions are omitted in the alignment and 1.9 A when all residues are considered, there are several notable differences in structure and flexibility which may be related to function. The clearest example of these is in the beta-turn from residues 69-72: the turn type found in the solution structure of TGF-beta 1 falls into the category of type II, whereas that present in the X ray crystal structure of TGF-beta 2 is more consistent with a type I turn conformation. This may be of functional significance as studies using TGF-beta chimeras and deletion mutants indicate that this portion of the molecule may be important in receptor binding. PMID- 8679614 TI - Transfer of a beta-hairpin from the functional site of snake curaremimetic toxins to the alpha/beta scaffold of scorpion toxins: three-dimensional solution structure of the chimeric protein. AB - The alpha/beta scorpion fold is shared by scorpion toxins, insect defensins, and plant thionins. This small and functionally versatile template contains an alpha helix and a triple beta-sheet linked by three disulfide bridges. With the view to introduce novel functional centers within this fold, we replaced the sequence (the cysteines and glycines excepted) of the original beta-hairpin of a scorpion toxin by the sequence of a beta-hairpin that forms part of the site by which snake neurotoxins bind to nicotinic acetylcholine receptors (AcChOR). The resulting chimeric protein, synthesized by chemical means, binds to AcChOR, though with a lower affinity than the snake toxins [Drakopoulou; E., Zinn-Justin, S., Guenneugues, M., Gilquin, B., Menez, A., & Vita, C. (1996) J. Biol. Chem. 271, 11979-11987]. The work described in this paper is an attempt to clarify the structural consequences associated with the transfer of the beta-hairpin. We report the determination of the three-dimensional solution structure of the chimeric protein by proton NMR spectroscopy and molecular dynamics calculations. Comparison of the structure of the chimera with those of the scorpion alpha/beta toxin and of the snake neurotoxin shows that (i) the new protein folds as an alpha/beta motif and (ii) the beta-hairpins of the chimera and of the curaremimetic toxin adopt a similar conformation. A closer inspection of the differences between the structures of the original and transferred beta-hairpins allows rationalization of the biological properties of the chimera. PMID- 8679615 TI - Determination of the nucleotide binding site within Clostridium symbiosum pyruvate phosphate dikinase by photoaffinity labeling, site-directed mutagenesis, and structural analysis. AB - Clostridium symbiosum pyruvate phosphate dikinase (PPDK) catalyzes the interconversion of adenosine 5'-triphosphate (ATP), orthophosphate (P(i)), and pyruvate with adenosine 5'-monophosphate (AMP), pyrophosphate (PP(i)), and phosphoenolpyruvate (PEP). The nucleotide binding site of this enzyme was labeled using the photoaffinity reagent [32P]-8-azidoadenosine 5'-triphosphate ([32P]-8 azidoATP). Subtilisin cleavage of the [alpha-32P]-8-azidoATP-photolabeled PPDK into domain-sized fragments, prior to SDS-PAGE analysis, allowed us to identify two sites of modification: one between residues 1 and 226 and the other between residues 227 and 334. Saturation of the ATP binding site with adenylyl imidodiphosphate afforded protection against photolabeling. Next, small peptide fragments of [gamma-32P]- 8-azidoATP-photolabeled PPDK were generated by treating the denatured protein with trypsin or alpha-chymotrypsin. A pair of overlapping radiolabeled peptide fragments were separated from the two digests, DMQDMEFTIEEGK (positions 318-330 in trypsin-treated PPDK) and RDMQDMEFTIEEGKL (positions 317 331 in alpha-chymotrypsin-treated PPDK), thus locating one of the positions of covalent modification. Next, catalysis by site-directed mutants generated by amino acid replacement of invariant residues of the PPDK N-terminal domain was tested. K163L, D168A, D170A, D175A, K177L, and G248I PPDK mutants retained substantial catalytic activity while G254I, R337L, and E323L PPDK mutants were inhibited. Comparison of the steady-state kinetic constants measured (at pH 6.8, 25 degrees C) for wild-type PPDK (kcat = 36 s-1, AMPK(m) = 7 microM, PP(i)K(m) = 70 microM, PEPK(m) = 27 microM) to those of R337L PPDK (kcat = 2 s-1, AMPK(m) = 85 microM, PP(i)K(m) = 3700 microM, PEPK(m) = 6 microM) and G254I PPDK (kcat = 0.1 s-1, AMPK(m) = 1300 microM, PP(i)K(m) = 1200 microM, PEPK(m) = 12 microM) indicated impaired catalysis of the nucleotide partial reaction (E.ATP.P(i) --> E PP.AMP.P(i) --> E-P.AMP.PP(i) in these mutants. The single turnover reactions of [32P]PEP to [32P]E-P.pyruvate catalyzed by the PPDK mutants were shown to be comparable to those of wild-type PPDK. In contrast, the formation of [32P]E PP/[32P]E-P in single turnover reactions of [beta-32P]ATP/P(i) was significantly inhibited. Finally, the location of the adenosine 5'-diphosphate binding site within the nucleotide binding domain of D-alanine-D-alanine ligase, a structural homologue of the PPDK N-terminal domain [Herzberg, O. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 2652-2657] indicates, by analogy, the location of the nucleotide binding site in PPDK. Residues G254, R337, and E323 as well as the site of photoaffinity labeling are located within this region. PMID- 8679616 TI - Alterations to the primer grip of p66 HIV-1 reverse transcriptase and their consequences for template-primer utilization. AB - Alanine scanning mutagenesis was undertaken to evaluate the structural significance of Met230-His235 of the 66 kDa subunit of p66/p51 human immunodeficiency virus reverse transcriptase (HIV-1 RT). Together with Glu224 Trp229, these residues provide the framework of the p66 "primer grip", whose proposed role is maintaining the primer terminus in an orientation appropriate for nucleophilic attack on an incoming dNTP. Of these residues, altering Leu234 results in a p66 subunit incapable of associating into heterodimer. The remaining selectively mutated enzymes were successfully reconstituted and purified to homogeneity for evaluation of RT-associated activities. We show here that alterations to any residue within the p66-Trp229-Met230-Gly231-Tyr232-quartet alter functions associated with both the DNA polymerase and ribonuclease H (RNase H) domains. Detailed analysis of mutant p66Y232A/p51 with an intact or a model "precleaved" RNA-DNA hybrid suggests an altered RNase H phenotype could result from relocation of template-primer in the nucleic acid binding cleft. As a consequence, template nucleotide-8 is positioned in the immediate vicinity of the RNase H catalytic center rather than nucleotide-17. PMID- 8679617 TI - Mutagenesis of photosystem I in the region of the ferredoxin cross-linking site: modifications of positively charged amino acids. AB - The psaD gene isolated from the cyanobacterium Synechocystis sp. PCC 6803 has been mutated in the region encoding a cross-linking site for ferredoxin. A glucose tolerant strain of Synechocystis 6803 was first deleted for psaD, and the resulting PS-I was characterised by EPR and flash absorption spectroscopy. The major modification related to the absence of the PsaD subunit is the disappearance of the first order reduction of ferredoxin which is replaced by a second order reaction. Reconstitution of the deleted PS-I with the purified PsaD polypeptide restored 80% of the fast photoreduction of ferredoxin. The deletion of PsaD has no apparent effect on the main biochemical features of the resulting depleted PS-I complex, with the exception of minor modifications to the FA/FB centers. The deleted strain was transformed by a series of psaD genes mutated at three conserved residues, all located close to the ferredoxin cross-linking site. The resulting photosystem I complexes were extensively studied by flash absorption spectroscopy. Unexpectedly, the change of Lys 106 involved in the cross-linking of ferredoxin for an uncharged amino acid has almost no effect (mutation K106A). However, the functional consequences of more drastic substitutions of either Lys 106 or Arg 111 indicate a role for these two basic amino acids in the binding and submicrosecond reduction of ferredoxin. Various mutations of the unique His at position 97 show that this amino acid is involved in the increased affinity of PS-I for ferredoxin when the pH is lowered. This histidine could be central in regulating in vivo the rate of ferredoxin reduction as a precise sensor of the local proton concentration. PMID- 8679618 TI - Excited state equilibration in the photosystem I-light-harvesting I complex: P700 is almost isoenergetic with its antenna. AB - Photosystem I with its full antenna complement (PSI-LHCI) has been prepared by mild detergent solubilization with octyl beta-D-glucopyranoside from maize thylakoids. A preliminary polypeptide analysis is presented. At room temperature, the steady-state fluorescence derives from an almost perfectly thermalized state, as demonstrated by a Stepanov analysis, in which about 90% of the excited states are associated with the red chlorophyll spectral forms absorbing above 700 nm. Equilibration is temperature-sensitive and is lost at T < 200 K. A careful analysis of fluorescence between 75 and 280 K clearly demonstrates the presence of at least three red chlorophyll spectral forms with emission maxima at 720, 730, and 742 nm, the absorption origin bands of which have been calculated at 714, 725, and 738 nm. On the basis of a minor deviation from thermal equilibration around 695 nm, it is suggested that at least 3-4 antenna chlorophylls, with an average absorption near 695 nm, are strongly coupled to P700. Thermodynamic analysis of absorption and fluorescence spectra indicates that the equilibrium, absorption-weighted excited state population of the P700 dimer is around 0.013 assuming that the low-energy exciton state possesses all the oscillator strength. The average free energy for excitation transfer from antenna to P700 is thus calculated to be -0.26 kT at room temperature. This indicates that P700 is almost isoenergetic with its antenna at room temperature when the red forms are taken fully into account. From the calculated excited state population of P700, we estimate that the primary charge separation rate in PSI is 1-2 ps-1. PMID- 8679619 TI - Resonance Raman/absorption characterization of the oxo intermediates of cytochrome c oxidase generated in its reaction with hydrogen peroxide: pH and H2O2 concentration dependence. AB - Effects of pH and H2O2 concentration on the reaction of cytochrome c oxidase (CcO) with H2O2 were studied with the high-performance Raman/absorption simultaneous determination technique reported previously (Proshlyakov et al., 1996). This reaction generates two intermediates called 607- and 580-nm forms, and we found that they show the same oxygen-isotope-sensitive RR bands as those of the intermediates in O2 reduction by CcO. In transient absorption spectra obtained under single turnover conditions, the 607-nm form appeared as the primary intermediate and subsequently the 580-nm and resting forms, suggesting that H2O2 serves as an oxidant for the resting enzyme but as a reductant for both the 607- and 580-nm forms in the peroxide cycle. The rise rate of absorption at 607 nm was insensitive to the H2O/D2O exchange, but the decay was significantly slower in D2O than in H2O. With the microcirculating system, each intermediate was maintained at a constant level under steady-state conditions by supplying H2O2 continuously. In the pH range between 7.4 and 10.0, the population of the 607-nm form decreased at higher pH and at higher concentrations of H2O2. The Fe=O stretching (VFe=O) frequencies of the oxo heme of the 607-nm form, observed at 804/769 cm-1 for their H2(16)O2/H2(18)O2 derivatives, were unaltered in this pH range and exhibited a D2O/H2O shift even at pH 10.0. This indicates that the iron bound oxygen is hydrogen-bonded to a distal residue in this pH range. When the 580-nm form is dominant under the nonsaturating level of H2O2, two other oxygen isotope-sensitive Raman bands have been observed at 785/750 cm-1 and 355/340 cm-1 at neutral pH, but the former disappeared above pH 8.5 and the latter above pH 9.0 without significant changes of absorption spectra, suggesting the presence of two separate species in the name of the 580-nm form. However, under the saturating concentration of H2O2, these Raman bands were unaltered between pH 7.4 and 10.0. In contrast, in the absence of excess peroxide, no oxygen-isotope sensitive RR bands were observed despite dominance of the 580-nm form. The disappearance of these Raman bands demonstrates the occurrence of oxygen exchange between the oxo heme and bulk water, whose rate surpasses the formation rate of the 580-nm form at alkaline pH and/or at low H2O2 concentration. Such an oxygen exchange did not take place in the 607-nm form. Under the identical experimental conditions for generating a particular steady state, the exchange of H2O with D2O caused significant depopulation of the 580-nm form and concomitant increase of the 607-nm form. This was satisfactorily interpreted in terms of the difference in the decay rate of the 607-nm form between H2O and D2O. Thus, the reduction of the 607-nm form to the 580-nm form is likely to be a key step of the redox-linked proton pumping in the O2 reduction. PMID- 8679620 TI - Functional properties of the histidine-aspartate ion pair of flavocytochrome b2 (L-lactate dehydrogenase): substitution of Asp282 with asparagine. AB - The FMN prosthetic group of flavocytochrome b2 or L-lactate dehydrogenase oxidizes lactate to pyruvate. The reducing equivalents are then transferred one by one, intramolecularly, to heme b2 and then to external acceptors. Substrate oxidation is thought to begin with abstraction of the substrate alpha-hydrogen as a proton by an enzyme base. It has been proposed that this role is played by His373, which lies close to the flavin in the crystal structure and interacts with Asp282. It has also been shown before, using hydrogen exchange measurements, that the pKa of His373 is substantially increased in the wild-type reduced enzyme compared to that in the oxidized state. We report here the enzymatic properties of the D282N mutant flavocytochrome b2. Steady-state rate measurements with [2 1H]lactate and [2-2H]-lactate indicate that, as predicted, the Michaelis complex stability is hardly affected, whereas the transition state for proton abstraction increases in energy by 2.8 kcal/mol. Steady-state inhibition studies were conducted with a number of active-site ligands: sulfite, D-lactate, pyruvate, and oxalate. Binding was found to be most affected for oxalate, but kinetic patterns indicated oxalate and pyruvate were still capable of binding to the enzyme both at the oxidized and semiquinone stages, whereas inhibition by excess substrate, due to lactate binding at the semiquinone stage, was lost. Finally, analysis of the intermolecular hydrogen transfer catalyzed by the enzyme between [2 3H]lactate and fluoropyruvate indicated that the substitution with asparagine facilitates exchange of the histidine-bound proton and hence induces a decrease in the pKa value of H373 in the reduced enzyme of about 1.4 pH units. Nevertheless, the rate constant value for exchange with the solvent of the enzyme bound substrate alpha-proton indicates that H373 is still protonated in the reduced mutant enzyme at neutral pH. Thus, the D282N mutation destabilizes the transition state for proton abstraction and decreases the pKa of H373 in the reduced enzyme but is insufficient to bring it back to a normal value. PMID- 8679621 TI - Inactivation of Escherichia coli ribonucleotide reductase by 2'-deoxy-2' mercaptouridine 5'-diphosphate. Electron paramagnetic resonance evidence for a transient protein perthiyl radical. AB - Ribonucleotide reductase catalyzes a key step in DNA biosynthesis and repair, supplying the cell with the four common deoxyribonucleotides. It is thus the target of antiproliferative agents. The enzyme consists of two subunits named protein R1 and protein R2. R1 provides the sites for the nucleotide substrates and redox-active cysteines required for catalysis. R2 harbors a tyrosyl radical essential for activity. We show here that 2'-deoxy-2'-mercaptouridine 5' diphosphate, a substrate analog, is a very efficient inactivator of ribonucleotide reductase (Ki = 35 microM, Kinact = 0.18 s-1). Inactivation is due to specific scavenging of the protein R2 tyrosyl radical. This unique feature sets this compound apart from other mechanism-based inhibitors such as 2'-azido or 2'-chloro-2'-deoxyribonucleotide which induce partial or total protein R1 inactivation. During reaction, a transient organic radical was detected by EPR spectroscopy. Its g anisotropy (gz = 2.0620, gy = 2.0265, and gx = 2.0019) and its hyperfine structure are consistent with a perthiyl RSS. radical. The loss of the hyperfine structure by deuterium labeling of the beta protons of R1 cysteines unambiguously shows that the perthiyl radical is located on protein R1. We thus conclude that inactivation of ribonucleotide reductase by 2'-deoxy-2' mercaptouridine 5'-diphosphate is due to an irreversible transfer of the radical located on protein R2 to a cysteine residue of protein R1. PMID- 8679622 TI - A kinetic study on the influence of nucleoside triphosphate effectors on subunit interaction in mouse ribonucleotide reductase. AB - For enzymatic activity, mouse ribonucleotide reductase must form a heterodimeric complex composed of homodimeric R1 and R2 proteins. Both substrate specificity and overall activity are regulated by the allosteric effectors ATP, dATP, dTTP, and dGTP, which bind to two different sites found on R1, the activity site and the substrate specificity site. We have used biosensor technique to directly observe the effects of these nucleotides on R1/R2 interactions. In the absence of effectors, positive cooperativity was observed with a Hill coefficient of 1.8 and a KD of 0.5 microM. In the presence of dTTP or dGTP, there was no cooperativity and subunit interaction was observed at a much lower R1 concentration. The highest R1/R2 affinity was in the presence of dATP or ATP with KDs of 0.05-0.1 microM. In all experiments, the molar stoichiometry between the subunits was close to 1:1. Our data support a model whereby binding of any of the effectors to the substrate specificity site promotes formation of the R1 dimer, which we believe is prerequisite for binding to the R2 dimer. Additional binding of either ATP (a positive effector) or dATP (a negative effector) to the activity site further increases R1/R2 association. We propose that binding of ATP or dATP to the activity site controls enzyme activity, not by changing the aggregation state of the R1/R2 proteins as proposed earlier, but rather by locally influencing the long range electron transport between the catalytic site of R1 and the tyrosyl free radical of R2. PMID- 8679623 TI - Escherichia coli diacylglycerol kinase is an alpha-helical polytopic membrane protein and can spontaneously insert into preformed lipid vesicles. AB - Escherichia coli diacylglycerol kinase (DAGK) is a 13.2 kDa enzyme which spans the cytoplasmic membrane three times. Functional DAGK was purified to homogeneity using a polyhistidine tag and Ni(II)-chelate chromatography. Transmission Fourier transform infrared spectroscopy (FT-IR) of DAGK in phosphatidylcholine multilayers led to the conclusion that > or = 90 of DAGK's native 121 residues are alpha-helical, consistent with a model in which DAGK consists of two amphipathic alpha-helices and three transmembrane helices. Polarized attenuated total reflection FT-IR studies of DAGK in oriented multilamellae yielded data consistent with a topological arrangement in which the three transmembrane helices are well-aligned with the bilayer normal while the two amphipathic helices are approximately parallel with the membrane plane. The ability of DAGK to spontaneously insert into preformed lipid vesicles was examined using a novel assay system involving DAGK-catalyzed phosphorylation of a fluorescently tagged diacylglycerol. When micellar DAGK is diluted into L alpha-phase vesicles spontaneous insertion of the enzyme is fairly efficient (ca. 30%). DAGK refolding and insertion from delipidated urea-solubilized DAGK into lipid vesicles is also modestly efficient (3.8 +/- 2.1%) above the gel to liquid crystalline phase transition temperature. The insertion studies indicate that the difference in energy barriers (delta delta G++) between pathways leading to catalytically productive folding and insertion of DAGK relative to unproductive pathways is < 4 kcal/mol. However, additional studies carried out with mutant forms of DAGK indicated that the differences between refolding/insertion pathways for DAGK in vivo and in vitro can be significant. PMID- 8679624 TI - Allosteric intermediates in hemoglobin. 1. Nanosecond time-resolved circular dichroism spectroscopy. AB - Time-resolved circular dichroism (TRCD) studies performed on photolyzed hemoglobin-CO complex (HbCO) probe room temperature protein relaxations in Hb, including the R --> T allosteric transition. TRCD spectroscopy of photolysis intermediates in the near-UV (250-400 nm) spectral region provides a diagnostic for T-like structure at the alpha 1 beta 2 interface via the effect of quaternary structure on the UV CD of aromatic residues. The TRCD of porphyrin-based transitions in the UV and Soret regions, reflecting transition-dipole couplings between hemes and aromatic residues over a radius wide enough to permit heme interface and inter-dimer interactions, is modulated by the tertiary and quaternary structure of photolysis intermediates. In the allosteric core model of Hb cooperativity, Fe-CO bond breakage initiates a heme structural change, thought to be heme doming, that is transmitted to the alpha 1 beta 2 interface via the F helix. The TRCD results, analyzed in light of kinetic information from time resolved absorption studies, suggest specific features for the mechanism by which the ensuing tertiary and quaternary conformational changes propagate through the protein. In particular, the UV-TRCD indicates that the alpha 1 beta 2 interface responds within several hundred nanoseconds to initial events at the heme by shifting from an R toward a T-like interface. The appearance of T-like character at the alpha 1 beta 2 interface tens of microseconds before the appearance of equilibrated T state deoxyHb indicates that the R --> T transition in photolyzed HbCO is a stepwise process, as previously suggested by time-resolved resonance Raman studies. PMID- 8679625 TI - Allosteric intermediates in hemoglobin. 2. Kinetic modeling of HbCO photolysis. AB - Nanosecond absorption spectra are measured in the Soret and near-UV spectral regions of human hemoglobin (Hb) after laser photolysis of the carbonyl adduct in order to study the dynamics of globin tertiary and quaternary conformational changes. Spectra and concentrations of physical intermediates, distinguished by extent of heme ligation and intraprotein relaxation, are obtained from a global analysis using a microscopic kinetic model that explicitly accounts for six observed relaxation and recombination processes. Three observed rate constants for CO rebinding and two intraprotein relaxation constants obtained are similar to constants determined by Hofrichter et al. [(1983) Proc. Natl. Acad. Sci. U.S.A. 80, 2235], the latter two comprising the 20-30-microseconds R --> T quaternary transition and a previously unassigned 1-microseconds intraprotein relaxation. On the basis of the modeled intermediate spectra, as well as UV circular dichroism results observed on this time scale [Bjorling, S.C., Goldbeck, R.A., Paquette, S.J., Milder, S.J., & Kliger, D.S. (1996) Biochemistry 35, 8619 8627], the 1-microsecond relaxation is assigned to heme conformational changes concomitant with a relaxation of protein conformation at the alpha 1 beta 2 interface corresponding to an initial step in a compound R --> T reaction path. PMID- 8679626 TI - Reactions between tunichrome Mm-1, a tunicate blood pigment, and vanadium ions in acidic and neutral media. AB - Tunichromes are yellow, polyphenolic tripeptides prevalent in blood cells of tunicates (suborders phlebobranchia and stolidobranchia). Spectrophotometric studies of reactions between tunichrome Mm-1 and VV or VIV ions were conducted in vitro in various media to crudely approximate cellular conditions: deionized water, aqueous methanol, and aqueous buffers at pH 2 and 7. Catechol was used in parallel studies for comparison to tunichrome and was found to be a good model for tunichrome reactivity. For VIV in pH 7 buffer, both catechol and Mm-1 formed complexes with VIV ions, and no redox products were found. For VV in pH 2 buffer, both catechol and Mm-1 were oxidized by VV ions. Room temperature EPR qualitatively showed that Mm-1 in pH 2 buffer reduced VV ions to free VIV ions. For VV in pH 7 buffer, Mm-1 was oxidized by VV ions and formed VIV complexes. At higher concentrations, the VIV complexes were observed by low temperature EPR [Grant, K. B. (1994) Dissertation, Columbia University; Grant, K. B., et al. (1996) J. Inorg. Biochem. (manuscript in preparation)]. Using a colorimetric assay for VIII, we found that reactions between Mm-1 and VV or VIV ions in pH 7 buffer clearly did not generate appreciable quantities of VIII products. Thus, the colorimetric VIII assay resolved the issue of VIII product formation raised in EPR studies of Mm-1 [cf. Ryan, D. E., et al. (1992) Biochemistry 35, 8651 8661]. Overall, the results provide insights into tunichrome-vanadium chemistry and identify conditions which promote complexation and/or redox reactions in vitro. PMID- 8679628 TI - Identification of an Spl-like element within the immunoglobulin kappa 3' enhancer necessary for maximal enhancer activity. AB - A number of functional DNA sequences have been identified within the murine immunoglobulin kappa 3' enhancer (kappaE3'). These DNA sequences were identified using plasmid reporter constructs in which the centrally active core region (or mutants of that region) of the enhancer was placed directly adjacent to the promoter of a reporter construct. Functional DNA sequences thus identified were found to bind to the transcription factors PU.1, NF-EM5, E2A, ATF-1, or CREM. In the studies reported here, we show that additional enhancer sequences that lie outside of the core region are necessary for maximal enhancer activity when the core region is not directly adjacent to the promoter. A series of progressive and internal deletion constructs shows that enhancer sequences between nucleotides 275 and 329 are important for enhancer activity. Progressive deletion to nucleotide position 329 resulted in a 4-fold reduction in enhancer activity. Using electrophoretic mobility shift assays, we show that this segment of the enhancer binds to ubiquitously expressed nuclear factors. Dimethyl sulfate methylation interference assays indicated protein-DNA interactions within a G rich sequence between positions 302 and 306 and an A-rich sequence between positions 319 and 329. Ultraviolet light protein-DNA cross-linking studies revealed nuclear factors of approximately 85 and 105 kDa that bind to the newly identified enhancer region. Oligonucleotide competition studies and binding studies with purified Sp1 or Sp1 antibodies indicate that Sp1 can bind to this sequence. These studies show that functional sequences within the kappaE3' enhancer include an Sp1-like site approximately 90 bp 5' of the central 132 bp region originally believed to account for most of the enhancer activity. PMID- 8679627 TI - Reactions between vanadium ions and biogenic reductants of tunicates: spectroscopic probing for complexation and redox products in vitro. AB - Several species of marine tunicates store oxygen-sensitive VIII in blood cells. A sensitive colorimetric VIII assay was used to survey the leading candidates for the native reducing agent of vanadate in tunicates (i.e., An-type tunichromes, glutathione, NADPH, and H2S) in reactions with VV or VIV ions under anaerobic, aqueous conditions at acidic or neutral pH. Except for the case of An-1 and VV ions in pH 7 buffer, the assay results for the biogenic reducing agents clearly showed that appreciable quantities of VIII products were not generated under the conditions tested. Therefore, the assay results place new limits on hypothetical mechanisms of VIII formation in vivo. For reactions between An-1 and VV ions in pH 7 buffer, low levels of VIII products could not be ruled out because of an interfering peak in the colorimetric assays. For similar reactions between VV ions and An-1, or an An-1,2 mixture, in mildly to moderately basic media, the product mixtures precipitated as greenish black solids. Analyses of the precipitated V/An mixtures using vanadium K-edge X-ray absorption spectroscopy (XAS) showed that the major products were tris(catecholate)-type VIV complexes (65 +/- 6%) and bis(catecholate)-type VIVO complexes (20 +/- 4%). XAS analysis of the V/An-1 product mixture also provided evidence of a minor VIII component (9 +/ 5% of total V), notable for possible relevance to tunicate biochemistry. The combined results of XAS studies, spectrophotometric studies [Ryan, D. E., et al. (1996) Biochemistry 35, 8640-8650], and EPR studies [Grant, K. B., et al. (1996) J. Inorg. Biochem. (manuscript in preparation)] consistently establish that reactions between tunichromes (Mm-1 or An-1) and VV ions generate predominantly VIV-tunichrome complexes in neutral to moderately basic aqueous media. PMID- 8679629 TI - Enzymatic reducibility in relation to cytotoxicity for various cholesterol hydroperoxides. AB - Phospholipid hydroperoxide glutathione peroxidase (PHGPX) is a selenoenzyme that can catalyze the direct reduction of various membrane lipid hydroperoxides and by so doing could play a vital role in cytoprotection against peroxidative damage. The activity of purified testicular PHGPX on several photochemically-generated cholesterol hydroperoxide (ChOOH) species was investigated, using high performance liquid chromatography with electrochemical detection for peroxide analysis and thinlayer chromatography with 14C-radiodetection for diol product analysis. The following ChOOH isomers were monitored: 5 alpha-OOH, 6 alpha-OOH, 6 beta-OOH (singlet oxygen adducts), and unresolved 7 alpha,7 beta-OOH (derived from 5 alpha-OOH rearrangement). Apparent first-order rate constants for GSH/PHGPX-induced peroxide loss (or diol accumulation) in Triton X-100 micelles, unilamellar liposomes, or erythrocyte ghost membranes increased in the following order: 5 alpha-OOH < 6 alpha-OOH approximately equal to 7 alpha,7 beta-OOH < 6beta-OOH. A similar trend was observed when the peroxides were incubated with Triton Iysates of Se-replete L1210 or K562 cells, implicating PHGPX in these reactions. Consistent with this, there was little or no ChOOH reduction if GSH was omitted or if lysates from Se-deprived cells were used. Liposomal 5 alpha-OOH was found to be much more cytotoxic than equimolar liposomal 6 beta-OOH, producing a 50% loss of L1210 clonogenicity at approximately 1/5 the concentration of the latter. Faster uptake of 5 alpha-OOH was ruled out as the basis for greater cytotoxicity, suggesting that relatively inefficient metabolism by the GSH/PHGPX system might be the reason. As supporting evidence, it was found that cells accumulate the diol reduction product of 5 alpha-OOH more slowly than that of 6 beta-OOH during incubation with the respective peroxides. Slow detoxification coupled with rapid formation makes 5 alpha-OOH potentially the most damaging ChOOH to arise in cells exposed to singlet oxygen. PMID- 8679630 TI - Catalytic mechanism of enterococcal kanamycin kinase (APH(3')-IIIa): viscosity, thio, and solvent isotope effects support a Theorell-Chance mechanism. AB - Bacterial resistance to the aminoglycoside antibiotics is manifested primarily through the production of enzymes which covalently modify these drugs. The Enterococci and Staphylococci produce an ATP-dependent kinase, APH(3')-IIIa, which phosphorylates such antibiotics as kanamycin, amikacin, and neomycin, and this enzyme shows a Theorell-Chance kinetic mechanism by traditional product and analogue inhibitor analysis and by the alternative substrate diagnostic [McKay, G. A., & Wright, G. D. (1995) J. Biol. Chem. 270, 24686-24692]. We report that the APH(3')-IIIa exhibits small solvent (VH/VD approximately equal to 1.50) and thio effects (VATP/VATP gamma S = 2) indicating hydroxyl group deprotonation and nucleophilic attack on ATP do not significantly contribute to the overall steady state rate. The enzymatic rates were determined with the viscogens PEG 8000, glycerol, and sucrose, and these experiments demonstrate that ATP binding and ADP release are diffusion controlled and that ADP release is solely rate limiting for APH(3')-IIIa. In addition, the slope of V/K for ATP vs relative viscosity is greater than the theoretical limit of 1, suggesting a possible enzyme conformational change upon binding of ATP. This new experimental evidence supports a Theorell-Chance mechanism for APH(3')-IIIa. PMID- 8679631 TI - Regiospecificity of aminoglycoside phosphotransferase from Enterococci and Staphylococci (APH(3')-IIIa). AB - The broad-spectrum aminoglycoside phosphotransferase, APH(3')-IIIa, confers resistance to several aminoglycoside antibiotics in opportunistic pathogens of the genera Staphylococcus and Enterococcus. The profile of the drug resistance phenotype suggested that the enzyme would transfer a phosphate group from ATP to the 3'-hydroxyl of aminoglycosides. In addition, resistance to the 3' deoxyaminoglycoside antibiotic, lividomycin A, suggested possible transfer to the 5"-hydroxyl of the ribose [Trieu-Cuot, P., & Courvalin, P. (1983) Gene 23, 331 341]. Using purified overexpressed enzyme, we have prepared and purified the products of APH(3')-IIIa-dependent phosphorylation of several of aminoglycoside antibiotics. Mass spectral analysis revealed that 4,6-disubstituted aminocyclitol antibiotics such as amikacin and kanamycin are monophosphorylated, while 4,5 disubstituted aminoglycosides such as butirosin A, ribostamycin, and neomycin B are both mono- and diphosphorylated by APH(3')-IIIa. Using a series of one- and two-dimensional 1H, 13C, and 31P NMR experiments, we have unambiguously assigned the regiospecificity of phosphoryl transfer to several antibiotics. The 4,6 disubstituted aminocyclitol antibiotics are exclusively phosphorylated at the 3' OH hydroxyl, and the 4,5-disubstituted aminocyclitol antibiotics can be phosphorylated at both the 3'- and 5"-hydroxyls. The first phosphorylation can occur on either the 3'- or 5"-hydroxyl group of neomycin B or butirosin A. Initial phosphotransfer to the 3'-position predominates for butirosin while the 5"-OH is favored for neomycin. These results open the potential for the rational design of aminoglycoside kinase inhibitors based on functionalization of either the 6-aminohexose or the pentose rings of aminoglycoside antibiotics. PMID- 8679632 TI - Mutational modulation of substrate bond-type specificity and thermostability of glucoamylase from Aspergillus awamori by replacement with short homologue active site sequences and thiol/disulfide engineering. AB - Rational protein engineering based on three-dimensional structure, sequence alignment, and previous mutational analysis served to increase thermostability and modulate bond-type specificity in glucoamylase from Aspergillus awamori. The single free cysteine, Cys320, became disulfide bonded in the Ala246 --> Cys mutant, thus enhancing T50 by 4 degrees C to 73 degrees C. Compared to wild-type, Ala246 --> Cys was roughly twice as active at 66 degrees C, but half as active at 45 degrees C. The alternative, elimination of the thiol group in Cys320 --> Ala, barely improved thermostability or altered activity. Secondly, to acquire exceptionally high specificity toward alpha-1,6 glucosidic linkages, characteristic of Hormoconis resinae glucoamylase, two short sequential mutants, Val181 --> Thr/Asn182 --> Tyr/Gly183 --> Ala(L3 glucoamylase) and Pro307 --> Ala/Thr310 --> Val/Tyr312 --> Met/Asn313 --> Gly (L5 glucoamylase), were made. These homologue mutants are located in the (alpha/alpha)6-fold of the catalytic domain in segments that connect alpha-helices 5 and 6 and alpha-helices 9 and 10, respectively. The kinetics of malto- and isomaltooligosaccharides hydrolysis clearly demonstrated that combination of the mutations in L3L5 compensated adverse effects of the single replacements in L3 or L5 glucoamylases to yield wild-type or higher activity. On alpha-1,4-linked substrates, typically Km increased 2-fold for L3, and Kcat decreased up to 15-fold for L5 glucoamylase. In contrast, on alpha-1,6-linked substrates L3 showed both a 2-fold increase in Km and a 3-fold decrease in kcat, while L5 GA caused a similar kcat reduction, but up to 9-fold increase in Km. L3L5 glucoamylase had remarkably low Km for isomaltotriose through isomaltoheptaose and elevated kcat on isomaltose, resulting in an approximately 2-fold improved catalytic efficiency (kcat/Km). Rational loop replacement thus proved powerful in achieving variants with enhanced properties of a highly evolved enzyme. PMID- 8679633 TI - A model of PSI dimerization: destabilization of the C278-G303 stem-loop by the nucleocapsid protein (NCp10) of MoMuLV. AB - We have shown that at low ionic strength (i.e., 100 mM NaCl) a short autocomplementary sequence spanning nucleotides C283 to G298 of MoMuLV RNA genome is involved in the process of PSI dimerization in vitro [Girard, P.-M., Bonnet Mathoniere, B., Muriaux, D., & Paoletti, J. (1995) Biochemistry 34, 9785-9794]. In order to identify other contributions of the PSI structure to RNA dimerization, we studied the kinetics of dimerization as a function of salt concentration of short RNA transcripts comprising or not the autocomplementary sequence C283-G298. We propose that, apart from the crucial role of this sequence in RNA dimerization, the 364-565 domain of PSI can interfere, in vitro, with the initiation of dimer formation. Intermolecular loop-loop recognitions involving the 364-565 domain could stabilize, in a salt concentration-dependent manner, a transient RNA dimer built around the loop-loop U288-A293 interaction. This dimer evolves toward a more stable structure which mainly corresponds to the annealing of two C283-G298 sequences. We also show that chemically synthesized NCp10 does not modify these steps but rather helps the system to pass over the energy barriers associated with the transition to stable RNA structures comprising the stem-loop C278-G303. Data obtained in the presence of NCp10 suggest a binding site size of 9 +/- 1 nucleotides per protein at 37 degrees C and a 10-20-fold increase in the rate constant (i.e., k1 = 24 000 +/- 7000 M-1 s-1) of dimer formation. PMID- 8679634 TI - Inability of RNA to form the i-motif: implications for triplex formation. AB - At slightly acidic or even neutral pH, oligodeoxyribonucleotides which include stretches of cytidines form a tetrameric structure involving C.C+ base pairs in a so-called i-motif. Such a structure, which is very stable at pH 6, is still detectable at neutral pH. This motif, whether intramolecular or intermolecular, was shown to act as an undesired, competing structure for triplex formation. Depending on the sequence and the experimental conditions, triple helix formation was inhibited or completely abolished. Thus, the sequence recognition repertoire of pyrimidine DNA third strands is more restricted than previously admitted; only T.A rich-oligopurine-oligopyrimidine sequences are amenable to triplex formation. On the other hand, cytosine-rich RNA oligoribonucleotides and their 2'-O-methyl derivatives were unable to form a stable autoassociated structure above pH 6. Concomitantly, they were shown to form a triplex with (C.G)-rich targets at pH 6. Thus, not only was the affinity for the duplex increased by DNA to RNA substitution, but the possibility of formation of an inactive form of the third strand was greatly reduced. Thus, i-motif formation is favored for cytosine-rich oligodeoxynucleotides, whereas triplex formation is favored for oligoribonucleotides. These properties make RNA pyrimidine oligonucleotides an attractive choice for triplex formation on a (C.G)-rich target, extending the practical sequence repertoire of pyrimidine triplexes to (C.G*C+)-rich sequences. PMID- 8679635 TI - Resonance Raman spectroscopy of 4-thiothymidine and oligodeoxynucleotides containing this base both free in solution and bound to the restriction endonuclease EcoRV. AB - The resonance Raman spectra of 4-thiothymidine [4ST] have been recorded (a) in the free deoxynucleoside form, (b) when incorporated into the single stranded oligodeoxynucleotide d(AG[4ST]-TC), and (c) within the double-stranded self complementary dodecamer d(GACGA[4ST]ATCGTC). Vibrational mode assignments of almost all the major Raman bands observed in each spectra have been made, mainly by comparison with the published assignments of related nucleosides and nucleotides. Differences between the spectra were observed, particularly when [4ST] and d(AG[4ST]TC) were compared to d(GACGA[4ST]ATCGTC). This is explained in terms of the variations in structure between single-and double-stranded DNA. Good quality spectra were obtained at nucleotide/oligonucleotide concentrations of between 100 and 500 microM and this coupled with an apparatus that uses small volumes (100 microL) allowed measurement of the spectrum of d(GACGA[4ST]ATCGTC) bound to the EcoRV endonuclease. This well characterised nuclease, for which crystal structures are available, recognizes d(GATAT) sequences. When this is replaced with d(GA[4ST]ATC), a poor substrate results but turnover can be prevented during data accumulation by omission of the essential cation Mg2+. Large shifts in several of the Raman bands were observed, and these have been related to the environment of the [4ST] base in the protein-bound oligonucleotide as deduced from the crystal structure. The wavenumber for the C = S stretch vibration in free d(GACGA[4ST]ATCGTC) has been used to calculate the strength of the Watson-Crick hydrogen bond between the sulphur atom in [4ST] and the 6-NH2 group on its partner dA. On binding to the enzyme, the shift in the wavenumber of the C = S stretch indicates this Watson-Crick hydrogen bond is weakened, in good agreement with X-ray structures. The advantage of using [4ST] as a resonance Raman probe is that it absorbs at 340 nm, a wavelength where other nucleic acid and protein absorbance is minimal. Thus the spectra obtained are very simple and consist of signals that arise predominantly from the thiobase alone, and this facilitates data interpretation. PMID- 8679636 TI - Biochemical and physicochemical properties of phosphorodithioate DNA. AB - The biochemical and physicochemical properties of DNA oligomers containing phosphorodithioate linkages in various configurations were evaluated. Duplex stability studies, which were carried out by thermal denaturation analysis with complementary unmodified DNA, indicated a highly cooperative process similar to completely unmodified duplexes. Oligomers containing phosphorodithioate linkages were found to have reduced melting temperatures relative to unmodified duplexes, with the degree of Tm depression paralleling the percent phosphorodithioate composition of the oligomer. Relative to activation of RNase H, DNA oligomers containing up to 50% phosphorodithioate linkages were able to direct RNase H degradation with the same efficiency as unmodified DNA while those containing from 50 to 100% acted with somewhat reduced efficiency. At limiting concentrations, an oligomer containing alternating phosphorodithioate and phosphate linkages was able to direct RNase H degradation of the target RNA in an extended incubation, while an unmodified oligomer did not. The nuclease resistance of phosphorodithioate-containing oligomers was evaluated in HeLa cell nuclear and cytoplasmic extracts, in human serum, and with nucleases S1 and DNase I. Oligomers containing alternating phosphorodithioate and phosphate were highly resistant to degradation in all systems. However, oligomers having more than one unmodified linkage separating phosphorodithioates were degraded rapidly by DNase I, while demonstrating stability to degradation in all other systems tested. These results indicate that phosphorodithioate-containing DNA oligomers are highly nuclease-resistant, are able to form stable duplexes with complementary nucleic acid sequences, and efficiently direct RNase H degradation of target RNA. PMID- 8679637 TI - Distinct molecular recognition of calmodulin-binding sites in the neuronal and macrophage nitric oxide synthases: a surface plasmon resonance study. AB - The neuronal nitric oxide synthase and the macrophage nitric oxide synthase are differently regulated by Ca2+/calmodulin. We investigated the dynamics of calmodulin binding to the putative calmodulin-binding sites in both nitric oxide synthases. Peptides derived from the putative calmodulin-binding sites were synthesized and immobilized to a dextran layer of a biosensor chip. Complex formation of calmodulin and the peptides was monitored by surface plasmon resonance spectroscopy and recorded as sensorgrams. We determined a dissociation constant KD of 5.0 x 10(-9) M for the neuronal nitric oxide synthase and calmodulin. The association rate constant and the dissociation rate constant were ka = 1.58 x 10(5) M-1 s-1 and kd = 7.87 x 10(-4) s-1, respectively. Sensorgrams obtained with the macrophage nitric oxide synthase peptide were remarkably different. Calmodulin, once bound to the peptide, did not dissociate. Association of calmodulin to the peptide occurred with the same rate constants (ka = 3 x 10(4) M-1 s-1) regardless of the presence or absence of Ca2+. The affinity was in the subnanomolar range (KD) < 0.1 x 10(-9) M). We conclude that the extremely tight binding of calmodulin to the NOS-II is solely controlled by the calmodulin binding segment and not by other parts of the protein. PMID- 8679638 TI - A novel hydrophobic omega-conotoxin blocks molluscan dihydropyridine-sensitive calcium channels. AB - A novel calcium channel blocking peptide designated omega-conotoxin-Tx VII has been characterized from the venom of the molluscivorous snail Conus textile. The amino acid sequence (CKQADEPCDVFSLDCCTGICLGVCMW) reveals the characteristic cysteine framework of omega-conotoxins, but it is extremely hydrophobic for this pharmacological class of peptides and further unusual in its net negative charge (-3). It is further striking that the sequence of TxVII, a calcium current blocker, is 58% identical to that of delta-conotoxin-TxVIA, which targets sodium channels. TxVII effects were examined in the caudodorsal cell (CDC) neurons from the mollusc Lymnaea stagnalis. The toxin has no significant effect on sodium or potassium currents in these cells, but it clearly blocks the calcium currents. TxVII most prominently blocks the slowly inactivating, dihydropyridine- (DHP-) sensitive current in CDCs, while blockade of the rapidly inactivating current is less efficient. This novel omega-conotoxin is apparently targeted to DHP sensitive calcium channels and thereby provides a lead for future design of selective conopeptide probes for L-type channels. PMID- 8679639 TI - Influence of chromatin structure on bleomycin-DNA interactions at base pair resolution in the human beta-globin gene cluster. AB - The DNA sequence specificity of bleomycin was examined in human cells and in purified genomic DNA. In each case, DNA damage sites were determined at nucleotide resolution in the human single-copy beta-globin promoter and the locus control region (LCR) hypersensitive site 2 (HS-2). Exponential amplification of gene-specific genomic fragments was achieved by ligation-mediated PCR, and labeled reaction products were analyzed directly by sequencing gel electrophoresis. Bleomycin was found to cleave DNA preferentially at GC, GT, and GA dinucleotides. This study represents the first occasion that the sequence specificity of bleomycin has been determined in intact human cells at the single copy gene level. The intensity of bleomycin damage sites in the LCR HS-2 was found to differ substantially between intact cells and purified DNA at putative transcription factor binding sites. Bleomycin activity was greatly reduced in cells at a tandem NF-E2/AP1 DNA sequence element. This footprint was strongest in K562 cells where the nuclear factor-erythroid 2 (NF-E2) is thought to bind. Protection and enhancement were also observed at other sequence elements in the HS-2 that associate with erythroid-specific and ubiquitous transcription factors. These results suggest that the activity of bleomycin is significantly reduced at the site of protein-DNA interactions in intact cells. This property of bleomycin is extremely useful in genomic "footprinting", where it has significant advantages over other commonly used agents. PMID- 8679640 TI - Distinct phosphate backbone contacts revealed by some mutant peptides of zinc finger protein Spl: effect of protein-induced bending on DNA recognition. AB - By using some mutant peptides of transcription factor Spl, phosphate backbone contacts with the DNA binding protein containing three zinc fingers have been investigated by alkylation interference, circular permutation, DNase I footprinting, and methylation protection methods. The ethylation interference analyses of Spl(R565S) and Spl(K595S) mutants demonstrate that arginine at 565 position and lysine at 595 position interact with the phosphate between G(3) and G(4) and with the phosphate between G(9) and G(10) in GC-box DNA, respectively. On the basis of the experimental results for Spl(K535G), Sp1(537-623), and Sp1(530-623), lysine and glutamine at 535 and 536 positions have been clarified to be in contacts with phosphate between G(7) and G(8) and with phosphate outside GC-box, respectively. In particular, glutamine at the N-terminal side of zinc finger 1 is a key amino acid residue to induce DNA bending and also participates in total base specificity of Sp1. The present study strongly indicates that (1) each zinc finger is not independent for the DNA interaction with Sp1 and (2) DNA base recognition of the zinc finger protein is influenced by local conformational change of DNA induced by the protein binding. PMID- 8679641 TI - Activation of cJun NH2-terminal kinase/stress-activated protein kinase by insulin. AB - One of insulin's many biological effects is the increased transcription of AP-1 regulated genes. cJun is the principal component of the AP-1 transcription complex, which is regulated by the newly discovered members of the MAPK superfamily referred to as cJun NH2-terminal kinases (JNKs) or stress-activated protein kinases (SAPKs). We show that insulin stimulates a dose- and time dependent increase in JNK activity in Rat 1 fibroblasts overexpressing human insulin receptors (Rat 1 HIR cells). Using two different polyclonal anti-JNK antibodies, JNK activity was measured after immunoprecipitation from whole cell extracts by phosphorylation of GSTcJun(1-79). Peak activation occurred 15 min after insulin addition, resulting in a 2.5-fold increase in GSTcJun(1-79) phosphorylation over unstimulated controls. Maximal JNK activation correlated with the onset of AP-1 DNA binding activity. Both insulin-stimulated JNK activity and insulin-induced AP-1 transcriptional activity were found to be Ras-dependent. These data suggest that in Rat 1 cells, JNK activation may play a role in insulin regulated AP-1 transcriptional activity leading to a mitogenic response. PMID- 8679642 TI - Stabilization of barstar by chemical modification of the buried cysteines. AB - The internal packing of residues in the small monomeric protein barstar was severely perturbed by chemical modification of the two buried cysteine residues with the thiol reagent 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) after prior unfolding of the protein using guanidine hydrochloride (GdnHCl). The modification produces mixed disulfides between 5-thio(2-nitrobenzoic acid) and the two Cys residues. To understand the effects of the modification of the individual cysteine residues, Cys40 and Cys82, the modification was also carried out on the two single Cys --> Ala mutant forms of barstar, C40A and C82A, whose structures, activities, and stabilities were first shown to be similar to those of wt barstar. Equilibrium GdnHCl-induced denaturation studies on wt barstar show that the modification causes the midpoint of the denaturation curve to increase by 0.6 M and the stability to increase by 1.3 kcal mol-1. Both C40A and C82A also denature at higher concentrations of GdnHCl after modification. Modification of Cys40 has approximately the same stabilizing contribution as does modification of Cys82. The structures of the modified and unmodified proteins have been compared using circular dichroism (CD) spectroscopy, UV difference absorption spectroscopy, and fluorescence spectroscopy. It is shown that the 5-thio(2 nitrobenzoic acid) groups introduced by reaction with DTNB are buried in hydrophobic environments in the modified C40A and C82A mutant proteins, as well as in modified wt barstar. The far-UV CD spectra of the modified and unmodified proteins are similar, but the mean residue ellipticity at 220 nm of wt barstar is reduced by 30% upon modification. Such a decrease is not seen for either C40A or C82A. The barnase-inhibiting activities of the three modified proteins are shown to be similar to those of the corresponding unmodified proteins. Thus, the severe perturbations of the internal packing, which result in a significant increase in stability, do not appear to affect the overall fold of barstar. PMID- 8679643 TI - Thermodynamic stabilization of nucleotide binding to thymidylate synthase by a potent benzoquinazoline folate analogue inhibitor. AB - The stabilization of dUMP, FdUMP, and dGMP binding to Escherichia coli thymidylate synthase (TS) in the presence and absence of a folate analogue inhibitor of TS, 1843U, was determined by differential scanning calorimetry. When the enzyme is thermally unfolded in the presence of dUMP, two separate temperature transitions are evident, although only one binding site/dimer was detected in equilibrium dialysis experiments. In the absence of dUMP, TS shows a major peak of unfolding at 45 degrees C with a shoulder at 47 degrees C. In the presence of increasing amounts of dUMP progressive changes in the size of each peak occur, each associated with a higher temperature of unfolding. At a ratio of dUMP/TS of 100, a major peak predominates with an unfolding temperature (Td) of 60 degrees C. FdUMP shows a similar profile, while dGMP does not alter the Td of the enzyme since dGMP alone does not bind to TS. Despite the fact that 1843U binds tightly to TS in the absence of nucleotide ligands [Dev, I. K., Dallas, W.S., Ferone, R., Hanlon, H., McKee, D.D., & Yates, B. B. (1994) J.Biol. Chem. 269, 1873-1882], it exhibits only a small effect on the Td profile of TS. However, when 1843U is present, in addition to the nucleotides (dUMP, FdUMP, or dGMP), a Td of 72 degrees C is achieved and the enthalpy of unfolding is increased by one-third. The stabilizing effect of substrate binding to TS by 1843U examined by thermodynamic parameters can be attributed to the considerable extra amount of free energy released on formation of the ternary complex of TS 1843U-nucleotide. The tightness of this complex is due to the stacking energy that results from Van der Waals contacts between the nucleotide purine or pyrimidine ring and the benzoquinazoline ring of 1843U [Weichsel, A., Montfort, W. R., Ciesla, J., & Maley, F. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 3493 3497], which induces a local conformational change in the protein. This conformational change is associated with a significant positive entropy change, which suggests that water is expelled from the active site region. PMID- 8679644 TI - Effect of 17 beta-estradiol on chondrocyte membrane fluidity and phospholipid metabolism is membrane-specific, sex-specific, and cell maturation-dependent. AB - In this study we examined the hypothesis that 17 beta-estradiol exerts both rapid and direct, nongenomic effects of cells in the endochondral pathway. To do this, we used a cell culture model in which chondrocytes at two distinct stages of cell maturation are isolated from the costochondral cartilage of male and female rats, and examined the short-term effect of 17 alpha- and 17 beta-estradiol on [14C]arachidonic acid turnover in the cell layer and phospholipase A2 specific activity in plasma membranes and extracellular matrix vesicles isolated from similarly prepared cultures. In addition, the effect of 17 alpha- and 17 beta estradiol on plasma membrane and matrix vesicle membrane fluidity was assessed. The effect of hormone on arachidonic acid turnover was rapid, time- and concentration-dependent, stereo-specific, and cell maturation-specific. Only resting zone cells from female rats were affected, and only 17 beta-estradiol elicited a response. Similarly, only female rat resting zone chondrocytes exhibited a change in phospholipase A2 activity after a 24 h exposure to hormone, causing an increase in enzyme activity in the matrix vesicles, but not plasma membranes. When isolated membranes were incubated directly with hormone, membrane fluidity was decreased in both plasma membranes and matrix vesicles isolated from female rat resting zone chondrocyte cultures. This nongenomic effect was dose dependent and stereo-specific and differentially expressed in the two membrane fractions with respect to time course and magnitude of response. These results support the hypothesis that 17 beta-estradiol has a rapid action on chondrocyte membrane lipid metabolism and suggest that specific membrane components, characteristic of a particular sex and state of cell maturation, are involved in the nongenomic effects of this sex hormone on isolated matrix vesicles and plasma membranes. PMID- 8679645 TI - The measurement of transmembrane electrical potential with lipophilic cations. AB - The binding of lipophilic cation probes of membrane potential to cells was re examined. Even concentrations of probe molecules as low as 100 nM were found to reduce delta psi and thus many commonly used techniques for delta psi determination are inappropriate. Binding was found to be a linear function of probe concentration and independent of pH. The proportionality constant for binding has been equated to an "apparent binding volume' for [3H]TPP+ with units of microliter/mg dry weight of cells. This "apparent binding volume' is thermodynamically equivalent to the volume of cell membrane multiplied by the partition coefficient of [3H]TPP+ for cell membrane and was equivalent to 9.10 +/ 0.33 microliters/mg dry weight in Enterococcus faecalis. It was concluded that the most accurate method for delta psi determination was to use nanomolar concentrations of lipophilic cations and appropriate correction for energy dependent binding. PMID- 8679646 TI - Association of hepatic system A amino acid transporter with the membrane cytoskeletal proteins ankyrin and fodrin. AB - System A activity is a highly regulated mechanism for the active transport of zwitterionic amino acids into mammalian cells. Monoclonal antibodies generated against a previously unidentified rat liver plasma membrane-associated protein were shown to immunoprecipitate solubilized System A transport activity. The immunoreactive protein was later determined by immunoblotting and peptide microsequencing to be rat liver alpha-fodrin (non-erythroid spectrin). Antibody against ankyrin, a protein that often serves as a bridge between integral membrane proteins and fodrin, also immunoprecipitated System A transport activity. Fractionation of solubilized plasma membrane proteins on sucrose gradients revealed that the System A transporter co-migrated as a complex with fodrin and ankyrin, even in the presence of detergent and urea. In contrast, the System N amino acid transporter does not co-migrate with ankyrin and fodrin, nor does the anti-fodrin antibody immunoprecipitate System N activity. The present data are the first to demonstrate an association between an organic solute transporter and the membranocytoskeletal proteins ankyrin and fodrin. PMID- 8679647 TI - Stable GDP analog-induced inactivation of G(i) proteins promotes cardiac adenylyl cyclase inhibition by guanosine 5'-(beta gamma-imino)triphosphate and muscarinic acetylcholine receptor. AB - Low concentrations of GDP and its stable analog guanosine 5'-O-(2 thio)diphosphate (GDP beta S) have been shown to stimulate adenylyl cyclase activity in canine cardiac sarcolemmal membranes independent from a phosphate transfer reaction. The mechanism of this stimulation was further examined. The stable GTP analog guanosine 5'-(beta gamma-imino)triphosphate (Gpp(NH)p) increased basal adenylyl cyclase activity and inhibited forskolin-stimulated activity with EC50 (half-maximal effective concentration) values of 0.7 mumol/l and 10 nmol/l, respectively. In the presence of GDP beta S (5 mumol/l), which increased basal activity by about 150%, addition of Gpp(NH)p inhibited adenylyl cyclase activity by up to 50% with an EC50 value of 40 nmol/l. Activation of cardiac muscarinic acetylcholine receptors by carbachol amplified this Gpp(NH)p induced inhibition of GDP beta S-stimulated adenylyl cyclase activity. The stimulatory effect of GDP beta S and the inhibitory effect of Gpp(NH)p on GDP beta S-stimulated adenylyl cyclase activity were both attenuated by increasing the Mg2+ concentration or substituting Mn2+ for Mg2+ in the assay. Furthermore, both effects were strongly reduced or abolished upon pretreatment of the sarcolemmal membranes with a low concentration of the SH reagent N-ethylmaleimide (10 mumol/l). These results suggest that the stimulatory effect of GDP beta S on basal adenylyl cyclase activity in canine cardiac sarcolemmal membranes is caused by inactivation of G(i) proteins, which are then rendered susceptible to activation by Gpp(NH)p and inhibitory receptors. PMID- 8679648 TI - Sulfate transport in human placental brush-border membrane vesicles. AB - Membrane transport pathways for transplacental transfer of sulfate were investigated by assessing the possible presence of a bicarbonate-coupled anion exchange mechanism for sulfate in the maternal facing membrane of human placental epithelial cells. The presence of a SO42-/HCO3- exchange mechanism was determined from 35SO42-tracer flux measurements in preparations of purified brush-border membrane vesicles. Under 10% CO2/90% N2 the imposition of an outwardly directed bicarbonate gradient (pH0 6/pHi 7.5) stimulated sulfate uptake to levels approximately 4-fold greater than observed at equilibrium. Maneuvers designed to offset the development of ion gradient-induced diffusion potentials (valinomycin, [K+]0 = [K+]i) significantly reduced bicarbonate gradient-induced sulfate uptake but concentrative accumulation of sulfate persisted. Early time point determinations performed in the presumed absence of membrane potential suggest the reduced level of bicarbonate gradient-induced sulfate uptake resulted from a more rapid dissipation of the imposed bicarbonate gradient. Concentrative accumulation of sulfate was not observed in the presence of a pH gradient alone under 100% N2. suggesting a preference of bicarbonate over hydroxyl ions as substrates for exchange. Static head determinations of opposing sulfate and bicarbonate gradients resulting in zero net flux of sulfate suggests the anion exchange mechanism mediates the electroneutral exchange of 2 bicarbonate or 1 carbonate for each sulfate. Sulfate uptake was increased with increasing intravesicular concentrations of carbonate at constant bicarbonate but was constant with increasing intravesicular concentrations of bicarbonate at constant carbonate suggesting carbonate as a substrate for anion exchange. The mechanism mediating bicarbonate gradient-induced sulfate uptake was sensitive to inhibition by stilbene derivatives, furosemide, bumetanide and probenecid. Substrate specificity studies suggest possible interactions of the anion exchange mechanism with salicylate, butyrate, thiosulfate, sulfite, selenate, chromate and oxalate. The results of this study provide evidence for the presence of a bicarbonate coupled anion exchange mechanism as an electroneutral pathway for sulfate transport across the maternal-facing membrane of human placental epithelial cells. PMID- 8679649 TI - Interactions of alkylglucosides with the renal sodium/D-glucose cotransporter. AB - To study the nature of the glucose binding pocket of the renal Na+/D-glucose cotransporter, we have evaluated the inhibitory potency of various alkylglucosides (AG) on sodium-dependent D-glucose uptake into hog kidney brush border membrane vesicles (BBMV). Inhibition at 0.1 mM AG level was found to be strongly dependent on the anomeric configuration, on the length and on the flexibility of the side chain. Beta-n-AG inhibited transport significantly more effectively compared to the corresponding alpha-anomer (n-octylglucoside: alpha anomer 15%, beta-anomer 84%) and AG with an unsaturated n-alkenyl side chain were significantly less effective inhibitors than the corresponding saturated compound (cis/trans 3-n-beta-hexenylglucoside 53% and 32%, beta-n-hexylglucoside 76%). A series of beta-n-AG increasing in side chain length from 1 to 13 carbon atoms revealed a global maximum in the inhibition pattern when beta-AG with side chains ranging from 8 to 11 carbon atoms were used, thus beta-methylglucoside inhibited glucose transport by 13%, beta-n-nonylglucoside by 92%, and beta-n tridecylglucoside showed no effect. Kinetic analysis of inhibition by beta-n octylglucoside revealed a fully competitive type of inhibition with an apparent K(i) of 10 +/- 2 microM. n-Octylglucoside at 0.1 mM did not inhibit sodium dependent L-alanine uptake; similarly, n-octylmannoside at 0.1 mM level did not affect D-glucose uptake. These results suggest that the inhibition of sodium dependent D-glucose uptake was, at least in the concentration range tested (up to 0.1 mM), not due to a detergent effect of AG, but due to interaction with the carrier. Optimum interaction requires a beta-anomer with a glycosidic bond that places the alkyl chain into an equatorial position with regard to the D-glucose molecule and the two main determinants of the sugar recognition site C2 and C3. In addition, the alkyl chain has to be highly flexible. The alkyl chains thus apparently interact with hydrophobic sites at the carrier in a slightly coiled conformation, thereby AG with a chain length up to 6 carbon atoms interact only with one hydrophobic site, AG with higher chain length probably with two sites. PMID- 8679650 TI - Effects of extracellular pH on intracellular pH-regulation and growth in a human colon carcinoma cell-line. AB - Mechanisms of intracellular pH (pHi) regulation seem to be involved in cellular growth and cell division. Little is known about how extracellular acidosis, known to occur in central regions of solid tumors, or alkaline conditions affect pHi regulation in colonic tumors. pHi changes in the colonic adenocarcinoma cell-line SW-620 were recorded by spectrofluorimetric monitoring of the pH-sensitive, fluorescent dye BCECF, and proliferative activity was assessed by [3H]thymidine uptake. Resting pHi in Hepes-buffered solution was 7.53 +/- 0.01 (n = 36). Both 1 mM amiloride and Na(+)-free solution inhibited pHi recovery from acidification and decreased pHi in resting cells. In HCO3-/CO2-buffered media resting pH1 was 7.42 +/- 0.01 (n = 36). Recovery from acidification was Na(+)-dependent, CI(-) independent, and only partially blocked by 1 mM amiloride. In the presence of amiloride and 200 microM H2DIDS pHi recovery was completely inhibited. In Na(+) free solution pHi decreased from 7.44 +/- 0.04 to 7.29 +/- 0.03 (n = 6) and no alkalinization was observed in CI(-)-free medium. Addition of 5 microM tributyltin bromide (an anion/OH-exchange ionophore) caused pHi to decrease from 7.43 +/- 0.05 to 7.17 +/- 0.08 (n = 5). The effects of pH0 on steady-state pHi, pHi recovery from acidification and proliferative activity after 48 h were investigated by changing buffer [CO2] and [HCO3-]. In general, increases in pH0 between 6.7 and 7.4 increased pHi recovery, steady-state pHi and growth rates. In summary, SW-620 cells have a resting pHi > 7.4 at 25 degrees C, which is higher than other intestinal cells. Acid extrusion in physiological bicarbonate media is accomplished by a pHi-sensitive Na+/H+ exchanger and a pHi-insensitive Na(+)-HCO3 cotransporter, both of which are operational in control cells at the resting pHi. No evidence for activity of a CI-/HCO3- exchanger was found in these cells, which could account for the high pHi observed and may explain why the cells continue to grow in acidic tumor environments. PMID- 8679651 TI - Pathway for Ca2+ influx into cells by trichosporin-B-VIa, an alpha aminoisobutyric acid-containing peptide, from the fungus Trichoderma polysporum. AB - Trichosporin (TS) -B-VIa, a fungal alpha-aminoisobutyric acid (Aib) -containing peptide consisting of 19 amino acid residues and a phenylalaninol, produced both 45Ca2+ influx into bovine adrenal chromaffin cells and catecholamine secretion from the cells. The secretion induced by TS-B-VIa at lower concentrations (2-5 microM) was completely dependent on the external Ca2+, while that induced by TS-B VIa at higher concentrations (10-30 microM) was partly independent of the Ca2+. The concentration-response curves (2-5 microM) for the TS-B-VIa-induced Ca2+ influx and secretion correlated well. The TS-B-VIa (at 5 microM) -induced secretion was not antagonized by diltiazem, a blocker of L-type voltage-sensitive Ca2+ channels. The treatment of fura-2-loaded C6 glioma cells with TS-B-VIa (2-5 microM) led to an increase in the intracellular free Ca2+ concentration ([Ca2+]i) in a concentration-dependent manner but the stimulatory effects of TS-B-VIa on [Ca2+]i were only slightly observed in Ca(2+)-free medium, indicating that TS-B VIa causes Ca2+ influx from the external medium into the C6 cells. The TS-B-VIa induced increase in [Ca2+]i in the C6 cells was not antagonized by diltiazem and by SK&F 96365, a novel blocker of receptor-mediated Ca2+ entry. High K+ increased neither [Ca2+]1 in the C6 cells nor Mn2+ influx into the cells, while TS-B-VIa increased Mn2+ influx. Also in other non-excitable cells, bovine platelets, similar results were obtained. These results strongly suggest that the mechanism of Ca2+ influx by TS-B-VIa at the lower concentrations is distinct from the event of Ca2+ influx through receptor-operated or L-type voltage-sensitive Ca2+ channels in both excitable cells (the chrornaffin cells) and non-excitable cells (the C6 cells and the platelets) and that TS-B-VIa per se may form Ca(2+) permeable ion channels in biological membranes. On the other hand, the peptide at the higher concentrations seems to damage cell membranes. PMID- 8679652 TI - Inhibition of calcium channel activation in GH3 cells by static magnetic fields. AB - Voltage-activated calcium channel function was examined in cultured GH3 cells using the whole-cell patch clamp technique. Exposure to a 120 mT static magnetic field resulted in a slight reduction in the peak calcium current amplitude and shift in the current-voltage relationship. The most significant change was a slowing of the channel activation rate without any change in the inactivation rate. All changes in channel function were reversible, with return to pre exposure values within 3 min after the field was turned off. These alterations in channel function were temperature-dependent. The present findings are consistent with a functional disruption of the intramembranous portion of the calcium channel by a magnetically induced membrane deformation. PMID- 8679653 TI - Exogenous heat shock protein hsp70 activates potassium channels in U937 cells. AB - With the use of patch clamp technique, the effect of exogenous heat shock protein hsp70 on ion channel properties in the plasma membrane of human promonocyte U937 cells has been examined. Cell-attached experiments showed that the addition of 30 100 micrograms/ml hsp70 to the pipette solution resulted in an activation of outward currents through potassium-selective channels of 9 pS unitary conductance. The activity of K(+)-selective channels did not depend on membrane voltage and could be controlled by the intracellular free calcium concentration as revealed in inside-out recordings. K+ channels with similar conductance and kinetic behaviour were found in normal cell-attached patches very rarely. Outside out experiments showed that the addition of hsp70 to the external solution induced a channel-like stepwise increase of inward current which may provide cation entry from the extracellular medium. The interaction of extracellular hsp70 with the membrane surface of the native cell and of the excised fragment was found to be different. The results suggest that hsp70-induced activation of Ca-dependent K channels in monocyte-macrophage cells may be due to a local increase of free Ca2+ concentration just near the inner membrane side. PMID- 8679654 TI - Iron transport into erythroid cells by the Na+/Mg2+ antiport. AB - Rabbit erythroid cells can take up non-transferrin-bound iron by a high-affinity and a low-affinity transport mechanism (Hodgson et al. (1995) J. Cell. Physiol. 162, 181-190). The latter process, which is present in mature erythrocytes as well as reticulocytes, was investigated in this study using rabbit reticulocytes and erythrocytes. Iron uptake was optimal in isotonic KCI (pH 7.0), was shown to be much greater for Fe(II) than Fe(III), to be saturable with a Km value of approx. 15 microM Fe(II), temperature-dependent and inhibited by inhibitors of cell energy metabolism, by Na+ and many divalent cations and by several known inhibitors of membrane cation transport mechanisms. Uptake was more rapid with rabbit than with rat or human erythrocytes. The Fe(II) transport process was much more sensitive to inhibition by Mg2+ than by Ca2+ and the inhibition by both Mg2+ and Na+ was of competitive type. Cells depleted of intracellular Mg2+ by the use of the ionophore A23187 had low rates of Fe(II) uptake. High rates of uptake could be achieved by replenishment of intracellular Mg2+, and the Mg(2+) dependent uptake of Fe(II) was inhibited by the same reagents which reduced the uptake by untreated cells. Many features of the Fe(II) transport process are very similar to those of the previously described Na+/Mg2+ antiport. These features, plus the stimulation of Fe(II) uptake by intracellular Mg2+ and inhibition by extracellular Mg2+ or Na+, strongly suggest that the iron is transported into the cells by the antiport. PMID- 8679655 TI - Inhibition of ATP-diphosphohydrolase(apyrase) of Torpedo electric organ by 5'-p fluorosulfonylbenzoyladenosine. AB - It has been shown previously that ATP is released into extracellular space from pre- and postsynaptic sources in peripheral synapses. The extracellular metabolism of ATP is likely to affect nucleotide- and nucleoside-mediated regulation of neurotransmission. The enzymes responsible for ATP breakdown are nucleotidases whose active site faces the extracellular space. ATPase and ADPase Ca(2+)-dependent activities were characterized in presynaptic plasma membrane preparation from the electric organ of Torpedo. Features described were in accordance with the presence of an ATP-diphosphohydrolase (apyrase EC 3.6.1.5) in this fraction. Active site studies using the affinity label 5' fluorosulfonylbenzoyladenosine were performed on Torpedo apyrase. ATPase and ADPase Ca(2+)-dependent activities were inhibited with 5' fluorosulfonylbenzoyladenosine. From this study it is concluded: (1) 5' fluorosulfonylbenzoyladenosine binds specifically to the active site of apyrase. (2) Divalent cations accelerate the apyrase inactivation rate. (3) Divalent cations are not required for the binding of either the substrate or the inhibitor to the active site. (4) The apyrase active site is more specific for highly phosphorylated nucleotides. The results presented may be extrapolated to apyrases from other sources. The importance of this enzyme and its regulation are discussed. PMID- 8679656 TI - Arginine uptake through a novel cationic amino acid:K+ symporter, System R+, in brush border membrane vesicles from larval Manduca sexta midgut. AB - A concentrative uptake of arginine into brush border membrane vesicles (BBMV) from the midgut of Manduca sexta larvae was driven by an inwardly directed K+ gradient. The pH-dependence of the initial rate of arginine uptake between pH 7 and 10.5 paralleled the titration curve of the amino acid, suggesting that cationic arginine is the principal ionic form that is transported. In the presence of K+, at pH 7.4, arginine uptake was cis-inhibited and trans-stimulated by arginine and lysine but not by any other naturally occurring amino acids; it was also cis-inhibited by homoarginine and ornithine. Taken together, these data argue that arginine, lysine and their analogues share a cationic amino acid:K+ symporter (cotransporter), which we will designate as System R+. This novel symporter has a substrate spectrum similar to that of the uniporter, System y+, in that it accepts arginine+, lysine+, homoarginine+ and ornithine+ and rejects histidine. However, it differs from y+ in that it is cation-dependent and is almost inactive at pH 5.5. PMID- 8679657 TI - Cationic lysine uptake by System R+ and zwitterionic lysine uptake by System B in brush border membrane vesicles from larval Manduca sexta midgut. AB - Lysine uptake was studied at pH 7.4 and 10.0 by rapid filtration methods in brush border membrane vesicles from fifth instar larvae of a model insect, the tobacco hornworm, Manduca sexta (Lepidoptera, sphingidae). At both pH values the uptake was mediated by K+ coupled symport. The uptake rate increased between pH 5.5 and 10, especially so in the alkaline range. The total lysine uptake could be divided into two components based upon lysine's ionic form as a function of pH. Lysine uptake at pH 7.4 was strongly cis-inhibited by arginine but at pH 10 was cis inhibited and trans-stimulated by many neutral amino acids, e.g. leucine, but not by arginine. Lysine uptake by the arginine-inhibitable component paralleled the titration curve of cationic lysine whereas uptake by the leucine-inhibitable component paralleled that of zwitterionic lysine. Evidently, the brush border membrane contains at least two separate, K(+)-dependent amino acid symporters (co transporters) that mediate lysine uptake. A cationic amino acid:K+ symporter selects cationic lysine and arginine but not histidine and other amino acids. One or more zwitterionic amino acid:K+ symporters select zwitterionic lysine, possibly arginine, histidine and neutral amino acids. Based upon these substrate repertoires, the zwitterionic symporters are B-type systems whereas the cationic symporter is identical with System R+, which partially resembles System y+. Arginine uptake in vivo is likely to be mediated mainly by System R+ whereas lysine uptake is likely to be mediated by System B-type symporters. PMID- 8679658 TI - Monomeric human red cell glucose transporter (Glut1) in non-ionic detergent solution and a semi-elliptical torus model for detergent binding to membrane proteins. AB - The self-association state of the human red cell glucose transporter (Glut1) in octaethylene glycol n-dodecyl ether (C12E8) and n-octyl beta-D-glucopyranoside (OG) solution was analyzed in the presence of reductant by gel filtration with light-scattering, refractivity and absorbance detection, and by ultracentrifugation. The C12E8-Glut1 complex was essentially monomeric, whereas OG-Glut1 also formed dimers and larger oligomers. C12E8-Glut1 retained substantial glucose transport activity even after depletion of endogenous lipids by gel filtration, as shown by reconstitution and transport measurements. Removal of endogenous lipids from OG-Glut1 abolished the activity unless phosphatidylcholine was included in the eluent. The binding of C12E8 and OG to Glut1 was determined by gel filtration with refractivity and absorbance detection or with radioactive tracer to be 1.86 +/- 0.07 and 1.84 +/- 0.09 g/g polypeptide, respectively. A structural model was proposed in which non-ionic detergent forms a semi-elliptical torus (SET) surrounding the transmembrane protein. The torus thickness was assumed to be equal to the radius (short half-axis) of a spherical (oblate ellipsoidal) free detergent micelle and the polar head groups of the detergent molecules were predicted to be situated just outside the hydrophobic surface of the protein. The experimental detergent binding values and those obtained from the SET model together confirmed that Glut1 was monomeric in C12E8 solution and provided constraints on the shape and size of the hydrophobic transmembrane region of Glut1 in alpha-helical and beta-barrel topology models. PMID- 8679659 TI - A kinetic characterization of putrescine and spermidine uptake and export in human erythrocytes. AB - Using human erythrocytes as a model system for the study of mammalian polyamine transport, detailed kinetic parameters regarding the uptake and export of putrescine and spermidine were determined. The putrescine uptake data indicated a multi-component uptake system comprised of a low-capacity saturable component and a non-saturable component. The saturable putrescine uptake component demonstrated a calculated Km of 21.0 microM and a V(max) of only 6.52 x 10(-13) M/s. The non saturable linear putrescine uptake rate was defined by a significant pH dependence, a lack of uptake inhibition by related polyamines, and a permeability pi of 3.19 x 10(-8) s-1. These findings suggested that non-saturable putrescine uptake involved a process of simple diffusion. Spermidine uptake exhibited Michaelis-Menten kinetics with a Km and Vmax of 12.5 microM and 1.36 x 10(-12) M/s, respectively. Spermidine uptake did not demonstrate pH dependence and was not significantly inhibited by any of the tested polyamines. The Arrhenius plot of spermidine uptake was determined to be biphasic with calculated activation energies of spermidine uptake of 135.2 kJ/mol for 19-21 degrees C and 59.3 kJ/mol for 21-35 degrees C. These data suggest the possibility of multiple spermidine uptake processes which are not mediated by simple diffusion across the cell membrane. The putrescine export process demonstrated both saturable and non saturable components. The calculated Km, V(max) and pi for putrescine export were 33.8 microM, 1.19 x 10(-11) M/s and 2.81 x 10(-7) s-1, respectively. The spermidine export process was non-saturable up to intracellular spermidine concentrations of 4 microM. At similar intracellular and extracellular concentrations of putrescine and spermidine, however, export processes displayed rates which were an order of magnitude greater than their respective uptake rates. This finding supports the possible presence of mediated putrescine and spermidine export processes different than simple diffusion. PMID- 8679660 TI - Cryptic receptors for insulin-like growth factor II in the plasma membrane of rat adipocytes--a possible link to cellular insulin resistance. AB - To further elucidate the mechanisms for short-term regulation of the receptor for insulin-like growth factor II (IGF-II), we investigated effects of insulin, cAMP and phosphatase inhibitors on cell surface 125I-IGF-II binding in rat adipocytes. Preincubation with the serine/threonine phosphatase inhibitor okadaic acid (OA, 1 microM) or the non-hydrolysable cAMP analogue N6-mbcAMP (4 mM) markedly impaired insulin-stimulated 125I-IGF-II binding. Furthermore, addition of OA enhanced the inhibitory effect exerted by N6-mbcAMP. N6-mbcAMP also induced an insensitivity to insulin which was normalized by concomitant addition of the tyrosine phosphatase inhibitor vanadate (0.5 mM). In contrast, vanadate did not affect the impairment in maximal insulin-stimulated 125I-IGF-II binding produced by either OA or N6-mbcAMP. Phospholipase C (PLC), which cleaves phospholipids at the cell surface, markedly enhanced cell surface 125I-IGF-II binding in a concentration dependent manner. Scatchard analysis demonstrated that the effect of PLC was due to an increased number of binding sites suggesting that "cryptic' IGF-II receptors are associated with the plasma membrane (PM). PLC (5 U/ml) also reversed the N6-mbcAMP-induced decrease of 125I-IGF-II binding at a low insulin concentration (10 microU/ml). Taken together, these data indicate that cAMP, similar to its effects on the glucose transporter GLUT 4 and the insulin receptor, may increase the proportion of functionally cryptic IGF-II receptors in the PM through mechanisms involving serine phosphorylation, possibly of a docking or coupling protein. Tyrosine phosphorylation appears to exert an opposite effect promoting the full cell surface expression of receptors. PMID- 8679661 TI - Caffeine as an antioxidant: inhibition of lipid peroxidation induced by reactive oxygen species. AB - Caffeine (1,3,7-trimethyl xanthine), an ingredient of coffee, has been investigated for its potential antioxidant activity against oxidative damage to rat liver microsomes. Such damage was induced by three reactive oxygen species of cardinal importance in causing membrane damage in vivo namely hydroxyl radical (.OH), peroxyl radical (ROO.) and singlet oxygen (1O2). The results obtained showed that caffeine was an effective inhibitor of lipid peroxidation, at millimolar concentrations, against all the three reactive species. The extent of inhibition was high against peroxidation induced by .OH, medium against 1O2 and low against ROO. In general, the antioxidant ability of caffeine was similar to that of the established biological antioxidant glutathione and significantly higher than ascorbic acid. Investigations into the possible mechanisms involved in the observed antioxidant effect reveal that the quenching of these reactive species by caffeine may be one of the possible factor responsible. The rate constant of caffeine with .OH was 7.3 x 10(9) M-1 s-1 and with 1O2 it was 2.9 x 10(7) M-1 s-1. Considering their potential for damage, half-life estimates and generation in biological systems, the ability of caffeine to inhibit oxidative damage induced by these reactive species in membranes suggest one more positive attribute of caffeine, whose daily intake as coffee may be considerable in most populations. PMID- 8679662 TI - Effect of vanadate on glucose transporter (GLUT4) intrinsic activity in skeletal muscle plasma membrane giant vesicles. AB - Maximally effective concentrations of vanadate (a phosphotyrosine phosphatase inhibitor) increase glucose transport in muscle less than maximal insulin stimulation. This might be due to vanadate-induced decreased intrinsic activity of GLUT4 accompanying GLUT4 translocation. Thus, the effect of vanadate (NaVO3) on glucose transporter (GLUT4) intrinsic activity (V(max) = intrinsic activity x [GLUT4 protein]) was studied in muscle plasma membrane giant vesicles. Giant vesicles (average diameter 7.6 microns) were produced by collagenase treatment of rat skeletal muscle. The vesicles were incubated for 1.5 h with concentrations of vanadate ranging from 3 to 40 mmol l-1 at 34 degrees C before being used for determination of glucose transport. The dose-response curve showed that vanadate decreased the specific D-glucose uptake by a maximum of 70% compared with a control preparation. The vanadate-induced decrease in glucose uptake was not due to a decrease in number of vesicles. To further verify the apparent vanadate induced decrease in GLUT4 intrinsic activity, the kinetics of glucose transport were also examined. In the presence of 10 mmol l-1 vanadate the V(max) and K(m) were decreased (P < 0.05, n = 6) 55% and 60%, respectively, compared with control. The plasma membrane GLUT4 protein content was not changed in response to vanadate. It is concluded that vanadate decreased glucose transport per GLUT4 (intrinsic activity). This finding suggests that regulation of glucose transport in skeletal muscle can involve changes in GLUT4 intrinsic activity. PMID- 8679663 TI - Membrane changes associated with the temperature-sensitive P85gag-mos-dependent transformation of rat kidney cells as determined by dielectrophoresis and electrorotation. AB - Conventional dielectrophoresis (cDEP) and electrorotation (ROT) measurements have been used to determine the dielectric properties of a clone of normal rat kidney cells, designated 6m2, that exhibits a transformed phenotype at 33 degrees C and a non-transformed phenotype at 39 degrees C. cDEP measurements of the crossover frequencies at which individual 6m2 cells experienced zero cDEP force performed as a function of the conductivity of the suspension medium revealed that, in response to a temperature shift from 33 degrees C to 39 degrees C for 24 h, the mean specific cell membrane capacitance and conductance fell significantly (P < 0.01) from 42.3 (+/-1.3) to 30.3 (+/-2.9) mF/m2 and 743 (+/-422) to 567 (+/-326) S/m2, respectively. ROT analyses demonstrated a similar reduction for the membrane capacitance from 37.2 (+/-7.3) to 27.4 (+/-6.1) mF/m2, and also showed that accompanying changes in the mean internal electrical conductivity and dielectric permittivity of the cells were insignificant. Scanning electron microscopy was used to examine the surface morphology of the cells and, in agreement with our previous reports for leukemia cells, the observed membrane capacitance values correlated closely with the morphological complexity of the cell membrane surface. The observed changes in the membrane dielectric properties are discussed in terms of their biological significance and their relationship to previously-detected changes in cell surface charge. PMID- 8679664 TI - Lindane suppresses the lipid-bilayer permeability in the main transition region. AB - The effects of a small molecule, the insecticide lindane, on unilamellar DMPC bilayers in the phase transition region, have been studied by means of differential scanning calorimetry and fluorescence spectroscopy. The calorimetric data show that increasing concentrations of lindane broaden the transition and lower the transition temperature, without changing the transition enthalpy significantly. Lindane therefore enhances the thermal fluctuations of the bilayer. The calorimetric data furthermore suggest that the bilayer structure is intact and not disrupted by even high concentrations (32 mol%) of lindane. Fluorescence spectroscopy was used to measure the passive permeability of unilamellar DMPC bilayers to Co2+ ions. The data show that lindane seals the bilayer for Co2+ penetration and that this effect increases with increasing lindane concentration. The results are discussed in relation to the effects on the permeability of other small molecules, e.g., anesthetics. PMID- 8679665 TI - Effect of glycation of albumin on its binding to renal brush-border membrane vesicles: influence of aging in rats. AB - Aging is associated with the loss of preferential urinary excretion of Amadori product glycated albumin. We have measured the binding of 125I-labeled glycated albumin to the renal brush-border membrane vesicles from young and old rats to determine whether a specific receptor-mediated endocytosis system may be involved. 125I-Glycated albumin was specifically bound by renal brush-border membrane vesicles in a time- and temperature-dependent manner; the binding was concentration-dependent, saturable and reversible. Scatchard plots gave an apparent dissociation constant Km of 488 +/- 17 nM, and a number of binding sites N of 33.5 +/- 3.4 pmol/mg protein/min in membrane vesicles from young (3 months old) rats; the binding of native [125I]albumin, gave a Km of 1194 +/- 200 nM (P < 2%) and N of 82.4 +/- 16.3 pmol/mg protein/min (P < 3%). Vesicles from 10-month old rats had a similar Km (619.6 +/- 135.3 nM) and N (21.91 +/- 2.98 pmol/mg protein/min), while those from older (30 months old) rats had significantly increased Km (1344 +/- 237 nM, P < 3%) and N (81.3 +/- 10.9 pmol/mg protein/min, P < 1%) for 125I-glycated albumin binding. 125I-Glycated HSA was not displaced by unlabeled native HSA in less than 100-fold excess and native [125I]HSA was only displaced by a 10-fold excess of unlabeled glycated HSA. The binding of native [125I]HSA was partly inhibited (85%) by unlabeled glycated HSA. Thus, there appear to be two different binding sites, one for glycated and the other for native albumin, lying close together; and the glycation site on albumin is the discriminatory recognition factor. PMID- 8679666 TI - cDNA sequence analysis and expression of cardiotoxin V and a new cardiotoxin VII from Naja naja atra (Taiwan cobra). AB - The cDNAs encoding cardiotoxin V and a new cardiotoxin VII were constructed from the cellular RNA isolated from the venom glands of Naja naja atra by reverse transcription-polymerase chain reaction. Although 95% nucleotide sequence homology was observed with the two cardiotoxins, there were nine amino-acid substitutions between cardiotoxin V and cardiotoxin VII. The cardiotoxins were subcloned into the expression vector pET 20b(+) and transformed into BL21(DE3) E. coli strain. The expressed protein was isolated from the inclusion bodies of E. coli, and purified by reverse-phase high-performance liquid chromatography. The purified recombinant cardiotoxin showed immunoreactivity with anti-cardiotoxin III antibodies as revealed by immunoblot analysis. PMID- 8679667 TI - Characterisation of the complex of plasminogen activator inhibitor type 1 with tissue-type plasminogen activator by mass spectrometry and size-exclusion chromatography. AB - Glycosylated human plasminogen activator inhibitor type 1 (PAI-1), produced in Chinese hamster ovary (CHO) cells, showed a variety of compounds with different molecular weights when subjected to electrospray mass spectrometry (ES-MS), owing to the heterogeneity of the carbohydrate chains. However, non-glycosylated human PAI-1, produced in E. coli, gave rise to a prominent species with a molecular weight of 42,774, consistent with the amino-acid sequence. A non-glycosylated mutant of the proteinase domain (B-chain) of tissue-type plasminogen activator (tPA) produced in C 127 cells, had a molecular weight of 28,168. Full-length, glycosylated, tPA showed a large heterogeneity in molecular mass. For a mass study, a tPA-PAI-1 complex was formed, composed of non-glycosylated PAI-1 and non glycosylated B-chain. This complex was remarkably stable at room temperature in buffer with a neutral pH. The mass spectrum of the complex provided two main species, a peptide with a mass of 3803 and a dominating species of 67,133. These masses are consistent with a complex where PAI-1 is cleaved at the P1-P1' position. A trace of a species with a molecular mass of 70,942 was also found, corresponding to the complete, non-dissociated complex with PAI-1. Separation of the cleaved peptide, corresponding to the hydrophobic C-terminal 33 amino-acid residues of PAI-1, from the complex, was achieved by size-exclusion chromatography in the presence of 30% acetonitrile. Thus, in the complex between tPA and PAI-1, the proteins are held together by a tight covalent bond, but the C terminal cleaved peptide of PAI-1 is only bound to the complex by hydrophobic forces. To assess whether this is specific to the tPA B-chain alone, experiments with the complex of full-length, glycosylated tPA and glycosylated PAI-1 were also performed, and it was possible to demonstrate the release of the C-terminal PAI-1 peptide by chromatography, mass spectrometry, as well as by SDS-PAGE. PMID- 8679668 TI - Calorimetric studies on solid alpha-chymotrypsin preparations in air and in organic solvents. AB - Differential scanning calorimetry was the method to investigate the thermostability of chymotrypsin. The transition temperature decreased by approx. 30 degrees C when the dry enzyme became highly hydrated. High degree of hydration corresponded to extensive conformational changes during protein denaturation, reflected by large enthalpy values. Sorbitol, lyophilized together with the enzyme, caused the destabilization of the complex within the whole range of water activities. When the enzyme was equilibrated through the apolar solvent, isooctane, stabilization of chymotrypsin was observed at high water activities, compared to equilibration in air. The presence of isooctane resulted in a remarkable stabilization of the chymotrypsin-sorbitol complex. A sorbitol concentration of 5 mmol/g of protein was prerequisite to induce stabilization when equilibrated through isooctane at high water activities. The transition enthalpy increased with increasing amounts of sorbitol. Different hydration isotherms were obtained for the air-equilibrated and solvent-equilibrated enzyme preparations. Increasing amounts of buffer salts within the chymotrypsin preparation caused the enhancement of both the temperature and the enthalpy of the transition at a water activity 0.97. Variations on the hydration of the preparations both offered the explanation to the thermal stability results and supported the evidence obtained from enzyme activity studies. Generally, the catalyst whose hydration was suppressed due to its environment exhibited low enzymatic activity. PMID- 8679669 TI - Identification of major rye secalins as coeliac immunoreactive proteins. AB - Six distinct gamma- and omega-type secalins, together with two new low molecular mass glycoproteins, have been identified as the major coeliac immunoreactive proteins from a chloroform/methanol soluble extract from rye endosperm. These components were characterized by a combination of reverse-phase high-performance liquid chromatography, immunoblotting using a coeliac serum and microsequencing analysis. This allowed the identification of a group of secalins with different molecular masses according to their N-terminal amino-acid sequence: one omega type secalin of 40 kDa (omega 1-40); three gamma-type secalins, one of 70 kDa (gamma-70) and two of 35 kDa (gamma-35); as well as two low molecular mass glycoproteins of 15 and 18 kDa, all exhibiting coeliac serum antigenicity. Moreover, four additional rye components, including two low molecular mass proteins, which did not react with coeliac sera, have also been identified. Analysis by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) of the three main purified coeliac immunogenic secalins, gamma-70, gamma-35 and omega 1-40, indicated molecular masses of 71457, 32240 and 39117 Da, respectively. The omega 1-40 secalin displays a significant absorption in the visible region which could be related to its peculiar low capacity to bind both coeliac sera antibodies and Coomassie brilliant blue dye. PMID- 8679670 TI - Purification and sequencing of multiple forms of Brassica napus seed napin small chains that are calmodulin antagonists and substrates for plant calcium-dependent protein kinase. AB - Six napin small (S) subunits and six napin large (L) subunits were resolved from the seeds of kohlrabi (Brassica napus var. rapifera) by a procedure involving extraction, batchwise elution from carboxymethylcellulose (CM52) and reverse phase HPLC after treatment with guanidine hydrochloride and 2-mercaptoethanol. The precise average molecular masses of the ca. 4.5 kDa small subunits and the ca. 10 kDa large subunits were determined by electrospray ionisation mass spectrometry (ESMS). The amino-acid sequences of six small subunits (S1A, S1B, S2, S3A, S3B and S4) were deduced from the ESMS-based masses of tryptic fragments, Edman sequencing and previously published data. The deduced structures were precisely consistent with this data and with the ESMS-based average molecular masses of these polypeptides. The structures of the small subunits (39 41 residues) are very similar with variations involving single substitutions at or near the N-terminus and 1 to 3 changes within the last 7 amino acids. Particular B. napus small and large chains are phosphorylated by plant Ca2+ dependent protein kinase (CDPK). The best site of phosphorylation on small chains is inferred to be either S34 or S39 of S1B. The napin-containing basic protein fraction from B. napus seeds largely abolishes the Ca2+-dependent fluorescence enhancement of dansyl-calmodulin and also inhibits calmodulin (CaM)-dependent myosin light chain kinase (MLCK). The resolved napin small chains also inhibit MLCK. All of the kohlrabi napin small chains, as well as homologous Brassicaceae small chains, have a central 23 amino-acid sequence that can potentially form an alpha-helix in which all the basic residues are located on one side. This structural element may be involved in the interaction of these proteins with CaM and the biological activity of antifungal proteins of this kind. PMID- 8679671 TI - Purification and sequencing of multiple forms of Brassica napus seed napin large chains that are calmodulin antagonists and substrates for plant calcium-dependent protein kinase. AB - Six napin large (L) chains (as well as six napin small chains) were resolved from the seeds of kohlrabi (Brassica napus var. rapifera) by a procedure involving extraction, batchwise elution from carboxymethylcellulose (CM52) and reversed phase HPLC after treatment with guanidine hydrochloride and 2-mercaptoethanol. The precise average molecular masses of the circa 4.5 kDa small subunits and the circa 10 kDa large subunits were determined by electrospray ionisation mass spectrometry (ESMS). Of six large subunits resolved (L1A), L1B, L1C, L2A, L2B and L2C), the complete amino acid sequences of four (L1A, L2A, L2B and L2C) and the near-complete sequences of two (L1B and L1C) were deduced from the ESMS-based masses of tryptic fragments, Edman sequencing and previously published data. The deduced structures are precisely consistent with this data and with the ESMS based average molecular masses of these polypeptides. ESMS analysis of unreduced napin extract revealed only seven circa 14.5 kDa complexes, the observed masses being in close agreement with those calculated for 1:1 complexes of particular small and large subunits assuming four disulfides in each napin complex. The structures of the napin large subunits (86-91 residues) are very similar and all amino acid differences observed are confined to only 25 positions. The L2A, L2B AND L2C large chains (but not the L1A, L1B and L1C large chains) are phosphorylated well by plant Ca2+-dependent protein kinase (CDPK). The CDPK catalyzed phosphorylation site on the large chain L2A is inferred to be S57 within the sequence LQQVIS57RIYQT (the site being S60 within the same sequence in L2B and L2C). The napin-containing basic protein fraction from B. napus seeds largely abolishes the Ca2+-dependent fluorescence enhancement of dansyl calmodulin and also inhibits calmodulin (CaM)-dependent myosin light chain kinase (MLCK). The resolved napin long chains also inhibit MLCK. Each kohlrabi large chain contains 2 sequences (corresponding to L(10)-Q(20) and Q(51)-L(64) of L1A) which have the potential to form amphipathic alpha-helices. Each large chain also contains a Q-rich 19 amino acid sequence (corresponding to L(30)-Q(48) of L1A) which has the potential to form a '2-sided' alpha-helix with basic residues confined to one side. These structural elements may be involved in the inferred interaction of these proteins with CaM and may be relevant to the biological activity of antifungal proteins of this kind. PMID- 8679672 TI - 2D-NMR studies of the effects of axial substitution on two helices in horse cytochrome c. AB - The sequential amino acids from Gly-1 to Cys-14 in the N-terminal segment and from Lys-88 to Glu-104 in the C-terminal segment of cytochrome c-imidazole complex (Im-cyt c) have been studied by two-dimensional nuclear magnetic resonance techniques. Resonance assignments for the main-chain and side-chain protons are reported. Qualitative interpretation of nuclear Overhauser enhancement data allows the secondary structure of the two segments to be described, which indicate the patterns of NOEs found are consistent with an alpha helix between Val-3 and Cys-14 in the N-terminus, and between Lys-88 and Asn-103 in the C-terminus. Two alpha-helices are found to be maintained. Comparison of the long-range NOEs of Im-cyt c relative to the crystal structure of native cytochrome c reveals apparent conformational changes of some side-chains especially those close to heme pocket within the N- and C-terminal helices resulting from the binding of imidazole to iron by displacing native Met-80 side chain. The explanation for ligand-induced changes within the N- and C-helices is therefore suggested. PMID- 8679673 TI - Physical properties of dinitrosyl iron complexes with thiol-containing ligands in relation with their vasodilator activity. AB - When studying the vasodilator activity of dinitrosyl iron complexes (DNIC) with thiol-containing ligands as NO donors, it should be taken into consideration that these complexes depending on the content of thiols in the environment can occur in either of two forms that differ by their EPR, gamma-resonance and optical characteristics and also by their vasodilator effect on isolated blood vessels. The more stable diamagnetic form appears at the ratio Fe2+:RS- = 1:2. It reversibly dissociates to the monomeric paramagnetic form [(RS-)2Fe+(NO+)2] on increasing the thiol content to the level 20-times and more exceeding the quantity of iron. It is suggested that stabilization of the dimeric form is provided by formation of RS(-)-NO+ bonds between monomeric components of the dimer. This process is favored by a corresponding orientation of the monomers relative to each other. A high stability of the DNIC dimeric form correlates with more prolonged vasodilator effect of this complex as an NO source. Replacement of cysteine by reduced glutathione in dimeric and monomeric forms of DNIC increases both stability of the complexes and the duration of their vasodilator effect. PMID- 8679674 TI - Influence of glycerol on the structure and stability of ferric horse heart myoglobin: a SAXS and circular dichroism study. AB - The influence of glycerol on the structural properties of Fe(III)-horse heart myoglobin has been investigated by absorbance, CD and SR-SAXS spectroscopy. The results obtained indicate that both the tertiary and the secondary (alpha-helix) conformations of the protein are influenced by glycerol; in particular, an increase of approx. 8% in helical content was observed. Further, analysis of both the acid- and guanidine-induced denaturation transitions points to a glycerol induced decreased stability of the tertiary structure; conversely, the alpha helix conformation is found to be stabilized by the organic solvent. Finally, the SR-SAXS data show that gyration radius, cross-section and thickness of the protein increase in the presence of the organic solvent; however, the protein maintains a compact state. PMID- 8679675 TI - Two amine oxidases from Aspergillus niger AKU 3302 contain topa quinone as the cofactor: unusual cofactor link to the glutamyl residue occurs only at one of the enzymes. AB - Amine oxidases (EC 1.4.3.6) from Aspergillus niger, AO-I (2 x 75 kDa) and AO-II (80 kDa), were examined to determine the cofactor structure. Inactivated with p nitrophenylhydrazine, they showed absorption and fluorescence spectra similar to those published for other copper amine oxidases and to topa hydantoin p nitrophenylhydrazone. After digestion by thermolysin and pronase, cofactor peptides were purified by HPLC and sequenced. For thermolytic peptides, a typical topa consensus sequence, Asn-X-Glu-Tyr, was obtained for AO-II, although in case of AO-I it overlapped with Val-Val-Ile-Glu-Pro-Tyr-Gly. For pronase peptides of AO-I, only the latter sequence was obtained. NMR and mass spectroscopy confirmed the residue X as topa p-nitrophenylhydrazone in AO-II and revealed the presence of a residue Z attached to the Glu in the peptide Val-Val-Ile-Glu(Z)-Pro of AO-I. This residue was separated from the peptide by hydrolysis and identified as a product derived from topa quinone. The data, together with amino-acid sequence of AO-I, confer strong evidence for topa quinone as the cofactor, bound in the typical consensus sequence. Raman spectra of the p-nitrophenylhydrazone derivative of AO-I and its pronase peptide showed essentially the same peaks matching to a model compound for topa p-nitrophenylhydrazone. However, there may exist an unusual ester link between the topa-404 and Glu-145 in the native enzyme. PMID- 8679676 TI - Kinetics of appearance of four hemorphins from bovine hemoglobin peptic hydrolysates by HPLC coupled with photodiode array detection. AB - The kinetics of appearance of hemorphins during peptic hydrolysis of bovine hemoglobin was investigated by reverse-phase high-performance liquid chromatography (RP-HPLC) coupled with a photodiode array detector. The degree of hydrolysis (DH) of hemoglobin by pepsin was determined and different defined DH of hydrolysates were obtained. The analysis of these hydrolysates by HPLC coupled with a photodiode array detector allowed us to identify and quantify the hemorphins in every hydrolysate and to determine the quantitative evolution of hemorphins as a function of DH. It indicated that hemoglobin was a direct precursor of LVV-hemorphin-5 and LVV-hemorphin-7. These peptides were demonstrated to be secondary substrates for pepsin to generate VV-hemorphin-5 and VV-hemorphin-7. Moreover, LVV-hemorphin-7 was more stable towards pepsin than LVV hemorphin-5. The affinity of pepsin towards some peptidic bonds was also demonstrated. PMID- 8679677 TI - Escherichia coli aminodeoxychorismate synthase: analysis of pabB mutations affecting catalysis and subunit association. AB - p-Aminobenzoic acid (PABA), an essential component of the vitamin folic acid, is derived from the aromatic branch-point precursor chorismate in two steps. 4-Amino 4-deoxychorismate (ADC) synthase converts chorismate and glutamine to ADC and glutamate, and is composed of two subunits, PabA and PabB. While various experiments have suggested that PabA and PabB act as a complex, attempts to isolate the intact complex have failed. We report here the first successful copurification of PabA and PabB by gel filtration chromatography. The association of PabA and PabB is greatly enhanced by the presence of 5 mM glutamine, and by preincubation at 37 degrees C. Conversely, the association is greatly reduced at cold temperatures. We also report the isolation and characterization of both chemically induced and site-directed mutations in PabB. Mutated PabB enzymes fall into three categories according to their properties: deficiency of chorismate amination coupled with failure to associate with PabA, deficiency of chorismate amination coupled with retention of PabA association, and competency of chorismate amination with failure of PabA association. PMID- 8679678 TI - In vitro activation of a 60-70 kDa histone H4 protein kinase from neutrophils by limited proteolysis. AB - Neutrophils stimulated with the chemotactic peptide fMet-Leu-Phe (fMLP) are known to exhibit a rapid and transient activation of a histone H4 kinase that may function in a stimulatory pathway downstream of phosphatidylinositol 3-kinase. The activity of this histone kinase in unstimulated neutrophils and cells treated with 1.0 microM fMLP for 10 sec was 8.8 +/- 5 and 43 +/- 2 pmol P/min per 10(7) cells, respectively. In this paper, we report that unstimulated neutrophils contain a latent H4 kinase in the 100,000 x g soluble fraction that can be markedly activated by treatment with trypsin. The values for the untreated and trypsin treated enzyme were 5.5 +/- 1.0 and 63.6 +/- 18 pmol P/min per 10(7) cell equivalents, respectively. This kinase was insensitive to a selective antagonist of protein kinase C (i.e., 50 microM 1-(5-isoquinolinylsulfonyl)-2 methylpiperazine (H-7)) but completely blocked by 100 nM staurosporine. Only a single peak of activity was observed for this enzyme when the 100,000 x g supernatant fraction was fractionated on either an exclusion (KW-803) or an anion exchange column (DEAE), or during isoelectric focusing. The molecular weight of the latent kinase was 64 +/- 6 kDa and the isoelectric point was 7.6 +/- 0.1. During all fractionation procedures, the H4 kinase co-chromatographed with a trypsin-activated kinase that catalyzed the phosphorylation of a peptide which corresponds to residues 297-331 of the 47 kDa subunit of the NADPH-oxidase complex (p47-phox). The properties of the trypsin-activated H4 kinase from unstimulated neutrophils are very similar to those reported for this enzyme from fMLP-stimulated cells. PMID- 8679679 TI - A proteinase inhibitor from egg yolk of hen is an ovoinhibitor analog. AB - A proteinase inhibitor, tentatively termed vitelloinhibitor, was purified from yolk of hen's ovarian follicles. It resembled egg-white ovoinhibitor not only in inhibitory spectrum (active for bovine trypsin and bovine chymotrypsin) but also in thermal stability, pH stability, antiserum reactivity and amino-acid composition. However, vitelloinhibitor had different molecular weight from that of ovoinhibitor. An alpha 2-proteinase inhibitor preparation, isolated from laying hen's serum in the present study, was found to exhibit two bands, and the larger one of the latter corresponded to vitelloinhibitor in molecular weight. The partial N-terminal amino-acid sequence of vitelloinhibitor was the same as those of the two components of serum inhibitor and all three agreed with that of ovoinhibitor. Vitelloinhibitor is likely to be an ovoinhibitor analog derived from a serum precursor, which might be the larger component of alpha 2-proteinase inhibitor. PMID- 8679680 TI - Chylomicron assembly and catabolism: role of apolipoproteins and receptors. AB - Chylomicrons are lipoproteins synthesized exclusively by the intestine to transport dietary fat and fat-soluble vitamins. Synthesis of apoB48, a translational product of the apob gene, is required for the assembly of chylomicrons. The apob gene transcription in the intestine results in 14 and 7 kb mRNAs. These mRNAs are post-transcriptionally edited creating a stop codon. The edited mRNAs chylomicrons from the shorter apoB48 peptide remains to be elucidated. In addition, the roles of proteins involved in the assembly pathway, e.g. apobec-1, MTP and apoA-IV, needs to be studied. Cloning of enzymes involved in the intestinal biosynthesis of triglycerides will be crucial to fully appreciate the assembly of chylomicrons. There is a need for cell culture and transgenic animal models that can be used for intestinal lipoprotein assembly. The catabolism of chylomicrons is far more complex and efficient than the catabolism of VLDL. Even though the major steps involved in the catabolism of chylomicrons are now known, the determinants for apolipoprotein exchange, processing of remnants in the space of Disse, as well as the mechanism of uptake of these particles by extra-hepatic tissue needs further exploration. PMID- 8679681 TI - 15-Hydroperoxyeicosapentaenoic acid inhibits arachidonic acid metabolism in rabbit platelets more potently than eicosapentaenoic acid. AB - The effect of 15-hydroperoxy-5,8,11,13,15-eicosapentaenoic acid (15-HPEPE), a hydroperoxy adduct of eicosapentaenoic acid (EPA), on the formation of 12-hydroxy 5,8,10,14-eicosatetraenoic acid (12-HETE), thromboxane (TX) B2 and 12-hydroxy 5,8,10-heptadecatrienoic acid (HHT) from exogenous arachidonic acid in washed rabbit platelets was examined. 15-HPEPE inhibited 12-HETE, TXB2 and HHT formation at concentrations ranging from 2 to 8 microM. The inhibitory effect of 15-HPEPE was dose-dependent (12-HETE, 16.0-82.9% inhibition; TXB2, 16.7-57.2% inhibition; HHT, 4.6-52.0% inhibition). EPA inhibited the production of these three metabolites, but the inhibitory effect was kept low (20-100 microM: 12-HETE, 8.3 31.1% inhibition; TXB2, 18.9-49.5% inhibition; HHT, 12.5-41.7% inhibition) as compared with 15-HPEPE. Experiments utilizing 15-hydroxy-5,8,11,13,15 eicosapentaenoic acid and hydroxyl radical scavengers (dimethyl sulfoxide and mannitol) revealed that 15-HPEPE exerted its effect in the form of the hydroperoxy adduct. These results suggest that 15-HPEPE has the potential to modulate the activities of the cyclo-oxygenase and 12-lipoxygenase in platelets. This may also be one convincing mechanism for the anti-thrombotic and anti atherosclerotic actions of EPA. PMID- 8679682 TI - The role of ceramides 1 and 2 in the stratum corneum lipid organisation. AB - A mixture of ceramide 1 and ceramide 2 (CER(1 + 2)) was isolated from pig stratum corneum and mixed in various molar ratios with cholesterol (CHOL) or with CHOL and palmitic acid (PA). The mixtures were hydrated in a buffer solution of pH 5.0 and their phase behaviour was studied by wide- and small-angle X-ray diffraction. The small-angle diffraction curve of the CHOL/CER(1 + 2) mixture at a molar ratio of 0.4 revealed the presence of only one peak at a spacing of 6.7 nm. Increasing the amount of CHOL to a molar ratio of 0.6 was accompanied by a shift of this peak to a smaller spacing (5.7 nm) and the appearance of two weak peaks at 11.8 and 4.1 nm spacings. Increasing the CHOL content to an equimolar ratio resulted in the appearance of two lamellar phases with periodicities of 5.5 and 12 nm, respectively. In a CHOL/CER(1 + 2) mixture at a molar ratio of 2 the periodicities of the two phases were 5.6 and 12 nm, respectively. From these observations it was concluded that the CHOL/CER(1 + 2) mixtures exerted similar phase behaviour, as reported earlier for intact SC (Bouwstra et al. (1995) J. Lipid Res. 36, 496-504) and for mixtures (Bouwstra et al. (1996) J. Lipid Res., in press) prepared from CHOL and total ceramide fraction (CER) isolated from pig stratum corneum. However, in the CHOL/CER mixtures a lower relative amount of CHOL was required to acquire these lamellar phases, indicating that at low CHOL contents, CER 3, 4, 5 and 6 play a crucial role in the formation of the lamellar phases. Furthermore, the solubility of CHOL in the mixtures increased in the presence of CER 1, suggesting its important role for the barrier function of the skin. When palmitic acid (PA) was included, the phase behaviour of the CHOL/CER(1 + 2)/PA mixture was more complex. Next to two lamellar phases, an additional phase with a spacing of 3.77 nm was observed, never seen in intact stratum corneum. In the absence of CHOL, the wide-angle diffraction pattern of the CER(1 + 2) revealed one sharp reflection at 0.456 nm and two diffuse reflections at 0.430, 0.417 nm and 0.395 nm, indicating the presence of a crystalline sublattice. In an equimolar mixture of CHOL/CER(1 + 2) no sharp 0.456 nm reflection was observed indicating a more disordered packing. Furthermore, phase separation of CHOL occurred, this conclusion is based on the presence of reflections corresponding to polycrystalline cholesterol monohydrate. These findings indicate that the lateral packing of mixtures of CHOL/CER(1 + 2) is more complex than that of the CHOL/CER mixtures that reveals a hexagonal lateral packing. PMID- 8679683 TI - Comparison of acceptor and donor substrates in the CoA-independent transacylase reaction in human neutrophils. AB - In human neutrophils (PMN) the ethanolamine-containing phosphoglyceride fraction (PE), principally plasmalogen-linked PE (1-O-alk-1'-enyl-2-acyl-sn-glycero-3 phosphoethanolamine), is the major store of arachidonic acid (AA). Exogenous AA is initially incorporated into 1-acyl-linked phosphoglycerides and is believed to be transferred into the 1-ether-linked phosphoglycerides via the action of a CoA independent transacylase (CoA-IT). We have investigated the selectivity for both the "acceptor' lysophospholipids and "donor' AA-containing phospholipid substrates in the CoA-IT reaction. Evidence suggests CoA-IT may also participate in the synthesis of platelet activating factor. The transfer of [3H]AA from endogenously labeled choline-containing phosphoglycerides (PC) to exogenously added alkenyl-lyso-PE (0-50 microM) was examined in saponin-permeabilized PMN. In these "donor' studies, we observed that [3H]AA was transferred from both alkyl- and diacyl-linked PC in a proportional manner. More detailed molecular species analysis showed that [3H]AA was deacylated from all the major AA-containing molecular species in both the alkyl and diacyl subclasses with no selectivity for either subclass. To investigate the "acceptor' selectivity, membrane fractions prelabeled with either [3H]alkyl-arachidonoyl-PE or -PC were utilized as donor substrates. Various unlabeled lysophospholipids (10 microM) were added and the generation of [3H]lyso-PE or -PC was monitored as a measure of CoA-IT activity. Significant subclass preference was observed upon addition of lyso-PE species (1 alkenyl > 1-alkyl > 1-acyl) however, little selectivity was seen with the corresponding lyso-PC species. On the other hand, lysophosphatidylserine, lysophosphatidylinositol, and lysophosphatidic acid all served as poor acceptor substrates in the reaction. These data from PMN are consistent with other evidence that the CoA-IT plays a pivotal role in the enrichment of AA into plasmalogen-linked PE. PMID- 8679684 TI - Regulation of prostaglandin synthesis in Madin Darby canine kidney cells: role of prostaglandin G/H synthase and secreted phospholipase A2. AB - The renal epithelial cell line MDCK (Madin Darby canine kidney) was used as a model system to investigate the contribution of the secreted phospholipase A2 type II(sPLA2) and cyclooxygenases to prostaglandin E2 (PGE2) synthesis. Activation of protein kinase C by the phorbol ester TPA led to an enhanced PGE2 synthesis within 1 hour, which continued for more than 20 hours. Treatment of the cells with TPA increased the activities of sPLA2 and cyclooxygenase. Activation of cyclooxygenase was reflected by an increase in cyclooxygenase-2 mRNA. Coincubation of the cells with TPA and a specific sPLA2 inhibitor (BM 16.2224) almost completely inhibited sPLA2 activity in the cell culture supernatants. TPA induced PGE2 synthesis was reduced by the inhibitor to about 50%. The inhibitor had no effect on cyclooxygenase activity or expression, indicating an involvement of sPLA2 in PGE2 synthesis. These experiments show that in resting cells, even in the presence of exogenous arachidonic acid, PGE2 synthesis was limited by the low abundance of cyclooxygenase. Enhanced expression and activity of cyclooxygenase, however, was not sufficient for increased prostaglandin synthesis. Availability of the precursor arachidonic acid seemed to be rate limiting in prostaglandin synthesis in stimulated MDCK cells. PMID- 8679685 TI - Correlation between level of (n - 3) polyunsaturated fatty acids in brain phospholipids and learning ability in rats. A multiple generation study. AB - The effects of dietary n - 3 polyunsaturated fatty acids (PUFAs) on major brain phospholipids were examined in the rat throughout four generations. Dietary fats were: a seal oil (22:6(n - 3) located mainly in the sn-1/3-position of the TG); a fish oil (22:6(n - 3) located mainly in the sn-2 position of the TG); or a vegetable oil containing 18:3(n - 3). The effect of the TG structure of the dietary fat and chain length of n - 3 PUFA on assimilation in the brain was compared with chow fed rats. The rats fed marine fats had significantly higher levels of long-chain n - 3 PUFAs in brain PE and PS, compared to the vegetable oil and chow fed rats, but no effects of TG structure of dietary fat were observed. Dietary 18:3(n - 3) raised the amount of 22:6(n - 3) compared to the control group, but not to the levels of the marine groups that received preformed 22:6(n - 3). Fish oil fed rats had higher levels of 20:5(n - 3) and 22:5(n - 3) compared with the seal oil fed rats, whereas 22:6(n - 3) were similar. Only minor changes in PI, PIP, and PIP2 were found. The fourth generation was tested for spatial learning ability in a Morris water maze. The experimental groups had similar learning abilities, which were increased compared to the control group. PMID- 8679686 TI - Inhibition of cholesterylester accumulation by 17 beta-estradiol in macrophages through activation of neutral cholesterol esterase. AB - Premenopausal women are at a lower risk of coronary heart disease relative to age matched men. However, the underlying mechanisms are not clearly understood. This article studies the effects of 17 beta-estradiol (17 beta-E2) at physiological concentrations on the cholesterylester metabolism in macrophages (J774 A.1 cells) with a particular focus on neutral cholesterol esterase (N-CEase). Cells were incubated with beta-VLDL, [1-14C]oleic acid and 17 beta-E2 (0.25 and 2.5 nM). 17 beta-E2 dose-dependently reduced cholesteryl-[1-14C]oleate (14C-CO) at 36 h and 48 h relative to the control. It also stimulated hydrolysis of 14C-CO in foam cells on 36 h and 48 h incubation. In addition, 17 beta-E2 markedly increased N CEase activity at 24 h and 36 h. This increase preceded the enhanced hydrolysis of cholesterylester, 17 alpha-E2 (inactive isomer), estrone and estriol had no stimulatory action on N-CEase, whereas progesterone and testosterone inhibited it. 17 beta-E2-treatment (24 h) increased the activity of cyclic AMP-dependent protein kinase (A-kinase). DEAE-cellulose column chromatography revealed that an isoform (type II) of A-kinase appeared in 17 beta-E2-treated cells in addition to type I of A-kinase found in the control cells. These results suggest that inhibition of cholesterylester accumulation in macrophages by 17 beta-E2 is mediated by an enhancement of N-CEase activity possibly through an increase in A kinase. PMID- 8679687 TI - Induction of lipid-protein mismatch by xenobiotics: kinetic cooperativity. AB - Lipophilic inhibitors such as general anaesthetics or drugs can conceivably act by displacing boundary lipid molecules that are required by many functional membrane proteins. The resulting lipid-protein mismatch has been analyzed previously in terms of multiple site kinetics (Sandermann H. (1993) Biochim. Biophys. Acta 1150, 130-133). Expressions for kinetic cooperativity are now derived, and data for the inhibition of dog kidney Na+,K+-ATPase and Escherichia coli lactose permease by organic solvents are presented and analyzed. Half maximal inhibitor concentrations were without diagnostic value because they were within the general range of critical solvent concentrations known for general anaesthesia and several membraneous and non-membraneous systems, as well as two specific liposomal parameters. The kinetic cooperativity of inhibition was of much higher diagnostic value because the cooperativity values for the solvent inhibition of Na+,K+-ATPase and lactose permease were characteristic for the lipid displacement mechanism, in contrast to cooperativity values of protein kinase C and luciferase. The latter enzymes are known not to require a boundary lipid layer, so that the degree of kinetic cooperativity provides a new diagnostic tool to distinguish between modes of action of lipophilic inhibitors. PMID- 8679688 TI - Reversible inhibition by protamine of human synovial and rabbit platelet secretory phospholipase A2. AB - We investigated the effects of protamine on the release and the activity of 14 kDa type II phospholipase A2 (sPLA2). Protamine blocks both release and activity of sPLA2 from thrombin-stimulated platelets in a concentration-dependent manner. Heparin, an anionic sulfate polysaccharide which has a high affinity for this enzyme, has no inhibitory effect on sPLA2 by itself but it is able to reverse the inhibitory effect of protamine. The liberation by thrombin of platelet factor 4, an alpha-granule constituent, unlike to that of ATP stored in dense bodies, was suppressed by protamine. Platelet aggregation, determined in parallel, was not affected by protamine. Also, protamine did not inhibit platelet arachidonic acid liberation, which is mainly produced by cytosolic PLA2. The non-proteinaceous polycationic hexadimethrine and acidic protein casein failed to inhibit platelet sPLA2 activity. By contrast, the basic polypeptides poly(L-arginine) and poly(L lysine) potently inhibited sPLA2 activity, indicating the important role of basic amino acids in the inhibitory effect evoked by protamine. Activities of the human recombinant sPLA2 and the unpurified synovial enzyme of patients with rheumatoid arthritis were also inhibited by the same range of protamine, poly(L-arginine) and poly(L-lysine) concentrations. Our results demonstrate that protamine, unlike heparin, blocks platelet sPLA2 release and exerts a reversible inhibitory effect on its activity, probably through the interaction of basic amino acids with the enzyme. PMID- 8679689 TI - Characterization of inositolphospholipids in Trypanosoma cruzi trypomastigote forms. AB - In vivo labeling experiments with [3H]palmitic acid, [3H]inositol, and [3H]glucose allowed the identification of two main classes of inositolphospholipids (IPLs) from the trypomastigote stage of Trypanosoma cruzi. Purification of these compounds was achieved by ion-exchange chromatography, high performance liquid chromatography and thin layer chromatography. Specific phosphatidyl-inositol phospholipase C digestion, dephosphorylation and acid methanolysis showed a ceramide structure for the lower migrating IPL1. Palmitoyldihydrosphingosine and palmitoylsphingosine were detected by reverse phase thin-layer chromatography. On the other hand, IPL2 showed to be a mixture of diacylglycero- and alkylacylglycero-phospholipids in a 1:1 ratio. After PI-PLC digestion, the lipids were separated by preparative TLC and individually analysed. The diacylglycerol contained mainly C18:0 fatty acid together with a low amount of C16:0. Hexadecylglycerol esterified with the C18:0 fatty acid was the only alkylacylglycerol detected. The C18:2 and C18:1 fatty acids, preponderant in the PI molecules of epimastigote forms, were not detected in trypomastigote forms. This is the first report on inositol phospholipids, putative precursors of lipid anchors in the infective stage of T. cruzi. PMID- 8679690 TI - The effect of leukotrienes B and selected HETEs on the proliferation of colon cancer cells. AB - Eicosanoids have been implicated in colon carcinogenesis, but very little is known on the potential role of leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) in this process; such compounds are produced by colonocytes and tumor infiltrating leukocytes. We studied the effect of LTB4, LTB4 methyl ester, LTB5, 12(R)-HETE, 12(S)-HETE and 15(S)-HETE (10(-10), 10(-8), 10(-6) M) on the proliferation rate, the cell cycle distribution, and the rate of apoptosis in HT 29 and HCT-15 human colon carcinoma cells. Our data show that LTB4, a lipoxygenase product, increased the proliferation rate of both cell lines in a time- and concentration-dependent manner. In HT-29 cells the concentration response curve was bell-shaped (maximal effect at 10(-8) M). The proliferative effects of LTB4 in HT-29 cells were inhibited by SC-41930, a competitive antagonist of LTB4, suggesting the existence of an LTB4 receptor in epithelial cells. The methyl ester of LTB4 stimulated the proliferation of these cells, but LTB5, an isomer of LTB4 derived from eicosapentaenoic acid, did not. Of the HETEs, only 12(R)-HETE, a P-450 product, stimulated the proliferation of both cell lines; the other HETEs, all lipoxygenase products, failed to affect the proliferation of these cells. None of these eicosanoids had any effect on cell cycle distribution or apoptosis in either cell line. Taken together with our previous data showing that PGs stimulate colon cancer cell proliferation (Qiao et al. (1995) Biochim. Biophys. Acta 1258, 215-223), these findings indicate that arachidonic acid products synthesized via at least three different pathways (cyclooxygenase, lipoxygenase, P-450) may not be able to modulate the growth of colon cancer, and suggest a potential role in human colon carcinogenesis for LTB4 and 12(R)-HETE. PMID- 8679691 TI - Mosaic structures of neurotoxins produced from Clostridium botulinum types C and D organisms. AB - We isolated the gene encoding a botulinum neurotoxin (BoNT) of 1285 amino acids with a molecular weight of 147,364 from the toxigenic bacteriophage d-sA of Clostridium botulinum type D strain South African (Dsa). The BoNT of Dsa (BoNT/Dsa) is composed of three regions on the basis of the homology to BoNT types C1 (BoNT/C1) and D (BoNT/D). The N-terminal (Met-1 to Val-522) and the C terminal regions (Trp-945 to Glu-1285) have high identity to corresponding regions of BoNT/D (96% identity) and BoNT/C1 (74% identity), respectively. The core region (Pro-523 to Lys-944) is common to three toxins (83% to 92% identity). These results suggest that neurotoxins produced from Clostridium botulinum types C and D are composed in a mosaic-like fashion. PMID- 8679692 TI - Molecular cloning and sequencing of a nuclear gene encoding tRNA(Gln) (UUG) from Arabidopsis thaliana. AB - A gene encoding cytoplasmic tRNA(Gln) (UUG) was isolated from an Arabidopsis DNA library. The coding sequence of the gene revealed 85% sequence identity with that of its animal counterparts. This is the first report of a nuclear tRNA(Gln) gene from higher plants. PMID- 8679693 TI - Cloning, sequencing and regulation of a cDNA encoding a small heat-shock protein from Schizosaccharomyces pombe. AB - We have isolated a Schizosaccharomyces pombe cDNA encoding a small heat-shock protein, designated Hsp9. The deduced amino acid sequence shares significant homology with the Saccharomyces cerevisiae Hsp12 gene product. Northern blot analysis identified a 600-base transcript which is expressed at a low level in S. pombe exponentially growing cells, but is strongly induced by heat-shock and upon entry into the stationary phase. An increase in the transcript level is also observed in response to glucose deprivation. PMID- 8679694 TI - Molecular cloning, expression and function of the murine CB2 peripheral cannabinoid receptor. AB - We have cloned the peripheral cannabinoid receptor, mCB2, from a mouse splenocyte cDNA library. The 3.7 kb sequence contains an open reading frame encoding a protein of 347 residues sharing 82% overall identity with the only other known peripheral receptor, human CB2 (hCB2) and shorter than hCB2 by 13 amino acids at the carboxyl terminus. Binding experiments with membranes from COS-3 cells transiently expressing mCB2 showed that the synthetic cannabinoid WIN 55212-2 had a 6-fold lower affinity for mCB2 than for hCB2, whereas both receptors showed similar affinities for the agonists CP 55,940, delta(9)-THC and anandamide and almost no affinity for the central receptor- (CB1) specific antagonist SR 141716A. Both hCB2 and mCB2 mediate agonist-stimulated inhibition of forskolin induced cAMP production in CHO cell lines permanently expressing the receptors. SR 141716A failed to antagonize this activity in either cell line, confirming its specificity for CB1. PMID- 8679695 TI - Molecular cloning of rabbit matrix metalloproteinase-2 and its broad expression at several tissues. AB - We have cloned cDNA encoding rabbit matrix metalloproteinase-2 (MMP-2, 72 kDa type IV collagenase) by a combination of conventional library screening, the 'single strand ligation to single-stranded cDNA (SLIC)' method and 'long and accurate PCR (LA-PCR)'. Deduced amino acid sequence was highly conserved through mammalian species. Northern blot analysis revealed that rabbit MMP-2 had 2 species of mRNA, 2.8 kbp and 3.5 kbp, and were expressed constitutively in all the tissues tested. This was totally different from mRNA expression of rabbit MMP 1, -3 and -9. PMID- 8679696 TI - Molecular cloning and sequencing of a cDNA encoding dihydropyrimidinase from the rat liver. AB - A cDNA encoding dihydropyrimidinase has been isolated from a rat cDNA library. The N-terminal and an internal amino acid sequences were determined, and PCR primers were designed based on these sequences. Using a cDNA fragment amplified by RT-PCR with these primers, three cDNA clones were isolated from a rat liver library. The clone with the longest insert of 2129 bp contained a 1557 bp open reading frame encoding a polypeptide of 519 residues with a molecular mass of 56,832 Da. PMID- 8679697 TI - Structural analysis of the mouse activin beta C gene. AB - Using a mouse activin beta C cDNA probe, we have cloned over 38 kb of genomic DNA encompassing the mouse activin beta C gene. Mouse activin beta C is encoded by 2 exons separated by a large 12.1 kb intron. Exon 1 encodes the 17 amino acid signal peptide and 88 amino acids of the propeptide. Exon 2 encodes the remaining 130 amino acids of the propeptide and the entire 117 amino acid mature peptide. Unlike the activin beta A and beta B expression patterns, Northern blot analysis of adult mouse tissues shows that the activin beta C mRNA is expressed only in the liver as a major species of approximately 2.1 kb. The liver-specific expression of activin beta C suggests an important role of dimeric activin beta C in normal liver function. These studies allow us to address the function of activin beta C in mammalian development. PMID- 8679698 TI - Cloning and characterization of cDNAs encoding two forms of avian stem cell factor. AB - Stem cell factor (SCF), also known as Steel factor, is a transmembrane cytokine involved in several developmental processes and the ligand for the receptor tyrosine kinase c-kit. In several mammalian species, two isoforms of stem cell factor have been reported, a long form in which soluble SCF is released after proteolytic cleavage of the extracellular domain and a short membrane-anchored form in which a region containing a cleavage site is deleted. Currently, only the longer, soluble form has been identified in birds. Therefore, the cDNAs encoding two forms of quail stem cell factor (qSCF) were obtained using RT-PCR with nested primers. The deduced amino acid sequence of the long form of qSCF showed a high degree of homology with chicken (98%) and relatively low homology (approximately 53%) with various mammalian SCFs. Northern blot analysis with the qSCF cDNA revealed the expression of a 5.9 and a 2.7 kb transcript in several quail tissues. PMID- 8679699 TI - Molecular cloning and sequence analysis of the cDNA encoding rat liver cysteine sulfinate decarboxylase (CSD). AB - The taurine biosynthesis enzyme, cysteine sulfinate decarboxylase (CSD), was purified to homogeneity from rat liver. Three CSD peptides generated by tryptic cleavage were isolated and partially sequenced. Two of them showed a marked homology with glutamate decarboxylase and their respective position on the CSD amino acid sequence was postulated accordingly. Using appropriate degenerated primers derived from these two peptides, a PCR amplified DNA fragment was generated from liver poly(A)+ mRNA, cloned and used as a probe to screen a rat liver cDNA library. Three cDNAs, length around 1800 bp, were isolated which all contained an open reading frame (ORF) encoding a 493 amino acid protein with a calculated molecular mass of 55.2 kDa close to the experimental values for CSD. The encoded protein contained the sequence of the three peptides isolated from homogenous liver CSD. Our data confirm and significantly extend those recently published (Kaisaki et al. (1995) Biochim. Biophys. Acta 1262, 79-82). Indeed, an additional base pair found 1371 bp downstream from the initiation codon led to a shift in the open reading frame which extended the carboxy-terminal end by 15 amino acid residues and altogether modified 36 amino acids. The validity of this correction is supported by the finding that the corrected reading frame encoded a peptide issued from CSD tryptic cleavage that was not encoded anywhere in the CSD sequence previously reported. PMID- 8679700 TI - Isolation and characterization of cDNA and genomic clones encoding human muscle type carnitine palmitoyltransferase I. AB - With a cDNA probe encoding rat muscle type carnitine palmitoyltransferase I (CPTI), we isolated cDNA and genomic clones encoding the human homologue and deduced the primary structure of human muscle type CPTI. By Northern analysis, we confirmed the dominant expression of this isoform in heart and skeletal muscle. PMID- 8679701 TI - The promoter-proximal, unstable IB region of the atp mRNA of Escherichia coli: an independently degraded region that can act as a destabilizing element. AB - Differential expression of the genes in the Escherichia coli atp (unc) operon is achieved via control of the translational initiation, translational coupling and mRNA stability of the respective genes. The atpIB region of the polycistronic mRNA is less stable than the remaining seven genes. We have investigated the functional half-lives of the atp genes in reconstructed versions of the operon. In order to be able to do this reliably, we have readdressed the interpretation of the complex functional inactivation data obtained by means of transcriptional inhibition using rifampicin. Our results indicate the usable information to be gleaned from this commonly applied technique, while identifying the potential errors in their quantitative interpretation. We estimate that the functional half life of atpB is slightly over one-half that of atpE and the other atp genes, while atpI is at least two times less stable than atpB. The instability of the atpI mRNA was also demonstrated by its rapid fragmentation. Relocation of atpIB to a position in the promoter-distal region of the operon between atpG and atpD did not change the inactivation rate of atpB. However, it did destabilize the atpG mRNA. Examination of the physical degradation of atpI mRNA shows particularly rapid cleavage in this gene, thus explaining the destabilization effect. The atpIB segment is therefore an autonomously unstable region that can act as a destabilizing element for upstream-located genes in a polycistronic environment. PMID- 8679702 TI - Effect of differential gene expression on the chromatin structure of the DHFR gene domain in vivo. AB - Photoactivated psoralen was used to probe region-specific chromatin structure in Chinese hamster ovary (CHO) cells. Specifically, the chromatin structure of six regions within the dihydrofolate reductase (DHFR) gene was probed with photoactivated psoralen in cells cultured in such ways as to differentially express the DHFR gene. Cells were irradiated with X-rays prior to the psoralen photocross-linking reaction in order to eliminate the influence of any DNA torsional tension on the psoralen binding and the sequence-specificity of psoralen binding was adjusted for. It was found that a region encompassing the promoter of the serum-regulated DHFR gene was about 50% more accessible to psoralen photocross-linking in serum-stimulated cells and about 90% more accessible in serum-starved cells than the other five regions of the DHFR gene analyzed and the genome overall. Treating serum-stimulated cells with the RNA polymerase II transcriptional inhibitor 5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole (DRB) or the topoisomerase I inhibitor camptothecin reversed the elevated accessibility of the DHFR promoter region. These results suggest that the accessible chromatin structure of the DHFR promoter is not dependent on serum stimulated poising of the gene for transcription, but may reflect the ability of the RNA polymerase to clear the promoter. PMID- 8679703 TI - Construction of single amino acid substitution mutants of cloned Bacillus stearothermophilus DNA polymerase I which lack 5'-->3' exonuclease activity. AB - Two individual amino acid substitutions were engineered at a selected site in the 5' --> 3' exonuclease domain of the cloned Bacillus stearothermophilus DNA polymerase I gene. These mutations resulted in the expression of enzymes lacking the 5' --> 3' exonuclease activity while maintaining normal polymerizing activity. The mutated and non-mutated enzymes were each constitutively expressed in an Escherichia coli host without the use of an exogenous or inducible promoter, and the mutated enzymes were demonstrated to be equivalent to the subtilisin large fragment of the native holoenzyme in sequencing reactions. PMID- 8679704 TI - Molecular cloning of the acr-2 gene which controls acriflavine sensitivity in Neurospora crassa. AB - The acr-2 gene of Neurospora crassa was cloned by complementation of the wild type strain by DNA from an acriflavine-resistant strain, acr-2. The transcript of the acr-2 gene is 2.3 kb long and contains two leader open reading frames (ORFs) that precede the acr-2 coding region and, if translated, they would generate sequences of 23 and 43 amino acid residues, respectively. The predicted ACR-2 protein contains 595 amino acids that include a putative Zn(II)Cys6 binuclear domain that is followed by a rather long serine/threonine-rich region near the amino-terminus. The acr-2 mutation, which confers acriflavine resistance, substitutes the amino acid residue at position 303 of the encoded protein from asparagine to lysine. Progeny that were hypersensitive to acriflavine were obtained by disruption of the acr-2 gene by repeat induced point mutation (RIP). The level of expression of the acr-2 gene is significantly higher in the acr-2 strain than in the wild-type strain. These results indicate that the acr-2 gene controls acriflavine sensitivity in N. crassa. PMID- 8679705 TI - In vitro analysis of the HIV-1 second strand-transfer reaction. AB - Two strand-transfer reactions are required during the retroviral reverse transcription. The second strand-transfer is believed to occur at the primer binding site (PBS). By using an in vitro model system derived from the human immunodeficiency virus type-1 (HIV-1), molecular events related to the second strand-transfer reaction were examined. The RNA-directed DNA synthesis catalyzed by the HIV-1 reverse transcriptase (RT) appears to pause twice, around the 2nd and the 11th bases downstream into the HIV-1 PBS. In either case, pausing seems to be caused by local sequence effects. From both these pause sites the nascent DNA strands can undergo transfer to PBS-homologous templates. The results confirm that pausing favors the internal strand-transfer. They also indicate that PBS mediated transfers proceed through displacement of the DNA strands from RNA donor molecules by the acceptor template, as in one of the models proposed by DeStefano et al. (DeStefano, J.J., Bambara, R.A. and Fay, P.J. (1994) J. Biol. Chem. 269, 161-168). Whereas no hydrolysis by the ribonuclease H activity of HIV-1 RT seemed to occur within the HIV-1 PBS, specific cleavage was observed outside of this sequence and noticeably 5 bases upstream from its 3' end relative to the DNA primer growing point. This particular cleavage event remained essentially unchanged when the second pause site downstream into the PBS, located 16 bases beyond, was removed by mutation. The experiments suggest that this prominent RNA degradation event could precede the PBS-mediated strand-transfers. PMID- 8679706 TI - Duplication and evolution of the P-glycoprotein genes in pig. AB - The P-glycoproteins (Pgp's) are a small family of proteins frequently associated with the multidrug resistance phenotype in drug-selected cell lines. The number of Pgp isoforms in different mammalian species is variable although the reason for having a larger or smaller number of isoforms is not known. Two isoform classes from human, and three from rodents have been extensively characterised and have been shown to have independent expression patterns and substrate preferences. We have cloned 3' terminal genomic fragments for five members of the Pgp multigene family from the pig, which is the largest number of Pgp genes found in any mammalian species to date. Sequential duplications of one class of Pgp gene have given rise to this large gene family since four genes show similarity to the drug resistance-causing Class I isoform of Pgp. The fifth pig Pgp gene shows similarity to the phosphatidylcholine-translocating Class III isoform. The history of the duplications creating this large gene family can be traced by atypical features which have been inherited in common. These include a mutation in the stop codon at the 3' end of four Class I Pgp genes, increasing the coding region by six amino acids, and a SINE element of the PRE1 family inserted into the 3' untranslated region of three Class I Pgp's. We demonstrate expression of Class I pgp in pig brain cultured capillary endothelial cells, and Class III pgp in the liver, two important sites of expression of Pgp in rodents and humans. Thus there appears to be strong phylogenetic conservation in mammals of both sequence and expression of these two Pgp isoforms. PMID- 8679707 TI - Intracellular distribution of HMG1, HMG2 and UBF change following treatment with cisplatin. AB - Cisplatin (CDDP) is a widely used cancer chemotherapeutic agent. CDDP forms well characterized intrastrand cross-links between adjacent purines in genomic DNA. In mammalian cells, these lesions are repaired by the nucleotide excision repair system. An early event in the recognition and processing of cis-Pt-DNA adducts may well involve the binding of specific proteins to the sites of damage. Several proteins have been identified, including high mobility group (HMG) proteins 1 and 2 and upstream binding factor (UBF), which recognize CDDP-DNA. However, the physiological significance of this binding has not been established. In this study, we have utilized antibodies to these proteins to examine the effect of CDDP on their intracellular distribution. Marked changes in the immunofluorescent staining pattern of HMG1/HMG2 were noted in cells treated with CDDP. At higher drug concentrations, the distribution of UBF also changed, from a clustered appearance associated with the nucleoli to more diffuse nuclear staining. These results demonstrate that HMG1/HMG2 and UBF respond to drug treatment, presumably by recognizing cis-Pt-DNA adduct formation in intact cells. Hence, these proteins may play an important role in directing the response of tumor cells following exposure to CDDP. PMID- 8679708 TI - Characterization of the human and mouse Fli-1 promoter regions. AB - Overexpression of the Fli-1 gene has been shown to be involved in retrovirus induced mouse tumors. Cloning of the 5' flanking sequence of the mouse and human Fli-1 exon 1 was performed. At least two major transcription initiation sites were localized respectively at 143 and 114 nucleotides upstream of the previously defined mouse Fli-1 cDNA 5' end. The sequences flanking the CAP sites show good conservation between human and mouse (94%). The promoter region contains a potential TATA box lying 30 bp from one of the major identified CAP sites. Several conserved elements, such as GATA, EBS, GC rich, AP-2, AP-3 elements and a repetition of GA were observed next to the two major CAP sites. Furthermore, this latter was shown to form a H-DNA structure in vitro by S1 nuclease sensitivity experiments. The highly conserved 5' non-translated region of exon 1 is predicted to form a very stable hairpin structure which could regulate the Fli-1 expression at the post-transcriptional level. In Cas-Br-E-induced tumors, all the proviruses are found clustered within 35 nucleotides directly upstream the Fli-1 ATG start codon, thus deleting the hairpin structure from the transcript. Promoter activity was tested using the CAT reporter gene transfected in mouse and human erythroid cell lines. No promoter activity could be detected with various mouse Fli-1 promoter-CAT constructs containing 600 bp of the 5' flanking region, the complete exon 1, the 5' end of intron 1 and/or retroviral LTR sequence. Constructions of the human homologue containing nearly 1.5 kbp of Fli-1 5' flanking region was also inactive in transfected cells. These results suggest that multiple levels of regulation might control the Fli-1 expression. PMID- 8679709 TI - Expression of ceruloplasmin gene in human and rat lymphocytes. AB - The acute phase plasma protein ceruloplasmin (Cp) appears to play some role in host defense. The possibility that production of Cp in extrahepatic sites may also be essential for the activation, effector functions and cytoprotection of immune cells in localized environments has received minimal attention. Here, we have surveyed various types of human and rat immune cells for the presence of Cp mRNA using RT-PCR with primers that span exons 17-19 as an initial step in addressing this possibility. Validated Cp RT-PCR bands were obtained from RNA samples isolated from resting and activated human lymphocytes, CD4 and CD8 T cells and B-cells. Semiquantitative RT-PCR indicated that Cp mRNA in immune cells is present at about 0.2% the level of Cp mRNA in HepG-2 human liver cell line. Various human cell lines derived from the immune system, rat splenic MNC and purified rat T-lymphocytes also constitutively express Cp gene. PMID- 8679710 TI - Analysis of foetal expression sites of human type II DNA topoisomerase alpha and beta mRNAs by in situ hybridisation. AB - We present the first analysis of the sites of expression of DNA topoisomerase II alpha and II beta mRNAs in human foetal tissues by in situ hybridisation, using 35S-radiolabelled probes. This revealed differential localisation of topoisomerase II alpha and II beta mRNAs in a range of foetal organs, including foetal kidney (developing structures within the neogenic zone), brain (cortical layers), small intestine (crypt epithelium and muscle), liver (hepatocytes), lung (smooth muscle, and epithelium in the lining of primitive lung buds) and placenta (trophoblastic epithelium). The intensity of expression of topoisomerase II alpha mRNA appeared higher than that of topoisomerase II beta, although topoisomerase II beta mRNA was expressed in a broader range of cell types. The distinct patterns of expression of topoisomerase II alpha and beta mRNAs indicate differential regulation of these genes, suggesting that the two isoforms may play important but different roles in foetal development, with topoisomerase II alpha being expressed most strongly in zones of proliferation. PMID- 8679712 TI - Neuronal differentiation of embryonic stem cells. AB - Neuronal differentiation from totipotent precursors in vitro, is thought to require two signals: first a biophysical state (cellular aggregation) followed by a biochemical signal (retinoic acid treatment). In investigating the properties of retinoic acid-differentiated embryonic stem cell lines. However, we noted that retinoic acid treatment without prior aggregation, is sufficient to induce expression of the neuronal markers GAP-43 and NF-165. In agreement, immunohistochemistry revealed the presence of GAP-43 positive cells in these embryonic stem cell monolayers after three days of retinoic acid (RA) treatment. Furthermore an NF-165 positive subpopulation of cells was clearly observed after 4-5 days of RA treatment. The expression of these neuronal markers coincided with the appearance of electrically excitable cells, as assayed with whole cell patch clamp recording. We conclude that for neuronal differentiation of totipotent embryonic stem cells in vitro, one biochemical signal, i.e. retinoic acid treatment, is sufficient. PMID- 8679711 TI - Complete inhibition of poly(ADP-ribose) polymerase activity prevents the recovery of C3H10T1/2 cells from oxidative stress. AB - Activation of the poly(ADP-ribose) polymerase after oxidative damage is implicated in different responses of the cells, for example, cell recovery after sublethal damage or cell death after lethal damage. However, the extent and mechanism of involvement of the enzyme in these two processes appear to be different. Inhibitors of this polymerase, such as benzamides, which do not completely inhibit PARP have been shown to protect the cells from killing by massive oxidant damage, could neither reduce the cellular recovery after mild oxidant damage nor completely inhibit DNA repair in vitro. We report here that 1,5-dihydroxyisoquinoline, which was earlier shown to be a strong inhibitor of this polymerase in vitro, is also its potent inhibitor in vivo. Using sensitive techniques for measuring low levels of cellular poly(ADP-ribose) polymer, we show that this inhibitor can completely abolish oxidant-induced activation of the polymerase in C3H10T1/2 cells. We show that only a minor fraction of the poly(ADP ribose) polymerase activity is sufficient in cellular recovery after sublethal oxidant damage. We also demonstrate that cells are unable to recover from oxidant damage in the complete absence of polymerase activity. PMID- 8679713 TI - Serum-starvation induces the extracellular appearance of FGF-1. AB - Autocrine/paracrine stimulation of cell growth by members of the fibroblast growth factor (FGF) family of polypeptides is dependent upon extracellular interactions with specific high affinity receptors at the cell surface. Acidic FGF (FGF-1) lacks a classical signal sequence for secretion, suggesting that intrinsic levels of this mitogen may not stimulate cell growth and utilizes a non classical pathway to gain access to the extracellular compartment. To evaluate the biological potential of intracellular FGF-1 more rigorously, human cDNA sequences for the growth factor were introduced into primary murine embryonic fibroblasts using retrovirally mediated gene transfer. Heparin affinity, Western analysis, mitogenic assays, in situ immunohistochemical techniques, induction of tyrosine phosphorylation and antibody inhibition studies were used to demonstrate functionality of the FGF-1 transgene in this experimental model. Under normal culture conditions, cells constitutively expressing intracellular FGF-1 exhibited a slight growth advantage. In contrast, when maintained in reduced serum, these cells adopted a transformed phenotype and demonstrated an enhanced growth potential, induction of FGF-specific phosphotyrosyl proteins and the nuclear association of the growth factor. Analysis of the conditioned media from these stressed cells indicated that serum starvation induces the secretion of FGF-1 as latent high molecular mass complexes requiring reducing agents to activate its full biological potential. PMID- 8679714 TI - Topological organization of the cytosolic activating complex of the superoxide generating NADPH-oxidase. Pinpointing the sites of interaction between p47phoz, p67phox and p40phox using the two-hybrid system. AB - Activation of the superoxide-generating NADPH-oxidase in phagocytic cells requires the assembly of a membrane-bound flavocytochrome b and cytosolic factors p47phox and p67phox under the control of the GTP-binding protein, Rac. A novel cytosolic component p40phox was recently identified. Most of the components of the complex contain SH3 domains and/or polyproline motifs which are likely to mediate protein-protein interactions occurring in the formation of the active NADPH-complex. The two-hybrid system was used to explore associations between the cytosolic factors. Various constructs of p47phox, p67phox and p40phox cDNAs coding for functional domains were inserted into two-hybrid system vectors, expressing fusion proteins either with the DNA binding protein Lex A or with the activation domain of Gal 4. The site of interaction of p67phox with p47phox was restricted to the C-terminal SH3 domain of p67phox and to the polyproline motif of p47phox. The polyproline motif of p47phox was also found to mediate interaction with the SH3 domain of p40phox, as well as intramolecular interaction within p47phox. The site of interation of p67phox with p40phox was found to be in the 150 amino acid stretch between the two SH3 domains of p67phox. As the C terminal tail of p40phox which interacts with p67phox contains neither a SH3 domain nor a polyproline consensus site, it is concluded that a novel type of interaction occurs between p40phox and p67phox. Taken together, the results of the two-hybrid experiments led us to formulate a model for oxidase activation, induced by phosphorylation, in which p40phox tends to prevent spontaneous activation. PMID- 8679715 TI - Evidence for a link between translocation and processing during protein import into soybean mitochondria. AB - The effect of metal chelators on protein import was investigated using isolated soybean mitochondria and soybean precursor proteins. Adding 1,10-phenanthroline, a metal chelator that can cross both mitochondrial membranes abolished import of both the alternative oxidase, and the F(A)d subunit of the ATP synthase, a matrix located protein. Other metal chelators such as EDTA, 1,7-phenanthroline and 4,7 phenanthroline, which cannot cross the mitochondrial membranes, had no effect on import. When processing, a known metal-dependent step inside mitochondria, was inhibited using a mutagenesis approach (changing a -2 arginine to a -2 glycine in the pre-piece of the precursor), so was import. Thus it would appear that in soybean, at least, translocation of proteins across the mitochondrial membrane, as well as processing, relies on a metal dependent step. Taken together, the data suggest the two processes may be directly connected in these mitochondria. PMID- 8679716 TI - Evidence for coordinated regulation of osteoblast function by 1,25 dihydroxyvitamin D3 and parathyroid hormone. AB - From several animal studies and clinical observations it became evident that at target tissue level 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and parathyroid hormone (PTH) must act in an interrelated manner. In the present study we examined the interaction between 1,25-(OH)2D3 and PTH in the target cell of these hormones in bone, the osteoblast. In addition we studied the role of PTH activated signal pathways. The three osteoblastic cell lines UMR 106, ROS 17/2.8 and MG-63 were used as model systems. In UMR 106 cells 1,25-(OH)2D3 and PTH caused a synergistic up-regulation of the vitamin D receptor (VDR) which was accompanied by a synergistic induction of VDR mRNA expression whereas in both ROS 17/2.8 and MG-63 cells no interaction was observed. In UMR 106 cells the effect of PTH on homologous up-regulation of VDR could be mimicked by the cAMP agonist forskolin and by dibutyrylic-cAMP. Phorbol ester activation of protein kinase C reduced basal as well as 1,25-(OH)2D3-induced up-regulation of VDR. 1,25-(OH)2D3 induced 24-hydroxylase activity in UMR 106 and MG 63 cells and, in contrast to VDR regulation, in both cell lines PTH and 1,25-(OH)2D3 synergistically induce 24 hydroxylase activity. Similar to VDR regulation the effect of PTH was mimicked by activation of cAMP production whereas protein kinase C activation reduced the induction by 1,25-(OH)2D3. Finally, we examined the interaction with respect to osteocalcin synthesis. In ROS 17/2.8 and MG-63 cells 1,25-(OH)2D3 stimulated osteocalcin production. In ROS 17/2.8 cells PTH as well as stimulation of cAMP production by forskolin enhanced 1,25-(OH)2D3-induced osteocalcin production whereas, as we have shown previously, activation of protein kinase C does not change 1,25-(OH)2D3-stimulated osteocalcin production. In MG-63 cells neither PTH nor forskolin significantly changed 1,25-(OH)2D3 induction of osteocalcin synthesis. From the present study it can be concluded that indeed at target cell level 1,25-(OH)2D3 and PTH act in a coordinated manner. On basis of the potentiation of 1,25-(OH)2D3 action by PTH in osteoblasts together with the previously reported inhibition of PTH-stimulated cAMP production by 1,25-(OH)2D3 we postulate a negative feedback-loop at target cell level. The activation of the cAMP pathway results in an enhancement of the 1,25-(OH)2D3 action whereas the protein kinase C pathway attenuates the 1,25-(OH)2D3 action. Finally, the present study provides a basis for the indications from in vivo observations about an interrelated action of 1,25-(OH)2D3 and PTH at the target cell. More generally it demonstrates on the basis of analyses of endogenous cellular responses evidence for an interplay between receptor-activated pathways of peptide and steroid hormones. PMID- 8679718 TI - Pioglitazone attenuates the inhibitory effect of phorbol ester on epidermal growth factor receptor autophosphorylation and tyrosine kinase activity. AB - A new anti-diabetic drug, pioglitazone, was tested as to whether it could ameliorate the decreased kinase activity of epidermal growth factor (EGF) receptor induced by phorbol ester (PMA) in A431 cells. The treatment of A431 cells with PMA decreased the tyrosine kinase activity of EGF receptors to 37% of normal in autophosphorylation and to 24% in tyrosine kinase activity toward Glu/Tyre synthetic polymers. Co-incubation of the cells with pioglitazone and PMA improved the receptor tyrosine kinase activity to 81% of control. Pioglitazone treatment alone did not change the kinase activity of EGF receptors. Pioglitazone did not decrease the PMA-activated protein kinase C activity and did not affect the protein tyrosine phosphatases activity in A431 cells. These results suggest that pioglitazone may act as a specific antagonist to the inhibitory effect by protein kinase C on the EGF receptor tyrosine kinase. PMID- 8679717 TI - cDNA cloning and characterization of rat Clk3, a LAMMER kinase predominately expressed in testis. AB - A cDNA clone of a protein kinase with high similarity to the Clk (Cdc2-like kinases) subfamily was isolated from a rat brain library and characterized. Its deduced amino acid sequence exhibited a 99% identity with human Clk3 and was therefore designated rat Clk3. In addition to the protein kinase domain, the sequence (490 amino acids) comprises an N-terminal domain with a strikingly high portion of basic amino acids. A glutathione S-transferase fusion protein of Clk3 catalyzed autophosphorylation of the kinase but not phosphorylation of the exogenous substrates histone or casein. By Northern blot analysis of different rat tissues, mRNA of Clk3 was detected predominately in testis, suggesting that this kinase regulates a predominately testicular function. PMID- 8679719 TI - Kinetics and specificity of human B-cell glucokinase: relevance to hexose-induced insulin release. AB - The present study reevaluates the relevance of human B-cell glucokinase activity to the process of hexose-induced insulin release. Taking into account a phenomenon of positive cooperativity (Hill number: 1.34), the Km of the enzyme for glucose ( < or = 5.1 mM) was lower than the concentration of the hexose required to cause half-maximal stimulation of insulin release in intact islets. Likewise, there were obvious discrepancies between the kinetics of glucose, mannose and fructose phosphorylation by B-cell glucokinase, e.g. in terms of maximal velocity, and the secretory and metabolic responses to these hexoses in intact islets. Glucose 6-phosphate decreased, modestly but significantly, B-cell glucokinase activity, such an inhibitory action being of the non-competitive type. Mannoheptulose caused competitive inhibition of B-cell glucokinase. It is concluded that the intrinsic catalytic properties of B-cell glucokinase cannot fully account for the concentration dependency and sugar specificity of the secretory response to D-glucose or other hexoses in pancreatic islets. PMID- 8679720 TI - Induction of murine erythroleukemia cell differentiation is associated with methylation and differential stability of poly(A)+ RNA transcripts. AB - Murine erythroleukemia (MEL) cells exposed to DMSO were assessed for their ability to methylate poly(A)+ RNA and accumulate RNA transcripts of globin and nonglobin genes (c-myc, beta-actin and MER5). Cells were pulse-labeled with L [methyl-3H]methionine, cytoplasmic RNA was isolated, selected for poly(A)+ RNA and analyzed by HPLC chromatography for methylated nucleosides. When MEL cells were exposed to inhibitors of RNA methylation (neplanocin A, 3-deazaneplanocin A and cycloleucine) and assessed for their ability to differentiate by DMSO, accumulate RNA transcripts, produce hemoglobin, methylate poly(A)+ and poly(A)- RNA and synthesize S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), we observed the following: (a) MEL cells treated with DMSO underwent hypermethylation in poly(A)+ RNA that preferentially occurred at the 5'-cap structures (7-methylguanosine and 2'-O-methylcytidine and 2'-O-methyluridine); (b) inducer-treated MEL cells exhibited a decrease in the intracellular level of SAH that led to a lower ratio of SAH/SAM, an event that favors methylation; and (c) treatment of MEL cells with inhibitors of RNA methylation suppressed methylation of poly(A)- and poly(A)+ RNA, reversed the ratio SAH/SAM seen in differentiated MEL cells and prevented differentiation to occur. Moreover, we observed that treatment of MEL cells with selective inhibitors of RNA methylation caused fragmentation of beta major globin and c-myc mRNAs, two RNA transcripts coded by developmentally regulated genes, while had no detectable effect on the structural integrity of poly(A)+ RNA transcripts transcribed by two housekeeping genes (beta-actin and MER5). These data indicate that induction of erythroid cell differentiation of MEL cells is associated with changes in methylation of poly(A)+ RNA and selective differential stability of RNA transcripts, two events that might be related to each other. PMID- 8679721 TI - [Acute abdomen in extensive thrombosis in the inferior vena cava collateral circulation]. AB - Variations of the inferior vena cava (IVC) because of either embryonal malformations or postthrombotic changes are not uncommon. The clinical symptoms include repetitive thrombotic events. We report on an atypical case of acute abdomen resulting from thrombotic occlusion of the IVC and the right renal vein as well as of the collateral vessels. PMID- 8679722 TI - [Leiomyosarcoma of the pulmonary artery]. AB - In a 58-year-old man, a leiomyosarcoma was found to be the cause of unclear thoracal pain on the right side. The initial diagnose was an embolus of the pulmonary artery. The MRI showed a suspicious area similar to an intravasal tumor. PMID- 8679723 TI - [Thrombosis of the upper thoracic inflow vessel. Spiral CT and 3-D reconstruction]. AB - Spiral-CT-Depiction and 3D-Reconstruction: A patient complaining of upper thoracic inlet syndrome after thyroidectomy underwent contrast-enhanced spiral CT. Coronal reconstructions and three-dimensional reconstructions were used to generate phlebographic images of the thoracic inlet veins thrombosis. The diagnosis of thrombosis was confirmed by phlebography. PMID- 8679724 TI - [Dose reduction in computerized tomography with a new scan procedure]. AB - A new investigation technique in computed tomography--the Smart Scan process--and the associated reduction in tube current are discussed. In addition, the reduced dosage values resulting from the reduced current values are compared with those of a standard measurement and image characteristics such as picture unit noise are evaluated. By means of three special water phantoms with dimensions corresponding to those of actual patient geometries and a pool of 183 patients, the Smart Scan process was tested by the control algorithm implemented on a spiral computer tomograph. The dosage values with and without the Smart Scan being activated were determined. Dosage reductions of up to 18% can be realized with this new examination technique. In particular, patients with transverse oval head profiles will benefit from this modality. PMID- 8679725 TI - [Quality control in diagnostic imaging--ROC curves]. PMID- 8679726 TI - [The value of MRI in staging gynecologic tumors]. AB - Traditionally gynecologic malignancies are staged by examination under anaesthesia which provides high accuracy as far as small tumors are concerned. In advanced tumors clinical staging is often inaccurate because of the difficulty to evaluate parametrial or myometrial tumor infiltration or lymphatic tumor spread. Therefore imaging modalities, such as sonography, computed tomography (CT), and magnetic resonance imaging (MRI), are required in most cases. The range of applications for MRI imaging includes staging, therapy planning, and follow-up examinations of uterine tumors and recurrent carcinoma. Based on its excellent soft tissue contrast, which allows a precise differentiation between several tissues and its direct multiplanar imaging capability, MRI is superior to sonography and CT. Only in the staging of ovarian carcinoma has the value of MRT not yet been defined, nevertheless it seems to offer diagnostic advantages over CT and sonography on account of its higher specificity. CT lose some of its value after the introduction of MRI into clinical practice. Indications for the use of CT are advanced space-occupying tumors with lymphatic spread or peritoneal implants as well as monitoring the tumor response to therapy for ovarian cancer. Sonography, as the technically simplest imaging modality, has consistently demonstrated its value as a screening method in the evaluation of benign gynecologic disease and is traditionally used for the detection of ovarian masses. PMID- 8679727 TI - [Ultrasound examination of the female breast: comparison of 7.5 and 13 MHz]. AB - PURPOSE: We investigated whether the high resolution ultrasound (13 MHz-scanner) shows smaller lesions and better differentiation than the 7.5 MHz-scanner. METHOD: Prospectively, sonography was performed on forty-seven patients with a 7.5 MHz-scanner as well as with a 13 MHz-scanner in identical slices. RESULTS: Obviously we could obtain more exact diagnoses by using the high resolution scanner. In two patients additional satellite of the primary tumor could be found. In four patients, unclear sonographic findings could be identified as cysts. A disadvantage in the usage of the 13 MHz-scanner is that mastopathy and benign lesions are more difficult to diagnose. With the high resolution more details could be seen although the inhomogeneity as well as the irregularity of the margins are seen more clearly and, therefore, the physician has to reestimate his point of view. To optimize the quality of the pictures made by high resolution ultrasound, it is necessary to regulate the system, which sometimes is quite difficult. CONCLUSION: The recognition of smallest lesions and the reliable presentation of cysts indicates that the 13 MHz-scanner is a good additive diagnostic parameter to the 7.5 MHz-scanner. Therefore, this method may become important for diagnosing multicentrity within carcinomas. PMID- 8679728 TI - [Results of radiologic follow-up of patients with automatic implantable cardioverter-defibrillators]. AB - In the follow-up of patients with automatic implanted cardioverter defibrillators (AICD), the serial radiographs give us important information concerning the cardiac function, signs of cardiac insufficiency may be a first sign of a dysfunction of the implanted aggregate or of the system of electrodes. Not only the short term but also the radiographs over a long period of time are important. The estimation of the correct positions of the electrodes is important too, for dislocation or disconnection of the electrodes lead to a misfunction of the AICD. On the other hand a kinging or a disconnection of the marker-stripe of plain surfaced electrodes needs no correction for they do not lead to a misfunctioning AICD. Beside the serial radiographs, radioscopy is important because a disconnection of the electrodes often is not visible except by radiography. PMID- 8679729 TI - [Use of digital luminescence radiography in voiding cystourethrography]. AB - PURPOSE: Optimization of image quality by use of digital luminescence radiography (DLR) in voiding cystoureterography (VCU) instead of a conventional screen film system. PATIENTS AND METHODS: 53 patients with a suspected vesicouretral reflux were examined with a VCU in analogous and digital technique. The X-rays were taken in a sitting position while simultaneously measuring the bladder pressure. An intraindividual comparison was omitted for X-ray saving reasons. In the follow up 3 patients were examined with the other system. Two radiologists and two urologists compared 60 VCU of 53 patients--30 VCU in conventional screen film and 30 in DLR technique presented in standard and edge-enhanced images--with regard to image quality according to 3-step score (A--good image quality, B--sufficient image quality, C--insufficient image quality). RESULTS: The 59 conventional films were scored 72 times with an A, 76 times with a B, and 72 times with a C, whereas the DLR films were scored 116 times with an A, 72 times with a B, and only 8 times with a C. Hereby the edge-enhanced images were the most useful for distinguishing the bladder shadow from the soft tissue of the thigh and for detecting reflux. Furthermore, the exposure dose when applying DLR could be decreased to 75% in grown-ups and to 57% in children without any significant loss of information. CONCLUSION: The DLR is highly superior to the conventional film screen system because of its relatively high tolerance towards wrong exposures, especially with respect of the sitting position during MCU. With the DLR we obtained 96% and with the conventional system only 63% films usable for diagnosis. PMID- 8679730 TI - [Dacryocystography in digital subtraction technique]. AB - The authors emphasize the usefulness of dacryography to approach patients affected by epiphora. Digital dacryocystography had improved the anatomic and functional assessment of lacrimal apparatus. The methodology allowed in all patients an accurate visualization of the lacrimal system and the identification, in twenty cases, of pathological causes of epiphora. One patient was examined after dacryocystorinostomy. Digital dacryocystography is a very valuable technique for better contrast resolution, the subtraction of images, and continuous acquisition. PMID- 8679731 TI - [Can pharmaco-DSA of the kidney replace intraoperative rapid biopsy diagnosis?]. AB - QUESTION: Can primary nephrectomy be performed without preliminary sample excision of the tumor if pharmaco-angiography of the kidney has demonstrated the typical tumor vascularization? MATERIAL AND METHOD: To clarify this question in 32 patients with "displacing mass" of the kidney, verified in sonography and computer-tomography, or hematuria of unknown origin, we prospectively performed and additional pharmaco-angiography of the respective kidney. RESULTS: In 18 patients with tumor vascularization in the pharmaco-angiography, intraoperatively we found 15 malignant renal cell carcinomas, 1 patient with transitional cell carcinoma of the renal pelvis, 1 leiomyosarcoma, and 1 high-differentiated tumor of only 2 cm in diameter with unclear dignity, which was treated by enucleation. CONCLUSION: In case of an intrarenal lesion of more than 3 cm in diameter and additional tumor vascularization seen in selective pharmaco-angiography, the kidney undoubtedly can be removed by primary nephrectomy without a preliminary sample excision to confirm the diagnosis. For tumors with a diameter of less than 3 cm and additional tumor-vascularization, the option should be enucleation. If there is a "tumor" without typical malignant vascularization, the exploration by sample excision should be performed. Depending on the histological result the tumor should be removed by enucleation or nephrectomy. PMID- 8679732 TI - [clinical application of multiplanar and 3D reconstruction of spiral CT in diagnosis of acetabulum fractures]. AB - This review describes recent visualizations of computed tomography for the diagnosis of acetabular fractures. The techniques of conventional and helical-CT for the imaging of the acetabulum are compared. Furthermore, the different methods of multiplaner and three-dimensional reconstructions e.g. shaded surface display, maximum intensity projection, and volume rendering are presented. Figures of each method are demonstrated and the diagnostic potential of multiplanar and three-dimensional imaging for fractures of the pelvis is discussed. PMID- 8679733 TI - [Upper inflow congestion as initial manifestation of idiopathic mediastinal fibrosis]. AB - In about 90% of superior vena caval obstructions the cause is a neoplasm, generally a carcinoma of the right upper lobe. Fewer than 5 percent are due to inflammatory disease of the mediastinum. A case of idiopathic, fibrosing mediastinitis with occlusion of the superior vena cava is described. The clinical symptoms, radiographic finding, diagnostic and therapeutic aspects are discussed. PMID- 8679734 TI - [Septic portal vein thrombosis as a rare complication of Crohn disease with retroperitoneal abscess]. AB - Portal vein thrombosis is a rare complication of inflammatory bowel disease and occurs particularly in patients with ulcerative colitis. This report describes a patient with known Crohn's disease since 1980 who developed retroperitoneal abscesses and subsequently a septic portal vein thrombosis. After 10 years of remission, clinical deterioration, jaundice, and fever occurred. An abdominal CT study confirmed the ultrasonic presumptive diagnosis of two retroperitoneal abscesses close to the pancreas tail. Another CT, one week later, showed furthermore a portal vein thrombosis. Only by intensive care treatment was it possible to control the critical situation. PMID- 8679735 TI - [MRI of musculature in myalgia--indications and image findings]. AB - This paper deals with the question of the clinical circumstances in which MRI seems to be promising in patients with myalgia. 241 patients suffering from myalgic symptoms were examined by axial scans of the muscular system with T1w and STIR-sequences. All patients underwent a complete neuromuscular examination, which included an MRI guided muscle-biopsy of 203 patients. The images were retrospectively analysed as to the typical characteristics of differential diagnosis. In cases of idiopathic or bacterial/viral induced myositis, primary vasculitis, and rhabdomyolysis, edematous changes of the muscles could always be found. Abscesses were only found in bacterial myositis. In cases of poly- and dermatomyositis as well as inclusion-body-myositis, MRI showed a uniform distribution pattern with emphasis on the quadriceps muscles. In contrast to other neuromuscular diseases in bacterial induced myositis, focal myositis, and rhabdomyolysis a strong contrast agent enhancement was seen. All patients with myalgic syndromes without any other additional neuropathological findings and 86% of the patients suffering from polymyalgia rheumatica had normal MR-findings. MRI allows a correct exclusion of an inflammatory, tumorous, or rhabdomyolitic cause of a myalgia and leads to pathognomonic findings for these diseases. Diseases belonging to the group of endocrine, toxic, or metabolic myopathies might be normal in MRI. We believe that an indication for MRI is given when muscular pain is associated with additional neuromuscular symptoms, especially if an inflammatory origin of the myalgia is suspected or if a muscle biopsy is planned. PMID- 8679736 TI - [MR-mammography: current status and perspectives]. AB - Dynamic MR imaging of the breast is viewed as an examination technique which is supplementary to mammography and sonography and which can provide important additional diagnostic information. Proven indications for MR mammography include examinations of patients who have undergone lumpectomy and patients with prosthetic breast implants. The method also appears to be useful to differentiate between postoperative scarring and carcinoma as well as to exclude a multicentric breast carcinoma prior to lumpectomy. The sensitivity of MR mammography, however, is limited in cases of DCIS. Hypervascular benign lesions can be difficult to distinguish from malignant lesions. PMID- 8679737 TI - [MR tomography (MRT) of the skeleton, peripheral soft tissues and joints--current overview]. AB - A review: The skeleton, the peripheral soft tissues, and the joints have become important indications to use MRI routinely. About 25-35% of daily examinations focus on these anatomic sites. Superior contrast resolution, the option of different imaging planes, and the unsurpassed visualization of bone marrow, fibrous and hyaline cartilage, ligaments, and tendons are the reasons for the overwhelming success of this imaging method. MRI often provides the direct way to diagnosis. More and more the so-called "step by step" approach to diagnosis by imaging methods is being abandoned in favor of the primary use of MRI. The present survey summarizes the main indications for MRI in the field of the musculoskeletal system, in adults as well as in children. Special topics like tumors, inflammation, ischemia, and trauma are discussed. Some anatomic sites like the carpal joint, the shoulder, and the knee are presented in more detail. PMID- 8679738 TI - [3-dimensional post-myelographic CT reconstruction in diagnosis and therapy planning of spinal dysraphism]. AB - Dysrhaphia is often associated with severe osseous aberrations of the spine such as, for example scoliosis, hemivertebra, and synostosis. With the advanced possibilities of the post-processing of CT-data (segmentation, three-dimensional reconstruction), post-myelo-CT is an excellent method for the evaluation of osseous structures and the myelon in preoperative planning. PMID- 8679739 TI - [Multiplanar imaging in the retroperitoneum: noninvasive diagnosis with a new spiral CT technique--anatomy and pathology]. AB - Both anatomic and pathologic structures are often not documented in sufficient detail to provide overall information in axial scans, and magnetic resonance imaging does not always provide the required spatial resolution. The spiral CT technique, in contrast, with use of the secondary image reconstruction is capable of clearly documenting these interrelations. We have examined 45 patients with pathologic changes in the retroperitoneum by means of a spiral CT scanner and used the secondary image reconstruction in the coronary and sagittal plane in all cases. The scan times ranged between 45 and 60 seconds at a selected slice thickness of 3 mm and a table feed of 4.5 mm. Up to 30 cm of the crania-caudal length of the patients could thus be documented. From the basic data, up to 170 overlapping images were calculated for a multiplanar image reconstruction, and every third axial scan was photographed. The post-processing time was 10 to 15 minutes. The patients received 120 ml of a non-ionic contrast medium, intravenous at a flow rate of 2.5 ml per second. The spiral CT examination was started 40 seconds after the injection had been begun. It could be performed in all patients under inspiration, without problems. The chosen scan times did not lead to significant overshadowing due to motion artefacts. The vascular structures of the aorta and its main branches as well as the vena cava and the portal vein could be identified in their whole lengths. The peritoneal duplications and the renal fascia could be clearly documented. The lymph nodes could be identified in all of them. In cases of tumours with metastases, the extent of the tumor was excellently visible in the multiplanar reconstructions and a thickened peritoneum could be differentiated in such cases. This standardized examination procedure offers a uniform and reproducible diagnostic basis with short examination times. The early detection even of small recurrences in the axial slices and the identification of pathologic changes of the lymph nodes enable a timely tumor treatment for curative purposes. PMID- 8679740 TI - [Quality assurance in stereotactic punch biopsy using a phantom]. AB - Lesions of the breast, which were only defined by mammography, can histologically be clarified by stereotaxic high-speed core cut biopsy. In a quality control procedure we have proved the accuracy of the localization unit and the biopsy equipment. A new acrylic-glass phantom allows visual detection of localization faults in the z-axis (direction of biopsy) for the first time with minimal coefficients of variation in all three axes. Quality control in the stereotaxic biopsy of breast lesions is absolutely essential for the practical use of this method. PMID- 8679741 TI - [Gastrointestinal metastasis of malignant melanoma]. AB - In this paper we present a case study of a patient suffering from a gastrointestinal metastasis of a malignant melanoma. Normally in this location multiple and solid metastases were observed in the submucosa. Extraordinary in this case is the fact, that a polycystic tumor with more than 15 cm diameter has been found. PMID- 8679742 TI - [Osteosarcoma of the skull cap. Differential diagnosis and clinical considerations]. AB - Differential Diagnosis and Clinical Aspects: Osteosarcoma is a rare type of bone tumor that usually occurs only towards the end of a long bone. This article reports the case of a primary osteosarcoma of the skull and discusses important clinical issues. CT played an important role in the assessment of the tumor. PMID- 8679743 TI - Cement proteins of the acorn barnacle, Megabalanus rosa. AB - Components of the proteinaceous cement secreted by barnacles have yet to be studied because of their insolubility. We solubilized and characterized the proteins of secondary cement, which is produced when the barnacle is detached from the substratum, in Megabalanus rosa. The cement was fractionated, according to its solubility in aqueous formic acid, into a soluble fraction, SF1 (21%); a fraction soluble after reduction, SF2 (37%); and a fraction insoluble after reduction, IF (42%). Analysis of the SF1 and SF2 by sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) revealed that they contained three polypeptides (SF1-60 k, -57 k, -47 k) and one polypeptide (SF2-60 k), respectively. The amino acid compositions of these polypeptides were similar and their N-terminal amino acid sequences were identical. These polypeptides had an unusual amino acid composition, rich in Ser, Thr, Ala, and Gly, like the tube cement of a marine polychaete, Phragmatopoma californica. The IF, solubilized in aqueous formic acid after cleavage with cyanogen bromide, was shown by SDS-PAGE to contain eight fragment peptides (CB-peptides). N-terminal amino acid sequences of the CB-peptides were also determined. We conclude that the barnacle cement is composed of at least two types of protein: highly hydroxylated protein in the SF1 and SF2 and insoluble protein in the IF. The SDS-PAGE pattern of CB-peptides from the secondary cement was identical to that of the primary cement produced while the barnacle is attached to a substratum. In addition, immunoblot analysis, using a polyclonal antibody against one of the CB-peptides from the secondary cement, also cross-reacted with a CNBr-fragment peptide of the primary cement. These results indicate that the primary and secondary cements are similar in protein composition. PMID- 8679744 TI - Univacuolar refractile hemocytes from the tunicate Ciona intestinalis are cytotoxic for mammalian erythrocytes in vitro. AB - A discontinuous, Percoll density gradient was used to separate hemocyte populations from the hemolymph of Ciona intestinalis. Hemocytes from each band were examined for their frequency, morphology, and cytotoxic activity against rabbit and sheep erythrocytes; results were expressed as a percentage of hemolysis. Statistical analysis revealed that only the "univacuolar" granulocytes from Band 5, which contain a vacuole of refractile material, were cytotoxic. Cytotoxic activity was inhibited by sphingomyelin. For the first time in tunicates, lytic activity against erythrocytes was assessed by an assay based on plaque-forming cells. Plaques of lysis were revealed against rabbit erythrocytes but not against sheep erythrocytes. PMID- 8679745 TI - Current status of the inferior epigastric artery. AB - The current trend is to use more arterial conduits for myocardial revascularization. The rationale for this trend is that the late patency rate of internal thoracic artery grafts has been shown to be superior to that of saphenous vein grafts. The desire to achieve complete myocardial revascularizations only with arterial conduits has led to consideration of new arteries as coronary artery bypass grafts. Recently, the inferior epigastric artery has been proposed as one of these alternative grafts. It is expected that this new conduit will provide the same advantages as the free internal thoracic artery used in similar circumstances, but this assumption has not been validated yet. This article will review the clinical experience currently gained with the use of the inferior epigastric artery as a coronary artery bypass graft. PMID- 8679746 TI - Complete revascularization with three or more arterial conduits. AB - A complete revascularization with three or more arterial conduits was achieved, giving the patient, if possible, three blood sources from the in situ arterial grafts (skeletonized bilateral internal thoracic arteries [ITAs] and right gastroepiploic artery). If one of these conduits was not available, a radial artery was used, the proximal anastomosis being constructed on an ITA. The inferior epigastric artery was used if a sequential anastomosis was not advisable or to lengthen another arterial graft. With this strategy, 247 patients underwent surgery from October 1991 through April 1995; 774 arterial conduits were used: 244 left ITAs, 187 right ITAs, 159 right gastroepiploic arteries, 114 radial arteries, and 70 inferior epigastric arteries. The in-hospital and late mortality rates were 1.2% (3 patients) and 1.6% (4 patients), respectively. Of the 240 patients alive, 235 (97.9%) are asymptomatic. We compared the 42-month survival and event-free survival curves of these patients with those of an historical cohort of patients who underwent surgery with mixed (1 left ITA and saphenous vein grafts) revascularization. Whereas the survival rate was similar (97.82% +/- 1.11% vs 99.35% +/- 0.65, P = .174), the event-free survival rate was significantly better in the total arterial group (93.72% +/- 2.1 % vs 85.62% +/- 2.84%, P = .021). We conclude that complete revascularization with three or more arterial conduits is technically feasible with a low mortality rate; the mid-term results allow us to continue this strategy of myocardial revascularization. PMID- 8679747 TI - Optimal use of the gastroepiploic artery. AB - In 10 years' experience with the right gastroepiploic artery graft for myocardial revascularization, excellent clinical and angiographic mid-term results have been reported. From our experience in 518 patients who underwent CABG with a gastroepiploic artery graft since 1986, early and late mortality rates were 2.3% and 1.0%, respectively. Early and mid-term (2 to 5 years) angiographic patency rates were 96% and 92%, respectively, in the in situ gastroepiploic artery grafts. The gastroepiploic artery is the second best arterial conduit next to the internal thoracic artery at present, and is most useful at reoperation or for patients with atherosclerotic ascending aorta. With proper basic knowledge and surgical technique, the gastroepiploic artery can be used without increasing surgical mortality and morbidity, and good long-term patency can be expected. PMID- 8679748 TI - Complete revascularization with internal thoracic artery grafts. AB - Saphenous vein graft atherosclerosis continues to be the major cause of late failures of coronary artery bypass operations (CABG). The internal thoracic artery (ITA) is an ideal bypass graft because it remains free of atherosclerosis at late follow-up in most patients. Myocardial revascularization with only ITA grafts has developed in an incremental manner from single grafts of the left ITA to the left anterior descending coronary artery (LAD), to use of bilateral, free and sequential ITAs, and now recently to the use of preconstructed grafts that attach the free right ITA to the left ITA. The microanatomy and vascular reactivity of the ITA have been recently defined, and they explain why the ITA remains free of obstruction. Our techniques and results of ITA grafting developed over the past 25 years are presented. PMID- 8679749 TI - Defining the role of the radial artery. AB - Our experience with the radial artery in 172 patients from October 1993 through February 1995 has been favorable, with no early or late deaths in a group of selected patients. In 35 of the first 72 patients, the proximal anastomosis of the radial artery was to the aorta, and in all other patients it was to the left internal thoracic artery (ITA). In the first 72 patients, there were 43 right ITA grafts, 13 gastroepiploic artery grafts, and 6 saphenous vein grafts (3.57 distals per patient). In the last 100 patients, only 2 other conduits (saphenous vein) were used (in addition to left ITA and radial artery) for 3.46 distals per patient, with complete revascularization achieved in all patients requiring it. Five perioperative infarctions, 2 reoperations for bleeding, 6 intra-aortic balloon pumps, 3 instances of myocardial hypoperfusion (1 requiring a balloon pump), and 1 mediastinal wound infection were noted. Four patients required catheterization for recurrent symptoms, and all had patent radial arteries (1 from the aorta and 3 from the left ITA), but 1 ITA was stenotic at the distal anastomosis. One patient was older, with preoperative heart failure that recurred, and 2 were younger, with diffuse coronary disease. This early favorable clinical experience, when combined with the early patency data of others, suggests that continued use of this conduit is appropriate with close observation of outcome. PMID- 8679750 TI - History of surgery for emphysema. AB - Throughout the 20th century, several operations have been advocated as methods of treatment for patients with emphysema and, often, they were promoted as offering potential cures. Unfortunately, most of these procedures attempted to treat the wrong physiological or anatomic deficit so that mid- or long-term results were unpredictable or frankly disastrous. Procedures such as costochondrectomy were designed to permit further enlargement of the lungs, whereas thoracoplasty was designed to reduce lung volume. Operations were performed to restore the curvature of the diaphragm or devised to increase blood supply to the lung. Almost every thoracic structure including chest wall, diaphragm, pleura, nerves, airways, lung, or esophagus became "at risk" for surgical intervention. Short of bullectomy for emphysematous bullous lung disease and perhaps volume reduction for diffuse emphysema, none of these procedures has stood the test of time. PMID- 8679751 TI - Lung volume reduction surgery for severe emphysema. AB - Lung volume reduction surgery is designed to alleviate symptoms of breathlessness and improve the quality of life for selected patients with severe emphysema. By resecting hyperinflated, nonfunctional areas of the lung, thoracic volume is reduced, chest wall and diaphragmatic mechanics are improved, and ventilation to the remaining portions of lung is improved. The operative procedure is designed to obtain maximum improvement with the least possible risk. Early mortality (less than 90 days) has been 3%, all from respiratory complications. Late mortality (more than 90 days) has been an additional 2%. Refinements in operative technique, including use of continuous staple line excision buttressed by bovine pericardium, creation of apical pleural tents, and avoidance of suction the chest tubes, have led to a steady decline in hospital stay, with the current average of 11 days and a median of 7 days. Ninety-nine of the 100 patients have been extubated at the end of the procedure, thus avoiding the need for postoperative ventilatory assistance. PMID- 8679752 TI - Radiology of pulmonary emphysema and lung volume reduction surgery. AB - Lung volume reduction surgery (LVRS), which involves the bilateral wedge resection of 20% to 30% of the most diseased lung through a median sternotomy, is emerging as a promising treatment option for select patients with severe, debilitating emphysema. This article details our observations and preliminary investigations related to the imaging evaluation of patients including selection criteria, postoperative findings, and structural changes in the thorax after surgery. Routine preoperative evaluation includes inspiratory and expiratory chest radiographs, computed tomography (CT) examination, and nuclear medicine lung scan. Investigational studies include quantitative CT to assess disease severity and dynamic magnetic resonance imaging to study respiratory movements. Postoperative improvement in FEV1, oxygenation, and exercise tolerance correlate with the degree of heterogeneity, hyperinflation, lung compression, upper lobe severity, and percentage of retained mildly diseased lung shown on preoperative imaging studies. Postoperative radiographic monitoring is important for detection of complications. Postoperative follow-up examinations show reduced thoracic distention, improved coordination of respiratory movement, and increased diaphragm curvature and excursion, supporting the hypothesis of improved respiratory mechanics as a major contributing factor to the success of LVRS. PMID- 8679753 TI - Evaluation of patients with emphysema for lung volume reduction surgery. Washington University Emphysema Surgery Group. AB - Lung volume reduction surgery (LVRS) is performed to alleviate the dyspnea of patients with emphysema and improve performance in the activities of daily living. Removing diseased and functionless lung may improve the function of remaining, less diseased lung by (1) increasing elastic recoil pressure, thereby increasing expiratory airflow rates, (2) decreasing the degree of hyperinflation resulting in improved diaphragm and chest wall mechanics, and (3) decreasing inhomogeneity resulting in decreased work of breathing and improved alveolar gas exchange. The guidelines used for patient assessment were (1) airflow limitation with a forced expiratory volume in 1 second (FEV1) less than 35%, (2) hyperinflation and air trapping with total lung capacity more than 125% and respiratory volume more than 250% predicted, and (3) regional heterogeneity of the emphysematous process providing target areas for resection. We sought to exclude patients with the following: (1) obliteration of the pleural space by previous disease or surgery, (2) severe structural abnormalities of the thoracic cage, (3) PaCo2 greater than 55 mm Hg. (4) mean pulmonary artery pressure greater than 35 mm Hg. (5) predominant airway disease such as asthma, bronchiectasis, or chronic bronchitis with persistent excessive purulent secretions, (6) significant coexisting disease, and (7) maintenance corticosteroid therapy in excess of 10 mg prednisone per day. The assessment process continues to be evaluated by analysis of patient outcome. PMID- 8679754 TI - Anesthetic management for bilateral volume reduction surgery. AB - Bilateral volume reduction surgery has been designed to reduce total thoracic volume and improve chest wall mechanics in patients with severe emphysema who, up to now, had very limited viable surgical options. This procedure has been performed in more than 120 such patients at our institution. We present the anesthetic considerations and our experience from their management. PMID- 8679755 TI - Results of lung volume reduction surgery in patients with emphysema. The Washington University Emphysema Surgery Group. AB - Between January 1993 and April 1995, 84 patients with emphysema underwent bilateral lung volume reduction surgery at Barnes Hospital, Fifty-three patients had completed 3 months; 37 patients, 6 months; and 19 patients, 1 year of follow up. Significant improvement was observed in spirometric parameters, oxygenation, 6-minute walking distance, dyspnea indices, and quality-of-life scores. The average increases in FEV1 were 52%, 51%, and 61%, at 3,6, and 12 months, respectively, after surgery. The most common postoperative complication, prolonged ( > 7 days) chest tube drainage, was present in 63% of the cases, and the mean duration of hospitalization in the survivors was 15 days (range 5 to 49 days). This has been reduced to 11 days (median 7.5 days) for the subsequent 40 patients. Five postoperative deaths occurred, 2 in the first, 2 in the third, and 1 in the fifth postoperative month, respectively. The overall mortality in the 84 patients was 6%, and the actuarial survival at 1 year was 93%. Volume reduction surgery is a promising therapeutic option for patients with an appropriate pattern of emphysema. Improvement has been sustained for more than 1 year, and long-term follow-up is planned to ascertain the duration of the benefits. PMID- 8679756 TI - Propranolol reduces the anxiety associated with day case surgery. AB - OBJECTIVE: To find out if propranolol, a non-cardioselective beta-blocker, can reduce the anxiety associated with day case surgery. DESIGN: Prospective randomized double blind trial. SETTING: University hospital, Ireland. SUBJECTS: An unselected group of 53 patients undergoing day case surgery. INTERVENTION: Subjects randomised to receive either propranolol (10 mg) or placebo on the morning of operation. MAIN OUTCOME MEASURES: Blood pressure; pulse, anxiety, pain score and patient satisfaction. RESULTS: Mean (SD) Hospital Anxiety and Depression score was significantly lower in the propranolol group than in the control group (2.5 (0.7) compared with 4.6 (0.7), p < 0.0001) before discharge. CONCLUSION: A low dose of propranolol given on the morning of day case surgery significantly reduced patients' anxiety. PMID- 8679758 TI - Thoracoscopic pulmonary surgery: indications and results. AB - OBJECTIVE: To report our experience of thoracoscopic pulmonary operations from May 1991 to May 1994. DESIGN: Prospective open study. SETTING: District hospital, Germany. SUBJECTS: 93 patients who underwent 120 thoracoscopic procedures. INTERVENTIONS: Wedge resection (n = 56), pleural biopsy (n = 21), early decortication (n = 16), partial pleurectomy (n = 9), pleurodesis (n = 5), pulmonary biopsy (n = 4), segmentectomy (n = 3), evacuation of haemothorax (n = 3), biopsy of mediastinal tumor (n = 2), and costal biopsy (n = 1). MAIN OUTCOME MEASURES: Morbidity, mortality, and avoidance of open thoracotomy. RESULTS: Indications for thoracoscopic intervention were: solitary pulmonary nodule (n = 37), recurrent pneumothorax (n = 17), pleural empyema (n = 14), diffuse pulmonary disease/multiple nodules (n = 10), recurrent pleural effusion (n = 11), haemothorax (n = 3), and mediastinal tumour (n = 1). In 29 of 37 patients in whom we attempted resection of a solitary pulmonary nodule we obtained enough tissue for diagnosis, and avoided thoracotomy in 18 patients. Complications included pulmonary embolus (n = 1), recurrent empyema (n = 1), haemorrhage (n = 2), infection of the drain site (n = 3), and two persistent air leaks. One was closed at a second thoracoscopy and the other required open thoracotomy after which he developed pulmonary failure and died. One patient with a haemothorax developed multiple system organ failure and died, and attempted resection of a mediastinal tumour was unsuccessful. Three thoracoscopic procedures had to be abandoned because of dense adhesions. CONCLUSIONS: Thoracoscopic surgery is a safe, well tolerated, and cost effective alternative to open thoracotomy in selected patients. PMID- 8679757 TI - Antimicrobial prophylaxis in surgery in Belgian hospitals: room for improvement. AB - OBJECTIVE: To evaluate the current practice of surgical antimicrobial prophylaxis in Belgium. DESIGN: Prospective multicentre incidence study. SETTING: 58 of the 206 acute hospitals in Belgium. SUBJECTS: 19746 patients who had operations between October 1992 and June 1993, with detailed analysis of 7983 procedures for which the antimicrobial regimens were known. RESULTS: Antibiotic prophylaxis was given before 14099 (71%) of the 19746 operations. It was given in 57% of the procedures for which prophylaxis is generally not recommended, but it was not used in 14% of procedures for which it is generally recommended, nor in 14% of all contaminated procedures. Duration of operation superseded degree of wound contamination, ASA (American Society of Anesthesiologists) score, and degree of urgency as a predictor of the use of prophylaxis. Prophylaxis was prolonged by more than 2 days postoperatively after 23% of the procedures and by more than 4 days in 8%. Five types of regimens accounted for 80% of all prophylaxis, but overall 234 different regimens were prescribed. Large differences were found in hospital university affiliation status. In general, trends were favourable compared with a study in 1986. CONCLUSION: Although there was improvement compared with 1986, antimicrobial prophylaxis in surgery could still be more appropriate in terms of indication, duration, and rational choice of drugs. PMID- 8679759 TI - Recurrent inguinal hernia: surgical repair with a sheet of Dacron mesh by the inguinal route. AB - In this report we describe our technique for repair of recurrent inguinal hernia, using a large sheet of Mersilene mesh placed by the inguinal route. After division of the epigastric vessels, the inguinal canal is opened widely. A large sheet of Dacron mesh is inserted and the muscles are closed without tension by the McVay technique. We have repaired 142 recurrent hernias by this method. One patient died (0.7%) and morbidity included hole in the bladder (n = 3), wound discharge-(n = 2), wound haematoma (n = 5), cardiac arrhythmia (n = 1), and urinary retention (n = 2). The mesh had to be removed in two cases. No further recurrences were observed. This technique, thanks the placement of a large "tension free" sheet of mesh, ensures solid, definitive repair and is recommended for initial treatment of recurrent inguinal hernia. PMID- 8679760 TI - Logic, hermeneutics, and informed consent. AB - A belief in the validity of informed consent is one of the most important consequences of the doctrine of autonomy in medical ethics. Truly informed consent requires full disclosure of all relevant information by the doctor, competence of the patient to appreciate what the information signifies, understanding of the facts and issues by the patient, a voluntary choice by the patient and an autonomous authorisation for treatment or entry into a trial. Each of these conditions is hard to fulfil. In particular, full autonomy cannot exist in illness, and this is acknowledged by the act of consultation. The issue is further complicated by the stochastic nature of biological systems and the responses to illness and treatment. Disclosure of likely outcomes is, of necessity, unsatisfactory when a patient seeks surety when entering the clinical process with a serious and life threatening disease. Neither strict logic nor the law provide answers to this problem. The legal and moral issues have become confused. This is unfortunate, because the legal concern often centres on avoidance of actions in law rather than on the more fundamental issue of benefit to the patient. There is a need to teach doctors that discussion is a necessary part of the doctor-patient relationship, that fully informed consent is seldom-if ever-possible, and that skill in understanding what the patient is seeking is more important than the development of rigid and legally "complete" consent forms. PMID- 8679761 TI - Effect of fundal mobilisation in Nissen-Rossetti fundoplication on oesophageal transit and dysphagia. A prospective, randomised trial. AB - OBJECTIVE: To assess the effect on postoperative dysphagia and oesophageal transit of fundal mobilisation during Nissen-Rossetti fundoplication. DESIGN: Prospective, randomised study. SETTING: University Hospital, Finland. SUBJECTS: 20 consecutive patients with confirmed gastro-oesophageal reflux who were referred for antireflux surgery. INTERVENTIONS: Fundoplication with either conventional Nissen-Rossetti procedure or an otherwise identical technique incorporating total fundal mobilisation (n = 10 in each group). MAIN OUTCOME MEASURES: Recurrent or persistent symptoms of dysphagia, and the oesophageal transit time of a liquid bolus labelled with radioactive nuclide. RESULTS: In both groups excellent relief of heartburn and regurgitation was achieved (only 2 patients in each group reported occasional symptoms), one patient had oesophagitis, and the pH returned to the normal range. The incidence of dysphagia was similar in both groups by 6 months postoperatively, but there was significant, though transient, impairment of oesophageal transit after findal mobilisation (p = 0.03). CONCLUSIONS: Fundal mobilisation did not seem to confer any advantage as fas as the incidence of postoperative dysphagia was concerned. On the contrary, it was associated with transient disturbance in the oesophageal transit time of a liquid bolus. Longer follow up is needed to show if this impairment is of any clinical relevance. PMID- 8679762 TI - Day case laparoscopic cholecystectomy: a safe and cost effective procedure. AB - OBJECTIVE: To evaluate the safety and cost effectiveness of laparoscopic cholecystectomy as a day case procedure. SETTING: District hospital, England. SUBJECTS: 103 patients undergoing laparoscopic cholecystectomy. INTERVENTIONS: Laparoscopic cholecystectomy by a standard four cannula technique. Propofol anaesthesia, prophylactic antiemetics and pre-emptive analgesia were given in all cases. MAIN OUTCOME MEASURES: Morbidity and cost. RESULTS: 103 patients have undergone laparoscopic cholecystectomy, 51 of them as day cases. Patients were selected for day treatment if they were under 60 years old, they wanted to go home the same day, they had no history of jaundice or any anaesthetic contraindication, and if there was an adult at home to look after them. Three of those selected as day cases required overnight admission, one because of severe pain and two who required a drain overnight. The median hospital stay was 12 hours (range 10-28 hours) and the cost of the operation was about pounds 419. CONCLUSION: This is a safe and cost-effective procedure and should be considered in selected patients. PMID- 8679763 TI - Anastomotic healing of small bowel with or without chronic radiation damage in protein-deficient malnourished rats. AB - OBJECTIVE: To assess the influence of protein malnutrition on anastomotic healing in rat small bowel with or without chronic radiation damage. DESIGN: Controlled laboratory study. SETTING: University hospital, Sweden. MATERIAL: 60 male Sprague Dawley rats. INTERVENTION: A short segment of the distal ileum was exteriorised and irradiated (n = 30) or only exposed (n = 30), and 20 weeks later an anastomosis was made within this segment. Two weeks before anastomosis half of the animals in each group received rat chow in which the protein content had been reduced to 25%; standard rat chow was given to the remaining animals. MAIN OUTCOME MEASUREMENTS: Weight changes, anastomotic bursting strength, amount of perianastomotic hydroxyproline, and number of anastomotic complications. RESULTS: 13 animals in the irradiated group and 11 animals in the non-irradiated group died of intestinal obstruction or respiratory distress leaving 17 and 19 animals that could be evaluated. Body weight was significantly reduced in animals with protein restriction (p < 0.001). A two way ANOVA showed an association between bursting strength and irradiation (p = 0.02) but not bursting strength and protein restriction. Anastomotic complications were more common in irradiated than in non-irradiated animals irrespective of the nutrition given (8/8 and 8/9 compared with 2/9 and 2/10, p = 0.0006). CONCLUSION: Protein malnutrition had no influence on anastomotic healing in rat intestine with or without chronic radiation damage. PMID- 8679764 TI - Primary small bowel anastomosis in generalised peritonitis. AB - OBJECTIVE: To find out if primary small bowel anastomosis of the bowel is safe in patients with generalised peritonitis who are treated by planned relaparotomies. DESIGN: Retrospective study. SETTING: University hospital, The Netherlands. SUBJECTS: 10 Patients with generalised purulent peritonitis caused by perforation of the bowel. INTERVENTIONS: Resection or wedge resection of the bowel and primary intestinal anastomosis followed by planned relaparotomies every 24-48 hours. MAIN OUTCOME MEASURES: Mortality and morbidity with special reference to anastomotic leaks. RESULTS: Two patients died. Four of 20 wedge excisions in one patient leaked. All 19 end-to-end anastomoses in 10 patients healed without complications. Two patients developed small bowel fistulas which were not related to the anastomoses. CONCLUSION: Primary end-to-end anastomosis of the small bowel followed by planned relaparotomies seems a safe alternative to the creation of an enterostomy in patients with generalised purulent peritonitis and perforation of the bowel. PMID- 8679765 TI - Modified venovenous bypass technique for resection of renal and adrenal carcinomas with involvement of the inferior vena cava. AB - Peripheric tumours with extension into the inferior vena cava pose difficult management problems. Venovenous bypass using a centrifugal pump to decompress the inferior vena cava may be useful adjunct during vascular isolation of the tumour. We have modified the technique by adding portal decompression to avoid visceral accumulation of toxic metabolites. We have used this technique in two patients who had intracaval extension of tumours, one renal and one adrenal carcinoma. PMID- 8679766 TI - Bleeding gastric ulcer complicating splenosis in type 1 Gaucher's disease. PMID- 8679767 TI - Lethal outcome of pelvic inflammatory disease in five women who were seropositive for HIV. PMID- 8679768 TI - Multiple aneurysms in a young patient--aetiological considerations. PMID- 8679769 TI - Adrenal and extra-adrenal phaeochromocytomas. contribution of histology, immunochemistry and DNA flow cytometry in the diagnosis of malignancy. PMID- 8679770 TI - [Disruption of processing of alkaline phosphatase as a result of single amino acid changes affects the composition and metabolism of phospholipids from Escherichia coli, secreting mutant proteins]. AB - Amino acid substitutions in the cleavage site of the E. coli alkaline phosphatase signal peptide Val for Ala(-1) or Pro for Arg(+1) result in the block of the enzyme processing. In cells secreting such mutant proteins the relative content and rate of turnover of anionic phospholipids (phosphatidylglycerol and cardiolipin) are increased. The rise of the transfer of the phosphoglycerol residue from phosphatidylglycerol to periplasmic membrane derived oligosaccharides or to the model substrate, arbutin performed by the activity of phosphoglycerol transferase I testifies to phosphatidylglycerol accumulation on the outer surface of the cytoplasmic membrane. The results suggest of phosphatidylglycerol interaction with the alkaline phosphatase precursor and their subsequent joint translocation through the cytoplasmic membrane of E. coli. PMID- 8679771 TI - [The role of SH-groups in guanidine thiols--new substrates for NO-synthase--in stimulating the activity of guanylate cyclase]. AB - Guanidine thiol derivatives--a new class of soluble guanylate cyclase activators- have been studied. Guanidine thiols contain in their molecule both the guanidine and thiol groups which act as donors acceptors of nitric oxide (NO), respectively. The role of the guanidine thiol SH-groups in the mechanism of soluble guanylate cyclase activation has been evaluated. The effect of three guanidine thiol derivatives: mercaptoethylguanidine (MEG), mercaptoethylguanidine disulfide (MEG disulfide) and S-methyl mercaptoethylguanidine (S-methyl MEG) on human platelet guanylate cyclase activity, has been examined. It was found that all the compounds tested in this study were substrates for NO-synthase and guanylate cyclase activators. The stimulatory effects of MEG and MEG disulfide surpassed the L-arginine-induced activation of guanylate cyclase-2- and 4-fold, respectively. The enzyme stimulation by S-methyl MEG was of the same order as that of L-arginine. The important role of S-acceptor groups of guanidine thiols in the mechanism of directed increase of guanylate cyclase activation was established. This mechanism explains the nature of differences in the intensity of guanylate cyclase activation by the guanidine thiols under study. The NO acceptor properties of disulfide bond of guanidine thiols in the case of the NO synthase mechanism of NO formation have been established. PMID- 8679772 TI - [Stability of human immunodeficiency virus to azidothymidine. II. Kinetic characteristics of "AZT-resistant" mutant forms of reverse transcriptase]. AB - Prolonged treatment of AIDS patients with azidothymidine results in the development of resistance to the drug which correlates with the appearance of point mutations in the reverse transcriptase (RT) coding region within the HIV-1 pol gene. Kinetic studies of interactions of wild type RT and its mutants harbouring the above mutations with substrates and azidothymidine 5'-triphosphate (AZTTP) have been carried out. The complete mutant containing all the above described mutations possess the highest resistance on all the templates tested. Significant increases in resistance for mutants 67,70,215 and 67,215 on all the templates have also been observed. Inhibition of mutant enzymes by AZTTP depends on the template used. PMID- 8679773 TI - [Physicochemical properties of recombinant luciferase from the firefly Luciola mingrelica and its mutant forms]. AB - Physico-chemical properties of the recombinant L. mingrelica luciferase synthesized by E. coli cells have been studied. The catalytic and spectral properties of recombinant luciferase were similar to those of the native enzyme but the former was less stable in the presence of the additional Cys residue. The mutant forms of L. mingrelica firefly luciferase with point mutations Cys-82- >Ala, Cys-260-->Ala, Cys-393-->Ala and Thr-204-->Asp, have been constructed using the method of site-specific mutagenesis. Mutations Cys-82,260,393-->Ala changed slightly the Km values for ATP and luciferin but did not influence kcat. The Cys 393-->Ala mutant appeared to be more stable in comparison with the native enzyme. Mutation Thr-204-->Asp resulted in a 8-fold increase in the ATP binding constant and in a 2-fold increase in the kcat, thus indicating that Thr-204 may be located in the ATP-binding region of luciferase. Dithiothreitol, ethylene glycol, bovine serum albumin and trehalose had a stabilizing effect on the native, recombinant and mutant luciferases. PMID- 8679774 TI - [Conjugates of alpha-chymotrypsin with polyalkylene oxides in hydrated reverse micelles]. AB - Conjugates of alpha-chymotrypsin (ChT) with poly(ethylene glycol) (PEG) and block copolymers of ethylene oxide and propylene oxide (proxanols) have been synthesized. The molecular mass of the polymers was 2 kDa. The conjugates contained 5 to 7 polymeric chains per enzyme molecule. Hydrolysis of N-trans cinnamoylimidazole catalyzed by conjugates of ChT with poly(alkylene oxides) was studied in 0.05 M Tris-HCl buffer, pH 8.0, and in hydrated reversed micelles of aerosol OT (AOT) in octane at 25 degrees C. The deacylation constant, k3, for the conjugates in the buffer solution was found to be 1.5-1.8-fold higher than the corresponding value for native ChT. The value of the [H2O]/[AOT] ratio corresponding to the maximum on the k3 versus [H2O]/[AOT] curves for the conjugates (around 16) allows the dimensions of their molecules to be characterized. The radius of the conjugate molecules was found to be approximately equal to 2.8 nm. The k3 value for the conjugate of ChT with PEG, as in the case of native ChT, remains constant when the concentration of AOT is varied. However, the deacylation constant for ChT conjugates with proxanols decreases with a rise in AOT concentration. This fact indicates that ChT conjugates with proxanols are able to interact with the micellar matrix, i.e., they possess membranotropic properties. PMID- 8679775 TI - [Structure of a new lysine-containing O-specific polysaccharide from Proteus mirabilis O26]. AB - The composition and structure of the O-specific polysaccharide chain of the bacterium Proteus mirabilis O26 lipopolysaccharide have been studied using one- and two-dimensional 1H- and 13C-NMR spectroscopy, including homonuclear correlation spectroscopy (COSY), H-detected 1H,13C heteronuclear multi-quantum coherence and rotating-frame nuclear Overhauser effect spectroscopy. It has been found that the polysaccharide is acidic due to the presence of D-galacturonic acid (D-GalA) residues, part of which are O-acetylated, while the other part form an amide with the alpha-amino group of L-lysine and is built up of tetrasaccharide repeating units having the following structure: [formula: see text] The P. mirabilis O26 polysaccharide is structurally similar to the O specific polysaccharide of P. mirabilis O28 studied earlier by us and containing amides of D-galacturonic acid with L-lysine and L-serine. PMID- 8679776 TI - [Conformation of apolipoprotein B-100--structure and functional classification of low density lipoproteins]. AB - Based on the model of an oil drop of the apolipoprotein B-100 lipoproteins (apo-B 100 LP) structure and physico-chemical and antigenic differences in their individual classes, an alternative model has been developed. If the apo-B-100 contains one hydrophilic ligand domain, two hydrophobic domains with predominating alpha-structures and two domains with predominating beta-folding, the molecule may acquire the conformation of a disc, one side of which is hydrophilic, while the other one is hydrophobic. The hydrophilic side of the disc comprises the ligand domain; on the hydrophobic side apo-B-100 forms nonpolar lipids. Apo-B-100 LP has the structure of a bilayer protein-lipid disc. Stepwise alterations in the apo-B-100 disc configuration during lipolysis determine the conversion of apo-B-100 LP in the blood flow: very low density LP-->low density LP. Conformational changes in the apo-B-100 disc form the basis for antigenic differences in each class of LP. Changes in the conformation of apo-B-100 disc in LP induce lipolysis and the formation of cholesterol esters circulating in the functional cycle, in which the cell is the indispensable step. The functional turnover of cholesterol in tissues integrates into one cycle lipoproteins of both high and low density. Equimolar substitution of triglycerides for more hydrophobic cholesterol esters associated with the C-terminal domain of apo-B-100 receptor of the cell. During triglyceride transport the apo-B-100 disc consecutively acquires three configurations--initial, intermediate and final. This hypothesis made the basis for functional classification of apo-B-100 LP in which the initial, intermediate and final classes can be singled out. Blockade of the functional cycle of cholesterol at various stages gives rise to individual hyperlipoproteinemia phenotypes. LP of one class only are accumulated in the blood for each type: the initial class in type III, the intermediate class in type IIb and the final class in type IIa. Each of the three apo-B-100 LP classes is distinguished for its peculiar structure and significant differences in the mechanism of their reception by the cells. PMID- 8679777 TI - [Phosphorylation of adrenal cortex proteins by protein kinase C induced by prolactin]. AB - The in vitro effect of prolactin (PRL) on protein phosphorylation in male guinea pig adrenal cortex has been studied. It was found that 60 min after addition of PRL (10 micrograms/ml) to slices of adrenocortical tissue the rate of protein phosphorylation increased considerably. Autoradiographic studies revealed that at least part of the proteins are substrates for protein kinase C, since their phosphorylation increased in the presence of specific activators of protein kinase C (Ca2+, diacylglycerol, phosphatidyl serine) in the incubation medium. The molecular masses of these proteins were 95, 93, 90, 12 and 10 kDa. In extracts of PRL-treated adrenocortical tissue phosphorylation of these proteins was especially well-pronounced. Addition of staurosporine (10 nM) during incubation of the slices abolished the PRL effect on protein phosphorylation without any effect on the rate of unstimulated phosphorylation. Taking into account the ability of isolated nuclei to respond to PRL by activation of protein kinase C, the time course of PRL stimulation of protein phosphorylation was studied using preparations of isolated nuclei. The maximal increase of 32P incorporation into the proteins from [gamma-32P]ATP was observed after 60 min. Staurosporine only slightly attenuated the PRL effect. PMID- 8679778 TI - [Oxidation of human hemoglobin]. AB - The processes of nonreversible autooxidation and chemical oxidation of human hemoglobin have been studied. The rate of autooxidation increased in the presence of SH-group containing compounds and Fe2+ ions. Modification of oxyhemoglobin by glutaric and malonic dialdehydes also increased both the rate of autooxidation and oxygen affinity. Modification of SH-groups of Cys-93 beta in hemoglobin increased the rate of autooxidation but decreased the rate of hemoglobin oxidation by potassium ferricyanide. The activation energy of chemical oxidation of hemoglobin at temperatures above 24 degrees C was 39 +/- 5 kJ/mol. PMID- 8679779 TI - [The role of oxygen radicals formed during function of the membrane redox chain, in damage of nuclear DNA]. AB - Nuclear DNA damage resulting from incubation of isolated rat liver nuclei in the presence of NADPH or NADH and ethylenediamine tetraacetic acid, or diethylenetriamine pentaacetic acid, or desferoxamine complexes with Fe3+, has been studied. The degree of DNA damage was assessed by agarose electrophoresis. The observed damage was prevented by catalase but not superoxide dismutase. The mechanism of oxidative damage of nuclear DNA during membrane redox chains functioning is discussed. PMID- 8679780 TI - [Mg2+,ATP-dependent transport of Ca2+ in the endoplasmic reticulum of myometrial cells]. AB - An in-depth study of the effects of Ca(2+)-precipitating anions (oxalate, phosphate), the Ca2+ ionophore A23187 and some highly effective selective inhibitors of the endo(sarco)plasmic reticulum Ca(2+)-pump (tapsigargin, cyclopiasonic acid) on ruthenium red (10 microM)-insensitive, Mg2+,ATP-dependent accumulation of Ca2+ in digitonin-permeabilized myometrium cells of nonpregnant estrogen-treated rats, has been carried out. Oxalate and phosphate stimulated Mg2+,ATP-dependent accumulation of Ca2+ in permeabilized smooth muscle cells. The Ca2+ ionophore A23187 (5 microM) added to the medium containing oxalate (10 mM) or phosphate (20 mM) prevented the energy-dependent accumulation of Ca2+. Tapsigargin (50 nM) and cyclopiasonic acid (10 microM) fully suppressed the Mg2+,ATP-dependent Ca2+ increase measured in the presence of the Ca(2+) precipitating anions. The kinetic data indicate that the tapsigargin affinity for the energy-dependent Ca2+ transporting system is much higher than that of cyclopiasonic acid: Ki app values are 0.9 nM and 0.6 microM, respectively. Oxalate (10 mM) added to the incubation medium initially containing tapsigargin (50 nM) failed to induce the Mg2+,ATP-dependent accumulation of Ca2+ in permeabilized myocytes. The data obtained provide biochemical evidence for the existence in myometrium cells of a Ca(2+)-pump providing the Mg2+,ATP-dependent accumulation of Ca2+ in the nonmitochondrial Ca2+ depot--the endoplasmic reticulum. This reaction is stimulated by precipitating penetrating anions and suppressed by selective inhibitors. PMID- 8679781 TI - [Specific segments of the amino acid sequence of plant peroxidase]. AB - Plant and some fungal peroxidases have been found to contain a specific site in the amino acid sequence which makes the above enzymes distinct from other known structural and functional protein families. This site allows an unambiguous identification of the protein by its amino acid sequence provided the former is related to the above enzyme groups even in the absence of its homology to these enzymes. PMID- 8679782 TI - [Certain features of monoclonal rheumatoid immunoglobulin M fragmentation by "hot" trypsin]. AB - Using analytical ultracentrifugation and affinity chromatography, it has been shown that "hot" trypsin (hydrolysis at 58-60 degrees C) releases two types of fragments from the monoclonal (Waldenstrom disease) immunoglobulin M possessing a rheumatoid activity (IgM-RF). The first fragment corresponds to a normal Fab fragment as can be judged from its molecular weight. The other fragment designated as a (Fc)*5-fragment has a much higher molecular weight as compared with typical (Fc)*5-fragment released from non-rheumatoid IgM. According to calculations, the (Fc)*5-fragment retains two uncleaved Fab-regions and displays a rheumatoid activity. The Fab-fragments pool cleaved from IgM-RF consists of non rheumatoid and rheumatoid components at an approximate ratio of 3:1. It seems, therefore, likely, that ten Fab-regions of IgM-RF are nonidentical with regard to their functional and structural properties. Most of those do not possess a rheumatoid activity and are more readily cleaved from IgM-RF by "hot" trypsin in comparison with rheumatoid active fragments. PMID- 8679783 TI - [Isolation and certain properties of mutant alkaline phosphatase of Escherichia coli]. AB - Natural and mutant alkaline phosphatases with amino acid substitutions in the processing site and N-terminal domain of the mature polypeptide chain Val for Ala(-1), Gln for Glu (+4) and simultaneously Gln for Glu (+4) and Ala for Arg (+1) have been isolated from the periplasm and cultural fluid of E. coli. It has been found that these substitutions have little effect on the dependence of the enzyme activity on pH, ionic strength and temperature but influence its isoenzymic spectrum and decrease (almost twofold) the maximal rate of the enzyme catalyzed reaction. Extracellular enzymes display, in contrast with periplasmic ones, other catalytic properties (Vmax) and binding activity (Km). After translocation through the outer membrane all the enzymes display decreased Vmax and increased Km. These changes are especially well-pronounced in case of the mutant protein PhoA46 which contains an uncleaved signal peptide due to the impossibility of processing resulting from the substitution of Val for Ala(-1). The Vmax for this protein is decreased 20 times, while the Km is increased 4 fold. The protein also shows a higher (in comparison with other proteins) sensitivity towards proteolytic enzymes and is less resistant upon storage. The experimental data suggest that the changes in the N-end of alkaline phosphatase located at a long distance from its active center influence the enzyme function. PMID- 8679784 TI - Functional lateralization of the prefrontal cortex during traditional frontal lobe tasks. AB - We attempted to identify brain regions functionally lateralized during cognitive tasks traditionally linked to the prefrontal cortex (PFC) by measuring regional cerebral blood flow with H2(15)O positron emission tomography (PET). Fourteen normal subjects were scanned six times while performing six different cognitive conditions comprising three task paradigms putatively sensitive to PFC integrity: the Wisconsin Card Sort (WCS), Delayed Response Alternation (DA), and the Spatial Delayed Response (SDR) Tasks, and three matched sensorimotor control tasks. Multivariate and repeated measures analyses indicated that for all three cognitive paradigms there were no significant hemisphere, hemisphere-by condition, or hemisphere-by-region effects. However, with more liberal statistical comparison (paired t tests), the superior frontal gyrus showed lateralization during both the WCS and SDR tasks (both R > L). These results suggest that, although some asymmetries may be found using liberal analyses, there is less evidence of lateralized brain function during performance of these tasks of PFC function, than in language and motor systems. Implications for testing PFC function in neuropsychiatric groups are discussed. PMID- 8679785 TI - Sleep onset abnormalities in depressed adolescents. AB - Sleep measures were obtained in 16 depressed and 21 control adolescents following 1 week of adherence to a uniformly imposed and strictly enforced sleep/wake schedule. Three nights of baseline electroencephalographic (EEG) sleep on the same 10:00 PM to 7:00 AM schedule revealed prolonged sleep latency and reduced rapid eye movement (REM) latency in the depressed adolescents. Following baseline measures, sleep was restricted for 2 nights (10:00 PM-4:00 AM) and measures of recovery sleep were obtained showing further sleep latency differences. There was no evidence for delta sleep changes or sleep continuity differences in depressed adolescents. These results suggest that control over sleep/wake schedules is an important methodological issue in adolescent sleep studies. Furthermore, the findings are consistent with a larger body of evidence indicating that dysregulation near sleep onset represents a primary psychobiological change in early-onset depression. PMID- 8679786 TI - Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. AB - In a longitudinal epidemiological study of young adults, we estimated the association between sleep disturbance and psychiatric disorders, cross sectionally and prospectively. A random sample of 1200 was drawn from all 21-30 year-old members of a large health maintenance organization (HMO) in Michigan; 1007 were interviewed in 1989 and 979 were reinterviewed in 1992. Lifetime prevalence of insomnia alone was 16.6%, of hypersomnia alone, 8.2%, and of insomnia plus hypersomnia, 8%. The gender-adjusted relative risk for new onset of major depression during the follow-up period in persons with history of insomnia at baseline was 4.0 (95% confidence interval [CI] 2.2-7.0) and in persons with baseline history of hypersomnia, 2.9 (95% CI 1.5-5.6). When history of other prior depressive symptoms (e.g., psychomotor retardation or agitation, suicidal ideation) was controlled for, prior insomnia remained a significant predictor of subsequent major depression. Complaints of 2 weeks or more of insomnia nearly every night might be a useful marker of subsequent onset of major depression. PMID- 8679787 TI - No association between alcoholism and multiple polymorphisms at the dopamine D2 receptor gene (DRD2) in three distinct Taiwanese populations. AB - This study examined whether there is evidence for an association between alcoholism and the alleles of the TaqI A, TaqI B, and short tandem repeat polymorphisms (STRP), both individually and as haplotypes, at the dopamine D2 receptor gene (DRD2) in males of three populations from Taiwan. We studied 46 Chinese Han (21 alcoholics and 25 nonalcoholics), 42 Atayal (21 alcoholics and 21 nonalcoholics), and 40 Ami (20 alcoholics and 20 nonalcoholics). Alcoholism was diagnosed according to DSM-III-R criteria and all individuals in the alcoholic groups were severely affected. Significant linkage disequilibrium occurs for the three polymorphic sites in all three populations. No significant association was observed between any of the three polymorphisms at the DRD2 locus, tested individually and as haplotypes, and alcoholism in the three subject groups. We conclude that no association exists between genetic variation at the DRD2 locus and alcoholism in Chinese Han, Atayal, and Ami males. PMID- 8679788 TI - Seasonal patterns in platelet ligand binding are related to membrane proteins. AB - A seasonal pattern of platelet [3H]imipramine (3H-IMI) binding was explained by a similar but inverted pattern in membrane protein levels in repeated measures of 20 normal volunteers. No seasonal pattern was evident when 3H-IMI binding was expressed on the basis of surface area rather than membrane protein. Platelet Bmax levels in 50 depressed patients were lower than those of controls when values were expressed in terms of platelet surface area. The results support previous reports of low Bmax values in unipolar major depression, but indicate that seasonal changes in 3H-IMI binding are due to fluctuations in membrane protein and not to changes in the number of receptive sites. The present findings also have similar implications for other platelet measures expressed in terms of membrane protein. PMID- 8679789 TI - Plasma homovanillic acid concentrations in catatonia. AB - We investigated the dopamine metabolite plasma homovanillic acid (plasma HVA) levels in 37 catatonic patients on the day of admission before initial medication as well as in 17 healthy controls. In a prospective study catatonic syndrome was diagnosed according to criteria of Lohr and Wiesniwski (1987) and Rosebush et al (1990) whereas comorbid diagnosis was made by Diagnostic and Statistical Manual of Mental Disorders, 3rd ed, revised (DSM III/R) (APA 1987). On the day of admission blood samples were taken before initial medication. Compared to controls (80.1 +/- 40.1 pmol/mliter) catatonic patients showed significantly (P = 0.0286) increased plasma HVA (140.9 +/- 53.6 pmol/mliter). Catatonic patients free of neuroleptic medication (n = 21) differed significantly (p = 0.0416) from controls whereas neuroleptically treated catatonics (n = 16) did not. Our findings of increased plasma HVA in catatonia are explained by an alteration in either mesolimbic or mesocortical dopaminergic function, as is assumed in the case of schizophrenia. As an alternative, it may be due to increased nigrostriatal function, which can lead, as shown in animal experiments with the dopamine agonist amphetamine, to hypokinetic states resembling catatonia in humans. PMID- 8679790 TI - Effects of thyrotropin-releasing hormone administration on the electroconvulsive therapy induced prolactin responses and seizure time. AB - The effects of thyrotropin-releasing hormone (TRH) administration on electroconvulsive therapy (ECT)-induced prolactin (PRL) secretion and the duration of the seizure were studied in 14 depressed women. In a balanced order crossover design the patients were given 0.4 mg TRH or placebo intravenously 20 min before ECT during the first two sessions. In the third ECT session TRH was given just prior to ECT. ECT elicited the expected PRL response when given alone and when given 20 min after TRH when PRL plasma levels were high. During the coadministration design (third ECT session) PRL levels were raised not as a sum of the two stimuli but even significantly more. TRH failed to modify the duration of the seizure induced by ECT. Therefore, if TRH is involved in seizure modulation during ECT, our findings suggest a postictal rather than ictal role for TRH. PMID- 8679791 TI - The construct validity of root-mean-square error for quantifying smooth-pursuit eye tracking abnormalities in schizophrenia. PMID- 8679792 TI - Relationship between delta activity during all-night sleep and negative symptoms in schizophrenia: a preliminary study. PMID- 8679793 TI - Longitudinal visual evoked potentials in Alzheimer's disease: a preliminary report. PMID- 8679794 TI - Phenomenology and comorbidity of adolescents hospitalized for the treatment of acute mania. PMID- 8679795 TI - Abnormal phosphatidylinositol (PI)-signalling in bipolar disorder. PMID- 8679796 TI - Power to the cingulate. PMID- 8679797 TI - Thyrotropin-releasing hormone: a potential comparator for the panicogenic effects of pentagastrin and CCK? PMID- 8679798 TI - [HIV infection in women]. PMID- 8679799 TI - [Human immunodeficiency virus infection in women]. AB - From last years eighty's decade the number of women with HIV infection have significantly increased. To know the epidemiological and clinic trades in this group we studied retrospectively 476 HIV infected patients attending in a General Hospital from January 1986 to June 1993. Seventy nine (16.5%) were female and 397 male. The mean female group was 25.8 years, 61.9% were IVDUs and 30.4% heterosexual transmission. This last transmission route was more important between females than males (5%) (p < 0.001) and in 1992 the 55% of women been infected by this way. The mean CD4 count was 643 cel/ml in the female group at the diagnostic time and 21.7% developed antigenaemia without difference with the male group. 59.7% of women were no symptoms at the diagnosis time and 14.3% were AIDS, no differences with men, but more in the female group developed AIDS along following time 39.5% in front of 24.7% in the male group (p < 0.05). Disseminated Tuberculosis (DTB) (29.1%) and Wasting Syndrome (WS) (29.1%) were the more frecuent AIDS defining conditions in the female group. The more frecuent complications were: Oropharynx Candidiasis 39.1%, Esophagus Candidiasis 6.3%, WS 11%, DTB 12.65%, PCP 10.12% and Neoplasias 5.06%. Fourteen women became pregnant during HIV infection, no clinical nor immunological differences were observed in this group with the control. The treatment (66%) and following (46.8%), compliance was better between women than men. The rise of women with HIV infection, the poor development in this group described by some authors, so far gynecological aspect and vertical transmission makes HIV infection in women an major health problem. PMID- 8679800 TI - [Study of prevalence of pain at the Juan Canalejo Hospital in La Coruna]. AB - A study of prevalence of pain conducted in 812 patients admitted in the Juan Canalejo Hospital in La Coruna (Spain). This is primarily an adult hospital. Of the 650 patients whose replies were deemed valid, 35.69% were suffering pain. Other findings were that the sociocultural level of the patients affected their assessment of pain and that 46.12% of those who were suffering pain were not receiving analgesics at that time. Magnesium dipyrone, a combination of paracetamol and codeine and morphine were the most commonly used drugs, although there was clearunderuse of analgesic. PMID- 8679801 TI - [Evaluation of the efficacy of naltrexone in alcoholism by the determination of serum carbohydrate-deficient transferrin]. AB - Naltrexone (NTX) has been shown to be a useful drug for the treatment of alcohol dependence (AD). Carbohydrate-deficient transferrin (CDT) in serum is a new biologic marker of alcohol abuse. To evaluate the efficacy of NTX (50 mg/d) in AD, a group of 20 alcoholics with CDT > 20 U/l was studied using monthly laboratory tests (CDT, ESR, AST, ALT, GGT) and specific psychological testing (CAGE). After the second month statistically significant differences in CDT levels were found. By the end of the study, 13 patients (responders) had normalized their CDT levels. There was no correlation between CDT values and the other laboratory markers. The difference in routine laboratory markers between responders and non responders was not significant. NTX was well tolerated by all the patients and significant alcohol abstinence was achieved. CDT was demonstrated to be a effective marker for the evaluation of alcoholic abstinence during treatment with NTX. Superior results were obtained in comparison with the routine customary markers for AD. PMID- 8679803 TI - [Severe weight loss at the beginning of mesenteric panniculitis]. AB - We report a case of mesenteric panniculitis that presented with a severe lost of weight. We stress the difficulty that entails the diagnosis of this unusual entity, and also the excellent response to corticoid therapy in our patient. The clinical, pathological and therapeutic features of mesenteric panniculitis are reviewed. PMID- 8679802 TI - [Study of the influence of anticonvulsant treatment on thyroid function]. AB - We studied in two groups of epileptic patients the thyroid alterations induced by anticonvulsant therapy (AC). Group I (28 cases): T4t and TSH were measured before and after 3 and 6 months on treatment with AC. Group II (75 cases on treatment): thyroid hormones were measured only once. In cases with low value of T4t or high TSH a TRH test and FT4 determination were performed. In group I two cases with low T4t were found after six months on treatment (7%), one of them with low FT4 and both with normal TSH. In group II we found 6 cases (7.8%) with low T4t and FT4, two of them with high TSH. It was not possible argue against factor and the low incidence reported argue against rutinary screening. Anycase, this screening will never be performed before the lag time observed (6 months). PMID- 8679804 TI - [Neuro-Behcet: a follow-up of 4 cases treated with chlorambucil]. AB - Four patients diagnosed with Behcet's disease developing neurologic manifestation are described. Central nervous system findings were observed in three of them and peripheral neuropathy in ther other patient. All the patients were treated with chlorambucil, 0.1-0.2 mg/kg/day as initial dose. Three of them ended the immunosuppressive therapy after a period of treatment between 12-18 months. None of the four patients suffered neurologic relapses once that the therapy with chlorambucil was started. In a similar way to other authors, we think that treatment with chlorambucil in neuro-Behcet's disease may be useful to reduce morbility related to neurologic relapses. PMID- 8679805 TI - [Thyrotoxic periodic paralysis: an exceptional case report in Spanish population]. AB - Thyrotoxic periodic paralysis is a rare clinical manifestation of thyrotoxicosis in spanish population. Patients show weakness and frecuently, paralysis and low levels of potassium in serum. The episode can be triggered by eating high carbohydrate diet, exercise, stress and some drugs. We present a new case of thyrotoxic periodic paralysis in a Grave's disease patient. Only four cases have been reported in the spanish literature. We conclude that a functional evaluation of thyroid gland is necessary in thyrotoxic periodic paralysis patients. PMID- 8679807 TI - [Extrahepatic manifestations of hepatitis C virus]. PMID- 8679806 TI - [Hemorrhagic shock and fulminant hepatic failure associated with valproate]. AB - Fulminant hepatic failure is an uncommon adverse effect of valproate treatment. Despite an increased use of valproate, since the drug was introduced in 1978, a decline in the number of reported cases has been observed. Here a case of hemorrhagic shock and fulminant hepatic failure in a patient treated with valproate is presented. We emphasize the diagnostic difficulties from the point of view of recognition of the clinical manifestations as well as the biochemical monitoring. PMID- 8679808 TI - [The anticonvulsant hypersensitivity syndrome caused by phenobarbital]. PMID- 8679809 TI - [Retroperitoneal leiomyosarcoma in a patient with fibromyalgia]. PMID- 8679810 TI - [Varicella pneumonia in adults]. PMID- 8679811 TI - [Addisonian crisis as initial manifestation of bilateral metastatic adrenal tumor]. PMID- 8679812 TI - [Angiodysplasia of the colon associated with aortic stenosis and renal insufficiency. Apropos of a case with massive digestive hemorrhage]. PMID- 8679813 TI - [Cranial polyneuritis as initial manifestation of Lyme disease]. PMID- 8679814 TI - [Retroperitoneal and mediastinal fibrosis with serum p-ANCA increase. A new evidence of immunological etiology?]. PMID- 8679815 TI - [Third-generation cephalosporins in the treatment of exacerbations in chronic obstructive lung diseases]. PMID- 8679816 TI - [Present and future of the antiretroviral therapy]. PMID- 8679817 TI - [Smoking cessation program using nicotine patch among physicians and pharmacists of Catalonia: results after 3-12 months]. AB - Smoking abstinence rates of a group of 300 physicians and pharmacists of Catalonia (Spain) who participated in an open non-controlled follow-up design study with nicotine patch, are presented. Were eligible all the individuals who regularly smoke more than 15 cigarettes/day and get Fagerstrom Test score of 5 or more. Those who smoke more than 20 cig/day were offered a 3-month 24-hour transdermal nicotine treatment (30-20-10 schedule) and those smoking between 15 and 20 cig/day, received the 20-20-10 schedule. A follow up of participants was carried out at 3, 6, 9 and 12 months. After one year, 12 participants (4%) were dropped out. The overall abstinence rates at 3, 6, 9 and 12 months were respectively 55.9% (IC95%: 50.2-61.6), 42.7% (IC95%: 37.0-48.4), 35.4% (IC95% 29.9-40.9), 33.7% (IC95%: 28.2-39.2). Among predictive cessation variables, only those who had mad 1 to 3 previous attempts and those with only "cold turkey" (or slow reduction) quit experience, obtained statistically better results at 3 months. These results seem to be as good as or even better than those obtained in other similar studies with nicotine patch. PMID- 8679819 TI - [Cyclosporin A in the treatment of Eaton-Lambert myasthenic syndrome]. AB - The Lambert-Eaton myasthenic syndrome (LEMS) is a disorder of he cholinergic neurotransmition at the presinaptic terminal of the neuromuscular junction. Clinically it is characterized by muscular weakness, hyporeflexia and autonomic dysfunction. In this entity thet presence of antibodies against calcium channels impair acetylcholine release. Whe used cyclosporin-A in a patient with LEMS and this resulted in a complete clinical and neurophysiological recovery after four months of therapy. PMID- 8679818 TI - [Use of averaged concentration of urea and whole body urea clearance in prescribing the length of a dialysis session]. AB - Urea kinetic-modelling was performed on 109 patients undergoing hemodialysis (518 urea kinetic studies). Then, the theoretic times for a target TAC = 50 mg/dl (TTAC) and a Kt/V = 1 (TKTV) were estimated. The differences and correlations of both times were calculated. Also the correlation of PCR and Kt/V was analyzed in relation to the range of Kt/V. For all cases no differences were found in dialysis session length (TTAC 221.4 +/- 42.6 min.; TKTV 222.9 +/- 48.9 min.). Mean Kt/V was 1.00 +/- 0.15 and mean TAC was 55.2 +/- 13.2. 313 studies (60.4%) have a TAC > 50 mg/dl. For Kt/V < 0.80, 15.6% have a TAC < 50 mg/dl, when Kt/V > 0.80 41.2% of cases have a TAC < 50 mg/dl (p < 0.01). A linear correlation of Kt/V and PCR was found (r = 0.36, p < 0.01). This correlation was stronger for Kt/V < 0.8 (r = 0.54, p < 0.01, n = 47). When TTAC was compared to TKTV a great variability was found: 20.1% have differences lesser than 15 minutes; and this difference was more than 30 minutes in 58.5%. In 107 cases (20.7%) the TTAC produced a Kt/V < 0.8. In all cases a significant (p < 0.01) linear correlation between TKTV and TTAC was found (r = 0.46). TKTV was greater than TTAC for real Kt/V < 1, and lesser than TTAC cuando the effective Kt/V was > 1. It is concluded that in patients treated by dialysis prescription of dialysis session length by TAC or by Kt/V produce rather different times for an unique patient. These differences are related to the PCR, which have a significant correlation with Kt/V. TAC tends toward under value dialysis session length in patients with inadequate dialysis. PMID- 8679820 TI - [Septic arthritis caused by Salmonella enteritidis in systemic lupus erythematosus]. AB - Systemic Lupus Erythematosus (SLE) is among the chronic diseases thought to predispose patients to severe Salmonella infections. However, arthritis and osteomyelitis due to this microorganisms are more frequently seen in patients with sickle-cell disease than SLE. We report two cases of SLE and osteoarticular infections by Salmonella enteritidis: A 36-years old woman with bilateral knee arthritis associated with femoral osteomyelitis and a 22-years-old woman who presented with left knee arthritis. PMID- 8679821 TI - [Pregnancy, breast cancer and tumor infarction]. AB - Breast cancer is infrequently associated with pregnancy. However, such cases often pose diagnostic and treatment problems. The infarction of breast lesions is likewise uncommon, and generally hinders intraoperative morphologic diagnosis. A 33-year-old woman in the 37th week of pregnancy presented with a breast tumoration of progressively increasing size and associating mastalgia. Following fine-needle aspiration and trut-cut biopsy with posterior amplified tumorectomy and axillary dissection, a ductal neoplasm was identified with an infarction affecting 90% of the tumoral surface. The where no axillary adenopathies, and the patient was estrogen receptor-negative. An analysis is made of this rare association of pregnancy and infarcted breast cancer, with an evaluation of the role of fine-needle aspiration and/or gestation may play in the occurrence of tumor infarction. PMID- 8679822 TI - [Invasive pulmonary aspergillosis associated with influenza virus]. AB - Invasive pulmonary aspergillosis can occur after viral influenza infection. It is described a previously healthy 58-year-old man with influenza virus infection who later suffered pulmonary aspergillosis. His response to amphotericin B was successful. The seven similar cases reported in the literature are revised and some common features established. Early antifungal therapy should be administered to any patient with previous flu illness presenting bilateral pulmonary infiltrates without response to antibiotics, if Aspergillus is isolated from the respiratory secretions. PMID- 8679823 TI - [Mediastinal large-cell lymphoma of B-cell (thymic?) type. An anatomo-clinical entity in development]. PMID- 8679824 TI - [Cerebral toxoplasmosis in patients with human immunodeficiency virus (HIV) infection. Clinico-radiological and therapeutic aspects in 63 patients]. AB - We have retrospectively reviewed 63 cases of encephalic toxoplasmosis (ET) in HIV infected patients in order to determine clinical and radiological characteristics, the diagnostic value of serologic determinations, and the response to antioxoplasmic therapy. ET was the AIDS-defining condition in 44% of the patients. Eighty of the patients had a CD4 cell count < 100/microliters when ET was diagnosed. Only 4.8% of the patients had been taking anti-Pneumocytis carinii prophylaxis with cotrimoxazol. The most frequent clinical presentation was focal neurologic signs in 80.9% of the patients, with headache and fever in 53.3% and 42.4%, respectively. The most frequent cerebral CT finding was hipodense lesions (92%) with ring enhancement (68.9%). They were most frequently had a hemisferic location. Seroconversion was detected in two patients (6%), whereas 55 patients had serologic evidence of latent infection by Toxoplasma gondii (87.3%). Ninety eight percent of the patients were treated with sulphadiazine plus pyrimethamine. However, such therapy should be discontinued in 22% of them and switched to clindamycin plus pyrimethamine. The overall mortality rate during the acute phase of the disease was 7.9%, but 41.4% of the survivors exhibited neurologic sequelae. Relapsing ET was detected in 33.3% of the patients, and it was usually due to discontinuation of treatment. The mean survival time after the diagnosis of ET was 11.5 months. ET is the most common opportunistic infection of the central nervous system among our AIDS patients. Primary prophylaxis for toxoplasmic infection seems advisable in our epidemiologic environment, when CD4 cell count is less than 200/microliters and there is serologic evidence of latent infection. Acute ET usually has a good response to therapy, and the acute mortality rate is low. However, most of the survivors will remain with neurologic sequelae. The high frequency of adverse effects to sulphamide therapy with clindamycin make the need of alternative treatment strategies urgent. PMID- 8679825 TI - [Laboratory contribution to the diagnosis of pheochromocytoma]. PMID- 8679826 TI - [Acute neutrophilic eccrine hidradenitis]. PMID- 8679827 TI - [Cutaneous metastasis of signet ring cell adenocarcinoma]. PMID- 8679828 TI - [Thrombotic thrombocytopenic purpura associated with ticlopidine]. PMID- 8679829 TI - [Spontaneous tumor regression and gastric cancer]. PMID- 8679830 TI - [Treatment of pyogenic liver abscesses]. PMID- 8679831 TI - [Acute staphylococcal pericarditis associated with multiple myeloma]. PMID- 8679832 TI - [Usefulness of lithium in neutropenia associated with AIDS]. PMID- 8679833 TI - [Immunosuppression and pulmonary nocardiosis]. PMID- 8679834 TI - [Parenteral S-adenosylmethionine compared to placebos in the treatment of alcoholic liver diseases]. AB - The improvements in the knowledge of the action of ethanol over the hepatic cell, its direct action over the cell, and the intracytoplasmatic structures membranes, point out the possibilities of use of sulfo-adenosil-L-metionina (SAMe); as an util drug inn the treatment of the altered metilation reactions, that take place in those membranes, facilitating their physiological functions. The primary end point in this study was to demonstrate the therapeutic worth os SAMe, by parenteral route in 45 patients with alcoholic liver disease, which were determined by clinical laboratory and hepatic function test, label qith 32 points or more of the discriminatory function index. Divided into two groups, placebo SAMe, randomized, double blind. As well as total plasmatic and reduced glutation and lipoperoxidation index, indirect form as malondehaldehyde. Were determined at the first visit anf after 8 and 15 days of treatment. Comparing the results of both groups there were a significative favorable results for the group treatment with SAMe and this confirms the utility of this drug in the treatment of patients with alcoholic liver disease with a discriminatory function index (Maddrey index), of 32 points or more. PMID- 8679835 TI - [Role of the fibrinolytic system in the physiology of stroke]. PMID- 8679836 TI - [Alterations of fibrinolysis in stroke]. AB - The fibrinolytic system has an important role as a controller of the coagulation, since plasmin digests and dissolves the fibrin clot. In this way, they have described many alterations in this system that are responsible of the thromboembolic disease, moreover stroke. This study tries to show the incidence of these alterations in a group of patients suffering from stroke, and the difference of this incidence between men and women. We obtained that the fibrinogen, tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI-1) levels are significantly increased (p < 0.01) in the group of patients, and in the same way, there are also differences (p < 0.01) between men and women, so in the control group as in the patients group; these differences should mean that women have a major risk for suffering an stroke, but it doesn't fits the fact that stroke is more frequent in men and that they are younger when they suffer from this disease. PMID- 8679837 TI - [Epidemiological study of tuberculosis in the health area of Santiago de Compostella in 1992, 1993 and 1994]. AB - An exhaustive search for the clinical records of patients diagnosed with tuberculous disease was done in the hospitals of the area under study, which involves 392,000 population. During the years 1992, 1993 and 1994. There were included: 1) patients who had positive bacilloscopy and/or positive Lowenstein's culture in any specimen: 2) patients younger than 35-years-old who had pleural effusion, significant Mantoux and adenosine deaminase (ADA) over 47 U/I in the pleural effusion. In total 814 patients remained in the study with an average age of 38.39(19.39 DE) in 1992, 39.02 (20.04 DE) in 1993, and 34.1 years-old (19.2 DE) in 1994, with extreme ages of 2 months and 87 years-old. The incidence/100,000 H was: in 1992: 67.86, in 1993: 66.58 and in 1994: 73.2. The contagious forms incidence/100,000 H was: 1.5 in 1992 and 1993; and 1.79 in 1994. The hospital mortality incidence/100,000 H was 2.04 in 1992, 2.30 in 1993 and 2.6 in 1994. We conclude that tuberculosis is endemic in our area with moderately high and stationary incidence. PMID- 8679838 TI - [Study of comparative immunity of patients with M. tuberculosis and atypical Mycobacteria infection and infection by human immunodeficiency virus (HIV)]. AB - The purpose of this retrospective study was to determine the basal immune status, in patients with human immunodeficiency virus (HIV) infection, who were affected from tuberculosis (TB) caused by Mycobacterium tuberculosis or atypical mycobacterium. In the current study, we report our experience with 280 patients diagnosed TB and HIV: fifty cases were eligible for enrollment at random with M. tuberculosis (group I) and we compare with 23 cases of atypical mycobacterias (group 2). When we analyze statistically both groups, we detected in group 2 the existence of a CD4 Lymphocytes count decrease and a mean IgA raised, opposite to group I (P < 0.0001). On other side, our investigation on survival showed that this was lower in atypical mycobacterias group (group 2) with a median time of survival of 10 months, opposite to 2,9 years in group I. PMID- 8679839 TI - [Bronchioloalveolar carcinoma]. AB - We studied 14 patients with bronchioalveolar carcinoma during the last 14 years. In all cases we evaluated the clinical history, the radiologic presentation, and the diagnostic procedures. The mean age of presentation of the illness was 58.5 years. The incidence of smokers was 35%. The time interval from clinical manifestations to diagnosis was 3,3 months. The most frequent symptoms were cough (57%) and dyspnea (43%). The 21% of the cases were asymptomatic. Two patients (14%) had copious amounts of sputum (bronchorrhea). The most revealing radiologic pattern was of alveolar type (43%), followed by multiple pulmonary nodules (29%) and solitary pulmonary nodule pattern (21%). The diagnosis was based in specimen obtained from transbronchial biopsy, bronchoalveolar lavage, transthoracic aspiration biopsy, thoracotomy, or during the necropsy study. Transbronchial biopsy was a sensitive diagnostic method. The 64% of patients were in a extent disease when the diagnosis was established. PMID- 8679840 TI - [Bronchioloalveolar carcinoma in a young woman]. AB - Bronchioloalveolar carcinoma is an infrequent malignant lung tumor, specially in patients younger than 50. Diagnosis is difficult and usually late, because its clinical and radiologic features are similar to other lung diseases and because its poor histopathologic differentiation from other primitive o metastatic adenocarcinoma. We report a case of multinodular, diffuse and bilateral bronchioloalveolar carcinoma in a young woman without previous lung disease which suspected diagnosis was by broncho-aspirated cytology and open lung biopsy was necessary for its confirmation. PMID- 8679841 TI - [Pancreatitis and inappropriate ADH secretion syndrome associated with amiodarone]. AB - We describe a case of hepatotoxicity, pancreatitis and inappropriate ADH secretion syndrome developed in a patient receiving chronic amiodarone treatment, not related to other causes. Hepatic toxicity is a well known condition. Inappropriate ADH secretion syndrome has not been described yet and there has been a single case-report of pancreatitis in the literature reviewed. PMID- 8679842 TI - [Inappropriate ADH secretion syndrome]. AB - Six patients are with inappropriate secretion of antidiuretic hormone syndrome are reported (two with bacterial acute meningitis, two with bacterial pneumonia, one with oat cell lung carcinoma, other with mediterranean fever boutonneuse) and the clinical manifestations were: mind changes (four cases) nausea-vomiting (two cases) and inappetence (six cases). All patients presented hyponatremia criteria, serum decreased osmolarity, urinary sodium and osmolarity increased, without edemas, renal disease endocrine (hypophysis, thyroids, adrenal) without diuretic treatment. Treatment was, effective water restriction in three patients and hydrochloride of demeclocycline in other three patients. PMID- 8679844 TI - [Segmental portal hypertension and cystic tumor of the pancreas]. AB - Isolated obstruction of the splenic vein constitute 5-10% of all patients with portal hypertension. The evaluation of splenic vein patency is important in assessing inflammatory or neoplastic diseases of the pancreas. Accurate preoperative diagnosis is therefore essential to allow the correct choice of operative procedure. A case of isolated splenic vein obstruction with left-sided portal hypertension secondary to cystadenocarcinoma of the pancreas is reported in order to discuss criteria of preoperative diagnosis between benign and malignant cystic lesions of the pancreas. PMID- 8679843 TI - [Varicella complicated by pericarditis and pneumonia]. AB - Varicella is a highly infectious disease mainly affecting young children under 14 years of age, and being generally mild. In adults immunodeficient children and neonates exposed in utero, the illness tends to be more severe with higher incidence of complications. The type of complication is linked to the age: in children, bacterial infection of skin lesions and acute cerebellar ataxia are more frequent while lower respiratory tract infection, Reye syndrome and encephalitis are less common. Varicella pneumonia is found typically in adult patients and diffuse encephalitis which course is worse than children could be less frequently. Acute pericarditis is an exceptional complication with a benign course, but only if myocarditis or pericardial effusion are not concurrent. It usually appears in teenagers and young adults; only a few times, it has been linked to other complications as pneumonia or arthritis. We report a varicella case in an adult patient who suffered from pneumonia and pericarditis, both of them were benign. PMID- 8679846 TI - [Light, more light. Some other concurrent hypotheses about etiopathogenesis of tuberculosis in our environment]. PMID- 8679845 TI - [Lipid metabolism and new dietetic recommendations in diabetes mellitus]. AB - Abnormalities of plasma lipids are highly prevalent in both types of diabetes, but there are important quantitative and qualitative differences that this paper reviews. The importance of abnormalities in lipoprotein metabolism as determinant of vascular risk in general population is similar in diabetes, where there is chronic hyperglycemia associated, but it is considered as an independent vascular risk factor. People with IDDM in adequate glycemic control generally have plasma lipid concentrations in normal levels, but in NIDDM, even in good glycemic control, there are another factors associated and usually there are hypertriglyceridemia and total hypercholesterolemia with reduced HDL fraction. Carbohydrate-rich diet increase plasma triglyceride levels and low HDL cholesterol levels in the majority of studies. Substitute monounsaturated fats in the diet to replace saturated fats lowers total cholesterol and LDL fraction and increase HDL, in addition it acts over others vascular risk factors. These findings were taken into account by ADA and recently revises their 1986 dietary recommendations with the same goals of medical nutrition therapy but with individualized approach appropriate for the personal life style to facilitate adherence to achieve the glycemic, lipid body weight and blood pressure aims with a good quality of live. PMID- 8679847 TI - [Pleural tuberculosis with negative ADA]. PMID- 8679848 TI - [A case of neuroleptic malignant syndrome]. PMID- 8679849 TI - [Supraventricular tachycardia during pregnancy: incidence and therapeutic management]. PMID- 8679850 TI - [Multiple symmetrical lipomatosis associated with idiopathic thrombocytopenic purpura]. PMID- 8679851 TI - [Migraine with pleocytosis: a little known entity]. PMID- 8679852 TI - [Fever as expression of corticoid withdrawal syndrome in chronic obstructive pulmonary disease]. PMID- 8679853 TI - [Bacteremic peritonitis caused by Aeromonas hydrophila in a woman with cirrhosis]. PMID- 8679854 TI - [Scar sarcoidosis of the skin: the role of silica]. PMID- 8679855 TI - [Prevention and health promotion in a client-provider model]. PMID- 8679856 TI - [Relationship between health care levels]. PMID- 8679857 TI - [Brief family therapy: an option for the treatment of somatoform disorders in primary care]. AB - OBJECTIVE: To study the application of the brief family therapy model to the treatment of somatoform disorders in scheduled primary care consultations. DESIGN: Intervention study. SETTING: Cazona Health Centre, Santander. PATIENTS: 18 patients who had suffered somatoform disorder for at least a year. INTERVENTIONS: A general practitioner trained in short-term family therapy applied this treatment under the supervision of a specially trained psychologist. MEASUREMENTS AND RESULTS: The variables of the research into the results of brief family therapy were collected. These showed 61.1% therapeutic success, 27.8% failure and 11.1% abandonment. There were no relapses at the six-month control. Total number of consultations varied between 1 and 11, average 4.6; the average interval between consultations was 27 days, with an average length of 48 minutes for each consultation. Time between the first and last consultation varied from 1 to 242 days, average 96 days. Brevity of treatment was related to its therapeutic success. CONCLUSIONS: Training in brief family therapy, with supervision at the start, can provide primary care doctors with a treatment alternative for resolving somatoform disorders without the patient having to accept a psychological reason for his/her complaints. PMID- 8679858 TI - [Trust of primary care physicians in the reliability of the vade mecum]. AB - OBJECTIVES: To assess the reliability which doctors grant to the International Vademecum as a source of information, up-dating and on-going training in pharmacotherapy; also to find their knowledge of the presence of Saccharose as an excipient in the composition of several pharmaceutical products commonly used in primary care. DESIGN: A descriptive, crossover study using a self-filled postal questionnaire. SETTING: Badajoz health sector. PATIENTS AND OTHER PARTICIPANTS: Primary care doctors (general and paediatricians) from three health areas in the province of Badajoz. MEASUREMENTS AND MAIN RESULTS: A total of 178 doctors filled in the questionnaire (57.6% of the 309 doctors from the health centres). All the information in the Vademecum is considered useful and trustworthy by 68.2% of the doctors. Nor were there any significant differences in the assessment of the Vademecum between doctors with MIR (intern) training (63.6%) and without (71.1%). The Vademecum is used as a source of updating and on-going training in pharmacotherapy by 33.7% of doctors. Its use increases in line with the doctor's age and the time worked in primary care. Knowledge among doctors of the presence of saccharose as one of the excipients in the five pharmaceutical products analysed varied between 21.2% and 46.4%. CONCLUSIONS: Widespread acceptance and use of the Vademecum by primary care doctors and scant knowledge of the presence of Saccharose as an excipient in the pharmaceutical products analysed. PMID- 8679859 TI - [A descriptive study of long-term medication authorized in the health district of Llefia (Badalona)]. AB - OBJECTIVE: Analysis of authorised long-term medication and assessment of the quality of prescription. DESIGN: Descriptive, crossover study. SETTING: Primary care. PARTICIPANTS: Of a total of 4,667 authorised medication cards (AMC), 400 were selected by systematic random sampling. MEASUREMENTS AND MAIN RESULTS: Variables considered: age, gender, Social Security regime, pharmaceutical speciality, composition, presentation, method of administration, dosage, authorisation time, group/subgroup of anatomical therapeutic classification (ATC) and HPV. RESULTS: Average age: 61; 64.8% were women and 35.2% men; 67.25% were pensioners. 447 pharmaceutical compounds and 304 different active principals (most prescribed drugs: paracetamol, hydrochlorothiazide, nitroglycerine, acetylsalicylic acid and salbutamol); presentation: tablets and capsules; main way of administration: oral. Average dosage: 1.63 (11.29% not figuring). Average authorisation time: 11.6 months; average medicines per AMC: 3.03. Distribution by ATC: cardiovascular (30.8%); CNS (20.76%); digestive and metabolic (15.57%); respiratory (10.6%). 83.8% of prescriptions had HPV. 84.35% were single drugs. CONCLUSIONS: The mean profile of the patient with an AMC corresponds to a woman, aged 61 and a pensioner, with 3 medicines authorised for a year, one an analgesic (paracetamol), another an antihypertensive (diuretic) and a third more variable. They are mainly taken orally and once or twice a day. The majority are special compounds with HPV. PMID- 8679860 TI - [Factors conditioning absenteeism among primary care physicians]. AB - OBJECTIVES: To find whether the variables age, gender, speciality, training and type of contract of primary care doctors, as well as the size of their patient lists and the sort of centre where they work, affect their absenteeism, as measured by time off work sick. DESIGN: An observational, crossover study. SETTING: Nou Barris, sub-division of Barcelona City, primary care (PC) district during 1994. PARTICIPANTS: Doctors. MEASUREMENTS AND MAIN RESULTS: In the PC district there were 121 doctors, counting PC teams (PC), traditional system (TS) and specialists. Bivariant epidemiological and statistical techniques were used to verify the relationships between variables. Alpha risk was 5%. 40% of the District's doctors had some time off sick during the year. There were 79 occasions of time off (74 were for short-term sickness and 5 for maternity). Total days lost were 2,477, an average of 31.35. Time off work was related to the age of the doctors and the number of patients attending. Centres where the reform had been implemented had very few cases of time off. CONCLUSIONS: Cases of time off work for sickness among primary care doctors are mainly concentrated in the non-reformed network. It would be useful to study ways of increasing these doctors' motivation. PMID- 8679861 TI - [Analysis of adverse drug reactions detected in a primary health care center]. AB - OBJECTIVE: To determine the incidence and epidemiological characteristics of adverse drug reactions (ADR) and to assess their relevance in primary health care. DESIGN: An open prospective descriptive study. PATIENTS: All patients cared for in one primary health care centre during 2 months. MEASUREMENTS AND MAIN RESULTS: 73 ADR were detected during the period of study (two of which corresponded to pediatric patients) with an incidence of 1.35% in adult general medicine and 0.36% in pediatric medicine. 67% of the patients were female, and all adult patients were distributed into three age groups (15-44, 45-64 and > or = 65 years of age). The frequency of ADR was similar in all three age groups. The ADR were most present in the GI tract, central nervous system, general symptoms and skin. Among the most frequently pharmacological groups implicated in the ADR were cardiovascular drugs, antibiotics and drugs for the central nervous system. Only in 12 cases the ADR was considered as clinically relevant, according with the criteria of the participating physicians; in 6 cases they were evaluated as avoidable. CONCLUSIONS: The ADR are not a relevant clinical problem, nor are they frequent in the outpatients primary health care. In most cases there are slight and self-limiting, which appeared in a limited number of patients. However clinically relevant and important ADRs appeared in 0.1-0.3% of the consultations, which, in practice, represent one to two serious ADRs per month and physician. PMID- 8679863 TI - [Self perception of health and complete evaluation of the elderly patient at a primary care center]. AB - OBJECTIVES: 1) To make an integrated evaluation of the cognitive status, functional capacity, chronic disorders and social situation of the over-75 age group. 2) To find this group's self-perception of their health. DESIGN: A descriptive crossover study. SETTING: The Gotic Health District in Barcelona. PARTICIPANTS: 316 people were included in the study. They were chosen by simple randomised sampling from the over-75s seen at the centre (n = 1,625). MEASUREMENTS AND MAIN RESULTS: To assess cognitive status, the Pfeiffer Short Portable Mental Status Questionnaire was used; for functional capacity, the Katz Index; and for chronic disorders, the medical records were reviewed. A questionnaire was used to find patients' social situation and assessed social relationships, social resources used and architectonic barriers. Self-perception of health status was evaluated using the Nottingham Health Profile. Prevalence of cognitive deterioration was 29.7%. 39.4% of patients were dependent in one or more basic activities of their daily life. 90.8% had a chronic disorder, the most frequent being AHT, arthrosis, obesity and dyslipemias. 28.3% lived alone and 26.7% used social services. CONCLUSIONS: We think this kind of assessment is useful in primary care. It would provide an integrated diagnosis (clinical, functional, medical and social) of elderly patients. PMID- 8679862 TI - [Prescription of platelet antiaggregants in secondary prevention of ischemic heart disease]. AB - OBJECTIVE: To find out how many patients older than 64 years of age seen in a primary health care (PHC) centre receive antiplatelet drugs for secondary prevention of coronary heart disease (CHD), as well as by whom they are prescribed, which drug is chosen, and what are its contraindications, unwanted effects and motives for ending therapy. DESIGN: Description of all cases of CHD among patients older than 64, identified through the audit of clinical records. SETTING: Urban health care centre with 23,702 inhabitants, with 2,742 over 64, 2,660 of whom have clinical records. SUBJECTS: Patients over 64 with CHD, seen in the health centre within 1993. MEASUREMENTS AND INTERVENTIONS: Age, sex, type of CHD, therapy with a platelet aggregation inhibitor, drug used, dose, prescriptor, adverse events, contraindications. RESULTS: We identified 179 cases of CHD, a prevalence of 6.7%, of which 60.9% were male. 94 patients received an antiplatelet drug: aspirin (88.3%), dypiridamol and triflusal (5.3% each) and ticlopidine (1 case). 111 patients were adequately treated, including 84 given aspirin or ticlopidine, 12 patients in which therapy was ended due to adverse events, and 15 patients in which use of antiaggregant drugs was contraindicated. All prescriptions originating from general practitioners were for aspirin, while specialists prescribed other drugs in 11% of cases. CONCLUSION: Two-thirds of patients with CHD were correctly treated. Aspirin is the antiaggregant drug most frequently used, particularly among PHC physicians. Even low doses of aspirin were associated with interruptions of therapy due to adverse events. PMID- 8679864 TI - [How are the patients informed at a hospital emergency service?]. AB - OBJECTIVE: To evaluate the clarity and efficacy of the information given to patients by doctors, in the hospital emergency ward (HEW) and the influence of accompanying people on such information. DESIGN: Descriptive transverse study. SETTING: HEW of the Hospital General of Segovia. PATIENTS AND OTHER PARTICIPANTS: 171 patients seen at the HEW between July and September of 1993. MEASUREMENTS AND MAIN RESULTS: An oral questionnaire consisting on 15 items including: age, sex and sociocultural profile of the patient, presence of a companion, knowledge the doctor's identity, oral information recived during the stay and oral and written recommendations at the time of discharge, was used. The report of discharge delivered to the patient was used for contrast. Only 20 patients (11.7%) knew the name of the doctor who attended them; a statistically significant difference (p > 0.01) was found in favour of those who were accompanied. In spite of the fact that 97.6% of the patients said that they had received a clear information and that 88.9% of them did referred to have no doubts, only 71.9% of them were able to repeat correctly the treatment recommended at the time of discharge. A 50% of the patients were able to read and understand the written report, while 19% of them did not understand it and another 20% considered it illegible. CONCLUSIONS: In order to guarantee the patient's compliance with recommendations given at the time of discharge of a HEW, it is necessary to improve oral and written information given to them, relying on the presence of a companion and checking their assimilation. PMID- 8679865 TI - [Infantile diarrhea: knowledge and attitudes of mothers at a primary care center]. AB - OBJECTIVE: To study the knowledge and attitudes of mothers at a health centre to babies' diarrhoea. DESIGN: A crossover, observational and prospective study. SETTING: Paediatrics clinic at a health centre in the city of Valencia. PARTICIPANTS: 142 mothers who attended the clinic of their own accord. MEASUREMENTS AND MAIN RESULTS: The mothers themselves filled out a questionnaire on what diarrhoea was, its causes, hygiene measures to prevent it and their response when it appeared. 80.3% accurately defined diarrhoea. 94.4% recognised that micro-organisms were the cause. All mothers of unweaned babies not being breast-fed sterilised the feeding bottle adequately and had a proper water supply. 89.4% said they washed correctly both hands and food before handling food. Although 89.4% knew they should give more liquid to their babies during diarrhoea, only 24.6% used an adequate oral rehydrating solution and 24.2% said they made their babies fast for long periods. Most said they would consult the doctor if their baby had diarrhoea (79.6%) and would go back to the doctor if they noticed complications (96.5%). CONCLUSIONS: Mothers attending a health centre in Valencia had a good attitude to diarrhoea prevention. They often committed errors in oral rehydration and feeding of a baby with diarrhoea, which might cause problems. However their frequent attendance at the doctor's may help avoid these problems. PMID- 8679866 TI - [Prior appointment, profile of the patient and accessibility]. AB - OBJECTIVES: To analyse the impact of the prior appointment system on still unevaluated care indicators and how the system connected with other factors affecting access to health care. DESIGN: Intervention study. SETTING: Santa Maria de Gracia Health Centre in Murcia. PATIENTS AND OTHER PARTICIPANTS: 831 and 724 patients seen at two general medical clinics at the health centre during the same period in two consecutive years, before and after the start of the prior appointment system. INTERVENTIONS: The start of the prior appointment system. A questionnaire given to patients at the end of their consultation. MEASUREMENTS AND MAIN RESULTS: Variables concerning patients' profiles and habitual conduct, resource use and distribution of waiting and consultation times, and health service use connected to other factors of access to care, were compared for before and after the introduction of the prior appointment system. There were significant differences in the distribution of waiting time, which became shorter (p < 0.01); and consultation time, with an increase in intermediate length and a decrease in extreme times (p < 0.05). Health service use also varied according to distance from the centre and place of residence of the patient: it increased for those living further away (p < 0.01). CONCLUSIONS: The prior appointment system, over and above a decrease in waiting time and increase in consultation time, meant a rationalisation of both time and health service use dependent on other factors connected with access to health care. The absence of modifications in patients' profiles and in their habitual conduct during the consultation were also confirmed. PMID- 8679867 TI - [Description and validation of a predictive model of the geographic distribution of chronic home-bound patients]. AB - OBJECTIVE: To find a predictive model for the geographical distribution of the homebound chronically ill in function of variables corresponding to censal areas. DESIGN: A study of an ecological type. SETTING: Raval Nord Health District, Barcelona. PATIENTS AND OTHER PARTICIPANTS: The study units are the 30 censal areas of Raval Nord. In each area researchers counted the number of homebound chronically ill recorded during the first three months of a home care programme (May 1994). MEASUREMENTS AND MAIN RESULTS: A multiple regression analysis was performed, with selection of the variables by the stepwise method of the SPSS-PC+ statistical package, taking as dependent variable "y" the number of homebound chronically ill per 1,000 inhabitants. The prognostic variables were taken from the 1991 municipal roll, and evaluated along with the distance in metres from each censal area to the primary care centre (PCC). The distribution of the homebound chronically ill in the different censal areas of Raval Nord was connected to 3 variables which, in order of analysis, were: distance to the PCC, the relationship with senile dependency and the index of family socio-economic capacity. CONCLUSIONS: Distance, senile dependence and economic resources are factors which condition the number and distribution of the homebound chronically ill. PMID- 8679868 TI - [Continuing education plan of the Spanish Society of Family and Community Medicine]. PMID- 8679869 TI - [Professional associations in general medicine]. PMID- 8679870 TI - [Concerning the denomination "family physician"]. PMID- 8679871 TI - [Symptoms of menopause and osteoporosis risk factors]. PMID- 8679872 TI - [Limitations of interventions against hypercholesterolemia]. PMID- 8679873 TI - [General practitioners/specialists: from encroachment to understanding]. PMID- 8679874 TI - [Evaluation of the type II diabetic population attended by a primary care team]. AB - OBJECTIVES: To find the degree of control, the prevalence of complications and cardiovascular risk factors (CVRF), and the drugs treatment used for type II diabetics. DESIGN: A descriptive crossover study. SETTING: Rekaldeberri Health Centre, Bilbao. PATIENTS: 202 diabetes II patients selected at random. INTERVENTIONS: Data were gathered by interviews, physical examinations and further tests. MAIN RESULTS: 52.2% of the sample were women. Average age was 66.6 50% of the diabetics had been diagnosed for 8 years or more. Microalbuminuria was detected in 21.9% of the patients, Microangiopathy in 24.8%, Neuropathy in 11.4% and diabetic foot in 10.4%. The years of evolution and appearance of complications had a significant connection. 64.4% of patients had a good or acceptable metabolic control. Worse metabolic control of diabetes was connected with the appearance of retinopathy and neuropathy. 47.5% were hypertensive. 21.3% smoked, 35.6% had cholesterol figures over 250 mgr/dl. Their mean Body mass index was 28.1. 40.6% were treated exclusively by diet, 9.9% with insulin and 35.6% with medicines taken orally. CONCLUSIONS: A high percentage of diabetics had a good or acceptable control of their disease. Prevalence of complications was less than in other studies, whereas CVRFs were similar. We do not discount the presence of bias in the comparison because of different diagnostic methods. PMID- 8679875 TI - [Maternity protection legislation: a tool for promoting mother-child health]. AB - OBJECTIVE: To describe the legislation existing in Spain on the protection of women in paid work after giving birth. SETTING: Spanish legislation was reviewed and the following aspects examined: time off for childbirth, leave to care for children, hours for breast-feeding, reduction in the working day for the care of small children and time off because of children being ill. MEASUREMENTS AND MAIN RESULTS: Time off for childbirth is 16 weeks, of which 6 must be after the birth. If both parents work, the father can opt for the last 4 weeks. The amount paid is 100% of the regulated basic wage and will be paid directly by the relevant managing body. Both workers under the general regimen and those under special regimens can receive this benefit. Workers in normal employment can have unpaid leave for a period of up to three years. Other measures are the daily period of one hour for breast-feeding a child under 9 months, the reduction in the working day by between a third and a maximum of half its length to care for children under 6 and the possibility of being away from work for two days because of a child's serious illness. CONCLUSIONS: The existence of specific legislation protecting maternity is an important, though insufficient, step towards guaranteeing equal opportunities for men and women in the labour market. Specially noteworthy is the reconciliation of paid work and family responsibilities. PMID- 8679876 TI - [Primary care physicians' referrals to a mental health unit]. AB - OBJECTIVE: To assess the differences between general practitioners (GP) and family and community medicine specialists (FM) in referring patients to the mental health unit (MHU) and the diagnostic agreement between both these groups of doctors and the mental health professionals. DESIGN: Observational crossover study. SETTING: Primary Care. The 5 health centres in the city of Badajoz. PATIENTS AND OTHER PARTICIPANTS: The 660 new patients sent to the MHU during 1994. MEASUREMENTS AND MAIN RESULTS: Primary care doctors (GP and FM) referred 660 new patients to the MHU, which amounted to 6.4% of the patients on their lists. GPs referred 6%, as against 6.9% by FMs. Average number of patients referred by each GP to the MHU was 11.76 +/- 8.19; and by each FM, 13.34 +/- 8.37 (no significant differences). Nor were there any differences in the sociodemographic features of the patients referred by the two groups of doctors. 64.6% of the patients sent by GPs were actually seen by the psychiatrist and/or psychologist, against 73% of those referred by the FMs. The diagnostic hypothesis was recorded on 94.6% of the referral forms sent by FMs, against 87.3% of those sent by GPs. There was diagnostic agreement for 73.7% of the patients sent by FMs against 43% of those sent by GPs. The pathology diagnosed in the Mental Health Unit was similar for the patients referred by the two groups of doctors. CONCLUSIONS: We found no significant differences between GP and FM in referral rates to the MHU in Badajoz, although there is greater diagnostic agreement for the patients referred by FMs. PMID- 8679877 TI - [Design of an information system for primary care. Task Force for the design of an information system for primary care]. AB - OBJECTIVE: To design an information system for the use of primary care professionals in the city of Barcelona's health districts, which breaks down the population and so assists the organisation of health care, identifies needs, establishes a monitoring system and evaluates the programmes set up. DESIGN: By consulting groups of experts. SETTING: Primary health care. PARTICIPANTS: Experts connected with primary care or with knowledge of community health measurement (general practitioners, paediatricians, public health technicians, primary care managers). MEASUREMENTS AND MAIN RESULTS: Discussion sessions defined the design of the information for the system. The information sources used needed to be accessible to the Municipal Health Institute of Barcelona (city roll of residents, population census, car, real estate, mortality, birth and vaccination registers and the register of notifiable diseases). An information system was designed with a population base which contributed information about community and health. CONCLUSIONS: The system designed broadens our knowledge of certain health determiners and of the health needs of the primary care team's catchment community. It can aid doctors' decision-making. PMID- 8679878 TI - [Association of metabolic risk factors and blood pressure in a natural population (Mora de Toledo)]. AB - OBJECTIVE: Evaluate relationships between the next variables in an adult natural population: total cholesterol, LDL-cholesterol, HDL-cholesterol, triglicerides, total cholesterol/HDL-cholesterol and glucose blood levels with blood pressure (systolic and diastolic). DESIGN: A crossover observation study with descriptive and analytic components. PATIENTS: Random sample of 251 individuals taken from census and representative of the adult general population from Mora de Toledo (with 10,000 inhabitants approximately). SETTING: A medical station in a health centre. MEASUREMENTS AND MAIN RESULTS: Blood pressure measurements and lipids and glucose blood levels were got in the selected patients. Some positive and significant relationships were got in the adult population from Mora de Toledo between systolic and diastolic blood pressure with the next variables: total cholesterol, LDL-cholesterol, total cholesterol/HDL-cholesterol, triglicerides and glucose blood levels. These associations are stronger in young people from 21 40 years-old. When we consider the relationship with HDL-cholesterol, we can see it is mildly positive but not significant. CONCLUSION: These results agree with others encountered in different countries and support the hypothesis that there is an association between blood pressure and the cardiovascular metabolic risk factors. PMID- 8679879 TI - [Precision and accuracy of the measurement of total cholesterol using the reflectometer Accutrend GC. Usefulness in primary care for diagnosis of hypercholesterolemia]. AB - OBJECTIVES: To determine the accuracy and precision of the Accutrend GC (AGC) in measuring cholesterol totals (CT) and its use as a screening test to detect hypercholesterolaemia. DESIGN AND PARTICIPANTS: Venous blood was drawn from 104 patients to measure CT by an enzymatic method (Hitachi 717). At the same time, their capillary blood was also measured with the AGC on two consecutive occasions. Values were divided in three groupings: CT > 149 mg/dl and < or = 199 mg/dl (n = 27); CT > 199 mg/dl and < or = 249 mg/dl (n = 59); and CT > or = 250 mg/dl (n = 18). Accuracy was calculated by obtaining the mean differences (MD) and the confidence intervals of the values obtained with the AGC in the three groupings and comparing them with the values obtained by the laboratory method. Precision was assessed by correlation, the comparison of paired means and the mean coefficient of variation of the values obtained with the AGC in the two successive measurements. MAIN MEASUREMENTS AND FINDINGS: In each grouping the MD of the values obtained with the AGC were lower than those obtained by the laboratory method, respectively. CONCLUSIONS: The AGC is useful as a screening test to detect hypercholesterolaemia, because of its high accuracy and precision. As it also determines glucose it is very useful for diabetics. PMID- 8679880 TI - [Epidemic outbreak of acute food poisoning caused by pesticides]. AB - OBJECTIVES: 1) To identify the causes of the outbreak. 2) To adopt the appropriate measures to control it. DESIGN: Observational crossover study. SETTING: San Benito Health District in Jerez de la Frontera (Cadiz). PATIENTS AND OTHER PARTICIPANTS: Diners who attended a family celebration. MEASUREMENTS AND MAIN RESULTS: On Friday 11th March 1994 there was an outbreak of acute food poisoning. The clinical notes of 9 ill diners were checked; they and 7 unaffected diners answered epidemiological questionnaires. A proportional comparison was then made between those not exposed and those exposed to each one of the foods consumed at this celebration. The clinical picture showed: high level of the Creatine phosphokinase enzyme, general myalgias, vomiting or nausea and visual problems. The average incubation period was 7 hours. The odds ratios of the foods involved was calculated. Although this reached 4 in some cases, the significance tests were not significant in any case because of the study's low statistical power. In the investigation of the trophic chain of the game-birds eaten, the presence of nitrogen or phosphorus atoms, compatible with the pattern of fonofos in the pesticide used on the hunting estate where the birds came from, was isolated. CONCLUSIONS: Epidemiological, clinical and biological evidence was found, which places us before acute organophosphorus poisoning. Coordination between the different institutions involved was decisive in finding the cause of the outbreak. PMID- 8679882 TI - [Influence of the journal Atencion Primaria on family medicine in Mexico]. PMID- 8679881 TI - [Allocation of resources for the health care of diabetics. Panel of Experts, Ministry of Health and Consumption]. PMID- 8679883 TI - [Costs of the treatment of iron-deficiency anemia]. PMID- 8679884 TI - [Care of women in primary health care]. PMID- 8679885 TI - [Spanish version of the OARS Multidimensional Functional Assessment Questionnaire: cross-cultural adaptation and validity measurement]. AB - OBJECTIVE: The linguistic and cultural adaptation of the OARS multidimensional functional assessment questionnaire (OARS-MFAQ) from its original English version. DESIGN: The methodology was translation and back-translation with the inconsistencies resolved between the research team and the authors at Duke University. The validity of the adaptation was checked. SETTING: Provincial capitals and country towns in the provinces of Granada, Malaga, Cordoba and Sevilla. PARTICIPANTS: Sample of 473 people over 60 living in the community. MEASUREMENTS AND MAIN RESULTS: After the cultural and linguistic adaptation was used by a previously trained researcher to fill in the questions on a home visit. The factor grouping coincided precisely in the social network, economic resources and physical health dimensions. In the capacity for self-care dimension two factors coincided, but one item in our factor analysis was different from in the North American version. In the mental health scale there was complete agreement, except that one North American factor divided into two in our findings. CONCLUSIONS: The cultural adaptation of the OARS-MFAQ to spanish was carried out. The spanish version was verified as equivalent to the original version. PMID- 8679886 TI - [Drug consumption by people over 60 years of age in a rural area]. AB - OBJECTIVES: To describe the frequency and distribution of the consumption of medicines in a census-based sample of people of 60 or over. To determine the association between the consumption of medicines and other socio-demographic and clinical (presence of disease) variables. DESIGN: An epidemiological crossover study based in the community. SETTING: Rural population: the Health District of Arevalo in Castilla y Leon. PARTICIPANTS: 825 subjects (446 women and 379 men) over 60, with an average age of 71,84. MEASUREMENTS: A standard questionnaire was used, containing medicine consumption, prescription, and clinical and demographic features. RESULTS: The consumption of medicines per person per day was 1,92. Therapeutic groups most consumed were, in this order, hypotension drugs, cardiotonics, antirheumatics, peripheral vasodilators, digestive system drugs, neurotropics and analgesics. The number of illnesses suffered by this age-group was 2,19. There is a strong connection between consumption of medicines and age, especially in the over 80's. CONCLUSIONS: 75% of the target population took some medicine each day. Consumption is higher among women than men. Cardiovascular drugs are the most frequently used therapeutic group. Consumption of medicines is directly related to age and the number of illnesses. PMID- 8679888 TI - [Health services accessibility in the Murcia region]. AB - OBJECTIVES: To find the geographical accessibility of primary care services and their support facilities. DESIGN: An observational, crossover study. SETTING: Primary health care. PATIENTS OR OTHER PARTICIPANTS: All those collective and single population groupings (354), included in the population register of the Murcia region with 100 or more inhabitants listed or with less inhabitants but with a health care post. MEASUREMENTS AND MAIN RESULTS: The time (crona) taken by the population of the different health districts and areas of the region to reach primary care and support services was determined by direct observation. Crona was defined as the average of three measurements of the time taken to reach these services by people using their normal means of transport and not exceeding the highway code's speed limits. 335 care posts were counted. Only 1,56% of the population, all belonging to Health Area 4, needed more than 30 minutes to reach their local doctor. 18,36% of the population needed more than 30 minutes to reach their referral hospitals. CONCLUSIONS: The number and distribution of facilities in the health care network guarantee adequate access to their services, except in Area 4. Specific studies will have to be designed to check that access problems are connected more to the road network and transport used than to the number and location of care centres. PMID- 8679887 TI - [Women and breast feeding: understanding their experiences and analyzing the performance of the health system]. AB - OBJECTIVE: To understand the conditioning factors which, whether negatively or positively, affect the success or failure of breast-feeding and to analyse the intervention of the health system to support it. DESIGN: A descriptive, prospective study which uses qualitative methodology in data gathering and analysis. SETTING: Health District of Santa Perpetua de la Mogoda, Barcelona. PARTICIPANTS: 56 in-depth interviews of 20 women were carried out at different moments of the pregnancy and suckling. MEASUREMENTS AND MAIN RESULTS: The decision to breast-feed was taken by women before or during their pregnancy under the influence of their social and family environment. The performance of the health system had little influence on the decision. The birth, even if it was pathological, did not prevent breast-feeding except when it was experienced as a failure. The days before the milk came increased women's insecurity about their capacity to suckle. Information from hospitals was evaluated as being scant. Fear of not feeding the baby well was the major source of breast-feeding failure. Mothers who breast-fed for longer felt they received more sympathy from paediatricians than those who gave up early. These felt blamed and did not seek doctors' advice on their decision. CONCLUSIONS: The health system has to plan an efficient intervention to support breast-feeding in the most crucial moments: after the birth and on arriving home. PMID- 8679889 TI - [The most common vital events in women 45-64 years of age. Repercussions as psychophysical stressors]. AB - OBJECTIVE: To find what vital events middle-aged women in our society most often experience and their influence as stress factors on physical health and subjective psychological well-being. DESIGN: A multivariant transversal study. SETTING: 5 primary care centres in Valencia and Alicante. PARTICIPANTS: 306 women chosen at random among those seen at these health centres. MEASUREMENTS AND MAIN RESULTS: Frequency analysis of vital events. Correlation analysis with questionnaires on physical symptoms and diseases, psychological well-being, work situation, emotional behaviour, sexuality and relationships with their partner. ANOVA: dividing the sample into 2 groups based on mean adaptive effort. The most common events numbered 23. The ANOVA showed a significant association between greater adaptive effort and negative emotional behaviour, personal control, material well-being, relationship with the partner, and physical and psychological symptoms. CONCLUSIONS: The relevance of daily events as generators of stress was confirmed, as was the impact of these and major events on these women's physical and psychological health. The importance of attending women at this stage of their lives from an integrated and interdisciplinary perspective, which tackles the physiological, psychological and cultural features together, was shown. PMID- 8679890 TI - [Impact of AIDS on premature mortality in La Rioja]. AB - OBJECTIVE: To describe the evolution of the number of potential years of life lost (PYLL) because of AIDS in La Rioja between 1986 and 1993. DESIGN: Descriptive study. SETTING: Autonomous Community of La Rioja. PATIENTS AND OTHER PARTICIPANTS: Secondary data from the regional Register of AIDS cases in La Rioja, from the Register of Deaths in La Rioja and from the mortality statistics found in the National Statistics Institute. MEASUREMENTS AND MAIN RESULTS: From 1986 the increase in PYLL because of AIDS as a percentage of all causes of premature death was constant. If proportional mortality because of AIDS is grouped in two periods (1986-1989 and 1990-1993), in the first period and for men 1.1% of all PYLL were due to AIDS, whereas in the second this figure was 7.7%. For women these figures went from 0.7 to 8,5. Expressed as a risk, for men the probability that PYLL was due to AIDS was 4 times greater in the second period than in the first. For women this probability was 12 times greater in the second period than in the first. Among men the rates of PYLL adjusted for age kept roughly constant or with a light downward tendency for all the causes studied except AIDS, which occupied second place in the last year studied. Rates of PYLL adjusted for age were more irregular over the years in the case of women, but the increase in AIDS was notable and in 1993 took third place. CONCLUSIONS: Interpreting the results of this study enables the impact of AIDS on premature mortality in La Rioja to be quantified. PMID- 8679891 TI - [Prevalence of hepatitis C virus infection in school children in an urban and suburban area of Madrid]. AB - OBJECTIVE: To find the prevalence of hepatitis C virus infection. DESIGN: Cross sectional study. SETTING: School children of the Autonomous Community of Madrid. PATIENTS AND OTHER PARTICIPANTS: 560 school children of 4 and 17 years-old. MEASUREMENTS AND MAIN RESULTS: ELISA II the anti-HCV appeared in 0,36% of population. CONCLUSIONS: Our prevalence is the same a other studies and we think that it haven't different factors in our community different of others with a similar prevalence in adults population. PMID- 8679892 TI - [Evaluation of a 4-year dental hygiene preventive program of the Les Planes health district in Sant Joan Despi (Barcelona)]. AB - OBJECTIVE: To evaluate the 4 years in operation of the preventive health programme for dental hygiene in children. DESIGN: Two epidemiological crossover and observational studies, retrospective over four years (1990-1994) in order to assess the incidence of dental caries in the target population (n = 800). SETTING: Les Planes Health District, Sant Joan Despi (Barcelona). PATIENTS: Children from 4 to 14 included in the caries prevention programme. INTERVENTIONS: This dental hygiene programme consisted of: school check-ups twice a year, monitoring children at risk of caries each term, education in oral hygiene, directly applied fluoride and sealing cracks at the health centre. MEASUREMENTS AND MAIN RESULTS: To assess the results of the programme, the difference in the incidence of caries between both groups was assessed with the CAO-D index, i.e. the average number of teeth affected by child caries. Overall and for ages, a decrease in the incidence of caries was noted. CONCLUSIONS: The programme has given positive results, which should encourage other health centres in their prevention programmes. PMID- 8679893 TI - [Reflections on drug prescriptions arising from a pharmaco-epidemiological course]. PMID- 8679894 TI - [How ill are my patients?]. PMID- 8679895 TI - [The future of general/family medicine in Spain]. PMID- 8679896 TI - [Vision screening in preschool children]. PMID- 8679897 TI - [Variability of costs at health centers]. PMID- 8679898 TI - Increased activation and altered ratio of interferon-gamma: interleukin-4 secreting cells in MRL-lpr/lpr mice. AB - Cytokine specific ELIspot assays were used to monitor the number of cells secreting IL-4 and IFN gamma in MRL-lpr/lpr mice of different ages. The cytokine repertoire expressed by MRL-lpr/lpr mice was skewed towards the over-production of IFN gamma (and away from IL-4) when compared to that of MRL-+/-/+/- and BALB/c mice. With increasing age and disease severity, the ratio of IFN gamma: IL-4 secreting cells rose in MRL-lpr/lpr mice but decreased in normal animals. This changing ratio of IFN gamma: IL-4 secreting cells correlated with changes in the ratio of IgG2a: IgG1 secreting cells in these mice. Our findings suggest that cytokine secreting CD4+ and CD8+ cells are hyperactivated in young MRL-lpr/lpr mice, and that disease progression is associated with a disruption in the normal ratio of Th1:Th2 production in vivo. PMID- 8679899 TI - Effect of histone and histone-RNA complexes on the disease process of murine systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is characterised by the production of a variety of autoantibodies against cell surface, nuclear and cytoplasmic antigens. The antigen or antigens responsible for the induction of this disease is/are unknown. We have analysed the antigenicity and pathogenicity of free histones and histones complexed with RNA in Balb/c, B10 Br, C57BL/6 and MRL-lpr/lpr mice by giving 1 microgram and 25 micrograms of each antigen intraperitoneally in complete and incomplete Freund's adjuvant. The same number of control animals were injected with either adjuvant or PBS. In the initial experiment we gave three doses of antigen at three weekly intervals. B10 Brown and C57BL/6 mice had no response to the antigens. Balb/c mice developed a mild transient antibody response against H1 histone, branched peptide of ubiquitinated H2A (peptide T4) and also against ssDNA. However in repeated experiments when the histone-RNA complex was injected into young MRL-lpr/lpr animals at two weekly intervals, a significantly increased antibody response was detected against H1, peptide T4 and some histone peptide residues (204-218 of H1, 1-20 and 65-85 of H2A, 1-25 of H2B, 1-21 of H3 and 1-29 of H4) compared to the control groups. Moreover, this group also showed elevated serum anti-DNA antibody levels and early impairment of renal function assessed by the urine protein levels. These experiments have demonstrated that there is a genetic variation in antibody responses against histones and histone-RNA complexes and that histone-RNA complexes exaggerate the disease in young MRL-lpr/lpr mice by inducing antibodies to basic regions of histones and other autoantigens. PMID- 8679900 TI - Antiphospholipid antibody production during Mediterranean spotted fever. AB - Antiphospholipid antibodies (aPLA) were discovered during the course of Mediterranean spotted fever (MSF) caused by Rickettsia conorii and characterized by endothelial cell (EC) damage resulting from this organism's tropism for EC. In two MSF patients, two types of aPLA were identified: antiphosphatidylethanolamine antibodies detected by immunological methods and lupus anticoagulant detected by clotting assays. The persistence of both aPLA for several months after the acute phase and clinical recovery might correspond to a durable immunological response to membrane damage of EC caused by R. conorii. Their possible role in the pathophysiology of microthrombi formation observed during MSF remains to be elucidated in a study on a larger number of patients. PMID- 8679901 TI - Linkage and association studies in insulin-dependent diabetes with a new dinucleotide repeat polymorphism at the GAD65 locus. AB - Glutamic acid decarboxylase (GAD) is an important autoantigen in insulin dependent diabetes mellitus (IDDM). The islet cell specific, 65 kDa form of GAD (GAD65) is encoded by a gene on chromosome 10p. Recently, a putative IDDM susceptibility gene has been localized to the same general region based on allele sharing for the anonymous marker D10S193. To determine whether variation in the GAD65 gene plays a role in genetic susceptibility to IDDM, possibly explaining the reported evidence for linkage on 10p, we isolated cosmid clones containing GAD65, and identified a highly polymorphic dinucleotide repeat physically linked to the gene. This GAD65 microsatellite marker, along with the other 10p markers D10S193 and D10S211, were used to genotype the members of 186 multiplex IDDM families with 2 or more affected siblings. Linkage analysis localized the GAD65 marker 5.6 cM from D10S193. Sharing of alleles identical by descent (IBD) in affected sib pairs for each of the markers was determined and compared to the expected 50:50 distribution under an assumption of no linkage. Analyses were also carried out after stratification of the data for sharing of HLA class.II alleles. The family data for GAD65 were further assessed for allelic association with IDDM using the transmission/disequilibrium test. No significant deviations from expected values were observed in any of these tests, suggesting that variation in the GAD65 gene does not play a significant role in genetic susceptibility to IDDM. PMID- 8679902 TI - Neonatal myasthenia gravis and the role of agalactosyl IgG. AB - Neonatal autoimmune diseases are thought to be due to the transfer of maternal autoantibodies. However, there is a puzzling lack of correlation between maternal autoantibody titres and disease in the neonate. So far, no factor reliably predictive of neonatal disease has been found. Agalactosyl IgG is a variable feature of normal IgG. Preliminary studies indicated that the percentage of agalactosyl IgG is lower in the serum of normal neonates, than in the serum of the mother at delivery. Since raised % agalactosyl IgG is often associated with autoimmune disease we sought to determine whether this relationship holds true in a neonatal autoimmune disease. We measured the % agalactosyl IgG in paired maternal-cord sera from patients with myasthenia gravis, some of whom had offspring with neonatal myasthenia gravis. We found that the percentage of agalactosyl IgG was significantly higher in affected than in unaffected neonates. Moreover % agalactosyl IgG was higher in sera of affected neonates than in serum from their mothers, while unaffected infants of mothers with myasthenia had %Gal(0) lower than their mothers, mimicking the normal situation. This suggests that in affected neonates a high proportion of the IgG is synthesised by the baby itself rather than derived from the mother. This agrees with previous evidence based on the presence of idiotypes not found in the mother which implied that the neonates with neonatal myasthenia gravis produce their own autoantibodies. PMID- 8679903 TI - Decreased levels of adenylate cyclase contribute to the down-regulation of beta adrenergic signal transduction in the salivary glands of the non-obese diabetic (NOD) mouse. AB - Stimulation of salivary gland secretion by treatment of NOD mice with the beta adrenergic receptor agonist, isoproterenol, was previously shown to cause a lower accumulation of intracellular cAMP than that found that in BALB/c controls (Hu et al., 1994, Am. J. Physiol. 266: G433). This was, in part, due to decreased levels of beta-adrenergic receptor localized in the plasma membrane. In the present investigation, basal levels of cAMP in the salivary glands of NOD mice were found to be similar to controls, while direct stimulation of adenylate cyclase by incubation of isolated membranes with forskolin showed a reduced cAMP accumulation in NOD mice versus BALB/c control mice. Using direct [3H]-forskolin binding, it was determined that the plasma membranes of NOD mice salivary glands contain reduced levels of membrane-associated adenylate cyclase. PMID- 8679905 TI - Are sulfatides ICA-specific antigens? PMID- 8679904 TI - Intrafamilial and case-control association analysis of D2S152 in insulin dependent diabetes. AB - We have performed intrafamilial and case-control association studies to examine the previously reported linkage disequilibrium between D2S152 and a type 1 diabetes susceptibility gene on chromosome 2q31-q33 (IDDM7). Significant linkage disequilibrium was observed in our subset of 47 Florida affected sibpair families (p < 0.02) but not in the other 57 USA families. We were not able to detect any significant associations between IDDM and D2S152 using case-control studies in a Caucasian data set of 270 unrelated diabetic patients and 370 normal controls ascertained from Florida, or in a Chinese data set of 90 patients and 169 normal controls. Our results suggest that linkage disequilibrium between IDDM7 and D2S152 must be very loose. PMID- 8679906 TI - Dilated cardiomyopathy defines serum autoantibodies against G-protein-coupled cardiovascular receptors. AB - In order further to identify the prevalence of anti-receptor autoantibodies in the sera of patients with dilated cardiomyopathy (DCM), we attempted to detect autoantibodies against a series of G-protein-coupled cardiovascular receptors in a well-defined population of DCM patients from Japan. Peptides corresponding to the sequences of the second extracellular loops of the human beta 1 and beta 2 adrenoceptors, alpha 1 adrenoceptors, M2 muscarinic acetylcholine receptors and angiotensin II-1 (AT1) receptors were used as antigens in an enzyme immunoassay to screen the sera from patients with DCM (n = 28). Nine sera from patients with DCM (32%) and 2 sera from healthy subjects (9%) recognized the beta 1 adrenoceptor peptide. Ten sera from patients (36%) and 3 sera from healthy subjects (13%) recognized the M2 receptor peptide. Thirty-six per cent of the patients with autoantibody against the beta 1 adrenoceptor peptide. Ten sera from patients (36%) and 3 sera from healthy subjects (13%) recognized the M2 receptor peptide. Thirty-six per cent of the patients with autoantibody against the beta 1 adrenoceptor had autoantibody against the M2 receptor. However, no significantly high frequencies of autoantibodies against the beta 2 adrenoceptor, alpha 1 adrenoceptor and AT1 receptor were found in DCM patients. Our results demonstrate that a subgroup of patients with DCM have a specific spectrum of autoantibodies which are specifically directed against the second extracellular loops of the beta 1 adrenoceptors and M2 muscarinic receptors rather than other cardiovascular receptors. PMID- 8679907 TI - Prevention of autoimmunity in nonobese diabetic (NOD) mice by neonatal transfer of allogeneic thymic macrophages. AB - Nonobese diabetic (NOD) mice spontaneously develop insulin dependent diabetes mellitus. The disease results from an autoimmune process which involves mononuclear cells surrounding and eventually infiltrating the pancreatic islets of Langerhans. Macrophages are thought to be the first cells to infiltrate the islets and are actively involved in the disease process because diabetes is prevented if host macrophages are depleted or inactivated. Several lines of evidence also suggest that NOD macrophages are phenotypically and functionally abnormal. In this study, allogeneic (CBA) macrophages derived from the thymus were inoculated into newborn NOD mice and these were followed for more than 250 days. Spontaneous diabetes was significantly reduced in female NOD mice (6% diabetic versus 45% of controls). Insulitis was also significantly reduced in both male and female mice compared to their control counterparts, and in most cases there were virtually no inflammatory cells in the pancreas. Allogeneic skin grafting and mixed leukocyte cultures indicated that the recipients were not tolerant of donor antigens, and donor-derived cells were not detected in the lymphoid tissues by either flow cytometry or immunohistochemistry. The results show that macrophages from diabetes-resistant donors will prevent insulitis and diabetes in most recipients, however, the mechanism for the protection is unclear, but does not appear to be due to long-term tolerance induction. PMID- 8679909 TI - [Neurophysiologic signal recording. New technical and general practice aspects of EEG recording electrodes]. AB - The problem of electrode selection for neurophysiological monitoring, whether for routine clinical applications or special scientific research, still remains to be resolved. In addition to the classical types of electrode-cup (silver/silver chloride or gold) or needle electrodes, new self adhesive electrodes (e.g. zipprep electrodes) for rapid application and reliable recording have recently come onto the market. However, this electrode type can lead to superficial lesions of the skin or inflammatory infiltration, which so far have not been investigated. New developments in the field of cortex electrodes and so-called active electrodes are additionally discussed. PMID- 8679908 TI - Presence of multiple anti-phospholipid antibody specificities in a pediatric population. AB - Thrombotic related events are thought to be associated with the presence of anti phospholipid antibodies (APA). However, the association of anti-cardiolipin antibody is much weaker than the association with antibodies to other phospholipids. Much of the literature equates antiphospholipid antibodies and anticardiolipin antibodies because of the relationship of APA and false positive tests for syphilis. However, recently the presence of antibodies to naturally occurring phospholipids other than cardiolipin have been reported. In fact, some investigators report that antibodies to phosphatidylserine appear to correlate more closely to disease processes than anti-cardiolipin antibodies. We describe here the presence of non-anti-cardiolipin antiphospholipid antibodies in a pediatric population that lack anti-cardiolipin antibodies and demonstrate the association of these antibodies with thrombotic disease. Antibodies to phosphatidic acid were the most prevalent and correlated (p < .001) with thrombotic disease and idiopathic thrombocytopenia purpura. The rank order of prevalence of antibodies to phospholipids was phosphatidic acid, phosphatidylglycerol, phosphatidylinosital, phosphatidylserine, cardiolipin and phosphatidylethanolamine. Antiphospholipid antibodies of the three major sera isotypes were present in the positive sera examined. These descriptive findings suggest that the significance of APA other than anti-cardiolipin antibodies in pediatric patients should be further investigated. PMID- 8679910 TI - Analysis of eddy currents originating from switched magnetic gradient fields in magnetic resonance imaging. AB - The fact that time-varying magnetic fields cause eddy currents in conductive objects is very well known. Switched magnetic gradient fields, used in echo planar imaging, were shown in the past to be able to elicit a stimulation process in peripheral nerves. We report about the distribution and values of induced current densities in the human torso, modeled by the Finite Element Method using isoparametric formulation. Since the applied numerical method is a frequency domain one, the trapezoidal waveform is decomposed into a Fourier series. The simulation was made for four different exposures to switched magnetic gradient fields: transverse (x- and y-gradients) coil systems, longitudinal (z-gradients) coil system and for all the three coil systems working simultaneously. Special attention was paid to the region of the heart, since stimulation of the heart muscle could be extremely dangerous for human health. Therefore, the three components of the current density in the region of the heart muscle were spatially analyzed in all directions (x, y, and z), trying to find out the 'worst case' position of the heart muscle relative to the gradient coil system at which the highest current density is induced. Finally, the calculated values were compared to existing recommendations, showing that the simulated 'worst case' amplitude is relatively close to the limiting value for sinusoidal currents. PMID- 8679911 TI - [Detection of rapid eye movement with rapidly adapting neuronal fuzzy systems in imprecise REM syntax]. AB - Both living beings and artificial neuronal networks are capable of 'learning' and behavioural adaptation. But also the fuzzy program designed to detect rapid eye movements (REM) during sleep and described here, can be provided with a self learning option that provides important information about REM sleep. The algorithm computes REM on the basis of horizontal and vertical EOG. EEG, EMG and actiography signals are employed to optimize the method and eliminate artefacts. In a second step, the fuzzy system learns to detect REM with the aid of a sample data set and a minimal set of syntax rules. From sample data and the actions and reactions of visual scorers, the program extracts additional rules and information, which are then used to build a complete fuzzy structure. Thereafter, the REM detection program optimizes the fuzzy logic structure, independently of visual monitoring, on its own. A direct comparison of the results of the algorithm in a 10-night analysis with those of two experienced visual scorers revealed a better than 95% agreement. Re-analysis with the algorithm showed a 100% concurrence. Complete visual measurement of the eye movements occurring in a single night requires several hours; this compares with only 15 minutes required by the algorithm. PMID- 8679912 TI - Body fixed ankle dynamometer for isometric tests in space flights. AB - To study neuromuscular variables in isometric contraction, a body-fixed ankle dynamometer with integrated electromyographic (EMG) system and software controlled load tests was developed. It consists of a footplate acting against a load cell in plantar flexion. Counteraction is supported by a perpendicular telescopic stand which runs from the heel to the thigh with the knee flexed at an angle of 90 degrees C. Additional to contraction force, force tremor and surface EMG from the triceps surae and tibialis anterior muscles are recorded. The software consists of three load tests to assess variables of muscle fatigue, motor performance and motor memory. The dynamometer was optimised in relation to functionality and selection of construction materials for the use on the Russian MIR space station. PMID- 8679913 TI - [Ceramic acetabulum cup inserts for hip endoprostheses]. AB - The articulating components of a total hip prosthesis are the spherical femoral head and the acetabular cup. Particularly high rates of wear are seen with cups made of polyethylene, and the abrasion particles cause osteolysis, which often makes surgical revision necessary. Despite considerable progress in the development of total hip replacement systems over the last 20 years, there is still a need to eliminate or further minimize the problem of osteolysis, which is also referred to as polyethylene disease. Clinical experience over the last 20 years has shown that by using Biolox (medical grade alumina) femoral heads and acetabular cups it is possible to achieve very low wear rates, which histological studies have shown to be readily tolerated. The secondary conditions needed to develop modern modular ceramic acetabular cup inserts are discussed. For the fixation of cup inserts, the well known taper fixation concept has proved to be of value. A concept taking into account the needs of the surgeon and the manufacturing constraints applying to ceramic materials is proposed. PMID- 8679914 TI - Electro-optics of membrane electroporation in diphenylhexatriene-doped lipid bilayer vesicles. AB - The electric (linear) dichroisms observed in the membrane electroporation of salt filled lipid bilayer vesicles (diameter O = 2 alpha = 0.32 micron; inside [NaCl] = 0.2 M) in isotonic aqueous 0.284 M sucrose-0.2 mM NaCl solution indicate orientation changes of the anisotropic light scattering centers (lipid head groups) and of the optical transition moments of the membrane-inserted probe 1,6 diphenyl-1,3,5-hexatriene (DPH). Both the turbidity dichroism and DPH absorbance dichroism show peculiar features: (1) at external electric fields E > or = Esat the time course of the dichroism shows a maximum value (reversal): Esat = 4.0 (+/ 0.2) MV m-1, T = 293 K (20 degrees C), (2) this reversal value is independent of the field strength for E > or = Esat, (3) the dichroism amplitudes exhibit a maximum value Emax = 3.0 (+/- 0.5) MV m-1, (4) for the pulse duration of 10 microseconds there is one dominant visible normal mode, the relaxation rate increases up to tau-1 approximately 0.6 x 10(6) s-1 at Esat and then decreases for E > Esat. The data can be described in terms of local lipid phase transitions involving clusters Ln of n lipids in the pore edges according to the three-state scheme C<-->HO<-->HI, C being the closed bilayer state, HO the hydrophobic pore state and HI the hydrophilic or inverted pore state with rotated lipid and DPH molecules. At E > or = Esat, further transitions HO<-->HO* and HI<-->HI* are rapidly coupled to the C<-->HO transition, which is rate-limiting. The vesicle geometry conditions a cos theta dependence of the local membrane field effects relative to the E direction and the data reflect cos theta averages. The stationary induced transmembrane voltage delta phi (theta, lambda m) = -1.5 aEf(lambda m) magnitude of cos theta does not exceed the limiting value delta phi sat = -0.53 V, corresponding to the field strength Em,sat = -delta phi sat/d = 100 MV m-1 (10(3) kV cm-1), due to increasing membrane conductivity lambda m. At E = Esat, f(lambda m) = 0.55, lambda m = 0.11 mS m-1. The lipid cluster phase transition model yields an average pore radius of rp = 0.35 (+/- 0.05) nm of the assumed cylindrical pore of thickness d = 5 nm, suggesting an average cluster size of = 12 (+/- 2) lipids per pore edge. For E > Esat, the total number of DPH molecules in pore states approaches a saturation value; the fraction of DPH molecules in HI pores is 12 (+/- 2)% and that in HO pores is 48 (+/- 2)%. The percentage of membrane area P approximately (lambda m/lambda i) x 100% of conductive openings filled with the intravesicular medium of conductance lambda i = 2.2 S m-1 linearly increases from P approximately 0% (E = 1.8 MV m-1) to P = 0.017% (E = 8.5 MV m-1). Analogous estimations made by Kinosita et al. (1993) on the basis of fluorescence imaging data for sea urchin eggs give the same order of magnitude for P (0.02-0.2%). The increase in P with the field strength is collinear with the increase in concentration of HI and HI* states with the field strength, whereas the HO and HO* states exhibit a sigmoid field dependence. Therefore our data suggest that it is only the HI and HI* pore states which are conductive. It is noted that the various peculiar features of the dichroism data cannot be described by simple whole particle deformation. PMID- 8679915 TI - Electric birefringence of kilobase-sized DNA molecules. AB - Transient electric birefringence has been used to characterize the rotational diffusion of linear, circularly permuted pBR322 and SV40 DNA molecules. The birefringence relaxation times vary with the site of linearization, suggesting that the circularly permuted DNAs have different conformations in solution. The longest relaxation times are observed for DNA sequence isomers linearized at the major bend centers identified by gel electrophoresis. SV40 sequence isomers linearized at other locations have faster, but approximately equal, terminal relaxation times, suggesting that their free solution conformations are relatively independent of the location of the bend center within the sequence. By contrast, the terminal relaxation times of the various pBR322 sequence isomers vary approximately in accord with their electrophoretic mobilities in large-pore polyacrylamide gels, suggesting that the different mobilities may reflect real conformational differences between the sequence isomers. PMID- 8679916 TI - Electric linear dichroism as a new tool to study sequence preference in drug binding to DNA. AB - An original approach using electric linear dichroism (ELD) and natural DNAs and polynucleotides of differing base composition has been developed with the aim to investigate the sequence-dependent recognition of DNA by drugs. Both intercalators and minor groove binders have been studied as well as certain hybrid molecules. The results indicate that the orientation of drugs upon binding to nucleic acids can change markedly according to the target sequence. Among the intercalators tested, only actinomycin D and hycanthone show a clear preference for GC- and AT-rich sequences, respectively. For minor groove binders, the linear dichroism showing a strong dependence on base composition of the DNA and polynucleotides is most pronounced. Netropsin and distamycin bind to DNA with a marked AT specificity. Hoechst 33258, berenil and DAPI exhibit positive and negative dichroism signals at AT and GC sites respectively, suggesting that at least two types of drug-DNA interaction are involved depending on the AT/GC content of the DNA. Further investigations using polynucleotides with inosine substituted for guanosine, and competition experiments with intercalative drugs suggest that Hoechst 33258, berenil and DAPI interact with GC sequences via a non classical intercalation process. PMID- 8679917 TI - Binding of biologically important molecules to DNA, probed using electro fluorescence polarization spectroscopy. AB - When small fluorescent tag molecules are bound with a single geometry to larger carrier molecules the fluorescence excited using polarized light may itself be partially polarized. If this is the case then alignment of the carrier molecules changes the fluorescence polarization. Electro-fluorescence polarization spectrometry (EFPS) makes use of the fluorescence polarization changes which occur when the carrier molecules are aligned by an electric field. EFPS allows the determination of the binding geometry of the small tag molecules to the larger carrier molecules. In this study, EFPS has been used to probe the interactions between DNA and a series of chromosomal stains and anti-neoplastic (anti-cancer) agents. Results are presented for calf thymus DNA, treated with the dyes acridine orange, ethidium bromide, proflavine, Hoechst 33258, Hoechst 33342, 4',6-diamidino-2-phenylindole and the anti-tumour agents, doxorubicin, daunomycin, actinomycin C and actinomycin V. PMID- 8679918 TI - Imaging of fluorescent molecule and small ion transport through human stratum corneum during high voltage pulsing: localized transport regions are involved. AB - During the application of high-voltage pulses across the skin, transport of two negatively charged fluorescent molecules through the stratum corneum is highly localized. The apparent size of these localized transport regions (LTR's) is initially 10 microns in diameter for both calcein and sulforhodamine. Appearance of LTR's occurred at or above transdermal voltages of 75 V. In the range of 75 to 160 V, the number of LTR's increases with voltage, but their initial size is the same at all voltages; with additional pulses LTR's increase in size, reaching diameters of approximately 40-80 microns. Small ion currents across the skin are also localized and include the LTR's; however, the areas of current flux appeared to be larger. There was no visible damage to the structure of the skin seen at 100 x magnification for any of the voltages used (< 170 V across the skin). Significantly, LTR's are not sweat ducts or hair follicles. PMID- 8679919 TI - Passive electrical properties of human stratum corneum in vitro depending on time after separation. AB - The passive electrical properties of human skin after separation from the body are predominated by the stratum corneum. Skin within a bath medium (150 mM phosphate buffered saline) at constant temperature (37 degrees C) exhibits a characteristic change of the passive electrical properties with time. Independent of the time the locus in the Z-plane is a depressed semicircular arc. The angle between the lines from the center of the arc to the points where the locus reaches the real axis remains unchanged. The difference between the high and low frequency resistivity (R0-Rx) increases over 10 h, reaches a plateau and decays after 20 h exponentially with a time constant of about 40 h. As model for the impedance we used a 5 element electrical circuit (R0, R1, R2, C1, C2), describing 3 pathways, (0) the dc path (appendages; R0), (1) tortuous pathways around the cell structures (R1, C1) and (2) direct pathways involving the corneocytes (R2, C2). There are characteristic changes with time in the elements of the equivalent circuit up to about 200 h after excision. Dramatic changes in C1 and R2 at about this time after separation strongly suggests destruction of the lipid structures. It will be suggested that the use of separated human stratum corneum as model for in vivo yields unreliable results after this time. PMID- 8679920 TI - Pore formation induced by the peptide melittin in different lipid vesicle membranes. AB - We investigated the interaction of the peptide melittin with differently sized vesicles consisting of various lipid compositions. This system was characterized by dynamic light scattering to estimate the size of vesicles. For SUV we obtained a radius of 12 nm, for LUV 53 nm. The pore forming process of melittin in vesicles was investigated by efflux of encapsulated fluorescent dyes at a self quenching concentration. The influence of the following parameters on efflux and pore formation was estimated: lipid composition (POPC and DOPC), vesicle size (SUV and LUV) and size of the encapsulated dye (carboxyfluorescein and FITC dextran). We found that under similar conditions vesicles of DOPC give always less leakage than vesicles of POPC independent of the fluorescent dye. For SUV and LUV we have obtained a different leakage behaviour at identical surface concentrations of melittin (if the same partition coefficient is assumed). From efflux measurements with different dyes we concluded that 6-20 molecules of melittin are necessary to form a pore. The possibility that not pore formation but fusion is the mechanism of melittin induced efflux was disproved by fusion experiments using a resonance energy transfer assay. PMID- 8679921 TI - Critical dependence of the solubilization of lipid vesicles by the detergent CHAPS on the lipid composition. Functional reconstitution of the nicotinic acetylcholine receptor into preformed vesicles above the critical micellization concentration. AB - The critical concentration of free detergent [Dw]c, which is necessary for lipid vesicle solubilization, is widely believed to be near to the critical micellization concentration (CMC) of the detergent. Here it is shown that [Dw]c and the critical detergent/lipid ratio Rc(M) in the mixed micelles strongly depend on the lipid composition. In agreement with the concept of packing constraints, phospholipids with a large head-group were solubilized by the detergent CHAPS at low CHAPS concentrations, for example [Dw]c = 0.27 mM for phosphatidyl-inositol and [Dw]c = 2.3 mM for phosphatidylcholine, T = 293 K (20 degrees C). In contrast, phospholipids (PL) with a small head-group required larger [CHAPS] values for (mixed) micelle formation: [Dw]c = 3.2 mM for phosphatic acid (PA) and [Dw]c = 5.2 mM for a mixture of palmitoyloleoylphosphatidylcholine (POPC), phosphatidylethanolamine (PE) and phosphatidylglycerol (PG), POPC:PE:PG = 30:60:10 (mol.-%). Values obtained for the partition coefficient K = Rc(M)/[Dw]c ranged from K = 0.12 mM-1 for dimyristoylphosphatidylcholine to K = 1.1 mM-1 for (soy) phosphatidylcholine:phosphatidylglycerol (50:50). After addition of 30 mol.-% cholesterol (Ch) or with dipalmitoylphosphatidylcholine below T = 308 K (35 degrees C), [Dw]c is > 10 mM, which is far above the CMC = 4 mM. This indicates that CHAPS micelles are formed before vesicle solubilization begins. The analysis of vesicle solubilization was a prerequisite for the controlled reconstitution of protein membrane proteins. AChR proteins reconstituted into preformed PL/Ch vesicles at [Dw] > CMC had a 4-5 time higher value of Li-influx compared to reconstitutions from completely solubilized lipid and proteins indicating a higher efficiency of right-side out AChR incorporation. PMID- 8679922 TI - Heme geometry in the 10 K photoproduct from sperm whale carbonmonoxymyoglobin. AB - We have measured the Soret band of the photoproduct obtained by complete photolysis of sperm whale carbonmonoxymyoglobin at 10 K. The experimental spectrum has been modeled with an analytical expression that takes into account the homogeneous bandwidth, the coupling of the electronic transition with both high and low frequency vibrational modes, and the effects of static conformational heterogeneity. The comparison with deoxymyoglobin at low temperature reveals three main differences. In the photoproduct, the Soret band is shifted to red. The band is less asymmetric, and an enhanced coupling to the heme vibrational mode at 674 cm-1 is observed. These differences reflect incomplete relaxation of the active site after ligand dissociation. The smaller band asymmetry of the photoproduct can be explained by a smaller displacement of the iron atom from the mean porphyrin plane, in quantitative agreement with the X ray structure analysis. The enhanced vibrational coupling is attributed to a subtle heme distortion from the planar geometry that is barely detectable in the X-ray structure. PMID- 8679923 TI - The conformation of xanthene dyes in the myosin sulfhydryl one binding site. Part I. Methods and model systems. AB - Derivatives of the fluorescent probes fluorescein and rhodamine specifically and covalently modify the highly reactive thiol (SH1) of myosin subfragment 1 (S1). Both probes develop circular dichroism (CD) upon modification of SH1 at the visible absorption band of the chromophore. A model system of chiral complexing agents (aromatic chiral amines) interacting with fluorescein in solvent develops a CD signal that mimics that produced by S1. The model system suggests that a specific interaction of the probe with an aromatic chiral residue in the SH1 binding pocket induces the CD signal. Several other spectroscopic signals, including absorption and fluorescence intensity and anisotropy, characterize the fluorescein or rhodamine binding to SH1. A coupled dipole method is adapted to interpret these spectroscopic signals in terms of the probe-S1 complex conformation. The computation of the orientation of the principal hydrodynamic frame (PHF) of S1 from its crystallographic alpha-carbon backbone structure permits the known orientation of the probe in the PHF of S1 to further constrain the conformation of the probe-S1 complex. The coupled dipole interpretation of spectroscopic data combined with constraints relating the probe dipole orientation to the PHF of S1 determines the conformation of the probe-S1 complex. The methods developed here are applied to the spectroscopic signals from fluorescein or rhodamine in the SH1 binding site of S1 to obtain an atomic resolution model of the probe-S1 conformation [Ajtai and Burghardt, Biochemistry, 34 (1995) 15943-15952]. PMID- 8679924 TI - The effect of ionic strength on melting of DNA modified by platinum(II) complexes. AB - Thermal denaturation of calf thymus DNA modified by antitumor cis diamminedichloroplatinum(II) (cis-DDP) and by two related Pt(II) compounds which had been shown to be clinically ineffective, viz. trans diamminedichloroplatinum(II) (trans-DDP) or monodentate diethylenetriaminechloroplatinum(II) chloride [[Pt(dien)Cl)]Cl], was studied by monitoring changes of absorbance at 260 nm. The melting of DNA platinated to different levels was investigated in neutral media containing varying concentrations of Na+. It has been shown that the ionic strength has a strong influence on the character and magnitude of changes in the melting temperature of DNA (Tm) induced by the platination. The modification of DNA by either platinum complex used in this work results in an increase of Tm if DNA melting is measured in media containing low Na+ concentrations (ca. 1 mM). This effect is reversed at higher Na+ concentrations. The concentration of Na+ at which this reversal occurs is, however, markedly lower for DNA modified by cis-DDP than for DNA modified by the other two platinum complexes. These results have been interpreted to mean that at least three factors affect the thermal stability of DNA modified by the platinum(II) complexes: stabilization effects of the positive charge on the platinum moiety and of interstand cross-links, and a destabilization effect of conformational distortions in DNA. Thus, in order to compare and interpret the melting behavior of DNA modified by different compounds, a great attention has to be paid to the composition of the medium in which the melting experiments are carried out. PMID- 8679925 TI - Assessment of the validity of the Adams and Fujita approximation for the higher oligomers of human spectrin. AB - Analysing the self-association behaviour of human erythrocyte spectrin is complicated by a large degree of nonideality. Adams and Fujita [1] proposed that, as a first order approximation, the logarithm of the activity coefficient of the protomer of a self-associating system can be considered to be linearly dependent on the total concentration of the protein, and that the same second virial coefficient could be considered to apply to all species. As a consequence of the Adams and Fujita approximation, the apparent equilibrium constant is equal to the thermodynamic equilibrium constant. The equilibrium concentrations at 30 degrees C of each oligomer spectrin species up to the 14-mer were determined after electrophoresis at low temperature. An apparent equilibrium constant for forming tetramer (K2,4) of (1.2 +/- 0.1) x 10(6) 1/mol was obtained, a value of (9.4 +/- 0.7) x 10(4) 1/mol was obtained for K4.6 and for all reactions forming oligomers higher than the hexamer an average approximate value of (2.7 +/- 0.4) x 10(5) 1/mol was obtained. The apparent equilibrium constants for the formation of all oligomer species of spectrin up to the tetrakaidecamer (14-mer) remain relatively independent of total spectrin concentration, and indicate that within the precision of the measurements a single virial coefficient is sufficient to account for the nonideality of spectrin self-association over the range 2-14 g/l, thus further justifying the use of the Adams and Fujita approximation for this protein over this concentration range. PMID- 8679926 TI - Communicative interaction of myosins along an actin filament in the presence of ATP. AB - Myosin molecules contacting an actin filament in the presence of ATP were found to regulate the filamental fluctuations due to ATP hydrolysis in a communicative manner along the filament. As an evidence of the occurrence of the communication, ATP-activated fluctuating displacements of the filament in the direction perpendicular to its longitudinal axis were identified to propagate at a finite velocity not less than about 0.2 micron/s unidirectionally along the filament. PMID- 8679927 TI - The fluorescence and circular dichroism of proteins in reverse micelles: application to the photophysics of human serum albumin and N-acetyl-L tryptophanamide. AB - Evidence is presented that a compartmentalised protein exists in its native state only within a particular size of aqueous cavity. This behaviour is shown to exist in AOT reverse micelles using fluorescence quenching and circular dichroism (CD) studies of human serum albumin (HSA). In particular, far ultraviolet CD measurements show that a reduction in quencher accessibility to the fluorophore is consistent with the protein being nearest to its native conformation at a waterpool size of around 80 A diameter. We also show that the biexponential fluorescence decay of N-acetyl-L-tryptophanamide (NATA) in AOT reverse micelles arises from the probe being located in two distinct sites within the interfacial region. The more viscous of these two sites is located on the waterpool side of the interface and the other is located on the oil side of the interface. PMID- 8679929 TI - Simulation of voltage-dependent interactions of alpha-helical peptides with lipid bilayers. AB - Pore formation in lipid bilayers by channel-forming peptides and toxins is thought to follow voltage-dependent insertion of amphipathic alpha-helices into lipid bilayers. We have developed an approximate potential for use within the CHARMm molecular mechanics program which enables one to simulate voltage dependent interaction of such helices with a lipid bilayer. Two classes of helical peptides which interact with lipid bilayers have been studied: (a) delta toxin, a 26 residue channel-forming peptide from Staphylococcus aureus; and (b) synthetic peptides corresponding to the alpha 5 and alpha 7 helices of the pore forming domain of Bacillus thuringiensis CryIIIA delta-endotoxin. Analysis of delta-toxin molecular dynamics (MD) simulations suggested that the presence of a transbilayer voltage stabilized the inserted location of delta-toxin helices, but did not cause insertion per se. A series of simulations for the alpha 5 and alpha 7 peptides revealed dynamic switching of the alpha 5 helix between a membrane associated and a membrane-inserted state in response to a transbilayer voltage. In contrast the alpha 7 helix did not exhibit such switching but instead retained a membrane associated state. These results are in agreement with recent experimental studies of the interactions of synthetic alpha 5 and alpha 7 peptides with lipid bilayers. PMID- 8679928 TI - Use of fluorescence decay times of 8-ANS-protein complexes to study the conformational transitions in proteins which unfold through the molten globule state. AB - The conformational transitions starting with the native protein, passing the molten globule state and finally approaching the unfolded state of proteins was investigated for bovine carbonic anhydrase B (BCAB) and human alpha-lactalbumin (alpha-HLA) by means of fluorescence decay time measurements of the dye 8 anilinonaphthalene-1-sulphonic acid (8-ANS). Stepwise denaturation was realized by using the denaturant guanidinium chloride (GdmCl). It was shown that 8-ANS bound with protein yields a double-exponential fluorescence decay, where both decay times considerably exceed the decay time of free 8-ANS in water. This finding reflects the hydrophobic environment of the dye molecules attached to the proteins. The fluorescence lifetime of the short-time component is affected by protein association and can be effectively quenched by acrylamide, indicating that 8-ANS molecules preferentially bind at the protein surface. The fluorescence lifetime of the long-time component is independent of the protein and acrylamide concentration and may be related to protein-embedded dye molecules. Changes of the long lifetime component upon GdmCl-induced denaturation and unfolding of BCAB and alpha-HLA correlate well with overall changes of the protein conformation. The transition from native protein to the molten globule state is accompanied by an increase of the number of protein-embedded 8-ANS molecules, while the number of dye molecules located at the protein surface decreases. For the transition from the molten globule to the unfolded state was the opposite behaviour observed. PMID- 8679930 TI - High expression of HBV S gene in Bombyx mori cell culture and in silkworms. AB - The coding sequence of human hepatitis B virus (HBV) subtype adr surface antigen S gene was inserted into the genome of the nuclear polyhedrosis virus of Bombyx mori (BmNPV) under control of the polyhedrin promoter, and a recombinant BmNPVS virus was constructed. Upon infection of the recombinant virus, the yield of HBsAg was 35.5 micrograms per 10(6) cells, 750 micrograms per larva, and 690 micrograms per pupa. Western blot and electron microscope observation of the preliminary purified HBsAg particles showed that they were well glycosylated and assembled as regular 22-nm (diameter) particles. The CsCl buoyant density was 1.2 g/mL, which is consistent with that of HBsAg in the blood of patients. PMID- 8679931 TI - Purification of recombinant human granulocyte-macrophage colony stimulating factor expressed in Escherichia coli. AB - Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) was expressed as inclusion bodies (IB) in E. coli. A simple and effective protocol has been worked out for the purification. IB collected after the breakage of bacteria through sonication were subjected to repeated washing followed by solubilization in TE buffer (50 mmol/L of Tris.HCl, 1 mmol/L of EDTA, pH 8.3) containing 8 mol/L urea and 10 mmol/L DL-dithiothreitol. By means of Sephacryl 200 HR, refolding, and Q Sepharose Fast Flow, rhGM-CSF was obtained with a purity of 99%. The total protein recovery was 10% and specific activity of rhGM-CSF was 1 x 10(7) u/mg. The sequence of N-terminal 16 amino acid residues of purified rhGM-CSF was determined and found to be identical to the native protein. This study provided useful parameters for mass production of rhGM-CSF. PMID- 8679932 TI - Kinetic models of batch and fed-batch culture of single-cell protein with double carbon sources. AB - Unstructured logistic models were applied to simulate the kinetic process of the SCP batch culture with two species of yeast, in which glucose, xylose, or a mixture of the two were used as carbon sources. A modified logistic growth model was used to describe the fed-batch process of using mixed carbon sources. The model parameters were determined by the simulated model with the experimental data. The simulated curves of the models were in agreement with the experimental data. PMID- 8679933 TI - High-concentration ethanol production from cooked corn starch by using medium temperature cooking process. AB - An improved process for high-concentration ethanol production from cooked corn starch by Saccharomyces sp. W4 has been well developed. Simultaneous cooking and liquefaction of corn starch were performed by using thermophilic alpha-amylase at 95 degrees to 105 degrees C. The mash was then saccharified at 60 degrees C by using high-efficiency glucoamylase. Saccharomyces sp. W4 could produce 18.3% (v/v) ethanol at 30 degrees C within 60 hrs, with 1.2% reducing sugar and 4.1% total sugar remaining in the fermented mash. It was found that ammonium sulfate could accelerate the fermentation rate. When 0.9 g of ammonium sulfate was added to 280 mL of the fermentation media, 18.9% (v/v) ethanol could be reached in the mash after 50 hrs of fermentation, leaving 0.27% reducing sugar and 3.1% total sugar in the fermented media. PMID- 8679934 TI - Biosensor based on chemiluminescence for serum uric acid determination. AB - A biosensor based on luminol chemiluminescent reaction and immobilized uricase column for serum uric acid determination has been developed. The response time by the sensor for various concentrations of serum uric acid was 47 sec with a 17 microliters sample volume at 40 samples per hr. The linear range of standard curve was from 1 mg/dL up to 20 mg/dL of serum uric acid. The imprecision within a day was 3.22% to 4.36%. The day-to-day imprecision was 6.18% to 7.80%. The recovery rate by the method was 93% to 109%. Compared with the standard colorimetric method employed, the enzymatic kit revealed that the linear regression and correlation coefficient were Y = 0.4 + 0.938x and r = 0.9909, respectively. The immobilized uricase column retained 94% of its original activity even after over 2000 runs for five and half months of continual usage. PMID- 8679935 TI - Cloning and overexpression of thermostable DNA polymerase gene in Escherichia coli. AB - Thermostable DNA polymerase genes had been amplified from Thermus aquaticus YT-1 using the PCR technique. The amplified 2.5-kb DNA fragment was inserted into pUC18 and confirmed to be a thermostable DNA polymerase gene by restriction mapping and DNA sequencing. The insert fragment was then combined into an expression vector, pBV221. This recombinant plasmid overexpressed a 94-kDa of recombinant protein in E. coli. A 100-mL E. coli. culture could yield 1.5 x 10(5) units of Taq DNA polymerase, which could be applied in the PCR. PMID- 8679936 TI - The factors affecting transformation efficiency of coryneform bacteria by electroporation. AB - High-voltage electroporation was performed to transfer plasmid DNA of pXZ10145 into different kinds of corynebacteria strains. A number of factors that affected transformation efficiency were investigated. Cells grown in the presence of 4% glycine and harvested in the early exponential growth phase (OD600 was about 0.2) were much more easily transformed. Transformation efficiency up to 8 x 10(6) transformants per microgram of plasmid DNA with homologously derived DNA was obtained. If heterologously derived DNA was used, transformation efficiency was 10(2) to 10(3) times lower than the former one. PMID- 8679937 TI - Study of cellulose acetate membrane-based glucose biosensors. AB - A new immobilization procedure was designed to covalently immobilize enzymes onto a cellulose acetate membrane that was simple and easy to handle. The resultant enzyme membrane was very stable, with high specific activity. A glucose oxidase membrane was prepared by using this method, which was combined either with an oxygen electrode or with a hydrogen peroxide electrode to construct a glucose biosensor. The response characteristics of both biosensors were compared. PMID- 8679938 TI - Protoplast culture and plant regeneration from the suspension cells of Gynostemma pentaphyllum (Thumb) Mak. AB - From the suspension cultures of Gynostemma pentaphyllum (Thumb) Mak. protoplasts were isolated and cultured in a different medium with liquid and nurse culture method. Cell division was observed within 4 days and microcalli were formed within 4 weeks. On an MS solid medium with 1 mg/L of KT and 0.5 mg/L of IAA, protoplast-derived calli differentiated into embryos. Stems and leaves were formed on the MS medium with 1 mg/L of 6-BA and 0.5 mg/L of IAA. Finally, complete plantlets were obtained on a hormone-free MS solid medium. PMID- 8679939 TI - Conformational restriction of Tyr and Phe side chains in opioid peptides: information about preferred and bioactive side-chain topology. AB - The side chain of Tyr and Phe was fixed into the gauche(-) or gauche(+) conformation by using the Tic Htc structures, and into the trans conformation by using an aminobenzazepine-type (Aba) structure. When incorporated into dermorphin or deltorphin II, the Tic and Htc analogues all showed a large decrease in both mu and delta affinities and activities. Fixation of Phe(3) in the trans rotamer resulted in a large increase in delta affinity in the dermorphin analogue, whereas in the [Aba(3)-Gly(4)] deltorphin II analogue, good delta affinity is maintained despite the removal of the Glu side chain. Whereas several authors propose a gauche(-) preferred conformation for the Phe(3) side chain, these results suggest a trans conformation at the delta receptor. The use of these conformationally constrained residues for evaluating the preferred solution conformation in the flexible N-terminal tripeptide Tyr-D-Ala-Phe is illustrated. The (1)H-nmr parameters--chemical shift, temperature dependence, and nuclear Overhauser effects to the D-Ala(2) methyl protons in the different analogues- provide direct evidence to confirm the proposed sandwich conformation in the native peptides. PMID- 8679940 TI - Binding of tacrine and 6-chlorotacrine by acetylcholinesterase. AB - Multiconfiguration thermodynamic integration was used to determine the relative binding strength of tacrine and 6-chlorotacrine by Torpedo californica acetylcholinesterase. 6-Chlorotacrine appears to be bound stronger by 0.7+/-0.4 kcal/mol than unsubstituted tacrine when the active site triad residue His-440 is deprotonated. This result is in excellent agreement with experimental inhibition data on electric eel acetylcholinesterase. Electrostatic Poisson-Boltzmann calculations confirm that order of binding strength, resulting in deltaG of binding of -2.9 and -3.3 kcal/mol for tacrine and chlorotacrine, respectively, and suggest inhibitor binding does not occur when His-440 is charged. Our results suggest that electron density redistribution upon tacrine chlorination is mainly responsible for the increased attraction potential between pronated inhibitor molecule and adjacent aromatic groups of Phe-330 and Trp-84. PMID- 8679941 TI - Structure optimization of an artificial neural filter detecting membrane-spanning amino acid sequences. AB - An artificial neural network has been developed for the recognition and prediction of transmembrane regions in the amino acid sequences of human integral membrane proteins. It provides an additional prediction method besides the common hydrophobicity analysis by statistical means. Membrane/nonmembrane transition regions are predicted with 92% accuracy in both training and independent test data. The method used for the development of the neural filter is the algorithm of structure evolution. It subjects both the architecture and parameters of the system to a systematical optimization process and carries out local search in the respective structure and parameter spaces. The training technique of incomplete induction as part of the structure evolution provides for a comparatively general solution of the problem that is described by input-output relations only. Seven physiochemical side-chain properties were used to encode the amino acid sequences. It was found that geometric parameters like side-chain volume, bulkiness, or surface area are of minor importance. The properties polarity, refractivity, and hydrophobicity, however, turned out to support feature extraction. It is concluded that membrane transition regions in proteins are encoded in sequences as a characteristic feature based on the respective side chain properties. The method of structure evolution is described in detail for this particular application and suggestions for further development of amino acid sequence filters are made. PMID- 8679942 TI - Stabilization of an isolated helical capping box in solution by hydrophobic interactions: evidence from the NMR study of bioactive peptides from the C terminus of human C5a anaphylatoxin. AB - Synthetic analogues of the C-terminal portion of C5a were designed and found to be agonists of the C5a receptor [J. A. Ember et al. (1992) Jounral of Immunology, Vol. 148, p. 3165]. Nuclear magnetic resonance experiments were carried out to determine the solution conformation of the most potent analogue, the peptide C5a 65-74 (Tyr65, Phe67) (Tyr65-Ser66-Phe67-Lys68-Asp69-Met70 -Gln71- Leu72-Gly73 Arg74). Medium-range nuclear Overhauser effects (NOEs) were observed for residues 65-70 of this C5a peptide, suggesting that this region adopts a folded conformation in a significant population of the solution conformational ensemble. Quantitative analyses of (3)J(NH-alphaH) coupling constants and sequential NOE cross peaks gave an estimated helical population of 65% in the region Ser66 Met70. Additional evidence supporting the presence of a helical turn includes reduced amide-proton temperature coefficients and lowered (3)J(NH-alphaH) coupling constants in the region of Phe67-Met70. Conformational behavior of this C5a analogue peptide was studied using molecular modeling incorporating observed NOEs as constraints. The side chains of Tyr65, Phe67, and Met70 consistently form a hydrophobic cluster in all the model structures. The side chains of residues Ser66 and Asp69 can form reciprocal hydrogen bonds with the backbone NH groups of these two residues, indicating that residues Ser66-Phe67-Lys68-Asp69 (or SFKD) form a helix-stabilizing capping box (E. T. Harper and G. D. Rose (1993) Biochemistry, Vol. 32, p. 7605; H. X. Zhou et al. (1994) Proteins: Structure, Function and Genetics, Vol. 18, p. 1] even within the single turn of helical structure found in the analogue C5a peptide. A comparison of nmr results obtained for the analogue peptide and the natural decapeptide C5a 65-74 (Ile65-Ser66-His67 Lys68-Asp-69- Met70-Gln71-Leu72-Gly73-Arg74) indicated that incorporation of residues Tyr65 and Phe67 helps stabilize an isolated capping box involving residues Ser66-Asp69 in the C5a peptides through more extensive hydrophobic/aromatic interactions between residues Tyr65, Phe67, and Met70 in the analogue peptide C5a 65-74 (Tyr65, Phe67). These results constitute the first experimental demonstration of hydrophobic determinants in helical capping-box interactions, proposed recently by a statistical analysis of protein structures [J. W. Seale et al. (1994) Protein Science, Vol. 3, pp. 1741-1745]. The stabilized helical turn may also account for the greater potency of the analogue peptide C5a65-74 (Tyr65, Phe67) in receptor-binding assays. PMID- 8679943 TI - New theoretical methodology for elucidating the solution structure of peptides from NMR data. II. Free energy of dominant microstates of Leu-enkephalin and population-weighted average nuclear Overhauser effects intensities. AB - A small linear peptide in solution may populate several stable states (called here microstates) in thermodynamic equilibrium; elucidating its dynamic three dimensional structure by multi- dimensional nmr is complex since the experimentally measured nuclear Overhauser effect intensities (NOEs) represent averages over the individual contributions. We propose a new methodology based on statistical mechanical considerations for analyzing nmr data of such peptides. In a previous paper (called paper I, H. Meirovitch et al. (1995) Journal of Physical Chemistry, 99, 4847-4854] we have developed theoretical methods for determining the contribution to the partition function Z of the most stable microstates, i.e. those that pertain to a given energy range above the global energy minimum (GEM). This relatively small set of dominant microstates provides the main contribution to medium- and long-range NOE intensities. In this work the individual populations and NOEs of the dominant microstates are determined, and then weighted averages are calculated and compared with experiment. Our methodology is applied to the pentapeptide Leu-enkephalin H-Tyr-Gly-Gly-Phe-Leu-OH, described by the potential energy function ECEPP. Twenty one significantly different energy minimized structures are first identified within the range of 2 kcal/mol above the GEM by an extensive conformational search; this range has been found in paper I to contribute 0.6 of Z. These structures then become "seeds" for Monte Carlo (MC) simulations designed to keep the molecule relatively close to its seed. Indeed, the MC samples (called MC microstates) illustrate what we define as intermediate chain flexibility; some dihedral angles remain in the vicinity of their seed value, while others visit the full range of [-180 degrees, 180 degrees]. The free energies of the MC microstates (which lead to the populations) are calculated by the local states method, which (unlike other techniques) can handle any chain flexibility. The NOE of MC microstate i is calculated as the average <1/r(3)>i(2), and an effective interatomic distance ri(eff) is defined as ri(eff) = i(-1/3), where r is the distance between two protons. Under "initial rate approximation," and neglecting angular modulations, the overall I is the average over ri(eff-6), weighted by the populations of the MC microstates. This treatment is justified under the assumption that the rates at which conformations interconvert within, and among, microstates are faster and slower, respectively, than the rotational reorientation of the molecule. I(-6) leads to the virtual theoretical distances, compared to the corresponding virtual experimental distances, which were obtained previously from a cryoprotective solution of Leu-enkephalin at 280 K. A reasonable fit is found between theory and experiment. Future research directions are outlined. PMID- 8679944 TI - Mechanical properties of tropomyosin and implications for muscle regulation. AB - Tropomyosin is a protein that controls the interactions of actin and myosin as a part of the regulation of muscle contraction. The 420 A long alpha-helical coiled coil molecules form long filaments, both in muscle and in crystals. The x-ray diffraction data from tropomyosin crystals have indicated large scale motions of the filaments that can be related to the inherent mechanical properties of the molecule, and by extension, to the role of tropomyosin in the cooperative activation of the thin filaments of muscle. Diffuse scattering analysis has provided information about the amplitudes of the motions that has been used to calculate the intrinsic flexibility of the molecule. It can then be shown that each tropomyosin molecule by itself can only mediate interactions of the nearest neighboring tropomyosin molecules along the filament. The repeating nature of the thin filament, however, allows the entire filament to activate cooperatively. PMID- 8679945 TI - Solution structure of dehydropeptides: a CD investigation. AB - A CD investigation of eleven dehydropeptides is reported. The compounds investigated include tri-, tetra-, hepta-, and octapeptides and contain one, two, or three dehydro-phenylalanine (deltaPhe) residues. The peptides showed different CD profiles depending on chain length, position, and number of dehydro residues. The CD data very much complemented that provided by nmr studies, confirming the conformational preference for beta-bend structures in small peptides (tripeptides), and 3(10)-helical or alpha-helical structures in longer peptides. The secondary structures were stable in chloroform solution and were denatured by addition of trifluoroacetic acid. Solvent titration experiments performed by measuring CD as a function of solvent composition provided evidence that the order < or > disorder conformational changes occurred as cooperative transitions. PMID- 8679946 TI - Topographic analysis of the S7 binding subsite of the tachykinin neurokinin-1 receptor. AB - Conformationally and configurationally restricted rotameric probes of phenylalanine have been incorporated in the sequence of substance P (SP)-Arg-Pro Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2-for analyzing the binding pockets of Phe7 (S7) and Phe8 (S8), in the neurokinin-1 receptor. These analogues of phenylalanine are (2S. 3R)- and (2S, 3S)-indanylglycines, E- and Z-alpha, beta dehydrophenylalanines, and 2(S)-alpha, beta-cyclopropylphenylalanines [delta E Phe. delta Z Phe. inverted delta E2 (S) Phe, and inverted delta Z 2 (S) Phe]. Binding data obtained with either conformationally (Ing diastereoisomers) or configurationally (delta E Phe, delta Z Phe) probes have unveiled large differences in the binding potencies of these rotameric probes. With the support of nmr data and energy calculations done on these SP-substituted analogues, we attempt to answer questions inherent to such study. First, none of these six probes prevents the formation of bioactive conformation(s) of the backbone of SP. Second, both diastereoisomers (S, S) and (S, R) of indanylglycine preferentially adopt, in the sequence of SP, the gauche (-) and trans side-chain orientations, respectively, as previously postulated from energy calculations with model peptides. However, in solution, the difference in energy between these rotamers included in the sequence of SP, compared to model peptides, is small since the other rotamer can be detected in [(2S, 3R)Ing7]SP. Finally, from this study we can hypothesize that the large variations observed in the affinities of Phe7 substituted analogues of SP must come from steric hindrance in the S7 binding site, which drastically restricts the space filling around the C alpha-C beta bond of residue 7. PMID- 8679947 TI - Conformational and stacking properties of 3'-5' and 2'-5' linked oligoribonucleotides studied by CD. AB - Comparative CD studies have been carried out to characterize the properties of 2' 5' and 3'-5' oligoriboadenylates and oligoribouridylates from dimer to decamer. The CD band of the 3'-5' oligoribonucleotides was larger than that of the 2'-5' oligoribonucleotides and increased with the increase in chain length, while the CD band of the 2'-5' oligoribonucleotides increased little beyond the dimer level. The CD analysis of the chain length dependency revealed that the 3'-5' oligoribonucleotides adopt mainly the base-base stacking interaction, while the base-sugar interaction is predominant in the 2'-5' oligoribonucleotides. The CD intensity of 3'-5' oligoribonucleotides decreased to a larger extent at elevated temperatures or in the presence of ethanol compared to that of the 2'-5' counterparts. Mg2+ or Mn2+ ion enhanced the magnitude of the CD of 3'-5' octariboadenylate, while a small decrease in the CD was observed by the presence of Mg2+ or Mn2+ ion to the 2'-5' octariboadenylate. The 3'-5' oligoribonucleotide is likely conformationally flexible and can form helical ordered structure with strong base-base stacking depending on changes in the environment such as temperature the presence of Mg2+ ion, or hydrophobicity of the solution. PMID- 8679948 TI - Characteristic interaction of Ca2+ ions with elastin coacervate: ion transport study across coacervate layers of alpha-elastin and elastin model polypeptide, (Val-Pro-Gly-Val-Gly)n. AB - Ion transport characteristics across a macrocoacervate layer membrane composed of aqueous elastin model polypeptides with a specific repeating pentapeptide sequence, H-(Val-Pro-Gly-Val-Gly)n-Val-OMe (n > or = 40), were investigated. Transmembrane potential responses for NaCl. MgCl2, and CaCl2 concentration-cell systems were measured and examined systematically by comparing with those across a coacervate membrane composed of bovine neck ligamental alpha-elastin. In the case of the NaCl and MgCl2 systems, potential responses across these protein liquid membranes were different noticeably from each other depending upon the molecular structure with and without charged peptide side chains, whereas in the CaCl2 systems the transmembrane potential responses across the noncharged polypentapeptide coacervate membrane were comparable with those across the alpha elastin coacervate membrane carrying both the positively and negatively charged amino acid residues as an amphoteric ion-exchange membrane. These results indicated that mechanisms of major Ca2+ ion transport are based on the specific and selective interactions with electrically neutral sites of elastin, such as the polypentapeptide backbone chain. PMID- 8679949 TI - Synthesis and characterization of the sweetness-suppressing polypeptide gurmarin and ent-gurmarin. AB - The sweetness-suppressing polypeptide gurmarin isolated from the leaves of Gymnema sylvestre consists of 35 amino acid residues including three intramolecular disulfide bonds. Herein, the total chemical synthesis of gurmarin was performed by the stepwise fluoren-9-ylmethoxy-carbonyl solid-phase method, the yield of reduced gurmarin being 1.9% based on the starting amino acid resin. Disulfide formation was carried out in the presence of a redox system of reduced glutathione/oxidized glutathione to give gurmarin in a yield of 35.5%. The product was identical to natural gurmarin by analytical reverse phase high performance liquid chromatography (RP-HPLC), mass spectroscopy (MS), and peptide mapping, and suppressed the responses to sucrose, D-glucose, and L-glucose in a rat. The D enantiomer (all D-amino acid gurmarin) was also synthesized, and was shown to be the mirror image of gurmarin. Interestingly, the D enantiomer (ent gurmarin) also suppressed the responses to sucrose, D-glucose, and L-glucose in a rat. PMID- 8679950 TI - Assignment of the helical structure in neuropeptide Y by HPLC studies of methionine replacement analogues and 1H-NMR spectroscopy. AB - The HPLC retention behavior of three complete single methionine and methionine sulfoxide replacement sets of two 18-mer model peptides and neuropeptide Y (NPY) were investigated. All peptides were prepared by multiple solid-phase peptide synthesis. Plotting the retention time differences between methionine and methionine sulfoxide analogues vs the position of replacement shows that potentially alpha-helical peptides become helical on binding during reversed phase high performance liquid chromatography. In the case of an amphipathic alpha helix, the retention time differences change periodically with a 3-4 repeat pattern, which allow the location of amphipathic helical structures. Replacements in nonamphipathic alpha-helical domains cause local preferential binding areas and lead to sequence-dependent retention time profiles. Methionine replacement studies of NPY suggest an unstructured or extended conformation from Tyr1 to Ala12 connected to a well-defined amphipathic alpha-helix from Pro13 to Arg35. The assignment is confirmed by comparison of nuclear Overhauser effects based two dimensional 1H-nmr spectroscopy and utilization of the C alpha H shift index method in 50% trifluoroethanol/50% water. PMID- 8679951 TI - Free energy simulations of axial contacts in sickle-cell hemoglobin. AB - Molecular dynamics simulations have been used to investigate the thermodynamic stability of axial contacts in sickle-cell hemoglobin (HbS). Free energy changes were evaluated for the point mutation beta 121 Glu --> Gln in the axial contact region of HbS crystals. The calculations predict a free energy change of-3.6 kcal/mol per contact for the mutation, which is in qualitative agreement with experimental observations of aggravated sickling found in the double mutant Hb D Los Angeles (beta 6 Glu --> Val. beta 121 Glu --> Gln) relative to HbS (beta 6 Glu --> Val). The beta 121 Glu is sequestered in a salt link with beta 17 Lys located on the same polypeptide chain, making the Glu interactions with its surroundings similar in aggregates and individual hemoglobins. Due to this cancellation of the large electrostatic Glu contributions, the weak nonspecific interactions between the Gln and the neighboring polypeptide chain are the main contributing factor to the enhanced aggregation of Hb D Los Angeles relative to HbS. Together with the previous study of the lateral contact [K. Kuczera et al. (1990) Proceedings of the National Academy of Science USA, Vol. 87, pp, 8481 8485], the present results provide a more complete picture of the forces driving the sickling aggregation. A comparison of different treatments of internal flexibility in free energy simulations and analysis of rate of convergence of the different calculated properties has also been performed. PMID- 8679952 TI - Molecular modeling of closed circular DNA thermodynamic ensembles. AB - Many modeling studies of supercoiled DNA are based on equilibrium structures from theoretical calculations or energy minimization. Since closed circular DNAs are flexible, it is possible that errors are introduced by calculating properties from a single minimum energy structure, rather than from a complete thermodynamic ensemble. We have investigated this question using molecular dynamics simulations on a low resolution molecular mechanics model in which each base pair is represented by three points (a plane). This allows the inclusion of sequence dependent variations of tip, inclination, and twist. Three kinds of sequences were tested: (1) homogeneous DNA, in which all base pairs have the helicoidal parameters of an ideal, average B-DNA; (2) random sequence DNA; and (3) curved DNA. We examined the rate of convergence of various structural parameters. Convergence for most of these is slowest for homogeneous sequences, more rapid for random sequences, and most rapid for curved sequences. The most slowly converging parameter is the antipodes profile. In a plasmid with N base pairs (bp), the antipodes distance is the distance dij from base pair i to base pair j halfway around the plasmid, j = i + N/2. The antipodes profile at time tau is a plot of dij over the range i = 1, N/2. In a homogeneous plasmid, convergence requires that the antipodes profile averaged over time must be flat. Even in the small plasmids examined here, the average properties of the ensembles were found to differ from those of static equilibrium structures. These effects will be even more dramatic for larger plasmids. Further, average and dynamic properties are affected by both plasmid size and sequence. PMID- 8679953 TI - Molecular dynamics simulations of small DNA plasmids: effects of sequence and supercoiling on intramolecular motions. AB - Small (600 base pair) DNA plasmids were modeled with a simplified representation (3DNA) and the intramolecular motions were studied using molecular mechanics and molecular dynamics techniques. The model is detailed enough to incorporate sequence effects. At the same time, it is simple enough to allow long molecular dynamics simulations. The simulations revealed that large-scale slithering occurs in a homogeneous sequence. In a heterogeneous sequence, containing numerous small intrinsic curves, the centers of the curves are preferentially positioned at the tips of loops. With more curves than loop tips (two in unbranched supercoiled DNA), the heterogeneous sequence plasmid slithers short distances to reposition other curves into the loop tips. However, the DNA is immobilized most of the time, with the loop tips positioned over a few favored curve centers. Branching or looping also appears in the heterogeneous sequence as a new method of repositioning the loop tips. Instead of a smooth progression of increasing writhing with increasing linking difference, theoretical studies have predicted that there is a threshold between unwrithed and writhed DNA at a linking difference between one and two. This has previously been observed in simulations of static structures and is demonstrated here for dynamic homogeneous closed DNA. Such an abrupt transition is not found in the heterogeneous sequence in both the static and dynamic cases. PMID- 8679954 TI - Depression. AB - According to the 1994-95 National Population Health Survey, close to 6% of Canadians aged 18 and over had experienced a major depressive episode in the previous 12 months. Univariate analysis shows that the prevalence of depression was higher among women than among men, but tended to decline at older ages both sexes. The prevalence of depression was also related to a number of socioeconomic characteristics such as marital status, education, and household income, and to several measures of stress, psychological resources and social support. However, multivariate analysis shows that not all of these variables were significantly associated with the odds of experiencing depression. In some instances, factors that increased the risk differed for men and women. For both sexes, chronic strain, recent negative events, lack of closeness, and low self-esteem increased the odds of depression. Traumatic events in childhood or young adulthood and a low sense of mastery were associated with a higher risk of depression for women, but not men. For men, being single and having moderate self-esteem heightened the risk of depression. A substantial proportion of both men and women who had suffered depression reported using drugs. As well, a notable share of people who had been depressed sought professional health care for emotional or mental problems. PMID- 8679955 TI - A healthy outlook. AB - The sense of coherence-a healthy outlook-can be thought of as a measure of positive health, that is, a factor promoting resilience which enables an individual to remain healthy. Based on National Population Health Survey (NPHS) data, three health measures were analyzed in relation to sense of coherence. The sense of coherence accounted for a substantial proportion of the total variance for two of the three measures. Theoretically, people with a healthy outlook are more able to cope successfully with trauma and stress. According to NPHS data, on average, those who reported at least one traumatic event had a lower sense of coherence than those who did not. For people who experienced trauma during childhood and young adulthood, yet had a strong sense of coherence, the impact of that trauma on their health was diminished. PMID- 8679956 TI - The health of Canada's immigrants in 1994-95. AB - The "healthy immigrant effect" observed in other countries also prevails in Canada. Immigrants, especially recent immigrants, are less likely than the Canadian-born population to have chronic conditions or disabilities. The effect is most evident among those from non-European countries, who constitute the majority of recent immigrants to Canada. This article compares the health status, health care utilization, and health-related behaviour of immigrants with the Canadian-born population, and is based on self-reported data from the 1994-95 National Population Health Survey. Health status is examined in terms of chronic conditions, disability and health-related dependency. The indicators of health care utilization are hospitalization, contact with physicians and dentists, and unmet needs for health services. The health-related behaviours analysed are smoking and leisure time physical activity. PMID- 8679957 TI - Chronic pain. PMID- 8679958 TI - Mental health statistics, 1982-83 to 1993-94. AB - The shift toward greater use of general hospitals for the treatment of mental disorders reflects the tendency to admit patients with the most serious diagnoses to psychiatric hospitals. However, admissions to both types of institution now tend to involve more serious cases than in early 1980s. To some extent, the increase in the number of patient-days provided for mental disorders, despite declining separation rates, is attributable to the time required for the treatment of disorders such as schizophrenia and affective psychoses. There is also growing emphasis on community care. Increasingly, mental disorders are treated on an outpatient basis without admission to hospital. The substantial annual fluctuations in the national number of separations-as many as 5,000 or 6,000 from one year to the next-may be due to the development of alternative facilities such as community health clinics. The opening of such a facility in one province could have noticeable impact on national figures on hospitalization for mental disorders. PMID- 8679959 TI - Rheology of blood coagulation. AB - There have been a number of investigations on coagulation reactions of blood as well as on coagulation factors including fibrinogen and thrombin. With the progress of clotting, the viscosity and rigidity of blood increase, facts related to the clot structure of fibrin. Therefore, rheological measurements make it possible to investigate the process of blood clotting as well as the properties of the fibrin clot. In this paper, our rheological studies on blood coagulation are summarized. The network structure of fibrin clots formed under different conditions is discussed from the kinetic analysis of the change of dynamic rigidity modulus during clotting. Also it will be shown that rheological techniques make it possible to analyze the initial coagulation reaction of blood in contact with components constituting the vascular vessel. The analysis indicates that a coagulation factor in plasma is activated on the erythrocyte surface. PMID- 8679960 TI - Model studies of leukocyte-endothelium-blood interactions. I. The fluid flow drag force on the adherent leukocyte. AB - Using a large scale model and the concept of dimensional similarity, we have developed a dimensionless correlation which permits the estimation of the drag force of blood flow in an in vivo vessel on a leukocyte adherent to the vessel wall. This relationship is [formula: see text] where Re is a Reynolds number, Cd is a drag coefficient, and d/D is the leukocyte-to-vessel diameter ratio. This function increases rapidly with increasing d/D when d/D is greater than 0.5. A relationship between the drag force on the leukocyte, Ff, and the commonly used wall shear stress in the absence of the adherent cell, tau w, has also been developed, and is given by [formula: see text] This study shows that the discrepancy between the in vivo and in vitro critical wall stresses (above which leukocytes do not adhere to endothelial cell layers) is not due to misrepresentation of the corresponding drag forces on the leukocytes. The discrepancy must be due to real differences in the flow and/or cellular conditions between the in vivo and in vitro experiments. PMID- 8679961 TI - Study of red blood cell aggregation by admittance measurements. AB - A method based on dielectric properties of cellular suspensions was developed to study red blood cell (RBC) aggregability. The time-dependent current in a Couette type viscometer was recorded after abrupt stoppage of shearing. Since the current reaches steady state 2 min after the end of shearing, the observed effects were quantified by the relative current difference, delta Irel = (I(2min)-I5s)/I2min, where subscripts designate the time of measurements. delta Irel increases with hematocrit, plasma and fibrinogen concentration. The dependence of delta Irel and of RBC aggregability on the concentration of dextran were similar. The experimental data and their analysis indicate that in suspensions with aggregating media, the delta Irel value measured in the field of the beta dispersion reflects the difference between the size of aggregates under steady state conditions and that of dispersed particles 5 s after the end of shearing. Therefore, this value may serve as a measure of RBC aggregability. PMID- 8679962 TI - The influence of suspending phase viscosity on the passage of red blood cells through capillary-size micropores. AB - Much attention has been paid to the study of blood flow in long, narrow tubes. While the influence of tube diameter and driving pressure have been examined in detail, the influence of suspending phase viscosity has generally been assumed only to affect the blood viscosity in a linearly proportional manner, hence the practice of normalizing apparent blood viscosity values by the suspending phase viscosity to give a relative viscosity (e.g., Pries et al., 1992). While this assumption is probably valid for long tubes, it apparently does not hold for blood flow in short tubes (and by extension also for flow in short or branching capillary segments in vivo) in which RBC deformation plays a more significant role. In this paper we present a series of experiments using the Cell Transit Analyzer (CTA) in which the influence of driving pressure and suspending phase viscosity on RBC passage through short, narrow tubes has been systematically evaluated. Over the range studied (1 to 10 cm water), the influence of driving pressure was found to be unremarkable, in that RBC velocity scaled directly and linearly with pressure. This finding is consistent with previous studies. However, a distinct intercept was observed in the linear relationship between RBC pore transit time and suspending phase viscosity, which presumably arises as a consequence of RBC deformation either at the pore entrance or within the pore. Two simple mathematical models for the suspending phase-viscosity/transit-time relationship were considered. The results show that making CTA measurements over a range of suspending medium viscosities is a simple and practical way to obtain additional information about RBC mechanical properties. PMID- 8679963 TI - Deformability of red blood cells from different species studied by resistive pulse shape analysis technique. AB - The Cell Transit Analyzer (CTA) is now being used widely in clinical hemorheology. Most of the data obtained by CTA are limited to human blood, although the CTA has an important potential to be used in experimental studies on animal models. However, behavior of red blood cells (RBC) from various species might be different in CTA. Eight parameters reflecting different aspects of cell passage through pores with 5 microns diameter and 15 microns length were determined or human, guinea pig, dog, rabbit, rat, mouse and sheep RBC, together with instrument precision and biological variation. These parameters have a wide range when measured in different species and correlate with cell volume. Sensitivity of these parameters to the glutaraldehyde-induced alterations in RBC deformability was not same for different laboratory mammals. The main reason for this difference seems to be related to the cell size and thus sensitivity might be significantly limited if 5 microns pore-size filters are used to test the smaller RBC. The results of this study may help in designing experimental studies on laboratory mammals using the CTA. PMID- 8679964 TI - Extrapunitive and intropunitive anger of HIV caregivers: nursing implications. AB - The purpose of this qualitative study was to investigate the anger of individuals who have provided direct patient care to loved ones who are living with or who have died from AIDS. The sample consisted of eight individuals who are currently involved in an AIDS service organization in northeast Tennessee. Data were collected using semistructured taped interviews. At the beginning of the study, two group interviews were conducted. Subsequently, each of the participants was interviewed privately. Extrapunitive and intropunitive anger were predominant themes in each of the interviews. Participants also reported ways of coping with their anger. Nurses can suggest these strategies to other caregivers who are experiencing anger. Recommendations for additional nursing interventions are offered. PMID- 8679965 TI - Quality of life and coping styles of HIV-positive women with children. AB - This descriptive study explored the quality of life and coping methods of HIV positive women (N = 52) with children. The sample consisted of women with HIV/AIDS who answered an adapted Padilla Quality of Life Index and the Jalowiec Coping Scale. Among the psychological, physical, and social quality of life subscales, social quality of life was rated highest and the psychological scale rated the lowest. Among the three styles of coping, confrontive was used most frequently, passive and emotive less frequently. Significant relationships between coping and quality of life were examined. It is essential that nurses working with women with HIV disease be aware of their common concerns and provide effective strategies to improve quality of life such as enhancing decision making and coping skills within the context of the family unit. PMID- 8679966 TI - Ethnography of an HIV hotel. AB - The human immunodeficiency virus (HIV) epidemic has created new communities of need among people infected with the virus who are already marginalized by poverty, sexual activity and identity, and drug use. An ethnography of one residential hotel in San Francisco, based on the concept of culture, reveals some themes including the meanings of the hotel as a supportive community for residents, the meanings of drug use in this culture, and the meanings of working in such sites for some nurses. PMID- 8679968 TI - Liposomal doxorubicin (Doxil). PMID- 8679969 TI - [Prognosis or clairvoyance?]. PMID- 8679967 TI - Perceived health, HIV illness, and mental distress in African-American clients of AIDS counseling centers. AB - The development of effective coping strategies may require that adults with HIV disease have an accurate, and to the extent possible, positive perception of their own health status. This has been found to be lacking among HIV-infected people with limited education/information, including many minority adults. The objective of this study was to test several hypotheses that predict depression and perceived health in African-American adults with HIV disease. Data were obtained from 255 HIV-infected black adults (age > 18) who sought support, counseling, and maintenance services from one of three HIV care and referral centers in the Mid-South. The results emphasized that perceived health status may fulfill a psychological distress moderating or distress-aggravating function for persons with HIV/AIDS. PMID- 8679970 TI - [The computed tomography of acute sigmoid diverticulitis]. AB - PURPOSE: To study the ranking of CT in the diagnosis of sigma diverticulitis. Comparison of results of the colon monocontrast enema with those obtained via CT and histopathology as gold standard. MATERIAL AND METHODS: 32 patients were included who were operated on for sigma diverticulitis. In 30 patients both CT and monocontrast enema were performed and in two patients CT only. RESULTS: Acute inflammatory wall alterations are identified by CT with a sensitivity of 89.7% vs 96.3% via contrast enema. Pericolic reactions of the environment were seen via CT with 89.7% sensitivity. In case of covered perforations CT yielded a sensitivity of 76.5% vs 46.7% via contrast enema. Sensitivity for abscesses and fistulas was in each case 100% with CT. RESULTS: CT may help to identify extraluminal inflammatory changes and complications in diverticulitis. The degree of the inflammation can be classified and the surgical approach suitably influenced, respectively modified. PMID- 8679971 TI - Quantification of carotid artery stenosis with various Doppler velocity parameters. AB - PURPOSE: To assess the Doppler indices best suited for detecting a stenosis of the internal carotid artery. MATERIAL AND METHOD: 358 patients (234 men, 124 women, mean age 59 years, range 25-83 years) were examined via duplex carotid sonography (US) and arteriography. Flow indices and B-mode real-time results of stenoses were compared with arteriographic findings. RESULTS: The accuracy of US in differentiating a 50% or more severe ICA stenosis was 93% and the correlation coefficient between angiographic and US stenosis was 0.94. Peak systolic velocity of the internal carotid artery (vpICA) and its ratio to the systolic (vpICA/vpCCA) and diastolic velocity of the common carotid artery were most accurate at 70% stenosis. The vpICA/vpCCA ratio was even slightly more accurate in cases of less severe stenosis. B-mode real-time measurement of diameter stenosis was most accurate at the < 30% level. There was large variation in the flow values of the ICA, mostly due to the variability of flow in the common carotid artery. The vpCCA was low in wide and higher in medium-sized or narrow common carotid arteries. Contralateral ICA stenosis also affected the flow and thus on the vpICA/vpCCA ratio and the differentiation between significant and non significant stenosis. CONCLUSIONS: At duplex US, B-mode real-time measurement is suitable for screening small carotid plaques and flow indices, especially vpICA and vpICA/vpCCA in severe stenoses. PMID- 8679972 TI - [Duplex sonography in functional thyroid diagnosis]. AB - PURPOSE: Assessment of the functional diagnostic value of Doppler sonographic or sonographic parameters, especially of the peak flow velocity in the inferior thyroid artery in patients with newly manifest autoimmunothyroiditis. MATERIAL AND METHOD: Morphological and Doppler sonographic measurements were done at the inferior thyroid artery on 69 patients suffering from newly manifest Graves' disease or Hashimoto's thyroiditis, as well as on a control group of 18 subjects. The measured data were correlated with thyroid hormone levels and with quantitative scintiscanning. RESULTS: A linear functional correlation was found between the peak flow velocities in the inferior thyroid artery and the fT3 or fT4 level. If the peak flow velocities were greater than 1.2 m/s, hyperthyroid metabolism prevailed, whereas at velocities below 0.3 m/s latent hypothyroidism was present. CONCLUSION: These results show that Doppler sonography of the inferior thyroid artery can supply pointers (capable of being recorded) to the state of functioning of the thyroid even before knowing the laboratory parameters. PMID- 8679973 TI - [Does the administration of a high dose of a paramagnetic contrast medium (Gadovist) improve the diagnostic value of magnetic resonance tomography in glioblastomas?]. AB - PURPOSE: To assess the efficacy of high-dose contrast enhanced magnetic resonance imaging (MRI) in detection and delineation of infiltrating tumour in glioblastoma. MATERIAL AND METHODS: In a phase II clinical trial 14 patients with suspected supratentorial glioblastoma underwent MRI with Gd-DO3A-butriol (Gadovist, Schering AG, Berlin) with doses of 0.1 up to 0.3 mmol/kg. RESULTS: Increasing the dose of Gd-DO3A-butriol resulted in improved enhancement (14/14) and better delineation of infiltrating tumour (9/14) up to 2 cm beyond enhancement after standard dose. In two of the 9 patients additional enhancement in the peritumoural oedema was only seen after the third injection. CONCLUSIONS: Successful surgery requires precise preoperative delineation of tumour borders. After high-dose MRI it might be possible to select those patients who would benefit from more radical attempts at eradicating the macroscopic as well as most of the microscopic compartment of glioblastoma. PMID- 8679974 TI - [MRT of the eye: the normal anatomy and detection of the smallest lesions with a high-resolution surface coil]. AB - PURPOSE: A new, high-resolution surface coil for MRI of the eye was evaluated with regard to practicability, image quality and sensitivity for small lesions. MATERIAL AND METHODS: 48 patients in whom a space-occupying lesion of the eye or orbit was suspected were examined (1.5 T tomograph, 5 cm surface coil, T1- and T2 weighted spin-echo sequences, the former before and after i.v. gadolinium DTPA). RESULTS: 45/48 patients tolerated MR with the high-resolution surface coil. No adverse effects were experienced by the patients. In 11/48 patients a space occupying lesion of the eye was detected (melanoma, 5; metastases, 2; haemorrhage, 1; malformation, hamartoma and scarring after melanoma, one each). The smallest detectable lesion had a thickness of < 1 mm. CONCLUSION: First experiences with the high-resolution surface coil indicate that this device is suited for detection of very small lesions of the eye. PMID- 8679975 TI - [High-resolution magnetic resonance tomography by means of an endorectal coil- the results in rectal tumors]. AB - PURPOSE: To assess the value of high-resolution MRI of the rectum using an endorectal coil. METHODS: 10 volunteers and in 31 patients with suspected rectal tumors were examined. In 17 patients (n = 17) with rectal carcinoma, of which 15 subsequently underwent radical surgery, the preoperatively obtained tumor stage was compared with histology. In 12 patients (n = 12) with rectal adenoma (severe and medium graded epithelial dysplasias according to the WHO) who underwent endoscopy the results of the endorectal surface coil examination were compared with endoscopy and histology. In 4 patients (n = 4) with large rectal adenomas the surface coil was used before and as follow-up after endoscopic electro laser resection and the absence of adenoma after therapy also in the deeper layers of the rectal wall could be confirmed. RESULTS: Visualization of anatomical structures of rectum and adjacent structures is improved by the use of the endorectal surface coil. The diagnosis of carcinoma and adenoma of the rectum and the documentation of the exact extension can be reached with high accuracy (85%). CONCLUSION: MRI with an endorectal surface coil may play an important role in the preoperative diagnosis of rectal carcinoma. This method is useful for primary diagnosis and follow-up of large rectal adenoma after endoscopic electro laser resection. PMID- 8679976 TI - [Percutaneous transluminal hydrodynamic thrombectomy--the initial results]. AB - PURPOSE: First clinical applications in the femoro-popliteal vessels of a new system for percutaneous, transluminal hydrodynamic thrombectomy are presented. MATERIAL AND METHOD: Three patients suffering from femoro-popliteal thromboembolic obstruction were treated. A new hydrodynamic 8-F catheter with two lumina was used. The jet leaving at the tip of the catheter shredded the thrombotic material. Using the Venturi effect the thrombus was collected. The shredded material was transported outside through the second channel of the catheter. RESULTS: All obstructions could be removed. Underlying degenerative vessel disease and older thromboemboli needed additional therapy like PTA or aspiration thrombectomy (PAT). CONCLUSIONS: The new catheter is helpful in removing arterial femoro-popliteal thromboembolic obstructions. Additional interventions may be necessary. More clinical experience is needed. PMID- 8679977 TI - [Quality assurance measures within DIN 6856: the adaptation of film viewing boxes and their specifications in the radiology department of a university hospital. Deutsche Industrie-Norm]. AB - PURPOSE: The aim of our study was to examine the quality and consistency of film viewing equipment and surroundings for radiological film viewing as stipulated by the recently released DIN 6856 standard specifications sheet. METHODS: 107 film viewers in 43 locations in the Department of General Radiology (Hospital of the Goethe University in Frankfurt, Germany) were examined with regard to viewer brightness (intrinsic luminous intensity) uniformity of viewbox brightness, colour of fluorescence tubes, dimensions, adjustable filters, positioning of the viewers and ambient light level. RESULTS: Requirements regarding brightness were met in 70%, whereas conditions regarding uniformity of brightness were fulfilled in only 27% and the required filters in only 20% of all cases. CONCLUSIONS: 89% of the examined film viewboxes did not comply with the strict specifications laid down in DIN 6856. The requirements regarding the ambient light level (recommended range 50-100 lx) were met by only 75% of the examined desks. PMID- 8679978 TI - [Extensive acute pulmonary embolism: fragmentation treatment with a rotatable pigtail catheter]. AB - A 58-year-old patient with extensive pulmonary embolism complicated by cardiogenic shock and contraindications to thrombolysis was treated by mechanical embolus fragmentation using a rotatable pigtail catheter system. Considerable recanalization of the left pulmonary arteries was rapidly achieved with relative ease of instrumentation. Subsequently, the hemodynamic condition stabilized. PMID- 8679980 TI - [Contrast medium administration in spiral computed tomography: the results of a consensus conference. Institute for Radiodiagnosis, Regensburg]. AB - The rapidity of spiral (helical-) computed tomography requires new protocols for i.v. contrast media administration. Flow rate, volume and delay are discussed controversially in the literature. Hence, a consensus meeting was initiated. In this meeting, problem related questions were designed, discussed and answered using a digital vote system. Spiral-CT-technology was found to be the ideal examination technique for thorax, liver, pancreas, kidney and the retroperitoneal space with an overall agreement between 89 and 97%. The exclusive use of nonionic contrast media and power injectors was recommended by 100% of the participants. More than 90% of the contributors did not accept native scans only for examinations of the neck, thorax, liver, pancreas, kidney and the retroperitoneal space. Regarding volume, flow rate, delay and physical CT-parameters the agreement laid between 50 and 100%. The meeting concluded that randomised controlled studies should be performed to evaluate detailed contrast media protocols for helical CT. PMID- 8679979 TI - [Thrombectomy using a high-speed rotatable catheter--initial results]. AB - Evaluation of the Amplatz rotational catheter for the recanalisation of acute thrombotic occlusions in various vascular regions. The Amplatz air-driven rotational catheter was used in 5 patients with acute vessel occlusion in various vascular regions: superficial and profundal femoral artery respectively and popliteal artery with tibiofibular trunk (case 1 and 2), a Collier-Shunt (case 3), the left main pulmonary artery (case 4) and the portal vein after TIPS procedure (case 5). A complete or partial recanalisation was achieved in all cases. Time accounted for recanalisation was between 40 and 90 seconds. No adjunctive intervention was necessary. No complications occurred. The Amplatz thrombectomy device allows a fast, safe and effective mechanical thrombectomy of peripheral arteries and haemodialysis shunts. Partial recanalisation of large caliber vessels is also possible. PMID- 8679981 TI - [Displacement of the guidewire into the arterial system during machine-guided injection via a Y connector]. PMID- 8679982 TI - [Lymphedema-associated angiosarcoma (the Stewart-Treves syndrome) of the lower extremity: its MRT imaging]. PMID- 8679983 TI - [Fracture of an ossified Achilles tendon]. PMID- 8679984 TI - [Computed tomographic demonstration of intraspinal air after an infection with peptostreptococci]. PMID- 8679985 TI - [Renovascular hypertension and hydronephrosis due to a renal artery aneurysm]. PMID- 8679986 TI - [Radiological thorax monitoring in ventilated intensive-care patients]. AB - PURPOSE: At many institutions chest x-rays (CXR) are routinely performed on mechanically ventilated patients on a daily basis. Among the aims of this study was the assessment of a) frequency of clinically relevant findings from routine CXR in surgical patients under mechanical ventilation, b) comparison of expectations of clinically important CXR findings with estimation of clinical relevance of findings once films were obtained, c) indications and clinical consequences of findings from CXR requested in addition to routine films. METHODS: Prospective study, 40 patients with 741 CXR. Standardised film reporting. Daily recording of clinical data by means of an evaluation score. Interview of intensive-care physicians for assessment of: what information was expected from any routine CXR? did CXR offer helpful information for further treatment planning? RESULTS: 26% of routine CXR had a considerable therapeutical impact. 43% of all routine CXR were expected to have an influence on patient management, 57% were not. 16% of those CXR that had been expected not to offer essential information, disclosed relevant findings. Of the additionally obtained CXR, 53% were performed to check position of endotracheal tube and catheters and 47% related to other indications. CONCLUSION: Critically ill surgical patients under mechanical ventilation should have daily CXR follow-up, as one-fourth of these films has an impact on the patient's management. PMID- 8679987 TI - [The role of component composition and gas transport functions of blood in the formation of fluctuating electrical properties of the epidermis and underlying tissue]. PMID- 8679988 TI - [Pathomorphological study of cat lungs in a model of pneumonia]. PMID- 8679989 TI - [Correction of hyperlipoproteinogenic microangiopathy and organ pathology at early stages of atherogenesis with thymalin and leu-enkephalin]. PMID- 8679990 TI - [Mobilization of intracellular Ca2+ by ADP and thrombin in platelets of patients with diabetes mellitus with vascular complications]. PMID- 8679991 TI - [Effect of the heptapeptide Semax on the human electroencephalogram]. PMID- 8679992 TI - [Correlation of the rate of liberation of hydrogen from brain tissue and parameters of rat respiration]. PMID- 8679993 TI - [Increase of frog bladder osmotic permeability by hyaluronidase]. PMID- 8679994 TI - [Change in rheologic properties of blood during its irradiation with helium-neon laser]. PMID- 8679995 TI - [Biodegradation and restoration of the intercellular matrix of conserved fragments of planar fibrous connective tissue during implantation into the recipient's body]. PMID- 8679996 TI - [Participation of endogenous mu- and delta-opiate receptor agonists in mechanisms of the anti-arrhythmia effect of adaptation]. PMID- 8679997 TI - [Indicators of lipid peroxidation in organs of rats with varying resistance to hypoxia]. PMID- 8679998 TI - [Microcirculatory system of paired hamster cheek pouches after blood loss and replacement]. PMID- 8679999 TI - [Changes in certain indicators of the functional status of the rabbit fetus depending on the dam's body position]. PMID- 8680000 TI - [Emergence of minute rhythms of small intestinal smooth muscle spike activity during adaptation]. PMID- 8680001 TI - [A chemiluminescent method for studying animals exposed to ionizing radiation]. PMID- 8680002 TI - [Basic forms of acute injury to cardiomyocytes determined by polarized microscopy of myofibrils]. PMID- 8680003 TI - [Multiply-modified disialyated low-density lipoproteins: physico-chemical properties]. PMID- 8680004 TI - [Role of the hemoglobin's affinity for oxygen in activating lipid peroxidation in fever]. PMID- 8680005 TI - [Effects of potentiation and rapid action in models of venous thrombosis in dogs upon combined administration of the plasminogen tissue activator and urokinase modified by fibrinogen]. PMID- 8680006 TI - [Effect of amiridine and tacrine on functional degeneration of the isolated neuron]. PMID- 8680007 TI - [Long-term effects of the harmful action of anthracycline antibiotics on the rat reproductive system]. PMID- 8680008 TI - [Effect of chlorofos on high-threshold potassium and calcium channels in the neuronal membrane]. PMID- 8680009 TI - [Dependence of the strength of anxiolytic effect of tranquilizers on the level of anxiety in a conflict situation]. PMID- 8680010 TI - [Immunologic correlates of morphine tolerance and diluted effect of naloxone in rats of various ages]. PMID- 8680011 TI - [Effect of ethanol concentration on the maximum specific growth rate and composition of biomass in a mutant strain of Yarrowia lipolytica No. 1]. PMID- 8680012 TI - [Evaluation of toxicity and protective effects of initiators and inhibitors of free radical reactions in a model of wild strains of Escherichia coli as well as those deficient in superoxide dismutase]. PMID- 8680013 TI - [Role of fibroblasts as a basic factor in differentiation of the epidermis]. PMID- 8680014 TI - [Effectiveness of liposomal forms of cytostatics]. PMID- 8680015 TI - [A comparative study of human MEL-7 melanoma metastasis in nude and beige/nude mice]. PMID- 8680016 TI - [Secretion of interleukin-1 beta and tumor necrosis factor by mononuclear cells in breast cancer patients: effect of body mass (composition), age and smoking]. PMID- 8680017 TI - [Effect of inversion of the light-dark schedule on various lengths of biological rhythms of the mitotic index in murine digestive tract epithelium]. PMID- 8680018 TI - [Electron-histochemical localization of collagenase in the liver]. PMID- 8680019 TI - The effect of ethanol upon early development in mice and rats. XXI. The effect of acute maternal ethanol intoxication upon in vitro hatching of mouse embryos. AB - The effect of acute ethanol intoxication (ethanol 33% in a.d.) in mice on day 4 of pregnancy (at 9 o'clock a.m.) upon in vitro hatching has been investigated. The embryos were cultured in modified Brinster medium (1963), at 37 degrees C and 5% CO2 in air beginning at 2 o'clock p.m. on day 4 of pregnancy. The control of the developmental stage of embryos from experimental and control groups on day 4 of pregnancy (at 9 o'clock a.m.) showed some numerical differences between the embryos found in early and mid blastocyst stages but no difference between advanced blastocysts. The control after 24 hours of culture showed in both experimental and control groups the presence of expanded blastocysts. No hatched or degenerated embryos were observed. The control at 48 hours revealed the following aspects: the inhibition of hatching revealed by a significantly lower percentage of in vitro hatching (16.3%) in the experimental as compared with the control group (36.6%); the percentage of degenerated embryos is significantly increased in the ethanol group (13%) as compared with the untreated group (6.10%); the percentage of embryos with the zona pellucida fractured does not differ significantly between experimental and control groups. Some problems related to the mechanism of in vitro and in vivo, hatching are discussed. PMID- 8680020 TI - The effect of ethanol upon early development in mice and rats. XXII. The effect of chronic consumption of nonalcoholic beer upon preimplantation development in rats. AB - The effect upon preimplantation development of chronic consumption of nonalcoholic beer was investigated in rats (controlled on day 5 of pregnancy) by using the following criteria: mean number of embryos/animal, oviductal-uterine migration of embryos, developmental rate and number of pathologically modified embryos. It resulted that this beverage had a noxious effect (less marked than normal beer) upon preimplantation development, manifested by the decrease of the mean number of embryos/animal and the presence of abnormal embryos. These results suggest a possible action of various congeners present in this beverage, which potentiate the noxious effect of ethanol in the case of normal beer. PMID- 8680021 TI - [Classification of cytokines in the cyclic morphofunctioning and the gestational endometrium]. PMID- 8680022 TI - The influence of beer, cognac and ethanol upon the follicular state of mouse ovaries on day 4 of pregnancy. AB - There exist few experimental and anatomo-clinical data with respect to the effect of preconceptional and intragestional ethanol (alcoholic beverages) intake upon ovarian morpho-physiology. In order to obtain an insight into this aspect of alcohol embryo- and fetopathy, the influence of acute intoxication with beer and cognac on the background of chronic intake (in mice) and of chronic ethanol intake (in rats) upon ovarian morphology was studied, on day 4 (mice) and 5 (rats), respectively. The following characteristics were registered: the percentage of various follicular developmental stages (I-V), of atreting follicles, of preantral and antral follicles, of follicles with precocious antrogenesis. Significant changes were round in mice with respect to antral and mature follicles (lower percentage induced by beer) and concerning atreting follicles (lower percentage induced by cognac). On the other hand, precocious antrogenesis (during follicular stage II) occurred by far more frequently than expected. PMID- 8680023 TI - Congenital ichthyosiform erythroderma (C.I.E.)--ultrastructural evidences of abnormal stratum corneum retention. AB - Congenital ichthyosiform erythroderma (C.I.E.) is a skin disorder which has been considered as a hyperkinetic hyperkeratosis. This study was performed in order to demonstrate that C.I.E. pathogenesis includes both basal cell hyperplasia and abnormal stratum corneum retention. Electron microscopic studies were carried out on 5 cases of C.I.E., clinically and histopathologically diagnosed. The following pathological changes were found in stratum corneum and stratum granulosum: persistence of desmosomes in outer layers of stratum corneum, increased volume of intercorneocyte material, loss of lamellar pattern of Odland bodies, important variability in size and shape of keratohyaline granules, abnormal aggregation of tonofilaments. These constitute ultrastructural evidences of abnormal stratum corneum retention in C.I.E. pathogenesis. PMID- 8680024 TI - Mechanisms involved in differential staining of BrdU substituted chromatids or chromosome regions. AB - PHA stimulated peripheral blood lymphocytes were in vitro labelled with BrdU for 72 h. before cells gathering. Chromosome spreads were obtained by a standard method and some different techniques were used for differential staining of sister chromatids: a) denaturation of BrdU substituted DNA by thermal (90 degrees C) and alkaline (pH 9) treatments: b) UV-induced photolysis of substituted DNA pretreated with intercalating fluorescent agents (acridinorange or 33258 Hoechst) followed by heat treatment (60 degrees C); c) UV-induced photolysis and heat treatment (60 degrees C) without any fluorescent dyes or buffers. With this technique, incorporation banding was also obtained in cells labelled with high concentrations of BrdU during the last round of DNA replication. In all these methods the slides were finally coloured with Giemsa solution. The results obtained with each of the techniques used were compared and the possible molecular mechanisms involved were discussed. Even if many experimental factors could be of importance for revealing the BrdU substituted chromatids or chromosome segments, UV-irradiation and/or heat treatment appear to be mandatory for both differential staining of sister chromatids and for incorporation banding. PMID- 8680025 TI - Chromosomal aberrations in peripheral blood lymphocytes from patients with dermatomyositis and their first-degree relatives. AB - Chromosomal abnormalities in cultured peripheral lymphocytes from 14 dermatomyositis patients and their first-degree relatives were examined. Fifteen normal subjects were also studied. A low increase was observed in the frequency of chromosome aberrations in patients who had not received any medical treatment but not significantly higher versus the controls; the detected chromosome aberrations were in the form of acentric fragments and dicentrics. The patients who had received medication showed an increased frequency of dicentrics, acentric fragments and chromosome breaks, although the frequency was not significantly higher than that of normal subjects. There were no statistically significant differences in the number of chromosome aberrations between men and women patients with dermatomyositis. Only one family member, (2.22%) a boy of 18 years old who suffered from the same disease like his mother, was found to have chromosomal abnormalities in peripheral blood lymphocytes. The presence of autoantibodies found in the sera of Dm patients could not be correlated with the presence of chromosomal anomalies. PMID- 8680026 TI - Micronucleus frequency in peripheral blood lymphocytes from patients with systemic lupus erythematosus. AB - In this study we evaluated the effect of immunosuppressive drug, cyclophosphamide, on lymphocytes from systemic lupus erythematosus (SLE), using the micronucleus test. Micronucleated peripheral blood lymphocytes were analyzed in cytochalasin B treated binucleated lymphocytes. There was significant increase in cells with micronuclei (P < 0.001) in SLE patients who had received cyclophosphamide (10.05 +/- 4.7) in comparison to the patients with SLE who had not received any medical treatment (6.24 +/- 2.42) and control normal subjects (5.48 +/- 2.24). The SLE patients who used cyclophosphamide showed a slightly higher frequency of micronucleated cells in the first 48 h after treatment. The present study emphasized the lack of correlation between age, sex and frequency of micronuclei. PMID- 8680027 TI - Practical study of the correlation between the shape of tumoral vessels (Folberg) and the histologic type of uveal malignant melanoma (Callender). AB - A practical study was carried out on 20 cases of uveal malignant melanoma (UMM), dealing with the histological aspect (according to Callender's classification modified by McLean et al. in 1983) and the shape of the tumor vessels (according to Folberg 1992). A correlation was reported in the literature between the histopathological type of UMM and the vascular aspect. Folberg et al. (1992) reported that a correlation exists between the histopathologic type of UMM and the aspect of the vascularization. Folberg et al. (1992) reported that in spindle cell UMM parallel or normal vessels prevail: in epitheloidal shaped cell UMM arc- or ring-shaped vessels are prevalent; and in mixed MMU parallel, ring- and arc shaped vessels and networks were noticed. The present study aimed at simplifying the correlation between the histopathologic type and vascularization in 5 categories with an easier applicability in the ophthalmologic practice. PMID- 8680029 TI - The effect of ethanol upon early development in mice and rats. XX. The effect of chronic biparental beer intake in mice upon early implantation events. AB - The effect of chronic biparental beer intake upon early implantation in mice was investigated. In order to study the changes taking place in the blastocyst and locally in the uterus at the site of blastocyst attachment, the uteri were tested for the presence of Evans blue areas (Psychoyos test), histochemically for alkaline phosphatase in the stroma and histologically examined. It resulted that the beverage used has a noxious effect upon the implantation process, manifested by: delayed attachment of blastocysts, decreased intensity or absence of decidual reaction, the presence of dead cells in the decidua, the desynchronisation of the implantation process and the diminution or absence of alkaline phosphatase reaction. These results may explain some of our previous observations regarding the late (fetal) effect of preconceptional intake of beer. PMID- 8680028 TI - Electronmicroscopic and histoenzymologic study regarding morphophysiopathologic visceral modifications during open heart operations under extracorporeal circulation. AB - Morphophysiopathologic modifications occurred in myocardium, liver and lung during open heart operations under extracorporeal circulation had been studied using histologic, histoenzymologic, ultrastructural and biochemical investigations. Preexisting myocardic and hepatic lesions subsequent to chronic stasis and hypoxia are accentuated due to the "controlled shock" state induced by extracorporeal circulation. Mitochondrial marker enzymes like SDH, LDH and ATP ase in the membrane are decreasing their levels and hydrolytic enzymes like acid phosphatase, nonspecific esterase (ANAE) and peroxidase are increasing their activity. These disseminated lesions can become irreversible under the conditions of a severe cardial insufficiency and of a prolonged operation. In the lung, the increase in the hydrolytic enzyme activity suggests the processes of phagocytosis and metabolization of red cells by macrophages. PMID- 8680030 TI - Gastrointestinal stromal tumors--a recently defined entity. Literature data and personal case report. AB - Stromal tumors of the gastrointestinal tract are controverted tumoral entities which were recently delimited. They were initially identified by immunohistochemical investigation and processing of the gastrointestinal muscular tumors and of the malignant and benign nervous tumors. Those investigations were subsequently amplified by electronmicroscopic studies and observations during the patient's prognostic follow-up. Within these circumstances, monoclonal tumors responsive to smooth muscular antigens (actin, SMA), to polyclonal antigens reacting to S-100, PGP 9.5, NSE and GEAP were identified. Thus, tumors with a nervous origin known as a gastrointestinal nerve tumors or plexosarcomas were differentiated, taking into account the difficulty of their distinguishing from gastrointestinal tumors (GIST) which also shows multinucleated great cells. There were also difficulties in defining bidirectionally differentiated tumors or those nonresponsive to any antigen, all these elements proving their origin from nondifferentiated mesenchymal cells. These data are presented in a personal case report of a 28-year old woman with an acute anteroenteral invagination due to a gastrointestinal stromal tumor, favorably removed by surgery and with a postoperative outcome. PMID- 8680031 TI - The International Classification of Impairments, Disabilities, and Handicaps (ICIDH): perspectives and developments (Part II) PMID- 8680032 TI - What does morbidity have to do with disability? AB - This study compares and contrasts survey data on disablement from six countries according to their distributions and prevalence of causes and underlying medical conditions, using a framework proposed by the author that includes morbidity as one important determinant of disablement. The main thesis of this paper is that the study of disablement (that is impairments, disabilities and handicaps) should be conceptualized and classified independently of illness and poor health. Disablement, by definition, is not an illness. Using the World Health Organization global definitions of health it is possible to be both healthy and disabled. The assertion, however, that disability is not an illness does not preclude the joint study of morbidity and disablement; nor does it diminish the significance of disease and injury in the explanation of rates of disablement. Disablement is classified through the use of the WHO International Classification of Impairments, Disabilities, and Handicaps (ICIDH). The WHO International Statistical Classification of Diseases and Related Health Problems (ICD-10) is the primary classification used for the study of morbidity. This paper demonstrates that statistical guidelines and instructions on the use of the ICD and the ICIDH, including the development of appropriate short-listings of codes, are needed in order to increase data comparability and to further encourage sound research. National survey data examined are from the United Nations International Disability Statistics Data Base, DISTAT. PMID- 8680033 TI - Measuring disability: the role of the ICIDH. AB - The ICIDH definition of disability has ensured that disability is treated as a continuous variable and therefore as a measurable concept. Even though the suggestions made in the ICIDH for the measurement of severity of disability are applicable only in certain contexts, the ICIDH classification of disabilities, when used flexibly, contributes greatly to the identification of the disabilities whose severities should be measured in both rehabilitation medicine and health interview surveys. There is still a great need to identify and devise instruments which measure the severity of many particular disabilities to an appropriate level of accuracy. Nevertheless, as the reduction of handicap is the ultimate aim of both health service planning and rehabilitation medicine, it is fight that the description and measurement of handicap should be the first priority. PMID- 8680034 TI - The Canadian database on disability issues: a national application of the ICIDH. AB - The need for a national database on persons with disabilities was articulated in early 1980 when members of the Canadian government conducted a nationwide consultation to establish the issues facing persons with disabilities in Canada. This paper will describe the development of this database and show how the International Classification of Impairments, Disabilities, and Handicaps (ICIDH) and the international community played an important role in the successful creation of a database which has been used to improve the quality of life for Canadians with disabilities. The Canadian database on disability issues now includes information from three major surveys: the 1983/84 Canadian Health and Disability Survey (CHDS '83), the 1986/87 Health and Activity Limitation Survey (HALS '86) and the 1991/92 Health and Activity Limitation Survey (HALS '91). PMID- 8680035 TI - Methodological issues in a disablement prevalence study: Mitchells Plain, South Africa. AB - The Mitchells Plain Disability Survey was undertaken primarily to expand a community-based rehabilitation programme in an underprivileged South African urban community. This descriptive survey used a proportional stratified random cluster sampling strategy (sample size 2424), with stratification by suburb and clusters consisting of 15 adjacent plots. A household screening questionnaire (based on the WHO disability questionnaire), identified people who reported health problems affecting their functional ability, while a second follow-up interview confirmed disablement status and obtained a medical, disablement and demographic profile of the disabled and ascertained their needs. This paper discusses different methodological issues related to the survey design and emphasizes the need for standardization of methods in the disablement field. Sampling issues include sample loss in a multi-staged data collection strategy as well as the non-independence of observations when sampling entire house- holds. The trade-off between studying disability across diagnostic, disablement and age categories, and wide confidence intervals for specific prevalence rates, is discussed. Because of the prohibitive costs validation of disablement status is often omitted in a low-budget project (as this one was), weakening the design of such studies. Even if the 'disabled' are correctly identified, the criteria for identifying respondents determine what type of disablement prevalence will be obtained, Different diagnoses reported on screening yielded different positive predictive values of disability--the most debilitating conditions yielding the highest proportion of disabled people. The quality of the data--evaluated through comparisons of initial and repeat screening interviews, and proxy and self reporting--is described. There is a need for disability research to continue developing suitable methods for a wide range of purposes. One such is a 'good enough' survey design which can be implemented rapidly, at relatively low cost, to yield useful results at local level. PMID- 8680036 TI - ICIDH in the calculation of health expectancy. AB - In this paper the use of the ICIDH in the field of calculating health expectancies is examined. The health indicator 'health expectancy' is an adaptation of the indicator 'life expectancy'; health expectancies reflect the expected number of years lived in good health in a population. To date, health expectancies have been calculated for many countries. However, many different concepts of health have been used. The theoretical framework of the ICIDH has been proposed to harmonize the calculations of health expectancy. In this paper we explore this idea. To examine the possibility to use the ICIDH framework, we calculated health expectancies for The Netherlands, trying to follow the ICIDH. Subsequently, we reviewed the health expectancies calculated for other countries, and tried to fit those into the ICIDH framework. Much of the work done could be fitted into this framework. An important exception, however, are those health expectancies that try to capture a concept of health that is more compassing than impairments, disabilities and handicaps. Although it is possible to classify different health expectancies according to the ICIDH, this does not make health expectancies within a certain class comparable. Both the calculations carried out for The Netherlands, and the comparison of instruments used internationally, show that the instruments used to measure, for example, disabilities, yield results which are not comparable. Continuing efforts to standardize measurement instruments are needed. PMID- 8680037 TI - Croatian initial experience with the suitability of the ICIDH for classifying health status. AB - As consequences of disease and disorders cannot be expressed with the International Classification of Diseases (ICD), the International Classification of Impairments, Disabilities, and Handicaps (ICIDH) was tested on a data sample of 1800 persons from the Croatian Register of Psychophysical Development Disorders and Other Disabilities (CRPDOD). Persons with either a visceral impairment, skeletal impairment, disfiguring impairment or one from the group of generalized, sensory and other impairments, were selected. Despite favourable results some amendments are suggested. These involve several examples of coding practice, modified elaboration of consciousness and continence impairments, newly created categories and subcategories in classifications I and D, as well as common codes for cases having several disability categories simultaneously. PMID- 8680038 TI - Cross-coding from the Swiss Disability Insurance listing to the ICIDH. AB - It has been suggested that converting, via a process of cross-coding, the listing used by the Swiss Disability Insurance (SDI) for their statistics into codes of the International Classification of Impairments, Disabilities, and Handicaps (ICIDH) would improve the quality and international comparability of disability statistics for Switzerland. Using two different methods we tested the feasibility of this cross-coding on a consecutive sample of 204 insured persons, examined at one of the medical observation centres of the SDI. Cross-coding is impossible, for all practical purposes, in a proportion varying between 30% and 100%, depending on the method of cross-coding, the level of disablement and the required quality of the resulting codes. Failure is due to lack of validity of the SDI codes: diseases are poorly described, consequences of diseases (disability and handicap, including loss of earning capacity), insufficiently described or not at all. Assessment of disability and handicap would provide necessary information for the SDI. It is concluded that the SDI should promote the use of the ICIDH in Switzerland, especially among medical practitioners whose assessment of work capacity is the key element in the decision to award benefits or propose rehabilitation. PMID- 8680039 TI - Disablement resulting from motorcycle crashes. AB - This retrospective study describes the nature and severity of disablement resulting from motorcycle crashes (both traffic and non-traffic). Two hundred and fifty motorcycle crash victims were randomly selected from the total population of motorcycle crash victims (n = 1510) who had received compensation for disablement in the year ending 31 March 1990. Information on the nature and extent of disablement was obtained from official accident compensation files and coded according to the International Classification of Impairments, Disabilities, and Handicaps. Extremity injuries predominated, especially to the lower limb. The majority of these were fractures. Most commonly impairments occurred in the areas of 'skeletal', 'disfiguring' and 'generalized' impairment. Mechanical impairment of a limb was reported in 68% of cases, often with associated disfigurement. Disability mostly involved problems with locomotion and problems coping with physical stresses at work. Occupational handicap was the most common handicap reported, with mobility handicap the next most common. The shortcomings of this study included its retrospective design and the variable quality of the information on disablement. It was most likely, though, that these factors contributed to an underestimation of disablement in the study group. PMID- 8680040 TI - The consequences of asthma in terms of the ICIDH and the role of physical activities. AB - The consequences of asthma are described in accordance with the definitions of the three levels of the International Classification of Impairments, Disabilities and Handicaps (ICIDH). Because asthma is a chronic disease, health care should emphasize how to cope with it. The goal of physical activities for persons with asthma is the learning of skills which can be used to control the physical situation. Breathing therapy and therapeutic drugs make it possible for the person to control the physical condition. In physical education and sport training, patients are taught to use these means in physically strenuous situations. PMID- 8680041 TI - An interdisciplinary model for the rehabilitation of visually impaired and blind people: application of the ICIDH concepts. AB - In rehabilitation centres for visually impaired and blind people the need for a common, conceptual framework was felt by the various disciplines working there. As a consequence an interdisciplinary model has been developed. This article gives a brief description of the two elements of the model: the concepts of the ICIDH and the path of rehabilitation. The classifications of the ICIDH have been adapted to suit our purposes better. The concepts of impairment, disability, and handicap can serve as a framework during an interdisciplinary consultation. In this context a visual profile, which contains information gained from the assessments done by the various disciplines, will be discussed. The visual profile makes it possible to gain general insight into the client's visual problems from all perspectives, which enables the team to draw up an interdisciplinary rehabilitation diagnosis. At present the model is being tested by practical experience in three regional rehabilitation centres for visually impaired and blind people. The model gives an outline of the application of the ICIDH concepts, and leaves open the possibility of working on the various aspects in more detail. PMID- 8680042 TI - Functional assessment of Chinese children with the ABILITIES index. AB - The diagnosis and classification of children with disabilities are persistent concerns in paediatric and habilitative services. These concerns are magnified in international contexts and restrict comparative research and policy development. Even within classifications such as mental retardation, hearing impairment and physical impairment, children can vary widely in the nature and severity of manifested conditions. In the fields of disability and rehabilitation there is a growing interest in functional measurement. Accompanying this awareness is a corresponding recognition of the value of classification approaches which are compatible with the WHO framework of the International Classification of Impairments, Disabilities, and Handicaps. This paper examines issues pertaining to the classification of children with disabilities and describes the development of the ABILITIES Index, a functional assessment measure yielding a profile of individual characteristics. The cross-cultural applicability of the measure is documented on the basis of data for children in the People's Republic of China. PMID- 8680043 TI - Frontiers in immunobiology and immunosuppression. Proceedings of a symposium. Minneapolis, Minnesota, August 26-27, 1995. PMID- 8680045 TI - Costimulation and its role in organ transplantation. AB - Antigen-specific T-cell activation depends initially on the interaction of the T cell receptor with peptide/major histocompatibility complex (MHC). In addition, a costimulatory signal, mediated by distinct cell surface accessory molecules such as CD28, is required for complete T-cell activation. One essential element of the CD28 costimulatory system that makes it an attractive target for immunotherapy is the selective effect of CD28 antagonists on activated T cells. Only cells encountering antigen presenting cells (APCs) without the appropriate CD28 ligand will be rendered functionally inactive as desired for any next-generation immuno suppressive drug. This brief review will focus on the role of CD28/B7 interactions in regulating organ graft rejection. In vitro and in vivo studies will describe the use of a soluble fusion protein antagonist of CD28/B7 (CTLA 4Ig), anti-B7 MAbs, and genetically altered CD28 "knockout" mice to study immune responses. The studies suggest that: 1) CTLA-4Ig induces long-term, antigen specific unresponsiveness in vivo; 2) two distinct ligands for CD28, B7-1 and B7 2, are differentially regulated during immune responses; and 3) both B7-1 and B7 2 costimulatory molecules are active, in vivo, although B7-2 plays a clearly dominant role in murine allograft rejection. PMID- 8680044 TI - Local cellular immunology of experimental transplant vascular sclerosis. AB - We have observed that most C57BL/6 (H-2b) recipients of DBA/2 (H-2d) heterotopic cardiac allografts retain their grafts for more than 60 days following treatment with anti-CD4 MAb (GK1.5), anti-VCAM-1 MAb (M/K-2), or gallium nitrate (GN). Nevertheless, many ongoing alloimmune responses are detectable more than 60 d post-transplant in these mice: (i) continuous inflammatory endothelial activation and low-grade cellular infiltration in the graft, (ii) modest frequencies of donor-reactive T cells in the graft and spleen, (iii) mRNA for various cytokines (IL-1, IL-2, IL-4, IL-6, IFN gamma, TNF alpha, TGF beta) in the graft, (iv) high levels of donor-reactive alloantibody in the circulation, (v) variable development of allogeneic chimerism in the recipient, and (vi) development of interstitial fibrosis and neointimal hyperplasia in the graft. Despite the widely differing targets of GK1.5, M/K-2, and GN, their therapeutic outcomes appear to be identical. Taken together, these observations suggest that long-term allograft survival in these experimental systems is not the result of immune acceptance, i.e. allogeneic tolerance. Although these therapies interrupt the destructive progression of acute rejection, they permit many related immune responses in the graft recipient in association with the development of chronic rejection-like histopathology. PMID- 8680046 TI - Chimerism after organ transplantation: is there any clinical significance? AB - Historically, attempts to clinically correlate microchimerism and cytotoxic T lymphocyte (CTL) dysfunction with allograft tolerance (via a "veto effect") have not been highly successful. We have re-examined this question by studying the case of JB, a maternal-renal allograft recipient who did not develop symptoms of acute or chronic rejection after ceasing immunotherapy of his own volition. A biopsy showed immunologic activity in the allograft that did not progress to full scale rejection. A polymerase chain reaction (PCR) assay showed traces of donor derived DNA in JB's peripheral blood leukocytes (PBL), which also were shown to display a "split tolerance" toward donor stimulators (MLC+/CTL-) in vitro. Subsequent experiments in our laboratory conclusively demonstrated that JB's suppressed CTL function was donor-specific and that small numbers of donor derived cells in his PBL could cause the CTL suppression similar to the "veto effect" observed by other researchers. This confirmed the clinical link between microchimerism, CTL dysfunction, and allograft tolerance in a single patient. We propose a testable model for this unusual type of allograft tolerance. The model is based on donor-derived predendritic cell lineages that survive in the host and that exert a powerful "veto effect" by interfering with the normal development and function of donor-specific CD8+ T cells, perhaps even leading to their apoptosis. Additional experiments to test the details of our hypothetical model are under way. PMID- 8680048 TI - Genetic engineering of endothelial cells to ameliorate xenograft rejection. AB - The prospect of clinical xenotransplantation using pigs as donors (a discordant combination) holds out a potential solution to the shortage of human organs, as well as potentially widening the spectrum of patients who might benefit from a transplant procedure. While generalized clinical trials of pig to human organ transplantation (of immediately vascularized organs, such as the heart or kidney) will probably not occur in the very near future, there are reasons for optimism that this approach, deemed impossible a few decades ago, may find its way to the bedside. This optimism is based on two factors: First, a great increase in our understanding of the probable underlying causes of rejection and, second, the development of a number of important therapeutic approaches, including genetic manipulation of the donor animal, to tackle the manifold problems inherent in rejection of such a transplanted organ. PMID- 8680047 TI - Molecular mechanisms of new immunosuppressants. AB - Maintenance immunosuppressive drugs act by partially blocking rate-limiting steps in the immune response. The new maintenance immunosuppressive drugs are either inhibitors of de novo synthesis of nucleotides (purines or pyrimidines), or are immunophilin-binding drugs that inhibit signal transduction in lymphocytes. The new inhibitors of de novo nucleotide synthesis include mycophenolate mofetil (MMF), mizoribine (MZ), brequinar (BQR), and leflunomide (LEF). MMF and MZ act to inhibit de novo purine synthesis, by inhibition of inosine monophosphate dehydrogenase (IMPDH). They create a selective immunodeficiency in T and B lymphocytes. MMF is hydrolyzed to mycophenolic acid (MPA), an uncompetitive inhibitor of IMPDH. MPA reduces the pools of guanine nucleotides, and increases some adenine nucleotides, inhibiting the cell cycle. Thus the number of specific effector T and B lymphocytes is reduced by limiting clonal expansion. MZ is a competitive inhibitor of IMPDH, which creates a similar defect. The relative clinical effectiveness of MMF versus MZ is not known. MMF has been approved in a number of countries; MZ has been approved in Japan. The inhibitors of de novo pyrimidine synthesis (BQR, LEF) act on the enzyme dehydroorotate dehydrogenase. Neither is currently in clinical trials in transplantation. The new immunophilin binding drugs inhibit either the calcium-dependent phosphatase calcineurin (CN) [tacrolimus (or FK-506) and the microemulsion form of cyclosporine (CsA)] or signaling from growth factor receptors [rapamycin (sirolimus)]. Tacrolimus binds to FK binding protein-12 (FKBP-12) to create a complex that inhibits CN. CsA binds to cyclophilin to create a complex that inhibits CN. Inhibition of CN prevents activation of cytokine genes in T cells. The relative clinic effectiveness of tacrolimus versus microemulsion CsA is unknown. Rapamycin inhibits signaling from growth factor receptors, such as IL-2R. Rapamycin binds to FKBP to create a complex that engages proteins called TOR (target of rapamycin), or RAFT (rapamycin and FKBP target), which may be kinases. The result is a block in the ability of cytokine receptors to activate cell cycling, interfering with clonal expression. Deoxyspergualin, a parenteral drug in development for induction or antirejection therapy, may inhibit intracellular chaperoning by Hsc70, a member of the heat shock protein family. It may have its principal effect by inhibiting the activation of transcription factor NF-kappa B in antigen-presenting cells and monocytes. PMID- 8680049 TI - Mycophenolate mofetil for maintenance therapy in kidney transplantation. AB - Mycophenolate mofetil (MMF) is a new immunosuppressive drug that selectively inhibits de novo purine synthesis. It has been tested in three large double-blind controlled trials for the prevention of rejection in renal transplant patients. These studies indicate that the use of MMF dramatically decreases the incidence of biopsy-proven rejection, the use of multiple courses of steroids for rejection, and the use of antilymphocyte preparations for treatment of rejection. The drug was well tolerated with an acceptable safety profile. The main side effects were gastrointestinal (nausea, vomiting, diarrhea), but seldom resulted in the cessation of drug therapy. Hematologic side effects similar to those with azathioprine occurred and were reversible. There was a slight increase in CMV invasive disease with the use of MMF, but no deaths. Rates of malignancy were within published ranges for transplant recipients. Mycophenolate mofetil is a safe and efficacious drug for prevention of rejection in kidney transplant recipients. PMID- 8680050 TI - Rescue therapy with mycophenolate mofetil. The Mycophenolate Mofetil Renal Refractory Rejection Study Group. AB - Research with human transplant recipients has shown that mycophenolate mofetil (MMF) is a powerful and selective immunosuppressant for maintenance therapy following renal transplantation. An additional body of work suggests that it might also be a valuable tool for arresting ongoing rejection episodes. One randomized, open-label, multicenter study has compared the efficacy and safety of MMF administered with cyclosporine and maintenance corticosteroids versus high dose intravenous corticosteroids (i.v. steroids) and conventional triple therapy, over a 6-month postenrollment period, for the treatment of refractory acute cellular renal allograft rejection. Treatment with MMF resulted in a 45% reduction in graft loss and death by 6 months postenrollment. (The number of deaths were the same in both treatment groups during the 6-month postenrollment period.) Treatment with MMF also significantly reduced the risk of experiencing a subsequent biopsy-proven rejection episode or treatment failure by almost 50%. The number of patients receiving one or more full courses of antilymphocyte therapy for a rejection episode subsequent to enrollment was more than twofold greater in the i.v. steroid group compared with the MMF group. Overall, and in most of the body systems, more adverse events were reported for patients in the MMF group, but the overall benefit-risk ratio for MMF supports its use with cyclosporine and maintenance corticosteroids for the treatment of refractory acute cellular renal allograft rejection. PMID- 8680051 TI - Mycophenolate mofetil (MMF) in heart transplantation: rejection prevention and treatment. AB - Mycophenolate mofetil (MMF), the morpholinoethylester of mycophenolic acid, inhibits the de novo pathway for purine synthesis. Evidence suggests that MMF suppresses lymphocyte function more than that of neutrophils, erythrocytes, and other rapidly dividing cell lines that can utilize salvage pathways for purine synthesis. While rigorous efficacy data await the completion of an ongoing, multicenter, prospectively randomized, placebo-controlled trial, long-term safety data are, however, available from numerous uncontrolled trials in cardiac transplantation. Dose-ranging trials in 49 heart recipients suggest that doses > or = 4000 mg/d are associated with significant, reversible gastrointestinal toxicity when compared with doses < 4000 mg/d (p < 0.001). Patients receiving > or = 1000 mg/d may have fewer rejection episodes. Even in the long term, changing from azathioprine to MMF is associated with increases in hematocrit (p < 0.001), total WBC count (p < 0.005), and absolute neutrophil count (p < 0.005). Successful use of MMF in refractory cardiac allograft rejection suggests an advantage over azathioprine. MMF is safe and appears to be at least as effective as azathioprine for immunosuppression following heart transplantation. PMID- 8680052 TI - Mycophenolate mofetil in liver transplantation. AB - PHARMACOKINETIC STUDIES. Eleven patients undergoing orthotopic liver transplantation (OLT) received mycophenolate mofetil (MMF) orally for prevention of rejection. Additional immunosuppressives used were cyclosporine (CsA) and steroids. Doses ranged from 3.5 to 4.5 g/d. Pharmacokinetic studies were performed between 11 d and 6 months after OLT. The Cmax and Tmax for mycophenolic acid (MPA) were 3.6-35.2 micrograms/mL and 0.5-4 h, respectively, and did not significantly change over 6 months. Oral clearance of MMF (dose of MMF/area under the curve for MPA) between d 11 and d 17 was significantly lower compared with d 21. Biliary diversion did not affect clearance. RESCUE THERAPY. Twenty-three patients with steroid- and OKT3-resistant acute rejection were converted to MMF (2-3.5 g/d) at a mean of 20 wk after OLT. Twenty-one patients responded, 14 with resolution of rejection and 7 with improvement. Sixteen patients remained on the drug. Eight patients had 14 infections, with cytomegalovirus (CMV) being the most common. The most common adverse events were diarrhea (4 patients) and leukopenia (3 patients). Four patients with chronic rejection all failed to improve after conversion to MMF. DOSE ESCALATION STUDIES--PRIMARY THERAPY. Seventeen patients received 3.5-5.0 g of MMF per d orally with reduced-dose CsA and prednisone as primary prophylaxis of rejection after OLT. Target CsA levels were 125-175 (whole blood high-performance liquid chromatography). Two patients were terminated from the study for possible study drug-related reasons: pancreatitis in one and unsatisfactory response in the other. Gastrointestinal side effects were the most common (10 patients), including gastritis, esophagitis, and duodenal ulcer. Two patients developed leukopenia and/or pancytopenia. Of 5 culture-proven infections, 2 were CMV. After 3 months of follow-up, 7 of 17 patients had no rejection. Of 10 patients with rejection, 7 were treated with pulse steroids and 3 required OKT3. DUAL THERAPY WITH MMF AND STEROIDS. Four patients with rejection and unacceptable toxicity secondary to either CsA or FK-506 were treated with MMF 2-4 g/d and 20 mg of prednisone. After 325-500 d of follow-up, 3 had resolved their rejection episode and 1 had recurrent rejection and was restarted on low dose CsA. CONCLUSION. MMF is a promising new immunosuppressive agent for both treatment of established rejection and primary rejection prophylaxis after OLT. More studies are needed to define its role further. PMID- 8680053 TI - Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF). AB - Mycophenolate mofetil (MMF) is a novel immunosuppressive drug that shows promise in preventing the rejection of organ allografts and in the treatment of ongoing rejection. Orally administered MMF is hydrolyzed by esterases in the intestine and blood to release mycophenolic acid (MPA), a potent, selective, noncompetitive inhibitor of the type 2 isoform of inosine monophosphate dehydroxygenase (IMPDH) expressed in activated human T and B lymphocytes. By inhibiting IMPDH, MPA depletes the pool of dGTP required for DNA synthesis. MPA has a more potent cytostatic effect on lymphocytes than on other cell types, and this is the principal mechanism by which immunosuppressive activity is exerted. MPA also depletes pools of GTP in human lymphocytes and monocytes, thereby inhibiting the synthesis of fucose- and mannose-containing saccharide components of membrane glycoproteins. These are recognized by the family of adhesion molecules termed selectins. By this mechanism, MPA could decrease the recruitment of lymphocytes and monocytes into sites of graft rejection. In addition to preventing allograft rejection, MMF suppresses graft-versus-host reactions in lethal and nonlethal murine models. MMF inhibits primary antibody responses more efficiently than secondary responses. MPA inhibits the proliferation of human B lymphocytes transformed by Epstein-Barr virus and is not mutagenic. Clinically attainable concentrations of MPA suppress the proliferation of human arterial smooth muscle cells. These two properties of MPA may decrease the risk of lymphoma development and proliferative arteriopathy in long-term recipients of MMF. PMID- 8680054 TI - From mice to man: the preclinical history of mycophenolate mofetil. AB - In vitro studies demonstrating that mycophenolic acid (MPA) held promise as a powerful immunosuppressant led to a series of in vivo studies to further evaluate this interesting new agent. Experiments in mice showed that MPA had powerful lymphocyte-selective immunosuppressive effects. A prodrug of MPA, mycophenolate mofetil (MMF), was developed to improve bioavailability on oral administration. Numerous tests demonstrated that MMF, alone or in combination with other immunosuppressives, prolonged allograft survival of various organs in several species and may be useful for reversing ongoing rejection. MMF also was found to be useful in prolonging xenograft survival. These animal experiments indicated that MMF had the benefit of relatively low toxicity and a good safety profile and drove early clinical trials of MMF. These trials showed that MMF is relatively safe and well tolerated in man and is of potential use for the prevention and treatment of acute allograft rejection. This article describes the preclinical history of the development of MMF, concentrating on the animal experiments and phase I and II trials that preceded the large-scale clinical testing of this new immunosuppressant. PMID- 8680056 TI - [Diagnostic, prognostic and therapeutic optimization in oncology. XIIth Grenoble Oncology meeting. 30-31 March 1995]. PMID- 8680055 TI - New concepts in tolerance. AB - Increasing the immunologic specificity of immunosuppressive therapies used to prevent graft rejection is one of the fundamental aims of research designed to develop new approaches for immunosuppression. The objective of work in this area is to identify both strategies and the mechanisms responsible for the induction of tolerance to alloantigens in vivo. Three topics in this area of transplantation immunobiology are considered: (i) The tools available for investigating the induction of tolerance to alloantigens, including T-cell clones, transgenic mice, and neonatal and adult models of tolerance induction. (ii) Strategies for tolerance induction that are being explored in experimental models and in clinical transplantation. These strategies can be divided into two categories: those that aim to induce tolerance in the long term after transplantation and those that aim to induce unresponsiveness at the time of grafting. (iii) The mechanisms responsible for the induction of tolerance to alloantigens. Five nonmutually exclusive hypotheses have been proposed to explain the induction of peripheral tolerance. These are, in broad terms, deletion, anergy, ignorance or helplessness, exhaustion and suppression. The immune status of the recipient may influence which of these mechanisms operates in any particular situation. What is apparent from all studies is that tolerance induction is a dynamic process, and any or all of these mechanisms may be operating at different stages of the induction and maintenance process. PMID- 8680057 TI - Quantitative microscopy and tumour cell proliferation. AB - The number of cell probes is rapidly increasing. During the last few years it has become possible to label total nuclear DNA (Feulgen), synthesized DNA (BrdU), specific A/T versus G/C rich DNA, cell cycle proteins (PCNA, Ki67), hormonal receptors (ER, PR, EGF), cdc genes and gene primary transcripts, etc. Taking advantage of this roster of cellular probes to assess cell kinetics in normal and malignant tissues implies not only quantitating their amount per cell but also analysing their intra-cellular respective distribution and inter-cellular variation. Image cytometry is the tool of choice for this purpose provided the quantitative results are properly interpreted. Confusions are often made between the respective meaning of i) reduced cell cycle speed (cell cycle duration), ii) increased proportion of proliferative cells (growth fraction), and iii) fraction of cells in S phase (SPF) and mitotic index (proportion of mitoses) which all tune the cell proliferative activity. The contribution of these biological cell population features to tumour growth is illustrated. Examples based on image cytometry are presented to define the individual tumour cell proliferation profile and tumour heterogeneity for proliferation profiles. It will be finely demonstrated how quantitative microscopy can turn the 'conventional static histological picture' of a tumour into a 'functional picture' that might support decision for therapeutic strategies. PMID- 8680058 TI - [Principles of flow cytometry]. AB - Flow cytometry (FCM) allows the simultaneous measurement of different parameters in a population of cell or sub-cellular particles, which are individually analysed at a rate of 500 to 5,000 objects/second. Results are displayed as univariate or bivariate histograms, giving the distribution of the population in relation to the studied parameters. Moreover, FCM offers the possibility to physically sort the sub populations defined by the analysis. PMID- 8680059 TI - [Image information systems]. AB - The notion of image information system (IIS) is introducted, based on an on-going experience in Grenoble's university hospital. The objectives and of a IIS are clarified, and the basic principles of its architecture are presented. PMID- 8680060 TI - [Dynamic characterization of the growth of brain tumors based on image sequences of nuclear magnetic resonance]. AB - The evolution of a high grade glioblastoma of a patient undergoing radio-therapy has been analysed by considering a mathematical model which simulates the brain tumour growth within a two-dimensional domain defined by the brain and ventricles geometry. This simulated behaviour was compared with morphological data obtained from successive nuclear magnetic resonance scans of the patient. The model parameters include the proliferation rate and the diffusion coefficient of the tumour cells as well as their sensitivity to the irradiation. They were estimated using optimisation techniques to minimise the distance between simulated tumour area and scan data from different brain sections. The relevance of this quantitative estimation for the prognosis and for the consideration of additional parameters in the pre and post therapeutic evaluation of glioma is discussed. PMID- 8680061 TI - [Progress in tomodensitometry. Applications in cancerology]. AB - Since 1992, spiral CT scanners replace conventional CT units in radiology departments. In the first part of this paper, we present some technical considerations concerning spiral CT (continuous rotation and emission of the source-detector; continuous translation of the patient at a constant rate through the gantry), as well as advantages and limitations of volumic acquisition. The main advantages can be summerized as: reduction of the acquisition time, optimization of contrast enhancement with intravenous opacification, and post processing allowing retrospective creation of overlapping images, multiplanar reconstructions, and 3-D reconstructions. Spiral CT improves lesions detection and characterization. Disadvantages are due to contrast media injection and radiation exposure. Then we describe clinical applications in the carcinologic field concerning pharyngo-laryngeal tumors, bronchogenic carcinoma, mediastinal tumors, pulmonary nodules, sub-diaphragmatic tumors. However, tumors of brain, spine, bone, and soft tissue are better explorated with MRI. Authors conclude on the future improvements of spiral CT. PMID- 8680062 TI - [A new X-ray source for medical imaging and radiotherapy research: synchrotron radiation]. AB - Whether for diagnosis or therapeutic purposes, X-rays have many applications in medicine. Synchrotron Radiation sources open new perspectives. This has already been the case for a number of years in molecular and cellular biology where the scope of absorption and diffraction work has been greatly extended. This could also be the case for medical imaging and radiotherapy where the characteristics of the beam (collimation, stability, flux) allow new approaches in the energy range of radiological X-rays, namely between 30 keV and 100 keV. Such a source exists today in Grenoble, with the European Synchrotron Radiation Facility (ESRF). The opening of a beamline dedicated to medical research for whole European scientific community is planned for the end of 1996. This beamline, coupled with the "microbeam" beamlines, will cover medical imaging (angiography, tomodensitometry, microtomography, X-ray microscopy) as well as radiotherapy. PMID- 8680063 TI - [Value of image cytometry to oncologic diagnosis and prognosis]. AB - For almost 100 years, malignant diseases diagnoses have been made by subjective evaluation of morphologic criteria in stained cellular preparations or tissue sections. This diagnosis remains the basis and the first step of any oncological work. Cell quantification by image analysis has only gained scientific but not yet routine application. However it is useful in screening, diagnosis and prognosis of malignant tumors. SCREENING: DNA quantification allows the distinction between non specific abnormalities and atypias considered as pre cancerous lesions in cervical neoplasia. DIAGNOSIS: althought not often used, image cytometry may be useful for the diagnosis between benign and malignant lesions as we demonstrated it in mammary tumors, studied after Feulgen staining of imprints. PROGNOSIS: grading of malignancy can be done using image cytometry. Numerous parameters have been found useful for the prognosis evaluation of various tumors. For breast tumors, these are: nuclear or nucleolar area, DNA content, proliferating rate, hormone receptors positive cell percentage.... Quantification of oncogene amplification or chromosomal aberrations are under evaluation. Thus, computerised microscopy is now a necessary tool for the pathologist. PMID- 8680064 TI - [Design, management and handling of a randomized trial]. AB - Before a newly developed treatment starts being used in practice it must pass through three clinical trial steps, called phase I, II, and III. The subject of this presentation are the phase III clinical trials. Their goal is to compare the treatment under study to the currently standard treatment (either to show the superiority of the new treatment, either to show it is equivalent in terms of efficacy with the standard one). The only way of ensuring a valid comparison is to perform a randomised clinical trial, meaning that for each patient the treatment is assigned randomly by a mechanism unknown by the investigator(s). Each clinical trial must start with the creation of a protocol. The protocol is a document that describes in details all the aspects of performing the trial. Normally, once the first patient is registered into the trial, the protocol shouldn't be modified any more. That's why it must foresee every problem that might show up during the trial, which makes it a difficult task. A crucial question which has to be answered before the trial begins is the 'sample size'- the number of patients needed. This number is based on several parameter. A bad choice of one of these parameters can completely compromise a trial. All data handling and administrative tasks are usually handled by data managers. They have a crucial role in collecting and validating all the data, and the quality of the whole clinical trial is closely related to the quality of their work. To help them in their tasks, a suitable computer system can be of invaluable help. One of the last steps of the trial is the statistical analysis itself. The statistical tests to be used must be predefined in the protocol and depend mainly on the end points used for assessing the efficacy. To avoid all bias the analyses must be done using the 'intent to treat' principle. Many problems can show up during the trial: ineligible patients or lost to follow up, protocol violations, etc. A well written and well respected protocol should help reducing this list to a minimum. Finally, all this work will only be useful if the results are widely presented in a clear and pertinent way. If the medical community is not convinced by the results, all those resources would have been wasted. PMID- 8680065 TI - Paradigm: towards an integrated platform for registration of patients in clinical trials. AB - A generalised registration-randomisation package, known as paradigm, has been developed by the Netherlands Cancer Institute and the MRC Cancer Trials Office initiated in association with the EORTC within the EuroCODE project and partially funded by the European Community. This randomisation software takes into account requirements of four major data centres in Belgium, France, The Netherlands and the UK and is suitable for use at further European Clinical Trial data centres to enable remote entry of patients into trials. The system became operational at the start of 1994, and is now in use at three hospitals and data centres. PMID- 8680066 TI - A computer based program to assist in adjuvant therapy decisions for individual breast cancer patients. AB - This paper describes a personal computer based tool to aid in decision making about whether a woman should receive adjuvant therapy for breast cancer. This tool can assist in engaging women with primary breast cancer in the discussion about: 1) her risk of breast cancer related mortality if she receives only local control measures, but no systemic adjuvant therapy, 2) how much receiving adjuvant therapy may reduce this risk, and 3) what the impact of receiving the adjuvant systemic therapy is in terms of survival. The tool utilizes life table analytical techniques to project outcomes after entry of patient age (used to calculate natural mortality rates), estimated risk of breast cancer related mortality (with a help tool allowing the physician to use estimates based on national database information), and estimate of the efficacy of adjuvant chemotherapy (with included tables of estimates based on the Early Breast Cancer Trialists' meta-analysis). Computer based tools can serve as valuable aids in patient and physician education, and the process of informed decision making. PMID- 8680067 TI - [Contribution of computers and telepathology in cancerologic pathology]. AB - The histologic or cytologic diagnosis of a tumoral lesion may be sometimes very difficult to do even for a senior pathologist. Nevertheless, it is necessary to recognize a malignant process with reliability and security. The usual way to solve some difficult problems is firstly to search documentations in books or atlas and then to discuss the slides in common. Sometimes it is necessary to dispatch the original documents to a national or international expert. Now computers are used in any private or public department of Pathology. Some new informatics developments allow to send good digitized pictures to an expert and to discuss with him. It is also possible to elaborate a data base of digitized images which can be edited on CD-Rom. We describe the development and the use of these technics in France and elsewhere. It seems that they could have an increasing role for quality assurance in tumoral pathology. PMID- 8680068 TI - [Place of computer-assisted surgery in the evaluation of lymphatics metastases in pelvic cancers. Exploration by retroperitoneoscopy]. AB - Extraperitoneal pelvioscopy is a surgical endoscopy without insufflation which enables exploration of the extraperitoneal space in order to obtain biopsy specimens of adenopathies and tumors. 189 extraperitoneal endoscopy have been performed since 1976. When made through an iliac approach, the Extraperitoneal Endoscopy explores iliac and pelvic lymph nodes. It is an indication when checking the extension of uterine, prostatic and bladder cancers. Recently, a system of computerized assistance has been added to the initial method. Its aim is to guide the movements of the surgical tool when the indication is difficult: overweight patient, small tumors, risky tumoral environment. The basic principle is to show recalculated RMI or CT scan sections of the patient during the intervention, on which appear in real time the positions of the endoscope and that of the target to biopsy. The authors describe the technical ways of the method, the system of tridimensional localisation included in the operating room and the sort of interface given to the surgeon. In the future, the realisation of a simulator of intervention will allow diffusion and teaching of this intervention. PMID- 8680069 TI - [Value of image guided neurosurgery in neuro-oncology]. AB - Brain tumor surgery, stereotactic or by resection, is based on the precise knowledge of the spatial position of the target and of their relationships with the normal brain structures. Modern computed neuroimaging allows image guidance of neurosurgical procedures, using robots driven by the coordinates of the target and of the entry point. We have developped a stereotactic robot as well as a robotized microscope which are guided from digitized images. They are used in routine daily practice and will become part of the standard neurosurgical equipment. PMID- 8680070 TI - [Radiosurgery by linear accelerators in the treatment of 84 arteriovenous malformations]. AB - We have treated in 1990 and 1991, 84 arteriovenous malformations (AVMs) by radiosurgery. Irradiation was realized by 5 to 7 arcs with 15 MV X rays circular minibeams of a GE-CGR Saturne 43 Linac diameter, at 100 cm 6 to 20 mm; the Betti arm chair and the Talairach frame. The prescribed peripheral dose containing the nidus was 25 Gy corresponding to the 60-70% isodose range (100% was the maximum dose). For the irradiation planning we used the 'associated targets methodology' and the ARTEMIS-3D TPS, both of which have been developped in the radiotherapy departement of the Tenon hospital. Evaluation was performed in February 1995, the follow-up range was 38 to 62 months. In 1990, 46 cases were treated for cure and were all evaluable, whereas in 1991, among the 38 irradiated cases one patient was not evaluable because of lack of arteriographic control. Thus this series consisted in 84 evaluable cases. The overall obliteration rate was 65/84 (78%), partial obliteration was seen in 18/84 (21%) and no change in 1 case. According to AVM volume, obliteration rate was: AVMs < 4200 mm3: 82% (46/56). For lesions > 4200 mm3 it was 68% (19/28). In one isocenter irradiation, the obliteration rate was 42/47 (89%); whereas it was 23/37 (62%) in multi-isocenters treatments. The obliteration rate was better for not previously treated cases: 39/44 (89%) than for previously treated nidus (mostly embolisation) 65% (26/40). In 23 spheroid AVMs obliteration rate was 87% (20/23) in 43 ellipsoid AVMs the obliteration rate was 77% (33/43); and in irregular rounded nidus, it was 67% (12/18). The peripheral dose of 25 Gys has been used in 78 cases (93%), the obliteration rate was 63/78 (81%); in 6 other cases treated with 15-23.5 Gy, it was 2/6 (33%). We observed two recurrences of haemorrhage at 4 and 6 months after radiosurgery (recurrent haemorrhage rate 2/84 = 2.4%) with total neurological recovery in one of the two patients. One patient died of myocardial infarctus 11 months after radiosurgery (there was a partial obliteration of his AVM at 8 months after radiosurgery). There was no AVM related death. One patient developed an epilepsy. PMID- 8680071 TI - [3-D conformal radiotherapy procedure and registration of pre- and intra radiotherapeutic data]. AB - The authors describe the different steps of 3-D conformal external irradiation. They mention as well two procedures of isocentric repositioning which are mandatory for the matching of anatomical data: the first one is acquired before the simulation and the second one just before the radiotherapy session. PMID- 8680072 TI - Aspects of enhanced three-dimensional radiotherapy treatment planning. AB - Advances in computer technology have led to the availability of sophisticated three-dimensional treatment planning systems for use in many radiotherapy centers. However, additional complexity in both the planning and delivery of treatments has accompanied their use. Thus, even more computer-aided tools are beginning to appear to address these needs. Aspects of recent enhancements to 3-D treatment planning at the University of Michigan are presented. PMID- 8680073 TI - Electronic portal imaging. AB - In our institute, we have developed an electronic portal imaging system based on a matrix of 256 x 256 ionisation chambers. By improvements to the electronics, the system produces images with the same quality as the original system but 3-10 times faster. Software for automatic image analysis has been applied to more than 10,000 images over the last two years. Using an off-line correction strategy, the systematic patient set-up error has been limited to 5 mm or less for 98% of the patients treated for prostate cancer. PMID- 8680075 TI - [Claude Lagarde]. PMID- 8680074 TI - [Contribution of computers to pharmacokinetics, Bayesian approach and population pharmacokinetics]. AB - A major objective for pharmacokineticians is to help practicians to define drug administration protocols. Protocols are generally designed for all the patients but inter individual variability would need monitoring for each patient. Computers are widely used to determine pharmacokinetic parameters and to try to individualize drug administration. Severals examples are summarily described: terminal half-life determination by regression; model fitting to experimental data; Bayesian statistics for individual dose adaptation; population pharmacokinetic methods for parameter evaluation. These methods do not replace the pharmacokinetician thought but could make possible drug administration taking into account individual characteristics. PMID- 8680076 TI - [Medical research in the European community. I]. PMID- 8680077 TI - [Dose optimization in clinical oncology: pharmacokinetic-pharmacodynamic relationship]. AB - The establishment of relationships between pharmacokinetics and pharmacodynamics of anticancer drugs might allow to individualize the dosing of these drugs. Our knowledge of this kind of relationship has grown markedly in recent years. After a review of the different causes of variability in pharmacokinetics and pharmacodynamics of these drugs, the different models used for establishing these correlations were analyzed and criticized. Finally, the three methods for adapting drug dosing based on pharmacokinetic data were proposed and the main applications of these concepts were reviewed. PMID- 8680078 TI - [Breast cancer during pregnancy]. AB - Breast cancer during pregnancy is a rare eventuality. The mean age of women is 34 years. The same histological types (essentially ductal) are found, but there are more inflammatory forms and/or node involvement and general metastasis. The hormonal receptors are usually negative. The clinical diagnosis is often difficult and delayed. The mammography is perturbed because of breast congestion, giving reason for histological verification. The treatment must consider the fetus as much as possible. The traditional mastectomy associated to axillary nodes dissection is replaced most of the time by a large tumorectomy with axillary node dissection with the condition not to delay the complementary radiotherapy fore more than three months and to take in consideration the toxicity in relation to the gestational age, the site of impact and the doses given. Also, chemotherapy, if indicated, must begin in the month following the diagnosis. The pronostic is not as good in general as that in the non pregnant woman, because of the delayed diagnosis, the ganglionic metastasis, and the aggravation of the forms accelerated by pregnancy. The prevention consists of a clinical examination of the breast early in pregnancy (particularly after 30 years) and by histologic verification in cases where there is the slightest doubt. PMID- 8680079 TI - [Is there a place for chemotherapy in the initial treatment of cervical cancer? Review of the literature]. AB - Despite their high efficiency in treating cancer of the uterine cervix, surgery and radiotherapy can not cure (local and/or metastatic disease) a certain number of patients with initially adverse risk factors, mostly local or regionally advanced cervical carcinoma (stage III-IVA) or early stage (IB-II) disease with bulky primary lesion or involved regional nodes. Since the 1980s, many investigators have tried to determine whether or not there is any benefit in introducing chemotherapy earlier in the therapeutic plan for these patients: either initially before surgery or radiotherapy (neoadjuvant), or during radiotherapy (concurrent), or after local treatment (adjuvant). In this review we seek to sum up the published data available and to determine if at present there is a place for chemotherapy in the initial treatment of cervical cancer. PMID- 8680080 TI - [Fibrinolysis of deep venous thrombosis on implantable perfusion devices. Apropos of a consecutive series of 57 cases of thrombosis and 32 cases of fibrinolysis]. AB - The main complication of totally implantable venous access devices is deep venous thrombosis on catheter. It may dramatically reduce the already limited venous capacity of patients undergoing chemotherapy and obturate catheters, causing pulmonary embolism or functional disorders. These thromboses usually involve veins of the superior vena cava system where the catheters are implanted. Generally, they occur early, are extensive and often asymptomatic. Doppler ultrasonography is the diagnostic investigation of choice, phlebography being reserved for particular cases or to specify the limits of the thrombus. In a series of 412 vein access devices implanted and systematically monitored by Doppler ultrasonography, we found 57 thromboses (13.8%), 15 partial and 42 complete. The lowest thrombosis rate was observed in the right internal jugular vein (10% vs 20 to 23%, p = 0.006). Thirty-two patients received a systemic fibrinolytic treatment, 16 with streptokinase (SK), five with urokinase (UK), four with tissue plasminogen activator (rt-PA) and seven with SK/UK association. No serious side effects were observed. Sixteen repermeabilizations (50% of fibrinolysis) were obtained. There were no significant differences with respect to the fibrinolytic, the initial characteristics of thrombosis or the patients. Patients without fibrinolysis received 3 weeks of low molecular weight heparin (curative doses) then warfarin. Only one patient was repermeabilized with this treatment (significative difference with fibrinolysis: p = 0.009). Fibrinolysis is indicated in symptomatic thrombosis and/or in cases of extension to the innominate vein or the superior vena cava. Systematic monitoring by Doppler ultrasonography and prophylactic anti-thrombotic treatment are recommended in patients with implantable venous access devices in order to decrease the occurrence of thromboses, to detect asymptomatic patients at an early stage and to increase the effectiveness of fibrinolysis. PMID- 8680081 TI - [Preoperative radio-chemotherapy of stage III unresectable non-small cell lung cancer: results of a pilot study]. AB - Prognosis of Stage III NSCLC remains dismal, particularly when mediastinal nodal involvement is present. In order to improve local control and to reduce early distant failures, we have treated Stage III patients with concurrent chemoradiotherapy since 1989. From September 1989 to February 1994, 140 patients were treated with concurrent chemoradiotherapy. Among these, 24 initially inoperable patients became operable after induction chemoradiotherapy. Characteristics: median age 51 years (35-70); squamous: 45.8%; non squamous: 41.7%; median tumor size: 8 cm; T3 (79.2%); T4a (12.5%); N2 (62.5%) and N3 (8.3%). Preoperative radiotherapy was delivered at a dose of 45 Gy (25 f) over 5 weeks to the mediastinum. Concurrent chemotherapy was continuous infusion cisplatin (n = 10) or cisplatin plus etoposide (n = 14). Five weeks later, radical surgery was carried out (lobectomy n = 14, pneumonectomy n = 10), followed by additional chemotherapy (n = 12) and/or radiotherapy (n = 6), according to histological response. Pathological CR rate was 29.2%. Grade III toxicities were digestive (12.5%), hematologic (8.3%) and infectious (4.2%). Three patients had severe non-lethal postoperative complications with one hemorrhage and two pneumothorax (12.5%). With a median follow-up of 41 months, overall survival at 2 and 5 years was 77.5%, and 72%, respectively. Actuarial local control at 5 years was 82.4%. Nine patients presented with distant metastases, including six with isolated brain metastases. This preoperative chemoradiotherapy regimen appears feasible without overwhelming toxicity and with an acceptable rate of postoperative complications. Despite a significant incidence of isolated brain metastases (25%), 5-year survival is highly encouraging since and appears substantially better than primary surgery. PMID- 8680082 TI - [Semen preservation and gonadal toxicity in the treatment of non Hodgkin lymphoma. Experience at the Gustave-Roussy Institute from 1980 to 1993]. AB - More than 50% of patients with non Hodgkin's lymphomas (NHL) are long-term survivors. We have retrospectively analysed the indication of semen cryopreservation and late gonadal toxicity for 213 males patients consecutively treated at the Gustave Roussy institute from 1980 to 1993 for NHL. The mean age was 30 years (15-42) and all patients received chemotherapy with or without radiotherapy. Initial spermograms and cryopreservation of semen were obtained in only 24 patients (half of them between 1991 and 1993). Spermogram characteristics were as follows: 11 normal; 13 abnormal with oligospermia (n = 7), asthenospermia (n = 7), and teratospermia (n = 8). No relation was found between the pretherapeutic status and the semen sample quality. Cryopreservation was possible in only 22 cases, and among the 16 surviving patients, two have undergone insemination and the remaining 14 are maintaining their cryopreserved semen samples. Long-term gonadal toxicity was assessed on spermograms of nine patients: three of whom had evidence of return to pretherapeutic status. FSH levels were assayed for 48 patients: at a threshold of 8 g/m2 of cyclophosphamide, 86% of patients had elevated values (P < 10(-6). Cumulated doxorubicin doses were not correlated with FSH elevation. Five patients have had children after treatment. In conclusion, chemotherapy for NHL seems to induce an intermediate level of gonadal toxicity which is between that of MOPP and ABVD. Complete information about gonadal toxicity of chemotherapy is warranted for young male patients who are to receive chemotherapy and semen cryopreservation should be suggested to this population. PMID- 8680083 TI - [Carboplatin and etoposide combination for the treatment of recurrent epithelial ovarian cancer]. AB - The objective of this phase II study was to determine the efficacy and toxicity of a combination of carboplatin and etoposide as salvage treatment, in previously treated patients with persistent or recurrent ovarian cancer following first-line cisplatin-based chemotherapy. PATIENTS AND METHODS: From July 1990 to August 1994, 58 patients were treated with 3-week cycles of chemotherapy consisting of carboplatin (200 mg/m2, D1) and etoposide (120 mg/m2, D1, D2). Criteria for evaluating previous response to cisplatin were strictly defined. RESULTS: The overall response rate was 36%, with five complete responses (CR, 9%), 16 partial responses (PR, 27%) and the median duration of response was 10 months (range: 4 to 38). In the group of patients who progressed during the first year following the diagnosis, the response was 1 CR and 2 PR (12%) and in the group of patients who progressed from the second year after diagnosis, 4 CR and 14 PR (56%), with a median survival of 8.5 and 21 months respectively (p = 0.0013). The response rate was 59% in the potentially platinum sensitive group versus 8.7% in the primary resistant group (0.02 < p < 0.05). Myelotoxicity was the main side-effect but did not appear to be cumulative. Grade 3 and grade 4 anemia were observed in 26% and 3% of the patients respectively, neutropenia in 14% and 2% and thrombocytopenia in 14% and 8.5%. One patient died of sepsis associated with neutropenia. CONCLUSION: Treatment was easily manageable and well tolerated. The advantage of carboplatin and etoposide combination in potentially responsive patients is represented by the reduced nephrotoxicity, neurotoxicity and ototoxicity as compared with cisplatin containing regimen, with durable feasibility in outpatients. This second-line chemotherapy for ovarian cancer is effective as salvage treatment in potentially responsive patients with late recurrent tumors, while paclitaxel is the drug of choice for patients who have developped primary or secondary resistance to platin therapy. PMID- 8680084 TI - [Severe 5-fluorouracil toxicity in a woman treated for breast cancer with concurrent osteogenesis imperfecta and dehydrogenase deficiency]. AB - Dihydropyrimidine dehydrogenase (DPD) is the principal enzyme involved in the catabolism of 5 fluorouracil (5 FU). The clinical importance of DPD has recently been demonstrated wit the identification of rare cases presenting a severe toxicity to 5 FU related to proven DPD deficiency. We report a new case in a patient with concurrent congenital osteogenesis imperfecta. We were surprised to find another similar association reported by Lyss. It is tempting to speculate that DPD activity may be abnormally regulated in osteogenesis imperfecta patients. PMID- 8680086 TI - [Screening of undifferentiated carcinoma of the nasopharynx]. AB - Screening for nasopharyngeal carcinoma (NPC) is being conducted as a quasi experiment in the south east of the People's Republic of China using serological markers of the Epstein-Barr virus. Several studies are available but the efficacy of screening in terms of impact on mortality from NPC has not yet been demonstrated. Valid experimental studies should be carried out before implementing population-based screening programmes in Chinese or North African populations which are known for their high risk of NPC. PMID- 8680085 TI - [Locally developed sarcoma of the thoracic wall]. AB - Important advances have been obtained in the care of soft tissue sarcoma in adults, mainly in the field of locoregional treatment. Surgery or combination of surgery and radiotherapy allow adequate tumor control with preservation of function for the majority of patients. However, the management of locally advanced primaries remains problematic. Moreover, although patients survival mainly depends on the metastatic risk of the disease, controversies remain in definition of pronostic factors as well as in the evaluation of the role of chemotherapy in curative therapeutical strategies. The case reported here allows a discussion of the different modalities of treatment for adults with soft tissue sarcomas and stresses the necessity of a multimodal approach in these patients. PMID- 8680087 TI - [Etoposide: specificity of prolonged oral administration]. AB - Etoposide is a major antineoplastic agent which was introduced in the clinic in the 1970s. Its clinical pharmacology was rediscovered at the end of the 1980s because optimal activity was demonstrated to be schedule dependent. The galenic adaptation of an oral form of the molecule led to more extensive studies investigating both the potential advantage of prolonged exposure to the drug and a better bioavailability at low doses. We reviewed current knowledge on clinical applications of continuous oral etoposide in various diseases and discussed the benefit of this mode of therapy over classical intravenous administration in terms of activity, cost and quality of life. PMID- 8680088 TI - [Therapeutic approaches of hematopoietic syndrome following accidental total whole body irradiation]. AB - Since the first radiation accidents which resulted in severe health effects in the workforce or the population, great progress has been made in the fields of diagnosis, prognosis and treatment of accidentally overexposed victims. Since then, progress has also been made in the medical management of diseases such as aplasia. Because of the relative scarcity of radiation accidents, there is a need for complementary researches, in order to take advantage of new techniques and medical approaches. After whole body overexposure, the key issue is the therapeutic decision, ie, the choice between bone marrow transplantation and other strategies. The indications of bone marrow transplantation cover only a short range of doses, provided the exposure is distributed uniformly within the body. The last accidental overexposures which happened in the world have demonstrated the possible efficiency of haematopoietic growth factors, most of them being still under clinical trials. Actions based on these various approaches are summarized, as well as the lessons which have been learned. PMID- 8680089 TI - [Cisplatin resistance in a murine leukemia cell line associated with defect of apoptosis]. AB - It has been recently reported that a number of anticancer drugs, including cisplatin, may exert their toxicity by inducing apoptosis. In order to investigate whether an alteration in the mechanisms involved in the process of apoptosis could contribute to cellular resistance, induction of apoptosis was studied in a cisplatin-resistant cell line (L1210/DDP) derived from a L1210 murine leukemia cell line (L1210/0). We first established that the mutant cell line resisted 5-azacytidine, a drug to which it was never exposed and which is known to have a very different mechanism of action from that of cisplatin. We then showed that these cells did not exhibit any DNA fragmentation or morphological changes typical of apoptosis, when exposed to toxic concentrations of either cisplatin or 5-azacytidine. The failure of these cells to undergo typical apoptosis upon cisplatin or 5-azacytidine exposure was correlated with the lack of a nuclear endonuclease activity present in wild type cell nuclei. However, staurosporine, a potent protein kinase C inhibitor, which exerted the same toxicity on both cell lines, induced the internucleosomal DNA fragmentation and morphological features of apoptosis in both of them. This indicates that a functional pathway for apoptosis is preserved in the resistant cells. The induction of this pathway can be correlated with the presence of a cytoplamic endonuclease activity whose specificity seems different from that operating in L1210/0 cells. In conclusion, our data indicate that the mechanisms which control activation of apoptosis in L1210/0 cells differ from those which operate in L1210/DDP cells. One of the differences concerns the nature and the subcellular localization of the endonuclease activity possibly involved in the internucleosomal DNA cleavage. PMID- 8680090 TI - [Role of interleukin 6 in hepatocellular carcinoma]. AB - Interleukin 6 (IL-6) is a pleiotropic cytokine which possesses a broad spectrum of action in diverse pathological conditions. It is mainly produced and metabolised in the liver where it carries out one of its best known actions in the mediation of the acute phase response. We studied its behaviour in hepatocellular carcinoma to evaluate its clinical prognostic role. We determined serum IL-6 concentrations in 39 patients with hepatocarcinoma (27 males and 12 females) and 25 healthy controls (15 males and ten females). Our results showed a significant increase in serum IL-6 concentrations in hepatocarcinoma subjects compared with controls (P < 0.005) and an elevated positive correlation (r = 0.616) between IL-6 and size of the hepatocarcinoma. Our study demonstrated that IL-6 is able to influence hepatocarcinoma progression by acting as an autocrine tumoral growth factor and depleting immune surveillance. PMID- 8680091 TI - [Results of a randomized study comparing combination of navelbine-cisplatin to combination of vindesine-cisplatin and to navelbine alone in 612 patients with inoperable non-small cell lung cancer]. AB - The combination of vindesine and cisplatin is considered a reference regimen in advanced NSCLC which has yielded a significant improvement in the duration of survival. A phase II study of a new semi-synthetic vinca alkaloid, Navelbine, reported an unusually high 29% response rate in stage III-IV NSCLC and a phase I II study established the feasibility of the combination of Navelbine and cisplatin. We, therefore, designed a prospective randomized trial to compare Navelbine and cisplatin (NVB-P) to vindesine and cisplatin (VDS-P) and to evaluate whether the best of these regimens affords a survival benefit compared to Navelbine alone (NVB), an outpatient regimen. Forty-five centers included 612 patients in this study: 206 in NVB-P, 200 in VDS-P and 206 in NVB. Navelbine was given at a dose of 30 mg/m2 weekly, cisplatin at 120 mg/m2 on day 1, day 29 and then every 6 weeks and vindesine at 3 mg/m2 weekly for 6 weeks and then every other week. Treatment was continued until progression or toxicity. Patients' characteristics were similar in the three groups with 59% of patients presenting with metastatic disease. An objective response rate was observed in 30% of patients in NVB-P versus 19% in VDS-P (P = .02) and 14% in NVB (P < .001). The median duration of survival was 40 weeks in NVB-P compared to 32 weeks in VDS-P and 31 weeks in NVB. The comparison of survival between the three groups demonstrated an advantage for NVB-P compared to VDS-P (P = .04) and NVB (P = .02). Neutropenia was significantly higher in the NVB-P group (P < .001) and neurotoxicity more frequent with VDS-P (P < .004). Since our results have demonstrated that NVB-P yields a longer survival duration and a higher response rate than VDS-P or NVB alone, with acceptable toxicity, this combination should be considered a reference regimen in advanced NSCLC. PMID- 8680092 TI - [Intraductal cancer of the breast in women under age 35 years]. AB - The incidence of intraductal carcinomas (IDC) of the breast is increasing. However, few cases have been reported in young women. Based on a series of 13,168 women treated for breast cancer at the Institut Curie over a 12-year period, this article analyses the prevalence, clinical presentation, prognosis and treatment of IDC in patients younger than 35 years. Of this series of 13,168 cancers, 882 occurred in women under the age of 35 years (6.7%). Sixteen of these cases (2%) were strictly intraductal lesions and therefore constituted the study population. The frequency of IDC in women under the age of 35 years was identical to that of IDC in the general population of this study. The circumstances of discovery were: palpable tumour in seven cases (44%), mammographic discovery in four cases (25%), nipple discharge in five cases (31%). Histological examination revealed a well differentiated IDC in two cases, moderately differentiated in seven cases and poorly differentiated in five cases (two cases not specified). Conservative treatment by lumpectomy and irradiation was performed in nine patients, and another seven patients were treated by mastectomy and low axillary lymph node dissection. The mean follow-up was 83 months (range: 5 to 156 months). A single patient has relapsed: an isolated invasive mammary recurrence, 6 years after conservative treatment. This patient in now in complete remission after mastectomy. All patients are therefore alive, with no evidence of disease, at 83 months. In the group of women younger than 35, the frequency of IDC appeared to be identical to that observed in the general population. Their prognosis after treatment is excellent, and identical to that of IDC in older women. Conservative treatment is justified in localized forms, but mastectomy with immediate reconstruction must be performed in the presence of extensive disease. PMID- 8680093 TI - [Precancerous and cancerous involvement of the uterine cervix. Results of a survey conducted by the "Genital Cancers" group of Ile-de-France, May 1990-May 1992, based on 8,805 biopsies]. AB - Results of a study conducted by the "cervix cancer group" of PETRI, in Ile-de France, from May 1990 to May 1992, and based on 8,805 biopsy specimens. In the absence of Cancer Registry in the Ile de France, no reliable data on invasive and preinvasive neoplasia of the cervix are available concerning this area. The aim of this survey, performed between May 15th, 1990 and May 15th, 1992 in 62 laboratories of pathology under the aegis of the Petri Association (Prevention et epidemiologie des tumeurs en Ile-de-France), was to obtain a better knowledge of this pathology, in which one of the major risk factors is the infection of the cervical epithelium by specific types of human papillomavirus. Over the course of these two years, 8,805 biopsy specimens, taken from neoplastic lesions of the cervix, were analyzed. Intra epithelial neoplasia represented more than 90% of the registered lesions. The average age at the time of the diagnosis was 32.4 years for the cases of condyloma, 32.7 years for CIN I, 33.8 years for CIN II, 36.3 years for CIN III, 45.7 years for micro-infiltrative carcinoma and 50.8 years for infiltrative squamous cell carcinoma. The breakdown of the different histological types of lesions is presented for three characteristic age groups (20-25, 30-35, and 60-70 years old). Differences observed in the eight departments belonging to the Ile-de-France are discussed. PMID- 8680094 TI - [Cytological detection of cervical cancer in black Africa: what are the perspectives?]. AB - The authors report the study of the cytological screening for cervical cancer in Africa on the basis of the experience from four West African countries (Ivory Coast, Guinea, Mali and Senegal). The study reveals that in all these countries, the yearly coverage is inferior to one cervical vaginal cytological screening per 100 women of 15 years of age and above. This rate (< 1%) is too weak to act on the rate of mortality and morbidity of cervical cancer. Consequently, the authors advise like WHO the African authorities to define and to apply cervical cancer screening programs to reach the following goal: carry out one cervical vaginal cytology in each woman near the age of 40. Cervicography can be associated. PMID- 8680095 TI - Two-year follow-up study of the effect of acid fog on adult asthma patients. AB - Acid fog is a complex mixture of atomospheric pollutants containing multiple stimuli that may be capable of inducing bronchoconstriction. To investigate the effect of ambient acid fog on bronchoconstriction, we examined the relation between the hospital visit for asthma symptoms of 102 patients and various meteorological conditions for over the two-year period from January 1992 to December 1993. Dense fog occurs frequently every summer in Kushiro, a city located in Hokkaido, northernmost island in Japan. The acidity of the fog ranged from pH 3.32 to 6.91 (mean pH = 5.05) during this period. A significant increase (p < 0.05) of hospital visits on a foggy day was found in 9 cases, and a tendency (p < 0.10) was found in 10 cases. The odds ratio for a hospital visit on a high water vapor pressure day (> 12 h Pa) was significantly high (p < 0.01) in 5 cases among the above 19 cases. To exclude the effect of high water vapor pressure, the data was restricted to the condition of a foggy day with low water vapor pressure (< 12 hPa); 9 patients had a significant increase (p < 0.05) in hospital visits on such a day. These results indicated that hospital visits for asthma symptoms was increased on acid fog days in 8.8% of adult asthma patients. Inhalation of naturally occurring acid fog may have adverse effects on the respiratory tract of the asthmatic patient. PMID- 8680096 TI - Phospholipid-dependent anti-beta 2-glycoprotein I (beta 2-GPI) antibodies and antiphospholipid syndrome. AB - A portion of anticardiolipin antibodies is defined as phospholipid-dependent anti beta 2-glycoprotein I (beta 2-GPI) antibodies and recognizes the conformationally altered beta 2 GPI which interacts with anionic phospholipids. We studied the clinical significance of IgG phospholipid-dependent anti-beta 2-GPI antibodies in patients with antiphospholipid syndrome (APS). The subjects consisted of 60 APS patients. IgG phospholipid-dependent anti-beta 2-GPI antibodies were detected by ELISA in 32 of the 60 patients (53%). Significantly higher incidences of prolonged APTT and lupus anticoagulants were found in patients with these anti beta 2-GPI antibodies. Moreover, significantly lower incidences of malar rash, serositis, LE cell preparation and anti-Sm antibodies were found in patients with these anti-beta 2-GPI antibodies. It was found that 88% of the patients with these anti-beta 2-GPI antibodies satisfied less than five of the revised criteria items for the classification of SLE. These findings indicate the clinical characteristics of APS patients with IgG phospholipid-dependent anti-beta 2-GPI antibodies. PMID- 8680097 TI - Malaria--eight years of experience in a Tokyo metropolitan hospital. AB - Malaria patients who were admitted to the Department of Infectious Diseases of the Tokyo Metropolitan Bokutoh General Hospital during the past 8 years are reviewed. Cases included 17 patients infected with Plasmodium falciparum (14 Japanese), 13 patients infected with P. vivax (9 Japanese), 3 patients infected with P. ovale (2 Japanese) and 1 Chinese patient with a mixed infection of P. falciparum and P. vivax. About 70% of Japanese patients infected with P. falciparum contracted the disease in Africa, about 90% P. vivax-infected Japanese patients contracted the disease in Asia and all P. ovale-infected patients contracted the disease in Africa. Only 13% of all (17% of Japanese) patients infected with P. falciparum who initially contracted doctors of other Japanese hospitals were correctly diagnosed, but 78% of all (67% of Japanese) patients infected with P. vivax who initially contacted doctors of other Japanese hospitals were correctly diagnosed. At present, malaria is not a rare disease in Tokyo among travelers to or from Africa or Asia. PMID- 8680098 TI - Histiocytic cytophagic panniculitis which developed during interferon-alpha therapy. AB - A 59-year-old woman developed edema of the face and eyelids during interferon (IFN)-alpha-2b therapy for chronic hepatitis C with a cumulative dose of 6 million x 47 units. Despite cessation of the therapy, the edema progressed and was followed by exophthalmos, pyrexia, liver dysfunction, pancytopenia, and disseminated intravascular coagulation. Two months after initial presentation, she died of hemorrhagic shock and was diagnosed with histiocytic cytophagic panniculitis at autopsy. This may be a hitherto unrecognized adverse effect of therapeutic IFN alpha. PMID- 8680099 TI - Nephrogenic diabetes insipidus induced by lobenzarit disodium treatment in patients with rheumatoid arthritis. AB - Nephrogenic diabetes insipidus (NDI) occurred in a 43-year-old woman who had received lobenzarit disodium for the treatment of rheumatoid arthritis (RA). Her urine output was initially 3 l/day and urine osmolarity was 203 mOsm/l. Based on a sodium chloride loading test and a vasopressin loading test, she was diagnosed as having lobenzarit-induced NDI. Seven days after the cessation of the use of lobenzarit disodium, polydipsia and polyuria disappeared, and the vasopressin test showed a normal response. These findings suggest that lobenzarit induces a reversible form of NDI as a side effect. The reports of lobenzarit-induced NDI in Japan during the past seven years are also reviewed. PMID- 8680100 TI - Adrenal tumor producing 11-deoxycorticosterone, 18-hydroxy-11-deoxycorticosterone and aldosterone. AB - A case of adrenal tumor producing 11-deoxycorticosterone, 18-hydroxy-11 deoxycorticosterone and aldosterone is reported. A 55-year-old woman had hypertension, hypokalemia, low plasma renin activity and an adrenal tumor. The plasma level of aldosterone was normal, and the levels of 11-deoxycorticosterone and 18-hydroxy-11-deoxycorticosterone were extremely high. After the tumor removal, the plasma level of aldosterone decreased and plasma levels of 11 deoxycorticosterone and 18-hydroxy-11-deoxycorticosterone were normalized. The tumor was benign adenoma and the production of steroid hormones was under control of adrenocorticotropic hormone. The enzyme activity of 21-hydroxylation in the tumor was elevated and that of 11 beta-hydroxylation was decreased compared with the adjacent tissue. PMID- 8680101 TI - A rare case of idiopathic hypoparathyroidism with varied neurological manifestations. AB - A 47-year-old man was admitted for evaluation of unsteady gait, postural instability, and dysarthria. On admission, neurological examinations revealed cerebellar ataxia, extrapyramidal signs including parkinsonism and positive Trousseau's sign. Laboratory findings revealed severe hypocalcemia and hyperphosphatemia, and serum intact parathyroid hormone was not detectable. Brain computed tomography revealed severe calcification of basal ganglia and dentate nuclei. He was diagnosed as idiopathic hypoparathyroidism; treatment with 1 alpha (OH) vitamin D3 brought marked improvement of neurological manifestations. We report a rare case of idiopathic hypoparathyroidism presenting with extrapyramidal and cerebellar dysfunction with a review of literature. PMID- 8680102 TI - Hypopituitarism associated with transient diabetes insipidus followed by an episode of painless thyroiditis in a young man. AB - A 16-year-old male complained of a headache and a high fever followed by polyuria. The endocrinological studies showed he had hypopituitarism and central diabetes insipidus, and magnetic resonance imaging (MRI) revealed a pituitary mass. Diabetes insipidus gradually improved and hydrocortisone treatment was begun at three months after onset, but a month later painless thyroiditis developed. An MRI demonstrated a spontaneous shrinkage of the pituitary mass nine months after onset. Lymphocytic hypophysitis followed by painless thyroiditis was the most probable diagnosis, although it is very uncommon especially among men. PMID- 8680103 TI - Captopril, an angiotensin-converting enzyme inhibitor, induced pulmonary infiltration with eosinophilia. AB - In this study, we investigated the association between the drug-induced pulmonary infiltration with eosinophilia (PIE) syndrome in a patient with hypertension and the angiotensin-converting enzyme inhibitor (ACE-I) captopril. Although the patient developed diffuse lung field infiltrates accompanied by productive cough and striking peripheral eosinophilia, these symptoms disappeared after termination of the administration of captopril, pronase and cephalexine. Furthermore, the results of the peripheral lymphocyte stimulation test, skin patch test and provocation test under informed consent showed a positive reaction only for captopril. Therefore, this patient was diagnosed as captopril-induced PIE syndrome. PMID- 8680104 TI - Primary adenoid cystic carcinoma of the trachea effectively treated with the endoscopic Nd-YAG laser followed by radiation. AB - We present a case of adenoid cystic carcinoma of the trachea. The tumor could not be resected due to extensive progression but it was effectively treated endoscopically with a Nd-YAG Laser followed by 70 Gy of conventional radiotherapy. Histologically-confirmed complete remission was achieved, and the patient has lived for nearly 9 years without recurrence of disease. PMID- 8680105 TI - T-cell lymphoma presenting with pericardial and pleural effusion as the initial and primary lesion: cytogenetic and molecular evidence. AB - A 90-year-old woman was admitted with progressive dyspnea. Chest roentgenogram and computed tomography revealed a massive pericardial effusion and bilateral pleural effusion, but no lymphomatous lesion was seen. A diagnosis of malignant lymphoma was made by cytological and immunological studies of the cells obtained from the pericardial effusion. Chromosome analysis showed a clonal abnormality and T-lineage clonality was determined by the rearrangement of the T-cell receptor gamma gene. The patient achieved remission with chemotherapy, but she later relapsed, with right pleural effusion, and died. She exhibited no lymphomatous features throughout the clinical course, indicating the possibility of malignant lymphoma originating from the pericardium and/or pleura. PMID- 8680106 TI - Steroid pulse therapy in lupus cystitis. AB - A middle-aged woman with lupus cystitis showed no other symptoms of lupus vasculitis. Cystoscopic findings revealed mucosal hemorrhage and hyperemia. Histological studies of the bladder showed mucosal edema, inflammatory cellular infiltration and the deposition of immune complexes along the vessels. She was treated with a combination of intravenous methylprednisolone pulse therapy and oral prednisolone. Cystoscopy and histological findings showed appreciable improvement. Elevated urinary levels of chemokines such as interleukin-8 (IL-8) and monocyte chemotactic and activating factor (MCAF) decreased during convalescence. These results suggest that the early diagnosis and treatment with steroid pulse therapy achieves improvement of an unusual vasculitis symptom, lupus cystitis. PMID- 8680107 TI - Intestinal perforation in temporal arteritis, associated with paroxysmal nocturnal hemoglobinuria. AB - Temporal arteritis (TA) is an adult-onset, focal granulomatous inflammatory disorder of the small and medium sized arteries. Intestinal perforation is a rare complication of TA. Regarding its etiology, steroid-induced or arteritis-induced ulceration have been proposed. We describe a patient who developed TA in addition to preceding paroxysmal nocturnal hemoglobinuria. During steroid therapy for TA, intestinal perforation manifested, and it was proven to be arteritis induced perforation on histological examinations. The patient may be the 5th reported case of TA complicated with arteritis-induced intestinal perforation. The possibility of polyangitis overlap syndrome of TA and polyarteritis nodosa is discussed. PMID- 8680108 TI - Tuberculous tenosynovitis in the elbow joint. AB - A 74-year-old woman was noted to have a mass lesion near the right elbow joint during medication for pulmonary tuberculosis. After discontinuation of medication, the mass gradually became enlarged with swelling and tenderness of the joint. Radiological evaluation disclosed tenosynovitis with an encapsulated abscess. Microscopic examination and culture of an aspiration biopsy specimen from the abscess showed no microorganisms. However, DNA extracted from the specimen contained mycobacterium tuberculosis DNA, permitting a diagnosis of tuberculous tenosynovitis. Mycobacterium is not always detected in biopsy specimens of tuberculous arthritis and tenosynovitis. In such cases, genetic diagnosis may be of great use. PMID- 8680110 TI - Lupus cystitis in the Japanese. PMID- 8680109 TI - Myocardial imaging of sympathetic nervous function by radiolabelled metaiodobenzylguanidine. PMID- 8680111 TI - Impaired endothelium-dependent vasodilation of coronary resistance vessels in hypercholesterolemic patients. AB - To determine the relationship between hypercholesterolemia and the endothelial function of coronary resistance vessels, we studied the changes in coronary blood flow (CBF) in response to acetylcholine, an endothelium-dependent vasodilator, and adenosine, an endothelium-independent vasodilator, in patients with hypercholesterolemia (n = 17) and in control patients (n = 17). All patients had normal epicardial coronary arteries. Serial 2-min infusions of acetylcholine, at 3 micrograms/min and 30 micrograms/min, caused a dose-dependent increase in CBF in each group. The acetylcholine-induced maximal increases in CBF were inversely correlated with the serum cholesterol level (r = -0.55, p < 0.01), and were significantly smaller in the hypercholesterolemic patients than in control patients. However, the adenosine-induced increases in CBF were similar in the two groups. These results suggest that the endothelium-dependent vasodilation of resistance vessels is lessened in patients with hypercholesterolemia even before the formation of atherosclerotic stenotic lesions in epicardial coronary arteries, and that hypercholesterolemia impairs endothelium-dependent vasodilation of coronary resistance vessels. PMID- 8680112 TI - Evaluation of cardiac sympathetic nervous function by 123I metaiodobenzylguanidine scintigraphy in insulin-treated non-insulin dependent diabetics with hypoglycemia unawareness. AB - The association between the lack of adrenergic symptoms during hypoglycemia and myocardial 123I-metaiodobenzylguanidine (MIBG) accumulation was investigated in 12 insulin-treated non-insulin-dependent diabetes mellitus (NIDDM) patients who had no evidence of heart disease. These patients were divided into 2 groups according to the presence (group A) or absence (group B) of adrenergic symptoms during hypoglycemia. Autonomic function tests revealed significantly severe autonomic dysfunction in group B compared to that in group A. Insulin infusion test indicated no significant difference in the catecholamine response between the two groups. 123I-MIBG scintigraphy showed that the heart/mediastinum ratio of MIBG uptake was significantly lower, and scintigraphic defect was greater in group B than in group A. There were no significant differences in the washout rate between the two groups. These results suggested that the lack of adrenergic symptoms during hypoglycemia may be associated with cardiac sympathetic nervous dysfunction in insulin-treated NIDDM patients, and this dysfunction is mainly due to cardiac sympathetic denervation. PMID- 8680113 TI - Advantages of using the midline incision right retroperitoneal approach for abdominal aortic aneurysm repair. AB - This study was conducted to compare the midline incision right retroperitoneal approach for repairing abdominal aortic aneurysms (AAA) with the transperitoneal approach. The intra- and postoperative course of 15 patients who underwent AAA repair using the transperitoneal approach between 1987 and 1991 and another 15 patients who underwent AAA repair using the retroperitoneal approach between 1991 and 1994 were evaluated. The incidence of postoperative wound complications was also assessed. There was no operative or hospital death in either group. Although a significantly longer interval was required from the incision to the aortic clamp using the extraperitoneal method, there were no statistical differences in the aortic clamping time, total operation time, or blood loss between the two groups. On the other hand, there was a statistically significant improvement in bowel function and a significant reduction in the length of postoperative hospitalization following the extraperitoneal procedure. Furthermore, no wound complications such as those associated with the left flank incision developed after the extraperitoneal procedure. Thus, we recommend the midline incision right retroperitoneal approach for AAA as it does not involve muscle division and is associated with fewer complications. PMID- 8680114 TI - The modulating effect of interferon alpha-2a on the antitumor activity of UFT against a human gastric carcinoma xenograft, SC-1-NU, in nude mice. AB - The modulating effect of recombinant human interferon alpha-2a (IFN) on the antitumor activity of UFT, a mixed compound of tegafur and uracil at a molar ratio of 1:4, was investigated against SC-1-NU, a human gastric cancer xenograft serially transplanted in nude mice. IFN was administered subcutaneously at a dose of 60,000 IU/mouse daily for 14 days, and UFT was given at a dose of 15 mg/kg as tegafur daily, except on Sundays, for 3 weeks. The agents were administered either alone or simultaneously. Synergistic antitumor activity on SC-1-NU was produced by the combination of IFN and UFT without any increment of side effects, and the combination therapy also increased intratumoral thymidylate synthetase (TS) inhibition and the amount of 5-fluorouracil (5-FU) in the intratumoral RNA. Thus, IFN seems to modulate the antitumor activity of UFT against SC-1-NU through an inhibition of DNA synthesis and RNA distortion, and therefore this combination could be useful for clinical application. PMID- 8680115 TI - The effects of thromboxane A2 synthetase inhibitor (OKY-046) on complete hepatic ischemia in rats with obstructive jaundice. AB - The effects of OKY-046, a thromboxane A2 synthetase inhibitor, on hepatic dysfunction produced by liver cell ischemia were studied in an experimental model of rats with obstructive jaundice. The experiments were performed 7 days after the rats underwent bile duct ligation. Warm total ischemia of the liver was induced by Pringle's method over a 20-min period and the animals were divided into two groups according to whether or not OKY-046 was administered. The reperfusion time was 30 min in each group. OKY-046 was administered via the femoral vein at a rate of 100 micrograms/kg per min from 15 min before the blockade to the end of the experiment. The level of ATP in the liver tissue of the OKY-046 group was elevated slightly, but not significantly, compared to that of the control group. The ratio TXB2/6-keto PGF1 alpha in the liver tissue was lower in the OKY-046 group than in the control group, and significant differences were found between the two groups in the water content of the liver and the mitochondrial score as examined by transmission electron microscopy. Thus, it was observed that an improvement in the balance of TXA2 and PGI2 associated with OKY 046 administration proctected the cellular structure of the mitochondria in the rat liver. PMID- 8680116 TI - The effects of intravenously infused catecholamines on hepatic blood flow in conscious dogs with experimental obstructive jaundice. AB - This study was conducted to examine how the effects of dopamine and dobutamine on hepatic blood flow were influenced by obstructive jaundice in a conscious canine model. Prior to biliary obstruction, portal venous blood flow (PVF) increased in response to the infusion of either dopamine or dobutamine: dopamine infused at 8 micrograms/kg per min produced an increase of 19 +/- 0% in PVF, while dobutamine infused at 16 micrograms/kg per min produced an increase of 30 +/- 2%. Although hepatic arterial blood flow (HAF) decreased dose-dependently in response to the infusion of dopamine, no significant change was observed in HAF in response to any dose of dobutamine. Obstructive jaundice attenuated or completely abolished the PVF-increasing effect of dopamine, whereas it did not significantly alter the effect of dobutamine on hepatic blood flow. In dogs with obstructive jaundice, dopamine at 16 micrograms/kg per min produced a decrease of 17 +/- 3% in PVF. These findings suggest that dobutamine is more effective than dopamine for increasing hepatic blood flow in patients with obstructive jaundice. PMID- 8680117 TI - The preventive effects of OK432 on endotoxin-induced liver injury: liver protection by the modulation of hepatic macrophage function. AB - The present study was conducted to clarify whether endotoxin-induced liver injury could be improved by modulating the function of hepatic macrophages using OK432, an immunostimulant derived from Streptococcus. OK432 elevated the capacity of hepatic macrophages to produce superoxide and tumor necrosis factor (TNF), and enhanced the mRNA expression of interleukin-1-alpha, -beta, and TNF-alpha in liver nonparenchymal cells (NPC). However, intravenous (iv) preadministration of OK432 reduced the mRNA expression of TNF-alpha in liver NPC enhanced by the endotoxin injection, decreased the serum level of GOT and lactic dehydrogenase (LDH), and improved the survival rate of endotoxin-injected rats. Histological examination revealed a significant reduction in cell vacuolization and focal necrosis in the livers of the endotoxin-injected rats pretreated with OK432. These results indicate that hepatic macrophages play a crucial role in endotoxin induced liver injury, and that TNF-alpha is one of the factors most likely to be implicated in the development of endotoxin-induced liver injury. Thus, it is suggested that the administration of OK432 provides liver protection by modulating the responsiveness of hepatic macrophages against endotoxin. PMID- 8680118 TI - The possible role of TNF-alpha and IL-2 in inducing tumor-associated metabolic alterations. AB - This study was conducted to investigate the role of tumor necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2) in inducing cancer cachexia, and the results were compared with those obtained from our previous study on Fisher 344 rats with methylcholanthrene-induced sarcoma. Three groups of male Fisher 344 rats received one of the following regimens: 4 x 10(4) IU of human recombinant TNF-alpha per rat per day subcutaneously (sc) for 5 consecutive days (n = 5), 3.5 x 10(5) U human recombinant IL-2 per rat per day sc for 14 consecutive days (n = 5), or normal saline (n = 5). The activities of both phosphoenolpyruvate carboxykinase (PEPCK) and malic enzyme (ME) were increased slightly in the IL-2 group. Furthermore, LPL activity was significantly increased in the adipose tissue of the TNF group and in the cardiac muscle of the IL-2 group, but not in that of the TNF group. These results show that there is a significant difference between the metabolic alterations seen in the tumor-bearing state and those induced by either TNF-alpha or IL-2 alone. Thus, it is unlikely that IL-2 or TNF-alpha is the sole mediator of cancer cachexia in this tumor and rat model. PMID- 8680120 TI - Leiomyoma of the lesser omentum: report of a case. AB - The case of a 67-year-old Japanese woman with leiomyoma arising from the lesser omentum is reported herein. Although the patient had no abdominal symptoms, findings of a routine abdominal ultrasound examination suggested a mass between the stomach and the lateral segment of the liver. Subsequent magnetic resonance imaging (MRI) demonstrated a 6-cm well-encapsulated tumor in the lesser omentum, and this was confirmed intraoperatively. Resection of the tumor was performed without any other procedure and the histological diagnosis was confirmed as leiomyoma. The patient has been well for the 6 months since her operation. To our knowledge, this is the first report in the English literature of leiomyoma arising from the lesser omentum. PMID- 8680119 TI - A case of transverse colon cancer secondarily involving the liver, duodenum, and pancreas. AB - A 68-year-old woman presented with transverse colon cancer invading the liver, duodenum, and pancreas. The patient underwent a curative resection including a right hemicolectomy, partial hepatectomy, and pancreaticoduodenectomy (PD). The pathological examination showed adenocarcinoma of the colon with a direct extension into the duodenum, liver, and pancreas. Several lymph nodes were also involved. The patient is still alive and disease-free 2 years and 6 months after the operation. This case illustrates that even in patients with locally advanced colon cancer, a favorable prognosis can be obtained by aggressive surgery incorporating the resection of the adjacent involved organs. PMID- 8680121 TI - Development of a de novo tumorous necrotic lesion in the liver after transcatheter arterial embolization combined with iodized oil infusion: report of a case. AB - We report herein the case of a 69-year-old woman in whom a hepatic tumorous necrotic lesion was discovered following transcatheter arterial embolization combined with iodized oil infusion (Lp-TAE) for a hepatoma. The lesion, which had not been evident prior to the Lp-TAE, was resected and analyzed pathologically. The portal area distribution in the necrotic lesion was the same as that in the surrounding hepatic tissue, suggesting that the lesion was derived from the nonneoplastic hepatic tissue. Moreover, extensive wall thickening and obstruction were observed in the intrahepatic portal vein and hepatic artery. These findings suggest that the lesion was a focus of hepatic infarction triggered by Lp-TAE. PMID- 8680122 TI - Effect of endogenous hypergastrinemia on carcinogenesis in the rat esophagus. AB - We surgically prepared a hypergastrinemia model in rats and studied the effects of hypergastrinemia on chemically induced carcinogenesis in the esophagus. Operations were performed on 5-week-old male Donryu rats as follows: (1) truncal vagotomy plus pyloroplasty (group V), (2) segmental gastrectomy plus pyloroplasty (group G), (3) antrectomy (group A), and (4) no operation (group C) as a control. From the age of 6 weeks, the animals were given 0.003% N-methyl- N amylnitrosamine (MAN) solution as drinking water for 8 weeks. After 20 weeks of MAN administration, the animals were bled and killed. The average serum gastrin levels in groups V and G were significantly higher than those groups C or A. There were significant differences between C and V in the incidence of carcinoma, and between V and A in the incidence of carcinoma including severe dysplasia. The incidence of histologically identified lesions per animal was determined, and significant differences were observed between C and both V and G in the incidence of carcinoma including severe dysplasia. Furthermore, we also detected gastrin receptors in the esophageal lesions produced by the oral administration of MAN to rats. The results of the present study suggest that endogenous hypergastrinemia has a positive influence on chemically induced carcinogenesis in the rat esophagus. PMID- 8680123 TI - Extreme hyperbilirubinemia induced by endoscopic injection sclerotherapy in a patient with esophageal varices and thalassemia: report of a case. AB - We describe herein the case of a 57-year-old man with thalassemia who developed acute liver failure after undergoing endoscopic injection sclerotherapy (EIS) to control hemorrhage from a ruptured esophageal varix. The patient, who had been confirmed as having liver cirrhosis due to chronic hepatitis C with thalassemia in 1989, was admitted to our department to undergo EIS for esophageal varices, at which time his serum total bilirubin level was 5.5 mg/dl. As a small amount of hematemesis occurred just after a percutaneous transhepatic portography was performed, emergency EIS was carried out, following which the serum total bilirubin level markedly increased, mainly with a direct fraction, until it reached 70 mg/dl. The patient eventually died from acute liver failure with extreme hyperbilirubinemia on the 27th day after experiencing hematemesis despite all treatment. This unfortunate case demonstrates that sclerotherapy could be an inappropriate method of treatment for patients with hemolytic disease. PMID- 8680124 TI - Periosteal chondroma developing in a rib at the side of a chest wall wound from a previous thoracotomy: report of a case. AB - We describe herein the case of a 45-year-old man who developed a periosteal chondroma in a rib at the site of a thoracotomy that had been performed 24 years previously. To our knowledge, this is only the third case of a periosteal chondroma in a rib to be documented in the world literature. Some authors have suggested that trauma, including that of surgery, may induce chondroma formation and this association could have been an important contributing factor in the induction of the tumor in this patient. PMID- 8680125 TI - Repair of a ruptured aortic arch aneurysm complicated by postoperative paraplegia: report of a case. AB - We report herein the rare case of a 79-year-old man who suffered permanent paraplegia after undergoing an otherwise successful total arch replacement for a ruptured aortic arch aneurysm. During cardiopulmonary bypass, perfusion to the distal aorta was maintained from the femoral artery, and postoperative aortography showed intact tributaries from the aorta including the intercostal arteries. Postoperative paraplegia is an extremely rare complication of operations on the aortic arch; however, we speculate that the paraplegia in this patient could be attributed either to a steal phenomenon involving the radicular artery, or to the anatomical particularity of the spinal cord artery described by Cole and Gutelius as the "segmental system". PMID- 8680126 TI - Successful treatment of bronchial mucoepidermoid carcinoma in an 11-year-old boy by bronchoplasty: report of a case. AB - We report herein the rare case of an 11-year-old boy in whom mucoepidermoid carcinoma of the right upper lobe bronchus was successfully treated by bronchoplasty. The patient underwent bronchoscopy to investigate the cause of relapsing respiratory infections over the past 2 years, which revealed a tumor at the orifice of the right upper lobe bronchus. Thus, a right upper sleeve lobectomy was effectively carried out, preserving right pulmonary function. The tumor was observed to partially invade the bronchial wall, but not the lung parenchyma. Histological examination confirmed a diagnosis of mucoepidermoid carcinoma, classified as grade 2 by Conlan's classification. The patient has been well and free of recurrence for 3 years postoperatively. PMID- 8680127 TI - Small bowel obstruction caused by a medication bezoar: report of a case. AB - We report herein the rare case of a 26-year-old woman who developed a small-bowel obstruction caused by a medication "bezoar" or enterolith, following the long term ingestion of magnesium oxide cathartics for constipation. Medication bezoars resulting from laxatives or cathartics have rarely been reported and we were only able to find two other such cases in the literature. PMID- 8680128 TI - Left ventricular outflow tract obstruction in hypertrophic cardiomyopathy: presurgical and postsurgical evaluation by computed tomography magnetic resonance imaging. AB - Along with hypertrophy of the left ventricle (LV), hypertrophic cardiomyopathy (HC) is characterized by LV outflow tract (LVOT) obstruction, partly from systolic anterior motion (SAM) of the anterior mitral leaflet; if obstruction is significant, excision of excess subaortic septal myocardium may be indicated. In this study, the ability of computed tomography magnetic resonance imaging (Cine MRI) to provide information about LVOT obstruction was assessed in a series of 37 HC cases undergoing evaluation, including echocardiography (0 to 14 days before), for possible septal myectomy; in 4 cases, Cine MRI was used postsurgically (5 to 25 months after). Blinded to echocardiography results, 3 reviewers analyzed by consensus the Cine-MRI LVOT-long-axis image-loops for SAM grade (none, mild, severe) and "aorta:LVOT signal ratio" (intensity in descending aorta/intensity in LVOT at maximum systolic-flow disturbance). Resting LVOT flow velocities were separately determined using Doppler analysis, permitting differentiation between insignificant (< 30 mm Hg) and significant (< or = 30 mm Hg) gradients. With echocardiography, significant resting obstruction was found in 62% of cases, including 92% treated surgically. A significant association between SAM grade and obstruction was found; all cases with a SAM grade of none had insignificant ([-] predictive value: 100%) and most with a severe grade had significant ([+] predictive value: 78%) obstruction. Signal ratio in the absence of a significant gradient was significantly lower than in its presence; a significant linear relationship between aorta:LVOT signal ratio and resting gradient was found: LVOT gradient = ([2.9] x [signal ratio]) + 22.8. SAM grade did not contribute significantly in obstruction categorization when signal ratio was known. In all cases studied after surgery, SAM grade had decreased from severe to insignificant levels and aorta:LVOT signal ratio had been significantly reduced. Insights into the dynamic nature of the LVOT in HC patients can be provided by Cine MRI, either during their evaluation for surgery or after their septal myectomy. PMID- 8680129 TI - Abnormalities of cardiac sympathetic neuronal and left ventricular function in chronic mitral regurgitation: assessment by iodine-123 metaiodobenzylguanidine scintigraphy. AB - Myocardial uptake of iodine-123 meta-iodobenzylguanidine (123I-MIBG) was measured using scintigrams at rest in 12 patients with isolated, nonischemic mitral regurgitation (MR; regurgitant fraction 64% +/- 7%) and was related to the left ventricular (LV) function assessed by cardiac catheterization. Iodine-123 meta iodobenzylguanidine activity in the upper mediastinum, liver, and lung was comparable between MR and control (n = 8) patients. The heart-to-mediastinum 123I MIBG activity ratio 4 hours after injection was significantly (p < 0.01) decreased in MR (2.0 +/- 0.1, mean +/- SE) compared with control (2.7 +/- 0.1) with the increased clearance of MIBG. In addition, MR patients had significantly greater heterogeneity in the 123I-MIBG distribution within the myocardial images (26.1% +/- 2.1% intraimage variability for MR versus 15.6% +/- 0.8% for control, p < 0.01). Myocardial 123I-MIBG activity correlated positively with cardiac index and negatively with pulmonary capillary wedge pressure and LV volume indexes. Thus, 123I-MIBG scintigrams can be a noninvasive method for assessing the contractile dysfunction in MR. PMID- 8680130 TI - Transesophageal echocardiographic color Doppler evaluation of pulmonary vein flow during ventricular pacing. AB - Hemodynamic changes induced by ventriculo-atrial retroconduction has been considered an important factor in pacemaker syndrome. The contraction of atrial muscles, when the mitral valve is closed, induces a reverse systolic flow into the pulmonary veins, because the outlet of the pulmonary vein in the left atrium is not protected by a valve. The profile of the pulmonary vein forward flow of 25 patients was examined using transesophageal echocardiography (TEE) technique. Doppler evaluation of velocity-time integrals of forward flow (fVTI) and reverse flow (rVTI) was measured both during sinus rhythm or fully automatic (DDD) pacing, and ventricular demand pacing (VVI) accompanied by ventriculoatrial (VA) retroconduction or atrioventricular (AV) dissociation. The mean fVTI was reduced from 21.1 cm +/- 6.2 cm in DDD or sinus rhythm (SR) to 16.4 cm +/- 6.6 cm in VVI (p < 0.001). The mean rVTI was increased from 1.4 cm +/- 0.8 cm in DDD or SR to 4.3 cm +/- 1.8 cm in VVI (p < 0.001). The degree of such alterations varied considerably from patient to patient and this may explain the variability of clinical symptoms reported for pacemaker syndrome. It has not been possible to establish a direct correlation between the magnitude of hemodynamic changes and the severity of the symptoms observed because all the patients were in sequential stimulation or in SR and were temporarily submitted to VVI stimulation during the echocardiographic examination. PMID- 8680131 TI - Valve design characteristics and cine-fluoroscopic appearance of five currently available bileaflet prosthetic heart valves. AB - Bileaflet prostheses are low profile, central flow orifice devices that show excellent hemodynamic performance and low thrombogenicity. Five models are currently used for heart valve replacement. Comprehensive and comparative studies regarding valve characteristics and functioning are lacking, making the updating and the familiarization by physicians and cardiologists with these prostheses difficult. We describe the valve design characteristics and evaluate the cine fluoroscopic appearance and functioning of 387 bileaflet prostheses that have been implanted in 367 consecutive patients. The valve types are St Jude Medical (n = 69), Edwards-Duromedics (n = 74), Carbomedics (n = 1290) Sorin Bicarbon (n = 88) and Jyros (n = 27). The prostheses' fluoroscopic appearance was evaluated through multiple radiographic views (Siemens-Elema equipment with C-arm); the prostheses' functional evaluation was performed by obtaining the "tilting disk projection" (ie, with the radiographic beam parallel to both the valve ring plane and the tilting axis of disks) to calculate opening, closing, and travel angles of the disks. This study shows that each of the five bileaflet valves has distinctive design characteristics. Fluoroscopy is an easy, readily available, and useful technique that correctly identifies the prosthesis type and properly evaluates its functioning in the majority of cases. PMID- 8680132 TI - Symposium: gender differences in cardiac imaging. PMID- 8680133 TI - Are there gender differences or issues related to angiographic imaging of the coronary arteries? AB - The use of coronary angiography and coronary interventions in women with suspected coronary artery disease has recently come under close scrutiny. Clear differences in the utilization of these procedures, including coronary artery bypass graft (CABG) surgery have led to concerns that a bias may exist against the use of these procedures in women. Alternative explanations of these perceived practice differences have focused on their propriety based on patients' ages, underlying disease severity, expected prevalence of coronary disease and comorbid conditions rather than physician bias. The possibility that these procedures are over utilized in men has also been suggested. Pertinent to this debate are historical observational data suggesting that women may be at higher risk of major complications of coronary interventions and CABG surgery. Because coronary artery disease is the most frequent cause of death among women in the United States, there is some sociopolitical urgency in addressing these important concerns. This article reviews the use and findings of diagnostic coronary angiography in women with suspected coronary artery disease. Specific risks to women who have coronary angiography performed are also discussed. Finally, the outcome of percutaneous coronary revascularization procedures in women compared to men is discussed. PMID- 8680134 TI - Gender-related imaging issues in assessment of coronary artery disease by nuclear techniques. AB - Heart disease is a major threat to women's health. However, noninvasive evaluation of women for the presence of significant heart disease is often problematic. Cardiovascular nuclear tests interrogate different consequences of physiologically significant coronary artery disease (CAD). Myocardial perfusion imaging supplies information about regional myocardial blood flow. Radionuclide angiocardiography provides information about ejection fraction and regional wall motion. Infarct and metabolic imaging yield information about myocardial viability. This article briefly discusses the concepts and radionuclides involved in cardiovascular nuclear testing and reviews published studies as they relate to assessment of coronary artery disease in women. Myocardial perfusion imaging is a reasonable test for detection of coronary artery disease in women, especially when attenuation artifacts from breast tissue are taken into account. Intravenous dipyridamole stress provides comparable overall accuracy in women and men although women reportedly have a higher incidence of side effects; gender specific data have not been reported for adenosine. Sufficient gender-specific data are also not currently available for either 99mTc or positron-emitting perfusion tracers. Exercise radionuclide angiography can help determine the probability of significant left main or severe three vessel disease but provides only limited prognostic information in women with CAD. Thus in women, although choice of testing using nuclear techniques depends in part on local experience and expertise, myocardial perfusion imaging appears preferable to radionuclide angiocardiography for detection of significant CAD. To determine the most accurate methods to evaluate women for the presence of significant CAD, all current and future studies of diagnostic testing for CAD should analyze data separately for women and men. PMID- 8680135 TI - Are there gender differences related to stress or pharmacological echocardiography? AB - Coronary artery disease (CAD) is the leading cause of adult mortality in the United States. Data collected from the era preceding contemporary revascularization techniques indicated that chest pain syndromes among women carried a more favorable cardiac prognosis than such symptoms in men. More recent information indicates that many women with chest pain do not have CAD and that, among those who do, clinical manifestations first appear an average of 10 years later than in men, at a time when risk factors and comorbidities such as diabetes, hypertension, and hypercholesterolemia are more prevalent. The toll that this disease exacts among women catches up with that among men after women go through menopause, so that coronary heart disease accounts for nearly equal annual mortality rates in the two genders and for more deaths among women than is attributable to all cancers. The initial, widely held impression that chest pain is more benign in women is being replaced by a growing awareness that coronary disease is not. It appears from published experience that any potential bias in the management of women with possible CAD is overcome once the diagnosis is established. It is clear that a reliable method for the evaluation of women with known or suspected CAD is required. Stress electrocardiography, perfusion imaging, and radioventriculography suffer from a number of limitations, particularly in women. This paper discusses the rationale for and performance of stress echocardiography. Although the specific application of this method in females has been the subject of relatively limited clinical investigations, we believe that it holds great promise as the diagnostic test of choice for women. PMID- 8680136 TI - Are there gender differences regarding coronary artery calcification. AB - This article reviews the current knowledge about coronary artery calcification in women, concentrating on the pathophysiology of atherosclerotic calcification, the gender and age differences in the detection of calcification by electron beam computed tomography (EBCT), and the clinical significance of detected coronary calcium. The effects of estrogen and vitamin D on vascular calcification are examined with respect to data that point to similarities between the processes of calcification and bone matrix formation. Gender and age differences in EBCT coronary calcium detection, with emphasis on differences and consequences of calcium prevalence, are also examined. Lastly, the diagnostic and prognostic significance of coronary calcification is discussed, noting that it is more significant in symptomatic, older, and high-risk adults than it is in younger individuals of either gender. PMID- 8680137 TI - Diagnosis of coronary artery disease in women: roles of three dimensional imaging with magnetic resonance or positron emission tomography. AB - Diagnosis and assessment of coronary artery disease (CAD) is especially difficult in women. The history of chest discomfort and various noninvasive tests each have particular problems, which indicate the need to consider more accurate tests such as cardiac magnetic resonance imaging (MRI) and positron emission tomography (PET). MRI of cardiac function at rest and during dobutamine stress has good accuracy, and MR Myocardial perfusion imaging (MPI) with gadolinium DTPA looks promising. The most exciting MR method is cineangiography (MRA), which images blood flow through the coronary arterial lumen as an intense signal. In an initial clinical trial this method showed excellent sensitivity and fair specificity in patients in whom adequate images could be obtained. MR spectroscopy (MRS) has imaged changes in high energy phosphates in patients with severe coronary stenoses during handgrip exercise, but is still experimental. PET MPI corrects the images for attenuation problems that limit the use of other radionuclide imaging procedures in women more than in men. Many studies show excellent sensitivity and specificity to diagnose CAD by PET MPI. In view of its clinical validation and the safety of dipyridamole relative to dobutamine, PET MPI appears to be the best test for assessing CAD in women. The greater accuracy of PET (or perhaps of fully developed MRI/MRA systems) will produce better clinical outcomes and cost-effectiveness for most patients than will less accurate modalities, despite their higher initial cost. PMID- 8680138 TI - Offline assessment of atherosclerotic coronary calcium from electron beam tomograms. AB - Coronary calcium screening using electron beam computed tomography (EBCT) is being applied clinically and for research purposes. We compared the accuracy of a specialized image analysis system with the standard proprietary software in the scanner's host computer. Sixty-seven symptomatic patients underwent coronary angiography and EBCT. Tomograms were analyzed using the proprietary software included in the scanner and with a specialized coronary calcium scoring work station. Sensitivities, specificities, and receiver operating characteristic curve areas were calculated for the proprietary software and the specialized system using the angiographic definition of disease of at least one stenosis causing greater than 50% luminal narrowing. There were no significant differences between the proprietary and the specialized software's accuracy. Receiver operating characteristic curve areas were 0.84 and 0.82 for proprietary software, respectively. During a 50 minute analysis session, the average number of studies analyzed were 12.6 +/- 1.7 using the proprietary software and 23.2 +/- 5.7 using the specialized software (P = .02).Image analysis was thus found to be more rapid using the specialized software. The specialized coronary calcium analysis system is as accurate as the proprietary software for scoring EBCT for coronary calcium. The reduction in analysis time makes the specialized system the preferable method. PMID- 8680139 TI - Adenosine triphosphate stress echocardiography in the detection of myocardial ischemia. AB - The purpose of this study was to assess feasibility and safety in the diagnosis of coronary artery in the diagnosis of coronary artery disease and myocardial ischemia using adenosine triphosphate (ATP) stress echocardiography. ATP, a product of human myocardial tissue, is more potent than adenosine in increasing coronary blood flow. Like adenosine, ATP also has a short half-life (<10 s). Left ventricular echocardiograms were recorded during step-wise infusions of ATP in 86 patients who underwent coronary angiography and stress thallium 201 scintigraphy. No serious complications occurred with ATP infusion and most of the side effects were mild and transient. Significant coronary artery disease (>75% diameter stenosis) was present in 34 of 48 patients who had normal echocardiograms at rest. The sensitivity and specificity of ATP-induced wall motion abnormalities for coronary artery disease was 65% (22 of 34) and 100% (14 of 14), respectively. The sensitivity was 50% (10 of 20) in those with one-vessel disease and 86% (12 of 14) in those with multivessel disease (P < .05). In patients with normal echocardiograms at rest and without prior myocardial infarction, the sensitivity of ATP stress echocardiography for the detection of myocardial ischemia assessed by 201Tl single proton emission computed tomography was 58%, with a specificity of 76%, and a diagnostic accuracy of 66%. The sensitivity was 43% in those with one-vessel disease, and 86% in those with multivessel disease (P = .05). In patients with prior myocardial infarction, the sensitivity of ATP stress echocardiography for the detection of viable but jeopardized myocardium was 81%, with a specificity of 91%. The patients with well-developed collateral circulation had a higher incidence of developing wall motion abnormality than those without collaterals (70% v 40%, P < .01). ATP stress echocardiography is valuable for the assessment of coronary artery disease in patients with multivessel disease, coronary collaterals, and with prior myocardial infarction. PMID- 8680140 TI - Three-dimensional transabdominal ultrasound identification of aortic plaque. AB - Tree-dimensional (3-D) reconstruction of acquired tomographic images in adults has recently been described. With an adaptation of this technique, we performed 3 D reconstruction of transabdominal images of the abdominal aorta to test the hypotheses that 3-D reconstruction of the abdominal aorta is feasible and that 3 D images have incremental value over 2-D in the detection of atheromatous plaque. Twenty-one patients undergoing contrast aortography (Aogram) for clinical indications (1 abdominal aorta (AA) aneurysm, 5 peripheral vascular disease, 1 renal artery stenosis, 14 renal donors) were studied using a 5-MHz annular array probe fitted to a mechanical registration device. In 13 of 21 patients, adequate 2-D ultrasound slices were acquired around a 180 degrees rotation and stored as a volumetric data set using a dedicated computer and 3-D images were reconstructed off-line. Three-dimensional and planar images were blindly compared with Aograms using the following scale: grade 1, normal; grade 2, increased echodensity of the intimal surface; grade 3, local intimal thickening and/or luminal irregularity; and grade 4, protruding mass. Analogous 3-D images were produced in all 13 patients with branching vessels visible in 3 of 13. In 10 patients, the Aogram was interpreted as normal. Compared with Aogram, blindly interpreted 3-D images were compared and correctly identified normal AA in 8 of 10 and atherosclerotic plaque (grade 3 or 4) in 2 of 3. Discordant results were present in 2 of 10 normal aortas and 1 of 3 disease aortas. When 2-D (planar) images were compared with Aograms, 8 of 10 identified normal AA and 3 of 3 aortas with grade 3 or 4 plaque. Thus, in 2 patients, 3-D and planar images suggested atherosclerotic changes not seen by Aogram. Transabdominal 3-D imaging of the abdominal aorta is a feasible technique. Early data suggest that 3-D imaging may distinguish normal from moderate to severe disease, but currently has no demonstrable incremental value over conventional 2-D images. These early results in a small number of patients suggest that this promising technique warrants further evaluation. PMID- 8680141 TI - Intravascular ultrasound imaging of coarctation of the aorta: animal and human studies. AB - Although the use of balloon dilation for treatment of native and recurrent coarctation of the aorta (coA) has become widespread, the optimal balloon size and postdilation vessel wall changes remain undetermined. Intravascular ultrasound (IVUS) imaging has emerged as a an important adjunct in the treatment and follow-up of patients with coronary artery and peripheral vascular lesions, and has been used for evaluation in a limited number of patients with CoA. We used a combination of balloon dilation/ultrasound imaging catheter in animals with experimentally-induced CoA. We used a combination balloon dilation/ultrasound imaging catheter in animals with experimentally-induced CoA . This technique provided real-time data regarding aortic wall morphology and luminal diameter during balloon angioplasty of the CoA. In humans, we used IVUS to study CoA before and after both transcatheter and surgical therapy. IVUS was more sensitive than angiography in the detection of intimal tears post-balloon dilation and in the evaluation of vessel wall changes and remodelling observed at follow-up after relief of CoA. IVUS may provide valuable information regarding vascular wall changes that predict aneurysm format ion, restenosis, or a successful result after balloon dilation. PMID- 8680143 TI - Diagnosis of myocardial stunning: a new use for myocardial contrast and dobutamine echocardiography. AB - Myocardial stunning is a recently described phenomenon in which myocardium subjected to short-lasted episodes of ischemia remains hypokinetic or even akinetic (stunned) after adequate flow is reestablished. Therefore, diagnostic technique that can assess regional perfusion could be of value in establishing this diagnosis. This postischemic abnormality in contractility can last minutes, hours, or days, but eventually recovers. Faster recovery of function occurs under inotropic stimulation, and this knowledge has been applied clinically to diagnose this entity, ie, with the use of dobutamine echocardiography. This article is a review of current literature on the use of dobutamine echocardiography and of myocardial contrast echocardiography, two techniques found to be useful in the diagnosis of myocardial stunning. PMID- 8680142 TI - Electron-beam computed tomographic detection of coronary calcification in patients undergoing percutaneous transluminal coronary angioplasty: predictability of restenosis. A preliminary report. AB - Coronary artery calcification is a recognized marker for coronary atherosclerosis; however, the relationship between calcification and the success of balloon angioplasty at a calcification site has not been determined. The purpose of this study was to evaluate whether the presence of coronary artery calcification, as detected by electron bean computed tomography (EBCT), was predictive of restenosis after percutaneous transluminal coronary angioplasty (PTCA). Site- specific coronary calcification was determined by EBCT in 20 patients with 24 lesions before, immediately after, and 2 to 18 month after PTCA. Calcification was scored using >130 Hounsfield units and >1.02-mm2 area criteria. Coronary calcium at the PTCA site was significantly greater in restenosed versus nonrestenosed patients (109.16 +/- 198.16 mm2 v 4.39 +/- 9.50 mm2) (P < .025). The amount of coronary calcium did not change as a result of the PTCA procedure (+2.72 +/- 22.31 mm2 v -4.81 +/- 7.82 mm2) (P = NS). The rate of progression of calcification was not greater in restenosed versus nonrestenosed patients (1.78 +/- 3.32 mm2/month v 0.09 +/- 0.19 mm2/mo) (P = NS). Site-specific coronary calcification as determined by EBCT appeared to be predictive of patients with an increased likelihood to restenose after PTCA. Further studies are needed to verify these observations in a considerably larger patient population. PMID- 8680144 TI - FDG uptake within regionally stunned myocardium. AB - Clinical cardiologists are now aware of several conditions in which myocardial function can be depressed in the absence of overt ischemia or infarction. Myocardial stunning refers to a particular situation in which the contractile state of the myocardium remains depressed after a brief period of ischemia and reperfusion. Positron emission tomography has been shown to be an important tool for identifying viability within stunned myocardium on the basis of enhanced fluorine 18-fluorodeoxyglucose (FDG) uptake relative to perfusion. This image pattern has been referred to as a ?flow-metabolism mismatch? and is predictive of patients who would benefit from reperfusion therapies. This review highlights the importance of considering the time course of altered FDG uptake within regionally stunned myocardium. PMID- 8680145 TI - Metastatic spread of cervical carcinoma to the right ventricle and pulmonary arteries: diagnosis by ultrafast computed tomography. AB - A case of previously undiagnosed cervical carcinoma metastatic to the right ventricular cavity and the central and peripheral pulmonary arteries is presented. The usefulness of ultrafast computed tomography in comparison with echocardiography for the evaluation of suspected metastatic diseases to the heart and pulmonary arteries is discussed. PMID- 8680146 TI - Microscopic evaluation of an occluded intracoronary Palmaz-Schatz stent removed before coronary artery bypass grafting. AB - Intracoronary implantation of stent devices is a new interventional technique with a promising role in the treatment of acute coronary occlusions caused by intimal dissection and suboptimal results of percutaneous transluminal coronary angioplasty. However, the prolonged presence of stent material embedded in the arterial wall may generate unknown late consequences. Major complications consist of subacute to chronic occlusion and restenosis. To elucidate the underlying cause we removed an angiographically occluded intracoronary artery Palmaz-Schatz stent before coronary artery bypass grafting. Scanning electron microscopy showed thorough coating of the metal struts of the stent by normal neoendothelial cells. Side branches arising at the level of the stent were patent. According the specific angiographic feature thrombotic occlusion originated distally of the stent. PMID- 8680147 TI - The effect of a handicapped child upon a family. AB - Each family is individual in the way it reacts and adjusts to a handicapped child. How and when staff first break the news is important. It can affect the way the parents are able to cope and adjust. If midwives and other staff handle and speak about the baby in a positive, accepting way, this will help the parents to do so too. Parents often need to grieve for the "normal" child they have lost. The parents' relationship may break down under the physical, social and financial strains. The health visitor or social worker may be able to help. Some families grow closer as a result of a handicapped child, others become dysfunctional. Siblings' needs may be overlooked. Here again, the health visitor or social worker may be able to help. PMID- 8680148 TI - Managing pregnancy sickness and hyperemesis gravidarum. AB - The causes of nausea and vomiting in pregnancy are still not clearly understood, nor is there one simple, effective treatment. Nausea and vomiting do not appear to be associated with fetal morbidity, malnutrition or death. Carbohydrate-rich snacks at frequent intervals seem to provide relief. Health education on healthy sandwiches and snacks should be given. Hyperemesis gravidarum-severe vomiting in pregnancy-requires management in hospital to restore electrolyte balance and prevent severe dehydration. PMID- 8680149 TI - Pregnancy sickness and symptoms: your questions answered. AB - A recent prospective study of 363 pregnant women found that 20% had no symptoms of nausea and vomiting, 28% just feel sick, and 52% feel sick and vomited. Symptoms peak at about the ninth week of pregnancy and often stop suddenly by about the 14th week. Two-thirds of women will have similar symptoms in successive pregnancies. Extrapolating from this study, it is likely that 8.5 million working days per year are lost because of pregnancy, nausea and vomiting. "Epsiodic daytime pregnancy sickness" is a more accurate term than "morning sickness" for this condition. PMID- 8680150 TI - Aids to breast feeding: a look at some of the products. AB - Education about breast feeding is important, as is correct positioning and practical support from midwife, health visitor or counsellor. A number of products can be purchased from pharmacies and other outlets which claim to help breast feeding in various ways. These include nipple creams and sprays, breast pads, nipple shields and shells, pumps, and equipment to store expressed breast milk. Mothers seem to find many of these helpful, often to overcome difficulties at a particular stage of breast feeding. Certain breast creams are currently prescribable on the NHS. A glass or polycarbonate receiver with PVC bulb can also be prescribed on form FP10. PMID- 8680151 TI - Remedies for common family ailments: 1. Indigestion and heartburn. AB - Antacids are a useful remedy for the common complaint of indigestion. But if indigestion persists, the patient should seek medical advice and look at whether his or her life-style is contributing. Antacids should be taken in response to symptoms, usually after meals, to react to the surge of acid produced by the body to digest food. Antacids can interfere with drug absorption, so patients on other medications should ask a pharmacist's advice on the timing of their antacid dose. Liquid or soluble preparations act faster than tablets. Take care before recommending an antacid if your patient is: a) pregnant (most over-the-counter antacids are not contraindicated in pregnancy, but it is safest to check with the doctor or pharmacist, particularly for someone in early pregnancy) b)suffering from symptoms which might suggest a more serious, undiagnosed condition, eg cancer. c) already on other medication or on a low-sodium diet. PMID- 8680152 TI - Children with special needs: a special challenge to us all. PMID- 8680153 TI - Preventing heart disease among school children. PMID- 8680155 TI - Cholesterol screening and heart disease. PMID- 8680154 TI - Update on the "sick placenta syndrome". Pre-eclampsia: still a difficult disease. AB - Pre-eclampsia (PE) and eclampsia is the leading cause of maternal death in the UK and a major cause of perinatal morbidity and mortality. PE is predominantly a disorder of first pregnancy. There is a genetic component. PE is a syndrome without a defined cause. The variability with which it presents, and the speed with which it progresses, make it hard to diagnose. High blood pressure and proteinuria, with or without oedema, are classic symptoms but it may also present in an unusual way, eg as jaundice; as proteinuria with normal blood pressure; as intra-uterine growth retardation; as abdominal pain. The placenta becomes "sick" because of restricted blood flow from the mother; an unknown factor causes disturbances to spread throughout the mother's circulation which may lead to blindness, strokes, liver rupture and death. Delivery of the placenta is the only effective treatment, but preventive options being explored include aspirin and calcium supplements. PMID- 8680156 TI - Why research and development? PMID- 8680157 TI - Teaching parents to look after children's teeth. AB - Children's toothpastes with fluoride help to prevent decay, but parents should ask their dentist before giving fluoride supplements to children. Overdosage is harmful. Sugars eaten as part of a meal do less harm to teeth than those eaten frequently as snacks. Sugar-free infant drinks and children's confectionery are now on the market and are more "tooth friendly". Look out for the "happy tooth" symbol. Babies can be registered with NHS dentists as soon as the first teeth start to come through, and should be taken regularly to the dentist throughout childhood. Under the NHS scheme, dentists are paid a capitation fee to provide continuing preventive care and treatment for children free of charge. PMID- 8680158 TI - Predicting preterm delivery: the fetal fibronectin test. AB - Preterm labour and delivery is a major problem and the leading cause of perinatal death in the UK. At present it is virtually impossible for doctors and midwives to predict when preterm labour is about to start. A new test may help with this problem. It detects the presence of fetal fibronectin in the vagina, which may indicate that the cervix is preparing to begin labour. Although these are early days, the fibronectin test looks promising. It is suitable at present for high risk patients. Further studies are needed before its use can be justified as a screening test for low-risk women. PMID- 8680159 TI - Remedies for common family ailments: 2. Coughs and colds. PMID- 8680160 TI - Child behaviour problems: contracting with parents. AB - The time of professional workers is limited and expensive and needs to be used effectively. Parents of young children with behaviour problems often ask health visitors and other professionals for help, but this can slip into long-drawn-out, unproductive interactions without clear goals. Making a contract with the parents can result in a more effective, clearly structured interaction which is economical of professionals' time. To make a successful contract requires the agreement of both professional and parents. There are three distinct stages to the process of making a successful contract: consultation, negotiation and intervention. Goals and objectives must be established and the contract should be written down and progress recorded. PMID- 8680161 TI - Teenagers and sex: a suitable case for education. AB - Approximately 1:5 sexually active girls become pregnant by the age of 20, and one third of these pregnancies end in termination. Low income and low social class are associated with high rates of contraceptive failure. Sexually active girls who have received sex education are significantly more likely to use an effective contraceptive method. Girls around the age of 18 are usually highly fertile. Barrier methods used over at least five years reduce the risk of cervical cancer. Mortality and morbidity rates are high in babies born to young teenage mothers. PMID- 8680162 TI - Analgesia in labour: a review of the TENS method. AB - Transcutaneous electrical nerve stimulation (TENS) applies controlled mild electrical stimulation to the skin by means of electrodes. Stimulating peripheral nerve endings in this way seems to inhibit the transmission of painful impulses at the dorsal horn of the spinal column, and/or activate some of the descending pain-inhibitory systems above the spine. TENS may also stimulate the body to produce natural endorphins and enkephalins, morphine-like substances which have an analgesic effect. TENS has been successfully used for the relief of short-term post-operative and post-traumatic pain and for chronic pain. Midwives are permitted to use TENS under their Code of Practice. There is no evidence that TENS causes any harm to mother and baby. Women seem to like using it in labour, perhaps partly because it is a method they themselves can control. This may confer a psychological benefit which in turn may make pain seem more manageable. Research findings tend to support the effectiveness of TENS for pain relief but several of the studies suffer from methodological drawbacks. One study compared TENS with Entonox, pethidine and epidural anaesthesia. Results showed that TENS and Entonox were both effective and popular methods with women who had short labours and needed no other form of analgesia. PMID- 8680163 TI - A public health nurse in Nepal. PMID- 8680164 TI - Episiotomy: does it have to hurt so much afterwards? AB - Episiotomy is one of the commonest surgical procedures in the UK. Many women suffer pain for several days sometimes weeks afterwards and dyspareunia may be a problem. Absorbable suture materials appear to be preferable to non-absorbable ones. Infiltrating the perineum with normal saline before suturing may help reduce postpartum perineal pain. Omitting sutures just below the skin surface may cause less pain. More research is needed. The skill of the operator seems to be a factor. Midwives need to evaluate their practice in repairing the perineum PMID- 8680165 TI - Modern management of genital warts in women. AB - Genital warts are common and are a sexually transmitted disease affecting all socioeconomic groups and life-styles. They are caused by the human papillomavirus (HPV) and are highly contagious. Genital warts are often symptomless, but occasionally cause itching, bleeding after intercourse burning and pain. Referral to a Genitourinary Medicine Clinic is recommended, where specialist treatment and counselling are available. Special care is needed with children or if the patient is pregnant. At the clinic, patients may be shown how to treat themselves at home with podophyllotoxin. PMID- 8680166 TI - Remedies for common family ailments: 4. Insect bites and stings. AB - For going abroad, taking the correct anti-malarial medication should have high priority. Insect-repellents are a useful preventative. Products to treat insect bites and stings include astringents local anaesthetics antihistamines corticosteroids and crotamiton. PMID- 8680167 TI - Talking with children: some basic counselling skills. AB - The ability to listen to a child is the starting point of a therapeutic relationship. The nurse should respect the child as an individual. An understanding of child development, particularly of language and thought processes, helps adults to communicate more effectively with children. Play may be an appropriate way of communicating with younger children. PMID- 8680168 TI - Disposables versus reusables: the nappy debate continues. PMID- 8680169 TI - Is direct entry the right route to midwifery? PMID- 8680170 TI - Aware of malaria? PMID- 8680171 TI - Advising your clients on a healthy holiday. AB - Immunisations often need to be started two or three months before departure, so advise clients to consult the practice in good time. A pre-travel health interview can be an excellent focus for health education. Parents of young children going abroad may benefit from advice on infant feeding avoiding sunburn and being up to date with immunisations. Advice on prevention and treatment of gastrointestinal infections is useful, especially for parents of young children. Giving the correct advice for malaria is particularly important. For example, many patients who formerly lived in malarious areas wrongly believe they are immune. These days more holiday makers are asking about HIV and sexual health, giving the nurse a good opportunity for health education about condoms, safer sexual practices and avoiding infection through contaminated needles and blood products. PMID- 8680172 TI - After a cot death: the impact of CONI. PMID- 8680173 TI - Diabetes and pregnancy: current dietary advice. PMID- 8680174 TI - Support after cot death: the CONI programme in action. AB - After a previous cot death, most parents approach the next baby with anxiety as well as joy. The Care of Next Infant (CONI). Programme offers structured support to the parents antenatally and through the first months of the baby's life Key features are weekly visits from the family health visitor, and providing the family with an apnoea monitor or weighing scales and a daily diary to record symptoms. Parents are taught resuscitation skills and the significance of temperature, smoking and positioning the baby on the back or side. Additional support is available from the general practitioner and paediatrician. Evaluation shows that most parents and health professionals consider this a useful scheme and that parents feel reassured by the extra support and advice. PMID- 8680175 TI - Gestational diabetes mellitus. AB - Diabetes sometimes appears for the first time during pregnancy. It is important that all cases are detected, so all pregnant woman should be screened for this condition. Screening protocols vary but usually involve urinalysis at all clinic visits plus a blood glucose test, taken after a meal, at 24-28 weeks. Risk factors include increasing maternal age (25 years upwards); obesity; family history of diabetes; and previous unexplained stillbirths or babies with congenital abnormalities. There is an increased frequency of gestational diabetes in Oriental women and those from the Indian subcontinent and the Middle East Once diagnosed, careful monitoring of diabetes is essential during pregnancy to minimise complications to mother and baby Mothers should be taught to monitor their own blood glucose levels. There is no place for urinalysis in the management of gestational diabetes mellitus. Advice from a dietitian is important and there should be easy access to a diabetes specialist nurse. The baby may be born large (macrosomia), with an increased risk of respiratory distress syndrome and hypoglycaemia. Hypocalcaemia and hyper-bilirubinaemia are other complications. Mothers may suffer birth trauma and require an assisted delivery because of the baby's large size. Although most women return to normal blood glucose levels in the puerperium, they are at considerably increased risk of developing non-insulin dependent diabetes mellitus in the following years. General education about recognising the symptoms of diabetes should be given, as well as advice about future pregnancies-including the need to seek preconceptual advice. PMID- 8680176 TI - How I coped emotionally with diabetes in my family. AB - Many people need to go through a period of emotional adjustment before they can accept their diabetes. Much skill, patience and understanding is needed from the health professional to help them through this process. Many diabetic people go through a pattern of emotional reactions which are similar to grief reactions. These include shock and disbelief, denial, anger, depression and withdrawal when they realise the diabetes will not go away, and mourning for the loss of a life style that was comfortable, familiar, secure. They also feel the loss of indulging in things they once found pleasurable, and the loss of independence. Finally comes the stage of acceptance. The person's fears of developing long-term complications-going blind, having heart disease, developing gangrene and so on need to be addressed fairly early on. Education about avoiding complications is important but may not be effective until the person has worked through feelings of fear and grief. To the health professional it may seem astonishing that the patient does not comply with the treatment and accept the good advice that is given, but these reactions can often be understood in the light of the emotional adjustments that are taking place. Knowledge alone is not enough. Although health professionals need to give patients information and advice, they also need to help them express their feelings and provide emotional support during the adjustment process. PMID- 8680177 TI - Educating the elderly diabetic at a day hospital. AB - Elderly people who develop diabetes should have an individual programme of education, tailor-made after assessing their physical and social needs. Avoid bombarding them with too much information, much of which may be inappropriate and even frightening. The Day Hospital, with its multidisciplinary team of nurse, doctor, social worker, physiotherapist and occupational therapist, is an ideal setting for educating and supervising the elderly diabetic. Ongoing assessment is provided through regular monitoring, education through games and group discussions, and home visits where necessary PMID- 8680178 TI - Remedies for common family ailments: 5. Sunscreen creams and lotions. AB - Prolonged exposure to strong sunlight significantly increases the risk of skin cancer. Sunscreens provide useful protection from sunburn if correctly used. Some sunscreens contain chemical compounds which work by absorbing UVB wavelengths. Others contain chemicals which act as reflectants of UVA waves, eg titanium dioxide. Stars on the packet indicate how much UVA protection the product provides-the more stars, the more protection. Products are labelled with their sunscreen protection factor (SPF). The higher the factor, the greater the protection. Products used on children should have an SPF of at least 15. Fair skinned and freckled people also need a high SPF as they burn easily. Use products according to the manufacturer's instructions and reapply at intervals and after swimming. Some products combine sunscreen properties with being water resistant perspiration-resistant or insect-repellent. Avoid folklore remedies like coconut oil. It is better to go or a scientifically formulated, branded product. A properly formulated after-sun lotion is advisable in order to counteract the drying effects of the sun on the skin. PMID- 8680179 TI - Tommy's campaign. PMID- 8680180 TI - Homoeopathy: 1--What is it? AB - Homoeopathy is a form of medical therapeutics discovered by Dr Samuel Hahnemann. It is not synonymous with "natural medicine". The principle is of "likes being able to treat likes". Medicines capable of curing symptoms are able to produce those same symptoms in a healthy person. The aim of the homoeopathic remedy is to stimulate the body's immune system to fight the illness Homoeopathic remedies may be drawn from herbs, metals or poisons but are safe because given in very dilute amounts. Homoeopaths treat the whole person rather than the disease itself and a detailed history of the patient's likes, dislikes and habits is taken before a remedy is prescribed. How homoeopathic remedies work is not fully understood but in practice they appear to be effective, as some double-blind studies have shown. Not all illnesses are suitable for homoeopathic remedies alone. PMID- 8680181 TI - Diary of a born-again student. PMID- 8680183 TI - Cystic fibrosis: the breakthrough to gene therapy. PMID- 8680182 TI - One-parent families: some contemporary issues. PMID- 8680184 TI - Sleep: what is normal at six months? AB - Health visitors and general practitioners are often asked for help because of what parents perceive as a baby's sleeping problem. Many parents expect that the baby will be sleeping continuously through the night from a given age, often as early as six weeks old. The conflict between the parents' expectations and the baby's behaviour leads the parents to seek help. Analysis of the first 640 questionnaires received from the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC). Study show that many six-month-old babies have broken nights. Only 16% slept through the night at six months old. Half woke occasionally, 9% woke most nights, 5% woke once every night and a further 17% woke more than once per night, ranging from twice to eight times. For 16% of six-month-olds there was no regular sleeping pattern. Parents use a variety of strategies when the baby wakes at night, including rocking or cuddling, giving a dummy or feeding with milk or another drink. By six months old, 61% of babies slept in a room on their own, but 15% were always or usually brought into the parents' bed if they woke, and 34% sometimes 28% of babies aged six months routinely slept in the parents' bedroom. Knowing that their baby's behaviour pattern is "normal" and shared by many other babies of the same age is often reassuring to parents. PMID- 8680185 TI - The Mid-Staffordshire survey. Getting consumers' views of maternity services. AB - In 1991 Mid-Staffordshire Health Authority surveyed a sample of 639 women living in the district who had given birth approximately seven to eight weeks previously. The response rate was 80%. Approximately three-quarters of women were satisfied with the care they had received from the maternity services, but the responses highlighted several areas for improvement. Main criticisms were lack of information, attitudes of some staff, and of staff having too little time to talk to them. Fewer women than expected were breast feeding, both in hospital and at home, and women reported having problems and wanting more help than they received. PMID- 8680186 TI - Remedies for common family ailments: 6. Analgesics for everyday aches and pains. AB - Injury or infection causes the tissues to release prostaglandins, which stimulate the nerve endings and are interpreted by the brain as pain. People have differing pain thresholds and usually if they say they are in pain, they are. Before advising an analgesic, ask yourself why the pain is there and, if necessary, refer the patient to a doctor for diagnosis. If analgesics are to achieve the optimum effect they should be taken regularly in appropriate doses at the onset of pain. It is wise to consult a pharmacist if the patient is already on other drugs. Analgesics fall into two main groups: the non-steroidal anti-inflammatory drugs (NSAIDs), eg aspirin, paracetamol, ibuprofen; and narcotics (eg codeine). NSAIDs are particularly good for muscle and joint pain. Paracetamol is reasonably safe to use for young children and, when appropriate, in pregnancy. Aspirin should not be given to children under 12 years. PMID- 8680187 TI - Deafness in childhood: 1. Diagnosis and treatment of deaf babies and children. AB - Recent technological advances make it possible to detect hearing impairments in very young babies. Babies as young as a few weeks old can now be helped with hearing aids and early language therapy. The earlier the diagnosis and start of treatment, the better the later performance in speech. Nurses and midwives, together with the parents, are often the first to suspect a baby has a hearing loss. Bear in mind the risk factors--low birth weight, neonatal jaundice, family history of deafness etc-and if in doubt, always refer. There are different degrees of hearing loss and it is possible to be misled into thinking a child with partial hearing can hear normally. Again, if in doubt, refer. Hearing aids are essential for almost all children with sensori-neural hearing loss and can also be helpful for moderate conductive hearing loss. Remember that while some parents are the first to suspect deafness and seek treatment, others may deny their suspicions and even refuse to accept a diagnosis of hearing loss. They want to be able to believe that their child is normal. PMID- 8680188 TI - Toxic shock syndrome. AB - TSS is rare. According to figures from the UK Public Health Laboratory Service there were, on average, 18 cases per year between 1985 and 1990 out of a total population of about 58 million. Only half the cases are associated with tampons. TSS can result from burns, insect bites or surgery and can affect anyone--men, women and children. Symptoms resemble -flu and there may also be a red rash. TSS is a serious illness which can occasionally be fatal, but most cases recover with prompt diagnosis and treatment with antibiotics. Good tampon hygiene can largely prevent the risk of tampon-related TSS. PMID- 8680189 TI - Homoeopathy: 2. In pregnancy and for the under-fives. AB - A correctly prescribed constitutional homoeopathic remedy can increase well-being in the preconceptual period. For infertility, orthodox investigations are essential but where tests are normal then homoeopathic treatment of both pariners can maximise their health and may improve the chances of conception. Homoeopathic remedies can be effective for morning sickness and before and during labour. Arnica is helpful for internal and external bruising of both mother and newborn infant. Some problems of breast feeding respond to the homoeopathic remedy Lac caninum. There is no harm in trying homoeopathy initially for postnatal depression, although severe cases will need orthodox medication. In most conditions there is time to try the holistic stimulus of a homoeopathic remedy to attempt to persuade the body to heal itself. This is a very different principle from the so-called enlightened attitude of some health professionals that there is no harm in trying homoeopathy when orthodox treatment can do no more for the patient. In babies, teething often responds to Chamomilla. The child's susceptibility to certain illnesses, eg recurrent tonsillitis, can be helped by a "whole-patient" homoeopathic remedy, although penicillin may be needed for acute attacks of tonsillitis. In chronic conditions of childhood such as eczema and asthma, homoeopathic doctors believe that correctly chosen remedies are often able to stimulate the body's innate healing ability, leading to an improvement. PMID- 8680190 TI - Health promotion in the home: 1. Food poisoning: the link with home hygiene. AB - The incidence of food poisoning in the UK is increasing substantially, with about 50% arising in the home. Many different organisms cause food-borne infections, including Salmonella, Campylobacter and Shigella. Storing food correctly is important. Many households shop only once a week and food is often kept for several days before being eaten. Standards of domestic kitchen hygiene must be improved if the incidence of food poisoning is to be reduced Hand washing, kitchen cleanliness and disinfection are essential. PMID- 8680191 TI - Problems of family relationships. PMID- 8680192 TI - Asthma in pregnancy: reassurance is justified. PMID- 8680193 TI - Schizophrenia in adolescence: early diagnosis is important. PMID- 8680194 TI - School nursing. Profile of five-year-olds in six primary schools. AB - The health of 295 five-year-olds was screened by a school nurse at six primary schools in a socially deprived area of Wakefield, West Yorkshire, between September 1991 and August 1992. 64% of children were reported by their parents to have a medical condition, mainly asthma and other chest-related conditions (40%), ENT problems (32%) and eczema (19%). The poor health of children identified in this report highlighted the need to strengthen the school nursing service, and improvements are now under way. PMID- 8680195 TI - Why further education for UK midwives? PMID- 8680196 TI - Homoeopathy: 3. Everyday uses for all the family. AB - Homoeopathy is a useful and safe therapeutic tool for all the family but cannot totally replace conventional medicine. It has a place in most chronic diseases; a tendency to recurrent attacks of acute illnesses; and acute conditions not treatable by conventional medicine or where the patient or parent wishes to avoid conventional drugs. The homoeopathic consultation involves a "whole person" approach and involves listening to the patient. Several homoeopathic remedies are suitable for the family medicine chest, eg. Arnica for bruising. Chamomilla for teething and Calendula cream for grazes and scalds. PMID- 8680197 TI - Teaching good care of older people. PMID- 8680198 TI - Overcoming sleep problems in babies and toddlers. AB - In infants, sleep patterns are not so well developed as in adults. More of the infant's sleep is active (REM sleep) than the adult's. There is a wide range of normal sleeping behaviour in infancy, from almost continuous sleeping to less than nine hours out of 24. Nursing advice to parents should be systematic and based on research findings. The nursing process offers a model. A sleep history and sleep diary are useful tools for assessing the problem. Feeding, room temperature and separation anxiety may be contributing to the problem. Bedtime routines may need to be modified. Working closely with the family and finding strategies the parents are comfortable with are important. The parent and the professional are partners in solving the problem. PMID- 8680199 TI - Nappy rash: a pharmaceutical approach. AB - Before dealing with nappy rash, first examine the cause. Simple precautions such as frequent changing of the nappy, cleaning the skin and applying a water repellent barrier cream can prevent some types of nappy rash from occurring. Creams and ointments for nappy rash contain a variety of ingredients such as emollients, water-repellents, antiseptics, astringents and anti-inflammatory agents. Nappy rash caused by Candida (thrush) needs to be treated with specific antifungals, eg clotrimazole, nystatin, miconazole. Rashes which do not settle or which recur frequently should be referred to a doctor for further investigation and treatment. PMID- 8680200 TI - Pregnant and disabled? Don't assume the professionals will understand. PMID- 8680201 TI - Osteoporosis: not just an issue for postmenopausal women. PMID- 8680202 TI - Introducing the new Child Growth Standards. AB - All children should have their length and weight regularly measured at birth and throughout childhood Growth is a major indicator of child health; deviation from the normal is an important pointer to disease or distress. Measurements must be plotted on a centile chart so that any deviation from the normal pattern of growth can be detected and action taken. The new Child Growth Standards supersede the old Tanner/Whitehouse Standards of the 1950s. The new Standards are compiled from measurements of approximately 30,000 children taken from two national surveys. They are more up-to-date and representative than the old data and should be introduced as soon as possible. Midwives have an important part to play by measuring the baby accurately at birth and measuring both parents' heights. Health visitors, school nurses and practice nurses should ensure growth is regularly measured throughout childhood and deviations promptly referred. PMID- 8680203 TI - Failure to grow: lack of food or lack of love? AB - One of the most important criteria for good health in childhood is normal growth. Taking regular accurate measurements of length and plotting them on a centile chart is essential to spot early signs of growth disorders. Be alert for a "zig zag" pattern on the chart: it could indicate psychosocial dwarfism (see opposite). Length is more important than weight for identifying growth disorders. Lack of love, or an adverse emotional or social environment, can cause growth failure even in a child who is eating enough. Such children have a condition called psychosocial dwarfism, which is due to hypopituitarism (too little growth hormone secretion from the pituitary gland). This condition does not respond to growth hormone treatment. Once the child is placed in an alternative environment, eg a good foster home, the hypopituitarism is reversed and rapid "catch-up" growth takes place. It often emerges that such children have been physically, emotionally or sexually abused. PMID- 8680204 TI - A community midwife's week. PMID- 8680205 TI - Remedies for common family ailments: 7. Head lice and scabies. PMID- 8680206 TI - Are all those antenatal visits really necessary? PMID- 8680207 TI - Visit to India: impressions of an English nurse. PMID- 8680208 TI - Deafness in childhood: 2. Are deaf children getting the education they need? AB - Under the 1981 Education Act, deaf children should be assessed for a "Statement of Educational Needs". Deaf children under school age are supported by a peripatetic teacher for the deaf. There are different schools of thought about the best methods for teaching deaf children. Systems include the oral/aural, "Total Communication" and sign language methods Speech and language therapy is important but provision in schools is patchy and there may be disputes about whether it comes under the education or health budget. Ideally, each health district should have a District Children's Hearing Assessment Unit, which accepts self-referrals as well as referrals from professionals. The National Deaf Children's Society recommends that each child should have a key worker to co ordinate the various services. At present the quality of schooling and support a deaf child receives is patchy and depends on the luck of where the parents happen to live. PMID- 8680209 TI - Tackling threadworms. AB - Threadworms are common parasites. They live in the intestine and migrate to the anus, sometimes causing an itchy bottom. Children are often affected, especially the under 10s. Threadworms are not a serious health hazard and parents can be reassured that neither the worms nor the treatment are likely to lead to any harm. The whole household should be treated on the same day. Mebendazole is an effective treatment. Tell the family to keep their nails short and wash their hands and scrub their nails after using the toilet and before meals. These precautions will help prevent a recurrence. Wash underwear and night-wear daily to destroy the eggs. Wear pyjamas or pants at night to help prevent fingers scratching the anal area. PMID- 8680210 TI - Entonox: too useful to be limited to childbirth? AB - Entonox, a nitrous oxide/oxygen gas widely used as an analgesic in child-bith, can be used for other patients undergoing a variety of painful procedures. It is highly effective, safe and easy to use and is under the patient's control. It takes effect within seconds and wears off quickly with no side-effects. It is being used successfully for children as well as adults. Nurses can administer Entonox with suitable in-service instruction, preferably from the local pain service team Portable apparatus is available, similar to that used by midwives in the home and by ambulance staff. There may be situations in general practice or patients' homes where community nurses could use Entonox to relieve pain. PMID- 8680211 TI - 1995: why community nurses need to know their pharmacology. PMID- 8680212 TI - From midwifery to Boots. PMID- 8680213 TI - Health education: what anthropology can teach us. AB - Understanding how or why people from different countries relate to a situation because of their cultural background and experience is helpful whenever health professionals are counselling or teaching. With direct input from the ethnic communities, NHS services are more likely to be responsive to the needs and beliefs of different cultures. Public health ideas from the developed West should never be imported to a developing country without a thorough understanding of the culture of that country. People's beliefs about disease are shaped partly by their cultural background. Lay people voice their experience of disease in a language passed on from generation to generation. A good working rule in health education is to "start where the people are", even if this sometimes means resisting the urge to impart the latest scientific knowledge. PMID- 8680214 TI - Q & A on colds and coughs in babies. PMID- 8680215 TI - Pain relief in labour: how much choice is there? PMID- 8680217 TI - The new maternity benefits: a better deal for some. PMID- 8680216 TI - Treating childhood asthma with nebulised steroids. AB - Nebulised steroids are a very effective form of treatment. A very small dose of steroids is inhaled from a nebuliser in the form of a fine spray of minute droplets which allows the drug to be spread over a wide area of the lungs and rapidly absorbed. Nebulisers can be used from one month old upwards, e.g. in wheezy infants and toddlers. Very ill children too breathless to use other types of inhaler often benefit from a nebulised therapy. Nebulisers often improve compliance, particularly with toddlers. In many children, nebulised therapy maintains lung function as effectively as oral prednisolone, while minimising the risk of systemic side-effects and improving the patient's quality of life. Experienced primary health-care teams can start a child on nebulised therapy in the community, but it should ideally be initiated in conjunction with a local paediatrician skilled in asthma management. Well managed nebuliser therapy can help prevent hospital admissions. PMID- 8680218 TI - Managing children's asthma in primary care. PMID- 8680219 TI - "Weaning and the weaning diet": a summary of the department of health report. PMID- 8680220 TI - "Weaning and the weaning diet": putting the theory into practice. PMID- 8680221 TI - Vaginal thrush: how can we help our clients? AB - Vaginal thrush is a common fungal infection. Recurrent infections occur in about 10% of women. It is important to complete the course of treatment (often clotrimazole (Canesten) pessaries) to eradicate the fungus. A partner who shows symptoms should also be diagnosed and treated. With recurrent thrush, test for diabetes. Simple self-help measures may be helpful, as may attention to personal hygiene. Postmenopausal women are often susceptible because of reduced vaginal lubrication. A vaginal jelly can be helpful. PMID- 8680223 TI - New guidelines for allergic rhinitis. PMID- 8680222 TI - Remedies for common family ailments: 7. What's new in POMs to Ps? AB - Tagamet and Pepcid PM-two potent H2 antagonists for dyspepsia, heartburn and other conditions produced by excess acid in the stomach-are now available from pharmacies without prescription. Making these effective medicines more widely available should help many indigestion sufferers. (NB: these medicines are not recommended during pregnancy or for the under-16s). Indigestion can sometimes be prevented by avoiding spicy foods, alcohol and stress. Enquire about other symptoms and if necessary refer the patient to a doctor. A pharmacist should be consulted if the patient is already taking other medication. Other medicines recently available from pharmacies without prescription are the antacid Mucaine, and Adcortyl in Orabase and Corlan pellets for gum and mouth lesions. Eczema patients can now obtain Hydrocortisone Topical direct from the pharmacy. It was previously not allowed to be sold to treat eczema Haemorrhoid sufferers can now obtain Anusol Plus (containing hydrocortisone) direct from the pharmacy. Hay fever patients can now get Syntaris Nasal Spray without prescription. PMID- 8680224 TI - Health education: learning the techniques of persuasion. AB - Know your audience and tailor your message accordingly. Keep the message simple and straightforward. Consider providing written hand-outs to back up a visual presentation. Provide practical details, e.g. where and when to go for a cervical smear. Repetition is a useful technique. Consider what factors are likely to make the presenter more persuasive--e.g. gender, credibility, appearance. Encourage audience participation. The more thought and effort they put into the session, the more they will retain the message. Nurses, health visitors and midwives should be given more training in how to promote their health messages. Too many health promotion campaigns have disregarded basic techniques of persuasion and the lessons to be learned from advertising and psychology. PMID- 8680225 TI - Treatment of enuresis: some European comparisons. PMID- 8680226 TI - Folic acid: the message we're failing to get across. PMID- 8680227 TI - Staff midwife in a regional SCBU. PMID- 8680228 TI - Iron deficiency in infants and young children. AB - If we are to reduce the incidence of iron deficiency, parents need more education in how to prevent it. Iron deficiency is the most common nutritional problem in early childhood in the UK and may adversely affect development. Breast milk, infant formulae and follow-on formulae all provide enough absorbable iron for the young infant, but the iron content in cow's milk is poorly absorbed. Problems may arise between the ages of six months and two years. While many commercial weaning foods are fortified with iron and vitamin C, there are indications that household foods ("home cooking") do not always provide enough iron. Studies are beginning to suggest that a significant proportion of infants and 2-5 year olds may not be getting enough iron. Foods which contain plenty of haem iron (meat, meat products, and poultry) provide the most readily absorbable iron. Non-haem iron, found in fruits, vegetables and cereals, is not well absorbed Vitamin C improves absorption of iron PMID- 8680229 TI - Advising your client on nicotine replacement aids. PMID- 8680230 TI - Support groups for couples waiting to adopt. AB - Most couples who adopt have been through years of unsuccessful infertility treatment and a rigorous selection procedure by an adoption agency. Adoptions of healthy babies are rare nowadays and couples benefit from a parenthood education and support group where they can meet others in the same position. Couples want professionals to appreciate the special nature of the adopters' position and the long, demanding process they have been through. Don't assume that couples who receive an adopted baby will not need your time or help because (i) they must be competent if they have passed the adoption agency's selection procedures and (ii) they have not been through labor and childbirth. Adoptive couples want you to understand that they are first time parents of a baby with short, turbulent history whom they have received often literally a few days' notice. Sensitive support from midwives, health visitors and practice nurses both before and after the baby arrives is usually needed and appreciated. Adoption of a normal healthy baby is an increasingly rare event in the UK. Only about 1,000 babies under one year old are available for adoption each year, in contrast to about 16,000 in the late 1960s. A couple chosen to receive a particular baby cannot believe their good luck, knowing the huge number of couples still waiting. A happy ending surely-but is it? PMID- 8680232 TI - Sports injuries. PMID- 8680231 TI - Nurses' contribution to the new-look child health services. PMID- 8680233 TI - When is it safe for babies to swim? AB - What factors are important when health professionals are asked "At what age is it safe to take my baby swimming in a public pool?". In a survey of primary health care doctors, no unified approach was identified but many considered immunisation essential before swimming. There is no evidence to support this view. Careful attention to the infant's body temperature is more important. PMID- 8680234 TI - One-to-one midwifery practice: a vision evaluated. PMID- 8680235 TI - The role of nebuliser therapy in cystic fibrosis. PMID- 8680236 TI - Special feeds for special infants: 2. Feeding the preterm baby. AB - Individual babies may differ considerably in the way in which feeds can be introduced, the problems they encounter while this is going on, their final feed requirements and the need for supplementation. Sucking and swallowing reflexes are poorly developed before 32-34 weeks' gestation. Respiratory illness is probably the main reason for delay in the start of milk feeding. Immediate aims are to prevent hypoglycaemia and provide normal fluid requirements, if necessary by IV infusion or tube feeding. Preterm babies have large energy requirements. The mother's breast milk is the best milk with which to begin feeding. If a formula milk is given, it should be a preterm, low birth weight formula which supplies extra energy, protein and minerals, not a standard formula intended for babies at term. PMID- 8680237 TI - Promoting secure attachment patterns in infancy and beyond. AB - The attachment an infant makes to its mother* has a powerful influence over subsequent development. Attachment patterns may be secure, insecure avoidant or insecure ambivalent. They are already established by the age of one year, and are likely to affect future adult relationships, including the marital relationship and relationships with the person's own children. Children with insecure attachments may be more prone to psychological or psychiatric ill health. Family therapy can recognise the relevance of attachment theory and incorporate it when helping families to find new patterns of relating to one another and resolving their difficulties. Early intervention by midwives, health visitors and other primary health care professionals can help prevent faulty attachment patterns from becoming established and so being transmitted from one generation to the next. PMID- 8680238 TI - Remedies for common family ailments: 9. Haemorrhoids. AB - Haemorrhoids or piles are varicosities in the anal canal caused by local pressure. Sometimes they prolapse. Symptoms may include itching, discomfort, pain and bleeding. Haemorrhoids are common in pregnancy. Constipation aggravates piles, so a healthy diet with plenty of water and fibre is advisable. Some sufferers need an appropriate laxative as well. Cleanliness of the anal area is important. Proprietary moist toilet tissues are sold for this purpose and can be soothing and helpful. Relief of symptoms is by haemorrhoid creams, ointments and suppositories. Active ingredients typically include antiseptics, anti inflammatories, anti-pruritics and local anaesthetics. Many are available from pharmacies without a prescription. If in doubt, always refer the patient to a doctor. For example, rectal bleeding may be due to some more serious condition, or pruritus to anal thrush. In the case of children the advice of a doctor should be sought. PMID- 8680239 TI - Government restricts the use of carbaryl for head lice. PMID- 8680240 TI - Work of an HV researcher. PMID- 8680241 TI - Nappies: the rise of reusables? PMID- 8680242 TI - Monitoring the uptake of Hib vaccine in Forth Valley. AB - Haemophilus influenzae type b (Hib) infection is an important cause of morbidity and mortality among young children in this country. Immunisation against the disease using protein conjugate Hib vaccine was introduced in the United Kingdom on 1 October 1992. To monitor the impact of this new vaccine in the routine childhood immunisation schedule in Forth Valley Health Board area, a survey of the parents of 200 children born during August 1992 was carried out. A total of 163 (82%) parents responded. While most parents had heard of Hib vaccine or of diseases caused by Hib, specific gaps in their knowledge were noted. In particular a substantial minority (31%) were not aware of the role of Hib vaccine in preventing meningitis. Among health professionals who advised parents on immunisation, the most important group identified by parents were health visitors, followed by family doctors. Leaflets produced by the Health Education Board for Scotland also formed an important and valuable source of information for parents, as did television, radio and newspapers. Monitoring the uptake of Hib vaccine in the sample of 200 children revealed a high uptake of the three recommended doses (96%), with only one child receiving no immunisations at all. If this level of uptake is achieved in other areas then the full potential of the new Hib vaccine in preventing infection among young children will be considerable. PMID- 8680243 TI - Stroke units: centres of nursing innovation. AB - The results of a survey of stroke units in the English regions of the NHS are reviewed. A total of 43 units were identified and contacted of which 34 responded. The article briefly discusses the nature and development of stroke units and considers features of stroke units that reflect the level of nursing development such as ward nursing philosophy, model of nursing used, method of ward organization, unit manpower and educational attainment. The overall results indicate that the respondent units have achieved a high level of development which has, until now, gone generally unnoticed. PMID- 8680244 TI - Parent participation. 2: Findings and their implications for practice. AB - A qualitative exploratory study was undertaken to examine parents' views and experiences of participation in the care of their child in hospital and to identify factors that inhibit or facilitate participation. Parents of children aged 2-5 years of age were interviewed within 2 months of discharge, using tape recorded, semi-structured interviews. The findings demonstrate that parents clearly wish to participate in their children's care at a level of their own choosing. However, they preferred professionals to be responsible for their children's clinical care, while they continue to be responsible for the children's normal day-to-day care. Problems were identified in the area of relationships between parents and professionals, centred on communication and the continuing paternalistic nature of these relationships. Parents of children who experienced single, short hospital admissions found involvement in their children's care particularly difficult. Guidelines were developed from the results, to facilitate parent participation in the care of children in this age group. PMID- 8680245 TI - The Egerton Convertible II and the Elite 3 bed system. AB - Low air loss bed systems have proved successful in the management of severe pressure sores but they tend to be expensive. The Convertible II promises to provide many of the features of a low air loss bed at a much reduced cost. It is essentially a mattress replacement that can be used for various beds, including contouring-base beds. It is a component of the Elite 3 bed system which comprises an electrically powered contouring bed (with its own air pump) and three different mattresses: the mattress of the Convertible II is Mattress 3 of this system; Mattress 2 is an alternating-pressure air mattress; and Mattress 1 is a static air mattress with a foam envelope. The advantages and disadvantages of these products are discussed and it is suggested that the allocation of patients to the various supports can be facilitated by using a pressure sore risk assessment score. PMID- 8680247 TI - Critical care nurses: what are we worth? PMID- 8680246 TI - Do we need physician assistants in the UK? PMID- 8680248 TI - Homicides and suicides by mentally ill people: resources highlighted. PMID- 8680249 TI - Peripherally inserted central catheters: expanding UK nurses' practice. AB - Peripherally inserted central catheters (PICCs) are a group of single- and double lumen central venous access devices, ranging in size from 2 to 6 FG. In the USA, these devices have been used to establish central venous access since the late 1970s, but they are only just beginning to be introduced into the UK. In the USA, suitably skilled nurses assume responsibility for the placement of the majority of PICCs, both in the hospital and home-care settings (Coulter, 1993). This article will explain how suitably skilled nurses in the UK could expand their clinical practice to include the placement of PICCs, and thereby improve the quality of intravenous access for many patients requiring parenteral therapies. PMID- 8680250 TI - Urinary incontinence management in the USA: the role of the nurse. AB - Urinary incontinence (UI) is a prevalent medical problem in the USA. Approximately 12 million Americans are incontinent of urine. Hu et al (1994) estimate that the costs of managing the problem are $10 billion annually. In persons aged 65 years and older the incidence of UI is 30% or more it is estimated that more than 60% of people with UI never mention their problem to a doctor of nurse. This is a sad fact considering that UI is a highly treatable, if not curable, problem. In the USA, advanced practice nurses, nurse practitioners and clinical nurse specialists who have advanced educational and master's degrees and clinical practice requirements are making a significant impact on the management of UI. This article outlines the role of advanced practice nurses in the diagnosis and behavioural management of UI. PMID- 8680251 TI - Revised mobility allowance: double disadvantage. PMID- 8680252 TI - Helping people with learning disabilities to grieve. AB - Historically, it was believed that people with a learning disability did not grieve. Today, however, new and creative ways of working with and supporting the bereft individual who has a learning disability are being sought. This article addresses the current issues for both the individual with a learning disability who has experienced a bereavement and his/her carers, it advocates the importance of competence in the carer to enable effective support, acknowledges proactive educational approaches to enable the individual to cope more healthily with loss, addresses the education and training forum from a pre- and postregistration perspective, and explores the current deficits and potential research areas within this specialist field. PMID- 8680253 TI - The "in-between' times: video analysis of peer interactions. AB - Research into day services for adults with severe learning disabilities continues to place great emphasis on the importance of structured activities (Seed, 1988). As a result, the policy for a service user's day tends to consist of timetabled activity with formal periods of learning and communication with staff (Social Services Inspectorate, 1992). In reality, however, there can be quite long gaps between activities, which are equally deserving of research interest. These are the 'in-between' times; times of the day when service users are waiting for an activity to be initiated by staff, or simply waiting for something to happen. It is suggested that the 'in-between' times offer similar potential for promoting learning and communication, through more informal and natural interaction. PMID- 8680254 TI - Self-advocacy skills workshop: a report. AB - This article is a report on a 3-day workshop for adults with a learning disability. The group work described formed part of the annual Self-Advocacy Skills Workshop held at the Hayes Conference Centre, Swanwick, Derbyshire. This year's workshop took place on 7-10 January 1996. It is suggested that user oriented events have a number of benefits, including the opportunity to share ideas and work together on important issues. There is considerable value for users in meeting people from other parts of the country. Opportunities for users to share experiences and develop their own self-advocacy and social networks should be encouraged. PMID- 8680255 TI - Rosicrucianism, Lutheran orthodoxy, and the rejection of Paracelsianism in early seventeenth-century Denmark. PMID- 8680256 TI - Medicine in the civic life of eighteenth-century Montpellier. PMID- 8680257 TI - Edwin Chadwick, "mutton medicine," and the fever question. PMID- 8680258 TI - "Simple methods" and "determined contraceptors": the statistical evaluation of fertility control, 1957-1968. PMID- 8680259 TI - Carl Gustav Jung's curriculum vitae from the year 1902. PMID- 8680260 TI - Scope of practice in audiology. Ad Hoc Committee on scope of Practice in Audiology. AB - This scope of practice in audiology statement is an official policy of the American Speech-Language Hearing Association (ASHA). The document was developed by the ASHA Ad Hoc Committee on the Scope of Practice in Audiology and approved in 1995 by the Legislative Council (8-95). Members of the ad hoc committee include David Wark (chair), Tamara Adkins, J. Michael Dennis, Dana L. Oviatt, Lori Williams, and Evelyn Cherow (ex officio). Lawrence Higdon, ASHA vice president for professional practices in audiology, served as monitoring vice president. This statement supersedes the Scope of Practice, Speech-Language Pathology and Audiology statement (LC 6-89), Asha, April 1990, 1-2. PMID- 8680261 TI - Scope of practice in speech-language pathology. Ad Hoc Committee on Scope of Practice in Speech-Language Pathology. AB - This scope of practice in speech-language pathology statement is an official policy of the American Speech-Language-Hearing Association (ASHA). It was developed by the Ad Hoc Committee on Scope of Practice in Speech-Language Pathology: Sarah W. Blackstone, chair; Diane Paul-Brown, ex officio; David A. Brandt; Rhonda Friedlander; Luis F. Riquelme; and Mark Ylvisaker. Crystal S. Cooper, vice president for professional practices in speech-language pathology, served as monitoring vice-president. The contributions of the editor, Jude Langsam, and select the widespread peer reviewers are grateful acknowledged. This statement supersedes the Scope of Practice, Speech-Language Pathology and Audiology statement (LC 6-89), Asha, April 1990, 1-2. PMID- 8680262 TI - Guidelines for the training, credentialing, use, and supervision of speech language pathology assistants. Task Force on Support Personnel. AB - These guidelines are an official statement of the American Speech-Language Hearing Association. They provide guidance on the training, credentialing, use, and supervision of one category of support personnel in speech-language pathology: speech-language pathology assistants. Guidelines are not official standards of the Association. They were developed by the Task Force on Support Personnel: Dennis J. Arnst, Kenneth D. Barker, Ann Olsen Bird, Sheila Bridges, Linda S. DeYoung, Katherine Formichella, Nena M. Germany, Gilbert C. Hanke, Ann M. Horton, DeAnne M. Owre, Sidney L. Ramsey, Cathy A. Runnels, Brenda Terrell, Gerry W. Werven, Denise West, Patricia A. Mercaitis (consultant), Lisa C. O'Connor (consultant), Frederick T. Spahr (coordinator), Diane Paul-Brown (associate coordinator), Ann L. Carey (Executive Board liaison). The 1994 guidelines supersede the 1981 guidelines entitled, "Guidelines for the Employment and Utilization of Supportive Personnel" (Asha, March 1981, 165-169). Refer to the 1995 position statement on the "Training, Credentialing, Use, and Supervision of Support Personnel in Speech-Language Pathology" (Asha, 37 [Suppl. 14], 21). PMID- 8680263 TI - Inclusive practices for children and youths with communication disorders. Ad Hoc Committee on Inclusion for students with Communication Disorders. AB - An array of inclusive service delivery models is recommended for the implementation of services to children and youths with communication disorders. Inclusive practices are intervention services that are based on the unique and specific needs of the individual, and provided in a context that is least restrictive. There are a variety of models through which inclusive practices can be provided, including a direct (pull-out) program, in classroom-based service delivery, community-based models, and consultative interventions. These models should be seen as flexible options that may change depending on student needs. The speech-language pathologist, in collaboration with parents, the student, teachers, support personnel, and administrators, is in the ideal position to decide the model or combination of models that best serves each individual student's communication needs. Implementation of inclusive practices requires consideration of multiple issues, including general education reform, cost effectiveness, and program efficacy. In addition, administrative and school system support, personnel qualifications, staff development, flexible scheduling, and the effects of inclusive practices on all learners need to be considered. At present, available research suggests guarded optimism for the effectiveness of inclusive practices. However, many critical questions have not yet been addressed and additional research is needed to assess the full impact of inclusive practices for students with communication disorders. PMID- 8680264 TI - Guidelines on the audiologist's role in occupational and environmental hearing conservation. Ad Hoc Committee on Occupational and Environmental Hearing Conservation. AB - This position statement is a policy of the American Speech-Language-Hearing Association (ASHA). The document was developed by the Ad Hoc Committee on Occupational and Environmental Hearing Conservation and adopted by the American Speech-Language-Hearing Association (ASHA) Legislative Council in December 1995. Members of the Ad Hoc Committee on Occupational and Environmental Hearing Conservation include Derek Dunn, Rena H. Glaser, Theresa Schulz (chair), Andrew Stewart, Maureen E. Thompson (ex officio), and Vickie Tuten. Lawrence Higdon, ASHA vice president for professional practices in audiology, served as monitoring vice president. This position statement supersedes the 1985 position statement, "The Audiologist's Role in Occupational Hearing Conservation" (LC7-84). PMID- 8680265 TI - Technical report of the Ad Hoc Committee on Multiskilling. AB - This technical report was prepared by the American Speech-Language-Hearing Association (ASHA) Ad Hoc Committee on Multiskilling: Brenda Adamovich, chair; Elise Davis-McFarland; William W. Green; and Arlene A. Pietranton, ex officio. Sandra R. Ulrich, 1993-1995 vice president for quality of service and John E. Bernthal, 1996-1998 vice president for quality of service, served as monitoring officers. The contributions of the Executive Board and select peer reviewers are gratefully acknowledged. Special thanks are extended to Michelle Ferketic and Kirsten Gardner for their assistance in editing this report. Technical reports provide information to members on special issues affecting the delivery of services and/or serve as a basis for the development of a position statement. PMID- 8680266 TI - Clinical practice by certificate holders in the profession in which they are not certified. Ethical Practice Board. AB - From time to time, the Ethical Practice Board or the Council on Professional Ethics determines that members and certificate holders can benefit from additional analysis and instruction concerning a specific issue of ethical conduct. Issues in Ethics statements are intended to heighten sensitivity and increase awareness. They illustrate the Code of Ethics and are intended to promote thoughtful consideration of ethical issues. They may assist members and certificate holders engage in self-guided ethical decision-making. These statements do not absolutely prohibit or require specified activity. The facts and circumstances surrounding a matter of concern will determine whether the activity is ethical. This Issues in Ethics Statement replaces the previous one of the same title. PMID- 8680267 TI - Reference list. Position statements, guidelines, and other relevant papers. PMID- 8680268 TI - Localized administration of sodium nitroprusside enhances its protection against platelet aggregation in stenosed and injured coronary arteries. AB - Sodium nitroprusside, a potent vasodilator, was evaluated for its effect on platelet aggregation in stenosed and endothelium-injured coronary arteries in a canine model. Twenty-five anesthetized dogs were studied; coronary blood flow velocity was continuously monitored. Recurrent intracoronary platelet aggregation and dislodgment (indicated by cyclic variations in coronary blood flow) were induced by mechanically injuring and stenosing the left anterior descending coronary artery. Sodium nitroprusside was administered either intrapericardially or intravenously 30 min after cyclic flow variations were established. Intrapericardial administration of saline (control) did not affect cyclic flow variations in any of 6 tested dogs. Sodium nitroprusside abolished cyclic flow variations in all 7 dogs (100%) when given intrapericardially and in 5 to 7 dogs (71%) when given intravenously (compared to intrapericardial salines, p < 0.01). A smaller dose of sodium nitroprusside was required to abolish cyclic flow variations when given intrapericardially than when given intravenously (1.6 +/- 0.5 micrograms.kg-1.min-1 vs 4.8 +/- 0.8 micrograms.kg-1.min-1, p < 0.01). The mean aortic pressure was reduced by 10 to 20 mmHg after intrapericardial sodium nitroprusside administration and by 30 to 40 mmHg after intravenous sodium nitroprusside administration. To investigate the mechanism of protection by sodium nitroprusside, NG-monomethyl-L-arginine, an inhibitor of nitric oxide synthetase, was used to induce cyclic flow variations in mildly injured and stenosed left anterior descending coronary arteries in 5 dogs. Intrapericardial sodium nitroprusside abolished the cyclic flow variations in all 5 dogs. Then oxyhemoglobin, an inhibitor of nitric oxide, was administered into the left anterior descending coronary arteries of these dogs, and it restored the sodium nitroprusside-abolished cyclic flow variations in all 5 dogs. Thus, sodium nitroprusside protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured canine coronary arteries, probably by the action of nitric oxide, and it is more effective and hemodynamically safer when administered intrapericardially than when administered intravenously. PMID- 8680269 TI - High-risk coronary angioplasty assisted by active hemoperfusion. A feasibility study. AB - We assessed the effectiveness of distal hemoperfusion support during gradual, prolonged balloon inflation during percutaneous transluminal coronary angioplasty in high-risk patients. The patients were identified as having a poor left ventricular ejection fraction ( < 35%), > 50% of viable myocardium at risk percutaneous coronary balloon angioplasty, or both. A total of 64 procedures were performed in 61 patients. Angiographic success was achieved in 83 of 86 (96.5%) lesions treated with hemoperfusion support. Hospital complications included 1 patient who had a non-Q-wave infarction, 1 who had to undergo redo percutaneous coronary balloon angioplasty, and 5 who required coronary artery bypass operations. The hospital mortality was 7.8% (5 patients). This preliminary study indicates that hemoperfusion support can enable expeditious, simple, economical, and effective percutaneous transluminal coronary balloon angioplasty in a subset of labile patients in whom procedural failure frequently leads to sudden death. PMID- 8680270 TI - Is prosthetic valve thrombogenicity related to design or material? PMID- 8680271 TI - Remembering Alexis Carrel and Charles A. Lindbergh. PMID- 8680272 TI - Current status of anticoagulation and thrombosis-related issues in mechanical valves. PMID- 8680273 TI - Carotid endarterectomy. Results in asymptomatic and symptomatic patients. AB - Objective evidence of the benefit of carotid endarterectomy in preventing stroke and its significant sequelae has recently been demonstrated by prospective trials. The salutary results depend on meeting strict operative outcome criteria as established by the American Heart Association. We retrospectively analyzed 265 consecutive carotid endarterectomies performed in 248 patients during 1 year at our institution. The perioperative mortality rate was 0; late mortality occurred 6 months postoperatively in 1 of 2 patients who experienced a perioperative stroke. The combined perioperative mortality and stroke rate was 0.8%. The combined mortality and stroke rate in patient subgroups was 0.7% (1/151) for asymptomatic patients, 1.6% (1/64) for symptomatic patients who had presented with a transient ischemic attack, and 0% (0/50) for symptomatic patients who had presented with a completed stroke. We conclude that the objective postoperative benefits of carotid endarterectomy in treating extracranial cerebrovascular disease can be achieved with low perioperative patient morbidity. PMID- 8680274 TI - Critical decision analysis for extracranial cerebrovascular disease. AB - Results from 6 major prospective studies that have recently been either completed, or terminated prematurely, provide compelling evidence of the benefit of carotid endarterectomy in treating certain groups of patients who have carotid stenosis. Results of these studies show that symptomatic patients (those experiencing transient ischemic attack, amaurosis, or completed mild stroke) with a 70% ipsilateral carotid stenosis have an absolute risk reduction of 39% to 65% for stroke or death when treated with carotid endarterectomy as opposed to medical therapy alone. Asymptomatic patients with a 60% ipsilateral carotid stenosis have 53% absolute risk reduction for stroke or death when treated with carotid endarterectomy, rather than medical therapy alone. Combined neurologic morbidity and perioperative mortality rates for treating carotid stenosis should not exceed 3% in the asymptomatic patient or 5% to 7% in the symptomatic patient, on the basis of criteria established by the American Heart Association. These studies show that prophylactic carotid endarterectomy can effectively reduce the risk of stroke in both asymptomatic and symptomatic patients. Centers specializing in vascular surgery can benefit patients by minimizing the operative risk to levels well below those established by the American Heart Association. PMID- 8680276 TI - Migration of an automatic implantable cardioverter-defibrillator patch causing massive hemothorax. AB - The automatic implantable cardioverter-defibrillator is composed of shocking electrodes (patches or coils), sensing electrodes, and a generator implanted in the abdominal wall. A number of complications with defibrillators have been reported, including migration of the various components. We describe a patient in whom one of the patches, originally sutured extrapericardially, migrated in the right hemithorax and eroded into the ipsilateral lung. The resultant massive hemothorax necessitated urgent thoracotomy, patch removal, and hematoma evacuation. A hybrid implantable cardioverter-defibrillator system was created as a replacement to minimize surgery while protecting the patient from sudden death. PMID- 8680275 TI - Submitral left ventricular aneurysm. Report of 2 surgical cases. AB - Submitral left ventricular aneurysm most commonly occurs among the black population. Nevertheless, this lesion has been described among whites. We report 2 cases of submitral left ventricular aneurysm that we treated successfully by surgery. Case 1 is that of a 52-year-old Brazilian black man with a submitral left aneurysm and mitral incompetence. Case 2 is that of a 25-year-old white man with a history of recurrent stroke; his echocardiographic study showed a small submitral left ventricular aneurysm. Due to the growing incidence of submitral left ventricular aneurysm among the white population, we emphasize the importance of a targeted echocardiographic study in all patients with a history of embolic episodes in the absence of apparent risk factors for embolism. PMID- 8680278 TI - Dissection of the atrial wall after mitral valve replacement. AB - We describe an unusual sequela of mitral valve replacement in a 50-year-old woman who had undergone a closed mitral commissurotomy in 1975. She was admitted to our hospital because of mitral restenosis in November 1993, at which time her mitral valve was replaced with a mechanical prosthesis. On the 8th postoperative day, the patient developed symptoms of heart failure; transesophageal echocardiography revealed dissection and rupture of the left atrial wall. At prompt reoperation, we found an interlayer dissection and rupture of the atrial wall into the left atrium. We repaired the ruptured atrial wall with a prosthetic patch. The postoperative course was uneventful, and postoperative transesophageal echocardiography showed normal prosthetic valve function and no dissection. PMID- 8680279 TI - Blunt traumatic injury of the thoracic aorta following commercial airline crashes. PMID- 8680280 TI - Acquired coarctation of the descending thoracic aorta. PMID- 8680277 TI - Pseudoaneurysm of the free wall of the left ventricle without obstruction of major coronary arteries. AB - We report a case of a 63-year-old woman who presented with pseudoaneurysm of the free wall of the left ventricle secondary to myocardial infarction, in the presence of angiographically normal major coronary arteries. This is the only such case we know of, in which the patient underwent successful surgical correction. At last follow-up, the patient was in good condition with no evidence of cardiac disease, at 9 years after surgery. PMID- 8680281 TI - Currarino-Silverman syndrome and congenital heart disease. PMID- 8680282 TI - Surgical treatment of type A aortic dissections. PMID- 8680283 TI - Subintimal hematoma of the aorta after deceleration injury. PMID- 8680284 TI - Cardiac surgery in Vietnam. PMID- 8680286 TI - New wine in old wineskins. Green Paper outlines rational new approach. PMID- 8680285 TI - Comparison of antegrade with antegrade/retrograde cold blood cardioplegia for myocardial revascularization. AB - There has been increasing interest in the use of retrograde coronary sinus perfusion for delivery of cardioplegic solution during myocardial revascularization. Despite evidence of improved cardiac protection, it is unclear if a combined antegrade/retrograde approach to myocardial preservation offers significant clinical benefits. One hundred twenty patients undergoing elective 1st-time coronary bypass surgery for 3-or-more-vessel disease received aortic root, antegrade cold blood cardioplegia (Group I, n=52) or combined antegrade/retrograde cardioplegia via coronary sinus cannulation (Group II, n=68). All preoperative variables were similar, including age, severity of coronary artery disease, functional status, and ejection fraction. Intraoperative and postoperative variables, including the degree of hypothermia, temperature of infusion solution, number of bypass grafts, defibrillation attempts and spontaneous return to sinus rhythm, the use of intraaortic balloon pump counterpulsation, and inotropic support during weaning from cardiopulmonary bypass, were not statistically different. Cardioplegia infusion time was longer in Group II than in Group I (2.5 +/- 0.8 vs 1.7 +/- 0.7 min, p < 0.05). The postoperative cardia output, electrocardiographic and cardiac enzyme evidence of ischemia, the need for temporary pacing, and 30-day morbidity were similar for both groups. The data indicate that in this non-risk-stratified group of patients, the route of cardioplegia administration is not a determinant of clinical outcome. PMID- 8680287 TI - Practitioners and health policy. Case of the Ontario Drug Benefit Plan. PMID- 8680288 TI - If family medicine certification is the answer, what was the question? PMID- 8680289 TI - "Archaic" coding needs update. PMID- 8680290 TI - Physicians' responsibility toward birth control. PMID- 8680291 TI - Stressing the importance of breastfeeding. PMID- 8680292 TI - Can folate prevent neural tube defects after conception? PMID- 8680293 TI - Current health policy initiatives and options. New-to-practice family physicians' attitudes. AB - OBJECTIVE: To obtain information about new-to-practice family physicians' attitudes toward current health policy options and initiatives. DESIGN: Cross sectional, mailed survey. SETTING: Ontario family practices. PARTICIPANTS: Residency-trained Ontario family physicians (395 of 564 eligible physicians replied) who were certified between 1989 and 1991. MAIN OUTCOME MEASURES: Extent of approval or disapproval for 14 health policy options and initiatives. RESULTS: A 70% response rate was achieved. More than half of surveyed physicians expressed approval for shifting resources from acute care into preventive care and health promotion (71.6% approved), stricter immigration requirements to limit licensing of foreign physicians in Canada (60.4%), offering physicians salaries as an alternative to fee-for-service (54.0%), and incentives to physicians who wish to practise in community health centres or other forms of salaried group practice (51.1%). Some diversity of opinion was associated with sex, type of practice, primary source of remuneration, and practice location. CONCLUSIONS: These new-to practice family physicians display diverse views and should not be seen as sharing a single opinion of health care policy options and initiatives. Many approve of changes to the health care system or are willing to consider policy alternatives. PMID- 8680294 TI - Evaluation of a computer tracking program for resident-patient encounters. AB - OBJECTIVE: To examine the effectiveness of a formal tracking system for residents' clinical experiences. DESIGN: We examined three shifts, selected at random, for each resident (without residents' knowledge) during emergency rotations. Information from patient charts was compared with residents' computerized records for rotation (location and preceptor) and patient (age, sex, diagnosis, and procedure) information. SETTING: The Northeastern Ontario Family Medicine Program, a program designed to provide remote, rural, and northern resident experience. PARTICIPANTS: First-, second-, and third-year residents on emergency rotations in the academic years 1992 to 1994. MAIN OUTCOME MEASURES: Compliance, reliability, and validity of tracking records. RESULTS: Residents recorded patient encounters 88% of the time. Compliance with rotation information was high (100% rotation, 94% preceptor). Agreement on patient age and sex was high. Procedure compliance was somewhat lower (83%). Intrarater reliability (91%) and inter-rater reliability (78%) are acceptably high, as is validity when compared with a gold standard entry (88%). CONCLUSIONS: Regular entry of reliable and valid data is facilitated by the computerized resident-patient encounter tracking program. This computer tool should prove useful for multilevel program evaluation in the future. PMID- 8680295 TI - Medical problems affecting musicians. AB - The physical demands of performing on musical instruments can cause pain, sensory loss, and lack of coordination. Five cases illustrate common problems. Knowledge of the interaction between the technique of playing the instrument and the particular musician can help physicians diagnose and resolve problems. PMID- 8680296 TI - [Early detection of residents in trouble]. AB - Early detection of residents' learning difficulties helps teachers offer appropriate help. During a series of educational workshops, a variety of behaviours associated with learning difficulties were described and four behavioural categories were established: limited cognitive response, disturbed affective response, deviant moral response, and diminished self-motivation. PMID- 8680297 TI - Timely referral of infants with jaundice: case report. AB - Family physicians should see all infants between 2 and 4 weeks of age to exclude persistent jaundice. Early identification of infants with jaundice due to liver disease might lead to better outcomes not only for infants with extrahepatic biliary atresia but for all infants with neonatal liver diseases. The case illustrates the consequences of late identification. PMID- 8680298 TI - Localized granuloma annulare and autoimmune thyroid disease. Are they associated? AB - This case report identifies a temporal relationship between the diagnosis of localized granuloma annulare and the subsequent development of primary hypothyroidism in a previously healthy 10-year-old girl. We suspect these disorders are associated, but any association between them requires further study. PMID- 8680299 TI - The query corner. Foramen of Winslow adenopathy. PMID- 8680300 TI - Re: the role of carbon dioxide and atmospheric air in double-contrast barium enema. PMID- 8680301 TI - MR imaging enhancement with superparamagnetic iron oxide in chronic liver disease: influence of liver dysfunction and parenchymal pathology. AB - PURPOSE: To analyze the influence of liver dysfunction and parenchymal pathology on the accumulation of superparamagnetic iron oxide (SPIO). METHODS: We evaluated MR images of 13 patients having small hepatic neoplasms before and after administration of SPIO (10 micronol/kg). Biopsy and laboratory data confirmed the presence of severe cirrhosis in two patients, mild cirrhosis in four, chronic hepatitis in five, and normal livers in two. Degrees of liver dysfunction or liver parenchymal pathology were correlated with reductions in signal intensity of the liver and spleen after administration of SPIO. Signal intensity reduction was evaluated using a 1.5 Tesla MR unit. RESULTS: Response to SPIO of the liver and spleen did not correlate with liver parenchymal pathology, although reductions in signal intensity of the liver were somewhat small in severely cirrhotic livers. There were slight correlations between signal intensity alterations of the liver and laboratory data such as the indocyanine green retention rate (correlation coefficient 0. 47), albumin (0.36), total bilirubin (0.36), and serum glutamic oxaloacetic transaminase (GOT) (0.46). Signal intensity reduction of spleen did not correlate with liver function tests except for serum GOT. In patients with cirrhosis, heterogeneous structures were detected in the nontumorous portions of the liver. However, these did not prevent the diagnosis of small hepatomas. CONCLUSION: The uptake of SPIO showed some correlation with liver function but not with chronic liver parenchymal pathology. SPIO provided sufficient contrast between tumor and surrounding liver parenchyma among patients with chronic liver disease. PMID- 8680302 TI - The query corner. Percutaneous gastrostomy. PMID- 8680303 TI - Heavy-metal-responsive genes in maize: identification and comparison of their expression upon various forms of abiotic stress. AB - To identify genes involved in defense against heavy-metal stresses, a cDNA library originating from mercuric chloride-treated maize (Zea mays L. cv. INRA 258) leaves was constructed and analysed by differential screening using cDNAs derived from treated and untreated plants. Transcriptionally activated cDNA clones, designated CHEM (chemically-activated), were isolated and characterized. They represent various known proteins, such as glycine-rich proteins, pathogenesis-related proteins, chaperones and membrane proteins. The expression of the genes encoding these proteins was studied in maize subjected to other forms of abiotic stress. Expression of glycine-rich proteins was greatly enhanced by heat stress, and also stimulated by NaCl, polluted rainwater, wounding and cold stress. Pathogenesis-related proteins were strongly induced by ultraviolet light and to a lesser extent by NaCl, polluted rainwater and wounding. Heat-shock protein was mainly induced by heat and cold, and ubiquitin by wounding. Expression of the membrane channel protein was stimulated by heat stress, NaCl, polluted rainwater and ultraviolet-light irradiation. PMID- 8680304 TI - Oleosin genes in maize kernels having diverse oil contents are constitutively expressed independent of oil contents. Size and shape of intracellular oil bodies are determined by the oleosins/oils ratio. AB - In seeds, the subcellular storage oil bodies have a matrix of oils (triacylglycerols) surrounded by a layer of phospholipids embedded with abundant structural proteins called oleosins. We used two maize (Zea mays L.) strains having diverse kernel (seed) oil contents to study the effects of varying the oil and oleosin contents on the structure of the oil bodies. Illinois High Oils (IHO, 15% w/w oils) and Illinois Low Oils (ILO, 0.5%) maize kernels were the products of breeding for diverse oil contents for about 100 generations. In both maize strains, although the genes for oil synthesis had apparently been modified drastically, the genes encoding oleosins appeared to be unaltered, as revealed by Southern blot analyses of the three oleosin genes and sodium dodecyl sulfate polyacrylamide gel electrophoresis with immunoblotting of the oleosins. In addition, both strains contained the same three oleosin isoforms of a defined proportion, and both accumulated oils and oleosins coordinately. Oleosins in both strains were restricted to the oil bodies, as shown by analyses of the various subcellular fractions separated by sucrose-density-gradient centrifugation. Electron microscopy of the embryos and the isolated organelles revealed that the oil bodies in IHO were larger and had a spherical shape, whereas those in ILO were smaller and had irregular shapes. We conclude that in seeds, oleosin genes are expressed independent of the oil contents, and the size and shape of the oil bodies are dictated by the ratio of oils to oleosins synthesized during seed maturation. The extensive breeding for diverse oil contents has not altered the apparent mechanism of oil-body synthesis and the occurrence of hetero-dimer or multimer of oleosin isoforms on the oil bodies. PMID- 8680305 TI - Characterization of a calcium/calmodulin-dependent protein kinase homolog from maize roots showing light-regulated gravitropism. AB - Roots of many species respond to gravity (gravitropism) and grow downward only if illuminated. This light-regulated root gravitropism is phytochrome-dependent, mediated by calcium, and inhibited by KN-93, a specific inhibitor of calcium/calmodulin-dependent protein kinase II (CaMK II). A cDNA encoding MCK1, a maize homolog of mammalian CaMK, has been isolated from roots of maize (Zea mays L.). The MCK1 gene is expressed in root tips, the site of perception for both light and gravity. Using the [35S]CaM gel-overlay assay we showed that calmodulin binding activity of the MCK1 is abolished by 50 microM KN-93, but binding is not affected by 5 microM KN-93, paralleling physiological findings that light regulated root gravitropism is inhibited by 50 microM KN-93, but not by 5 microM KN-93. KN-93 inhibits light-regulated gravitropism by interrupting transduction of the light signal, not light perception, suggesting that MCK1 may play a role in transducing light. This is the first report suggesting a physiological function for a CaMK homolog in light signal transduction. PMID- 8680306 TI - Glucan phosphorylases in Vicia faba L.: cloning, structural analysis and expression patterns of cytosolic and plastidic forms in relation to starch. AB - We have isolated and characterised cDNA sequences from a Vicia faba cotyledonary library encoding a plastidic isoform (VfPho1) and a cytosolic isoform (VfPho2) of an alpha-1,4-glucan phosphorylase (EC 2.4.1.1; Commission on Plant Gene Nomenclature 1994). The Pho1 isoform is characterized by the presence of a plastidial transit peptide and an 81-residue stretch of additional amino acids in the middle of the polypeptide which are not found in the Pho2 isoform. We define the position of this so-called insertion sequence differently from previous authors. The Pho1 transcripts were found predominantly in the early seed coat and in cotyledons, and accumulated until the late desiccation phase, whereas Pho2 transcripts were about equally abundant in all investigated tissues. Activity patterns of both enzymes in cotyledons roughly followed mRNA accumulation patterns, with the exception of the late desiccation phases when mRNAs were degraded but enzyme activities remained at high level, even in long-stored seeds. The distinct Pho1 and Pho2 gene expression patterns in seed coats coincided with the transient accumulation pattern of starch. Similarly, in-situ hybridisation revealed a relationship between Pho1 gene expression and starch granule formation in developing cotyledons. Expression data and enzyme activity patterns were associated with starch formation during seed development, and could simply reflect a continuous accumulation of enzyme protein, ensuring immediate participation in starch degradation during germination. PMID- 8680307 TI - Subcellular distribution of carbonic anhydrase in Solanum tuberosum L. leaves: characterization of two compartment-specific isoforms. AB - The intracellular compartmentation of carbonic anhydrase (CA; EC 4.2.1.1), an enzyme that catalyses the reversible hydration of CO2 to bicarbonate, has been investigated in potato (Solanum tuberosum L.) leaves. Although enzyme activity was mainly located in chloroplasts (87% of total cellular activity), significant activity (13%) was also found in the cytosol. The corresponding CA isoforms were purified either from chloroplasts or crude leaf extracts, respectively. The cytosolic isoenzyme has a molecular mass of 255,000 and is composed of eight identical subunits with an estimated Mr of 30,000. The chloroplastic isoenzyme (Mr 220,000) is also an octamer composed of two different subunits with Mr estimated at 27,000 and 27,500, respectively. The N-terminal amino acid sequences of both chloroplastic CA subunits demonstrated that they were identical except that the Mr-27,000 subunit was three amino acids shorter than that of the Mr 27,500 subunit. Cytosolic and chloroplastic CA isoenzymes were found to be similarly inhibited by monovalent anions (Cl-, I-, N3- and NO3-) and by sulfonamides (ethoxyzolamide and acetozolamide). Both CA isoforms were found to be dependent on a reducing agent such as cysteine or dithiothreitol in order to retain the catalytic activity, but 2-mercaptoethanol was found to be a potent inhibitor. A polyclonal antibody directed against a synthetic peptide corresponding to the N-terminal amino acid sequence of the chloroplastic CA monomers also recognized the cytosolic CA isoform. This antibody was used for immunocytolocalization experiments which confirmed the intracellular compartmentation of CA: within chloroplasts, CA is restricted to the stroma and appears randomly distributed in the cytosol. PMID- 8680308 TI - Integration of foreign sequences into the tobacco plastome via polyethylene glycol-mediated protoplast transformation. AB - A new vector, pFaadAII, for transformation of plastids of Nicotiana tabacum L. has been developed. It harbours a chimeric gene consisting of the aadA coding region from Escherichia coli, the 16S rDNA promoter from tobacco combined with a synthetic ribosome-binding site, a 500-bp fragment containing the 3' untranslated transcript region (UTR) of the Chlamydomonas rbcL gene and 3.75-kb (5') and 0.95 kb (3') tobacco plastome sequences allowing for targeting the foreign sequences to the intergenic region between the rpl32 and trnL genes of the tobacco plastome. The vector thus targets foreign sequences to the small single-copy region of the plastome, which has so far not been modified by transformation. Leaf protoplasts of Nicotiana tabacum L. were treated with polyethylene glycol (PEG) in the presence of the vector. The protocol for PEG treatment aiming at plastome transformation was optimized. Cell lines were cultured in the presence of spectinomycin and streptomycin using a novel and efficient protoplast culture and selection system. Regenerants were characterized by polymerase chain reaction (PCR) analysis, Southern hybridization and reciprocal crossing. The transformation procedure is described in detail and parameters influencing its efficiency are presented. Special effort is placed on analyzing suitable selection conditions. Only a proportion of the cell lines with a resistant phenotype could be confirmed by molecular analysis and/or reciprocal crossings to represent plastome transformants. Integration of the plastome specific aadA cassette into the nuclear genome accounted for a fraction of the resistant cell lines. Still, as many as 20-40 plastome transformants can be expected from the treatment of 10(6) protoplasts. Therefore, the improved protocol for PEG-mediated plastome transformation in combination with the new aadA-vector supplies a simple, reproducible and cost-efficient alternative to the biolistic procedure. PMID- 8680309 TI - Starch debranching enzyme (R-enzyme or pullulanase) from developing rice endosperm: purification, cDNA and chromosomal localization of the gene. AB - Starch debranching enzyme (R-enzyme or pullulanase) was purified to homogeneity from developing endosperm of rice (Oryza sativa L. cv. Fujihikari) using a variety of high-performance liquid chromatography columns, and characterized. A cDNA clone encoding the full length of the rice endosperm debranching enzyme was isolated and its nucleotide sequence was determined. The cDNA contains an open reading frame of 2958 bp. The mature debranching enzyme of rice appears to be composed of 912 amino acids with a predicted relative molecular mass (Mr) of 102,069 Da, similar in size to its Mr of about 100,000 Da estimated by polyacrylamide gel electrophoresis in sodium dodecyl sulfate. The amino acid sequence of rice debranching enzyme is substantially similar to that of bacterial pullulanase, while it bears little similarity to that of bacterial isoamylase or to glycogen debranching enzymes from human muscle and rabbit muscle. Southern blot analyses strongly suggest that the debranching enzyme gene is present as a single copy in the rice genome. Analysis by restriction fragment length polymorphism with a probe including the 3'-untranslated region of cDNA for rice debranching enzyme confirmed that the debranching enzyme gene is located on chromosome 4. PMID- 8680310 TI - Germination-specific lipid transfer protein cDNAs in Brassica napus L. AB - Three cDNA clones encoding lipid transfer proteins (LTPs) were isolated by applying the rapid amplification of cDNA ends (RACE) protocol to imbibed seeds and germinating seedlings Brassica napus. The deduced amino-acid sequences show a great degree of homology and they exhibit the common features shared by all LTPs. Their expression pattern indicates a strong developmental, hormonal, and environmental regulation. They are expressed only in cotyledons and hypocotyls of germinating seedlings and their levels of expression increase upon treatment with cis-abscisic acid and NaCl. Their distribution in the cotyledons of young seedlings is suggestive of a role related to the mobilization of lipid reserves. PMID- 8680311 TI - The expression of mRNAs for light-stress proteins in barley: inverse relationship of mRNA levels of individual genes within the leaf gradient. AB - Two cDNAs coding for putative light-stress proteins of barley (Hordeum vulgare L.) were cloned and the expression of the corresponding mRNAs analyzed in the barley leaf and compared to that of the well-studied ELIP (early-inducible protein) mRNA. During greening the mRNA for clone HL No. 2, which shows homology to two rice proteins of as yet unknown function, was transiently induced; its level rose more slowly and remained elevated for a longer time than was described for ELIP mRNAs. The mRNA corresponding to clone HL No. 13 was recognized as homologous to subunit P of pea glycine decarboxylase, a nuclear-encoded mitochondrial protein involved in photorespiration. Its mRNA level rose more slowly with cellular development than that of the mRNA for LHC II, the apoprotein of the chlorophyll-a/b-binding protein of PSII. The mRNAs of both novel proteins were induced by high light up to an irradiance of 2000 W.m-2. Their levels remained elevated under high light for up to 9 h, the longest time span examined, while after return to culture light conditions the mRNAs rapidly decayed, each with an individual time course. In green barley leaves the mRNA for clone HL No. 2 was expressed to the highest level in the most basal segment, similar to that of ELIPs, while in contrast the mRNA for subunit P of glycine decarboxylase accumulated to the highest level in the leaf apex where the fully developed cells and mitochondria reside. The latter finding strongly indicates that photorespiration is regulated by high light also at the level of mRNA transcription or mRNA accumulation. In addition, we show that perception of light stress is under the control of cellular development and differentiation. PMID- 8680313 TI - Choosing to change. PMID- 8680312 TI - Chase the ouchies away: an interdisciplinary collaboration for pediatric pain management. PMID- 8680314 TI - But what about the patient? PMID- 8680315 TI - Quality Q & A. Visual quality models. PMID- 8680316 TI - Using formulas and functions in spreadsheets. PMID- 8680317 TI - Seven functions for network accreditation. PMID- 8680318 TI - Limits on government nurses' free speech. PMID- 8680319 TI - A storyboard to improve patient care in the emergency department. PMID- 8680320 TI - When the quality improvement team stops functioning. PMID- 8680322 TI - How do you communicate with your staff? PMID- 8680321 TI - Restraints: improving their use and documentation. PMID- 8680323 TI - What behaviors help nurses deliver quality critical care? PMID- 8680324 TI - PROs: cooperative projects. PMID- 8680325 TI - Separating fact from fantasy. PMID- 8680326 TI - Four Cs to help nurses make changes. PMID- 8680327 TI - Spreadsheet concepts: graph terminology. PMID- 8680328 TI - Improving patient and family education through diagnosis-driven protocols and documentation. PMID- 8680329 TI - Decreasing elopement through interdisciplinary teamwork. PMID- 8680330 TI - Celebrating the success of the quality improvement team. PMID- 8680331 TI - Quality Q & A. Developing patient questionnaires. PMID- 8680333 TI - Educating managers in quality improvement. PMID- 8680332 TI - Interdisciplinary team decreases infections. PMID- 8680334 TI - Brainstorming: how to generate creative ideas. PMID- 8680335 TI - Cardiac response of elderly adults to normal activities and aerobic walking. AB - To assess the cardiac response of elderly adults, three sedentary men and six women (M = 68 years) with no known cardiovascular disease had their cardiac responses to activities done in a laboratory setting (walking, climbing stairs, carrying bags, shuffleboard); normal daily activities and aerobic walking (pace at 60% of the age-adjusted heart rate) were assessed by a 24-hour holter monitor. Supraventricular and ventricular ectopies were common during the 24 hours of monitoring, but none occurred during any of the activities. Bradycardia occurred at night, along with some supraventricular and ventricular ectopy, none clinically significant. Heart rate increased as the intensity of the activity increased (e.g., 68/ minute for carrying 5 pounds of groceries to 90/ minute during aerobic walking). When prescribing exercise or activity limitations, the chronotropic effects of usual daily activities must be considered in counseling sedentary, apparently healthy older adults. PMID- 8680337 TI - Is there a place for action research? PMID- 8680336 TI - Mediators of depression in adults with diabetes. AB - Several factors have been related to depression for people with diabetes, but mechanisms of depression in this population remain unclear. The purpose of this research was to test mastery and self-esteem as mediators of disease-related depression in people with diabetes. A sample of 180 adults ages 21 to 81 participated in the cross-sectional, correlational study. Mastery and self-esteem mediated the relationships between depression and two predictors, effects of diabetes complications and general social support. Feelings of self-esteem alone mediated the effect of regimen demands. The effect of diabetes on daily activities had a significant, direct (i.e., nonmediated) relationship to depressive symptoms. The entire model predicted 53% of variance in depression scores (p = .0001). These findings suggest nursing strategies for managing depression in patients with diabetes. PMID- 8680338 TI - Relationship of cues to assessed infant pain level. AB - Cues that 46 pediatric nurses with a BS in Nursing reported as key to their pain assessments of 88 videotaped infants, ages 0 to 12 months, are identified. Frequencies with which these cues were used for infants of different ages and the relationships between key cues and assessed levels of pain are described. Greater pain was strongly associated with tears, stiff posture, guarding, and fisting. Greater pain was moderately associated with inadequate type or dosage of analgesia, more recent surgery, inconsolability, difficult to distract, does not focus on surroundings, frown, grimace, wrinkled face, flushed face, pain cry, and increased arousal in response to touch of sore area. Internurse variability in cue use was sizable. Most of the often-used cues had weak or no association with assessed pain level. Only consolability, pain cry, grimace, and stiff posture were frequently used and correlated > .51 with assessed level of pain. PMID- 8680339 TI - The relationship of behavioral cues to assaultive behavior. AB - The purpose of this 2-year, case control study was to determine whether differentiation between assaultive and nonassaultive patients can be made based on behavioral assessments and/or sociodemographic variables. For each assault incident, the chart of the patient who assaulted and a randomly chosen patient who did not assault on that day were reviewed (N = 72 subjects or 26 pairs). Various scales were used to evaluate the subjects retrospectively (the day prior to the assault), and patients who assaulted staff were interviewed when possible. An analysis found no differences between patients who assaulted and controls on sociodemographic variables. Those who assaulted had significantly more prior assaults (p = .04) and more difficulty verbalizing angry feelings appropriately on their units (p < .01). Prior to the assault, assaultive patients were more verbally hostile (p = .037) and showed more increased motor activity (p = .001) than controls. PMID- 8680340 TI - Women's perceptions of fatigue during pregnancy and postpartum: the impact of length of hospital stay. AB - Women's experiences during late pregnancy and the early postpartum period were examined relative to time of discharge from the hospital. Women who were discharged in 3 days or sooner were compared to women who were discharged after 3 days or sooner were compared to women who were discharged after 3 days, with respect to fatigue. A rest and activity questionnaire was completed by the women in the third trimester of pregnancy, in postpartum Week 1, and in postpartum Week 4. Few differences were found with respect to hours slept, number of sleep interruptions, perceptions of tiredness, and impact of tiredness on daily life; tiredness was a major aspect of women's experience, regardless of how long they stayed in hospital. The information will help nurses preparing women for their late pregnancy and postpartum experiences and will ease the concern of those who believe women will be more tired if they leave hospital soon after birth. PMID- 8680341 TI - Couples' evaluations of foreknowledge of fetal impairment. AB - The Western cultural presumption that knowledge is a right and a good is integral to current discussions of prenatal diagnosis. Little is known, however, about how couples obtaining positive fetal diagnoses evaluate this knowledge for their own lives and whether, or how, they are advantaged in relation to couples learning about their baby's impairment after birth. Findings from 40 interviews with expectant parents obtaining positive prenatal diagnoses suggest that couples both value and question the value of fetal foreknowledge and that this knowledge temporally relocates, rather than substantively alters, parental responses and infant outcomes. PMID- 8680342 TI - CABG discharge information: addressing women's recovery. AB - Women's descriptions of the coronary artery bypass surgery recovery experience were elicited for development of a preparatory discharge information intervention. In a convenience sample, 20 women (mean age = 67 years) were interviewed about the physical sensations, emotions, and concerns they experienced after CABG at three measurement points: discharge, 2 days after discharge, and 3 weeks following discharge. Many of the recovery experiences reported by women in this study are not addressed in traditional CABG discharge information. PMID- 8680343 TI - Mechanisms and management of allergic reactions in the surgical patient. AB - The use of anesthetic agents, drugs and chemicals during anesthesia induces a certain number of anaphylactoic or anaphylactoid reactions. The incidence of anaphylaxis during general anesthesia, according to a recent study, is 1:4500. Despite appropriate treatment, mortality is about 6%. Different mechanisms are involved in mortality. Multiple risk factors have been identified in at-risk patients. With adequate understanding of the pathophysiological events that occur during anaphylaxis, anesthetists may avoid the occurrence of allergic reaction or be better prepared to manage these serious situations that may become fatal. This article covers different areas associated with anaphylactic and anaphylactoid reactions. Focus is placed on the different mechanisms of allergic reaction, and special attention is given to the clinical aspects of this complication. Treatment of these reactions as well as steps in prevention perioperatively are highlighted. PMID- 8680344 TI - Allergic drug reactions. PMID- 8680345 TI - Anaphylactic reactions to high molecular weight dextran during hysteroscopic surgery. AB - Dextran solutions are used for plasma expanders, thromboembolic prevention, and as a distention and irrigating fluid for various endoscopic procedures. High molecular-weight dextrans are accompanied by significant side effects including pulmonary edema, allergic reactions, renal failure, and altered coagulation profiles. The following is a case report of an allergic reaction to 32% Dextran 70 during a hysteroscopic examination and biopsy of a 67-year-old woman. A discussion follows outlining the adverse effects of high viscosity dextrans alerting the anesthetist to the possibilities of intraoperative complications. PMID- 8680346 TI - Protamine reaction in a patient undergoing coronary artery bypass grafting. AB - The neutralization of heparin anticoagulation is accomplished by the administration of protamine. While the administration of protamine is generally uneventful, allergic reactions can occur. This article describes such a reaction in a patient having cardiac surgery. Classification of protamine reactions and signs and symptoms are discussed. Treatment and management of high risk patients is highlighted. PMID- 8680347 TI - Latex allergy: who, what, when, where, why, and how. AB - Patients with an allergy to latex are being encountered more often by healthcare providers than ever before in the past. Latex allergy is also common among healthcare providers. This article will describe who, what, when, where, why and how to deal with these patients and colleagues. Latex allergy can be as minor as a rash on the hands or as life threatening as an anaphylactoid reaction. Healthcare in a latex-free environment is necessary when providing care for these patients. Therefore, it is necessary to remove all latex products from the area where care will be provided. It may also be beneficial to pretreat the patient with steroids and other medications. The best prevention for an allergic reaction to latex is to take a thorough history for every patient before providing care. PMID- 8680348 TI - Clinical case conference: alcoholism and head trauma. PMID- 8680349 TI - Anesthetic drug interactions. PMID- 8680350 TI - Valvular heart disease: a review for nurse anesthetists. AB - Those who do not regularly participate in cardiac surgery are often anxious when faced with the patient with valvular dysfunction. The need for periodic review by anesthetists is critical for quality patient care. A review of the physiology and anesthetic management of aortic stenosis, mitral stenosis, aortic insufficiency, mitral regurgitation, and mitral valve prolapse is presented. PMID- 8680351 TI - Cardiovascular changes associated with aging: the anesthetic implications. AB - Successful anesthesia care of the elderly patient is highly dependent on the anesthesia care provider's knowledge of the physiological alterations on the cardiovascular system associated with aging. It is projected that by the year 2000, the elderly segment of the population will increase to 13% and by the year 2030, 52 million Americans, or 17% of the population will be older than age 65. More people than ever before are reaching old age, with the latest statistics indicating that life expectancy for a man of 45 years has increased from 70.4 to 77.3 years and from 77.0 to 82.8 years for a woman. One of the primary factors associated with the increase in longevity is the decrease in mortality from cardiovascular diseases. Since the 1960s, there has been a decline in cardiovascular mortality of about 3% per year. Recent technological advances and healthier lifestyles are among the reasons contributing to this trend. With these positive changes impacting the elderly population, anesthesia care providers must become better prepared to select and administer the appropriate agents that will ultimately influence perioperative outcome. PMID- 8680352 TI - Penetrating mine injury to the heart with a pericardial tamponade. AB - Cardiac tamponade is a life-threatening emergency. Immediate recognition and surgical intervention is essential to preserve myocardial function and maintain cardiac output. The following is a case report of a penetrating mine injury to the heart with a resulting pericardial tamponade. The positive outcome and the facilities in which the resuscitation and surgical repair occurred make this a unique case report. PMID- 8680353 TI - Calcium channel blockers. AB - Calcium ions are essential for the chain of events that leads to myocardial contraction. Its role in the cardiac cycle has been studied extensively for years. Calcium is thought to be effective in the slow channels. Calcium channel blockers were first introduced in this country, more than 20 years ago. The pharmacological effects, usages, side effects, and dosages of some of the most commonly used calcium channel blockers are discussed. In addition, some anesthetic considerations and the latest controversy regarding calcium channel blockers are reviewed. PMID- 8680354 TI - Reduced blood loss with hemodynamic stability during controlled hypotensive anesthesia for LeFort I maxillary osteotomy using high-dose fentanyl: a retrospective study. AB - The hazards of blood transfusion today include the transmission of serious and sometimes life-threatening viral illnesses such as hepatitis and acquired immunodeficiency syndrome. The anesthesia provider can reduce the need for operative transfusion by intentionally lowering a patient's blood pressure during surgery. Two techniques for controlled hypotensive anesthesia (CHA) were compared retrospectively to examine differences in surgical blood loss for an operation that has the potential for high volume blood loss, maxillary osteotomy. The intravenous use of 30 micrograms/kg fentanyl was compared with vasodilators in CHA, without compromising the quality or safety of the surgical procedure. The use of fentanyl as the independent variable significantly reduced the estimated blood loss for comparable populations undergoing similar operations when compared with intravenous vasodilators, because of it's ability to stabilize the hemodynamic responses to surgical stress. PMID- 8680355 TI - A comparison of antiarrhythmic drugs. AB - Frequently the nurse anesthetist encounters a patient who is receiving antiarrhythmic therapy. As a practitioner, the anesthetist should be aware of the affect that a specific antiarrhythmic drug has on the patient, and the potential adverse effects that each drug may have. These patients require special consideration when planning their anesthetic care, as they have a higher potential for perioperative problems. This article describes the antiarrhythmic drug classification, and gives a brief summary of each of the drugs listed in the antiarrhythmic classification. PMID- 8680356 TI - Anesthetic drug interactions. PMID- 8680357 TI - Anesthesia and the endocrine system. PMID- 8680358 TI - Cardiac complications of laparoscopy: anesthetic implications. AB - Enormous technical advances have occurred in the field of endoscopic surgery during the last 20 years, increasing the number of surgeries performed using this technique. Today, laparoscopy has become one of the most frequent gynecologic operative procedures performed. The anesthesia provider must be aware of the potential complications and risks of the surgery. A review of the possible cardiac complications associated with laparoscopic surgery is presented. PMID- 8680359 TI - The role of the staff developer: the last decade, the next decade. PMID- 8680360 TI - Getting your arms around productivity. PMID- 8680361 TI - Staff development self-help. Five-minute antidote for inertia. PMID- 8680362 TI - Expanding a nursing competency program to a house-wide competence program. PMID- 8680363 TI - Ten tools for the real (or perceived) department of one. PMID- 8680365 TI - Confronting our ethical dilemmas: the right road. PMID- 8680364 TI - Literacy for employees: the program development. PMID- 8680366 TI - Eight ethical dilemmas facing educators. PMID- 8680367 TI - Personal mastery: sharing your wisdom and expertise. PMID- 8680368 TI - Perfecting preparation: the ultimate checklist. PMID- 8680369 TI - Role expansion. Performance punishment or professional opportunity? PMID- 8680370 TI - Survey of congenital rubella syndrome, Montreal, Laval, and Monteregie, Quebec, 1985-1991. PMID- 8680371 TI - Surveillance of congenital rubella syndrome and other rubella-associated adverse pregnancy outcomes. PMID- 8680372 TI - Survey of postpartum rubella vaccination, Montreal, Laval, and Monteregie, Quebec, 1992. PMID- 8680374 TI - The diagnostic value of tuberculostearic acid in tuberculous pleural effusions. AB - Tuberculostearic acid (TBSA) (10-methyloctadecanoic acid) is a structural component of mycobacteria and is not normally present in human tissues. The detection of this fatty acid in various clinical specimens, such as sputum, bronchial aspirate, pleural fluid and cerebrospinal fluid, is a rapid, sensitive and specific test for the diagnosis of tuberculosis. As rapid diagnostic methods are also needed in tuberculous pleurisy, this study was planned on 21 patients with pleurisy. The methods of gas chromatography, mass spectrophotometry combined with selected ion monitoring were used. The patients were divided into two groups: 11 with tuberculous effusion and 10 with nontuberculous patients. In the tuberculous group, TBSA was detected in 6 of the 11 patients, whereas in the nontuberculous group it was detected in 12 of the 10 patients. The sensitivity of the test was 54%, the specificity was 80%, the positive predictive value was 75%, the negative predictive value was 61%, and the efficacy was 66%. Therefore, tuberculostearic acid cannot be considered to be more useful than conventional methods in the diagnosis of tuberculous effusions, due to low sensitivity and high cost. PMID- 8680375 TI - Opposite effects of inhaled bradykinin and [desArg9]-bradykinin on tracheobronchial clearance in normal humans. AB - Kinins may affect lung mucociliary clearance in man by interacting with specific surface receptors designated B1 and B2. To evaluate this possibility, we have compared the effect of inhaled bradykinin and [desArg9]-bradykinin on mucociliary clearance in healthy volunteers. Four subjects attended the laboratory on three separate occasions to undertake tracheobronchial clearance studies, by a noninvasive radioisotopic technique, followed by inhalation with either bradykinin (8 mg.mL-1), [desArg9]-bradykinin (8 mg.mL-1), or vehicle placebo 30 min after radioaerosol inhalation. Half-hourly whole lung counts were measured for 6 h with two collimated scintillation counters and a tracheobronchial clearance curve was plotted for each subject on each occasion. In all the subjects studied, mucociliary clearance, expressed as the area under the tracheobronchial radioaerosol retention curve calculated for the first 6 h (AUCo 6h) was enhanced after inhaling bradykinin and prolonged following exposure with [desArg9]-bradykinin when compared to placebo. The median values (range) for AUCo 6h were significantly reduced from 123 (83-152)%.h to 92 (51-133)%.h with placebo and bradykinin, respectively, and significantly augmented to 269 (144-331)%.h after exposure with [desArg9]-bradykinin. This small study suggests that acute exposure with inhaled bradykinin accelerates, whilst [desArg9]-bradykinin delays, tracheobronchial clearance in normal human airways. PMID- 8680373 TI - AIDS and tuberculosis control programmes: an integrated approach at educational level. AB - In developing countries with a high prevalence of individuals co-infected by human immunodeficiency virus (HIV) and tuberculosis (TB), urgent public health measures should be implemented to prevent the spread of both diseases. This study was performed by a combined acquired immune deficiency syndrome (AIDS)-TB health team with the following aims: 1) to assess knowledge, attitudes and practice towards AIDS; 2) to identify target groups for health education (HE); 3) to evaluate HE impact; 4) to circulate correct information on AIDS and TB through target groups; and 5) to evaluate integration of AIDS and control TB activities. Secondary school students of Arua District, Uganda, participated in a standardized HE session (covering the key-points of AIDS and TB control) preceded by a pretest (multiple choice) questionnaire and followed 3 months later by the same questionnaire (post-test). The impact of HE on AIDS control was evaluated by comparing answers to pre- and post-test questionnaires and its influence on the TB programme by evaluating case-finding performances in the period preceding and following the survey. We analysed 1,478 questionnaires. The results of our study gave information on knowledge about AIDS, identified females and students < 16 yrs of age as good targets for HE, revealed that the impact of HE was significantly associated with improved knowledge, contributed to improved TB case finding and offered suggestions for the integration of programmes. The survey represented an opportunity to create a stable AIDS/TB health team at district level. PMID- 8680376 TI - Exercise-induced hypoxaemia in emphysematous type chronic obstructive pulmonary disease. AB - To investigate gas exchange response to exercise, we studied 16 male patients with moderate-to-serve airflow obstruction (forced expiratory volume in one second (FEV1) 39 +/- 10% of predicted value), mild-modest arterial hypoxaemia (arterial oxygen tension (Pa,O2) 9.6 +/- 0.87 kPa) and no arterial hypercapnia (arterial carbon dioxide tension (Pa,CO2) 5.04 +/- 0.45 kPa), referred to as emphysematous-type chronic obstructive pulmonary disease (COPD) clinical pattern. During maximal exercise tests, Pa,O2 increased by more than 0.3 kPa in eight patients (Group A) and fell by more than 0.3 kPa in the other eight patients (Group B). Pulmonary function tests, maximal inspiratory pressure at the mouth, values at maximum cycle incremental exercise and baseline arterial blood gases did not differ significantly between the two groups. We, therefore, showed that common pulmonary function measurements at rest and during exercise were not useful in identifying patients who underwent exercise-induced hypoxaemia. Furthermore, we suggest that patients with the same clinical pattern of chronic obstructive pulmonary disease and the same degree of airflow obstruction and gas exchange impairment could develop a different adaptation to a maximal exercise test, and that the presence of exercise-induced hypoxaemia might be related to pathological features of emphysema more than to different respiratory functional measurements. PMID- 8680377 TI - Sarcoidosis-tuberculosis association: a case report. AB - The association of sarcoidosis and tuberculosis is rare and, its differentiation is sometimes very difficult. We report the case of a young man who presented with type III sarcoidosis complicated by pulmonary tuberculosis within 17 months of the diagnosis, leading to a fatal outcome. A change in antimycobacterial antigen complex A60 immunoglobulin G (IgG) titres, as seen in our case, may be helpful in differentiating between the two diseases. PMID- 8680378 TI - Pulmonary changes in a man affected by von Recklinghausen's disease. AB - Lung involvement in von Recklinghausen's disease is very rare and only sporadic cases have been reported in the literature. We present the case of a man affected by neurofibromatosis type 1 (NF1). The man complained of shortness of breath of 3 4 years duration. Chest radiograph and computed tomographic (CT) scan showed the presence of severe bullous emphysema, with extensive widespread bulky subpleural bullae, involving mainly the upper lobes and apical segments of the lower lobes, bilaterally. Functional respiratory tests documented a picture of severe obstruction associated with marked alveolar hyperinflation (vital capacity (VC) 80% of predicted, forced expiratory volume in one second (FEV1) 49% pred, maximal mid-expiratory flow (MMEF) 22% pred, residual volume (RV) 151% pred). Capillary alveolar diffusion was also markedly altered (transfer factor of the lungs for carbon monoxide (TL,co) 41% pred). The eventual prospect of a lung transplant, never previously considered for this disease, has been advised by the thoracic surgeons. In the light of this possibility, multidisciplinary assessment and monitoring of respiratory function over time are indispensable, in order to identify the transplant window correctly. PMID- 8680379 TI - New treatment strategies in cystic fibrosis: rhDNase. AB - Cystic fibrosis (CF) is the commonest inherited disease of the Caucasian population, with a high morbidity and mortality from pulmonary disease. The high viscoelasticity of CF sputum is due, in part, to the high deoxyribonucleic acid (DNA) content. Recombinant human deoxyribonuclease I (rhDNase) has been developed and in vitro studies have shown that it reduces the viscoelasticity of CF sputum. This article reviews the in vivo clinical studies conducted to determine the safety and efficacy of rhDNase in the treatment of pulmonary disease in CF. Initial Phase I studies showed preliminary safety and some evidence of clinical benefit. Subsequently, two Phase II studies were conducted in the US and UK during which patients received rhDNase for 10 days. A Phase III study of 24 weeks duration involving 968 patients in 51 centres in North America is also reported in detail. Longer term open-label studies, the results of intermittent administration, administration to severely ill patients and the use of different delivery systems are reviewed. The Phase II study reported improvements in pulmonary function and had a good safety profile. The Phase III study showed improvement in forced expiratory volume in one second (FEV1) of 5.8 and 5.6% in patients treated once and twice daily, respectively. The risk of developing an exacerbation was reduced by 28% with once daily treatment and 37% with twice daily treatment compared to placebo. The drug was safe and there was some improvement in quality of life data. Recombinant human deoxyribonuclease is a new therapy for pulmonary disease in cystic fibrosis which has been shown to benefit patients when used in conjunction with conventional therapy. PMID- 8680381 TI - Imaging of pleural diseases. AB - The main pleural disorders are: effusion, thickening, masses and pneumothorax. Chest radiography is the first approach to evaluation of pleural disease; further evaluation is based upon ultrasounds (US), computed tomography (CT), and high resolution CT (HRCT). The typical appearance of free pleural effusion is a homogeneous opacity with concave upper boundary; subpulmonic or intrafissural collections may also occur; the exudative effusions can be organized by adhesions between the pleural layers; consequently, loculated collections result. Radiographs allow us to assess the presence, amount and arrangement of effusions, but US and, especially, CT are needed to detect the modifications of the underlying pleura: circumferential thickenings, irregular and more than 1 cm thick are mostly malignant and denote mesothelioma or metastases: subtle and regular thickening is the typical appearance of fibrosis; a normal pleura does not exclude a malignant effusion. CT plays a major role in the diagnosis and management of empyema and in differentiating it from the pulmonary abscess. With CT it is also possible to differentiate the true pleural thickening from the false one due to a simple increase of extrapleural fat, and to disclose the activity of a fibrothorax through the detection of a small amount of fluid between the pleural layers. Pleural plaques are clearly visible by conventional radiography, especially with oblique views; US and CT are needed in the assessment of pleural tumors (fibroma, lipoma, fibro- and liposarcoma) and in determining the involvement of the lung and the chest wall. Pneumothorax is easily detected by conventional radiographs in the upright patient; when supine, the air collects in the anterobasal regions and particular projections are required; CT can reveal small amounts of air and is recommended in critically ill or trauma patients. PMID- 8680380 TI - Methotrexate in the treatment of systemic glucocorticoid-dependent severe persistent asthma: a word of caution. AB - Methotrexate should not be prescribed to every systemic glucocorticoid-dependent asthmatic. In fact, while methotrexate may be advantageous in selected patients, every attempt to control asthma with regular anti-asthma agents should be made. Most studies on the effects of methotrexate in the treatment of systemic glucocorticoid-dependent asthmatics include small numbers of patients and are all of relatively short duration. Thus, large long-term multicentre trials are urgently needed. In these studies, a uniform accepted definition of systemic glucocorticoid-dependent asthmatics should be used. For the time being, we reinforce the recommendation of the NHLBI/ WHO panel that methotrexate and other systemic glucocorticoid sparing drugs should be considered experimental medications, and used only in selected patients under the supervision of an asthma specialist with previous experimental experience. PMID- 8680382 TI - The role of cytokines in human lung fibrosis. AB - Fibrosis is a disorder characterized by a qualitative and quantitative alteration of the deposition of extracellular matrix with accumulation of mesenchymal cells in replacement of normal tissue. The sequence of events leading to fibrosis of an organ involves the subsequent processes of injury with inflammation and disruption of the normal tissue architecture, followed by tissue repair with accumulation of mesenchymal cells in this area. A similar sequence of events occurs in wound healing with formation of normal, limited and transient granulation tissue, while in fibrosis, a maladaptive repair leads to an extensive, exaggerated process with functional impairment. Inflammatory cells (mainly mononuclear phagocytes), platelets, endothelial cells, and type II pneumocytes play a direct and indirect role in tissue injury and repair. The evaluation of several human fibrotic lung diseases, five diffuse (idiopathic pulmonary fibrosis (IPF); adult respiratory distress syndrome (ARDS); coal workers' pneumoconiosis (CWP); Hermansky-Pudlak syndrome (HPS); systemic sclerosis (SS)) and two focal (tumour stroma in lung cancer; and obliterative bronchiolitis (OB) after lung transplantation), has shown that several cytokines participate in the local injury and inflammatory reaction (interleukin-1 (IL-1), interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), and tumour necrosis factor-alpha (TNF-alpha)), while other cytokines are involved in tissue repair and fibrosis (platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-beta), and basic-fibroblast growth factor (b-FGF)). A better understanding of the cytokines and cytokine networks involved in lung fibrosis leads to the possibility of new therapeutic approaches. PMID- 8680383 TI - Computerized patient record for a department of respiratory rehabilitation. AB - A computerized patient record (CPR) system plays an essential support role in the efficient functioning of the clinical and research services of a medical centre. We report the experience gained in developing a CPR for the Respiratory Rehabilitation Department (RRD) of the Tradate Medical Center of the Salvatore Maugeri Foundation, with specific reference to Out-patient (OP) and In-patient (IP) Units. The CPR was developed locally under the guidance of the Bioengineering Department. Several items implemented and strategies adopted are described and grouped in relation to broader objectives, such as the improvement of health-care quality, the enhancement of personnel productivity and reduction in costs, the support of clinical and health service research and the accommodation of future developments. In particular, we describe the design and implementation of anamnestic, physical and admission data collection, specifically orientated to respiratory diseases. Daily use of the CPR in the OP and IP units and its potential outcome for research and management support are also studied in detail. On the basis of our experience (1,251 out-patient examinations, 650 in-patient clinical admission cards), the computerized patient record seems a useful way of providing better health-care and a more comprehensive coverage of the rehabilitation process of patients in a Respiratory Rehabilitation Department. PMID- 8680384 TI - Long-term treatment of pulmonary tuberculosis with ofloxacin in a subject with liver cirrhosis. PMID- 8680385 TI - Pharmacological interventions for smoking cessation. PMID- 8680386 TI - Non-pharmacological interventions for smoking cessation: their relative role in a stepwise approach. PMID- 8680387 TI - Near-fatal asthma and mechanical ventilation. PMID- 8680388 TI - Self-awareness of deficits in adults with traumatic brain injury: how best to measure? AB - Some method of assessing self-awareness of deficits in patients with traumatic brain injury (TBI) is required to increase our understanding of the phenomenon, and to then evaluate strategies for clinical intervention with patients who lack such self-awareness. Options for the assessment of self-awareness of deficits following TBI are reviewed. The most commonly used method is comparison of patients' self-ratings on questionnaires of functional abilities with ratings by relatives or staff on the same questionnaires. An additional method of assessment, an interviewer-rated semi-structured interview is proposed (the Self Awareness of Deficits Interview), and some preliminary inter-rater reliability data are presented. However, quantitative methods of evaluating self-awareness have shortcomings, and qualitative research may be more appropriate in some circumstances. An approach which makes use of multiple measures to evaluate self awareness of deficits is recommended. PMID- 8680389 TI - Use of a comprehensive programme of external cueing to enhance procedural memory in a patient with dense amnesia. AB - This case study describes rehabilitation efforts with a 24-year-old woman who exhibited dense amnesia secondary to status epilepticus following a motor vehicle accident. She was 20 months post-injury upon entry into our day treatment programme. The functional severity of her amnesia was reflected in numerous ways, including no recall of what she wore from day to day and an inability to find the toilet after 2 weeks in the programme. A multidisciplinary comprehensive programme of external cueing was established to exploit her preserved procedural memory. Objective measures of functional compliance were gathered over time and contrasted with both standard neuropsychological test scores and early levels of functioning in rehabilitation. Results demonstrated enhanced functioning via utilization of procedural memory. In addition, the patient actually demonstrated increased independent generalization of strategies and techniques over time. Practical treatment implications are reviewed and discussed. PMID- 8680390 TI - Relatives' perceptions of role change, social support and stress after traumatic brain injury. AB - There is general agreement between researchers and clinicians alike that relatives of people with head injuries experience heightened stress as a result of the injury and its consequences. In the present study a single structured interview, including both verbally administered and written response questionnaires, was completed by 18 parents and 11 partners. Measures included the Daily Hassles and Uplifts Scale, the Arizona Social Support Interview Schedule and questions regarding role change and health problems. The combined parents and partners group indicated that they experienced moderate levels of stress and role change. A relatively small proportion of participants reported experiencing health problems. Partners indicated a slightly higher degree of stress and a greater degree of role change than parents, and a larger proportion of partners indicated the presence of health problems. Qualitative differences between the two groups were found in terms of sources of stress. There was little quantitative or qualitative difference between the two groups in sources, utilization of and satisfaction with social support. Positive correlations were found between stress and role change and stress and health problems. PMID- 8680391 TI - Vocational outcome of aphasic patients following severe traumatic brain injury. AB - The incidence and course of aphasia, and its impact on vocational outcome, were determined in a group of 351 patients with severe traumatic brain injury (TBI). Aphasia was found in 11.1%, the common forms being amnestic (56%, 22/39), expressive (10.3%, 4/39) and receptive (10.5%, 8/39), as found on the first language assessment. No age difference was found between the aphasic and non aphasic patients. Coma was more common in the aphasics than the non-aphasics (95% and 82%, respectively), although its mean duration was shorter. Aphasics had more severe locomotor deficits (p < 0.01, Fisher test) and tended towards more severe cognitive disorders (p = 0.07, Fisher test). There was no difference between the groups in incidence of behavioural disturbances or occupational outcome. Most of the aphasic patients improved after therapy, and two recovered completely. The presence of aphasia did not have negative prognostic implications for occupational outcome. PMID- 8680392 TI - Incidence of mild and moderate brain injury in the United States, 1991. AB - The 1991 National Health Interview Survey was analysed to describe the incidence of mild and moderate brain injury in the United States. Data were collected from 46 761 households and weighted to reflect all non-institutionalized civilians. The report of one or more occurrences of head injury resulting in loss of consciousness in the previous 12 months was the main outcome measure. Each year an estimated 1.5 million non-institutionalized US civilians sustain a non-fatal brain injury that does not result in institutionalization, a rate of 618 per 100,000 person-years. Motor vehicles were involved in 28% of the brain injuries, sports and physical activity were responsible for 20%, and assaults were responsible for 9%. Medical care was sought by 75% of those with brain injury; 14% were treated in clinics or offices, 35% were treated in emergency departments, and 25% were hospitalized. The risk of medically attended brain injury was highest among three subgroups: teens and young adults, males, and persons with low income who lived alone. The incidence of mild and moderate brain injury in the United States is substantial. The National Health Interview Survey is an important national source of current outpatient brain-injury data. PMID- 8680393 TI - Obsessive-compulsive disorder after closed head injury: review of literature and report of four cases. AB - An increasing number of recent reports has pointed to the underlying neuropathological substrate for obsessive-compulsive disorder (OCD). Neuropsychological testing may suggest underlying organicity even though the neuroimaging studies and the neurological examination may be normal. Earlier reports are not in agreement about the laterality of deficits. Abnormalities in frontal regions, limbic areas and basal ganglia are noted in functional neuroimaging and neuropsychological studies. In closed head injury the damage tends to be diffuse, and it is not easy to clearly localize deficits or to determine their laterality. In this paper we review the various theories and literature on OCD and organicity, and report on four individuals who developed OCD symptoms after closed head injury. We also discuss their neuroimaging and neuropsychological testing results. PMID- 8680395 TI - The effectiveness of traumatic brain injury rehabilitation: a review. AB - The rehabilitation of traumatic brain injury (TBI) has undergone tremendous development over the past 20 years. A much more aggressive, extended and comprehensive approach is now common and clinically accepted. Multiple new forms and sites of treatment are utilized such as cognitive, behavioural, sub-acute and post-acute rehabilitation programmes. While there has been widespread clinical acceptance of these treatments the appearance of well-designed experimental or quasi-experimental studies actually evaluating the results of such treatment have been, until recently, generally lacking. This review article selects, analyses, and critiques the most salient of recent studies published regarding the overall clinical benefit, and to some extent the cost benefit, of TBI treatment programmes in their multiple forms. A conclusion which is reached following this survey is that while truly randomized controlled studies still have not been achieved, an impressive variety of studies of quasi-experimental design have been completed. The overall conclusion from these studies is that the efficacy (and cost-effectiveness) of TBI rehabilitation is strongly supported. PMID- 8680394 TI - Level of care options for the low-functioning brain injury survivor. AB - During the early stages of recovery from severe brain injury many patients are comatose or minimally responsive. Rehabilitation for these low-functioning survivors traditionally includes acute medical care and transfer to a skilled nursing facility or acute rehabilitation. Concerns have been expressed that customary treatment options are ineffective, costly, or both. In response, 'intermediate'-level programmes designed to provide effective, cost-efficient rehabilitation have emerged. The purpose of this paper is to provide information regarding outcome of severe brain injury and the early rehabilitation needs of survivors. Common characteristics, advantages, and disadvantages of various intermediate programmes, including 'subacute' and 'transitional' rehabilitation, are discussed and contrasted. PMID- 8680396 TI - Variability in the perceptual and physiological features of dysarthria following severe closed head injury: an examination of five cases. AB - The perceptual and physiological features of the dysarthric speech of five severely closed-head-injured (CHI) subjects were examined in a case-by-case analysis. The five male CHI subjects included in the study were selected to reflect the range of severity and types of dysarthria evident in the CHI population. The perceptual profiles of each subject consisted of the findings of a perceptual speech analysis, the Frenchay Dysarthria Assessment (FDA) and the Assessment of the Intelligibility of Dysarthric Speakers (ASSIDS). The subjects' physiological profiles included the results of instrumental assessments of the respiratory, laryngeal, velopharyngeal and articulatory subsystems of the speech production mechanism. The case studies highlighted the variability among the individual subjects with respect to the location, physiological nature, and severity of impairment in their speech-production mechanisms. In addition, the interdependence of the various speech subsystems in determining speech outcome, the presence of differential subsystem impairment in dysarthria following CHI, and the varied therapeutic requirements of the individual subjects were identified. Clinically, the case studies highlighted the importance of developing individual treatment programmes based on comprehensive perceptual and physiological evaluations of the speech mechanism in each CHI subject with dysarthric speech. PMID- 8680397 TI - Personality and psychosocial function after brain injury. AB - A total of 74 brain-injured patients and 46 non-neurologically matched controls consecutively admitted to a specialist medical rehabilitation unit, were administered the 'Headley Court psychosocial rating scale' and four questionnaires examining personality traits of 'locus of control', 'use of humour', 'optimism' and 'easy-going disposition'. Both pre- and post-injury personality ratings were obtained. The relatives of all participants were sent the same scales. Personality changes are reported in each of the four areas; however, time post-injury appears to be a significant factor in the type of change reported; in this cross-sectional study, at 6 and 12 months post-injury, changes are noted in all variables except locus of control, whereas at 18 months post-injury only 'easy-going disposition' showed significant change, at 24 months post-injury changes were noted in all variables except optimism, and at 30 months post-injury no changes were noted. In the present study, examining a period of 2.5 years post-injury, the personality changes remain static once they have occurred. Despite widespread reports in the literature on the importance of pre- and post-trauma personality to good psychosocial functioning, the present study found that it was only an 'easy-going disposition' post-trauma that was consistently related to good psychosocial functioning. Reasons for this are discussed. PMID- 8680398 TI - Neuropsychological problems in everyday life: a 5-year follow-up study of young severely closed-head-injured patients. AB - The aim of this follow-up study was to examine the long-term disabilities and handicaps caused by severe head injuries and their effects on the everyday life of patients and their relatives. The group studied consisted of 19 subjects who had suffered a severe closed-head injury during 1984 and had been rehabilitated in the Kapyla Rehabilitation Center. In 1989 a thorough functional assessment of these patients was carried out. In addition, information concerning the quality of life, activities of daily living (ADL) and social situation was gathered by means of questionnaires filled in by the patient and, if possible, by a close relative. The results indicated the importance of changes in cognitive functions, personality and emotional reactions. Changes in personality and emotional reactions were especially emphasized by the relatives. We also correlated the patients' and their relatives' estimates of the occurrence of memory problems, whereas tests of visual memory, though able to discriminate the brain-injured from normal subjects, did not correlate on a statistically significant level with the estimates of patients and relatives. The implications of the results for methods of assessment and the planning of rehabilitation programmes are discussed. PMID- 8680399 TI - Protracted post-traumatic confusional state treated with physostigmine. AB - A case study is presented of confusion in a head-injured man, lasting for more than 2 years, when intermittent treatment with physostigmine resulted in progressive improvement in both confusion and usable cognitive functions. Aetiological mechanisms and implications for treatment plans are discussed. PMID- 8680400 TI - Models of brain injury rehabilitation. AB - Rehabilitation services for patients with brain injury have been slower to develop than those with other disabilities, but have rapidly improved over the past 10-15 years. A range of different, specialized brain injury programmes has evolved. The literature is reviewed and the author describes and discusses the relative merits of these models from personal experience and observation in Australia and other countries. The importance of an integrated network of specialized brain injury rehabilitation services is emphasized. PMID- 8680401 TI - Neurolaw: towards a new medical jurisprudence. AB - Traumatic brain injuries and spinal cord injuries occur in a variety of accidents which may become the subject of civil litigation. A new field of medical jurisprudence, called neurolaw, is emerging to join health-care professionals and attorneys in a common quest to employ legal remedies to enhance the quality of life for individuals with neurological injury and their families. Presented here is a review of the underpinnings of this developing area of inquiry. PMID- 8680402 TI - Applications of heteroduplex analysis for mutation detection in disease genes. AB - Double-stranded heteroduplex molecules that form between a mutant and wild-type DNA strand are often distinguished from homoduplex molecules upon gel electrophoresis. This method, heteroduplex analysis (HA), can be performed rapidly without radioisotopes or specialized equipment. Modifications and enhancements of the HA method have been developed that increase the sensitivity of detection of single-base pair alterations. PMID- 8680403 TI - Molecular genetics of mucopolysaccharidosis type I: diagnostic, clinical, and biological implications. AB - Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive disease caused by mutations in the alpha-L-iduronidase (IDUA) gene. These mutations lead to a deficiency of the glycosidase alpha-L-iduronidase (IDUA), which is required for the degradation of heparan sulphate and dermatan sulphate and thus the storage of these glycosaminoglycans in the lysosome. There is a wide range of clinical phenotypes in MPS-I (eponyms: Hurler syndrome, severe; Hurler/Scheie syndrome, intermediate; Scheie syndrome, mild), which makes prediction of disease severity and genetic counselling difficult. However, since cloning of the IDUA gene, mutation analysis has provided some molecular explanations for the range of MPS-I phenotypes, in turn facilitating the selection and evaluation of patients undergoing experimental treatment protocols such as bone marrow transplantation. A total of 46 mutations now have been defined for MPS-I consisting of 8 nonsense mutations, 21 missense mutations, 3 splice site mutations, and 14 minor deletions and/or insertions. Furthermore, 30 polymorphisms or nonpathogenic sequence variants have been defined, including 7 amino acid substitutions. Among patients of European origin, there are two major MPS-I mutations and a number of less frequent mutations. It is possible to follow mutation analysis of 292 patients, which can be divided into eight main patient groups of different ethnic and/or geographic origin with significant variation in mutant allele frequencies. A complex picture of molecular heterogeneity is emerging, building a valuable database for genotype/phenotype correlation. Mutation analysis is also providing some of the first clues into the structure and function of IDUA. PMID- 8680404 TI - Analysis of mutational changes at the HLA locus in single human sperm. AB - Using a simple and efficient single sperm PCR and direct sequencing method, we screened for HLA-DPB1 gene mutations that may give rise to new alleles at this highly polymorphic locus. More than 800 single sperm were studied from a heterozygous individual whose two alleles carried 16 nucleotide sequence differences clustered in six polymorphic regions. A potential microgene conversion event was detected. Unrepaired heteroduplex DNA similar to that which gives rise to postmeiotic segregation events in yeast was observed in three cases. Control experiments also revealed unusual sperm from DPB1 homozygous individuals. The data may help explain allelic diversity in the MHC and suggest that a possible source of human mosaicism may be incomplete DNA mismatch repair during gametogenesis. PMID- 8680405 TI - Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations. AB - The mitochondrial DNAs (mtDNA) from 17 Caucasian 11778-positive and 30 Caucasian 11778-negative Leber's hereditary optic neuropathy (LHON) patients were PCR amplified and subjected to high resolution restriction endonuclease analysis. Concurrently, all patient mtDNAs were screened for the common primary LHON mtDNA mutations at nucleotide pairs (nps) 3460, 11778, and 14484, the ambiguous intermediate-risk LHON mtDNA mutations at nps 5244 and 15257, and the secondary LHON mtDNA mutations at nps 3394, 4216, 4917, 7444, 13708, and 15812. Phylogenetic analysis was performed using mtDNA haplotype data from the 47 LHON patients and 175 non-LHON Caucasian controls. The superimposition of the LHON mutation screening results upon the Caucasian mtDNA phylogeny revealed (1) 35 different LHON haplotypes, (2) that all three common primary mutations have occurred multiple times in Caucasians, (3) that while recurrent mutation is common for the primary mutations, secondary mutations tend to be lineage specific, (4) that the np 15257 mutation was confined to a single mtDNA lineage but may be etiologically important in some LHON cases since it was found in a LHON pedigree which lacked a common primary mutation; complete sequence analysis of the proband mtDNA revealed only a single other candidate missense mutation (at np 10663 of the ND4L gene) of uncertain pathological significance; and (5) that the np 14484 mutation may be less pathogenic than either the np 3460 or np 11778 mutations, as this mutation most commonly occurred on a single mtDNA lineage and almost always in association with secondary LHON mutations. A phylogenetic approach to this genetically heterogeneous disease has thus provided key genetic data bearing on the relative pathogenicity of the LHON-associated mtDNA mutations. PMID- 8680406 TI - Cystic fibrosis mutation analysis: report from 22 U.K. regional genetics laboratories. AB - We have collated the results of cystic fibrosis (CF) mutation analysis conducted in 22 laboratories in the United Kingdom. A total of 9,807 CF chromosomes have been analysed, demonstrating 56 different mutations so far observed and accounting for 86% of CF genes in the native Caucasian population of the United Kingdom. delta F508 is the most common at 75.3% of CF mutations (range 56.5 83.7%), followed by G551D (3.08%; range 0.71-7.60%), G542X (1.68%; range 0.85 3.66%), 621 + 1 (G > T) (0.93%; range 0.41-3.16%), 1717-1(G > A) (0.57%; range 0.17-1.14%), 1898 + 1)(G > A) (0.46%), R117H (0.46%), N1303K (0.46%), and R553X (0.46%). The data show a clear geographical variation in the distribution of some of the mutations, most notably a marked regional variation in the distribution of 621 + 1 (G > T) and 1989 + 1(G > A), which are both apparently more frequent in Wales. R560T and R117H appear to be more frequent in Ireland and Scotland, and G551D more frequent in Scotland. In summary, these data illustrate that the mutations present within a particular population need to be defined in order to provide meaningful carrier screening and testing for rare mutations in affected individuals. Furthermore, it is apparent that the ethnic origin of a patient, even within a small country such as the United Kingdom, should be taken into account. PMID- 8680407 TI - French CF family genotype analysis shows that the R297Q mutation is a rare polymorphism. AB - The authors describe a cystic fibrosis family genotype analysis showing that the R297Q amino acid change is a rare polymorphism rather than a deleterious mutation as previously reported. Indeed in this family two healthy subjects have the following genotypes: delta F508/R297Q and N1303K/R297Q. PMID- 8680409 TI - A 12-bp deletion (7818del12) in the c-kit protooncogene in a large Italian kindred with piebaldism. PMID- 8680408 TI - Efficient strategy for the detection of mutations in acrogeric Ehlers-Danlos syndrome type IV. AB - cDNA encoding the C-terminal domain (nt2283 to 3714) of type III collagen was amplified by PCR in five overlapping products and examined for mutations in 13 patients with Ehlers-Danlos syndrome type IV (EDS IV) with uncharacterised lesions and in five control patients with known single base mutations. Six different point mutations were detected by denaturing gradient gel electrophoresis (DGGE), in addition to those in the known controls. Four of seven patients who had no point mutations in this region were shown to lack complete exons from their amplified cDNA. Mutations were detected in all patients with typical or acrogeric EDS IV, but only in one of four individuals with the atypical form of the disease. PMID- 8680410 TI - Twenty-five novel mutations of the factor IX gene in haemophilia B. PMID- 8680411 TI - Mutations of human butyrylcholinesterase gene in a family with hypocholinesterasemia. PMID- 8680412 TI - Two new mutations in the acid sphingomyelinase gene causing type a Niemann-pick disease: N389T and R441X. PMID- 8680413 TI - Effect of a single intravenous injection of N-methyl-D,L-aspartic acid on secretion of luteinizing hormone and growth hormone in Holstein bull calves. AB - The role of N-methyl-D-aspartate (NMDA) receptor activation in the central regulation of luteinizing hormone (LH) and growth hormone (GH) was tested by administering a bolus intravenous dose of N-methyl-D,L-aspartic acid (NMA), a NMDA receptor agonist, to 24-week-old intact (n=5), estradiol-treated intact (n=3) and castrated (n=3) Holstein bull calves. The calves were bled for 12h pre- and 100 min post-NMA injection (1.75 mg-/kgBW) periods at 10 min intervals. Concentrations of LH and GH in plasma were measured by specific RIA. Prior to administration of NMA, the average concentration of LH, but not GH, differed significantly among the 3 groups. As expected, administration of estradiol prevented the normal ontogeny of pulsatile LH secretion, while castration resulted in an increased frequency of LH discharges. Injection of NMA resulted in an acute (P<0.001) release of LH in 3 of 5 intact and 3 of 3 estradiol-treated intact calves with the peak response being observed at 20 min (3.18 +/- 1.3 and 5.58 +/- 1.3 ng/ml, respectively) following the challenge. Treatment with NMA did not alter the release of LH in castrate calves. Concentrations of GH in plasma increased (P<0.001) within 20 to 30 min after administration of NMA in intact, estradiol-treated intact and castrate calves with a similar response being observed in each group. Based on these findings, we suggest an involvement of glutamatergic neurotransmission in the hypothalamic or supra-hypothalamic control of LH and GH secretion, and that the excitatory effects of NMDA receptor activation on LH release are overtly influenced by gonadal steroids in bull calves. PMID- 8680414 TI - Role of CRH in glucopenia-induced adrenomedullary activation in rats. AB - Acute glucoprivation profoundly stimulated hypothalamic-pituitary-adrenocortical (HPA) and adrenomedullary outflows. Whether these responses reflect a single central mechanism regulated by corticotropin-releasing hormone (CRH) has been unclear. This study examined the role of endogenous CRH in HPA and adrenomedullary responses to hypoglycemia in Sprague-Dawley rats, by using anti CRH immune serum or a CRH antagonist (alpha-helical h/r CRH9-41, and in Lewis rats, a strain characterized by deficient hypothalamic CRH responses during stress. In conscious Sprague-Dawley rats with indwelling arterial and venous cannulas, insulin (0.3 U/kg was injected iv, and responses of serum glucose concentrations and plasma levels of corticotropin (ACTH) and catechols (including epinephrine, EPI; norepinephrine, NE; dihydroxyphenylalanine, DOPA; dihydroxyphenylglycol, DHPG; and dihydroxyphenylacetic acid, DOPAC) were assessed, with or without pretreatment with anti-CRH immune serum (0.5 or 1.0 ml iv or 10 microl icv) or alpha-helical h/r CRH9-41 (130 nmol iv or 13 nmol icv). Responses to insulin (1.0 U/kg iv) were also measured in conscious juvenile Lewis and Fischer 344/N rats. Insulin-induced hypoglycemia markedly increased plasma levels of EPI and ACTH in all groups. Pretreatment iv with 1/0 ml of anti-CRH immune serum blocked the ACTH response to insulin but failed to attenuate the EPI response. alpha-helical h/r CRH9-41, whether given iv or icv, failed to alter ACTH or EPI responses to insulin, although the antagonist did block EPI responses to icv CRH. Hypoglycemia elicited similar increments in ACTH levels in Lewis rats and Fischer 344/N control rats; and although Lewis rats had lower baseline EPI and smaller responses of NE, DHPG, DOPA, and DOPAC levels, the groups did not differ in proportionate increments in EPI levels. The results indicate that the ACTH response to hypoglycemia depends on availability of CRH outside the blood brain barrier--presumably in the pituitary gland. The findings with icv alpha helical h/r CRH9-41 can be explained by failure of the antagonist to reach effective concentrations at central sites of action of endogenous CRH, or by mechanisms other than CRH release determining the adrenomedullary response to hypoglycemia. Lewis rats seem to have less adrenomedullary secretion at baseline and smaller responses of NE synthesis and release during hypoglycemia than do Fischer 344/N rats. Neurochemical evidence for differential adrenomedullary and sympathoneural responses during hypoglycemia in all three rat strains is inconsistent with Cannon's view of a functionally unitary sympathoadrenal system. Lewis rats have deficient CRH responses to some stressors but not to others, or else pituitary-adrenomedullary responses in this setting depend on mechanisms other than CRH release in the brain. Both explanations are inconsistent with the doctrine of non-specificity, the main tenet of Selye's stress theory. PMID- 8680415 TI - Immunocytochemical localization of progesterone receptors in galanin neurons in the guinea pig hypothalamus. AB - A double-label immunocytochemical technique was used to determine whether progesterone receptor-containing neurons in the female guinea-pig hypothalamus also contained galanin. Adult ovariectomized guinea-pigs were primed by estradiol to induce progesterone receptors and injected intracerebroventricularly with colchicine to visualize galanin-immunopositive neurons. A small proportion of progesterone receptor-containing perikarya in the medial preoptic area and the mediobasal hypothalamus were bound to be immunoreactive for galanin. The medial preoptic, periventricular and arcuate nuclei showed the greatest concentration of double-labelled cells. Galanin varicosities appeared in close proximity to neurons with progesterone receptor-containing nuclei. These results provide neuroanatomical evidence that a subset of hypothalamic galanin-immunoreactive neurons is directly regulated by progesterone. PMID- 8680416 TI - The effect of photoperiod on plasma levels of melanin-concentrating hormone in the trout. AB - The neurohypophysial melanin-concentrating hormone, MCH, plays a role in adaptive colour change in teleost fishes inducing pallor when the fish is placed in pale coloured surroundings. The present study shows that its plasma concentration, measured in groups of white-adapted fish, is not uniformly high throughout the day but follows a clear diurnal pattern. Over a 24 h cycle, plasma concentrations rise gradually during the morning to reach peak values around the middle of the photophase, after which they decline significantly before night. Lowest concentrations are observed during the dark period. This pattern was observed under a long photoperiod in summer and a short photoperiod in winter. The peak was shifted within a week of changing the onset of either light or dark. When dawn was delayed by 6 h for fish held under short photoperiod conditions, then peak concentrations were attained 6 h precociously. Fish from a long photoperiod placed in constant light showed a pattern of MCH release which approximated to the normal over the first 24 h period but plasma values then became raised and periodicity was no longer discernible. Plasma hormone concentrations were much reduced in trout kept in black coloured tanks in which nocturnal and daytime values differed, but significant differences during the photophase were not demonstrable. The results suggest that an illuminated white background can initiate the early morning release of MCH, and that an endogenous pacemaker underlies the pattern of MCH secretion. PMID- 8680417 TI - Activation of magnocellular vasopressin responses to non-osmotic stress after chronic adrenal demedullation in rats. AB - Increases in plasma VP in response to osmotic stimulation are critical for water conservation, while VP released into the pituitary portal circulation is an important regulator of ACTH secretion and does not contribute to plasma VP levels. The role of the adrenal medulla in the specificity of these responses was studied in rats subjected to osmotic and non-osmotic stress two months following adrenal demedullation or sham operation. Basal and stimulated plasma corticosterone, aldosterone, ACTH and PRA levels in adrenal demedullated rats were similar to those in the sham operated groups indicating recovery of adrenocortical function. Basal plasma VP level were similar in sham operated controls and adrenal demedullated rats (0.93 +/- 0.13 and 1.0 +/- 0.1 pg/ml, respectively) and rose to comparable levels in both groups following 48 h osmotic stimulation by water deprivation (14.4 +/- 1.3 and 20.7 +/- 3.4, respectively). On the other hand, while in sham operated rats, immobilization for 15 min, a non osmotic stress, had no effect on plasma VP levels in control or water deprived (2.0 +/- 0.9 and 15.0 +/- 2.7 pg/ml), in adrenal demedullated rats, caused dramatic increases in plasma VP from 1.0+/-0.1 to 126.0+/029.9 pg/ml in controls, and from 20.7 +/- 3.4 to 155 +/- 37 pg/ml in water deprived rats. Intraperitoneal hypertonic saline injection, a combination of osmotic and painful stress, caused much higher increases in plasma VP in adrenal demedullated rats (138.0 +/- 22.1 compared with 34.7 +/- 3.7 pg/ml in sham operated rats). Water deprivation potentiated this response to 70.0 +/- 8.3 and 295 +/- 24 pg/ml in sham operated and adrenal demedullated rats, respectively. VP mRNA measured by in situ hybridization, and irVP measured by immunohistochemistry, were elevated in magnocellular neurones in the hypothalamus of adrenal demedullated rats. The demonstration of marked plasma VP responses to non-osmotic stimuli in adrenal demedullated rats, suggests a modulatory role for the adrenal medulla in the specificity of the secretory responses of the magnocellular and parvicellular vasopressinergic systems. PMID- 8680418 TI - Regulation of vasopressin (VP) gene expression in the bed nucleus of the stria terminalis: gonadal steroid-dependent changes in VP mRNA accumulation are associated with alterations in mRNA poly (A) tail length but are independent of the rate of VP gene transcription. AB - Forebrain vasopressin (VP) neurons of the bed nucleus of the stria terminalis (BNST) contrast with hypothalamic VP neurons in exhibiting nuclear gonadal steroid receptors which may directly effect steroid-induced changes in VP gene expression observed in BNST cells. A transcription and Northern mRNA analysis has been performed to determine the mechanism through which gonadal steroids regulate VP gene expression in the BNST. In addition to confirming a distinctive, sexually dimorphic pattern of VP mRNA expression in the BNST as compared with the hypothalamic supraoptic nuclear (SON), our results show that the marked decrease in BNST VP mRNA levels observed two weeks after castration is not associated with a change in transcriptional activity of the VP gene. Similarly, VP gene transcription is not increased, relative to castrated animals, in the BNST of castrated rats treated with testosterone which exhibit normal or somewhat elevated levels of VP mRNA in the BNST. A post-transcriptional mechanism therefore appears to underlie the gonadal steroid-regulated changes in VP gene expression in the BNST. Since modulation of mRNA size (due to changes in poly (A) tail length) was also observed following castration and testosterone treatment it is apparent that the post-transcriptional mechanism may involve regulated changes in VP mRNA poly (A) tail length. The present findings contrast with the osmotic up-regulation of VP mRNA levels in the SON which is primarily a transcriptional response, and provide a demonstration of the potential physiological importance of post-transcriptional mechanisms of hormonal gene regulation. PMID- 8680419 TI - Inhibitory effects of natriuretic peptides on vasopressin neurons mediated through cGMP and cGMP-dependent protein kinase in vitro. AB - The effects of natriuretic peptides on electrical activity and cellular cGMP levels were studied in neurons of the supraoptic nucleus (SON) of rat hypothalamic slice preparations. Intracellular and extracellular recordings showed that bath application of A type natriuretic peptide (ANP) at 100 nM or B type natriuretic peptide (BNP) at 100 to 300 nM decreased the firing rate and hyperpolarized the membrane potential in phasically firing (putative vasopressin) neurons. Non-phasically firing (putative oxytocin) neurons did not respond to these natriuretic peptides in firing rate or membrane potential. The membrane permeable cGMP analogue 8-bromo cGMP at 0.5 mM and the phosphodiesterase inhibitor 3/isobutyl-1-methylxanthine (IBMX) at 50 microM mimicked the inhibitory effects of ANP and BNP. The specific inhibitor of cGMP phosphodiesterase 1-(3 chloroanilino)-4-phenylphthalazine+ ++ (MY5445) at 30 microM also decreased the firing rate of SON neurons. The cGMP-dependent protein kinase inhibitor N-(2 (methylamino)ethyl)-5-isoquinoline-sulfonamide dihydrochloride (H8) at 1 microM abolished the inhibition by natriuretic peptides. We measured cGMP and cAMP contents in discrete SON regions and compared the change of contents before and after application of ANP and BNP. The increases in cellular cGMP accumulation were 430% for ANP and 120% for BNP, although they did not cause significant change of cAMP accumulation. The results suggest that the inhibitory effects of natriuretic peptides on putative vasopressin neurons are mediated through cGMP and cGMP-dependent protein kinase. PMID- 8680420 TI - Vasopressin anti-idiotypic antibody staining in the rat brain: colocalization with [35S] [pGlu4, Cyt6]AVP(4-9) binding sites. AB - Vasopressin and its fragment peptides such as [pGlu4, Cyt6]AVP(4-9) (AVP(4-9) represent putative neuromodulators within central nervous homeostatic, memory and behavioural circuits. To localize their central receptor systems, the previously characterized monoclonal anti-idiotypic antibody mAb 237 was employed in immunocytological investigations of rat brain tissue sections. This antibody was raised to the monoclonal idiotypic anti-AVP antibody mAb 113 which preferentially binds to the acyclic C-terminal portion of the AVP molecule and is therefore also capable of binding the naturally occurring AVP(4-9) fragment. Immunoreactive magnocellular neurones were detected in the AVP-synthesizing supraoptic but not paraventricular nuclei. Dense staining was observed within circumventricular organs lacking a blood-brain barrier (BBB). These structures include the subfornical organ, the organum vasculosum laminae terminalis, the internal layer of the median eminence, the body of the pineal gland, the choroid plexus and the area postrema, where immunoreactivity was found on capillaries, neurones and fibres. Further staining was found in the nucleus of the solitari tract and the arcuate nucleus, endowed with a leaky BBB. Distinct cell patches in the ependymal lining of the third ventricle as well as dendritic processes of juxtaependymal neurones were labelled by the anti-idiotypic antibody mAb 237. The observed staining pattern did not parallel that obtained in autoradiographic studies performed using either radiolabelled AVP or a V1-receptor antagonist, but that found with the [35S]-labelled AVP(4-9) fragment. Using [35S]-labelled AVP(4-9) fragment, specific high density binding sites could be localized autoradiographically in structures within and outside the BBB, in complete agreement with the anti-idiotypic immunoreactivity. Since the anti-idiotypic methodology is based on transfer of complementary structures, and the epitope recognized by the corresponding idiotypic antibody resembles the sequence of AVP(4-9), the anti-idiotypic antibodies might recognize the AVP(4-9) receptor with high affinity. PMID- 8680421 TI - Depolarizing action of secretory granule protein 7B2 on rat supraoptic neurosecretory neurons. AB - A novel precursor neuropeptide termed 7B2 is present within specific brain areas, including the hypothalamic magnocellular neurosecretory neurons, and appears to be processed to smaller fragments. In order to determine whether specific C terminal fragments of 7B2 might exert local effects on neurosecretory cells, we used intracellular current-clamp recordings in supraoptic neurons maintained in superfused hypothalamic explants to evaluate membrane potential and resistance changes in 25 supraoptic nucleus neurons during bolus applications of 7B2 174-186 and two other C-terminal peptide fragments 7B2 156-173 and 7B2 141-150. In 15 supraoptic neurons, only the 7B2 174-186 fragment induced a gradual 2-8 mV membrane depolarization that lasted for 4 to 30 min and was accompanied by 15+/ 8% reduction in input resistance. Immunocytochemical identification of the recorded cells revealed that both vasopressin (VP)- and oxytocin (OT)-containing neurons were depolarized by 7B2 174-186. These data suggest that 7B2 174-186 is a biologically active fragment of 7B2 and may regulate the excitability of magnocellular supraoptic nucleus neurons. PMID- 8680422 TI - Decreased population spike in CA1 hippocampal area of adrenalectomized rats after repeated synaptic stimulation. AB - Population spikes, evoked in the CA1 hippocampal area by simulation of the Schafer collaterals at various intensities, were recorded over a period of 70 min in slices from 7-day adrenalectomized (ADX) or sham-operated rats. Slices from sham-operated rats with intermediate plasma corticosterone levels (between 0.5 and 5 micrograms corticosterone/100 ml plasma) at the start of the experiment displayed very stable synaptic responses. However, the responses recorded in slices from rats with lower or higher corticosterone levels gradually declined, with repeated stimulation. Similarly, a significant decline of the population spike over time was observed in slices from ADX rats, particularly with low stimulus intensities; characteristics of the compound EPSP were much more stable. The decline of the population spike amplitude was alleviated when: 1) single rather than repeated stimulation was applied; 2) the experiments were performed in the presence of 20 mM glucose; or, 3) moderately high (10(-8) or 10(-7) M) concentrations of corticosterone were administered in vitro; low (10(-9) M) or high (10(-6) M) corticosterone concentrations in vitro did not improve the stability of the synaptic response in slices from ADX rats. These data suggest that intermediate levels of corticosterone are necessary to maintain the stability of the Schaffer collateral input to CA1 neurons. With very low or high corticosterone levels, CA1 neurons apparently fail to respond to synaptic stimulation, over time. The possible mechanisms underlying this bell-shaped dose response curve for corticosterone are discussed. PMID- 8680423 TI - Neurons in the paraventricular nucleus of the hypothalamus that project to the sexually dimorphic lower lumbar spinal cord concentrate 3H-estradiol in the male rat. AB - The location and distribution of estradiol-concentrating neurons in the hypothalamus afferent to segments of lumbar spinal cord that contain the sexually dimorphic spinal nucleus of the bulbocavernosus (SNB) were determined by combining retrograde fluorescent tract tracing with steroid hormone autoradiography. Injections of Fluorogold were made into segments of L5-L6 of the spinal cord of adult male rats and 12 days later animals were castrated. One week following castration, males received injections of [3H]estradiol and were perfused. Their brains were then processed for steroid hormone autoradiography. Following exposure times of 11 to 12 months, autoradiograms were developed and the hypothalamus was analyzed for neurons that concentrate estradiol and project to the spinal cord. Numerous neurons in the hypothalamus projected to the spinal cord, specifically neurons in the paraventricular nucleus (PVN), the lateral hypothalamus and the dorsal area of the hypothalamus. Although many subnuclei of PVN, as well as lateral hypothalamus, contained Fluorogold labelled neurons and estradiol concentrating neurons, the majority of double labeled cells were found in the lateral parvocellular (LP) subnucleus of PVN. Approximately 30% of the neurons in the lp subnucleus that projected to spinal cord also concentrated estradiol. Up to one half of the estradiol-concentrating neurons in lp sent axons to the lower lumbar spinal cord. These results suggest that some of the effects of gonadal steroid hormones on SNB development, plasticity and function may in fact, be indirect, via steroid-sensitive afferents. PMID- 8680424 TI - Effects of morphine and naloxone on prolactin and growth hormone gene expression in the male rat pituitary gland. AB - It is generally admitted that opioids can stimulate the release of both prolactin (PRL) and growth hormone (GH). In order to investigate the role of opioids in the regulation of PRL and GH gene expression in the rat pituitary, we studied the effects of chronic administration of the opioid drug morphine and an opiate receptor antagonist naloxone on both PRL and GH gene expression as measured by in situ hybridization. Four-day treatment with morphine (40 mg/kg/day) produced a 12% increase in PRL mRNA levels. Conversely, naloxone (4 mg/kg/day) decreased the autoradiographic reaction by 10%. The concomitant administration of morphine and naloxone induced no significant changes in PRL gene expression. On the other hand, treatment with morphine produced a 22% decrease in GH mRNA levels, an effect which was prevented by the concomitant administration naloxone. When injected alone, naloxone did not modify the hybridization signal. These results clearly indicate that opioids are involved not only in the regulation of GH and PRL release but also in the gene expression of the two hormones. The discordance observed between the acute effects of morphine on GH release and the effect of the opioid drug on mRNA levels remains to be clarified. PMID- 8680425 TI - Mating-induced FOS-like immunoreactivity in the rat forebrain: a sex comparison and a dimorphic effect of pelvic nerve transection. AB - Previous research has shown that mating induces the expression of the immediate early gene, c-fos, as detected by the increased presence of nuclear FOS-like immunoreactivity (FOS-IR), in specific forebrain regions of both male and female rats. In the male both olfactory-vomeronasal (O/V) and genital/somatosensory (G/S) inputs appear to contribute to the neural FOS response to mating whereas in the female G/S input carried by the pelvic nerves appears to mediate the forebrain FOS response. To date, however, no direct sex comparison of the mating induced forebrain FOS response has been made in rats maintained under the same steroidal conditions nor has the contribution of afferent sensory input from the pelvic nerves been assessed in males. We first compared the level of FOS-IR in brain regions of mated and unpaired gonadectomized male and female rats given 5 micrograms/kg estradiol benzoate (EB) for 7 days and 500 micrograms progesterone (P) 4 h prior to testing. One h after experiencing 1 ejaculation, both sexes showed increased FOS-IR in the medial preoptic a (MPOA), bed nucleus of the stria terminalis (BNST), medial amygdala, the ventro-lateral portion of the ventromedial nucleus of the hypothalamus (VMN), and the midbrain central tegmental field (CTF). This increase was significantly greater in the MPOA and medial amygdala of mated females than of males. Bilateral transection of the pelvic nerves significantly attenuated the increase in FOS-IR after mating in the CTF of male rats and in the MPOA, BNST, VMN, medial amygdala and CTF of females. Thus, following mating there is no sex difference in the brain regions which express c-fos, but there is a dimorphism in the contribution of afferent information conveyed by the pelvic nerves to the mating-induced FOS response. The neural FOS response of the female to mating is heavily dependent upon the G/S afferent inputs carried by the pelvic nerves whereas the male's neural c-fos response may depend on O/V input plus G/S input conveyed via other efferent pathways such as the pudendal nerves. PMID- 8680426 TI - Formation of neurons in the sexually dimorphic anteroventral periventricular nucleus of the preoptic area of the rat: effects of prenatal treatment with testosterone propionate. AB - An examination was made of neurogenesis in the anteroventral periventricular nucleus (AVPv) of the preoptic area of the rat using bromodeoxyuridine (BrdU), a thymidine analog, and a BrdU-specific antibody. Cells in the AVPv of adult rats were labeled with the antibody when BrdU was injected into pregnant rats once during day 13 to 18 of gestation, but not during day 10 to 12 nor 19 to 20 of gestation nor on postnatal day 1, indicating the neurogenesis of the AVPv occurs during a limited period from day 13 to 18 of gestation. Next, to examine the effects of androgen on neurogenesis, BrdU was injected once on day 15 into pregnant rats that also received injections of testosterone propionate (TP). The number of BrdU-labeled cells in the AVPv was similar in control female and male fetuses and female fetuses from pregnant rats that received daily injections of TP during days 14 to 16, when fetuses were examined on day 17 of gestation. These results suggest that the neurogenesis that was recognized by labeling with BrdU was not affected by the treatment with TP. On day 21 of gestation, BrdU-labeled cells in the AVPv of control male fetuses and female fetuses that received TP during days 14 to 18 were fewer in number than those in female fetuses of the control group, whereas treatments with TP during days 14 to 16 and during days 17 to 18 did not cause any significant decrease in number of BrdU-labeled cells. These findings can support the hypothesis that elimination of a population of cells, for example, by cell death as described previously, is enhanced in male fetuses and in female fetuses treated with TP repetitively. PMID- 8680427 TI - Electrophysiological effects of pressure-ejected bombesin-like peptides on hamster suprachiasmatic nucleus neurons in vitro. AB - The suprachiasmatic nuclei (SCN) of the rodent hypothalamus function as a light entrainable circadian pacemaker. The SCN contain moderate to high concentrations of a number of neuropeptides including peptides showing structural homology with the amphibian derived tetradecapeptide, bombesin (BN), called bombesin-like peptides (BNLPs). BNLPs include the 27 amino acid peptide, gastrin releasing peptide (GRP1-27), a smaller decapeptide (GRP18-27) and another decapeptide with less structural homology, neuromedin B (NmB). Immunoreactivity for BN and receptors for BNLPs have been demonstrated in the region of the rat SCN receiving photic input. We studied the effects of local pressure ejections of BNLPs dissolved in saline/1% bovine serum albumin (BSA) vehicle on the extracellularly recorded firing rates of Syrian hamster SCM neurons in a hypothalamic slice preparation. In one study, an ejecting electrode containing BN (10(-8) to 10(-4) M) was positioned 20 to 60 microm from a recording electrode. Of 74 cells tested with BN, 50 (67.6%) showed significant increases in firing rate, while 3 of 29 cells (15.8%) tested with vehicle ejections were activated. In a second study, a single electrode was used for both recordings and pressure ejections. Of 48 cells tested, BN (10(-6) to 10(-4) M) activated 30 (62.5%) and suppressed firing in 4 (8.3%). Of 208 cells tested with GRP1-27 (10(-9) to 10(-4) M), 105 (50.5%) were activated and 2 (1.0%) were suppressed. The percentage of cells responding increased with the concentration of GRP1027 used in the electrode. No circadian variation in responsiveness to GRP1-27 was detected. GRP18-27 (5 x 10(-5) to 10( 4) M) activated 10 out of 18 cells tested (55.6%), while NmB (10(-4) M) activated 2 out of 30 cells tested (6.7%) and vehicle ejections activated 1 out of 36 cells tested (2.8%). GRP1-27, GRP18-27 and BN, the BNLPs showing the greatest degree of structural homology, activate approximately 50% of SCN cells, apparently via the BN/GRP-preferring receptor subtype, and may play a role in photic entrainment. PMID- 8680428 TI - Dynorphin 1-17 delays the vasopressin induced mobilization of intracellular calcium in cultured astrocytes from the rat neural lobe. AB - Opioid peptides are present in nerve terminals in the rat neural lobe where they partially coexist with vasopressin. Morphological findings suggest that these neuropeptides are released onto pituicytes, which is in agreement with a possible role for the pituicyte in oxytocin and vasopressin release from the neural lobe. Pituicytes in culture respond to vasopressin with a mobilization of calcium from intracellular stores. In the present study this vasopressin induced increase in intracellular free calcium levels was both delayed and decreased by pre-exposure to dynorphin 1-17, while dynorphin 1-17 by itself did not affect basal calcium levels. All effects of dynorphin 1-17 could be blocked with naloxone. The present results suggest that opioid receptors are present on pituicytes and are coupled to a second messenger pathway by which opioid peptides may inhibit inositol phosphate dependent calcium mobilization by other neuropeptides, such as vasopressin. PMID- 8680429 TI - Short-term regulation of gonadotropin subunit mRNA levels by estrogen: studies in the hypothalamo-pituitary intact and hypothalamo-pituitary disconnected ewe. AB - In this study the levels of mRNA for the pituitary gonadotropin hormone subunits luteinizing hormone beta (LHbeta), follicle stimulating hormone beta (FSHbeta) and the common alpha-subunit were assessed during the acute feedback stages of estradiol benzoate (EB) action in ovariectomized (OVX) ewes with and without hypothalamo-pituitary disconnection (HPD). In OVX/HPD ewes maintained on hourly pulses of 250 micrograms of gonadotropin-releasing hormone (GnRH) a single i.m. injection of EB in oil caused a biphasic (decrease and then increase) change in plasma LH levels and a monophasic decrease in FSH levels. There was a decrease in pituitary alpha-subunit and FSHbeta mRNA levels during the acute negative (8 h post EB) and through the positive feedback (20 h post EB) stages of the response. No significant change was seen in LHbeta mRNA levels following treatment with EB. In hypothalamic-pituitary intact OVX ewes the same EB treatment as above caused a biphasic change in LH secretion with the positive feedback component being much greater than in GnRH-pulsed OVX-HPD ewes. The levels of mRNA for all three gonadotropin subunits were reduced by 8 h after EB injections and remained low throughout the positive feedback period. These data suggest that the LH surge in this experimental model does not require an increase in LHB mRNA levels. Furthermore, the fall in LHbeta subunit mRNA seen after estrogen injection of OVX ewes is most likely due to an effect of estrogen to decrease GnRH secretion, since pulsatile GnRH replacement prevents this effect. These data also show that estrogen feedback can effect rapid alterations in pituitary gonadotropin subunit mRNA levels. Short-term changes in FSHbeta mRNA are reflected in changes in FSH secretion; the same is not true for LH. PMID- 8680430 TI - Plasticity in expression of immunoreactivity for neuropeptide Y, enkephalins and neurotensin in the hypothalamic tubero-infundibular dopaminergic system during lactation in mice. AB - In lactating nursing vs lactating pup-deprived mice, single or multiple immunolabeling was performed to compare immunoreactivities (ir) for neuropeptide Y (NPY), enkephalins (ENK) and neurotensin (NT) in the tyrosine hydroxylase (TH) ir (ENK) and neurotensin (NT) in the tyrosine hydroxylase (TH)-ir hypothalamic tubero-infundibular dopaminergic (TIDA) system. NPY-, ENK- and NT-irs were intensely expressed and coexisted in virtually all TH-ir endings in the median eminence (ME) of nursing mice. Removal of the pups induced a marked depletion of the peptide-irs from the ME TH-ir endings. In the arcuate nucleus (ARC) of colchicine-treated nursing mice which received peripheral injections of Fluoro Gold (FG) to retrogradely label neuroendocrine cells, virtually all dorsal A12 TH ir perikarya simultaneously expressed, with individual variations, NPY-, ENK- and NT-irs, and all contained FG. These results suggest that the synthesis of NPY, ENK and NT is enhanced in TIDA neurons during lactation and that these neuromessengers may be co-released together with DA from the ME to regulate the suckling-induced prolactin secretion at the hypothalamic and/or pituitary levels. PMID- 8680431 TI - Antiovulatory doses of antagonists of LH-RH inhibit LH and progesterone but not FSH and estradiol release. AB - The differential regulation of immunoactive FSH and LH secretion by endogenous LH RH was studied using LH-RH antagonists (Ac-D-Trp1,2, D-Cpa2, D-Lys6, D-Ala10LH-RH (MI-1544) and (Ac-D-Nal1, D-Phe(pCl2), D- Trp3, D-Cit6, D-Ala10LH-RH (SB-030) in ovariectomized (OVX) and regularly cycling rats. Single injections of 10 micrograms and 100 micrograms doses and long-term treatment with 10 micrograms doses of MI-1544 were used in OVX animals. Serum and pituitary LH and FSH, as well as serum estradiol and progesterone was determined by RIA during and/or after the treatment. Single injections of MI-1544 in OVX animals caused prompt (in 2 h) and long-lasting (for more than 24 h) suppression of the serum LH, while no or late decrease (after more than 6 h) of the serum FSH. Long-term treatment with the same analog decreased the serum LH (by 50%) and moderately increased the pituitary LH (by 21%) but did not change the serum and the pituitary FSH concentrations. In normal rats, long-term treatment with both of our analogs also resulted in divergent alterations in the LH and FSH concentrations. Serum LH dropped to undetectable levels,while serum FSH did not change significantly. Pituitary LH increased (by 31 to 41%), while FSH decreased (by 27 to 38%). Marked depression was found in the serum progesterone (by 64%) but no significant change in the serum estradiol levels, after the long-term treatment for 21 days. The ovarian cycles were interrupted, and no ovulation appeared during the treatment. Significant decrease was detectable in the weight of the ovaries (by 46%), whereas the weight of the uteri did not change or slightly elevated (by 22%), after the treatment with SB-030 or MI-1544, respectively. PMID- 8680432 TI - Photoperiod regulates the LH response to central glutamatergic stimulation in the male Syrian hamster. AB - This study investigated central glutamatergic function in relation to photoperiodically-induced changes in the secretion of luteinizing hormone (LH). The experimental approach was to compare the central effects of glutamate agonists on LH secretion in reproductively active hamsters kept in long days (LD) with those in photoinhibited hamsters kept in short days (SD) for 6 weeks and having regressed testes. Agonists were delivered via a cannula into the III ventricle of freely moving hamsters, and blood samples collected 10 to 15 min after the start of the infusion. A high dose (3.0 nmole) of N-methyl-D-L aspartate (NMDA) induced significant (P<0.01) increases in serum concentrations of LH in hamsters in both photoperiods, though the NMDA-induced increase relative to endogenous LH concentrations was greater in SD than in LD. However, a lower dose of NMDA (0.3 nmole revealed a difference in sensitivity. This dose significantly increased serum LH (P<0.05) in hamsters in SD but had no effect in those in LD. The seasonal difference in response to NMDA was compared with the response to an equimolar dose of alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA), a non-NMDA agonist. This dose of AMPA (0.3 nmole) induced a two-fold increase (P<0.05) in serum concentrations of LH in hamsters in both photoperiods, relative to vehicle-treated controls. In a third experiment the dose-response effects of central AMPA on LH secretion were examined more closely. The sensitivity of LH secretion to stimulation with AMPA did not differ between SD- and LD-housed hamsters. Thus the photoperiod-related difference in sensitivity to stimulation with glutamate agonists is specific for NMDA receptor mediated activation, rather than a passive reflection of differences in the capacity to secrete GnRH/LH in SD and LD photoperiods. To investigate the site of action of NMDA, the expression of the c-fos immediate-early gene, as assessed by immunocytochemistry for its protein product Fos, was used as a marker of neuronal activation, because previous studies in rodents indicate that a high proportion of GnRH neurons express c-fos at the time of the mid-cycle LH surge. NMDA induced widespread expression of c-fos in many periventricular regions including the medial preoptic area (POA) and ventromedial hypothalamic nucleus. However, dual ICC revealed that in neither photoperiod was Fos present in GnRH-positive neurons 1 h after infusion of 3 nmole of NMDA, despite the increases in LH secretion induced by the infusion. AMPA injected icv at doses which released LH did not enhance expression of c-fos in the hypothalamus. Thus, in the male, enhanced expression of c-fos cannot be detected in GnRH neurons at the time of increased secretion of this hormone induced by glutamate agonists. In conclusion, these results show that both NMDA and non-NMDA glutamatergic pathways potentially regulated LH secretion in the Syrian hamster. The increased sensitivity to NMDA but unaltered sensitivity to AMPA in photoinhibited hamsters in SD is consistent with the view that changes in photoperiod might induce specific alterations in NMDA-mediated pathways that ultimately regulate GnRH neurosecretory activity. PMID- 8680433 TI - Gonadal steroids have paradoxical effects on brain oxytocin receptors. AB - Specific brain receptors for oxytocin have been described in several mammalian species. The distribution of these receptors differs greatly across species and in the rat, receptor binding in specific brain regions appears to depend upon gonadal steroids. This study used in vitro receptor autoradiography to examine the effects of testosterone on oxytocin receptor binding in the mouse forebrain. Three groups of male mice were compared: castrates treated with blank capsules, castrates treated with testosterone filled capsules, and intact males. Irrespective of steroid treatment, the distribution of oxytocin receptors in mouse forebrain differed markedly from patterns previously described in the rat. In addition to these species differences in receptor distribution, testosterone had effects in the mouse which differed from the induction of receptors previously reported in the rat. In the mouse ventromedial nucleus of the hypothalamus, binding in the untreated castrate males was approximately double that observed in either the intact or the testosterone-treated castrates. In other regions of the mouse brain, such as the intermediate zone of the lateral septum, binding to oxytocin receptors was increased with testosterone treatment. These results suggest that the brain oxytocin receptor varies across species not only in its distribution but also in its regional regulation by gonadal steroids. These apparently paradoxical changes in oxytocin receptor binding may result from either direct or indirect effects of gonadal steroids in mouse brain. PMID- 8680434 TI - P-chlorophenylalanine facilitates copulatory behavior in septal lesioned but not in preoptic lesioned male rats. AB - Effects of p-chlorophenylalanine (pCPA), synthesis-inhibitor of serotonin, on copulatory behavior were examined in testosterone (T) treated castrated male rats with lesions in the lateral septum (LSL) or in the medial preoptic area (MPOL). Three weeks after the operation, all animals were chronically treated with T using silastic capsules. Behavioral tests were carried out at 10 and 20 days after the implantation of T. In half of the males in each group, 100 mg/Kg pCPA was injected daily for 4 days before each test. The other half of the group was injected with saline instead of pCPA. In saline-treated groups, the males with LSL or MPOL showed extremely lower frequencies of mount and intromission than control males without brain surgery. pCPA-treated control males showed higher copulatory activities than saline-treated control males. In contrast, even after the treatment with pCPA, severe impairment of sexual behavior was observed in males with MPOL. On the other hand, pCPA-treated LSL males displayed copulatory behavior more frequently than saline-treated LSL males. These results agreed with previous reports that both the medial preoptic area and the lateral septum play an excitatory role in regulating male sexual behavior. Furthermore, these results suggest that the inhibitory function of serotonergic neurons govern dependently on the function of the medial preoptic area, but independently on the function of the lateral septum. PMID- 8680435 TI - Immunocytochemical and biochemical evidence for aromatase in neurons of the retina, optic tectum and retinotectal pathways in goldfish. AB - Using an animal model in which neural aromatase is apparently overexpressed (the goldfish, Carassius auratus) and an anti-human placental antibody which specifically crossreacts with goldfish brain aromatase, aromatase-immunoreactive neuronal cell bodies and fibers have been localized within the retina. These include a subset of horizontal cells, bipolar cells, and amacrine cells of the inner nuclear layer, some fibers of the outer and inner synaptic layers and certain cells of the ganglion cell layer; photoreceptors were never labeled. Some ganglion cell projections to the brain via the optic nerve and optic tract were aromatase-positive, as were small neurons of the stratum periventriculare (SPV) and fibers of two other strata of the optic tectum. Aromatase activity, as measured by [3H]androgen by tissue homogenates and cell cultures, confirmed the presence of aromatase in retina and in brain regions containing the optic tectum. This localization of the rate-limiting enzyme in estrogen biosynthesis suggests that neuroestrogen derived from circulating androgen m ay modulate transmission and integration of visual information important for reproduction in this species. PMID- 8680436 TI - Differential effects of estrogen and progesterone on levels of POMC mRNA levels in the arcuate nucleus: relationship to the timing of LH surge release. AB - Beta-endorphin is thought to be an important inhibitor of LHRH neuronal activity and also to play a role in conveying information about changes in steroid levels to LHRH neurons. We have previously shown that the mRNA encoding the precursor of beta-endorphin, proopiomelanocortin (POMC), fluctuates during the estrous cycle with the most dramatic changes occurring on proestrus. POMC mRNA levels decline before the onset of LH surge release but then dramatically rise and remain elevated during the surge. In the present studies we tested the hypothesis that the decline in POMC mRNA levels immediately before the proestrus LH surge is mediated by estrogen and the rise during the surge by progesterone. To test this hypothesis, we compared changes in POMC mRNA levels between ovariectomized (OVX) and OVX estrogen (E2)-treated rats and between OVX E2-treated rats with and without progesterone. Animals were examined at hourly intervals after the administration of progesterone, then at every 4 h during the LH surge. Using in situ hybridization histochemistry, we found that E2 decreased POMC mRNA levels in OVX rats before the onset of the LH surge and further suppressed levels during the surge. Compared to animals treated with E2 alone, progesterone advanced the time at which both the LH surge began and the time at which POMC mRNA levels declined. After a transient decline, POMC mRNA levels rose in these progesterone treated animals and remained elevated throughout the period of the LH surge. These results support the hypothesis that progesterone times the LH surge and limits its appearance to one day be exerting a biphasic effect on the activity of beta-endorphinergic neurons of the arcuate nucleus. PMID- 8680437 TI - Effects of excitatory amino acid receptor agonists and antagonists on the secretion of melatonin, luteinizing hormone and prolactin in the ram. AB - To assess the role of excitatory amino acids (EAA) as neurotransmitters in the transmission of light information from the retina to the pineal gland, we have determined whether the systemic injection of EAA agonists in Soay rams will mimic the suppressive effect of light on the secretion of melatonin, and whether pretreatment of rams with EAA antagonists will block this effect. In addition, the efficacy of the drugs in affecting neuroendocrine systems was investigated by measuring the changes in the secretion of luteinizing hormone (LH) and prolactin. Injections fo the EAA receptor agonist, NMDA (N-methyl-D,L-aspartate: 4.0 mg/kg iv), and the non-NMDA type EAA receptor agonist, AMPA (DL-alpha-amino-3-hydroxy-5 methylisoxazole-propionic acid: 0.2 mg/kg iv) given at night to rams exposed to long days (16 h light: 8 h darkness), caused no change in the blood plasma concentrations of melatonin. The treatments induced an acute increase in the concentrations of LH, and NMDA, but not AMPA, caused a sustained increase in the concentrations of prolactin. Injections of the specific NMDA-type receptor antagonist, CGP (CGP 37849: 1.0 mg/kg iv) and the non-NMDA-type receptor antagonist, DNQX (6,7 Dinitroquinoxaline-2,3-dione: 0.5 mg/kg iv), given prior to a 1-h light period at night, in rams under long days, caused no change in the light-induced decrease in blood plasma concentrations of melatonin. The drug treatments had no effect on the plasma concentrations of LH, but CGP, and not DNQX, stimulated an acute increase in the plasma concentrations of prolactin. These results provide support for the hypothesis that EAA mechanisms operate in the hypothalamus to regulate the release of peptides and catecholamines which control the secretion of LH and prolactin from the pituitary gland; different sub types of EAA receptors are involved in the control of the two pituitary hormones. The failure of the treatments to affect the secretion of melatonin may indicate that EAA receptor activation is not involved in the photic relay to the pineal gland, or may merely reflect the inability of the drugs to penetrate into the retina/SCN/pineal neural circuits to produce a response. PMID- 8680438 TI - Secretogranin II: regulation of synthesis and post-translational proteolysis in bovine adrenal chromaffin cells. AB - Secretogranin II (SgII), also called chromogranin C, is an acidic tyrosine sulfated secretory protein found in secretory granules in a wide variety of endocrine cells and neurones. Although less abundant than chromogranin A (CGA) and chromogranin B (CGB), SgII is found in adrenal medullary chromaffin granules. In the present study we investigated the regulation of SgII biosynthesis in bovine chromaffin cells maintained in primary culture. Cellular proteins were labelled with [35S]methionine and the heat stable chromogranin enriched fraction was isolated. Following electrophoretic separation, the 86 kDa SgII band was identified by sequence analysis using the Edman degradation procedure. The radioactivity incorporated in the 86 kDa SgII band was used as an index of the SgII synthesis rate. We found that stimulation of chromaffin cells with nicotine and histamine and to a smaller extent with angiotensin II and bradykinin significantly enhanced the rate of SgII synthesis. In contrast direct depolarization with K+ may not be sufficient to induce modifications in SgII synthesis suggesting that the raise of cytosolic calcium evoked by high K+ may not be sufficient to induce modifications in SgII synthesis . The possible second messenger pathways involved in the control of SgII biosynthesis were investigated by using protein kinase C and adenylate cyclase activators. We observed that 12-O tetradecanoylphorbol 13-acetate (TPA) and forskolin increased the basal rate of SgII synthesis. Incubation with both TPA and forskolin was required to obtain an effect comparable to that produced by nicotine or histamine suggesting that these secretagogues recruit both protein kinase C- and cyclic AMP-dependent mechanisms to stimulate SgII synthesis. PMID- 8680439 TI - Facilitation and feedback in the hypothalamo-pituitary-adrenal axis during food restriction in rats. AB - After 4 weeks of food restriction to 50% of ad libitum intake in rats, plasma corticosterone levels were increased, without any change in adrenal weight, and with no evidence of sympathetic nervous system activation (as measured by Tyrosine Hydroxylase and Phenylethanolamine N-Methyl Transferase activities in the adrenal gland). Plasma corticosterone levels were normalized wih the addition of 35% of the calories as sugar. The adrenocortical axis activity was therefore investigated in more detail (nycthemeral cycle of corticosterone levels, ACTH and corticosterone response to a CRF challenge) in ad libitum fed rats and in animals fed 85% or 50% of the intake of the control animals, just before switching the lights off in order to maintain the diurnal rhythm of food intake. Food restriction to 85% did not change mean plasma corticosterone levels but sharpened the peak of corticosterone measured in the evening, indicating that the adrenocortical axis is more sensitive to the endogenous signals responsible for its diurnal cycle of activity. Indeed, the ACTH response to CRF was also increased. A 50% food restriction regimen increased mean corticosterone levels and attenuated the day/night difference, with high corticosterone levels maintained throughout the day. However, the ACTH response to CRF was not different from that measured in ad libitum fed rats, but the corticosterone response was lower, confirming that the adrenal gland is hyposensitive to ACTH. The results are discussed in terms of the balance between inhibiting/activating mechanisms and endocrine/neural influences at each level of the hypothalamo hypophyso-adrenal axis, depending on the level of food deprivation. PMID- 8680441 TI - Autonomic control of penile erection: modulation by testosterone in the rat. AB - The role of testosterone on peripheral autonomic control of penile erection was studied in rats. Erectile response to cavernous nerve stimulation was measured by intracavernous pressure associated with arterial blood pressure monitoring in anesthetized adult males. Comparison was performed between control (Co), castrated (Ox) and castrated, testosterone-replaced (OxT) rats. Ox rats exhibited smaller erectile responses. Testosterone replacement restored these responses in OxT rats. To identify the peripheral target of testosterone, postganglionic neurons of the major pelvic ganglion, innervating the corpora cavernosa through the cavernous nerves, were separated from the spinal cord by preganglionic axotomy of the pelvic nerves in three other groups of rats (PNx). Erectile response was unchanged in PNx rats, decreased in OxPNx more than in Ox rats, and restored by testosterone replacement (OxPNxT rats). We ruled out the participation of a somatic component in the erectile response in this model as there was no difference between curarized and Co rats. We infer that testosterone enhances the erectile response of cavernous nerve stimulation, acting peripherally to the spinal cord. Arguments are provided that the sites of action for testosterone or its metabolites are situated on neurons rather than on penile erectile tissue. Proerectile postganglionic parasympathetic neurons seem to be the exact target for gonadal steroids. PMID- 8680440 TI - Identification and localization of 23,000 and glycosylated rat prolactin in subcellular fractions of rat anterior pituitary and purified secretory granules. AB - Rat pituitary homogenates were submitted to differential and density gradient centrifugation. Subcellular fractions as well as the purified secretory granules were examined in electron microscopy, radioimmunological techniques, protease digestion, alkaline treatment and immunoblotting. The global outcome of these experiments was that: 1) the glycosylated rPRL was foremost recorded in the crude secretory granular fraction, also in the microsomal fraction and the cytosol, but virtually not in the plasma membrane fraction; 2) in purified secretory granules glycosylated rPRL appeared as an array of near Mr, such as was formerly obtained by enzymatic deglycosylation; 3) protease digestion and ice-cold alkaline treatment of the secretory granules showed that 23,000 rPRL appears in three different physicochemical states in these organelles: unsequestered within a closed system, membrane-bounded and bound state; 4) likewise treatment of microsomal vesicles showed that 23,000 and glycosylated rPRL are sequestered in these bodies, but apparently 23,000 rPRL appears as both integral membrane-bound and released from the lumen, whereas glycosylated rPRL is chiefly retained as an integral membrane protein. 5) dopamine alters the pattern of glycosylation as well in Mr as in relative percentages of the molecular variants. The systematical occurrence of the array of near Mr glycosylated rPRL is biosynthesized as a pool of proteins with a different degree of glycosylation. On the basis of our data, we speculate that selection of definite molecular variants from this pool could play an important role in the biological function of 23,000 rPRL and that oligosaccharides could perhaps target the glycosylated forms of rPRL to specific sites of action. PMID- 8680442 TI - Differential seasonal regulation of melatonin receptor density in the pars tuberalis and the suprachiasmatic nuclei: a study in the hedgehog (Erinaceus europaeus, L.). AB - Using quantitative autoradiography, we have studied the seasonal changes of high affinity melatonin receptor density in both the SCN and PT of the hedgehog, a seasonal breeder and an hibernator. Animals in 3 different physiological states were studied: sexually active animals, and sexually inactive animals during the hibernation period, being then either euthermic or hypothermic. In sexually active animals, Bmax were 75.8 +/- 7.1 fmol/mg protein in PT and 9.1 +/- 0.5 fmol/mg protein in SCN; and Kd values were: 94 +/- 22 pM in the PT and 101 +/- 15 pM in the SCN. This specific binding was strongly decreased in the PT of sexually inactive animals. Moreover, this decrease was significantly stronger in hypothermic than in euthermic hedgehogs. Saturation studies and Scatchard analysis revealed that the observed decrease in the PT resulted from change in the Bmax but not in the Kd, Bmax values being respectively 56.4 +/- 5.9 and 29.5 +/- 1.9 fmol/mg protein in euthermic and hypothermic sexually at rest animals. In none of the different physiological states, did the density of melatonin receptors of the SCN show any changes, Bmax values being respectively 9.8 +/- 0.5 and 9.8 +/- 0.4 fmol/mg protein in euthermic and hypothermic sexually at rest animals. This shows for the first time a tissue-specific regulation of melatonin receptor density occurring in the PT but not in the SCN. Furthermore, this decrease of binding in the PT is correlated with both sexual inactivity and hibernation period. This strongly suggests that the mediation of the photoperiodic effect on seasonal functions like seasonal hypothermia and reproduction involves an effect of melatonin on the PT rather than on the SCN. PMID- 8680443 TI - Expression of growth hormone receptor gene in rat hypothalamus. AB - Growth hormone receptor (GHR) mRNA-expressing cells in the hypothalamus were observed using hybridization histochemistry in adult male rats. Digoxigenin labeled cRNA corresponding to the extracellular part of rat GHR was used as a probe. Northern blotting analysis of hypothalamic total RNA from adult male rats revealed that the 4.5 kilobase (kb) transcript of the GHR gene corresponding to the GHR messenger RNA (mRNA) predominated over the 1.2 kb transcript corresponding to GH-binding protein mRNA. GHR mRNA-containing cells were observed in the arcuate nucleus (ARC), the periventricular nucleus (PeV), ventrolateral region of the ventromedial nucleus, the paraventricular nucleus and the supraoptic nucleus. To further understand the significance of the GHR gene expression in the hypothalamus, the effect of in vivo manipulation of GH on the somatostatin (SS) gene expression in the ARC and PeV, and the GRF gene expression in the ARC was observed among adult male rats using in situ hybridization histochemistry. Ten days after hypophysectomy, the SS mRNA level in the ARC as well as PeV was significantly lower than that in the respective nuclei of sham operated control rats, while the GRF mRNA level in the ARC was significantly higher than that in the ARC of control animals. Subcutaneous injection of recombinant human GH (0.33 mg) to hypophysectomized rats every 12 h for 5 days restored the SS mRNA level in the ARC and PeV, and reduced the GRF mRNA level in the ARC to that of control animals. The data suggest that GH directly acts on the hypothalamic PeV and ARC, and alters the gene expression of SS and GRF. PMID- 8680444 TI - Regulation of cholecystokinin receptors in the hypothalamus of the rat: reciprocal changes in magnocellular nuclei induced by food deprivation and dehydration. AB - Cholecystokinin (CCK) has been suggested to mediate satiety in a number of non primate species via its peripheral actions as well as a possible central mechanism involving magnocellular and parvocellular oxytocin release. Quantitative in vitro autoradiography employing [125I]-Bolton-Hunter labelled CCK 8S ([125I]-CCK-8S) was used to examine the distribution and density of CCK receptors in sections of brain from normal rats and rats deprived of food, water or both food and water for 4 days. In food-deprived rats, specific [125I]-CCK-8S binding was reduced by 64 +/- 5% in the hypothalamic supraoptic nucleus (SON) and by 44 +/- 13% in the paraventricular nucleus of the hypothalamus (PVN). In contrast, water deprivation increased binding of [125I]-CCK-8S by 128 +/- 15% in the SON and by 196% +/- 24% in the PVN, while combined food and water deprivation produced smaller increases in both nuclei (30 +/- 5% and 98 +/- 26% in SON and PVN respectively). Changes in receptor density in the PVN appeared to be most prominent in the magnocellular (especially oxytocin-rich) subdivisions. None of the treatments employed produced changes in [125I]-CCK-8S binding in the ventromedial hypothalamic nucleus or the reticular thalamic nucleus. Both CCK-A and CCK-B receptor subtypes were visualized in the nucleus of the solitary tract and the area postrema of normal rats, but levels of binding to both of these subtypes were unaffected by the experimental treatments. These selective alterations demonstrate the plasticity of CCK receptors in the SON and PBN, and are probably associated with changes in the level of neurochemical activity of magnocellular oxytocinergic neurones in these areas. These results, together with reports of changes in the level of CCK synthesis in cells of the SON and PVN after hyperosmotic stimuli, suggest that CCK may act in an autocrine fashion on these neurones and that both CCK receptors and peptide levels are altered in the same direction following cellular activation or inhibition. PMID- 8680445 TI - Antidopaminergic-induced hypothalamic LHRH release and pituitary gonadotrophin secretion in 12 day-old female and male rats. AB - In previous studies we have shown that the developing rat provides an interesting physiologic model in which the dopaminergic control of both LH and FSH is well defined in contrast to the controversial results obtained in adult rats. We wished to establish the role of testosterone in antidopaminergic induced gonadotrophins release in 12 day-old male and female rats, and evaluate the effect of antidopaminergic drugs at the hypothalamic level during this developmental stage. Haloperidol, an antidopaminergic drug, increased both LH and FSH in female 12 day-old rats but not in male littermates. The effect was blocked by bromocriptine and not by phentolamine indicating that haloperidol acted on the dopaminergic receptor, and that unspecific stimulation of the noradrenergic system was not involved. Haloperidol was ineffective when female rats were previously ovariectomized and injected with testosterone propionate at 9 days of age. If females were treated on the day of birth with testosterone propionate, haloperidol-induced FSH and LH release was also abolished. In control males haloperidol had no effect on the release of LH or FSH. But if males were orchidectomized at birth or at 9 days of age, haloperidol released both LH and FSH during the infantile period. In an attempt to establish the site of action of antidopaminergic drugs on gonadotrophin release, hypothalami (mediobasal and preoptic-suprachiasmatic area) from 12 day-old infant female rats were perifused with either haloperidol or domperidone (2*10(-6) M). Both drugs increased LHRH release into the perifusate. Besides haloperidol did not modify the release of LH or FSH from adenohypophyseal cells incubated in vitro. We therefore conclude that antidopaminergic-induced gonadotrophins release is modulated by serum testosterone concentrations, and that the site of action is probably the LHRH secreting neuron of the hypothalamus. PMID- 8680447 TI - The network link: an interview with Vangie Paschall, R.N., C.N.O.R., laser endoscopy coordinator, Gwinnett Hospital System, Lawrenceville, GA. PMID- 8680446 TI - Changes in pro-opiomelanocortin and pre-proenkephalin mRNA levels in the ovine brain during pregnancy, parturition and lactation and in response to oestrogen and progesterone. AB - In the female sheep opioids act centrally to influence both oxytocin release and maternal behaviour. We have used in situ hybridization and histochemistry to investigate the changes in mRNA expression of the two opioid precursor genes, pro opiomelanocortin (POMC) and pre-proenkephalin (PPE), in discrete hypothalamic nuclei as a function of pregnancy, parturition and lactation and following treatment with oestrogen and progesterone. Quantitative in situ hybridization histochemistry demonstrated that POMC mRNA expression in the arcuate nucleus (ARC) decreased at parturition and increased during lactation compared to late pregnant and ovariectomized animals. Oestradiol and progesterone treatments increased POMC mRNA expression compared to ovariectomized controls. Pre proenkephalin mRNA expression was quantified in three discrete hypothalamic nuclei, the ventromedial nucleus (VMN), the paraventricular nucleus (PVN) and the suprachiasmatic nucleus (SCN). In the VMN, PPE mRNA expression increased during lactation compared to late pregnancy and parturition. Expression levels during late pregnancy and parturition were decreased compared to ovariectomized animals. Oestradiol increased, and progesterone decreased, PPE mRNA levels compared to ovariectomized controls. Combined progesterone followed by oestrogen treatment produced significant increases in PPE mRNA expression. In the PVN, PPE expression increased at parturition compared to late pregnant, lactating and ovariectomized animals. Expression levels in late pregnant animals were decreased compared to lactating or ovariectomized ones. However, sex steroid treatment produced no changes in PPE expression in the PVN. No changes were observed in PPE mRNA expression in the SCN in response to any of the experimental conditions. This data shows that both POMC and PPE mRNA levels are altered in the sheep brain during pregnancy, parturition and lactation and in response to sex steroids, although the direction of the changes is not always the same and in the case of PPE only the VMN and PVN are affected. PMID- 8680449 TI - The use of laparoscopic surgery in the treatment of urinary stress incontinence. PMID- 8680448 TI - Sterilization of reusable medical devices: evaluation of a liquid chemical sterilization process using peracetic acid. PMID- 8680450 TI - Complications of laparoscopic cholecystectomy after hospital discharge. PMID- 8680451 TI - The popularity of minimally invasive procedures. PMID- 8680452 TI - Assess OR, specialty and patient needs for effective i.v. conscious sedation program. PMID- 8680454 TI - MEDWatch provides voluntary incident reporting system for practitioners. PMID- 8680453 TI - New definitions of patients safety apply to nursing role in i.v. conscious sedation. PMID- 8680455 TI - The regulation of adipose tissue distribution in humans. AB - The regulation of adipose tissue distribution is an important problem in view of the close epidemiological and metabolic associations between centralized fat accumulation and disease. With visceral fat accumulation multiple endocrine perturbations are found, including elevated cortisol and androgens in women, as well as low growth hormone (GH) and, in men, testosterone (T) secretion. These abnormalities probably derive from a hypersensitive hypothalamo-pituitary-adrenal axis, with hyperinsulinemia related to a marked insulin resistance as a consequence. These hormonal changes exert profound effects on adipose tissue metabolism and distribution. At the adipocyte level cortisol and insulin promote lipid accumulation by expressing lipoprotein lipase activity, while T, GH and probably estrogens exert opposite effects. The consequences will most likely be more expressed in visceral than subcutaneous adipose tissues because of a higher cellularity, innervation and blood flow. Furthermore, the density of cortisol and androgen receptors seems to be higher in this than other adipose tissue regions. The endocrine perturbations found in visceral obesity with an abundance of the lipid accumulating hormones cortisol and insulin, and a relatively low secretion of the lipid mobilizing sex steroid hormones and GH would therefore be expected to be followed by visceral fat accumulation. The potential significance of local synthesis of steroid hormones in adipose tissue requires more attention. Although studies in vitro are informative when elucidating detailed mechanisms of hormonal interactions, they might not give a true picture of the regional integrated regulation of adipose tissue lipid storage and mobilization. Such information can be obtained by regional measurements of lipid mobilization by free fatty acid turnover or by microdialysis techniques, both showing lower rates of mobilization in leg than in upper body adipose tissues. More detailed information can be obtained by physiological oral administration of triglycerides, labelled with a small amount of oleic acid, followed by measurements of the regional uptake and turn-over of adipose tissue triglycerides. Such studies show lipid uptake in the order omental = retroperitoneal > subcutaneous abdominal > subcutaneous femoral adipose tissues in men, with a similar rank order for half-life of the triglyceride, indicating also a turn-over of triglycerides in that order. T amplifies these differences in men. In premenopausal women subcutaneous abdominal has a higher turnover than femoral adipose tissue. Results of studies in vitro indicate that this difference is diminished at the menopause, and restored by estrogen substitution, suggesting that the functional effects of estrogens in women are similar to those of T in men. The mechanisms are, however, probably indirect because of the apparent absence of specific estrogen and progesterone receptors in human adipose tissue. This interpretation from the studies referred to above fits well with physiological, and clinical conditions with increased visceral fat mass, where the balance between the lipid accumulating hormone couple (cortisol and insulin) and the hormones which prevent lipid accumulation and instead activate lipid mobilization pathways (sex steroid hormones and GH) is shifted to the advantage of the former. Such conditions include Cushing's syndrome, the polycystic ovary syndrome, menopause, aging, GH-deficiency, depression, smoking and excess alcohol intake. With appropriate interventions against hypercortisolemia and substitution of deficient sex steroids and GH, visceral fat mass is decreasing. Based on this evidence from physiological, clinical, interventional observations and detailed studies of mechanisms at cellular and molecular levels it is suggested that the combined endocrine abnormalities in the syndrome of visceral obesity direct storage fat to visceral adipose depots. Therefore, measurements of visceral fat accumulat PMID- 8680457 TI - Clustering of metabolic disorders and hyperinsulinemia in Mexico City. AB - OBJECTIVE: To investigate the relationship between fasting insulin concentrations and several metabolic and anthropometric variables in the Mexico City population. DESIGN: Cross-sectional, randomized, stratified by age, sex and economically active and inactive. SUBJECTS: 700 healthy adults, older than 20 years, 396 males and 304 females. MEASUREMENTS: Body mass index, waist to hip ratio, systolic and diastolic blood pressure, insulin, glucose, triglycerides, total, HDL and LDL cholesterol and lipoprotein(a). RESULTS: Means for age were 39 +/- 13 years for men and 41 +/- 12 for women (p < 0.05). In males, the mean values of body mass index, waist-to-hip ratio, systolic and diastolic blood pressure, triglycerides, glucose and LDL-cholesterol : HDL-cholesterol increased significantly with higher insulin levels. A significant inverse tendency was observed for the mean concentrations of HDL-cholesterol and lipoprotein(a). Age, total cholesterol and LDL-cholesterol were not related to the insulin levels. A similar pattern was observed in women, significance, however, was only obtained for the body mass index, triglycerides, glucose, HDL-cholesterol and lipoprotein(a). Age-adjusted multiple regression analysis showed that insulin was directly and independently associated to triglyceride levels and inversely with lipoprotein(a) concentrations for both sexes, and with HDL-C, only in males. CONCLUSIONS: The prevalence of insulin resistance related metabolic disorders was high in a random sample of the Mexico City population. Increased cardiovascular risk factors associated with the insulin resistance syndrome were observed with higher insulin levels, and lipoprotein(a) was inversely and significantly related to insulin. Preventive strategies are urgently needed to avoid the already increased incidence of morbidity and mortality associated to atherosclerotic disease. PMID- 8680456 TI - Weight loss maintenance in young adulthood: prevalence and correlations with health behavior and disease in a population-based sample of women aged 55-69 years. AB - OBJECTIVE: To describe the prevalence of weight loss maintenance and other weight change patterns in early adulthood (ages 18-50 years), and their association with disease prevalence in older age (average age 62 years). DESIGN: Cross-sectional survey. SUBJECTS: 17233 postmenopausal women aged 55-69 years. MEASUREMENTS: Weight change categories based on recalled body weight at age 18, 30, 40 and 50 years. RESULTS: Weight loss of 10% or more between ages 18 and 30 years followed by maintenance within 5% up to age 50 years, and weight loss of 10% or more followed by a 10% or more regain were equally common, yet rare, weight change patterns (1.6% and 1.8%, respectively). Among those who were overweight at age 18, maintaining a stable weight was associated with increased odds of diabetes (OR = 5.48) and hypertension (OR = 1.98), relative to normal weight-weight stable women. However, overweight women who lost weight had similar odds of diabetes and hypertension as normal weight-weight stable women. In both overweight and normal weight women, weight loss followed by regain was associated with higher odds of disease relative to weight stability. However, the highest odds of disease were associated with continuous weight gain or an initial weight gain that was maintained. CONCLUSIONS: Weight gain is associated with higher odds of disease compared to weight stability, which is associated with lowest odds of disease. Weight loss maintenance in the overweight is associated with lower odds of obesity-related diseases such as diabetes and hypertension. PMID- 8680458 TI - Insulin response to a spontaneously ingested standard meal during the development of obesity in GTG-injected mice. AB - OBJECTIVES: (1) To determine glucose and insulin levels in response to ingestion of a standard meal during the development of gold-thioglucose (GTG)-induced obesity. (2) To examine whether the pancreatic beta-cells of GTG-injected mice possess sufficient insulin secretory capacity to compensate for the increasing tissue insulin resistance that occurs with the development of this obesity. DESIGN: The insulin secretory response to a standard meal of chow was examined in chronically catheterised conscious mice 2, 5 and 10 weeks after induction of obesity by a single injection of GTG. RESULTS: At 2 weeks after administration of GTG both the basal insulinaemia and the incremental area under the curve (iAUC) of insulin release after a chow meal were increased compared with age-matched lean control mice (2 week control: 1004 +/- 316 min/microU/ml; 2 week GTG: 1968 +/- 300 min/microU/ml; P < 0.05). By 5 weeks, the GTG-injected mice were approximately 42% heavier than their lean controls and showed a marked glucose intolerance. This was accompanied by hyperinsulinaemia in both the basal state and also in response to ingestion of the chow meal as indicated by the increase in the iAUC of insulin (5 week control: 1113 +/- 331 min/microU/ml; 5 week GTG: 2682 +/- 295 min/microU/ml; P < 0.05). At 10 weeks after GTG administration body weight was further increased, as was the degree of glucose intolerance. Plasma insulin levels, in both the basal state and in response to the ingestion of chow, were also further elevated by 10 weeks following GTG injection (10 week control: 1234 +/- 311 min/microU/ml; 10 week GTG: 6640 +/- 1198 min/microU/ml; P < 0.05). CONCLUSIONS: It is apparent that the secretion of insulin in response to a standard chow meal increases progressively with the development of obesity. This finding, in conjunction with an earlier study showing that the insulin secretory response to intravenously administered glucose becomes impaired in the latter stages of the development of obesity in GTG-injected mice [Blair SC, Caterson ID, Cooney GJ. Diabetes 1993; 42: 1153-1158], suggests that the ability of beta-cells of GTG-obese animals to produce and secrete insulin is not impaired but that the beta-cells may become insensitive to glucose within the circulation. PMID- 8680459 TI - Clinical characteristics associated with binge eating in obese females: a descriptive study. AB - OBJECTIVE: To investigate differences in clinical characteristics of obese female participants based on presence and degree of binge eating behavior. DESIGN: Descriptive comparison of various clinical characteristics of obese women diagnosed with binge eating disorder (BED) assessed by semi-structured interview to those for similar weight participants reporting subthreshold BED and those who do not binge eat. SUBJECTS. 185 healthy women seeking obesity treatment (age: 20 55 y, BMI: 28.4-51.5 kg/m2). MEASUREMENTS: Baseline self-report questionnaires included the Weight and Eating Patterns (QEWP), Eating Disorders Questionnaire (EDQ), Beck Depression Inventory (BDI); clinical interviews included the Hamilton Depression Rating Scale (HDRS) and Structured Clinical Interview for DSM-III-R Patient Version (SCID-P). RESULTS: In comparison to other obese women, obese participants meeting full BED criteria report an earlier onset of binge eating, increased food cravings, increased diet pill use, decreased fasting, greater fear of gaining weight, increased body perception disturbance, and increased depressive symptomatology and general psychopathology. CONCLUSIONS: Obese women with BED report greater eating-related and general psychopathology than non-binge eating disordered women of comparable weight. Although endorsement of food cravings unrelated to hunger was associated with binge eating diagnosis, the role of dietary restriction among this population remains unclear and requires further investigation. Theoretical and clinical implications that binge eating episodes for individuals with BED may be related to negative affect states and increased dietary disinhibition are discussed. PMID- 8680460 TI - Two year maintenance of weight loss after a VLCD and behavioural therapy for obesity: correlation to the scores of questionnaires measuring eating behaviour. AB - OBJECTIVE: To investigate changes in weight, Three Factor Eating Questionnaire and Binge eating scores during a two-year period from the start of a VLCD (Nutrilett) and behavioural modification therapy for obesity. DESIGN: Prospective study of a 17-weeks weight loss programme with one- and two-year follow-up visits. SUBJECTS: 62 healthy, overweight subjects without previous eating disorders. The mean (+/- SD) age 41 +/- 8 years and BMI 36.4 +/- 2.6 kg/m2. MAIN OUTCOME MEASURES: Weight loss, Binge eating scale, Bulimic Investigatory Test and Three Factor Eating Questionnaire before and after therapy and at 1 and 2 year control visits. RESULTS: The mean weight loss (+/- SD) at the end of the treatment was 14.9 +/- 4.6 kg (n = 59) and at the two-year control 5.8 +/- 7.6 kg (n = 57). After two years 20 (32%) patients had a weight loss of more than 10% (good result), 24 patients a weight loss of 0-10% of their initial weight (partial result) and 13 patients weighed more than before therapy (poor result). The mean binge eating, disinhibition and hunger scores decreased in all patients by the end of the therapy. At the end of two years these improvements in the scores were maintained in patients with a good result but the scores returned to the pretreatment levels in the patients with partial or poor result. The mean restraint scores increased in all patients after treatment and were maintained in those with a good or partial result. CONCLUSIONS: VLCD combined with behaviour modification is a useful mode of therapy for obesity with low drop-out rate and majority (71%) of patients below pretreatment weight at the two-year control. One third of the patients succeeded to maintain positive changes in the scores measuring eating behaviour which was associated with sustained weight loss. PMID- 8680461 TI - Changes in glucose and lipid metabolism following weight loss produced by a very low calorie diet in obese subjects. AB - OBJECTIVE: To study the effects of a very low calorie diet (VLCD) on glucose and lipid metabolism in obese subjects, in particular, the effects on insulin sensitivity and the activities of the key enzymes of glucose disposal, glycogen synthase (GS) and the pyruvate dehydrogenase complex (PDHC). DESIGN: Clinical dietary intervention study (1.67 MJ (400 kcal)/day) until weight loss of > 10%. SUBJECTS: 11 (seven male, four female) non-diabetic, obese subjects (age: 27-62 y; BMI: 40.5 +/- 1.4 kg/m2). MEASUREMENTS: Whole body glucose disposal (by euglycemic hyperinsulinemic clamp), respiratory quotient (RQ), resting energy expenditure (REE), glucose and lipid oxidation (by indirect calorimetry), insulin stimulated PDHC and GS activity (in muscle biopsies) both before and immediately after VLCD (i.e. while still in a hypocaloric state), serum hormone and metabolite levels throughout the dietary period. RESULTS: Weight loss was accompanied by reduced insulin and elevated NEFA levels, improved insulin sensitivity due to increased nonoxidative glycolysis with no increase in PDHC or GS activities. The rate of weight loss was inversely related to the initial RQ. PDHCa was strongly age-related. CONCLUSION: A low RQ may be used as a predictor of the efficacy of VLCD treatment and that while VLCD improves nonoxidative glycolytic flux, changes in oxidative glucose disposal and muscle glucose storage are prevented by high NEFA availability during this catabolic phase of dietary intervention. PMID- 8680462 TI - Does visceral adipose tissue differ from subcutaneous adipose tissue in fatty acid content? AB - OBJECTIVE: To determine whether intra-abdominal adipose tissue differs from subcutaneous adipose tissue in fatty acid content. DESIGN: Cross-sectional study of patients undergoing exploratory laparotomy, with adipose tissue sampling from subcutaneous, omental, mesenteric and retroperitoneal sites. SUBJECTS: Nineteen subjects, 8 men and 11 women, with a mean age of 64 (range 39-80), mean weight 78.9 kg (range 51-157) and mean body mass index of 27.5 (range 19.2-51.4). Fourteen of the 19 were undergoing surgery for colorectal cancer. MEASUREMENTS: Fatty acid content was assessed by gas chromatography and was compared between sites and between patients using general linear modeling. Spearman correlation coefficients were used to assess the association between subcutaneous and visceral adipose tissue. RESULTS: For each of 17 fatty acids analyzed, there was a statistically significant difference in mean fatty acid values across individuals (p < 0.001). For seven of the fatty acids, there was a borderline or significant difference in mean fatty acid values across site, but there was no consistent pattern for one site differing from the others. Subcutaneous adipose tissue fatty acid content was highly correlated to visceral adipose tissue for saturated, unsaturated and trans fatty acids (p < 0.05 for 13 of 17 fatty acids). Variability across individuals was much greater than across site. The total explained variability (R2) for each fatty acid ranged between 49 and 93%, with the vast majority contributed by differences between individuals. CONCLUSION. Fatty acid content of subcutaneous abdominal adipose tissue is a good approximation of visceral adipose tissue. Because variability in fatty acid content is much larger between individuals than within a single individual across sites, subcutaneous abdominal adipose tissue fatty acid content can be used as a distinguishing characteristic among human populations. PMID- 8680463 TI - Immune response to obesity and moderate weight loss. AB - OBJECTIVE: To study the effect of moderate energy restriction (4.19-5.44 MJ or 1200-1300 kcal per day) in obese females on a variety of both innate and adaptive immune function measures including mitogen-stimulated lymphocyte proliferative response, and monocyte and granulocyte phagocytosis and oxidative burst. Obese and nonobese subjects were also compared at baseline. DESIGN: Measurement of body composition and immune function was conducted in all subjects before and after a 12-week diet intervention period for the obese subjects, with data analyzed using a two (obese and nonobese groups) x two (pre- and post-study) repeated measures design. SUBJECTS: Thirteen obese (42.3 +/- 0.8% body fat) and 10 nonobese (21.2 +/- 1.0%) healthy, normoglycemic, premenopausal females. MEASUREMENTS: Pre- and post-study body composition, nutrient intake, and immune function, with the reducing diet monitored through weekly random 24-h dietary recalls. RESULTS: Data from this study indicate that despite large differences in body fat mass between the obese and nonobese groups, immune function, as measured in this study, was similar between groups. Weight loss, however, even though relatively moderate (9.9 +/- 1.4 kg), was associated with significant decreases relative to the nonobese in several measures of T, B, monocyte and granulocyte function. CONCLUSION: These data do not support the contention that mild-to-moderate obesity is associated with alterations in immune function. The data are consistent, however, with the viewpoint that weight loss, even at a moderate rate, is associated with a decrease in the function of certain aspects of the immune system. PMID- 8680464 TI - The concentrations of monoamine metabolites and neuropeptides in the cerebrospinal fluid of obese women with different body fat distribution. AB - DESIGN AND SUBJECTS: Several studies suggest neuroendocrine abnormalities in, particularly, abdominal, central obesity in humans, a condition with high morbidity and mortality. Therefore the concentrations of neuropeptides and catecholamines in cerebrospinal fluid (CSF) were analysed in 48 obese women, subdivided into groups with central, abdominal and gluteo-femoral distribution of body fat, utilising the waist-to-hip circumference ratio (WHR) for division. RESULTS: In comparisons with non-obese control women concentration of 5 hydroxyindol acetic acid (5-HIAA), methoxyhydroxyphenylglycol (MHPG), corticotropin releasing hormone (CRH), beta-endorphins (END) and neuropeptide Y (NPY) were lower, while homovanillic acid (HVA) was not different in obese women, HIAA, HVA and END correlated negatively with the WHR only in abdominally obese women, suggesting a threshold effect. HIAA vs HVA as well as CRF vs END correlated strongly in the total and both subgroups. An interrelationship between all these four substances was found in abdominal but not in gluteo-femoral obesity, suggesting a tighter functional coupling in the former group. Several correlations were found between CSF substance levels and appetite registrations, including END vs voracious eating, and for carbohydrate craving vs HIAA and vs HVA (negatively). This was also found only in abdominally obese women. CONCLUSION: Although the concentrations of monoamine metabolites and neuropeptides in the CSF sampled at the level of the lumber spine might not be representative for those at regulatory centers in the brain, the findings suggest that low 5-HIAA is characteristic of human obesity, and coupled to CRH as well as eating abnormalities, particularly in abdominal obesity. Since CRH is regulating the balance between the autonomic nervous systems, insulin secretion and thermogenesis in animals, corresponding anomalies in abdominal obesity in humans may have a central origin. PMID- 8680465 TI - Obesity and self-perceived health in Sweden. AB - Data on self-perceived health in relation to relative body weight from the nationally representative adult Swedish population (12988 men and 13414 women) obtained from Statistics Sweden were analysed. The results are adjusted for age, socio-economic groups, self-reported chronic disease and marital status. Obesity was associated with 40% higher prevalence of severe pains from several joints in men and women and higher consumption of analgetics (OR = 1.6, 95% CI 1.2-2.2, in men, OR = 1.9, 95% CI 1.6-2.3, in women). Overweight and more often obese subjects reported physical impairment and in particular reduced mobility (OR = 1.9, 95% CI 1.5-2.5 in obese men and OR = 2.4, 95% CI 2.0-2.9 in obese women). Intake of vitamins was 20-40% significantly lower in overweight and obese than in normal weight subjects; the intake of iron pills was 60% lower in obese women. Dental status was worse in overweight and obese subjects. Dentures were found more often in overweight (OR = 1.5, 95% CI 1.3-1.7) and obese women (OR 2.2, 95% CI 1.9-2.7) in comparison to those with normal weight. Underweight was associated with adverse self-perceived health with regard to all these indicators. Our findings suggest that already moderate overweight in particular in women results in reduced mobility and physical impairment. PMID- 8680466 TI - Attempted weight loss during pregnancy. AB - OBJECTIVE: To assess the prevalence and correlates of weight loss during pregnancy. DESIGN: Cross-sectional telephone survey from 47 states and the District of Columbia. SUBJECTS: 1794 women who reported that they were pregnant at the time of the survey. MEASUREMENTS: Self-reported weight, height, disease and behaviors. RESULTS: A minority (3.7%; 95% CI, 2.6-4.9%) of women who reported being pregnant (n = 1794) also reported trying to lose weight. However, pregnant women who reported both drinking alcohol in the past month and currently smoking had the highest prevalence of attempted weight loss (12.7%), followed by women in their first trimester (9.4%), women with reported diabetes (9.0%) and women with very high BMIs (6.9%). After adjustment for survey design and other characteristics, women in their first trimester were four times more likely to attempt weight loss than those in the third trimester. CONCLUSION: These results suggest that weight loss attempts among women who report being pregnant are uncommon, but are more likely to occur in the first trimester and possibly among women who smoke and drink, have diabetes or are very overweight. PMID- 8680467 TI - Anthropometric tips. PMID- 8680468 TI - Cellular and Molecular Biology of Adipose Cell Development and Growth. Proceedings of an international symposium. Ottawa, Ontario, Canada, 17-18 August 1994. Dedicated to the memory of Daniel AK Roncari. PMID- 8680469 TI - Effects of fat depot site on differentiation-dependent gene expression in rat preadipocytes. AB - Variability in physiological characteristics among adipose depots could be caused, in part, by mechanisms intrinsic to cells comprising the depots. To evaluate the contribution of intrinsic mechanisms to depot variability, we studied levels of differentiation-dependent mRNAs in differentiating cultured rat epididymal and perirenal preadipocytes and in fat cells isolated from these depots. The magnitude of the change in levels of adipsin and glycerol-3 phosphate dehydrogenase mRNAs, which increase late during differentiation, was greater in perirenal than epididymal preadipocytes. The magnitude of the change in beta actin mRNA, which decreases early during differentiation, was not site-dependent. Effects of anatomic site on changes in differentiation-dependent mRNAs observed in differentiating preadipocytes in vitro were similar to effects of site on these mRNAs in freshly isolated fat cells: those mRNA species whose levels increase late during preadipocyte differentiation were present in greater abundance in perirenal than epididymal fat cells. Hence, mechanisms which underlie site-dependent variability in adipose function may be intrinsic and could become evident midway through the differentiation process. PMID- 8680470 TI - Increasing vimentin expression associated with differentiation of human and rat preadipocytes. AB - Alterations in the cytoskeletal apparatus constitute some of the earliest changes during assumption of an adipogenic phenotype. We examined three major cytoskeletal elements, beta-actin, alpha-tubulin and vimentin, during adipogenesis in euploid cells from human and rat adipose tissue. As reported with 3T3 sub-lines, mRNA level for beta-actin and alpha-tubulin were decreased upon differentiation. However, in contrast to reports with 3T3 cells, levels of vimentin were increased during differentiation. Furthermore, immunological analyses confirmed that there was no decrease in vimentin protein levels during adipogenic development. As well as highlighting a difference between 3T3 cell lines and preadipocytes isolated from fat depots, these studies indicate that the pattern of cytoskeletal gene expression undergoes complex changes early during preadipocyte differentiation. PMID- 8680471 TI - Analysis of cholesteryl ester transfer activity in adipose tissue. AB - Transfer of cholesteryl ester (CE) between lipoproteins is mediated by a plasma glycoprotein called cholesteryl ester transfer protein (CETP) which plays an important role in reverse cholesterol transport between peripheral tissues and the liver. Adipose tissue is a major site of cholesterol storage and lipoprotein interactions. CE transfer activity in cultured adipose tissue from several species was analyzed by using a CE transfer assay in vitro. Significant amounts of CE transfer activity were detected in conditioned media of cultured adipose tissues from human, hamster and transgenic mice expressing CETP. The amount of CE transfer activity released from cultured adipose tissue varied among species and adipose regions. Monoclonal antibodies against human CETP (subclone TP2) inhibited CE transfer activity released from cultured adipose tissue of hamsters and CETP transgenic mice. CE transfer activity was also assayed in the aqueous phase of adipose tissue homogenates. Accumulation of CE transfer activity in the medium was associated with a reciprocal decrease in adipose tissue activity positively correlated to the amount of CETP mass in the conditioned medium and the aqueous phase of tissue homogenates from cultured hamster adipose tissue. The results of the present study indicate that the measurement of CE transfer activity in adipose tissue reliably characterizes the secretion and storage of CETP in adipose tissue. PMID- 8680472 TI - Paracrine interactions in adipose tissue development and growth. PMID- 8680473 TI - The Gs alpha/Gi alpha 2 axis controls adipogenesis independently of adenylylcyclase. AB - Adipogenesis is the commitment of embryonic stem cells to the highly differentiated phenotype of the adipocyte, a cell specialized to regulate, in a dynamic fashion, lipid storage. The mouse embryonic 3T3-L1 fibroblasts provide a useful model in which to probe the control differentiation in general and adipogenesis in particular. The G-proteins Gs alpha and Gi alpha 2 have been shown to modulate commitment of fibroblasts to adipocytes in response to inducers such as dexamethasone and meythylisobutylxanthine. Cellular levels of Gs alpha decline sharply in response to inducers as cells commit to the adipogenic phenotype. The molecular strategies of antisense DNA technology and expression of constitutively-activated mutants of Gi alpha 2 reveal that either suppression of Gs alpha or expression of constitutively-active Gi alpha 2 dramatically accelerate the ability of inducers to stimulate adipogenesis or act as inducers themselves. These roles of Gs alpha and Gi alpha 2 are expressed in ambient or elevated intracellular cyclic AMP, demonstrating a critical role of G-proteins in cellular differentiation independent of adenylylcyclase. PMID- 8680474 TI - Beta-adrenergic receptors and G-proteins in the ob/ob mouse. AB - The ob/ob mouse white epididymal adipose tissue is endowed with very low lipolytic activity, due to abnormally low adenylyl cyclase activation in response to beta-adrenergic agents. The abundance of the two principal G-proteins that are responsible for the transduction of adenylyl cyclase is also decreased in several tissues of the ob/ob mouse, compared to levels in the lean mouse. By contrast, beta-adrenergic receptor levels appear normal in adipose tissue (Am J Physiol 1992; 263: C121-C129) and are elevated in liver (Am J Physiol 1994; 265: C1664 C1672), suggesting that the diminished abundance of G-proteins was responsible for the low lipolytic activity. We reassessed the relative importance of beta adrenergic receptors and G-proteins in view of the discovery of the beta 2 adrenergic receptor. The major beta-AR isoform in mouse white adipose tissue is the beta 3-AR and its levels is severely decreased in the obese mouse. This indicates that the lipolytic defect in the ob/ob mouse is due to lack of beta 3 receptor function. Furthermore the extremely high sensitivity of this receptor to the ambient concentrations of GTP, explains the lack of response of adenylyl cyclase activity to the inhibitory effect of GTP in adipose tissue of the ob/ob mouse. PMID- 8680475 TI - Signal transduction in brown adipose tissue recruitment: noradrenaline and beyond. AB - The classical effect of noradrenaline on brown adipose tissue is stimulation of heat production. However, it is likely that noradrenaline is also the major regulator of proliferation and differentiation. The adrenergic receptors involved include at least beta 1, beta 3, alpha 2 and alpha 1. Heat production is mainly stimulated via beta 3 receptors and cAMP. Cell proliferation is mainly stimulated via beta 1 receptors and cAMP. Cell differentiation is also adrenergically promoted; at least the expression of the gene for the tissue-specific uncoupling protein thermogenin is controlled via beta 3 receptors and cAMP. There is a switch in beta-receptor endowment between young (beta 1) and mature (beta 3) cells. The expression of several transcription factors is also under adrenergic control: c-Fos gene expression depends synergistically on beta- and alpha 1 stimulation mediated via cAMP and [Ca2+]i increases. C/EBP beta gene expression is regulated only via beta-receptors, but the expression of the C/EBP alpha gene shows a switch during differentiation: in young cells, the expression is represented through both beta- and alpha 1-receptors; in mature cells, the expression is stimulated via b-receptors. It is likely that noradrenaline exerts its proliferation- and differentiation-promoting action through alterations in the expression of these or other transcription factors. PMID- 8680476 TI - Structure and activation of the large latent transforming growth factor-beta complex. AB - Most cell types express transforming growth factor-beta (TGF-beta) as a large latent TGF-beta complex that must be converted to an active form before TGF-beta can interact with cell surface TGF-beta receptors. This conversion involves the release of mature TGF-beta from the complex by disrupting noncovalent interactions between mature TGF-beta and its propeptide, latency associated peptide. A critical step in regulating TGF-beta effects may be the activation of the large latent TGF-beta complex. Activation of the complex can be achieved by chemical and enzymatic treatments, or by various cell systems. We have identified that coculturing bovine endothelial and smooth muscle cells generates active TGF beta. Coculture activation of the large latent TGF-beta complex occurs through a plasmin-dependent mechanism that requires concentration of reactants on the cell surface and/or extracellular matrix. The mechanism of latent TGF-beta activation self-regulates through effectors of plasmin generation. PMID- 8680477 TI - The insulin/Ras pathway of adipocytic differentiation of 3T3 L1 cells: dissociation between Raf-1 kinase and the MAPK/RSK cascade. AB - Insulin-induced differentiation of 3T3 L1 cells can be mimicked by expression of transfected ras oncogenes but is completely blocked by expression of dominant negative Ras mutants, demonstrating that Ras proteins mediate insulin signaling in these mammalian cells. In contrast, transfection of tyrosine kinase oncogenes including trk and src dose not result in adipocytic differentiation. Transfected raf-1 oncogenes induce partial adipocytic differentiation, while dominant negative raf mutants block partially the insulin-induced differentiation process. Exposure of 3T3 L1 cells to insulin results in formation of the active Ras-GTP complex without GAP tyrosine phosphorylation. Insulin treatment of untransfected 3T3 L1 cells also induced quick activation of cytosolic 42 kDa mitogen-activated protein kinase (MAPK) and a 90 kDa S6 kinase (RSK). The activation of these cytosolic serine-threonine kinases was also mimicked by Ras expression (in the absence of insulin) in the same cells transfected with inducible ras oncogenes. Furthermore, insulin-induced activation of MAPK and RSK could be blocked by expression of a transfected, inducible dominant negative Ras mutant (N17). These results indicate that Ras proteins are obligatory intermediates in the activation of cytosolic ERKs by insulin. Insulin treatment of 3T3 L1 cells or expression of transfected ras oncogenes resulted also in hyperphosphorylation of cellular Raf 1. Insulin-induced Raf hyperphosphorylation was inhibited by expression of an inducible, dominant negative Ras mutant (N17). Interestingly, however, expression of transfected raf oncogenes did not induce MAPK or RSK activation, and the insulin-induced activation of these kinases was not blocked by expression of transfected dominant negative raf mutants. These results suggest a functional dissociation between Raf-1 and MAPK/RSK activation in insulin/Ras signaling pathways leading to 3T3 L1 differentiation and are consistent with Raf-1 kinase acting in a parallel pathway to the MAPK/RSK pathway after Ras activation in these cells. PMID- 8680478 TI - The possibility of active form of vitamins A and D as suppressors on adipocyte development via ligand-dependent transcriptional regulators. AB - The study aimed to systematically examine the effects of fat soluble vitamins and their analogs on terminal differentiation of adipocytes on the cellular and molecular aspects. It is well known that fat soluble vitamins especially vitamins A and D inhibit the differentiation of adipocytes in cultured cells. Furthermore, it has been revealed that the low level of dietary fat soluble vitamins, especially vitamin A and carotenoid actively stimulate the development of adipose tissue, namely bovine marbling in vivo. We have shown that the expression of retinoic acid receptor (RAR) alpha and gamma, retinoid X receptor (RXR) alpha and beta, and vitamin D receptor (VDR) mRNA were abundant in rat adipose tissue and 3T3-L1 cells. The autoregulated amplification and reduction of RAR, RXR and VDR mRNA by their own ligands, were observed in 3T3-L1 cells. Finally, we proposed the model of vitamins A and D as suppressors on adipocyte development through retinoid/thyroid/vitamin D/fatty acid-activated/peroxisomal proliferator activated receptor's subfamily. PMID- 8680479 TI - Endocrine and paracrine negative regulators of adipose differentiation. AB - Obesity which is characterized by an abnormal adipose tissue development is a first degree public health hazard in industrialized countries. One important aspect in the study of adipose tissue development is to investigate the hormonal control of proliferation and differentiation. Any qualitative or quantitative change in these hormones or their receptors can result in abnormalities in the process of proliferation and/or differentiation possibly leading to obesity. Therefore, it is important to identify these factors and investigate their mechanism of action. We have concentrated our efforts in the study of factors triggering differentiation (positive regulators) and also of factors inhibiting differentiation (negative regulators). The present paper provides evidence of the importance of EGF/TGF-alpha and of PGF2 alpha as differentiation inhibitors for adipocyte precursors in primary culture. Data presented here also demonstrate that TGF-alpha is expressed in adipose tissue and that its expression is specifically stimulated by PGF2 alpha, thus suggesting the existence of an amplification mechanism between two differentiation inhibitors within the adipose tissue. The importance of these two types of differentiation inhibitors in the regulation of adipose tissue development is discussed. PMID- 8680480 TI - Characterization of Pref-1 and its inhibitory role in adipocyte differentiation. AB - Differentiation of preadipocytes to mature adipocytes is accompanied by marked increases in enzymes of lipid metabolism and cytoskeletal remodelling of fibroblastic preadipocytes to rounded lipid-filled mature adipocytes. Studies to date indicate this process is under the control of specific transcription factors, cell-cell and cell-environment interactions. Preadipocyte factor-1 (pref 1), a member of the EGF-like protein family, was identified during the differential screening of cDNAs expressed in differentiating preadipocytes. Multiple forms of the protein are present in 3T3-L1 preadipocytes with heterogeneity attributable both to alternate splicing and various post translational modifications. Pref-1 is unique in that its expression is completely abolished during the maturation of preadipocytes to adipocytes. Moreover, blocking down-regulation via constitutive expression of pref-1 in preadipocytes inhibits their differentiation. The expression pattern of pref-1 in embryonic tissues and its presence in tumors indicate that in addition to its function in adipocyte differentiation, pref-1 may have a broader role in differentiation and development. PMID- 8680481 TI - Unravelling the nature of massive obesity: the research of Daniel AK Roncari. PMID- 8680482 TI - A novel method for studying preadipocyte differentiation in vitro. AB - In vitro differentiation of rat preadipocytes has typically been induced in medium supplemented with pharmacological concentrations of hormonal mixtures. These conditions probably do not reflect the milieu within adipose tissue in vivo. We have developed a new method for inducing differentiation of preadipocytes using culture medium which has been conditioned by isolated adipocytes (ACM). In the presence of ACM, 70%-80% of test preadipocytes contained lipid inclusions compared to < 5% of control. When differentiation was assessed by assay of glycerol-3-phosphate dehydrogenase activity, ACM activity was shown to be reproducible and the consistency of response to ACM by different pools of preadipocytes was comparable to that induced by standard differentiation procedures. We have also demonstrated that the adipogenic activity of ACM may not depend on prostaglandin secretion by adipocytes. We propose that use of paracrine factors produced by components of adipose tissue provides a new approach to preadipocyte differentiation induction which may more closely reproduce the adipose tissue environment. PMID- 8680484 TI - The roles of tissue inhibitors of metalloproteinases in tissue remodelling and cell growth. AB - Tissue inhibitors of metalloproteinases (TIMPs) are secreted proteins that block the activities of the extracellular matrix (ECM)-degrading metalloproteinases (MMPs). As key determinants of ECM integrity and turnover, TIMPs are involved in the establishment and maintenance of tissue architecture and may indirectly influence ECM-dependent cells signaling. In addition, TIMPs exert both positive and negative effects on cell growth through mechanisms that are independent of MMP inhibition. The three members of the mammalian TIMP family differ in structure, biochemical properties and expression, suggesting that they have distinct physiological roles. Here, we review recent advances in our understanding of TIMP protein function and gene regulation. We discuss the potential relevance of MMPs and TIMPs in obesity with regard to effects on the processing of tumor necrosis factor-alpha. PMID- 8680483 TI - Control of cell cycle regulated histone genes during proliferation and differentiation. AB - Proliferation is a requirement during the initial stages of cell and tissue specialization. In most biological systems the down-regulation of proliferation is necessary for initiation of key steps in the differentiation process. We have examined regulatory mechanisms controlling expression of the cell cycle-dependent histone genes, which are functionally coupled with DNA synthesis, in proliferating cells and during the onset of differentiation in several phenotypes including adipocytes. In proliferating cells transcription of the histone genes is up-regulated at the onset of S phase. We have identified a histone H4 proximal promoter element, designated Site II, that mediates cell cycle transcriptional control. The factor interacting with Site II include cdc2, cyclin A, an RB related protein and interferon regulatory factors (IRFs). Mutational analysis indicates that the distal part of Site II is critical for cell cycle regulation. Equally important for the developmental transcriptional control, histone gene expression is repressed when differentiation is initiated. In vivo, we have established loss of Site II occupancy by regulatory proteins; in vitro, factor binding to Site II is not observed post-proliferatively. Deletion analysis indicates that proximal Site II mediates the differentiation response of H4 gene transcription in adipocytes. PMID- 8680485 TI - Control of adipocyte differentiation by CCAAT/enhancer binding protein alpha (C/EBP alpha). AB - Upon differentiation of 3T3-L1 preadipocytes into adipocytes transcription of many adipose-specific genes is coordinately activated. A differentiation-induced factor, later identified as C/EBP alpha, binds to and transactivates the promoters of these genes. Vector-directed expression of antisense C/EBP alpha RNA in preadipocytes blocked expression of C/EBP alpha, as well as adipose-specific mRNAs, and also prevented cytoplasmic triglyceride accumulation. Rescue of the 'adipocyte phenotype' was accomplished by transfection of the antisense cells with a complementary sense C/EBP alpha RNA expression vector. Using an IPTG inducible double-vector LacSwitch C/EBP alpha expression system, it was found that differentiation can be induced without exogenous hormone inducers. These findings indicate that C/EBP alpha is not only required, but is sufficient, to trigger differentiation of 3T3-L1 preadipocytes. The C/EBP alpha gene promoter possesses a C/EBP binding site through which C/EBP alpha autoactivates its own expression. A nuclear protein referred to as CUP (C/EBP undifferentiated protein) that binds to a bipartite element in the C/EBP alpha promoter just 5' to the C/EBP binding site has been purified and characterized. During differentiation of preadipocytes, expression of CUP activity decreases as expression of C/EBP alpha increases. Evidence suggests that a CUP-containing protein complex bridges between the CUP (repression) and C/EBP (autoactivation) elements in the promoter and may maintains the C/EBP alpha gene in the repressed state prior to differentiation. PMID- 8680486 TI - Perilipin: possible roles in structure and metabolism of intracellular neutral lipids in adipocytes and steroidogenic cells. AB - Perilipins are a family of unique proteins intimately associated with the limiting surface of neutral lipid storage droplets in adipocytes and in steroidogenic cells. Lipid hydrolysis in these cells is initiated by cAMP, which leads to phosphorylation of hormone-sensitive lipase in adipocytes and cholesteryl esterase in steroidogenic cells by protein kinase A. Although the concurrent phosphorylation of perilipin by this kinase suggests a role for these proteins in lipid breakdown, a role for these proteins in lipid packaging or in maintaining the lipid droplet structure cannot be excluded. PMID- 8680487 TI - Making mistakes. PMID- 8680489 TI - Cardiac dysrhythmia during sleep in the critically ill: a pilot study. AB - BACKGROUND: Few investigators have examined the hemodynamic status related to circadian and sleep-related cardiovascular events in critically ill patients. OBJECTIVE: To describe the relationships among nocturnal angina, myocardial infarction, and sleep, and to describe the cardiac rhythm, heart rate, and frequency of premature supraventricular and ventricular contractions during the sleep of critical care patients with cardiovascular disease. METHODS: A descriptive survey was done on nine patients in the medical intensive care unit of a large medical center. All subjects had cardiovascular disease and were studied during one night of sleep. RESULTS: There were no incidences of chest pain during the study and no changes in baseline cardiac rhythm associated with sleep staging. There was a significant statistical difference in mean heart rate among waking, stage 1 nonrapid-eye-movement sleep, and stage 2 nonrapid-eye movement sleep; a lower heart rate was observed in stage 2 nonrapid-eye-movement sleep. The mean heart rate decreased by 3% to 4% from the waking state to sleep. No clinical or statistically significant differences in the frequency of premature supraventricular and ventricular contractions between sleep stages or sleeping and waking were found. CONCLUSIONS: The results of this pilot investigation do not suggest that dysrhythmia occurs more frequently during certain sleep stages or during the sleep state in critical care unit patients with cardiovascular disease. The mean heart rate slowed by 3% to 4% during rapid eye-movement and nonrapid-eye-movement sleep, but decreases in heart rate were not as great as those noted in normal, healthy subjects. PMID- 8680488 TI - The Cardiac Arrhythmia Suppression Trial: Implications for nursing practice. AB - BACKGROUND: Care of patients with ventricular arrhythmia after myocardial infarction requires careful nursing management, including assisting with arrhythmia monitoring and testing. Because ventricular premature depolarization is a known risk factor for sudden cardiac death, it was hypothesized that the suppression of asymptomatic or mildly symptomatic ventricular premature depolarization would improve survival in these patients. OBJECTIVE: To review the Cardiac Arrhythmia Suppression Trial findings and provide implications for nursing practice for patients after myocardial infarction. METHODS: The Cardiac Arrhythmia Suppression Trial was a multicenter, randomized, placebo-controlled trial designed to determine whether the suppression of ventricular premature depolarizations in postmyocardial infarction patients would improve survival. Three class I antiarrhythmic drugs were used: encainide, flecainide, or moricizine. Patients for whom the drug suppressed their arrhythmia 80% or more were randomly assigned to that drug and dose or its matching placebo and were followed every 4 months (main study). Patients with 1% to 79% suppression were randomly assigned to the drug or its placebo that best treated their arrhythmia and followed every 4 months. RESULTS: Suppression of asymptomatic or mildly symptomatic ventricular premature depolarization in patients using encainide, flecainide, or moricizine failed to improve patient survival and was even harmful in some cases. CONCLUSIONS: Our results showed that in the absence of effective antiarrhythmic drug therapy, supportive nursing care and arrhythmia monitoring is important until appropriate therapy for the management of these arrhythmias in patients who have had a myocardial infarction can be found. Clinical trials are essential to provide an evaluation of therapies and direction for further studies, as well as a basis for practicing clinicians. PMID- 8680490 TI - Comparison of four methods of assessing heart rate variability in patients with heart failure. AB - BACKGROUND: Heart rate variability reflects autonomic tone and is used to assess progression and prognosis in a variety of illnesses. However, multiple heart rate variability methods exist and are not necessarily equivalent. OBJECTIVES: To compare four methods of heart rate variability in heart failure patients and healthy subjects. METHODS: Twenty-four-hour Holter recordings were obtained in 50 heart failure patients and 50 age- and gender-matched control patients. From these recordings, heart rate variability was assessed by histograms, standard deviation, Poincare plots, and spectral analysis. RESULTS: For R-R interval histograms, standard deviation, and Poincare plots, diminished heart rate variability was identified in 65% to 100% of heart failure patients versus 0% to 8% of controls. Agreement among these tests ranged from 69% to 96%. Spectral values varied greatly over the recording period, even in the same subject, possibly because of variations in activity. Only 16% of heart failure patients had spectral values that were identified as abnormal. Agreement between spectral analysis and the other methods ranged between 58% and 67%. CONCLUSIONS: Heart rate variability assessed over a 24-hour period with different techniques yields similar but not identical results. Heart rate variability assessed from spectral analysis of short periods of data varied markedly in a 24-hour period and should not be compared with measures obtained from 24-hour methods. Standardization of subject activity and recording time is necessary for comparison of spectral analysis of brief periods. Further research is required to determine if differences among methods assessing 24-hour heart rate variability yield complementary information. PMID- 8680491 TI - Cost containment in critical care. AB - Increasing emphasis will be placed on the efficient delivery of healthcare. This article concentrates on recommendations for cost containment including increased cost consciousness, elimination of waste, improved quality of care, and use of the team approach to cost containment. The resources over which bedside nurses and managers in critical care have direct or indirect control are the focus of this discussion. PMID- 8680493 TI - Critical care nurses' knowledge of pulmonary artery catheters. AB - BACKGROUND: Earlier studies indicate that nurses and physicians have a knowledge deficit regarding pulmonary artery catheters. OBJECTIVE: To evaluate critical care nurses' knowledge of pulmonary artery catheters. METHODS: A 31-item, multiple-choice questionnaire was administered to 168 critical care nurses from institutions in a southern California metropolitan area. Fourteen demographic questions were included to determine variables such as critical care nursing experience, educational background, work area, and frequency of pulmonary artery catheter use that may have affected participants' scores. The investigators traveled to the institutions to explain and conduct the study. RESULTS: The mean knowledge score was 16.4 of 29 questions (56.8% items correct), with a standard deviation of 3.74. The range of correct scores was 8 to 25. Two questions were not factored into the statistical analysis because they were specific to the physician's role in pulmonary artery catheter insertion. The variables that correlated with higher scores were CCRN certification, attendance at a pulmonary artery catheter class, years of critical care experience, and frequent use of the pulmonary artery catheter. Of the respondents, 39% were unable to identify a pulmonary artery wedge measurement value from a waveform recording. CONCLUSIONS: Critical care nurses' knowledge of pulmonary artery catheters is related directly to the frequency of their exposure to it, critical care nursing experience, attendance at a pulmonary artery catheter class, and CCRN certification. Additional research is needed on a larger scale to validate these findings and determine if critical care nurses' knowledge of pulmonary artery catheters is sufficient to maintain quality standards of safety and optimal patient care. PMID- 8680492 TI - Effectiveness of a jet injection system in administering morphine and heparin to healthy adults. AB - BACKGROUND: Jet injection eliminates the risk of contaminated needlestick injuries when giving intramuscular or subcutaneous medications. Clinical efficacy of the Biojector System was equivalent to that of needle and syringe injection in unpublished trials with vaccines, but had not been studied using other drugs. OBJECTIVE: To compare the effectiveness of the Biojector with conventional needle and syringe injection in administering intramuscular morphine and subcutaneous heparin to healthy adults, as measured by plasma drug concentration. METHODS: Intramuscular injections of morphine 8 mg (5 mg if weight < or = 65 kg) were given 24 hours apart with the jet injector and with a needle and syringe to 30 subjects at the deltoid site and 10 subjects at the dorsogluteal site. Blood samples for plasma concentrations of free morphine were drawn at 15, 30, 45, 60, 120, and 240 minutes and were analyzed using radioimmunoassay. Abdominal subcutaneous injections of heparin 3500 U were given every 8 hours for 5 days with both injection methods to 29 subjects, with 48 hours between the two series. Daily blood samples for plasma heparin were analyzed by colorimetric assay for antifactor Xa activity. RESULTS: Mean free morphine concentration, peak value, and area under the curve did not differ significantly between the deltoid and dorsogluteal sites or between the jet injector and needle and syringe. Values of mean daily heparin concentrations and area under the curve were low and did not differ between the two injection methods. CONCLUSION: Plasma drug concentrations provided by the Biojector were equivalent to those provided by conventional needle and syringe when administering intramuscular morphine and low-dose subcutaneous heparin. PMID- 8680494 TI - Emerging technology in critical care: continuous intra-arterial blood gas monitoring. AB - The blood-conserving technology of continuous intra-arterial blood gas monitoring has recently been introduced into the field of critical care. This type of monitoring is a real-time method for concomitantly assessing oxygenation, ventilation, and acid-base status in pediatric and adult populations through an indwelling (in vivo) sensor residing in a peripheral artery. This article examines the technology underpinning in vivo blood gas monitoring and reviews research documenting clinical performance, as well as benefits and clinical applications of three-analyte systems in critically ill patients. A majority of research has revealed clinically acceptable accuracy and reliability of in vivo blood gas sensors in critically ill adults subjected to a variety of adverse, but common, physiological conditions. Although most clinical research in critically ill adults has revealed good clinical performance of in vivo blood gas sensors, reports of aberrant blood gas values and sensor problems remain; no reports have been published to date evaluating continuous intra-arterial blood gas monitoring in children or infants. Many benefits of this technology have been postulated, and research examining its effect on patient and cost outcomes in critically ill populations is pending. Clinicians in critical care must keep abreast of this emerging technology, because it holds significant potential for improving the quality of care and outcomes of critically ill patients. PMID- 8680495 TI - Fluid delivery by pressure monitoring systems in the pediatric intensive care unit: a retrospective comparative analysis of two systems. PMID- 8680496 TI - Development of a model of advanced practice. AB - BACKGROUND: The acute care nurse practitioner role is relatively new and not yet clearly defined. Our institution is in the first phase of a role delineation study that includes model development, validity testing, model revision, and dissemination. OBJECTIVES: To identify domains of practice, activities within each domain of practice, and common conceptual strands that cut across each domain, and to synthesize this information into a usable format to guide practice and role development. METHODS: A nonexperimental study design was used, including review of literature, expert consultation, brainstorming, and review of practice. RESULTS: The patient is central to the model. The identified domains of practice include direct comprehensive care, support of systems, education, research, and publication, and professional leadership. The conceptual strands include empowerment, collaboration, and scholarship. A continuum of experience from novice to expert was also identified within each domain. CONCLUSIONS: The development of the model is the first and most important phase in the role delineation process. We believe that the model is accurate but still in need of testing. Nevertheless, our model can be used to guide institutions and individual practitioners. PMID- 8680497 TI - Managing agitation in critically ill patients. AB - Managing agitation in critically ill patients is challenging and complex. Advances in the field of critical care impose strains on patients that can lead to disorientation and agitation, especially as more severe illnesses are treated successfully. Although the adverse effects of agitation are well-known, their impact on morbidity, mortality, length of stay, and cost are only beginning to be addressed. Meeting these challenges requires an understanding of the potential adverse effects of agitation, its causes and contributing factors, the advantages and limitations of available pharmacologic agents, and the role of nonpharmacologic interventions. This article reviews each of these issues, with a focus on clinical applications and strategies. PMID- 8680498 TI - Therapeutic Intervention Scoring System used in the care of patients in pentobarbital-induced coma to determine nurse-patient ratios. AB - BACKGROUND: Critical care patients generally require extensive interventions, thereby consuming a large percentage of healthcare resources. Induced pentobarbital coma for the management of increased intracranial pressure is one such intervention, required to maintain patient stability. Quantification of these interventions, as well as the amount of nursing work required, has not been addressed in the literature. OBJECTIVE: To use the Therapeutic Intervention Scoring System to analyze and quantify how interventions affect nurse-patient ratios in the management of patients in pentobarbital coma for refractory increased intracranial pressure. METHODS: The medical records of patients with subarachnoid hemorrhage from aneurysmal rupture and subsequent increased intracranial pressure, in whom pentobarbital coma was salvage therapy, were reviewed retrospectively. The Therapeutic Intervention Scoring System was used to quantify the number of interventions required before, during, and after coma induction. The data were analyzed and daily Therapeutic Intervention Scoring System scores correlated with serum pentobarbital levels. Typically, a critical care nurse can manage a patient caseload of 40 to 50 Therapeutic Intervention Scoring System points. By quantifying the interventions, the score reflected the amount of care required to manage the patient in barbiturate coma. RESULTS: The intensity of interventions correlated with the level of coma, length of time in coma, and associated complications. CONCLUSIONS: The scores indicated the intensity of interventions used in pentobarbital coma and the use of resources. Nursing care and complications involved with this therapy were quantified and nurse-patient ratios were established. PMID- 8680499 TI - Cardiomyoplasty: A potential alternative to cardiac transplantation. PMID- 8680500 TI - Salm-Net facilitates collaborative investigation of an outbreak of Salmonella tosamanga infection in Europe. AB - Twenty-eight cases of Salmonella tosamanga infection were identified in six western European countries during the first half of 1995. Salm-Net, a European system for collaborative surveillance of gastrointestinal infection, detected the outbreak and coordinated its investigation. There were 28 cases, 14 of each sex, with a broad age distribution. Interviews with cases to identify common food and other exposures failed to generate a working hypothesis. The initial cluster occurred in a period of eight weeks and, since only one further case occurred in June, the investigation was closed. This incident shows that Salm-Net is effective in identifying international outbreaks of human salmonellosis. Practical difficulties in the field investigation of the outbreak are discussed. PMID- 8680501 TI - Outbreaks of infectious intestinal disease in schools and nurseries in England and Wales 1992 to 1994. AB - We present data on outbreaks of infectious intestinal disease in schools and nurseries obtained from the surveillance scheme of all general outbreaks of infectious intestinal disease in England and Wales reported to the PHLS Communicable Disease Surveillance Centre between 1992 and 1994. A minimum set of data was received for 1280 outbreaks, 95 of which (7%) arose in schools and nurseries. The commonest pathogens were salmonellas, Shigella sonnei, and small round structured viruses. The mode of transmission was described as mainly from person to person in 55 outbreaks and mainly foodborne in 30. The mean attack rate was 30% and median duration was 10 days. The attack rate and duration varied with the pathogen involved. Forty-five of the 3118 people reported to have been ill were admitted to hospital. Outbreaks in schools and nurseries are common. Attack rates are high and such outbreaks are often prolonged. Effective infection control policies and appropriate training of staff are needed. Good local systems for surveillance can help identify outbreaks quickly and allow control measures to be applied early. PMID- 8680502 TI - Food poisoning: notifications, laboratory reports, and outbreaks--where do the statistics come from and what do they mean? AB - Three main routine sources of data on food poisoning are used in England and Wales. The first is the statutory notification system, in which clinicians notify the 'proper officer' of their local authorities of cases or suspected cases of food poisoning, and the data are collated by the Office for National Statistics. Second and third are the reporting schemes for laboratory confirmed infections and general outbreaks of infectious intestinal disease, both of which are coordinated by the PHLS Communicable Disease Surveillance Centre. This review discusses the strengths and weaknesses of the three sources. PMID- 8680503 TI - Meningococcal infection in children visiting Majorca. PMID- 8680504 TI - Meningococcal infection in Africa. PMID- 8680505 TI - Epidemic methicillin resistant Staphylococcus aureus. PMID- 8680506 TI - Occult bacteremia or occult clinical acumen? PMID- 8680507 TI - Viral encephalitis in children. AB - Knowledge about the role of viruses in encephalitis and other diseases of the central nervous system has been greatly expanded since the advent of polymerase chain reaction testing. It is known that the spectrum of disease caused by herpes simplex virus, for example, is much wider than was previously recognized. Evidence is mounting that infectious agents may have a causative role in diseases such as recurrent febrile seizures and Rasmussen encephalitis. This review examines the recent advances in treating viral encephalitis and puts these developments into perspective. PMID- 8680508 TI - Falciparum malaria in children. AB - Recent reports have substantiated claims that the clinical spectrum of falciparum malaria is different in African children as compared with nonimmune adults. The SPf66 vaccine has been tried in African children with varying success, but only insecticide-treated bed nets have reduced the mortality. Developments in ancillary treatment may reduce the morbidity and mortality of severe falciparum malaria. PMID- 8680509 TI - Update on immunization. AB - By 1995, measles, mumps, and rubella were eliminated from Finland, acellular vaccines for pertussis were showing great promise, and the global eradication of poliomyelitis by the year 2000 looked possible. The meningococcus was replacing Haemophilus influenzae type b as the main cause of childhood meningitis, and 75 countries were vaccinating their children against hepatitis B. The United States recommended varicella vaccination for children, effective vaccines were available for hepatitis A, and new vaccines for rotavirus and cholera were being tested; malaria and HIV offer a continuing challenge. PMID- 8680510 TI - Umbilical cord blood as a new and promising source of unrelated-donor hematopoietic stem cells for transplantation. AB - A rapidly accelerating number of transplantations of hematopoietic stem cells from human umbilical cord blood have been performed for malignancies and for congenital disorders. Umbilical cord blood presents multiple advantages over bone marrow as a source of stem cells. Harvesting presents no donor risk or discomfort, the product carries less likelihood of infectious disease transmission, and collection can be targeted to include minority groups underrepresented in bone marrow donor registries. Furthermore, the interval from initiation of a search to the transplantation procedure has been much shorter than for bone marrow, and the lack of mature T lymphocytes in cord blood reduces the incidence and severity of graft-versus-host disease in transplant recipients. Potential problems under current investigations include whether cord blood provides a sufficient quantity of stem cells for adult recipients or an effective level of "graft-versus-leukemia" effect. PMID- 8680511 TI - Respiratory infections and wheezing in children. AB - Thirty percent of infants will wheeze in the early years of life. Of these, two thirds of cases are due to structural characteristics, and the wheeze will cease with growth. One third of cases continue and manifest as childhood asthma. Another 10% of children develop asthma after the first few years of life. Viral infections may have a biphasic influence on asthma, with asthma and atopy more likely in the relative absence of early infections but with attacks commonly precipitated by these infections once asthma is present. PMID- 8680512 TI - Bone marrow failure in children. AB - Bone marrow failure in the pediatric patient places the hematologist at the junction of clinical medicine, cellular biology, and molecular genetics. The pathophysiology of these disorders is rapidly being elucidated in many laboratories. Treatments such as bone marrow transplantation and the nascent modality of gene therapy are firmly grounded in these modern sciences. This year's progress in the understanding, diagnosis, and treatment of a wide variety of predominantly pediatric bone marrow failure states is a direct result of the union between the "laboratory bench and the patient bedside." PMID- 8680513 TI - Bone marrow transplantation in children with hereditary disorders. AB - Hereditary disorders represent a very heterogenous group of diseases affecting the hematopoietic system. Bone marrow transplantation is the treatment of choice for immunodeficiencies, mucopolysaccharidosis, thalassemia, Fancoli's anemia, osteopetrosis, and other rare disorders. Indications for bone marrow transplantation are well known when an HLA-identical sibling is identified. Results of alternative donor transplantations are still under investigation. Recently, progress has been made in the analysis of the mechanism of the disease at the molecular level and in the identification of gene mutations. Clinical implications of these discoveries might modify the future indications for bone marrow transplantation. PMID- 8680514 TI - Malignancies in pediatric AIDS. AB - Patients with immunodeficiency disorders, including children infected with HIV type 1, are at increased risk to develop a malignancy. Although the exact incidence is not clear, an excess of non-Hodgkin's lymphomas, soft tissue tumors, and, in the case of adolescent girls, cervical carcinomas, has been reported in HIV-infected children. Kaposi's sarcoma is rare in children as compared with HIV infected adults. To understand the pathogenesis of these disorders, one must take into account the multiple interactions between the immunodeficient host, the cytokine dysregulations, and the concurrent infection with many, potentially oncogenic, viruses. Treatment is often complicated by multiple HIV-associated organ dysfunctions as well as drug interactions and infectious complications secondary to severe immmunosuppression. Nonetheless, preliminary results with dose-intensive short-duration chemotherapeutic regimens have been encouraging, and HIV-infected children who develop cancer are likely to benefit from antineoplastic therapy and supportive care. PMID- 8680515 TI - A 4-month-old boy with severe emaciation, normal linear growth, and a happy affect. PMID- 8680516 TI - Orthopedics. PMID- 8680517 TI - Neonatal infections. AB - Neonatal infection still carries a high mortality and morbidity. The spectrum of infection is broad and includes congenital syphilis and viral infections. Sadly, nosocomial infection is common, particularly due to coagulase negative staphylococci. Very low birth weight infants are at high risk, particularly following prolonged central venous catheterization; continuous low-dose vancomycin may offer a solution to this important problem. Early identification of infected infants can be facilitated by measurement of interleukin-6 levels. The premature newborn, deficient in white cells and humoral immunity, is at high risk of infection; treatment rather than prophylaxis of such patients with immunoglobulin is efficacious. Exciting new management strategies appear to be the use of granulocyte colony-stimulating factor to enhance neutrophilia and zidovudine to reduce vertical transmission of HIV infection. PMID- 8680518 TI - Congenital hand and forearm anomalies. AB - Congenital anomalies of the hand and forearm remain a continuing challenge for the patient and the patient's family. Health care professionals, including the pediatrician, the orthopedic surgeon, and the hand surgeon, all have roles to play in the treatment of these patients. This article reviews the literature for the past year with special emphasis on recent developments in the genetic transmission of some of these interesting congenital differences. PMID- 8680519 TI - Orthopedic aspects of myelodysplasia in children. AB - A review of new developments in spina bifida shows that many cases are preventable by administration of periconceptual folic acid, reducing the relative risk by up to 86%. Currently, however, 50% of women of reproductive age have no folic acid in their usual diet. The Centers for Disease Control as recommended folic acid at 0.4 mg/d for all women anticipating pregnancy. The long-term outcomes of sacral level patients show a surprising decline in adult ambulatory status. Adult ambulatory status in spina bifida is significantly predictive (89% accurate) by two variables: motor level and sitting balance. Studies regarding hip dislocation, foot deformities in thoracic level children, the prevalence of spondylolisthesis, and surgical treatment of kyphosis are also reviewed. PMID- 8680520 TI - Endocrine disorders and orthopedic problems in children. AB - Endocrine excesses or deficiencies frequently result in alterations of height as compared with age-matched children. Less clinically obvious are significant alterations in bone metabolism leading to osteoporosis, which can affect the child and may affect the patient as an adult. Slipped capital femoral epiphysis appears to be associated with a variety of endocrine disorders, particularly hypothyroidism. The hormonal treatment of various endocrine and nonendocrine disorders has been associated with alterations of bone metabolism, or of bone maturation, as well as with producing or aggravating orthopedic disorders. PMID- 8680521 TI - Primary bone malignancies in children. AB - The evaluation and treatment of primary bone malignancies in children have evolved considerably over the past decade, with a measurable improvement in prognosis. Disease-free survival has improved mainly due to intensive multiple agent chemotherapy, refinement in radiotherapeutic techniques, better imaging, and wide surgical resection. Reconstruction techniques after "limb-sparing" surgery have used allograft, composite allograft-prosthesis, or "expandable" prostheses reconstruction after adequate removal of the tumor with wide margins. The diagnosis and understanding of these tumor has also improved with advances in molecular genetics. Both osteosarcoma and Ewing's sarcoma treatment have undergone this dramatic change; recent advances in molecular genetics, treatment, magnetic resonance imaging, and "limb-sparing" surgery are highlighted. PMID- 8680522 TI - Fever without apparent source on clinical examination, lower respiratory infections in children, other infectious diseases, and acute gastroenteritis and diarrhea of infancy and early childhood. AB - This section focuses on issues in infectious disease that are commonly encountered in pediatric office practice. Paul McCarthy discusses recent literature regarding the evaluation and management of acute fevers without apparent source on clinical examination in infants and children and the evaluation of children with prolonged fevers of unknown origin. Jean Klig reviews recent literature about lower respiratory tract infection in children. Eugene Shapiro discusses recent developments in the literature concerning several infectious diseases commonly facing practitioners in the office. Michael Baron reviews recent literature about gastroenteritis and diarrhea of infancy and early childhood. PMID- 8680523 TI - Gene expression in rainbow trout (Oncorhynchus mykiss) following intramuscular injection of DNA. AB - Expression of the firefly luciferase gene under the control of viral or fish promoters was observed in fish tissue after direct DNA injection of plasmid DNA. Plasmid DNA containing the firefly luciferase gene was injected into the skeletal muscle of rainbow trout (Oncorhynchus mykiss), and levels of luciferase activity were found to be dependent on the controlling promoter and the amount of injected DNA. Plasmids using the cytomegalovirus immediate early promoter (CMV-IEP) consistently produced the highest levels of luciferase activity. Maximal activity was observed five to seven days postinjection with 50 micrograms of DNA. This activity persisted in the tissues for as long as 115 days postinjection. When the DNA was examined up to two months postinjection, the predominant form was unreplicated, unintegrated DNA in linear and relaxed circular conformation. Expression of injected DNA was found predominantly within muscle cells along the injection path and in scattered muscle cells anterior to the injection site. PMID- 8680524 TI - Genetic immunization of rainbow trout (Oncorhynchus mykiss) against infectious hematopoietic necrosis virus. AB - Plasmid vectors encoding the infectious hematopoietic necrosis virus (IHNV) nucleoprotein or glycoprotein gene under the control of a cytomegalovirus promoter were used to immunize rainbow trout (Oncorhynchus mykiss) against IHNV. The plasmid DNA was injected into the skeletal muscle of rainbow trout fry, and immunization was determined by the detection of virus-neutralizing and enzyme linked immunosorbent assay antibody activity, and by protection against live virus challenge. Fish injected with the glycoprotein-encoding plasmid pCMV4-G, either alone or in combination with the nucleoprotein-encoding plasmid pCMV4-N, generated glycoprotein-specific and virus-neutralizing antibody responses. The vaccinated fish were also protected from subsequent IHNV challenge. Fish receiving pCMV4-N alone did not produce measurable virus-specific antibody and were killed by IHNV infection. These studies show that DNA vaccination will protect rainbow trout against the lethal effects of IHNV infection. PMID- 8680525 TI - Genetics of scnDNA polymorphisms in juvenile oysters (Crassostrea virginica). Part I: Characterizing the inheritance of polymorphisms in controlled crosses. AB - The amplification of DNA by polymerase chain reaction followed by restriction enzyme digestion was used to examine five anonymous single-copy nuclear DNA polymorphisms in 11 pair crosses for juvenile oysters (Crassostrea virginica). There was an overall 7% frequency of aberrant (non-Mendelian) offspring genotypes among 174 total pair-cross progeny. Strict Mendelian inheritance of alleles was observed for two of the five loci. Possible explanations for the aberrant offspring genotypes include nonamplifiable alleles owing to priming site polymorphism or aneuploidy, or paralogous amplification. Analysis of more pair crosses is needed to test these explanations. PMID- 8680526 TI - Use of PCR-RFLP assays to detect genetic variation at single-copy nuclear loci in striped bass (Morone saxatilis). AB - We developed three assays that detect genetic variation at single-copy nuclear loci in striped bass (Morone saxatilis). Because these assays are based on restriction enzyme digests of DNA amplified by the polymerase chain reaction (PCR RFLP), they are easy to perform on large numbers of samples. Breeding trials demonstrated that the alleles identified in each of the three assays are inherited in a Mendelian fashion as codominant alleles at single-copy loci. To demonstrate the utility of these PCR-RFLP assays, we compared the genetic composition of striped bass populations from the Congaree River in South Carolina and from the Choptank River in Maryland. Allele frequencies were significantly different at the SB14 locus, suggesting that the two populations may be genetically distinct. Furthermore, during the development of the PCR-RFLP assays, we demonstrated that the GT(n) microsatellite-associated DNA regions (MSA regions) contained RFLPs at a frequency 9-fold higher than that observed for randomly chosen segments of DNA. If MSA regions proved to be variable in other organisms as well, they could provide a valuable source of intraspecific variation. PMID- 8680528 TI - Case management study: heel pain in the adult. PMID- 8680527 TI - Insulin-like growth factor IEa2 is the predominantly expressed form of IGF in common carp (Cyprinus carpio). AB - An insulin-like growth factor (IGF) complementary DNA (cDNA) was isolated from a liver cDNA library of adult common carp, Cyprinus carpio. The identity of this cDNA clone was confirmed by nucleotide sequence determination. Sequence comparison with other vertebrate and rainbow trout IGFs showed that this cDNA encodes a particular subtype of IGF-I, IGF-IEa2. A reverse transcription polymerase chain reaction (RT-PCR) assay showed that this IGF-I is expressed mainly in the liver (hepatopancreas) of adult common carp. Analyses of 26 other cDNA clones isolated from the same library (using a probe carrying the conserved region of the common carp IGF-IEa2 cDNA clone) showed that these clones represent different insert sizes of the same IGF-IEa2. In conclusion, IGF-IEa2 is the predominantly expressed IGF in the liver of adult common carp. PMID- 8680529 TI - Spinal stenosis. PMID- 8680530 TI - Rheumatic diseases and inherited complement deficiencies. AB - Deficiencies of individual complement proteins may be accompanied by SLE or related syndromes. Deficiencies of the classic activation pathway are often involved. In cases of C4 and C2 deficiency, there is evidence that this association occurs more frequently than would be expected by chance. The clinical picture differs from classic SLE. There is an increased frequency of skin involvement, a decreased frequency of renal disease, low or absent levels of antibody to native DNA, and increased levels of anti-Ro (SS-A). The mechanism for the association probably involves the effects of C3 and C4 on the precipitation of immune complex solubility, or on their processing through cell surface c4b/c3b receptors on phagocytes. Disseminated or recurrent Neisseria infections are common in patients lacking the constituents of the terminal MAC that are important in killing these organisms. PMID- 8680531 TI - Tissue concentrations and correlations of prostaglandins in healthy and inflamed human esophageal and jejunal mucosa. AB - The PGE2, PGF2 alpha, PGI2, and TXB2 content in biopsies of healthy esophageal mucosa and inflamed mucosa and from subjects with chronic esophagitis was measured and statistically analyzed. No significant differences were found between the tissue concentrations of prostaglandins in the inflamed and the healthy mucosa, except for elevated PGI2 content in the inflamed esophageal mucosa in comparison to healthy mucosa. The prostaglandin content of jejunal mucosa was unchanged in jejunitis and in atrophy compared to findings in healthy subjects. Regression analysis revealed a significant negative correlation between the PGF2 alpha and PGI2 content in both inflamed esophageal and inflamed jejunal mucosa. In healthy mucosa, no correlation was found between the tissue concentrations of these two prostaglandins, either in the esophagus or in the jejunum. These results suggest the redistribution of cyclic endoperoxide metabolism under certain pathological conditions. PMID- 8680532 TI - Effects of activated granulocytes and O2- on microcirculatory injury in acute gastric mucosal lesion in rats induced by sodium cinchophen. AB - The contribution of granulocytes and their byproducts to acute gastric mucosal lesion (AGML) is unclear. Our previous study showed that granulocytes produced O2 in the gastric mucosa of rats treated with 300 mg/kg of cinchophen (cinchophen ulcer, CU) and in rats subjected to 30 min-ischemia-reperfusion (IR). The present study investigated the effects of granulocytes and O2- on microcirculatory injury (MCI) in the gastric mucosa in both models. To evaluate MCI, we measured the amount of extravasated Evans blue, and monitored changes in blood flow and the formation of vascular casts in the gastric mucosa of rats with and without leukopenia. Mucosal levels of interleukin-8 (IL-8) were also measured, to determine granulocyte migration into the stomach. Our findings were: (1) IL-8 was decreased 30-45 min after CU injection (C-I) or after the start of occlusion (S O), and levels had increased 90 min after either treatment. (2) Evans blue increased 120-150 min after C-I or S-O. These increases were lower in leukopenic than in non-leukopenic rats. (3) The blood flow decreased after C-I or reperfusion and continued at the same level during the 180-min measurement period. In CU leukopenic rats, the blood flow decreased slowly and was restored gradually. In IR leukopenic rats, the blood flow did not decrease. (4) There was a partial lack of capillary network, narrowing of capillaries, and extravasation of resin 90-120 min after C-I and S-O, and the disturbances were reduced in leukopenic rats in both models. (5) The extravasation of resin was reduced by the administration of superoxide dismutase (SOD) at the time O2- from granulocytes was being produced. (6) These reductions in the extravasation of resin due to leukopenia or SOD were smaller in CU than in IR rats. These findings indicate that granulocytes and O2- contribute to some extent to the MCI in CU rats. PMID- 8680533 TI - Spontaneous antibody-secreting cells in the stomach of gastric cancer patients. AB - The gastric mucosa has been regarded as an active site of humoral immunity since the discovery of Helicobacter pylori. The present study was conducted to determine the in vivo activity of gastric B cells in 53 gastric cancer patients. B-cell activity was measured by protein-A plaque assay, in which IgA-, IgM-, and IgG-plaque-forming cells (PFC) were counted. The number of PFC was associated with the stage of cancer, but the response of lymphocytes in a non-tumorous area (NML) and tumor-infiltrating lymphocytes (TIL) differed. PFC in both sites were decreased compared to n0 cancer in n1 lymph node metastasis-positive cancer, while only NML showed raised PFC in n2 + (P < 0.05, vs TIL). Cancer cells penetrating the submucosa caused the PFC of TIL (but not of NML) to decrease. Invasion of the intratumor capillary (V) or lymphatic (Ly) vessels also caused PFC to change, showing differences of Ig class; there was a decrease of PFC in V2 (IgG- and IgM-PFC) and in Ly2 (all Ig-PFC). IgA-PFC in Ly1 differed in TIL (decrease of PFC) and NML (increase). PFC also differed in TIL and NML in cancer cells, as follows: TIL < NML in tubular and poorly differentiated adenocarcinoma and TIL > NML in papillary and signet ring cell adenocarcinoma. Changes in lymph node (LNL) and blood lymphocytes were similar to those in gastric PFC whose IgA value was 10 times as much as that of LNL. The 5-year survival rate was significantly better in patients with lower rather than higher PFC such as 89% vs 68%. Gastric B cells thus appear to be active and to reflect gastric mucosal immunity. PMID- 8680535 TI - Validity of various diagnostic tests to evaluate cure of Helicobacter pylori infection. AB - Many diagnostic methods have been developed and used for detecting Helicobacter pylori to evaluate the success of treatment of H. pylori infection. We investigated and compared the suitability of the rapid urease test (RUT), polymerase chain reaction (PCR), 13C-urea breath test (13C-UBT), and serology with culture for evaluating cure of H. pylori infection. Forty-seven H. pylori positive gastric ulcer patients received dual therapy of lansoprazole (30 mg u.i.d.) and clarithromycin (200 mg b.i.d.). Four weeks after the completion of treatment, RUT, PCR, 13C-UBT, and culture were performed and the negative rates of these tests were compared. Anti-H. pylori IgG antibodies were measured by enzyme-linked immunosorbent assay (ELISA) before and 4 weeks after completion of the treatment to evaluate changes of titers during the treatment. The negative rate of RUT (55%) was significantly greater than that of culture (27%). Significant declines in titers were seen in the patients who had negative culture results, while the decline in the titer was not significant in the patients who had positive results. PCR assay and 13C-UBT were suitable for the evaluation of H. pylori eradication, but RUT was not suitable, because of its sensitivity. By monitoring anti-H. pylori IgG antibody titers, therapeutic failure can be detected early after completion of treatment. PMID- 8680534 TI - Effects of pirenzepine on omeprazole-induced hypergastrinemia and acid suppression in peptic ulcer patients. AB - Omeprazole effectively suppresses acid secretion, resulting in the long-term elevation of intragastric pH and serum gastrin level. Pirenzepine has been reported to inhibit gastrin secretion. This study was carried out to examine the effects of additional pirenzepine treatment on the hypergastrinemia and gastric acid suppression induced by omeprazole. Concentrations of serum gastrin and plasma somatostatin were measured in 28 peptic ulcer patients before treatment, after omeprazole treatment (20 mg/day) for 2 weeks, and after omeprazole and pirenzepine (100 mg/day) treatment for 2 weeks. The acid inhibitory effect of pirenzepine treatment in addition to omeprazole was evaluated by 24-h intragastric pH measurement in six healthy volunteers. Serum gastrin level was increased significantly, to 2.4-fold the pretreatment level, by omeprazole treatment. Additional treatment with pirenzepine suppressed serum gastrin level to 0.6-fold the omeprazole-treatment level. The serum somatostatin level was not altered significantly either by omeprazole treatment or by omeprazole and pirenzepine treatment. In healthy volunteers whose pH 3 holding time on 24-h intragastric pH monitoring was 70% by omeprazole treatment, omeprazole and pirenzepine treatment markedly increased the pH 3 holding time, to 89%. These findings suggest that pirenzepine is useful in reducing the undesirable effects of omeprazole-induced hypergastrinemia, i.e., the excessive trophic effect of omeprazole on the acid-secreting part of the stomach and the overstimulation of acid secretion. The additional pirenzepine treatment is also effective in suppressing acid secretion. PMID- 8680536 TI - Effect of the eradication of Helicobacter pylori on duodenal ulcer healing and ulcer relapse: randomized controlled study in Japan. AB - To investigate the effect of the eradication of Helicobacter pylori on the healing and relapse of duodenal ulcers. 50 patients with active duodenal ulcer and H. pylori infection were randomly allocated to two treatment groups. One group (cimetidine group) received cimetidine 400 mg twice daily for 6 weeks and the other group (double-therapy group) received 300 mg amoxicillin granules and 250 mg metronidazole thrice daily for 2 weeks, in addition to the same regimen of cimetidine as the cimetidine group. Forty-two patients completed the study. After confirmation of ulcer scar, all patients were followed up for 6 months while receiving treatment with teprenone, an agent that does not affect acid secretion or the eradication of H. pylori. The healing rates at 6 weeks were 90% in the cimetidine group and 95.5% in the double-therapy group. H. pylori eradication occurred in 0% of the cimetidine group and in 73.7% of the double-therapy group (P = 0.004). The cumulative relapse rates in the two groups at 6 months were 64.3% and 11.1%, respectively (P = 0.0007). In the double-therapy group, the cumulative relapse rate at 6 months in the patients in whom H. pylori persisted was 50% (2/4); the rate was 0% (0/14) in the patients in whom H. pylori had been eradicated (P = 0.005). Histological gastritis significantly improved compared with the baseline in the double-therapy group, but no such improvement was seen in the cimetidine group. White scarring was found in 7.1% of the cimetidine group and in 83.3% of the double-therapy group after 6 months (P < 0.0001). The eradication of H. pylori markedly decreased the relapse rate in duodenal ulcer patients, and it significantly improved both the grade of gastritis and the quality of the ulcer scar. PMID- 8680537 TI - Population changes in immunoglobulin-containing mononuclear cells in dextran sulfate sodium-induced coltitis. AB - To investigate the relation of immunoglobulin-containing cells in the colonic mucosa to mucosal inflammation, we immunohistochemically examined the localization of immunoglobulin-containing mononuclear cells in the lamina propria in dextran sulfate sodium induced colitis in mice. Mice were treated repeatedly with 3% dextran sulfate sodium (MW 54,000) solution or distilled water for a total of 170 days (chronic model), or for 85 days (subacute model) or for 10 days (acute model). IgG, IgA, and IgM-containing mononuclear cells were studied by enzyme immunostaining. The number of IgA- and IgG-containing cells gradually and significantly increased in the acute, subacute, and chronic models, in that order (P < 0.01 or 0.05). However, the numbers of IgM-containing cells in the three models were similar to that in the controls. These findings resembled those of human ulcerative colitis. In this dextran sulfate sodium-induced colitis, IgA containing mononuclear cells may play an essential role in the mucosal immune system is the acute, subacute, and chronic phases. The finding that IgG containing mononuclear cells increased substantially in the chronic phase suggests that IgG plays an important role in the mucosal inflammatory reaction during the chronic phase. PMID- 8680538 TI - Selective uptake of intraluminal dextran sulfate sodium and senna by macrophages in the cecal mucosa of the guinea pig. AB - The involvement of macrophages in the passage of intraluminal substances into the lamina propria was examined in the large intestine of the guinea pig. Dextran sulfate sodium (DSS) and senna, which, experimentally, induce ulcerative colitis and melanosis coli, respectively, were chosen for examination, since these substances are visible under the microscope without any special treatment. DSS (MW 50,000) and senna were orally administered to guinea pigs. In tissue sections of the intestine, the presence of DSS was demonstrated by toluidine blue staining, while senna was visible under the light microscope as brown pigment. In the large intestine of guinea pigs, macrophages were most numerous in the cecum, decreasing in number towards the rectum. Metachromatic reaction due to DSS was first recognized in the epithelium of the cecum, and was subsequently incorporated by macrophages. The presence of DSS, either in the epithelium or in macrophages, was not recognized in the small intestine or the distal colon. Senna pigmentation was also limited to the cecum and proximal colon, in which pigmented macrophages aggregated in the lamina propria. The two different substances administered orally were taken up in the cecum, and partly also in the proximal colon; the substances passed through the epithelium and were incorporated by macrophages. This finding suggests the existence of a weak point in the intestinal barrier in this particular portion of the intestine. PMID- 8680539 TI - Extraintestinal manifestations of granulomatous enterocolitis induced in rabbits by long-term submucosal administration of muramyl dipeptide emulsified with Freund's incomplete adjuvant. AB - We examined whether extraintestinal manifestations of granulomatous enterocolitis in rabbits might be produced by the long-term administration of muramyl dipeptide which represents the basic fragment of the bacterial cell wall, emulsified with Freund's incomplete adjuvant. Muramyl dipeptide emulsion was injected submucosally at six sites in the rectum and colon, 10 cm proximal to the anus, each time with a flexible endoscope. Seven rabbits were injected nine times or more every month, and all were sacrificed 1 month after the last injection. The histological changes in the colon in the seven rabbits were mononuclear cell infiltration, epithelioid granulomas, granulomatous lesion, and denuded and regenerative epithelia, although the changes differed in degree. In five of the seven rabbits, histological examination of the liver showed pericholangitis and periductal fibrosis, findings analogous to sclerosing cholangitis in patients with inflammatory bowel disease. In four of the seven rabbits, fibrosis bridging mainly between portal and portal veins, and, in places, between portal and central veins, was seen. Two of the seven rabbits developed polyarthritis. The histological changes in our model suggest that continuous stimulation with bacterial cell wall fragments may be involved in the extraintestinal manifestations of chronic intestinal inflammation such as that seen in inflammatory bowel disease. PMID- 8680540 TI - Proliferative activity of mixed hyperplastic adenomatous polyp/serrated adenoma in the large intestine, measured by PCNA (proliferating cell nuclear antigen). AB - The proliferative activity of serrated adenomas of the large intestine was determined by examining proliferating cell nuclear antigen (PCNA). The PCNA labeling index, determined by visual inspection, and the PCNA area rate, determined with the newly developed image processor for analytical pathology (IPAP), of serrated adenoma were found to be similar to the values for tubular adenoma, and indicated the presence of high proliferative activity in the bottoms of crypts. Determination of the pattern of distribution of PCNA-positive cells indicated the presence of a proliferative zone in the lower region or bottom of the serrated adenoma. However, 5 of the 20 serrated adenomas exhibited an irregular on widely extended proliferative zone, and 2 were complicated by cancer. These findings indicated that serrated adenoma is also a highly proliferative tumor and that it may be complicated by cancer if atypia is increased and disturbance of the proliferative zone is present. PMID- 8680541 TI - Distribution of nitric oxide synthase-containing nerves in the aganglionic intestine of mutant rats: a histochemical study. AB - We examined the distribution of nerves containing nitric oxide synthase in the intestine of congenitally aganglionic rats, using a reduced nicotinamide adenine dinucleotide phosphate diaphorase histochemical method for whole-mount and cryostat specimens. A constricted intestinal segment extends from the terminal ileum to the anus in this mutant. No nerve elements with the activity were found in the affected terminal ileum, cecum and proximal colon. Although intrinsic ganglionic neurons were absent along the constricted intestine, nerve fibers with the activity were found in both the submucous and intermuscular layers distal to the proximal colon. These fibers increased in density towards the rectum, forming hypertrophic nerve bundles and unusual fiber networks. However, positive fibers were never seen within the circular and longitudinal musculature of the constricted lesion. Some of these hypertrophic nerve bundles were continuous with ectopic ganglia that were situated in the adventitial connective tissue around the lower rectum and in the submucosa near the anus. The hypertrophic nerve bundles seemed to have an extrinsic origin; some of them may have originated from ectopic ganglia. These results suggest that the defective distribution of nerves containing nitric oxide synthase may be involved in the pathogenesis of congenital colonic aganglionosis. PMID- 8680542 TI - Serotyping of hepatitis C virus in chronic type C hepatitis in Taiwan: correlation with genotypes. AB - To evaluate the usefulness of a new serologic assay to group hepatitis C virus (HCV), genotypes identified by this serotyping method were compared to those identified by a polymerase chain reaction (PCR) assay with type-specific primers in 71 Taiwanese patients with chronic type C hepatitis. The group-specific antibodies against different HCV genotypes were detected by using an enzyme linked immunosorbent assay (ELISA) based on group-specific recombinant peptides (C14-1 and C14-2) within the NS4 region. Among 71 patients positive for current second-generation HCV antibodies, HCV RNA was detected in 55 patients by PCR with primers from the 5' untranslating region, and in 52 by genotype-specific PCR. In 49 (89%) of 55 viremic patients, the results of serotyping by ELISA showed complete agreement with those determined by PCR genotyping, and none of the patients showed a group opposite to that of HCV genotype. The positive rate of group-specific antibodies (69/71;97%) was even better than that of the PCR (55/71;78%). We conclude that this new serotyping assay is highly sensitive and specific for the determination of HCV genotypes, and will be useful in future epidemiologic studies, as well for clinical application. PMID- 8680543 TI - Hepatic transport of serum bilirubin, bromsulfophthalein, and indocyanine green in patients with congenital non-hemolytic hyperbilirubinemia and patients with constitutional indocyanine green excretory defect. AB - We carried out a retrospective study of 71 patients with congenital non-hemolytic hyperbilirubinemia who had been treated at our institution over the 25 years from 1965 to 1990. Twenty patients had Gilbert's syndrome, 1 had Crigler-Najjar syndrome, 1 had new type unconjugated hyperbilirubinemia, 21 had Dubin-Johnson syndrome, and 28 had Rotor's syndrome. We also reviewed 20 patients with constitutional indocyanine green (ICG) excretory defect. The study focused on the hepatic transport of serum bilirubin, bromsulfophthalein (BSP), and ICG. In Dubin Johnson syndrome, a defect appeared in late-stage transport, while uptake and storage capacity were normal. In Rotor's syndrome, defects were found in the early stage, and storage capacity was reduced, while excretion into bile was slightly suppressed. A secondary rise in serum ICG was seen in 5 of the 10 patients with Dubin-Johnson syndrome. The transport defect in Gilbert's syndrome was unclear. It could not be considered to be homogeneous, but it may exist at multiple sites, from the conjugation with serum proteins to excretion into bile. Following phenobarbital administration, the ICG secondary rise in the 5 patients with Dubin-Johnson syndrome disappeared, and ICG was rapidly cleared from blood. However, in patients with Dubin-Johnson syndrome, BSP clearance in serum did not show any change before and after phenobarbital administration. ICG excretion in patients with constitutional ICG excretory defect was due only to the impairment o ICG transport, and the defect was suggested to be hepatic uptake. These results indicate that studies of the hepatic transport of bilirubin, BSP, and ICG are useful for determining the etiological factors involved in congenital hyperbilirubinemia and constitutional ICG excretory defect. PMID- 8680544 TI - Serum hyaluronate in patients with acute and fulminant hepatitis. AB - We evaluated serum hyaluronate (HA) levels in 17 patients with acute hepatitis and 9 with fulminant hepatitis (FH). Upon admission, patients with FH showed increased levels of serum HA and these levels showed significant correlation with biochemical parameters such as human hepatocyte growth factor, hepaplastin test, and prothrombin activity. In patients with AH, the levels of serum HA decreased during convalescence. Higher serum HA levels were observed in patients with type A acute hepatitis than in patients with non-A type. In patients with FH, serum HA levels were decreased in the survivors, while they were elevated in the non survivors. These findings suggest that serum HA levels may be a useful indicator for evaluating the prognosis of patients with acute and fulminant hepatitis. Further study is necessary to determine whether there is a causal relationship between elevated serum HA levels and the type of hepatitis virus. PMID- 8680545 TI - Serum type IV collagen in various liver diseases in comparison with serum 7S collagen, laminin, and type III procollagen peptide. AB - The clinical significance of the immunoreactive triple helical domain of type IV collagen in serum was evaluated in 73 healthy controls and 161 patients with various biopsy-proven liver diseases. Although serum levels of type III procollagen peptide were increased in all liver diseases, those of type IV collagen, 7S collagen, and laminin were principally increased in chronic liver diseases associated with hepatic fibrogenesis/fibrosis. In both non-alcoholic and alcoholic liver diseases, 7S collagen was increased in serum, while type IV collagen and laminin in serum were particularly increased in alcoholic liver diseases and in hepatocellular carcinoma, in which latter the sensitivity was greater for type IV collagen than for laminin. Gel filtration analysis in Sephacryl S-400 revealed type IV collagen in serum to be a single molecular form with a molecular weight that correspond to type IV collagen, whereas 7S collagen was recognized as several heterogeneous macromolecules. These findings indicate that serum type IV collagen is derived from the type IV protocollagen pool, and is a sensitive marker for the fibrogenetic process in hepatic basement membranes. PMID- 8680546 TI - Duration of anti-cholecystokinin (CCK) action on the rat exocrine pancreas of new CCK receptor antagonist FK480 administered orally. AB - We assessed the duration of the anti-cholecystokinin (CCK) action of FK480, a new non-peptide CCK-A receptor antagonist developed in Japan, in an in vivo study in rats, comparing it with CR 1505. Pancreatic exocrine secretion stimulated by intravenous infusion of CCK-8 (0.06 microgram/kg per h) was measured at intervals of 0-24 h after the oral administration of FK480 (1.5 mg/kg) and CR 1505 (30 mg/kg). FK480 significantly inhibited both CCK-stimulated pancreatic juice volume flow and amylase output 0, 4, 8, and 12 h after oral administration, whereas the inhibitory effect of CR 1505 had completely disappeared by 8 h after oral administration. It was concluded that orally administered FK480 has a prolonged anti-CCK action. PMID- 8680547 TI - Tryptophan modulates exocrine secretory function in rat pancreatic acini. AB - We investigated the effect of tryptophan (Trp) on exocrine secretory function, using isolated rat pancreatic acini. Trp inhibited cholecystokinin-octapeptide (CCK-8)-stimulated amylase secretion, causing a downward shift in the dose response curve. The inhibitory effect of Trp was dose-dependent and was observed only on the sustained secretion, there being no effect on the initial phase of amylase secretion. Trp (10mM) also inhibited amylase secretion in response to carbachol and bombesin, as well as fluoride, a potent activator of guanine nucleotide binding proteins. Since Ca2+ influx is necessary for sustained secretion, we examined the effect of Trp on Ca2+ influx and efflux. Trp increased the CCK-8-stimulated Ca2+ influx rate without affecting Ca2+ efflux, suggesting that Trp elevates intracellular Ca2+ levels. Increasing intracellular Ca2+ levels with A23187 resulted in the inhibition of CCK-8-stimulated amylase secretion. These results indicate that Trp inhibits CCK-stimulated sustained amylase secretion, in part by increasing Ca2+ influx into acinar cells. PMID- 8680548 TI - Endoscopic injection sclerotherapy for esophageal variceal hemorrhage in a patient with idiopathic myelofibrosis. AB - A 74-year-old female with idiopathic myelofibrosis (IMF) was admitted to our hospital because of massive hematemesis and melena. Immediate upper gastrointestinal endoscopy revealed an intermittent spurting hemorrhage from extensive esophageal varices. Endoscopic injection sclerotherapy (EIS) was carried out and the bleeding ceased. After five courses of EIS, all the esophageal varices were eradicated. About 15 months later, the patient died, due to a cerebral hemorrhage, without further variceal bleeding. A postmortem examination was carried out and the portal hypertension was considered to be due not only to extramedullary hematopoiesis in the sinusoids, but also to increased splenic blood flow. We are confident that EIS is an effective therapeutic procedure for patients with IMF showing esophageal variceal hemorrhage. EIS should be the preferred choice of treatment for esophageal varices in patients with IMF, since it is less invasive than splenectomy. PMID- 8680549 TI - Diffuse ganglioneuromatosis with plexiform neurofibromas limited to the gastrointestinal tract involving a large segment of small intestine. AB - A rare case of diffuse ganglioneuromatosis with plexiform neurofibromas limited to the gastrointestinal tract in a 20-year-old man is reported. The patient had no cafe-au-lait spots or any apparent tumorous lesions affecting other organs. A fan-shaped resection of the mesentery, including 200cm of the ileum, together with ileocecal resection was done, and the diagnosis was histologically confirmed. The relationship between this benign tumor and other neurogenic disorders is discussed, along with a review of the literature. Long-term follow up of this patient is required because of the possible development of von Recklinghausen's disease or multiple endocrine neoplasia type IIb. PMID- 8680550 TI - Primary diaphragmatic schwannoma with a typical target appearance: correlation of CT and MR imagings and histologic findings. AB - A rare case of benign diaphragmatic schwannoma in a 38-year-old female is reported. Precontrast computed tomography (CT) showed an encapsulated well defined round homogeneous tumor with central calcification, measuring approximately 5 cm in diameter, arising from the left diaphragm. Contrast enhanced CT and gadolinium-enhanced T1-weighted magnetic resonance (MR) imaging showed focal enhancement in the central portion of the tumor. The tumor showed a typical target appearance of increased peripheral signal intensity and decreased central signal intensity on unenhanced T2-weighted images. Pathological examination of resected specimens of the tumor showed two zonal histological components: a hypercellular portion of spindle cells with nuclear palisading (Antoni A tissue) and a hypocellular portion of cells with cystic degeneration, together with focal calcification and hemangeomatous vascular changes (Antoni B tissue). We consider the radiological characteristics of diaphragmatic schwannoma on CT and MR imagings to represent the geographic difference between the histologic zones of the tumor. PMID- 8680551 TI - Acute varicella hepatitis in human T-cell lymphotrophic virus types I and II infection. AB - Varicella (chicken pox) is a common viral infection in children and generally runs a benign course. However, in adults, and especially in immunocompromised subjects such as those on immunosuppressant therapy or with AIDS, varicella infection is particularly severe and is associated with the formation of hemorrhagic skin lesions and visceral involvement. These patients are at an increased risk of developing varicella hepatitis, which frequently results in fulminant hepatic failure and death. In the present report, we describe for the first time the course of disease and the histological appearance of varicella hepatitis in a patient infected with the human T cell lymphotropic viruses (HTLV) I and II; these viruses have many characteristics in common with the human immunodeficiency virus (HIV). Our patient had a relatively benign illness, suggesting that varicella infection in the presence of HTLVI and II may not run as severe a course as it does in patients with HIV infection. PMID- 8680552 TI - Large spleno-caval shunt not accompanied by cirrhosis or encephalopathy. AB - A 40-year-old man with a large spleno-caval shunt through the azygos vein is described. This was considered a rare case, because the patient had no accompanying advanced liver disease, or episodes of hepatic encephalopathy. During checks after abnormal liver function test results, a shunt vessel was detected incidentally by ultrasonography. Computed tomography, magnetic resonance imaging, and angiography demonstrated that it was a large shunt between the splenic vein and superior vena cava through the coronary and azygos veins. The patient was a hepatitis B virus carrier and was positive for anti-HBe, and had a history of heavy drinking. However, on laparoscopic examination, the liver was not cirrhotic and the biopsy revealed only mild chronic hepatitis without bridging fibrosis. There were no esophageal varices or hepatosplenomegaly. On hemodynamic evaluation, the wedge hepatic vein pressure was slightly elevated and hepatic blood flow was reduced to half the normal value. Despite the large portal systemic shunt, the patient had no history or signs of hepatic encephalopathy. The clinical features of this rare case are discussed. PMID- 8680553 TI - Primary biliary cirrhosis associated with idiopathic thrombocytopenic purpura. AB - A case of primary biliary cirrhosis (PBC) associated with idiopathic thrombocytopenic purpura (ITP) is reported. The patient is a 59-year-old man. When he was 49 years old, he was diagnosed with ITP and received steroid therapy that successfully increased platelet numbers. However, the steroid therapy failed to normalize the elevated gamma-glutamyl transpeptidase. Ten years after this episode, he suffered from general itching and malaise and exhibited a gradual increase of serum biliary enzyme levels. Immunologically, IgM was increased and anti-mitochondrial antibody was positive. Histological findings of liver needle biopsy showed chronic non-suppurative destructive cholangitis, confirming the diagnosis of PBC. To date, very few PBC cases associated with ITP have been reported. Our case is the second one in Japan. PBC and ITP in our patient seemed to develop simultaneously, but the effect of steroid therapy on the two conditions was different. This result suggests that the autoimmune process may have been different in PBC and ITP in the present patient. PMID- 8680554 TI - Second cancer during long-term survival after resection of biliary tract carcinoma. AB - Curative surgery for biliary tract malignancy has improved the prognosis of patients; however, during long-term follow up after extensive surgery, four of our patients (two with gallbladder carcinoma and two with bile duct carcinoma) developed a second primary cancer (one each in the duodenum, skin, descending colon, and lung). Regular examination of the upper gastrointestinal tract, colorectum, and lungs, and testing for tumor markers (carcinoembryonic antigen and CA19-9) were performed as follow-up studies. As a result, the second cancers were all found at a relatively early stage and all four patients are still alive 6-14 years after the initial operation. A review of the annual autopsy reports over the last 5 years in Japan showed that the incidence of second cancer was 14.8% in patients with gallbladder carcinoma and 13.5% in those with bile duct carcinoma. Furthermore, the rate of second gastric and colorectal carcinoma was significantly higher in patients with primary bile duct cancer than in those with primary gallbladder cancer. In conclusion, the incidence of a second cancer after resection of biliary tract malignancy is more than 10%, but this second cancer can be detected relatively easily and treated at an early stage during the course of regular long-term follow up for the first cancer. PMID- 8680555 TI - Bacteria closely resembling Helicobacter pylori detected immunohistologically and genetically in resected gallbladder mucosa. AB - A microorganism with close immunohistological and genetic resemblance to Helicobacter pylori was found in the resected gallbladder mucosa of a 41-year-old woman. The woman was admitted to hospital complaining of fever and right hypochondrial pain. Cholecystectomy was carried out under the diagnosis of gallstones and cholecystitis. A microorganism resembling H. pylori (stained with H&E, Giemsa, and Wartin-Starry) was detected incidentally on pathological examination. The microorganism was also positive for immunohistochemical staining. An amplification reaction was seen on genetic examination by the polymerase chain reaction (PCR) method (urease beta-genes). Our findings suggest that H. pylori may be present in tissues other than gastric mucosa. PMID- 8680556 TI - Induction of E-selectin expression on vascular endothelium by digestive system cancer cells. PMID- 8680557 TI - Ischemic colitis treated with short chain fatty acids: report of two cases. PMID- 8680558 TI - [Changes in the rat small intestine under conditions of disordered sympathetic and parasympathetic innervation]. AB - Comparative study of vagotomy and desympathization results, performed by similar methods and in similar terms demonstrated that disturbance of sympathetic and parasympathetic innervation of small intestine is accompanied with acquiring of morphofunctional alterations, similar in reaction of local immune apparatus and in disorders of digestive, absorptive and excretory functions. Specific properties of vagotomy and desympathization effects mainly concern dynamics of destructive, dystrophic (atrophic), inflammatory and vascular changes, extent of expression of secretory function disturbances and of intensity of intestinal epithelium proliferation. PMID- 8680559 TI - [The morphometric characteristics of the serotonin-producing cells of the intestines in the red-cheeked suslik during its spontaneous arousal]. AB - Duodenal serotonin-producing cells of the hibernating rodent (Citellus erythrogenys Brandt) were studied at its spontaneous arousal. Morphometric analysis of EC cells revealed alterations in endoplasmic reticulum and Golgi complex changes of numeral density and ratio of different types of ribosomes, retardation of granule content resorption at the spontaneous arousal of the animal. It is concluded that synthetic processes in EC-cells are rapidly activating, which probably restores the serotonin reserves, necessary for the normal course of hibernation. PMID- 8680560 TI - [The effect of sodium diethyldithiocarbamate on the development of organ anlagen in the mouse]. AB - The effect of noradrenaline-depressing natrium diethyldithiocarbamate (DDK) on embryonic tissue was studied in histological preparations. Degenerative changes in cells were found in tissues, exposed to the effect on 10th day of the development. Masses of detrite appear to remove into the cavities of the organs and into the amniotic cavity of the saccus vitellinus which is the characteristic peculiarity of the degenerative changes. After effect on 9-day-year-old embryos degenerative changes were expressed in a different extent-from light in some embryos up to the massive ones in the others. Degenerative changes in giant trophoblast cells, nervous tube, eye rudiment etc were observed in the survived embryos, Prevailing location of the processes was not demonstrated. DDK manifests strong cytotoxic effect. This phenomenon is probably connected with the copper containing enzymes depression, including those participating in noradrenaline synthesis. PMID- 8680561 TI - [The role of thymic peptides in regulating ovarian morphogenesis]. AB - Morphological analysis of the postnatal ovary development in mice treated with diverse T-activine doses during first 48 hours has shown that change of the thymic peptides content during neonatal period (single injection of the drug in doze 1,0-25,0 micrograms/l g body weight) results in negative ovariotropic effect, manifestations of which are doze-depending. In the case of administration of 5,0, 10,0, 25,0 micrograms/l kg of T-activine ovaritropic effect is limited with transitory disturbances of follicle genesis and therefore, with the delay of pubescence with the following (by the 10th month) reproductive function rehabilitation. After administration of T-activine 1 micrograms/l g in doze ovary dysgenesis with the regular reproductive disturbances was observed. Morphological and functional manifestations of the ovarian pathology in the case under discussion were similar with that of genetically non-thymus and neonatally thymus ectomized animals, which, probably, may be considered to be the proof of the suggestion that thymic peptides dysbalanse on the early ontogenesis stages plays an important role in pathogenesis of the ovarian dysfunction in non-thymus animals. PMID- 8680562 TI - [The colony-forming capacity of the precursor cells of granulomonocytopoesis in bone marrow aplasia]. AB - Retrospective analysis of 80 patients with aplastic anaemia (AA) was performed in order to examine clonogenic properties of granulomonocytopoiesis precursors and to specify the extent of disorder of hemopoiesis in AA. Sharp decrease of clonogenic properties of precursors, especially in severe form of AA was established to be present in 95% of patients, while only in 5% of patients initial indexes of the clonogenic ability were discovered to be normal. After treatment with ALG, prednisolum and androgen and also after splenectomy, clonogenic ability increased appropriately in 43%, 16.6% and 76.9% of patients, although the effect was not steady. The best results were obtained after allogenic transplantation of bone marrow (TBM), when the clonogenic properties normalization was observed against the background of remission 1-3 years lasted. Thus, low indexes of clonogenic properties of the precursors of granulomonocytopoiesis in AA, and positive effect of TBM may indicate the lesion of the precursor. At the same time normal initial indexes in some patients, and diverse effect of different methods of therapy make it possible to admit the probability of the lesion of stromal microenvironment cells. PMID- 8680563 TI - [The initiation of normal follicular growth and in imbalance of the stromal and follicular components of the ovary in the mouse]. AB - Cyclophosphamide administration to pregnant mice results in germ cells reduction in their progeny. Dynamics of follicular growth initiation was studied in these conditions. Results of the investigation confirmed the presence of dependence between the level of follicular growth and the size of the quiescent pool. This dependence was found to be non-linear-two threshold areas of values for the germ cell number with the changing dependence were discovered. The contribution of growing follicles tends to increase as the entire germinative population reduces in size. Increase of the share of growing follicles correlates with the increase of the ovarian stroma relative volume. This allows to suggest the possibility of participation of the latter in the regulation of follicular growth initiation. PMID- 8680564 TI - [The reaction of mammary tissue basophils to oxytocin]. AB - By means of staining with base brown and toluidin blue mast cells were revealed in paraffine sections of the lactating albino mouse mammalian gland. The character of mast cells distribution in the gland tissue was studied, the distribution density was assessed and the complex morphometric analysis of the mast cells population in normal and 20 min, after administration of oxytocin, stimulating the milk elimination from the alveoli and the following secrete forming in the gland cells was performed. Under initial conditions of the experiment at the inhibition of the secretory process the mast cells degranulation index made 30% while after the administration of oxytocin in increased up to 52%. Correlation between the mast cells groups with the diverse extent of granule content in cytoplasm was changing. Thus, oxytocine effect appears to be the factor, influencing the mast cells population functional activity. PMID- 8680565 TI - [The functional activity of the lymphoid cell population in the decidua in the late period of pregnancy]. AB - Cytotoxic and suppressor activity of decidual cells lymphoid population were analysed in 14 women with normal pregnancy and labour, in 8 women with light pre eclampsia and 11 women with early and premature rupture of amniotic sac. In late stages of pregnancy decidua is characterised by high suppressor activity of the lymphoid cell population. In early and premature rupture of amniotic sac suppressor activity of decidual cell lymphoid population was significantly decreased. PMID- 8680566 TI - [A method for determining the refractive index of the basic substance of dentin]. PMID- 8680567 TI - [The current problems of cardiac morphology]. PMID- 8680568 TI - [The potentials and means for raising the cognitive activity of students in departments of anatomy]. PMID- 8680569 TI - [The prenatal development of the normal kidney and in gestoses]. AB - Kidneys of the foetuses in cases of normal pregnancy (37) and in gestosis (31) were studied in following gestative terms; 24-28, 30-36 and 39-40 weeks. Dynamics of specific volume of structural elements of cortical substance (CS) and of external and internal zones of medullary substance (MS) of kidney was established in normal pregnancy and in gestosis. In normal pregnancy specific volume of the CS vessels and tubules increases in proportion with gestative term. Differences in dynamics of specific volume of vessels and tubules were found in external and internal zones of MS. Specific volume of nephrogenic blastema and tubules of cortex and medulla reduces in gestosis, placental insufficiency and hypoxia of the foetus. Specific volume of the CS stroma and vessels of both zones also increases in combined gestosis, while in the one without combination with other diseases specific volume of the cortical and medullary stroma increases. Correlative analysis revealed that the growth of these structures of cortex and medulla is dependent on the increase of the number of the connections in proportion with the gestative term. Number, direction and significance of correlative connections, reflecting adaptive possibilities of the foetal kidney structures in conditions of prolonged hypoxia were found to alter in gestosis. PMID- 8680570 TI - [The epithelial reaction of the gastrointestinal tract in dog salmon fry to exposure to an organophosphorus cholinesterase inhibitor]. AB - Reaction of the gastrointestinal tract epithelium of Siberian salmon kept in fresh and salt water exposed to the effect of irreversible cholinaestherase inhibitor was studied by means of transmissive and scanning electron microscopy. Excessive secretory processes of cells, tetanus of the digestive tract smooth muscles and elements of the epitheliocyte, swelling and vesiculation of cytoplasm and other osmotic effects were noted. Different changes were discovered after poisoning in fish, kept in fresh and salt water. PMID- 8680571 TI - [The ensemble organization of the sensorimotor cortex in ontogeny]. AB - Examination of sensomotor zone of the human brain cortex in human subjects (from newborns up to 20 year-olds) with yearly intervals revealed the presence of all neuroglia-vascular ensembles components without any relationship in composition by the moment of birth. Significant increase of the cortical layers and sublayers thickness, connected with growth of the volume of all type neurons and development of dendritic-axonic networks, vessels and glia were noted. Stair-like groups of neurons are present by the moment of birth, and so called racemose groups, the composition of which is diverse in different fields form by the age of three when vertical and horizontal contacts system grows more complicate and the astrocyte glia differentiates. The size of pyramidal neurons (Betz cells included), fusiform and stellate neurons increases by the age of six. By 10-12 years intraensemble, interensemble and transcortical contacts attain the high level of development. By 16-18 years ensemble organization of the cortex reaches the level, characteristic to adults in main parameters of its architectonics. PMID- 8680572 TI - [The ultrastructure of the capillaries and pericapillary area in the formations of the rat forebrain in hypokinesia]. AB - Capillaries and pericapillary tissue were studied in central and lateral nuclei of amygdala, cingulate cortex, hippocampal fields CA1 and CA3 and sensomotor, cortex in rats, exposed to hypokinesia 40, 90 and 120 days lasted. Changes, growing more numerous and variable in proportion with the time of hypokinesia were found. The most essential changes were hypertrophy of glial elements with either decreased or increased functional activity. Alteration of the endotheliocyte structure, pinocytosis, hypertrophy and increase of nuclear and cytoplasmic osmophilia, decrease of the folding were noted. Capillaries with significantly increased folding and narrow or containing unidentified substance lumen were encountered in 120-days hypokinesia. In limbic structures pericapillary glia is represented mostly with astrocytes, in neocortex-also with oligodendrocytes. PMID- 8680573 TI - [The structural-metabolic bases of the action of vibration on the thalamic structures of the brain]. AB - By means of histochemistry and light and electron microscopy one of the links of the postero-ventro-lateral thalamus (PVLT) exposed to the vibration of low frequency (VLF) (95 dB, 8 Hz) was studied. Diffuse mild alterations of PVLT of dystrophic or compensatory nature resembling that in hypoxia were discovered. Disturbances of oxidative metabolism (activation of succinic acid oxidase link of Krebs cycle, use of NADPH potentials and pentose cycle energy in neurons energetics) were alike with that in hypoxia. Shortening of active zone, astrocyte muff presence, overloading with vesicles were found in synapses. Interneuronal contacts disturbance combined with hypoxic alterations appears to be an important mechanism, resulting in negative consequences of the vibration effect. PMID- 8680574 TI - [The origins of the formation of the initial portion of the vertebral nerve in the cat]. AB - Retrograde transport of horse radish peroxidase revealed the sources of forming of the initial part of the vertebral nerve in cat. The enzyme was applied on the central region of the nerve near its outlet in ganglion stellatum. Most nerve fibers the vertebral nerve contains are the processes of neurons in ganglion stellatum. Bodies of the labeled neurons in the ganglion are located in the area, attached to the site of the vertebral nerve outlet. It also contains certain number of the afferent fibers of the II-VII thoracic segments spinal ganglia. Axons of motor neurons, the bodies of which are located in ventral cornua of the spinal cord II thoracic segments may also be present. Thus, the cat vertebral nerve is mixed in the site of its forming. PMID- 8680575 TI - [Osteogenesis during the correction of burns with alpha-tocopherol]. AB - Macro- and microscopic transformations were studied in burned animals skeleton after treatment with alpha-tocopherolum. The antioxidant was found to optimize osteogenesis, disturbed in burn lesion. PMID- 8680576 TI - [Ultrastructural changes in the skeletal muscles during local endurance training (a morphometric study)]. AB - Biopsies of m. triceps surae were studied in physically active students volunteers. Flexion of the foot sole 40 minutes in duration with 30% maximum voluntary strength was performed during 8 weeks 3-4 times a week. The frequency of the moves made 60 times per minute. In the course of morphometrical study greater attention was paid on mitochondrial parameters. Mitochondrial volume density did not change, while their number as well as the volume density of lipid inclusions tend to increase. Mitochondrial number, area and volume density of inclusions in the central zone of m. triceps surae were compared (before training: number per 100 microns2--2+3; area--0,13 +/- 0,010 microns2, volume density--2.7 +/- 0.3%, after training: number--48 +/- 4, area--0,110 +/- 0,01 microns2, volume density--2,7 +/- 0,3%) with the data available in literature on another muscles of elite sportsmen. It was concluded that high mitochondrial volume density in muscles of endurance trained sportsmen may result either from mitochondrial hypertrophy or increase of their number or from either of these factors, which is likely to be the concrete reflection of specificity of the sport efficiency. PMID- 8680577 TI - [The development of the thymus gland in rat embryogenesis with progesterone administration]. AB - Thymus structure was studied in 16 and 20-days-old embryos after everyday administration of 0,3 microgram (treatment doze) and 3,0 micrograms/100 g body weight of progesterone. It was established by morphologic methods that on 16th day blast forms amount in experimental animals is significantly lower than that in control animals. Amount of the hormone, 10 times exceeding the previous ones was administered in the same terms and caused reduction of the mitotic activity. The data on the cell by that time were absent. Progesterone administration during placenta forming does not change neither does thymus location nor its structure in 20-days-old foetuses. Treatment doze causes increase of the share of the section area occupied with the cortical matter. 10-times exceeding doze results in more significant decrease of the lymphoid cells number than those caused by treatment doze. Progesterone dissolvent (apricot oil) does not cause significant changes in thymus structure indexes studied. Thus, changes in the thymus structure observed result from progesterone effect on the thymus rudiment during placenta forming. PMID- 8680579 TI - [A topographic anatomical basis to approaches for instrumental interventions in diseases of the organs of the retroperitoneal space]. AB - Retroperitoneoscope was introduced through the 11 and 10 intercostal space by linea axillaris media and anterior Differences of the accesses between each other and between those in lumbocostal angle are statistically significant. The access to 11 intercostal space was proved to be the most convenient one for the examination of the entire kidney surface, while the one to 10 intercostal space for the endoscopy of adrenals and caudal region of the pancreas. The caput of the pancreas may be examined both through 11 intercostal space and lumbocostal angle. Clinical observations of 129 patients, operated by means of retroperitoneoscope through 11 intercostal space confirmed the effectivity of the method. Positive effects of retroperitoneoscopy_-minimal traumatization of tissues, normal postoperative period and good cosmetic effect make it suitable for wide introduction into the surgical practice. PMID- 8680578 TI - [The compensatory-adaptive reactions of the thyroid and adrenal adrenergic structures in the postnatal ontogeny of sympathectomized rats]. AB - The study was performed in albino rats treated during first two postnatal weeks with guanetidin isotonic solution injected subcutaneously in dose 20 mg/kg body weight to obtain desympathization. Control animals received similar volume of the solution during equal terms. Thyroid and adrenal glands were studied in 1- and 6 month-old rats both by light and electron microscopes. Serotonin and catecholamines were revealed by fluorescent-histochemical method. In experimental 1-month-old animals morphological indexes indicate the thyroid gland hyperfunction. In these animals serotonin and catecholamines content is lower in parafollicular endocrinocytes, mast cells and in adrenergic fibres, the density of which is significantly lower than that in control animals. The adrenal gland weight in experimental animals increases due to the medulla. Serotonin and catecholamine content is essentially higher. Thyroid gland in 6-month-old experimental rats is hyperfunctioning. Adrenal fibres density in its stroma is close to control indexes. Catecholamines and serotonin adrenal glands medulla grows with age and remains higher than the appropriate control level, which indicates active participation of adrenal glands in adaptive reactions is desympathized animals. Serotonin plays an important role in local regulation of thyroid glands. Parafollicular endocrinocytes perform the function of local biogenic amines-producers, while mast cells regulate the serotonin content. PMID- 8680581 TI - Proceedings of the 19th International Symposium on Column Liquid Chromatography. Innsbruck, Austria, 28 May-2 June 1995. Part II. PMID- 8680580 TI - [The quantitative characteristics of the fibroblastic series of cells in the tunica submucosa of the human bronchi]. AB - Quantity of cells of fibroblastic cells in the wall of human bronchi was studied in age aspect. The quantity of these cells in tunica submucosa of the bronchi belongs to different generations, in juvenile age approaching the level of the adults. In senile age numeral density of cells is less than that in infancy. Changes of cell numbers in all the age groups studied are more expressed in large bronchi. Numerical density of the cells of fibroblastic series in tunica submucosa of bronchial walls correlates with their diameter. In sites of bronchi branching into further generations numeral density of cells of fibroblastic series increases, which is, probably, connected with mechanical impact of the air flow on bronchial walls in these regions. PMID- 8680582 TI - Automated determination of polyamines by high-performance liquid chromatography with simple sample preparation. AB - Recently, a new fully endcapped reversed-phase packing material, Inertsil, was introduced, especially suitable for the determination of basic compounds. We used this packing material to separate ophthaldialdehyde (OPA) derivatives of amino acid derivatives completely from the OPA derivatives of spermine (SPM), spermidine (SPD), putrescine (PUT) and cadaverine (CAD). The obtained separation made the commonly used off-line extraction procedure redundant and thus an on line sample clean-up was introduced. This enabled automation of the procedure resulting in a better reproducibility and a more efficient use of equipment. Furthermore, no studies are required to determine the extraction recovery. The present method has a cycle time of 30 min. A linear response for each polyamine was found up to 250 pmol, with an R2 ranging from 0.9981 (SPM) to 0.9998 (CAD). The limit of detection, calculated at a signal-to-noise ratio of 3, was 0.1 pmol, corresponding to a plasma concentration of 0.1 mumol/l. The coefficient of variation (C.V.) for the peak area was below 3% and for retention times below 0.5% (n = 15). In order to evaluate the applicability of the method, three different types of sample were chromatographed, e.g. urine (obtained from healthy human volunteers), pig plasma and sulfosalicylic acid homogenates of pig intestine biopsies. Tissue homogenates and urine-specimen could easily be quantitated, while plasma concentrations were just above the limit of detection, resulting in a plasma C.V. ranging from 4.8% (SPM) to 13.6% (SPD) and a tissue C.V. ranging from 2.1% (SPM) to 8.5% (CAD), The urinary C.V.s were not determined. In conclusion, the present method provides an easy way to measure polyamine concentrations for most applications. PMID- 8680583 TI - In vivo microdialysis determination of collagen-induced serotonin release in rat blood. AB - We developed a sensitive microbore HPLC method coupled with an on-line microdialysis system to simultaneously measure endogenous 5-hydroxytryptamine (serotonin; 5-HT) and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the rat blood in vivo. A dialysis tube was placed in the right jugular vein. The validity of the procedure is demonstrated because analysis of the aggregating agents, collagen (1 mg/kg) plus epinephrine (0.3 mg/kg) after intravenous injection, showed that they induced an increase in 5-HT and 5-HIAA levels in the jugular vein of the rat. PMID- 8680584 TI - Determination of alpha-methyldopa in human plasma by validated high-performance liquid chromatography with fluorescence detection. AB - A sensitive reversed-phase gradient elution high-performance liquid chromatographic method with fluorescence detection has been developed for the determination of alpha-methyldopa (AMD) in human plasma. Separation of the investigated compound and the 3,4-dihydroxyphenylalanine (DOPA) internal standard was achieved on a Nucleosil 7 C18 column with a 5 mM heptanesulphonic acid sodium salt containing 0.05 M potassium dihydrogenphosphate (pH 3.2)-acetonitrile mobile phase. The composition of the mobile phase was changed according to a linear gradient time program. Detection was performed at 270 nm fluorimetric excitation and 320 nm emission. The compounds were isolated from plasma by Bond-Elut C18 solid-phase extraction. The limit of quantitation was found to be 10 ng/ml plasma. The assay was validated with respect to accuracy, precision and system suitability. All validated parameters were found to be within the 20% required limits. On the basis of the sensitivity, linearity and validation parameters the developed analytical method was found to be suitable for application in a bioequivalency study. PMID- 8680585 TI - High-performance liquid chromatographic profiling of indolylacryloylglycine and its possible precursors in body fluids. AB - Indolylacryloylglycine (IAcrGly) is one of the physiological components of urine, although its source and its role in the human organism have not yet been unambiguously established. Changes in the IAcrGly excretion level have been found under some physiological (age dependence, seasonal variations) and pathological (photodermatoses, muscle dystrophy, liver cirrhosis) conditions. The proposed method for IAcrGly, indolylacrylic acid and its possible precursors, namely indolyllactic and indolylpropionic acids, involves deproteinization and extraction of urine on a Sep Pak C18 cartridge. HPLC analysis was carried out using a DataApex liquid chromatograph, equipped with an LCD 2082 UV detector, signals being acquired with a CSW workstation. The chromatographic column was Spherisorb ODS, 5 microns (125 x 4 mm I.D.), the mobile phase for isocratic elution was ethanol-1% acetic acid (27:73) and the flow-rate was 0.7 ml/min. The lower response limit is about 1 mumol/l for all metabolites at 280 nm. PMID- 8680586 TI - Simultaneous determination of uric acid and creatinine in biological fluids by column-switching liquid chromatography with ultraviolet detection. AB - A column-switching liquid chromatographic method for the simultaneous determination of uric acid and creatinine in human serum and urine was developed. Creatinine and uric acid were separated by size-exclusion chromatography on a hydrophilic gel column (C1) and creatinine eluted from C1 was separated from proteins by filtration through a longer hydrophilic gel column (C2). The creatinine fraction eluted from C2 was transferred to a weakly acidic cation exchange column (C3) and then to a strongly acidic cation-exchange column (C4). Uric acid eluted from C1 after creatinine was transferred to an anion-exchange column (C5) and then to a hydrophilic gel column (C6). The mobile phase was a mixed buffer of pH 5.1 (propionic acid-succinic acid-NaOH, 60:15:60 mmol/l in water). Diluted serum and urine could be injected onto C1, and C1 was backflushed after the transfer of uric acid from C1 to C5. Creatinine and uric acid in the eluate were determined by measuring their ultraviolet absorption at 234 and 290 nm, respectively. The recovery of uric acid and creatinine added to diluted serum (20-fold dilution, concentration 20 and 5 mumol/l, respectively) was 98.9 +/- 0.56% and 100.9 +/- 1.29%, respectively. The recovery of uric acid and creatinine added to diluted urine (100-fold dilution, concentration 50 and 100 mumol/l, respectively) was 99.4 +/- 0.72% and 98.7 +/- 1.45%, respectively (mean +/- R.S.D., n = 6). PMID- 8680587 TI - Preliminary experiments for the analysis of tetrahydrotetrols of benz[a]anthracene and benzo[a]pyrene derived from their hemoglobin adducts using a coupled-column high-performance liquid chromatographic system. AB - Improved technologies for the detection of polycyclic aromatic hydrocarbon adducts are required for human biomonitoring. Therefore, a coupled-column high performance liquid chromatographic method, with system-integrated sample processing, has been developed and its applicability for determination of tetrahydrotetrols of polycyclic aromatic hydrocarbons in acid hydrolysates of human hemoglobin has been investigated. A novel column-switching technique applying "thermotransfer' is used to separate tetrahydrotetrols of benzo[a]pyrene and benz[a]anthracene more efficiently. Derivatives of polycyclic aromatic hydrocarbons from blood hydrolysates are concentrated on a pre-column and then transferred to the analytical column by applying an electrical current to heat the solvent eluting the pre-column. This method allows for rapid and quantitative transfer of the analytes from the pre-column to the analytical column, after HPLC integrated sample processing. PMID- 8680588 TI - Determination of gentiopicroside, mangiferin, palmatine, berberine, baicalin, wogonin and glycyrrhizin in the traditional Chinese medicinal preparation sann joong-kuey-jian-tang by high-performance liquid chromatography. AB - High-performance liquid chromatography was employed to determine the contents of several marker substances such as gentiopicroside, mangiferin, palmatine, berberine, baicalin, wogonin and glycyrrhizin in Sann-Joong-Kuey-Jian-Tang. The separation was performed on a Cosmosil 5C18-AR column by gradient elution with 0.03% (v/v) phosphoric acid-acetonitrile (0 min, 90:10; 10 min, 87:13; 17-27 min, 77:23; 40 min, 62:38; 50 min, 55:45) as the mobile phase at a flow-rate of 1.0 ml/min, with detection at 254 nm. n-Propylparaben was used as the internal standard and seven regression equations revealed linear relationships between the peak-area ratios (marker substances/internal standard) and concentrations. The repeatability and reproducibility (relative standard deviation) of the method were in the ranges 0.02-1.78% and 1.44-4.95%, respectively. PMID- 8680589 TI - Determination of heterocyclic amines by pneumatically assisted electrospray liquid chromatography-mass spectrometry. AB - Electrospray ionization mass spectrometry was applied to the study of the amines IQ, Trp-P-1, Trp-P-2, PhIP and A alpha C and the co-mutagens harman and norharman. The results obtained on a triple quadrupole mass spectrometer equipped with a pneumatically assisted electrospray source are reported. The chromatographic conditions were optimized with a reversed-phase column (1 mm I.D.) using acetonitrile-5 mM ammonium acetate (pH 6.7) (50:50) as the mobile phase at a flow-rate of 50 microliters min-1. Different parameters influencing the mass spectra were investigated. For these compounds [M + H]+ in the positive ion mode and also some fragments produced through collisionally activated decomposition in the interface were observed. Detection limits of 5.4-44 pg were obtained for standard solutions of these amines. Analysis of a meat extract was performed by HPLC-MS using single-ion monitoring after a solid-phase extraction clean-up. PMID- 8680590 TI - Capillary column high-performance liquid chromatographic-electrospray ionization triple-stage quadrupole mass spectrometric analysis of proteins separated by two dimensional polyacrylamide gel electrophoresis. Application to cerebellar protein mapping. AB - A method is presented for the structural characterization of proteins separated by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). The method includes separation of a protein mixture by 2D-PAGE, recovery of proteins from the gel spots revealed by copper staining and analysis of the proteins by triple stage quadrupole mass spectrometry using an electrospray ionization interface (ESI-TSQMS). Prior to the mass spectrometric analysis, the extracted proteins were passed through a small reversed-phase column (10 x 4.0 mm I.D.) to remove salts and gel-derived contaminants and then introduced into the mass spectrometer through a reversed-phase capillary column with 0.25 mm I.D. Application of the method to the analysis of rat cerebellar proteins suggests that the molecular mass could be accurately determined with sub-picomole amounts of protein samples derived from one or two 2D gels. The method was also useful for peptide mapping and determination of amino acid sequences of proteins micro-prepared from the 2D gel. Because 2D-PAGE has an excellent resolving power in protein separation and because capillary LC-ESI-TSQMS provides structural information with very small amounts of samples, the combined system of 2D-PAGE and capillary LC-ESI-TSQMS described here should allow wide applications to molecular studies of genes and proteins, such as identifications of protein spots on 2D gels, confirmation of gene/protein sequences and analysis of post-translational modification of proteins present naturally in tissue/cell extracts or expressed by recombinant DNA techniques. PMID- 8680591 TI - Quantitative determination of heparinoid mimetics in human and rat plasma by micellar electrokinetic chromatography. AB - The investigated new class of heparinoid mimetics are spaced persulfated carbohydrates designed to increase the success rate of angioplasty and bypass surgery by preventing restenosis without increasing the risk of bleeding. Due to the presence of sulfate groups, these compounds are highly charged and, for preclinical kinetic investigations only small sample volumes of rat plasma were available. Therefore, capillary electrophoresis (CE) was applied. A bioanalytical method based on micellar elektrokinetic chromatography (MEKC) with UV-detection was developed for the selective quantitation of heparinoid mimetics (e.g., Ro 48 0843, Ro 48-3151, Ro 47-6199 and Ro 48-8722) in plasma. Using this method, only small volumes of plasma were required, which could be introduced directly into the separation capillary after 1:1 dilution with 100 mM aqueous sodium dodecyl sulfate (SDS). For increased sample throughput, an additional ultrafiltration step was performed after SDS-dilution of the plasma sample, improving both reproducibility and robustness of the method considerably. The sensitivity of the new method (3 micrograms/ml) was sufficient to follow plasma levels in pharmacokinetic studies. The practicability of this easy and rapid assay was demonstrated by the analysis of more than 350 plasma samples from pharmacokinetic studies performed in rats. PMID- 8680592 TI - Application of extraction disks in dissolution tests of clenbuterol and levothyroxine tablets by capillary electrophoresis. AB - Sample preparation procedures using octadecyl (C18) extraction disks were developed to obtain accurate and reproducible results for determinations of clenbuterol(20 micrograms per dose) and levothyroxine (100 micrograms per dose) in dissolution media of solid oral dosage forms. Preconcentration of samples allowed final concentrations of 1.1 micrograms/ml of clenbuterol and 4.0 micrograms/ml of levothyroxine to be reached prior to CE analysis. The results obtained by CE were in good agreement with those of HPLC. The precision of the migration time, peak area, peak height and accuracy were determined in both intra day (n = 6) and inter-day (n = 18) assays. Linearity was demonstrated over the ranges 0.5-80.0 micrograms/ml of clenbuterol and 1.0-30.0 micrograms/ml of levothyroxine. The mean recoveries were higher than 94.0%, ranging from 50 to 125% levels with respect to dose potencies. The proposed methodology may be generally applied to determine drugs at ng/ml concentrations. PMID- 8680593 TI - Comparison of capillary electrophoretic and liquid chromatographic determination of hypoxanthine and xanthine for the diagnosis of xanthinuria. AB - A capillary electrophoretic (CE) method for the determination of hypoxanthine and xanthine in urine was developed to diagnose xanthinuria. The linearity was excellent up to 200 mumol l-1 for the two compounds and the limit of quantitation was 2 mumol l-1. A comparison o the results obtained using CE was made with those obtained by the high-performance liquid chromatographic (HPLC) technique described previously. With regard to specificity, sensitivity and reproducibility, the results are similar but CE is more rapid than HPLC. PMID- 8680594 TI - Rational experimental design for bioanalytical methods validation. Illustration using an assay method for total captopril in plasma. AB - Generally, bioanalytical chromographic methods are validated according to a predefined programme and distinguish a pre-validation phase, a main validation phase and a follow-up validation phase. In this paper, a rational, total performance evaluation programme for chromatographic methods is presented. The design was developed in particular for the pre-validation and main validation phases. The entire experimental design can be performed within six analytical runs. The first run (pre-validation phase) is used to assess the validity of the expected concentration-response relationship (lack of fit, goodness of fit), to assess specificity of the method and to assess the stability of processed samples in the autosampler for 30 h (benchtop stability). The latter experiment is performed to justify overnight analyses. Following approval of the method after the pre-validation phase, the next five runs (main validation phase) are performed to evaluate method precision and accuracy, recovery, freezing and thawing stability and over-curve control/dilution. The design is nested, i.e., many experimental results are used for the evaluation of several performance characteristics. Analysis of variance (ANOVA) is used for the evaluation of lack of fit and goodness of fit, precision and accuracy, freezing and thawing stability and over-curve control/dilution. Regression analysis is used to evaluate benchtop stability. For over-curve control/dilution, additional to ANOVA, also a paired comparison is applied. As a consequence, the recommended design combines the performance of as few independent validation experiments as possible with modern statistical methods, resulting in optimum use of information. A demonstration of the entire validation programme is given for an HPLC method for the determination of total captopril in human plasma. PMID- 8680595 TI - Resveratrol content of some wines obtained from dried Valpolicella grapes: Recioto and Amarone. AB - Resveratrol (trans-3,5,4'-trihydroxystilbene), a phenolic substance present in both grape skin and wines, is a phytoalexin involved in grey mould resistance. A new interest has surfaced in recent years related to the antioxidative actions of resveratrol, which in vivo could be related to the prevention of cardiovascular diseases linked to lipid metabolism, particularly HDL production, while the antifungal activity may be of interest in wine production technology. These aspects have led to the publication of a number of papers reporting data on the resveratrol content of several kind of wine: for Italian wines, it ranges between 0.5 and 10 ppm, depending on cultivar, area of cultivation, climate and wine making technology. In this work, resveratrol was quantified in samples of two unusual Italian wines, Recioto (sweet) and Amarone (dry), produced with the same cultivar mixture in the same area (Valpolicella, Verona, Italy) and with the same grape conditioning technique. After resveratrol extraction, reversed-phase HPLC analysis was carried out and several elution conditions were tested. The resveratrol content of Recioto and Amarone wines was lower than the values reported in the literature for other wines, ranging between 0.05 and 0.8 ppm. PMID- 8680596 TI - Rapid reversed-phase liquid chromatographic determination of patulin in apple juice. AB - A rapid, simple and economical method using a limited amount of organic solvent is described for the determination of patulin in apple juice. The sample was extracted with ethyl acetate and the extract was cleaned up by extraction with sodium carbonate solution. Patulin was then determined by reversed-phase liquid chromatography using a MicroPack C18 column and a variable-wavelength UV-Vis detector set at 276 nm. Patulin and 5-hydroxymethylfurfural were completely resolved by using water-acetonitrile (99:1, v/v) as the mobile phase at a flow rate of 1.0 ml/min. The detection limit was < 5 micrograms/l and the recovery was 98%. PMID- 8680597 TI - Determination of serotonin released from coffee wax by liquid chromatography. AB - A simple hydrolysis and extraction method was developed for the release of serotonin (5-hydroxytryptamine) from a coffee wax sample obtained from decaffeination of coffee beans. The recoverable amount of serotonin was determined by reversed-phase high-performance liquid chromatography with gradient elution and UV detection, using the standard addition method. Different type of basic deactivated chromatographic columns were used for the separation. PMID- 8680598 TI - Simultaneous high-performance liquid chromatographic determination of visoltricin, acuminatopyrone and chlamydosporols in Fusarium cultures on maize. AB - Visoltricin (VIS), acuminatopyrone (ACP), clamydosporol (CL), isochlamydosporol (ICL) and chlamydospordiol (DIOL), recently characterized Fusarium metabolites, were separated on a polymeric RP-18 column eluted with acetonitrile-0.01% ammonia solution (35:65) at 1 ml/min and detected with a diode-array UV detector. The presence of ammonia in the mobile phase improved the shape of the CL and VIS peaks. The use of a polymeric column was required owing to the basic pH of the mobile phase. Maize cultures of several strains of F.tricinctum and F. chlamydosporum were analysed with this procedure after extraction with aqueous methanol, partitioning with methylene chloride and clean-up with a C18 minicolumn. VIS was produced only by F. tricinctum, whereas ACP and chlamydosporols were produced by both Fusarium species. PMID- 8680599 TI - Analysis of bitter essential oils from orange and grapefruit by high-performance liquid chromatography with microbore columns. AB - The analysis of bitter orange and grapefruit essential oils (non-volatile fraction) was carried out by HPLC in normal- and reversed-phase mode with UV detection. These oils were compared with the sweet orange and mandarin essential oils, analyzed previously. For the identification of chromatographic peaks, fractionation by RP-HPLC was carried out. The purified fractions were analyzed by GC-MS and LC-MS. Some new compounds were found, together with many others already identified in different citrus essential oils. PMID- 8680600 TI - Subcellular localization of docosahexaenoic acid and arachidonic acid omega hydroxylation activity in the brain, liver and colonic adenocarcinoma. AB - A homogenate of rat brain, rat liver or human colonic well differentiated adenocarcinoma was prepared in 250 mM sucrose isoosmolaric buffer (pH 7.6) and fractionated by differential centrifugation at 10(3), 10(4) and 10(5) g. Each precipitate or supernatant was incubated with NADPH and docosahexaenoic acid or arachidonic acid as a substrate for 30 min at 37 degrees c under aerobic conditions. omega-Hydroxydocosahexaenoic acid or omega-hydroxyeicosatetraenoic acid from an incubation mixture was detected by reversed-phase high-performance liquid chromatography-thermospray mass spectrometry with selected-ion monitoring. omega-Hydroxy polyunsaturated fatty acids were characterized by high intensity of the molecular ion (MH+) although common hydroxy polyunsaturated fatty acids were characterized by high intensity of the MH+ -H2O ion. For the rat brain, omega hydroxylation activity (the amount of omega-hydroxy product produced in 30 min) was concentrated to a 10(3) g precipitate although the specific activity (the activity per 1 mg of protein) in the 10(3) g precipitate did not indicate superiority over other fractions. However, the specific activity of the rat brain increased on addition of a 10(4) or 10(5) g precipitate. For the rat liver, although omega-hydroxylation activity was concentrated to a 10(3) g precipitate, the specific activity was concentrated to a 10(5) g precipitate and the subcellular localization differed from that of rat brain. In the human colonic well differentiated adenocarcinoma, although omega-hydroxylation activity was relatively high in the 10(3) g supernatant, the specific activity was relatively high in the 10(3) g precipitates. These results suggest that there is a difference regarding subcellular localization of the omega-hydroxylation activity depending on the species of the organs. PMID- 8680602 TI - Scandinavian Society for the Study of Diabetes 31st annual meeting. Tromso, Norway, 26-28 April 1996. Abstracts. PMID- 8680603 TI - Machine-related occupational injuries in farm residents. AB - Farm machinery is an important contributor to the high rates of occupational injury in agriculture. As part of a population-based case-control study, we studied risk factors for machine-related farm injuries. Case patients were farm residents residing in a geographically defined area of central Wisconsin who experienced a farm injury associated with a tractor, farm implement, or other machine which required medical or chiropractic care from May 1990 through April 1992. Controls were selected from an ad hoc census of farm residents in the same area. Telephone interviews regarding demographic characteristics, safety behaviors, and farming practices were completed for 97.8% of 90 case patients and for 82.8% of 221 control subjects. Personal characteristics significantly associated with an increased risk of machine-related injury included the number of hours worked per week and working primarily as a farmer. Dairy farms, farms with nonresident workers, and large farms were associated with an increased risk of injury while farms with registered cows and farms where cows were fed in the barn even in summer experienced fewer injuries. Based on a logistic regression model, the independent risk factors for machine-related farm injury included hours worked per week (2% increased risk/nonresident workers on farm (odds ratio) (OR) = 2.32; 95% confidence interval (CI): 1.07 to 5.06), cows fed in barn in summer (OR = 0.28; 95% CI: 0.12 to 0.64), and registered cows on farm (OR = 0.36; 95% CI: 0.17 to 0.79). Farm safety practices did not appreciably influence the risk of machine-related farm injury. PMID- 8680601 TI - Simple and sensitive multi-sugar-probe gut permeability test by high-performance liquid chromatography with fluorescence labelling. AB - Enteral intake of a mixture of inert, non-metabolic monosaccharide and disaccharide probes, followed by measurement of their urinary probe ratio, is a well known method to investigate gut permeability. However, most applications lack sensitivity, thus a large amount of especially the disaccharide lactulose has to be ingested. This may cause diarrhoea, which influences the outcome of the test. Recently, a new fluorescent label 9-fluorenylethyl chloroformate hydrazine (FMOC-hydrazine) was introduced, which reacts with reducing sugars to form stable and highly fluorescent single peak derivatives in organic medium. We applied this reagent to develop a sensitive measurement of reducing sugar probes in aqueous samples (e.g., urine). The presented method has a linear response for each sugar derivative between 1 and 1250 pmol with an R2 ranging from 0.9997 for lactulose to 0.9999 for rhamnose. The limit of detection, calculated as a signal-to-noise ratio of three, was 0.05 pmol for lactulose and 0.01 pmol for rhamnose, xylose and 3-O-methyl-D-glucose, corresponding to urine concentrations of 0.11 micromol/l for lactulose and 0.02 micromol/l for rhamnose, xylose and 3-O-methyl D-glucose. Compared to other tests, the limit of detection is very low. This enabled a reduction in the enteral intake of the disaccharide lactulose from 6-10 g to 1.5 g, thereby minimizing the chance of introducing diarrhoea. The coefficient of variation was below 3% both in standards and urine samples. After spiking the urine with the saccharides a recovery of 102% for lactulose, 101% for rhamnose, xylose and 3-O-methyl-D-glucose was found. In order to evaluate the presented method we compared the lactulose rhamnose ratio measured in urine of healthy human volunteers and kept the ingested dose in agreement with literature values. Furthermore, the ratio was measured after 3, 6 and 9 h to establish the minimal response time required to measure correct ratios. We found that even after 3 h the ratio was stable at a value of 0.0133 which is comparable to literature values (0.008-0.052). PMID- 8680604 TI - Attributable risks for bladder cancer in northern Italy. AB - Attributable risks (ARs) for bladder cancer were computed in relationship to cigarette smoking, coffee consumption, low intake of vegetables, history of cystitis, and occupation using data from a case-control study conducted in northern Italy between 1985 and 1993. Cases were 431 patients with histologically confirmed bladder cancer, and controls were 491 patients admitted to the same network of hospitals for acute, nonneoplastic, and non-urinary-tract diseases. Overall, the AR estimates were 49% for cigarette smoking, 23% for coffee consumption, 16% for low intake of vegetables, 12% for history of cystitis, and 4% for occupation. These five factors together explained more than 70% of bladder cancer cases in this population. The AR for cigarette smoking was significantly higher among men (56%) than women (17%), whereas coffee consumption, low vegetable intake, and cystitis were more important (but not significantly so) among women. These results suggest that more than 2500 of the 5400 deaths due to bladder cancer in Italy in 1990 could have been prevented by the elimination of cigarette smoking. With some appropriate dietary modification and intervention to prevent urinary tract infections and occupational exposures, this figure could approach 4000 avoidable deaths. Thus, bladder cancer could become a rare cause of death in this population. PMID- 8680605 TI - Mortality from coronary heart disease and stroke for six ethnic groups in California, 1985 to 1990. AB - Coronary heart disease and stroke death rates were compared for six ethnic groups (non-Hispanic white, Hispanic, African-American, Chinese, Japanese, and Asian Indian) by sex and age (25 to 44, 45 to 64, 65 to 84, and 25 to 84 years old) using California census and 1985 to 1990 death data. African-American men and women in all age groups had the highest rates of death from coronary heart disease, stroke, and all causes (except for coronary heart disease in the oldest men). Hispanics, Chinese, and Japanese in all age-sex groups had comparatively low death rates for coronary heart disease and stroke, although stroke was proportionally an important cause of death for Chinese and Japanese groups. Coronary heart disease was an important cause of death for Asian Indians although death rates were generally not higher than those for other ethnic groups. Ethnic differences were most marked for women and younger age groups. PMID- 8680606 TI - The injury severity score--importance and uses. AB - The development and attributes of the Abbreviated Injury Scale (AIS) and the Injury Severity Score (ISS) are reviewed. The ISS was proved to be an excellent method for retrospective comparison of overall injury data between populations differing in time or space. Its strengths, purpose, and appropriate uses are emphasized, together with specific comments on statistical analyses and combined scales of anatomic and physiologic injury. PMID- 8680607 TI - Problems in interpreting HIV sentinel seroprevalence studies. AB - Estimating human immunodeficiency virus (HIV) prevalence from sentinel seroprevalence studies is difficult. We characterize these studies and show that most are investigations of incompletely defined (hypothetical) cohorts and are usually based on nonprobability samples. Prevalence in HIV sentinel serosurveys is also time-averaged and vulnerable to several time-dependent sources of bias (e.g., migration, deaths, and changes in incidence). Assumptions must be made that these time-dependent biases did not meaningfully affect the data, and this can be helped by reducing the period of investigation. Furthermore, we show that "reliability" can not be adequately measured by standard error, that "internal validity" is vulnerable to self-selection bias and laboratory problems, and that "generalizability" is limited. We propose that what is needed is a procedure (like formal metaanalysis methods) incorporating information from several separate HIV sentinel seroprevalence studies, in a manner that is reproducible and can take into consideration the differences between studies. PMID- 8680608 TI - Depression in black and white women. The role of marriage and socioeconomic status. AB - The degree to which the relationship between race and depression in US black and white women is modified by socioeconomic and marital status was investigated. Data on 534 black and 836 white women, 25 to 64 years old, obtained from the 1986 Americans' Changing Lives national survey were utilized. Depression was measured by the Centers for Epidemiologic Studies Depression scale. Poverty status and education were used as indicators of socioeconomic status (SES). For both black and white women, the prevalence of depression was higher among those with lower as compared to higher SES, and among the unmarried as compared to the married. The unstratified, age-adjusted odds of depression for black women was twice that for white women (odds ratio (OR) = 2.2; 95% confidence interval (CI), 1.7 to 2.8); however, when stratified by poverty status, race effects were observed for nonpoor (OR = 2.2; 95% CI, 1.6 to 3.0) but not for poor women (OR = 1.3; 95% CI, 0.7 to 2.1). Race effects were also more pronounced among married (OR = 2.0; 95% CI, 1.4 to 2.9) than unmarried women (OR = 1.6; 95% CI, 1.1 to 2.4). Controlling for known confounders did not alter these results. Additional analyses revealed that the black excess risk for depression was concentrated among higher SES, married women, with marital difficulties appearing to pay a major role in their elevated depression scores. PMID- 8680609 TI - The insulin resistance atherosclerosis study (IRAS) objectives, design, and recruitment results. AB - The Insulin Resistance Atherosclerosis Study (IRAS) is the first epidemiologic study designed to assess the relationships between insulin resistance, insulinemia, glycemia, other components of the insulin resistance syndrome, and prevalent cardiovascular disease (CVD) in a large multiethnic cohort. Over 1600 men and women were recruited from four geographic areas to represent a range of glucose tolerance (normal, impaired, and diabetic) and ethnicity (hispanic, non Hispanic white, and African-American). Insulin resistance was assessed directly using the frequently sampled intravenous glucose tolerance test with minimal model analysis. Intimal-medial carotid artery wall thickness, an indicator of atherosclerosis, was measured using B-mode ultrasonography. Prevalent CVD was assessed by questionnaire and resting electrocardiography. This report describes the design of the study and provides the recruitment results. Forthcoming cross sectional analyses will help to disentangle the association between insulin resistance and CVD, apart from the concomitant hyperinsulinemia and related CVD risk factors. PMID- 8680610 TI - Measurement of lactose consumption reliability and comparison of two methods. AB - The objective of this study was to assess the reliability of lactose consumption measured with a food-frequency questionnaire and to compare food-frequency data to prospectively recorded data. A self-administered food-frequency questionnaire (FF1) was completed by 295 women ages 38 to 49. Two months later, 75 received the same food-frequency questionnaire (FF2), and 75 received a 1-week diet diary listing 23 commonly eaten lactose-containing foods. Estimated mean intake of lactose was 16.1 g/d with FF1. Intake was slightly (but not significantly) higher at follow-up: Mean difference (95% confidence interval) was 1.4 (-0.8, 3.7) g/d for FF2 versus FF1, and 0.5 g (1.3, 2.3) g/d for the diet diary versus FF1. A moderate level of correlation was found: r = 0.57 between FF1 and FF2, and r = 0.65 between FF1 and the diet diary. Smaller subsets of items (n = 15 and n = 7) could be used to estimate lactose, with 89% and 82% agreement within tertiles, respectively. Since relatively few foods contain substantial amounts of lactose, a limited food-frequency or structured diary may be useful in research studies on the association between lactose consumption and ovarian cancer or other diseases. PMID- 8680611 TI - Relationship of cigarette smoking, alcohol use, and dietary habits with sigmoid colon adenomas. AB - The relationship between cigarette smoking, alcohol use, and dietary factors and the risk of adenomas of the sigmoid colon was examined in male self-defense officials who received a preretirement health examination at three Self-Defense Forces hospitals in Japan. In the comparison between 228 patients with sigmoid adenomas and 1484 control subjects with normal colonoscopy findings (> or = 60 cm from the anus), a clear dose-response relationship was observed between cigarette smoking and risk of adenoma. After adjustment for rank, body mass index, alcohol use, and physical activity as well as for hospital and survey season, the odds ratios (and 95% confidence intervals (CIs)) for the categories of 0, 1 to 399, 400 to 799, and 800 or more cigarette-years were 1.0, 2.1 (1.2 to 3.5), 2.8 (1.8 to 4.3), and 3.5 (2.1 to 5.8), respectively. Current alcohol drinkers tended to have an increased risk, but without a dose-response relation. Among four types of alcoholic beverages (shochu, sake, beer, and whiskey), only whiskey showed a weak association with risk of adenoma. None of the 13 dietary items studied (including meat and rice consumption) was measurably associated with adenoma risk. The present findings provide additional evidence that cigarette smoking is a risk factor for colon adenomas. It is inconclusive regarding alcohol intake's association with adenoma risk. PMID- 8680612 TI - Validity of 24-hour dietary recall interviews conducted among volunteers in an adult working community. AB - There is considerable uncertainty regarding the validity of dietary data collected from free-living populations. Nevertheless, few attempts have been made to validate dietary assessment instruments. To address this issue, we compared average daily protein intake estimated from 24-hour dietary recall interviews to protein intake estimated from urinary nitrogen excretion in 24-hour samples. Among 244 community-dwelling adults who volunteered for a hypertension study, men (n = 139) overreported dietary protein intake by 12 to 19%. In contrast, women (n = 105) reported a dietary protein intake almost exactly in agreement with estimates based on urinary nitrogen levels. Thin men reported about one-third more protein intake than was reflected in their urinary nitrogen measurements. Our results suggest that the accuracy of dietary recall estimates may vary across subgroups of the population. Additional information from sufficiently large validation studies would be helpful in determining the role of dietary assessment instruments which are already in wide use in epidemiologic research. Until such information is obtained, doubts will remain regarding the validity of inferences drawn from nutritional epidemiologic studies. PMID- 8680613 TI - Serum zinc and serum lipid profiles in 778 adults. AB - There has been increasing use of high-dosage zinc supplementation in the population, in particular as a potential treatment for age-related macular degeneration. We examined the relationship between fasting serum zinc and serum lipid levels in 778 adults, aged 22 to 80 years, who were control subjects in a multicenter, clinic-based case-control study. The samples were taken during 1987 to 1990, a time when vitamin/mineral supplementation was becoming increasingly common. We found that higher serum zinc levels, most notably those above the highest quintile, were associated with higher levels of total serum cholesterol, low-density-lipoprotein cholesterol, and triglycerides. No significant trend was noted for high-density-lipoprotein cholesterol. Previous studies demonstrated that high-dosage zinc supplements raise serum zinc levels. The possibility that use of such supplements can adversely affect serum lipid profiles suggests that chronic ingestion of such supplements should not be done without adequate medical supervision. PMID- 8680614 TI - Comparison of HHV-6 antibody titers in West Africa and the Caribbean. AB - Human herpesvirus-6 (HHV-6) infection seems to be ubiquitous early in life, but antibody responses vary by geographic area. We compared HHV-6 antibody titer in 123 West African and 122 Caribbean serum samples. A quantitative immunofluorescence assay (IFA) using antigens derived from an HSB-2 cell line was used to test for IgG HHV-6 (GS strain) antibodies. The prevalence of HHV-6 antibodies was high (98%) in both sites. African samples had a significantly higher geometric mean titer (GMT: 697) than did Caribbean samples (GMT: 99). There was no difference between males (GMT: 260) and females (GMT: 270) overall. Children up to and including 9 years old had significantly higher titers (GMT: 483) than did all others (GMT: 237), and female children tended to have higher titers than did male children. In both areas there was a trend towards highest titer at younger age, followed by a decrease in titer during adulthood and middle age, and a secondary rise in titer in the oldest age group. Environmental and host factors may explain these geographic differences in antibody responses between two groups of African origin. PMID- 8680615 TI - Dietary approaches to stop hypertension. PMID- 8680616 TI - American college of epidemiology statement of principles. PMID- 8680617 TI - Statement of principles. Epidemiology and minority populations. PMID- 8680618 TI - Federal scene. Introducing Annals of Epidemiology Federal scene section. PMID- 8680619 TI - The shape of the relationship between income and mortality in the United States. Evidence from the National Longitudinal Mortality Study. AB - A follow-up study based on a large national sample was used to examine differences in the well-established inverse gradient between income and mortality at different income levels. The study showed the income-mortality gradient to be much smaller at high income levels than at low to moderate income levels in the working age (25 to 64 years) and elderly (over 65 years) populations for men and women both before and after adjustment for other socioeconomic variables. In addition, a much larger gradient existed for working age women at extreme poverty levels than for those women at low to moderate income levels. The income mortality gradient was much smaller in the elderly than in the working age population. The study also examined the ability of several different mathematic functions of income to delineate the relationship between income and mortality. The study suggested that the health benefits associated with increased income diminish as income increases. PMID- 8680620 TI - Lyme disease surveillance in Maryland, 1992. AB - The incidence of Lyme disease (LD) reported to the Maryland Department of Health and Mental Hygiene during 1992 was 6.5/100,000 population, ranging from 29.3 cases/100,000 on the Eastern Shore (74.4% of all cases) to no cases in the mountains of western Maryland. Among the 317 reported patients, 44.4% gave a history of tick exposure and 78.9% had positive serologic test results. For the 187 (59.0%) patients meeting the Centers for Disease Control and Prevention (CDC) surveillance case definition, erythema migrans (EM) occurred in 69.5%, with arthritic (26.7%), neurologic (13.4%), and cardiac (2.1%) manifestations being less frequent. Patients not meeting the surveillance case definition were significantly more likely to have influenza-like symptoms, a smaller rash, and arthralgia. Patients meeting the CDC criteria were more likely to have an onset during the major transmission season in the summer (odds ratio (OR): 2.1; confidence interval (CI): 1.2 to 3.6) since this was the time when most (115/130) patients with EM were detected. Positive serologic results were more likely (OR: 2.2; CI: 1.2 to 4.2) in those not meeting the case definition. The treatment given to patients thought to have LD was almost always that recommended in the literature and there was no difference between treatment prescribed for patients meeting and those not meeting the case definition. These data show that physicians in Maryland are treating many patients for LD who are clinically diagnosed as having LD (e.g., febrile patients with flulike symptoms, patients with arthralgias or erythematous rashes < 5 cm in size) and who have positive serologic test results but who do not meet the CDC surveillance case definition. These patients and the large number of unreported patients being seen and treated for LD or tick bites must be added to the overall burden of LD in the state. PMID- 8680621 TI - Relationship between blood lead and dietary iron intake in preschool children. A cross-sectional study. AB - The relationship between dietary iron intake and blood lead levels in urban preschool children was investigated in a cross-sectional study of 299 children from 9 months to 5 years old. Mothers of children attending the University of Maryland Pediatric Ambulatory Clinic volunteered for the children and themselves to join the study. The data collected included nutritional status, socioeconomic status, medical history, and potential sources of lead exposure. Blood samples from all participants were evaluated for levels of blood lead, serum iron (ferritin), free erythrocyte protoporphyrin, calcium, and hematocrit. The average blood lead level (standard deviation) in the studied population was 11.4 (7.3) micrograms/dL. With multiple linear and logistic regression analyses to adjust for covariates, a negative association (P = 0.03) between blood lead and dietary iron intake was found. This finding is consistent with similar results from experimental studies. It is concluded that there is evidence that higher dietary iron intake is associated with lower blood lead among urban preschool children in the studied population. PMID- 8680622 TI - Is birth order associated with adult mortality? AB - The objective of this study was to determine whether birth order is associated with total or cause-specific adult mortality and whether the association differed by sex, was confounded by age, number of siblings, or socioeconomic status, or was mediated by personality, education, or health behaviors. Teachers throughout California identified intellectually gifted children as part of a prospective study begun in the 1920s by Lewis Terman. Information on birth order was available on 1162 subjects (85% of cohort) who have since been followed for over 70 years. Cox proportional hazards models indicated that birth order was not associated with adult all-cause, cardiovascular, or cancer mortality. Among women, middle children were more likely than oldest children to die from causes of death other than cardiovascular disease or cancer, although the numbers in this category were small. This study did not provide evidence that birth order is associated with adult mortality in this highly intelligent, middle-class cohort. PMID- 8680623 TI - Recruiting minorities into the profession of epidemiology. Surveying the applicants' mail. American College of Epidemiology Committee on Minority Affairs. AB - The underrepresentation in epidemiology of members of racial/ethnic minority groups is greater than in medicine and health fields in general. Using printed recruitment materials, we evaluated the impression that epidemiology programs might make on prospective minority students. Mainstream recruitment materials were solicited from all identifiable U.S. epidemiology programs (n = 70) by requesting copies of typical mailings to prospective students. Of 51 respondents, 46 sent materials that could be analyzed by tabulating and evaluating minority related content in text and pictures. Materials reflected a generally low-key approach to epidemiology student recruitment. Most minority-related text referred to affirmative action or financial aid and was at the school level rather than specific to the epidemiology programs. Few minority-related epidemiology course titles or research interests were identified. We recommend including more information about epidemiology and its relevance to minority health in mainstream recruitment materials as one possible strategy for increasing the number of minority applicants. PMID- 8680624 TI - Food and nutrient intake and risk of cataract. AB - The relationship between cataract extraction and diet was considered in a case control study conducted in northern Italy. A total of 207 patients who had cataract extraction and 706 control subjects in a hospital for acute, nonneoplastic, nonoculistic, nondigestive tract diseases were interviewed during their hospital stay. Odds ratios (ORs) and their 95% confidence intervals (CIs), according to the intake of alcohol, coffee, tea, and cola, and frequency of intake of 34 food items and 8 micronutrients were derived from multiple logistic regression equations, including terms for age, sex, education, smoking status, body mass index, diabetes, and total calorie intake. Alcohol, coffee, decaffeinated coffee, tea, and cola intakes were not associated with cataract extraction. Among food items, reduced ORs for cataract extraction (highest tertile of intake compared to the lowest), with a significant inverse trend in risk, were found for intake of meat (OR 0.6, 95% CI 0.4 to 0.9), cheese (OR 0.7, 95% CI 0.5 to 1.0), cruciferae (OR 0.5, 95% CI 0.3 to 0.8), spinach (OR 0.6, 95% CI 0.4 to 0.9), tomatoes (OR 0.5, 95% CI 0.4 to 0.8), peppers (OR 0.7, 95% CI 0.4 to 1.1), citrus fruit (OR 0.5, 95% CI 0.2 to 1.3), and melon (OR 0.5, 95% CI 0.4 to 0.8). A significant increase in risk was found for the highest intake of butter (OR 2.8, 95% CI 1.2 to 6.4), total fat (OR 1.8, 95% CI 1.2 to 2.8), and salt (OR 2.4, 95% CI 1.4 to 4.0) compared to the lowest, and for consumption of oil other than olive oil (OR 1.6, 95% CI 1.1 to 2.2). Among micronutrients, lower ORs for cataract extraction (highest quintile of intake compared to the lowest) were found for intake of calcium (OR 0.5, 95% CI 0.3 to 0.8), folic acid (OR 0.4, 95% CI 0.2 to 0.7), and vitamin E (OR 0.5, 95% CI 0.3 to 1.0), while estimated intakes of methionine, retinol, beta-carotene, and vitamins A, C, and D were not associated. Thus, this study indicates that diet plays a considerable role in the risk of cataract extraction in this Italian population, with a protective action played by some vegetables, fruit, calcium, folic acid,and vitamin E, and an increased risk associated with elevated salt and fat intake. PMID- 8680625 TI - Reproducibility of the women's module of the Behavioral Risk Factor Surveillance System questionnaire. AB - The Behavioral Risk Factor Surveillance System (BRFSS) is designed to provide statewide estimates of the prevalence of preventive health practices, including screening. We assessed the reproducibility of responses to the women's health module, which covers breast and cervical cancer screening, hysterectomy, and pregnancy. A random sample of women in Massachusetts (n = 91; response rate for the repeat interview, 70.0%) and a separate random sample of minority women in the state (n = 179; response rate for the repeat interview, 69.4%) were interviewed by telephone twice, 21 to 94 days apart. Differences across administrations in mean prevalence of screening were small. Concordance exceeded 85% for almost all the variables examined, but tended to be lower for nonwhite respondents. After correction for agreement occurring by chance, moderate to excellent values of kappa (range, 0.41 to 0.86) were observed. The women's health module of the BRFSS questionnaire yields highly consistent group mean estimates of prevalence when administered repeatedly to the same individuals. Individual reproducibility is excellent, but may be reduced among minority respondents. PMID- 8680626 TI - Exercise during pregnancy among US women. AB - This report describes the prevalence and pattern of exercise during pregnancy among US women. It is based on 9953 randomly selected women who gave birth to live infants in 1988 and participated in the National Maternal and Infant Health Survey, a cross-sectional survey with a stratified systematic sampling in 48 states, the District of Columbia, and New York City. Self-reported exercise before and during pregnancy, specific activities, and number of months of exercise were examined in relation to maternal demographic characteristics, reproductive history, and prenatal care. Forty-two percent of all women reported exercising during pregnancy, half of whom exercised longer than 6 months. Walking was the leading activity (43% of all activities reported), followed by swimming (12%) and aerobics (12%). Older mothers and women who had multiple gestations, previous children, or an unfavorable reproductive history were less likely to exercise during pregnancy. Given this high prevalence of exercise in pregnancy, more research is warranted on both the beneficial and adverse maternal and fetal effects of exercise in pregnancy. PMID- 8680627 TI - Antioxidants and age-related eye disease. Current and future perspectives. AB - Oxidative mechanisms may play an important role in the pathogenesis of age related eye disease, in particular cataract and macular degeneration, the two most important causes of visual impairment in older adults. For this reason, there is considerable interest in determining whether vitamins and trace minerals with antioxidant properties can be of benefit in preventing the onset or progression of disabling eye disease. Basic research studies have shown that antioxidants can protect against the cumulative effects of oxidative stress in animal models of cataract and macular degeneration. Data from observational epidemiological studies in humans, however, are inconclusive. While results from several studies, primarily cross-sectional and case-control, are compatible with a possible protective role for micronutrients in disease development, data for specific nutrients or specific disease types have often been inconsistent. Further, these observational studies are limited because of the inherent imprecision of dietary exposure data and the likely effects of uncontrolled confounding. Thus, reliable data regarding a potentially important benefit of vitamin supplementation in eye disease will emerge mainly from well-designed, large-scale, randomized trials. PMID- 8680628 TI - Diabetes mellitus, race, and socioeconomic status. A population-based study. AB - To identify factors associated with diabetes mellitus and to determine whether racial differences in these factors, especially socioeconomic status, explain the high prevalence of diabetes among African-Americans, we performed a cross sectional study using a population-based, representative sample from three US communities. The participants comprised 975 white and 418 African-American adults, aged 35 to 54 years. The main outcome variable was the presence of diabetes defined by either self-report or abnormal results on the oral glucose tolerance test (serum glucose level > 10.0 mmol/L (180 mg/dL) 1 hour after 50-g oral glucose dose). Compared to their white counterparts, African-American participants were more overweight, displayed greater central adiposity, and had lower socioeconomic status. Diabetes was over twice as prevalent among African Americans (10.3%) as compared to whites (4.6%; odds ratio (OR) = 2.38; 95% confidence interval (95% CI): 1.50, 3.75; P = 0.0001). After adjustments for racial differences in age, socioeconomic status, overweight, and central adiposity, African-Americans remained over twice as likely to have diabetes compared to whites (OR = 2.35; 95% CI: 1.49, 3.73; P = 0.0003). The excess prevalence of diabetes in African-Americans was greatest in individuals of low socioeconomic status (OR = 4.09) and least among individuals of high socioeconomic status (OR = 1.90; P < 0.001 for trend). Racial differences in obesity and socioeconomic status do not appear to explain fully the higher prevalence of diabetes among African-Americans. African-American race seems to be a strong, independent risk factor for diabetes, especially among individuals of low socioeconomic status. PMID- 8680629 TI - Correlates of leukocyte counts in men. AB - Because of previously reported associations between a high leukocyte count and risk of ischemic heart disease (IHD), we examined the relation of leukocyte counts to various characteristics among 3591 white and 506 black 31- to 45-year old men. The mean leukocyte count was approximately 1000 cells/microL higher among whites than among blacks, and approximately 1900 cells/microL higher among current smokers than among nonsmokers. The leukocyte count was also higher among men who had recently stopped smoking and among men who reported their general health as poor or fair. Independent of these relations, the leukocyte count was associated positively with the platelet count (r = 0.29), triglyceride level (r = 0.21), heart rate (r = 0.15), and use of corticosteroids and beta-blockers; and inversely with alcohol consumption and prothrombin time (r = -0.10). The examined characteristics could together account for 37% of the variability in leukocyte counts. These relatively strong associations indicate that it may be difficult to disentangle the relation of the leukocyte count to IHD from that of other risk factors. PMID- 8680630 TI - Occupation and suicide among males in the US Armed Forces. AB - During the period 1980 to 1992, 95% of the 3178 military suicide victims were men and 92% enlisted; of the men, 71% were aged 20 to 34, 82% were white, and 61% used a firearm. Information extracted from the Report of Casualty of the Worldwide Casualty System maintained by the Department of Defense was used to describe the occupational risk among military men. Occupations related to the use of or access to firearms were associated with a significant risk of suicide when compared to other military occupations. Collectively, military security and law enforcement specialists had a significant occupational rate ratio (1.25; 95% confidence interval: 1.02, 1.53; P < 0.05). This corresponds to findings from national civilian labor force fatality data where police and detectives are also at an elevated risk of suicide. Because the scope and work of these military high risk groups may differ from service to service, additional occupational information should be examined to facilitate a better understanding of the complex etiology of suicide and to develop appropriate prevention strategies. PMID- 8680631 TI - Vertical banded gastroplasty by laparoscopic technique in the treatment of morbid obesity. AB - From October 1993 through May 1994, 38 consecutive morbidly obese patients underwent a laparoscopic vertical banded gastroplasty (VBG). During the operation a gastric window was made by a 25-mm circular stapler; and the vertical staple line, establishing the gastric pouch, was constructed by using a 60-mm, four-row linear stapler. The outflow stoma was reinforced by a Gore-Tex band and calibrated to have an internal diameter of 9 mm. Three patients had to be converted to open surgery during the initial laparoscopic procedure because of insufficient operative access. Another three patients had to be reoperated during subsequent postoperative courses, one laparoscopically to reinforce a vertical staple line defect caused by a transected nasogastric tube, another because of an open reoperation during the first postoperative day for a rupture in the vertical staple line, and, finally, a patient was reexplored because of the present of postoperative fever with a left-sided pleuropneumonia and subphrenic accumulation of fluid. However, during the operation no leakage or any other local complications were detected. The subsequent postoperative courses were uneventful in all these patients. Compared with the reference group comprising the latest consecutive 17 obese patients operated with open VBG before the introduction of the laparoscopic technique, the laparoscopy group had less postoperative pain and had mobilization sooner. In the latter group, we recorded an improved respiratory status during the early postoperative period, as reflected by increased oxygen saturation and peak exspiratory flow rates as well as a lower body temperature. In conclusion, laparoscopic VBG is technically feasible and can be safely performed. Our early postoperative experiences suggest that these patients have a shorter and less cumbersome postoperative recovery period compared with conventionally operated obese patients. The long-term follow-up of these patients will determine whether these initial advantages of the laparoscopic approach are corroborated by comparable effects on weight control. PMID- 8680632 TI - Establishing a laparoscopic antireflux program: a private practice experience. AB - Laparoscopic antireflux surgery is an exciting new option in the treatment of gastroesophageal reflux disease. Establishing a successful antireflux program depends on obtaining proper education as well as generating a suitable flow of patients. Being outside a university-based referral center presents the surgeon in private practice with a unique challenge as to how to meet these goals effectively. A personal account of education, training, and patient recruitment methods is presented. Different modalities for stimulating interest in both the medical and lay communities, including methods for direct patient contact, such as advertising are described. This is followed by a review of a series of 57 antireflux procedures performed during the first year of this program in a private practice in a retirement community setting. PMID- 8680633 TI - Chronic acalculous cholecystitis: laparoscopic treatment. AB - From 1990 through 1993, we treated 36 patients with recurrent typical biliary colic but who showed no ultrasonic evidence of cholelithiasis by laparoscopic cholecystectomy. Associated symptoms included nausea (75%), bloating (56%), fatty food intolerance (53%), vomiting (17%), weight loss (31%), bowel irregularity (28%), reflux or dyspepsia (25%), and fever (17%). Diagnostic evaluation included ultrasound (100%), upper gastrointestinal series (36%), oral cholecystogram (14%), computed tomographic scan (39%), endoscopic retrograde cholangiopancreatography (17%), upper gastrointestinal endoscopy (14%), and hepatobiliary scan (92%). Quantitative hepatobiliary scans in 33 patients revealed a low gallbladder ejection fraction (EF) of less than 35% in 29 patients (88%; mean EF = 9%), and 13 patients experienced reproducible pain after cholecystokinin provocation. All patients underwent attempted laparoscopic cholecystectomy; one case of unsuspected acute acalculous cholecystitis was converted to open laparotomy because of unclear anatomy. Gross and histological examination of the gallbladders revealed chronic inflammation (83%), cholesterolosis (31%), cholesterol crystals or small stones (17%), acute inflammation (8%), polyps (6%), and normal histology (6%); however, blind retrospective scoring of gallbladders revealed significant chronic inflammation in only 38%. In the 2 to 40 months (mean, 14 months) since operation, there have been no deaths (97% follow-up). Laparoscopic cholecystectomy relieved pain in 93% of patients with a low preoperative EF compared with 75% of patients with a normal EF (nonsignificant p value). Persistent abdominal or gastrointestinal complaints included flatulence (31%), loose stools or fecal urgency (29%), belching (29%), indigestion (20%), nausea (11%), and "typical" gallbladder pain (9%). We conclude that many patients with symptoms of biliary colic and scintigraphic evidence of biliary dyskinesia have histologic findings of chronic cholecystitis. Although laparoscopic cholecystectomy usually eliminates biliary colic, persistent nonbiliary complaints are frequent. PMID- 8680634 TI - Laparoscopic repair of large incisional hernias. AB - Conventional repair of large incisional hernias is often associated with a painful postoperative recovery and a delayed return to normal activities. We describe here a technique of laparoscopic incisional hernia repair and review our experience with 30 cases. Hernias ranging in size from 10 to 420 cm2 (mean, 104 cm2) were repaired using a polytetrafluoroethylene patch (16 cases) and a Prolene mesh (14 cases). Operating room time ranged from 45 mins to 190 min (mean 108 mins). Postop stay ranged from 1 to 17 days (mean, 4.3 days; median, 3 days). Follow-up extends beyond 18 months. Postoperative complications included ileus (three cases) trocar site infection (one case) and urinary retention (two cases). There has been one hernia recurrence to date. Our experience with the laparoscopic repair of incisional hernias reveals it to be technically feasible with minimal morbidity, allowing patients prompt resumption of regular activities. Prospective comparison with conventional repair and longer follow-up are needed. PMID- 8680635 TI - Laparoscopic splenectomy for idiopathic thrombocytopenic purpura: comparison of laparoscopic surgery and conventional open surgery. AB - In chronic idiopathic thrombocytopenic purpura (ITP), the two main therapeutic choices are steroid treatment or splenectomy. The adult form of ITP is described as a disease found primarily in young adults, with a female predominance. Treatment with steroids effects a complete response in less than 30% of patients, whereas splenectomy is successful in more than 60% of patients who undergo it. The minimal access afforded by laparoscopic splenectomy is considered highly desirable for these patients. The purpose of this study was to compare the clinical benefits of a laparoscopic splenectomy with those of conventional open surgery for patients with ITP. From 1968 to 1993, splenectomy was performed on 51 patients: 10 operations done laparoscopically and 41 performed conventionally. Complications, postoperative pain, recovery, and hospital charges were then compared. Laparoscopic splenectomy involved minimal incisions, and a significantly lower frequency of analgesia was required for postoperative abdominal pain (1.3 vs. 3.3); hospital stay was shorter (8.2 vs. 20.1 days) (p < 0.005). Operative time was significantly longer for the laparoscopic surgery (249.2 vs. 99.8 min) (p < 0.0001), but blood loss was less (176.0 vs. 511.7 g) (p < 0.01). No intraoperative or postoperative major complications occurred with the laparoscopic procedures, compared with 46.3% with conventional surgery. Finally, the total hospital costs were lower with laparoscopic splenectomy, especially for postoperative care (p < 0.05). A laparoscopic splenectomy may well be considered the surgical treatment of choice for patients requiring a splenectomy in view of both quality of life and economy. PMID- 8680636 TI - Adhesion formation after laparoscopic anterior resection in a porcine model: a pilot study. AB - Although decreased adhesion formation is one of the accepted advantages of laparoscopic colorectal surgery, no prospective studies have been done to support this claim. Therefore, we prospectively assessed adhesion formation following laparoscopic anterior resection of the rectum in a porcine model. Five domestic female pigs underwent the procedure with a double-stapled intracorporeal anastomosis. After completion of the laparoscopic procedure, 50 cm of ileum was retrieved through the right lower port site. Controlled serosal abrasion of the antimesenteric surface was performed using a fresh knife. The abraded loop was returned into the peritoneal cavity and the fascia closed at all port sites. All animals underwent a midline laparotomy 3 weeks later to assess adhesions using a 0-3 score according to the density vascularity, and extent of adhesions. All animals survived the study period. The mean level of the anastomosis was 8 cm (range, 7-10) above the anal verge; all anastomoses were intact and completely healed. None of the animals had adhesions to the port sites. The anastomotic site was completely free of adhesions in four animals, and only one animal (20%) had grade 1 adhesions between the urine horns and the anastomosis. Conversely, all animals had adhesions of the abraded loop involving 60 cm (range, 40-75) of bowel and 7 cm (range, 4-9) of the abdominal wall (remote to the port sites); no other adhesions were noted. In this pilot study, serosal abrasion of the small bowel resulted in severe adhesion formation in the porcine model. However, laparoscopic anterior resection of the rectum in the same animals was associated with only minimal insignificant adhesions. Furthermore, unlike in laparotomy incisions, adhesions to port sites did not occur. PMID- 8680637 TI - Laparoscopic Nissen fundoplication: cost, morbidity, and outcome compared with open surgery. AB - We report a retrospective review of all patients undergoing both open and laparoscopic Nissen fundoplication from January 1990 through December 1993. Computer data were reviewed to determine the length of hospital stay, hospital costs, and perioperative complications. Questionnaires were sent to patients undergoing Nissen fundoplication. During the study period, 232 patients underwent Nissen fundoplication, and 72 patients underwent laparoscopic Nissen fundoplication. The open group had an average hospital stay of 6.1 days, the laparoscopy group, 1.5 days (p < < 0.001). Total hospital costs for the open group averaged $8,616 versus $4,331 for the group that underwent laparoscopic procedure (p < 0.001). Operating room time averaged 10 min longer for the laparoscopic procedure (p value, nonsignificant). In-hospital morbidity was significantly greater for the open group. In follow-up questionnaires, the laparoscopy group experienced an earlier return to "general health" (p < 0.005) and an earlier return to work. PMID- 8680638 TI - Laparoscopic knot security. AB - The security of several types of laparoscopic and open knots and varying suture materials was tested in an attempt to improve suture and knot selection for advanced laparoscopic procedures. Six different types of knots and five suture materials were tested. All sutures were of 2-0 size, and laparoscopic knots were tied using a pelvic trainer. A typical number of square throws was used for each suture. Stress was gradually applied by withdrawing the ends of a manual digital tensiometer until either the knot slipped or the suture parted. The maximum stress withstood by the knot-suture complex was recorded, as was whether the knot was secure (i.e., whether the knot held until the suture broke). The data were analyzed using analysis of variance to compare the knot security of the various knot types and the different sutures using a given knot. No significant difference was found in security or stress resistance between laparoscopic square and open square knots or in the Dacron, polypropylene, and expand polytetrafluoroethylene (ePTFE) extracorporeal and intracorporeal knots, with the exception of ePTFE intracorporeal knots, which were significantly less secure (p = 0.028). Silk suture was significantly less secure than all the other sutures tested for all knots tested (p < 0.0001). The Roeder's and Fisherman's knots were the least secure of all laparoscopic knots in all sutures tested (p < 0.0001), with the exception of polyglactin tied with a fisherman's knot, which was as secure as the extracorporeal and intracorporeal polyglactin knots. These experiments showed laparoscopic square knots to be as secure as open square knots; removing the operating finger from the knot does not seem to affect the security of a well-tied square knot. Furthermore, of the permanent sutures tested, there was no substantive difference in the security of laparoscopic intracorporeally and extracorporeally tied knots, except that ePTFE was more secure when tied with extracorporeal throws. Our data also suggest that silk is not as secure as other permanent suture materials. PMID- 8680639 TI - Laparoscopic reoperation on failed antireflux procedures: report of two patients. AB - Two cases are presented that demonstrate the feasibility of using the laparoscopic transabdominal approach for failed antireflux procedures. The first patient had two previous Belsey hemifundoplications that had both failed and had intractable reflux unresponsive to conservative treatment. The Belsey operation was taken down and a floppy Nissen fundoplication performed; the patient had only transient postoperative dysphagia. The second patient had a standard floppy Nissen fundoplication performed over a large bougie and developed a postoperative motility problem that failed to respond to medication and dilation. The Nissen was taken down laparoscopically and converted to a Toupet procedure; the patient had total relief of the dysphagia. Neither patient had intra-abdominal complications, and both have had total relief of their heartburn and regurgitation. PMID- 8680640 TI - Biliary-cutaneous fistula: an uncommon complication of retained gallstones following laparoscopic cholecystectomy. AB - A biliary-cutaneous fistula occurring as a late complication of laparoscopic cholecystectomy is described. The fistula was associated with retained gallstone fragments following intra-operative spillage and attempted retrieval. The fate of intra-peritoneal gallstones is reviewed and preventative measures discussed. PMID- 8680641 TI - Strangulated incisional hernia at trocar site. AB - An incisional hernia at a trocar site after laparoscopy may arise from infection, premature suture disruption, or failure to adequately reapproximate fascial wound edges. The condition is accurately diagnosed postoperatively on physical examination, and a bulge at a previous port site should immediately raise suspicion. A case is reported in which an incisional hernia strangulated soon after an elective laparoscopic inguinal herniorrhaphy in which, the fascia of the 10-mm trocar site was not closed. This report underscores the importance of meticulous closure of all abdominal port sites > 5 mm. Furthermore, early diagnosis of an incarcerated hernia may avoid the morbidity of an extensive intestinal resection. PMID- 8680642 TI - Laparoscopic management of intussusception caused by colonic lipomata: a case report and review of the literature. AB - We describe the case of a 57-year-old woman who presented with colocolic intussusception due to a lipoma. The lesion was removed by laparoscopic right hemicolectomy. Benign colorectal pathology, such as colonic lipoma, is ideally suited for laparoscopic treatment. PMID- 8680643 TI - Esophageal endoscopic mucosal resection (EEMR) tube. PMID- 8680644 TI - Laparoscopic treatment of esophageal achalasia. AB - An observational cohort study evaluated the initial results of using laparoscopic approach cardioesophageal myotomy with Dor-type anterior fundoplicature for esophageal achalasia. The study involved our first 12 patients: five men and seven women whose median age was 51 years. Esophageal motility was vigorous in four patients; the other eight had aperistalsis. Conversion to laparotomy was required in one case. No postoperative mortality occurred. Postoperative complications included one left subdiaphragmatic abscess secondary to perforation of the esophageal mucosa, which was sutured. Median postoperative hospital stay was 5 days (confidence interval, 4.7-6.7 days). Symptom relief (disappearance of dysphagia) was recorded in 10 cases; relief with partial persistence of dysphagia was observed in the remaining two patients, who were treated by postoperative dilatation. As to the postoperative manometric results, the median basal pressure of the lower esophageal sphincter was reduced from 26.3 mm Hg preoperatively to 15.5 mm Hg postoperatively, with a tendency toward statistical significance (p = 0.08); the median esophageal isotopic retention after 15 min decreased from 60% preoperatively to 24.5% after surgery, with a tendency toward statistical significance (p = 0.07). Cardiomyotomy with Dor fundoplicature through a laparoscopic approach seems effective in treating esophageal achalasia. PMID- 8680645 TI - Thoracoscopic versus laparoscopic placement of defibrillator patches. AB - Nonthoracotomy lead systems have been developed to reduce the morbidity associated with cardioverter/defibrillator implantation. Total endocardial lead systems are effective in only about 50% of patients with standard monophasic waveforms; so patch placement is frequently required. We developed a new patch design and surgical techniques for thoracoscopic patch placement over the left ventricle and laparoscopic placement under the diaphragm. To compare the efficacy of these approaches, patches were placed in both locations in pigs acutely with a right ventricular coil serving as the anode for defibrillation. Defibrillation testing was performed, alternating between patches. The energies associated with 50% (DF50) and 90% (DF90) probability of successful defibrillation with biphasic shocks with determined. Defibrillator thresholds were significantly lower with intrathoracic than with subdiaphragmatic patches. Animal autopsy following more than 30 shocks from each patch revealed no gross damage to the lung or diaphragm in any animal. PMID- 8680646 TI - Laparoscopic gastrectomy: five cases. AB - We present the results of five patients who underwent gastrectomy using a laparoscopic technique. All patients had an intracorporeal resection of the antrum followed by an antecolic intracorporeal gastrojejunostomy (Billroth II). Two patients also had bilateral truncal vagotomy, and one had a Roux-en-Y component to the gastrojejunostomy. Indications were (a) intractable ulcer disease in two patients; (b) gastric outlet obstruction due to duodenal ulcer in one; (c) chronic, severe gastrointestinal blood loss from bile reflux gastritis in one; and (d) palliation of a superficial carcinoma in one. Except for one patient who had postoperative gastric atony, there were no complications or operative mortality. Short-term follow-up ranging from 9 to 34 months has revealed one patient with recurrent ulcer symptoms, but the other four have had control of their disease. PMID- 8680647 TI - Congress on Cell and Tissue Culture. Research Triangle Park, North Carolina, June 4-7, 1994. Abstracts. PMID- 8680649 TI - NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin-2-induced capillary leak syndrome in healthy mice. AB - We tested whether NG-nitro-L-arginine methyl ester (L-NAME), a potent inhibitor of NO synthesis, can prevent interleukin-2 (IL-2)-induced capillary leakage. Healthy C3H/HeJ female mice were treated with: nothing; IL-2 (10 injections; 35,000, 15,000, or 7,500 Cetus U i.p. every 8 h); IL-2 + L-NAME (0.01, 0.1, 0.5, and 1 mg/ml of drinking water starting 1 day before IL-2 therapy and ending with IL-2 therapy); or L-NAME alone. In the first series of experiments, mice were killed 1 h after last IL-2 injection to measure pleural effusion, and water content of the lungs, spleen, and kidney (markers of capillary leakage), as well as NO2- + NO3- levels in the serum and pleural effusion. In the two additional series, the survival of treated mice was followed. All doses of IL-2-induced capillary leak syndrome as indicated by pleural effusion, pulmonary edema, and fluid retention in the spleen and kidney. NO production was positively correlated with manifestation and severity of this syndrome. NO2- + NO3- levels in the pleural effusion were directly related to IL-2 dose, and L-NAME treatment reduced both the NO production and severity of capillary leakage, excepting fluid retention in the kidney. However, L-NAME therapy prevented IL-2-induced mortality only when combined with a middle range IL-2 dose (15,000 U/injection). In summary, oral L-NAME therapy effectively prevented IL-2-induced capillary leakage in healthy mice, suggesting its potential value as a supplement in IL-2-based immunotherapy of cancer and infectious diseases. PMID- 8680650 TI - Potentiation of antiproliferative effects of monoclonal antibody Lym-1 and immunoconjugate Lym-1-gelonin on human Burkitt's lymphoma cells with gamma interferon and tumor necrosis factor. AB - A type I ribosome inactivating protein, gelonin, was linked to Lym-1, a murine monoclonal antibody reactive with a polymorphic determinant of class II HLA-DR histocompatibility leukocyte antigen (HLA) on human lymphoma cells, via a disulfide linkage using the heterobifunctional cross-linking agent, N succinimidyl-3-(2-pyridyldithio) propionate. This immunotoxin was purified from unreacted gelonin and unconjugated Lym-1 by fast protein liquid chromatography using sephacryl S-300 gel filtration and blue sepharose affinity gradient separation. Binding of Lym-1-gelonin immunoconjugate to human Raji Burkitt's lymphoma cells was demonstrated by indirect immunofluorescence using flow cytometry. Lym-1-gelonin was very active in 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium salt and sulforhodamine B in vitro cytotoxicity assays against the Raji lymphoma cell line and confirmed the fact that monoclonal antibody Lym-1 internalizes into human lymphoma cells. A weaker cytostatic antiproliferative effect was also noted for unconjugated Lym-1. gamma-interferon augmented the antiproliferative effects of Lym-1-gelonin conjugate and unconjugated Lym-1, by having a direct cytotoxic effect on the Raji cells. Tumor necrosis factor-alpha also enhanced the antiproliferative effect of unconjugated Lym-1, but did not significantly augment the cytotoxic activity of the Lym-1 gelonin conjugate. These results suggest that anti-HLA class II monoclonal antibodies may be useful in constructing immunotoxins for the treatment of human lymphomas and leukemias expressing HLA class II antigens, and that unconjugated anti-HLA class II monoclonal antibodies may be therapeutically useful in conjunction with recombinant cytokines, especially gamma-interferon. PMID- 8680648 TI - Changes in an HER-2 peptide upregulating HLA-A2 expression affect both conformational epitopes and CTL recognition: implications for optimization of antigen presentation and tumor-specific CTL induction. AB - The HER-2/neu protooncogene (HER-2) is overexpressed in a significant number of breast and ovarian tumors. Peptides of HER-2 sequence were recently found to reconstitute recognition of cytotoxic T lymphocytes (CTLs) from tumor-associated (TALs) and tumor-infiltrating (TILs) lymphocytes, indicating that they reconstitute natural epitopes recognized by CTLs on HLA-A2+ tumors. Because HER-2 is an important antigen (Ag) for tumor-specific CTL induction and the immunogenicity of peptides for CTL induction is dependent on their presentation as stable complexes with HLA-A2, we identified peptides of high and low stabilizing activity from the sequence of HER-2 and the folate-binding protein (FBP). Distinct sequence patterns in the region positions (P)3-P5 and P1 were found for peptides with high (HSA) and low (LSA) stabilizing ability. A low-HLA A2-affinity HER-2 peptide, P1 of the CTL epitope, was found to be permissive to substitutions that enhanced HLA-A2-stabilizing ability and conserved CTL recognition. In contrast, the region P3-P5 was not permissive to sequence changes. We conclude that the selective permissivity of P1 and P9 in the tumor epitope sequence may have important implications for optimization of tumor Ag presentation, and "neoantigenicity" of self-antigens, aiming toward induction of tumor-reactive CTLs of defined affinity and specificity for target Ags. PMID- 8680651 TI - Phase I trial of an anti-CD19 deglycosylated ricin A chain immunotoxin in non Hodgkin's lymphoma: effect of an intensive schedule of administration. AB - In a phase I trial, eight patients with non-Hodgkin's B-cell lymphoma received mouse IgG1k monoclonal antibody HD37 specific for CD19 conjugated to deglycosylated ricin A chain (dgA) administered in four doses at 4-h intervals with total doses ranging from 4-12 mg/m2. This schedule generated serum levels of immunotoxin which were sustained over 36 h. The plasma half-life of HD37-dgA was 17 +/- 4 (SD) h. The HD37-dgA conjugate was stable in vivo as demonstrated by serum levels of HD37-dgA conjugate comparable to those of total HD37 antibody. Peak serum levels attained after the fourth dose ranged from 0.36 to 5.63 micrograms/ml. Two of seven evaluable patients developed modest human anti immunotoxin antibody responses. Toxicity in patients 1-7 consisted of dose dependent capillary leak syndrome with hypoalbuminemia, orthostatic hypotension, and weight gain. Patient 8 died on day 8 with severe capillary leak, bronchopneumonia, and rhabdomyolysis. All patients had progressive disease at 4 weeks except patient 8, who exhibited a near-complete remission before his death. This intensive schedule appears to produce inordinate toxicity with a maximal tolerated total dose of 8 mg/m2. PMID- 8680653 TI - A phase II trial of interleukin-2 and interferon-alpha in the treatment of metastatic colorectal carcinoma. AB - A total of 29 patients with stage IV colorectal cancer were entered into a phase II trial of bolus interleukin-2 (IL-2) and interferon-alpha (IFN alpha) (3 x 10(6) U/m2 of each cytokine given i.v. q8h x 15 doses and repeated in 2 weeks). Immunologic parameters measured on isolated peripheral blood lymphocytes revealed increased activated T cells with upregulated natural killer and lymphokine activated killer activity. Among 24 evaluable patients, there were 4 partial responses (17%) of short duration ( < or = 6 months). Three of the responding patients had been refractory to prior chemotherapy. Overall median survival in the 24 evaluable patients was 18.5 months. Therapy necessitated an inpatient setting, with the most common toxicities being hypotension, hepatic insufficiency, fever, hypocalcemia, nausea/vomiting, and renal insufficiency. There were two treatment-related deaths. Because neither IL-2 nor IFN alpha alone has significant activity against colorectal cancer, the responses observed in this study suggest a potential synergistic effect between the two cytokines. However, the toxicity and short duration of response without survival benefit do not support the routine use of this regimen as a therapeutic modality for this tumor histology. PMID- 8680652 TI - HLA associations in the antitumor response against malignant melanoma. AB - In this study we analyzed the human leukocyte antigen (HLA) pattern of North American Caucasian patients with metastatic melanoma as compared with the North American Caucasian (NAC) population. We also investigated whether the HLA type of melanoma patients had an effect on their tolerance and response to interleukin-2 (IL-2)-based therapy. Four hundred twelve serologic phenotypes of Caucasian melanoma patients referred to the National Cancer Institute, National Institutes of Health, from February 1989 through December 1993 were collected by typing the patient's peripheral blood lymphocytes. Furthermore, 74 melanoma patients were typed for HLA class II by high-resolution sequence specific primer-polymerase chain reaction. Response rate and treatment-related toxicity in those patients receiving IL-2-based treatment (N = 272) were compared with HLA serologic types. The frequency of four HLA-B alleles was significantly different in the melanoma compared with the NAC population: of these, HLA-B5, -B8, and -B15 had a frequency falling between the NAC and the Northern European population. No other significant differences between melanoma patients and NAC population were noted for other HLA loci. A correlation was noted between HLA-DR3 and -DR4 alleles and decreased tolerance to IL-2, whereas homozygosity for HLA-DR decreased the chance of response. There were no significant associations between HLA type and response. It is unlikely that the associations noted between some HLA-B alleles and melanoma bear significantly on the etiology of the disease. The differences seen between American melanoma patients and the NAC population are probably best explained by geographical ancestry. The association between HLA-DR and tolerance to IL-2 therapy noted in this study may offer insight toward the understanding of mechanisms regulating the cascade of events after the systemic administration of IL-2. PMID- 8680654 TI - Melanoma tumor-infiltrating lymphocytes derived from four distinct anatomic sites obtained from a single patient: comparison of functional reactivity and melanoma antigen recognition. AB - Tumor-infiltrating lymphocytes (TILs) were grown from four distinct anatomic sites from a patient with metastatic melanoma. The metastatic sites included a tumor-involved lymph node, a subcutaneous lesion obtained from the chest wall, a portion of bowel, and adrenal gland. TILs grown from each anatomic site over the course of 20 days in the presence of 6,000 IU/ml recombinant interleukin-2 exhibited comparable growth rates. Between days 30 and 45, the TILs were a mixture of CD3+ CD4+ and CD3+ CD8+ lymphocytes expressing the alpha beta form of the T-cell receptor. TILs derived from each anatomic site specifically lysed autologous tumor obtained from all four anatomic sites. In fine specificity analysis, the TILs exhibited human leukocyte antigen (HLA-A2)-restricted lysis of fresh tumor targets and cultured melanoma cell lines. Each TIL recognized a product of the MART-1 gene, and specifically, the monomer peptide MART-1(27-35). Thus lymphocytes reactive with the MART-1 melanoma antigen appeared to be widely distributed in diverse metastases in this patient. This information, along with previous data on the reactivity of multiple patients to this antigen, attests to its dominance in the immune reactivity of humans to melanoma. PMID- 8680655 TI - Thyroid dysfunction in 281 patients with metastatic melanoma or renal carcinoma treated with interleukin-2 alone. AB - The purpose of this prospective study was to determine the incidence of thyroid dysfunction in cancer patients receiving immunotherapy with interleukin-2 (IL-2) alone, and to assess the relationship of hypothyroidism to clinical response. A cohort of 281 consecutive patients with metastatic melanoma or renal carcinoma were treated with IL-2 alone from July 1, 1989 until June 30, 1993. The majority (n = 216) received high-dose IL-2 and the remainder (n = 65) received low-dose therapy. Thyroid function was measured before, during, and after immunotherapy. Forty-one percent of initially euthyroid patients developed thyroid dysfunction after starting high-dose IL-2-alone therapy. The most common abnormality was hypothyroidism, occurring in 35% of patients, although moderate or severe hypothyroidism requiring thyroid hormone replacement occurred in 9% of patients. Hypothyroidism was related to duration of IL-2 therapy and was not associated with clinical response. Hyperthyroidism developed in 7% of previously euthyroid patients receiving high-dose IL-2. Overall, the incidence of thyroid dysfunction was similar in the high- and low-dose IL-2 regimens. In conclusion, thyroid dysfunction is a common sequela of IL-2 therapy. Thyroid function should be measured routinely in cancer patients receiving IL-2-based treatment. It is recommended that thyroid hormone replacement be given to patients with moderate or severe hypothyroidism. PMID- 8680656 TI - [Nursing documentation on a ward of a nursing home for the aged]. PMID- 8680657 TI - [An operating room documentation for everyone. Documentation by checking off can mean considerable time savings]. PMID- 8680659 TI - [Nursing symposium for students in Lubeck. Tomorrow's nursing will be teamwork]. PMID- 8680658 TI - [Prevention of thrombosis. Drug therapy, legal aspects and considerations as to standards. III]. PMID- 8680660 TI - [We have no money anyway--even less for cheap things]. PMID- 8680661 TI - [Falls and their prevention]. PMID- 8680662 TI - [The misery with nursing process documentation or when does the hamster finally jump out of the running wheel?]. PMID- 8680663 TI - Should the American Thoracic Society seek a separate corporate structure apart from the American Lung Association? PMID- 8680665 TI - Pneumonia in intubated patients: role of respiratory airway care. AB - In order to assess potential risk factors for pneumonia within the first 8 d of ventilation, we studied 83 consecutive intubated patients undergoing continuous aspiration of subglottic secretions (CASS). Multivariate analysis showed the protective effect of antibiotic use (relative risk [RR] = 0.10; 95% confidence interval [CI] = 0.01 to 0.71), whereas failure of the CASS technique (RR = 5.29; 95% CI = 1.24 to 22.64) was associated with a greater risk of pneumonia. In addition, there was a trend toward a higher risk of pneumonia (RR = 2.57; 95% CI = 0.78 to 8.03) among patients with persistent intracuff pressures below 20 cm H2O. The remaining factors analyzed were not significant. Failure of CASS did not influence the development of pneumonia among patients undergoing antibiotic treatment (33.0% versus 38.5%, p > 0.20), but was strongly associated with pneumonia (42.1% versus 8.3%, p < 0.01) among intubated patients not receiving antibiotics. When multivariate analysis was repeated in this subpopulation, failure of CASS (RR = 7.52, 95% CI = 1.48 to 38.07) and persistent intracuff pressure below 20 cm H2O (RR = 4.23, 95% CI = 1.12 to 15.92) were factors independently associated with the development of pneumonia. We conclude that leakage of colonized subglottic secretions around the cuff of the endotracheal tube is the most important risk factor for pneumonia within the first 8 d of intubation. This study confirms the importance of maintaining adequate intracuff pressure and effective aspiration of subglottic secretions in preventing pneumonia in intubated patients not receiving antibiotic treatment. PMID- 8680664 TI - Pulmonary complications of HIV infection in Dar es Salaam, Tanzania. Role of bronchoscopy and bronchoalveolar lavage. AB - To determine the pulmonary complications in HIV-1-infected patients in Dar es Salaam, Tanzania, and to evaluate the diagnostic utility of bronchoscopy and bronchoalveolar lavage, we carried out a prospective study of 237 patients with acute respiratory disease who were hospitalized at Muhimbili Medical Center (MMC). Diagnoses were made using well-defined criteria. Of the total, 127 (54%) were HIV-1-seropositive and 110 (46%) were seronegative. Tuberculosis was the most common diagnosis occurring in 95 (75%) HIV-1-seropositive and 87 (79%) seronegative patients. Bacterial pneumonia was the next most common diagnosis occurring in 18 (14%) HIV-1-seropositive and 17 (15%) seronegative patients. Pneumocystis carinii pneumonia was diagnosed in one and Kaposi's sarcoma was seen in only two HIV-1-seropositive patients. Bronchoscopy with bronchoalveolar lavage was the sole source of a diagnosis in nine (8%) seropositive and six (5%) seronegative patients. We conclude that the HIV seroprevalence rate among patients hospitalized for acute respiratory disease at MMC is extremely high. Tuberculosis was the most common cause of pulmonary disease, regardless of HIV serostatus, and other HIV-associated opportunistic pulmonary infections were unusual. Bronchoscopy with bronchoalveolar lavage added little to the diagnosis and thus should not be high-priority procedures for the routine workup in resource-poor areas where tuberculosis is endemic. PMID- 8680666 TI - Mortality of nosocomial pneumonia in ventilated patients: influence of diagnostic tools. AB - The overmortality induced by nosocomial infections, especially pneumonia in ventilated patients (VNP), is still a matter of controversy because it is difficult to know precisely the respective effects of VNP per se and both the underlying illness and the severity of the disease that indicates ICU stay. During a 3-yr period, for each patient mechanically ventilated for more than 48 h we recorded underlying illness, reason for mechanical ventilation, clinical and therapeutic data collected during the first 48 h of ventilation, and death in the ICU. Patients with suspicion of VNP (S-VNP) according to clinical, radiologic, and biologic criteria underwent bronchoscopy with protected specimen brush (PSB) and bronchoalveolar lavage culture (BAL-C). VNP was confirmed (C-VNP) if PSB > or = 10(3) cfu/ml and/or BAL-C > or = 10(4) cfu/ml. Prognostic multivariate analysis was performed introducing S-VNP and C-VNP as time-dependent covariates. Of the 387 studied patients, 112 S-VNP and 56 C-VNP were observed with overall mortality of 43% (168 patients). MacCabe, APACHE II score, shock, use of sedatives and absence of enteral nutrition were additively associated with an increased mortality as well as C-VNP (relative risk [RR]: 1.8, p = 0.007). Nevertheless, when S-VNP and C-VNP were simultaneously introduced in the Cox model, only S-VNP remained associated with increased mortality. In patients suspected of VNP, confirmation of VNP using PSB and/or BAL-C adds no prognostic information. Whether this could be explained by the lack of sensitivity of protected distal samples or the severity of underlying conditions of S-VNP patients is still an open issue. A multivariate analysis based on follow-up data during the ICU course of ventilated patients will be initiated in the near future. PMID- 8680667 TI - Respiratory tract colonization and infection in patients with chronic tracheostomy. A one-year study in patients living at home. AB - The high rate of complications, especially respiratory tract infection (RTI), reported in patients with chronic tracheostomy (CT) has discouraged physicians from using this method. However, previous studies of CT have concerned mainly hospitalized patients. We have followed the bacterial colonization patterns of the upper and lower respiratory tract and recorded all RTIs in 39 outpatients with CT during a 12-mo period. Patients were colonized with one or more potential pathogens at the stomal site and in the trachea in 95% and 83%, respectively, of all sampling occasions. Staphylococcus aureus, gram-negative enteric bacteria (GNEB), and Pseudomonas aeruginosa were the most common colonizing bacteria at these sites. Seventy percent of bronchial-protected brush cultures were negative, despite simultaneous heavy colonization of the stomal site or the trachea. Only 18 of 39 (46%) patients were treated with antibiotics because of RTIs on a total of 30 occasions during the study year. Of these, only five episodes of pneumonia in four patients were registered, corresponding to an incidence of about 10 per 100 person years. We conclude that outpatients with chronic tracheostomy can be managed with a low risk for developing severe RTIs, despite massive airway colonization with potentially pathogenic bacteria. PMID- 8680668 TI - Exposure-sensitization relationship for alpha-amylase allergens in the baking industry. AB - Fungal alpha-amylase is an important occupational allergen in the bakery industry. Epidemiologic studies focusing on the relationship between alpha amylase allergen exposure and work-related respiratory allergy, however, have not been reported yet. In this cross-sectional study, sensitization to occupational allergens and work-related symptoms were studied in 178 bakery workers and related to allergen exposure. Alpha-amylase allergen concentrations were measured in personal dust samples, using a sandwich enzyme immunoassay. All workers were categorized into groups on the basis of their job histories and the alpha-amylase exposure levels of their job titles. Of all workers 25% had one or more work related symptoms. As much as 9% of the bakery workers showed a positive skin prick test reaction to fungal amylase, and in 8% amylase-specific IgE was demonstrated. Alpha-amylase exposure and atopy appeared to be the most important determinants of skin sensitization, with prevalence ratios for atopy of 20.8 (95% CI, 2.74 to 158) and for medium and high alpha-amylase exposure groups of 8.6 (95% CI, 1.01 to 74) and 15.9 (95% CI, 1.95 to 129), respectively. Furthermore, a positive association was found between positive skin prick tests to alpha-amylase and work-related respiratory symptoms. In conclusion, this study has shown that there is a strong and positive relationship between alpha-amylase allergen exposure levels in bakeries and specific sensitization in bakery workers. PMID- 8680669 TI - The risk of asthma attributable to occupational exposures. A population-based study in Spain. Spanish Group of the European Asthma Study. AB - The prevalence of occupational asthma has usually been estimated from registers of cases rather than population surveys. We examined the causes and derived estimates of the risk of asthma attributable to occupational exposures in a randomly selected population of five areas of Spain. The study is part of the EC Respiratory Health Survey and comprises 2,646 subjects age 20 to 44 yr. Bronchial reactivity was determined in 1,797 subjects and atopy in 2,164. Twenty-one occupational sets were defined using information on current occupation, or in subjects reporting change of occupation due to respiratory problems, their occupation at that time. The highest risk of asthma was observed for laboratory technicians, spray painters, bakers, plastics and rubber workers, welders, and cleaners. The risk of asthma attributed to occupational exposures after adjusting for age, sex, residence, and smoking status was 5.0% when asthma was defined as "bronchial reactivity and a report of wheezing or whistling in the chest during the last 12 mo," and 6.7% when asthma was defined as "bronchial reactivity and a report of asthma-related symptoms or medication." Estimates of the attributable risk for adult onset asthma were higher. Occupational exposures constitute a substantial cause of asthma in the young adult Spanish population. PMID- 8680670 TI - Segregation analysis of physician-diagnosed asthma in Hispanic and non-Hispanic white families. A recessive component? AB - The inheritance of asthma, evident from its high family concordance, is not well understood. To investigate whether asthma may be inherited through a major gene with two alleles, segregation analyses were conducted in 3,369 individuals from 906 nuclear families enrolled, without selection, in a longitudinal study of respiratory health in Tucson, Arizona. Physician-diagnosed asthma and its age of onset were ascertained for each family member when children were at a mean age of 7 yr. Age of asthma diagnosis was allowed for in analyses, and the impact of the covariate total serum IgE level on age of onset was examined. Segregation analyses were conducted with and without residual family effects, with and without the covariate IgE. The hypothesis of a single two-allele locus for asthma was rejected. However, depending on the method of assessment of the residual familial effects, either a polygenic/multifactorial mode of inheritance alone, or an oligogenic model with some evidence of a recessive component present in the population with the high frequency of 0.67, were compatible with the data. Results were unchanged with the addition of the covariate IgE. PMID- 8680671 TI - Tuberculosis screening for immigrants and refugees. Diagnostic outcomes in the state of Hawaii. AB - The effectiveness of the required overseas tuberculosis (TB) screening for immigrants and refugees to the United States has not been evaluated since new guidelines were introduced in 1991. Using data from the Hawaii State TB register for 1992-1993, patient records, and data from the U.S. government notifications of suspect TB among aliens, we determined the percentage of persons either classified as having active TB (B1), inactive TB (B2), or considered "normal" overseas, who were evaluated and subsequently diagnosed with active TB within 1 yr of arrival in the United States. Of the 124 TB cases among immigrants and refugees evaluated within 1 yr of arrival, 78 (63%) had been classified overseas as B1, 17 (14%) as B2, and 29 (23%) as "normal." The proportion of TB cases diagnosed after arrival in the United States was 14.0% for B1s and 2.1% for B2s. This proportion decreased with increasing age. A positive skin test was a strong predictor (OR: 10.7; 95% CI: 1.4-80.1) of culture-confirmed TB. These data document that immigrants and refugees with B1 and B2 TB status have a high prevalence of active TB. They should be promptly evaluated after arrival in the United States to determine the need for curative or preventive therapy. PMID- 8680672 TI - The effects of albuterol on the lung function of hospitalized patients with cystic fibrosis. AB - Twenty-four hospitalized patients with cystic fibrosis were enrolled into a 2-d, double-blind, placebo-controlled, randomized crossover trial comparing albuterol inhalation aerosol with a saline placebo. Aerosols were administered with the first three of four chest physiotherapy sessions given 4 h apart. Spirometry was measured before and 45 min after 7:00 A.M. and 3:00 P.M. therapy and before therapy at 7:00 P.M. and 7:00 A.M. the next morning. The mean percent change in FVC, FEV1, and FEF25-75% at 7:00 A.M. was 10.7, 14.8, and 19.6% with albuterol versus 2.4, 1.0, and -0.8% with placebo (p = 0.0012, < 0.0001, and = 0.003, respectively). A greater than 8% change in FEV1 separated changes with albuterol versus placebo with 96% specificity and occurred in 75% of all patients with albuterol; 71% at 7:00 A.M. versus 24% at 3:00 P.M. The reduction in response at 3:00 P.M. (p < 0.01) was presumably due to prolonged effects of morning therapy ( > 4 h). Individual changes in spirometry were significantly more positive and homogeneous with albuterol versus placebo at both 7:00 A.M. and 3:00 P.M. The mean percent change for the FVC, FEV1, and FEF25-75 across the day (7:00 A.M. pretherapy to 7:00 P.M. pretherapy) was 8.1, 10.1, and 9.7% with albuterol versus 3.9, 3.5 and 2.6% with placebo (p = 0.029, 0.036, and 0.232, respectively). The more positive and homogeneous changes in spirometry with albuterol, along with greater changes in these measures across the day when compared with placebo, suggest that albuterol improves pulmonary function in a majority of hospitalized patients with cystic fibrosis. PMID- 8680673 TI - Measurement of low-frequency respiratory impedance in infants. AB - Low-frequency respiratory impedance (Zrs) data permit the separate estimation of the mechanical properties of the airways and the tissues, but they are difficult to collect in humans because of the need for apneic conditions. We exploited the apneic phase produced by invoking the Hering-Breuer reflex with end-inspiratory airway occlusion in five sedated infants aged 9 to 16 mo. A computer-controlled pump and solenoid valves were used to inflate the supine infants through a face mask to a transrespiratory pressure of 20 cm H2O and to affect the airway occlusion. A loudspeaker-in-box system was connected to the mask through a side arm, and small-amplitude pseudorandom oscillations containing 23 frequency components between 0.5 and 20.75 Hz were applied for 6 s. Four consecutive measurements were made in each infant, and the averaged Zrs spectra were evaluated on the basis of a model containing the frequency-independent resistance (Raw) and inertance (law) of the airways, and the viscous damping (G) and elastance (H) parameters of the constant-phase compartment of the chest wall and parenchymal tissues. The measured Zrs values were consistent with the model up to 15 Hz, and the average fitting error was 0.89 +/- 0.11 (SD) cm H2O.s/L. The following parameter values were obtained: Raw = 10.0 +/- 2.1 cm H2O.s/L, law = 0.061 +/- 0.014 cm H2O.s2/L, G = 28.6 +/- 4.9 cm H2O/L, H = 141 +/- 55 cm H2O/L. The tissue hysteresivity (G/H) values were 0.218 +/- 0.061. Our results indicate that, in short apneic periods evoked by the Hering-Breuer reflex, reliable low frequency Zrs data can be collected to partition the tissue and airway impedances in sedated infants. PMID- 8680674 TI - Rapid-eye-movement-specific sleep-disordered breathing: a possible cause of excessive daytime sleepiness. AB - Some patients referred for polysomnography with complaints of excessive daytime sleepiness (EDS) and clinically suspected obstructive sleep apnea (OSA) have a respiratory disturbance index (RDI) < 10. Many would consider these patients not to have OSA. We reviewed 34 such patients to determine whether respiratory disturbances confined primarily to rapid eye movement (REM) sleep correlated with an objective criterion for EDS: a mean sleep latency (MSL) < 10 min. REM-specific events were quantified with indices calculated for REM sleep alone. Univariate linear regression showed that a REM-specific respiratory disturbance index (REM RDI) and the transient arousal index (TAI) computed for REM sleep (REM-TAI) were associated with a low MSL (R2 = -0.35, p = 0.001; and R2 = -0.27, p = 0.01, respectively). In our subjectively sleepy patients with an overall RDI < 10, a REM-RDI > or = 15 had the highest predictive accuracy (82%) for an MSL < 10 min. Seventeen of the 34 study patients had a REM-RDI > or = 15. Their mean MSL was 8.3 +/- 0.8 min. We conclude that within a group of patients with daytime sleepiness, suspected OSA, and a normal RDI, there may be a subset who have clinically significant REM-specific sleep-disordered breathing. PMID- 8680675 TI - Insulin resistance and sleep-disordered breathing in healthy humans. AB - Fifty healthy, normotensive individuals (34 women) with a mean age of 44.3 +/- 13.2 yr and a mean body mass index of 27.1 +/- 5.4 kg/m2 were tested for the presence or absence of insulin resistance and sleep-disordered breathing. The hypothesis of this investigation was that insulin resistance is associated with sleep-disordered breathing. In vivo insulin action with determination of steady state plasma glucose (SSPG) and insulin was measured using simultaneous intravenous infusion of somatostatin, glucose, and insulin via a Harvard pump. Determination of sleep-disordered breathing was performed through clinical assessment and portable nocturnal monitoring using a validated sleep apnea recorder. Individuals with > or = 10 hypoxic respiratory events per hour of sleep were significantly more insulin-resistant than subjects without sleep-breathing disorders. After adjusting the relationship between insulin resistance and sleep disordered breathing for potential confounding variables, it was found that this relationship was entirely dependent on body mass. PMID- 8680676 TI - Simulated driving performance in patients with obstructive sleep apnea. AB - To assist in determining ability to drive in patients with obstructive sleep apnea (OSA), we developed a divided attention driving test (DADT) based on the work of Moskowitz and Burns (6). We first examined its ability to detect impaired performance by testing normal subjects both sober and impaired by alcohol (mean blood alcohol level, 95 +/- 25 mg/dl). Subsequently, 21 male patients with OSA (age 49.3 +/- 12.7 [SD] yr; apnea hypopnea index [AHI] 73 +/- 29) and 21 age- and sex-matched control subjects underwent polysomnography followed by daytime sleep latency testing (MSLT). Before each day-time nap, subjects were given the DADT for 20 min. Patients who performed much worse than control subjects in all measures, with the largest difference noted in tracking error (OSA, 228 +/- 145 cm versus control 71 +/- 31 cm, p < 1 x 10(-9)). Half of the patients were worse than any control subject, with some showing performance worse than control subjects impaired by alcohol. However, MSLT and AHI explained less than 25% of the variance in tracking error, making individual prediction problematic. We concluded that in laboratory driving performance skills are markedly impaired in over half our group with sleep apnea. Further testing and comparing on-road performance should aid in predicting ability to drive. PMID- 8680677 TI - Trimethoprim and tetracycline inhibit airway epithelial sodium absorption. AB - Despite their frequent use in the treatment of chronic lung disease, the effect of antibiotics on the airway mucosa has not been defined. We have assessed the effect of a number of antibiotics on the ion transport processes of airway epithelia. Initial evaluation performed on sheep tracheal epithelium in vitro demonstrated that trimethoprim and tetracycline induced a rapid decrease in electrogenic ion transport. These responses were fully reversible, mediated through the mucosal surface, and reduced by amiloride pretreatment, suggesting inhibition of Na+ absorption. Serosal application of erythromycin produced a gradual decrease in short-circuit current, whereas other antibiotics (ampicillin, ceftazidime, colistin, chloramphenicol, gentamicin, and sulfamethoxazole) caused no significant change within 30 min of addition. In healthy human volunteers, trimethoprim and tetracycline induced a rapid decrease in nasal potential difference, which was attenuated by amiloride pretreatment. In subjects with cystic fibrosis, who exhibit increased Na+ absorption across respiratory epithelia, the responses to trimethoprim and tetracycline were enhanced, providing further evidence that these drugs inhibit Na+ absorption. In conclusion, this study has identified two antibacterial agents that also reduce the Na+ absorption found in CF. These drugs may offer combined effects for the treatment of CF. PMID- 8680678 TI - Mouth leak with nasal continuous positive airway pressure increases nasal airway resistance. AB - Nasal congestion, dry nose and throat, and sore throat affect approximately 40% of patients using nasal continuous positive airway pressure (CPAP). The mechanisms causing nasal symptoms are unclear, but mouth leaks causing high unidirectional nasal airflow may be important. We conducted a study to investigate the effects of mouth leak and the influence of humidification on nasal resistance in normal subjects. Nasal resistance was measured with posterior rhinomanometry in six normal subjects who deliberately produced a mouth leak for 10 min while using nasal CPAP. Nasal resistance was measured regularly for 20 min after the challenge. A series of tests were performed using air at differing temperatures and humidities. There was no change in nasal resistance when subjects breathed through their noses while on CPAP, but a mouth leak caused a large increase in resistance (at a flow of 0.5 L/s) from a baseline mean of 2.21 cm H2O/L/s to a maximum mean of 7.52 cm H2O/L/s at 1 min after the challenge. Use of a cold passover humidifier caused little change in the response (maximum mean: 8.27 cm H2O/L/s), but a hot water bath humidifier greatly attenuated the magnitude (maximum mean: 4.02 cm H2O/L/s) and duration of the response. Mouth leak with nasal CPAP leads to high unidirectional nasal airflow, which causes a large increase in nasal resistance. This response can be largely prevented by fully humidifying the inspired air. PMID- 8680679 TI - Comparison of computed density and microscopic morphometry in pulmonary emphysema. AB - The purpose of this prospective study was to verify whether the percentage area of lung occupied by lowest attenuation values on high-resolution computed tomography (HRCT) scans reflects microscopic emphysema and to compare this quantification with the information yielded by the most widely used pulmonary function tests (PFT). Preoperative HRCT scans were obtained with 1-cm intervals in 38 subjects. With a semiautomatic evaluation procedure, the percentage areas occupied by attenuation values inferior to thresholds ranging from -900 Hounsfield units (HU) to -970 HU were calculated for the lobe or lung to be resected. Emphysema was microscopically quantified by using a computer-based method, measuring the perimeters and interwall distances of alveoli and alveolar ducts. The strongest correlation was found for -950 HU. As a second step, we evaluated possible correlations between PFT and microscopic measurements. Finally, considering the microscopic measurements as a standard, we tried to investigate their relationships with each of the PFT and with the relative area occupied by attenuation values lower than -950 HU for both lungs. This revealed that the diffusing capacity for carbon monoxide associated with HRCT quantification is sufficient to predict microscopic measurements. We concluded that the percentage area of lung occupied by attenuation values lower than -950 HU is a valid index of pulmonary emphysema. PMID- 8680680 TI - The effect of an anti-CD3 monoclonal antibody on bleomycin-induced lymphokine production and lung injury. AB - Acute lung injury was produced in C57BL/6 mice by the intratracheal (i.t.) administration of bleomycin (BLM). Following injection of 0.1 U BLM, CD3+ lymphocytes and the production of the T-helper-1 (Th1) lymphokines interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) were increased in lung and lymph nodes. The production of the Th2 cytokine IL-4 by lung lymphocytes was decreased. Intraperitoneal (i.p.) injection of a rat antimurine CD3 (YCD3) monoclonal antibody (mAb) blocked the accumulation of pulmonary CD3+ cells for up to 14 d and effectively suppressed IL-2 and IL-4 but not IFN-gamma production by lung lymphocytes throughout the protocol. Secretion of all of the above lymphokines by lymph node cells was inhibited by YCD3 treatment. Administration of YCD3 diminished pulmonary fibrosis and increased survival (p < 0.01) following BLM administration compared with mice treated with an isotype-matched control mAb. Initiating treatment with YCD3 at Days 5-7 following BLM also decreased pulmonary fibrosis and significantly reduced mortality (p < 0.02). We conclude that BLM yields a potentially lethal fibroinflammatory response in the lung that is markedly diminished by antagonizing the functional activities of CD3+ cells in vivo. PMID- 8680681 TI - Inflammatory events in the blood and airways of guinea pigs immunized to toluene diisocyanate. AB - Toluene diisocyanate (TDI)-induced asthma is a common cause of occupational lung disease. We used a model to investigate the course of bronchopulmonary inflammation following immunization with TDI. Guinea pigs were immunized by weekly intradermal injections and challenged with TDI 7 d after the third injection. The animals were killed at different times after challenge and prepared for histologic examination of central and peripheral airways, for immunohistochemical studies of T lymphocyte and eosinophil distribution, and for hematologic and serologic investigations. Specific IgG1 against TDI were present only in immunized animals. In immunized TDI-challenged animals there was a significant increase in the number of metachromatic cells (at 24 h) and a late increase of eosinophils (at 48 h) in the peripheral blood. Mast cells and eosinophils were also increased in the submucosa of central airways of immunized TDI-challenged animals. A similar pattern was observed in the animals' peripheral airways. Additionally, a significant increase of T-lymphocytes and eosinophils was found in the lamina propria at 6 h after exposure in immunized TDI-challenged animals as compared with control animals. In these immunized animals, TDI challenge caused a significant increase of eosinophils, T-lymphocytes, and CD4+ T cells. These findings indicate that intradermal injections of TDI induced a specific antibody response as well as an inflammatory process in both central and peripheral airways. T cells, particularly CD4+ T cells and eosinophils, are the key cells in the immunopathologic alterations induced by TDI in the guinea pig lung. PMID- 8680682 TI - Nitric oxide synthase in neurons and nerve fibers of lower airways and in vagal sensory ganglia of man. Correlation with neuropeptides. AB - The mediator accounting for the major relaxant responses to electrical field stimulation of human airways was previously identified as nitric oxide (NO). In the present study, we examined the distribution of the neuronal isoform of the NO generating enzyme, nitric oxide synthase (bNOS, type I NOS) in nerve fibers of the human airways (trachea, large and small bronchi, bronchioli) as well as in human intrinsic and sensory ganglia of airway innervation by means of quantitative histochemistry (NADPH-diaphorase technique) and immunohistochemistry. Correlation with substance P (SP) and vasoactive intestinal peptide (VIP) was performed by double-labeling immunohistochemistry. NOS containing nerve fibers were found to be present in the airway smooth muscle, around submucosal glands, around blood vessels and, very rarely, in the lamina propria. The innervation density of airway smooth muscle by NOS-containing nerve fibers decreased significantly from trachea to large-diameter bronchi to small diameter bronchi, whereas NOS-containing nerve fibers were completely absent from bronchioli. Colocalization of NOS with VIP but not with SP was frequent in these nerve fibers. In airway intrinsic ganglia, the number of NOS-containing neuronal cell bodies increased from 57% in the trachea up to 83% in small bronchi. Around these perikarya, many nerve fibers displaying VIP-immunoreactive (VIP-IR) or SP IR were found. In the superior vagal sensory (i.e., jugular) ganglion most of the neuronal cell bodies contained either NOS-IR or SP-IR; a colocalization of both was not as frequent. These data contribute to the understanding of the morphologic basis underlying the functional differences of the neural relaxant responses mediated by NO at different levels of the airway tree. PMID- 8680683 TI - Acute safety and effects on mucociliary clearance of aerosolized uridine 5' triphosphate +/- amiloride in normal human adults. AB - Impaired mucociliary clearance contributes to the pathophysiology of several airways diseases including cystic fibrosis, asthma, and chronic bronchitis. Extracellular triphosphate nucleotides (adenosine 5'-triphosphate [ATP], uridine 5'-triphosphate [UTP]) activate several components of the mucociliary escalator, suggesting they may have potential as therapeutic agents for airways diseases. We conducted initial (Phase I) studies of acute safety and efficacy of aerosolized UTP alone and in combination with aerosolized amiloride, the sodium channel blocker, in normal human volunteers. Safety was assessed by measurement of pulmonary function. Neither UTP alone nor in combination with amiloride caused any clinically significant adverse effects on airway mechanics, (subdivisions of) lung volumes, or gas exchange. Acute efficacy of UTP and amiloride alone and in combination, was assessed by measuring changes in the clearance of inhaled radiolabeled particles. A 2.5-fold increase in mucociliary clearance was seen in response to UTP alone and in combination with amiloride. We conclude that aerosolized UTP +/- amiloride clearly enhances mucociliary clearance without acute adverse effects in normal adults, and may have therapeutic potential to enhance airways clearance in diseases characterized by retained airways secretions. PMID- 8680684 TI - Cellular infiltration of the airways in asthma of varying severity. AB - We have tested the hypothesis that airway infiltration by inflammatory cells reflects the severity of asthma by comparing the inflammatory cell infiltrates in fatal severe asthma and in subjects with mild to moderate asthma who died of unrelated causes. Sections of lung tissue from 25 fatal asthma cases and eight asthmatics who died of unrelated causes were immunostained by monoclonal antibodies (mAbs) using streptavidin-biotin peroxidase technique. The following cells were identified: mast cells (AA1:tryptase), eosinophils (EG1:stored cationic protein and EG2: secretory form of cationic protein), monocytes/macrophages (CD68), neutrophils (elastase), CD3+ and CD8+ T cells (CD3 polyclonal Ab and CD8+ mAb, respectively). Positive cells were counted in the epithelium and airway wall. The airways were divided into two groups: larger airways with internal perimeter (Pi) > 2 mm and smaller airways with Pi < 2 mm. All airways together were studied first, followed by larger and smaller airways examined separately. The numbers of intraepithelial CD3+ T cells were significantly lower in fatal asthma than in mild-moderate asthma both when all airways were considered (0.35 versus 0.86 cells/mm, p = 0.034) and in the larger airways alone (0.08 versus 1.05 cells/mm, p = 0.039). The numbers of EG1- and EG2 positive eosinophils infiltrating the airway wall of the larger airways were greater in fatal asthma than in mild-moderate asthma (78.2 versus 22.8 cells/mm2, p = 0.012 and 138.1 versus 31.7 cells/mm2, p = 0.022). In the smaller airways no significant difference was found between the two groups. We conclude that in fatal asthma there is a redistribution of CD3+ T cells away from the epithelium and proximal enhancement of the eosinophil inflammatory infiltrate. These findings have implications for the pathophysiology of asthma that results in death. PMID- 8680685 TI - Effect of oxitropium bromide on histamine-induced airway goblet cell secretion. AB - To determine whether histamine affects airway goblet cell secretion and, if so, whether cholinergic mechanism is involved, we studied guinea pig airways by a semiquantitative morphometric method. The goblet cell secretion was assessed in histologic sections of the tracheal mucosa stained with Alcian blue and periodic acid-Schiff (PAS) by determining the mucus score, which is inversely related to the magnitude of mucus discharge. Inhaled or intravenously administrated histamine dose dependently decreased the mucus score, an effect that was similarly observed in cartilaginous and muscular portions. Inhalation of the anticholinergic agent oxitropium bromide at doses of 1.5 micrograms and higher greatly attenuated the decrease in mucus score produced by intravenous histamine but not by inhaled histamine. Likewise, cutting of bilateral vagus nerves or atropine abolished intravenous histamine-induced goblet cell secretion. The response of the mucus score to inhaled histamine was abolished by cimetidine, whereas the response to intravenous histamine was reduced by mepyramine but not by cimetidine or thioperamide. These results suggest that inhaled histamine increases airway goblet secretion, probably by stimulating histamine H2-receptors on goblet cells, and that intravenous histamine produces a similar effect through a stimulation of histamine H1-receptor-mediated release of acetylcholine from cholinergic nerve terminals, presumably involving vagal reflex. PMID- 8680686 TI - Eosinophil apoptosis and the resolution of airway inflammation in asthma. AB - Asthma is accompanied by the accumulation of potentially damaging eosinophils within inflamed airways. How eosinophils may be removed from the airways is not clear. The phagocytic removal of eosinophils in vitro requires that they undergo apoptosis, a form of cell death. We postulated that eosinophil apoptosis may occur in vivo, promoting the removal of airway eosinophils and the resolution of inflammation in asthma. We examined eosinophil apoptosis in sputum samples obtained from 11 subjects during an asthma exacerbation and 2 wk after corticosteroid treatment of the exacerbation. Airway function improved following corticosteroid treatment, and eosinophilic inflammation subsided, with significant decreases occurring in the number of airway eosinophils and the percentage of activated eosinophils. The proportion of apoptotic airway eosinophils increased significantly following corticosteroid treatment, and eosinophil products were apparent within macrophages. Our findings indicate that eosinophil apoptosis is clinically relevant in asthma. Apoptosis may represent a mechanism that promotes the resolution of eosinophilic inflammation in asthma. PMID- 8680687 TI - Greater ozone-induced inflammatory responses in subjects with asthma. AB - In order to test the hypothesis that ozone (O3)-induced changes in lung function and respiratory tract injury/inflammation are greater in subjects with asthma than in normal subjects, we exposed 18 asthmatic subjects, on separate days, to O3 (0.2 ppm) and filtered air for 4 h during exercise. Symptom questionnaires were administered before and after exposure, and pulmonary function tests (FEV1, FVC, and specific airway resistance [SRaw]) were performed before, during, and immediately after each exposure. Fiberoptic bronchoscopy, with proximal airway lavage (PAL) of the isolated left main bronchus and bronchoalveolar lavage (BAL; bronchial fraction, the first 10 ml of fluid recovered) of the right middle lobe, was performed 18 h after each exposure. The PAL, bronchial fraction, and BAL fluids were analyzed for the following endpoints: total and differential cell counts; total protein, lactate dehydrogenase (LDH), fibronectin, interleukin-8 (IL-8), granulocyte-macrophage colony-stimulating factor (GM-CSF), myeloperoxidase (MPO), and transforming growth factor-beta (TGF beta 2) concentrations. We found a significant O3 effect on FEV1, FVC, SRaw (p < 0.04) and lower respiratory symptoms (p < 0.001) for the asthmatic subjects. Ozone exposure also significantly increased the percent neutrophils in PAL (p < 0.01); percent neutrophils, total protein, and IL-8 in the bronchial fraction (p < 0.001, p < 0.05, and p < 0.01, respectively); and the percent neutrophils, total protein, LDH, fibronectin, IL-8, GM-CSF, and MPO in BAL (p < 0.001, p < 0.01, p < 0.01, p < 0.001, p < 0.05, p < 0.01, and p < 0.001, respectively) for the asthmatic subjects. There were no significant differences in the lung function responses of the asthmatic subjects in comparison with a group of normal subjects (n = 81) previously studied using an identical protocol, although there was a trend toward a greater O3-induced increase in SRaw in the asthmatic subjects (p < 0.13). In contrast, the asthmatic subjects showed significantly greater (p < 0.05) O3-induced increases in several inflammatory endpoints (percent neutrophils and total protein concentration) in BAL as compared with normal subjects who underwent bronchoscopy (n = 20). Our results indicate that asthmatic persons may be at risk of developing more severe O3-induced respiratory tract injury/inflammation than normal persons, and may help explain the increased asthma morbidity associated with O3 pollution episodes observed in epidemiologic studies. PMID- 8680688 TI - Prejunctional inhibition of cholinergic responses by prostaglandin E2 in human bronchi. AB - The effect of prostaglandin E2 (PGE2) on cholinergic responses elicited by electrical field stimulation (EFS) (8 Hz, 1 ms, 8 V for 10 s every 100 s) of human isolated human bronchi was studied. Indomethacin (1 microM) was found to produce approximately a 100% increase in the cholinergic response. In the presence of indomethacin, PGE2 (1-300 nM) was found to concentration-dependently inhibit the cholinergic responses to EFS. A maximal inhibition was obtained with 100 nM PGE2 which produced an 80% inhibition of the cholinergic response. By contrast 100 nM PGE2 was without significant effect on the concentration response curve to exogenously added acetylcholine. The inhibitory effect of PGE2 on the EFS-induced cholinergic responses was not modified by the large conductance Ca(2+)-activated K+ channel inhibitor charybdotoxin (100 nM). These results suggest that endogenously released prostaglandins, presumably PGE2, act to inhibit cholinergic responses by a prejunctional mechanism in human isolated bronchi. In contrast to other autocoids, this inhibition does not involve the activation of large-conductance Ca(2+)-activated K+ channels. PMID- 8680690 TI - The American Lung Association Conference on re-establishing control of tuberculosis in the United States. PMID- 8680689 TI - Endogenous nitric oxide is decreased in asthmatic patients by an inhibitor of inducible nitric oxide synthase. AB - Exhaled nitric oxide (NO) may be derived from constitutive NO synthase (NOS) in normal airways, but the increased concentration in asthma is likely to be derived from inducible NOS expressed in inflamed airways. To investigate this, we administered a nonselective NOS inhibitor, NG-nitro-L-arginine methyl ester (L NAME), and a selective inhibitor of inducible NOS, aminoguanidine, by nebulization in a double-blind, placebo-controlled manner in both normal subjects and subjects with asthma. L-NAME resulted in a significant reduction in exhaled NO compared with saline control in eight normal subjects (maximum fall from baseline, 53 +/- 7.6% versus 8.9 +/- 6.5%; P < 0.05) and in seven patients with asthma (maximum fall, 67 +/- 7.4% versus 10 +/- 7.4% versus 10 +/- 9.3%; p < 0.05). Aminoguanidine at the same molar concentration decreased exhaled NO in subjects with asthma (maximum fall, 53 +/- 7.2% versus 7.1 +/- 10.4%; p < 0.05), but caused no significant change in normal volunteers (maximum fall, 28 +/- 9.3 versus 15 +/- 11). No rise in blood pressure, fall in FEV1, or adverse effects were observed in either subject group. We have demonstrated that NOS inhibitors can safely be given by inhalation in a single does in normal subjects and subjects with asthma. The raised exhaled NO concentration in patients with asthma may be attributable to induction of NOS, with that in normal subjects reflecting basal constitutive NOS activity. PMID- 8680691 TI - ATS recommendations for DLCO. PMID- 8680692 TI - Does the protective effect of neonatal BCG vaccination correlate with vaccine induced tuberculin reactions? PMID- 8680693 TI - Non-invasive determination of cardiac output in patients with severe airflow limitations. PMID- 8680694 TI - The 1995 update of recommendations for a standard technique for measuring the single-breath carbon monoxide diffusing capacity (transfer factor) PMID- 8680695 TI - PEF variability, bronchial responsiveness and their relation to allergy markers in a random population (20-70 yr). AB - We investigated the coherence of bronchial hyperresponsiveness (BHR) and peak expiratory flow (PEF) variability in their relation to allergy markers and respiratory symptoms in 399 subjects (20-70 yr). Bronchial hyperresponsiveness to methacholine was defined by both the provocative dose causing a fall in FEV1 of 20%, and the dose-response slope. PEF variability was determined as diurnal PEF variation (amplitude percent mean) and between-day PEF variation. Skin tests positivity, serum total IgE, and specific IgE (RAST) for house-dust mite (HDM), cat, timothy grass, and birch ("pollen") were determined, as well as the number of peripheral blood eosinophils. Wheeze and nocturnal dyspnea were defined as asthma-like symptoms; dyspnea > or = grade 3, cough and phlegm as chronic obstructive pulmonary disease (COPD)-like symptoms. The reciprocal of the dose response slope and PEF variability were significantly correlated (r = -0.39). Subjects with a positive skin test for HDM (odds ratio [OR] = 3.9), cat (OR = 8.3), or pollen (OR = 3.6), or specific IgE for HDM (OR = 2.3), cat (OR = 3.4), or pollen (OR = 1.9) had increased risk of BHR compared with the reference group (all p values < 0.05). Higher levels of serum total IgE were significantly associated with higher odds for BHR (OR = 2.5 per log unit). There was no significant association between skin test positivity, serum total IgE, or presence of specific IgE and PEF variability. Neither BHR nor PEF variability were associated with higher numbers of peripheral blood eosinophils. There are different associations of BHR and PEF variability with allergy markers. Although BHR and PEF variability are significantly correlated, they cannot be used interchangeably in epidemiologic settings. PMID- 8680696 TI - The interaction of alpha 1-proteinase inhibitor and tissue kallikrein in controlling allergic ovine airway hyperresponsiveness. AB - We reported previously that the development of airway hyperresponsiveness (AHR) 24 h after antigen challenge in allergic sheep was associated with increased tissue kallikrein activity (TK) and decreased alpha-1-proteinase inhibitor (alpha 1-PI) activity in bronchoalveolar fluid (BAL). The inverse correlation between TK and alpha 1-PI in these experiments suggested that administration of alpha 1-PI might reduce TK activity and block AHR. To test this hypothesis, airway responsiveness, as determined by calculating the cumulative carbachol breath units (BU) that increased specific lung resistance by 400% (PC400), was measured before and 24 h after aerosol challenge with Ascaris suum antigen in seven sheep hypersensitive to this antigen. On the next day, 30 min before the 24 h PC400 measurement, the sheep were treated with either aerosol alpha 1-PI (Prolastin, 10 mg/5 ml) or denatured (DN) prolastin (10 mg/5 ml), which had only 10% of its original activity. BAL was also performed before and 24 h after challenge for the measurement of TK and alpha 1-PI activity. Treatment with DN-Prolastin at 24 h after antigen challenge did not block antigen-induced AHR: PC400 fell from a baseline (mean +/- SE) of 26.0 +/- 3.2 BU to 11.2 +/- 1.5 BU after challenge (p < 0.05). This AHR was associated with increased TK (363%, p < 0.05) and decreased alpha 1-PI activity (65%, p < 0.05). Prolastin treatment at 24 h blocked the AHR: PC400 was 21.0 +/- 2.8 before and 23.2 +/- 3.7 after challenge (p < 0.05 versus DN-Prolastin) and the changes in BAL TK (28% increase) and alpha 1-PI activities (15% increase) were not different from baseline (both p < 0.05 versus DN Prolastin). There was a significant inverse correlation between alpha 1-PI activity and TK activity in BAL, as well as the changes between baseline and 24 h in alpha 1-PI activity and TK activity in BAL Pretreatment (30 min before antigen challenge) with Prolastin also protected against the antigen-induced AHR. The effect of Prolastin was also seen against aerosol challenge with high-molecular weight kininogen (HMWK), a substrate of TK. HMWK caused bronchoconstriction which was blocked by Prolastin (p < 0.05), and the bradykinin B2 antagonist, NPC-567 (indicating that kinins were generated), but not DN-Prolastin or the elastase inhibitor, ICI 200, 355. Although the negative association between alpha 1-PI activity and TK activity identified in this study does not prove cause and effect, our findings do raise the possibility that in vivo alpha 1-PI may regulate TK activity and allergen-induced AHR. PMID- 8680697 TI - Muscarinic inhibitory autoreceptors in different generations of human airways. AB - The present study was undertaken to investigate the functional presence of inhibitory muscarinic M2 autoreceptors on postganglionic cholinergic nerve endings in different generations of human airways. To this end, the effects of the M2-selective muscarinic receptor antagonists AQ-RA 741 and gallamine were studied on electrical field stimulation-induced twitch contractions of preparations from trachea and from bronchial airways of varying diameter. Furthermore, electrically evoked release of endogenous acetylcholine from human bronchial preparations, and the effect of the muscarinic receptor antagonist atropine thereon, was measured by high-performance liquid chromatography. On average, twitch contractions were significantly but only slightly (11 to 15%) potentiated by M2-selective concentrations of AQ-RA 741 and gallamine, despite approximately half of the preparations showing no potentiation at all. A subdivision into airway generations showed that M2 autoreceptor function was not readily detectable in bronchioles and subsegmental bronchi. By contrast, both with AQ-RA 741 and gallamine a clear potentiation (26 to 36%) of the twitch contractions was observed in approximately half of the terminal bronchi and in all central airway preparations. Moreover, the evoked release of endogenous acetylcholine in terminal and subsegmental bronchi was significantly facilitated by atropine, to 162 to 189% of controls. These results provide strong and partly direct evidence for the existence of inhibitory muscarinic M2 receptors on postganglionic cholinergic nerve endings in human central airways and subsegmental and terminal bronchi, but not in bronchioli. It remains to be established, however, why these M2 receptors exhibit a rather variable functionality in regulating cholinergic nerve-mediated contraction in different airway generations. PMID- 8680698 TI - Shared amino acid motifs in T-cell receptor beta junctional regions of bronchoalveolar T cells in patients with pulmonary sarcoidosis. AB - To clarify the nature of the accumulated lung T cells of pulmonary sarcoidosis, we studied bronchoalveolar and peripheral blood (PB) lymphocytes from Japanese patients for expressed T-cell receptor beta-chain variable (TCR V beta) gene usage. Quantitative polymerase chain reaction technique revealed that the V beta repertoires of bronchoalveolar and PB T cells were heterogeneous. However, the bronchoalveolar lymphocytes from five out of 10 patients showed overrepresentation of T cells, with a few TCR V beta families, which varied among individuals, possibly reflecting a difference in the human leukocyte antigen (HLA) backgrounds. Nucleotide sequence analysis of third complementarity determining region (CDR3) segments in overrepresented V beta families demonstrated limited diversity of the transcripts. Two HLA-DR 12(5)+ individuals with overrepresented V beta 6 gene transcripts in the lungs shared a common amino acid motif within their CDR3. By contrast, non-overrepresented TCR V beta transcripts did not show clonal expansion, and the oligoclonal clones in the lung were not found in PB of the corresponding patient. These results showed that, at least in subsets of Japanese patients with pulmonary sarcoidosis, a limited number of T-cell clones are accumulated in the lung in response to a specific antigen. They may mediate an immune response to shape pathology of the disease. PMID- 8680699 TI - Bronchoscopic surfactant administration in patients with severe adult respiratory distress syndrome and sepsis. AB - The present study was performed on 10 patients with severe adult respiratory distress syndrome (ARDS), all suffering from sepsis (mean lung injury score [LIS] (1): 3.25 +/- 0.1; duration of mechanical ventilation upon study entry: 3.1 +/- 0.6 d). Ex vivo analysis of the alveolar surfactant system, obtained by bronchoalveolar lavage (BAL), showed severe impairment of surfactant function. Three hundred milligrams of natural surfactant/kg body weight (Alveofact) was delivered bronchoscopically in separate doses to each segment of both lungs. This caused an immediate increase in PaO2/FlO2 from 85 +/- 7 mm Hg to 200 +/- 20 mm Hg (p < 0.001), mainly due to a decrease in shunt flow (42 +/- 4 to 20 +/- 2% [p < 0.001]). Reanalysis of the alveolar surfactant showed that its function was significantly improved. In five patients the increase in arterial oxygenation was partially lost within the next few hours, and a second dose of 200 mg/kg surfactant was applied 18 to 24 h later, again increasing PaO2/FlO2 values. Eight patients survived the subsequent 14-d observation period with progressive improvement of gas exchange, and five patients were definitely weaned from the respirator. All fatalities were due to non-respiratory causes. We conclude that the bronchoscopic application of a high dose of surfactant aimed at overcoming inhibitory factors in the alveolar space of these patients, may offer a feasible and safe approach to improving gas exchange in severe ARDS. PMID- 8680700 TI - Panic anxiety, dyspnea, and respiratory disease. Theoretical and clinical considerations. AB - There is intriguing evidence suggesting pathophysiologic relationships among dyspnea, hyperventilation, and panic anxiety. The symptoms of panic attacks and pulmonary disease overlap, so that panic anxiety can reflect underlying cardiopulmonary disease and dyspnea can reflect an underlying anxiety disorder. The pathogenesis of panic may be related to respiratory physiology by several mechanisms: the anxiogenic effects of hyperventilation, the catastrophic misinterpretation of respiratory symptoms, and/or a neurobiologic sensitivity to CO2, lactate, or other signals of suffocation. In a subset of patients with PD, incipient pulmonary dysfunction may also contribute to their anxiety symptoms. Patients with pulmonary disease, particularly those with obstructive lung disease, have a high rate of panic symptoms and PD. There is reason to believe that pulmonary disease constitutes a risk factor for the development of panic related to repeated experiences with dyspnea and life-threatening exacerbations of pulmonary dysfunction, repeated episodes of hypercapnia or hyperventilation, the use of anxiogenic medications, and the stress of coping with chronic disease. Panic in pulmonary patients may carry significant morbidity, including phobic avoidance of activity, overly aggressive treatment with anxiogenic medications, and more prolonged and frequent hospitalization. Successful treatment of panic in these patients can improve functional status and quality of life by relieving anxiety and dyspnea. Nonpharmacologic treatment of panic, including cognitive behavioral approaches, can be useful in patients with concomitant respiratory disease. Sedating medications such as benzodiazepines should be used with caution in patients with pulmonary disease to avoid respiratory depression. Serotonergic antidepressants (SSRIs) and anxiolytics (buspirone) may be effective treatments for panic or generalized anxiety in pulmonary patients and have relatively little potential for significant adverse effects. PMID- 8680701 TI - Diaphragmatic fatigue following voluntary hyperpnea. AB - The purpose of this study was to determine whether diaphragmatic fatigue occurs after voluntary hyperpnea to task failure. Ten male subjects were asked to breathe at minute ventilation (V1) equal or slightly greater than 60% of their 12 s maximum voluntary ventilation (MVV) until task failure. Transdiaphragmatic pressure (Pdi) was measured during bilateral supramaximal stimulation of the phrenic nerves before and 10, 30, 60, and 120 min after hyperpnea. For the group, V1 averaged 107.1 +/- 7.1 L/min (SE) (range, 71-154 L/min), which represented 60 +/- 2% of the MVV. After voluntary hyperpnea, seven of the 10 subjects displayed at least a 10% reduction in twitch Pdi during transcutaneous stimulation, while all 10 subjects had a greater than 10% reduction in twitch Pdi during cervical magnetic stimulation. For the group, transcutaneous twitch Pdi was significantly decreased from 27.0 +/- 1.9 at baseline to 21.4 +/- 1.7 cm H2O (p < 0.0001) at 10 min posthyperpnea. Magnetic twitch Pdi was also significantly decreased from 36.0 +/- 2.1 at baseline to 28.7 +/- 1.9 cm H2O (p < 0.0001) at 10 min posthyperpnea. Twitch Pdi remained significantly decreased from baseline for at least 1 h after hyperpnea. After hyperpnea, the mean percentage decrease from baseline in twitch Pdi was virtually identical with the two stimulation techniques. The percentage fall in twitch Pdi after hyperpnea with the two techniques was not significantly correlated (r = 0.4). In conclusion, long-lasting contractile fatigue of the diaphragm reliably occurs after voluntary hyperpnea at levels sufficient to induce task failure. Cervical magnetic stimulation can detect diaphragmatic fatigue after a fatiguing task, but the results obtained with this technique may differ from those obtained with transcutaneous stimulation in individual subjects. PMID- 8680702 TI - Serial measures of total body oxygen consumption in an awake canine model of septic shock. AB - We examined serial changes in total body oxygen consumption (Vo2) in a permanently tracheotomized canine sepsis model. On Day 0, beagles had an Escherichia coli-infected (septic) or sterile (control) clot surgically placed in the peritoneum. During the 21-d study, 10 of the 16 septic animals and none of the six control animals died (p = 0.02). After clot placement septic versus control animals had decreased mean arterial blood pressure (mm Hg; Day 1: 106 versus 128, p = 0.055; Day 2: 95 versus 125, p = 0.004, respectively) and left ventricular ejection fraction (Day 1: 0.44 versus 0.69, p = 0.0006; Day 2: 0.33 versus 0.57, p = 0.0001, respectively). Despite significant lethality and cardiovascular dysfunction, in the septic group on Days 1 and 2, septic versus control animals had no significant differences in mean metabolic cart measured (Vo2DIR, ml/kg/min; Day 1: 11.9 versus 12.4, p = 0.81; Day 2: 14.2 versus 13.5, p = 0.72, respectively) and intravascular catheter calculated (Vo2INDIR, ml/kg/min; Day 1: 11.2 versus 11.2, p = 0.99; Day 2: 12.8 versus 15.4, p = 0.49, respectively). On Day 1 in septic and control animals, volume infusion produced increases (p < 0.001) in oxygen delivery (Do2). In septic and control animals these changes in Do2 were similar and were associated with similar increases in Vo2DIR (p = 0.001), and Vo2INDIR (p = 0.001). In fact, at all time points studied (baseline, Day 1, 2, and 21), both before and after volume infusion, levels of Do2, Vo2DIR, and Vo2INDIR did not differ between septic and control animals, nor did they differ between septic survivors and nonsurvivors. Because levels of Vo2DIR and Vo2INDIR were similar in both groups, we pooled data from septic and control animals. Throughout the study, Vo2 showed a moderate association with Vo2INDIR (r = 0.55, p = 0.003), but mean Vo2DIR was lower at baseline (p = 0.001) and on Day 21 (p = 0.07) and greater on Day 2 (p < 0.01). In summary, our techniques, which detected small changes in both Vo2DIR and Vo2INDIR occurring with volume infusion, did not demonstrate differences in these parameters comparing control and septic animals. These results in euvolemic septic animals suggest that total body Vo2 may not reflect pathogenetic mechanisms during sepsis and septic shock. Furthermore, these results suggest that although the level of total body Vo2 may reflect the effects of therapeutic interventions such as volume loading, it should not itself serve as a therapeutic target. PMID- 8680703 TI - Changes in the inflammatory response of the lung during acute respiratory distress syndrome: prognostic indicators. AB - We studied paired bronchoalveolar lavage (BAL) in patients with sepsis-associated acute respiratory distress syndrome (ARDS). Patients were evaluated at one institution and underwent bronchoscopy with BAL within 48 h of the onset of ARDS. Patients were restudied with bronchoscopy and BAL after 4 d of treatment. Fifty eight patients were initially studied, with 44 patients having follow-up bronchoscopy after 4 d. The overall 30-d survival for the ARDS group was 60%. In the initial lavage, there was no difference in the neutrophils between the survivors and nonsurvivors (survivors: 59 [0-98]%; Median [Range]; nonsurvivors: 55 [0-92]%). The follow-up lavage demonstrated a significant drop in the neutrophils for the survivors (36 [4-89]%, p < 0.002) which was not seen for the nonsurvivors (70 [26-95]%). Initial IL-8 concentrations in the BAL fluid were not significantly different between the two groups. In the follow-up lavage, there was a significant fall for the IL-8 concentrations for the survivors but not the nonsurvivors. We conclude that neutrophil influx in ARDS may rapidly resolve within a week of the onset of ARDS. The resolution of neutrophils was associated with a good prognosis. PMID- 8680704 TI - Benefits of the low pressure multichannel endotracheal ventilation. AB - Mechanical ventilation using a modified endotracheal tube, allowing bypass and washout of the endotracheal dead space (McETV), was compared with conventional controlled mechanical ventilation (CMV) in healthy and in surfactant-depleted rabbits. In healthy animals, shifting from CMV to McETV led to an increase in PaO2 (89 +/- 16 versus 104 +/- 13 mm Hg; p < 0.05) and a decrease in PaCO2 (41.5 +/- 3 versus 30 +/- 3 mm Hg; p < 0.05). As a result of reducing the peak inspiratory pressure (PIP) from 21 +/- 2 to 12 +/- 2 cm H2O (p < 0.05), it was possible in McETV mode to maintain comparable ventilation to that achieved by CMV. In surfactant-depleted animals, compared with CMV, McETV produced a rise in PaO2 without change in thoracic volume (from 100 +/- 40 to 150 +/- 60 mm Hg, p < 0.05) and a fall in PaCO2 (from 46 +/- 5 to 37 +/- 4 mm Hg, p < 0.05). After 4 h of ventilation, the surfactant-depleted animals from the CMV group developed thoracic overdistension quicker (at hour 1, p < 0.05) and, consequently, more animals died from pneumothorax compared with the McETV group (five versus two). We concluded that McETV ensured adequate gas exchanges with lower insufflation pressures and could diminish positive pressure ventilation-induced injury. PMID- 8680705 TI - Effect of ventilator-associated pneumonia on mortality and morbidity. AB - The aim of this study was to evaluate the attributable mortality and excess intensive care unit (ICU) stay as linked to ventilator-associated pneumonia (VAP) in a medical-surgical ICU. We performed a matched cohort study. The diagnosis of VAP was established when clinical, biologic, and radiologic signs of VAP were associated with the presence of at least one microorganism at a concentration > or = 10(3) CFU/ml on the protected specimen brush sample. Each case patient with VAP was matched to one control patient on the basis of the following potential confounding factors: same diagnosis and same indication for mechanical ventilation, same age +/-5 yr, same sex, same APACHE II score +/-5 on admission. In addition, control patients had to be ventilated for at least as long as the case patient prior to the onset of VAP, and date of admission of the case and control patients had to be matched within 1 yr. In 85 of the 97 patients with VAP, we were able to match one case patient with one control patient. Mortality was similar in both case (40%) and control (38.8%) patients. The duration of mechanical ventilation was increased in survivor case patients (27.2 +/- 24.7 d) compared with survivor control patients (18.5 +/- 15.7 d) (p < 0.01). The duration of hospitalization in ICU was increased in survivor case patients (34.9 +/- 23.6 d) compared with survivor control patients (26.1 +/- 18.6 d) (p < 0.02). When confounding factors were controlled, VAP did not appear to increase mortality. PMID- 8680706 TI - Evaluation of surfactant treatment strategies after prolonged graft storage in lung transplantation. AB - We have previously documented alterations in endogenous surfactant after lung transplantation and improved graft function in some dogs after instillation of bovine lipid extract surfactant (bLES) into the recipient. To determine the effect of bLES delivery method and timing of treatment on physiologic response and surfactant recovery, 21 canine left lung grafts were divided into four groups: (1) Treatment of the donor for 3 h with aerosolized bLES prior to graft storage (Donor Aerosol); (2) Treatment of the recipient with instilled bLES immediately after transplantation (Recipient Instilled); (3) No bLES treatment (Control); and (4) Aerosolized bLES in donors and instilled bLES in recipients (Combined Therapy). Aerosolized bLES was labeled with [3H] dipalmitoylphosphatidylcholine (DPPC) and instilled bLES with [14C]-DPPC. Grafts were stored for 36 h, transplanted and reperfused for 6 h. The native right and transplanted left lungs were then lavaged and protein yield, surfactant aggregates, and bLES recovery were measured. After 6 h of reperfusion, PO2/FlO2 ratio was significantly better after Combined Therapy (372 +/- 52 mm Hg) than in the Recipient Instilled (117 +/- 47 mm Hg) and Control groups (87 +/- 26 mm Hg), with intermediate values in Donor Aerosol dogs (232 +/- 64 mm Hg). The recovery of donor aerosolized bLES from transplanted lungs was increased in dogs given Combined Therapy versus Donor Aerosol treatment alone (p = 0.03). Furthermore, with Combined Therapy there was an increased percentage of instilled bLES recovered from transplanted lungs compared with the Recipient Instilled group. We conclude that surfactant treatment strategies influence physiologic response and bLES recovery after prolonged lung preservation. Treatment of lung donors with exogenous surfactant prior to graft storage was associated with less severe lung injury. Combined donor and recipient bLES therapy resulted in a superior physiologic response during reperfusion in this model. PMID- 8680707 TI - Involvement of endothelin in the pressor response following injection of NMDA to the periaqueductal gray area of rats. AB - Microinjection of N-methyl-D-aspartate (NMDA) (0.068 to 6.8 nmol) into the periaqueductal gray area (PAG) of anaesthetized rats caused dose-dependent increases in blood pressure. Preinjection (10 min before) of FR 139317 (an ETA receptor selective antagonist; 5 nmol) or SB 209670 (an ETA/ETB receptor non selective antagonist; 5 nmol) to the PAG reduced the pressor response to NMDA whereas BQ-788 (an ETB receptor selective antagonist; 5 nmol) did not affect the NMDA-induced hypertension. Pretreatment with DL-2-amino-5-phosphono valeric acid (2-APV) (an NMDA receptor selective antagonist, 5 nmol) also abolished the pressor response induced by NMDA. Dose-dependent increases in blood pressure induced by injection of angiotensin II (0.1-10 nmol) to the PAG were unaffected by FR 139317 or SB 209670. Thus, our data indicate that endogenous ET-1, via an action on ETA receptors, contributes to the pressor effects of NMDA within the brain. PMID- 8680708 TI - Blockade by sigma site ligands of N-methyl-D-aspartate-evoked responses in rat and mouse cultured hippocampal pyramidal neurones. AB - 1. The effects of a range of structurally-dissimilar compounds which possess affinity for sigma binding sites were examined on the responses of cultured hippocampal pyramidal neurones to the excitatory amino acid analogues N-methyl-D aspartate (NMDA), kainate and (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4 propionic acid (AMPA). 2. In mouse hippocampal neurones under whole-cell voltage clamp, the compounds tested reversibly attenuated NMDA-, but not kainate- or AMPA , evoked currents with a rank order potency (IC50 values in microM): ifenprodil (0.8) > (+)-N-allylnormetazocine (1.1) > dextromethorphan (1.8) = haloperidol (1.9) > (+)-pentazocine (7.2) > 1S,2R-(-)-cis-N-methyl-N-[2-(3, 4-dichlorophenyl) ethyl]-2-(1-pyrrolidinyl)cyclohexylamine (17) = rimcazole (18) > 1,3-di(2 tolyl)guanidine (37) > opipramol (96) > caramiphen (110) = carbetapentane (112) > > (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (485). 3. The attenuation of NMDA-evoked responses was not mediated through interactions with the agonist, glycine (except haloperidol) or polyamine (except ifenprodil) binding sites on the NMDA receptor-channel complex but, in the light of the voltage- and, in some cases, use-dependent nature of their antagonism, an interaction with the ion channel appears to be a likely mechanism of action for many of the compounds. 4. Micromolar concentrations of selected sigma site ligands also reduced NMDA-evoked rises in intracellular free calcium concentration in Fura-2-loaded cultured hippocampal neurones of the rat with the same rank order potency as observed in the electrophysiological studies. 5. The data indicate that, at micromolar concentrations, the sigma site ligands tested act as NMDA receptor antagonists, an action which does not appear to be mediated by high-affinity sigma binding site(s). The functional effects of micromolar concentrations of sigma site ligands cannot, therefore, be attributed exclusively to interactions with high affinity sigma binding sites. PMID- 8680709 TI - Blockade by sigma site ligands of high voltage-activated Ca2+ channels in rat and mouse cultured hippocampal pyramidal neurones. AB - 1. The effects of a series of structurally-dissimilar sigma site ligands were examined on high voltage-activated Ca2+ channel activity in two preparations of cultured hippocampal pyramidal neurones. 2. In mouse hippocampal neurones under whole-cell voltage-clamp, voltage-activated Ca2+ channel currents carried by barium ions (IBa) were reduced with the rank order (IC50 values in microM): 1S,2R (-)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]- 2-(1 pyrrolidinyl)cyclohexylamine (7.8) > rimcazole (13) > haloperidol (16) > ifenprodil (18) > opipramol (32) > carbetapentane (40) = 1-benzylspiro[1,2,3,4 tetrahydronaphthalene-1,4-piperidine] (42) > caramiphen (47) > dextromethorphan (73). At the highest concentrations tested, the compounds almost abolished IBa in the absence of any other pharmacological agent. 3. The current-voltage characteristics of the whole-cell IBa were unaffected by the test compounds. The drug-induced block was rapid in onset and offset, with the exceptions of carbetapentane and caramiphen where full block was achieved only after two to three voltage-activated currents and was associated with an apparent increase in the rate of inactivation of IBa. 4. In rat hippocampal neurones loaded with the Ca(2+)-sensitive dye Fura-2, rises in intracellular free Ca2+ concentration evoked by transient exposure to 50 mM K(+)-containing medium, either in the absence or in the presence of 10 microM nifedipine (to block L-type high voltage activated Ca2+ channels), were also reversibly attenuated by the sigma ligands. The rank order potencies for the compounds in these experimental paradigms were similar to that observed for blockade of IBa in the electrophysiological studies. 5. These results indicate that, at micromolar concentrations, the compounds tested block multiple subtypes of high voltage-activated Ca2+ channels. These actions, which do not appear to be mediated by high-affinity sigma binding sites, may play a role in some of the functional effects previously described for the compounds. PMID- 8680711 TI - Blockade of acetylcholine release at the motor endplate by a polypeptide from the venom of Phoneutria nigriventer. AB - 1. The mechanisms underlying the muscle relaxation effect of a fraction (PF3) isolated from the Phoneutria nigriventer spider venom were assessed on mouse diaphragm and chick biventer cervicis muscle preparations. 2. PF3 (0.25-4 micrograms ml-1) produced a concentration-dependent blockade of the nerve elicited muscle twitch of the mouse diaphragm (IC50 = 0.8 micrograms ml-1) without affecting the directly induced muscle twitch. In similar preparations, the crude venom (1-10 micrograms ml-1) produced muscle contracture and blocked both the direct and indirectly induced muscle twitches. 3. In the chick biventer cervicis muscle, PF3 (1-5 micrograms ml-1) blocked the nerve stimulated muscle twitch (IC50 = 1.26 micrograms ml-1), but did not alter the postjunctional response to exogenous acetylcholine (ACh, 10 microM-10 mM). 4. PF3 (2-8 micrograms ml-1) reduced the frequency of miniature endplate potentials (m.e.p.ps) recorded intracellularly from the mouse diaphragm muscle fibers by 58 to 64%, and diminished the amplitude of m.e.p.ps by 20 to 40% of control. The relationship between log m.e.p.p. frequency and log [Ca2+]o was shifted rightwards in the presence of 4 micrograms ml-1 PF3. 5. Raising the frequency of m.e.p.ps with high K+ medium or theophylline (3 mM) did not prevent the toxin induced depression of spontaneous ACh release. 6. The quantal content of e.p.ps (m), determined in cut-diaphragm muscle fibres, was reduced by 53% and 77% of control by 1 and 4 micrograms ml-1 PF3, respectively. At 1 microgram ml-1 the toxin shifted the relationship between log m and log [Ca2+]o towards higher values without apparent change of the slope. 7. E.p.p. trains elicited at 10 to 50 Hz in the presence of PF3 (1 microgram ml-1) exhibited irregular amplitudes and facilitation related to the frequency of nerve stimulation. 8. It is concluded that PF3 blocks neuromuscular transmission by acting prejunctionally and reducing the nerve-evoked transmitter release. The effect was related to a diminished Ca2+ entry into the nerve terminal associated with inhibition of exocytosis. PMID- 8680710 TI - Modulation by prednisolone of calcium handling in skeletal muscle cells. AB - 1. Increased calcium (Ca2+) influx has been incriminated as a potential pathological mechanism in the chronic skeletal muscle degeneration exhibited by Duchenne muscular dystrophy (DMD) patients. We have studied the influence of the glucocorticoid alpha-methylprednisolone (PDN), the only drug known to have a beneficial effect on the degenerative course of DMD, on Ca2+ handling in the C2 skeletal muscle cell line. 2. PDN, when added 3 days (when myoblasts start to fuse into myotubes) after cell seeding, led to a 2 to 4 fold decrease in cellular Ca2+ uptake. This decrease was independent of the extracellular Ca2+ concentration applied to cells. The effect took at least 24 h in order to become established (PDN of 10(-5) M) and took longer for lower PDN concentrations (EC50 of ca. 10(-6) M at day 5, 10(-6.5) M at day 7 and 10(-7.5) M at day 9 in culture). 3. Cellular calcium accumulation was also decreased in PDN-treated myotubes exposed to 45Ca(2+)-containing medium for 1 to 6 days. 4. No effect of PDN was seen on 45Ca2+ efflux; a decrease in the amount of 45Ca2+ released was observed due to the reduction of cellular 45Ca2+ loading. 5. PDN treatment led to an approximately 2 fold decrease in basal cytosolic Ca2+ concentration. 6. Three antioxidant drugs (lazaroids), previously shown to enhance in vitro skeletal muscle cell differentiation to the same extent as PDN, induced a similar decrease in Ca2+ influx. 7. Our results suggest that long-term incubation of C2 cells with PDN leads to a decrease of the size of the cellular Ca2+ pools and to reduced resting cytosolic Ca2+ levels. Part of the beneficial effect of PDN in DMD patients could be attributed to a reduction of Ca2+ influx and of the size of Ca2+ pools in dystrophic muscle fibres. PMID- 8680712 TI - Characterization of metabotropic glutamate receptor-stimulated phosphoinositide hydrolysis in rat cultured cerebellar granule cells. AB - 1. The pharmacology of excitatory amino acid (EAA)-stimulated phosphoinositide (PI) hydrolysis, monitored via [3H]-inositol monophosphate accumulation, was investigated in primary cultures of rat cerebellar granule cells. 2. EAA stimulated PI hydrolysis peaked after 4-5 days in vitro and subsequently declined. 3. The agonist order of potency was found to be (EC50): L-quisqualic acid (Quis) (2 microM) >> L-glutamate (50 microM) > (1S,3R)-1-aminocyclopentane 1,3-dicarboxylic acid ((1S,3R)-ACPD) (102 microM). L-Glutamate (Emax = 873% of basal activity) elicited the largest stimulation of PI hydrolysis, whereas Quis (Emax = 603%) and (1S,3R)-ACPD (Emax = 306%) produced somewhat lower stimulations. 4. Several phenylglycine derivatives were found to be active in inhibiting 2 microM Quis-stimulated PI hydrolysis, in order of potency (IC50): (S)-4-carboxy-3-hydroxyphenylglycine (41 microM) > or = (S)-4 carboxyphenylglycine (51 microM) >> (+)-alpha-methyl-4-carboxyphenylglycine (243 microM). 5. Cultured cerebellar granule cells of the rat appear to have Group I mGluR pharmacology similar to that reported for cloned mGluR1 and provide an ideal system for investigating novel mGluR1 ligands in a native environment. PMID- 8680713 TI - In situ hybridization studies of prostacyclin receptor mRNA expression in various mouse organs. AB - 1. Expression of prostacyclin receptor (IP receptor) mRNA was examined in various mouse organs, and the cells expressing IP receptor mRNA were identified by in situ hybridization studies. Co-localization of mRNA for the IP receptor with that for preprotachykinin A (PPTA), a precursor protein for substance P, with mRNA for the prostaglandin E receptor subtypes (EP1, EP3 and EP4), and with renin mRNA, was examined by double in situ hybridization studies in the dorsal root ganglion and kidney, respectively. 2. IP receptor mRNA was expressed in the thymus and spleen. Expression in the thymus was found exclusively in the medulla, where mature thymocytes expressed transcripts for the IP receptor. Expression in the spleen was found as scattered signals over the white pulp and as punctate signals in the red pulp. The former was found in splenic lymphocytes and the latter in megakaryocytes. 3. IP receptor mRNA was also expressed in the vascular tissues of various organs such as the aorta, coronary arteries, pulmonary arteries and the cerebral arteries, where its expression was confined to smooth muscle cells. No expression was found in veins. In the kidney, IP receptor mRNA was detected in the interlobular arteries and glomerular arterioles but not in the juxtaglomerular (JG) cells which were labelled with the renin mRNA probe. 4. IP receptor mRNA was expressed in about 40% of the neurones in the dorsal root ganglion. Both small- and large-sized neurones were labelled but no labelling was found in the glia. Expression of PPTA mRNA was found in about 30% of total neurones. About 70% of these neurones expressed IP receptor mRNA, and about half of the IP receptor-positive neurones expressed PPTA mRNA. In addition to IP mRNA, mRNAs for EP1, EP3 and EP4 receptors were expressed in about 30%, 50% and 20%, respectively, of the dorsal root ganglion neurones. About 25%, 41% and 24% of the IP receptor-positive neurons co-expressed the EP1, EP3 and EP4 receptor, respectively. 5. These results not only verified IP receptor expression in various cells and tissues known to be sensitive to prostacyclin, but also revealed its expression in other systems, which urges the study of the actions of prostacyclin in these tissues. They also indicated that the actions of prostacyclin on blood vessels and platelets are mediated by the same type of receptor. Absence of IP receptor mRNA in the JG cells suggests that the action of prostacyclin on renin release may be indirect. PMID- 8680714 TI - Activation of nicotinic acetylcholine receptors expressed in quail fibroblasts: effects on intracellular calcium. AB - 1. The aim of these experiments was to determine the ability of the muscle-type nicotinic acetylcholine receptor (AChR) stably expressed in quail fibroblasts (QF18 cells) to elevate intracellular calcium ([Ca2+]i) upon activation. Ratiometric confocal microscopy, with the calcium-sensitive fluorescent dye Indo 1 was used. 2. Application of the nicotine agonist, suberyldicholine (SDC), to the transfected QF18 cells caused an increase in [Ca2+]i. Control [Ca2+]i levels in QF18 cells were found to be 164 +/- 22 nM (mean +/- s.e. mean; n = 40 cells) rising to 600 +/- 81 nM on addition of SDC (10 microM; n = 15 cells), whereas no increase in [Ca2+]i was seen in non-transfected control QT6 fibroblasts (before: 128 +/- 9 nM, n = 40; after; 113 +/- 13 nM, n = 15). 3. The increase in [Ca2+]i caused by application of SDC was dose-dependent, with an EC50 value of 12.7 +/- 5.9 microM (n = 14). 4. The responses to SDC in QF18 cells were blocked by prior application of alpha-bungarotoxin (200 nM), by the addition of Ca2+ (100 microM), by removal of Na+ ions from the extracellular solution, or by the voltage sensitive calcium channel blockers nifedipine and omega-conotoxin, which act with IC50 values of 100 nM and 100 pM respectively. 5. We conclude that activation of the nicotinic AChRs leads to a Na(+)-dependent depolarization and hence activation of endogenous voltage-sensitive Ca2+ channels in the plasma membrane and an increase in [Ca2+]i. There is no significant entry of Ca2+ through the nicotinic receptor itself. PMID- 8680715 TI - The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase. AB - 1. We have investigated whether (i) endotoxaemia caused by E. coli lipopolysaccharide in the anaesthetized rat causes a multiple organ dysfunction syndrome (MODS; e.g. circulatory failure, renal failure, liver failure), and (ii) an enhanced formation of nitric oxide (NO) due to induction of inducible NO synthase (iNOS) contributes to the MODS. In addition, this study elucidates the beneficial and adverse effects of aminoethyl-isothiourea (AE-ITU), a relatively selective inhibitor of iNOS activity, and NG-methyl-L-arginine (L-NMMA), a non selective inhibitor of NOS activity on the MODS caused by endotoxaemia. 2. In the anaesthetized rat, LPS caused a fall in mean arterial blood pressure (MAP) from 117 +/- 3 mmHg (time 0) to 97 +/- 4 mmHg at 2 h (P < 0.05, n = 15) and 84 +/- 4 mmHg at 6 h (P < 0.05, n = 15). The pressor effect of noradrenaline (NA, 1 micrograms kg-1, i.v.) was also significantly reduced at 1 to 6 h after LPS (vascular hyporeactivity). Treatment of LPS-rats with AE-ITU (1 mg kg-1, i.v. plus 1 mg kg-1 h-1 starting at 2 h after LPS) caused only a transient rise in MAP, but significantly attenuated the delayed vascular hyporeactivity seen in LPS rats. Infusion of L-NMMA (3 mg kg-1, i.v. plus 3 mg kg-1 h-1) caused a rapid and sustained rise in MAP and attenuated the delayed vascular hyporeactivity to NA. Neither AE-ITU nor L-NMMA had any effect on either MAP or the pressor effect elicited by NA in rats infused with saline rather than LPS. 3. Endotoxaemia for 6 h was associated with a significant rise in the serum levels of aspartate or alanine aminotransferase (i.e. GOT or GPT), gamma-glutamyl-transferase (gamma GT), and bilirubin, and hence, liver dysfunction. Treatment of LPS-rats with AE ITU significantly attenuated this liver dysfunction (rise in GOT, GPT, gamma GT and bilirubin) (P < 0.05, n = 10). In contrast, L-NMMA reduced the increase in the serum levels of gamma GT and bilirubin, but not in GOT and GPT (n = 5). Injection of LPS also caused a time-dependent, but rapid (almost maximal at 2 h), increase in the serum levels of urea and creatinine, and hence, renal dysfunction. This renal dysfunction was not affected by either AE-ITU (n = 10) or L-NMMA (n = 5). In rats infused with saline rather than LPS, neither AE-ITU (n = 4) nor L-NMMA (n = 4) had any significant effect on the serum levels of GOT, GPT, gamma GT, bilirubin, creatinine or urea. 4. Endotoxaemia for 6 h resulted in a 4.5 fold rise in the serum levels of nitrite (9.13 +/- 0.77 microM, P < 0.01, n = 15), which was significantly reduced by treatment with AE-ITU (6.32 +/- 0.48 microM, P < 0.05, n = 10) or L-NMMA (5.10 +/- 0.40 microM, P < 0.05, n = 5). In addition, endotoxaemia for 6 h was also associated with a significant increase in iNOS activity in lung and liver homogenates, which was significantly reduced in lung or liver homogenates obtained from LPS-rats treated with either AE-ITU or L NMMA. 5. Thus, AE-ITU or L-NMMA (i) inhibits iNOS activity in LPS-rats without causing a significant increase in MAP in rats infused with saline and, hence inhibition of endothelial NOS activity, and (ii) attenuates the delayed circulatory failure as well as the liver dysfunction caused by endotoxaemia in the rat. Thus, an enhanced formation of NO may contribute to the development of liver failure in endotoxic shock. PMID- 8680716 TI - Effect of morphine on the nerve terminal impulse and transmitter release from sympathetic varicosities innervating the mouse vas deferens. AB - 1 The effect of morphine on both the propagation of the nerve terminal impulse along the sympathetic varicose axons as well as the evoked and spontaneous transmitter release has been evaluated. 2 Morphine (1 microM) did not significantly change the shape or the regularity by which the nerve terminal impulse was recorded while evoked transmitter release was greatly reduced. 3 Morphine induced a uniform decrease in evoked transmitter release irrespective of the release probability of individual varicosities of their position along terminal branches. 4 Procedures which are thought to increase intracellular calcium concentration such as increasing the extracellular calcium concentration, stimulation of the nerve with trains of impulses and increasing the duration of the action potential with 4-aminopyridine reduced the ability of morphine to decrease evoked transmitter release. 5 Morphine had to act directly on the varicosities to induce a decrease in evoked transmitter release. 6 The decrease in evoked quantal release does not involve an affect on the nerve terminal impulse or the vesicle release process and morphine may affect the dependence of the secretory process on calcium. PMID- 8680717 TI - Effect of chronic morphine treatment on transmitter release from sympathetic varicosities of the mouse vas deferens. AB - 1 Transmitter release from sympathetic varicosities of mouse vasa deferentia removed from animals which were chronically treated with morphine for 7 to 9 days has been evaluated. 2 In control preparations increasing the extracellular calcium concentration ([Ca2+]o) from 1 to 2 mM increased transmitter release by 3 fold while increasing [Ca2+]o from 6 to 8 mM increased transmitter release by about 0.9 fold. Introduction of morphine (1.0 microM) produced a uniform decrease in transmitter release, shifting the relationship between transmitter release and [Ca2+]o to the right. 3 Only sympathetic varicosities with probabilities of transmitter release greater than 0.01 were chosen for this study. In these varicosities the decrease in transmitter release induced by morphine in control preparations (bathed in [Ca2+]o 2.0 mM) was not observed following 7 to 9 days of morphine treatment. When the morphine was acutely withdrawn from these preparations transmitter release was more than 6 times the average level of transmitter release from control preparations. 4 The morphine induced increase in facilitation of transmitter release while stimulating with short trains of nerve impulses was not observed when the preparations were removed from animals which had been exposed to morphine for 7 to 9 days. When these preparations were acutely withdrawn from morphine there was a further decrease in the level of facilitation and a significant increase in depression of transmitter release when compared to control. 5 The morphine induced decrease in probability of transmitter release when naive sympathetic varicosities in vitro were bathed with morphine (1 microM) was not observed following chronic morphine treatment of the animals for 7 to 9 days. When the morphine was acutely withdrawn from chronically morphine treated preparations the underlying increase in probabilities of transmitter release of sympathetic varicosities was unmasked. PMID- 8680718 TI - Inducible nitric oxide synthase activity and expression in a human colonic epithelial cell line, HT-29. AB - 1 We have determined which cytokines regulate the expression of human inducible nitric oxide synthase (iNOS) mRNA and nitrite generation in the human colonic epithelial cell line HT-29. 2 Growth arrested cell cultures were stimulated with the human recombinant cytokines interleukin-1 alpha (IL-1 alpha), tumour necrosisfactor-alpha (TNF-alpha), interferon gamma (IFN-gamma) or vehicle added alone or in combination. Human iNOS mRNA was determined by Northern blot analysis and nitrite generation by the use of a fluorometric assay. 3 Unstimulated cells produced a small time-dependent increase in nitrite generation of 50 +/- 4, 75 +/ 8, and 103 +/- 8 nM per 10(6) cells at 24 h, 48 h, and 72 h respectively. This nitrite generation was unaffected by cycloheximide (5 micrograms ml-1) pretreatment and iNOS mRNA was not detected. 4 None of cytokines alone induced either iNOS mRNA expression or an increase in nitrite generation. The combination of IL-1 alpha/IFN-gamma produced a highly significant (P < 0.001) 4 fold increase in nitrite production at 48 h, compared to basal values, while no other pair of cytokines was effective. 5 Time course studies with IL-1 alpha/IFN-gamma combination revealed significant (P < 0.001) increases in nitrite at 24 h (153 +/ 7), 48 h (306 +/- 24), and 72 h (384 +/- 15) compared to basal values of 50 +/- 4, 75 +/- 8, and 103 +/- 8 nM per 10(6) cells respectively. 6 Studies with IL-1 alpha/IFN-gamma combination demonstrated a time dependent expression of iNOS mRNA, first observed at 6 h, peaked at 24 h and was undetectable by 72 h. IL-1 alpha (0.3-10 ng ml-1) and IFN-gamma (10-300 u ml-1) in combination induced a concentration-dependent expression of iNOS mRNA at 24 h. 7 Pretreatment with cycloheximide before IL-1 alpha/IFN-gamma stimulation reduced nitrite levels to basal values. These data suggest that the IL-1 alpha/IFN-gamma-induced nitrite production by HT-29 cells is dependent on de novo protein synthesis, probably the iNOS enzyme. 8 The addition of TNF-alpha produced a significant (P < 0.001) 3 fold increase of IL-1 alpha/IFN-gamma-induced nitrite generation. In marked contrast the presence of TNF-alpha had no effect on IL-1 alpha/IFN-gamma-induced iNOS mRNA expression by HT-29 cells. These findings suggest that the up regulation by TNF-alpha of IL-1 alpha/IFN-gamma-induced nitrite generation is at the post-transcriptional level. 9 These data suggest that pro-inflammatory cytokines induce NO production in colonic epithelial cells probably due to the induction of iNOS and these cells may be a major source of NO generation in inflammatory bowel disease. PMID- 8680719 TI - Distribution and effects of pituitary adenylate cyclase activating peptide in cat and human lower oesophageal sphincter. AB - 1. The localization, tissue concentrations, and effects of pituitary adenylate cyclase activating peptide (PACAP) 27 and 38 were investigated in cat and human lower oesophageal sphincter (LOS), and compared with those of vasoactive intestinal peptide (VIP) and helospectin. 2. PACAP-immunoreactive nerve structures were found in the cat and human LOS, with an abundance in the circular smooth muscle layer. PACAP 27-immunoreactivity was often co-localized with VIP immunoreactivity. 3. In cat tissue, PACAP (PACAP 27 plus PACAP 38) concentrations were 50 fold lower than VIP concentrations; in human tissue they were 10 fold lower. 4. PACAP 27, PACAP 38, helospectin I, and VIP induced concentration dependent relaxations in circular smooth muscle preparations from cat and human LOS. The order of potency was: VIP > helospectin I > or = PACAP 27 > PACAP 38. NG nitro-L-arginine, scopolamine, or apamin, did not influence the relaxant effects of PACAP 27 or VIP. 5. In cat preparations, both cyclic AMP and cyclic GMP levels were increased after exposure to PACAP 27 and helospectin I, whereas exposure to VIP was followed by an increase in cyclic AMP levels only. In human preparations, there was an increase in cyclic AMP levels without any change in cyclic GMP levels. 6. These results suggest that in the cat and human LOS, PACAP 27 and VIP can occur within the same nerve structures. PACAP 27 has a potent relaxant action, but its functional importance has to be established. PMID- 8680720 TI - Modulation of the isoprenaline-induced membrane hyperpolarization of mouse skeletal muscle cells. AB - 1. The hyperpolarization of the resting membrane potential, Vm, induced by isoprenaline in the lumbrical muscle fibres of the mouse, was investigated by use of intracellular microelectrodes. 2. In normal Krebs-Henseleit solution (potassium concentration: K+o = 5.7 mM, 'control'), Vm was -7.40 +/- 0.2 mV; lowering K+o to 0.76 mM ('low K+o') resulted in either a hyperpolarization (Vm = 95.7 +/- 2.9 mV), or a depolarization (Vm = -52.0 +/- 0.3 mV). 3. Isoprenaline (> or = 200 nM) induced a hyperpolarization of Vm by delta Vm = -5.6 +/- 0.4 mV in control solution. 4. When Vm hyperpolarized after switching to low K+o, the addition of isoprenaline resulted in increased hyperpolarization Vm: delta Vm = 16.3 +/- 3.2 mV to a final Vm = -110.1 +/- 3.4 mV. Adding iso-prenaline when Vm depolarized in low K+o, leads to a hyperpolarization of either by -11.6 +/- 0.5 mV to -63.6 +/- 0.8 mV or by -51.7 +/- 2.7 mV to -106.9 +/- 3.9 mV. 5. Ouabain (0.1 to 1 mM) did not suppress the hyperpolarization by isoprenaline in 5.7 mM K+o (delta Vm = -6.7 +/- 0.4 mV) or the hyperpolarization of the depolarized cells in low K+- (delta Vm = -9.7 +/- 1.5 mV). 6. The hyperpolarization is a logarithmically decreasing function of K+o in the range between 2 and 20 mM (12 mV/decade). 7.IBMX and 8Br-cyclic AMP mimicked the response to isoprenaline whereas forskolin (FSK) induced in low K+o a hyperpolarization of -7.0 +/- 0.7 mV that could be augmented by addition of isoprenaline (delta Vm = -8.2 +/- 1.8 mV). 8. In control and low K+o, Ba2+ (0.6 mM) inhibited the hyperpolarization induced by isoprenaline, IBMX or 8Br-cyclic AMP. Other blockers of the potassium conductance such as TEA (5 mM) and apamin (0.4 microM) had no effect. 9. We conclude that in the lumbrical muscle of the mouse the isoprenaline-induced hyperpolarization is primarily due to an increase in potassium permeability. PMID- 8680721 TI - Coupling of an endogenous 5-HT1B-like receptor to increases in intracellular calcium through a pertussis toxin-sensitive mechanism in CHO-K1 cells. AB - 1. Chinese hamster ovary cells (CHO-K1) express an endogenous 5-hydroxytryptamine (5-HT)1B-like receptor that is negatively coupled to adenylyl cyclase through a pertussis toxin (PTX)-sensitive mechanism. Furthermore, the human adenosine A1 receptor when expressed in CHO-K1 cells (CHO-A1) has been shown to mobilize intracellular Ca2+ through a PTX-sensitive mechanism. Therefore the aim of this investigation was to determine whether the endogenous 5-HT1B-like receptor was able to stimulate increases in intracellular free [Ca2+] ([Ca2+]i) in CHO-A1 cells. 2. In agreement with previous studies using CHO cells, 5-hydroxytryptamine (5-HT) elicited a concentration-dependent inhibition of forskolin-stimulated [3H] cyclic AMP production in CHO-A1 cells (p[EC50] = 7.73 +/- 0.13). 5-HT (1 microM) inhibited 47 +/- 5% of the [3H]-cyclic AMP accumulation induced by 3 microM forskolin. Forskolin stimulated [3H]-cyclic AMP accumulation was also inhibited by the 5-HT1 receptor agonists (p[EC50] values) 5-carboxyamidotryptamine (5-CT; 8.07 +/- 0.08), RU 24969 (8.12 +/- 0.33) and sumatriptan (5.80 +/- 0.31). 3. 5-HT elicited a concentration-dependent increase in [Ca2+]i in CHO-A1 cells (p[EC50] = 8.07 +/- 0.05). In the presence of 2 mM extracellular Ca2+, 5-HT (1 microM) increased [Ca2+]i from 174 +/- 17 nM to 376 +/- 22 nM. The 5-HT1 receptor agonists (p[EC50] values), 5-carboxyamidotryptamine (5-CT; 7.9 +/- 0.02), RU 24969 (8.1 +/- 0.07) and sumatriptan (5.9 +/- 0.11) all elicited concentration dependent increases in [Ca2+]i. Similar maximal increases in [Ca2+]i were obtained with each agonist. The selective 5-HT1A receptor agonist, 8-OH-DPAT (10 microM) did not stimulate increases in [Ca2+]i. 5-HT (100 microM) and 5-CT (10 microM) did not stimulate a measurable increase in [3H]-inositol phosphate accumulation in CHO-A1 cells. 4. 5-HT (1 microM)-mediated increases in [Ca2+]i were insensitive to the 5-HT receptor antagonist, ritanserin (5-HT2; 100 nM), ketanserin (5-HT2; 100 nM), LY-278,584 (5-HT3; 1 microM) and WAY 100635 (5-HT1A; 1 microM). The response to 5-HT (100 nM) was antagonized by the non-selective 5 HT1 antagonist, methiothepin (pKb = 8.90 +/- 0.09) and the 5-HT1D antagonist GR 127935 (pKb = 10.44 +/- 0.06). 5. Pretreatment with PTX (200 ng ml-1 for 4 h) completely attenuated the Ca2+ response to 100 microM 5-HT. 6. In untransfected CHO-K1 cells, 5-HT (1 microM), RU 24969 (1 microM), and 5-CT (1 microM) elicited increases in [Ca2+]i similar to those observed in CHO-A1 cells. 7. These data demonstrate that in CHO-K1 cells the endogenously expressed 5-HT1B-like receptor couples to the phospholipase C/Ca2+ signalling pathway through a PTX-sensitive pathway, suggesting the involvement of Gi/Go protein(s). PMID- 8680722 TI - Selective blockade of M2 and M3 muscarinic receptors by hexahydrobenzyl fourdapine and a comparison with zamifenacin. AB - 1. 4-Diphenylacetoxy-N-cyclohexylmethyl-piperidine HCl (hexahydro-benz-4DAP) is more active as an antagonist of carbachol at receptors in guinea-pig isolated ileum, log K (pA2) = 6.64 +/- 0.14 (s.e. 7 results), than at receptors in guinea pig isolated atria, log K = 5.43 +/- 0.14 (7). In the presence of neostigmine bromide (0.2 microM) the value for atria was 5.62 +/- 0.19 (4), so the lower activity on atria cannot be attributed to hydrolysis of the compound by cholinesterases present in this tissue. 2. The limit of solubility of the free base in Krebs solution (pH 7.6) is about 50 microM for both hexahydrobenz-4DAP and benzyl-fourdapine (benz-4DAP). 3. In experiments on guinea-pig isolated ileum with hexahydro-benz-4DAP given together with 4-DAMP methobromide, the combined dose-ratio was consistent with competition: similar results were obtained with benz-4DAP. 4. In rats anaesthetized with pentobarbitone, hexahydro-benz-4DAP antagonized the effects of bethanechol on blood-pressure in doses that had little effect on heart rate or airflow. There was a limit to the effect which could be obtained, however, and the slopes of the Schild plots were less than one. The effects on rat blood-pressure had a half-life of at least 30 min. 5. In similar experiments with zamifenacin the slopes of the Schild plots were close to 1 and the compound was 10 to 20 times as active on blood-pressure at it was on heart rate. 6. The limited solubility of the base probably accounts for the flat Schild plots obtained with hexahydro-benz-4DAP, which had about 10 fold selectivity for effects on blood-pressure and was more active than expected from tests on isolated ileum. PMID- 8680723 TI - Investigation of the inhibitory effects of PGE2 and selective EP agonists on chemotaxis of human neutrophils. AB - 1. The aims of this study were to investigate the inhibitory effects of prostaglandin E2 (PGE2) on chemotaxis of N-formyl-methionyl-leucine-phenylalanine (FMLP)-stimulated human neutrophils, and to test the hypothesis that cyclic AMP is the second messenger involved. For this purpose, the inhibitory effect of selective EP agonists, and the modulatory effects of the adenylate cyclase inhibitor, SQ 22536, the protein kinase A (PKA) inhibitors H-89 and Rp-cAMPs, and the type IV phosphodiesterase (PDE) inhibitors, rolipram and Ro20-1724 have been examined. 2. Chemotaxis has been measured using blindwell chambers. When human neutrophils were stimulated with FMLP (100 nM), PGE2 inhibited chemotaxis in a concentration-dependent manner (0.01-10 microM), with an EC50 of 90 +/- 24.5 nM, a maximum effect ranging from 45-75% and a mean inhibition of 64.5 +/- 2.4%. 3. The EP2-receptor agonists, 11-deoxy PGE1, butaprost and AH 13205 also inhibited chemotaxis. The order of potency of these agonists was PGE2 > butaprost (EC50 = 106.4 +/- 63 nM) > 11-deoxy PGE1 (EC50 = 140.9 +/- 64.7 nM) > AH 13205 (EC50 = 1.58 +/- 0.73 microM). Correlation of the ability of EP2 agonists to increase cyclic AMP and to inhibit chemotaxis was poor (r = 0.38). 4. The IP agonist, cicaprost gave similar increases in cyclic AMP to those achieved with PGE2, yet produced 50% of the maximum inhibition of chemotaxis observed with PGE2. 5. Slight potentiation of the inhibitory effects of PGE2 after type IV PDE block was observed with rolipram (EC50 for PGE2 = 57.2 +/- 5.9; 35.2 +/- 6.8 nM) but not Ro20-1724 (EC50 for PGE2 = 216.0 +/- 59.7; 97.8 +/- 50.6 nM). Type IV PDE inhibitors are themselves potent inhibitors of chemotaxis with EC50 values of 23.0 +/- 2.3 and 73.6 +/- 10.3 nM for rolipram and Ro20-1724, respectively. 6. Inhibition of cyclic AMP production with the adenylate cyclase inhibitor SQ 22,536 (0.1 mM) failed to antagonize inhibition of chemotaxis by PGE2 (EC50s for PGE2 of 57.2 +/- 5.9 and 56.8 +/- 27.3 nM, in the absence and presence of SQ 22,536, respectively) despite a reduction in the increase in cyclic AMP induced by PGE2. 7. Inhibition of PKA with either H-89 (10 microM) or Rp cyclic AMPS (10 microM) similarly failed to antagonize inhibition of chemotaxis by PGE2; EC50 for PGE2 of 90 +/- 40 and PGE2 + H-89 60 +/- 17 nM; PGE2 216.0 +/- 58.7 and PGE2 + Rp cyclic AMP 76.9 +/- 14.7 nM. 8. Of the two PKA inhibitors tested, H-89 (10 microM) and Rp cyclic AMPS (10 microM), the more effective inhibitor of PGE2 induced inhibition of neutrophil superoxide anion generation was H-89 (EC50s for PGE2 were 0.36 +/- 0.1 and > 10 microM, respectively). We have previously shown this to be a cyclic AMP-dependent effect of PGE2. 9. Confirmation of block of PKA by H-89 was suggested by the finding that H-89 blocked inhibition of superoxide anion generation observed with the type IV PDE inhibitors rolipram and Ro20-1724; EC50s of 12.9 +/- 8.9 nM for rolipram alone and rolipram+H-89 > 1 microM; Ro20 1724 alone 59.5 +/- 28.1 nM and Ro20-1724 + H-89 > 1 microM. 10. The results suggest that inhibition of chemotaxis by PGE2 and EP2 agonists is not mediated by increased neutrophil cyclic AMP levels. PMID- 8680724 TI - A novel P2-purinoceptor expressed by a subpopulation of astrocytes from the dorsal spinal cord of the rat. AB - 1. Astrocytes from the dorsal spinal cord express P2-purinoceptors which, when stimulated, produce a rise in the intracellular level of free Ca2+ ([Ca2+]i). Previously we have found that the P2Y class of receptor is expressed by nearly all astrocytes from the dorsal horn. To determine whether other metabotropic P2 purinoceptor classes are also present, in this study we investigated the effects of UTP. 2. Application of UTP (1-500 microM, 5-20 s) produced a transient rise in [Ca2+]i in a subpopulation of astrocytes. The magnitude of the peak increase in [Ca2+]i was dependent upon UTP concentration and the EC50 was found to be 5.2 +/- 0.2 microM. Ca2+ responses were maximum at 100 microM UTP. 3. The rise in [Ca2+]i in response to UTP was not affected by removal of extracellular Ca2+. On the other hand, application of the sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase inhibitor, thapsigargin, abolished responses to UTP. These findings indicate that UTP stimulates the release of Ca2+ from a thapsigargin-sensitive intracellular pool. 4. The Ca2+ response to UTP was unaffected by treatment with pertussis toxin, suggesting that UTP responses may be mediated via a pertussis toxin insensitive G protein. 5. While all cells tested (n = 52) responded to the P2Y purinoceptor agonist, 2-methylthio-ATP, only a subpopulation of astrocytes (n = 67/93) was responsive to UTP. The presence of UTP-sensitive and UTP-insensitive cells requires the existence of two discrete types of receptor. One receptor, expressed by UTP-insensitive cells, appears to be activated selectively by 2 methylthio-ATP. 6. To investigate whether UTP and 2-methylthio-ATP activate a common type of receptor in UTP-responsive cells, a cross-desensitization strategy was used. Desensitization with prolonged exposure to a high concentration of 2 methylthio-ATP failed to affect responses to UTP and vice versa, indicating that receptors activated by UTP are distinct from those activated by 2-methylthio-ATP. 7. The P2-purinoceptor antagonist, suramin (100 microM), blocked Ca2+ responses to UTP and to 2-methylthio-ATP. 8. Pyridoxalphosphate-6-azophenyl-2',4' disulphonic acid (PPADS), has been reported to block responses mediated by P2X- and P2Y-purinoceptors in other systems and therefore we investigated its effects on responses to 2-methylthio-ATP and to UTP. PPADS was found to block Ca2+ responses to 2-methylthio-ATP in a concentration-dependent manner with an IC50 of 0.92 +/- 0.1 microM. PPADS also blocked UTP-evoked responses and the IC50 was 7.2 +/- 1.9 microM. At a concentration of 10 microM, PPADS produced a rightward shift in the dose-response curve for UTP and did not affect the maximum response. 9. Calcium responses evoked by the muscarinic agonist, carbachol, were unaffected either by suramin (100 microM) or by PPADS (50 microM). 10. The present results indicate the presence of a novel class of metabotropic P2U-purinoceptor in dorsal spinal astrocytes. In contrast to P2Y-purinoceptors, the P2U-purinoceptor is expressed only by a subpopulation of astrocytes and its sensitivity to suramin and PPADS distinguish this receptor from P2U-purinoceptors found in other tissues. PMID- 8680725 TI - Nitric oxide is a mediator of tachykinin NK3 receptor-induced relaxation in rat mesenteric artery. AB - 1. The mechanism of vasodilatation induced by tachykinin peptides was studied in isolated mesenteric arteries of rats. 2. Senktide, a selective NK3 agonist, elicited potent endothelium-dependent relaxation of arteries precontracted with phenylephrine (10(-5) M), but an NK1 agonist did not. 3. A non-peptide NK3 antagonist, SR 142801, inhibited senktide-induced relaxation. However, a non peptide NK1 antagonist, CP-96,345, and a peptide-based NK2 antagonist, L-659,877, had no effect on senktide-induced relaxation. 4. N omega-nitro-L-arginine (L NOARG), a nitric oxide synthesis inhibitor, markedly attenuated the relaxant response to senktide. 5. These results suggest that the endothelium of rat mesenteric arteries possesses tachykinin NK3 receptors, and that NK3 agonist induced vasodilatation is mediated by release of nitric oxide (NO) from the endothelium. PMID- 8680726 TI - An endogenous protectant effect of cardiac cyclic GMP against reperfusion-induced ventricular fibrillation in the rat heart. AB - 1. After a period of myocardial ischaemia, reperfusion of the myocardium can elicit cardiac arrhythmias. Susceptibility to these arrhythmias declines with time, such that a preceding period of more than approximately 40 min ischaemia is associated with few reperfusion-induced arrhythmias. We have tested the hypothesis that this decline in susceptibility occurs, in part, because of protection by endogenous guanosine 3':5'-cyclic monophosphate (cyclic GMP). 2. Rat isolated hearts were subjected to 60 min left regional ischaemia followed by reperfusion (n = 10 per group). Methylene blue (20 microM), a soluble guanylate cyclase inhibitor, raised the incidence of reperfusion-induced ventricular fibrillation (VF) from 10% in control hearts to 80% (P < 0.05). This effect of methylene blue was abolished by co-perfusion with zaprinast (100 microM), a phosphodiesterase inhibitor which, in the rat heart, is cyclic GMP-specific (specific for the type-V phosphodiesterase isozyme). 3. Methylene blue reduced cyclic GMP levels in the ischaemic, non-ischaemic and reperfused myocardium (P < 0.05) to 50 +/- 10, 52 +/- 12 and 70 +/- 7 fmol mg-1 tissue wet weight, respectively from control values of 143 +/- 38, 147 +/- 43 and 156 +/- 15 fmol mg 1. Co-perfusion with zaprinast prevented this effect, and cyclic GMP levels were actually elevated (P < 0.05) to 366 +/- 102, 396 +/- 130 and 293 +/- 22 fmol mg-1 in ischaemic, non-ischaemic and reperfused myocardium, respectively. Zaprinast by itself also elevated cyclic GMP content. Cyclic AMP levels were not affected by zaprinast or methylene blue. 4. In conclusion, when endogenous cardiac cyclic GMP synthesis is reduced, susceptibility to reperfusion-induced VF after sustained ischaemia is substantially increased. The effect is prevented by inhibiting cyclic GMP degradation. Therefore cyclic GMP appears to be an endogenous intracellular cardioprotectant, and its actions may account for the low susceptibility to VF normally encountered in hearts reperfused after sustained ischaemia. PMID- 8680727 TI - Interaction between the mu-agonist dermorphin and the delta-agonist [D-Ala2, Glu4]deltorphin in supraspinal antinociception and delta-opioid receptor binding. AB - 1. In rats, the interaction between the mu-opioid agonist dermorphin and the delta-opioid agonist [D-Ala2, Glu4]deltorphin was studied in binding experiments to delta-opioid receptors and in the antinociceptive test to radiant heat. 2. When injected i.c.v., doses of [D-Ala2, Glu4]deltorphin higher than 20 nmol produced antinociception in the rat tail-flick test to radiant heat. Lower doses were inactive. None of the doses tested elicited the maximum achievable response. This partial antinociception was accomplished with an in vivo occupancy of more than 97% of brain delta-opioid receptors and of 17% of mu-opioid receptors. Naloxone (0.1 mg kg-1, s.c.), and naloxonazine (10 mg kg-1, i.v., 24 h before), but not the selective delta-opioid antagonist naltrindole, antagonized the antinociception. 3. In vitro competitive inhibition studies in rat brain membranes showed that [D-Ala2, Glu4]deltorphin displaced [3H]-naltrindole from two delta-binding sites of high and low affinity. The addition of 100 microM Gpp[NH]p produced a three fold increase in the [D-Ala2, Glu4]deltorphin Ki value for both binding sites. The addition of 10 nM dermorphin increased the Ki value of the delta-agonist for the high affinity site five times. When Gpp[NH]p was added to the incubation medium together with 10 nM dermorphin, the high affinity Ki of the delta-agonist increased 15 times. 4. Co-administration into the rat brain ventricles of subanalgesic doses of dermorphin and [D-Ala2, Glu4]deltorphin resulted in synergistic antinociceptive responses. 5. Pretreatment with naloxone or with the non-equilibrium mu-antagonists naloxonazine and beta-funaltrexamine completely abolished the antinociceptive response of the mu-delta agonist combinations. 6. Pretreatment with the delta-opioid antagonists naltrindole and DALCE reduced the antinociceptive response of the dermorphin-[D-Ala2, Glu4]deltorphin combinations to a value near that observed after the mu-agonist alone. At the dosage used, naltrindole occupied more than 98% of brain delta opioid receptors without affecting mu-opioid-receptors. 7. These data suggest that in the rat tail-flick test to radiant heat, mu- and delta-opioid agonists co operate positively in evoking an antinociceptive response. Although interactions between different opioid pathways cannot be excluded, in vitro binding results indicate that this co-operative antinociception is probably mediated by co activation of the delta-opioid receptors at the cellular level by the mu- and delta-agonist. PMID- 8680728 TI - Comparison of the effects of fenamates on Ca-activated chloride and potassium currents in rabbit portal vein smooth muscle cells. AB - 1. The perforated patch and conventional whole-cell recording techniques were used to study the action of flufenamic, mefenamic and niflumic acid on calcium activated chloride and potassium currents in rabbit portal vein smooth muscle cells. 2. In K-conditions at a holding potential of -77 mV flufenamic acid and mefenamic acid decreased the amplitude of spontaneous transient inward currents (STICs, calcium-activated chloride currents, ICl(Ca)) in a concentration dependent manner. The potency sequence was niflumic > flufenamic > mefenamic acid. 3. At -77 mV 1 x 10(-5) M flufenamic acid increased the STIC exponential decay time constant (tau). At higher concentrations the STIC decay was described by 2 exponentials with an initial decay (tau f) faster than the control tau value and a second exponential (tau s) which had a time constant slower than the control tau value. Low concentrations of mefenamic acid had no effect or decreased the tau value whereas in higher concentrations biphasic currents were recorded. 4. In K-free conditions the inhibitory effect of both flufenamic and mefenamic acid on STIC amplitude was greater at +50 mV compared to -50 mV, showing that the effect of these agents was voltage-dependent. 5. In cells held at 0 mV in K-containing conditions the fenamates reduced both the frequency and amplitude of spontaneous transient outward currents (STOCs, calcium-activated potassium currents, IK(Ca)). The concentration range to produce these effects was higher than that to decrease STIC amplitude and the potency sequence was flufenamic > niflumic > or = mefenamic acid. 6. All these compounds in concentrations greater than 5 x 10(-5) M evoked a 'noisy' potassium current at 0 mV which reached a maximum after approximately 3 min. This current was readily reversible on washout of the drug and could be elicited several times in the same cell. The current-voltage relationship of the fenamate-evoked current exhibited pronounced outward rectification characteristic of IK(Ca). 7. The current evoked by 2 x 10(-4) M flufenamic acid and 5 x 10(-4) M niflumic acid was not affected by 1 x 10(-5) M glibenclamide but was markedly inhibited by 1 x 10(-3) M tetraethylammonium. Furthermore, large currents were activated by flufenamic and niflumic acid in the presence of caffeine and cyclopiazonic acid (an inhibitor of the sarcoplasmic reticulum Ca-ATPase) to deplete intracellular Ca-stores. 8. Conventional whole-cell recording was performed with pipette solutions in which the ability to buffer changes in intracellular calcium was varied by altering the concentration of the calcium chelator (2-aminophenoxy)-ethane-N,N,N',N' tetraacetic acid (BAPTA). Flufenamic acid (2 x 10(-4) M) and niflumic acid (5 x 10(-4) M) both evoked large outward currents when recordings were made with either 1 x 10(-4) M or 1 x 10(-2) M BAPTA. Furthermore, bathing the cells in nominally calcium-free extracellular solution did not reduce the amplitude of the evoked currents. 9. It is concluded that both flufenamic and mefenamic acid inhibit ICl(Ca) by a mechanism similar to niflumic acid, possibly open channel blockade. Furthermore, at concentrations greater than 5 x 10(-5) M all three fenamates inhibited STOC activity and evoked directly an outward current which resembled IK(Ca). PMID- 8680729 TI - The effects of temperature on the interactions between volatile general anaesthetics and a neuronal nicotinic acetylcholine receptor. AB - 1. Completely isolated identified neurones from the right parietal ganglion of the pond snail Lymnaea stagnalis were investigated under two-electrode voltage clamp. Neuronal nicotinic acetylcholine receptor (AChR) currents were studied at low acetylcholine concentrations (< or = 200 nM). 2. Inhibition of the ACh induced currents by three volatile general anaesthetics (halothane, isoflurane and methoxyflurane) and the specific inhibitor (+)-tubocurarine was studied as a function of temperature (over the range 4-25 degrees C). 3. The inhibition by the volatile anaesthetics increased (inhibition constants decreased) with decreasing temperature while the inhibition by (+)-tubocurarine did not change significantly near room temperature, but decreased at lower temperatures. The (+)-tubocurarine inhibition appeared to be competitive in nature and showed no significant voltage dependence. 4. The van't Hoff plots (logarithms of the dissociation constants against reciprocal absolute temperature) were linear for the anaesthetics, but markedly non-linear for (+)-tubocurarine. From these plots, values for the changes in the standard Gibbs free energy delta G degrees water-->AChR, enthalpy delta H degree water-->AChR, entropy delta S degree water-->AChR and heat capacity delta Cp degree water-->AChR were determined. Tubocurarine was found to bind very much tighter to the receptor than the volatile anaesthetics due, entirely, to a favourable increase in entropy on binding. 5. A comparison between the temperature-dependence of the anaesthetic inhibition of the ACh receptor and that of general anaesthetic potencies in animals indicates that the temperature dependence of animal potencies might be simply accounted for in terms of changes in anaesthetic/receptor binding. PMID- 8680730 TI - The promotion of patent airways and inhibition of antigen-induced bronchial obstruction by endogenous nitric oxide. AB - 1. The aim of the present study was to investigate the role of nitric oxide (NO), histamine and leukotrienes in bronchial obstruction. For this, guinea-pigs immunised against ovalbumin were studied under anaesthesia during challenge with antigen or agonists. 2. Challenge with nebulised antigen (0.1-1 mg) elicited dose dependent increases in insufflation pressure which were abolished by combined administration of histamine and leukotriene antagonists. 3. Challenge with nebulised antigen (0.1-1 mg) also elicited dose-dependent increases in the concentration of endogenous nitric oxide in the exhaled air. After an initial peak, exhaled NO concentrations returned to pre-challenge levels. 4. The increase in insufflation pressure and in exhaled NO caused by ovalbumin challenge was inhibited by combined administration of histamine and leukotriene antagonists. 5. In non-immunised guinea-pigs, challenge of the airways with nebulised histamine (10-1000 nmol) or leukotriene C4 (LTC4, 30-300 pmol) elicited dose-dependent increases in insufflation pressure and in concentrations of endogenous NO in exhaled air. 6. The increase in exhaled NO correlated with the increase in insufflation pressure in response to ovalbumin, histamine and LTC4. An inhibitor of endogenous NO synthesis, N omega-nitro-L-arginine methylester (L-NAME, 30 mg kg-1 i.v.) abolished NO exhalation, and markedly augmented the airway responses to ovalbumin, histamine, or LTC4. 7. The potentiation by L-NAME of the increase in insufflation pressure in response to ovalbumin or histamine was prevented by exogenous NO (20 p.p.m.) in the inhaled air. 8. The results indicate that endogenous NO has an inhibitory effect on bronchial obstruction. Increased NO release during allergen challenge is likely to be due to actions of histamine and leukotrienes. PMID- 8680731 TI - Comparative effects of angiotensin II and its degradation products angiotensin III and angiotensin IV in rat aorta. AB - 1. In the present study, the contractile effects of angiotensin III (AIII) and angiotensin IV (AIV) compared with those of angiotensin II (AII) were determined in rat aortic ring preparations. 2. All three peptides caused concentration dependent contractions with similar maximal responses. AIII proved approximately 4 times less potent than AII, whereas AIV was about 1000 times less active than AII. 3. The selective AT1-receptor antagonist, losartan (10-300 nM) caused parallel rightward shifts of the concentration-response curves (CRC) for all three peptides. The Schild plot slopes for the effect of losartan on AIII curves were significantly lower than unity (P < 0.05). The selective AT2-receptor antagonist, PD123177 did not influence the CRCs for AII and AIV. However, the AIII curves were moderately shifted leftward in the presence of PD123177 (0.1 and 1 microM). 4. Destruction of the endothelium or incubation with the NO-synthesis inhibitor NG-monomethyl-L-arginine acetate (L-NMMA) (0.1 mM) significantly enhanced the contractile responses to all three peptides. 5. Tachyphylaxis was investigated by constructing a second CRC for all three peptides, after an interval of 1 h. The presence of endothelium significantly enhanced the development of tachyphylaxis to all three peptides. However, in endothelium denuded preparations, the Emax value of the second curve elicited by AII was about 50%, compared with the first one, whereas for AIII and AIV Emax values were as high as 90% and 100%, respectively. 6. Our results indicate that both AIII and AIV are less potent but similarly efficacious vasoconstrictor agents compared with AII. Their contractile effects are also mediated by AT1-receptors and probably modulated by endothelium. Tachyphylaxis induced by AIII and AIV proved weaker than that for AII. Tachyphylaxis appears to be enhanced by the presence of an intact endothelium. PMID- 8680732 TI - Inhibition of sympathetic vasoconstriction in pigs in vivo by the neuropeptide Y Y1 receptor antagonist BIBP 3226. AB - 1. Recently, a potent non-peptide antagonist of neuropeptide Y (NPY)-Y1 receptors has been developed. In this study, the selectivity of this compound, BIBP 3226, as a functional Y1 receptor antagonist, and the possible role of endogenous NPY in sympathetic vasoconstriction in different vascular beds have been investigated in anaesthetized pigs. 2. BIBP 3226 specifically displaced [125I]-NPY binding with an IC50 value of 7 nM in membranes of pig renal arteries, which also were responsive to a Y1 receptor agonist, but had only minor effects in the pig spleen (IC50 55 microM), where instead [125I]-NPY binding was markedly inhibited by a Y2 receptor agonist. IC50 values in the same nM range for BIBP 3226 were also observed in rat and bovine cortex and dog spleen. 3. In anaesthetized control pigs in vivo BIBP 3226 (1 and 3 mg kg-1) markedly inhibited the vasoconstrictor effects of the Y1 receptor agonist [Leu31, Pro34] NPY(1-36), without influencing the responses to the Y2 receptor agonist N-acetyl [Leu28, Leu31] NPY(24-36), or to noradrenaline, phenylephrine, alpha,beta-methylene adenosine triphosphate or angiotensin II. 4. High frequency stimulation of the sympathetic trunk in control pigs caused a biphasic vasoconstrictor response in nasal mucosa, hind limb and skin: there was an immediate, peak response, followed by a long-lasting vasoconstriction. BIBP 3226 (1 and 3 mg kg-1) reduced the second phase by about 50% but had no effect on the peak response. In the spleen, kidney and mesenteric circulation (which lack the protracted response) BIBP 3226 was likewise without effect on the maximal vasoconstriction, and did not influence noradrenaline overflow from spleen and kidney. 5. The corresponding S-enantiomer BIBP 3435 had only marginal influence on [125I]-NPY binding (microM range) and did not inhibit the vasoconstrictor effects of any of the agonists used, including the Y1 receptor peptide agonist. Furthermore, BIBP 3435 did not affect the response to sympathetic nerve stimulation. Both BIBP 3435 and BIBP 3226 caused a slight transient decrease in mean arterial blood pressure (by about 5 and 15 mmHg at 1 mg kg-1 and 3 mg kg-1, respectively), accompanied by splenic and mesenteric vasodilatation, suggesting that this effect was unrelated to Y1 receptor blockade. 6. The peptide YY (PYY)- and NPY-evoked vasoconstriction in the kidney of reserpine-treated pigs was markedly reduced (by 95%) by BIBP 3226 while the vasoconstrictor effect in the spleen was attenuated by only 20%. BIBP 3226 did not influence stimulation-evoked NPY release. The vasoconstrictor response in reserpine-treated pigs to single impulse stimulation, which is observed only in nasal mucosa and hind limb, was unchanged regarding maximal amplitude and the integrated effect was only moderately reduced (by about 25%) in the presence of BIBP 3226 (1 mg kg-1). BIBP 3226 (1 mg kg-1) markedly reduced (by 55-70%) the long-lasting vascular response (total integrated blood flow reduction) evoked by sympathetic nerve stimulation at high frequency (40 impulses at 20 Hz) in spleen, kidney, nasal mucosa and hind limb. Furthermore, the maximal amplitude of the vasoconstriction was reduced mainly in the kidney (by 60%) and also in the spleen (by 40%). 7. It is concluded that BIBP 3226 can act as a selective Y1 receptor antagonist in the pig. Endogenous NPY via Y1 receptor activation may play a role in evoking the long-lasting vasoconstriction seen in nasal mucosa, hind limb and skin after high frequency stimulation of sympathetic nerves in control pigs. Furthermore, NPY via Y1 receptor mechanisms seems to be of major importance for the long-lasting component of the reserpine resistant sympathetic vasoconstriction in many vascular beds, and for the maximal vasoconstrictor response in the kidney. Circulating NPY and PYY induce splenic vasoconstriction via Y2-receptors in contrast to neuronally released NPY which mainly activates Y1 receptors. PMID- 8680733 TI - Effects of chronic vitamin E deficiency on vascular function--a study of sympathetic nerves, smooth muscle and endothelium of the mesenteric arterial bed of the rat. AB - 1. Male rats were deprived as weanlings of dietary vitamin E for 2, 4, 6, 10 and 12 months. Mesenteric arterial beds from these rats and from age-matched controls were isolated and perfused with Krebs solution at a constant flow rate (5 ml min 1). The function of perivascular sympathetic nerves, smooth muscle and endothelium was assessed. 2. At 12 months vitamin E deficient rats exhibited the characteristic symptoms of vitamin E deficiency, namely poor coat condition, muscle wasting, kyphoscoliosis and impaired gait. In the isolated mesenteric arterial bed electrical field stimulation (EFS) of perivascular nerves (4-32 Hz, 90 V, 1 ms, for 30 s) elicited frequency-dependent vasoconstrictor responses which were unaffected by vitamin E deficiency except at 12 months, at which age responses were significantly greater than those of the controls at 24 and 32 Hz (P < 0.01). 3. Exogenous noradrenaline (NA; 0.15-500 nmol) elicited dose dependent vasoconstriction which was similar in vitamin E-deficient and control preparations at all ages. Potassium chloride (0.15 mmol) also produced similar vasoconstrictor responses in vitamin E-deficient and control preparations at each age. 4. Tone of the preparations was raised by continuous perfusion with methoxamine (4-70 microM), producing similar increases in perfusion pressure in vitamin E-deficient and control preparations at each age. Endothelium-dependent dose-dependent vasodilatation to adenosine 5'-triphosphate was significantly impaired in mesenteric arterial beds from 12 month-old vitamin E-deficient rats compared with the controls (P < 0.05). Relaxation to acetylcholine was not significantly different at any age. 5. Endothelium-independent vasodilatation to sodium nitroprusside was similar in vitamin E-deficient rats and age-matched controls. 6. These results suggest that long term (12 months) deprivation of dietary vitamin E may impair endothelial function in mesenteric arteries of the rat. Sympathetic perivascular nerve constrictor function was increased at 12 months. There were no functionally expressed changes in the vascular smooth muscle, which appears to be more resilient to the effects of oxidative stress in vitamin E deficiency. PMID- 8680734 TI - Behavioural interactions between 5-hydroxytryptophan, neuroleptic agents and 5-HT receptor antagonists in modifying rodent responding to aversive situations. AB - 1. The ability of 5-hydroxytryptophan, 5-HT2 receptor antagonists and typical and atypical neuroleptic agents to modify behavioural responding to aversive situations was investigated in the mouse light/dark test and rat social interaction. 2. The administration of 5-hydroxytryptophan inhibited rat social interaction and the exploratory behaviour of mice in the light/dark test. 3. The 5-HT2 receptor antagonists, ketanserin, ritanserin, MDL11939, methysergide and RP62203, the neuroleptic agents, spiperone, haloperidol and benperidol, and the atypical neuroleptic agent, clozapine, when administered alone failed to modify mouse or rat behaviour. In contrast, when administered alone, sulpiride in rats and mice and thioridazine in rats disinhibited behaviour. 4. Methysergide, RP62203, ketanserin, ritanserin and MDL11939 antagonized the inhibitory effects of 5-hydroxytryptophan or reversed the inhibitory effects to one of disinhibition. 5. Low doses of spiperone (but not haloperidol or benperidol) also antagonized the inhibitory effects of 5-hydroxytryptophan in the rat but not the mouse. Higher doses of the three neuroleptic agents caused locomotor depression in both rats and mice which obscured any specific changes in behavioural responding to the aversive situations. 6. The disinhibitory profile of sulpiride in both mice and rats and thioridazine in rats was evident during their interaction with 5-hydroxytryptophan. Thioridazine in the mouse and clozapine in rats and mice also reversed the inhibitory effects of 5-hydroxytryptophan to one of disinhibition. 7. In summary, we present evidence that the atypical neuroleptic agents, thioridazine and clozapine, with their known affinity for the 5-HT2 receptors, can mimic the actions of reference 5-HT2 receptor antagonists to antagonize the inhibitory effects of 5-hydroxytryptophan in rodent models of anxiety. The results are intepreted in terms of drug action on different 5-HT2 and other 5-HT receptor subtypes. In addition, thioridazine and sulpiride have disinhibitory effects in their own right which remain to be explained. PMID- 8680735 TI - Calcium compartments in vascular smooth muscle cells as detected by aequorin signal. AB - 1. To examine whether cytosolic Ca2+ in smooth muscle cells distributes evenly, cytosolic Ca2+ levels were measured with two different Ca2+ indicators in the ferret isolated portal vein; a fluorescent indicator, fura-PE3, that shows the average Ca2+ level, and a photoprotein, aequorin, that preferentially shows a high Ca2+ compartment. 2. A noradrenaline (10 microM)-induced sustained contraction was associated with a sustained increase in the fura-PE3 signal, or a transient increase followed by small sustained increase in the aequorin signal. A high K(+)-induced contraction was associated with a sustained increase in both the fura-PE3 and aequorin signals. 3. A second application of noradrenaline or high K+ induced reproducible contractions and fura-PE3 signals. In contrast, the aequorin signal resulting from a second application of noradrenaline or high K+ was much smaller than the first signal. 4. Following a 13 h but not a 3 h resting period, the aequorin signal stimulated by noradrenaline or high K+ recovered, without any change in the contractile response. 5. In Ca(2+)-free solution, high K+ was ineffective, whereas noradrenaline induced only a small aequorin signal and contraction compared to those obtained in the presence of external Ca2+. After the addition of Ca2+, the first application of noradrenaline induced a large aequorin signal and a large contraction, although a second application induced a much smaller aequorin signal accompanied by a large contraction. 6. These results suggest that high K+ and noradrenaline increase Ca2+ in at least two cytosolic compartments; a compartment that is coupled to the contractile mechanism ('contractile' Ca2+ compartment; major portion of cytoplasm containing contractile elements) and a compartment that is not coupled to contractile mechanisms ('non-contractile' Ca2+ compartment; small sub-membrane area that does not contain contractile elements). On stimulation, the Ca2+ level in the 'contractile' compartment may increase to a level high enough to stimulate myosin light chain kinase but not so high as to consume aequorin rapidly. In contrast, the Ca2+ level in the 'non-contractile' compartment may increase so greatly that aequorin in this compartment is rapidly consumed. These two compartments may be separated by a diffusion barrier and, during a resting period, aequorin may slowly diffuse from the 'contractile' compartment to the 'non-contractile' compartment and thus restore the full aequorin signal. An increase in Ca2+ in the 'non-contractile' compartment seems to be dependent mainly on Ca2+ influx and partly on Ca2+ release. PMID- 8680736 TI - Pentobarbitone modulation of NMDA receptors in neurones isolated from the rat olfactory brain. AB - 1. The action of pentobarbitone on the N-methyl-D-aspartate (NMDA) receptors of neurones freshly dissociated from the olfactory bulb and olfactory tubercle has been studied using patch-clamp techniques. 2. Pentobarbitone produced a concentration-dependent depression of the currents evoked by NMDA with an IC50 value of c. 250 microM. 3. Analysis of the NMDA-evoked noise produced power spectra that could be fitted by the sum of two Lorentzians with corner frequencies of 17 and 82 Hz. Pentobarbitone increased the corner frequency of the high frequency component but did not alter the apparent single channel conductance estimated from the noise. 4. Single channel recordings in either the cell-attached or outside-out patch configurations revealed that NMDA (20 or 50 microM) opened channels with a main conductance level around 55 pS and a principal subconductance around 44 pS. The uncorrected mean open time of the channels was 3.4 ms and mean burst length was 6.0 ms. Mean cluster length was about 12 ms. 5. Pentobarbitone produced a concentration-dependent reduction in both mean open time and burst length. Mean cluster length was much less affected. Pentobarbitone did not decrease unitary current amplitude or bias the open-state current amplitude distribution in favour of a particular substate. 6. From these data it appears that pentobarbitone depresses the inward current evoked by NMDA by reducing the probability of channel opening and this results from a shortening of the lifetime of the channel open state and by decreasing burst length. PMID- 8680737 TI - Dual mechanisms of GABAA response inhibition by beta-lactam antibiotics in the pyramidal neurones of the rat cerebral cortex. AB - 1. The effects of beta-lactam antibiotics on the gamma-aminobutyric acid (GABA) induced Cl- current were investigated in pyramidal neurones freshly dissociated from the rat frontal cortex by the use of a nystatin-perforated patch recording mode under voltage-clamp conditions. 2. The GABA-induced inward current increased in a concentration-dependent manner with an EC50 of 6.7 x 10(-6) M at a holding potential of -40 mV. The GABA response was accompanied by an increase in the membrane conductance and reversed at near the Cl- equilibrium potential. 3. All beta-lactams (penicillin, imipenem, aztreonam and cefotiam) inhibited the 10(-5) M GABA-induced response in a concentration-dependent manner with an IC50 and Hill coefficient of 1.3 x 10(-3) M and 0.64 for penicillin, 9.6 x 10(-4) M and 0.83 for imipenem, 2.5 x 10(-3) M and 9.99 for aztreonam, and 2.9 x 10(-4) M and 1.03 for cefotiam. 4. Imipenem inhibited the GABA-response competitively while penicillin inhibited the same response in a noncompetitive fashion. 5. The inhibitory action of imipenem showed no voltage-dependency, whereas the effect of penicillin was voltage-dependent. 6. It is thus proposed that some classes of beta-lactams, including imipenem may have a mechanism that is different from penicillin and competitively affects the GABAA receptor. PMID- 8680738 TI - Stereoselective uptake of beta-lactam antibiotics by the intestinal peptide transporter. AB - 1. The stereoselective transport of beta-lactam antibiotics has been investigated in the human intestinal epithelial cell line, Caco-2, by use of D- and L enantiomers of cephalexin and loracarbef as substrates. 2. The L-isomers of cephalexin, loracarbef and dipeptides displayed a higher affinity for the oligopeptide/H(+)-symporter in Caco-2 cells than the D-isomers. This was demonstrated by inhibition of the influx of the beta-lactam, [3H]-cefadroxil. 3. By measurement of the substrate-induced intracellular acidification in Caco-2 cells loaded with the pH-sensitive fluorescent dye BCECF (2',7'-bis(2 carboxyethyl)-5-(6)-carboxy-fluorescein), it was demonstrated for the first time that L-isomers of beta-lactams not only bind to the peptide transporter with high affinity but are indeed transported. 4. Efficient proton-coupled transport of L beta-lactam antibiotics was also shown to occur in Xenopus laevis oocytes expressing the cloned peptide transporter PepT1 from rabbit small intestine. 5. Both cell systems therefore express a stereoselective transport pathway for beta lactam antibiotics with very similar characteristics and may prove useful for screening rapidly the oral availability of peptide-derived drugs. PMID- 8680739 TI - Cellular localization of the inhibitory action of relaxin against uterine spasm. AB - 1. The aim of this study was to determine whether the site of action of relaxin as a relaxant of rat myometrium is at the cell membrane or at an intracellular site. Therefore, the potency of relaxin was determined against spasms reliant predominantly upon either extracellular Ca2+ or intracellular Ca2+. Uterine spasms dependent upon extracellular Ca2+ were elicited by (i) oxytocin (0.2 nM) (ii) Bay K 8644 (1 microM) in 10 mM K(+)-rich PSS and (iii) KCl (80 mM). Uterine spasm dependent upon intracellular Ca2+ was elicited by oxytocin (20 nM) in the presence of nifedipine (500 nM). The effects of relaxin against these spasmogens were compared with those of levcromakalim, nifedipine and salbutamol. 2. Relaxin (0.2-6.3 nM), levcromakalim (25-800 nM), salbutamol (1-63 nM) and nifedipine (1 250 nM) caused concentration-dependent inhibition of the spasm evoked by oxytocin (0.2 nM) and relaxin was the most potent relaxant. 3. Relaxin and nifedipine were slightly less potent against the spasm induced by Bay K 8644 (1 microM) than against spasm induced by oxytocin (0.2 nM) (15 fold and 13 fold respectively). Levcromakalim and salbutamol were equipotent against the spasm evoked by Bay K 8644 (1 microM) and that evoked by oxytocin (0.2 nM). 4. Relaxin induced only 47 +/- 7% inhibition of the KCl (80 mM)-evoked spasm at a concentration of 0.8 microM. Levcromakalim was much less potent (427 fold) against the spasm evoked by KCl (80 mM) than against the spasm evoked by oxytocin (0.2 nM). The potency of salbutamol against the spasm evoked by KCl (80 mM) was modestly reduced (14 fold) compared to that against the spasm evoked by oxytocin (0.2 nM). The potency of nifedipine against the KCl (80 mM)-evoked spasm was not different from that against the oxytocin (0.2 nM)-evoked spasm. 5. The potencies of relaxin and levcromakalim against the spasm evoked by oxytocin (20 nM) + nifedipine (500 nM) were greatly reduced (74 fold and 234 fold respectively) compared to their potencies against the spasm evoked by oxytocin (0.2 nM). The potency of salbutamol against these two spasmogens was not different. 6. Relaxin was much less potent against the spasm dependent upon intracellular Ca2+ (that induced by oxytocin (20 nM) + nifedipine (500 nM)) than against the spasms dependent upon extracellular Ca2+, those induced by oxytocin (0.2 nM) and Bay K 8644 (1 microM). In this regard, relaxin resembled levcromakalim and nifedipine rather than salbutamol. Therefore, the major site of action of relaxin appears to be located at the plasma membrane rather than at an intracellular level. The observation that relaxin was less effective against the KCl (80 mM)-induced spasm than against the oxytocin (0.2 nM)-evoked spasm may indicate that relaxin has a minor action involving K(+)-channel opening. 7. High concentrations of relaxin (up to 1 microM) induced significant inhibition of the spasm dependent upon intracellular Ca2+. Thus at high concentrations relaxin also appears to have an additional intracellular action. PMID- 8680740 TI - Identification of a prostanoid FP receptor population producing endothelium dependent vasorelaxation in the rabbit jugular vein. AB - 1. Prostaglandin F2 alpha (PGF2 alpha) and its synthetic analogue, fluprostenol, potently relaxed the precontracted isolated jugular vein of the rabbit (RJuV). The vasorelaxant activity of PGF2 alpha and fluprostenol was dependent upon an intact vascular endothelium. Although removal of the vascular endothelium abolished activity associated with PGF2 alpha-like agonists, it did not significantly alter the relaxant effects of prostaglandin E2 (PGE2). 2. The nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), at 100 microM significantly inhibited the endothelium-dependent relaxations induced by PGF2 alpha. Lower doses (1 microM, 10 microM) of L-NAME had little or no effect. The relaxant effects of PGE2 were not affected by L-NAME (1-100 microM). D-NAME at 100 microM was without effect on the vasorelaxant responses to either PGF2 alpha or PGE2. 3. The potassium (K)-channel blockers tetraethylammonium (TEA, 1 mM), barium (1 mM) and quinine (100 microM), each tested in the presence of the inactive enantiomer D-NAME (100 microM) did not significantly affect the response to PGF2 alpha. Unexpectedly, both TEA and barium significantly and partially reversed the inhibitory effects of 100 microM L-NAME, whereas quinine had no effect. In similar studies, none of the three potassium channel blockers had any effect on relaxations elicited by PGE2 when given with D-NAME or L-NAME. 4. These results indicate that the PGF2 alpha-sensitive prostanoid receptors found in the vascular endothelium of the rabbit jugular vein are of the FP receptor subtype. Nitric oxide (NO) appears to be the predominant messenger involved in PGF2 alpha-induced relaxation of the rabbit jugular vein. Potassium channels may have a minor role in mediating the vasorelaxation response to PGF2 alpha. When both NO synthesis and K-channels are simultaneously blocked, inhibition of PGF2 alpha-induced vasorelaxation by L-NAME is opposed by K-channel blockers. This diminution of the inhibitory effect of L-NAME by TEA and barium suggests that K-channels may possibly serve a compensatory role via the NO pathway. PMID- 8680741 TI - Enhancement of the haemodynamic effects of NG-monomethyl-L-arginine by transforming growth factor-beta 1 in conscious, normal, but not endotoxaemic, rats. AB - 1. Male, Long Evans rats (350-450 g) were chronically instrumented for the measurement of regional haemodynamics, and the effects of TGF-beta 1 (25 micrograms kg-1 i.v. bolus) were assessed during infusion of saline (n = 9) or lipopolysaccharide (LPS, 150 micrograms kg-1 h-1; n = 12). In the same animals, responses to NG-monomethyl-L-arginine (L-NMMA 10 mg kg-1 bolus; 10 mg kg-1 h-1 infusion) were determined 18 h after administration of TGF-beta 1. In a separate experiment, the effects of the endothelin antagonist, SB 209670 (10 micrograms kg 1 min-1) on responses to TGF-beta 1 and to L-NMMA subsequently, were determined. 2. In the absence of LPS, TGF-beta 1 had slow-onset bradycardic and pressor effects accompanied by mesenteric and hindquarters, but not renal, vasoconstriction. Eighteen hours after TGF-beta 1, these effects had gone, but the bradycardic, pressor, and mesenteric vasoconstrictor responses to L-NMMA were enhanced. The haemodynamic changes following TGF-beta 1, and the augmentation of the subsequent responses to L-NMMA, were inhibited by SB 209670. These results are consistent with TGF-beta 1 stimulating the synthesis and release of endothelin, and an involvement of the latter in responses to L-NMMA. 3. The pressor effects of TGF-beta 1 were similar in LPS-infused and saline-infused animals, but in the former group the mesenteric vasoconstriction was enhanced and the hindquarters vasoconstriction diminished. Since, in the absence of TGF-beta 1, LPS-infused animals showed a developing hindquarters vasodilatation and mesenteric vasoconstriction, it is feasible that, in the presence of TGF-beta 1 and LPS together, the haemodynamic profile represented an amalgam of the individual effects of the two interventions, rather than a specific effect of TGF beta 1 on the haemodynamic sequelae of endotoxaemia. 4. In the presence of LPS, haemodynamic responses to L-NMMA were suppressed, and TGF-beta 1 generally did not affect this suppression. A possible explanation of this observation is that LPS increased circulating endothelin levels, and thus resulted in desensitization to the effects of endothelin released following administration of L-NMMA. PMID- 8680742 TI - Neuromuscular blocking profile of the vecuronium analogue, Org-9487, in the rat isolated hemidiaphragm preparation. AB - 1. The neuromuscular effects of the short-acting aminosteroid muscle relaxant Org 9487 have been studied in the in vitro rat phrenic nerve/hemidiaphragm preparation by use of twitch tension and electrophysiological recording techniques. 2. Org-9487 (5-100 microM) produced a concentration-dependent decrease in the amplitude of twitches (0.1 Hz) and tetanic contractions (50 Hz) evoked by motor nerve stimulation. The compound produced fade of force during both 50 Hz stimulation and train-of-four stimulation at 2 Hz, indicating a prejunctional component of action. 3. Anticholinesterases only partially reversed the effect of Org-9487 on twitch responses. This was possibly because, at the concentrations required to block twitches in the rat, Org-9487 itself was found to possess significant anticholinesterase activity. 4. Org-9487 (3 microM) increased the rundown of endplate current amplitudes during a 2 s train of 50 Hz nerve stimulation. This was because Org-9487 increased the quantal content of the first endplate current in the train without affecting acetylcholine release towards the latter part of the train. 5. Org-9487 (10 microM) produced a voltage dependent decrease in the time constant of decay of endplate currents at 32 degrees C and 0.5 Hz, indicative of a block of endplate ion channels. The blocking rate constant increased with membrane hyperpolarization. PMID- 8680743 TI - Antithrombotic effect of a novel recombinant hirudin analogue, CX-397, in a rat arterial thrombosis model. AB - 1. The antithrombotic effect of a new specific thrombin inhibitor, CX-397, was examined in a photochemically-induced arterial thrombosis model in the rat femoral artery and compared with that of heparin. 2. Pretreatment with CX-397 (10, 20 and 40 micrograms kg-1 min-1, i.v.) from 15 min before the experiment prolonged the time required for thrombotic occlusion of the artery in a dose dependent manner. The antithrombotic efficacy of CX-397 was associated with modest increases in activated partial thromboplastin time (APTT) and template bleeding time. 3. On the other hand, heparin at a dose of 450 micrograms kg-1 markedly prolonged APTT and the bleeding time, but did not inhibit thrombo occlusion. 4. CX-397 selectively inhibited platelet aggregation and concurrent secretion of 5-hydroxytryptamine (5-HT) and thromboxane A2 (TXA2) production from platelets in response to thrombin, but not to collagen and ADP, in a dose dependent manner (5-100 ng ml-1). 5. CX-397 at 10 micrograms kg-1 combined with vapiprost, a TXA2 receptor antagonist, at 0.1 mg kg-1 significantly prevented occlusion, whereas, at these doses, neither drug alone had much effect. 6. These results demonstrate that CX-397 may prove to be more efficient for preventing platelet-rich thrombosis than heparin. Thrombin may play an important role in the rat thrombosis model. 7. The additive antithrombotic effect of the combination of thrombin inhibitor and TXA2 receptor antagonist at low doses suggests that thrombin and TXA2 may work in concert to produce thrombosis. PMID- 8680744 TI - The ineffectiveness of the NO-cyclic GMP signaling pathway in the atrial myocardium. AB - 1. This study was performed to determine whether nitric oxide (NO) has direct effects on force of contraction (Fc) in atrial myocardium from rats, rabbits, guinea-pigs, frogs, and man. 2. Glyceryl trinitrate, isosorbide dinitrate, 3 morpholino-sydnonimine hydrochloride (SIN-1), and S-nitroso-N-acetylpenicillamine (SNAP) did not significantly reduce Fc in the various preparations investigated, either given alone or after stimulation of alpha- or beta-adrenoceptors. 3. SNAP did not change the time course of contractions in rat, guinea-pig and human preparations. 4. 8-Bromo-guanosine-3':5'-cyclic monophosphate (8-Br-cyclic GMP) produced a negative inotropic effect in rat, guinea-pig and human atrial preparations and shortened time to peak tension and relaxation time in human preparations. 5. High K+ (85 mmol l-1)-induced contracture in rat heart muscle was reduced by 8-Br-cyclic GMP but not by SIN-1. 6. N-monomethyl-L-arginine (L NMMA), an inhibitor of NO synthase, failed to influence muscarinic effects on Fc or frequency from rat and guinea-pig hearts. 7. We conclude that NO, under the experimental conditions described here, has no direct effects on the heart, although cyclic GMP may be involved in the regulation of myocardial contraction. PMID- 8680747 TI - Editing for amino-acid type in CBCACONH experiments based on the 13C beta-13C gamma coupling. PMID- 8680746 TI - Effects of chronic vitamin E deficiency and a high polyunsaturated fatty acid diet on rat mesenteric arterial function. AB - 1. Male rats were deprived as weanlings of dietary vitamin E and fed on a high polyunsaturated fatty acid (PUFA) diet for 6 months. Rats fed on a high PUFA or on an untreated diet served as controls. Mesenteric arterial beds were isolated and perfused at a constant flow rate (5 ml min-1) and the function of sympathetic nerves, smooth muscle and endothelium was assessed. 2. Electrical field stimulation (4-32 Hz, 90 V, 1 ms, for 30 s) elicited frequency-dependent vasoconstriction of the mesenteric arterial preparations. Response curves were similar between untreated control and PUFA-fed control groups. Maximum vasoconstrictor responses (at 24 and 32 Hz) were significantly attenuated in rats deprived of vitamin E and on a high PUFA diet compared to the PUFA-fed controls (P < 0.05). 3. Exogenous noradrenaline (NA; 0.15-500 nmol) elicited dose dependent constriction of the mesenteric arterial beds. Preparations from rats fed on a high PUFA diet elicited significantly smaller responses compared to the control group. There was no significant difference in constrictor responses of PUFA rats deprived of vitamin E compared to the PUFA controls. Vasoconstrictor responses to doses of adenosine 5'-triphosphate (ATP) (5-5000 nmol) were significantly impaired in vitamin E-deficiency with a high PUFA diet compared to a high PUFA diet alone (P < < 0.001). Constrictor responses to potassium chloride (0.15 mmol) were significantly impaired in vitamin E-deficient PUFA rats compared to the PUFA-fed control group (P < 0.05). 4. Vasodilator responses were assessed in preparations in which tone was raised by continuous perfusion with methoxamine (4-25 microM). Mesenteric arterial beds from PUFA-fed rats deprived of vitamin E acquired significantly less tone, 59.8 +/- 4.6 mmHg (n = 7), than PUFA-fed controls 116.9 +/- 7.6 mmHg (n = 7) (P < 0.001) and were refractory to further increases in tone with further additions of methoxamine. Methoxamine-induced tone of PUFA-fed controls was greater than in P that in the untreated controls (83.9 +/- 7.4 mmHg; n = 5) (P < 0.05). Responses to the endothelium-dependent vasodilators acetylcholine (ACh) and ATP were significantly reduced in preparations from rats fed on the vitamin E-deficient high-PUFA diet compared to PUFA controls. Vasodilator responses to ACh were greater in PUFA controls than in untreated controls and this reached statistical significance at 5 nmol ACh. 5. Vasodilator responses to sodium nitroprusside, which acts directly on the vascular smooth muscle, were similar in untreated control and PUFA control groups. Responses were significantly attenuated in vitamin E-deficient PUFA rats compared to the PUFA control group (P < < 0.001). 6. These results indicate that a combination of a high PUFA diet and vitamin E deficiency impairs mesenteric arterial function at the level of the vascular smooth muscle. A high PUFA diet alone attenuates responses to NA and augments endothelium-dependent vasodilation. The detrimental effects of loss of antioxidant activity due to vitamin E deficiency on vascular function may be exacerbated by a high PUFA diet. PMID- 8680745 TI - The involvement of ATP-sensitive potassium channels and adenosine in the regulation of coronary flow in the isolated perfused rat heart. AB - 1. The roles of adenosine 5'-triphosphate (ATP)-sensitive potassium channels (KATP) and endogenous adenosine in the regulation of coronary flow have been assessed in the isolated, buffer-perfused heart of the rat. 2. In the presence of glibenclamide 10 microM there was a significant (P < 0.001) reduction in coronary flow from a baseline value of 8.78 +/- 0.76 ml min-1 g-1 to 3.89 +/- 0.59 ml min 1 g-1. This change was accompanied by a significant (P < 0.01) reduction in cardiac mechanical performance as shown by the decrease in the pressure-rate product from 21,487 +/- 2,577 mmHg min-1 to 6,950 +/- 1,104 mmHg min-1. 3. The non-selective adenosine antagonist 8-phenyltheophylline (10 microM) also caused a significant (P < 0.001) reduction in coronary flow from a basal value of 10.4 +/- 0.6 ml min-1 g-1 to 6.32 +/- 0.60 ml min-1 g-1. The subsequent addition of glibenclamide, in the presence of 8-phenyltheophylline, brought about a further significant (P < 0.001) reduction in coronary flow to 3.05 +/- 0.55 ml min-1 g-1 and this value was similar to that in the presence of glibenclamide alone. 4. In hearts perfused under constant flow conditions, exogenous adenosine caused dose related reductions in coronary perfusion pressure described by a maximum reduction in pressure of 30.7 +/- 3.9 mmHg and an ED50 of 977 +/- 813 pmol. Addition of glibenclamide caused a significant (P < 0.01) increase in coronary perfusion pressure of 44.7 +/- 7.2 mmHg and a significant (P < 0.05) rightward shift of the dose-response curve for the depressor effects of adenosine (ED50 = 13.5 +/- 3.8 nmol), with a depression (P < 0.05) of the maximum (16.3 +/- 2.4 mmHg). 5. In conclusion, both KATP and endogenous adenosine make major contributions towards coronary vascular tone and the regulation of coronary flow in the rat isolated heart. Furthermore, in the coronary vasculature a significant proportion of the vasodilator action of adenosine is mediated through the activation of KATP. PMID- 8680748 TI - Fumonisin generation. PMID- 8680749 TI - Subchronic toxic effects of Fusarium moniliforme and fumonisin B1 in rats and mice. AB - Fumonisins are mycotoxins produced by the fungi Fusarium moniliforme, F. proliferatum, and other Fusarium species. Fumonisin B1, the most commonly found fumonisin, causes the fatal diseases equine leukoencephalomalacia and porcine pulmonary edema. Fumonisins are suspected human carcinogens because of the extraordinarily high incidences of esophageal cancer coincidentally found in areas of southern Africa and China where F. moniliforme-contaminated corn is consumed as a dietary staple. The subchronic (up to 90 days) effects of F. moniliforme-contaminated corn, corn cultures of this fungus, and purified fumonisin B1 (FB1) in rats and mice were systematically studied to determine target organs, characterize organ-specified lesions, and obtain dose-response data. The liver is a target organ in both species. Serum chemical findings indicative of hepatocellular injury and morphological findings, including apoptosis, appeared qualitatively similar in both species. The kidney is also a target organ in rats, but not mice. Lesions which include apoptosis and cellular degeneration are predominately found in the outer medella. Results of several investigations showed that the kidney was consistently affected at lower doses than the liver. The "no-observed-effect" level for nephropathy in rats was also consistently lower in males than females, suggesting a sex-related difference in nephrotoxic response to fumonisins. Other findings suggest that toxigenesis may be mediated by disruption of de novo sphingolipid biosynthesis. Hepatic and renal sphingolipid profiles, specifically sphinganine concentration and sphinganine-to sphingosine ratio, were altered in rats fed FB1 at levels that did not cause serum chemical, organ weight, or histopathological evidence of toxicity. PMID- 8680750 TI - Studies on the reproductive effects of Fusarium moniliforme culture material in rats and the biodistribution of [14C] fumonisin B1 in pregnant rats. AB - Fumonisins are mycotoxins produced by Fusarium moniliforme and other Fusarium species. They are commonly found in corn and corn-based foodstuffs. Fumonisins inhibit sphingolipid (SL) biosynthesis, alter cellular SL profiles, and thus may affect cell proliferation and differentiation, both of which are important processes for reproduction. However, there are few reports of the effects of F. moniliforme or fumonisins on mammalian reproduction or development. To study the reproductive effects of this fungus, diets formulated with culture material of toxic F. moniliforme strain MRC 826 (CM) to provide 0, 1, 10, or 55 ppm fumonisin B1 (FB1) were fed to male and female rats beginning 9 and 2 weeks before mating, respectively, and continuing throughout mating, gestational, and lactational phases of the study. CM caused nephropathy, typical of FB1, in males fed > or = 10 ppm and females fed 55 ppm FB1. No significant reproductive effects were found in males (n = 12/group), dams, and fetuses examined on gestation day 15 (G15) (n > or = 8/group), or dams and litters through day 21 postpartum (n > or = 9/group). Litter weight gain in the 10 or 55 ppm FB1 groups was slightly decreased; however, gross litter weight and physical development of offspring were not affected. Altered SL ratios indicative of fumonisin exposure, specifically increased sphinganine to sphingosine ratios, were found in the livers of dams from the 55-ppm FB1 group on G15. However, SL ratios of abdominal slices, containing liver and kidney, of fetuses from control and high-dose litters did not differ. In a second experiment, two dams were injected intravenously on G15 with 101 micrograms [14C]FB1 (3.179 x 10(5) dpm). After 1 hr, which allowed for ca. 98% of the dose to be cleared from the maternal blood, negligible amounts of radioactivity were found in the fetuses. Together, these results indicate that the CM, and by inference FB1, did not have significant reproductive effects at doses which are minimally toxic, and further suggest that little in utero FB1 exposure occurred through G15. PMID- 8680751 TI - Evidence for disruption of sphingolipid metabolism as a contributing factor in the toxicity and carcinogenicity of fumonisins. AB - Fumonisins are inhibitors of the biosynthesis of sphingosine and more complex sphingolipids. In eucaryotic cells, fumonisin inhibition of sphingolipid biosynthesis is a result of inhibition of the enzyme ceramide synthase. Large increase in free sphinganine concentration in plant and animal cells are observed within a few hours after exposure to fumonisins and/or Alternaria toxins (AAL toxins). Some of the sphinganine is metabolized to other bioactive intermediates, and some is released from cells. In animals, free sphinganine accumulates in tissues and quickly appears in blood and urine. Free sphingoid bases are toxic to most cells, and complex sphingolipids are essential for normal cell growth. Fumonisin B1 stimulates sphinganine-dependent DNA synthesis in Swiss 3T3 cells, but is mitoinhibitory in other cell types. In cultured cells the accumulation of bioactive long-chain sphingoid bases and depletion of complex sphingolipids are clearly contributing factors in growth inhibition, increased cell death, and (in Swiss 3T3 cells) mitogenicity of fumonisins. While disruption of sphingolipid metabolism directly affects cells, it may indirectly affect some tissues. For example, fumonisin B1 impairs the barrier function of endothelial cells in vitro. Adverse effects on endothelial cells could indirectly contribute to the neurotoxicity and pulmonary edema caused by fumonisins. It is hypothesized that fumonisin-induced changes in the sphingolipid composition of target tissues could directly or indirectly contribute to all Fusarium moniliforme-associated diseases. PMID- 8680753 TI - Response of growing swine to dietary exposure to pure fumonisin B1 during an eight-week period: growth and clinical parameters. AB - Consumption of corn or corn-based products contaminated with Fusarium moniliforme/fumonisins has been associated with a variety of animal and human diseases and is a major food/feed safety issue. This study focused on the clinical toxicity and performance parameters in growing swing exposed to low to moderate levels of pure fumonisin B1 (FB.) for 8 weeks. Male (castrated) and female pigs were fed diets containing 0,0.1,1.0, and 10 mg FB1/kg diet (ppm). Weight gains and feed consumption were measured weekly. Blood samples were collected throughout the study, and various clinical and hematological parameters were measured. Because fumonisins are potent inhibitors of sphingolipid biosynthesis, sphinganine and sphingosine concentrations were determined in the liver, lung, and kidney. Organ weights and carcass quality were measured at the end of the trial. In general, male pigs were more adversely affected by FB1 in the diet than females. The average daily gain for males decreased by 8% for pigs fed 1.0 ppm and by 11% at 10.0 ppm, when compared to the control (0 ppm). Males fed 0.1 ppm showed an erratic growth pattern during the first 5 weeks of the experiment. Feed consumption for the same animals was somewhat higher than that of the controls during each of the first 4 weeks but thereafter was 6-7% lower each week as compared to controls. Female pigs fed FB1-diets showed a general enhancement of feed consumption until week 4. Among clinical chemistry parameters, cholesterol increased in males for the 1.0 and 10.0 ppm diets as compared to controls after 2 weeks, while the levels in both sexes were elevated for the 1.0 ppm diet only by the end of the experiment. Serum liver enzyme concentrations were altered during week 2 only. Changes were observed in the weight of the pancreas and adrenals for male pigs fed FB1 diets as compared to controls. The free sphinganine to free sphingosine ratio (biomarker of exposure in FB1-consuming animals) increased in all three organs for the 10 ppm diet, regardless of sex. The study indicated that FB1 can cause different effects at each dose level, at concentrations as low as 0.1 ppm (showing erratic growth) followed by a reduced growth and biochemical abnormalities in blood (1.0 ppm) and sphingolipid alterations in tissues (10.0 ppm). Some of these effects occurred below the exposure level that caused alteration in sphingolipid metabolism. PMID- 8680752 TI - Intravenous fumonisin B1 induces cell proliferation and apoptosis in the rat. AB - In the rat, the target organs of fumonisin B1, a mycotoxin produced by Fusarium moniliforme, are the kidney and liver. Fumonisin B1 is also hepatocarcinogenic in the rat and is associated epidemiologically with esophageal cancer in humans. We investigated the effect of a single intravenous dose of fumonisin B1 on cell proliferation, lesion development, and glutathione status in the major target organs of the rat. Male Sprague-Dawley rats were injected intravenously with fumonisin B1 at 0 or 1.25 mg/kg and were euthanized at 12 hr or, 1,2,3, or 5 days. An intraperitoneal injection of 5-bromo-2'-deoxyuridine at 100 mg/kg was given 90 min prior to euthanasia. In fumonisin B1 treated rats, serum cholesterol and serum urea nitrogen were elevated; however, the activity of hepatic enzymes was unaffected. Hepatic and renal glutathione concentrations were depressed at 12 and 24 hr, respectively, with subsequent recovery. Histologic changes were most prominent in the outer medulla of the kidney, with cell proliferation and apoptosis followed by nephrosis. Cell proliferation also occurred in the liver and esophagus, but in the absence of tissue injury. The labeling index peaked on day 1 for the liver and on day 3 for the esophagus. These results confirm that the primary target organ of fumonisin B1 in the rat is the kidney and support the concept that fumonisin B1-induced mitogenesis may be the mechanism of carcinogenesis. PMID- 8680754 TI - Leukoencephalomalacia and hemorrhage in the brain of rabbits gavaged with mycotoxin fumonisin B1. AB - Two of five pregnant rabbits gavaged with purified fumonisin B1 at 1.75 mg/kg/day died, one after 9 and one after 13 doses. Microscopic examination revealed focal small hemorrhages in cerebral white matter in both animals, with malacia and hemorrhage also present in the hippocampus of one. The lesions were bilateral. Both animals also had marked degeneration of renal tubule epithelium and of hepatocytes. Apoptosis was the dominant degenerative change in kidney and liver. Fumonisin is known to cause leukoencephalomalacia and hemorrhage in equines, but CNS changes associated with exposure to fumonisins apparently have not been reported in other species. This preliminary observation in rabbits is reported to alert other investigators of a potential model of the disease in equines, as well as for investigation of potential mechanisms of toxicity to the CNS. PMID- 8680755 TI - British Society for Rheumatology XIIIth annual general meeting. Brighton, 8-10 May 1996. Abstracts. PMID- 8680756 TI - [Methodology of the study of pleural effusion cells]. AB - Discusses the methods for assessing the intensity of cytochemical reactions of leukocytes of pleural exudation and blood. Visual assessment of the intensity of cytochemical staining depends on the size of the cell. Morphometric methods revealed that pleural exudation cells differ in size from blood leucocytes, and hence errors occur during routine assessment of the intensity of cytochemical reactions. Corrective coefficients for L. Kaplow's formula to rule out such errors are proposed. PMID- 8680757 TI - [Quantitative criteria of a rhinocytogram of healthy subjects]. AB - Presents qualitative and quantitative characteristics of normal rhinocytograms obtained by cytologic investigations of smears impressions from the surface of the anterior portion of the inferior turbinate bone and processing of the results by variation statistics methods. Actually only solitary scales and superficial cells of multilayer squamous epithelium and small groups of ciliary epithelium cells may be reliably present in a normal rhinocytogram of man. PMID- 8680759 TI - [Iron deficiency in the inhabitants of Siberia]. PMID- 8680758 TI - [Preoperative diagnosis of thyroid cancer by karyometry of thyrocytes]. AB - Karyometry revealed that the distribution of thyrocyte nuclei by the size of their area on histograms depends on the type of thyroid disease. If the ratio of the share of thyrocyte nuclei area in the second and third ranges on distribution histograms is more than 1, thyroid cancer is diagnosed, if it less than 1, it may mean follicular adenoma, autoimmune thyroiditis, nodular colloid or diffuse toxic goiter. PMID- 8680760 TI - [Determination of the absorption capacity of peripheral blood neutrophils and monocytes]. AB - The absorption capacity of peripheral blood neutrophils and monocytes has been studied in 32 donors using color (red) latex made in Russia. The method is simple, cheap, and provides good quantitative and reproducible results. PMID- 8680761 TI - [Quantitative determination of DNA in human lymphocytes and study of DNA fragility]. AB - Turbidimetric method for measuring DNA is proposed. Modifications for assessing the share of double-stranded DNA in a mixture of single- and double-stranded DNA has been developed. The fragility of DNA has been studied in a group of regular donors at a blood transfusion center as an indicator of stability of this macromolecule to destructive exposures. PMID- 8680762 TI - [Determination of non-erythrocyte hemoglobin of blood plasma (serum) by the hemiglobincyanide method]. AB - The authors propose a modification of the method for assessment of nonerythrocytic hemoglobin suggested by L.D. Levina et al. in 1993. The disadvantage of the prototype method is relationship between the results of analysis and bilirubin concentration in the serum (plasma). Use of the bichromatic method for recording the results and a shorter, just 1-2-min incubation of samples helps eliminate this flaw. PMID- 8680763 TI - [Methodological and diagnostic aspects of the determination of calcium contents]. PMID- 8680764 TI - [Sensor for rapid measurement of blood glucose]. AB - Bacterial biosensor consisting of Gluconobacter oxydans cells immobilized on the surface of oxygen electrode was used for measuring glucose concentration in human blood serum. The results were compared with those of standard clinical method (color reaction with ortho-toluidine). The proposed biosensor permits highly accurate measurements (mean quadratic deviation no more than 2% of the mean arithmetic), the coefficient of correlation with the results of standard method being 0.970. PMID- 8680765 TI - [Study of salivary lactoferrin in prophylactic examinations]. AB - Immunochemical testing of salivary samples of 73 patients revealed a positive correlation between increased level of lactoferrin and the presence of chronic pancreatoduodenal diseases (gastroduodenitis, gastroduodenal ulcers, polyps of the antral portion of the stomach, cholecystitis, cholangitis, cholelithiasis, hepatitis, and pancreatitis, correlation coefficient 0.9). The test is proposed as a cheap and informative method for screening of the above diseases. PMID- 8680766 TI - [First results of accreditation of cytological services in St, Petersburg]. PMID- 8680767 TI - [Assessment of proteinograms obtained using the Beckman Paragon system]. AB - A high resolving capacity of agarose gel in electrophoretic separation of blood serum proteins permits the isolation of 7 or 8 fractions instead of 5 routinely isolated by paper or acetate cellulose film electrophoresis. The strips on proteinograms obtained using Beckman Paragon device are identified. The authors emphasize that reference values should be determined for each laboratory and present the proteinograms of 80 normal subjects they obtained. If M-gradient appears on the proteinogram, the zone of its localization should be specified in comments. PMID- 8680768 TI - [Features of insulin secretion and thromboelastography values in chronic pancreatitis]. AB - The function of pancreatic beta-cells in patients with chronic pancreatitis is insufficient, which manifests by hyposecretion of basal and stimulated insulin into the blood. Moreover, blood-clotting activity is increased in chronic pancreatitis. A conclusion is made that timely prevention of exacerbations of this disease should include laboratory check-ups of insulin production and assessment of blood coagulation in the patients. PMID- 8680770 TI - [Nephelometry as optic immunochemical method in the laboratory practice]. AB - The authors offer a modification of the nephelometric method for clinical immunology laboratory to be used for measuring proteins (albumin, C3-complement, IgG, IgA, IgM, and alpha 2-macroglobulin) in human biological fluids. The original method making use of only Russian-made reagents and equipment has been used on a full scale for measuring the proteins in the blood serum, cerebrospinal fluid, urine, and saliva of normal subjects. The sensitivity and specificity of the method depend predominantly on the physicochemical parameters of the study. PMID- 8680769 TI - [Clinical significance of gel electrophoresis of blood lipoproteins in primary biliary cirrhosis]. AB - Gel electrophoresis was used for separation of lipoproteins of the blood sera in patients with primary biliary cirrhosis (PBC) of the liver and cholelithiasis. Increased level of beta-lipoproteins in parallel with a reduction of total alpha- and pre-beta-lipoproteins were revealed in patients with PBC, these shifts being more expressed at later stages of the disease. An appreciable increase of beta- to alpha-lipoprotein ratio in PBC was observed. In patients with cholelithiasis no shifts in the lipoprotein profile of the blood serum were observed. The authors claim that the beta- to alpha-lipoprotein ratio is diagnostically significant in chronic hepatobiliary diseases. PMID- 8680771 TI - [Determination of circulating immune complexes by immunoenzyme method]. AB - Enzyme immunoassay is proposed to be used for measuring the content of circulating immune complexes (CIC) in human blood serum. S. aureus protein in a concentration of 1 to 5 micrograms/ml optimal for the sensitization of plates is used as the first sandwich layer. The method permits registration of CICs formed by immunoglobulins of different classes. Investigations of the blood sera of donors and cancer patients by the proposed method and by other methods (V. Haskova et al. and M. Digeon et al.) to assess complex formation showed a good correlation of the results of all measurements. PMID- 8680772 TI - [A method of detecting soluble immune complexes in tissue biopsies]. AB - Pretreatment of cryostat slices of tissue biopsy specimens with 30-50% water ethanol mixture increases the rate of detection of immune complexes in the intercellular substance of the epidermis to 100% in patients with acantholytic pemphigus. This method permitted the detection of immune complexes in all the examined cases with benign familial Hailey-Hailey pemphigus, which has never been reported heretofore. The authors believe that 30-50% water-ethanol mixture is capable of soft denaturation of proteins, stabilizes the slightly affine antibody antigen relations, and aggregates soluble immune complexes into larger protein formations, this preventing their washing out from tissues. PMID- 8680773 TI - [Comparative characterization of results of the immunoenzyme method of interleukin-1 determination in blast transformation reaction with indomethacin]. AB - Comparison of the results of blast transformation test and enzyme immunoassay of interleukin-1 in the blood serum and culture fluid demonstrated that assessment of phytohemagglutinin (PHA)-effected level of proliferative activity of lymphocytes is more informative for the diagnosis of manifest forms of HIV infection. Combined addition of PHA and indomethacin to cell culture by shifting the balance between prostaglandin E and interleukin-1 helps assess the contribution of macrophages to the development of HIV infection. PMID- 8680774 TI - [Indication of hepatitis C virus antibodies with separation into IgM and IgG classes and its clinical significance]. AB - A method for indication of anti-HCV antibodies with separation into IgM and IgG has been developed. Trials of the method in 182 patients with hepatitis C confirmed its value for the differentiation between acute and chronic forms of the disease. Antibodies of both classes were found in patients with acute hepatitis C, and the titer of IgG anti-HCV increased as the disease progressed. In chronic infection the level of anti-HCV IgG was stable, and there were no early antibodies. Appearance of anti-HCV IgM in chronic forms corresponded to exacerbation of the infectious process. PMID- 8680775 TI - [Possibilities of the use of parameters of membrane assembly of immunoglobulin receptors of B-lymphocytes in the differential diagnosis of intestinal diseases in children]. AB - Children with different forms of enteric malabsorption were examined using an original method for assessing the parameters of the process of membrane assembling for immunoglobulin receptors of B-lymphocytes, which helps single out several additional criteria for the differential diagnosis of variants of the malabsorption syndrome. The authors consider the phase coefficients characterizing each stage and the general coefficient reflecting the regularities of the kinetics of membrane assembly of receptors in general to be the most essential. Use of this method in pediatrics offers new potentialities in the differential diagnosis, prediction of disease course, and monitoring of the treatment efficacy. PMID- 8680776 TI - [Effects of drugs on the results of passive hemagglutination test]. AB - Study on the effects of some drugs on the results of passive hemagglutination test used for the detection of antitetanus antibodies in the blood serum showed that some drugs had a pronounced dose-dependent effect on antibody titers in experiments in vitro with standard antitoxic serum. The possibility of such errors should not be disregarded when assessing the results of the test. PMID- 8680777 TI - [K-antigen as a marker of Klebsiella pneumoniae and its use in clinical and epidemiological analysis (literature review)]. PMID- 8680778 TI - [Use of bacteriophages as selective factors in bacteriological diagnosis of mixed infections]. AB - A new method is proposed for detecting aerobic and anaerobic bacteria during diagnostic culturing by exposure of mixed microorganism populations to bacteriophages. By lysing homologous bacteria, the phages facilitate the detection and isolation of associates resistant to them in pure cultures. The proposed method is compared with the selective media techniques and a conclusion is made on the advantages of selective decontamination of biological samples by bacteriophages in experiments and diagnostic culturing of material from patients with pyo-inflammatory processes. PMID- 8680779 TI - [Use of morphometry and DNA flow cytometry in the differential diagnosis, prognosis and treatment of primary tumors of the liver (review of the literature)]. PMID- 8680780 TI - Stump the experts. Lymphocytoma cutis. PMID- 8680781 TI - Current status of tumescent liposuction in the United States. National survey results. AB - BACKGROUND: Tumescent liposuction is an extremely safe method of liposuction that can be performed entirely under local anesthesia. OBJECTIVE: To determine evolving trends in the current practice of tumescent liposuction in 15,336 patients treated by 66 dermatologic surgeons. METHODS: A survey questionnaire was sent to 1,778 Fellows of the American Society for Dermatologic Surgery in February 1994. The comprehensive questionnaire requested information on the number of patients treated with tumescent liposuction, complications, and various practice issues. RESULTS: Sixty-six dermatologic surgeons provided data on 15,336 patients; 44,014 body areas were treated. The complications that developed were infrequent and minor and have been reported previously. The average amount of fat removed per patient was 1,276 cc. An average of 33 cc of blood was lost per patient per procedure. Cannulas of 4.0 mm or less in diameter were commonly used. The abdomen and outer thighs were the most common areas treated in women. The flanks/love handles and abdomen were the most common areas treated in men. Intraoperative monitoring of vital signs was common. CONCLUSIONS: Tumescent liposuction is an evolving technique that has virtually eliminated blood transfusions and the major complications of liposuction under general anesthesia. Large amounts of fat can be removed using small diameter cannulas. The fat can be safely removed with a minimum risk of minor complications. PMID- 8680782 TI - Tumescent dermasanding with cryospraying. A new wrinkle on the treatment of rhytids. AB - BACKGROUND: The art of dermasanding has been recently rediscovered, revived, and refined. This renewed interest follows on the wake of intense interest in the new carbon dioxide resurfacing lasers. Tumescent dermasanding with cryospraying is a simple, inexpensive, highly effective, reliable and safe method of wrinkle removal. Personal experience with over 130 patients with ongoing refinement of existing dermasanding techniques plus the addition of tumescent analgesia, cryospraying, and specific postoperative instructions has resulted in outcomes at least equivalent to those obtained with laser resurfacing. METHODS: A detailed description and pictorial display of preparation, treatment, and postoperative care is presented. Its special attributes as well as its shortcomings versus laser resurfacing are briefly described. CONCLUSION: Strict attention to detail should produce excellent, consistent, and reproducible results with minimal complications. PMID- 8680783 TI - Efficacy of corneal eye shields in protecting patients' eyes from laser irradiation. AB - BACKGROUND: The continuing development of new types and applications of lasers has appeared to surpass the development of specific eye protection for these lasers. There are a variety of eye shields on the market, but few are specifically designed for laser protection. OBJECTIVE: Our purpose was to test a variety of eye shields by two parameters, light transmission and temperature rise, and to determine from these measurements the most protective shield for patients. METHODS: We tested four plastic shields, one metal shield, and two sets of tanning goggles for temperature rise and light transmission when irradiated with a beam from a flashlamp-pumped, pulsed-dye laser. RESULTS: The temperature rise at the surface of the shield opposite the laser impacts was no more than 0.2 degree C in any case. White light was transmitted at significant levels through several of the shields, but yellow light transmittance was noted only through the green eye shield. CONCLUSION: Our measurements indicate that all except the green shield appeared safe from transmission of the 585-nm radiant energy. However, the optimal laser eye shield, in our opinion, would be a composite of several different shields' characteristics. PMID- 8680784 TI - Dermabrasion, chemabrasion, and laserabrasion. Historical perspectives, modern dermabrasion techniques, and future trends. AB - BACKGROUND: Modern skin resurfacing techniques began with wire brush surgery. Chemabrasion techniques were developed combining the peel and fraise surgery. The newer CO2 lasers provide technology to also resurface the skin and provide an alternative approach to correct facial defects and facilitate facial rejuvenation. OBJECTIVE: This review article focuses on important aspects of dermabrasion, chemabrasion, and laserabrasion. An emphasis is placed on indications, preoperative skin conditioning, modern equipment, anesthesia, and postoperative dressings. RESULTS: The mainstay of therapy for skin resurfacing continues to be chemical peels. Combinations with dermabrasion are important for deeper lesions such as acne scars, or combined with laserabrasions for deeper rhagades. CONCLUSIONS: With a thorough understanding of the important principles of skin resurfacing and wound healing, the management of complexion improvement becomes straight forward, complications become manageable, and patient satisfaction is excellent. PMID- 8680785 TI - Leiomyosarcoma of the skin. Treatment of 34 cases. AB - BACKGROUND: Leiomyosarcoma is a rare soft tissue sarcoma that is one of the least common malignant lesions found in the skin. OBJECTIVE: We discuss the clinical, histopathologic, and prognostic factors related to superficial leiomyosarcoma from cases reported in the literature as well as from the Mayo Clinic experience from 1964 through 1994 with 34 patients. CONCLUSIONS: The vast majority of tumors were treated by excisional surgery with wide margins, but conceptually, Mohs' micrographic surgery should prove useful for the treatment of this tumor as it has with other skin cancers displaying contiguous growth. PMID- 8680786 TI - Venous thromboembolism in association with prolonged air travel. AB - OBJECTIVE: To study risk factors for the development of air travel-related acute venous thromboembolism. METHODS: A retrospective study of 254 patients admitted from 1988 to 1993 under the diagnosis of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) identified 44 patients who developed symptoms during or after air flight. RESULTS: There were 24 males and 20 females with a mean age of 63 years. Flight times were 5-17 hours. Twenty-eight patients (63.6%) had DVT only, five patients (11.4%) PE only, and 11 patients (25%) DVT and PE. Ninety five percent had extension of the thrombus above the calf: popliteal vein, 10 patients; superficial femoral vein, 13 patients; common femoral vein, six patients; and iliac vein, eight patients. Five patient-related risk factors were identified: history of previous DVT (34%), presence of chronic disease or malignancy (25%), hormone therapy (16%), recent lower limb injury (11%), and recent surgery or femoral catheterization (9%). CONCLUSIONS: We can speculate about the role of seven cabin-related risk factors: low humidity, hypoxia, diuretic effect of alcohol, insufficient fluid intake, smoking, "coach" position, and immobilization. In travelers with patient-related risk factors, the cabin related risk factors are superimposed and may increase the risks for air travel related acute venous thromboembolism. Active prophylaxis is recommended. PMID- 8680787 TI - Topically applied recombinant tissue plasminogen activator for the treatment of venous ulcers. Preliminary report. AB - BACKGROUND: Increasing evidence suggests that fibrin deposition is an important pathogenic component of venous ulceration and that fibrin removal could accelerate ulcer healing. OBJECTIVE: We sought to determine whether topical application of recombinant tissue plasminogen activator (tPA) compounded in 1% hyaluronate acid (HA) can be used safely in venous ulcers and whether it can accelerate healing. METHODS: Twelve patients were randomized in a double-blind fashion in three sequential groups of four subjects each, so as to receive daily topical application of either placebo (HA alone, one patient) or tPA/HA (three patients) at escalating doses of 0.25, 0.5, and 1.0 mg/ml of tPA for 4 weeks. RESULTS: No safety problems occurred, and we found a close direct correlation between mean ulcer reepithelialization, fibrin removal, and the dose of topically applied tPA (r = 0.991). CONCLUSION: In this first study to examine its usefulness, topically applied tPA appears to be a safe and promising agent for treating venous ulcers. PMID- 8680788 TI - Saphenofemoral incompetence treated by ultrasound-guided sclerotherapy. AB - BACKGROUND: Published long-term recurrence rates are higher after sclerotherapy than after surgery for the treatment of varicose veins involving greater saphenous tributaries associated with saphenofemoral incompetence (SFI). Duplex ultrasound has recently become the gold standard for the diagnosis of venous disorders, and over the past 5 years, has been utilized during sclerotherapy to guide injections more precisely. OBJECTIVE: To determine greater saphenous vein recanalization and recurrence rates of varicose veins associated with SFI after duplex ultrasound-guided outpatient sclerotherapy. METHODS: Ambulatory patients with varicose veins deriving from greater saphenous vein reflux associated with SFI documented by duplex ultrasound from two private practices were treated by duplex ultrasound-guided compression sclerotherapy using 3% sodium tetradecyl sulphate. Patients were followed by clinical and duplex examinations annually. RESULTS: Forty-eight of 202 (23.8%) limbs were found to have recanalized by duplex ultrasound at 1 year, and 0/28 (0%) at 2 years (48/202, 23.8% cumulative rate). Clinical recurrences (visible varicosity or symptoms occurred in 46/202 (22.8%) of limbs at 1 year, and 10/28 (35.7%) at 2 years (56/202, 27.2% cumulative rate). There were no intra-arterial injections or other complications. CONCLUSION: Duplex ultrasound enhances the precision and therefore, both the efficacy and safety of saphenous vein sclerotherapy when performed by experienced practitioners. While awaiting long-term follow-up to document the progressive recurrence rate over time, our results at 2 years are superior to those after conventional sclerotherapy, and compare favorably with those after surgical interruption. PMID- 8680789 TI - Maneuver to facilitate ambulatory phlebectomy. AB - BACKGROUND: In the course of phlebectomy varicose veins often brake under traction. When this happens, a great number of stab incisions are needed and veins must be extracted piecemeal. OBJECTIVE: To describe a traction maneuver that facilitates vein extraction. METHODS: Holding the exteriorized vein with the tip of the mosquito forceps pointed toward the skin, and pushing (rather than pulling) the vein out. RESULTS: This maneuver allows extraction of longer vein segments without breaking the vein. CONCLUSIONS: Easier removal and longer segments of veins can be extracted using this maneuver, thereby decreasing the number of "micro-incisions" needed. PMID- 8680790 TI - Hemodynamic principles of varicose vein therapy. PMID- 8680791 TI - Feminist fallacies: a reply to Hakim on women's employment. PMID- 8680792 TI - The sexual division of labour and women's heterogeneity. PMID- 8680793 TI - Age related distributive justice and claims on resources. AB - The ageing population structure, and claims on resources by non-working groups, are seen by many to be contributing to a growing welfare crisis. In their arguments, relations between age groups and generations will become increasingly fraught, and welfare arrangements will be undermined, as 'unacceptable' levels of taxation blight the experience of a contracting workforce, required to resource a growing welfare population. However, more seems to be known about researchers' views on distributive justice than is known about the perceptions of their subject populations. It has not been demonstrated that members of age groups share interests which are consonant with their cohort experience, or perceive their interests to be in conflict with those members of other age groups or generations. This paper analyses empirical evidence on people's perceptions of who should get, and do, what, in developing an argument that standard processes do not place age groups or generations in antagonistic relationship. Understanding the relations between age groups and generations is essential to explaining change in patterns of inequality, but the interdependence of these relations suggest that they are part of a coherent social structure, and not likely to give rise to crisis in the ways predicted. PMID- 8680794 TI - Public perceptions of childhood criminality. AB - This paper begins with the Jamie Bulger murder in Britain in late 1993 and sets out to examine the sociological contexts of the waves of shock and reaction that were manifested in the public perceptions of this event. Traditional conceptions of the child through modernity and their social and moral implications for generating a particular view of innocence and dependency are considered as providing the baseline from which childhood today appears to drift. Public reaction is analysed in terms of mass media content, against a general ignorance of the actual child's point of view. The paper concludes with the broader idea that images of childhood have become closely aligned with expectations of social integration and any fracture of one subsequently threatens the other. PMID- 8680795 TI - Down-regulation of c-myc mRNA after completion of liver regeneration in transgenic mice expressing hepatocyte growth factor in liver. AB - Hepatocyte growth factor (HGF) is the potent mitogen for liver parenchymal cells. It has been demonstrated that HGF enhances liver regeneration in transgenic mice which express HGF highly and exclusively in hepatocytes. In HGF transgenic mice where DNA synthesis of hepatocytes is active, c-myc is induced through an increased transcription rate by HGF. Therefore, expression of c-myc is up regulated by HGF in this condition. However, relations between c-myc, HGF and cell growth still remain unclear. To clarify regulatory mechanisms of c-myc, we measured c-myc mRNA, HGF mRNA, proliferating nuclear antigen (PCNA) mRNA, PCNA protein and labeling index after a two thirds partial hepatectomy in livers from transgenic mice which express HGF in liver. We found that expression of c-myc mRNA was high on day 1 and day 3, and decreased drastically on day 5 when liver regeneration had completed in HGF transgenic mice (Shiota, et al., 1994). Levels of PCNA protein and labeling index on day 1 after liver regeneration were higher in HGF transgenic mice than those of normal siblings, but no differences were observed between HGF transgenic and wild type ]nice on day 3. Endogenous expression of HGF was observed only on day 1, although transgene expression was almost constant during liver regeneration. These data suggest that cell-to-cell contact is more important for regulation of c-myc than levels of HGF mRNA. PMID- 8680796 TI - Gene expression of hypothalamic growth hormone (GH)-releasing hormone and somatostatin does not correlate with pulsatile secretion of GH in the adult mouse. AB - The secretion of growth hormone (GH) shows a pulsatile pattern in many mammalian species, and depends on the interaction of two hypothalamic hormones, GH releasing hormone (GHRH) and somatostatin (SRIH). A surge of GHRH secretion into the hypophysial portal blood induces peak secretion of GH from the anterior pituitary. To study whether the rhythmic and reciprocal oscillation in secretion of GHRH and SRIH are associated with changes in synthesis of these peptides, we examined the expression of hypothalamic GHRH and SRIH mRNA by Northern blotting during trough and peak phases of GH secretion in male mice. Hypothalamic GHRH and SRIH mRNA levels did not differ between trough and peak phases of GH secretion. This result suggests that changes in GHRH and SRIH secretion have little association with changes in the synthesis of these peptides at the hypothalamus in the male mouse. PMID- 8680797 TI - Suppressive effect of TNF-alpha on increased production of FdUMP by IFN-alpha. AB - Interferon-alpha (IFN-alpha) exhibits synergistic antitumor activity when combined with tumor necrosis factor-alpha (TNF-alpha) in vitro and in vivo and increases the cytotoxicity of 5-fluorouracil (5-FU) in vitro. Using a colon cancer cell line transplanted into nude mice, we examined the effects of pretreatment for 3 days with IFN-alpha (10(6) IU) and/or TNF-alpha (2.9 x 10(3) JRU) on 5-FU metabolism. 5-FU 30 mg/kg was administered after the pretreatment. IFN-alpha increased the tumor level of 5-fluorodeoxuridine monophosphate (FdUMP), and decreased the free level of thymidylate synthetase. Pretreatment with TNT alpha alone decreased HUMP whereas TNF-alpha plus IFN-alpha abolished the enhancement of FdUMP production by IFN-alpha. TNF-alpha also suppressed thymidine kinase activity. Neither IFN-alpha nor TNF-alpha altered the incorporation of 5 FU into RNA. PMID- 8680798 TI - TEMPOL, a superoxide dismutase mimic, ameliorates light-induced retinal degeneration. AB - The efficacy of 4-hydroxy-2,2,6,6-tetramethylpiperidine-l-oxyl (TEMPOL), a metal independent superoxide dismutase (SOD) mimic, in ameliorating light-induced retinal degeneration was investigated. Thirty-six Lewis albino rats were exposed to green fluorescent light (490-580 nm, 160-180 foot-candles) for 24 hr, after dark adaptation for 24 hr. The animals received six intraperitoneal (IP) injections of TEMPOL (100 mg/kg) or an equivalent volume of saline solution (vehicle-treated control groups) at 6 hr intervals starting 6 hr before the light exposure and ending 24 hr after light exposure. Another six rats were used as unexposed controls. The animals were killed at 6 hr, 6 days and 14 days after light exposure. Retinal damage was assessed by light and electron microscopy, measurements of outer nuclear layer (ONL) thickness and rhodopsin levels and counting of macrophages in the subretinal space. After light exposure, the TEMPOL treated rats showed mild edema of the retinal pigment epithelium (RPE), less densified inner segments (IS) at 6 hr and better preserved photoreceptors at 6 days and 14 days compared with vehicle-treated control groups. Morphometrically the ONL was thicker in the TEMPOL-treated rats than in the vehicle-treated control at 6 days (p<0.01) and 14 days (p<0.05) but no significant difference occurred at 6 hr (p>0.05). Rhodopsin levels in the TEMPOL-treated rats were significantly higher at 6 days (p<0.05) but not at 6 hr (p>0.05) or 14 days (p>0.05). Our results demonstrated that TEMPOL ameliorated light-induced retinal degeneration in rats. These findings are consistent with the hypothesis that superoxide radicals may play a crucial role in mediating light-induced retinal degeneration. PMID- 8680799 TI - Developmental changes in cerebellar endothelin-1 receptors in the neurologic mouse lurcher mutant. AB - In order to elucidate the role of neuromodulator endothelin-1 (ET-1) in cerebellar degeneration we determined ET-1 receptor binding in the control and lurcher mice cerebella at different postnatal (P) ages. The lurcher mutant is a suggested animal model for human cerebellar ataxias. The cerebellar membranes were prepared from 5 to 20 day old lurcher mice and littermate controls. ET-1 receptor binding was determined using radioligand assay and affinity cross linking. There was a significant decrease in [125I]ET-1 receptor binding with increasing postnatal age in the control and lurcher mice cerebella. Lurcher mice showed a significant increase in [125I]ET-1 receptor binding at P 9 to P 20 as compared with the controls. Whereas, at P5 to P7 no significant change was observed. By autoradiography, ET-1 receptors were localized in tile granule cell layer of 15 day old control and lurcher mice cerebella. Whereas, the lUrcher mice showed an increase in [125I]ET-1 binding in the cerebellum as compared with the littermate controls. The results of the present study suggest that the increase in ET-1 receptor binding as early as P9 (when neuronal loss is minimal) in the lurcher mutant may reflect upregulation of ET-1 receptors in the degenerating neurons. At P 15 to P 20, when about 50% to 75% neurons are lost respectively, these changes may also reflect astrogliosis. PMID- 8680800 TI - Role of endotoxin in wound healing impairment. AB - We studied the effect of endotoxin on cutaneous wound healing and the mechanism involved. Rats underwent dorsal skin incision and subcutaneous placement of plastic nylon wound chambers. Immediately after this procedure, lipopolysaccharide (LPS) was administered intraperitoneally at doses of 1 to 10 mg/kg. In the rats given LPS at doses of 3 mg/kg or higher, the wound breaking strength and the production of hydroxyproline in the wound chambers were significantly reduced in a dose-dependent manner. The wound fluid serially collected from the wound chambers after surgery was examined for the effect on the growth of fibroblast. While the wound fluid from control rats showed a marked fibroblast growth-accelerating activity on postoperative day 7, this activity in the wound fluid from LPS-treated rats was significantly decreased. In the wound fluid from LPS-treated rats, the fibroblast growth-accelerating activity recovered to the control level by the addition of anti-TNF-alpha neutralizing antibody. These results suggested the following: wound healing is accelerated as a result of the production of fibroblast growth factor(s) in the site of the wound. The production of tumor necrosis factor-alpha (TNF-alpha) induced by endotoxin inhibits the effect of the growth factor(s) in the wound area, which results in decreased collagen production. Subsequently the wound healing process is impaired. PMID- 8680801 TI - Cytotoxic and cell transforming effects of the insecticide, lindane (gamma hexachlorocyclohexane) on BALB/c 3T3 cells. AB - Further information was gathered on the possible carcinogenic hazard associated to the exposure to the insecticide lindane (gamma-hexachlorocyclohexane). The parameters studied were the cytotoxic and cell transforming activities of the pesticide on BALB/c 3T3 cells in an in vitro experimental model system in the absence or in the presence of rat liver S-9 mix-induced metabolic activation of the chemical. Lindane did not exert cytotoxic effects at all the tested doses (ranging from 10 micrograms/ml to 200 micrograms/ml) in the absence of bioactivation. However, dose-related cytotoxic effects were observed in the presence of the metabolizing system. Furthermore, lindane showed statistically significant and dose-dependent cell transformation activity at all the tested doses (10 micrograms/ml, 50 micrograms/ml and 100 micrograms/ml ) either in the absence or in the presence of bioactivation. This activity was related with cell proliferation since it was exerted in a level-II transformation test by replating cells and allowing the amplification of the cell transforming effects of the chemical. The formation of radicals and of reactive oxygen species, resulting from the chemical metabolism, could account for lindane activity as carcinogenesis promoting agent, although contemporary genotoxic effects induced by the pesticide could not be excluded. PMID- 8680802 TI - Changes in the analgesic effects of mianserin associated with altered plasma protein binding in experimental cancer. AB - In a group of mice bearing experimentally induced tumors, the protein binding of mianserin in vitro was measured and compared with a control group. The analgesic effect and the brain uptake of drug was also compared with a control group after an intraperitoneal dose of mianserin. The unbound percentage of mianserin in the plasma of mice with experimental cancer decreased with respect to control animals (5.20 +/- 0.12 vs 6.06 +/- 0.26; p<0.05) and alpha1-acid glycoprotein (AAG) levels, measured as plasma mucoprotein concentrations, were significantly increased (p<0.05). The brain/plasma drug concentration ratio of mianserin decreased in mice with experimental cancer when compared with control mice (1.11 +/- 0.03 vs 1.42 +/- 0.10; p<0.02). In both groups of mice, the mianserin analgesic effect was evaluated by the hot plate test after intraperitoneal drug administration. When the analgesia response-dose curve (0-60 mg/kg) was studied, a significant decrease in the response in mice with experimental cancer versus control mice was observed. These results suggest that resistance to the mianserin analgesic response may occur in animals with cancer disease. This resistance may be associated, in part, with an altered plasma protein binding, but other mechanisms could be involved. PMID- 8680803 TI - Regio- and stereo-selective oxidation of phenylbutane by rat liver. AB - Regio- and stereo-selective oxidation of butylbenzene (1) has been examined in vitro by rat liver supernatant fraction(S-9). When phenylbutane (1 ) was incubated at 37 degrees C for 1 hr with S-9, asymmetric oxidation occurred regioselectively at benzylic and omega-1 positions to afford preferentially (R)- and (S)-alcohol (2, 4), respectively. This enzymatic propensity was the case for the production of 1, 3-diols. (1R, 3S)- or (1R, 3R)-Butanediols(3a, 3b) were also obtained at 87% and 27%, respectively. This oxidation was induced by phenobarbital (PB) or beta-napthoflavone(beta-NF), and significant sex-related differences in control and PB pre-treated rats have been observed. Since these oxidations were inhibited with SKF-525A and CO, it was inferred that cytochrome P 450 was responsible for the oxidation. PMID- 8680804 TI - Enhancement of bismuth toxicity by l-cysteine. AB - Bismuth-induced encephalopathies observed in France about twenty years ago have never received convincing explanation. In previous papers we have shown in animal experiments that L-cysteine enhanced Bi absorption without leading to encephalopathies. in this paper we have studied in greater detail the toxicity and the pharmacokinetics of Bi, and L-cysteine, given by intraperitoneal route to mice, singly and simultaneously as a Bi-L-cysteine complex. Bismuth and L cysteine, were nontoxic singly since their LD50 were higher than 15 mmol/kg, but were toxic (LD50 = 0.3 mmol/kg) when they were given as a complex. The complex was about 50 times more toxic than the separate products. The changes in the levels of Bi and L-cysteine in blood versus time after the injection of the Bi-L cysteine complex suggests that the complex entered into the blood under a non dissociated form but just afterwards the complex dissociated and the levels of Bi decreased rapidly whereas the levels of L-cysteine remained high. The concentrations of Bi in tissues, blood, brain, kidney and liver were higher when it was given as the Bi-L-cysteine complex than alone. But the increase of the levels of Bi in tissues induced by L-cysteine was not sufficient to explain the 50 fold increase of the toxicity of the complex in comparison with Bi and L cysteine given alone. Since the increase of the levels of Bi induced by L cysteine was not sufficient to explain the increase of the toxicity of the complex, another explanation is required. We suggest that this increase results from the stimulation of peroxidation by bismuth and L-cysteine, as already observed for iron and L-cysteine. Other experiments are needed to verify the validity of this hypothesis. PMID- 8680805 TI - Relative zinc-binding capacity of metallothionein in hepatic cytosols of zinc injected rats. AB - In order to determine the zinc-binding capacity of metallothionein in hepatic cytosols of zinc-injected rats, we examined the relationship between zinc contents in cytosols and metallothionein fraction in rat livers. Each rat was injected intraperitoneally once with 0.9 % NaCl or zinc (10, 20, 40 or 60 mg zinc/kg b.w.) and was killed 14 h after injection. The distribution profiles of the hepatic cytosols of zinc-injected rats on a Sephadex G-75 column showed that the increased zinc was attributable to the metallothionein and high molecular weight proteins. Our results demonstrated that 63% of the increased zinc in hepatic cytosols of zinc-injected rats was bound to metallothionein and that 23% of the increased zinc was bound to high molecular weight proteins. These results suggest that the mechanisms of zinc accumulation in rat liver are different from those of cadmium accumulation. PMID- 8680806 TI - A possible non-aluminum oral phosphate binder? A comparative study on dietary phosphorus absorption. AB - The aim of this study was to highlight a possible new non-aluminum phosphate binder to limit hyperphosphatemia in patients with renal failure. Lanthanum chloride hydrate was evaluated as a dietary phosphate binder in rats. Aluminum chloride hexahydrate was evaluated as a reference. Animals were divided in five groups (6 animals per group): 1 control group (C), 2 aluminum groups (Al1 and Al2), receiving different doses of aluminum chloride hexahydrate and 2 lanthanum groups (La1 and La2), receiving different doses of lanthanum chloride hydrate. During the treatment, urine and stools were collected. At the end of the treatment animals were sacrificed and plasma and different organs were collected (liver, spleen, kidneys, brain and femur). To highlight the possible transfer of lanthanum in rat tissues, a long-term (100 days) study was carried with a high dose. At the end of the treatment, lanthanum determinations were carried out on several tissues (liver, spleen, kidneys, brain, femur and lungs). Determinations of phosphorus and calcium levels in plasma indicated that lanthanum chloride hydrate showed as good results as aluminum chloride hexahydrate. Lanthanum chloride hydrate significantly (p < 0.01) reduced the bone phosphorus burden. Decreases of urinary excretion and increases in fecal excretion of phosphorus indicated a severe phosphorus depletion in all treatments (Al and La). Unfortunately, in the long-term study, lanthanum traces could only be determined in the different tissues but not in plasma. However, in comparison with the equivalent aluminum treatment, the transfer of lanthanum was less important than aluminum transfer. Consequently, lanthanum could provide a possible alternative to aluminum. PMID- 8680807 TI - Effects of monoisoamyl meso-2,3-dimercaptosuccinate on arsenite-induced maternal and developmental toxicity in mice. AB - The therapeutic efficacy of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS), on arsenite-induced maternal and developmental toxicity was evaluated in the pregnant mouse. Sodium arsenite (12 mg/kg) was intraperitoneally injected into Swiss mice on day 9 of gestation, whereas Mi-ADMS was given subcutaneously at 0.25, 5, 24, and 48 hr after arsenite exposure. Amelioration by Mi-ADMS of arsenite-induced maternal and embryofetal toxicity was assessed at 23.8, 47.5, and 95 mg/kg/day. Controls received 0.9% saline with or without arsenite. Cesarean sections were performed on gestation day 18. In the positive control group (treated with arsenite only), 20.8% of the pregnant animals died, whereas 37.5% of the dams were carrying completely resorbed litters. No arsenite-induced maternal lethality was seen following treatment with Mi-ADMS at 23.8, 47.5 and 95 mg/kg/day. Also, administration of the drug at these doses significantly reduced the embryolethality, as well as the incidence of some skeletal variations provoked by sodium arsenite. Although based on these findings, Mi-ADMS might be suggested as a potential antidote to prevent the arsenite-induced maternal and developmental toxicity, due to their reduced toxicity compared to Mi-ADMS, DMSA and DMPS would probably be more advisable for pregnant women exposed to arsenite. PMID- 8680808 TI - Effect of glutathione depletion by buthionine sulfoximine on doxorubicin toxicity in mice. AB - The role of the glutathione (GSH) system in vivo or in drug resistance has received much attention, since GSH is a major component of the cellular detoxification system. We Studied the effect of GSH depletion by buthionine sulfoximine (BSO), a potent inhibitor of gamma-glutamylcysteine synthetase, on doxorubicin (DOX) toxicity in mice. The administration of BSO (30 mM in drinking water for 5 days) significantly decreased the tissue GSH. The GSH depletion in various tissues by BSO was associated with a decrease in the detoxification of DOX in mice. A single dose of 20 mg/kg of DOX significantly reduced body weight and rectal temperature in mice 3 days after injection. The combination with BSO and cepharanthine (biscoclaurine alkaloid), a P-glycoprotein (P-gp) inhibitor, significantly potentiated decrease in body and hypothermia induced by DOX. The study demonstrates that BSO markedly increases the toxicological effect of DOX with the alterations in GSH of tissues and Suggests that the intracellular accumulation of DOX is not a factor. PMID- 8680809 TI - Intracellular binding of the anti-inflammatory drug niflumic acid in the liver. AB - Intracellular binding of niflumic acid in the perfused rat liver was analyzed according to the model of Scatchard. The data for the binding isotherm were obtained from previously published indicator dilution experiments. The intracellular bound niflumic acid was calculated as the difference between total concentration and the concentration of the free form. The intracellular concentration of the free form was inferred from the concentration of the free form in the extracellular space under the assumption of equilibrative distribution. A Scatchard model with two classes of binding sites fits very well to the experimental curve. The high affinity class has a dissociation constant of 26.10 +/- 0.69 microM and a maximal binding capacity of 2.21 +/- 0.03 micromol (ml intracellular space)(-1); the low affinity class has a dissociation constant of 721.90 +/- 229.0 microM and a maximal binding capacity of 5.96 +/- 0.67 micromol (ml intracellular space)(-1). Probably, under in vivo conditions, the binding capacity in the cellular space exceeds that of the extracellular space. This phenomenon explains, partly at least, the high intracellular concentrations of niflumic acid found under in vivo conditions. PMID- 8680810 TI - The rat homologue of the Wilson's disease gene was partially deleted at the 3' end of its protein-coding region in Long-Evans Cinnamon mutant rats. AB - LEC mutant rats exhibit an abnormal hepatic copper accumulation, due to the defection of the rat homologue of the Wilson's disease gene. In this study, we found a definitive evidence that the rat Wilson's disease gene of LEC rats was partially deleted at the 3' end of its protein-coding region, by performing Southern blot analysis. Furthermore, in Northern blot analysis, we confirmed that expression of the rat Wilson's disease gene was deficient in the liver of LEC rats. The partial deletion of the rat Wilson's disease gene should be responsible for the deficient expression of that gene in LEC rats. PMID- 8680811 TI - The first ten years: the perspective from the president's desk. PMID- 8680812 TI - The effectiveness of antenatal care in preventing intrauterine growth retardation and low birth weight due to preterm delivery. AB - A case-control study was conducted to assess the effectiveness of antenatal care in preventing intrauterine growth retardation (IUGR) and low birth weight due to preterm delivery (PD), using data from 1837 births which took place in 25 hospitals in Mexico City during 1984. Women with an inadequate number of visits for gestational age had 63% greater odds of IUGR (95% CI: 1.01, 2.65) and 51% greater odds of PD (95% CI: 1.02, 2.23) than women with an adequate number. The content of antenatal visits showed no independent effect on the prevention of IUGR. Women having had poor content showed a PD OR of 1.76 (95% IC: 1.33, 2.34). An important reduction in the incidence of births with IUGR and PD could be expected if women could attend an adequate number of antenatal visits (11 and 9% reductions, respectively). Eighteen per cent of the PD births would probably be prevented if antenatal care could include at least six procedures: blood pressure, height and weight, urine and blood samples, and pelvic examination. PMID- 8680813 TI - Improving the use of information in medical effectiveness research. AB - There is increased emphasis on improving the quality of health care by obtaining and disseminating information about the effectiveness and outcomes of care and by facilitating more consumer input participation in decision-making. We examine barriers to information use and the challenges that these barriers pose for effectiveness research. We divide our discussion into four goals of effectiveness research. These are: (1) to provide more information so that consumers, providers and policymakers can make "rational" decisions; (2) to incorporate patient preferences into health care decisions; (3) to develop guidelines that incorporate both individual perspectives and societal perspectives; (4) to use information to improve the practice of health care. We discuss four recommendations for improving the use of information: (1) the evidence on how people actually make decisions should be used to inform the design and implementation of effectiveness research; (2) decision-making should be structured through guidelines and policies; (3) criteria should be developed for determining which guidelines should fully incorporate patient preferences; (4) safeguards should be established to guard against misuse of information. PMID- 8680814 TI - The evaluation of screening methods to identify medically unnecessary hospital stay for patients with pneumonia. AB - OBJECTIVES: This study compared three methods to screen charts of pneumonia patients for excess days. METHODS: A derivation data set was used to statistically derive a severity measure to predict length of stay for pneumonia patients and to refine a clinical algorithm for identifying excess stay. A validation data set was used to compare three computerized methods to screen for unnecessary hospital days: (1) an observed length of stay greater than a target value; (2) an observed stay greater than predicted for the specific patient; and (3) an algorithm that tested whether there were clinical justifications for the entire hospital stay. RESULTS: The sensitivity and specificity for detecting excess stay for the three methods were (1) 0.48 and 0.85 for the observed stay greater than the target value; (2) 0.56 and 0.73 for observed stay greater than predicted; and (3) 0.83 and 0.85 for the algorithm. CONCLUSIONS: These results suggest that computerized clinical algorithms may provide a useful method to detect unnecessary hospital stay. PMID- 8680815 TI - Factors associated with inappropriate emergency hospital admission in the UK. AB - This paper reports an attempt to assess the factors associated with inappropriate acute hospital admission using the technique of logistic regression. Data were obtained from two separate studies of acute hospital utilization in south-west England, conducted between 1992 and 1994. The appropriateness of admission was assessed using explicit standardized criteria in the form of the intensity severity-discharge review system with adult criteria (ISD-A). Up to 19 explanatory variables were available for the analyses. These variables were modelled for each centre separately, using logistic regression to produce final sets of factors independently related to the appropriateness of admission. For one centre, the final model contained age/ specialty and use of community services. For the other, the final model contained two measures of health status on admission-coping failure and admission with stroke. It is concluded that the complex interplay between the characteristics of patients, referrers, alternative forms of care and the acute hospital may result in quite different types of inappropriate admissions in different locations. PMID- 8680816 TI - Evaluating the appropriateness of red blood cell transfusions: the limitations of retrospective medical record reviews. AB - OBJECTIVE: Several studies have looked at the appropriateness of red blood cell transfusions, using retrospective chart reviews to assess compliance with guidelines. The goal of this study was to determine the quality of medical chart documentation, and assess the validity and the feasibility of using retrospective chart review data as part of a quality improvement (QI) program, to evaluate the appropriateness of peri-operative transfusions. DESIGN: The charts of 188 patients admitted for elective orthopedic surgery were reviewed. Both intra operative and post-operative transfusion events (n = 353) were analyzed. RESULTS: Only 68% of post-operative transfusion events on the day of surgery and 35% of transfusion events on days after surgery were accompanied by documentation of blood loss and/or change in vital signs. Symptoms were recorded in only 10% of post-operative transfusion events. The rationale for transfusion was recorded in only 16% of post-operative transfusion events on the day of surgery, in 27% on post-operative days and in 95% of intra-operative transfusions. The documentation of rationale was not different for transfusion events involving autologous blood (31%) or allogeneic blood (32%). This study provided information on transfusion practices. Single unit transfusions occurred in only 47 and 34% of patients receiving autologous and allogeneic blood, respectively. Only 19% of patients transfused with more than one allogeneic blood units, were clinically reassessed between blood units, compared to 34% of patients receiving more than one autologous blood unit. We conclude that retrospective chart reviews are limited by inadequate documentation and may not be the optimal source of information to determine the appropriateness of a transfusion. Improved methods (e.g. prospective reviews, or other system-level data collection methods) are needed for QI programs to influence practice. Despite its limitations, the information obtained suggests that current practice could be improved. PMID- 8680817 TI - Pediatric hospitalization due to ambulatory care-sensitive conditions in Valencia (Spain). AB - BACKGROUND: Studies in the United States have demonstrated that rates of hospitalization for conditions sensitive to primary care are related to socioeconomic factors. Our objective was to identify those sociodemographic and primary care factors associated with pediatric hospitalization for ambulatory care-sensitive conditions, in a country (Spain) with a health system that provides universal coverage. METHODS: Cross-sectional survey of 504 children hospitalized in a District General Hospital in Valencia, Spain. Data were gathered on sociodemographic variables, type of physician providing primary care and ambulatory care use prior to hospitalization. Analysis consisted of bivariate statistical tests and logistic regression techniques. RESULTS: Children who were under 2 years old and female were at significantly higher risk for hospitalization due to ambulatory care-sensitive conditions. Socioeconomic variables, type of physician or a previous visit to primary care services were not associated with a different risk of hospitalization due to these conditions. CONCLUSION: Characteristics unrelated to difficulties in access, or to type of provider, influence the risk of hospital admissions for conditions that could be prevented or managed without hospitalization. More specific classification of conditions potentially could be useful for determining which factors of structure or process of health services are related to hospitalization. PMID- 8680818 TI - Cost and prevention of pressure ulcers in an acute teaching hospital. AB - The cost of pressure ulcer treatment is much greater than the cost of prevention. Treating a pressure ulcer incurs considerable cost to the patient and hospital, especially if the pressure ulcer has advanced beyond stage one. In this paper, the cost of the intensive treatment required for patients who developed a pressure ulcer for two procedures, coronary artery bypass and hip replacement, in an Australian teaching hospital for the three years 1990, 1991 and 1992 was investigated. The average length of stay for all patients who had these two procedures was calculated and compared with the average length of stay for those patients who suffered a pressure ulcer. Results indicated statistical significance at the 5% confidence level for coronary artery bypass (t-test = 8.85, p = < 0.01) and for hip replacement (t-test = 5.39, p = < 0.01) for the three years 1990, 1991 and 1992. Preventive strategies were evaluated and results in this study indicated that the incidence rate improved when the pressure ulcer was detected earlier, and when positioning and appliance use were better reported, which was demonstrated for hip replacement in 1992. PMID- 8680819 TI - Two-dimensional outcome analysis as a guide for quality assurance of prostatectomy. AB - PURPOSE: To find outlier centers in different aspects of quality of care by comparing two different outcomes and adjusting to case mix in benign prostatic hypertrophy (BPH) patients undergoing prostatectomy. MATERIALS AND METHODS: An observational study including 537 consecutive patients undergoing prostatectomy for BPH in three medical centers in Israel between 1991 and 1992. Data were collected from medical charts and by a structured interview. Outcomes examined included immediate surgical complications and postoperative symptom effect level. Regression analysis was employed to adjust for case mix and to determine the additional contribution of medical centers. RESULTS: We found significant variability among centers in crude symptom effect, but not after case mix adjustment. An outlier was detected in both the crude and case mix-adjusted urological complications. CONCLUSIONS: Centers may differ with various outcomes. This may reflect variability in different levels of performance within different aspects of the process of care in prostatectomy procedures. PMID- 8680820 TI - Quality assurance in Taiwan, the Republic of China. PMID- 8680821 TI - Implementation of total quality management at Baskent University. PMID- 8680822 TI - Quality assurance in developing countries. Report on a consultative meeting held in St. Johns, Newfoundland, in May 1995, in conjunction with the 12th ISQua World Congress. PMID- 8680823 TI - The British Association of Urological Surgeons annual meeting. Edinburgh, 25-27 June 1996. Abstracts. PMID- 8680824 TI - Association of Surgeons of Great Britain and Ireland annual meeting. Glasgow, 22 24 May 1996. Abstracts. PMID- 8680825 TI - Regional distribution of lead in human milk from Egypt. AB - Bioaccumulation of lead during chronic exposure and its mobilization and secretion with mother's milk constitute a serious health hazard to the newly born children. Lead levels in human breast milk of 120 Egyptian women representing 20 different governorates throughout Egypt were determined using a graphite furnace Atomic Absorption spectrometer. According to the daily permissible intake (DPI) value established by the WHO of 5.0 micrograms/kg/d in mother's milk, the mean values of lead were around the permissible level in most of the Egyptian governorates. However, lead levels in mother's milk from Alexandria, Assiut and Cairo were significantly higher than the permissible value. Higher lead levels in mother's milk from these governorates may be attributed to heavy automobile traffic using leaded gasoline in addition to the use of lead water pipelines in these areas. PMID- 8680826 TI - Photocatalytic degradation of PCBs in TiO2 aqueous suspensions. AB - A generator-column technique was used to prepare aqueous solutions of PCBs. The degradation of 2-chlorobiphenyl, Aroclor 1248, Aroclor mixture (1221, 1016, 1254, and 1260) and St. Lawrence River water by simulated sunlight or sunlight has been investigated in the presence of aqueous suspensions of TiO2. The effect of TiO2 concentration and pH on the degradation rate of PCBs have been studied. The reaction rate followed apparent first-order kinetics and increased with increasing TiO2 concentration. The half-life of the degradation process for 2 chlorobiphenyl is 20 minutes at pH 10 and 9 minutes at pH 3 in the presence of 25 mg/L of TiO2. Less chlorinated PCBs decomposed faster than higher chlorinated ones. The rate constants and half-lives of individual PCBs in the commercial PCB mixture and St. Lawrence River water were also measured. PMID- 8680827 TI - Factors affecting the biodegradation of toluene in soil. AB - The biodegradation of toluene in soil microcosms was examined in order to identify the physical, chemical, and biological factors which determine the fate and lifetime of organic chemicals in soils. Toluene degradation rates were proportional to the initial substrate concentration and these rates reached a maximum at a concentration of 200 micrograms/g. No degradation occurred above this concentration presumably due to the toxicity of the hydrocarbon to the soil microorganisms. Small differences were observed in the degradation rates in soils at different moisture content. However, the availability of water in soil appeared to limit toluene degradation only at a very low water content. The lifetime of toluene in soil was also related to the initial level and activity of the soil microorganisms. Toluene was metabolized rapidly in those soils which initially contained high levels of degrading microorganisms. Furthermore, exposure of the soil to toluene resulted in an increase in the number of degrading organisms. The lack of inorganic nutrients such as nitrogen prevented complete degradation of toluene in a clay soil which contained high levels of degrading microorganisms. The biodegradation of organic chemicals in soil is not an intrinsic property of the molecule and cannot be predicted without first delineating the environment in which it is found. The biodegradation of a compound is defined by the biological, physical, and chemical characteristics of the soil environment. The lifetime of a chemical in soil results from a combination of all three of these parameters. PMID- 8680828 TI - Occurrence of nitro and non-nitro benzenoid musk compounds in human adipose tissue. AB - Nitro benzenoid musk compounds (Musk tibetene [CAS no. 145-39-1], Musk ambrette [83-66-9], Musk moskene [116-66-5], Musk ketone [81-14-1] and Musk xylene [81-15 2]) and non-nitro benzenoid musks (Celestolide [13171-00-1], Galaxolide [1222-05 5]) and Fixolide [1506-02-1] [21445-77-7] were analysed in 15 human adipose tissue samples from Switzerland by gas chromatography/high resolution mass spectrometry. The levels of Musk xylene and Galaxolide ranged up to 288 ng/g lipids and 171 ng/g lipids, respectively. The concentrations of non-nitro benzenoid musks found in human adipose tissue raise concern since very few toxicological data are available. PMID- 8680829 TI - Hydrophobicity and sorption of chlorophenolates to lipid membranes. AB - We have studied sorption of ionized species of chlorophenols and pentahalophenols to lipid membranes using egg-phosphatidylcholine (egg-PC) vesicles and measuring their zeta-potential as a function of aqueous concentration of the phenolates. The zeta-potential isotherms can be understood in terms of a sorption model that is a combination of the Gouy-Chapman model of the electrical double layer at the membrane-water interface and the Langmuir model for sorption. Two intrinsic sorption parameters were determined: the linear partition coefficient beta m, which relates the membrane surface density of the phenolates to their aqueous concentration and the area of the adsorption site, Ps. The linear partition coefficient is the measure of the affinity of phenolates to the lipid membrane. It depends strongly on the molecular structure: 2,6-dichlorophenolate beta m = (0.45 +/- 0.08) x 10(-7); m; 3,5-dichlorophenolate beta m = (0.22 +/- 0.02) x 10( 6) m; 2,4,6-trichlorophenolate beta m = (0.63 +/-0.06) x 10(-6) m; 2,4,5 trichlorophenolate beta m = (0.11 +/- 0.01) x 10(-5) m; 2,3,5,6 tetrachlorophenolate beta m = (0.56 +/- 0.07) x 10(-5) m; 2,3,4,5 tetrachlorophenolate beta m = (0.55 +/- 0.06) x 10(-5) m; pentachlorophenolate beta m = (0.34 +/- 0.05) x 10(-4) m; pentafluorophenolate beta m = (1.00 +/- 0.13) x 10(-7) m and pentabromophenolate beta m = (0.19 +/- 0.04) x 10(-3) m. Ps was found to be independent of phenolate structure, Ps = 3.3 +/- 0.1 nm2. The membrane affinity of chlorophenolates was compared with the octanol-water partition coefficients of un-ionized chlorophenols. It was shown that the free energy of transfer of chlorophenolates from water into the lipid membrane can be divided into non-electrostatic and electrostatic contributions. The no nelectrostatic contribution corresponds to the hydrophobicity parameter alpha = 3.94 +/- 0.0.08 kcal per nm2 of molecular surface area. The electrostatic contribution contains a term inversely proportional to the molecular radius of the phenolate ion which has the physical meaning of the work of transfer of the phenolate ion from water into the membrane. The polarity of the sorption region of egg-PC membranes is given in terms of the dielectric constant and was estimated to be 12.4 (range 10.5-13.4). PMID- 8680830 TI - Microcalorimetric study of metabolic inhibition by humic acids in mitochondria from Oryctolagus cuniculus domestica liver cells. AB - The metabolic thermogenesis curves of mitochondria isolated from Oryctolagus cuniculus domestica liver tissue have been determined by using an LKB-2277 bioactivity monitor. After isolation, mitochondria maintain activity when stored in appropriate nutrients. The thermokinetic equation: [formula: see text] was established for the activity recovery phase of metabolism. For these studies, the order of metabolism was found to be zero. The metabolic activity of mitochondria was inhibited by humic acid, a potential toxicant in Kashin-Beck and Keshan diseases. Experimental results indicate that humic acid will effect the heat output and lag time of mitochondrial metabolism. PMID- 8680831 TI - Field examination of ground water quality as an indicator of microbiological activity at gasoline contaminated sites. AB - Various portable electrodes and an on-line colorimetric test kit were used in the field to examine ground water quality as an indicator of natural bioremediation across two sites in Connecticut having subsurface gasoline contamination. The parameters examined included dissolved oxygen, dissolved carbon dioxide, direct redox potential (Eh), nitrate, ammonia and pH. These parameters permitted delineating regions of aerobic and anaerobic microbiological activity. Variations in these parameters over an eighteen month period along with gas chromatographic analyses of certain gasoline components in the ground water indicated that in situ bioremediation was effective at containing the petroleum contamination at both sites. It was found that a new on-line colorimetric test kit for the determination of oxygen was more accurate than a commonly used dissolved oxygen electrode. PMID- 8680833 TI - Pulmonary artery pressure during exercise in the horse after inhibition of nitric oxide synthase. PMID- 8680832 TI - Determination of PCB metabolites in Canadian human milk. AB - Chlorinated biphenyl methylsulfones and biphenylols were determined in samples of human milk from Canadian donors. Fifty samples containing an average of 10.8 ng g 1 (w/w) of total PCBs were found to contain an average of 68 pg g-1 of chlorinated biphenyl methylsulfone. The major congeners were 3-methylsulfonyl 2,2',4',5,5',-pentachlorobiphenyl, 4-methylsulfonyl-2,2',3',4',5, pentachlorobiphenyl and 4-methylsulfonyl-2,2',3',5,5',6'-hexachlorobiphenyl. Twelve of these samples were analyzed for five chlorinated biphenylols and the 4 methoxy-2,2',3,4',5,5',6-heptachlorobiphenylol congener was detected in all at an average concentration of 1.9 pg g-1. The chlorinated biphenylols appear to be minor residual metabolites in human milk from the general population. The fifty samples with an average of 8.4 ng g-1 of p,p'-DDE also contained an average of 16.5 pg g-1 of the corresponding methylsulfone. Both the total PCB methylsulfone and p,p' DDE methylsulfone were correlated with total PCB and p,p' DDE contents, respectively. PMID- 8680834 TI - Equine babesiosis (piroplasmosis): a problem in the international movement of horses. PMID- 8680835 TI - PRRS: trans-Atlantic cooperation and new ideas. PMID- 8680836 TI - Monitoring vaccines, diagnostic reagents and biotherapeutics for contaminating viruses. PMID- 8680837 TI - Chirality and the actions of anti-inflammatory drugs. PMID- 8680838 TI - Equine piroplasmosis an update on diagnosis, treatment and prevention. AB - Two haemoprotozoan parasites, Babesia caballi and Babesia equi, can cause equine piroplasmosis. Due to the presence of potential tick vectors in areas so far unaffected by equine babesias, import and export regulations often require the serum testing of animals for evidence of infection. Although the complement fixation test (CFT) has been recommended for detecting the presence of antibodies to Babesia spp., it has been demonstrated to have several disadvantages, including false-positive results and low sensitivity for detecting latent infections. An enzyme-linked immunosorbent assay (ELISA) may be an alternative for increased and sensitive detection of acute and latent babesial infections, but its development to date has been hindered by a limited antigen supply and poor specificity. In vitro cultivation of both parasite species and the identification of parasite proteins for diagnostic use has facilitated the development of a highly sensitive and specific ELISA. For the direct detection of the parasites, DNA probes are now available. Several drugs are available for the treatment of equine piroplasmosis. For instance, diminazene diaceturate is effective in the chemosterilization of B. caballi and in the elimination of clinical signs in B. equi infections. Antitheilericidal drugs such as buparvaquone have been demonstrated to be effective in combatting disease due to B. equi and may--in combination with imidocarb--also eliminate the parasite. The control of equine piroplasmosis must include effective tick control, seromonitoring of animals and the application of chemotherapy. PMID- 8680839 TI - Porcine reproductive and respiratory syndrome (PRRS): a review, with emphasis on pathological, virological and diagnostic aspects. AB - Despite early attempts to control the spread of the disease, porcine reproductive and respiratory syndrome (PRRS) has now become endemic in many countries including Britain. The occurrence of subclinical herd infections, the prolonged circulation of virus within herds and probable aerogenic virus spread all mitigated against the success of control measures. The origin of the disease is unknown but the causative agent has been shown to be an arterivirus with shared features to lactate dehydrogenase virus of mice. There is evidence of extreme genetic and antigenic variability between American and European isolates. PRRS virus has a predilection for alveolar macrophages and does not grow in most cell lines. In infected pigs, viraemia can persist for many weeks in the face of circulating antibodies and little is known about the mechanisms by which immunity to infection develops. A wide spectrum of disease has been reported from the field, accompanied in some cases by heavy economic losses. Reproductive and perinatal losses were most prominent when the disease first appeared. In the endemic phase, PRRS may be more significant as a contributory factor to a post weaning respiratory syndrome of young pigs of 3-8 weeks. On-farm techniques have been developed to reduce the recycling of PRRS virus from older infected nursery pigs to the younger newly weaned pig. Vaccines are now marketed for the control of PRRS, but are not licensed for use in Britain. Improvements in knowledge of virion composition and antigenic stability and in the nature of the immune response of the pig should result in genetically engineered subunit vaccines becoming available. Diagnosis of PRRS is still difficult as many animals do not show clinical signs and may only be detected by serology and often only when other respiratory diseases are being investigated. Now that the infection is widespread, serological testing must be properly targeted and interpreted to give meaningful results about virus circulation. An increasing arsenal of diagnostic methods are becoming available to detect virus in both fresh and fixed specimens. The pathogenic mechanisms of PRRS remain poorly defined and more work is needed to reveal the nature of the interaction between PRRS virus and other factors in disease. PMID- 8680840 TI - Foetal infections with bovine viral diarrhoea virus in Argentina. AB - The frequency of isolation of bovine viral diarrhoea virus (BVDV) from primary tissue cultures and organs from bovine foetuses was studied between 1992 and 1994. Around 25% of primary tissue cultures were BVDV positive. Primary testis cultures were inoculated with homogenates of spleen, kidney, lung and liver from 52 foetuses. Cells were passaged twice and BVDV antigen investigated by indirect immunofluorescence. Non-cytopathic BVDV was detected in at least one organ in 11/52 foetuses (21.2%): 6/10 spleens, 4/7 kidneys, 7/9 lungs and 3/5 livers. Cytopathic BVDV was detected in lung and kidney from two foetuses. Since only gamma-irradiated sera are used in the laboratory and only inactivated BVDV vaccines are applied in Argentina, it was concluded that these isolations represented field infections. In addition to the 11 virus positive foetuses, two foetuses were positive for BVDV antibodies, which suggested a 25% prevalence of infection. These results stress the need for disease control on a herd basis and the requirement for biological reagents of bovine origin for the detection of BVDV. PMID- 8680841 TI - Pharmacodynamics and chiral pharmacokinetics of carprofen in calves. AB - The non-steroidal anti-inflammatory drug, carprofen, was administered intravenously as the racemate at a dose rate of 0.7 mg kg-1 to six Friesian bull calves aged 8-10 weeks. Anti-inflammatory properties were indicated by attenuation of temperature rise at sites of intradermal injection of the irritants, carrageenin and dextran, but responses were not statistically significant at most recording times. Carrageenin- and dextran-induced swelling were not significantly reduced by carprofen. Carprofen reduced ex vivo serum thromboxane B2 synthesis but this effect was also not significant at most sampling times. Enantioselective pharmacokinetics of carprofen was demonstrated, plasma concentrations of the R(-) enantiomer predominating at all sampling times. It is concluded that inhibition of cyclo-oxygenase is unlikely to be the sole mechanism of action of carprofen in calves. PMID- 8680842 TI - Evaluation of carprofen in calves using a tissue cage model of inflammation. AB - The arylpropionate anti-inflammatory drug, carprofen, was administered intravenously as the racemate at a dose rate of 0.7 mg kg-1 body weight to six Friesian bull calves aged 16-17 weeks. Anti-inflammatory and pharmacokinetic properties were investigated using a tissue cage model of inflammation based on intracaveal injection of the mild irritant, carrageenin. Carprofen displayed enantioselective pharmacokinetics, with the R(-) enantiomer predominating in plasma at all measuring times. Elimination half-life and mean residence time were shorter and volume of distribution and clearance were greater for the S(+) than for the R(-) enantiomer. Penetration of both enantiomers into transudate (non stimulated tissue cage) was poor but penetration into exudate (carrageenin stimulated tissue cage) was good. Carprofen failed to reduce exudate concentration of prostaglandin E2 and the reductions in 12 hydroxyeicosatetraenoic acid were non-significant at most sampling times. The long elimination half-life of both R(-) and S(+) carprofen enantiomers and their ready penetration into and slow clearance from inflammatory exudate indicate that the drug is likely to have a long duration of action in calves. The mechanism of action is unknown but it is unlikely to involve inhibition of either cyclooxygenase or 12-lipoxygenase. PMID- 8680845 TI - Hock angles of dairy heifers in two management systems. AB - Hock angles were measured in 30 Holstein heifers in one herd housed either indoors on concrete slats or out of doors on dirt. Two examinations were made, i.e. at 12-13 and 24-26 months of age. Overall, the heifers had straight limbs; the mean value of the hock angle was 167.3 degrees +/- 0.7 (SEM) (range 154.3 177.4 degrees). Hock angles decreased with age in each group, but the difference between the first and second examinations was significant only for outdoor-housed heifers (P < 0.05). At the first examination, mean hock angles were not significantly different between the two groups (169.5 degrees +/- 1.6 vs 168.1 degrees +/- 1.6), but at the second examination indoor-housed heifers had significantly greater mean hock angles than heifers housed out of doors (167.4 degrees +/- 1.0 vs 164.2 degrees 1.3) (P < 0.05). Heifers housed indoors on concrete slats appeared to retain their straight-angled hocks. PMID- 8680843 TI - Chemical restraint of southern elephant seals (Mirounga Leonina); use of medetomidine, ketamine and atipamezole and comparison with other cyclohexamine based combinations. AB - A study was conducted to assess the effectiveness of the alpha-2 agonist medetomidine for sedation of pre-moulting, mature female southern elephant seals (Mirounga leonina). Two animals were sedated with a single intramuscular dose of medetomidine (0.013 and 0.027 mg kg-1). A further two groups of five animals received medetomidine (0.017 mg kg-1) combined with ketamine (1.90 mg kg-1) and, 20 min later, either saline or the alpha-2 antagonist atipamezole (0.04 mg kg-1) intravenously. Medetomidine alone did not give sufficient restraint to permit intravenous access. The response appeared to be similar to previous findings with ketamine and xylazine. Administration of atipamezole had little effect upon the level and timecourse of restraint. Ketamine and medetomidine seem to offer few advantages over ketamine and xylazine or other cyclohexamine-drug combinations for routine chemical restraint of southern elephant seals. PMID- 8680844 TI - Seasonal variations in the semen quality of young British goats. AB - Physical characteristics of semen quality were studied over a 12 month period in 10 post pubertal, young male goats (7-19 months of age) maintained under the naturally prevailing climatic conditions characteristic of the South of England (latitude N 51 degrees 46'). Semen was collected fort-nightly using an artificial vagina and an ovariectomized, oestrogenized teaser doe. The physical appearance of the ejaculates varied from a yellow or whitish-yellow colour during September December to a creamy-white colour during the remainder of the year. Ejaculate volume decreased from 0.96 +/- 0.06 ml in October to the minimum value of 0.39 +/ 0.03 ml in April and 0.38 +/- 0.02 ml in July, after which there was a sharp increase to the highest value, 1.04 +/- 0.05 ml, in September. Sperm cell concentration per ml was lowest (3.66 +/- 0.16 x 10(9)), during November and highest (6.56 +/- 0.29 x 10(9)) during May. However, the total sperm per ejaculate were highest during the September and lowest in December. The mass and individual motilities were higher during August-December than in the remainder of the year. The percentages of dead and morphologically abnormal spermatozoa were highest during May. The effect of the months and seasons of the year on all parameters of semen quality were significant (P < 0.01). PMID- 8680846 TI - Connections of octaval and lateral line nuclei of the medulla in the goldfish, including the cytoarchitecture of the secondary octaval population in goldfish and catfish. AB - Cytoarchitectural analyses combined with injections of the tracer horseradish peroxidase in various structures in the brain of the goldfish, Carassius auratus, have defined some of the major components of acoustic and lateral line mechanosensory circuits between the medulla and midbrain. The main acoustic receptor in Carassius, the saccule, is known to provide a major input to the dorsomedial zone of the descending octaval nucleus. The dorsomedial zone in turn projects bilaterally to the secondary octaval population (SO) and to nucleus centralis of the torus semicircularis. The SO is composed of three major subdivisions which are also present in a related otophysan, the catfish Ictalurus punctatus. The SO in Carassius projects bilaterally to nucleus centralis and to the saccular recipient zones of the ipsilateral descending octaval nucleus. By contrast, the mechanosensory lateral line receptors are known to direct most of their input to nucleus medialis. Nucleus medialis in turn projects bilaterally to nucleus praeeminentialis, nucleus ventrolateralis of the torus semicircularis, and the optic tectum, and to the contralateral nucleus medialis. We also provide evidence for a bilateral projection of nucleus medialis to the sensory trigeminal nucleus, and for a reciprocal input from the sensory trigeminal nucleus to the ipsilateral nucleus medialis. PMID- 8680847 TI - Spinally projecting neurons of the dorsal column nucleus in a reptile: locus of origin and trajectory of termination. AB - Interconnections between the dorsal column nucleus and the spinal cord were investigated in a reptile, Caiman crocodilus. After placement of an anterograde tracer into the dorsal column nucleus, descending fibers are seen to leave this nucleus to enter the dorsal funiculus where they course ventrally to terminate in lamina V of the spinal cord as far caudally as C2. Placement of a retrograde tracer into cut fibers of the cervical spinal cord identified the relay cells of the dorsal column nucleus that project to the spinal cord. These neurons were mainly clustered in a caudal and ventral part of this nucleus. The soma of these spinally projecting cells were small and were generally round or oval in shape. A number of these neurons had the long axis of their soma oriented dorsoventrally, with a primary dendrite extending dorsally. Fibers in the dorsal funiculus that originated from the spinal cord enter the caudal part of the dorsal column nucleus and turn ventral. In the dorsal column nucleus, these axons run parallel to the vertically oriented dendrites of these spinally projecting cells before termination in close relation to the cell bodies of these neurons. Quantitative observations (mean +/- standard error) were made on well labeled neurons and included several measurements: area, perimeter, and degree of eccentricity (greatest width/greatest length) in both the transverse as well as the sagittal plane. These spinally projecting neurons in Caiman are located in the dorsal column nucleus in a position similar to that of spinally projecting cells in cats. PMID- 8680848 TI - Afferent and efferent connections of the central prosencephalic nucleus in the Pacific hagfish. AB - Injections of horseradish peroxidase, or the carbocyanine dye Dil, into the central prosencephalic nucleus of hagfishes reveal reciprocal connections with the septum, preoptic area, habenula, thalamus and hypothalamus. Efferent projections also occur to the olfactory bulb, pallium, posterior tubercle and tegmentum and to the contralateral central prosencephalic nucleus. These connections suggest that the central prosencephalic nucleus of hagfishes may be homologous to portions of the medial pallium and ventral thalamus of other craniates. PMID- 8680849 TI - Differences in hippocampal volume among food storing corvids. AB - The hippocampal complex (hippocampus and parahippocampalis) is known to play a role in spatial memory in birds and is known to be larger in food-storing versus non-storing birds. In the present study, we investigated the relative volume of the hippocampal complex in four food-storing corvids: gray-breasted jays (Aphelocoma ultramarina), scrub jays (Aphelocoma coerulescens), pinyon jays (Gymnorhinus cyanocephalus), and Clark's nutcrackers (Nucifraga columbiana). The results show that Clark's nutcrackers have a larger hippocampal complex, relative to both body and total brain size, than the other three species. Clark's nutcrackers rely more extensively on stored food in the wild than the other three species. Clark's nutcrackers also perform better during cache recovery and operant tests of spatial memory than scrub jays. Thus, greater hippocampal volume is associated with better performance in laboratory tests of spatial memory and with stronger dependence on food stores in the wild. PMID- 8680850 TI - Left and right 6-hydroxydopamine lesions of the medial prefrontal cortex differentially alter subcortical dopamine utilization and the behavioral response to stress. AB - The effects of left and right prefrontal cortical dopamine (DA) depletion on circling behavior, stress-escape behavior and subcortical DA function were examined in rats exhibiting left or right turning biases. 6-Hydroxydopamine lesions of the medial prefrontal cortex (PFC) caused significant DA depletions when assessed in separate studies at 3 days and 3-4 weeks. However, depletions were smaller at 3-4 weeks and there was a significant increase in DA concentration on the left side following right lesions. Significant increases in striatal DA content were observed following lesions of either side at 3-4 weeks, but not at 3 days. No changes in DA concentration were observed in the nucleus accumbens septi (NAS). Left circling rats significantly increased their circling behavior following right sided lesions and showed disrupted footshock-escape behavior following left sided lesions. Performance of the footshock-escape task exerted an effect on striatal and NAS DA utilization as indicated by the ratio of 3,4-dihydroxyphenylacetic acid (DOPAC) to DA. The effects of footshock on NAS DA utilization were greater following left PFC lesions as compared to the right lesion and sham conditions. These lesion effects were also greater in left- than in right-turning animals. The data indicate that an intrinsic asymmetry in brain DA systems interacts with left and right PFC lesions to differentially determine subcortical DA function and behaviors that it subserves. PMID- 8680851 TI - Effect of progesterone, testosterone and their 5 alpha-reduced metabolites on GFAP gene expression in type 1 astrocytes. AB - Astrocytes possess steroid receptors as well as several enzymes typical of steroid target cells, such as 5 alpha-reductase, which converts testosterone (T) and progesterone (P) into their respective 5 alpha-reduced metabolites, and the 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD). Because of this, it was deemed of interest to analyze whether the original hormones P and T, and their 5 alpha reduced metabolites dihydrotestosterone (DHT), 5 alpha-androstan-3 alpha, 17 beta diol (3 alpha-diol), dihydroprogesterone (DHP) and 5 alpha-pregnan-3 alpha-ol-20 one (THP), might exert some effects on the expression of the most typical astrocytic marker, i.e. the glial fibrillary acidic protein (GFAP). Cultures of rat type 1 astrocytes were exposed to the various steroids for 2, 6, and 24 h, and the variations of GFAP mRNA were measured by Northern blot analysis. A significant elevation of GFAP mRNA levels was observed after exposure to either P or DHP; the effect of DHP appeared more promptly (at 2 h) than that of P (at 6 h). This result suggests that the effect of P might be linked to its conversion into DHP; this hypothesis has been confirmed by showing that the addition of finasteride (a specific blocker of the 5 alpha-reductase) is able to completely abolish the effect of P. After exposure to DHP or THP, a decrease of GFAP gene expression was observed at later intervals (24 h). In the case of androgens, T and 3 alpha-diol did not change GFAP expression at any time of exposure, while DHT produced a significant decrease of GFAP mRNA only after 24 h of exposure. Taken together, the data indicate that the 5 alpha-reduced metabolites of P and T may modulate the expression of GFAP in type 1 rat astrocytes. PMID- 8680852 TI - Effects of infusion of cholinergic drugs into the prefrontal cortex area on delayed matching to position performance in the rat. AB - Rats trained on a Delayed Matching To Position (DMTP) task displayed mediating behavior during delays to solve the task. Infusion of the cholinergic antagonist scopolamine into the medial Prefrontal Cortex area (mPFC), dose dependently impaired performance independent of delay. These results indicate that scopolamine does not specifically affect working memory. Infusion of the cholinesterase inhibitor physostigmine, muscarinic subtype receptor antagonists, the dopamine (D1) antagonist SCH23390, and of the GABA-A receptor antagonist bicuculline, did not affect performance in the DMTP task. In a post-hoc analysis scopolamine was found to impair discriminability in a delay-dependent manner only in animals that used mediating behavior in the majority of the trials. Furthermore, a time sampling method indicated that scopolamine infusions into the mPFC disrupted mediating behavior during the task. Results suggest that cholinergic systems in the mPFC play a role in directing attention to task relevant behavior. PMID- 8680853 TI - Melatonin effect on the cyclic GMP system in the golden hamster retina. AB - Melatonin effect on retinal cyclic GMP accumulation, guanylate cyclase activity, cyclic GMP content and cyclic GMP phospho-diesterase activity was examined in the Syrian hamster retina. Melatonin increased significantly cyclic GMP accumulation at picomolar concentrations and in a time-dependent manner. The kinetic analysis of guanylate cyclase activity revealed a significant increase of both apparent Vmax and K(m), induced by 10 nM melatonin. The effect of melatonin was higher in the absence, than in the presence of the phoshodiesterase inhibitor (IBMX), suggesting an effect on cyclic GMP catabolism. Phosphodiesterase activity was significantly decreased by melatonin. The results show a dual effect of melatonin on cyclic GMP levels, i.e. by increasing the synthesis and inhibiting the degradation, both resulting in an increase of cyclic GMP levels. Taking into account the key role of cyclic GMP in visual mechanisms, the results would suggest the participation of melatonin in retinal physiology. PMID- 8680854 TI - Angiotensin II receptor subtypes in the duck subfornical organ: an electrophysiological and receptor autoradiographic investigation. AB - The pharmacology of angiotensin II (AngII) receptors was investigated in the brain of ducks using receptor autoradiographic and electrophysiological methods. Using 125I[Val5]AngII as a ligand, specific binding was observed in sections of the duck adrenal gland and in several brain areas involved in body fluid homeostasis. Displacement studies using the same antagonists as used for classifying mammalian AngII receptor subtypes revealed that the rank order of potencies in competition with AngII receptors in the adrenal gland and in the subfornical organ was: AngII > CGP-42112A > losartan > PD-123319. Electrophysiological recordings from spontaneously active neurons of duck SFO slices revealed that the majority of neurons could be excited by AngII (10(-7) M). The excitatory effect of AngII could be partially inhibited by CGP-42112A (10(-5) M), which proved to be more effective than equimolar losartan and far more effective than PD-123319. These data suggest that the neuronal AngII receptors in the SFO are pharmacologically distinct from the mammalian AT1- and AT2-receptors. Further, central AngII receptors of ducks share common pharmacological characteristics with AngII receptors in the duck adrenal gland and peripheral organs of other bird species. PMID- 8680855 TI - Topographic organization of Fos-like immunoreactivity in the rostral nucleus of the solitary tract evoked by gustatory stimulation with sucrose and quinine. AB - Fos immunohistochemistry was used to elucidate the pattern of activation elicited by two qualitatively and hedonically distinct taste stimuli, sucrose and quinine, within the first-order gustatory relay, the rostral division of the nucleus of the solitary tract. Compared to unstimulated controls, both sucrose and quinine elicited significant increases in Fos-like immunoreactivity in the rostral central subnucleus, the region of the rostral solitary nucleus that receives the densest primary afferent input. Within the rostral central subnucleus, neurons that exhibited Fos-like immunoreactivity following quinine stimulation were concentrated medially, but neurons that exhibited Fos-like immunoreactivity following sucrose stimulation were distributed more evenly along the mediolateral axis. Despite their differential distribution, sucrose- and quinine-activated neurons also demonstrated notable intermingling. Further, the chemotopic arrangement was only partially consistent with what would be predicted if chemotopy was merely an outcome of orotopy. Our results suggest that a rough chemotopy characterizes the organization of taste responses in the nucleus of the solitary tract, and that the topographic pattern of taste afferent terminations in this nucleus is related to their chemosensitivity as well as to their peripheral spatial distribution. PMID- 8680856 TI - Voltage-gated calcium currents in whole-cell patch-clamped bullfrog dorsal root ganglion cells: effects of cell size and intracellular solutions. AB - Acutely dissociated bullfrog dorsal root ganglion (DRG) cells could be divided into two classes by measurement of cell capacitance. A bimodal distribution of cell capacitance was found and a value of 75 pF was used to divide frog DRG cells into 'small' and 'large' types. Two distinct voltage-activated Ca2+ currents were evoked in both classes of cells: a rapidly inactivating, low-voltage-activated current and a slowly-inactivating, high-voltage-activated current. When the recording pipette contained CsCl, greater peak inward current values and densities were seen in large cells compared to small cells. No significant differences were observed in the distribution of low-and high-voltage-activated currents in small and large cells. Replacement of pipette solutions containing CsCl with solutions containing equimolar concentrations of Cs glutamate, L arginine Cl, or N-methyl-D-glucamine significantly increased both the reversal potential and the maximum amplitude of the Ca2+ currents in both small and large DRG cells. These increases indicate that internal substitutions with organic ions suppresses outward currents more effectively than does CsCl. In contrast to findings with CsCl, when organic ions were used in the pipette solution a significantly higher proportion of low-threshold Ca2+ channels was observed in small cells compared to large cells. These observations indicate that when organic solutions were used internally, significant differences in the proportion of low-threshold to high-threshold Ca2+ channels were observed in small and large cells. The composition of the internal solution is a critical variable when determining the type and amount of inward Ca2+ current in different types of neurons. PMID- 8680857 TI - Differential vasopressin and oxytocin innervation of the human parabrachial nucleus: no changes in Alzheimer's disease. AB - The distribution of vasopressin and oxytocin immunoreactive fibers was examined in the pontine parabrachial nucleus of the human brain using purified polyclonal antibodies. The results revealed a striking predominance of vasopressin in this brain region. No obvious density difference, either in vasopressin or in oxytocin innervation, was found between Alzheimer's disease patients and matched controls. The present study corroborates other reports that suggest that in Alzheimer's disease the vasopressin innervation in the caudal part of the human brain is not affected. PMID- 8680858 TI - Diurnal rhythm in ornithine decarboxylase activity and noradrenergic and cholinergic markers in rat submaxillary lymph nodes. AB - Diurnal variations in lymph node ornithine decarboxylase activity were examined in submaxillary lymph nodes of rats injected with Freund's complete adjuvant or its vehicle. After immunization, lymph node ornithine decarboxylase activity increased by about 10-fold. Both in immunized and non-immunized rats, a significant diurnal variation in ornithine decarboxylase activity was found, with a maximal activity at early (i.e. 13.00 h, vehicle) or late afternoon (i.e. 17.00 h, Freund's adjuvant). Injection of Freund's adjuvant during daylight or at night resulted in similar day-night differences in submaxillary lymph node ornithine decarboxylase activity. In rats subjected to the sympathetic postganglionic denervation (by ipsilateral superior cervical ganglionectomy) or the preganglionic parasympathetic decentralization (by chorda tympani section) of submaxillary lymph nodes, nyctohemeral variations in ornithine decarboxylase were still present, showing a maximum at 17.00 h. Superior cervical ganglionectomy augmented lymph node ornithine decarboxylase while chorda tympani section decreased it. When a unilateral superior cervical ganglionectomy plus chorda tympani section was performed, the diurnal changes in ornithine decarboxylase were abolished. [3H]Norepinephrine uptake and tyrosine hydroxylase activity attained their maxima in submaxillary lymph nodes at early night. After immunization, these two presynaptic indicators of sympathetic activity in submaxillary lymph nodes augmented significantly. Neuronal [3H]choline uptake and [3H]choline conversion into acetylcholine (two indicators of cholinergic activity) also augmented in lymph nodes of rats injected with Freund's adjuvant. In immunized rats, maxima in [3H]choline uptake and [3H]acetylcholine synthesis were found at 13.00-17.00 h while in non-immunized rats, a maximum in acetylcholine synthesis was found at 17.00 h. The results are compatible with the view that the autonomic nervous system plays a role in circadian changes of immune responsiveness in lymphoid tissue and that a significant augmentation of presynaptic autonomic activity takes place during immunization in lymphoid tissue. PMID- 8680859 TI - Stereological analysis of galanin and CGRP synapses in the dorsal horn of neuropathic primates. AB - The present study investigates the nature of the galanin (GAL) increase and the calcitonin gene-related peptide (CGRP) decrease in the dorsal horn following peripheral nerve injury. These two peptides are known to colocalize in primary afferent terminals. Primates which had a tight ligation of the L7 spinal nerve demonstrated a variety of neuropathic symptoms 2 weeks postsurgery, including mechanical and cold allodynia, and heat hyperalgesia. Computer-enhanced image analyses of L7 spinal cord sections demonstrated an increase in GAL immunostaining and a decrease in CGRP immunostaining in the experimental compared to the control dorsal horn. Stereological analyses demonstrated that neither the numbers of GAL-labeled synapses nor the numbers or diameters of the dense-core vesicles in each GAL terminal changed after the lesion. However, there was a significant increase in the number of GAL-labeled glial cell bodies and processes on the experimental side, which accounted for the increased staining density observed at the light microscopic level. In contrast, the number of CGRP-labeled terminals was decreased on the experimental side, accounting for the decreased staining density seen at the light level. Thus, the decrease in number of CGRP synapses combined with the stable number of GAL synapses suggests that many GAL terminals no longer colocalize with CGRP after peripheral nerve lesion. This may indicate increased antinociceptive activity after nerve lesions. If so, there is less of a morphologic and more of a functional and chemical plasticity for GAL than may be presently envisioned. The possible role of GAL in neuropathic pain is discussed. PMID- 8680860 TI - Endotoxin produces a depressive-like episode in rats. AB - Activation of the immune system produces psychological and physiological effects, which resemble the characteristics of depression. The present study was designed to investigate further, in rats, the similarity between the behavioral effects of immune activation and a model of depression in animals. Reduction in the preference for and consumption of saccharin solutions and suppression of sexual behavior were used as models of one essential feature of depression, the inability to experience pleasure (anhedonia). Other measures testing this model were the reduction in food consumption, body weight, locomotor activity, and social interaction. It was found that systemic injection of lipopolysaccharide (endotoxin), which is a potent activator of the immune system, significantly decreased saccharin preference in fluid-deprived rats. Lipopolysaccharide (LPS) also decreased free consumption of saccharin, but not water, in non-deprived rats. Several indices of male sexual behavior were significantly suppressed following LPS administration. Chronic, but not acute, treatment with the tricyclic antidepressant imipramine abolished the suppressive effect of LPS on saccharin preference. Moreover, chronic, but not acute, treatment with imipramine also reduced and facilitated the recovery from the suppressive effects of LPS on food consumption, body weight, social interaction and activity in the open-field test. The results suggest that activation of the immune system in rats produces anhedonia and other depressive-like symptoms, which can be attenuated or completely blocked by chronic treatment with an antidepressant drug. PMID- 8680861 TI - Monoamine oxidase B expression is selectively regulated by dexamethasone in cultured rat astrocytes. AB - The influence of dexamethasone on monoamine oxidase (MAO) A and B expression and activity was investigated in primary cultures of rat type 1 astrocytes cultured under serum free, defined conditions. Dexamethasone treatment resulted in a dose- and time-dependent induction of MAO-B, but not of MAO-A, activity. The selective MAO-B increase was substantially reduced by the antagonist RU 486, thus suggesting a glucocorticoid receptor-mediated action of the hormone. Kinetic analysis showed an increase in Vmax of MAO-B with no change in apparent K(m). The dexamethasone-induced selective rise in MAO-B activity appeared to be due to enhanced enzyme synthesis, since MAO-B mRNA was markedly increased by dexamethasone treatment and the recovery of MAO-B activity after its irreversible inhibition by deprenyl was more pronounced in the presence than in the absence of the hormone. Furthermore, the dexamethasone effect was abolished by the protein synthesis inhibitors actinomycin D or cycloheximide. The present study demonstrates that dexamethasone is able to selectively induce MAO-B in type 1 astrocytes and leads to speculation of a possible role for glucocorticoids in the increase in brain MAO-B associated with neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases. PMID- 8680862 TI - Cellular responses of cultured cerebellar astrocytes to ethacrynic acid-induced perturbation of subcellular glutathione homeostasis. AB - Glutathione (GSH) and glutathione-related enzyme systems in astrocytes play an important role in cellular defense against oxidative stress in the nervous system. The present study was designed to characterize the cellular responses of cultured astrocytes to chemically-induced perturbations of mitochondrial and cytosolic GSH homeostasis. Treatment of astrocytes in culture with ethacrynic acid (EA), a mitochondrion-penetrating thiol reagent, induced rapid and extensive depletion of both cytosolic and mitochondrial pools of GSH. Concomitant with the effects of EA on cellular GSH were significant and concentration-dependent increases in intracellular generation of reactive oxygen species (ROS) as indicated by the oxidation of preloaded 2',7'-dichlorofluorescein diacetate. Significant elevation of intracellular ROS occurred by 15 min following exposure to 100 microM EA and reached peak levels by 30 min which were approximately 7 fold higher than corresponding control levels. Ethacrynic acid-induced GSH depletion and intracellular ROS elevation was followed by marked decreases in glutathione reductase (GR) activity in mitochondria, and to a lesser extent, in cytosolic fractions of cultured astrocytes. This inhibitory effect was time- and concentration-dependent, and other GSH-related enzymes, glutathione peroxidase and glutathione S-transferase, were not or only slightly affected. Kinetic studies showed that EA markedly diminished V(max) values of both mitochondrial and cytosolic GR without affecting K(m), suggesting noncompetitive inhibition of this thiol-dependent enzyme. Another thiol-dependent enzyme glyceraldehyde-3 phosphate dehydrogenase was also markedly inhibited by EA in a time-dependent fashion. Subsequent decline of mitochondrial transmembrane potential (rhodamine 123 uptake) and cellular ATP production following EA treatment occurred prior to the onset of loss of cell viability as indicated by lactate dehydrogenase leakage. These results suggest that the loss of mitochondrial GSH may render the astrocytes unable to combat the pathological sequelae of endogenous oxidative stress, leading to perturbations of thiol-dependent enzyme activities, mitochondrial function and energy metabolism. PMID- 8680863 TI - Cardiovascular effects induced by the stimulation of neuropeptide FF receptors in the dorsal vagal complex: an autoradiographic and pharmacological study in the rat. AB - Previous studies have suggested that central administration of neuropeptide FF related peptides may modulate cardiovascular parameters in the rat. In the present study, we investigated the role of dorsal vagal complex neuropeptide FF receptors in the central regulation of cardiovascular parameters. The fate of neuropeptide FF receptors in normal and nodose ganglionectomized rats was investigated using an autoradiographic approach with 125I-[DTyr1, (NMe)Phe3]NPFF as ligand for these receptors. We showed that neuropeptide FF binding sites are preferentially located postsynaptically with respect to the vagal afferent fibers in the nucleus tractus solitarius. Thus, ganglionectomy reduced by only 30% and 17% the density of peptide binding sites in the rostral and caudal regions of this nucleus, respectively. Bilateral microinjection of neuropeptide FF (1 nmol) into the commissural nucleus tractus solitarius produced an increase in blood pressure (+13.8 +/- 0.8 mmHg, n = 6), bradycardia (-29.0 +/- 3.2 bpm) and a significant inhibition (-47.6 +/- 3.1%) of the cardiac component of the baroreceptor reflex. Further studies with doses below 1 nmol indicate that NTS microinjections of the neuropeptide produced a dose-dependent decrease in heart rate. Similar cardiovascular effects were observed after bilateral NTS microinjections of one analog neuropeptide FF receptor agonist, [DTyr1, (NMe)Phe3]NPFF (1 nmol). Pretreatment with prazosin (100 micrograms/kg), an alpha 1-adrenoreceptor antagonist, inhibited the neuropeptide FF-evoked blood pressure effect. In addition, the neuropeptide FF-induced heart rate decrease was abolished by pretreatment with atropine (30 micrograms/kg), a muscarinic receptor antagonist. Taken together, these anatomical and pharmacological data suggest that neuropeptide FF receptors within the nucleus tractus solitarius, preferentially located on the postsynaptic component, are involved in the central reflex regulation of cardiovascular parameters. PMID- 8680864 TI - Chronic hypoxia in vivo renders neocortical neurons more vulnerable to subsequent acute hypoxic stress. AB - We studied the neurophysiology of neurons from the central nervous system (CNS) of rats that were exposed to a long-term (3-4 weeks) low oxygen (FiO2 = 9.5 +/- 0.5%) environment (exposed). Age-matched normoxic animals served as controls (naive). We measured membrane potential (Vm) and input resistance (Rm) at rest and in response to two levels (20% and 0% O2) of acute in vitro hypoxia using intracellular recordings in the brain slice from two areas of the CNS, layer 2/3 of the neocortex (NCX) and the hypoglossal nucleus in the brainstem (XII). Resting Vm and Rm were not different between exposed and naive neurons. However, acute hypoxia elicited dramatic differences between exposed and naive NCX neurons. Exposed NCX depolarized 5 x more (delta Vm = 53.2 +/- 7.0 mV; n = 13; mean +/- S.E.M.) than naive NCX (delta Vm = 10.6 +/- 2.0; n = 8) in response to 20% O2. In 0% O2, naive NCX showed anoxic depolarization (delta Vm > 20 mV/min) much sooner (mean latency of 4.8 +/- 0.4 min; n = 18) than naive NCX (8.8 +/- 1.0 min; n = 19). Rm decreased 2-4 times more in exposed NCX compared to naive NCX in response to O2 deprivation. In addition, while all naive NCX recovered to baseline Vm and Rm when re-oxygenated, exposed NCX exhibited a much slower recovery compared to naive NCX, and almost 20% of the exposed NCX failed to recover Vm and Rm following in vitro hypoxia. In contrast to NCX, there was little difference between exposed XII and naive XII. We conclude that chronic hypoxia renders neurons in the neocortex more vulnerable to subsequent acute stress such as O2 deprivation. PMID- 8680865 TI - Ultrastructural study of phenylethanolamine-N-methyltransferase, corticotropin releasing factor and neurotensin immunoreactive neurons in the external cuneate nucleus of the gerbil. AB - The present study examined the existence of catecholamine-, corticotropin releasing factor (CRF)- and neurotensin (NT)-containing neurons in the external cuneate nucleus (ECN) of the gerbil using single label pre-embedding immunocytochemistry in an attempt to shed light on the increasing evidence for autonomic involvement of the ECN. Peroxidase immunoreactivity of phenylethanolamine-N-methyl-transferase (PNMT), CRF or NT was identified in the heterogeneous population of the ECN neurons characterized by a deeply infolded nucleus. The label was localized in their somata, dendrites, myelinated axons and axon terminals. The immunolabelled dendrites were contacted by spherical (S) and flattened (F) types of presynaptic boutons containing spherical and flattened synaptic vesicles, respectively. The PNMT-labelled dendrites, however, were postsynaptic to an additional type of axon terminals containing pleomorphic (P) synaptic vesicles. Among the immunoreactive axon terminals, the PNMT-labelled boutons consisted of two types: S and F; in the CRF- and NT-labelled axon terminals, only the S type was observed. The catecholamine-containing ECN neurons differed from the CRF- and NT-immunoreactive neurons in their synaptic organization. The latter two were considered to be of the same cell population because of their similarities in ultrastructural features and synaptic relations. In view of a high frequency (48% for PNMT, 50% for CRF and 46% for NT) of the F typed boutons associated with the three categories of immunolabelled neurons in the ECN, it is possible that they are under considerable inhibitory control. The presence of catecholamine, CRF and NT in the ECN suggests that the nucleus may be involved in the integration of proprioception-, exercise- or stress-evoked autonomic responses. PMID- 8680866 TI - Two components of metabotropic glutamate responses in acutely dissociated CA3 pyramidal neurons of the rat. AB - The excitatory and inhibitory actions of metabotropic glutamate receptor (mGluR) agonists were investigated in acutely dissociated rat hippocampal CA3 pyramidal neurons, using the conventional whole-cell and nystatin-perforated patch recording configurations under the voltage-clamp condition. With the conventional whole-cell recording, glutamate (Glu) and quisqualic acid (QA) induced only ionotropic inward currents accompanied by increased membrane conductance at a holding potential (VH) of -45 mV. The response was reversibly blocked in the presence of D-2-amino-5-phosphonopentanoic acid (D-AP5) and 6-cyano-7 nitroquinoxaline-2,3-dione (CNQX), the antagonists of N-methyl-D-aspartate (NMDA) receptor and non-NMDA receptor, respectively. With nystatin-perforated patch recording, mGlu responses insensitive to both D-AP5 and CNQX were observed. Fifty five % of the cells responded by a slow inward current accompanied by conductance decrease (ImGlui) at a VH of -44 mV. One % of the neurons showed an outward current with conductance increase (ImGluo), and 34% of the neurons showed ImGluo followed by ImGlui. The onset of ImGluo occurred approximately 900 ms after the response to 30 mM K+. The time to peak of ImGluo were 32- to 79-times longer than those of ionotropic responses. ImGlui appeared at lower concentrations than ionotropic Glu responses, whereas ImGluo appeared at similar concentrations as ionotropic responses. The rank order of affinity was QA > Glu > (+/-)-1 aminocyclopentane-trans-1, 3-dicarboxylic acid (tACPD) for both ImGlui and ImGluo. Half-maximal effective concentrations (EC50) and the threshold concentrations for the three agonists were four- to tenfold lower for ImGlui than for ImGluo. The current-voltage relationship showed that the reversal potentials of ImGlui and ImGluo shifted 55 and 59 mV, respectively, for a tenfold change in extracellular K+ concentration, indicating that K+ is the charge carrier of both mGlu responses. During ImGlui, both the leakage current and muscarine-sensitive voltage-dependent K+ current (M current) were suppressed. ImGluo induced by 10( 4) M tACPD was abolished by 3.10(-7) M charybdotoxin and 10(-6) M ryanodine. These results show that there are two components of mGlu responses in CA3 pyramidal neurons and that ImGlui and ImGluo show different pharmacological properties. PMID- 8680867 TI - Spatial learning alters hippocampal calcium/calmodulin-dependent protein kinase II activity in rats. AB - This study investigated the role of hippocampal CaM-kinase II (calcium/calmodulin dependent protein kinase II) in spatial learning. In Experiment I, three groups of rats received 1, 2 or 5 days of training on a spatial task in the Morris water maze with a hidden platform, while a control group was trained on a nonspatial task with a visible platform. The acquisition rate in the spatial task was slower than that in the nonspatial task. However, rats receiving 5 days of spatial training had the highest Ca(2+)-independent activity of CaM-kinase II compared with the controls receiving nonspatial training and rats having 1 or 2 days of spatial training. Furthermore, the level of hippocampal Ca2+-independent CaM kinase II activity was correlated with the final performance on the spatial task. In Experiment II, rats received intra-hippocampal injections of a specific CaM kinase II inhibitor-KN-62-before each training session. In comparison with the vehicle-injected controls, pretraining injection of KN-62 retarded acquisition in the spatial task but had no effect on the nonspatial task. These results, taken together, indicated that the activation of CaM-kinase II in the hippocampus is not only correlated to the degree of spatial training on the Morris water maze, but may also underlie the neural mechanism subserving spatial memory. PMID- 8680868 TI - Strain differences in autotomy levels in mice: relation to spinal excitability. AB - The consequences of combined transection of the sciatic and femoral nerves were investigated in mice of the ICR and C3HEB strains. Whereas all the animals of the C3HEB strain showed very clear self mutilatory behavior of the denervated limb (autotomy) none of the ICR mice showed autotomy. Further tests, using the hot plate and tail flick methods, show that C3HEB mice were more sensitive to noxious thermal stimuli than ICR mice. Finally, spinalization at the lumbar level revealed a markedly higher level of spinal excitability in C3HEB mice as evident from a marked decrease in nociceptive thresholds in these animals. No such threshold decrease was observed in spinalized ICR mice. The results suggest that different levels of spinal excitability underlie the susceptibility for the emergence of autotomy in mice. It is proposed that such different levels of excitability may also underlie the susceptibility for the emergence of neuropathic pain. PMID- 8680869 TI - Inhibition of noradrenaline stimulated increase in [Ca2+]i in cultured astrocytes by chronic treatment with a therapeutically relevant lithium concentration. AB - Chronic treatment of mouse astrocytes in primary cultures with 1 mM lithium chloride for 7-14 days decreased the basal level of free cytosolic calcium concentration ([Ca2+]i) from 50-70 nM to approximately 70% of this value and reduced the increase in [Ca2+]i caused by exposure to 1 microM noradrenaline (normally to 500-700 nM) by almost one half. A similar, but much smaller, response to serotonin was unaffected by chronic treatment with lithium. Acute exposure to lithium (30 min) had no effect on either basal or noradrenaline stimulated [Ca2+]i. The dependence on chronic, versus acute treatment suggests that this effect may be related to the therapeutic effect of lithium as a mood stabilizing drug, which likewise requires chronic treatment. Since good evidence is found that noradrenaline increases [Ca2+]i by activation of the phosphoinositol second messenger system the present findings are also consistent with literature data that lithium acts by interfering with this system. PMID- 8680870 TI - Immunohistochemical detection of Bax and Bcl-2 proteins in gerbil hippocampus following transient forebrain ischemia. AB - Time-course expression of Bax and Bcl-2 proteins, identified as apoptosis regulating molecules, was assessed in gerbil hippocampus following transient forebrain ischemia. Brain sections from animals sacrificed at 48, 72, 96 h and 7 days following 5 min ischemia were immunohistochemically evaluated using polyclonal antibodies specific for Bax and Bcl-2 proteins, respectively. The intensity of Bax expression in CA1 neurons increased with time and peaked at 72 h, and immediately disappeared at 96 h following 5 min ischemia. No expression of Bcl-2 in the CA1 neurons was recognized in all the time evaluated. PMID- 8680871 TI - DSP-4 treatment influences olfactory preferences of developing rats. AB - Control cagemates of rats treated with the norepinephrine (NE) neurotoxin DSP-4, showed normal olfactory learning as infants, but abnormal aversion to home-cage odors as juveniles. Neither age nor social housing conditions influenced the odor preferences of DSP-4-treated rats: they showed tolerance or attraction to familiar odors at both developmental stages. Controls, but not DSP-4-treated juveniles, housed in mixed treatment groups, showed elevated concentrations of a serotonin metabolite and reduced NE concentrations in the hippocampus, suggesting that this social situation was particularly stressful for the controls. DSP-4 treated juveniles, but not infants, produced odors that were discriminable from controls'. Thus, conflicting olfactory signals in the home-cages of mixed juvenile groups may have led to the development of stress in controls. NE depletion appeared to lessen social stress effects in their DSP-4-treated cagemates. These findings support other data suggesting that NE modulates the biobehavioral effects of the social environment. PMID- 8680872 TI - Survival and regeneration of neurons of the supraoptic nucleus following surgical transection of neurohypophysial axons depend on the existence of collateral projections of these neurons to the dorsolateral hypothalamus. AB - The aim of the present study was to compare the postlesional responses of vasopressin-producing (VP) and oxytocin-producing (OT) neurons of the supraoptic nucleus (SON) to transection of neurohypophysial axons. At different times after sectioning the median eminence of adult rats, immunocytochemical staining of both types of neuronal cell bodies and axons indicated that: (1) the number of OT neurons detected within the SON was only slightly decreased as compared with controls (-20%), whereas the number of VP neurons was severely decreased (-60%); and (2) the large majority of axonal sprouts that regenerated into the external layer of the median eminence were OT neurohypophysial axons. The injection of a retrograde tracer into various areas surrounding the SON further showed that numerous SON neurons could be retrogradely labeled when the injection was centered in the lateral hypothalamus dorsal to the SON. The immunocytochemical identification of these retrogradely labeled neurons demonstrated that most of them were OT neurons. When animals were subjected to median eminence transection and to a unilateral surgical cut placed in the lateral hypothalamus above the SON, the survival of both OT and VP neurons was dramatically reduced in the SON ipsilateral to the hypothalamic lesion, as compared to the contralateral SON. Taken together, these data indicate that OT (and to a lesser extent VP) neurons of the SON display collateral projections towards the lateral hypothalamus that protect them from retrograde degeneration following the lesion of their neurohypophysial projections. PMID- 8680873 TI - Neuronal activity in human right lateral temporal cortex related to visuospatial memory and perception. AB - Neuronal activity was recorded extracellularly from 22 neurons in the right lateral temporal cortex of 12 patients undergoing awake craniotomy for surgical treatment of epilepsy during tests of visuospatial function. These included: measures of short-term visuospatial memory; face, complex figure and line matching; labeling of facial emotional expressions; and a language task, object naming. Six neurons demonstrated significant changes during one or more of the three 1.3-s epochs following test presentation. All 6 of these neurons demonstrated inhibition during short-term visuospatial memory entry, or retrieval, or both. Four of the neurons also showed significant changes during one or more matching tasks; 8 of 10 of these changes were excitatory. One neuron also demonstrated excitation with labeling of facial emotional expression and another with naming. These data demonstrate in human right lateral temporal cortex a pattern of inhibition of neuronal activity during short-term visuospatial memory that contrasts with excitation during other functions, particularly figure matching. PMID- 8680874 TI - Calbindin-containing non-specific thalamocortical projecting neurons in the rat. AB - Immunoreactivity for calcium binding proteins was used to demonstrate the neurochemical profiles of non-specific thalamocortical neurons located in the ventromedial nucleus, the centrolateral nucleus, and the nucleus reuniens that project to the somatosensory cortex in the adult rat. Cortical injections of fluorescent tracers combined with immunohistochemistry for calcium binding proteins revealed that retrogradely labeled neurons in these three thalamic nuclei are immunoreactive for calbindin. The present results suggest the presence of a chemically distinct non-specific thalamocortical system which terminates in the neocortex. PMID- 8680875 TI - Stimulus interaction between CO and CO2 in the cat carotid body chemoreception. AB - Since high PCO in the dark works like hypoxia in the carotid body chemoreceptors and since hypoxia shows a stimulus interaction with CO2, it is hypothesized that high PCO will show a similar interaction with PCO2 in the chemosensory excitation in the dark. We tested the hypothesis using cat carotid body perfused and superfused in vitro with Po2 of about 100 Torr. In one series, the chemosensory discharges were tested at three levels of PCO2 at high PCO of 500 Torr in the absence and presence of light. In the dark, normocapnia (PCO2 approximately 30 Torr) with high PCO promptly stimulated the sensory discharges to a peak, subsiding to a lower level. In hypocapnia (PCO2 approximately 18 Torr) with high PCO, all phases of activities were significantly lower than those of normocapnia, showing stimulus interaction. Hypercapnia saturated the activity with high PCO and seems to preclude a clear demonstration of stimulus interaction. In another series, an intermediate level of PCO (approximately 150 Torr), which showed a half-maximal activity in normoxia, showed a clear interaction with hypercapnia in the dark. With high PCO, bright light promptly reduced the activity to baseline at all PCO2 levels. This then increased somewhat to a steady-state. Withdrawal of the light was followed by a sharp rise in the activity to a peak which then fell to a somewhat lower level of steady-state. The peak discharge rate in the presence of light did not differ significantly from those of PCO2 alone. PMID- 8680877 TI - Prolonged and extensive IgG immunoreactivity after severe fluid-percussion injury in rat brain. AB - The relationships between protein extravasation, morphological changes in neurons, and reactive changes in axons were evaluated in rats subjected to right lateral fluid-percussion injury to the brain (4.8-5.6 atm, 20 ms). Serial sections of the brain were immunostained with antibodies to rat immunoglobulin G (IgG) and 68-kDa neurofilament at 1 h to 2 weeks after injury or sham injury. Ischemic changes in neurons were noted in the injured cortex at 6-48 h after injury, and macroscopic hemorrhages were noted in the right corpus callosum and external capsule at 1 h to 1 week after injury. Extracellular IgG immunostaining was observed in the right cortex and right hippocampus at 1 h to 1 week after injury, and in the cortices and hippocampi bilaterally at 2 weeks after injury, but was most prominent in those regions at 24 h after injury. Intracellular IgG staining was noted in the neurons of cortices, hippocampi, brainstem, and cerebellum at 1 h to 2 weeks after injury. The number of IgG immunoreactive neurons was greatest at 1 week after injury. Thickened IgG immunoreactive axons and reactive axonal changes seen with neurofilament immunostaining were both in the similar region of the brainstem at 1 h to 1 week after injury. It appears that prolonged and widespread breakdown of the blood-brain barrier to plasma protein occurs after severe concussive brain injury and that this breakdown is not always accompanied by morphological changes. Intra-axonal IgG immunostaining provides additional clues to the pathogenesis of axonal damage following diffuse brain injury. PMID- 8680876 TI - Amygdaloid neurons respond to clozapine rather than haloperidol in behaving rats pretreated with intra-amygdaloid amphetamine. AB - Single-unit activity was recorded from the amygdaloid complex in freely moving rats during an infusion of amphetamine directly into the recording site. Relative to the quiet resting period prior to the infusion, amphetamine routinely increased neuronal activity within 5-15 min after infusion onset, and this response continued for at least another 30 min. It was generally accompanied by marked increases in sniffing, rearing, locomotion, and grooming as well as by a tendency to turn to the ipsilateral side. Haloperidol and clozapine, typical and atypical antipsychotic drugs, respectively, were then tested in their ability to reverse these neuronal and behavioral effects. Both antipsychotics were administered subcutaneously at behaviorally effective doses within 10 min after termination of the amphetamine infusion. Haloperidol (1.0 mg/kg) failed to reverse the amphetamine-induced increase in amygdaloid neuronal activity and required more than 20 min to exert a partial blockade of the accompanying behavioral activation. Clozapine (10.0 mg/kg), in contrast, blocked the excitatory effects of amphetamine on all tested neurons and also blocked most amphetamine-induced behaviors within 10 min. Taken together, these results, which support other lines of electrophysiological evidence, point to the amygdala as a critical site in the differential behavioral effects of typical and atypical antipsychotic drugs. PMID- 8680878 TI - In vivo evidence for progesterone dependent decreases in serotonin release in the hypothalamus and midbrain central grey: relation to the induction of lordosis. AB - The effects of progesterone (P) on serotonin (5HT) overflow in the ventromedial hypothalamus (VMH), preoptic area (POA) and midbrain central grey (MCG) were studied using in vivo microdialysis. Ovariectomized rats, pretreated with 5 micrograms estradiol, were anesthetized with chloral hydrate and stereotaxically implanted with dialysis probes directed towards one of the respective brain sites. Extracellular 5HT levels stabilized 3 to 5 h following probe implantation. Under stable baseline conditions, perfusion of 1 microM tetrodotoxin through the dialysis probe resulted in 60-65% reduction in 5HT overflow in the brain areas studied. In experiments testing the effect of P on 5HT overflow, rats were subcutaneously injected with 0.5 mg P or propylene glycol vehicle. Samples were analyzed for 5HT at 20 min intervals for 4 h after treatment. Perfusate levels of 5HT were not significantly changed in the VMH, POA or MCG in vehicle-treated rats. Similarly, P treatment failed to significantly alter 5HT overflow in the POA. In the VMH, perfusate levels of 5HT were significantly reduced 60 min after P treatment. Decreases in perfusate 5HT levels were detected 20 min after P in the MCG. The decreases in 5HT overflow measured in the VMH and MCG following P treatment persisted for the remainder of the sampling period with the exception of 1 time point in the VMH. The results provide in vivo evidence for P-influenced decreases in 5HT release in the VMH and MCG. The rapid decrease in extracellular 5HT in the MCG suggests that this effect may represent a non-genomic action of P. These results are discussed in relation to the role of 5HT in the regulation of lordosis behavior. PMID- 8680879 TI - Dual actions of nitric oxide in N-methyl-D-aspartate receptor-mediated neurotoxicity in cultured retinal neurons. AB - This study was performed to elucidate the role of nitric oxide (NO) in N-methyl-D aspartate (NMDA) receptor-mediated glutamate neurotoxicity in the retina. The experiments were done with primary retinal cultures obtained from 17- to 19-day old rat fetuses. The NOS activity measured by monitoring the conversion of [3H]arginine to [3H]citrulline was approximately 5 pmol/min/mg protein. A 10-min exposure of the cultured cells to glutamate (1 mM) or NMDA (1 mM) followed by a 1 h incubation in a normal medium consistently resulted in 60% cell death. The concomitant addition of an inhibitor of NOS, Nomega-nitro-L-arginine (300 microM), with glutamate or NMDA reduced cell death by 70%. A brief exposure of the cells to sodium nitroprusside (SNP, 500 microM) or S-nitrosocysteine (SNOC, 500 microM), NO-generating agents, caused 60% cell death. Depletion of NO by reduced hemoglobin prevented the cell death induced by either glutamate, NMDA, or NO generating agents. Fifty microM SNOC alone had no effect on the cell viability. However, pretreatment with 50 microM SNOC as well as simultaneous application of 50 microM SNOC with NMDA inhibited cell death induced by NMDA. These findings indicate that a low concentration of NO plays a protective role in glutamate neurotoxicity via closing the NMDA receptor gated ion channel. However, elevated concentrations of NO, interacting with oxygen radicals, become toxic and mediate glutamate-induced neurotoxicity in the cultured retinal neurons. PMID- 8680880 TI - Direct quantification of HIV-1 RNA in human plasma by free solution capillary electrophoresis (FSCE). AB - SUMMARY: The levels of human immunodeficiency virus type 1 (HIV-1) RNA have been directly quantitated, after an isolation step, in plasma from patients with primary HIV-1 infection by free solution capillary electrophoresis (FSCE) with ultraviolet detection. HIV-1 RNA was detected and quantified at physiological levels by measuring the absorbance by FSCE. All the patients with primary infection showed concentrations in a range of 1.08-1.71 x 10(8) virions/ml of plasma. No signals were observed in seronegative donors. This procedure represents a practical alternative to other methods to quantify HIV-1 RNA and may be useful in assessing the efficiency of antiretroviral agents, especially during the early stage when other conventional viral markers are often negative. PMID- 8680881 TI - Overexpression of monosialoganglioside GM3 on lymphocyte plasma membrane in patients with HIV infection. AB - SUMMARY: This study was undertaken to analyze both the GM3 expression on peripheral blood lymphocytes of HIV-infected patients and the relationship between ganglioside content and anti-GM3 reactivity. GM3 expression was determined as a percentage of lipid-bound sialic acid and by cytofluorimetric analysis in 25 AIDS patients, 20 anti-HIV+ asymptomatic subjects, 25 patients with different viral disease, and 25 healthy donors. GM3 distribution was analyzed by immunofluorescence and immunoelectron microscopy. A follow-up study to detect anti-lymphocytic GM3 antibodies was performed in progressive and nonprogressive anti-HIV+ subjects. Lymphocytes from HIV-infected patients showed a significant increase of plasma membrane GM3 content; no difference was found between CD4+ and CD8+ cells. Immunofluorescence and immunoelectron microscopic analysis showed that GM3 was distributed in large clusters over the cell plasma membrane. The follow-up study revealed that the occurrence of anti-lymphocytic GM3 antibodies was significantly higher in patients with progressive disease, compared with asymptomatic non-progressive subjects. These findings revealed that (1) the increased GM3 content in HIV-infected patients is detected at the plasma membrane level, (2) GM3 overexpression is able to induce an increased reactivity with anti-GM3 antibodies, and (3) the appearance of anti-lymphocytic GM3 antibodies in asymptomatic anti-HIV+ subjects could have prognostic relevance for the risk of developing AIDS. PMID- 8680882 TI - Canventol inhibits HIV-1 replication by Tat-induced Tar-independent mechanism. AB - SUMMARY: Canventol (2-isopropyl-4-isopropyldencyclohex-2-ene-l-ol), a blocker of tumor necrosis factor alpha (TNF-alpha) release, inhibits human immunodeficiency virus type (HIV-1) production in chronically and acutely infected cells. This effect of Canventol on virus replication could be correlated with its inhibitory influence on necrosis factor (NF)-kappa B activation and HIV-1 long terminal repeat (LTR)-driven reporter gene expression in Jurkat cells and these could be overcome by the administration of TNF-alpha. Canventol inhibits activation of the promoter by the viral protein Tat through a TAR-independent mechanism. The HIV-1 promoter is synergistically upregulated when both the TAR-independent and the TAR dependent modes of Tat action are in operation. Tat-induced downstream events, such as the production of cytokines like TNF-alpha and NF-kappa B activation, are central for this upregulation. Inhibitors of the respective modes of action of Tat downregulate HIV-1 LTR activation and virus replication. PMID- 8680884 TI - JCV-DNA and BKV-DNA in the CNS tissue and CSF of AIDS patients and normal subjects. Study of 41 cases and review of the literature. AB - SUMMARY: We studied the distribution and localization of the human papova-viruses JCV and BKV in the central nervous system (CNS) and cerebrospinal fluid (CSF) of HIV-positive patients with and without progressive multifocal leukoencephalopathy (PML) as compared with HIV-seronegative patients. The presence of JCV-DNA and BKV DNA was evaluated by nested polymerase chain reaction (PCR) and in situ hybridization (ISH) on CNS autopsy tissues of AIDS patients with (group A, n = 13) and without (group B, n = 16) PML and of HIV-negative patients (group C, n = 12). PCR for JCV-DNA and BKV-DNA was also performed on CSF samples collected 7 420 days before death in all the 29 AIDS patients. Tissue PCR for JCV-DNA was positive in all the cases in group A, in 44 percent of the patients in group B, and in 33 percent of the patients in group C. ISH was positive in all the cases with PML and in three AIDS cases without PML (12 percent), but negative in all the HIV-negative cases. BKV-DNA was detected in two cases from group A and in one case from group B. CSF was PCR-positive for JCV-DNA in 8 of 13 (62 percent) AIDS patients with PML, but in none of the HIV patients without PML, irrespective of the presence of JCV-DNA in CNS tissues. No CSF sample was positive for BKV-DNA. Our data demonstrates that JCV-DNA and, rarely, BKV-DNA can be detected in the CNS of immunocompromised patients with and without PML and also in the CNS of HIV negative subjects. However, only HIV-positive patients with clinically evident PML and JCV-DNA in the brain have PCR-detectable JCV-DNA in their CSF. PMID- 8680883 TI - Wild-type and transactivation-defective mutants of human immunodeficiency virus type 1 Tat protein bind human TATA-binding protein in vitro. AB - SUMMARY: Tat regulates human immunodeficiency virus type 1 (HIV-1) gene expression by increasing both the rate of transcription initiation and the efficiency of transcription elongation. The ability of Tat to facilitate HIV-1 transcription preinitiation complex formation suggests that components of the basal transcriptional machinery may be targeted by Tat. Previous studies have demonstrated that Tat interacts directly with the human TATA-binding protein (TBP) and specific TBP-associated factors (TAFS) that comprise the TFIID complex. Here, in vitro glutathione S-transferase protein binding assays containing fully functional or transactivation-defective mutant Tat proteins have been used to investigate the functional significance of the direct interaction between Tat and TBP relative to Tat transactivation. Results demonstrate that full-length Tat, as well as the activation domain of Tat alone, binds human TBP in vitro. Site directed mutations within the activation domain of Tat (C22G and P18IS) that abrogate transactivation by Tat in vivo fail to inhibit Tat-TBP binding. Full length Tat, the activation domain of Tat alone, and a transactivation-defective mutant of Tat that lacks N-terminal amino acid residues 2-36 bind with equal efficiencies to TBP provided that the H1 alpha helical domain that maps to amino acids 167-220 within the highly conserved carboxyl terminus of TBP is maintained. These data indicate that an activity mapped within the activation domain of Tat, which is distinct from Tat-TBP binding. is required for transactivation by Tat. PMID- 8680885 TI - Pilot study of topical trifluridine for the treatment of acyclovir-resistant mucocutaneous herpes simplex disease in patients with AIDS (ACTG 172). AIDS Clinical Trials Group. AB - SUMMARY: Twenty-six AIDS patients were enrolled in an open label pilot study to evaluate the efficacy and toxicity of topical 1 percent ophthalmic trifluridine solution for the treatment of chronic mucocutaneous herpes simplex virus disease unresponsive to at least 10 days of acyclovir therapy. Susceptibility testing to acyclovir, trifluridine, and foscarnet was determined by plaque reduction assay. Twenty-four patients were evaluable for efficacy and 25 for toxicity analyses. Seven patients (29 percent) had complete healing of lesions. The overall estimated median time to complete healing was 7.1 weeks. An additional seven patients had > or = 50 percent reduction in lesion area. The overall estimated median time to 50 percent healing was 2.4 weeks. Ten (42 percent) patients discontinued treatment for reasons other than primary treatment failure and seven (29 percent) for failure to respond to therapy. Baseline patient characteristics associated with greater reduction in lesion area included higher Karnofsky score (p = 0.05), fewer lesions (p = 0.07), smaller lesion area (p = 0.11), and trifluridine susceptibility (p = 0.07). Eight (33 percent) patients developed new lesions outside of the treatment area while on study, reflecting the local nature of this therapy. No dose-limiting toxicity attributable to trifluridine was reported. Given the limited options for the treatment of acyclovir-resistant herpes simplex disease, topical trifluridine may be a useful alternative in selected patients. PMID- 8680886 TI - Double-blind placebo-controlled pilot trial of acemannan in advanced human immunodeficiency virus disease. AB - SUMMARY: We assessed the safety and surrogate markers' effect of acemannan as an adjunctive to antiretroviral therapy among patients with advanced HIV disease receiving zidovudine (ZDV) or didanosine (ddI) in a randomized, double-blind, placebo-controlled trial of acemannan (400 mg orally four times daily). Eligible patients of either sex had CD4 counts of 50-300/microl twice within 1 month of study entry and had received 26 months of antiretroviral treatment (ZDV or ddI) at a stable dose for the month before entry. CD4 counts were made every 4 weeks for 48 weeks. P24 antigen was measured at entry and every 12 weeks thereafter. Sequential quantitative lymphocyte cultures for HIV and ZDV pharmacokinetics were performed in a subset of patients. Sixty-three patients were randomized. All were males (mean age 39 years). The mean baseline CD4 counts were 165 and 147/microl in the placebo and acemannan groups, respectively; 90 percent of the patients were receiving ZDV at entry. Six patients in the acemannan group and five in the placebo group developed AIDS-defining illnesses. There was no statistically significant difference between the groups at 48 weeks with regard to the absolute change or rate of decline at CD4 count. Among ZDV-treated patients, the median rates of CD4 change (ACD4) in the initial 16 weeks were - 121 and - 120 cells per year in the placebo and acemannan groups, respectively ( p = 0.45), ACD4 from week 16 to 48 was 0 and - 61 cells per year in the acemannan and placebo groups (p = .11), respectively. There was no statistical difference between groups with regard to adverse events, p24 antigen, quantitative virology, or pharmacokinetics. Twenty-four patients, 11 receiving placebo and 13 receiving acemannan, discontinued study therapy prematurely, none due to serious adverse reactions. Our results demonstrate that acemannan at an oral daily dose of 1600 mg does not prevent the decline in CD4 count characteristic of progressive HIV disease. Acemannan showed no significant effect on p24 antigen and quantitative virology. Acemannan was well tolerated and showed no significant pharmacokinetic interaction with ZDV. PMID- 8680887 TI - Long-term administration of aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia in infants and children with symptomatic human immunodeficiency virus infection. The Italian Pediatric Collaborative Study Group on Pentamidine. AB - SUMMARY: We assessed the long-term feasibility, safety, and tolerability of two regimens of aerosolized pentamidine (AP) as primary prophylaxis of Pneumocystis carinii pneumonia (PCP) in a large sample of infants and children with symptomatic HIV infection in 21 pediatric departments. One hundred forty children were assigned to receive 60 mg every 2 weeks (n = 60) or 120 mg every 4 weeks (n = 80) of AP, delivered by the ultrasonic nebulizer Fisoneb under the supervision of trained personnel. Children underwent monthly clinical and laboratory controls for toxicity and/or development of PCP for an 18-month period. Baseline characteristics were similar in the two treatment groups. The median age was 5 years. The feasibility of administering AP was excellent in 84 (60 percent) and good in 38 (27 percent) children. All children aged <2 years showed excellent or good feasibility. Long-term compliance was good with both regimens. No child had severe adverse reactions requiring discontinuation of the treatment. Cough, sneezing, and bronchospasm were the most frequent side effects occurring, respectively, in 12, 3.7, and 0.7 percent of the 60-mg treatments and in 19.1, 6. 1, and 2.8 percent of 120-mg treatments (p < 0.05). Their incidence was not different in children younger or older than 5 years. Two episodes of PCP were observed in the group receiving 120 mg monthly, whereas none of the 60 children in the biweekly schedule had PCP (p = 0.20). AP can be safely administered to very young children with few adverse side effects. PMID- 8680889 TI - The use of auxiliary events to improve the analysis of survival for HIV-infected patients: application to the French Prospective Multicenter Cohort (SEROCO). AB - SUMMARY: A multicenter prospective cohort study, including 512 patients for whom date of HIV infection was known, showed that the use of an appropriate auxiliary event can improve the analysis of survival data and lead to an earlier detection of risk factors for HIV patients. Age at seroconversion and primary symptomatic infection were used as risk factors. Two age groups were defined as age at seroconversion >30 years (n = 203) and < or = 30 years (n = 309). Patients with primary symptomatic infection PSI (n = 215) were compared with patients without any clinical manifestation during primary infection (n = 297). Death was considered as the endpoint of primary interest and occurred in 76 patients in the study. Classical non-parametric methods (Kaplan-Meier estimate and long-rank test) and parametric regression model (Weibull model) were used for a standard analysis of survival data. A parametric approach using auxiliary information was used to estimate the survival function and to test the effect of age at seroconversion and PSI. We also applied a recently proposed distribution-free method to produce a non-parametric estimate of the survival function and to test age at seroconversion and PSI with respect to survival estimates. Both methods are compared for two distinct auxiliary events (Karnofsky score below 75 and a first drop of CD4 lymphocyte counts below 200 cells/MM3). The use of CD4 lymphocyte counts below 200 cells/MM3 as an auxiliary event improved the analysis of survival data available in December 1994. For both methods incorporating CD4 counts below 200 cells/mm3 in addition to survival data, the effect of age at seroconversion on survival was significant in April 1992 whereas it was not significant with standard methods. For PSI exposure group, results shown in this work do not indicate any improvement in using auxiliary information. Conditions for using an appropriate auxiliary event as well as advantages and shortcomings of both methods are discussed. Methods used in this work, with appropriate auxiliary information, are promising either through a reduction in the time to follow-up to detect risk factors for cohort studies or the time needed for drug development in clinical trials. PMID- 8680888 TI - Inhibition of murine AIDS by combination of AZT and dideoxycytidine 5' triphosphate. AB - SUMMARY: A combination of antiretroviral drugs acting on different cell types (lymphocytes and macrophages) was evaluated in a murine retrovirus-induced immunodeficiency model of AIDS (MAIDS). In a first experiment, C57BL/6 mice were infected with a single i.p. administration of LP-BM5 and treated with 0.125 or 0.25 mg/ml AZT in drinking water for 3 months. AZT treatment was found to reduce lymphadenopathy (60 and 65 percent, respectively), splenomegaly (37 and 50 percent, respectively), and hypergammaglobulinemia (6 and 50 percent, respectively). Furthermore, at the highest AZT concentration, BM5d proviral DNA content in lymph nodes and in the spleen showed a reduction of 78 and 70 percent, respectively, compared to untreated animals. In a second experiment, infected mice were treated with AZT (0.25 mg/ml in drinking water) and with 2',3' dideoxycytidine 5'-triphosphate (ddCTP) encapsulated into autologous erythrocytes for macrophage protection. Combined treatments resulted in a further reduction of lymphadenopathy (a further 33 percent with respect to the single treatment of AZT) and splenomegaly (a further 28 percent respect to the single treatment of AZT) but not of gammaglobulinemia. Proviral DNA in lymph nodes and spleen showed a reduction of 82 and 77 percent, respectively, compared to infected mice. Stimulation index of T cells was also significantly increased in animals receiving both treatments versus AZT only. In conclusion, the selective administration of antiviral drugs that preferentially protect different cell types seems to provide additional advantages compared to single-agent therapy. PMID- 8680890 TI - An intensive chemotherapy of adult T-cell leukemia/lymphoma: CHOP followed by etoposide, vindesine, ranimustine, and mitoxantrone with granulocyte colony stimulating factor support. AB - SUMMARY: An intensive combination chemotherapy regimen supported by granulocyte colony-stimulating factor (G-CSF) was evaluated in adult T-cell leukemia/lymphoma (ATLL) patients in a multiinstitutional, cooperative study. Vincristine 1 mg/m2 i.v. day 1, Adriamycin 40 mg/m2 i.v. day 1, cyclophosphamide 400 mg/m2 i.v. day 1, prednisolone 40 mg/m2 i.v. days 1 to 3 and 8 to 10, etoposide 35 mg/m2 i.v. days 1 to 8, vindesine 2 mg/m2 i.v. day 8, ranimustine 50 mg/m2 i.v. day 8, mitoxantrone 7 mg/m2 i.v. day 8, and G-CSF 50 mg/m2 s.c. days 9 to 21 were given for 2 to 4 courses every 3 weeks to 83 patients with ATLL. Complete remission (CR) and partial remission (PR) were achieved in 35.8 and 38.3 percent, respectively, of 81 evaluable patients. The median survival of all patients was 8.5 months, with a predicted 3-year survival of 13.5 percent by the Kaplan-Meier method. The median duration of response was 7.6 months (range 0.2-42.7), and 13 patients were alive. Their median survival time was 29.1 months (range 19.2 44.7). In 67.6 percent of courses, white blood cell (WBC) nadirs were < 1.0 x 10(9)/L. Days required for the recovery of WBC from the nadir to > 1.0 x 10(9)/L were <5 days in 71.4 percent of the treatment courses. The G-CSF supported an intensified chemotherapy regimen for ATLL and yielded better response rate and longer survival compared to previous reports in Japan. Because duration of remission is still short, further studies of postremission therapy or other strategies are warranted. PMID- 8680891 TI - Mother-to-child transmission of human T-cell lymphotropic virus types I and II (HTLV-I/II) in Gabon: a prospective follow-up of 4 years. AB - SUMMARY: For 4 years. we determined the mode and risk of mother-to-child transmission of HTLV-I in a prospective cohort of 34 children born to seropositive mothers in Franceville, Gabon. We also determined the prevalence of antibodies to HTLV-I/II in siblings born to seropositive mothers. Antibodies to HTLV-I/II were detected by Western blot, and the proviral DNA was detected by the polymerase chain reaction (PCR). The risk of seroconversion to anti-HTLV-I for the 4 years of follow-up was 17.5 percent. Anti-HTLV-I/II and proviral DNA were only detected after age 18 months. We observed a seroprevalence rate of 15 percent among the siblings born to HTLV-I/II seropositive mothers. Furthermore, we report a case of mother-to-child transmission of HTLV-II infection in a population of HTLV-II-infected pregnant women that is emerging in Gabon. The lack of detection of HTLV-I/II proviral DNA in cord blood and amniotic fluid and, furthermore, the late seroconversion observed in the children indirectly indicate that mother-to-child transmission occurred postnatally, probably through breast milk. PMID- 8680892 TI - Male-to-female transmission of human T-cell lymphotropic virus types I and II: association with viral load. The Retrovirus Epidemiology Donor Study Group. AB - SUMMARY: Risk factors for male-to-female sexual transmission of human T lymphotropic virus types I and II (HTLV-I/II) were investigated among HTLV seropositive volunteer blood donors and their long-term (> or = 6 month) sex partners. Direction of transmission in concordantly seropositive pairs was assessed by analyzing risk factors for HTLV infection. Donors and their partners were also questioned regarding sexual behaviors during their relationships; HTLV antibody titers and viral load were determined for specimens from male partners. Among 31 couples in whom HTLV-infected men likely transmitted infection to their partners (11 HTLV-I and 20 HTLV-II) and 25 male-positive, female-negative couples (8 HTLV-I and 17 HTLV-II), HTLV transmitter men had been in their relationships longer (mean 225 months vs. 122 months) and had higher viral loads (geometric mean 257,549 vs. 2,945 copies/300,000 cells for HTLV-I; 5,541 vs. 118 copies/300,000 cells for HTLV-II) than non-transmitters (P = 0.018 and P = 0.001 for duration of relationship and viral load, respectively, logistic regression analysis). Transmitter men also tended to have higher antibody titers against various env and whole virus proteins than non-transmitters. The identification of high viral load and duration of relationship as risk factors provides a biologically plausible framework in which to assess risk of sexual transmission of the HTLVs. PMID- 8680893 TI - The prevalence of additional injection-related HIV risk behaviors among injection drug users. AB - SUMMARY: This study assesses the prevalence of injection-related behaviors that may facilitate HIV transmission even when syringes are not directly shared. Subjects who self-reported practicing these "indirect sharing" behaviors are described, the prevalence of these behaviors are compared with the direct sharing of syringes, and variables independently associated with indirect sharing are determined. Injection-related risks were assessed among 585 injection drug users (IDUs) in Denver, Colorado. Respondents were classified into three groups based on their self-reported injection behaviors: IDUs who directly and indirectly share syringes, IDUs who indirectly share only, and IDUs who neither directly or indirectly share. Indirect sharing was twice as prevalent as direct sharing. IDUs who injected heroin or speedballs were less safe in their injection behavior than those who did not. Drug treatment did not protect against injection-related risk behaviors; however, exposure to community HIV prevention efforts was protective. Indirect sharing behaviors are common, yet their link to HIV transmission remains unrecognized by many IDUs. IDUs must be informed about these additional risk behaviors. PMID- 8680894 TI - Proviral HTLV-I and HTLV-II in the Efe pygmies of northeastern Zaire. PMID- 8680895 TI - Long survival in AIDS-related cytomegalovirus retinitis. PMID- 8680897 TI - Drug resistance in cytomegalovirus: current knowledge and implications for patient management. PMID- 8680896 TI - Utility of SHIV for testing HIV-1 vaccine candidates in macaques. AB - SUMMARY: Intravenous injection of SHIV (simian/human immunodeficiency virus, chimeric virus) into rhesus macaques resulted in a viremia in peripheral blood lymphocytes (PBL) and the generation of anti-HIV-1 (human immunodeficiency virus type 1) envelope immune responses. A challenge stock of a SHIV containing HIV-1 HXBc2 envelope glycoproteins was prepared from infected rhesus monkey peripheral blood mononuclear cells (PBMC). The minimum animal infectious dose of the SHIV stock was determined and used in a challenge experiment to test protection. The vaccination of two rhesus monkeys with whole inactivated HIV-1 plus polydicarboxylatophenoxy phosphazene (PCPP) as the adjuvant protected the animals from becoming infected by a SHIV challenge. This experiment demonstrated for the first time that monkeys immunized with HIV-1 antigens can be protected against an HIV-1 envelope-containing virus. As the challenge virus was prepared from monkey PBMC, human antigens were unlikely to be involved in the protection. Protection of rhesus monkeys from SHIV challenge may help,define protective immune responses stimulated by HIV-1 vaccine candidates. PMID- 8680898 TI - 5-aminosalicylates in inflammatory bowel disease--the more the merrier? PMID- 8680899 TI - Inflammatory cytokines, naturally occurring regulators of inflammation, and inflammatory bowel disease. PMID- 8680900 TI - Comparison of the efficacy and safety of 1.5 compared with 3.0 g oral slow release mesalazine (Pentasa) in the maintenance treatment of ulcerative colitis. Dutch Pentasa Study Group. AB - OBJECTIVE: To investigate a possible dose-effect relationship with two dosages of oral slow-release mesalazine in patients with quiescent ulcerative colitis. METHOD: One hundred and sixty-nine patients with ulcerative colitis in remission were treated with either 1.5 or 3.0 g/day mesalazine for 1 year or until relapse into active colitis. RESULTS: Fewer of the 3.0 g dose group relapsed than of the 1.5 g dose group (33 compared with 46%). This difference failed to reach statistical significance (P = 0.057). A significant relationship between age and relapse rate was established. No dose-related adverse events were found. Three serious drug-related adverse events were, however, reported. All of the serious adverse reactions resolved after the medication was discontinued. CONCLUSION: There is a trend for high doses of oral mesalazine to be more effective in prevention of relapse of ulcerative colitis. These higher doses are not associated with a higher incidence of adverse reactions. PMID- 8680901 TI - Interleukin-1 receptor antagonist in differential diagnosis of inflammatory bowel diseases. AB - BACKGROUND: Immunoregulatory properties of cytokines may mediate disordered inflammatory events in inflammatory bowel diseases (IBDs). On the basis of data obtained in experimental colitis, the hypothesis has been advanced that in IBD the balance between interleukin-1 (IL-1) and the naturally occurring IL-1 receptor antagonist (IL-1ra) might influence disease expression. OBJECTIVE: We studied the profiles of IL-1ra and acute phase proteins produced by activated macrophages to determine whether the level of IL-1ra in peripheral blood is a marker of disease activity in IBD and a possible differential diagnostic marker. PATIENTS AND METHODS: Levels of IL-1ra, serum neopterin, urinary neopterin, alpha 1-glycoprotein and C-reactive protein (CRP) were measured in 80 patients with ulcerative colitis, Crohn's disease or infectious colitis. RESULTS: Levels of IL 1ra were markedly increased in patients with active ulcerative colitis or active Crohn's disease compared with those in patients with infectious colitis. Patients with active Crohn's disease had significantly higher serum IL-1ra levels than patients with active ulcerative colitis. Moreover, a positive correlation was found between levels of C-reactive protein, alpha 1-glycoprotein, and serum neopterin and the level of IL-1ra in active Crohn's disease but not in active ulcerative colitis, strongly suggesting that the pathogenesis of the two conditions differs. CONCLUSION: Levels of IL-1ra in the peripheral blood of patients with IBD are of clinical relevance, representing a potent marker of disease activity and a possible differential diagnostic marker. PMID- 8680902 TI - Circulating soluble adhesion molecules in inflammatory bowel disease. AB - OBJECTIVE: To determine levels of soluble forms of the cell adhesion molecules (CAM), ICAM-1, E-Selectin and VCAM-1 in relation to prevalence, treatment and disease activity in inflammatory bowel disease. PATIENTS AND METHODS: Plasma was obtained from patients with ulcerative colitis (n = 49), patients with ulcerative colitis who had undergone restorative proctocolectomy (n = 32, eight of whom had a clinical pouchitis), Crohn's disease patients (n = 34) and 24 healthy controls. RESULTS: Plasma soluble ICAM-1 levels [medians (ranges in ng/ml)] were significantly higher in patients with active ulcerative colitis [270 (90-510)], pouchitis [415 (310-670)] and active Crohn's disease [305 (200-630)] than in those with inactive ulcerative colitis [225 (140-425), P = 0.031], non-inflamed ileoanal pouch [260 (140-380), P = 0.0004] and inactive Crohn's disease [245 (90 520), P = 0.045], respectively, and controls. The soluble E-Selectin levels were also significantly higher in patients with active ulcerative colitis [55 (40 140)], pouchitis [90 (45-145)], and active Crohn's disease [78 (30-115)] than in those with inactive ulcerative colitis [45 (20-80, P = 0.003], non-inflamed ileoanal pouch [45 (20-90), P = 0.001] and inactive Crohn's disease [48 (25-90, P = 0.020], respectively, and controls. CONCLUSIONS: The present study suggests that increased levels of soluble ICAM-1 and soluble E-Selectin occur during active inflammatory bowel disease and pouchitis, which may be used as sensitive markers of continuing inflammation. PMID- 8680903 TI - Inflammatory Bowel Disease Questionnaire: cross-cultural adaptation and further validation. AB - OBJECTIVES: The Inflammatory Bowel Disease Questionnaire (IBDQ) is a disease specific quality of life instrument. We translated and adapted the questionnaire and tested its reliability and (cross-cultural) validity. METHODS: We surveyed 271 patients with inflammatory bowel disease. The inflammatory Bowel Disease Questionnaire and its dimensional scores (bowel, systemic, social and emotional) were correlated with disease activity, health care use, medication and three other indices of quality of life. RESULTS: The reliability coefficient of the Inflammatory Bowel Disease Questionnaire was high (0.93). Patients with higher disease activity had significantly lower quality of life on all Inflammatory Bowel Disease Questionnaire dimensions (P < 0.001). Inflammatory Bowel Disease Questionnaire scores were significantly correlated with health care use (P < 0.01) but not with medication. Almost all Inflammatory Bowel Disease Questionnaire dimensions correlated highly (0.43-0.79, P < 0.001) with the corresponding scales of the standard quality of life indices, except for the bowel dimension. Modified Dutch Inflammatory Bowel Disease Questionnaire scores were consistent with Canadian Inflammatory Bowel Disease Questionnaire norms. CONCLUSIONS: These results support the Inflammatory Bowel Disease Questionnaire as a reliable and valid measure of the quality of life of inflammatory bowel disease patients in multicultural research settings. PMID- 8680904 TI - Abnormal sensitivity to duodenal lipid infusion in patients with functional dyspepsia. AB - BACKGROUND AND OBJECTIVES: Patients with functional dyspepsia exhibit increased sensitivity to gastric distension (mechanoreceptors) and to meals rich in fat (chemoreceptors). The aim of this study was to test whether these patients were abnormally sensitive to intraduodenal lipid, and whether this stimulus altered gastric mechanosensitivity. METHODS AND DESIGN: Experiments were conducted on 10 patients and 10 healthy controls. The stomach was distended with a flaccid bag during duodenal infusion of either 10% Intralipid or 0.9% saline. Intragastric pressure was recorded continuously, and the participants were asked to report gastric sensations of fullness and discomfort. RESULTS: Intragastric pressure profiles during distension were similar in patients and controls. Lipid decreased intragastric pressure and reduced phasic contractility. Patients showed enhanced sensitivity to gastric distension compared with controls during both saline and lipid infusions. In the controls, threshold volumes for fullness and discomfort were higher during lipid than saline infusion. In the patients, the sensation of fullness occurred at lower volumes during lipid infusion, whereas discomfort occurred at similar volumes but lower intragastric pressures. Most patients experienced nausea and bloating and three patients vomited during lipid infusion, but remained asymptomatic during saline infusion. Controls reported no symptoms during either infusion. CONCLUSION: Dyspeptic patients have increased sensitivity to both gastric distension and intraduodenal lipid. In contrast to controls, lipid sensitizes their stomachs to distension. PMID- 8680905 TI - Influence of adrenoceptor agonists and antagonists on fluid secretion in small bowel obstruction. AB - OBJECTIVES: To investigate the importance of adrenoceptors on fluid losses in small bowel obstruction. DESIGN: Evaluation of the effects of adrenergic agonists and antagonists on in-vivo net fluid secretion in chronic small bowel obstruction in rats. METHODS: Net fluid transport in a jejunal segment was continuously registered in vivo after 18 h of mechanical obstruction of the small bowel in anaesthetized rats. The effect on net fluid transport of adrenoceptor agonists and antagonists and of isotonic saline was quantified. RESULTS: Clonidine, an alpha 2-agonist, had a significant (P < 0.05) anti-secretory effect, while yohimbine, an alpha 2-antagonist, significantly (P < 0.05) increased net fluid secretion. Phenylephrine, an alpha 1-agonist, and prazosin, an alpha 1 antagonist, lacked significant effects on net fluid transport. Similarly, prenalterol, a beta 1-agonist, and metoprolol, a beta 1-antagonist, had no significant effect on the net fluid transport. The beta 2-agonist salbutamol significantly (P < 0.001) decreased net fluid secretion, while the beta antagonist propranolol significantly (P < 0.001) decreased net fluid secretion. CONCLUSION: Activation of alpha 2-adrenoceptors and blockade of beta 2 adrenoceptors significantly reduce net fluid secretion in small bowel obstruction. Results also demonstrate a continuous stimulatory effect on fluid secretion mediated by beta 2-receptors and a continuous inhibitory effect mediated by alpha 2-receptors. PMID- 8680906 TI - Aspirin renders the oesophageal mucosa more permeable to acid and pepsin. AB - OBJECTIVE: To examine the effects of aspirin on the oesophageal mucosa and on acid- and pepsin-induced oesophagitis. DESIGN AND METHODS: The effects both of intraluminal (18 mg/ml) and of parenteral (100 mg/kg per h) aspirin on an in-vivo rabbit model of oesophagitis induced by acidified pepsin (pH 2) were studied. Oesophageal injury was assessed by macroscopic and microscopic scoring including the cell proliferation immunohistochemical parameter mib1. The mucosal barrier function was determined by hydrogen, potassium and haemoglobin flux rates. RESULTS: Acidified saline alone caused no damage, but the addition of aspirin induced mucosal barrier damage (P < 0.05). The exposure of the oesophageal mucosa to acidified aspirin and then acidified pepsin significantly increased mucosal injury and mucosal barrier dysfunction compared with control experiments (exposure to acidified saline and acidified pepsin). This damage was significantly (P < 0.05) reduced (> 40%) by prostaglandin cotherapy (prostaglandin E2) administered before acidified aspirin exposure. Mucosal damage was less severe (P < 0.05) when the oesophageal mucosa was exposed to a pH 6 aspirin solution. Parenterally administered aspirin also increased the oesophageal damage induced by acidified pepsin compared with control experiments, but the damage was 23% lower than that obtained with intraluminal aspirin. Cell proliferation studies showed a significant increase in the number of positive cells in those experiments with a higher degree of damage and in those treated with prostaglandins. CONCLUSION: Aspirin renders the oesophageal mucosa more permeable to acid and pepsin. These effects are in part pH-dependent and might be partially reversed by prostaglandin E2 cotherapy. PMID- 8680907 TI - Intra-operative laser-induced photodynamic therapy in the treatment of experimental hepatic tumours. AB - OBJECTIVE: To examine the effect of photodynamic therapy (PDT) on experimental liver tumours in rats. DESIGN: An experimental liver tumour model was used. Each of a group of rats had two tumours simultaneously inoculated into its liver. The tumour located in the left hepatic lobe was used for PDT, and the other one, in the median lobe, as a control. The haem precursor delta-amino laevulinic acid (ALA), at a dose of 30 mg/kg body weight, was injected 60 min before laser irradiation. Rats in group I received ALA through a femoral vein. Those in group II received ALA through the portal vein. Group III had an injection of ALA solution through the portal vein plus hepatic inflow occlusion. Three and 6 days after the treatment, the rats were killed, and the tumours were measured, and ultrastructural changes were examined using scanning electron microscopy. SETTING: Lund University Medical Laser Centre, Lund, Sweden. RESULTS: The mean tumour volume of the treated tumours increased by factors of 1.9, 1.5 and 1.7 in groups I, II and III, respectively, compared with the pretreatment baseline value. However, the mean tumour volume in the control tumours increased by factors of 9.5, 4.3 and 4.8 in the respective groups. Under the light microscope, marked necrosis of the treated tumour and the surrounding liver tissue was observed. Scanning electron microscopy revealed heavy damage to the cells and vessels in the treated tumour. CONCLUSION: PDT with ALA is an effective treatment modality for rat liver tumours. PMID- 8680908 TI - Serum hepatocyte growth factor levels in primary biliary cirrhosis. AB - BACKGROUND: Recent studies have shown that serum levels of hepatocyte growth factor, a potent mitogen for hepatocytes, are increased in patients with fulminant liver failure and with advanced stages of liver cirrhosis. DESIGN: Retrospective study. METHODS: Serum levels of hepatocyte growth factor (HGF) were determined in 26 patients with advanced stages of liver cirrhosis by means of an enzyme-linked immunosorbent assay. In 23 of these patients, liver biopsies were obtained before treatment with ursodeoxycholic acid and investigated for hepatocyte expression of the proliferating cell nuclear antigen (PCNA) and the Ki 67 antigen by immunocytochemical methods. RESULTS: In 25 of the 26 patients, serum HGF levels did not differ from those of patients with histologically normal livers. Levels did not vary between the different stages of primary biliary cirrhosis but increased moderately when re-evaluated after a period of 24 +/- 4.9 months or 54 +/- 10.7 months. An abnormally increased serum HGF level was observed in only one patient, who had end-stage liver cirrhosis before liver transplantation. Both PCNA and Ki-67 antigen labelling indices were significantly higher at all stages of primary biliary cirrhosis than in normal liver, indicating increased hepatocyte proliferation, but the labelling indices did not correlate with the HGF concentrations in serum. CONCLUSION: Serum HGF levels in almost all patients with primary biliary cirrhosis were within normal limits despite increased hepatocyte proliferation. The results support the hypothesis that HGF serum levels may reflect liver dysfunction rather than active hepatocyte proliferation. PMID- 8680909 TI - Middle cerebral artery blood flow velocity in patients with cirrhosis. AB - BACKGROUND: Brain dysfunction is common in patients with advanced liver disease; it is often manifested as hepatic encephalopathy, but its cause is not clearly understood. METHODOLOGY: Intracranial blood flow velocity parameters, including peak systolic velocity, end diastolic velocity and mean velocity of both middle cerebral arteries were measured by transcranial Doppler ultrasonography in 37 patients with cirrhosis without encephalopathy (16 Child's A, 10 Child's B and 11 Child's C) and 12 normal controls. The cause was alcohol-related in 24 and non alcohol-related in 13. RESULTS: No significant differences in any of the Doppler parameters were detected in Child's group A when compared with controls. However, a statistically significant decrease in middle cerebral artery blood flow velocity was evident when Child's B and C patients without clinically apparent encephalopathy were compared with controls irrespective of the cause. Our results demonstrate that intracranial blood flow is abnormal in patients with advanced liver disease without clinically apparent encephalopathy. PMID- 8680910 TI - Cholescintigraphy in patients with acute cholecystitis before and after percutaneous gallbladder drainage. AB - OBJECTIVE: To investigate gallbladder function by use of cholescintigraphy in patients with acute cholecystitis before and after percutaneous gallbladder drainage. DESIGN: A cholescintigraphy was performed in 40 patients with acute cholecystitis before and after the performance of percutaneous gallbladder drainage. During the post-drainage cholescintigraphies, a cholecystokinin stimulation was performed to investigate gallbladder emptying in 12 selected patients. Gallbladder pressure and volume were measured before drainage in another group of 12 patients with acute cholecystitis. RESULTS: As expected, no gallbladder activity was observed in the cholescintigraphies before drainage, except in a patient with an occluding stone in the common bile duct. Cystic duct patency and gallbladder activity were seen in 80% of patients in cholescintigraphies performed after drainage but before any other treatment. Post drainage cholescintigraphy revealed a mean gallbladder ejection fraction of 24%, which is significantly lower than the corresponding value in normal individuals and gallstone patients without cholecystitis (n = 12). Gallbladder pressure and volume were markedly increased compared with normal values. CONCLUSION: The relief of increased gallbladder pressure and volume appears to be important for the re-establishment of gallbladder function. PMID- 8680911 TI - Antral G-cell hyperplasia: a vanishing disease? AB - The diagnosis and management of antral gastrin-(G-) cell hyperplasia was a major topic of interest in the 1970s. Following the discovery of Helicobacter pylori in the 1980s, little attention was paid to this condition until it was shown that H. pylori infection was associated with hypergastrinaemia and that eradication of the organism returned the gastrin level to normal. Recent reports have examined the relationship between H. pylori and antral G-cell hyperplasia. H. pylori infection is present in about 50% of cases of antral G-cell hyperplasia and, importantly, eradication of the organism normalizes not only the gastrin level but also the antral G-cell count. Eradication treatment should be the therapy of choice. It is also of interest that H. pylori-negative antral G-cell hyperplasia or hyperfunction does exist. The historical aspects, the relationship between antral G-cell hyperplasia and H. pylori and recent case reports are reviewed. PMID- 8680912 TI - Pharmacological regulation of gastric mucous glycoprotein secretion. AB - Gastric mucous glycoproteins (GMGs) are an important protective component of the gastric 'mucus bicarbonate barrier'. The characterization of drug effects on GMG metabolism is difficult because the quantification of GMGs poses analytical problems and because indirect drug effects (e.g. on other gastric secretory functions) can influence GMG metabolism or quantification and thereby complicate the interpretation of in-vivo experiments. The use of suitable in-vitro systems, in particular of isolated gastric mucous cells, helped to resolve the latter problem and enabled the characterization of direct effects of prostaglandins, gastric acid secretagogues, peptide hormones, growth factors, adrenoceptor agonists, and synthetic compounds (e.g. teprenone) on GMG metabolism. Furthermore, from these experiments, evidence has accumulated that the cyclic AMP system, the inositol trisphosphate/calcium/protein kinase C system and the cyclic GMP system are involved in the intracellular transmission of drug effects on GMG metabolism. PMID- 8680913 TI - Oesophageal ulceration by tuberculosis: a rare cause of dysphagia. AB - We report on a 58-year old female patient from Afghanistan, who developed a dysphagia within 3 weeks of arrival. On the basis of radiological and endoscopic examination, an oesophageal ulcer was regarded as a malignant tumour, but because of weight loss, fever and night sweats (B symptoms) the question of tuberculosis was also considered by the pathologist. Histological assessment of biopsies produced proof of epithelioid cell granulomas with marginally polygonal giant cells of Langhans-type, as of acid-fast bacilli. In a bacteriological test, three different types of mycobacteria were found. With adequate anti-tuberculosis therapy, the oesophageal ulcer and the mediastinal lymph nodes visible in the computed tomograph soon disappeared, and the patient became free of symptoms. The clinical picture was interpreted as a primary oesophageal tuberculosis with mediastinal lymph nodes as the primary complex. In cases of oesophageal ulcer or dysphagia, tuberculosis should be included in the differential diagnosis, particularly in patients from Asia. PMID- 8680914 TI - Criteria for CME certification by the European Gastroenterology Board. PMID- 8680915 TI - Squamous cell carcinoma of the canine nasal cavity and frontal sinus: eight cases. AB - Squamous cell carcinoma of the canine nasal cavity and frontal sinus was diagnosed in eight cases between May 1988 and April 1994. The most common presenting complaints were nasal discharge, including epistaxis; sneezing; and facial deformity or exophthalmos. Metastasis was not identified in any case, but bone lysis and invasion into tissues outside the nasal cavity were noted in five cases. Computed tomograms were performed in five cases and were more useful than radiographs in determining the extent of neoplastic involvement. Euthanasia was performed within one week of diagnosis in three cases at the owner's request; one case died at home within one month; and the remaining four cases were euthanized within eight months due to progressive clinical signs. The mean survival time in these eight cases was three months, with a range of zero weeks to eight months. PMID- 8680916 TI - Focal myasthenia gravis as a paraneoplastic syndrome of canine thymoma: improvement following thymectomy. AB - A 10-year-old, neutered male cocker spaniel-cross experienced regurgitation, dry retching, and weight loss. A large, mediastinal mass and dilatation of the esophagus were seen on thoracic radiographs. Cytological, histopathological, immunohistochemical, and serological findings were consistent with a lymphoepithelial thymoma and focal, esophageal myasthenia gravis. Surgical removal of the mass resulted in rapid resolution of the megaesophagus and a decrease in serum acetylcholine-receptor antibody concentration. The dog was clinically normal until the thymoma recurred six months postoperatively. Clinical signs, diagnostic evaluation, management, and treatment of a dog with thymoma and megaesophagus are described. PMID- 8680917 TI - A histomorphological study of sarcoptic acariasis in the dog: 19 cases. AB - Nineteen cases of canine sarcoptic acariasis (Sarcoptes scabiei var. canis) were diagnosed histologically by identifying sarcoptic mites present in the stratum corneum. The inflammatory responses to these mites could be staged as early, fully developed, or late lesions. No histomorphological features were identified that could serve as reliable markers of infestation in the absence of a sectioned mite. PMID- 8680918 TI - Spirocerca lupi infection in the dog: aberrant migration. AB - The nematode Spirocerca lupi (S. lupi), a parasite of dogs and other carnivores, affects mainly the esophagus and the aorta leading to gastrointestinal, respiratory, and circulatory signs. Aberrant migration of the worm to unusual anatomical structures, especially the thoracic cavity, resulting in atypical clinical signs is being reported more frequently. Aberrant migration of S. lupi is reviewed, and two such cases (i.e., migration to the heart, causing an aortico pulmonary "window-like" opening, and to a subcutaneous abscess in the caudal thoracic region) are presented. PMID- 8680919 TI - Canine mucosal leishmaniasis. AB - Four dogs infected with Leishmania had proliferative lesions on the mucosae of the penis, tongue, oral cavity, prepuce, or nose. These mucosal, nodular lesions produced by parasites of the genus Leishmania have not been described previously in the dog. Leishmaniasis should be considered in the differential diagnosis of tumor-like lesions of mucous membranes. PMID- 8680920 TI - Bronchopulmonary and disseminated granulomatous disease associated with Aspergillus fumigatus and Candida species infection in a golden retriever. AB - A seven-year-old, female golden retriever was referred for a paroxysmal, chronic cough and dyspnea, dysphagia, facial pruritus, anterior uveitis, and deteriorating general condition. A severe, mixed interstitial and alveolar pattern, with poorly defined amorphous lesions, was seen on thoracic radiographs. Multiple, whitish nodules disseminated on the hyperemic respiratory mucosa were noted on bronchoscopy. Escherichia coli and Aspergillus fumigatus were cultured from the bronchoalveolar lavage. Granulomatous lesions in numerous organs were identified during necropsy, and Aspergillus fumigatus and Candida spp. were cultured from lung and kidney tissues. Microscopic granulomatous lesions were compatible with mycotic infection; however fungal organisms were not observed. PMID- 8680921 TI - Pancreatic pseudocyst associated with chronic-active necrotizing pancreatitis in a cat. AB - A 13-year-old, neutered female domestic shorthair was referred for evaluation of chronic, intermittent vomiting of approximately two years' duration. On physical examination, a fluctuant mass was palpated in the left cranial abdominal quadrant. Significant laboratory findings included neutrophilia, hyperglycemia, hyperlipasemia, and proteinuria. A distinct mass within the left cranial quadrant was noted on abdominal radiographs. Ultrasonographically, the pancreas appeared slightly hyperechoic with a hypoechoic mass arising from its left lobe. A cystic mass in the left lobe of the pancreas was identified during an exploratory celiotomy. The mass and affected areas of the pancreas and a portion of the spleen were resected. The cat recovered completely. Cytological, histological, and laboratory evaluations of the mass were consistent with pancreatic pseudocyst formation, which has been reported in dogs and humans but has not yet been reported in cats. PMID- 8680922 TI - Bordetella bronchiseptica infections in cats. AB - Eleven cats from 10 different households or catteries were diagnosed with Bordetella bronchiseptica (B. bronchiseptica) infections. Seven cases proved fatal, in which B. bronchiseptica pneumonia was a primary or significant cause of death. The majority of cases (seven of 11) were in kittens less than eight weeks old. A universal complaint was coughing. Bacterial cultures from transtracheal washes or lung tissue were successful in diagnosing bordetellosis in all cases. This report indicates that B. bronchiseptica should be a consideration in a cat presenting with a primary complaint of coughing and may be a relatively common disease in catteries or shelter environments. PMID- 8680923 TI - Atypical Addison's disease in the dog: a retrospective survey of 14 cases. AB - Fourteen dogs diagnosed with Addison's disease and having atypical serum electrolyte levels are described. Seventy-eight percent were female, and most showed signs of inappetence, weakness, or vomiting. Ninety-three percent of the cases had either hyponatremia without hyperkalemia or normal serum electrolyte concentrations. Hemogram features were variable and were not useful in suggesting a diagnosis of hypoadrenocorticism. The results of this study show that normal or mild serum electrolyte changes in a dog with clinical signs compatible with Addison's disease should not exclude this diagnosis from consideration. Definitive diagnosis depends on the demonstration of inadequate adrenocortical response to adrenocorticotropic hormone (ACTH) stimulation. PMID- 8680924 TI - Comparison of seven different suture materials in the feline oral cavity. AB - Seven different suture materials were implanted into the oral tissues of 12 cats. The sutures and surrounding tissues were retrieved en bloc from each of two cats on days one, three, seven, 14, 21, and 28 postimplantation. Tissue reaction and suture duration were evaluated by gross visual observation and histological examination. Chromic gut disappeared between days three and seven; polyglactin 910 disappeared between days 14 and 21; and polyglycolic acid disappeared as early as seven to 14 days. Polydioxanone still was intact at day 28 and is recommended as an absorbable material for procedures in which longer healing time is anticipated. All the nonabsorbable suture materials (i.e., polypropylene, stainless steel, and nylon) were intact at day 28 postimplantation. Visual inspection showed polypropylene to have the least tissue reaction. PMID- 8680925 TI - Hypoadrenocorticism. PMID- 8680926 TI - Vaccine site-associated sarcomas in cats: clinical experience and a laboratory review (1982-1993). AB - Recent information regarding vaccine site-associated sarcomas in cats suggest a relationship to either feline leukemia virus or rabies vaccines. The authors' initial case was in a cat that had received neither of these vaccines. Review of the available hospital records revealed an increasing number of vaccine site associated sarcomas, none of which were related to feline leukemia virus vaccines. Only one was related to the use of a rabies vaccine, and this tumor occurred in the thigh as opposed to between the shoulder blades. The laboratory data supported an increasing incidence of vaccine site-associated sarcomas, the majority of which occurred in the interscapular area and were associated with routine prophylactic vaccinations. PMID- 8680927 TI - Aggressive, undifferentiated sarcoma with widespread metastasis in a six-month old Neopolitan mastiff. AB - A six-month-old Neopolitan mastiff presented for a rapidly growing cervical mass. Undifferentiated sarcoma was diagnosed at post mortem based on histopathology and immunohistochemistry. Metastases to mediastinum, pleura, lungs, liver, kidneys, omentum, mesentery, and multiple lymph nodes were present. Soft-tissue sarcomas are reported infrequently in children and young dogs. The cell of origin often is difficult to determine due to poor differentiation and rapid growth of these neoplasms. PMID- 8680928 TI - Hybridization of DNA targets to glass-tethered oligonucleotide probes. AB - Hybridization of nucleic acids to surface-tethered oligonucleotide probes has numerous potential applications in genome mapping and DNA sequence analysis. In this article, we describe a simple standard protocol for routine preparation of terminal amine-derivatized 9-mer oligonucleotide arrays on ordinary microscope slides and hybridization conditions with DNA target strands of up to several hundred bases in length with good discrimination against mismatches. Additional linker arms separating the glass surface from the probe sequence are not necessary. The technique described here offers a powerful tool for the detection of specific genetic mutations. PMID- 8680929 TI - Development of a novel, rapid processing protocol for polymerase chain reaction based detection of bacterial infections in synovial fluids. AB - We describe the development of a molecular detection system designed for use with synovial fluid (SF)-based infections. The methodology employs a lysis/extraction procedure that effectively disrupts microorganisms allowing for release of the microbial DNA and its amplification by polymerase chain reaction (PCR). We tested the effectiveness of adding a mixed-bed, ion-exchange resin to the extract to remove PCR inhibitory components present in the SF. After centrifugation to separate the resin, DNA contained in the supernatant is subjected to PCR using oligonucleotide primers designed for broad-spectrum microorganism detection. Amplification products are analyzed by agarose gel electrophoresis and/or DNA hybridization methodology. We report here the detection sensitivity and specificity of the protocol using SF inoculated with Escherichia coli and Staphyloccocus aureus. We have applied this new methodology to clinical SF specimens with results superior to standard laboratory culturing assays. PMID- 8680930 TI - Expression and purification strategies for the production of single-chain antibody and T-cell receptor fragments in E. coli. AB - This work describes protocols for the production of single-chain antibody and T cell receptor fragments in E. coli. A choice of methods is given for the purification of the recombinant fragments that rely on the use of either immunoaffinity or metal chelate affinity chromatography. The TCR fragments may have to be denatured and refolded before the fragments attain their proper conformation. PMID- 8680931 TI - One-step purification of recombinant proteins with the 6xHis tag and Ni-NTA resin. AB - The 6xHis/Ni-NTA system allows rapid and efficient affinity purification of recombinant proteins from virtually any expression system. Protocols and tips for purification under both native and denaturing conditions are provided, as well as a rapid spin procedure for protein minipreps. PMID- 8680932 TI - A general assay for restriction endonucleases and other DNA-modifying enzymes with plasmid substrates. AB - A procedure for measuring the activities of enzymes that alter the covalent structure of DNA is described. The assay utilizes covalently closed circles of DNA as the substrate and yields quantitative data on the fraction of this DNA converted to both open-circle and linear forms. PMID- 8680933 TI - Determination of the molecular weight of DNA-binding proteins using UV crosslinking and SDS-PAGE. AB - We describe the use of UV-crosslinking in combination with SDS-PAGE to determine the approximate molecular weight of DNA-binding proteins. A 5-bromo-2' deoxyuridine (5-BrdU)-substituted, radioactively labeled double-stranded oligonucleotide representing the protein binding site is incubated with a crude nuclear extract containing the protein of interest. Following irradiation with a UV light source, the DNA/protein complex is subjected to SDS-PAGE and its molecular weight determined by comparison with appropriate protein standards. PMID- 8680936 TI - Direct transformation of Neisseria gonorrhoeae by gel-isolated DNA. AB - The naturally competent organism, Neisseria gonorrhoeae, can efficiently transform a marker carried on DNA purified in low-melting-temperature agarose without prior purification or dilution. Neither the agarose or buffer components inhibit transformation frequencies, but exposure to UV irradiation completely abrogates transformation. PMID- 8680934 TI - Two-dimensional DNA typing: A cost-effective way of analyzing complex mixtures of DNA fragments for sequence variations. AB - By two-dimensional (2D) DNA typing, multiple DNA fragments can be analyzed in parallel for all possible sequence variations. The method involves electrophoretic separation in polyacrylamide gels, first by size and subsequently on the basis of basepair sequence in a denaturing gradient. The system has been automated partly and a dedicated image analysis system for rapid interpretation of the often complex spot patterns was developed. In this review, the basic principles of 2D DNA typing, its methodology, and some major applications in genetic studies of animals, plants, and microorganisms will be discussed, with the emphasis on human genetics. PMID- 8680937 TI - Amplitude and timing of electromyographic activity during sprinting. AB - The aim of this study was to make descriptive analyses of the muscle activities in the lower extremity during maximal sprinting. Nine healthy sprinters were examined during maximal sprinting using telemetric electromyography (EMG). Seven muscles of the lower extremities were investigated: biceps femoris, medial hamstrings (semimembranosus and semitendinosus), rectus femoris, gluteus maximus, tibialis anterior, lateral gastrocnemius and medial gastrocnemius. The recorded EMG levels during running were expressed as percentage of maximum voluntary isometric contractions (%max EMG). For each muscle, the normalized EMG was plotted during the whole running stride cycle and is presented for each muscle. The reason for using this method is to show that it is possible to compare different muscle activities in a runner as well as to make comparisons between runners. Lateral and medial hamstrings and gluteus maximus showed similar activities with peak levels of EMG during foot-strike. Rectus femoris had a two peak activity, with one peak at the middle of the stance phase and the other during the swing phase. The tibialis anterior also showed a two-peak activity, but with the peaks at the beginning of the swing phase and just before foot strike. The highest activities of the medial and lateral gastrocnemius occurred just before toe-off. PMID- 8680938 TI - Postexercise recovery period: carbohydrate and protein metabolism. AB - The essence of the postexercise recovery period is normalization of function and homeostatic equilibrium, and replenishment of energy resources and accomplishment of the reconstructive function. The repletion of energy stores is actualized in a certain sequence and followed by a transitory supercompensation. The main substrate for repletion of the muscle glycogen store is blood glucose derived from hepatic glucose output as well as from consumption of carbohydrates during the postexercise period. The repletion of liver glycogen is realized less rapidly. It depends to a certain extent on hepatic gluconeogenesis but mainly on supply with exogenous carbohydrates. The constructive function is founded on elevated protein turnover and adaptive protein synthesis. Whereas during and shortly after endurance exercise intensive protein breakdown was found in less active fast-twitch glycolytic fibers, during the later course of the recovery period the protein degradation rate increased together with intensification of protein synthesis rate in more active fast-twitch glycolytic oxidative and slow twitch oxidative fibers. PMID- 8680935 TI - Bacteriophage resistance in Lactococcus. AB - Lactic acid bacteria are industrial microorganisms used in many food fermentations. Lactococcus species are susceptible to bacteriophage infections that may result in slowed or failed fermentations. A substantial amount of research has focused on characterizing natural mechanisms by which bacterial cells defend themselves against phage. Numerous natural phage defense mechanisms have been identified and studied, and recent efforts have improved phage resistance by using molecular techniques. The study of how phages overcome these resistance mechanisms is also an important objective. New strategies to minimize the presence, virulence, and evolution of phage are being developed and are likely to be applied industrially. PMID- 8680939 TI - Mild overcooling increases energy expenditure during endurance exercise. AB - Intensive cooling has been shown to increase energy expenditure (EE) during work as well as to decrease physical performance. Two different levels of moderate cooling (10 degrees C vs 15 degrees C) were studied during light endurance exercise in order to examine the effect of the increased heat loss on EE. Twelve subjects performed a 90-min low intensity exercise (100 W) on a cycle ergometer, wearing a water-cooled calorimeter suit for controlled cooling. The lower temperature resulted in a 4.3 +/- 3.8% (mean +/- SD) higher EE, increased total heat loss and lowered skin temperatures. No differences in central core body temperature, heart rate or respiratory quotient (RQ) were recorded. There was a relation between differences in the rate of heat loss and the corresponding increase in EE. Even a small increase in cooling during endurance exercise increased EE which may be a relevant problem in winter sports. PMID- 8680940 TI - Biochemical markers of bone metabolism during distance running in healthy, regularly exercising men and women. AB - The purpose of the present study was to evaluate the effects of long distance running on bone metabolism, using the biochemical markers ICTP (the carboxyterminal cross-linked telopeptide of type I collagen), PICP (the carboxyterminal propeptide of type I procollagen), osteocalcin and bALP (bone specific alkaline phosphatase) as well as parathyroid hormone (PTH) and serum calcium. Twenty healthy, regularly exercising individuals, 10 women and 10 men, participated in a running competition. The mean age was 38 (range 22-55) and 39 (range 22-53) years respectively, the performed distance 15 (range 5-30) and 28 (range 15-30) km respectively, with a speed of 5:30, 5:02 per kilometer respectively. Fasting blood samples were drawn in the morning the day before the race, and also the day after and two days after. A decrease of PICP concentrations among women was evident the day after the competition (from 170 +/ 17 micrograms/l to 158 +/- 17 micrograms/l) which returned to pre-exercise levels two days after the race (167 +/- 19 micrograms/l). Furthermore, a decrease of osteocalcin could be seen in the men one day after the exercise (from 12.1 +/- 1.1 micrograms/l to 10.3 +/- 1.1 micrograms/l). In the men, there was also an increase of ICTP concentrations two days after (3.98 +/- 0.35 micrograms/l) this long-term and demanding exercise, when compared with pre-exercise levels (3.67 +/ 0.28). One single bout of long-term, exhaustive running exercise in well-trained men and women seems to induce a temporary inhibition of bone formation as well as a stimulation of bone resorption. PMID- 8680941 TI - Low back pain in elite cross-country skiers. A retrospective epidemiological study. AB - Low back pain is a common complaint among competitive cross-country skiers. Fifty three top male and 34 female skiers in the age group 16-25 were interviewed with a questionnaire regarding anthropometric parameters, training variables, back pain and other injuries. The frequency of back pain was 64% in the whole group, men affected slightly more often than women. Back pain was defined as previous or present recurrent skiing correlated backache that more or less affected skiing ability. Diagonal skiing style was the most commonly back pain-inducing style, whereas no skier experienced back pain when "skating" only. The low back was the predominant location of pain. Anthropometric and training variables seemed to be of little value in predicting back pain. PMID- 8680943 TI - Soccer injuries in Iceland. AB - We investigated the frequency, cause and location of injuries in Icelandic elite soccer in 1991. The incidence of injuries for the individual player was 34.8 +/- 5.7 per 1000 game-hours and 5.9 +/- 1.1 per 1000 practice-hours. The most common types of injuries were muscle strains (29%), ligament sprains (22%), contusions (20%), and other injuries (29%). The frequency of reinjury was markedly high, where 44% of the strains and 58% of the sprains were registered as reinjuries. Strains occurred mainly during sprinting, sprains by tackling, and contusion during other contact. Significantly more injuries occurred on artificial turf than on grass or gravel in correlation to number of hours in games and practices. Teams who had the longest pre-season preparation period obtained significantly fewer injuries during the season. PMID- 8680944 TI - Effect of goal orientation on achievement beliefs, cognition and strategies in team sport. AB - Nicholls' motivation conceptual framework pertaining to achievement goals was used to study the relationship between two implicit goal orientations (task and ego) and achievement cognitions and beliefs about the competitive team sport experience. The study examined the relationship between the goal orientations and purposes of team sport, motivational climate, satisfaction, sources of satisfaction, achievement strategies, and perception of ability in team sport. The subjects were 148 students experienced in team sport at a Norwegian university. The scales were translated specifically for the study and factor analyses used to determine the factor structure of the scales. Seventeen factors along the 6 dimensions emerged, and canonical analysis determined that predominantly task-oriented subjects focused on health-related activities within purposes, preferred mastery climates and focused on mastery-oriented criteria to determine satisfaction and other achievement-related beliefs. In contrast, predominantly ego-oriented subjects focused on status enhancement for purpose, preferred performance-oriented climates and focused on ego-oriented criteria to determine satisfaction and other achievement beliefs. PMID- 8680942 TI - Patterns of intense physical activity among 15- to 30-year-old Finns. The Cardiovascular Risk in Young Finns Study. AB - Previous studies have reported increasing trends in physical activity in the Finnish population. These reports have not, however, included the perspective of cardiorespiratory stress in adolescent and young adults. We examined the present patterns of physical activity among Finnish adolescents and young adults in 1992. We specifically assessed whether the young people experience the volume of physical activity that is believed to stress the cardiorespiratory system appropriately in order to increase the level of fitness. The subjects in the present study were participants of a large multicenter study of atherosclerosis precursors in children and young adults. Physical activity was measured with a self-administered questionnaire in 2255 adolescents and young adults (1015 males and 1240 females). The proportion of subjects undertaking the volume of physical activity believed to benefit the cardiorespiratory system appropriately was 19%. The proportion was higher in males than in females (26 vs 13%). The proportion of active subjects became smaller in older age groups in both sexes. Half the study population (51% of the males; 48% of the females) reported frequent leisure-time physical activity less than once a month. In conclusion, Finnish adolescents and young adults have low levels of physical activity on the average, and many young Finns seldom undertake the volume of physical activity believed to benefit the cardiopulmonary system. Young males seem to be physically more active than females. PMID- 8680945 TI - Pseudoarthrosis between a patellar tendon ossicle and the tibial tuberosity in Osgood-Schlatter's disease. AB - We report a case of pseudoarthrosis between a patellar tendon ossicle and the tibial tuberosity. A man, 18 years of age, had persistent symptoms of Osgood Schlatter's disease from the left knee for 3 years. Conservative treatment was without effect. Excision of the ossicle resulted in complete relief of symptoms. Histologic examination showed a pseudoarthrosis covered with cartilage and no sign of inflammation. Persistent symptoms of Osgood-Schlatter's disease for more than 2 years indicate exploration. PMID- 8680946 TI - Medical and commercial supports for scoliotic patients, 1819-1935. PMID- 8680947 TI - The evolution of the progressive-era hemocytometer. PMID- 8680948 TI - Anatomical comparisons, metaphysical conceits: poets, physicians, and the motions of the heart. PMID- 8680949 TI - Redefining death in America, 1968. PMID- 8680950 TI - Chemotherapy Foundation Symposium XIII, Innovative Cancer Chemotherapy for Tomorrow. New York City, NY, USA. Abstracts. PMID- 8680951 TI - Food allergy and atopic disease. PMID- 8680952 TI - Regulation of IgE production and other immunopathogenetic mechanisms. PMID- 8680954 TI - Food allergy in children. AB - The diagnosis of hypersensitivity reactions to foods in infancy and childhood requires the use of clinical skills and laboratory diagnostic methods to identify suspect foods. Patients and parents occasionally may need to keep food/symptom diaries to explore the association of foods and adverse reaction. Skin testing or RAST may shorten the list of potential allergens because of their excellent negative predictive value. Except for obvious serious allergic reactions after ingestion of a single food, confirmation of the reaction may be ideally confirmed by a DBPCFC, especially if the reported symptoms are subjective in nature. Equivocal responses should be repeated. Although many in vitro and in vivo diagnostic methods have been developed to potentially improve the diagnosis of food allergy in children, no test has been able to predict the results of the DBPCFC with any greater accuracy than skin tests or RAST. The "perfect" test with excellent positive and negative predictive values has yet to be developed. PMID- 8680953 TI - Clinical features of food allergy in infants. PMID- 8680955 TI - Strategies for prevention. AB - Allergy prevention is antigen specific. Elimination of native CMP from the diet in at-risk infants decreases the incidence of CMPA, but evidence for a decreased incidence of other atopic diseases is lacking. Clinical trials comparing the efficacy of different types of hydrolysates are needed. PMID- 8680956 TI - Host, season and year do not play an important role on genetic variability in a trichostrongyle nematode as assessed from allozymes. AB - The isolates of the trichostrongyle nematode Teladorsagia circumcincta in sheep may vary from one site to another as assessed from allozyme studies. This genetic variability could be host (on the parasitic stages) or/and environmentally (on the free-living stages) induced. In the present study the role of host (susceptible to the establishment of the parasite and partly resistant ones) and environmental changes expressed by season (Autumn versus Spring) or year of sampling (1990 or 1992) were investigated. Five polymorphic enzymes were studied: glucose-phosphate-isomerase (GPI), lactate dehydrogenase (LDH), malate dehydrogenase (MHD), mannose-phosphate isomerase (MPI), and phosphoglucomutase (PGM). No significant difference in allelic frequencies was recorded between 4 susceptible lambs from a flock grazed in 1990 as well as in 3 lambs selected on their susceptibility or resistance to natural infection in a flock grazed in 1992. The mode of infection (natural--frequently repeated small infections, versus experimental--3 repeated large infections) did not modify the allelic frequencies of the nematodes. The allelic frequencies remained stable along the seasons and during the 2 years investigated. The largest distance of Rogers (0.07) and Fst (0.012) were recorded between worms originating from susceptible and resistant lambs or in Autumn versus Spring populations of worms (0.08 and Fst 0.010). A deficiency in heterozygotes of the same magnitude was recorded in the worm populations obtained from the different infections. The stability of allelic frequencies and genetic structure are surprising when one considers the evolution of the same parasite in several generations of laboratory conditions. This stability could be related to the fact that levels of disturbance on parasitic and free-living stages are neither too low (as in laboratory conditions) nor too high (as in farms when anthelmintic treatment are used regularly and destroy the adult stages). PMID- 8680957 TI - [Early ultrastructural lesions of kidney cells after intravenous administration of 239 plutonium citrate in rats]. AB - After intravenous administration of (5 x 2.3 kBq and 5 x 9.25 kBq) plutonium citrate in adult male Sprague Dawley rats, their kidneys are withdrawn and prepared for observation under a transmission electron microscope. Seven days after the first injections, deep cellular alterations are observed in the proximal convoluted tubules. These alterations are mainly mitochondrial. The affected mitochondria are of swollen aspect and have their cristae partially or completely destroyed. Nevertheless within the same tubule we observe non altered cells directly in contact with deeply altered cells. In all the cases the lysosomes of the altered cells appear to be perfectly normal. The cell nuclei are mostly unaltered but a few cases of nuclear fragmentation exist. We also notice some architectural modifications in the brush border and in the betacytomembranes of the proximal convoluted tubule. Equally important mitochondrial alterations are also noticed in the different varieties of glomerular cells. We observe no other glomerular alterations. The major subcellular alterations in the proximal convoluted tubules and in the different varieties of glomerular cells deeply contrast with the distal convoluted tubules which are found to be totally unaltered. These mitochondrial alterations may be due to the alpha particle disintegration of plutonium which may either directly react with the mitochondria or, through the products of radiolysis of water react with the mitochondria respiration process. However the direct chemotoxicity of plutonium cannot be neglected. PMID- 8680958 TI - Early defect of immunoregulatory T cells in autoimmune diabetes. AB - A potential immunoregulatory function has recently been attributed to the discrete subset of major histocompatibility complex (MHC) class I-restricted TCR alpha beta mature thymocytes expressing an unusual V beta 8-biased T cell receptor repertoire. This T cell subset which also selectively express the CD44 marker is the main IL-4 producer in the thymus. Nonobese diabetic (NOD) mice were found to have a marked deficit in the number and functional capacity of CD44+ TCR alpha beta+ thymocytes from as early as 3 weeks of age. The deficiency in IL-4 production was completely corrected after incubation with interleukin-7 (IL-7), a selective growth factor for CD44+ TCR-alpha beta+ mature thymocytes. This abnormality in T cell differentiation could explain the Th2 functional deficiency that may be a key element in the emergence of Th1-driven autoimmune disease in NOD mice. PMID- 8680959 TI - Mutations at the capsid-nucleocapsid cleavage site of gag polyprotein of Moloney murine leukemia virus abolish virus infectivity. AB - Capsid protein CAp30 and nucleocapsid protein NCp10 of Moloney murine leukemia virus (MoMuLV) are the 2 major proteic components of the virion core and are generated by processing of the gag polyprotein precursor, Pr65gag, by the viral protease. In the virion core, several hundred NCp10 molecules are bound to the genomic RNA dimer forming the nucleocapsid structure. In the course of virus assembly, NC protein, as the mature NCp10 and/or as the gag precursor, appears to direct genomic RNA packaging. In vitro, NCp10 has nucleic acid binding and annealing activities and promotes viral RNA dimerization and the annealing of replication primer tRNAPro to the primer binding site (PBS) which is necessary for the initiation of reverse transcription. To investigate whether maturation of NCp10 is required for virus formation, we substituted charged residues for the hydrophobic amino acids at the capsid-nucleocapsid protein cleavage site in order to prevent maturation of NCp10. Here we report that these mutations abolished maturation of capsid protein CAp30 and NCp10 by the viral protease in vitro. When these mutations were introduced into an infectious MoMuLV molecular clone, Pr65gag precursor was synthesized in transfected cells but virion production was strongly diminished and mutant viruses were not infectious. These results suggest that maturation of NCp10 is required for optimal virion release and production of infectious virus. PMID- 8680961 TI - Biotin synthesis in higher plants: isolation of a cDNA encoding Arabidopsis thaliana bioB-gene product equivalent by functional complementation of a biotin auxotroph mutant bioB105 of Escherichia coli K12. AB - Biotin synthase is involved in the conversion of dethiobiotin to biotin in bacteria, yeast and higher plants. We isolated a complete cDNA (1.3 kb) encoding A. thaliana bioB-gene product by functional complementation of the bioB105 biotin auxotroph mutant of Escherichia coli K12 using an A. thaliana cDNA library. The open reading frame encodes a predicted protein of 378 amino acids and molecular mass of 41.634 Da. The bioB-gene product from A. thaliana shows specific regions of homology with the bioB-gene products of E. coli, Serratia marcescens, Bacillus sphaericus, and Saccharomyces cerevisiae. The predicted amino acid sequence of the plant protein contains the consensus region GXCXEDCXYCXQ involved in the [2Fe 2S] cluster binding. Furthermore, it does not present a transit peptide in its N terminal region suggesting that the A. thaliana bioB-gene product reported in this paper is located in the cytosolic compartment. PMID- 8680960 TI - Molecular cloning and structural analysis of cDNAs that encode 3 small GTP binding proteins from sugar beet. AB - Isolation of homologous ras-related genes from sugar beet has never been reported. Screening cDNA library from Beta vulgaris L. Hilma resulted in the isolation of 3 ras-homologous clones. Two of these genes (rab1Bv and rab2Bv) belong to the Rab/Ypt group. The deduced polypeptidic sequences from them show strong homologies to Ara3 (93% with Rab1Bv) of Arabidopsis thaliana and Rgp2 (97% with Rab2Bv) of Oryza sativa. The third gene (rho1Bv) belongs to the Rho family. The homology of Rho1Bv protein with Rho1Ps from Pisum is very high (98%). Rho1Bv is the second representative plant Rho protein described in the literature. The homologies of all these 3 small GTP-binding proteins indicate that these proteins are conserved in plant families like Chenopodiaceae, Brassicaceae, Fabaceae and Poaceae and could control important transductional pathways conserved along the processes of evolution. PMID- 8680962 TI - Research and clinical care: maintaining the balance. PMID- 8680963 TI - Nasopalatine canal cyst: a rare sequelae of surgical rapid palatal expansion. PMID- 8680964 TI - Temporomandibular joint pain as a neuropathy. PMID- 8680965 TI - Evaluation of results with three-point visualization of zygomaticomaxillary complex fractures. AB - OBJECTIVE: To retrospectively evaluate the results of three-point visualization and liberal rigid fixation for the treatment of unilateral zygomaticomaxillary fractures by assessing the incidence and severity of complications. STUDY DESIGN: Fourteen patients were examined an average of 19 months after 3-point visualization with multiple points of rigid fixation for their unilateral zygomaticomaxillary fractures. Patients were evaluated for asymmetry in globe position, superior tarsal fold size, diplopia, lateral canthus height, and malar projection. RESULTS: The following were found: two patients with significant changes in globe position, none with diplopia in direct gaze, two with diplopia in extreme gazes, two with severe tarsal fold asymmetry, five with mild tarsal fold asymmetry, and two with noticeable malar asymmetry. CONCLUSION: Three-point visualization and liberal rigid fixation for zygomaticomaxillary fracture treatment results in a low incidence of complications that are proportional in severity to the trauma sustained. PMID- 8680966 TI - Comparison of the morbidity associated with maxillary fractures treated by maxillomandibular and rigid internal fixation. AB - OBJECTIVE: To compare the type and incidence of morbidity encountered by two groups of patients with maxillary fractures, one treated by closed reduction and maxillomandibular fixation and the other by open reduction and rigid internal fixation. STUDY DESIGN: This was a retrospective review of records for all patients with maxillary fractures treated over a 10-year period. Age, sex, mechanism of injury, anatomic location of fracture, treatment modality, and complications were identified. Two populations of patients, those treated with closed reduction and maxillomandibular fixation and those treated with open reduction and rigid internal fixation, that were similar in size (n = 50), age, sex, and anatomic distribution of fractures were compared. RESULTS AND CONCLUSIONS: This study indicates that patients with maxillary fractures treated with either closed reduction and maxillomandibular fixation or open reduction and rigid internal fixation will encounter postoperative problems with a near equal frequency (60% to 64%). Regardless of the technique used, no relationship could be established between age, sex, or cause of injury. The more superior the level of the fracture, the higher the rate of adverse sequelae. PMID- 8680967 TI - Intraoral reconstruction with innervated forearm flap: a comparison of sensibility and reinnervation in innervated versus noninnervated forearm flap. AB - OBJECTIVE: To evaluate the cutaneous sensibility and sensory reinnervation in patients who underwent intraoral reconstruction with an innervated or noninnervated forearm flap. STUDY DESIGN: Results of the use of innervated forearm flaps in oral reconstruction was compared with the use of noninnervated flaps. The evaluation of sensibility and reinnervation comprised clinical sensibility tests and immunohistochemical investigation of postoperative biopsy specimens against S-100 and neurofilament. RESULTS: The innervated flaps (4 patients) provided earlier and qualitatively better recovery of sensation than the noninnervated flaps (9 patients). Immunohistochemical investigation revealed the existence of a larger number of regularly arranged sensory nerve fibers in the cutaneous tissue of the innervated flaps than in the noninnervated flaps. Examination with an electron microscope found the structure of these nerve fibers to be well preserved in the innervated flaps, whereas nerve fibers in the noninnervated flaps were degenerative. CONCLUSION: These findings suggest (1) that the innervated flaps are superior to the noninnervated flaps not only for the repair of defects but also for the restoration of function and (2) that the innervated flaps contribute to the improvement of the quality of life for patients. PMID- 8680968 TI - Nuclear dacryoscintigraphy: its role in oral and maxillofacial surgery. AB - Obstruction of the lacrimal drainage apparatus may result in excessive tearing or epiphora. This may occur as a result of a traumatic injury or accumulation of debris, mucus, or pus. In nuclear dacryoscintigraphy, a radioactive solution is introduced into the conjunctival sac by pipette and allowed to follow the flow of the tear solution through the lacrimal drainage system. This article will review normal lacrimal anatomy and indications for nuclear dacryoscintigraphy in oral and maxillofacial surgery. PMID- 8680969 TI - Radiographic study of bone loss of mandibular lingual cortical plate accompanied by third molar development. AB - OBJECTIVE: The purpose was to determine the features of mandibular lingual cortical bone loss around the root of the mandibular third molar. STUDY DESIGN: We examined occlusal radiographs in 2210 persons aged 11 to 78 years. RESULTS: Prominent increase of incidence of bone loss was evident in subjects in their third decade compared with those in their second decade. The incidence was not decreased into the sixties. The incidence of bone loss in men was significantly higher than that in women. The incidence was not influenced by inflammation around the tooth crown of the third molar, by tooth caries, or by metal fillings present in the third molar. CONCLUSIONS: The present observations suggest that bone loss is induced by physiologic processes that accompany root formation of the third molar after mandibular growth. PMID- 8680970 TI - HIV-infected patients and dental care: nondisclosure of HIV status and rejection for treatment. AB - OBJECTIVE: To investigate reports of nondisclosure of HIV-seropositivity to dentists by HIV-infected patients and their rejection for dental treatment. STUDY DESIGN: An anonymous self-administered questionnaire was completed by 101 consecutive consenting HIV-infected patients. RESULTS: Eighty percent of respondents (mean age, 36 years) had visited a dentist since their HIV diagnosis; 15% of these reported that they had been refused treatment because the dentist did not want to treat HIV-infected patients. Rejection was reported by 25% of respondents with heterosexual and 14% with homosexual risk factors, 11% of recipients of blood or blood products, and 8% with unknown or multiple risk factors. Refusal was not associated with economic factors. Nondisclosure of HIV seropositivity to their current dentist was reported by 13% of respondents. No respondents attending hospitals or health units reported nondisclosure, compared with 18% of respondents attending private dental offices (p < 0.05). CONCLUSION: More research is required with a larger sample to improve generalizability and to permit subgroup analysis. PMID- 8680971 TI - Dental anxiety and the absorption of orally administered erythromycin stearate. AB - Erythromycin stearate is an acid labile antibiotic, therefore fear and apprehension, which are known to affect gastric motility, may produce erratic absorption resulting in lower serum levels. The mean (SD) serum erythromycin concentration 75 minutes after a 1.5 gm oral dose of erythromycin stearate to 45 patients was 8.7 (4.8) mg/L and ranged widely from 0.4 to 20.5 mg/L. The serum concentration of erythromycin was below therapeutic levels (1.0 mg/L) in two patients. No significant association was found between anxiety and serum levels of erythromycin when age, gender, and gastric distress were taken into account. It is concluded that dental anxiety may indirectly influence the uptake of oral erythromycin stearate; but this relationship is complex, and there is no evidence from this study that increased dental anxiety decreases the uptake of the drug. PMID- 8680972 TI - Acro-osteolysis (Hajdu-Cheney) syndrome: report of a case with abnormal tooth structure. AB - The acro-osteolysis (Hajdu-Cheney) syndrome is a rare disorder of bone metabolism characterized by progressive dissolution of a number of bones. Although previous reports have detailed several dental abnormalities associated with this syndrome, this is the first report describing structural changes in the dentin and cementum of teeth. PMID- 8680973 TI - In memoriam: Jens J. Pindborg, August 17, 1921 to August 6, 1995. PMID- 8680975 TI - An unusual intraosseous melanoma in the maxillary alveolus. AB - A case is reported of a 31-year-old white man who presented with a solitary melanoma in the maxillary alveolus. The lesion was located between and had displaced the roots of the lateral incisor and canine and was relatively well circumscribed on radiography. No mucosal origin or potential primary lesion was found, and a marginal excision resulted in the patient remaining free from disease after 7 years of follow-up. Metastasis of melanoma to the jaws is rare even in disseminated disease, and this solitary lesion is unusual. Although metastasis from a regressed primary tumor cannot be excluded, some of the features raise the possibility that this melanoma may have arisen as a primary tumor within bone. PMID- 8680974 TI - Oral melanoma: case reports and review of the literature. AB - Oral melanomas occur most often on the palate and gingiva with the maxillary arch affected 80% of the time. Melanosis may exist many years before a definitive biopsy. Long-standing lesions may ulcerate but lack rolled borders or induration, features commonly associated with squamous cell carcinoma. Melanoma that involves oral mucosa is rare with an extremely poor prognosis. Surgical management remains the preferred treatment in combination with chemotherapy. Irradiation therapy is used occasionally as a primary modality in the elderly and medically compromised patients. Lymph node dissection is not routinely practiced. The poor prognosis of oral melanomas requires that pigmented lesions of undetermined origin be routinely biopsied. PMID- 8680976 TI - Primitive neuroectodermal tumor of maxilla in an adult. AB - Primitive neuroectodermal tumor is primarily a central nervous system tumor. These tumors are generally manifest in infancy or early childhood. The following article reports a rare case of primitive neuroectodermal tumor in posterior maxilla in an adult. Treatment for primitive neuroectodermal tumor in extracranial sites in adults is not clearly defined in the literature. This case was treated by combined chemotherapy followed by radiotherapy, which failed to cause regression of the lesion. PMID- 8680977 TI - Congenital epulis and granular cell tumor: a histologic and immunohistochemical study. AB - OBJECTIVES: Although it is now reasonably certain that granular cell tumors derive from Schwann cells, the histogenesis of congenital epulis, which is largely isomorphic with granular cell tumor, remains unclear. A study was undertaken to compare the immunophenotype of these tumors with particular emphasis on the expression of matrix proteins and macrophage markers because such information is not available in the literature. STUDY DESIGN: Four granular cell tumors and two congenital epulis were immunostained with a panel of 29 antibodies. Two congenital epulis and one granular cell tumor were investigated by electron microscopy, the latter also by immunoelectron microscopy. RESULTS: Many similarities in immunostaining were found, for example, both tumor types were CD68+, Ki-M1P+, lysozyme-, vimentin+, fibronectin+, laminin+, lectin PHAE+, and lectin WGA+. However, differences were also noted, for example, granular cell tumor was always S100 protein+, but only one congenital epulis case was reactive (weak reactivity after microwave treatment), and staining with the proliferation markers anti-proliferating cell nuclear antigen and MIB 1 was found only in congenital epulis. Both tumor types exhibited pericellular and diffuse cytoplasmic staining for fibronectin and laminin. CONCLUSIONS: The hypothesis that congenital epulis and granular cell tumor would exhibit similar reactivity for macrophage markers was confirmed: both were reactive with anti-CD68 and Ki M1P and nonreactive with MAC387, anti-lysozyme, and 3A5. Intracytoplasmic staining for fibronectin and laminin, which has not been described previously in these tumors, appears to be a characteristic feature common to both tumors. This finding suggests that there could be a disturbance of synthesis and secretion of extracellular matrix proteins or a derangement of their receptor systems. This theory could be supported by the finding of intracytoplasmic CD49e-positive material in two cases. PMID- 8680978 TI - Heat shock (stress) proteins and gamma delta T lymphocytes in oral lichen planus. AB - OBJECTIVE: Heat shock proteins (Hsps), a highly conserved class of protective cellular proteins that are produced under various conditions of environmental challenge, have been implicated as the antigenic stimulus in autoimmune diseases. Because lichen planus (LP) appears to be an autoimmune or hyperimmune condition (mediated by T cells), Hsps may have a role in the pathogenesis of this disease. We believe that if keratinocyte Hsps are antigenic targets of a cellular immune response, upregulation of these proteins should be demonstrable in tissue sections. STUDY DESIGN: Immunohistochemistry was used to evaluate expression of several families of Hsps in oral lichen planus tissues. The number and distribution of gamma delta T cells, a subset of T lymphocytes with an immune surveillance function that may contribute to autoimmunity, were also evaluated. Monoclonal antibodies to Hsps 27, 60, 70, 90, gamma delta receptor, and CD3 (pan T lymphocyte marker) were incubated with frozen sections of LP (n = 22) and normal oral mucosa (n = 17) followed by an avidin-biotin-peroxidase labeling method. Antibodies to bacterial Hsps (GroEL and DnaK) were used as negative controls, and antibody to constitutive eukaryotic Hsp (Hsc70) was used as a positive control. RESULTS: In six cases of LP, basal keratinocytes stained intensely for Hsp27, whereas controls showed only slight staining. Otherwise LP and normal tissues showed comparable positive staining of upper level keratinocytes with anti-Hsp27. Subjective increases in antibody staining were noted for Hsp60 in LP, which was due in part to staining of infiltrating lymphocytes and in part to keratinocyte expression. Normal tissues showed weak basal cell antibody staining for Hsp60. Hsp70 staining was observed at a less intense level in LP than in controls. Except for more intense basement membrane staining with anti-Hsp90 antibody in gingiva and palate, no differences in the occurrence of this protein were found. Absolute numbers of gamma delta T cells were increased in LP when compared with those in control specimens (n = 10 vs n = 1, respectively, per high-power field). However, gamma delta T cells represented less than 1% of the CD3+ lymphocytes. CONCLUSIONS: It was concluded that normal oral mucosa expresses Hsps 27, 60, 70, and 90 and contains few gamma delta T cells. Although the expression of Hsps was altered in LP, the differences demonstrated were slight and were therefore inconclusive. The Hsps expressed in LP could have contributed to the persistence or chronicity of the disease, or they could have simply reflected cellular injury. PMID- 8680979 TI - Dramatic response to levamisole and low-dose prednisolone in 23 patients with oral lichen planus: a 6-year prospective follow-up study. AB - The purpose of this prospective study was to evaluate the short-term and long term clinical efficacy of levamisole used with low-dose prednisolone in patients with refractory oral lichen planus. Twenty-three patients with OLP who had been treated unsuccessfully with other modalities were given 150 mg/day levamisole and 15 mg/day prednisolone for 3 consecutive days each week. Twelve patients showed dramatic remission of signs and symptoms within 2 weeks, whereas 11 had partial remission. All 23 reported significant pain relief and showed no evidence of erosive oral lichen planus after 4 to 6 weeks of treatment. All 23 also remained free from symptoms for 6 to 9 months after the treatment ended. There were few side effects from this treatment besides minor skin rash, headache, and insomnia from the levamisole in three cases. We conclude that the addition of levamisole to prednisolone may produce improved results in the management of erosive oral lichen planus. PMID- 8680980 TI - Neural elements in dental pulp and dentin. AB - This article addresses the structural and quantitative aspects of human tooth innervation and briefly considers the functions and clinical relevance of tooth axons. The classification of peripheral axons, the pulpal and dentinal innervation, and the theories of dentin sensitivity are discussed. Quantitative studies on tooth innervation are also reviewed. Human premolars receive about 2300 axons at the root-apex of which about 13% are myelinated and 87% are nonmyelinated fibers. Most apical myelinated axons are fast-conducting A delta fibers with their receptive fields located at the pulpal periphery and inner dentin. These fibers are probably activated by a hydrodynamic mechanism and conduct impulses that are perceived as a short well-localized sharp pain. Most C fibers are slow-conducting fine sensory afferents with their receptive fields located in the pulp and transmit impulses that are experienced as dull poorly localized and lingering pain. In addition to the nociceptive alarm signaling, the intradental sensory axons may play a regulatory role in the maintenance and repair of the pulpodentinal complex. PMID- 8680981 TI - Effect of reduced air pressure on dye penetration in standardized voids. AB - OBJECTIVE: This study determined the correlation between the degree of dye penetration in standardized voids to various reduced pressures. STUDY DESIGN: Standardized voids of 0.50 and 0.22 mm in diameter were created in 60 human roots; specimens were divided into five groups. Four groups were subjected to a 2% filtered aqueous methylene blue dye solution under different conditions of atmospheric pressure for 7 days and reduced pressures of a 10 torr, a 260 torr, and a 510 torr for 30 minutes. The conditions for the fifth group were similar to the last group except that ethyl alcohol was substituted for water in the dye. RESULTS: All positive control specimens showed complete dye penetration. The least linear dye penetration was observed in passively immersed specimens. The results were significantly different from those when reduced pressure had been used (p < 0.001). There were no significant differences among the groups with reduced pressure. No significant difference was found at any pressure level between the means of dye diffusion in the 0.50 and the 0.22 mm voids. The smallest standard deviations were observed for the most reduced air pressure of 10 torr, followed by the group of the least reduced pressure of 510 torr, with the use of the tincture dye solution. CONCLUSIONS: A 10-torr reduced pressure and an application of the tincture dye solution would provide an improved method for microleakage studies. PMID- 8680982 TI - Periapical neural changes after pulpectomy. AB - Pulpectomy and pulpal necrosis result in severance of the nerves that supply the pulp as well as loss of their target organ. Inflammatory changes commonly extend into the periapical region to involve those nerves. The neural response to pulpal loss combined with periapical inflammation is a derangement of the periodontal plexus normally located in the center of the periodontal space around the apical third of the root; the result is the formation of a disorganized group of sprouting and branching axons that have some features in common with neuromas. The inflammatory and neural responses continue for at least a year even when pulpectomy is followed by canal debridement and obturation. Then the responses are reduced but not eliminated by steroids. Root canal therapy with techniques that do not leave residual inflammation still results in increased periapical innervation; the increase seems to be an organized addition to the normal periradicular plexus. PMID- 8680983 TI - Temporomandibular joint imaging: a comparative study of diagnostic accuracy for the detection of bone change with biplanar multidirectional tomography and panoramic images. AB - This in vitro investigation compares biplanar (sagittal and coronal) temporomandibular joint images produced by multidirectional tomographic and panoramic techniques for diagnostic accuracy in the detection of simulated degenerative lesions. A series of dentin chips placed at four locations on the head of a temporomandibular joint condyle in a dried human skull were imaged with tomographic and panoramic modalities. Equal numbers of images with and without chips were scored by four examiners with the use of confidence levels for presence or absence of the lesion. To assess intra-examiner reliability, each examiner viewed one of the modalities twice. Responses were assessed by generating receiver operating characteristic curves and analyzing the area (A(z)) under the curves with analysis of variation methods. Biplanar tomography provided significantly more accurate assessment of condylar lesions than biplanar panoramic images (p = 0.007). No statistical difference by location (p = 0.592) was found. The effects of observer and repeated observation were marginally significant at p = 0.046 and p = 0.030, respectively. PMID- 8680984 TI - Radiographic differentiation of osteogenic sarcoma, osteomyelitis, and fibrous dysplasia of the jaws. AB - Biopsy and histopathologic analysis may fail to consistently separate osteogenic sarcoma, osteomyelitis, and fibrous dysplasia. OBJECTIVES: To establish useful radiographic characteristics to differentiate these diseases, an objective preliminary study of radiographs of 30 cases of these diseases was done. STUDY DESIGN: After precisely defining several radiographic characteristics and completing a calibration study, three observers unaware of the diagnosis examined study cases that were randomly ordered. RESULTS: Despite using trained observers and strict criteria, differentiation of the three conditions is difficult on the basis of radiographic features alone. In osteogenic sarcoma, the distinguishing features were: permeative lesion borders, stippled bone pattern, destruction of cortical outlines, perpendicular spiculations of periosteal new bone, destruction of lamina dura, and widening of the entire periodontal ligament space. Presence of sequestra and laminations of periosteal new bone were the most useful distinguishing features in cases of osteomyelitis that otherwise resemble fibrous dysplasia. In fibrous dysplasia, superior displacement of the mandibular canal and a fingerprint bone pattern were pathognomonic. Displacement of the maxillary sinus cortex, alteration of lamina dura to the abnormal bone pattern, and narrowing of the periodontal ligament space were also useful distinguishing features. CONCLUSIONS: Our findings indicate that diagnosis cannot rely on radiographic characteristics alone, although some radiographic findings were more useful than others. PMID- 8680985 TI - Occipital neuralgia manifesting as orofacial pain. AB - This is a case report and brief review of the literature on occipital neuralgia presenting as dental pain. A patient with a chief complaint of long-standing pain in the maxillary right posterior quadrant was evaluated. Dental examination demonstrated the pain was not of odontogenic origin. The patient was referred to a neurologist who was a chronic pain specialist and was diagnosed with a rare neurologic disorder, occipital neuralgia referring to the facial region. After conservative treatment, local nerve blocks, and physical therapy, the patient reported a dramatic improvement of symptoms and total absence of all orofacial pain. The case demonstrates an unusual cause of orofacial pain. PMID- 8680986 TI - Oral mucosal injury caused by denture cleanser tablets: a case report. AB - A case of chemical injury to the oral mucosa that resulted in obstructive sialadenitis of the submandibular glands is presented. The injury occurred when a patient chewed, swished, and expectorated an immersion-type denture-cleansing tablet attempting to clean a fixed bridge. The literature is reviewed for similar oral mucosal injury caused by improper use of denture-cleansing products. Suggestions for the prevention of such injuries are made. PMID- 8680987 TI - Age-related characterization of atrial adenosine A1 receptor activation: direct effects on chronotropic and inotropic function in the Fischer 344 rat. AB - Adenosine, an endogenously produced nucleoside, has direct negative chronotropic and inotropic effects on right and left atrial tissues, respectively. Age-related differences in the effects of A1 adenosine receptor activation on atrial rhythmic and contractile function were investigated in adult (6-8 months) and senescent (23-24 months) Fischer 344 (F344) rats. Senescent right atria (RA) were more sensitive to the negative chronotropic effects of R-phenylisopropyladenosine (R PIA), a selective A1 receptor agonist, than adult RA (EC50: 4.8 +/- 0.7 vs 10.8 +/- 1.5 nM). However, senescent left atria (LA) were 15.4% less responsive to the maximal negative inotropic effects of R-PIA than adult LA. R-PIA did not significantly change resting force from basal values in either age group, but 90% relaxation time was prolonged threefold in senescent LA compared with adults. Radioligand binding experiments with 1,3-[3H]dipropyl-8-cyclopentylxanthine, a selective adenosine A1 receptor antagonist, showed a 56% greater density (Bmax) of adenosine A1 receptor in senescent than adult without differences in affinities (Kd). The increased sensitivity of senescent RA to the negative chronotropic effects of adenosine A1 receptor stimulation suggests a role for adenosine in abnormal sinus node function that occurs more frequently with age. Adenosine A1 receptor stimulation has more effect on relaxation than contraction in senescent LA compared with LA from adult F344 rats. However, the increase in density of adenosine A1 receptors suggests a functional dissociation between the availability of binding sites and receptor activation. PMID- 8680988 TI - Training-induced enhancement of insulin action in human skeletal muscle: the influence of aging. AB - Age-induced reduction of whole body insulin action has been attributed to decreased insulin action in skeletal muscle. Physical training improves insulin action, but the effect has never been investigated specifically in aged human skeletal muscle. Seven young men [age: 23 +/- 1 yr (mean +/- SE; range, 21-24 yr); weight: 70 +/- 1 kg; body fat: 8 +/- 1%] and eight aged men [59 +/- 1 yr (range, 58-64 yr); 83 +/- 2 kg; 20 +/- 2%] performed one-legged bicycle training on a modified ergometer cycle for 10 weeks, 6 days/week, at 70% of VO2 peak. Glucose clearance rates in whole body and leg were measured 16 hr after training by a hyperinsulinemic (28, 88, and 480 mU.min-1.min-2), isoglycemic clamp combined with leg balance technique. Peak oxygen uptake during the bicycle test was always lower (p < .05) in aged vs. young subjects. Furthermore, VO2 peak was higher after training in trained (T) vs. untrained (UT) (p < .05) legs. Whole body glucose clearance rate was lower in aged vs. young subjects (p < .05) when expressed per kg body weight, but similar when expressed relative to fat free mass. Leg blood flow was always lower in aged vs. young men (p < .05). At basal and during insulin infusion, leg blood flow in young men did not differ significantly in T vs. UT legs (maximum insulin: 81 +/- 7 vs. 71 +/- 5 ml.min 1.kg leg-1), while in aged subjects it increased (p < .05) with training (maximum insulin: 57 +/- 5 vs. 48 +/- 5 ml.min-1.kg leg-1). Leg glucose extraction was always higher in aged vs. young men during the two last clamp steps (p < .05). Furthermore, leg glucose extraction was increased by training in young (p < .05) but not significantly in aged subjects. Leg glucose clearance rates increased (p < .05) with training and was similar in aged men (T: 1 +/- 1, 8 +/- 1, 21 +/- 2, and 24 +/- 2; UT: 1 +/- 1, 6 +/- 1, 14 +/- 2, and 20 +/- 2 ml.min-1.kg leg-1) and young men (T: 1 +/- 1, 12 +/- 3, 23 +/- 3, and 26 +/- 3; UT: 1 +/- 1, 8 +/- 2, 17 +/- 2, and 21 +/- 2 ml.min-1.kg leg-1). Therefore, insulin action in muscle is not reduced by aging. At high insulin concentrations, the leg blood flow is lower, whereas glucose extraction is higher in aged compared with young men. Training increases overall insulin action on glucose clearance in skeletal muscle identically in aged and young subjects. PMID- 8680989 TI - Short intertrial intervals impair water maze performance in old Fischer 344 rats. AB - Male and female Fischer 344 rats (N = 55) aged approximately 18, 21, and 24 months were tested for spatial learning in the water maze with intertrial intervals of 1-4 min (Massed) or 23-33 min (Spaced). Animals tested in the Massed condition showed an age-related impairment on trials to criterion; rats aged 24 months performed more poorly than younger subjects. Spaced animals did not differ at any age nor did they differ from 18- or 21-month-old Massed subjects. The youngest rats in both groups were comparable to animals aged 7-8 months tested under Massed conditions. Tests on swim distance, swim speed, and escape latency produced similar results. Our data suggest that acquisition deficits in 24-month old rats tested with long intertrial intervals are due at least in part to increased susceptibility to fatigue and/or thermal stress. Caution should be used, therefore, when interpreting age-related impairments in water maze performance. PMID- 8680990 TI - Longitudinal assessment of the nutritional status of elderly veterans. AB - Elderly persons are at risk for developing malnutrition due to a number of age related factors, and conversely, malnutrition can worsen declining physiological and psychosocial conditions. The purpose of this study was to determine the nutritional status of an elderly, ambulatory outpatient population, and to evaluate change in nutritional status over a 2-year period. The 209 subjects were male veterans, over 65 years of age without acute disease-related nutritional risk factors. Nutrient intake was determined through food recalls and food frequency questionnaires. Anthropometrics included circumferences and skinfolds. Laboratory measures included selected minerals and vitamins, as well as hematological and lipid profiles. Mean intake of nutrients generally met or exceeded the Recommended Dietary Allowances with the exception of calories, although > 25% of subjects consumed inadequate amounts of thiamine, vitamin A, vitamin C, and calcium. Few subjects were found to be extremely underweight or obese, although skinfolds decreased over the two years. Mean laboratory measures were within normal range with the exception of selenium, cholesterol, and low density lipoprotein. Dietary, biochemical, and anthropometric data indicate good nutritional status in general, although dietary vitamin C, vitamin A, and calcium may be poor in subgroups; body fat as assessed by skinfolds appeared to decline; and selenium, lipid profiles, and hematological profiles warrant further investigation. PMID- 8680991 TI - A study of low-nutrient diets used for aging studies in the rat. AB - The effects of diets of low caloric value on rats used in aging studies were investigated. Groups of 85 Sprague-Dawley rats were fed ad libitum from 3 months of age on three different diets containing 8 or 10 Megajoule (MJ) of metabolizable energy and 80 or 100 g of crude protein/kg. Body weights, food consumption, and morphological and biochemical parameters were monitored throughout life. Kidneys were examined histologically. Rats given the diet with highest energy and protein ate less food, attained greater weights, and had larger abdominal fat deposits than those on the lower energy diets. They had a raised proteinuria, and nearly half developed glomerulosclerosis and tubulo interstitial damage by 26 months. There was no significant difference in mortality between the groups, and no other serious abnormalities were observed. It is concluded that rats can be maintained into old age with no signs of nutritional inadequacy on diets with lower energy and protein contents than those in general use. PMID- 8680993 TI - Failure to confirm increased longevity in Drosophila melanogaster submitted to a food restriction procedure. AB - Several studies have shown that, contrary to what occurs in rodents and in some invertebrate species, food restriction has no positive effect on longevity in Drosophila melanogaster. However, Chippindale et al. (1993) reported that flies subjected to food restriction, by modulating the yeast level, could live longer. In the present study we used the same yeast levels as Chippindale et al. in an attempt to confirm these results. No positive effect of food restriction on longevity could be observed in either sex in mated and virgin flies. PMID- 8680992 TI - Reduced immune responses in rhesus monkeys subjected to dietary restriction. AB - Dietary restriction (DR) has emerged as a major paradigm in experimental gerontology. The effects of DR on rodents are numerous and include reduced rates of immunologic aging, delayed morbidity, and increases in longevity. The effects of DR on primate species remain largely unknown. We began a randomized trial of long-term, adult-onset DR in rhesus monkeys (Macaca mulatta) in 1989. This report describes some early differences in immunologic function after two to four years of DR. Peripheral blood mononuclear cells were studied for mitogen-induced proliferation, natural killer (NK) cell lysis, and expression of cell surface antigens. Antibody response to influenza vaccine and the number of peripheral blood lymphocytes were also measured. Unexpectedly, concanavalin A and pokeweed mitogen response measures were reduced in restricted monkeys compared to controls (p < or = .01). NK activity and antibody responses were also reduced (p < .05). Neither cell surface antigens nor peripheral blood lymphocyte counts appear affected by DR thus far. PMID- 8680994 TI - Selection for longevity favors stringent metabolic control in Drosophila melanogaster. AB - Models of the evolution of life span predict, and gerontological studies show, a relation between nutrient use and life span. This study examines the role and comparative use of nutrients in long- and short-lived populations of D. melanogaster selectively bred for age-at-reproduction, without respect to metabolism or feeding rate. We test the hypotheses that selection for life span has favored the restriction of nutrient use and that the observed effect of low population density during development is a consequence of modifying nutrient use. The use of nutrients was measured here by the uptake of radiolabeled glucose, its incorporation into lipid and protein, and by the in vivo metabolic flux through the pentose shunt. Measurements show that uptake, incorporation, and flux are severely limited in long-lived stocks, compared to short-lived populations of the same stage and stage of development. Raising long-lived stocks at low population numbers relieves the restriction on metabolism in larvae, increasing incorporation and flux, and causes adult life span to decline. Larvae of long lived populations appear to feed less actively, suggesting that the reduction in use of nutrients could simply be from reduced intake. Changes in total soluble protein correspond with measurements of uptake, incorporation, and flux. Soluble protein is substantially less in long-lived stocks, before pupation, but catches up in early adulthood to that in the short-lived populations. Despite different nutrient use by larval populations, only slight differences are found in development rate. They are insufficient to account for the differences observed in longevity. PMID- 8680995 TI - Accelerated senile amyloidosis induced by amyloidogenic Apoa-II gene shortens the life span of mice but does not accelerate the rate of senescence. AB - The SAMP1 strain is a mouse model for accelerated senescence and severe senile amyloidosis. We studied the effects of the amyloidogenic apolipoprotein A-II gene (Apoa2c) on senile amyloidosis and the life span and progress of senescence of congenic mice (R1.P1-Apoa2c) which have Apoa2c of the SAMPI strain on the genome of the normally aging SAMR1 strain. Age-associated and severe amyloid deposits were detected in R1.P1-Apoa2c, as well as a 20% shorter life span than that of SAMR1. The scores of senescence increased more rapidly with age in R1.P1-Apoa2c than that of SAMR1, and the Gompertz function showed a bigger Y intercept but the same slope of regression line. These results suggest that severe senile amyloidosis induced by the Apoa2c gene shortens the life span of mice but does not accelerate the rate of senescence. PMID- 8680996 TI - The 6-minute walk as an appropriate exercise test in elderly patients with chronic heart failure. AB - BACKGROUND: The value of the 6-minute walk in a population of elderly patients with chronic heart failure (CHF) has not yet been established, as it has been in a younger population. METHODS: In a prospective trial, 2 exercise tests were compared: the 6-minute walk (6 MW) and a treadmill test with progressive increments in workload. 37 patients (mean age 81.3, SD 5.6 years): 11 untrained controls, 16 patients with New York Heart Association (NYHA) class II and 10 patients with NYHA class III participated. The main outcome measures were the distance walked in 6 minutes, the symptomatic VO2max in the progressive treadmill test and the degree of CHF as scored by the NYHA classification and the Boston Study Group (BSG) score. RESULTS: For both the 6 MW and the treadmill test there was a significant difference in distance between NYHA class II and III patients (p < .001), between the controls and NYHA class III patients (p < .001), but not between the controls and NYHA class II patients. The distance walked in the 6 MW was well correlated with the distance walked in the treadmill test (p < .001). Eight participants (22%), however, were unable to perform this treadmill test and 6 participants (17%) covered very low distances compared to the 6 MW. The VO2max was lower in NYHA class III than in class II patients (p = .032). NYHA classification and BSG score correlated reasonably well. CONCLUSION: A treadmill exercise test with VO2max measurement in elderly patients with CHF is difficult to accomplish. On the contrary, the 6 MW gives a good impression of the remaining exercise capacity. It is well correlated with the treadmill test. The 6 MW is well tolerated by elderly patients and differentiates between NYHA classes II and III. Untrained controls could not be differentiated from NYHA class II patients. PMID- 8680997 TI - Prognostic factors for functional outcome of total knee replacement: a prospective study. AB - BACKGROUND: The objective was to investigate whether baseline physical functioning, medical, psychosocial, or demographic variables predict functional outcome in patients undergoing total knee replacement. METHODS: A prospective cohort study was performed between December 1991 and August 1993. Consecutive, unilateral tricompartmental total knee replacement patients aged > or = 55 yr with osteoarthritis, who met criteria, were enrolled and evaluated one month before and 3 months after total knee replacement. The primary outcome measure was the Medical Outcome Study 36 Item Short Form Health Survey (known as the SF36) Physical Functioning Scale score. The outcome evaluator was not involved in patient care. RESULTS: A hierarchical multiple regression analysis was performed to calculate the contribution of baseline variables to TKR outcome. Of the 27% of outcome variance explained by the model, demographic variables accounted for 4%, psychosocial variables (motivation, role functioning-emotional, and social functioning) for 19% (p = .013), medical variables (previous reconstruction, comorbidity, body mass index, bodily pain) for 2%, and baseline physical function for 2%. CONCLUSIONS: Psychosocial variables are significantly related to total knee replacement functional outcome. Assessment of baseline psychological and social functioning may identify a subset of patients at risk for worse outcome. Specific interventions for these patients should be developed and evaluated as components of patient management prior to and after the procedure. PMID- 8680998 TI - The predictors of surgical procedure and the effects on functional recovery in elderly with subcapital fractures. AB - BACKGROUND: It has been demonstrated that the majority of hip fracture patients do not regain their prefracture level of functioning and usually decline in function following fracture. Little is known about the effectiveness of surgical procedure performed (hemiarthroplasty vs internal fixation) on functional recovery of subcapital fracture patients. This study examines the factors related to the type of the surgical procedure chosen and the effect of this selection on physical activities of daily living (PADL) and instrumental activities of daily living (IADL). METHODS: The sample consists of 312 patients with subcapital fractures age 65 and older admitted from the community to one of seven Baltimore area hospitals between 1984 and 1986. Baseline information was obtained during hospitalization through structured interviews with both patients and their significant others (proxy). The follow-up interviews were administered to proxies at two months, six months, and one year after discharge from hospital. Information on disease diagnoses, fracture severity, and surgical procedures performed was obtained from medical charts. RESULTS: Patients with a displaced fracture were seven times more likely to receive a hemiarthroplasty (OR = 7.0, 95% CI 3.7-13.1). During the short-term recovery (2 months after surgery), patients who received hemiarthroplasty were doing better in transferring, meal preparation, and shopping than those who received internal fixation. For the long term functional recovery (one year), the overall PADL and IADL functions were not statistically significantly different between the two surgical procedures performed. CONCLUSIONS: The severity of fracture was found to be the most important determinant of surgical procedure. Patients with a subcapital fracture who received hemiarthroplasty tended to have a better functional recovery in the short term. Further study of other benefits of using as hemiarthroplasty is needed. PMID- 8680999 TI - Relative heart rate, heart rate reserve, and VO2 during submaximal exercise in the elderly. AB - BACKGROUND: The purpose of this study was to examine the relationships among relative maximal heart rate (%HRmax), maximal heart rate reserve (%HRmax reserve), and maximal oxygen uptake (%VO2max) during submaximal exercise by elderly subjects. METHODS: VO2max and HRmax were determined on 36 women and 19 men, 60 to 80 yrs of age, by a maximal treadmill test to volitional exhaustion. On a separate day, subjects underwent a submaximal treadmill protocol consisting of three 6-min exercise stages at treadmill speeds and grades estimated to elicit 40%, 60%, and 80% of HRmax reserve. Cardiorespiratory responses were determined during mins 4-5 and 5-6 of each stage. RESULTS: Measured exercise intensities expressed by the three methods were: %HRmax reserve = 36, 55, and 79%; %HRmax = 65, 75, and 88%; %VO2max = 53, 69, and 88%. %HRmax was greater (p < .05) than %VO2max at 53 and 69% of VO2max. %HRmax reserve was less (p < .05) than %VO2max for all three intensities. Slopes and intercepts for the linear regression equations relating %VO2max with %HRmax and with %HRmax reserve differed between men and women (p < .05). The regression equation relating %VO2max and %HRmax was y = -22.8 + 1.2 (%HRmax) -13.0 (Gender) + 0.2 (%HRmax x Gender): standard error of the estimate (SEE) = 9.7% and R2 = .71. The regression equation relating %VO2max and %HRmax reserve was y = 32.4 + 0.7 (%HRmax reserve) -10.9 (Gender) + 0.2 (%HRmax reserve x Gender): SEE = 9.8% and R2 = .70 (Gender: F = 0; M = 1). CONCLUSIONS: The data indicate that there is considerable variability among methods of expressing exercise intensity and that %HRmax more closely represents %VO2max than does %HRmax reserve (p < .05) in older adults. These results are in contrast to what has been shown with younger subjects and with American College of Sports Medicine guidelines for exercise prescription. PMID- 8681000 TI - Effectiveness of a psychosocial intervention, interpersonal counseling, for subdysthymic depression in medically ill elderly. AB - BACKGROUND: Subdysthymic depression occurs in 20-50% of hospitalized elderly and is associated with physical and social disability, delayed recovery, and excess health service use. Despite this, little is known regarding the nature of such depressive symptomatology, or its responsivity to treatment. To address this, a randomized clinical trial assessing the feasibility and efficacy of Interpersonal Counseling (IPC), a short-term psychotherapy, was conducted. METHODS: Patients 60+ with a Geriatric Depression Scale (GDS) score > 10 not meeting DSM-III-R criteria for major depression or dysthymia were recruited from the acute hospital. Thirty-five individuals were randomized to IPC and 41 to usual care (UC). IPC was delivered following hospital discharge by psychiatric clinical nurse specialists. Interviews were conducted at recruitment and 3, 6, and 12 months later. Primary outcomes were GDS scores, health ratings, and measures of physical and social functioning. RESULTS: At 3 months, IPC group members showed greater improvement than UC members on all outcome variables; between-group differences did not reach statistical significance. At 6 months, a statistically significant difference in the rate of improvement in GDS, indicated by scores of 10 or less, was observed for IPC compared to UC members (60.6% vs 35.1%). Multivariate analyses confirmed a positive treatment effect on depressive symptoms. Similar multivariate analyses showed a statistically significant positive treatment effect on self-rated health but not on physical or social functioning. CONCLUSIONS: IPC appears feasible, acceptable, and effective in short-term depressive symptom reduction and in improvement in self-rated health. Implementation of IPC interventions for subdysthymic hospitalized elderly is recommended. PMID- 8681001 TI - Application of a growth curve approach to modeling the progression of Alzheimer's disease. AB - BACKGROUND: Studies using clinical measures to track AD progression often assume linear declines over the entire course of the disease, which may not be justified. The objective of this study was to model change in measures of the clinical severity of Alzheimer's disease (AD) over time. METHODS: We developed a method to apply growth curve models to prospective data and characterize AD patients' functional change over time. Data from the modified Mini-Mental State Examination (mMMSE) and measures of basic and instrumental ADL, administered semiannually for up to 5 years to 236 patients with probable AD, were modeled. RESULTS: The rate of decline in mMMS scores per 6-month interval gradually increased as scores dropped from the maximum of 57 to 20. The rate of decline then decreased as scores approached 0, resulting in an inverse "S" curve. The rate of increase in instrumental ADL scores per interval attenuated as the scores increased, while that for basic ADL scores across intervals was constant. CONCLUSIONS: Differences in the pattern of progression of the three measures is in part a function of their psychometric properties. The progression curves may also reflect content-specific features of the instruments. Superimposition of the modeled decline in these three content areas suggests a hypothetical model of the relative timing of cognitive and functional changes in AD. PMID- 8681002 TI - Utility of Mini-Mental State Exam scores in predicting functional impairment among white and African American dementia patients. AB - BACKGROUND: The Mini-Mental State Exam (MMSE) is widely used to assess cognitive impairment. Although education and race have been shown to affect the validity of the MMSE in detecting dementia, whether race and education influence the validity of the MMSE in gauging severity of dementia is unknown. METHODS: Patients diagnosed with Alzheimer's and other dementias (59 African American, 112 White) were administered the MMSE, and information was gathered on patient functional impairment, including Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), and the Memory and Behavior Problems Checklist (MBPC). Demographic information, including patient and caregiver education, and patient age, was also assessed. RESULTS: African American and White patients did not differ significantly on the MMSE or functional impairment variables, but White patients had higher educational attainment. Hierarchical multiple regression analysis showed that race and education did not predict functional impairment, and MMSE scores were strong predictors of ADL and IADL levels for both African American and White patients. MMSE predicted variability in MBPC scores for White patients only, perhaps related to racial differences in subjective caregiver report of behavioral problems. CONCLUSIONS: While race and education may affect the validity of the MMSE in detecting the presence of cognitive impairment, the MMSE can be a useful predictor of degree of ADL and IADL impairment in patients diagnosed with dementia, regardless of race. PMID- 8681003 TI - What can functional imaging do for cardiology? PMID- 8681004 TI - In vivo assessment of neurotransmitter system in cardiovascular diseases. Clinical issues. AB - Cardiac neurotransmitter systems, especially the adrenergic receptor pathway, are impaired in heart diseases. In patients with heart failure, these abnormalities contribute to arrhythmogenesis and to progression of cardiac dysfunction. The use of MIBG with single photon imaging has provided useful information on the mechanisms of ventricular arrhythmias, and on the causes of death in patients with heart failure or hypertrophic cardiomyopathy. It has been suggested as a prognostic indicator in patients with heart failure. Positron Emission Tomography (PET) now allows us to obtain noninvasively the quantitative determination of regional receptor density and affinity in humans as well as innervation integrity and functioning. These measurements are based upon the synthesis of a radioligand, usually either a selective receptor antagonist or a false neurotransmitter labeled with a positron-emitting radioisotope. Mathematical compartmental models are fitted to activity-versus-time curves obtained during saturation or displacement experiments in order to calculate the rate constants and the receptor density in the myocardium. PET has only recently begun to be applied to the study of cardiac physiology and disease. PET and SPECT cardiac neuroimaging techniques are able to demonstrate the physiological regulation of receptors, and to provide the possibility of studying regional abnormalities of cardiac neurotransmission, especially in arrhythmogenic cardiomyopathy. Furthermore these non invasive techniques could be useful in exploring the alteration of neurotransmission in the early stage of heart disease and could allow repeated scintigraphic examinations in order to evaluate the effects of cardiac medications. PMID- 8681005 TI - Tracers and contrast agents in cardiovascular imaging: present and future. AB - This brief article addresses the current status and future potential of nuclear medicine, X-ray computed tomography (CT), ultrasound (US), and magnetic resonance (MR) imaging in the diagnosis of cardiovascular diseases. The currently perceived advantages and disadvantages, as well as the possible future roles, of each of the modalities with regard to the evaluation of coronary artery disease are delineated. The certain advent of MR and US myocardial contrast agents, combined with the inexorable pressures of health care reform, will alter the future usage patterns of all four modalities. Future debates about which modality should be used in which clinical situation will be based not on "anatomy vs function", nor on which specialty owns which "turf", but rather on the issues of cost effectiveness and patient outcomes. PMID- 8681006 TI - Nuclear medicine techniques and magnetic resonance imaging in coronary artery disease. AB - Primary modalities for non-invasive imaging of coronary artery disease (CAD) and related disorders include nuclear medicine techniques and magnetic resonance imaging (MRI). Nuclear medicine has contributed greatly to the diagnosis of CAD and the assessment of the extent of functional abnormalities. Thallium-201 has a long history as a perfusion agent and is currently also used to study myocardial viability. Developments in radiopharmaceutical chemistry has provided us with 99mTc-labelled agents with better counting statistics and qualities for SPECT imaging. Other radiopharmaceuticals allow insight in metabolic disorders, hypoxia and disturbance of the adrenergic system of the myocardium. MRI has many unique applications in cardiovascular diseases. This imaging technique provides excellent structural information and, during ECG triggering, fine display of left ventricular function. Current development using intravascular contrast agents will soon lead to the possibility to evaluate myocardial perfusion. Improved techniques to evaluate coronary artery anatomy and flow are currently under clinical study. Although cardiac MRI is an exciting new tool with great potential for the diagnosis of CAD it is presently not considered a valid alternative for nuclear medicine imaging techniques. Important developments in the next lustrum may change this view. PMID- 8681007 TI - Registration of multi-modal biomedical images of the heart. AB - Integration of multi-modal biomedical images of the heart (PET, SPET, MRI, Echocardiography) is a diagnostic procedure of increasing interest. Different registration techniques can be used to spatially correlate two independent tomographic scans of the same patient, each technique presenting relative merits and limitations. Integration of cardiac with respect to neurological images is difficult, because the heart is a non-rigid and moving organ. The experiences of this approach of integrated diagnosis are thus limited to date. However, registration of PET, SPET, MRI, Echocardiographic images has been described with accuracy considered acceptable for clinical applications. Registration techniques for the integration of multi-modal biomedical images of the heart, the clinical applications of cardiac image fusion and the experiences reported in the literature are presented in this paper. PMID- 8681008 TI - Old tools for sophisticated diagnosis: electrocardiography for the assessment of myocardial viability. AB - The identification of residual myocardial viability in patients with a previous myocardial infarction has important clinical implications. Various methods have been developed for the detection of viable myocardium, however most of them are expensive and available only to high-tech centers. In the attempt to obtain reliable information at a low cost, exercise-ECG has been proposed as a useful technique. The results of a series of studies show that ST segment elevation and ventricular arrhythmias elicited by exercise are reliable signs of the presence of reversible myocardial damage. PMID- 8681009 TI - Myocardial perfusion imaging: perspectives from a turbulent twenty-five years. AB - It is almost twenty-five years since stress myocardial perfusion imaging was first described for the detection of ischemia. Since that time, significant refinements have occurred in the technology of making the measurements, and in the range of clinical indications to perform these measurements. In parallel with the growth of radionuclide techniques, other imaging technologies have developed substantial tools to examine the heart. Although radionuclide imaging remains unique in its ability to visualize the regional distribution of perfusion, the value of perfusion imaging is being called into question by practitioners of the competing technologies. To address these comments, every facet of the examination should be reviewed, and the examination tailored to answer the specific clinical question raised by the patients condition. Particular attention should be paid to data interpretation and the specific choice of words used to describe the images in the report. In addition, the information provided by the examination can be enriched by adding measurements of ejection fraction, regional wall motion and regional wall thickening to the procedure. This combination of additional data and a clear, clinically focussed report make the information more valuable to the referring clinician. Several new techniques are on the horizon, including 99mTc glucarate imaging, to identify acute myocardial necrosis, and direct identification of myocardial hypoxia with 99mTc labeled nitroimidazoles. Initial studies in humans with glucarate suggest that acute necrosis can be identified with one hour of onset of chest pain. Experimental studies with the nitroimidazoles suggest that they will be valuable to identify myocardial ischemia as a zone of increased uptake. Both techniques may be useful in the evaluation of patients presenting with chest pain syndromes in the emergency room. Other areas of potential promise include the possibility of detecting residual clots following thrombolytic therapy and identifying macrophages in unstable plaque. PMID- 8681010 TI - Comparison of nuclear cardiology in the United States and Europe. AB - Nuclear Cardiology is widely available and a widely accepted tool for diagnosis and management of coronary artery disease both in the US and in Europe. Although the most common indications for nuclear studies are similar in the US and Europe, different social and economical environments may affect the practice of Nuclear Cardiology. The aim of this paper is to identify key issues and to provide some information on the similarities and differences which characterize the practice of Nuclear Cardiology in the US and Europe. This paper takes into account the training requirements, the relationships between different professional societies, the accessibility, the choice of imaging protocols, tracers and stressors, the impact of managed care and the role of cardiologists, nuclear physicians and technologists in nuclear labs. The economical differences which may affect the field of high technology, imply a wide range of variability concerning the availability of nuclear cardiology studies in different countries (1:1/10). Moreover the legislation which regulates the practice of nuclear medicine may differ from country to country. Thus in our opinion there are several important factors both in the US and Europe limiting the development of nuclear cardiology independently of its intrinsic clinical value. PMID- 8681011 TI - Statistical, epidemiological and fiscal issues in the evaluation of patients with coronary artery disease. AB - The application of myocardial perfusion scintigraphy to patient care in the era of health care cost containment is a difficult issue. The traditional diagnosis based approach to testing, although effective, is incompletely applied, as evidenced by the number of low likelihood of coronary artery disease patients referred for testing. A prognosis- or risk-based testing approach may be applied to both patients with or without known coronary artery disease by utilizing clinical and scan information to estimate the projected risk of adverse outcomes (cardiac death or myocardial infarction) and planning subsequent patient strategy based upon this estimate. Patients at high risk for these events are more likely to benefit from referral to catheterization while those patients at lower risk may benefit from medical therapy alone. Irrespective of the approach utilized to evaluate testing, consideration of patient population selection and its implications must be considered when reviewing the results of testing or published literature. Further, scrutiny of both the statistical methods used for evaluation of the value of testing and the economic implications of testing in particular patient subgroups are of importance. PMID- 8681012 TI - Expanding concepts in ischaemic heart disease: implications for clinical practice and research. AB - In the late Eighties, a series of observations from several institutions around the world has dramatically revolutionized the traditional notion that the occurrence of myocardial infarction was related most of the time to the development of critical flow-limiting coronary stenosis. All these studies showed that the infarct-related artery had only minimal or mild stenosis in about two thirds of the cases. Therefore, contrary to our previous beliefs, in clinical practice the detection of coronary stenosis has a lesser role in the prognostic assessment of patients with ischaemic heart disease, unless associated with extensive ischemia or with phases of instability. In fact, the major determinants of prognosis are represented by age, left ventricular function, effort tolerance and especially by the clinical stability or instability of angina. According to the Bayesian an theorem, in low risk patients any diagnostic test has a very low predictive accuracy, unless very high specificity criteria are used. The value of diagnostic tests in the assessment of patients' prognosis should be evaluated in intermediate risk groups. The emphasis of clinical research has, therefore, shifted from the detection of flow-limiting stenosis to the study of the multiple and varied dynamic causes of stable and unstable ischaemia, where the possibilities of making new, seminal observations are greater. PMID- 8681013 TI - Evaluating the benefits of nuclear cardiology. AB - This paper reviews the role of nuclear cardiology in the context of health care evaluation and resource utilisation. Nuclear cardiology procedures are used to detect disease, to define the extent of disease, to predict the outcome of therapy and to monitor the response to treatment. The evaluation of the effectiveness will depend on the role for which the tests are being used. The evaluation of diagnostic tests most commonly follows the five level Fineberg classification. I) Technical capacity; II) diagnostic accuracy; III) diagnostic impact; IV) therapeutic impact; V) patient outcome. Tests may succeed or fail at each of these hierarchical levels. In addition to the clinical impact which is evaluated, the appropriate use of health care resources has to be considered, i.e. the cost effectiveness of the investigation. For this the costs of diagnosis and treatment in the resources used, together with the direct cost on the patient and patient carers needs to be considered. In addition to these direct costs to the community and to the patient and the carers the secondary downstream costs and opportunity costs have to be taken into account. The common methods for assessing the costs and benefits include cost minimalisation, cost effectiveness, cost utility, and cost benefit studies. The advantages and disadvantages and appropriate use of these methods are reviewed. There are seven clinical methods for evaluating diagnostic tests in nuclear cardiology which are: I) case reports; II) consensus studies; III) databases; IV) case control studies; V) modeling techniques; VI) management impact studies; VII) randomised control trial. Each of these has a role with advantages and disadvantages which are reviewed. It is no long sufficient to investigate the usefulness of a diagnostic test used in nuclear cardiology in isolation but it has to be within the context of the health care system and the resources used. PMID- 8681014 TI - Assessment of myocardial perfusion and metabolism for assessment of myocardial viability. AB - Identifying preserved myocardial viability in the presence of severe regional left ventricular dysfunction is becoming increasingly more important for clinical decision-making to better select those patients with coronary artery disease who will benefit most from revascularization. 201Tl remains the most commonly employed radionuclide for detecting both ischemia and viability. A post-exercise defect showing complete or partial redistribution on delayed images implies transient ischemia and preserved viability with a 90% chance of exhibiting improved 201Tl uptake with repeat testing after coronary revascularization. Mild persistent defects with < 50% 201Tl uptake on 4-hour redistribution images also imply viability with a 60-70% probability of showing improved 201Tl uptake after repeat imaging following revascularization with concomitant enhancement of regional systolic function. In contrast, a severe persistent defect with < 50% 201Tl uptake compared to peak uptake has only a 15% chance of exhibiting improved perfusion and corresponding improved function after revascularization. Detection of defect reversibility on 201Tl imaging is enhanced by "reinjection" of a second 201Tl dose after acquisition of redistribution images. Initial and 4-hour rest/redistribution imaging has proven most useful for detection of viability in the resting state in patients with ischemic cardiomyopathy. The greater the extent of preoperative viability, the greater is the improvement in regional and global function after revascularization. 99mTc sestamibi has also been demonstrated to be extracted by myocardial cells in proportion to regional blood flow in the presence of viable myocites. Although this agent does not redistribute after intravenous injection, its > 50% uptake of the tracer implies viability and predicts improved regional function after revascularization. Finally, positron emission tomography with 18F fluorodeoxyglucose (FDG) is perhaps the most sensitive noninvasive imaging technique for detection of viability in stunned or hibernating myocardium. A mismatch pattern between regional flow and FDG uptake has approximately an 80-85% positive predicted value for predicting improved function in asynergic myocardial regions after revascularization. A match pattern where flow and FDG uptake are both reduced has an 80% negative predicted value for lack of functional recovery after revascularization. PMID- 8681015 TI - Detection of myocardial viability with 99mTc-labelled myocardial perfusion agents. AB - Detection of myocardial viability is an important clinical issue in the time course of acute myocardial infarction and in chronic coronary artery disease. The wide availability of myocardial revascularization procedures requires a refinement of specific indications for revascularization whenever left ventricular failure is the most prominent feature of coronary artery disease. In this instance the risk/benefit ratio has to be attentively evaluated with diagnostic tests able to predict favourable changes in regional and global left ventricular function, symptoms, life quality, risk of adverse events and ultimately prognosis. 201Tl has been shown to provide clinically televant information regarding the presence of myocardial viability in patients with extensive regional or global ventricular dysfunction. However, the increasing use of 99mTc labeled myocardial perfusion agents requires a careful evaluation of diagnostic and predictive accuracy of these agents also for the issue of myocardial viability. The widely accepted opinion of a lower predictive accuracy of these agents compared to 201Tl could be no longer true. The available clinical and experimental data indicate, at least for 99mTc-sestamibi, a comparable accuracy when independent and clinically relevant gold standard of viability like post-revascularization functional recovery is considered. Preliminary data indicate that protocols, like nitrate administration, slow infusion or delayed imaging, and accurate quantitation of 99mTc-sestamibi SPECT studies could enhance the predictive accuracy to a level comparable or even better than that of 201Tl and similar to the more demanding PET technology. PMID- 8681016 TI - Quantitative assessment of myocardial perfusion: is it of clinical relevance? AB - Positron emission tomography provides unique qualitative and quantitative information on myocardial perfusion, metabolism and membrane function which potentially has an important impact on diagnostic workup and treatment in patients with known or suspected coronary artery disease (CAD). CAD contributes up to one third of all deaths among persons between the ages of 35 to 60 in western countries. Risk factors and symptoms turned out to have low specificity to identify persons with the disease and thus, will not help to establish objective diagnostic workup. Assessing severity of CAD by coronary angiography and means of binary classification (disease yes/no) of morphological abnormalities, i.e. stenosis > 50%, has shown to poorly correlate with coronary blood flow and, thus, might not serve as an optimal reference standard for the disease. Cardiac PET using N-13 ammonia and Rb-82 represents a well validated and clinically usable technique for both quantitative and qualitative (semiquantitative) assessment of myocardial blood flow. However, the clinical benefit of absolute flow values for diagnosis and localisation of CAD remains controversial. Most centers rely on qualitative image interpretation due to the technical requirements for image processing needed for determination of absolute flow values. However, quantitative assessment of myocardial blood flow might offer advantages when measurement of coronary flow reserve in response to medical or interventional therapy is necessary and in addition may provide early detection of CAD in asymptomatic patients who have risk factors. PMID- 8681017 TI - Thallium imaging in management of post-revascularization patients. AB - The role of myocardial perfusion imaging in the evaluation of post revascularization patients has not been well defined. Published data with special emphasis on the results from the Emory Angioplasty versus Surgery Trial (EAST) indicate that the frequency of adverse cardiac events (death, MI, repeat revascularization) following PTCA or CABG is equal in symptomatic and asymptomatic patients with ischemic thallium defects. Current American Heart Association Guidelines recommend radionuclide studies only in symptomatic patients. Recently reported data support the need for non invasive testing in asymptomatic as well as symptomatic patients at 1 year post-revascularization. Prognostic variables including transient and permanent left ventricular dilatation and thallium lung uptake in addition to stress perfusion defect reversibility on myocardial thallium SPECT scans are important prognostic indicators in post revascularization patients. PMID- 8681018 TI - The role of coronary microvascular dysfunction in the genesis of cardiovascular diseases. AB - Positron emission tomography (PET) offers the unique capability of measuring specific flow (flow per unit of mass) in man by means of a regional, tridimensional, noninvasive approach. Using PET, myocardial perfusion abnormalities secondary to microvascular disorders have been investigated in arterial hypertension (AH), dilated and hypertrophic cardiomyopathy (CM), as well as in ischemic heart disease (CAD). In AH, regional perfusion at rest is within the normal range, while the coronary reserve and flow response to increase in metabolic demand are blunted. These flow abnormalities are independent of the degree of cardiac hypertrophy and the severity of AH; appropriate anti ipertensive therapy is able to improve the perfusion abnormalities after long term treatment, independently of the effect on myocardial hypertrophy. Both dilated and hypertrophic CM demonstrate abnormal vasodilating capability, which has been shown to be present in the subclinical form of dilated DM; the reduction of coronary reserve is not related to the presence and extent of the hemodynamic impairment in dilated CM, and involves also nonhypertropied myocardium in asymmetric hypertrophic CM. These findings indicate a primary involvement of coronary microcirculation in non advanced forms of dilated and hypertrophic CM. Finally, in patients with CAD, myocardial territories supplied by angiographically normal coronary arteries show abnormal coronary reserve and flow during pacing tachycardia, indicating that, even in absence of epicardial coronary artery obstruction, microcirculation is impaired in subjects with coronary atherosclerosis. This abnormality can smooth perfusion differences between control and jeopardized regions. Accordingly, the absence of a perfusion defect during stress might indicate the presence of either a non significant stenosis or a diffuse impairment in microcirculatory function. Nuclear perfusion imaging with conventional perfusion tracers does not allow measurements of absolute blood flow, rather it provides an estimation of perfusion inhomogeneities. Although the agreement with the angiographic documentation of coronary artery disease has been frequently considered to characterize the diagnostic reliability of these techniques, the evaluation of myocardial perfusion provides an independent tool for the functional assessment of patient with heart disease. The possibility to obtain measurements of regional myocardial blood flow, provided by positron emission tomography, helps to identify the mechanisms affecting flow regulation in the myocardium. This tool thus provides a new rationale for the application of perfusion imaging, to obtain a more precise characterization of these patients, beyond the agreement with the morphological angiographic picture. PMID- 8681019 TI - Nuclear cardiology and echocardiography for the assessment of myocardial viability. AB - The review aims to make a comparative analysis of the nuclear cardiology and echocardiographic approaches for the assessment of myocardial viability on the basis of the most recent literature. Preliminarily the most extensively used methods are described: 1) metabolic tracers, especially as regards FDG-F18 (quantitative uptake; mismatch FDG uptake/perfusion); 2) sarcolemmal integrity tracers (201Tl- with stress-redistribution-reinjection or with rest redistribution protocols; rest MIBI 99mTc); 3) low dose dobutamine stress echocardiography (LDDSE) for the detection of residual contractility reserve. Global sensitivity values of thallium studies are reported to be similar to those of LDDSE, but in selected patients populations with akinetic or severely hypokinetic segments the LDDSE sensitivity seems to be significantly lower, when metabolic viability assessed by FDG studies is assumed as gold standard. According to the Authors' opinion thallium study with a protocol including a rest injestion can be considered at the moment the first choice for myocardial viability assessment because of its convenience, reproducibility, possibility of technical and interpretative standardization, amount of clinical and experimental validations. Anyway further clinical trials with adequate follow-up are necessary in order to define the scintigraphic and echocardiographic patterns that provide the best accuracy in the prediction of the post-revascularization clinical outcome. PMID- 8681020 TI - [Malignancy in autoimmune diseases]. AB - Association between antecedent autoimmune diseases and malignancy, including lympho-proliferative disorders (LPD), has been reported in generalized autoimmune diseases such as systemic lupus erythematosus (SLE), dermatomyositis (DM) and rheumatoid arthritis (RA), and also in organ-specific autoimmune diseases such as Sjogren's syndrome (SS) and chronic thyroiditis. In this paper, LPD were summarized for DM, SLE, RA and SS, and some etiologic factors were considered. In surveying previous Japanese literature on the topic, it was revealed that LPD occur frequently in DM similar to various types of cancer. The period between the occurrence of cancer and DM is usually within 12 months, suggesting that the etiologic factor may differ between cancer and LPD in DM. Sixty one cases (20.0%) of monoclonal non-malignant LPD were observed among our 306 patients with SS. Fifteen cases (5.0%) of malignant LPD such as malignant lymphomas (13 cases) and Waldenstrom's macroglobulinemias (2 cases) were also seen among our SS patients. The activation of rheumatoid factor genes such as Humkv 325 and Vg was considered as one of the triggering factors to advance LPD from the benign to malignant state. A high amount of the bcl-2 protein expression was detected in lymphoepithelial lesions of salivary glands in patients with SS, suggesting that the activation of this gene plays an important role in the progression of the lesion from benign to malignant LPD. Accumulation of many genetic abnormalities including bcl-2 and p 53 genes by chronic stimulation of T and B cells at the site of the autoimmune reaction may be important in the high occurrence of LPD in patients with autoimmune diseases. PMID- 8681021 TI - [A case of Takayasu arteritis diagnosed by magnetic resonance imaging]. AB - We report a case of Takayasu arteritis. A woman, 24 years old, was admitted because of fever of unknown etiology. Infection was ruled out. Bruit and asymmetrical pulsation were not found. Ga-scintigram showed abnormal uptake in her upper abdomen. Abdominal echogram revealed neither evidence of abscess nor lymphadenopathy. On abdominal computed tomography, a wall thickening of the abdominal aorta was revealed. In addition, abdominal magnetic resonance imaging(MRI) showed a wall thickening and an enhanced image by gadrinium enhancement. Although we could not carry out conventional aortography because of an allergy to lidocaine, she was diagnosed as having Takayasu arteritis. In response to steroid therapy, the fever promptly dropped and the data indicating inflammation were improved. On the MRI examination after 40 days of steroid therapy, the wall thickening of the abdominal aorta was found to be less prominent. We conclude magnetic resonance imaging is useful for diagnosis and follow-up of early and acute stage of Takayasu arteritis. PMID- 8681022 TI - [Mucin antigen gene and host immune response]. PMID- 8681023 TI - [The IgA immune system for mucosal vaccine: role of levels one and two Th2 cytokine producing T cells]. PMID- 8681024 TI - [In situ PCR: its applications and problems]. PMID- 8681025 TI - [Recent findings on antigens reactive to antiphospholipid antibodies]. PMID- 8681026 TI - [The role of p21ras oncoprotein in signal transduction mediated through B cell antigen receptor (BCR)]. AB - Ligation of B cell antigen receptor (BCR) with antigen or anti IgM leads to enter cells into the proliferation and differentiation to produce specific Ig. Protein tyrosine kinase (PTK) and CD 45 protein tyrosine phosphatase (PTP) both are involved in the early phase of BCR-mediated B cell signaling. We have investigated the role of p 21ras(ras) in B cell signal transduction using TNP specific TA3 7.9 murine B cells. B cell stimulation with either TNP6-OVA(Ag) or anti-IgM resulted in rapid accumulation of GTP-bound(active) ras as well as induction of a number of tyrosine phosphorylated substrates. The accumulation of GTP-bound ras was blocked by the treatment with either PTK inhibitors(genistein) or PTP inhibitors(PAO), suggesting that BCR-mediated ras activation is regulated by both PTK and PTP including CD 45. As phosphorylation on tyrosine residues of Lyn, Fyn, and Blk protein tyrosine kinases occurred upon BCR stimulation, these PTKs may be candidates being involved in an induction of not only tyrosine phosphorylation of substrates but also p 21ras activation. Furthermore we found that rasGAP activity is suppressed following Ag stimulation, accompanied by the phosphorylation on tyrosine of rasGAP and its associated protein p 62. These data indicate that protein tyrosine kinases may alter rasGAP activity to induce p 21ras activation in B cells. PMID- 8681027 TI - [Expression and characterization of CD46, membrane cofactor protein, in human colonic mucosa]. AB - CD 46, membrane cofactor protein (MCP), is a membrane regulatory glycoprotein of the complement system, and acts as a cofactor of factor I, which inactivates C3b and C4b bound on autologous cell membrane. MCP is present on human peripheral blood cells except erythrocytes, fibroblasts, epithelial and endothelial cells, and has been proved to exist in other organs including gastrointestinal tract recently. In this study the expression and characterization of MCP on normal human colonic mucosa was investigated. Immunohistochemical study showed MCP in the colonic mucosal epithelium. Western blot analysis revealed that MCP protein was expressed as a broad band of 50-65 kDa in all cases and another faint band of 43-46 kDa in 3 out of 20 cases, though the latter band was highly suspected to be originated from contaminated mononuclear cells in the colon. PMID- 8681028 TI - The expression of lymphocyte function associated antigen-1, intercellular adhesion molecule-1 on peripheral blood lymphocytes in patients with systemic lupus erythematosus. AB - The ratios of CD11a, CD18, HLA-DP on T cells and CD54 on B cells of 54 patients with active systemic lupus erythematosus (SLE) were examined. The ratios of LFA-1 alpha, beta, ICAM-1, HLA-DP among SLE patients were significantly higher when compared with normal healthy controls, and the significant correlation between the ratio of LFA-1+ T cells and HLA-DP+ T cells, and LFA-1+ T cells and ICAM-1+ B cells was recognized. These results may suggest that LFA-1, ICAM-1 is related to the mutual action between activated T cells and B cells. PMID- 8681029 TI - [TNF-alpha gene therapy for nonimmunogenic tumor using immunogenic variant induced with mutagen (N-methyl-N'-nitro-N-nitrosoguanidine)]. AB - We have already reported that a combination of TNF-alpha and immunogenic variant was effective for immunotherapy of nonimmunogenic tumor. Immunogenic variants (A2 and A7) were obtained from nonimmunogenic fibrosarcoma (parent cell: 1767-3) by mutagen treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). In this study, we studied about the possibility of TNF-alpha gene immunotherapy for nonimmunogenic tumor. We established two types of TNF-alpha producing cell lines. One is TNF-alpha producing nonimmunogenic variant (1767 TR 2), and another is TNF alpha producing immunogenic variant (A7 TR3). We compared them about the ability of producing specific immunity against parent tumor. TNF-alpha producing immunogenic variant (A7TR3) could induce strong specific immunity to parental cell compared to TNF-alpha producing nonimmunogenic variant (1767TR2). Immunogenicity of tumor is very important when we want to perform TNF-alpha gene immunotherapy against cancer. PMID- 8681030 TI - [Demonstration and characterization of CD46, membrane cofactor protein in the stomach]. AB - CD46, membrane cofactor protein, is a glycoprotein widely present on the cell membranes and is different in molecular weight among organs or cells in the same individual. It acts as a cofactor of I of the complement system, which inactivates C3b bound to the autologous cells, and protects them from the attack of the complement. In this study CD46 was demonstrated in the stomach immunochemically. Gastric CD46 was expressed strongly in the mucosal epithelium, mucosa and endothelial cells of the vessels in the submucosal layer, whereas expressed weakly in the submucosa and muscle. Western blot analyses revealed that gastric CD46 was expressed as one broad band with molecular weight ranging from 60 kDa to 69 kDa, which was distinct from that of lymphocytes in the peripheral blood. PMID- 8681031 TI - [A new approach to the determining immunoglobulin free light chains in serum by TIA nephelometry]. AB - Immunoglobulin light chains exist in two distinct forms, as linked to heavy chains by disulfide bonds, and as free light chains (FLc). Neoplastic B-cell disorders are responsible for the major absolute elevations of FLc, which are almost all monoclonal. Free light chains are nephrotoxic, and patients with renal failure have elevated blood concentrations of FLc. Light chains of immunoglobulins have attracted clinical attention as one of the proteins constituting the amyloid fibrils. Moreover, the concept of light chain deposition disease as independent entity has recently been advocated. In these circumstances TIA nephelometry using commercially available antibodies has been developed for the quantitation of both free kappa and lambda light chains of immunoglobulins in serum. This method is simple and rapid, and enable to analyze a large number of samples at a time, thus the method may be proved to be useful in clinical practice. PMID- 8681032 TI - [A case of rheumatoid arthritis associated with multiple myeloma]. AB - Previous reports have stressed the association between autoimmune disease and lympho-proliferative neoplasm. Here we report a patient in whom multiple myeloma developed about 30 years after the onset of rheumatoid arthritis. A 79 year-old woman with an about 30-year history of rheumatoid arthritis was admitted because of lumbago in December, 1993. Laboratory findings revealed M-proteinemia (IgA 2,380 mg/dl, IgG 728 mg/dl, IgM 51 mg/dl) and serum immunoelectrophoresis showed monoclonal IgA with lambda type light chain. Bone marrow aspirate contained 66.0% plasma cells. Serological tests of rheumatoid factor were positive. X-ray findings revealed radiolucent myelomatous foci in the skull and typical destructive changes of rheumatoid arthritis in multiple joint. From these findings, IgA lambda-type multiple myeloma with rheumatoid arthritis was diagnosed. Although the pathogenesis of the association between rheumatoid arthritis and multiple myeloma is unknown, prolonged antigenic stimulation manifested by rheumatoid arthritis is considered to be a possible pathogenetic factor in the development of multiple myeloma. PMID- 8681033 TI - Transcription factors 3: nuclear receptors. PMID- 8681034 TI - Single-cell investigation by laser scanning confocal microscopy of cytochemical alterations resulting from extracellular oxidant challenge. AB - Confocal laser scanning fluorescence microscopy coupled to image analysis was employed in order to develop and evaluate procedures for the appraisal at the single-cell level of: (1) protein-bound 4-hydroxynonenal, the specific product of membrane peroxidation (by means of immunocytochemistry with biotin-avidin revelation); (2) protein oxidation (by reaction of protein carbonyls with 2, 4 dinitrophenyl-hydrazine followed by immunocytochemistry of dinitrophenyl moieties); and (3) cellular protein thiols (by direct alkylation of sulfhydryl groups with thiol-specific fluorescent reagents possessing different cell permeabilities). The procedures proved able to reveal the subcellular distribution of cytochemical parameters useful as indices of oxidative stress conditions, and may allow "redox phenotyping" of isolated cells, which would provide an efficient tool in selected experimental models. PMID- 8681035 TI - Three-dimensional analysis of the substrate-dependent invasive behavior of a human lung tumor cell line with a confocal laser scanning microscope. AB - Matrigel and collagen G gels were used as models for basement membrane and interstitial space-collagen, respectively, to study the invasive behavior of cells of the human lung tumor cell line EPLC 32M1, which was derived from a squamous cell carcinoma. For three dimensional analysis of the invasive process, cells were seeded onto the gels in a slide chamber and observed with a confocal laser scanning microscope. Optical sectioning in the xy and xz directions and image reconstruction with computer programs allowed us readily to obtain a three dimensional overview of the invasive process in situ. Both types of gel showed a smooth surface. Matrigel had a granular structure whereas collagen G revealed a fiber-like morphology. The tumor cells showed a matrix-dependent behavior. On Matrigel, within 24 h of incubation, a network of cells appeared on the surface, which developed further within 72 h to interconnected multicellular cords also invading the gel. Tumor cells seeded on collagen G remained individual. They formed pseudopodia and achieved tight contact with the matrix, eventually also invading the gels in a time-dependent manner. Therefore, the composition of the substrate crucially influences the invasion path. PMID- 8681036 TI - Distribution of hyaluronan in articular cartilage as probed by a biotinylated binding region of aggrecan. AB - The proportion of total tissue hyaluronan involved in interactions with aggrecan and link protein was estimated from extracts of canine knee articular cartilages using a biotinylated hyaluronan binding region-link protein complex (bHABC) of proteoglycan aggregate as a probe in an ELISA-like assay. Microscopic sections were stained with bHABC to reveal free hyaluronan in various sites and zones of the cartilages. Articular cartilage, cut into 20 microns-thick sections, was extracted with 4 M guanidinium chloride (GuCl). Aliquots of the extract (after removing GuCl) were assayed for hyaluronan, before and after papain digestion. The GuCl extraction residues were analyzed after solubilization by papain. It was found that 47-51% of total hyaluronan remained in the GuCl extraction residue, in contrast to the 8-15% of total proteoglycans. Analysis of the extract revealed that 24-50% of its hyaluronan was directly detectable with the probe, while 50 76% became available only after protease digestion. The extracellular matrix in cartilage sections was stained with the bHABC probe only in the superficial zone and the periphery of the articular surfaces, both sites known to have a relatively low proteoglycan concentration. Trypsin pretreatment of the sections enhanced the staining of the intermediate and deep zones, presumably by removing the steric obstruction caused by the chondroitin sulfate binding region of aggrecans. Enhanced matrix staining in these zones was also obtained by a limited digestion with chondroitinase ABC. The results indicate that a part of cartilage hyaluronan is free from endogenous binding proteins, such as aggrecan and link protein, but that the chondroitin sulfate-rich region of aggrecan inhibits its probing in intact tissue sections. Therefore, hyaluronan staining was more intense in cartilage areas with lower aggrecan content. A large proportion of hyaluronan resists GuCl extraction, even from 20-micrograms-thick tissue sections. PMID- 8681037 TI - Evidence that extrahepatic cells express vitronectin mRNA at rates approaching those of hepatocytes. AB - Although the liver is the major source of the adhesive glycoprotein vitronectin (Vn) in vivo, we recently demonstrated low levels of extrahepatic Vn transcription. In this report, in situ hybridization was employed to identify the Vn-producing cells at these extrahepatic sites. In the central nervous system (CNS), high levels of Vn transcripts were prominent in arachnoid cells and in cells frequently present in the vicinity of brain capillaries. Significant amounts of Vn mRNA were also detected in selected peripheral organs. In the myocardium, the signal was localized to cells in the endomysium and subepicardial fat. Additionally, the pulmonary alveolar walls contained Vn-positive cells. The parenchyma of the kidney and spleen were negative. Moreover, larger blood vessels and adjacent cells in the CNS and peripheral organs were devoid of the Vn transcript. Unexpectedly, the rate of Vn gene expression in subsets of cells present in the CNS was similar to that of hepatocytes. These results suggest that the low level of Vn gene expression detected by quantitative PCR may reflect relatively high levels of synthesis by a small subset of cells, and raise the possibility that tissue Vn may, in part, be derived from local biosynthesis rather than from plasma. PMID- 8681038 TI - Immunocytochemical evaluation of the blood-brain barrier to endogenous albumin in the olfactory bulb and pons of senescence-accelerated mice (SAM). AB - The blood-brain barrier (BBB) to endogenous albumin was studied in the olfactory bulb and pons of the senescence-accelerated prone (SAMP8) mouse and senescence accelerated resistant (SAMR1) mouse strains by using a quantitative immunocytochemical procedure. Ultrathin sections of Lowicryl K4M-embedded samples were exposed to anti-mouse albumin antiserum followed by protein A-gold. Morphometric analysis of the electron micrographs revealed that in the olfactory bulb of both groups of animals, especially in the internal granular layer, some percentage of capillaries and slightly larger microvessels showed leakage of albumin. However, this percentage was larger in SAMP8 than in SAMR1 mice. In the pons, no significant differences in the permeability of blood microvessels were observed in both groups of mice, although a small fraction of capillaries in SAMP8 mice showed limited extravasation of blood plasma albumin. These observations indicate that the BBB in the olfactory bulb of control and SAMP8 mice is not as tight as it is in the pons or in the previously examined cerebral cortex. The labelling density of the neuropil was slightly higher than in the cerebral cortex, suggesting that albumin may have extravasated locally, in addition to having acces to the parenchyma of the olfactory bulb and pons from neighbouring areas supplied with the non-BBB-type of microvasculature. Furthermore, the data obtained suggest that there is limited (segmental), premature age-related impairment of the BBB function in SAMP8 mice. PMID- 8681039 TI - Localization of collagens and alkaline phosphatase activity during mineralization and ossification of human first rib cartilage. AB - The localization of type X collagen and alkaline phosphatase activity was examined in order to gain a better understanding of tissue remodelling during development of human first rib cartilage. First rib cartilages from children and adolescents showed no staining for type X collagen and alkaline phosphatase activity. After onset of mineralization in the late second decade, a peripheral ossification process preceded by mineralized fibrocartilage could be distinguished from a more central one preceded by mineralized hyaline cartilage. No immunostaining for type X collagen was found in either type of cartilage. However, strong staining for alkaline phosphatase activity was detected around chondrocyte-like cells within fibrocartilage adjacent to the peripheral mineralization front, while a weaker staining pattern was observed around chondrocytes of hyaline cartilage near the central mineralization front. In addition, the territorial matrix of some chondrocytes within the hyaline cartilage revealed staining for type I collagen, suggesting that these cells undergo a dedifferentiation process, which leads to a switch from type II to type I collagen synthesis. The study provides evidence that mineralization of the hyaline cartilage areas in human first rib cartilage occurs in the absence of type X collagen synthesis but in the presence of alkaline phosphatase. Thus, mineralization of first rib cartilage seems to follow a different pattern from endochondral ossification in epiphyseal discs. PMID- 8681040 TI - Expression of CD44 isoforms during bleomycin-or radiation-induced pulmonary fibrosis in rats and mini-pigs. AB - The distribution of CD44s and CD44v molecules in normal and injured lung tissue of rats and mini-pigs was studied by examining the immunohistochemical binding of monoclonal antibodies against CD44 isoforms. We showed that the expression of CD44v and CD44s varies greatly among different pulmonary fibrosis samples and that some tissues express either enhanced expression of CD44s, particularly in the interstitium and on alveolar macrophages, or very low levels of CD44v in the alveolar epithelium. Normal type II pneumocytes expressed the CD44s and CD44v molecules at the basolateral aspect of the cell. Such localisation favours a role for CD44 in epithelial cell-fibroblast interaction during lung development and repair. PMID- 8681041 TI - Pre- and post-embedding immunoelectron microscopy of Ki-M1P immunoreactive germinal center macrophages using ultra-small gold probes with silver enhancement. AB - The Ki-M1P protein is primarily detected in cells deriving from the monocyte/macrophage cell lineage. The aim of this study was to investigate the occurrence of Ki-M1P immunoreactivity in germinal center macrophages by immunohistochemical and immunocytochemical staining techniques. Ultra-small (0.8 nm) gold probes combined with silver enhancement were used as a detection system for pre- and post-embedding immunostaining both at the light and electron microscopic level. Ki-M1P-positive macrophages were observed at a constant frequency in the germinal centers of the follicles throughout the tonsillar lymphatic tissue. The specific immunostaining was localized in the cytoplasm of these cells. Electron microscopic examination demonstrated the presence of abundant lysosomes in the cytoplasm, and some of the germinal center macrophages contained phagocytosed cells (tingible bodies) showing signs of various degrees of digestion. Ki-M1P immunoreactivity, as revealed by depositions of silver enhanced ultra-small gold probes, was confined to the periphery of the lysosomes and tingible bodies. The results obtained demonstrate that the use of silver enhanced ultra-small gold probes is a highly sensitive and specific detection system for pre- and post-embedding immunostaining of the Ki-M1P protein, and provides, in general, a flexible system for combined light and electron microscopic examination of tissue antigens. Furthermore, in the cytoplasm of the germinal center macrophages a spatial association between the Ki-M1P protein and lysosomes and tingible bodies was observed. These findings may indicate that the Ki-M1P protein is connected with phagocytosis and/or processes related to intracellular digestion in these cells. PMID- 8681042 TI - Reflectance enzyme histochemistry (REH): visualization of cerium-based and DAB primary reaction products of phosphatases and oxidases in cryostat sections by confocal laser scanning microscopy. AB - In the present study the reflectance mode of confocal laser scanning microscopy was adapted to detect and to assess semiquantitatively cerium-based primary reaction products of oxidases [Ce(IV) perhydroxide] and phosphatases [Ce(III) hydroxyphosphate converted into Ce(IV) perhydroxyphosphate] as well as of the 3,3'-diaminobenzidine (DAB)-based primary reaction product of cytochrome c oxidase in cryostat sections. Confocal laser scanning microscopy offers a unique way of making visible histochemical reaction products which are weakly absorbant but sufficiently reflective. It was easily possible to record simultaneously the reflectance signals at the wavelength of the exciting laser (preferentially 488 nm) and the autofluorescence signals ( > 580 nm in our set-up) of glutaraldehyde fixed tissue. The results of an imbibition study of cerium-containing model precipitates indicate that the cerium, generally, should be oxidized prior to observation because the index of refraction of Ce(IV) compounds is considerably higher than that of the corresponding Ce(III) compounds. An attempt at comparative numerical assessment of reflection intensities from reflectant parts in morphologically similar sections is presented. The proposed technique may open new possibilities in enzyme- and immunohistochemistry. PMID- 8681043 TI - Weight-related attitudes and behaviors of women who diet to lose weight: a comparison of black dieters and white dieters. AB - Obesity is a significant health problem among black women in the United States. Black women are two to three times more likely than white women to be obese. The present study sought to examine race difference in attitudes and beliefs about dieting, motivations underlying dieting efforts, and actual dieting strategies and behaviors. To achieve this aim, a subset of female survey respondents (n = 324) was drawn from a pool of more than 20,000 subscribers to Consumer Reports. All survey respondents had made at least one dieting effort within 3 years of the time of the study. For this study, we used all black female respondents (n = 162) and a matched sample (i.e., matched on age, educational attainment, and personal income) of white women (n = 162). Black women did weigh significantly more than Caucasian women, therefore, BMI was used as a covariate in all subsequent analyses. Black and white women were significantly different in a number of domains. Compared to white women, black women experienced less social pressure about their weight, initiated dieting later in life, and were significantly less likely to diet at each developmental milestone. However, the two groups of women did not differ in reasons for undertaking their most recent dieting efforts, or in the types of weight loss strategies they had employed. Nor were there differences between the black and white women in methods for coping responses with dietary relapse or in rates of disordered eating. These findings are discussed in terms of their implications for both treatment and prevention of obesity in black women. PMID- 8681044 TI - Comparison of Osborne-Mendel and S5B/PL strains of rat: central effects of galanin, NPY, beta-casomorphin and CRH on intake of high-fat and low-fat diets. AB - The effects of central administration of galanin, neuropeptide Y (NPY), beta casomorphin(1-7) and corticotropin releasing hormone (CRH) on intake of either a high-fat or low-fat diet have been compared in two strains of rat, the dietary fat-sensitive Osborne-Mendel (OM) rat and the dietary fat-resistant S5B/Pl rat. Injection of galanin (0.1, 0.3 nmoles) into the 3rd cerebral ventricle stimulated the intake of both a high-fat and a low-fat diet in OM rats in a dose dependent manner but the response was significantly smaller in rats fed the low-fat diet. In S5B/Pl rats, galanin had a small stimulatory effect on food intake but only at a high dose (2 nmole). Beta-casomorphin(1-7) (5 nmoles), an opioid-like peptide, increased the intake of the high-fat but not the low-fat diet in OM rats, whereas S5B/Pl rats fed either a high-fat or low-fat diet did not respond to beta casomorphin(1-7). Both strains showed a similar stimulatory response to NPY (0.1, 0.5 nmoles) on the intake of the high-fat or low-fat diet, but the magnitude of the response was attenuated in S5B/Pl rats. In contrast, the anorectic effects of CRH (0.26 nmoles) on food deprived animals was similar in both strains for both diets. We speculate that the regulatory system controlling the intake of fat activated by galanin and beta-casomorphin(1-7) may be defective in S5B/Pl rats. PMID- 8681045 TI - Genetic pleiotropy for resting metabolic rate with fat-free mass and fat mass: the Quebec Family Study. AB - Shared genetic and familial environmental causes for the associations among resting metabolic rate (RMR), fat-free mass (FFM), and fat mass (FM) were investigated in families participating in phase 2 of the Quebec Family Study. A multivariate familial correlation model assessing the pattern of significant cross-trait correlations between family members (e.g., RMR in parents with FFM in offspring) was used to infer the etiology of the associations. For each of FM and FFM with RMR, significant sibling, parent-offspring, and intraindividual cross trait correlations suggests the associations are familial. Furthermore, the lack of significant spouse cross-trait correlations suggests that the familial aggregation is primarily genetic. Bivariate heritability estimates suggest that as much as 45% to 50% of the shared variance between FFM and RMR may be genetic, and as much as 28% to 34% for FM and RMR. This study supports the notion that the gene(s) affecting each of FFM and FM also influence the RMR. Moreover, the lack of any familial associations between FFM and FM suggests that the effects of each body size component on RMR are independent, i.e., more than one genetic source on the RMR-body size association. The possibility that RMR is an oligogenic trait (i.e., more than one underlying genetic etiology) should be further investigated using more complex multivariate segregation methods until specific genes can be tested. PMID- 8681046 TI - Abnormal regulation of hepatic glucocorticoid receptor mRNA and receptor protein distribution in the obese Zucker rat. AB - This study examines the cellular distribution of glucocorticoid receptor (GR) protein and transcriptional activity of the GR gene in the liver of Zucker obese (fa/fa) rats. Immunoabsorption and Western blotting showed an increase in nuclear GR protein level but a decrease in cytosolic GR levels in the liver of 5-week old male obese rats (fa/fa) compared to their lean littermates (Fa/-). These changes were confirmed by receptor-ligand binding assays with [3H]-dexamethasone which showed a sixfold increase in average obese nuclear GR binding and a twofold reduction in cytosolic GR binding. HSP90, but not HSP70, levels were reduced in hepatic cytosol and increased in hepatic nuclei prepared from obese rats. Using Northern blot analysis of hepatic RNA, we demonstrated a twofold increase in hepatic mRNAs for GR, malic enzyme (ME), tyrosine aminotransferase (TAT), and glyceraldehyde 3-PO4-dehydrogenase in the obese rat. Increased transcription of GR and ME mRNAs in obese nuclei was indicated in nuclear run-on assays. These data suggest that there is increased nuclear localization of GR in the liver of obese rats and suggests that increased transcription of GR gene may contribute to this effect. The described changes may contribute to the abnormal regulation by glucocorticoids of some hepatic genes in the Zucker fa/fa rat. PMID- 8681047 TI - Body position, age and mass effect of adiposity on adipose tissue red cell flux in morbid obesity. AB - OBJECTIVE: To measure red cell flux of adipose tissue in morbidly obese patients' pannus in the upright and supine position to determine factors which would render the lower pannus susceptible to ischemic necrosis. DESIGN: A cohort study of morbidly obese subjects without ischemic necrosis. SETTING: University teaching hospital. PATIENTS: Twenty-three consecutive morbidly obese patients referred for gastroplasty. MEASUREMENTS: Red cell flux, measured as RMS voltage by a laser Doppler velocimeter. An optical fiber with a tip diameter of 250 mu was inserted into the upper and lower pannus and output recorded in the upright and supine positions. Other variables recorded were age, BMI, blood pressure and serum lipids. RESULTS: Adipose tissue red cell flux demonstrates considerable spatial and temporal heterogeneity from subject to subject and in various locations in the pannus. No differences in red cell flux were detected in response to change in position. However, regression analysis demonstrated that the gradient between the upper and lower abdomen in the supine position was increasingly positive with age and in the upright position it was increasingly positive with increasing weight or BMI. CONCLUSIONS: These data suggest that red cell flux is heterogeneously distributed in the abdominal pannus and is not greatly influenced by body position. However, with increasing age and adiposity there is a gradient for decreased red cell flux to the lower portion of the pannus. This may be a factor in rendering this part of the pannus prone to ischemic fat necrosis. PMID- 8681048 TI - Disordered eating: can women accurately recall their binging and purging behaviors 10 years later? AB - OBJECTIVE: To test women's ability to recall their past binging and purging behaviors. DESIGN: Ten-year follow-up study of women who had participated in a cross-sectional survey during college. SUBJECTS: In 1982, a sample of freshman and senior women at a large university in the Boston area were questioned about their weight, dieting history, bulimic symptoms, and eating patterns, attitudes, and concerns. In 1992, all subjects who responded to the 1982 survey were followed up to assess changes in bulimic symptoms and ability to recall past behaviors. RESULTS: Among the 476 women who responded to both surveys, the percentage in 1992 who reported having ever binged and/or purged was less than the percentage in 1982, indicating that the recall of past behaviors was less than perfect. Denial in 1992 of ever having engaged in the behaviors ranged from 22% among the women who were self-inducing vomiting in 1982 to 64% among the women who had reported current fasting or strict dieting in 1982. Recall of past behaviors in 1992 was better among the women who had been current bingers or purgers in 1982. CONCLUSION: Our results demonstrate that ability to recall past binging and purging is only modest. Therefore to better understand the mental and physical health consequences of these behaviors this information should be collected prospectively. PMID- 8681049 TI - Role of intraduodenally administered enterostatin in rats: inhibition of food. AB - Central and peripheral administration of enterostatin have been reported to reduce fat or high-fat food intake in rats. Enterostatin is formed in the intestinal lumen by tryptic cleavage of pancreatic procolipase during intraluminal fat digestion. The present experiments were designed to test if enterostatin following intraintestinal infusion would affect food intake in a similar way as intracerebraventricularly or intravenously administered enterostatin. Female Sprague-Dawley rats were fitted with a duodenal catheter and adapted to feeding schedule for 6 hours each day. After 10 days enterostatin (5.65 and 11.3 nmol/kg/min) or saline were infused into the duodenum and food intake measured. Enterostatin significantly reduced high-fat food intake during the 6 hours of feeding, but had no inhibitory effect on low-fat food intake. Addition of tetracaine to the enterostatin infusates blocked the satiating potency of intestinal enterostatin. These results support the hypothesis of a preabsorptive site of action for enterostatin. PMID- 8681050 TI - Quantitation and localization of regional body fat distribution--a comparison between magnetic resonance imaging and somatometry. AB - The emerging concept that various fat compartments are metabolically active and play separate and decisive roles in the pathogenesis of coronary atherosclerosis, hypertension, insulin resistance, diabetes and stroke, has given obesity research a new direction. Of particular interest is the relative amount of intra-abdominal fat thought to be responsible for the metabolic complications. We studied the precise fat distribution and its correlations with the metabolic parameters in 44 non-human primates (Macaca fascicularis). Intra-abdominal, subcutaneous, and total abdominal fat (IAF, SAF, TAF) were assessed by magnetic resonance imaging (MRI) and somatometry. Quantitative computer analyses of abdominal MRI scans revealed predominant IAF distribution. Box plot analysis of IAF and SAF revealed wide diversity in the amounts of fat, especially in monkeys with body mass index (BMI) < 30 kg/m2. Primates with similar BMI in each quartile revealed an extensive heterogeneity in IAF as well as SAF. Numerous significant correlations within site-specific somatometric measurements as well as within the MRI determinants of abdominal fat were seen. However, only body weight correlated with IAF and skinfolds could predict SAF. After adjusting for body weight, partial correlation analysis showed a significant correlation (P < 0.05) between total cholesterol and IAF. CONCLUSION: MRI revealed considerable heterogeneity of IAF, SAF and TAF in cohort of primates believed to be homogeneous by somatometric definition. Male cynomolgus monkeys appear to be a valuable model for a systematic evaluation of fat. Individuals with identical body weight and height may show a diverse pattern of fat distribution. PMID- 8681051 TI - Changes in self-efficacy following obesity treatment. AB - Self-efficacy is an important component in the treatment of obesity. However, there is limited research examining changes in self-efficacy following obesity treatment. In this quasi-experimental study, 26 obese subjects demonstrated significant improvement on the Weight Efficacy Life-Style Questionnaire (WEL) following participation in a 26-week multidisciplinary VLCD program. Subjects demonstrated significant improvement from pre- to post-treatment on total WEL scores and on all five of the situational factors: Negative Emotions, Availability, Social Pressure, Physical Discomfort and Positive Activities. These results provide further construct validity for the WEL and offer guidelines for the amount of change that subjects may demonstrate on the WEL following obesity treatment. PMID- 8681052 TI - Starvation as a creative force. PMID- 8681053 TI - Body fat distribution and the distribution and the distribution of scientific knowledge. PMID- 8681054 TI - An experiment with the specialized investigation. 1904. PMID- 8681055 TI - Actuarial Society of America. Transactions. 1901-1903. PMID- 8681056 TI - Sexual differentiation. A determinant factor of the forms of obesity. 1947. PMID- 8681057 TI - The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. 1956. PMID- 8681058 TI - [Cardiologic progress in China, 1995]. PMID- 8681059 TI - [Gastroenterologic progresses in China, 1995]. PMID- 8681060 TI - [Progresses in respiratory diseases in China, 1995]. PMID- 8681061 TI - [Progresses in nephrology in China, 1995]. PMID- 8681062 TI - [Progresses in hematology in China, 1995]. PMID- 8681063 TI - [Progresses in diabetology in China, 1995]. PMID- 8681064 TI - [Progresses in neurology in China, 1995]. PMID- 8681065 TI - [Progresses in psychiatry in China, 1995]. PMID- 8681066 TI - [Progresses in communicable diseases in China, 1995]. PMID- 8681067 TI - [Progresses in the study on tuberculosis in China, 1995]. PMID- 8681068 TI - [Progresses in tropical medicine in China, 1995]. PMID- 8681069 TI - [Progresses in general surgery in China, 1995]. PMID- 8681070 TI - [Progresses in thoracic surgery in China, 1995]. PMID- 8681071 TI - [Progresses in orthopedics in China, 1995]. PMID- 8681073 TI - [Progresses in neurosurgery in China, 1995]. PMID- 8681072 TI - [Progresses in urology in China, 1995]. PMID- 8681074 TI - [Progresses in cardiovascular surgery in China, 1995]. PMID- 8681075 TI - [Progresses in microsurgery in China, 1995]. PMID- 8681076 TI - [Progresses in burn surgery in China, 1995]. PMID- 8681077 TI - [Progresses in traumatology in China, 1995]. PMID- 8681078 TI - [Progresses in organ transplantation in China, 1995]. PMID- 8681079 TI - [Progresses in anesthesiology in China, 1995]. PMID- 8681080 TI - [Progresses in gynecology in China, 1995]. PMID- 8681081 TI - [Progresses in prenatal medicine in China, 1995]. PMID- 8681083 TI - [Progresses in pediatrics in China, 1995]. PMID- 8681082 TI - [Progresses in family planning in China, 1995]. PMID- 8681084 TI - [Progresses in pediatric surgery in China, 1995]. PMID- 8681085 TI - [Progresses in child health in China, 1995]. PMID- 8681086 TI - [Progresses in ophthalmology in China, 1995]. PMID- 8681087 TI - [Progresses in otorhinolaryngology in China, 1995]. PMID- 8681088 TI - [Progresses in orodentofacial surgery in China, 1995]. PMID- 8681089 TI - [Progresses in emergency medicine in China, 1995]. PMID- 8681090 TI - [Progresses in physical and rehabilitation medicine in China, 1995]. PMID- 8681091 TI - [Progresses in dermatology and venereology in China, 1995]. PMID- 8681092 TI - [Progress in the study of endemic diseases in China, 1995]. PMID- 8681093 TI - [Progress in occupational diseases in China, 1995]. PMID- 8681094 TI - [Progresses in clinical epidemiology in China, 1995]. PMID- 8681095 TI - [Progresses in geriatrics in China, 1995]. PMID- 8681096 TI - [Progresses in radiology in China, 1995]. PMID- 8681097 TI - [Progresses in nuclear medicine in China, 1995]. PMID- 8681098 TI - [Progresses in laboratory medicine in China, 1995]. PMID- 8681099 TI - [Progresses in laser medicine in China, 1995]. PMID- 8681100 TI - [Progresses in pathology in China, 1995]. PMID- 8681101 TI - [Progresses in pathophysiology in China, 1995]. PMID- 8681102 TI - [Progresses in microcirculation in China, 1995]. PMID- 8681103 TI - [Progresses in medical genetics in China, 1995]. PMID- 8681104 TI - [Progresses in microbiology and immunology in China, 1995]. PMID- 8681105 TI - [Admission documentation of multiple trauma patients using the Zurich Trauma Protocol--initial experiences]. AB - A new protocol to document multiply injured patients in presented. It consists of 23 pages and is indexed on the right side. The pages are structured according to the Abbreviated Injury Scale (AIS): head/neck, face, thorax, abdomen, extremities/pelvis and integument. Different checklists on the right side of each page help to enter data efficiently; schemes and templates on the left side provide further support to visualize and classify the injuries. Summaries for diagnosis, therapies and for further investigations provide a standardized overview of the patient. The experiences of 22 residents were analyzed after one year of the protocol use. The trauma protocol was shown to be easy to learn, it was well accepted, and it increased the exchange of information between the emergency room and the intensive care unit. However, some residents considered this data entry to more laborious compared with the traditional medical record system. The trauma protocol was designed for prospective data acquisition of intensive care patients; it provides also a uniform structure for retrospective analysis and is therefore a helpful tool to increase quality control and quality assurance. PMID- 8681106 TI - [Percutaneous tracheostomy: a minimally invasive procedure on the intensive care unit]. AB - INTRODUCTION: In 1985 Ciaglia [2] introduced percutaneous tracheostomy as a minimal invasive procedure. Since October 1991 percutaneous tracheostomy has been performed in 40 patients at the University Hospital in Zurich. This paper compares our complication rate using the Cook-system with the conventional open technique in the literature. MATERIALS AND METHODS: 40 patients, mean 53.6 years of age, 26 male, 14 female. Indications were: inability to perform sufficient bronchial suction, recurrent atelectasis, long term ventilation, difficult or prolonged weaning (i.e. neurotrauma). The tracheal tube is introduced following stepwise dilatation after making skin incision, according to the Seldinger technique. RESULTS: In all patients tracheostomy was carried out as an elective procedure in the Intensive Care Unit. Time between primary intubation and tracheostomy varied between O and 51 days, mean 15.9 days. Complications occurred in 5/40 cases (12.5%), with only one serious complication: the tracheostoma was misplaced, requiring intubation. Beside that we have seen 2 minor hematomas, 1 bradycardia and 1 subcutaneous emphysema. CONCLUSIONS: Percutaneous tracheostomy can be safely performed at bedside in the ICU. The method is simple and has a lower complication rate compared to the conventional open technique as reported by Hazard [7] and Griggs [8]. PMID- 8681108 TI - [Proximal humeral multiple fragment fractures--failures after T-plate osteosynthesis]. AB - Dislocated compound fractures of the proximal humerus are often difficult to treat. The choice of treatment influences the final functional result. From 1984 1991 108 patients with dislocated compound fractures of the proximal humerus were operated with a T-plate osteosynthesis, retrospectively examined and classified according to the Neer-Classification. At an average follow up time of 5 years 72 patients had a clinical and radiological examination. 68% of these patients with 3-fragment fractures and 80% with 4-fragment fractures showed a modest to unsatisfactory result caused by fracture biology, imprecise fracture reduction or poor surgical procedure. Incorrect position of T-plates and inadequate material were distinguishable. The T-plate which was widely used in the late eighties for internal fixation has to be considered a failure for these particular types of fractures and should be limited for Collum chirurgicum fractures. PMID- 8681107 TI - [Reconstruction of chronic symptomatic acromioclavicular joint dislocation (Rockwood III-V) using the modified Weaver-Dunn method. 24 operated patients (1988-95), surgical technique, results]. AB - In literature there is a great controversy about the treatment of acute acromio clavicular (AC) joint dislocations. Nevertheless some patients continue to suffer from chronic pain due to the persistent instability of the AC-joint. This can even lead to an impingement syndrome, going as far as tearing the rotator cuff. In 1972 Weaver and Dunn described a new procedure for the treatment of instable AC-joints. From 1988 to 1995 we used a modified version of this technique on 24 patients suffering from chronic AC-joint dislocation (Rockwood III-V). After the resection of the AC-joint and the preparation of the coraco-acromial ligament, we transposed the acromial end of this ligament together with a small piece of bone from the acromion tip to the lateral end of the clavicle. The results of this modified method were excellent. All patients had no pain anymore, regained a full shoulder movement, could participate in sport again and returned to work after an average of 3.3 months. This new procedure seems to be the treatment of choice for chronically instable AC-joint dislocations. PMID- 8681109 TI - [Osteosynthesis of the hand--indications, technique, results]. AB - Between January 1st 1992 and December 31st 1993 140 non-complex (i.e. nerve, vascular, tendon injuries) fractures of the peripheral hand skeleton were operated at the Policlinic of the Kantonsspital Basel. In a retrospective study we analyzed results, complications and absence from work. We treated 110 male and 30 female patients with a mean age of 47 years. 45 fractures were treated by plate fixation, 45 by screw fixation, 53 times we applied k-wires and once a mini fix-ex (AO-Prototype). Plate and screw fixation were performed with AO-mini implants. 90% of our patients had an uneventful postoperative course. In spite of functional after-treatment we noted in 8.6% of the patients a relevant loss of movement leading to operative tenolysis in 7 patients. Fractures at the level of PIP were most frequently associated with loss of movement. Absence from work was 59 days in average (1-206)! CONCLUSIONS: Peripheral osteosynthesis of the hand (non-complex) are effectively treated on an out-patient basis. In spite of functional after-treatment about 10% of patients have a relevant postoperative reduction in motility. Absence from work is relatively long after operative treatment of peripheral hand fractures. PMID- 8681110 TI - [External fixator in severe traumatic injuries of the pelvis: results apropos of 20 consecutive cases]. AB - From August 91 to December 94, 20 external fixators were used for severely injured patients (avg. ISS 25.2). The fractures were essentially open book with or without lateral compression and vertical lesions. The indication for fixation was treatment of shock and stabilization in 8 cases, stabilization alone in 9 cases, and in 3 cases as complementary fixation after internal fixation of posterior lesions. The fixation of the pelvis was effective on the amount of blood loss. One acetabulum fracture required surgery, two patients had internal fixation for loss of reduction and two others for late pubic and posterior pain. The clinical results are good; they are more related to the severity of the initial lesion than to the mode of fixation or the quality of the reduction. No superficial sepsis or osteitis was observed in relation to the pins. PMID- 8681111 TI - [Postoperative stress on by dynamic hip screw or endoprostheses treated femoral neck and pertrochanteric femoral fractures in elderly patients]. AB - Fractures of the neck and the pertrochanteric region of the femur in elderly patients are often treated with dynamic hip screw or endoprothesis. In the aftercare, specially in fractures that have been stabilised with a DHS, partial weight-bearing is recommended. Some other authors describe immediate full weight bearing after osteosynthesis with the same implant. For elderly patients it is often difficult to apply partial weight-bearing on one limb only. Remobilisation as soon as possible is very important to these patients, to avoid postoperative complications. Therefore the allowance of full weight-bearing enables us to rehabilitate these old patients more appropriate. We have studied the rates of systemic and local complications in patients with different weight bearing on the operated hip with means of the data of the ASIF-documentation records. In patients who bear full weight on the operated limb immediately after operation, the rates of systemic complications are lower. The rates of local complications increased with the instability of the fracture. Both results are though not statistically significant. PMID- 8681113 TI - [Intraoperative ultrasonography of the liver]. AB - INTRODUCTION: In many centers specialized in hepatobiliary surgery intraoperative sonography (IOUS) has become a mandatory intraoperative diagnostic tool for intraoperative decision making. We have started applying this technique during liver recections and operations for cancer of the colon in 1988. This presentation is a retrospective report on the first author's personal experience with this technique. PATIENTS AND METHODS: Ninety-two patients were examined intraoperatively, either at Zurich University Hospital or Groote Schuur Hospital in Cape Town. There were 37 female and 55 male patients aged 21 to 84 years (average: 56 yrs). Thirteen patients had primary malignanctes of the liver (group 1) and37 patients underwent IOUS during liver resection for secondary liver tumors (group 2). 14 patients were scanned during operation for benign lesions of the bile ducts and liver (group 3). 28 patients were screened for metastases during resection of gastrointestinal cancers (group 4). The equipment consisted of an Aloka Echocamera SSD 630 and a T-shaped 5 MHz small part in Zurich and a Siemens SI 400 unit with a similar scanner in Cape Town. RESULTS: In group 1 IOUS demonstrated additional information in 9 patients and changed operational procedure in 7 cases. In group 2 IOUS improved on preoperative imaging in 17 cases and changed the approach in 14. Seven patients with benign lesions profitted from IOUS. Additional information changing surgical procedure was gained by IOUS in 6 patients of group 4. CONCLUSIONS: IOUS is a valuable intraoperative imaging technique which is easily performed by the surgeon himself. It should be part of every operation for cancer of the colon and every resection of the liver. PMID- 8681112 TI - [Initial clinical results in the treatment of peripheral arterial occlusive diseases using new percutaneous atherectomy equipment (REDHA-CUT)]. AB - In 11 female and 13 male patients 29 symptomatic femoropopliteal occlusions were treated with a novel intraluminal endarterectomy device (REDHA-CUT). The pre existing stenoses (71 +/- 9%) could be reduced to 29 +/- 18% (means +/- s.d.). The arteriectomy procedure with this device took on average 5 +/- 3 min. Neither perforations nor dissections nor distal embolisms or any other complications were observed. In comparison with other percutaneous transluminal angioplasty procedures the clinical use of the novel REDHA-CUT device is safe, simple and fast and allows for the retrieval of plaque biopsies. PMID- 8681114 TI - [Thoracic sympathectomy in palmar hyperhidrosis: comparison of open with thorascopic procedure]. AB - Between 1976 and 1994 we performed 26 thoracic sympathectomies for treatment of therapy-resistant palmar hyperhidrosis. Until the end of 1992 the operation was performed using an open transaxillary approach, since 1993 sympathectomy was done by video-assisted thoracoscopy. Both procedures consisted in excision of the thoracic ganglia T2 to T5. The only complication was a pneumothorax in the open surgery group (successfully treated by drainage). Compensatory sweating occurred in 70% of our patients, compared to results in the literature of 60-90%. We did not note further complications, e.g. no Horner's syndrome. All of our patients were satisfied with the result of the operation. Comparison of the two collectives shows significant advantages for video-assisted thoracoscopic surgery. the procedure is easier to perform, exposure is better, cosmetic results are favourable, operation-time and hospital stay are reduced. PMID- 8681115 TI - [Follow-up and results of liver transplantation for primary biliary cirrhosis]. AB - Primary biliary cirrhosis is regarded as one of the optimal indications for orthotopic liver transplantation in adults. With the decrease in the operative mortality, the analysis of the potential long-term complications including disease recurrence is becoming increasingly relevant. The purpose of this study was to evaluate the long-term results of liver transplantation for primary biliary cirrhosis in our center. From 1988, 14 patients were transplanted for this indication and all of them were alive with a mean follow-up of 43 months by the end of June 1995. At that time, all complications related to chronic liver disease were reversed by the transplant except for osteopenia. Lumbar column fractures and overweight were the major inconveniences encountered. Hypertension and diabetes related to antirejection therapy disappeared during the first year of follow-up in all but one patient. Recurrence of the disease was not encountered in this series where a triple association of immunosuppressive therapy was maintained in each patient. At long-term, the frequency of disease recurrence in the liver allograft seems quite low and even in this situation immunosuppressive agents may alter the evolution of the disease. All patients (n 12) who had at least 1 year of follow-up had a normal level of bilirubin and their quality of life was good to excellent. These results, confirmed by the international experience, support the notion that patients suffering from primary biliary cirrhosis should be transplanted as early as complications from this chronic liver disease occur. PMID- 8681116 TI - [Choledochus carcinoma in choledochal cyst--a rarity. Presentation of the disease with a case report]. AB - Around 1800 choledochal cysts are described in the literature, of which around 6% have turned malignant. The incidence of malignant degeneration increases with age and amounts to as much as 28%. As the prognosis for malignant choledochal cysts is poor, the only therapy is an early cystectomy before the appearance of malignant changes. The diagnosis of the cyst is made using sonography, ERCP and abdominal CT. Histology alone provides conclusive diagnosis of malignant degeneration. The case of a 29-year-old-woman who entered our clinic with non specific right-side abdominal pains is presented. A choledochal cyst was diagnosed by means of sonography, ERCP and abdominal CT. Intraoperatively, a choledochal carcinoma was found in the choledochal cyst (type Ia according to Todani), with infiltration to the surrounding area as well as liver metastasis. A cystectomy and Roux-Y-hepatico-jejunostomy were performed. The patient died 8 months after the diagnosis. PMID- 8681117 TI - [laparoscopic cholecystectomy and acute cholecystitis--feasibility and morbidity]. AB - This quality control study was devised to establish, wether laparoscopic cholecystectomy is recommendable for acute cholecystitis. Of 314 prospectively recorded laparoscopic cholecystectomies 59 were done for histologically proven acute cholecystitis within 3 years. 29 cases (49.2%) were converted to open cholecystectomy due to unsatisfactory exposure and recognition of anatomical structures or haemorrhage. Morbidity with laparoscopic cholecystectomy without conversion was 16.6% (5/30 patients), mortality zero. There were no common bile duct injuries. Our results show that, if the operation is performed by an experienced laparoscopic surgeon or under one's supervision, laparoscopic cholecystectomy for acute cholecystitis is safe. A low threshold for converting to open laparotomy must be observed particularly when anatomical structures are not clearly identified. PMID- 8681118 TI - [Necrotizing panniculitis of the colon--a rare form of mesenterial panniculitis]. AB - A 37-year old man was admitted with colics in the upper right abdomen. Since the laparoscopy revealed a massive thickening of the right colonic flexure a hemicolectomy was performed. The histologic examination yielded the diagnosis of a necrotizing panniculitis of the colon, a rare variant of mesenterial panniculitis usually occurring in the small intestine. Signs and symptoms, diagnostics, and therapeutic approaches of this disorder of unknown cause are discussed. PMID- 8681120 TI - [Swiss Surgery--the first volume in the readers' opinion (assessment of the December 1995 questionnaire)]. PMID- 8681119 TI - [Kaposi sarcoma of the glans penis with meatal obstruction. Case report and literature review]. AB - Kaposi sarcoma was first described by Moritz Kaposi 1872. It is a disease of the reticuloendothelial system. Preferred manifestations are mainly skin, mucosa and gastrointestinal tract. Location of penile glans with meatal obstruction has been mentioned to date in 4 cases. We report a patient with acquired immune deficiency syndrome who presented a meatal obstruction caused by Kaposi-sarcoma. In this patient with a survival time of 8 months meatotomy and locoregional radiotherapy was an adequate therapy. PMID- 8681121 TI - [Treatment concept in deep pelvic-leg venous thrombosis]. AB - The treatment of choice in acute deep vein thrombosis continues to be controversial. Conservative treatment with heparin and anticoagulation, systemic thrombolysis, thrombectomy and the combination of local thrombolysis and surgical unblocking are possible therapies. Regarding long term results; both after non operative treatment or after venous thrombectomy, many authors describe a majority of patients who suffer from chronic venous insufficiency in varying clinical severity. Requirements for normal venous function are complete phlebographic patency and valvular competence without venous reflux. Our proposed treatment for thromboses not older than 7 days combines local thrombolysis with venous thrombectomy to achieve these requirements and contains the following operative proceeding: An incision is made in the groin or - for more distal thromboses - on the proximal end of the clot. For the removal of the clot in the iliac vein a Fogarty-catheter is used. Urokinase is administered through a vein puncture in the instep while the blood flow is blocked by a pneumatic cuff around the thigh. After at least 20-30 minutes the clots can be removed through the proximal incision after removal of the cuff and manual massage of the leg. During this procedure the vein proximal of the venotomy is occluded by a soft clamp. An analysis of the results of 34 patients on average 3 1/2 years after combined therapy confirms normal valvular function of the popliteal vein in 27 (79%) cases. This improved long term outcome is going to be checked in an prospective study evaluating anticoagulation versus our treatment concept. PMID- 8681122 TI - A case of acute mesenteric ischemia that responded to a combined treatment concept. AB - Acute mesenteric ischemia (AMI) is still associated with a high mortality rate. Early diagnosis and treatment are mandatory since irreversible bowel damage occurs within a few hours of total ischemia. Reactive vasoconstriction, high postoperative vascular reocclusion rate and the release of toxic substances from the damaged bowel followed by bacterial translocation are all part of the disease process. A combined treatment plan for AMI devides to combat the unrelenting disease process on different levels involving early operation, perioperative intraarterial fibrinolytic and vasodilative treatment and anticoagulation, selective small bowel decontamination and mandatory second look operation is presented. The rationale of this concept and its successful outcome in a highly complex case are discussed. PMID- 8681124 TI - [Latex covering and mechanical analysis of balloon expandable stents]. AB - To the moment a few stents of metallic coils or meshes are available with a sealing coverage. In the present study balloon-expandable stents have been covered with a thin layer of natural rubber latex. The physical properties of these impervious stents were compared to the conventional stents. The expansion, the loss of expansion and the deformity during and after balloon inflation have been analyzed. In the pressure zone of 4-6 bar the mechanical characteristics of the impervious stents were similar to the conventional stents. The stents were expanded at 100% related on the balloon diameter used for expansion. Additional pressure of 1 bar was necessary to expand the impervious stents. At balloon pressure below 4 bar the stents tied the balloons in the midzone. The impervious stents, expanded at 6, 8 and 10mm, underwent a loss of expansion of 10% after withdrawal of the balloons. Their configuration was barrel-shaped (4% central enlargement) due to the latex rubber, constricting the wire meshes at both ends. These preliminary results are encouraging and allow further investigations. PMID- 8681123 TI - [Incidence, clinical aspects and therapy of late pericardial tamponade following heart surgery]. AB - Late cardiac tamponade is a very severe condition that presents with subtle signs and symptoms within days or weeks after cardiac surgery. In a consecutive series of 3782 patients, 33 developed this complication, mostly due to overdosage of anticoagulants or to unsafe combination of 2 anticoagulation regimen. Diagnosis can be difficult and is best confirmed by echocardiography; in patients with primary uneventful recovery and sudden cardiocirculatory deterioration, intensive work-up should be performed to exclude or confirm the suspicion of late pericardial tamponade. The treatment of late pericardial tamponade should not be delayed and consists in subxyphoidal drainage. Re-sternotomy might be necessary to assume complete decompression of the heart in case of well-localized and posterior tamponade and/or organized pericardial fluid. Since this complication can happen in any patient transferred to peripheral hospital for postoperative recovery after cardiac surgery, we believe that this complication should be recognized very early and should be treated, in case of necessity, by general surgeons. Usually, no active bleeding is found at revision. PMID- 8681125 TI - [Regionalization of perinatal medicine in Germany]. PMID- 8681127 TI - [Centralization in obstetrics: pros and cons]. AB - Possible advantages and disadvantages of a general centralization of German obstetric facilities are analysed in the study. The need for centralization of risk cases, especially premature births (regionalization) is pointed out. Centralization appears appropriate, since every fifth maternity unit in Germany (19.78%) has 300 or fewer deliveries per year. This one fifth of perinatal clinics accounts for 6.3% of all deliveries (N = 49450). There are appreciable differences between the old and new federal states (Bundeslander): in the recently acceded federal states, 48.7% of all perinatal clinics have deliveries of 300 and less per year. This group of perinatal clinics accounts for 29% of all deliveries in the new federal states. We have carried out a survey of the mother's attitude to centralization: out of 416 patients in the Detmold women's hospital whose mean age was 29.0 +/- 4.2 years, 90.4% were not in favor of general centralization of obstetrics. 43% were also against a centralization of risk cases (regionalization). 75% of the women surveyed objected to centralized obstetrics because of the 'possible absence of the family', the 'possible absence of students and trainees' (44.9%), the 'unfamiliarity with staff and premises' (41.8%) and 'fear of anonymity' (44.5%). The majority of all women (84.1%) did not want to have a drive more than 20 km to an obstetrics center. Fear of 'delivery in a taxi'(78.6%), the 'fear that the husband will come too late to the delivery' (65.4%) and that the 'overall course of the delivery might not be adequate for reasons of time'. The presence of a pediatrics department in conjunction with the perinatal clinic was rated very positively (93%). It is concluded from the data and further juridical considerations that centralization of risk cases (regionalization) is indispensable in the near future and that somewhat more further into the future decentralization should be carried out by closing obstetrics departments with substantially less than 350 deliveries per year. Attention is drawn to some consequences of such a structural reform which will probably have to be initiated by the German Association of Gynecologists and Obstetricians. PMID- 8681126 TI - [Fetal atrioventricular blood flow velocity in the 2nd half of pregnancy: a Doppler echocardiographic study]. AB - Pulsed Doppler velocimetry of both fetal atrioventricular valves derived in the four-chamber-view were performed in 94 uncomplicated pregnancies between the 20th and the 40th week of gestation. The maximal velocities in early (E-peak) and late diastole (A-Peak) as well as the E/A Ratio were calculated for both tricuspid (TV) and mitral valves (MV). Normal ranges for the six measured parameters were constructed and correlated with gestational age. In the second half of pregnancy an increase of the E-wave for both valves was found (TV r = 0,59; MV r = 0,48) with higher values through the TV compared with the MV. In comparison the A velocities showed a flat increase during the observation time (TV r = 0,32, MV r = 0,24). The E/A Ratio for both valves which is < 1 in the fetus showed an increase throughout pregnancy, mainly due to the increase of the E-wave in the observed period of time. These intracardiac Doppler flow measurements enable an insight into the physiology of fetal circulation. They give a basis for the analysis of blood flow under pathological conditions, like in congenital heart defects or in intrauterine growth retardation. PMID- 8681128 TI - [Doppler sonographic flow measurements of the middle cerebral artery in end diastolic zero flow in the umbilical arteries in relation to fetal outcome]. AB - Absent or reverse end-diastolic flow velocities (AREDFV) of the umbilical arteries are associated with fetal distress. We studied 74 fetuses with AREDFV with respect to the resistance index of the middle cerebral artery (MCA). The change in the resistance index of MCA was applied to the fetal outcome. The fetuses were retrospectively divided into 3 groups: 1) The fetuses in the first group did not show any changes in the course of observation of the MCA. 2) In the second group a drop followed by an increase in the resistance index of the MCA was confirmed. This is known in literature as "cerebral oedema". 3) The third group showed only a drop in the resistance index, described in literature as "brain-sparing-effect". The increase in the resistance index of the MCA points to a danger for the fetus, since the incidence of fetal acidosis, low birth weight, severe idiopathic respiratory distress syndrome in these fetuses was extremely high. In particular every second fetus in this group showed neurological complications. The change in the cerebral perfusion known as "cerebral oedema" which is extremely dangerous for the fetus has to be avoided. PMID- 8681129 TI - [Color Doppler sonography of peripheral and cerebral fetal vessels in comparison as prognostic criterion in predicting intrauterine distress]. AB - Doppler sonography of the fetal descending aorta, renal artery, middle cerebral artery and umbilical artery in a population of 74 fetuses with a abdominal circumference below the fifth percentile of the reference limits were done. All fetuses were free from structural and chromosomal abnormalities. The pulsatility- and the resistance indices as well as the ratios between these indices from peripheral and cerebral vessels were calculated and correlated to the fetal distress. The measurement of the pulsatility index of the middle cerebral artery provided the best results in predicting the development of fetal distress. Better results were achieved by the use of ratios of pulsatility-indices of various vessels than by the examination of the vessels alone. Our results suggest the usefulness of the examination of the middle cerebral artery and their ratios compared to the renal artery. PMID- 8681130 TI - [Intrapartum therapy-resistant fetal bradycardia--color Doppler sonographic diagnosis of umbilical cord compression due to fetal grasping]. AB - Fetal heart rate pathology is seen in up to 40% of complications of the umbilical cord. We report a case in which long lasting bradycardia was associated with fetal grasping of the umbilical cord. Using colour doppler, the reason for the bradycardia could be detected. After vibro-acoustic stimulation the fetus released the grasp of the umbilical cord, following by a normalisation of the fetal heart rate and a spontaneous delivery two hours later. This case report underlines the importance of colour doppler for the diagnosis of fetal heart rate pathology. PMID- 8681131 TI - [Iatrogenic esophageal perforation-- severe complication in the care of premature infants]. AB - Two preterm neonates were referred to our institution, one with suspected oesophageal atresia and one with the definite diagnosis of oesophageal atresia for further treatment. Diagnostic procedures identified an iatrogenic perforation of the oesophagus which was caused by a feeding tube in both patients. The treatment was based on broad-spectrum antibiotic therapy and parenteral nutrition. The perforations healed without long term sequelae. PMID- 8681132 TI - [Indications for home monitoring]. PMID- 8681133 TI - Karyotype distributions in a stochastic model of reciprocal translocation. AB - A random process of reciprocal translocation for a fixed number k of chromosomes (or arms) will have an equilibrium distribution of chromosome lengths. In this paper we calculate this distribution, by analytical means for k = 2 and partially for k = 3, and simulate the means of the marginal distributions for higher k. We compare this with a random (i.e., ahistorical) distribution of genomic DNA among k chromosomes and to a selection of karyotypes of real organisms. The results motivate a revised model where translocations giving rise to undersize chromosomes are disadvantaged. PMID- 8681134 TI - High-quality automated DNA sequencing primed with hexamer strings. AB - The finishing phase of genome sequencing projects is expensive, in part, because of the cost of de novo synthesis of custom primers and the management burden associated with obtaining and using them for primer walking. One approach to reduce these high costs is the use of a presynthesized library of short oligonucleotides (8-10 bases) rather than long primers. The use of such a library eliminates the need for custom synthesis of oligonucleotides, providing the convenience of priming from any site by combining two to three short oligonucleotides to form a string with the required specificity. The first practical implementation of this strategy presented a robust protocol for using hexamer strings with radioisotopic labelling. Whereas versions of this technique have subsequently been implemented on fluorescent sequencers we felt that there was a need to develop and extensively test a protocol that consistently gave read lengths comparable to dye-terminator sequencing with longer primers. We have developed a new two-cycle fluorescent Sequenase terminator procedure for using hexamer strings. We tested this procedure using a set of 32 different 3 hexamer primer strings, each known to be functional to some degree in radioisotopic sequencing, on single-stranded M13mp18 template and ABI 373 DNA sequencers. The overall success rate of priming with these hexamer primer strings is 97% with the failure of only one string. In this case, the corresponding 18-mer primer also failed to produce usable sequence from M13mp18 template. The average read length from reactions successfully primed with the 31 different hexamer strings was 461 bases with > 99% base-calling accuracy. The current protocol is robust enough to be used in virtually any situation where primer walking on single-stranded templates is used. The success rate and read lengths make it universally applicable to the sequencing of single-stranded templates on automated sequencers. It is also amenable to automation. PMID- 8681135 TI - A physical map of chromosome 2 of Arabidopsis thaliana. AB - A yeast artificial chromosome (YAC) physical map of chromosome 2 of Arabidopsis thaliana has been constructed by hybridization of 69 DNA markers and 61 YAC end probes to gridded arrays of YAC clones. Thirty-four YACs in four contigs define the chromosome. Complete closure of the map was not attained because some regions of the chromosome were repetitive or were not represented in the YAC library. Based on the sizes of the YACs and their coverage of the chromosome, the length of chromosome 2 is estimated to be at least 18 Mb. These data provide the means for immediately identifying the YACs containing a genetic locus mapped on Arabidopsis chromosome 2. PMID- 8681136 TI - Transcriptional map of the Treacher Collins candidate gene region. AB - Treacher Collins syndrome (TCOF1) is a dominant disorder of craniofacial development that has been linked previosuly to a region of chromosome 5q31.3-32. Identification of recombination events in affected individuals has reduced the candidate gene region to a 0.5-Mb area between the loci RPS14 (proximal) and ANX6 [distal]. A transcriptional map of this candidate gene region, generated by analysis of exon amplification clones, has identified the genomic location of four genes, heparan sulfate-N-sulfotransferase-N-deacetylase, glutathione peroxidase, as well as two novel, previously uncharacterized genes. Each of these genes, based on their location, must be considered candidates for TCOF1 locus. PMID- 8681137 TI - Identification of 4370 expressed sequence tags from a 3'-end-specific cDNA library of human skeletal muscle by DNA sequencing and filter hybridization. AB - A systematic study on the mRNA species expressed in the human skeletal muscle is presented in this paper. To carry on this study, a new method has been developed for the construction of unbiased cDNA libraries specially designed for the production of ESTs corresponding to the 3'-end portion of the mRNAs. The method has been applied to human skeletal muscle, where the analysis of the transcription profile is particularly difficult for the presence of several very abundant transcripts. To detect and quantify high-level mRNAs, the first 1054 ESTs were obtained from randomly selected clones. The 10 most abundant transcripts accounted for > 45% of the clones. Subsequently, these transcripts were identified by filter hybridization, thus making DNA sequencing more productive. Overall, 4370 clones were identified: 3372 by DNA sequencing and 998 by filter hybridization. The number of groups of sequences identifying individual transcripts was relatively low compared with other tissues, resulting in a total of 934 groups out of 4370 ESTs. Of these, 719 groups were represented by only one sequence. PMID- 8681138 TI - Structural Organization of the WD repeat protein-encoding gene HIRA in the DiGeorge syndrome critical region of human chromosome 22. AB - The human gene HIRA lies within the smallest critical region for the DiGeorge syndrome (DGS), a haploinsufficiency developmental disorder associated with instertitial deletions in most patients in a juxtacentromeric region of chromosome 22. The HIRA protein sequence can be aligned over its entire length with Hir1 and Hir2, two yeast proteins with a regulatory function in chromatin assembly. The HIRA transcription unit was found to spread over approximately 100 kb of the DGS critical region. The human transcript is encoded from 25 exons between 59 and 861 bp in size. Domains of highest conservation with Hir1 and Hir2 are encoded from exons 1-11 and 13-25, respectively. The amino- and carboxy terminal regions of homology are separated from each other by a domain unique to HIRA that is encoded from a single exon. Seven WD repeats are conserved between yeast and man in the amino-terminal region of the HIR proteins. Individual repeats were found to be encoded from one, two, or three exons of the HIRA gene. End sequences have been obtained for all 24 introns, opening the way to PCR amplification of the entire coding sequence starting from genomic DNA. Point mutations can also be sought in 16 of the 24 introns that are readily PCR amplifiable. PMID- 8681139 TI - PCR-LIS-SSCP (Low ionic strength single-stranded conformation polymorphism)--a simple method for high-resolution allele typing of HLA-DRB1, -DQB1, and -DPB1. AB - We have developed a simple and efficient procedure with which to form single stranded DNA [ssDNA] and then applied HLA-DRB1, -DQB1, and -DPB1 allele typing. This method is referred to as low ionic strength single-stranded conformation polymorphism (LIS-SSCP), and is based on the diversity in the electrophoretic mobility of ssDNA formed by heat denaturation in low ionic strength solutions. This method detected DNA polymorphisms, including point mutations at a variety of positions in the DNA fragments of the HLA-DRB1, -DQB1, and -DPB1 genes. Under our experimental conditions, stable ssDNA could be kept at room temperature > or = 5 hr without having been cooled on ice immediately after heat denaturation. A total of 41 HLA-DRB1, 14 HLA-DQB1, and 17 HLA-DPB1 alleles from 220 healthy people were analyzed using a combination of PCR-LIS-SSCP with group-specific amplification. All of the alleles analyzed were discriminated among the DRB1, DQB1, and DPB1 groups except for DPB1*0402 and 0201. The efficiency of ssDNA formation using the LIS-SSCP procedure was higher than that of the traditional formamide method, and the SSCP profiles were clearer than those of the original SSCP. This procedure is useful for screening new alleles as well as the donor-recipient molecular matching of HLA class II genes. It is simple, rapid, and cost effective, requiring neither radioisotopes nor enzymes to confirm the typing results of other methods. PMID- 8681140 TI - Long RT-PCR of the entire 8.5-kb NF1 open reading frame and mutation detection on agarose gels. AB - Previous approaches to mutation detection in mRNA from the neurofibromatosis 1 (NF1) locus have required the PCR amplification of five or more overlapping cDNA segments to screen the entire 8.5-kb open reading frame (ORF). Systematically, these assays do not detect deletions that span the region of overlap (usually 1-3 exons) of any two consecutive target segments. In such cases, amplification from the mutant region of the disease-causing allele fails because binding sites for the PCR primers are missing, but amplification from the normal allele proceeds, yielding only the normal product. To alleviate this problem, we have developed a protocol to reverse transcribe and amplify the entire protein-coding sequence of NF1 as a single PCR product, starting with total RNA from lymphoblast cell lines or from whole blood. The 8.7-kb RT-PCR product was prepared from nine NF1 patients with known deletions or insertions, ranging in size from a 30-bp deletion within 1 exon to a 2.4-kb deletion that removes 12 exons. Agarose gel analysis of the initial products detected deletions as small as 341 bp. Restriction endonuclease digestion with Asel and Fspl, followed by agarose gel electrophoresis, revealed the predicted abnormal bands in all nine patients. All mutant bands were identified readily by observers with no knowledge of the patients' mutations. This simple assay should detect a great variety of insertion/deletion mutations in the NF1mRNA internal to the primer binding sites, including all possible single and multiple exon dropouts and approximately 30% of all previously reported NF1 mutations. PMID- 8681141 TI - Are you star material? PMID- 8681142 TI - Safe care of the latex-sensitive trauma patient. AB - Latex protein allergies are becoming more commonplace in the healthcare setting and pose a challenge to first responders and trauma resuscitation team members. The authors present an overview of latex sensitivity and its prevalence and outline signs and symptoms. They also identify commonly used assessments and treatment tools that may contain latex, and suggest possible substitutes. Suggestions for proactive ways to create a latex-free environment are included. PMID- 8681143 TI - Delayed splenic rupture. AB - Due to its location in the abdominal cavity, the spleen is a prime target for damage from blunt injury. Splenic rupture can occur immediately or it can be delayed up to 14 days following injury. A case report is presented involving a patient who sustained a ruptured spleen 2 weeks following an altercation. PMID- 8681144 TI - Blood substitutes and bloodless surgery. PMID- 8681145 TI - Top 10 ways to balance trauma patient care with attention to price tag. PMID- 8681147 TI - Making the diagnosis of allergy. AB - A thorough and continuing history is the primary means for establishing the diagnosis of inhalant allergy. Confirmation of offending allergens may be accomplished by either skin tests or in vitro methods. Clinical judgment is necessary to draw appropriate inferences from the allergy history, confirmatory physical examination, adjunctive tests and specific allergen skin tests or in vitro assays. PMID- 8681146 TI - Double-blind cross-over controlled clinical trial of vegetable oil versus xerolube for xerostomia: an expanded study abstract. PMID- 8681148 TI - Attachment of the adjustable tracheostoma valve and housing from the view of a laryngectomee. PMID- 8681149 TI - Postoperative head and neck cancer patients with artificial airways: the effect of saline lavage on tracheal mucus evacuation and oxygen saturation. AB - The practice of normal saline bolus instillation prior to suctioning is being questioned as to its harmful effects on patients' oxygenation levels. However, there are no clinical data to support halting its use on patients undergoing major head and neck procedures with unique airway concerns. MATERIALS AND METHODS: Twenty postoperative nonventilated head and neck cancer patients with a tracheostomy were studied at the Pittsburgh Cancer Institute/University of Pittsburgh Medical Center. The authors were interested in evaluating arterial oxygen saturation elicited by suctioning with and without a 5-cc saline bolus and the amount of secretions obtained by the different methods of suctioning. Measures of SaO2 values were monitored at baseline and immediately after suctioning, as well as 15, 30, and 45 seconds, and 1, 2, 3, and 5 minutes following the end of suctioning. Methodology was a quasi-experimental, single case, repeated-measures design which allowed patients to serve as their own controls. RESULTS: The mean sputum weight with normal saline was 7.75 g, and 4.53 g without saline. Findings concerning SaO2 showed that no saturation levels dropped below 95%. CONCLUSION: We concluded that using normal saline instillation as part of the suctioning procedure does significantly enhance mobilizing bloody mucus tracheal secretions common in postoperative head and neck cancer patients and does not cause oxygen desaturation. PMID- 8681150 TI - Address of the president of the American Nurses' Association. PMID- 8681151 TI - Nursing values: the heritage of our past; the foundation of our future. PMID- 8681152 TI - [Effects of presentation mode on visual-spatial working memory performance in children and adults]. AB - We report two studies investigating the effects of several experimental manipulations on visuo-spatial memory performance in children and adults. In particular, we were interested in memory for the location of objects. A picture reconstruction task was used where picture-like arrangements of four to six items were briefly presented and then reconstructed. In the first experiment with 5- and 8-year-olds and adults, the degree of visual differentiation of the items as well as presentation mode (simultaneous versus serial) were varied. Contrary to our hypothesis, there was a negative effect of simultaneous presentation in children, but only if the degree of visual differentiation was low. There was no such effect in adults. In a second experiment with 6- and 8-year-olds and adults, we again varied presentation mode, but excluded the scene-like character of the arrangements. All the age groups were slightly better with serial presentation. However, reducing the available schematic knowledge led to a severe performance decrease. The results are related to the current discussion about a further fractionation of the VSSP and to different assumptions about internal representations of location information. PMID- 8681153 TI - [Working memory and work with memory: visual-spatial and further components of processing]. AB - Empirical and theoretical evidence for the concept of working memory is considered. We argue that the major weakness of this concept is its loose connection with the knowledge about background perceptive and cognitive processes. Results of two relevant experiments are provided. The first study demonstrated the classical chunking effect in a speeded visual search and comparison task, the proper domain of a large-capacity very short term sensory store. Our second study was a kind of extended levels-of-processing experiment. We attempted to manipulate visual, phonological, and (different) executive components of long-term memory in the hope of finding some systematic relationships between these forms of processing. Indeed, the results demonstrated a high degree of systematicity without any apparent need for a concept such as working memory for the explanation. Accordingly, the place for working memory is at all the interfaces where our metacognitive strategies interfere with mostly domain-specific cognitive mechanisms. Working memory is simply our work with memory. PMID- 8681154 TI - Strength training early after myocardial infarction. AB - BACKGROUND: Many activities of daily living require significant amounts of muscular strength. Time lines for current strength training guidelines preclude many myocardial infarction patients from receiving strength training as part of their cardiac rehabilitation program. This study was designed to examine the effectiveness and safety of low-to-moderate level strength training in patients early after myocardial infarction. METHODS: Fifty-seven low-risk men ( < 61 years of age, 6-16 weeks post-infarction) were randomly assigned to a control group or one of three treatment groups. All groups trained aerobically, three times per week for 12 weeks. The three treatment groups performed additional strength exercises on each training day of the last 10 weeks. These groups differed in their strength training stimulus with Group 20 performing 20 reps of 20% of 1 repetition maximum (1 RM), Group 40 performing 10 repetitions of 40% of 1 RM, and Group 60 performing 7 repetitions of 60% of 1 RM. RESULTS: Maximal strength remained unchanged in the control group (+0.5%), but increased in Groups 20, 40, and 60 by +10.5%, +11.9%, and +13.5%, respectively. The increases in strength in the treatment groups were all significantly different (P < .001) from the results of the control group, but were not significantly different from each other. For the three treatment groups, 30 of 42 subjects had one or more cardiovascular complication (arrhythmias, angina, ischemia, hypertension, hypotension) during the aerobic exercises as compared to only 1 subject with complications during the resistive exercises (P < .01). CONCLUSIONS: In selected patients, low-to-moderate intensity strength training performed early after infarction is effective and may have lower rates of cardiovascular problems than aerobic exercise. PMID- 8681155 TI - Psychological predictors of subsequent medical care among patients hospitalized with cardiac disease. AB - BACKGROUND: There have been numerous reports indicating a relation between psychological distress and coronary artery disease. The authors tried to determine whether psychological distress in patients hospitalized for coronary artery disease is associated with the amount of medical care required after discharge. METHODS: Using a prospective clinical cohort, 210 patients who had been admitted for myocardial infarction (n = 67), percutaneous transluminal coronary angioplasty (n = 75), or coronary artery bypass grafting (n = 68) were followed for 6 months. Index psychological status was determined from questionnaires measuring depression and anxiety. Disease severity was assessed by the index hospitalization medical record of left ventricular ejection fraction, number of stenotic vessels, and number of noncardiac comorbidities. The amount of subsequent medical care delivered was based on the number of days of rehospitalization for cardiac-related illness and for any reason within 6 months after discharge. This was determined from a combination of computer medical record and patient self-report. RESULTS: The authors first determined that both psychological depression and disease severity each predicted days of rehospitalization. (Anxiety was not predictive of rehospitalization.) Next, disease severity was controlled for using partial correlation, and depression was still predictive of rehospitalization. Finally, the authors combined the predictor variables using a regression model to predict rehospitalization. Depression was a significant main effect in all models predicting rehospitalization. CONCLUSIONS: Psychological depression appears to be an important predictor of rehospitalization among persons who have been admitted with coronary artery disease. PMID- 8681156 TI - Cholesterol awareness and treatment in patients with coronary artery disease participating in cardiac rehabilitation. AB - OBJECTIVES: To survey cholesterol management practices among patients with coronary artery disease enrolled and not enrolled in cardiac rehabilitation. BACKGROUND: The National Cholesterol Education Program (NCEP) initially established guidelines regarding cholesterol awareness and treatment in 1987. Serum cholesterol reduction is most effective for reducing cardiac events in patients with established coronary artery disease, yet surveys of cholesterol awareness and treatment have not included these patients. METHODS: Three hundred seventy-nine men and women with coronary artery disease were surveyed according to cholesterol awareness, serum cholesterol level, frequency of lipid-lowering medication use, and frequency of achievement of a serum total cholesterol < 5.2 mmol/L (200 mg/dL) corresponding the 1987 NCEP guidelines for coronary artery disease patients, which were in place at the time of the study survey. RESULTS: Overall, 72% of the patients were aware of their cholesterol level, with an average serum total cholesterol of 5 5 +/- 1.0 mmol/L (213 +/- 39 mg/dL). Use of lipid-lowering medication was 26%. Forty-three percent had a total cholesterol < 5.2 mmol/L (200 mg/dL). Patients enrolled in a long-term cardiac rehabilitation program demonstrated enhanced cholesterol awareness (78%), lower total cholesterol values (5.2 +/- 0.9 mmol/L [203 +/- 36 mg/dL]), higher use of lipid lowering the therapy (34%), and more frequent achievement of total serum cholesterol of < 5.2 mmol/L (200 mg/dL) (48%) compared to the other patient groups (all P < .05). CONCLUSIONS: Patients with coronary artery disease demonstrate relatively low rates of cholesterol awareness, lipid-lowering medication use, and achievement of total serum cholesterol < 5.2 mmol/L (200 mg/dL) corresponding to the 1987 NCEP guidelines. Participation in long-term cardiac rehabilitation is associated with enhancement of these rates. Further efforts to educate physicians and develop programs to optimize cholesterol management in patients with coronary artery disease are needed. PMID- 8681157 TI - Women's views of cardiac rehabilitation programs. AB - BACKGROUND: Previous approaches to understanding participation in cardiac rehabilitation programs based on middle-aged men may not be useful to explain the participation of women. The focus group research method produces unique data about attitudes and experiences that can serve as an adjunct to other forms of data collection in an effort to develop models explaining cardiac rehabilitation participation. The aim of this pilot study was to examine the perceptions and experiences of women participating in a cardiac rehabilitation program using focus groups. METHODS: Ten women (mean age 72 years) who had recently participated in a cardiac rehabilitation program were interviewed in focus groups of 6 and 4 members each using a semi-structured interview guide. Verbatim transcriptions of the focus group interviews were analyzed by two individuals using content analysis methods. RESULTS: Results indicated that prior to participation women had no idea what to expect in a cardiac rehabilitation program. Features women liked most about the program included: (1) feeling "safe" during exercise because they were monitored; (2) peer group support during rehabilitation; and (3) pleasant, encouraging staff. Women desired more: (1) social interaction during the cardiac rehabilitation exercise sessions; (2) emotional support from staff members about all dimensions of cardiac recovery; and (3) exercise options other than cycle or treadmill. CONCLUSIONS: Several cardiac rehabilitation program design and operational features are perceived by women as not meeting their needs. Although limited by its small sample size, findings from this study provide valuable insights into women's perceptions of cardiac rehabilitation programs. PMID- 8681158 TI - Value of gas exchange analysis in heart disease. PMID- 8681160 TI - Internships in cardiopulmonary rehabilitation. Think win-win. AB - From a student's perspective, completing an internship program is the final, and maybe the most important step in his or her academic career. He or she finally gets a chance to put theory into practice and to see if he or she truly enjoys his or her chosen field. Through hard work and dedication, the efforts should provide her/himself with the practical skills and experiences necessary to propel her/himself into the work force. For the program, having interns can be viewed as just having an "extra hand," but with the proper commitment it can be much more rewarding. It is a unique opportunity to get a fresh new perspective on your own program, and a chance to mold students into eager young professionals. The internship experience truly is a "Win-Win" situation. Through the efforts of combined education--the internship site and the cardiopulmonary rehabilitation program working together--they can ensure that tomorrow's practitioners will be of the highest quality. PMID- 8681159 TI - Value of gas exchange analysis in heart disease. PMID- 8681161 TI - Vocal cord dysfunction. A syndrome that mimics asthma. PMID- 8681162 TI - The effect of a submaximal exercise orientation on cardiopulmonary cycle ergometer stress test results in older adults. AB - BACKGROUND: Orientation sessions are sometimes used to habituate subjects before exercise stress testing. The extent of habituation in older subjects has not been clearly defined. Additionally, the use of repetitive maximal stress testing as an orientation method may not be necessarily applicable in the aged. METHODS: To determine if the employment of a submaximal orientation session would effect cardiopulmonary cycle ergometer exercise results, 266 older adults (68.6 +/- 5.0 years) male (n = 100) and female (n = 166) subjects participated in this study. One hundred thirty-one subjects received an orientation before stress testing. One hundred thirty-five did not. RESULTS: Analysis of resting values revealed no significant differences. Separate gender analysis was performed at submaximal workloads. Men were examined at 0, 60, and 105 Watts; women at 0, 45, and 75 Watts. Oriented subjects displayed significantly lower heart rates for both males and females at all submaximal workloads. Oxygen uptake was significantly lower for oriented women at 45 Watts (P < or = .05) and men at 60 Watts (P < or = .05). Oriented males displayed significantly lower systolic blood pressure at 0 Watts (P < or = .05), 60 Watts (P < or = .01), and 105 Watts (P < or = .05). The oriented group reached ventilatory threshold (VeT) at a higher workload (P < or = .001), lower heart rate (P < or = .001), and higher VO2 uptake (P < or = .05). Nonoriented subjects obtained a significantly higher maximal heart rate than oriented subjects (147 +/- 15.7 beats per minute (bpm) vs. 140 +/- 17.1 bpm, P < or = .01). Separate gender analysis revealed a significant difference (P < or = .01) in maximal heart rate in males (oriented = 137.4 +/- 18.8 bpm vs. nonoriented = 147.7 +/- 15.7 bpm). Although nonoriented women achieved a higher maximal heart rate, the difference was not significant (146.9 +/- 15.8 bpm vs. 142.6 +/- 16.0 bpm). CONCLUSION: These results indicate that both male and female older subjects display significant modification in physiologic performance from habituation after a single submaximal exercise orientation session. This effect was greater at submaximal than maximal workloads, and appears to be greater than that previously reported in younger subjects. PMID- 8681163 TI - [Lost science in the third world]. PMID- 8681164 TI - [Scientific journals in Spanish]. PMID- 8681165 TI - [Telematics and neurology]. PMID- 8681166 TI - [Neuropsychology of left-handedness: current knowledge]. AB - About 10% of the population is left-handed or non-right handed. Its brain organization and cognitive skills could differ in relation to right-handed subjects. Our current knowledge is far of get to know its etiology. The scientific literature is sufficiently wide as interesting to review its main contributions. The experimental studies undertake the last 30 years, but this current revision is centred on studies from the last 10 years. From them it is concluded that in Neuropsychology of the left-handedness there are great disagreements. The investigation needs to distinguish types of left-handedness or non-right-handedness, while it is not demonstrated that there is a single type of left-handedness. PMID- 8681167 TI - [Home mechanical ventilation in neuromuscular diseases]. AB - In most patients with neuromuscular disorders, respiratory insufficiency and problems arising from this are what determine whether or not they survive. Treatment for failure of the respiratory pump by mechanical ventilation in the patient's own home has become more common thanks to the advent of non-invasive methods of treatment such as the nasal mask. Home mechanical ventilation has improved both the survival rate and the quality of life of many of these patients. We review the different types of home ventilation, describing the advantages and disadvantages of each one, with the intention of making information regarding this kind of treatment more easily available. PMID- 8681168 TI - [First adult seizures]. AB - This review analyses the diagnostic, prognostic and therapeutic aspects of a first epileptic crisis occurring in adult patients. Although it is generally accepted that a cranial CT scan is indicated after the first crisis in order to rule out a structural cerebral lesion after the first crisis, the need for cerebral MR studies in such cases is debatable. The decision to begin anticonvulsant treatment is very controversial, mainly because of the difficulty in assessing the risk of recurrence in any given person. In each case this decision should be reached after bearing in mind the factors indicating risk of recurrence, the patient's personal condition, their work and their own opinion. PMID- 8681169 TI - [Diet and migraine]. AB - Some foods in our diet can spark off migraine attacks in susceptible individuals. Some foods can bring an attack on through an allergic reaction. A certain number such as citrus fruits, tea, coffee, pork, chocolate, milk, nuts, vegetables and cola drinks have been cited as possible allergens associated with migraine. This mechanism has however been criticized: an improvement in symptoms by eliminating some food(s) from our diet does not necessarily mean an immunologically based allergic reaction. The high IgE incidence rate is not greater in such patients than in the population at large. Other allergic reactions unrelated to diet may also be associated with migraine attacks. On the other hand substances in food may be the cause of modifications in vascular tone and bring migraine on in those so prone. Among such substances are tyramine, phenylalanine, phenolic flavonoids, alcohol, food additives (sodium nitrate, monosodium glutamate, aspartame) and caffeine. Another recognized trigger for migraine is hypoglycemia. Such foods as chocolate, cheese, citrus fruits, bananas, nuts, 'cured' meats, dairy products, cereals, beans, hot dogs, pizza, food additives (sodium nitrate, monosodium glutamate in Chinese restaurant food, aspartame as a sweetener), coffee, tea, cola drinks, alcoholic drinks such as red wine, beer or whisky distilled in copper stills, all may bring on a migraine attack. For every patient we have to assess which foodstuffs are involved in the attack (not necessarily produced by consuming the product concerned) in order to try to avoid their consumptions as a means of prophylaxis for migraine. PMID- 8681170 TI - [Callosotomy in the treatment of drug-resistant epilepsy]. AB - At the present time corpus callosotomy is a valuable option in the management of some patients with drug-resistant epilepsy who are not candidates for resective procedures. The records of six patients who underwent callosotomy at 'Hospital Virgen de las Nieves' (Granada, Spain) in the past four years were retrospectively analyzed. The patients all had intractable primary or secondarily generalized seizures, were severely handicapped by its frequency and nature (especially with drop attacks and multiple injuries) and were not suitable for other surgical procedure. The results of surgery (five anterior callosotomies and one subtotal section) are described after an average follow-up period of 2.5 years. Overall, four patients achieved significant improvement (at least 50% reduction in seizure frequency, severity, or both, affecting quality of life), with a marked reduction (> 75%) in two of them. There was no clinical deterioration, significant surgical complication nor relevant additional long term neuro-psychological deficit in any case. Previous studies have been reviewed mainly to find those prognostic factors associated with a better seizure outcome or with the occurrence of complications. The best results are obtained in those patients with drop attacks (including atonic seizures) as the most frequent and disabling seizure type. According to the type of epilepsy, patients with localization-related epilepsy (especially when symptomatic of a focal brain damage) and those with the Lennox-Gastaut syndrome are the most likely to benefit from the procedure. It is suggested that, in the first place, a two-thirds anterior callosotomy should be performed particularly with atonic seizure are the most frequent seizure type. We may proceed with completion of callosal division as a second stage in those patients in whom a significant improvement has not been observed. In severely retarded patients with multiple seizure types, one stage complete section may be performed. The procedure is relatively safe, with a low incidence of morbidity and clinically significant long-term neuro psychological deficits. Further larger clinical studies are necessary to elucidate many aspects which are still unresolved. More uniformity would be desirable in the evaluation of patients, surgical technique, follow-up and presentation of results. PMID- 8681171 TI - [Multiple cerebral hematomas: review of 7 cases]. AB - We present seven patients with multiple spontaneous cerebral haemorrhages, diagnosed by CT scan, in a 10-year period in the Hospital 12 de Octubre. The clinical presentation, radiologic features, and prognosis of this entity are analyzed, and the diverse etiologic factors are discussed. All of the patients in this series were over 50 years of age, the majority not hypertensive (57%, n = 4), and in almost half the cases (43%, n = 3) the brain haemorrhages were associated with diverse coagulation disorders. The localization of the haemorrhages was exclusively supratentorial. Four patients presented with a moderate global confusional state, and one patient with deep coma. All the patients had focal signs. The mortality was elevated, with three patients dying, but the clinical evolution and outcome of those who survived was favourable. PMID- 8681172 TI - [Transient global amnesia. Case-control study of 24 cases]. AB - Transient global amnesia (AGT) is a well-defined syndrome of unknown aetiology. It is generally believed to be of vascular origin. Other theories suggest epilepsy or migraine as the cause. We studied the clinical features and associated risk factors in 24 patients with AGT, comparing them with two control groups with 24 people in each group, paired for age and sex. The first control group contained healthy individuals (CN) and the second patients with transient ischaemic attacks (AIT). Of the patients with AGT, 70% were women and 30% men. Their average age was 60 (range 14-76). The attacks were abrupt in onset in 100%. In 8% there was a recognisable trigger factor (driving, physical exercise, etc). The average duration was 7 hours. On study of the cardiovascular risk factors, it was found that 36% were hypertensive, 24% had cardiopathy, 12% had diabetes mellitus, 8% were smokers, 4% had polycythaemia, 16% had hyperlipidaemia, 4% were alcoholics. There was a history of migraine in 29%. No patient had a past history of epilepsy. Further investigation showed ECG changes in 12%. In 24% there were non-specific changes in the EEG. On cerebral CT scan there were lesions compatible with ischaemia in 12.5% of the patients. Levels of arterial hypertension were significantly higher in the AGT group as compared to the normal control group (Odds ratio 7.86; CI. 1.29-11.38). A past history of migraine was seen to be a risk factor associated with AGT as compared with both groups of controls (AGT/CN Odds ratio 9.47; CI 1.01-444.92; AGT/AIT Odds ratio > 1.72). PMID- 8681173 TI - [Cerebral arterio-venous malformations in children under 10 years]. AB - INTRODUCTION: Arteriovascular malformations are anomalies of the embryonic development of cerebral vessels. They usually appear at between 10 and 30 years of age, being infrequent in infants. OBJECTIVE: Describe our experience of angiomas in small children. MATERIAL AND METHOD: The histories of all children under 10 years of age with the diagnosis of arteriovenous malformation admitted to our department between November 1984 and May 1995 were reviewed. RESULTS: Nine patients, aged between 3 months and 10 years; seven cases presented as intracranial haemorrhage, one with epileptic crises and another with general clumsiness and a hemicerebellar syndrome. The diagnosis was confirmed by angiography and/or study by the pathologist in all cases. Six patients were treated surgically and the other three by embolization. Of the latter, two also received radiosurgical treatment. The complications seen were; two children died, one during the acute phase and the other four years later as direct consequence of the haemorrhage. Six patients had residual neurological defects. One child had no complications. CONCLUSIONS: Intra-parenchymatous haemorrhage is the commonest manifestation of angiomas in children under 10 years of age. The high risk and serious consequences of bleeding make it necessary for treatment to be as radical as possible. PMID- 8681174 TI - [Home mechanical ventilation by nasal mask in a patient with Duchenne's disease]. AB - The clinical course of Duchenne's dystrophy is characterized by respiratory insufficiency secondary to failure of the breathing pump. Up to ten years ago, this respiratory insufficiency was corrected by mechanical ventilation via a tracheostomy. In recent years, nasal mechanical ventilation has been a considerable advance in the treatment of these patients' respiratory problems. We describe a patient with Duchenne's dystrophy who was satisfactorily treated by non-invasive mechanical ventilation. PMID- 8681175 TI - [Vertigo as an atypical symptom of intraspinal cord tumor]. AB - Vertigo is an unpleasant sensation of movement of the subject or of his surroundings. There are many causes of vertigo. Traditionally these are divided into 'central' and 'peripheral'. It is unusual to find it as a symptom of myelopathy. We describe the case of a 67 year-old woman with no significant previous clinical history who complained of the sudden onset of vertigo a few hours previously, which worsened on turning her neck towards the left. On examination, the vertigo recurred on turning her neck to the left after a latent period of a few seconds together with the appearance of ipsilateral conjugated nystagmus, which gradually disappeared. On neurological examination, there was amyotrophy of both arms with weakness, considerably reduced reflexes, except for clonus of the left wrist. There was slight paraparesia with bilateral cutaneoplantar flexion and a level of sensitivity at C2-C3. The sensitivity disorder was more marked in the arms with a bilateral distribution approximately at C5-C7 affecting predominantly thermoanalgesia. Cervical MRI showed a mass consistent with ependymoma. This was removed surgically 2 weeks after admission. The findings of the intraoperative biopsy confirmed the radiological diagnosis. The vertigo improved one week after admission, although the patient died of pneumonia one month after operation. Despite the vertigo was an atypical symptom, it was the clue that led to the diagnosis. Hypotheses about the cause of vertigo are discussed. PMID- 8681176 TI - [Familial paroxysmal ataxia: a new case]. AB - Over the last years several families affected of a clinical syndrome characterized by sudden ataxia, related to physical or mental stress, and lasting a few days have been described. Intercritical exploration is otherwise normal. We describe a new case which presents the clinical, laboratory and neuroradiological data characteristic of periodic familial ataxia. The patient is a 34 year old male who from his 23 has suffered three crisis of gait inestability, ataxia of trunk and limbs and spontaneous nystagmus in every direction, which increased in association with head movement. These episodes were always in relation with fatigue and stress and have decreased in severity. Mean duration of crisis has been 4 to 6 days. After starting treatment with acetazolamide there have no new crisis. In this case we have found no family history of the disease as it was the rule in previous description. PMID- 8681178 TI - [Ulegyria and epilepsy]. AB - Ulegyria is a derangement of the architecture of the cerebral cortex characterised by the presence of multiple small cerebral convolutions. It is caused by hypoxic-ischaemic damage of these convolutions in the perinatal period. This differentiates it from polimcrogyria which is due to damage during the period of late neuronal migration or early postmigration. The clinical findings vary from cases with hardly any symptoms to more severe forms which show psychomotor retardation, convulsive crises and/or motor defects. We describe the case of a 21-year-old patient who suffered anoxia during delivery, with a very low Apgar score, who presented with epileptic crises in childhood (motor foci which became generalized) with good anticonvulsant control. On examination, there was a slight mental handicap. On magnetic resonance an uligyric area was seen in the occipital cortex. High resolution magnetic resonance allows the diagnosis of this type of change in the cerebral cortex in the living patient since the differences between grey and white matter can be distinguished better than with computerized tomography. PMID- 8681177 TI - [Acute intermittent familial ataxia: report of a new family]. AB - INTRODUCTION. Acute intermittent familial ataxia is a rare disorder with autosomal dominant inheritance and unknown etiology which usually in childhood or adolescence. CASE 1. A 33-years-old woman who suffered from giddiness, gait ataxia, dysarthria and somnolence episodes. These episodes lasted between 4 and 72 hours. They generally occurred within a framework of emotional or physical stress. The following tests were performed: hemogram and biochemistry, blood and urine toxicology, immunological tests, cerebrospinal-fluid study, electrocardiogram, electroencephalogram, trunk and visual evocated potentials, cerebral computed tomography and cerebral magnetic resonance imaging. None of them gave significative results. CASE 2. A 12-years-old boy, son of the previous woman, who suffered from somnolence, gait ataxia and dysarthria with acute beginning. The same tests than in the above case were performed together with metabolic studies. There were no pathological findings in this case, either. The symptoms disappeared gradually in 6 days. His familial history led to a diagnosis of acute intermittent familial ataxia. A year later he suffered from a similar disorder and he was immediately treated with acetazolamide. The symptoms disappeared in 2 hours. CONCLUSIONS. Acute intermittent familial ataxia is a disorder of difficult identification. It can be easily confused with other periodical ones, because its diagnosis has to be based on the clinical findings and on the familial history. For this purpose, a therapeutic test with acetazolamide can be useful, since in most cases a spectacular clinical improvement has been observed. PMID- 8681179 TI - [Dementia, parkinsonism and myoclonic seizures in a 58-year-old woman]. PMID- 8681180 TI - [Biblical neurology]. PMID- 8681181 TI - [Magnetic resonance imaging in Binswanger's encephalopathy]. PMID- 8681182 TI - [Drug-induced and masked drug parkinsonism]. PMID- 8681184 TI - [Juvenile epilepsy: a psychological view]. PMID- 8681183 TI - [Episodic depression in electroencephalography and midazolam]. PMID- 8681185 TI - [Peer review in medical journals]. PMID- 8681186 TI - [Data banks in epilepsy: clinical usefulness]. PMID- 8681187 TI - [Current aspects of nociceptive transmission: peripheral mechanisms and spinal modulation]. AB - Nociceptive transmission shows unusual features of sensorial physiology, due to the complex modulation which occurs from the start of the impulse until its final perception. In recent years the dynamic role played in nociception by peripheral structures, such as the 7 and spinal nociceptors and the second order neurones, has been recognized. It is fairly clear how a number of modulators activate and make nociceptors sensitive, accounting for the appearance of clinical features such as primary hyperalgesia, and their persistance. Thus eico sanoides, histamine, bradykinin and others allow considerable control of nociceptor activity. Also, the dorsal horn neurones play an important part in other clinical signs associated with pain, such as mechanical (secondary) hyperalgesia. At this level, some neurotransmitters such as glutamate or the neurokinins seem to be important in central sensibilization phenomena which occur when a painful stimulus is maintained. In fact, continued release of these neurotransmitters implies the expression of certain genes and the production of certain proteins. Knowledge of the relationship between the different neurochemical systems and subsequent changes in their expression in different pathological situations may help to explain the pathophysiology of some clinical signs of neuropathic pain which are at present inexplicable. PMID- 8681188 TI - [Basic neurobiology of hippocampal formation]. AB - The hippocampal formation constitutes a SNC region of a great interest for neurobiologists and neurologists, since it plays a key role in cognitive processes such as memory and learning, as revealed by numerous experimental studies and clinical cases. Anatomically, the hippocampus belongs to the archicortex, comprising three neuronal layers. Neighbour regions (gyrus dentatus, subiculum and entorhinal cortex) together with the hippocampus made up the hippocampal formation. Neurochemical studies have revealed the existence of several neurotransmitters such as glutamate, acetylcholine, GABA and catechols. Glutamate and their receptors represent the basis of a phenomenon of long-lasting increase in synaptic efficacy, called long-term potentiation or LTP. Long-term potentiation appears to be a synaptic mechanism related to memory and learning processes. Hippocampus and limbic system as a whole, show a slow electrical rhythm, of an irregular 4-10 Hz pattern, called theta rhythm. Theta rhythm has been proposed to reflect the "gating' of information through the hippocampal circuits. Hippocampal formation is a lamellar region, with a basic trisinaptic circuit, including short and long loops. This structure has led to the connectionist hypothesis, stating that the hippocampus behaves as an autoassociate neural network. Such a hypothesis sheds new lights on how processes such as short-term memory, cognitive mapping, non-association learning and discrimination are carried out within hippocampus. PMID- 8681189 TI - [Prion-type pathologies: from scrapie to prion-related dementias. On the borderline between veterinary and human pathology]. PMID- 8681190 TI - [Cerebrovascular complications of Takayasu's disease]. AB - We report four young women with Takayasu's arteritis who developed an ischemic stroke. In three of these patients, this complication heralded the onset of the disease. Three patients also had seizures. In all cases, the diagnosis was suspected on the basis of an abnormal cardiovascular examination showing absent carotid or radial pulses, carotid bruits or significant asymmetries in blood pressure determinations. The aortogram showed that three patients had Takayasu's arteritis type I, with affection confined to the aortic arch and supra-aortic trunks, and the other patient had Takayasu's arteritis type III with additional involvement of the descending aorta. Three patients had an elevated erythrocyte sedimentation rate and were treated with corticosteroids. Takayasu's arteritis should be suspected in young patients, especially women, presenting with a cerebral infarct or seizures who also have an abnormal cardiovascular examination. The diagnosis is usually confirmed by aortography, following Ishikawa's diagnostic criteria. Corticosteroid therapy may be of value in patients with an elevated erythrocyte sedimentation rate. PMID- 8681191 TI - [Stroke incidence in Asturias, 1990-1991]. AB - BACKGROUND: Stroke, with a rate of 121/100,000 was the second cause of death in Asturias, Spain. Here we communicate the results of a population based stroke register in the oriental health districts of Asturias. METHOD: The study took place between October 1, 1990 and May 30, 1991, covering a population of 652,549. Surveillance was both active and passive and included the public and private hospitals, and the primary health care. Death certificates could not be checked due to legal reasons. We defined case following the WHO criteria. RESULTS: During the eight months of study 708 case occurred. The crude incidence rate of first stroke was 132.4/100,000 and that of any stroke, 162.7/100,000. The age adjusted incidence to the world population was, respectively, 61.3/100,000 and 73.6/100,000. There were no differences in the incidence across sexes. Age showed a strong effect in cerebral infarctation and less marked in intracerebral hemorrhage Infarcts are very rare in women before 50. Distribution of stroke type was: infarct: 77%; intracerebral hemorrhages: 14%: subarachnoid hemorrhage: 4% and unspecified stroke: 4%. Almost 50% of the strokes occurred in the morning hours, from 6:00 am to 12:00 am also during the cold season, winter and fall, the proportion of stroke was higher than during the warm season. CONCLUSION: Stroke is an important cause of morbi-mortality in Asturias. The magnitude of mortality is larger than the expected from the incidence. It maybe explained by a high case/fatality ratio in Asturias due to proportion of hemorrhagic stroke, the ageing of the population and the distribution of competing causes of death. However, we cannot rule out a small incomplete registration of cases, mostly in patients over 85. We estimated the incidence of any stroke, given underegistration, to be 176/100,000 for any stroke. PMID- 8681192 TI - [Perinatal asphyxia, hypoxic-ischemic encephalopathy and neurological sequelae in full-term newborns: an epidemiological study (1)]. AB - INTRODUCTION: Perinatal asphyxia, and its neurologic manifestations (hypoxic ischemic encephalopathy) is the most important cause of brain injury and neurologic sequelae in full-term infants. OBJECTIVE: The aim of this study was to know the incidence of perinatal asphyxia, hypoxic-ischemic encephalopathy and neurologic sequelae in our full-term infants. MATERIAL AND METHOD: Prospective epidemiologic study of perinatal asphyxia in full-term infants born in Universitary Hospital San Juan (Alicante, Spain) between November 1991-February 1995. Perinatal asphxyia was graded as non severe (1-minute Apgar score < or = 6 and/or umbilical artery pH < 7.20, with abnormal fetal heart rate patterns and/or meconiumstained amniotic fluid, and the need for immediate neonatal resuscitation) and severe (1-minute Apgar score < or = 3 and umbilical artery pH < 7.10). Hypoxic-ischemic encephalopathy was graded as mild, moderate and severe based on classification of Levene and Sarnat & Sarnat. Neurologic sequelae in 12 24 months follow-up was graded as mild, moderate and severe based on classification of Finer and Amiel-Tison. RESULTS: During the study period there were 3.342 full-term, live births. Perinatal asphyxia developed in 156 (31 severe and 125 non-severe), with an incidence of 4.66 cases per 100 full-term newborns. Neurologic manifestations was present in 25.6% of 156 term infants with perinatal asphyxia: 40 cases of hypoxic-ischemic encephalopathy (mild in 30, moderate in 5 and severe in 5). The incidence of hypoxic-ischemic encephalopathy was 1.19 cases per 100 full-term infants. The asphyctic newborns were regularly assessed. Ten infants was lost to follow-up. The incidence of neurologic sequelae, in 115 asphyxiated full-term infants follow-up at least 12-24 months, was 16.5%. CONCLUSIONS: Despite the widespread use of the term perinatal asphyxia, there is little uniformity on the clinical definition of asphyxia, which makes comparison of incidence, treatment and outcome very difficult. The main epidemiologic differences in the studies of perinatal asphyxia and hypoxic-ischemic encephalopathy are due to little agreement on their definition. A consensus is necessary. PMID- 8681193 TI - [Etiology in complex partial epilepsy. I. Neuroimaging studies]. AB - With the appearance of MR, a great advance has been made in the study of the aetiology of epilepsy. This technique can show anomalies not detected in CT scans, obtain images of multiple planes, improve the differentiation of cerebral tissues and allow improved visualization of the temporal lobe, making it very useful in the study of patients with complex partial crises (CPC). We studied 151 epileptics with CPC by means of CT scan and MR in all cases; the anomolous topography was the same in all cases, but the diagnosis was not. In patients with a previously normal CT scan, on MR anomalies were detected in 24 cases. We found a statistical differences on evaluation of the MR anomaly depending on whether the CT scan was normal or abnormal. Statistical differences were also found when there were a greater number of anomalies on MR depending on the frequency of crises at the onset of the disorder. PMID- 8681194 TI - [Epilepsy and learning]. AB - This report deals with cerebral processing in terms of simultaneous and successive processing in a sample of 33 epileptic children at ages 3 to 12 years. Epileptic children were selected according to the following criteria: two clinical seizures with convulsive movements, with unconsciousness, with no fever, with focus in intercritical EEG and normal brain scanner. All of them attended ordinary school. A sample of 261 normal children was used as a control group. The K-ABC battery was administered to both epileptic and control group. The results were analyzed in terms of Student's t-test, chi 2 test, stratified chi 2 test, and factor analysis. It is concluded that a kind of epilepsy may be associated with poorer performance in successive processing. PMID- 8681195 TI - [Periodical EEG pattern modifications in herpetic encephalitis treated with acyclovir]. AB - The presence of PLED or localized or lateralized periodic activity in encephalitis strongly suggests that the encephalitis is due to the herpes simplex virus. Nevertheless, there has been controversy over its clinical significance. In addition, since the introduction of antiviral drugs in the treatment of herpes encephalitis in its initial stages, the prognosis of the disease has improved. We studied nine patients all diagnosed as having herpes encephalitis and treated with acyclovir. The presence or absence of periodic activity and its characteristics were analyzed. It was seen that either there was no such activity, or if there was, it was not exactly as classically described. PMID- 8681196 TI - [Meningiomas of the lateral ventricles: a case report]. AB - We describe the case of a patient with an intraventricular meningioma, which initially manifested as transient mental impairment. Meningiomas are slowly growing, bening tumours, which usually remain asymptomatic or show only insidious clinical manifestations for long periods. In our case the distinct localization of the tumor gives rise to a peculiar clinical picture, with special reference to the episodic nature of symptoms. In this case we want to remark the role of both the clinical and neuroradiological data in the diagnosis of this pathology. PMID- 8681197 TI - [Cervical intramedullary neurofibroma]. AB - Spinal neurofibromas make up a third of all tumours of the medulla. They are usually found to be intradural and extramedullary. Exceptionally they may be intramedullar. We describe the case of a patient with signs of slowly progressive compression of the medulla, who was operated on surgically for an intramedullary neurofibroma, after imaging studies. We review the previously published cases and analyse the different histogenic theories concerning this tumour. PMID- 8681198 TI - [Atypical internuclear ophthalmoplegia in a patient with subacute lymphocytic meningitis]. AB - The local expression of tuberculous meningitis has an high incidence. They respond to a Koch bacillus direct lesion or vasculitis disease. The clinic implication of ocular movement is frequent and usually answers to a nervous trunk direct injury. Exceptionally the clinic expression of the oculomotor disturbance is due to a conjugate ocular tract or nucleus damage. The posterior internuclear ophthalmoplegia is a well-known manifestation and correspond with a dwindle of the medial longitudinal fasciculus electrical transmission and lies in falling of the medial rectus to move synchronously with the contralateral rectus on attempted lateral gaze to either side. In such a case the medial longitudinal fasciculus is damaged between the sith nerve nucleous below and the opposite third nerve nucleus above. A patient with AIDS B3 category who presents right internuclear ophthalmoplegia and right eye vertical conjugate gaze impairment with left vertical nystagmus due to a paramedial mesencephalic stroke as debut of a linfocitary subacute meningitis is present. PMID- 8681200 TI - [Phenotype variability in adrenoleukodystrophy. Presentation of three new cases and a review of literature]. AB - INTRODUCTION: Adrenoleukodystrophy is a hereditary recessive sex-linked disorder with very variable phenotype expression, including classical infantil ALD, adrenomyeloneuropathy (AMN) in adults and sex-linked Addison's disease. Clinical observations. Three affected patients are presented. The first showed signs of myeloneuropathy from the age of 38 and diagnosis was made by showing raised serum and fibroblasts levels of very long chain fatty acids (C26:0). In the second case symptoms started at the age of 13 and cerebral and peripheral nervous system changes developed progressively. This patient's brother was the third case, showing symptoms when he was 21 and developing cerebral, medullary and peripheral nervous system involvement. In the latter two cases, diagnosis was made by showing intracytoplasmatic trilaminary inclusions in the nervous system. CONCLUSIONS: It is important to recognize the different varieties of this disease in view of the possibilities of genetic counselling and of the therapeutic implications which are currently being evaluated. PMID- 8681199 TI - [Sensory-motor polyneuropathy associated with lung tuberculosis: presentation of two new cases]. AB - The association of active tuberculosis with changes in the peripheral nervous system is not well defined, although it is included amongst the neuro-muscular disorders of the peripheral nerve diseases due to infective agents. We describe the case of two patients with sensory-motor polyneuropathy and coexistant active pulmonary tuberculosis which was untreated prior to diagnosis of the peripheral nervous system disorder. In both cases the condition was sub-acute and did not improve until treatment was begun. Anti-tuberculosis treatment was followed by marked improvement of both the pulmonary tuberculosis and of the polyneuropathy. The close chronological relationship of both clinical pictures with the therapeutic response supports the hypothesis of the pathogenesis of the peripheral nervous system disorder being mediated by an anomolous immune response, initiated by the infection with Koch's bacillus. PMID- 8681201 TI - [A transcultural view of neurological and mental pathology in a Tzeltal Maya community of the Altos Chiapas]. AB - OBJECTIVES: This anthropological study forms part of field-work undertaken in Mahosik, a Tzeltal Maya community of 250 inhabitants in the Altos de Chiapas, to obtain insight into the neurological and psychosomatic pathology in an ethnic and cultural setting different to ours. MATERIAL AND METHOD: Accompanied by a Tzeltal translator we interviewed various witch-doctors and faith healers of the Tzeltal Maya tribe to find out their ideas about neurological and mental diseases and the treatments used. RESULTS: Headache or "k'ux jolol' is the fourth most common cause of consultation after acute respiratory and gastrointestinal disorders and fevers. To relieve it, the boiled leaves of the bush "payte' ("Tagetes neisonii') are used as a medicinal bath. Migraine, "yaxti-wanjol chawaj' is treated with the raw, crushed roots of the herbs "chopak pox' and "bakte pox' together with the practice of cutting the patient with a piece of glass in the temporal region, deep enough to make him bleed. Epilepsy or "tub tub ikal' is caused by an abuse suffered by the animal spirit which accompanies the individual, after a fight between the animal-companions or spirits which serve the forces of Good and Evil. The person with chronic crises is considered a witch. Depression or "melotan' is fairly common. This is treated with camomile tea containing an orange and a lime leaf. "Xiwel' or fear is one of the commonest psychosomatic disorders. The faith healer has to return the lost spirit to its owner in a ceremony involving prayer, alcohol and the sacrifice of a fowl. Psychosis or "jowijel' may be due to alcohol, dog bite or witch craft and has no cure. Madness "chawaj' is caused by bewitchment during a nightmare. It is treated with the sap of "viborana' mixed with wild beans. PMID- 8681203 TI - [Dysphagia, dysphonia and Horner's syndrome as a form of presentation of right subclavian artery aneurysm]. PMID- 8681202 TI - [Molecular factors of cerebral hypoxia-ischemia]. AB - In recent years much has been learned about the cellular and molecular events underlying cerebral hypoxia-ischemia (HI). We review, from a molecular standpoint, the main pathogenetic theories in hypoxic-ischemic cerebral injury, including excitotoxicity, free radical damage, and the role of growth factors, proto-oncogenes and heat shock proteins. The various forms of cell death in the developing and adult brain (necrosis, apoptosis and delayed neuronal death) are reviewed, with an emphasis on gene regulation of naturally-occurring and HI associated cell death. We report the expression of the immediate early gene c-fos and c-jun mRNAs and of HSP72 mRNA and protein in several models of cerebral HI. Gel agarose electrophoresis of extracted DNA and in situ end-labeling of fragmented DNA revealed that cell death in these models was associated with endonuclease(s) activation. We also pre-treated some animals with dexamethasone, a neuroprotective drug in a model of perinatal HI. High-dose dexamethasone prevented c-fos induction in cerebral regions sensitive to HI. This effect may be due to a functional antagonism, at the transcriptional level, between Fos and the glucocorticoid receptor. PMID- 8681205 TI - [Author and Subject Index. Czech and Slovak Ophthalmology vol. 41-50]. PMID- 8681204 TI - [Mortality factors in subarachnoid hemorrhage]. PMID- 8681206 TI - Strategies for successful clinical information system selection. AB - The CIS market is volatile. With consumer pressure to develop and the current interest in CISs, clinicians recommended reassessing the market again in 18 months. Even without fully mature systems, there are foundational CISs available on the market. Strategies for successful CIS selections are many: Decide to be a developer or buyer early in the process. Entering into a long-term relationship with a vendor to develop customized capabilities will mandate different requirements than purchasing a ready-to-use system. Use a systematic method for evaluating systems, preferably multimethod. Force structure into the evaluation process with vendors, especially for the system demonstration. Structure will ensure that each system function, or lack of function, is exposed and assessed and will allow for consistent and fair evaluations across vendors. Make the vendor commit to distinguishing between existing and proposed functions during system demonstrations. Often, vendors promise the very functions you want to be in the next release. Most vendors will cooperate with structured schedules. However, some vendors may resist structure because it interferes with marketing strategies. If, despite requests for specific materials and schedules, vendors fill the time with unsolicited material, ask yourself why and beware: they may not have the functions you requested. Use a brief clinical scenario as a preview into system functions, integration, and system usability. Ask vendors for conceptual models of system functional and technical architecture. Use an interdisciplinary team. Focus subgroups in specialty areas for efficiency and effectiveness in evaluation. Consider tape-recording the joint group sessions for later confirmation or analysis. Consider application integration as one of the major requirements for future CISs, especially between ambulatory and inpatient arenas. PMID- 8681208 TI - A format for surveying computer-related learning needs in health care settings. PMID- 8681207 TI - Implications for nursing education. A virtual Mrs. Chase and cyberspace learning. PMID- 8681209 TI - Impact of clinical information systems on nursing practice. Nurses' perspectives. AB - This article adds to the literature on the impact of computerized clinical information systems by asking nurses important questions about their nursing practices. A research tool was developed from collaborative work with clinicians who have used computers in their daily practice for more than two decades. A statewide study then was conducted on how nurses believed computer technology impacted their practice. This study also examined the different views that computer users and nonusers held. Questions were posed relating to resource consumption, nursing work practices, and professional and patient outcomes. It was found that nurses, whether computer naive or knowledgeable, clearly do not expect the technology to have negative impact on practice. The two groups differed mostly in the strength of their beliefs. One startling outcome, that slow computer response time delayed care, was identified within the computer-user group and direct action was taken as a result. PMID- 8681210 TI - Attitudes toward computers. A test of construct validity. AB - A study was undertaken to examine the factors that influence student and registered nurse attitudes toward computers. This article provides a report of the psychometric findings related to the use of Stronge and Brodt's Nurses' Attitudes Toward Computerization questionnaire. The convenience sample consisted of 394 registered nurses employed in a large metropolitan hospital and 299 baccalaureate student nurses. Principal component analysis was performed identifying three factors for the nurse sample, including nurses' work, organizational issues, and barriers to use. Four factors emerged in the student sample: nurses' work, barriers, organizational issues, and efficiency issues. These findings were inconsistent with previous studies and the underlying categories identified by Stronge and Brodt. Further development of the understanding of the substantive components of attitudes toward computers is recommended. PMID- 8681211 TI - Improving organizational processes for gains during implementation. AB - Reengineering work processes has not been a traditional part of health care automation. With the new emphasis on quality and cost cutting, users are more receptive to improving processes as they are automated in new or replacement systems. The authors describe a process flowcharting technique, which, as part of the implementation design phase, assists users in understanding and engineering the processes impacted during the implementation. Also described is a strategy for securing cooperation from physicians and other key players. PMID- 8681212 TI - The effects of individual and nursing-unit characteristics on willingness to adopt an innovation. A multilevel analysis. AB - In this study, the authors investigate the effects of efficacy and cooperativeness on willingness to adopt an innovation at the individual and nursing-unit levels. The results of a field report showed that efficacy was significantly associated with willingness to adopt an innovation at both the individual and nursing-unit levels, whereas cooperativeness was significant only at the individual level. These results suggest that examining innovation adoption at multiple levels provides more valid information than does examining it at a single level. PMID- 8681213 TI - User expectations and perceptions of a patient management information system. AB - The use of computers in health care has become increasingly common. However, implemented systems at times have not met the expectations of the user group, resulting in disconfirmed expectations. This article takes a first tentative look at the notion of disconfirmed expectations and the possible impact disconfirmed expectations may have upon the perceptions of the system the user group may develop. Seventy-two pre-users and 30 users completed a questionnaire regarding their system expectations (pre-users) or system perceptions (user). Analysis examined occupation and use (pre-user/user) ratings. Results found vast differences in both use and occupation. When examining the observed differences in use (pre-user/user), a discriminant analysis identified nine factors that discriminated significantly between these groups, with 'user support' being the main factor. When examining the groups by occupation (clerical, nursing, other) it was found that differences were explained by how effective the system was at meeting their daily work requirement needs. These results are discussed in relation to system implementation strategies. PMID- 8681214 TI - [Classification of fractures in children]. PMID- 8681215 TI - [Nursing care]. PMID- 8681216 TI - [The management of Farid during hospitalization]. PMID- 8681217 TI - [Supracondylar fractures in children]. PMID- 8681218 TI - [Redon: nursing surveillance and removal]. PMID- 8681219 TI - [Drugs in pediatrics]. PMID- 8681220 TI - [Health project in a rural milieu]. PMID- 8681222 TI - [Specific management of fractures in the child]. PMID- 8681221 TI - [EMLA cream in hematology]. PMID- 8681223 TI - [Pediatric liason form]. PMID- 8681224 TI - [Pediatric emergencies: hernias, pyelonephritis]. PMID- 8681225 TI - [Trauma and fractures in children]. PMID- 8681226 TI - [Epidemiology of fractures]. PMID- 8681227 TI - [The psychological dimension of deafness]. PMID- 8681228 TI - [Severe and profound perceptual deafness. Social management]. PMID- 8681229 TI - [Severe and profound perceptual deafness. Specialized management]. PMID- 8681230 TI - [Severe and profound hearing deficiencies: prosthetic rehabilitation]. PMID- 8681231 TI - [Cochlear implant: evaluation and intervention]. PMID- 8681232 TI - [Individualized nursing care plans]. PMID- 8681233 TI - [Enuresis]. PMID- 8681234 TI - [Management of a handicap]. PMID- 8681235 TI - [Infant nutrition]. PMID- 8681236 TI - [Pediatric emergencies: fractures, convulsions]. PMID- 8681238 TI - [Screening of hearing disorders in children]. PMID- 8681237 TI - [Multidisciplinary management]. PMID- 8681239 TI - [Pediatric oncology. The parents' role]. PMID- 8681240 TI - [Pediatric oncology. Family admission]. PMID- 8681241 TI - [Pediatric oncology. Nursing management]. PMID- 8681242 TI - [Pediatric oncology. Antineoplastic chemotherapy]. PMID- 8681243 TI - [Lumbar puncture with intrathecal injection]. PMID- 8681244 TI - [Prevention of mucositis]. PMID- 8681246 TI - [A trip up the mountain]. PMID- 8681245 TI - [Pediatric oncology. The role of the nurse]. PMID- 8681248 TI - [The hospitalization of a child]. PMID- 8681247 TI - [Inservice training of probationers]. PMID- 8681249 TI - [Nutritional needs]. PMID- 8681250 TI - [Pediatric emergencies: pyloric stenosis, urticaria]. PMID- 8681251 TI - [To be a nurse in pediatric oncology]. PMID- 8681252 TI - [Pediatric oncology. A multidisciplinary team]. PMID- 8681253 TI - Depression associated with multiple sclerosis: an etiological conundrum. AB - OBJECTIVE: Although depression frequently occurs in multiple sclerosis (MS), an association with cerebral pathology is unclear. This sets MS apart from other common neurological disorders. The reasons for this are explored. METHOD: The literature on depression and magnetic resonance imaging (MRI) is reviewed and methodological issues are critically evaluated. RESULTS: Failure to demonstrate cerebral correlates of depression is in part a function of poor study design. However, the diffuse nature of cerebral demyelination creates difficulties in image analysis peculiar to MS. CONCLUSIONS: More research using valid psychiatric assessment procedures, high field strength MRI and automated lesion detection is needed to resolve the issue. It is premature to reject psychosocial causes at this stage. PMID- 8681254 TI - Clinical management of Tourette's syndrome and associated disorders. AB - OBJECTIVE: To review the clinical management of Tourette's syndrome (TS) and the associated disorders, namely obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) with an emphasis on the pharmacologic intervention strategies. METHOD: English language literature on the pharmacologic management of TS and the associated disorders published between 1985 and 1994 was critically reviewed. RESULTS: Pharmacologic management was placed in the context of the overall clinical management. Pharmacologic strategies for treatment of TS, OCD and ADHD were organized according to the therapeutic agent class. CONCLUSIONS: The treatment of TS and its associated disorders requires the application of the full range of psychiatric skills to achieve a favourable outcome. PMID- 8681255 TI - Conceptual models and integrative therapy: anorexia nervosa as a prototype. AB - OBJECTIVE: To demonstrate how an integrative approach to psychiatric treatment can confer specific advantages. METHOD: The impact of conceptual models on clinical information processing and therapeutic intervention, and the potential benefits resulting from the incorporation of multiple treatment modalities are outlined. These principles are applied using anorexia nervosa (AN) as a prototypical disorder. RESULTS: A brief, structured review of the broad range of models which have been applied to AN illustrates the impact of conceptualization on outcome. The opportunity for positive integrative effects in the treatment of AN are demonstrated. They are seen to be related to 6 factors: flexibility, patient-treatment matching, stage-treatment matching, facilitation, complementarity, and synergism. CONCLUSION: Integrative methods can address some limitations in clinical information processing associated with the exclusive application of a single conceptual model. Positive integrative effects are demonstrated in the context of AN; however, the approach is recommended for more general application. PMID- 8681256 TI - The euthanasia debate: attitudes, practices and psychiatric considerations. AB - OBJECTIVE: To review the current status of the euthanasia debate by examining public and physician attitudes towards euthanasia, the practice of euthanasia in the Netherlands, recent developments in Canada and other countries, psychosocial considerations related to the desire for death in terminally ill patients, and the roles that psychiatrists may be asked to play in the event of legislative reform involving discriminalization. METHODS: A literature review was conducted focusing on recent surveys regarding physician and patient attitudes towards euthanasia, the role of psychiatrists and empirical data pertaining to the mental state of patients who request physician-hastened death. RESULTS: Psychiatric morbidity among patients requesting physician-hastened death is considerable. CONCLUSION: As a special case of suicide, euthanasia and physician-assisted suicide are of particular relevance to mental health professionals. PMID- 8681257 TI - Cigarette smoking during pregnancy. AB - OBJECTIVES: To determine: 1. the prevalence of regular smoking in the latter half of pregnancy in a sample of Canadian prenatal patients; 2. the psycho-social and demographic characteristics that differentiate smoking from nonsmoking patients; 3. the characteristics that differentiate prenatal patients who smoke more than 10 cigarettes per day from those who smoke 1 to 10 cigarettes per day; and 4. the psychiatric morbidities or psychological attitudes associated with smoking in pregnancy. METHODS: Consecutive consenting women 20 or more weeks pregnant were given, at a prenatal clinic, the General Health Questionnaire (GHQ), the Fetal Health Locus of Control (FHLC), and a study questionnaire to complete. RESULTS: Five-hundred and forty-five women completed the questionnaires. Eighty-nine (16.3%) women reported regular daily cigarette smoking in the second half of pregnancy, while 43 (7.9%) smoked more than 10 cigarettes per day. Women who smoked were more likely than nonsmokers to be under 21, born in Canada, have only elementary education, be unemployed and unmarried, eat unhealthy diets, drink alcohol, use nonprescription and illicit drugs, have unplanned pregnancies, histories of emotional and physical problems, and have suffered physical abuse before and during pregnancy. Smokers were more likely than nonsmokers to meet case status on the GHQ and on the FHLC to believe "chance" and less likely to believe that "internal control" or "powerful others" affected the health of their fetuses. "Social disorganization", "health risks", and "poor health" factors accounted for 83.1% of the total variance. CONCLUSIONS: Women who smoke in pregnancy have a higher rate than nonsmokers of other health risk behaviours, social disadvantage, and emotional disturbance. Psychiatrists can play an important role in identifying and treating emotional and psychiatric morbidity in women of reproductive age to facilitate a reduction in smoking rates in this high risk population. PMID- 8681258 TI - Self-esteem and cancer: theory and research. AB - OBJECTIVE: To examine the relationship between self-esteem and the psychosocial response to cancer. METHODS: The authors review methodological issues associated with measuring self-esteem in patients with cancer and examine existing empirical studies in light of these issues. RESULTS: Self-esteem in cancer has been variously viewed as an outcome variable, a mediator of other psychosocial outcomes, and as a personal resource that facilitates coping. Unidimensional measures of global self-esteem have been most often employed in research studies, despite increasing recognition that self-esteem is multidimensional. Evaluation of global self-esteem has generally revealed no differences between cancer patients and controls. Aspects of multidimensional self-esteem, particularly body self-esteem, appears to be disturbed in many patients with cancer. CONCLUSIONS: The clinical and theoretical literature have emphasized the importance of self esteem to the psychosocial response to cancer. Empirical study of self-esteem in cancer has been limited by conceptual and methodological issues. Strategies for future research are discussed. PMID- 8681259 TI - An overview of treatment in paranoia/delusional disorder. AB - OBJECTIVE: To examine delusional disorder (formerly paranoia) which has re emerged as an important diagnosis in psychiatry and familiarize present generation psychiatrists with this disorder and its treatment. To benefit other researchers, a bibliography is appended. METHOD: Approximately 1,000 articles on paranoia/delusional disorder were analyzed in detail. These articles date from 1961 with the greater majority dating from 1980 onward. Case descriptions were often vague and only cases identifiable by DSM-IV diagnostic criteria were accepted. Eventually 257 cases were accumulated, but it was only possible to report on treatment aspects of 209 of these, due to lack of detail. RESULTS: Because the data are so disparate, and the literature is confusing in therapeutics aspects, only the broadest conclusions can be drawn. However, it does appear that when adequately treated, delusional disorder is an illness with a reasonably good prognosis. Cases respond equally well to treatment, whatever the specific delusional content, and pimozide currently appears to be the neuroleptic which produces the best results. CONCLUSIONS: There is an urgent need to raise standards in the study of delusional disorder and its treatment. PMID- 8681260 TI - Suggestions for implementing community psychiatry training in existing residency programs. AB - OBJECTIVE: To demonstrate how an experience of partnership evolved when a group of psychiatry residents moved beyond the traditional hospital setting and began to question their current training. METHOD: We describe our experience in the context of the current literature and suggest ways of implementing community psychiatry training in existing residency programs. RESULTS: Principles of community psychiatry--partnership, respect and shared responsibility--are good standards in psychiatric care. CONCLUSIONS: Community psychiatry training may be possible in existing resident rotations, although teaching in the community setting may also be of value. Research and clinical work in "community psychiatry" need to be valued. Problems may be enriching if they are resolved collaboratively. PMID- 8681261 TI - The clozapine experience from a family perspective. AB - OBJECTIVE: To examine how the lives of family members of clozapine-treated patients with schizophrenia have been affected by this treatment. METHODS: Through the use of a questionnaire and an interview of family members, this qualitative study focused on the families' perceptions of change in their family member and the impact on the family unit. RESULTS: Fourteen patients and their family members participated. The family interview was conducted an average of 1.78 years after clozapine initiation (range 0.58 years to 3.73 years). Global ratings of behavioural change were positively and significantly correlated between all raters: patients, family members, and clinicians. Family members were positive about clozapine's effect on their relatives and the impact on the family. CONCLUSION: A positive response to clozapine decreases the burden on the family. This is in part the result of a decreased need for rehospitalization. PMID- 8681262 TI - Antidepressant-induced mania. PMID- 8681263 TI - Capgras and Fregoli's syndrome, aggression and mental retardation: a report of two cases. PMID- 8681264 TI - Augmentation of antidepressant therapy by buspirone: three geriatric case histories. PMID- 8681265 TI - Therapeutic dilemma: psychosis and Parkinson's disease. PMID- 8681266 TI - Classification of eating disorders. PMID- 8681267 TI - Stayin' alive: an introduction to survival analysis. AB - In some studies, the outcome of interest is the time until some event occurs: readmission to hospital, the next manic episode, or even death. Survival analysis is a technique which can be used to analyze such data. It has added usefulness because it allows us to use data from subjects who drop out of sight over the course of the follow-up period as well as from those who do not experience the event by the time the study ends. This article introduces this technique and provides some guidelines for designing follow-up trials. PMID- 8681268 TI - Views on classification and diagnosis of eating disorders. AB - OBJECTIVE: To highlight developments in the taxonomy of eating disorders since Russell's original description of bulimia nervosa (BN) in 1979 and through 3 versions of the Diagnostic and Statistical Manual. METHOD: Criteria for anorexia nervosa (AN), BN and binge eating disorder (BED) are systematically described. RESULTS: While criteria for AN remain largely unchanged between DSM-III-R and DSM IV, the subclassification of binge/purge and restricter subgroups endorses previous research findings. For BN, the definition of "binge" has occupied considerable attention both in quantitative and qualitative terms. The arbitrary choice of 2 episodes per week as a minimum frequency is also discussed in light of recent data from the Ontario Health Supplement. A third eating disorder, BED, is now included in the appendix of DSM-IV under Eating Disorders--Not Otherwise Specified category. The potential overlap between this disorder and nonpurging BN is discussed. Finally, the relationship between eating disorders and other psychiatric disorders including depression, schizophrenia, obsessional, and conversion disorders is considered as well as the continuum from preoccupation with weight to eating disorder. CONCLUSION: While significant advances have been made in understanding and classifying eating disorders during the past 15 years, further empirical work is necessary to clarify areas of uncertainty. PMID- 8681269 TI - Treatment of seasonal affective disorder: a review. AB - OBJECTIVE: To review the status of current treatment of seasonal affective disorder (SAD). METHOD: Treatment studies of SAD published between January 1989 and March 1995 were identified using a computerized MEDLINE literature search. Additional citations were obtained from the reference sections of these articles. Studies included in this review were selected using operational methodologic criteria. RESULTS: Many studies support the efficacy of bright light therapy using a fluorescent light box. The best studied protocol is > 2500 lux white light for 2 hours per day, but newer protocols using 10,000 lux for 30 minutes have comparable response rates. Studies of light visors and other head-mounted devices also report similar response rates, but have not yet shown superiority over putative control conditions. There are fewer medication studies in SAD, but controlled studies suggest that fluoxetine, d-fenfluramine and propranolol are effective. Other treatments such as dawn simulation require further study. No studies of psychological treatments for SAD were found. Many studies had methodologic limitations, including brief treatment periods, small sample sizes, and lack of replication, that limit the generalizability of findings. CONCLUSION: There are several well-studied, effective treatments for SAD, including light therapy and medications. However, further research must be done to demonstrate sustained treatment response over time, to clarify the intensity-response relationship of light therapy, to clarify the role of light therapy and medications, and to assess combination treatments. PMID- 8681270 TI - Comparative analysis of Native admissions and registrations to northwestern Ontario treatment facilities: hospital and community sectors. AB - OBJECTIVE: To study Native and non-Native admissions to acute psychiatric care in the northwestern region of Ontario in 1992. METHOD: To replicate a 1986 to 1987 study comparing Native to non-Native admissions to acute psychiatric care in the northwestern region of Ontario in 1992 and examine Native registrations to community mental health agencies in the first 6 months of 1993. RESULTS: The comparative analysis of hospital admissions revealed that: Natives are still being admitted at 33% more than the rate expected on the basis of population; depression appears to be underdiagnosed for Natives; they continue to be admitted mainly for reasons other than major psychiatric conditions; substance abuse and forensic history are commonly involved; they stay in hospital for twice as long as their non-Native control; they more often come from rural settings; and they are less likely to be followed by the outpatient service and more likely to be followed by the criminal justice system. The examination of registrations to community mental health agencies revealed that: the same overrepresentation of Natives; mood- and thought-presenting problems of Natives in this sector were identical to non-Natives; and their length of stay was similar. The psychiatric hospital appears to be providing acute care treatment, not for the serious psychiatric illnesses for which it is mandated, but for atypical admissions that result from economic, social and cultural dislocation. There may be underdiagnosis of atypical depression in the Native hospitalized population. When asked what they are being treated for the diagnostic profile of Natives and non Natives is identical on mood and thought dimensions. CONCLUSION: No appreciable change has occurred over the 5 years in the way hospital psychiatric services are used by Natives. Cultural stereotypes may be influencing the diagnosis of Natives in inappropriate ways. Enhancing Native control of treatment programs and community development may provide a partial solution. Properly mandated and accountable community agencies (both generic- and culture-specific) will help reduce unnecessary hospitalization. PMID- 8681271 TI - [Dangers and therapist obligations: Canadian perspective]. AB - OBJECTIVE: To clarify the position Canadian therapists must adopt regarding their obligation to protect others against patients' potentially violent actions. This obligation is based on jurisprudence which has been well established in the United States since the Tarasoff case, but which does not apply in Canada. METHOD: A review of jurisprudence in Canada and recent clinical recommendations. The latter are then discussed in the Canadian context and followed by a range of suggested avenues to explore. CONCLUSION: Professional standards could be established but they should be reviewed on a regular basis and allow flexibility for clinicians. PMID- 8681272 TI - Looking at legislative and judicial views of psychic trauma--fluctuating recognition and discrimination. AB - OBJECTIVE: To describe how Canadian courts and legislation have viewed psychic or emotional trauma in the past century and the principles that are used. METHODS: The author reviews major trends in legislation and judicial findings pertaining to emotional trauma and gives examples of the fluctuating and ambivalent recognition by the courts. RESULTS: The courts have progressed from refusing to acknowledge emotional trauma, to accepting emotional trauma when accompanied by physical trauma, and finally acknowledging emotional trauma even in the absence of physical injury and the "indirect" emotional trauma suffered by the relatives of victims. However, from time to time, the courts or legislation may appear to deny the distress, dysfunction or the rights of a person who suffers significant emotional symptoms after an injury. This occurred recently in Ontario where injured persons in motor vehicle accidents who suffered emotional trauma were not allowed to sue for compensation from June 1990 to January 1994. Combined efforts by a coalition of mental health professionals with victims of trauma at least partially reversed the discriminatory laws. CONCLUSIONS: Psychiatrists must continue to play a vital role in the education of the courts, politicians and the public about the realities of emotional trauma and mental illness and their long term impact so that fair compensation can be assessed by the courts and discriminatory legislation reversed. PMID- 8681273 TI - Group supervision of group psychotherapy. AB - OBJECTIVE: To explore the practice of group supervision of group psychotherapists using a process model. METHOD: The need for supervision and the advantages of the supervisory group setting are discussed highlighting the varying levels of interaction between the therapeutic system and the supervisory system. Assumptions basic to successful supervision are discussed. CONCLUSION: The processes leading therapists to understand that their experience in the supervision system can be an unconscious retelling of their clients' experience in the therapy group are explored. PMID- 8681274 TI - Re: Psychiatrists' attitudes to multiple personality disorder. PMID- 8681275 TI - Post-traumatic stress disorder: personal disability, social cost, and prevention. PMID- 8681276 TI - Sertraline-associated hyponatremia. PMID- 8681277 TI - Bilateral cerebral pathology and the genesis of delusional misidentification. PMID- 8681278 TI - Paresthesia as a side effect of the new antidepressant, nefazodone. PMID- 8681279 TI - Immunosuppressive drug therapy. PMID- 8681280 TI - An ethicist's commentary on whether a veterinarian should write a prescription of a branded drug in return for a financial incentive. PMID- 8681282 TI - Surgical removal of a fish bone from the canine esophagus through gastrotomy. PMID- 8681281 TI - Evaluation of clinicopathological parameters in cattle grazing timber milkvetch. AB - The purpose of this study was to determine whether hematological and serum biochemical parameters could be used to diagnose poisoning in cattle grazing timber milkvetch (Astragalus miser var. serotinus), a nitropropanol-containing legume. Blood samples were obtained from 20 Hereford cattle on timber milkvetch range in southern British Columbia during 1992 and 1993. Relevant changes in blood parameters were not detected and the parameters could not be used to predict nitropropanol ingestion or intoxication. The same parameters were measured in dosing trials with cattle with rumen fistulas, but relevant changes were not detected. Succinate dehydrogenase is the key target in nitropropanol intoxication and an assay for this enzyme may provide a probe for diagnosis. PMID- 8681283 TI - Tissue and serum concentrations of amikacin after intramuscular and intrauterine administration to mares in estrus. AB - Concentrations of amikacin in endometrial tissue and plasma were studied in mares in estrus after intrauterine infusion of 1.0 or 2.0 g once a day for 3 consecutive d, and after 9.7 or 14.5 mg/kg body weight (BW) had been injected intramuscularly once a day for 3 consecutive d to determine concentrations of amikacin sulfate in plasma and endometrial tissues, and whether parenteral administration provides any advantages over intramuscular infusion. No amikacin was detected in serum at the 1.0 g dose. At the infusion dose of 2.0 g once a day, very low levels of serum amikacin were detected at 1 and 4 h postinfusion on the 1st treatment day. Amikacin was found to penetrate the endometrium after intramuscular injection; however, the levels attained were not as high as those achieved following intrauterine infusion. Based on the tissue and serum concentrations of amikacin, an intrauterine infusion at a dose of 4.4 mg/kg BW/d would appear to be an appropriate therapeutic regimen for the treatment of gram negative endometritis. PMID- 8681284 TI - Calcinosis circumscripta in the footpad of a dog. PMID- 8681285 TI - The public health response to suspected rabies exposure in British Columbia (1989 1994). PMID- 8681286 TI - Metastatic thymoma in a goat. PMID- 8681287 TI - Cutaneous mast cell tumor in a Siamese kitten. PMID- 8681288 TI - Evaluation of dogs as sero-indicators of the geographic distribution of Lyme borreliosis in British Columbia. PMID- 8681289 TI - Umbilical artery marsupialization in a calf. PMID- 8681290 TI - Tracheal defect and embryonal rhabdomyosarcoma in a young dog. PMID- 8681291 TI - A case of Ehrlichia equi in an adult horse in British Columbia. PMID- 8681292 TI - Update on bovine virus diarrhea in Ontario. PMID- 8681293 TI - Diagnostic parasitology. PMID- 8681294 TI - Cervical line lesions: an update. PMID- 8681295 TI - Diagnostic ophthalmology. Retinal degeneration. PMID- 8681296 TI - Pancreatic carcinoma in perspective. A continuing challenge. AB - There are approximately 27,000 new cases of carcinoma of the pancreas each year and most afflicted patients will die of the disease. Although smoking is a common denominator, chronic pancreatitis is considered an important precursor lesion in a smaller number of cancers. Pancreatic cancer is primarily a disease of the pancreatic ducts. The molecular events are under intense study, but c-K-ras mutation is involved in approximately 80% of the cases and p53 to a slightly lesser degree (60-80%). Early manifestations are usually occult, but jaundice is a common manifestation in patients with cancers of the pancreatic head. Thin slice computed tomography, portography, and endoscopic retrograde cholangiopancreatography are currently the most sensitive detection techniques. The developing use of endoscopic ultrasound and laparoscopy appear to enhance detection and are under evaluation. In many patients with advanced disease, endoscopic bypass may eliminate the need for unnecessary surgery, although gastrointestinal bypass is still required in some patients (10-15%). Curative resection is possible in selected patients (perhaps 10-15%), with expectation of extended survival ranging from 6->20% in some series. The survival differences may be related to stage, patient selection, and the expertise of the operative team. Preoperative chemotherapy/radiation is under study and may improve outcome. Clinical trial participation is essential for improvement in treatment outcomes. PMID- 8681297 TI - Preoperative chemoradiotherapy for localized pancreatic carcinoma. A perspective. AB - BACKGROUND: The role of chemotherapy (CTX) in the treatment of localized adenocarcinoma of the pancreas must be enhanced if current results are to be surpassed. It is postulated that histologic response to various chemotherapeutic agents may offer an assessable endpoint intermediate to and perhaps as or more meaningful than survival analysis. METHODS: A history of trials assessing the value of adjuvant preoperative and postoperative chemotherapy and radiation therapy (RT) is provided. Experiences with histologic assessment of treatment response are reviewed. RESULTS: There has been no clear benefit from adjuvant CTX, either when delivered with RT or as postoperative maintenance. Imaging tests were much less sensitive than histologic grading in determining responses (7% vs. 71% partial responses) of patients with resected pancreatic cancers previously treated with RT/CTX. This suggests that standard imaging assessments of pancreatic carcinoma response to chemotherapy and radiation therapy may be inaccurate. CONCLUSIONS: Preresectional delivery of chemotherapeutic agents with RT allows response rates to be quantified histologically. This method of response analysis, being much more sensitive than analysis by computed tomographic scanning, may allow the more rapid development of improved chemotherapeutic programs for this malignancy. PMID- 8681298 TI - Intraoperative radiotherapy for pancreatic carcinoma. Experimental and clinical studies. AB - Intraoperative radiotherapy (IORT) is an innovative treatment approach that has been tested in several Phase I-II studies and small Phase III trials in patients with resectable and unresectable pancreatic cancer. The technical approach and dose guidelines for adjacent normal tissues have been established in a series of experiments using a large animal (canine) model. This article reviews the experimental and clinical studies of IORT in cancer of the pancreas. PMID- 8681299 TI - Palliation. Surgical and otherwise. AB - Carcinoma of the pancreas remains a disease with a grim prognosis. The majority of patients are not resectable for cure at the time of presentation, with less than 20% of affected patients surviving 1 year after diagnosis. Because cure is unlikely for most patients, palliation of symptoms (obstructive jaundice, duodenal obstruction, and pain) is of primary importance. Obstructive jaundice is the most common presenting symptom for cancer of the pancreas and can be managed by both surgical and nonoperative techniques. Although prospective randomized studies support an early advantage to the nonoperative techniques, concern for late complications, including recurrent jaundice and duodenal obstruction, favor a surgical approach. The management of pain due to unresectable carcinoma of the pancreas remains a significant problem. A recent prospective randomized study has shown that intraoperative chemical splanchnicectomy with 50% alcohol significantly relieves or prevents pain when compared with a placebo treatment. For patients not undergoing surgery, a percutaneous celiac nerve block can be performed quickly with overall good results. The decision to perform nonoperative versus surgical palliation for pancreatic cancer is influenced by the patient's symptoms, overall health status, projected survival, and the expected procedure related morbidity and mortality. The major advantage for surgical palliation is the ability of a single procedure to combine adequate long term palliation for all three primary symptoms of the disease. Most surgical series report acceptable hospital morbidity and mortality, and a reasonable postoperative length of hospital stay. PMID- 8681300 TI - Depression in patients with pancreatic carcinoma. Diagnostic and treatment issues. AB - BACKGROUND: Cancer of the pancreas is a highly malignant illness with a very poor prognosis. Unfortunately, there has been little in the way of improvement in prognosis over the past 20 years. It is feared by patients because of its reputation as a deadly and often painful disease. Given these realities, it is not surprising that depression and cancer of the pancreas often occur co morbidly. Depression and anxiety occur more frequently in patients with cancer of the pancreas than they do in patients with other forms of cancer. The etiology of depression in patients with cancer of the pancreas may be traced to more than the disease's poor prognosis, the pain it causes, or existential issues related to death and dying. METHODS: Clinical and research data on the connection between depression and cancer of the pancreas were reviewed. RESULTS: In many instances, symptoms of depression and anxiety may even precede knowledge of the diagnosis; one of several observations that have raised speculation that mood and anxiety syndromes are related to disruption in one of the physiologic functions of the pancreas (i.e., secretion of hormones, neurotransmitters, digestive enzymes, or bicarbonate). CONCLUSIONS: Whatever its etiology, the identification and treatment of depression associated with cancer of the pancreas is an important way in which oncologists and mental health professional can collaborate to enhance quality of life in this unfortunate population of patients. Diagnosis and treatment of depressive disorders as they applied to patients with cancer of the pancreas were reviewed, and psychologic and pharmacologic treatment strategies to deal with these issues were outlined. PMID- 8681301 TI - A rationale for expanding the endpoints for clinical trials in advanced pancreatic carcinoma. AB - BACKGROUND: Using classical endpoints, such as response rate and survival, as the sole measures of benefit, little progress has been made in the treatment of advanced pancreatic carcinoma in the past 30 years. We challenge the assumption that response rate and survival are the only appropriate endpoints for clinical trials in this disease setting. METHOD: A review of the literature and roundtable discussion were undertaken. RESULTS: Using current imaging techniques, it is inherently difficult to distinguish pancreatic tumor from normal pancreas, inflammatory tissue, local fibrosis, and unopacified bowel. As a result, objective tumor measurements are often imprecise, unreliable, and irreproducible. This difficulty may explain the wide variation in response rates reported in clinical trials even when the same therapies are used. Tumor-related symptoms, such as anorexia, weight loss, severe pain (requiring opioid analgesia), and impaired functional status, are prevalent and debilitating characteristics of this disease. Tools that can assess these symptoms in a consistent fashion over time have been developed and have been integrated into clinical trials to evaluate new drugs in this setting. CONCLUSIONS: Systematic assessment of the impact of a new therapy on tumor-related symptoms may provide a sensitive and accurate way to identify useful new treatments for patients with advanced pancreatic carcinoma. Such analyses can be a useful complement to the classical endpoints of response rate and survival. PMID- 8681302 TI - Activity of gemcitabine in patients with advanced pancreatic carcinoma. A review. AB - BACKGROUND: In early phase II trials in advanced pancreatic cancer, gemcitabine demonstrated modest antitumor activity. The investigators in these studies reported that gemcitabine should be studied further in view of the degree and frequency of symptomatic improvement observed, the durability of some of the remissions, and the favorable toxicity profile. METHODS: In order to quantify such symptomatic improvement, a rigorous endpoint of Clinical Benefit was developed that incorporated measures including pain intensity, analgesic consumption and performance status, which have been shown to be reliable and valid endpoints in other studies. RESULTS: Two trials have been conducted using this methodology in patients with advanced pancreatic carcinoma. CONCLUSIONS: The results of these studies suggest that gemcitabine is the first cytotoxic agent with any meaningful impact on survival and disease-related symptoms in advanced pancreatic adenocarcinoma. The degree of improvement seen is one which patients with cancer often consider to be most important. Further studies will be required to define more fully the role of gemcitabine in the treatment of pancreatic cancer. PMID- 8681303 TI - Pain management in patients with pancreatic carcinoma. AB - Pancreatic cancer has a very poor prognosis and is often associated with severe pain. A variety of pain syndromes and pain pathophysiologies can be identified. Information about the analgesic efficacy of available oncological treatments is very limited, but the available data suggest that pharmacological and non pharmacological approaches can be effective in the majority of cases. Guidelines have been developed for drug administration that emphasize indications, selection of routes, optimal dosing, and side effect treatment. Celiac plexus block can be considered for a subgroup of patients who fail to benefit from drug therapy. Optimally, pain management should be provided within a broader model of palliative care, which can address the many problems associated with this challenging disease. PMID- 8681304 TI - Chemotherapy for pancreatic carcinoma. AB - BACKGROUND: Pancreatic cancer is an aggressive disease and its patients typically have a short survival, usually marked by pain and rapid debilitation. The disease has been considered relatively chemoresistant, although many chemotherapy regimens have been described. METHODS: Clinical results with chemotherapy, since the first publication of response in 1960, were reviewed for efficacy and toxicity. Emphasis was given to prospective trials with adequate power and clear evaluation criteria and endpoints. RESULTS: Published response rates vary enormously in this disease, with rates in earlier single-institution trials tending to be much higher than those in studies with stringent response criteria, particularly recent cooperative group trials. Using stringent criteria, the upper limit of the objective response rate is approximately 20%. No convincing improvements in median survival can yet be attributed to chemotherapy. Few trials have measured quality of life, but symptomatic palliation rates may exceed objective response rates. Some low-toxicity regimens (such as those based on infusional 5-FU) yield response rates as high as some more toxic combinations. CONCLUSIONS: Many early trials significantly overstate the efficacy of chemotherapy for patients with pancreatic cancer, apparently due to flexibility of response criteria. However, useful symptomatic palliation may occur even without an objective partial response. It is possible that slow resolution of the desmoplastic component of these tumors may underestimate tumor killing. Thus, quality of life is an important parallel endpoint (with survival and response) in chemotherapy trials in this disease. PMID- 8681305 TI - Regional chemotherapy for inoperable pancreatic carcinoma. AB - BACKGROUND: Survival for adenocarcinoma of the pancreatic remains unchanged over the last two decades. The majority of patients (85%) are diagnosed with an inoperable tumor. Patterns of failure reveal that pancreatic cancer involves three compartments: the pancreatic bed and regional lymph nodes, the liver and the peritoneal surfaces. Twelve patients with advanced, unresectable pancreatic cancer, Stage II/III, were treated with regional intra-arterial chemotherapy and extracorporeal hemofiltration directed towards the pancreatic tumor-bearing area and the liver. METHODS: Five patients had an arterial catheter/port system placed within the celiac axis; the rest had an angiographically placed arterial catheter. All patients had a 16 Fr PFM filtration catheter inserted in the vena cava positioning the tip at the level of the diaphragm and then connected to a hemofiltration unit. Mitomycin C was infused over 25 minutes followed by 5-FU over 10 minutes. The hemofiltration was begun before the drug infusion and continued for 70 minutes. The twelve patients underwent 33 cycles of regional chemotherapy plus hemofiltration. RESULTS: Five patients had a partial response (45.5%), five had stable disease (45.5%), and one had progression (9%). Four patients were re-explored with one patient undergoing a curative resection. The average survival for patients with unresectable pancreatic adenocarcinoma is 13 months. Tumor implantation and progression on the peritoneal surfaces remains the major site of treatment failure. CONCLUSIONS: Regional chemotherapy plus hemofiltration with MMC and 5-FU appears to improve the response of Stage II/III inoperable pancreatic cancer and can convert some patients to resectability without significant complications and with no mortality. PMID- 8681306 TI - Preclinical studies of chemotherapy and radiation therapy for pancreatic carcinoma. AB - The use of radiation therapy combined with 5-fluorouracil (5-FU) in the treatment of pancreatic cancer has been well established. It has been hypothesized that any benefit from combined 5-FU and radiation has been due to radiosensitization. Improved therapy could result from a better understanding of the mechanism of radiosensitization and the development of compounds capable of providing better radiosensitization. This article reviews preclinical findings on the mechanism of cytotoxicity and radiosensitization for 5-FU, fluorodeoxyuridine, thymidine analogs, and gemcitabine (2',2'-difluorodeoxycytidine) and discusses the clinical implications of these findings. PMID- 8681307 TI - Clinical implications of tumor-associated neovascularization and current antiangiogenic strategies for the treatment of malignancies of pancreas. AB - There is now a substantial body of evidence that tumor growth is angiogenesis dependent, and that neovascularization is also necessary for tumor invasion and metastasis. In addition, the assessment of microvessel count or density in a primary tumor may ultimately prove to be significant and independent prognostic parameter for clinical outcome with respect to tumor recurrence, metastasis, and ultimately, overall patient survival. As our knowledge of the pathways, steps, and factors involved in the underlying pathogenesis of tumor-associate angiogenesis increases, therapeutic agents and modalities aimed at inhibiting angiogenesis by blocking one or more of these steps or factors may be devised and evaluated for their potential to inhibit cancer growth and spread. Ultimately, the inhibition of tumor-associated angiogenesis and associated processes could conceivably form the foundation upon which the treatment of aggressive malignancies is based. PMID- 8681308 TI - Systemic and adjuvant therapy for patients with pancreatic carcinoma. AB - BACKGROUND: Pancreatic cancer is a highly lethal disease with < or = 5% of patients surviving 5 years. There is no curative therapy for patients who cannot be surgically resected. Chemotherapy and radiation therapy can provide palliation but have not had a significant impact on 5-year survival. METHODS: Newer approaches for improving the survival of patients with pancreatic cancer integrating chemotherapy, radiation therapy, and surgery are being evaluated. New chemotherapeutic agents (e.g., gemcitabine, camptothecins, taxanes, thymydilate synthase inhibitors, and fluorouracil-related compounds) are being studied alone and in combination with each other or different agents (e.g., trimetrexate or platinum-related compounds). RESULTS: Increased knowledge about the biology of pancreatic cancer (including high frequency of ras and p53 mutations in neoplastic cells or the expression of a number of growth factor receptors on the cell surface) has lead to preclinical evaluation of novel approaches attempting to specifically target these. These novel approaches include gene therapy, vaccines, and antisense oligonucleotides targeted to genes important for proliferation or survival of pancreatic cancer cells. CONCLUSIONS: Continued development of new approaches is needed to improve the treatment and survival of patients with pancreatic cancer. PMID- 8681309 TI - Gabapentin: pharmacokinetics, efficacy, and safety. AB - Gabapentin is a new antiepileptic drug (AED) with an attractive pharmacokinetic profile. It is absorbed by an active and saturable transport system, and has a high volume of distribution. Gabapentin is not bound to plasma proteins, does not induce hepatic enzymes and is not metabolized. At steady state, it has a half life of 6-8 h, and is eliminated unchanged by renal route with a plasma clearance proportional to the creatinine clearance. It is devoid of significant drug-drug interactions when administered with the established AEDs or with oral contraceptives. Gabapentin used as an add-on AED significantly reduced the frequency of partial seizures and secondarily generalized tonic-clonic seizures in three large double-blind, placebo-controlled, parallel-group clinical trails. It is well tolerated, with transient somnolence and dizziness being the most frequent adverse effects. Although the mechanism of action of gabapentin is not fully established, there is strong evidence to suggest a novel mechanism of action. Gabapentin is a unique and promising drug that could improve the quality of life of patients with epilepsy and is a welcome addition to the armamentarium of currently available AEDs for the treatment of patients with seizures of partial onset. PMID- 8681310 TI - The nitric oxide pathway: potential implications for treatment of neuropsychiatric disorders. AB - The freely diffusible gaseous compound nitric oxide (NO) has recently been discovered to be an important cellular messenger in many organ systems throughout the body. The importance of NO as an intermediary in cell communication in the brain is highlighted by the fact that the excitatory amino acid glutamate, the most abundant central neurotransmitter, is an initiator of the reaction that forms NO. In this article, background information about the discovery of NO, its biochemistry, and a brief summary of some of its peripheral and central actions are given to provide a complete picture of this remarkable novel second messenger. We also discuss how an improved understanding of NO pathway may lead to the identification of novel medications for the treatment of a number of neuropsychiatric conditions, including memory deficits, pain, drug addiction, seizures, bipolar disorder, psychosis, eating disorders, and the treatment of the sequelae of various brain injuries. PMID- 8681311 TI - The pharmacokinetics of subcutaneously administered recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis: relation to parameters of the acute-phase response. The ALS CNTF Treatment Study (ACTS) Phase I-II Study Group. AB - Fifty-seven patients with amyotrophic lateral sclerosis (ALS) were randomly assigned to receive single subcutaneous doses of 0.5, 1, 3, 7, 10, or 30 micrograms/kg recombinant human ciliary neurotrophic factor (rHCNTF) or placebo. Peak plasma concentrations occurred 180 to 260 min after dosing. rHCNTF plasma concentrations then appeared to decay, with an apparent elimination half-life of 120-400 min. Eight of 12 patients who received the highest dose had measurable plasma rHCNTF levels 24 h after dosing. Peak plasma concentrations of rHCNTF in patients receiving 30 micrograms/kg rHCNTF were in the range that has been shown to support the survival of embryonic rat and human motor neurons in tissue culture. Systemic exposure to rHCNTF increased with increasing dose. The elimination of rHCNTF, over the dose range evaluated, appeared to follow first order processes. Elevations in body temperature and evidence of activation of the acute phase response were observed. PMID- 8681312 TI - A phase I study of recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis. The ALS CNTF Treatment Study (ACTS) Phase I-II Study Group. AB - Fifty-seven patients with amyotrophic lateral sclerosis (ALS) were randomly assigned to receive 0.5, 1, 3, 7, 10, or 30 micrograms/kg recombinant human ciliary neurotrophic factor (rHCNTF) or placebo subcutaneously 3 times a week for 2 weeks. Dose-limiting toxicity, consisting of febrile reactions in some patients, fatigue, and nonproductive cough, was observed at a dose level of 30 micrograms/kg. Dose-related changes in parameters of the acute-phase response were noted, consistent with the relationship of CNTF and its receptor system to the cytokine interleukin-6 (IL-6) and its receptor. No adverse neurologic consequences of rHCNTF administration were observed. Antibodies to rHCNTF were observed in sera of most patients tested after 2 weeks of continuous treatment and 4 weeks' withdrawal period. rHCNTF was safe and tolerated within acceptable limits when administered to patients with ALS in this study at doses of up to 30 micrograms/kg 3 times a week for 2 weeks. Further studies to explore the efficacy of rHCNTF in the treatment of human motor neuron diseases are justified. PMID- 8681313 TI - Dopamine receptor agonist- and antagonist-induced behaviors in primates previously treated with dopamine receptor antagonists: the pathogenetic mechanisms of acute oral dyskinesia. AB - Eight Cebus apella monkeys previously treated with dopamine D1 and D2 receptor antagonists were used to elucidate the pathophysiology of acute oral dyskinesia. Five monkeys had mild oral tardive dyskinesia because of previous antagonist treatment. Interactions between the dopamine (DA) D1 receptor agonist SKF 81297 and the DA D2/D3 receptor agonist quinpirole, DA D1 and D2 receptor antagonists, and the anticholinergic biperiden were investigated. SKF 81297, 0.3 mg/kg, induced acute oral dyskinesia and grooming, which were each inhibited by the DA D1 receptor antagonist NNC 756 in a dose-dependent manner. The DA D2 receptor antagonist raclopride enhanced SKF 81297-induced acute oral dyskinesia and suppressed SKF 81297-induced grooming, each with bell-shaped dose-effect curves. Quinpirole, 0.1 mg/kg, induced a hyperarousal syndrome (i.e., increased arousal, stereotypy, and locomotion). Concomitant treatment with SKF 81297 and quinpirole caused an extreme hyperarousal syndrome but antagonized acute oral dyskinesia and grooming, suggesting a synergistic effect of high-efficacy DA D1 and D2/D3 receptor agonists regarding the induction of the hyperarousal syndrome and the antagonism of acute oral dyskinesia and grooming. Biperiden, 0.25 mg/kg, antagonized both the SKF 81297-induced and raclopride-induced acute oral dyskinesia. The results suggest that oral dyskinesia and grooming are independent but most often simultaneously occurring behaviors. Grooming is induced by DA D1 receptor agonists and antagonized by D1 and D2 antagonists and D2/D3 agonists. Acute oral dyskinesia is induced by D1 agonists and lower doses of D2 antagonists, but antagonized by D1 antagonists, D2/D3 agonists, and anticholinergics. These results suggest varying interactions between dopaminergic receptor subtypes in different types of dopaminergic behaviors. PMID- 8681314 TI - ACE Inhibitors in Heart Failure: Advancing Clinical Practice. Proceedings of a symposium. Geneva, Switzerland, May 21-25, 1995. PMID- 8681315 TI - Interruption of the progression of heart failure: are ACE inhibitors the solution? AB - Our options for the medical management of heart failure are aimed at preventing the development of the condition, relieving symptoms, modifying the underlying pathophysiology, and delaying or preventing disease progression. The principal symptoms of heart failure are edema, dyspnea and fatigue. Diuretics are effective in relieving edema, and dyspnea resulting from pulmonary edema. Once pulmonary edema has been treated relatively few agents are effective against residual exercise-induced dyspnea, possibly because of the numerous possible causes of this symptom. Angiotensin-converting enzyme (ACE) inhibitors have, however, been shown to improve dyspnoea by mechanisms that are not related to hemodynamic actions. These agents also improve skeletal muscle blood flow and function, thereby relieving fatigue in heart failure patients. Treatment strategies aimed at modifying the underlying pathophysiology or preventing disease progression have, with the exception of the ACE inhibitors, met with limited success. Large scale trials have shown, however, that ACE inhibitors improve survival in patients with moderate or severe heart failure, and prevent the development of heart failure in asymptomatic patients. These agents, therefore, represent an important advance in the management of heart failure, and it is anticipated that new insights into their optimal use will follow as the mechanisms by which they exert their beneficial effects become clear. PMID- 8681317 TI - Ventricular remodeling. AB - Ventricular remodeling is a repair process. It can follow myocardial infarction, mechanical overload (for example, in hypertension or valvular heart disease), and also occurs in inflammation and dilated cardiomyopathy. Remodeling can be an (early) adaptive process followed by a maladaptive (late) phase and involves all cells that are present in the myocardium - the myocyte, the interstitial cells, the vascular endothelium, and the immune cells. Despite the varying etiopathology that these different aspects of heart disease share, a similar sequence of molecular, biochemical and mechanical events that can lead to heart failure, myocyte hypertrophy, extensive extracellular matrix production and fibrosis, even in patients who were previously unaffected by the original disease process (for example, inflammation or infarction). Heart failure can be influenced by treatment of the underlying disease and by modification of the remodeling process, for example, by ACE inhibitors (cardioreparation). In experimental animals it has been clearly demonstrated that ACE inhibitors may even prevent a genetically predetermined left ventricular hypertrophy (cardioprevention). PMID- 8681316 TI - Myocardial infarction: when and how should we initiate treatment with ACE inhibitors? GISSI-3 Investigators. AB - Recent trials have shown that angiotensin-converting enzyme (ACE) inhibitors can reduce mortality and the occurrence of severe left ventricular dysfunction (LVD) when started within the first day after acute myocardial infarction and continued for 4-6 weeks thereafter. When started within this time window, ACE inhibitors are safe in relatively unselected myocardial infarction (MI) patients provided they are clinically and hemodynamically stable. GISSI-3, ISIS-4 and CCS-1 studies show that more than half of the lives are saved by ACE inhibitor treatment within the first week of therapy. Although the benefit from ACE inhibitors is larger in patients presenting with congestive heart failure (Killip class > 1), the number of lives saved in patients at low risk, who represent the majority of the population, is relevant. This supports the approach of treating all hemodynamically stable MI patients. Treatment could be stopped after about 1 month in patients without evidence of LVD while those with LVD should follow a long-term therapy with ACE inhibitors. PMID- 8681319 TI - Identification, diagnosis and treatment of heart failure: could we do better? AB - Numerous studies have shown that it is very difficult to diagnose mild heart failure accurately on clinical grounds alone. Routine echocardiography would help to solve this problem but studies have shown that this technique is greatly underused. Providing open access echocardiography, and/or targeting this resource to the most deserving cases by measuring plasma natriuretic peptides may help to optimize the use of this technique while improving the diagnosis of heart failure patients. Studies have also demonstrated the value, but apparent underuse, of angiotensin-converting enzyme (ACE) inhibitor therapy. Further questions for the management of heart failure patients have been presented by these investigations. Uncertainty remains over the appropriate timing of ACE inhibitor therapy and whether low or high doses are more effective. The ongoing ATLAS study aims to answer these questions and promotes an improvement in the treatment of heart failure patients. PMID- 8681318 TI - Current controversies with ACE inhibitor treatment in heart failure. AB - Although the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors on symptoms, morbidity and mortality have been proven beyond any doubt, some controversies remain. First, surveys have shown that a minority of patients in whom ACE inhibition is indicated, actually receive ACE inhibitors. Moreover, the majority of patients on ACE inhibitors use doses that are far lower than the target dose used in the large trials. These lower doses may be less effective. There is limited evidence to show that low-dose ACE inhibition is as effective as high-dose ACE inhibition. However, two ongoing trials--ATLAS and NETWORK--will determine the relative efficacy of high- and low-dose ACE inhibition. Second, the large ACE inhibitor trials have shown major variations in mortality, suggesting that differences between the efficacy of ACE inhibitors exist. However, the major differences in mortality are related mainly to the variations in inclusion criteria, suggesting a class effect of ACE inhibition. A study, assessing the relative efficacy of various ACE inhibitors seems unrealistic at this time. Third, mortality data on asymptomatic left ventricular dysfunction are conflicting, suggesting that initial treatment can wait until symptoms of heart failure appear. However, studies are consistent in showing reduction of events. Thus, early treatment in asymptomatic dysfunction may be warranted. Finally, it has been demonstrated that ACE inhibitors act favorably on volume and pressure overload, electrolytes and autonomic function. Nevertheless, the ACE inhibitor trials have failed to demonstrate that reduction of mortality is related to reduction of malignant ventricular arrhythmias/sudden death. This issue needs further study as specific antiarrhythmic strategies may be appropriate for arrhythmias. PMID- 8681320 TI - The cost-effective way forward for the management of the patient with heart failure. AB - Heart failure is a huge healthcare issue not only for clinicians but for healthcare managers also, with increasing pressure to demonstrate the cost effectiveness of therapies especially for common chronic conditions. The cost effectiveness of heart failure treatments relate to their effects on the progression of the disease, the associated quality of life for the patient, and the actual cost of the disease management. Direct costs are usually associated with hospitalization. Indirect costs, such as the loss of production through absence from work, are more difficult to determine. Studies such as CONSENSUS, SOLVD, SAVE and the Munich Heart Failure trial have all shown that angiotensin converting enzyme inhibitors offer effective therapy in all these aspects. Non pharmacological strategies that have also been shown to favorably influence both the costs and benefit include the addition of a nurse practitioner to assist in patient management. PMID- 8681321 TI - General principles of chaotic dynamics. PMID- 8681322 TI - Temporal chaos in the microcirculation. AB - In vivo, spontaneous rhythmic contraction and dilatation of the vessel wall and the nonlinear rheological properties of blood both contribute to irregular fluctuations in microcirculatory blood flow over time. In isolated vessels, vasomotion exhibits patterns of behaviour that are highly characteristic of many non-biological nonlinear systems, including exactly integral periodicity and well characterized routes for the transition from periodic to chaotic dynamics such as period-doubling. Nonlinear mathematical analysis of the effects of specific pharmacological interventions suggests the participation of a minimum of 4 key control variables which, at the cellular level, appear to involve Ca(2+)-induced Ca2+ release from intracellular stores and inward Ca2+ and outward K+ fluxes at the cell membrane. Four dominant variables may thus be [Ca2+] in the cytosol, [Ca2+] in the sarcoplasmic reticulum, membrane potential and the open state probability of certain K+ channel subtypes. Nonlinear analysis also indicates that nitric oxide synthesis by the vascular endothelium and changes in intraluminal flow and pressure are not significant determinants of the complexity of the underlying dynamics. Chaotic systems exhibit extreme sensitivity to initial conditions and their behaviour may appear highly unpredictable. This potentially accounts for variability in response to both pharmacological interventions and altered conditions of perfusion. The sensitivity of chaotic systems to perturbation can nevertheless be exploited to bring about large changes in state with minimum expenditure of energy, so that chaotic dynamics may confer a high degree of flexibility in overall control. Indeed, relatively simple control techniques based on negative feedback can readily stabilize the irregular responses of isolated arteries as periodic or steady-state behaviour but, alternatively, may also lead to an increase in overall dynamical complexity. At the present time, however, it remains unknown whether the chaotic nature of vasomotion confers specific benefits over and above those obtainable with sinusoidal control of vascular calibre (e.g.) in the regulation of vascular resistance, mass transport and tissue pressure. PMID- 8681323 TI - Chaos and non-linear phenomena in renal vascular control. AB - Renal autoregulation of blood flow depends on the functions of the tubuloglomerular feedback (TGF) system and the myogenic response of the afferent arteriole. Studies of the dynamic aspects of these control mechanisms at the level of both the single nephron and the whole kidney have revealed a variety of non-linear phenomena. In halothane-anesthetized, normotensive rats the TGF system oscillates regularly at 2-3 cycles/min because of the non-linearities and the time delays within the feedback system. Oscillations are present in single nephron blood flow, tubular pressure and flow, and in the tubular solute concentrations. Nephrons deriving their afferent arteriole from the same cortical radial artery are entrained, and consequently oscillate at the same frequency. Experimental studies have shown that the synchronization is due to an interaction of the TGF between nephrons. A necessary condition for the interaction is that the nephrons derive their blood supply from the same cortical radial artery. Development of hypertension is associated with a shift from periodic oscillations of tubular pressure to random-like fluctuations. Numerical analyses indicate that these fluctuations are an example of deterministic chaos. Experimental studies show that the development of hypertension is associated with an increase in strength of the interaction between nephrons. Mathematical models suggest that an increased nephron-nephron interaction could cause a bifurcation in the dynamics of TGF from periodic oscillations to deterministic chaos. In addition to the TGF mediated oscillation, experimental studies have also demonstrated the presence of a faster oscillation, this having a frequency of 120-160 mHz. This is caused by a mechanism intrinsic to the vascular wall, and presumably represents the well known phenomenon of vasomotion. Using newly developed non-linear analytical methods non-linear interactions between vasomotion and the TGF mediated oscillation were detected both in single nephron and in whole kidney blood flow. The physiological significance of these non-linear phenomena in renal vascular control is discussed. PMID- 8681324 TI - Linear and non-linear analyses of heart rate variability: a minireview. AB - To complete traditional time- and frequency-domain analyses, new methods derived from non-linear systems analysis have recently been developed for time series studies. A panel of the most widely used methods of heart rate analysis is given with computations on mouse data, before and after a single atropine injection. PMID- 8681325 TI - Chaos in blood pressure control. AB - A number of control mechanisms are comprised within blood pressure regulation, ranging from events on the cellular level up to circulating hormones. Despite their vast number, blood pressure fluctuations occur preferably within a certain range (under physiological conditions). A specific class of dynamic systems has been extensively studied over the past several years: nonlinear coupled systems, which often reveal a characteristic form of motion termed "chaos". The system is restricted to a certain range in phase space, but the motion is never periodic. The attractor the system moves on has a non-integer dimension. What all chaotic systems have in common is their sensitive dependence on initial conditions. The question arises as to whether blood pressure regulation can be explained by such models. Many efforts have been made to characterise heart rate variability and EEG dynamics by parameters of chaos theory (e.g., fractal dimensions and Lyapunov exponents). These method were successfully applied to dynamics observed in single organs, but very few studies have dealt with blood pressure dynamics. This mini review first gives an overview on the history of blood pressure dynamics and the methods suitable to characterise the dynamics by means of tools derived from the field of nonlinear dynamics. Then applications to systemic blood pressure are discussed. After a short survey on heart rate variability, which is indirectly reflected in blood pressure variability, some dynamic aspects of resistance vessels are given. Intriguingly, systemic blood pressure reveals a change in fractal dimensions and Lyapunov exponents, when the major short-term control mechanism--the arterial baroreflex--is disrupted. Indeed it seems that cardiovascular time series can be described by tools from nonlinear dynamics [66]. These methods allow a novel description of some important aspects of biological systems. Both the linear and the nonlinear tools complement each other and can be useful in characterising the stability and complexity of blood pressure control. PMID- 8681326 TI - Comparison of chaotic and sinusoidal vasomotion in the regulation of microvascular flow. AB - OBJECTIVE: In order to elucidate the physiological consequences of irregular vasomotion on microvascular flow we have compared the theoretical hydrodynamic consequences of sinusoidal and chaotic fluctuations in the diameter of a single resistance vessel. METHODS: In initial experimental studies vasomotion was induced by histamine in isolated rabbit ear resistance arteries (approximately 150 microns diameter) perfused with physiological buffer under both controlled flow and controlled-pressure conditions. The phase relationships between the observed oscillations in flow and pressure were used to validate a theoretical electrical circuit in which vasomotion was simulated as sinusoidal or as chaotic fluctuations in distal resistance, with compliance incorporated as a parallel capacitance. RESULTS: In both the experimental and theoretical situation, oscillations in flow led those in pressure by approximately 90 degrees in controlled-flow mode, whereas they were approximately 180 degrees out of phase in controlled-pressure mode. In the theoretical model an increase in the amplitude of sinusoidal or chaotic diameter fluctuations enhanced flow, but "paradoxically" increased both time-averaged resistance and conductance. The model showed that with sinusoidal fluctuations the "efficiency" of perfusion (i.e., flow/viscous work expended in perfusing the vessel undergoing vasomotion) exhibited a peak whose magnitude was a function of vasomotion amplitude and the proximal capacitance in the circuit, and was attributable to transient release of charge from this capacitance. This phenomenon was not observed in simulations with chaotic vasomotion. Hydrodynamic effects specific to the presence of chaotic dynamics (e.g., abrupt increases or decreases in flow under the variation of a single parameter) were also evident when the intrinsic complexity of the vasomotion, rather than its amplitude, was varied. CONCLUSIONS: The model suggests (i) that vasomotion may serve to increase flow, (ii) that conductance provides a more accurate physiological measure of the functional consequences of active vasomotion than resistance, (iii) that chaotic vasomotion dissipates transients more readily than sinusoidal vasomotion, thereby conferring greater stability to microcirculatory perfusion and (iv) that specific modes of chaotic vasomotion may influence flow independently of their amplitude. PMID- 8681327 TI - Short- and long-term variations in non-linear dynamics of heart rate variability. AB - OBJECTIVES: The purpose of the study was to investigate the short- and long-term variations in the non-linear dynamics of heart rate variability, and to determine the relationships between conventional time and frequency domain methods and the newer non-linear methods of characterizing heart rate variability. METHODS: Twelve healthy subjects were investigated by 3-h ambulatory ECG recordings repeated on 3 separate days. Correlation dimension, non-linear predictability, mean heart rate, and heart rate variability in the time and frequency domains were measured and compared with the results from corresponding surrogate time series. RESULTS: A small significant amount of non-linear dynamics exists in heart rate variability. Correlation dimensions and non-linear predictability are relatively specific parameters for each individual examined. The correlation dimension is inversely correlated to the heart rate and describes mainly linear correlations. Non-linear predictability is correlated with heart rate variability measured as the standard deviation of the R-R intervals and the respiratory activity expressed as power of the high-frequency band. The dynamics of heart rate variability changes suddenly even during resting, supine conditions. The abrupt changes are highly reproducible within the individual subjects. CONCLUSIONS: The study confirms that the correlation dimension of the R-R intervals is mostly due to linear correlations in the R-R intervals. A small but significant part is due to non-linear correlations between the R-R intervals. The different measures of heart rate variability (correlation dimension, average prediction error, and the standard deviation of the R-R intervals) characterize different properties of the signal, and are therefore not redundant measures. Heart rate variability cannot be described as a single chaotic system. Instead heart rate variability consists of intertwined periods with different non-linear dynamics. It is hypothesized that the heart rate is governed by a system with multiple "strange" attractors. PMID- 8681328 TI - Chaos-related deterministic regulation of heart rate variability in time- and frequency domains: effects of autonomic blockade and exercise. AB - OBJECTIVES: To study non-linear complexity or chaotic behaviour of heart rate in short time series and its dependence on autonomic tone. METHODS: Ten healthy individuals (5 men, mean age 44 years) were investigated at rest, after intravenous injections of propranolol (0.15 mg/kg), followed by atropine (0.03 mg/kg). On another occasion, investigation was made during exercise on a bicycle ergometer at 40% and at 70% of maximal working capacity. Heart rate variability was assessed by: local sensitive dependence on initial conditions as quantitated by the dominant Lyapunov exponent, coefficient of variation of heart rate, power spectral analysis of high- and low-frequency bands and the 1/f-slope of the very low-frequency band and time domain analysis. RESULTS: The approximate dominant Lyapunov exponent was positive at rest and remained positive during autonomic blockade and during exercise. The exponent decreased significantly with propranolol+atropine and even more so during exercise but did not attain zero. At baseline approximate predictability was lost after about 30 s whereas after autonomic blockade or exercise it was lost after about 60 s. The 1/f-slope remained unaltered around -1. As expected, power in high- and low-frequency bands as well as time domain index decreased significantly with autonomic blockade. The low-frequency band and time domain index were affected by exercise. CONCLUSIONS: Heart rate variability of sinus rhythm in healthy individuals has characteristics suggestive of low-dimensional chaos-like determinism which is modulated but not eliminated by inhibition of autonomic tone or by exercise. The dominant Lyapunov exponent characterises heart rate variability independent or the other investigated measures. PMID- 8681329 TI - The application of methods of non-linear dynamics for the improved and predictive recognition of patients threatened by sudden cardiac death. AB - OBJECTIVES: This study introduces new methods of non-linear dynamics (NLD) and compares these with traditional methods of heart rate variability (HRV) and high resolution ECG (HRECG) analysis in order to improve the reliability of high risk stratification. METHODS: Simultaneous 30 min high resolution ECG's and long-term ECG's were recorded from 26 cardiac patients after myocardial infarction (MI). They were divided into two groups depending upon the electrical risk, a low risk group (group 2, n = 10) and a high risk group (group 3, n = 16). The control group consisted of 35 healthy persons (group 1). From these electrocardiograms we extracted standard measures in time and frequency domain as well as measures from the new non-linear methods of symbolic dynamics and renormalized entropy. RESULTS: Applying discriminant function techniques on HRV analysis the parameters of non-linear dynamics led to an acceptable differentiation between healthy persons and high risk patients of 96%. The time domain and frequency domain parameters were successful in less than 90%. The combination of parameters from all domains and a stepwise discriminant function separated these groups completely (100%). Use of this discriminant function classified three patients with apparently low (no) risk into the same cluster as high risk patients. The combination of the HRECG and HRV analysis showed the same individual clustering but increased the positive value of separation. CONCLUSIONS: The methods of NLD describe complex rhythm fluctuations and separate structures of non-linear behavior in the heart rate time series more successfully than classical methods of time and frequency domains. This leads to an improved discrimination between a normal (healthy persons) and an abnormal (high risk patients) type of heart beat generation. Some patients with an unknown risk exhibit similar patterns to high risk patients and this suggests a hidden high risk. The methods of symbolic dynamics and renormalized entropy were particularly useful measures for classifying the dynamics of HRV. PMID- 8681330 TI - Characterization of complex heart rate dynamics and their pharmacological disorders by non-linear prediction and special data transformations. AB - OBJECTIVE: The aim of the presented method was the characterization of different complex heart rate dynamics in conscious rabbits as well as during general anaesthesia and vagal blockade. This was done by non-linear prediction of original measured and special surrogate data in the phase space. METHOD: The development of the prediction error in dependence on the prediction time interval was investigated in the phase space. Two kinds of surrogate data were produced and tested with regard to non-linearities and orientation in the phase space. Typical characteristics of prediction error development were shown for simulated uncorrelated stochastic, correlated stochastic, regular deterministic, and deterministic chaotic signals. These characteristics were used to evaluate the measured heart rate data in connection with tests of surrogate data. RESULTS: It could be shown that heart rate fluctuation cannot be described by one of these ideal models alone. Common consideration of all investigated prediction characteristics indicated chaos in the heart rate of conscious rabbits as well as during anaesthesia and vagal blockade, where non-linear correlated stochastic properties could not be excluded. The different amount of non-linearities and orientation was described quantitatively. CONCLUSIONS: Detailed analysis of prediction error development in the phase space, connected with tests for non linearities and orientation, enabled a specific quantitative characterization of complex heart rate dynamics and their pharmacological disorders. PMID- 8681331 TI - Non-linear dynamics and chaotic indices in heart rate variability of normal subjects and heart-transplanted patients. AB - OBJECTIVES: Heart rate variability (HRV) is characterised by a variety of linear, non-linear, periodical and non-periodical oscillations. The aim of the present study was mainly to investigate the role played by neural mechanisms in determining non-linear and non-periodical components. METHODS: Analysis was performed in 7 recently heart transplanted patients and in 7 controls of similar age whose HRV signal was collected during 24 h. Parameters that quantify non linear dynamic behaviour, in a time series, were calculated. We first assessed the specific non-linear nature of the time series by a test on surrogate data after Fourier phase randomization. Furthermore, the D2 correlation dimension, K2 Kolmogorov entropy, and H self-similarity exponent of the signal were estimated. From this last parameter, the dimension D = 1/H can be obtained. In order to assess whether the dynamics of the system are compatible with chaotic characteristics, the entire spectrum of Lyapunov exponents was calculated. We used return maps to graphically represent the non-linear and non-periodical behaviours in patients and controls. RESULTS: Surrogate data suggest that the HRV time courses have unique non-linear characteristics. D2, K2 and 1/H parameters were significantly lower in transplanted subjects than in controls. Positivity of the first Lyapunov exponent indicates divergence of trajectories in state-space. Furthermore, the display of return maps on projections obtained after Singular Value Decomposition, especially in low-complexity data (as in transplanted patients), shows a structure which is suggestive of a strange attractor. These findings support the hypothesis that chaotic dynamics underlie HRV. CONCLUSION: These results indicate that non-linear dynamics are likely to be present in HRV control mechanisms, giving rise to complex and qualitatively different behaviours. System complexity decreases in transplanted patients and this may be related to loss of the neural modulation of heart rate. PMID- 8681332 TI - Linear and non-linear properties of heart rate in postnatal maturation. AB - OBJECTIVE: An investigation was made of how postnatal maturation of cardiac control can be described by linear and non-linear methods of time series analysis. METHODS: Sixteen healthy and term newborns were studied during their first 6 months of life. Power spectrum analysis including total power (TP), low frequency power (LF), high frequency power (HF) and LF/HF ratio were performed on the instantaneous heart rate (IHR) time series and mean heart rate (HR) was derived. The largest Lyapunov exponent (LLE) was calculated using a modified Wolf algorithm and checked by means of the surrogate-data test. RESULTS: There is an age dependency for the parameters LLE, HR, TP, HF, LF, LF/HF for active and LLE, HR, TP, HF, LF/HF for quiet sleep. HR is characterised by a steep increase between the 5th and 7th day. HF demonstrates a distinct development with high values around the first week and 90-180th day and low values around the 10-60th day. TP, LF and LF/HF show significantly higher values in active sleep in comparison to quiet sleep. For all ages and sleep stages, positive LLE were found, indicating sensitivity to initial conditions, a hall-mark of chaos. For the period between the 7 and 90th days of life, the LLE for active sleep took on larger values compared with the LLE of quiet sleep. CONCLUSIONS: This study shows that by linear as well as non-linear analysis one can reveal the complexity of the IHR development in humans and may gain insight into the system controlling the heart during the period considered. The positive LLE indicate that there is a non-linear component in the heart rate control. There is no "straight line" development for the parameters analysed within the first 6 months. This may result from manifold influences on the autonomic system, due to structural and functional maturation in this period of life. PMID- 8681333 TI - Deterministic--chaotic and periodic properties of heart rate and arterial pressure fluctuations and their mediation in piglets. AB - OBJECTIVE: Only the simultaneous analysis of periodic and nonlinear properties of heart rate fluctuations (HRF) can describe completely this complex physiological process. Up to now there is, apart from a study of our own, no systematic and correlative investigation using both parameter groups, also not in early development. Thus, we tried to describe in this manner these properties of HRF, the corresponding mean arterial pressure fluctuations (MAPF) and respiratory movements (RM) and their mutual relations in neonatal pig. METHODS: In 6 term newborn piglets, periodic properties of HRF, RM, and MAPF were analyzed by spectral and coherence analysis, and deterministic-chaotic properties by calculation of correlation dimension (CD), Lyapunov exponent (LE), and construction of phase space plots. The assumption of deterministic chaotic components was supported by Theiler's test for nonlinearity, by always positive leading LEs, and by the results of a nonlinear deterministic model. These analyses were done in sleep states, general anaesthesia, hypoxic hypoxia, in ventilated state, and during cholinergic and additional beta-adrenergic blockade. RESULTS: In all experimental states, HRF and MAPF have periodic and nonlinear, very probably deterministic-chaotic properties, but in different relations. In anaesthetized piglets, periodic properties of HRF and MAPF dominate. In hypoxia the decreasing LE and CD of HRF and CD of MAPF were connected with increasing MAPF power density. Cholinergic blockade caused a decreased overall HRF and MAPF power and a decreasing LE and CD, but beta-adrenergic blockade decreased a small part of power density of both in 0.02-0.08 Hz only. The results of CD, LE, Theiler's test and the low dimensional deterministic model data suggested mainly deterministic-chaotic properties in the nonlinear part of HRF and MAPF. CONCLUSIONS: Already in neonatal piglets, both periodic and nonlinear, very probably deterministic chaotic properties of HRF and MAPF exist which change both during hypoxia and cholinergic blockade. They are partly cholinergically and--to a small extent--also beta-adrenergically mediated. The decrease of nonlinear complexity of HRF and MAPF during hypoxia suggests characteristic pathological change even in early development. PMID- 8681334 TI - Distribution of connective tissue proteins during development and neovascularization of the epicardium. AB - OBJECTIVE: The epicardium is the site of initial cardiac neovascularization and formation of the coronary circulatory system. Recent evidence indicates that vascular progenitor cells are influenced by the connective tissue proteins of their extracellular environment, yet little is known about the composition or function of the embryonic epicardial extracellular matrix (ECM). This study examines the distribution of ECM proteins during the migration, growth and maturation of epicardial cells and also during the development of the coronary vascular network. METHODS: Immunofluorescence microscopy was used to determine the distributions of vitronectin, fibronectin and a newly described fibrillin like protein, the JB3 antigen, in the embryonic chicken heart. Immunoblot analysis was performed to compare the relative electrophoretic mobilities of the JB3 antigen and fibrillin-1. RESULTS: The data show that vitronectin and fibronectin are present at sites of initial migration of the epicardial cells. The expression of vitronectin (and also fibronectin) becomes more pronounced as the epicardium thickens, undergoes remodeling and differentiates. The JB3 antigen is prominently expressed in the coronary arteries, allowing visualization of their connection to the systemic circulation and to the heart muscle, as well as vessel wall formation and organization. Immunoblot analysis suggests that the JB3 antibody recognizes a fibrillin-like polypeptide that is distinct from fibrillin 1. CONCLUSIONS: The observed distributions of vitronectin and fibronectin are consistent with roles in migration of epicardial cells, in remodeling of the epicardium and as substratum components during blood vessel formation. The observed distribution of the JB3 antigen indicates a structural/organizational role in coronary arterial wall assembly and suggests that the JB3 antibody be considered an early marker for maturing coronary arteries. PMID- 8681335 TI - Coronary vascularization during development in the rat and its relationship to basic fibroblast growth factor. AB - OBJECTIVE: Our overall aims were to elucidate the temporal and spatial sequence of coronary vascularization during development in the rat, and to determine whether basic fibroblast growth factor expression corresponds to any phase of the vascularization process. METHODS: Immunohistochemical, histochemical, morphometric and in situ hybridization analyses were performed on prenatal and postnatal hearts of various ages. RESULTS: Coronary vascularization, which begins at embryonic day 13 (E13) with blood island-like structures in the epicardium, progresses from this layer toward the endocardium as indicated by a transmural gradient of vascular volume throughout the ventricles. Vascular smooth muscle first appears in E17 hearts at the time a capillary-like plexus coalesces and penetrates the aorta to form the main coronary arteries. These vessels maintain an anastomatic morphology and must undergo subsequent remodeling in order to assume adult branching characteristics. The early postnatal period is characterized by development of the arterial tree and the enzymatic differentiation of the arteriolar and venular ends of the capillary bed. Although bFGF is expressed both prenatally and postnatally, the highest mRNA expression was noted during the early period of vascularization (E14 and E15), and the early neonatal period (1-6 days) which corresponds to a period of substantial microvascular growth. CONCLUSIONS: Coronary vascularization follows a temporal sequence which includes transmural expansion of the capillary bed, arteriolar formation subsequent to vascular penetration of the aorta, and postnatal growth, differentiation, and remodeling. Since high levels of bFGF expression are correlated with key time points in coronary vascular growth, bFGF may play an important role in this process. PMID- 8681336 TI - Distribution of blood flow between embryo and vitelline bed in the stage 18, 21 and 24 chick embryo. AB - OBJECTIVE: We defined the distribution of blood flow between the embryo and the extraembryonic vascular bed as an initial step in understanding the control of flow distribution in the early developing heart. METHODS: Dorsal aortic blood flow of stage 18, 21, and 24 chick embryo (n > or = 7 at each stage) was measured with a 20 MHz pulsed-Doppler velocity meter. Analog waveforms were digitally sampled at 500 Hz. 1-5 x 10(3) yellow microspheres in saline suspension were injected into the vitelline vein. The embryo and the extraembryonic vascular bed were harvested and separated from each other. The dye on the microspheres from each portion was extracted and extrapolated from the standard curve of the absorbance of dye concentrations per number of microspheres quantified by spectrophotometry. Blood flow was calculated from the integral of blood velocity and aortic cross-sectional area multiplied by the fraction distribution of microspheres in the embryo and extraembryonic vascular bed. Data were presented as mean +/- standard error of the mean. RESULTS: The proportion distribution of microspheres between embryo and extraembryonic vascular bed shifted from 18.7 +/- 2.5 vs. 81.3 +/- 2.5% at stage 18, 25.1 +/- 3.0 vs. 74.9 +/- 3.0% at stage 21, and 34.2 +/- 2.4 vs. 65.8 +/- 2.4% at stage 24. Indices of blood flow normalized to wet weight (mean +/- 95% confidence interval) were similar between the embryo and the extraembryonic vascular bed, but increased throughout the stages. CONCLUSION: During embryogenesis, blood flow per unit mass is evenly distributed between the metabolically active embryo and the extraembryonic vascular bed. PMID- 8681337 TI - Nitroprusside selectively reduces ventricular preload in the stage 21 chick embryo. AB - OBJECTIVE: Embryonic cardiovascular function is dynamically regulated at the tissue level. Nitric oxide (NO) regulates vascular tone and influences cardiovascular function in neonatal and mature circulations. However, the role of NO in regulating embryonic cardiovascular function is undefined. We hypothesized that NO released from nitroprusside alters embryonic vascular tone with secondary effects on ventricular function. METHODS: We measured ventricular pressure and calculated ventricular volume from area using ellipsoid geometry for 180 s after suffusion of 0.0, 0.1, 1.0, or 2.5 micrograms of nitroprusside in 10 microliters of KHB buffer, or after acute venous hemorrhage in stage 21 chick embryos (n > or = 8 per group). We plotted pressure-volume loops and analyzed standard parameters of cardiovascular function by ANOVA, regression analysis, and ANCOVA. RESULTS: Following nitroprusside, heart rate was unchanged, end-diastolic volume (EDV), stroke volume (SV), and end-systolic pressure decreased (P < 0.05 at 180 s). For 1.0 microgram of nitroprusside, EDV decreased by 27 +/- 6%, SV decreased by 36 +/ 6%, and end-systolic pressure decreased by 28 +/- 3%. The EDV vs. SV relationship was unchanged with the exception of the 2.5 micrograms nitroprusside dose. Arterial elastance was unchanged with the exception of the 2.5 micrograms nitroprusside dose. The EDV vs. SV relationship and arterial elastance during preload reduction suggest that ventricular afterload did not decrease following NO. CONCLUSIONS: In contrast to the mature circulation, NO reduced preload without decreasing ventricular afterload. Thus, vasoactive agents may have unique roles in the regulation of cardiovascular structure and function during embryogenesis. PMID- 8681338 TI - Ventricular relaxation in the stage 24 chick embryo following changes in volume and blockade of Na+ and Ca2+ channels. AB - OBJECTIVE: Early in cardiac development, regulation of cytosolic Ca2+ has been thought to depend primarily on sarcolemmal Ca2+ transport. We hypothesized that perturbation of cytosolic Ca2+ in the embryonic ventricle would result in a change in ventricular relaxation which could be quantified by a monoexponential model. We reasoned that since it has been difficult to selectively block the Na(+)-Ca2+ exchanger in vivo, that blockade of Na+ (lidocaine) or Ca2+ (verapamil) channels in the embryonic heart may perturb cytosolic Ca2+ and thereby alter ventricular relaxation. METHODS: All studies were performed in ovo in Hamilton-Hamburger stage 24 chick embryos. Isovolumic relaxation time (mean +/ standard deviation, 58 +/- 19 ms) was derived from dorsal aortic flow and atrioventricular inflow during 61 cardiac cycles in 4 embryos. Ventricular pressure was digitally recorded from 13 embryos during 188 cycles following intravenous injection of chick Ringer's solution (5 embryos), verapamil (4 embryos) or lidocaine (4 embryos). Ventricular relaxation was characterized by a monoexponential model: P(t) = P infinity + Poe-1/tau where P(t) = pressure at time (t), P infinity = pressure asymptote, Po = pressure at the onset of relaxation and tau = the isovolumic relaxation constant. Non-linear least-squares regression was used to estimate tau and P infinity during isovolumic relaxation at baseline and at 30 s and 60 s post-injection. RESULTS: Ventricular end diastolic pressure was increased by all three interventions. Both lidocaine and verapamil prolonged cycle length. Lidocaine prolonged tau while chick Ringer's solution and verapamil did not. No significant change in P chi was observed. CONCLUSIONS: This study demonstrates that blockade of Na+ channels with lidocaine slows ventricular relaxation presumably by perturbing cytosolic Ca2+ via the Na(+)-Ca2+ exchange system. Changes following Ca2+ channel blockade with verapamil are less evident in the stage 24 chick embryo. Evaluation of ventricular relaxation may provide a useful way to study developmental aspects of Ca2+ transport. PMID- 8681339 TI - Thyroid hormone regulates Na(+)-Ca2+ exchanger expression during postnatal maturation and in adult rabbit ventricular myocardium. AB - OBJECTIVES: Expression of the cardiac Na(+)-Ca2+ exchanger (NCX) is high at birth and declines rapidly to adult levels by approximately 21 days in rabbits. The aim was to evaluate the role of thyroid hormone in regulating cardiac NCX expression. METHODS: Adult New Zealand White rabbits were made hypothyroid by treatment with propylthiouracil or hyperthryoid by administration of sigma-thyroxine. Hypothyroidism was induced in immature rabbits by exposure to propylthiouracil from gestational day 25 through the first 21 days after birth. NCX steady-state mRNA levels were quantitated using Northern slot blots with poly(A+) RNA isolated from ventricular myocardium of treated and age-matched euthyroid animals. As a control, steady-state levels of cardiac sarco(endo)plasmic reticulum calcium ATPase (SERCA2a) were measured in each group. Thyroid status was confirmed with serum T4, ventricular weight and body weight measurements. Immunoreactive NCX protein levels were assessed using Western blots. RESULTS: Compared with euthyroid controls, NCX steady-state mRNA levels increased to 189 +/- 20% in hypothyroid adults and decreased to 55 +/- 15% in hyperthyroid adults. Opposite effects were observed for SERCA2a expression (58 +/- 7% in hypothyroidism and 130 +/- 15% in hyperthyroidism). In hypothyroid 21-day-old rabbits, NCX steady-state mRNA levels were elevated to 205 +/- 30% of age-matched euthyroid controls. SERCA2a levels were unaffected in the immature animals, possibly due to inability to reduce thyroid levels sufficiently to affect SERCA2a expression in this model. Changes in NCX mRNA levels produced comparable changes in immunoreactive NCX protein levels. CONCLUSIONS: Thyroid hormone reciprocally regulates NCX and SERCA2a expression in the ventricles of adult rabbits. Hypothyroidism resulted in sustained high levels of NCX expression in 21-day-old rabbits. These results suggest that the postnatal thyroid hormone surge is important for the normal down regulation of cardiac NCX expression during the first 3 weeks after birth in developing rabbits. PMID- 8681340 TI - Contractile and coronary vascular effects of pituitary adenylate cyclase activating polypeptide in neonatal pig hearts. AB - OBJECTIVE: The purpose was to investigate the influence of the 38-amino-acid neuropeptide, pituitary adenylate cyclase activating polypeptide (PACAP38), on contractile function and coronary vascular tone in neonatal hearts. METHODS: Isolated, paced (150 bpm), isovolumically-beating, piglet hearts (n = 19) underwent retrograde aortic perfusion at constant coronary flow (approximately 2.5 ml/min/gwet) with an erythrocyte-enriched (Hct 15-20%) solution (37 degrees C). Agonists were injected into the aortic root of hearts, and the changes in +dP/dtmax and -dP/dtmax (reflecting contractility), and coronary perfusion pressure (reflecting vascular tone) were determined. Responses to PAPCAP38 were compared to isoproterenol, and to the truncated peptide PACAP6-38. RESULTS: PACAP38 (0.1 and 0.5 nmol) increased +dP/dtmax from 1387.4 +/- 134.6 to 1619.0 +/ 118.7, and from 1296.2 +/- 93.4 to 1872.2 +/- 111.4 mmHg/s (P < 0.05); changed dP/dtmax from -1087.6 +/- 107.5 to -1206.6 +/- 93.6, and from -1025.0 +/- 46.8 to -1375.4 +/- 80.9 mmHg/s (P < 0.05) and decreased coronary perfusion pressure from 61.8 +/- 2.5 to 51.0 +/- 3.8, and from 62.5 +/- 1.0 to 45.3 +/- 3.3 mmHg (P < 0.005), respectively. In comparison, isoproterenol (0.1 nmol) increased +dP/dtmax from 1313.6 +/- 62.8 to 1679.0 +/- 74.4 (P < 0.05), and -dP/dtmax from -1026.4 +/ 54.1 to -1222.6 +/- 57.4 mmHg/s (P < 0.05). PACAP6-38 reduced PACAP38's coronary vasodilatory, but not its contractile, effect. When compared to our previous studies of the 27-amino-acid neuropeptide PACAP27, PACAP38 had less potent contractile, but similar vasodilatory effects. CONCLUSIONS: PACAP38 enhanced contractility and produced coronary vasodilation in piglet hearts, which may make PACAP38 a promising cardiotonic agent for the treatment of neonates with heart failure. PMID- 8681341 TI - Cardiovascular morphogenesis in zebrafish. PMID- 8681342 TI - Regulation of cardiac gene expression during development. PMID- 8681343 TI - Contractile protein phenotypic variation during development. AB - A diverse set of contractile protein genes and alternatively spliced isoforms is expressed during the process of cardiac maturation. A large variety of functional sarcomeric units may occur at various stages of development, in different regions of the heart and in pathologic states. In this review, the developmental program of individual contractile protein gene families is discussed with an emphasis on the functional effects of maturational changes, particularly in the human myocardium. PMID- 8681345 TI - Formation of the coronary vasculature: a brief review. AB - Myocardial vascularization is initiated after endothelial cell precursors from the region of the liver or septum transversarium migrate to the newly formed epicardium. Blood island-like structures appear and form vascular channels along the epicardium and into the myocardium. Prior to this time myocardial cells receive nutrition directly from the ventricular lumen, a process which is facilitated by the highly trabecular arrangement of the ventricles. A venous system is formed prior to any evidence of arteries or arterioles. The formation of a vascular plexus in the region of the outflow tract is followed by penetration of these microvessels into the wall of the aorta. These ingrowing vessels merge, acquire a muscular coat and form the left and then the right coronary vessels. These events occur during a short period of time, e.g., 2 weeks in humans, 4 days in rats. Maturation of the arterial tree occurs primarily after birth. Our knowledge of the regulation of coronary vascularization during development is very limited. Accordingly, future studies need to focus on the role of growth factors, chemotactic factors, extracellular matrix molecules, and mechanical events. PMID- 8681346 TI - Developmental cardiac electrophysiology recent advances in cellular physiology. AB - This overview of cardiac ion channel development does not suggest any particular theme underlying the expression or regulation of all channel subtypes. Calcium and potassium channels generally exhibit increased expression in more mature hearts. However, this increase in channel number or activity as determined under voltage clamp conditions may not be translated into increased activity in vivo. Concomitant changes in other physiological factors such as local intracellular Ca2+ accumulation, increased resting membrane potential and decreased heart rate in mature heart may inhibit or augment channel activity. Na(+)-Ca2+ exchange activity appears to decrease with development, possibly reflecting its decreasing role in both systolic and diastolic Ca2+ regulation. Na+ channel activity follows a middle course, exhibiting little change in channel conductance. The reported shift in the voltage dependence of channel inactivation toward more negative membrane potentials may reflect a concomitant shift in the resting membrane potential in mature heart. However, this change is in the direction opposite to that reported for L-type Ca2+ channel inactivation, suggesting that the regulation of these channels is not modulated by a common factor such as membrane surface charge. A detailed characterization of multiple channel subtypes in mature myocardium has resulted in significant advances in models of the cardiac action potential and excitation-contraction coupling. Recently, developmental changes in ion channel physiology have been described, setting the stage for a comparable elucidation of the ontogeny of the cardiac action potential. Ca2+ and K+ channel currents generally become more prominent with development. In contrast, developmental changes in Na+ currents are less dramatic and Na(+)-Ca2+ exchange currents appear to decrease with age. These changes may, in part, be reflected by the increasingly important role of transsarcolemmal Ca2+ influx in triggering Ca2+ release from the SR in mature heart as compared to its direct role of providing Ca2+ for cell contraction in immature heart. These developmental changes in ion channel expression and function are likely to have a significant effect on the generation of the action potential in individual myocytes. Developmental changes in the characteristics of the action potential may then have a major influence on the initiation, propagation and termination of autonomic, triggered, and re-entrant arrhythmias. Progress in this area provides an essential foundation for the evolution of a systematic approach to pediatric arrhythmias comparable to that under development for mature heart [3]. PMID- 8681344 TI - Early embryonic vascular development. AB - Establishment of a functional vascular system is imperative for normal embryonic growth and development. Building on the excellent descriptive studies of endothelial cell position and behavior, it is now possible to begin to define the mechanisms directing endothelial cell differentiation, commitment, migration and organization into a tube. What are the factors that control differentiation of mesoderm into angioblasts and what is needed for these angioblasts to organize into a vascular bed? These processes involve the careful orchestration of a diverse group of molecules including components of the extracellular matrix, cell adhesion receptors, growth factors and their receptors. This review has discussed just a few of the components that have been implicated as potentially important in the establishment of the vascular system. However, our understanding of how vessels form in the embryo is really quite rudimentary. We are just beginning to understand the delicate balance of both angiogenic and angiostatic processes that result in the intricate patterning and diverse function that is characteristic of developing endothelial cells. We have not even discussed important factors such as the role of blood flow and apoptosis in maintaining and remodeling vascular beds within the embryo nor have we addressed the development of endothelial heterogeneity in the mature animal [reviewed in Ref. 98]. There are certain to be new molecules identified as well as the delineation of new roles for known molecules. In addition, advances in genetic manipulation and improvements in both in vitro and in vivo model systems should provide important new insights into this critical process of vascular ontogeny. PMID- 8681347 TI - Regulation of intracellular calcium concentration in the developing heart. PMID- 8681348 TI - Autonomic receptor--effector coupling during post-natal development. AB - In summary, there are marked age-dependent alterations in the myocardial alpha 1 adrenergic, beta-adrenergic and muscarinic signal transduction cascades. With maturation, an inhibitory alpha 1-adrenergic response appears, which differs from the pre-existing excitatory response both with respect to the specific receptor subtype involved and its G protein coupling. Neurally released NPY appears to play a critical role in regulating the expression of the inhibitory alpha 1 adrenergic response. Likewise, sympathetic innervation appears involved in the loss of an excitatory muscarinic response during development. Again, this response, which is M1 mediated, differs in receptor subtype from that of the M2 inhibitory response characteristic of the adult. Both responses are PT-sensitive, which suggests the involvement of a PT-sensitive G protein in each case, although not necessarily the identical G protein. The role of innervation in developmental regulation of the beta-adrenergic response is unknown. While a distinct beta 1 adrenergic response exists through development, and appears to change predominantly only with respect to magnitude, the beta 2-adrenergic cascade would seem to have somewhat more complex regulation. Not only is the adult normally far less sensitive to beta 2-agonists than the neonate, but the classical beta adrenergic effect to enhance relaxation along with the increase in force is absent in the adult when the beta 2 (but not beta 1) receptors are activated. It is apparent from the above summary that in the case of all three autonomic receptor systems, the functional signal transduction cascades in the neonate seem designed to favor excitation (chronotropic and/or inotropic) over inhibition. The alpha 1-adrenergic system is exclusively excitatory in the newborn, with an opposing inhibitory cascade only becoming evident after the onset of sympathetic innervation. Similarly, prior to sympathetic innervation the muscarinic system exhibits both excitatory and inhibitory effects, with the excitatory response being lost with development. Finally, while the beta-adrenergic system appears exclusively excitatory at all ages, in the neonate the beta 1- and beta 2 cascades both contribute to the total positive inotropic response to low concentrations of agonist, while in the adult the beta 2-component only contributes at high agonist concentrations. While the reasons for the favoring of excitation cascades in the neonate is not known, it is tempting to speculate on this point. In this respect it is worth noting that in the young, increasing heart rate, rather than stroke volume, is the primary mechanism by which cardiac output is increased [62]. In this situation, excitatory autonomic mechanisms may be advantageous. Also, at the time of birth in the rat (and at other times in different species) there is a period of potential autonomic imbalance when the parasympathetic innervation to the heart is established but the sympathetic innervation is not yet well developed. During this period, having a positive chronotropic component to muscarinic action, and a positive rather than negative alpha 1-adrenergic response, could serve to compensate for any imbalance between the two limbs of the autonomic nervous system. Finally, while the sympathetic innervation of the heart is not fully developed at birth, there can be circulating catecholamines from the adrenal medulla, and these would be primarily epinephrine rather than norepinephrine. Since epinephrine has a much higher affinity than norepinephrine for beta 2-adrenergic receptors, the presence of a strong beta 2-adrenergic cascade in the neonate could be designed to respond to the circulating, rather than neuronal, catecholamines. Lastly, one should not forget that the final physiologic response depends not only on the proximal events of receptor-effector coupling, but on more distal elements that provide the substrate for these autonomic agonists.(ABSTRACT TRUNCATED AT 400 WORDS) PMID- 8681349 TI - Inhibition of outflow cushion mesenchyme formation in retinoic acid-induced complete transposition of the great arteries. AB - OBJECTIVE: Endocardial cushion tissue formation, the primordia of valves and septa, is a critical event in cardiac morphogenesis. Maternally administrated all trans retinoic acid is known to induce complete transposition of the great arteries (TGA) in the mouse embryo. To address the mechanisms of TGA, the effect of retinoic acid on cushion tissue formation was examined. METHODS: Using a three dimensional collagen gel culture model, we performed various types of endothelial mesenchymal transformation assays of co-cultured endocardium with myocardium obtained from 9.5-day mouse embryonic hearts. In vivo immunohistochemical detections of extracellular matrices, fibronectin and type I collagen, were also performed. RESULTS: Endothelial-to-mesenchymal transformation at the onset of cushion tissue formation was suppressed in the outflow tract of embryos exposed to retinoic acid in culture. This inhibitory effect of retinoic acid was spatially restricted to the outflow tract and reversed by treatment with embryonic myocardial conditioned medium enriched in extracellular inductive molecules. Mesenchyme formation in the outflow tract was inhibited at a lower concentration of retinoic acid (10(-10) mol/l) than that which inhibited the atrio-ventricular canal (10(-7) mol/l) in culture. The fibronectin and type I collagen depositions in pre-migratory outflow tract cardiac jelly in retinoic acid-treated embryonic heart were reduced compared to those in the control. CONCLUSIONS: Exogenously applied retinoic acid inhibits outflow tract cushion mesenchyme formation in the embryonic heart with TGA. It is suggested that retinoic acid inhibits the expression of extracellular matrices and inductive molecules synthesized by myocardium in the outflow tract. PMID- 8681351 TI - Postnatal development of the putative neuropeptide-Y-mediated sympathetic- parasympathetic autonomic interaction. AB - OBJECTIVE: Intense stellate ganglion stimulation causes a long-lasting inhibition of cardiac vagal responses in adult dogs. This inhibition is thought to result from the release of neuropeptide Y from sympathetic nerve terminals, which, in turn, blocks the release of acetylcholine from parasympathetic neurons. The purpose of this study was to characterize the developmental expression of this autonomic interaction in the dog. METHODS: We studied and compared the effects of 5-min trains of right stellate ganglion stimulation on cardiac chronotropic responses to supramaximal vagal stimulation trains in 10 neonatal dogs, 8 one month-old puppies, 8 two-month-old puppies and 8 adult dogs. RESULTS: In the adult group, after 5 min of stellate stimulation, inhibition of the vagal chronotropic response was observed in 7 of 8 (87.5%). Inhibition was observed in 100% of the one-month-olds and in 87.5% of the two-month-olds. In contrast, in the neonates, inhibition was observed in only 4 of 10 (40%) (P < 0.05). The maximum percent inhibition of the cardiac vagal response was significantly less in the neonates than in the older puppies (P < 0.001) and adults (P < 0.01), and the summated inhibition also tended to be less in the neonates (P < 0.05 compared to one- and two-month-old puppies). Finally, in 60% of the neonates and 37.5% of all other animals vagal responses after stellate stimulation were facilitated, i.e. at least 20% greater than the pre-stellate stimulation values. CONCLUSION: The putative neuropeptide-Y-mediated, sympathetic-parasympathetic interaction is not fully expressed in the canine neonate. It appears to develop quite rapidly postnatally, being fully expressed by 1 month of age. We hypothesize that this developmental change is likely the result of maturation of sympathetic nervous system function after birth. The facilitation of the vagal chronotropic response, observed in some animals after stellate stimulation, is a new finding, and may represent yet another type of autonomic interaction. PMID- 8681350 TI - Expression of exogenous protein and analysis of morphogenesis in the developing chicken heart using an adenoviral vector. AB - OBJECTIVES: Recombinant retroviral vectors have been shown to be useful tools for marking cells so as to follow their fates during development. The aim of this study was to determine the utility and advantages of an adenoviral vector as a tool to study the heart as it develops from a simple tube into a complex four chambered organ. METHODS: Replication-defective adenovirus (10(7) pfu) expressing beta-galactosidase (beta-gal) under the control of the RSV-LTR was applied to the external surface of embryonic stage 13-21 chick hearts in ovo. Embryos were incubated for up to an additional 96 h. Hearts were harvested at 12-24 h intervals and (1) whole-mount-stained for beta-gal and sectioned, (2) examined by electron microscopy and (3) homogenized and beta-gal activity measured with a luminescent assay. RESULTS: beta-gal expression peaked at 48 h, when a significant percentage of the myocytes in the atrial and ventricular walls expressed the protein, and it comprised 0.5% of total heart protein. Significant levels were still expressed at 96 h. When applied to early-stage (13-16) embryos, expression occurred predominantly in cardiomyocytes. beta-gal marking of cells enabled us to identify the following morphogenic patterns: (1) cells of the conus region compact into the bulbis cordis; (2) by applying the virus at later stages, e.g. 21-22, it was evident that the epicardium invests the heart, after stage 17, in a dorsal to ventral and caudal to rostral direction; (3) at lower titers (10(5) pfu), the virus serves as a clonal marker through several cell divisions, with an estimated cell doubling time of 24 h. CONCLUSIONS: Application of an adenoviral vector to early-stage embryonic chick heart results in substantial expression of exogenous protein in a significant percentage of cardiomyocytes without grossly affecting heart development. Adenoviral vectors are useful for following the fate of cells as the heart develops from a simple tube into a complex four-chambered organ and hold promise for enabling the expression of exogenous proteins which might alter cell behavior. PMID- 8681352 TI - [Anabolic androgenic steroids: a nightmare for control of doping or a drug?]. AB - In addition to the therapeutic use of anabolic androgenic steroids with must foresee also in future their abuse by sportsmen and other population groups and take into consideration that in future they probably will be part of male contraception. Therefore it is important to consider carefully possible risks of their administration, record all hitherto known undesirable side-effects, restrict the use of preparations involving the highest risk and pay attention to research into long-term administration of selected anabolic androgenic steroids. PMID- 8681353 TI - [Pathophysiologic mechanisms of early changes in renal hemodynamics in diabetes mellitus]. AB - The early stages of diabetes mellitus are in some patients associated with renal haemodynamic changes resulting in increased glomerular filtration. This "diabetic hyperfiltration" is considered to be one of pathophysiological mechanisms and risk factors for the development of diabetic nephropathy. The aim of this paper is to review some contemporary views on pathophysiological mechanisms leading to this disorder with emphasis on the role impaired activity of humoral factors influencing renal haemodynamics. In addition to poor metabolic control due to insulinopenia there is a convincing experimental evidence suggesting the role of atrial natriuretic factor and endothelium-derived nitric oxide in mediating renal haemodynamic changes in diabetes. Enhanced renal activity of angiotensin I converting enzyme resulting in local overproduction of angiotensin II and accelerated degradation of kinins may be another factor contributing to the genesis of diabetic hyperfiltration. Hyperglycaemia induces changes in cellular signalling of these vasoactive systems. Furthermore, diabetes is a state of decreased capability of renal vascular bed to autoregulate blood flow likely due to altered activity of tubuloglomerular feedback and ion channels. PMID- 8681354 TI - [Neurosarcoidosis. Role of new examination methods for early diagnosis and therapy]. AB - BACKGROUND: Affection of the nervous system is one of the most serious forms of sarcoidosis. The objective of the present work was to evaluate the prevalence and manifestations of this disease, contemporary opportunities of its diagnosis and the importance of early adequate therapy. METHODS AND RESULTS: Neurosarcoidosis was diagnosed in seven patients (4 men and 3 women) from a total number of 211 patients with sarcoidosis in 1977 to 1993. The mean age of the patients with neurosarcoidosis was 47 years. In six patients affection of the nervous system was the first clinical manifestation of the disease. In four patients it was paresis of the facial nerve, in two instances diabetes insipidus, in two instances affection of the spinal cord with subsequent spastic triparesis or paraparesis of the lower extremities, in one instance the disease was manifested by neuralgia of the trigeminal nerve. The serious character of the disease is apparent from the fact that only in two instances complete regression of symptoms occurred. In three patients regression was partial, in one instance the affection persisted without changes and in one instance it progressed to metabolic breakdown with a fatal outcome. In the differential diagnosis examination of the nervous system by computed tomography, magnetic resonance and possibly perimyelography proved to be helpful. In all instances there was a typical finding in cerebrospinal fluid. Lymphomonocytic pleocytosis was present, a raised protein content, elevated gammaglobulin levels. The diagnosis was assisted by radiograms of the chest and biopsy. The latter was made from intrathoracic or subcutaneous nodes, in one instance from muscle. As auxiliary methods the following were used: tuberculin test, bronchoalveolar lavage, pulmonary gallium scintigraphy, serum level of angiotensin converting enzyme and immunological examination. CONCLUSIONS: The authors emphasize the necessity of early diagnosis and intensive initial treatment with corticoids or antimalaria drugs, which may prevent the development of irreversible changes. Magnetic resonance appears to be the most promising examination method in neurosarcoidosis. PMID- 8681355 TI - [Computed tomography of the upper respiratory tract in patients with apnea]. AB - BACKGROUND: When deciding on the therapeutic procedure in sleep apnoea syndrome (SAS) it is important to know the anatomical conditions of the upper airways. METHODS AND RESULTS: We examined on account of SAS, verified by all night monitoring, using the MESAM4 method a total of 60 patients by means of computed tomography (CT). SAS without associated disease was diagnosed in 48 patients. To facilitate comparison of results of (CT) and MESAM4 we defined the MESAM4 score (M4) as the number of desaturations per hour multiplied by their depth (difference between mean minimal and basic saturation). Axial sections, 5mm thick at 5mm intervals were made from the level of the hard palate to the upper trachea in a vertical position to the longitudinal axis of the pharynx in the patient awake at the peak of the inspirium. The air-filled area, sagittal and coronary sections were measured at five levels (nasopharyngeal, velopharyngeal, retrobasilingual, at the level of the hyoid bone and trachea). The results differed significantly from the normal population examined by the same protocol (foreign standards). Macroglossia as a factor promoting SAS was also examined. CONCLUSIONS: The frontal and sagittal reformation reflected, on account of numerous inaccuracies, the actual state only partly. When the borderline between mild and more severe apnoea was set at M4 = 300, the correlation with the retrobasilingual section and coronary and velopharyngeal section was best. The authors suggest a simpler CT examination protocol which improves further the prediction of severity of SAS. The correlation with the body mass index (BMI) and the neck circumference (p < 0.001) confirmed the asset of CT parameters. PMID- 8681356 TI - [Is chromium an essential or a toxic element?]. AB - Chromium holds a frequent and important place in toxicological literature. The large number of more or less important toxicological facts (e.g. allergic dermatoses, ulcer, perforations of the nasal septum, bronchitis, cancerogenity etc.) are the reason why chromium is conceived rather as a toxic element. On the other hand in the non-toxicological literature favourable actions of chromium are described (its relationship to carbohydrate utilization, the glucose tolerance factor, diabetes etc.) which may induce us to consider chromium an essential element. Is chromium toxic or essential? It is both. The concept of essential or toxic cannot be conceived statically, these terms are relative and depend on a number of other facts and data (dose, time, chemical form, individuality of the organism, interaction with other substances in the environment etc). This relative view has a more general validity not only for chromium but for trace elements in general and it is very important in particular with regard to prevention of health damage caused by deficiency or excess of a substance. PMID- 8681357 TI - [The first case of leukocyte integrin deficiency syndrome in the Czech Republic and successful prenatal diagnosis in the affected family]. AB - The syndrome of leukocyte adhesion deficiency (LAD) is a rare congenital immunodeficiency which is usually manifested from birth by serious infections of the skin and mucosal membranes. The molecular basis of the disease is heterogeneous: quantitative or qualitative disorders of the beta 2 integrin sub unit are involved which lead to the absence or substantially reduced expression of adhesive molecules of the CD11/CD18 complex on leukocytes. The authors describe the case of a boy who suffered from this syndrome. The diagnosis was established at the age of four years, based on the typical clinical picture and confirmed by examination of integrins on lymphocytes and granulocytes which were zero. During the mother's subsequent pregnancy prenatal diagnosis was made by puncture of the umbilical cord during the 22nd week of gestation. Affection of the foetus by this syndrome was ruled out by examination of integrin expression on foetal leukocytes, a normal finding was confirmed also after delivery. During delivery umbilical blood was collected which was frozen and later used for therapeutic transplantation to the sibling suffering from LAD. This is the first case of this syndrome in the Czech Republic and first prenatal diagnosis which led to aimed collection of umbilical blood used for treatment of this rare immunodeficiency. PMID- 8681358 TI - [Conceptual aspects of panic disorders]. AB - Pathophysiological mechanisms of panic disorder, which is at present the most frequently investigated psychiatric affection have been elaborated at the level of neurotransmitter systems of the central nervous system and belong into intermedical disciplines (psychopharmacology, neuroradiology, neurophysiology etc.) On this basis neurobiological pathogenetic concepts of panic disorder were postulated: the neuroanatomical hypothesis (1989) and theorem on the hypersensitivity of respiratory centres of the brain stem (false alarm of suffocation) with the corresponding syndrome of hyposensitivity of respiratory centres (syndrome of primary central apnoea - 1993). A special though rather labile interpretation of the genesis of panic disorder is provided by the cognitive concept. Conversion of both approaches would make further advances in research of this interesting clinical entity possible. PMID- 8681359 TI - [Langerhans cells and cutaneous immune reactions]. AB - The epidermis is a metabolically highly active organ where in addition to other substances important cytokines are formed which play a key role in many physiological and pathophysiological reactions. They are produced in the epidermis but influence not only keratinocytes but also other epidermal cells among which for immune reactions the Langerhans cells are most important. The complexity of immune reactions anywhere in the organism greatly hampers research of this vitally important important function. The best experimental model is, however, allergic contact eczema and irritant reactions. Experimental investigations of both provide and certainly will provide findings which will clarify in an important way immune cascades of all types and thus will have a substantial impact on knowledge of the pathogenesis and will make possible quite new approaches to treatment not only of allergic diseases but also viral diseases, and last not least, also new approaches to the treatment of malignant tumours. The authors make the reader familiar with the most recent findings, their own and published ones, from the sphere of immune dermal skin reactions in conjunction with the cells of Langerhans and cytokines. PMID- 8681361 TI - [Changes in bone metabolism in girls with Turner's syndrome]. AB - BACKGROUND: Data of the prevalence of osteoporosis in girls with Turner's syndrome are not uniform, and its causes have not been fully elucidated. Information on the mineralization of osseous tissue is controversial. The objective of the present work was to examine some more recent indicators of bone metabolism in a group of girls with Turner's syndrome. METHODS AND RESULTS: A group of girls aged 4-20 years was examined where genetic examination had revealed karyotype 45 X (7 patients) or mosaic 45 X (46 XX) (9 patients). On X ray examination osteoporosis was found in 71%, densitometric evidence of reduced bone density was provided in 2% of the examined patients. As to biochemical osteologically oriented examinations, a significantly reduced osteocalcin value was found (1.18 +/- 0.42 mug/l, as compared with 11.38 +/- 0.03 in controls, p < 0.001), reduced values of alkaline phosphatase (2.67 mukat/l as compared with 8.46 +/- 4.16 mukat/l in controls, p < 0.005) and reduced values of the bone isoenzyme of alkaline phosphatase (1.47 mukat/l as compared with 6.04 +/- 0.27 in controls, p < 0.001). The values of calcemia (2.63 / 0.13 mmol/l) and phosphataemia (1.36 +/- 0.25 mmol/l) did not differ significantly from values recorded in controls. To six patients the authors administered for a period of three months 1,25(OH)2D3, 0.25 mg on alternate days. The osteocalcin values rose to 5.27 +/- 3.14 micrograms/l, similarly as alkaline phosphatase (6.32 +/- 1.83 mukat/l) and the bone isoenzyme of alkaline phosphatase (2.42 +/- 1.95 mukat/l), not evaluated statistically because of the small number of patients. CONCLUSIONS: In girl with Turner's syndrome a reduced bone density was revealed in 25%, reduced values of osteocalcin, alkaline phosphatase and its bone isoenzyme indicate a reduced osteoblast activity. It appears that administration of 1,25(OH)2D3 can have a favourable effect. PMID- 8681360 TI - [Levels of tissue-type plasminogen activator (T-PA), its inhibitor (PAI-1) and fibrinogen in the blood of patients with type 1 and 2 diabetes mellitus]. AB - BACKGROUND: Fibrinogen (Fgb), the tissue activator of plasminogen (t-PA) and its inhibitor (PAI-1) are described as so-called cardiovascular risk factors. The objective of the present investigation was to assess the occurrence of the mentioned risk factors (Fbg, t-PA and PAI-1) in diabetes mellitus (DM) type 1 and 2, compare them with findings in a healthy control group and the two types of diabetes mutually. METHODS AND RESULTS: Fifty patients with type 1 DM were examined (mean BMI 23.8), 59 patients with type 2 DM (mean BMI 28) and 33 healthy subjects as controls (mean BMI 24.6). Both groups of diabetics were compensated. To assess the t-PA and PAI-1 concentration the ELISA test was used, Fbg was assessed by Clauss' method. The euglobulin fibrinolysis time (ECLT) was also examined. In both groups of patients with DM higher concentration of t-PA were found (DM type 7.06 +/- 2.4 ng/ml, p < 0.05, DM type 2 15.15 +/- 6.07 ng/mg, control 4.67 +/- 2.87 ng/ml, p < 0.05). In patients with DM type 1 a higher concentration of t-PA was found in patients with retinopathy (8.2 +/- 1.7 ng/ml than in patients with DM type 1 without retinopathy (6.9 +/- 1.3 ng/ml), p < 0.05). The PA-1 concentration was, as compared with controls, raised only in type 2 diabetics (DM type 2 124.57 +/- 47.22 ng/ml, control 88.57 +/- 15.7 ng/ml p < 0.05). Between the two groups also a difference in the PAI-1 level was found (DM type 179.25 +/- 17.95 ng/ml, vs. DM type 2, p < 0.05). With these findings corresponded the ECLT activation in DM type 1 (203.4 +/- 76.8 min. vs. ECLT in the control group 276.08 +/- 84.87 min., p < 0.05) and conversely a reduction of the euglobulin fibrinolysis in type 2 DM (448 +/- 117 min.), as compared with the controls (p < 0.05), as well as compared with DM type 1 (p < 0.05). The fibrinogen level was also elevated only in DM type 2 (3.619 +/- 0.69 g/l) as compared with the control group (2.42 +/- 0.42 g/l, p < 0.05) as well as compared with DM type 1 (2.53 +/- 0.47 g/l, p < 0.05). No difference was found in the fibrinogen level between DM type 1 and the control group. CONCLUSIONS: In both groups of patients with diabetes mellitus type 1 and 2 among the mentioned cardiovascular risk factors only a raised t-PA concentration was recorded. Concurrent elevation of PAI-1 and fibrinogen was found only in diabetes mellitus type 2. PMID- 8681362 TI - [Variation in transfer resistance to cefotaxime, ceftazidime and aztreonam in strains of Acinetobacter sp., Enterobacter sp. and Citrobacter sp. isolated from the same university hospitals]. AB - BACKGROUND: In the last decade were in SR documented new problems in resistance to the newer antibiotics that with regard to their structure and antibacterial properties resisted to the known mechanism of bacterial resistance. The emergence of multiple drug resistance to the new betalactams is connected both with frequent application of these drugs in the hospitals and transfer of R plasmids. METHODS AND RESULTS: We studied composition and transferability of resistance to newer betalactam antibiotics in strains of Acinetobacter sp., Enterobacter sp, and Citrobacter sp. isolated during one month in patients from two teaching University Hospitals. All strains studied were resistant to cefotaxime (CTX), ceftazidime (CAZ) and aztreonam (ATM) but Acinetobacter strains, although resistant also to CAZ and ATM transferred the resistance to CTX only. Thus, resistance to CAZ and ATM has a chromosomal origin in these strains. A strain of Citrobacter sp., resistant to CTX, CAZ and ATM, produced a ESBL betalactamase detectable in a double-disk diffusion method (Fig. 1). An Enterobacter cloacae strain transfers directly the resistance to all new betalactams indicated. Their hydrolysis by these strains points to their production of new types of extended spectrum beta-lactamases ESBL). CONCLUSIONS: We strongly recommend to be strictly rational in the use of new betalactams of CTX, CZA or ATM type because it is suspected that, especially in so-called empirical prophylaxis or treatment, they exert a strong selective pressure toward the prevalence of mutants with transferable ESBL-producing nosocomial bacteria resistant to these drugs. PMID- 8681363 TI - [Journal selection for Index Medicus/Medline]. PMID- 8681364 TI - [Ethical and psychological aspects in gynecologic oncology]. AB - Treatment of women suffering from malignant disease of reproductive organs has its specific ethical, deontological and psychological aspects. The disease is affecting the organs of "feminine identity" and has a very strong emotional impact on each woman. The awareness of the nature of the disease and its treatment brings a long-term stress for each patient. There is a very delicate moment in the relation between the patient and the physician: to inform about the nature of the disease, treatment and its consequences. Such information should be released only in proper time and in proper way, considering the individual character of the patient, her age, intelligence and her present somatic and psychic status. Response of each woman and her adaptability to the disease and its treatment is very individual--depending on the woman's personality, her age, education and, of course, her social background. The physician, as well as, the other personnel must be aware of this fact. They have to choose the most proper psychotherapy and provide the patient with the adequate social support. PMID- 8681365 TI - [The fate of Czechoslovak physicians in the Krusnohorska Medical Association 1937 1938 and 1945-1948]. PMID- 8681366 TI - [Mental dysfunction in Parkinson's disease]. AB - In Parkinson's disease, mental disturbances frequently accompany the typical motor disorder. Subcortical dementia develops in 10 to 20% of patients. Contrary to the dementia of Alzheimer's type, the apraxia-aphasia-amnesia syndrome is uncommon. Depression and specific impairment of speech, visuospatial functions, and memory are present in an important proportion of patients. As a principal feature of cognitive disorder, deficit of executive functions can be characterised by decreased mental flexibility and inability to cope with changing external conditions. Further, psychiatric complications of pharmacological treatment of Parkinson's disease are briefly described. Finally, presumed pathophysiological mechanisms of cognitive dysfunction are characterized involving dopaminergic and non-dopaminergic changes and complex interactions on the subcortico-cortical level. PMID- 8681367 TI - [Head-upright tilt table test: a new method for diagnosis of vasovagal neurocardiogenic syncope]. AB - The head upright tilt table test (HUT) has been unambiguously included into the screening algorithm of syncopes. The HUT is based on exposing patients to orthostatic stress. This easy, cheap and safe test makes it possible to diagnose neurally-mediated vasovagal syncope (NMS). The pathophysiology of the NMS is based on the hypercontractility of the myocardium, when with the body being orthostatic, the venous return to the heart is lower and then followed by protecting mechanism--vasodilatation and bradycardia--both controlled by the CNS. Nowadays there is a tendency to integrate examination schedules of the HUT and all possible types of responses have been defined. PMID- 8681368 TI - [Adenomatous and inflammatory colorectal polyps: antioxidative enzyme activity in the colon]. AB - BACKGROUND: Reactive types of oxygen play an important part also in carcinogenesis. Antioxidant enzymes are the primary defence against their damage. The objective of the present work was to glutathione peroxidase in the mucosa and polyps of the colon in subjects with colorectal adenoma and idiopathic proctocolitis. METHODS AND RESULTS: The authors examined 18 controls, 43 patients with colorectal adenoma and 12 subjects with idiopathic proctocolitis. During endoscopy bioptic specimens of the mucosa and from polyps were taken for histological and enzymological examination: Cu/Zn superoxide dismutase, catalase, glutathione peroxidase. In subjects with colorectal adenoma a raised glutathione peroxidase activity was found in the colon and an elevated activity of superoxide dismutase in the adenoma. In patients with idiopathic proctocolitis in the stage of clinical remission in the mucosa a lower glutathione peroxidase activity was found but a high activity of all enzymes was recorded in the inflamed polyps. CONCLUSIONS: The cause of elevated activities of antioxidant enzymes in subjects with colorectal adenoma in the colonic mucosa and in adenomas is not known and calls for further studies. In patients with idiopathic proctocolitis the increased level of antioxidant enzymes in the mucosa is probably produced by a higher production of reactive oxygen types by activated leucocytes in the inflamed tissues. PMID- 8681369 TI - [Nucleotomy--a new method in the treatment of lumboischiadic syndrome]. AB - BACKGROUND: Degenerative changes in the lumbosacral portion of the spine are frequently associated with the lumboischiadic syndrome (LI syndrome). Its treatment is traditionally conservative or surgical. In the seventies and eighties to these two procedures percutaneous punctures were added. The objective of the authors is to present their own experience with a new puncture method of LI syndrome--APLD (automated percutaneous lumbar discectomy). METHODS AND RESULTS: The number of operated patients in 1991-1994 comprised 45 patients, 19 men and 28 women, mean age 40.7 years (18-64 years). APLD was performed 47 times (four times at the level of L3/4, 30 times at the level of L4/5 and 13 times at the level of L5/S1; in two subjects the operation was repeated because the first operation was not effective. APLD is a miniinvasive method made under local anaesthesia with skiascopic control, using special instruments of Surgical Dynamics, USA. Patients with the LI syndrome are selected for treatment according to strict clinical and radiological criteria, the effectiveness of treatment depends on the selection of patients. In the published group treatment was successful in 83% (17% not improved, 38% improved, 45% cured) which is consistent with the experience of others, in particular authors abroad. Only in one instance a minor peroperative complication occurred; the authors did not record any postoperative complications. CONCLUSIONS: APLD is an effective and safe method of invasive treatment of prolapse of lumbar intervertebral discs in an indicated group of patients. It does not replace surgical treatment but reduces the period of conservative treatment. If this treatment is not successful after 4-6 weeks, APLD should be the method of choice. Therefore doctors who are the first to treat these patients should become familiar with the clinical indications. PMID- 8681370 TI - [Clinical significance of IgM anti-HCV determination in chronic hepatitis C]. AB - BACKGROUND: In the majority of patients with acute viral hepatitis C the early antibody IgM anti-HCV in serum is positive. However, a substantial portion of the patients with chronic hepatitis C has also positive IgM anti-HCV as a sign of the continuing replication of the virus. The objective of the work was to assess the presence of IgM anti-HCV in patients with confirmed chronic hepatitis C, in subjects with HBsAg negative chronic hepatitis and in excluded blood donors. Moreover, the authors assessed the relationship between IgM anti-HCV positivity and the activity of serum transaminases and whether the presence of IgM anti-HCV has an impact on the histological finding in the liver. METHODS AND RESULTS: 88 patients were examined (44 women and 44 men), average age 48 years. In 47 subjects histological examinations of the liver were made. IgG anti-HCV were assessed by the Monolisa anti-HCV Sanofi Pasteur test and IgM anti-c22 by an Abbott kit IgM HCV EIA: With regard to the results of the serological examination the patients were divided into three groups which were mutually compared. Group 1 comprised 24 patients with a positive IgG and IgM anti-HCV, group 2 38 patients with a positive IgG anti-HCV only and group 3 26 patients with a negative IgG and IgM anti-HCV. Of 88 examined patients 62 had positive IgG anti-HCV (70%). Of 62 IgG anti-HCV positive subjects 24 (39%) had positive IgM anti-c22. A total of 24 patients had blood transfusions (39%) but only 9 of them had positive IgM anti c22 (37.5%). The mean ALT serum activity was significantly higher in subjects with positive IgM than in those without IgM (p = 0.006), however, for AST the difference was not significant (p = 0.09). Comparison of patients with a confirmed histological finding in the liver revealed that two-thirds of patients with a positive IgM anti-c22 either suffered from cirrhosis or chronic active hepatitis, while anti-HCV positive patients without IgM anti-c22 had cirrhosis or chronic active hepatitis only in one third of the cases. CONCLUSIONS: The results suggest that in chronic hepatitis C some 40% of the patients have positive IgM anti-c22; these subjects have a significantly higher serum ALT activity and a more advanced histological finding in the liver than subjects without IgM anti c22. Assessment of IgM anti-c22 is important not only for diagnosis but also for treatment of chronic HCV infection with antiviral drugs. PMID- 8681371 TI - [Analysis of nutritional habits in patients with familial combined hyperlipidemia]. AB - BACKGROUND: Our objective was to analyze dietary habits of patients with the IIb phenotype of familial combined hyperlipidaemia. These patients were instructed on the proper composition of their diet and they thought that they adhered to these recommendations. METHODS AND RESULTS: The authors examined 41 patients with IIb phenotype of familial combined hyperlipidaemia. Based on their seven-day dietary records their daily intake was calculated and compared with recommended daily allowances as regards energy intake, intake of plant and animal proteins, fats, linoleic acid, carbohydrates, calcium, iron, potassium, fibre, vitamin A, thiamin, pyridoxine, vitamin C, E, cholesterol and NaCl (Progana programme). With the above results the total serum cholesterol, serum triglyceride, HDL and LDL serum cholesterol and nutritional status (body mass index, percentage of body fat and waist hip/ratio) were compared. When the energy intake was acceptable (99% of the recommended allowance), the fat intake was excessive (138%) as well as the intake of animal protein (148%), cholesterol (145%) and NaCl (159% of the recommended allowance), while the intake of plant proteins and fibre and some vitamins was inadequate. A statistically significant relationship was revealed only as regards the linoleic acid intake and total serum cholesterol (inverse relationship at the 95% probability level, r = 0.43), the other investigated relationships were insignificant. The body mass index values (in men and women 26) and the percentage of body fat (22% in men and 34% in women) are above the recommended range. CONCLUSIONS: Dietary errors in the investigated group thus did not pertain, to the quantity of the diet but its composition. From the results ensures that doctors should pay great attention to explaining dietary principles to their patients. PMID- 8681373 TI - Regulating S phase: CDKs, licensing and proteolysis. PMID- 8681372 TI - A license to kill. PMID- 8681374 TI - A hot topic: the origin of hyperthermophiles. PMID- 8681375 TI - The origin and early evolution of life: prebiotic chemistry, the pre-RNA world, and time. PMID- 8681376 TI - Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. AB - Fas/APO-1 and p55 tumor necrosis factor (TNF) receptor (p55-R) activate cellular mechanisms that result in cell death. Upon activation of these receptors, Fas/APO 1 binds a protein called MORT1 (or FADD) and p55-R binds a protein called TRADD. MORT1 and TRADD can also bind to each other. We have cloned a novel protein, MACH, that binds to MORT1. This protein exists in multiple isoforms, some of which contain a region that has proteolytic activity and shows marked sequence homology to proteases of the ICE/CED-3 family. Cellular expression of the proteolytic MACH isoforms results in cell death. Expression of MACH isoforms that contain an incomplete ICE/CED-3 region provides effective protection against the cytotoxicity induced by Fas/APO-1 or p55-R triggering. These findings suggest that MACH is the most upstream enzymatic component in the Fas/APO-1- and p55-R induced cell death signaling cascades. PMID- 8681377 TI - FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. AB - To identify CAP3 and CAP4, components of the CD95 (Fas/APO-1) death-inducing signaling complex, we utilized nano-electrospray tandem mass spectrometry, a recently developed technique to sequence femtomole quantities of polyacrylamide gel-separated proteins. Interestingly, CAP4 encodes a novel 55 kDa protein, designated FLICE, which has homology to both FADD and the ICE/CED-3 family of cysteine proteases. FLICE binds to the death effector domain of FADD and upon overexpression induces apoptosis that is blocked by the ICE family inhibitors, CrmA and z-VAD-fmk. CAP3 was identified as the FLICE prodomain which likely remains bound to the receptor after proteolytic activation. Taken together, this is unique biochemical evidence to link a death receptor physically to the proapoptotic proteases of the ICE/CED-3 family. PMID- 8681378 TI - cul-1 is required for cell cycle exit in C. elegans and identifies a novel gene family. AB - The gene cul-1 (formerly lin-19) is a negative regulator of the cell cycle in C. elegans. Null mutations cause hyperplasia of all tissues. cul-1 is required for developmentally programmed transitions from the G1 phase of the cell cycle to the GO phase or the apoptotic pathway. Moreover, the mutant phenotype suggests that G1-to-S phase progression is accelerated, overriding mechanisms for mitotic arrest and producing abnormally small cells. Significantly, diverse aspects of cell fate and differentiation are unaffected in cul-1 mutants. cul-1 represents a conserved family of genes, designated cullins, with at least five members in nematodes, six in humans, and three in budding yeast. PMID- 8681379 TI - Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. AB - The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. NBCCS maps to chromosome 9q22.3. Familial and sporadic BCCs display loss of heterozygosity in this region, consistent with the gene being a tumor suppressor. A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region. Mutation analysis revealed alterations of PTC in NBCCS patients and in related tumors. We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types. PMID- 8681380 TI - An Mll-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: a method to create fusion oncogenes. AB - Homologous recombination in embryonal stem cells has been used to produce a fusion oncogene, thereby mimicking chromosomal translocations that frequently result in formation of tumor-specific fusion oncogenes in human malignancies. AF9 sequences were fused into the mouse Mll gene so that expression of the Mll-AF9 fusion gene occurred from endogenous Mll transcription control elements, as in t(9;11) found in human leukemias. Chimeric mice carrying the fusion gene developed tumors, which were restricted to acute myeloid leukemias despite the widespread activity of the Mll promoter. Onset of perceptible disease was preceded by expansion of ES cell derivatives in peripheral blood. This novel use of homologous recombination formally proves that chromosomal translocations contribute to malignancy and provides a general strategy to create fusion oncogenes for studying their role in tumorigenesis. PMID- 8681381 TI - PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. AB - A mouse platelet-derived growth factor A chain (PDGF-A) null allele is shown to be homozygous lethal, with two distinct restriction points, one prenatally before E10 and one postnatally. Postnatally surviving PDGF-A-deficient mice develop lung emphysema secondary to the failure of alveolar septation. This is apparently caused by the loss of alveolar myofibroblasts and associated elastin fiber deposits. PDGF alpha receptor-positive cells in the lung having the location of putative alveolar myofibroblast progenitors were specifically absent in PDGF-A null mutants. We conclude that PDGF-A is crucial for alveolar myofibroblast ontogeny. We have previously shown that PDGF-B is required in the ontogeny of kidney mesangial cells. The PDGFs therefore appear to regulate the generation of specific populations of myofibroblasts during mammalian development. The two PDGF null phenotypes also reveal analogous morphogenetic functions for myofibroblast type cells in lung and kidney organogenesis. PMID- 8681382 TI - The YTA10-12 complex, an AAA protease with chaperone-like activity in the inner membrane of mitochondria. AB - The mitochondrial members of the highly conserved AAA family, Yta10p and Yta12p, constitute a membrane-embedded complex of about 850 kDa. As an ATP dependent metallopeptidase (AAA protease), the YTA10-12 complex mediates the degradation of nonassembled inner membrane proteins. In contrast to nucleotide-dependent complex formation and substrate binding, proteolysis of bound polypeptides depends on the hydrolysis of ATP and the metallopeptidase activity of both subunits. Independent of its proteolytic function, the chaperone-like activity of the YTA10-12 complex is required for assembly of the membrane-associated ATP synthase. We propose that proteolytic and chaperone-like activities in the YTA10-12 complex mediate assembly and degradation processes of membrane protein complexes and thereby exert key functions in the maintenance of membrane integrity. PMID- 8681383 TI - Cell type-specific chromatin structure determines the targeting of V(D)J recombinase activity in vitro. AB - A common V(D)J recombinase that recognizes a conserved recombination signal sequence (RSS) mediates the assembly of immunoglobulin (Ig) and T cell receptor (TCR) genes in B and T cell precursors. The rearrangement of particular Ig and TCR gene segments, however, is tightly regulated with respect to cell lineage and developmental stage. Using an in vitro system, we analyzed recombinase cleavage of RSSs flanking Ig and TCR gene segments in nuclei. We found that both the lineage-specificity and temporal ordering of gene rearrangement is reflected in the accessibility of RSSs within chromatin to in vitro cleavage. PMID- 8681384 TI - Daughter of sevenless is a substrate of the phosphotyrosine phosphatase Corkscrew and functions during sevenless signaling. AB - The SH2 domain-containing phosphotyrosine phosphatase Corkscrew (CSW) is an essential component of the signaling pathway initiated by the activation of the sevenless receptor tyrosine kinase (SEV) during Drosophila eye development. We have used genetic and biochemical approaches to identify a substrate for CSW. Expression of a catalytically inactive CSW was used to trap CSW in a complex with a 115 kDa tyrosine-phosphorylated substrate. This substrate was purified and identified as the product of the daughter of sevenless (dos) gene. Mutations of dos were identified in a screen for dominant mutations which enhance the phenotype caused by overexpression of inactive CSW during photoreceptor development. Analysis of dos mutations indicates that DOS is a positive component of the SEV signaling pathway and suggests that DOS dephosphorylation by CSW may be a key event during signaling by SEV. PMID- 8681385 TI - DOS, a novel pleckstrin homology domain-containing protein required for signal transduction between sevenless and Ras1 in Drosophila. AB - The specification of the R7 photoreceptor cell in the developing eye of Drosophila is dependent upon activation of the Sevenless (SEV) receptor tyrosine kinase. By screening for mutations that suppress signaling via a constitutively activated SEV protein, we have identified a novel gene, daughter of sevenless (dos). DOS is required not only for signal transduction via SEV but also in other receptor tyrosine kinase signaling pathways throughout development. The presence of an amino-terminally located pleckstrin homology domain and many potential tyrosine phosphorylation sites suggests that DOS functions as an adaptor protein able to interact with multiple signaling molecules. Our genetic analysis demonstrates that DOS functions upstream of Ras1 and defines a signaling pathway that is independent of direct binding of the DRK SH2/SH3 adaptor protein to the SEV receptor tyrosine kinase. PMID- 8681386 TI - Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid. AB - The structure of inosine-5'-monophosphate dehydrogenase (IMPDH) in complex with IMP and mycophenolic acid (MPA) has been determined by X-ray diffraction. IMPDH plays a central role in B and T lymphocyte replication. MPA is a potent IMPDH inhibitor and the active metabolite of an immunosuppressive drug recently approved for the treatment of allograft rejection. IMPDH comprises two domains: a core domain, which is an alpha/beta barrel and contains the active site, and a flanking domain. The complex, in combination with mutagenesis and kinetic data, provides a structural basis for understanding the mechanism of IMPDH activity and indicates that MPA inhibits IMPDH by acting as a replacement for the nicotinamide portion of the nicotinamide adenine dinucleotide cofactor and a catalytic water molecule. PMID- 8681387 TI - Crystal structure of the conserved core of HIV-1 Nef complexed with a Src family SH3 domain. AB - The crystal structure of the conserved core of HIV-1 Nef has been determined in complex with the SH3 domain of a mutant Fyn tyrosine kinase (a single amino acid substitution, Arg-96 to isoleucine), to which Nef binds tightly. The conserved PxxP sequence motif of Nef, known to be important for optimal viral replication, is part of a polyproline type II helix that engages the SH3 domain in a manner resembling closely the interaction of isolated peptides with SH3 domains. The Nef SH3 structure also reveals how high affinity and specificity in the SH3 interaction is achieved by the presentation of the PxxP motif within the context of the folded structure of Nef. PMID- 8681388 TI - Regulation of dynein activity within Chlamydomonas flagella. PMID- 8681389 TI - Regulation of dynein-driven microtubule sliding by an axonemal kinase and phosphatase in Chlamydomonas flagella. AB - The following is a summary of physiological and pharmacological studies of the regulation of dynein-driven microtubule sliding in Chlamydomonas flagella. The experimental basis for the study is described, and data indicating that an axonemal cAMP-dependent protein kinase can regulate inner arm dynein activity are reviewed. In addition, preliminary data are summarized indicating that an axonemal type 1 phosphatase can also regulate dynein-drive microtubule sliding velocity. It is predicted that the protein kinase, phosphatase, and an inner dynein arm component form a regulatory complex in the axoneme. PMID- 8681390 TI - Mechanisms of flagellar motility probed with microtechniques. PMID- 8681391 TI - Biophysical aspects and modelling of ciliary motility. AB - The dominance of viscous forces in the generation of propulsive thrust by cilia is emphasised. Fourier analysis indicates that ciliary bends consist of circular arcs joined by linear segments; this arc-line shape appears to be a property associated with the molecular mechanism responsible for bending the cilium and is unchanged by variations in the external viscous loading on the organelle. The flexibility of a computer-generated model of axonemal structure is demonstrated by the incorporation of recent data concerning the surface lattice of the microtubules. Computer simulations using the model show that predictions based on stochastic, rather than co-ordinated, dynein arm activity provide a qualitative match to experimental observations of microtubules gliding over fields of dynein molecules. PMID- 8681392 TI - Regulation of ciliary beat frequency by a dynein light chain. PMID- 8681393 TI - Flagellar kinesins: new moves with an old beat. PMID- 8681394 TI - Multi-dynein hypothesis. AB - Axonemal dyneins and cytoplasmic dynein have evolved separate strategies to perform their tasks. The multi-dynein hypothesis accurately describes the highly specialized axonemal isoforms; each isoform is encoded by a separate gene, is located in a precise place, produces specific forces which contribute to the overall generation of propagated bending, and is not functionally interchangeable with other isoforms. In contrast, cytoplasmic dynein, although carrying many different cargoes, appears to be one isoform. An intriguing question is to determine whether there are additional cytoplasmic dyneins, heretofore uncharacterized, which, like their axonemal counterparts, are customized to perform specific tasks. PMID- 8681395 TI - Functional dissection of the dynein motor domain. AB - The highly conserved lysine residue in the putative hydrolytic ATP-binding motif of the yeast cytoplasmic dynein heavy chain was replaced with leucine. The mutation was generated by a two-stage transformation method designed for genomic site-directed mutagenesis. Preliminary observations show that the effects of this alteration on the cellular roles of dynein are indistinguishable from those of a disruption mutation in which the entire motor domain is not expressed. PMID- 8681396 TI - Dynein family of motor proteins: present status and future questions. AB - Analysis of sequence relationships in dynein heavy chains shows that dynein motor proteins comprise a single homologous family with three main branches, cytoplasmic dynein, axonemal dynein, and a third branch represented by DYH1B that lies between the other two. In all branches of the family the dynein heavy chain has four copies of the P-loop motif for a nucleotide-binding site spaced approximately 300 residues apart in its midregion, with the amino acid sequence GPAGTGKT in the P-loop of the hydrolytic ATP-binding site. Cytoplasmic dyneins appear more primitive in that the heavy chain usually occurs as a homodimer, with traces of the early evolution of its four P-loop motifs by gene duplication being recognizable. In the axonemal subfamily the heavy chain occurs as heterodimers or heterotrimers encoded by multiple genes, and their non-hydrolytic P-loop motifs are much more divergent with little trace of their origin by gene duplication. The DYH1B subfamily is more closely related to the cytoplasmic dyneins in sequence, but appears related to axonemal dyneins in function since it becomes upregulated during reciliation and has not been found in organisms, such as yeast and Dictyostelium, that are totally without cilia or flagella. PMID- 8681398 TI - Recombinant expression of the brush border myosin I heavy chain. AB - Although the specific functions of myosin I motors are not known, their localization to membrane structures suggests a function in membrane motility. Different myosin I isoforms in the same cell or in different cells can possess different localizations. To determine if the localization and biochemical activity of the best-characterized mammalian myosin I, chicken intestinal epithelium brush border myosin I, was dependent on determinants of the membrane or actin cytoskeleton specific to epithelial cells, we transfected the cDNA for the heavy chain of this myosin into COS cells. Transient transfection of COS cells with the chicken brush border myosin heavy chain resulted in the production of recombinant myosin I. Recombinant brush border myosin I localized to protrusions of the plasma membrane, particularly at spreading edges, and also to unknown cytoplasmic structures. Some cells expressing particularly high levels of brush border myosin I possessed a highly irregular surface. Recombinant brush border myosin I purified from COS cells bound to actin filaments in an ATP dependent manner and decorated actin filaments to form a characteristic appearance. The recombinant myosin also catalyzed calcium-sensitive, actin activated MgATPase activity similar to that of the native enzyme. Thus, any cellular factor required for the general membrane localization or biochemical activity of brush border myosin I is present in COS cells as well as intestinal epithelium. PMID- 8681399 TI - Ciliary motility: an anniversary celebration. Bronx, New York, May 1, 1995. Proceedings of a symposium. PMID- 8681397 TI - Actin filaments in honeybee-flight muscle move collectively. AB - To investigate the pattern of actin-filament translation in the intact myofibrillar matrix, we carried out electron micrographic experiments on the "rigor-stretch" model of insect-flight muscle. In this model, thin filaments are mechanically severed from their connections to the Z-line and may then slide freely over the myosin filaments when activated. The model is similar to the in vitro motility assay in that untethered actin filaments slide over myosin, but here the natural filament lattice is retained: sliding takes place through the lattice of thick filaments. We find, in this model, that while the extent of thin filament translation is variable from sarcomere to sarcomere, filaments never translate far enough to enter the opposite I-band. Unlike the in vitro motility assay, where the actin filament translates over the entire thick filament even with "incorrectly" polarized cross-bridges as the sole driver, in this intact filament-lattice model, cross-bridges are apparently unable to move filaments in both directions. We also find that the pattern of filament translation is collective. Although the extent of translation may vary among sarcomeres, in any given half-sarcomere all actin filaments translate by the same degree. Further, the extent of translation is the same in both halves of a given sarcomere. In rare instances where the extent of translation exhibited a transverse gradient across the myofibrillar half-sarcomere, the gradient was similar on both sides of the sarcomere. Filament translation within the sarcomere is thus collective. Some mechanism ensures that nearby but distinctly separated actin filaments move together and that cooperative-like behavior therefore extends to the supramolecular level. PMID- 8681400 TI - Landmarks in cilia research from Leeuwenhoek to us. PMID- 8681401 TI - Role of cilia in human health. PMID- 8681402 TI - Exploring the function of inner and outer dynein arms with Chlamydomonas mutants. AB - Chlamydomonas flagella contain as many as 11 different dynein heavy chains, three in the outer arm and eight in the inner. Several lines of evidence suggest that these different dyneins are functionally diverse. This diversity may be important for the generation of axonemal undulating movement. PMID- 8681403 TI - Marine natural products. XXXVI. Biologically active polyacetylenes, adociacetylenes A, B, C, and D, from an Okinawan Marine sponge of Adocia sp. AB - Adociacetylenes A (1), B (2), C (3), and D (4) were isolated as new polyacetylenes from an Okinawan marine sponge of Adocia sp. Their chemical structures have been elucidated on the bases of their chemical and physicochemical properties. Adociacetylenes A (1), C (3), and D (4) exhibited inhibitory activity in the in vitro endothelial cell-neutrophil leukocyte adhesion assay. PMID- 8681404 TI - Structure-activity relationships of non-peptide vasopressin V1a antagonists: 1-(1 multi-substituted benzoyl 4-piperidyl)-3,4-dihydro-2(1H)-quinolinones. AB - During our systematic studies on the arginine vasopressin receptor V1a antagonistic activity of 1-(1-benzoyl substituted 4-piperidyl)-3,4-dihydro-2(1H) quinolinones, we found a general substituent effect on the benzene ring. Hydrogen bonding ability at the ortho position was especially important for enhancement of the affinity of multi-substituted analogs. Details of the syntheses and structure activity relationships for this series are presented. PMID- 8681405 TI - Synthesis and biological activity of novel 1,3-benzoxazine derivatives as K+ channel openers. AB - A new series of 1,3-benzoxazine derivatives with a 2-pyridine 1-oxide group at C4 was designed to explore novel K+ channel openers. Synthesis was carried out by using a palladium(0)-catalyzed carbon-carbon bond formation reaction of imino triflates with organozinc reagents and via a new one-pot 1,3-benzoxazine skeleton formation reaction of benzoylpyridines. The compounds were tested for vasorelaxant activity in tetraethylammonium chloride (TEA) and BaCl2-induced and high KCl-induced contraction of rat aorta to identify potential K+ channel openers, and also for oral hypotensive effects in spontaneously hypertensive rats. An electron-withdrawing group with the proper shape at C6 and a methyl or halogeno group at C7 of the 1,3-benzoxazine nucleus were required for the development of optimal vasorelaxant and hypotensive activity. In particular, 2-(6 bromo-7-chloro-2,2-dimethyl-2H-1,3-benzoxazin-4-yl)pyridine 1-oxide (71) showed more potent vasorelaxant activity (EC50 = 0.14 microM) against TEA and BaCl2 induced contraction and longer-lasting hypotensive effects than cromakalim (1). PMID- 8681406 TI - Antiandrogen. III. 11-oxapregnane steroids. AB - 11-Oxachlormadinone acetate (17-acetoxy-6-chloro-11-oxapregna-4,6-diene-3,20 dione) and 2,11-dioxachlormadinone acetate (17-acetoxy-6-chloro-2,11-dioxapregna 4,6-diene-3,20-dione) were prepared as potential antiandrogenic agents. The effect of the latter compound on antiandrogenic activity when tested in the castrated rat was shown to be more potent than that of the parent compound, chlormadinone acetate. PMID- 8681407 TI - Stereoselective synthesis and thromboxane A2 (TXA2) receptor antagonistic activity of optically active phenol derivatives. AB - Enantiomers of four potent nonprostanoid thromboxane A2 (TXA2) receptor antagonists, (+/-)-7-(4-fluorophenyl)-7-(2-hydroxyphenyl)heptanoic acids (1-4), were synthesized stereoselectively by direct ortho-alkylation of phenols under modified Mitsunobu conditions. The reaction of 5 eq of phenols (6a-c) with 1 eq of (S)- or (R)-methyl 7-(4-fluorophenyl)-7-hydroxyheptanoate ((S)- or (R)-7) afforded ortho-alkylated phenol derivatives (6a-c) enantioselectively in 33 to 42% chemical yield and 90 to 93% ee. In these compounds, the (R)-enantiomers (1 4) exhibited potent TXA2 receptor antagonistic activity and the (S)-isomer (3) was much less active. In particular, compound (R)-3 strongly inhibited U-46619 induced human platelet aggregation (IC50 = 48 nM), and also showed a very potent inhibitory effect with a minimum effective dose (MED) of 0.3 mg/kg (p.o.) on U 46619-induced bronchoconstriction in guinea pigs. PMID- 8681408 TI - Design and synthesis of 6-chloro-3,4-dihydro-4-methyl-2H-1,4-benzoxazine-8 carboxamide derivatives as potent serotonin-3 (5-HT3) receptor antagonists. AB - Several 3-substituted 5-chloro-2-methoxybenzamides were synthesized and evaluated for serotonin-3 (5-HT3) receptor binding affinity. The 5-HT3 receptor antagonistic activity of zacopride, a representative 5-HT3 receptor antagonist, was unchanged by the replacement of the 4-amino substituent on the aromatic moiety by a 3-dimethyl-amino substituent. This finding prompted a structural modification of azasetron, another 5-HT3 receptor antagonist. Consequently, a new series of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamides was obtained and these compounds were found to be more potent than 3,4-dihydro-3-oxo-2H-1,4-benzoxazine 8-carboxamides. In particular, (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-3,4 dihydro-4-methyl-2H-1,4 -benzoxazine-8-carboxamide showed a high affinity for 5 HT3 receptors K(i) = 0.051 nM) and especially potent antagonistic activity against the von Bezold-Jarisch reflex (ED50 = 0.089 micrograms/kg i.v.) in rats. PMID- 8681409 TI - Synthesis and thromboxane A2 antagonistic activity of [[1-aryl(or benzyl)-1 (benzenesulfonamido)methyl]phenyl]alkanoic acid derivatives. AB - In order to find new antiasthmatic and antithrombotic agents, various [[1-aryl(or benzyl)-1-(benzenesulfonamido)methyl]phenyl]alkanoic acid derivatives were synthesized. Evaluation of these compounds for thromboxane A2 (TXA2) antagonistic activities indicated that 4-[4-[(4 chlorobenzenesulfonamido)phenylmethyl]phenyl]butyric acid (6h) ,4-[4-[1-(4 chlorobenzenesulfonamido)-2-phenylethyl]phenyl]butyric acid (6y) and many other compounds have potent inhibitory effects on U-46619-induced guinea-pig platelet aggregation. No significant difference in the inhibitory effect between (+)-6h and its antipode could be detected, although (+)-6h and its antipode could be detected, although (+)-6y was about 10 times more potent than (-)6y. The pKb values of 6h and 6y were estimated to be 8.9 and 10, respectively on U-46619 induced contraction of guinea-pig trachea as a pharmacological measure of TXA2 antagonistic activity. These compounds also showed potent inhibitory effects on U 46619-induced bronchoconstriction in guinea-pig after oral administration in vivo. They were also evaluated for other related pharmacological effects involving the arachidonic acid cascade. It was found that these compounds possess TXA2 synthase inhibitory activity together with TXA2 antagonistic activity, and 6h also possesses weak leukotriene D4 (LTD4) antagonistic activity. Structure activity relationships for TXA2 antagonistic activity of these derivatives are discussed. PMID- 8681410 TI - Studies on cerebral protective agents. X. Synthesis and evaluation of anticonvulsant activities for novel 4,5,6,7-tetrahydrothieno[3,3-c]pyridines and related compounds. AB - Novel 4,5,6,7-tetrahydrothieno[3,2-c]pyridines, 1-thienyl-1,2,3,4 tetrahydroisoquinolines and related compounds, in which the benzene rings of (+) 1 (FR115427) were replaced with heteroaromatic rings such as thiophene, furan, benzothiophene and indole, were synthesized and evaluated for anticonvulsant activity against i.c.v. N-methyl-D-aspartate (NMDA)-induced seizures in mice. Among these compounds, (+)-4-methyl-4-phenyl-4,5,6,7-tetrahydrothieno[3,2 c]pyridine hydrochloride ((+)-2a), (+)-4-methyl-4-(2-thienyl)-4,5,6,7 tetrahydrothieno[3,2-c]pyridine hydrochloride ((+)-2g), and (-)1-methyl-2-(2 thienyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride ((-)-3a) showed significant anticonvulsant activity. The structure-activity relationships with regard to the anticonvulsant activity of this series of compounds are discussed. PMID- 8681412 TI - Adsorption behavior of serum albumin on electrode surfaces and the effects of electrode potential. AB - The adsorption behavior of serum albumin onto the surface of platinum, gold, and glassy carbon electrodes was studied in relation to the electrode potential, by using cyclic voltammetry and a quartz-crystal microbalance. The kinetics of adsorption was significantly dependent on the electrode potential. The adsorption was highly accelerated by the application of positive potential to the electrode, suggesting an electrostatic interaction between the negatively charged albumin molecules and the positively polarized electrode as the origin of the accelerated adsorption. The adsorption of albumin on the electrodes was irreversible with respect to dilution of the albumin solution, while the quartz-crystal microbalance data showed that albumin forms a monomolecular layer on the electrode surface. Protein adsorption on electrode surface in serum was also examined. PMID- 8681411 TI - Structure-activity relationships of 3-methyl and 3,3-dimethyl analogs of 2-(2,4 difluorophenyl)-3-(omega-substituted alkyl)sulfonyl-1-(1H-1,2,4-triazol-1-yl)-2 propanols. AB - 3-Methyl and 3,3-dimethyl analogs of 2-(2,4-difluorophenyl)-3-(omega-substituted alkyl)sulfonyl-1-(1H-1,2,4-triazol-1-yl)-2-propanols were synthesized and evaluated for their antifungal activities against Candida albicans and Aspergillus fumigatus. The 3,3-dimethyl analogs were found to have more potent activity both in vitro and in vivo than the corresponding 3-mono-methyl analogs. The prophylactic efficacy of the lead compounds against murine systemic candidiasis and aspergillosis was improved significantly by dimethylation of the 3-position. PMID- 8681413 TI - Five new triterpene saponins, polygalasaponins XXVIII-XXXII from the root of Polygala japonica Houtt. AB - Five new oleanane-type saponins, polygalasaponins XXVIII-XXXII, along with one known saponin, polygalasaponin XXIV, and one known acylated sucrose, tenuifoliside C, were isolated from the root of Polygala japonica. The structures of these new compounds were elucidated as 3-O-beta-D-glucopyranosyl pesenegenin 28-O-beta-D-xylopyranosyl (1-->4)-alpha-L-rhamnopyranosyl (1-->2)-beta-D fucopyranosyl ester, 3-O-beta-D-glucopyranosyl presenegenin 28-O-beta-D galactopyranosyl (1-->5)-beta-D-apiofuranosyl (1-->4)-beta-D-xylopyranosyl (1- >4)-alpha-L-rhamno-pyranosyl (1-->2)-beta-D-fucopyranosyl ester, 3-O-beta-D glucopyranosyl presenegenin 28-O-beta-D-galactopyranosyl (1-->4)-beta-D xylopyranosyl (1-->4)-alpha-L-rhamnopyranosyl (1-->2)-[4-O-p-methoxycinnamoyl] [beta-D-glucopyranosyl (1-->3)]-beta-D-fucopyranosyl ester, 3-O-beta-D glucopyranosyl presenegenin 28-O-alpha-L-arabinopyranosyl (1-->3)-beta-D xylopyranosyl (1-->4)-[beta-D-apiofuranosyl (1-->3)]-alpha-L-rhamnopyranosyl (1- >2)-[4-O-3,4,5-trimethoxycinnamoyl]-beta-D-fucopyranosyl ester, 3-O-beta-D glucopyranosyl persenegenin 28-O-alpha-L-arabinopyranosyl (1-->3)-beta-D xylopyranosyl (1-->4)-[beta-D-apiofuranosyl (1-->3)-alpha-L-rhamnopyranosyl (1- >2)-[4-O-p-methoxycinnamoyl]-[alpha-L-rhamnopyranosyl (1-->3)-beta-D fucopyranosyl ester, respectively, on the basis of spectroscopic and chemical evidence. PMID- 8681414 TI - Studies on the constituents of Calliandra anomala (Kunth) Macbr. III. Structure elucidation of six acylated triterpenoidal saponins. AB - Six new triterpenoidal saponins, called calliandra saponins G(1), H(2), I(3), J(4), K(5) and L(6), were isolated from the branches of Calliandra anomala (Kunth) Macbr. The structures of these compounds were established on the basis of NMR spectra, FAB-MS, and chemical evidence. These saponins, interestingly, have an N-acetyl glucosamine at the 3 position of the genin, and one or two monoterpene glycosides at the position of the sugar chain. PMID- 8681415 TI - Isolation of inhibitors of TPA-induced mouse ear edema from Hoelen, Poria cocos. AB - Triterpene carboxylic acids were isolated from the methanol extract of Hoelen, Poria cocos, and found to inhibit 12-O-tetradecanoylphorbol 13-acetate (TAP) induced mouse ear edema. Their chemical structures were identified as 3 beta,-16 alpha-dihydroxylanosta-7,9(11),24-trien-21-oic acid, 16 alpha hydroxydehydropachymic acid, 16 alpha-hydroxytrametenolic acid and dehydrotumulosic acid. PMID- 8681416 TI - Effect of inhibitor or immobilization on reduction of benzoylpyridines by baker's yeast. PMID- 8681417 TI - Structure-activity relationships of dermorphin analogues containing chiral piperazin-2-one and piperazine derivatives. AB - The amide and ester carbonyl groups of four piperazin-2-one derivatives (N,N' ethylene-bridged dipeptide ethyl esters) constructed from (R)- or (S) phenylalanine and glycine were reduced with borane-tetrahydrofuran complex to produce the corresponding piperazine derivatives in 70-80% yields. These piperazin-2-one or piperazine derivatives were used as the carboxyl-terminal residues of eight dermorphin analogues (H-tyrosyl-D-alanyl-piperazine derivatives were used as the carboxyl-terminal residues of eight dermorphin analogues (H tyrosyl-D-alanyl-piperazin-2-one or piperazine derivatives) whose opiate activities were examined in vitro by use of the guinea pig ileum and the mouse vas deferens assays. It was found in the guinea pig ileum assay that the configuration of pheylalanine and the replacement of the piperazin-2-one ring with a piperazine ring are important for enhancing or reducing the opiate activities of these analogues. PMID- 8681418 TI - Modification of a glassy carbon electrode with diols for the suppression of electrode fouling in biological fluids. AB - The surface of a glassy carbon (GC) electrode was modified covalently with ethyleneglycol, diethyleneglycol, 1,2-propanediol, and 1,3-propanediol by electrochemical oxidation in order to suppress the electrode fouling originating from non-specific adsorption of serum proteins. Human serum albumin (HSA) was adsorbed significantly on the surface of a bare GC electrode, which was monitored by cyclic voltammetry in the presence of Fe(CN)6(4)-/Fe(CN)6(3)-ions. In contrast, the diol-modified GC electrodes were scarcely fouled in HSA solution and even in human serum. The results were explained reasonably based on the hydrophilic nature of the diol-modified GC surface. PMID- 8681419 TI - Effect of nonionic surfactants on the percutaneous absorption tenoxicam. AB - The effect of 14 types of nonionic surfactants on the permeation of Tenoxicam (TEN) through guinea pigs from propylene glycol solution was investigated in vitro. The flux of TEN was significantly enhanced by polyoxyethylene alkyl ether and polyoxyethylene monoalkyl carboxylate as hydrophilic surfactants, and by polyglyceryl trialkylate, glyceryl monoalkylate, sorbitan monoalkyl carboxylate and sorbitan trialkyl carboxylate as hydrophobic surfactants. In the presence of these surfactants, the flux was increased about 2 to 4 times, as compared to the flux without them. The mechanism of nonionic surfactant action was analyzed and classified by recent methods. the including HLB of surfactants, the solubility of the drugs in vehicle and the hemolysis of erythrocytes. The results suggested that vital factors in the enhancement of skin permeation by nonionic surfactants include the affinity of the surfactants to the stratum corneum, the solubility of the drugs in vehicle and the penetration of surfactants to the stratum corneum. PMID- 8681420 TI - Highly selective cleavage of pyroglutamyl-peptide bond in concentrated hydrochloric acid. AB - Highly selective cleavage reaction of pGlu-peptide bond is described. Two model peptides, pGlu-X-Ala-Phe-OH (X = Ile and Ser), and dog neuromedin U-8 (d-NMU-8) (1-7)-OH (pGlu-Phe-Leu-Phe-Arg-Pro-Arg-OH) were hydrolyzed in concentrated HCl at 0 degree C for from 6 days to 6 weeks to give the predominant cleavage products of pGlu-X linkage of pGlu-X-Ala-Phe-OH and the pGlu-Phe linkage of d-NMU-8 (1-7) OH, respectively. The ring-opening reaction of the pyrrolidone moiety of the pGlu residue occurred to a considerably lesser extent. PMID- 8681421 TI - Phospholipase D and signal transduction in mammalian cells. PMID- 8681422 TI - Regulation of phospholipase D by tyrosine kinases. AB - Activation of phospholipase D (PLD) represents part of an important signalling pathway in mammalian cells. Phospholipase D catalyzed hydrolysis of phospholipids generates phosphatidic acid (PA) which is subsequently metabolized to lyso-PA (LPA) or diacylglycerol (DAG). While DAG is an endogenous activator of protein kinase C (PKC), PA and LPA have been recognized as second messengers as well. Activation of PLD in response to an external stimulus may involve PKC, Ca2+, G proteins and/or tyrosine kinases. In this review, we will address the role of protein tyrosine phosphorylation in growth factor-, agonist- and oxidant-mediated activation of PLD. Furthermore, a possible link between PKC, Ca2+, G-proteins and tyrosine kinases is discussed to indicate the complexity involved in the regulation of PLD in mammalian cells. PMID- 8681423 TI - Messenger functions of phosphatidic acid. AB - Under physiological conditions, phosphatidic acid (PA) is an anionic phospholipid with moderate biological reactivity. Some of its biological effects can be attributed to lyso-PA and diacylglycerol generated by the action of cellular hydrolases. However, it is clear that the parent compound exhibits biological activities of its own. Early studies implicated PA in the transport of Ca++ across plasma membranes as well as in the mobilization of intracellular stored calcium. Both responses may be induced as a consequence of other cellular processes activated by PA, as opposed to being directly mediated by the lipid. PA may be involved in the activation of certain functions confined to specialized groupings of cells, such as the neutrophil superoxide-generating enzyme or actin polymerization. Recent studies implicate PA as an activator of intracellular protein kinases, and a PA-dependent superfamily of kinases involved in cellular signalling has been hypothesized. Deployed on the outer surface of the plasma membrane, PA potentially provides a method of communication between cells in direct contact. This review will explore the known functions of PA as an intracellular mediator and extracellular messenger of biological activities and address ways in which these functions are potentially regulated by cellular enzymes which hydrolyse the phospholipid. PMID- 8681424 TI - The N-acylation-phosphodiesterase pathway and cell signalling. AB - Long-chain N-acylethanolamines (NAEs) elicit a variety of biological and pharmacological effects. Anandamide (20:4n-6 NAE) and other polyunsaturated NAEs bind to the cannabinoid receptor and may thus serve as highly specific lipid mediators of cell signalling. NAEs can be formed by phospholipase D-catalyzed hydrolysis of N-acylethanolamine phospholipids or by direct condensation of ethanolamine and fatty acid. So far, most of the latter biosynthetic activity has been shown to be the reverse reaction of the NAE amidohydrolase that catalyzes NAE degradation. Thus, increasing evidence supports the hypothesis that the N acylation-phosphodiesterase pathway yields not only saturated-monounsaturated NAEs, but polyunsaturated ones, including anandamide, as well. PMID- 8681425 TI - Phospholipase D in platelets and megakaryocytic cells. AB - Phospholipase D (PLD) is stimulated in platelets by various agents. Phosphatidylcholine is the major substrate for PLD. This enzymatic pathway generates phosphatidic acid selectively. Guanine nucleotides also stimulate PLD in platelet membranes. Furthermore, tyrosine kinase may also be involved in platelet PLD regulation. It appears that multiple signals acting sequentially or in parallel converge on PLD. Among others, PLD has been proposed to play a role in platelet secretion and PLA2 regulation. PLD is also present in platelet percursor megakaryocytric cells and can be activated by platelet agonists. In these cells both PKC and G-proteins (e.g. Rho) may regulate PLD activity. The significance of PLD in megakaryocytes awaits investigation. These recent developments offer new avenues of research to further elucidate the biochemistry of platelet and megakaryocyte function. PMID- 8681426 TI - Sphingoid bases and phospholipase D activation. AB - There is increased interest in physiological functions and mechanisms of action of sphingolipids metabolites, ceramide, sphingosine, and sphingosine-1-phosphate (SPP), members of a new class of lipid second messengers. This review summarizes current knowledge regarding the role of these sphingolipids metabolites in the actions of growth factors and focuses on the second messenger roles of sphingosine and its metabolite, SPP, in the regulation of cell growth. We also discuss possible interactions with intermediates of the well known glycerophospholipid cycle. Sphingosine and SPP generally provide positive mitogenic signals whereas ceramide has been reported to induce apoptosis and cell arrest in several mammalian cell lines. Stimulation of phospholipase D leading to an increase in phosphatidic acid, a positive regulator of cell growth, by sphingosine and SPP, and its inhibition by ceramide, might be related to their opposite effects on cell growth. This also indicates that sphingolipid turnover could regulate the diacylglycerol cycle. Cross-talk between sphingolipid turnover pathways and the diacylglycerol cycle increases complexity of signaling pathways leading to cellular proliferation and adds additional sites of regulation. PMID- 8681427 TI - Biochemistry and cell biology of phospholipase D in human neutrophils. AB - Neutrophils play a major role host defense against invading microbes. Recent studies have emphasized the importance of the phospholipase D (PLD) in the signalling cascade leading to neutrophil activation. Phospholipase D catalyzes the hydrolysis of phospholipids to generate phosphatidic acid with secondarily generation of diradylglycerol; both of these products have been implicated as second messengers. Herein, we discuss the regulation and the biochemistry of the receptor-regulated PLD in human neutrophils. In vivo and in vitro studies suggest an activation mode in which initial receptor-linked activation of phospholipase C generates diacylglycerol and inositol trisphosphate. The resulting calcium flux along with the diacylglycerol activate a conventional isoform of protein kinase C (PKC), probably PKC beta 1. This PKC, in turn phosphorylates a plasma membrane component resulting in PLD activation and a second outpouring of diradylglycerol. The small GTP-binding proteins, RhoA and ARF, also participate in this process, and synergize with a 50 kDa cytosolic regulatory factor. PMID- 8681428 TI - Enzymology of mammalian phospholipases D: in vitro studies. AB - The existence of multiple forms of phopholipase D was clearly established in a large number of biochemical studies that described and characterized the enzymological properties of the different PLD activities. This review summarizes the in vitro evidence showing differential subcellular localization and chromatographic properties of putative PLD isozymes, their phospholipid and alcohol substrate specificities, their modulation by various divalent cations, small G proteins and protein kinase c isozymes, and the role of phosphatidylinositol 4,5-bisphosphate as a cofactor of phospholipase D. PMID- 8681429 TI - Phosphatidate phosphohydrolase and signal transduction. AB - A Mg(2+)-independent and N-ethylmaleimide-insensitive phosphatidate phosphohydrolase (PAP-2) has been identified in the plasma membrane of cells and it has been purified. The enzyme is a multi-functional phosphohydrolase that can dephosphorylate phosphatidate, lysophosphatidate, sphingosine 1-phosphate and ceramide 1-phosphate and these substrates are competitive inhibitors of the reaction. The action of PAP-2 could terminate signalling by these bioactive lipids and at the same time generates compounds such as diacylglycerol, sphingosine and ceramide which are also potent signalling molecules. In relation to phosphatidate metabolism, sphingosine (or sphingosine 1-phosphate) stimulates phospholipase D and thus the formation of phosphatidate. At the same time sphingosine inhibits PAP-2 activity thus further increasing phosphatidate concentrations. By contrast, ceramides inhibit the activation of phospholipase D by a wide variety of agonists and increase the dephosphorylation of phosphatidate, lysophosphatidate, sphingosine 1-phosphate and ceramide 1 phosphate. These actions demonstrate "cross-talk' between the glycerolipid and sphingolipid signalling pathways and the involvement of PAP-2 in modifying the balance of the bioactive lipids generated by these pathways during cell activation. PMID- 8681430 TI - ARF-regulated phospholipase D: a potential role in membrane traffic. AB - Phospholipase D activity is stimulated rapidly upon occupation of cell-surface receptors. One of the intracellular regulators of phospholipase D activity has been identified as ADP ribosylation factor (ARF). ARF is a small GTP binding protein whose function has been elucidated in vesicular traffic. This review puts into context the connection between the two fields of signal transduction and vesicular transport. PMID- 8681431 TI - Regulation of phospholipase D by protein kinase C. AB - In nearly all mammalian cells and tissues examined, protein kinase C (PKC) has been shown to serve as a major regulator of a phosphatidylcholine-specific phospholipase D (PLD) activity. At least 12 distinct isoforms of PKC have been described so far; of these enzymes only the alpha- and beta-isoforms were found to regulate PLD activity. While the mechanism of this regulation has remained unknown, available evidence suggests that both phosphorylating and non phosphorylating mechanisms may be involved. A phosphatidylcholine-specific PLD activity was recently purified from pig lung, but its possible regulation by PKC has not been reported yet. Several cell types and tissues appear to express additional forms of PLD which can hydrolyze either phosphatidylethanolamine or phosphatidylinositol. It has also been reported that at least one form of PLD can be activated by oncogenes, but not by PKC activators. Similar to activated PKC, some of the primary and secondary products of PLD-mediated phospholipid hydrolysis, including phosphatidic acid, 1,2-diacylglycerol, choline phosphate and ethanolamine, also exhibit mitogenic/co-mitogenic effects in cultured cells. Furthermore, both the PLD and PKC systems have been implicated in the regulation of vesicle transport and exocytosis. Recently the PLD enzyme has been cloned and the tools of molecular biology to study its biological roles will soon be available. Using specific inhibitors of growth regulating signals and vesicle transport, so far no convincing evidence has been reported to support the role of PLD in the mediation of any of the above cellular effects of activated PKC. PMID- 8681432 TI - p53 tumor suppressor gene: from the basic research laboratory to the clinic--an abridged historical perspective. PMID- 8681433 TI - Role of connexin genes in growth control. PMID- 8681434 TI - Targeted disruption of the DNA repair methyltransferase gene renders mice hypersensitive to alkylating agent. AB - Alkylation of DNA at the O(6)-position of guanine is one of the most critical events leading to induction of mutation as well as to cancer. The enzyme O(6) methylguanine-DNA methyltransferase repairs this and related lesions in DNA. By means of gene targeting, we established mouse lines deficient in the methyltransferase gene and tissues from these mice contained no methyltransferase activity. Administration of methylnitrosourea to these gene-targeted mice led to early death, and normal mice treated in the same manner showed no untoward effects. In mice given methylnitrosourea treatment, the bone marrow became hypocellular and there was a drastic decrease in the number of leukocytes and platelets, thereby indicating an impaired reproductive capacity of hematopoietic stem cells. Methyltransferase apparently protected these mice from the pancytopenia caused by the alkylating agent. PMID- 8681435 TI - Enhancement of genomic instability by 17beta-estradiol in minisatellite sequences of X-ray-transformed mouse 10T1/2 cells. AB - The female hormone 17beta-estradiol is involved in the development of breast cancer, an effect usually attributed to its capacity to stimulate the replication of preneoplastic and malignant cells. In this study, we report that 17beta estradiol enhances the onset of genomic rearrangements, a type of genomic instability, in minisatellite sequences of malignant 10T1/2 mouse cells. Two malignant clones, X-ray-9 and F-17a, previously transformed in vitro by X-rays (600 cGys), and two non-transformed 10T1/2 mouse cell subclones (10T1/2b and 10T1/2c) were divided into two groups. The first group was incubated in the presence of 10(-5) M of 17beta-estradiol (dissolved in ethanol) for 5 days, while the second group was incubated for the same period in culture media containing 0.1% of ethanol. After the incubation both groups of cells were then subcloned, and their DNA was extracted and analyzed with the DNA fingerprinting assay using the probe M (core sequence: 5'-AGGC). A high frequency of genomic rearrangements was observed in the transformed subclones treated with 17beta-estradiol. Nine deletions or additions in minisatellite alleles were observed in six F-17a subclones, while 28 of those genomic rearrangements were found in the 12 X-ray-9 malignant subclones. On the other hand, for the non-transformed 10T1/2b and 10T1/2c cells, no genomic rearrangements were induced by the hormone. After the withdrawal of 17beta-estradiol from the transformed clone X-ray-9, no new genomic rearrangements were detected; while a second incubation with the hormone induced new deletions or additions in minisatellite alleles. This preferential enhancement of genomic instability in malignant 10T1/2 mouse cells suggests that 17beta-estradiol may accelerate the accumulation of mutations, and therefore may represent a mechanism by which the female hormone contributes to breast cancer development. PMID- 8681436 TI - Dietary fat and fiber differentially alter intracellular second messengers during tumor development in rat colon. AB - The effect of fat, fiber and carcinogen on colonic epithelial intracellular second messengers 1,2-diacyl-sn-glycerol (DAG), ceramide, and the steady-state level of phospholipase C (PLC-gamma1) was determined in 160 male Sprague-Dawley rats (10 rats per group). The study was a 2 x 2 x 2 x 2 factorial design with two types of fat (corn oil or fish oil), two types of fiber (cellulose or pectin), two injected subgroups (with or without azoxymethane (AOM), and two time points (15 and 37 weeks). At the final time point (37 weeks) there were an additional 20 rats per diet in each of the carcinogen-treated groups for tumor analyses only (n = 80), for a total of 240 animals in the entire study. At each time point (15 and 37 weeks), 80 rats were killed and colonic mucosa obtained for DAG, ceramide and PLC-gamma1 assays. At the first time point (15 weeks), there was no microscopic evidence of tumors. At the final time point (37 weeks), fish oil resulted in a lower proportion of animals with adenocarcinomas relative to corn oil feeding (56.1 % versus 69.6 %, P < 0.05). There was no significant main effect of fiber on the percentage of animals with tumors. At 15 weeks post-injection, AOM injected animals fed corn oil-containing diets had a significantly (P < 0.001) higher DAG mass and steady-state levels of PLC-gamma1 compared with AOM-injected animals fed fish oil and saline injected rats on all diets. Animals fed corn oil diets also had a significantly (P < 0.01) elevated mucosal ceramide mass compared with fish oil fed animals. Moreover, rats injected with AOM had a significantly (P < 0.02) elevated colonic mucosal DAG/ceramide ratio versus saline injected animals. In contrast, dietary fiber had no effect on any of the parameters measured at 15 weeks. However, at 37 weeks post-injection, dietary fiber significantly altered DAG (P < 0.02), and PLC-gamma1 expression (P < 0.05) in the absence of an effect on tumor incidence. These data demonstrate that the ability of dietary fish oil to reduce experimental colon carcinogenesis may be mediated by changes in colonic intracellular mediators during the initial stages of tumorigenesis. PMID- 8681437 TI - Estrogen receptor levels and occupancy in hepatic sinusoidal endothelial and Kupffer cells are enhanced by initiation with diethylnitrosamine and promotion with 17alpha-ethinylestradiol in rats. AB - We report the presence of estrogen receptors (ER) in rat liver sinusoidal endothelial (SEC) and Kupffer cells (KC), which exhibited comparable saturation kinetics and receptor affinity (Kd) for 17alpha-estradiol, as characterized for the rat hepatocyte ER. The ER levels in both cell types were significantly decreased by ovariectomy, indicating a regulatory role of estrogens. Initiation of ovariectomized rats with a single dose (200 mg/kg) of diethylnitrosamine (DEN) or saline (S), followed by chronic exposure to 17alalpha-ethinylestradiol (EE2), 90 microg/kg/day for 30 weeks packed in cholesterol (C) resulted in significant changes of ER levels in both the endothelial and Kupffer cells. The isolation of enriched liver SEC and KC populations by centrifugal elutriation allowed for the evaluation of chronic EE2 exposure and DEN-induced alterations on each cell type. The DEN-EE2 regime significantly enhanced gamma-gluta-myltranspeptidase activity in SEC (5-fold) and KC (6.6-fold) compared to the S/C treated animals. Nuclear ER levels were elevated 5.1-fold in the SEC and 6.5-fold in the KC, and both cell types exhibited significant increases in the proportion of occupied nuclear ER compared to the S/C derived cells, suggesting that exogenous estrogens could influence SEC and KC function through changes in ER levels and occupancy. ER occupancy was approximately 50% of the total ER in SEC and KC from DEN-EE2 rats. Increases in ER and occupancy for SEC and KC were similar to those observed for hepatocytes. Cellular growth was clearly modified in DEN-EE2 animals as indicated by a 4- to 10-fold increase in the proportion of SEC, KC or hepatocytes in S phase as shown by flow cytometry. However, unlike hepatocytes, the epidermal growth factor receptor (EGFR) was not detected in SEC or KC using a monoclonal EGFR antibody. These findings suggest that the EGFR at 30 weeks is not involved in EE2-mediated stimulation of mitogenesis in SEC and KC which may be different from hepatocytes. In summary, our studies demonstrate that SEC and KC contain significant amounts of high-affinity ER and that ER pathways may modulate some activities of the SEC and KC, but that ER-EGFR interactions may be different in these cells from hepatocytes. PMID- 8681438 TI - Selective dieldrin promotion of hepatic focal lesions in mice. AB - Chronic exposure to a number of chlorinated pesticides, including dieldrin, results in an increased incidence and/or multiplicity of hepatocellular neoplasia in mice, with no such effect in similarly treated rats. One possible explanation of this observed selective carcinogenicity is species-specific hepatic tumor promotion. In the present study we examined the dose-response effect of dieldrin (at several doses) on focal lesion growth (tumor promotion), hepatocyte apoptosis and DNA synthesis in rat and mouse liver. Preneoplastic focal hepatic lesions were produced by diethylnitrosamine (DEN). After the lesions developed, mice and rats were placed into one of the following dose groups: control (NIH-07 diet) or 0.1, 1.0 or 10.0 mg dieldrin/kg diet. Increased focal lesion volume, number of foci per liver and focal DNA synthetic labeling index were observed in 10 mg dieldrin/kg diet-treated mice, but not in similarly treated rats. Dieldrin at dietary concentrations of 0.1 and 1.0 mg/kg diet produced an increase in the number of preneoplastic lesions (0.1 mg/kg diet at 7 days only) and focal volume (0.1 mg/kg diet at 7 and 30 days, 1.0 mg/kg diet at 30 days), but these concentrations did not increase focal DNA labeling index. At dietary concentrations of 0.1, 1.0 and 10 mg dieldrin/kg diet no significant change in lesion percent volume, number of preneoplastic lesions per liver or preneoplastic lesion DNA labeling index was seen in treated rats compared with control rats. Apoptosis, a form of programed cell death, was not decreased in foci by any concentration of dieldrin in either rats or mice. Thus our results suggest that dieldrin may function as a mouse-specific tumor promoter through increased lesion DNA synthesis. PMID- 8681439 TI - Cell proliferation and global methylation status changes in mouse liver after phenobarbital and/or choline-devoid, methionine-deficient diet administration. AB - Our laboratory is testing the hypothesis that hypomethylation of DNA [a decreased content of 5-methylcytosine (5MeC) compared with cytosine] facilitates aberrant oncogene expression involved in tumorigenesis, using a model system of mouse strains with differing susceptibilities to liver tumorigenesis. The B6C3F1 (C57BL/6 x C3H/He) mouse serves as the relatively susceptible strain and C57BL/6 serves as the relatively resistant strain. Phenobarbital (PB) and/or administration of a choline-devoid, methionine-deficient diet (CMD) were employed as non-genotoxic hepatocarcinogens. We have examined hepatocyte and nonhepatocyte proliferation in conjunction with an assessment of global methylation changes in liver DNA of B6C3F1 and C57BL/6 mice following these promoter treatments. Bromodeoxyuridine incorporation into DNA, used to measure cell proliferation indirectly, was visualized by immunohistochemistry and quantified by a Macintosh based image analysis system. Increased hepatocyte proliferation was demonstrated following all three treatments. This increase was larger in C57BL/6 (the relatively resistant strain) as compared with B6C3F1. In contrast, global hypomethylation was evident to a larger extent in the B6C3F1 mouse, as compared with C57BL/6. PB led to hypomethylation (>20% decrease as compared with controls) at weeks 1, 2 and 4 in B6C3F1, but not in C57BL/6 at the same time points. CMD diet administration led to hypomethylation in both strains. At week 1, 21 and 9% decreases in global methylation status were observed in B6C3F1 and C57BL/6 respectively. Evaluation of these data suggests that the heightened sensitivity of the B6C3F1 mouse compared with the C57BL/6 is due, in part, to a decreased capacity for, or fidelity of, maintaining normal methylation status. The relatively resistant strain is better able to maintain the normal methylation status of DNA in the face of a higher level of cell proliferation. PMID- 8681440 TI - Staurosporine induces a complete program of terminal differentiation in neoplastic mouse keratinocytes via activation of protein kinase C. AB - Staurosporine (stsp) is a kinase inhibitor which induces cornified envelope assembly and terminal differentiation in normal and neoplastic mouse keratinocytes. In the tumorigenic cell lines 308 and SP-1 experiments were performed to determine if this effect was due only to activation of transglutaminases (TGases) already residing within the cell, or whether stsp was capable of inducing a full program of differentiation. Assessment of keratinocyte differentiation-specific protein expression in neoplastic cells revealed that expression of the suprabasal marker SPR-1 and the granular markers loricrin and filaggrin were induced by stsp. Protein expression was controlled by changes in mRNA expression, determined by Northern blotting. Transcripts for the TGase isoforms TGK and TGE were also induced by stsp in SP-1 cells, whereas only TGK expression was increased in 308 cells, which appear not to express TGE. Protein kinase C (PKC) activation is required for differentiation in normal mouse keratinocytes. To determine if stsp induces differentiation in neoplastic cells by regulation of this signaling pathway cells were treated with the specific PKC inhibitor GF 109203X or with different concentrations of bryostatin 1 to down regulate specific isoforms of PKC prior to and during treatment with stsp. Stsp induced protein cross-linking and marker expression were inhibited by GF 109203X, suggesting paradoxical activation of PKC by stsp. PKC alpha, epsilon and delta, but not PKC eta and zeta, were down-regulated by treating both cell types with bryostatin; pre-treatment of cells with bryostatin inhibited stsp-induced protein cross-linking and marker expression, suggesting a necessity for the alpha, delta and/or epsilon isoforms in stsp-induced differentiation. PMID- 8681441 TI - Tumor progression and oxidant-antioxidant status. AB - Severity of prognosis factors in breast cancer cases was found to be associated with an increase in plasma vitamin E and a decrease in plasma malondialdehyde (peroxidability index). The first aim of this study was to determine whether this association is also present in other cancers. Measurements were taken before therapy on 129 patients with various carcinomas. Cholesterol was also investigated, as vitamin E is closely related to this analyte. Patients were classified by tumor size (T < or = 5 cm and T > 5 cm) and by invasion status, assessed by the presence of nodes and/or metastasis. The vitamin E/total cholesterol concentration ratio was higher and the cholesterol and malondialdehyde concentrations were significantly lower in the plasma of patients with large tumors or in whom nodes and/or metastasis were present, whatever the site. The multivariate analysis performed to measure the association of these analyte concentrations with tumor progression showed that the presence of nodes and/or metastases was inversely associated with a low vitamin E/total cholesterol ratio (OR, 0.5; CI, 0.3-1.1) and, directly associated with low plasma concentrations of cholesterol and malondialdehyde (OR, 3.0; CI, 1.3-6.8 and OR, 2.8; CI, 1.2-6.7 respectively). The same types of associations were identified with large tumors, but were less strong. Together these findings supported an alteration of lipid parameters related to the oxidant-antioxidant status in cancer patients. This alteration appears to be associated with tumor growth and progression in patients with various cancer sites. PMID- 8681442 TI - Antioxidants inhibit the enhancement of malignant cell transformation induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin. AB - The mechanisms of the tumor promoting activity of 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD) were studied using as in vitro model the enhancement ('promotion') of malignant transformation of C3H/M2 mouse fibroblasts induced by N-methyl-N' nitro-N-nitrosoguanidine or 3-methylcholanthrene. In this assay, the promoting effect of TCDD was maximal at a very low concentration of 1.5 pM and was comparable to the effect of the reference tumor promoter, 12-O tetradecanoylphorbol-13-acetate (TPA, 0.25 microg/ml). The role of reactive oxygen species in the promoting action was investigated: mannitol, a scavenger of hydroxyl radicals, or antioxidants, i.e. ascorbic acid plus alpha-tocopherol, abolished the in vitro promoting effects of TPA and TCDD. Furthermore, the involvement of protein kinase C (PKC) activation was studied: the protein kinase inhibitor H-7 markedly reduced the in vitro promoting activity of TPA but did not affect the promotion by TCDD. In accord with these results, TPA, but not TCDD, enhanced the PKC activity in C3H/M2 fibroblasts. Since the TPA-mediated activation of PKC was not affected by ascorbate plus alpha-tocopherol, it is concluded that the antioxidants interfere with tumor promotion at a step beyond PKC activation. Thus, the results suggest that the enhancement of malignant cell transformation by TPA and TCDD is dependent on a common mechanism, possibly induced by oxygen radicals, and, in addition, on further mechanisms that may involve agent-specific signalling pathways (e.g. PKC activation by TPA). PMID- 8681443 TI - 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) inhibits the binding activity of T4 endonuclease V to UV-damaged DNA. AB - 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is a mutagen/carcinogen derived from cooked foods which enhances the induction of mutations and chromosome aberrations by UV without microsomal activation. These co-mutagenic effects are considered to arise from inhibition of DNA excision repair at the incision step. However, the inhibition mechanism has not been clarified. In this study we show, using agarose gel electrophoresis, that Trp-P-1 inhibits incision by T4 endonuclease V, which cleaves DNA at the site of cyclobutane dimers. Trp-P 1 also inhibits the binding of this enzyme to UV-damaged DNA in a gel shift assay. In addition, the results of DNA unwinding assay with topoisomerase I suggest that Trp-P-1 intercalates into DNA molecules. The known intercalators ethidium bromide and acriflavine demonstrate similar effects in these experiments. However, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which showed no co-mutagenic effects in our previous study, does not demonstrate such effects. These results suggest that Trp-P-1 changes DNA conformation by intercalation, causing inhibition of binding of repair enzymes to UV-damaged DNA, and this in turn leads to inhibition of DNA excision repair and to co-mutagenic effects. PMID- 8681444 TI - Use of a microsome-mediated test system to assess efficacy and mechanisms of cancer chemopreventive agents. AB - There is a growing need for short-term assays which can assess the mechanisms and efficacy of cancer chemopreventive agents. In the present study we have employed a microsome-mediated test system concomitantly with DNA adduct detection to assess the efficacy of five chemopreventive agents, N-acetylcysteine, butylated hydroxytoluene (BHT), curcumin, oltipraz, and ellagic acid. 32P-Postlabeling analysis of DNA incubated with benzo[a]pyrene (BP) in the presence of Aroclor 1254-induced microsomes produced two major adducts: one derived from the interaction of benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) with deoxyguanosine (dG) and the other from further activation of 9-OH-BP (309 and 34 adducts/10(7) nucleotides, respectively). With the exception of N-acetylcysteine, all test agents significantly altered BP-DNA adduct levels: Intervention with ellagic acid and oltipraz substantially (64-94%) inhibited both BPDE-dG and 9-OH-BP adducts, while intervention with curcumin and BHT inhibited the BPDE-dG adduct (57% and 38%, respectively) and enhanced the 9-OH-BP adduct (230% and 650%, respectively). Furthermore, ellagic acid was the only test agent observed to inhibit the anti BPDE-dG adduct in the absence of microsomal enzymes, which is consistent with the known conjugation of ellagic acid with BPDE. These results suggest that oltipraz may be acting as an inhibitor of P4501A1, the isozyme involved in activation of BP to BPDE, or by conjugation of the electrophilic species by a metabolite of oltipraz. A plausible mechanism for inhibition of the BPDE-dG adduct and enhancement of the 9-OH-BP adduct by curcumin and BHT includes inhibition of epoxide hydrolase. Our results also indicate that N-acetylcysteine does not act as an electrophilic trapping agent of BP metabolites but may exert its protective effect in vivo by various other means, including modulation of detoxification enzymes and altering DNA repair processes. These data suggest that this cell-free system in conjunction with the sensitive 32P-postlabeling DNA adduct analysis may prove a viable test system for assessing the mechanisms and efficacy of chemopreventive agents. PMID- 8681445 TI - Suppressing effect of perilla oil on azoxymethane-induced foci of colonic aberrant crypts in rats. AB - We have investigated the modulatory effect of dietary perilla oil which is rich in the n-3 polyunsaturated fatty acid, alpha-linolenic acid, on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in male F344 rats. Animals were given three weekly subcutaneous injections of AOM (15 mg/kg body weight) to induce ACE. The rats were fed a basal diet containing either 12% olive oil, 12% safflower oil, 12% perilla oil, 6% perilla oil plus 6% olive oil, or 3% perilla oil plus 9% olive oil for 5 weeks, starting 1 week before the first dosing of AOM. All rats were sacrificed 2 weeks after the last AOM injection. The amount of food consumed and body weight gain were identical among every dietary group. The frequency of ACF was significantly lower in the rats fed 12% perilla oil than in those fed 12% olive oil or 12% safflower oil (P < 0.01 and P < 0.05, respectively). The suppressive effect of perilla oil was dose-dependent, as the number of ACF was 20.7, 40.7 and 47.4% of those of the 12% olive oil-fed controls in rats fed 12% perilla oil, 6% perilla oil plus 6% olive oil and 3% perilla oil plus 9% olive oil, respectively. Perilla oil significantly reduced ras expression as well as the AgNORs count (cell proliferation biomarkers) in the colonic mucosa, as compared with olive oil or safflower oil (P < 0.01, respectively). Marked increases in n-3 polyunsaturated fatty acids in membrane phospholipid fractions and decreased PGE2 levels were observed in colonic mucosa of perilla oil-fed rats. These results suggest that perilla oil, even in small amounts, suppresses the development of aberrant crypt foci, and is therefore a possible preventive agent in the early stage of colon carcinogenesis. PMID- 8681446 TI - 32P-postlabelling of diastereomeric 7-alkylguanine adducts of butadiene monoepoxide. AB - The reaction of 3,4-epoxy-1-butene (BMO) with deoxyguanosine-3'-monophosphate (3' dGMP) resulted in the formation of two pairs of diastereomeric 7-alkyl-3'-dGMP derivatives corresponding to two isomers C?-1 and C?-2. The T4 polynucleotide kinase-mediated phosphorylation with [gamma-32P]-ATP showed preferential labelling of diastereo- mers of the C?-1 isomer. The diastereomers 1 and 2 of the C?-1 isomer had labelling efficiencies of 42%. However, the labelling efficiencies of diastereomers 3 and 4 of the C?-2 isomer were 11 and 10%, respectively. The 32P-postlabelling of BMO-modified DNA yielded four isomers in the ratio of 4:4:1:1 with overall recoveries being 14%. The two isomers had a half-life of 270 min (C?-1 isomer) and 300 min (C?-2 isomer) which is in accordance with the stability predicted by other similar adduct experiments. The molecular modelling experiments showed more pronounced restricted rotation of butadiene residue in C?-2 isomers due to steric interaction between butadiene residue at N-7 and O(6) atom of guanine than in C?-1 isomer. The butadiene residue also leads to steric overcrowding at 3'-phosphate in C?-2 isomer which probably restricts the access to the active site of T4 polynucleotide kinase. PMID- 8681447 TI - Effects of the phytochemicals, curcumin and quercetin, upon azoxymethane-induced colon cancer and 7,12-dimethylbenz[a]anthracene-induced mammary cancer in rats. AB - Curcumin and quercetin were evaluated in rats for their ability to modulate the carcinogenic activity of azoxymethane (AOM) in the colon and 7,12 dimethylbenz[a]anthracene (DMBA) in the mammary gland. In the AOM-induced colon cancer model, male Fischer 344 rats at 8 weeks of age started to receive either curcumin (8 and 16 g/kg) or quercetin (16.8 and 33.6 g/kg) in the diet and 1 week later, were administered AOM (30 mg/kg body wt.) by subcutaneous injection. The animals continued to receive the two agents in the diet until sacrificed 45 weeks later. Curcumin mediated a dose-dependent inhibition of the incidence and multiplicity of adenomas from 47% and 0.58 +/- 0.12 adenomas/rat in the AOM treated control group to 19% and 0.22 +/- 0.08 and 0.06% and 0.08 +/- 0.06 adenomas/rat for the low and high dose groups, respectively. A low yield of adenocarcinomas (0.06 +/- 0.04 adenocarcinomas/rat) was induced by AOM which was not significantly altered by curcumin. Treatment with quercetin caused a dose dependent increase in the yield of AOM-induced tumors in the colon from 0.06 +/- 0.04 adenocarcinoma/rat to 0.64 +/- 0.12 and 1.14 +/- 0.17 for the low and high dose groups, respectively. In the DMBA-induced mammary cancer model, curcumin or quercetin was administered at either 10 or 20 g/kg diet, beginning 7 days prior to DMBA and continually throughout the remainder of the experiment. Neither curcumin nor quercetin significantly altered the incidence of animals with tumors or the tumor multiplicity, while the high concentration of both agents significantly increased tumor latency. These results demonstrate different responses to these agents in the two models. While curcumin was highly effective as a chemopreventive agent in the colon model, it was only weakly effective in the mammary model. In contrast, quercetin which was also only weakly effective in the mammary model, caused a dose-dependent enhancement of tumors induced by AOM in the colon model. PMID- 8681448 TI - p53 polymorphisms and haplotypes in breast cancer. AB - Three polymorphisms in the human tumor suppressor gene p53 (BstUI and MspI RFLPs in exon 4 and intron 6 respectively and a 16 bp duplication in intron 3) and their haplotype combinations were studied in patients with breast cancer and controls. A significant increase in the codon 72 BstUI A1 (pro) allele frequency (P = 0.016) and of individuals carrying the pro allele (pro/pro and pro/arg) (OR, 1.47; P = 0.01 4; 95 % CI, 1.08-2.00) was observed in breast cancer. This increase was most pronounced in highly differentiated breast cancer. Significant associations were found only in BstUI and haplotypes containing this polymorphism, which indicates that the codon 72 pro allele may be functionally involved in low malignancy breast cancer. The distributions of genotypic combinations in breast cancer patients and controls were significantly different (P = 0.005). Two BstUI-16 bp-MspI combinations were significantly overrepresented; 2-1, 1-1, 2-2 (OR, 1.61; 95% CI, 1.13-2.30) and 1-1, 2-1, 2-1 (OR, 2.94; 95% CI, 1.37-6.27). PMID- 8681449 TI - Detection of microcystins, a blue-green algal hepatotoxin, in drinking water sampled in Haimen and Fusui, endemic areas of primary liver cancer in China, by highly sensitive immunoassay. AB - An epidemiological survey for the causes of a high incidence of primary liver cancer (PLC) in Haimen city, Jian-Su province and Fusui county, Guangxi province in China, found a close correlation between the incidence of PLC and the drinking of pond and ditch water. With an aim to clarify whether microcystins (MC), a hepatotoxic peptide produced by water bloom algae, contaminate the drinking water in the endemic areas of PLC in China, a highly sensitive enzyme-linked immunosorbent assay with a detection limit of 50 pg/ml, was introduced to monitor the MC. Three trials to survey the drinking water were carried out in 1993-1994. Samples, 1135 in total, were collected from different sources such as: ponds, ditches, rivers, shallow wells and deep wells in Haimen city. The first survey in September 1993 found that three out of 14 ditch water specimens were positive for MC, with a range of 90-460 pg/ml. Several toxic algae such as Oscillatoria agardhii were present in some of the ditches. In the second trial, samples were collected from five ponds/ditches, two rivers, two shallow wells and two deep wells monthly for the whole year of 1994. These data showed that MC was highest in June to September, with a range of 62-296 pg/ml. A third trial on the 989 different water samples collected from the different types of water sources in July 1994 revealed that 17% of the pond/ditch water, 32% of the river water, and 4% of the shallow-well water were positive for MC, with averages of 101, 160 and 68 pg/ml respectively. No MC was detected in deep well water. A similar survey on 26 drinking water samples in Fusui, Guangxi province, demonstrated a high contamination frequency of MC in the water of ponds/ditches and rivers but no MC in shallow and deep wells. These data support a hypothesis that the blue-green algal toxin MC in the drinking water of ponds/ditches and rivers, or both, is one of the risk factors for the high incidence of PLC in China. Based on previous findings on the epidemiology of PLC and the present results from the mass screening of MC in the drinking water, an advisory level of MC in drinking water was proposed to below 0.01 microg/l. The combined effect of a potent hepatocarcinogen AFB1 and an intermittent intake of MC in drinking water in the summer season was discussed as an etiology of PLC. PMID- 8681450 TI - Different patterns of expression of ornithine decarboxylase mRNAs in rat liver after acute administration of hepatocarcinogens. AB - In the present study, we have evaluated the induction of ornithine decarboxylase (ODC) activity in rat liver after acute in vivo administration of different hepatocarcinogens, and correlated the ODC activity peaks with the accumulation of the three ODC-related mRNA species in rat liver at different times after the intraperitoneal injection of different hepatocarcinogens. ODC activity peaked 16 h after 2-acetylaminofluorene (2-AAF) treatment, while accumulation of the three ODC-mRNAs, starting 4 h after the injection, was maximal 6 h later. Thioacetamide (TAA) administration caused a single peak of ODC activity 20 h after treatment, while there had been the maximum increases of the three ODC-mRNAs 4-h earlier. The first ODC activity peak occurred 20 h after treatment with 3'-methyl-4 (dimethylamino)azobenzene (MDAB), at the same time that accumulation of the ODC mRNAs was maximum. There was no increase in ODC-mRNA accumulation at 28 h or 36 h after MDAB treatment, the time at which ODC activity once again peaked. All the ODC-related transcripts accumulated after MDAB treatment, although to different degrees. The 1.7 kilobase (kb) transcript accumulated the most after 2-AAF treatment. After TAA treatment, the 2.2 kb mRNA was the most abundantly expressed. In neonatal liver, in which ODC activity is physiologically high, the 1.7 kb mRNA is expressed more abundantly than the other two ODC-related transcripts. These results demonstrate that the peak of ODC enzyme activity does not always correspond in time with the peak of ODC-mRNA accumulation; that different hepatocarcinogens induce different patterns of accumulation of the ODC related transcripts; and that the minor ODC-related transcript (1.7 kb) in rat liver seems to be expressed not only constitutively but is also inducible. PMID- 8681451 TI - Covalent DNA adducts formed in mouse epidermis by benzo[g]chrysene. AB - The metabolic activation in mouse skin of benzo[g]chrysene (B[g]C), a moderately carcinogenic polycyclic aromatic hydrocarbon (PAH) present in coal tar, was investigated. Male Parkes mice were treated topically with 0.5 micromol B[g]C and DNA was isolated from the treated areas of skin at various times after treatment and analysed by 32P-post-labelling. Seven major adduct spots were detected, at a maximum level of 6.55 fmol adducts/microg DNA. Mouse skin treated with the PAH benzo[c]phenanthrene (B[c]Ph) gave a total of 0.24 fmol adducts/microg DNA. B[g]C DNA adducts persisted in skin for at least 3 weeks. Treatment of mice with 0.5 micromol of the optically pure putative proximate carcinogens, the (+)- and (-) trans benzo[g]chrysene-11,12-dihydrodiols, led to the formation of adducts which comigrated on TLC and HPLC with those formed in B[g]C-treated mice, which suggested that the detected adducts were formed by the fjord region B[g]C-11,12 dihydrodiol-13,14-epoxides (B[g]CDEs). To test this, the four optically pure synthetic B[g]CDEs were reacted in vitro with DNA and the heteroco-polymers poly(dA x dT) and poly(dG x dC) and these samples 32P-postlabelled. Co chromatography, on both TLC and HPLC, of in vitro and in vivo adducts indicated that B[g]C is activated in mouse skin through formation of the (-)-anti (11R,12S,l3S,14R) and (+)-syn-(11S,12R,13S,14R) B[g]CDEs. (-)-anti-B[g]CDE formed five adducts with DNA, two of them with adenine and three with guanine bases. (+) syn-B[g]CDE formed one adduct with each of these bases in DNA. The adenine adducts accounted for 64% of the total major adducts formed in B[g]C-treated mouse skin. The route of metabolic activation or B[g]C is similar to that reported for B[c]Ph, but the extent of activation to the fjord region diol epoxides is significantly greater in the case of B[g]C, as demonstrated by the higher levels of adduct formation in vivo. PMID- 8681452 TI - Effect on the expression of c-met, c-myc and PPAR-alpha in liver and liver tumors from rats chronically exposed to the hepatocarcinogenic peroxisome proliferator WY-14,643. AB - The induction of rodent hepatic tumors by peroxisome proliferators (PP) appears to depend on focal growth of hepatocytes. Expression of the oncogenes c-met and c myc is altered following regenerative stimuli in rat liver, suggesting involvement of their protein products in hepatocyte replication. In addition, increases in c-myc and c-met mRNA expression are observed in multiple types of human and rodent tumors, including hepatocellular carcinoma. A study was designed to test the hypothesis that development of PP-induced hepatic neoplasms occurs as a result of overexpression of c-met or c-myc. Male F344 rats were exposed to WY 14,643 for 22 or 78 weeks (1000 p.p.m. in the diet). Messenger RNA was extracted from liver tumors (78 weeks) and surrounding non-lesion liver of exposed rats and non-lesion liver from age-matched control rats. Levels of mRNA expression were compared using Northern analysis. Significant increases in c-met (approximately 6 fold) and c-myc (approximately 7-fold) mRNA levels were observed in liver tumors compared with liver from control rats. A slight but non-significant increase in mRNA for both of these genes was observed in tumors compared with surrounding non lesion liver tissue (approximately 2-fold). Increases in mRNA expression of c-met (approximately 3-fold) and c-myc (approximately 5-fold) were also detected in non lesion liver from WY-14,463-exposed animals compared with non-lesion liver from naive rats. PP exposure in rats increased c-met and c-myc expression in liver and liver tumors, but in a manner which does not correspond to the rapid proliferation of hepatocytes present in tumors. To determine the potential involvement of the PP-activated receptor in PP-induced hepatocarcinogenesis, tumors were also examined for PP-activated receptor expression relative to surrounding liver and liver from naive rats. PP-activated receptor-alpha mRNA levels were significantly increased (approximately 6-fold) in tumors compared with naive liver, but only slightly increased over surrounding non-lesion liver tissue. These results suggest that modulation of c-met, c-myc and PP-activated receptor-alpha are not major determinants of PP-induced hepatocarcinogenesis. PMID- 8681453 TI - The influence of flaxseed and lignans on colon carcinogenesis and beta glucuronidase activity. AB - Flaxseed, the richest source of mammalian lignan precursors, such as secoisolariciresinol diglycoside (SD), has been shown over the short term to decrease some early markers of colon cancer risk. This study determined whether over the long term flaxseed still exerts a colon cancer protective effect, whether its effect may, in part, be due to its high content of SD and whether any change in beta-glucuronidase activity plays a role in the protective effect. Six groups of male Sprague-Dawley rats were fed for 100 days either a basal high fat (20%) diet (BD), BD supplemented with 2.5 or 5% flaxseed or 2.5 or 5% defatted flaxseed (equivalent to the respective flaxseed diets) or BD with a daily gavage of 1.5 mg SD. All rats were injected with a single dose of azoxymethane (15 mg/kg body wt) 1 week prior to commencing the dietary treatments. Urinary lignan excretion, which is an indicator of mammalian lignan production, was significantly increased in the flaxseed and defatted flaxseed groups. The total activity of cecal beta-glucuronidase was significantly increased in a dose dependent manner by the flaxseed and defatted flaxseed diet groups. Compared with the control the number of aberrant crypts per focus was significantly reduced in the distal colon of the treated rats. Four microadenomas and two polyps were observed in the control group, but not in the treated groups. The total activity of beta-glucuronidase was positively correlated with total urinary lignan excretion and negatively with the total number of aberrant crypts and the total number of aberrant crypt foci in the distal colon. There were no significant differences between the flaxseed and the corresponding defatted flaxseed groups. It is concluded that flaxseed has a colon cancer protective effect, that it is due, in part, to SD and that the protective effect of flaxseed is associated with increased beta-glucuronidase activity. PMID- 8681454 TI - In vitro exposure to cadmium in rat L6 myoblasts can result in both enhancement and suppression of malignant progression in vivo. AB - Cadmium (Cd), a carcinogenic metal in humans and rodents, has been shown to transform cells in vitro. Cd in certain instances can also be anti-carcinogenic. The effects of Cd have been studied in different mammalian cell culture systems, where it has been shown to increase expression of several proto-oncogenes. In the present study the ability of Cd to affect malignant transformation was systematically investigated in L6 cells. Cells were grown in monolayer culture with concentrations of either 0 or 0.5 microM CdCl2 in the medium. Cell cultures treated with Cd for 9 weeks showed growth of large colonies in soft agar, while untreated control cells did not. When injected s.c. into athymic nude mice the 9 week Cd-treated cells gave rise to large, highly malignant sarcomas, resulting in high host mortality (9 dead/9 injected, 100%) by 7 weeks. Mice injected with untreated control cells also developed tumors, but of significantly smaller size and growth rate and associated with a lower host mortality (4/10, 40%, P A transversions in the first base, with 29 A-->T transversions and one A-->G transition in the second base. Twenty five of 31 CEMS-induced hepatomas had mutations in the same codon, which consisted of seven C-->A transversions in the first base, with eight A-->T transversions and 10 A-->G transitions in the second base. These mutation spectra are quite different to that noted by others in spontaneous hepatomas in untreated B6C3F1 mice. These data appear to result from the covalent binding of these carcinogens to the liver DNA. PMID- 8681457 TI - Monoclonal development of squamous cell carcinomas from polyclonal papillary or nodular hyperplasias in the forestomach of C3H/HeN<-->BALB/c chimeric mice treated with N-methyl-N-nitrosourea or diethylnitrosamine. AB - The clonality of epithelial proliferative lesions of forestomach carcinogenesis was immunohistochemically investigated in C3H/HeN<-->BALB/c chimeric mice using a specific antibody to C3H strain specific antigen (CSA) and as well as in terms of microsatellite DNA polymorphism patterns. The C3H/HeN<-->BALB/c chimeric mice were produced by an aggregation procedure. Male chimeric, C3H/HeN, and BALB/c animals were given N-methyl-N-nitrosourea (MNU) 0.5 mg/mouse once a week for a total of 10 times by intragastric intubation or 30 p.p.m. diethylnitrosamine (DEN) in their drinking water for 20 weeks. Those treated with MNU were killed at weeks 11, 25 and 45 and with DEN at week 35. Normal chimeric forestomach epithelium was found to demonstrate mixtures of epithelial cell groups composed of either CSA positive or negative cells. The same was the case for all simple hyperplasias. Papillary and nodular (PN) hyperplasias increased with time even after cessation of MNU treatment and many of them consisted of both CSA positive and negative cell groups. In one case, a CSA positive and a negative cancer were observed to have developed independently in the same PN-hyperplasia consisting of both parental cell types. In 28 tumor bearing chimeric mice, all squamous cell carcinomas (SCCs) were composed entirely of either CSA positive or negative tumor cells. However, in two animals with advanced CSA positive cancers and negative cancers, tiny cancer nests composed of both parental type cells were found in association. Microsatellite DNA polymorphism patterns of DNAs sampled from histological sections completely conformed with the outcomes of immunohistochemical staining. The results suggest that PN-hyperplasias are aggregates (polyclonal) of preneoplastic changes from which monoclonal SCCs are derived. Polyclonal cancers may also arise secondarily at low incidence during progression, due to two or more lesions coalescing. PMID- 8681458 TI - Flaxseed and its lignan and oil components reduce mammary tumor growth at a late stage of carcinogenesis. AB - Flaxseed, a rich source of mammalian lignan precursor secoisolariciresinol diglycoside (S.D.) and alpha-linolenic acid (ALA), has been shown to be protective at the early promotion stage of carcinogenesis. The objective of this study was to determine whether supplementation with flaxseed, its lignan or oil fractions, beginning 13 weeks after carcinogen administration, would reduce the size of established mammary tumors (present at the start of treatment) and appearance of new tumors in rats. Dietary groups consisted of the basal diet (BD, 20% corn oil) alone or supplemented with a gavage of 2200 nmol/day S.D. [S.D., equal to level in 5% flaxseed (F)], 1.82% flaxseed oil (OIL, equal to level in 5% F) or 2.5% or 5% flaxseed (2.5% F and 5% F, respectively). After 7 weeks of treatment, established tumor volume was over 50% smaller in all treatment groups (OIL, 2.5% F, 5% F, P < 0.04; S.D., P < 0.08) while there was no change in the BD group. New tumor number and volume were lowest in the S.D. (P < 0.02) and 2.5% F (P < 0.07) groups. The combined established and new tumor volumes were smaller for the S.D., 2.5% F and 5% F groups (P < 0.02) compared to the OIL and BD groups. The high negative correlation (r = -0.997, P < 0.001) between established tumor volume and urinary mammalian lignan excretion in the BD, S.D., 2.5% F and 5% F groups indicates that the reduction in tumor size is due in part to the lignans derived from the S.D. in flaxseed. However, there was no relationship between new or total tumor development and urinary lignan levels. The effect of flaxseed oil may be related to its high ALA content. In conclusion, the S.D. in flaxseed appears to be beneficial throughout the promotional phase of carcinogenesis whereas the oil component is more effective at the stage when tumors have already been established. PMID- 8681459 TI - TPA decreases the p53 response to benzo[a]pyrene-DNA adducts in vivo in mouse skin. AB - TPA, a well-known tumor promoter, decreased the response of nuclear p53 immunoreactivity to benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE)-DNA adducts in C57BL/6 mouse skin in vivo. A dose-dependent increase in both the level of BPDE DNA adducts and nuclear p53 immunoreactivity was found in mice treated topically with 50-750 microg benzo[a]pyrene. Such a positive correlation between the adducts and p53 positivity was suggested by an earlier study. Since p53 probably functions in DNA damage control, interference by TPA with the p53 response could be a mechanism in TPA-induced tumor promotion. Whether such a mechanism is more general in tumor promotion deserves further study. PMID- 8681460 TI - Chemopreventive effects of phenethyl isothiocyanate on lung and pancreatic tumorigenesis in N-nitrosobis(2-oxopropyl)amine-treated hamsters. AB - The chemopreventive effects of phenethyl isothiocyanate (PEITC) were investigated in N-nitrosobis(2-oxopropyl)-amine (BOP)-treated hamsters. Female 5-week-old Syrian golden hamsters were divided into six groups. Animals in groups 1-3, each consisting of 30 hamsters, were given BOP by two subcutaneous injections 7 days apart at a dose of 20 mg/kg body weight, plus either 100, 10 or 0 micromol of PEITC in corn oil by gavage 2 h prior to each BOP treatment, respectively per group. Animals in groups 4 and 5, each consisting of 10 hamsters, were given 100 and 10 micromol of PEITC alone in corn oil, and 10 animals in group 6 served as a vehicle control. Animals were sacrificed 52 weeks after the first BOP injection. Both the incidences and multiplicities of lung adenomas and/or adenocarcinomas were significantly decreased in a dose-dependent manner by PEITC treatments (P < 0.01 or 0.05). The lung tumor incidences were inhibited by 100% with 100 micromol PEITC and by 82% with the 10 micromol dosage. In addition, the high dose of PEITC also significantly inhibited pancreatic carcinogenesis (P < 0.05) and showed a tendency to lower the incidences of liver and renal tumors, although these effects were not statistically significant. Under the present experimental conditions, PEITC itself did not cause any apparent toxicity. Our results thus indicate that PEITC is a remarkably effective chemopreventive agent for the BOP induced lung and pancreatic tumors in hamsters. PMID- 8681461 TI - Inhibition of aflatoxin Ml excretion in rat urine during dietary intervention with oltipraz. AB - 4-Methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz) is an effective chemopreventive agent against several classes of carcinogens in many target organs. Induction of carcinogen detoxication enzymes, particularly glutathione S transferases, appears to be an important component of the protective actions of oltipraz. It has recently been observed that addition of oltipraz to rat liver microsomes or to cultured human hepatocytes blocks the oxidative metabolism of aflatoxin B1 (AFB1) to its 8,9-oxide and the hydroxylated derivative aflatoxin Ml (AFM1). 0ltipraz is a competitive and perhaps irreversible inhibitor of cytochromes P450 1A2 and 3A4. To determine whether oltipraz can affect cytochrome P450-dependent metabolism of AFB1 in vivo we have assessed the effect of oltipraz on the urinary excretion of oxidative metabolites of AFB1 before, during and after a transient intervention. Male F344 rats, housed individually in glass metabolism cages, were gavaged daily with 25 microg [3H]AFB1 for 28 consecutive days. Starting on day 6 and extending to day 16 half of the rats were fed a diet supplemented with 0.075% oltipraz. Sequential 24 h urine samples were collected and a subset analyzed for AFB1 metabolites. AFM1 was the major metabolite detected in all urine samples, accounting for 2-6% of the administered dose. The excretion of AFM1 was greatly reduced (77%) during the active phase of the intervention, when oltipraz was added to the diet, but rapidly returned to control levels after cessation of oltipraz administration. This inhibition of AFM1 excretion was not seen in animals receiving oltipraz by gavage 24 h prior to dosing with AFB1. Collectively these data are consistent with the view that oltipraz or a short-lived metabolite inhibits cytochrome P450 1A2 in vivo. PMID- 8681462 TI - Induction of gap junctional intercellular communication by vitamin D in human skin fibroblasts is dependent on the nuclear Induction of gap junctional intercellular communication by vitamin D in human skin fibroblasts is dependent on the nuclear vitamin D receptor. AB - The physiologically active metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D3 (calcitriol), induces gap junctional intercellular communication in human skin fibroblasts 161BR at a concentration of 10(-7) M. In human skin fibroblasts, FIB5, devoid of a functional nuclear vitamin D receptor (VDR), there is no effect on gap junctional intercellular communication. Parallel to the increase in cell cell communication, we observed a VDR-dependent increase in connexin43 protein and connexin43 mRNA levels. These results suggest that 1alpha,25-dihydroxyvitamin D3 affects gap junctional intercellular communication at the level of transcription or of mRNA stability via the nuclear VDR. PMID- 8681463 TI - Guidelines to candidates for the EEG board examination. PMID- 8681465 TI - Diagnostic usefulness of linear and nonlinear quantitative EEG analysis in Alzheimer's disease. AB - The sensitivity of the EEG in early AD is somewhat limited. In this respect spectral analysis is little better than visual assessment. In this study we address the question whether a new type of EEG analysis derived from chaos theory can improve the sensitivity of the EEG. EEGs were recorded in 15 control subjects and 15 patients with mild AD. The EEG recorded at 02 and 01 during eyes closed and eyes open conditions was subjected to spectral analysis (relative power) and nonlinear analysis (calculation of the correlation dimension D2). AD patients had more relative theta power and impaired reactivity in alpha, delta and theta bands. Also, reactivity of the D2 was impaired in AD subjects. For a specificity of 100%, relative theta power had the highest sensitivity (46.7%). Alpha band reactivity at O1 had a sensitivity of 40% and D2 reactivity at O1 had a sensitivity of 33.3%. Combining theta power with alpha reactivity resulted in a sensitivity of 53.3%; combining theta with D2 reactivity resulted in a sensitivity of 60%. Used in isolation, linear analysis was superior in differentiating AD patients from controls. The best results were obtained by combining linear with nonlinear measures. This approach does not seem practical yet, but deserves further study. PMID- 8681466 TI - Does caffeine cessation increase firing rates of diffuse paroxysmal slowing dysrhythmia? A serendipitous observation. AB - As part of a quantitative EEG study of caffeine withdrawal a serendipitous observation suggested that individuals with Diffuse Paroxysmal Slowing (a minor EEG dysrhythmia) in their baseline resting EEGs had an increased firing rate of this pattern while undergoing a period of caffeine abstinence. For all EEGs, individual bursts of Diffuse Paroxysmal Slowing were identified by consensus rating and the firing rate for this pattern expressed as the number of bursts per 10 minutes of alert waking activity. The firing rate of this pattern was seen to increase markedly during 4 days of verified abstinence and to return to baseline or lower than baseline levels following reintroduction of caffeine. Some possible implications of this phenomenon are discussed. PMID- 8681464 TI - Quantitative EEG in frontotemporal dementia. AB - Accurate diagnosis of the major degenerative dementias continues to be problematic. Although diagnostic precision for Alzheimer's disease (AD) approaches 90%, for Frontotemporal dementias (FTD) it has been less than 20%. Previous work has shown that AD patients have both focal and generalized slowing, while in FTD the EEG is normal. We studied 26AD,13FTD and 27 health control subjects with Quantitative Electroencephalography (QEEG). Using only five QEEG measures with stepwise discriminant function analysis, we distinguished the AD from FTD groups each with 84.6% accuracy, and controls (100%) from FTD groups (84.6%) with high accuracy. The most informative QEEG variables for distinguishing FTD and AD were relative power from the temporal region in beta-2 band, and from the parietal region in the theta and alpha and beta-2 bands. These results suggest that QEEG may be helpful in distinguishing subjects with AD from subjects with FTD. PMID- 8681467 TI - Inter- and intrahemispheric EEG coherence during light drowsiness. AB - The present study was conducted to examine inter- and intrahemispheric EEG coherence in 14 healthy, right-handed adults during wakefulness and light drowsiness as assessed by eye movement and EEG activity. Interhemispheric coherence was significantly lower during light drowsiness than during wakefulness for O1-O2 in the alpha-1 band and for F3-F4 in the beta-1 band. Intrahemispheric EEG coherence was significantly higher during light drowsiness for C4-O2 in the theta-1 and beta-1 bands. These findings indicate that light drowsiness can alter both inter- and intrahemispheric EEG coherence when compared with wakefulness, suggesting that cerebral functional organization changes during light drowsiness. It is important, therefore, to control arousal level of subjects in future studies dealing with the relationship between EEG coherence and various pathological conditions. PMID- 8681468 TI - Diffuse theta activity and spindle-like bursts during coma after cardiac arrest. AB - An usual combination of diffuse theta activity with intermittent bursts of spindle-like activity, followed by 2-3 Hz rhythmic discharges and lasting about 7 seconds, was noted in a coma patient after cardiac arrest. We speculate that the theta pattern coma and spindle-like bursts originated in the pontine region, and that those bursts in turn triggered or recruited rhythmic slow-wave complexes similar to absence discharges. PMID- 8681469 TI - Progressive deterioration of brainstem auditory evoked potentials in Creutzfeldt Jakob disease: clinical and electroencephalographic correlation. AB - Brainstem auditory evoked potentials (BAEP) were recorded and correlated with the clinical and electroencephalographic (EEG) findings in three verified cases of Creutzfeldt-Jakob disease (CJD). In contrast to previous reports, there was progressive deterioration of the BAEPs, through initial asymmetry of wave latencies to abnormal wave morphology, and increased interpeak latencies. Consequently, in two of the patients, disorganization of the wave pattern and generalized conduction-time slowing appeared by the time there was a fully developed clinical picture of CJD with periodic EEG waves. In the third, clinically mild CJD, asymmetry of wave latencies in the BAEP emerged, correlating with the appearance of periodicity on EEG. Our findings are consistent with the late, progressive involvement of the brainstem by the pathological process in CJD. PMID- 8681470 TI - Acquired blepharoptosis. AB - A review is given of the aetiology and possible treatment of acquired (non congenital), blepharoptosis, which is a common but not specific sign of neurological disease. The diagnostic categories of upper eyelid drooping are scheduled as (a) pseudo-ptosis due to a local process or overactivity of eye closure, including blepharospasm, and (b) true ptosis due to a paresis of the eyelid levators (m. tarsalis superior or m. levator palpebrae) or to a disinsertion of the m. levator palpebrae (aponeurotic ptosis). A paresis of the m. tarsalis is due to a lesion in the central, intermediate or peripheral neuron of the sympathetic chain and constitutes one of the components of Horner's syndrome. A paresis of the m. levator palpebrae may be due to a failure in central innervation, in oculomotor (n.III) function, in neuromuscular transmission or to a lesion in the muscle itself. PMID- 8681471 TI - Solitary cerebral metastasis from melanoma: value of the 'en bloc' resection. AB - The authors report 19 cases of solitary cerebral metastases from malignant melanoma. In 15 patients, the primary lesion was known at the time the metastasis was diagnosed; deltoid-scapular in 4 cases, thoracic in 5, inguinal in 4 and neck in 2. The primary location was unknown in 4 patients. Presenting symptoms were: epileptic seizures in 9 cases, headache in 8, strength deficit of the limbs in 2. In 3 patients (16%) neurological symptoms were the first clinical sign of the systemic tumor; in 16 cases (84%) there was a long interval between treatment of the primary and appearance of the cerebral metastasis (average 3.8 years; median 3.4 years). All patients were submitted to surgery and radiotherapy (whole-brain in 14 and radiosurgery in 5). In 10 cases the lesion was removed 'en bloc' (no internal touch technique). Average survival was 9 months (median 8 months) and was influenced by 'en bloc' resection and whole-brain irradiation. None of the patients operated by the 'no touch technique' presented a recurrence. PMID- 8681472 TI - Tumoral form of cerebral schistosomiasis mansoni. A report of four cases and a review of the literature. AB - We describe four cases of the tumoral form of cerebral schistosomiasis mansoni. The patients had symptoms of increased intracranial pressure and focal neurological signs that varied according to the site of the lesion. Computerized tomography showed a hyperdense, enhancing lesion located in the cerebellum (2 patients), frontal lobe and thalamus (1 patient), and temporal subdural region (1 patient), with associated mass effects. The lesion was resected in three patients and a stereotactic biopsy was performed in one. Histopathologic specimens of all four patients revealed multiple schistosomal granulomas in various evolutive phases. Two of these patients differ from previously described cases; one because of the subdural location of the lesion, mimicking a meningioma, and the other one because two lesions were present. PMID- 8681473 TI - Pure motor hemiplegia including the face induced by an infarct of the medullary pyramid. AB - Four autopsy cases of pure motor hemiparesis due to medullary pyramid infarcts have been previously reported. The deficits that were described included overt limb weakness and "slight facial weakness". According to current neurological teaching, the lesion responsible for an upper motor neuron facial palsy affects the corticobulbar tract at the level of the midpons or more rostrally. PMID- 8681474 TI - Subependymoma of the cervical cord. AB - Subependymomas are benign lesions of the central nervous system. Their occurrence in the spinal cord is rare. It is important to recognize these lesions because their total surgical excision is feasible and leads to long term symptom remission-a case of a spinal subependymomas localized in the cervical region is discussed and a review of the relevant literature is presented. PMID- 8681475 TI - Lipomas of the frontal lobe. AB - An extremely rare case of lipomas on the cerebral surface in a 65-year-old female is reported. The tumors were located both in an unusual fissure of the right frontal convexity and under the right frontal lobe associated with and surrounded by areas of focal cortical dysplasia. Angiograms revealed dilated branches of the right anterior cerebral artery associated with angiomatous tumor blushes. The etiology of the combination of the lipomas and the anomalies, and the angiographic features, are briefly discussed. PMID- 8681476 TI - Craniospinal and spinal enterogenous cysts--report of three cases. AB - We report three cases of enterogenous cyst, one craniospinal and two spinal manifesting with features of spinal cord compression. In one the cyst was intramedullary in location and in the other two it was intradural, extramedullary. The unusual clinical presentation, location and magnetic resonance imaging (MRI) characteristics are discussed. None of the three patients had any vertebral anomaly or other congenital malformation. All patients had excellent outcome following surgery. PMID- 8681477 TI - Mononeuropathia multiplex and idiopathic intracranial hypertension. AB - A young obese woman with menstrual irregularities presented with bilateral papilledema, abducens nerve paresis, visual obscurations and severe headache. Neuroimaging studies were normal but CSF opening pressure was elevated. The diagnosis of idiopathic intracranial hypertension was made. Insertion of a shunt quickly alleviated the symptoms. A few weeks later the patient developed a left femoral nerve paresis and an ulnar nerve paresis on the right. Electrodiagnostic tests confirmed the diagnosis of mononeuropathia multiplex. Bone marrow histology showed a vasculitis. We hypothesize that the vasculitis is underlying both, idiopathic intracranial hypertension and mononeuropathia multiplex. PMID- 8681478 TI - Disappearance of essential tremor after small thalamic hemorrhage. AB - Stereotactic thalamotomy has been reported to be effective in the control of various tremors, including essential tremor. We report a 69-year-old female who experienced spontaneous thalamotomy with a small thalamic hemorrhage, resulting in disappearance of essential tremor on the contralateral side to the hematoma, which involved the nucleus ventralis intermedius (Vim) of the thalamus and a portion of the posterior limb of the internal capsule. PMID- 8681479 TI - Dopa-responsive dystonia: clinical and family study in Taiwanese. AB - We report the clinical features of four female patients with dopa-responsive dystonia (DRD), and the survey of the family members. The patients were 2 sisters and 2 sporadic patients from 3 families. Their age of onset ranged between 5 and 13 years. The clinical manifestation was characterized by limb dystonia which was relieved by L-dopa treatment. Diurnal fluctuation disappeared 15 years later in one patient. There was a wide spectrum of Parkinsonian features and variability of dystonia. Response of L-dopa was still excellent 20 years later. In survey of the family members, there was neither bradykinesia, rigidity, tremor nor dystonia. PMID- 8681480 TI - Endosellar meningiomas: report of 2 cases and review of the literature. AB - Two cases of endosellar meningiomas are presented. The clinical and radiological picture is not always sufficiently specific to distinguish meningiomas from other types of sellar lesions, but pre-operative diagnosis is of fundamental importance in choosing the best surgical approach. In both cases, the transsphenoidal approach was used, and due to the dense consistency of the tumors, only biopsies were performed. One of the two patients was reoperated on using the sub-frontal approach for radical removal of the tumor. In the authors' experience, craniotomy proved to be the more favorable approach than the transsphenoidal route for radical excision of endosellar meningiomas. Literature on the classification of sellar meningiomas for radiological diagnosis and surgical strategy of endosellar meningiomas is reviewed. PMID- 8681481 TI - Traumatic dissection of the internal carotid artery as unusual cause of hypoglossal nerve dysfunction. AB - A dissection of the internal carotid artery (ICA) in a 50-year-old man with hypoglossal nerve dysfunction is reported. This case illustrates how non-invasive imaging techniques, such as computed tomography and magnetic resonance angiography, can demonstrate this unusual etiology. PMID- 8681482 TI - Isolated cerebellar dysarthria associated with a heat stroke. AB - Patients presenting with heat stroke may develop an acute pancerebellar syndrome. A patient presenting with an isolated cerebellar dysarthria after a heat stroke is reported. The dysarthria lasted two weeks. An isolated cerebellar dysarthria has been previously described in lesions of the paravermal zone of the rostral cerebellum. It is suggested that this region of the cerebellum is particularly vulnerable to fever. PMID- 8681483 TI - Was Maurice Ravel's illness a corticobasal degeneration? AB - The French composer Maurice Ravel (1875-1937) was struck down at the peak of his career by an aphasia and apraxia that destroyed his artistic realization but preserved his musical sensibility and judgment. He died after craniotomy. Multiple hypotheses have been formulated to explain the exact nature of his illness, probably corticobasal degeneration. However, in the absence of a post mortem examination, the diagnosis must remain speculative despite the accurate descriptions of the symptoms in numerous biographies, the neuro-psychological notes of Theophile Alajouanine and the operative findings of Clovis Vincent. PMID- 8681484 TI - Friedreich's ataxia, with retained lower limb tendon reflexes, in a Saudi Arabian family. AB - Friedreich's ataxia (FA) was studied in a large inbred Arab family living near Jeddah, Saudi Arabia, in which DNA linkage studies localised the disease gene to 9q13-q21.1. Five siblings (aged 19-35 years), and their 27 year old cousin, had the typical features of FA, however in two patients, tendon reflexes were retained and were indeed brisk in the lower limbs, 13 and 19 years respectively after onset of symptoms: retention of lower limb tendon reflexes is exceptional in FA. Another 6 deceased individuals from two related families are presumed to have had FA. PMID- 8681485 TI - Pharmacokinetics of the aldose reductase inhibitor tolrestat: studies in healthy young and elderly male and female subjects and in subjects with diabetes. AB - Tolrestat is an aldose reductase inhibitor undergoing clinical trials in diabetic subjects that may reduce the severity of chronic tissue damage associated with hyperglycemia. These studies were conducted to evaluate the pharmacokinetics of tolrestat in healthy young and elderly male and female subjects and in young and elderly subjects with diabetes. The drug was administered in a multiple-dose regimen, and steady-state parameters were obtained. There were no important gender-related differences, but mean values for apparent oral clearance, renal clearance, and corresponding unbound parameters were significantly lower for the elderly healthy subjects than for the young healthy subjects. The drug is highly bound to plasma proteins, and the unbound fraction (0.75%) did not differ among the subjects. The results from young and elderly diabetic subjects suggest that diabetes per se has no influence on tolrestat disposition but that there is an age-related reduction in apparent oral clearance (30 versus 18 ml/hr/kg) and a corresponding increase in the minimum steady-state plasma concentration (1.2 versus 1.9 micrograms/ml). These data indicate a possible need to reduce the dose of tolrestat in elderly subjects, assuming the same concentration-response relationship. PMID- 8681486 TI - Antipyrine as a probe for human oxidative drug metabolism: identification of the cytochrome P450 enzymes catalyzing 4-hydroxyantipyrine, 3 hydroxymethylantipyrine, and norantipyrine formation. AB - BACKGROUND AND OBJECTIVE: Antipyrine has been widely used as a probe drug for human oxidative drug metabolism. To evaluate the role of antipyrine as a model drug, we have identified the cytochrome P450 enzymes involved in 4 hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine formation. METHODS: We used the following methods for this study: (1) determination of enzyme kinetics for antipyrine metabolite formation in human liver microsomes, (2) inhibition studies with antibodies and inhibitors, and (3) formation of metabolites by stable expressed human P450 enzymes. RESULTS: Antipyrine biotransformation could be described by Michaelis-Menten kinetics: norantipyrine: maximum rate of metabolite formation (Vmax), 0.91 +/- 0.04 nmol . mg-1 . min-1; Michaelis-Menten constant (Km), 19.0 +/- 0.8 mmol/L; 4-hydroxyantipyrine: Vmax, 1.54 +/- 0.08 nmol . mg-1 . min-1;Km,39.6 +/- 2.5 mmol/L. Antibodies against CYP3A4 inhibited the formation of 4-hydroxyantipyrine by 25% to 65%. LKM-2 antibodies (anti-CYP2C) caused a 75% to 100% inhibition of norantipyrine and a 58% to 80% inhibition of 3-hydroxymethylantipyrine formation. Sulfaphenazole inhibited the formation of 3-hydroxymethylantipyrine and norantipyrine by about 50%. Furafylline and fluvoxamine inhibited norantipyrine, 4-hydroxyantipyrine, and 3-hydroxymethylantipyrine formation by about 30%, 30%, and 50%, respectively. Ketoconazole reduced formation of norantipyrine, 3-hydroxymethylantipyrine, and 4 hydroxyantipyrine by up to 80%. Formation in stable expressed enzymes indicated involvement of CYP1A2, CYP2B6, CYP2C, and CYP3A4 in metabolite formation. CONCLUSION: Antipyrine metabolites are formed by at least six hepatic cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, and CYP3A4). 4 Hydroxylation is mainly catalyzed by CYP3A4 and, to a lesser extent, by CYP1A2. The CYP2C subfamily contains the predominant enzymes for norantipyrine formation, and CYP1A2 is also involved. Formation of 3-hydroxymethylantipyrine is mediated by CYP1A2 and CYP2C9. Because several cytochrome P450 enzymes are involved in the formation of each metabolite, antipyrine is not well suited as a probe for distinct human cytochrome P450 enzymes. PMID- 8681487 TI - The effect of liver disease on urine caffeine metabolite ratios. AB - OBJECTIVES: A number of caffeine metabolite ratios (CMRs) have been proposed to measure CYP1A2 activity in vivo. The effect of liver disease on these ratios is not clear. The objective of this study was to determine the influence of liver disease on caffeine metabolite ratios. STUDY DESIGN: Two studies were performed. First, in healthy control subjects and in subjects with cirrhosis, caffeine clearance was measured by intravenous infusion of stable isotope-labeled caffeine while subjects consumed oral caffeine. Second, spot urine samples were collected from control subjects and from subjects with either chronic hepatitis or cirrhosis while they consumed caffeine. RESULTS: In study 1, caffeine clearance was decreased in subjects with cirrhosis (control mean, 0.14 L/hr/kg; cirrhosis mean, 0.04 L/hr/kg; p = 0.003). CMRs were affected by liver disease (e.g., ratio characterizing paraxanthine demethylation [AAMU + 1X + 1U/17U], control median, 8.3; cirrhosis median, 6.2; p = 0.005). AAMU + 1X + 1U/17U correlated significantly with caffeine clearance in the control group (r2 = 0.68; p = 0.0001) and in subjects with cirrhosis (r2 = 0.41; p = 0.05). In study 2, there was a significant difference between control subjects and subjects with cirrhosis for AAMU + 1X + 1U/17U (median for control subjects, 6.2; median for subjects with cirrhosis, 4.3; p = 0.001) but not between control subjects and patients with chronic hepatitis. CONCLUSIONS: We conclude that AAMU + 1X + 1U/17U is affected by liver disease and reflects the decrease in CYP1A2 activity in subjects with cirrhosis. AAMU + 1X + 1U/17U measured from a spot urine sample reflects caffeine clearance in subjects with cirrhosis and may be useful as a hepatic function test. Despite the large interindividual variation observed, the test can be repeated easily in the same patient and an individual patient's decline in CYP1A2 activity, such as in patients with progressively deteriorating liver function, can be monitored. PMID- 8681488 TI - Use of an indirect pharmacodynamic stimulation model of MX protein induction to compare in vivo activity of interferon alfa-2a and a polyethylene glycol-modified derivative in healthy subjects. AB - Interferon alfa-2a was chemically modified by the covalent attachment of a polyethylene glycol (PEG) moiety to enhance its circulating half-life and to reduce its immunogenicity. A comparative evaluation of the pharmacokinetics of the PEG-modified interferon alfa-2a showed a greater than twofold increase in the circulating half-life as a result of this chemical modification. An indirect physiologic response model was developed to characterize the time course of the MX protein response after subcutaneous administration of single ascending doses of either interferon alfa-2a or PEG-interferon alfa-2a in healthy volunteers. Analysis of the pharmacokinetic-pharmacodynamic relationship suggested that the PEG-modified interferon alfa-2a could not be administered less than twice weekly and therefore offered little therapeutic advantage over its unmodified counterpart, which is administered three times weekly. These results were consistent with findings in phase II trials. This study substantiates the usefulness of pharmacodynamic modeling as a tool for the development of dose recommendations and for the early selection of drug candidates in the drug development process. PMID- 8681489 TI - Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles, C gamma P2C19m1 in exon 5 and C gamma P2C19m2 in exon 4, in Japanese subjects. AB - The pharmacokinetic profile of omeprazole was examined in 27 healthy Japanese volunteers, and the results were analyzed in relation to genotype for the two mutations, CgammaP2C19m1 in exon 5 and CgammaP2C19m2 in exon 4, associated with the poor metabolizer phenotype. Of the 27 individuals analyzed, 10 were homozygous for the wild-type (wt) allele in both exon 5 and exon 4 (wt/wt; 37.0%, pattern GI), five were heterozygous for the CgammaP2C19m1 (wt/m1; 18.5%, G2), five were heterozygous for the CgammaP2C19m2 (wt/m2; 18.5%, G3), two were heterozygous for the two defects (m1/m2; 7.4%, G4), and five were homozygous for the CgammaP2C19m1 (m1/m1; 18.5%, G5). The allele frequencies of the m1 and m2 mutation were 0.31 and 0.13, respectively. A correlation between the rate of metabolism of omeprazole and genotype was observed. The mean clearance values of omeprazole in patterns G1, G2, G3, G4, and G5 were 1369.0, 332.7, 359.0, 70.8, and 89.5 ml/hr/kg, respectively. The relative area under the serum concentration time curve (AUC) ratio of omeprazole to 5-hydroxyomeprazole in patterns G1, G2, G3, G4, and G5 was 1:2.8:3.4:16:17.2. A similar relation was observed in the omeprazole/5-hydroxyomeprazole serum concentration ratio, determined 3 hours after drug intake (1:3:4:18.8:20.3). There were significant (p < 0.05 to 0.01) differences in the disposition kinetics of omeprazole between the subjects with patterns G1, G2, and G3 and the subjects with patterns G4 and G5. The results indicate that the 5-hydroxylation pathway of omeprazole is clearly impaired in subjects with m1/m2 and m1/m1. PMID- 8681490 TI - Effects of short-term use of nicotine gum in pregnant smokers. AB - OBJECTIVES: To compare blood concentrations of nicotine and cotinine and maternal and fetal hemodynamic effects resulting from use of nicotine gum versus cigarette smoking in pregnant smokers. METHODS: Pregnant women (24 to 36 weeks' gestation) who smoked chronically were randomly assigned with a 1:2 randomization scheme to either a group that smoked cigarettes (n = 10) or to a group that stopped smoking and chewed at least six pieces of nicotine gum (2 mg nicotine per piece) per day (n = 19). Blood nicotine and cotinine concentrations, maternal heart rate and blood pressure, uterine resistance index, and fetal heart rate and umbilical artery resistance index were obtained before and after one cigarette was smoked at baseline and after 5 continuous days of either chewing gum or smoking. RESULTS: A significant reduction from baseline in nicotine (p < 0.0001) and cotinine (p < 0.0025) concentrations was observed in those who chewed nicotine gum compared with those who smoked cigarettes. No significant differences in the changes in maternal or fetal hemodynamic parameters from baseline to estimated time of peak nicotine exposure were observed between those who smoked cigarettes and those who chewed nicotine gum. CONCLUSION: Short-term use of nicotine gum delivers less nicotine than usual cigarette smoking in pregnant women. PMID- 8681492 TI - Angiotensin converting enzyme inhibition and sympathetic activity in healthy subjects. AB - BACKGROUND: One suggested mechanism for the reduction in mortality rates resulting from the use of angiotensin converting enzyme inhibitors in congestive heart failure is the inhibition of the angiotensin II-mediated norepinephrine release. Direct evidence for this mechanism is lacking in humans. SUBJECTS AND METHODS: We examined the effects of captopril, 25 mg three times a day, or matched placebo for 7 days on sympathetic activity during a 10 mEq/day sodium diet in seven healthy male subjects aged 30 +/- 3 (SEM) years. A tritiated norepinephrine radioisotope dilution technique was used to measure sympathetic activity, both at rest and during isometric handgrip exercise. RESULTS: Captopril blunted the increase in mean arterial pressure during isometric handgrip exercise (placebo, from 81 +/- 4 to 112 +/- 2 mm Hg; captopril, from 78 +/- 3 to 101 +/- 2 mm Hg; p < 0.01). However, the increase in systemic norepinephrine spillover during isometric handgrip exercise was not blunted by captopril. Captopril had no effect on resting mean arterial pressure or systemic norepinephrine spillover. CONCLUSIONS: Captopril did not attenuate baseline or static exercise-stimulated sympathetic activity in healthy subjects. These findings would indicate that angiotensin converting enzyme inhibition does not decrease sympathetic activity at rest or during the stimulus of isometric handgrip exercise. PMID- 8681491 TI - Pharmacokinetics of F105, a human monoclonal antibody, in persons infected with human immunodeficiency virus type 1. AB - F105 is a human monoclonal antibody that binds to the CD4 binding site of human immunodeficiency virus type 1 gp120 and neutralizes clinical and laboratory isolates of the human immunodeficiency virus. This phase I study investigated the disposition of the antibody in humans. F105 was administered over a 60-minute period at two dose levels, 100 and 500 mg/m2. Blood samples were obtained for up to 56 days. The clearance of the antibody was 0.33 ml/min with a corresponding half-life of approximately 13 days. Peak concentrations achieved at the higher dose level were 216.19 +/- 9.62 micrograms/ml. The disposition of the drug was linear for the doses studied. Simulations were performed to design future studies aimed at investigating the efficacy of the antibody. This study concluded that F105 can be administered as a bolus dose every 21 days. PMID- 8681493 TI - Incremental dosage of the new antipsychotic mazapertine induces tolerance to cardiovascular and cognitive effects in healthy men. AB - OBJECTIVES: Mazapertine is a structurally novel antipsychotic compound with high affinity for D2, D3, 5-HT1a, and alpha 1 receptors. The objectives were to determine whether tolerance to orthostatic hypotension caused by this compound could be induced by slowly increasing the dose administered and to investigate its effect on cognitive and motor functions. METHODS: Thirteen healthy male subjects received incremental oral doses of mazapertine (from 5 to 50 mg over 7 days; n = 10) or placebo (n = 3) in part I and single doses in parts II (20 or 30 mg or placebo) and III (40 mg or placebo) in a double-blind fashion. Blood pressure, heart rate, cardiac hemodynamics, cognitive functions, and occurrence of acute extrapyramidal symptoms were investigated. RESULTS: Mazapertine appears to be safe and well tolerated when administered orally for 7 days to normal healthy men. No accumulation of serum prolactin occurred after multiple dosing, suggesting limited potential for inducing galactorrhea. The drug was rapidly absorbed, and kinetics appeared to be dose dependent, without accumulation. The elimination half-life was about 5 to 10 hours. No evidence of any positive or negative cognitive effects could be detected. Mild motor symptoms were observed only at high doses (not statistically significant). Mazapertine had a minimal effect on cardiac output and stroke volume. Tolerance to hypotension could be induced by slowly increasing the dose administered. CONCLUSIONS: Mazapertine is well tolerated when administered orally for seven days, and tolerance to hypotension can be induced by slowly increasing the dose administered. Therefore, nothing precludes further clinical testing on patients with schizophrenia. PMID- 8681494 TI - Hemodynamic and hormonal effects of quinaprilat in patients with congestive heart failure. AB - OBJECTIVE: To assess the pharmacodynamic activity and safety of rising single and multiple doses of intravenous quinaprilat compared with placebo in patients with New York Heart Association (NYHA) class III and IV congestive heart failure who were receiving digitalis or diuretic therapy or both. METHODS: Patients were randomly assigned to three treatment groups to receive low (0.5 to 1.0 mg), medium (1.0 and 2.5 mg), or high (5.0 and 10.0 mg) single intravenous doses of quinaprilat or placebo on day 1. On the basis of responses observed on day 1, the three treatment groups received stable multiple intravenous doses of either quinaprilat or placebo every 6 hours on days 2 and 3. Hemodynamic measurements, hormonal assessments, and safety were evaluated before and at specified intervals during the study. RESULTS: Compared with placebo, single and multiple doses of quinaprilat increased cardiac index and reduced pulmonary capillary wedge pressure, mean arterial pressure, systemic vascular resistance, and right atrial pressure in a dose-related manner. No clinically important change in heart rate was observed. Hemodynamic changes after multiple-dose quinaprilat administration were similar to those observed after single doses and were generally sustained during the 6-hour dosing interval. Relative to placebo, quinaprilat reduced plasma angiotensin converting enzyme (ACE) activity, angiotensin II concentration, and aldosterone concentration and increased plasma renin activity; no prominent changes in plasma catecholamine and atrial natriuretic peptide concentrations were observed. There were no clinically important drug-related changes in the safety parameters. CONCLUSIONS: Single and multiple intravenous doses of 0.5 to 10 mg quinaprilat are well-tolerated and produce favorable dose dependent hemodynamic effects and hormonal changes consistent with those expected of an ACE inhibitor in patients with NYHA class III and IV congestive heart failure. PMID- 8681495 TI - [Synergic effect of albendazole plus metronidazole association in the treatment of metronidazole-resistant giardiasis]. AB - Twenty patients with intestinal giardiasis, already resistant to 3-5 previous courses of oral metronidazole, were randomly distributed into 2 different groups: 10 subjects were given oral albendazole (440 mg/two times per day for 7 days) and 10 were submitted to the association of albendazole (400 mg/two times per day for 7 days) plus metronidazole (250 mg/three times per day for 7 days). All patients were evaluated both for clinical and parasitological status, immediately before and after therapy and, then, 4 weeks later. Only 3 patients of those treated with albendazole alone, showed a clinical and parasitological remission at the end of therapy, and one of them relapsed 4 weeks later. All patients who underwent albendazolemetronidazole association responded to the therapy and all except one were defined as "cured" 4 weeks later. Our study demonstrates that albendazole alone is not an effective therapeutic alternative for "metronidazole-resistant" giardiasis. The association of metronidazole plus albendazole seems synergic and deserves further studies. PMID- 8681496 TI - [Therapy of arrhythmia induced by myocardial ischemia. Association of L carnitine, propafenone and mexiletine]. AB - To assess the anti-arrythmic effect of L-carnitina, propafenone and mexiletine, we tested the drugs in 50 patients with effort angina and ventricular ectopic beats (VEB). The patients were randomized in 5 groups: Group A: was treated with oral L-carnitine at the dose of 2 g x 3 for two weeks. Group B: oral propafenone at the dose of 300 mg x 3 for two weeks. Group C: as group B+L-carnitine+g x 3 at the second weeks. Group D: oral mexiletine at the dose of 200 mg x 3 for two weeks. Group E: as group D+L-carnitine 2 gr x 3 at the second week. After 7 and 14 days of treatment, in all patients an Holter examination was performed. Our results show that L-carnitine exerts a significant reduction of the VEB and its administration potentiates the anti-arrythmic effect of propafenone and mexiletine. PMID- 8681497 TI - [Current clinical interest in monitoring digoxinemia]. AB - After a short introduction about the current role of digitalis in the treatment of the supraventrical arrhythmias and about the factors that make often problematic the achievement of an optimal posology of the drug, the results relative to more recent 340 digoxinaemia determinations in patients of Policlinico in Palermo or in outpatients are presented. Just the 43.8% of the patients had a digoxinaemia value in the range considered therapeutic; just 45 patients (32.1%), out of the 140 in which the digoxinaemia had been monitored for, at least, 5 days, were in the therapeutic range at the first determination; the 47.8% of the patients were underdosed and the 38.8% of them showed higher values than the therapeutic range. Determination 5 or more days later showed digoxinaemia values in the therapeutic range in 112 patients (80%). According to the reported results, it may be presumed that the posology correction effectuated by the physician on these patients might have been driven by the digoxinaemia values, whose determination must be considered an unavoidable guide to the digitalis treatment. PMID- 8681498 TI - [Ecology and thermal parks in the context of the environment. Psychological and possible therapeutic aspects: trends in medicine]. AB - Thermal parks are considered whether on account of their favourable effects on human well-being or as possible patterns of qualificated areas. Information on italian so called "thermal" ecology are given. In according to viewpoint of environmental psychology, the various natural side effects are remembered; the influences exerted by wood and park lands--also as meteorological factors--on human beings are stressed. The possible trends in the treatment of some psychosomatic, cardiovascular, digestive and metabolic diseases are pointed. PMID- 8681499 TI - [Tolrestat in the therapy of diabetic peripheral neuropathy: is this drug really useful?]. AB - The authors have studied the effect of the treatment with an aldose reductase inhibitor, tolrestat, on the peripheral diabetic neuropathy during a placebo controlled randomised trial. 74 diabetics affected by peripheral neuropathy were divided in two groups of 39 (group A) and 35 (group B) patients comparable as to age, sex, duration of diabetes and severity of the neurological symptoms. The group A was treated with tolrestat orally 200 my once daily for six months, the group B was treated with placebo. After six months an improvement of analysed symptoms (pain and paraesthesias) and objective assessments (NCV-DB) was observed in patients treated with tolrestat (group A) significantly higher than in patients treated with placebo (group B). A light improvement was found also during a control effected after three months of treatment with tolrestat. The improvement after six months of therapy was mild but significant; therefore the authors conclude that the tolrestat is an useful drug in the treatment of the peripheral diabetic neuropathy in addition to attainment of a better glycemia's control. PMID- 8681500 TI - [Evaluation of the efficacy and tolerance of doxazosin vs. enalapril inaged patients with light to moderate arterial hypertension]. AB - The above study was performed as a single blind trial in 70 elderly patients (average age 66 years) who were randomized into two groups of 36 and 34 subjects respectively. After clinical and laboratory evaluation without treatment for at least two weeks, the two groups were treated with enalapril 5-10 or 20 mg daily plus doxazosin at the dosage of 1-2-4- or 8 mg daily; they were observed for 24 weeks. During the trial, pressure values, both systolic and diastolic, were seen to diminish significantly in both groups. This effect was accompanied by minor, usually transient side effects. At echocardiography at the end of the treatment period, doxazosin was found to reduce some volumetric cardiac parameters, thus showing to be apt to counteract left ventricular hypertrophy. These findings go to counteract left ventricular hypertrophy. These findings go to show that alpha 1 inhibitors are a valid alternative in the "first step" of antihypertensive therapy, especially in patients at risk for cardiovascular complications. PMID- 8681501 TI - [Recurrent rheumatism and idiopathic osteoporosis in young adults. Coincidence or association?]. AB - Although in literature are not reported any cases of an association between palindromic rheumatism and idiopathic osteoporosis, the Authors describe two patients, to whom the above-mentioned diseases appeared and were diagnosed at the same time, suggesting a possible interrelationship. PMID- 8681502 TI - [Deterministic chaos in biology]. AB - Higher physiological organisms are characterised by a complex interaction of multiple control systems. This interaction permits man to adapt those unexpected demands given by experimental changes. The idea of complexity results basically from the non linearity of dynamic systems that are correlated to each other through feedback cycles. These systems fluctuate in an apparent chaos. The improvidence and the non uniformity of biological systems are basic qualities that define the state of health. It is anyhow possible to discriminate in them a certain repeatability of interaction that succeeded each other; this repeatability makes the system fit for a fractal interpretation. PMID- 8681503 TI - [Diagnostic accuracy of computerized tomography. Preoperative staging of gastric cancer]. AB - "Imaging techniques" have assumed greater clinical value in the further assessment of an endoscopically or radiologically verified neoplastic lesion of the stomach through the ability to evaluate its extent of invasion, metastatic involvement of lymphnodes and/or distant organs. US, CT, and more recently NMR are non-invasive modalities that provide an accurate preoperative assessment of potential surgery decision making. Common current practice of preoperative CT in gastric cancer and relevant results documented in letterature, have inclined many clinicians in its use in staging this disease. The aim of the study is to evaluate and assign the efficacy of CT imaging in the preoperative staging of gastric cancer by comparing the results obtained with this imaging technique with the postoperative histopatologic findings of 25 patients with adenocarcinoma of the stomach. CT demonstrates the primitive lesion as a gastric wall differentiate T1 (parietal invasion extending to the lamina propria and submucosa) and T2 (invasion of the muscolaris propria and the submucosa). The performance values of CT in detecting tumor extension to the sierosa were as follows: sensitivity of 78%, specificity of 63%; and overall accuracy of 72%. The sensitivity and specificity of CT in demonstrating adjacent organ involvement were approximately 75% and 85% respectively, and overall accuracy of 84%. In the detection of metastatic involvement of lymphnodes CT demonstrated to be 70% sensitive, 62% specific with an efficacy of 68%. In terms of M-stage, CT imaging identified liver metastases in 3 patients (2 located in the VII segment and 1 in the IV) and 1 metastasis to the adrenal gland. All were confirmed by specimen histopathologic findings. PMID- 8681504 TI - [Magnetic resonance in AIDS-related encephalopathy]. AB - Fifty-eight patients with AIDS disease were studied with MR imaging in the aim of detecting the grade of brain involvement. The examinations were performed with a 1.5 Tesla magnet. Thirty-seven showed white matter lesion (63.5%), twenty-five patients showed cerebral atrophy (43%), in eight patients the MR appearance was consistent with toxoplasmosis infection (13.5%), two patients showed a linfoma (3.4%) and two patients micrococcosis (3.4%). Seventeen out of the thirty-seven patients with white matter disease showed focal well circumscribed lesion (46%), while twenty showed diffuse involvement. Between the twenty-five patients with cerebral atrophy, twelve showed a prevalence of the cortical involvement and eight a subcortical atrophy. In five patients a concomitant, cortical and subcortical atrophy was found. Between the eight patients with neurotoxolesion and two of them a widespread encephalitis picture. The MR appearance of the two limphomas was that of periventricular, space occupying, masses. In two patients with micrococcis a nodular aspect of leptomeningeal lesions was found. PMID- 8681505 TI - [Reduction of the Nordin index after therapy with oral alendronate in patients with postmenopausal osteoporosis]. AB - The authors observe a significant reduction in value of the Nordin's Index (a sensible test for the screening of the "fast-losers" patients) in 10 women with post-menopausal osteoporosis after therapy with alendronate 5 mg daily per os for six months. The authors propound the measurement of the Nordin's Index in order to assess the alendronate's therapy per os in the post-menopausal osteoporosis. PMID- 8681506 TI - [After the benzodiazepines]. AB - After the diazepines, new agents have appeared: sleep-inducing cyclopyrrolones, pure anxiolytic serotoninergic agents such as buspirone or 5HT2 antagonists such as ritanserine, there is also renewed interest for beta-blockers and alpha 2 adrenergic agonists, calcium blocking agents and some NMDA blockers. PMID- 8681507 TI - [Hypothyroidism associated with retrobulbar optic neuritis. A clinical case]. AB - The authors have described a hypothyroidism clinic event with both non-specific symptoms and retrobulbar neuritis. They conclude that the above-mentioned pathology is somewhat insidious since, affecting the whole body, it can arise with non-specific symptoms thus averting towards a wrong diagnosis. PMID- 8681508 TI - The effect of first written language on the acquisition of English literacy. AB - The relationship between first and second language literacy was examined by identifying the skills and processes developed in the first language that were transferred to the second language. The performance of 40 university students from The People's Republic of China, Hong Kong, Vietnam and Australia were compared on a series of tasks that assessed phonological awareness and reading and spelling skills in English. The results indicated that the Hong Kong students (with non-alphabetic first language literacy) had limited phonological awareness compared to those students with alphabetic first language literacy. The reading and spelling tasks showed no differences between the groups on real word processing. However, the students from Hong Kong had difficulty processing nonwords because of their poor phonological awareness. The results supported the hypothesis that people learning English as a second language (ESL) transfer their literacy processing skills from their first language to English. When the phonological awareness required in English had not been developed in the first language, ESL students were limited to a whole-word, visual strategy. The findings indicate that students from non-alphabetic written language backgrounds might have difficulties with new, or unfamiliar words when attending universities where English is the medium of instruction. PMID- 8681509 TI - Encoding operation and transcoding as the major loci of the frequency effect. AB - The present study used a lexical naming task as well as a regular naming task and a lexical decision task for locating the frequency effects in lexical decision and naming. The naming of Chinese characters in the lexical naming task (pseudocharacters also presented as in the lexical decision task) involves decision processes, while they are absent in the regular naming task. Since naming a Chinese character necessarily involves lexical access, a decision component of the frequency effect in lexical decision can be isolated. This procedure will not work for alphabetic orthographies, because sublexical processes underestimate the frequency effect in the regular naming task. As a consequence, not only can a prelexical component of the frequency effect in lexical decision be estimated, but a postlexical component of the frequency effect in naming can be estimated. PMID- 8681510 TI - Phonological mediation and the graphemic buffer disorder in spelling: cross language differences? AB - Caramazza and Miceli's (1990) theory of the organization of the graphemic buffer in writing is assessed by comparing the performance of an English language graphemic buffer patient, AS, with their Italian language patient, LB. In many qualitative and quantitative aspects the writing of the two patients is remarkably similar. However, there is no trace in the writing of AS of the relative preservation in writing words with simple-CV structures over ones with complex-CV structures found in LB, which was the basis for Caramazza and Miceli's hypothesis of an orthographic syllable tier in the organization of the graphemic buffer. Possible differences in the relative salience of syllables between Italian and English and of differences in regularity of the sound-to-spelling transformations in the two languages are considered. It is argued, however, that the fundamental difference may arise through a greater reliance on phonological mediation by LB, with the relatively preserved syllabic level organization in his writing being phonologically rather than orthographically based. PMID- 8681511 TI - A hypothesis-assessment model of categorical argument strength. AB - According to the proposed hypothesis-assessment model, the strength of inductive categorical arguments, such as {All Robins Have Substance X therefore All Birds Have Substance X}, is determined by the same factors that affect hypothesis plausibility in the everyday social milieu. The premises of such arguments are viewed as evidence and the conclusion is viewed as a hypothesis. Specifically, the proposed model predicts that the perceived strength of general-conclusion categorical arguments will be a function of (a) the number of premises that instantiate the conclusion; (b) the scope of the conclusion; and (c) the number of accessed alternatives to the conclusion. In Experiment 1, one group rated the strength of individual arguments and another constructed superordinate hypotheses in response to the premise information alone. Most of the variance in perceived argument strength was accounted for by the proposed predictors, R = .94. Experiment 2 employed a new set of arguments and included an additional forced choice condition in which subjects had to choose the stronger of two arguments. Again, the correlation between predictors and argument strength was high, R = .91, and, all significant forced-choice preferences except one were correctly predicted by the model. The one unpredicted preference suggests the need to include conclusion accessibility as a fourth factor. Also, on a subset of the forced-choice pairs in which no significant preference was observed, two distinct patterns of responding were detected-one predicted and the other unanticipated. Some strengths and limitations of the proposed hypothesis-assessment model are discussed in light of these results. PMID- 8681512 TI - The language user as an arithmetician. AB - Dutch, like other languages, has approximative expressions with two numerals, for example: "twee, drie boeken" (lit. two, three books; two or three books). This construction is analysed. It turns out that the choice of number words is not arbitrary. Various kinds of factor are involved, as is shown using language materials from large corpora of Dutch texts. The interval between the two numbers has to be 1, 2, 2 1/2 or 5, multiplied by 10n, at least in the decimal number system. It is argued that in daily life this set of so-called "favourite numbers" has a special role. Coins and banknotes, prices of special offers, bidding conventions in auctions are based on, or make use of, this set of numbers. An explanation for this favouritism is offered in the framework of the triple-code model of human number processing proposed by Dehaene. The explanation substantiates Dehaene's claim of the existence of an analogue magnitude code used in estimating and comparing. Human cognition seems to be able to perform simple calculations with quantities (e.g., halving and doubling), independently of any counting or number system. PMID- 8681513 TI - A method for adjusting caries increments for reversals due to examiner misclassification. AB - Two types of reversals occur in longitudinal caries studies, remineralization (true reversals) and reversals due to examiner misclassification (D3 to S; F to S). Since 1966, the standard practice has been to subtract examiner reversals from the crude increment (CCI), resulting in a net caries increment (NCI). The use of the NCI has been based on the assumption that examiners make an equal number of false positive and false negative errors both at baseline and follow-up examination. Consequently, the difference between the two caries prevalence scores would provide an unbiased estimate of caries incidence between examinations. The NCI considers all reversals to be true reversals which is an extreme strategy, particulary when the level of diagnosis is set at lower thresholds. In this study we compromised between the NCI and CCI by creating a simple formula to calculate the caries increment using a prevalence-based adjustment for reversals. The formula is ADJCI = y2(1-(y3/(y3 + y4))), where y2 = S to D or F; y3 = D or F to S; y4 = D to D/F or F to F. The impact of this adjustment is illustrated using data from a random sample of 452 older black and white adults followed over a 3-yr period. The ADJCI was more likely to result in higher caries increments and more observed intergroup differences than the NCI, a finding that has implications for clinical trials. For example, the crude 3-yr coronal DS increment for whites was 0.62, the NCI was 0.26 and the ADJCI was 0.56. There were significant black-white differences for the CCI and ADJCI, but not the NCI. We conclude that the NCI was too severe of an adjustment for reversals for this study population. PMID- 8681514 TI - Relative contribution of dental services to the changes in caries levels of 12 year-old children in 18 industrialized countries in the 1970s and early 1980s. AB - The contribution of health services to improvements in health is contentious. The main aim of the present study was to assess the relative contribution that dental services may have made to the changes in dental caries (decayed, missing or filled permanent teeth) level of 12-year-old children in some industrialized countries in the 1970s and early 1980s. A secondary aim was an analysis of the association of the changes in caries levels with broad socioeconomic factors. In this study aggregate (ecological) data from 18 industrialized countries were analyzed at a national level. Data were obtained from published papers and official publications and included 3 kinds of variables: caries, presence of dental service and broad socioeconomic factors (including fluoridated toothpastes). Dental services explained 3% of the variation in changes in 12-year old caries levels in the 1970s and early 1980s period whereas broad socioeconomic factors (including or excluding fluoridated toothpastes) explained 65%. The findings suggest that dental services were relatively unimportant in explaining the differences in changes in 12 year-old caries levels in the 1970s and early 1980s in the 18 countries. The view that fluoride in toothpaste was the only important cause of the declines in decayed, missing or filled permanent teeth in industrialized countries was questioned. A possible important contribution of the dental services to the declines was a change in the diagnostic and treatment criteria of caries. PMID- 8681515 TI - Caries prevalence and patterns in 3-6-year-old Beijing children. AB - A total of 400 Beijing children, 3-6-yr-old, equally distributed by age and sex, were examined for dental cares. Results were analyzed with the traditional dmfs/t index and with the Caries Analysis System. The system differentiated between caries patterns and examined the percentage of affected children (Prevalence), the degree to which these children were affected (Severity), and the proportion of total caries each disease pattern represented (Distribution). Over 67% of the children experienced caries, a level comparable to other reports from China and other developing countries, but 50% greater than those seen in United States preschool children. Nearly all children with caries experienced fissure caries. In 3-yr-olds maxillary anterior caries was the next most prevalent pattern with 43% affected, whilst in the 6-yr-olds, posterior proximal caries was the second most prevalent pattern with 68% affected. Since maxillary anterior caries was so prevalent, and because the presence of this pattern has been shown to be a risk factor for future caries, preventing the maxillary anterior pattern may markedly reduce caries in this population. PMID- 8681516 TI - Cross-sectional comparisons of caries time trends in nursery school children in Sendai, Japan. AB - The aim of this study was to clarify the trends in caries experience in the primary dentition of nursery school children in Sendai, Japan, over a period of 20 yr. An annual clinical dental examination of children aged 2-5 yr at 13 nursery schools in Sendai City was carried out in 1972, 1977, 1982, 1987 and 1992. Data obtained from all five surveys were compared in each age group respectively. The percentages of 2-, 3- and 4-yr-olds free from caries increased remarkably until 1977, while that in 5-yr-olds started increasing several years later. After such increments, percentages in all age groups except 3-yr-olds remained almost at the same level with slight fluctuations. The mean deft and defs values per child in 2-, 3- and 4-yr-olds decreased remarkably until 1977, but then remained almost at the same level thereafter. That in 5-yr-olds continued decreasing slightly during the 20-yr period. The marked reduction of caries experience in nursery school children shown during the 1970's did not continue through the 1980's or the beginning of the 1990's. PMID- 8681517 TI - Predictors of fixed orthodontic treatment in 15-year-old adolescents in South Australia. AB - An understanding of the determinants of the provision of fixed orthodontic treatment would be beneficial in the planning of any system aimed at rationalising supply. The aim of this longitudinal study was to determine those factors which were predictive of the provision of fixed orthodontic treatment in adolescents. Baseline data, at age 13 years, on oral health, the history of orthodontic consultation and interceptive orthodontic care, a dental appearance score (DAI), socio-demographic characteristics and self and parental perceptions of both dental appearance and need for fixed orthodontic treatment were obtained from 2793 adolescents under the care of the South Australian School Dental Service who had not undergone fixed orthodontic treatment. Data on the orthodontic care provided to these adolescents in the ensuing 2 years were collected. At the end of the 24-month period 433 adolescents (15.5%) had undergone fixed orthodontic treatment. Significant bivariate associations were found between the provision of fixed orthodontic treatment and the DAI score, sex of the adolescent, familial history of fixed orthodontic treatment, income, private insurance, orthodontic consultation and interceptive orthodontic care before the age of 13 years and self and parental perceptions of both dental appearance and the need for fixed orthodontic treatment. Logistic regression was used to produce a predictive model of fixed orthodontic treatment. The model explained 30.2% of the variance, with a specificity of 0.94, a sensitivity of 0.49 and a hit rate of 0.84%. Odds ratios greater than one were found for the DAI score, private insurance, females, self and parental perception of need, higher incomes and orthodontic consultation and interceptive orthodontic care before the age of 13 years. PMID- 8681518 TI - Dentist's ratings of child dental-patients' anxiety. AB - This study investigates the extent to which dentists giving treatment are able to evaluate the (changes in) child patients' levels of fear, based on a comparison between direct behavior observations of a group of highly anxious children during sequential dental visits and video observations of the same group made by two independent evaluators using the measuring instrument described by Venham et al. (9). A significant difference was found between the fear scores given by the two dentists giving treatment and also between their fear scores and those by the independent observers. Both the fear and behavior scores of the two dentists giving treatment, however, clearly correlated with the fear scores of the observers. It is concluded that in this study the two dentists giving treatment were unable to award an unbiased fear score for each treatment given to a child but it was not possible to show that the bias was caused by experiences from previous sessions with the same child. After video training dentists giving treatment are capable of giving a picture of changes in children's fear levels during sequential dental visits. PMID- 8681520 TI - Comparison of oral health data from self-administered questionnaire and clinical examination. AB - In order to assess the validity of self-reported oral health data 319 subjects randomly selected from the respondents to an oral health survey were examined clinically. The level of agreement between the two methods of examination was estimated by the kappa statistic. Substantial agreement (kappa = 0.65) was found between the reported and observed number of remaining teeth and the difference between underreporting and overreporting was small. The results indicate that valid data for planning purposes and for monitoring changes in such oral health indicators as the proportion of individuals having 28 or more teeth, the proportion of subjects having a minimum of 20 functional teeth, the level of edentulousness and the presence of complete and partial dentures, can be obtained from postal questionnaires. PMID- 8681519 TI - Dental health and treatment needs in institutionalized psychiatric patients in Italy. AB - The caries prevalence, oral hygiene status, periodontal health and the treatment needs were assessed in a group of institutionalized psychiatric patients in Catanzaro, Italy. Of the total sample of 297 subjects, 165 (55.6%) were males, the mean age was 55.1 yr, the great majority (90.6%) was able to care for themselves, on average they had been institutionalized for 12.9 yr, and almost two-thirds were schizophrenic (65%). They did not receive any assistance in daily oral hygiene procedures, only 7.4% had visited a dentist and exclusively for emergency care. A total of 33 (11.1%) patients were edentulous, and the multiple logistic regression analysis showed a highly significant increase of edentulousness with increasing age (P < 0.001). No caries-free subjects were found and among the dentate the DMFT and DMFS scores for all age groups were respectively 15.5 and 88.6. The stepwise linear regression analysis showed that the mean DMFT index increased with age (t = 6.86; P < 0.001), and in the partly or totally helpless patients it was significantly higher than in the self sufficient patients (t = 2.78; P = 0.006). Of the 264 dentate subjects, only 25 (9.5%) had no need of dental treatment; 213 (80.7%) required extractions with a mean number per person of 6.3 and the need for conservative dental care was recorded in 154 (58.3%) patients with a mean need for patient of 2.8. Mean OHI-S score was 4.2 and the stepwise linear regression analysis showed that it increased with age (t = 5.73; P < 0.001) and with the length of institutionalization (t = 3.42; P < 0.001). Only 0.9% of the entire sample was found with healthy periodontal tissue; bleeding on probing or a higher score was found in 4.6% of examined sextants; calculus in 10.1%; shallow pockets and deep pockets in 19.6% and 64.8% of all sextants. The results of the multiple logistic regression analysis indicated that the number of subjects with deep pockets as highest score increased with increasing age (P<0.001), and with the increasing length of institutionalization (P=0.005). The findings of this study demonstrate high caries prevalence, poor oral hygiene and periodontal health, and extensive unmet needs for dental treatment. More coordinated efforts between the social and dental care sector must be maintained to serve adequately the need of this disadvantaged group. PMID- 8681521 TI - Perception of dental and other individual problems: adolescents versus young adults. AB - The importance of dental problems in comparison with general health problems and psychological problems was judged by 642 adolescents. The methods used were paired comparison and direct ranking of nine stimuli. Adolescents were quite consistent in their choices. The agreement within the group was statistically significant. Adolescents judged dental problems as less important than general health problems and as more important than psychological problems. The correlation between the methods of paired comparison and direct ranking was high. The results were compared retrospectively with findings from a study of 51 older subjects. Adolescents and adults did not differ much from each other except for the ordering of the nine problems. Adults ranked dental problems as the least important. PMID- 8681522 TI - Comparison of ideal and actual behavior of patients and dentists during dental treatment. AB - The ideal behavior of dentists and patients has seldom been studied with the aim of determining whether it is similar to the actual behavior of the two groups. Thus, the purpose of this study was to compare whether the ideal behavior of dentists and patients differed from their actual behavior. Thirty-three volunteering dentists and 271 of their patients from the public and private sectors in different parts of Finland participated in the study. The dentists first filled out a questionnaire with 5-scale Likert-type statements about the ideal patient and questions concerning their own background variables. In connection with normal dental practice their dental nurses selected 10 patients, who before treatment filled out a questionnaire containing statements about the desired behavior of an ideal dentist and their own background variables. Immediately after the treatment, both dentists and patients filled out another questionnaire containing similar statements, which this time indicated whether the dentist/patient actually behaved according to the ideal. Differences between each individual and the independent ideal and actual scores were compared by cross-tabulation and percentage agreement. With regard to the ideal behavior that was directly related to the treatment procedure, the expectations of both dentists and patients were usually met. In general, the patients did not disrupt the procedures and the dentists were able to concentrate on the treatment. The discrepancies most often found between the ideal and the actual behavior concerned the level of communication. The patients often would like to have been talked to more and wanted to be encouraged. The dentists were not sure whether their patients were interested in or motivated about the treatment or whether they followed the home care instructions. In general, there evidently is a clear gap in communication between dentists and patients, which may lead to frustration on both sides. It is thus suggested that when dentists are trained, more emphasis be placed on communication skills. PMID- 8681523 TI - Electronic-mail: a new tool for data collection in dental public health. PMID- 8681524 TI - Dental caries among children in New Zealand. PMID- 8681525 TI - Early auditory experience and the ontogeny of alarm-call discrimination in Belding's ground squirrels (Spermophilus beldingi). AB - Because young ground squirrels are vulnerable to predation, selection would favor the early ability to respond to alarm calls. This requires discrimination of classes of alarm calls from each other as well as from non-alarm calls. Pre emergent auditory experience may influence the development of discrimination. As a means of determining when Belding's ground squirrels (Spermophilus beldingi) can discriminate among calls, cardiac responses to alarm calls and control stimuli were recorded from 2 rearing groups that differed in the frequency of alarm-call exposure. Results suggest that before natal emergence, young can discriminate between 2 classes of alarm calls but they may not discriminate these calls from control stimuli. No differences in responses were found between the rearing groups; thus experience with calls may not influence the onset of discrimination. Early discrimination may facilitate the rapid development of post emergent behavioral alarm-call responses. PMID- 8681526 TI - A study of long-term odor memory in squirrel monkeys (Saimiri sciureus). AB - Five squirrel monkeys (Saimiri sciureus) were trained to discriminate between pairs of odors, and their ability to recognize these as positive or negative was tested at intervals of up to 7 months. Retention was excellent up to 15 weeks and remained significantly above chance even after 30 weeks. Good performance at the shorter intervals was not due to rapid relearning, although at the longer intervals considerable savings were demonstrated by the animals' ability to reach criterion more rapidly than with novel odors. Thus, squirrel monkeys possess a robust memory for odors and show flat forgetting curves consistent with reports for human subjects. PMID- 8681527 TI - Odor preferences of female house mice (Mus domesticus) in seminatural enclosures. AB - Preferences for male odors by female house mice (Mus domesticus) were examined with respect to age, dominance status, and spatial relationships. Mice were free living in 6 field enclosures. Estrous or nonestrous females were placed in an aquarium with soiled bedding from live traps as the odor source. Females were tested for preferences between (a) adult and juvenile male odors, (b) dominant and subordinate male odors, and (c) "near" and "far" male odors. In dominance odor tests, estrous females preferred odors from dominant males; nonestrous females exhibited no significant preferences. In adult-juvenile and spatial odor tests, there were no significant differences between odor preferences of estrous and nonestrous females. However, most females preferred odors from adult and "near" males. Male dominance status appears to be the strongest influence on female odor preference in these seminatural enclosures. PMID- 8681528 TI - Macaque social culture: development and perpetuation of affiliative networks. AB - Maternal affiliative relations may be transmitted to offspring, similar to the way in which maternal rank determines offspring rank. The development of 23 captive female rhesus monkeys (Macaca mulatta) was followed from the day of birth until adulthood. A multivariate analysis compared relations among age peers with affiliative relations, kinship, and rank distance among mothers. Maternal relations were an excellent predictor of affiliative relations among daughters, explaining up to 64% of the variance. Much of this predictability was due to the effect of kinship. However, after this variable had been controlled, significant predictability persisted. For relations of female subjects with male peers, on the other hand, maternal relations had no significant predictive value beyond the effect of kinship. One possible explanation of these results is that young rhesus females copy maternal social preferences through a process of cultural learning. PMID- 8681529 TI - Laboratory studies of antipredator behavior in the Mongolian gerbil (Meriones unguiculatus): factors affecting response attenuation with repeated presentations. AB - A series of experiments was conducted to study the properties of the attenuation of responding to repeated presentation of overhead visual transients in the gerbil (Meriones unguiculatus). Results suggest that this attenuation consists of habituation to the repeated association of a potentially threatening sensory stimulus with an increasingly familiar spatial context. The results of these experiments further suggest that the likelihood of eliciting fleeing is a conjoint function of the degree of risk posed by an overhead sensory transient and the degree of safety that is to be gained by fleeing. Results are discussed in the context of the ecology of predator recognition and the structural organization of the rodent visual system. PMID- 8681530 TI - Learning and male-male sexual competition in Japanese quail (Coturnix japonica). AB - Male Japanese quail (Coturnix japonica) were trained individually to discriminate between 2 sounds presented at opposite ends of an outdoor aviary. One of the sounds (the positive conditioned stimulus [CS+]) was associated with the release of a female, and the other (the negative CS [CS-]) was presented alone. Which of the 2 sounds served as the CS+ (and which served as the CS-) was counterbalanced across subjects. The subjects came to approach their CS+ but did not move away from their CS-. After having been conditioned individually, the subjects were tested in pairs, with a single female released after the presentation of a stimulus that was the CS+ for one of the males and the CS- for the other male. During most of these tests, the male for whom the prefemale stimulus was the CS+ copulated with the female before the male for whom the prefemale stimulus was the CS-. These results indicate that learning can have an important role in competition for access to a reproductive partner. PMID- 8681531 TI - Effects of paced mating and intromissive stimulation on feminine sexual behavior and estrus termination in the cycling rat. AB - The effects of differential mating stimulation on sexual behavior and estrus length were examined in cycling rats that could or could not self-regulate, or pace, the timing of sexual contact. Female rats (Rattus norvegicus) received 30 paced, 30 nonpaced, or 15 nonpaced followed by 15 paced intromissions during mating tests. Decreases in sexual responsiveness were seen during the second half of testing; pacing was associated with greater inter-intromission intervals, decreased proceptivity, and increased rejection behavior at this time. Female rats pacing during the second test half behaved similarly, regardless of prior treatment, showing that the number rather than the timing of prior intromissions affected subsequent behavior. However, estrus length was decreased by prior paced mating. These data suggest that changes in sexual responsivity occur throughout estrus and that the nature of these changes is differentially dependent on the type of mating stimulation received. PMID- 8681532 TI - The von Restorff effect in rats (Rattus norvegicus). AB - Two experiments examined the functional equivalence of memory in the rat (Rattus norvegicus) with memory in humans for serially presented items. Memory was assayed with an 8-arm radial maze, in which rats were allowed access to 5 arms of the maze and were then removed. Following a retention interval of 16 min, the rats were replaced in the maze and allowed to retrieve pellets from the 3 unvisited arms. The errors in reentering previously visited arms were noted. Both primacy and recency effects were found as with humans. Presenting a stimulus change after entry to 1 of the maze arms improved recall for that arm relative to when no change occurred. This effect was found using both handling and tone cues, and irrespective of whether the change consisted of presentation or nonpresentation of the cue. These results suggest that rats are subject to a von Restorff-like effect similar to that in humans. PMID- 8681533 TI - Lateral bias for rotational behavior in tufted capuchin monkeys (Cebus apella). AB - This research examined lateral bias for rotational behavior in tufted capuchin monkeys (Cebus apella). A symmetrical distribution of rotational bias was noted, with approximately equal numbers of subjects preferring to turn to the right and to the left. As a group, adults did not exhibit a lateral rotational bias. Immatures preferentially rotated to the left. Across subjects, the strength of rotational bias was positively related to the incidence of right-eyed looking. Rotational bias was not related to hand preference. The finding of analogous age dependent patterns of rotational bias in capuchins and in humans suggests that the rotational behavior of Cebus apella can be used to model an asymmetric response pattern that has been linked to development in Homo sapiens. PMID- 8681534 TI - Social learning in the golden hamster (Mesocricetus auratus). AB - This study investigates whether golden hamster (Mesocricetus auratus) pups can acquire a new behavior by interacting with an experienced adult conspecific. The behavior consisted of using teeth and forepaws to retrieve a piece of food dangling from a small chain. Instrumental learning techniques were used to train the demonstrators. Four groups of pups were exposed to different kinds of social experience. In the first group, the pups interacted with their skilled mother; in the second group, they did the same with their inexperienced mother; in the third group, they interacted with inexperienced littermates; and in the fourth group, the pups were tested individually. At the end of an acquisition period, the pups were tested individually to assess their performance. The results demonstrate that interacting with a skilled mother has a remarkable effect on the acquisition of a new feeding behavior by hamster pups. PMID- 8681535 TI - Long-lasting allergic patch test reactions to nickel sulfate: analysis by nickel quantification and immunocytochemistry. AB - We previously showed the median duration of positive patch test reactions to nickel sulfate (5% pet.) was 9 days, and defined as long-lasting (LLAPTR) the 14.3% of reactions that persisted for 17 days or longer. The pathomechanisms of LLAPTR are unclear, but may involve either localized antigen persistence or abnormal downregulation of the cellular immune response. In this study, we compared (a) the nickel concentration and (b) the immunocytochemical nature of the local immune reaction, between biopsies from LLAPTR (n = 8) and normally resolving allergic patch test reactions (NRAPTR) (n = 8) to nickel sulfate. The concentration of nickel in LLAPTR (median 0.56 microgram/g, range 0.25-3.87 micrograms/g, mean 0.83 microgram/g, 95% CI 0.35-1.31) and NRAPTR (median 0.58 microgram/g, range 0.2-1.85 micrograms/g, mean 0.88 microgram/g, 95% CI 0.02 1.74) was similar. Activated T lymphocytes, expressing surface IL-2 receptor, HLA DR, DR alpha 1, DP, DQ, and CD2 > CD8 > CD4 antigens, were seen throughout the dermis and occasionally infiltrating the suprabasal layer of the epidermis in all biopsies. CD1 and HLA DR, DR alpha 1, DP, and DQ-expressing Langerhans cells were present throughout the epidermis and occasionally seen in the papillary dermis. HLA DR, DR alpha 1, DP, and DQ antigen expression were also seen on the surface of non-dendritic cells in the epidermis (probably either keratinocytes or T lymphocytes) and vascular endothelial cells in the papillary dermis. There were no significant qualitative or quantitative differences in the immunocytochemical nature of the localized immune reaction between LLAPTR and NRAPTR. These findings suggest that the pathomechanism of LLAPTR to nickel sulfate is unlikely to be explained simply on the basis of nickel concentration or the nature of the localized immune reaction at the patch test site. PMID- 8681536 TI - Exposure to selected fragrance materials. A case study of fragrance-mix-positive eczema patients. AB - The aim of the present study was to assess exposure to constituents of the fragrance mix from cosmetic products used by fragrance-mix-positive eczema patients. 23 products, which had either given a positive patch and/or use test in a total of 11 fragrance-mix-positive patients, were analyzed. In all cases, the use of these cosmetics completely or partly explained present or past episodes of eczema. Between 1 to 6 constituents of the fragrance mix were found in 22 out of 23 products. The cosmetics of all the patients sensitive to hydroxycitronellal, eugenol, cinnamic alcohol and alpha-amylcinnamic aldehyde were found to contain the respective substances. Exposure concentrations were seen to cover a large range. The content of hydroxycitronellal was, on average, 5 x higher in cosmetics from hydroxycitronellal-sensitive patients, compared to cosmetics from hydroxycitronellal-negative patients. It is concluded that exposure to constituents of the fragrance mix is common in fragrance-allergic patients with cosmetic eczema, and that the fragrance mix is a good reflection of actual exposure. PMID- 8681537 TI - Nonspecific hypersensitivity: false-positive responses with the use of Freund's complete adjuvant. AB - While conducting a guinea pig sensitization protocol, using the maximization test, it was discovered, at challenge, that the test animals were more responsive to the vehicle (acetone) than they were to the proprietary test material. During rechallenge, conducted to clarify the specific immune status of the test animals, it was determined that they were also hyperreactive to an alternate vehicle (diethyl phthalate), to which they were naive. This bizarre set of data is presented and it is suggested that this type of response is the prototype for the presence of false-positive responses experienced by toxicologists using this test. The test conditions imposed on the immune system by the maximization test that could result in these anomalous results are discussed. These data suggest that investigators need cautiously to interpret data that are produced by the injection of Freund's complete adjuvant (FCA). PMID- 8681538 TI - Variation in response of human skin to irritant challenge. AB - A major obstacle to the establishment of a protocol for in vivo irritant skin testing in humans is the apparent variability of responses between individuals. This study of the threshold response of normal human skin to a standard irritant (sodium lauryl sulfate 0.3-10%), in a group of 22 subjects, revealed a marked interindividual variation in their threshold reaction. The results demonstrate that this phenomenon does exist and that it will have to be allowed for in future human irritant test systems or assays. PMID- 8681539 TI - Methyldibromoglutaronitrile is an important contact allergen in The Netherlands. AB - From 15 May to 15 December 1994, 2943 patients suspected of having contact dermatitis (1955 women, 988 men) were patch tested with methyldibromoglutaronitrile 0.3%, 0.1% and 0.05% pet. 119 patients (4.0%; women 4.1%, men 3.8%) proved to be allergic. 71% of the reactions were considered to be relevant. In 2/3 of the patients, causative products were cosmetics, in 1/3 moistened toilet tissues. Testing with methyldibromoglutaronitrile at lower concentrations (0.05% and 0.1%) and with commercial allergens (Euxyl K 400 and methyldibromoglutaronitrile, both containing methyldibromoglutaronitrile 0.1%), resulted in a number of false-negative reactions. All preservatives in the European standard series had lower scores than the 4% positive reactions to methyldibromoglutaronitrile (formaldehyde 2.0%, MCI/MI (Kathon CG) 3.2%, parabens 1.0%, quaternium-15 1.3%). It is concluded that methyldibromoglutaronitrile (present in the commercial preservative Euxyl K 400) is an important contact allergen in the Netherlands in cosmetics and moistened toilet tissues. It should be added to cosmetics series and to proctological series. The optimal test concentration is unknow, but may be 0.3% pet. The concentration of 0.1% methyldibromoglutaronitrile in the currently available commercial allergens appears to be too low, resulting in a number of false-negative reactions. PMID- 8681540 TI - Allergic and irritant patch test reactions and atopic disease. AB - This study presents a profile of patients with chronic recalcitrant eczematous disease referred by dermatologists for contact allergy evaluation. Allergic contact dermatitis (ACD) and irritant responses were carefully defined, as was the presence or absence of atopy obtained by history. Of 410 patients studied, 44% had no history of atopic disease and 46% were classed as definitely atopic. Among relevant ACD patch test reactors (n = 198), 51.5% had atopy, compared with 40.9% with no atopy but this difference was not significant. Likewise, among atopics (n = 189), 54% had definite, relevant ACD patch test responses while 33.9% had negative ACD (again not significant). Significance was seen in the higher mean number of positive allergic patch tests in the atopic group (2.7 versus 2.0, p = 0.0223). Irritant patch tests were highest among patients with both ACD and atopy (p = 0.0308) and the proportion of irritant responses correlated with increasing numbers of positive ACD tests. We conclude that atopics are at least as likely to have ACD as are non-atopics. Irritancy is increased in these patients with chronic dermatitis and the frequency of irritant reactions correlates with both greater numbers of ACD responses and with presence of atopy. PMID- 8681541 TI - Occupational skin diseases in dental laboratory technicians. (I). Clinical picture and causative factors. AB - In Germany, occupational skin disease (OSD) in dental technicians (DT) has been steadily rising in recent years and causing considerable costs for medical care and rehabilitation. Our objective in this study was to: (i) examine affected workers; (ii) perform patch tests to identify causative agents; (iii) develop strategies of prevention. 7 dental laboratories were inspected as to materials used, working habits, safety regulations, etc. A computer data base was developed for products (trade name, active ingredient, additives, etc.). A questionnaire regarding development of OSD was sent out to 1132 dental technicians (45 questions). 55 DT with suspected OSD were examined and patch tested with the standard series, an extensive series of methacrylates, and own materials. Working conditions, and knowledge of potential hazards, varied greatly in the laboratories visited. The safety data sheets of working materials were of little use and required supplementation by the computer data base, which provided rapid access to allergological information (e.g., type of acrylate, concentration). In the questionnaire (173 answers), 36% reported skin lesions attributed to work and 1/3 suspected plastic materials as their primary cause. Among the 55 DT examined, allergic contact dermatitis was diagnosed in 63.6% and irritant contact dermatitis in 23.6%. Most of the allergens identified (74%) were found in plastic materials (methyl methacrylate (MMA), 9 patients (16%); 2-hydroxyethyl methacrylate (2-HEMA), 18 patients (33%); ethyleneglycol dimethacrylate (EGDMA), 15 patients (27%)). In 16 patients, multiple sensitizations to various methacrylates were found. The fingertips were primarily involved in allergic contact dermatitis (93%), whereas in irritant contact dermatitis, the dorsa of the fingers (especially of the dominant hand) were affected (80%). 9 patients also showed lesions on the face, neck and forearms. The main irritant factors included wet work, contact with plaster, mechanical friction and thermal changes. Based on experience with DT, various preventive measures have been tried and found to be effective (reduction of skin contact, 4H Gloves, etc.). In conclusion, better knowledge of OSD in dental laboratories (in physicians, DT and their employers) would lead to a reduced rate of new cases. PMID- 8681542 TI - Irritant effects of a detergent in wash, chamber and repeated open application tests. AB - Development of irritant contact reactions in a wash test, in a repeated open application test (ROAT) and in chamber tests were compared with each other in 14 atopic and 14 non-atopic Caucasian medical students. In the wash test, the students washed their upper arm skin with 10% dishwashing liquid for 1 min 2 x a day for 1 week. In the ROAT, they applied the same detergent solution to 1 antecubital fossa 2 x daily for 1 week. Chamber tests were performed with the same detergent using 8 mm, 12 mm and 18 mm Finn Chambers applied to the upper back skin for 48 h. Additional 4 h and 24 h occlusion times were used with the 12 mm Finn Chambers. Test results were evaluated on days 0, 2, 4 and 7 by eye and by using an Evaporimeter EP1 for transepidermal water loss and a Minolta Chroma Meter CR-200 for skin colour. No statistically significant differences between atopics and non-atopics were found in any of the tests. The results of the tests did not correlate with each other, with the exception of the 12 mm/48 h chamber test and the wash test in atopics (R = 0.61, p = 0.02). It seems that other individual factors in addition to atopy influence the development of irritant contact dermatitis. The results of the chamber test and ROAT predicted poorly the result of the wash test. PMID- 8681543 TI - Water tester's dermatitis due to a para-phenylenediamine derivative. PMID- 8681544 TI - Delayed cell-mediated hypersensitivity to tetrazepam. PMID- 8681545 TI - Facial dermatitis and eyelid dermatitis: a comparison of patch test results and final diagnoses. PMID- 8681546 TI - Allergic contact dermatitis from strawberry lipsalve. PMID- 8681547 TI - Occupational hypersensitivity to isothiazolinone derivatives in a radiology technician. PMID- 8681548 TI - Hand dermatitis in florists. PMID- 8681550 TI - Allergic contact dermatitis from a rubber bracelet. PMID- 8681551 TI - Allergic contact dermatitis from hydrocolloid dressings. PMID- 8681549 TI - Contact dermatitis from amorolfine-containing cream and nail lacquer. PMID- 8681552 TI - No cross-sensitization between MCI/MI, benzisothiazolinone and octylisothiazolinone. PMID- 8681553 TI - Contact sensitization to cocamidopropyl PG-dimonium chloride phosphate in a cosmetic cream. PMID- 8681554 TI - Allergic contact dermatitis of the eyelids and conjunctivitis from diclofenac. PMID- 8681555 TI - Contact allergy to methyldibromoglutaronitrile and certain other preservatives. PMID- 8681556 TI - Effect of pentoxifylline on patch test response. PMID- 8681557 TI - Erythema-multiforme-like contact dermatitis from budesonide. PMID- 8681558 TI - Fixed drug eruption induced by sulfasalazine. PMID- 8681560 TI - Allergic contact dermatitis from Dragophos S, a new emulsifier. PMID- 8681559 TI - Delayed allergic skin reactions due to subcutaneous heparin-calcium, enoxaparin sodium, pentosan polysulfate and acute skin lesions from systemic sodium-heparin. PMID- 8681561 TI - Contact dermatitis from sodium fusidate. PMID- 8681562 TI - Sensitive skin and stratum corneum reactivity to household cleaning products. AB - Products intended for individuals with sensitive skin are being increasingly developed by formulators of household cleaning products. However, there is currently no consensus about the definition and recognition of the biological basis of sensitive skin. We sought to determine the relation between the nature of environmental threat perceived as aggressive by panelists, and the stratum corneum reactivity to household cleaning products as measured by the corneosurfametry test. Results indicate substantial differences in irritancy potential between proprietary products. Corneosurfametry data show significant differences in stratum corneum reactivity between, on the one hand, individuals with either non-sensitive skin or skin sensitive to climate/fabrics, and, on the other hand, individuals with detergent-sensitive skin. It is concluded that sensitive skin is not one single condition. Sound information in rating detergent sensitive skin may be gained by corneosurfametry. PMID- 8681563 TI - Eczematous-like drug eruption induced by synergistins. AB - The authors report 4 cases of eczematous-like drug eruption after oral ingestion of synergistins, pristinamycin (3 cases) and virginiamycin (1 case). The lesions occurred after contact sensitization with topical virginiamycin. The clinical symptoms appeared a few hours after ingestion: a generalized maculopapular eruption, sometimes with general symptoms of anaphylactic reaction. Eczema appeared again on initial areas of contact dermatitis. There is a common allergenic group between these 2 antibiotics, which is a macrocyclic lactone. Physiopathology of this drug eruption is not clear: allergic reaction of the delayed type or anaphylactic reaction. Patients allergic to virginiamycin should be strongly cautioned against oral pristinamycin. PMID- 8681564 TI - Pre-treatment of nickel test areas with sodium lauryl sulfate detects nickel sensitivity in subjects reacting negatively to routinely performed patch tests. AB - A fair % of patients with a clinical history of nickel allergy show negative patch test results. To improve the response rate to NiSO4 5% pet. patch tests, a testing procedure utilizing pre-treatment of the test area by a 24-h application of sodium lauryl sulfate (SLS) was introduced. 46 women with a clinical history of nickel sensitivity, who exhibited negative reactions to nickel sulfate 5% pet. patch tests, were studied. Patients underwent 6 patch tests on adjacent sites on the volar surface of the forearms. 4 patch tests were performed with a 72-h application of 40 mg nickel sulfate 5% pet. While 1 of these patch tests served as control, 3 test areas underwent 24-h pre-treatment with 40 microliters SLS, 1 with 0.1% and 2 with 0.5% solution. To evaluate differences in the reactivity to SLS plus nickel sulfate related to the site on the forearm, 0.5% SLS pre treatment was performed both on a proximal and on a distal test site. At the 72-h evaluation, 19 subjects out of 46 showed positive reactions to nickel sulfate 5% pet. at skin sites pre-treated with 0.1% SLS, whereas 23 patients reacted positively at 0.5% SLS pre-treated areas. Echographic values of skin thickness and of hypo-echogenic dermal areas at positive pre-treated nickel test areas were higher than at control test areas, confirming the clinical evidence of an increased response to NiSO4 after SLS pre-treatment. The inflammatory reaction, as evaluated clinically and echographically, was much higher at distal skin areas (0.1% SLS and distal 0.5% SLS) than at proximal 0.5% SLS ones. PMID- 8681565 TI - Contact allergy to colophony and hand eczema. A follow-up study of patients with previously diagnosed contact allergy to colophony. AB - Colophony is commonly used in many products that we are exposed to both at work and during leisure. At our Department, about 5% of patch tested dermatitis patients show positive reactions to colophony. 83 patients in whom contact allergy to colophony had been diagnosed were followed up after 9-13 years. They were interviewed, examined and retested. At least 30% had current hand eczema on follow-up examination. Among those in whom the dermatitis had started on the hands, there were proportionally more individuals with current hand eczema than among those in whom the onset had been on other parts of the body. 72% of the participants were still patch-test-positive to colophony, and more than 1/2 had additional positive reactions to other allergens. Some of these additional reactions were new compared to the previous test occasion. The degree of exposure to colophony throughout the years was difficult to estimate. Contact allergy to colophony was considered occupational in individuals with, e.g., soldering jobs. PMID- 8681566 TI - Evaluation of gas exchange, pulmonary compliance, and lung injury during total and partial liquid ventilation in the acute respiratory distress syndrome. AB - OBJECTIVE: To investigate whether pulmonary compliance and gas exchange will be sustained during "total" perfluorocarbon liquid ventilation followed by "partial" perfluorocarbon liquid ventilation when compared with gas ventilation in the setting of the acute respiratory distress syndrome (ARDS). STUDY DESIGN: A prospective, controlled, laboratory study. SETTING: A university research laboratory. SUBJECTS: Ten sheep, weighing 12.7 to 25.0 kg. INTERVENTIONS: Lung injury was induced in ten young sheep, utilizing a right atrial injection of 0.07 mL/kg of oleic acid followed by saline pulmonary lavage. Bijugular venovenous extracorporeal life support access, a pulmonary artery catheter, and a carotid artery catheter were placed. When the alveolar-arterial O2 gradient was >/= 600 torr and PaO2 42%) than in those patients with normal (24% to 42%) or decreased (<24%) values. In contrast, no significant differences were found among these three groups with respect to age, initial Glasgow Coma Scale score, intracranial pressure, cerebral perfusion pressure, PaCO2, total hemoglobin content, and time from injury when the initial measurements were performed. CONCLUSIONS: Initially increased cerebral extraction of oxygen appears to indicate global cerebral viability rather than cerebral ischemia in patients with acute traumatic diffuse brain swelling. PMID- 8681598 TI - Hand-held blood gas analyzer is accurate in the critical care setting. AB - OBJECTIVE: To determine the accuracy of a new, portable battery-powered blood gas analyzer when used by nonlaboratory-trained clinicians in the critical care setting. DESIGN: Prospective analysis of blood samples from critically ill patients. SETTING: Large tertiary critical care unit. PATIENTS: Heterogeneous group of medical and surgical critically ill patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred thirty-nine split blood samples from intensive care patients were analyzed by clinicians in the critical care environment using a new, portable, battery-powered blood gas analyzer (Immediate Response Mobile Analyzer [IRMA], Diametrics Medical, St. Paul, MN). Near-patient measurements were compared with measurements obtained by laboratory technologists using an IL-1312 blood gas analyzer (Instrumentation Laboratories, Lexington, MA) in an established near-patient critical care laboratory. Precision and coefficients of variation were also determined using repeated testing of quality control samples at three levels of pH, PO2, and PCO2. There was good agreement between IRMA determinations and the laboratory. Correlation coefficients ranged from 0.96 to 0.99. Bias and precision (+/-2 SD), respectively, were 0.02 and 0.036 units for pH, -0.3 torr (1.8 kPa) (-0.04 kPa) and 7.2 torr (0.96 kPa) for PCO2 and -3.9 torr (0.52 kPa) and 13.8 torr (1.8 kPa) for PO2. Precision on repeated testing of quality control samples ranged from 0.022 to 0.04 units for a pH of 7.2 to 7.6, 1.2 to 4.6 torr (0.16 to 0.61 kPa) for a PCO2 of 20 to 60 torr (2.7 to 8 kPa), and 3.0 to 7.4 torr (0.40 to 0.99 kPa) for a PO2 of 70 to 160 torr (9.3 to 21.3 kPa). Coefficients of variation ranged from 0.15% to 0.28% for a pH of 7.2 to 7.6, 2.0% to 3.7% for a PCO2 of 20 to 60 torr (2.7 to 8.0 kPa), and 1.7% to 3.6% for a PO2 of 70 to 160 torr (9.3 to 21.3 kPa). Mean turnaround time was 16.5 +/-10.1 mins for the near-patient laboratory and 2+/-0.5 mins for IRMA. CONCLUSIONS: IRMA is accurate and reproducible when used in the clinical setting by nonlaboratory-trained individuals. Nonlaboratory-trained individuals can obtain laboratory results in the critical care setting comparable with the results obtained by trained laboratory technologists. Bedside laboratory testing decreases turnaround time compared with a near-patient laboratory. PMID- 8681599 TI - Prospective, controlled study of the outcome of human immunodeficiency virus-1 antibody-positive children admitted to an intensive care unit. AB - OBJECTIVE: Intensive care resources are both scarce and costly in South Africa. We set out to ascertain whether human immunodeficiency virus (HIV) status affects the spectrum of disease and the prognosis in children treated in pediatric intensive care units (ICUs). DESIGN: A prospective, case-controlled study. SETTING: The pediatric ICU at Kind Edward VIII Hospital, Durban, South Africa. PATIENTS: HIV-positive cases were classified as "acquired immunodeficiency syndrome," "symptomatic HIV," and "HIV-unrelated diseases." Controls were matched for age, race, gender, severity of disease, and admitting diagnosis. MEASUREMENTS AND MAIN RESULTS: THe clinician was blinded to the serostatus of patients. Informed consent and Ethics Committee approval were obtained for HIV testing and the study. Outcome measures were the duration of intermittent positive-pressure ventilation and ICU stay, maximum ventilatory requirements, infectious complications, and mortality. There were 11 cases of acquired immune deficiency (AIDS), 24 cases of symptomatic HIV, and 13 cases of HIV-unrelated diseases. Mortality rates for the three groups were as follows: 100% in patients with AIDS compared with 55% in their controls (p<.01); 38% in patients with symptomatic HIV and 46% in controls. Cytomegalovirus and Pneumocystis carinii infections were significantly increased (p<.01, p<.002, respectively) in patients with AIDS as compared with controls. Outcome measures were similar in those patients with symptomatic HIV and those patients with HIV-unrelated diseases, as compared with their respective controls. CONCLUSIONS: Outcome in children with AIDS admitted to the pediatric ICU was significantly worse than the outcome in HIV-uninfected children. However, the number of AIDS patients studied was small. HIV antibody positive children without AIDS do as well as uninfected controls. Ethics committees in resource-constrained countries may be assisted by such data when making difficult decisions on the admissions of HIV-infected patients to pediatric ICU facilities. PMID- 8681600 TI - Private attending physician status and the withdrawal of life-sustaining interventions in a medical intensive care unit population. AB - OBJECTIVE: To assess the influence of private attending physician status on the withdrawal of life-sustaining interventions among patients dying within a medical intensive care unit (ICU). DESIGN: Retrospective cohort analysis. SETTING: An academic tertiary care center. PATIENTS: One hundred fifty-nine consecutive patient deaths occurring in the medical ICU during a 12-month period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Withdrawal of life-sustaining interventions (i.e., mechanical ventilation, dialysis, and/or vasopressors), duration of mechanical ventilation, length of intensive care unit stay, medical care costs, and patient charges were recorded. Life sustaining interventions were actively withdrawn from 69 (43.4%) patients prior to death. Patients without a private attending physician were significantly more likely to undergo the withdrawal of life-sustaining interventions compared with patients having a private attending physician (odds ratio = 2.5; 95% confidence interval = 1.8, 3.6, respectively; p = .005). A correlation was found between the possession of private health insurance and private attending physician status (r2 = .39, p < .001). Multiple logistic regression analysis was subsequently used to control for demographic factors and severity of illness. Three independent predictors for the withdrawal of life-sustaining interventions were identified in this patient cohort (p < .05) having a planned therapeutic trial of life-sustaining interventions outlined in the medical record (adjusted odds ratio 9.4; 95% confidence interval = 5.6 to 15.6; p < .001); lack of a private attending physician (adjusted odds ratio = 4.4; 95% confidence interval = 2.9 to 6.5; p < .001); and the presence of clearly defined advance directives regarding patient preferences for medical care (adjusted odds ratio = 3.6; 95% confidence interval = 2.3 to 5.7; p. = .005). Patients with private attending physicians had significantly greater medical care costs and medical care charges compared with patients without a private attending physician. CONCLUSION: Among patients dying within a medical ICU, those patients without a private attending physician are more likely to undergo the active withdrawal of life-sustaining interventions. PMID- 8681601 TI - Breathing measurement reduces false-negative classification of tachypneic preextubation trial failures. AB - OBJECTIVES: There is increased awareness of imposed work of breathing contributing to apparent ventilatory dependency. This study evaluates the impact of tachypnea as an indicator of ventilatory failure during a room air-5 cm H2O continuous positive airway pressure, spontaneous breathing, preextubation trial when associated with increased imposed work of breathing. DESIGN: Prospective, descriptive, 1-yr data collection. SETTING: University hospital trauma intensive care unit (ICU). PATIENTS: Mechanically ventilated trauma ICU patients surviving to discharge. INTERVENTION: Patients were weaned to minimal mechanical ventilator support and underwent a 20-min room air-continuous positive airway pressure preextubation trial (FIO2 = 0.21, continuous positive airway pressure = 5 cm H2O [0.5 kPa]). When passed (PaO2 >/= 55 torr [>/= 7.3 kPa], PaCO2 /= 7.35, respiratory rate 1.1 joule/L, imposed work of breathing was measured, and if residual "physiologic" work of breathing (patient work of breathing minus imposed work of breathing) was 30 breaths/min. Of these, 97 were successfully extubated despite tachypnea ranging from 32 to 56 breaths/min, when combined with either a patient work of breathing 95% viable. Enterocytes cultivated in 20% oxygen were confluent, but those enterocytes cultivated in hypoxia were not confluent and were fewer in number compared with enterocytes cultivated in normoxia. Compared with enterocytes grown in normoxia, enterocytes cultivated in 5% and 10% oxygen internalized greater numbers of each of seven strains of enteric bacteria, including Listeria monocytogenes (two strains), Enterococcus faecalis (two strains), and P. mirabilis, E. coli (two strains), with statistically significant increases noted for five of these seven bacterial strains. Intracellular survival of L. monocytogenes and P. mirabilis was assayed. Both species survived intracellularly for 22 hrs, with no noticeable differences in the numbers of intracellular bacteria recovered from enterocytes cultivated in 20%, 10%, and 5% oxygen. CONCLUSION: These in vitro results suggest that augmented bacterial endocytosis by enterocytes might at least partially explain the increased frequency of bacterial translocation associated with tissue ischemia. PMID- 8681604 TI - Myocardial dysfunction after successful resuscitation from cardiac arrest. AB - OBJECTIVE: To investigate the functional and metabolic changes in the myocardium after successful resuscitation from cardiac arrest. DESIGN: Prospective, randomized, sham-controlled study. SETTING: Animal laboratory at a university center. SUBJECTS: Domestic pigs. INTERVENTIONS: Electric induction of ventricular fibrillation by alternating current delivered to the right ventricular endocardium through a pacing electrode. Electric defibrillation was attempted after an interval of 12 mins of ventricular fibrillation, which included 4 mins of untreated ventricular fibrillation and 8 mins of precordial compression in 13 animals, seven of which were successfully resuscitated. Seven additional animals were randomized to serve as "sham" controls, in which cardiac arrest was not induced. MEASUREMENTS AND MAIN RESULTS: Left ventricular pressure-volume relationships utilizing the conductance method were obtained in conjunction with conventional hemodynamic and metabolic measurements at baseline and during a 6-hr interval after successful cardiac resuscitation. Progressive and striking increases in left ventricular volumes were observed after successful cardiac resuscitation. The end-diastolic volume increased from a prearrest level of 89 +/ 21 mL to a maximum of 154 +/- 53 mL (p<.05) at 360 mins after successful resuscitation. The time-coincident end-systolic volume increased from 54 +/- 21 to 126 +/- 54 mL (p<.05), such that the ejection fraction was reduced from 0.41 +/- 0.10 to 0.20 +/- 0.07 ( p<.05). Ventricular dilation was associated with marked reductions in stroke volume and ventricular work. However, compensatory increases in heart rate maintained cardiac output at levels that sustained adequate systemic oxygen delivery. The slope of the end-systolic pressure-volume relationships progressively decreased from 5.04 +/- 1.88 to 2.00 +/- 0.57 mm Hg/mL (p<.05) at 360 mins after successful resuscitation. The volume intercept at left ventricular pressure of 100 mm Hg increased from 43 +/- 19 to 94 +/- 51 mL (p=.03). Both the decrease in the slope and the increase in the volume intercept were characteristic of progressive impairment in contractile function. The rate of left ventricular pressure decrease was unchanged. Accordingly, no substantial changes in lusitropic properties were identified. Despite large increases in end diastolic volume, the end-diastolic pressure remained unchanged. CONCLUSION: Postresuscitation myocardial dysfunction in this animal model was characterized by impaired contractile function, decreased work capability, and ventricular dilation. PMID- 8681605 TI - Infantile colic: natural history and treatment. PMID- 8681606 TI - Pelvic inflammatory disease in adolescents. PMID- 8681607 TI - Esterase patterns of species in the Drosophila buzzatii cluster. AB - A comparative analysis was made of the esterase isoenzyme patterns of eight iso female lines, four of Drosophila serido (B31 D1, A55, B59, Q1, B50Q3), two of D. koepferae (B20D2 and B25D7), one of D. seriema (A95) and one of D. buzzatii (Buz). In all, 43 bands in the spectrum of esterase isoenzymes were detected by electrophoresis in polyacrylamide gels. They showed variations in specific reactions with alpha and beta-naphthyl acetate, number of patterns yielded in their intra-isofemale line combinations, frequencies of such combinations and the thickness and staining degree of some bands, in different individuals, lines and species. Among bands detected exclusively in males, seven may be considered sex specific (5 alpha-esterases and 2 beta-esterases). These male-specific alpha esterases have in common the inability to cleave beta-naphthyl acetate in the absence of alpha-naphthyl, denoting a possible common function. The similarity index (SI) and analysis of dependence were calculated in an attempt to quantify the differentiation of the iso-female lines studied, on the basis of esterase bands. SI mean value allowed the separation of the isofemale lines into five classes. Each species had its own pattern of esterase bands, but some bands were shared. A divergence hypothesis for the isofemale lines and the species is discussed. PMID- 8681608 TI - Leukaemic B-cell maturation: studies on immunoglobulin secretion mediated by two signalling systems in vitro. AB - The in vitro production and secretion of the immunoglobulins IgM, IgG, Kappa and lambda light chains by peripheral blood lymphocytes from chronic lymphocytic leukaemia patients was examined. The ELISA system was employed to quantitate the immunoglobulins secreted in the culture supernatants. Lipopolysaccharide and phorbol esters with CA++ ionophore were used as lymphocyte stimulators. The maturation of cultured lymphocytes was demonstrated by synthesis of cytoplasmic immunoglobulins and Ig secretions typical for plasma cells. In one case an isotype switch C mu for C gamma was observed. PMID- 8681609 TI - A study of some factors affecting the efficiency of in vitro mussel tissue culture for chromosome preparation. AB - In the course of a series of cultures of mussel mantle tissue three types of limiting factors to the efficiency of the method were identified. They are concerned with medium composition, and tissue culture and explant harvesting procedures. To reduce their negative effects, three changes with respect to the original technique are proposed: (1) incorporation of chick embryo extract in the place of egg yolk for culture medium enrichment; (2) replacement of 1 mm2 explants by 4 mm2 explants so as to suppress centrifugation, thereby gaining time; and (3) avoiding the use of male mantle tissue when it contains mature spermatozoa since this is cumbersome for slide analysis. Conversely, female mantle tissue can be employed without any disadvantage throughout the year especially as mature oocytes give suitable metaphase plates for meiotic chromosome study. PMID- 8681610 TI - The barbarism of managed care. PMID- 8681611 TI - Intrapleural fibrinolytics in management of empyema thoracis. AB - STUDY OBJECTIVE: To determine the success and complication rates of fibrinolytic therapy (FL) in the treatment of thoracic empyema. DESIGN AND PATIENTS: Between December 1992 and November 1994, all patients referred with empyema thoracis (ET) were offered FL. FL consisted of streptokinase (275,000 +/- 170,000 IU) or urokinase (121,000 +/- 57,000 IU) daily for a mean of 6.2 +/- 2.1 days. SETTING: The University of New Mexico Health Sciences Center and the Albuquerque Veterans Affairs Medical Center. RESULTS: Twenty-six patients were treated. Sixty-two percent (16/26) had complete resolution (CR) of symptoms, near or complete normalization of chest radiographic findings, and required no surgery or empyema tubes. Eight percent (2/26) had relief of symptoms and partial resolution (PR) of radiographic abnormalities and were discharged from the hospital with empyema tubes in place. All patients with PR had empyema tubes removed within 30 days of hospital discharge. Thirty-one percent (8/26) of patients failed to completely improve clinically or radiographically (nonresponse) and were treated with decortication or empyema tubes for greater than 30 days. Bleeding occurred in a single patient (4%). There was no mortality associated with FL use. CONCLUSIONS: The use of FL is associated with resolution of ET in 69% (18/26) of patients. This modality is safe, effective, and spares most patients with empyema the morbidity and mortality of thoracotomy. PMID- 8681612 TI - Detection of soluble adhesion molecules in pleural effusions. AB - PURPOSE: Multiple immune functions such as activation of T cells and monocytes or cytolysis of tumor cells are mediated via the adhesion receptor/ligand pairs CD2/LFA-3 and LFA-1/ICAM-1. Because soluble forms of LFA-3 (sLFA-3) and ICAM-1 (sICAM-1) can interfere with these functions, we asked whether increased levels of sLFA-3 and/or sICAM-1 can be found in malignant or inflammatory effusions compared with transudates. METHODS: sLFA-3 and sICAM-1 levels were measured by enzyme-linked immunoassays in pleural effusions from 70 patients (6 transudates, 10 inflammatory, 47 malignant, and 7 other effusions). Twenty pleural fluid samples were tested in parallel for the complete sLFA-3 molecule or sLFA-3-domain 1 only. RESULTS: Increased levels of sICAM-1 were found in all types of exudates compared with transudates. Highest levels of sICAM-1 were measured in malignant exudates, particularly in effusions caused by mesotheliomas, non-small lung cancers, and gynecologic malignancies. This was also true for sLFA-3. However, sLFA-3 levels were not increased in inflammatory effusions. sLFA-3 levels correlated significantly with protein, cholesterol, lactate dehydrogenase, and sICAM-1 levels. Comparison of sLFA-3-domain 1 and the complete sLFA-3 molecule revealed identical sLFA-3 levels, suggesting the absence of nonfunctional split products. CONCLUSIONS: Elevated levels of the complete sLFA-3 molecule were found in malignant pleural effusions, while sICAM-1 level was elevated in both inflammatory and malignant effusions. Secretion of sICAM-1 and sLFA-3 by tumor cells might block T-cell-mediated immune functions such as tumor cytotoxicity. Alternatively, secretion of soluble adhesion molecules might reflect the generalized inflammation within the pleural space. PMID- 8681613 TI - Contribution of lung and chest wall mechanics following emphysema resection. AB - OBJECTIVE: To determine the contributions of (1) chest wall (Pcw) and (2) lung elastic recoil pressure (PL) to (3) total elastic recoil pressure exerted by the respiratory system (Prs) in 18 patients (12 men) aged 66 +/- 6 years (mean +/- 1 SD) with severe emphysema who underwent video-assisted thoracoscopic bilateral lung volume reduction surgery under paralyzed (vecuronium) general anesthesia (isoflurane). DESIGN: We measured preoperative and 6-week postoperative lung function studies, and intraoperative inspiratory lung conductance (GL), PL, Pcw, and Prs (cm H2O) at end-expiratory lung volume (EELV), EELV plus 0.60 +/- 0.0 L, and EELV plus 1.15 +/- 0.0 L. All values are mean +/- SEM. RESULTS: Preoperative vs postoperative FVC was 1.9 +/- 0.1 L vs 2.3 +/- 0.1 L (p = 0.03); FEV1 was 0.6 +/- 0.1 L vs 0.9 +/- 0.1 L (p < 0.02); total lung capacity was 7.4 +/- 0.4 L vs 5.9 +/- 0.3 L (p < 0.001); functional residual capacity was 5.7 +/- 0.4 L vs 4.4 +/- 0.2 L (p = 0.001). At EELV preoperative vs postoperative, PL was 0.0 +/- 0.3 vs 1.1 +/- 0.05 (p = 0.04), Pcw was 5.0 +/- 0.7 vs 2.4 +/- 0.9 (p = 0.02), and Prs was 5.0 +/- 0.8 vs 3.5 +/- 0.7 (p = 0.08). AT EELV plus 0.60 L, PL was 3.2 +/ 0.6 vs 6.1 +/- 0.9 (p < 0.001), Pcw was 8.8 +/- 0.8 vs 7.0 +/- 0.9 (p = 0.12), and Prs was 12.0 +/- 0.8 vs 13.1 +/- 0.7 (p = 0.80). At EELV plus 1.15 L, PL was 6.8 +/- 0.9 vs 10.3 +/- 1.1 (p < 0.001), Pcw was 13.5 +/- 1.0 vs 11.2 +/- 1.2 (p = 0.12), and Prs was 20 +/- 1.2 vs 21.5 +/- 1.0 p = 0.93). AT EELV plus 0.06 L, GL was 0.09 +/- 0.00 L/S/cm H2O vs 0.16 +/- 0.01 (p < 0.01). At EELV plus 1.15 L, GL was 0.12 +/- 0.01 vs 0.21 +/- 0.03 (p < 0.05) with similar preoperative vs postoperative GL/PL slopes. CONCLUSION: The increase in PL and decrease in Pcw following LVRS for emphysema may be responsible for the increase in spirometry and airway conductance. PMID- 8681614 TI - Nasal-CPAP, surgery, and conservative management for treatment of obstructive sleep apnea syndrome. A randomized study. AB - STUDY OBJECTIVE: To assess separately the effectiveness and safety of nasal continuous positive airway pressure (N-CPAP) and that of surgery in comparison to conservative management in patients with obstructive sleep apnea syndrome (OSAS). DESIGN. A randomized study with 1-year follow-up. SETTING: A university hospital acting as a referral center for OSAS. PATIENTS: Symptomatic patients with OSAS (72 male and 4 female patients aged 18 to 65 years), who had oxygen desaturations in the overnight recording. INTERVENTIONS: After the initial diagnostic workup, patients were considered to be candidates for either N-CPAP (44 patients) or surgical treatment (uvulopalatopharyngoplasty [UPPP] with or without mandibular osteotomy) (32 patients). Within the groups, the patients were then randomized to either the assigned treatment or conservative management. MAIN OUTCOME MEASURES: The number of nocturnal oxygen desaturation events of 4% or more per hour in bed (ODI4); daytime somnolence; side effects. RESULTS: N-CPAP Group: Compliance with N-CPAP therapy at 1 year was 13 of 21. The most common reason for noncompliance was general intolerance of CPAP. All compliant patients had a normal ODI4 ( < 10), whereas 1 of 20 of their control subjects had a normal finding. Patients receiving active treatment were significantly less somnolent than their control subjects at 1 year (p < 0.05). SURGERY GROUP: At 1 year, 7 of 18 of the surgically treated and 1 of 14 of the conservatively treated patients had a normal ODI4 (p < 0.001). Daytime somnolence was significantly less severe in the surgically treated patients compared with their control subjects (p < 0.001) both at 3 and 12 months. The overall postoperative complication rate was 22%. CONCLUSIONS: N-CPAP is an effective therapy for OSAS, but compliance is a problem. Surgical therapy (UPPP with or without mandibular osteotomy) needs further evaluation. PMID- 8681615 TI - Respiratory effort during sleep apneas after interruption of long-term CPAP treatment in patients with obstructive sleep apnea. AB - Apneas generally reappear in patients with obstructive sleep apnea (OSA) when treatment with continuous positive airway pressure (CPAP) is interrupted. However, a single-night treatment interruption may be associated with a lesser severity of sleep apneas than before treatment. We hypothesized that this decrease in severity of sleep apneas reflects changes in the respiratory response to upper airway obstruction. Therefore, we compared indexes of respiratory effort during sleep in 25 patients with OSA before and after 1 year of CPAP treatment. Respiratory effort was assessed by means of an esophageal balloon. After 1 year of CPAP treatment, there was a decrease in the maximal end-apneic esophageal pressure swings (Pes) (from 56.7 +/- 5.4 to 30.3 +/- 2.6 cm H2O; p = 0.000; mean +/- SEM), in the overall increase in Pes during an apnea (35.2 +/- 3.6 vs 16.5 +/ 1.5 cm H2O; p = 0.000), as well as the rate of increase in Pes (1.1 +/- 0.1 vs 0.6 +/- 0.1 cm H2O/s; p = 0.000). Although body mass index (BMI) did not change significantly, the individual changes in BMI significantly correlated with the changes in respiratory effort after 1 year of CPAP treatment. Apnea duration and apnea-related oxygen desaturation also decreased significantly. We conclude that long-term CPAP treatment induces changes in respiratory control that persist at least on the first night of treatment interruption. PMID- 8681616 TI - Chest wall oscillation at 1 Hz reduces spontaneous ventilation in healthy subjects during sleep. AB - STUDY OBJECTIVE: The objective was to determine whether external chest wall oscillation (ECWO) during sleep (1) reduced spontaneous ventilation while maintaining adequate gas exchange over several hours, (2) influenced the quality and distribution of sleep, and (3) increased the number of respiratory events. DESIGN: Prospective controlled study with counterbalanced order of intervention. SETTING: Pulmonary function sleep laboratory. PARTICIPANTS: Seven healthy volunteers. INTERVENTION: One night of ECWO at 1 Hz (I:E = I:I; oscillation mean [SEM] from - 11.1 [0.7] to 6.0 [0.7] cm H2O) and a night during which the cuirass was applied without ECWO. MEASUREMENTS AND RESULTS: ECWO resulted in a significant decrease in spontaneous minute ventilation (VE) in all stages of sleep. ECWO was associated with a reduction in the total sleep time and a reduction in rapid eye movement (REM) sleep. The number of stage changes and the sleep efficiency did not change significantly. The mean PCO2 was similar between the control and cuirass nights (44 to 46 mm Hg). There was a significant decrease in the mean PCO2 during stage 1 (41 [2] mm Hg) and stage 2 (42 [2] mm Hg) sleep during the ECWO night. The mean arterial oxygen saturation (SaO2) was maintained at 96 to 97% throughout sleep during the control, cuirass, and ECWO nights. The apnea + hypopnea index increased (p < 0.05) during ECWO mostly due to an increase in the number of hypopneas in stage 2 sleep. During ECWO, 18 of 30 respiratory events were associated with an arousal, whereas only 2 events were associated with an arousal during the control night. CONCLUSIONS: ECWO can be tolerated for several hours and will assist ventilation while maintaining normal mean PCO2 and mean SaO2 during sleep. Monitoring of the apnea + hypopnea index and the SaO2 is recommended at the time of application. Clinical trials to define the most appropriate indications for ECWO are now necessary. PMID- 8681617 TI - The safety of i.v. pentamidine administered in an ambulatory setting. AB - I.v. pentamidine is well known to cause severe multiorgan adverse effects and is usually given to hospitalized patients under close monitoring. The primary purpose of this retrospective quality assurance study is to assess the safety of administering i.v. pentamidine in the medical daycare unit (MDCU) for outpatients. Thirty-five outpatients infected with the HIV made 306 visits to the MDCU from January 1991 to December 1993. They received i.v. pentamidine in a dosage of either 300 mg once a month for prophylaxis or 4 mg/kg/d 5 days a week for treatment of Pneumocystis carinii pneumonia (PCP). BP was monitored every 15 to 30 min over 3 to 4 h and clinical side effects were noted. CBC count, BUN, creatinine, amylase, and blood glucose values were taken twice a week. The records were reviewed retrospectively and analyzed for clinical and biochemical derangement. GI side effects occurred in 59 of 306 (19%) visits; 43 (73%) of the side effects were nausea. Routine normal saline solution boluses before and after pentamidine infusion prevented the drop in BP and actually significantly elevated BP after i.v. pentamidine. The most common biochemical derangement was elevated BUN level in eight patients and creatinine in nine patients, but they were mild and required no intervention. Significant neutropenia occurred in three, anemia in two, hyponatremia in two, hyperamylasemia in two, and hyperglycemia in two patients. No palpitation or irregular pulse was encountered. No death was associated with the administration of i.v. pentamidine. Three patients required hospital admission. Only one hospital admission was definitely related to adverse drug effects. In conclusion, the side effects of i.v. pentamidine are common but minor. We conclude that it is safe to administer i.v. pentamidine in carefully selected patients with appropriate monitoring in an ambulatory setting. This has a major health economic implication, because ambulatory i.v. pentamidine can result in significant cost savings and can also enhance quality of life. Further studies regarding the feasibility of home administration of i.v. pentamidine is warranted as even further cost savings and improvement in the quality of life of HIV-infected patients may be achieved. PMID- 8681618 TI - An effectiveness community-based clinical trial of Respirgard II and Fisoneb nebulizers for Pneumocystis carinii prophylaxis with aerosol pentamidine in HIV infected individuals. Toronto Aerosol Pentamidine Study (TAPS) Group. AB - STUDY OBJECTIVE: To compare the effectiveness of a standard jet nebulizer, Respirgard II, and a standard ultrasonic nebulizer, Fisoneb, for the administration of aerosolized pentamidine (AP) as primary and secondary prophylaxis against Pneumocystis carinii pneumonia (PCP) in HIV-infected individuals. DESIGN: A retrospective, nonrandomized, parallel group comparative study. SETTING: Patients were enrolled in a community-based AP program (APP) between May 1989 and April 1992 in Ontario, Canada. They received AP in either (1) a centralized treatment facility ("clinic") or (2) their attending physician's office or regionalized centers ("nonclinic"). Clinic administration of pentamidine was via Fisomeb; nonclinic via Respirgard II. PATIENTS: The study group comprised of 1,762 HIV-infected individuals requiring AP for either primary (CD4 < 200/mm3) or secondary PCP prophylaxis. Of these, 1,151 used Fisoneb (clinic) and 611 used Respirgard II (nonclinic). RESULTS: In the primary prophylaxis group, 41 of the 892 patients using Fisoneb (4.6%; mean follow-up, 18 months) compared with 16 of 435 patients using Respirgard II (3.7%; mean follow up, 14.6 months) developed PCP (p = 0.44). A total of 28 of 259 (10.8%; mean follow-up, 15.3 months) patients using Fisoneb for secondary prophylaxis compared with 11 of 176 (6.3%; mean follow-up, 14.4 months) patients using Respirgard II for secondary prophylaxis developed PCP (p = 0.1). CONCLUSIONS: Despite the difference in dosage (120 mg/mo vs 300 mg/mo), type of nebulizer (ultrasonic vs jet), and frequency of administration (twice vs once monthly), the results of this study indicate that both regimens of AP provide comparable protection against PCP. This study further supports the effectiveness of AP as a solid second-line prophylaxis for HIV-infected individuals who are intolerant to trimethoprim/sulfamethoxazole or dapsone. PMID- 8681619 TI - Immediate effects of intravenous cocaine on the thoracic aorta and coronary arteries. A transesophageal echocardiographic study. AB - STUDY OBJECTIVES AND DESIGN: Arterial vasoconstriction is thought to play a role in the etiology of cocaine-induced cardiovascular complications, but little is known about the immediate effects of cocaine on the thoracic aorta and coronary arteries. To examine these effects, we used transesophageal echocardiography to examine the thoracic aorta and coronary arteries before and immediately after intravenous (i.v.) cocaine (1.2 mg/kg) in 15 subjects. MEASUREMENTS AND RESULTS: Immediately after cocaine infusion, average heart rate, systolic BP, and double product were increased compared with baseline (22%, 15%, 35%, respectively). There was no significant change in the diameters of the ascending aorta (27.5 vs 27.1 mm; p = 0.85), the descending aorta (19.8 vs 20.4 mm; p = 0.62), or the left main coronary artery (4.3 vs 4.7 mm; p = 0.15). However, there was a trend for an increase in coronary blood flow immediately after cocaine (226 vs 309 mL/min; p = 0.10). CONCLUSIONS: We conclude that in the 15 subjects studied, there was no evidence of thoracic aorta of coronary artery vasoconstriction immediately after i.v. cocaine. Instead, we found that the diameters of the thoracic aorta and the left main coronary artery were unchanged, and that there was a trend for augmentation of coronary artery blood flow. PMID- 8681620 TI - Akinesis becoming dyskinesis during dobutamine stress echocardiography. A predictor of poor functional recovery after surgical revascularization. AB - BACKGROUND: Akinesis becoming dyskinesis at high-dose dobutamine stress echocardiography (DSE) has been disregarded as a marker of myocardial ischemia. However, to our knowledge, the relationship between this pattern and myocardial viability has not been assessed. METHODS: We studied 42 patients with myocardial infarction who underwent DSE (up to 40 micrograms/kg/min) before coronary artery bypass surgery, and resting echocardiogram 3 months after surgery. Viability in akinetic segments was considered to be present if systolic thickening occurred with low-dose dobutamine (LDD). RESULTS: During high-dose DSE, dyskinesis occurred in 35 of the 164 akinetic segments (group A). The remaining 129 segments comprised group B. Segments of group B had a higher prevalence of viability pattern with LDD (18% vs 0%; p < 0.01) and a higher prevalence of functional improvement (20% vs 0%; p < 0.005) compared with group A. In absence of viability pattern with LDD, postoperative improvement occurred in 10% of segments in group B and in none of segments in group A, resulting in a higher negative predictive value of LDD in group A vs B (100% vs 90%; p < 0.05). CONCLUSION: The phenomenon of akinesis becoming dyskinesis with high-dose DSE is associated with absence of viability pattern with LDD and poor functional outcome after surgical revascularization. Observation of this pattern provides additional data to those obtained only with LDD echocardiography. PMID- 8681621 TI - Exhaled ethane and antioxidant vitamin supplements in active smokers. AB - To determine the effect of nutritional agents on lipid peroxidation, 10 smokers were given 6 mg beta carotene, 200 IU vitamin E, and 250 mg vitamin C 4 times daily for 3 weeks. Lipid peroxidation was assessed by measuring baseline and postsupplementation levels of exhaled ethane. There was a 29% decrease in mean (+/-SD) exhaled ethane (4.06 +/- 1.49 vs 2.90 +/- 1.29 pmol.kg-1.min-1), with individual levels decreasing in 8 of the 10 smokers (p < 0.05, Wilcoxon sign rank test). Three nonsmokers had very low baseline levels of ethane that did not change with supplementation. Ethane production correlated with active (packs per day) and lifelong (pack-years) tobacco consumption. Also, a strong correlation was found between the decline in ethane output after micronutrient supplementation and the presupplement FEV1. Therefore, antioxidant vitamin supplementation resulted in attenuation of smoking-related lipid peroxidation, and the decreases in ethane production appears to be associated with preserved lung function. PMID- 8681622 TI - Retreatment of patients surviving cancer-free 2 or more years after initial treatment of small cell lung cancer. AB - STUDY OBJECTIVE: To assess the outcome after retreatment of patients with small cell lung cancer (SCLC) who redevelop small cell cancer (SCC) 2 or more years after initial therapy. DESIGN: Retrospective analysis. SETTING: Single government institution: the National Cancer Institute. PATIENTS: Twenty patients who redeveloped SCC among 65 patients who survived 2 or more years after starting treatment for their initial cancer. MEASUREMENTS: The response rate of patients after retreatment, the survival duration from the time of redevelopment of SCC, and the toxicities of retreatment. RESULTS: Twenty patients redeveloped SCC: 18 with a relapse and 2 with a second primary cancer. Sixteen received treatment after they redeveloped SCLC while four did not. Eleven patients were retreated with chemotherapy alone, two patients received chemotherapy plus chest radiotherapy, one patient received radiotherapy alone, one patient underwent lobectomy, and one patient was treated with a monoclonal antibody followed by chemotherapy. Nine of 16 patients (56%) treated after they redeveloped SCLC had an objective response (3 complete and 6 partial). The median survival of all 20 patients after they redeveloped SCC was 3.9 months (range, 0 to 46 months). The median survival of the patients who were retreated was 6.5 months (range, 1 to 46 months). CONCLUSIONS: Patients who suffer relapses with SCLC 2 or more years from diagnosis are candidates for retreatment. PMID- 8681623 TI - Usefulness of airway visualization in the diagnosis of nosocomial pneumonia in ventilated patients. AB - Clinical diagnosis of nosocomial pneumonia in ventilated patients remains a challenge in the ICU as none of the clinical biological and radiologic parameters can predict its diagnosis. To our knowledge, however, the accuracy of direct visualization of the bronchial tree has never been investigated. PURPOSE: To evaluate the interest of airway visualization and to select independent parameters that predict nosocomial pneumonia in ventilated patients. SETTING: A ten-bed medical-surgical ICU. METHODS: All consecutive patients suspected of having nosocomial pneumonia who underwent bronchoscopy with protected specimen brush, culture examination of BAL, and direct examination of BAL were studied. Clinical and biological data and airways findings were recorded prospectively. Patients were classified as having pneumonia or not according to the results of distal bacteriologic samples, follow-up, and histologic study. Respective accuracies of each variable were calculated using univariate analysis and stepwise logistic regression. RESULTS: Ninety-one patients with suspected nosocomial pneumonia were studied. Patients were randomly assigned to a construction group (n = 46) and a validation group (n = 45). Using multivariate analysis, 3 factors were associated with pneumonia (a decrease in PaO2/fraction of inspired oxygen ratio > or = 50 mm Hg, odds ratio [OR] = 9.97, p = 0.026; the presence of distal purulent secretions, OR = 7.46, p = 0.044; the persistence of distal secretions surging from distal bronchi during exhalation, OR = 12.25, p = 0.013). These three factors remained associated with pneumonia in the validation group. Interobserver repeatability of the bronchoscopic parameters was good. Having 2 or more of these 3 independent factors was able to predict pneumonia with a 94% sensitivity and a 89% specificity in the construction group and with a 78% sensitivity and a 89% specificity in the validation group. CONCLUSION: We conclude that direct visualization of the bronchial tree can immediately and accurately predict nosocomial pneumonia in ventilated patients before obtaining definite results of protected samples. PMID- 8681624 TI - Mechanisms of relief of exertional breathlessness following unilateral bullectomy and lung volume reduction surgery in emphysema. AB - STUDY OBJECTIVE: To explore mechanisms of relief of exertional breathlessness following surgery to reduce thoracic gas volume in patients with emphysema. MATERIALS AND METHODS: We studied 8 patients with emphysema (FEV1 = 39 +/- 3% predicted; residual volume [RV] = 234 +/- 12% predicted; mean +/- SEM) who were severely breathless despite optimal pharmacotherapy and who underwent unilateral bullectomy for giant bullae (greater than one third hemithorax); 4 of these also had ipsilateral lung reduction (pneumectomy). Pulmonary function and cycle exercise performance (n = 6) were evaluated before and 13 +/- 3 weeks after surgery. Chronic breathlessness was measured with the Baseline Dyspnea Index and the Medical Research Council dyspnea scale. Exertional breathlessness was measured using Borg ratings at a standardized work rate (BorgSTD). RESULTS: FEV1, FVC, and maximal inspiratory pressures increased postsurgery by 29 +/- 7% (p < 0.05), 24 +/- 10% (p = 0.06), and 39 +/- 12% (p < 0.01), respectively. Plethysmographic total lung capacity, RV, and functional residual capacity fell by 14 +/- 2%, 30 +/- 4%, and 18 +/- 3%, respectively (p < 0.001). All measures of chronic breathlessness improved significantly (p < 0.05). During exercise at a standardized work rate, BorgSTD fell 45% (p < 0.05), end-expiratory lung volume (EELV) fell 22% (p < 0.01), and breathing frequency (F) fell 25% (p = 0.08). By multiple stepwise regression analysis, 99% (p = 0.007) of the variance in symptom relief (delta BorgSTD) was explained by the combination of decreased ratio of the end-expiratory lung volume to total lung capacity, decreased F, and diminished mechanical constraints on tidal volume (tidal volume to vital capacity ratio). CONCLUSION: Reduced exertional breathlessness at a given workload after volume reduction surgery was attributed to a combination of reduced thoracic hyperinflation, reduced F, and reduced mechanical constraints on lung volume expansion. PMID- 8681625 TI - Intrinsic positive end-expiratory pressure during one-lung ventilation for thoracic surgery. The influence of preoperative pulmonary function. AB - OBJECTIVE: To detect and to quantify intrinsic positive end-expiratory pressure (PEEPi) during thoracic surgery in the dependent lung of patients intubated with a double-lumen endotracheal tube (DLT) in the lateral position. METHODS: Twenty consecutive patients undergoing elective pulmonary resection were anesthetized, paralyzed, and intubated with a DLT. Their lungs were ventilated (Siemens Servo 900 C ventilator; Siemens Elevna; Solna, Sweden) with constant inspiratory flow. Fraction of inspired oxygen, tidal volume (10 mL/kg), frequency (10/min), and inspiratory time/total time (0.33) were kept constant during the study. PEEPi and ventilatory data were measured in the dependent lung in the supine then in the lateral position with a closed hemithorax. The obtained data were analyzed according to the presence (group PH) or absence (group N) of pulmonary hyperinflation determined from the preoperative pulmonary function data as higher than 120% of predicted value of functional residual capacity (FRC) and residual volume (RV). DATA ANALYSIS: In the dependent lung of patients in group PH (n = 11), PEEPi was present in the supine (n = 8) and in the lateral (n = 11) positions in the range of 1 to 10 cm H2O. In group N (n = 9), PEEPi was detected in one patient and only in the supine position. In the whole group of 20 patients, the preoperative value of FRC (% predicted) and RV (% predicted) was statistically significantly correlated to the presence of PEEPi, whereas the preoperative FEV1 (% predicted) was poorly related to PEEPi in both positions. There was no significant correlation between the value of PaCO2 and PEEPi during one-lung ventilation (OLV) but patients in group PH had a significantly higher PaCO2 during OLV than group N (p = 0.012). CONCLUSIONS: In patients with chronic obstructive lung disease and pulmonary hyperinflation, PEEPi occurs commonly during the period of OLV and only occasionally in patients with normal lungs. As the ventilatory pattern, the size of DLT, and the side of surgery were similar in the two groups of patients, we conclude that the occurrence of PEEPi in our patients was influenced mainly by the preexisting pulmonary hyperinflation and airflow obstruction. PMID- 8681626 TI - Central venous catheter placement in patients with disorders of hemostasis. AB - OBJECTIVE: To define the incidence of bleeding complications from central venous access procedures performed by a critical care service in patients with disorders of hemostasis. DESIGN: Prospective, consecutive sample, collection of clinical data. SETTING: University teaching hospital. PATIENTS: Seventy-six consecutive patients with disorders of hemostasis who required central venous access for clinical management between October 1992 and October 1993. MEASUREMENTS: Age, sex, clinical diagnosis, most recent platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT) were recorded from the medical record of patients with known coagulation or platelet abnormalities. The site of central venous catheter placement, the number of needle passes necessary to complete the procedure, and the occurrence of complications were reported by the critical care attending physician performing or supervising the procedure. RESULTS: One hundred four central venous access procedures were performed on 76 patients with disorders of hemostasis. Seventy-three percent of catheters were placed in patients with platelet counts less than 100,000/mL and 40% of catheters were placed in patients with abnormalities of PT, aPTT, or both. Thirteen percent of patients had abnormalities of both platelets and coagulation profile. There were no serious complications. Bleeding complicated 7 (6.5% of the procedures; 5 patients had bleeding from the skin (from the suture sites in four), and 2 patients developed small periosteal hematomas. All patients with bleeding complications had thrombocytopenia with mean platelet counts of 22,000/mL and a range of 6,000 to 37,000/mL. Most patients with platelet counts in this range did not have clinically evident bleeding. CONCLUSIONS: Central venous access procedures can be done safely in patients with disorders of hemostasis by skilled physicians who frequently perform these procedures. Patients most likely to experience bleeding from these procedures are patients with severe thrombocytopenia. In this series, only a single patient, with a platelet count of 6,000/mL, required therapeutic blood product administration. PMID- 8681627 TI - Endothelin-1 does not mediate the endothelium-dependent hypoxic contractions of small pulmonary arteries in rats. AB - Various pulmonary artery preparations in vitro demonstrate sustained endothelium dependent contractions upon hypoxia. To determine whether endothelin-1 could mediate this phenomenon, we examined the effect of bosentan, a new antagonist of both the ETA and ETB subtypes of the endothelin receptor. Small (300 pm) pulmonary arteries from rats were mounted on a myograph, precontracted with prostaglandin F2 alpha and exposed to hypoxia (PO2, 10 to 15 mm Hg, measured on line) for 45 min. Endothelium-intact control rings exhibited a biphasic response, with a transient initial vasoconstriction (phase 1) followed by a second slowly developing sustained contraction (phase 2). Expressed in percent of the maximal response to 80 mmol/L KCl, the amplitudes of phase 1 (peak tension) and 2 (tension after 45 min of hypoxia) averaged 37 +/- 12% and 17 +/- 14%, respectively (n = 11). In endothelium-denuded rings, phase 1 persisted while the amplitude of phase 2 was reduced to 2 +/- 12% (p < 0.05, n = 8), showing the endothelium dependence of this contraction. Neither phase was significantly decreased in rings treated with 10(-5) mmol/L bosentan (38 +/- 15% and 17 +/- 12%, respectively, n = 6). The PO2 threshold for onset of hypoxic contraction was not significantly different among these three groups and averaged 32 +/- 24 mm Hg. In a separate experiment, we assessed the inhibitory effect of 10(-5) mol/L bosentan on the response to 10(-8) mol/L endothelin-I. Rings treated for 45 min with 10(-8) mol/L endothelin-1 alone exhibited a maximal contraction of 75 +/- 27% (n = 6). This was reduced to 4 +/- 17% (p < 0.01, n = 6) in rings treated with both 10(-8) mol/L endothelin-1 and 10(-5) mol/L bosentan. We conclude that complete blockade of all endothelin receptor subtypes has no effect on either endothelium-dependent or -independent hypoxic contractions in this preparation. This suggests that endothelial factors other than endothelin-I mediate the acute hypoxic contractions of small pulmonary arteries in the rat. PMID- 8681628 TI - Transvisceral lactate fluxes during early endotoxemia. AB - The pathogenesis of hyperlacticemia during sepsis is poorly understood. We investigated the role of lung, kidney, gut, liver, and muscle in endogenous lactate uptake and release during early endotoxemia in an intact, pentobarbital anesthetized dog model (n = 14). Ultrasonic flow probes were placed around the portal vein and hepatic, renal, and femoral arteries. After splenectomy, catheters were inserted into the pulmonary artery, aorta, and hepatic, left renal, and femoral veins. Whole blood lactate and blood gases from all catheters, organ flows, and cardiac output were measured before and 30 to 45 min after a bolus infusion of Eacherichia coli endotoxin (1 mg/kg). After endotoxin infusion, mean arterial blood lactate level increased from 0.92 +/- 0.11 to 1.60 +/- 0.15 mmol/L (p < 0.0001). Lung lactate flux changed from uptake to release of lactate adding a mean of 9.97 +/- 16.23 mmol/h (p < 0.05) to the systemic circulation. Liver and muscle lactate fluxes remained neutral at all times, while kidney and gut took up lactate from the circulation both before and after endotoxin infusion (mean renal uptake, 2.73 +/- 3.85 mmol/L; p < 0.001; mean gut uptake, 2.46 +/- 2.31 mmol/h; p < 0.002). Except for the kidney, where a decrease in blood flow correlated with diminished uptake, there was no correlation between changes in transvisceral lactate fluxes and organ or systemic oxygen delivery during endotoxemia. A positive correlation between lactate uptake and oxygen consumption during endotoxemia was seen for both gut (p < 0.0001) and kidney (p < 0.002). We conclude that, in the dog, the pathogenesis of endotoxin-induced hyperlacticemia is complex. The lung may be responsible for significant lactate release, and other viscera that normally take up lactate are unable to adequately clear this increased lactate. PMID- 8681629 TI - Lung volume reduction. A breath of fresh air? PMID- 8681630 TI - Lung volume reduction surgery for emphysema. AB - There has been dramatic resurgence of interest in surgical treatment of emphysema, particularly "lung volume reduction" procedures. Recent studies have demonstrated improvements in pulmonary function, lung mechanics, exercise tolerance, and quality of life in selected patients following volume reduction procedures. However, considerable uncertainty remains regarding overall benefit, optimal patient selection, operative techniques, and duration of response. This summarizes current approaches to lung volume reduction surgery, available clinical outcome information, selection criteria, and physiologic mechanisms of response, and discusses the potential role for surgical volume reduction in treatment of emphysema. Recent data appear to support the efficacy of bilateral staple lung volume reduction surgery in patients with severe symptomatic heterogeneously distributed emphysema. Further studies will be needed to determine relative value of different operative techniques and benefit in patients with other clinical presentations. PMID- 8681631 TI - Necrotizing fasciitis. AB - Necrotizing fasciitis is an uncommon soft-tissue infection, usually caused by toxin-producing, virulent bacteria, which is characterized by widespread fascial necrosis with relative sparing of skin and underlying muscle. It is accompanied by local pain, fever, and systemic toxicity and is often fatal unless promptly recognized and aggressively treated. The disease occurs more frequently in diabetics, alcoholics, immunosuppressed patients, i.v. drug users, and patients with peripheral vascular disease, although it also occurs in young, previously healthy individuals. Although it can occur in any region of the body, the abdominal wall, perineum, and extremities are the most common sites of infection. Introduction of the pathogen into the subcutaneous space occurs via disruption of the overlying skin or by hematogenous spread from a distant site of infection. Polymicrobial necrotizing fasciitis is usually caused by enteric pathogens, whereas monomicrobial necrotizing fasciitis is usually due to skin flora. Tissue damage and systemic toxicity are believed to result from the release of endogenous cytokines and bacterial toxins. Due to the paucity of skin findings early in the disease, diagnosis is often extremely difficult and relies on a high index of suspicion. Definitive diagnosis is made at surgery by demonstration of a lack of resistance of normally adherent fascia to blunt dissection. Treatment modalities include surgery, antibiotics, supportive care, and hyperbaric oxygen. Early and adequate surgical debridement and fasciotomy have been associated with improved survival. Initial antibiotic therapy should include broad aerobic and anaerobic coverage. If available, hyperbaric oxygen therapy should be considered, although to our knowledge, there are no prospective, randomized clinical trials to support this. Mortality rates are as high as 76%. Delays in diagnosis and/or treatment correlate with poor outcome, with the cause of death being overwhelming sepsis syndrome and/or multiple organ system failure. PMID- 8681632 TI - Clinical experimentation. Lessons from lung volume reduction surgery. AB - Although the advancement of medical science can occur only with the systematic evaluation of new interventions, novel therapies continue to be introduced and accepted prior to thorough study. The recent development of lung volume reduction surgery for emphysema provides an illustration of the unwillingness or the inability of the medical community, unconstrained by legal or reimbursement limitations, to assure the safety and efficacy of a new procedure prior to widespread utilization. Medical practitioners must learn to recognize the experimental nature of new procedures independent of the courts and third-party payers. The nature of the informed consent that must be obtained for an experimental therapy is different from that which is required for standard medical practice and this difference can provide a test of whether a new treatment is experimental. A comparison between the introduction of lung volume reduction surgery and the rigorous scrutiny required of any pharmacologic interventions for emphysema underscores the double standard that exists for evaluating new surgical (and some medical) innovations. Such a double standard cannot be defended on ethical or scientific grounds. Specific changes in the way experimental therapies are introduced and disseminated are suggested. Until all new medical and surgical interventions are required to undergo a thorough evaluation prior to becoming standard of case, the promise of evidence-based medicine can never be fulfilled. PMID- 8681633 TI - How academic medicine and the VA are being influenced by changes in health-care delivery. PMID- 8681634 TI - Intermittent enteral feeding in mechanically ventilated patients. The effect on gastric pH and gastric cultures. AB - OBJECTIVE: To evaluate the effect of intermittent (16 h/d) enteral feeding (IEF) on gastric pH and gastric microbial growth in mechanically ventilated patients. DESIGN: Prospective, case-controlled study. SETTING: Medical ICU and infectious disease research laboratory in a university hospital. PATIENT POPULATION: Thirteen mechanically ventilated patients receiving continuous enteral feeding (CEF). METHODS: Gastric pH and quantitative gastric cultures were obtained while patients received CEF. Each patient's feeding schedule was changed to IEF. Daily gastric pH and quantitative gastric cultures were obtained for 5 consecutive days. RESULTS: Gastric microbial growth was found in 85% (11/13) of patients receiving CEF. Implementation of IEF did not clear gastric microbial growth, as only one patient subsequently reverted to negative culture. Similar gastric microbial growth continued in 90% (10/11) of patients after institution of IEF. Gastric pH did not decrease with the administration of IEF (gastric pH with IEF, 3.8 +/- 0.6 vs 4.7 +/- 0.5 with CEF (not significant [NS]). The amount of microbial growth was also unchanged with IEF (total growth with IEF, 7.8 x 10(5) +/- 5.2 x 10(5) cfu/mL vs 8.7 x 10(5) +/- 4.6 x 10(5) cfu/mL with CEF) (NS). Thirty-eight percent (5/13) of patients developed new Gram-negative rod growth in gastric cultures while receiving IEF. Gram-negative rod isolates increased from 25% of total isolates (CEF) to 40% (IEF). CONCLUSION: Our preliminary data suggest gastric pH was not lowered and existing microbial growth was not cleared in ventilated patients receiving IEF after previously receiving CEF. Further controlled study in a larger group of patients is necessary to determine whether IEF is of benefit in decreasing gastric colonization and nosocomial pneumonia. PMID- 8681635 TI - Patients with amyotrophic lateral sclerosis receiving long-term mechanical ventilation. Advance care planning and outcomes. AB - OBJECTIVE: To examine advance care planning and outcomes of patients with amyotrophic lateral sclerosis (ALS) receiving long-term mechanical ventilation (LTMV). DESIGN: Case series. SETTING: Population-based study in homes and chronic care facilities in four states, and Home Ventilator Program of California Kaiser Permanente. PATIENTS: Seventy-five ALS patients receiving LTMV were identified; 11 died prior to interview, and 6 were totally locked in; 50 of 58 (86%) who were able to communicate consented to structured interviews, of whom 36 lived at home and 14 in an institution. RESULTS: Thirty-eight patients (76%) had completed advance directives, and 96% wanted them. Thirty-eight patients wished to stop LTMV in certain circumstances, of whom 30 had completed advance directives. Those who had completed advance directives were more likely to have communicated their preference, to stop LTMV to family and physician than those who had not (76 vs 29%; p = 0.05). Patients living at home rated their quality of life on a 10-point scale better than those in an institution (7.2 vs 5.6; p = 0.0052), and their yearly expenses were less ($136,560 vs $366,852; p = 0.0018). CONCLUSIONS: Most ALS patients receiving LTMV would want to stop it under certain circumstances, and the process of advance care planning enhances communication of patient preferences to family and physicians. Home-based LTMV is less costly and associated with greater patient satisfaction. PMID- 8681636 TI - Cost-effectiveness in clinical cardiology. II. Preventive strategles and arrhythmla therapies. PMID- 8681638 TI - A woman with episodic hemoptysis. PMID- 8681637 TI - Grain dust and endotoxin inhalation challenges produce similar inflammatory responses in normal subjects. AB - STUDY OBJECTIVE: To compare the physiologic and inflammatory response following inhalation of corn dust extract (CDE) and lipopolysaccharide (LPS) solutions in normal subjects. DESIGN: Randomized, double-blind crossover design. PARTICIPANTS: Fourteen healthy, nonatopic, nonasthmatic, never-smoking volunteers. INTERVENTIONS: On separate visits, subjects underwent a series of four inhalation challenges to LPS or CDE, each containing either a high (6 micrograms/mL) or low (0.9 microgram/mL) endotoxin concentration, and administered at equal Xolumes. RESULTS: Chest tightness, cough, dyspnea, and sputum production were experienced following both LPS and CDE exposures and with similar frequency at both high and low endotoxin concentrations. LPS and CDE inhalations caused acute declines in FEV1, and the changes in FEV1 from baseline following exposure to both inhalants were not significantly different at both high and low endotoxin concentrations. Following exposure to the high-endotoxin LPS and CDE, no consistent differences in total cell and cytokine (tumor necrosis factor-alpha [TNF-alpha], interleukin 1 beta [IL-1 beta], IL-6, IL-8) concentrations were seen between exposures, although the neutrophil concentration was greater following the LPS exposure (p = 0.01). BAL cellularity and cytokine concentrations following the low-endotoxin LPS and CDE exposure revealed no differences, except for IL-1 beta, which was greater following LPS exposure (p = 0.05). The high-endotoxin LPS and CDE exposures resulted in greater increases in BAL neutrophils and cytokines in comparison to its respective low-endotoxin exposure. CONCLUSIONS: At exposure levels of endotoxin, LPS and CDE result in similar symptoms, changes in airflow, and increases in BAL inflammatory cells and mediators. Moreover, the physiologic and inflammatory response to LPS and CDE appears to be related to the exposure level of endotoxin. PMID- 8681639 TI - Severe alkalemia, hyponatremia, and diabetic ketoacidosis in an alcoholic man. PMID- 8681640 TI - Cavitary lung lesion in a patient with congestive heart failure. PMID- 8681641 TI - A death associated with therapy for nosocomially acquired multidrug-resistant tuberculosis. AB - Treatment of multidrug-resistant tuberculosis is difficult and has been associated rarely with severe side effects. We report the nosocomial transmission of multidrug-resistant tuberculosis to a health-care worker who was seronegative for HIV infection. She died because of liver failure associated with treatment for active multidrug-resistant tuberculosis. PMID- 8681642 TI - Lung volume reduction in patients with severe diffuse emphysema. A retrospective study. AB - BACKGROUND: For most authors, surgery of emphysema is restricted to resection of large bullae, whereas resection of small bullae or lung volume reduction is generally considered to have poor results. STUDY OBJECTIVE: To report our experience of lung volume reduction in patients with severe emphysema without large bullae. PATIENTS: Thirteen patients were operated on from 1982 to 1992. Before surgery, they all had severe diffuse emphysema with a dyspnea grade 4 or 5 and mean FEV1 values of 18 +/- 5% of predicted. Seven patients had a PaCO2 greater than 42 mm Hg. On radiologic evaluation, they had either small bullae or, most often, areas of destroyed lung. INTERVENTION: The surgical procedure was unilateral in 11 patients and bilateral in 2. MEASUREMENTS AND RESULTS: Postoperative assessment included dyspnea grading, FEV1 measurements, and blood gas analysis followed at 6- to 12-month intervals. There was no perioperative mortality and the morbidity was limited. At 6, 12, 18, 24, and 36 months postoperatively, a symptomatic improvement was observed in 92%, 85%, 54%, 31%, and 31% of the patients, respectively, with FEV1 increasing by at least 20% in 92%, 46%, 46%, 31%, and 24% of the patients, respectively. CONCLUSION: Our data show that lung volume reduction may result in symptomatic and spirometric improvement in patients with severe emphysema without large bullae. PMID- 8681643 TI - Bronchioloalveolar carcinoma accompanied by severe bronchorrhea. AB - We report an unusual case of bronchioloalveolar carcinoma characterized by production of a large quantity of sputum accompanied by drastic electrolyte and fluid loss. The sputum contained a high level of gastrointestinal cancer associated antigen (CA19-9) and carcinoembryonic antigen (CEA). An immunohistochemical study of tumor cells showed the specific distribution of gastrointestinal cancer-associated antigen and carcinoembryonic stains, which were localized in the apical region of tumor cells. PMID- 8681644 TI - Primary systemic amyloidosis complicated by massive thrombosis. AB - We present a case of primary systemic amyloidosis complicated by multiple thrombotic events and initially presenting with a massive thrombosis of the inferior vena cava. Widespread infiltration of the vascular tree by amyloid was found at the time of autopsy. In addition, we report successful treatment of the massive inferior vena cava thrombosis with systemic thrombolysis. PMID- 8681645 TI - Steroid-responsive pulmonary hypertension in a patient with Langerhans' cell granulomatosis (histiocytosis X). AB - We report the case of a man with biopsy-proved pulmonary Langerhans' cell granulomatosis (histiocytosis X) and pulmonary precapillary hypertension. Pulmonary vascular resistances and mean pulmonary artery pressure decreased with corticosteroid therapy and dyspnea improved. PMID- 8681646 TI - High-altitude pulmonary edema with primary pulmonary hypertension. AB - A 43-year-old woman had two episodes of lung edema at moderate altitudes. She had taken slimming pills containing fenfluramine hydrochloride and diethylpropion hydrochloride. At sea level, catheterization of the right side of the heart showed a mean pulmonary artery pressure of 16 mm Hg, which increased to 34 mm Hg with mild exercise in a supine position. An extensive workup failed to identify a cardiac or a pulmonary cause of pulmonary hypertension. This patient experienced mild primary pulmonary hypertension related to the intake of anorexigens, which was revealed by high-altitude pulmonary edema. PMID- 8681647 TI - Pulmonary infiltrates following administration of paclitaxel. AB - The clinical spectrum of hypersensitivity reactions reported with paclitaxel has not included the occurrence of pulmonary infiltrates. This report describes three patients who developed transient pulmonary infiltrates after receiving paclitaxel. These infiltrates were noted 2 days to 2 weeks after administration of paclitaxel. The infiltrates resolved spontaneously in all the patients but one of them did receive steroid therapy. This syndrome of transient pulmonary infiltrates did not reoccur in the two patients who were rechallenged with paclitaxel. Physicians should be made aware of this unique occurrence during the course of treatment with paclitaxel. PMID- 8681648 TI - Acute and chronic lung allograft rejection during pregnancy. AB - Young women who undergo lung transplantation may regain normal fertility and become pregnant. Currently, little is known about the outcome of pregnancy after lung transplantation. We present a case of pregnancy after bilateral lung transplantation complicated by acute and chronic allograft rejection, resulting in irreversible loss of lung function. PMID- 8681649 TI - Extensive pulmonary metastases in malignant pleural mesothelioma. A rare clinical and radiographic presentation. AB - We report a case of malignant pleural mesothelioma in a patient who presented with pleural effusion and reticulonodular shadow on chest radiograph. Pulmonary metastases were diagnosed by transbronchial lung biopsy specimen and the patient died of extensive pulmonary metastases. This pattern of clinical and radiographic presentation is seldom reported for malignant pleural mesothelioma. PMID- 8681650 TI - Keep testing the waters. PMID- 8681651 TI - Occupation and asthma. Through a glass, darkly. PMID- 8681652 TI - Reliability of the polymerase chain reaction in the diagnosis of mycobacterial infection. PMID- 8681653 TI - Diagnostic testing of ICU-acquired pneumonia. PMID- 8681654 TI - The cost of treatment of spontaneous pneumothorax with the thoracic vent compared with conventional thoracic drainage. PMID- 8681655 TI - The mortality of untreated pulmonary embolism. PMID- 8681656 TI - Chest X-ray screening does not improve outcome in lung cancer. PMID- 8681657 TI - Late intracapsular hemorrhage in an anticoagulated patient with a breast implant. PMID- 8681658 TI - Is the result of methacholine challenge accurate for assessing the bronchoprotective effects of long-acting beta-adrenergic bronchodilators? PMID- 8681659 TI - Loss of bronchoprotection with salmeterol. PMID- 8681660 TI - Is delayed introduction of inhaled corticosteroids harmful in patients with obstructive airways disease (asthma and COPD)? The Dutch CNSLD Study Group. The Dutch Chronic Nonspecific Lung Disease Study Groups. AB - BACKGROUND: The institution of inhaled corticosteroids is generally advocated for effective treatment of patients with asthma. It is yet unknown what is the best time to start inhaled corticosteroid therapy and especially whether delayed introduction is harmful. PHASE 1: In a previous study in patients with asthma and COPD, we found that 2.5 years of treatment with a beta 2-agonist plus inhaled corticosteroid (BA + CS) was more effective in improving the FEV1 and the provocative concentration of histamine causing a 20% reduction in FEV1 (PC20) than treatment with a beta 2-agonist plus anticholinergic (BA + AC) or placebo (BA + PL). PHASE 2: We extended this study with 6 months to investigate whether delayed introduction of inhaled CS therapy (800 micrograms beclomethasone dipropionate) in the groups previously not treated with inhaled CS (BA +/- AC) could also improve FEV1 and PC20 to the same degree. A distinction was made between patients with predominantly asthma (high baseline reversibility, delta FEV1 > or = 9% of predicted), and predominantly COPD (low baseline reversibility, delta FEV1 < 9% of predicted). RESULTS: Improvement of FEV1 percent predicted by inhaled CS was comparable both in the asthmatics between phase 1 (13.8% predicted) and phase 2 (8.5% predicted; p = 0.31) as well as in the patients with COPD (2.5% and 1.5% predicted, respectively). PC20, however, increased significantly more in the asthmatics in phase 1 (1.77 doubling concentration [DC]) than in phase 2 (0.79 DC; p = 0.03). Improvement of PC20 in the patients with COPD was not significantly higher in phase 1 (0.74 DC) than in phase 2 (0.00 DC; p = 0.19). CONCLUSIONS: Our study indicates that although delayed introduction of inhaled CS in asthmatics leads to similar improvements in FEV1, improvements in PC20 are significantly less. These findings in patients with longer-existing asthma concur with other findings in newly detected asthma. We suggest that institution of inhaled CS therapy should not be postponed in asthmatics with documented airways obstruction and reversibility. PMID- 8681661 TI - Continuous vs intermittent albuterol, at high and low doses, in the treatment of severe acute asthma in adults. AB - Adult patients suffering from acute asthma presenting to the Emergency Department with an FEV1 of less than 40% of predicted were randomized into four treatment groups. They were treated with nebulized albuterol at a high (7.5 mg) or standard (2.5 mg) dose given either continuously through 1 h, or intermittently every hour, for 2 h. When the FEV1 improvements for the different groups at 2 h were compared, the groups treated with continuous nebulization had the greatest improvement. The improvements (1.07 L for the high-dose group, and 1.02 L for the standard-dose group) were significantly greater than the improvement seen with standard-dose intermittent treatment (0.72 L; p < 0.05). The improvement in FEV1 of the high-dose, hourly treated group was intermediate in magnitude between these (0.09 L). There was no difference in the improvement seen between the two groups treated with continuous nebulization. The potassium fall, present in all groups, was more pronounced in the groups treated with high doses of albuterol. Only one person (high dose, continuous treatment group) developed hypokalemia of less than 3.0 mmol/L. The high-dose hourly treated group had the highest incidence of side effects, and the standard-dose continuously treated group had the lowest. The standard-dose continuous-treatment regimen had the greatest improvement in FEV1 with the least number of side effects. PMID- 8681663 TI - Bronchodilator therapy of COPD. A reanalysis suggests new roles and new concerns. PMID- 8681662 TI - Results of a program to improve the process of inpatient care of adult asthmatics. AB - OBJECTIVE: To assess the effectiveness of a program to improve care of adult patients hospitalized for asthma. DESIGN: Retrospective analysis of patient and house staff education, patterns of medication use, spacer use, peak flowmeter use, and length of stay before and after team intervention. SETTING: A 960-bed teaching hospital in New York City. PATIENTS: All patients admitted to the hospital with a primary diagnosis of acute asthma exacerbation for 2 separate similar calendar periods, 1 year apart, before and after program intervention. We excluded patients who were hospitalized for less than 24 h or greater than 10 days. The preintervention group comprised 61 patients and the postintervention group 65 patients, well matched in their demographic characteristics and severity of disease. INTERVENTIONS: Using a team approach, we analyzed the process of inpatient treatment of asthma exacerbation, identified root causes for quality deficiency, and implemented specific improvements in the process. These included dedicated nurses who focused on the education of care providers and patients, a personalized attending-intern educational approach, and improvement in the supply and delivery of spacers, peak flowmeters, and medications to the patients. RESULTS: There was a significant increase in use of spacers, peak flowmeters, and inhaled corticosteroids. Systemic corticosteroid and methylxanthine use declined. Length of stay was reduced without increasing early hospital readmission rates. CONCLUSIONS: This program improved the treatment process of adults hospitalized for asthma. PMID- 8681664 TI - A 1-year comparison of turbuhaler vs pressurized metered-dose inhaler in asthmatic patients. AB - An open, randomized, parallel-group study was conducted to investigate whether asthmatic patients, considered adequately treated with a corticosteroid and/or short-acting beta 2-agonist via pressurized metered-dose inhaler (pMDI), could be transferred to a corresponding nominal dose of budesonide and/or terbutaline via Turbuhaler, an inspiratory flow-driven multidose dry powder inhaler (Astra Draco; Lund, Sweden), without a decrease in the effect of treatment. One thousand four patients (555 women; mean age, 44 years; mean peak expiratory flow [PEF], 102% predicted normal value) were randomized and treated with either pMDI (current therapy) or Turbuhaler for 52 weeks. The variables studied were asthma-related events, morning PEF, and inhaler-induced clinical symptoms. Asthma-related events were defined in two ways: (1) sum of health-care contacts plus doublings or additions of steroids, and (2) number of 2 consecutive days with PEF less than 80% of baseline. Baseline was obtained from a 2-week run-in period while receiving previous therapy. No statistically significant difference was found in asthma-related events according to definition 1. According to definition 2, there was a statistically significant difference between the groups in favor of Turbuhaler (p = 0.008). The mean number of events was 1.7 with Turbuhaler and 2.2 with pMDI. The mean number of weeks per patient with a PEF less than 90% of baseline was 4.5 with Turbuhaler compared with 6.0 with pMDI (p = 0.002). The sum of inhaler-induced symptoms after 1 year of use was statistically significantly lower with Turbuhaler (0.40) than with pMDI (0.75) (p = 0.0001). In conclusion, budesonide and terbutaline in Turbuhaler offered a superior alternative to corticosteroids and bronchodilators delivered by pMDIs in the maintenance treatment of asthma. PMID- 8681665 TI - Incidence of occupational asthma and persistent asthma in young adults has increased in Finland. AB - To investigate the incidence of occupational asthma and its relationship to new cases of persistent asthma, the data was collected from two national registers which cover practically all new cases of both diseases. In 1986 to 1993, the annual incidence of persistent asthma in adults (from 15 to 64 years) increased from 6,645 to 8,056 (21%). The incidence of asthma in women increased from 3,302 to 4,717 (43%). In the age group of 15 to 29 the increase was 91%, in 30 to 49 it was 60%, and in 50 to 64 the increase was 7%. Among men, the annual incidence remained stable. However, in the age group of 15 to 29 it increased by 87%, in 30 to 49 by 46%, while a decrease of 43% was detected in the age group of 50 to 64 years. During the same period, the annual incidence of occupational asthma increased from 227 to 386 (70%), from 109 to 185 (70%) in women and from 118 to 201 (70%) in men. In 1993 the population in Finland in the age range from 15 to 64 was 2.026 million. Thus, the incidence of persistent asthma was 0.4%. The proportion of newly diagnosed occupational asthma out of all new cases of asthma was 4.8%. PMID- 8681666 TI - Do we really know the value of surveillance lung biopsies? PMID- 8681667 TI - Extended therapy with ipratropium is associated with improved lung function in patients with COPD. A retrospective analysis of data from seven clinical trials. AB - OBJECTIVE: Bronchodilators are routinely used in the long-term therapy of patients with COPD. These drugs are generally evaluated for their short-term bronchodilatory effects. Long-term and short-term benefits, however, are not necessarily equivalent. We evaluated, therefore, the effects of extended therapy with inhaled bronchodilators in patients with COPD. DESIGN: Data were obtained from seven clinical trials in which ipratropium was compared with a beta-agonist over a 90-day treatment interval. This comprised all the available data from clinical trials performed for registration of ipratropium and included 1,445 evaluable patients. Results of pulmonary function tests were evaluated prior to and after short-term administration of bronchodilator both before and after the 90-day treatment period. In addition, data were analyzed after stratification for smoking status and for lung function. RESULTS: Long-term therapy with ipratropium resulted in improvement in baseline (ie, before short-term administration of bronchodilator) FEV1 (28 mL; p < 0.01) and FVC (131 mL; p < 0.01), while long term therapy with beta-agonist resulted in no significant change in FEV1 (1-mL decline; p > 0.2) or in FVC (20-mL improvement; p > 0.2). The improvement in baseline function in the ipratropium-treated patients was most marked in ex smokers (average duration of abstinence, 9 years). Short-term administration of ipratropium following the 90-day treatment interval resulted in similar response in average FEV1 (6 mL more improvement after the extended therapy; p > 0.2) and an increased response in average FVC (44 mL more improvement after extended therapy; p < 0.01). In contrast, extended therapy with beta-agonist resulted in significantly less response to the short-term administration of beta-agonist for both FEV1 (49 mL less response; p < 0.0001) and FVC (74 mL less response; p < 0.0001). Assessed as the percentage of patients who achieved a 15% improvement in lung function, most patients responded to both treatments both before and after extended therapy. There was, however, a significant decline in the number of patients who responded after extended therapy, and this was more marked for the beta-agonist treated group. CONCLUSION: Long-term benefits of bronchodilator therapy appear to differ from short-term effects. Extended administration of ipratropium appears to be associated with improved baseline lung function and perhaps with improvement in the response to acute bronchodilation. Extended administration of beta-agonist, in contrast, appears to have little effect on baseline lung function, but may decrease response to acute bronchodilation. PMID- 8681668 TI - Evaluating pleural fluid. PMID- 8681669 TI - Ventilation-perfusion response after fenoterol in hypoxemic patients with stable COPD. AB - BACKGROUND: The effects of vasoactive drugs, including bronchodilators, on vascular and pulmonary dynamics are interrelated, complex and difficult to measure, but important because of potential deleterious effects on gas exchange. METHODS: To assess the effects of fenoterol at both high and low dose on pulmonary gas exchange in 24 hypoxemic patients with stable COPD: fenoterol, 5 mg; fenoterol, 1 mg and ipratropium bromide, 0.5 mg; ipratropium bromide, 0.5 mg; or matched placebo were nebulized in a double-blind, placebo-controlled fashion. Spirometry, ventilation, systemic hemodynamics, and respiratory and inert gases were measured before and 15, 60, and 120 min after each treatment. RESULTS: Compared with placebo, heart rate (p < 0.002) and cardiac output (p = 0.05) increased after high-dose fenoterol therapy to return to baseline values by 120 min. Following fenoterol at high dose, mean maximum PaO2 change from baseline decreased by 6.3 +/- 1.1 mm Hg (SD) and both alveolararterial oxygen pressure difference (P[A-a]O2), by 8.3 +/- 4.0 mm Hg, and ventilation-perfusion (VA/Q) mismatching increased, as evidenced by increments of the dispersion of pulmonary blood flow, without reaching significance; likewise, low-dose fenoterol therapy increased VA/Q inequalities while both PaO2 and P(A-a)O2 remained unchanged. CONCLUSIONS: In this population of COPD patients, high-dose fenoterol therapy [corrected] significantly increased heart rate and cardiac output resulting in minor adverse consequences on arterial oxygenation and VA/Q relationships. PMID- 8681670 TI - Alpha 1-antitrypsin deficiency deaths in the United States from 1979-1991. An analysis using multiple-cause mortality data. AB - OBJECTIVE: To describe trends of reported alpha 1-antitrypsin deficiency mortality in the United States from 1979-1991. METHODS: We analyzed death certificate reports in the multiple-cause mortality files compiled by the National Center for Health Statistics. RESULTS: Of the 26,866,600 deaths that occurred during the 13-year period, 1,930 had alpha 1-antitrypsin deficiency listed as a cause of death. Over this period, we would have expected 5,400 to 13,400 persons with this condition to die. The age-adjusted mortality rate with reported alpha 1-antitrypsin deficiency listed increased 86%, from 4.3 per 10 million in 1979 to 8.0 per 10 million in 1991. alpha 1-Antitrypsin deficiency mortality rates were higher among whites than among blacks or persons of other races. alpha 1-Antitrypsin deficiency was listed in 2.7% of all deaths with obstructive lung disease among persons aged 35-44 years old and in 1.2% of all deaths listing hepatic disease among children aged 1 to 14 years old. CONCLUSIONS: alpha 1-Antitrypsin deficiency is an important risk factor for obstructive lung disease and hepatic disease in the United States, and it was reported with increasing frequency through the study period, although it is still likely underreported. PMID- 8681671 TI - The problem of drug resistance in tuberculosis. PMID- 8681672 TI - Diagnostic yield of bronchoscopies after isolated lung transplantation. AB - Lung transplantation has become an acceptable therapeutic option for end-stage pulmonary diseases. The most common causes of long-term mortality after transplantation are infections and obliterative bronchiolitis (OB). While acute rejection has been shown to be associated with an increased risk of development of OB, cytomegalovirus (CMV) pneumonitis is more controversial as a risk factor for OB. Surveillance bronchoscopies are therefore advocated as a method of detecting silent episodes of CMV pneumonitis or acute rejection. We performed 226 bronchoscopies in 43 lung transplant recipients over 34 months. One hundred fifty seven of the 226 bronchoscopies were performed according to a surveillance protocol. Acute rejection was diagnosed if lung histologic study revealed grade 2 to 4 rejection or if prompt reversal of clinical deterioration occurred after initiation of pulse steroid therapy. CMV pneumonitis was diagnosed when transbronchial biopsy histologic specimens revealed evidence of CMV inclusion bodies, or when CMV was recovered on BAL fluid in the presence of allograft deterioration. The proportion of patients who were free from any episode of acute rejection or CMV pneumonitis after transplantation was determined by Kaplan-Meier analysis. Twenty-one percent of our transplant recipients were free from acute rejection or CMV pneumonitis after a mean follow-up of 13 months. All patients who had acute rejection or CMV pneumonitis had the initial episode in the first 4 months after transplantation. Patients free of acute rejection or CMV pneumonitis 4 months after transplantation continued to be event free for the duration of follow-up. Our data suggest that surveillance bronchoscopy can be aborted in patients who are free from acute rejection or CMV pneumonitis by 4 months after transplantation. The role of surveillance bronchoscopy in decreasing the incidence of OB or improving survival can be determined only by future randomized prospective trials. PMID- 8681673 TI - Activation of eosinophils and fibroblasts assessed by eosinophil cationic protein and hyaluronan in BAL. Association with acute rejection in lung transplant recipients. AB - Lung transplantation has become an accepted therapy for end-stage lung disease. Acute rejection of the transplanted hung still remains a major clinical problem since it decreases graft survival. Eosinophil cationic protein (ECP) from activated eosinophils, hyaluronan (HYA) from fibroblasts, and circulating intercellular adhesion molecule 1 (1CAM-1) have been associated with acute rejection in kidney and liver grafts. We investigated whether these, as well as other molecules, were increased in acute rejection of lung allografts. Serum and BAL fluid from 38 bronchoscopies performed in 9 single lung, 2 bilateral lung, and 4 heart-lung transplant patients were studied. Differential cell counts were made from the BAL fluid. Levels of ECP, myeloperoxidase (MPO), and HYA were used as indirect markers for activation of eosinophils, neutrophils, and fibroblasts, respectively. In addition, levels of circulating ICAM-1, cVCAM-1, and cE-selectin were analyzed. Twenty-two episodes with acute rejection were diagnosed. Of these, 7 were minimal, 13 were mild, and 2 were of moderate character. We found increased levels of ECP and HYA in BAL fluid during mild acute rejection of the allograft. Numbers of eosinophils were also increased. Activation of neutrophils or neutrophil numbers were not significantly increased. Levels of circulating ICAM-1, cVCAM-1, and cE-selectin did not differ between the groups. This retrospective study shows that measurements of ECP and HYA can give information about the inflammatory process present during acute rejection in patients who have undergone lung transplants. Analysis of cCAMS, however, appears to be of limited value as markers for acute rejection. PMID- 8681674 TI - Pleural fluid to serum cholinesterase ratio for the separation of transudates and exudates. AB - STUDY OBJECTIVE: To evaluate the usefulness of two new parameters for separating pleural transudates and exudates: pleural fluid cholinesterase level and pleural fluid to serum cholinesterase ratio, and to compare the results with the other well-established criteria. DESIGN: Prospective evaluation of the patients referred for diagnostic thoracentesis. SETTING: Pulmonary sections of a community hospital and a university hospital. PATIENTS: One hundred ninety-three consecutive patients. Forty were excluded for different reasons. MEASUREMENTS: The following criteria for separating the pleural effusions in transudates and exudates were analyzed: Light's criteria, the pleural fluid cholesterol level, the pleural fluid to serum cholesterol ratio, the pleural fluid cholinesterase level, and the pleural fluid to serum cholinesterase ratio. RESULTS: One hundred fifty-three patients had conditions diagnosed. Thirty-five were classified as having transudates and 118 as exudates. The percentage of effusions misclassified by each parameter was as follows: Light's criteria, 7.8%; pleural fluid cholesterol, 7.8%; pleural fluid to serum cholesterol ratio, 6.5%; pleural fluid cholinesterase, 8.5%; and pleural fluid to serum cholinesterase ratio, 1.3%. CONCLUSIONS: The pleural fluid to serum cholinesterase ratio is the most accurate criterion for separating pleural transudates and exudates. If further studies confirm our results, the cholinesterase ratio could be used as the first step in the diagnosis of pleural effusions. PMID- 8681675 TI - A re-evaluation of deontology in the practice of orthopaedics and traumatology. PMID- 8681676 TI - Dysphagia due to cervical osteophytosis. AB - Cervical lesions caused by diffused idiopathic skeletal hyperostosis may cause compression of the upper respiratory and digestive paths. Horizontal anterior osteophytes that are not fused can cause dysphagia and dysphonia, large prevertebral ossifications extended or segmental may cause difficulty in breathing. A series of 6 cases with dysphagia, dysphonia, dyspnea due to duffused idiopathic skeletal hyperostosis, with cervical lesions is reported. In 3 cases, affected with moderate dysphagia, conservative treatment with anti-inflammatory drugs and a proper diet allowed for the symptoms to be controlled, and for spontaneous evolution of the lesions to occur, with fusion and remodeling of the compressive osteophytes. These patients continue to be asymptomatic 2-7 years after the first observation. In 3 cases affected with severe respiratory and/or nutrition deficit, the osteophytes and ossifications were surgically removed by prevascular extrapharyngeal approach, and rapid resolution of symptoms ensued. The follow-up 1-2 years after treatment showed that patients were asymptomatic and that radiographically there was no recurrence of lesions. PMID- 8681677 TI - Complications of varus derotation osteotomy in the treatment of CHD during growth. AB - Complications of varus derotation osteotomies in the treatment of congenital hip displacement (CHD) are reported. Only "true" complications were considered, that is, those related to errors in technique, while those related to errors in indications were excluded. An analysis of 150 cases with a mean follow-up of 4.2 years revealed that "true" complications are a rare occurrence. Among these the most frequent are dysmetria (20%), and infection (2.6%). There was only one case of osteochondrosis (0.6%). The dysmetria (usually under 2 cm) rarely required further surgical treatment involving temporary epiphysiodesis of the homolateral knee, while the infection responded satisfactorily to combined conservative and surgical treatment. PMID- 8681678 TI - Girdlestone arthroplasty for loosening of the total hip prosthesis: evaluation and results. AB - A total of 72 patients (73 hips) who had been submitted to Girdlestone arthroplasty to treat aseptic (63%) and septic (37%) loosening of total hip replacement, and who had been followed-up after an average of 6.8 years, were reviewed. Good pain control was obtained in nearly 60% of the patients. Functional results were poor, but 52% of the patients said that they were satisfied. Mean score based on the Harris Hip Score was 54. Infection was dominated in 92.6% of the cases. The best results were obtained in younger patients, while we did not observe any differences based on the cause of loosening (aseptic or septic). Despite the limits of the method, Girdlestone arthroplasty continues to constitute an effective indication for the treatment of loosening in total hip replacement, when the choice of reimplantation exposes the patient to a high risk of further failure. PMID- 8681679 TI - Internal fixation in unstable fractures of the pelvis. Preliminary notes. AB - The authors report the preliminary results of the surgical treatment of unstable fractures of the pelvic ring. Between 1989 and 1993 a total of 12 unstable fractures were treated by internal fixation. Short-term radiographic and functional results were satisfactory. The authors attribute an essential role to preoperative planning by conventional radiographic assessment and CT scan with multiplanar reconstructions, associated with carefully performed internal osteosynthesis. PMID- 8681680 TI - Supracondylar fractures of the humerus in children. A comparison between non surgical treatment and minimum synthesis. AB - The authors propose a comparison between methods used to treat supracondylar fractures of the humerus in children. The study included: 33 patients treated at the Ist Orthopaedic Clinic in Padova by non-surgical reduction and thoracobrachial plaster, and 33 patients treated at the Division of Orthopaedics and Traumatology at the Treviso Hospital by minimum synthesis and brachiometacarpal plaster. Mean follow-up was 7 years. The results were classified based on the Lagrange and Rigault system and the following parameters were also considered: time of hospitalization, cost-benefit relationship, loss of reduction of the fracture, any dysmetria. The two methods are equal in terms of time required for healing, and axial deviations, which were always less than 15, although somewhat better results were observed in cases judged to be excellent, with hospitalization under 2.5 days, and when minimum synthesis was used. PMID- 8681681 TI - Diagnostic accuracy of CT scan in intra-articular lesions of the knee (arthroscopic confirmation of 100 cases). AB - The results obtained for 100 CT scans of the knee confirmed by arthroscopy are analyzed in order to determine the probability of error in the various lesions and thus establish indications for the use of CT scan. This test was particularly reliable in traumatic lesions of the meniscus and in chronic breakage of the anterior cruciate ligament. It was more difficult to make an evaluation of degenerative meniscus tear or so-called "menisci at risk for tear". First and second degree chondropathies cannot be evaluated, while third and fourth degree ones may easily be evaluated on plane surfaces (tibial plate and patella), but not so easily on spherical surfaces (femoral condyles). PMID- 8681682 TI - Meniscus repair: cases and review of the literature. AB - The authors present 39 patients submitted to meniscus repair, and then analyze the various techniques used for suturing, emphasizing advantages, disadvantages, and complications. The results obtained with arthrotomic repair are not significantly different from those obtained with arthroscopic repair, except for the fact that the former method is less invasive. The stability of the knee is of essential importance to healing of a meniscal lesion. A long-term evaluation of the results obtained with meniscus repair is needed, as repetitive tearing has been described even after as many as three years. PMID- 8681683 TI - Should total prosthetization of the patella be used in knee surgery? A review of the literature and personal experience. AB - Based on an analysis of patellar complications during total knee arthroplasty, the authors report the conclusions of the most important studies in the literature as to whether or not the patella should be prosthetized. In particular, several important parameters to be taken into consideration before performing patellar prosthetization are discussed: the conditions of the cartilage and of the patellar bone, preoperative clinical symptoms, age, habits, body weight of the patient. The results of 50 Miller-Galante prostheses implanted between January 1989 and September 1993 is reported. The patella was prosthetized in 40% of the cases; there were no fractures or vascular necroses, nor was there breakage or detachment of the prosthetic button. Patellar pain was manifested in 5 cases (10%), 2 of which with a prosthetized patella, including 1 case of external dislocation and 1 case of breakage of the patellar tendon; another case of external dislocation, in a non-prosthetized patella, was clinically asymptomatic; pain was manifested after delay in wound healing in 2 cases. Only one patient with breakage of the patellar tendon was submitted to further surgery. The authors conclude that in light of the numerous studies published prosthetization of the patella may offer overall better clinical results, but they advise that indications should be carefully evaluated for each individual case, and that details in surgical technique should be observed (correct execution of bone resection and of lateral release when necessary, preservation of Hoffa pad, accurate hemostasis). PMID- 8681684 TI - Fragment fracture of the femoral head: a description of two cases. AB - Fragment fracture of the femoral head is a rare occurrence. The authors report two cases, in both of which there was dislocation of the hip, that was reduced non-surgically without at the same time obtaining reduction of the fractured fragment. In the first case the fragment was removed surgically while in the second case it was treated non-surgically as the cephalic lesion was unknown. At clinical-radiographic follow-up 2 years later, there was good functional recovery with no pain in the first patient, while early arthrosis developed in the second patient requiring prosthetic replacement surgery. PMID- 8681685 TI - Calcific tendinitis of the gluteus maximus. AB - Four cases of calcific tendinitis of the gluteus maximus are presented. Knowledge of the precise anatomic location of the calcium deposit achieved with conventional radiography and computed tomography and the clinical history are characteristic of this disorder. PMID- 8681686 TI - Dysplasia epiphysealis hemimelica of the radius. PMID- 8681687 TI - Kiloh-Nevin syndrome: a clinical case of compression of the anterior interosseous nerve. AB - Anterior interosseous nerve syndrome is a rare occurrence. One particular case, in terms of its etiopathogenesis, and its clinical findings that involved isolated lesion of the long flexor muscle of the thumb is reported. Healing occurred after approximately 10 months. Medical and physiotherapeutic treatment were carried out. PMID- 8681688 TI - [Development of guidelines in medicine--art or knowledge?]. PMID- 8681689 TI - [Standards in surgical medicine, their value and problems]. PMID- 8681690 TI - [Self determination and capacity for informed consent by the patient in medical intervention]. PMID- 8681691 TI - [Responsibility for patient education and explanation of consent for treatment]. PMID- 8681692 TI - [Current proctology--modern functional diagnosis]. AB - The large majority of pathological conditions in proctology can be recognized and distinguished from each other by clinical and endoscopic means of diagnosis. Manometric and neurophysiological investigations are especially useful for understanding pathophysiology; these methods are of great clinical value whenever their results contribute to a specific concept of therapy. Functional tests are able to distinguish among the various causes of sphincteric dysfunction. Defaecography might provide the decisive hint for operative treatment for manometric investigations of the ano-rectum, balloons, perfusion tubes and microtransducers are available. In cases of incontinence, especially in females, endosonography is the investigation of choice, providing most relevant information with regard to possible surgical reconstruction of the sphincter muscle. PMID- 8681693 TI - [Hemorrhoidectomy: current status]. AB - The many treatments for haemorrhoids highlight a lack of consensus. Differences in patients' and surgeons' priority make objective evaluation of haemorrhoid treatment difficult; different types of haemorrhoids are being treated in patients from different socio-economic backgrounds by surgeons of varying expertise from within different cultural settings. In this article we have reviewed the results of common treatments for haemorrhoids and give an outline of our operative technique when performing haemorrhoidectomy. PMID- 8681694 TI - [Fistula, fissure, abscess]. AB - Anal fistulas, anal fissures and anal abscesses are common disorders of the anorectal region that can often only be cured durably by operation. The acute anal fissure can usually be treated successfully by conservative means, whereas the chronical anal fissure can be cured by local fissurectomy as a rule. Primary anal abscesses and anal fistulas are different phenomena resulting from an infection of the proctodeal glands. The acute form, the anal abscess, always requires wide opening and drainage. Caudal intersphincteric and -trans sphincteric anal fistulas can be cured by the division method. Types of anal fistulas that occur higher can be treated effectively by a special operative technique developed on the basis of the method of Parks. PMID- 8681695 TI - [Pathophysiology of the abdominal wall]. AB - The use of biomaterials for closure of incisional hernias requires meshes adjusted to the physiological forces. The intraabdominal pressure is mainly influenced by the activity of the transverse muscles. The abdominal fascia of corpses withstands forces of 60-80 N/cm in horizontal and 20-30 N/cm in vertical direction; tearing of sutures occurs below 30 N/cm in horizontal direction. Assuming the abdominal cavity to be a thin hollow sphere, the rupture forces are approximately 4-16 N/cm for a diameter of 8-3 cm. The meshes currently in use are much stronger than this, rupturing at 40-100 N/cm. The curvature of the abdominal surface can be measured by 3D-photogrammetry and is highly significantly reduced following mesh implantation (t-test, 2-sided, P < 0.01). Reduction of the mesh material can decrease the rate of local wound complications and the stiffness of the abdominal wall. PMID- 8681696 TI - [Liver metastases in breast carcinoma. Results of partial liver resection]. AB - Within 11 years we performed 35 liver resections in 34 patients with liver metastases of breast cancer. The median age was 47 years. The median interval between the primary operation and the liver resection was 27.3 months. 59% of the patients had a solitary metastases. A curative (R0) resection was possible in 86%. Operative mortality was 3% (n = 1). Overall 5-year survival was 18.4% (median 27 months). Prognosis was significantly (p < 0.001) better following R0 resection (22%, median 41.5 months) than after R1/2-resection (maximum 20 months, median 5 months). Beside the radicality an unfavorable influence on the prognosis could be demonstrated only for a prior local recurrence of the primary tumor (p < 0.05). If a R0-resection was possible stage of the primary tumor, number and size of the metastases, and extension of the operative procedure were without prognostic significance. We conclude that patients with isolated liver metastases of breast cancer can have a long lasting benefit from liver resection. In individual cases even cure may be possible. PMID- 8681697 TI - [Current therapy of bile duct cysts. II. Intrahepatic cysts (Caroli syndrome)]. AB - 17 patients with a Caroli's syndrome are reviewed with emphasis on clinical features and late results (follow-up: 2-10 years). The group consists of 9 women and 8 men ranging in age from 17 to 80 years (mean of 42.6). 14 patients had a diffuse form, 5 of whom had periportal fibrosis with secondary biliary cirrhosis, which in 3 cases resulted in a portal hypertension with hepatic failure. In only 3 cases the dilatation was limited to the left lobe of the liver. 9 of the patients had previously undergone surgery in the form of cholecystectomy and choledocholithotomy elsewhere. The disease was complicated by lithiasis (14 intrahepatic, 9 extrahepatic). Curative treatment was only possible in the 3 patients with unilobar Caroli's syndrome (partial liver resection). In 5 patients we performed a cholecystectomy and choledocholithotomy combined in 2 cases with a transduodenal sphincterotomy. There was no operative death. Endoscopic treatment consisted in removal of stones and decompression of the biliary tree by sphincterotomy in 9 cases and endoscopic retrograde biliary drainage (endoprosthesis) in 5 cases. Excepting the 3 curative operated patients who are asymptomatic respectively 2, 4 and 5 years after surgery, the remaining cases had repeated bouts of acute pains accompanied by recurrent episodes of cholangitis. A late mortality of 23.5% (4 patients) is proof of the poor prognosis of this disease. PMID- 8681698 TI - [Long-term outcome of surgical therapy of acute necrotizing pancreatitis]. AB - This paper discusses the long-term results after surgical treatment of necrotizing pancreatitis. Thirty-one patients were examined 3 years after the operation. The development of diabetes was the main problem in 29% of the patients and depended on the amount of pancreatic tissue resected (never after necrosectomy, in 47% after pancreatic resection; P = 0.005, Fischer's exact test). Of the patients, 77% were in good general condition and 68% were able to work. In 50% of the patients abdominal wall function was impaired but most of them could cope with this insufficiency. Of the patients with alcohol-induced pancreatitis, 75% were abstinent. Considering the severity of the disease, long term results after surgical treatment of necrotizing pancreatitis are satisfactory. PMID- 8681699 TI - [Mechanical duodenal stump suture. Report of experiences: metal staples versus resorbable staples]. AB - The main observation criterion of the present retrospective study is the insufficiency rate after machine closing of the duodenal stump (TA-clip seam device, Auto-Suture), as a consequence of gastrectomy, resection of the stomach with Billroth II respective Roux-Y reconstruction, depending on the used type of clip. Between January 1, 1985 and October 2, 1989 the closing of the duodenal stump was routinely carried out with metal clips (n = 253) in the City Hospital Offenbach. Between October 3, 1989 and December 31, 1991 polysorb staples (n = 96) were exclusively used. The patient collectives were comparable regarding age, sex, health status, basic diseases, accompanying diseases and surgical methods. Closing of the duodenal stump by polysorb staples demonstrated with 13.5% more dehiscent seams than with metal clips (4.7%). As a result of the present study, we cannot recommend the use of polysorb clips for the closing of the duodenal stump. PMID- 8681700 TI - [Efficacy of basic surgical diagnosis in acute abdominal pain]. AB - This report describes a retrospective study concerning 314 patients suffering from acute abdominal pain admitted to the surgical emergency unit of Zurich University Hospital in 1992. Basic diagnostic work-up (history, physical examination, blood tests, sonography and abdominal X-ray) revealed the final diagnosis in 188 patients. Sonography was essential in 77 cases. Only 33 patients required additional examinations, such as CT-scan, gastroscopy or contrast X rays. Ninety-three patients were discharged with a final diagnosis of "non specific abdominal pain" (NSAP) after their symptoms had improved. A follow-up examination of these patients 6-18 months later resulted in a final diagnosis of somatic diseases in 8% of cases. This study demonstrated that the basic surgical diagnostics are efficient and reveal the final diagnosis with minimal delay. Abdominal sonography is the most important diagnostic tool in this context and should, therefore, be mastered and employed by the surgeon himself. PMID- 8681701 TI - [Abdominal trauma and pelvic injury in the growth period]. AB - Children with pelvic fractures usually are polytraumatized. Concomitant abdominal and pelvic injuries are not uncommon. Medical records and X-rays of 54 children, in which a pelvic fracture was diagnosed at our institution from 1974-1993, were reviewed. Children ages < or = 16 years and treated as in-patients were included in this study. The fractures were classified according to the AO-Classification. 47 patients (87.0%) had concomitant injuries. The mean Polytrauma Score was 23.7 (mean Injury Severity Score 30.5). Nine Children sustained an open pelvic fracture with rectal and/or vaginal tear. 15 genitourinary lesions were found in 13 children. 18 patients underwent laparotomy. A large pelvic/retroperitoneal hematoma was found in 11 cases. There were 7 liver lacerations, 7 splenic injuries, 2 mesenteric tears, 2 kidney injuries and 1 small bowel lesion. Eight children (14.8%) died with 5 of them due to retroperitoneal or/and abdominal bleeding complications. A recent follow-up examination (81.8%) with a mean follow up of 11.3 years showed that long-term morbidity usually was attributed to pelvic concomitant injuries. PMID- 8681703 TI - [The musculus pectoralis major rib flap. Personal experiences with 7 cases]. AB - We present a report of our experience with one-step reconstruction of the mandible after resection in tumor cases using an osteomyo-cutaneous flap. We performed a pectoralis major flap with a segment of the fifth rib, blood supplied by the periosteum. In seven cases we had one pseudoarthrosis. The complications in the donor site were none. We see in the pectoralis major-rib flap an alternative to microsurgical techniques, especially in patients with defects in the horizontal part of the mandible. PMID- 8681702 TI - [Is preoperative site diagnosis in organic hyperinsulinism from the viewpoint of the surgeon still necessary today? Results of a consecutive series and analysis of the literature]. AB - To answer the open question whether a preoperative localization diagnostic is necessary in organic hyperinsulinism we prospectively investigated our 28 patients with an organic hyperinsulinism who were operated on between September 1, 1985 and December 31, 1994. Additionally we performed an analysis of the literature. In case of a solitary adenoma the preoperative localization diagnostic had a sensitivity between 28.4% (sonography) and 84% (endosonography). The combination of all preoperative localization procedures had a sensitivity between 70% (literature) and 90% (own patient material). With palpation and intraoperative sonography 97.1% (own patient material 100%) of all solitary adenomas could be found during first exploration. Multiple adenomas and reoperations have special problems. The pre- and intraoperative localization diagnostic failed in every fourth patient. In conclusion, in case of a primary operation without a MEN syndrome a preoperative localization procedure is not necessary due to the high sensitivity of the intraoperative diagnostic. In case of a MEN syndrome or reoperation a preoperative localization diagnostic is still advisable although the sensitivity is low. PMID- 8681704 TI - [Traumatic bronchus rupture. Pathogenesis, surgical and postoperative management]. AB - Tracheobronchial injuries are rare and associated with other injuries. We report about a traumatic rupture of the left main bronchus into the segmental bronchus of the lower lobe. After resection of the lower lobe a bronchoplastic repair of the main and upper bronchus was performed. PMID- 8681705 TI - [Universal stripper for varicose vein surgery]. AB - We report on new stripper guides that facilitate the introduction of the stripper from the proximal side. At the same time they allow for smaller skin incisions and fewer nerve lesions. The 60-cm-long cable instead of the conventional one (90 cm long) is adequate for partial stripping. Due to its shortness, it is less annoying in the operation field and it allows rotational control of the Tiemann guide. The "dolphin" and the "torpedo" help to remove segments of the saphenous vein that are left behind. All these instruments are available as a set in a small box, which is handy for the scrub nurse. PMID- 8681707 TI - [Pre-syncope and syncope at the operating table--diagnostic and therapeutic possibilities]. AB - Standing in long-lasting operations can be a trigger for neurocardiogenic syncopes for the personal in the operating theatre. We report on a 37-year-old surgeon who suffered since childhood from more than 100 syncopes and presyncopes. That was the reason for him to think of giving up his profession. The head-up tilt-test proved the mechanism of a neurocardiogenic syncope. No further syncope has occurred for 16 months during the therapy with theophyllin. PMID- 8681706 TI - [From pneumoperitoneum to coelioscopy: Georg Kelling (1866-1945)--the pioneer of laparoscopy]. PMID- 8681708 TI - [Proteinase blockade as active principle against HIV]. PMID- 8681709 TI - [Euphoria in HIV therapy]. PMID- 8681710 TI - [Metformin undervalued]. PMID- 8681711 TI - [Vascular thickness and cytostatic-resistant bronchial carcinoma]. AB - BACKGROUND AND OBJECTIVE: A new way of treatment of malignant tumours was suggested by blocking angiogenesis and thus creating subpopulations of cells which, due to their decreased oxygen content, react differently to treatment. The relationship between angiogenesis (vessel density) and resistance to cytostatic drugs was investigated. PATIENTS AND METHODS: Results were analysed retrospectively for 83 untreated patients (73 men, 10 women; mean age 60 [37-75] years) with non-small cell bronchial carcinoma. Vessel density and resistance proteins were determined immunohistochemically. Radioactive incorporation of nucleic acid precursors with and without doxorubicin was measured with the in vitro short-term test. RESULTS: There were significant differences between vessel density and various resistance proteins. With low vessel density (less than mean value) glutathione-S-transferase pi (P < 0.01), thymidylate synthase (P < 0.05) and metallothioneine (P < 0.05) were significantly increased. P-glycoprotein showed a corresponding relationship, but it was not statistically significant, while there was no relationship with topoisomerase II. Bronchial carcinoma with low vessel density was more frequently resistant in vitro to doxorubicin than carcinomas with higher vessel density (P < 0.05). CONCLUSIONS: Non-small cell bronchial carcinoma with low vessel density more frequently expresses resistance proteins and is more commonly resistant to doxorubicin. Blocking angiogenesis to improve the results of treatment is therefore problematic. PMID- 8681713 TI - [Balloon mitral valve commissurotomy in pregnancy]. AB - HISTORY AND CLINICAL FINDINGS: A 31-year-old woman with known postrheumatic mitral valve stenosis developed for the first time left heart failure in the 19th week of her fifth pregnancy. After intensive drug treatment she was in stage 3 (New York Heart Association classification). Apart from that the patient was in a good general condition and obstetrical status was according to the estimated duration of pregnancy. Auscultation revealed an apical diastolic murmur and mitral opening snap. INVESTIGATIONS: Echocardiography demonstrated a mitral valve opening area of 0.85 cm2 (pressure-half time method); the mean gradient was 19 mm Hg. TREATMENT AND COURSE: Because of the severity of the findings a percutaneous transvenous balloon valvotomy (according to Inoue) was performed in the 27th week of pregnancy, after careful lead shielding of abdomen and pelvis. Radiological screening time was 10 min. The invasively measured transvalvar pressure gradient was reduced from 28 to 4 mm Hg, echocardiographically determined mitral opening area increased to 1.5 cm2. Delivery was induced in the 36th week of pregnancy because of third-degree renal pelvis congestion. A healthy child, weighing 2850 g was delivered vaginally. CONCLUSION: High-grade symptomatic mitral stenosis can, if necessary, be treated with a low-risk to mother and child by percutaneous balloon valvotomy. PMID- 8681712 TI - [Immune response to a single dose of a novel kind of hepatitis A vaccine following splenectomy]. AB - BASIC PROBLEM AND OBJECTIVE: The immune response to parenteral antigens is reduced in persons without spleen. The seroconversion rate was measured after application of a new type of vaccine against hepatitis A (immunopotentiating reconstituted influenza virus virosome [IRIV]) in patients who had undergone a splenectomy after trauma. PATIENTS AND METHODS: 26 patients (23 men and 3 women, mean age 34.9 +/- 9.7 [25-65] years) with anti-hepatitis A virus (HAV) antibody titres < 20 mIU/ml (maximally 17 mIU/ml) were given a single dose of 0.5 ml of the IRIV hepatitis A vaccine 1 to 14 (mean 9.4) years after splenectomy. Immediately after the immunisation and 14 and 28 days afterwards anti-HAV titres were determined. A titre rise to < 20 mIU/ml was counted as seroconversion. At the first and last titre measurement immunoglobulins, neopterin and beta microglobulin levels were also measured as additional markers. RESULTS: The seroconversion rate was 69.2% (18/26) after 14 days (geometric titre mean: 39 mIU/ml) and rose to 88.5% (23/26) after 28 days (geometric titre mean 74 mIU/ml). Seroconversion occurred in the three nonresponders after a second dose of the vaccine. All measurements of the immunological markers were within normal limits. CONCLUSION: A single dose of a new type of vaccine against hepatitis A confers adequate protection even in those persons who had a splenectomy. PMID- 8681714 TI - [Diagnosis of acute liver failure]. PMID- 8681716 TI - [Selection of candidates by the qualification committee in the sale of a practice. Opinion of the Social Court Munster, 10-5-1995]. PMID- 8681715 TI - [Unstable angina pectoris. Pathogenesis, risk assessment and therapy]. PMID- 8681717 TI - [Hazards of cannabis consumption]. PMID- 8681718 TI - [Therapy of alopecia areata in atopy]. PMID- 8681720 TI - [AIDS therapy on the upwind]. PMID- 8681719 TI - [Eruptive xanthoma as an early manifestation of type I diabetes mellitus]. PMID- 8681721 TI - [A case-control study for the recognition of nonoccupational risk factors for tumors of the lower urinary tract]. AB - OBJECTIVE: A case-control study was performed to assess various nonoccupational factors (smoking, eating and drinking habits, intake of analgesics) that may be aetiological factors in the development of tumours of the lower urinary tract, while vitamins may be protective. PATIENTS AND METHODS: 150 patients (125 men, mean age 66.4 years; 25 women, mean age 68.2 years) with histologically confirmed malignant tumour of bladder or other part of the lower urinary tract and a comparable group of controls, matched for age, sex and home location, were asked in a standardised personal interview about their life-long habits of smoking, eating and drinking, as well as intake of analgesics. RESULTS: Smoking was the greatest risk factor. In men there was a significant positive dose-effect relationship between the number of cigarettes smoked and relative carcinoma risk, compared with nonsmokers, by a factor of 3.68 among those with the highest dosage (> 40 pack-years). Because of the small number of cases this relationship could not be proven in women, but twice as many female tumour patients than controls were smokers (8 vs 4). In men, even after adjusting for smoking, increased coffee consumption increased the risk by a factor of 2 (2-4 cups: odds ratio 2.14 [P < 0.05]; > 5 cups: odds ratio 2.22 [not significant]). An increased beer consumption had no apparent effect on the development of tumours. Findings regarding vitamin C were ambiguous. More prolonged and increased intake of phenacetin-containing analgesics in men showed a tendency towards a higher tumour risk. CONCLUSION: Smoking cigarettes is one of the main risk factors for the development of bladder and other lower urinary tract tumours. The influence of other risk factors needs to be elucidated. PMID- 8681722 TI - [Varicella-zoster-virus myelitis without herpes. An important differential diagnosis of the radicular syndrome]. AB - HISTORY AND CLINICAL FINDINGS: A 43-year-old woman was admitted with a 14-day history of general malaise, subfebrile temperature, radicular dysaesthesias in the "riding breeches" area, severe pain in the lumbar region and progressive disorders of bladder and rectal emptying. Physical examination showed a conus cauda syndrome. Differential diagnosis was between myelitis (inflammatory or infectious), space-occupying intraspinal mass or vascular lesion. INVESTIGATIONS: Cerebrospinal fluid contained 1700/3 cells and there was intrathecal antibody synthesis against varicella zoster virus (VZV) and positive VZV-DNA analysis in the polymerase chain reaction. Magnetic resonance imaging of the lumbar spine revealed an inflamed enlarged conal and epiconal area with small haemorrhagic spots. There was no evidence of an underlying immune-modulated disease. TREATMENT AND COURSE: With the diagnosis of varicella zoster myelitis with cutaneous changes having been established the clinical signs and symptoms regressed almost completely with aciclovir administration (10mg/kg intravenously for 14 days). CONCLUSION: VZV without cutaneous involvement should be considered in the differential diagnosis of the radicular pain syndrome. When clinical signs of beginning myelitis or encephalitis are present, immediate investigations and therapy are necessary. PMID- 8681723 TI - [The popliteal artery entrapment syndrome in an older patient. Its diagnosis after unsuccessful laser-assisted percutaneous transluminal angioplasty]. AB - HISTORY AND FINDINGS: A 52-year-old patient complained of progressively increasing pain in his left leg when walking. The pain-free walking distance was 50-100 m. He was smoking about 20 cigarettes daily. No pulses were palpable in the left leg below the inguinal fossa. Recapillarisation time was normal in both legs and there were no trophic changes. INVESTIGATIONS: The Doppler perfusion pressure values were up to 40 mm Hg less in the left than the right leg. Ankle oscillography record showed a definite stenosis curve on the left. Digital subtraction angiography of the left leg showed a short occlusion of the popliteal artery with many collaterals and atypical medical deviation of the artery. The findings were interpreted as indicating peripheral arterial vascular disease. TREATMENT AND COURSE: Laser-assisted percutaneous transluminal angioplasty with balloon dilatation merely achieved a narrow lumen which again closed on plantar flexion of the left foot. The reversible occlusion suggested popliteal artery entrapment. At operation the popliteal artery coursed atypically over the dorsal medial aspect of the medial head of the gastrocnemius muscle. The arterial segment in the stenotic area was replaced by an autologous venous graft and the gastrocnemius muscle fixed laterally. The patients no longer experienced any impairment on walking and repeat angiography showed unimpeded flow through the graft even on plantar flexion. CONCLUSION: Popliteal artery entrapment is rare in the elderly and may be overlooked without provocation test and complete visualisation of the leg and pelvic arteries. PMID- 8681724 TI - [Conservative therapy of acute liver failure]. PMID- 8681725 TI - [New aspects of food allergy]. PMID- 8681727 TI - [Hepatitis C]. PMID- 8681726 TI - [The medical duty of confidentiality with patients on methadone]. PMID- 8681728 TI - [Calcium and vitamin D protect against osteoporosis fractures]. PMID- 8681729 TI - [German Cancer Award 1996]. PMID- 8681730 TI - [Thrombolysis in acute stroke with tissue plasminogen activator]. PMID- 8681731 TI - [Palliative surgical treatment of bone metastases. Improved quality of life by early intervention?]. AB - OBJECTIVE: To find out to what extent early operative treatment of osteolysis or pathological fractures, resulting from improved interdisciplinary treatment of malignant tumours, affects quality of life. PATIENTS AND METHOD: Using a standardised scheme of self-evaluation in a retrospective study, quality of life was assessed in 67 patients (18 men, 49 women; mean age 64.5 +/- 11.6 years) who were operated for osteolyses or pathological limb fractures due to malignant tumour metastases. RESULTS: Interlocking osteosynthesis was performed in 37 patients, endoprosthetic joint replacement in 30. Duration of operation and hospital stay were significantly shorter in those 17 patients operated for osteolysis than those 50 patients with a pathological fracture (P < 0.01 and P < 0.07, respectively). There were seven hospital deaths. Postoperative survival time averaged 13.4 months. 41 of the 60 patients discharged to outpatient follow up were again capable of leading a normal life, 13 were clearly impaired, six required nursing care, 46 patients did not or only sporadically require analgesics postoperatively. CONCLUSION: Early operative treatment of osteolysis before the occurrence of fractures is justified by the low operative mortality and complication rates and the better quality of life that is achieved. PMID- 8681732 TI - [Results after coronary bypass operation]. AB - OBJECTIVE: To determine the influence of various risk factors on 30-day postoperative mortality rate of aortocoronary bypass operation at different centres. PATIENTS AND METHODS: Data on 227 patients (179 men, mean age 63 [40-87] years; 48 women, mean age 68 [44-81] years), 219 first operations, 8 second operations) were retrospectively analysed. In all patients the indications for aortocoronary bypass surgery had been established in the last 3 months of 1993. The operations had been performed at six cardiac centres in Germany (five in Hessen [H1-H5]) and in three hospitals elsewhere in Europe outside of Germany (E1 E3). RESULTS: The operative mortality was relatively high (5.3%), 152 patients (67%) presenting with one or more risk factors accounting for an increased perioperative mortality. The mortality rate was significantly higher for: clearly impaired left ventricular function (ejection fraction < 40%): 20 vs 3% with an ejection fraction > or = 40% (P < 0.001); emergency operation: 16.6 vs 2.7% for elective operation (P < 0.001); advanced age (> or = 70 years): 10.9 vs 3.1% for younger patients (P < 0.025); and unstable angina: 9.2 vs 2.9% with stable angina (P < 0.05). Most of the bypasses were done with the internal mammary artery (63.9%, usually combined with venous bypasses (exclusive use of venous bypasses in 35.2%), but the proportion of arterial bypasses differed greatly between centres (96% in H3, 19% in H4). CONCLUSIONS: (1) Aortocoronary bypass operations are done on many patients with important risk factors, resulting in a relatively high 30-day postoperative mortality rate. (2) The proportion of internal mammary artery bypasses markedly differs between centres in Hessen. PMID- 8681733 TI - [Treatment of radiotherapy-induced gastroparesis with erythromycin]. AB - HISTORY: A 75-year-old woman who had undergone a hysterectomy with adnexectomy followed by radiotherapy for endometrial carcinoma complained of postprandial nausea with vomiting after eating solid foods and of cramp-like abdominal pain, but her appetite was good. She had lost 25 kg in weight over 13 months. EXAMINATION: Physical examination, laboratory tests, radiology and gastroscopy were unremarkable. Gastric scintigraphy showed abnormally prolonged emptying. TREATMENT AND COURSE: Nausea and vomiting stopped at once after erythromycin (a motilin agonist) had been administered. It was at first given intravenously after meals (50 mg three times daily for 5 days), then orally for 10 weeks (250 mg three times daily before meals). Subsequent examination revealed normal gastric emptying. The symptoms did not recur after erythromycin had been discontinued. CONCLUSION: Erythromycin is an effective drug against gastroparesis caused by radiotherapy, because it acts even when the enteric nerves are damaged. PMID- 8681734 TI - [Clinical manifestation of adrenal cortex insufficiency during thyroid hormone substitution]. AB - HISTORY AND CLINICAL FINDINGS: For 4 months a 37-year-old woman had been treated for Hashimoto thyroiditis with L-thyroxine, at first 25, then 50 micrograms. From the moment the higher dose had been started she experienced weakness, dizzy spells, nausea, vomiting, weight loss and hyperpigmentation. Her blood pressure was reduced to about 80/60 mm Hg. INVESTIGATION: The cortisol level was 5.4 nmol/l. When adrenocorticotrophic hormone was administered the cortisol level rose inadequately. Serum ACTH was raised to 3993 pg/ml. TREATMENT AND COURSE: When hydrocortisone was administered (10 mg in the morning plus 5 mg three times daily) her condition immediately improved and L-thyroxine (50 micrograms/d) was now well tolerated. CONCLUSION: Substitution with thyroid hormone causes an increased cortisol breakdown in the liver. It is likely that this will have accentuated the previously latent cortisol deficiency resulting from adrenal cortical insufficiency (caused by an autoimmune mechanism) thus producing typical addisonian signs. PMID- 8681735 TI - [Diverticular disease]. PMID- 8681736 TI - [Therapy of bleeding varicosities]. PMID- 8681737 TI - [Thrombolytic therapy for myocardial infarction in oral anticoagulation]. PMID- 8681738 TI - [Pancreatic (acinar) metaplasia of the gastric mucosa]. PMID- 8681739 TI - [How HIV-1 gets into the cell]. PMID- 8681740 TI - [The thrombophilic status of patients with inflammatory diseases]. AB - BASIC PROBLEM AND OBJECTIVE OF STUDY: Inflammatory reactions are taken to be nonspecific defensive measures of the organism and are associated with complex changes at cellular and humoral level. Activation of blood coagulation plays an important part in this, especially as it is accompanied by an increased risk of thromboembolism. It was the aim of this investigation to assess this risk by measuring sensitive markers of coagulation activation. PATIENTS AND METHODS: Biochemical markers of coagulation activation (prothrombin-fragment F1 + 2 and thrombin-antithrombin III complex [TAT]) and fibrin formation (D-dimer) were measured in 130 patients (61 men, 69 women; mean age 56.9 [20-89] years). 44 had pneumonia, 44 bronchitis and 42 urinary tract infections. A healthy control group for comparison consisted of 11 men and 15 women (mean age 48.7 [23-79] years). RESULTS: F1 + 2, TAT and D-dimer were significantly increased, compared with the controls, in all three patient groups (P < 0.01). The greatest rises occurred in the patients with pneumonia: F1 + 2: median 1.2 vs 0.6 nmol/I, TAT: 6.2 vs 2.1 micrograms/l and D-dimer 2476 vs 223 ng/ml. CONCLUSION: These findings underline the importance of consistent thrombosis prophylaxis in patients with inflammatory disease, especially those at an increased risk. PMID- 8681741 TI - [The Schnitzler syndrome as a cause of recurrent fever of unknown origin]. AB - HISTORY AND CLINICAL FINDINGS: For 4 years a 56-year-old woman had been suffering from chronic urticaria. In the past two years she had developed recurrent fever, each 1-3 days in duration. In the last 6 to 8 months she also had severe aching in the legs. There were no significant findings on physical examination other than non-itching urticarial rash over trunk and limbs. INVESTIGATIONS: Blood sedimentation rate was increased (maximum 88/110 mm), as were WBC count (16,200/microliter, 83% neutrophils) and the activity of alkaline leucocyte phosphatase (225 U/l). Monoclonal IgM gammopathy type kappa and circulating IgM immune complex (15.4 mg/dl) were demonstrated in serum. Skin biopsy of a new urticarial lesion revealed vasculitis. Iliac crest biopsy was unremarkable and showed no lymphoid cell infiltration. Bone scintigraphy revealed bilaterally increased storage in femur and tibia. Magnetic resonance imaging demonstrated marrow infiltration without space-occupying features in the affected femur and tibia. TREATMENT AND COURSE: Conjunction of fever, generalised urticaria, joint/bone pain and monoclonal gammopathy of kappa type having established the diagnosis of Schnitzler's syndrome, treatment with ibuprofen was started (initially 1,200 mg daily by mouth, followed by reduction to 600 mg daily). All symptoms rapidly improved and the bone changes regressed, but not the monoclonal gammopathy. But when the ibuprofen dosage had been decreased to 600 mg daily, the urticaria recurred, though in milder form. CONCLUSION: This case demonstrates the efficacy of ibuprofen in the treatment of the Schnitzler's syndrome. Furthermore reversibility of scintigraphic bone lesions could be demonstrated under ibuprofen treatment. PMID- 8681742 TI - [The therapy of a macroprolactinoma with the intramuscular application of a long acting bromocriptine preparation]. AB - HISTORY AND CLINICAL FINDINGS: Three years ago, a now 26-year-old woman with secondary amenorrhoea was found to have a prolactinoma which was treated with bromocriptine. However, because of side effects and psychosocial problems she took the drug only irregularly. There were no neurological symptoms and the visual fields were normal. Her weight was 97 kg and her height 168 cm. INVESTIGATIONS: Without treatment the serum prolactin concentration was 6978 microU/ml, while other endocrine parameters were unremarkable. Cranial computed tomography showed a suprasellar adenoma (craniocaudal diameter 1.0 cm). TREATMENT AND COURSE: Renewed treatment with bromocriptine (5 mg three times daily) brought prolactin concentration to within normal limits, but then rose again to at least 52,600 microU/ml when the patient took the drug irregularly, and the tumour grew to 2.8 cm. As the obesity (her weight now 120 kg) made neurosurgical intervention very risky a treatment trial with long-acting bromocriptine preparation (50 mg bromocriptine every 28 days intramuscularly), was undertaken. Serum prolactin concentration, measured at the end of the 28-day period, rapidly fell (6470 microU/ml after 3 months). Radiological examination indicated significant tumour shrinkage ( < 1.0 cm after 2 years). CONCLUSION: Repeated intramuscular administration of bromocriptine was an effective, well tolerated alternative (but not yet licensed in Germany) to oral dopamine agonists in the treatment of macroprolactinoma. PMID- 8681743 TI - [Schonlein-Henoch syndrome with severe abdominal involvement in an adult]. PMID- 8681744 TI - [Duplex sonography in tumor diagnosis]. PMID- 8681745 TI - [Chronic urticaria and Helicobacter pylori]. PMID- 8681746 TI - [Histaminosis]. PMID- 8681747 TI - [Is there a magnesium-deficiency anemia?]. PMID- 8681748 TI - [CA 19-9 and Helicobacter pylori]. PMID- 8681749 TI - [Pronounced phenprocoumon overdosage as a consequence of an unclear physician's order]. PMID- 8681750 TI - [Acute HIV-1 infection--an internal medicine emergency?]. PMID- 8681751 TI - [The Aids Research Prize 1996]. PMID- 8681752 TI - [The determination of patient satisfaction as a part of quality management in the hospital]. AB - BASIC PROBLEM AND OBJECTIVE OF STUDY: Patient-satisfaction is an important part of the quality of results of medical treatment in hospital. Such satisfaction can be measured with a standardised multi-dimensional questionnaire which takes into account all relevant parts of a hospital. An enquiry was undertaken on patients in a university department of urology to find out whether a scientifically based measurement of patient-satisfaction is possible and whether organisational improvement can result from it. PATIENTS AND METHODS: Dimensions of patients satisfaction included "care by doctors", "care by nursing staff", "food and accommodation", and "administration and daily activity". A questionnaire with a scale for answers (total of 65 items with closed answers) was developed for each of the dimensions. A one-month pretest served to ascertain acceptance and understanding of the questionnaire. In the three-month main test period questionnaires were given to all in-patients over 16 years old on admission. Participation was voluntary and anonymous. RESULTS: 232 patients took part (172 men, 60 women; median age 57 years), a response rate of 61%. The scales were shown to have a high internal consistency. The answers provided, for example, the means for simple and directly applicable improvement in patient information and the organisation of daily routine. Making the results known had a positive effect on the motivation of the staff. CONCLUSION: The work and cost involved in such a study are reasonable. This is the more so since in future investigation on patient-satisfaction will be undertaken every year or two as part of the demanded quality management in hospitals. However, scientific principles in the methodology must be taken into account when evaluating the results. PMID- 8681753 TI - [Percutaneous transluminal coronary angioplasty (PTCA) as primary therapy in acute myocardial infarct]. AB - BASIC PROBLEM AND OBJECTIVE: Percutaneous transluminal coronary angioplasty (PTCA) is being increasingly considered as an alternative to thrombolytic treatment of acute myocardial infarction. Studies performed so far, some on selected groups of patients, have produced high initial results of success. This prospective study was undertaken to determined primary success, complications and recurrence after primary PTCA in acute myocardial infarction (AMI). PATIENTS AND METHODS: Primary treatment in the form of immediate PTCA of the infarct vessel was undertaken in 111 patients (84 men, 27 women; mean age 58.6 +/- 10.3 years) with AMI. PTCA was judged successful if the infarct vessel had been reopened to perfusion grade 3 and restenosis was < 50%. No thrombolytic treatment was given, but heparin infusions were given during and for 24-48 hours after the procedure. 13 patients (11.7%) were in cardiogenic shock or required cardiopulmonary resuscitation for infarct-related arrhythmias. RESULTS: The primary success rate of PTCA for the whole group was 91% (101 of 111 patients), but only 77% (ten of 13) among patients in cardiogenic shock and (or) after resuscitation. Acute re occlusion (0-6 days after PTCA) occurred in seven patients. Eight patients (7.2%) died during the hospital phase (0-4 weeks), seven of whom had been in shock or required resuscitation (death rate 54%). The overall complication rate of the intervention was 6.3%. No emergency aortocoronary bypass was necessary. Repeat coronary angiography was performed in 71 of the 101 successfully treated patients 6 or 12 weeks after the PTCA. Re-occlusion was demonstrated in four (5.6%), a restenosis of more than 50% in 25% of patients. Mean left ventricular ejection fraction, obtained by planimetry from the levocardiogram was 58.6 +/- 9.3%. CONCLUSION: PTCA, performed immediately after acute myocardial infarction is an effective therapeutic measure with a high primary success rate. PMID- 8681754 TI - [Acute intrahepatic bleeding in a male patient with focal nodular hyperplasia]. AB - HISTORY AND CLINICAL FINDINGS: A 45-year-old man had acute bouts of pain in the right lower thorax with radiation to the mid-thorax and upper abdomen. For 3 years he was known to have coronary heart disease, for 4 years arterial hypertension and for 8 months, as an accidentally discovered finding, a liver cyst 2.5 cm in diameter, as well as an inhomogeneous focal lesion, demonstrable only by sonography, lying dorsally and close to the diaphragm in the right lobe of the liver, 3.0 x 3.5 cm which was not detected by computed tomography or magnetic resonance imaging. Physical examination at admission detected epigastric pain on pressure but no other abnormalities. INVESTIGATIONS: Sonography showed the inhomogeneous hepatic lesion now to be 6.0 x 7.5 cm. Computed tomography demonstrated a space-occupying mass, 7.5 cm in diameter, dorsal to the hepatic cyst, partly hypo-, partly hyper-dense with marginal spotty enhancement after contrast-medium injection. TREATMENT AND COURSE: As acute bleeding into the focal hepatic lesion was suspected, a laparotomy was performed and liver segments VII and VIII resected. On inspection there was a sharply demarcated yellowish-white tumor with a central haemorrhagic softening. Histology revealed focal nodular hyperplasia (FNH) without signs of malignancy. CONCLUSION: In the case of a known but not definitively diagnosed focal hepatic lesion, acute upper abdominal pain can be a sign of acute bleeding into the lesion. PMID- 8681756 TI - [Diagnostic and classification criteria in rheumatology: collagenoses]. PMID- 8681755 TI - [The diagnosis and therapy of acquired factor-VIII inhibitors in combination with lupus anticoagulants]. AB - HISTORY AND CLINICAL FINDINGS: A 63-year-old woman, known to have a primary factor VIII inhibitor (FFI) in combination with lupus anticoagulants (LA) was hospitalised because of life-threatening bleeding from mouth and neck. INVESTIGATIONS: The activity of coagulation factor VIII was 9% under substitution, while the factor VIII inhibitor titre was 123 U/ml. A lupus anticoagulant test was positive. Antibodies against varicella-zoster virus and Epstein-Barr virus were demonstrated. The right adrenal was found to be enlarged on computed tomography. TREATMENT AND COURSE: Coagulation became normal on administration of porcine factor VIII concentrate. Three cycles of a combination of three protein A immunoadsorptions, cyclophosphamide (twice 1.0 g intravenously), IgG (30 g daily for 5 days) as well as long-term oral cyclophosphamide administration (150 mg daily) during the interval were undertaken to reduce the inhibitor and produce immuno-tolerance. The factor VIII inhibitor titre was stabilised at a low level, but factor VIII activity could not be normalised without substitution. CONCLUSIONS: The simultaneous presence of specific and non-specific inhibitors makes laboratory diagnosis and treatment more difficult. Porcine factor VIII and a combination of immunoadsorption and suppression are important components in the treatment of bleeding episodes and the production of immunotolerance. PMID- 8681757 TI - [The diagnosis, clinical significance and therapy of patent foramen ovale]. PMID- 8681758 TI - [The provisos for substitutes in formulaic elective performance agreements. The problems due to the new Schedule of Charges for Physicians]. PMID- 8681759 TI - [Heterotopic gastric mucosa in the esophagus]. PMID- 8681760 TI - [Chest pains after drinking coffee]. PMID- 8681761 TI - [Are biopsies of the esophagus and stomach to be recommended during the endoscopic diagnosis of reflux esophagitis?]. PMID- 8681762 TI - [Selection of live donors for segmental liver transplantation in children]. AB - OBJECTIVE: To analyse selection criteria and complications in living related donors of liver segments with a view to introducing standardised guidelines for the selection of such donors. PATIENTS AND METHODS: Forty-two mothers and 31 fathers (median age 31 [19-50] years) were tested between October 1991 and July 1994 for their suitability as donors of a liver segment. RESULTS: 24 of the potential donors (33%) were found not to be suitable. Reasons for this were: poor immunological match of the donor liver as transplant (13), risk factors for thromboembolism (5), and psychological or socioeconomic factors (6). 35 live related donor liver segment transplantations were performed, 34 of the left lateral liver segment, and one of the left liver lobe. The average duration of the operation was 4.5 (3.0-6.0) hours. No foreign blood transfusions were needed. There was one death from pulmonary emboli, and various complications: cerebral seizure (1), gallbladder leak (1), incisional hernia (2) and duodenal ulcer (2). CONCLUSION: Risk of thromboembolism as well as psychological and social factors are the most important exclusion criteria in the selection of donors for live liver segment transplantation. PMID- 8681763 TI - [Pneumatosis cystoides intestinalis]. AB - HISTORY AND CLINICAL FINDINGS: A 56-year-old man was admitted to hospital for investigation of meteorism and severe flatulence for 10 months and irregular stools. He had no previous illness. On examination his abdomen was quite distended, with very active but low-pitched peristalsis. INVESTIGATION: Plain x ray of the abdomen showed multiple round translucencies along the wall of the left hemicolon. Coloscopy revealed multiple firm-walled cysts in the descending and sigmoid colon which contained H2 in high concentration. Histologically there was slight inflammatory infiltration of the submucosa as well as some slit-like hollow spaces, pointing to the diagnosis of pneumatosis cystoides intestinalis. The H2 breath test, done to confirm the diagnosis, indicated increased H2 concentration, both on fasting and after lactulose. TREATMENT AND COURSE: A diet low in flatulence-producing carbohydrates satisfactorily controlled the symptoms, but the local findings remained unchanged over 4 years. CONCLUSION: Pneumatosis cystoides intestinalis should be included in the differential diagnosis of meteorism and flatulence. Diet can satisfactorily control the symptoms of this rare disease. PMID- 8681764 TI - [Bronchiolitis obliterans with organizing pneumonia: differential diagnosis of pneumonia refractory to antibiotics]. AB - HISTORY AND FINDINGS: A previously healthy 58-year-old woman was admitted with rapidly worsening dyspnoea, dry cough and subfebrile temperature. Chest radiogram showed spotty infiltrations, especially in the bases of both lungs. She was dyspnoic with mild tachypnoea (24/min) and mild cyanosis of the lips. Fine, non resonant rales were heard over the middle and lower lobes bilaterally. INVESTIGATIONS: Erythrocyte sedimentation rate was markedly raised (97/110 mm), arterial oxygen partial pressure slightly decreased (45 mm Hg), CO2 partial pressure was 32 mm Hg. Bronchoalveolar lavage was unremarkable. TREATMENT AND COURSE: Because of the respiratory impairment broad antibiotic treatment was at once commenced empirically with gentamycin, cefotaxim, erythromycin, rifampicin and fluconazole. As the response was poor, a transbronchial lung biopsy was performed. This merely showed nonspecific lymphoplasmacellular bronchitis. An open biopsy then revealed bronchiolitis obliterans with organizing pneumonia (BOOP). Treatment with initially 75 mg prednisone daily quickly brought about improvement and the patient was entirely well after 6 months. CONCLUSION: The described constellation of history and clinical as well as radiological findings should strongly suggest BOOP. With adequate treatment the prognosis is excellent. PMID- 8681765 TI - [Use of positron-emission tomography in oncology]. PMID- 8681766 TI - [Diagnosis in portal hypertension]. PMID- 8681767 TI - [Changes in the functional scope of a chief physician]. PMID- 8681768 TI - [Persistent candidiasis due to swimming pool water?]. PMID- 8681769 TI - [Development of pneumococcal meningitis while receiving piperacillin therapy]. PMID- 8681770 TI - [Predictive value of carcinoembryonic antigens]. PMID- 8681771 TI - [Wheezing in the first 3 years of life--what becomes of it?]. PMID- 8681772 TI - [Secondary prevention of diabetic retinopathy in type I diabetes mellitus. Dependence on retinopathy status before the intervention]. AB - OBJECTIVE: To assess prospectively the effect of improving the metabolic state on the course of diabetic retinopathy in relation to the extent of retinal changes before intervention. PATIENTS AND METHODS: 140 patients with type I (insulin dependent) diabetes mellitus (IDDM) (55 men, 85 women; mean age 30 +/- 11 years; mean duration of illness 11 +/- 8 years), underwent intensified insulin treatment and were then followed for 4 years. At the beginning of the trial fundoscopy was unremarkable in 68 patients (stage 0), a few microaneurysms and (or) punctate bleeding (stage 1) in 21, nonproliferative retinopathy (stage 2) in 27, preproliferative retinopathy (stage 3) in six, proliferative retinopathy (stage 4) in 14, and proliferative retinopathy with complications (stage 5) in four. The average retinopathy stage was 1.2 +/- 1.0, mean HbA1c value 7.0 +/- 1.3%). RESULTS: The retinopathy remained unchanged in 94 patients (group A), it improved in 16 (group B), and deteriorated in 30 (group C). There was no significant change in mean HbA1c value in any of the groups (A: 6.2 +/- 0.9%; B: 6.4 +/- 1.0%; C: 6.3 +/- 6.0%). There were also no differences with respect to blood glucose, M-value according to Schlichtkrull, frequency of hypoglycaemia, serum lipids, blood pressure and renal biopsy parameters. However, significant differences (P < 0.001 C vs. A and B) were found in relation to duration of diabetes (A: 9.3 +/- 7.2 years; B: 8.8 +/- 8.6 years; C: 16.9 +/- 7.8 years) and mean retinopathy stage at beginning of the study (A: 0.8 +/- 0.8; B: 1.2 +/- 0.7; C: 2.4 +/- 1.6). CONCLUSION: Decisive for the course of retinopathy in patients with IDDM of long duration and secondarily optimised metabolic state is the duration of illness and especially the degree of fundal changes when intensified insulin treatment is undertaken. PMID- 8681773 TI - [Recurrent arterial thromboembolism in hereditary hypoplasminogenaemia]. AB - HISTORY: A 26-year-old man sustained a wasp bite 5 years ago which caused arterial embolism to the right brachial artery. Now he again had a wasp bite with allergic reaction and an arterial embolus to the left brachial artery. 2 days later, after embolectomy and heparinisation, he had a cerebrovascular accident due to an embolus to the left internal carotid artery. 15 days later, despite oral anticoagulation (Quick value 10%), he had an embolism to the left femoral artery. INVESTIGATIONS: The source of the emboli was found by echocardiography to be a spherical floating thrombus on the aortic valve. The plasminogen level was only 45-61%. His mother and sister also had a low plasminogen level, i.e. he had congenital plasminogen deficiency. TREATMENT AND COURSE: At surgery, when the thrombus had been removed, a slit-like defect was found on one of the aortic leaflets and covered with a pericardial patch. At first heparin then phenprocoumon were administered, plus 250 mg ticlopidine twice daily. There have been no further complications. CONCLUSION: As the patient's fibrinolysis activity was normal, additional, probably allergic, factors must have been present to disturb the equilibrium between thrombogenesis and fibrinolysis thus causing thrombosis at a predisposed site. PMID- 8681774 TI - [Asymptomatic choledochal cyst]. AB - HISTORY AND FINDINGS: A 45-year-old woman sustained an ankle fracture in an accident. At examination she was found to have marked pallor of skin and mucosae. There was no hint for melaena or haematemesis. INVESTIGATIONS: Biochemical tests showed marked iron deficiency anaemia (haemoglobin 7.5 g/dl) and raised serum bilirubin and C-reactive protein levels (1.94 mg/dl and 85.2 mg/l, respectively). Abdominal sonography revealed a cystic space-occupying mass (8 x 4.5 cm) projecting onto the gallbladder, interpreted as a choledochal cyst of unknown origins without bleeding. After treatment of the ankle fracture an endoscopic retrograde cholangiopancreatography was performed. This showed a large cyst of the choledochal duct into which the cystic and choledochal ducts entered, without evidence of tumour or haematoma. There was also a 1 cm prepapillary common choledochal and Wirsung duct. TREATMENT AND COURSE: With these findings, the diagnosis of a congenital choledochal cyst (type Ia of Todani) could be made. After healing of the ankle fracture the cyst was removed and a Roux Y-anastomosis created. The cystic tissue was benign. At follow-up 6 months later the patient was symptom-free and no longer anaemic. CONCLUSIONS: Congenital choledochal cysts are very rare in Europeans. The symptom-free course with anaemia and no manifestation until adulthood is also very unusual. PMID- 8681775 TI - [Therapy of chronic pancreatitis]. PMID- 8681777 TI - [Competitor clause in practice takeover contracts. Opinion of the Higher Regional Court Koblenz, 5-25-1994]. PMID- 8681776 TI - [Wilson's disease]. PMID- 8681778 TI - [Autoimmune neutropenia]. PMID- 8681779 TI - [Recanalization of chronically stenosed infarct vessels in one-vessel coronary disease]. PMID- 8681780 TI - Maturation promoting factor in ascidian oocytes is regulated by different intracellular signals at meiosis I and II. AB - Using the fluorescent dye Calcium Green-dextran, we measured intracellular Ca2+ in oocytes of the ascidian Ciona intestinalis at fertilization and during progression through meiosis. The relative fluorescence intensity increased shortly after insemination in a single transient, the activation peak, and this was followed by several smaller oscillations that lasted for approximately 5 minutes (phase 1). The first polar body was extruded after the completion of the phase 1 transients, about 9 minutes after insemination, and then the intracellular calcium level remained at baseline for a period of 5 minutes (phase 2). At 14 minutes postinsemination a second series of oscillations was initiated that lasted 11 minutes (phase 3) and terminated at the time of second polar body extrusion. Phases 1 and 3 were inhibited by preloading oocytes with 5 mM heparin. Simultaneous measurements of membrane currents, in the whole-cell clamp configuration, showed that the 1-2 nA inward fertilization current correlated temporally with the activation peak, while a series of smaller oscillations of 0.1-0.3 nA amplitude were generated at the time of the phase 3 oscillations. Biochemical characterization of Maturation Promoting Factor (MPF) in ascidian oocytes led to the identification of a Cdc2-like kinase activity. Using p13suc1 sepharose as a reagent to precipitate the MPF complex, a 67 kDa (67 x 10(3) Mr) protein was identified as cyclin B. Histone H1 kinase activity was high at metaphase I and decreased within 5 minutes of insemination reaching a minimum level during phase 2, corresponding to telophase I. During phase 3, H1 kinase activity increased and then decayed again during telophase II. Oocytes preloaded with BAPTA and subsequently inseminated did not generate any calcium transients, nonetheless H1 kinase activity decreased 5 minutes after insemination, as in the controls, and remained low for at least 30 minutes. Injection of BAPTA during phase 2 suppressed the phase 3 calcium transients, and inhibited both the increase in H1 kinase activity normally encountered at metaphase II and second polar body extrusion. PMID- 8681781 TI - Posterior end mark, a novel maternal gene encoding a localized factor in the ascidian embryo. AB - Ascidian embryogenesis is regarded as a typical 'mosaic' type. Recent studies have provided convincing evidence that components of the posterior-vegetal cytoplasm of fertilized eggs are responsible for establishment of the anteroposterior axis of the embryo. We report here isolation and characterization of a novel maternal gene, posterior end mark (pem). After fertilization, the pem transcript is concentrated in the posterior-vegetal cytoplasm of the egg and later marks the posterior end of developing ascidian embryos. Despite its conspicuous localization pattern, the predicted PEM protein shows no significant homology to known proteins. Overexpression of this gene by microinjection of synthesized pem mRNA into fertilized eggs results in development of tadpole larvae with deficiency of the anteriormost adhesive organ, dorsal brain and sensory pigment-cells. Lineage tracing analysis revealed that the anterior epidermis and dorsal neuronal cells were translocated posteriorly into the tail region, suggesting that this gene plays a role in establishment of anterior and dorsal patterning of the embryo. The ascidian tadpole is regarded as a prototype of vertebrates, implying a similar function of pem in vertebrate embryogenesis. PMID- 8681782 TI - Nonradial migration of interneurons can be experimentally altered in spinal cord slice cultures. AB - During development, many migrating neurons are thought to guide on radially oriented glia to reach their adult locations. However, members of the 'U-shaped' group of cholinergic interneurons in embryonic rat spinal cord appeared to migrate in a direction perpendicular to the orientation of radial glia. This 'U shaped' group of cells was located around the ventral ventricular zone on embryonic day 16 and, during the next two days, the constituent cells dispersed into the dorsal horn or around the central canal. During this period, these cells could be identified with either ChAT immunocytochemistry or NADPH-diaphorase histochemistry and they appeared to be aligned along commissural axons, suggesting that such processes, rather than radial glia, might guide their migration. An organotypic spinal cord slice preparation was developed and utilized for three different experimental approaches to studying this migration. In the first experiments, slices of embryonic day 16 cervical spinal cord were cultured for one, two or three days, and a relatively histotypic dorsal migration of 'U-derived' cells could be inferred from these sequential cultures. A second set of experiments focused on the direct observation of dorsally directed migration in living spinal cord cultures. Embryonic day 16 slices were injected with a lipophilic fluorescent label near the dorsal boundary of the 'U-shaped' cell group and the dorsal movement of labeled cells was observed using confocal microscopy. These experiments confirmed the dorsal migratory pattern inferred from sequentially fixed specimens. A third experimental approach was to transect embryonic day 16 slice cultures microsurgically in order to disturb the migration of 'U-derived' cells. Depending upon the amount of ventral spinal cord removed, the source of cells was excised and/or their guidance pathway was perturbed. The number and position of 'U-derived' cells varied with the amount of ventral cord excised. If more than 400 microns was removed, no 'U-derived' diaphorase-labeled cells were present, whereas if only 200-300 microns was removed, the cultures contained such cells. However, in this instance, many of the 'U-derived' neurons did not move as far dorsally, nor did they display their characteristic dorsoventral orientation. When results from these three experiments are taken together, they provide strong evidence that nonradial neuronal migration occurs in developing spinal cord and that the 'U-derived' neurons utilize such a migration to move from their ventral generation sites to their dorsal adult locations. PMID- 8681783 TI - Basic fibroblast growth factor induces notochord formation and the expression of As-T, a Brachyury homolog, during ascidian embryogenesis. AB - The tadpole larva of an ascidian develops 40 notochord cells in the center of its tail. Most of the notochord cells originate from the A-line precursors, among which inductive interactions are required for the subsequent differentiation of notochord. The presumptive-endoderm blastomeres or presumptive-notochord blastomeres themselves are inducers of notochord formation. Notochord induction takes place during the 32-cell stage. In amphibia, mesoderm induction is thought to be mediated by several growth factors, for example, activins and basic fibroblast growth factor (bFGF). In the ascidian, Halocynthia roretzi, treatment with bFGF of presumptive-notochord blastomeres that had been isolated at the early 32-cell stage promoted the formation of notochord at a low concentration of bFGF (0.02 ng/ml), while activin failed to induce notochord differentiation. The effect of bFGF reached a maximum at the end of the 32-cell stage and rapidly faded at the beginning of the subsequent cleavage, the time for full induction of notochord being at least 20 minutes. The expression of As-T, a previously isolated ascidian homolog of the mouse Brachyury (T) gene, starts at the 64-cell stage and is detectable exclusively in the presumptive-notochord blastomeres. The present study showed that presumptive-notochord blastomeres, isolated at the early 32-cell stage, neither differentiated into notochord nor expressed the As-T gene. However, when the presumptive-notochord blastomeres were coisolated or recombined with inducer blastomeres, transcripts of As-T were detected. When presumptive-notochord blastomeres were treated with bFGF, the expression of the As-T gene was also detected. These results suggest that inductive interaction is required for the expression of the As-T gene and that the expression of the As-T gene is closely correlated with the determined state of the notochord-precursor cells. PMID- 8681784 TI - Modulation of Xenopus embryo mesoderm-specific gene expression and dorsoanterior patterning by receptors that activate the phosphatidylinositol cycle signal transduction pathway. AB - A role for the phosphatidylinositol (PI) cycle signal transduction pathway in Xenopus mesoderm induction has been revealed by observations of PI cycle activation coincident with this process, combined with the demonstration that Li+ (a PI cycle inhibitor) blocks this response and hyperdorsalizes mesoderm induction in intact embryos or augments growth factor-mediated induction in animal caps. It has been suggested that spatially restricted PI cycle activity in the marginal zone might modulate (but not, itself, activate) mesoderm induction. To better characterize the ability of PI cycle activity to modulate the pattern of mesoderm-specific gene expression elicited by mesoderm-inducing growth factors we have expressed in the embryo exogenous 5-hydroxytryptamine receptors that activate the PI cycle. In embryos, ventral expression and activation of these receptors during mesoderm induction are without obvious effect, whereas dorsal expression and activation yield dorsoanterior-deficient tadpoles. In animal caps induced with activin, simultaneous activation of exogenous 5-hydroxytryptamine receptors inhibits both convergent extension movements associated with dorsal mesoderm induction and the expression of goosecoid, a dorsal-specific gene, but is without effect on expression of a 149 generic mesodermal marker, Xbra. All of these effects of a 149 PI cycle-stimulating receptor are the opposites of those previously reported for the PI cycle inhibitor, Li+. PI cycle activity thus proves able to modulate the dorsal/ventral character of early mesodermal gene expression elicited by growth factor, suggesting a model for mesodermal patterning. PMID- 8681785 TI - Time-dependent responses to glp-1-mediated inductions in early C. elegans embryos. AB - In an embryo of the nematode Caenorhabditis elegans, two blastomeres at the 4 cell stage, ABa and ABp, are born with equivalent developmental potential. Subsequently, interactions with the P2 blastomere at the 4-cell stage and the MS blastomere at the 12-cell stage generate differences in developmental fate among descendants of ABa and ABp. We have reproduced these inductions in vitro using embryonic blastomeres isolated in cell-culture medium. We show that during these inductions only the responding AB descendants require the activity of the glp-1 gene, which is similar in sequence to Drosophila Notch, supporting models in which GLP-1 protein acts as a receptor for both the P2 and MS signals. We also show that P2 signaling requires the activity of the apx-1 gene, similar in sequence to Drosophila Delta, and that MS signaling requires the putative transcription factor SKN-1. We present evidence that the primary factor determining the different responses to these two signals is the age of the AB descendants, not the identity of the signaling cell or ligand. Therefore, we suggest that time-dependent changes in factors within AB descendants are responsible for their different responses to inductive signals that use a common receptor. PMID- 8681786 TI - How is embryo size genetically regulated in rice? AB - It is unclear how embryo size is genetically regulated in plants. Since cereals have a large persisting endosperm, it is expected that embryo size is affected by endosperm development. Nine single recessive mutations, four reduced embryo mutations representing three loci, REDUCED EMBRYO1, REDUCED EMBRYO2 and REDUCED EMBRYO3, four giant embryo mutations derived from a single locus GIANT EMBRYO, and one endospermless mutation endospermless1-2 were analyzed. Every reduced embryo mutation caused reduction of all the embryonic organs including apical meristems and the enlargement of the endosperm. The giant embryo mutants have a reduced endosperm and an enlarged scutellum. However, shoot and radicle sizes were not affected. All the reduced embryo and giant embryo mutations did not largely affect postembryonic development. Accordingly, the expression of genes analyzed are seed-specific. In reduced embryo and giant embryo mutations, abnormalities were detected in both embryo and endosperm as early as 2 days after pollination. endospermless1-1 resulted in an early loss of endosperm, yielding a giant embryo, suggesting that embryo growth was physically limited by the endosperm. A double mutant between giant embryo-2 and club-shaped embryo1-1, which has a normal endosperm and a minute undifferentiated embryo, resulted in a club-shaped embryo1-1 embryo and a reduced endosperm of giant embryo-2, indicating that GIANT EMBRYO regulates the endosperm development. Double mutants between giant embryo-2 and three reduced embryo mutants exhibited the reduced embryo phenotype in both embryo and endosperm, suggesting that reduced embryo mutations cause the enlarged endosperm. Further, a double mutant of reduced embryo3 and endospermless1-1 showed the enlarged embryo in endospermless seed. This confirms that reduced embryo3 does not regulate embryo size but enlarges endosperm size. Together with the results of the other double mutant analysis, REDUCED EMBRYO1, REDUCED EMBRYO2, REDUCED EMBRYO3 and GIANT EMBRYO are concluded to regulate endosperm development. PMID- 8681787 TI - Oligodendrocyte progenitors are generated throughout the embryonic mouse brain, but differentiate in restricted foci. AB - Recent evidence from studies mapping the expression of putative oligodendrocyte progenitor specific mRNAs has suggested that oligodendrocyte progenitors arise during embryogenesis, in specific foci of the neuroectoderm. In order to test this hypothesis, we have assayed different regions of the embryonic central nervous system for their ability to generate oligodendrocytes following transplantation into neonatal cerebrum. To allow identification of donor-derived oligodendrocytes in wild-type host brain, we used the MbetaP transgenic mouse, which expresses lacZ in oligodendrocytes, as donor tissue. We found that tissue fragments derived from several levels of the anterior-posterior axis of the neural tube at E14.5 and E12.5, chosen to include (hindbrain, cervical and lumbar spinal cord), or exclude (dorsal telencephalon) putative foci of oligodendrocyte progenitors, all produced oligodendrocytes following transplantation. In addition, these same regions taken from E10.5, prior to the appearance of putative oligodendrocyte progenitor markers, also all yielded oligodendrocytes on transplantation. This indicates that precursor cells that can generate oligodendrocytes are widespread throughout the neuroectoderm as early as E10.5. We have also used the oligodendrocyte lineage-specific glycolipid antibodies O4, R-mAb and O1 to identify those regions of the developing brain that first support the differentiation of oligodendrocytes from their progenitor cells. We found that the first oligodendrocytes arise in prenatal brain at E14.5, in a restricted zone adjacent to the midline of the medulla. These cells are mitotically inactive, differentiated oligodendrocytes and, using light and electron microscopy, we show that they become functional, myelin-bearing oligodendrocytes. We have mapped the subsequent appearance of differentiated oligodendrocytes in the prenatal brain and show that they appear in a restricted, tract-specific manner. Our results suggest that oligodendrocytes are generated from neuroectodermal cells positioned throughout the rostrocaudal axis of the neural tube, rather than at restricted locations of the neuroectoderm. By contrast, the differentiation of such cells into oligodendrocytes does occur in a restricted manner, consistent with local regulation of oligodendrocyte progenitor differentiation. PMID- 8681788 TI - Expression domains of a zebrafish homologue of the Drosophila pair-rule gene hairy correspond to primordia of alternating somites. AB - her1 is a zebrafish cDNA encoding a bHLH protein with all features characteristic of members of the Drosophila HAIRY-E(SPL) family. During late gastrulation stages, her1 is expressed in the epibolic margin and in two distinct transverse bands of hypoblastic cells behind the epibolic front. After completion of epiboly, this pattern persists essentially unchanged through postgastrulation stages; the marginal domain is incorporated in the tail bud and, depending on the time point, either two or three paired bands of expressing cells are present within the paraxial presomitic mesoderm separated by regions devoid of transcripts. Labelling of cells within the her1 expression domains with fluorescein-dextran shows that the cells in the epibolic margin and the tail bud are not allocated to particular somites. However, allocation of cells to somites occurs between the marginal expression domain and the first expression band, anterior to it. Moreover, the her1 bands, and the intervening non-expressing zones, each represents the primordium of a somite. This expression pattern is highly reminiscent of that of Drosophila pair-rule genes. A possible participation of her1 in functions related to somite formation is discussed. PMID- 8681789 TI - Involvement of bone morphogenetic protein-4 and bone morphogenetic protein-7 in the differentiation of the adrenergic phenotype in developing sympathetic neurons. AB - The neurotransmitter phenotype of sympathetic neurons is specified by interactions with the surrounding embryonic tissues. Adrenergic differentiation is elicited early during development in the vicinity of notochord and dorsal aorta and the importance of axial midline tissues for adrenergic differentiation has been well documented. We now provide evidence that bone morphogenetic proteins, BMP-4 and BMP-7 are signals produced by the dorsal aorta that direct sympathetic neuron differentiation. BMP-4 and BMP-7 are expressed in the dorsal aorta at critical times during sympathetic neuron differentiation and have the ability to enhance the formation of adrenergic sympathetic neurons both in cultures of neural crest cells and when ectopically expressed in the developing embryo. PMID- 8681790 TI - A novel regulatory mutation in the C. elegans sex determination gene tra-2 defines a candidate ligand/receptor interaction site. AB - Sex determination in the nematode C. elegans is dependent on cell-to-cell communication, which appears to be mediated by the predicted membrane protein TRA 2A and the secreted protein HER-1. In XO males, HER-1 is hypothesised to function as a repressive ligand that inactivates the TRA-2A receptor. In XX animals, HER-1 is absent and TRA-2A promotes hermaphrodite development by negatively regulating the FEM proteins. This paper describes the molecular and genetic characterisation of a novel class of feminising mutations called tra-2(eg), for enhanced gain-of function. In XX animals, mutant tra-2(eg) activity promotes entirely normal hermaphrodite development. However, the tra-2(eg) mutations generate an XO specific gain-of-function phenotype, because they transform XO mutants from male into hermaphrodite. Therefore, the tra-2(eg) mutations identify a major regulatory site, which may be the TRA-2A/HER-1 interaction site. All ten tra 2(eg) mutations encode identical missense changes in a predicted extracellular domain of TRA-2A, named the EG site. It is proposed that the tra-2(eg) mutation encodes a TRA-2A protein that functions constitutively in XO animals, because it is defective in HER-1 binding. Phenotypic characterisation of sexually transformed XO tra-2(eg) hermaphrodites reveals that their fertility is strongly affected by dosage compensation mutations, suggesting that dosage compensation plays a role in normal gametogenesis. PMID- 8681791 TI - Mothers against dpp encodes a conserved cytoplasmic protein required in DPP/TGF beta responsive cells. AB - The proteins necessary for signal transduction in cells responding to ligands of the TGF-beta family are largely unknown. We have previously identified Mad (Mothers against dpp), a gene that interacts with the TGF-beta family member encoded by decapentaplegic (dpp) in Drosophila. Assay of Mad's role in the DPP dependent events of embryonic midgut development demonstrates that Mad is required for any response of the visceral mesoderm or endoderm to DPP signals from the visceral mesoderm. Replacement of the normal DPP promoter with a heterologous (hsp70) promoter fails to restore DPP-dependent responses in Mad mutant midguts. Experiments utilizing Mad transgenes regulated by tissue-specific promoters show that MAD is required specifically in cells responding to DPP. Immunohistochemical studies localize MAD to the cytoplasm in all tissues examined. Experiments in Xenopus embryos demonstrate that Drosophila MAD can function in the signaling pathway of BMP-4, a vertebrate homolog of dpp. Based on these results, we propose that Mad is a highly conserved and essential element of the DPP signal transduction pathway. PMID- 8681792 TI - Profilin is required for posterior patterning of the Drosophila oocyte. AB - We have investigated the role of the actin cytoskeleton during mid-oogenesis and have found that disrupting the actin cytoskeleton with cytochalasin D induces microtubule bundling and microtubule-based cytoplasmic streaming within the oocyte, similar to that which occurs prematurely in cappuccino and spire mutant oocytes. After examining a number of mutants that affect the actin cytoskeleton, we have found that chickadee, which encodes the actin-binding protein, profilin, shares this phenotype. In addition to the microtubule misregulation, mutants in chickadee resemble cappuccino in that they fail to localize STAUFEN and oskar mRNA to the posterior pole of the developing oocyte. Also, a strong allele of cappuccino has multinucleate nurse cells, similar to those previously described in chickadee. In an independent line of experiments, we have identified profilin as a CAPPUCCINO interactor in a two-hybrid screen for proteins that bind to CAPPUCCINO. This, together with the similarity of mutant phenotypes, suggests that profilin and CAPPUCCINO may interact during development. PMID- 8681793 TI - NF-kappaB activity in transgenic mice: developmental regulation and tissue specificity. AB - The transcription factor family NF-kappaB/Rel is responsible for the regulation of a large number of cellular genes and some viruses. Since there is a strong similarity between the NF-kappaB/Rel family members and the Drosophila melanogaster protein DORSAL, which is activated early during embryogenesis, we were interested in determining the pattern of NF-kappaB activity during mouse development. Two lacZ reporter constructs, each driven by promoter elements that are dependent on the presence of nuclear NF-kappaB/Rel activity, were used to produce transgenic mice. The analysis of these mice did not identify nuclear NF kappaB/Rel activity in early development prior to implantation or during the gastrulation processes. Earliest expression of the lacZ transgene was detected on day E12.5. Before birth lacZ expression was seen in discrete regions of the rhombencephalon of the developing brain, in the spinal medulla, in some of the blood vessels and in the thymus. After birth, the NF-kappaB/Rel activity in the thymus remained but nuclear activity was also found in the bone marrow, in the spleen and in the capsule of the lymph nodes. In the central nervous system, drastic changes in NF-kappaB/Rel activity could be observed in the first 3 weeks after birth, when the cortex and the cerebellum reach functional and morphological maturity. Considering the results of the p50, p65, relB and c-rel knock-out mice and our present findings, we believe that the NF-kappaB/Rel proteins known so far are probably not implicated in processes of early development and differentiation of the different tissues, but rather in maintaining their function once matured. PMID- 8681794 TI - Symmetry breakage in the development of one-armed gonads in nematodes. AB - Whereas the hermaphrodite gonad of Caenorhabditis elegans has two symmetric arms (didelphy), the female/hermaphrodite gonad of many nematode species features a single anterior arm (monodelphy). We examined how gonadal cell lineages and intercellular signalling evolve to generate these diverse structures. In C. elegans, the two arms develop symmetrically from two somatic precursor cells, Z1 (anterior) and Z4 (posterior). Each first gives rise to one distal tip cell (which promotes arm growth and germ line proliferation), two ovary precursors and three uterine precursors in the center of the developing gonad. In monodelphic species, Z1 and Z4 have different fates. The first visible asymmetry between them is in the relative timing of their divisions, followed by asymmetric cell movements. The putative posterior distal tip cell is then eliminated in all but one species by programmed cell death. In some species the posterior ovary precursors form a small vestigial posterior arm, the post-vulval sac; in other species, they stay undivided, or die. In Cephalobus sp. PS1197, the specific fate of Z4 progeny is induced by Z1 (or its daughters). In the uterus in C. elegans, symmetric lateral signalling between Z1.ppp and Z4.aaa renders them equally likely to become the anchor cell, which links the uterus to the vulva. In the different monodelphic species, anchor cell specification is biased, or fully fixed, to a descendant of either Z1 or Z4. Replacement regulation upon anchor cell ablation is conserved in some species, but lost in others, leading to a mosaic-type development. Differentiation between Z1 and Z4 is thus manifested at this later stage in the breakage of symmetry of cell interactions in the ventral uterus. PMID- 8681795 TI - Persistence of rhombomeric organisation in the postsegmental hindbrain. AB - Rhombomeres are morphological varicosities of the neural tube that are present between embryonic day (E) 1.5 and E5 and are characterised by compartment organisation, segmentally neuronal organisation and spatially restricted patterns of gene expression. After E5, the segmented origins of the hindbrain become indistinct, while the adult hindbrain has an longitudinal columnar nuclear organisation. In order to assess the impact of the early transverse pattern on later longitudinal organisation, we have used orthotopic quail grafts and in situ hybridisation to investigate the long-term fate of rhombomeres in the embryonic chick hindbrain. The uniformity of mixing between quail and chick cells was first verified using short-term aggregation cultures. The dispersal of the progeny of individual rhombomeres (r) was then assessed by the unilateral, isochronic and orthotopic transplantation of either r2, r3, r4, r5 or r6 from quail to chick at embryonic day E2. In addition, orthotopic, partial rhombomere grafts, encompassing an inter-rhombomere boundary and adjacent rhombomere bodies were used to assess cell mixing within rhombomeres. Operated embryos were incubated to either E7 or E10 when chimaeric brains were removed. Quail cells were identified in whole mounts or serial sections using the quail-specific antibody QCPN. Subsequently, radial glia morphology was assessed either by immunohistochemistry or DiI labelling. A series of fixed hindbrains between E6 and E9 were probed for transcripts of Hoxa-2 and Hoxb-1. Fate-mapping reveals that the progeny of individual rhombomeres form stripes of cells running dorsoventrally through the hindbrain. This pattern of dispersal precisely parallels the array of radial glia. Although the postmitotic progeny of adjacent rhombomeres spread to some extent into each others' territory in intermediate and marginal zones, there is little or no mixing between rhombomeres in the ventricular zone, which thus remains compartmentalised long after the rhombomeric morphology disappears. Segmental gene expression within this layer is also maintained after E5. A more detailed analysis of mixing between proliferating cells, using partial rhombomere grafts, reveals that both mixing and growth are non-uniform within the ventricular layer, suggesting, in particular, that longitudinal expansion within this layer is restricted. Together, these observations suggest that rhombomeres do not disappear at E5, as has previously been supposed, rather they persist in the ventricular zone to at least E9, ensuring a continuity in the presumed segmental cues that specify neuroepithelial cells in the hindbrain. PMID- 8681796 TI - Mad acts downstream of Dpp receptors, revealing a differential requirement for dpp signaling in initiation and propagation of morphogenesis in the Drosophila eye. AB - Decapentaplegic (Dpp), a member of the TGF-beta family of cytokines, has been implicated in many patterning processes in Drosophila, including the initial steps of pattern formation in the developing eye. We show that the Mothers against dpp (Mad) gene is required for dpp signaling during eye development. Clonal analysis demonstrates a cell-autonomous function for Mad and genetic interactions indicate that Mad is an essential component of the signal transduction pathway downstream of the Dpp receptors in responding cells. Mad mediated dpp signaling is absolutely required for the initiation of the morphogenetic furrow in the eye, but has only a minor role in its subsequent propagation across the eye disc. We also present evidence for the repression of wingless transcription by dpp signaling. PMID- 8681797 TI - Expression of the met receptor tyrosine kinase in muscle progenitor cells in somites and limbs is absent in Splotch mice. AB - Hepatocyte growth factor/scatter factor (HGF/SF) stimulates proliferation, dissociation, migration and morphogenesis of cells in culture. To investigate a possible role for HGF/SF and its receptor, the Met tyrosine kinase, in embryonic development, we have analyzed their expression in mouse embryos from day 7.5 of gestation by whole-mount in situ hybridization. Met expression is first detected in the ventral portion of somites at day 9.25 of gestation (22 somite embryo) at the level of fore limb buds. As somites mature, met expression is detected in caudal somites, and is confined to the lateral and media] tips of the dermomyotome and dermomyotome/myotome respectively. In contrast, HGF/SF is expressed exclusively in the mesodermal core of the limb bud. As the dermomyotome elongates ventrolaterally, the met-expressing cells at the lateral tip appear to detach from the somite, invade the limb bud and localize at the dorsal and ventral limb sides in close proximity to HGF/SF-expressing cells. At later stages, both met- and HGF/SF-expressing cells appear to migrate distally and localize to the digit forming area of the developing hand plate. Met expression in the lateral dermomyotome and limb bud coincides with expression of Pax-3, a marker for migrating muscle precursor cells in the somite and limb. Splotch-2H and Splotch-delayed mice, which harbor mutations in Pax-3, show major disruptions in early limb muscle development. Significantly, no met-expressing cells were observed in the limbs of homozygous Splotch-2H and Splotch-delayed animals, whereas HGF/SF expression was not affected. The restricted expression of met to a sub-population of Pax-3-expressing cells in the lateral tip of the dermomyotome, demonstrates that met represents a unique molecular marker for this migratory cell population. From these observations, together with the biological activities of HGF/SF, we propose that in homozygous Splotch embryos the failure of muscle precursors to migrate into and populate the limb bud results from a loss of met expression in the cells at the ventrolateral edge of the somitic dermomyotome. PMID- 8681798 TI - Retinal dysplasia and degeneration in RARbeta2/RARgamma2 compound mutant mice. AB - The eye is the organ whose development is the most frequently altered in response to maternal vitamin A deficiency [VAD; Warkany, J. and Schraffenberger, S. (1946). Archs Ophthalmol. 35, 150-169]. With the exception of prenatal retinal dysplasia, all the ocular abnormalities of the fetal VAD syndrome are recapitulated in mouse mutants lacking either RARalpha and RARbeta2, RARalpha and RARgamma, RARgamma and RARbeta2, or RXRalpha [Lohnes, D., Mark, M., Mendelsohn, C., Dolle, P., Dierich, A., Gorry, P., Gansmuller, A. and Chambon, P. (1994) Development 120, 2723-2748; Mendelsohn, C., Lohnes, D., Decimo, D., Lufkin, T., LeMeur, M., Chambon, P. and Mark, M. (1994) Development 120, 2749-2771; Kastner, P., Grondona, J. Mark, M., Gansmuller, A., LeMeur, M., Decimo, D., Vonesch, J.L., Dolle, P. and Chambon, P. (1994) Cell 78, 987-1003], thus demonstrating that retinoic acid (RA) is the active vitamin A metabolite during prenatal eye morphogenesis. Whether retinoids are also involved in postnatal eye development could not be investigated, as VAD newborns are not viable and the above RAR double null mutants and RXRalpha null mutants died in utero or at birth. We report here the generation of viable RARbeta2/RARgamma2 double null mutant mice, which exhibit several eye defects. The neural retina of newborn RARbeta2gamma2 mutants is thinner than normal due to a reduced rate of cell proliferation, and from day 4 shows multiple foci of disorganization of its layers. These RARbeta2gamma2 mutants represent the first genetically characterized model of retinal dysplasia and their phenotype demonstrates that RARs, and therefore RA, are required for retinal histogenesis. The RARbeta2gamma2 retinal pigment epithelium (RPE) cells display histological and/or ultrastructural alterations and/or fail to express cellular retinol binding protein I (CRBPI). Taken altogether, the early onset of the RPE histological defects and their striking colocalisation with areas of the neural retina displaying a faulty laminar organization, a reduced neuroblastic proliferation, and a lack of photoreceptor differentiation and/or increased apoptosis, make the RPE a likely target tissue of the RARbeta2gamma2 double null mutation. A degeneration of the adult neural retina, which may similarly be secondary to a defective RPE, is also observed in these mutants, thus demonstrating an essential role of RA in the survival of retinal cells. Moreover, all RARbeta2gamma2 mutants display defects in structures derived from the periocular mesenchyme including local agenesis of the choroid and of the sclera, small eyelids, and a persistence of the primary mesenchymal vitreous body. A majority of the RARbeta2 single null mutants also exhibit this latter defect, thus demonstrating that the RARbeta2 isoform plays a unique role in the formation of the definitive vitreous body. PMID- 8681800 TI - A direct measurement of increased divalent cation influx in fertilised mouse oocytes. AB - On fertilisation of mouse oocytes, the fusing spermatozoon triggers a series of repetitive calcium (Ca2+) spikes. The Ca2+ spikes seem to be necessary for successful progression through the cell cycle and are regulated in a cell-cycle dependent manner. The spikes appear to require the linkage of continuous Ca2+ influx to the periodic release of Ca2+ from intracellular stores by a process of Ca(2+)-induced Ca2+ release. The precise role of Ca2+ influx was explored using the manganese (Mn2+)-quench technique to monitor unidirectional cation influx into single mouse oocytes. There was a marked stimulation of cation influx associated closely with the upsweep of the first and subsequent fertilisation Ca2+ spikes. A smaller but significant increase in the rate of cation influx persisted in the interspike period in fertilised oocytes. Spike-associated entry was not as apparent in oocytes stimulated to spike repetitively by thimerosal or acetylcholine application. Instead, there was a continuous increase in cation influx underlying Ca2+ spiking which commenced with the onset of the first spike. Using the specific microsomal inhibitor thapsigargin and the Ca2+ ionophore ionomycin, we found evidence for a capacitative entry mechanism in mouse oocytes. We propose that the persistent influx of Ca2+ observed in response to all stimuli examined is controlled by a capacitative mechanism and sets the frequency of spiking by determining the time taken to refill the internal stores to a point where they are again sensitive enough to initiate the next spike. PMID- 8681799 TI - E(z): a polycomb group gene or a trithorax group gene? AB - The products of the Polycomb group of genes are cooperatively involved in repressing expression of homeotic selector genes outside of their appropriate anterior/posterior boundaries. Loss of maternal and/or zygotic function of Polycomb group genes results in the ectopic expression of both Antennapedia Complex and Bithorax Complex genes. The products of the trithorax group of genes are cooperatively involved in maintaining active expression of homeotic selector genes within their appropriate anterior/posterior boundaries. Loss of maternal and/or zygotic function of trithorax group genes results in reduced expression of both Antennapedia Complex and Bithorax Complex genes. Although Enhancer of zeste has been classified as a member of the Polycomb group, in this paper we show that Enhancer of zeste can also be classified as a member of the trithorax group. The requirement for Enhancer of zeste activity as either a trithorax group or Polycomb group gene depends on the homeotic selector gene locus as well as on spatial and temporal cues. PMID- 8681801 TI - The vegetal determinants required for the Spemann organizer move equatorially during the first cell cycle. AB - Embryos with no dorsal axis were obtained when more than 15% of the egg surface was deleted from the vegetal pole of the early 1-cell embryo of Xenopus laevis. The timing of the deletion in the first cell cycle was critical: dorsal-deficient embryos were obtained when the deletion began before time 0.5 (50% of the first cell cycle) whereas normal dorsal axis usually formed when the deletion was done later than time 0.8. The axis deficiency could be restored by lithium treatment and the injection of vegetal but not animal cytoplasm. Bisection of the embryo at the 2-cell stage, which is known to restore the dorsal structures in the UV ventralized embryos, had no effect on the vegetal-deleted embryos. These results show clearly that, in Xenopus, (1) the dorsal determinants (DDs) localized in the vegetal pole region at the onset of development are necessary for dorsal axis development and (2) the DDs move from the vegetal pole to a subequatorial region where they are incorporated into gastrulating cells to form the future organizing center. A model for the early axis formation process in Xenopus is proposed. PMID- 8681802 TI - Dual function of the region-specific homeotic gene spalt during Drosophila tracheal system development. AB - We report that the region-specific homeotic gene spalt affects the Drosophila tracheal system at two different stages of embryonic development. Both lack-of function and gain-of-function experiments show that blastodermal spalt activity restricts tracheal development to 10 bilaterally positioned pairs of tracheal placodes in the trunk region by repressing placode formation in parasegments 2, 3 and 14. The results suggest that the activity of the zinc-finger type transcription factor encoded by spalt suppresses the molecular pathway that establishes tracheal development. spalt function is also necessary for the directed migration of the dorsal trunk cells, a distinct subset of tracheal cells. This process is a prerequisite for the formation of the dorsal trunk generated by fusion of adjacent tracheal metameres into a common tubular structure. The directed cell migration, in which spalt gene function participates, seems to be independent of branch fusion and general tracheal cell migration processes. PMID- 8681803 TI - Specification of cell fates at the dorsal margin of the zebrafish gastrula. AB - Using fate mapping techniques, we have analyzed development of cells of the dorsal marginal region in wild-type and mutant zebrafish. We define a domain in the early gastrula that is located just at the margin and centered on the dorsal midline, in which most cells generate clones that develop exclusively as notochord. The borders of the notochord domain are sharp at the level of single cells, and coincide almost exactly with the border of the expression domain of the homeobox gene floating head (flh; zebrafish homologue of Xnot), a gene essential for notochord development. In flh mutants, cells in the notochord domain generate clones of muscle cells. In contrast, notochord domain cells form mesenchyme in embryos mutant for no tail (ntl; zebrafish homologue of Brachyury). A minority of cells in the notochord domain in wild-type embryos develop as unrestricted mesoderm, invariably located in the tail, suggesting that early gastrula expression of flh does not restrict cellular potential to the notochord fate. The unrestricted tail mesodermal fate is also expressed by the forerunner cells, a cluster of cells located outside the blastoderm, adjacent to the notochord domain. We show that cells can leave the dorsal blastoderm to join the forerunners, suggesting that relocation between fate map domains might respecify notochord domain cells to the tail mesodermal fate. An intermediate fate of the forerunners is to form the epithelial lining of Kupffer's vesicle, a transient structure of the teleost tailbud. The forerunners appear to generate the entire structure of Kupffer's vesicle, which also develops in most flh mutants. Although forerunner cells are present in ntl mutants, Kupffer's vesicle never appears, which is correlated with the later severe disruption of tail development. PMID- 8681804 TI - PTP-NP, a new member of the receptor protein tyrosine phosphatase family, implicated in development of nervous system and pancreatic endocrine cells. AB - The regulation of protein tyrosine phosphorylation is an important mechanism for developmental control. We describe here a new member of the protein tyrosine phosphatase (PTP) family, called PTP-NP (for neural and pancreatic). The cDNA sequence indicates a receptor-type transmembrane molecule. At early organogenesis, in situ hybridization with a probe for the PTP-NP extracellular region detects expression confined to the region of the developing pancreas, an organ of medical importance, but poorly understood with regard to molecular mechanisms of developmental control. This localized expression appears early, even before morphological differentiation of the pancreas, and is found in presumptive precursors of the endocrine cells by the earliest times that they can be distinguished. In neural development, an alternate RNA with a different or missing extracellular region is expressed transiently at early stages of neurogenesis and the full-length PTP-NP RNA appears later. To search for a ligand of PTP-NP, a fusion protein probe was made with the extracellular domain fused to an alkaline phosphatase tag. This probe bound strongly to pancreatic islets, providing evidence for a ligand-receptor interaction that could be involved in endocrine cell regulation. The results show PTP-NP is an especially early marker for pancreatic development and suggest it may be a receptor that could control the development of pancreatic endocrine cells. PMID- 8681805 TI - Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene. AB - The int-3 oncogene was identified as a frequent target in Mouse Mammary Tumor Virus (MMTV)-induced mammary carcinomas and encodes the intracellular domain of a novel mouse Notch gene. To investigate the role of the int-3 proto-oncogene in mouse development and carcinogenesis, we isolated cDNA clones corresponding to the entire coding potential of the int-3 proto-oncogene. We propose to name this gene Notch4 and reserve the int-3 nomenclature for references to the oncogenic form. The deduced amino acid sequence of Notch4 contains conserved motifs found in Notch proteins; however Notch4 has fewer epidermal growth factor (EGF)-like repeats and a shorter intracellular domain than other mouse Notch homologues. Comparison of the coding potential of the int-3 gene to that of Notch4 suggests that loss of the extracellular domain of Notch4 leads to constitutive activation of this murine Notch protein. In situ hybridization revealed that Notch4 transcripts are primarily restricted to endothelial cells in embryonic and adult life. Truncated Notch4 transcripts were detected in post-meiotic male germ cells. The distinct Notch4 protein features and its restricted expression pattern suggests a specific role for Notch4 during development of vertebrate endothelium. PMID- 8681806 TI - Dpp receptors are autonomously required for cell proliferation in the entire developing Drosophila wing. AB - The mammalian growth factor TGFbeta negatively regulates cell proliferation in various systems. Here we provide evidence that another TGFbeta superfamily member, Drosophila Decapentaplegic (Dpp), stimulates cell proliferation. In the developing wing blade, somatic clones lacking the Dpp receptors Punt or Thick veins (Tkv), or lacking Schnurri, a transcription factor involved in Dpp signal interpretation, fail to grow when induced early in larval development. Furthermore the spatial requirement for these signaling components indicates that Dpp has to travel several cell diameters from its source in order to reach all cells that require its signal. The requirement for Tkv also depends on the distance of cells from the source of the Dpp signal. We propose that Dpp can act at a distance to positively control cell proliferation. PMID- 8681807 TI - Developmentally regulated gene expression of thrombomodulin in postimplantation mouse embryos. AB - Embryonic lethality of thrombomodulin-deficient mice has indicated an essential role for this regulator of blood coagulation in murine development. Here, the embryonic expression pattern of thrombomodulin was defined by surveying beta galactosidase activity in a mouse strain in which the reporter gene was placed under the regulatory control of the endogenous thrombomodulin promoter via homologous recombination in embryonic stem cells. The murine trophoblast was identified as a previously unrecognized anatomical site where TM expression is conserved between humans and mice and may exert a critical function during postimplantation development. Targeted reporter gene expression in mesodermal precursors of the endothelial cell lineage defined thrombomodulin as an early marker of vascular differentiation. Analysis of the thrombomodulin promoter in differentiating ES cells and in transgenic mice provided evidence for a disparate and cell type-specific gene regulatory control mechanism in the parietal yolk sac. The thrombomodulin promoter as defined in this study will allow the targeting of gene expression to the parietal yolk sac of transgenic mice and the initiation of investigations into the role of parietal endoderm in placental function. PMID- 8681808 TI - The tumor suppressor gene, lethal(2)giant larvae (1(2)g1), is required for cell shape change of epithelial cells during Drosophila development. AB - Inactivation of the lethal(2)giant larvae (l(2)gl) gene results in malignant transformation of imaginal disc cells and neuroblasts of the larval brain in Drosophila. Subcellular localization of the l(2)gl gene product, P127, and its biochemical characterization have indicated that it participates in the formation of the cytoskeletal network. In this paper, genetic and phenotypic analyses of a temperature-sensitive mutation (l(2)glts3) that behaves as a hypomorphic allele at restrictive temperature are presented. In experimentally overaged larvae obtained by using mutants in the production of ecdysone, the l(2)glts3 mutation displays a tumorous potential. This temperature-sensitive allele of the l(2)gl gene has been used to describe the primary function of the gene before tumor progression. A reduced contribution of both maternal and zygotic activities in l(2)glts3 homozygous mutant embryos blocks embryogenesis at the end of germ-band retraction. The mutant embryos are consequently affected in dorsal closure and head involution and show a hypertrophy of the midgut. These phenotypes are accompanied by an arrest of the cell shape changes normally occurring in lateral epidermis and in epithelial midgut cells. l(2)gl activity is also necessary for larval fife and the critical period falls within the third instar larval stage. Finally, l(2)gl activity is required during oogenesis and mutations in the gene disorganize egg chambers and cause abnormalities in the shape of follicle cells, which are eventually internalized within the egg chamber. These results together with the tumoral phenotype of epithelial imaginal disc cells strongly suggest that the l(2)gl product is required in vivo in different types of epithelial cells to control their shape during development. PMID- 8681810 TI - Redundant control of Ultrabithorax by zeste involves functional levels of zeste protein binding at the Ultrabithorax promoter. AB - Many biological processes appear to be controlled by functionally redundant genes or pathways, but it has proven difficult to understand the nature of this redundancy. Here, we have analyzed a redundant regulatory interaction between the Drosophila transcription factor zeste and the homeotic gene Ultrabithorax. Mutations in zeste do not affect the cis-regulation of the endogenous Ultrabithorax gene; however, the expression of small Ultrabithorax promoter constructs is strongly dependent upon zeste. We show that this difference is due to redundant cis-regulatory elements in the Ultrabithorax gene, which presumably contain binding sites for factors that share the function of zeste. We also provide evidence suggesting that zeste and the gene encoding the GAGA factor have an overlapping function in regulating Ultrabithorax. Furthermore, we show that the zeste protein is bound at equal levels in vivo to a Ultrabithorax promoter construct, which zeste strongly activates, and to the identical promoter region in the endogenous Ultrabithorax gene, which zeste redundantly regulates. These results suggest that zeste is significantly active in the wild-type animal and not simply a factor that is induced as a back-up when other activators fail. PMID- 8681809 TI - Sensitivity of proneural genes to lateral inhibition affects the pattern of primary neurons in Xenopus embryos. AB - We have compared the roles of XASH-3 and NeuroD, two basic helix-loop-helix transcription factors, in the formation of primary neurons in early Xenopus embryos. When ectopically expressed in Xenopus embryos, XASH-3 and NeuroD induce ectopic primary neurons in very different spatial patterns. We show that the pattern of primary neurons induced by XASH-3 and NeuroD can be accounted for by a difference in their sensitivity to inhibitory interactions mediated by the neurogenic genes, X-Delta-1 and X-Notch-1. Both NeuroD and XASH-3 promote the expression of the inhibitory ligand, X-Delta-1. However, XASH-3 appears to be sensitive to the inhibitory effects of X-Delta-1 while NeuroD is much less so. Consequently only a subset of cells that ectopically express XASH-3 eventually form neurons, giving a scattered pattern, while the ectopic expression of NeuroD leads to a relatively dense pattern of ectopic neurons. We propose that differences in the sensitivity of XASH-3 and NeuroD to lateral inhibition play an important role during their respective roles in neuronal determination and differentiation. PMID- 8681811 TI - Variation in the number of activated torso receptors correlates with differential gene expression. AB - Activation of receptor tyrosine kinases triggers many developmental decisions, yet we do not understand how activation of a single receptor can be transduced into different cell responses. The torso pathway in Drosophila provides a model to address this issue since it generates more than one response in the embryo. The torso receptor tyrosine kinase is activated at the embryonic poles under the control of trunk, a protein with similarities to several types of extracellular growth factors. Activation of torso is responsible for the development of a variety of structures, whose appearance can be correlated with activation of at least two different genes along the terminal region. In this study we have analyzed mutations in torso and trunk that express low levels of the respective proteins. We show that different amounts of torso or trunk molecules correlate with the expression of different zygotic genes, implicating changes in the number of activated torso molecules as one of the mechanisms defining differential gene expression. We suggest that variation in the number of activated receptors at the cell surface is a general mechanism that leads to differential gene expression and thus the generation of different cell responses. PMID- 8681812 TI - [Are antibiotics necessary for a child with the flu?]. PMID- 8681813 TI - [Interferon-beta in the treatment of multiple sclerosis]. PMID- 8681814 TI - [When a patient wants to die]. PMID- 8681815 TI - [Tissue banks]. PMID- 8681816 TI - [The prosody of speech and wordless messages]. PMID- 8681817 TI - [Percutaneous canalization of the gallbladder in the treatment of cholecystitis and common bile duct obstruction]. PMID- 8681818 TI - [Triploidy--a cause of fetal growth retardation and less than normal amniotic fluid]. PMID- 8681819 TI - [Superficial siderosis of the central nervous system]. PMID- 8681820 TI - [Pulmonary edema after upper airway obstruction]. PMID- 8681821 TI - [Treatment of non-insulin dependent diabetes with an insulin infusion system]. PMID- 8681822 TI - [Pheochromocytoma, pulmonary nodule and hypercalcemia]. PMID- 8681823 TI - [What is required of a person performing ultrasound diagnosis?]. PMID- 8681824 TI - [Puerperal fever or wound infection?]. PMID- 8681825 TI - [What can we learn about mega-trials of drugs?]. PMID- 8681826 TI - [Psychiatric drug treatment and drug plasma levels]. PMID- 8681827 TI - [New medication for herpesvirus infections]. PMID- 8681828 TI - [Oral antifungal drugs]. PMID- 8681829 TI - [Treatment of commonly occurring skin infections]. PMID- 8681830 TI - [The treatment of atrial fibrillation]. PMID- 8681831 TI - [Treatment of unstable angina pectoris]. PMID- 8681832 TI - [Glucocorticoid treatment]. PMID- 8681833 TI - [Use of hematopoietic growth factors]. PMID- 8681834 TI - [Beta-2 adrenergic receptor agonists in asthma treatment]. PMID- 8681835 TI - [Current anti-epilepsy drugs]. PMID- 8681836 TI - [What is used as a drug for problem drinking?]. PMID- 8681837 TI - [Drugs for impotence]. PMID- 8681838 TI - [Calcium sensitizers]. PMID- 8681839 TI - [Antibodies as medication]. PMID- 8681840 TI - [Computer-designed site-specific drugs--myth or reality?]. PMID- 8681841 TI - [Upsetting experience results in diagnostic problem]. PMID- 8681842 TI - [Does outpatient general anesthesia fulfill all expectations?]. PMID- 8681843 TI - [How does HIV-1 and other retroviruses affect the nervous system?]. PMID- 8681845 TI - [Unilateral pulmonary edema in an infant]. PMID- 8681844 TI - [Prevalence of cervical adenocarcinoma in Finland]. PMID- 8681846 TI - [Cronkhite-Canada syndrome: a new disease in Finland]. PMID- 8681847 TI - [Rapidly progressive paresis and hypokalemia]. PMID- 8681848 TI - [Vigabatrin in the treatment of infantile spasms]. PMID- 8681850 TI - [Acute bilateral shoulder dislocation in an elderly patient]. PMID- 8681849 TI - [Pseudohypertension--a rare or common problem in the treatment of hypertension]. PMID- 8681851 TI - [Pre-hospital care for patients with multiple injuries]. PMID- 8681853 TI - [Methods in inguinal hernia repair]. PMID- 8681852 TI - [Post-traumatic stress disorder]. PMID- 8681854 TI - [Prevention and treatment of anaphylaxis caused by insect stings]. PMID- 8681855 TI - [Epidural anesthesia in the treatment of painful diabetic neuropathy]. PMID- 8681856 TI - [Elite or cheat research units?]. PMID- 8681857 TI - Normal variability of the amplitude and phase of steady-state VEPs. AB - The present study quantifies the amplitude and phase variability of steady-state VEPs (S-VEPs) and compares this variability between subjects and between individual runs. The S-VEPs were recorded repeatedly in 14 normal subjects with varying spatial and temporal frequencies of sinusoidal gratings; 6 spatial frequencies (range 0.5-8.0 c/deg) with 3 temporal frequencies (4, 6 and 8 Hz) were used. A total of 75 responses were averaged and analyzed by the Fourier method. Four recordings were obtained in each spatio-temporal combination. In general, the phase data showed small inter- and intrasubject variability. As anticipated, the amplitude data showed a large degree of intersubject variability, although the intrasubject variability was very small. In addition, in some stimulus conditions the inter- and intrasubject variability increased, which thus suggested the existence of an optimal spatio-temporal combination. Therefore, these stimulus parameters should be taken into consideration when S VEPs are applied in clinical practice. PMID- 8681858 TI - The effect of binocular stimulation on each component of transient and steady state VEPs. AB - We recorded the monocular and binocular VEPs to the alternation of sinusoidal gratings in order to evaluate the binocular interaction in each component of transient and steady-state VEPs in 13 normal subjects. Three spatial frequencies (1.3, 2.6 and 5.3 c/deg) with a 90% contrast were used as visual stimuli. The latencies and amplitudes of N70 and P100 of the transient VEPs were measured. The steady-state VEPs were Fourier analyzed, and both the phase and amplitude of the second (2F) and fourth (4F) harmonic responses were obtained. Binocular interaction was influenced by spatial frequency such that a binocular summation or even an inhibition occurred. For the transient VEPs, a binocular summation was more pronounced in the amplitude of N70 than in that of P100 at all spatial frequencies. There were no significant effects of binocular stimulation on latencies of N70 or P100. However, the latencies of N70 and P100 showed different spatial frequency characteristics. For the steady-state VEPs, the amplitude of 2F revealed a binocular summation that was more pronounced at 5.3 c/deg, whereas the 4F amplitude showed binocular inhibition at 2.6 and 5.3 c/deg. The 2F phase showed binocular inhibition at all spatial frequencies, whereas no such inhibition was observed in the 4F phase. These results suggest that individual components of transient and steady-state VEPs are physiologically distinct and may therefore be generated from different neuronal populations in striate cortex. PMID- 8681859 TI - Brain-stem somatosensory dysfunction in a case of long-standing left hemispherectomy with removal of the left thalamus: a nasopharyngeal and scalp SEP study. AB - We have studied median nerve somatosensory evoked potentials (SEPs) in a patient who had undergone early surgical removal of the left cerebral hemisphere and left thalamus. Stimulation of the right side evoked normal latency P9, P11 and P13 potentials at scalp as well as at nasopharyngeal (NP) leads, while P14 and N18 potentials were absent. These SEP abnormalities, that have been described previously in cervico-medullary lesions and in comatose patients with upper brain stem involvement, suggest that in our patient the removal of the left thalamus has caused retrograde degeneration of the cuneate-thalamic projections. Moreover, this study confirms that P13 and P14 potentials have different generators. PMID- 8681860 TI - Somatic evoked high-frequency magnetic oscillations reflect activity of inhibitory interneurons in the human somatosensory cortex. AB - High-frequency potential oscillations in the range of 300-900 Hz have recently been shown to concur with the primary response (N20) of the somatosensory cortex in awake humans. However, the physiological mechanisms of the high-frequency oscillations remained undetermined. We addressed the issue by analyzing magnetic fields during wakefulness and sleep over the left hemisphere to right median nerve stimulation with a wide bandpass (0.1-2000 Hz) recording with subsequent high-pass (> 300 Hz) and low-pass (< 300 Hz) filtering. With wide bandpass recordings, high-frequency magnetic oscillations with the main signal energy at 580-780 Hz were superimposed on the N20m during wakefulness. Isofield mapping at each peak of the high-pass filtered and isolated high-frequency oscillations showed a dipolar pattern and the estimated source for these peaks was the primary somatosensory cortex (area 3b) very close to that for the N20m peak. During sleep, the high-frequency oscillations showed dramatic diminution in amplitude while the N20m amplitude exhibited a moderate increment. This reciprocal relation between the high-frequency oscillations and the N20m during a wake-sleep cycle suggests that they represent different generator substrates. We speculate that the high-frequency oscillations represent a localized activity of the GABAergic inhibitory interneurons of layer 4, which have been shown in animal experiments to respond monosynaptically to thalamo-cortical input with a high-frequency (600 900 Hz) burst of short duration spikes. On the other hand, the underlying N20m represents activity of pyramidal neurons which receive monosynaptic excitatory input from the thalamus as well as a feed-forward inhibition from the interneurons. PMID- 8681861 TI - Estimating reliability of evoked potential measures from residual scores: an example using tibial SSEPs. AB - A normative study of tibial SSEPs was performed in 74 healthy subjects, and the effects of the variables sex, age and height on SSEP parameters were assessed. In a subgroup of 20 subjects a test-retest study was also performed, which allowed us to estimate the reliability of the different parameters by means of the intraclass correlation coefficient. We demonstrated that the intraclass correlation coefficient may be biased by predictable effects of subject-related variables (such as age, height and sex), if it is computed from raw original values. This bias can be eliminated by estimating reliability indices on residual scores calculated as the differences between observed values and those predicted by subject's age, height and sex. PMID- 8681862 TI - Effect of stimulus rate on the cortical posterior tibial nerve SEPs: a topographic study. AB - We performed topographical mapping of somatosensory evoked potentials (SEPs) in response to posterior tibial nerve stimulation delivered at 2, 5 and 7.5 Hz in 15 healthy subjects. P37 was significantly attenuated at 5 and 7.5 Hz and the N50 component attenuated only at 5 Hz, its amplitude remaining stable for further increases in stimulus frequency. Frontal N37 and P50 potentials showed no significant decrease when the stimulus repetition frequency was changed from 2 to 7.5 Hz. P60 showed an attenuation of the amplitude only at 7.5 Hz. Latency and scalp topographies of all cortical components examined remained unchanged for the 3 stimulus rates tested. The optimal stimulus rate for mapping of tibial nerve SEPs was lower than 5 Hz. The distinct recovery function of the contralateral. N37-P50 and ipsilateral P37-N50 responses suggests that these potentials arise from separate generators. PMID- 8681863 TI - Temporal integration in auditory sensory memory: neuromagnetic evidence. AB - The cortical mechanisms of auditory sensory memory were investigated by analysis of neuromagnetic evoked responses. The major deflection of the auditory evoked field (N100m) appears to comprise an early posterior component (N100mP) and a late anterior component (N100mA) which is sensitive to temporal factors. When pairs of identical sounds are presented at intervals less that about 250 msec, the second sound evokes N100mA with enhanced amplitude at a latency of about 150 msec. We suggest that N100mA may index the activity of two distinct processes in auditory sensory memory. Its recovery cycle may reflect the activity of a memory trace which, according to previous studies, can retain processed information about an auditory sequence for about 10 sec. The enhancement effect may reflect the activity of a temporal integration process, whose time constant is such that sensation persists for 200-300 msec after stimulus offset, and so serves as a short memory store. Sound sequences falling within this window of integration seem to be coded holistically as unitary events. PMID- 8681864 TI - Topography and sources of electromagnetic cerebral responses to electrical and air-puff stimulation of the hand. AB - SEPs and SEFs after air-puff stimulation of index and little fingers have been studied and compared to the responses following electrical stimulation of the same digits and of the median nerve at the wrist in 5 subjects. The differences in morphology of the evoked signals are described and the generator characteristics are analysed for SEFs by means of a moving dipole model inside a homogeneous sphere. In our measurements the magnetic fields following electrical finger stimulation show a 30 msec component, which was absent following air-puff stimulation. This could not be seen in the electric field activity. The generators of the first component of SEFs after air-puff finger stimulation proved to be deeper (8 mm on average across all subjects and for both fingers) than in the case of electrically evoked SEFs. A similar behaviour was also observed for the second component of SEFs for the 2 stimulus modalities. PMID- 8681865 TI - Laser-evoked potentials: exogenous and endogenous components. AB - The aim of this study was to distinguish the exogenous component (related to the physical properties of the stimulus) and the endogenous component (reflecting event-related cognitive processing) of the laser-evoked potential (LEP). Short painful radiant heat pulses generated by a CO2-laser were applied to the dorsum of the right and left foot. LEPs were recorded with 5 scalp electrodes in the midline versus linked earlobes in 26 healthy subjects. In order to identify the exogenous component, the LEP was recorded during a standardised distraction task (reading a short story). To identify the endogenous component P3 for the LEP, a 2 stimulus oddball paradigm was used (20% probability of targets). When the task of the oddball paradigm consisted of pressing a button, a movement-related long latency negativity (N 1200) was recorded in frontal leads that was absent in a counting task. The LEP of targets, frequent non-targets and during distraction was dominated by a single large positivity. The amplitude of this positivity was task-dependent and increased the more attention the subject payed to the laser stimuli (distraction < neutral < non-target < target). The laser-evoked positivity during distraction had a peak latency of about 400 msec (P400) and a maximum amplitude at the vertex, which was independent of inter-stimulus interval. The P3 following laser stimulation had a significantly later peak at about 570 msec (P570) and a different scalp topography with a parietal maximum. Its amplitude decreased when the interstimulus interval was reduced from 10 to 6 sec. Under neutral instructions, the LEP positivity consisted of a superposition of both the exogenous P 400 and the endogenous P570. PMID- 8681866 TI - Topography of auditory evoked cortical potentials in children with severe language impairment: the N1 component. AB - Topographic maps of late auditory evoked potentials (AEPs) were obtained in a group of 20 children, aged 9-15 years, with severe language impairment (LI) and an age-matched control (C) group of 20 normal children. The study was focused on differences in the latency, amplitude and topography of the N1 component between the two groups and the potential diagnostic value of these variables. The stimulus was a pure tone at 500 Hz with a duration of 100 msec and a rise and fall time of 20 msec. The intensity was 75 dB HL. Six test sequences of 50 stimuli at an interval of 1.0 sec were presented to the left and right ear separately. The AEPs were recorded and analyzed with the Bio-Logic Brain Atlas III program. In the topographic maps a focus corresponding to N1 (FN1) was seen in 15 subjects after left-ear stimulation and in 17 subjects after right-ear stimulation in the LI group. In the C group FN1 was identified in all 20 subjects after left-ear stimulation and in 19 subjects after right-ear stimulation. The position of FN1 was in front of the interaural line and with a dominance on the side contralateral to the ear stimulated in both groups. Among the subjects with an FN1, 6 in the LI group and 4 in the C group had deviating topography. Non focal maps were seen in 5 LI subjects and 1 C subject. The latencies of N1 were longer in the LI group and there was no decrease in latency with age. There were no differences in FN1 amplitudes between groups. The prolonged latencies in the LI subjects compared to the C subjects may be explained by a slower processing in central auditory pathways and the lack of decrease in latencies with age in the LI subjects might indicate that the disturbance persists and is not a pure delay of maturation. The diagnostic sensitivity of N1 latency, amplitude and topography, in selecting the LI subjects, was 40% with a specificity of 90%. Statistical mapping of a time epoch of 70-140 msec and corresponding to FN1 in the map showed regions of > or = 3 S.D. in 10 LI and 2 C subjects, which corresponds to a sensitivity of 50% and a specificity of 90%. The variability of results within the LI group may reflect different pathophysiological factors underlying the language impairment. In conclusion, topographic evaluation of auditory long-latency potentials may become a diagnostic tool in speech and language disorders. PMID- 8681868 TI - Suppression of F-VEP during isoflurane-induced EEG suppression. AB - We recorded visual evoked potentials (VEPs) to flash stimuli in moderately deep anaesthesia when EEG showed burst suppression pattern. Flash VEPs could consistently be recorded in all 8 test subjects during bursts but not during suppressions. We conclude that during isoflurane-induced EEG suppression VEPs to flash stimuli are also suppressed. This effect should be taken into account in evoked potential testing during anaesthesia. PMID- 8681867 TI - Strength-duration curve of conductive spinal cord evoked potentials in cats. AB - Strength-duration curves of the ascending and descending conductive spinal cord potentials (SCEPs) in cats were obtained using constant current stimuli. For the formulation of numeric indices of excitability, the rheobase is defined as the minimal current strength below which response cannot occur even if the current continues, and the chronaxie is defined as the minimal duration of a current required to evoke the potential at twice the rheobase strength. The chronaxies and rheobases were calculated from the constructed strength-duration curves. The purpose of this study is to produce strength-duration curves and to evaluate the utility of chronaxies and rheobases for SCEPs. This study showed the following results: (1) there was a hyperbolic relationship between stimulus strength and stimulus duration at threshold values, similar to that seen in peripheral nerves; (2) the ascending and descending tracts of SCEP were mediated through the same pathway (based on the similar chronaxies and rheobases); (3) following spinal cord compression the chronaxie and rheobase increased significantly (P < 0.05), which is similar to peripheral nerve disturbance. However, the rheobase decreased significantly following slight spinal cord compression (P < 0.05) and systemic cooling (P < 0.01), and the strength-duration curve shifted showing a tendency towards decrease of the galvanic threshold, therefore, amplitude augmentation with slight compression and with decrease in temperature seems to contribute to the reduction of the threshold. The strength-duration curve, the chronaxie and the rheobase may be useful in assessing spinal cord function. PMID- 8681869 TI - Inter-hospital comparison of Ganzfeld ERG photostimulators. AB - The periodic calibration and control of electroretinographic (ERG) stimulators is often neglected due to the difficulties in accurate measurements of the stimuli. Comparison of measurements carried out in different laboratories has been very difficult, as the accurate parameters of the stimuli used usually are not known. In some cases it is assumed that if the stimulator type is known, comparisons can be carried out. We have tested the Ganzfeld flash stimulators used in the departments of clinical neurophysiology of 3 major hospitals in Finland, namely Kuopio University Hospital, Turku Central University Hospital, and Tampere University Hospital, Measurements, performed with a new type of photometer, show that the intensities varied by 42% between the highest and lowest intensity stimulators at nominally identical settings. The measurements underline the findings that identical stimulators will not necessarily produce identical stimuli. These observations also indicate that the stability of the stimuli can be improved by the proper choice of stimulator output settings. PMID- 8681870 TI - [Abuse of psychotropic drugs during driving]. AB - The responsibility of psychotropic drugs as a cause of road traffic accidents remains difficult to evaluate with precision. Different studies performed in many countries provide a certain precision in relation to percentage of injured drivers whose blood contained psychotropic substances (8 to 10% according to studies). On the other hand, it is practically impossible to really know either these products were or were not the cause of the accidents because underlying or associated pathologies can equally create problems such as lack of attention and other vigilance deficits. There is also a possibility of suicidal or aggressive tendencies. A certain number of circadian and other chronobiological parameters also complicate the problem since the schedule (hour) as well as the day of the week or even the season can considerably modify vigilance and reaction time. Available medications able to create such problems are numerous and their mechanisms of action varied. They can influence vision, impulsiveness and vigilance. They can act either by direct mechanisms of sedation or, on the contrary, by raising inhibition through secondary mechanisms: delay in drug elimination or provoked insomnia. For the most part, incriminated medications belong to the different classes of sedative medicines: benzodiazepines, antiepileptics, some antihistaminic agents, some antidepressants, some thymo regulators and some anti-hypertensives. Also included are desinhibitors or stimulant classes: amphetamines and related drugs, caffeine and codeine. Some of them can be used for their psychodysleptic properties: codeine and anticholinergic drugs. Finally, drug and medicinal associations can have unforeseen effects: for example, anticholinergics + alcohol + valpromide, etc. If it appears methodologically impossible that research could ever precisely quantify the share of responsibility of psychotropic drugs in causing road traffic accidents, this relation remains highly probable. It is therefore necessary that in the course of university and post-academic training, potential prescribers might regularly be advised of these risks. Lastly, public needs to be constantly informed. PMID- 8681871 TI - [Depression and smoking]. AB - Lifetime history of major depressive disorder is more than double in ever smokers than in never smokers. Conversely, adjusted odds ratios of nicotine dependence are significantly elevated for major depressive disorder alone (3,11) or associated with an anxiety disorder (4,38). There is also a significant relationship between depressive symptoms' severity (CES-D) and ever smoking. A history of major depressive disorder is associated with a lower chance to quit smoking. One of the reasons is that smokers who try to quit smoking experience more withdrawal symptoms--including a depressive mood--and relapse more frequently if they have a history of major depressive disorder. Few trials experimenting the usefulness of antidepressants in smoking cessation were published. Only a limited trial concerning doxepin showed a significant action on withdrawal symptoms and abstinence rate at 4 weeks. Other trials with fluoxetine and moclobemide failed to show clearly a significant effect on abstinence rate, perhaps because the medication was initiated too soon before quit day. The nature of the association between smoking and depression has been explored in recent studies, which used a cohort follow-up or the evaluation of a female twin population. The conclusions were that there is probably no causal relationship but rather that the association arises largely from common familial factors that are probably genetic, at least in women. Concurrently, tobacco smoke has monoamine oxidase inhibitory properties, and smokers have lower monoamine oxidase activity than no smokers. Hence, it is possible that smoking has antidepressant properties. While smoking prevalence regularly decreases, one can assume that the relative risk of depressive disorder will increase in smokers. PMID- 8681873 TI - [External validity, reliability and basic score determination of the Toronto Alexithymia Scales (TAS and TAS-20) in a group of alcoholic patients]. AB - The criterion validity of the Toronto Alexithymia Scales (TAS and TAS-20) was assessed by administering the scales to 47 alcoholic inpatients. The 47 subjects were inpatients meeting the Research Diagnostic Criteria for alcoholism. The subjects were assessed by two raters using the Beth Israel Questionnaire in the first week following their hospitalization. They filled out the TAS and one week later the TAS-20. Among the 47 alcoholics, 31 were alexithymic and 16 were non alexithymic. The TAS and the TAS-20 scores of the alexithymics were significantly higher than that of the non alexithymics. The mean (sd) of the TAS in the alexithymics and the non alexithymics were respectively (m = 76.13, sd = 9.56; m = 64.2, sd = 13.88; t = 3.38, df = 45, p = 0.0015). The mean (sd) of the TAS-20 in the alexithymics and the non alexithymics were respectively (m = 54.1, sd = 8.81; m = 43.18, sd = 11.5; t = 3.62, df = 45, p = 0.0007). The one-week test retest was r = 0.17, p < 0.001. On the basis of these findings, TAS and TAS-20 cutoff scores were suggested. A range of potential cutoff scores around the mean TAS or TAS-20 score were tested using four methods to assess the goodness of a diagnostic test (sensitivity, specificity, Younden's coefficient, positive predictive value). The best scores that maximizes the diagnostic validity of the TAS and TAS-20 in identifying alexithymic subjects were respectively 73 and 56. On the basis of the mean TAS and TAS-20 score for the non alexithymic group and the means that we have obtained with normal groups, scores of 64 and 44 were respectively selected as the cutoff level for the identification of non alexithymic subjects. PMID- 8681872 TI - [The patient record form in psychiatry: nomenclature of the types of management]. AB - The patient form (PF) is a data carrier in mental health, established by the French General Department of Health to improve the annual report of each psychiatric sector, the assessment of the care given and the patients involved. We suppose that despite of national efforts to standardize the use of the PF, in practice are noticed: 1) different operative senses given to the codes of care; 2) a hierarchical system of treatments and a counting far from being unequivocal. This study undertaken in Centre Hospitalier Specialise de Maison Blanche investigates and compares: 1) the different operative senses given to the codes of care; 2) the use of these codes to transcribe and to count psychiatric treatments. These goals were fulfilled by a strictly anonymous questionnaire survey that ensures an analysis of the replies individually, in relation to occupational groups and to psychiatric sectors. In particular, all the psychiatrists, the nurse supervisors and the medical secretaries who worked in the hospital for at least 9 months, including 6 months at least in their current sector at the time of the survey, in the previous calendar year were concerned. Altogether that comes to 207 subjects. The administrative staff and the employees of the Medical Information Department were not involved. Upon 207 questionnaires, 58 replies were sent back i.e. a general reply rate of 28.02 +/- 6.12%. The secretaries took a more active part in the survey: 43.06 +/- 11.44% (31/72) significantly higher than the general rate (p = 0.03). The results show that regardless of the occupational groups neither the coding of treatments nor their counting are carried out the same way in different sectors respectively 70.69 +/- 11.71% and 77.59 +/- 10.73%. The operative senses of some codes like CO, AT, AP, AJ vary a lot. Sometimes the multiplicity of treatments coming under a code lead to these changes. At other times local initiatives explain the divergences. When senses are unequivocal, the hierarchical system of treatments is rather a problem. So, in case of several treatments the same day, the study makes obvious: 1) a giving up of the hierarchical system and as a result, the one of the incompatibility between some codes; 2) the coding and the count of as many as possible services the same day. The outpatient care is the 3rd of the three kinds of treatment according to the hierarchical system. It is the one for which codings and counts vary the most. It is essentially without hotel element. On the other hand accommodation twenty-four hours a day characterizes the full-time (inpatient) care. The part-time care, between both previous is a patchwork where predominates sometimes a mode of accommodation and sometimes a place for care. It is less accurate than the full-time care. The PF serves many purposes among which some are irreconcilable. It certainly allows a more accurate count of the patients who refer to a sector during a year period; but the various care and treatments are less assessed. The main subdivisions of the nomenclature of patient care maintain the dichotomy inpatient care/outpatient care. The links between the PF and the Information System Medicalization Program (ISMP) can no longer be concealed. Unfortunately, even the analysis of the data collected by the PF, for a financial assessment of the sectors, leads to very biased outcomes because of the qualitative and quantitative underestimation of care, treatments and all the necessary activities. The patient form looks like a multipurpose tool serving the minimum requirements for either descriptive, analytic or evaluative epidemiology; hospital management; planning; etc. Even though this multipurpose vocation could be a weakness, advantage could be also be taken of it to make a more efficient instrument, hence the need for some suggestions. PMID- 8681874 TI - [Neuroimaging and neurobiology of obsessive compulsive disorder: review of recent developments in research]. AB - Morphological and functional changes seen in obsessive-compulsive disorder (OCD) are reviewed. OCD and neurology are closely linked: some neurological diseases involving basal ganglia are sometimes associated with OCD symptoms; conversely, OCD patients often present neurological soft signs. Structural neuroimaging has shown reduced caudate nucleus volume among OCD patients. Functional neuroimaging demonstrated repeatedly an activation of the caudate nucleus and orbitofrontal cortex areas which reversed after treatment. Recent studies showed a correlation between induced OCD symptoms and an increase of the blood flow of the right caudate nucleus and the orbitofrontal cortex. A circuit linking the orbital cortex, the striatum and the thalamus is probably involved in OCD symptoms. However, it is not yet possible to find a causal lesion for this trouble. PMID- 8681875 TI - [Frontal lobe dysfunction and depressive state: relation to endogenous character of depression]. AB - A dysfunction of dorsolateral prefrontal cortex (DLPF) in major depression is suggested by functional imagery and comparative neuropsychology. However, assessment of frontal lobe syndrome with DLPF-dependent tests led to controversial results. To clarify these findings, we administered 5 of these tests (Wisconsin Card Sorting Test, Stroop Test, Trail Making Test, Tower of Toronto, verbal fluency) to 16 major depressive subjects and their 16 controls, before and after 21 days of treatment. Furthermore, we tried to assess the prognostic value of frontal lobe dysfunction, and its relation with the endogenous or exogenous nature of the depression on the one hand, the severity of the depression on the other hand. Our results suggest that the presence of a frontal lobe syndrome (defined by impaired performances at 3 tests or more) is only noted in endogenous depression; after treatment, no impairment is detected. No correlation is found with the severity of the depression. Frontal lobe syndrome does not seem to indicate poorer prognosis for current depressive episode. PMID- 8681876 TI - [Value of clozapine in treatment of psychotic disorder in Parkinson disease]. AB - Psychosis secondary to dopaminergic therapy can limit the ability to manage motor symptoms of advanced Parkinson's disease (PD). Scholz and Dichgans (1985) were the first to report the use of clozapine in drug-induced psychosis in PD. The rationale for use of clozapine in parkinsonian patients is supported by his original pharmacological profile with weak extra-pyramidal side effects. A Medline search was performed of literature from 1985 to 1994. The literature search was not limited to the English language. Numerous authors (23 articles) using case reports or open trials among more than 100 patients suggested that clozapine would be useful in treating drug-induced psychosis in PD. We analysed the available information addressing: 1) clinical efficacy, 2) clinical predictors of outcome, 3) delay of action, 4) influence of clozapine on extrapyramidal symptomatology, 5) adverse effects and treatment withdrawal causes, 6) long-term follow-up data. However, the partially negative result of the only double-blind placebo-controlled trials, it may be stated that in some clinical situation of psychosis in PD, the use of clozapine may represent an opportune alternative when other therapeutic strategies have failed. PMID- 8681878 TI - [Apropos of: characteristics of parallel visual process in alexithymic healthy subjects. Application of the Toronto Alexithymia Scle and the parallel visual information processing list]. PMID- 8681877 TI - [Status of thymoleptics in the treatment of bipolar disorders]. AB - The widening of the concept of bipolar disorders to embrace the notion of a "spectrum" of disorders leads to the supposition that almost 5% of the general population may affected. Thymoleptics are the key treatment, but they should be prescribed over many years, and it is necessary to determine the threshold above which treatment should be considered. Lithium salts remain the reference thymoleptic treatment, but they are insufficiently effective in 30 to 60% of patients. They have a narrow therapeutic margin and are frequently accompanied by adverse effects. Numerous studies, mainly open, have confirmed the value of anti epileptic thymoleptics (carbamazepine and valpromide) in mood disorders. They are comparable in efficacy to lithium salts, both in first-time treatment and in prophylactic use. Their main indications are as follows: marked progression of the mood disorder with the presence of mixed disorders or rapid-cycling disorders, concomitant organic pathology, substance abuse or personality disorder, poor response to lithium salts. PMID- 8681879 TI - [Seasonal affective syndrome and phototherapy: theoretical concepts and clinical applications]. AB - Since 1984, there has been a great interest in the phenomenon of a particular seasonally recurrent mood disorder called seasonal affective disorder (SAD) or winter depression and its treatment: the phototherapy. Seasonal affective disorder is a syndrome described by Rosenthal in 1984. This mood disorder is characterized by depression with onset recurrent in autumn or winter and spontaneous spring or summer remission. It is associated with hypersomnia, anergia, increased appetite, weight gain and carbohydrate craving. The population prevalence in the north of the USA is estimated between 3 and 5%, but it changes with sex, age and also latitude. A long time ago, we know that animals are photoperiod sensitive and that the melatonin secretion in mammals is suppressed by the light. In 1980, Czeiler reported for the first time that human melatonin secretion can be suppressed by high light exposure (+/- 1500 lux). In 1982, Rosenthal, Lewy and al. reported an antidepressant effect of light exposure of a manic-depressive patient. The phototherapy was born. To treat the SAD, the most common procedure of phototherapy is to expose the subject during 2 hours early in the morning, between 06:00 and 09:00 AM. The subject is sitting before a light screen, he can work and has to fix the screen one time every minute. The most common side effects are headache, eyestrain, muscle pain. The ocular phototoxicity is controversed and it seems to be potentially dangerous if phototherapy is associated with tricyclic antidepressants, neuroleptics and other medication containing a tricyclic, heterocyclic or porphyrin ring system. Since this finding, many questions are asked about photoperiod and its effects in the human being. Lewy proposes for the winter depression the hypothesis of a phase delayed circadian rhythm, that can be treated by a morning light exposure. At the present time, many trials are going on to study the effects of phototherapy in other problems like insomnia, maladaptation to night work, jet lag and Alzheimer disease. PMID- 8681880 TI - [Apropos of: evaluation scales of anhedonia. Methodological problems in the article by F. Assouly-Besse et al.: French translation of the Chapman Social and Physical Anhedonia Questionnaire]. PMID- 8681881 TI - Foreign bodies in the gastrointestinal tract. AB - Management of foreign bodies of the gastrointestinal tract is not standardized among the various specialties and subspecialties of physicians who care for these patients. This article gives a true emergency department approach to the patient with an ingested or inserted gastrointestinal foreign body. Evaluation and management of the foreign body by location are presented. Controversial issues such as Foley catheter removal of esophageal foreign bodies, management of sharp objects in the stomach, and management of body packers and body stuffers are discussed. Examples of foreign bodies encountered by the typical emergency physician are demonstrated. PMID- 8681882 TI - Upper gastrointestinal tract bleeding. AB - Upper GI bleeding is a serious and common emergency. Most upper GI bleeding will stop spontaneously but determining which patients will continue to bleed or rebleed is very difficult in the ED. Resuscitation and stabilization are the primary goals of the emergency physician. Hemorrhage control with pharmacotherapy or balloon tamponade may be necessary until urgent or emergent consultation with a gastroenterologist or surgeon is obtained. Early detection and treatment of H. pylori and the development of safer NSAIDs should alter the future of upper GI bleeding dramatically. PMID- 8681884 TI - Esophageal emergencies. AB - Esophageal disorders are commonly seen in the emergency department. Dysphagia (difficulty swallowing) should always be taken seriously and should never be considered a functional complaint, whereas odynophagia (painful swallowing) is usually caused by an inflammatory process. This article addresses dysphagia/odynophagia, as well as esophagitis, neoplasms, gastroesophageal reflux disease, esophageal trauma, and the often difficult differentiation of chest pain of esophageal origin. PMID- 8681885 TI - Vascular abdominal emergencies. AB - Vascular emergencies are an uncommon but significant cause of abdominal pain, back pain, hemorrhagic shock, and death in adults. This article reviews abdominal vascular anatomy, risk factors, signs and symptoms, abdominal vascular thrombosis, mesenteric ischemia and infarction, and abdominal vascular emboli and aneurysms. PMID- 8681883 TI - Lower gastrointestinal tract bleeding. AB - Lower GI bleeding can be slow and chronic or massive and fatal. ED evaluation of these patients begins with history directed at determining the severity and amount of bleeding, and eliciting symptoms of volume depletion. Physical examination determines orthostasis, exclusion of an upper GI source for bleeding, and rectal examination. Laboratory evaluation is directed at determining baseline status of hemoglobin/hematocrit and platelet adequacy, as well as assessing concomitant medical problems. Although many of these patients are elderly, resuscitation is vigorous and should not be deterred by other medical problems. Differential diagnosis can be broad in the ED, but the vast majority of bleeding is caused by diverticulosis or angiodysplasia. Diagnostic capabilities are limited in the ED, but our skill at stabilization and resuscitation has helped decrease morbidity and mortality in acute lower GI bleeding. PMID- 8681886 TI - Unusual causes of abdominal pain. AB - Common and uncommon GI and other intraperitoneal illnesses may present in unusual ways. In addition, many systemic or extraperitoneal disease processes frequently include abdominal pain as a clinical manifestation. The clinician should suspect an unusual cause of abdominal symptoms in patients with repeated visits to the ED without a diagnosis, those who appear ill or complain of severe abdominal pain with disproportionately negative abdominal physical examination findings, those with constitutional or extraperitoneal symptoms or signs, and the elderly or immunocompromised. After initial resuscitation and stabilization have taken place, early evaluation of the need for urgent surgical evaluation and operative management is crucial in the patient with abdominal pain, even when the cause of the symptoms is unclear. A thorough history and careful and complete abdominal and nonabdominal physical examination, paired with appropriate but judicious diagnostic testing, are essential to detecting these unusual causes of abdominal pain and to preventing needless morbidity and mortality. PMID- 8681887 TI - Evaluation of abdominal pain in the elderly. AB - Evaluation of the older patient presents a unique challenge to the emergency physician. The increased age of the population, a high incidence of comorbidity, general poverty of history and clinical signs in acute abdominal conditions, poor reliability of diagnostic procedures, and the variable presentations of diseases with significant morbidity and mortality summarize the problems to be encountered with the complaint of abdominal pain in the elderly. The correct diagnosis is often difficult to establish and coexisting complicating diseases influence the patient's condition and the ED management. The emergency physician must maintain a wide differential and have a low threshold for admission and more extensive evaluation in this patient population. PMID- 8681889 TI - Neuron specific enolase and status epilepticus-induced neuronal injury. PMID- 8681888 TI - The evaluation of acute abdominal pain in children. AB - The infant or child that presents with abdominal pain must be evaluated with a careful history, physical examination, and selective laboratory studies. There are a few diagnoses that the emergency physician should always consider as "life threatening." In the event of any uncertainty in the diagnosis of conditions like appendicitis, pyloric stenosis, or intussusception, the child or infant should be observed carefully over time with appropriate laboratory/radiologic studies ordered to further delineate pathology. Ultrasound evaluation of children with abdominal pain continues to be one of the most valuable tools to help diagnose different conditions. PMID- 8681890 TI - Magnetic resonance spectroscopy. AB - Magnetic resonance spectroscopy (MRS) is noninvasive and may be readily combined with magnetic resonance imaging (MRI). Attention has focussed on proton (1H) and phosphorus (31P) MRS, and studies have been undertaken by using single voxels or many voxels simultaneously (chemical-shift imaging, magnetic resonance spectroscopic imaging). The latter is more difficult and prone to artefact but potentially yields significantly more information. 1H MRS has principally yielded data on concentrations of N-acetyl aspartate (NAA), choline, creatine, and phosphocreatine. NAA is located primarily within neurons, and reduction of the ratio of NAA to choline, creatine, and phosphocreatine is a marker of neuronal loss and dysfunction. This technique may be useful as a noninvasive tool for localizing epileptogenic foci, but its role requires further evaluation. As with all functional imaging methods, coregistration with high-quality MRI is essential for interpreting data. 1H MRS can be used also to estimate cerebral concentrations of several neurotransmitters: glutamate, glutamine, and gamma aminobutyric acid (GABA). This may prove useful for characterizing the neurometabolic profiles of patients with different epilepsy syndromes and for evaluating the effects of medical and surgical treatments. 31P MRS can detect adenosine triphosphate, phosphodiesters, phosphomonoesters, phosphocreatine, and inorganic phosphate, and estimate intracerebral pH. Abnormalities that have been associated with epileptogenic brain areas include increased inorganic phosphate, reduced phosphomonoesters, and increased pH. Only small numbers of patients have been studied, however, so that conclusions are not definitive, and the clinical role of this technique is not yet established. PMID- 8681891 TI - Neuron-specific enolase, a marker of acute neuronal injury, is increased in complex partial status epilepticus. AB - PURPOSE: To determine whether complex partial status epilepticus (CPSE) causes brain injury in humans. Serum neuron-specific enolase (s-NSE) is an accepted marker of acute brain injury, and increases in s-NSE have been correlated with the duration and outcome of generalized convulsive status epilepticus. s-NSE levels in CPSE are unknown. Increase in s-NSE in CPSE would provide new information about the degree of brain injury in CPSE and would help confirm that CPSE is a medical emergency. METHODS: This was a pilot prospective study of serial levels of s-NSE and outcome in CPSE. Eight patients with confirmed CPSE and no acute neurologic deficit were identified prospectively. Results were compared with those of normal and epileptic control groups, and outcome was assessed at hospital discharge or at 7 days with the Glasgow Oucome Scale (GOS). RESULTS: The mean peak s-NSE was 21.81 ng/ml, which for the 8 patients with CPSE was four times higher than that of normal controls (mean s-NSE = 5.36 SD = 1.66, p = 0.0003) and epileptic controls (mean s-NSE = 4.61 SD = 1.74, p. = 0.001). CONCLUSION: The increase in s-NSE provides new evidence that CPSE causes brain injury in humans. PMID- 8681892 TI - Influence of D-cycloserine on the anticonvulsant activity of phenytoin and carbamazepine against electroconvulsions in mice. AB - PURPOSE: D-Cycloserine (DCS) is a high-efficacy partial agonist at the strychnine insensitive glycine modulatory site within the N-methyl-D-aspartate (NMDA) receptor/ionophore complex. Previous studies demonstrated that DCS exhibits anticonvulsant activity in a variety of experimental epilepsy models. In this study, we determined the influence of DCS in subprotective doses on the anticonvulsant action of phenytoin (PHT) and carbamazepine (CBZ) in mice. METHODS: Two electroconvulsive tests were used, i.e., determination of seizure threshold and maximal electroshock seizures. Antiepileptic drug-induced motor and long-term memory deficits were quantified by using the chimney test and the passive-avoidance test, respectively. In addition, plasma levels of PHT and CBZ were measured by fluorescence polarization immunoassay to exclude any pharmacokinetic interactions. RESULTS: DCS, when used alone in doses of 80 and 160 mg/kg, significantly increased the threshold for electroconvulsive seizures. DCS in a wide range of doses (1.25-40 mg/kg) was combined with either PHT or CBZ and tested in electroconvulsive tests. DCS, at doses of 2.5 and 10 mg/kg, was the most effective in potentiating the threshold-increasing action of PHT; higher doses of DCS (20 and 40 mg/kg) were required to achieve a similar effect of CBZ. In maximal electroshock-induced seizures, DCS (10 mg/kg) augmented the protective action of PHT, but was ineffective at a dose of 40 mg/kg with CBZ. DCS did not potentiate the neurotoxicity produced by PHT and CBZ in the chimney test. Both PHT and CBZ induced impairments of long-term memory; PHT-induced memory adverse effects were counteracted by DCS (10 mg/kg). There was no such effect on CBZ induced memory impairment, and a worsening influence was observed. Any pharmacokinetic interactions were excluded by measuring total and free plasma levels of both antiepileptic drugs. CONCLUSION: Our results suggest that combining DCS with PHT and CBZ may be beneficial in treating epileptic seizures. PMID- 8681893 TI - Competitive NMDA-receptor antagonists, LY 235959 and LY 233053, enhance the protective efficacy of various antiepileptic drugs against maximal electroshock induced seizures in mice. AB - PURPOSE: The objective of this study was to evaluate an interaction of two competitive N-methyl-D-aspartate (NMDA)-receptor antagonists, LY 235959 l(-) 3R,4aS,6R,8aR-6-(phosphonomethyl)-decahydroiso-qu inoline-3-carboxylic acid; < or = 0.5 mg/kg] or LY 233053 cis-(+/-)-4-[(2H-tetrazol-5-yl) methyl]piperidine-2 carboxylic acid; < or = 5 mg/kg] with carbamazepine, diphenylhydantoin, phenobarbital, or valproate magnesium against maximal electroshock-induced convulsions in mice. METHODS: Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the end point) delivered by a Hugo-Sachs stimulator (Type 221, reiburg, FRG). Adverse effects were evaluated in the chimney test (motor performance) and passive-avoidance ask (long-term memory). Plasma levels of antiepileptic rugs were measured by immunofluorescence. RESULTS: Both LY 235959 and LY 233053 ( < or = 0.5 and 5 mg/kg, respectively) did not influence the electroconvulsive threshold but potentiated the anticonvulsant action of all antiepileptics studied. The combined treatment of LY 233053 (5 mg/kg) with carbamazepine, diphenylhydantoin, or phenobarbital (providing a 50% protection against maximal electroshock) resulted in the impairment of long-term memory. No adverse effects were observed with combinations of LY 235959 with these antiepileptics. The combined treatment of valproate with either LY 235959 or LY 233053 was superior to valproate alone, as regards motor impairment, but not the impairment of long-term memory. Neither NMDA-receptor antagonist elevated the total plasma levels of antiepileptic drugs studied. CONCLUSIONS: It may be concluded that NMDA-receptor blockade leads to the enhanced anticonvulsive action of conventional antiepileptics against maximal electroshock-induced seizures. A pharmacokinetic interaction does not seem probable. PMID- 8681894 TI - Epilepsy surgery in infants. AB - PURPOSE: We report 12 infants who had frontal (n = 3), temporal (n = 2), or temporoparieto-occipital (n = 2) resection or functional hemispherectomies (n = 5) at age 2.5-29 (mean 15.3) months for catastrophic epilepsy due to focal cortical dysplasia (n = 5), Sturge-Weber syndrome (n = 3), ganglioglioma (n = 3), or hemimegalencephaly (n = 1). Seizures began at 1 day to 14 months (mean, 4.0 months) after birth, occurred frequently (often many times per day, and were refractory to antiepileptic drugs. Patients were evaluated for surgery at 2.5-24 (mean 12.4) months of age. Seven patients had hemiparesis and eight had slowed cognitive development. Seizures were characterized by arrest or marked reduction of behavioral motor activity with nuclear level of consciousness (n = 4, with temporal or temporoparietal EEG seizures), focal clonic activity (n = 3, with perirolandic EEG seizures), generalized tonic stiffening (n = 3, with temporoparieto-occipital, parietal, or frontal EEG seizures), or infantile spasms and hypsarrhythmia (n = 2, with a frontal tumor or temporoparieto-occipital cortical dysplasia). METHODS: Magnetic resonance imaging (MRI) revealed the epileptogenic lesion in all but two patients, both with cortical dysplasia localized by interictal positron-emission tomography (PET) and other clinical or EEG features and confirmed on histopathologic examination of resected tissue. RESULTS: At follow-up 4-86 (mean 32) months after surgery, six patients were seizure free (Engel outcome class I), three had rare seizures with none in at least the previous 6 months (Engel class II), and two had worthwhile improvement (Engel class III). Except for the severely developmentally delayed infant with hemimegalencephaly, several patients had marked "catch-up" developmental progress after class I, II, or III outcome. Postoperative complications included subdural hematoma over the contralateral hemisphere (one patient) and entrapment and enlargement of the ipsilateral temporal horn (one patient) after hemispherectomy, both corrected uneventfully with a second surgical procedure. One patient died of unexplained causes several hours after frontal lobectomy. No patients had new neurologic deficits after surgery, and one patient had resolution of progressive fluctuating hemiparesis after resection of temporoparieto-occipital cortical dysplasia. CONCLUSIONS: Our results agree with previous reports that epilepsy surgery can provide relief from catastrophic epilepsy in carefully selected infants. PMID- 8681895 TI - Vigabatrin as initial therapy for infantile spasms: a European retrospective survey. Sabril IS Investigator and Peer Review Groups. AB - PURPOSE: The efficacy and tolerability of vigabatrin (VGB) as an add-on therapy in the treatment of infantile spasm (IS) prompted physicians to explore its use as the first drug in this seizure type. METHODS: Our retrospective study included 250 infants diagnosed with IS; the data obtained were subjected to peer-group review. Of this infant population, 192 infants were considered to have classic IS and had received VGB as their first treatment for the spasms. There was a slight preponderance of boys (57%) in this population. Mean age of IS onset was 5.8 months; 60% had typical hypsarrhythmia. RESULTS: Initial suppression of spasms was obtained in 68% of infants with a median time to response of 4 days at an average VGB dose of 99 mg/kg/day. The best response was seen in those infants with tuberous sclerosis (96% response) and in those younger than 3 months at onset of spasms (90% response). Of these infants, 43 (22%) of 192 subsequently had other types of seizures, and a recurrence of infantile spasms occurred in 28 (21%) of 131 responders. At the end of this study, 96 of 192 infants who could be evaluated were seizure free with VGB monotherapy. Treatment appeared to be well tolerated, with only 33 (13%) infants with adverse events, of which the most common were somnolence (15 patients) and hyperkinesia (eight patients). In only two cases did adverse events require VGB withdrawal. CONCLUSION: This study supports the opinion that VGB may be considered an initial treatment for IS regardless of cause. PMID- 8681896 TI - Nonconvulsive status epilepticus in the emergency room. AB - PURPOSE: The study reviewed emergent cases of nonconvulsive status epilepticus (NCSE) to evaluate causes of diagnostic and management delay and examined frequent diagnostic features suggestive of NCSE. METHODS: In a retrospective study, we assessed the clinical presentation of 23 patients with one or more NCSE episodes, their medical history, EEG, and antiepileptic drug (AED) treatment. We also evaluated causes of diagnostic delay in patients referred to the emergency room (ER) in confusional states. RESULTS: There was considerable overlap in clinical features of patients with complex partial SE (CPSE) and generalized nonconvulsive SE (GNSE). Delays in seeking medical attention were common. Diagnosis was significantly delayed in 10 patients. Three cases illustrate the possible markedly different presentations of NCSE. CONCLUSIONS: NCSE often goes unrecognized or is mistaken for behavioral or psychiatric disturbance. The pleomorphic clinical presentation of NCSE indicates that EEG and a therapeutic trial of AEDs afford the best diagnostic measures in acute waxing and waning confusional states associated with agitation, bizarre behavior, staring, increased tone, mutism, or subtle myoclonus. PMID- 8681897 TI - Routine EEG and temporal lobe epilepsy: relation to long-term EEG monitoring, quantitative MRI, and operative outcome. AB - PURPOSE: To investigate the relation among routine EEG, long-term EEG monitoring (LTM), quantitative magnetic resonance imaging (MRI), and surgical outcome in temporal lobe epilepsy (TLE). METHODS: We evaluated 159 patients with intractable TLE who underwent an anterior temporal lobectomy between 1988 and 1993. The epileptogenic temporal lobe was determined by ictal LTM. A single awake-sleep outpatient EEG with standard activating procedures was performed before LTM. EEGs were analyzed by a blinded investigator. RESULTS: MRI scans showed unilateral medial temporal atrophy (109 patients) or symmetrical hippocampal volumes (50 patients). The surgically excised epileptogenic brain tissue revealed mesial temporal sclerosis, gliosis, or no histopathologic alteration. Routine EEG revealed temporal lobe epileptiform discharges in 123 patients. Routine EEG findings correlated with the temporal lobe of seizure origin (p < 0.0001) and the results of MRI volumetric studies (p < 0.0001). Interictal epileptiform discharges were seen only during LTM in 24 patients. Routine EEG was disconcordant with interictal LTM in another 20 patients. MRI-identified unilateral medial temporal lobe atrophy was a strong predictor of operative success (p < 0.0001). There was no significant relation between the routine EEG findings and operative outcome (p > 0.20). CONCLUSIONS: Results of this study modified our approach in patients with TLE. Interictal epileptiform discharges localized to one temporal lobe on serial routine EEGs or during LTM may be adequate to identify the epileptogenic zone in patients with MRI-identified unilateral medial temporal lobe atrophy. PMID- 8681898 TI - Coupling of cortical and thalamic ictal activity in human partial epilepsy: demonstration by functional magnetic resonance imaging. AB - PURPOSE: To localize metabolic coupling between a cortical seizure focus and other brain regions by using functional magnetic resonance imaging (fMRI) data of ictal events obtained in a patient with frequent partial seizures involving his right face. METHODS: Cross-correlation analysis was used to examine time dependent alterations in regional signal intensity that correlated with signal intensity changes from a well-characterized cortical seizure focus in a patient with frequent partial seizures. RESULTS: Signal changes in the left ventrolateral thalamus showed a high degree of temporal correlation with signal changes in the left frontal cortical seizure focus, demonstrating close corticothalamic coupling of metabolism. CONCLUSIONS: A significant role for thalamocortical interactions in the pathophysiology of epilepsy has been suggested by studies in animal models and human patients. This finding provides further support for the integral involvement of the thalamus in human focal epilepsy and underscores the potential for identifying neuronal networks by using cross-correlation analysis of fMRI data. PMID- 8681899 TI - Subdural recording of ictal DC shifts in neocortical seizures in humans. AB - PURPOSE: Invasive ictal EEG recording is often necessary to delineate epileptogenic areas in patients with intractable partial epilepsy, but even intracranial ictal recordings often reveal ill-defined onset zones in neocortical epilepsy. We studied the physiologic significance of ictal direct current (DC) potentials recorded intracranially in human epilepsy. METHODS: We made intracranial ictal EEG recordings in three patients with intractable partial seizures arising from frontal, lateral temporal, and parietal neocortical areas by using closely spaced subdural electrodes (platinum in two patients and stainless steel in one patient) with both standard (1.5 Hz) and open (0.016 Hz) low-frequency filter (LFF) settings. RESULTS: The initial ictal pattern was localized to two to nine subdural electrodes and characterized by very low voltage and high-frequency rhythmic activity ("electrodecremental pattern"). A slow-rising negative potential (DC potential) was seen in a slightly more restricted area (two to six electrodes) and occurred 1-10 s before the initial ictal EEG discharges in two patients. CONCLUSIONS: These results agree with those of previous studies of ictal DC shifts in animals and suggest that ictal DC shifts may be helpful in delineating the epileptogenic area more precisely in human epilepsy. PMID- 8681900 TI - Systematic testing of medical intractability for carbamazepine, phenytoin, and phenobarbital or primidone in monotherapy for patients considered for epilepsy surgery. AB - PURPOSE: To assess medical intractability in patients considered for restrictive epilepsy surgery. METHODS: Seventy-four patients received single drug treatment with carbamazepine (CBZ), phenytoin (PHT), and either phenobarbital (PB) or primidone (PRM). Medical intractability was established if seizure control was not obtained despite maximum tolerable doses of the drug. In all, 120 single drug treatments were administered with the drugs that has not been administered at maximal doses in monotherapy before the study. RESULTS: Complete seizure control was not achieved in any patient. However, 7 patients (9.5%) had significant seizure reduction of at least 80%. In 4 patients, only the third antiepileptic drug (AED) proved effective. CONCLUSION: The poor result of AED monotherapy in our patients may be attributed to the patients' long-standing chronic epilepsies and high seizure frequencies. Our findings suggest that despite the failure of one or two major AEDs in controlling seizures completely, further single drug treatment may still improve the quality of life in some patients who are candidates for epilepsy surgery. PMID- 8681901 TI - Learned helplessness, attributional style, and depression in epilepsy. Bozeman Epilepsy Surgery Consortium. AB - PURPOSE: We wished to examine the relevance of the theory of learned helplessness in general, and attributional style in particular, to the understanding of depression among patients with epilepsy. METHODS: Patients with lateralized temporal lobe epilepsy (TLE) (right = 73, left = 70) were administered two self report depression inventories [Beck Depression Inventory (BDI), Center for Epidemiological Studies-Depression scale (CES-D)]. Depression scores were examined in relation to a key component of the revised theory of learned helplessness (attributional style) using the Optimism/Pessimism Scale. RESULTS: Attributional style was significantly associated with increased self-reported depression and remained significant when the effects of several confounding variables were controlled [age, age at onset, laterality of TLE, sex, and method variance]. CONCLUSIONS: The results indicate that the concept of learned helplessness in general, and attributional style in particular, are related to the genesis of depression in epilepsy. Because they are known to be related to depression in the general population, and because specific techniques for intervention and prevention are available, greater consideration of learned helplessness and attributional style in the genesis of depression in epilepsy may be worthwhile. PMID- 8681902 TI - Effect of L-carnitine supplementation on acute valproate intoxication. AB - We analyzed urinary valproate (VPA) metabolites and carnitine concentrations in a child who accidentally ingested 400 mg/kg VPA. The concentration of 4-en VPA, the presumed major factor in VPA-induced hepatotoxicity, was markedly increased, without liver dysfunction or hyperammonemia. The other major abnormality was decreased beta-oxidation and markedly increased omega-oxidation. After L carnitine supplementation, VPA metabolism returned to normal. The level of valproylcarnitine was not increased and therefore was not affected by L carnitine. L-Carnitine may be useful in treating patients with coma after VPA overdose. PMID- 8681903 TI - Paroxysmal staring and masticatory automatisms during postural hypotension in a patient with multiple system atrophy. AB - PURPOSE: We studied a 51-year-old man with multiple system atrophy and autonomic insufficiency. He had repeated episodes of loss of contact, staring, and masticatory automatisms. METHODS: Blood pressure during these events documented a systolic pressure of 60 mm Hg. Cardiovascular reflex tests provided evidence of autonomic failure. Head computed tomography (CT) revealed moderate, diffuse cortical and cerebellar atrophy. RESULTS: These events were strictly related to blood pressure decreases and could be reproduced consistently by having the patient sit up after a meal. Ictal polygraphic recordings showed EEG changes consistent with anoxia, preceded by sudden hypotension with fixed heart rate. CONCLUSIONS: Cerebral anoxia during a syncopal attack may therefore precipitate transient, sudden neurologic dysfunction that closely mimics complex partial seizures. Masticatory automatisms may represent a release phenomenon resulting from inactivation of neocortical structures by cerebral anoxia or reticular disconnection. PMID- 8681905 TI - Proceedings of the 29th Congress of the Japan Epilepsy Society. Beppu, Ohita, Japan, October 5-6, 1995. PMID- 8681904 TI - Tooth-brushing epilepsy: a report of a case with structural and functional imaging and electrophysiology demonstrating a right frontal focus. AB - Patients with reflex epilepsies may provide insights into cerebral pathophysiology. We report a patient with an unusual form of reflex epilepsy in whom seizures are induced by tooth brushing. Magnetic resonance imaging (MRI) demonstrated a right posterior frontal low-grade tumor predominantly involving the precentral gyrus. Video-telemetry demonstrated right-sided epileptiform activity during a typical induced complex partial seizure. An ictal single photon emission computed tomography (SPECT) scan showed an area of hyperfusion that corresponded to the MRI lesion on coregistration with a surface-matching technique. A subsequent coregistered interictal SPECT scan demonstrated hypoperfusion in the same region. Ours is the first report to demonstrate a structural focus in this unusual form of reflex epilepsy. Possible mechanisms to explain the induction of the seizures are discussed. PMID- 8681906 TI - Intractable epilepsy in children. AB - Although most children with epilepsy have a good prognosis, a small but significant minority have seizures that either do not respond to conventional antiepileptic drugs (AEDs) or have significant adverse reactions to AEDs. Many children may benefit from epilepsy surgery. Surgical treatment of epilepsy is becoming a well-established therapy for infants and young children with severe, medically intractable seizures. As in older children and adults, the presurgical evaluations of possible surgical candidates typically consist of a detailed history, neurologic and neuropsychologic examination, and anatomic and functional neuroimaging. The "gold standard" test, however, is the recording of ictal events by using simultaneous EEG and videomonitoring. Although temporal lobe resection is the most commonly performed surgery in older children and adults, nontemporal lobe resection, corpus callosotomy, and hemispherectomy are commonly performed in younger children. Efficacy of surgery in children compares favorably with results from adult patients. In addition, because the immature brain is more plastic than the mature brain, recovery of function is often greater after surgery in children than in adults. Early surgery in children with intractable epilepsy is recommended. PMID- 8681907 TI - Clinical and EEG findings and prognosis of seizure disorders in children. PMID- 8681908 TI - Quality of life in children with epilepsy. AB - To study quality of life in school children with epilepsy, we surveyed families of 443 elementary and junior high school children with epilepsy, as well as their school teachers. Approximately 80% responded. Seizures were controlled in 70% of the children. Of the children with epilepsy, 27% received education for disturbed children. Main family concerns were the future of their child, seizures, and school performance. Main concerns of the children were medication and seizures. The majority of both families and teachers agreed that children should participate in all physical education and school events based on individual considerations. Many teachers expressed the opinion that correct information about epilepsy and close communication between teachers and physicians are necessary. To establish comprehensive medical care that satisfies the needs of children with epilepsy and their families, further training of medical specialists in epilepsy, establishment of more hospitals specializing in epilepsy, and enhancement of the network among relevant organizations are needed. For children with intractable epilepsy, special considerations include associated handicaps and antiepileptic drug side effects. PMID- 8681909 TI - Recommendation of early surgery from the viewpoint of daily quality of life. AB - We surveyed pre- and postoperative levels of satisfaction with a range of the daily quality-of-life (QOL) domains in 132 sets of epilepsy surgery patients and their families. All patients underwent resective surgery for temporal lobe epilepsy and were monitored for > 2 years. Patient and family assessments showed patients' overall QOL markedly improves after surgery, depending on freedom from seizures. However, factors such as social contacts, family relations, or financial status improved little. Some families and patients were not satisfied with the postsurgical status, despite freedom from seizures. Patients who had surgery at a later age were not so satisfied with their postsurgical status as were patients who had surgery at a younger age, particularly on the QOL domains of role activities, memory function, leisure activities, or emotional well-being. This lower satisfaction level in older patients likely results from a variety of problems affecting patients during the long-lasting epileptic process; social handicaps, psychologic conflicts, and deterioration of cognitive/behavioral functions. Based on each case, we recommend that investigations start at an early stage of the illness, so that surgical intervention may be considered as early as possible. PMID- 8681911 TI - An anthropological view of quality of life: therapeutic objectives and social contradictions. AB - The improvement of quality of life (QOL) is now widely accepted as an important goal of health care. Underlying the acceptance of QOL is the unspoken assumption that therapies and practices associated with QOL are inherently beneficial. The uses of QOL in the treatment of epilepsy need scrutiny. Close attention must be given to the effects of policies instituted in the name of QOL, as significant social consequences may result from these policies. PMID- 8681910 TI - Quality of life in adult patients with epilepsy. AB - Quality of life (QOL) must be determined from the patients' subjective viewpoint. To determine QOL in epilepsy, it is necessary to use disease-specific scales. We introduced the Side Effects and Life Satisfaction (SEALS) scale to Japan and performed a comparative study on adult patients with epilepsy and normal subjects. The results for patients with epilepsy were determined by the number of prescribed antiepileptic drugs (AEDs), the total dosage, and the type of epilepsy. Problems in patients with epilepsy were expressed by vertically crossing lines. A horizontal line expressed the severity of disease, and a vertical line expressed the psychosocial functioning. Therefore we cannot separate the severity and QOL when considering the influence of epilepsy disorders on individual patients. These two components compose the biphasic dimensions of QOL and thus are analyzed coincidentally. The concepts of QOL and comprehensive management in epilepsy are closely related, but the fundamental viewpoints are located at opposite positions. The former is based on the physicians' viewpoints and the latter on the patients' viewpoints. Although ideally these two concepts should be in harmony, they are in reality frequently dissociated. In comprehensive management, the treating physician must vigorously consider the influence of therapy on the patients' QOL. PMID- 8681912 TI - Long-term prognosis of Lennox-Gastaut syndrome. AB - We investigated the long-term prognosis of Lennox-Gastaut syndrome (LGS) in 72 patients followed up for > 10 years. Long-term seizure and intellectual outcomes were poor, as previously reported. The diagnosis of LGS was first made in the age range from 2 to 15 years with peak occurrence at 5 years. Progressive IQ score deterioration with age was apparent. At the last examination, 33% of patients with cryptogenic and 55% with symptomatic LGS had lost the characteristics of LGS, and their seizure disorders were classifiable as symptomatic generalized epilepsies, severe epilepsy with multiple independent spike foci, or localization related epilepsies. Disabling drop attacks appeared in 46% of patients and tended to occur at older than 10 years. Gait deterioration was recognized in 12 patients and seemed to be due largely to progression of the epileptic encephalopathy. The gait disturbances, as well as increased frequency of violent drop attacks, were disabling in daily life and resulted in some patients being wheelchair bound. PMID- 8681913 TI - Evolution of Lennox-Gastaut syndrome: a long-term longitudinal study. AB - In 102 patients with Lennox-Gastaut syndrome (LGS) observed for an average of 16 years (range, 10-20 years), 12 of the patients worked normally, 36 worked part time or at a sheltered workshop, and most of the remaining 54 were under home care or institutionalization. LGS evolved from West syndrome or from unspecified epilepsies, or as the primary form, mostly in childhood and rarely in adolescence or adulthood. At the worst stage, there were diverse types of generalized seizures, slow spike-and-wave EEG complexes, fast rhythms, and multiple spike-and wave complexes. Mental subnormality progressively worsened. Characteristic symptoms of LGS continued in one third of patients, and various abortive forms of LGS were seen in the other two thirds, although LGS did not evolve into a localization-related epilepsy during the survey period. The evolution of seizure and EEG epileptic discharges suggests that LGS has a characteristic clinical course as it progresses. The persistent generalized tonic seizures of various magnitude over a long time in the vast majority of patients indicate that the brainstem rather than the cortical mantle is involved as the seat of seizure generating mechanisms in LGS. PMID- 8681914 TI - Neonatal seizures: historic note and present controversies. PMID- 8681915 TI - Mesial temporal lobe epilepsy in childhood. AB - To clarify the clinical picture of mesial temporal lobe epilepsy (MTLE) in childhood, we carried out a clinical, electroencephalographic, and neuroradiologic study of 19 patients. MTLE was noted in 19 (0.82%) of 2,319 epileptic patients with childhood onset. Three types of initial seizure were recognized: febrile convulsion, afebrile generalized convulsion, and complex partial seizure (CPS). As presumed causes, various prolonged convulsions (persisting for > 30 min) were found in 12 (63.2%) cases. Regardless of the presence of preceding convulsions (febrile or afebrile), the clinical course was not uniform, with CPS in the early period temporarily controlled in some cases and intractable from the early period in others. Unilateral hippocampal abnormalities were confirmed on magnetic resonance imaging (MRI) before the age of 5 years in two cases, suggesting that mesial temporal sclerosis (MTS) is formed within a relatively short period in some cases. Seizures were controlled for > 6 months in only two (10.5%) cases and persisted in 17. In four (21.1%) cases, surgical treatment was considered to be available. PMID- 8681916 TI - Mesial temporal lobe epilepsy: clinical features and seizure mechanism. AB - To study the clinical features of mesial temporal lobe epilepsy, 24 cases were selected based on two criteria: (a) the origin of seizure was localized to the mesiotemporal region on phase 2 monitoring, and (b) a class 1 or 2 postoperative result was obtained after selective mesiotemporal resection. A history of febrile convulsion, particularly in the form of status epilepticus, seems to be a prognostic factor. As for presurgical evaluation, electroencephalography (EEG), magnetic resonance imaging (MRI), magnetoencephalography (MEG), and ictal single photon emission-computed tomography (SPECT) are important tests. Recording of spontaneous seizures by means of intracranial electrodes is the most reliable for diagnosis. Ammon's horn sclerosis and mesial temporal sclerosis are the most frequent pathologic findings. The seizure mechanism was studied by means of depth EEG recordings and ictal SPECT. The hippocampal formation is more responsible than the amygdala for the origin of seizures. Preferential pathways for seizure spread may be the fornix and stria terminalis, amygdalofugal fibers, and uncinate fasciculus. The concept of mesial temporal lobe epilepsy is valid for selecting medically refractory but surgically remediable patients for surgical treatment. PMID- 8681917 TI - Hypertension and neuropsychological performance in men: interactive effects of age. AB - Potentially interactive effects of hypertension and age on the performance of neuropsychological and information processing tests were examined in 123 untreated hypertensive and 50 normotensive men. After covarying education, average alcohol consumption, trait anxiety, and depression scores, results indicated an interaction of age and hypertension. Young hypertensive men (23-40 years) scored significantly worse than young normotensive men on tests of attention/executive function and working memory; middle-aged hypertensive (41-56 years) and normotensive participants were not distinguished by any measures. Hypertensive men performed significantly more poorly than normotensive men on tests of manual dexterity. Results suggest that neuropsychological sequelae of hypertension are more pronounced in young than in middle-aged hypertensive individuals and are independent of various demographic, psychosocial, and alcohol related factors. PMID- 8681918 TI - Relations among age, exercise, and psychological variables in a community sample of women. AB - Age, exercise status, and their interaction were examined in relation to self motivation, exercise self-efficacy, and attitudes toward exercise among a community sample of women aged 20 to 85 years. Random digit telephone dialing yielded 121 participants, stratified by age and exercise status. Age was negatively related to attitudes toward exercise and exercise self-efficacy but was unrelated to self-motivation. Age also interacted with exercise status; the belief that exercise would be enjoyable and beneficial decreased with increasing age only among nonexercisers. Finally, exercisers were significantly more self motivated, had greater exercise self-efficacy, and had more positive attitudes toward exercise than did nonexercisers. PMID- 8681920 TI - Methodological considerations in participant event monitoring of low-base-rate events in health psychology: children's injuries as a model. AB - The present article outlines the advantages of the participant event monitoring methodology for the investigation of unpredictable, low-base-rate events in children. Several methods for assessing the quality of participant event monitoring data are advanced with a data set showing participant event monitoring of children's minor injuries by 61 children and their mothers. Child-mother correspondence and debriefing data suggest good accuracy for frequency estimates. Home- and laboratory-based simulations illustrate the participant event monitors' accuracy for major details. Traditional measures of data quality show good overall coder and test-retest reliability, and cross-observer reports show acceptable estimates of validity for objective aspects of the events and the expected lower estimates for the more subjective aspects. Conceptual and pragmatic difficulties of the method are considered, and suggestions for future research are advanced. PMID- 8681919 TI - Changing AIDS risk behavior: effects of an intervention emphasizing AIDS risk reduction information, motivation, and behavioral skills in a college student population. AB - This research used the Information-Motivation-Behavioral Skills (IMB) model of AIDS risk behavior change (J. D. Fisher & Fisher, 1992a) to reduce AIDS risk behavior in a college student population. College students received an IMB model based intervention that addressed AIDS risk reduction information, motivation, and behavioral skills deficits that had been empirically identified in this population, or were assigned to a no-treatment control condition. At a 1-month follow-up, results confirmed that the intervention resulted in increases in AIDS risk reduction information, motivation, and behavioral skills, as well as significant increases in condom accessibility, safer sex negotiations, and condom use during sexual intercourse. At a long-term follow-up, the intervention again resulted in significant increases in AIDS preventive behaviors. PMID- 8681922 TI - Social support and adjustment to cancer: reconciling descriptive, correlational, and intervention research. AB - Several research literatures are reviewed that address the associations of emotional, informational, and instrumental social support to psychological adjustment to cancer. Descriptive studies suggest that emotional support is most desired by patients, and correlational studies suggest that emotional support has the strongest associations with better adjustment. However, the evidence for the effectiveness of peer discussion groups aimed at providing emotional support is less than convincing. Moreover, educational groups aimed at providing informational support appear to be as effective as, if not more effective than, peer discussions. Reasons for inconsistencies between the correlational and intervention literatures are discussed, and future directions are outlined. PMID- 8681921 TI - Present versus future time perspective and HIV risk among heterosexual college students. AB - Because safer sex behaviors require planning and forethought and their primary motivations lie in the future, the hypothesis that behaviors that might reduce exposure to HIV would positively correlate with future time orientation, whereas risky behaviors would correlate with present time orientation, was tested in a survey of 188 heterosexual college students. As expected, those high in future time orientation were less likely to be sexually experienced and had fewer sexual partners. In contrast, present time orientation positively related to those measures. Those high in future orientation were more likely to use alternate methods of reducing exposure to HIV (e.g., inquiring about partner's sexual history, delaying or abstaining from sex). Time perspective also interacted with both gender and fear of AIDS. The responses of women and individuals low in fear were more related to time orientation. PMID- 8681923 TI - A randomized trial of breast cancer risk counseling: interacting effects of counseling, educational level, and coping style. AB - The authors evaluated the impact of individualized breast cancer risk counseling (BCRC) on breast-cancer-specific distress and general distress in 239 women with a family history of breast cancer. Following a baseline assessment of demographics, risk factors, coping styles, and distress, participants were assigned randomly to receive either BCRC or general health education (GHE; i.e., control group). After controlling for education level, women who received BCRC had significantly less breast-cancer-specific distress at 3-month follow-up compared with women who received GHE. A significant Education Level x Treatment Group interaction indicated that the psychological benefits of BCRC were greater for women with less formal education. In both the BCRC and GHE groups, participants who had monitoring coping styles exhibited increases in general distress from baseline to follow-up. PMID- 8681924 TI - Osteoporosis prevention in premenopausal women: using a stage model approach to examine the predictors of behavior. AB - The precaution adoption process model was used to examine the predictors of 2 behaviors recommended to reduce the risk of developing osteoporosis: calcium consumption and weight-bearing exercise. A total of 452 premenopausal women completed a mailed questionnaire assessing stage in the precaution adoption process and 12 knowledge and attitudinal variables. Participants were also given an opportunity to request information about osteoporosis. In all, 11 of the 12 knowledge and attitudinal variables were associated with calcium stage; 8 were associated with exercise stage. Information requests were associated with both calcium and exercise stage. Findings provide substantial support for the precaution adoption process model and suggest that the model can be usefully applied in this area to increase understanding of why many women do not practice behaviors that could reduce their risk of developing osteoporosis. PMID- 8681925 TI - Marital history at midlife as a predictor of longevity: alternative explanations to the protective effect of marriage. AB - The association between marital history at midlife (in 1950) and mortality (as of 1991) was studied in a group of intelligent, educated men and women (N = 1,077) who participated in the Terman Life-Cycle Study initiated by Lewis Terman in 1921. Results confirm that consistently married people live longer than those who have experienced marital breakup but suggest that this is not necessarily due to the protective effects of marriage itself. Individuals who were currently married, but had previously experienced a divorce, were at significantly higher mortality risk compared with consistently married individuals. Furthermore, individuals who had not married by midlife were not at higher mortality risk compared with consistently married individuals. Part of the relationship between marital history and mortality risk may be explained by childhood psychosocial variables, which were associated with both future marital history and mortality risk. PMID- 8681926 TI - A video-based method for evaluation of low-back load in long-cycle jobs. AB - A method for evaluation of the physical load on the lumbar spine in industrial work is presented. It is suitable for identification of high spinal loads and their time duration. The method is based on biomechanical analysis of video recordings. It takes into account the posture of the body as such, as well as the possible occurrence of external load and support. Compression of the L5-S1 intervertebral disc and strain on the lumbodorsal fascia is determined at 5-s intervals in each work task. PMID- 8681927 TI - Influence of two different modes of resistance training in female subjects. AB - In resistance training, it has been empirically accepted that muscle hypertrophy is developed by low intensity and high volume training, while muscle strength and power are developed by high intensity and low volume training. The purpose of the present study was to investigate the influence of two different modes of resistance training on isokinetic strength and muscle cross-sectional area (CSA) in females. Eleven females, who had no experience in resistance training, participated in this study and were randomly divided into two groups. The former consisted of 4-5 sets of 15-20 RM (repetition maximum) with sufficient rest between sets (Group H), while the latter consisted of 8-9 sets of 4-6R M with 90 s of rest between sets (Group S). The former was assumed to be appropriate for muscle hypertrophy and the latter muscle strength, respectively. All subjects completed isotonic knee extension exercise three times a week for 8 weeks. Measurements were made on quadriceps muscle cross-sectional area (CSA) and isokinetic torques at 0, 60, 180, and approximately 300 degrees before training, at the fifth week and the end of training period. Muscle CSA was defined as the sum of CSA measured at 30, 50 and 70% of femur length. After training, muscle CSA had significantly increased in both groups: 3.3 +/- 0.7% (p < .05) for group H and 3.6 +/- 1.1% (p < .05) for group S, respectively. While the changes in isokinetic torque were 43.4 +/- 47.5% (p < .05) for group H and 27.4 +/- 31.3% (p < .05) for group S, respectively. In both groups the percentage changes of the isokinetic strength were significantly higher than those of the CSA. No significant difference in these variables were found between the two groups. These results suggest that during the early phase of resistance training two different modes of resistance training may have similar effects on muscle CSA and isokinetic strength in untrained females. PMID- 8681928 TI - Effects of asymmetric dynamic and isometric liftings on strength/force and rating of perceived exertion. AB - A laboratory study was undertaken to determine the postural and physical characteristics and subjective stress during dynamic lifting of a usual load (10 kg) compared with during isometric lifting. The authors also aimed to clarify the effects of asymmetric lifting on these parameters. The subjects were thirteen male college students. They were asked to lift a box weighing 10 kg. They performed sixteen different lifting tasks from the floor to a height of 71 cm, involving a combination of three independent factors: two lifting modes (isometric lifting and dynamic lifting), four lifting angles in relation to the sagittal plane (sagittal plane, right 45 degree, right 90 degree and left 90 degree planes) and two lifting postures (squat and stoop). For each lifting task, strengths or forces and ground reaction forces were measured. At the end of each task, the authors asked the subjects to rate their perceived exertion (RPE) during lifting at ten sites of the body. Angle factor had a significant effect on isometric strengths and dynamic peak forces. Isometric strengths during the maximum 3 s were highest in lifting in the right 45 degree plane, followed by that in the sagittal plane, while those in the right 90 degree and left 90 degree planes were the lowest. However, peak forces in dynamic lifting were the highest in the lifting in the sagittal plane, followed by that in the right 45 degree plane, while those in the right 90 degree and left 90 degree planes were the lowest. Postural factor had a significant effect on height at peak force, which is higher in squat lifting than in stoop lifting. RPEs for the left arm, the backs and the right whole body in isometric lifting were significantly higher than in dynamic lifting of 10 kg. There were remarkably high RPEs for the ipsilateral thigh to the box in right 90 degree and left 90 degree planes during both isometric and dynamic liftings. Locations of the resultant force consisting of three component forces on the force plate were closer to the foot on the same side as the box in asymmetric lifting. Thus, some similarities and differences were found between isometric lifting and dynamic liftings regarding the indexes of strength used in this experiment. The authors consider that the subjects used the foot nearer to the box as a fulcrum during asymmetric lifting. Dynamic measurement using the 10 kg weight is less stressful than the conventional isometric measurement. It was possible to obtain the height data at peak force and time-based changes in the force and the box location during lifting only through dynamic lifting measurement. The results provide new knowledge about the biomechanical features of dynamic lifting tasks. PMID- 8681929 TI - Analysis of ocular surface area for comfortable VDT workstation layout. AB - This paper proposes a comfortable visual display terminal (VDT) workstation layout based on an analysis of ocular surface area (OSA). A large OSA induces eye irritation and eye fatigue because the eye surface is highly sensitive to various stimuli. The authors considered that OSA must be one of the useful indices of visual ergonomics and applied it to evaluate VDT workstation layout. Each subject was asked to perform a word processing task using four different VDT workstation layouts. It was found that the main factor affecting OSA was not cathode ray tube (CRT) height itself but the distance between the CRT and keyboard. Thus the following workstation layout is recommended to realize comfortable VDT operation: (1) the desk height should be adjusted to the user's height; and (2) the CRT display should be set closer to the keyboard to provide a smaller OSA. PMID- 8681930 TI - Interactions between memory scanning and visual scanning in display monitoring. AB - Many real-world tasks require the simultaneous performance of memory scanning of several memorized items and visual scanning of several physically separated sources of information in the visual field. This paper reports a study that was conducted to quantify the possible interactions between memory scanning and visual scanning. A quantitative model was derived to integrate Sternberg's linear model of memory scanning and Neisser's linear model of visual scanning. The derived model was tested through two experiments. The experiments simulated a process controller's task of monitoring an array of instrument meters to detect if any of them indicated a system error. The subjects were required to keep a number of items in their working memory (the definition of errors) and search through an organized array of instrument meters to decide whether any of the meters carried an item that matched any of the memorized items in their working memory. Two experimental factors were investigated in both experiments: the number of memorized items and the number of circles needed to be searched. These defined memory scanning demand and visual scanning demand respectively. Experiment 1 employed a different set of memorized items for each experimental trial, whereas experiment 2 employed the same set for all the trials that had the same experimental condition. The experiments identified both the strengths and the limitations of the derived model. Implications for human-machine interface design and human performance modelling are discussed. PMID- 8681931 TI - A method for measuring the CO2 dead space volume in facial visors and respiratory protective devices in human subjects. AB - The external CO2 dead space volume (Vd) in facial visors and respiratory protective devices is difficult, but important, to measure in human subjects. The lack of proper methods for its assessment has hampered the development of standards and the improvement of visor and device design. We have improved and evaluated a method for measuring Vd and the mean inspired fraction of CO2 (FI,CO2) in human subjects wearing facial visors or respiratory protective devices. The method is based on indirect measurements of inspiratory volumes using a calibrated respiratory inductive plethysmograph (RIP), and measurements of FCO2 with a mass spectrometer. The accuracy of the RIP method was assessed in eight subjects and its repeatability was studied during nasal and oral breathing, at rest and after bicycle ergometer work. We related the Vd,RIP results to two known external VdS (with the effective Vd equal to the geometric volume; 15 ml and 320 ml), through which the subjects breathed, using RIP and a pneumotachometer (PTM) simultaneously (Vd,RIP and Vd,PTM). The repeatability of Vd and mean FI,CO2 results was determined from duplicate recordings during the wearing of a welding visor. Initial RIP calibration was accepted if the inspiratory tidal volume error was < or = 10%. This resulted in an acceptable Vd,RIP error (< or = 20%; Vd = 320 ml) in six eight subjects. The validation technique allowed us to separate the Vd,RIP error into a volumetric error and an error related to CO2 measurement. Poor RIP volumetric accuracy over the initial portion of inspiration was detrimental to Vd accuracy. Using the welding visor, Vd and mean FI,CO2 were less at rest than after work and less during nasal breathing than during oral breathing. The intra-individual variability of Vd and mean FI,CO2 were lower during nasal breathing than during oral breathing. To summarize, the improved RIP based method can accurately (< or = 20% error) assess Vd and mean FI,CO2 in facial visors and respiratory protective devices in standardized work situations. A meticulous RIP calibration procedure and repeated validations of RIP volume and CO2 measurement accuracy must, however, be applied. PMID- 8681933 TI - Evidence of strategic effects in the modulation of orienting of attention. AB - Two models of visual orienting of attention are frequently described. Voluntary orienting is usually induced by central cues that direct subjects' attention to a given location in the visual space. Automatic orienting is provoked by presentation of peripheral cues. It is shown that automatic orienting induces greater attentional costs and benefits, and is less under a subject's control (Jonides 1981). Furthermore, it is not similarly affected by factors such as signal eccentricity (Umilta et al. 1991). The present experiment was undertaken to investigate how sensitive automatic orienting produced by peripheral cues is to voluntary modulations of attention. In experiment 1, subjects facing situations daily in which attentional requirements are high, were compared to non practiced ones. In experiment 2, other groups of practiced subjects facing high or low attentional-demanding situations were tested. In both experiments, subjects were asked to respond to signals, presented in rapid succession, in one of two possible locations in space, on each side of central fixation point. The cue signal automatically oriented attention to one of the two locations in which a first stimulus was presented with 100% probability; 100 ms after the first response (RT1), a second response signal (RT2) was delivered either in the same location (valid condition) or in the opposite location (invalid condition). Four cue probabilities were manipulated for this second stimulus: 100%/0%, 80%/20%, 50%/50%, and 20%/80%. Two eccentricities of 3 degrees and 6 degrees were tested. RT2 data demonstrated that (1) there was no eccentricity effect; (2) the higher the cue probability, the greater were the attentional costs; (3) the attentional effects were smaller in the practiced subjects who faced attention-demanding situations daily, than in the other groups. Put together, these data suggest that automatic orienting of attention can be modulated by voluntary attentional processes, according to cue probability. Furthermore, experienced subjects seem to be able to better distribute their attentional resources in space, with increased task requirements. The adoption of an optimal criterion might lead to the use of a cost minimizing strategy. PMID- 8681932 TI - A simple polynomial that predicts low-back compression during complex 3-D tasks. AB - While most existing models that predict loads on the low back for occupational risk analysis are restricted to assessing moments in the sagittal plan, a few have the ability to determine spine compression from three-dimensional (3-D) loading. The objective of this work was to find a method to estimate low-back compression forces during 3-D loading tasks from a model that contains as much biological content validity as the authors could incorporate, such as the effects of muscle co-contraction, but was simple enough to be implemented into a model appropriate for industrial use. The problem that had to be solved was how to represent the anatomical reality that a given muscle force vector contributes simultaneously to all three moments, flexion or extension, lateral bend and axial twist. Simply summing the compression components of independent equivalent muscles in each plane unrealistically assumes that muscles are uncoupled (i.e. each one works independently to support only one moment). In this study, loads in the various tissues of the low back that resulted from the simultaneous generation of moments about the three orthopaedic axes during 3-D tasks were estimated by an anatomically detailed 90 muscle model. A four-dimensional regression equation was developed to predict low-back compression from the three moments generated about the three axes (R2 = 0.94). Comparison of compression estimates from an uncoupled model showed that accounting for muscle coupling reduces compression by 22% on average. The predictive equation is presented to simplify analysis of complex 3-D industrial tasks for those who would like to incorporate it into their own models that produce moments of force in three plans of the L4/L5 level of the lumbar spine. PMID- 8681934 TI - Spatial reference frames and driver performance. AB - A survey of the relationship between visual reference frame dependence and driving performance is presented. Inter-individual differences in driving are related to three spatial reference frames: visual, gravito-inertial and egocentred. Their pertinence in driving is shown both in theory and experimentally. The experiment (with 36 subjects) presented here studied the basic activity of steering control in a simulated driving task. Results showed that steering control quality (estimated by time to line crossing) was significantly better among subjects who are relatively independent of visual or egocentred reference frames. PMID- 8681935 TI - Effects of control order, augmented feedback, input device and practice on tracking performance and perceived workload. AB - Virtual interfaces to advanced human-machine systems will present operators with a variety of perceptual-motor challenges. To inform the virtual interface design processes, the present experiments examined the effects of track order, level of knowledge of performance, type of control device, and the extent of practice on tracking performance and associated mental workload. Tracking was assessed by root mean square error. Subjective workload was measured using both the NASA Task Load Index (TLX) and the Subjective Workload Assessment Technique (SWAT). Results indicated non-linear effects, where tracking error and subjective workload both increased non-proportionally with track order. Trackball use resulted in more accurate performance and was judged to be of lower subjective workload than input using a mouse. Augmented knowledge of performance had little effect on either performance or workload. There was a number of interactions affecting performance that were replicated in perceived workload. Over acquisition trials, second-order tracking exhibited continuous improvement. This capability was retained even after a 30-day rest interval. Decrease a workload followed performance improvement in both initial acquisition and subsequent retention phases. The two subjective workload scales were essentially equivalent in terms of their sensitivity to task manipulations. These results support the direct association between workload and performance and confirms the use of workload in helping to evaluate the influence of diverse task-related demands. The implications for the design of virtual interfaces to real-world systems are examined in the light of these findings. PMID- 8681936 TI - Grip posture and forces during holding cylindrical objects with circular grips. AB - Individual finger position and external grip forces were investigated while subjects held cylindrical objects from above using circular precision grips. Healthy females (n = 11) and males (n = 15) lifted cylindrical objects of various weights (0.5, 1.0 and 2.0 kg), and varied diameters (5.0, 7.5 and 10.0 cm) using the 5-finger grip mode. The effects of 4-, 3- and 2-finger grip modes in the circular grip were also investigated. Individual finger position was nearly constant for all weights and for diameters of 5.0 and 7.5 cm. The mean angular positions for the index, middle, ring and little fingers relative to the thumb were 98 degrees, 145 degrees, 181 degrees, and 236 degrees, respectively. At the 10-cm diameter, the index and middle finger positions increased, while the ring and little finger positions decreased. There were no differences in individual finger position with regard to gender, hand dimension, or hand strength. Total grip force increased with weight, and at diameters greater or lesser than 7.5 cm. Total grip force also increased as the number of fingers used for grasping decreased. Although the contribution of the individual fingers to the total grip force changed with weight and diameter, the thumb contribution always exceeded 38% followed by the ring and little fingers, which contributed approximately 18 23% for all weights and diameters. The contribution of the index finger was always smallest (> or = 11%). There was no gender difference for any of the grip force variables. The effects of hand dimension and hand strength on the individual finger grip forces were subtle. PMID- 8681937 TI - Environmental Mutagen Society, 27th annual scientific meeting. Victoria, British Columbia, Canada, March 23-28, 1996. Abstracts. PMID- 8681938 TI - DNA-replication fidelity, mismatch repair and genome instability in cancer cells. AB - It has been suggested that an early event in the multistep progression of a normal cell to a tumor cell could be a defect that leads to an elevated mutation rate, thus providing a pool of mutants upon which selection could act to yield a tumor. Such a mutator phenotype could result from a defect in any of several DNA transactions, including those that determine the DNA replication error rate or the ability to correct replication errors. Recent evidence for the latter is the mutator phenotype observed in tumor cells of patients having a hereditary form of colon cancer. These patients have a germline mutation in genes required for post replication DNA mismatch repair. A second mutation arises somatically, yielding a greatly elevated mutation rate due to an inability to correct DNA replication errors. This connection between cancer, DNA replication errors and defective mismatch repair is the subject of this review, wherein we consider the key steps and principles for high fidelity replication and how their perturbation results in genome instability. PMID- 8681939 TI - Synthetic alleles at position 121 define a functional domain of human interleukin 1 beta. AB - The non-conservative substitution of the tyrosine residue at position 121 of human interleukin-1 beta (IL-1 beta) generates protein mutants showing strong reduction of the capacity to induce (a) prostaglandin E2 (PGE2) release from fibroblasts and smooth muscle cells, (b) murine T-cells proliferation and (c) activation of interleukin-6 (IL-6) gene expression. It is generally accepted that these functions are mediated by the type-I interleukin-1 receptor (IL-1RI). However, the mutant proteins maintain the binding affinity to the types-I and II IL-1 receptors, which is the same as the control IL-1 beta, suggesting that this amino acid substitution does not alter the structure of the molecule, except locally. Thus we have identified a new functional site of IL-1 beta different from the known receptor binding region, responsible for fundamental IL-1 beta functions. Moreover, we show that the same mutants maintain at least two hypothalamic functions, that is, the in vitro short-term PGE2 release from rat hypothalamus and the induction of fever in rabbits. This result suggests that there is yet another site of the molecule responsible for the hypothalamic functions, implying that multiple active sites on the IL-1 beta molecule, possibly binding to more than one receptor chain, trigger different signals. PMID- 8681940 TI - Successive amino-terminal proteolysis of the large subunit of ribulose 1,5 biphosphate carboxylase/oxygenase by vacuolar enzymes from French bean leaves. AB - Mainly using the protein immunoblot technique, we observed the decrease in amounts of the large subunit (LSU) and the small subunit (SSU) of ribulose 1,5 biphosphate carboxylase/oxygenase (Rubisco) in detached primary leaves of French bean plants during senescence under the light or in darkness, but detected no significant degradation products of these subunits. Treatment of the detached leaves with 0.6% (mass/vol.) dimethyl sulfoxide, 0.05% (mass/vol.) Tween 80 considerably promoted the senescence, as estimated by the reduction in content of the soluble protein, and also in the amounts of LSU and SSU, but no degradation product of either subunit was found. When extracts prepared from the primary leaves were incubated at pH 5.4 or pH 7.4, the amount of LSU of 53 kDa decreased and concurrently 50-kDa and 42-kDa polypeptides were formed. Since the results suggested that Rubisco may be degraded by vacuolar enzymes, we incubated Rubisco with vacuolar lysates prepared from the senescing primary leaves and found that the LSU, but not SSU, was degraded to a 41-kDa polypeptide through three intermediates of 50 kDa, 48 kDa and 42 kDa. Determination of amino-terminal amino acid sequences of these fragments indicated that each of the proteolysis steps occurred by removal of a small amino-terminal peptide. Experiments with various inhibitors of proteases as well as with a purified Vigna mungo vacuolar protease, termed SH-EP [Mitsuhashi, W. & Minamikawa, T. (1989) Plant Physiol. 89, 274-279] suggested the involvement of two types of proteases in these steps: a cysteine protease that is the same type of enzyme as SH-EP catalyzes the steps from the LSU to the 48-kDa polypeptide through the 50-kDa polypeptide, and a serine protease catalyzes the steps from the 48-kDa polypeptide to the 41-kDa polypeptide through the 42-kDa polypeptide. PMID- 8681941 TI - The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. AB - The peptide FA-LL-37, previously termed FALL-39, was originally predicted from on ORF of a cDNA clone isolated from a human bone marrow library. This peptide was synthesized and found to have antibacterial activity. We have now characterized and sequenced the complete gene for FA-LL-37, termed FALL39. It is a compact gene of 1963 bp with four exons. Exons 1-3 code for a signal sequence and the cathelin region. Exon 4 contains the information for the mature antibacterial peptide. Our results indicate that FALL39 is the only member of the cathelin gene family present in the human genome. Potential binding sites for acute-phase-response factors are identified in the promoter and in intron 2. A possible role for the cytokine interleukin-6 in the regulation of FALL 39 is discussed. Anti-(FA-LL-37) IgG located the peptide in granulocytes and we isolated the mature peptide from these cells after degranulation. Structural analysis determined the mature peptide to be LL-37. To obtain LL-37 for antibacterial assays, synthetic FA-LL-37 was degraded with dipeptidyl-peptidase I. This analysis showed that mature LL-37 is a potent antibacterial peptide. PMID- 8681942 TI - Conversion of the Kunitz-type module of collagen VI into a highly active trypsin inhibitor by site-directed mutagenesis. AB - The recombinant Kunitz protease inhibitor module (domain C5) of human collagen alpha 3(VI) chain was previously shown to lack inhibitory activity for proteases with trypsin-like specificity and some other proteases. We have now prepared mutants in the binding loop region including the P1' site (D2889-->A), the P2' site (F2890-->R) and the P3 site (T2886-->P) and in a more remote region (W2907- >V) either as individual substitutions or combinations of them. These mutants were analyzed for their kinetics of binding to trypsin by surface plasmon resonance and for their capacity to inhibit various proteases. Single substitutions (D-->A, T-->P, W-->V) showed an effect only for D->A which bound to trypsin with Kd = 0.25 microM. A 25-100-fold increase in affinity was observed for the double mutants T-->P/D-->A and F-->R/D-->A and approached the affinity of aprotinin (Kd approximately 0.01 nM) in two different triple mutants. These affinities correlated well with the inhibitory capacities of the mutants for trypsin in the cleavage of a large protein and a small peptide substrate. A similar but not completely identical improvement in inhibitory capacity was also observed for leucocyte elastase but not for thrombin. These data could be interpreted in terms of steric interferences or lack of hydrogen bonding of a few critical residues based on three-dimensional structures available for the C5 domain. PMID- 8681943 TI - The evolutionary conservation of a novel protein modification, the conversion of cysteine to serinesemialdehyde in arylsulfatase from Volvox carteri. AB - A novel post-translational protein modification has recently been described in two human sulfatases, by which a cysteine is replaced by a serinesemialdehyde (2 amino-3-oxopropionic acid) residue [Schmidt, B., Selmer, T., Ingendoh, A. & von Figura, K. (1995) Cell 82, 271-278]. This cysteine is conserved among all known eukaryotic sulfatases. Here we report the presence of this modification in arylsulfatase from the green alga Volvox carteri. The evolutionary conservation of this novel protein modification between sulfatases of V. carteri and man lends further support to the assumption that this modification is required for the catalytic activity of sulfatases and may be present in all sulfatases of eukaryotic origin. PMID- 8681944 TI - Nuclear-magnetic-resonance determination of the electron self-exchange rate constant of Clostridium pasteurianum rubredoxin. AB - The iron ion of rubredoxins efficiently exchanges one electron between the Fe(II) and Fe(III) oxidation states in mixtures of oxidized and reduced protein. The conditions under which the relaxation properties of the NMR signals can provide information about this exchange process have been worked out. The rate constant for the rubredoxin electron self-exchange ranges between 1.5 x 10(5) M-1 s-1 at 12 degrees C and 3 x 10(5) M-1 s-1 at 30 degrees C with an activation energy of the order of 24-30 kJ mol-1 in 50 mM potassium phosphate, pH 7. The increase of the electron self-exchange rate constant with ionic strength suggests that neutralizing electrostatic repulsion between the active sites of two molecules further accelerates the already fast electron exchange. PMID- 8681945 TI - Purification and characterization of the phosphatidylinositol-3,4,5-trisphosphate phosphatase in bovine thymus. AB - Using phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] prepared from phosphatidylinositol 4,5-bisphosphate and inositolphospholipid 3-kinase, we identified in bovine thymus extracts the enzyme activity which catalyzed dephosphorylation of PtdIns(3,4,5)P3, to produce phosphatidylinositol biphosphate. Since bovine thymus exhibited the highest level of activity among tissues screened, we tried to purify this enzyme PtdINs(3,4,5)P3 phosphatase from bovine thymus. After sequential chromatographies using S-Sepharose, heparin Sepharose, blue Sepharose, and Toyopearl HW55, the enzyme was purified 1875-fold with a yield of 10%. SDS/PAGE analysis revealed that a 120-kDA protein band copurified with the enzyme activity. The apparent molecular mass of the active protein was 120 kDa on size-exclusion chromatography, suggesting that the 120-kDa band on SDS/PAGE is the PtdIns(3,4,5)P3 phosphatase. Since PtdIns(3,4,5)P3 phosphatase seemed to be the only activity that metabolized PtdIns(3,4,5)P3, and the enzyme did not hydrolyze phosphatidylinositol 4,5-biphosphate, the enzyme may play a critical role in the inositolphospholipid 3-kinase signalling. PMID- 8681946 TI - Occurrence and structural analysis of highly sulfated multiantennary N-linked glycan chains derived from a fertilization-associated carbohydrate-rich glycoprotein in unfertilized eggs of Tribolodon hakonensis. AB - This study represents the first detailed investigation of the nature of highly sulfated (keratan-sulfate-like) complex-type asparagine-linked glycans having a tetraantennary core structure and shows the effectiveness of fast-atom bombardment mass spectrometric (FAB-MS) methods incorporating derivatization and mild methanolysis for analyzing such complex types of sulfated glycans. The structure of the N-glycan chains was unambiguously established by a combination of compositional analysis, methylation analysis, mild methanolysis for desulfation, hydrazinolysis/nitrous acid deamination, enzymatic (endo-beta galactosidase and peptide:N-glycosidase F) digestions, and instrumental analyses (1H-NMR spectroscopy and FAB-MS) which revealed the novel repeating sulfated carbohydrate sequences, +/- Gal beta 1-->4Gal beta 1[-->(HSO3-->6)GlcNAc beta 1- >3(+/- Gal beta 1-->4)Gal beta 1]n--> (see Structure I; p + q + r + s approximately 14). This sequence is unique in: (a) the skeletal structure is similar to that of keratan sulfate but is completely devoid of 6-O-sulfated Gal residues and (b) the presence of branched Gal residues in the sequence -->4GlcNAc beta 1-->3(Gal beta 1-->4)Gal beta 1-->. [formula: see text] PMID- 8681947 TI - Localization and regulation of the putative membrane fatty-acid transporter (FAT) in the small intestine. Comparison with fatty acid-binding proteins (FABP). AB - The expression of the putative membrane fatty-acid transporter (FAT) was investigated in the small intestine. The FAT mRNA level was higher in the jejunum than in the duodenum and was lower in the ileum, as observed for cytosolic fatty acid-binding proteins (FABP) expressed in this tissue. No FAT transcript was found in the stomach or colon. FAT mRNA was constitutively expressed in the epithelial cells located in the upper two thirds of villi, while it was undetectable in the crypt cells and submucosal cells. In jejunal mucosa, immunochemical studies showed that FAT protein was limited to the brush border of enterocytes. No fluorescence was found in the goblet cells. To determine whether FAT responded to changes in fat intake, as reported for FABP, the effect of two high-fat diets, which essentially contained either medium-chain fatty acids or long-chain fatty acids (sunflower-oil diet), was investigated. The sunflower-oil diet greatly increased FAT mRNA abundance throughout the small intestine. In contrast, a weak effect of medium-chain fatty acids was observed only in the jejunum. As found for FABP expression, treatment with the hypolipidemic drug bezafibrate affected FAT expression. These data demonstrate that FAT and FABP are co-expressed in enterocytes, as has been shown in adipocytes, myocytes and mammary cells. The data suggest that these membrane and cytosolic proteins might have complementary functions during dietary-fat absorption. PMID- 8681948 TI - Structure of the human gene encoding the phosphorylase kinase beta subunit (PHKB). AB - We have determined the cDNA sequence and the gene structure of the human phosphorylase kinase beta subunit (PHKB). With 95% amino acid sequence identity, the predicted primary structure is highly similar to that of the rabbit beta subunit. At least 140 kilonucleotides in length, the gene is large and consists of 33 exons. Exons 26 and 27 are two homologous, mutually exclusively spliced exons in the middle of the gene, and exon 2 is a facultatively utilized cassette exon encoding an alternative N-terminus of the beta subunit. The previous assignment of the PHKB gene to chromosome 16 is confirmed by the successful screening of a chromosome 16-specific genomic library. Plaque hybridization at reduced stringency led to the isolation of two processed pseudogenes, PHKBP1 and PHKBP2, but of no other PHKB-related sequences. PMID- 8681949 TI - The antenna complexes of the purple non-sulfur photosynthetic bacterium Rhodocyclus tenuis. Structural and spectral characterization. AB - The photoreceptor complex (B885-RC) and the peripheral antenna complex (B800-860) were isolated from photosynthetic membranes of the purple non-sulfur bacterium Rhodocyclus tenuis DSM 109 using a detergent combination of Deriphate-160 and octyl glucoside and subsequent linear sucrose gradient centrifugation. The two complexes were characterized by room-temperature absorption, circular dichroism and fluorescence spectroscopy. The B800-860 complex has a more red-shifted B860 absorbance band. The alpha,beta-polypeptides were purified with a reverse-phase HPLC system and resolved at a ratio of 1:1 in the B800-860 complex and at an overall ratio of 1:1 for the B885-RC complex. The complete amino acid sequences of the alpha and beta polypeptides of the B800-860 and B885-RC complexes were determined by micro-sequencing analysis and mass spectrometry. The B800-860-alpha polypeptide possesses an identical N-terminal domain (the first 15 residues) to Rhodobacter sphaeroides B800-850-alpha polypeptide. The central hydrophobic and C terminal domains of the B800-860-alpha,beta polypeptides show a number of B870/880-like structural elements in which, of special interest, is the WWSEF cluster in the C-terminal domain of the B800-860-alpha polypeptide which is very similar to the WWEF cluster in the same region of Rhodopseudomonas viridis B1015 alpha polypeptide. The more red-shifted absorption characteristic of the 860-nm bacteriochlorophylls could most probably be related to the B870/880-like polypeptide features in the central hydrophobic domains and the C-terminal domains of the B800-860-alpha,beta polypeptides. The hydropathy plot of the B800 860-alpha polypeptide exhibits an extended C-terminal hydrophobic segment indicative of a second membrane-contacting domain, which has not been found in the antenna polypeptides of the purple bacteria with intracytoplasmic membranes. Further sequence analysis revealed the existence of multiple forms of the B885 alpha,beta polypeptides, the B885-alpha 1,alpha 2 polypeptides, and the B885-beta 1,beta 2 polypeptides. The B885-Alpha 2 polypeptide shows an identical sequence to the B885-alpha 1 polypeptide, but it is 12 amino acid residues shorter than the B885-alpha 1 polypeptide at the C-terminal. The two species of the B885-beta polypeptides were identified as an identical sequence with only one amino acid residue variation at sequence position 34, where the B885-beta 1 has a valine residue and the B885-beta 2 polypeptide an isoleucine residue. The possible correlation between the intensity of the near-infrared circular dichroic signal and the specific structural features of the alpha and beta core antenna polypeptides is also discussed. PMID- 8681950 TI - Primary structure, expression and developmental regulation of a Dictyostelium calcineurin A homologue. AB - cDNA clones for the catalytic subunit of Ca2+/calmodulin(CaM)-dependent protein phosphatase (calcineurin A, protein phosphatase 2B) from Dictyostelium discoideum were isolated by functional screening of a lambda gt11 lysogen expression library with labeled Dictyostelium CaM. A complete cDNA of 2146 bp predicts a protein of 623 amino acids with homology to calcineurin A from other organisms and a similar molecular architecture. However, the Dictyostelium protein contains N-terminal and C-terminal extra domains causing a significantly higher molecular mass than found in any of its known counterparts. Recombinant Dictyostelium calcineurin A was purified from Escherichia coli cells and shown to display similar enzymatic properties as the enzyme from other sources. On Western blots specific antibodies against the protein recognized a band of approximately 80 kDa that migrated with an endogenous CaM-binding activity. Both the mRNA for calcineurin A and the protein are expressed during the growth phase. During early development the abundance of the protein is reduced and then increases to peak after 10 h of starvation, when tight aggregates have formed. PMID- 8681952 TI - Two additional 5' exons in the human Vigilin gene distinguish it from the chicken gene and provide the structural basis for differential routes of gene expression. AB - Vigilin, a 150-kDa protein, contains 14 tandemly arranged domains, each consisting of a KH RNA-binding motif and a spacer region. Here, we report on the physical structure of the human Vigilin gene with 29 exons, thereby outnumbering the chicken gene by two additional 5' exons. These additional exons, 1A and 1B, are alternatively though concurrently spliced to exon 1C which is homologous to the first exon in the chicken gene. None of the additional human exons code for an amino-terminal extension of Vigilin, due to in-frame stop codons. Structural features of exon 1A, however, would allow the translation of a 13-amino-acid peptide from an upstream open reading frame preceding the vigilin open reading frame. We suggest that exons 1A and 1B have been gained during evolution, allowing alternative routes of expression control of the human Vigilin gene. PMID- 8681951 TI - trans-Acting factors, detoxication enzymes and hepatitis B virus replication in a novel set of human hepatoma cell lines. AB - A panel of four novel human hepatoma cell lines was isolated from a single tumor from a male individual. BC1, B16 and B16A2 lines were well differentiated, while cells of the B9 line were only poorly differentiated, being essentially negative for the functions analyzed. These cell lines have been surveyed for expression of a large set of plasma proteins, accumulation of liver-specific mRNAs and DNA binding activity of ubiquitous and liver-enriched transcription factors. BC1 cells expressed the highest levels of albumin mRNA, whereas B16 and B16A2 cells accumulated the largest amounts of haptoglobin mRNA. In addition, B16 and B16A2 cells were unique in that they expressed CYP2E1 mRNA, a species absent from the available human liver cells, including HepG2 hepatoma cells, and 3 methylcholanthrene-inducible CYP1A2 mRNA. The activities of genes encoding transcription factors were evidenced in all four cell lines which expressed mRNAs for nuclear factor interleukin 6 and hepatocyte nuclear factor 1 (HNF) together with the DNA-binding activity of NFY and AP1 nuclear proteins. Strikingly, HNF-1 and HNF-4-like DNA-binding activities were restricted to BC1, B16 and B16A2 cells, supporting the idea of the potential role of these (or closely related) factors in the maintenance and/or in the establishment of the differentiated phenotype. B9 cells contained variant HNF1-like DNA-binding activity, similar to dedifferentiated rat hepatoma cells of the H5 line. CCAAT/enhancer-binding protein and HNF-3-like activities were found in all cell lines, although at a lower level and/or activity in B9 cells. Finally, transfection experiments of plasmids containing the whole hepatitis-B virus genome demonstrated that B16 cells, but not B9 cells, were able to support hepatitis-B virus replication and virion production, in agreement with the notion that HNF-1 activity is necessary for viral replication. We believe that the specific complement of transcription factors expressed in the differentiated BC1, B16 and B16A2 cells, and in the poorly differentiated B9 cells, will allow studies on the regulation of hepatic gene expression in these human lines, and will also aid the analysis of xenobiotic metabolism and the biology of hepatitis-B virus replication. PMID- 8681953 TI - Purification of Escherichia coli pro-haemolysin, and a comparison with the properties of mature alpha-haemolysin. AB - Pro-haemolysin (approximately 110 kDa), the inactive precursor of the membrane lytic toxin alpha-haemolysin, has been purified from an overproducing strain of Escherichia coli. Pro-haemolysin forms aggregates in aqueous media, like the mature protein, suggesting an amphipathic structure. Direct measurements of protein binding to liposomal membranes, following a novel procedure, show that pro-haemolysin can bind the lipid bilayers to a similar extent as alpha haemolysin. This is confirmed by the observed changes in the intrinsic fluorescence emission of the protein upon binding the bilayers. However, pro haemolysin is totally unable to induce liposomal membrane lysis. Binding of Ca2+, that is essential for the lytic activity of alpha-haemolysin, is greatly diminished in the precursor protein, as shown both by direct measurements of 45Ca(2+)-binding and by fluorescence measurements. The results suggest that binding of a fatty acyl residue in the activation step brings about an important conformational change in the protein that involves the Ca(2+)-binding domain. PMID- 8681954 TI - NMR investigation of the solution conformation of oxidized flavodoxin from Desulfovibrio vulgaris. Determination of the tertiary structure and detection of protein-bound water molecules. AB - Desulfovibrio vulgaris flavodoxin has been investigated with a combination of homo- and hetero-nuclear two-dimensional and three-dimensional NMR spectroscopy. The analysis of NOE, hydrogen exchange and J-coupling data led to a set of 1349 NOE, 63 hydrogen bond and 109 backbone phi-angle restraints which were used to determine the solution structure of the oxidized flavodoxin applying the distance geometry program DIANA combined with restrained energy minimization methods. Flavodoxin in solution consists of a five-stranded parallel beta-sheet which is pairwise flanked by four alpha-helices. The solution structure has been compared with the known crystal structure. While the global fold is identical, differences have been detected concerning local conformations. In addition, protein-bound water molecules have been localized by NOE effects which were detected in NMR experiments avoiding solvent suppression. The locations of these water molecules have been compared with those found in the X-ray structure. PMID- 8681955 TI - NMR detection of arginine-ligand interactions in complexes of Lactobacillus casei dihydrofolate reductase. AB - 1H-NMR and 15N-NMR signal assignments have been made for the eight arginine residues in Lactobacillus casei dihydrofolate reductase in its binary complex with methotrexate and in its ternary complex with methotrexate and NADPH. 1H-NMR chemical shifts for the guanidino groups of two of the arginines (Arg57 and Arg43) were sensitive to different modes of binding of the guanidino groups with charged oxygen atoms of the ligands. In the complexes formed with methotrexate, Arg57 showed four non-equivalent NH eta proton signals indicating hindered rotation about the N epsilon-C zeta and C zeta-N eta bonds. The NH eta 12 and NH eta 22 protons showed large downfield shifts, which would be expected for a symmetric end-on interaction of these protons with the charged oxygen atoms of a carboxylate group in methotrexate. These effects were not observed for the complex formed with trimethoprim, which does not contain any carboxylate groups. In the complex formed with NADPH present, Arg43 showed a large downfield chemical shift for its NH epsilon proton and a retardation of its rate of exchange with water. This pattern of deshielding contrasts with that detected for Arg57 and is that expected for a side-on interaction of the guanidino group protons with charged oxygen atoms of the ribose 2'-phosphate group of NADPH. PMID- 8681956 TI - Phosphorylated T cell receptor zeta-chain and ZAP70 tandem SH2 domains form a 1:3 complex in vitro. AB - The zeta polypeptide is part of the T cell antigen receptor (TCR). The zeta-chain contributes to efficient cell-surface expression of the TCR and accounts for part of its signal transduction capability. TCR recognition triggers a complex set of events that result in cellular activation. The protein tyrosine kinase (PTK) Lck phosphorylates the zeta-chain, which in turn associates with another PTK, ZAP70, and stimulates its phosphorylation activity. Here we report the expression of the intracellular part of the zeta-chain and its biochemical characterization. The recombinant protein does not dimerize by itself in solution. Circular-dichroic analysis reveals a random coil conformation. zeta, phosphorylated using recombinant Lck, associates with recombinant ZAP70 tandem-SH2 domains. All three T cell activation motifs in zeta bind ZAP70 tandem-SH2 domains in vitro, forming a 1:3 complex. This result extends the picture, derived from earlier studies, of a mechanism for signal amplification. PMID- 8681957 TI - Synthesis and differential properties of creatine analogues as inhibitors for human creatine kinase isoenzymes. AB - Fourteen new creatine analogues, all with a guanidine function and either a polar or an apolar group instead of the creatine carboxylic function, were tested as potential inhibitors for human creatine kinase by kinetic analysis of their effects on the reaction rate. Only compounds bearing an apolar aromatic moiety, which was spaced from the guanidine function by at least two bonds, proved to have a significant inhibitory activity and showed a mixed-type inhibition similar to that of creatine. Among these compounds 2,6-dichlorobenzylguanidine (Ki = 5.6 mM and 39.8 mM for muscle-type and brain-type creatine kinases, respectively) and 3-(2,6-dichlorophenyl)propylguanidine (Ki = 15 mM and 4.5 mM) were the more potent inhibitors and showed a significant isoenzyme selectivity between muscle- and brain-type creatine kinases. Our results are in agreement with recent data that suggest the location of a hydrophobic pocket near the guanidine-binding domain of the enzyme. The observed selectivity in isoenzyme inhibition may be useful to study structural differences in catalytic centers. PMID- 8681959 TI - Effects of overexpression of the transferrin receptor on the rates of transferrin recycling and uptake of non-transferrin-bound iron. AB - The possibilities that the recycling of the transferrin receptor is a rate limiting step in the efflux of endocytosed transferrin, and that the receptor functions as a trans-membrane Fe transporter were investigated in untransfected Ltk- cells and in cells transfected with different levels of DNA for wild-type, mutant and chimeric human transferrin receptors. The uptake of transferrin-bound Fe and non-transferrin-bound Fe(II), and the surface binding, endocytosis and recycling of transferrin were measured. In cells that expressed increasing numbers of surface transferrin receptors, the rate of Fe uptake increased at a slower rate than the number of receptors. By measurement of the rates of endocytosis and recycling of transferrin it was shown that this effect was not due to a deficiency of endocytosis, but to a slower rate of recycling as the receptor numbers increased. Hence, a restricted recycling rate of the transferrin receptor appeared to be responsible for the slower rate of Fe uptake by cells with high receptor numbers, presumably because one or more cytosolic components required for recycling were in limited supply. The rate of uptake of non transferrin-bound Fe(II) was not influenced by the number of transferrin receptors present on the surface of the cells even though this varied more than 20-fold between the different cell lines. Hence, this investigation does not support the hypothesis that the receptors play a direct role in the transport of Fe(II) across cell membranes, as has been proposed previously [Singer, S. J. (1989) Biol. Cell 65, 1-5]. PMID- 8681958 TI - Phosphorylation of proteasomes in mammalian cells. Identification of two phosphorylated subunits and the effect of phosphorylation on activity. AB - The proteasome, a multimeric protease, plays an important role in nonlysosomal pathways of intracellular protein degradation. This study was undertaken to determine which subunits of mammalian proteasomes are phosphorylated and to investigate the possible role of phosphorylation in regulating proteasome activity and the association with regulatory components. Rat-1 fibroblasts were grown in the presence of [32P]phosphate and proteasomes were immunoprecipitated from cell lysates with proteasome-specific polyclonal antibodies. Subsequent analysis by two-dimensional polyacrylamide gel electrophoresis showed two radiolabeled proteasome subunits which were identified using monoclonal antibodies as C8 and C9. Treatment of human embryonic lung cells (L-132), under identical conditions, also showed the same two phosphorylated subunits. Phosphoamino acid analysis revealed phosphoserine to be present in both C8 and C9. Examination of the sequence of C9 showed a potential cGMP-dependent phosphorylation site (-Arg3-Arg-Tyr-Asp-Ser-Arg8-), whilst C8 contains several potential casein kinase II phosphorylation sites. Following immunoprecipitation by a monoclonal antibody and dephosphorylation by acid phosphatase, proteasomes were observed to have significantly lower activities when compared to phosphorylated proteasomes, implying that phosphorylation may be an important mechanism of regulating proteasome function. Free proteasomes were separated by gel-filtration from those complexed with regulatory complexes to form the 26S proteinase. The ratio of phosphorylation of C8 and C9 was found to be very similar in the two complexes but the level of phosphorylation was higher in the 26S proteinase than in free proteasomes. PMID- 8681960 TI - A new method for the determination of specific 13C enrichment in phosphorylated [1-13C]glucose metabolites. 13C-coupled, 1H-decoupled 31P-NMR spectroscopy of tissue perchloric acid extracts. AB - A 31P-NMR method for the determination of 13C enrichment in phosphorylated [1 (13)C]glucose metabolites was developed by taking advantage of the 13C satellites detectable for 31P-NMR signals of metabolites such as UDP-hexoses, UDP-N acetylhexosamines and other phosphorylated compounds generated during glycolysis and subsequent anabolism. HT-29 cells were incubated in culture medium containing 4.5 g/l [1-(13)C]glucose for 24 h prior to cell extraction, and high-resolution 31P-NMR spectra were acquired from perchloric acid extracts. Since glucose and its phosphorylated products are key metabolites for many different metabolic processes, this method may be very helpful for studying specific metabolic pathways involving phosphorylated glucose metabolites. PMID- 8681962 TI - The identification of 11 beta-hydroxysteroid dehydrogenase as carbonyl reductase of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone. AB - The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NC), which is generated by nitrosation of nicotine, requires enzymatic activation by cytochrome-P450-mediated alpha-carbon hydroxylation to yield particularly powerful carcinogenic alkylating intermediates. Pyridine-N-oxidation and carbonyl reduction are detoxification pathways, the latter by providing the functional hydroxy moiety necessary for glucuronosylation and final excretion of NC. For more than a decade, the enzyme responsible for NC carbonyl reduction has awaited characterization. In the present study, we demonstrate that the NC carbonyl reductase is identical to 11 beta-hydroxysteroid dehydrogenase (11 beta HSD), the physiological function of which is the oxidoreduction of glucocorticoids. We conclude that the expression of 11 beta-HSD (together with glucuronosyl transferase) may have profound influence on the carcinogenic potency of NC and that many compounds of endogenous and exogenous origin, which are known to be substrates or inhibitors of 11 beta-HSD, may modulate NNK-induced carcinogenicity by competing for the same enzyme. In light of the known species and tissue differences in the expression of 11 beta-HSD isozymes, important aspects of NNK-induced tumorigenesis, such as metabolic activation versus inactivation or organospecificity, can now be re-evaluated. PMID- 8681961 TI - Developmental expression of CYP2E1 in the human liver. Hypermethylation control of gene expression during the neonatal period. AB - Cytochromes P-450 are responsible for the biotransformation of drugs and other hydrophobic molecules by the liver. Several isoforms coexist which display an asynchronous onset during the perinatal period suggesting the involvement of multiple mechanisms of regulation. In this paper, we have shown that the CYP2E1 protein and its associated activity could not be detected in the fetal liver and rise during the first few hours following birth independently of the gestational age (between 25-40 weeks). During this period, the CYP2E1 RNA content remains fairly low: the stabilization of the low amount of existing CYP2E1 protein by endogenous ketone bodies could explain the early neonatal rise of the protein level. From 1 month to 1 year, the protein content gradually increases and is accompanied by the accumulation of CYP2E1 RNA, suggesting a transcriptional activation of the gene during the late neonatal period. We examined the methylation status of CpG residues in the 5' flanking region, first exon and first intron of CYP2E1 gene cleaved with HpaII/MspI. Genomic DNA from fetal liver shows several hypermethylated spots in the first-exon-first-intron region, which progressively disappear in neonatal samples. We conclude that during the neonatal period, the accumulation of hepatic CYP2E1 RNA is correlated with the degree of methylation at the 5' end of the CYP2E1 gene. PMID- 8681963 TI - Functional characteristics of a variant thyrotropin receptor. AB - A claim has been made that a variant of the human thyrotropin receptor in which Pro52 is replaced by Thr ([Thr52]thyrotropin receptor) is associated with autoimmune thyroid diseases and displays increased responsiveness to thyrotropin. We have analysed the functional characteristics of this variant receptor. Equivalent numbers of of the wild type and of the variant thyrotropin receptor, measured both by 125I-thyrotropin binding and by flow cytofluorimetry, were transiently expressed in COS-7 cells. Under these conditions, the two receptors showed the same degree of constitutive activity for the cAMP pathway, the same affinity for bovine thyrotropin, and a virtually identical responsiveness to bovine thyrotropin for activation of both the cAMP and inositol-phosphate regulatory pathways. Our results show that the [Thr52]thyrotropin receptor variant of the human thyrotropin receptor, which is present in the 12% of the population, does not affect receptor function and represents most likely a simple polymorphism. PMID- 8681964 TI - 11 beta-hydroxylase activity in recombinant yeast mitochondria. In vivo conversion of 11-deoxycortisol to hydrocortisone. AB - In mammals, the final 11 beta-hydroxylation step of the hydrocortisone biosynthesis pathway is performed by a mitochondrial enzyme, namely cytochrome P 450(11 beta), together with the electron carriers adrenodoxin and NADPH adrenodoxin oxidoreductase. Successful production of a functional steroid 11 beta hydroxylase activity was obtained in recombinant yeast in vivo. This conversion was achieved by coexpression of a mitochondrially targeted adrenodoxin and a modified bovine P-450(11 beta) whose natural presequence was replaced by a yeast presequence, together with an unexpected yeast endogenous NADPH-adrenodoxin reductase-like activity. Adrenodoxin and P-450(11 beta) behave as a mitochondrial matrix and membrane protein, respectively. Saccharomyces cerevisiae apparently produces a mitochondrial protein which is capable of transferring electrons to bovine adrenodoxin, which in turn transfers the electrons to P-450(11 beta). The endogenous adrenodoxin oxidoreductase gains electrons specifically from NADPH. The notion that a yeast microsomal NADPH P-450 oxidoreductase can transfer electrons to mammalian microsomal P-450s can be extended to mitochondria, where an NADPH adrenodoxin oxidoreductase protein transfers electrons to adrenodoxin and renders a mitochondrial mammalian P-450 functional in vivo. The physiological function of this yeast NADPH adrenodoxin oxidoreductase activity is not known. PMID- 8681966 TI - Recombinant prespore-specific antigen from Dictyostelium discoideum is a beta sheet glycoprotein with a spacer peptide modified by O-linked N acetylglucosamine. AB - Prespore-specific antigen (PsA) is a putative cell-adhesion molecule of the cellular slime mould Dictyostelium discoideum, which has a similar molecular architecture to several mammalian cell-surface proteins. It has an N-terminal globular domain presented to the extracellular environment on an O-glycosylated stem (glycopeptide) that is attached to the cell membrane through a glycosyl PtdIns anchor. The sequence of PsA suggests that PsA may belong to a new family of cell-surface molecules and here we present information on the structure of the N-terminal globular domain and determine the reducing-terminal linkage of the O glycosylation. To obtain a sufficient amount of pure protein, a secreted recombinant form of PsA (rPsA), was expressed in D. discoideum and characterised. 1H-NMR spectra of rPsA contained features consistent with a high degree of beta sheet in the N-terminal globular domain, a feature commonly observed in cell adhesion proteins. Solid-phase Edman degradation of the glycopeptide of rPsA indicated that 14 of the 15 threonines and serines in the spacer region were glycosylated. The chemical structures of the O-glycosylations were determined to be single N-acetylglucosamine residues. PMID- 8681965 TI - Dissociation of the complex between the neuroendocrine chaperone 7B2 and prohormone convertase PC2 is not associated with proPC2 maturation. AB - 7B2 is a highly conserved neuroendocrine protein that is associated with the proform of the prohormone convertase PC2 in the early stages of the secretory pathway in intermediate pituitary cells of Xenopus laevis. Subsequent processing of 7B2 and dissociation of the 7B2/proPC2 complex is thought to be associated with the conversion of proPC2 to the mature enzyme. Here, we report that, in both Xenopus and mouse intermediate cells, proPC2 maturation does not take place when the proenzyme is associated with the 7B2 precursor and that, in contrast to the previous notion, dissociation of the complex between proPC2 and the N-terminal 7B2 fragment precedes, and is thus not directly linked to, proPC2 maturation. In vitro, conversion of newly synthesized proPC2 was efficiently blocked by recombinant 7B2 and studies with truncation mutants indicated that a short segment in the C-terminal region of 7B2 is necessary and sufficient for this inhibitory effect. Our results indicate that, after 7B2 precursor processing and dissociation of the N-terminal fragment, the C-terminal fragment of 7B2 may remain associated with proPC2, thereby preventing autocatalytic conversion of the proenzyme until the appropriate site for activation in the secretory pathway is reached. PMID- 8681968 TI - Study of the coordination chemistry of prostaglandin G/H synthase by resonance Raman spectroscopy. AB - Resonance Raman spectra of prostaglandin G/H synthase (PGHS) in its ferric and ferrous states have been obtained by Soret excitation. In native PGHS, which contained only 0.25 heme/monomeric apoprotein, the ferric heme was in a high-spin hexacoordinated state. The presence of a vibration at 289 cm-1 that was responsive to H(2)16O -> H(2)18O replacement was taken as evidence for the presence of a H-bonded H2O molecule as the sixth ligand of the Fe. A study, by CD and resonance Raman spectroscopy, of heme incorporation into the apoprotein showed that, for heme/protein ratios lower than 0.5, the heme was in the same ferric high-spin hexacoordinated state as in the native enzyme. For heme/protein ratios higher than 0.5, the concomitant formation of two minor species was observed: a low-spin hexacoordinated species which could be due to the axial coordination of a distal histidine to the Fe trans to its proximal histidine ligand; and a high-spin pentacoordinated species that corresponded to non specific binding of the heme to the apoprotein. In the reduced state, the heme of PGHS contained a high-spin pentacoordinated Fe(II) with a histidine as the proximal ligand. However, this species shifted spontaneously towards a low-spin hexacoordinated Fe(II) species in which the iron was probably coordinated by a distal histidine as the sixth axial ligand. The PGHS Fe(II).CO derivative displayed an Fe-CO stretching mode at 529 cm-1, which is in the range observed for peroxidases. Such a high frequency could be due to H-bonding between the oxygen atom of the CO ligand and the distal histidine, His207. Since this histidine plays an important role, by coordination of Fe(II) or Fe(III) of PGHS and stabilization of the ligands of the Fe, H2O or CO by H-bonding, it is suggested that this histidine could also play a key role in the cleavage of the O O bond of peroxides by peroxidases. PMID- 8681967 TI - Synthesis, characterization and preliminary crystallographic data of N6-(6 carbamoylhexyl)-FAD-D-amino-acid oxidase from pig kidney, a semi-synthetic oxidase. AB - The FAD analogue, N6-(6-carboxyhexyl)-FAD, carrying a hexanoic acid residue at the N6 position of the adenine moiety was synthesized. A new semi-synthetic oxidase, N6-(6-carbamoylhexyl)-FAD-D-amino acid oxidase, was prepared by reacting the succinimido ester of N6-(6-carboxyhexyl)-FAD with apo-D-amino-acid oxidase from pig kidney in the presence of benzoate. Reaction conditions and methods have been developed for preparing pure semi-synthetic and fully active N6-(6 carbamoylhexyl)-FAD-D-amino acid oxidase that contains 1 covalently bound FAD analogue/subunit, as verified by redialysis, ultraviolet spectrophotometry, electrospray ionization (ESI)-MS and peptide mapping. Presumably, the N6-(6 carbamoylhexyl)-FAD moiety of this semi-synthetic D-amino-acid oxidase (DAAO), selectively bound to Lys163, has a structurally similar position to that of the non-covalently bound FAD of the native holoenzyme, since both DAAO forms show very similar kinetic properties (semi-synthetic DAAO, Vmax(app) = 17.7 mumol min 1 mg-1; KM(app) = 4.5 mM; native holo-DAAO, Vmax = 12.2 mumol min-1 mg-1; KM = 1.8 mM). Compared with the native holo-D-amino acid oxidase. this new semi synthetic N6-(6-carbamoylhexyl)-FAD-D-amino acid oxidase is a considerably more stable enzyme that shows meso-thermostability and withstands inactivation on dilution. Probably, the lack of dissociation of FAD and, consequently, the absence of the instable apoenzyme are responsible for these phenomena. Preliminary investigations resulted in finding convenient and reproducible crystallization conditions for N6-(6-carbamoylhexyl)-FAD-D-amino acid oxidase. The single crystals, obtained by the sitting-drop method using ammonium sulfate as precipitant, belong to the tetragonal space group I422 with cell dimensions a = 16.3 nm, c = 13.6 nm. The crystals diffract to 0.3-nm resolution, with two molecules being present in the asymmetric unit, demonstrating the two-subunit quarternary structure of this semi-synthetic D-amino-acid oxidase. PMID- 8681969 TI - Acetylcholinesterase in Dendrobaena veneta (Oligochaeta: Opisthopora) is present with forms sensitive and insensitive to phosphatidylinositol phospholipase C. Biochemical characterization and histochemical localization in the nervous system. AB - Three distinct acetylcholinesterases were detected in the annelid oligochaete Dendrobaena veneta. Two enzymes (alpha, beta), copurified from a Triton-X-100 soluble extract of whole animals by affinity (edrophonium-Sepharose) chromatography, were separately eluted from a Sephadex G-200 column. Gel filtration chromatography, sedimentation analysis and SDS/PAGE showed the alpha and beta forms to be a globular dimer (110 kDa, 7.0 S) and a hydrophilic monomer (58 kDa, 5.0 S) respectively, both weakly linked to the cell membrane. The third form (gamma), also purified to homogeneity by slower filtration through an edrophonium-Sepharose matrix, proved to be an amphiphilic globular dimer (133 kDa, 7.0 S) with a phosphatidylinositol anchor giving cell membrane insertion, detergent (Triton X-100, Brij 96) interaction and self-aggregation. The alpha acetylcholinesterase showed a fairly low substrate specificity: the beta form hydrolyzed propionylthiocholine at the highest rate and was inactive on butyrylthiocholine; the gamma acetylcholinesterase, showing a marked active-site specificity with differently sized substrates, was likely functional in cholinergic synapses. Studies with inhibitors showed incomplete inhibition of all three acetylcholinesterase by 1 mM eserine and different sensitivity for edrophonium or procainamide. The alpha and beta forms, sensitive to 1,5-bis(4 allyldimethylammoniumphenyl)-pentan-3-one dibromide, were unaffected by tetra(monoisopropyl)-pyrophosphortetramide, while both these agents inhibited the gamma enzyme. All three forms showed excess-substrate inhibition by acetylthiocholine. Enzyme activity was histochemically localized in the nerve ring and its minor branches. Monomeric acetylcholinesterase (beta) is likely the only form present in the ganglionic glial framework. PMID- 8681970 TI - The effect of linoleic acid on pH inside sodium bis(2-ethylhexyl)sulfosuccinate reverse micelles in isooctane and on the enzymic activity of soybean lipoxygenase. AB - The effective pH of sodium bis(2-ethylhexyl)sulfosuccinate (AOT) reverse micelles (pHrm), containing buffers of different pH (pHst) and various amounts of linoleic acid, was studied within the range of compositions used to study the activity of soybean lipoxygenase in reverse micelles. Significant shifts of pHrm versus pHst were observed for the solutions of relatively higher pHst, dependent on linoleic acid and buffer concentrations. The effect diminished as pHst became closer to 7. When low-ionic-strength buffers were added to AOT solutions in isooctane, a significant buffering effect of linoleic acid in reverse micelles was observed. Solubilization of > 3 mM linoleic acid in micellar solutions containing 25 mM buffers gave the observed pHrm values almost independent of pHst. This effect diminished with the ionic strength of the buffering solution, but did not vanish even at 200 mM buffer. The observed effects result from the balance between ionization of linoleic acid and its partition between the water pool and the micellar interface. The enzymic activity of soybean lipoxygenase in the AOT reverse micellar solutions of the determined pHrm values was also studied. A significant reduction of the kinetics of the enzymic activity was observed, for all studied reverse micellar solutions. Changes of pHrm, caused by the presence of acidic substrate (linoleic acid) do not explain the observed reduction of activity directly through the effect on the enzyme. Due to unfavourable partition of the substrate between the microphases present in the systems, enhanced by reduction of pH at higher total concentrations of linoleic acid, the saturation of the enzyme with the substrate was not observed in the system and is difficult to attain experimentally in reverse micelles. A shift of the lipoxygenase activity/pHrm profile but negligible shift of the activity/pHst profile, with respect to aqueous buffer solutions, were observed. This indicates that either the information given by pH indicators used does not reveal the true pH of the enzyme in these reverse micelles, or that the sample of the enzyme is pH insensitive over a broader pH range than results from the relationship observed for linoleic acid in aqueous solutions. The latter conclusion is consistent with the data on lipoxygenase activity towards linoleyl sulfate in aqueous solutions [Bild, G. S., Ramadoss, C. S. & Axelrod, B. (1977) Lipids 12, 732-735]. Conditions for measuring pH-independent lipoxygenase activity in reverse micelles are discussed. PMID- 8681971 TI - Interferon-modulated expression of genes encoding the nuclear-dot-associated proteins Sp100 and promyelocytic leukemia protein (PML). AB - Promyelocytic leukemia protein (PML) and Sp100 are transcription-regulatory proteins which colocalize in discrete nuclear dots and play a role in autoimmunity, oncogenesis and virus-host interaction. Interferons (IFNs) were shown previously to increase strongly the levels of Sp100 mRNA and protein. Here, we examined which mechanisms lead to upregulation of Sp100 gene expression and whether IFNs also increase expression of the promyelocytic leukemia (PML) gene. We found that both mRNA and protein levels of PML are also strongly upregulated by IFNs. In addition, new Sp100 and PML proteins were detected immunologically after IFN treatment of cells. Nuclear run-on analysis revealed protein-synthesis independent, rapid IFN-enhanced transcription rates as well as synergistic activation of the Sp100 and PML genes by type-I and type-II IFNs. These data demonstrate that PML and Sp100 belong to the growing family of IFN-stimulated genes (ISGs) upregulated most likely by the transcription factor ISGF3, and indicate that IFNs also qualitatively alter the expression of these two genes. PMID- 8681972 TI - Crystal structure of pig pancreatic alpha-amylase isoenzyme II, in complex with the carbohydrate inhibitor acarbose. AB - Two different crystal forms of pig pancreatic alpha-amylase isoenzyme II (PPAII), free and complexed to a carbohydrate inhibitor (acarbose), have been compared together and to previously reported structures of PPAI. A crystal form obtained at 4 degrees C, containing nearly 72% solvent, made it possible to obtain a new complex with acarbose, different from a previous one obtained at 20 degrees C [Qian, M., Buisson, G., Duee, E., Haser, H. & Payan, F. (1994) Biochemistry 33, 6284-6294]. In the present form, six contiguous subsites of the enzyme active site are occupied by the carbohydrate ligand; the structural data indicate that the binding site is capable of holding more than the five glucose units of the scheme proposed through kinetic studies. A monosaccharide ring bridging two protein molecules related by the crystal packing is located on the surface, at a distance of 2.0 nm from the reducing end of the inhibitor ligand; the symmetry related glucose ring in the crystal lattice is found 1.5 nm away from the non reducing end of the inhibitor ligand. PMID- 8681973 TI - Translocation and aggregation of hepatic glycogen synthase during the fasted-to refed transition in rats. AB - Changes in the activation state and intracellular distribution of liver glycogen synthase have been studied during the fasted-to-refed transition in rats. Glycogen synthase activity and activation state were measured in supernatants and pellets obtained after centrifugation of liver homogenates at 9200 g. Upon refeeding, the glycogen synthase activity ratio increased, in a time-dependent manner, in both fractions. The total activity of the enzyme decreased in supernatants and was quantitatively recovered in the pellets. Therefore, refeeding induced both the activation of glycogen synthase and its translocation from the soluble to the pelletable fraction. Immunocytochemical evidence indicates that refeeding induced the formation of clusters of glycogen synthase, which were recovered in the 9200 g sediments. However, the enzyme clusters did not locate with the glycogen particles in the pelletable fraction. The glycogen synthase activation state responded almost as an of-off switch to changes in the intracellular glucose 6-phosphate concentration in the range 0.2-0.3 mM. The amount of enzyme present in the pellets correlated linearly with the intracellular glucose 6-phosphate levels. These results indicate that glucose 6 phosphate is the key signal for both the activation and changes in intracellular localization of hepatic glycogen synthase in vivo. PMID- 8681974 TI - Adenosine stimulates calcium influx in isolated rat hepatocytes. AB - The mechanism of stimulation of Ca2+ entry into hepatocytes by adenosine was investigated. When Fura-2-loaded hepatocytes were suspended in a nominally Ca(2+) free buffer, adenosine produced only a small transient increase in the cytosolic free Ca2+ concentration ([Ca2+)i). However, on restoration of an extracellular Ca2+ concentration of 1.3 mM, a rapid increase in [Ca2+]i occurred, which indicates activation of a Ca(2+)-influx pathway. Adenosine augmented the rate of Ca2+ influx triggered by maximally effective concentrations of thapsigargin or cAMP, but was without effect on the rate of Ca2+ entry that resulted from phospholipase-C-linked-receptor activation by maximally effective concentrations of vasopressin or ATP. However, in contrast to vasopression and ATP, adenosine did not stimulate Mn2+ entry. The rate of Mn2+ influx after stimulation of the hepatocytes with vasopressin was not increased by adenosine treatment. The stimulation of hepatocytes with adenosine did not result in significant accumulation of inositol phosphates or cAMP. Furthermore, the rate of adenosine induced Ca2+ entry in hepatocytes was only slightly reduced in the presence of the P1 purinoceptor antagonist 8-phenyltheophylline. In contrast, the receptor mediated-Ca(2+)-entry antagonist SK&F 96365 nearly completely blocked the Ca(2+) entry response without any effect on internal-Ca(2+)-pool mobilisation by adenosine. It is concluded that adenosine activates the internal-pool-regulated pathway of Ca2+ entry and an additional pathway that appears comparable to the previously reported receptor-dependent pathway, except that Mn2+ entry is not stimulated. PMID- 8681975 TI - c-fos protooncogene transcription can be modulated by oligonucleotide-mediated formation of triplex structures in vitro. AB - A homopurine.homopyrimidine sequence of the c-fos promoter was chosen as a target for a triple helix oligonucleotide. Eight DNA oligonucleotides that ranged from 14 to 31 bp were shown to form a triple helix with three sequences within the c fos promoter region. Reactive derivatives of homopyrimidine oligonucleotides bearing the 5'- or 3'-terminal DNA alkylation aromatic 2-chloroethylamino group were also synthesized. It was concluded, based on the physical properties of the DNA oligonucleotide complex, that the oligonucleotide forms a colinear triplex with the duplex binding sites. We investigated in detail, using electrophoretic mobility and footprinting protection, whether such oligonucleotide.DNA complexes are of benefit in designing high-affinity probes for a natural DNA sequence in the mouse c-fos gene. Our results demonstrate that four different DNA targets within the c-fos promoter region can form triplex structures with synthetic oligonucleotides in a sequence-specific manner. Moreover, in vitro modifications of the retinoblastoma-gene-product-binding site of the c-fos promoter at position -83 in front of the cAMP/cAMP-responsive element binding site and fos-binding site 3/activator-protein-2-like (FBS3/AP-2-like) site at position -431 by triple helix forming oligonucleotides cause dramatic suppression of fos-chloramphenicol acetyltransferase activity in endothelial cells. These results provide a basis for the development of a specific oligonucleotide target forming triplex-DNA complex, and emphasize the importance of a target forming triplex as a basis for control of gene expression and cell proliferation. PMID- 8681976 TI - Once-daily dosing of aminoglycosides. AB - Since their introduction one or more decades ago, aminoglycosides have generally been administered in multiple daily (i.e. twice- or thrice-daily) dosing regimens. However, nephrotoxicity can be reduced in animal models by administering the same total daily dose as one large dose instead of as multiple small doses. In addition, in vitro and in vivo studies that considered the impact of dosing regimens on efficacy suggest that once-daily dosing is equally or more effective compared to multiple daily dosing. Once-daily versus multiple daily dosing regimens have been compared for amikacin, netilmicin, and gentamicin in 24 randomized, clinical trials including a total of 3,181 patients. An analysis of these studies revealed superior results for once-daily regimens with respect to clinical efficacy (89.5% vs. 84.7%, p < 0.001) as well as bacteriological efficacy (88.6% vs. 83.4%, p < 0.01). No statistically significant differences were noted for toxicity. Nevertheless, both nephrotoxicity and ototoxicity occurred less frequently during once-daily dosing (4.5% vs. 5.5% and 4.2% vs. 5.8%, respectively). Finally, once-daily dosing is more economical, since less nursing time and infusion material are required and the efforts for drug monitoring can be reduced. In conclusion, amikacin, netilmicin, and gentamicin can be administered once a day. PMID- 8681977 TI - Plasma endotoxin and cytokine levels in neutropenic and non-neutropenic bacteremic patients. AB - Plasma endotoxin, tumor necrosis factor-alpha (TNF-alpha), interleukin 1 beta (IL 1 beta), interleukin 1 receptor antagonist (IL-1ra), and interleukin 6 (IL-6) concentrations in 69 bacteremic patients were compared with those in 54 nonbacteremic patients suffering from suspected bacterial infections. Only three (11%) of the 27 patients with gram-negative bacteremia showed detectable levels of endotoxin. TNF-alpha was detected in 6% of the bacteremic patients and in none of the nonbacteremic patients. Median IL-6 levels were significantly higher in bacteremic than in nonbacteremic patients (55 vs. 0 pg/ml, p = 0.0008). IL-6 concentrations were similar in neutropenic and non-neutropenic bacteremic patients (median 55 vs. 74 pg/ml). In contrast, neutropenic bacteremic patients had significantly lower concentrations of IL-1ra than non-neutropenic bacteremic patients (250 vs. 1,950 pg/ml, p < 0.0001). Patients with fatal bacteremia had significantly higher concentrations of IL-6 and IL-1ra than the survivors (median, 450 vs. 40, p = 0.012 and 7,600 vs. 420 pg/ml, p = 0.0075, respectively). Determinations of endotoxin or TNF-alpha in patients with suspected bacteremia failed to offer clinically relevant data on the prognosis of these patients. IL-6 levels correlated with both the presence of bacteremia and the risk of death. Granulocytopenic patients with bacteremia had lower levels of circulating IL-1ra than patients with normal granulocyte counts, and these levels correlated with poor outcome. PMID- 8681978 TI - Detection of Mycobacterium tuberculosis complex in clinical specimens by a commercial polymerase chain reaction kit. AB - A total of 722 respiratory and 86 nonrespiratory specimens obtained from 456 patients were tested for detection of Mycobacterium tuberculosis complex by a commercial polymerase chain reaction (PCR) kit (Amplicor, Roche Diagnostic Systems) and the results compared with those of microscopy and culture (solid and radiometric media). Respiratory and nonrespiratory specimens were analysed separately. Of the respiratory specimens, 54 were positive for Mycobacterium tuberculosis complex both in the PCR and in culture, five were positive in the PCR but negative in culture, and eight were positive in culture but negative in the PCR. Four cultures were positive for mycobacteria other than Mycobacterium tuberculosis; none of these gave a positive result in the commercial test. Resolution of discrepant results was performed by analysis of patients' clinical data. For respiratory specimens the sensitivity of the commercial test was 87.6%, the specificity 99.6%, the positive predictive value 96.6%, and the negative predictive value 98.7%. For nonrespiratory specimens the sensitivity was 60%, whereas the specificity ranged as high as 98.6%. For this group the positive predictive value was 85.7% and the negative predictive value 94.9%. When respiratory specimens are used, the commercial PCR test for detection of Mycobacterium tuberculosis complex, with its high sensitivity and specificity, is a good complementary diagnostic tool for rapid diagnosis of bronchopulmonary tuberculosis in a routine mycobacterial laboratory. PMID- 8681979 TI - A simple and inexpensive method for the identification of Staphylococcus epidermidis and Staphylococcus hominis. AB - Eight hundred and ninety-two strains of Staphylococcus species were identified by means of desferrioxamine susceptibility and fermentation results of three carbohydrates, with the API Staph system (bioMerieux, France) as reference method. No identification could be obtained for 34 strains with API Staph. Of the remaining 858 strains, identical identification was obtained with 842 (98.1%). All 707 strains identified as Staphylococcus epidermidis or Staphylococcus hominis by the API Staph system were found to be desferrioxamine susceptible, and all but 5 (3.3%) of 151 strains identified as other staphylococcal species were found to be resistant, yielding an identification correlation of 99.4% for desferrioxamine. The five additional strains which were susceptible to desferrioxamine were identified as Staphylococcus capitis (2 strains), Staphylococcus lugdunensis (2 strains), and Staphylococcus warneri (1 strain) by API Staph, and as Staphylococcus epidermidis (1 strain), Staphylococcus hominis (3 strains), and one other staphylococcal species by the experimental system. PMID- 8681980 TI - Fluorescence-based DNA fingerprinting elucidates nosocomial transmission of phenotypically variable Pseudomonas aeruginosa in intensive care units. AB - DNA fingerprinting based on automated laser fluorescence analysis of randomly amplified polymorphic DNA (RAPD-ALFA) is a rapid and convenient technique for detecting clonal relatedness of bacterial isolates of nosocomial concern. During an outbreak of Pseudomonas aeruginosa among five patients in a medical intensive care unit, transmission was not suspected because of the phenotypic variability of the initial isolates. However, DNA fingerprinting by RAPD-ALFA and macrorestriction analysis identified a single genotype (strain A) for isolates from three patients and another genotype (strain B) for isolates from the remaining two patients. Strain A isolates displayed three phenotypes defined by different antibiotypes and distinct colony appearance. Retrospective analysis of DNA fingerprints demonstrated that strain A had been transmitted to the index patient one year previously in a different intensive care unit. The study demonstrates that genetic typing approaches are warranted should epidemiological relatedness be identified between phenotypically variant pathogens. Automated laser fluorescence analysis of PCR fingerprints may facilitate routine screening of bacterial isolates for in-house epidemiological surveillance. Antibiograms are an unsuitable approach for the typing of Pseudomonas aeruginosa. PMID- 8681981 TI - Immune response to Chlamydia trachomatis heat-shock protein in infertile female patients and influence of Chlamydia pneumoniae antibodies. AB - A total of 446 sera from 245 patients with primary or secondary infertility, all of whom were examined laparoscopically, 117 patients with Chlamydia trachomatis positive cervical swabs, and 84 control persons (50 obstetric patients and 34 female blood donors) were tested for antibodies to Chlamydia trachomatis and to Chlamydia pneumoniae with the microimmunofluorescence (MIF) test. MIF test antibody rates were highest in patients with complete tubal occlusion (73%) and in patients with proven Chlamydia trachomatis infection (74%), whereas only 9 to 10% of the control group showed Chlamydia trachomatis antibodies. Reaction to the 60 kDa antigen of Chlamydia trachomatis, a heat-shock protein (hsp) analogue, has been suggested as a possible marker for the development of chronic sequelae after Chlamydia trachomatis infection. Immunoblot analysis of 222 sera (169 infertility patients, 20 antigen-positive patients, and 33 mothers) showed a significantly higher anti-hsp antibody rate in patients with complete tubal occlusion than in infertility patients with normal fallopian tubes (76% vs. 19%, p < 0.001). The presence of antibodies not only to Chlamydia trachomatis but also to Chlamydia pneumoniae in the MIF test was associated with a significantly higher rate of anti-hsp antibodies and with complete tubal occlusion. This association did not appear to be due to cross-reactivity between Chlamydia pneumoniae and Chlamydia trachomatis antibodies in the MIF test. PMID- 8681982 TI - Role of immunoglobulin G subclasses in Q fever. AB - The progression of Q fever to either acute or chronic disease has been attributed both to biological characteristics of the bacteria and to the host immune response. In order to determine whether a specific immunoglobulin G (IgG) subclass distribution could play a diagnostic or prognostic role in Q fever, IgG subclass levels were measured in patients with acute or chronic disease. It was observed that (i) IgG1 and IgG3 levels were elevated in patients with chronic Q fever compared to patients with acute disease or normal controls; (ii) variations over time reflected inverse complementary relationships of subclass levels, such as between IgG1 and IgG3 compared with IgG2 and IgG4, or an inverse relationship between IgG1 and IgG2; (iii) variations in IgG2 and IgG3 total subclass levels during follow-up of patients with chronic Q fever showed a decrease in IgG2 with a concomitant increase in IgG3 two years from disease onset. These findings indicate that measurements of IgG subclasses may be a simple, additional tool useful in the diagnosis of Q fever. This data raises the question of an unusual immunoregulatory mechanism in Q fever that is implicated in the presentation of the clinical disease. PMID- 8681983 TI - Comparison of fresh versus sodium acetate acetic acid formalin preserved stool specimens for diagnosis of intestinal protozoal infections. AB - The use of sodium acetate acetic acid formalin (SAF)-preserved stool specimens was compared with that of nonpreserved specimens for the recovery of intestinal protozoa. A total of 247 patients, 170 with diarrhea of more than one week's duration and 77 refugees, were asked to collect a stool specimen. Each specimen was placed into two vials, one empty, the other containing SAF fixative. Laboratory investigations included microscopic examination of the concentrated sediment and direct wet smears from both types of stool specimens and the microscopic examination of a permanent stained smear from the unsedimented, SAF preserved stool specimens. Examination of SAF-preserved stool specimens revealed intestinal protozoa in 149 of the 247 patients. With the conventional procedure using unpreserved stool specimens, intestinal protozoa were found in 89 of the 247 patients. The results show that the examination of SAF-preserved stool specimens, consisting of the microscopic examination of both the concentrated sediment and the permanent stained smear from the unsedimented material, increases the chance of recovering intestinal protozoa as compared to the conventional procedure. PMID- 8681984 TI - Recurrent bacteremia due to Brevibacterium casei in an immunocompromised patient. AB - A case of an immunocompromised patient who experienced two episodes of septicemia caused by a coryneform bacterium is reported. Biochemical characteristics and analysis of cellular fatty acids and of cell wall components showed two identical strains of Brevibacterium casei to be responsible for these infections. The lack of easy-to-perform methods for identification may have led, in the past, to an underestimation of the role of this bacterium, especially in immunocompromised patients. PMID- 8681986 TI - Bacteremia and chorioamnionitis due to cryptic genospecies of Haemophilus Influenzae biotype I. AB - Nontypable strains of Haemophilus influenzae are well-known causes of maternal and neonatal infections. Using DNA-DNA hybridization techniques, some of these strains have been shown to belong to a cryptic genospecies of Haemophilus, which is distantly related to Haemophilus influenzae and Haemophilus hemolyticus. This report describes the first case of sepsis and chorioamnionitis due to Haemophilus influenzae biotype I, which was identified using the RapIDNH system and then confirmed by multilocus enzyme electrophoresis to belong to this cryptic genospecies of Haemophilus. The electromorph type 92 of the isolate was consistent with that of biotype I of the cryptic genospecies. PMID- 8681985 TI - Endocarditis caused by Arcanobacterium haemolyticum. AB - A 33-year-old, active intravenous drug-abusing male infected with the human immunodeficiency virus developed endocarditis due to Arcanobacterium haemolyticum. Empirical treatment with ampicillin plus gentamicin failed to achieve a marked clinical improvement. When the results of antibiotic susceptibility were available (ampicillin MIC < or = 0.06 mg/l; ampicillin MBC 2 mg/l; MBC:MIC ratio > 32) therapy was changed to vancomycin plus gentamicin. During the following days progressive clinical and radiological improvement was observed. The patient received antibiotics for 30 days and no relapse occurred during a 14-month follow-up. The literature of endocarditis due to this uncommon bacterium is reviewed here. PMID- 8681987 TI - An approach to the identification of the pathogens of bacterial meningitis by the polymerase chain reaction. AB - A combination of universal and species-specific primers was used to detect and differentiate by nested polymerase chain reaction (PCR) the four species most commonly causing bacterial meningitis. Primers recognising conserved sequences in the 16S and 23S ribosomal RNA genes were employed to amplify the 16S-23S spacer region from Neisseria meningitidis, Haemophilus influenzae (type b), Streptococcus pneumoniae, and Streptococcus agalactiae (group B streptococcus). The sequence of the most abundant spacer product was determined in each case and used to deduce species-specific primers. A nested PCR using universal primers in the first round and a species-specific primer in the second were able to detect and distinguish between the four common pathogens, in the presence of human DNA. Streptococcus pneumoniae DNA was detected in the cerebrospinal fluid of a meningitis patient with negative culture and Gram-stain results. PMID- 8681988 TI - Acinetobacter baumannii outbreak isolates characterized by three typing methods. AB - Forty-two strains of Acinetobacter baumannii were isolated from 15 patients hospitalized in a French intensive care unit. An epidemiological study based on the typing of these isolates was carried out using biotyping, antibiotyping, and ribotyping to recognize the transmission of multiresistant strains by transfer of a patient from one hospital to another. Fifteen strains from the outbreak (1 strain for each patient), five Acinetobacter baumannii strains isolated before the outbreak in Bellevue Hospital (St. Etienne), and five strains isolated in Cochin Hospital (Paris) were included. The three methods gave a good correlation: the epidemic strains had the same antibiotic resistance pattern, the same biotype, and the same ribotypes obtained with three different endonucleases. PMID- 8681989 TI - Evaluation of pulsed-field gel electrophoresis and rep-PCR for the epidemiological analysis of Ochrobactrum anthropi strains. AB - Pulsed-field gel electrophoresis and polymerase chain reaction genome fingerprinting based on repetitive chromosomal sequences (rep-PCR) were used for typing 14 strains of Ochrobactrum anthropi. Six strains isolated during an outbreak of bacteraemia in patients who had received a contaminated rabbit anti thymocyte globulin gave identical patterns by both techniques. Different patterns were found in sporadic and reference strains, except for one clinical isolate received from another hospital that showed the same pattern as the epidemic clone. This patient had also received rabbit anti-thymocyte globulin from the same source at the time of the outbreak. This study illustrates the advantages of genetic typing methods in terms of high typeability and discriminating power, even for rare pathogens. Furthermore, it highlights the need for interhospital communication for effective identification of common sources of outbreaks related to intrinsic drug contamination. PMID- 8681990 TI - Evaluation of the automicrobic system for the identification of Streptococcus mutans. AB - The performance of the Automicrobic System with the Vitek gram-positive identification card (bioMerieux, France) in identifying strains of Streptococcus mutans was studied. Of 160 strains assayed, 72.5% were confirmed to be Streptococcus mutans; the remainder were identified as other species of streptocci (Streptococcus bovis, Streptococcus uberis, Streptococcus anginosus, Streptococcus sanguis I and II, Streptococcus intermedius, and Streptococcus constellatus). PMID- 8681992 TI - Hepatitis E in Ireland. PMID- 8681991 TI - In vitro activity of MDL 62,879 against gram-positive bacteria and Bacteroides species. AB - The new thiazolyl peptide antibiotic MDL 62,879 (GE2270 A) showed excellent in vitro activity in testing against staphylococci and streptococci, with MIC90s ranging from 0.23 to 0.9 mg/l. It was very active against Clostridium difficile and Propionibacterium acnes (MIC90 0.06 mg/l in each case) and had variable activity against Bacteroides spp. MDL 62,879 had exceptionally good activity against Enterococcus faecalis, including against a collection of high-level aminoglycoside-resistant isolates where it had an MIC90 of 0.047. The antibiotic was bacteriostatic for enterococcal isolates but bactericidal for a methicillin resistant isolate of Staphylococcus aureus. PMID- 8681993 TI - Usefulness of culture in the diagnosis of Clostridium difficile infection. PMID- 8681994 TI - Evaluation of CPS ID2 medium for diagnosis of urinary infections. PMID- 8681995 TI - Beware of pain or even absence of pain in emergency calls. PMID- 8681996 TI - Converting enzyme inhibition and left ventricular hypertrophy. PMID- 8681997 TI - Local latency of conduction time during premature stimulation: a real or apparent phenomenon? PMID- 8681998 TI - Myocardial ischaemia and the sympathetic nervous system. PMID- 8681999 TI - Chest pain in mitral valve prolapse. PMID- 8682001 TI - How iatrogenic and preventable is infective endocarditis? PMID- 8682000 TI - Pointers from recent multicentre trials using ambulatory monitoring--placing placebo in perspective. PMID- 8682002 TI - Treadmill exercise protocols for therapeutic interventions: what's the best test? PMID- 8682003 TI - Alcohol and coronary heart disease. PMID- 8682004 TI - Safety in numbers: waiting and weighting for coronary surgery. PMID- 8682005 TI - Interventional catheterization in paediatric cardiology. AB - The primary role of interventional procedures in the management of some congenital heart diseases is established and their clinical utility broadens every day. Yesterday's relatively crude procedures have been replaced by safe and more effective techniques. Improvements and new developments in specifically designed paediatric equipment have played a significant role. In order to meet the cardiologist's drive to refine existing techniques and develop new ones, further investment into paediatric cardiac catheterization equipment is mandatory. More and more "heart operations' will be performed in cardiac catheterization laboratories in the future, and this will have clear implications on costs, as most non-surgical techniques are cheaper than surgery, and hospitalization is much shorter. New methods, tested within research protocols in specialized centres, combined with continuous critical evaluation of established techniques will ensure improved and sustained results. The primary consideration of practising paediatric cardiologists should not be whether it is possible to perform such techniques, but whether their clinical utility, morbidity and mortality justifies a non-surgical approach for their centre. Interventional catheterization, in other words has to "compete' with the results of surgery prior to new techniques being recommended for general use. Despite this "competition' it has been welcome to see a collaboration between paediatric cardiologists and paediatric cardiac surgeons in planning staged repairs of complex congenital heart disease. A typical example of this is the fenestrated Fontan procedure, in which the immediate post-operative course has dramatically improved due to the deliberate placement of a residual atrial shunt, which is then closed with an umbrella in the catheter laboratory. This type of cooperation is bound to increase further and is already contributing to a far better outcome for many of the complex congenital heart lesions. PMID- 8682006 TI - Does the exercise protocol matter when assessing the anti-anginal effects of drug therapy? AB - Four exercise test protocols (Bruce, Balke, Ellestad and Steep) were compared in 16 patients with proven coronary artery disease in demonstrating the anti-anginal effects of sublingual glyceryl trinitrate in a randomization double-blind trial. Glyceryl trinitrate significantly improved the time, heart rate and rate pressure product to peak exercise, onset of angina and 1 mm ST segment depression in all four protocols (P < 0.05) (except rate pressure product to angina in the Balke protocol). The increase in exercise time was greatest for the Balke protocol at peak exercise (188.1 +/- 187.1) (mean +/- SD in s), at onset of angina (251.9 +/- 247.1) and at 1 mm ST depression (233.6 +/- 243.8), followed by the Steep and Bruce protocols, and was lowest for the Ellestad protocol 41.9 +/- 42.4, 96.5 +/- 65.8, 82.6 +/- 74.0, respectively. Increase in time to peak exercise with glyceryl trinitrate was significantly greater for the Balke protocol in comparison with the other three protocols and for the Bruce and Steep protocols when compared to the Ellestad protocol. Time to 1 mm ST depression with treatment was significantly greater on the Balke and Bruce protocols than the Ellestad protocol, and to onset of angina for the Balke compared to other three protocols. There were no significant differences between the Bruce and Steep protocols for any of the endpoints. The magnitude of treatment effect in the different protocols was accompanied by correspondingly greater inter-patient variability such that no protocol was more, or less, sensitive than another in detecting treatment effect. Changes in heart rate and rate pressure product with treatment were generally similar between the different protocols. In conclusion, a protocol with small and frequent increments (Balke), although able to show greater increase in exercise duration with glyceryl trinitrate than more aggressive protocols, is no more sensitive at detecting treatment effect. PMID- 8682008 TI - Ambulance despatchers' estimation of intensity of pain and presence of associated symptoms in relation to outcome in patients who call for an ambulance because of acute chest pain. AB - BACKGROUND: A large number of patients who call for an ambulance because of acute chest pain have an acute ischaemic event, but some do not. AIM. To relate the ambulance despatcher's estimated severity of pain and presence of associated symptoms, in patients who call for an ambulance because of acute chest pain, to whether they develop acute myocardial infarction (AMI) and to the risk of early death. PATIENTS: All those with acute chest pain who contacted the despatch centre in Goteborg over a 2-month period. RESULTS: In all, 503 patients fulfilled the inclusion criteria. Patients judged as having severe chest pain (68%) developed AMI during the first 3 days in hospital on 26% of occasions as compared with 13% among patients judged as having only vague chest pain (P = 0.0004). The difference was less marked among the elderly and women. The presence of any of the following associated symptoms, dyspnoea, nausea, vertigo, cold sweat or syncope, tended to be associated with a higher infarction rate (24%) than if none of these symptoms was present (17%, P = 0.06). Mortality during the pre-hospital and the hospital phase was not associated with the estimated severity of pain or the presence of associated symptoms. CONCLUSIONS: The despatcher's estimation of the severity of pain and the presence of associated symptoms appears to be associated with the development of AMI but not with early mortality. PMID- 8682007 TI - Effects of amlodipine on transient myocardial ischaemia in patients with a severe coronary condition treated with a beta-blocker. Amlor-Holter Study Investigators. AB - The purpose of this trial was to study the additional anti-ischaemic effects of amlodipine in coronary patients with ambulant ischaemia despite beta-blocker therapy. Beta-blockers are the most effective drug therapy for reducing the frequency and duration of ambulatory ischaemic episodes. However, the therapeutic advantage of combined calcium antagonist-beta-blocker treatment remains questionable. Three hundred and thirteen patients with documented coronary artery disease, a positive exercise test within 6 months before entry and background beta-blocker therapy, were screened. Inclusion criteria (> or = 4 episodes of transient ST segment depression of > or = 1.0 mm and/or > or = 20 min of ischaemia) were demonstrated in a 48 h ECG during the placebo run-in period in 84 (25%) of the patients. Eighty-nine percent of the ischaemic episodes were silent. The eligible patients were then randomized in a 2-week, double-blind, parallel group study comparing placebo to amlodipine 10 mg daily added to the beta blocker. The anti-ischaemic efficacy of the combination therapy was assessed by 48 h ECG monitoring and exercise tests. Compared to placebo, amlodipine did not significantly reduce either the frequency (3.7 +/- 4.3 vs 4 +/- 4.8 episodes in the amlodipine group) or the duration of ambulatory ischaemia (mean duration: 43.9 +/- 57.1 vs 39.6 +/- 65.7 min, total duration 3.1 +/- 6.7 vs 2.8 +/- 6.1 h). Exercise-induced ST segment depression tended to decrease with amlodipine (58% vs 73% in the placebo group) and the ischaemia-free workload capacity was increased (+1.7 stage vs 0.7 stage in the placebo group, P = 0.08). These results suggest that 2 weeks treatment with amlodipine may not provide any additional anti ischaemic benefit in patients with ambulant ischaemia resistant to a beta-blocker therapy. PMID- 8682009 TI - Inferior ST segment depression as a useful marker for identifying proximal left anterior descending artery occlusion during acute anterior myocardial infarction. AB - To determine whether or not ST segment deviation on admission electrocardiograms can identify patients with anterior acute myocardial infarction due to proximal left anterior descending artery occlusion, the magnitude and location of ST segment elevation or depression were compared between patients with proximal left anterior descending artery occlusion (group A, n = 47) and those with distal left anterior descending artery occlusion (group B, n = 59). ST segment depression in each of the inferior leads was significantly greater in group A than in group B. The incidence of ST segment depression > or = 1 mm in each of the inferior leads (II; 81% vs 27%, III; 85% vs 54%, aVF; 87% vs 47%, P < 0.01) was significantly higher in group A than in group B. In addition, the incidence of ST segment depression > or = 1 mm in all of the inferior leads was significantly greater in group A than in group B (77% vs 22%, P < 0.01). In group A, maximal ST segment elevation was more frequent in lead V2 alone (43% vs 14%, P < 0.01). Group A had greater ST segment elevation in lead aVL than group B, and the incidence of ST segment elevation > or = 1 mm in lead aVL was significantly higher in group A than in group B (66% vs 47%, P < 0.05). ST segment depression > or = 1 mm in all of the inferior leads was most valuable for identifying group A patients (77% sensitivity and 78% specificity). In contrast, the maximal ST segment elevation in lead V2 alone or ST segment elevation > or = 1 mm in lead aVL had a low diagnostic value (43% sensitivity and 86% specificity, 66% sensitivity and 53% specificity, respectively). In conclusion, this study indicates that analysis of ST segment deviation in the inferior leads is useful for identifying patients with acute anterior myocardial infarction due to proximal left anterior descending occlusion. PMID- 8682010 TI - Platelet and leukocyte activation after myocardial infarction. Influence of enalapril. AB - In this double-blind placebo-controlled study with enalapril, 74 patients with acute myocardial infarction were followed at 0, 7, 30, 60 and 180 days after the event. Platelets and leukocytes were activated during the first 7 days. During the 6-month period fibrinogen, leukocytes, elastase, and B beta 30-43 remained elevated in 50, 15, 30 and 80% of the patients, respectively, but there was no detectable angiotensin converting enzyme activity in platelets. Enalapril did not modulate fibrinogen, leukocyte count or elastase, while B beta 30-43 peptide showed decreased levels, although the proportion of patients with values above the reference limit did not differ from placebo. In conclusion, in the 6-month post acute myocardial infarction period, while platelet function is activated only during the first week after acute myocardial infarction, fibrinogen and leukocyte function continue to be activated throughout the 6 months in a considerable proportion of patients. These signs may indicate an ongoing atherosclerotic process. Enalapril has no major influence on these reactivities. PMID- 8682011 TI - Further elevation of the ST segment during the first hour of thrombolysis. A possible early marker of reperfusion. AB - OBJECTIVES: To evaluate the clinical implications of early electrocardiographic changes during thrombolysis in a randomized study in patients with an acute myocardial infarction. BACKGROUND: Re-elevation of a rapidly resolving ST segment during thrombolysis is currently interpreted as a sign of re-occlusion, but a further elevation at very early stages of lytic therapy may not necessarily have the same implications. METHODS: In 214 patients with a first transmural acute myocardial infarction of < or = 4 h randomized to fibrinolytic (streptokinase group, n: 110) vs non fibrinolytic medical therapy (control group, n: 104), a standard 12 lead ECG was continuously recorded during the first 60 min and at 2, 4, 10, 16 and 24 h. Serial enzymes were measured during 72 h, and in 156 patients (73%) a coronary angiogram was performed at 10-15 days. RESULTS: Within the first 20-40 min there was an additional ST segment elevation in 50 patients (45%) from the streptokinase group and in 19 from control group (18%) (P < 0.0001) but the increment was greater in the streptokinase group (1.2 +/- 1.4 vs 0.3 +/- 1.4 mm, P < 0.0001). In the streptokinase group, the interval from onset of pain to peak creatine kinase MB was shorter in patients with additional ST segment elevation than in those without it (699 +/- 193 vs 856 +/- 299 min, P < 0.01). Moreover, in hospital mortality tended to be lower in patients whose ST segment was elevated than in those without such elevation (2150, 4%, vs 6160, 10%). Incidence of recanalization was high but comparable in these two subsets. In recanalized patients, with or without additional ST segment elevation, the ST segment declined significantly at 1 h (-1.0 +/- 1.7, P < 0.001, vs 0.1 +/- 1.5 mm, ns). CONCLUSIONS: Additional ST segment elevation is frequently observed during the first hour of intravenous thrombolysis with streptokinase. Its' association with a subsequent early decline of ST elevation, reduced mortality, a shorter time interval to peak creatine kinase, and a high rate of late recanalization, suggest that in some patients it is one of the earliest markers of reperfusion. PMID- 8682012 TI - Fibrinogen in the offspring of men with premature coronary artery disease. AB - We examined whether the levels of fibrinogen are elevated in the offspring of middle-aged coronary patients. One hundred and seventy-six young subjects were divided into two groups. Group A consisted of 100 children and youngsters (mean age 17 +/- 6 years) whose fathers had sustained a myocardial infarction under the age 55 years without associated history of diabetes mellitus or hypertension. Seventy-six healthy young subjects (mean age 18 +/- 5 years) matched for gender, dietary and smoking habits without familial history of coronary artery disease, diabetes mellitus or hypertension served as the control group (group B). Fibrinogen, total cholesterol, triglycerides, high and low density lipoprotein cholesterol, apolipoprotein A-1, apolipoprotein B and lipoprotein (a) were measured. Sons and daughters with a history of premature paternal myocardial infarction had higher levels of fibrinogen compared with control subjects (304.1 +/- 60 vs 274 +/- 53 mg. dl-1, P < 0.001). This difference was maintained when the above groups were divided into single sex groups. Total cholesterol, low density lipoprotein cholesterol, apolipoprotein B and lipoprotein (a) were also significantly higher in group A. Children of affected individuals who had a good lipid profile also had significantly higher fibrinogen levels compared to control group. The results support the hypothesis that the higher plasma levels of fibrinogen in the offspring of middle-aged coronary men could partially explain their predisposition for coronary artery disease. Since the levels of fibrinogen have a major genetic component, they could be a useful marker in identifying children at high risk for coronary artery disease, especially among those with no lipid abnormalities. PMID- 8682013 TI - Incidence and correlates of complex ventricular arrhythmias during dobutamine stress echocardiography after acute myocardial infarction. AB - Although previous studies have confirmed the safety of dobutamine stress echocardiography, complex ventricular arrhythmias have been reported. Our aim was (1) to identify the markers of increased arrhythmic risk during dobutamine stress echocardiography and (2) to assess whether the occurrence of major ventricular arrhythmias during the test may represent a clinically useful marker of electrical instability. Three hundred and seventy-seven consecutive survivors from acute myocardial infarction, off cardioactive therapy, underwent dobutamine stress echocardiography 11.4 days after the acute event. Holter monitoring with assessment of heart rate variability and echocardiographic determination of left ventricular ejection fraction. In addition, exercise stress testing, signal averaged ECG and coronary angiography were carried out, respectively, in 357, 150 and 273 patients. Ten subjects showed complex ventricular arrhythmias (eight non sustained and one sustained ventricular tachycardia and one ventricular fibrillation) during dobutamine stress echocardiography (group A), whilst 366 did not (group B). Complex ventricular arrhythmias were detected by Holter monitoring in 8/10 patients in group A and 45/367 patients in group B (odds ratio 28.6, 95% CI 5.4-92.2) and by exercise testing in 4/10 patients in group A and 33/347 patients in group B (odds ratio 6.3, 95% CI 1.4-27.2). Ejection fraction < 40% was present in 3/10 patients in group A and 50/367 in group B (odds ratio 2.7, 95% CI 0.3-12.2), whilst multivessel disease was present, respectively, in 8/10 and 176/263 patients (odds ratio 1.9, 95% CI 0.3-25.5). Reduced heart rate variability and the presence of late potentials on signal averaged ECG were found in, respectively, 40/367 and 13/140 patients in group B, but none were found in group A. A total of 61 events (35 CABG, 15 PTCA, four cardiac deaths and seven non-fatal reinfarctions) occurred during the follow-up (11.4 months, range 6 to 20): four in group A and 57 in group B. No documented major arrhythmic event was reported. We conclude that (1) complex arrhythmias during dobutamine stress may occur in patients early after acute myocardial infarction; (2) the preexisting evidence of frequent, as well as repetitive, arrhythmias represents a potential marker of increased risk in this connection and, finally, (3) dobutamine-induced arrhythmias seem to represent an uncommon, even though potentially dangerous, event but not a useful new "window' on electrical instability of post-MI patients. PMID- 8682014 TI - Effect of metoprolol on death and cardiac events during a 2-year period after coronary artery bypass grafting. The MACB Study Group. AB - PURPOSE: To evaluate the effect of long-term treatment with metoprolol after coronary bypass grafting on death and cardiac events. METHODS: Patients in western Sweden on whom coronary artery bypass grafting was performed between June 1988 and June 1991 were evaluated for inclusion during the first 3 weeks after surgery. Major exclusion criteria were age > 75 years, concomitant valve surgery, traditional contraindications to beta-blockers and unwillingness to participate. Patients were randomized in a double-blind fashion to 100 mg of metoprolol/placebo daily for 2 weeks and thereafter 200 mg daily for 2 years. RESULTS: Of 2365 patients who were operated on, 967 were randomized to either metoprolol (n = 480) or placebo (n = 487). Primary end points (death, non-fatal myocardial infarction, unstable angina pectoris, need for coronary artery bypass grafting or percutaneous transluminal angioplasty), were reached by 42 patients in the metoprolol group (8.8%), as compared with 39 in the placebo group (8.0%) (P = 0.73). Of all the patients randomized to metoprolol, 34% withdrew from blind treatment prematurely compared with 44% for placebo (P < 0.01). CONCLUSION: Prophylactic treatment with metoprolol over a 2-year period after coronary artery bypass grafting did not reduce death or the development of cardiac events. However, the 95% confidence limits ranged from the possibility of a 30% reduction in events to a 68% increase in events if patients were treated with metoprolol as compared with placebo. PMID- 8682015 TI - Pre-hospital thrombolytic therapy with either alteplase or streptokinase. Practical applications, complications and long-term results in 529 patients. AB - OBJECTIVE: To assess the practical application, safety and long-term outcome of pre-hospital thrombolytic intervention with either alteplase or streptokinase in patients with extensive myocardial infarction. DESIGN: Prospective study. SUBJECTS: Patients with chest pain of more than 30 min duration, presenting within 6 h of symptom onset and with electrocardiographic evidence of extensive evolving myocardial infarction. METHODS: Eligibility of patients was established by the general practitioner or the ambulance nurse using a standardized questionnaire with (contra-) indications for thrombolytic therapy. Computerized ECG was recorded by ambulance nurses. In the presence of extensive ST segment elevation (sum ST deviation of at least 1.0 mV), eligible patients received either 100 mg alteplase (n = 246) or 50 mg alteplase in the ambulance followed by 0.75 x 10(6) IE streptokinase in hospital (n = 90), or 1.5 x 10(6) IE streptokinase intravenously (n = 193). MAIN OUTCOME MEASUREMENTS: Death and life threatening complications (ventricular fibrillation, cardiac arrest) and side effects (hypotension, allergic reactions) during transportation to hospital and in the first 24 h following hospitalization, and survival up to 5 years follow up. RESULTS: From 1988-1993, 529 patients received thrombolytic treatment initiated pre-hospital. The time gained by pre-hospital administration of thrombolysis amounted to 50 min. The rate of complications during transportation and during the first 24 h after hospitalization was low. Hospital mortality was 2% and 1-year mortality 3%. Cumulative survival at 5 years was 92%. This was superior to the 84% 5-year survival observed in a matched group of 239 patients with similar baseline characteristics treated with alteplase in hospital. CONCLUSIONS: Pre-hospital administration of either alteplase or streptokinase is feasible and safe and results in significant time gain. The long-term prognosis is excellent in spite of extensive evolving myocardial infarction upon admission. PMID- 8682016 TI - Reduction in sudden deaths and coronary mortality in myocardial infarction patients after rehabilitation. 15 year follow-up study. AB - The study was set up to evaluate the long-term effects on mortality of a comprehensive rehabilitation and secondary prevention programme lasting 3 years after acute myocardial infarction. The study group consisted of 375 consecutive, non-selected patients under 65 years of age randomly allocated to an intervention group (188 patients) or a control group (187 patients). After 15 years follow-up significantly lower incidence of sudden death (16.5% vs 28.9%, P = 0.006) and coronary mortality (47.9% vs 58.5%, P = 0.04) were seen in the intervention group compared with controls. Total mortality was 64.4% and 66.8%, respectively (ns). The incidence of cancer death was 16 in the intervention group and three in the controls. Cardiac failure, enlarged heart, New York Heart Association functional class II or more and membership in the control group were significantly associated with coronary mortality during the first 3 years, and after 3 years enlarged heart, diabetes and reinfarction were associated with late coronary death. Thus, comprehensive multifactorial intervention after acute myocardial infarction had favourable long-term effects on coronary mortality and sudden death but no effect on total mortality. PMID- 8682017 TI - Hyperdynamic performance of remote myocardium in acute infarction. Correlation between regional contractile function and myocardial perfusion. AB - During and after myocardial infarction (MI), compensatory contractile and structural changes taking place in the remote uninvolved myocardial regions have been well described, in both experimental and clinical settings. However, quantitative information on the changes in perfusion in these regions in relation to their altered contractile function have not been available. This study was designed to assess the in vivo relationship between contractile function and perfusion in remote uninvolved hypercontractile myocardial regions, subtended by angiographically normal coronary arteries in patients with MI and single-vessel coronary artery disease. We utilized two-dimensional echocardiography and 15O water positron emission tomography imaging to assess regional contractile function and myocardial blood flow, respectively. Measurements were performed in nine patients with single-vessel coronary artery disease and angiographically confirmed recanalization of the infarct-related artery, 1-2 days after MI (group A). Only patients demonstrating severely impaired wall motion of the infarcted area and reactive hypercontractility of the remote uninvolved regions were enrolled. Seven patients with previous non-reperfused MI (6-8 months post-MI) served as a control (group B). Systolic wall thickening and regional myocardial blood flow data sets were created for the remote myocardial segments perfused by angiographically detected patent coronary arteries by assigning regions on the tomograms to equivalent echocardiographic segments. In the remote regions, wall thickening and regional myocardial blood flow were higher in group A patients by 26% (43 +/- 6% vs 34 +/- 4%; P = 0.005) and 20% (1.06 +/- 0.15 vs 0.89 +/- 0.06 ml.g-1 per minute; P = 0.019), respectively. For both groups of patients, a significant correlation (r = 0.67; P = 0.004) between systolic wall thickening and regional myocardial blood flow was obtained. Infarcted regions in both groups showed no systolic wall thickening. In this selected group of patients these data demonstrate: (1) a proportionate increase in contractility and regional myocardial blood flow in uninvolved territories in patients with recent and old MI; (2) the in vivo relationship between contractile function and myocardial perfusion in man in these regions. When infarcted zones in both groups are equally affected, enhanced levels of catecholamines and sympathetic drive as well as different loading conditions may account for the hyperkinetic performance and consequently for the increased perfusion level in uninvolved segments in patients with recent MI. PMID- 8682018 TI - Exogenous insulin-like growth factor II enhances post-infarction regional myocardial function in swine. AB - OBJECTIVES: Insulin-like growth factor II (IGF-II) promotes cardiac myocyte growth and contractility in vitro. This study was designed to investigate the effect of exogenous IGF-II on regional myocardial function at the area of infarct in the pig. METHODS: Myocardial infarction was induced in 12 female anaesthetized pigs by affigel blue beads, embolizing microvessels of the left anterior descending coronary artery distribution. In the experimental group (n = 6), IGF II (0.12 microgram.kg-1 in two animals and 0.6 microgram.kg-1 in four) was incorporated into the beads and delivered by them to the infarct area. Myocardial function was followed echocardiographically, and the excised heart was analysed immunohistochemically and histopathologically. RESULTS: Myocardial function in injured zones, inversely related to an echocardiographic segmental wall motion score (mean +/- SEM), was similar between the two groups at baseline, but at 4 weeks post-infarction was significantly (P = 0.008) reduced in the control group (0.58 +/- 0.38 vs 3.42 +/- 0.84), in contrast to nearly baseline values in the experimental group (0.58 +/- 0.33 vs 1.17 +/- 0.42, P = 0.41). Cardiac performance in injured segments was significantly better after myocardial injury in the experimental group (P = 0.04). Tissue samples from both groups (4 weeks post-infarction), stained with haematoxylin and eosin demonstrated peri-infarct myocyte hypertrophy, corresponding to regions selectively stained by an antibody for CD56, which highlights growing cardiac myocytes. By image analysis semi quantification, staining for CD56 was significantly (P = 0.04) higher in the peri infarct region of the experimental group, as compared with controls (106.5 +/- 2.8 vs 92 +/- 4.4 gray level units). Microvessels stained for von-Willebrand factor were similar in number in both groups (P = 0.8), as were mesenchymal cells stained for vimentin (P = 0.7). CONCLUSIONS: Exogenous IGF-II, delivered to the infarct area ameliorates regional cardiac function in the pig, perhaps by inducing peri-infarct myocyte growth. PMID- 8682019 TI - Comparison between regional myocardial perfusion reserve and coronary flow reserve in the canine heart. AB - Diameter stenosis and flow reserve are indices of morphological and functional severity of coronary artery stenosis. Flow reserve can be determined at coronary arterial or at myocardial level. In the presence of functional collateral circulation, coronary flow reserve and myocardial perfusion reserve may differ. We studied coronary flow, coronary flow reserve and myocardial perfusion reserve in an open chest dog model with intact collateral circulation, before and after induction of coronary artery stenosis. Coronary flow was determined with perivascular ultrasonic flow probes and myocardial perfusion reserve from digital angiographic images, in the stenotic as well as the adjacent non-stenotic coronary arteries. Before induction of a stenosis, a significant correlation existed between coronary flow reserve and myocardial perfusion reserve of the left anterior descending (r = 0.59; P < 0.005) and the left circumflex arteries (r = 0.84, P < 0.005). In stenotic arteries, coronary flow reserve and myocardial perfusion reserve decreased significantly (P < 0.005), but in the adjacent non stenotic arteries coronary flow reserve was not affected. Myocardial perfusion reserve in the non-stenotic adjacent left anterior descending artery decreased significantly (P < 0.05) and no correlation was found between coronary flow reserve and myocardial perfusion reserve, whereas in the adjacent non-stenotic left circumflex artery there was no statistically significant decrease (4.1 +/- 1.6 --> 3.5 +/- 1.4) but there was a good correlation between coronary flow reserve and myocardial perfusion reserve (r = 0.85; P < 0.005). This study demonstrates that, in the presence of a stenosis and functioning collateral circulation, coronary flow reserve is not a reliable predictor of myocardial perfusion reserve; both parameters provide mutually complementary information. PMID- 8682020 TI - Exercise echocardiography performed early and late after percutaneous transluminal coronary angioplasty for prediction of restenosis. AB - The purpose of this prospective study was to examine the incidence of exercise induced ischaemia before and after angioplasty as well as 4 months later by exercise echocardiography, to evaluate the prognostic value of exercise echocardiography performed after angioplasty as regards the development of restenosis and to determine whether serial exercise tests increase the accuracy of detecting angiographically relevant restenosis. Fifty patients (39 males; mean age 52 +/- 9 years) without prior Q wave infarction entered the study protocol. Exercise echocardiography was performed 2 days prior to angioplasty, 13 +/- 6 days after successful angioplasty as well as at routine follow-up angiography 3.8 +/- 1.6 months after angioplasty. Angiographically successful angioplasty was achieved in 94% (47150) of patients, and early and late follow-up examinations were performed in all 47 patients. Average luminal diameter stenosis decreased from 65 +/- 5% to 26 +/- 9% immediately after angioplasty. Control angiography showed significant restenosis in 30% (14147) of patients. Exercise echocardiography before angioplasty was positive in 90%, continued to be positive in 30% of patients after angioplasty and was positive in 43% at control angiography. The exercise echocardiogram performed early after angioplasty had an overall accuracy for prediction of restenosis of 70%, with a positive predictive value of 50%, and a negative predictive value of 79%. Sensitivity for detection of restenosis at control angiography was high (86%), but specificity (76%) was moderate. Exercise echocardiograms showing deterioration from 2 weeks to 4 months after angioplasty were taken as a sign of restenosis and resulted in an increased specificity of 94%. Sensitivity, however, decreased to 36%, indicating that some patients with an early positive stress echo had already suffered restenosis 13 days after angioplasty. In conclusion, exercise echocardiography documents improvement in regional function after angioplasty. However, a significant proportion of patients continue to have a positive exercise echocardiogram even though angioplasty was angiographically successful, probably due to persistent ischaemic regions or early restenosis. While exercise echocardiography performed early after angioplasty is of insufficient value for the prediction of restenosis, if performed at late follow-up it has a good diagnostic accuracy for detecting restenosis. PMID- 8682021 TI - Vital exhaustion, extent of atherosclerosis, and the clinical course after successful percutaneous transluminal coronary angioplasty. AB - It has been observed that vital exhaustion, a state characterized by unusual tiredness, increased irritability and feelings of demoralization not uncommonly precedes myocardial infarction in apparently healthy individuals. This observation raised the question as to whether vital exhaustion is a marker of subclinical coronary disease. To answer that question the condition was assessed in 105 male patients (mean age 54.8 year) before and 2 weeks after successful percutaneous transluminal coronary angioplasty (PTCA) by the Maastricht questionnaire. Vital exhaustion was found to be significantly correlated with the number of diseased vessels before PTCA and to decrease significantly after PTCA. However, the association was rather modest (R2 = 0.08) and most patients remained exhausted after PTCA. During a follow-up period of 1.5 years, 32 patients (30%) experienced a new cardiac event (cardiac death, myocardial infarction, coronary artery bypass grafting, repeat PTCA, a new coronary lesion or recurrent angina with documented ischaemia). Univariate and multivariate analyses showed that the number of diseased vessels, hypercholesterolaemia, and vital exhaustion were independently associated with future events. The odds ratios were 3.74 (P = 0.02), 3.08 (P = 0.08) and 3.07 (P = 0.04), respectively. It is concluded that the tiredness preceding a cardiac event is only modestly associated with the extent of coronary artery disease and that a state of exhaustion after PTCA increases the risk for a new cardiac event. PMID- 8682022 TI - Ventilation and dyspnoea during exercise in patients with heart failure. AB - Patients with chronic heart failure have an increased ventilation/carbon dioxide production ratio (VE/VCO2) during exercise. Recently it was discussed whether the cause of this increase was a ventilatory stimulus driven other than by CO2. Dyspnoea during exercise is thought to be related to impaired respiratory function. However, clinical confirmation is scarce. Ninety-two patients (age 51 +/- 9 years) with heart failure due to idiopathic dilated cardiomyopathy exercised on a bicycle ergometer to exhaustion, and measurement of ventilatory gases and Swan-Ganz catheterization were performed. The maximal oxygen consumption corrected for body weight (VO2max. kg-1) was 16.6 +/- 5.5 ml x min-1 x kg-1. The increase in (VE/VCO2) during exercise was related to an increase in respiratory rate (r = 0.43; P < 0.00001) but not to an increase in cardiac index or capillary wedge pressure. Nineteen patients stopped exercising because of dyspnoea. Their maximal tidal volume and VO2max . kg-1 were lower than the 67 patients who stopped exercise because of fatigue (P < 0.001 and P < 0.00001 respectively). Other variables showed no significant difference. In conclusion, the increase in VE/VCO2 during exercise may reflect a non-CO2 driven ventilatory stimulus as it cannot be attributed to increased pulmonary vascular pressures or an insufficient increase in cardiac output leading to a ventilation-perfusion mismatch. Low oxygen uptake is a prominent finding in patients with chronic heart failure who experienced dyspnoea during exercise, and dyspnoea is in part related to impaired respiratory function. PMID- 8682023 TI - Fosinopril attenuates clinical deterioration and improves exercise tolerance in patients with heart failure. Fosinopril Efficacy/Safety Trial (FEST) Study Group. AB - This study was a 12-week, double-blind, placebo-controlled, multinational trial of fosinopril in 308 patients with mild to moderately severe heart failure (New York Heart Association [NYHA] functional class IIS 17%, IIM 48%, and III 35%; mean ejection fraction [+/-SD] 26.5% [+/-6.9%]; bicycle exercise duration 1 to 11 min). An initial dose of 10 mg once daily was titrated as tolerated to 40 mg once daily. Patients all received diuretic therapy; digoxin was optional. The primary endpoint was maximal bicycle exercise time; a secondary endpoint was occurrence of the following prospectively defined, ordered clinical events indicative of worsening heart failure: death, study discontinuation, hospitalization, emergency room visits, and need for supplemental diuretic. At study endpoint (last value obtained for each patient), bicycle exercise time increased more with fosinopril (38.1 s) than with placebo (23.5 s) (P = 0.101 by ANCOVA and 0.010 by prospectively defined dropout-adjusted endpoint analysis). More patients remained free of clinical events indicative of worsening heart failure when treated with fosinopril (89%) than with placebo (75%), and the worst events of fosinopril treated patients tended to be less severe than those of placebo patients (P = 0.001). Analysis of the occurrence of individual clinical events showed that the need for supplemental diuretic was markedly reduced with fosinopril (8% vs 20%, of patients, P = 0.002), as were hospitalizations (3% vs 12% of patients, P = 0.002) and study discontinuations (2% vs 12% of patients, P < 0.001) for worsening heart failure; the two groups had similar incidences of death (3% of patients in the fosinopril group vs 2% in the placebo group, P = 0.723). In addition, symptoms of dyspnoea (P = 0.017), fatigue (P = 0.019), and NYHA functional class (P = 0.008) improved with fosinopril relative to placebo. In conclusion, fosinopril, at an initial dose of 10 mg once daily, subsequently titrated as tolerated to 40 mg once daily, increased exercise tolerance and reduced the frequency of clinical events indicative of worsening heart failure. PMID- 8682024 TI - Effects of granulocyte colony-stimulating factor upon coxsackievirus B3 myocarditis in mice. AB - Granulocyte colony-stimulating factor is a potent activator of mature granulocytes, and subsequently enhances superoxide release. The purpose of this study was to investigate the effects of granulocyte colony-stimulating factor upon murine coxsackievirus B3 myocarditis in relation to free radical-mediated cardiac damage. Two-week-old, male, C3H/He mice were inoculated intraperitoneally with coxsackievirus B3. Granulocyte colony-stimulating factor 20 micrograms.kg 1.day-1, polyethylene glycol-conjugated superoxide dismutase (an enzyme catalyzing the conversion of O2- to H2(O2)) 1 x 10(3) U.kg-1.day-1 and granulocyte colony-stimulating factor 20 micrograms.kg-1.day-1, plus polyethylene glycol-conjugated superoxide dismutase 1 x 10(3) U. kg-1. day-1, were injected subcutaneously daily on days 0 to 14. Treated groups were compared to the infected, untreated group. The survival rate in the polyethylene glycol conjugated superoxide dismutase group was higher than that of the untreated group on day 14, but on day 7, cardiac pathology was not significantly different among the four groups. On day 14, the scores of cellular infiltration, myocardial necrosis and calcification were lower in the polyethylene glycol-conjugated superoxide dismutase group and in the granulocyte colony-stimulating factor plus polyethylene glycol-conjugated superoxide dismutase group than in the untreated group. The myocardial virus titres on days 7 and 14 did not differ significantly among the four groups. The number of total white blood cell and neutrophil counts were significantly greater in the granulocyte colony-stimulating factor group than in the untreated group on day 7. Taken altogether with the previous reports and present evidence that the administration of granulocyte colony-stimulating factor did not exacerbate coxsackievirus B3 myocarditis, it may be that oxygen free radicals appeared to be derived not from leukocytes but from other components in this experimental model of myocarditis, whereas the myocardium was inflamed with leukocytes. PMID- 8682025 TI - Organ-specific cardiac autoantibodies in dilated cardiomyopathy. Frequency and clinical correlates in Polish patients. AB - Organ- and disease-specific cardiac autoantibodies are found in a third of dilated cardiomyopathy patients from the U.K. and Italy and represent markers of autoimmune involvement. The role of autoimmunity may vary in dilated cardiomyopathy patients from different countries due to differences in genetic susceptibility to autoimmune diseases. The aim of this study was to assess the frequency of organ-specific cardiac autoantibodies detected by immunofluorescence in a consecutive series of patients with dilated cardiomyopathy and in disease and normal control subjects from Poland. The study groups included 79 patients with idiopathic (WHO criteria) dilated cardiomyopathy, 55 patients with other cardiac disease and 60 normal subjects. Cardiac antibody tests were performed by indirect immunofluorescence on human heart; skeletal muscle was used to identify cross-reacting antibodies. The frequency of organ-specific cardiac autoantibodies was higher in patients with dilated cardiomyopathy (21/79, 27%) than in controls with other cardiac disease (1/55, 2% P < 0.001) or in normal subjects (7/60, 12% P < 0.02). Conversely, cross-reactive antibodies were detected in similar proportions in patients with dilated cardiomyopathy (5/79, 6%), disease controls (7/55, 13%) and normal subjects (6/60, 10%, P = ns). The organ-specific antibody was more common in patients with dilated cardiomyopathy with insidious onset of disease (17/34, 50%) compared to those who did not exhibit this feature (4/45, 9%, P < 0.0001). Organ- and disease-specific cardiac autoantibodies were found in 27% of Polish patients with dilated cardiomyopathy at diagnosis; this is evidence for autoimmune involvement in a subset of patients from our country, as seen in a previously reported series of Western European origin. The association of antibody status with insidious onset of symptoms is in keeping with the long latency period observed in other autoimmune disorders. PMID- 8682026 TI - Time domain analysis of the signal averaged electrocardiogram in patients with a conduction defect or a bundle branch block. AB - Doubts have been expressed about the clinical usefulness of time domain analysis of the signal averaged electrocardiogram in patients with prolonged QRS complex duration. We studied 147 patients using a signal averaged ECG (40-250 Hz) whose QRS complex was longer than 100 ms. A baseline electrophysiology study was also performed in 128 of these patients. Seventy-seven patients had a minor (QRS < 120 and > 100 ms) conduction defect. Thirty-seven of these 77 had either induced or spontaneous sustained ventricular tachycardia (group I) and 40 had no sustained ventricular tachycardia (group II). Seventy patients had a major (QRS > or = 120 ms) conduction defect, 44 of whom had sustained ventricular tachycardia (group A). The remaining 26 without this condition formed Group B. Group I compared to group II patients had a longer filtered QRS duration (120.8 +/- 14 vs 104.5 +/- 9.5 ms, P < 0.001), a longer low amplitude signal duration (41 +/- 12.1 vs 31 +/- 12.6 ms, P < 0.0001) and a lower root mean square of the last 40 ms of the filtered QRS complex (27 +/- 29.8 vs 35 +/- 25.3 microV, P = ns). Group A compared to group B had a longer filtered QRS duration (157.7 +/- 20.2 vs 140.7 +/- 15.7 ms, P < 0.001), a longer low amplitude signal duration (57.3 +/- 24.9 vs 37.8 +/- 20.3 ms P < 0.001) and a lower root mean square of the last 40 ms of the filtered QRS complex (14.3 +/- 11.2 vs 22.0 +/- 10.5 microV, P < 0.01). Using conventional late potential criteria, the sensitivity and specificity of the signal averaged ECG for the detection of sustained ventricular tachycardia patients with a minor conduction defect were 89% and 75%, respectively. The same criteria applied to patients with a major conduction defect were sensitive (sensitivity: 87%) but non-specific (specificity: 50%). However, by using modified late potential criteria, such as the presence of two of any of the following three signal averaged parameters: filtered QRS duration > or = 145 ms, low amplitude signal duration > or = 50 ms, root mean square of the last 40 ms of the filtered QRS complex < or = 17.5 microV, we derived a non-optimal but still acceptable combination of sensitivity (68%) and specificity (73%). We conclude that traditional late potential criteria can be applied in patients with a minor conduction defect, but modification of these criteria is necessary to derive useful clinical information for risk stratification of patients with a QRS complex duration > or = 120 ms. PMID- 8682027 TI - Prolongation of conduction time during premature stimulation in the human atrium is primarily caused by local stimulus response latency. AB - BACKGROUND: Conventional clinical electrophysiological techniques cannot accurately differentiate between local stimulus response latency and propagation time of the atrial response. The purpose of this study was to identify and distinguish local stimulus response latency from impulse propagation time in the human right atrium during programmed electrical stimulation. METHODS: Pacing was performed from two atrial sites (high and low right atrium) in 19 patients, using monophasic action potential recording/pacing combination catheters (interelectrode distance < 2 mm). Local stimulus response latency (interval between stimulus artifact and upstroke of the local monophasic action potential), and propagation time (interval between local and remote monophasic action potential upstroke) were evaluated at a basic cycle length (S1-S1) of 600 ms and as a function of the extrastimulus proximity (interval between extrastimulus and effective refractory period). Data are presented as means +/- SEM. RESULTS: During basic stimulation, local latency was very small (3.8 +/- 1.7 ms). During premature extrastimulation (proximity < 70 ms), local latency increased progressively with decreasing coupling intervals. Prolongation of local latency was most pronounced during stimulation close to the effective refractory period with local stimulus response latency increasing to 18.3 +/- 1.4 ms (380 +/- 7.9%) at 10 ms proximity (P < 0.002) and to 27.9 +/- 3.7 ms (630 +/- 13.2%) at 5 ms proximity, respectively (P < 0.0001). The impulse propagation time between the stimulation site and the remote recording site was on average 54.5 +/- 14.3 ms during basic stimulation, and increased up to 62.1 +/- 13.5 ms (14.0 +/- 8.4%), which was not significant. CONCLUSIONS: The intra-atrial impulse propagation remained essentially unchanged during the entire range of premature stimulation. Local stimulus response latency was negligible and constant during late coupling intervals but increased dramatically when extrastimulation approached the preceding repolarization phase. This has the following clinical impact: first, local stimulus response latency during premature extrastimulation curbs the targeted atrial response interval second, local stimulus response latency, not propagation time, seems responsible for the greater functional than effective refractory period during electrical stimulation; third, local stimulus response latency should be considered in pace mapping for accurate comparison of conduction time before pacing with that during pacing. PMID- 8682028 TI - Cardiac outflow of endothelin, neuropeptide Y and noradrenaline in relation to hyperaemia in coronary sinus flow following electrical conversion of induced ventricular fibrillation in man. AB - The implanted cardioverter defibrillator represents an alternative therapy for patients with drug-refractory malignant ventricular arrhythmias. Implantation and testing of the device requires that ventricular fibrillation be evoked and converted, thus providing a situation in which cardiovascular haemodynamics can be studied. In this study we have evaluated the effects of electrically induced ventricular fibrillation, followed by defibrillation, on coronary sinus blood flow and cardiac outflow of endothelin- and neuropeptide Y-like immunoreactivity (-LI) and of noradrenaline. Twelve patients were studied during implantation of a defibrillator. Ventricular fibrillation was induced and terminated after 17 +/- 1 s 5 +/- 1 times in each patient. In six patients coronary sinus blood flow was measured continuously. Plasma samples were obtained from four of these patients and another six patients, from the coronary sinus, radial artery and central vein before and during fibrillation and at two time points ( < 30 s and 5 min). Basal coronary sinus blood flow decreased to 38% at 14 +/- 2 s of ventricular fibrillation. Immediately following defibrillation there was a short-lasting increase in coronary sinus blood flow to 244% and a significant increase in the levels of neuropeptide Y-LI (146%) and noradrenaline (158%) in the coronary sinus while endothelin-LI remained unchanged (97%). Neither fibrillation nor defibrillation evoked any changes in the peripheral arterial and venous levels of endothelin-, neuropeptide Y-LI or noradrenaline. It is concluded that coronary sinus blood flow is markedly reduced during fibrillation and that restoration of normal impulse activity is followed by short-lasting hyperaemia. There was no evidence for effects on the vascular endothelium as assessed by endothelin levels. PMID- 8682029 TI - Effect of flecainide on atrial and ventricular refractoriness and conduction in patients with normal left ventricle. Implications for possible antiarrhythmic and proarrhythmic mechanisms. AB - We studied the effects of intravenous flecainide (2 mg.kg-1) on atrial and ventricular refractoriness and conduction during sinus rhythm, induced atrial fibrillation and atrial pacing at rates of 100, 120 and 150 ppm, in 14 patients with normal left ventricle. Flecainide caused a significant increase in QRS duration during sinus rhythm (mean +/- SD: 87.2 +/- 8.4 ms vs 102.8 +/- 9.1 ms, P < 0.001), atrial fibrillation (87.8 +/- 10.0 ms vs 108.8 +/- 13.7 ms, P < 0.001) and at all paced rates. The duration of the atrial electrogram was significantly increased during sinus rhythm (54.9 +/- 13.2 ms vs 64.8 +/- 16.6 ms, P = 0.003) and at all pacing rates. The PA interval was also significantly prolonged, as was the pacing stimulus-to-atrial-electrogram interval at all pacing rates. There was increased QRS duration and atrial electrogram prolongation at higher pacing rates. Atrial refractoriness was prolonged during sinus rhythm (216.4 +/- 28.2 vs 228.6 +/- 36.1, P = 0.02), but not during atrial pacing at any rate. The QT interval, but not the JT interval or ventricular refractoriness, was significantly prolonged during sinus rhythm and at all pacing rates. Flecainide slows atrial conduction in a use dependent manner and increases atrial refractoriness during sinus rhythm but not during faster atrial pacing, thus not displaying a use-dependent effect. QRS duration is prolonged in a use-dependent manner without a commensurate increase in ventricular refractoriness. In the presence of rapidly conducted atrial fibrillation, which was not found to be slowed by flecainide, this effect may constitute a proarrhythmic mechanism even in patients with no apparent myocardial abnormality. PMID- 8682030 TI - Spectral turbulence analysis of the signal-averaged electrocardiogram for predicting inducible sustained monomorphic ventricular tachycardia in patients with and without bundle branch block. AB - Spectral turbulence analysis of the signal-averaged electrocardiogram is a new method for identifying patients prone to sustained monomorphic ventricular tachycardia. In contrast to analysis in the time domain, it has been claimed to be applicable in patients with bundle branch block. The aim of this study was to assess the predictive value of spectral turbulence analysis, in relation to the inducibility of sustained monomorphic ventricular tachycardia, in patients with and without bundle branch block. One hundred and sixty nine patients, of whom 120 had a QRS duration > or = 120 ms, were studied. Forty-seven patients had inducible sustained monomorphic ventricular tachycardia and were compared to 122 control patients. The overall sensitivity of the spectral turbulence analysis for predicting inducible ventricular tachycardia was 77%, the specificity 35% and the total predictive accuracy 47%. The limited predictive accuracy was mainly due to a lack of difference between patients with and without ventricular tachycardia in patients with a QRS duration > or = 120 ms. In patients with QRS < 120 ms, however, there were significant differences in all spectral turbulence parameters and the method had a sensitivity of 75%, a specificity of 72% and a total predictive accuracy of 73%. The diagnostic usefulness of spectral turbulence analysis is dependent upon normal QRS duration and the method is applicable only to patients without bundle branch block. PMID- 8682031 TI - Safety of flecainide versus propafenone for the long-term management of symptomatic paroxysmal supraventricular tachyarrhythmias. Report from the Flecainide and Propafenone Italian Study (FAPIS) Group. AB - In order to compare the long-term safety of flecainide and propafenone, an open label, randomized, parallel group study was performed in 335 patients with paroxysmal atrial fibrillation (n = 200) or paroxysmal supraventricular tachycardia (n = 135), and no history of heart disease. Patients were treated with an initial daily dose of flecainide 100 mg (n = 72) or propafenone 450 mg (n = 63) for paroxysmal supraventricular tachycardia and flecainide 200 mg (n = 97) or propafenone 450 mg (n = 103) for paroxysmal atrial fibrillation. Dose escalations were permitted after > or = 2 attacks, up to a maximum of flecainide 300 mg or propafenone 900 mg.day-1.Follow-up duration was 12 months, or when patients stopped the treatment as a result of inadequate efficacy or adverse experiences. Twelve patients on flecainide reported 16 cardiac adverse experiences, of whom six discontinued the treatment. Seven propafenone patients had eight cardiac adverse experiences, of whom five discontinued the treatment. Serious proarrhythmic events were infrequent: one case of ventricular tachycardia on propafenone: two cases of atrial fibrillation with rapid ventricular response on flecainide, associated in one patient with pulmonary oedema. An intention-to treat analysis showed that the probability of 12 months' safe and effective treatment of paroxysmal supraventricular tachycardia was 93% for flecainide and 86% for propafenone (P = 0.24), whereas in paroxysmal atrial fibrillation it was 77% for flecainide and 75% for propafenone (P = 0.72). In conclusion, flecainide and propafenone were safe in the long-term treatment of patients with paroxysmal supraventricular tachyarrhythmias and without evidence of clinically significant heart disease. PMID- 8682032 TI - Lung function in relation to haemodynamic status after atrial redirection for transposition of the great arteries. AB - To assess the interplay between haemodynamic sequelae and lung function after atrial redirection for transposition of the great arteries, we investigated 15 Mustard (age 12.0-22.0 years), and 15 Senning patients (age 7.2-12.1 years). As diagnosed at cardiac catheterization and ultracardiography, 16 (11 Mustard) had major haemodynamic sequelae, including systemic ventricle dysfunction, pulmonary hypertension, pulmonary venous obstruction, systemic venous obstruction and atrial septal defects. Static and dynamic lung volumes, ventilation distribution and diffusion capacity were assessed by body plethysmography, spirometry, the single-breath nitrogen test (N2slope) and the single-breath method for diffusion capacity (DLCO) respectively. Apart from DLCO, our own reference values were used for comparison. We found small lung volumes, a high functional residual capacity, a high N2slope and a low DLCO. Tests of > 2SD in the abnormal direction were more prevalent in the Mustard group (P = 0.06) and significantly more prevalent in patients with pulmonary hypertension. Six had normal lung function tests, 15 had unclassified abnormalities, three had small lungs and three had central airway obstruction. Peripheral airway obstruction was only present in three of four subjects with moderate or severe pulmonary hypertension. The study confirms some previous reports indicating a high frequency of lung function abnormalities in these patient groups and discusses a possible relationship to haemodynamic status. PMID- 8682033 TI - Normal coronary flow reserve in patients with mitral valve prolapse, a positive exercise test and normal coronary arteries. AB - We studied 12 patients (eight females and four males), ages 30-46 years, with echocardiographically documented mitral valve prolapse and clinical suspicion of coronary artery disease, based on a history of chest pain (five patients), angina like pain (three patients), a positive exercise stress electrocardiogram (12 patients) and a focally positive thallium-201 stress perfusion scan (three patients), who were referred for cardiac catheterization and found to have normal coronary arteries. Ten patients without evidence of heart disease served as controls. In all mitral valve prolapse patients, coronary flow velocity reserve was determined successively in the left anterior descending, left circumflex and right coronary arteries as the ratio of the maximum (after intracoronary papaverine) to the resting mean coronary flow velocity. Coronary flow reserve values were fairly similar in the mitral valve prolapse and control patients; all 12 mitral valve prolapse patients had normal coronary flow reserve ( > or = 3.5) in all three coronary arteries with no significant differences among the arteries tested. Mean values +/- 1 standard deviation of the coronary flow reserve (mitral valve prolapse vs control patients) were 4.7 +/- 0.5 vs 4.6 +/- 0.6 for the left anterior descending, 4.6 +/- 0.4 vs 4.6 +/- 0.3 for the left circumflex and 4.5 +/- 0.4 vs 4.4 +/- 0.5 for the right coronary artery (all P = non-significant). The subsets of mitral valve prolapse patients with different clinical "ischaemic' manifestations were similar in terms of the calculated coronary flow reserve in all three major epicardial coronary arteries. In conclusion, this study demonstrated that an inadequate regional coronary flow reserve does not account for the clinical manifestations of myocardial ischaemia and positive exercise tests in patients with mitral valve prolapse and normal coronary arteries. PMID- 8682034 TI - Procedures associated with infective endocarditis in adults. A case control study. AB - OBJECT: To assess the relative risk of infective endocarditis associated with various procedures and the protective efficacy of antibiotic prophylaxis by a case-control study. BACKGROUND: Recommendations for the prevention of infective endocarditis are based on the hypothesis of a relationship between procedures and infective endocarditis which is supported by anecdotal reports and data from experimental models. METHODS: Cases met the Von Reyn's diagnostic criteria modified with echocardiographic and macroscopic findings Controls were recruited from cardiology or medicinal wards. Cases (n = 171) and controls were matched as regards sex, age and underlying cardiac condition. They were requested to indicate all the medical, surgical or dental procedures within the previous 3 months. Among potential confounding factors, infectious episodes and skin wounds in the previous 3 months were reported. Antibiotic prophylaxis administration was documented for type, dosage, duration and administration schedule. RESULTS: Cases significantly more frequently than controls had undergone at least one procedure (matched odds ratio, 1.6; 95% confidence interval, 1.01 to 2.53). Dental procedures considered as a whole were not associated with an increased risk, although scaling and root canal treatment showed a trend towards a higher risk of infective endocarditis (P = 0.065). Among non-dental procedures, only surgery appeared to be at risk (matched odds ratio, 4.7; 95% confidence interval, 1.02 to 22). Considering all procedures, the risk of infective endocarditis increased significantly with the number of procedures. While general co-morbid conditions did not differ between the two groups, cases significantly more frequently than controls had experienced an infectious episode or a skin wound. In multivariate analysis, only infectious episodes and skin wounds significantly increased the risk of infective endocarditis. Scaling was the only independent risk factor for viridans streptococcal infective endocarditis. The 46% protective efficacy of antibiotic prophylaxis was not significant. CONCLUSIONS: Procedures do increase the risk of infective endocarditis. The interpretation of the apparent low risk associated with dental procedures may be as a result of the current practice of antibiotic prophylaxis. Our data suggest that surgery should be more clearly mentioned in future guidelines, and reemphasize that a rigorous treatment of any focal infection in cardiac patients is mandatory. From the efficacy rate of antibiotic prophylaxis,it can be estimated that the overall incidence of infective endocarditis might be reduced by 5 to 10% in France by appropriate use of antibiotic prophylaxis in cardiac patients. PMID- 8682035 TI - Infective endocarditis due to Streptococcus bovis. A report of 53 cases. AB - Fifty-three patients (42 men; 11 women) with Streptococcus bovis infective endocarditis attended a tertiary cardiology hospital between 1980 and 1991, and constituted 11% of the total number of infective endocarditis cases hospitalized there during that period. The mean age was 59 +/- 15 years; 15 had previously suffered valvular disease (12) or had a valvular prosthesis (3); one patient had had a previous infective endocarditis. The infective episode involved the aortic valve in 26 patients, both the aortic and mitral valves in 18 patients, the mitral valve only in six and other valves in three. Echocardiographic examination showed one or more vegetations in 44 patients. Cardiac failure was diagnosed in 35 patients and embolic episodes in 22, of whom 11 were cerebrovascular accidents. The patients became afebrile 19 +/- 39 days after starting antibiotic treatment. Valve replacement was performed in 37 patients during their initial hospitalization, and in four during follow-up. After a mean follow-up of 4.6 +/- 3.1 years with a 100% follow-up, 15 patients died: 1 preoperatively, one in the first 30 days after operation, 13 later (8141 operated patients and 5/12 non operated patients). Actuarial survival was 73% at 5 years. Gastrointestinal signs were present in 12 patients; 43 patients (81%) had a full colonic examination which showed polyps in 20 patients and adenocarcinomas in seven. Of 11 late deaths four were related to a malignant colonic tumour. This study confirms that Streptococcus bovis infective endocarditis is 'relatively benign', but it stresses the frequency and potential severity of the associated colonic lesions, requiring colonoscopy and making the treatment of high risk lesions mandatory. PMID- 8682036 TI - Left ventricular systolic function after marked reduction of ventricular hypertrophy induced by 5 years' enalapril treatment. AB - OBJECTIVES: To determine the effects of long-term treatment of essential hypertension with an angiotensin-converting enzyme inhibitor as regards arterial pressure at rest and during exercise, left ventricular mass and functional sequelae. PATIENTS AND METHODS: Twenty-six patients with previously untreated essential hypertension took enalapril 20 mg twice daily for 5 years. Cardiovascular parameters were determined by two-dimensionally guided M-mode echocardiography in a pre-treatment placebo phase, 8 weeks and 1, 3 and 5 years after the start of therapy, and 8 weeks after drugs were discontinued. RESULTS: Therapy reduced resting arterial pressure from 156/105 to 128/84 mmHg (P < 0.001) and arterial pressure during exercise from 205/113 to 172/94 mmHg (P < 0.0011). After 1, 3 and 5 years' therapy, left ventricular mass index had decreased by 15, 28 and 39% respectively (P < 0.001 in each case). Eight weeks after treatment was halted, arterial pressure at rest and during exercise had returned to pre treatment values, but decreased left ventricular mass was maintained. Left ventricular pump function had improved after 5 years' treatment, and this improvement was maintained during the 8 weeks without treatment. CONCLUSIONS: Significant reductions in arterial pressure at rest and during exercise were achieved by 8 weeks' treatment with enalapril and maintained during 5 years' further treatment, while a marked reduction in left ventricular mass took place progressively throughout the 5 year period. Reduction of myocardial hypertrophy by enalapril appeared to be beneficial rather than detrimental to cardiac pump performance. PMID- 8682037 TI - Trends in blood pressure levels over time in middle-aged and elderly Jerusalem residents. AB - Change in blood pressure levels over time was investigated in Jerusalem, in two cross-sectional surveys in 1970 and in 1986 among residents of a neighbourhood aged 50 years and more. The study population comprised 1397 individuals in 1970 and 1858 in the 1986. Age-adjusted mean systolic and diastolic blood pressure levels were lower in 1986 than in 1970 by 6.9 mmHg and 4.7 mmHg, respectively. The prevalence of blood pressure levels above 160 and/or 95 mmHg in 1986 was lower by 50% and there was a twofold increase in current treatment for hypertension. The reduction in blood pressure in both sexes remained evident upon control for confounding effects of age, ethnic group, education, body mass index and reported treatment for hypertension. The proportion of people who had blood pressure levels below 140/90 and did not report being under treatment, increased. The possibility of methodological problems inherent in this type of study were considered. More effective antihypertensive treatment in 1986 can explain only part of the reduction. The decrease in levels of blood pressure as revealed by this study may reflect a real reduction in the population that could explain part of the striking decline in cardiovascular mortality in Israel. PMID- 8682038 TI - Unbalanced haemostatic changes following strenuous physical exercise. A study in young sedentary males. AB - During acute exercise both coagulant and fibrinolytic potential increase. Since strenuous exertion is associated with an enhanced risk for cardiac events, especially in untrained individuals, it is important to determine whether the initial haemostatic balance is maintained during exercise. Twenty-nine sedentary males (20-30 years) were subjected to a standardized cycle ergometer test. Blood samples were obtained at two exercise levels, 70% VO2max (submaximal), 100% VO2max (maximal) and during 25 min recovery. Both during submaximal and maximal performance, tissue type plasminogen activator antigen, urokinase plasminogen activator antigen and tissue type plasminogen activator activity were increased. A concomitant enhancement of clotting activity of factors VII, VIII, IX, XII and fibrinogen resulted in a shortening of clotting times. Following correction for changes in plasma volume, the results for factor VII:c were reversed, and factor XII:c and fibrinogen no longer demonstrated exercise-related changes. Increases in coagulant (activated partial thromboplastin time) and fibrinolytic (tissue type plasminogen activator activity) potential proceeded in parallel during exercise. However, during recovery while there was a sustained increase in coagulant potential, fibrinolytic potential demonstrated a sharp fall. We conclude that during physical activity, while parallel changes in coagulant and fibrinolytic activity occur, this haemostatic balance is not maintained during recovery. This phenomenon could constitute an enhanced risk for coronary artery thrombosis which may contribute to exercise-related cardiovascular events. PMID- 8682039 TI - Acute myocardial infarction related to myocardial bridging. PMID- 8682041 TI - Post coital coronary artery dissection. PMID- 8682040 TI - Single coronary artery: morphological and functional evaluation by magnetic resonance imaging. PMID- 8682042 TI - Cardiac angiosarcoma presenting as diffuse pulmonary disease. PMID- 8682043 TI - Supraventricular tachycardia detected by means of an oesophageal Holter ECG in a patient with third-degree AV block and a VVI pacemaker. PMID- 8682044 TI - Spontaneous echo contrast and Chiari's network. PMID- 8682045 TI - Left atrial paralysis after mitral valve replacement. PMID- 8682046 TI - Orthostatic tachycardia due to hypovolaemia and beta-adrenergic hypersensitivity. PMID- 8682047 TI - Morphological change of the 5th aortic arch with tetralogy of Fallot and pulmonary atresia: echocardiographic and angiographic findings. PMID- 8682048 TI - Analysis of heart rate variability in a patient with paroxysmal atrial fibrillation. PMID- 8682049 TI - Detection of spontaneous echo contrast in pulmonary artery and paradoxical cerebroembolism. PMID- 8682050 TI - Can panic disorder be considered as an angina equivalent? PMID- 8682051 TI - Atrial septal defect type Ostium secundum with and without prolonged atrioventricular conduction. PMID- 8682052 TI - Intramural aortic haematoma following intra-aortic balloon counterpulsation. Documentation by transoesophageal echocardiography. PMID- 8682053 TI - Heart Failure '95. Neurohormonal modulation of heart failure: ACE inhibition and beyond. Amsterdam, The Netherlands, 1-4 April 1995. Proceedings and abstracts. PMID- 8682054 TI - Aldosterone escape during ACE inhibitor therapy in chronic heart failure. AB - In the setting of chronic heart failure (CHF), therapy with angiotensin converting enzyme (ACE) inhibitors generally reduces serum aldosterone levels acutely. However, long-term ACE inhibition is associated with aldosterone suppression that is weak, variable, and unsustained, i.e. aldosterone 'escape'. Magnesium loss caused by aldosterone and by diuretics can contribute to coronary artery spasm and arrhythmias. Aldosterone can block noradrenaline uptake by the myocardium; extracellular catecholamines may lead to arrhythmias and ischaemia. Aldosterone has been shown to have an acute arrhythmogenic effect as well as a potential detrimental effect on baroreflex function, a marker of prognosis in CHF. Both angiotensin II and aldosterone may stimulate myocardial fibrosis, which is associated with a higher incidence of malignant ventricular arrhythmias. ACE inhibition initiated early in the progression of CHF may prevent development of patchy myocardial fibrosis and its inherent arrhythmias and thus reduce the incidence of sudden death. Spironolactone therapy added to the regimen of an ACE inhibitor and diuretic can induce natriuresis and magnesium retention, increase myocardial noradrenaline uptake, and reduce the incidence of arrhythmias. PMID- 8682055 TI - ACE inhibitor co-therapy in patients with heart failure: rationale for the Randomized Aldactone Evaluation Study (RALES). AB - Angiotensin converting enzyme (ACE) inhibitor therapy in conjunction with loop diuretics and, possibly, digoxin, is associated with a relatively high incidence of recurrent heart failure and death. Even high doses of ACE inhibitors may not completely suppress the renin-angiotensin-aldosterone system; aldosterone "escape' may occur through non-angiotensin II dependent mechanisms involving corticotropin, atrial natriuretic peptide, serum potassium, and deficient high density lipoprotein cholesterol concentrations. Addition of spironolactone (an aldosterone receptor blocker) to an ACE inhibitor regimen causes marked diuresis and symptomatic improvement. The Randomized Aldactone Evaluation Study (RALES) was organized to explore the role of combination therapy with spironolactone in patients with heart failure. Patients with New York Heart Association Functional Class II-IV heart failure and left ventricular ejection fractions < or = 40% who were on regimens comprising an ACE inhibitor, loop diuretic, and, possibly, digoxin were randomized to receive placebo or spironolactone in doses of 12.5, 25, 50, or 75 mg per day. Eve at the lowest dose of spironolactone, a significant decrease in plasma N-terminal pro-atrial natriuretic peptide occurred, with concomitant increase in concentrations of plasma renin and urinary aldosterone. As prophylaxis for heart failure, a daily dose of 25 mg of spironolactone and monitoring of serum potassium concentrations are recommended; symptomatic therapy in refractory or severe heart failure may require doses as high as 100 mg b.i.d. The RALES Mortality Trial will follow up 1400 similar patients for 3 years to determine the effect of the addition of spironolactone on combined mortality and hospitalization for heart failure. PMID- 8682056 TI - Structural remodelling of the heart by fibrous tissue: role of circulating hormones and locally produced peptides. AB - Symptomatic heart failure is accompanied by diastolic ventricular dysfunction due largely to an extensive reactive and reparative fibrosis. Experimental evidence suggests a clear association between myocardial fibrosis and chronic inappropriate elevations in circulating angiotensin II (Ang II) and/or aldosterone. Although not entirely elucidated, injury follows Ang II-associated release of adrenal medullary catecholamines and aldosterone-induced myocardial potassium depletion. Increasing evidence indicates locally produced cardiac Ang II plays an important role in tissue repair that may underlie myocardial remodelling, the fibrous tissue accumulation both at and remote to the site of myocardial infarction (MI). Angiotensin converting enzyme (ACE) binding density markedly increases at these fibrous tissue sites after experimental MI, indicating an involvement in wound healing regardless of the cause and location of fibrosis; cells expressing Ang II receptors are primarily myofibroblasts. Therapy with ACE inhibitors and aldosterone receptor antagonist have each been shown to attenuate development of fibrosis. PMID- 8682057 TI - The ageing spontaneously hypertensive rat as a model of the transition from stable compensated hypertrophy to heart failure. AB - Spontaneously hypertensive rats (SHR) of advanced age exhibit depressed myocardial contractile function and ventricular fibrosis, as stable compensated hypertrophy progresses to heart failure. Transition to heart failure in SHR aged 18-24 months was characterized by impaired left ventricular (LV) function, ventricular dilatation, and reduced ejection fraction without an increase in LV mass. Studies of papillary muscles from SHR with failing hearts (SHR-F), SHR without failure (SHR-NF), and age-matched Wistar Kyoto (WKY) rats allowed examination of changes in the mechanical properties of myocardium during the transition to heart failure. Papillary muscles of SHR-F exhibited increased fibrosis, impaired contraction, and decreased myocyte fractional area. These findings in papillary muscles were correlated with a higher concentration of hydroxyproline and increased histological evidence of fibrosis in the LV free wall. While a depression in active tension accompanied these structural alterations in papillary muscles, it was not evident when active tension was normalized to myocyte fractional area. Together, these data suggest that individual myocyte function may be preserved but that myocyte loss and replacement by extracellular matrix contribute substantially to the decrement in active tension. An absent or negative inotropic response to isoproterenol is observed in SHR-F and SHR-NF papillary muscles and may result in part from age related alterations in beta-adrenergic receptor dynamics and a shift from alpha- to beta-myosin heavy chain (MHC) protein. During the transition to failure, ventricles of SHR exhibit a marked increase in collagen and fibronectin mRNA levels, suggesting that an increase in the expression of specific extracellular matrix genes may contribute to fibrosis, tissue stiffness, and impaired function. Transforming growth factor-beta 1 (TGF-beta 1) mRNA levels also increase in SHR F, consistent with the concept that TGF-beta 1 plays a key regulatory role in remodelling of the extracellular matrix gene during the transition to failure. The renin-angiotensin-aldosterone system is also implicated in the transition to failure: SHR treated with the angiotensin converting enzyme inhibitor captopril starting at 12 months of age did not develop heart failure during the 18-24 month observation period. Captopril treatment that was initiated after rats were identified with evidence of failure led to a reappearance of alpha-MHC mRNA but did not improve papillary muscle function. Research opportunities include investigation of apoptosis as a mechanism of cell loss, delineation of the regulatory roles of TGF-beta 1 and the renin-angiotensin-aldosterone system in matrix accumulation, and studies of proteinase cascades that regulate matrix remodelling. PMID- 8682058 TI - Molecular aspects of myocardial differentiation. AB - The embryonic heart can pump blood in a single direction without one-way valves. With the development of molecular cell markers specific for contraction and relaxation, functional aspects of myocardial differentiation have been addressed through the use of in situ hybridization. In this study, we report how expression of the cardiac sarcoplasmic reticulum calcium-adenosine triphosphatase (SERCA2) and phospholamban (PLB) in the rat may partly explain why the embryonic atrium and ventricle function essentially as they do in the adult. SERCA2 is expressed in a craniocaudal gradient from as early as 10 embryonic days (ED) of development. PLB is first expressed at 12 ED but in a gradient essentially opposite to that seen for SERCA2. This spatial pattern of expression is maintained throughout much of fetal development. The spatial distribution of skeletal alpha-actin in the developing human heart indicates that alpha-actin isoform gradients or switching are not important in the establishment of unidirectional blood flow in the absence of valves, but it may serve as a marker for cardiac maturation. PMID- 8682059 TI - Post-infarction myocardial remodelling: why does it happen? AB - Myocardial remodelling is currently the subject of intense investigative interest. The question "Why does it happen?' is not clearly answerable by today's methods; however, the work of many basic scientists and clinicians has allowed an improved understanding of the process. Multiple mechanisms are probably operative in the cardiac remodelling process, including cell drop-out, myocyte slippage, collagen replacement and growth, and myocyte hypertrophy. The concept of heart failure as primarily a structural problem rather than the result of a specific biochemical "defect' is advanced. There is now direct evidence that cardiac myocytes are enlarged in both experimental and clinical left ventricular remodelling. Possible signal processing cascades are potential pathways to myocyte remodelling. Although not proven, the enlarged and elongated cardiac myocyte may be at a structural disadvantage, thus contributing functionally to the clinical syndrome of heart failure. Reversal of established cardiomegaly- regression of myocardial remodelling--is an unusual but occasional event in patients with cardiomyopathy that can be observed experimentally. PMID- 8682060 TI - Myocardial infarction and the myocyte IGF1 autocrine system. AB - To determine the effects of acute myocardial infarction on the extent and distribution of mural stress on surviving myocardial tissue, coronary artery occlusion was surgically produced in rats. Following haemodynamic measurements in vivo, the characteristics of cardiac anatomy were determined and found to consist of an increase in mid-chamber lumenal diameter and a decrease in wall thickness. The combination of these phenomena resulted in an eight-fold increase in diastolic wall stress on the remaining viable portion of the wall and severe impairment of left and right ventricular performance. Since insulin-like growth factor-1 (IGF1) and its receptor (IGF1R) are required for cell growth in vitro, the possibility was raised that an autocrine IGF1-IGF1R system may be present in vivo and may become activated in viable ventricular myocytes shortly after infarction. Therefore, the unaffected myocytes of the left ventricle were enzymatically dissociated and the expression of IGF1R and IGF1 mRNAs were measured at 12 h and at 1, 2-3, and 7 days after surgery. The level of IGF1R mRNA increased at 12 h and remained elevated at 1 and 2-3 days following coronary artery ligation. In addition, an increased level of IGF1R protein was found on these cells. This phenomenon was coupled with the enhanced expression of IGF1 mRNA in the muscle cells at all points. Thus, the marked elevation in ventricular loading after coronary occlusion may activate the IGF1-IGF1R autocrine system of the unaffected cells, modulating the cellular growth processes implicated in short-term ventricular remodelling of the infarcted heart. PMID- 8682061 TI - Does ACE inhibition limit structural changes in the heart following myocardial infarction? AB - A recent series of experiments in our laboratory were designed to elucidate the cellular changes that underlie the cardiac remodelling response following myocardial infarction (MI) in the rat as well as the potential role of the renin angiotensin system (RAS) in this response. Inhibition of the RAS interferes with cardiomyocyte hypertrophy, interstitial cell DNA synthesis, and collagen deposition; these effects are mediated through the angiotensin II AT1 receptor subtype. Also, vascular outgrowth is functionally diminished, an effect that seems to depend on AT2 receptor activation. The intracardiac RAS may be involved in the wound healing response in the infarct area. However, we found no evidence for activation of the RAS in the remnant myocardium, which suggests that myocyte hypertrophy and interstitial fibrosis depend on activation of the systemic RAS. During the first weeks following MI, therapy of choice should thus inhibit the systemic RAS while allowing the wound-healing response of the intracardiac RAS, i.e. selective AT1 antagonists are appropriate early after MI. AT2 antagonists administered at that time can inhibit the cardiac vascularization response and cause a further decrease in level of cardiac function. PMID- 8682062 TI - Changes in neurohumoral systems during the development of congestive heart failure: impact on cardiovascular and renal function. AB - The results of studies in animals indicate that in left ventricular (LV) dysfunction and early heart failure, vasodilative-natriuretic mechanisms effectively antagonize vasoconstrictive-anti-natriuretic systems; this balancing effect contributes to preservation of circulatory and renal function. Progression to overt heart failure is characterized by a shift of this balance, with dysfunction of vasodilator systems and activation of vasoconstrictor systems. In patients, neurohumoral activation is observed early in asymptomatic LV dysfunction and is related to the severity of LV dysfunction in the progression of the syndrome. Neurohumoral activation precedes overt heart failure, and it has independent prognostic value for the development of heart failure. Activation of the renin-angiotensin system and of the sympathetic nervous system, as well as the possible stimulation of vasopressin secretion, may contribute to the transition from LV dysfunction to heart failure and may, therefore, provide targets for early pharmacological intervention. PMID- 8682063 TI - Angiotensin converting enzyme inhibition in asymptomatic left ventricular systolic dysfunction and early heart failure. AB - Benefit achieved through use of angiotensin converting enzyme (ACE) inhibitors in patients with reduced left ventricular (LV) systolic function is not confined to those with clinical manifestations of heart failure. Although rates of adverse clinical events are lower in asymptomatic patients, within this population ACE inhibitors have been shown to prevent adverse ventricular remodelling, prevent the development of clinical heart failure, reduce rates of hospitalization for heart failure and, in some studies, reduce mortality. Most of the benefit derived appears to be associated with preventing the progression of LV hypertrophy, dilatation, and dysfunction, resulting in prevention of heart failure. Additionally, the incidence of myocardial infarction is decreased, although the exact physiological basis for this benefit remains uncertain. Given the enormity and growth of heart failure as a public health problem and the potential for influencing the underlying pathophysiology, ACE inhibitor treatment offers substantial benefit for patients with asymptomatic LV systolic dysfunction. PMID- 8682064 TI - Neurohormonal activation and congestive heart failure: today's experience with ACE inhibitors and rationale for their use. AB - Treatment with angiotensin converting enzyme (ACE) inhibitors delays deterioration and improves survival in chronic congestive heart failure and left ventricular dysfunction. In two large placebo-controlled trials with survivors of acute myocardial infarction, but with left ventricular dysfunction, mortality was significantly lower in the ACE inhibitor arms, with risk reductions of 19% (with captopril) and 27% (with ramipril). A study of left ventricular dysfunction in more than 4000 patients resulted in significantly fewer myocardial infarctions among patients given enalapril than in those receiving placebo; the risk reduction was 24%. Knowledge of the degree of neurohormonal activation in patients with congestive heart failure (New York Heart Association [NYHA] Functional Class II-III) appears to be of major importance in determining the efficacy of ACE inhibition. Patients with plasma concentrations above normal show the greatest increase in survival when treated with ACE inhibitors compared to similarly treated patients with low or normal neurohormonal plasma levels as well as those treated with placebo or direct-acting vasodilators. In a study of 239 patients with NYHA Class IV heart failure, randomized to receive enalapril or placebo, mortality was significantly reduced in patients receiving enalapril who had plasma noradrenaline, adrenaline, angiotensin II, aldosterone, or atrial natriuretic peptide levels above median values. No significant differences in survival between groups were found in patients with hormone levels below the median. A study in 804 men with congestive heart failure who received either enalapril or hydralazine plus isosorbide dinitrate showed the greatest reduction in mortality after 2 years in enalapril treated patients with plasma noradrenaline levels > 900 pg.ml-1 or plasma renin levels > 16 ng.ml-1.h-1. These results indicate that the main rationale for ACE inhibition in chronic congestive heart failure, in left ventricular dysfunction, and after myocardial infarction is the modulation of prolonged neurohormonal activation. Knowledge of this effect may provide the means to forestall disease progression and thus offer long-term treatment benefits. PMID- 8682065 TI - Neurohormonal modulation in heart failure: ACE inhibition and beyond. AB - Angiotensin converting enzyme (ACE) inhibition undoubtedly has become the cornerstone of heart failure treatment. Useful in each stage, it should possibly be considered first-line treatment in many patients with mild heart failure in whom fluid retention is not clearly present. Careful consideration of the optimal dose for the individual is important. Until further data are available concerning the efficacy and tolerability of high and low doses, the clinician should consider the target doses used in large controlled heart failure trials. Even under optimal dosing conditions, it is likely that ACE inhibition may not suffice in completely modulating the extensive neurohormonal stimulation extant in heart failure. In part this may result from a breakthrough of the ACE inhibitor effect as well as from activation of hormones and peptides that may not be affected by ACE inhibition. Also, a substantial proportion of patients may not tolerate sufficient ACE inhibition. Alternative or additional therapy aimed at modulating neurohormonal activation concerns interference with other parts of the renin angiotensin system, such as angiotensin II receptor and aldosterone receptor antagonism. Sympathetic activity and catecholamine levels may decrease with dopaminergic D2 agonists and, possibly, beta-blockade; in the latter, this may be confined to patients with pre-existing sympathetic over-activation. Increasing circulating levels of atrial natriuretic peptide via neutral endopeptidase inhibition may offer an alternative way to increase diuresis and natriuresis without neuroendocrine stimulation. Novel possibilities that have not yet been tested sufficiently in patients with heart failure include endothelin receptor antagonism, arginine vasopressin antagonism, and renin inhibition. Finally, digitalis glycosides may be considered neurohormonal modulators in addition to being positive inotropes. Heart failure is a complex condition that involves many organs and systems besides the heart. Polypharmacy tailored to the individual is mandatory. It is thus necessary to investigate approaches to the modulation of neurohormonal activation beyond ACE inhibition. PMID- 8682066 TI - Mechanisms of angiotensin II formation in humans. AB - Various organs, including the heart and blood vessels, apparently contain tissue renin-angiotensin systems. Through autocrine and paracrine activity, locally produced angiotensin II (Ang II) may well play an important role in cardiovascular homeostasis; in pathological conditions. Ang II may also contribute to the remodelling of the heart and vasculature. In addition to angiotensin converting enzyme (ACE), a cardiac Ang II forming serine proteinase (human heart chymase) has been identified in the left ventricle of the human heart. The different cellular and regional distributions of ACE and chymase in the heart as well as in the blood vessels suggest distinct pathophysiological roles for these two Ang II forming enzymes. Several reports indicate that both ACE-dependent and ACE-independent Ang II formation appear to occur in hypoxic or ischaemic hearts or blood vessels in vivo and seem to be involved in the pathological changes seen in these organs. However, chymase-dependent Ang II formation--which is chymostatin sensitive but aprotinin insensitive--does not explain all ACE-independent Ang II formation. Therefore, it is important to elucidate the mechanisms of tissue Ang II formation in humans and their contribution to the pathophysiological changes in cardiovascular disease. PMID- 8682067 TI - The biological cascade leading to cardiac hypertrophy. AB - Cardiac hypertrophy, one of the major risk factors in hypertension, is associated with a high incidence of congestive heart failure and sudden death. Despite efforts over the last 20 years, the underlying molecular mechanisms of cardiac hypertrophy are still poorly understood, thus making it difficult to develop new therapeutic strategies. A growing body of evidence suggests that cardiac hypertrophy results from mechanical stress that triggers paracrine and autocrine signal transduction pathways. Furthermore, whereas hypertrophy leads to isoform switches in some contractile proteins, increased protein synthesis is largely based on increased translational capacity. Cardiac growth under physiological as well as pathological conditions is regulated by several recently identified transcription factors. Among the factors that are capable of transmitting hypertrophic stimuli to the nucleus is the early growth response gene-1 (Egr-1). Whereas female gender is already an established cardioprotective factor in clinical trials, some very recent data indicate that oestrogens and the nuclear oestrogen receptor may directly modulate gene expression in the development of cardiac hypertrophy. Future pharmacological interventions could be directed towards modifying the nuclear signal transduction cascade involving multiple protein kinases and phosphatases. PMID- 8682068 TI - Effects of angiotensin receptor antagonists in heart failure: clinical and experimental aspects. AB - In addition to inhibition of the circulating renin-angiotensin system, specific inhibition of the cardiac effects of angiotensin II (Ang II) represents an important therapeutic goal in the treatment of clinical heart failure. Subtype 1 specific Ang II receptor (AT1) antagonists have been developed to overcome potential limitations of angiotensin converting enzyme inhibitors, e.g. insufficient control of tissue Ang II production and bradykinin-related side effects. Clinical studies have demonstrated beneficial effects of AT1 antagonists. In a single-dose study, the AT1 antagonist losartan decreased the mean arterial pressure and pulmonary arterial pressure while increasing the cardiac index. Effects were dose dependent. Haemodynamic effects were greater with higher doses, but neurohormonal counter-regulation probably also increased, leading to relatively high levels of circulating Ang II with the 150-mg dose, A decrease in plasma levels of noradrenaline, atrial natriuretic factor, and aldosterone reached partial significance. Administration of multiple doses of losartan for 12 weeks also led to favourable haemodynamic and clinical results. Arterial blood pressure, pulmonary capillary wedge pressure, and systemic vascular resistance decreased. The neurohormonal effects of 12 weeks' administration of AT1 antagonists consisted in a decrease in plasma aldosterone concentrations. Whereas AT1 antagonists may counteract the effects of Ang II on the vasculature, and therefore are effective vasodilators, their direct myocardial effects are less clear. The subtype AT2, which represents the dominant, receptor in both healthy and failing human myocardium, is not blocked by AT1 inhibition. Angiotensin receptors on isolated human cardiac fibroblasts stimulate cellular proliferation via a yet undertermined receptor subtype. AT1 antagonists exert beneficial haemodynamic and neurohormonal effects in human heart failure. Their direct myocardial effects require further investigation. PMID- 8682069 TI - Aldosterone: intracellular receptors in human heart. AB - It has been suggested that aldosterone exerts direct effects on heart functioning, in particular by inducing cardiac fibrosis. We examined human heart tissue for the expression of aldosterone receptors (mineralocorticoid receptors, MRs) and of the MR-protecting enzyme, 11 beta hydroxysteroid dehydrogenase (11 beta HSD). In situ hybridization using cRNA probes specific for human MRs revealed the presence of mRNA encoding for MRs in cardiomyocytes. Immunohistochemistry with specific antibodies against the MR exhibited the expression of MR protein in cardiomyocytes. In contrast, intramyocardial small blood vessels showed no evidence of immunolabelling. A distinct 11 beta HSD activity, which was nicotinamide-adenine dinucleotide dependent, was also demonstrated in human cardiac tissue. These results illustrate that all the components required for a specific aldosterone effect are present in the human heart. PMID- 8682070 TI - Aldosterone and heart failure. AB - In untreated congestive heart failure, aldosterone plasma concentrations are elevated in proportion to the severity of the disease and are further increased by the use of diuretic treatment. Angiotensin II, plasma potassium concentration, and corticotropin are the major stimulators of aldosterone synthesis. During angiotensin converting enzyme (ACE) inhibition, the role of alternative major or minor regulatory mechanisms may become significant. This may explain why during continuous ACE inhibition, after an initial reduction, plasma aldosterone measurements may subsequently increase to pretherapeutic levels. In addition to causing sodium and water retention, aldosterone contributes to hypokalaemia and hypomagnesaemia, which may induce electrical instability and death of cardiac myocytes. Aldosterone is also one factor involved in cardiac hypertrophy and fibrosis, which, together with myocardial cell death, may underlie progressive adverse myocardial remodelling. Evidence for a direct vascular effect of aldosterone suggests that this hormone may contribute to generalized vasoconstriction. Elevated plasma aldosterone levels can also contribute to depression of baroreflex sensitivity, and they are associated with increased mortality in patients with severe heart failure. Experimental and clinical research should be further expanded to investigate the potential benefits of opposing the effects of aldosterone by use of specific antagonists or other potentially more potent pharmacological agents with favourable side-effect profiles. PMID- 8682071 TI - Diagnosis and treatment in dilated heart muscle disease. Proceedings. Berlin, Germany, 7-9 September 1994. PMID- 8682072 TI - Mitochondrial DNA mutations in myocardial diseases. AB - Recent genetic studies have revealed that some patients with primary cardiomyopathy (CM) possess mutations in the mitochondrial (mt) DNA of the myocardium (mtCM). Somatically acquired mutations such as deletions in mtDNA are caused mainly by hydroxyl radical damage to mtDNA. Cumulative accumulation of these somatic mutations during the life of an individual causes a bioenergetic deficit leading to myocardial dysfunction and cell death. The base-sequencing of the entire mtDNA from 48 individuals revealed that germ-line point mutations accelerate oxygen free radical damage and deletions, leading to the generation of many hundreds of types of mtDNA minicircles. These accelerated somatic mutations are expressed as premature ageing of the patients with mtCM. The comprehensive analyses of the entire mtDNA, including the base-sequencing and deletions correlating to the oxygen free radical damage, have revealed clear relationships between the genotype and its phenotype, with regard to, for example, the severity of clinical symptoms and the survival time of the patients. Extensive generation of mtDNA minicircles caused by the hydroxyl radical implies a close relationship between somatic mtDNA mutation and the programmed cell-death machinery. PMID- 8682073 TI - Immunohistochemistry in dilated cardiomyopathy. AB - The aetiology of dilated cardiomyopathy is unknown by definition. Viral myocarditis is often viewed as an early stage in the progression of the disease leading to cardiomyopathy and heart failure in humans. The chronic inflammatory process is manifested histologically as a sparse, diffuse lymphocytic infiltration of the myocardium, classified as borderline or ongoing myocarditis according to the Dallas classification. Because of limitations of light microscopy, chronic myocarditis remains an enigmatic condition to diagnose and to treat. In contrast to routine histological staining procedures, immunohistochemical methods enable better identification and quantification of infiltrating cells and also provide further evidence that the activated immunological process within the myocardium is ongoing. In 176 patients with clinically suspected dilated cardiomyopathy, borderline myocarditis was diagnosed in only 14 cases (8%) histologically. However, using immunohistological analysis of endomyocardial biopsies, pathologically increased lymphocytic infiltration was revealed in 67 biopsy specimens (38%), and activated lymphocytes or activated macrophages in all analysed inflamed cardiac tissues. All positive biopsies showed an activated vascular endothelium, demonstrated by the enhanced expression of different adhesion molecules. Various cytokines were locally released from activated inflammatory cells. This may cause a cytokine-rich micro-environment which could be responsible for the enhanced expression of adhesion molecules and thereby contribute to the inflammatory traffic of immune cells into inflamed myocardial areas. These observations underline the hypothesis that the immune process is still active in a group of patients with clinically suspected dilated cardiomyopathy, causing progression of the disease. PMID- 8682074 TI - The renin-angiotensin-aldosterone system and myocardial collagen matrix remodelling in congestive heart failure. AB - In chronic heart failure, various regulatory systems including the Frank-Starling mechanism, the neuro-hormonal response, cardiac growth and peripheral oxygen delivery may be operative. Recently, the inter-relationship of the renin angiotensin-aldosterone system (RAAS) and cardiac growth has drawn clinical interest. In the pressure-or volume-overloaded heart, the development of myocyte growth is primarily dependent on ventricular loading. Non-myocyte cell growth involving cardiac fibroblasts may also occur but this is not primarily regulated by the haemodynamic load. Cardiac fibroblast activation is responsible for the accumulation of fibrillar type I and type III collagens within the interstitium and adventitia of intramyocardial coronary arteries. In addition to relaxation abnormalities due to impairment of sarcoplasmic Ca(2+)-ATPase activity, this remodelling of the cardiac interstitium represents a major determinant of pathological hypertrophy in that it accounts for abnormal myocardial stiffness, leading to ventricular diastolic and systolic dysfunction and ultimately the progression of symptomatic heart failure. The effector hormones of the RAAS, angiotensin II (AngII) and aldosterone (Aldo), appear to be primarily involved in promoting the adverse structural remodelling of the myocardial collagen matrix. In cultured adult cardiac fibroblasts, AngII and Aldo have been shown to stimulate collagen synthesis while AngII additionally inhibits matrix metalloproteinase I activity, which is the key enzyme for degradation of fibrillar collagen in the cardiac interstitium, leading to excessive collagen accumulation. These findings may serve as rationale as to why angiotensin converting enzyme inhibition or blockade of the RAAS represents such remedial therapy beyond the effect of simply unloading the heart in patients with congestive heart failure. PMID- 8682075 TI - The cardiomyopathy of overload: an unnatural growth response. AB - The poor prognosis in heart failure, which can be reproduced by overloading the normal heart, may reflect molecular abnormalities associated with cardiac hypertrophy. Because terminally differentiated adult cardiac myocytes have little or no capacity to divide, overload-induced hypertrophy represents an unnatural growth response. The mechanism by which this unnatural growth response shortens survival remains speculative, but may involve apoptosis caused when overload reactivates growth factors to which the adult heart cannot respond with normal cell division. The ability of converting enzyme inhibitors and nitrates, which have growth inhibitory as well as vasodilator effects, to improve prognosis in heart failure may reflect the ability of these drugs to modify this unnatural growth response. PMID- 8682076 TI - Contributions of 31P-magnetic resonance spectroscopy to the understanding of dilated heart muscle disease. AB - In the present work, we studied clinical and haemodynamic correlates of impaired cardiac high-energy phosphate metabolism in patients with heart failure due to dilated cardiomyopathy (DCM). Myocardial 31P-magnetic resonance (MR) spectra were obtained at 1.5 T in 14 volunteers and 23 patients with DCM (mean ejection fraction 34%) in order to quantify the creatine phosphate (CP)/ATP ratio. In addition, patients underwent cardiac catheterization and echocardiography. Compared to volunteers (2.02 +/- 0.11), CP/ATP ratios were significantly reduced in DCM patients (1.54 +/- 0.10; P < 0.05), indicating impaired high-energy phosphate metabolism. CP/ATP ratios correlated with the clinical severity of heart failure estimated from the NYHA class (r = 0.47, P < 0.01); also, CP/ATP correlated with left ventricular ejection fraction (r = 0.54, P < 0.01) and left ventricular end-diastolic wall thickness (r = 0.51, P < 0.01). Thus, 31P-MR spectroscopy can detect abnormal cardiac high-energy phosphate metabolism in patients with heart failure due to DCM. These abnormalities correlate with clinical and haemodynamic parameters. Future studies will have to determine whether 31P-MR spectroscopy can contribute to the routine clinical evaluation of patients with heart failure. PMID- 8682077 TI - Non-invasive detection of myocyte necrosis in myocarditis and dilated cardiomyopathy with radiolabelled antimyosin. AB - The 'gold standard' for the diagnosis of myocarditis is endomyocardial biopsy. Although the specificity of this invasive method is good, its sensitivity is questionable. Therefore, a non-invasive diagnostic method with greater sensitivity (even if it were overly sensitive) would constitute a useful screening tool for identification of patients who should undergo endomyocardial biopsy. Antimyosin immunoscintigraphy fits such a criterion since it is highly sensitive and specific for diagnosis of myocardial necrosis, which is one of the two obligatory components for the diagnosis of myocarditis. Therefore studies were performed on patients with clinical histories suggestive of myocarditis such as acute onset of dilated cardiomyopathy, myocarditis masquerading as acute myocardial infarction and patients presenting with unexplained life-threatening ventricular tachyarrhythmias. In all these studies, antimyosin imaging had higher sensitivity than endomyocardial biopsy for the diagnosis of myocarditis. A rationale is provided for the increased sensitivity and specificity of antimyosin immunoscintigraphy for diagnosis of myocyte necrosis associated with myocarditis, relative to endomyocardial biopsy. PMID- 8682078 TI - Myocardial catecholamines in primary heart muscle disease: fact or fancy? AB - The pathophysiological role of myocardial catecholamines in cardiomyopathies is still not completely understood. We there-fore assessed myocardial catecholamine concentrations (MCC) in 34 patients with hypertrophic cardiomyopathy (HCM) (76.5% males; mean age 46.7 +/- 11.6 years; left ventricular ejection fraction [LVEF] 75.3 +/- 9.8%) and in 32 patients with dilated cardiomyopathy (DCM) (87.5% males, mean age 43.1 +/- 12.5 years, LVEF 34.9 +/- 8.3%). Initial assessment included clinical work up, cardiac catheterization and endomyocardial biopsy. Myocardial norepinephrine (MNEC), epinephrine (MEC), and dopamine (MDC) concentrations in endomyocardial biopsy samples were measured using the catechol-O- methyl transferase radioenzymatic method. Significantly higher MNEC and MEC were demonstrated in HCM than in DCM patients (MNEC: 781.9 +/- 125.8 ng.g-1 fresh myocardial tissue (ft) HCM vs 262.6 +/- 68.9 ng.g-1 ft DCM, p < 0.01; and MEC: 91.6 +/- 13.9 ng.g-1 ft HCM vs 35.8 +/- 6.2 ng.g-1 ft DCM, P < 0.01). The difference in MDC did not reach statistical significance (76.1 +/- 8.3 ng.g-1 ft HCM vs 70.1 +/- 11.8 ng.g ft DCM; P > 0.05). In addition, we compared the MCC levels in 24 patients, clinically presented as dilated cardiomyopathy categorized according to the various aetiologies: 12/24 with primary DCM (75.0% males, mean age 49.6 +/- 9.5 years; LVEF 25.8 +/- 63%), 7/24 with alcohol-induced heart disease (85.7% males, mean age 46.8 +/- 7.1 years; LVEF 26.4 +/- 4.6%), and 5/24 with hypertensive heart disease (100% males, 45.1 +/- 10.6 years; LVEF 25.6 +/- 9.1%), but no significant difference was found among them (P > 0.05). There was no significant difference in tissue dopamine concentrations. PMID- 8682079 TI - Adrenergic beta-blocking agents in congestive heart failure due to idiopathic dilated cardiomyopathy. AB - The use of Beta-blockers for treatment of chronic heart failure due to idiopathic dilated cardiomyopathy has now begun to be accepted among cardiologists after having been used sporadically for 19 years. Pooled data from several minor controlled trials performed during the last 13 years which have shown consistent improvement of myocardial function, specifically in patients with idiopathic dilated cardiomyopathy, have recently been confirmed by two major trials using the selective beta-blockers metoprolol (MDC trial) and bisoprolol (CIBIS trial). There was a decrease of 34% in the combined number of deaths and patients needing a heart transplantation (P = 0.058) in the MDC trial. Bisoprolol, as well as reducing the overall mortality significantly, was found, in a retrospective subgroup analysis, to reduce mortality in idiopathic dilated cardiomyopathy. The MDC trial showed improvement in ejection fraction by 7 units compared with placebo and 13 units compared with baseline after 12 months treatment (P < 0.0001). There was also an increase in exercise time compared with placebo at 12 months follow-up. There was a 39% reduction in the number of readmissions to hospital due to heart failure and arrhythmias (P < 0.04) and a 32% reduction in the CIBIS trial (P < 0.01). Possible mechanisms for improvement after beta blockers are improvement in myocardial energetic balance, protection against calcium overload or normalization of myocardial catecholamine kinetics. The role of upregulation of beta-adrenergic receptors remains controversial since this could not be seen in the action of all beta-blockers. The question of whether mortality can be reduced remains unsolved and will require large prospective trials which are now in progress. PMID- 8682080 TI - ACE inhibitors in non-ischaemic heart failure: results from the MEGA trials. AB - Large-scale trials have demonstrated a consistent mortality reduction from angiotensin converting enzyme (ACE) inhibitor therapy for chronic heart failure. Nonetheless, the pharmacologic and physiologic mechanisms of this favourable affect and the appropriate target population remain controversial. ACE inhibitors exert vasodilator, neurohormonal inhibiting and growth inhibiting effects that may contribute to the clinical response. They improve pump function and prevent ventricular remodelling, but they also may exert an antiarrhythmic effect. They may prevent coronary ischaemic events but appear to reduce cardiovascular event rates even more in non-ischaemic than in ischaemic heart disease. Their efficacy in early stages of asymptomatic heart disease and the optimal dose of the drugs for long-term benefit require further study. PMID- 8682081 TI - Heart transplantation in dilated heart muscle disease and myocarditis. AB - A detailed analysis of outcome with reference to pre-transplant diagnosis was performed in 14 055 cardiac transplant recipients to determine whether the diagnosis of dilated heart muscle disease predicted survival. Overall survival at one year was greater than 80% in all patients. In general, those with dilated heart muscle disease had a small but significantly improved survival compared to those with other diagnoses. Outcome in women, which is significantly poorer than men, showed similar diagnosis-specific results. Multivariate analysis confirmed the significant difference (P = 0.02) with a minimal reduction in risk (relative risk 0.927). In conclusion, carefully selected patients with dilated heart muscle disease are excellent candidates for cardiac transplantation. PMID- 8682082 TI - Immunomodulating agents for the management of heart failure with myocarditis and cardiomyopathy--lessons from animal experiments. AB - We have developed murine models of viral myocarditis induced by the encephalomyocarditis (EMC) virus in which there is a high incidence of severe myocarditis, congestive heart failure and dilated cardiomyopathy. From these models, we have learned of their natural history and pathogenesis and assessed new diagnostic methods and therapeutic and preventive interventions. Our recent studies showed that increased circulating cytokines have been detected in patients with acute myocarditis and cardiomyopathy and suggest that cytokines may play some role in the pathogenesis of myocardial injury in these diseases. In our animal model of EMC virus myocarditis, plasma tumour necrosis factor-(TNF)-alpha was elevated in the acute stage and exogenously administered anti-TNF-alpha antibody improved survival and reduced the myocardial lesion, suggesting the importance of TNF-alpha in the pathogenesis. A recently developed positive inotropic agent, vesnarinone, was effective in the treatment of EMC virus myocarditis by its immunomodulating effects such as inhibition of production of TNF-alpha The plasma angiotensin II level was increased in EMC virus myocarditis, and a new angiotensin II type I antagonist, TCV-116, prevented development of myocarditis. PMID- 8682083 TI - Can recombinant DNA technology provide useful vaccines against viruses which induce heart disease? AB - In the panoply of armaments against viral infections, both drugs and vaccines have been employed. Numerous vaccines have enjoyed spectacular success in either eradicating or controlling various viral diseases, whereas there are still few, effective anti-viral drugs. Coxsackie B viruses are agents of human inflammatory heart disease and may trigger events leading to a failing heart. We believe that enteroviral heart disease could be controlled or eradicated through the use of vaccines, in much the same manner as poliovirus-induced poliomyelitis has been controlled through vaccination. We present here preliminary data which deal with an approach to the development of enterovirus vaccines and the use of a chimeric coxsackievirus B3 (CVB3) vaccine in a murine model of CVB3-induced inflammatory heart disease. PMID- 8682084 TI - Subclassification of dilated cardiomyopathy and interferon treatment. AB - Seventy-seven consecutive patients with dilated cardiomyopathy underwent left ventricular endomyocardial biopsy. In 20 biopsies (26%) enteroviral RNA was detected by in-situ hybridization. After an average observation period of more than 2 years only one patient had died in the enterovirus positive (ev+) group compared with 11 deaths and four heart transplantations in the enterovirus negative (ev-) group. After a mean follow-up of 16 +/- 9 months haemodynamic evaluation of the surviving ev+ patients showed significantly better results with respect to left ventricular ejection fraction and left ventricular end-diastolic diameter. The four ev+ patients with haemodynamic deterioration were given interferon-alpha, 3 million units subcutaneously every other day for six months. No severe side effects were seen and all four patients improved according to their haemodynamic and clinical parameters. In two of the four patients enteroviral RNA was not detectable in a subsequent biopsy. PMID- 8682085 TI - Genetics of coxsackievirus B3 cardiovirulence. AB - The human enteroviruses, especially the coxsackie B viruses, have been established as aetiologic agents of human inflammatory heart disease, a condition which may lead to dilated cardiomyopathy and heart failure. It is clear from murine models of coxsackievirus B3-induced inflammatory heart disease that not all strains of the virus are cardiovirulent (able to cause disease). Here, we present preliminary data mapping the site in a coxsackievirus B3 genome which determines a cardiovirulent phenotype. PMID- 8682086 TI - Interferon and thymic hormones in the therapy of human myocarditis and idiopathic dilated cardiomyopathy. AB - It is becoming increasingly apparent that idiopathic dilated cardiomyopathy (IDC) probably results from an acute viral myocarditis. One reasonable hypothesis is that persistent viral infection causes myocardial destruction leading to left ventricular dilatation and heart failure. The aim of this study was to evaluate the efficacy of interferon-alpha (IFN) and thymomodulin in the treatment of idiopathic myocarditis and IDC. Clinical, immunological, haemodynamic and histological evaluation was performed in 40 patients before inclusion in the study. Patients were randomized into three treatment groups: (a) conventional therapy plus IFN, (b) conventional therapy plus thymomodulin and (c) conventional therapy alone. Two-year follow-up included repeated endomyocardial biopsy, echocardiographic evaluation, treadmill exercise test, Holter monitoring study and radionuclide assessment of left ventricular function during exercise. Left ventricular ejection fraction increased during follow-up in most of the IFN-and thymomodulin-treated patients, and only in a few of conventionally treated patients. Left ventricular reserve was significantly higher at 2-year follow-up in patients treated with immunomodulators. No serious adverse effects were noticed during treatment. Our results suggest that treatment of myocarditis and/or IDC with IFN or thymomodulin induces an earlier and significantly superior clinical improvement than conventional therapy alone. PMID- 8682087 TI - Immunosuppressive treatment for myocarditis and dilated cardiomyopathy. AB - This overview examines the immunological rationale for immunosuppressive and immunomodulating therapy in man and experimental animals. The controversy of whether immunosuppressive treatment is beneficial in myocarditis will continue even after the Myocarditis Treatment Trials has been published. It is known that in viral heart disease immunosuppressive drugs should be avoided, but in autoreactive forms of myocarditis with proven humoral and cellular effector mechanisms they may be used in controlled randomized trials to validate or refute their benefit. Immunomodulating factors, e.g. immunostimulatory or antiviral substances such as ribaverin, the interleukins and interferons have demonstrated some effect in experimental animal myocarditis but proof of their benefit in man is still lacking. Hyperimmunoglobulin therapy appears to be of particular interest because it incurs few side effects and has positive results in cytomegalovirus-associated myopericarditis in man and suspected myocarditis in children. PMID- 8682088 TI - The Myocarditis Treatment Trial: design, methods and patients enrollment. AB - The Myocarditis Treatment Trial was a multicentre clinical trial conducted to determine the efficacy of immunosuppressive therapy for treatment of biopsy documented myocarditis, and to improve understanding of the immunological mechanisms in the development of myocarditis. Thirty-one centres screened 2305 patients with unexplained heart failure, and 2233 patients underwent an endomyocardial biopsy which provided adequate tissue for diagnosis. Those with a positive biopsy and a left ventricular ejection fraction (LVEF) less than 45% were randomly assigned to receive immunosuppressive therapy plus conventional drug therapy for congestive heart failure (66 patients) or conventional therapy only (45 patients) for 24 weeks. For 28 additional weeks all patients received conventional therapy only. In addition to diagnostic and clinical data, serum and myocardial tissue for immunological marker analysis and histopathologic evaluation were collected at baseline and at 12, 28 and 52 weeks after randomization. The primary analysis of efficacy was designed as a comparison of the mean increase in LVEF at week 28 between treatment limbs. Secondary objectives were to evaluate survival differences, and changes in the histopathology of the disease and immunological markers. Randomized patients were relatively young (mean age, 42.0 years +/- 13.8 standard deviation (sd) and entered the Trial with a mean LVEF percent of 24.3 +/- 10.1 sd) and mean exercise treadmill duration of 9.4 (+/- 5.3 sd) minutes. The incidence of biopsy documented myocarditis was low (9.6%). The analyses of outcome and immunological data are reported elsewhere. PMID- 8682089 TI - Treatment of chronic myocarditis with corticosteroids. AB - Dilated cardiomyopathy (DCM) continues to be an aetiologically unknown heart muscle disease. Recent clinical and experimental data have suggested a temporal relationship with viral myocarditis. The clinical diagnosis of a chronic myocarditis is unspecific. The evaluation of endomyocardial biopsies by light microscopy and their histological classification according to the Dallas criteria is limited by the difficulty in differentiating and quantifying infiltrating lymphocytes from non-inflammatory interstitial cells. Using immunohistological methods that allow better identification and quantification of infiltrating lymphocytes and which provide further evidence for an activated immunological process within the myocardium, myocarditis was diagnosed on endomyocardial biopsy in 48 of 130 patients (37%). According to both haemodynamic and immunohistological findings, 31 of these patients were allocated for immunosuppressive treatment. After a 6 month treatment period with 6 methylprednisolone, 23 patients reported an improvement according to the NYHA classification. Lymphocytic infiltrations were abolished by corticoid treatment in 24 patients. Left ventricular systolic function was improved in 20 patients (64%) as indicated by an increased ejection fraction and stroke volume with a concomitant decrease of left ventricular end diastolic pressure. Our study suggests that immunosuppressive treatment in a subgroup of patients with dilated cardiomyopathy who have a continuing active immunohistologically proven inflammatory process results in a clinical, haemodynamic and immunohistological improvement in 60-70% of patients. PMID- 8682090 TI - The European Study of Epidemiology and Treatment of Cardiac Inflammatory Disease (ESETCID). AB - Diagnosis of myocarditis has improved with the application of new techniques such as immunohistochemistry, polymerase chain reaction, in situ hybridization and Southern blot in endomyocardial biopsies. Treatment of inflammatory heart disease is still difficult and not yet validated by a study with patient numbers sufficient to allow statistical analysis. The European Study of Epidemiology and Treatment of Cardiac Inflammatory Disease (ESETCID) addresses problems of aetiology, pathogenesis and specific treatment of myocarditis. It is the first multicentre, double-blind placebo-controlled randomized study, apart from the Myocarditis Treatment Trial, to discriminate between different forms of myocarditis. Patients with cytomegalovirus-induced myocarditis are treated by hyperimmunoglobulin compared to placebo. Patients with enterovirus-positive myocarditis will receive interferon alpha vs placebo. Patients with virus negative myocarditis, which is considered autoimmune, will be treated with immunosuppression compared to placebo. The primary endpoint of this study is an improvement in ejection fraction of more than 5%. This trial may give a better understanding of the course of myocarditis, leading to more specific treatment which may in turn reduce the number of patients with post-myocardial heart muscle disease who require heart transplantation as a final therapeutic remedy. PMID- 8682091 TI - Shifting the paradigm for the treatment of dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) has emerged as a major health problem during the past two decades. In spite of recent advances, it has become clear that the underlying heart disease is relentlessly progressive in almost all patients who develop symptoms of overt failure; morbidity and mortality continues to be unacceptably high with an incidence of approximately 30% for death or hospital admission at one year. Cardiac transplantation remains the only current prospect for dramatically improving survival in many patients. Trying to enhance cardiac function during the later stages of heart failure is ultimately fruitless; it cannot be done over the long term. The solution to failure lies in defining and preventing its causes or arresting and reversing its evolution. We propose a model where the target for therapeutic intervention becomes the arrest of progressive myocardial disease throughout the course of the cardiomyopathy. In this paradigm, the selection of therapeutic agents for the treatment of heart failure takes into consideration both the stage of the disease and differences in pathogenesis. In addition it broadens our approach from one which focuses on enhancing myocardial function to one which encompasses strategies which are designed to inhibit the progressive loss of myocytes and the inexorable deterioration of the failing myocardium. PMID- 8682092 TI - A non-cardiovirulent strain of coxsackievirus B3 causes myocarditis in mice with severe combined immunodeficiency syndrome. AB - The most extensively studied animal model of coxsackievirus B3 (CVB3)-induced inflammatory heart muscle disease is the murine model. In the acute and chronic phase of the disease, it has been suggested that autoimmune mechanisms play a major role in the pathogenesis of the disease. In this study, C3H mice without functional T- and B-lymphocytes (C3H SCID) were inoculated either with a cardiovirulent (CVB3/20) or a non-cardiovirulent (CVB3/0) strain of coxsackievirus B3. Both viruses caused myocarditis in SCID mice. Furthermore, it could be demonstrated, that CVB3/0 had mutated to a cardiovirulent phenotype, able to cause myocarditis in immunocompetent mice. PMID- 8682093 TI - Frequency of familial dilated cardiomyopathy. AB - Based on evaluation of 59 probands and their families, we previously demonstrated that over 20% of patients with idiopathic dilated cardiomyopathy (DCM) have familial disease. We acquired 36 additional probands and found familial disease in 24.2% of the 95 probands in this expanded consecutively ascertained cohort. The family history, as reported by the patient and relatives, is often an unreliable indicator of familial disease because patients may be unaware of the significance of a family history of sudden death, arrhythmia or stroke. We demonstrate that careful family history with review of medical records identifies more familial cases than merely asking the patient if there is a family history of DCM. However, even such a careful family history does not identify all familial cases. Some familial cases are identified only by echocardiographic investigation of asymptomatic relatives. We found no clinical attributes of probands, other than family history, which predicted familial disease. PMID- 8682094 TI - New aspects of murine coxsackie B3 myocarditis--focus on heavy metals. AB - The magnitude of inflammatory lesions in the hearts of coxsackie B3 (CB3)-virus infected mice can be affected by the potentially toxic heavy metals cadmium (Cd), nickel (Ni) and methyl mercury (MeHg). The infection is associated with a changed distribution, such as Cd accumulation in the spleen and kidneys. New target organs for Ni during the infection were the heart, pancreas and lungs in which inflammatory lesions were present. This increased uptake was correlated with the disturbed function of immune cells and an increased inflammatory reaction. Ni and MeHg appeared to have a direct effect on immune cells that resulted in changed natural killer cell activity and decreased mobilization of macrophages, CD4+ and CD8+ cells into the inflammatory lesions. Although MeHg increased spleen T cell activity and gamma-interferon (IFN-gamma) levels, the inflammatory lesions in the heart increased. Another detrimental effect of MeHg treatment was evident by an increased calcium and decreased zinc content in the inflamed heart, which may partly explain the more severe inflammatory lesion. The host's response, CB3 infection, changed the distribution of each metal in a specific way, a fact which may subsequently result in altered target organ toxicity and resistance to the infection. PMID- 8682095 TI - The role of transgenic knockout models in defining the pathogenesis of viral heart disease. AB - The pathogenesis of viral myocarditis involves contributions from the virus, the immune system and myocytes. In defining the molecular contributions in the disease process, modulations of the components of the immune system through transgenic knockout models provide useful insights. Advantages of the transgenic knockout models are that they allow biological evaluation of the importance of a particular molecule in the physiological context of an intact organism. Furthermore, the techniques of transgenic knockout models are now standardized, even though they are still technically challenging and time consuming. An example in myocarditis is the IRF-1 knockout mouse, where there is a complete absence of the inducible form of nitric oxide synthetase in the tissues. These animals are exquisitely sensitive to coxsackieviral infection, with extremely high mortality. On the other hand, CD4 knockouts appear to still have myocarditis in an autoimmune myocarditis model, while p56lck knockouts (the T-cell tyrosine kinase signalling molecule) appears to be free of viral myocarditis. These elegant systems of molecular manipu-lation should allow us unique insights into the pathogenesis of myocarditis. PMID- 8682096 TI - Left ventricular haemodynamics in murine viral myocarditis. AB - In susceptible DBA/2 mice infection with coxsackievirus B3 leads to severe inflammatory and necrotic lesions in the heart. There is a temporal discrepancy of peak concentrations of replicative virus in the heart and maximal cardiac inflammation. Aims of this study were, first, to determine whether haemodynamic changes occur in coxsackievirus B3-induced murine myocarditis and, second, the time frame in which those alterations may be apparent. By puncture of the left ventricle, pressures and the first derivative dp/dt as parameters of left ventricular function could be obtained on several days of the infection. Haematoxylin-eosin stains of cross-sections of the heart showed the course of inflammatory lesions in the heart; a plaque forming assay assessed virus titres in the heart. Cardiac concentrations of replicative virus peaked on day 3, inflammatory lesions in the heart were maximal on day 7. Left ventricular function was almost preserved until day 5 of the infection, then dropped significantly until day 10. The study suggests that either a cumulative virus mediated destruction of the myofibres or virally triggered immune reactions to heart cells lead to impairment of left ventricular function. PMID- 8682097 TI - Depressed unloaded sarcomere shortening velocity in acute murine coxsackievirus myocarditis: myocardial remodelling in the absence of necrosis or hypertrophy. AB - We used right ventricular papillary muscles to study cellular dysfunction in acute murine coxsackievirus myocarditis. We measured unloaded sarcomere shortening velocity (V0) with laser diffraction (HeNe, lambda = 623.8 nm) 7 days after coxsackievirus infection (M) (n = 7) and after infection + monoclonal antibodies to eliminate T cells (T) (n = 4) and in normals (N) (n = 8). A servomotor rapidly shortened a muscle until slack early in contraction and V0 was measured at the onset of zero force. V0 in N was 4.14 +/- 0.84 microns.s-1 at Sl = 2.08 +/- 0.09 microns, 1.70 +/- 0.33 microns.s-1 at 2.06 +/- 0.08 microns in M and, in preliminary experiments, 4.75 +/- 0.96 microns.s-1 at 2.06 +/- 0.07 microns in T. Resting force and stiffness were normal in M. Ventriculor weights in M and T were the same as N. There was an increase in mononuclear cells in M papillary muscles, but no fibrosis or necrosis. Thus, V0 was markedly reduced in acute viral myocarditis in the absence of tissue disruption or hypertrophy, but not if T cells were absent. Pyrophosphate gel electrophoresis showed a shift from predominantly fast in N to a slow myosin isoform in M. Myosin remodelling and reduced unloaded sarcomere shortening velocity occur early in acute coxsackievirus myocarditis and are dependent on immune responses to the virus, but are not a result of histopathological changes. PMID- 8682098 TI - The epidemiology of infectious myocarditis, lymphocytic myocarditis and dilated cardiomyopathy. AB - Infectious myocarditis is a common condition which often passes unrecognized, and the true incidence is thus unknown. Lymphocytic myocarditis has been recorded in 1.06% of 12,747 unselected routine autopsies performed over a 10-year period. Dilated cardiomyopathy (DCM) has an estimated frequency of 7.5-10% per 100,000 inhabitants per year. Overall, the enteroviruses, and particularly the Coxsackie B viruses, predominate among viruses as the cause of myocarditis. As new molecular biological techniques have become available, the cytomegaloviruses (CMV) seem to have emerged as a more common cause of myocarditis than was previously recognized. Among the bacterial myocarditides, diphtheric myocarditis has become a serious threat in Russia and adjacent states during the 1990s. Among newly identified bacteria, Borrelia burgdorferi infection is accompanied by cardiac involvement in 1-8% of cases, where myocarditis with conduction disturbances is the most prominent feature. Chlamydia pneumoniae may be associated with myocarditis and sudden unexpected death. In AIDS, myocarditis with variable aetiology occurs in up to 50% of patients, although asymptomatic in most cases. In lymphocytic myocarditis and DCM, enteroviral-specific nucleotide sequences have been detected in about 30% of patients, and CMV-specific nucleotide sequences in 14%. Borrelia burgdorferi may occasionally be implicated in DCM. In this contribution we focus also on sudden unexpected death (SUD) in young athletes, since, in Sweden, an increased frequency of SUD has recently been observed in young orienteers and myocarditis was a common feature. PMID- 8682099 TI - Enterovirus-infected immune cells of spleen and lymph nodes in the murine model of chronic myocarditis: a role in pathogenesis? AB - Molecular hybridization studies have demonstrated that human enteroviruses, including group B coxsackieviruses (CVB), are detectable not only in endomyocardial biopsies of patients with acute enterovirus myocarditis but also in those with chronic disease. Such infections are observed in some patients with end-stage dilated cardiomyopathy, indicating the possibility of persistent heart muscle infection. Enterovirus persistence in the human heart is supported by the recent discovery in various murine models of enterovirus myocarditis that chronic inflamed heart muscle lesions are consistently associated with enterovirus persistence. Application of in-situ hybridization in a multiorgan study of CVB3 infected immunocompetent mice now reveals that, in addition to the myocardium, spleen and lymph nodes are persistently infected. During acute myocarditis, the majority of infected spleen cells was found to be located within the follicles of spleen and lymph nodes. At later stages of the disease, enteroviral infection was shown to be restricted to cells of the germinal centre in secondary follicles of spleen and lymph nodes. Thus, infected immunocompetent cells may play an important role in dissemination of the virus in the host and maintenance of a non cardiac viral reservoir. PMID- 8682100 TI - Cytomegalovirus-associated heart muscle disease. AB - Human cytomegalovirus (CMV) can persist in many organs after primary infection. Not only is it suspected to cause morbidity during reactivation in patients under immunosuppression, but it may also induce long-term latency by chronic disease, e.g. in the myocardium. Endomyocardial biopsies of 27 patients with active myocarditis, 35 patients with healing, 41 patients with healed and 25 patients with ongoing myocarditis according to the Dallas Criteria and 52 patients with dilated cardiomyopathy (DCM) and the biopsies of 25 healthy heart donors were studied for persisting CMV-DNA by polymerase chain reaction (PCR) and in-situ hybridization (ISH). CMV-DNA could be assessed in 5-14% of patients in the different stages of myocarditis and in 22% of patients with DCM. Although two biopsies of the control group showed a positive result, studies by in-situ hybridization demonstrated that in patients with heart muscle disease CMV persists in all cell types including myocytes, whereas in the controls it is only found in interstitial cells. CMV antigens could not be detected in the myocardium with our methods. It must be assumed that infection by CMV is more a persistent or latent than an active infection. PMID- 8682101 TI - Molecular genetics of dilated cardiomyopathies. AB - The application of molecular genetics in cardiology is currently producing important results in the study of the pathogenetic mechanisms underlying cardiomyopathies. Recent clinical surveys have indicated that genetic factors play a major pathogenetic role in idiopathic dilated cardiomyopathy (IDC). Familial IDC is frequent (20-30%) and is probably a heterogeneous entity, as suggested by the clinical variability and the different pattern of inheritance in the affected families. Molecular genetic studies have demonstrated the existence of heterogeneity also at the genetic level. In a series of families with X-linked IDC, the disease gene has been identified as the dystrophin gene. In familial right ventricular cardiomyopathy (or right ventricular dysplasia), a new nosological entity characterized by isolated right ventricular involvement that can mimic IDC, the disease gene has been localized in the long arm of chromosome 14. In families with matrilineal transmission, the cardiomyopathy could be linked to mitochondrial DNA alterations. Autosomal dominant familial IDC, considered to be the most frequent form, is currently under active investigation. Our preliminary data have excluded a large series of candidate genes, among which are the cardiac beta-myosin heavy chain and several other genes encoding for cardiac contractile proteins, genes of the HLA region, and about 60 genes involved in the immune regulation. PMID- 8682102 TI - Dilated heart muscle disease associated with HIV infection. AB - As more effective therapies have produced longer survival times for HIV-infected patients, non-infectious complications of late stage HIV infection such as the development of severe global left ventricular dysfunction (dilated heart muscle disease) have emerged. The demographic and clinical characteristics of HIV infected patients who develop dilated heart muscle disease as well as potential risk factors are, as yet, poorly characterized. Of 174 patients enrolled in a prospective longitudinal study, a total of nine patients, all with CD4 T cell counts < 200 mm-3, developed symptomatic heart disease (congestive heart failure n = 7, sudden cardiac death n = 1 and cardiac tamponade n = 1); three of these patients developed progressive cardiac dysfunction leading to primary cardiac failure and death. An additional 55 HIV-infected patients referred to our Cardiomyopathy Service were found to have global left ventricular dysfunction, with 84% having New York Heart Association Class III or IV congestive heart failure on presentation. Clinical characteristics associated with severe symptomatic cardiac dysfunction included low CD4 T cell counts, myocarditis associated with non-permissive cardiotropic virus infection on endomyocardial biopsy and persistent elevation of anti-heart antibodies. No relationships to any specific HIV risk factor or opportunistic infection were found. These findings suggest that a severe form of HIV-related dilated heart muscle disease is largely a disease of late stage HIV infection. Virus-related myocarditis and cardiac autoimmunity may play a role in the pathogenesis of progressive cardiac injury. Long-term longitudinal studies of larger HIV-infected cohorts are warranted to identify clinical, behavioral and immunologic risk factors. PMID- 8682103 TI - Coxsackievirus-induced chronic myocarditis in murine models. AB - Challenge of several murine strains with two highly myocarditic variants of coxsackievirus B3 (CVB3) induced acute and chronic myocarditis, detectable at 21 and 45 days post-inoculation (p.i.). In-situ hybridization of coronal heart sections showing chronic inflammation with a radiolabelled CVB3 probe detected viral genomic RNA at day 7 p.i. but rarely at 21 or 45 days p.i., suggesting few murine heart cells actively replicate virus during chronic myocardial inflammation. Data will be presented that favour an alternative hypothesis, i.e. autoimmune responses to shared epitopes among CVB3 proteins, cardiac myosin and myocardial cell surface proteins (molecular mimicry) can affect the severity of chronic inflammation. Mice inoculated with human cardiac myosin (HM) prior to a CVB3m challenge develop less myocarditis than mice inoculated with virus only, suggesting that antibodies stimulated by HM bind virus, reduce the virus burden and provide protection. Mice inoculated with HM only develop non-neutralizing antibodies against purified CVB3m particles. Several strains of mice inoculated with specific synthetic peptides of HM produce antibodies against CVB3m and/or develop cardiomyopathy. Thus antigen-challenged mice can produce antibodies which cross-react among CVB3m HM or cardiac cells to protect or exacerbate heart disease. PMID- 8682104 TI - Impairment of left ventricular function in combined immune deficiency mice after transfer of peripheral blood leukocytes from patients with myocarditis. AB - Autoimmune mechanisms are suspected to play an important role in the pathogenesis of human myocarditis. In order to evaluate the significance of autoimmune leukocytes for the development of human myocarditis (MC) and subsequent heart failure, we transferred 15 x 10(6) or 50 x 10(6) peripheral blood leukocytes (PBLs) from patients with immunohistologically proven MC and impaired left ventricular function into severe combined immune deficiency (SCID) mice that possess neither B nor T lymphocytes. PBLs from seven patients and five healthy controls were transferred into three SCID mice each by intraperitoneal injection. After 60 days human PBLs could be demonstrated in the peripheral blood of SCID mice, representing up to 10% of peripheral blood mononuclear cells. Likewise, human immunoglobulins were present in all transfused SCID mice (up to 3 mg.ml-1 IgG and IgM); however, autoantibodies against the adenine nucleotide translocator, a myocardial autoantigen, were only present in the mice receiving PBLs from patients with MC. Infiltrating human lymphocytes were also only found in the hearts of SCID mice having received PBLs from MC patients, but not in those receiving PBLs from normal controls. When we measured the slope of the left ventricular pressure pulse by direct puncture under ether anaesthesia, we found it to be decreased (dp/dt = 1750 +/- 194 mmHg.s-1 in mice receiving PBLs from MC patients, compared with mice receiving PBLs from controls (dp/dt = 2456 +/- 92 mmHg.s-1 or receiving no transfusion (dp/dt = 2576 +/- 142 mmHg.s-1. These results demonstrate that the impairment of the ventricular function seen in patients with MC can be transferred to SCID mice by transfer of PBLs. This proves the significance of autoimmune mechanisms for the pathogenesis of MC. PMID- 8682105 TI - The role of the ADP/ATP carrier in the pathogenesis of viral heart disease. AB - The ADP/ATP carrier is an autoantigen in myocarditis and dilated cardiomyopathy, both of which are diseases related to virus infections. Sera of these patients bear carrier-specific autoantibodies inhibiting transmembrane nucleotide transport on isolated mitochondria. To further assess the role of the ADP/ATP carrier in viral heart disease, guinea pigs were immunized with the isolated ADP/ATP carrier protein and A-strain mice were infected with coxsackie B3 virus. Both species generated specific and carrier-inactivating antibodies after immunization/infection. The transport activity of the ADP/ATP carrier-estimated from the cytosolic-mitochondrial difference of the phosphorylation potential of ATP (delta G[cyt-mit])-markedly declined in guinea pig and mice hearts. A close relationship was observed between the magnitude of reduction of delta G(cyt-mit) and the decrease of cardiac function. Therefore, it seems plausible that carrier dysfunction induced by viral infection creates an imbalance in myocardial energy metabolism, and is responsible for the impairment of cardiac function. The underlying mechanism might be an autoimmune reaction triggered via molecular mimicry or a modulation of the expression of ADP/ATP carrier isoforms changing the overall transport capacity of the cardiac ADP/ATP carrier. PMID- 8682106 TI - Organ-specific cardiac autoantibodies in dilated cardiomyopathy--an update. AB - Autoimmune disease is characterized by the presence of organ- and disease specific autoantibodies in patients and first degree relatives; antibody detection may precede disease onset by several years. We investigated potential involvement of organ-specific autoimmunity in dilated cardiomyopathy (DCM). Using indirect immunofluorescence and absorption studies, organ- and disease-specific IgG cardiac antibodies were found in one-third of DCM patients. Antibody status at diagnosis was associated with better exercise capacity; at 1-year follow-up two-thirds of antibody-positive patients became negative. These findings suggest that antibodies are early markers; their absence in the majority of patients at diagnosis may relate to long-standing pre-clinical DCM. Antibody screening was performed in asymptomatic DCM relatives, 177 from 33 families with > 1 affected individual (familial DCM) and 165 from 31 pedigrees with non-familial DCM. Antibodies were detected in 37 (58%) pedigrees and were more common among relatives than in normals (20% vs 3.5%, P = 0.0001). Antibody-positive relatives were younger, had larger left ventricular end-systolic dimension and reduced % fractional shortening compared to antibody-negative relatives. These findings provide evidence for autoimmunity in a subset (58%) including both familial and non-familial DCM; cardiac-specific antibodies may identify relatives at risk of developing DCM. PMID- 8682108 TI - An ultrastructural study on experimental autoimmune myocarditis with special reference to effector cells. AB - The previously described animal model of autoimmune myocarditis induced by immunization of Lewis rats with cardiac myosin was investigated pathologically, ultrastructurally and immunohistologically. Cardiac dendritic cells and infiltrating macrophages were dominantly encamped at the front of the myocarditis. The macrophages accompanied by neutrophils infested cardiocytes, forming rosette figures as a sign of active cardiocytolysis. The dendritic cells reached into intact muscle at a short distance from the inflammation. T cells, the most important candidate for effector cells in this animal model, were generally found at a distance from active muscle necrosis. PMID- 8682107 TI - Cellular immune mechanisms in myosin-induced myocarditis. AB - Cardiac myosin-induced myocarditis proved to be a valuable virus-free murine model with which to investigate autoimmunological mechanisms in inflammatory heart disease. The disease was shown to be T cell-mediated. In this contribution the functional role of CD4 and CD8 molecules and the conditions that are required to make the cardiac tissue susceptible to an autoimmune attack are discussed. PMID- 8682109 TI - Molecular biological and quantitative abnormalities of ADP/ATP carrier protein in cardiomyopathic hamsters. AB - The adenine nucleotide translocator or ADP/ATP carrier protein (AAC) is an integral protein present in the inner mitochondrial membrane, which performs the exchange of cytoplasmic and intramitochondrial ADP and ATP. The myocardial AAC content was studied in J-2-N cardiomyopathic hamsters. The AAC content was found to be significantly decreased in J-2-N hamsters. For molecular biological analysis, hamster AAC (T1 isoenzyme) cDNA was cloned by the plaque hybridization method. This AAC cDNA hybridized specifically with AAC mRNA, so RNA dot-blot hybridization was performed. The highest AAC mRNA level was observed in control hamsters followed by J-2-N hamsters with mild myocardial damage, J-2-N hamsters with severe myocardial damage and Bio 14-6 cardiomyopathic hamsters. These results suggest that a decreased AAC content may contribute to the pathogenesis of cardiomyopathy and that a decrease of AAC mRNA levels may explain the abnormalities of AAC in J-2-N cardiomyopathic hamsters. PMID- 8682110 TI - Characterization of relevant membrane antigens by two-dimensional immunoblot and n-terminal sequence analysis in patients with myocarditis. AB - In myocarditis an antigen-specific immune response to cardiac epitopes has been demonstrated by several investigators. In 25 patients with histologically proven myocarditis, autoantibodies to cardiac tissue were observed in 65% by immunofluorescence assay. By immunoblot analysis 46% of sera reacted with cardiac tissue. These antibodies were preferentially directed against proteins with molecular weights of 43 and 67 kDa. Many of these antibodies have been demonstrated to be cytolytic to isolated cardiocytes in vitro. However, their corresponding antigens on heart muscle cells still remains unclear. To characterize the epitopes recognized by the autoantibodies, isoelectric focusing followed by SDS-PAGE was used to separate the complex mixture of proteins from human heart. Immunoblot analysis of antigens revealed proteins in the range of 30 67 kDa at isoelectric points of 6.5-8.5 to be of particular interest. Five of these proteins were identified by immunoblot analysis and two were identified by n-terminal sequence analysis (Edman Degradation) as creatine kinase and a sarcomeric isoenzyme. As creatine kinase is an intracellularly located enzyme, the pathogenetic role of the autoantibodies directed against it remains to be elucidated further. PMID- 8682111 TI - The beta 1-adrenoceptor as antigen: functional aspects. AB - The sera of patients with myocarditis and idiopathic dilated cardiomyopathy contain agonistic autoantibodies that bind to the beta 1-adrenoceptor. These antibodies recognize epitopes on either the first or second extracellular loop of this receptor and exert in cultured neonatal rat heart myocytes a positive chronotropic effect. This effect is eliminated by beta 1-adrenoceptor blockade as well as by peptides corresponding to the first or second extracellular loop of the human beta 1-adrenoceptor. The antibodies realize their effects mainly via the beta-adrenoceptor-adenylate cyclase-protein kinase A cascade. PMID- 8682112 TI - Anti-peptide antibodies against an autoimmune epitope on human muscarinic receptor mimic functional autoantibodies against the same epitope in patients with idiopathic dilated cardiomyopathy. AB - A synthetic peptide corresponding to the sequence 169-193 of the second extracellular loop of the human muscarinic receptor-2 was used to raise antibodies in rabbits. Affinity-purified antibodies were able to interfere with muscarinic receptor radioligand binding and to recognize the muscarinic receptor protein in rats. The antibodies could also exert the physiological effects of muscarinic agonist stimulation as demonstrated by decreases in isoproterenol stimulated cAMP accumulation in Guinea-pig ventricles, heart beating frequency in cultured meonatal cardiomyocytes, the maximal rate of rise of ventricular pressure and heart rate in rats in-vivo. These results demonstrate that the second extracellular loop of the muscarinic acetylcholine receptor-2 is an immunologically and functionally important domain and that rabbit antibodies have properties comparable to those found for autoantibodies against the same epitope in patients with idiopathic dilated cardiomyopathy. PMID- 8682113 TI - SR-Ca2+ ATPase as an autoimmunogen in experimental myocarditis. AB - The concept of autoimmunity in the pathogenesis of myocarditis or dilated cardiomyopathy is gaining impetus. Since systolic functional impairment and subsequent recovery are frequently observed in myocarditis, we reasoned that the development of autoimmunity to cardiac sarcoplasmic reticulum calcium ATPase (SR Ca2+ ATPase), which could interfere with intracellular calcium regulation and therefore affect myocardial contractility, should lead to immune-mediated myocarditis in experimental animals. Murine monoclonal antibody 4C11-20.21 (IgM class) generated against canine cardiac SR-Ca2+ ATPase inhibits the cardiac but not the skeletal ATPase activity. Immunization of CAF1/J mice with 4C11-20.21 affinity-column-purified cardiac SR-ATPase produced a time-dependent induction of myocardial injury consistent with the diagnosis of myocarditis. Furthermore, the antibody 4C11-20.21 alone can induce myo-necrosis in severe combined immunodeficiency (SCID) mice indicating a mechanism of cardiomyopathy independent of the cytotoxic T-cell mediated autoimmunopathy. Administration of 4C11-20.21 into immunocompetent CAF1/J mice resulted in minimal myocardial abnormality (40% with perivascular and/or interstitial mononuclear lymphoplasmacytoid aggregates, 10% with borderline myocarditis and 10% with lesions consistent with focal myocarditis). All control animals had normal hearts. Immunoperoxidase electron microscopic examination of the involved cardiac tissues showed antibody localization in the subsarcolemmal myotubular system and focal staining of the immediately adjacent sarcolemma in mice injected with 4C11-20.21 but not with 2C12.1B5. The time-dependent association between cardiac SR-Ca2+ ATPase administration and development of myocardial lesions, as well as potentiated induction of myonecrosis with anti-cardiac SR-Ca2+ ATPase antibody in SCID relative to immunocompetent mice, suggest a potential autoimmunopathogenic role of cardiac SR-Ca2+ ATPase in experimental myocarditis. PMID- 8682114 TI - Cytometric analysis of ventricular myocyte nuclei in idiopathic dilated cardiomyopathy: a tool for evaluation of disease progression? AB - The progression of idiopathic dilated cardiomyopathy (IDC) is governed by factors that remain obscure. The disease pathway toward cell degeneration or death results in irreversible myocyte change including nuclear cytometric alterations which may be evaluable and ultimately correlated with other measures of disease evolution. Using a novel image cytometry system, we analysed differences in ventricular myocyte nuclear morphology and DNA content and distribution in right and left ventricular free wall myocardium and in ventricular septal myocardium from 11 normal and 13 IDC human autopsy hearts. Nine morphological features of IDC myocyte nuclei differed significantly (P < 0.001) from normal. These were used to establish a classification matrix and cytometry-based assessment and allowed correct categorization of left and right ventricular and ventricular septal myocyte nuclei in concordance with their respective pathological diagnosis (i.e. normal or IDC) 71%, 81% and 77% of the time. Additionally, four photometric features were significantly different (P < 0.005) in IDC versus normal hearts, as were three discrete texture features (P < 0.001). Thus, the spectrum of myocyte nuclei seen in IDC have highly characteristic and measurable morphologic, photometric and texture features. Our findings indicate the potential value of cytometry in the classification of myocytes with regards to a disease continuum and suggest its applicability in both clinical and experimental studies. PMID- 8682115 TI - Calcium channel blockers or beta receptor antagonists for patients with ischaemic heart disease. What is the best choice? PMID- 8682117 TI - Comparison of exercise stress testing with simultaneous dobutamine stress echocardiography and technetium-99m isonitrile single-photon emission computerized tomography for diagnosis of coronary artery disease. AB - The object of our study was to compare the value of exercise stress testing with simultaneous dobutamine stress echocardiography and technetium-99m isonitrile single-photon emission computed tomography for the diagnosis of coronary artery disease. Sixty-nine patients with either suspected or proven coronary artery disease underwent simultaneous dobutamine technetium-99m isonitrile single-photon emission computed tomography and stress echocardiography, and treadmill exercise electrocardiography. Dobutamine echocardiography and technetium-99m isonitrile single-photon emission computed tomography revealed a higher overall sensitivity than exercise testing (94 vs 60%, P < 0.001), but dobutamine stress echocardiography showed a higher specificity than both technetium-99m isonitrile single-photon emission computed tomography and exercise testing (86 vs 64%, P < 0.05, for both tests). In addition, the diagnostic accuracy of dobutamine stress echocardiography and technetium-99m isonitrile single-photon emission computed tomography was higher than that of exercise testing (91 vs 61%, P < 0.001; 86 vs 61%, P < 0.001, respectively). Dobutamine stress echocardiography and technetium 99m isonitrile single-photon emission computed tomography are superior to exercise testing in the diagnosis of coronary artery disease, and dobutamine stress echocardiography can act as an alternative to technetium-99m isonitrile single-photon emission computed tomography. PMID- 8682116 TI - Total Ischaemic Burden European Trial (TIBET). Effects of ischaemia and treatment with atenolol, nifedipine SR and their combination on outcome in patients with chronic stable angina. The TIBET Study Group. AB - OBJECTIVE: To study the relationship between presence or absence of ischaemic events on Holter monitoring and occurrence of a hard or hard+soft endpoint. DESIGN: A randomized double-blind parallel group study of atenolol, nifedipine and their combination, with ambulatory monitoring off-treatment and after 6 weeks of randomized treatment and prospective follow-up of 2 years on average. SETTING: Europe. SUBJECTS: 682 men and women with a diagnosis of chronic stable angina and who were not being considered for surgery. MAIN OUTCOME: Hard endpoints were cardiac death, nonfatal myocardial infarction and unstable angina; soft endpoints were coronary artery bypass surgery, coronary angioplasty and treatment failure. RESULTS: The study showed no evidence of an association between the presence, frequency or total duration of ischaemic events on Holter monitoring, either on or off treatment, and the main outcome measures. There was a non-significant trend to a lower rate of hard endpoints in the group receiving combination therapy. Compliance, as measured by withdrawal from trial medication, was clearly poorest in the nifedipine group with similar withdrawal rates in the atenolol and combination therapy groups. CONCLUSION: The recording of ischaemic events in 48 h Holter monitoring failed to predict hard or hard+soft endpoints in patients with chronic stable angina. PMID- 8682118 TI - What is the ideal study design for evaluation of treatment for heart failure? Insights from trials assessing the effect of ACE inhibitors on exercise capacity. AB - There is a wealth of evidence that angiotensin converting enzyme (ACE) inhibitors improve symptoms, morbidity and mortality in patients with heart failure. In this context the use of ACE inhibitors could be considered a tool with which to assess the effect of trial design and methodology on the ability to detect improvement in symptoms and exercise performance. Thirty-five published, double-blind, randomized placebo-controlled trials, involving a total of 3411 patients, which compared the effect of ACE inhibitors and placebo on exercise capacity in patients with symptomatic chronic heart failure were identified. Studies were examined in relation to whether they used cross-over or parallel group study design, study size, use of treadmill vs bicycle exercise test, year of publication, patient entry criteria, duration of follow-up and the particular ACE inhibitor used. Exercise duration improved in 23 of the studies, while symptoms improved in 25 of the 33 studies which evaluated this. In the majority of the trials (27 of 33) there was concordance between the effect on symptoms and on exercise capacity. There were six trials which showed discrepant results. Study size, duration of follow-up and method of exercise testing used were found to be major factors affecting the outcome. Trials using treadmill exercise tests were more likely to be positive than those using bicycle ergometry. All nine trials with study size more than 50, follow-up of 3-6 months and using treadmill exercise tests showed improved exercise capacity as well as symptoms. These findings may be useful in designing future trials for evaluating treatment for heart failure. PMID- 8682119 TI - Clinical value of echocardiographic tissue characterization in the diagnosis of myocarditis. AB - Inflammatory changes in the myocardium have been visually observed as alterations on echocardiograms. The goal of this study was to determine how these myocardial changes affect the texture of echocardiographic images, and how these could be described through quantitative texture analysis. The results of 142 endomyocardial biopsies were compared with those of texture analysis in echocardiograms of 106 patients suspected of having myocarditis. There were 52 cases of biopsy-proven acute myocarditis, 12 of persistent myocarditis, nine of healed myocarditis without fibrosis, 17 of healed myocarditis with fibrosis, and 35 cases of cardiomyopathy. Eight myocardial biopsies exhibited no pathological changes and nine patients had other cardiac problems. The echocardiograms of a control group of 24 healthy subjects were also evaluated by texture analysis. Three texture parameters were able to differentiate between normal and abnormal myocardium. The mean grey value, i.e. average brightness, was appreciably higher in cases of myocarditis than in control subjects, whereas one co-occurrence and one run length feature had markedly decreased. We conclude that myocarditis and fibrosis induce changes in echocardiographic image texture, i.e. increases in brightness, heterogeneity, and contrast. Performing digital image texture analysis of echocardiograms makes it possible to distinguish between myocarditis and normal myocardium. PMID- 8682120 TI - Prevalence of left ventricular hypertrophy in a hypertensive population. AB - AIMS: This investigation was set up to study the prevalence of left ventricular hypertrophy in a hypertensive population with reference to a normotensive control group. From the general population 3498 men and women aged 35, 45, 55 and 65 years old were invited to a health examination. Participants with blood pressure above 160 mmHg systolic or 95 mmHg diastolic or those taking antihypertensive medication or having done so during the previous 6 months were asked to undergo an echocardiographic examination. Normotensive controls were randomly selected from the same population. Of 552 participants in the final study population, 194 were normotensive controls and 358 were in the hypertensive group. Echocardiographic measurements were made according to the Penn conventions and indexed for body surface. Cut-off values for left ventricular hypertrophy were 134 g.m-2 for males and 102 g.m-2 for women. RESULTS: Overall, the prevalence of left ventricular hypertrophy was 14%/20% (men/women) in normotensives and 25%/26% in hypertensives (P < 0.01). After subdivision by age and sex, there was a significant difference in the prevalence of left ventricular hypertrophy between normotensives and hypertensives only in the 65-year-old group (P < 0.02 for males and P < 0.05 for females). CONCLUSIONS: The association between blood pressure and left ventricular hypertrophy in the general population is weak. Left ventricular hypertrophy is only significantly more frequent among hypertensives as compared to normotensives in older people. PMID- 8682121 TI - Resolution of rate-related left bundle branch block after nitrate therapy. PMID- 8682122 TI - How does a continuous coronary perfusion catheter work in coronary artery dissection? Assessment by intravascular ultrasound. PMID- 8682123 TI - An unusual case of restrictive cardiomyopathy in a patient with reactive arthritis caused by Staphylococcus epidermidis. PMID- 8682124 TI - Paradoxical acute brain thromboembolism during prostacyclin (PGI2) acute challenge for primary pulmonary hypertension. PMID- 8682125 TI - Prostacyclin in primary pulmonary hypertension. PMID- 8682127 TI - Selecting the most appropriate reperfusion therapy for acute myocardial infarction. How useful are guidelines? PMID- 8682126 TI - The impact of myocardial blood flow quantitation with PET on the understanding of cardiac diseases. PMID- 8682128 TI - The international rank order of clinical cardiology. AB - A cardiological ranking list was prepared based on papers published in 1981-1992. The nations studied comprised the G-7 countries, Belgium, Denmark, Finland, the Netherlands, Norway, Sweden and Switzerland. The number of citations received by these publications was checked. In general the output and citation frequency in the last decade increased, although often temporarily. These data were also related to population size and expenditure on research and development. They show that the United States leads research in clinical cardiology. In most G-7 nations, however, the quality and quantity of cardiological publications lag behind those of the smaller West-European countries. This may be partly due to differences in funding and/or publication in a language other than English. PMID- 8682129 TI - Using exercise endpoints in heart failure trials: design considerations. PMID- 8682130 TI - Acute myocardial infarction: pre-hospital and in-hospital management. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. PMID- 8682131 TI - Echocardiographic tissue diagnosis. PMID- 8682132 TI - Estimated gain in life expectancy. A simple tool to select optimal reperfusion treatment in individual patients with evolving myocardial infarction. AB - Currently several modes of reperfusion therapy for acute myocardial infarction are available. Streptokinase, accelerated alteplase and direct angioplasty are the most frequently used. These options are increasingly effective, but are also increasingly complex and costly. Since, unfortunately, physicians are often restricted by budget limitations, choices must be made in clinical practice to provide optimal therapy to individual patients. In order to guide such decision making, we developed a model to predict the expected benefit of therapy in terms of gain in life expectancy. Patients' life expectancy will decrease after infarction. Part of this loss can be prevented by early reperfusion therapy. The clinical benefit of therapy ranges from negligible gain in patients with small infarcts treated relatively late to an expected gain of more than 2 years in patients with extensive infarction treated within 3 h of onset of symptoms. The expected benefits are presented in a set of tables and depend on age, previous infarction, estimated infarct size, treatment delay and intracranial bleeding risk. With the help of these table, resources will be allocated in such a manner that patients who will benefit the most will receive the most effective therapy. Patients with similar expected treatment benefit will be offered the same mode of therapy. Future life years were discounted at 5% per year. The arbitrary thresholds currently applied for decision making at the Thoraxcenter are: no reperfusion therapy when the estimated gain in discounted life expectancy was < 1 month, streptokinase for 1-4 months and accelerated alteplase for a gain > or = 5 months. Direct angioplasty is recommended in patients with an estimated gain > or = 12 months, and in patients with an increased risk of intracranial bleeding. In this way, approximately 80% of our patients will be treated with thrombolytics (40% streptokinase and 40% accelerated alteplase), while in 10% direct angioplasty will be initiated. Patients with small infarcts presenting late will not receive reperfusion therapy. These threshold values have been chosen arbitrarily, and different thresholds may be selected in other centres. However, the developed model would guarantee that treatment decisions are made in a consistent manner, to provide optimal therapy for patients with evolving myocardial infarction, in spite of limited resources. PMID- 8682133 TI - Left ventricular hypertrophy and hypertension. PMID- 8682134 TI - Effects of metoprolol vs verapamil in patients with stable angina pectoris. The Angina Prognosis Study in Stockholm (APSIS) AB - OBJECTIVE: To study long-term treatment effects of metoprolol or verapamil on combined cardiovascular end points and psychological variables in patients with stable angina pectoris. DESIGN: Randomized, double-blind, double-dummy trial. PATIENTS: The study included 809 patients under 70 years of age with stable angina pectoris. The mean age of the patients was 59 +/- 7 years and 31% were women. Exclusion criteria were myocardial infarction within the previous 3 years and contraindications to beta-blockers and calcium antagonists. The patients were followed between 6 and 75 months (median 3.4 years and a total of 2887 patient years). INTERVENTION: The patients were treated with either metoprolol (Seloken ZOC 200 mg o.d.) or verapamil (Isoptin Retard 240 b.i.d.). Acetylsalicylic acid, ACE inhibitors, lipid lowering drugs and long acting nitrates were allowed in the study. END POINTS: Death, non-fatal cardiovascular events including acute myocardial infarction, incapacitating or unstable angina, cerebrovascular or peripheral vascular events. Psychological variables reflecting quality of life i.e. psychosomatic symptoms, sleep disturbances and an evaluation of overall life satisfaction. RESULTS: Combined cardiovascular events did not differ and occurred in 30.8% and 29.3% of metoprolol and verapamil treated patients respectively. Total mortality in metoprolol and verapamil treated patients was 5.4 and 6.2%, respectively. Cardiovascular mortality was 4.7% in both groups. Non-fatal cardiovascular events occurred in 26.1 and 24.3% of metoprolol and verapamil treated patients, respectively. Psychosomatic symptoms and sleep disturbances were significantly improved in both treatment groups. The magnitudes of change were small and did not differ between treatments. Life satisfaction did not change on either drug. Withdrawals due to side effects occurred in 11.1 and 14.6% respectively. CONCLUSION: This long term study indicates that both drugs are well tolerated and that no difference was shown on the effect on mortality, cardiovascular end points and measures of quality of life. PMID- 8682135 TI - Incidence of complete atrioventricular block following attempted radiofrequency catheter modification of the atrioventricular node in 880 patients. Results of the Multicenter European Radiofrequency Survey (MERFS) The Working Group on Arrhythmias of the European Society of Cardiology. AB - The Multicenter European Radiofrequency Survey (MERFS) retrospectively analysed the incidence of procedure-related complications in 4463 patients who had undergone radiofrequency catheter ablation in 69 European institutions between 1987 and 1992. Of these 4463 patients, 880 underwent modification of the atrioventricular node to cure atrioventricular nodal reentrant tachycardia. This report presents a detailed analysis of the incidence of complete atrioventricular block with respect to the target site and the number of patients reported per institution. The most common complication of modification of the atrioventricular node was the unintended induction of complete atrioventricular block (41 of 880 patients, 4.7%). In 684 of 880 patients (78%), detailed information about the approached target site for modification of the atrioventricular node was available. Complete atrioventricular block occurred significantly more often in patients who underwent ablation of the fast pathway (19/361, 5.3%) or in whom ablation of the slow and fast pathway was attempted after failure at the initial site (4/25, 16%) than in patients who underwent slow pathway ablation (6/298, 2.0%, P < 0.05). The overall incidence of complete atrioventricular block was significantly higher (6.3%) in centres with limited experience in radiofrequency modification of the atrioventricular node ( < or = 30 patients treated; group I: n = 526) compared to centres that had treated > 30 patients (group II: n = 354; 2.3%; P < 0.05). In addition, in those patients in whom the target site was available, the incidence of complete atrioventricular block after fast pathway ablation was significantly higher in group I (n = 168 patients) when compared to group II (n = 193 patients) (7.7% vs 3.1%, P < 0.05) and also tended to be higher after slow pathway ablation in group I (2.4% in group I vs 1.5% in group II; P = ns). CONCLUSIONS: In this analysis of collaborative data, radiofrequency catheter modification of the atrioventricular node carried a risk of approximately 5% of complete atrioventricular block. The incidence of complete atrioventricular block was significantly higher in patients who underwent fast pathway ablation or fast and slow pathway ablation after failure at the initial site compared with slow pathway ablation. In addition, the results indicate that there is a learning curve, regarding the incidence of complete atrioventricular block, which is a significant complication of the procedure, when modifying the atrioventricular node. Thus, caution is recommended when performing radiofrequency modification of the atrioventricular node using the so-called anterior approach to abolish fast pathway conduction, especially when the experience of the institution or investigator/s is limited. PMID- 8682136 TI - Implementation of a pre-hospital decision rule in general practice. Triage of patients with suspected myocardial infarction. AB - OBJECTIVE: To improve pre-hospital triage of patients with suspected acute cardiac disease. DESIGN: Prospective study. SUBJECTS. Patients with symptoms suggestive of acute cardiac pathology, who were seen by a general practitioner, for whom acute admission into hospital was requested, and in whom a pre-hospital electrocardiogram was recorded by the ambulance service. METHODS: The study consisted of two phases. In the first phase, a decision rule was developed based on clinical characteristics and electrocardiographic findings in 1005 patients with suspected acute cardiac pathology. In the second phase, the decision rule was prospectively validated. Symptoms were recorded by a standardized questionnaire by the general practitioner and a computerized electrocardiogram was made by the ambulance nurses at the patient's home. Three electrocardiographic outcomes were available: 'normal electrocardiogram', 'possible myocardial infarction' or 'extensive myocardial infarction'. By use of the predictive model, the general practitioner could decide if hospitalization was necessary or not. MAIN OUTCOME MEASUREMENTS: Identification of patients at low (stable angina, atypical chest pain, other pathology) and high (myocardial infarction, unstable angina) probability of acute cardiac pathology. RESULTS: Among 977 patients with a complete pre-hospital evaluation in the validation phase of the study, the decision rule recommended 'no hospitalization' in 227 patients (23%). The general practitioner followed this advice in 44% of these patients. Although seven of them developed a non-Q wave myocardial infarction, no complications occurred in patients not admitted. In addition, the general practitioner did not hospitalize 19 (2%) of 750 patients for whom the decision rule recommended admission. Pre-hospital triage by the general practitioner resulted in a 12% (118 of 977 patients) reduction of the number of patients admitted to the Coronary Care Units. CONCLUSIONS: Pre-hospital triage by the general practitioner was facilitated using a standardized questionnaire and pre hospital electrocardiography, and resulted in a reduction in the number of patients admitted to the Coronary Care Unit, and proved to be safe. PMID- 8682137 TI - Platelet glycoprotein IIb/IIIa receptor antagonists in coronary artery disease. PMID- 8682139 TI - Differences in gallbladder bile lithogenicity in patients after gastrectomy and colectomy. AB - The differences in lithogenicity of gallbladder bile, biliary lipid composition, cholesterol saturation index (CSI), cholesterol nucleation time (NT), bilirubin, and ionized calcium were compared in patients who had previously undergone gastrectomy or colectomy. The increased CSI and the rapid NT were absent in gastrectomized patients, while colectomy significantly increased the CSI and accelerated the NT. The levels of ionized calcium and unconjugated bilirubin, possibly responsible for pigment stone formation, were significantly higher in patients after gastrectomy, but were nearly absent in patients after colectomy. The results suggest that after gastrectomy the gallbladder bile indicates a trend towards pigment stone formation, whereas there is a trend towards cholesterol gallstones after colectomy. The different alterations of the gallbladder bile lithogenicity are clinically important. PMID- 8682138 TI - The Total Ischaemic Burden European Trial (TIBET). Effects of atenolol, nifedipine SR and their combination on the exercise test and the total ischaemic burden in 608 patients with stable angina. The TIBET Study Group. AB - OBJECTIVES: To determine the effects of atenolol, nifedipine and their combination on exercise parameters and ambulatory ischaemic activity in patients with mild chronic stable angina. SETTING: Multicentre, multinational study involving 608 patients from 69 centres in nine countries. DESIGN: Placebo washout followed by double-blind parallel-group study comparing atenolol 50 mg bd, nifedipine SR 20 mg bd, and their combination. Patients underwent maximal exercise testing using either a bicycle (n = 289) or treadmill (n = 319) and 48 h of ambulatory ST segment monitoring outside the hospital environment at the end of the placebo washout period and after 6 weeks of active therapy. RESULTS: Both medications alone and in combination caused significant improvements in exercise parameters and significant reductions in ischaemic activity during daily activities, when compared with placebo. There were, however, no significant differences between groups, for any of the measured ischaemic parameters although combination therapy resulted in a greater fall in resting systolic and diastolic blood pressure than either treatment alone. CONCLUSIONS: In the management of mild chronic stable angina there appears to be little advantage gained from using combination therapy for ischaemia reduction. PMID- 8682140 TI - Evaluation of the protective effect of a novel prostacyclin analog on mesenteric circulation following warm ischemia. AB - The protective effect of a novel prostacyclin (PGI2) analog, OP-2507, on mesenteric circulation was investigated in a canine warm ischemia model. In 20 mongrel dogs, the entire portion of the intestine supplied by the superior mesenteric artery (SMA) and drained by the superior mesenteric vein (SMV) was completely isolated, maintaining the blood and lymph vessels intact. Sixty or 120 min of complete warm ischemia (WI) of the intestine was induced by clamping SMA and SMV, followed by reperfusion for 120 min. Animals were divided into five groups (each n = 4): group 1, sham operation; group 2, 60 min WI; group 3, 120 min WI; group 4, 60 min WI with PGI2 analog administration; group 5, 120 min WI with PGI2 analog administration. The analog was administered at a rate of 6 micrograms.kg-1.h-1 immediately after laparotomy until the end of the observation period. Mean arterial pressure, SMA blood flow (SMABF), SMV pressure were monitored and total mesenteric vascular resistance (TMVR) was calculated. To evaluate the endothelial activation, endothelin, which is secreted from the endothelium under hypoxic stress, was assayed from blood samples of SMV. None of the animals showed significant changes in mean arterial pressure. In groups 2 and 3, SMABF decreased significantly to less than 60% of preoperative value (15 ml.kg 1.min-1) and TMVR significantly increased from 8.1 and 7.3 mm Hg.ml-1.kg.min before WI to 14.0 and 16.4 mm Hg.ml-1.kg.min after 120 min reperfusion, respectively, resulting in delayed hypoperfusion. In contrast, in groups 4 and 5, SMABF increased to over 100% of preoperative level, while TMVR declined from 7.8 and 8.4 mm Hg.ml-1.kg.min before WI to 6.2 and 6.3 mm Hg.ml-1.kg.min after 120 min reperfusion. After 60 min reperfusion, SMABF and TMVR showed a significant difference between the treated and nontreated groups. Only in group 3, high endothelin concentrations (over 20 pg/ml) were observed even after 120 min reperfusion. It was concluded that the PGI2 analog was able to suppress the endothelial activation and the disturbance of mesenteric circulation caused by WI and reperfusion. PMID- 8682141 TI - Anastomotic tissue oxygen tension during esophagectomy in patients with esophageal carcinoma. AB - Submucosal tissue oxygen tension (PtO2) was measured in 20 patients with cervical esophagogastrostomy after resection of esophageal carcinoma, using a Clark-type oxygen electrode. The mean gastric baseline PtO2 was 54.6 +/- 10.7 mm Hg. Following ligature of the vasa brevia and the left gastroepiploic artery PtO2 decreased to 45.8 +/- 9.9 mm Hg, ligature of the left gastric artery caused a decrease to 34.2 +/- 9.7 mm Hg and resection of the lesser curvature and pulling up of gastric tube led to 25.5 +/- 9.0 mm Hg. Clinical value and practicability of intraoperative PtO2 measurements could be proven. PMID- 8682142 TI - Biomaterials for primary closure of a choledochotomy in dogs. AB - Since primary closure of the common bile duct is often not undertaken because of the risks of biliary leakage and peritonitis, we have evaluated feasibility and reliability of closure using biomaterials. In three groups of dogs, an unsutured choledochotomy was closed with circular glued patches: a scleroprotein patch in 4 dogs and an oxidized, compressed human collagen patch reinforced (n = 6) or not (n = 6) with three stitches. The scleroprotein patch (n = 4) was resorbed too soon, and in 2 dogs the unstitched collagen patches became unglued; biliary leakage was the result in both instances. The bile duct healed successfully within 1 month in the other 10 animals fitted with collagen patches, despite one common bile duct stricture. Safe primary closure of a choledochotomy may be envisioned in humans if the duct suture is protected by this new collagen biomaterial. PMID- 8682143 TI - Cyclosporin A delays the presentation of intimal hyperplasia in an experimental model of arterial autograft. AB - A study was made of the effect of cyclosporin A on intimal hyperplasia in an experimental model of arterial autograft. Fifty female Sprague-Dawley rats weighing 250-300 g were employed. Using a microsurgical technique, an arterial autograft measuring approximately 5 mm in length was implanted in right common iliac artery. Two groups were established: group I (control), consisting of 25 animals subjected only to arterial autograft, and group II (preoperative cyclosporin A), also consisting of 25 animals, which received a daily subcutaneous dose of 5 mg/kg cyclosporin A (Sandimmun, Sandoz) for 4 days before the surgical procedure. The animals were sacrificed on postoperative days 7, 14, 21, 30 or 50. Specimens were studied by optical microscopy, transmission and scanning electron microscopy, autoradiography, and morphometry. Endothelialization of the graft zone was slow in the cyclosporin-treated group. Hyperplasia was delayed notably, but at 30 days the hyperplastic process had improved and at 50 days it was similar to that of the control group. In the cyclosporin-treated group, thymidine was not taken up by the medial layer; the absence of medial thymidine uptake correlated with ultrastructural evidence of medial degeneration with lipid vacuolization of the smooth muscle cells and the presence of macrophages. These results suggest that cyclosporin A does not inhibit intimal hyperplasia but instead delays its occurrence, probably because of the drug's toxicity for smooth muscle cells. PMID- 8682144 TI - In vitro attachment of endothelial cells to different graft materials. AB - The purpose of this study was to compare the degree of endothelial cell attachment to different synthetic vascular graft materials. Human microvessel endothelial cells were labelled with indium-111-oxine, injected into 9 different vascular grafts and left to adhere for 40 min. Unattached cells were removed and radioactivity of the grafts measured. Grafts were flushed with 20 ml phosphate buffered saline during 5 s to remove cells with poor attachment and radioactivity was measured again. Attachment differed between the grafts. In order of decreasing attachment the grafts were albumin-coated Dacron (47%), preclotted Dacron (35-44%), gelatin-coated Dacron (20%), gelatin-coated polyurethane (17%), collagen-coated Dacron (12%), preclotted expanded polytetrafluoroethylene (ePTFE; 3%). Albumin-coated Dacron showed the highest degree of cell attachment of ePTFE the lowest. Statistically significant differences exist between ePTFE and all other grafts and between albumin-coated and collagen-coated Dacron, gelatin coated polyurethane and gelatin-coated Dacron. PMID- 8682145 TI - Endotoxin-induced release of interleukin 6 and interleukin 1 beta in human blood is independent of tumor necrosis factor alpha. AB - It has been suggested that tumor necrosis factor alpha (TNF alpha) acts not only by direct toxicity, but also as a proximal mediator which is able to induce the production of other cytokines, especially interleukin 6 (IL-6) and interleukin 1 beta (IL-1 beta). In order to test the dependence of the release of these two cytokines from leukocytes upon induction by TNF alpha, we stimulated whole blood in vitro with TNF alpha and compared the cytokine levels with those induced by endotoxin. The cytokine release was also determined after stimulation by endotoxin with added TNF alpha and by endotoxin with monoclonal antibodies against TNF alpha (anti-TNF alpha) added in order to reduce TNF alpha. Unstimulated blood samples were used as controls. The plasma levels of both IL-6 and IL-1 beta were significantly higher after stimulation with endotoxin than after stimulation with TNF alpha. TNF alpha did not induce cytokine levels significantly higher than controls. The cytokine levels were the same whether or not anti-TNF alpha was included together with the endotoxin. Plasma from samples with added anti-TNF alpha had no detectable TNF alpha. Our results indicate that the leukocyte-derived production of IL-6 and IL-1 beta in whole blood is stimulated directly by endotoxin and is not mediated by TNF alpha. PMID- 8682146 TI - Changes of bile duct mucosa after choledochoduodenostomy in rats. AB - This study investigated the changes of bile duct mucosa in rats after choledochoduodenostomy. Wistar rats were divided into three groups: group I (n = 6) was treated with sham operation as control; group II (n = 10) was treated with common bile duct ligation without choledochoduodenostomy, and group III (n = 12) had both common bile duct ligation and choledochoduodenostomy creation 4 days after common bile duct ligation. From our observations, retrograde induced cholangitis due to enteric reflux into the common bile duct is the possible cause of chronic inflammation after choledochuduodenostomy. At the end of the study, Choledocholithiasis developed in 5 of 12 rats. Severe dysplasia was present in the bile duct mucosa in 6 of 12 rats in group III, but not in group I or II. A technique for silver staining of nucleolar organizing regions (AgNOR) was applied. This technique demonstrated differences in AgNOR counts between normal mucosa and dysplasia. Under AgNOR stain, the number of AgNOR was significantly greater than in the normal or benign counterparts and gradually increased from the normal bile duct mucosa group to the severe dysplasia group (group I 2.1 +/- 0.8, group II 3.2 +/- 1.0, group III 5.3 +/- 1.1). All of these observations suggest that 'sump syndrome' and bile stasis could occur after choledochoduodenostomy in rats and can result in chronic inflammation of the bile duct. It has been well established that calcium bilirubinate is the major type of choledocholithiasis in Orientals. beta-Glucuronidase from bacteria, such as Escherichia coli present in the biliary tree, hydrolyzes bilirubin diglucuronide to bilirubin. Bilirubin combines with calcium in the bile flow to form calcium bilirubinate. Bacterial infection plays a key role in calcium bilirubinate stone formation. Since choledochoduodenostomy did increase reflux cholangitis, and bacterial infection would increase mucin overproduction, bile deconjugation and eventually new calcium bilirubinate stones would be formed. The dysplastic changes in the bile duct mucosa could possibly be related to the prolonged exposure to the biochemically altered infected bile. Thus choledochoduodenostomy might not be the perfect choice in treating calcium bilirubinate choledocholithiasis in Orientals. PMID- 8682147 TI - Origin of intravascular fluid recruited by vasodilatation during epidural anaesthesia. AB - Arterial hypotension during induction of epidural anaesthesia is caused by peripheral vasodilatation and promotes intravascular fluid distribution. The excess fluid in the blood may result from either diffusion across the capillaries or enrichment of the fluid that is routinely infused intravenously to prevent severe hypotension. These alternatives were assessed in 40 urology patients who received 10 ml kg-1 of Ringer acetate solution without or with 0.5% glucose during onset of epidural anaesthesia. The result shows that arterial hypotension (systolic pressure down by > 25%) promoted mild dilutional hypoglycaemia when the infusion was glucose-free (-6% in hypotensive vs. +2% in normotensive) and hyperglycaemia when glucose was given (+15% in hypotensive vs. +7% in normotensive). The consistent deviation of the blood glucose level towards the concentration of the infused fluid suggests that the excess intravascular fluid associated with epidural-induced hypotension is derived directly from the ongoing infusion rather than by transcapillary transport. PMID- 8682148 TI - Effects of the Pringle maneuver on hemodynamics during laparoscopic liver resection in the pig. AB - The Pringle maneuver (PM) is recognized in conventional liver surgery as a method of controlling bleeding. To determine the hemodynamic effects of the PM during pneumoperitoneum (PP) for laparoscopic liver resection, we measure hemodynamic and blood gas changes in 7 healthy pigs. All variables were recorded 5 min before and 10 and 30 min after employing PP or PM and 10 min after discontinuation of PM. After the induction of PP, cardiac index and arterial carbon dioxide tension significantly increased, accompanied by a significant decrease in pH. After the beginning of PM, cardiac index and mean arterial and central venous pressures decreased significantly, whereas the heart rate rose markedly. After discontinuation of the PM, the systemic vascular resistance index decreased, and the heart rate remained elevated. These results demonstrate severe hemodynamic deterioration with PP and a subsequent PM. The latter should, therefore, be considered only as a last resort for the control of bleeding during laparoscopic liver surgery. PMID- 8682149 TI - The Jak-STAT pathway: specific signal transduction from the cell membrane to the nucleus. AB - The Jak-STAT pathway is a newly discovered intracellular signal transduction pathway that is used by a growing number of extracellular signalling proteins (ESPs) for transcriptional activation of target genes. Binding of ligands to their transmembrane receptors leads to activation of members of the Jak tyrosine kinase family. The activated receptor-kinase complexes recruit members of the STAT family and activate them by phosphorylation. As a consequence, the phosphorylated STAT proteins dimerize, translocate into the nucleus, bind response elements in the promoter of target genes and stimulate the transcription of these genes. Their dual role as signalling molecules and transcription factors is reflected in the name: STAT stands for Signal Transducers and Activators of Transcription. Different ligands specifically activate different members of the Jak and STAT families. Signal transduction through the Jak-STAT pathway contributes to the specificity and diversity of cellular responses to peptide hormones, growth factors, cytokines and interleukins. PMID- 8682150 TI - Apolipoprotein E2 (Arg-136-->Cys), a variant of apolipoprotein E associated with late-onset dominance of type III hyperlipoproteinaemia. AB - Type III hyperlipoproteinaemia (HLP) is usually associated with homozygosity for apolipoprotein (apo) E2 (arg-158-->Cys). We identified a 46-year-old white female with severe hyperlipidaemia and the heterozygous apo E3/2* phenotype. Typical clinical characteristics of type III HLP, i.e. palmar xanthomas (orange-yellowish discolorations of the palmar creases) and tuberoeruptive xanthomas, were present in the patient. Without therapy the patient's serum triglycerides (1.098 mg dL( 1)), cholesterol (546 mg dL(-1)), very low-density lipoprotein (VLDL) cholesterol (372 mg dL(-1)) and the apo E concentration (25.0 mg dL(-1)) were distinctly elevated as well as her VLDL cholesterol to serum triglyceride (TG) ratio at 0.34 (normal ratio about 0.2). Direct sequencing of polymerase chain reaction (PCR) amplified segments of the apo epsilon gene identified a thymine for cytosine (C- >T) exchange in the first base of codon 136 that is predictive for a Cys (TGC) for Arg (CGC) substitution in the encoded amino acid sequence. Two children, an 18-year-old female with the heterozygous apo E4/2* phenotype, a 25-year-old female with the heterozygous apo E3/2* phenotype and the 73-year-old father of the proband with the heterozygous apo E3/2* phenotype are also carriers of the rare mutant. The father has severe atherosclerosis and lipid values compatible with the diagnosis of type III HLP. The affected children have hyper/dyslipidaemia but as yet no clinical expression of the disease. We propose that in the analysed family this rare apo E2 (Arg-136-->Cys) variant is associated with late-onset dominance of type III HLP. PMID- 8682151 TI - Serial changes in serum vitamin K1, triglyceride, cholesterol, osteocalcin and 25 hydroxyvitamin D3 in patients after hip replacement for fractured neck of femur or osteoarthritis. AB - Serum vitamin K1 concentrations were measured at presentation (just before surgery) and then at weekly intervals for 3 weeks in two groups of elderly patients requiring either hemiarthroplasty for fractured neck of femur (FON, n = 13) or total hip replacement for osteoarthritis of the hip (OA, n = 16). In comparison with healthy elderly volunteers (n = 25), serum vitamin K1 concentrations were significantly lower in both groups at presentation, and fell significantly within 24 h after surgery to concentrations approaching non detectable, subsequently returning to pre-operative values within 3 weeks. Serum vitamin K1 tended to be lower in the fracture group both before and after operation, although calculation of a vitamin K1-triglyceride ratio reduced the apparent difference as triglyceride concentrations were lower in the fracture group. Osteocalcin concentrations were similar and fell significantly after operation in both groups, returning to pre-operative levels within 7 days. No differences in the two forms of osteocalcin (carboxylated and undercarboxylated) were observed either before or after operation in either group. 25-Hydroxyvitamin D3 concentrations were not significantly different between the two groups at any time. Vitamin K1 status may be lower than desirable in certain groups of the elderly population, and supplementation should be considered as prophylactic therapy. PMID- 8682152 TI - Altered release of endothelin-1,2 and thromboxane B2 from trophoblastic cells in pre-eclampsia. AB - The aim of the study was to investigate whether pre-eclampsia is associated with an altered release of vasoactive substances from trophoblastic cells in vitro. Trophoblastic cells from 15 uncomplicated control pregnancies and 18 pre eclamptic pregnancies at preterm (weeks 31-36; n = 12) and term (weeks 37-40; n = 21) were cultured for 5 days. The concentrations of angiotensin II (AII), endothelin-1,2 (ET-1,2), thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (6 keto-PGF1 alpha) and leukotriene B4 (LTB4) were measured daily in culture media for 5 days by radioimmunoassay. In pre-eclampsia, concentrations of ET-1,2 were decreased (P < 0.01) at both preterm and term, TXB2 concentrations were increased (P < 0.05) only at preterm and the TXB2-6-keto-PGF1 alpha ratio was increased at both preterm and term (P < 0.01) as compared with the controls. Concentrations of AII, 6-keto-PGF1 alpha and LTB4 were similar to the controls. The data suggest that pre-eclampsia is associated with a decreased release of ET-1 and an increased release of TXB2 from trophoblastic cells in vitro. PMID- 8682153 TI - Decreased release of glutathione into the systemic circulation of patients with HIV infection. AB - Low glutathione (GSH) in patients with HIV infection could contribute to their immune deficiency since GSH plays an important role in the function of lymphocytes and sulphydryls decrease the expression of HIV in vitro. In order to gain more insight into the mechanisms responsible for the deranged sulphydryl homeostasis in HIV infection, the release of GSH into the circulation, an estimate of the systemic production of GSH, was determined using a pharmacokinetic approach. The basal plasma concentrations of free GSH (3.3 +/- 1.3 vs. 5.3 +/- 1.9 mumol L(-1)) and cysteine (7.7 +/- 2.6 vs. 13.4 +/- 4.9 mumol L(-1)) were significantly lower in eight HIV-infected patients than in eight controls. Upon infusion of GSH at a constant rate of 1 mumol min-1 kg-1, GSH in plasma reached a new plateau. The increment in plasma GSH was significantly larger in the HIV-infected patients than in the controls. The input of GSH into the circulation (12.9 +/- 5.7 vs. 30.1 +/- 11.7 mumol min-1; P < 0.01) and the clearance of GSH (25 +/- 7 vs. 35 +/- 7 mL min-1 kg-1) were significantly lower in patients with HIV-infection. During infusion of GSH the concentration of cysteine in peripheral blood mononuclear cells of the HIV-infected patients increased significantly. Nevertheless, intracellular GSH did not increase. Thus, the consumption of GSH is not increased in HIV infection. Rather, the present data suggest that GSH in patients with HIV infection is low because of a decreased systemic synthesis of GSH. PMID- 8682154 TI - Immunosuppressive effects of endotoxins and bile acids in vivo in the rat. AB - Cell-mediated immunity is impaired during cholestasis. The aim of this study was to evaluate in vivo the effects on this immune defect of high serum levels of endotoxin and bile acids. Heterotopic cardiac allotransplantations were performed in the DA/Lewis rat combination. Cholestasis, induced by ligation/section of the common bile duct, was responsible for a significant delay in the rejection time (16 +/- 0.5 vs. 7.1 +/- 0.4 days in controls, P < 0.01). Elimination of Gram negative intestinal bacteria from cholestatic rats by a vancocin/colimycin/tobramycin (VCT) mixture induced a significant reduction in endotoxin levels and a reduction in rejection times (9.5 +/- 1.0 days, P < 0.01) that remained, however, significantly longer than those of controls (P < 0.05). Oral administration of chenodeoxycholic acid in non-cholestatic rats significantly enhanced the serum concentration of total bile acids (60.6 +/- 15.3 mumol L(-1) vs. 17.4 +/- 1.9 mol L(-1) in controls, P < 0.01) and postponed allograft rejection (10.7 +/- 0.6 days, P < 0.01 vs. controls). These data suggest that increased endotoxin level and serum bile acid concentration may play a role in the immunosuppressive effect of cholestasis. PMID- 8682155 TI - Smoking further increases platelet activity in patients with mild hypertension. AB - In this study the authors examine whether smoking further heightens platelet activity and reduces fibrinolysis above that already present in mild hypertension. Ten smokers and 11 non-smokers, all with mild hypertension (defined as a diastolic pressure between 90 and 110 mm Hg) were compared for their platelet activity in vitro and in vivo and for their fibrinolytic activity. Successive measurements were made with the patients lying at rest after they had assumed the erect posture for 10 min and at the end of a 5-min moderately strenuous exercise test. The threshold for platelet aggregation by ADP in vitro was significantly lower in samples taken from the smokers at rest (1.4 +/- 0.9 mumol L(-1)) than in the non-smokers (3.5 +/- 2.5 mumol L(-1)), and the difference persisted both in the upright posture and after exercise. The level of platelet release of beta-thromboglobulin was, likewise, higher in the smokers in the upright posture. Neither standing up nor physical exercise had any significant influence on either of these two indices of platelet activity. The euglobulin clot lysis time was slightly longer in the smokers than in the non smokers in all three experimental situations, but the differences were not significant. Inhibitor of tissue plasminogen activator was not materially different in the two groups (Table 2). The results indicate that smoking adds a further element of heightened platelet activity to that inherently present in hypertension. PMID- 8682156 TI - Regulation of platelet-activating factor production in gastric epithelial cells. AB - The authors have previously reported that platelet-activating factor (PAF), a phospholipid mediator with potent proinflammatory activities, is produced in the gastric mucosa and stimulates gastric acid secretion in humans and animals. In the present study they used the human gastric tumour cells HGT1 (clone 6) to examine whether PAF production is regulated by neuromediators. PAF was extracted by ethanol and assayed by the washed platelet aggregation test. HGT1 cells produced PAF spontaneously (110 +/- 20 pg 10(6) cells). The addition of vasoactive intestinal peptide (VIP; 10(-9) to 10(-7) mol L(-1)) or of histamine (10(-5) to 10(-3) mol L(-1)) increased PAF production by three- to fivefold, while the addition of carbachol (10(-7) to 10(-4) mol L(-1)) increased PAF production up to sevenfold. PAF production was also increased up to 10- to 13 fold, in a dose- and time-dependent manner, by the addition of calcium and two- to threefold by the addition of phorbol myristate acetate (PMA; 10(-7) to 10(-5) mol L(-1)). However, the addition of dibutyryl cyclic AMP (dBcAMP; 10(-6) to 10( 4) mol L(-1) was without any effect. This is the first report showing PAF production by gastric epithelial cells in response to histamine, VIP and carbachol. Furthermore, the findings are consistent with a central role of calcium in this production. The results of this study, together with those of previous studies from the authors' laboratory, support the hypothesis that PAF is a physiological mediator of gastric acid secretion. PMID- 8682157 TI - Reduction in thyroid volume after radioiodine therapy of Graves' hyperthyroidism: results of a prospective, randomized, multicentre study. AB - The reduction in thyroid size in 92 patients treated with radioiodine for Graves' thyrotoxicosis was monitored by ultrasound volumetry. The patients were randomly treated with either a standard 131I activity of 555 MBq or an activity calculated to deliver a thyroid dose of 100 Gy. Within 1 year after radioiodine treatment, a remarkable volume reduction of about 71% (median) (quantile 25% (Q 25) = 49%, Q 75 = 82%, n = 67) was observed. The bulk of this reduction (median 57%, Q 25 = 21%, Q 75 = 74%, n = 92) was found within the first 6 months. Statistical analysis reveals that the effect was clearly related to the thyroid dose actually achieved during therapy. The median reduction obtained 6 months after radioiodine application was 45% for < 100 Gy, 56% for 100-200 Gy and 67% for > 200 Gy (n = 28, 39, 25 respectively). Twelve months after radioiodine application, the effect became less evident: 53%, 68% and 75% respectively (n = 17, 29, 21). The higher median thyroid dose actually achieved by standard than by calculated activity (215 Gy vs. 116 Gy) explains the more pronounced volume reduction in the standard group than in the calculated group; 60% vs. 47% 6 months (n = 47, 45) after radioiodine treatments and 74% vs. 66% 12 months (n = 31,36) after radioiodine application. The relative reduction in thyroid size was just as marked in patients with large thyroids as in those with small glands. The goitre prevalence (thyroid volume > 20 mL in women and > 25 mL in men) was reduced from 73% to only 16% 1 year after radioiodine treatment. In patients with a thyroid volume of more than 60 mL, the median pretherapeutic thyroid volume of 102 mL was reduced to 29 mL. In conclusion, radioiodine treatment in Graves' hyperthyroidism sufficiently reduces thyroid volume in a dose-dependent manner. The findings of this study demonstrate that radioiodine is also an attractive mode of therapy for Graves' patients with substantial thyroid enlargement. PMID- 8682158 TI - Erythrocyte Na(+)-H+ exchanger kinetics and Na(+)-Li+ countertransport activity in essential hypertensive patients. AB - The authors measured Na(+)-H+ exchanger kinetics together with Na(+)-Li+ countertransport V(max) in the erythrocytes of 21 subjects with essential hypertension and 16 normotensive control subjects. Na(+)-H+ exchange V(max) appeared to be increased in patients with essential hypertension, while the Na(+) H+ exchanger affinity for intracellular proton sites (K50%) proved to be unchanged and the index of cooperativity among intracellular proton binding sites as measured by Hill's coefficient (Hill's n) decreased as compared with normotensive control subjects. Na(+)-Li+ countertransport V(max) appeared to be higher in patients with essential hypertension than in control subjects. The authors were unable to find any correlations between Na(+)-H+ exchanger kinetic parameters and metabolic variables such as parameters of insulin resistance and plasma lipids. On the basis of the data obtained, erythrocyte Na(+)-H+ exchanger activity was found to be abnormal in two kinetic variables in essential hypertensive patients and showed no simple linear correlations with the main variables of glucose metabolism, plasma lipids, renin or aldosterone. PMID- 8682159 TI - Co-regulation of apo A-I, apo C-III and apo A-IV gene expression in human intestinal biopsies. AB - The apo A-I gene is expressed in the liver and small intestine. In order to study the role of human intestinal transcription of the apo A-I gene in determining plasma high-density lipoprotein, (HDL)-cholesterol and apo lipoprotein (apo) A-I concentrations, the authors measured the relative mRNA levels of apo A-I in human intestinal biopsies. Biopsies were taken from 50 fasting subjects (25 males and 25 females). At the same time blood was taken for lipid and lipoprotein analysis. Plasma HDL-cholesterol correlated linearly with plasma apo A-I protein. No correlation could be demonstrated between intestinal apo A-I mRNA and plasma apo A-I or HDL-cholesterol levels. The apo A-I gene resides in an apolipoprotein cluster with the apo C-III and apo A-IV genes. To assess whether there is a coordinated expression of this locus, Northern blot analysis of intestinal RNA was performed. The authors have demonstrated that under fasting conditions mRNA levels of apo A-I, C-III and A-IV are co-regulated in the intestine. PMID- 8682160 TI - Sex differences in initial clearance of palmitate by human hepatocytes. AB - To determine if the sex differences in clearance of long chain fatty acids by the liver observed in the rat are relevant to humans, the authors isolated hepatocytes from human adult males and females (five per group) and measured the initial (unidirectional) clearance of [3H]-palmitate from buffer containing albumin. The clearance was significantly higher (about twofold) in hepatocytes from females because of a higher permeability of the plasma membrane to the fatty acid. The livers had been perfused with University of Wisconsin (UW) solution and stored for 12-16 h before isolation of the cells. The magnitudes of the clearances in humans were similar to those in the rat when the livers were stored similarly, but lower than in cells isolated from fresh rat liver. When hepatocytes isolated from fresh rat liver were stored in UW solution, clearance of [3H]-palmitate was unaffected. Thus, hepatocytes prepared from intact liver stored for several hours in UW solution do not have as good preservation of function as hepatocytes isolated from fresh liver and then stored in UW solution. PMID- 8682161 TI - High tissue factor concentration in the omentum, a possible cause of its hemostatic properties. AB - The hemostatic properties of the pedicled omentoplasty turned out to be helpful in difficult hemorrhages in extensive surgery. As suggested by others, a high concentration of tissue factor (TF) in the omentum could be responsible for this favourable property. The authors investigated the nature of that property in 11 patients who underwent laparotomy. In omentum and striated muscle (controls) the TF-concentrations in both tissues were estimated by the ELISA method. A significant difference between TF-concentration in omentum and striated muscle could be demonstrated. PMID- 8682162 TI - Induction of glutathione-S-transferase-pi by short-chain fatty acids in the intestinal cell line Caco-2. AB - Glutathione S-transferases (GSTs) are a multigene family of detoxification and metabolizing enzymes that have been linked with the susceptibility of tissues to environmental carcinogens. In addition to their role as the main energy source in the colonic mucosa, short-chain fatty acids (SCFAs) have been found to act as potent antiproliferative and differentiating agents in various cancer cell lines. The objective of this study was to evaluate the effects of SCFAs on the induction of GSTpi in the intestine as a possible new anticarcinogenic mechanism of SCFAs. Studies were performed in Caco-2 cells, a cell line resembling functionally normal enterocytes. Cells, cultured in DMEM supplemented with 10% fetal calf serum, were studied from day 0 dpc (days post confluence) until 21 dpc and culture. SCFAs (acetate, propionate, butyrate) were added to give a final concentration of 5 mmol L(-1). At 0, 3, 6, 9, 15, and 21 dpc, protein, lactate dehydrogenase (LDH), alkaline phosphatase (AP) and GSTpi were measured. Butyrate supplementation significantly (P < or = 0.01) increased GSTpi levels compared with controls in a concentration-dependent manner. The effect was detectable within 3 dpc with a maximum at 15 dpc. In contrast to butyrate, the other SCFAs tested had no (acetate) or little effect (propionate). In conclusion, the data suggest that the anticancer effect of butyrate in part may be based on the induction of GSTpi activity, resulting in an enhanced detoxification capacity of the gut. PMID- 8682163 TI - A comparative study of the effects of customized facemask therapy or headgear to the lower arch on the developing Class III face. AB - This retrospective, cephalometric study examined the effects of treatment in a group of 83 Class III, Skeletal III children, who were considered suitable for orthodontic correction of their malocclusions. All children completed therapy successfully: 44 individuals were treated with headgear to the mandibular dentition and for 39 a customized facemask was prescribed. These two groups were compared with 30 untreated Class III controls. Data were examined at the beginning and end of active treatment for the treated groups, and over a similar time interval for the controls. Where differences between the sexes were apparent, data for each sex are given separately. Where no significant differences were seen, data are pooled. In order to standardize the results, treatment (or observation) effects are presented as average changes per year. Surprisingly, despite the very different methods of applying the extra-oral force, the two treated groups showed strikingly similar therapeutic effects. The reverse overjet was corrected with little alteration in overbite. Upper incisors proclined whilst the lowers retroclined, becoming less prominent in relation to APo. The mandible hinged downwards and backwards, whilst the maxillary complex advanced. Lower face height increased more than would be expected by growth alone. Mirroring the hard tissue changes, the soft tissue profile improved and the relationship between the upper and lower lips became more harmonious. For only three parameters did the facemask children demonstrate a significantly better performance than their headgear peers: the overjet and the antero posterior position of the lower lip and chin in females. It was concluded that, despite their differing approaches, the customized facemask and headgear to the mandibular dentition have very similar treatment effects. Both are clinically effective. However, treatment can begin earlier, and both the skeletal and profile changes are marginally superior when a facemask is worn. PMID- 8682164 TI - Four measurements for assessing facial deformity. AB - Four lateral cephalometric measurements which localize the anterior maxilla and chin in the horizontal and vertical planes are presented and evaluated against three control methods, in a pilot study of 40 patients. It was found that in 27 out of 30 comparisons (90%) the frequency of agreement between the proposed and each of the control methods was greater than the agreement between the control methods themselves. In three out of 30 comparisons (10%) it was found that the frequency of agreement between the proposed and the control methods was the same as between the controls themselves. In addition, there was a greater agreement reached between methods when measurements were related to the cranial base. In view of the close relationship between cranial and facial development, it was considered that measuring ratios should portray the facial deformity not just in relation to the cranial base but to the individual's own cranial base and not to a population norm. The results also confirm the findings of previous work in the literature which demonstrate disagreement between cephalometric methods for localization of a given landmark. PMID- 8682165 TI - Nasorespiratory characteristics and craniofacial morphology. AB - The relationship between respiration and craniofacial morphology has been debated for many years. Despite numerous studies, the term 'mouth breathing' remains ill defined. Still, medical and surgical treatments are performed in order to modify respiration and 'improve' facial growth. This clinical belief continues, in the absence of conclusive evidence, that a causal relationship exists between oral respiration and facial growth, or that such treatment modalities and their associated risks actually modify respiratory mode. Moreover, diagnostic indicators have been postulated for the identification of patients for whom such therapy would be beneficial. The purpose of this study was to investigate the strength of association between mode of respiration and craniofacial morphology. In addition, the precision level was calculated for two popular cephalometric tests for possible nasal impairment. The results suggest that: (1) cephalometric analyses are poor indicators of nasal impairment and should not be used in clinical decision making, and (2) facial morphology and respiratory mode are unrelated. PMID- 8682166 TI - Associations among different orofacial dysfunctions in 9-11-year-olds. AB - This study is the second part of a longitudinal investigation on different orofacial dysfunctions in growing individuals. The aim of the present report was to determine, in 219 children with and without articulatory speech disorders, whether certain associations among misarticulations of speech, craniomandibular disorders (CMD), and problems in oral motor skills still were found at the age of 9-11 years, as they had been in these children at the age of 6-8 years. Multiple logistic regression models showed that certain aspects of dental malocclusion such as large overjet, anterior open bite and lateral cross-bite, and certain signs of CMD such as palpatory tenderness of the TMJ, jaw deviation on opening and bruxism were related to misarticulations of speech. Children with sounds produced too far posteriorly seemed to have a smaller maximal opening but larger laterotrusive and protrusive movement capacities of the mandible than children with correct speech articulation. Despite maturation of the oral motor skills with age, among 9-11-year-olds various orofacial dysfunctions still seemed to be associated with each other. This probably indicates fixation of certain speech misarticulations rather than immaturity of the fine motor control. PMID- 8682167 TI - The influence of incisal malocclusion on the social attractiveness of young adults in Finland. AB - The aim of this study was to investigate the importance of dentofacial appearance on the perceived social attractiveness of young adults in Finland. The dental arrangements studied were incisal crowding, median diastema, protruding incisors, and ideal incisal occlusion. Facial photographs of six young adults were obtained and modified, so that for each face, four different dental arrangements could be portrayed. The photographs were shown to 1007 Finnish students to estimate social and personal characteristics of the person in the photograph. Dental arrangement had a significant influence on the perceived beauty and success of the persons. Test faces with incisal crowding and median diastema were ranked as significantly less intelligent, beautiful and sexually attractive, and judged to belong to lower social class than the same faces with ideal occlusion. Protruded incisors did not affect the ratings compared to ideal occlusion. On the average, female test faces were judged more favourably than the male ones. The results indicate that among Finnish students conspicuous incisal crowding or spacing represent a social disadvantage compared to normal or protruded incisors. PMID- 8682168 TI - An investigation of the association between overjet size, lip coverage, and traumatic injury to maxillary incisors. AB - This study investigated the association between overjet size and lip coverage when assessing the likelihood of traumatic injury to maxillary incisors. Eleven hundred-and-thirty-seven 11- and 12-year-olds were examined in school for traumatic injury to their maxillary incisors. The size of overjet and the adequacy of lip coverage of the maxillary incisors was assessed for each child. One-hundred-and-sixty-seven (15 per cent) had experienced traumatic injury to their maxillary incisors. Both increased overjet and inadequate lip coverage of the maxillary incisors were found to be significant risk factors. However, inadequate lip coverage was the single most important independent predictor of traumatic injury (P < 0.001), with a relative odds ratio of 2.62. The results suggest that much of the predictive value of increased overjet may be explained by inadequate lip coverage. PMID- 8682169 TI - Outcome prediction in open bite cases. AB - Some anterior open bites close spontaneously, others do not. It would be advantageous if the orthodontist had some means of predicting the spontaneous outcome in open bite patients. One-hundred-and-twenty-seven patients having open bite were recorded longitudinally for a minimum period of 3 years using cephalometric radiographs. The open bite closed spontaneously in 50 per cent of a prepuberal group aged between 7 and 10 years, in 49 per cent of a puberal group aged 11-14 years, and in 44 per cent of a post-puberal group aged between 14 and 21 years when first seen. Data from cephalometric analysis of the first film in each case was analysed using discriminant function analysis. The analysis correctly predicted the outcome in 88 per cent of the prepuberal group, in 74 per cent of the puberal group, and in 94 per cent of the post-puberal group. The accuracy of the prediction equation was checked in a new sample of 35 subjects with open bite observed over at least 2 years so that the spontaneous outcome was known. The equation correctly predicted the outcome in 79 per cent of prepuberal, in 80 per cent of puberal, and in 100 per cent of post-puberal patients in the second sample. PMID- 8682170 TI - Growth changes in the cranial base and the face: a longitudinal cephalometric study of linear and angular changes in adult Norwegians. AB - The purpose of this study was to examine the natural growth changes which occur between 22 and 33 years of age. The material consisted of two series of cephalograms of 74 females and 90 males with approximately 11 years between the two series. None of the subjects had orthodontic retainers when the first exposure was undertaken, or orthodontic treatment, or surgery during the observation period. The measurements were carried out by using a modified Dentofacial Planner program SHORT, and both linear and angular measurements were made. The overall changes were an increase in anterior facial height which mostly occurred in the lower face, and an increase in the length of the mandible. These changes were statistically significant in both genders. The females also had a significant posterior rotation of the mandible. There was a significant decrease in the thickness of the upper lip both in females and males, and the males had a significant increase in thickness of the soft tissue on the mandibular profile. Although there were some statistical changes in the observation period, none of the linear changes exceeded 1.35 mm. The largest angular change was a 1.44 degrees retroclination of the upper incisors in females. The differences between the genders were statistically significant only in three angular and two soft tissue measurements. PMID- 8682171 TI - Torsional bond strength and failure pattern of ceramic brackets bonded to composite resin laminate veneers. AB - The objectives of this study were to investigate the torsional bond strength of ceramic brackets bonded to composite resin veneer laminates and to human enamel. Microfilled resin veneers were bonded directly to prepared, etched bovine teeth embedded in epoxy resin. Brackets [Allure IV (NSB), Fascination, Starfire TMB, and Transcend 2000] were bonded to abraded, acid-etched resin veneers with a light-cured or a chemically-cured adhesive. Brackets were also bonded to human teeth with light-cured and chemically-cured adhesives for comparison purposes. After 24 hours storage in water, specimens were subjected to torsional stress and the maximum shear stress tau max, was calculated. The debonded brackets, the veneer, and enamel surfaces were examined under a stereomicroscope and a SEM to study the failure modes. Three-way ANOVA with a Tukey multiple comparisons test revealed significant differences in bond strengths among bracket types and bonding substrate at P = 0.05 level. Highest bond strength was observed in brackets with a combination of micromechanical retention and chemical adhesion. Significant interactions among bracket, substrate (enamel or resin) and mode of cure of adhesive were observed. Analysis of the failure pattern of brackets revealed adhesive and/or cohesive resin failures in all brackets studied, while cohesive bracket failures occurred in the single-crystal Starfire TMB bracket and the polycrystalline Transcend 2000 bracket. Debonding ceramic brackets under a steady torsional load caused no substrate surface alterations regardless of adhesive used. PMID- 8682172 TI - 1,25-Dihydroxyvitamin D3 and transforming growth factor-beta act synergistically to override extinction of liver/bone/kidney alkaline phosphatase in osteosarcoma hybrid cells. AB - In this study, a somatic cell genetic approach was used to study the regulation of liver/bone/kidney alkaline phosphatase (ALPL) gene expression in osteoblasts. ALPL plays an important role in skeletal mineralization and serves as a good index of bone formation. A series of intertypic hybrids constructed by fusion of the human osteosarcoma TE-85 with the mouse fibrosarcoma La-t- demonstrated a 10 fold reduction of ALPL steady-state mRNA and enzyme activity, a phenomenon termed extinction. Hybrid subclones which reexpressed ALPL contained reduced numbers of fibroblast chromosomes compared to earlier passages. This suggests that a trans acting negative regulatory factor expressed from the fibroblast genome regulates ALPL expression. Two factors known to influence ALPL expression are 1,25 dihydroxyvitamin D3 (1,25D3) and transforming growth factor-beta1 (TGFbeta1). 1,25D3 is involved in mobilizing bone calcium stores and TGFbeta1 plays a critical role in bone remodeling. The extinguished hybrids were exposed to 1,25D3, TGFbeta1, and a combination of these factors. For two hybrids, the combination induced reexpression of ALPL activity to levels comparable to the TE 85 parent, indicating a competition between the factors and the extinguisher(s). Neither factor alone could induce ALPL reexpression to the levels observed with the combination. In only one hybrid, the combination of factors synergistically increased ALPL expression. These data help define the cis sequence element(s) in the ALPL promoter which are involved in the negative regulation of this gene. PMID- 8682174 TI - Improvement of the pupillary light reflex of Royal College of Surgeons rats following RPE cell grafts. AB - Retinal pigment epithelial grafts to the subretinal space improve the visual function of Royal College of Surgeons rats. No such effect is seen when grafts of fibroblasts or the carrier medium are transplanted. PMID- 8682173 TI - Xenotransplantation of porcine fetal ventral mesencephalon in a rat model of Parkinson's disease: functional recovery and graft morphology. AB - Neurotransplantation of human fetal dopamine (DA) neurons is currently being investigated as a therapeutic modality for Parkinson's disease (PD). However, the practical limitations of human fetal transplantation indicate a need for alternative methodologies. Using the 6-hydroxydopamine rat model of PD, we transplanted dopaminergic neurons derived from Embryonic Day 27 porcine fetuses into the denervated striatum of cyclosporine-A (CyA)-treated or non-CyA-treated rats. Functional recovery was assessed by amphetamine-induced rotation, and graft survival and morphology were analyzed using neuronal and glial immunostaining as well as in situ hybridization with a porcine repeat element DNA probe. A significant, sustained reduction in amphetamine-induced rotational asymmetry was present in the CyA-treated rats whereas the non-CyA-treated rats showed a transient behavioral recovery. The degree of rotational recovery was highly correlated to the number of surviving transplanted porcine dopaminergic neurons. TH+ neuronal survival and graft volume were significantly greater in the CyA treated group as compared to the non-CyA group. By donor-specific neuronal and glial immunostaining as well as donor-specific DNA labeling, we demonstrate that porcine fetal neuroblasts are able to survive in the adult brain of immunosuppressed rats, mediate functional recovery, and extensively reinnervate the host striatum. These findings suggest that porcine DA neurons may be a suitable alternative to the use of human fetal tissue in neurotransplantation for PD. PMID- 8682175 TI - Toxicity of replication-defective adenoviral recombinants in dissociated cultures of nervous tissue. AB - Replication-defective human type 5 adenoviral recombinants (AVR) are very efficient means of introducing foreign genes into neurons in vitro and in vivo; however, a significant reduction in the number of cells expressing reporter genes has been reported to occur over time. In vitro, this may be due to direct toxicity of the protein product of the transgene or adenoviral molecules. In vivo, in addition, an immune attack by the host could eliminate the transduced cells. To assess the direct toxicity of AVR or reporter gene products, a quantitative study of survival of transduced neurons over a period of 4 weeks was conducted in primary neural cultures. Cultures of dissociated murine spinal cord dorsal root ganglia were exposed to AVR containing the Escherichia coli lacZ (E. coli lacZ) gene under control of either the very efficient cytomegalovirus enhancer/promoter or the fast muscle troponin I promoter, which is not active in these cells. Two factors contributed to loss of neuronal and nonneuronal cells: (i) direct toxicity of (E1 + E3)-deleted replication-incompetent AVR at high titers [> or = 5 x 10(8) viral particles/ml or multiplicity of infection (m.o.i.) 1000] and (ii) high levels of expression of the reporter gene product, beta galactosidase, at titers that result in 55-75% transduction efficiency (5 x 10(7) 5 x 10(8) viral particles/ml or m.o.i. 100-1000). Despite the efficacy of adenoviral vectors in introducing foreign genes into primary, postmitotic cells, specific precautions must be taken in their use because of the narrow margin between concentrations of recombinants that transduce a sufficient percentage of cells and those that are cytotoxic. PMID- 8682176 TI - Reconstruction of transected postcommissural fornix in adult rat by Schwann cell suspension grafts. AB - Schwann cell (SC) transplantation has emerged as a powerful tool to promote regeneration in the lesioned central nervous system (CNS). Most studies focused on the use of guidance channels to introduce the SCs into CNS neuropil; a technique that itself causes extensive damage to host tissue and is only applicable in superficial brain areas. The present study examines the efficacy of microinjected SC suspensions to promote structural reconstruction of the transected postcommissural fornix in the adult rat. Stereotactic, unilateral fornix transection was performed using a tungsten wire knife. Immediately after transection lesion cavities received either a Dulbecco's modified Eagle's medium injection or a pure SC suspension graft derived from a highly purified SC culture that was prepared from syngeneic rat (P1) sciatic nerves. After 4 days to 8 months, the implant characteristics as well as the structural reconstruction of the tract were analyzed using immunocytochemical methods and anterograde tracing techniques. Numerous SCs of the graft could be identified for up to 8 months. They rapidly dispersed from the injection site and migrated freely for considerable distances into the host tissue. The SCs exhibited a low proliferation activity that ceased within 2 weeks after transplantation. They did not prevent retrograde axonal degeneration of the fornix tract for a short distance (600 micron) but promoted structural reconstruction of the transected fornix tract. Regenerating fibers traversed the lesion site and extended along their former pathway up to the mammillary body, their proper target. Moreover, the applied transplantation technique allowed remyelination of the regenerating fibers by host oligodendrocytes. In conclusion, microtransplantation of SC suspensions represents a promising strategy for promoting structural reconstruction of lesioned CNS projections. PMID- 8682177 TI - Cyclosporine treatment promotes survival of human fetal neural retina transplanted to the subretinal space of the light-damaged Fischer 344 rat. AB - We have reported that xenografts of human fetal neural retina survive in the subretinal space of cyclosporine-immunosuppressed rats. In view of the current controversy regarding the role of cyclosporine, we wished to determine if cyclosporine immunosuppression was an absolute requirement for retinal xenograft survival. Neural retinas from human fetal eyes obtained within 1 h of termination of pregnancy were stored in Optisol medium (Chiron Vision, Irvine, CA) at 4 degrees C for 2 and 7 days. Retinas were then transplanted to the subretinal space of either cyclosporine-treated (10 mg/kg/day) light-damaged Fischer 344 rat eyes (17 animals, 28 eyes) or to the subretinal space of light-damaged Fischer 344 rat eyes (9 animals, 15 eyes) receiving no cyclosporine treatment. Grafted eyes were observed clinically at 10, 20, and 30 days posttransplantation. At 30 days, the animals were sacrificed and the grafts observed histologically. Human fetal retina xenografted to the subretinal space of immunosuppressed rats survived (9/17 animals, 12/28 eyes), showed good integration with the host retina and initial photoreceptor differentiation. Tissue xenografted to the subretinal space of non-cyclosporine-treated rats was not observed to survive (0/9 animals, 0/15 eyes). A low level cellular reaction was seen around three of the injection sites within the nonimmunosuppressed rats. We conclude that immunosuppression is necessary for the survival of human fetal neural retina xenografted to the subretinal space. PMID- 8682178 TI - Exacerbation of apoptosis in the dentate gyrus of the aged rat by dexamethasone and the protective role of corticosterone. AB - Glucocorticoid-induced cell loss in the dentate gyrus of rats of various ages was studied using the TUNEL procedure to detect apoptotic cells. A highly significant increase in the incidence of apoptosis was observed within the dentate hilus and granule cell layer within 24 h of a single injection of dexamethasone (DEX) in rats aged between 1 and 36 months; DEX-induced apoptosis was more pronounced with increasing age. Corticosterone (CORT) did not cause an increase in the rate of apoptosis above that found in age-matched controls. However, CORT pretreatment (3 h) resulted in a significantly attenuated DEX-induced apoptosis in both areas of the dentate gyrus. Serum CORT levels in saline-treated rats peaked at 6 months of age and reached a nadir at 36 months of age. The results indicate that (i) aged subjects are more susceptible to DEX in terms of dentate gyrus cell loss by apoptosis, (ii) CORT, which binds to Type I corticosteroid receptors with a high affinity, might serve to protect against the damaging effects of DEX which is a ligand of the Type II glucocorticoid receptor, and (iii) declining endogenous levels of CORT may increase the vulnerability of the dentate gyrus of aged rats to insult by DEX. PMID- 8682179 TI - Actions of systemic theophylline on hemidiaphragmatic recovery in rats following cervical spinal cord hemisection. AB - This study assesses the effects of theophylline on enhancing phrenic nerve discharge and functional hemidiaphragmatic recovery after C2 spinal cord hemisection in adult female rats. There were three separate groups of spinal hemisected rats and one nonhemisected group studied. Twenty-four hours following C2 spinal hemisection, ipsilateral phrenic nerve activity was recorded under standardized, normoxic and then hypoxic conditions. After 30 min, theophylline was administered and the recordings were repeated in group 1 animals. In group 2, activity in both phrenic nerves was recorded simultaneously before and after drug administration. In a third group of rats, both ipsilateral phrenic nerve and hemidiaphragmatic activities were monitored before and after the drug. In control nonhemisected animals under standardized recording conditions, the effects of theophylline were quantitatively assessed by determining the mean area under integrated phrenic nerve discharge waveforms before and after drug administration. Generally, theophylline induced biphasic effects; i.e., at a low dose (15 mg/kg) it evoked excitation, while at a high dose (30 mg/kg) depression of respiratory activity predominated. In group 2 animals, respiratory activity was induced in the nerve ipsilateral to the hemisection and enhanced in the contralateral phrenic nerve for up to 3 h after a single standard dose of theophylline (15 mg/kg). Prior to drug administration, there was an absence of respiratory-related activity in both the phrenic nerve and hemidiaphragm ipsilateral to C2 spinal cord hemisection. A standard dose of theophylline, however, induced recovery of activity in both the phrenic nerve and the left hemidiaphragm ipsilateral to the hemisection in group 3 animals. In control (nonhemisected) animals, theophylline enhanced phrenic nerve activity, but decreased the duration of respiratory bursts. These results show for the first time that theophylline can activate latent respiratory motor pathways and thus restore the respiratory drive to phrenic motoneurons lost by spinal cord injury. Respiratory activity is not only reestablished in the phrenic nerve made quiescent by hemisection, but it is also enhanced in the contralateral phrenic nerve. The drug also restores function to the hemidiaphragm paralyzed by the spinal cord hemisection. The findings may have clinical relevance to human cases of cervical spinal cord injury in which respiratory function is compromised. PMID- 8682180 TI - Growth factors rescue embryonic dopamine neurons from programmed cell death. AB - Poor survival of embryonic dopamine neurons is a primary problem limiting the value of neurotransplantation for Parkinson's disease. Several neurotrophic factors have been shown to promote dopamine neuron survival when used individually in culture. We have found that two peptides, insulin-like growth factor-I (IGF-I) and basic fibroblast growth factor (bFGF), have additive effects on cell survival when used in combination. These growth factors reduced the number of dopamine cells undergoing apoptotic cell death. The neurotrophic factors induced proliferation of astrocytes but not dopamine neurons. When cell proliferation was blocked by cytosine arabinoside, the beneficial effects of IGF I and bFGF were abolished, suggesting that effects of the growth factors were mediated, at least in part, by factors associated with glia. These results indicate that growth factors in combination may prove useful for enhancing dopamine neuron survival for neurotransplantation. PMID- 8682181 TI - Regeneration of entorhino-dentate projections in organotypic slice cultures: mode of axonal regrowth and effects of growth factors. AB - Explants of Embryonic Day 18 (E18) rat entorhinal cortex were cocultured with Postnatal Day 6 mouse hippocampal slices to study CNS regeneration in vitro. The present report describes a double-labeling paradigm for quantitative analysis of the type of new growth seen in immature cultures. Entorhinal projection neurons in living static cocultures were retrogradely labeled with DiI or Texas red dextran at 6 days in vitro and with dextran-FITC at 13 days. An intervening lesion to the entorhinodentate pathway was made at 8 days by replacing the hippocampal slices with fresh ones. About one-third of the new efferent entorhinal projections labeled with the second tracer could be characterized as true regeneration of axons from previously projecting entorhinal neurons by virtue of their being double labeled. The remaining two-thirds comprised new, late-arriving axons from previously nonprojecting cells. Earlier studies have shown that rat entorhinal axons will reinnervate hippocampal slices only if the lesions are made before 2-3 weeks in culture, equivalent to a postnatal age of 11 18 days. In a second series of experiments we tested whether treatment with trophic factors could overcome this age-related failure of regeneration characteristic of mature preparations. E18 explants were lesioned after 4 weeks in vitro and grown for a further 2 weeks in medium supplemented with either Schwann cell conditioned medium or acidic fibroblast growth factor plus heparin. A significant increase in outgrowth was seen in both cases, although the effects of each factor were not additive when they were applied in combination. These results show that our model of CNS lesions in vitro can be used to assess the effectiveness of growth factors in ameliorating the decline in regenerative ability with increasing developmental age. PMID- 8682182 TI - Neuroprotective effects of the pyrrolopyrimidine U-104067F in 3-acetylpyridine treated rats. AB - The neuroprotective effects of U-104067F[(9-(2-morpholinyl)ethyl) 2,4-di-l pyrrolidinyl-9H-pyrimidino (4,5-b)(4,5indole monohydrochloride hydrate], a pyrrolopyrimidine antioxidant, were investigated in 3-acetylpyridine (3-AP) treated Wistar rats. A significant (P < 0.01) reduction in cerebellar cGMP and ATP was observed at 96 h after treatment with 3-AP (500 micromol/kg ip). Oral administration of U-104067F significantly attenuated 3-AP-induced reductions in cGMP and ATP, and this effect was dose related. Consistent with the neurochemical effect, U-104067F prevented 3-AP-induced loss of motor coordination. 3 Acetylpyridine produced a significant (P < 0.01) loss of neurons in the inferior olivary nucleus. Treatment with U-104067F partially, but significantly (P < 0.01), prevented the loss of inferior olivary neurons. The physiological and neurochemical parameters were maintained within normal limits by U-104067F in 3 AP-treated rats despite only partial preservation of inferior olivary neurons. PMID- 8682183 TI - BMP-2 and BMP-4, but not BMP-6, increase the number of adrenergic cells which develop in quail trunk neural crest cultures. AB - The bone morphogenetic proteins (BMPs) are members of the TGF beta superfamily of growth factors. We have investigated the effects of BMP-2, BMP-4, and BMP-6 on the development of quail trunk neural crest cells in tissue culture. The presence of human recombinant BMP-2 or BMP-4 resulted in a dramatic increase in the number of tyrosine hydroxylase (TH)-immunoreactive cells which developed after 7 days in vitro. In contrast, BMP-6 showed little or no effect. Total cell number was not altered significantly by BMP-2, BMP-4, or BMP-6. However, in the presence of BMP 2 and BMP-4, but not BMP-6, the fraction of the cell population that became melanocytes was reduced to about two-thirds the control value. Addition of BMP-2 and BMP-4 also increased the number of Islet-1-immunoreactive and Hu immunoreactive cells, but the magnitude of these increases was less than that observed for the TH-immunoreactive cell population. The Islet-1-immunoreactive cells were a subset of the TH-immunoreactive cells, while the Hu-positive cells were distinct from the TH-immunoreactive population. Analysis using bromodeoxyuridine labeling indicated that the increased numbers of TH immunoreactive cells observed in the presence of BMP-2 and BMP-4 were not due to an increased rate of cell division in committed TH precursors. Further experiments, in which cultures were initiated from single cells, showed that the presence of BMP-2 resulted in colonies containing numerous catecholamine-positive cells without altering the overall number of colonies which survived and developed. In summary, our findings indicate that BMP-2 and BMP-4 are potent regulators of the adrenergic development of avian trunk neural crest cells. PMID- 8682184 TI - Choline acetyltransferase mRNA plasticity with Pavlovian conditioning. AB - Choline acetyltransferase mRNA and somal area increased selectively in the ventral nucleus basalis of rats trained that a tone signals immediate shock (i.e., predicts danger). Retrograde tracing showed the affected cells correspond to those that project to the auditory cortex. Behavior responses and mRNA increased significantly above those of control groups trained with the tone not signaling immediate shock. In one of those control groups, animals learned that the same tone signaled a shock-free period before shock. These animals showed a visibly decreased riboprobe and a trend toward smaller somal areas. These results implicate transcriptional regulation of choline acetyltransferase in long-term memory storage. Selective attention and inattention to the tone are possible components of memory encoded by the molecular changes reported here. PMID- 8682185 TI - Purification and characterization of N-acetylglucosaminidase from Trypanosoma cruzi. AB - N-Acetyl-beta-D-glucosaminidase activity was recovered in cell-free extracts of Trypanosoma cruzi epimastigotes. This enzyme was identified on the basis of its ability to hydrolyze the fluorogenic substrate 4-methylumbelliferyl-N-acetyl-beta D-glucosaminide. This activity was purified to apparent homogeneity by anion exchange and molecular sieve high-performance liquid chromatography. It eluted at a native molecular weight of approximately 48,000 Da and migrated as a single band upon reducing or nonreducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The optimum pH of the activity was around pH 5.4 and the enzyme gave a single peak of activity on a chromatofocusing column with an isoelectric point of 4.2. The enzyme hydrolyzed 4-methylumbelliferyl-GlcNAc, suggesting that it should be characterized as a N-acetyl-beta-D glucosaminidase, with a K(m) value of 1.5 mM from Lineweaver-Burk plots. Many inhibitors as potential enzyme effectors were investigated. PMID- 8682186 TI - Tritrichomonas foetus: isolation and characterization of the Golgi complex. AB - An effective methodology to isolate and characterize the Golgi complex of Tritrichomonas foetus is described in this work. Using sucrose density gradient centrifugation, two highly enriched Golgi fractions (GF1 and GF2) were obtained. Enzymatic assays of GF1 and GF2 showed a strong enrichment in galactosyltransferase activity (20- and 7-fold, respectively), with minimal contamination with other organelles. The GF fraction was further subfractionated by alkaline treatment, which resulted in the production of Golgi content and membrane subfractions. Electron microscopic observations of intact cells or Golgi fractions fixed in solutions containing glutaraldehyde and tannic acid, as well as of deep-etched replicas of isolated fractions, revealed the presence of discrete bridges only between closely apposed cisternae. PMID- 8682187 TI - A novel inhibitor of factor X activation from the salivary glands of the bed bug Cimex lectularius. AB - Cimex lectularius salivary gland homogenate delayed the recalcification time of human citrated plasma. Separation of the salivary gland homogenate by molecular sieving HPLC chromatography resulted in a single major peak of anticlotting activity with an apparent molecular mass of 17,000. The anticoagulant principle inhibited the activation of factor X to factor Xa in the tenase complex (FVIII, FIXa, FX, phospholipids, and calcium). However, it did not directly inhibit already activated factor Xa, suggesting that the anticlotting activity is not an anti-factor Xa. Additionally, this salivary gland anticoagulant further retarded the recalcification time of factor VIII- and factor IX-deficient plasmas, suggesting that the anticlotting principle is not directly inhibiting either the coagulation factor VIII or factor IXa. Altogether these data suggest that the anticlotting activity is an inhibitor of the activation of factor X to factor Xa in the tenase complex. PMID- 8682188 TI - Aedes aegypti: induced antibacterial proteins reduce the establishment and development of Brugia malayi. AB - The effect of host immune activation on the development of Brugia malayi in one susceptible and four refractory strains of Aedes aegypti and in Armigeres subalbatus was assessed. A. aegypti that were immune activated by the injection of saline or bacteria 24 hr before feeding on a B. malayi-infected gerbil had significantly reduced prevalences and mean intensities of infection from those of naive controls when exposed to bloodmeals with low (105 mf/20 microliters) and medium (160 mf/20 microliters) microfilaremias. At a higher microfilaremia (237 mf/20 microliters) there were no significant differences in mean intensities, suggesting that the number of parasites ingested may affect the host's ability to mount an effective defense response. Because the major immune proteins in A. aegypti are defensins, we did Northern analyses of fat body RNA 8 hr after immune activation or bloodfeeding. All mosquitoes demonstrated rapid transcriptional activity for defensins following immune activation by intrathoracic inoculation with either saline or bacteria. However, no strain of A. aegypti, susceptible or refractory to B. malayi, nor Ar. subalbatus produced defensin transcripts after bloodfeeding on an uninfected or a B. malayi-infected gerbil. These data suggest that inducible immune proteins of mosquitoes can reduce the prevalence and mean intensity of infections with ingested parasites, but these proteins are not expressed routinely after parasite ingestion and midgut penetration and probably do not contribute to existing refractory mechanisms. Immune proteins such as defensins, however, represent potential candidates to genetically engineer mosquitoes for resistance to filarial worms. PMID- 8682189 TI - Fasciola hepatica: irradiation-induced alterations in carbohydrate and cathepsin B protease expression in newly excysted juvenile liver fluke. AB - Irradiation has been successful in the attenuation of infective stage parasites for use as vaccines against a number of parasites including Fasciola spp. The mechanisms of action of irradiation-attenuated vaccines, however, are not clearly understood. In this study, we examined the effect of 3, 10, and 40 krad of gamma irradiation on the expression of carbohydrates and cathepsin-B by newly excysted juvenile Fasciola hepatica (NEJ). Following irradiation of metacercariae, the expression of concanavalin A (ConA)-specific sugars was decreased on the surface of NEJ and the expression of wheat germ agglutinin (WGA)-specific sugars was increased in the gut and reduced on the surface of NEJ. Cathepsin proteases are a major component of liver fluke excretory/secretory material (ES) and can cleave host immunoglobulin (Ig). Cathepsin-B protease was localized in nonirradiated NEJ to the gut lumen and to secretory granules within the gut epithelia. Irradiation of fluke with 3, 10, and 40 krad of gamma-rays significantly reduced the tissue expression of cathepsin-B at 8 hr postirradiation in an apparently dose-dependent manner. After a further 24 hr culture tissue expression of cathepsin-B was significantly reduced in 10- and 40-krad-irradiated NEJ. Protease activity of ES samples collected over a 24-hr period from irradiated and nonirradiated NEJ cultured in vitro were tested using a rabbit Ig cleavage assay. The proteolytic activity of ES from 10- and 40-krad-irradiated NEJ was reduced during the initial 6 hr in culture and between 12 and 24 hr when compared to ES from nonirradiated controls. Biosynthetic labeling experiments using [35S]methionine and [35S]cysteine indicated that ES material was actively synthesised during 48 hr in vitro culture. Therefore, from this study, we conclude that gamma-irradiation of NEJ alters expression of cathepsin-B protease and WGA- and ConA-specific sugars which may be detrimental to parasite invasion and contribute to the protective immune responses generated in the host by irradiation-attenuated metacercariae of Fasciola spp. PMID- 8682190 TI - Tritrichomonas foetus: iron acquisition from lactoferrin and transferrin. AB - Acquisition of iron from lactoferrin and transferrin by a parasitic protozoon Tritrichomonas foetus has been studied in vitro. Specific, time-dependent, and saturable binding of iodinated ligands to the outer membrane of T. foetus at 4 degrees C was demonstrated for 125I-labeled lactoferrin only. About 1.7 x 10(5) binding sites of a single class with Kd approximately equal to 3.6 microM was estimated by means of Scatchard analysis. Internalization of the bound lactoferrin was observed at 37 degrees C. The cell-associated radioactivity after 30 min incubation of the parasite with 125I-lactoferrin at 37 degrees C was about 3.5-fold higher than the amount bound at 4 degrees C. The majority of internalized 125I-lactoferrin was released within 15 min of cell reincubation at 37 degrees C in the presence of a 100-fold excess of nonlabeled lactoferrin. Released lactoferrin displayed unchanged mobility on autoradiography. In contrast to lactoferrin, binding of 125I-transferrin was nonspecific and did not display saturable kinetics. The growth of T. foetus in iron-restricted media was stimulated by both lactoferrin and transferrin. The ability of the cells to remove and accumulate iron from both proteins was therefore examined using 59Fe saturated lactoferrin and transferrin. It was found that trichomonads acquired a comparable amount of iron from both lactoferrin and transferrin during 60 min incubation at 37 degrees C (495 and 577 pmole Fe/mg of protein, respectively). The pH of the assay medium (PBS) decreased from pH 7.4 to 5.6 after incubation with trichomonads. At this pH, marked release of iron from transferrin (up to 47%) but not from lactoferrin (4%) was determined in cell-free media. These results indicate that T. foetus is able to utilize both lactoferrin and transferrin to cover its iron requirements. However, mechanisms of iron acquisition from these host proteins appear to be different. Specific binding and internalization of lactoferrin suggests the possible involvement of receptor mediated endocytosis in the acquisition of lactoferrin-bound iron, while retrieval of iron from transferrin may depend on the extracellular release of iron from this ligand. PMID- 8682191 TI - Plasmodium knowlesi: secondary processing of the malaria merozoite surface protein-1. AB - Secondary processing of the Plasmodium falciparum malaria merozoite surface protein-1 (MSP-1) is defined as a single proteolytic cleavage within the carboxy terminal membrane-bound component of the MSP-1 protein complex on the free merozoite surface. The N-terminal cleavage product (MSP-1(33)) is shed from the parasite surface along with a number of other polypeptides, whereas the C terminal processing product remains bound to the merozoite surface and is the only part of MSP-1 detectable in the newly invaded host cell. We report that secondary processing of MSP-1 takes place in a similar manner on invasive merozoites of the simian malaria parasite Plasmodium knowlesi. Processing can take place to a limited extent in pure isolated merozoites; however, within 10 min of the addition of purified invasive merozoites to rhesus erythrocytes, processing and shedding of MSP-1 has gone to completion only in those parasites which have undergone invasion; residual free merozoites remain uniformly reactive with antibodies against MSP-1(33). Successful invasion is therefore associated with complete shedding of MSP-1(33) from the merozoite surface. The nucleotide sequence of the 3' domain of the P. knowlesi MSP-1 gene is also presented. PMID- 8682192 TI - Trypanosoma cruzi: involvement of intracellular calcium in multiplication and differentiation. AB - The possible role of intracellular Ca2+ level on Trypanosoma cruzi differentiation was explored. The addition to epimastigotes of a Triatoma infestans intestinal homogenate, which that triggers off the differentiation to the infective metacyclic form, induced a sudden rise in [Ca2+]i from the basal value, 94 +/- 28 to 584 +/- 43 nmole/liter. This increase was not affected by the presence of EGTA in the medium. Trypsin-treated intestinal homogenate did not alter the [Ca2+]i of epimastigotes. Calmodulin inhibitors (Calmidazolium, Trifluoperazine, and Chlorpromazine) blocked differentiation. Although the calcium ionophore ionomycin increased [Ca2+]i to 342 +/- 29 nmole/liter, it was unable to induce differentiation by itself. BAY K8644 and Methoxyverapamil (agonist and antagonist of Ca2+ channels, respectively) were unable to affect [Ca2+]i by themselves, or when added to stimulated parasites, and did not exert a stimulatory or inhibitory effect on morphogenesis. BAPTA/AM, a Ca2+ chelator, partially blocked the rise in [Ca2+]i and morphogenesis; this effect was reversed by ionomycin. The requirement of intracellular Ca2+ on epimastigote multiplication was also evaluated. The addition of EGTA to the culture medium led to a decrease in epimastigote multiplication till it practically ceased in the sixth passage. When such parasites were transferred to LIT they partially recovered the growth rate. Parasites from passages III, IV, and V in the Ca(2+) depleted medium maintained their basal [Ca2+]i, but when treated with the intestinal homogenate, the rise in [Ca2+]i was abrogated. Accordingly, the differentiation percentages of such parasites dropped significantly compared with controls. PMID- 8682193 TI - Plasmodium falciparum: the small GTPase rab11. PMID- 8682194 TI - A plasmid shuttle vector bearing an rRNA promoter is extrachromosomally maintained in Crithidia fasciculata. PMID- 8682195 TI - Stereochemical constraint in the evolution of pyridoxal-5'-phosphate-dependent enzymes. A hypothesis. AB - In the transamination reactions undergone by pyridoxal-5'-phosphate-dependent enzymes that act on L-amino acids, the C4' atom of the cofactor is without exception protonated from the si side. This invariant absolute stereochemistry of enzymes not all of which are evolutionarily related to each other and the inverse stereochemistry in the case of D-alanine aminotransferase might reflect a stereochemical constraint in the evolution of these enzymes rather than an accidental historical trait passed on from a common ancestor enzyme. Conceivably, the coenzyme and substrate binding sites of primordial pyridoxal-5'-phosphate dependent enzymes had to fulfil the following prerequisites in order to allow their development toward effective catalysts: (i) the negatively charged alpha carboxylate group of the amino acid substrate had to be positioned as far as possible away from the negatively charged phosphate group of the cofactor, and (ii) the C alpha-H bond had to be oriented toward the protein. Compliance with these two criteria implies, under the assumption that C4' is protonated by an acid-base group of the protein, the observed stereochemical feature. PMID- 8682196 TI - The allosteric regulation of pyruvate kinase. AB - Crystallographic and mutagenesis studies have unravelled the general features of the allosteric transition mechanism in pyruvate kinase. The enzyme displays a dramatic conformational change in going from the T- to the R-state. All three domains forming each subunit of the tetrameric enzyme undergo simultaneous and concerted rotations, in such a way that all subunit and domain interfaces are modified. This mechanism is unprecedented since in all tetrameric allosteric enzymes, characterised at atomic resolution, at least one of the domain or subunit interfaces remains unchanged on the T- to R-state transition. The molecular mechanism of allosteric regulation here proposed provides a rationale for the effect of single site mutations observed in the human erythrocyte pyruvate kinase associated with a congenital anaemia. PMID- 8682197 TI - Unusual dehydrations in anaerobic bacteria: considering ketyls (radical anions) as reactive intermediates in enzymatic reactions. AB - Dehydratases have been detected in anaerobic bacteria which use 2-, 4- or 5 hydroxyacyl-CoA as substrates and are involved in the removal of hydrogen atoms from the unactivated beta- or gamma-positions. In addition there are bacterial dehydratases acting on 1,2-diols which are substrates lacking any activating group. These enzymes contain either FAD, or flavins + iron-sulfur clusters or coenzyme B12. It has been proposed that the overall dehydrations are actually reductions followed by oxidations or vice versa mediated by these prosthetic groups. Whereas the gamma-hydrogen of 5-hydroxyvaleryl-CoA is activated by a transient two-election alpha, beta-oxidation, the other substrates are proposed to require either a transient one-electron reduction or an oxidation to a ketyl (radical anion). PMID- 8682198 TI - A structural model for the membrane-integral domain of succinate: quinone oxidoreductases. AB - Many succinate:quinone oxidoreductases in bacteria and mitochondria, i.e. succinate:quinone reductases and fumarate reductases, contain in the membrane anchor a cytochrome b whose structure and function is poorly understood. Based on biochemical data and polypeptide sequence information, we show that the anchors in different organisms are related despite an apparent diversity in polypeptide and heme composition. A general structural model for the membrane-integral domain of the anchors is proposed. It is an antiparallel four-helix bundle with a novel arrangement of hexa-coordinated protoheme IX. The structure can be applied to a larger group of membrane-integral cytochromes of b-type and has evolutionary and functional implications. PMID- 8682199 TI - The Ninth Datta Lecture. Molecular biology of transmissible spongiform encephalopathies. AB - The prion, the transmissible agent that causes spongiform encephalopathies such as scrapie, bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease, is believed to be devoid of nucleic acid and identical with PrPSc, a modified form of the normal host protein PrPC which is encoded by the single copy gene Prnp. The 'protein only' hypothesis proposes that PrPSc, when introduced into a normal host, causes the conversion of PrPC into PrPSc; it therefore predicts that an animal devoid of PrPC should be resistant to prion diseases. We generated homozygous Prnp(olo) ('PrP knockout') mice and showed that, after inoculation with prions, they remained free of scrapie for at least 2 years while wild-type controls all died within 6 months. There was no propagation of prions in the Prnp(olo) animals. Surprisingly, heterozygous Prnp(ol+) mice, which express PrPC at about half the normal level, also showed enhanced resistance to scrapie disease despite high levels of infectious agent and PrPSc in the brain early on. After introduction of murine PrP transgenes Prnp(olo) mice became highly susceptible to mouse but not to hamster prions, while the insertion of Syrian hamster PrP transgenes rendered them susceptible to hamster but to a much lesser extent to mouse prions. These complementation experiments paved the way to the application of reverse genetics. We have prepared animals transgenic for genes encoding PrP with amino terminal deletions of various lengths and have found that PrP lacking 48 amino proximal amino acids, which comprise four of the five octa repeats of PrP, is still biologically active. PMID- 8682200 TI - The Escherichia coli trigger factor. AB - E. coli trigger factor is an abundant cytosolic protein originally identified by its ability to maintain the precursor of a secretory protein in a translocation competent form. Recent studies shed new light on the function of this protein. Trigger factor was found to be a peptidyl-prolyl-cisltrans-isomerase capable of catalysing protein folding in vitro, to associate with nascent cytosolic and secretory polypeptide chains, and to cooperate with the GroEL chaperone in promoting proteolysis of an unstable polypeptide in vivo. These findings suggest roles for trigger factor in various folding processes of secretory as well as cytosolic proteins. PMID- 8682201 TI - Structure and function of PCD/DCoH, an enzyme with regulatory properties. AB - The bifunctional protein PCD/DCoH is both an enzyme involved in the phenylalanine hydroxylation system and a transcription coactivator forming a 2:2 heterotetrameric complex with the nuclear transcription factor HNF1. The discovery of a bacterial homologue and the expression pattern during Xenopus embryogenesis suggest a regulatory function not only restricted to HNF1. The crystal structures of the tetrameric rat and the dimeric bacterial PCD/DCoH have led to the proposal of substrate and HNF1 binding sites. The saddle-shaped beta sheet surfaces of the DCoH dimers likely represent binding sites for as yet unknown macromolecular interaction partners. Possible mechanisms for DCoH-induced transcriptional regulation are discussed in the light of the three-dimensional structures. PMID- 8682202 TI - Iron-sulphur clusters as genetic regulatory switches: the bifunctional iron regulatory protein-1. AB - In the eighties, iron regulatory protein-1 (IRP-1) was identified as a cytoplasmic mRNA-binding protein that regulates vertebrate cell iron metabolism. More recently, IRP-1 was found to represent the functional cytoplasmic homologue of mitochondrial aconitase, a citric acid cycle enzyme. Its two functions are mutually exclusive and depend on the status of an Fe-S cluster: the (cluster less) apoIRP-1 binds to RNA, while the incorporation of a cubane 4Fe-4S cluster is required for enzymatic activity. Cellular signals including iron levels, nitric oxide and oxidative stress can regulate between the two activities posttranslationally and reversibly via the Fe-S cluster. Recent reports suggest that other regulatory proteins may be controlled by similar mechanisms. PMID- 8682203 TI - Green fluorescent protein: applications in cell biology. AB - The green fluorescent protein (GFP) of Aequorea victoria is a unique in vivo reporter for monitoring dynamic processes in cells or organisms. As a fusion tag GFP can be used to localize proteins, to follow their movement or to study the dynamics of the subcellular compartments to which these proteins are targeted. Recent studies where GFP technology has revealed new insights regarding physiological activities of living cells are discussed. PMID- 8682204 TI - Dynamin and receptor-mediated endocytosis. AB - The internalization of receptor-bound ligands involves concentration of cell surface receptors in specialized areas of the plasma membrane and subsequent formation of clathrin-coated vesicles. The complex process of invagination, constriction and budding of clathrin-coated vesicles employs the coordinated actions of several proteins. This review is focused on the GTPase dynamin, which plays a key role in the constriction of coated pits. PMID- 8682205 TI - And still they are moving.... dynamic properties of caveolae. AB - Caveolae are structures found on the surface of many mammalian cells. In the last few years the biogenesis and the function of these organelles have been intensively investigated but many challenging questions remain. One of these is whether caveolae are statically attached to the cytoplasmic surface of the plasma membrane or are moving to other intracellular organelles. Also the cycling of the caveolar coat component, VIP21-caveolin, is a subject of intensive discussion. The solution to these problems could give an insight into the understanding of caveolar function. PMID- 8682206 TI - Endosomal proteolysis of internalized proteins. AB - Endosomal proteases have been implicated in the degradation of internalized regulatory peptides involved in the control of metabolic pathways and in the processing of intracellular antigens for cytolytic immune responses. Processing in the endocytic vesicles is regulated by changes in endosomal acidity due to the presence of an ATP-dependent proton pump which modulates protease activity, protein unfolding and receptor-ligand interactions. A limited number of proteases appear to reside in endosomes which do not contain the full complement of active proteases capable of completely degrading all internalized polypeptides. Retention of some acid hydrolases in endosomes is apparently related to their association with undefined endosomal membrane receptors. The limited number of proteases and the pH gradient from neutral to acidic (pH 7 to 5) within endosomes make possible a selective and controlled processing environment in comparison to lysosomes. The full set of endo- and exopeptidases that break down proteins to amino acids are active later in the pathway in lysosomes. PMID- 8682207 TI - Potential roles of heterotrimeric G proteins of the endomembrane system. AB - Heterotrimeric G proteins are recognized as versatile switches linking cell surface receptors to cellular effectors. Beside their location at the plasma membrane G proteins are found on intracellular membranes. Studies with modulators of G protein activity suggest that G proteins associated with organelle membranes are involved in various steps of secretion and vesicular function. In contrast to hormonal responses involving G proteins little is currently known about possible receptors or activators and effectors interacting with intracellular G proteins. This short review focuses on recent developments elucidating the role of organelle-associated G proteins. PMID- 8682208 TI - Molecular mechanisms in the disassembly and reassembly of the mammalian Golgi apparatus during M-phase. AB - The mitotic disassembly and reassembly of the mammalian Golgi apparatus is an ideal system to study the molecular mechanisms involved in biogenesis and maintenance of membranous organelles. As cells enter M-phase, Golgi stacks are converted into Golgi clusters of small membrane fragments, which are dispersed throughout the cytoplasmic space during metaphase. Disassembly is dependent on the action of cdc2-kinase and at least two distinct pathways contribute to the fragmentation: one involves the budding of COP I-coated vesicles from Golgi cisternae, the other is a less well characterised COP I-independent pathway. During telophase, the Golgi fragments reassemble and fuse into a fully functional Golgi stack, using at least two distinct ATPase-mediated fusion pathways. PMID- 8682210 TI - Protein import into the nucleus. AB - The transport of proteins from the cytoplasm into the nucleus is a multistep process. The nuclear localization sequence (NLS) of a transport substrate associates with the heterodimeric NLS-receptor which binds to a subset of proteins of the nuclear pore complex (NPC). Translocation through the NPC is energy-dependent and requires the small GTPase Ran. Proteins that interact with Ran in either the GDP-bound or the GTP-bound state coordinate transfer through the NPC. Lastly, the NLS-receptor/ substrate complex and Ran reach the nuclear side of the NPC where the complex disassembles. PMID- 8682209 TI - The Saccharomyces cerevisiae kinetochore. AB - Accurate chromosome segregation is dependent on a specialized chromosomal structure, the kinetochore/centromere. The only essential constituent of the S. cerevisiae kinetochore established today is CBF3, a multisubunit complex that binds to S. cerevisiae centromere DNA. Therefore CBF3 and its four components, Cbf3a, Cbf3b, Cbf3c and Cbf3d, will form the centerpiece of this review. In addition, we will describe proteins that are putatively involved in kinetochore function specifically in the context with CBF3 interaction. Furthermore, we discuss the role of the S. cerevisiae kinetochores in a putative cell cycle checkpoint control and in microtubule attachment. PMID- 8682211 TI - Molecular genetic strategies in Toxoplasma gondii: close in on a successful invader. AB - Toxoplasma gondii is an obligate intracellular parasite with an exceptional ability to invade, survive and replicate within nearly all nucleated cells. Upon differentiation into an encysted form (bradyzoites), the parasites escape the host immune defenses and thus persist long enough in man and other hosts to ensure maintenance of transmission. This protozoan parasite has long been known to cause severe congenital infections in humans and animals but has recently gained additional notoriety as an opportunistic pathogen associated with AIDS. Development of a DNA transfection system for T. gondii has provided a new tool for exploring molecular aspects of important processes such as invasion and differentiation. Additional strategies associated with genetic transformation have been devised and elaboration of even more desirable molecular tools is in progress. PMID- 8682212 TI - Sequencing and functional analysis of the genome of Bacillus subtilis strain 168. AB - The international programme to sequence the 4.2 Mb genome of Bacillus subtilis, a model Gram-positive bacterium, is a joint project involving European, Japanese and US research groups. To date ca. 3.0 Mb of the genome has been sequenced, with the remaining 1.2 Mb expected to be completed in 1997. The amenability of B.subtilis to genetic manipulation, combined with the availability of extensive expertise on its biochemistry and physiology, makes this bacterium a valuable organism in which to investigate the properties of genes for which functions cannot be readily ascribed by standard methods. PMID- 8682213 TI - The Sulfolobus solfataricus P2 genome project. AB - Over 800 kbp of the 3-Mbp genome of Sulfolobus solfataricus have been sequenced to date. Our approach is to sequence subclones of mapped cosmids, followed by sequencing directly on cosmid templates with custom primers. Using a prototype automated system for genome-scale analysis, known as MAGPIE, along with other tools, we have discovered one open reading frame of at least 100 amino acids per kbp of sequence, and have been able to associate 50% of these with known genes through database searches. An examination of completely sequenced cosmids suggests a clustering of genes by function in the S. solfataricus genome. PMID- 8682214 TI - Genomic simple repetitive DNAs are targets for differential binding of nuclear proteins. AB - The biological meaning of abundant simple repetitive DNA sequences in eukaryote genomes is obscure. Therefore, (GAA)n, (GT)n, and composite (GT)n(GA)m, blocks were characterized for protein binding in the repeat and flanking sequences of cloned genomic DNA fragments. In gel mobility shift and competition assays the binding of nuclear proteins to the repeats was specific (including some flanking single copy sequences). DNase footprinting revealed the target sequences within and adjacent to the repeats. Chemical modifications (OsO4, DEPC) demonstrated non B DNA structures in the polypurine blocks. The binding of nuclear proteins in and around simple repeat sequences refute biological insignificance of all of these ubiquitously interspersed elements. PMID- 8682215 TI - Genomes with distinct function composition. AB - The functional composition of organisms can be analysed for the first time with the appearance of complete or sizeable parts of various genomes. We have reduced the problem of protein function classification to a simple scheme with three classes of protein function: energy-, information- and communication-associated proteins. Finer classification schemes can be easily mapped to the above three classes. To deal with the vast amount of information, a system for automatic function classification using database annotations has been developed. The system is able to classify correctly about 80% of the query sequences with annotations. Using this system, we can analyse samples from the genomes of the most represented species in sequence databases and compare their genomic composition. The similarities and differences for different taxonomic groups are strikingly intuitive. Viruses have the highest proportion of proteins involved in the control and expression of genetic information. Bacteria have the highest proportion of their genes dedicated to the production of proteins associated with small molecule transformations and transport. Animals have a very large proportion of proteins associated with intra- and intercellular communication and other regulatory processes. In general, the proportion of communication-related proteins increases during evolution, indicating trends that led to the emergence of the eukaryotic cell and later the transition from unicellular to multicellular organisms. PMID- 8682216 TI - My experience with 33 patients infected with HIV. PMID- 8682217 TI - Radiology at the centennial: Roentgen's ray proves durable. PMID- 8682218 TI - Plaintiffs are patients too. PMID- 8682219 TI - Why is health care reform faltering? Delaware's experience. AB - Many managed care plans propose short-term economics, without stressing quality, assuring universal access, supporting research, or caring for the poor. None provide much in the way of preventive services. In the absence of any major national changes to assure universal access to health services, local health care providers and state regulatory agencies need to be freed from many restrictive federal laws and regulations. Relief is needed from well-intended federal controls which have usually made the health care system more expensive 1) by applying federal anti-trust regulations to prevent physicians from self regulation and working to improve the health care system, 2) by making it difficult for physicians to do office laboratory work for their patients' convenience, 3) by making "safe" drugs expensive because of FDA regulations, 4) by sequentially spawning PRO, PSRO, and now the Health Care Quality Improvement Program (HCQIP) to "assure quality control" (they probably have not paid for themselves), 5) by not using the RBRVS system (accepted by HCFA as a way to relate a physician's fees to the resources required to perform a service) to stimulate physicians to enter primary care practice, 6) by giving tax breaks for insurance costs to big corporations but not to small businesses, and 7) by protecting self-insured businesses from state regulations. States should be allowed to obtain waivers from ERISA (which incidentally would improve competition) so states could regulate health insurers, try such proposals as a single payer system, or at least restore community rating and equity. This should improve access to technological advances in prevention and health care for all. More commissions and studies and federal laws are not the answer. Health care providers should be able to work together freely to deliver efficient, cost effective health care. States should be able to assure preventive services, clinical research, public health support, professional education and care for the poor. PMID- 8682220 TI - Meetings of the American Society for Biochemistry and Molecular Biology, American Society for Investigative Pathology, the American Association of Immunologists. New Orleans, Louisiana, June 2-6, 1996. Abstracts. PMID- 8682221 TI - [Safety and tolerability of beta-blockers in severe cardiac decompensation from dilated cardiomyopathy]. AB - BACKGROUND: Several reports from controlled and uncontrolled studies, mainly in the setting of heart failure due to dilated cardiomyopathy (DCM), indicate that chronic betablockade may improve hemodynamics and clinical function. There are few reports on the effects of betablockers in patients with severe heart failure. METHODS: Thirty-five patients (27 M; 8 F; mean age 44.3 +/- 16.7 years; range 14 66 years) with DCM, advanced functional (NYHA III-IV) and severe left ventricular dysfunction (LVEF < or = 25%) underwent a test dosage with metoprolol (5 mg b.i.d.). Five patients (14%) did not tolerate the drug; 30 were chronically treated with metoprolol (mean dosage 127 +/- mg/die). No differences in baseline characteristics were observed between tolerant and not tolerant patients, except for the E-deceleration time (103 +/- 42 ms vs 84 +/- 17 ms; p<0.05). Seven alive patients did not reach a minimum follow up of 18 months. Nineteen patients (54.3%) had a follow up of at least 18 months. They were classified as ?improved? (11 pts; and ?not improved? (8 pts; 42%) on the basis of a score, which included left ventricular ejection fraction (> or = 0.10), left ventricular end diastolic diameter (> or = 10%), regression of restrictive filling pattern, NYHA functional class (> or = 1), cardio-thoracic ratio (> or = 10%) and exercise time (> or = 2 min). No differences were observed at baseline between ?improved? and ?not improved? patients, with exception for a history of slight hypertension (p<0.01), congestive heart failure score (p<0.04) and right ventricular function (p<0.05). RESULTS: An overall improvement of all the main clinical-instrumental parameters were observed in the 19 long term treated patients. At the end of follow up 16 long term treated patients were in NYHA class > or = 2 and in 9 LVEF was > or = 40%. During follow up, among the 30 patients who tolerated the drug, 1 pt died suddenly after 12 months of betablocker therapy and 5 pts were transplanted. No major events occurred among ?improved? patients, after 24 +/- 6 months of follow up. The actuarial survival curve of our study population shows that survival at 1, 2, 3 and 4 years was respectively 87%, 75%, 67% and 66%. These results confirm previous trials evidence that a progressively increasing dose of beta-blockers confers functional benefit in DCM with severe heart failure. PMID- 8682222 TI - [Primary coronary angioplasty for acute myocardial infarction associated with severe left ventricular dysfunction. Results in 50 patients]. AB - BACKGROUND: Considerable controversy exists about the therapeutic value of primary coronary angioplasty for acute myocardial infarction. The available data suggest that primary angioplasty may improve the outcome in patients with cardiogenic shock, while some clinical studies have found no benefit in routine angioplasty in patients with acute myocardial infarction that were considered at high risk because of severe left ventricular dysfunction associated with myocardial infarction. METHODS AND RESULTS: During a 16-month period, 50 patients with acute myocardial infarction and severe left ventricular dysfunction underwent primary coronary angioplasty. Patients were enrolled if angiographic left ventricular ejection fraction was > or = 40% and symptom duration <6 hours, or >6 hours if there was evidence of ongoing ischemia. Optimal angiographic success (<30% stenosis associated with TIMI grade 3 flow) was achieved in 45 patients (90%), and a suboptimal result (>30% and <50% stenosis associated with TIMI grade 3 flow, or <30% stenosis associated with TIMI grade 2 flow) was achieved in 3 patients (6%), while in 2 patients angioplasty failed to reopen the infarct related vessel or was associated with a refractory no-reflow phenomenon. In 5 patients an optimal angiographic result was achieved after coronary stenting. Emergency repeated coronary angioplasty was required in 1 patient with reocclusion of a stented vessel, and after unsuccessful repeated coronary angioplasty, the patient underwent bypass surgery on a semi-elective basis. In 6 patients with multivessel disease, after successful primary angioplasty of the infarct-related vessel, a more complete revasculariziation was achieved with a second coronary angioplasty or bypass surgery before discharge. The in-hospital mortality rate was 6%. The follow-up of 47 patients surviving initial hospitalization was 171 +/- 163 days. There were 2 deaths (4%), both due to congestive heart failure, and 1 nonfatal reinfarction. Two patients (4%), were readmitted to the hospital for recurrent ischemia and both underwent successful repeated coronary angioplasty for restenosis. CONCLUSIONS: The results of this study suggest that in patients with acute myocardial infarction associated with severe left ventricular dysfunction, primary coronary angioplasty may be considered a first choice treatment because of high reperfusion rate, relative low in-hospital mortality and few recurrent myocardial ischemic events. PMID- 8682223 TI - [Acute myocardial infarction in young age and drug dependence. Review of the literature and personal experience]. AB - The authors' personal experience in drug abuse-related acute myocardial infarction (AMI) is reported. STUDY POPULATION: Between January 1991 and May 1994, 6 drug-addict (5 occasional) male patients (pts.) aged 37 +/-3 yrs (Group A) were admitted to our CCU for AMI. Just before hospital admission 4 pts. had inhaled cocaine and 1 had assumed ?ecstasy? tablets; one patient had been heroine dependent for 5 years and was in an attack of abstinence. The clinical features were compared to those of 17 not drug-addict pts. (Group B) aged <45 years (15 males). DEMOGRAPHIC DATA: In Group A 3/6 pts. were graduated (vs 29.4% in Group B pts.), and nobody belonged to the working class (vs 29.4%); 5/6 pts. (83.3%) were admitted during the week-end (vs 29.4%, p<0.03) and presented a longer time delay between symptoms' onset and hospital admission (7.1 +/- 6.9 hrs in Group A pts. vs 4.7 +/- 4.2 hrs. in Group B pts.). RISK FACTORS: All Group A pts. were smokers (37 +/- 12 cigarettes/day vs 21 +/- 14, p<0.02); 4/6 were heavy alcohol drinkers (vs 29.4%); 1/6 had a family history of ischemic heart disease (vs 35%); nobody was hypertensive(vs 29.4%) or diabetic (vs 5.8%). CLINICAL AND INSTRUMENTAL FINDINGS: On admission, Group A pts. (83.3%) were in Killip class I (vs 82.3%) infarct location was anterior in 3/6 pts. (vs 47%); all pts. were given thrombolitic agents. No significant coronary artery stenosis was found in 3/5 (60%) Group A pts. (vs 23.5% in Group B pts.), where 1 had one-vessel disease (vs 64%%) and 1 had two-vessel disease (vs 11.8%). Ejection fraction was similar in the two groups. No death was observed during follow-up (mean 14.4 +/- 9.6 months, range 3-39 months), 1 patient (Group A) had post AMI angina and reinfarction during coronary angioplasty and 2 pts. continued drug abuse. CONCLUSIONS: AMI in drug addict subjects has to be taken into consideration in particular when the patient is young, male, alcohol consumer, heavy cigarette smoker, and is admitted during the week-end. Further study are warranted to better define therapeutic guidelines. PMID- 8682224 TI - [Evaluation of cardiorespiratory function in children and adolescents with repaired tetralogy of Fallot]. AB - METHODS: To evaluate the cardiopulmonary exercise response of children and youngs operated upon for Tetralogy of Fallot (ToF) and to establish possible relationship with clinical and echocardiographic parameters we studied 24 pts, 14 males and 10 females, aged 14.5 +/- years; the age at repair was 5.2 +/- years and follow-up after correction was 8.6 +/- 3.2 years. All the pts were in NYHA functional class I; 8 pts had residual hemodynamic sequelae and 3 pts were on oral treatment. Cardiopulmonary exercise response with bicycle ergometer and incremental workload (25 watts/2 minutes), respiratory gas measurement with peak oxygen consumption (peak VO2) and ventilatory anaerobic threshold (VAT), were investigated in each patient. The data obtained were compared with those of control group of 103 healthy children and adolescents (59 males, 44 females, age 12.9 +/- 2.4 years) to the purpose of statistical analysis. RESULTS: The series of operated ToF pts showed 15-20% reduction in cardio-respiratory parameters, compared to healthy controls. a) Pts operated after the age of 5 years showed a significant reduction in peak VO2 compared to those operated at an earlier age (21 +/- 3.4 vs 35.4 +/- 7.5, p = 0.001) with; b) inverse correlation between peak VO2 and age at operation (r = -0.5, p = 0.01); c) 8 pts with residual hemodynamic sequelae (pulmonary regurgitation and/or ventricular outflow obstruction) showed the worse cardio-pulmonary capacity (peak VO2 27.5 +/- 7 vs 36.1 +/-8.1, p<0.02; VAT 20.4 +/- 5.2 vs 29.5 +/- 4.4, p<0.02; d) a chronotropic limitation was also observed in the group of pts when compared to healthy controls (peak HR 177 +/- 17 vs 188 +/- 11, p<0.001). CONCLUSION: Our study on pts operated upon for ToF showed a significant relation between age at surgery, hemodynamic sequelae and cardiopulmonary exercise response. Since this study has considered pts repaired in the two past decades, we believe that the present approach to ToF with early correction through atriotomy if possible and small outflow patch, may further improve the exercise capacity at a long-term follow-up. PMID- 8682225 TI - [Early and late anthracycline-induced cardiotoxicity in childhood: non-invasive evaluation of contractility in 116 patients]. AB - In order to evaluate the incidence and the characteristics of anthracycline induced cardiotoxicity we studied 116 children treated with anthracyclines with echocardiography, by using load dependent and independent indexes of contractility (respectively: 1-shortening fraction of the left ventricle (D%), velocity of circumpherential shortening (VCF), telesystolic wall stress (Ses) and 2-the regression curves between D% and Ses VCF and Ses). Eighty-six were off therapy, and 30 were evaluated during induction and reinduction. Off therapy patients had a D% lower than that of controls (37.5 +/- 5.7 vs 41.3 +/- 5.0, p<0.001), but it was clearly depressed only in 8% of them. VCF was also lower than in controls (1.7% +/- 0.5 vs 2.0 +/- 0.6, p<0.001), but in no patient it was clearly depressed. Ses was higher than in controls (63.8 +/- 20.6 vs 44.5 +/- 10.5, p<0.001) and elevated in 47% of them; it was positively related to the dose of anthracyclines administered (r = 0.25, p<0.05). The regression curves between D% and Ses and VCF and Ses showed a depressed contractility in off therapy patients. Dilated cardiomyopathy was present only in 1 of them (1.16%) and regional hypokinesia in 3 (3.5%). Children studied during the acute phase had normal D%, VCF, Ses and regional wall motion during the all period of study. These results indicate that 1) anthracycline-induced cardiotoxicity in childhood is mostly a late event, 2) a long term follow-up of these patients is necessary, 3) the use of Ses and of load independent indexes, more than that of D% and VCF, is mandatory to detect the cardiac damage. PMID- 8682226 TI - [Cardiologic application of a clinical database with graphic extension and its utilization in inter-hospital teleconsultation]. AB - A local area network of personal computers has been operative in our Cardiology Department for seven years, to collect and retrieve on-line character-based data. At present, the network is based on 2 servers and 21 workstations. DBF and DOS files are used by a Clipper 5.2d compiled program to handle demographic data, clinical reports (32,000/year) and diagnostic codes of more than 52,000 patients. In the last two years, we started entring ECG tracings using: RS232 connection, floppy disk transfer, and modem connection with commercially available machines as well as by image scanner. We integrated our clinical database with three dedicated subsystems, written in Assembly and C languages, to manage drawings, digital ECGs and complete reports. Mass storage is provided by a 10 Gbyte magneto optical disk autochanger physically connected to a dedicated server running an original software manager to optimize routine access to the optical disks. Interhospital network connections were established with two different institutions to allow clinical information sharing, long distance consultation and ECG transfer. The system has been found to be fast, user-friendly and suitable for daily operation of a large cardiological database. Standardized versions of the system are running in seven other cardiology institutions in Italy. PMID- 8682227 TI - [Potential risks of the Valsalva maneuver during reciprocating tachycardia in patients with WPW: a case report]. AB - A 42-year-old man with cardiac preexcitation syndrome due to a left postero septal anomalous pathway, showed an atrio-ventricular reciprocating tachycardia. During a Valsalva manouvre the arrhythmia changed into atrial fibrillation with ventricular rate and consequent hemodynamic worsening. The authors discuss the possible untoward effect of this manouvre in patients with anomalous a-v conduction pathways. They suggest that Valsalva manouvre should not be used outside of the hospital in patients with accessory pathways defined ?at risk? on the basis of the electrophysiologic study. PMID- 8682228 TI - [Left atrial myxoma evidenced by silent acute myocardial infarction]. AB - A 64-year-old female patient was in-hospital admitted due to a traumatic femoral fracture. A routinely performed ECG showed signs of anterior acute myocardial infarction, clinically silent, and pathological levels of myocardial serum enzyme were recorded. The echocardiographic-Doppler examination confirmed the LV dyssynergy of contraction and, unexpectedly, revealed a large peduncolated and mobile mass in left atrium, connected to the interatrial septum and prolapsing in left ventricle, referable to myxoma. In the clinical history of the patient, a previous cerebral transitory ischemic attack was present (probably due to myxomatous embolization), but no any other cardiovascular symptoms. The patient successfully underwent coronary angiography, which showed no coronary artery disease, and cardiac surgery for tumoral removal. On the basis of clinical and instrumental data, also acute myocardial infarction may be considered a very likely consequence of a intracoronary embolus. Systemic embolization from left atrial myxomas are frequent; however, the involvement of coronary tree, with clinical manifestations and diagnosis during life, is extremely rare. Complete lack of symptoms due to atrial myxoma and myocardial infarction, and the fortuitous diagnosis of both diseases are peculiar findings of the reported case. Many systemic embolizations from myxomas, although sources of tissue damages, may likely occur without symptoms and may be unrecognized during acute period. PMID- 8682229 TI - [Myocardial hypertrophy and arterial hypertension]. AB - Myocardial hypertrophy in different cardiac diseases is considered to be an adaptive mechanism to the increase of hemodynamic load which might restore to normal radius/wall thickness ratio and consequently to normalize wall stress. However, it has been widely demonstrated that beside the hemodynamic load, other factors contribute to the development of myocardial hypertrophy. It has been shown that in hypertensive patients, functional abnormalities (increased contribution of atrial systole to total diastolic filling, increased isovolumic relaxation period, prolonged diastolic duration, slowed ventricular filling and altered diastolic distensibility) precede the development of myocardial hypertrophy. Thus, in hypertensive patients, sign and symptoms of heart failure could be manifested in absence of myocardial hypertrophy, and might be exclusively due to diastolic dysfunction (with normal systolic function). Systolic function might be involved and compromised late when focal myocardial cell death and fibrosis occur and consequently ?adequate? hypertrophy is shifted to ?inadequate?. This evolution is accompanied by morphological and functional changes of the myocardium similar to those encountered in dilated cardiomyopathy. Impairment of systolic function in ?inadequate? hypertrophy is also due to structural changes; altered ratio between sarcomers and mitochondria, increased intercapillary distance, sarcoplasmatic reticulum dysfunction, increase of collagene component with a consequent increment of wall rigidity, hypertrophy of arterial tunica media, which alters coronary flow and coronary reserve. The progression of these morpho-functional abnormalities is a very slow process, in which adaptive mechanism mediated by several enzymes and contractile protein, contribute to maintain myocardial viability. However, over the long course, disseminated focal myocardial cell necrosis and fibrosis, which is an evolving process, is considered to be the main responsible factor for the irreversible myocardial damage and systolic dysfunction in advanced myocardial inadequate hypertrophy. PMID- 8682230 TI - [How to read a scientific article? 5. How to choose a treatment?]. PMID- 8682231 TI - [Left coronary aneurysm]. PMID- 8682232 TI - [Rubric of good and not-so-good drugs. Old medications: dihydroergotoxin]. PMID- 8682233 TI - [Percutaneous closure of congenital and iatrogenic coronary arterial fistulas]. AB - Coronary arteriovenous fistulas (CAF) are the most common hemodinamically significant congenital coronary anomalies. Surgery has been the only therapeutic option for ages. We describe three cases of percutaneous occlusion of CAF, congenital and iatrogenic, that we treated with different devices, to fit their different anatomic and functional characteristics. Case 1). Male patient (pt) 20 years old, asymptomatic, affected with CAF between the right coronary artery and the right ventricle, with aneurysmatic vessel dilatation and occlusion of the posterolateral branches. CAF has been occluded with a detachable, valvulated latex balloon, wedged into the proximal neck of the aneurysm. Case 2). Female pt 63 years old, who was symptomatic for exertion angina, affected with multiple CAF which originated from proximal and distal circumflex artery, proximal left anterior descending artery (LAD), all of which flowed into the left inferior lobar pulmonary artery. The fistulas have been occluded with steel and tungsten coils. Case 3). Male pt 62 years old, who underwent orthotopic cardiac transplantation in 1990 for dilated cardiomyopathy. Coronary angiogram at one year was normal, but subsequently a multilocular CAF between LAD in the middle portion and the right ventricle became evident. During angiographic follow-up an increase of the size of the fistula was observed, together with a reduction of that of distal LAD. For this reason a percutaneous occlusion with multiple tungsten coil has been performed. The three procedures have had a favorable outcome and we did not observe any acute or late complications; clinical and angiographic follow-up confirmed this satisfactory results at six months. Based on the data of the literature and on this experience, we conclude that percutaneous occlusion is the first line therapy of CAF and that the different devices can be tailored to meet different anatomic and functional characteristics. PMID- 8682234 TI - [Use of high doses of atropine during dipyridamole echocardiography: safety and efficacy of the combined test]. AB - BACKGROUND: Recent reports demonstrated an increased accuracy of dipyridamole echocardiography test with the intravenous infusion of 0.25 to 1 mg of atropine in 1-4 consecutive administrations at the end of the test. The effect of higher doses of atropine during dipyridamole echocardiography, potentially able to further increase heart rate and myocardial oxygen consumption, has not been evaluated. The aim of the study was to evaluate the effect of high doses of atropine during dipyridamole echocardiography and to investigate the possible pharmacological interference between dipyridamole and atropine. METHODS: One hundred consecutive patients (M = 81, F = 19; mean age 58 yrs) without inducible wall motion abnormalities at 14th minute of a high-dose (0.84 mg/Kg in 10') dipyridamole echocardiography test were studied. Seventy-five patients referred to the test in pharmacological wash-out were randomly divided in three groups: 25 patients (Group 1) received 10 mcg/Kg of atropine in 60"; 25 patients (Group 2) received 15 mcg/Kg of atropine in 120"; 25 patients (Group 3) received 20 mcg/Kg of atropine in 120"; moreover, 25 patients with a full-dose oral beta-blocker therapy (Group 4) received 20 mcg/Kg of atropine in 120". Atropine was infused during the 15th and 16th minute of the test. Heart rate (HR) changes and new wall motion abnormalities induced by atropine were considered and compared for each Group. In 60 patients (15 randomly selected from each Group) the effect on mean HR and R-R interval (msec) of the same dose of atropine infused during dipyridamole echocardiography was evaluated in resting conditions 24 hours apart. RESULTS: The dipyridamole-atropine test was well tolerated and accomplished in all patients. HR increased significantly in all Groups of patients in comparison with pre-atropine HR values (Group 1: +14 +/- 8 b/m', p < 0.0001; Group 2: +19 +/ 8 b/m', p < 0.0001; Group 3: +22 +/- 9 b/m', p < 0.0001; Group 4: +19 +/- 8 b/m', p < 0.0001; Groups 2, 4 vs Group 1: p = 0.03, Group 3 vs Group 1: p = 0.002). No patients in Group 1 (0%), 3 patients in Groups 2 and 3 (12%), and 5 patients in Group 4 (20%) showed new wall motion abnormalities after atropine infusion (Group 4 vs Group 1: p = 0.06). Effects of atropine on HR and mean R-R interval were significantly more pronounced in resting conditions than during dipyridamole test (HR: +25 +/- 11 vs +18 +/- 9 b/m', p < 0.001; R-R: -256 +/- 122 vs -127 +/- 68 msec, p < 0.0001). CONCLUSIONS: High doses of atropine during dipyridamole echocardiography test are safe and more effective for induction of new wall motion abnormalities than usual doses, particularly in patients tacking beta-blockers. The likelihood of an antagonistic mechanism between atropine and endogenous, dipyridamole-induced adenosine on sinus node is supported from our results. PMID- 8682235 TI - [Elective electric cardioversion of atrial fibrillation in adults with underlying heart disease: a proposal of optimizing the procedure]. AB - BACKGROUND: Synchronized direct current cardioversion (DC) is widely used for atrial fibrillation (AF) conversion to sinus rhythm. With the purpose to identificate the optimal procedure for the effective DC of AF, we compared the results obtained following traditional free-multiple shock sequence to simple two shock sequence in two groups of adults with underlying heart disease submitted to elective DC for AF in our Dept. of Cardiology. METHODS: The first group, retrospectively considered, included 84 episodes of AF occurred in 79 patients. DC started on an energy level of 100 joules (J) and, when unsuccessful, repeated on increasing levels, from 150J to 360J, depending on physician preference. An additional shock of 360J was always delivered when the last shock-dose proved to be ineffective. The second group, prospectively considered, included 61 episodes of AF occurred in 61 patients. The protocol provided for an initial shock of 200J followed, when necessary, by a second one of 360J and no additional shocks. RESULTS: Conversion rate (86.9% vs. 85.2%) showed no statistical difference (p = NS) between groups. Following the two-shock protocol, a significant reduction of the mean amount of energy used for effective conversion (258.5J vs. 345.0J; p < 0.001), of the mean amount of total energy delivered to patients (302.9J vs. 439.6J; p < 0.001), particularly to non responders (560.0J vs. 1067.2J; p < 0.0001) was found. Using the first procedure only 13.1% of patients were cardioverted delivering 100J and 35.8% of them needed additional 200J. In the second group, the initial shock of 200J cardioverted 54.1% of patients. In both studies no patients had adverse effects either during or early after DC or during the four-week follow-up, where haemorrhagic and thromboembolic complications has been also considered. CONCLUSIONS: Two-shock protocol seems to provide better success/total energy delivered ratio, to reduce the total amount of energy delivered to each patient and to shorten the DC procedure when compared to free multiple shock sequence usually performed, reducing the total time of anesthesia. PMID- 8682236 TI - [Presence of patent foramen ovale in different heart diseases: incidence in 211 consecutive patients studied by transesophageal echocardiography]. AB - BACKGROUND: Contrast echocardiography during the decompression phase of the Valsalva manoeuvre in course of transesophageal echo study is the ideal method to identify patent foramen ovale. METHODS: In order to evaluate the incidence of patent foramen ovale in patients with different cardiac diseases we performed contrast injection in 211 consecutive pts submitted to TEE (Transesophageal Echocardiography) in our laboratory between march 1991 and march 1993. RESULTS: Fiftythree of 211 pts (25%) presented a patent foramen ovale. The incidence in the different cardiac diseases was as follows: 0% in rheumatic mitral disease, 23% in aortic valve disease, 17% in mitral and/or aortic valve prosthesis, 29% in congenital heart disease other than interatrial septal defect, 44% in mitral valve prolapse and 92% in atrial septal aneurysm. CONCLUSIONS: This study indicates that patent foramen ovale is a common finding in different cardiac pathologies and frequent in mitral valve prolapse and even more in atrial septal aneurysm. In case of peripheral embolism of likely cardiac origin, the patency of the foramen ovale must be recognized, especially when these two latter cardiac anomalies are identified. PMID- 8682237 TI - Remnant of the common pulmonary vein: usefulness of magnetic resonance imaging in improving diagnosis. A case report in a child. AB - Abnormal incorporation of the common pulmonary vein can result in a fibromuscular partition of the left atrium, often appearing as an elongated mass on transthoracic echocardiographic examination. Differentiation from an atrial thrombus or tumour may sometimes be difficult. We report a case of a young patient with a left atrial mass detected by ultrasound study and correctly diagnosed by magnetic resonance imaging as remnant of the common pulmonary vein. PMID- 8682238 TI - [Acute anterior myocardial infarction in a patient with left atrial myxoma during pregnancy]. AB - It is a case report of a patient who had an acute anterior myocardial infarction during the 22th week of pregnancy, probably due to coronary embolization from a large left atrial myxoma. The patient had a previous operation for a right adrenal adenoma causing a Cushing Syndrome. It is hypotized an association between adrenal adenoma and atrial myxoma, like "Carney Syndrome". PMID- 8682239 TI - [Magnesium sulfate in acute myocardial infarction]. AB - Magnesium sulphate has antiarrhythmic and antithrombotic properties, a coronary and systemic vasodilating action, a direct myocardial protective effect in experimental and clinical models of ischemia-reperfusion injury. Two meta analyses have pooled the results of several small studies that had analyzed the effect of controlled hypermagnesiemia in acute myocardial infarction before the advent of thrombolytic and antithrombotic therapies. The results have shown a more than 50% mortality reduction, with a minimum estimated benefit of about 30%, and a reduction in ventricular arrhythmias of about 50%. In LIMIT-2, a double blind trial of 2,316 patients where magnesium was administered as a 8 mMol bolus followed by a 24-hour infusion of 65 mMol, a 24% reduction in mortality was observed. However, these data have not been confirmed in the more than 58,000 patients of the ISIS-4 trial. In this study magnesium, at the same dose of the LIMIT trial, did not reduce 5-week mortality, neither in the general population (7.64% versus 7.24% in control patients, p = n.s.) nor in specific subgroups. The results of ISIS-4 have excluded the routine use of magnesium sulphate in acute myocardial infarction in the era of fibrinolysis and aspirin, beta-blockers and ACE-inhibitors. Nevertheless, magnesium administration could still be considered in certain clinical situations, such as 1) the presence of contraindications to fibrinolysis and aspirin, 2) the treatment of ventricular tachyarrhythmias unresponsive (or as an alternative) to lidocaine, 3) severe hypertension when beta-blockers are not indicated. PMID- 8682240 TI - [Heart failure: causes and therapy of unstableness]. PMID- 8682241 TI - [Rescue angioplasty: when?]. PMID- 8682242 TI - [Therapy of arrhythmias in hypertrophic cardiomyopathy]. PMID- 8682243 TI - [Intraoperative echocardiography. Heart diseases in adults]. PMID- 8682244 TI - [Intraoperative transesophageal echocardiography in pediatric cardiology]. PMID- 8682245 TI - [Hyperlipemia in children]. PMID- 8682246 TI - [Cardiological evaluation in the preparation for vascular surgery]. PMID- 8682247 TI - [Genetics of dilated cardiomyopathies]. PMID- 8682249 TI - [Arrhythmogenic dysplasia of the right ventricle: diagnostic problems]. PMID- 8682248 TI - [Vascular remodeling]. PMID- 8682250 TI - [Treatment of heart failure in children]. PMID- 8682251 TI - [The stent in the treatment of acute coronary occlusion after angioplasty]. PMID- 8682252 TI - [Indications for and choice of coronary stents]. PMID- 8682253 TI - [Endomyocardial biopsy in pediatric cardiovascular pathology]. PMID- 8682254 TI - [Echocardiographic and Doppler markers of heart valve prosthesis dysfunction]. PMID- 8682255 TI - [Alert! What future for cardiology?]. PMID- 8682256 TI - [Prognostic significance of normal exertion myocardial scintigraphy in asymptomatic subjects with abnormal ergometric test]. AB - AIM OF THE STUDY: ST-segment depression on exercise stress test (EST) is an independent predictor of future cardiac events. Nevertheless, in apparently healthy subjects without angina the occurrence of false positive results is frequent. Thallium myocardial imaging (TMI) may improve diagnostic and prognostic accuracy of EST. The aim of the present study was to assess the role of a normal exercise TMI for excluding a coronary artery disease in subjects with asymptomatic abnormal EST. METHODS: Subjects referred for TMI from 1/1980 to 5/1991 with an abnormal EST and without history of ischemic, congenital, or valvular heart disease or abnormal resting ECG were included into the study. 137 subjects (98 men, 39 women), mean age 53 +/- 8 yrs (range 37-74 yrs) were enrolled and followed-up for 6.4 yrs (range 3-13 yrs). Clinical indications for EST were: atypical chest pain in 56 (41%) cases, check-up in 52 (38%) cases, sport activity in 29 (19%) cases. All subjects had a maximal symptom-limited EST. Abnormal EST was defined by a horizontal or downsloping > or = 1 mm or upsloping > or = 1.5 mm ST-segment depression at 0.08 sec. from J-point, in at least 2 leads. EST was discontinued for fatigue in 129 (94%) cases, for ST-segment depression > or = 3 mm in 8 (6%) cases. None had chest pain during EST. All subjects selected for the study had normal TMI. Criteria for normal TMI were homogeneous Thallium uptake on postexercise images and a normal washout in the delayed images by qualitative analysis. Planar images were obtained in 118 (86%) cases, and tomographic SPECT images in 19 (14%). RESULTS: During the follow-up period no subject died for cardiac causes and only 9 subjects (1%/yr) had non fatal cardiac events: 4 (0.45%/yr) had a non fatal myocardial infarction (one subject had coronary angiography for postinfarction angina and subsequent 3 coronary bypass graft for multivessels disease), 2 subjects (0.2%/yr) became symptomatic for unstable angina (both had coronary angiography and subsequent PTCA for critical left main coronary artery stenosis) and 3 (0.34%/yr) developed stable angina (one had coronary angiography and subsequent bypass graft for a critical stenosis of left main coronary artery). Four further subjects died for non cardiac events. Comparing clinical data and TE results of subjects with and without coronary events, we found that some parameters were related to a higher incidence of cardiac events: hypertension (78% vs 31% respectively in subjects with and without cardiac events, p < 0.01), hypercholesterolemia (33% vs 4.7%, p < 0.01); > or = 2 conventional coronary risk factors (56% vs 17%, p < 0.02); and a slow regression of abnormal ST-segment depression during recovery (2.8 +/- 2 vs 1.5 +/- 1 min, p < 0.01). CONCLUSIONS: In conclusion, in subjects without typical chest pain and with abnormal asymptomatic EST, a normal exercise TMI identifies subjects with very low risk of future cardiac events (1%/yr). Our data suggest that subjects with abnormal asymptomatic EST should be routinely submitted to exercise TMI. PMID- 8682257 TI - [Transcatheter radiofrequency ablation in supraventricular tachycardia in children: immediate results and mid-term follow-up]. AB - OBJECTIVES: The purpose of this study was to evaluate the efficacy and safety of radiofrequency ablation of supraventricular tachycardias due to a reentry circuit in a group of closely followed-up pediatric patients. PATIENTS: Forty-six pediatric patients (mean age 12.6 years, range 3-18) underwent a total of 48 radiofrequency ablation procedures for reciprocating supraventricular tachycardia. Thirty-nine had an orthodromic reentry tachycardia, 6 an atrioventricular node reentry tachycardia and 1 a permanent junctional reciprocating tachycardia. METHODS: To ablate the overt accessory pathways, the Kent potential (K) was identified and then the shortest A-K, and delta wave-K intervals were measured. The shortest V-A interval was identified for those concealed. For the left-sided accessory pathways, we used the retrograde transaortic approach in 10 procedures and the transseptal approach in 18. Atrioventricular node reentry tachycardia was ablated at the site where the slow pathway electrogram was recorded. Follow-up clinical data, electrocardiogram, 24 hours Holter monitoring and transesophageal atrial stimulation were obtained and evaluated. RESULTS: Early: We performed a total of 48 procedures. Among 41 procedures performed in the 39 patients with accessory pathway, 38 were successful (92,6%). Mean fluoroscopy time was 31 +/- 18 min. For left sided accessory pathways, mean fluoroscopy time of procedures with retrograde approach was 45 +/- 10 min and with transseptal 23 +/- 12 min (p < 0.01). Ablation of slow pathway in patients with intranodal reentry tachycardia was successful in 3/6 cases (50%). The patient with permanent junctional reciprocating tachycardia was successfully ablated. Late: All patients are alive and none was lost during the follow-up after a mean time of 12.9 months (range 5-33). Success at last follow up was 100% in patients with an accessory pathway and 33% in patients with atrioventricular node reentry. In patient with permanent junctional reciprocating tachycardia, the arrhythmia appeared again one month after the procedure, thus a second successful attempt was performed. COMPLICATIONS: Major complications (6,5%) including a right femoral vein thrombosis (one patient), an hematoma without pulse loss (one patient) and a non-sustained monomorphic ventricular tachycardia (one patient). CONCLUSIONS: Our data show high efficacy of radiofrequency ablation in pediatric patients with accessory pathways. The risks are low at follow-up evaluation, but might be helpful a longer-term follow-up in order to evaluate the risk of a long fluoroscopy time and the arrhythmogenic effect of the scar. PMID- 8682258 TI - [Quantitative evaluation of the dynamics of the coronary wall in man: description of a new method based on tridimensional time-dependent reconstruction of intravascular ultrasonographic images]. AB - BACKGROUND: Intravascular ultrasound imaging provides information on vascular lumen and arterial wall structure and it has potential application in arterial wall dynamic study. The aim of this study was to develop a computer assisted system for analysing digitised cross sectional ultrasound images of coronaries to easily display and quantify coronary dynamic and its relationship with arterial wall morphology. METHODS AND RESULTS: To extract the anatomical regions of interest from the digitised sonograms, automatic image segmentation and interactive procedures for manual correction were implemented. This step included the recognition of the lumen edge and an analysis of gray level intensity of the wall. Subsequently, a virtual 3D reconstruction of lumen and vessel wall was done in a Cartesian system where the XY plane was parallel to each cross-sectional sonogram, while the Z axis corresponded to the acquisition time. The baricentre of vascular lumen was used as a reference for alignment. We obtained a cylinder like solid representing the behavior of the arterial cross-sectional sonogram in time, with the possibility to look either at the wall or at the lumen. In this virtual solid it was possible to measure the variation of lumen area and of 16 hemidiameters; in addition, the derivatives of these values, allowing an estimate of the velocity of events, can be obtained. CONCLUSIONS: The described computerised system for the analysis of intravascular ultrasound images could become a very useful tool for 3D representation and quantitative monitoring of coronary compliance and their relationship with segmental arterial wall morphology. PMID- 8682259 TI - [Radiofrequency catheter ablation of atrial tachycardia: technique, results and follow-up]. AB - BACKGROUND: Recently radiofrequency (RF) catheter ablation (CA) of atrial tachycardia (AT) showed to be highly effective with a low incidence of compliance. Aim of our study was to report the results and follow-up of RFCA of drug-refractory AT in 59 consecutive patients (pts). METHODS: Two mapping techniques were used to localize the ablation site of AT: the earliest atrial activation and the pace-mapping. Traumatic interruption of AT was used to verify the ablation site identified by the previous procedures. Moreover we evaluated the sensitivity, specificity and the positive predictive value of the three mapping techniques. RESULTS: AT was successfully treated in 55/59 (93.2%) pts with a mean of 4.0 +/- 3.8 (range 1-16) RF pulses for patient. The mean procedure time was 185.2 +/- 48.5 min with a mean rx-time of 41.5 +/- 21.3 min. An interval between the onset of the intracavitary atrial deflection and the onset of the P wave, during atrial tachycardia, (AP interval) > or = 30 ms and pace-mapping concordant sequence were highly sensitive (90.9% and 89.1%) but less specific (49.2% and 33.9%) in identifying the site of ablation. By using atrial tachycardia traumatic interruption combined with the AP interval > 30 ms or the pace-mapping concordant sequence we obtained a specificity of 78.7% and 77.0% respectively and a positive predictive value of 48.0% and 46.8% respectively. Four recurrences (7.3%) were observed during a mean follow-up of 23.4 +/- 13.3 months. In the 22 (37.3%) pts with dilated cardiomyopathy, chest Xr and echocardiography showed a significant decrease of cardiothoracic index (0.56 +/- 0.08 pre ablation, 0.43 +/- 0.07 post ablation, p < 0.001) and end-diastolic diameter (64 +/- 8 mm pre ablation, 52 +/- 8 mm post ablation, p < 0.001) and a significant improvement of left ventricular ejection fraction (37 +/- 9% pre ablation, 48 +/- 11% post ablation, p < 0.05). CONCLUSION: The RFCA of AT was effective and safe. Moreover we observed a hemodynamic improvement in patients with reduced ejection fraction and increased cardiac volumes. An AP interval > or = 30 ms and the pace-mapping concordant sequence were reliable features to predict the outcome of the ablation procedure. Traumatic ablation of atrial tachycardia improved the specificity and the positive predictive value of these two mapping techniques and was able to predict the response to radiofrequency with a high specificity. PMID- 8682260 TI - [Hypertension, hyperpotassemia and normal glomerular filtration (Gordon's syndrome): a case report]. AB - We describe a case of a 26 year old patient affected by a rare syndrome characterized by hyperkalemia, arterial hypertension and normal glomerular filtration rate (Gordon's syndrome), probably due to a renal tubular defect in the reabsorption of sodium or chloride. The patient, who had hyperkalemia since the age of 4 years, was referred to our Centre because of hypertension not well controlled with antihypertensive treatment. After drug therapy wash-out, we confirmed the existence of hypertension (180/100 mm Hg; ambulatory BP monitoring: 24-h mean BP = 151/91 mm Hg; 7 am-11 pm = 157/95; 11 pm-7 am: 133/82) and blood and urine tests showed hyperkalemia (6.6 mEq/L), hyperchloremia (115 mEq/L), mild metabolic acidosis (pH = 7.35, HCO3 = 19 mEq/L), low levels of plasma renin activity ( < 0.2 ng/ml/h), slight increase of plasma (1.08 nM/L) and daily urine aldosterone (129 nM) and normal serum creatinine (1.1 mg/dl) and glomerular filtration rate (91 ml/min). These data allowed to exclude the presence of renal failure and hyporeninemic hypoaldosteronism, which are the most common diseases with hypertension and hyperkalemia, and suggested the diagnosis of Gordon's syndrome. After 1 month of treatment with chlorthalidone (12.5 mg o.i.d) we observed the normalization of BP (130/80 mm Hg; ambulatory BP monitoring: 24-h BP: 132/76 mm), serum potassium (5,1 mEq/L) and the other blood and urine tests. These results were confirmed 6 months later and at present the patient has good clinical conditions. PMID- 8682261 TI - Recurrent perimyocarditis following a non penetrating chest trauma. A case report. AB - A young man, after a non penetrating chest trauma, developed recurrent episodes of fever, chest pain, pleural and pericardial effusion, without laboratory evidence of viral infections, or positivity for conventional autoimmunity markers. A clearcut positivity for more specific cardiac autoantibodies, against Beta 1 adrenoceptors (AB1AA), was found (at all dilutions from 1:20 to 1:160). A full dosage of Prednisone rapidly relieved all symptoms, whereas antibiotic therapy had been previously uneffective. At a follow-up control after three months, the patient was healed and AB1AA were positive only at dilutions 1:20 and 1:40. As silent viral myocarditis was apparently ruled out by serological negativity for viral infections, it is possible that autoimmunity could have played a primary pathogenetic role for the development of pericarditis in this patient. Further work is needed to ascertain whether or not AB1AA detection could be a specific marker of cardiac autoimmunity phenomena. PMID- 8682262 TI - [Company Wide Quality Control (total quality): methodological principles and intervention techniques for step-by-step improvement]. AB - The concept of Quality is particularly up to date and not a new one for the Journal. The need for better Quality is a must also in Medical care. Quality doesn't mean additional costs and excessive burden for the co-workers. On the contrary, initial costs can be compensated for through a more rational utilisation of the resources. The consequent better service for the patient results in an ameliorated working environment, with high profits. Fundamental requirements for reaching concrete results are: 1) the convinced involvement in the idea of all levels (division, service, laboratory) in order to have the different groups act in synergism towards common goals; 2) the knowledge of appropriate methods. The Authors examine this last point with a deep analysis of the techniques involved in Company Wide Quality Control (C.W.Q.C.) or Total Quality. The improving process has to the continuous and proceed in small steps, each time being constituted by 4 different phases, represented by the PDCA cycle, or Demining wheel, where: P = PLAN, which means plan before acting; D = DO, perform what has been planned; C = CHECK, verify the results; A = ACT, standardize if the results are positive, repeat the process if negative. Each process of improvement implies a prior precise definition of a project, i.e. a problem whose solution has been planned. The project must always presume: a specific subject--a goal--one or more people to reach it--a limited time to work it out. The most effective way to ameliorate Quality is performing projects. Step by Step amelioration is synonymous of performance of many projects. A brilliant way to produce many projects remains their "industrialization", which can be reached by means of 6 basic criteria: 1) full involvement of the Direction; 2) potential co-working in the projects of all employees; 3) employment of simple instruments; 4) respect of a few procedural formalities; 5) rewarding of personnel; 6) continuous promotion of the concepts of quality and ongoing improvement. The Authors describe for each of the previous criteria approaching methods and best operative techniques, according C.W.Q.C. PMID- 8682264 TI - [Psychological characteristics of patients with infarction: results of the GISSI 2. Italian Group for the Study of Survival in Myocardial Infarction (GISSI)]. AB - OBJECTIVE: To provide a thorough psychological examination of patients with documented myocardial infarction (MI) enrolled in a multicenter randomized clinical trial (GISSI-2). The psychosocial variables examined include: state variables (anxiety, health-related fears, depression), psychophysical well-being in the three months preceding the acute event (depressive mood, impaired sense of well-being, perceived stress) and trait variables (Type-A Behavior (TAB), neuroticism, introversion/extroversion, social anxiety and feelings of guilt in interpersonal relationships). POPULATION AND SETTING: A total of 2705 patients (12.5% females) admitted to 166 Italian Coronary Care Units. METHODS: Patients were administered the CBA-H, a standardized questionnaire with dichotomous responses (true/false), for a total of 152-item grouped into 16 scales. For each scale, the frequency of scores above cut-off values was computed and compared to patients' clinical and sociodemographic profile. RESULTS: Over one third of all patients scored above the clinical cut-off for anxiety and health-related fears, and 15% showed a depressive pattern. Forty percent of patients reported depressive mood and a diminished sense of well-being in the past three months preceding MI, and more than half perceived themselves as stressed. About one third of the sample overtly exhibited TAB traits and half reported neuroticism scores in the clinical range. One half of our sample could be identified as extrovert, and 14% as introverted. Feelings of guilt and social anxiety were registered respectively in 40% and 12% of the sample. A worse psychological profile was associated to female gender, older age, lower education, living alone and a worse cardiac asset. CONCLUSION: The study has documented the association between clinical, sociodemographic and psychological variables in a large sample of patients with IMA. While the impact of psychological variables upon patients' clinical outcome is to be evaluated, these data may be helpful in promoting the comprehensive and effective care of IMA patients. PMID- 8682263 TI - [Effects of filtering techniques on time-domain analysis of signal-averaged ECG after acute myocardial infarction: a multicenter study, GISS-3 arrhythmia sub project]. AB - AIM OF THE STUDY: To evaluate the influence of different filtering techniques on the measurement of ventricular late potentials (VLP) the Sottoprogetto Aritmie of GISSI-3 collected signal-averaged ECG (SAECG) from 647 patients. METHODS: Data were recorded after myocardial infarction (10 +/- 4 days) in 20 Italian Coronary Units. Three main filtering algorithms were used in the different commercial devices: Bidirectional Filter (ART, Aerotel, Fidelity Medical) (BF: 340 Patients), Spectral Filter (Marquette) (SF: 258 Patients) and Del Mar Filter (Del Mar Avionics) (DF: 49 Patients). QRS duration (QRSD), low amplitude signal duration (LAS40) and root mean-square-voltage (RMS40), were measured with various filters set at 40-250 Hz high and low pass frequencies. RESULTS: After correction for clinical variables the measurements of VLP in the three different groups were different. QRSD value obtained by BF (100.6 +/- 13 ms) was shorter than that obtained by SF (109.1 +/- 12 ms). No differences were found in LAS40 and RMS40 values between SF and BF, while DF gave longer LAS40 and lower RMS40 than SF and BF. Residual noise was lower in BF (0.3 +/- 0.1 muV). than in SF and DF (0.5 +/- 0.1 muV). Applying standard criteria DF gave a higher prevalence of VLP (48.9%) than BF (23.8%) and SF (19%) groups. CONCLUSIONS: This study demonstrates that the use of different filters produces discordant result on VLP measurements. For correct application of SAECG analysis in risk stratification after myocardial infarction, normal and abnormal values must be specifically established for the different filter techniques. PMID- 8682265 TI - [Blood interface in environmental and occupational exposure to industrial chemical pollutants]. AB - The concentration of 12 environmental chemical pollutants was measured in the blood of the general population. With reference to the 12 different pollutants, the blood samples tested varied from 88 for acetone to 431 for benzene. Nine of these agents (benzene, toluene, styrene, cumene, xilene, n-hexane, nitrous oxide (N20), acetone and carbon disulphide) were present in all or almost all (100-94%) blood samples. The three chlorides (chloroform, trichloroethylene and tetrachloroethylene) were present only in 60-85% of samples. After acetone and carbon disulphide, with blood concentrations in microgram/l (mean 840 micrograms/l and 2.4 micrograms/l respectively), the highest mean blood levels were those of toluene (1097 ng/l), chloroform (955 ng/l), N2O (915 ng/l), and n hexane (642 ng/l). Trichloroethylene and free carbon disulphide had similar values (458 and 438 ng/l, respectively). Finally, benzene, styrene and tetrachloroethylene had the lowest values (262, 217 and 149 ng/l, respectively). There was generally a significant difference between rural and urban workers in terms of blood benzene (200 ng/l vs. 264 ng/l), trichloroethylene (180 ng/l vs 763 ng/l) and tetrachloroethylene (62 ng/l vs. 263 ng/l). In a group of subjects potentially exposed to industrial solvents, classed as chemical workers, blood benzene, toluene, chloroform and n-hexane were significantly higher than in rural and urban workers. Smokers showed a significantly higher blood concentration than non-smokers for benzene (381 ng/l vs. 205 ng/l), toluene (1431 ng/l vs. 976 ng/l) and n-hexane (803 ng/l vs. 505 ng/l). PMID- 8682266 TI - [Reference values for xenobiotics in biological matrixes: the state of the art]. AB - The basic concepts of reference values of xenobiotics in biological matrixes have been extensively discussed over the last 3-4 years by transferring the principles from clinical chemistry. In this paper three topics of current interest, i.e. the control of variability factors, metanalysis procedure for production of reference values, the reference values as a part of the system of guide values, are dealt with. The control of variability factors is identified as the most important procedure to guarantee the quality and consequently the usefulness of the reference values. Metanalysis is not considered as a correct method to produce reference values, but rather a method to compare the investigation published and to compel the investigators to standardize their working methods. Lastly reference values should be considered as the first step of an integrated system of values (action levels, limit values) which enable us to correctly interpret the significance of biological monitoring. PMID- 8682268 TI - [Statistical aspects of the definition of reference values]. AB - The criteria adopted in the study of reference values have a great influence on the statistical analysis of the data. To avoid a poor statistical treatment of the data, the scope of the study must be well defined: a study to establish reference values for a chemical in the body fluids of a population is not a survey to prove relations among variables and the chemical. In this latter case, criteria to select subjects and methods are different. Confusion between the two types of surveys can lead to poor results. Reference subjects must be selected with precision, using reproducible criteria. It can be suggested to pick-up subjects from a variety of sub-groups of the population. It must be used selection criteria strictly defined to exclude from the study groups of subjects having specified characteristics (patients, resident in contaminated-zone...). The use of partition criteria is useful to know the distribution of some characteristics in the population, or to describe reference values in particular subgroups. On the contrary, partition can not be used to study relationships. Particular attention must be payed in choosing number of strata and variable of partition. When a population is analysed for reference values, the choice of subjects and relevant variables must be made after consulting a statistician. PMID- 8682267 TI - [Reference values in biological monitoring of occupational exposure to mutagens and carcinogens]. AB - This work reports values of biological markers indicating mutagenic/carcinogenic risk in professionally non-exposed populations. The main confounding factors for most of these biomarkers are tobacco smoke, diet and air pollution. With the sole exception of compounds specifically present in work environments, in which determination in biological fluids of unchanged substances or their metabolites has high sensitivity and specificity (e.g., some aromatic amines), other biomarkers (urinary mutagenicity, DNA adducts and cytogenetic analyses), in order to be used properly as reference values, require ad hoc study of suitable control groups paired for the main confounding factors. Analytical determination of some protein adducts appears to be promising, due to its sensitivity and specificity. PMID- 8682269 TI - [Multiple occupational exposure to solvents]. AB - This article review papers published over the last 20 years on multiple occupational exposure to solvents. At low-levels of exposure the toxicokinetic interferences between solvents have generally not been observed in man and presumably a threshold limit exists. Conversely, at exposure levels close to the "limit values" metabolic interference has sometimes been observed and the behaviour of the biological indicators differs from what would be expected. Toxicodynamic interference between solvents can give rise to additive, potentiation, synergistic, antagonistic effects. For the identification of "limit values", it has generally been suggested in the literature that the possible effects deriving from multiple exposure be considered as additive. However, numerous potentiation effects have frequently been reported for combined exposure to substances of widespread use. In this paper lists of multiple exposure in which the doses of the substances, the types of interferences and the behaviour of the biological levels have been drawn up and proposed as a tool for easy consultation. PMID- 8682270 TI - [Interference of acetone in styrene metabolism in subjects exposed to both solvents]. AB - Thirty-seven workers exposed to styrene and acetone in fiberglass industry were monitored on Monday and Thursday for 8 hours (two subsequent samplings of 4 hours each) using passive dosimeters (mod. TK200). The charcoal disks of the passive dosimeters were analysed by gas-chromatography. Urine samples were collected at the end of the workshift and before the start of the workshift the next morning (Tuesday and Friday). Mandelic acid (MA) and phenylglyoxylic acid (PGA) were measured in the urine, using a HPLC method; values were expressed in mg/g of creatinine. The 8-h TWA exposure values ranged from 10 to 522 and 13 to 1581 mg/m3 on Monday and 8 to 423 and 10 to 579 mg/m3 on Thursday for styrene and acetone, respectively. Styrene TWA exposure values significantly correlated with the sum of metabolites at the end of workday (r = 0.72 on Monday and r = 0.91 on Thursday) and also the next morning (r = 0.88 on Tuesday and r = 0.85 on Friday). A calculated styrene exposure level of 213 mg/m3 (ACGIH-TLV) was associated with an excretion of metabolites (MA+PGA) higher on Thursday (814 mg/g creat.) than on Monday (600 mg/g creat.). The same observation was made on Friday (409 mg/g creat.) as compared with Tuesday (302 mg/g creat.). In conclusion, the TLV of styrene was associated with different values of metabolites at the beginning and at the end of the work-week. Moreover our data show that the simultaneous exposure to acetone does not modify the excretion of MA. PMID- 8682271 TI - [Evaluation of urinary excretion of ethylenethiourea in subjects occupationally and non-occupationally exposed to ethylenebis(dithiocarbamates)]. AB - Ethylenebisdithiorcabamate (EBDC) fungicides are broken down metabolically and in the environment to ethylenethiourea (ETU), a suspected carcinogen. Urinary ETU was assayed in control groups and subjects occupationaly exposed to EBDC and was found to be an excellent indicator of exposure both to ETU and EBDC. Correct use of protective clothing greatly reduced exposure and urinary excretion of ETU. ETU was excreted, albeit in low concentrations, in a high percentage (91% and 30%) of subjects in both control groups, demonstrating its utility as an indicator of widespread EBDC contamination. PMID- 8682273 TI - [Life style as a confounding factor in the study of biological effects of the occupational exposure to chemical substances]. AB - The evaluation of health status of workers exposed to a variety of chemicals is usually performed by means of several laboratory indices. Our aim was to assess the influence of some lifestyle characteristics (alcohol intake and cigarettes smoking) on these parameters. 103 subjects occupationally exposed to chemicals and 146 non occupationally exposed subject were studied. A significant increase in gamma-GT, MCV e UDGA was observed among drinkers (> or = 5 g alcohol/day) as compared with non drinkers and among cigarette smokers (> or = 5 cigarettes/day) as compared with non smokers. Statistically cigarette smoking and alcohol intake influenced parameters independently from any occupational exposure to chemicals. Among the explored indices, UDGA only was significantly and positively associated to occupationally exposure to chemicals. Alcohol intake and cigarettes smoking are responsible for a modification of some laboratory parameters in healthy workers. The medical surveillance of workers exposed to chemicals should include a careful evaluation of alcohol intake (when gamma-GT and ADGU are measured) and cigarette smoking (when MCV and ADGU are measured). PMID- 8682272 TI - [Biological indicators and reference values]. AB - For biological indicators of exposure, effect or susceptibility, appropriate reference values should be available for a comparative evaluation at individual or at group level. Reference values can be either measured in the same subjects before the exposure starts (internal reference), or extrapolated from an appropriately selected group (external reference). In both cases, confounding factors as well as possible sources of variability (biological and analytical), must be taken into account and controlled. Proceeding from clinical chemistry to occupational and environmental medicine, different exclusion and partition criteria in producing reference values should be adopted. Whereas clinical chemistry is aimed at discriminating people as having or not diseases, preventive medicine deals with healthy subjects to prevent effects derived from abnormal exposure to xenobiotics. To this purpose, it is mandatory that general requirements are satisfied, such as the clear definition of the reference population, the conditions under which the specimens were obtained, the adequacy of the indicator itself to provide information, provided that all laboratory results were produced by adequately standardized methods under sufficient quality control. Since we are shifting from macro to microdoses, reference values would help in discriminating natural or man-made sources of exposure. PMID- 8682274 TI - [Occupational exposure and individual factors influencing urinary elimination of hippuric acid]. AB - The influence of not occupational factors (smoking, alcohol, coffee, drugs, sport, sex, age and body weight) on hippuric acid excretion was analyzed in two groups of healthy male subjects. A group was constituted of 710 painters occupied in wood and coach workings and the other one of 109 not occupational. The 5 degrees, 50 degrees, 95 degrees percentiles of the two distribution were 208, 605, 1784 and 153, 538, 1700 mg/g creatinine respectively. The analysis of variance undertaken on exposed subjects showed that there was a significative difference between urinary hippuric acid levels of subjects consuming alcohol and the not ones. Multiple regression analysis on hippuric acid excretion values distribution in not exposed group showed that only the variable "coffee consumption" resulted statistically significative (Ln hippuric acid = 5.0287 + 0.8062; R2 = 01221). Coffee consumption increase excretion rate (mg/hour) of hippuric acid likely an exposure to a toluene air concentration of 50 mg/m3. The authors suggest an action of caffeine on endogenous amount of benzoic acid. PMID- 8682275 TI - Digestive Disease Week and the 96th annual meeting of the American Gastroenterological Association. San Francisco, California, May 19-22, 1996. Abstracts. PMID- 8682277 TI - [Inpatient management in Germany in comparison with other countries]. PMID- 8682276 TI - [Urinary diversion after anterior or total exenteration in advanced tumors of the female genitals]. PMID- 8682279 TI - [Three-dimensional ultrasound study (3-D sonography) of the female breast]. AB - Three-dimensional sonography of the mamma with a Voluson annular array transducer (10 MHz) (Kretztechnik, Austria) is a new method applicable in differential diagnosis of mamma foci. 50 patients (19 of them with breast cancer) were thus pre-surgically examined. Both sectional and stereoscopic representations were made use of. The suspected diagnoses and their correspondences with post-surgical findings were compared to the correspondences obtained through 2D-sonography. 3D sonography produced 4 cases of the incorrectly positive diagnosis breast cancer, 2D-sonography 2 cases of incorrectly negative diagnoses. Other advantages of 3D sonography over 2D-sonography include: better judgement of the conditional of focal environs (infiltration), existence and form of intracystic structures and of multifocal disease, short duration of examination, possible re-diagnosing of stored data. PMID- 8682278 TI - [Predictive medicine--ethical and social aspects of genetic diagnosis]. PMID- 8682280 TI - [Value of high speed punch biopsy after mammographic stereotactic localization in diagnosis of non-palpable breast changes]. AB - To investigate the accuracy of a single high-speed core biopsy, in 159 stereotactically localised nonpalpable breast lesions a single high-speed core biopsy was performed prior to open surgery. All pathological findings of the specimen, core biopsies and open biopsies, were compared. Two biopsies were technically insufficient. In 31 of 49 malignancies a single high-speed core biopsy revealed histologically positive results. In 108 benign lesions the benign findings were found in both samples. The specificity for diagnosis of the carcinomas was 100%, the sensitivity 63%. In lesions without calcifications the accuracy was superior to those with calcifications (88% resp. 84%). As the result of this study it is emphasised that multiple high-speed core biopsies--compared with data from recent literature--improve the sensitivity and the diagnostic value of high-speed core biopsies. PMID- 8682281 TI - [MRI-controlled intervention in suspected lesions of the breast]. AB - PURPOSE: To evaluate two different systems for magnetic resonance (MR) imaging guided breast interventions. MATERIALS AND METHODS: 41 patients with 41 lesions detected exclusively with contrast-enhanced MR imaging underwent 68 interventional procedures (27 needle biopsies and 41 preoperative wire localisations) with two different systems. An add-on device for surface coils was used in 39 cases, and a dedicated single breast biopsy coil was used in 29. For needle biopsies, material was aspirated with nonmagnetic 19.5 gauge needles. For preoperative localisations, nonmagnetic wires were used. RESULTS: Surgical excision verified the cytological findings in 23 of the 27 cases sampled for biopsy. Cytological diagnosis was impossible in three cases. One technical failure occurred with the biopsy coil. Open biopsy performed after MR imaging guided localisation successfully removed 38 of the 41 lesions. One missed carcinoma was found at repeat localisation and removed. Two technical failures occurred with the biopsy coil. In these cases, the lesions were close to the chest wall. CONCLUSIONS: Both systems are suitable for MR-guided fine-needle biopsy and preoperative localisation of breast lesions seen exclusively on MR images. PMID- 8682283 TI - [Breast carcinoma and breast saving therapy--a critical comment from the viewpoint of the pathologist]. AB - The pathologist's contribution to decision-making for or against breast conserving treatment is based on his examination of the specimen from primary tumour surgery. First-line criteria for the assessment of the specimen are completeness, contour and versus plurifocal/multicentric spread), intracanalicular tumour components, lymphangiosis and haemangiosis. Second-line criteria are the histological and cytological grade of malignancy, preconditions for breast conserving treatment are favorable in consolidated in situ carcinomas up to 25 mm in diameter and in unifocal invasive carcinomas up to stage pT2 with low grade malignancy and without additional intraductal spread or angiosis. Breast conserving treatment is not indicated for multifocal or pT4 carcinomas and for carcinomas with extensive intraductal components or angiosis. When considering an unselected group of breast cancer patients, the pathological anatomic preconditions for breast conserving treatment will be very favourable in one-quarter of the cases. This approach will be feasible with limitations only in another one-fourth of the cases, whereas in about 50% of the patients, breast conserving treatment is dubious or should be rejected. PMID- 8682282 TI - [Value of immunohistochemical determination of receptors, tissue proteases, tumor suppressor proteins and proliferation markers as prognostic indicators in primary breast carcinoma]. AB - OBJECTIVE: We tested whether immunohistochemical detection of oestrogen and progesterone receptor (ER, PR), the oestrogen-dependent protein pS2, the growth hormone receptors p 185neu and EGF-R, the tumour suppressor protein p53, the tissue proteases Cathepsin D and Urokinase, and the proliferation marker PCNA are of prognostic relevance in breast cancer patients. METHODS: Expression of the proteins listed above was evaluated in formalin-fixed and paraffin-embedded sections of 311 primary breast cancer specimens using modified Avidin-Biotin Complex methods. Results were correlated to clinical and morphological parameters (age, menopausal status, nodal status, tumour size, tumour grade), and clinical course of disease (complete follow-up in 301 women, median observation time 62 months) utilising univariate and multivariate statistical analyses. RESULTS: If univariate analyses and multivariate regression analyses according to the Cox model were applied, only Cathepsin D correlated to an elevated risk for recurrence in nodally negative patients (n = 135). In nodally positive women (n = 161), increasing tumour size, tumour grade, lack of ER and PR, expression of p185neu, p53, and PCNA indicated a significantly increased relative risk. CONCLUSIONS: Immunohistochemistry allows the detection of parameters which may indicate prognosis in subgroup of breast cancer patients. PMID- 8682284 TI - [High dose chemotherapy in treatment of breast carcinoma: current status and limits of this method of therapy]. AB - Current Status and Limits: High-dose chemotherapy with autologous haematopoietic stem cell rescue has become in recent years a widely accepted therapeutic modality for advanced stage breast cancer in North America. The emergence of modern supportive measures like peripheral blood stem cell rescue has significantly decreased the toxicity and cost of high-dose chemotherapy. The rationale for use of escalated chemotherapy doses in breast cancer is the establishment of a dose-response relationship, with higher doses producing increased response rates in preclinical studies as well as in clinical trials. The dose limiting myelotoxicity of several active agents in breast cancer can only be overcome by rescue with previously cryopreserved autologous haematopoietic stem cells. Two phase II clinical trials with high-dose chemotherapy as adjuvant measure in high-risk breast cancer patients with multiple positive axillary nodes have been published so far. Disease-free survival is these 2 studies was 71 and 84% after 5 and 3 years of follow-up, and hence significantly longer compared to historic controls. Randomised phase III trials are urgently needed to confirm these promising results. Several reports of high-dose chemotherapy in disseminated breast cancer have been published so far. Most of these studies could establish a high response rate of about 70%, half of which were complete responses. However, most tumour regressions were short lived and overall survival was not prolonged compared with historic controls. Therefore, high-dose chemotherapy cannot be recommended for disseminated breast cancer patients outside of innovative clinical trials. To improve on the results in disseminated breast cancer patients the use of repeated cycles of high dose chemotherapy or the value of tumour cell purging of the stem cell product are being currently explored by different groups. In general, breast cancer patients should only be treated with high dose chemotherapy in context with a clinical trial. PMID- 8682285 TI - [137 local recurrences after breast carcinoma--a retrospective study]. AB - A retrospective study was performed to follow up the course of the disease in 137 female premenopausal and postmenopausal patients in whom local recurrence of carcinoma of the breast had occurred. Particular attention was given to the dependence of the recurrence-free interval on the tumorobiological parameters of the primary tumour. In 23% of the cases the local recurrence was an expression of generalisation of the tumour with simultaneous occurrence of distant metastases. The average recurrence-free interval was four years, but more than half of the recurrences were seen during the first two postoperative years. For the following parameters we found a statistically significant correlation with the recurrence free interval: size of the primary tumour (p = 0.0003), the nodal status (p = 0.0006) and in this connection also the number of the metastatically involved lymphatic node level (p = 0.00001). There was also a significant correlation between the duration of the recurrence-free interval and the immunohistochemical oestrogen and progesterone receptor status (p = 0.0005) and the growth fraction (p = 0.0106) determined with the monoclonal antibody Ki67. However, although there was no correlation between recurrence-free survival and the kind of surgical primary therapy that had been employed, adjuvant therapy did exercise a decisive influence: there was significant later incidence of local recurrences (p = 0.00001) subsequent to adjuvant radiotherapy. PMID- 8682287 TI - [Axillary metastases of unknown primary carcinoma]. AB - S.R., a 66-year old woman, was referred to our department because of an axillary mass in the right side. The patient had observed an increasing, painless swelling in the right axilla for the last two months. In the region of the right axilla in the middle axillary line an ovoid and solid tumour of 3 cm in diameter, quite well distinguishable, moving against the skin and the surrounding tissue, could be palpated. A subsequent mammography yielded an unsuspicious visualisation of both breasts and the left axilla. In the right axilla a circular solidification was detected, which then turned out on ultrasound examination to be a 2.6-cm diameter axillary lymph node. In the course of the lymph node extirpation of the right axilla two lymph nodes were dissected with histological evidence of metastatic nodes of a solid tumour, most likely in accordance with a breast carcinoma. Several immunohistochemical methods had been applied to determine the origin of the tumour cells and were thus identified as breast cancer cells. To detect primary causative carcinoma, different examinations were performed postoperatively without identifying any cancerous lesions. At least accurate research concerning the history of the patient was required to reexamine the histologic material of an operation of the right breast in 1989. The histological diagnosis of the dissected node of that time had been defined as a benign intracanaliculary papilloma in the right side without evidence of malignancy. The reexamination of the paraffin-embedded material from the operation of the right breast in 1989 revealed a lobular carcinoma of the right breast. The "occult" (undetectable) carcinoma of the breast occurs in less than 1% of all breast carcinomas. Thus it represent a rare clinical event and hence no standardised therapy schemata exist. To confirm the diagnosis of an occult carcinoma of the breast efficient reexamination of histological material from earlier breast operations indicated. PMID- 8682286 TI - [Lobular cancer transformation of the female breast. Mammography diagnosis and clinical relevance]. AB - Lobular cancerisation was diagnosed in 101 women between 1976 and 1980. Calcification in the mammograms and follow-up without mastectomy were analysed. Therapy was simple biopsy, because the term lobular cancerisation was not established at that time. Surgery was done at the University Clinic for Women and the Elim Hospital at Hamburg. Retrospective analysis of the specimens was performed at the Department of Gynaecological Histopathology of the Hamburg University Clinic. Mammograms were available in 72 cases, showing calcifications in 40 cases. It was impossible to match the calcifications in the mammograms and the histological slides. Hence, a further 23 cases from 1980 to 1990 were analysed, suffering from lobular cancerisation and ductal carcinoma in situ (DCIS). Comparing 13 mammograms showing calcifications, with large-area scans, only two showed corresponding calcifications. Based on these data a specific diagnosis of lobular cancerisation by mammography is impossible. The follow-up of 88 patients with breast-preserving surgery and lobular cancerisation showed ipsilateral invasive carcinoma in three cases (0.35% in a total of 100 follow-up years), ipsilateral DCIS in five, and contralateral invasive breast cancer in one case. The therapy of lobular cancerisation should depend on the coexisting DCIS. There is no additional risk of local recurrence by lobular cancerisation. PMID- 8682288 TI - [Paraneoplastic cerebellar degeneration: case report of a patient with breast carcinoma]. AB - Case Report on a Breast Cancer Patient: A description of medical history, diagnosis and therapy of a patient with breast cancer is presented. The patient showed primary symptoms of vertigo and truncal and gait ataxia. The cause of this cerebellar disorder was a paraneoplastic cerebellar degeneration (PCD) characterized by anti-Purkinje cell antibodies (anti-Yo) directed against specific epitops shared by Purkinje and tumour cells. The presence of these antibodies in some patients suggests an autoimmune mechanism, although their role in pathogenesis has not been established. Usually malignancies of the breast and the ovaries are associated with anti-Yo positive PCD. The intensive search for the underlying neoplasma led to the identification of a malignant tumour of the right breast. Tumour excision of subsequent immunosuppressive treatment resulted in a progression of PCD. Antibody titers remained nearly unchanged during the course of the disease. PMID- 8682289 TI - SR proteins and splicing control. PMID- 8682290 TI - Bone morphogenetic proteins: multifunctional regulators of vertebrate development. PMID- 8682291 TI - Multiple determinants controlling activation of yeast replication origins late in S phase. AB - Analysis of a 131-kb segment of the left arm of yeast chromosome XIV beginning 157 kb from the telomere reveals four highly active origins of replication that initiate replication late in S phase. Previous work has shown that telomeres act as determinants for late origin activation. However, at least two of the chromosome XIV origins maintain their late activation time when located on large circular plasmids, indicating that late replication is independent of telomeres. Analysis of the replication time of plasmid derivatives containing varying amounts of chromosome XIV DNA show that a minimum of three chromosomal elements, distinct from each tested origin, contribute to late activation time. These late determinants are functionally equivalent, because duplication of one set of contributing sequences can compensate for the removal of another set. Furthermore, insertion of an origin that is normally early activated into this domain results in a shift to late activation, suggesting that the chromosome XIV origins are not unique in their ability to respond to the late determinants. PMID- 8682292 TI - Regulation of mRNA export in response to stress in Saccharomyces cerevisiae. AB - The response of eukaryotic cells to heat shock and other forms of stress occurs at both transcriptional and post-transcriptional levels. We used in situ hybridization to determine whether stress affected the subcellular distribution of poly(A)+ RNA in Saccharomyces cerevisiae. Following induction of stress by either heat shock (42 degrees C) or addition of a high concentration of ethanol (10%), the nucleocytoplasmic export of most poly(A)+ RNA was blocked. In situ hybridization indicated that heat-inducible SSA4 and SSA1 mRNAs were exported from nuclei under these same conditions. On the other hand, both GAL1 and URA3 transcripts expressed from the SSA4 promoter accumulated in nuclei following heat shock. Sequences within either the 5' 1600 or the 3' 500 nucleotides of SSA4 mRNA were sufficient to direct GAL1 mRNA to the cytoplasm during stress. The export of SSA4 mRNA following stress required functional nuclear pore complexes, as SSA4 mRNA accumulated in nuclei following heat shock of cells containing temperature sensitive nucleoporins. However, the selective export of SSA4 mRNA was maintained in heat-shocked cells carrying temperature-sensitive alleles of RNA1, PRP20, or an inducible dominant-negative allele of GSP1, the S. cerevisiae homolog of RAN/TC4. The results reported here suggest that there is selective export of mRNA in yeast. PMID- 8682293 TI - Targeted disruption of p107: functional overlap between p107 and Rb. AB - To explore the physiological role of p107, a member of retinoblastoma gene (Rb) family, we disrupted the mouse gene by homologous recombination in embryonic stem cells. p107 homozygous mutant mice were viable, fertile, and displayed no obvious abnormalities. To investigate possible functional overlap between p107 and Rb, mice with mutations at both loci were generated. Rb+/-;p107-/- mice have a pronounced growth retardation and increased mortality rate during the first 3 weeks after birth. The Rb+/-;p107-/- pups that survive to adulthood did not show any altered tumor predisposition when compared with Rb+/- mice but developed multiple dysplastic lesions of the retina. Embryos homozygous for both Rb and p107 died at approximately 11.5 days of gestation, 2 days earlier than embryos homozygous for Rb alone. Histological examination revealed accelerated apoptosis in the liver and the central nervous system of Rb-/-;p107-/- embryos relative to Rb-/- embryos. These results provide the first in vivo evidence that p107 and Rb have overlapping functions in some tissues of the developing and adult mouse. PMID- 8682294 TI - Shared role of the pRB-related p130 and p107 proteins in limb development. AB - The p130 protein shares extensive sequence similarity with pRB, the product of the retinoblastoma gene, and is a major E2F-associated protein in quiescent cells. To investigate its biological function, we have mutated p130 via gene targeting in the mouse. Homozygous mutation of p130 had little discernible effect on development or on the growth of mouse embryo fibroblasts in culture. Much of the E2F activity that normally associates with p130 in serum-starved mouse embryo fibroblasts associated instead with the highly related p107 protein. To determine whether p130 and p107 have overlapping biological roles, we produced mice having simultaneous inactivation of the p130 and p107 genes. Such mice exhibited deregulated chondrocyte growth, defective endochondral bone development, shortened limbs, and neonatal lethality. These findings indicate that p130 and p107 play an important role in limb development through their abilities to control chondrocyte proliferation. Thus, in certain settings p107 and p130 perform growth-regulatory functions that are not fulfilled by pRB. PMID- 8682295 TI - Regulation of cell-cell contacts in developing Drosophila eyes by Dsrc41, a new, close relative of vertebrate c-src. AB - In Drosophila, Dsrc64 is considered a unique ortholog of the vertebrate c-src; however, we show evidence to the contrary. The closest relative of vertebrate c src so far found in Drosophila is not Dsrc64, but Dsrc41, a gene identified for the first time here. In contrast to Dsrc64, overexpression of wild-type Dsrc41 caused little or no appreciable phenotypic change in Drosophila. Both gain-of function and dominant-negative mutations of Dsrc41 caused the formation of supernumerary R7-type neurons, suppressible by one-dose reduction of boss, sev, Ras1, or other genes involved in the Sev pathway. Dominant-negative mutant phenotypes were suppressed and enhanced, respectively, by increasing and decreasing the copy number of wild-type Dsrc41. Colocalization of Dsrc41 protein, actin fibers and DE-cadherin, and Dsrc41-dependent disorganization of actin fibers and putative adherens junctions in precluster cells suggested that Dsrc41 may be involved in the regulation of cytoskeleton organization and cell-cell contacts in developing ommatidia. PMID- 8682296 TI - The gene encoding bone morphogenetic protein 8B is required for the initiation and maintenance of spermatogenesis in the mouse. AB - Bone morphogenetic protein 8B (BMP8B) is a member of the TGFbeta superfamily of growth factors. In the mouse, Bmp8b is expressed in male germ cells of the testis and trophoblast cells of the placenta, suggesting that it has a role in spermatogenesis and reproduction. To investigate these possibilities, we have generated mice with a targeted mutation in Bmp8b. Here, we show that homozygous Bmp8b(tm1blh) mutant males exhibit variable degrees of germ-cell deficiency and infertility. Detailed analysis reveals two separable defects in the homozygous mutant testes. First, during early puberty (2 weeks old or younger) the germ cells of all homozygous mutants either fail to proliferate or show a marked reduction in proliferation and a delayed differentiation. Second, in adults, there is a significant increase in programmed cell death (apoptosis) of spermatocytes, leading to germ-cell depletion and sterility. Sertoli cells and Leydig cells appear relatively unaffected in mutants. This study therefore provides the first genetic evidence that a murine germ cell-produced factor, BMP8B, is required for the resumption of male germ-cell proliferation in early puberty, and for germ-cell survival and fertility in the adult. PMID- 8682297 TI - Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. AB - We have studied the initial development of pluripotent gut endoderm to hepatocytes using a tissue explant system from mouse embryos. We not only find cellular interactions that specify hepatic differentiation but also those that block hepatogenesis in regions of the endoderm that normally give rise to other tissues. The results implicate both positive and negative signaling in early hepatic specification. In vivo footprinting of the albumin enhancer in precursor gut endoderm shows that the transcriptionally silent but potentially active chromatin is characterized by occupancy of an HNF-3 site. Upon hepatic specification, a host of other factors bind nearby sites as the gene becomes active. Genes in pluripotent cells therefore may be marked for potential expression by entry points in chromatin, where additional factors bind during cell type specification. The findings also provide insight into the evolutionary origin of different endodermal cell types. PMID- 8682298 TI - A nuclear cap-binding complex facilitates association of U1 snRNP with the cap proximal 5' splice site. AB - The mechanism by which intron-containing RNAs are recognized by the splicing machinery is only partly understood. A nuclear cap-binding complex (CBC), which specifically recognizes the monomethyl guanosine cap structure carried by RNA polymerase II transcripts, has previously been shown to play a role in pre-mRNA splicing. Using a combination of splicing complex and psoralen cross-linking analysis we demonstrate that CBC is required for efficient recognition of the 5' splice site by U1 snRNP during formation of E (early) complex on a pre-mRNA containing a single intron. However, in a pre-mRNA containing two introns, CBC is not required for splicing of the cap distal intron. In this case, the presence of an intact polypyrimidine tract in the cap-proximal intron renders splicing of the cap-distal intron independent of CBC. These results support models in which the splice sites in a pre-mRNA are originally recognized by interactions spanning exons. The defects in splicing and U1 snRNP binding caused by CBC depletion can be specifically reversed by recombinant CBC. In summary, efficient recognition of the cap-proximal 5' splice site by U1 snRNP is facilitated by CBC in what may be one of the earliest steps in pre-mRNA recognition. Data in Colot et al. (this issue) indicate that this function of CBC is conserved in humans and yeast. PMID- 8682300 TI - Advanced mRNA differential display: isolation of a new differentially regulated myosin heavy chain-encoding gene in amphibian limb regeneration. AB - In an effort to make mRNA differential display more amenable as a molecular screen, we have optimized the technology for the isotopic and non-isotopic detection of differentially regulated mRNAs. The number of amplification rounds in the displays was significantly reduced, resulting in the semi-quantitative detection of expression patterns of both low- and high-abundance transcripts. Moreover, we extended the method beyond the display of mRNAs by introducing a direct sequencing approach for the fast molecular analysis of isolated cDNAs. Applying this improved technique to the regenerating amphibian limb system, we have identified cDNA PCR products with a temporal difference in expression. This differential regulation was confirmed by Northern analysis, and DNA sequencing uncovered a novel newt differentiation-specific transcript encoding a skeletal myosin heavy chain (MHC). PMID- 8682299 TI - The yeast splicing factor Mud13p is a commitment complex component and corresponds to CBP20, the small subunit of the nuclear cap-binding complex. AB - The mechanism by which pre-mRNAs are initially recognized by the splicing machinery is not well understood. In the yeast system, commitment complexes are the earliest identified splicing complexes. They contain pre-mRNA, U1 snRNP, and the splicing factor Mud2p and probably correspond to the mammalian E complexes, which contain pre-mRNA, U1 snRNP, and the splicing factor U2AF. To identify other yeast commitment complex components, we have characterized mutant strains that are synthetic lethal with viable U1 snRNA mutations. We report here that MUD13 is a nonessential gene that encodes the yeast homolog of CBP20, the small subunit of the vertebrate nuclear cap-binding complex (CBC). Characterization of splicing in the delta-MUD13 strain and extract indicates that Mud13p is a yeast splicing factor and is the second identified non-snRNP commitment complex component. The observations also suggest that CBC interacts with other commitment complex components as well as with the substrate cap. Taken together with the accompanying results for a mammalian system, our data indicate that cap-binding proteins as well as the pre-mRNA cap contribute to early steps in spliceosome assembly. PMID- 8682301 TI - Cloning and characterization of extended hammerheads from a diverse set of caudate amphibians. AB - Satellite 2 (sat2) elements from six species representing four caudate amphibian families were cloned and analyzed. Despite differences in the abundance of this element, the tandemly repeated genomic organization found for sat2 in earlier investigations was conserved in the newly investigated species. The ability of sat2 transcripts to catalyze their own site-specific self-cleavage using an extended hammerhead (HH) motif had also been conserved. This motif is similar to the HH found in a number of infectious plant RNAs, but has an abbreviated stem III region and an internally looped stem I extension that distinguish it from the prototypical HH. The extended HH analyzed in this survey can be further organized into two groups on the basis of shared sequences and structural details in the peripheral stem-loop structures. HH derived from the family Salamandridae constitute one group, whereas HH from all other salamanders that have been investigated belong to the other group. Although many of the natural variants did not cleave efficiently in vitro, examples of relatively active variants for each design were found. This survey has therefore identified two designs that are suitable starting models for the structural and functional analysis of the extended HH. PMID- 8682302 TI - Analysis of VNTR loci in fish genomes using synthetic oligodeoxyribonucleotide probes. AB - A set of synthetic oligodeoxyribonucleotide (oligo) probes, OAT18, OMS1 and OAT24 carrying the (TGG)6, (GGAT)4 and (GACA)6 repeat motifs, respectively, was used to analyze the variable number tandem repeat (VNTR) loci in the genomes of Oncorhyncus mykiss (rainbow trout; family Salmonidae), Oreochromis mossambicus and Oreochromis niloticus (both tilapia belonging to family Cichlidae). Of all the oligos and enzymes (AluI, MboI, HaeIII and HinfI) used, the OAT18/HaeIII combination was found to be most informative for detecting DNA fingerprinting in rainbow trout, while the OMS1/MboI combination gave the most informative pattern for the Or. niloticus genome. In the rainbow trout genome, all three repeat loci were hypervariable, revealing varying degrees of polymorphism as compared to tilapia genomes. Startlingly, the OAT24 probe did not cross-hybridize with Or. mossambicus and lamprey salmon (Lampertra japonica) although GACA repeats have been reported to be evolutionarily conserved in all eukaryotes studied thus far. Cluster analysis with respect to GGAT repeat loci revealed that Or. niloticus diverged from Or. mossambicus before the separation of On. mykiss, suggesting the relatively recent evolution of these loci in rainbow trout, compared to the tilapia genomes. These highly informative probes will find application in various genetic studies of fishes. PMID- 8682303 TI - The mouse Wnt-10B gene isolated from helper T cells is widely expressed and a possible oncogene in BR6 mouse mammary tumorigenesis. AB - From libraries made from activated mouse T lymphocytes, we have isolated cDNAs encoding Wnt-10B, a new member of the Wnt family of developmental control genes. This protein appears to be the mammalian orthologue of Wnt-10B, first identified in several non-mammalian vertebrates and recently in mouse. The mRNA expression pattern of mouse Wnt-10B indicates that it is induced following activation of helper T cells, but is also expressed in a variety of other tissues and cells of fetal or adult origin. 93 bp at the 5' end of the cDNA clone are identical to sequences previously reported as 3' flanking genomic DNA adjacent to a mouse mammary tumor virus (MMTV) provirus in the MMTV-induced BR6 mammary tumor, W26. Sequence analysis of tumor-derived genomic DNA confirms that the entire Wnt-10B gene is immediately adjacent to the provirus, suggesting that MMTV integration drives transcription of Wnt-10B, possibly contributing to the oncogenic process. Consistent with this idea is the detection of hybrid MMTV-Wnt-10B transcripts in BR6 tumor cells. T cells which produce abundant Wnt-10B mRNA were also found to produce protein. PMID- 8682304 TI - Cloning and analysis of a cDNA encoding farnesyl diphosphate synthase from Artemisia annua. AB - A cDNA encoding farnesyl diphosphate (FPP) synthase (FPPS) has been cloned from a cDNA library of Artemisia annua. The sequence analysis showed that the cDNA encoded a protein of 343 amino acid (aa) residues with a calculated molecular weight of 39420 kDa. The deduced aa sequence of the cDNA was highly similar to FPPS from other plants, yeast and mammals, and contained the two conserved domains found in polyprenyl synthases including FPPS, geranylgeranyl diphosphate synthases and hexaprenyl diphosphate synthases. The expression of the cDNA in Escherichia coli showed enzyme activity for FPPS in vitro. PMID- 8682305 TI - A 14-kDa Arabidopsis thaliana RNA polymerase III subunit contains two alpha motifs flanked by a highly charged C terminus. AB - We have sequenced a cDNA and a gene, AtRPC14, from Arabidopsis thaliana (At) (ecotype Columbia) that encode a protein related to the yeast RNA polymerases (Pol) I and III subunits, yAC19. Polyclonal antibodies raised against the recombinant At polypeptide (AtC14) bind to the Pol I and/or III subunits of about 13-15 kDa, but do not bind to any Pol II subunit in Pol purified from cauliflower, wheat or At. The amino acid (aa) sequence derived from the AtRPC14 cDNA and genomic clones consists of 122 aa, as compared to the 142 aa in the yeast yAC19 subunit and 143 aa in a putative Caenorhabditis elegans CeAC16 subunit. AtC14, yAC19 and CeAC16 contain a conserved sequence of about 85 aa which is related to two motifs in the alpha subunit of Escherichia coli (Ec) Pol. AtC14 lacks a highly charged N terminus of about 50 aa found in both yAC19 and CeAC16, but has a highly charged C terminus of about 30 aa not found in yAC19 and CeAC16. PMID- 8682306 TI - Cloning, characterization and transient expression of the gene encoding a rice U3 small nuclear RNA. AB - A rice U3 small nuclear RNA (snRNA)-encoding gene has been isolated. The coding region of this gene contains all five conserved sequence boxes common to plant U3 snRNAs. The upstream and downstream regions of the gene harbour characteristic sequence elements required for transcription with RNA polymerase III (pol III), as well as three monocot-specific promoter (MSP) elements [Connelly et al., Mol. Cell Biol.14 (1994) 5910-5919], two of them comprising a palindromic G+C-rich segment. The sequence (TTTAAAA) of the TATA-box in this gene does not fit the established consensus [Marshallsay et al., Plant Mol. Biol. 19(1992) 973-983], making this gene unique among reported snRNA-encoding genes of plants. An RNase protection assay showed that the gene is expressed properly in cucumber protoplasts. We thus suggest that, with other promoter elements present, the TATA box for RNA pol III-specific snRNA-encoding genes may not be as well conserved as that for RNA pol II-specific genes. PMID- 8682307 TI - Structure and expression of a developmentally regulated cDNA encoding a cysteine protease (pseudotzain) from Douglas fir. AB - We report the complete sequence and expression of a cDNA clone (Pm3-3) encoding a cysteine protease (CysP) from Pseudotsuga menziesii [Mirb] (Pm) Franco (Douglas fir). The sequence consists of a 5' untranslated region (UTR) of 153-bp followed by an open reading frame (ORF) of 1362 bp encoding a putative mature CysP flanked by N- and C-terminal propeptides. A 364-bp 3' UTR contains multiple putative AU rich elements (ARE) that may be involved in the destabilization of transcripts. The deduced primary structure of the Pm CysP (designated pseudotzain) contains the same invariant amino acid (aa) residues that are involved in the catalytic reaction and make up the catalytic center of CysP from plants and animals. Northern blot analysis showed that cysP transcripts were most abundant in the megagametophyte (MGP) after germination and not detected in the MGP or embryo during embryogenesis. Various osmotic stresses slightly enhanced cysP transcript levels during early seedling development, whereas abscisic acid (ABA), gibberellin (GA) and other plant growth regulators and environmental conditions had little or no effect. The cysP transcripts were present in different amounts in the cotyledons, root and seed coat of 10-day-old seedlings, but were most abundant in the MGP, suggesting a role for this protease in storage protein mobilization. Phylogenetic analysis of mature CysP groups pseudotzain with other angiosperm CysP having both N- and C-terminal propeptides, suggesting a conserved function and/or targeting of this subgroup of enzymes. PMID- 8682308 TI - Controlled gene expression in mammalian cells via a regulatory cascade involving the tetracycline transactivator and lac repressor. AB - Regulatory cascades or regulons control pathways at multiple points or multiple genes by one initial signal. In this paper, we describe the construction of an artificial regulatory cascade in CHO cells, which responded to various concentrations of tetracycline (Tc) and/or IPTG. The system consists of the constitutively produced transactivator (TTA) of the Tc operon (tet), which induced the expression of a lacI gene controlled by tet operator (tetO) and upstream CMV promoter (p*CMV) sequences. LacI repressed the activity of a cat gene by binding to lacO sites in its upstream RSV promoter (pRSV) region. However, this repression could be alleviated by exposure to Tc or IPTG, which inhibited the binding activities of TTA and LacI, respectively. Hence, treatment with either Tc or IPTG led to a tenfold increase in CAT activity. After the withdrawal of the inducer, cat expression reverted to basal levels. Regulation by Tc showed a phenotypic lag, and full induction was reached after 192 h, whereas IPTG addition led to full induction within 24 h. When cells were treated with both Tc and IPTG, full induction of cat was reached in 24 h and maintained thereafter while in the presence of Tc alone. This suggests that regulation by Tc is fast and that the phenotypic lag may be due to slow turnover of the LacI repressor. This TTA/lacI regulatory system may serve as an example in which cat expression was used as a reporter. The data indicate that regulatory cascades regulated at multiple points can be constructed with any cloned gene in mammalian cells. PMID- 8682309 TI - A vaccinia virus transfer vector using a GUS reporter gene inserted into the I4L locus. AB - A vaccinia virus (VV) transfer vector is described which enables integration of heterologous sequences into the I4L locus (ribonucleotide reductase-encoding gene) through co-insertion of a GUS selection marker. I4L- VV recombinants formed blue plaques when an agarose overlay containing XGluc (5-bromo-4-chloro-3-indolyl beta-glucuronide) was added to the infected cell monolayer. Viruses already containing a lacZ reporter gene were also suitable recipients for the selection procedure since infection with a VV lacZ recombinant did not produce any blue plaques with XGluc. The addition of a synthetic early promoter downstream from the GUS cassette initiated the predicted-size transcript during an infection. Insertion of genes with VV p7.5-promoters into the I4L, J2R and K1L loci of the same virus produced viable virus recombinants even though recombination between these loci could be demonstrated. These techniques should be valuable for the further development of VV as a polyvalent vector. PMID- 8682310 TI - The Drosophila melanogaster gene vha14 encoding a 14-kDa F-subunit of the vacuolar ATPase. AB - A Drosophila melanogaster (Dm) cDNA (vha14) encoding the 14-kDa F-subunit of the vacuolar H(+)-ATPase (V-ATPase) has been cloned via homology with the corresponding Manduca sexta (Ms) gene. Its deduced translation product is a 124 amino-acid polypeptide sharing 90% identity with the Ms polypeptide and 50% identity with an analogous polypeptide of Saccharomyces cerevisiae, and a more distant similarity to a subunit of the Na(+)-transporting ATPase of Enterococcus hirae. Homology was also found with expressed sequence tags from man, Arabidopsis thaliana, Caenorhabditis elegans and C. briggsiae, Oryza sativa and Plasmodium falciparum, indicating that the subunit is phylogenetically conserved. The Dm gene (vha14) is present as a single copy at cytological position 52B on the second chromosome, and gives rise to an mRNA species of 0.65 kb. Expression of the latter shows relatively little variation during development, or between adult head, thorax and abdomen, suggesting that the F-subunit is a relatively ubiquitous component of the V-ATPase. PMID- 8682311 TI - Try29F, a new member of the Drosophila trypsin-like protease gene family, is specifically expressed in the posterior embryonic midgut. AB - The Drosophila melanogaster try29F gene encodes a protein that shares all known features of serine proteases, like residues known to be involved in substrate specificity, catalysis and disulfide bond formation. In situ hybridization to mRNA in whole mount embryos shows that the expression of try29F is restricted to the posterior midgut during late embryogenesis. PMID- 8682312 TI - The Drosophila melanogaster similar bHLH-PAS gene encodes a protein related to human hypoxia-inducible factor 1 alpha and Drosophila single-minded. AB - The Drosophila melanogaster (Dm) similar (sima) gene was isolated using a low stringency hybridization screen employing a Dm single-minded gene basic helix loop-helix (bHLH) DNA probe. sima is a member of the bHLH-PAS gene family and the conceptual protein shares a number of structural features, including a bHLH domain, PAS domain, and homopolymeric amino acid stretches. Sima is most closely related to the human hypoxia-inducible factor 1 alpha bHLH-PAS protein. In situ hybridization experiments reveal that sima is transcribed in most or all cells throughout embryogenesis. It has been cytologically mapped to position 99D on the third chromosome, and is not closely linked to other known bHLH-PAS genes. PMID- 8682313 TI - Manduca sexta hemolymph ferritin: cDNA sequence and mRNA expression. AB - A cDNA clone encoding a subunit of the tobacco hornworm Manduca sexta (Ms) hemolymph (serum) ferritin (Fer) has been identified and sequenced. The deduced amino acid (aa) sequence shows approx. 50% similarity to vertebrate Fer subunit sequences, and the nucleotide sequence contains a stem-loop structure in the 5' untranslated region that could serve as an iron-responsive element (IRE). The stem-loop of this putative IRE exhibits high identity to vertebrate IRE that play an essential role in the control of Fer synthesis. The Ms Fer subunit lacks one of the three Tyr residues required for the rapid biomineralization of iron shown in vertebrate heavy-chain Fer. In addition, aa residues that comprise the putative ferroxidase centers generally are not conserved, suggesting that the Ms Fer subunit more closely resembles the vertebrate light-chain subunit. Northern blot analyses indicate that the fer mRNA is expressed in the midgut, fat body and hemocytes, with the greatest expression in the midgut. PMID- 8682314 TI - The stringlike genes of the limpet Patella vulgata. AB - As a first step in analyzing the function of a cdc25 homolog during the embryonic development of Patella vulgata (Pv), genomic clones encoding these stringlike proteins (Stl) were isolated and characterized. These clones belong to four groups which are derived from different regions of the Pv genome. As the sequences of Stl genes from two of these groups are almost identical, we suggest that these genes represent copies of the same gene. The Stl3 gene, which has been analyzed in detail, consists of four exons separated by three introns. Its sequence encodes a 250-amino-acid protein with a calculated weight of 28 kDa. The Stl protein contains regions conserved in all other cdc25 proteins. Stl messengers are not stored maternally in Pv oocytes and Stl transcription only starts after the first embryonic cleavages. PMID- 8682315 TI - Accelerated evolution of Trimeresurus okinavensis venom gland phospholipase A2 isozyme-encoding genes. AB - Three Trimeresurus okinavensis (To; himehabu snake, Crotalinae) venom gland phospholipase A2 (PLA2) isozymeencoding genes, gPLA2-o1, gPLA2-o2 and gPLA2-o3, were isolated from its genomic DNA library. The nucleotide (nt) sequence analysis revealed that two of the three genes (gPLA2-o2 and gPLA2-o3) occasionally have been converted to inactivated genes by introduction of one base insertion or substitution. It was confirmed from Southern blot analysis that the To haploid genome contains only three venom gland PLA2 isozyme genes herein isolated. Comparison of these genes showed that nonsynonymous nt substitutions have occurred more frequently than synonymous nt substitutions in the protein-coding regions, except for the signal-peptide coding domain, implying that To venom gland PLA2 isozyme genes have evolved via accelerated evolution. Such an evolutionary feature of To venom gland PLA2 isozyme genes proves the general universality of accelerated evolution previously drawn for venom gland PLA2 isozyme genes of other crotalinae snakes. The variability in the mature protein coding regions of three To venom gland PLA2 isozyme genes appears to have been brought about by natural selection for point mutations. PMID- 8682316 TI - The cloning and characterization of a cDNA encoding Xenopus laevis DNA ligase I. AB - A cDNA clone coding for DNA ligase I (LigI) was isolated from a Xenopus laevis oocyte cDNA library. The 3766-bp sequence showed a putative ORF capable of encoding a 1070-amino-acid protein whose overall identity with two mammalian sequences is 63%. This identity, however, rises to 72.5% in the C-terminal portion of the protein that contains the active site. Expression of the cDNA in a prokaryotic system produces a protein that is immunologically identical to LigI and can be adenylated. The 180-kDa size of the recombinant protein is similar to the LigI detected in oocyte. Northern blot analysis of ovary and embryo RNAs revealed the expression of two (4.1 and 6 kb) LigI transcripts. PMID- 8682317 TI - Cloning and characterization of the promoter for murine 84-kDa heat-shock protein. AB - The 90-kDa heat-shock (HS) proteins (HSP90) are members of the HSP family. Their synthesis is inducible by HS and a variety of stress signals. HSP90 is also abundant under normal physiological conditions and its synthesis can be regulated during growth and differentiation. Therefore, HSP90 is speculated to have important biological functions, in addition to its role in mediating stress responses. However, the mechanism(s) regulating hsp90 gene expression in nonstressed cells is poorly understood. As a prerequisite towards understanding the basis for hsp90 regulation, we have cloned and characterized the 5' flanking region of murine hsp84, one of two genes which code for HSP90 proteins. Full basal promoter activity of hsp84 was found to be associated with a 627-bp region immediately upstream from the transcription start point (tsp). Sequence analysis revealed several putative regulatory elements, including a HS element (HSE), an AP1-binding site (AP1), a cyclic AMP response element (CRE), and four stimulatory protein-1-binding sites (SP1). HS inducibility required the HSE which was bound by HS transcription factor-1(HSF-1) present in extracts prepared from cells exposed to HS. The HSE was not required for basal (non-HS) expression, but, interestingly, two protein-HSE complexes, devoid of HSF-1 and HSF-2, were formed under these conditions. The potential significance of these findings to the expression of hsp84 under normal physiological conditions is discussed. PMID- 8682318 TI - Developmental regulation of murine integrin beta 1 subunit- and Hsc73-encoding genes in mammary gland: sequence of a new mouse Hsc73 cDNA. AB - A partial integrin beta 1 subunit-encoding cDNA (Itg beta 1) and a new heat-shock protein 70-like-encoding cDNA (Hsc73) homologous to rat Hsc73 were cloned by differential display and RT-PCR from mouse mammary gland. Their developmental regulation during pregnancy, lactation and involution is reported. The Itg beta 1 mRNA content was stable in the first half of gestation, decreased to a minimum during lactation and increased markedly in early involution. Hsc73 gene expression was high in the first half of gestation and decreased to a minimum during lactation. The possible significance of the two observed patterns of expression is discussed. PMID- 8682319 TI - Identification and characterization of Zic4, a new member of the mouse Zic gene family. AB - The mouse Zic genes encode zinc-finger (Zf) proteins expressed only in the cerebellum of the adult brain. The genes are the vertebrate homologues of the Drosophila pair-rule gene, odd-paired (opa). We identified a novel gene, Zic4, which belongs to the Zic gene family, through a genomic and cDNA cloning study. Zic4 is highly similar to Zic1, Zic2 and Zic3, especially in its Zf motif. An analysis of the genomic organization of Zic4 showed that the gene shares a common exon-intron boundary with Zic1, Zic2, Zic3 and opa. The chromosomal location of Zic4 was determined to be mouse chromosome 9 in the vicinity of Zic1, using an interspecific backcross panel. An RNase protection study showed that Zic4 is expressed only in the cerebellum during the adult stage, as are the other Zic genes. The temporal profile of mRNA expression in the developing cerebellum is similar to that of Zic3 which has a peak on postnatal day 5. These findings suggest that Zic4 is a gene which works cooperatively with other Zic genes during cerebellar development. PMID- 8682320 TI - Recombinant rabbit Fab with binding activity to type-1 plasminogen activator inhibitor derived from a phage-display library against human alpha-granules. AB - The display of panels of antibody (Ab) fragments on the surface of filamentous bacteriophage offers a way of making Ab with defined binding specificities. Because rabbit Ab are routinely utilized as immunologic probes in a variety of biological techniques, the aim of this study was to design and utilize primers for the amplification of mRNAs encoding rabbit kappa light and gamma heavy chains for the construction of an Ab library from this species. Using the polymerase chain reaction, a diverse Ab library with a repertoire of 2 x 10(7) clones was derived from the spleen and bone marrow of a rabbit that had been immunized with purified human platelet alpha-granules. From this library, specific clones were isolated after three rounds of affinity selection with binding activity to type-1 plasminogen activator inhibitor, a trace protein contained in platelet alpha granules. These data indicate that recombinant phage-displayed Ab libraries obtained after immunization with complex biological antigens can be employed for the isolation of rabbit monoclonal Fab against specific antigens contained in the biological sample. PMID- 8682321 TI - Isolation and sequencing of the cDNA encoding phosphatidylinositol transfer protein from rabbit lung. AB - The cDNA clones encoding rabbit lung phosphatidylinositol transfer protein (PI TP) were isolated and sequenced. The putative polypeptide consisted of 270 amino acid (aa) residues, the same as human PI-TP, but one aa residue less than the PI TP of rat and mouse. PI-TP RNA expression in various tissues of a pregnant rabbit was analyzed by Northern blot. Brain, placenta and fallopian tube had the highest PI-TP RNA expression. PI-TP RNA expression in alveolar epithelial type-II cells isolated from rabbit lung markedly increased after a 24-h culture, suggesting that PI-TP RNA expression in type-II cells can be modified by ambient factors. PMID- 8682322 TI - Cloning, sequencing and functional expression of a DNA encoding pig cytosolic malate dehydrogenase: purification and characterization of the recombinant enzyme. AB - Using the polymerase chain reaction, DNA encoding cytosolic malate dehydrogenase (cMDH) has been cloned from a pig heart cDNA library. Large amounts of the enzyme (30 mg per litre of original culture) have been produced in Escherichia coli using an inducible expression vector (pKK223-3) in which the 5'-non-coding region of the gene was replaced with the tac promoter. The complete nucleotide sequence of the DNA is reported for the first time. The recombinant cMDH purified was shown to be identical to the native enzyme according to: chromatographic behaviour, isoelectric point, N-terminal amino acid sequence, and physiochemical and catalytic properties. PMID- 8682323 TI - Structural organization and mapping of the human mitochondrial glycerol phosphate dehydrogenase-encoding gene and pseudogene. AB - Mitochondrial glycerol phosphate dehydrogenase (mtGPD) is the rate-limiting enzyme in the glycerol phosphate shuttle, which is thought to play an important role in cells that require an active glycolytic pathway. Abnormalities in mtGPD have been proposed as a potential cause for non-insulin-dependent diabetes mellitus. To facilitate genetic studies, we have isolated genomic clones containing the coding regions of the human mtGPD-encoding gene (GPDM). The gene contains 17 exons and is estimated to span more than 80 kb. All splice junctions contain GT/AG consensus sequences. Introns interrupt the sequences encoding the leader peptide, the FAD-binding site, the calcium-binding regions, and a conserved central element postulated to play a role in glycerol phosphate binding. Fluorescence in situ hybridization was used to map this gene to chromosome 2, band q24.1. A retropseudogene was identified and mapped to chromosome 17. PMID- 8682325 TI - Internet resources on aging: research. PMID- 8682324 TI - Heterogeneity in the third intracytoplasmic region of the oxytocin receptor encoding gene. AB - The oxytocin receptor (OTR), a member of the seven-transmembrane domain guanine nucleotide-binding protein (G protein) coupled receptor family plays a central role in lactation, ovarian cyclicity and reproductive behaviour. Recent cloning and sequencing unexpectedly revealed that the third intracytoplasmic region (3ICR) of the sheep receptor has 3 and 2 additional amino acids (aa) relative to the rat and human receptors, respectively. We have now confirmed, by sequencing polymerase chain reaction (PCR)-derived genomic fragments coding for the OTR 3ICR from a variety of ruminant and non-ruminant species, that additional aa are a general phenomenon in ruminants. PMID- 8682326 TI - Minority perspectives from the Health and Retirement Study. Introduction: health and retirement among ethnic and racial minority groups. PMID- 8682327 TI - The role of ethnicity in the disability and work experience of preretirement-age Americans. AB - Using the 1992 HRS, this study examines the effects of social and demographic risk factors, including ethnicity, as well as health and job characteristics on disability and work status among 8,701 preretirement-age Americans with work history. Analytic results indicated that non-Anglo ethnicity was not a significant predictor of disability status but that being African American was a strong significant predictor of being a past versus current worker. The primary predictors of disability and work status were health behaviors, effects of health conditions, job characteristics, and workplace adaptations, factors that lend themselves to policy manipulation. PMID- 8682328 TI - Disentangling the effects of disability status and gender on the labor supply of Anglo, black, and Latino older workers. AB - Utilizing data from the 1991 Health and Retirement Study Early Release File, this article examines the effects of disability status on labor force participation and earnings of preretirement workers aged 50 to 64. Results from our hierarchical regression models suggest that poor health and the presence of a work disability significantly reduced the labor force participation and earnings of older men and women. These analyses also suggest that economic well-being was constrained by the costs associated with additional "minority statuses." For example, the odds of being employed were reduced by approximately 46% for black men with disabilities. Further, the earnings of black men were 17% lower than the earnings of their nondisabled counterparts. PMID- 8682329 TI - Race differences in labor force attachment and disability status. AB - We used the first wave of the Health and Retirement Survey to study the effect of health on the labor force activity of black and white men and women in their 50s. The evidence we present confirms the notion that health is an extremely important determinant of early labor force exit. Our estimates suggest that health differences between blacks and whites can account for most of the racial gap in labor force attachment for men. For women, when participation rates are comparable, our estimates imply that black women would be substantially more likely to work than white women were it not for the marked health differences. We also found for both men and women that poor health has a substantially larger effect on labor force behavior for blacks. The evidence suggests that these differences result from black/white differences in access to the resources necessary to retire. PMID- 8682330 TI - Physical function among retirement-aged African American men and women. AB - Prior attempts to identify factors associated with physical function (here, major lower body movements) among African Americans have been constrained by a narrow range of measures, small sample sizes, or both. The 1992 Health and Retirement Study (HRS) contains a substantial over-sample of African Americans (649 men and 957 women self-respondents aged 51 to 61 years), and detailed measures of high risk behaviors, disease prevalence and severity, impairment, and physical function. We extend the natural history of disease to the natural history of functional status and model sociodemographic characteristics, high-risk behaviors, disease prevalence and severity, and impairments as direct and indirect influences on physical function in this African American sample. This natural history of functional status model fits the data well for both men (ROC = .88) and women (ROC = .83), although there are gender differences. Slightly over one-half of the women report some difficulty in physical function, compared with one-third of the men. Women also have a higher mean body-mass and report a greater prevalence and severity in 6 of 9 chronic diseases and more pain, but are less likely to smoke or abuse alcohol than men. Importantly, many of the factors with the largest direct and indirect associations with difficulty in physical function among these African American men (alcohol abuse, smoking, body mass, diabetes, heart disease, cerebrovascular disease, arthritis, and pain) and women (alcohol abuse, body mass, arthritis, and respiratory illness) are all potentially preventable or manageable. PMID- 8682332 TI - The health-wealth connection: racial differences. AB - This article examines the theoretical connection between health capital and financial capital in an economic life-cycle model, exploring possible explanations for racial differences in capital accumulation behavior. Using data from the Health and Retirement Survey, detailed descriptive analysis and a comparison of regression models for health and financial capital are presented. The results, although preliminary and based on cross-section data, suggest possible racial differences in the connection between health and wealth and deserve further study. PMID- 8682333 TI - Racial differences in home ownership and home equity among preretirement-aged households. AB - This article measures the racial disparities in home ownership and home equity among preretirement-aged households. It computes the proportion of the racial gap explained by discrimination in housing and credit markets. Maximum likelihood and nonlinear least squares estimates are obtained for models of home ownership probabilities and home equity, conditional on home ownership, yielding computations for expected home equity for black and white households. The results reveal an average discriminatory gap in expected home equity as a percent of the actual gap of 55%. In the top third of the family income distribution, the measured discriminatory gap is 82%; in the middle third it is 83%; in the lowest third it is 62%. PMID- 8682331 TI - The extent of private and public health insurance coverage among adult Hispanics. AB - Data from the Health and Retirement Survey reveal extremely low levels of health insurance coverage among Hispanics and, especially, among Mexican Americans. The data reveal that this lack of insurance is associated with lower rates of employer-based and privately purchased coverage. Even after controlling for a large number of insurance-related factors, Hispanics have rates of health insurance coverage that are lower than those of either non-Hispanic blacks or whites. This serious lack of health insurance coverage among preretirement-age Hispanics has serious implications both for health, because the lack of insurance represents a major barrier to health care, and for the adequacy of retirement coverage, because private insurance represents an important supplement to Medicare. PMID- 8682334 TI - The role of bridge jobs in the retirement transition: gender, race, and ethnicity. AB - We used the first wave of the new Health and Retirement Study (HRS) to document the importance of transitional stages--bridge jobs--between career employment and complete labor force withdrawal in the early 1990s. We describe the labor force status of a sample of about 9,500 older Americans with some work experience after age 49, and the transition patterns of those for whom we can identify a career job. We observe significant bridge job activity, including part-time work and movement between self-employment and wage-and-salary jobs. Subsequent waves of the HRS will permit researchers to follow this large sample through the labor force withdrawal process and to analyze the determinants and consequences of alternative retirement routes. PMID- 8682335 TI - Retirement expectations: differences by race, ethnicity, and gender. AB - Analyses by race and ethnicity of several important dimensions of labor market behavior have been constrained in the past by limited samples of the African American and Hispanic populations. This article uses data from the first wave of the Health and Retirement Survey, which oversamples these populations, to compare the retirement plans of African American, Hispanic, and white married men and women. Findings suggest that retirement expectations may accurately forecast retirement behavior and that the differences by race and ethnicity, as well as by gender, that are evident in retirement plans are likely to be reflected in retirement outcomes. PMID- 8682336 TI - Complex marital histories and economic well-being: the continuing legacy of divorce and widowhood as the HRS cohort approaches retirement. AB - We use data from the first wave of the Health and Retirement Survey (HRS) to examine the marital histories of this cohort of women and men on the verge of retirement. The legacy of past increases in divorce rates is evident in the complex marital histories of HRS households and the relationship between those histories and current economic status. Couples in a first marriage now make up only one-quarter of black households and fewer than half of all white and Hispanic households. In over one-third of all married-couple households, at least one spouse had a previous marriage that ended in divorce or widowhood. These couples have significantly lower incomes and assets than couples in first marriages. Contrary to the popular notion that private and public insurance better provide for the security of widows than divorced persons, currently widowed households and couples in which the prior marriage of one spouse had ended in widowhood are no better off than are their divorced peers. This holds true for both black and white households. From a single cross-section, one cannot tell what caused these differences in income and wealth across marital status groups although it is clear that women and blacks spend a higher percentage of their lifetime outside of marriage than do men and whites. We also speculate from estimates of widowhood expectations for a subset of married respondents that underestimating the chances of widowhood--because both men and women overestimate their chances of joint survival--may be a factor in the relatively low economic status of widows. Because couples in life-long marriages have been the traditional standard upon which marital property reform and the survivorship rules of private and public programs are based, their diminishing importance among all households raises concern about the protection provided by these institutions against the long-term economic consequences of past and future marital dissolution. PMID- 8682337 TI - Social Security and the myth of the entitlement "crisis". AB - Although public support for Social Security remains high, confidence in the viability of the program has declined. The decline in confidence reflects confusion generated by public dialogue about various crises, the most recent being the "entitlement crisis." This article discusses two central ideological themes of the entitlement crisis, that entitlement spending is crowding out funds for other social needs and that current trends are unsustainable. It questions the substantive basis of these themes and then critically evaluates two proposals for the restructuring of Social Security, means-testing and privatization. PMID- 8682338 TI - Reverse mortgages and the economic status of elderly women. AB - Data from the 1990 Census of Population and Housing are used to estimate the potential demand for reverse mortgages among elderly women householders. A reverse mortgage product is simulated using parameters based on the Home Equity Conversion Mortgage insurance demonstration, and its effect on poverty and income distribution among this group is calculated. Approximately 1.8 million women with low incomes and home equity of $40,000 and above could see a significant increase in income under such a program. PMID- 8682339 TI - Aging research and the Puerto Rican community: the use of an elder advisory committee of intended respondents. AB - This article reports on the use of a Puerto Rican Elder Advisory Committee and the role it played in the development and implementation of a four-year research project. The use of an advisory committee composed of the ultimate beneficiaries of a study increases the likelihood that the results will meet their needs. This article provides suggestions for how best to utilize this important resource in all phases of a research project. PMID- 8682340 TI - [Joseph Baron, physician, scientist, educator, humanist]. PMID- 8682341 TI - [Effect of ovariectomy and natural menopause on levels of selected pituitary hormones, 17-beta estradiol and lipid profile in blood serum]. AB - The main goal of this study was to measure changes in pituitary and sex hormone levels as a result of surgical or natural menopause, assess influences and correlation's between concentration of hormones and selected parameters of lipid profile important in the atherogenesis in the early period after surgical ovariectomy and during natural menopause. The first group consisted of 59 women (age +/- 3, 7) on whom hysterectomy with bilateral ovariectomy were performed. Blood samples were taken before operation and on 9th day after the operation. The second group consisted of 28 postmenopausal women (age 53 +/- 4). Methods hormonal measures were performed by radioimmunometric assays in blood serum (FSH, LH, PRL, 17-beta estradiol, testosterone, androstenedione and SHGB). The assessment of particular parameters of lipid profile: total cholesterol, HDL-C, LDL-C and triglycerides was performed by biochemical methods. RESULTS: We found statistically important, negative correlation between levels of estradiol and gonadotrophins; after surgical ovariectomy and natural menopause there are time depended changes in lipid profile. Early period after surgical ovariectomy is characterized by decrease in concentration of 17-beta estradiol and increase of atherogenic lipid parameters. Among postmenopausal women there is negative correlation between 17-beta estradiol concentration and atherogenic factor and total cholesterol. Changes of the lipid profile in the serum of the blood may be connected with hormonal homeostatic disturbances, decreased level of oestrogen's and rising level of gonadotrophins. PMID- 8682342 TI - [Molecular basis of polycystic ovarian syndrome]. AB - Polycystic ovarian syndrome (PCO) is a relatively poorly defined type of steroidogenic abnormality, dependent on an overproduction of lutropin (LH). The PCO is characterized by infertility, amenorrhea or oligomenorrhea, obesity and hirsutism. The clinical symptoms are associated with typical morphological changes of the ovaries. It has been suggested that hyperplastic secondary interstitial cells and theca cells are the main site of excess androgen production. In PCO the elevation of androgens is observed, while the estrogen level is normal or slightly decreased. In the ovarian sex steroidogenic pathways, 17 alpha-hydroxylase, which produces androgens and aromatase, which converts androgens to estrogens are important regulatory enzymes. Major components of 17 alpha-hydroxylase and aromatase are cytochromes P450 17 alpha and P450 arom. Histochemical investigations revealed increased immunoreactivity with the antibody directed against P450 17 alpha in theca cells. In this review data from literature are presented and discussed regarding endocrinological and molecular background of PCO. PMID- 8682343 TI - [Pharmacologic treatment for polycystic ovary syndrome]. AB - The study an evaluation of pharmacological treatment of PCOS with regard to inhibition in increase of hirsutism, regulation of the menstrual cycle, infertility and acne. During treatment the following pharmacological agents were used; sequential estrogen-progestagens, oral contraceptives, antiandrogens, clomiphene citrate and dexamethasone. The regular menstrual non-ovulating cycles were achieved in 82%, improvement of hirsutism in 73.8% and retreat in 92.9% fertility by 76.9% of patients after conservative treatment. PMID- 8682344 TI - [Human gonadal hilar cells--histogenesis, differentiation, role]. AB - Identification hilar cells in fetus and adult gonads two sex and dysgenetic gonads were based on histochemical and immunohistochemical methods. The hilar cells were detected in 40% of fetus gonads (ovarian testis), two time more in adult and dysgenetic gonads. The attention was put to their connection with nervous system. On the bases of specific markers there was established their mesenchymal origin, ability to response to gonadotropin induction and synthetization steroid hormones, mainly androgens. Hilar cells in dysgenetic gonads and postmenopausal women may be responsible for clinical manifestation of virilisation. PMID- 8682345 TI - [Beta-endorphin--physiologic role and menstrual cycle disorders]. AB - There are three classes of endogenous opioid peptides: endorphins, enkephalins, dynorphins. Beta-endorphin is the main representative of endogenous opioid peptides. Beta-endorphin plays a role in the regulation of the normal menstrual cycle and possibly in the onset of puberty. This peptide is also involved in the pathophysiology of such menstrual disorders as: exercise-associated amenorrhoea, stress-induced amenorrhoea, weight loss related amenorrhoea and premenstrual syndrome. Probable mechanism is that alterations in the levels of beta-endorphin may change the pulsatile release of GnRH. This article reviews contemporary views on the role of beta-endorphin in the physiology and disorders of the menstrual cycle. PMID- 8682346 TI - [Evaluation of beta-endorphin levels and gonadotropin, prolactin, cortisol and estradiol in serum of girls with secondary amenorrhea associated with weight loss]. AB - Levels of beta-endorphin, FSH, LH, PRL, cortisol and estradiol in blood serum were measured in 20 girls with weight loss related amenorrhoea. Serum beta endorphin levels were also measured in a group of 15 young, regularly menstruating healthy girls (control group). Levels of beta-endorphin were significantly lower in examined group than in control one. Serum levels of FSH, LH, estradiol were low. Serum levels of PRL and cortisol were normal. These observations suggest, that beta-endorphin is involved in the pathogenesis of weight loss related amenorrhoea. PMID- 8682348 TI - The British Society of Gastroenterology spring meeting 20-22 March 1996. Abstracts. PMID- 8682347 TI - [Hormonal aspects of obesity]. AB - Our article concerns the obesity, and its relationship with the menstrual disorders. This article also discusses contemporary opinions on the role of the hypothalamus, and peripheral hormonal glands in the pathophysiology of the obesity. PMID- 8682349 TI - [Head injuries in the Bible]. AB - 3 cases of head injury are described in the Bible: the death of Sisera by the hand of Jael (Judges 4: 21; 5: 25); the skull fractures of Avimelech incurred at the tower of Tevetz, (Judges, 9: 53, 54); and the slaying of Goliath by David, (Samuel I 17: 49-51). The various attempts to understand the mechanisms of these head injuries using philology, knowledge of the art of biblical warfare and modern medical considerations are reviewed. We try to identify the site of the mortal blow to Sisera's head, to understand why Avimelech asked to be killed, and to decide whether the giant from Gath was a rugged warrior or just an endocrinological cripple. PMID- 8682350 TI - [Neurological symptoms associated with vitamin E deficiency]. AB - Children deficient in vitamin E have various neurologic symptoms. 2 cases representing different mechanisms of this vitamin deficiency are reported. A 15 year-old boy with fat malabsorption due to cystic fibrosis who was diagnosed as being vitamin E deficient (< 0.5 mg/l), had typical neuropathies. On the other hand, a 12-year-old Beduin girl had isolated vitamin E deficiency, as well as neurological symptoms suggestive of Friedrich's ataxia. Vitamin E supplementation by intramuscular injection in the first case and per os in the second led to significant improvement in neurological symptoms. PMID- 8682351 TI - [Joubert syndrome]. AB - Joubert syndrome was first described in 1969 and 100 cases have been published so far. It includes: partial or complete agenesis of the vermis, episodic hyperpnea, ataxia, a disorder of ocular movement and mental retardation. It is autosomal recessive and there are descriptions of families with involvement of multiple children, both boys and girls. Since dysmorphic signs are not prominent in this syndrome, diagnosis is often delayed. To the best of our knowledge, Joubert syndrome has not been previously described in Israel. We present a family with 3 siblings with this syndrome. Increased awareness will lead to earlier diagnosis, proper developmental treatment, and accurate genetic counseling. PMID- 8682352 TI - [Limb injuries at the Aerodium hover sport facility in Eilat]. AB - The Aerodium hover sport facility in Eilat has been in operation for the past 4 years and 33 patients have been treated for injuries caused by falls while hovering. The Aerodium is a new sport facility in Israel, similar to others in the US and Switzerland. It includes a 4-meter-wide wind tunnel with air pushed vertically upwards toward its center. Air flow velocity is adjustable and ranges between 120 and 140 km/hr, with a maximum of approximately 180 km/hr. Participants wear special suits and jump into the center of the column of air to hover. The hover suits are very wide, and puff up like a balloon; the sleeves and leggings have vents through which air escapes. Participants hover with their arms spread out and their legs slightly spread apart. The inexperienced hover at a height about 2 m. and the more experienced at heights of up to 5 m. During falls the person hovering lands on air mattresses surrounding the air column. Failure to follow rules and procedures, usually while changing limb position during hovering, can unbalance the inexperienced participant and lead to uncontrolled spins and falls. PMID- 8682353 TI - [Evaluation of sexual abuse in an infant with condyloma acuminatum]. AB - Condyloma acuminatum is a skin infection affecting the anogenital area caused by the human papilloma virus and is usually sexually transmitted in adults. The disease in children is rare and the mode of transmission is controversial. Because of the possibility that children with condyloma acuminatum have been sexually abused, a thorough medical and social evaluation is essential. However, the physician should bear in mind the possibility of nonsexual transmission. Effective management of condyloma acuminatum in prepubertal children involves a multidisciplinary approach and cooperation. We present an 11-month-old girl with genital lesions of condyloma acuminatum. Similar lesions were found in her father's penile area. These findings suggested the possibility of sexual abuse as the cause of the infection. However, detailed, meticulous investigation of the case did not support this suspicion. Our final impression was that transmission was probably nonsexual, as there was no evidence for sexual abuse. PMID- 8682354 TI - [Tuberculous choroiditis]. AB - Tuberculosis is a rare cause of choroiditis. In most cases there is only a presumptive diagnosis based on a history of TB, its clinical picture, and a positive skin test. A 79-year-o;d man complained of acute, right visual loss. On examination, choroiditis was found. During his 20s he had had pulmonary tuberculosis; his Mantoux test was positive. PMID- 8682355 TI - [Acute renal failure as a complication of cholera]. AB - We present a 72-year-old man who had episodes of severe, acute renal failure during severe attacks of diarrhea caused by Vibrio cholerae. Patterns of acute tubular necrosis and tubulointerstitial nephritis developed following hypotension and decrease in renal blood flow, causing secondary renal ischemia. There was severe dehydration with profound hypovolemia and infection. The clinical picture included fever, weakness, arthralgia, pedal edema, mild bilateral pleural effusions, anemia, leukocytosis, azotemia with a maximum of 330 mg/dl of urea, creatine to a maximum of 9.8 mg/dl, hypoproteinemia, severe metabolic acidosis, marked increase in lactate dehydrogenase (LDH) and creatine phosphokinase (CPK), microscopic hematuria, sterile leukocyturia, normoglycemic glucosuria and phosphaturia with diminished tubular reabsorption of phosphorus. A short oliguric phase was followed by a polyuric phase lasting about 10 days, and glomerular and tubular function became normal after about 3 weeks. Treatment was by intensive infusions of fluids, electrolytes, sodium bicarbonate, salt-free albumin and antibiotics. To the best of our knowledge, this renal complication of cholera has not yet been described in Israel. PMID- 8682356 TI - [Wisdom of the body and microbial resistant to antibiotics]. PMID- 8682358 TI - [A pediatrician's guide to the Internet]. PMID- 8682357 TI - [The harmful human body and ways of protection]. PMID- 8682359 TI - [Living related liver transplantation]. PMID- 8682360 TI - [New therapeutic modalities for pulmonary disease in cystic fibrosis]. PMID- 8682361 TI - [Male osteoporosis]. PMID- 8682363 TI - [Drug treatment in multiple sclerosis--1995]. PMID- 8682362 TI - [Transesophageal echocardiography in the operating room: new applications]. PMID- 8682364 TI - [Clinical use of intravenous amiodarone for supraventricular arrhythmias]. PMID- 8682365 TI - [Nasal positive pressure ventilation--renewal of ventilation technique]. PMID- 8682366 TI - [Subclinical vitamin A deficiency--health implications in children]. PMID- 8682367 TI - [Acquired immunodeficiency syndrome--1995 (Part II)]. PMID- 8682368 TI - [Maimonides' treatise on asthma. Part I: Background]. PMID- 8682369 TI - [Motor potentials evoked by magnetic stimulation--a tool for objective assessment of motor conduction along the spinal cord and its roots]. AB - Magnetic stimulation of the motor cortex and nerve roots in conjunction with F wave recording was used for assessment of central and peripheral motor conduction times in 98 patients suffering from myelopathy and cervical or lumbo-sacral radiculopathy. Significant prolongation of the central motor conduction times was found in the myelopathy group. The Motor Evoked Potential was of low amplitude and distorted shape. The amplitude of the F-wave was markedly increased. The main feature of the radiculopathy group was prolonged motor root conduction time as evident by delayed F-wave. Motor evoked potentials proved to be a reliable objective tool in the functional evaluation of conduction along the spinal cord and its roots. PMID- 8682370 TI - [Immediate breast reconstruction with transverse abdominal myocutaneous flap]. AB - Mastectomy in 16 consecutive patients with carcinoma of the breast was immediately followed by reconstruction with a transverse abdominal, myocutaneous flap. Surgery was performed simultaneously by a team of general surgeons and a team of plastic surgeons. The final cosmetic result was considered very good by most patients. Complications were only minor and were treated conservatively. We consider breast reconstruction by this method, after mastectomy for breast carcinoma, to be the method of choice. PMID- 8682371 TI - [Chloral hydrate--is it safe?]. AB - Chloral hydrate is widely used as a sedative or hypnotic, especially in geriatric and pediatric patients. In therapeutic doses blood pressure and respiration are only minimally affected. We describe a 9-year-old boy in whom a life-threatening cardiac arrhythmia dominated the clinical presentation of chloral hydrate intoxication. In spite of its widespread use, the dangers of chloral hydrate overdosage, especially cardiac arrhythmias, are not sufficiently appreciated. PMID- 8682372 TI - [Ultrasound-guided aspiration of pleural fluid]. AB - We review the outcome of guided, percutaneous, catheter drainage of pleural collections in 102 patients over a 2-year period. In 87% diagnostic aspiration of small or loculated collections was performed. Drainage of malignant and nonmalignant effusions in high-risk patients, or after failure of drainage without imaging guidance, was performed in 13%. All aspirations were successful and the only complication was a small pneumothorax in a single patient. If the collection was a small pneumothorax in a single patient. If the collections were large and easy to aspirate, we marked the best location for aspiration on the skin and sent the patient back to the ward for aspiration. We conclude that the use of sonography increases the proportion of successful drainage of small pleural collections and results in few complications. PMID- 8682373 TI - [Cotard syndrome]. AB - We describe a schizophrenic paranoid patient, who developed a unique clinical state that fits the Cotard syndrome. The article deals with the course of the disease, the clinical characteristics, the difficulties of treatment. The process of diagnosis and its difficulties, and the rareness of the symptoms are emphasized. Various etiological causes of the syndrome are discussed. PMID- 8682374 TI - [Disease at any price: psychological challenge and the financial costs of somatization]. AB - In clinical medicine we sometimes deal with patients with unexplained somatic complaints. In a 45-year-old woman with multiple somatic complaints, 2 years of medical examinations in search of a disease diagnosis cost almost 250,000 shekels (about +84,000). The differential diagnosis between somatization, hypochondriasis and psychosomatic pain, and the reasons why physicians are tempted to participate in the "investigation dance" are presented. PMID- 8682375 TI - [The necessity of mechanical bowel preparation in colo-rectal surgery]. PMID- 8682376 TI - [Primary angiitis of the central nervous system]. PMID- 8682377 TI - [Molecular genetics of Huntington's disease]. PMID- 8682378 TI - [Psychiatric aspects of menopause]. PMID- 8682379 TI - [Cigarette smoking in diabetes]. PMID- 8682380 TI - [Amplification of protooncogenes and expression of the HER2/neu oncogene in invasive breast cancer]. AB - The protooncogene HER2/neu was analyzed in 27 women with invasive breast cancer and in 26 with benign breast conditions. Gene amplification was found in 3 patients, 1 in stage 3 and 2 in stage 4. In 3 patients in stage 2 overexpression of protein was found. Although amplification of the gene was found to be a significant predictor of clinical outcome (p < 0.05), high expression of the gene did not correlate with prognosis. In women with benign breast conditions there were no alterations of HER2/neu amplification may become a molecular marker in some malignancies. It should be noted that since few tumors show amplification, examination of a small series may not reveal clinical association with these alterations. Therefore, our conclusions require confirmation on a larger scale with long-term clinical follow-up. PMID- 8682381 TI - [Burnout among rehabilitation professionals]. PMID- 8682382 TI - [Suggested clinical algorithm for the management of mild head injuries in the emergency department]. PMID- 8682384 TI - [Iatrogenic damage]. PMID- 8682383 TI - [Maimonides' treatise on asthma, Part II: Text]. PMID- 8682386 TI - [Symposium on drowsy driver--a round-table discussion. Sheba Medical Center, Tel Hashomer, June 6, 1995]. PMID- 8682385 TI - [Perihilar and mediastinal lymphadenopathy in a young man with fever]. PMID- 8682387 TI - [Late solitary metastases of breast origin presenting as primary colonic carcinoma]. AB - The case of a 72-year-old woman with 2 solitary metastases to the colon of breast origin with mimicked primary colonic cancer is presented. The primary breast lesion was an infiltrating duct carcinoma and the metastases to the colon were discovered 6 years later. Some of the regional lymph nodes draining the colon were infiltrated by tumor, probably originating from the 2 colonic metastases. This is an unusual condition that has not as yet yet been reported. PMID- 8682388 TI - [Guidelines for treating low back pain in primary care. The Israeli Low Back Pain Guideline Group]. AB - Low back pain (LBP) is a common problem in primary care, the successful management of which poses special challenges for patients and practitioners alike. It has been estimated that all adults will suffer LBP sometime during their lifetimes. It is one of the most frequent reasons for visiting a primary care physician, yet practitioners often find it difficult and frustrating to treat. This medical protocol is concerned with the diagnosis, treatment, and follow-up of low back pain in adults. It was developed for community-based, primary care physicians (general practitioners, family physicians, and internists) to serve as a general outline, to be adjusted in accord with the individual's circumstances. The protocol provides a "Ten Commandments" for the care of LBP, outlines the background of the problem, presents an overall algorithm and deals with issues of diagnosis, imaging, and treatment. In general, LBP in primary care is conceived of as a benign ailment, and emphasis is placed on reducing pain, resuming functioning and returning to work. The main task of the physician is to distinguish the less than 10% of cases with serious, specific causes of LBP from the more than 90% with nonspecific etiologies. In the great majority of patients, imaging studies such as X-ray, CT, MRI, and bone scan, and also EEG are unnecessary. PMID- 8682389 TI - [Huntington's disease: molecular basis and detection of carriers]. AB - Huntington's disease (HD) results from extensive damage to the nerve cells of the brain cortex and basal ganglia. The gene associated with these changes was mapped in 1983 to the short arm of chromosome 4, at 4p16.3. A decade later it was cloned and the mutation was identified as an increase in the number of CAG repeats in the coding sequence. In the normal gene there are up to 34 repeats but in HD there are more than 36. This is termed dynamic mutation and is found in several other diseases, most of which manifest neurological symptoms. We summarize our studies of 10 families with HD, and 20 individuals with no known history of the disease. Our studies suggest that Jewish patients with HD exhibit the same dynamic gene mutation found in non-Jews. The number of repeats, both in diseased patients and normal controls, is similar to that found in non-Jews. Paternal inheritance was associated with increased severity of symptoms and earlier clinical manifestation, similar to what has been reported. Our experience testing for Huntington gene mutations indicates that this is a relatively simple, reliable and accurate test which can be used in the diagnosis of the disease, in identifying carriers, and for prenatal diagnosis. PMID- 8682390 TI - [Successful single-lung transplantation in emphysema]. AB - Lung transplantation is now considered acceptable therapy for end-stage lung disease. Until recently therapy for emphysema was disappointing, but lung transplantation has brought new hope for those terminally ill with the disease. We present our early experience with single-lung transplantation in 5 men and 1 woman with emphysema, 40-61 years old. All recovered following surgery, with remarkable improvement in lung function and functional capacity. They are now 6 20 months post-transplantation, do not need oxygen supplementation and are able to perform their normal daily activities. Shortage of donor organs is the limiting factor for single-lung transplantation in these patients. PMID- 8682391 TI - [An epidemic of respiratory syncytial virus bronchiolitis among infants in northern Israel]. AB - In the wake of a community outbreak of bronchiolitis in northern Israel from December 1993 to March 1994, we conducted a retrospective study of 108 infants aged 2 weeks to 14 months with proven respiratory syncytial virus (RSV) infection (diagnosed by a rapid RSV antigen test in nasopharyngeal secretions). 47% of the infants were less than 8 weeks old. Mean hospital stay was 6.6 days (range 1-60). The characteristic clinical findings were: cough in all patients, dyspnea in 96%, rhinitis in 95% and fever in 55%. In those younger than 8 weeks, or in those with underlying diseases, hospitalization was longer, the disease was more serious and complications more frequent (p < 0.002). 4 children (3%) died, 3 of whom had severe congenital heart defects. All children were treated with oxygen and beta agonist inhalations. The 33% who also received corticosteroids were older and most had a history of pulmonary diseases, such as asthma or bronchopulmonary dysplasia. There was no difference between those who did or did not receive corticosteroids with regard to severity of disease or rate of complications. Ribavirin was used to treat 19 (17.5%), most of whom had underlying lung disease. The others were otherwise healthy infants younger than 8 weeks. 13 were cared for in the intensive care unit, 11 of whom required mechanical ventilation. A rapid test for detection of RSV infection enabled prompt isolation of infected patients so that the risk of nosocomial infection was reduced and Ribavirin therapy could be started early, if required. PMID- 8682392 TI - [Incidence, risk factors and causes of stroke in young adults]. AB - A 1-year, nation-wide study was conducted to determine the incidence, risk factors and causes of stroke in young adults. Permanent residents of Israel of both genders, aged 17-49 years, who were referred to 23 general hospitals with a first, acute stroke from 1 Nov. 1992 to 31 Oct. 1993, were studied. Briefed investigators administered a prospective questionnaire pertaining to demographic and socioeconomic variables; past, present and family histories; and condition on admission and discharge. 253 subjects, 17-49 years of age, of whom 62.8% were men, had a first stroke during the year. The incidence was 10.3/100,000/year, increasing with age. 80.6% of strokes were due to infarctions, 9.9% intracerebral hemorrhages, 7.9% subarachnoid hemorrhages, and 1.6% were of undetermined type. There was no seasonal variation in incidence; 45.6% occurred in the morning. The main risk factors were smoking (53.6%), hypertension (43.4%), hyperlipidemia (22%) and diabetes (21%). Atherosclerosis was the main cause of the strokes (52%). In 3.5% there was no residual damage, 10.3% were left with minimal damage, 40.3% remained with minor disability, 19% with moderate disability, 17.4% with severe disability and 9.9% died. The data on incidence concur with those published from western Europe. However, the data on risk factors differ from those of young adults and are identical with those of the older population. Although these risk factors can be modified, preventive measures were insufficiently used. More comprehensive diagnosis is needed to determine stroke etiology in each patient and establishing a national stroke registry is important for planning and improving services. PMID- 8682393 TI - [Complications of exchange transfusion in term and preterm newborns]. AB - Exchange transfusion has an important role in the treatment of hyperbilirubinemia of the newborn. It is used in attempts to prevent kernicterus when bilirubin levels are high. We describe our experience in 203 exchange transfusions performed on 143 infants (81 males and 62 females) with hyperbilirubinemia during 1983-1992. In only 30% of cases was there a specific etiological diagnosis of the jaundice based on a positive Coombs test, G6PD deficiency, or the presence of sepsis or maternal diabetes; the rest were idiopathic. 57% of the neonates were premature (26-36 weeks of gestation). Premature neonates underwent more transfusions than full-term infants (1.6 vs 1.2). There was no direct death from exchange transfusion; morbidity was 6.3% (including bradycardia, apnea, thrombocytopenia, hypoglycemia and hyponatremia). Most complications occurred in preterm infants and those severely ill. All complications were treated immediately and there were no sequelae. PMID- 8682394 TI - [Enforced psychiatric hospitalization for dementia by the district psychiatrist]. AB - Dementia syndromes in the elderly are characterized by progressive deterioration and clinical and functional heterogeneity. At times a psychiatric picture prevails, and at other times, somatic as well as cognitive aspects. Accordingly, management is conducted in separate facilities, psychiatric or geriatric, which are not closely connected. The Israel Mental Health Act practically permits psychiatric commitment of every case of dementia at a certain stage of the illness. We describe a 75-year-old woman with dementia who was committed to a psychiatric hospital by order of the district psychiatrist. After attenuation of psychiatric symptoms, she remained in hospital unnecessarily. Further deterioration in physical, as well as cognitive condition, required transfer to a nonpsychiatric facility. However, due to difficulties in transfer from psychiatric to geriatric facilities, this was not accomplished. We therefor suggest broadening the authority of the district psychiatrist to include transfer of patients with dementia to appropriate, nonpsychiatric, long-term treatment facilities on termination of psychiatric treatment. PMID- 8682395 TI - [Placebo in in medicine--treatment and research facets]. PMID- 8682397 TI - [Artificial intelligence and its medical applications]. PMID- 8682396 TI - [Adhesion molecules in the development of inflammatory processes-- clinical and investigational implications]. PMID- 8682398 TI - [Homosexuality]. PMID- 8682399 TI - [Hypertensive treatment in light of the latest discoveries in the renin angiotensin system]. PMID- 8682400 TI - [Postmenopausal estrogen replacement therapy--does it reduce morbidity and mortality from ischemic heart disease?]. PMID- 8682401 TI - [Endothelin-1]. PMID- 8682402 TI - [Rhabdomyolysis and influenza infections]. PMID- 8682403 TI - [Annual activities of a regional occupational health service]. AB - The scope and content of the services provided by a regional, occupational health service are described in quantitative terms. Many of its activities are in compliance with state regulations. In this respect this service differs greatly from other, regular, clinical services. About 22,000 examinations are performed annually, and there are about 140,000 employed persons in the region, so that about 1 in 5 workers is examined by the service annually. The 3 main activities of the clinic are pre-employment examinations, periodic surveillance of certain groups of workers and evaluating work capacity. Most of the abnormal findings identified in such examinations relate to musculo-skeletal disorders, noise induced hearing loss and, to a much lesser degree, lung and skin problems. Some of the ways in which service is provided in remote and small work sites are described, and issues of availability and accessibility presented. Based on the data collected, suggestions are made with respect to future changes, including computerization and quality assurance methods. PMID- 8682404 TI - [Results of treatment of multiple trauma in 130 children]. AB - Trauma remains the leading cause of death in the pediatric age group, despite recent advances in prevention and treatment. We retrospectively analyzed 130 cases of multiple trauma among 725 pediatric patients with injuries treated here during 1988-1989. Road accidents and falls from heights were the most common causes of injury. Mean age was 7 years (range 0.5-15) and the male to female ratio 2.7:1.0. Overall mortality was 9.2%. 57 patients (44%) did not get any prehospital medical care and 5 of them with injury severity scores (ISS) greater than 25 died. In contrast 11/18 (61%) of patients with ISS greater than 25 who were treated by medical teams survived. On arrival at the emergency room, 15% were hypothermic ( < 34 degrees C), and 6 were in hypovolemic shock--5 of whom died. Most common injuries were head trauma (91), limb injuries (69), abdominal trauma (34) and thoracic trauma (34). In 39 injury was severe, with pediatric trauma score (PTS) 6 or less, 12 of whom died. All deaths except 1 were associated with severe head injury and with ISS more than 25. There was no mortality in those with PTS more than 7 or ISS less than 25. Thus, the prehospital care of pediatric patients with head injury is associated with high mortality. Absence of mortality in patients with PTS of more than 7 emphasizes the importance of designated trauma centers for these patients. PMID- 8682405 TI - Progress in studies on Central Asian foci of zoonotic cutaneous leishmaniasis: a review. AB - In this paper, studies on zoonotic cutaneous leishmaniasis (ZCL) are reviewed that were performed during the last ten years largely by scientists of the Martsinovsky Institute of Medical Parasitology and Tropical Medicine. New data on the taxonomy of Leishmania circulating in populations of Rhombomys opimus, their main host, and the results of field and laboratory studies allowed revision of certain concepts generally accepted in epidemiology and epizootology of ZCL in Central Asia. PMID- 8682406 TI - Ultrastructural study of Sarcocystis muriviperae development in the intestine of its snake hosts. AB - The ultrastructure of the endogenous stages--merozoites, microgamonts, macrogamonts and oocysts, of Sarcocystis muriviperae from the snakes Vipera palaestinae and Coluber jugularis is described. Snakes were infected via white mice fed on sporocysts obtained from naturally infected snakes of the same species. Snakes examined 4 days post-infection contained only young and premature gamonts. Infection in snakes sacrificed on day 7 post-infection consisted predominantly of mature microgamonts and macrogamonts; snakes examined on day 10 post-infection revealed only oocysts. The fine structure of the endogenous stages from the two snakes, including size and contents of the wall-forming bodies, was identical, confirming their suggested conspecificity. Observed endogenous stages also conformed in their major details with the same developmental stages of other Sarcocystis species studied from other snakes and mammalian definitive hosts and from in vitro culture. However, they differed from the latter in size and contents of the wall-forming bodies. The observed fertilization process was reminiscent of that described earlier in S. bovicanis. PMID- 8682407 TI - Ceratomyxa drepanopsettae in the gallbladder of Atlantic halibut, Hippoglossus hippoglossus, from the northwest Atlantic Ocean. AB - Trophozoites of Ceratomyxa drepanopsettae Averintsev, 1907 (Myxosporea: Ceratomyxidae) containing prominent refractile granules were found in the gallbladders of all but one of eight halibut, the exception being a single juvenile. They ranged in shape and size from globular forms 5-10 micron in diameter, to rounded structures with pseudopodia and one or more processes that were up to 500 micron in length and packed with refractile granules. Some trophozoites were free in the bile, while others were attached to the epithelium of the gallbladder wall by pseudopodia which extended between the microvilli. Many free trophozoites were attached to each other by septate junctions between their pseudopodia. There were small cylindrical papillae on the surface of the trophozoites, and the rounded portions contained two vegetative nuclei, generative cells (some attached by junctions) and, in many cases, feeding vacuoles. During sporogony, a binucleate sporoplasmic cell and the capsulogenic cells of some sporoblasts were engulfed by valvogenic cells before they began to differentiate; whereas other sporoblasts consisted of six cells attached to each other, two being capsulogenic cells containing external tubes, two sporoplasmic cells and two valvogenic cells. There was a septate junction around the opening of the rounded polar capsule of the spore, between the capsulogenic and valvogenic cell. Sporoplasmosomes appeared to form in smooth membraned vesicles, possibly part of the Golgi apparatus. Spores had thin, delicate membrane, and elongate shell-valves, most of which were asymmetric, and bent or folded. A sporoplasm extended on either side of the distinct, straight suture line, but did not penetrate into the valves. PMID- 8682408 TI - Myxosporeans infecting the gills of bigmouth buffalo (Ictiobus bubalus) in Illinois, USA. AB - Four myxosporean species were found on the gills of Ictiobus bubalus from Illinois (USA). Myxobolus endovasus (Davis, 1947) Grinham et Cone, 1990 is revised. Three new species are recorded. Myxobolus enoblei sp. n. has spores ovoid in frontal view, 14.3 x 13 microns in size. Myxobolus morrisonae sp. n. has spores subcircular in frontal view, 10 x 9.5 microns in size; the surface of shell valves appears hairy when studied by SEM. Triangula illinoisensis sp. n. has spores rounded semicircular in frontal view, 10.2 x 12.8 microns in size. Triangula illinoisensis is the fourth species of its genus to be described from fishes. PMID- 8682409 TI - Viability of pathogenic Acanthamoeba and Naegleria and virulence of N. fowleri during long-term cryopreservation. AB - This is a followup report on the viability of pathogenic Acanthamoeba castellanii, Naegleria australiensis, and N. fowleri during 5 years of cryopreservation and the virulence of N. fowleri during 30 months of cryostorage, all at -70 degrees C. The greatest decrease in viability occurred during the first year of freezing and was 10-fold greater than the average yearly decrease during years 2-5. At 5 years of cryostorage viability was 33% for A. castellanii, 38% for N. fowleri and 51% for N. australiensis. Virulence of N. fowleri did not decrease during 30 months of freezing and what appeared to be an increase in virulence during cryopreservation may be the result of reduced viability of the less virulent amebae in a culture. PMID- 8682410 TI - The development of Procamallanus (Spirocamallanus) neocaballeroi (Nematoda: Camallanidae), a parasite of Astyanax fasciatus (Pisces) in Mexico. AB - The development of the nematode Procamallanus (Spirocamallanus) neocaballeroi (Caballero-Deloya, 1977), an intestinal parasite of the characid fish, Astyanax fasciatus (Cuvier) in Mexico, was studied in the experimental copepod intermediate host, Mesocyclops sp. After the copepod's ingestion of free first stage larvae of the nematode, these penetrate into the haemocoel of the intermediate host; they moult twice (on the 3rd and 4-5th day p.i. at 21-22 degrees C) before they attain the third, infective stage. The third-stage larva already possesses the large buccal capsule subdivided into an anterior broad portion with eight spiral thickenings (as observed in lateral view) and a narrow posterior portion, and its tail tip bears three conical processes. The definitive host acquires infection by feeding on infected copepods; in the intestine of this fish, the nematode larvae undergo two more moults (on the 10th and 14-15th day p.i. at 25-32 degrees C) before attaining their maturity. The prepatent period is approximately two months. PMID- 8682411 TI - Comparative study of infectivity caused by promastigotes of Leishmania infantum MON-1, L. infantum MON-24 and L. donovani MON-18. AB - The mechanisms which permit Leishmania to survive inside macrophages are not totally understood although it is known that prolonged culture in vitro results in loss of virulence. One of the cell surface molecules often implicated in virulence mechanisms is the glycoprotein of 63 kDa (gp63). In this work we studied changes in infectivity of L. infantum promastigotes maintained in vitro by subcultures, correlated with the proteolytic activity of gp63. It was observed that L. infantum MON-1 promastigotes became unable to establish an infection after 6 subcultures in vitro independently of the size of inoculum. This corresponded to a diminution of proteolytic activity of gp63. L. infantum MON-1 promastigotes inoculated in hamsters visceralize in the mononuclear phagocytic system accompanied by an antibody response. A correlation between antibody response, inoculum size and promastigote origin was verified. L. donovani MON-18 and L. infantum MON-24 promastigotes produced a specific humoral response but failed to establish an infection in hamsters regardless of all the passages tested. PMID- 8682412 TI - Nymphal sexual dimorphism in the sheep tick Ixodes ricinus (Acari: Ixodidae). AB - Unfed nymphs of Ixodes ricinus (L.) can be divided into two morphological groups according to the length of idiosoma, scutum, hypostome and palpal segment III, and the number of dorsal alloscutal setae. Specimens of greater body dimensions and more numerous dorsal alloscutal setae moulted predominantly into females. The frequency of different nymphal length categories in field-collected ticks followed a normal distribution. The length of unfed nymphs correlates well with the length (r = 0.7248 +/- 0.0711, P < 0.001) and weight (r = 0.6519 +/- 0.0782, P < 0.001) of engorged nymphs, however, it varies in ticks of different origin. In field-collected ticks, freshly engorged female nymphs were 2.30-2.94 mm long, male nymphs 2.14-2.46 mm long. Feeding period (P < 0.05) and premoulting period (P < 0.001) were significantly longer in female nymphs both in field-collected and laboratory-derived I. ricinus. The engorgement weight was found to be the best criterion for differentiation of male and female nymphs of ixodid ticks. In field-collected nymphs engorged on BALB/c mice, 98.6% of females moulted from nymphs weighting more than 3.60 mg, while in laboratory-derived ticks, 98.4% of females emerged from nymphs of 3.42 mg body mass or more. PMID- 8682413 TI - A high fatal postmortem blood concentration of cocaine in a drug courier. AB - A fatality in a teenage drug courier who swallowed multiple packages of a controlled drug for concealment in the gastrointestinal tract is described. There were a couple of burst-open short cylindrical packages of cocaine and several with damaged external latex wrapping. A hazardous breakage or leakage has been considered unlikely with similar type of cocaine packages otherwise. The deceased succumbed to a remarkably high fatal postmortem blood cocaine concentration of 104 mg/l, having curiously survived the usual lethal range for cocaine toxicity. The phenomenon of postmortem release and redistribution of drugs and spontaneous biodegradation of cocaine which may confound the postmortem toxicology is briefly discussed. There is a comparable forensic problem in estimating the time of drug ingestion from the rate of gastric emptying or transit in the gut as a crude guide to deduce the time of death. PMID- 8682414 TI - Allele frequencies of four VNTR loci in the Chinese population in Hong Kong. AB - DNA specimens isolated from the blood samples of 209 unrelated Chinese persons were characterised with four probes, i.e. MS1 (D1S7), YNH24 (D2S44), pH30 (D4S139) and TBQ7 (D10S28), in conjunction with the restriction enzyme HaeIII to establish a population DNA-profile database. Each locus showed a fairly wide distribution of alleles and high heterozygosity. The sizes of alleles ranged between 0.73 and 19.95 kb for the D1S7 locus, between 0.78 and 4.72 kb for the D2S44 locus, between 2.53 and 15.74 kb for the D4S139 locus, and between 0.66 and 6.53 kb for the D10S28 locus. The heterozygosities for the D1S7, D2S44, D4S139 and D10S28 loci were 97.6%, 92.3%, 86.6% and 96.2%, respectively. Allele frequencies were determined using the "fixed-bin' approach. The bins were based on the 30-band pattern of the molecular size marker used in this laboratory (GIBCO BRL 4401SA). The most commonly observed bin frequencies for the four loci ranged from 9% to 19%. When a default minimum bin frequency of 10% and the product rule based upon the principles of Hardy-Weinberg equilibrium were used to calculate the most common genotype frequencies, the values ranged from 2.1% to 6.4%. The minimum composite discriminating potential of the four loci, expressed as the product of the frequency of the most common genotype for each locus, was about 1 in 770,000. PMID- 8682415 TI - Various mechanisms of death and their possible association with alcoholism. AB - Alcoholics who died because they were run over by trains, by precipitation, or were smoking in bed, were compared with a group of controls. A higher number of alcoholics were run over by trains, the manner of death most often being suicide. There was a significantly higher number of controls who fell from a height. The manner of death in the group "smoking in bed' was more often accidental and occurred more frequently in alcoholics. Preventive measures are suggested. PMID- 8682416 TI - Immunohistochemical characterization of alveolar macrophages and pulmonary giant cells in fatal asphyxia. AB - It is in dispute whether the occurrence of numerous alveolar macrophages and in particular pulmonary giant cells in cases of fatal asphyxia is associated with agonal activation and proliferation. The nature of these alveolar cells was investigated in selected fatalities with protracted final oxygen lack using immunohistochemistry (APAAP method) and a semi-quantitative graduation. The study included opiate-involved deaths (n = 22), fatal strangulations (n = 10) and a control group of sudden cardiovascular deaths (n = 10). Positive immunohistochemical reactions were observed with the monoclonal antibodies PG-M1 (general marker of macrophages, detection of nearly 100% of pulmonary macrophages and giant cells in all subgroups) and 25 F 9 (late stage inflammation marker, detection of pulmonary macrophages/giant cells in 70%/50% of opiate-involved fatalities, 70%/20% of strangulations and 40%/30% of control cases). The antibodies LN-4 (macrophages), 27 E 10 (early stage inflammation marker), AMH 152 (activated macrophages) and MIB 1 (proliferation marker) did not react with these cell populations. CONCLUSIONS: pulmonary giant cells and numerous alveolar macrophages are not restricted to asphyxia. Their appearance is not of pathognomonic value for this diagnosis. Both cell types seem to be of heterogeneous nature (different functional state) as only one marker was expressed by all cells. The results do not suggest prefinal immigration, mobilization or proliferation of alveolar cells, but rather point to a longer pre existence of macrophages and giant cells in pulmonary tissue (25 F 9 as late stage inflammation marker positive). PMID- 8682417 TI - Species identification by the positional analysis of fatty acid composition in triacylglyceride of adipose and bone tissues. AB - In a new attempt at species identification, the total composition and positional distribution of fatty acid in triacylglyceride (TG) of adipose and bone tissues were analyzed in human, bovine, pig, dog, cat and chicken tissues. Although the total fatty acid compositions of bovine and pig tissues were significantly different from those of human (different in more than half the fatty acids tested), dog, cat and chicken tissues showed a comparatively similar composition to human fatty acids composed of TG in both tissues. The TG in these tissues was also subjected to stereospecific analysis using pancreatic lipase, that is, the fatty acid distribution in positions 1,3 (not distinguished between 1 and 3) and 2 of the TG were determined. The distribution of fatty acids among the positions 1,3 and 2 in the TG of animal adipose and bone tissues was non-random. The distribution between position 2 and positions 1,3 seems to be governed by chain length and unsaturation in each animal. The shorter and more unsaturated fatty acids showed a greater tendency to occupy position 2 of TG. Although this rule appeared in all animals except the pig, the distribution of each fatty acid into position 2 was species-specific. The positional distribution of fatty acid in TG was identical among the same species and in different regions of the same body. Thus, even when species identification is difficult using the pattern of total fatty acid composition, the analysis of the positional distribution of fatty acid makes it possible to determine the species. From the present results, the evaluation of positional distribution of fatty acid in the TG is a useful tool for the identification of human tissues. PMID- 8682418 TI - Distribution of the AMPFLPs YNZ22, 3'Apob and COL2A1 in the population of Galicia (NW Spain). AB - Two different electrophoretic methods were used for typing three amplified fragment length polymorphisms (AMPFLPs), (3'ApoB, YNZ22 and COL2A1) in a Galician (NW Spain) population sample. Because of the problems of anomalous mobility for the 3'ApoB system and the intermediate alleles found in the COL2A1 system, the use of automated sequencers and denaturing conditions is recommended for typing these two systems. Nevertheless, simple electrophoretic methods, such as the PhastSystem, can be used for YNZ22 typing. Although intermediate COL2A1 alleles can be distinguished with the sequencers, a binning approach was adopted for comparison purposes. The population sampled was in Hardy-Weinberg equilibrium for the three systems using an exact test. This type of statistical analysis is more appropriate when the number of alleles in a system is high. No significant differences with other Caucasian populations were found for the three systems studied. The characteristics of the polymorphisms, shown by 3'ApoB, YNZ22 and COL2A1, reflected in the statistical parameters studied, demonstrate that these AMPFLPs are of considerable interest for forensic purposes. PMID- 8682419 TI - Enantiomeric composition of amphetamine and methamphetamine derived from the precursor compound famprofazone. AB - Fourteen different metabolic precursors of amphetamine or methamphetamine have previously been identified. Many of these drugs are available only by prescription and several are only available in some parts of the world and not in others. One of these drugs, famprofazone, is available over-the-counter which complicates the interpretation of methamphetamine urine drug testing results. To assist in the interpretation of typical laboratory results, a study was conducted to determine the enantiomeric composition of the methamphetamine and amphetamine produced from the metabolism of famprofazone. Fifty mg of famprofazone was administered to a volunteer followed by collection of urine for the next 6 days. The resulting quantity, enantiomeric composition and percent conversion from famprofazone to the product amphetamine and methamphetamine was determined. The results showed the amphetamine and methamphetamine to include both the d- and l enantiomers. Percent conversion and peak concentrations were similar to those reported in previous studies. PMID- 8682420 TI - Identification of volatile organic compounds in blood by purge and trap PLOT capillary gas chromatography coupled with Fourier transform infrared spectroscopy. AB - A purge and trap concentrator with a Tenax trap was coupled to gas chromatography Fourier transform infrared spectrometry for the identification of volatile organic compounds in blood samples. A styrene-divinyl benzene porous layer capillary column allowed the separation of compounds such as household and medical gases, solvents and alcohol congeners. The identification limits in blood, measured by comparison to an in-house vapour phase spectrum library, generally ranged from 0.05 to 10 mg/l, depending on the analyte structure. Low molecular weight alcohols had identification limits up to 100 mg/l. Six actual casework examples were collected during a 1-year period of routine use to demonstrate the feasibility of the method. PMID- 8682421 TI - Suicides in two Scandinavian capitals--a comparative study. AB - Suicides from the city and county of Copenhagen, Denmark, and from the two police districts Oslo and Asker and Baerum, Norway, two comparable Scandinavian capital populations, were studied with regard to age, gender, suicide methods, marital status, nationality, month of year, somatic and psychiatric disease, previous suicidal attempts or suicidal threats, and suicide location. The incidence of suicides was higher in the Copenhagen material than in the Oslo material. In both cities the preferred method was intoxication by prescription drugs. In Copenhagen suffocation by means of a plastic bag was a frequently used method, while the Norwegians more often hanged or shot themselves. While hanging was very uncommon among the Copenhagen females, this was not the case in the Oslo population. Both materials had a male preponderance. Attention is also drawn to the well known phenomenon that the suicide rate may increase due to publicity about a suicide method. PMID- 8682422 TI - Comparison of German population data on the apoB-HVR locus with other Caucasian, Asian and black populations. AB - A population study of 505 unrelated individuals from Southwestern Germany was carried out on the 3'-apoB hypervariable region (HVR). After amplification via polymerase chain reaction (PCR) and agarose gel electrophoresis, 15 different alleles and 47 genotypes were observed. The most common alleles were hypervariable elements (HVE) 37 and 35 with an allele frequency of 0.374 and 0.244, respectively. The heterozygosity index was calculated to be 78.4%. Allele frequencies of this study are compared with results from other databases obtained from a French, a Spanish, an Asian and an American (Black) population. PMID- 8682424 TI - [Implantation of defibrillators--under defined circumstances]. PMID- 8682423 TI - Cytoskeleton immunohistochemical study of early ischemic myocardium. AB - Previous studies on cytoskeletal changes of in vitro and in vivo animal models of ischemic myocardium have suggested the possibility of using alterations in cytoskeleton proteins as an early marker for the post-mortem diagnosis of myocardial ischemia in cases of sudden death due to coronary artery disease (CAD). In the present study, using the technique of ABC-immunohistochemistry, we examine the changes of three cytoskeletal proteins: vinculin, desmin and alpha actinin in human myocardial samples taken from 14 cases of CAD sudden death and 13 cases of non-CAD death. Results of these examinations are compared with immunohistochemical changes of myoglobin and histochemical staining of hematoxylin and eosin and phosphotungstic acid, and Masson trichrome. Patchy and extensive loss of the three cytoskeletal proteins was demonstrated in the myocardium of victims who died 1 h or later following the onset of symptoms of ischemic myocardium. The pattern of cytoskeleton change is equivocal in the cases of CAD who died less than 1 h after the onset of symptoms and of the cases of non CAD. In these cases, no significant histological change was observed. With less non-specific background changes and stronger positive staining, immunohistochemical staining of the three cytoskeletal proteins is more reliable than myoglobin, which has attracted the attention of many pathologists searching for anatomic evidence of ischemic myocardium in coronary artery disease. PMID- 8682425 TI - [Implantable defibrillators--current status of guidelines. Recognized and possible indications--prerequisites]. AB - Ten to twenty percent of the patients, who were resuscitated as a result of a persistent ventricular tachycardia or ventricular fibrillation outside of an acute myocardial infarction, die of sudden cardiac death already in the first year after this event. Anti-arrhythmic agents also do not decisively improve this unfavorable prognosis. There is no doubt that the implantable cardioverter/defibrillator (ICD) safely and reliably terminates ventricular tachycardias and ventricular fibrillation and has thus led to an improvement in the care of these high risk patients. Studies have shown that the ICD reduces the risk of sudden cardiac death to 1-2% per year. However, whether the reduction of sudden cardiac death is also accompanied by a reduction in overall mortality has not yet been substantiated. It was, however, been assumed that especially patients with good left ventricular function, whose mortality risk is mainly sudden cardiac death, also profit from the overall prognosis of an ICD. The following presentation and discussion of the indication catalogue for the implantation of defibrillators is based on a guideline paper published by the study group "Interventional Electrophysiology" in the German Society for Cardiology. The statements clearly show how difficult it is to make long-term binding and valid recommendations due to insufficient scientific data and rapid technical development. Identifying patients who should be treated with an ICD requires complete noninvasive and invasive cardiological diagnostics and should ultimately be limited to cardiological centers which possess a large arsenal of diagnostic and therapeutic procedures. PMID- 8682426 TI - [Lipid metabolism disorders--diagnosis and therapy in general practice. 1: Hypercholesterolemia]. PMID- 8682427 TI - [The physical and psychological health of new German citizens]. PMID- 8682428 TI - [Treatment of persistent diarrhea with S. boulardii in returning travelers. Results of a prospective study]. AB - AIM: The efficacy and tolerability of Saccharomyces boulardii (S.b.) were investigated in patients with diarrhea contracted while travelling abroad. METHOD: The efficacy of S.b. was determined on the basis of the frequency and consistency of stools (fewer than 3 unformed stools a day), and symptom changes. A total of 95 patients (49 females, 46 males) aged between 19 and 69 (mean age 32) years were treated with S.b. at a daily dose of between 150 and 450 mg (mean 428 mg) (3 x 1-3 capsules). RESULTS: Prior to admission to the study, diarrhea had persisted for an average of 11 days; under treatment with S.b. it cleared up after a mean of 5 days. A tendency towards greater efficacy in patients returning from The Middle East and South America was noted. Tolerability was assessed to be very good or good by almost all participants, with side effects occurring in only 2 cases. CONCLUSION: The study demonstrates that S.b. is both effective and well tolerated when used for the treatment of persistent diarrhea (mean duration 11 days) that had often failed (67% of the cases) to respond to previous antidiarrheal or antibiotic drugs. PMID- 8682429 TI - [Hepatic minimal encephalopathy. The most frequently overlooked, clinically occult "metabolic syndrome" on the cirrhosis patient]. AB - The syndrome of minimal hepatic encephalopathy is used to describe discrete psychomental and neuro-psychological abnormalities in patients with chronic liver disease (cirrhosis) or portosystemic shunt, in whom classical clinical investigations reveal no evidence of mental or cerebro-neurological disorders, and who cannot be assigned to any of the usual stages of hepatic encephalopathy. Disorders of cerebral function, such as lack of concentration, impaired ability to think logically, loss of comprehension, impairment of space perception and the recognition of numbers and letters can be very reliably detected by simple psychometric tests (number-connection test, line-tracing test, handwriting), and are present in as many as 70% of cirrhotics. This may be expressed in everyday life by an impairment of driving ability, and at work by impaired ability to operate a machine. The use of established means of lowering blood ammonia levels (lactulose, ornithine-aspartate) results in a rapid improvement in the symptoms of encephalopathy. PMID- 8682430 TI - [Disorders of lipid metabolism--diagnosis and therapy in general practice. 2. Hypercholesteremia--diagnostic-therapeutic procedure in relation to total cholesterol concentration]. PMID- 8682431 TI - [Prevention of thrombosis with fraxiparin 0.3 after ambulatory surgery]. AB - AIMS AND METHODOLOGY: Between September 1993 and January 1994, a post surveillance study involving 113 physicians in private practise was carried out to investigate the efficacy and safety of the low-molecular-weight heparin. Fraxiparin 0.3. The aim of the study was to obtain information about the usual prescription of approved drugs. In this case, the efficacy based on the incidence of thromboembolic events (deep vein thrombosis in the leg, pulmonary embolism) and tolerability on the basis of the recording of undesired adverse reactions were to be investigated in a large group of patients undergoing ambulatory operations. RESULTS: Participants in the study comprised 1028 men and women aged between 13 and 93 years who, for the most part, underwent operations on the lower limbs with subsequent immobilization. As a preventive measure against thromboembolic complications, all patients received a daily subcutaneous injection of fraxiparin 0.3. The duration of the prophylaxis was determined by the physician on an individual basis and was 9 days on average. During the course of the drug monitoring, 12 cases of deep vein thrombosis of the leg (1.2%) and 2 pulmonary embolism (0.2%) occurred. Eight of the 14 patients with thromboembolic complications also had additional risk factors. In ten of these 14 cases, patients were younger than 40 years (average age of the overall group: 42.8 years). A noteworthy observation was the fact that in four cases, the venous thromboses in the leg occurred only after the last injection of heparin. The results confirm that preventive Fraxiparin 0.3 provides reliable protection against thromboembolic disease in patients undergoing ambulatory surgery. The low rate of undesired side-effects (1.3%) underscores the high level of tolerability of this drug. PMID- 8682432 TI - [Management of demented patients is typically the primary care physician's responsibility. Interview on the topic "The primary care physician as case manager". Interview by Dr. med. Klaus Janssen]. PMID- 8682433 TI - [Nerve compression syndrome--present status of microvascular decompression]. PMID- 8682434 TI - [Receptor mediated Ca influx and Ca-permeable channels]. PMID- 8682435 TI - [A case of SLE with the onset of pleuritis showing eosinophilia and elevation of serum IgE]. AB - A 19 year old female was admitted to our hospital with complaints of fever, dyspnea and chest pain. Chest x-ray film showed a massive right pleural effusion. She was diagnosed to have systemic lupus erythematosus (SLE) because of malar rash, serositis (pleuritis), positive antinuclear antibody and positive anti-DNA antibody. Then she was successfully treated with 50 mg/d prednisolone. This case was unusual and of interest in that she had eosinophilia in the peripheral blood and exudative pleural effusion and a marked elevation of serum IgE level despite no history of allergic diseases and no evidence of parasite infections. PMID- 8682436 TI - Coronary angiography by electron beam tomography. AB - Electron Beam Tomography (EBT), a non-invasive imaging method with very high spatial and temporal resolution, is well suited for cardiac imaging. We established a protocol for the visualization of the coronary arteries by EBT and have so far evaluated the method in 88 patients. EBT imaging was performed using an Evolution scanner with a matrix of 512 x 512, a field of view of 15 cm and a slice thickness of 3 mm. After venous injection of contrast agent, 40 axial cross sections of the heart were obtained triggered to the ECG at 80% of the R-R interval in inspiratory breathhold. With a lower threshold of 80 HU, 3D reconstructions of the heart and coronary arteries were rendered using shaded surface display and maximum-intensity projection techniques. In all patients, the coronary arteries and, if present, aorto-coronary bypass grafts, were evaluated as to their visibility and presence or absence of haemodynamically relevant stenoses. All results were compared to the X-ray angiograms obtained by selective catheterization in a blinded manner. In 90% of cases, image quality was sufficient for evaluation. In 10% of the investigations, the EBT images could not be evaluated, mainly due to respiration artifacts. While the left anterior descending coronary artery was represented in very good image quality, the right coronary artery and left circumflex coronary artery showed decreased image quality due to motion artifacts and close correlation to venous structures such as the coronary sinus and atrial appendages. In a subgroup of 30 patients in which EBT results were compared to quantitative coronary angiography, the correlation of the vessel diameter in EBT and quantitative angiography was 0.82. Twelve out of 14 high-grade stenoses and 5/5 occlusions of the left anterior descending coronary artery as well as 3/4 highgrade stenoses and 1/2 occlusions of the right coronary artery and 2/4 high-grade stenoses of the left circumflex coronary artery were correctly identified. Nine patients were reinvestigated by EBT after successful angioplasty of high-grade coronary artery stenoses. The increase in vessel diameter could be documented in all cases. Twelve patients had a total of 28 aorto-coronary bypass grafts. Except for one mammarian artery graft which could not be evaluated due to small vessel lumen and clip artifacts, graft patency (21 cases) or occlusion (6 cases) was correctly diagnosed by EBT. EBT is a non-invasive method which permits the visualization of the coronary arteries. Stenoses of coronary artery bypass grafts and of the left anterior descending coronary artery can be reliably diagnosed, while reduced image quality, mainly due to faster vessel motion, impairs the results obtained for the right and left circumflex coronary artery. PMID- 8682437 TI - Non-invasive visualization of coronary arteries with and without calcification by electron beam computed tomography. AB - Coronary artery disease (CAD) is one of the leading causes of mortality and morbidity in the western industrialized countries. Recent studies demonstrate the feasability of successful primary and secondary prevention. However, the detection of early stages of coronary artery disease is an unresolved issue. Whereas sensitivity and specificity of traditional risk factor assessment and stress tests are limited, the analysis of coronary calcification allows to obtain a direct sign of coronary atherosclerosis. This concept has been applied using fluoroscopy and conventional computed tomography (CT). However, the exact localization and quantification of coronary calcification only became possible with the advent of electron beam CT (EBCT). This new method showed a high prevalence of coronary calcification in the asymptomatic population. With the definition of a standardized "calcium score" the normal age-specific distribution and amount of coronary calcification was investigated. EBCT proved to be more sensitive in the diagnosis of both non-obstructive and obstructive coronary artery disease than risk factor analysis and stress testing, respectively. Obstructive coronary artery disease, however, cannot yet be predicted with high enough accuracy. A close correlation of EBCT coronary calcification was found to a) the total coronary plaque volume defined by histo-pathology, b) intracoronary ultrasound findings, c) the number of coronary risk factors, d) the coronary prognosis. Using EBCT, a reliable non-invasive identification of persons at risk was obtained for the first time. Guidelines for the use of EBCT in the early diagnosis and treatment of coronary artery disease are being developed. PMID- 8682439 TI - [Stress echocardiography versus myocardial scintigraphy: comparative value in coronary heart disease]. PMID- 8682438 TI - Intravenous coronary angiography with dichromography using synchrotron radiation. AB - Dichromography represents a digital subtraction angiography mode based on energy substraction which allows imaging of fast moving subjects like the heart. For logarithmic subtraction 2 images with X-rays just below and above the iodine K edge (33.17 keV) are simultaneously obtained in a line scan mode. Monochromatic X rays of sufficient intensity to visualize coronary arteries of 1 mm diameter with extremely low iodine concentrations (1 mg/cm2) after venous injection is only provided by synchrotron radiation. The system NIKOS (non-invasive coronary arteriography with synchrotron radiation) at the Deutsches Elektronen Synchrotron (DESY) consists of 6 components: a wiggler, a monochromator, a safety system, a scanning device, a detector and a computer system. After experimental studies in dogs patients are imaged since 1990. Initial results demonstrate feasibility and safety of synchrotron radiation coronary angiography. Large scale studies are designed to further evaluate sensitivity and specificity. When compact synchrotron radiation sources become available, this technique could be used for follow-up studies and for evaluation of certain high coronary risk populations. PMID- 8682440 TI - The dawn of a new era--non-invasive coronary imaging. PMID- 8682441 TI - Intravascular ultrasound for evaluation of coronary arteries. AB - Intravascular ultrasound (IVUS) has emerged form a research tool to an intrinsic part of modern invasive cardiology. The main reason is the capability to obtain "in vivo" histology. For the first time it is possible to base decisions not only on lumenograms but also on vessel wall assessment. The capabilities of IVUS can be divided in its (a) diagnostic and (b) intervention associated potentials. Diagnostic strength of IVUS is the ability to monitor compensatory coronary artery enlargement as a response to arteriosclerosis, to assess intermediate lesions, to reveal occult left main stem disease, and angiographycally "silent" arteriosclerosis. The intervention associated potentials of IVUS are the ability to allow optimal device selection, i.e. rotablators in calcified lesions or atherectomy devices in large plaque burden. The effects of PTCA on vessel wall morphology can be studied in great detail and the effect on luminal gain can be assessed almost on-line. Several groups showed, that the residual plaque area even after angiographycally successful PTCA lies still in the range of 60%. A significant reduction of this number may influence longterm outcome after PTCA. Minimal luminal areas and residual plaque area after PTCA seem to be an indicator of restenosis, while the presence or absence of dissections seem to be less predictive. Intravascular monitoring of stent expansion led to high-pressure stent deployment with significant increase in post-procedural luminal diameters and finally the ability to withhold anticoagulation in patients with optimal stent deployment. In the future, integrated devices, like balloons on intravascular ultrasound catheters, steerable catheters, integrated flow and pressure transducers, tissue characterization, and 0.018 "intravascular ultrasound guide-wires will further enhance the usefulness of IVUS. PMID- 8682442 TI - Coronary artery imaging by magnetic resonance. AB - Non-invasive visualization of the coronary arteries represents a major challenge in modern cardiology, but this goal may be achieved in the near future by MR angiography. Possible applications are non-invasive diagnosis of coronary artery disease, and follow-up examinations for therapy control after PTCA, in order to detect restenosis at an early stage. A multiple slice technique (2 mm slice thickness, with a spatial resolution of 1 x 1 mm, Philips Gyroscan ACS-II, 1.5 Tesla) was used. Ten volunteers were imaged and 10 patients with coronary artery disease were examined before and after PTCA. MR measurements were validated by quantitative coronary angiography. The diameters of the proximal coronary arteries as measured by both methods were compared, and a good correlation was found (r = 0.76). Thus, it is concluded that non-invasive visualization of the coronary arteries is possible before and after PTCA and allows to determine potential restenoses. However, patient cooperation is essential for good image quality. Moreover, limited spatial image resolution and breathing artifacts restrict MR coronary angiography today to be used as a routine diagnostic tool for the diagnosis of coronary artery disease. PMID- 8682444 TI - 2nd Alps-Adria Congress on Hepato-Pancreato-Biliary Surgery and Medicine. Pavia, Italy, September 13-16, 1995, Abstracts. PMID- 8682443 TI - Coronary imaging using MRI. AB - Without use of ionizing radiation and injection of contrast material magnetic resonance imaging (MRI) can be applied to generate signal from flowing blood and create tomographic images of the bloodstream in coronary arteries, which resemble conventional contrast enhanced X-ray angiograms. The tortuosity, small diameter and motion of the coronary arteries provided technically demanding problems, which had to be solved before MR coronary angiography became realistic. Faster pulse sequences, dedicated radiofrequency receiver coils, cardiac and respiratory gating techniques were introduced and are still in the process of constant development to improve the quality of the images. To date, most clinical experience has been obtained using 2D approaches necessitating repetitive breath holds to encompass the coronary artery tree. A substantial part of the proximal and middle parts of the coronary arteries can be visualized, which has proven to be accurate in identifying anomalous coronary anatomy and patency of proximal coronary artery bypass grafts. However, the technique is currently not sensitive enough to reliably detect coronary artery stenoses. Another approach is a single acquisition respiratory gated 3D technique which is less operator and patient dependent, requires less imaging time for an entire coronary protocol and is more comfortable for the patient than the 2D breath-hold approach. Initial experience demonstrates the capability to identify the major epicardial coronary vessels. But here too, further development is required to demonstrate coronary stenoses. A unique feature of MR imaging is the feasibility to non-invasively quantitate flow in the coronary arteries. This offers the potential to selectively determine the flow reserve of coronary arteries and to assess the functional and physiological implications of moderately severe stenoses. It can be envisaged that, although currently not apt to replace conventional coronary angiography, MR coronary angiography and flow measurement will become of use in the evaluation of specific, well defined clinical issues in coronary artery disease. PMID- 8682445 TI - Is necroinflammation a prerequisite for fibrogenesis? PMID- 8682446 TI - Aminoterminal propeptide of type III procollagen: a marker of hepatic fibrosis after bile duct obstruction in the monkey. AB - BACKGROUND/AIMS: In an experimental study in monkeys, liver fibrosis development after segmental bile duct obstruction was investigated and correlated with the aminoterminal propeptide of type III procollagen (PIIINP). MATERIALS AND METHODS: Segmental bile duct obstruction was produced by ligation and section of the left hepatic bile duct in all monkeys. Fibrosis induction was examined by intravenous leukotriene C4 (LTC4, 5 nmol/kg) application, endogenous LT-production stimulated by endotoxin (LPS,salmonella abortus equi, 50 ng/kg), fibrosis inhibition by dexamethasone (1 mg/kg) intramuscularly and subsequent endogenous LT-production stimulation by LPS (50 ng/kg). Ligated and unligated liver lobe biopsies were taken 3, 7 and 12 weeks after ligation. All portal areas were measured morphometrically. PIIINP was measured by a specific radioimmunoassay each week and correlated with the morphometric results. RESULTS: Bile duct obstruction leads to secondary sclerosing cholangitis with bile duct vanishing and subsequent biliary cirrhosis combined with perivenous sclerosis and cavernous transformation of the terminal vein. The collagen concentration increased in the nonligated lobe from mean +/-SEM 1.05 +/- 0.03% to 1.53 +/- 0.19% only after LTC4 and with no difference in the other groups. In the ligated lobe collagen concentration increased significantly in all groups continuously from 1.05 +/- 0.03% up to: controls 6.1 +/- 0.9%, dexamethasone 5.9 +/- 0.8%, LPS 8.2 +/- 0.8%, LTC4 9.075 +/- 1.4%. PIIINP concentration rose within 6 weeks in the controls with hepatic bile duct obstruction from 34.43 +/- 15 ng/ml up to 57 +/- 13.27 ng/ml, after dexamethasone to 48.5 +/- 18.23 ng/ml, after LPS to 57 +/- 13.27 ng/ml, after LTC4 to 80.25 +/- 16.04 ng/ml. After 12 weeks, PIIINP decreased in the controls resp. after dexamethasone to 41.25 +/- 6.94 ng/ml resp. 33.5 +/- 7.72 ng/ml and increased after LPS resp. LTC4 up to 64.25 +/- 17.07 ng/ml resp.104 +/- 22.46 ng/ ml. The correlation of collagen deposition and PIIINP was in the controls r = 0.83, after dexamethasone r = 0.71, after LPS r = 0.83 after LTC4 r = 0.91. CONCLUSION: PIIINP determination after segmental bile duct obstruction correlates with collagen deposition and allows evaluation of hepatic fibrosis activity. PMID- 8682447 TI - Endoscopic sphincterotomy for bile duct calculi-factors influencing the success rate. AB - BACKGROUND/AIMS: Endoscopic sphincterotomy is an established treatment of retained or recurrent common bile duct calculi after cholecystectomy and in the majority of patients with an intact gallbladder. In order to identify patients ultimately requiring additional endoscopic procedures or surgery, factors predictive of decreased endoscopic bile duct clearance were sought. MATERIAL AND METHODS: Between 1981 and 1992 endoscopic sphincterotomy was performed in 393 consecutive patients with either intact gallbladders (n = 246), recurrent (n = 92) or retained (n = 55) calculi. RESULTS: There was a 9.4% overall early complication rate for the procedure and a 30-day mortality rate of 0.5% (two patients, non-procedure related). Complete removal of all bile duct calculi failed in 35/393 patients (8.9%). In patients with intact gallbladder the clearance rate at first attempt was higher (p = 0.002; Chi-square test) in the presence of solitary as compared to multiple stones. The same was found in patients with recurrent stones as well (p < 0.001). In non-cholecystectomized patients with single or multiple stones smaller than 10 mm, the clearance rate was higher at first (p = 0.02) as well as at final (p < 0.002) attempt as compared to patients with larger stones. Single small ( < 10 mm) compared to single large stones in patients with intact gallbladder had a higher clearance rate at final (p = 0.002) but not at first (p = 0.18) attempt. Patients with intact gallbladder and pancreatitis had higher clearance rate at first attempt compared to patients with jaundice (p = 0.001) or patients without concomitant pancreatobiliary disease (p = 0.002). Clearance rate was the same in patients with and without endoscopic sphincterotomy complications, except for patients with basket impaction, in whom the clearance rate was decreased (p = 0.02). CONCLUSIONS: Thus, in patients with intact gallbladder surgery should be considered after failed complete bile duct clearance at first attempt. PMID- 8682448 TI - Xanthogranulomatous cholecystitis: a complication of metallic biliary stent placement. AB - We present a case of 70-year-old female patient who was admitted due to progressive jaundice. Our clinical impression of cholangiocarcinoma (Klatskin tumor), was confirmed by ultrasound, abdominal CT scan, and percutaneous transhepatic cholangiography. Two self-expanding metallic stents were placed in both intrahepatic ducts through a single transhepatic tract. After successful biliary stenting, the jaundice subsided and she was discharged as improved. However, progressive right upper quadrant pain was noted a few days after discharge and persisted for about 5 months, thus the was readmitted. During admission, she was febrile, exhibiting leukocytosis, with clinical signs of impending septic shock. Gallbladder empyema with hilar cholangiocarcinoma were diagnosed. Percutaneous transhepatic cholecystotomy and drainage (PTCCD) was done to alleviate the symptoms and cholecystectomy was performed thereafter. Pathologic report was compatible with xanthogranulomatous cholecystitis. Post operative recovery was fair at follow-up examination. PMID- 8682449 TI - Hepatopancreatoduodenectomy for superficially spreading bile duct carcinoma: a report of two 5 year survivals. AB - We have treated two bile duct carcinoma patients using HPD and they have both survived for more than 5 years postoperatively. In this article, we report on the details of these two cases and discuss the indications for HPD in the treatment of bile duct carcinoma. PMID- 8682450 TI - Endoscopic aspects of choledochoceles. AB - BACKGROUND/AIMS: To date, since so little information has been published on the incidence of choledochoceles, we undertook a retrospective study of the incidence of choledochoceles. MATERIALS AND METHODS: Out of 9,850 patients who had been submitted to ERCP investigation in our department, the medical histories of the patients found to have choledochoceles were analysed. RESULTS: Ten out of the 9,850 had a choledochocele, 3 of which were symptomatic, 3 questionably symptomatic and 4 asymptomatic. In 6 patients with symptomatic or questionably symptomatic choledochoceles, endoscopic treatment in the form of endoscopic papillotomy was carried out. Following this intervention, 4 of the patients became symptom-free. CONCLUSIONS: Smaller choledochoceles tend to be asymptomatic while the larger are symptomatic. The diagnostic method of choice in ERCP. PMID- 8682451 TI - Biliary stricture due to mucosal hyperplasia of the common bile duct: a case report. AB - A 71-year-old man with a tumorous lesion of the common bile duct is presented. Although histological examination of tumor biopsy specimens taken at the time of duodenoscopy or percutaneous transhepatic choledochoscopy showed mucosal hyperplasia, cancer could not be ruled out; therefore, the patient underwent pancreatoduodenectomy. However, histology showed nodular mucosal hyperplasia and an ectopic pancreas adjacent to the papilla of Vater, which was suspected to have contributed to the development of the lesion by stimulating the mucosa of the papilla and the distal common bile duct. PMID- 8682452 TI - Chemotactic and suppressor cytokine networks. PMID- 8682453 TI - Calcium chemoprevention in colorectal cancer. AB - BACKGROUND/AIMS: There are genetic, endoengenous, and exogenous factors responsible for colorectal cancer. Calcium may play a chemopreventive role in high risk groups. Binding fatty and biliary acids and their reduced absorbtion, with a consequent decrease of proliferative stimulation and reduction of secondary carcinogenic compounds, may explain this role. MATERIAL AND METHODS: 175 patients with adenomatous polyps after polypectomy and with calcium chemoprevention were evaluated for polyps recurrence. Another three groups of patients with colorectal cancer without chemoprevention (A,B) and with chemoprevention (group C) were followed concerning survival after surgery. RESULTS: The cumulative survival rate of patients after surgery due to colorectal carcinoma is significantly higher in a calcium chemopreventive group. Adenomatous polyps recurrences after polypectomy are lower (12.9%) in the chemoprevention group than in the group without prevention (55%) with a mean time of follow-up 3.1 yrs. CONCLUSIONS: Calcium is an important chemopreventive agent in adenomatous polyps after polypectomy and after colorectal surgery for colorectal cancer. PMID- 8682454 TI - Temporary exclusion of the perforated esophagus using a linear vascular stapler: a new surgical treatment. AB - BACKGROUND/AIMS: A new technique using a linear staple suture for temporary exclusion of the perforated esophagus is presented. MATERIALS AND METHODS: The procedure is combined with diversion of esophageal fluid by nasogastric tube and drainage of the periesophageal compartments by silicon drains. A gastrostomy is used to drain the stomach for 48 hours, and later for enteral nutrition. Since the suture line reopens spontaneously after approximately 10 days there is no need of reoperation. RESULTS: This method allows diversion of esophageal fluids and therefore enhances effective healing of esophageal perforations after primary repair. Complete spontaneous recanalization of the esophagus occurs approximately two weeks after operation. CONCLUSIONS: The combination of primary repair of an esophageal perforation with esophageal exclusion by using a linear stapler and diversion of esophageal fluid contents by naso-esophageal tube and gastrostomy is a simple effective procedure. Further experience and studies may be needed to verify the usefulness and place of this technique in armamentarium of the visceral surgeon. PMID- 8682455 TI - Manometric assessment of Heller-Dor operation for esophageal achalasia. AB - BACKGROUND/AIMS: The aim of this study was to evaluate changes occurring in esophageal motility through a systematic manometric study performed before, during and after Heller-Dor operation (8) and to correlate the possible post operative symptoms to the manometric and pH-recording patterns detected, in order to provide useful elements that may optimize surgical therapy for esophageal achalasia. MATERIALS AND METHODS: Between January 1981 and January 1991, 27 patients affected by esophageal achalasia underwent Heller's operation with Dor's anti-reflux procedure. Assessment involved clinical, radiological and manometric investigations. RESULTS: Intra-operative manometry was performed on 11 patients, in whom LES pressure reached values lower than 5 mmHg. Post-operative control, performed 2 years after operation on 25 patients, showed the complete absence of dysphagia in 22 (88%) and occasional dysphagia in 3 (12%). Post-operative manometry in all the patients showed a decreased LES resting pressure (from 32.6 to 7.2 mmHg, p < 0.001), LES residual pressure (from 16.4 to 5.0 mmHg, p < 0.001) and esophageal tone (from 4.8 to -3.5 mmHg, p < 0.001). Patients free of dysphagia presented LES basal and residual pressures lower than the other patients (6.2 and 4.6 vs 15.1 and 7.7 mmHg respectively, p < 0.01 and p < 0.05). 24-hour-esophageal pH-metry showed pathologic reflux in 3 patients with reflux symptoms and in 1 without symptoms. All had LES basal and residual pressures equivalent to non refluxing patients (5.7 and 5.0 vs 7.5 and respectively 4.9 mmHg, p = n.s. and p = n.s.). On the contrary, a difference was found in abdominal LES length between the two groups (0.5 vs 1.6 cm, p < 0.01). Patients with intra-operative manometry presented a lower incidence of residual dysphagia than patients without it (0% vs 21.5%), but a higher incidence of reflux (18.2% vs 7.3%). CONCLUSION: Heller-Dor operation induces a definitive disappearance of dysphagia when it is complete in depth and length. Prevention of gastro esophageal reflux requires the preservation of a sufficiently long portion of esophagus in the abdomen. PMID- 8682456 TI - Primary carcinoid tumor of the gallbladder. AB - We present the clinical course of a 77-year old woman who died of tumor cachexia 26.5 months after diagnosis of a primary carcinoid tumor of the gallbladder. To our knowledge, this is the 28th case reported in the world literature. The diagnosis was established coincidentally during histologic work-up of the gallbladder resected for cholecystolithiasis. The entity of this rare tumor type is discussed with regard to the literature. PMID- 8682458 TI - Retrospective analysis of iatrogenic Mallory-Weiss tears occurring during upper gastrointestinal endoscopy. AB - BACKGROUND/AIMS: This study was made to determine the incidence and natural history of iatrogenic Mallory-Weiss tears. PATIENTS AND METHODS: We retrospectively analyzed twelve cases of iatrogenic Mallory-Weiss tears identified from 2,461 consecutive upper gastrointestinal endoscopies performed at our institution over a period of twenty-two months. RESULTS: In all cases, bleeding stopped spontaneously without the need of blood transfusions, endoscopic hemostasis therapy or any other interventions. Eight patients (67%) had retching or struggling during the procedure. Hiatus hernias were noted in three patients (25%). CONCLUSIONS: Iatrogenic Mallory-Weiss tears are rare and generally have a benign course. They tend to occur mostly in patients who have experienced excessive retching or struggling during endoscopy. PMID- 8682457 TI - Endoscopic appearances of hemorrhagic peptic ulcers and efficacy of H2-receptor antagonists. AB - BACKGROUND/AIMS: In this retrospective study, we compared the effects of histamine H2-receptor antagonists to those of antacids and anticholinergics in patients with hemorrhagic ulcers with various endoscopic appearances of bleeding. PATIENTS AND METHODS: Patients with hemorrhagic ulcers (n = 376) were examined by emergency endoscopy and were treated with 1) antacids and anticholinergic drugs or 2) H2-receptor antagonists. RESULTS: In ulcer patients with oozing or fresh red coagulation, H2-receptor antagonists ceased further hemorrhage more effectively (65.9% of the cases) than antacids and anticholinergic drugs (46.7%). In patients with projectile bleeding, both of the treatments failed to stop hemorrhage. There were no significant differences in favorable outcome in the patients only with old black coagulation between antacid and anticholinergic drugs-treated group and H2-receptor antagonists-treated group (94.4% and 93.8%, respectively). CONCLUSIONS: The results suggest that H2-receptor antagonists are more effective than antacids and anticholinergic drugs in patents with peptic ulcer with fresh coagulation or oozing, but not with projectile bleeding or old black coagulation. The results also indicate that endoscopic appearances of peptic ulcer bleeding are good predictors for the effects of medication. PMID- 8682459 TI - Surgical treatment for advanced gastric cancer. AB - BACKGROUND/AIMS: We herein report on the clinicopathological factors related to the unresectability of far advanced gastric cancer and the prognostic effect of gastrectomy on these cases. MATERIAL AND METHODS: There are four main prognostic factors for advanced gastric cancer including 1) peritoneal dissemination, 2) hepatic metastasis, 3) lymph node involvement and 4) invasion to adjacent organs. RESULTS: The rate of unresectability was high in the cases demonstrating both histologically undifferentiated type cancer and cancers located in the lower third of the stomach. It was difficult to resect the main tumor based on an increase in the factors regulating the macroscopical stage. The rate of unresectability tended to be higher in cancers with peritoneal dissemination or invasion to adjacent organs. The pancreas was the most frequently invaded organ. accounting for the unresectability of the disease. The prognosis for cases with unresected gastric cancers was poor and all died within 2 years of the operation. In addition, the prognosis for cases with Stage IV gastric cancer, demonstrating either 1 or 2 factors, improved after gastrectomy while no such improvement was seen in cases with 3 or 4 factors. CONCLUSIONS: To improve prognosis, gastrectomy should be performed when a patient has far advanced gastric cancer but only demonstrates 1 or 2 of the above 4 factors. PMID- 8682460 TI - Surgical treatment of gastric adenocarcinoma: impact on survival and quality of life. A prospective ten year study. AB - BACKGROUND/AIMS: The objective of this prospective study was to compare the results of total (TG) versus subtotal (SG) gastrectomy in patients with adenocarcinoma of the lower two-thirds of the stomach. PATIENTS AND METHODS: Two hundred and twenty-seven patients underwent curative operation. Preoperative nutritional assessment, postoperative tumor stage, postoperative morbidity/mortality, five-year survival, postgastrectomy dietary intake and nutritional sequelae were recorded in all patients. RESULTS: Postoperative mortality rate was 2.8% in the TG group and 1.1% in the SG group. The number of reoperations, anastomotic dehiscence rate and the length of postoperative stay were higher in the TG group. Five-year survival was closely related to lymph node involvement and gastric wall invasion. The extent of gastric resection did not influence survival when patients were matched for cancer stage. In the SG group, no recurrence in the gastric stump was observed. SG group showed a higher dietary energy intake than the TG group (p < 0.01). This might explain the ability of the SG group to increase body weight more than the TG group (p < 0.01). Only the TG group needed a monthly parenteral vitamin B12 supplements starting 36 months after surgery. CONCLUSION: The results suggest that SG should be considered the treatment of choice of the gastric adenocarcinoma when a cancer-free proximal resection margin can be guaranteed. PMID- 8682461 TI - Treatments for second malignancies after gastrectomy for stomach cancer. AB - BACKGROUND/AIMS: Metachronous primary cancers after stomach cancer were reported as a cause of late death. It is necessary to treat these second malignancies to improve the result of surgical treatment for gastric cancer. MATERIAL AND METHODS: Among 3,570 patients who underwent gastrectomy during 1961-1986, 160 second primary malignancies were observed as of December of 1991. Liver (27 patients) and colorectal (18 patients) cancers were the largest in number. RESULTS: By the end of 1992, for 32 liver tumors small resection, transcatheter arterial embolization and percutaneous ethanol injection were carried out and 3 year survival of resected cases (6 patients; 80.0%) was better than that of nonresected cases (26; 3.8%) (p < 0.05). In 19 colorectal cancers, surgical resection (13/19) and combined locoregional chemotherapy (2/19) were actively performed, and 5-year survival of resected cases (13; 55.4%) was better than that of nonresected cases (6; 0%) (p < 0.05). CONCLUSION: With an intensive long-term follow-up after gastrectomy for cancer, early diagnosis and effective therapy for second primary malignancies is improved. PMID- 8682462 TI - Portal blood velocity and portal blood flow in patients with chronic viral hepatitis: relation to histological liver fibrosis. AB - BACKGROUND/AIMS: This study represents an attempt to correlate portal hemodynamics in patients with chronic hepatitis. MATERIALS AND METHODS: Portal blood velocity and portal blood flow were determined using the duplex Doppler system in 47 patients with chronic viral hepatitis, and findings were compared with the hepatic histological features. RESULTS: Portal blood velocity decreased with the progress of chronic hepatitis, and closely correlated with the histological degree of liver fibrosis (p < 0.0001). The portal blood velocity in patients who had severe bridging fibrosis was significantly lower than that in the patients who had mild bridging fibrosis. However, the portal blood flow in patients with chronic persistent hepatitis and chronic active hepatitis was comparable with that in the controls, and did not correlated with liver histological findings. CONCLUSIONS: These findings suggest that the portal blood velocity is a more sensitive indicator for assessing portal hemodynamics than portal blood flow in chronic viral hepatitis, and may be a useful test for differentiating chronic hepatitis with severe fibrosis from chronic hepatitis with mild fibrosis. PMID- 8682463 TI - Special topic--hepatic inflammation and fibrogenesis. PMID- 8682464 TI - Endoscopic sphincterotomy prior to laparoscopic cholecystectomy for the treatment of cholelithiasis. AB - BACKGROUND/AIMS: Laparoscopic cholecystectomy is the standard treatment for symptomatic cholecystolithiasis; however, there is debate on the management of patients with concomitant common bile duct stones. Several options have been suggested; endoscopic sphincterotomy and laparoscopic common bile duct exploration seemed to be the preferred methods at this moment. MATERIALS AND METHODS: We performed endoscopic sphincterotomy prior to laparoscopic cholecystectomy in 51 cases of acute symptomatic cholelithiasis. RESULTS: Endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy procedure-related complication rate was 5.4%, including 1 pancreatitis, 1 cholangitis, and 2 major bleeds. After follow up period of 15-42 months, recurrent stones were found in 2 patients. CONCLUSION: Endoscopic sphincterotomy combined with laparoscopic cholecystectomy is a safe and effective therapy for symptomatic cholecystolithiasis with concomitant choledocholithiasis. Recurrent stones did occur, but further studies are needed to compare the incidence of recurrent stones after endoscopic sphincterotomy and after laparoscopic common bile duct exploration. PMID- 8682465 TI - Intraoperative ultrasonography for pancreatic insulinomas. AB - BACKGROUND/AIMS: Islet cell adenomas of the pancreas are both single and benign tumors in more than 90% of the cases. Even with the use of increasingly innovative diagnostic techniques, a percentage of tumors are not located in the preoperative or, sometimes, even intraoperative phase. This study compares the results of various diagnostic techniques and provides a brief review of the literature. MATERIALS AND METHODS: Between January 1978 and December 1994, 15 patients (11 females and 4 males) averaging 49 years of age (range 27-70) affected by pancreatic insulinoma underwent surgery at the Department of General Surgery of the "R. Silvestrini" Hospital. RESULTS: In 8 cases the tumor intrapancreatic position was indicated in the preoperative stage. On the contrary, intraoperative ultrasonography allowed the correct location in all the cases, but one. Surgery allows for the complete cure from the diseases when the removal of adenoma is complete. All of our patients underwent surgery which involved enucleation or resection of the distal portion of the pancreas. CONCLUSION: The choice of the type of operation to perform, as well as the consequential morbidity and mortality, seems to depend essentially on the size and position of the insulinoma. All of the patients, except for one who died because of a pancreatic fistula, are alive and normoglycaemic. PMID- 8682466 TI - Locoregional chemotherapy versus locoregional combined immuno-chemotherapy for patients with advanced metastatic liver disease of colorectal origin: a prospective randomized study. AB - BACKGROUND/AIMS: This reports presents the results of a prospective randomized controlled study of combined locoregional targeted immuno-chemotherapy for treatment of patients with liver metastasis from primary colorectal malignancies. MATERIALS AND METHODS: Forty eight patients were randomly assigned into one of two groups. Group A (n = 15) included patients who had post-operatively locoregional chemotherapy and Group B (n = 33) included patients who had combined locoregional immuno-chemotherapy. RESULTS: Statistical analysis shows a clear superiority in the survival and responses of patients treated with immuno chemotherapy versus chemotherapy alone. Forty five percent of patients in Group B are alive with a mean survival of 20.3 months, ranging from 13 to 29 months, as opposed to no survivors from Group A and a mean survival of only 9.9 months, ranging from 3.6 to 22.5 months. Additionally, 64% of the immuno-chemotherapy group had a positive response while only 13% of the chemotherapy had such a response. CONCLUSIONS: Our data supports the value of combined immuno chemotherapy as a treatment for advanced metastatic liver disease. PMID- 8682467 TI - Fibrin glue effectiveness and tolerance after elective liver resection: a randomized trial. AB - BACKGROUND/AIMS: The propensity of fibrin glue to achieve ultimate control of the liver raw surface and its tolerance after hepatic resection, were evaluated by a prospective study. MATERIALS AND METHODS: Seventy seven patients undergoing elective liver resection for benign lesions (n = 35) and malignant lesions (n = 42) including 7 with cirrhosis were studied. Randomization took place only at peritoneal closure and after completion of hemostasis and biliostasis. RESULTS: In the group with fibrin glue (n = 38), a single dose of 5 ml was applied to the liver cut surface. The appearance of the liver margin at abdominal closure was judged as dry in 34/35 (97%) patients with fibrin glue, versus 34/42 (81%) in those without (p = 0.016). Although postoperative morbidity and mortality were not different between the 2 groups, the mean total fluid drainage during the three postoperative days and bilirubin concentration were significantly lower in the group with fibrin glue; respectively 242 +/- 249 ml vs 505 +/- 666 ml and 24 +/- 21 mmoles/l vs 65 +/- 47 mmoles/l. CONCLUSIONS: Our results indicate that fibrin glue application to the hepatic stump after hepatic resection provides effective sealing with good systemic and local compatibility. PMID- 8682468 TI - Arterial reconstruction of the posterior segment after central bisegmentectomy and caudate lobectomy. AB - A 71 year old woman was admitted with jaundice and found to have a tumor originating from the cystic and common hepatic ducts, which infiltrated the origins of the right bile duct and duct of Spiegel. The tumor was also shown to encase the right hepatic artery. A central bisegmentectomy with concurrent caudate lobectomy was performed using the right gastroepiploic artery for reconstruction of the posterior segmental branch of the right hepatic artery. Celiac angiography conducted 3 weeks postoperatively confirmed the patency of the hepatic segmental arterial anastomosis. The patient had an uneventful recovery with no evidence of liver failure, and was discharged home thirty-two days. Tumors infiltrating the right hepatic artery, which have traditionally been treated with extensive liver resection, can be managed with hepatic segmentectomy and reconstruction of the segmental hepatic artery. PMID- 8682469 TI - Serum levels of circulating intercellular adhesion molecule 1 in hepatocellular carcinoma. AB - BACKGROUND/AIMS: This is a comparative study of the relationship between. MATERIAL AND METHODS: Serum levels of circulating intercellular adhesion molecule 1 (cICAM-1) were measured by ELISA assay in four patients with chronic hepatitis (CH), 16 with liver cirrhosis (LC), 38 with hepatocellular carcinoma (HCC), and in nine healthy controls. RESULTS: No significant difference in cICAM-1 levels was observed between LC and HCC. The cICAM-1 level in HCC did not correlate with tumor markers but correlated well with tumor size. cICAM-1 level in HCC Stage III + IV was significantly higher than that of Stage I, and was higher in HCC with liver metastasis as opposed to HCC without metastasis. Furthermore, the cICAM-1 level of HCC decreased significantly after hepatectomy. CONCLUSION: These findings showed a close relationship between cICAM-1 and the progress of intrahepatic metastasis of HCC, indicating a possibility for using cICAM-1 as a prognostic marker. PMID- 8682470 TI - Hepatic blood flow after acute biliary obstruction and drainage in conscious dogs. AB - BACKGROUND AIMS: Obstructive jaundice is a factor which effects hepatic blood flow and the relative contribution of the hepatic arterial flow and portal venous flow. In this study, and were measured in conscious dogs and the influence of biliary obstruction and drainage was investigated. MATERIAL AND METHODS: Hepatic arterial flow (HAF) and portal venous flow (PVF) after biliary obstruction and subsequent drainage were continuously measured in conscious dogs using implantable transit time ultrasonic flow-meters. RESULTS: After biliary obstruction hepatic arterial flow rapidly increased compared to the pre obstructed values(p < 0.01), while portal venous flow was significantly decreased (p < 0.01). Total hepatic blood flow was initially increased (p < 0.01) until 2 hours after obstruction. It then decreased gradually. After 2 weeks, it was less than the pre-obstructed values, but this was not significant. Biliary drainage was performed after 2 weeks. Hepatic arterial flow subsequently decreased (p < 0.01) and portal venous flow increased (p < 0.05). Blood flow did not change. CONCLUSION: Biliary obstruction resulted in significant changes in liver circulation. Biliary drainage facilitated recovery from these changes. PMID- 8682471 TI - Liver abscess concomitant with hemobilia due to rupture of hepatic artery aneurysm: a case report. AB - Hepatic artery aneurysm is an uncommon lesion, usually extrahepatic and rarely intrahepatic. Rupture of hepatic artery aneurysm into the biliary tract is a rare cause of hemobilia. Angiography is the diagnostic method of choice and surgical intervention is the procedure of choice for extrahepatic rupture. Interventional angiography with embolization is optimal for inaccessible intrahepatic aneurysm and extremely poor risk patients. Reported here is a rare case of left intrahepatic artery aneurysm ruptured into the intrahepatic bile duct in the course of liver abscess. Embolization of the hepatic artery resulted in cessation of bleeding. PMID- 8682472 TI - Hepatic adenoma: an observation from asymptomatic stage to rupture. AB - A 39 year old female, who took oral contraceptives for about ten years, was found to have an asymptomatic hepatic adenoma during an episode of acute hyperlipidemic pancreatitis. The diagnosis was confirmed by sonography, CT scan, angiography, and liver biopsy. She refused operation and was followed at the outpatient clinic. Initially, the tumor decreased its size after withdrawal of oral contraceptives, but enlarged again on subsequent examinations. She came back to emergency room with hemoperitoneum and intratumoral hemorrhage eighteen months after the initial diagnosis. Her hepatic adenoma was removed surgically and was found to be ruptured. She has been well for two years. PMID- 8682473 TI - Cystic neoplasms of the liver: a report of two cases with special reference to cystadenocarcinoma. AB - We herein present two cases with cystic neoplasms of the liver, both successfully treated by a surgical resection. One patient underwent a tumor enucleation, while the other had a left hepatic lobectomy and left caudate lobectomy. Although the follow-up period is still relatively short, both patients are doing well without any sign of recurrence. The specimens were histopathologically examined including immunohistochemical staining. Both tumors were unilocular-cystic and contained mucus. One tumor was considered to have originated from a cystadenoma with a mesenchymal stroma, which has been espoused by Wheeler and Edmondson, while the other tumor was considered to have originated from the bile duct. Therefore, the diagnosis of one patient was cystadenocarcinoma, while the other was considered to be a mucin-producing papillary adenocarcinoma of the intrahepatic bile duct. No invasive growth to the liver parenchyma or the surrounding tissues was observed in either case. Thus, a surgical resection should be the first choice of treatment for cystic neoplasms of the liver. Furthermore, a malignant transformation of cystadenoma with a mesenchymal stroma should be given a special entity in cystadenocarcinoma. PMID- 8682475 TI - Clinicopathological characteristics and surgical procedures for carcinoma of the papilla of Vater. AB - BACKGROUND/AIMS: In the present study, clinicopathological characteristics of carcinoma of the papilla of Vater and suitable operative procedures for treatment were investigated. MATERIAL AND METHODS: Sixty cases (40 male and 20 female) of resected carcinoma of the papilla of Vater were studied clinicopathologically. RESULTS: Among the patients, a polypoid type without ulceration and an ulcer formation type, with regard to the gross appearance, were found in 37 cases and 23 cases, respectively. Submucosal invasion, invasion to the sphincter Oddi, pancreatic parenchymal invasion and lymph node involvement were found more frequently in the ulcer-formation type than in the polypoid type without ulceration. Postoperative survival curves revealed that the prognosis was poor when either lymph node involvement, invasion to pancreatic parenchyma or ulcer formation was found. Local resection was performed in seven cases, in all of whom carcinoma was found histologically in the cut surface of the tumor. This is easily explained by the fact that mucosal spread or interstitial infiltration was frequently found even in cases with carcinoma at a relatively early stage. CONCLUSIONS: Local resection for carcinoma of the papilla of Vater is inadequate as a curative resection, and pylorus-preserving pancreatoduodenectomy should be the treatment of choice for carcinoma of the papilla of Vater. However, since there were no differences between the postoperative survival curves of patients who underwent pancreatoduodenectomy or local resection, local resection may still be suitable for patients with other major diseases or a poor condition. PMID- 8682474 TI - Carcinosarcoma of the liver with mesenchymal differentiation: a case report. AB - Carcinosarcoma of the liver with mesenchymal differentiation are very rare in adult patients. A case is reported with an exhaustive pathologic examination and review of the literature. A 61-year old man presented with general fatigue and dull abdominal pain. Two liver masses were diagnosed and resected by a right hepatectomy. Specimen pathology revealed that the tumor and lymph node consisted of two cancerous components. One carcinomatous component corresponding to a hepatocellular carcinoma and a sarcomatous component characterized by a diffuse proliferation of spindle shaped cells with chondrosarcomatous and osteosarcomatous changes. Patient died 9 months later of a diffusion of the tumor. For the first time, to our knowledge, a mesenchymal differentiation is demonstrated in liver carcinosarcoma. PMID- 8682476 TI - Bleeding of the pancreatic stump following pancreatoduodenectomy for cancer. AB - BACKGROUND/AIM: The purpose of this study was to determine the characteristics of bleeding of the pancreatic stump after pancreatoduodenal resection with pancreatojejunal anastomosis. PATIENTS AND METHODS: Between February 1970 and December 1990, 223 patients underwent a Whipple resection for cancer. RESULTS: Twenty patients (9%) had post-operative hemorrhage. In 10 patients bleeding arose within the operative field and in the 10 later within the gastrointestinal tract. Six patients bled from the gastroenterostomy and 4 (1.7%) from the pancreatic cut surface. In all four severity of the hemorrhage required urgent relaparotomy. CONCLUSIONS: Diagnosis and hemostasis could be achieved through a jejunostomy near the pancreatic anastomosis. Two patients had pancreatic fistula,one of them died. PMID- 8682477 TI - Treatment for dehiscence of pancreaticojejunostomy after pancreaticoduodenectomy: is resection of the residual pancreas necessary? AB - BACKGROUND/AIMS: Partial or total disruption of pancreaticojejunostomy (PJ) is a rare but serious complication after pancreaticoduodenectomy (PD). The recommended option of treatment is completion pancreatectomy. However, the mortality remains high as most patients were too critical to withstand the procedure. PATIENTS AND METHODS: 12 consecutive patients with dehisced PJ after PD were treated by oversewing the pancreatic stump without resection of the residual pancreas. RESULTS: Although a high morbidity rate (75%) occurred after our management, ten patients survived reoperation, without recurrent pancreatic fistula or the need for insulin injection. CONCLUSION: A complete pancreatectomy is not necessary for a dehisced PJ, if acute pancreatitis is not found in the residual pancreas. PMID- 8682478 TI - Secural pancreaticojejunal anastomosis for the pancreaticoduodenectomy. AB - BACKGROUND/AIMS: This report presents the results of two methods for minimizing complications following a Whipple operation. MATERIALS AND METHODS: In the past five years, continuous duct to mucosal suture with end to side anastomosis of the pancreaticojejunostomy was utilized in 30 patients. Another 50 patients received interrupted duct to mucosal suturing with end to side anastomosis of the pancreaticojejunostomy in the past five to ten years. RESULTS: None of the first set of 30 patients suffered leakage after the operation. Ten of the 50 patients (20%) developed leakage postoperatively and 3 (6%) died. The group with continuous duct to mucosal suture had significantly less complications than those with interrupted duct to mucosal suturing (P < 0.05). Late follow up of the patients with continuous duct to mucosal suture using echogram, no one had stricture of the anastomosis. CONCLUSION: The continuous duct to mucosal suture of the pancreaticojejunostomy is a very safe procedure, minimizing the operative morbidity and mortality of the Whipple operation. PMID- 8682479 TI - The management of bleeding from a pancreatic pseudocyst: a case report. AB - Hemorrhage from pancreatic pseudocyst or a pseudoaneurysm is a rare, fatal complication of chronic pancreatitis. Elastase may cause erosion of adjacent vessels in the course of acute pancreatitis and spontaneous bleeding may occur. One therapeutic modality is embolotherapy, but surgery is the traditional therapy. Resection of the bleeding site of the pancreas, ligation of the affected vessels or compression by occluding the cyst with a balloon are good alternatives. We present a case having massive gastric hemorrhage from the splenic artery after cystogastrostomy, treated by occluding the artery with a foley catheter. PMID- 8682480 TI - Spontaneous internal drainage of a pancreatic pseudocyst: a case report. AB - A 72 year old patient was admitted to our department with progressive abdominal symptoms caused by chronic pancreatitis. Physical examination and laboratory data were unremarkable, ultrasound showed a cystic lesion beneath the pancreatic head. Initial endoscopic examination demonstrated a duodenal stenosis; in the second examination the stenosis had resolved by spontaneous perforation of the pseudocyst into the duodenal bulb. Pancreatic and peri-pancreatic pseudocysts are common in acute and chronic pancreatitis; the frequency of their diagnosis increased following the advent of ultrasonography and computed tomography as diagnostic tools and more intensive clinical monitoring. Our knowledge about the incidental course of the disease is still limited. When the diagnosis is established, a lot of questions referring to the choice of therapeutic regime conservative treatment, percutaneous intervention, endoscopic or surgical procedures arise. Therapeutic possibilities and their advantages are discussed. PMID- 8682481 TI - Longterm outcome of endoscopic sclerotherapy of variceal bleeding: comparative study between schistosomiasis and others. AB - BACKGROUND/AIMS: This comparative study was conducted on 111 patients to evaluate the long term outcome of endoscopic variceal therapy in patients with portal hypertension, and particularly with schistosomiasis. PATIENTS AND METHODS: There were 45 patients with chronic liver disease due to schistosomiasis, 31 with chronic hepatitis B and 21 with chronic NNb hepatitis. The remaining 14 had chronic liver disease of other etiologies. The mean follow up period was 40 months. RESULTS: Esophageal varices were completely sclerosed in 32 out of 111 patients in 5 sessions (average) over a mean duration of 8 months. A comparison of patients with schistosomal and non-schistosomal liver diseases revealed that 68% of the schistosomal group patients were in child's A classification, compared to 30% of the patients in the non-schistosomal group. There was no significant difference with respect to early rebleeding and recurrence of oesophageal varices. The outcome of sclerotherapy in schistosomal group was better with respect to survival span over a 5 year period of 78% while for the nonschistosomal group it was less than 59%. CONCLUSIONS: This study has shown that injection sclerotherapy for bleeding oesophageal varices gives best results when liver function is usually well preserved and for chronic schistosomal liver disease. PMID- 8682482 TI - Endoscopic treatment of bronchobiliary fistula: report on 11 cases. AB - BACKGROUND/AIMS: There are reports of treatment of biliary cutaneous fistulae by endoscopically placed nasobiliary drains. We report our fistulae treatment results from this method. MATERIALS AND METHODS: We treated 11 patients with bronchobiliary fistulas (BBFs) endoscopically during the last 6 years. In most cases, the BBF's were the result of Hydatid cyst operations. Six patients had simultaneous biliocutaneous fistula (BCF). RESULTS: All BBFs and BCFs closed after the nasobiliary drain placement without any complication. Three patients who developed fistula recurrence healed with endoscopic treatment. CONCLUSION: Endoscopic treatment is a viable alternative to surgical treatment. PMID- 8682483 TI - A comparative trial of recombinant interferon alpha 2A versus alpha 2 beta on myelosuppression in healthy adult volunteers. AB - BACKGROUND/AIMS: Recombinant interferon (r-IFN) is an antiviral agent used to treat patients with chronic viral hepatitis patients. Unfortunately, the use is often limited due to its myelosuppressive properties. Currently, there are two forms of r-IFN commercially available: r-IFN alpha-2a and rIFN alpha-2b. Although both are thought to be equally effective, a comparative study of their myelosuppressive properties has not been undertaken. MATERIALS AND METHODS: In the present study, three groups of healthy adult volunteers (n = 6/group) were randomized to receive a two week course of either r-IFN alpha-2a or r-IFN alpha 2b (5 million units, subcutaneously, thrice weekly) or no treatment. All subjects were then followed for an additional two week post treatment; observation period. RESULTS: The results of the study revealed that both forms of r-IFN alpha caused a significant and similar decrease in white blood cell counts (maximum declines of 37.9 +/- 6.8% for alpha-2a and 39.5 +/- 6.0% for alpha-2b at day 4) and platelet counts (maximum declines of 19.5 +/- 8.6% for alpha-2a and 20.2 +/- 8.4% for alpha-2b at day 2) from baseline values. Following discontinuation of therapy, white blood cell and platelet counts returned to pretreatment levels. Hemoglobin levels remained unchanged throughout the study period. CONCLUSION: The results of this study indicate that r-IFN alpha causes a prompt and significant decrease in white blood cell and platelet counts. However, no differences exist between r-IFN alpha-2a and r-IFN alpha-2b in terms of their myelosuppressive properties in humans. PMID- 8682485 TI - A long-term investigation of transcatheter splenic arterial embolization for hypersplenism. AB - BACKGROUND/AIMS: This study investigated longterm changes in the parameters of blood and liver function tests following TSAE. PATIENTS AND MATERIALS: Twenty five patients received transcatheter splenic arterial embolization (TSAE) as a treatment for hypersplenism, and their post- TSAE conditions were monitored for over a year. We evaluated changes in blood and liver function tests, and examined changes of platelet associated immunoglobulin G (PA-IgG), liver and spleen volumes and hemodynamics in order to consider the mechanism of liver function improvement following TSAE. RESULTS: In blood tests, platelet and WBC counts significantly increased one year after TSAE and this increased level continued up to the fifth year. In liver function tests, levels of serum total protein, albumin, total cholesterol, and results of the hepaplastin test significantly improved after the one year, and these levels remained even over one year. CONCLUSIONS: Results of this study indicated involvements of decreased platelet pool in the spleen and probable immunological mechanisms in association with PA IgG in platelet count increase. Indocyanine green clearance (15') were improved in 5 of 8 patients (62.5%) after TSAE. These points may indicate an involvement of hemodynamic changes in the improvement of liver function parameters. PMID- 8682484 TI - A randomized trial of pefloxacin plus klindamicin and cefoxitin in hepatobiliary and pancreatic surgery. AB - BACKGROUND/AIMS: The efficacy and safety of pefloxacin plus klindamicin with cefoxitin were studied in patients undergoing hepatobiliary or pancreatic surgery. MATERIALS AND METHODS: Seventy-five patients with biliary tract, hepatic, or pancreatic pathology were randomly allocated in a prospective open study to receive a combination of either i.v or oral pefloxacin (800mg per day) plus klindamicin (2,400mg per day) or an i.v. cefoxitin (4,000mg per day). RESULTS: Twenty patients had to be withdrawn from the trial because of negative baseline culture or because of isolation of bacteria resistant to the study drugs. In the remaining fifty-five patients, the clinical cure rates were excellent in more than ninety five percent and similar for both groups, the bacteriological success rates were 100% in the pefloxacin plus klindamicin group and 89.1% in the cefoxitin group. No patients were withdrawn from the study because of side effects. CONCLUSION: In our study we have shown the excellent results of the antibacterial therapy with pefloxacin and klindamicin of the patients who underwent complicated hepatobiliary and pancreatic surgery. PMID- 8682486 TI - Lymphocyte-endothelial cell interactions in hepatic inflammation. PMID- 8682487 TI - Lymphocyte and macrophage populations in the liver. PMID- 8682488 TI - Extracellular matrix proteins and hepatic fibrosis. PMID- 8682490 TI - Pathobiology of hepatic stellate cells. PMID- 8682489 TI - Matrix turnover in fibrogenesis. PMID- 8682491 TI - Mediators of hepatic fibrogenesis. PMID- 8682492 TI - Prevalence of carriers of the most common medium-chain acyl-CoA dehydrogenase (MCAD) deficiency mutation (G985A) in The Netherlands. AB - The G985A mutation represents about 90% of all medium-chain acyl-CoA dehydrogenase (MCAD) allele mutations that cause the clinical symptoms of MCAD deficiency. The prevalence of carriers varies between different European populations, with high frequencies in the northwestern part of Europe. To determine the prevalence of MCAD carriers with the G985A mutation in The Netherlands, we collected 6195 Guthrie cards of newborns. Mutation detection was performed with the polymerase chain reaction (PCR), in which a NcoI restriction site was created in the presence of a G985A mutation in the PCR product, followed by NcoI digestion, and gel electrophoresis. We detected a G985A carrier frequency of 1 in 59 (95% CI 1/50-1/73) in The Netherlands. The total prevalence of carriers was estimated to be 1 in 55 (95% CI 1/46- 1/68), based on a relative G985A frequency of 94% in The Netherlands. PMID- 8682493 TI - Short direct repeats at the breakpoints of a novel large deletion in the CFTR gene suggest a likely slipped mispairing mechanism. AB - In the cystic fibrosis conductance transmembrane regulator (CFTR) gene a few small deletions and only a large, complex, 50-kb deletion have been described so far. We report a second large deletion, which had been hypothesized in a patient affected by cystic fibrosis on the basis of an abnormal pattern of inheritance of the intragenic microsatellites IVS17b/TA and IVS17b/CA. Southern blot analysis revealed the presence of an anomalous band in the patient and her father, in the region encompassing exons 13 - 19, approximately 0.6 kb shorten than the one present in normal controls, in addition to the band of the correct size. Cloning and sequencing the DNA fragments spanning the region of interest demonstrated the presence of a 703-bp deletion causing complete removal of exon 17b in the paternal cystic fibrosis chromosome. This analysis revealed the presence of two short direct repeats flanking the breakpoints. The 3' repeat partially overlapped the IVS17b/CA microsatellite and the number of CA repeated units present in the paternal cystic fibrosis allele was the shortest ever found among chromosomes so far analyzed. These data may suggest that the mechanism for the generation of the deletion may have involved a slipped mispairing during DNA replication, which has not previously been described in the CFTR gene. PMID- 8682494 TI - High parental age is associated with sporadic hereditary retinoblastoma: the Dutch retinoblastoma register 1862-1994. AB - We wished to determine the influence of parental age at the birth of a retinoblastoma patient on the risk of sporadic hereditary retinoblastoma. The parental age at birth of 941 patients of the Dutch retinoblastoma register (1862 1994) was identified and compared between sporadic hereditary and nonhereditary patients. In a subcohort (1936-1994), a comparison was made with parental age at birth in the general population, as obtained from the Central Bureau of Statistics. Missing birth dates of the parents of retinoblastoma patients were traced with the help of the municipal registries and the Central Bureau of Genealogy. The mean paternal age was 10.7 months higher and the mean maternal age was 11.0 months higher in the sporadic hereditary retinoblastoma patients than in parents of nonhereditary patients. In the subcohort, the mean paternal and maternal ages of sporadic hereditary patients were also higher (12.4 and 11.5 months, respectively) than those of the general population. All differences were statistically significant. This study shows that a high parental age is associated with an enhanced risk of sporadic hereditary retinoblastoma. PMID- 8682495 TI - The human mitochondrial citrate transporter gene (SLC20A3) maps to chromosome band 22q11 within a region implicated in DiGeorge syndrome, velo-cardio-facial syndrome and schizophrenia. AB - The gene encoding the human mitochondrial citrate transporter designated SLC20A3 was mapped to chromosome 22 by analyzing its segregation in a panel of human hamster somatic cell hybrids. This assignment was confirmed by fluorescence in situ hybridization to metaphase chromosomes, and the gene was further localized to band 22q11.21. The gene is located in a critical region associated with allelic losses in a variety of clinical syndromes, including DiGeorge syndrome, velo-cardio-facial syndrome and a subtype of schizophrenia. PMID- 8682496 TI - Two novel gene mutations (Glu174-->Lys, Phe383-->Tyr) causing the "hepatic" form of carnitine palmitoyltransferase II deficiency. AB - Carnitine palmitoyltransferase II (CPT II) deficiency has two different clinical forms, one with "hepatic" and the other with "muscular" symptoms. We studied the molecular basis of the "hepatic" form in two Japanese siblings. Their CPT II activity in lymphoblasts was reduced to 3% of the level observed in normal controls. cDNA analysis showed that the proband was a compound heterozygote. One allele carried a new mutation, G621-->A (Glu174-->Lys). The other carried three single-base substitutions; a new mutation, T1249-->A (Phe383-->Tyr), and two previously reported polymorphisms. The brother had the same four substitutions. Neither of the two new mutations in this study was detected in the 60 alleles of 30 Japanese control subjects. Secondary structure prediction analysis of the mutated CPT II protein was different from that of the normal protein. We concluded that these mutations caused the "hepatic" form of CPT II deficiency in the probands. PMID- 8682497 TI - Detection of a de novo R1066H mutation in an Italian patient affected by cystic fibrosis. AB - Search for mutations in a cystic fibrosis patient, compound heterozygous for 1717 1G-->A and another uncharacterized molecular defect, revealed the presence of a de novo R1066H mutation on the affected chromosome of paternal origin. Three additional rare mutations (R1066C, R1066S and R1066L), occurring at the CpG dinucleotide at position 3328-3329 of the cystic fibrosis transmembrane conductance regulator gene, have so far been reported. The identification of a R1066H de novo mutation further suggests that this dinucleotide may constitute a mutational hotspot. PMID- 8682499 TI - Frequent DNA variant in exon 2a of the survival motor neuron gene (SMN): a further possibility for distinguishing the two copies of the gene. AB - An intragenic single-strand conformation polymorphism (SSCP) variant in exon 2a of the survival motor neuron gene (SMN) has been identified. The SSCP band shift is caused by a silent mutation (AGC-->AGT) at codon 28, which is the first codon of exon 2a. Five exchanges of base pairs at the 3'-end of the gene have been described that allow the two copies of SMN (telSMN and cenSMN) to be distinguished, whereas no DNA variant has been found at the 5'-end. The new DNA variant belongs to cenSMN and may be important for the assignment of point mutations to one of the two copies of SMN in spinal muscular atrophy (SMA) patients. The frequency of this variant is lower in SMA patients (10%) than in controls (24%). PMID- 8682498 TI - Assignment of the NTRK4 (trkE) gene to chromosome 6p21. AB - Reverse transcriptase-polymerase chain reactions using foetal brain RNA with reverse and forward primers of the first, second and third NTRK4 region allowed us to obtain three amplified NTRK4 fragments. The specificity of amplified fragments was checked by digestion with restriction endonucleases AvrII, HindIII and PspII for the first, second and third regions, respectively. Each restriction site was specific for each amplified fragment. The fragment of the NTRK4 first region was also sequenced and the sequence determined was identical to the human NTRK4 sequence. The three amplified fragments were cloned in pBS. For the Southern technique, plasmid pBS-NTRK4a (with an insert of 1052 bp) detected a human 9-kb HindIII sequence which was localised unambiguously on chromosome 6. For fluorescence in situ hybridisation, the three plasmids, pBS-NTRK4a, pBS NTRK4b (insert 924 bp) and pBS-NTRK4c (insert 1114 bp) were pooled and used as a probe. This NTRK4 probe was localised on 6p21. Of 50 metaphases analysed, 49 contained twin spot signals on both sister chromatids. PMID- 8682501 TI - Mosaicism for the Charcot-Marie-Tooth disease type 1A duplication suggests somatic reversion. AB - A female patient with clinical signs and symptoms of a demyelinating neuropathy was shown to have a duplication of the 1.5-Mb region on chromosome 17p11.2, typical of the great majority of cases of Charcot-Marie-Tooth disease type 1A (CMT1A). However, analysis of DNA extracted from peripheral blood revealed a 2:2.4 instead of the usual 2:3 ratio between the 7.8- and 6.0-kb EcoRI fragments in the proximal and distal repetitive extragenic palindromic (REP) elements of CMT1A. Detection of a 3.2-kb EcoRI/SacI kb junction fragment with probe pLR7.8 confirmed the CMT1A duplication. The dosage of this junction fragment, compared with a 2.8-kb EcoRI/SacI fragment of the proximal REP elements of CMT1A, was 2:0.58 instead of the expected 2:1 dosage for heterozygous CMT1A duplications. We hypothesized that the lower dosages of these restriction fragments specific for the CMT1A duplication were due to mosaicism; this was confirmed by fluorescence in situ hybridization analysis with the D17S122-specific probe pVAW409R1. In peripheral blood lymphocytes the percentage of interphase nuclei with a duplication in 17p11.2 was 49%. In interphase nuclei extracted from buccal mucosa, hair-root cells or paraffin-embedded nervous tissue the duplication was detectable in 51%, 66% and 74%, respectively. This is the first report of mosaicism in a patient with a CMT1A duplication identified by three different and independent techniques. PMID- 8682500 TI - Fine mapping of the 1q21 breakpoint of the papillary renal cell carcinoma associated (X;1) translocation. AB - A combination of Southern blot analysis on a panel of tumor-derived somatic cell hybrids and fluorescence in situ hybridization (FISH) techniques was used to map a series of DNA markers relative to the 1q21 breakpoint of the renal cell carcinoma (RCC)-associated (X;1)-(p11;q21) translocation. This breakpoint maps between several members of the S100 family which are clustered in the 1q21 region and a conserved region between man and mouse containing the markers SPTA1-CRP APCS-FcER1A-ATP1A2-APOA2. The location of the breakpoint coincides with the transition of a region of synteny of human chromosome 1 with mouse chromosomes 3 and 1. PMID- 8682502 TI - Turner syndrome: a study of chromosomal mosaicism. AB - We report the results of a molecular investigation of 25 patients who had Turner syndrome and who had previously been subject to analysis using cytogenetic techniques. When in situ hybridization and polymerase chain reaction (PCR) techniques were applied, a larger number of mosaic individuals were observed than were detected by cytogenetic methods. This was mainly because of the presence of the cell line 46,XX. The most frequent mosaics were 45,X/46,XX (36%); the presence of isochromosomes comprised 24% and fragments 12%. The patients who had been previously diagnosed with mosaicism displayed a higher complexity in their karyotypes because of the presence of new cellular lines. The isodicentric X chromosome for the long arm, idic(Xq), gave rise to complex mosaics of up to nine cell lines. The application of fluorescence in situ hybridization and PCR led to a clearer definition of alterations at the centromeric level and the identification of the nature of chromosome fragments. PMID- 8682503 TI - Preliminary studies on the molecular basis of hyperphenylalaninemia in Egypt. AB - Mutation analysis at the phenylalanine hydroxylase (PAH) locus was undertaken in 56 Egyptian hyperphenylalaninemic patients. Selected screening for 11 known mutations and denaturing Gradient gel electrophoresis (DGGE) analysis of the entire coding sequence and exon/intron boundaries led to the identification of a new mutation (I224T), four previously described mutations, and several polymorphisms. Overall, 18 mutant alleles could thus be characterized. In contrast to the high mutation detection rate typical of the DGGE-based scanning approach, only 6 of 16 mutant alleles tested were identified. Since BH4 deficiency could not be excluded in any of these patients, the latter results may be explained by the occurrence of mutations affecting the genes controlling the synthesis and recycling of tetrahydrobiopterin: the cofactor of PAH. An alternative hypothesis is also discussed. PMID- 8682504 TI - DNA analysis of the immunoglobulin IGHG loci in a Mandenka population from eastern Senegal: correlation with Gm haplotypes and hypotheses for the evolution of the Ig CH region. AB - This study presents restriction fragment length polymorphism (RFLP) and serological analyses of the immunoglobulin CH loci in a sample of 100 individuals from a Senegalese Mandenka population. The RFLP variability is mostly the result of large DNA insertions or deletions in the non-coding flanking regions of the IGHG genes, and to variable number of tandem repeat-like patterns within their 5' switch sequences. However, part of the IGHG3 polymorphism also corresponds to a variable number of exons coding for the flexible hinge segment of the IgG3 antibody (the 4-exon and 3-exon forms, and a newly described 2-exon form). This diversity presents relevant associations with Gm haplotypes, suggesting that molecular rearrangements of the G3 hinge are related to the evolution of the Gm polymorphism. Non-significant correlation coefficients are found between Gm haplotypes and A2m alleles in the Mandenka, indicating that these loci may have reached equilibrium through recombination. The effect of recombination on linkage disequilibrium is more generally revealed, across the Ig CH genomic region, by a significant decrease of D' values with increasing physical distances between the loci on the chromosome. PMID- 8682505 TI - Superoxide dismutase 1: identification of a novel mutation in a case of familial amyotrophic lateral sclerosis. AB - Mutation analysis of the superoxide dismutase gene SOD1 in a familial case of amyotrophic lateral sclerosis revealed a T --> C transition at codon 151 of exon 5. This mutation results in the substitution of an isoleucine for a threonine. It appears to affect formation of dimers of the protein and is the most C-terminal amino acid change in SOD1 described to date. PMID- 8682506 TI - Novel rhodopsin mutation in an autosomal dominant retinitis pigmentosa family: phenotypic variation in both heterozygote and homozygote Val137Met mutant patients. AB - A family affected with autosomal dominant retinitis pigmentosa (RP) is presented. Two clinically affected patients (mother and daughter) were heterozygous for the same novel missense mutation (Val137Met) of the rhodopsin gene (RHO). Both heterozygous and homozygous cases were observed among their few symptomatic relatives. Wide clinical variation was exhibited among the individuals with mutations in this family. None of the controls showed this change in RHO, nor has it been previously reported in other RP families. No other RHO mutation was observed. Additional genetic or environmental factors could play a role in modulating the penetrance and clinical expression of this RHO mutation. PMID- 8682507 TI - Rapid detection of trisomies 21 and 18 and sexing by quantitative fluorescent multiplex PCR. AB - Aneuploidies involving chromosomes 21, 18, 13, X and Y account for over 95% of all chromosomal abnormalities in live-born infants. Prenatal diagnosis of these disorders is usually accomplished by cytogenetic analysis of amniotic or chorionic cells but this is a lengthy procedure requiring great technical expertise. In this paper, we assess the diagnostic value of using a quantitative fluorescent polymerase chain reaction (PCR) suitable for the simultaneous and rapid diagnosis of trisomies 21 and 18 together with the detection of DNA sequences derived from the X and Y chromosomes. Samples of DNA, extracted from amniotic fluid, fetal blood or tissues, and peripheral blood from normal adults were investigated by quantitative fluorescent PCR amplification of polymorphic small tandem repeats (STRs) specific for two loci on each of chromosomes 21 and 18. Quantitative analysis of the amplification products allowed the diagnosis of trisomies 21 and 18, while sexing was performed simultaneously using PCR amplification of DNA sequences derived from the chromosomes X and Y. These results indicate the advantages of using two sets of STR markers for the detection of chromosome 21 trisomies and confirmed the usefulness of quantitative fluorescent multiplex PCR for the rapid prenatal diagnosis of selected chromosomal abnormalities. PMID- 8682508 TI - Complex mutational events at the HumD21S11 locus. AB - We have studied length and sequence variability at the HumD21S11 locus in five different populations to obtain more detailed information about the structure of this short tandem repeat system. In all populations studied so far two types of alleles have been described. The consensus alleles (type I) consist of three regions with variable numbers of TCTR units and one constant region comprising 43 bp. Alleles of type II (so-called interalleles) show the same basic sequence structure except for the occurrence of a TA insertion at a fixed position in variable region 3. Additional sequence variability exists in the Ovambo and Papuan populations with gross changes in two of the three variable regions and in the constant region. Due to these extreme variations the Ovambos and Papuans showed a better fit to the infinite allele model than to the stepwise mutation model. In the German, Japanese and Chinese populations no significant bias towards one of the two models could be observed. Population genetic studies showed no significant deviation from Hardy-Weinberg equilibrium. PMID- 8682509 TI - Chinese achondroplasia is also defined by recurrent G380R mutations of the fibroblast growth factor receptor-3 gene. AB - Achondroplasia is the most common form of dwarfism in humans. A recurrent glycine to-arginine mutation at codon 380 (G380R) of the transmembrane domain of fibroblast growth factor receptor-3 (FGFR-3) was identified in the majority of Western and Japanese patients, which is uncommon in other autosomal dominant genetic diseases. To determine whether this mutation is also common in Chinese patients, we examined the G380R mutation in Chinese patients with achondroplasia. Of ten patients studied, including eight sporadic cases and one family with two affected members, all have the same G380R mutation with a G-to-A transition. Our results support the argument that the G380R mutation of FGFR-3 is the most frequent mutation causing achondroplasia across different populations. PMID- 8682510 TI - Wiskott-Aldrich syndrome: no strict genotype-phenotype correlations but clustering of missense mutations in the amino-terminal part of the WASP gene product. AB - The Wiskott-Aldrich syndrome protein (WASP) gene was found to be mutated in patients presenting with WAS and in patients showing X-linked thrombocytopenia. Mutation analysis in 19 families of German, Swiss and Turkish descent by single strand conformation polymorphism and sequencing resulted in the detection of seven novel and 10 known mutations. A striking clustering of missense mutations in the first four exons contrasted with a random distribution of nonsense mutations. More than 85% of all known missense mutations were localized in the amino-terminal stretch of the WASP gene product; this region contained a mutational hot spot at codon 86. No genotype-phenotype correlation emerged after a comparison of the identified mutations with the resulting clinical picture for a classical WAS phenotype. A substitution at codon 86 resulted in an extremely variable expression of the disease in a large Swiss family. An extended homology search revealed a distant relationship of this stretch to the vasodilator stimulated phosphoprotein (VASP), which is involved in the maintenance of cyto architecture by interacting with actin-like filaments. PMID- 8682511 TI - Identification and characterization of NF1-related loci on human chromosomes 22, 14 and 2. AB - Neurofibromatosis type 1 (NF1) is a frequent hereditary disorder. The disease is characterized by a very high mutation rate (up to 1/10000 gametes per generation). NF1-related loci in the human genome have been implicated in the high mutation rate by hypothesizing that these carry disease-causing mutations, which can be transferred to the functional NF1 gene on chromosome arm 17q by interchromosomal gene conversion. To test this hypothesis, we want to identify and characterize the NF1-related loci in the human genome. In this study, we have localized an NF1-related locus in the most centromeric region of the long arm of chromosome 22. We demonstrate that this locus contains sequences homologous to cDNAs that include the GAP-related domain of the functional NF1 gene. However, the GAP-related domain itself is not represented in this locus. In addition, cosmids specific to this locus reveal, by in situ hybridization, NF1-related loci in the pericentromeric region of chromosome arm 14q and in chromosomal band 2q21. These cosmids will enable us to determine whether identified disease-causing mutations are present at the chromosome 22-associated NF1-related locus. PMID- 8682512 TI - Beta-thalassaemia in indigenous Belgian families: identification of a novel mutation. AB - The molecular basis of beta-thalassemia was investigated at the DNA level in 28 Belgians from 14 unrelated families. All the patients were heterozygous for beta thalassaemia. Seven different mutations were identified using a combination of dot-blot hybridization with allele-specific oligonucleotide probes and direct automated fluorescence-based DNA sequencing. Among these mutations, four are commonly found in the Mediterraneans - codon 8 (-AA), IVS-I-1 (G --> A), IVS-I-6 (T --> C) and codon 39 (C --> T)-and two have occasionally been reported initiation codon (T --> C) and codon 35 (C --> A). The last mutation, a -CC deletion at codons 38/39, appears to be a novel mutation and can routinely be investigated by AvaII restriction on amplified DNA. We report our findings, discuss the diversity of the mutations found in Belgium and show the usefulness of direct DNA sequencing in a population in which the molecular defects of beta thalassaemia have yet to be characterized and in which screening is hampered by the wide range of potential mutations. PMID- 8682513 TI - Confirmation of susceptibility locus on chromosome 13 in Australian breast cancer families. AB - Two major genes determining predisposition to breast cancer, termed BRCA1 and BRCA2, have been mapped to the long arms of chromosomes 17 and 13, respectively. Each locus is believed to account for approximately 40% of cases of familial breast cancer. We used linkage and haplotype analysis with simple tandem repeat polymorphisms at chromosomal bands 17q21 and 13q12 to determine the contribution of the BRCA1 and BRCA2 genes to predisposition to breast cancer in four Australian breast cancer kindreds, one of which had two male cousins with breast cancer. Surprisingly all families segregated a haplotype of markers on 13q and showed positive lod scores supporting linkage to BRCA2. In addition, haplotype analysis identified an informative recombination between D13S260 and D13S171 in one affected individual, which refines the localisation of BRCA2 to between D13S260 and D13S267; a distance of 2-3 cM. Tumours of the stomach and cervix, as well as melanoma and leukaemia/lymphoma also occur in these pedigrees but the numbers are too low to determine whether they may be significantly associated with BRCA2 carrier status. Our results confirm the existence of BRCA2 on the long arm of chromosome 13 and support previous findings that this locus is likely to confer risk in families with affected males. Furthermore, our observations suggest that the BRCA2 gene may also contribute to the development of other neoplasma. PMID- 8682514 TI - A molecular anatomical analysis of mosaic trisomy 16. AB - A one-month-old child presenting with an aortic coarctation was found to have a left single transverse palmar crease and proportionate growth delay on physical examination, prompting a peripheral blood chromosome analysis. This showed a mosaic trisomy of chromosome 16, subsequently observed to decrease with the passage of time. As her phenotype was relatively benign, further analysis was performed to define more precisely the extent of her mosaicism given the supposedly lethal nature of the aneuploid cell line. Fluorescence in situ hybridisation and CA repeat polymorphism studies demonstrated the aneuploidy in multiple tissues, including the structurally affected aorta. Molecular analysis showed both maternal chromosomes 16 to be present in the trisomic cells, but maternal heterodisomy was not present in the diploid cells. Given the increasing number of individuals described with aneuploid mosaicism, we suggest that the study of multiple tissues is a necessary approach, the eventual goal being the appreciation of the relationship between the characteristics of a somatic mosaicism and the phenotype it imparts. PMID- 8682515 TI - The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus. AB - The dopamine D4 receptor gene (DRD4) has an expressed polymorphism in the third exon that may have functional relevance. The polymorphism exists at two levels. At the higher level there is an imperfect tandem repeat of 48 base pairs (bp) coding for 16 amino acids; alleles have been identified with 2 (32 amino acids) to 10 (160 amino acids) repeats. The imperfect nature of the repeats is responsible for a more subtle level of variation since alleles with the same number of repeats can differ in the exact sequences or in the order of the variants of the 48-bp unit. We have undertaken a global survey of this expressed polymorphism as one approach to understanding the evolutionary significance and origins of the polymorphism as well as understanding what selective forces, if any, may be operating at this locus. As the first step, we have determined the repeat number genotype of the DRD4 repeat polymorphism in 1,327 individuals from 36 different populations. The allele frequencies differ considerably among the different populations. The 4-repeat allele was the most prevalent (global mean allele frequency = 64.3%) and appeared in every population with a frequency ranging from 0.16 to 0.96. The 7-repeat allele was the second most common (global mean = 20.6%), appearing quite frequently in the Americas (mean frequency = 48.3%) but only occasionally in East and South Asia (mean frequency = 1.9%). The 2-repeat allele was the third most common (global mean frequency = 8.2%) and was quite frequent in East and South Asia (mean frequency = 18.1%) while uncommon in the Americas (mean frequency = 2.9%) and Africa (mean frequency = 1.7%). The universality of the polymorphism with only three common repeat-number alleles (4, 7, and 2) indicates that the polymorphism is ancient and arose before the global dispersion of modern humans. The diversity of actual allele frequencies for this expressed polymorphism among different populations emphasizes the importance of population considerations in the design and interpretation of any association studies carried out with this polymorphism. PMID- 8682516 TI - Kinematics, kinetics, and psychophysical perceptions in symmetric and twisting pushing and pulling tasks. AB - The use of material handling devices (MHDs) to eliminate the repetitive lifting components of industrial jobs has introduced a new set of issues for industrial ergonomics. Worker performance and safety when using MHDs depends on the mass and distance moved, the asymmetry of the postures, and the positioning accuracy required at each endpoint of the movement. Ten participants moved loads of up to 68 kg and placed them in targets of different sizes. In one experiment they maintained sagittally symmetric postures; in the another they were required to rotate their entire body 180 degrees to complete the task. Measured peak push and pull hand forces ranged from 40 to 120 N and peak hand velocities ranged from 1.0 to 1.6 m/s in both studies. Psychophysical ratings were significantly correlated with peak push and pull hand forces but not peak velocity. Averages of peak hand force and velocity are used to develop some general recommendations for improved implementation of MHDs in industry. PMID- 8682517 TI - A survey of automatic teller machine usage across the adult life span. AB - The purpose of this study was to analyze automatic teller machine (ATM) usage across the adult life span. We conducted an extensive survey of 9000 people in the Memphis and Atlanta metropolitan areas. Approximately 17% of those people responded. The survey assessed detailed demographic information, experience with technology in general, experience specifically related to ATMs, problems and dislikes with ATMs, and reasons that people do not use ATMs. The survey provided a valuable set of data. First, we have detailed information about the demographics and individual characteristics of ATM users and nonusers; importantly, these data are stratified across the adult life span. In addition, we know the likes and dislikes of ATM users and the types of problems they typically have using ATMs. Moreover, we have detailed analysis of why adults of all ages may choose not to use ATMs. Training and design implications of these data are discussed. PMID- 8682518 TI - Isoperformance curves in applied psychology. AB - Isoperformance is a technique for reading information out of a data-analytic model, comparable to expected mean square or omega squared analyses. It results in a trade-off function (an isoperformance curve) among the determinants of performance. The technique was developed primarily to generate trade-off functions between personnel aptitude and time in training or on the job. However, the technique is general and can be applied in any trade-off situation. In part, the purpose of this paper is to recall the antecedents of isoperformance in psychophysics and to recount the origins and development of the isoperformance readout. Its main purpose, however, is to present several examples of isoperformance curves in applied psychology and to make the case for their usefulness. PMID- 8682519 TI - Application of a three-dimensional auditory display in a flight task. AB - The effectiveness of a three-dimensional (3D) auditory display in conveying directional information was investigated in a flight simulation experiment. While flying a simulated fighter aircraft, participants followed a target aircraft that suddenly disappeared and reemerged at an unknown position. The task was to locate and trail the target as quickly as possible. In all conditions the participants viewed a computer-generated outside image, on which they could spot the target only when it was at short range, and a three-dimensional (3D) tactical display indicating the target position at all distances within a limited field of view. Additional displays were a bird's-eye-view radar display, which also indicated whether the target was above or below the own plane, and a 3D auditory display, which generated a warning sound from the relative direction of the target. The auditory display used individualized head-related transfer functions to create a virtual sound source and a head-tracking device to decouple the position of the source from head movements. Results show that the radar and auditory displays caused about the same significant reduction in search time in comparison with the tactical display only. A further reduction was found when the two additional displays were presented simultaneously. PMID- 8682520 TI - Effectiveness of individual and dyadic training protocols: the influence of trainee interaction anxiety. AB - The present study focuses on the consequences of the social dynamics that are created whenever two or more individuals are brought together for the purpose of training. An investigation of the role of individual differences in interaction anxiety on training outcomes demonstrated that the comparative effectiveness of dyadic versus individual protocols for computer-based training is moderate by trainees' level of interaction anxiety. Specifically, assignment to a dyadic protocol adversely affected the performance of high-interaction-anxiety participants but appeared to be advantageous for low-interaction-anxiety participants. Implications are discussed for changing the design and implementation of computer-based protocols for training groups and individuals in military and industrial training centers. PMID- 8682521 TI - The impact of cross-training on team functioning: an empirical investigation. AB - The effects of cross-training (presence vs. absence) and workload (high vs. low) on team processes, communication, and task performance were examined. Eighty male undergraduate students were randomly assigned to one of four training conditions: cross-training, low workload; cross-training, high workload; no cross-training, low workload; and no cross-training, high workload. Results indicated that cross training was an important determinant of effective teamwork process, communication, and performance. Predicted interactions between cross-training and workload were not supported. Implications for the design and implementation of cross-training as a means to improve team functioning are discussed. PMID- 8682523 TI - Detection of simulated osteoporosis in maxillae using radiographic texture analysis. AB - An effective mass screening tool for detecting osteoporosis is currently lacking. Alveolar bone, routinely examined during periodic dental examinations, may provide a window into the status of systemic bone density. The primary objective of this investigation was to compare the performance of various textural features, computed from dental radiographs, in detecting early simulated osteoporosis of alveolar bone. Five specimens of human maxillary alveolar bone were progressively decalcified and the percentage calcium lost at each decalcification stage quantified. Two radiographs of each specimen, together with an aluminum stepwedge, were exposed at 70 kVp at each stage. The test set of 140 radiographs was digitized, identical bony regions of interest selected from the density-corrected images of each specimen, the regions digitally filtered to reduce film-grain noise, and textural features computed on a line-to-line basis. Correlation analysis identified a set of features whose changes consistently exhibited a moderate-to-strong linear association with bone mineral loss over a wide range of decalcification. Repeated measures analysis of variance was subsequently applied to this set to measure the minimal decalcification that could be detected by each feature under optimal conditions of x-ray beam angulation (0 degrees) and suboptimal conditions (+/- 5 degrees). The best performing features were mean intensity, gradient, Laws' texture energy measures, and fractal dimension which detected 5.7% bone decalcification at optimal beam angulation and 9.4-12.6% at suboptimal angulation. PMID- 8682522 TI - Morphological model of human colon tissue fluorescence. AB - Fluorescence spectroscopy of tissue is a promising technique for early detection of precancerous changes in the human body. Investigation of the microscopic origin of the clinically observed tissue fluorescence can provide valuable information about the tissue's histology. The objective of this study was the development of a morphological model of colon tissue fluorescence which connects the clinically observed spectra with their underlying microscopic origins. Clinical colon tissue fluorescence which connects the clinically observed spectra with their underlying microscopic origins. Clinical colon tissue fluorescence spectra were modeled by measuring the intrinsic fluorescence properties of colon tissue on a microscopic level and by simulating light propagation in tissue using the Monte-Carlo method. The computed spectra were in good agreement with the clinical spectra acquired during colonoscopy, and exhibited the characteristic spectral features of the in vivo collected spectra. Our analysis quantitated these spectral features in terms of the intrinsic fluorescence properties of tissue and its general histological characteristics. The fluorescence intensity difference between normal and adenoma observed in vivo was found to be due to the increased hemoglobin absorption, the reduced mucosal fluorescence intensity, and the absence of submucosal fluorescence in adenomatous polyps. The increased red fluorescence in adenoma was found to be associated with the dysplastic crypt cell fluorescence. PMID- 8682524 TI - Assessment of acute pulmonary edema in dogs by electrical impedance imaging. AB - Acute pulmonary edema was assessed quantitatively in 12 experiments on six anesthetized dogs. Thirty-two copper foil electrodes were placed around each animal's thorax at the level of the third intercostal space. A real-time electrical impedance tomograph was used to form images of the electrical admittivity of the thorax in and near the plane of these electrodes. The lungs were identified by studying the change in admittivity associated with inspiration. Mean admittivity in these lung regions was assessed at 40-min intervals for the next 3-6 hours. In six control experiments, each having a duration of 200 min, the initial admittivity of the lung regions was 102 +/- 16(SD) mS/m. Lung admittivity usually increased during the first 80 min, and then remained within 2 mS/m of its value at 80 min for the remaining 120 min. In six experiments with pulmonary edema, an initial period of change followed by stability was observed. When stability had been attained, 0.07 ml/kg of oleic acid was injected slowly into a central venous site. Five animals received oleic acid, the sixth received a sham injection of saline. In the five receiving oleic acid, lung admittivity rose steadily for the remainder of the experiment. The increase in lung admittivity in these five animals was between 4 and 16 mS/m. In the sham injected experiment, the lung admittivity changed by 1 mS/m. We conclude that impedance imaging can provide semiquantitative assessment of the development of acute pulmonary edema. PMID- 8682525 TI - Electrical impedance tomography: induced-current imaging achieved with a multiple coil system. AB - An experimental study of induced-current electrical impedance tomography verifies that image quality is enhanced by employing six rather than three induction coils by increasing the number of independent measurements. However, with an increasing number of coils, the inverse problem becomes more sensitive to measurement noise. Using 16 electrodes to measure surface voltages, it is possible to collect 6 x 15 = 90 independent measurements. For comparison purposes, images of two-dimensional conductivity perturbations are reconstructed by using the data for three and six coils with the truncated pseudoinverse algorithm. By searching for the optimal truncation index that minimizes the noise error plus the resolution error, the signal-to-noise ratio of the data acquisition system was established as 58 db. Images obtained with this six-coil system reveal the sizes and locations of the conductivity perturbations. This system also provides images within the central region of the object space, a capability not achieved in previous experimental studies using only three circular coils. Nevertheless, the three-coil system can identify the conductivity perturbations near the periphery. However, it displays shifts in the locations and spread in the sizes of perturbations near the center of the object. PMID- 8682526 TI - Evaluation of isometric antagonist coactivation strategies of electrically stimulated muscles. AB - The performance of various coactivation strategies to control agonist-antagonist muscles in functional electrical stimulation (FES) applications was examined in a cat model using the tibialis anterior and soleus muscles to produce ankle isometric dorsiflexion and plantarflexion torques, respectively. Three types of coactivation strategies were implemented and tested. The first strategy was based on coactivation maps described in the literature as consisting of decreasing antagonistic activity as the input command to the agonist was increased. The second type of strategy was based on the physiologic coactivation data collected from normal subjects exhibiting joint stabilization during the full range of contractions. These strategies included scaled increasing antagonist activity and therefore joint stiffness with increasing agonist input command. A third strategy was devised which at low force levels mimicked the strategies described in the literature and at high force levels resembled strategies exhibited by normal subjects. The three strategies were evaluated based on their ability to track a linear or sinusoidal input command and their efficiency of torque transmission across the joint. Coactivation strategies using increasing antagonist activity resulted in decreased maximal joint torque and efficiency, decreased signal tracking capability for linear inputs, and increased harmonic distortion for sinusoidal inputs. Peak efficiency and tracking ability appeared when a moderate degree of antagonist activity was engaged near the neutral joint position. Signal tracking quality improved with earlier engagement of the antagonist muscles. Our results suggest that strategies combining low-level coactivation as described in the physiological literature and previous FES studies could satisfactorily address the issues of controllability, efficiency, and long-term joint integrity. PMID- 8682527 TI - The effect of stimulus pulse duration on selectivity of neural stimulation. AB - Choice of stimulus parameters is an important consideration in the design of neural prosthetic systems. The objective of this study was to determine the effect of rectangular stimulus pulsewidth (PW) on the selectivity of peripheral nerve stimulation. Computer simulations using a cable model of a mammalian myelinated nerve fiber indicated that shorter PW's increased the difference between the threshold currents of fibers lying at different distances from an electrode. Experimental measurements of joint torque generated by peripheral nerve stimulation demonstrated that shorter PW's generated larger torques before spillover and created a larger dynamic range of currents between threshold and spillover. Thus, shorter PW's allowed more spatially selective stimulation of nerve fibers. Analysis of the response of a passive cable model to different duration stimuli indicated that PW dependent contributions of distributed sources to membrane polarization accounted for the observed differences in selectivity. PMID- 8682528 TI - Closed-loop control of ankle position using muscle afferent feedback with functional neuromuscular stimulation. AB - This paper describes a closed-loop functional neuromuscular stimulation system that uses afferent neural activity from muscle spindle fibers as feedback for controlling position of the ankle joint. Ankle extension against a load was effected by neural stimulation through a dual channel intrafascicular electrode of a fascicle of the tibial nerve that innervated the gastrocnemius muscle. Ankle joint angle was estimated from recordings of tibialis anterior and lateral gastrocnemius spindle fiber activity made with dual channel intrafascicular electrodes. Experiments were conducted in neurally intact anesthetized cats and in unanesthetized decerebrate cats to demonstrate the feasibility of this system. The system was able to reach and maintain a fixed target ankle position in the presence of a varying external moment ranging in magnitude between 7.3 and 22 N cm opposing the action of the ankle extensor, as well as track a sinusoidal target ankle position up to a frequency of 1 Hz in the presence of a constant magnitude 22- or 37-N-cm external moment. PMID- 8682529 TI - Methods for onset detection of voluntary motor responses in tremor patients. AB - Accurate onset detection of the voluntary response is a prerequisite in reaction time studies when used in investigations on human motor control. The detection algorithm required performs a transformation of the continuous physical signal (e.g., force, movement) containing the response into a discrete event from which the reaction time (RT) is derived. Therefore, RT always comprises both the cognitive and/or motor delay component imaging the duration of the initiation process conducted by the sensorimotor system and, in addition, some spurious delay caused by the detection algorithm. As a standard method, onset detection is realized by the measurement device itself (e.g., the release of a micro switch) by defining the response onset as the point where the observed signal passes a certain threshold. Thus, weak and abnormal response profiles which are typical for a variety of central motor disorders (e.g., Parkinson's disease) may introduce high RT variability as well as systematic errors. The aim of this study was to improve accuracy of onset detection by application of an appropriate filter to the measured signal before entering the final decision stage. Three algorithms (lowpass differentiator, inverse filter, linear autoregressive (AR) predictor) were implemented and tested on simulated and real data under both on line and off-line conditions with special interest to the influence of quasi periodic background activity like tremor. It is shown that a significant improvement in onset detection accuracy, compared with the simple switch, can be achieved by using appropriate low order adaptive filters with the AR-predictor being the most efficient solution. PMID- 8682530 TI - Adaptive estimation of latency changes in evoked potentials. AB - Changes in latency of evoked potentials (EP) may indicate clinically and diagnostically important changes in the status of the nervous system. A low signal-to-noise ratio of the EP signal makes it difficult to estimate small, transient, time-varying changes in latency, or delays. Here, we present an adaptive algorithm that estimates small delay (latency change) values even when EP signal amplitudes are time-varying. When the delay is time invariant, the adaptive algorithm produces an unbiased estimate with delay estimation error less than half of the sampling interval. A lower estimation error variance is obtained when, in a pair of signals, the adaptive algorithm delays the signal with the higher SNR. The adaptive algorithm delays the signal with the higher SNR. The adaptive delay estimation algorithm was tested on intra-operative recordings of somatosensory EP, and analysis of those recordings reveals that the anesthetic etomidate produces a step change in the amplitude and latency of the EP signals. PMID- 8682531 TI - A new method for analysis of atrial activation during chronic atrial fibrillation in man. AB - To further clarify the mechanisms maintaining chronic atrial fibrillation (CAF), a method identifying preferable activation patterns of the atria during fibrillation, by time averaging of multiple discrete excitation vectors, was developed. Repeated recordings, each of 56 atrial bipolar electrograms simultaneously acquired during 8 s, were made at multiple sites in the right atrial free wall and the left atrial appendage in 16 patients with CAF using a 2.17 x 3.54 cm electrode array. The local activation times (LAT's) in each recording were estimated as the median activation time at the respective measurement point. By calculating the time difference between the LAT's at adjacent measurement points in two spatial dimensions, a direction vector was created for each activation wave passing each set of measurement points, a total of 42 sets. By time averaging of the individual direction vectors (typically n = 55) at each set of measurement points, preferable activation patterns were determined. Three types of activation patterns were found: 1) inconsistent activation (n = 5), 2) consistent activation with preferential propagation directions (n = 7) and 3) consistent activation with impulses originating from a localizable site within the recording area (n = 4). All activation patterns were reproducible and the two latter patterns were proven significant using statistical tests. We conclude that this new method is useful in further clarification of the mechanisms involved in the maintenance of atrial fibrillation. PMID- 8682532 TI - Computer simulation of epicardial potentials using a heart-torso model with realistic geometry. AB - Previous cardiac simulation studies have focused on simulating the activation isochrones and subsequently the body surface potentials. Epicardial potentials, which are important for clinical application as well as for electrocardiographic inverse problems studies, however, have usually been neglected. This paper describes a procedure of simulating epicardial potentials using a microcomputer based heart-torso model with realistic geometry. Our heart model developed earlier is composed of approximately 65,000 cell units which are arranged in a cubic close-packed structure. An action potential waveform with variable in duration is assigned to each unit. The heart model, together with the epicardial surface model constructed recently, are mounted in an inhomogeneous human torso model. Electric dipoles, which are proportional to the spatial gradient of the action potential, are generated in all the cell units. These dipoles give rise to a potential distribution on the epicardial surface, which is calculated by means of the boundary element method. The simulated epicardial potential maps during a normal heart beat and in a preexcited beat to mimic Wolff-Parkinson-White (WPW) syndrome are in close agreement with those reported in the literature. PMID- 8682533 TI - Distinguishing between activated and nonactivated eosinophils by AC impedance measurements. AB - A cellular electrical impedance device which can detect the activated state of eosinophils has been developed and tested. This impedance device consists of a small gold electrode (50 microns x 50 microns) and a large gold electrode (1.5 cm x 0.5 cm) on a glass substrate, and it was fabricated by standard photolithographic techniques. Eosinophils, which belong to the granulocytic class of white blood cells, exhibit different physical properties when they change from the nonactivated state to the activated state. Hypothetically, these changes should correspond to a change in the measured electrical impedance. In this paper, data from the measured electrical impedance of eosinophils is presented. The measurements show that the average impedance of the activated eosinophils is 26% lower than the average impedance of the nonactivated eosinophils. Statistical analysis of the measured data shows that there is a significant difference between the measured impedances of activated and nonactivated eosinophils. PMID- 8682534 TI - Sensing platform for acoustic startle responses from rat forelimbs and hindlimbs. AB - A sensing platform with two piezoelectric transducers was designed and fabricated to measure acoustic startle responses from forelimbs and hindlimbs in the rat. Testing with a vibrator showed that separate forces were measured from 5 to 25 Hz with mean sensitivities of 2.395 and 2.022 V/N and mean linearity errors of 3.23 and 2.98% FS for the forelimb and hindlimb sensors, respectively. Forelimb and hindlimb response waveforms of male Sprague-Dawley rats had shapes similar to the commonly recorded wholebody response but were smaller in amplitude. PMID- 8682535 TI - The effect of noise and high-pass filtering on the estimation of mean blood velocity using wide and narrow ultrasound beams. AB - Recently, a new method of analysis has been proposed for the calculation of a Doppler frequency proportional to mean blood velocity for the case where the Doppler beam is assumed to be of negligible thickness compared to the vessel diameter, and the velocity profile is axisymmetric and monotonic increasing from the vessel wall to the vessel center. Such analysis of the Doppler signal is an alternative to that commonly performed under the assumption that the beam insonates the vessel uniformly. Errors in each method are found and compared for the case where the Doppler signal is contaminated by noise, and for the case where the signal is subjected to an ideal high-pass filter. The frequency resulting from the new method of analysis is affected by low-frequency perturbations approximately twice as much as that resulting from the standard method. However, the new method is much more immune to high frequency perturbations. If each method is used with the beam shape for which it is appropriate then, for a given velocity profile, each method is equally affected by the use of the same ideal high-pass filter. PMID- 8682536 TI - The effect of geometrical spectral broadening on the estimation of mean blood velocity using wide and narrow ultrasound beams. AB - If an ultrasound beam uniformly insonates the cross section of a blood vessel then the Doppler signal can be analyzed to give a frequency proportional to the spatial mean blood velocity. This is also possible if the beam can be thought of as negligibly thin compared to the blood vessel radius, centrally placed, and the blood velocity profile is axisymmetric and monotonic, although the analysis takes a different form. The immunity of these mean velocity estimators to broadening of the ideal frequency spectrum is studied. If the broadening of a frequency component is such that its mean frequency, weighted by intensity, is unchanged then the analysis with a uniformly insonating beam still leads to the correct mean velocity. In contrast, for any such broadening, the analysis if the beam is negligibly thin produces an underestimate of the mean velocity. Error expressions are derived for idealized cases and some practical results given. PMID- 8682537 TI - Ultrasonic assessment of human and bovine trabecular bone: a comparison study. AB - A comparison study is reported on the ultrasonic assessment of human trabecular and bovine trabecular bone samples. Both ultrasonic velocity and ultrasonic attenuation were evaluated through a transmission insertion technique and correlated with bone mineral density as determined with single photon absorptiometry. For a 1-MHz ultrasonic transducer pair and the human cancellous bone samples the correlations were 0.91 and 0.89 between density and velocity and attenuation, respectively. For a 500-kHz ultrasonic transducer pair the correlations were 0.89 and 0.81 between density and velocity and attenuation, respectively. For the bovine bone samples, the correlations were 0.90 and -0.31 for the velocity and attenuation, respectively, for the 1 MHz transducer pair. For the 500-kHz transducers, the correlations were 0.85 and -0.17 for the velocity and attenuation, respectively. By combining both velocity and attenuation in a multivariate regression, an improvement was achieved in the estimation of bone density in the human samples for both the 500-kHz and 1-MHz transducer pairs. No significant improvement was achieved in the multivariate regressions for the bovine bone samples. In conclusion, the results indicate that ultrasonic measurements are in general highly correlated with bone mineral density in trabecular bone samples. This correlation is more consistent and strong in relatively low density human samples compared with the higher density bovine samples. PMID- 8682538 TI - Evaluation of differential optical flow techniques on synthesized echo images. AB - The performance of three methods for evaluation of motion on synthesized 2-D echo image sequences with features similar to real ones are examined. The selected techniques based on the computation of optical flow are of the differential type and assume that the image brightness pattern is constant over time. They differ in the choice of the smoothing term and in the local or global treatment of the domain. The images were synthesized by simulating the process of echo formation, considering the interaction between ultrasonic fields and human tissues. Moreover, two different approaches were followed to generate the sequences: 1) a known motion field was applied to the intensity distribution of the synthesized images; 2) a known motion field was applied directly to the point scatterer distribution of the tissue. Favorable results were obtained by applying Lucas Kanade and Horn-Schunck techniques to the sequences of the first type, while all the techniques produced large errors when applied to the other type of sequences. A discussion about the suitability of the above-mentioned techniques for evaluation of motion on real echocardiographic images is also presented together with some results. PMID- 8682539 TI - Experimental investigation of an adaptive feedback algorithm for hot spot reduction in radio-frequency phased-array hyperthermia. AB - A computer-controlled adaptive phased array radiofrequency hyperthermia system for improved therapeutic tumor heating is experimentally investigated. Adaptive array feedback techniques are used to modify the electric-field in hyperthermia experiments with a homogeneous saline phantom target. A hyperthermia phased-array antenna system has been modified to implement adaptive nulling and adaptive focusing algorithms. The hyperthermia system is a ring phased-array antenna applicator with four independently controlled RF transmitter channels operating at a CW frequency of 100 MHz. The hyperthermia phased array is made adaptive by software modifications which invoke a gradient-search feedback algorithm that controls the amplitude and phase of each transmitter channel. The gradient-search algorithm implements the method of steepest descent for adaptive nulling (power minimization) and the method of steepest ascent for adaptive focusing (power maximization). The feedback signals are measured by electric-field short-dipole probe antennas. The measured data indicate that with an adaptive hyperthermia array it may be possible to maximize the applied electric field at a tumor position in a complex scattering target body and simultaneously minimize or reduce the electric field at target positions where undesired high-temperature regions (hot spots) occur. PMID- 8682540 TI - Generalized Wiener estimation of three-dimensional current distribution from biomagnetic measurements. AB - This paper proposes a method for estimating three-dimensional (3-D) biocurrent distribution from spatio-temporal biomagnetic data. This method is based on the principle of generalized Wiener estimation, and it is formulated based on the assumption that current sources are uncorrelated. Computer simulation demonstrates that the proposed method can reconstruct a 3-D current distribution where the conventional least-squares minimum-norm method fails. The influence of noise is also simulated, and the results indicate that a signal-to-noise ratio of more than 20 for the uncorrelated sensor noise is needed to implement the proposed method. The calculated point spread function shows that the proposed method has very high spatial resolution compared to the conventional minimum norm method. The results of computer simulation of the distributed current sources are also presented, including cases where current sources are correlated. These results suggest that no serious errors arise if the source correlation is weak. PMID- 8682541 TI - A high-order coupled finite element/boundary element torso model. AB - We describe here a high-order (cubic Hermite) coupled finite element/boundary element procedure for solving electrocardiographic potential problems to be ultimately used for solving forward and inverse problems on an anatomically accurate human torso. Details of both numerical procedures and the coupling between them are described. Test results, illustrating the accuracy and efficiency of this combination for both two-dimensional (2-D) and three dimensional (3-D) problems, are also given. PMID- 8682542 TI - EEG localization accuracy improvements using realistically shaped head models. AB - A model of the head must be used in making estimates of the locations of electrical sources in the brain using electroencephalograms (EEG's) measured on the scalp. In part, the accuracy of these estimates is dependent on how accurately the model represents the actual head. In most work performed to date, spherical models of the head have been used. This paper presents results in which the estimates of source location are made in realistically shaped head models. Techniques for accurately and conveniently developing realistically shaped head models from CT's, MRI's, X rays, and/or physical measurements are also presented. Realistically shaped head models are developed for three subjects with electrical sources implanted at known locations in the brain. Localization accuracy is found to be significantly better in the realistically shaped head models than in spherical models if EEG's with good signal-to-noise ratio are used. PMID- 8682543 TI - A generalized cable equation for magnetic stimulation of axons. AB - During magnetic stimulation, electric fields are induced both on the inside (intracellular region) and the outside (extracellular region) of nerve fibers. The induced electric fields in each region can be expressed as the sum of a primary and a secondary component. The primary component arises due to an applied time varying magnetic field and is the time derivative of a vector potential. The secondary component of the induced field arises due to charge separation in the volume conductor surrounding the nerve fiber and is the gradient of a scalar potential. The question, "What components of intracellular fields and extracellular induced electric fields contribute to excitation?" has, so far, not been clearly addressed. In this paper, we address this question while deriving a generalized cable equation for magnetic stimulation and explicitly identify the different components of applied fields that contribute to excitation. In the course of this derivation, we review several assumptions of the core-conductor cable model in the context of magnetic stimulation. It is shown that out of the possible four components, only the first spatial derivative of the intracellular primary component and the extracellular secondary component of the fields contribute to excitation of a nerve fiber. An earlier form of the cable equation for magnetic stimulation has been shown to result in solutions identical to three dimensional (3-D) volume-conductor model for the specific configuration of an isolated axon in a located in an infinite homogenous conducting medium. In this paper, we extend and generalize this result by demonstrating that our generalized cable equation results in solutions identical to 3-D volume conductor models even for complex geometries of volume conductors surrounding axons such as a nerve bundle of different conductivity surrounding axons. This equivalence in the solutions is valid for several representations of a nerve bundle such as anisotropic monodomain and bidomain models. PMID- 8682544 TI - Noise and neuronal populations conspire to encode simple waveforms reliably. AB - Sensory systems rely on populations of neurons to encode information transduced at the periphery into meaningful patterns of neuronal population activity. This transduction occurs in the presence of intrinsic neuronal noise. This is fortunate. The presence of noise allows more reliable encoding of the temporal structure present in the stimulus than would be possible in a noise-free environment. Simulations with a parallel model of signal processing at the auditory periphery have been used to explore the effects of noise and a neuronal population on the encoding of signal information. The results show that, for a given set of neuronal modeling parameters and stimulus amplitude, there is an optimal amount of noise for stimulus encoding with maximum fidelity. PMID- 8682545 TI - A new double modeling approach for dynamic cardiac PET studies using noise and spillover contaminated LV measurements. AB - A new double modeling approach for dynamic cardiac studies with positron emission tomography (PET) to estimate physiological parameters is proposed. This approach is exemplified by tracer fluorodeoxyglucose (FDG) studies and estimation of myocardial metabolic rate of glucose (MMRGlc). A separate input function model characterising the tracer kinetics in plasma is used to account for the measurement noise and spillover problems of the input curve obtained from the left ventricular region on the PET images. Measured left ventricle (LV) plasma time-activity and tissue time-activity curves are fitted simultaneously with cross contaminations by this input function model and the FDG model. The results indicate that the MMRGlc can be estimated much more accurately and reliably by this new approach. Compared with the traditional method, an improvement of about 20% in the estimated MMRGlc was achieved when the bidirectional spillover fractions are 20% at different noise levels studied. This new double modeling approach using two models fitting both the input and the output functions simultaneously is expected to be generally applicable to a broad range of system modeling. PMID- 8682546 TI - Instrumentation for assessment of tremor, skin vibrations, and cardiovascular variables in MIR space missions. AB - A versatile and simple to use biomedical instrumentation for noninvasive examinations of cosmonauts at the Russian MIR space station was developed. It consists of a comfortable sensor jacket to assess signals from the body surface, a precision hand dynamometer to produce muscular and cardiovascular loads, and a small interactive microprocessor unit that controls the examination and stores measurement data. The sensor jacket includes highly sensitive piezo-resistive accelerometers, pulse sensors, an ECG system, and a skin-mountable mechanical vibrator. The functionality of this instrumentation was evaluated during long term space flights and also proved very useful in laboratory and clinical studies. PMID- 8682547 TI - An efficient tissue classifier for building patient-specific finite element models from X-ray CT images. AB - We developed an efficient semiautomatic tissue classifier for X-ray computed tomography (CT) images which can be used to build patient- or animal-specific finite element (FE) models for bioelectric studies. The classifier uses a gray scale histogram for each tissue type and three-dimensional (3-D) neighborhood information. A total of 537 CT images from four animals (pigs) were classified with an average accuracy of 96.5% compared to manual classification by a radiologist. The use of 3-D, as opposed to 2-D, information reduced the error rate by 78%. Models generated using minimal or full manual editing yielded substantially identical voltage profiles. For the purpose of calculating voltage gradients or current densities in specific tissues, such as the myocardium, the appropriate slices need to be fully edited, however. Our classifier offers an approach to building FE models from image information with a level of manual effort that can be adjusted to the need of the application. PMID- 8682548 TI - Issues in cardiac pacing: optimising pacemaker therapy. PMID- 8682549 TI - New closure devices for left-to-right shunt. PMID- 8682550 TI - Protein C levels in ischaemic heart disease. AB - Protein C is a circulating glycoprotein with anticoagulant properties. Functional and immunological levels of protein C were determined in 34 cases of ischaemic heart disease and 12 healthy age-matched controls. The sensitive colorimetric assay was used to determine the functional levels and ELISA for antigenic levels. Mean protein C activity and antigenic levels were found to be elevated in these patients as compared to controls. Protein C levels in the three individual subgroups-acute myocardial infarction, previous myocardial infarction and chronic stable angina pectoris-were also raised as compared to controls. The elevation was significant in the case of the acute myocardial infarction group. These results further support the hypothesis that the body synthesises increased amounts of protein C in ischaemic heart disease to compensate for the hypercoagulable state that exists in this disorder, thus playing a protective role. PMID- 8682551 TI - Ischaemic preconditioning: an intracoronary electrocardiographic study. AB - Brief episodes of myocardial ischaemia may enhance the tolerance to subsequent ischaemic episodes. This phenomenon has been called ischaemic preconditioning. Intracoronary electrocardiograms (ECG) were obtained during coronary angioplasty in 15 patients (13 males, 2 females; age 49 +/- 12 years) by attaching the external end of the balloon angioplasty guide wire to the V1 lead on the surface electrocardiogram. Surface leads I, II and III and intracoronary ECG were recorded at baseline and during balloon occlusion. The pattern of ST segment change during the first and subsequent inflation were compared. A significant reduction in ST segment deviation was observed in intracoronary ECG between the first and second inflation (10 +/- 1 vs 5 +/- 3 mm, p < 0.05). However, surface ECG showed no significant difference in ST segment deviation between the two inflations (3 +/- 1 vs 2 +/- 1 mm, p = NS). Thus, intracoronary ECG detects acute ischaemia more readily as compared to the routinely monitored surface ECG. A significant reduction noted in ST segment deviation during the second inflation suggests the phenomenon of ischaemic preconditioning in humans. PMID- 8682552 TI - Comparison of electrophysiologic effects and efficacy of single-dose intravenous and long-term oral amiodarone therapy in patients with AV nodal reentrant tachycardia. AB - Electrophysiologic effects and the efficacy of single-dose intravenous (i.v.) amiodarone were compared with those of long-term oral therapy in 9 patients of AV nodal reentrant tachycardia (AVNRT) utilising slow pathway (SP) for anterograde and fast pathway (FP) for retrograde conduction. Electrophysiologic data were obtained by programmed electrical stimulation (PES) before, 15 to 30 minutes after i.v. amiodarone (5 mg/kg body-weight over 10 minutes) and a mean of 64.6 +/ 23.7 days after oral therapy, on a maintenance dose of 200 to 400 mg daily. There was no significant influence on the sinus cycle length and infranodal conduction (HV) by i.v. or oral amiodarone as compared to pre-drug values. AV nodal conduction, evaluated by AH interval, increased significantly and comparably with both (8% after i.v., 10% after oral; p = NS). Anterograde conduction through SP, as evidenced by pacing cycle length producing AH block, was prolonged by both (31% after i.v., 52% after oral; p = NS). Oral amiodarone, however, was more effective than i.v. in lengthening the effective refractory period (ERP) of anterograde FP (45% vs 17%, p < 0.05). Although both depressed retrograde conduction significantly, long-term oral amiodarone was more effective in prolonging the paced cycle length (PCL) producing ventriculoatrial (VA) block (79% vs 50%; p < 0.05) and ERP of VA conduction system (72% vs 42%; p < 0.01). AVNRT was successfully terminated in 7 patients after i.v. amiodarone. However, tachycardia was reinducible in 3 patients after i.v. and in none after long-term oral therapy. None had clinical recurrence of tachycardia on maintenance oral therapy. The mean concentration of the drug was 3.1 +/- 1.81 micrograms/ml after i.v. and 1.3 +/- 0.47 micrograms/ml after oral therapy (p < 0.05). These results. suggest that i.v. amiodarone terminated AVNRT by depressing both anterograde and retrograde limbs of the reentrant circuit and eventually blocking one of these. Oral therapy prevented recurrence and reinducibility by its predominant effect in prolonging refractoriness of the atrium and ventricle, and depressing conduction through the retrograde FP. It is concluded that i.v. amiodarone is an effective drug in acute termination of tachycardia mediated by AV nodal reentry and that long-term oral therapy is excellent in preventing recurrence and reinducibility of tachycardia. There are significant differences in the electrophysiologic properties and mechanism of action between the two forms, not influenced by the blood levels of amiodarone. PMID- 8682553 TI - Early intrinsic deflection--a marker for successful radiofrequency ablation of overt accessory pathways. AB - Precise localization of accessory pathways (APs) is crucial to minimize radiofrequency (RF) energy applications in the Wolff-Parkinson-White (WPW) syndrome. Although several markers have been described for identifying APs, no gold standard has thus far been established. The present study attempted to validate the hypothesis that an early intrinsic deflection (ID) would be identifiable in the unipolar ventriculogram, if this was recorded at or near the site of endocardial breakthrough of the AP. The electrograms of 23 patients with the WPW syndrome who underwent RF ablation were analysed using a computer-based system. A total of 50 electrograms (19 successful and 31 unsuccessful RF energy applications) were studied. The downstroke of the unipolar ventriculogram was measured at 1 msec intervals for the dV/dt; the maximal dV/dt (the most rapid segement of the downstroke) was considered as the ID. The following parameters were found to differentiate between successful and unsuccessful RF ablation attempts: (i) Timing of the ID relative to the delta wave onset (ID-delta = plus 11 +/- 21 msec versus minus 18 +/- 22 msec, p < 0.001). (ii) Timing of the ID relative to the onset of the unipolar ventriculogram (Vu-ID = 14 +/- 7 msec versus 29 +/- 15 msec, p < 0.001). (iii) Maximal dV/dt in the initial 20 msec of the unipolar ventriculogram (367 +/- 146 microV/msec versus 207 +/- 97 microV/msec, p < 0.001). The other parameters (probable AP potential, bipolar ventriculogram timing, continuous electrical activity, unipolar signal morphology) were not helpful in this regard. Hence, the identification of the ID and measurement of its timing is helpful in localising overt APs for successful delivery of RF energy. PMID- 8682554 TI - Transcatheter closure of atrial septal defect using buttoned device--Indian experience. AB - Transcatheter closure of secundum atrial septal defect (ASD) < 21 mm in diameter with adequate septal margins, assessed by transthoracic echocardiography (TTE) was attempted using Sideris buttoned device under fluoroscopic and TTE guidance in 27 patients (age range 5-35 years). The stretched diameter of ASD estimated by balloon sizing at cardiac catheterization was, on an average, 3 mm larger than assessed on TTE. A 25 to 50 mm second-generation Sideris device could be successfully implanted in 24 patients, with disappearance of left-to-right shunt, assessed by colour flow mapping on TTE in 17 patients. Residual shunt of 0.12 0.54 L/min/m2 was seen on day one in 7 patients which increased on follow-up in 3 patients over a period of 12 months. The maximum shunt in one patient was 1.1 L/min/m2. On follow-up (14.5 +/- 3.8 months), the device was in a stable position in all patients evaluated by fluoroscopy and TTE, and intracardiac ultrasound study in two patients. The procedure was unsuccessful in 3 patients, due to unbuttoning of the device in one and recurrent slippage of the device through the ASD in two patients. Mitral regurgitation was detected in 5 patients on follow-up (mild in 4 and moderate in 1). There was no mortality and none of the patients required any surgical intervention. It is concluded that transcatheter closure of some selected cases of secundum ASD can be safely and effectively done using Sideris buttoned device through a small sheath; however, a centering device is likely to close larger defects with less interference with mitral valve function. PMID- 8682555 TI - Sequential external counterpulsation: an adjunctive therapy for patients with chronic coronary artery disease and left ventricular dysfunction. AB - We assessed the clinical and haemodynamic improvement with 3 weeks of sequential external counterpulsation (SECP) therapy in 23 patients with chronic coronary artery disease (CAD) and left ventricular (LV) dysfunction who were refractory to maximal tolerated doses of medical therapy and in whom intervention or surgery was not contemplated. All patients were subjected to one-hour duration of SECP for 3 weeks. SECP is a new noninvasive tool which increases coronary artery filling utilizing external pressure in a sequential manner from calf to thigh. A detailed clinical and echocardiographic evaluation was done before and after the completion of therapy to assess the utility of SECP. There were 18 males and 5 females with a mean age of 53 years. On coronary angiography, 39 percent patients had single, 8.7 percent had double and 48 percent had triple vessel disease. Four patients had coronary artery bypass graft (CABG) surgery in the past. Out of all patients, 48 percent had diffuse or distal coronary artery disease which was considered not suitable for CABG, 22 percent were not willing for intervention and 30 percent had other systemic diseases making them unfit for surgery. After 3 weeks of SECP, the anginal frequency reduced from 9 episodes/week to 1 episode/week. Before SECP, 74 percent patients were in NYHA class III, whereas only 8.7 percent were class III symptomatic after SECP. All patients claimed symptomatic improvement of a mean of 6.8 +/- 1.4 on a visual analog scale of 1 10. After SECP, the LV diastolic dimensions reduced from 54.6 +/- 7 to 51 +/- 7 mm, systolic dimensions reduced from 40 +/- 8 to 36 +/- 8 mm and LVEF increased from 32.7 +/- 9 to 37.4 +/- 8.5 percent. In conclusion, 3 weeks of therapy with SECP produces significant improvement in symptomatic status and cardiac function in patients with chronic CAD and LV dysfunction, refractory to medical therapy. PMID- 8682556 TI - Thrombolysis utilisation in acute myocardial infarction in Bahrain. AB - We retrospectively studied 114 consecutive patients of acute myocardial infarction diagnosed in the Accident and Emergency department of our hospital, to determine the percentage of eligible patients who actually received thrombolytic therapy, the number of those excluded from receiving such therapy and the various exclusion criteria. We found that 66 patients (57.9%) received thrombolysis with either streptokinase or tissue plasminogen activator (tPA). The remaining 48 (42.1%) were excluded because of delayed presentation to hospital after the onset of symptoms (23.7%), old age or other contraindications. Although the percentage of thrombolysis utilisation in acute myocardial infarction in our centre is much higher as compared to others in the world, we find that there is a scope for improving these figures by reducing the number of patients excluded because of late presentation through health education and improved utilisation of ambulance services. PMID- 8682557 TI - Management of severe pulmonary hypertension during surgery for congenital heart disease. PMID- 8682559 TI - Complete heart block as a first manifestation of acute rheumatic fever. PMID- 8682558 TI - Familial occurrence of a rare combination of dilated cardiomyopathy with palmoplantar keratoderma and curly hair. PMID- 8682560 TI - Myocardial infarction due to embolism of the right coronary ostium from chronic rheumatic mitral valvular disease. PMID- 8682561 TI - Concurrent balloon dilatation of coexisting congenital pulmonary and aortic valve stenosis. PMID- 8682562 TI - Congenital intrapericardial aneurysm of the left atrium. PMID- 8682563 TI - Severe intravascular haemolysis following coil occlusion of patent ductus arteriosus. PMID- 8682564 TI - Bilateral coronary arterio-cameral fistulae in a case of tetralogy of Fallot. PMID- 8682566 TI - Status of inspiratory increase in the height of 'a' wave of jugular venous pulse in diagnosing right ventricular infarction. PMID- 8682565 TI - Role of electrophysiologic evaluation in patients with ventricular arrhythmias. AB - The decision to perform electrophysiologic testing in patients with ventricular arrhythmia should be based on the presence, if any, of underlying heart disease and the clinical type of ventricular arrhythmia. Clinical presentations range from asymptomatic premature ventricular complexes identified on routine surface ECG to out-of-hospital cardiac arrest. Ventricular arrhythmias range from benign monomorphic ventricular ectopy to polymorphic VT and ventricular fibrillation. The goal in evaluating patients with ventricular arrhythmia is to identify those at high risk of suffering a life-terminating arrhythmic event. Risk stratification should be based on history, physical examination, clinical data and the likelihood that anti-arrhythmic therapy will prevent symptoms and more importantly, prolong life. Noninvasive evaluation with routine surface ECG, Holter monitoring, signal-averaged ECG and echocardiography are valuable tools in the risk stratification process. However, electrophysiologic testing in most forms of ventricular tachyarrhythmia is the optimal means of diagnosing, risk stratifying and managing potentially life-threatening ventricular arrhythmias. PMID- 8682567 TI - The epidemiology of functional gastrointestinal disorders in North America. AB - This article has summarized the epidemiology of several disorders commonly seen in a gastroenterologist's practice. The emphasis has been on population-based data because many people with these disorders never seek health care, and psychological features have been shown to be strongly associated with health care seeking behavior. Each of these disorders is common in the community; in fact, the majority of the population experiences intermittent gastrointestinal symptoms. In general, the national surveys sponsored by the U.S. Public Health Service have been shown to underestimate the prevalence of these conditions. In part, this is due to the fact that subjects are asked to report diagnoses rather than symptoms, and current coding schemes do not provide specific codes for each of the functional gastrointestinal disorders. Still, these studies have demonstrated the large number of physician visits and overall costs attributable to these disorders. A number of surveys of more limited populations have been done to assess the prevalence of these disorders. Rates have varied because of the definitions used and the degree to which organic diagnoses are excluded. These studies have been helpful in demonstrating the burden of illness in the community. Age and gender differences in the community have been much less marked than those identified in clinic-based studies, thus highlighting the importance of population-based research. Future studies need to focus on the incidence and natural history of these disorders. Studies of incidence cases can best evaluate the role of etiologic factors, whereas studies of prevalent cases are best for assessing the burden of disease in the community. Understanding the natural history of these disorders is important in determining the efficacy of future therapeutic interventions. The fact that these disorders represent 50% of visits to a gastroenterologist practice highlights the importance of these disorders and the potential contribution of gastrointestinal dysmotility in clinical practice. PMID- 8682568 TI - Functional dyspepsia. Insights on mechanisms and management strategies. AB - The instability of the clinical manifestations of functional dyspepsia is notorious. This instability is manifested in two forms: temporal instability and circumstantial instability. It is probably in the latter context that stress and other psychological factors influence the symptoms of dyspepsia. It is conceivable that, after all, most dyspeptic patients manage to get by thanks to the concerted beneficial action of physician reassurance, placebo effects, drug effects, and spontaneous improvement. PMID- 8682569 TI - Gastric and small intestinal motility in health and disease. AB - Although symptoms possibly related to motor dysfunction appear to be common, primary disorders of the foregut motor apparatus, defined on the basis of a discrete myoneural pathology, are notably rare. This phenomenon may as much reflect the relatively primitive nature of diagnostic methods as the true rarity of such disorders. Although diagnostic methodologies increase in sophistication and availability, their clinical impact has been limited by an imperfect relationship between symptoms and dysfunction and by a relatively poor ability of such tests to predict response to available therapeutic strategies. An ever increasing understanding of the complex, often interrelated motor and sensory phenomena that contribute to symptoms, together with the development of consensus on the use and interpretation of motility tests and the more widespread application of sophisticated histologic, immunologic, biochemical, and molecular biologic methodologies to the study of these disorders, should lead, in the years to come, to much needed progress in this area. PMID- 8682570 TI - Colonic motility in health and disease. AB - Being the final pathway for chyme and digestive residues, the colorectum influences bowel function critically. The most important and relevant symptoms of colonic dysfunction are diarrhea, constipation, urgency, and pain. Despite the effects of many investigators, over several decades, the motor physiology of the human colon is still relatively obscure. Most is known about patterns of colonic transit. In practice, measurements of transit are the best characterized and most widely available tests of colonic motor function. Colonic hypersensitivity, implying an abnormality of afferent signaling, is assuming greater importance in the pathophysiology of conditions as common as IBS and inflammatory bowel disease. PMID- 8682571 TI - Anorectal and pelvic floor function. Relevance of continence, incontinence, and constipation. AB - Anorectal tests need to be tailored to the presentation of the individual patient. Clearly the tests are most useful when they identify anatomic or physiologic abnormalities for which there are successful treatments. For the incontinent patient, anal manometry is the most useful test. Sphincter injuries should be repaired, whereas neurogenic incontinence is best treated initially with biofeedback. Three tests are more useful for the constipated patient: colonic transit time, degree of pelvic floor descent on straining, and balloon expulsion. Colonic inertia responds to total colectomy and pelvic floor dysfunction to biofeedback. Meanwhile, patients with irritable bowel syndrome require rereferral back to their physicians. PMID- 8682572 TI - Histopathology of the enteric neuropathies. From silver staining to immunohistochemistry. AB - The gut is abundantly supplied with neurons, extrinsic and intrinsic nerve fibers. Knowledge regarding the structure of the enteric nervous system derives principally from the classic silver-staining methods. Because silver stains do not provide information on the molecular constituents of neurons, these data only facilitate classification and may have diagnostic significance. Studies using histochemistry and immunohistochemistry are now completing the morphologic picture and laying the groundwork for the formulation of therapeutic strategies based upon demonstrable chemical defects in enteric disease. PMID- 8682573 TI - Gastrointestinal motility in neonatal and pediatric practice. AB - Caring for children with gastrointestinal motility disorders requires an understanding of age-related changes in gastrointestinal function and in the clinical expression of disease. Successful evaluation of the child with a gastrointestinal motility disorder necessitates an approach that takes into account not only the child's symptoms, but also the stage of development. This article reviews the ontogeny of gastrointestinal motility; the techniques available for the study of gastrointestinal motility in children; and the presentation, pathophysiology, and treatment of pediatric functional bowel diseases. Differences in children compared to adults in performing and analyzing motility testing and in evaluating motility disorders are emphasized. A more complete understanding of pediatric motility disorders may provide important insights in approaching functional bowel diseases in adults. PMID- 8682574 TI - Psychosocial aspects of functional gastrointestinal disorders. AB - Increased numbers of psychiatric diagnoses and increased levels of psychological distress are seen in the majority of medical clinic patients with gastrointestinal motility disorders. In IBS, psychological symptoms are believed to be comorbid conditions, which do not cause the motility disorder but which do influence the patient's decision to consult a physician. In functional dyspepsia, psychological symptoms are present in many patients, but their role is not known; the available data suggest that psychological symptoms do not predict which patients will consult a physician. Among constipated patients, anxiety is believed to contribute to the development and course of pelvic floor dyssynergia by increasing pelvic floor muscle tension. Constipated patients without physiologic abnormalities to explain their constipation appear to have more psychological symptoms than those with delayed colonic transit, but there is significant psychological distress even in patients with slow transit constipation. Psychological symptoms do not seem to predict which constipated patients will consult a physician. There is an increased incidence of psychiatric diagnoses in patients with esophageal motility disorders as well, but the role that these psychological symptoms play in the course of the disorder is not known. Patients with the most common gastrointestinal motility disorders, IBS and dyspepsia, report experiencing more stressful life events, and IBS patients appear to show a greater increase in gastrointestinal symptoms when exposed to stressors. Laboratory studies document that acute psychological stressors do alter gastric, small bowel, and colonic motility, and patients with IBS appear to show a greater change in colonic and ileal motility with stress than healthy controls. Greater reactivity has not been demonstrated for the esophagus or stomach, however, and it has not been demonstrated for other gastrointestinal motility disorders. A characteristic of many patients who consult gastroenterologists for IBS and other motility disorders is a tendency to report multiple somatic complaints (including many nongastrointestinal complaints) and to overuse medical resources. This pattern of behavior is referred to as somatization or abnormal illness behavior. One source of abnormal illness behavior is childhood social learning, which occurs (1) when parents provide gifts or special privileges to a child who reports somatic symptoms or (2) when parents model abnormal illness behaviors themselves. PMID- 8682575 TI - Therapeutic strategies for motility disorders. Medications, nutrition, biofeedback, and hypnotherapy. AB - Gastrointestinal motility is regulated by a complex balance of inhibitory and excitatory neuronal, humoral, and mechanical factors. The goal in the management of motility disorders is to maintain adequate nutrition while decreasing symptoms. This can be accomplished by medications and support of nutrition and biofeedback; the application of these therapeutic strategies to patients with gut motility disorders is reviewed. PMID- 8682576 TI - Gastrointestinal sensation. Mechanisms and relation to functional gastrointestinal disorders. AB - This article reviews the basic anatomy and physiology of visceral afferent function and its application to a clearer understanding of visceral pain and symptoms in patients with functional gastrointestinal disorders. Recent investigations have focused on the potential role of visceral tone, different afferent (A delta and C) fibers, dorsal column neurons, and supraspinal modulation in the elicitation of visceral perception of noxious and nonnoxious stimuli arising in the gut. Greater understanding of these pathomechansims and their pharmacologic manipulation offers an opportunity for future therapeutic strategies for these disorders. PMID- 8682577 TI - Upper esophageal sphincter and pharyngeal function and oropharyngeal (transfer) dysphagia. AB - Through the application of videoradiography and solid-state manometry, much insight has been gained into the pathophysiology of oropharyngeal dysphagia, and considerable guidance has been provided toward appropriate therapies for the multitude of conditions causing this symptom. As noted earlier, a multidisciplinary approach to these patients often provides the most effective diagnosis and treatment regimen. In the diagnostic evaluation, barium videoradiography and solid-state intraluminal manometry should be considered as complementary procedures, with each providing important aspects of the overall assessment of the swallowing mechanism. It is important to note that controlled evaluations of the various treatment modalities are lacking and that therapy, although directed by information provided by the radiographic and manometric assessment, is primarily empiric. Despite this limitation, great strides have been made in the overall management of these patients during the past decade. PMID- 8682578 TI - Esophageal motility and reflux testing. State-of-the-art and clinical role in the twenty-first century. AB - Esophageal function testing has an important place in the investigation of a significant proportion of patients with esophageal disorders. Appropriate application of these tests requires a proper understanding of their capabilities and limitations and careful primary assessment by other modalities. Esophageal manometry is most useful for assessing significant troublesome dysphagia in the absence of organic obstruction. Esophageal pH monitoring is an important adjunct to clinical assessment and endoscopy in the diagnosis of reflux disease. Although it is the gold standard for the measurement of esophageal acid exposure and assessment of the relationship of symptoms to reflux, there are weakness in both of these functions that should be understood when applying the test to the diagnosis of reflux disease. PMID- 8682579 TI - Typical and atypical presentations of gastroesophageal reflux disease. The role of esophageal testing in diagnosis and management. AB - Gastroesophageal reflux disease (GERD) is a common disease with many typical and atypical forms of presentation. In the classic presentations of GERD with heartburn and regurgitation, esophageal testing, except for endoscopy, is only required for poorly responding patients or prior to surgical therapy. The atypical presentations of GERD, including chest pain, asthma, and ear, nose, and throat complaints, frequently are not associated with heartburn or regurgitation. Esophageal testing, particularly 24-hour pH monitoring is key to making the diagnosis and ensuring adequate acid suppression. PMID- 8682580 TI - Decreased frequency of HLA-DRB1 13 alleles in Frenchwomen with HPV-positive carcinoma of the cervix. AB - Specific types of human papillomaviruses (HPV) are associated with most cases of pre-invasive and invasive neoplasia of the uterine cervix. HLA phenotype influences susceptibility and resistance to viral infections and may therefore influence the course of HPV-associated tumors. Some data suggest that specific HLA class-II alleles may be associated with protection from or susceptibility to papillomavirus-associated lesions, but these results are still controversial. Using molecular probes, we looked for associations between specific DQA1, DQB1, DRB1 HLA class-II alleles, HPV types and cervical cancer. The analysis was performed on a population of 126 patients with invasive cervical cancer. For HLA typing, 165 healthy individuals were taken as controls. The DRB1 1301/02 allele frequency significantly decreased in patients (11%) as compared to controls (29%). This difference in frequency was dependent on the HPV-positive status of tumors and was no longer significant in the group of HPV-negative lesions. The same trends were observed with the DRB1 1301/02-DQA1 0103-DQB1 0603 haplotype frequency. An increase in the frequency of the DRB1 1401/07 and DRB1 03 alleles was observed in patients under 40. Contrary to what has been reported in the literature, no increase in the DRB1 15 allele frequency was observed in our series and only a slight increase in the DQB1 03 frequency was found in patients (70%) compared to controls (58%). In our study, no positive correlations between cervical cancer in Frenchwomen and specific HLA DR-DQ haplotypes has been found. In contrast, a negative correlation between DRB1 1301/ 02 alleles and HPV positive tumors has been observed. This may suggest a protective effect of DR13 against HPV-associated lesions of the cervix. PMID- 8682581 TI - Assessment of EGFR and TGF-alpha expression in relationship to HPV status and Ki 67 distribution in cervical intraepithelial neoplasms. AB - Expression of epidermal-growth-factor receptor (EGFR), transforming growth factor alpha (TGF-alpha) and Ki-67 proliferation antigen in cervical intra-epithelial neoplasms were analyzed. To examine the interrelationship of TGF-alpha, EGFR, Ki 67 and HPV status in dysplasia and carcinoma in situ, formalin-fixed tissue sections of 92 women were immunostained with monoclonal antibodies to EGFR, TGF alpha and Ki-67. The presence of HPV was assessed by in situ DNA hybridization. The highest positive TGF-alpha expression was seen in the group of mild dysplasia. The difference was significant between the relatively high expression in mild dysplasia and the low occurrence in severe dysplasia and carcinoma in situ as well. The same relation could be found between TGF-alpha expression in papilloma-virus-negative dysplasia and those with the presence of HPV 16/18. In contrast to these findings, the Ki-67 proliferation marker was intensely detectable in severe dysplasia and carcinoma in situ. Ki-67-stained neoplastic cell nuclei were found in a significantly higher percentage of HPV-positive than in HPV-negative lesions. TGF-alpha over-expression is obviously combined with low proliferating activity and vice versa. Irrespective of the grade of dysplasia or HPV status, EGFR was expressed abnormally as compared with normal squamous epithelium. Over-expression of TGF-alpha in mild dysplasia could be associated with the autocrine pathway of cell-growth regulation. In the presence of HPV 16/18 the EGFR/TGF-alpha pathway for growth stimulation is probably not involved. PMID- 8682582 TI - Immunohistochemical detection of adhesion molecule CD44 splice variants in lymph node metastases of cervical cancer. AB - Expression of specific cell adhesion molecule CD44 isoforms (splice variants) has been shown to be associated with poor prognosis in human cervical cancer. We used 3 different variant exon sequence-specific murine monoclonal antibodies (MAbs) to epitopes encoded by exons v5, v6 and v7-v8 of human variant CD44 to study the expression of CD44 splice variants in 35 primary squamous-cell carcinomas of the cervix and pelvic lymph node metastases by means of immunohistochemistry. Primary tumors showed expression of CD44 splice variants CD44v5, CD44v6 and CD44v7-8 in 93%, 73% and 33% of cases, respectively. Lymph node metastases expressed CD44v5, CD44v6 and CD44v7-8 in 83%, 53% and 21% of cases, respectively. Tumors with expression of CD44v6 in pelvic lymph node metastases showed metastatic spread to 2 or more pelvic lymph nodes significantly more often compared to patients without expression of splice variant CD44v6. Patients suffering from tumors with lymph node metastases expressing splice variant CD44v6 had a poorer recurrence free survival compared to patients without CD44v6 expression in lymph node metastases, but this trend was not statistically significant. Expression of CD44 splice variants containing epitopes encoded by exon v6 in primary tumors and pelvic lymph node metastases of cervical cancer patients is consistent with a prominent role of CD44 in the process of metastasis formation. PMID- 8682583 TI - Two distinct p53 immunohistochemical patterns in human squamous-cell skin cancer, precursors and normal epidermis. AB - Specimens of squamous-cell neoplasms (81 invasive cancers, 36 in situ cancers, 70 dysplasias, 5 keratoacanthomas, 19 papillomas) and normal skin were immunostained with p53 antibody. Nuclear accumulation of p53 was visualized as following 2 distinct patterns: dispersed or compact. The former is interpreted as a reversible reaction to sunlight, whereas the latter, after microdissection and sequencing of DNA, has been shown to reflect clonal multiplication of keratinocytes with mutated p53. The dispersed pattern was diffusely distributed and usually only involved a small proportion of epidermal cells. The compact pattern was characterized as a contiguous area of homogeneously stained cells sharply demarcated from its surroundings. It involved patches of normal epidermis or large areas of dysplastic or malignant squamous epithelium. Immature cells were always stained, whereas immunoreactivity was variably present in differentiating keratinocytes. Dispersed patterns occurred in 94.7% of strongly UV-exposed skin (mainly face) and to a lesser extent in less exposed parts of the body. It showed no correlation to the age of the individual. About two-thirds of biopsies from individuals over age 50 displayed compact patterns in sun-exposed, otherwise normal, epidermis. About 65% of pre-malignant and malignant squamous cell neoplasms had a compact pattern. The presence of p53 immunoreactivity as a compact pattern supports the idea that mutations of the p53 gene are early events in the sequence from dysplasia to invasive squamous-cell cancer of the skin. Also, even in the absence of cellular atypia, patches of epidermal cells can accumulate p53 in a way that is indistinguishable from that of cancer and pre cancer. PMID- 8682584 TI - p53 expression and proliferative activity predict survival in non-invasive thymomas. AB - We performed p53 immunohistochemistry, DNA flow cytometry and analysis of the argyrophilic nucleolar organizer regions (AgNORs) in formalin-fixed, paraffin embedded sections from 46 non-invasive thymomas and correlated the results with the traditional clinicopathologic features of the tumor. p53 immunopositivity was detected in 21 of 46 cases; it was not associated with any clinicopathologic features nor DNA content but significantly correlated with AgNOR counts. On univariate analysis, 10-year survival rates were 100% for p53-negative cases but only 71% for p53-positive cases and 93% for patients with low AgNOR counts but only 77% for patients with high AgNOR counts. Age, sex, histologic type, myasthenia gravis and DNA content did not correlate with survival. Our results indicate that p53 staining and evaluation of proliferative activity allow assessment of prognosis in non-invasive thymomas, when all of the other parameters are insufficient. Furthermore, the high rate of p53 expression in non invasive thymomas suggests that abnormal p53 immunoreactivity may occur early in the neoplastic process. PMID- 8682585 TI - Prognostic value of E-cadherin expression in 413 gastric carcinomas. AB - E-cadherin is a Ca(2+)-dependent intercellular adhesion molecule known to exert an invasion-suppressor function. In the present study, E-cadherin expression was immunohistochemically investigated in a retrospective series of 413 RO-resected gastric carcinomas using the monoclonal antibody (MAb) 5H9. Of these cases, 108 tumors revealed a preserved E-cadherin expression similar to that of normal gastric mucosa. In 95 tumors, E-cadherin expression was moderately reduced and in 86 tumors highly reduced. In 124 tumors, no or only a very weak dotted expression could be detected. There was a significant correlation between the degree of E cadherin expression and the grade of tumor differentiation, as well as with histological type according to the Lauren and the WHO classifications. In contrast, no correlation could be demonstrated between E-cadherin expression and the prognostic parameters depth of invasion, lymph node involvement and vascular invasion. As shown by univariate Cox regression analysis, patients with E cadherin-positive tumors had significantly better 3-and 5-year survival rates than patients with E-cadherin-negative tumors. This prognostic impact remained present in a multivariate Cox regression analysis, including the prognostic parameters pT category, pN category and vascular invasion. PMID- 8682586 TI - p53 mutations as a possible predictor of response to chemotherapy in metastatic colorectal carcinomas. AB - Although intrahepatic infusion therapy with 5-fluorouracil for unresectable colorectal liver metastases may lead to improved overall survival for some patients, it is not clear why a response is not observed in others. Gene alterations in oncogenes or tumor-suppressor genes are critical events in tumor formation, and some of them could play a role in the process of drug resistance. The tumor-suppressor gene p53, which is known to trigger cell arrest or apoptosis in response to DNA damage, is found to be mutated in a wide range of human tumors. The aim of this work is to establish whether a relationship is found between p53 mutations and survival in patients undergoing adjuvant chemotherapy for advanced Dukes' D colorectal cancers. Seventeen tumors from patients treated with 5-fluorouracil regimen via intrahepatic infusion for unresectable colorectal hepatic metastasis were considered. p53 mutations from tumor DNA were detected, after amplification by PCR of exons 5 to 8, by non-radioactive single-strand conformation polymorphism and direct DNA sequencing. Patients with mutated p53 colorectal tumors had short survival, whereas prolonged survival was associated with the presence of wild-type p53 (p = 0.019). Our data suggest that mutated p53 colorectal tumors had a weak response, or even no response, to chemotherapeutic treatment. Routine assessment of p53 status would be helpful in selecting patients with only wild-type p53 gene who have a predictably better response to chemotherapy. PMID- 8682587 TI - Sialosyl-Tn antigen as a marker of gastric cancer progression: an international study. AB - Sialosyl-Tn, a mucin-associated carbohydrate antigen, is not expressed by normal mucus-producing cells of the stomach but becomes expressed in metaplastic, pre malignant and malignant gastric tissues. Reports vary as to the frequency of STn expression and its prognostic role in gastric cancer. To determine whether these differences might be due to inter-country variations in gastric cancer biology, we immunohistochemically analyzed 340 gastric cancers from 2 countries at high risk (high incidence) for gastric cancer (Japan and Chile), one with intermediate risk (Brazil) and one with low-risk (USA). Expression of STn was correlated with clinico-pathological features of the tumors and with cancer-related survival. Regardless of country, the frequency of STn-positive tumors was lower in non invasive ("early") than in advanced gastric cancer. Consequently, high-risk countries where early gastric cancer is more common demonstrated a lower overall frequency of STn-positive tumors. In all 4 countries, STn expression directly correlated with depth of invasion, stage, and lymph node involvement. In addition, STn expression correlated with a poor prognosis in all 4 countries, but the effect of STn on survival was not independent of tumor stage. Our findings indicate the need to consider the inherent gastric cancer risk and prevalence of early gastric cancer in the study population when reporting frequency of STn expression in gastric cancer. Regardless of country, however, STn expression is a marker of gastric cancer progression suggesting that cancer-associated mucins play a role in the malignant behavior of this tumor. PMID- 8682588 TI - p53 accumulation and mutation are prognostic indicators of poor survival in human gastric carcinoma. AB - The aim of our study was to examine the prognostic significance of p53 protein accumulation and gene mutation in a series of 116 gastric carcinomas from a low incidence population. Formalin-fixed, paraffin-embedded tumour sections were used to investigate p53 protein accumulation by immunostaining with monoclonal antibody (MAb) DO-7 and p53 gene mutation by single-strand conformation polymorphism analysis of exons 5-8. Nuclear p53 accumulation was detected in 23% of tumours and mutation in 28%. Concordance between the 2 alterations was observed in 73% of cases. p53 protein accumulation was more frequent in tumours with lymph node metastasis, while p53 mutations were more frequent in tumours from older patients. The histopathological parameters of depth of invasion, grade and histological type showed no significant associations with either p53 alteration. In univariate analysis, both alterations were associated with significantly shortened patient survival. The 5-year survival rate for patients with a p53 mutation was 9% compared to 42% for those without a mutation. In multivariate analysis adjusted for the other histopathological parameters, p53 gene mutation but not immunohistochemically-detected p53 protein accumulation was an independent prognostic indicator of poor survival in gastric carcinoma. PMID- 8682589 TI - Prognostic and predictive value of tumour angiogenesis in ovarian carcinomas. AB - Experimental studies suggest that angiogenesis plays an important role in the pathogenesis of ascites and progression of ovarian cancer. To evaluate the association of intratumoral microvessel density (IMD) with the conventional clinicopathologic features and to determine the capability of these factors in predicting responsiveness to platinum-based chemotherapy and overall survival (OS) we studied 112 ovarian carcinomas. IMD was determined using the anti-CD31 antibody and immunocytochemistry. In the entire series, we correlated IMD with the other features. In the subgroup of patients with FIGO stage III-IV (60 cases), we correlated the factors studied, determined prior of treatment, with response to therapy and prognosis. The median IMD value, in the "hot spot", in the entire series was of 48 microvessels/field. IMD values were significantly higher in mucinous carcinomas than in the other histologic types. In FIGO stage III-IV patients IMD, age and performance status (PS) were significantly associated with the probability of pathologic response to chemotherapy in univariate analysis. However, only IMD and PS retained significance in multivariate analysis. The overall capability of the 2 variables to predict response was high. In FIGO stage III-IV patients IMD, age, PS, the amount of post operative residual disease (PORD), histologic type and response to chemotherapy were significant prognostic indicators of OS in univariate analysis. In multivariate analysis only histologic type, PORD and PS retained significance. The overall capability of these 3 variables to predict OS was satisfactory. PMID- 8682590 TI - Overexpression of the met/HGF receptor in renal cell carcinomas. AB - The c-met oncogene encodes the receptor for hepatocyte growth factor/scatter factor (HGF/SF), a multifunctional cytokine able to mediate morphogenesis as well as mitogenesis, motogenesis and invasiveness of epithelial cells. HGF/SF has been implicated in branching tubulogenesis of the developing kidney and in regeneration after renal injury and nephrectomy. We have examined the expression of the met/HGF receptor in normal human kidney and tissues of the genito-urinary tract, and in 50 kidney neoplasms of different histotypes, using monoclonal antibodies (MAbs) against the met/HGF receptor and immunohistochemistry. In normal kidneys, weak staining restricted to the distal tubules was observed. Transitional cell carcinomas were consistently negative, whereas increased expression at various levels was found in 87% of renal cell carcinomas with different cytological features and histological patterns. Western blot analysis of samples showed that the met/HGF receptor found in the malignant cells exhibits features of the normal receptor. The met/HGF receptor is also overexpressed in a renal cell carcinoma cell line, whose motility is triggered by HGF/SF. Our data suggest that expression of the met/HGF receptor may be involved in the onset and progression of renal cell carcinomas. PMID- 8682591 TI - CD44 standard and variant isoform expression in human epidermal skin tumors is not correlated with tumor aggressiveness but down-regulated during proliferation and tumor de-differentiation. AB - CD44 isoforms have been reported to be involved in tumor invasion and metastasis formation. Normal human skin expresses high levels of CD44 isoforms, but little is known about their expression in epidermal skin tumors. Expression of CD44 standard (CD44s) and variant exon (CD44v3, -v4, -v5, -v6, -v9)-encoded gene products has been studied in 74 benign, semi-malignant and malignant human epithelial skin tumors using a panel of well-characterized, variant exon-specific monoclonal antibodies (MAbs). Sensitivity and resolution of the immunohistochemical staining in paraffin sections was substantially improved by using microwave-based antigen retrieval and an optimized streptavidin-biotin peroxidase technique. Immunostaining was evaluated semi-quantitatively and correlated with tumor type and degree of histological differentiation by non parametric statistical tests. Furthermore, the relationship between CD44 expression and cellular proliferation rate as defined by the Ki-67 antigen was analyzed in basal cell carcinomas. We found a significant correlation between tumor type and CD44 isoform expression. Basal cell carcinomas exhibited the weakest staining and keratoacanthomas the strongest. Squamous cell carcinomas ranged in between, with a tendency to down-regulate CD44 expression upon de differentiation. In basal cell carcinomas, an inverse relationship between CD44 expression and proliferation rate was directly demonstrated at the cellular level using double immunolabelling. Our data indicate that qualitative and quantitative changes in CD44 splicevariant expression in human skin tumors do not correlate with invasive and metastatic potential but are rather related to the degree of tumor differentiation. PMID- 8682592 TI - Genetic alterations in esophageal cancer and their relevance to etiology and pathogenesis: a review. AB - Cancer of the esophagus exists in 2 main forms with different etiological and pathological characteristics-squamous cell carcinoma (SCC) and adenocarcinoma (ADC). This review focuses on the occurrence of genetic alterations in SSC and ADC of the esophagus and on their possible implications for the elucidation of the etiology and pathogenesis of these cancers. The most common alterations found in esophageal cancers include allelic losses at chromosomes 3p, 5q, 9p, 9q, 13q, 17p, 17q and 18q, as well as mutations of p53 (mostly missense), Rb (deletions), cyclin DI (amplifications) and c-myc (amplifications). The sequence of occurrence of these alterations with respect to histopathological tumor progression is discussed. Our findings underscore the different etiology and pathogenesis of SCC vs. ADC and suggest that the genetic alterations observed may represent molecular fingerprints of critical risk involved in the development of these 2 cancers. PMID- 8682593 TI - Association of p53 gene mutation with decreased chemosensitivity in human malignant gliomas. AB - Loss of p53 function is involved in tumorigenesis of various human cancers, but the relation between mutation of the p53 tumor-suppressor gene and the chemo- and radiosensitivity of tumors remains unclear. Mutated p53 gene in malignant glioma is often associated with progression and recurrence of malignancy, and these events are closely linked with increased resistance to both chemotherapy and radiation. We have examined the status of the p53 gene in malignant gliomas obtained from 34 patients (glioblastoma: 29 cases, anaplastic astrocytomas: 5 cases). The chemosensitivities of these specimens using 28 kinds of anti-cancer agents were determined using an in vitro assay system. Overall, 12 mutated cases of p53 gene were found in malignant glioma samples. The mean numbers of effective agents were 0.58 for the tumor samples with p53 mutations and 5.00 for tumors without mutations. Our data indicate that p53 gene mutation predisposes to decreased cell killing via chemotherapy in malignant gliomas. PMID- 8682594 TI - A detailed analysis of K-ras point mutations in relation to tumor progression and survival in colorectal cancer patients. AB - Point mutations in codon 12, 13, and 61 of the K-ras gene are an early event in tumorigenesis of colorectal cancer, but the impact of number, type, and position of such mutations on the progression of adenomas as well as the clinical behaviour of colorectal carcinomas is not clearly established. A series of 35 adenomas and 117 carcinomas at various stages was subjected to single-strand conformation polymorphism (SSCP) to analyse type, position and number of exon-I K ras point mutations and to relate the results with patients survival. From our data we conclude that the number of K-ras point mutated tumors shows a trend to increase with tumor progression. The number of multiple K-ras point mutations, however, significantly increases with stage. Most mutations occur in the 1st or 2nd base of codon 12, whereas point mutations in the 3rd base are rare. In adenomas mutations, particularly G-T transversions, in the K-ras gene could indicate a propensity to malignant transformation. G-A transitions and G-C transversions of the second base are associated with metastasized tumors. Regarding survival, patients with K-ras point mutated tumors did worse than their non-mutated counterparts. G-A transitions in the 1st and 2nd base and G-C transversions in the 2nd base were associated with a poor prognosis as compared with G-T transversions in both the 1st and 2nd base. Patient survival therefore is related to the occurrence and type, but not the location, of K-ras point mutations. PMID- 8682595 TI - Myocardial perforation associated with the use of the Gensini ventriculography catheter. AB - We describe myocardial perforation during left ventriculography using the Gensini catheter in two patients with aortic valve disease. In each case this occurred despite careful catheter positioning and prior 'test' injection of contrast agent. The use of the Gensini catheter for left ventriculography in this circumstance is seriously questioned. PMID- 8682596 TI - Comparison of the effect of left ventricular volume and pressure overload on beta adrenoceptor density in left heart valvular disease. AB - The sympathetic responses in left heart valvular disease may depend on the ventricular load conditions. We proposed to evaluate this possibility by comparing the effects of left ventricular pressure (LVP) and volume (LVV) overload on beta-adrenoceptor density and ligand binding affinity in lymphocytes and in the four myocardial chambers in rheumatic heart valvular patients. Receptor activity was determined by radioligand binding using [125I]iodocyanopindolol. In the lymphocytes (n = 45), the beta-adrenoceptor density was reduced by 88% (P < 0.001) in LVP patients (n = 15) and 79% (P < 0.001) in LVV patients (n = 30) compared with 23 controls. In the myocardium, the receptor density of the LVP (n = 12) was attenuated by 55% (P < 0.05) in the left ventricle, 42% in the right ventricle, 13% in the left atrium, and 37% in the right atrium, while in LVV patients (n = 22) it decreased by 73% (P < 0.01) in the left ventricle, 62% (P < 0.05) in the right ventricle, 30% in the left atrium, and 34% in the right atrium compared with 15 controls. Thus, the reduction in density was greatest in lymphocytes and least in the atria in both groups. The decrease in ventricular density of the LVV group was similar to the reduction in the lymphocytes and two-fold higher than in the atrial density. These alterations were significantly greater for the LVV than for the LVP group. The Kd for the myocardial receptor binding to [125I]iodocyanopindolol was not significantly influenced in either group, but was lower in the lymphocytes. These findings suggest that in patients with left heart valvular disease, there is a significant attenuation in both peripheral and myocardial beta-adrenoceptor density. The decrease in receptor density is significantly greater in the left ventricular volume overload than in the left ventricular pressure overload patients. PMID- 8682597 TI - A comparison of nifedipine once daily (Adalat LA), isosorbide mononitrate once daily, and isosorbide dinitrate twice daily in patients with chronic stable angina. AB - The efficacy of nifedipine gastrointestinal therapeutic system (GITS), 60-90 mg o.d., isosorbide dinitrate, 40-60 mg b.d., and isosorbide mononitrate slow release, 50-100 mg o.d. was assessed in a six week double-blind, parallel-group study in patients with stable angina on chronic beta-blocker treatment. Of 339 patients who entered the study, 229 were eligible for the valid case analysis of efficacy and 335 for the safety analysis. Nifedipine GITS was significantly better than isosorbide dinitrate (P < or = 0.025) in prolonging time to 1 mm ST segment depression, time to maximum ST-segment depression, time to occurrence of angina and total exercise duration, in addition to reducing the number of angina attacks and glyceryl trinitrate consumption after six weeks therapy. Nifedipine GITS was also significantly better than isosorbide mononitrate (P < or = 0.025) in prolonging time to occurrence of angina and time to 1 mm ST-segment depression after six weeks therapy. The incidence of headache was considerably higher in both the isosorbide dinitrate and isosorbide mononitrate groups (40% and 41%, respectively) than in the nifedipine GITS group (9.5%, P < or = 0.001), and was the main reason for withdrawal from the study (isosorbide dinitrate 18/99, isosorbide mononitrate 17/99, nifedipine GITS 2/95). Peripheral oedema was more common in patients treated with nifedipine GITS (12.5%) compared to nitrates (2% in both groups, P < or = 0.01), but resulted in withdrawal of only one patient (treated with nifedipine GITS). This study suggests that the efficacy and tolerability of nifedipine GITS is superior to long acting nitrates as second line therapy to beta-blockade in the treatment of chronic stable angina. PMID- 8682598 TI - Time course of endothelial function in epicardial conduit coronary arteries and in the microcirculation in the long-term follow-up after cardiac transplantation. AB - BACKGROUND: Endothelial dysfunction has been reported in epicardial conduit coronary arteries and in the microcirculation after cardiac transplantation. It has been assumed that endothelial dysfunction may precede hemodynamically relevant transplant vasculopathy. In this study the long-term course of endothelial function was investigated in conduit coronary arteries and in the microcirculation after cardiac transplantation. METHODS: Patients were stratified according to time after transplantation (group I, up to 2 years after transplantation; group II, 2 to 4 years after transplantation; group III, more than 4 years after transplantation). Changes of the diameter of proximal, mid and distal segments of the left anterior descending coronary artery and the circumflex branch of the left coronary artery were investigated after endothelium dependent and endothelium-independent stimulation with acetylcholine (ACh, 50 and 100 micrograms i.c.) and nitroglycerin 0.3 mg i.c. Coronary flow changes were assessed endothelium-dependently (ACh 50 and 100 micrograms i.c.) and endothelium independently (dipyridamole 0.56 mg/kg i.v.) utilizing an 8 F Judkins-style Doppler catheter. RESULTS: Application of 50 micrograms/100 micrograms ACh resulted in a reduction of coronary artery diameter in proximal, mid and distal vascular segments of the left anterior descending coronary artery and the circumflex branch of the left coronary artery. The vasoconstrictive effect did not differ significantly between groups I,II and III. Nitroglycerin 0.3 mg i.c. increased coronary artery diameters in groups I, II and III. ACh (50 micrograms/100 micrograms) increased coronary flow index by 217 +/- 70%/236 +/- 110% (P < 0.05 vs. baseline) in group I, 113 +/- 26%/77 +/- 22% (P < 0.05 vs. baseline) in group II and 108 +/- 26%/109 +/- 21% (P < 0.05 vs. baseline) in group III. Dipyridamole increased coronary flow index by 296 +/- 78% (P < 0.05 vs. baseline) in group I, by 63 +/- 16% (P < 0.05 vs. baseline and vs. group I) in group II and by 113 +/- 30% (P < 0.05 vs. baseline and vs. group I) in group III. CONCLUSION: A constant vasosonstrictor response to ACh was observed in epicardial coronary arteries after cardiac transplantation indicating endothelial dysfunction independent of the time course. Endothelial dysfunction in these vessels may not be an early indicator of hemodynamically relevant transplant vasculopathy. Endothelium-dependent and endothelium-independent flow reserves decreased 2 years after transplantation and remained constant thereafter. PMID- 8682599 TI - The comparison of vascular reactivities of arterial and venous grafts to vasodilators: management of graft spasm. AB - Graft spasm in the perioperative or postoperative period increases the risk of morbidity and mortality after coronary revascularization and hence necessitates urgent treatment. We have studied the effects of various vasodilators against noradrenaline- and endothelin-1-induced spasms in saphenous vein, internal mammary artery and gastroepiploic artery. In internal mammary and gastroepiploic arteries, the nitrovasodilators, sodium nitroprusside and glyceryl trinitrate, effectively reversed the spasms induced either with noradrenaline (for sodium nitroprusside; internal mammary artery: 101.07% +/- 1.63%; gastroepiploic artery: 94.10% +/- 2.07%) or endothelin-1 (for sodium nitroprusside; internal mammary artery: 97.67% +/- 4.94%; gastroepiploic artery: 90.69% +/- 2.61%). However, in saphenous vein contracted with endothelin-1, the responsiveness to nitrovasodilators was significantly blunted (for sodium nitroprusside: 52.33% +/- 5.19%) than that of rings contracted with noradrenaline (for sodium nitroprusside: 95.04% +/- 1.94%). Both arterial and venous grafts exhibited moderate beta-receptor function in response to isoproterenol. Isoproterenol was less effective in inhibiting the contractions of endothelin-1 in saphenous vein and gastroepiploic artery but not in internal mammary artery. On the other hand, nifedipine and papaverine were fully effective in reversing all the spasms in three of the graft materials. From these results, it can be deduced that saphenous vein is refractory against cyclic guanidine monophosphate (cGMP) dependent and beta-receptor mediated relaxations when endothelin-1 was used as the spasmogenic agent. Internal mammary artery is the most responsive graft material to the vasodilators regardless of the nature of spasmogenic stimulus. Gastroepiploic artery exhibits functional similarity with internal mammary artery, with the exception of beta-receptor responsiveness. PMID- 8682600 TI - Altered coronary endothelial function in a patient with asymptomatic left ventricular dysfunction. AB - Coronary endothelial dysfunction has been demonstrated in patients with symptomatic heart failure. Furthermore the endothelium has been implicated in the pathogensis of cardiomyopathy in patients with normal coronary angiograms and no other known causes of heart failure. Herein we describe an asymptomatic patient with an early cardiomyopathy and abnormal coronary endothelial function. There was no evidence for coronary disease by both angiography and intravascular ultrasound. Epicardial coronary artery vasoconstriction and a decrease in coronary blood flow was noted during the intracoronary infusion of graded concentrations of acetylcholine. This case demonstrates that endothelial dysfunction occurs in the setting of asymptomatic left ventricular dysfunction and highlights the potential importance of the endothelium in the early development of heart failure. PMID- 8682601 TI - Early diastolic regional function of the hypertrophied left ventricle. AB - We analyzed cardiac catheterization data from 7 patients with aortic stenosis and 10 patients with nonobstructive hypertrophic cardiomyopathy to compare left ventricular regional diastolic function. Left ventriculogram in the right anterior oblique projection was analyzed by the area method, and regional wall stress and regional area were computed for 4 regions in the mid-portion of the left ventricle. For each region, we assessed the percent area changes (normalized by end-diastolic regional area) and time constant for regional wall stress decrease during the isovolumic relaxation period. Regional non-uniformity during the isovolumic relaxation period was then evaluated by standard deviations for the percent area changes and for regional time constants of the 4 ventricular regions. In patients with hypertrophic cardiomyopathy, both the standard deviations for the percent area changes and the regional time constants were greater (P < 0.05) than those in patients with aortic stenosis, suggesting the presence of pronounced non-uniformity of regional relaxation in hypertrophic cardiomyopathy. The time constant of left ventricular pressure decrease during early relaxation phase was significantly greater (P < 0.01), and the early diastolic peak filling rate of the global left ventricle was significantly smaller (P < 0.05) in patients with hypertrophic cardiomyopathy. Thus, early diastolic left ventricular regional non-uniformity was more pronounced in hypertrophic cardiomyopathy than in aortic stenosis, which was associated with the impairment of relaxation and early filling of the global left ventricle. These findings suggest that different mechanisms are responsible for diastolic dysfunction in primary versus secondary myocardial hypertrophy. PMID- 8682602 TI - Natural history of abnormal conduction and its relation to prognosis in patients with dilated cardiomyopathy. AB - To investigate the natural history of disturbances in ventricular activation, atrioventricular conduction, and ventricular cavity size, we retrospectively studied 58 patients from a total of 296 patients with dilated cardiomyopathy seen within 4 years. A total of 309 computerised electrocardiograms (ECGs) and 135 M mode echocardiograms were analysed. In the majority of the patients, PR interval, QRS duration and QT interval prolonged progressively, though heart rate changed little. Their increase was much more striking in patients who died (n = 10) or had a pacemaker inserted (n = 9), compared to that in the clinically stable patients, though at entry all these values, as well as age and left ventricular cavity size, were similar. There were no significant differences between patients who died and those with a pacemaker inserted, except for QRS axis, which had shifted rightwards in 8 out of 10 who died, but only in 3 of 9 who subsequently had a pacemaker inserted and 14 of the 29 stable patients. A QRS duration over 160 ms was found in 8 out of the 10 patients who died, 6 of 9 who had a pacemaker and only in 5 out of the 39 stable patients (P < 0.001). The sum of PR interval and QRS duration over 375 ms was not found in any stable patient but was present in 6 of the 7 patients who were in sinus rhythm and died (P < 0.001). Left ventricular cavity size also increased with time, but did not correlate significantly with ECG progression, nor did it identify patients who subsequently died. Thus, a combination of increasing PR interval and QRS duration, particularly along with rightwards shift of QRS axis, appears to be a marker of high risk in patients with dilated cardiomyopathy. PMID- 8682604 TI - Accuracy and precision of angiographic volumetry methods for left and right ventricle. AB - We imaged and quantified 60 ventricle casts (30 LV, 30 RV) to evaluate the accuracy and reliability of angiographic ventricle volumetry. We analyzed the seven biplane methods most frequently used in clinical routine: Arcilla, Arvidsson, Dodge, Ferlinz, Simpson (LV + RV) and Wynne. The ventricle contours were defined by (1) manual drawing on the computer screen, (2) manual drawing using a graphical tablet and (3) automatic contour detection. A high inter-class variation in volume accuracy between the different methods was observed (S.D. = 12.7 ml). The volume methods for the LV (mean differences MDLV: [-2.2, +8.5] ml, average MDLV = 1.8 ml) are more accurate than for the RV (MDRV: [-11.4, +33.1] ml, average MDRV = 12.1 ml). The intrinsic error is about the same for all approaches and is very high: average S.D. = 20 ml, RMS = 185 ml. Manual contour definition results in a volume over-estimation (average MDman = +32.8 ml, r = 0.731) compared with automatic contour detection (average MDauto = +6.2 ml, r = 0.810). LV hypertrophy results in a volume under-estimation of the LV (MDLV = -7 ml) and an over-estimation of the RV (MDRV = +6 ml). RV hypertrophy leads to the opposite effect. It was shown that ventricle volumetry and the calculation of derived parameters (ejection fraction) is extremely case dependent and can only be an estimate of the actual value. PMID- 8682603 TI - Signal-averaged electrocardiography and echocardiography in the evaluation of myocardial involvement in progressive systemic sclerosis. AB - To assess the myocardial involvement in progressive systemic sclerosis we evaluated the presence of late potentials by signal-averaged electrocardiography (signal-averaged ECG) and the left ventricular function by M-mode, two dimensional and Doppler echocardiography. Fifteen outpatients, 7 with diffuse progressive systemic sclerosis and 8 with CREST syndrome variant, without clinical or electrocardiographic evidence of cardiac disease were studied and compared with 18 normal subjects. Late potentials occurred in 5 out of 15 progressive systemic sclerosis patients (33%) with a significant difference versus controls (P < 0.05) and were present only in the patients with diffuse progressive systemic sclerosis (P < or = 0.001 vs. controls). All progressive systemic sclerosis patients showed a normal left ventricular systolic function. Abnormal left ventricular filling was found in 9 progressive systemic sclerosis patients (5 with diffuse progressive systemic sclerosis and 4 with CREST). A more severe impairment of the mean values of diastolic function indexes was found in diffuse progressive systemic sclerosis than in CREST. In all diffuse progressive systemic sclerosis patients at least one method showed altered results, whereas half the CREST patients showed no pathological findings with both techniques. These results confirm a lower myocardial involvement in the CREST syndrome than in diffuse progressive systemic sclerosis and consequently this is probably related to a better prognosis. PMID- 8682606 TI - Association for Research in Vision and Ophthalmology 1996 annual meeting. Fort Lauderdale, Florida, April 21-26, 1996. Abstracts. PMID- 8682605 TI - The value of computed tomography in combination with a percutaneous transluminal coronary angioplasty guide wire for identifying the definite course of an anomalous left anterior descending artery. AB - When the left anterior descending artery (LAD), originating from the right sinus of Valsalva, follows an anomalous course between the aorta and pulmonary artery it can be associated with ischaemia, infarction or sudden death. Patients with such a LAD should be treated with coronary artery bypass grafting (CABG). It is therefore important to determine the exact course of the aberrant vessel. We describe two patients in whom the course of the anomalous LAD was determined and confirmed by computed tomography (CT) scan in combination with a percutaneous transluminal coronary angioplasty (PTCA) guide wire positioned in the aberrant vessel. PMID- 8682607 TI - An antisense promoter within the hepatitis B virus X gene. AB - Sequences of the Hepatitis B virus X (HBx) gene are preferentially retained on chromosomally integrated viral DNA and thereby the precore/core promoter as a part of its reading frame. The existence of a second promoter mapping to the same DNA region is suggested by an antisense (AS) RNA which has been described earlier by Standring's group. Here, the capacity of sequences upstream to this AS RNA to function as a bidirectional promoter was analyzed. On a cloned monomer of viral DNA a segment spanning the start codon of the HBx gene and a site within the HBx frame was replaced by a luciferase reporter gene (Photinus pyralis) plus a downstream polyadenylation signal of SV40 origin. Insertion in HBx and AS orientation allowed to compare the apparent strengths of the respective promoter activities. Both DNA constructs expressed luciferase to levels above the one induced by a reference plasmid expressing the gene under control of the SV40 promoter. In the context of a reporter plasmid a 241-bp subregion of the HBx gene with enhancer II in its center part functioned bidirectionally as AS and as core promoter. For the expression of a putative AS factor two effector plasmids driven by the autologous and a heterologous promoter, respectively, were established which stimulated in co-transfection experiments a c-myc target gene to a higher degree than a corresponding HBx effector construct. PMID- 8682608 TI - Hepatitis B virus HBx gene and hepatocarcinogenesis. AB - The association between hepatitis B virus (HBV) and hepatocellular carcinoma (HCC) has been known over the past 20 years. We have shown that the HBx gene of HBV induces HCC in transgenic mice and that HBx protein may be involved in hepatocarcinogenesis in human chronic HBV infection. To further characterize the role of the HBx gene in carcinogenesis, we analyzed the preneoplastic liver in HBx transgenic mice. From the age of 2 months, there appeared preneoplastic liver foci, which consisted of hepatocytes with cytoplasmic vacuolations, but they did not increase in size until the age of 12 months. Hepatocytes in these foci which showed higher levels of HBx protein in the cytoplasm than those in the surrounding tissues demonstrated increased DNA synthesis in their nuclei. We then established mouse fibroblast cell lines in which the expression of the HBx gene is under the control of a hormone-regulated promoter. Upon induction of the HBx gene, resting cells began to enter the S-phase of the cell cycle. These results indicate that the HBx gene has mitogenic activity both in vivo and in vitro and suggest that the HBx gene may contribute to hepatocarcinogenesis by driving cells into deregulated cell cycle control. We propose a mechanism for hepatocarcinogenesis in which continuous stimulation for cell cycle progression in vivo may lead to the development of HCC by placing hepatocytes in a subthreshold state for transformation. PMID- 8682609 TI - In vitro transformation by hepatitis B virus DNA. AB - There is strong epidemiological evidence that the hepatitis B virus (HBV) contributes to the development of hepatocellular carcinoma (HCC). In several immortalized cell lines, an in vitro transforming activity of HBV DNA and expression vectors for the viral protein X (HBx) has now been demonstrated. Furthermore, it appears as if still unknown parts of the HBV genome other than HBx contribute to the transforming activity of HBV DNA in vitro. Only one of several studies found that HBx-transgenic mouse lines develop HCC. A mouse line transgenic for the large surface protein of HBV develops HCC due to concomitant necroinflammatory infection. Growing evidence shows the importance of recombination of integrated viral DNA and cellular DNA for HCC development. A direct transforming potential of one of these viral integrates has been demonstrated. Chemical carcinogens are more effective in HBV-containing cell lines or transgenic mice. PMID- 8682610 TI - Viral, host and environmental risk factors for hepatocellular carcinoma: a prospective study in Haimen City, China. AB - To identify specific environmental, viral, and genetic risk factors for hepatocellular carcinoma (HCC) and the interaction of such factors, we are conducting a prospective study in a high-incidence area of China. Questionnaires were completed and biosamples collected by 60,984 men ages 30-64 years, at study entry. Within 2.5 years, 183 deaths from HCC had occurred. Each HCC case was matched with 5 controls and compared for items on the questionnaire. In addition to chronic hepatitis B virus (HBV) infection, the significant risk factors were: occupation (peasant), corn consumption (in the 1970s), family history of HCC, and history of an episode of acute hepatitis as an adult. HBV, consumption of aflatoxins, a genetic factor, and possibly a second hepatitis virus infection contribute to the risk of HCC. PMID- 8682611 TI - Hepatitis C virus as a causative agent of hepatocellular carcinoma. AB - HCV infection has shown to be strongly linked to the development of hepatocellular carcinoma in epidemiological studies. However, the mechanism of carcinogenesis by HCV is poorly understood. Unlike other human oncogenic viruses, HCV is a typical RNA virus, and thus there is no integration of the viral genome or a piece of the genome into host chromosomes. Moreover, trans-acting transcriptional factors which are coded by other human oncogenic viruses and required primarily for virus replication and often involved in cell immortalization, may not be coded by HCV. Although regeneration of hepatocytes in an HCV-infected liver may be of primary importance in driving hepatocytes to the malignant stage, an additional unknown carcinogenic function of HCV may also exist. For this reason, clarification of the molecular mechanism of virus replication in hepatocytes should be emphasized. PMID- 8682612 TI - Genomic instability involved in virus-related hepatocarcinogenesis. AB - In spite of the epidemiological link between the hepatitis C virus (HCV) infection and the incidence of hepatocellular carcinoma (HCC), there is currently no data to prove the direct oncogenicity of HCV. In this situation, we must consider not only the viral but also the nonviral factor which may accelerate hepatocarcinogenesis. Previously, we showed that a 60-bp subgenomic HBV DNA (15AB, nt 1555-1914 of HBV DNA) is a hot spot for the genomic recombination, and the cellular protein binding to 15AB may be the putative recombinogenic protein. In this paper, we show that the 15AB-like sequence exists in the human chromosomal DNA. The 15AB-binding proteins, candidates for the cellular recombinogenic protein, are now isolated and being characterized. We showed the possibility that, in HCV- as well as HBV-associated chronic active liver diseases, the recombinogenic proteins are expressed more abundantly than in the normal liver, and their functions are triggered by the binding to the recombinational hot spot in the chromosomal DNA. PMID- 8682613 TI - Human papillomavirus DNA in genital cancers, metastases, and lymph nodes. AB - To evaluate the utility of human papillomavirus (HPV) DNA as molecular marker for diagnostic screening of lymph nodes for cancer metastases, we examined 16 involved and 124 histologically cancer-free nodes of 34 patients with cervical, vulval, or vaginal carcinomas associated with HPV 6, 16, 18, 31, 33, 45, or X. All metastases of HPV-positive tumors contained viral DNA of the same type as the primary cancer but in one case the copy number of viral genomes was dramatically reduced. In a varying proportion of histologically normal nodes of 7 of 23 patients with HPV 16-positive cancers HPV 16 DNA was revealed by Southern blot hybridization and/or PCR. Histologic reevaluation showed a metastasis in one case. Three examples of tumor heterogeneity regarding physical state or copy number of viral DNA are presented. Tumor heterogeneity is discussed as possible explanation for apparently inconsistent results such as HPV-negative metastases of HPV-positive tumors. PMID- 8682614 TI - Transgenic models for papillomavirus-associated multistep carcinogenesis. AB - To investigate the physiological and pathological in vivo functions of molecularly cloned genes, the transgenic mouse is one of the most useful experimental animal systems. Many kinds of transgenic mice carrying papillomavirus genes have been produced, and the studies have revealed several new aspects in the field of papillomaviral oncology. Among these transgenic mice, the mechanism of skin carcinogenis in the bovine papillomavirus (BPV) transgenic mouse has been well characterized, demonstrating that numbers of genetic alterations in specific cellular genes were deeply involved in tumor progression as well as in the expression of transforming genes encoded by the viral genome. Comparable mechanisms were found in testicular tumorigenesis in the HPV 16 E6E7 transgenic mouse. Here we discuss the mechanism of testicular tumorigenesis in the HPV 16 E6E7 transgenic mouse together with that of skin carcinogenesis in the BPV transgenic mouse in order to clarify some part of papillomavirus-associated carcinogenesis. PMID- 8682615 TI - Occurrence of the antibody against human papillomavirus type 16 virion protein L2 in patients with cervical cancer and dysplasia. AB - Infection with HPV 16 is believed to be a major risk factor for cervical cancer. To correlate HPV 16 infection and carcinogenesis in the cervix, we examined by ELISA 326 sera from healthy females and patients with cervical cancer, cervical intraepithelial neoplasia, or dysplasia, for the presence of IgG antibodies against HPV 16 virion protein L2 expressed in Escherichia coli. Whereas 2 of 208 were positive in the healthy females, 4 of 23 and 6 of 90 were positive in the patients with cervical cancer and dysplasia, respectively. The findings indicate that infection with HPV 16 is related to cancer and dysplasia of the cervix. The anti-L2 antibody did not occur coincidentally with the antibodies against the HPV 16 early proteins E4 and E7, which are specifically but independently associated with patients with cervical cancer. PMID- 8682616 TI - Natural history of cervical human papillomavirus lesions. AB - A total of 87 HPV-positive patients with grade I and II cervical intraepithelial neoplasia (CIN I and II) were followed up by cytology and colposcopy every 3 months for more than 5 years following the first biopsy. These patients were classified into three groups (progressive, persistent, and regressive disease) according to the results. The human papillomavirus (HPV) genome and viral types were identified by Southern blot hybridization at Tm-40 degrees and Tm-20 degrees with DNA extracted from exfoliated cervical cells. The lesion progressed to CIN III in 4/87 patients (4.6%), persisted in 39 patients (44.8%), and regressed in 44 patients (50.6%). In the progressive disease group, HPV 16 was detected in 2 patients, HPV 33 in 1 patient, and HPV 52 in 1 patient. In the persistent disease group, HPV 58 was predominant (28%), whereas in the regressive disease group, there was no predominant HPV type. In 10/39 patients from the persistent disease group, cytological examination transiently revealed severe dysplasia and/or findings similar to carcinoma in situ. These patients showed severe cytological abnormalities only once or twice during the follow-up. These results suggest that the natural history of CIN possibly depends upon the type of HPV that infects the cervix, and the relative risk of progression was similar to that shown by previous cross-sectional studies. PMID- 8682617 TI - Novel hypotheses for the roles of EBNA-1 and BHRF1 in EBV-related cancers. AB - Epstein-Barr virus has been linked to several types of human cancer including Burkitt's lymphoma and nasopharyngeal carcinoma but the mechanisms by which the virus might contribute to cancer remain obscure. Here we consider the possibility that EBNA-1, which is expressed in both tumours, directly transactivates cell genes. The EBNA-1 protein was tested for transcription transactivation domains and the human genome was screened for high-affinity EBNA-1-binding sites that might mediate transactivation. None were found, although novel low-affinity binding sites in the EBV genome were detected. We also investigated the expression of BHRF1, the viral homologue to bcl-2, in epithelial cells and showed that it is expressed in vivo in the EBV replication found in oral hairy leukoplakia. A novel hypothesis is proposed for nasopharyngeal carcinoma in which BHRF1 expression protects cells against apoptotic death caused by environmental DNA damaging agents and thus contributes to the early stages of cancer development. PMID- 8682618 TI - Nitric oxide inhibits Epstein-Barr virus DNA replication and activation of latent EBV. AB - Nitric oxide (NO), a mediator of biological functions, has antimicrobial activity against a variety of pathogens including viruses. Effects of NO donors on EBV replication in two EBV lytic systems, Raji cells infected with P3HR-1 virus and P3HR-1 cells activated with TPA plus n-butyrate, were studied. S-nitroso-N acetylpenicillamine (SNAP), which generates NO when placed in an aqueous solution, and 3-morpholinosydnonimine (SIN-1), which liberates NO and O2-, resulting in the formation of peroxynitrite, were used as NO donors. Immunoprecipitation analysis showed that in superinfected Raji cells, SNAP inhibited EBV late protein synthesis but not EBV early protein expression. Analysis of the structure of EBV DNA termini demonstrated that SNAP suppressed the amplification of EBV DNA in superinfected Raji cells at a dose which did not affect synthesis of EBV early proteins required for EBV DNA replication. In TPA plus n-butyrate-treated P3HR-1 cells, SNAP inhibited synthesis of both early and late proteins of EBV. Northern blot analysis of RNA expressed in TPA plus n butyrate-treated P3HR-1 cells demonstrated that expression of EBV immediate-early mRNAs coded from BZLF1 and BRLF1 genes was inhibited by SNAP. SIN-1 showed no or little effect on EBV replication in both cell systems. Cell viability and cellular protein synthesis were not affected by either NO donor under the conditions used. These findings suggest that NO prevents EBV replication by inhibiting EBV DNA amplification during the lytic phase of the life cycle as well as by blocking activation of the latent EBV genome. The mechanism for inhibiting of EBV replication by NO was discussed in relation to the role of NO in EBV latency in vivo. PMID- 8682619 TI - Pathogenic role of Epstein-Barr virus in human cancer. AB - Epstein-Barr virus (EBV) is detected in several human cancers, such as Burkitt's lymphoma (BL), nasopharyngeal carcinoma, gastric cancer, and peripheral T-cell lymphoma. However, the role of EBV in the development of these cancers is still controversial. During cultivation of the EBV-positive BL line Akata, we found that EBV DNA is lost from some of the cells. Isolation of EBV-positive and negative cell clones with the same origin made it possible to examine the effects of EBV in BL cells. The results indicate that malignant phenotypes of BL, such as the growth in low serum, anchorage-independent growth, and tumorigenicity in nude mice, are dependent on the presence of EBV genomes and underline the oncogenic function of EBV in human cancer. PMID- 8682620 TI - c-Jun, c-Fos and their family members activate the transcription mediated by three 21-bp repetitive sequences in the HTLV-I long terminal repeat. AB - Transcription of human T-cell leukemia virus type I is regulated by a viral transactivatior Tax, through the 21-bp sequence in the long terminal repeat (LTR). We found that cellular transcription factor AP-1 (c-Jun/c-Fos heterocomplex) bound to the 21-bp sequence. The binding affinity of the complex increased in proportion to the number of the 21-bp sequence, and the transcriptional activation by AP-1 became evident only when the reporters had more than three 21-bp sequences. Thus, AP-1 may play a role in the viral transcription from the LTR with three 21-bp sequences in the absence of Tax, such as in the early stage of the virus infection. PMID- 8682621 TI - Chronic progressive myeloneuropathy in WKAH rats induced by HTLV-I infection as an animal model for HAM/TSP in humans. AB - We immortalized rat T cells with helper-inducer phenotype, by HTLV-I superinfection. These immortalized cells had integrated human T-cell lymphotropic virus (HTLV)-I provirus genomes and showed nuclear polymorphism resembling adult T-cell leukemia cells. Among HTLV-I carrier rats of several strains, only WKAH strain rats developed a chronic progressive myeloneuropathy with spastic paraparesis of the hind limbs (HAM rat disease), after a long incubation period. Clinical and neuropathological features of HAM rat disease generally mimic those of HAM/TSP in humans, although T-cell infiltration is absent in the affected spinal cord lesions in the case of HAM rat disease. The collective evidence suggests that the major pathogenetic pathway of HAM rat disease appears to be closely related to apoptotic death of myelin-forming cells, oligodendrocytes and Schwann cells. Putative factors involved in apoptosis of these cells are discussed in relation to HTLV-I infection. PMID- 8682622 TI - Epidemiological features of HTLV-I and adult T cell leukemia. AB - Adult T-cell leukemia (ATL) patients and human T-cell leukemia virus type I (HTLV I) carriers are clustered in limited groups in the world, especially among Japanese in Asia, Blacks in Central Africa, Melanesians in Papua New Guinea and Andeans in South America. The major transmission routes of HTLV-I under natural conditions are from mother-to-child through breast milk and from man-to-woman through semen. The whole life risk of ATL among persistent HTLV-I carriers is estimated at 2-6%. The detailed manifestation mechanism of ATL is not yet clarified; however, it is certain that HTLV-I infection in infancy is the main cause of ATL. Therefore, the prevention measure against mother-to-child transmission of HTLV-I is indispensable from a viewpoint of public health. PMID- 8682623 TI - New treatments for multiple sclerosis. PMID- 8682624 TI - Current issues in the management of breast cancer. PMID- 8682625 TI - Hormonal treatment of prostate cancer. PMID- 8682626 TI - New sign to confirm the presence of groin hernia in infants and small children. PMID- 8682627 TI - Clinical dilemmas in the management of minimal and mild endometriosis. PMID- 8682628 TI - Vogt Koyanagi Harada (VKH) syndrome. PMID- 8682629 TI - Education prior to the 1970s: a sad indictment of Irish society. PMID- 8682630 TI - The management of partial seizures. PMID- 8682632 TI - Immediate and follow-up results of coronary angioplasty--lessons for the future. AB - In a series of 129 patients having coronary angioplasties in St. James's Hospital in 1989, the average age was 54.8 (30-77 years). There were 102 (79%) men and 27 (21%) females. Clinical indications were unstable angina 62, stable angina 26, post myocardial infarction 39 and asymptomatic ischaemia 2. The distribution of coronary disease was single vessel 62%, double vessel 28%, triple vessel 7% and previous coronary bypass surgery 3%. Only 10 patients had more than one vessel dilated. Primary success was achieved in 119 (92%), there were no deaths, 3 patients had abrupt closure of the vessel during angioplasty and sustained a nonfatal myocardial infarction, 1 patient required urgent bypass surgery and 2 patients had peripheral vascular complications requiring surgery. There were 6 failed angioplasties, 4 of which had chronic total occlusion. At a mean follow-up of 5.3 months, 85 patients had no symptoms, 34 had angina, 2 developed myocardial infarction and 1 died suddenly at 5 months. Repeat angiography was performed in 96 (79%) patients. At follow-up, no symptoms were present in 69% of those with single vessel disease and 70% of multivessel disease. Of those who had more than one vessel dilated in multivessel disease, 80% were asymptomatic (P = NS). There were 11 patients with initial total occlusion at presentation, 4 had failed angioplasties, 5 recurrent angina of which 4 reoccluded and 1 restenosed and only 2 were asymptomatic and without restenosis. Angioplasty was performed with primary success (92%) and follow up results (70% asymptomatic). Those with single or multivessel disease had similar clinical outcome, favouring the use of target vessel angioplasty. Long term results following angioplasty of chronic total occlusions were poor and suggests the need for additional treatment. PMID- 8682631 TI - Babies born before arrival at the Coombe Women's Hospital, Dublin. AB - We report a study of all births occurring before arrival at the Coombe hospital from 1988-91 inclusive. Of the 27,554 babies weighing 500g or more, 106 (0.4%) were Born Before Arrival (BBA). BBA was associated was an increased perinatal mortality (p < 0.01) compared with hospital-born infants. Prematurity was the main contributing factor to the increased mortality. Analysis also revealed two distinct groups. The first was 14 women who had neither booked nor attended for antenatal care. Ten of these 14 were first time mothers, 13 were unmarried and 7 were under 21 [corrected] years of age. It is disturbing that in the 1990's young single expectant mothers fail to register for antenatal care. The second group was made up of 92 women booked for antenatal care: only 4 of these 92 were first time mothers. Many of the multiparous women had a history of prelabour spontaneous rupture of the membranes but delayed coming into hospital. Improved antenatal education could potentially reduce the incidence of BBA and its adverse consequences. PMID- 8682634 TI - Storage and handling of vaccines by family doctors. AB - The aim of this study is to see if vaccine storage and handling procedures used by family doctors in a health board region maintain vaccines at maximum potency. All 144 family doctors in the region were invited to be part of the study. Doctors were interviewed in their practice premises about procedures used in dealing with vaccines. Following the interview, practice fridges were examined and temperature recorded. Samples of oral polio were taken from 20 randomly selected fridges for potency testing. Cold chain monitors and freeze watch indicators were used to monitor batches of vaccine stored. Of the 144 doctors, 142 (98.6%) agreed to participate. Of these, 140 used 111 fridges to store vaccine, 2 doctors store vaccine at room temperature. Of the 111 fridges, 6 (5.4%) had the power supply safeguarded, 9 (8.1%) had thermometers, and 36 (32.4%) had vaccine only stored therein. During defrosting, the vaccine in 22 (19.8%) of the fridges was not adequately protected. Of the 138 doctors who use multi-dose vaccine vials, 133 (97.2%) keep them for further use at the end of a day/session, of whom 3 store them at room temperature. The temperature recorded in 42 (37.8%) fridges was outside the recommended range. Thirteen (28.2%) cold chain monitors indicated vaccine exposed to more than 10 degrees C. Eighteen (90%) of the oral polio samples showed a reduction in total titre of live virus, however, none were below the minimum acceptable. This study indicates that vaccine potency could be seriously compromised due to breaks in the cold-chain and suggests the need for guidelines to be drawn up, implemented and monitored to ensure the integrity of immunisation schemes. PMID- 8682633 TI - Human Mycobacterium bovis infection in the south-west of Ireland 1983-1992: a comparison with M. tuberculosis. AB - Epidemiological and bacteriological aspects of human Mycobacterium bovis disease were investigated in south-west Ireland (counties Cork & Kerry, population 536,000) over the years 1983-92 inclusive and compared to M. tuberculosis. Results showed a small, stable incidence of culture positive M. bovis human disease, mean annual incidence 0.56 per 100,000 population compared to a higher but declining incidence of culture positive M. tuberculosis (15.3 per 100,000 in 1983, 9.0 per 100,000 in 1992). Male patients were the majority, 63.4 per cent of M. bovis; 62.4% of M. tuberculosis (p = 0.03). Fifty three per cent of M. bovis cases (n = 30) were pulmonary, compared to 85% of M. tuberculosis (n = 626; p = 0.0001). M. bovis patients were older (p = 0.02), mean age 58.4 years (SD 18.9) compared to 48.5 (SD 22.2). The mycobacterial smear positive rate was similar in both groups taken as a whole. No rural-urban difference in incidence was found in either disease, suggesting in the case of M. bovis initial infection in childhood via contaminated milk in the pre-pasteurisation era. PMID- 8682635 TI - Patient's evaluation and recall of the preoperative anaesthetic visit. AB - We have looked at the ability of 104 patients to recall their preoperative anaesthetic visit. 26.9% of those seen could not remember ever being assessed by an anaesthetist. We think this has important medical, medico legal and manpower implications which need to be addressed. PMID- 8682636 TI - Koro-like syndrome associated with brief reactive psychosis in an Irish male. AB - Koro is a psychiatric syndrome rare outside certain areas of South East Asia. Most cases described outside of this area are associated with other primary psychiatric syndromes. In this case a primary Koro like syndrome precipitated a brief reactive psychosis in a 32 year old single Irish male. PMID- 8682637 TI - Meningococcal infection. PMID- 8682638 TI - Frontiers of atherosclerosis and lipoprotein research. Special issue in memory of Professor Shlomo Eisenberg. PMID- 8682639 TI - Triglycerides and coronary risk. PMID- 8682640 TI - Lipid lowering and coronary risk. AB - Clinical trials have provided increasing evidence of the value of lipid lowering in preventing clinical coronary events. With the advent of more potent lipid regulating agents, a greater degree of cholesterol lowering--particularly of cholesterol carried in low density lipoproteins--is now possible. Trials monitored by angiography or ultrasound have demonstrated slowed progression and even regression of atherosclerotic lesions in subjects in whom lipid lowering was accomplished by diet and other lifestyle modifications, drugs, and/or partial ileal bypass surgery, but the changes measured in the vessel lumen or wall are often modest compared with the reduction in clinical events, suggesting that clinical benefit may be derived from mechanisms other than the absolute decrease in lesion size. Possible mechanisms include lesion stabilization, improved endothelial function, increased vascular reactivity, and decreased inflammatory response. The identification of risk factors besides elevated blood cholesterol level, such as lipoprotein oxidation, blood triglyceride level and insulin resistance, may provide additional targets for intervention. PMID- 8682641 TI - Coronary heart disease prevention and the infarctogenic plaque. AB - The characteristics of a subset of atherosclerotic plaques that is responsible for myocardial infarction (infarctogenic plaques) are increasingly well defined. They include moderate size, a thin fibrous cap, and a large lipid pool. Fissuring of the cap leads to thrombotic occlusion and often to an acute coronary event. Physical stresses on, and proteolytic weakening of, the cap--both related to effects of hyperlipidemia on the plaque--increase the risk of fissuring. Treatment of hyperlipidemia leads to regression of experimental atherosclerosis, promotes regression and reduces progression of human coronary artery disease. The arterial changes in humans are predictive of reduced incidence of coronary events. This sequence of events may reflect gradual depletion of plaque lipids, and also a more rapid depletion of chronic inflammatory cells in the plaque cap that are the source of collagenase and other proteases. The primary objective of lipid-lowering therapy appears to be the induction of these changes in infarctogenic plaques, and vigorous treatment should be targeted on patients likely to harbor such plaques. PMID- 8682642 TI - Hemostatic variables in the prediction of coronary risk: results of the 8 year follow-up of healthy men in the Munster Heart Study (PROCAM). Prospective Cardiovascular Munster Study. AB - Myocardial infarction is usually due to the acute formation of an occlusive thrombus within the coronary arteries, in most cases against a background of pre existing coronary atherosclerosis. Both of these factors may be promoted by a procoagulant state of the hemostatic system. Plasma fibrinogen, factor VIIc, blood pressure, and lipid parameters were measured in 2,781 healthy men aged 40 65 in the Munster Heart Study (formerly known as the PROCAM Study). After 8 years of follow-up 130 coronary events (15 sudden cardiac deaths, 22 fatal myocardial infarctions, and 93 nonfatal myocardial infarctions) were observed. Plasma fibrinogen concentration and factor VIIc activity were significantly greater among men who suffered a coronary event. The mean plasma fibrinogen level of the event group exceeded that of the non-event group by 0.32 g/l [2.59 +/- 0.58 vs. 2.91 +/- 0.58 (mean +/- SD) respectively, P < 0.001]. The incidence of coronary events among men within the upper tertile of fibrinogen concentration was three times higher than among men within the lower tertile. Plasma factor VIIc activity was 112.4 +/- 20.1% in the event group and 108.7 +/- 21.4% in the non-event group (P < 0.05). Among men in the upper tertile of factor VIIc activity, the incidence of coronary events was 1.6 times that of men in the lower tertile. When fibrinogen and low density lipoprotein (LDL) concentration were considered together, there was a graded and dramatic eightfold increase in 8 year risk from 17 per 1,000 of population among men with both fibrinogen and LDL cholesterol in the lower tertiles to 130 per 1,000 in men with both of these parameters in the upper tertile. In men with LDL cholesterol in the lowest tertile, increasing fibrinogen levels did not increase the risk of a coronary event. The coagulation variables, fibrinogen concentration, and factor VIIc activity thus markedly improve our ability to predict coronary risk. PMID- 8682643 TI - Lipoprotein metabolism in renal replacement therapy: a review. AB - Lipoprotein disorders are considered an important cause for the high cardiovascular morbidity and mortality in patients with end-stage renal disease and following renal transplantation. This article reviews the disease-associated changes of lipids and lipoproteins in these patients and, where known, the underlying causes and mechanisms. Further, we discuss the perturbed lipoprotein system in relation to the cardiovascular risk of patients on renal replacement therapy. Patients treated by hemodialysis are often hypertriglyceridemic with increased very low density lipoprotein (VLDL) levels and a type IV Frederickson pattern of hyperlipidemia. Total and LDL cholesterol concentrations are usually normal or subnormal. Treatment of end-stage renal disease by peritoneal dialysis results in increased total, VLDL and LDL cholesterol concentrations. Both treatment modalities are accompanied by a decrease of high density lipoprotein (HDL) cholesterol and apolipoprotein AI, whereas lipoprotein(a) [Lp(a)] concentrations are significantly elevated in both groups. Following renal transplantation a high incidence of hypercholesterolemia and hypertrigylceridemia is observed, which is attributed, at least in part, to the immunosuppressive therapy. Most patients normalize HDL cholesterol values and Lp(a) decreases to pre-disease plasma concentrations. Several studies have described elevated levels of cholesterol, triglycerides and Lp(a) in patients with cardiovascular complications during different phases of renal replacement therapy, which indicates a predictive (causative) role of these parameters for atherosclerotic diseases. PMID- 8682645 TI - Diabetic dyslipidemia: effects of diabetes control, diet and drug therapy. PMID- 8682644 TI - Hyperlipoproteinemia of aminonucleoside-induced nephrotic syndrome--modulation by glucocorticoids and triiodothyronine. AB - Triamcinolone or triiodothyronine (T3) was administered to rats with nephrosis induced by aminonucleoside of puromycin and to control nontreated rats. Triamcinolone produced hyperglycemia, hyperinsulinemia and liver glycogen deposition in control rats and to a lesser extent in nephrotic rats. Triamcinolone treatment did not affect plasma protein and albumin levels but increased the level of plasma triglycerides and cholesterol in the very low density lipoprotein (VLDL) and LDL but not high density lipoprotein fractions. The exacerbation of hyperlipoproteinemia was attributed both to increase hepatic lipid synthesis and delayed removal, since it was associated with the induction of hepatic acetyl-CoA carboxylase, the regulatory enzyme of lipogenesis, as well as with marked suppression of adipose tissue lipoprotein lipase (LPL). The hepatic lipase activity was found to be elevated in nephrotic rats but was suppressed by triamcinolone treatment, indicating a reduced capacity of VLDL to LDL conversion. T3 treatment resulted in serum glucose and insulin increases similar to triamcinolone, but more moderate in nephrotic vs. control rats, and in marked reduction in liver glycogen content. Plasma protein levels were not affected, but contrary to control rats, T3 treatment produced an elevation in serum triglycerides and cholesterol in nephrotic rats. The activity of several hepatic lipogenic enzymes, including acetyl-CoA carboxylase, was markedly elevated, as was the activity of gluconeogenic enzymes. Thus, the hyperlipoproteinemia on T3 treatment appeared to be mainly due to predomination of lipid synthesis over removal, since the activities of enzymes responsible for plasma lipid disposal, adipose tissue LPL and hepatic lipase were enhanced both in control and nephrotic rats. It is remarkable that both T3 and triamcinolone induce the lipogenic enzymes and apolipoproteins in the liver of nephrotic rats, already pronouncedly stimulated to replace the excreted plasma proteins. Thus, the nephrotic liver is able to respond to hormonal stimulation with further specific protein and lipid synthesis. It is also pertinent that the recovery from immunosuppressive treatment of human nephrosis, developing on an immune background, may result in more impressive amelioration of proteinuria and hypoproteinemia than of hyperlipoproteinemia because of the lipidemic effect of glucocorticoids. PMID- 8682646 TI - The H.E.L.P. system: an efficient and safe method for plasma therapy in the treatment of severe hypercholesterolemia. AB - The H.E.L.P. procedure (heparin-induced extracorporeal low density lipoprotein: fibrinogen precipitation) provides an efficient means of lowering high concentrations of low density lipoprotein (LDL) in severe hypercholesterolemia, with the additional effect of lowering lipoprotein(a) and fibrinogen, while high density lipoprotein levels are increased during long-term treatment. The H.E.L.P. treatment also significantly improves plasma viscosity, erythrocyte aggregation and erythrocyte filtration. Overall treatment tolerance is very good, and no major complications have been observed after approximately 70,000 single treatment sessions. Some patients are treated for more than 10 years. In combination with HMG-CoA reductase inhibitors, a mean interval value of -75% to 80% for LDL as compared to the starting concentration may be achieved. The treatment has the advantage that the patient is not exposed to foreign proteins or compounds, with their attendant immunological problems. It displays a high degree of reproducibility and a standardized capacity, guaranteeing a constant therapy independent of the clinic or institution performing the treatment. The clinical experience with the H.E.L.P. system has proved its clinical utility- there is a regression of coronary heart disease, a decrease in coronary heart disease events, and a remarkable improvement in acute as well as chronic impairment of microcirculation. For the future, the availability of this safe and efficient apheresis technique may provide help for many patients who previously could not be treated adequately. PMID- 8682648 TI - Synthesis and secretion of lipoprotein lipase in heparan sulfate-deficient Chinese hamster ovary cells. AB - Synthesis and secretion of lipoprotein lipase was studied in two mutants of Chinese hamster ovary (CHO) cells which, due to a lack of xylosyl transferase (pgsA-745) or galactosyl transferase (pgsB-761), respectively, were deficient in heparan sulfate and chondroitin sulfate. One of the mutants (pgsB-761) was two- to threefold more active in synthesis and secretion of catalytically active lipoprotein lipase than the other mutant, which was about as active as the wild type (K1) cells. A similar relation was found when lipoprotein lipase was metabolically labelled with 35S-methionine and then immunoprecipitated. Heparin stimulated secretion from all three cell types to a similar extent (about twofold). Heparin-releasable binding of 125I-labelled lipoprotein lipase was lower to either of the mutant cells than to the wild-type cells. Binding to the wild-type cells was reduced by heparitinase, while the low binding to the mutants was not affected. By immunogold labelling of cryosections, lipoprotein lipase was detected on the plasma membranes and on the inside of secretory vesicles of both wild-type and mutant cells, suggesting that some carrier could be involved. Inhibition of vesicular transport by monensin caused accumulation of lipoprotein lipase in the cells. In wild-type cells the lipase was mainly on the inside of vesicular structures, while in the mutants the main part was associated with membranous bodies that formed within the vesicles during a chase period. These results suggest that if lipoprotein lipase needs a carrier during intracellular assembly and transport, this function can be fulfilled by some structure other than heparan sulfate. PMID- 8682647 TI - Heparan sulfate proteoglycan/low density lipoprotein receptor-related protein pathway involved in type III hyperlipoproteinemia and Alzheimer's disease. AB - The heparan sulfate proteoglycan (HSPG)/low density lipoprotein (LDL) receptor related protein (LRP) pathway plays a critical role in apolipoprotein (apo) E containing lipoprotein metabolism in hepatocytes and other cells, including neurons. In this review, it will be shown that the HSPG sequestration step (i.e., the recruitment and trapping of remnant lipoproteins in the space of Disse in the liver) is an important component of remnant metabolism mediated by apo-E. In vitro studies indicate that the apo-E-containing lipoproteins must first interact with HSPG; only then does the LRP mediate lipoprotein uptake. The differential interaction of apo-EIII and the various mutant forms of apo-E with this pathway before internalization appears to be one factor that modulates the expression of recessive versus dominant type III hyperlipoproteinemia. Furthermore, it is now apparent that the HSPG/LRP pathway is involved in the delivery of apo-E to neurons, where apo-E alters neurite growth and cytoskeletal activity in these cells. Specifically, apo-EIV, which has been associated with the pathogenesis of Alzheimer's disease, inhibits neurite extension and microtubule formation subsequent to the interaction of apo-EIV with the HSPG/LRP pathway. PMID- 8682649 TI - Cellular metabolism of apoprotein-B containing lipoproteins: the role of apoproteins, heparan sulfate and cellular receptors. PMID- 8682650 TI - Heparan sulfate-dependent and low density lipoprotein receptor-related protein dependent catabolic pathways for lipoprotein lipase in mouse embryonic fibroblasts. AB - Heparan sulfate and low density lipoprotein receptor related protein (LRP) have been shown to participate in the uptake and degradation of the enzyme lipoprotein lipase (LPL). Yet, the contribution of each of these pathways to LPL metabolism and their possible dependence is unknown. In the present study we examined the metabolism of 125I-labeled LPL in untreated and heparinase-treated primary wild type mouse embryonic fibroblasts (MEF) and in mouse fibroblasts that express single LRP allele (PEA-10) or are lacking the LRP (PEA-13). The degradation of LPL in PEA-13 cells was 30% lower than in MEF and PEA-10 cells. Heparinase treatment decreased the LPL degradation by 58%, 79% and 92%, whereas heparin reduced such degradation by 87%, 90% and 94% in MEF, PEA-10 and PEA-13 cultures, respectively. Assuming that a) heparinase treatment abolished the heparan-sulfate pathway, and that b) the degradation remaining in heparin-treated cultures represents nonspecific values, it appears that heparan sulfate contributes about 61%, 83% and 95% of total LPL degradation, whereas the LRP pathway contributes 39%, 17% and less than 5% of LPL degradation in MEF, PEA-10 and PEA-13 cells, respectively. In addition, the data indicate that LPL interaction with heparan sulfate and the LRP pathways is independent of each other. The study shows that these cells possess both a heparan sulfate-dependent pathway and an LRP-dependent pathway for LPL metabolism and that the two pathways are independent of each other. PMID- 8682651 TI - Diurnal heterogeneity in structure and function of low density lipoproteins of normolipidemic males. AB - Structural changes in low density lipoproteins (LDL) have been shown to alter their metabolism and atherogenic potential. We investigated the diurnal changes in size and composition of LDL in seven healthy, non-obese, normolipidemic male volunteers consuming a standard diet (14.5% protein, 31.9% fat, 53.6% carbohydrate and 383 mg cholesterol/day) and continuing their daily routine. The food was divided into three meals and three snacks, and blood samples were obtained at 7 AM (after 12 h fasting), noon, 8 PM, midnight and 3 AM. LDL were isolated by both sequential and density gradient ultracentrifugation (d = 1.019 - 1.050 g/ml), and analyzed for lipids, apolipoproteins, size, and affinity to LDL receptors. Diurnal LDL preparations differ from fasting LDL in both chemical and physical parameters. The former get richer in triglyceride (TG/cholesterol weight ratio 0.23 vs. 0.16), larger in diameter (21.2 +/- 0.2 vs. 22.4 +/- 0.1 nm), and enriched in a more buoyant fraction (74.0 +/- 4.6 vs. 41.9 +/- 3.8% of LDL cholesterol in d = 1.019 - 1.035 g/ml). These structural changes in LDL were associated with enhanced affinity to LDL receptors in both human skin fibroblasts and HepG2 cells, as demonstrated by competition experiments with fasting human 125I-LDL. The observed diurnal heterogeneity in both the structure and the function of LDL may be attributed to the absorptive state as it did not occur during prolonged fasting. These diurnal changes may be important for better understanding LDL metabolism in vivo and for the elucidation of the atherogenic process. PMID- 8682652 TI - Small dense low density lipoprotein: formation and potential mechanisms for atherogenicity. PMID- 8682653 TI - Oxidized low density lipoprotein--an extreme example of lipoprotein heterogeneity. AB - The intense interest in the possibility that oxidative modification of low density lipoprotein (LDL) plays an important role in atherogenesis has led to an explosion in the number of papers dealing one way or another with "oxidized LDL". A great deal has been learned about the biological properties of "oxidized LDL", the complex chemical processes accompanying oxidation and its pathogenetic role in experimental animal models. Yet the term itself--"oxidized LDL"--is woefully inadequate. In this short essay to honor the memory of my friend and colleague, Shlomo Eisenberg, I will attempt to indicate the questions that need to be asked; I do not provide the answers. PMID- 8682654 TI - Effect of dietary supplementation of beta-carotene on human monocyte-macrophage mediated oxidation of low density lipoprotein. AB - Oxidative modification of low density lipoprotein (LDL), a key step in early atherosclerosis, is protected by the lipoprotein-associated antioxidants. The present study analyzes the effect of beta-carotene in plasma, in LDL and in monocyte-macrophages, on macrophage-mediated oxidation of LDL. We investigated the effect of dietary supplementation of beta-carotene on plasma lipid peroxidation [induced by AAPH (2,2-Azobis-2-amidinopropane hydrochloride)] and on cell-free and cell-mediated oxidation of LDL by human monocyte-derived macrophages (HMDM) in the presence of CuSO4. Significant enrichment with beta carotene was noted in plasma (twofold), in LDL (2.6-fold) and in HMDM (1.6-fold) 2 weeks after dietary supplementation with 180 mg/day of beta-carotene. Plasma lipid peroxidation analyzed by conjugated dienes generation decreased by 22% (P < 0.01) and LDL susceptibility to oxidation analyzed by malondialdehyde generation decreased by 40% (P < 0.01). After beta-carotene supplementation, beta-carotene enrichment of HMDM capacity to oxidize native LDL, whereas beta-carotene enrichment of LDL significantly reduced LDL oxidation. In conclusion, then, our results suggest that beta-carotene content of LDL, but not that of the macrophages, is responsible for the inhibition of oxidation of LDL. PMID- 8682655 TI - Macrophage activation with phorbol myristate acetate is associated with cellular lipid peroxidation. AB - The present study analyzed the association between two major processes that occur during atherogenesis: macrophage activation and peroxidation of the cellular lipids. Macrophage activation was achieved by cell incubation with phorbol myristate acetate (PMA) for 24 h at 37 degrees C, and was determined as: a) PMA concentration-dependent increment in the release of beta-glucuronidase, b) decrement in the procoagulant activity, and c) increment in the release of superoxides from the cells. PMA-induced macrophage activation was accompanied by cellular lipid peroxidation, as measured by increased formation of lipid peroxides (by 435%), thiobarbituric acid-reactive substances (TBARS) (by 26%), and conjugated dienes (by 77%) in comparison with control nonactivated cells. The maximal effect of PMA on lipid peroxidation in macrophages was achieved within 1 h of cell incubation with PMA. This effect was demonstrated in J-774 A.1 macrophages, as well as in mouse peritoneal, macrophages, U-937 and P-338 macrophage cell lines. Upon incubation of macrophages with 4 alpha phorbol 12, 13 didecanoate, an analogue of PMA (which, unlike PMA, does not activate protein kinase C), macrophage lipid peroxidation was lower compared with PMA, suggesting a role for protein kinase C in cellular lipid peroxidation. Analysis of cellular antioxidants under PMA-induced macrophage activation revealed a decrease of 50% in total glutathione, and in catalase levels following treatment with 100 nM PMA compared with control cells. In summary, our study demonstrates that PMA activated macrophages undergo significant lipid peroxidation, which is associated with reduced activity of the cellular antioxidative system. PMID- 8682656 TI - High density lipoprotein and heart disease: induced mutant mouse studies. PMID- 8682657 TI - Effects of hypolipidemic drugs on the expression of genes involved in high density lipoprotein metabolism in the rat. AB - Since plasma high density lipoprotein (HDL) concentrations are inversely related to the development of atherosclerosis, induction of HDL after pharmacological treatment is considered of benefit. To study whether currently used hypolipidemic drugs affect HDL metabolism by modulating the expression of genes involved in HDL metabolism, liver and intestinal apolipoprotein (apo) AI, apo-AII and apo-AIV gene expression was evaluated in rats treated with different classes of hypolipidemic drugs, and correlated to the changes in plasma lipid and apolipoprotein concentrations. In rats, the most pronounced hypolipidemic effects were observed after treatment with the fibrates clofibrate and fenofibrate, which lowered plasma lipid, apo-AI and apo-AIV concentrations. This decrease was accompanied by lowered liver apo-AI, apo-AII and apo-AIV mRNA levels. None of the other compounds tested affected plasma cholesterol, whereas probucol and simvastatin decreased plasma triglyceride concentrations. Apo-AI and apo-AII mRNA remained constant after nicotinic acid and probucol, whereas liver apo-AIV mRNA levels decreased. Cholestyramine increased hepatic apo-AI and apo-AII, but not apo-AIV mRNA levels. Simvastatin treatment increased apo-AI mRNA nearly threefold, whereas apo-AII and apo-AIV decreased by more than 50%. Similarly as after cholestyramine, the alteration in hepatic apo-AI mRNA levels did not result in changed plasma apo-AI concentrations. Remarkably, none of the drugs tested significantly affected intestinal apolipoprotein mRNA levels. These results indicate that hypolipidemic drugs may act on plasma lipoprotein metabolism by regulating apolipoprotein gene expression. Further studies in humans and primates are therefore warranted. PMID- 8682658 TI - Apolipoprotein-AI-containing particles and atherosclerosis. PMID- 8682659 TI - Anti-atherogenicity of high density lipoprotein. PMID- 8682661 TI - Israel Heart Society annual scientific meeting. Tel Aviv, Israel, 29-30 April 1996. Abstracts. PMID- 8682660 TI - On health and obesity in Talmudic and Midrashic lore. PMID- 8682662 TI - Managed care and psychiatric-mental health nursing services: implications for practice. AB - Our current health care system is in a period of major change. To help control rising costs and improve management, health care reforms have been proposed, prompting the rapid development of managed care. The impact of managed care on the psychiatric-mental health system has become quite evident over the past few years with a resultant restriction of services, closing of inpatient units, and shift from inpatient to outpatient care. These cost control measures raise serious concerns regarding the quality and availability of necessary services. Managed care could have a devastating effect on the progress made in mental health treatment over the last 40 years if these issues are not addressed and remedied. The issue of how managed care influences mental health services is addressed, and implications for practice are presented. PMID- 8682663 TI - Ethics and mental health service delivery under managed care. AB - The delivery of mental health services under managed care takes on different dimensions affecting the ethical considerations of providers and patients. In this article, we explore five key issues that are especially relevant to the psychiatric population: conflict of interest, confidentiality, patients' rights, underserved patients and allocation, and levels of ethical analysis. Implications for nursing are also discussed. PMID- 8682664 TI - An organizational and economic framework for restructuring psychiatric nurse labor use. AB - A conceptual framework of psychiatric nurse labor use is developed based on organizational and economic theories. The relationship between staffing decisions and quality of care is presented. Implications for restructuring the workforce within the context of managed care and increased cost containment pressures are discussed. The importance of using a conceptual framework to guide staffing evaluations, research, and management decisions is emphasized. PMID- 8682665 TI - Testing innovative nursing care: home intervention with depressed rural women. AB - Major depressive disorder (MDD) is common among women and especially so among the disadvantaged. Despite this, nurses' roles in the treatment of MDD have been described only recently and have received little systematic evaluation. Testing of nursing efficacy in treating MDD is critical because nurses predominate among professionals in health care institutions typically accessed by women. In this article, I describe a research demonstration project to test a short-term nursing intervention for disadvantaged depressed rural women. The Women's Affective Illness Treatment (WAIT) Program has been implemented to eliminate depressive morbidity and develop specific self-care and prevention skills. Impoverished, premenopausal rural women with MDD participate in one of two experimental approaches. Several outcome and treatment effectiveness variables are monitored pre- and posttreatment for a period of 12 months. PMID- 8682666 TI - Establishing linkages in a changing mental health practice environment. AB - Mental health care reform in Washington State has resulted in redistribution of funded mental health services for acutely and chronically mentally ill individuals into regional care delivery systems. Collaboration between service providers in an Inpatient Program and providers of mental health services in a five-country regional community mental health system has established communication linkages that are critical to ensure continuity of care during health care reform. The role of the Inpatient Program in the establishment of linkages with community providers is described. PMID- 8682667 TI - Practical outcome evaluation: patient behavioral health care demonstration project. AB - A cost-effective outcome evaluation project for inpatient psychiatric units was designed and implemented for use in a busy clinical setting. The project consisted of (a) a behavioral health care management team that was committed to developing program evaluation, (b) use of direct care clinical staff, (c) computerized data management, and (d) feedback to clinical staff and administrators. The outcome evaluation project demonstrated that clinical databases and direct care staff can be used to implement a continuous quality loop that has the potential to improve patient care and to increase available data for marketing and program planning decisions. PMID- 8682668 TI - Maintenance of effects in the nonmedical treatment of headaches during pregnancy. AB - In a previous study, 30 pregnant women suffering from headaches were treated with physical therapy, relaxation training, and biofeedback. Eighty percent of these women experienced significant relief of headaches following treatment. Although this study demonstrated the effectiveness of nonmedical treatment during pregnancy, little is known about the influence of changing hormones during pregnancy on fluctuations in headache. One purpose of this study was to present a follow-up of the women who were included in the previous study to determine whether the results from the nonmedical treatment were maintained up to a year after giving birth. In addition, this study examined the influence of headache diagnosis and breastfeeding on changes in headache activity and maintenance of treatment effects. The results indicate that the reductions in headache activity were maintained at follow-up in the majority of the women treated, with 67.5% of the sample maintaining a significant decrease in headache up to 1 year after giving birth. Neither IHS diagnosis nor breastfeeding was related to maintenance of headache improvement. We conclude that the beneficial effects of nonpharmacological treatment of headaches during pregnancy demonstrated in a previous study are maintained up to 1 year following delivery. Headache diagnosis and breastfeeding were not related to treatment outcome, a finding that contradicts the reports of many retrospective studies. PMID- 8682669 TI - Early and transient side effects of repetitive intravenous dihydroergotamine. AB - Side effects associated with administration of repetitive intravenous dihydroergotamine (DHE) were prospectively studied in 72 patients with chronic daily headache who were hospitalized in a dedicated inpatient headache treatment program. All patients received 11 consecutive doses of DHE, starting with 0.25 mg and increasing by 0.25 mg up to a maximum dose of 1.25 mg, depending on side effects and/or headache relief. The adverse events were recorded after each dose administered. The great majority of patients (91.6%) reported at least one side effect. The most common were: nausea (72.2%), increase in previous headache (47.2%), lightheadedness (33.3%), "new" headache (27.8%), and leg cramps (23.6%). The overall number of side effect complaints did not increase proportionally with the strength of the dose of DHE administered. These complaints declined from the earlier to the later doses of DHE, except for leg cramps, which were more common with the later doses. Side effects determined the strength of subsequent doses of DHE in only 18.1% of patients. Only four patients had to have a decrease in dosage and none required termination of DHE due to side effects. Although repetitive intravenous DHE causes frequent side effects, they are usually mild and transient and decrease with subsequent doses, even at higher doses. PMID- 8682670 TI - Specificity of IHS criteria in childhood headache. AB - We prospectively assessed the relative specificity of the International Headache Society (IHS) criteria in 30 children referred to a pediatric neurologist. An important cause of headache, including raised intracranial pressure with slit ventricle syndrome, would have been missed in 4 children if one had relied on IHS criteria alone. Specific revisions have been proposed to minimize misclassification and further enhance the relevance of the IHS document for children. PMID- 8682671 TI - Self-report of cognition and objective test performance in posttraumatic headache. AB - The Cognitive Difficulties Scale, a self-report measure of cognitive functioning, was administered to 111 consecutive adult referrals with posttraumatic head pain subsequent to mild to moderate head and/or cervical flexion-extension injuries who were treated at a clinic specializing in head pain and neurological disorders. Factor analysis of the Cognitive Difficulties Scale yielded seven meaningful factors corresponding to the types of memory inefficiencies often associated with neurological dysfunction. Further analyses comparing the Cognitive Difficulties Scale factor scores to objective tests of mental status, memory, and depressed mood demonstrated limited relationships between specific Cognitive Difficulties Scale factor scores and these measures of cognitive performance and behavior. The Cognitive Difficulties Scale appears helpful in assisting this patient population with treatment planning and specific remediation tied to everyday situations. PMID- 8682673 TI - Putative neuroimmunological mechanisms in cluster headache. An integrated hypothesis. AB - During the last decade, numerous studies have been carried out to explore the function of the immune system in cluster headache and the release of reciprocal informational molecules from pain-sensitive structures. These neuroimmunological findings in cluster headache syndrome, although carefully considered, have varied from genetic aspects (HLA antigens) to functional activity of the immune system (NK cytotoxicity), and from study of the receptor expression of classical neurotransmitters of pain (5-HT, histamine) on immunocompetent cells, to the study of cytokines with a potent pro-inflammatory activity (interleukin-1). Other aspects considered have ranged from the study of the effectiveness of substances possessing a wellknown activity on the immune system (prednisone, lithium carbonate) in shortening cluster attacks to the 5-HT receptor expression changes observed on a peripheral substrate (monocytes) after the administration of sumatriptan. Although this was an exciting area of pioneering research, we have always interpreted our findings cautiously. In summary, we now believe that the neuroimmunological aspects of cluster headache can be proposed as an integrative model and that this immunological mechanism could improve our understanding of the pathogenic basis for this still obscure disease. PMID- 8682672 TI - Nitric oxide, endothelin-1, and transcranial Doppler in migraine. Findings in interictal conditions and during migraine attack. AB - The role of vascular phenomena taking place during an attack of migraine are poorly understood. The aim of this study was to measure systemic levels of nitric oxide and endothelin-1, two of the most potent vasoactive mediators known, and to assess vasomotor responses through transcranial Doppler ultrasound monitoring in patients suffering from migraine without aura, both during the headache event and in headache-free periods as well as after pharmacologically induced pain relief. Seven patients (mean age 31.3 years, range 24 to 49 years), five women and two men, were enrolled in the pilot study. Transcranial Doppler recordings were performed according to conventional procedure. Endothelin-1 concentrations were measured by means of radioimmunoassay, whereas nitric oxide levels were estimated using electron paramagnetic resonance spectroscopy. Ultrasound evaluation did not show significant changes during migraine attacks compared to the interictal condition. Nitric oxide levels showed only slight differences between basal and attack conditions (0.85 +/- 0.46 versus 1.56 +/- 0.88, expressed as arbitrary units), and were raised after pharmacological intervention (2.91 +/- 1.93, P < 0.05). Plasma endothelin-1 concentrations decreased during migraine attacks with respect to interictal conditions (3.99 +/- 1.21 pg/mL versus 4.23 +/- 1.19), and returned to basal values (4.44 +/- 1.08 pg/mL) after relief of pain. Coupling the measurements of systemic levels of nitric oxide and endothelin-1 with transcranial Doppler velocity results will provide useful information on the hemodynamic changes of cerebral blood flow regulation in migraineurs, thereby adding new insights into the mechanisms of the migraine attack. PMID- 8682674 TI - The epidemiology of migraine in medical students. AB - The purpose of this study was to investigate the prevalence of migraine in medical students, as well as its clinical aspects and impact. All 595 medical students of Santa Casa School of Medicine of Sao Paulo, Brazil were asked if they had experienced any kind of headache in the past year. Those who responded positively were further investigated by an appropriate questionnaire. Diagnosis of migraine was based on the International Headache Society criteria of 1988. Forty percent of students suffered from some kind of headache; 40.2% of these headaches were migraine. The prevalence of migraine was 54.4% in women and 28.3% in men. Migraine headaches were unilateral in 24.2%, had a gradual onset in 69%, and were of a throbbing type in 88.3%. Migraine was considered incapacitating by 53.9% of students. Migraine with aura caused more disability than migraine without aura. Women experienced more intense migraine than men, and migraine with aura was especially more severe than migraine without aura. Photophobia, phonophobia, and nausea were more commonly encountered in migraine with aura. Despite the high prevalence, the high rate of disability, and the need for analgesic medication, only 7.1% of students with migraine had sought medical treatment. PMID- 8682675 TI - Migraine with aura: segregation analysis and heritability estimation. AB - A genetic study was performed in a group of 60 migraine patients and their first degree relatives as well as in a group of sex- and age-matched controls. Segregation analysis showed that multifactorial inheritance seems to be the most probable mode of genetic transmission. Heritabilities were estimated according to the sex of probands and relatives. Our findings favor multifactorial inheritance, but the contribution of a major gene can not be excluded. PMID- 8682676 TI - Cerebrovascular reactivity measured by transcranial Doppler in migraine. AB - Changes in the diameter of intracranial arteries might have a major role in the pathophysiology of migraine. Though several studies have found alterations in velocity of blood flow and in cerebral vasomotor reactivity of intracranial arteries in migraineurs in headache-free periods, as well as during migraine attacks, the results are inconclusive. To determine if intracranial hemodynamic characteristics of patients with migraine differ from those of controls, we measured baseline velocity of blood flow by transcranial Doppler in the middle cerebral arteries in headache-free periods in 51 migraine patients and in 101 age matched controls. Cerebrovascular reactivity was measured after intravenous administration of acetazolamide in 12 migrainous patients and in 19 controls. Baseline mean velocity was significantly higher in the migraine group (70 versus 65 and 72 versus 65 cm/s with P = 0.02 and P = 0.0007 on the left and right sides, respectively). The difference stayed significant during acetazolamide stimulation, but the course of response did not differ between controls and migraineurs. Despite statistical significance, absolute differences were small. Therefore, middle cerebral artery velocity measurements and the acetazolamide test are not useful for the diagnosis of migraine in the interictal period. PMID- 8682677 TI - Vasospasm-induced myocardial infarction with sumatriptan. AB - Sumatriptan, a 5-hydroxytryptamine1, (5-HT1) receptor agonist is an effective abortive agent for migraine headaches. A common side effect in 3% to 7.9% of patients is chest pain. Although most cases of chest pain are not thought to be of cardiac origin, its mechanism is not entirely understood. Rare examples of electrocardiogram changes consistent with transient ischemia have been reported. Isolated instances of angina, arrhythmia, myocardial infarction, and death have been temporally associated with sumatriptan administration. In most cases, it is unclear whether underlying cardiovascular disease existed or contributed to this adverse event. We report the history of a 56-year-old female patient with migraine who experienced a myocardial infarction shortly after using sumatriptan, despite having had a normal cardiovascular evaluation. As she had a normal cardiac catheterization after the event, we find it probable that sumatriptan induced coronary vasospasm and myocardial infarction. PMID- 8682678 TI - Migraine and angina pectoris by coronary artery spasm. AB - A migrainous patient who experienced chest pain attributed to angina pectoris by coronary artery spasm during a migraine attack is reported. Previous reports have already mentioned the association of these two conditions and suggested that it might be the manifestation of a generalized vasospastic disorder. This new report offers an opportunity to review and discuss the available data on such an association. PMID- 8682680 TI - 41st annual meeting of the Health Physics Society. Seattle, Washington, 21-25 July 1996. Abstracts. PMID- 8682679 TI - Migraine headache following stellate ganglion block for reflex sympathetic dystrophy. AB - The alteration of extracranial blood flow in conjunction with clinical signs of autonomic nervous system dysfunction have led to various explanations concerning the pathophysiology of migraine headache. Reflex sympathetic dystrophy, a painful disorder of the sympathetic nervous system, can be treated by blocking the sympathetic nerves located in the stellate ganglion, resulting in vasodilation, ptosis, miosis, and anhydrosis. In theory, these changes could trigger a migraine headache attack secondary to autonomic dysfunction reflecting an imbalance between sympathetic and parasympathetic nervous systems. This may be especially true in a patient with a previous history of meningitis that may have resulted in a disorder of cerebrovascular regulation. We report a 56-year-old man with no previous history of migraine who developed migraine with aura after a stellate ganglion block. These episodic headaches occurred with decreasing frequency and severity for over 6 months, with eventual complete resolution. This interesting phenomenon has not been reported in the English literature and may help to better understand the pathophysiology of migraine. PMID- 8682681 TI - Frequency, manifestations, and correlates of impaired healing of saphenous vein harvest incisions. AB - OBJECTIVE: To describe the frequency, manifestations, and correlates of impaired healing of saphenous vein (SV) harvest incisions in hospitalized patients who had undergone coronary artery bypass grafting (CABG). DESIGN: Prospective, descriptive, correlational. SETTING: West Coast university-affiliated medical center. PATIENTS: Thirty-two English-speaking adults who had undergone CABG. OUTCOME MEASURES: Impaired wound healing of SV-harvest incisions. RESULTS: The overall incidence of impaired healing was 43.8%. The most frequent manifestations of impaired wound healing at discharge were prolonged erythema (8/32), prolonged drainage (8/32), and both prolonged erythema and drainage (2/32). Correlates of impaired healing of SV-harvest incisions were body mass index (product-moment correlation = 0.39, p = 0.026) and preoperative use of diuretics (point biserial correlation = 0.42, p = 0.016). CONCLUSIONS: Impaired healing of SV-harvest incisions in this sample occurred more frequently than previously indicated in the literature. Although severe wound infections were infrequent, a high degree of impaired healing occurred (43.8% of patients who had undergone CABG). Future studies need to explore the long-term effects of impaired healing and test interventions to mitigate impaired healing in this population. PMID- 8682682 TI - Effects of modified positioning and mobilization of back pain and delayed bleeding in patients who had received heparin and undergone angiography: a pilot study. AB - OBJECTIVE: To examine the effects that a modified positioning and mobilization routine had no back pain and delayed bleeding in patients who had received heparin and undergone cardiac angiography. DESIGN: An experimental research design was used. Each patient was assigned randomly to either the control group, which required 6 hours of bed rest after cardiac angiography, or the experimental group. The experimental group had modified positioning, in which the head of the bed was elevated to a maximum of 45 degrees, and modified mobilization, in which they were ambulated briefly at the bedside 4 hours after angiography. SETTING: Two cardiology units of a 700-bed urban teaching hospital in western Canada. SAMPLE: All patients admitted for nonemergent cardiac angiography were approached for consent, to attain a sample of 29 patients, and were randomly assigned to the experimental or the control group. METHOD: Each patient was randomly assigned before cardiac angiography. The assignment was confidential until the patient was admitted to the cardiac unit after angiography. A demographic tool and the McGill Present Pain Intensity Scale were used to collect data. Perception of pain was evaluated over four observation periods. A research assistant monitored sanguineous drainage on the dressing and hematoma to evaluate the presence of delayed bleeding. DATA ANALYSIS: Demographic information was analyzed primarily through descriptive statistics. Results were analyzed to compare back pain and delayed bleeding between the two groups. Wilcoxon scores and t tests both were used for analysis and correlated well with each other. RESULTS: The group with the modified positioning and mobilization routine experienced significantly less pain overall (p = 0.02), less pain at each interval, and significantly less pain intensity (p < 0.05). There was no difference in bleeding. One person in each group had an estimated blood loss of more than 100 ml through the pressure dressing. CONCLUSION: This pilot study supports our hypothesis that modifying the immobilization of patients after cardiac angiography is associated with a reduction in back pain and with no increase of delayed bleeding at the femoral access site. The results support the need for further investigation of ambulation interventions after cardiac angiography. PMID- 8682683 TI - The pathogenesis of septic shock. AB - A new age of treating patients with septic shock is rapidly approaching. A multidrug approach will likely be used to interrupt the systemic inflammatory response to infection, with use of new immune and inflammatory modulating therapies. In this article are reviewed the advances made in understanding the cellular events that cause septic shock. Critical care nurses need to update themselves on this new information to provide optimal care that patients with septic shock demand. Symptoms of septic shock, its hemodynamic characteristics, and the actions of principal inflammatory mediators that cause vasodilation and capillary leak are discussed. PMID- 8682684 TI - Acetaminophen-induced hypotension. AB - Through 30 years of widespread use, acetaminophen has been shown to be a remarkably safe medication in therapeutic dosages. The potential for acetaminophen to produce cardiovascular toxicities is very low. However, acetaminophen has been demonstrated to produce symptoms of anaphylaxis, including hypotension, in sensitive individuals. This article describes two critically ill patients in whom transient episodes of hypotension reproducibly developed after administration of acetaminophen. Other symptoms of allergic reactions were not clinically detectable. The hypotensive episodes were severe enough to require vasopressor administration. The reports illustrate the need for clinicians to consider acetaminophen in patients with hypotension of unknown origin. PMID- 8682685 TI - Socialization of new graduate nurses in critical care. AB - OBJECTIVE: To examine the modified contingency theory of role socialization with new graduate nurses in critical care. DESIGN: Descriptive comparative. SETTING: Six midwestern hospitals with 12 types of critical care units. SAMPLE: Fifty new graduate nurses and 89 experienced registered nurses in critical care. OUTCOME MEASUREMENTS: The socialization variables of precepting, support systems, assignment congruence, role conception, self-confidence, affective responses, commitment, job satisfaction, confronting reality, mutual influence, resolution of outside life conflicts, and resolution of conflicting demands at work were measured. New graduates responded to questionnaires about socialization at 1 to 2 weeks, 3 months, and 6 months of employment. Experienced nurses completed a questionnaire about socialization once, simultaneously with the 1- to 2-week data collection for new graduates. RESULTS: At initial employment new graduates differed from experienced nurses in role conception, self-confidence, and commitment to profession. After 6 months of employment new graduates differed from experienced nurses in self-confidence and mutual influence. For new graduates, positive precepting experiences, support systems, and assignment congruence were related to high self-confidence, low anxiety, high commitment, high job satisfaction, and low role conflict and ambiguity. These variables were also associated with the development of role conception. CONCLUSIONS: The study results lend considerable support to the modified contingency theory of role socialization. Positive precepting experiences, support systems, and assignment congruence contributed to successful socialization for the new graduates in this study. PMID- 8682686 TI - Heliox inhalation in status asthmaticus and respiratory acidemia: a brief report. AB - A 28-year-old woman in status asthmaticus and respiratory acidemia refused orotracheal intubation and mechanical ventilation in the emergency department. In view of this situation, a mixture of helium-oxygen gas (heliox) was initiated with a nonrebreathing oxygen mask. Within 2 hours of treatment, the patient's respiratory acidemia had been corrected, and heliox inhalation therapy was discontinued without further incident. PMID- 8682687 TI - Submandibular tissue obstruction of tracheostomy tube: reversal with "chin sling". AB - We report on a 55-year-old woman with a tracheostomy who had unexplained respiratory failure from acute nocturnal shortness of death. During the second day of admission, the patient noticed that her "second chin" folded over the tracheostomy on neck flexion, occluding her artificial way. The patient jury rigged a strap to retain the submental tissue from occluding the opening of the tracheostomy tube. She was subsequently free from obstructive symptoms with good oxygen saturation even with neck flexion. She was consequently discharged with a presumptive diagnosis of acute upper airway obstruction. We believe that this unusual complication of the tracheostomy tube may be more common than appreciated. Accordingly, patients with a tracheostomy should be evaluated through a full range of body and neck positions. Increases in body fat and tissue relaxation should be suspected as possible causes occlusion of tracheostomy tubes. The application of a "chin sling" can reverse this unusual upper airway obstruction until definitive correction by surgical lipectomy is performed. PMID- 8682688 TI - Effect of intravascular surveillance and education program on rates of nosocomial bloodstream infections. AB - BACKGROUND: Because of high proportions of central line-related bloodstream infections (BSIs), an intravascular surveillance and education program (IVSP) was instituted in the study institution in 1987. METHODS: A 6 1/2-year historical prospective study was conducted to evaluate the effects of the IVSP on incidence of nosocomial BSIs. With use of Centers for Disease Control and Prevention criteria, concurrent data on nosocomial BSIs were collected by two infection control professionals before, during, and for 3 years after the IVSP. RESULTS: Hospital-wide BSIs during the 3-year IVSP and for 3 years after were 0.9% and 0.9% (p = 0.58) or 1.4 and 1.2/1000 patient-days (p = 0.24). Central line-related BSIs represented 29%, 24%, and 29% of the total BSIs 6 months before, 3 years during, and 6 months after the intervention, respectively (p = 0.62). CONCLUSIONS: The IVSP resulted neither in a reduction in the total intravascular catheter-related BSIs nor in a change in the proportion of potentially preventable central line-related BSIs. To be successful, an intervention must include the authority to mandate practice changes; education and feedback without such authority were inadequate. PMID- 8682689 TI - Streptococcus bovis endocarditis and vertebral osteomyelitis. AB - Streptococcus bovis recovered from blood cultures may represent bacteremia alone, bacteremia from an extravascular source, or endocarditis. Patients with S. bovis endocarditis frequently have a gastrointestinal focus. S. bovis has been associated with many gastrointestinal diseases and in particular with colon carcinoma. S. bovis endocarditis may be complicated by embolic events or osteomyelitis. Vertebral osteomyelitis is a rare complication of S. bovis endocarditis. We report the third known case of S. bovis endocarditis with vertebral osteomyelitis. PMID- 8682690 TI - Dobutamine stress echocardiography: a new, noninvasive method for detecting ischemic heart disease. AB - Pharmacologic induction of exercise with dobutamine hydrochloride, coupled with the technology of echocardiography, is an alternate method for evaluating ischemic heart disease. Dobutamine stress echocardiography involves obtaining echocardiographic images before, during, and after a titrated dobutamine infusion is administered. The study is positive if global or regional ventricular wall motion abnormalities develop. With our changing health care environment, this cost-effective, noninvasive diagnostic procedure is becoming a standard for determining the presence of coronary artery disease in those individuals who are unable or unwilling to undergo exercise stress testing. PMID- 8682691 TI - Anxiety and depression after acute myocardial infarction. AB - OBJECTIVES: To assess the following: (1) symptoms of anxiety and depression in hospitalized patients who had acute myocardial infarction (AMI); (2) the association between sex, infarct severity, history of previous AMI, and symptoms of anxiety and depression in hospitalized patients; (3) symptoms of anxiety and depression during the first year after AMI in a select group of patients; and (4) the association between educational and occupational status and symptoms of anxiety and depression at the time of hospitalization in a select group of patients. DESIGN: Cross-sectional survey (objectives 1 and 2) and prospective trial with random assignment (objectives 3 and 4). SETTING: Six university affiliated hospitals in a Canadian city. PATIENTS: Seven hundred eighty-five hospitalized patients with AMI, with 1-year follow-up of 201 selected patients from this sample. INSTRUMENTS: State-Trait Anxiety Inventory and the short form of the Beck Depression Inventory. INTERVENTION: Data collection was initiated in the hospital 3 days after AMI, and patients were followed-up 14, 24, 41, and 56 weeks after AMI. RESULTS: Student t tests, analysis of variance, and descriptive statistics were used. When the patients were in the hospital the mean state (S anxiety) and trait (T-anxiety) scores were 43 and 44, respectively. Ten percent had S-anxiety scores and 14% had T-anxiety scores that were higher than the mean scores reported for psychiatric patients. During the 1-year follow-up in the select group of subjects, the mean S-anxiety and T-anxiety scores were both 48 in hospital, and decreased to 42 and 46, respectively, by 14 weeks and remained at these levels for the remainder of the year. During the course of the year, 16% of the patients had State-Trait Anxiety Inventory scores consistent with psychiatric conditions. The in-hospital Beck Depression Inventory mean score was 3, and 9% of the patients had scores consistent with moderate to severe depression. During the first 24 weeks, symptoms of moderate to severe depression were reported by 10% of the select group of patients. No associations were found between anxiety and depression and sex, creatine phosphokinase level, previous AMI, education, or occupational status. CONCLUSIONS: Symptoms of anxiety were prevalent among hospitalized patients who had an AMI, whereas depressive symptoms were rare. There was no association between anxiety and depression and sex, infarct severity, history of previous AMI, or educational or occupational status. PMID- 8682693 TI - Behaviour of the transposable elements copia and mdg1 in hybrids between the sibling species Drosophila melanogaster and D. simulans. AB - The behaviour of the retrotransposons copia and mdg1 was analysed in hybrids between Drosophila melanogaster and D. simulans. Females of a highly inbred line of D. melanogaster were crossed with D. simulans males from three natural populations. The insertion site profiles for the two elements were determined in F1 hybrid larvae by in situ hybridization to polytene chromosomes, and were compared with that of their parents. No somatic transposition events were detected after this genomic stress of interspecific hybridization for the two transposable elements concerned. PMID- 8682692 TI - Genetics of larval urea tolerance in Drosophila melanogaster. AB - The genetic control of larval tolerance to urea, a nitrogenous waste-product occurring naturally in crowded Drosophila cultures, was investigated in a set of five laboratory populations of D. melanogaster that had been successfully subjected to selection for increased larval urea tolerance. Larva to adult survivorship and development time at three different levels of urea were assayed on the five selected populations, their five matched controls and a set of 10 F1 hybrid populations derived from reciprocal crosses between pairs of selected and control populations. As expected from the results of previous studies, the selected populations exhibited greater larval tolerance to the toxic effects of urea, relative to their controls. Comparison of the hybrid and parental populations with respect to both survivorship and development time indicated that the genetic control of urea tolerance in the selected populations is largely dominant, and has a significant X-linked component. The data also suggested that females from the selected populations exercise a nongenetic maternal effect on the development time of their progeny, regardless of urea level. PMID- 8682694 TI - The relationship between structural variation and dysgenic properties of P elements in long-established P-transformed lines of Drosophila simulans. AB - Ten lines of Drosophila simulans were investigated with respect to P activity, P susceptibility and the number and structure of their P copies, eight years after transformation with the P element. All 10 were found to have reached a steady state. They exhibited varying levels of P activity (from 0 per cent to 96 per cent GD sterility) and, with the exception of one line, were not P-susceptible. In contrast with P element behaviour in D. melanogaster: (i) no relationship was found between the molecular pattern of P copies in a line and its ability to induce or to repress P expression in D. simulans; (ii) peculiar P element derivatives were observed in this species; (iii) the average number of P copies per genome was only half of that in D. melanogaster. This may result from transposon-host genome interactions, which lead to a low invading power of the P element in D. simulans. PMID- 8682695 TI - Nasopharyngeal conidiobolomycosis in a horse. AB - Nasopharyngeal conidiobolomycosis caused by Conidiobolus coronatus was diagnosed in a horse after endoscopic and histopathologic examinations of a biopsy specimen. The fungal lesions in the nasopharynx were substantially reduced in size after intralesional injection of amphotericin B through the biopsy channel of a videoendoscope in combination with i.v. administration of sodium iodide and oral administration of potassium iodide during a 2-month period. Endoscopy performed 15 months after initial examination revealed regression of the granulomatous masses in the nasopharynx and complete disappearance of the nasal masses. Two months later, clinical signs recurred, and the owner elected euthanasia without evaluation and treatment. Nasopharyngeal conidiobolomycosis may be treated successfully with intralesional injection of amphotericin B in combination with administration of sodium iodide and potassium iodide, but there is a possibility of recrudescence of infection. PMID- 8682696 TI - Comparison of tilmicosin with long-acting oxytetracycline for treatment of respiratory tract disease in calves. AB - OBJECTIVE: To compare the effect of a single parenteral injection of tilmicosin with that of a single dose of a long-acting oxytetracycline as treatment in the early stages of naturally acquired undifferentiated respiratory tract disease in young dairy calves. DESIGN: Prospective clinical trial, randomized block design. ANIMALS: 40 dairy calves. PROCEDURES: 78 calves from 5 farms were examined weekly until 3 months old. When respiratory tract disease was diagnosed by a veterinarian, the calf was assigned to 1 or 2 treatment groups. Transtracheal wash samples were acquired to characterize the pathogens. The veterinarian, who was unaware of treatment assignments, examined calves for 3 days after treatment and evaluated severity, using a scoring system. Growth rates were measured. RESULTS: On the basis of response to initial treatment, relapse rates, and effect on growth rates, the antibiotics were determined to be equally effective. Severity of clinical disease was significantly (P < 0.03) less for the tilmicosin treated calves on days 2 and 3 after treatment. Findings from analysis of transtracheal wash samples indicated Pasteurella multocida (25/40), P haemolytica (4/40), Haemophilus somnus (4/40), Actinomyces pyogenes (3/40), and Aspergillus sp (2/40). Mycoplasma was isolated in association with bacterial isolates in 22 calves. CLINICAL IMPLICATIONS: Tilmicosin and oxytetracycline are effective in treatment of respiratory tract disease in young calves, even when Mycoplasma spp are involved. Tilmicosin is more effective in resolving clinical signs. Early treatment of dairy calves with respiratory tract disease may decrease detrimental effects on growth. PMID- 8682697 TI - Comparison of passive immunoglobulin transfer to dairy calves fed colostrum or commercially available colostral-supplement products. PMID- 8682698 TI - Laparoscopic surgical approach and anatomy of the abdomen in llamas. AB - OBJECTIVE: To describe 3 laparoscopic approaches for, and the normal laparoscopic anatomy of, the abdomen in adult llamas and to evaluate the effects of laparoscopy in those llamas. DESIGN: Prospective clinical trial. ANIMALS: Six adult castrated male llamas. PROCEDURE: After induction of general anesthesia, 3 surgical approaches to the abdomen were performed: left paralumbar, ventral midline, and right paralumbar. The abdomen was systematically examined, and anatomic features described. After recovery from anesthesia, all llamas were examined daily for 10 days and CBC was repeated 24, 72, and 120 hours after laparoscopy. RESULTS: Laparoscopy was successfully performed in all llamas by use of the ventral midline and right paralumbar approaches. The laparoscope was inadvertently placed into the left retroperitoneal space in 1 of the 6 llamas when the left paralumbar approach was used. Also, hemorrhage into the abdomen limited the view from the left side in another llama. Various approaches allowed viewing of the first and third forestomach compartments, liver, spleen, kidneys, small intestine, ileum, proximal loop of the ascending colon, spiral colon, and urinary bladder. Postoperative findings included subcutaneous emphysema and edema. Mean WBC count peaked 24 hours after surgery (mean, 23,500 cells/microliter). Generally, neutrophil count increased and lymphocyte count decreased during the 120 hours after surgery. CLINICAL IMPLICATIONS: Laparoscopy may be used for differentiation of medical and surgical lesions in the abdomen of llamas. The site for laparoscopy should be chosen on the basis of the most likely site of the suspected lesion. PMID- 8682699 TI - Visna-like disease in a ram with chronic demyelinating encephalomyelitis. PMID- 8682700 TI - More thoughts on animal rights and animal liberation. PMID- 8682701 TI - More thoughts on animal rights and animal liberation. PMID- 8682702 TI - More thoughts on animal rights and animal liberation. PMID- 8682703 TI - More thoughts on animal rights and animal liberation. PMID- 8682704 TI - What is your diagnosis? Accumulation of a large volume of a uniformly anechoic fluid within the left vaginal tunic. PMID- 8682706 TI - Disaster medicine--the veterinarian's role. PMID- 8682705 TI - What is your neurologic diagnosis? Intervertebral disk protrusion at C5-6. PMID- 8682707 TI - Modified distraction-stabilization technique using an interbody polymethyl methacrylate plug in dogs with caudal cervical spondylomyelopathy. AB - A modified technique for distraction-stabilization that used an interbody polymethyl methacrylate plug was performed in 22 dogs with confirmed caudal cervical spondylomyelopathy. Myelographically, all compressive lesions were dynamic and predominantly located ventral to the spinal cord. Nineteen of 21 (90%) dogs for which success/failure could be determined had a successful outcome, and 11 of 22 (50%) dogs attained normal neurologic status. The 2 cases that were considered failures involved dogs that were nonambulatory tetraparetic prior to surgery and failed to improve to a functional status. Complications were self-limiting and included ventral displacement of the cement without loss of distraction in 1 dog and diskosponsylitis at an adjacent disk space in another dog. Evidence of fusion of the affected vertebrae, in the distracted position, was radiographically evident in all dogs. Use of the interbody polymethyl methacrylate plug appears to be a viable surgical treatment of caudal cervical spondylomyelopathy in dogs. PMID- 8682708 TI - Hypoglycemia associated with intra-abdominal leiomyoma and leiomyosarcoma in six dogs. AB - Intra-abdominal leiomyoma or leiomyosarcoma was diagnosed in 6 dogs that had hypoglycemia (resting blood glucose concentration < 50 mg/dl). Tumors were large (12 to 24 cm) and arose from intra-abdominal structures including the jejunum, pylorus, duodenum, stomach, and liver. Four dogs had a leiomyoma, and 2 dogs had a leiomyosarcoma. In those dogs in which the tumor was successfully removed at surgery, blood glucose concentration returned to the reference range after tumor resection. Four dogs lived for at least 12 months after tumor resection, without redeveloping hypoglycemia. PMID- 8682709 TI - Surgical management of a large colorectal diverticulum in a dog. PMID- 8682710 TI - Supraventricular tachycardia in four young dogs. AB - Rapid, clinical supraventricular tachycardia (SVT), without apparent underlying heart disease, was identified in 3 young Labrador Retrievers and 1 Labrador Retriever-type dog. The electrocardiographic characteristics, identification of ventricular preexcitation in 2 dogs, age at onset, response to antiarrhythmic agents, and recent electrophysiologic documentation of a concealed accessory pathway in another young Labrador Retriever suggested orthodromic atrioventricular reciprocating tachycardia as the mechanism of SVT. PMID- 8682711 TI - Use of a modified toggle pin for repair of coxofemoral luxation in dogs with multiple orthopedic injuries: 14 cases (1986-1994). AB - OBJECTIVE: To develop modifications of the toggle pin procedure for use as a ligament of the head of the femur (LHF) prosthesis and to assess outcomes when used for coxofemoral luxation (CFL) in dogs with multiple orthopedic injuries. DESIGN: Retrospective case series. SAMPLE POPULATION: 14 dogs with CFL as a component of orthopedic polytrauma. PROCEDURE: Modifications to previous descriptions of the technique for use of a toggle pin for LHF prosthesis included deletion of the osteotomy of the greater trochanter in 12 of 16 joints with CFL, drilling of the femoral tunnel from a distal-to-proximal direction, deletion of a second femoral bone tunnel for suture placement, and use of a 2-hole polypropylene button to secure the LHF prosthetic suture. RESULTS: Mean age at time of injury, weight, and duration between injury and definitive surgery was 4.1 +/- 1.1 years, 19.7 +/- 2.8 kg, and 5.8 +/- 2.7 days, respectively. Weightbearing began 3.0 +/- 0.4 days after surgery. Mean postoperative follow-up period for dogs with maintained coxofemoral reduction of longer than 1 month (n = 13) was 19.5 +/- 6.1 months. Owners reported good or excellent clinical results, which were confirmed by semiquantitative assessment methods. Radiographic signs of degenerative joint disease were minimal. There was no significant difference between hind limbs when comparing mid-thigh limb circumference at the time of follow-up examination. CLINICAL IMPLICATIONS: A modified toggle pin procedure for LHF prosthesis can maintain coxofemoral reduction and allow early weightbearing in dogs with coxofemoral luxation as a component of multiple orthopedic injuries. PMID- 8682712 TI - Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979-1993). AB - OBJECTIVE: To evaluate clinical and laboratory findings in 225 dogs with naturally occurring hypoadrenocorticism diagnosed over a 14-year period. DESIGN: Retrospective case series. ANIMALS: 220 dogs with primary hypoadrenocorticism and 5 dogs with secondary hypoadrenocorticism (primary ACTH deficiency). PROCEDURE: We reviewed medical records of all dogs with naturally occurring hypoadrenocorticism examined at The Animal Medical Center between 1979 and 1993 or at Tufts University, Foster Hospital for Small Animals, between 1987 and 1993. RESULTS: Dogs ranged from 4 months to 14 years old. Most (71%) were female, and female dogs had a significantly higher relative risk of developing hypoadrenocorticism than did males. Great Danes, Portuguese Water Dogs, Rottweilers, Standard Poodles, West Highland White Terriers, and Wheaton Terriers had a significantly higher relative risk of developing hypoadrenocorticism than did dogs of other breeds. Common owner complaints included lethargy, poor appetite, and vomiting, whereas lethargy, weakness, and dehydration were common abnormalities detected on physical examination. Serum biochemical testing at the time of diagnosis revealed moderate-to-severe azotemia and hyperphosphatemia in most dogs. In 99 of 172 (57.6%) dogs that had a pretreatment urinalysis performed, urine specific gravity was < 1.030 even though dogs were azotemic. Serum electrolyte changes included hyperkalemia (n = 215), hyponatremia (183), hypochloremia (94), and hypercalcemia (69). Five of the 220 dogs with primary hypoadrenocorticism and the 5 dogs with secondary hypoadrenocorticism did not have hyperkalemia at time of diagnosis. In all dogs, ACTH stimulation testing revealed a low to low-normal baseline serum cortisol concentration with little to no rise after ACTH administration. Endogenous plasma ACTH concentration measured in 35 dogs with primary hypoadrenocorticism was markedly high; whereas ACTH concentration was undetectable to low in the 5 dogs with secondary hypoadrenocorticism. CLINICAL IMPLICATIONS: hypoadrenocorticism is a rare disease in dogs, most commonly affecting young to middle-aged females; some breeds are at greater risk of developing the disease than others. In general, clinical signs are nonspecific and similar to manifestations of more common diseases. Serum electrolyte disturbances of hyperkalemia and hypernatremia are characteristic in dogs with primary hypoadrenocorticism, but concentrations may be normal in dogs with early or mild primary or secondary hypoadrenocorticism. Diagnosis of hypoadrenocorticism is best confirmed by demonstration of a low baseline serum cortisol concentration with a subnormal or negligible response to ACTH administration. Determination of endogenous plasma ACTH concentrations is valuable in differentiating primary from secondary hypoadrenocorticism, particularly in dogs with normal serum electrolyte concentrations. PMID- 8682713 TI - Fatal musculoskeletal injuries incurred during racing and training in thoroughbreds. AB - OBJECTIVE: To characterize and contrast data from Thoroughbreds that incurred a fatal musculoskeletal injury (FMI; injury resulting in death or euthanasia) during racing or training and data from all California race entrants during a 9 month period in 1991. DESIGN: Case-control study. ANIMALS: Thoroughbreds that incurred a FMI during racing or training at a California race-meet and all California race entrants from January through June and October through December 1991. PROCEDURE: Age and sex were compared with chi 2 and Fisher's exact tests among horses fatally injured while racing and training. A log-linear model was fit to assess the relationship between race-meet and age and sex of California race entrants. Incidence risk of racing FMI was estimated per 1,000 race entrants, and the relationship between the occurrence of FMI during racing with race-meet, age, and sex was evaluated by logistic regression. RESULTS: Injury type and sex-specific age distributions differed among the horses fatally injured during racing and training. Age and sex distributions of the race entrants were not independent and varied among race-meets. Overall incidence risk of racing FMI was estimated at 1.7/1,000 race entrants. Risk of racing FMI in male horses was about twofold that in female horses, and in 4-year-olds was twofold that in 3 year-olds. CLINICAL IMPLICATIONS: Age and sex-related differences in risk of incurring a FMI during racing should be considered when comparing fatal injury rates among race-meets. PMID- 8682714 TI - Subcutaneous emphysema in a neonatal foal. AB - A 16-hour-old foal was examined because of subcutaneous emphysema, which began developing 3 hours after a routine delivery. Physical examination did not reveal soft-tissue or musculoskeletal trauma, and there were no skin injuries to explain the subcutaneous accumulation of air. Results of CBC and serum biochemical analysis were within reference limits, and findings on endoscopy of the pharyngeal area, trachea, and esophagus were within normal limits other than observation of dorsal pharyngeal compression. A pulmonary bulla, pneumomediastinum, and pneumothorax were detected on thoracic radiography. Because of the apparent association of the subcutaneous emphysema and thoracic abnormalities, a diagnosis of primary subcutaneous emphysema was made. A tracheostomy tube was placed to facilitate ventilation and to provide an exit point for the trapped air. Supportive care was provided. The foal's condition resolved over the subsequent 8 days. PMID- 8682715 TI - Epi-cochlioquinone A, a novel acyl-CoA : cholesterol acyltransferase inhibitor produced by Stachybotrys bisbyi. AB - A novel acyl-CoA : cholesterol acyltransferase (ACAT) inhibitor, designated epi cochlioquinone A has been isolated from the fermentation broth of Stachybotrys bisbyi SANK 17777. The molecular formula, physicochemical properties, NMR spectroscopic analysis and X-ray crystallographic analysis revealed that this compound was a stereoisomer of cochlioquinone A, which has been previously reported as a nematocidal agent. It inhibited ACAT activity in an enzyme assay using rat liver microsomes with an IC50 value of 1.7 microM. However, it showed about 10-fold less potent inhibitory effect on plasma lecithin cholesterol acyltransferase (LCAT) than on ACAT. In addition, it inhibited in vivo cholesterol absorption in rats by 50% at 75 mg/kg. PMID- 8682716 TI - Andrastins A-C, new protein farnesyltransferase inhibitors produced by Penicillium sp. FO-3929. I. Producing strain, fermentation, isolation, and biological activities. AB - New protein farnesyltransferase inhibitors, andrastins A-C, have been discovered in the cultured broth of Penicillium sp. FO-3929. Andrastins extracted from broth supernatant were purified by silica gel chromatography, ODS chromatography and HPLC. The IC50 of andrastins A, B, and C against protein farnesyltransferase were 24.9, 47.1, and 13.3 microM, respectively. PMID- 8682718 TI - Hydroxymycotrienins A and B, new ansamycin group antibiotics. AB - New ansamycins designated hydroxymycotrienins A and B were isolated from culture broths of Bacillus sp. BMJ958-62F4. The two antibiotics inhibited more strongly the growth of human cervical cancer cell lines of human papilloma virus (HPV) positive than that of HPV negative cell lines. The structures, some biological and biochemical properties are reported. PMID- 8682717 TI - Andrastins A-C, new protein farnesyltransferase inhibitors produced by Penicillium sp. FO-3929. II. Structure elucidation and biosynthesis. AB - The structures of new protein farnesyltransferase inhibitors, andrastins A-C, were elucidated. The cyclopentane ring of andrastins exhibited keto-enol tautomerism, which made the structure hard to elucidate. Therefore, the structure of andrastin A was elucidated by INADEQUATE and 13C-13C couplings using 13C labeled andrastin A. The absolute configuration of the p-bromobenzoyl derivative of andrastin A was elucidated by X-ray crystallographic analysis and its skeleton was shown to be ent-5 alpha,14 beta-androstane. The biosynthesis of andrastin A was also studied by the incorporation of 13C-labeled acetates. Though the andrastins had a common androstane skeleton, they were biosynthesized from a sesquiterpene and a tetraketide. PMID- 8682719 TI - New cineromycins and musacins obtained by metabolite pattern analysis of Streptomyces griseoviridis (FH-S 1832). I. Taxonomy, fermentation, isolation and biological activity. AB - Chemical screening using thin layer chromatography and various staining reagents offers the opportunity to visualize a nearly complete picture of a microbial secondary metabolite pattern (metabolic finger-print). This approach can be used advantageously for both, the detection of so-called "talented" strains, and for qualifying microbial strain collections, especially as a fundamental step of efficiently applied biological high-throughput assays. Based on their metabolic finger-print, microbial isolates can be classified in: (i) non-producing organisms, which gave no indication of the formation of secondary metabolites up to a defined detection limit, (ii) organisms of narrow productivity, which produce one or two secondary metabolites as main products with a restricted dependence to alteration of the culture conditions, and (iii) talented organisms, which are able to synthesize an array of structurally different secondary metabolites. As an example, the talented strain, Streptomyces griseoviridis (FH-S 1832), was studied in detail. Investigations in its taxonomical characterization, fermentation, as well as the isolation and purification procedures leading to 14 membered macrocyclic lactones of the cineromycin-type (cineromycin B and three new congeners) and to the musacins A to F are reported. Musacin C exhibits anthelminthic and weak antiviral activities. PMID- 8682720 TI - New cineromycins and musacins obtained by metabolite pattern analysis of Streptomyces griseoviridis (FH-S 1832). II. Structure elucidation. AB - A detailed analysis of the secondary metabolite pattern produced by Streptomyces griseoviridis (strain FH-S 1832) using a chemical screening method resulted in the detection, isolation and structure elucidation of new 14-membered lactones of the cineromycin B-type [dehydrocineromycin B (5), oxycineromycin B (7), and 2,3 dihydrocineromycin B (8)], as well as new gamma-lactones related to nigrosporalactone and 4,5-dihydroxy-octa-2,6-dienoic acid esters named musacins A to F (10, 13 approximately 15, 17, 18 and 21). The constitution of these metabolites were deduced from spectroscopic data as well as chemical transformations. The configuration of musacin D (10) was determined by derivatization with chiral acids (Helmchen's method). PMID- 8682721 TI - New metabolites with nematicidal and antimicrobial activities from the ascomycete Lachnum papyraceum (Karst.) Karst. VIII. Isolation, structure determination and biological activities of minor metabolites structurally related to mycorrhizin A. AB - Five new minor metabolites, papyracon D (6), 6-O-methylpapyracon B (9), 6-O methylpapyracon C (10), lachnumfuran A (11) and lachnumlactone A (12a), together with the known chloromycorrhizinol A (4), have been isolated from extracts of the culture fluids of the ascomycete Lachnum papyraceum. The compounds, which structures were determined by spectroscopic methods, are structurally related to the nematicidal and antibiotic mycorrhizin A (1), which also is produced by the fungus. The nematicidal, antibiotic and cytotoxic activities of the new compounds are weaker compared to those of mycorrhizin A (1). Papyracon D (6) possesses the highest antibiotic activities while lachnumlactone A (12a) is the most nematicidal and cytotoxic. PMID- 8682722 TI - Selective inhibition of IL-2 gene expression by trichostatin A, a potent inhibitor of mammalian histone deacetylase. AB - During screening for inhibitors of T cell activation, we have found that trichostatin A (TSA), known as a potent inhibitor of histone deacetylase, showed selective inhibitory activity against IL-2 gene expression. From luciferase reporter experiments on human leukemic Jurkat T cells, TSA was found to inhibit the expression of the luciferase reporter gene directed by the IL-2 enhancer and promoter with a 50% inhibitory concentration value of 0.073 microM. On the other hand, TSA, at the same concentration, enhanced the expression of the luciferase reporter gene directed by the c-fos enhancer and promoter. The result of RT-PCR experiments also indicates that TSA has selective inhibitory activity against IL 2 gene expression in Jurkat cells. These results suggest that the change in chromatin structure caused by the hyperacetylation of histone might affect the regulation of IL-2 and c-fos gene expression. PMID- 8682723 TI - Enzymatic 2'-N-acetylation of arbekacin and antibiotic activity of its product. AB - Aminoglycoside antibiotics (AGs) with a free 2'-amino group were subjected to enzymatic N-acetylation using a cell free extract that contained an aminoglycoside 2'-N-acetyltransferase, AAC (2'), derived from a kasugamycin producing strain of Streptomyces kasugaensis. TLC and antibiotic assay of the incubated reaction mixtures revealed that a modified compound retaining substantial antibiotic activity was formed from arbekacin (ABK), while modification of the other AGs resulted in the marked decrease in antibiotic activity. Structure determination following isolation from a large scale reaction mixture showed the modified ABK to be 2'-N-acetyl ABK. In addition, 2',6'-di-N acetyl ABK was formed as a minor product. The same conversion also occurred with dibekacin (DKB) resulting in the formation of 2'-N-acetyl DKB and 2',6'-di-N acetyl DKB. MIC determination showed antibacterial activity (1.56 approximately 3.13 micrograms/ml) of 2'-N-acetyl ABK against a variety of organisms. By contrast, 2'-N-acetyl DKB showed no substantial antibiotic activity. We believe 2'-N-acetyl ABK has the highest and broadest antibacterial activity, compared with known N-acetylated AGs. PMID- 8682725 TI - Synthesis and modification of a novel 1 beta-methyl carbapenem antibiotic, S 4661. AB - We describe an efficient method for introducing a sulfamoylamino group into the C 2' position of pyrrolidine using the Mitsunobu reaction. S-4661, its N-methyl analogues and stereoisomers were synthesized using this method and their structure-activity relationships were investigated. PMID- 8682724 TI - 3-Keto-11,12-carbazate derivatives of 6-O-methylerythromycin A synthesis and in vitro activity. AB - The 11,12-cyclic carbazate of 3-keto-6-O-methylerythromycin A (4) was prepared. This compound shows in vitro antibacterial activity comparable to erythromycin A (1) against erythromycin-susceptible organisms and increased activity against some erythromycin-resistant organisms. Using 4 as a lead, a series of analogues was prepared by acylation or alkylation of the carbazate nitrogen. Several of the N-alkylated derivatives showed dramatically improved antibacterial activity against both susceptible and resistant organisms as compared to erythromycin A. PMID- 8682726 TI - A new inhibitor of melanogenesis, albocycline K3, produced by Streptomyces sp. OH 3984. PMID- 8682727 TI - Isolation of novel saquayamycins as inhibitors of farnesyl-protein transferase. PMID- 8682729 TI - Synthesis and antibacterial activity of 6-deoxysporeamicin A. PMID- 8682728 TI - Screening of inhibitor of eukaryotic DNA polymerases produced by microorganisms. PMID- 8682730 TI - Synthesis and antibacterial activities of novel C(7)-catechol-substituted cephalosporins (I). PMID- 8682731 TI - Synthesis and antibacterial activities of novel C(7)-catechol-substituted cephalosporins (II). PMID- 8682732 TI - Fosfomycin monophosphate and fosfomycin diphosphate, two inactivated fosfomycin derivatives formed by gene products of fomA and fomB from a fosfomycin producing organism Streptomyces wedmorensis. PMID- 8682733 TI - A preliminary procedure for predicting the positive and negative effects of reinforcement-based procedures. AB - In the current investigation, a modification was made to the preference assessment described by Pace, Ivancic, Edwards, Iwata, and Page (1985) to predict the effects of stimuli when used in a differential-reinforcement-of-other behavior (DRO) schedule for 2 clients with severe self-injurious behavior (SIB) and profound mental retardation. Based on the results of the preference assessment, three types of stimuli were identified: (a) high-preference stimuli associated with high rates of SIB (HP/HS), (b) high-preference stimuli associated with relatively lower rates of SIB (HP/LS), and (c)low-preference stimuli associated with low rates of SIB (LP/LS). Consistent with the results of the preference assessment, the DRO schedule with HP/HS stimuli resulted in increased SIB, and the DRO schedule with LP/LS stimuli resulted in no change in SIB when used in a DRO schedule. Thus, the stimulus preference assessment may be useful clinically in some situations for predicting both the beneficial and the negative side effects of stimuli in DRO procedures. PMID- 8682734 TI - Responding maintained by intermittent reinforcement: implications for the use of extinction with problem behavior in clinical settings. AB - Results of basic research have demonstrated that behavior maintained on an intermittent schedule of reinforcement (INT) will be extinguished more slowly than behavior maintained on a continuous schedule (CRF). Although these findings suggest that problem behaviors may be difficult to treat with extinction if they have been maintained on INT rather than on CRF schedules, few applied studies have examined this phenomenon with human behavior in clinical settings. The purpose of this study was to determine whether problem behavior maintained on CRF schedules would be extinguished more rapidly than behavior maintained on INT schedules. Three individuals diagnosed with profound mental retardation participated after results of pretreatment functional analyses had identified the sources of reinforcement that were maintaining their self-injury, aggression, or disruption. Subjects were exposed to extinction following baseline conditions with CRF or INT schedules alternated within reversal or multielement designs. Results suggested that problem behavior may not be more difficult to treat with extinction if they have been maintained on INT rather than CRF schedules. However, switching from an INT to a CRF schedule prior to extinction may lower the baseline response rate as well as the total number of responses exhibited during extinction. PMID- 8682735 TI - Increasing self-determination: teaching people with mental retardation to evaluate residential options. AB - The community living preferences of 4 institutionalized adults with mild mental retardation were identified using photographs that depicted a variety of residential characteristics. Individuals then were taught to obtain information regarding their preferences during tours of community group homes, to report that information to their social workers, and to evaluate the homes based on the information obtained. A multiple baseline across participants design showed that all 4 participants substantially increased their skills at asking questions, reporting information, and evaluating homes. the results indicate that people with mental retardation can take an active role in major lifestyle decisions that others have typically made for them. PMID- 8682736 TI - A comparison of reinforcer assessment methods: the utility of verbal and pictorial choice procedures. AB - We compared three methods of stimulus preference assessment for verbal children and specifically evaluated the utility of a verbal choice procedure for assessing relative reinforcer value. Using a token system, relative preference for five categories of reinforcers, representing 15 different stimuli, was assessed by three methods: a reinforcer survey, a verbal stimulus-choice questionnaire, and a pictorial stimulus-choice procedure. Results showed that the verbal and pictorial stimulus-choice assessments accurately identified high- and low-preference categories for 3 of 4 participants. Survey results alone often rated multiple categories as high preference, were less likely to identify low-preference categories, and were less likely to correspond with the results of a reinforcer assessment. PMID- 8682737 TI - A methodology for distinguishing between extinction and punishment effects associated with response blocking. AB - We present one method for distinguishing between extinction and punishment effects. The proportion of responses that produced a consequence (blocking) was varied while hand mouthing was treated in a man diagnosed with profound mental retardation. Response patterns across the schedule changes suggested that the blocking procedure functioned as a punishing event. PMID- 8682738 TI - On the reinforcing effects of the content of verbal attention. AB - During a functional analysis, a boy with autism and oppositional defiant disorder displayed destructive behavior that was maintained by attention in the form of verbal reprimands (e.g., "Don't hit me"). In a second analysis, contingent verbal reprimands produced higher rates of the behavior than contingent statements that were unrelated to the target response (e.g., "It is sunny today"), suggesting that some forms of attention were more reinforcing than others. A treatment based on these analyses reduced the behavior to near-zero levels. PMID- 8682739 TI - The treatment of covert self-injury through contingencies on response products. AB - Assessment and treatment of covert self-injurious behavior are complicated because it is difficult to quantify and apply differential consequences to covert responses. In this study, both tangible and social reinforcers were identified using reinforcer assessment methods. These reinforcers were then provided contingent upon the absence of tissue damage identified during physical examinations, resulting in near 100% success in physical assessment checks that was maintained over 10 months. PMID- 8682740 TI - A comparison of simultaneous and delayed reinforcement as treatments for food selectivity. AB - This study compared the relative efficacy of providing simultaneous or delayed reinforcement on food acceptance during meals. The participant was a 7 year-old boy with pervasive developmental disorder and a history of food selectivity. Results indicated that both procedures were effective in increasing acceptance; however, the simultaneous reinforcement procedure produced more rapid behavior change and a higher overall percentage of food acceptance. PMID- 8682741 TI - Analysis of free-time contingencies as positive versus negative reinforcement. AB - Providing a short break contingent on completed work may increase responding through positive reinforcement (e.g., access to preferred activities) or negative reinforcement (e.g., escape form work). In this investigation, three analyses conducted with a boy with profound mental retardation showed that (a) a 20-s break increased responding more than a positive reinforcer (cola) did, and (b) the reinforcing effect of a 20-s break were affected by the availability of positive reinforcers during the break were affected by the availability of positive reinforcers during the break. PMID- 8682742 TI - Feed the hungry bee: using positive peer reports to improve social interactions and acceptance of a socially rejected girl in residential care. AB - We studied how rewarding peers for publicly reporting positive aspects of a socially rejected girl's behavior affected her social interactions and acceptance. The results indicated that positive peer reports reduced negative social interactions (to near zero) and increased positive interactions (to above 70%). In addition, social acceptance ratings of the girl increased from pre- to postintervention. PMID- 8682743 TI - Use of assisted reading to increase correct reading rates and decrease error rates of students with learning disabilities. AB - The effects of assisted reading on 3 elementary students with learning disabilities were evaluated using a multiple baseline design. Data were collected from the students' oral reading from their basal texts. The results indicated an increase in number of words read correctly as well as a decrease in the number of words read incorrectly when assisted reading was used in the classroom. PMID- 8682744 TI - Are persons with nervous habit nervous? A preliminary examination of habit function in a nonreferred population. AB - In this study, 44 individual were exposed to three conditions (anxiety, bored, and neutral) while being covertly videotaped. The videotapes were then scored for the occurrence of five classes of habits including hair, face, and object manipulation; object mouthing; and repetitive movement of the limbs. Results showed that hair and face manipulation increased during the anxiety condition, whereas object manipulation increased in the bored condition. The implications of this research are discussed. PMID- 8682745 TI - Practitioner questions about research. PMID- 8682746 TI - The role of fathers. PMID- 8682747 TI - Can disability benefits make children sicker? PMID- 8682748 TI - TCA cardiotoxicity: the latest. PMID- 8682749 TI - Combined pharmacotherapy for TS and OCD. PMID- 8682750 TI - Melatonin for sleep problems. PMID- 8682751 TI - Presentation and course of major depressive disorder during childhood and later years of the life span. AB - OBJECTIVE: To examine whether major depressive disorder (MDD) in childhood, adolescence, and adulthood represents essentially the same diagnostic entity. METHOD: Recent publications on clinically referred patients with MDD that met certain selection criteria were examined to abstract information on six phenomenological features of the disorder: episode number, symptom presentation, psychiatric comorbidity, recovery from the index episode, recurrence of MDD, and switch to bipolar illness. The studies included both inpatients and outpatients with an age range of 6 to 80+ years. RESULTS: Synthesizing the information across broad age groups revealed that clinically referred depressed youths, compared with adults and the elderly, are almost exclusively first-episode probands, evidence comparable symptom pictures, have similar rates of psychiatric comorbidity, recover somewhat faster from their index episode of MDD, have a similar recurrence rate, and are at greater risk for bipolar switch. CONCLUSIONS: MDD in clinically referred youths is similar in many regards to MDD in adults and the elderly. However, the findings that the risk of recurrent MDD among children approximates the rate among adults but, on average, about 20 years earlier in their lives, and that youths with unipolar depression convert to bipolar illness more frequently than do adults, suggest that very early onset MDD is a particularly serious form of affective illness. PMID- 8682752 TI - Increased prevalence of alcoholism in relatives of depressed and bipolar children. AB - OBJECTIVE: Previous publications from the "Nortriptyline in Childhood Depression: Follow-up Study" reported increased prevalence rates of mood disorders and alcoholism in the relatives of prepubertal depressed subjects. This article presents data on the association versus independent transmission of alcohol and mood disorders in the families of these subjects. METHOD: The follow-up study included 6- to 12-year-olds with major depressive disorder (MDD) and matched normal controls. After 2 to 5 years of follow-up, bipolarity developed in 31.7% of the MDD subjects. Family history data for the first- and second-degree relatives and first cousins of the 76 nonadopted MDD subjects and the 31 controls were obtained from the subjects' mothers, using the Family History-Research Diagnostic Criteria. RESULTS: The prevalence of alcoholism among the relatives of the MDD and bipolar probands was two to three times that reported for control relatives and twice that reported for the relatives of adult MDD and bipolar probands. Mood disorders and maternal alcoholism were independently transmitted while paternal alcoholism increased the risk for mood disorder in offspring. CONCLUSIONS: The potential psychosocial and genetic effects of familial alcoholism need to be considered for the clinical management and investigation of childhood-onset mood disorders. PMID- 8682753 TI - Childhood psychopathology in children from families of alcoholic female probands. AB - OBJECTIVE: To determine the prevalence of DSM-III disorders among children who had been selected for study based on their maternal family history of alcoholism (either multigenerational alcoholism in the case of the high-risk group or no alcohol dependence in first- and second-degree relatives in the case of the control children). METHOD: Thirty-four boys and 42 girls with a mean age of 11.3 years (range 8 to 18) were evaluated. An equal number of children comprised the high- and low-risk groups and were gender- and age-matched using a yoked control design. RESULTS: The high-risk children manifested more psychiatric diagnoses overall, and significantly more internalizing disorders than controls. The relative odds of a high-risk child's having a diagnosed disorder were increased when the child lived with a biological mother and a custodial father (biological, step, or adoptive) who were both alcoholic. This relationship was exacerbated by the child's being older than 13 years of age. CONCLUSIONS: Vertical transmission of maternal alcoholism is manifested in childhood and adolescence by the presence of increased psychopathology. This psychopathology occurred in offspring of alcoholics screened for major comorbidity, suggesting that it is unlikely that the increased psychopathology is due to cotransmission of affective or other psychopathology. The elevated risk of psychopathology in association with having an alcoholic mother was not further increased by the child's being older than 13 years of age, if the father (custodial or only biological) was not alcoholic. PMID- 8682754 TI - Child Behavior Checklist findings further support comorbidity between ADHD and major depression in a referred sample. AB - OBJECTIVE: To examine the convergence of categorical and empirical diagnostic systems to evaluate whether psychiatric comorbidity of juvenile major depression with attention-deficit hyperactivity disorder (ADHD) is due to assessment bias. METHOD: Using total predictive value and the odds ratio, the authors evaluated the convergence of Child Behavior Checklist (CBCL) scales with structured interview-derived diagnoses in 94 children with major depression, 97 with ADHD, and 115 normal control children with neither diagnosis. RESULTS: The CBCL Anxious/Depressed scale discriminated depressed from nondepressed children irrespective of comorbidity with ADHD, and the Attention Problems scale discriminated ADHD from non-ADHD children irrespective of comorbidity with major depression. Children with major depression comorbid with ADHD had CBCL correlates of both syndromes. CONCLUSIONS: Since the CBCL is an empirically derived taxonomic system, the correspondence between the content-congruent CBCL scales and DSM-III-R categorical diagnoses of major depression and of ADHD indicates that previously reported findings of high overlap between these two disorders using structured diagnostic interview methodology and trained raters were not due to rater biases. PMID- 8682755 TI - Predictors of comorbid alcohol and substance abuse in depressed adolescents. AB - OBJECTIVE: To identify clinical profiles discriminating depressed adolescents on the basis of comorbid alcohol/substance use disorders and to determine whether or not profiles with high predictive power are gender-specific. METHOD: One hundred three adolescent inpatients with major depression (65 girls, 38 boys) participated in a comprehensive diagnostic evaluation. Independent assessments of depression, suicidality, and psychosocial adjustment were conducted using well validated instruments. RESULTS: Gender-specific clinical profiles were identified that predicted alcohol/substance abuse in depressed adolescents with high levels of sensitivity (90%). The significant discriminant function for depressed girls included the following predictors: longer depressive episodes, more conduct problems and psychosocial impairment, and more active involvement in relationships with boys. The significant discriminant function for depressed boys included conduct disorder, older age, and schoolwork problems. These profiles correctly identified most depressed adolescents with comorbid alcohol/substance abuse. CONCLUSIONS: Given that alcohol abuse and depression are associated with highly impaired social functioning and increased risk of self-harm, sensitivity in case identification is critical. Clinicians should conduct comprehensive assessments of alcohol/substance abuse in depressed adolescents with the identified clinical profiles. PMID- 8682756 TI - Motor activity and severity of depression in hospitalized prepubertal children. AB - OBJECTIVE: To determine whether there is an association between activity levels and the severity and nature of depressive symptoms. METHOD: Locomotor activity was quantified in 27 consecutively selected hospitalized prepubertal children. Activity was measured in 5-minute epochs over a period of 72 hours using belt worn monitors. Depressive symptoms were rated using the Children's Depression Rating Scale-Revised, the Children's Depression Inventory, and an observer rating scale for nursing staff. RESULTS: Measures of reduced daytime activity correlated with scores on the Children's Depression Rating Scale and the observer rating scale, but not the Children's Depression Inventory. Stepwise regression indicated that the strongest association occurred between a composite measure of severity, age, and percentage of low-level diurnal activity periods (r = .724, p < .0005). Activity measures correlated with clinical ratings of sadness, low self-esteem, anhedonia, and physical complaints, and to a lesser degree with ratings of hypoactivity, fatigue, and slow speech. CONCLUSIONS: Reduced levels of activity correlated significantly with clinical ratings of depressive severity across diagnostic groups. The development of objective measures of depressive severity may have prognostic and therapeutic implications. PMID- 8682757 TI - Response to oCRH in depressed and nondepressed adolescents: does gender make a difference? AB - OBJECTIVE: To examine the hypothesis that hypothalamic-pituitary-adrenal responses to stress vary across gender, contributing to gender differences in the prevalence of depression. METHOD: This study examined gender differences between depressed (n = 21) and control (n = 20) adolescents in adrenocorticotropic hormone (ACTH) and cortisol response to two ovine corticotropin-releasing hormone (oCRH) tests, at baseline and following a cognitive stressor. RESULTS: Boys had higher (p < .05) measures of ACTH than girls, regardless of depression status, whereas corresponding cortisol parameters were similar in both groups. Cortisol measures were higher (p < .05) at time 1 than at time 2 in both groups, a phenomenon that might reflect the novelty of the situation. CONCLUSIONS: Gender differences in hormone responses may be related to differences in peripheral metabolism of ACTH, resulting in changes of immunoreactivity but not bioactivity or a different set point of the hypothalamic-pituitary-adrenal axis. The pattern of ACTH and cortisol responses to oCRH and the 24-hour excretion of free cortisol was normal in adolescents with depression, probably reflecting normal negative feedback mechanisms at this age or that most of these patients suffer from atypical rather than melancholic depression. PMID- 8682759 TI - Affective language between depressed mothers and their children: the potential impact of psychotherapy. AB - OBJECTIVE: To determine whether depressed mothers who had had psychotherapy were more able to communicate accurately about emotions than depressed mothers who had not had treatment. METHOD: Three groups of mother-child pairs were studied: mothers without psychiatric diagnosis or treatment (n = 31), depressed mothers without treatment (n = 10), and depressed mothers with psychotherapy (n = 43). Photographs of infants expressing emotions were viewed and discussed by the mother-child pair and were rated independently. RESULTS: A comparison by analysis of variance and Duncan procedures revealed significant differences between groups in both mothers' and children's accuracy scores. Mothers who had had psychotherapy were more able to interpret emotional expression with accuracy (p < .05), particularly about negative emotions such as anger and sadness (p < .01), than were the mothers of the depressed no treatment group. Depressed mothers without treatment were more inaccurate (for example, sadness interpreted as anger). CONCLUSIONS: Psychotherapy may contribute to the depressed mother's achievement of accuracy in speaking with her child about emotions. The depressed mother whose depressive illness goes untreated is more inclined to be inaccurate and may pass these inclinations on to her child. The generality of the psychotherapy variable makes these findings preliminary. PMID- 8682758 TI - Response of families to two preventive intervention strategies: long-term differences in behavior and attitude change. AB - OBJECTIVE: To explore the long-term impact of two forms of preventive intervention designed to diminish risk to children in families in which one or both parents suffered from affective disorder. METHOD: Fifty-four parents in 18 families were initially assessed and randomly assigned to one of two interventions--a clinician-facilitated, manual-based, psychoeducational preventive intervention or a standardized lecture-group discussion in which similar educational information was presented. Assessments included standard diagnostic interviews, child behavior scales, and semistructured interviews with parents about the effects of the intervention. Follow-up assessments were conducted three times over the 3-year follow-up interval. RESULTS: No harmful effects were reported for either intervention, and ratings of degree of upset about reported concerns declined across time for both conditions. Families receiving the clinician-facilitated intervention reported more behavior and attitude changes than did lecture-group families when assessed after intervention. The difference between the two groups was sustained at further follow-up assessments. CONCLUSION: Although both preventive interventions produced changes in behaviors and attitudes, parents in the clinician-facilitated intervention reported more benefit. These data support the hypothesis that linking cognitive information to the family's life experience produces long-term changes. PMID- 8682760 TI - Traits of separation anxiety in boys with gender identity disorder. AB - OBJECTIVE: To assess the presence of traits of separation anxiety disorder in boys referred clinically for gender identity disorder. METHOD: One hundred fifteen boys were referred to a specialty clinic for concerns about their gender identity development. They were divided into two subgroups: one group met the complete diagnostic criteria for gender identity disorder; the other group did not meet the complete diagnostic criteria. The mothers of the boys were administered a structured interview schedule pertaining to separation anxiety disorder according to DSM-III criteria. RESULTS: A conservative definition of separation anxiety disorder showed no significant association with gender identity disorder; however, a liberal definition of separation anxiety disorder showed that it occurred significantly more often in the subgroup of boys who met the complete criteria for gender identity disorder than in the subgroup who did not meet the complete criteria (64.4% versus 38.1%, respectively). CONCLUSIONS: Boys with gender identity disorder show a high rate of co-occurring traits of separation anxiety. Reasons for this linkage require additional empirical study. PMID- 8682761 TI - Case study: sex reassignment in a teenage girl. AB - The etiology of gender identity is explored through the case history of a teenager with intersex raised without stigmatization as a girl but who declared himself male at age 14 years. Psychological ramifications of such complex medical anomalies as ambiguous genitalia demand a role for child psychiatry. PMID- 8682762 TI - Long-term consistency in speech/language profiles: I. Developmental and academic outcomes. AB - OBJECTIVE: This study examined the 7-year developmental and academic outcome of speech/language-impaired and control children selected from a community sample. METHOD: Speech/language and psychiatric measures were administered to the children at ages 5 and 12.5 years. Using children's age 5 speech/language test results, a cluster analysis was performed to ascertain whether specific linguistic subgroups would emerge. The long-term consistency of these subgroups was explored. The association between time 1 speech/language clusters and linguistic, cognitive and academic measures at time 2 were examined. RESULTS: Four groups were identified in the cluster analysis: high overall, poor articulation, poor comprehension, and low overall. Children with pervasive language problems continued to perform poorly on linguistic, cognitive, and academic measures, while those with comprehension problems fared slightly better but still had more difficulties than those with normal language. The poor articulation cluster had few articulation errors at follow-up. CONCLUSIONS: Empirically supported speech/language classifications identified as early as age 5 continued to be relevant into late childhood. Pervasive speech/language impairment in early childhood was associated with increased risk of poor linguistic and academic outcome at follow-up, while isolated articulatory problems improved over time. These findings reveal the urgent need for early intervention among children with pervasive speech/language impairment. PMID- 8682763 TI - Long-term consistency in speech/language profiles: II. Behavioral, emotional, and social outcomes. AB - OBJECTIVE: This study examined the 7-year behavioral, emotional, and social outcome of speech/language-impaired and control children selected from a community sample. METHOD: Speech/language and psychosocial measures were administered to the children at ages 5 and 12.5 years. Using children's age 5 speech/language test results, a cluster analysis was performed to ascertain whether specific linguistic subgroups would emerge. The association between speech/language cluster at age 5 and psychosocial functioning at age 12.5 was examined. RESULTS: Children with receptive and pervasive speech/language problems at age 5 demonstrated greater behavioral disturbance than children without such impairment. Controlling for initial behavioral status, early childhood language profile was still associated with behavioral and social competence ratings, 7 years later. Children without receptive language problems showed superior social adjustment. CONCLUSIONS: Empirically supported speech/language classifications identified as early as age 5 were associated with behavioral disturbance in late childhood. Receptive and pervasive speech/language impairment in early childhood was associated with the greatest risk at follow-up. Early auditory comprehension problems may be a specific risk factor for later aggressive and hyperactive symptoms. These findings identify the need for effective intervention with speech/language-impaired children. PMID- 8682764 TI - A pharmacological approach to the quagmire of comorbidity in juvenile mania. PMID- 8682766 TI - Starvation- and Stationary-phase-induced resistance to the antimicrobial peptide polymyxin B in Salmonella typhimurium is RpoS (sigma(S)) independent and occurs through both phoP-dependent and -independent pathways. AB - A common stress encountered by Salmonella serovars involves exposure to membrane permeabilizing antimicrobial peptides and proteins such as defensins, cationic antibacterial proteins, and polymyxins. We wanted to determine if starvation induces cross-resistance to the membrane-permeabilizing antimicrobial peptide polymyxin B (PmB). We report here that starved and stationary-phase (Luria Bertani [LB] medium) cells exhibited ca. 200- to 1,500-fold-higher (cross )resistance to a 60-min PmB challenge than log-phase cells. Genetic analysis indicates that this PmB resistance involves both phoP-dependent and -independent pathways. Furthermore, both pathways were sigma(S) independent, indicating that they are different from other known sigma(S) -dependent cross-resistance mechanisms. Additionally, both pathways were important for PmB resistance early during C starvation and for cells in stationary phase in LB medium. However, only the phoP-independent pathway was important for P-starvation-induced PmB resistance and the sustained PmB resistance seen in 24-h-C-starved (and N starved) or stationary-phase cells in LB medium. The results indicate the presence of an rpoS- and phoP-independent pathway important to starvation- and stationary-phase-induced resistance to membrane-permeabilizing antimicrobial agents. PMID- 8682767 TI - Cloning and transcriptional analysis of two threonine biosynthetic genes from Lactococcus lactis MG1614. AB - Two genes, hom and thrB, involved in threonine biosynthesis in Lactococcus lactis MG1614, were cloned and sequenced. These genes, which encode homoserine dehydrogenase and homoserine kinase, were initially identified by the homology of their gene products with known homoserine dehydrogenases and homoserine kinases from other organisms. The identification was supported by construction of a mutant containing a deletion in hom and thrB that was unable to grow in a defined medium lacking threonine. Transcriptional analysis showed that the two genes were located in a bicistronic operon with the order 5' hom-thrB 3' and that transcription started 66 bp upstream of the translational start codon of the hom gene. A putative -10 promoter region (TATAAT) was located 6 bp upstream of the transcriptional start point, but no putative -35 region was identified. A DNA fragment covering 155 bp upstream of the hom translational start site was functional in pAK80, an L. lactis promoter probe vector. In addition, transcriptional studies showed no threonine-dependent regulation of hom-thrB transcription. PMID- 8682765 TI - Calcium signalling in bacteria. PMID- 8682770 TI - Mutagenesis of hydroxylamine oxidoreductase in Nitrosomonas europaea by transformation and recombination. AB - Mutagenesis of Nitrosomonas europaea was achieved by electroporation and recombination. To demonstrate this, an aminoglycoside 3'-phosphotransferase (kan) gene was specifically inserted into each of the three gene copies of hao individually. Southern hybridizations and PCR analysis showed the incorporation of the kan gene at the chosen genetic loci. The isolation of mutant strains was achieved in 7 to 14 days when the strains were grown on solid medium. The induced mutations were stable even in the absence of kanamycin-selective pressure for periods of up to 45 days in culture. The mutant strains did not show an observable phenotype different from that of the wild type when grown under the same conditions. PMID- 8682769 TI - Relative levels and fractionation properties of Bacillus subtilis sigma(B) and its regulators during balanced growth and stress. AB - sigma B is a secondary sigma factor that controls the general stress response in Bacillus subtilis. sigma B-dependent genes are activated when sigma B is released from an inhibitory complex with an anti-sigma B protein (RsbW) and becomes free to associate with RNA polymerase. Two separate pathways, responding either to a drop in intracellular ATP levels or to environmental stress (e.g., heat, ethanol, or salt), cause the release of sigma B from RsbW. rsbR, rsbS, rsbT, and rsbU are four genes now recognized as the upstream half of an operon that includes sigB (sigma B) and its principal regulators. Using reporter gene assays, we find that none of these four genes are essential for stationary-phase (i.e., ATP-dependent) activation of sigma B, but rsbU and one or more of the genes contained within an rsbR,S,T deletion are needed for stress induction of sigma B. In other experiments, Western blot (immunoblot) analyses showed that the levels of RsbR, RsbS, Rsb, and RsbU, unlike those of the sigB operon's four downstream gene products (RsbV, RsbW, RsbX and sigma B), are not elevated during sigma B activation. Gel filtration and immunoprecipitation studies did not reveal the formation of complexes between any of the four upstream sigB operon products and the products of the downstream half of the operon. Much of the detectable RsbR, RsbS, RsbT, and RsbU did, however, fractionate as a large-molecular-mass (approximately 600-kDa) aggregate which was excluded from our gel filtration matrix. The downstream sigB operon products were not present in this excluded material. The unaggregated RsbR, RsbS, and RsbU, which were retarded by the gel matrix, elated from the column earlier than expected from their molecular weights. The RsbR and RsbS fractionation profile was consistent with homodimers (60 and 30 kDa, respectively), while the RsbU appeared larger, suggesting a protein complex of approximately 90 to 100 kDa. PMID- 8682768 TI - Isolation and characterization of a novel oxygenase that catalyzes the first step of n-alkane oxidation in Acinetobacter sp. strain M-1. AB - In the Finnerty pathway for n-alkane, oxidation in Acinetobacter sp., n-alkanes are postulated to be attacked by a dioxygenase and the product, n-alkyl hydroperoxide, is further metabolized to the corresponding aldehyde via the peroxy acid [W. R. Finnerty, P. 184-188, in A. H. Applewhite (ed.), Proceedings of the World Conference on Biotechnology for the Fats and Oil Industry, 1988]. However, no biochemical evidence regarding the first-step reaction is available. In this study, we found a novel n-alkane-oxidizing enzyme that requires only molecular oxygen, i.e., not NAD(P)H, in our isolate, Acinetobacter sp. strain M 1, and purified it to apparent homogeneity by gel electrophoresis. The purified enzyme is a homodimeric protein with a molecular mass of 134 kDa, contains 1 mol of flavin adenine dinucleotide per mol of subunit, and requires CU2+ for its activity. The enzyme uses n-alkanes ranging in length from 10 to 30 carbon atoms and is also active toward n-alkenes (C12 to C20) and some aromatic compounds with substituted alkyl groups but not toward a branched alkane, alcohol, or aldehyde. Transient accumulation of n-alkyl hydroperoxide was detected in the course of the reaction, and no oxygen radical scavengers affected the enzyme activity. From these properties, the enzyme is most probably a dioxygenase that catalyzes the introduction of two atoms of oxygen to the substrate, leading to the formation of the corresponding n-alkyl hydroperoxide. The enzymatic evidence strongly supports the existence of an n-alkane oxidation pathway, which is initiated by a dioxygenase reaction, in Acinetobacter spp. PMID- 8682771 TI - Polyamines decrease Escherichia coli outer membrane permeability. AB - The permeability of the outer membranes of gram-negative bacteria to hydrophilic compounds is mostly due to the presence of porin channels. We tested the effects of four polyamines (putrescine, cadaverine, spermidine, and spermine) on two processes known to depend on intact porin function: fluxes of beta-lactam antibiotics in live cells and chemotaxis. In both cases, inhibition was observed. Measurements of the rate of permeation of cephaloridine and of chemotaxis in swarm plates and capillary assays were used to determine the concentration dependence of this modulation. The effective concentration ranges depended on the nature of the polyamine and varied from submillimolar for spermine to tens of millimolar for cadaverine. Both OmpC and OmpF porins were inhibited, although the effects on OmpC appeared to be milder. These results are in agreement with our observations that polyamines inhibit porin-mediated ion fluxes in electrophysiological experiments, and they suggest that a low-affinity polyamine binding site might exist in these porins. These results reveal the potential use of porins as targets for blocking agents and suggest that polyamines may act as endogenous modulators of outer membrane permeability. PMID- 8682772 TI - Detection and characterization of the flagellar master operon in the four Shigella subgroups. AB - Strains in the genus Shigella are nonmotile, but they retain some cryptic flagellar operons whether functional or defective (A.Tominaga, M. A.-H. Mahmoud, T. Mukaihara, and M. Enomoto, Mol. Microbiol. 12:277-285, 1994). To disclose the cause of motility loss in shigellae, the presence or defectiveness of the flhD and flhC genes, composing the master operon whose mutation causes inactivation of the entire flagellar regulon, was examined in the four Shigella subgroups. The flhD operon cloned from Shigella boydii and Shigella sonnei can activate, though insufficiently, the regulon in the Escherichia coli flhD or flhC mutant background. The clone from Shigella dysenteriae has a functional flhD gene and nonfunctional flhC gene, and its inactivation has been caused by the IS1 element inserted in its 5' end. The operon of Shigella flexneri is nonfunctional and has suffered an IS1-insertion mutation at the 5' end of the flhD gene. Comparison of restriction maps indicates that only the central 1.8-kb region, including part of the flhC gene and its adjacent mot operon, is conserved among the four Shigella subgroups as well as in E. coli, but in Salmonella typhimurium the whole map is quite different from the others. Motility loss in shigellae is not attributable to genetic damage in the master operon of a common ancestor, but it occurs separately in respective ancestors of the four subgroups, and in both S. dysenteriae and S.flexneri IS1 insertion in the master operon might be the primary cause of motility loss. PMID- 8682773 TI - Growth phase-dependent transcription of the sigma(54)-dependent Po promoter controlling the Pseudomonas-derived (methyl)phenol dmp operon of pVI150. AB - Transcription from Pseudomonas-derived -24, -12 Po promoter of the pVI150-encoded dmp operon is mediated by the sigma 54-dependent DmpR activator in response to the presence of aromatic pathway substrates in the medium. However, global regulatory mechanisms are superimposed on this regulatory system so that the specific response to aromatic effectors is absent in cultures until the stationary phase is reached. Here we genetically dissect the system to show that the growth phase response is faithfully mimicked by a minimal system composed of the dmpR regulatory gene and the Po promoter regulatory region and can be reproduced in heterologous Escherichia coli. Using this system, we show that the growth phase-dependent DmpR-mediated response to aromatic compounds is limited to fast-growing cultures. Thus, during exponential growth of cultures in minimal media containing different carbon sources, the response to aromatics is immediate, while the response is suppressed in cultures grown on rich media until the exponential-to-stationary phase transition. Elements known to be involved in the DmpR-mediated transcription from Po were analyzed for the ability to influence the growth phase response. Most dramatically, overexpression of DmpR was shown to completely abolish the growth phase response, suggesting that a negatively acting factor may mediate this level of regulation. The possible mechanism of action and integration (of the specific regulation of the dmp operon encoded catabolic enzymes with the physiological status of the bacteria are discussed. PMID- 8682774 TI - The capsule polysaccharide synthesis locus of streptococcus pneumoniae serotype 14: Identification of the glycosyl transferase gene cps14E. AB - To identify a chromosomal region of Streptococcus pneumoniae serotype 14 involved in capsule polysaccharide synthesis, two strategies were used: (i) Tn916 mutagenesis, followed by the characterization of four unencapsulated mutants, and (ii) cross-hybridization with a capsule polysaccharide synthesis gene (cps) probe from S. agalactiae, which has a structurally similar capsule. The two approaches detected the same chromosomal region consisting of two adjacent EcoRI fragments. One of these EcoRI fragments was cloned and hybridized with a cosmid library. This resulted in clone cMKO2. A similar cosmid clone was obtained from an unencapsulated Tn916 mutant, Spnl4.H. Sequence analysis of the two cosmid clones revealed that in the Tn916 mutant, a gene, cps14E, which is homologous to other bacterial genes encoding glycosyl transferases, had been inactivated. An open reading frame immediately downstream of cps14E, designated cps14F, shows no significant homology with any known genes or proteins. A functional assay showed that cps14E encodes a glycosyl transferase and that a gene-specific knockout mutant lacks this enzyme activity, whereas inactivation of cps14F does not have this effect. PMID- 8682775 TI - Membrane insertion of the F-pilin subunit is Sec independent but requires leader peptidase B and the proton motive force. AB - F pilin is the subunit required for the assembly of conjugative pili on the cell surface of Escherichia coli carrying the F plasmid. Maturation of the F-pilin precursor, propilin, involves three F plasmid transfer products: TraA, the propilin precursor; TraQ, which promotes efficient propilin processing; and TraX, which is required for acetylation of the amino terminus of the 7-kDa pilin polypeptide. The mature pilin begins at amino acid 52 of the TraA propilin sequence. We performed experiments to determine the involvement of host cell factors in propilin maturation. At the nonpermissive temperature in a LepBts (leader peptidase B) host, propilin processing was inhibited. Furthermore, under these conditions, only full-length precursor was observed, suggesting that LepB is responsible for the removal of the entire propilin leader peptide. Using propilin processing as a measure of propilin insertion into the plasma membrane, we found that inhibition or depletion of SecA and SecY does not affect propilin maturation. Addition of a general membrane perturbant such as ethanol also had no effect. However, dissipation of the proton motive force did cause a marked inhibition of propilin processing, indicating that membrane insertion requires this energy source. We propose that propilin insertion in the plasma membrane proceeds independently of the SecA-SecY secretion machinery but requires the proton motive force. These results present a model whereby propilin insertion leads to processing by leader peptidase B to generate the 7-kDa peptide, which is then acetylated in the presence of TraX. PMID- 8682776 TI - Role of the propilin leader peptide in the maturation of F pilin. AB - F-pilin maturation and translocation result in the cleavage of a 51-amino-acid leader sequence from propilin and require LepB and TraQ but not the SecA-SecY secretion pathway. The unusual propilin leader peptide and the dependence of its cleavage on TraQ suggested that TraQ recognition may be specific for the leader peptide. An in vitro propilin cleavage assay yielded propilin (13 kDa), the pilin polypeptide (7 kDa), and a 5.5-kDa protein as the traA products. The 5.5-kDa protein comigrates with the full-length 51-amino-acid leader peptide, and [14C]proline labeling confirmed its identity since the only proline residues of propilin are found within the leader peptide. The in vitro and in vivo propilin processing reactions proceed similarly in a single polypeptide cleavage step. Furthermore, TraQ dependence is a property of F-pilin maturation specifically rather than a property of the leader peptide. A propilin derivative with an amino terminal signal sequence generated by deleting codons 2 to 28 required TraQ for processing in vivo. On the other hand, a chimeric protein with the propilin wild type leader peptide fused to the mature portion of beta-lactamase was processed in a TraQ-independent manner. Thus, despite its unusual length, the propilin leader peptide seems to perform a function similar to that of the typical amino terminal signal sequence. This work suggests that TraQ is not necessary for the proteolysis of propilin and therefore is likely to act as a chaperone-like protein that promotes the translocation of propilin. PMID- 8682777 TI - Loss of overproduction of polypeptide release factor 3 influences expression of the tryptophanase operon of Escherichia coli. AB - Expression of the tryptophanase (tna) operon of Escherichia coli is regulated by catabolite repression and by tryptophan-induced inhibition of Rho-mediated transcription termination. Previous studies indicated that tryptophan induction might involve leader peptide inhibition of ribosome release at the stop codon of tnaC, the coding region for the operon-specified leader peptide. In this study we examined tna operon expression in strains in which the structural gene for protein release factor 3, prfC, is either disrupted or overexpressed. We find that prfC inactivation leads to a two- to threefold increase in basal expression of the tna operon and a slight increase in induced expression. Overexpression of prfC has the opposite effect and reduces both basal and induced expression. These effects occur in the presence of glucose and cyclic AMP, and thus Rho-dependent termination rather than catabolite repression appears to be the event influenced by the prfC alterations. prfC inactivation also leads to an increase in basal tna operon expression in various rho and rpoB mutants but not in a particular rho mutant in which the basal level of expression is very high. The effect of prfC inactivation was examined in a variety of mutants with alterations in the tna leader region. Our results suggest that translation of tnaC is essential for the prfC effect. The tryptophan residue specified by tnaC codon 12, which is essential for induction, when replaced by another amino) acid, allows the prfC effect. Introducing UAG or UAA stop codons rather than the normal tnaC UGA stop codon, in a strain with an inactive prfC gene, also leads to an increase in the basal level of expression. Addition of the drug bicyclomycin increases basal operon expression of all mutant strains except a strain with a tnaC'-'lacZ fusion. Expression in the latter strain is unaffected by prfC alterations. Our findings are consistent with the interpretation that ribosome release at the tnaC stop codon can influence tna operon expression. PMID- 8682778 TI - Efficient translation of the RpoS sigma factor in Salmonella typhimurium requires host factor I, an RNA-binding protein encoded by the hfq gene. AB - The RpoS transcription factor (also called sigma Sor sigma 38) is required for the expression of a number of stationary-phase and osmotically inducible genes in Escherichia coli. RpoS is also a virulence factor for several pathogenic bacteria, including Salmonella typhimurium. The activity of RpoS is regulated in response to several different signals, at the transcriptional and translational levels as well as by proteolysis. Here we report that host factor I (HF-I), the product of the hfq gene, is required for efficient expression of rpoS in S. typhimurium. HF-I is a small, heat-stable, site-specific RNA-binding protein originally characterized for its role in replication of the RNA bacteriophage Q beta of E. coli. Its role in the uninfected bacterial cell has previously been unknown. Assays of Beta-galactosidase in strains with rpoS-lac fusions, Western blot (immunoblot) analysis, and pulse-labeling and immunoprecipitation of both fusion proteins and native RpoS show that an S. typhimurium hfq mutant has a four to sevenfold reduction in expression of rpoS that is attributable primarily to a defect in translation. These results add a new level of complexity to the regulation of RpoS activity. PMID- 8682780 TI - Role of CodY in regulation of the Bacillus subtilis hut operon. AB - Bacillus subtilis mutants deficient in amino acid repression of the histidine utilization (hut) operon were isolated by transposon mutagenesis. Genetic characterization of these mutants indicated that they most likely contained transposon insertions within the codVWXY operon. The codY gene is required for nutritional regulation of the dipeptide permease (dpp) operon. An examination of hut expression in a delta codY mutant demonstrated that amino acid repression exerted at the hutOA operator, which lies immediately downstream of the hut promoter, was defective in a delta codY mutant. The codY gene product was not required for amino acid regulation of either hut induction or the expression of proline oxidase, the first enzyme in proline degradation. This indicates that more than one mechanism of amino acid repression is present in B. subtilis. An examination of dpp and hut expression in cells during exponential growth in various media revealed that the level of CodY-dependent regulation appeared to be related to the growth rate of the culture. PMID- 8682779 TI - Two-step secretion of the Serratia marcescens extracellular nuclease. AB - The extracellular nuclease of Serratia marcescens is one of a wide variety of enzymes secreted into the growth medium. Its appearance occurs late in the growth of a culture, and its gene, nucA, is transcriptionally regulated in a complex fashion by growth phase and other factors. Pulse-labeling studies reveal that extracellular secretion of nuclease occurs as a two-step process. In the first step, nuclease is rapidly translocated across the cytoplasmic membrane into the periplasm, where it accumulates as a mature active nuclease. A precursor protein, nuclease still carrying its signal sequence, was detected in the presence of carbonyl cyanide m-chlorophenylhydrazone or sodium azide, suggesting that this initial translocation and signal processing step involves an energy-dependent and Sec-dependent pathway in S. marcescens. The second step of secretion across the outer membrane is a slow process requiring between 30 to 120 min, depending on growth conditions. PMID- 8682781 TI - Changes in patterns of ADP-ribosylated proteins during differentiation of Streptomyces coelicolor A3(2) and its development mutants. AB - Mutants resistant to 3-aminobenzamide, a known inhibitor of ADP ribosyltransferase, were obtained from Streptomyces coelicolor A3(2). One (strain 27) was analyzed in detail. Mutant 27 had a reduced ADP-ribosyl-transferase activity, exhibited substantial changes from the wild type in ADP-ribosylated protein profile during cell aging, and was defective in producing aerial mycelium and antibiotics. A 92-kDa ADP-ribosylated protein disappeared at the onset of differentiation in the parent strain but was present in mutant 27. Four ADP ribosylated proteins (39, 41, 43, and 46 kDa) appeared at the onset of differentiation in the parent strain but were missing in mutant 27. Failure to ADP-ribosylate these four proteins was detected when the parent strain was grown in the presence of subinhibitory amounts of 3-aminobenzamide. Genetic analysis showed that the mutation, named brgA, conferring resistance to 3-aminobenzamide, cosegregated with the altered phenotypes (i.e., defects in ADP-ribosylation and aerial mycelium formation) and was mapped to a new locus near uraA. The brgA mutants were nonconditionally deficient in producing aerial mycelium and antibiotics, as determined by using various media, and had a morphological and physiological phenotype quite different from that of a bldG mutant carrying a mutation which was previously mapped near uraA. Among the known bld mutants, bldA, bldD, and bldG mutants exhibited a ADP-ribosylated protein profile similar to that of the wild type, while like mutant 27, bldB, bldC, and bldH mutants failed to ADP-ribosylate certain proteins. PMID- 8682782 TI - Active efflux of fluoroquinolones in Mycobacterium smegmatis mediated by LfrA, a multidrug efflux pump. AB - The lfrA gene cloned from chromosomal DNA of quinolone-resistant Mycobacterium smegmatis mc2-552 conferred low-level resistance to fluoroquinolones when present on multicopy plasmids. Sequence analysis suggested that lfrA encodes a membrane efflux pump of the major facilitator family (H. E. Takiff, M. Cimino, M. C. Musso, T. Weisbrod, R. Martinez, M. B. Delgado, L Salazar, B. R. Bloom, and W. R. Jacbos, Jr., Proc. Natl. Acad. Sci. USA 93:362-366, 1996). In this work, we studied the role of LfrA in the accumulation of fluoroquinolones by M. smegmatis. The steady-state accumulation level of a hydrophilic quinolone, norfloxacin, by M. smegmatis harboring a plasmid carrying the lfrA gene was about 50% of that by the parent strain but was increased to the same level as that of the parent strain by addition of a proton conductor, carbonyl cyanide m chorophenylhydrazone. Norfloxacin efflux mediated by LfrA was competed for strongly by ciprofloxacin but not by nalidixic acid. Furthermore, we showed that portions of norfloxacin accumulated by starved cells were pumped out upon reenergization of the cells, and the rates of this efflux showed evidence of saturation at higher intracellular concentrations of the drug. These results suggest that the LfrA polypeptide catalyzes the active efflux of several quinolones. PMID- 8682784 TI - Oxygen-controlled regulation of the flavohemoglobin gene in Bacillus subtilis. AB - A gene, hmp, which encodes a ubiquitous protein homologous to hemoglobin was isolated among genes from Bacillus subtilis that are induced under anaerobic conditions. The hmp protein belongs to the family of two-domain flavohemoproteins, homologs of which have been isolated from various organisms such as Escherichia coli, Alcaligenes eutrophus, and Saccharomyces cerevisiae. These proteins consist of an amino-terminal hemoglobin domain and a carboxy terminal redox active site domain with potential binding sites for NAD(P)H and flavin adenine dinucleotide. The expression of hmp is strongly induced upon oxygen limitation, and the induction is dependent on a two-component regulatory pair, ResD and ResE, an anaerobic regulator, FNR, and respiratory nitrate reductase, NarGHJI. The requirement of FNR and NarGHJI for hmp expression is completely bypassed by the addition of nitrite in the culture medium, indicating that fnr is required for transcriptional activation of narGHJI, which produces nitrite, leading to induction of hmp expression. In contrast, induction of hmp was still dependent on resDE in the presence of nitrite. A defect in hmp in B. subtilis has no significant effect on anaerobic growth. PMID- 8682783 TI - Two-component regulatory proteins ResD-ResE are required for transcriptional activation of fnr upon oxygen limitation in Bacillus subtilis. AB - Bacillus subtilis can grow anaerobically in the presence of nitrate as a terminal electron acceptor. The two component regulatory proteins, ResD and ResE, and an anaerobic gene regulator, FNR, were previously shown to be indispensable for nitrate respiration in B. subtilis. Unlike Escherichia coli fnr, B. subtilis fnr transcription was shown to be highly induced by oxygen limitation. fnr is transcribed from its own promoter as well as from a promoter located upstream of narK, the first gene in the narK-fnr dicistronic operon. DNA fragments containing the narK promoter, the fnr promoter, and both of the promoters were used to construct three lacZ fusions to examine the transcriptional regulation of the narK-fnr operon. ResDE was found to be required for transcriptional activation of fnr from the fnr-specific promoter, and FNR was required for activation of narK fnr transcription from the FNR-dependent narK operon promoter under anaerobiosis. In order to determine if the requirement for ResDE in nitrate respiration is solely to activate fnr transcription, fnr was placed under control of the IPTG (isopropyl-beta-D-thiogalactopyranoside)-inducible promoter, Pspac. The observed defect in anaerobic growth of a Pspac-fnr delta resDE mutant in the presence of IPTG indicated that resDE has an additional role in B. subtilis anaerobic gene regulation. PMID- 8682785 TI - Identification of two genes with prepilin-like leader sequences involved in type 4 fimbrial biogenesis in Pseudomonas aeruginosa. AB - Type 4 fimbriae are surface filaments produced by a range of bacterial pathogens for colonization of host epithelial surfaces. In Pseudomonas aeruginosa, they are involved in adhesion as well as in a form of surface translocation called twitching motility, and sensitivity to infection by fimbria-specific bacteriophage. Analysis of the 2.5-kb intergenic region between the previously defined pilR and pilV genes on P. aeruginosa genomic SpeI fragment E has identified three new genes, fimT, fimU, and dadA*. The predicted 18.5-kDa products of the fimT and fimU genes contain prepilin-like leader sequences, whereas the third gene, dadA*, encodes a protein similar to the D-amino acid dehydrogenase of Escherichia coli. Isogenic mutants constructed by allelic exchange demonstrated that the fimU gene was required for fimbrial biogenesis and twitching motility, whereas the fimT and dada* mutants retained wild-type phenotypes. However, overexpression of the fimT gene was found to be able to functionally replace the lack of a fimU gene product, suggesting a subtle role in fimbrial biogenesis. The identification of these proteins increases the similarity between type 4 fimbrial biogenesis and the supersystems involved in macromolecular traffic, such as extracellular protein secretion and DNA uptake, all of which now possess multiple protein species that possess prepilin-like leader sequences. PMID- 8682786 TI - Mecillinam resistance in Escherichia coli is conferred by loss of a second activity of the AroK protein. AB - Mecillinam, a beta-lactam antibiotic specific to penicillin-binding protein 2 (PBP 2) in Escherichia coli, blocks cell wall elongation and, indirectly, cell division, but its lethality can be overcome by increased levels of ppGpp, the nucleotide effector of the stringent response. We have subjected an E. coli K-12 strain to random insertional mutagenesis with a mini-Tn10 element. One insertion, which was found to confer resistance to mecillinam in relA+ and relA strains, was mapped at 75.5 min on the E. coli map and was located between the promoters and the coding sequence of the aroK gene, which codes for shikimate kinase 1, one of two E. coli shikimate kinases, both of which are involved in aromatic amino acid biosynthesis. The mecillinam resistance conferred by the insertion was abolished in a delta relA delta spoT strain completely lacking ppGpp, and it thus depends on the presence of ppGpp. Furthermore, the insertion increased the ppGpp pool approximately twofold in a relA+ strain. However, this increase was not observed in relA strains, although the insertion still conferred mecillinam resistance in these backgrounds, showing that mecillinam resistance is not due to an increased ppGpp pool. The resistance was also abolished in an ftsZ84(Ts) strain under semipermissive conditions, and the aroK::mini-Tn10 allele partially suppressed ftsZ84(Ts); however, it did not increase the concentration of the FtsZ cell division protein. The insertion greatly decreased or abolished the shikimate kinase activity of AroK in vivo and in vitro. The two shikimate kinases of E. coli are not equivalent; the loss of AroK confers mecillinam resistance, whereas the loss of Arol, does not. Furthermore, the ability of the aroK mutation to confer mecillinam resistance is shown to be independent of polar effects on operon expression and of effects on the availability of aromatic amino acids or shikimic acid. Instead, we conclude that the AroK protein has a second activity, possibly related to cell division regulation, which confers mecillinam sensitivity. We were able to separate the AroK activities mutationally with an aroK mutant allele lacking shikimate kinase activity but still able to confer mecillinam sensitivity. PMID- 8682787 TI - Mutation in the structural gene for release factor 1 (RF-1) of Salmonella typhimurium inhibits cell division. AB - A temperature-sensitive mutant of Salmonella typhimurium LT2 was isolated. At the nonpermissive temperature cell division stopped and multinucleated filaments were formed. DNA, RNA, or protein synthesis was not affected until after about two generations. Different physiological conditions, such as anaerobiosis and different growth media, suppress the division deficiency at high temperatures. Certain mutations causing a reduced polypeptide chain elongation rate also suppress the division deficiency. The mutation is recessive and shown to be in the structural gene for release factor I (prfA). DNA sequencing of both the wild type (prfA+) and mutant (prfA101) allele revealed a GC-to-AT transition in codon 168. Like other known prfA mutants, prfA101 can suppress amber mutations. The division defect in the prfA101 mutant strain could not be suppressed by overexpression of the ftsQAZ operon. Moreover, at the nonpermissive temperature the mutant shows a normal heat shock and SOS response and has a normal ppGpp level. We conclude that the prfA101-mediated defect in cell division is not directed through any of these metabolic pathways, which are all known to affect cell division. We speculate that the altered release factor I induces aberrant synthesis of an unidentified protein(s) involved in the elaborate process of septation. PMID- 8682788 TI - Plasmid recombination by the RecBCD pathway of Escherichia coli. AB - Previously, we demonstrated that exonuclease I-deficient strains of Escherichia coli accumulate high-molecular-weight linear plasmid concatemers when transformed with plasmids carrying the chi sequence (5'- GCTGGTGG-3') (M. M. Zaman and T. C. Boles, J. Bacteriol. 176:5093-5100, 1994). Since high-molecular weight linear DNA is believed to be the natural substrate for RecBCD-mediated recombination during conjugation (A. J. Clark and K. B. Low, p. 155-215, in K. B. Low, ed., The Recombination of Genetic Material, 1988), we analyzed the recombination frequencies of chi+ and chi0 plasmids in sbcB strains. Here, we report that chi sites stimulate plasmid recombination frequency by 16-fold in sbcB strains. Chi stimulated plasmid recombination is dependent on RecBCD but is independent of RecF pathway genes. The distribution of recombination products suggests that high molecular-weight linear plasmid DNA is a substrate for RecBCD-mediated recombination. Surprisingly, our data also suggest that chi+ plasmids also recombine by the RecBCD pathway in rec+ sbcB+ cells. PMID- 8682789 TI - Homologous pairs of regulatory proteins control activity of Bacillus subtilis transcription factor sigma(b) in response to environmental stress. AB - In Bacillus subtilis, activity of the general stress transcription factor sigma B is controlled posttranslationally by a regulatory network that transmits signals of environmental and metabolic stress. These signals include heat, ethanol, or osmotic challenge, or a sharp decrease in cellular energy levels, and all ultimately control sigma B activity by influencing the binding decision of the RsbW anti-sigma factor. In the absence of stress, RsbW binds to sigma B and prevents its association with RNA polymerase core enzyme. However, following stress, RsbW binds instead to the RsbV anti-anti-sigma factor, thereby releasing sigma B to direct transcription of its target genes. These two principal regulators of sigmaB activity are encoded in the eight-gene sigB operon, which has the gene order rsbR-rsbS-rsbT-rsbU-rsbV-rsbW-sig B-rsbX (where rsb stands for regulator of sigma B). Notably, the predicted rsbS product has significant amino acid identity to the RsbV anti-anti-sigma factor and the predicted rsbT product resembles the RsbW anti-sigma factor. To determine the roles of rsbS and rsbT, null or missense mutations were constructed in the chromosomal copies or each and tested for their effects on expression of a sigma B-dependent reporter fusion. On the basis of this genetic analysis, our principal conclusions are that (i) the rsbS product is a negative regulator of or" activity, (ii) the rsbT product is a positive regulator, (iii) RsbS requires RsbT for function, and (iv) the RsbS-RsbT and RsbV-RsbW pairs act hierarchically by a common mechanism in which key protein protein interactions are controlled by phosphorylation events. PMID- 8682790 TI - Multicopy suppressors of the cold-sensitive phenotype of the pcsA68 (dinD68) mutation in Escherichia coli. AB - The Escherichia coli strain cs2-68 is a cold-sensitive (c) mutant that forms a long filamentous cell at 20 degrees C with a large nucleoid mass in its central region. We have recently shown that the pcsA68 mutation causing the cs phenotype is a single-base substitution within the dinD gene, a DNA damage-inducible gene which maps at 82 min. Since null mutants of the pcsA (dinD) gene are viable, with no discernible defect in cell growth, the cs phenotype is attributed to a toxic effect by the mutant protein. In an attempt to identify a target(s) for the toxic pcsA68 mutant protein, we screened for chromosomal fragments on multicopy plasmids that could suppress the cs phenotype. Three different BamHI fragments were found to suppress cold sensitivity, and the lexA, dinG, and dinI genes were identified to be responsible for the suppression in each fragment. DinG shares multiple motifs with many DNA helicases. The complete sequence of dinI revealed that DinI is a small protein of 81 amino acids. It is similar in size and sequence to ImpC of the Salmonella typhimurium plasmid TP110 and to a protein (ORFfs) of the retronphage phi R67, both of which are also under the control of LexA. PMID- 8682791 TI - Comparative genomic analysis of the Haloferax volcanii DS2 and Halobacterium salinarium GRB contig maps reveals extensive rearrangement. AB - Anonymous probes from the genome of Halobacterium salinarium GRB and 12 gene probes were hybridized to the cosmid clones representing the chromosome and plasmids of Halobacterium salinarium GRB and Haloferax volcanii DS2. The order of and pairwise distances between 35 loci uniquely cross-hybridizing to both chromosomes were analyzed in a search for conservation. No conservation between the genomes could be detected at the 15-kbp resolution used in this study. We found distinct sets of low-copy-number repeated sequences in the chromosome and plasmids of Halobacterium salinarium GRB, indicating some degree of partitioning between these replicons. We propose alternative courses for the evolution of the haloarchaeal genome: (i) that the majority of genomic differences that exist between genera came about at the inception of this group or (ii) that the differences have accumulated over the lifetime of the lineage. The strengths and limitations of investigating these models through comparative genomic studies are discussed. PMID- 8682792 TI - The D-Alanyl carrier protein in Lactobacillus casei: cloning, sequencing, and expression of dltC. AB - The incorporation of D-alanine into membrane-associated D-alanyl-lipoteichoic acid in Lactobacillus casei requires the 56-kDa D-alanine-D-alanyl carrier protein ligase (Dcl) and the 8.9-kDa D-alanyl carrier protein (Dcp). To identify and isolate the gene encoding Dcp, we have cloned and sequenced a 4.3-kb chromosomal fragment that contains dcl (dltA). In addition to this gene, the fragment contains three other genes, dltB, d1tC, and a partial dltD gene. dltC (246 nucleotides) was subcloned from this region and expressed in Escherichia coli. The product was identified as apo-Dcp lacking the N-terminal methionine (8,787.9 Da). The in vitro conversion of the recombinant apo-Dcp to holo-Dcp by recombinant E. coli holo-ACP synthase provided Dcp which accepts activated D alanine in the reaction catalyzed by Bcl. The recombinant D-alanyl-Dcp was functionally identical to native D-alanyl-Dcp in the incorporation of D-alanine into lipoteichoic acid. L. casei Dcp is 46% identical to the putative product of dltC in the Bacillus subtilis dlt operon (M. Perego, P. Glaser, A. Minutello, M. A. Strauch, K. Leopold, and W. Fischer, J. Biol. Chem. 270:15598-15606, 1995), and therefore, this gene also encodes Dcp. Comparisons of the primary sequences and predicted secondary structures of the L. casei and B. subtilis Dcps with that of the E. coli acyl carrier protein (ACP) were undertaken together with homology modeling to identify the functional determinants of the donor and acceptor specificities of Dcp. In the region of the phospho-pantetheine attachment site, significant similarity between Dcps and ACPs was observed. This similarity may account for the relaxed acceptor specificity of the Dcps and ACPs in the ligation Of D-alanine catalyzed by Dcl. In contrast, two Dcp consensus sequences, KXXVLDXLA and DXVKXNXD, share little identity with the rest of the ACP family and, thus, may determine the donor specificity of D-alanyl-Dcp in the D alanylation of membrane-associated D-alanyl-lipoteichoic acid. PMID- 8682793 TI - FtsZ ring formation in fts mutants. AB - The formation of FtsZ rings (Z rings) in various fts mutants was examined by immunoelectron microscopy and immunofluorescence. In two temperature-sensitive ftsZ mutants which form filaments with smooth morphology, the Z ring was unable to form. In ftsA, ftsI, and ftsQ mutants, which form filaments with an indented morphology, Z rings formed but their contraction was blocked. These results indicate that fully functional ftsA, ftsQ, and ftsI genes are not required for Z ring formation and are unlikely to have a role in localization of the Z ring. The results also suggest that one function of the Z ring is to localize the activity of other fts gene products. PMID- 8682794 TI - Cloning and sequencing a human homolog (hMYH) of the Escherichia coli mutY gene whose function is required for the repair of oxidative DNA damage. AB - We have cloned the human mutY gene (hMYH) from both genomic and cDNA libraries. The human gene contains 15 introns and is 7.1 kb long. The 16 exons encode a protein of 535 amino acids that displays 41% identity to the Escherichia coli protein, which provides an important function in the repair of oxidative damage to DNA and helps to prevent mutations from oxidative lesions. The human mutY gene maps on the short arm of chromosome 1, between p32.1 and p34.3. PMID- 8682795 TI - Nitrate reductase activity and heterocyst suppression on nitrate in Anabaena sp. strain PCC 7120 require moeA. AB - Mutants of Anabaena sp. strain PCC 7120 that form heterocysts when grown on nitrate-containing media were isolated following nitrosoguanidine mutagenesis. Six independent mutants were isolated, and the characterization of one mutant, strain AMC260, which forms 6 to 8% heterocysts in the presence of nitrate, is presented. A 1.8-kb chromosomal fragment that complemented the AMC260 mutant was sequenced, and a 1.2-kb open reading frame, named moeA, was identified. The deduced amino acid sequence of the predicted Anabaena sp. strain PCC 7120 MoeA polypeptide shows 37% identity to MoeA from Escherichia coli, which is required for the synthesis of molybdopterin cofactor. Molybdopterin is required by various molybdoenzymes, such as nitrate reductase. Interruption of the moeA gene in Anabaena sp. strain PCC 7120 resulted in a strain, AMC364, that showed a phenotype similar to that of AMC260. We show that AMC260 and AMC364 lack methyl viologen-supported nitrate reductase activity. We conclude that the inability of the moeA mutants to metabolize nitrate results in heterocyst formation on nitrate containing media. Northern (RNA) analysis detected a 1.5-kb moeA transcript in wild-type cells grown in the presence or absence of a combined nitrogen source. PMID- 8682796 TI - Disruption of the serine proteinase gene (sep) in Aspergillus flavus leads to a compensatory increase in the expression of a metalloproteinase gene (mep20). AB - The serine proteinase gene (sep) in Aspergillus flavus was disrupted by homologous recombination with a hygromycin resistance gene as the marker. The gene-disrupted mutant GR-2 contained a single-copy insertion of the marker gene and did not express the sep gene. Serine proteinase activity, 36-kDa protein labeled by 3H-diisopropylfluorophosphate, and immunologically detectable proteinase were not detected in the culture fluid of GR-2. Despite the absence of the serine proteinase, the total elastinolytic activity levels in the mutant and the wild-type A.flavus were comparable. Immunoblots revealed that the mutant secreted greater amounts of an elastinolytic metalloproteinase gene (mep20) product than did the wild type. Furthermore, mep20 mRNA levels, measured by RNase protection assay, in the mutant were higher than those in the wild type. Inhibition of the serine proteinase by Streptomyces subtilisin inhibitor (SSI) in the culture medium of wild-type A.flavus also resulted in an elevation of mep20 gene products. Although no serine proteinase activity could be detected, the level of elastinolytic activity of the SSI-treated culture was comparable to that of the control. Immunoblots revealed that the addition of SSI caused an elevation in the levels of metalloproteinase and its mRNA. These results suggest that the expression of the genes encoding serine and metalloproteinases are controlled by a common regulatory system and the fungus has a mechanism to sense the status of extracellular proteolytic activities. PMID- 8682797 TI - Identification of a major cis-acting DNA element controlling the bidirectionally transcribed penicillin biosynthesis genes acvA (pcbAB) and ipnA (pcbC) of Aspergillus nidulans. AB - The beta-lactam antibiotic penicillin is produced as a secondary metabolite by some filamentous fungi. In this study, the molecular regulation of the Aspergillus (Emericella) nidulans penicillin biosynthesis genes acvA (pcbAB) and ipnA (pcbC) was analyzed. acvA and ipnA are divergently oriented and separated by an intergenic region of 872 bp. Translational fusions of acvA and ipnA with the two Escherichia coli reporter genes lacZ and uidA enabled us to measure the regulation of both genes simultaneously. A moving-window analysis of the 872-bp intergenic region indicated that the divergently oriented promoters are, at least in part, overlapping and share common regulatory elements. Removal of nucleotides -353 to -432 upstream of the acvA gene led to a 10-fold increase of acvA-uidA expression and simultaneously to a reduction of ipnA-lacZ expression to about 30%. Band shift assays and methyl interference analysis using partially purified protein extracts revealed that a CCAAT-containing DNA element within this region was specifically bound by a protein (complex), which we designated PENR1, for penicillin regulator. Deletion of 4 bp within the identified protein binding site caused the same contrary effects on acvA and ipnA expression as observed for all of the deletion clones which lacked nucleotides -353 to -432. The PENR1 binding site thus represents a major cis-acting DNA element. The intergenic regions of the corresponding genes of the beta-lactam-producing fungi Penicillium chrysogenum and Acremonium chrysogenum also diluted the complex formed between the A. nidulans probe and PENR1 in vitro, suggesting that these beta-lactam biosynthesis genes are regulated by analogous DNA elements and proteins. PMID- 8682798 TI - RNase E polypeptides lacking a carboxyl-terminal half suppress a mukB mutation in Escherichia coli. AB - We have isolated suppressor mutants that suppress temperature-sensitive colony formation and anucleate cell production of a mukB mutation. A linkage group (smbB) of the suppressor mutations is located in the rne/ams/hmp gene encoding the processing endoribonuclease RNase E. All of the rne (smbB) mutants code for truncated RNase E polypeptides lacking a carboxyl-terminal half. The amount of MukB protein was higher in these rne mutants than that in the rne+ strain. These rne mutants grew nearly normally in the mukB+ genetic background. The copy number of plasmid pBR322 in these rne mutants was lower than that in the rne+ isogenic strain. The results suggest that these rne mutations increase the half-lives of mukB mRNA and RNAI of pBR322, the antisense RNA regulating ColE1-type plasmid replication. We have demonstrated that the wild-type RNase E protein bound to polynucleotide phosphorylase (PNPase) but a truncated RNase E polypeptide lacking the C-terminal half did not. We conclude that the C-terminal half of RNase E is not essential for viability but plays an important role for binding with PNPase. RNase E and PNPase of the multiprotein complex presumably cooperate for effective processing and turnover of specific substrates, such as mRNAs and other RNAs in vivo. PMID- 8682799 TI - Cloning, sequencing, and characterization of the nucH gene encoding an extracellular nuclease from Aeromonas hydrophila JMP636. AB - An Escherichia coli clone expressing activity on DNase agar was obtained by cloning chromosomal DNA of Aeromonas hydrophila JMP636 into plasmid pUC19. Examination (of the clone's nuclease activity on a sodium dodecyl sulfate (SDS) polyacrylamide gel containing DNA as a substrate revealed an activity band at approximately 100 kDa. Subsequently, subcloning localized the gene, designated nucH, to a 3.6-kb DNA fragment (pJP9521). Southern blotting of the nucH gene against chromosomal DNA of JMP636 confirmed that it had originated from this strain and demonstrated that it was present in a single copy, although additional faint bands were also detected. Analysis of the subclone using in vivo transcription and translation revealed only a single polypeptide of approximately 110 kDa. Sequencing of pJP9521 predicted an open reading frame of 3,213 bp encoding a protein of 1,070 amino acids and having a molecular mass of 114 kDa. Comparison of the deduced nucleotide sequence and the NucH predicted protein sequence with relevant databases indicated that no known homologs have previously been identified. A signal sequence was predicted from these data, and cellular fractionation of a nucH clone in E. coli indicated that the protein was able to be processed to the periplasm. An activity similar in size was detected in an extracellular protein sample of JMP636, while inactivation of the nucH gene resulted in loss of this activity band. By native SDS-polyacrylamide gel electrophoresis, NucH substrate specificity, cofactor requirements, and sensitivity to denaturing agents were assessed. PMID- 8682800 TI - Population genetic analysis of Helicobacter pylori by multilocus enzyme electrophoresis: extensive allelic diversity and recombinational population structure. AB - Genetic diversity and relationships in 74 Helicobacter pylori isolates recovered from patients assigned to distinct clinical categories were estimated by examination of allelic variation in six genes encoding metabolic housekeeping enzymes by multilocus enzyme electrophoresis. Seventy-three distinct allele profiles, representing multilocus chromosomal genotypes, were identified. All six loci were highly polymorphic, with an average of 11.2 alleles per locus. The mean genetic diversity in the sample was 0.735, a value that exceeds the level of diversity recorded in virtually all bacterial species studied by multilocus enzyme electrophoresis. A high frequency of occurrence of null alleles (lack of enzyme activity) was identified and warrants further investigation at the molecular level. Lack of linkage disequilibrium (nonrandom association (of alleles over loci) indicates that horizontal transfer and recombination of metabolic enzyme genes have contributed to the generation of chromosomal diversity in H. pylori. In this sample of isolates, there was no statistically significant association of multilocus enzyme electrophoretic types or cluster of related chromosomal types and disease category. PMID- 8682801 TI - Caulobacter and Asticcacaulis stalk bands as indicators of stalk age. AB - The prosthecae (stalks) of dimorphic caulobacters of the genera Caulobacter and Asticcacaulis are distinguished among such appendages by the presence of disk like components known as stalk bands. Whether bands are added to a cell's stalk(s) as a regular event coordinated with the cell's reproductive cycle has not been settled by previous studies. Analysis of the frequency of stalks with i, i + 1, i + 2, etc. bands 'among more than 7,000 stalks of Caulobacter crescentus revealed that in finite (batch) cultures (in which all offspring accumulate), the proportion of stalks with i + 1 hands was regularly 50% of the proportion of stalks with i bands. This implied that the number of bands correlated with the number of reproductive cycles completed by a stalked cell. In chemostat maintained perpetual cultures, the proportion was greater than 50% because stalked cells, with their shorter reproductive cycle times, contributed a larger proportion of offspring to the steady-state population than did their swarmer siblings. In Asticcacaulis biprosthecum cells, which bear twin prosthecae, the twins on a typical cell possessed the same number of bands. For both genera, stalk bands provide a unique morphological feature that could be employed in an assessment of age distribution and reproductive dynamics within natural populations of these caulobacters. PMID- 8682803 TI - Sulfate transport in Penicillium chrysogenum plasma membranes. AB - Transport studies with Penicillium chrysogenum plasma membranes fused with cytochrome c oxidase liposomes demonstrate that sulfate uptake is driven by the transmembrane pH gradient and not by the transmembrane electrical potential. Ca2+ and other divalent cations are not required. It is concluded that the sulfate transport system catalyzes the symport of two protons with one sulfate anion. PMID- 8682802 TI - Cloning, characterization, and regulation of nifF from Rhodobacter capsulatus. AB - The Rhodobacter capsulatus nifF gene and upstream sequence were cloned by using a probe based on the N-terminal sequence of NifF. nifF was found to not be contained in the previously described nif regions I, II, and III. Comparison of the deduced amino acid sequence showed that it is highly similar to NifF from Azotobacter vinelandii and NifF from Klebsiella pneumoniae. Analysis of translational fusions demonstrated that the regulation of transcription was the same as previously reported at the protein level. Insertional mutagen esis showed that NifF contributes significantly to nitrogenase activity under normal nitrogen fixing conditions and that it is absolutely required for nitrogen fixation under iron limitation. PMID- 8682804 TI - The activity of the high-affinity K+ uptake system Kdp sensitizes cells of Escherichia coli to methylglyoxal. AB - Expression of the Kdp system sensitizes cells to methylglyoxal (MG) whether this electrophile is added externally or is synthesized endogenously. The basis of this enhanced sensitivity is the maintenance of a higher cytoplasmic pH (pHi) in cells expressing Kdp. In such cells, MG elicits rapid cytoplasmic acidification via KefB and KefC, but the steady-state pHi attained is still too high to confer protection Lowering pHi further by incubation with acetate increases the sensitivity of cells to MG. PMID- 8682805 TI - A simple gel electrophoretic method for analyzing the muropeptide composition of bacterial peptidoglycan. AB - The muropeptide composition of bacterial peptidoglycan is currently most efficiently determined by reverse-phase high-pressure liquid chromatography (HPLC). Though sensitive, the HPLC procedure is technically demanding and has been applied to a relatively small number of bacterial strains and species. We have found that fluorescence-assisted carbohydrate electrophoresis (FACE) is a simple, rapid method by which reducing muropeptides from multiple peptidoglycan samples can be visualized. Individual reducing muropeptides were covalently labeled with the fluorescent molecule 8-aminonaphthalene-1,3,6-trisulfonic acid, after which they were separated by electrophoresis through a 35% polyacrylamide gel and visualized by exposure to UV light. FACE detected the appropriate numbers of reducing muropeptides in the proper proportions for four bacteria: Escherichia coli, Pseudomonas aeruginosa, Enterobacter cloacae, and Yersinia enterocolitica. As little as 2 to 5 pmol per muropeptide was detected when the intensity of the fluorescent signal was measured with a charge-coupled device camera, at a level of sensitivity between 50 and 250 times higher than that of the classic HPLC technique. Thus, FACE may be used to identify interesting peptidoglycan samples prior to more-extensive analysis by HPLC, or FACE may eventually replace HPLC for some applications. PMID- 8682806 TI - Use of PCR to isolate genes encoding sigma54-dependent activators from diverse bacteria. AB - Degenerate PCR probes were used to amplify gene fragments encoding the catalytic domain of sigma54-dependent transcription activators. The procedure should be widely applicable, as it recovered both known and novel gene fragments: 5 from Rhizobium meliloti, 13 from Myxococcus xanthus, and 3 from Bacillus subtilis. No fragments were obtained from Synechococcus sp. strain PCC 7002 or Saccharomyces cerevisiae. PMID- 8682807 TI - Structure modification induced in the narG promoter by binding of integration host factor and NARL-P. AB - Interaction of integration host factor (IHF) with linear DNA fragments containing the narG promoter region induced an apparent sharp bend in the DNA centered at the IHF-binding site. Binding of NARL-P to two sites adjacent to the IHF site did not induce bending or modify the apparent bending induced by IHF. PMID- 8682808 TI - PstB protein of the phosphate-specific transport system of Escherichia coli is an ATPase. AB - The PstB protein of the phosphate-specific transport (Pst) system of Escherichia coli bound and hydrolyzed ATP, producing ADP. Urea-treated denatured PstB did not bind ATP. The N-terminal amino acid sequence of the immune serum-precipitable PstB protein was determined, and it corresponded to that deduced from the DNA sequence. PMID- 8682809 TI - A glutamate-dependent acid resistance gene in Escherichia coli. AB - Stationary-phase cultures of Escherichia coli can survive several hours or exposure to extreme acid (pH 2 to 3), a level well below the pH range for growth (pH 4.5 to 9). To identify the genes needed for survival in extreme acid, a microliter screening procedure was devised. Colonies from a Tn10 transposon pool in E. coli MC4100 were inoculated into buffered Luria broth, pH 7.0, in microtiter wells, grown overnight, and then diluted in Luria broth, pH 2.5, at 37 degrees C for 2 h. From 3,000 isolates screened, 3 Tet(r) strains were identified as extremely acid sensitive (<0.1% survival at pH 2.5 for 2 h). Flanking sequences of the Tn10 inserts were amplified by inverse PCR. The sequences encoded a hydrophobic partial peptide of 88 residues. A random-primer-generated probe hybridized to Kohara clones 279 and 280 at 32 min (33.7 min on the revised genomic map EcoMap7) near gadB (encoding glutamate decarboxylase). The gene was designated xasA for extreme acid sensitive. xasA::Tn10 strains grown at pH 7 to 8 showed 100-fold-less survival in acid than the parent strain. Growth in mild acid (pH 5 to 6) restored acid resistance; anaerobiosis was not required, as it is for acid resistance in rpoS strains. xasA::Tn10 eliminated enhancement of acid resistance by glutamic acid. xasA was found to be a homolog of gadC recently sequenced in Shigella flexneri, in which it appears to encode a permease for the decarboxylated product of GadB. These results suggest that GadC (XasA) participates in a glutamate decarboxylase alkalinization cycle to protect E. coli from cytoplasmic acidification. The role of the glutamate cycle is particularly important for cultures grown at neutral pH before exposure to extreme acid. PMID- 8682810 TI - The binding site of the IclR repressor protein overlaps the promoter of aceBAK. AB - In Escherichia coli, repression of the aceBAK operon is mediated by the IclR protein. We used an in vitro oligonucleotide selection technique to determine the consensus recognition sequence for MR. Mutational analysis confirmed the contribution of this sequence to repression in vivo and identified the -35 element of the promoter. PMID- 8682811 TI - Physical map of the Western X-disease phytoplasma chromosome. AB - A physical map of the chromosome of the western X-disease phytoplasma was constructed and represents the first physical map of a phytoplasma chromosome. The western X-disease phytoplasma is a nonculturable, plant-pathogenic member of the class Mollicutes and is the causal agent of a severe disease of fruit trees in North America. The map was generated by performing restriction digests of the chromosome and resolving the restriction fragments by pulsed-field gel electrophoresis. Southern blot analysis using cloned phytoplasma probes confirmed the arrangement of contiguous restriction fragments. The locations of 20 restriction sites for the enzymes SalI, XhoI, BssHII, RsrII, SmaI, and NotI were mapped on the chromosome, which is circular and comprises approximately 670 kb. The locations or the two rRNA operons and of four previously cloned fragments of chromosomal DNA were also placed on the map. PMID- 8682812 TI - The Herbert screw for fractures of the scaphoid. PMID- 8682814 TI - Established nonunion of the scaphoid treated by volar wedge grafting and Herbert screw fixation. AB - We reviewed 26 consecutive men of mean age 28 years who had wedge bone grafting and Herbert screw fixation for symptomatic established nonunion of the waist of the scaphoid. The period between injury and operation averaged 30 months (10 to 96), and 11 of the 26 patients had had previous operations, seven with bone grafts. At a mean follow-up of 14 months (6 to 42) 25 fractures (95%) had united at a median time of four months. Symptoms were improved in all patients. The outcome was not related to the time between injury and surgery or to pre-existing degenerative changes. Previous surgery carried a worse prognosis. The technique is difficult but can achieve union even when previous surgery and bone grafting have failed. The usual result is improved function and some relief of pain. PMID- 8682813 TI - Herbert screw fixation of scaphoid fractures. AB - We reviewed the records of 431 patients who had open reduction and internal fixation of the scaphoid performed by one surgeon (TJH) over a 13-year period. The Herbert bone screw provided adequate internal fixation without the use of plaster immobilisation, promoting a rapid functional recovery. On average, patients returned to work 4.7 weeks after surgery and wrist function was significantly improved, even when the fracture failed to unite. Healing rates for acute fractures were better than those reported for plaster immobilisation and were independent of fracture location. In the case of established nonunions, healing depended on the stage and location of the fracture, but the progress of arthritis was halted and carpal collapse significantly improved. Internal fixation of the scaphoid using the Herbert bone screw, although technically demanding, has few complications and appears to offer significant advantages over other methods of treatment. PMID- 8682815 TI - Carpal Box radiography in suspected scaphoid fracture. AB - We have assessed the value of using a simple apparatus,the Carpal Box, in patients with suspected scaphoid fracture, to produce elongated and magnified radiographs of the carpus. The interobserver agreement between 60 observers of standard scaphoid radiographs and longitudinal and transverse Carpal Box radiographs (X-CB) was compared in 11 patients. Three-phase bone scanning was used as a comparative standard. If at least 75% of the observers agreed and the result was confirmed by three-phase bone scanning, the outcome was termed reliable. Scaphoid radiographs and the longitudinal X-CB films were reliable in four patients and the transverse X-CB films in six patients. The bone scan suggested a scaphoid fracture in five of the 11 patients. Agreement in the interpretation of the standard scaphoid radiographs was acceptable in only 36% of patients: in interpretation of transverse Carpal Box radiographs this figure increased to 55%. PMID- 8682816 TI - Soft-tissue balance and recovery of proprioception after total knee replacement. AB - Decreasing proprioception of the knee is multifactorial and is a function of age and degenerative joint disease. Soft-tissue release during total knee replacement may have an influence. We have quantified soft-tissue imbalance at the time of knee replacement and attempted to eliminate it at full extension, using established methods. We studied the influence of residual soft-tissue imbalance on postoperative proprioception, assessing this in 38 patients before total knee replacement and at three and six months postoperatively. We found that proprioception improved in varus knees at three and six months after soft-tissue balancing procedures. Knees balanced in full extension and in flexion (< +/- 2 degrees) showed a significant improvement in proprioception (p < 0.0005) whereas those which were not balanced in flexion but fully balanced in extension had no significant improvement. We conclude that soft-tissue balance in both flexion and extension is important to allow satisfactory postoperative proprioception of the knee. PMID- 8682817 TI - Hypersensitivity in aseptic loosening of total hip replacements. The role of constituents of bone cement. AB - Aseptic loosening is seen in a significant proportion of cemented total hip replacements (THR). In a small subgroup of patients who suffer early loosening polyethylene debris is unlikely to be responsible. We recently reported one case of allergic contact dermatitis to N,N-dimethylparatoluidine (DMT), an accelerator used in bone cement. We have therefore investigated this using skin-patch tests to a variety of substances including metals, polyethylene and the separated individual components of Simplex cement. We studied 70 patients, 15 with aseptic loosening less than two years after THR, 25 with satisfactory long-term cemented fixation, five with infected loosening of cemented THRs and 25 awaiting hip arthroplasty. We found seven positive reactions to DMT, all of them in patients with the rapid onset of aseptic loosening. Allergy to DMT is recognized in the dental profession in respect of the 'denture sore mouth' syndrome, and could also be an occupational hazard since some industrial glues contain DMT. Our results suggest the need for awareness of possible previous dental or occupational exposure of the constituents of bone cement. We recommend the use of skin-patch testing in high-risk cases. PMID- 8682818 TI - Graded compression stockings for prevention of deep-vein thrombosis after hip and knee replacement. AB - We performed a prospective, randomised controlled trial in 177 patients who were having either total hip or knee replacement, to evaluate the use of both above- and below-knee graded compression stockings in the prevention of deep-vein thrombosis (DVT). With above-knee stockings, we found no significant reduction of the overall, proximal or major calf (> 5 cm) DVT rates. With below-knee stockings, the overall thrombosis rate was similar to that of the control group but the stockings appeared to have altered the pattern of thrombosis. Patients who had total hip replacement and wore below-knee stockings had a significantly higher rate of proximal or major calf DVT (p = 0.03). This pattern was reversed in patients with total knee replacement who developed a significantly lower rate of proximal or major calf DVT with below-knee stockings (p < 0.05). Our results showed that, with the exception of below-knee stockings in knee replacement patients, graded compression stockings were ineffective in preventing DVT after hip or knee replacement surgery. PMID- 8682819 TI - Short-term recovery from hip and knee arthroplasty. AB - There are many studies of long-term recovery from major point arthroplasty, but little is known about the first days and weeks after operation. We measured function, emotional state and life evaluation before arthroplasty and at seven and 50 days after in a consecutive series of 40 hip and 23 knee replacements. Pain was relieved significantly at seven days after hip arthroplasty and even more at 50 days. In knee patients, pain relief was modest and was not apparent until 50 days. Functional ability was much improved by 50 days in hip patients, but hardly changed in knee patients. Positive mood and life satisfaction did not improve in either group. Our findings will help with more accurate information for patients before operation and also in judging the rate of recovery. PMID- 8682820 TI - The omega lateral approach to the hip. AB - We describe a modified lateral approach to the hip which exploits the function continuity of gluteus medius and vastus lateralis and their dense crescentic attachment to the greater trochanter. The gluteus medius is not incised or split, but is detached and mobilised with gluteus minimus as one unit. This facilitates reattachment of the glutei and helps to preserve abductor function. PMID- 8682821 TI - Medial ankle pain after lateral ligament rupture. AB - After a severe ankle sprain the incidence of residual complaints, particularly on the medial side of the joint, is high. We studied a consecutive series of 30 patients who had operative repair of acute ruptures of lateral ligaments. During operation, arthroscopy revealed a fresh injury to the articular cartilage in 20 ankles, in 19 at the tip and/or anterior distal part of the medial malleolus as well as on the opposite medial facet of the talus. In six patients, a loose piece of articular cartilage was found. We conclude that in patients with a rupture of one or more of the lateral ankle ligaments after an inversion injury, an impingement occurs between the medial malleolus and the medial facet of the talus. Patients with a lesion of the lateral ankle ligament caused by a high velocity injury (a faulty landing during jumping or running) had a higher incidence of macroscopic cartilage damage (p < 0.01), medially-located pressure pain (p = 0.06) and medially-located complaints at one-year follow-up (p = 0.02) than those with low-velocity injury (a stumble). PMID- 8682822 TI - Comparison of two conservative methods of treating an isolated fracture of the lateral malleolus. AB - We compared two conservative methods of treating Weber B1 (Lauge-Hansen supination-eversion 2) isolated fractures of the lateral malleolus in 65 patients. Treatment by immediate weight-bearing and mobilisation resulted in earlier rehabilitation than immobilisation for four weeks in a plaster cast. There was no significant difference in the amount of pain experienced or in the requirement for analgesics and early mobilisation was not associated with any complications. We therefore advocate early mobilisation for these stable ankle fractures. PMID- 8682823 TI - MRI in acute knee dislocation. A prospective study of clinical, MRI, and surgical findings. AB - We treated 17 knees in 15 patients with severe ligament derangement and dislocation by open repair and reconstruction. We assessed the competence of all structures thought to be important for stability by clinical examination, MRI interpretation, and surgery. Our findings showed that in these polytrauma patients clinical examination was not an accurate predictor of the extent or site of soft-tissue injury (53% to 82% correct) due mainly to the limitations of associated injuries. MRI was more accurate (85% to 100% correct) except for a negative result for the lateral collateral ligament and posterolateral capsule. The detail and reliability of MRI are invaluable in the preoperative planning of the surgical repair and reconstruction of dislocated knees. PMID- 8682824 TI - Reamed or unreamed nailing for closed tibial fractures. A prospective study in Tscherne C1 fractures. AB - We performed a prospective, randomised study on 50 patients with Tscherne C1 tibial diaphyseal fractures comparing treatment with reamed and unreamed intramedullary nails. Our results show that reamed nailing is associated with a significantly lower time to union and a reduced requirement for a further operation. Unreamed nailing should not be used in the treatment of the common Tscherne C1 tibial fracture. PMID- 8682825 TI - Thermal necrosis after tibial reaming for intramedullary nail fixation. A report of three cases. AB - We present three young men who sustained closed diaphyseal fracture of the tibia and later developed severe osteocutaneous necrosis induced by heat during intramedullary reaming. They all had a narrow medullary cavity and in all a tourniquet had been used. Each developed a pretibial cutaneous blister soon after operation. In the following month severe osteomyelitis ensued, requiring segmental resection and osteocutaneous reconstruction. PMID- 8682826 TI - Fractures of the distal end of the radius treated by internal fixation and early function. A preliminary report of 20 cases. AB - Fractures of the distal end of the radius should be treated on the same principles as other fractures involving joints. Displaced articular fractures require open reduction to allow anatomical reconstruction of both the radiocarpal and the radio-ulnar joints. For extra-articular fractures with severe comminution and shortening this enables the radial length to be re-established achieving radio-ulnar congruency. Stable internal fixation can be achieved with two 2.0 AO titanium plates placed on each of the 'lateral' and the 'intermediate' columns of the wrist at an angle of 50 degrees to 70 degrees. This gives good stability despite the tiny dimensions of the plates, and allows early function. We report a series of 20 fractures treated by this method of internal fixation with satisfactory results in all. PMID- 8682827 TI - Questionnaire on the perceptions of patients about shoulder surgery. AB - We developed a 12-item questionnaire for completion by patients having shoulder operations other than stabilisation. A prospective study of 111 patients was undertaken before operation and at follow-up six months later. Each patient completed the new questionnaire and the SF36 form. Some filled in the Stanford Health Assessment Questionnaire (HAQ). An orthopaedic surgeon assessed the Constant shoulder score. The single score derived from the questionnaire had a high internal consistency. Reproducibility, examined by test-retest reliability, was found to be satisfactory. The validity of the questionnaire was established by obtaining significant correlations in the expected direction with the Constant score and the relevant scales of the SF36 and the HAQ. Sensitivity to change was assessed by analysing the differences between the preoperative scores and those at follow-up. Changes in scores were compared with the patients' responses to postoperative questions about their condition. The standardised effect size for the new questionnaire compared favourably with that for the SF36 and the HAQ. The new questionnaire was the most efficient in distinguishing patients who said that their shoulder was much better from all other patients. The shoulder questionnaire provides a measure of outcome for shoulder operations which is short, practical, reliable, valid and sensitive to clinically important changes. PMID- 8682828 TI - Shoulder pain in long-term haemodialysis patients. A clinical study of 166 patients. AB - We reviewed 166 adult patients on long-term haemodialysis, dividing them into three groups according to the presence and type of shoulder pain. The 24 patients in group A, with spontaneous pain related to a supine posture, had been under haemodialysis for significantly longer than the others, and had a much higher incidence of carpal tunnel syndrome. Open or arthroscopic resection of the coracoacromial ligament in 21 shoulders relieved pain during haemodialysis and night pain, and histological examination showed amyloid deposits and inflammatory cell infiltration in the subacromial bursa in almost all cases, and in the tenosynovium of the bicipital groove in some. We conclude that one type of shoulder pain experienced by patients on long-term haemodialysis is caused by the subacromial impingement of amyloid deposits. This should be distinguished from other types of shoulder pain, because it can be relieved by resection of the coracoacromial ligament. PMID- 8682829 TI - The afferent pathways of discogenic low-back pain. Evaluation of L2 spinal nerve infiltration. AB - The afferent pathways of discogenic low-back pain have not been fully investigated. We hypothesised that this pain was transmitted mainly by sympathetic afferent fibres in the L2 nerve root, and in 33 patients we used selective local anaesthesia of this nerve. Low-back pain disappeared or significantly decreased in all patients after the injection. Needle insertion provoked pain which radiated to the low back in 23 patients and the area of skin hypoalgesia produced included the area of pre-existing pain in all but one. None of the nine patients with related sciatica had relief of that component of their symptoms. Our findings show that the main afferent pathways of pain from the lower intervertebral discs are through the L2 spinal nerve root, presumably via sympathetic afferents from the sinuvertebral nerves. Discogenic low-back pain should be regarded as a visceral pain in respect of its neural pathways. Infiltration of the L2 nerve is a useful diagnostic test and also has some therapeutic value. PMID- 8682830 TI - The cervical spine in athetoid cerebral palsy. A radiological study of 180 patients. AB - We have reviewed the cervical spine radiographs of 180 patients with athetoid cerebral palsy and compared them with those of 417 control subjects. Disc degeneration occurred earlier and progressed more rapidly in the patients, with advanced disc degeneration in 51%, eight times the frequency in normal subjects. At the C3/4 and C4/5 levels, there was listhetic instability in 17% and 27% of the patients, respectively, again six and eight times more frequently than in the control subjects. Angular instability was seen, particularly at the C3/4, C4/5 and C5/6 levels. We found a significantly higher incidence of narrowing of the cervical canal in the patients, notably at the C4 and C5 levels, where the average was 14.4 mm in the patients and 16.4 mm in normal subjects. The combination of disc degeneration and listhetic instability with a narrow canal predisposes these patients to relatively rapid progression to a devastating neurological deficit. PMID- 8682831 TI - Torticollis secondary to ocular pathology. AB - We report a series of 15 children, six male and nine female, of average age 20 months, seen at a paediatric orthopaedic clinic with torticollis. Orthopaedic examination revealed a normal range of neck movement in all cases but in seven there was palpable tightness in the absence of true shortening or contracture of the sternomastoid muscle. The patients were prospectively referred for ocular examination. In five of the 15 an ocular cause for the torticollis was detected with underaction of the superior oblique muscle in three, paresis of the lateral rectus muscle in one and nystagmus in one. Another two patients were found to have an abnormal ocular examination which was thought to be unrelated to their torticollis. Three of the patients with ocular torticollis required extra-ocular muscle surgery to abolish the head tilt and one of these had a tight sternomastoid muscle. Two of the non-ocular group had surgical release of the sternomastoid muscle; in the rest, the condition either resolved with physiotherapy or required no active treatment. We recommend that all patients with torticollis and no clear orthopaedic cause are referred for ocular assessment since it is not possible clinically to distinguish ocular from non ocular causes. PMID- 8682832 TI - Management of Perthes disease of late onset in southern India. The evaluation of a surgical method. AB - We analysed the short-term outcome after varus osteotomy for Perthes' disease in 48 older children from south-west India, comparing them with 30 historical controls. The children were between 7 and 12 years of age at the onset of the disease. All had stage-I or stage-II disease, with half or more of the epiphysis involved. The operated children had an open-wedge subtrochanteric varus osteotomy with derotation or extension and a trochanteric epiphyseodesis. Weight-bearing was avoided until late stage III. The non-operated children had been treated symptomatically by conservative methods. At the time of healing, 62.5% of the operated group had spherical femoral heads compared with 20% of those treated non operatively (p < 0.001). Of the operated children with Catterall group-IV involvement, 48% had good results as against 24% of the non-operated group (p < 0.05). The percentage increase in the radius of the affected femoral head compared with the normal side was significantly lower in children who had operations (14.68 v 25.65; p < 0.001). We have shown that the short-term results of early surgical containment in children over seven years of age are satisfactory. PMID- 8682833 TI - Avascular necrosis and the Pavlik harness. The incidence of avascular necrosis in three types of congenital dislocation of the hip as classified by ultrasound. AB - We analysed the incidence of avascular necrosis in 101 hips of 90 infants with congenital dislocation treated with Pavlik harness and followed up for more than one year. Using ultrasonography in the flexed-abducted position the hips were classified as type A when the femora head was displaced posteriorly, but within the socket and making contact with the posterior inner wall of the acetabulum; type B when it was in contact with the posterior margin of the acetabulum, with its centre at this level or anterior to it; and type C when it was displaced out of the socket, with its centre posterior to the posterior rim of the acetabulum. Eighty-seven hips were reduced by the harness (86%), and seven of these developed avascular necrosis (8%). All 69 hips with type-A dislocation were reduced and only one (1.4%) showed slight avascular necrosis. Eighteen (78.3%) of 23 hips with type-B dislocation were reduced, and six developed avascular necrosis (33.3%). In one hip, the femoral head was severely damaged. None of the nine hips with type-C dislocation was reduced in the harness. We concluded that the Pavlik harness is indicated for type-A but not for type-B or type-C dislocations. PMID- 8682834 TI - Hip abnormalities detected by ultrasound in clinically normal newborn infants. AB - We have followed the natural progress of newborn infants in whom ultrasound examination showed abnormalities in hips which appeared to be clinically normal. Over six years we saw 306 such children out of 9952 examined (31 per 1000 live births). The examination was repeated at two to three months and those who still showed an abnormality were followed up further. At four to five months a standard radiograph was obtained, and treatment began if this and another ultrasound scan were both abnormal. At this stage, 291 infants had normal hips. In the 15 infants with abnormal hips there was no pronounced deterioration, none developed a frank dislocation, and all became normal after treatment in an abduction splint. Newborn infants with abnormal and suspicious ultrasound findings who are normal on clinical examination do not need treatment from birth; most of these hips will settle spontaneously. Treatment can be postponed until the age of four to five months unless clinical instability develops or ultrasound shows dislocation. The criteria for treatment should be based on measurements by both ultrasound and radiography: both should show an abnormality before intervention is considered necessary. PMID- 8682835 TI - Periprosthetic bone resorption. Particles versus movement. AB - Using a rat model, we created a bone-to-titanium interface and applied phagocytosable high-density polyethylene particles between the bone and implant, either initially or when the interface had matured. No fibrous membrane developed and no bone resorption was found. If sliding movements were initiated at the interface after two weeks, there was formation of a fibrous membrane. The additional application of particles did not change the thickness of the membrane, and there were only minor qualitative changes. Creation of a membrane by movement followed by cessation of movement and the application of particles caused the membrane to persist, whereas in a particle-free control group bone-to-metal contact was re-established. Our findings suggest that mechanical stimuli are of primary importance for prosthetic loosening, and that particles may modulate the later stages of the loosening process. PMID- 8682836 TI - Influence of materials for fixation implants on local infection. An experimental study of steel versus titanium DCP in rabbits. AB - Resistance to infection may be influenced by foreign bodies such as devices for fracture fixation. It is known that stainless steel and commercially-pure titanium have different biocompatibilities. We have investigated susceptibility to infection after a local bacterial challenge using standard 2.0 dynamic compression plates of either stainless steel or titanium in rabbit tibiae. After the wounds had been closed, various concentrations of a strain of Staphylococcus aureus were inoculated percutaneously. Under otherwise identical experimental conditions the rate of infection for steel plates (75%) was significantly higher than that for titanium plates (35%) (p < 0.05). PMID- 8682837 TI - The outcome and functional results of diaphyseal endoprostheses after tumour excision. AB - Improvement in the life expectancy of patients with primary bone tumours has led to increased emphasis on limb salvage and preservation of function. Between 1979 and 1994 we used custom-made endoprostheses in 18 patients to reconstruct diaphyseal defects after excision of primary bone tumours. The mean age at operation was 26 years (9 to 64) and the median follow-up 65 months (6 to 188). Fifteen patients have survived and are free from local or metastatic disease. Local recurrence developed in one patient. Using the modified Enneking functional scoring system, 77% of the patients achieved 80% or more of their premorbid functional capability. Mechanical loosening, limb shortening and secondary osteoarthritis were the main complications. There were no infections. We conclude that diaphyseal endoprostheses offer a good clinical and functional outcome in the lower limb. PMID- 8682838 TI - Surgical resection of primary soft-tissue sarcoma. Incidence of residual tumour in 95 patients needing re-excision after local resection. AB - We reviewed retrospectively 236 consecutive patients seen in our soft-tissue sarcoma clinic. Of these, 95 had had a primary soft-tissue sarcoma excised elsewhere, but with histologically inadequate resection margins. All these patients had a secondary and wider re-excision. The tissues removed at the secondary re-excision were examined histologically for the presence of residual tumour. Definite tumour tissue was found in 29 of 55 lower-limb specimens, 16 of 25 upper-limb, 7 of 10 trunk and 4 of 5 head and neck specimens. In 31 cases some residual tumour was visible macroscopically, and in 56 of the 95 patients (59%) the primary tumour had been incompletely excised. Our results indicated that surgical assessment of the adequacy of excision is very inaccurate and that most local recurrences are the consequence of inadequate primary surgery. The large number of patients who had inadequate initial treatment emphasises the need for a co-ordinated multidisciplinary approach to the management of patients with soft tissue sarcoma. PMID- 8682839 TI - Spontaneous resolution of an osseous bridge affecting the distal tibial epiphysis. PMID- 8682840 TI - Prosthetic replacement of a chondrosarcoma of the upper end of the femur: a 43 year follow-up. PMID- 8682841 TI - Recurrent locking of the wrist due to dorsal midcarpal subluxation. PMID- 8682842 TI - Idiopathic osteolysis of the acetabulum: a case report. PMID- 8682843 TI - CT-guided trephine excision of an infected iliac pin site after pelvic fracture. PMID- 8682844 TI - Chronic anterior glenohumeral instability. PMID- 8682845 TI - Incidence of cancer after total hip replacement. PMID- 8682846 TI - Conservative treatment of complete ACL tears. PMID- 8682847 TI - Conservative treatment of complete ACL tears. PMID- 8682848 TI - Quantifying osteonecrosis of the femoral head using MRI. PMID- 8682849 TI - RSA in the assessment of aseptic loosening. PMID- 8682850 TI - Eosinophilic synovitis. PMID- 8682851 TI - Acute compartment syndrome in tibial diaphyseal fractures. PMID- 8682853 TI - Orthopaedic proceedings, 1994-1995. Abstracts. PMID- 8682852 TI - Percutaneous autogenous bone-marrow grafting. PMID- 8682855 TI - The yeast nucleoporin Nup188p interacts genetically and physically with the core structures of the nuclear pore complex. AB - We have isolated a major protein constituent from a highly enriched fraction of yeast nuclear pore complexes (NPCs). The gene encoding this protein, Nup188p, was cloned, sequenced, and found to be nonessential upon deletion. Nup188p cofractionates with yeast NPCs and gives an immunofluorescent staining pattern typical of nucleoporins. Using immunoelectron microscopy, Nup188p was shown to localize to both the cytoplasmic and nucleoplasmic faces of the NPC core. There, Nup188p interacts with an integral protein of the pore membrane domain, Pom152p, and another abundant nucleoporin, Nic96p. The effects of various mutations in the NUP188 gene on the structure of the nuclear envelope and the function of the NPC were examined. While null mutants of NUP188 appear normal, other mutants allelic to NUP188 exhibit a dominant effect leading to the formation of NPC-associated nuclear envelope herniations and growth inhibition at 37 degrees C. In addition, depletion of the interacting protein Pom152p in cells lacking Nup188p resulted in severe deformations of the nuclear envelope. We suggest that Nup188p is one of a group of proteins that form the octagonal core structure of the NPC and thus functions in the structural organization of the NPC and nuclear envelope. PMID- 8682854 TI - Nic96p is required for nuclear pore formation and functionally interacts with a novel nucleoporin, Nup188p. AB - The amino-terminal domain of Nic96p physically interacts with the Nsp1p complex which is involved in nucleocytoplasmic transport. Here we show that thermosensitive mutations mapping in the central domain of Nic96p inhibit nuclear pore formation at the nonpermissive temperature. Furthermore, the carboxyterminal domain of Nic96p functionally interacts with a novel nucleoporin Nup188p in an allele-specific fashion, and when ProtA-Nup188p was affinity purified, a fraction of Nic96p was found in physical interaction. Although NUP188 is not essential for viability, a null mutant exhibits striking abnormalities in nuclear envelope and nuclear pore morphology. We propose that Nic96p is a multivalent protein of the nuclear pore complex linked to several nuclear pore proteins via its different domains. PMID- 8682856 TI - Dynamic localization of the nuclear import receptor and its interactions with transport factors. AB - Characterization of the interactions between soluble factors required for nuclear transport is key to understanding the process of nuclear trafficking. Using a synthetic lethal screen with the rna1-1 strain, we have identified a genetic interaction between Rna1p, a GTPase activating protein required for nuclear transport, and yeast importin-beta, a component of the nuclear localization signal receptor. By the use of fusion proteins, we demonstrate that Rna1p physically interacts with importin-beta. Mutants in importin-beta exhibit in vivo nuclear protein import defects, and importin-beta localizes to the nuclear envelope along with other proteins associated with the nuclear pore complex. In addition, we present evidence that importin-alpha, but not importin-beta, mislocalizes to the nucleus in cells where the GTPase Ran is likely to be in the GDP-bound state. We suggest a model of nuclear transport in which Ran-mediated hydrolysis of GTP is necessary for the import of importin-alpha and the nuclear localization signal-bearing substrate into the nucleus, while exchange of GDP for GTP on Ran is required for the export of both mRNA and importin-alpha from the nucleus. PMID- 8682857 TI - A biosynthetic regulated secretory pathway in constitutive secretory cells. AB - It has frequently been proposed that while the constitutive secretory pathway is present in all cells, the regulated secretory pathway is found only in specialized cells such as neuronal, endocrine, or exocrine types. In this study we provide evidence that suggests that this distinction is not as restrictive as proposed. We have identified a population of post-Golgi storage vesicles in several constitutive secretory cells using [35S]SO4-labeled glycosaminoglycan (GAG) chains as a marker. A fraction of this pool of vesicles can undergo exocytosis in response to stimuli such as cytoplasmic Ca2+ and phorbol esters. The effect of Ca2+ was demonstrated both in intact cells in the presence of the ionophore A23187 and in streptolysin-O-permeabilized semi-intact cells. N ethylmaleiimide, under conditions known to block regulated and constitutive secretion, inhibited the stimulated secretion from these cells, suggesting that the observed release of labeled GAG chains was not due to a leakage artefact. Subcellular fractionation revealed that the stored GAG chains were in low-density membrane granules (d approximately 1.12 g/ml), whose size was greater than that of synaptic-like vesicles found in PC12 cells. In addition, in CHO cells that express epitope-tagged rab 3D, the labeled GAG chains were found to cofractionate with the exogenous rab protein. When expressed in the regulated cell line AtT-20, this tagged rab protein was found to colocalize with ACTH-containing dense-core granules by indirect immunofluorescence. Taken together, these results provide evidence for the presence of a cryptic regulated secretory pathway in "constitutive" cells and suggest that the regulated secretory pathway is more widespread amongst different cell types than previously believed. PMID- 8682858 TI - Oligomerization and maturation of Na,K-ATPase: functional interaction of the cytoplasmic NH2 terminus of the beta subunit with the alpha subunit. AB - Subunit assembly plays an essential role in the maturation of oligomeric proteins. In this study, we have characterized the main structural and functional consequences of the assembly of alpha and beta subunits of Na,K-ATPase. Xenopus oocytes injected with alpha and/or beta cRNA were treated with brefeldin A, which permitted the accumulation of individual subunits or alpha-beta complexes in the ER. Only alpha subunits that are associated with beta subunits become resistant to trypsin digestion and cellular degradation. Similarly, assembly with beta subunits is necessary and probably sufficient for the catalytic alpha subunit to acquire its main functional properties at the level of the ER, namely the ability to adopt different ligand-dependent conformations and to hydrolyze ATP in an Na(+)- and K(+)-dependent, ouabain-inhibitable fashion. Not only the alpha but also the beta subunit undergoes a structural change after assembly, which results in a global increase in its protease resistance. Furthermore, extensive and controlled proteolysis assays on wild-type and NH2-terminally modified beta subunits revealed a K(+)-dependent interaction of the cytoplasmic NH2 terminus of the beta subunit with the alpha subunit, which is likely to be involved in the modulation of the K(+)-activation of the Na,K-pump transport activity. Thus, we conclude that the ER assembly process not only establishes the basic structural interactions between individual subunits, which are required for the maturation of oligomeric proteins, but also distinct, functional interactions, which are involved in the regulation of functional properties of mature proteins. PMID- 8682859 TI - Mutations in the Drosophila hook gene inhibit endocytosis of the boss transmembrane ligand into multivesicular bodies. AB - Transmembrane ligands can be internalized across cell boundaries into receptor expressing cells. In the developing Drosophila eye imaginal disc, the bride of sevenless transmembrane protein (boss) is expressed on the surface of R8 cells. After internalization into neighboring R7 cells, the boss protein accumulates in multivesicular bodies. In a search for genes that affect this cell-type-specific pattern of boss endocytosis, we found that mutations in the hook gene inhibit the accumulation of boss in multivesicular bodies of R7 cells. In addition, hook flies exhibit pleiotropic phenotypes including abnormal bristle morphology and eye degeneration. The wild-type-pattern of boss endocytosis was restored in hook mutants by a genomic rescue fragment containing the hook gene or by a hook cDNA expressed in R7 cells under control of a sevenless (sev) enhancer. The hook gene encodes a novel cytoplasmic protein of 679 amino acids with a central coiled-coil domain of some 200 amino acids. Truncated, epitope-tagged hook proteins coimmunoprecipitated the full-length protein, indicating dimerization mediated by the coiled-coil domain. The hook protein localizes to vesicular structures that are part of the endocytic compartment. The requirement of the hook protein in R7 cells for the accumulation of boss protein in multivesicular bodies, and the localization of the hook protein to endocytic vesicles indicate that the hook gene encodes a novel component of the endocytic compartment that plays an important role in the endocytosis of transmembrane ligands or their transport to multivesicular bodies. PMID- 8682860 TI - Annexin II in exocytosis: catecholamine secretion requires the translocation of p36 to the subplasmalemmal region in chromaffin cells. AB - Annexin II is a Ca(2+)-dependent membrane-binding protein present in a wide variety of cells and tissues. Within cells, annexin II is found either as a 36-kD monomer (p36) or as a heterotetrameric complex (p90) coupled with the S-100 related protein, p11. Annexin II has been suggested to be involved in exocytosis as it can restore the secretory responsiveness of permeabilized chromaffin cells. By quantitative confocal immunofluorescence, immunoreplica analysis and immunoprecipitation, we show here the translocation of p36 from the cytosol to a subplasmalemmal Triton X-100 insoluble fraction in chromaffin cells following nicotinic stimulation. A synthetic peptide corresponding to the NH2-terminal domain of p36 which contains the phosphorylation sites was microinjected into individual chromaffin cells and catecholamine secretion was monitored by amperometry. This peptide blocked completely the nicotine-induced recruitment of p36 to the cell periphery and strongly inhibited exocytosis evoked by either nicotine or high K+. The light chain of annexin II, p11, was selectively expressed by adrenergic chromaffin cells, and was only present in the subplasmalemmal Triton X-100 insoluble protein fraction of both resting and stimulated cells. p11 can modify the Ca(2+)- and/or the phospholipid-binding properties of p36. We found that loss Ca2+ was required to stimulate the translocation of p36 and to trigger exocytosis in adrenergic chromaffin cells. Our findings suggest that the translocation of p36 to the subplasmalemmal region is an essential event in regulated exocytosis and support the idea that the presence of p11 in adrenergic cells may confer a higher Ca2+ affinity to the exocytotic pathway in these cells. PMID- 8682861 TI - The synaptic vesicle cycle: a single vesicle budding step involving clathrin and dynamin. AB - Strong evidence implicates clathrin-coated vesicles and endosome-like vacuoles in the reformation of synaptic vesicles after exocytosis, and it is generally assumed that these vacuoles represent a traffic station downstream from clathrin coated vesicles. To gain insight into the mechanisms of synaptic vesicle budding from endosome-like intermediates, lysed nerve terminals and nerve terminal membrane subfractions were examined by EM after incubations with GTP gamma S. Numerous clathrin-coated budding intermediates that were positive for AP2 and AP180 immunoreactivity and often collared by a dynamin ring were seen. These were present not only on the plasma membrane (Takei, K., P.S. McPherson, S.L.Schmid, and P. De Camilli. 1995. Nature (Lond.). 374:186-190), but also on internal vacuoles. The lumen of these vacuoles retained extracellular tracers and was therefore functionally segregated from the extracellular medium, although narrow connections between their membranes and the plasmalemma were sometimes visible by serial sectioning. Similar observations were made in intact cultured hippocampal neurons exposed to high K+ stimulation. Coated vesicle buds were generally in the same size range of synaptic vesicles and positive for the synaptic vesicle protein synaptotagmin. Based on these results, we suggest that endosome-like intermediates of nerve terminals originate by bulk uptake of the plasma membrane and that clathrin- and dynamin-mediated budding takes place in parallel from the plasmalemma and from these internal membranes. We propose a synaptic vesicle recycling model that involves a single vesicle budding step mediated by clathrin and dynamin. PMID- 8682862 TI - Ultrastructural and biochemical characterization of autophagy in higher plant cells subjected to carbon deprivation: control by the supply of mitochondria with respiratory substrates. AB - Autophagy triggered by carbohydrate starvation was characterized at both biochemical and structural levels, with the aim to identify reliable and easily detectable marker(s) and to investigate the factors controlling this process. Incubation of suspension cells in sucrose-free culture medium triggered a marked degradation of the membrane polar lipids, including phospholipids and galactolipids. In contrast, the total amounts of sterols, which are mainly associated with plasmalemma and tonoplast membranes, remained constant. In particular, phosphatidylcholine decreased, whereas phosphodiesters including glycerylphosphorylcholine transiently increased, and phosphorylcholine (P-Cho) steadily accumulated. P-Cho exhibits a remarkable metabolic inertness and therefore can be used as a reliable biochemical marker reflecting the extent of plant cell autophagy. Indeed, whenever P-Cho accumulated, a massive regression of cytoplasm was noticed using EM. Double membrane-bounded vacuoles were formed in the peripheral cytoplasm during sucrose starvation and were eventually expelled into the central vacuole, which increased in volume and squeezed the thin layer of cytoplasm spared by autophagy. The biochemical marker P-Cho was used to investigate the factors controlling autophagy. P-Cho did not accumulate when sucrose was replaced by glycerol or by pyruvate as carbon sources. Both compounds entered the cells and sustained normal rates of respiration. No recycling back to the hexose phosphates was observed, and cells were rapidly depleted in sugars and hexose phosphates, without any sign of autophagy. On the contrary, when pyruvate (or glycerol) was removed from the culture medium, P-Cho accumulated without a lag phase, in correlation with the formation of autophagic vacuoles. These results strongly suggest that the supply of mitochondria with respiratory substrates, and not the decrease of sucrose and hexose phosphates, controls the induction of autophagy in plant cells starved in carbohydrates. PMID- 8682863 TI - Traffic, polarity, and detergent solubility of a glycosylphosphatidylinositol anchored protein after LDL-deprivation of MDCK cells. AB - Glycosylphosphatidylinositol-anchored proteins, GPI-proteins, are selectively delivered to the apical surfaces of many types of morphologically polarized epithelial cells. It has been proposed that the unit for targeting GPI-proteins to the apical surface is a membrane lipid domain. This sorting domain or molecular cluster has been equated to detergent (Triton X-100)-insoluble membrane fractions that are enriched in enriched in GPI-proteins, glycosphingolipids, and cholesterol. To determine the role of cholesterol in the formation of sorting domains and to examine its importance in the intracellular traffic and membrane polarity of GPI-proteins, we studied the behavior of a model GPI-protein, gD1 DAF, in MDCK cells cultured for 3 or 14 d without their principal source of cholesterol, serum LDL. LDL deprivation affects the intracellular traffic of gD1 DAF. Surface expression of gD1-DAF is reduced in LDL-deprived cells; this reduction is most marked after 3 d of LDL deprivation. We also find a great reduction in the fraction of gD1-DAF that is detergent-insoluble in these cells and a change in its membrane milieu defined by susceptibility to cleavage with PI specific phospholipase C. Despite these changes, the surface polarity of gD1-DAF is no different in LDL-deprived cells than in control cells. PMID- 8682864 TI - Synthetic lethality screen identifies a novel yeast myosin I gene (MYO5): myosin I proteins are required for polarization of the actin cytoskeleton. AB - The organization of the actin cytoskeleton plays a critical role in cell physiology in motile and nonmotile organisms. Nonetheless, the function of the actin based motor molecules, members of the myosin superfamily, is not well understood. Deletion of MYO3, a yeast gene encoding a "classic" myosin I, has no detectable phenotype. We used a synthetic lethality screen to uncover genes whose functions might overlap with those of MYO3 and identified a second yeast myosin 1 gene, MYO5. MYO5 shows 86 and 62% identity to MYO3 across the motor and non-motor regions. Both genes contain an amino terminal motor domain, a neck region containing two IQ motifs, and a tail domain consisting of a positively charged region, a proline-rich region containing sequences implicated in ATP-insensitive actin binding, and an SH3 domain. Although myo5 deletion mutants have no detectable phenotype, yeast strains deleted for both MYO3 and MYO5 have severe defects in growth and actin cytoskeletal organization. Double deletion mutants also display phenotypes associated with actin disorganization including accumulation of intracellular membranes and vesicles, cell rounding, random bud site selection, sensitivity to high osmotic strength, and low pH as well as defects in chitin and cell wall deposition, invertase secretion, and fluid phase endocytosis. Indirect immunofluorescence studies using epitope-tagged Myo5p indicate that Myo5p is localized at actin patches. These results indicate that MYO3 and MYO5 encode classical myosin I proteins with overlapping functions and suggest a role for Myo3p and Myo5p in organization of the actin cytoskeleton of Saccharomyces cerevisiae. PMID- 8682865 TI - Actin organization, bristle morphology, and viability are affected by actin capping protein mutations in Drosophila. AB - Regulation of actin filament length and orientation is important in many actin based cellular processes. This regulation is postulated to occur through the action of actin-binding proteins. Many actin-binding proteins that modify actin in vitro have been identified, but in many cases, it is not known if this activity is physiologically relevant. Capping protein (CP) is an actin-binding protein that has been demonstrated to control filament length in vitro by binding to the barbed ends and preventing the addition or loss of actin monomers. To examine the in vivo role of CP, we have performed a molecular and genetic characterization of the beta subunit of capping protein from Drosophila melanogaster. We have identified mutations in the Drosophila beta subunit-these are the first CP mutations in a multicellular organism, and unlike CP mutations in yeast, they are lethal, causing death during the early larval stage. Adult files that are heterozygous for a pair of weak alleles have a defect in bristle morphology that is correlated to disorganized actin bundles in developing bristles. Our data demonstrate that CP has an essential function during development, and further suggest that CP is required to regulate actin assembly during the development of specialized structures that depend on actin for their morphology. PMID- 8682867 TI - A novel member of the rho family of small GTP-binding proteins is specifically required for cytokinesis. AB - Several members of the rho/rac family of small GTP-binding proteins are known to regulate the distribution of the actin cytoskeleton in various subcellular processes. We describe here a novel rac protein, racE, which is specifically required for cytokinesis, an actomyosin-mediated process. The racE gene was isolated in a molecular genetic screen devised to isolate genes required for cytokinesis in Dictyostelium. Phenotypic characterization of racE mutants revealed that racE is not essential for any other cell motility event, including phagocytosis, chemotaxis, capping, or development. Our data provide the first genetic evidence for the essential requirement of a rho-like protein, specifically in cytokinesis, and suggest a role for these proteins in coordinating cytokinesis with the mitotic events of the cell cycle. PMID- 8682866 TI - A novel suppressor of ras1 in fission yeast, byr4, is a dosage-dependent inhibitor of cytokinesis. AB - A novel gene, designated byr4, was identified in Schizosaccharomyces pombe that affects the mitotic cell cycle and shows genetic interactions with the ras1 signaling pathways. Null alleles of byr4 cause cell cycle arrest in late mitosis and permit multiple rounds of septation. The multiple septa typically divide two nuclei, but the nuclei frequently do not stain equally with 4',6-diamidino-2 phenylindole (DAPI), suggesting that byr4 is required for proper karyokinesis. Overexpression of byr4 inhibits cytokinesis, but cell cycle progression continues leading to multinucleate cells. When byr4 is overexpressed, the early steps in the cytokinesis pathway, including formation of the medial F-actin ring, occur normally; however, the later steps in the pathway, including contraction of the F actin ring, septation, and rearrangement of the medial F-actin following mitosis, rarely occur, byr4 shows two genetic interactions with ras1. The inhibition of cytokinesis by byr4 overexpression was exacerbated by null alleles of ras1 and scd1, suggesting a link between pathways needed for cell polarity and cytokinesis. Overexpression of byr4 also partially bypasses the need for ras1 for sporulation. The electrophoretic mobility of the byr4 protein varied in response to mutants that perturb cytokinesis and karyokinesis, suggesting interactions between byr4 and these gene products. A more rapidly migrating byr4 protein was found in cells with mutations in cdc16, which undergo repeated septation, and in cdc15, which fail to form a medial F-actin ring in mitosis. A slower migrating byr4 protein was found in cells with a mutation in the beta-tubulin gene, which arrests cells at the metaphase-anaphase transition. PMID- 8682869 TI - Active transport of photoactivated tubulin molecules in growing axons revealed by a new electron microscopic analysis. AB - To determine whether tubulin molecules transported in axons are polymers or oligomers, we carried out electron microscopic analysis of the movement of the tubulin molecules after photoactivation. Although previous optical microscopic analyses after photobleaching or photoactivation had suggested that most of the axonal microtubules were stationary, they were not sufficiently sensitive to allow detection of actively transported tubulin molecules which were expected to be only a small fraction of total tubulin molecules in axons. In addition, some recent studies using indirect approaches suggested active polymer transport as a mechanism for tubulin transport (Baas, P.W., F.J. Ahmad. 1993. J. Cell Biol. 120:1427-1437; Yu, W., V.E. Centonze, F.J. Ahmad, and P.W. Bass, 1993, J. Cell Biol. 122:349-359; Ahmad, F.J., and P.W. Bass. 1995. J. Cell Sci. 108:2761-2769). So, whether transported tubulin molecules are polymers or not remain to be determined. To clear up this issue, we made fluorescent marks on the tubulin molecules in the axons using a photoactivation technique and performed electron microscopic immunocytochemistry using anti-fluorescein antibody. Using this new method we achieved high resolution and high sensitivity for detecting the transported tubulin molecules. In cells fixed after permeabilization, we found no translocated microtubules. In those fixed without permeabilization, in which oligomers and heterodimers in addition to polymers were preserved, we found much more label in the regions distal to the photoactivated regions than in the proximal regions. These data indicated that tubulin molecules are transported not as polymers but as heterodimers or oligomers by an active mechanism rather than by diffusion. PMID- 8682868 TI - Yeast ubiquitin-like genes are involved in duplication of the microtubule organizing center. AB - KAR1 is required for duplication of the Saccharomyces cerevisiae microtubule organizing center, the spindle pole body (SPB) (Rose, M.D., and G.R. Fink, 1987. Cell. 48:1047-1060). Suppressors of a kar1 allele defective for SPB duplication were isolated in two genes, CDC31 and DSK2 (Vallen, E.A., W.H., M. Winey, and M.D. Rose. 1994. Genetics. 137:407-422). To elucidate the role of DSK2 in SPB duplication, we cloned the gene and found it encodes a novel ubiquitin-like protein containing an NH2 terminus 36% identical to ubiquitin. The only other known yeast ubiquitin-like protein is encoded by the nucleotide excision repair gene RAD23 (Watkins, J.F.,P. Sung, L. Prakash, and S. Prakash. 1993. Mol. Cell. Bio. 13:7757-7765). Unlike ubiquitin, the NH2-terminal domain of Dsk2p is not cleaved from the protein, indicating that Dsk2p is not conjugated to other proteins. Although the DSK2-1 mutation alters a conserved residue in the Dsk2p ubiquitin-like domain, we detect no differences in Dsk2p or Cdc31p stability. Therefore, DSK2 does not act by interfering with ubiquitin-dependent protein degradation of these proteins. Although DSK2 is not essential, a strain deleted for both DSK2 and RAD23 is temperature sensitive for growth due to a block in SPB duplication. In addition, overexpression of DSK2 is toxic, and the DSK2-1 allele causes a block in SPB duplication. Therefore, DSK2 dosage is critical for SPB duplication. We determined that CDC31 gene function is downstream of DSK2 and KAR1. Dsk2p is a nuclear-enriched protein, and we propose that Dsk2p assists in Cdc31 assembly into the new SPB. PMID- 8682870 TI - Tubulin transport in neurons. AB - A question of broad importance in cellular neurobiology has been, how is microtubule cytoskeleton of the axon organized? It is of particular interest because of the history of conflicting results concerning the form in which tubulin is transported in the axon. While many studies indicate a stationary nature of axonal microtubules, a recent series of experiments reports that microtubules are recruited into axons of neurons grown in the presence of a microtubule-inhibitor, vinblastine (Baas, P.W., and F.J. Ahmad. 1993.J. Cell Biol. 120:1427-1437: Ahmad F.J., and P.W. Baas. 1995. J. Cell Sci, 108:2761-2769; Sharp, D.J., W. Yu, and P.W. Baas. 1995. J. Cell Biol, 130:93-103; Yu, W., and P.W. Baas. 1995. J. Neurosci. 15:6827-6833.). Since vinblastine stabilizes bulk microtubule-dynamics in vitro, it was concluded that preformed microtubules moved into newly grown axons. By visualizing the polymerization of injected fluorescent tubulin, we show that substantial microtubule polymerization occurs in neurons grown at reported vinblastine concentrations. Vinblastine inhibits, in a concentration-dependent manner, both neurite outgrowth and microtubule assembly. More importantly, the neuron growth conditions of low vinblastine concentration allowed us to visualize the footprints of the tubulin wave as it polymerized and depolymerized during its slow axonal transport. In contrast, depolymerization resistant fluorescent microtubules did not move when injected in neurons. We show that tubulin subunits, not microtubules, are the primary form of tubulin transport in neurons. PMID- 8682871 TI - Mice expressing a mutant desmosomal cadherin exhibit abnormalities in desmosomes, proliferation, and epidermal differentiation. AB - Desmogleins are members of the cadherin superfamily which form the core of desmosomes. In vitro studies indicate that the cytoplasmic domain of desmogleins associates with plakoglobin; however, little is known about the role of this domain in desmosome recognition or assembly in vivo, or about the possible relation of desmoglein mutations to epidermal differentiation and disease. To address these questions we used transgenic mouse technology to produce an NH2 terminally truncated desmoglein (Pemphigus Vulgaris Antigen or Dsg3) in cells known to express its wild-type counterpart. Within 2 d, newborn transgenic animals displayed swelling of their paws, flakiness on their back, and blackening of the tail tip. When analyzed histologically and ultrastructurally, widening of intercellular spaces and disruption of desmosomes were especially striking in the paws and tail. Desmosomes were reduced dramatically in number and were smaller and often peculiar in structure. Immunofluorescence and immunoelectron microscopy revealed no major abnormalities in localization of hemidesmosomal components, but desmosomal components organized aberrantly, resulting in a loss of ultrastructure within the plaque. In regions where desmosome loss was prevalent but where some adhesive structures persisted, the epidermis was thickened, with a marked increase in spinous and stratum corneum layers, variability in granular layer thickness, and parakeratosis in some regions. Intriguingly, a dramatic increase in cell proliferation was also observed concomitant with biochemical changes, including alterations in integrin expression, known to be associated with hyperproliferation. An inflammatory response was also detected in some skin regions. Collectively, these findings demonstrate that a mutation in a desmoglein can perturb epidermal cell-cell adhesion, triggering a cascade of changes in the skin. PMID- 8682872 TI - The phosphoprotein stathmin is essential for nerve growth factor-stimulated differentiation. AB - Stathmin is a ubiquitous cytosolic protein which undergoes extensive phosphorylation in response to a variety of external signals. It is highly abundant in developing neurons. The use of antisense oligonucleotides which selectively block stathmin expression has allowed us to study directly its role in rat PC12 cells. We show that stathmin depletion prevents nerve growth factor (NGF)-stimulated differentiation of PC12 cells into sympathetic-like neurons although the expression of several NGF-inducible genes was not affected. Furthermore, we found that stathmin phosphorylation in PC12 cells which is induced by NGF depends on mitogen-activated protein kinase (MAPK) activity. We conclude that stathmin is an essential component of the NGF-induced MAPK signaling pathway and performs a key role during differentiation of developing neurons. PMID- 8682873 TI - Intracellular pH regulation during spreading of human neutrophils. AB - The regulation of the intracelluar pH (pHi) during spreading of human neutrophils was studied by a combination of fluorescence imaging and video microscopy. Spreading on adhesive substrates caused a rapid and sustained cytosolic alkalinization. This pHi increase was prevented by the omission of external Na+, suggesting that it results from the activation of Na+/H+ exchange. Spreading induced alkalinization was also precluded by the compound HOE 694 at concentrations that selectively block the NHE-1 isoform of the Na+H+ antiporter. Inhibition of Na+/H+ exchange by either procedure unmasked a sizable cytosolic acidification upon spreading, indicative of intracellular acid production. The excess acid generation was caused, at least in part, by the activation of the respiratory burst, since the acidification closely correlated with superoxide production, measured in single spreading neutrophils with dihydrorhodamine-123, and little acid production was observed in the presence of diphenylene iodonium, a blocker of the NADPH oxidase. Moreover, neutrophils from chronic granulomatous disease patients, which do not produce superoxide, failed to acidify. Comparable pHi changes were observed when beta 2 integrins were selectively activated during spreading on surfaces coated with anti-CD18 antibodies. When integrin engagement was precluded by pretreatment with soluble anti-CD18 antibody, the pHi changes associated with spreading on fibrinogen were markedly reduced. Inhibition of microfilament assembly with cytochalasin D precluded spreading and concomitantly abolished superoxide production and the associated pHi changes, indicating that cytoskeletal reorganization and/or an increase in the number of adherence receptors engaged are required for the responses. Neutrophils spread normally when the oxidase was blocked or when pHi was clamped near physiological values with nigericin. Spreading, however, was strongly inhibited when pHi was clamped at acidic values. Our results indicate that neutrophils release superoxide upon spreading, generating a burst of intracellular acid production. The concomitant activation of the Na+/H+ antiport not only prevents the deleterious effects of the acid released by the NADPH oxidase, but induces a net cytosolic alkalinization. Since several functions of neutrophils are inhibited at an acidic pHi, the coordinated activation of pHi regulatory mechanisms along with the oxidase is essential for sustained microbicidal activity. PMID- 8682875 TI - Managed care approaches to diabetes mellitus. PMID- 8682876 TI - Understanding mammography findings. PMID- 8682874 TI - Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. AB - Activated rhoA, a ras-related GTP-binding protein, stimulates the appearance of stress fibers, focal adhesions, and tyrosine phosphorylation in quiescent cells (Ridley, A.J., and A. Hall, 1992. Cell. 70:389-399). The pathway by which rho triggers these events has not been elucidated. Many of the agents that activate rho (e.g., vasopressin, endothelin, lysophosphatidic acid) stimulate the contractility of smooth muscle and other cells. We have investigated whether rho's induction of stress fibers, focal adhesions, and tyrosine phosphorylation is the result of its stimulation of contractility. We demonstrate that stimulation of fibroblasts with lysophosphatidic acid, which activates rho, induces myosin light chain phosphorylation. This precedes the formation of stress fibers and focal adhesions and is accompanied by increased contractility. Inhibition of contractility by several different mechanisms leads to inhibition of rho-induced stress fibers, focal adhesions, and tyrosine phosphorylation. In addition, when contractility is inhibited, integrins disperse from focal adhesions as stress fibers and focal adhesions disassemble. Conversely, upon stimulation of contractility, diffusely distributed integrins are aggregated into focal adhesions. These results suggest that activated rho stimulates contractility, driving the formation of stress fibers and focal adhesions and elevating tyrosine phosphorylation. A model is proposed to account for how contractility could promote these events. PMID- 8682877 TI - Leg pain and kidney disease in a 38-year-old man. PMID- 8682878 TI - Calcium channel blockers and hypertension: 1. New trials. AB - The long-term benefits and risks of using calcium channel blockers to treat hypertension have been called into question by reports of increased incidence of myocardial infarction and death among patients taking these drugs. There is now a worldwide effort, involving more than 30 countries and 100,000 patients, to provide a comprehensive data-base for making informed decisions. PMID- 8682879 TI - CPR: a plea for patient selection. PMID- 8682880 TI - Early treatment of herpes zoster. AB - Although varicella virus vaccine may eventually decrease the incidence of herpes zoster, the disease will continue to plague patients and physicians for at least the next several decades. Recognition of shingles early in its vesicular stage is important, since that is when antiviral treatment is effective. Moreover, a variety of agents are now available for symptomatic relief of postherpetic neuralgia. PMID- 8682881 TI - The haunting memory of a trauma patient. PMID- 8682882 TI - A woman with "atypical" atypical pneumonia. PMID- 8682883 TI - Breast swelling after pacemaker placement in an elderly woman. PMID- 8682884 TI - Weakness and a slow pulse in a 40-year-old woman. PMID- 8682885 TI - A multiplicity of bowel problems. AB - A 55-year-old man presented with a 12-pound weight loss and acute diarrhea. He had had three watery stools a day for 12 days, as well as fever, chills, abdominal pain, nausea, and vomiting. He had not had any bowel movements at night, but noted that the first one each morning was tinged with blood. PMID- 8682886 TI - Vermiforms. PMID- 8682887 TI - Sports participation. PMID- 8682888 TI - Idiopathic anaphylaxis: a purely internal reaction. AB - Episodes are clinically identical to classic anaphylaxis, yet no external allergen or psychological disorder can be identified as the cause of the patient's symptoms and signs. Combinations of a corticosteroid, an H1-histamine receptor blocker, and a sympathomimetic amine are highly effective at inducing control and can often achieve a remission. PMID- 8682889 TI - Emerging roles of nitric oxide in inflammation. AB - The short-lived, highly reactive NO radical arises in two ways: 1) a rapidly triggered process well suited for homeostatic fine-tuning of blood pressure and 2) a prolonged high-level production best suited for microbicidal activity. Roles in vascular "leakiness" and leukocyte extravasation are also emerging. Continued investigation may yield new therapies addressing individual facets of inflammation. PMID- 8682890 TI - Where have all the patrons gone? PMID- 8682891 TI - Sifting the causes of microscopic hematuria. AB - Among the goals of the primary care workup are detection of serious disease and determination of whether referral--such as to a urologist or nephrologist--is indicated. Diagnosis is facilitated when hematuria is accompanied by other findings; isolated hematuria presents a more complex challenge. Measurement of serum complement levels may be helpful in narrowing the differential. PMID- 8682892 TI - Annotation: developmental issues in obsessive-compulsive disorder. PMID- 8682893 TI - Annotation: contemporary approaches to the teaching of reading. PMID- 8682894 TI - Proximity and sociable behaviours in autism: evidence for attachment. AB - Sixteen autistic, 16 normal and 16 Down syndrome children (aged 3-6 years) were observed with their mother and a female stranger in a laboratory playroom. Proximity and sociable behaviours were recorded continuously during three observation sessions. The autistic children showed behaviours indicating that they were clearly attached to their mothers: like the normal and Down syndrome children, they showed all behaviours preferentially to the mother and directed proximity behaviours almost exclusively to her. These attachments were functionally similar to those of the comparison children. The deficits identified in the autistic group were restricted to a set of behaviours which have to do with social interaction such as Show, Give and Mutual Play. Descriptions of the aloof, unattached autistic child were not confirmed. PMID- 8682895 TI - Can children with autism be taught to understand false belief using computers? AB - A specially designed computer version of the Sally-Anne false task belief task was used to teach understanding of false belief to three groups: children with autism, children with Down's Syndrome and young normal children. In an initial assessment children were selected for teaching only if they failed four false belief tasks: the dolls version of the Sally-Anne task (close transfer task) and three other false belief tasks involving different scenarios (distant transfer tasks). Following teaching, all three groups were able to pass the Sally-Anne task, but the children with autism alone were unable to pass the distant transfer tasks. The possibility that the children with autism had developed an alternative strategy in order to pass the instruction task is discussed. PMID- 8682896 TI - Types of dyslexia and the shift to dextrality. AB - The prediction of the right shift theory that there are two types of dyslexia with different distributions of handedness was examined in a large cohort of school children. Dyslexics with poor phonology were less biased to dextrality than controls, while dyslexics without poor phonology tended to be more dextral than controls on measures of hand preference and hand skill. Relatives also differed for handedness, as expected if phonological dyslexics were less likely than nonphonological dyslexics and controls to carry the hypothesized rs + gene. PMID- 8682897 TI - Shy girls and boys: a new look. AB - A new look at shyness in young children involves selecting for shyness, using criteria involving both natural and laboratory contexts, categorizing children (including a group between the two extremes), and including the sex of the child in analyses. Children of both sexes differed significantly across low, medium, and high shy groups, with negative mood, worries and fears, and problem behaviour in preschool being associated with high shyness. Although boys in general and high shy boys in particular had the highest problem behaviour scores in preschool (including acting out behaviour), maternal interactions with high shy boys were positive: significantly more positive than with boys who were high shy in natural settings but low shy in the laboratory, or with high shy girls. Of the girls, maternal style was most positive for the medium shy girls, who also received the highest relative frequency of positive maternal actions during a brief task significantly higher than medium shy boys, as well as high shy girls. PMID- 8682898 TI - Hyperactivity and delay aversion. III: The effect on cognitive style of imposing delay after errors. AB - The claim that impulsiveness associated with hyperactivity is the result of deficits in inhibition of responses over time was examined. The cognitive style of hyperactive children was studied under two conditions. As in previous studies hyperactive children appeared impulsive (i.e. gave shorter latencies and made more errors than controls) under conditions where this style led to shorter trials. In contrast, in a revised condition where each error led to an enforced/fixed trial length, hyperactive children waited as long as controls before responding, but still made more errors. Hyperactive children withheld responses when this offered them the best chance of avoiding extra delay. They were however, unable to use the extra time provided as effectively as controls. The link between hyperactive children's aversion to delay and their poor use of time is discussed. PMID- 8682899 TI - The Diagnostic Interview Schedule for Children (DISC-2.1) in Spanish: reliability in a Hispanic population. AB - The reliability across time, informants and interviewers of the Spanish translation of the DISC-2.1 was tested on a Puerto Rican Hispanic sample using a test-retest design. Levels of reliability between clinic and community samples and between younger and older children were compared to explore the sources of low reliability for certain psychiatric disorders. Parents' reports tended to be more reliable than those of their children, although the difference was less obvious with older children. Reliability was generally higher for the externalizing disorders and when the second interviewer was a psychiatrist rather than a lay interviewer. PMID- 8682900 TI - Body size, parental appraisal, and self-esteem in blind children. AB - This study of self-esteem, body size, and parental views in 9-11-year-old blind children found positive views about self-presentation with no sex or weight differences. Lower self-esteem emerged in children who thought they were judged by parents as too thin but being fat, being appraised as fat, or believing they are thought of as fat by parents, showed no effect on self-esteem. Their responses to questions about the causes, characteristics, and psychosocial functioning of obesity suggest an innate desire and possible need for a more robust stature, a bigger presence, and a feeling of weight which appeared to supercede any acquired negative attitudes to fatness. PMID- 8682901 TI - Fears in American, Australian, Chinese, and Nigerian children and adolescents: a cross-cultural study. AB - The fears of childhood and adolescence may differ from one cultural context to another. We explored this possibility in 1200 American, Australian, Chinese, and Nigerian children and adolescents between 7 and 17 years of age. Responses to a standard fear survey schedule revealed significant differences in the number, content, pattern, and level of fears. Nigerian children and adolescents endorsed fears at higher levels than American, Australian, or Chinese youth who did not differ from one another. However, differences in the pattern and content of fears for boys and girls of different ages were noted across the countries. Results were interpreted within a cultural context, which suggested that cultures which favor inhibition, compliance, and obedience serve to increase levels of fear. Alternative interpretations are offered and limitations of cross-cultural research are explored. PMID- 8682902 TI - Preschoolers of dysphoric mothers. AB - Dysphoric mothers rated their preschool children as having more internalizing and externalizing behavior problems than children of nondysphoric mothers. Observers rated the dysphoric mothers as having more negative affect during play interactions, although their children's affect was not rated more negatively. The dysphoric mother-infant dyads were also rated as having a poorer quality interaction. These data suggest that mothers' chronic dysphoria (75% were chronically dysphoric) has a negative impact on the mothers' perceptions of their children as well as the mothers' and children's interaction behavior. PMID- 8682904 TI - Control of action and thought: normal development and dysfunction in autism: a research note. AB - Thirty-six children with autism, 24 children with learning difficulties (matched with the autistic group for sentence comprehension), and 41 normally-developing preschoolers were given two simple tasks: a hand-game requiring inhibitory control, and a delayed-reward situation tapping metacognitive awareness of strategies for coping with the delay period. For both clinical groups, performance on the two tasks was correlated, even when the effect of comprehension level was partialled out. However, no such correlation was observed for the preschoolers, once age was taken into account. The results are discussed in terms of potential links between executive-function and mental-state awareness. PMID- 8682903 TI - Relationships between serum free fatty acids and zinc, and attention deficit hyperactivity disorder: a research note. AB - The purpose of this study is to evaluate the relationships between serum free fatty acids (FFA) and zinc, and attention deficit hyperactivity disorder (ADHD). Forty eight children with ADHD (33 boys, 15 girls) were included in the patient group and 45 healthy volunteer children (30 boys, 15 girls) constituted the control group. The mean serum FFA level in the patient group was 0.176 +/- 0.102 mEq/L and in control group, 0.562 +/- 0.225 mEq/L (p < .001). The mean serum zinc level of patient group was 60.6 +/- 9.9 micrograms/dl and that of the control group, 105.8 +/- 13.2 micrograms/dl (p < .001). A statistically significant correlation was found between zinc and FFA levels in the ADHD group. These findings indicate that zinc deficiency may play a role in aetiopathogenesis of ADHD. Although we observed decreased FFA levels in ADHD cases, it is necessary to determine whether this condition is a principal cause of ADHD or is secondary to zinc deficiency. PMID- 8682905 TI - Psychological response to the Oklahoma City bombing. AB - The bombing of the Alfred P. Murrah Federal Office Building in Oklahoma City was the most devastating terrorist activity that has occurred in America. Prevention of revictimization of persons seriously affected by the bombing was central to the planned response to this tragedy. Coordination and collaboration among local, state, and national agencies promoted effective clinical services provision, research facilitation, and prevention of revictimization. Information gathered from this cooperative effort will contribute to the effort to minimize the potential for such tragedies in the future as well as help to develop prevention and intervention strategies to reduce the effects when the next such disaster occurs. PMID- 8682906 TI - Measurement and correlates of internalized homophobia: a factor analytic study. AB - We developed a scale to measure internalized homophobia in men who have sex with men, which is comprised of items derived from theoretical and clinical reports of internalized homophobia. Two hundred two men who have sex with men and who attend "Man to Man" sexual health seminars in a midwestern U.S. city completed the scale at baseline. Orthogonal factor analysis revealed four dimensions of internalized homophobia: public identification as gay, perception of stigma associated with being homosexual, social comfort with gay men, and the moral and religious acceptability of being gay. Factor scoring of these dimensions indicated that they were associated significantly with relationship satisfaction, duration of longest relationship, extent of attraction to men and women, proportion of social time with gay people, membership of gay/bisexual groups, HIV serostatus, and disclosure of sexual orientation. Internalized homophobia is measurable and consists of four dimensions that are associated significantly with low disclosure, shorter length of and satisfaction with relationships, lower degree of sexual attraction to men and higher degree of attraction to women, and lower social time with gay people. PMID- 8682907 TI - Social maladjustment indicators in PTSD patients' families of origin. AB - We compared the frequencies with which PTSD patients, psychiatric controls, and hospital employee controls reported that their fathers, mothers, and oldest siblings of each sex had been incarcerated or had received psychiatric/psychological treatment. We also compared estimates of the number of psychiatric hospitalizations, incarcerations, courses of outpatient treatment, treatment sessions, and days of institutionalization undergone by the relatives. Only a chance number of significant differences appeared, which suggests that general psychosocial maladjustment in one's family of origin does not appear to increase trauma survivors' risk for PTSD. PMID- 8682908 TI - Further study of the diagnostic and screening efficiency of the ST-Depression Adjective Check Lists. AB - In order to provide additional data on the diagnostic efficiency of the DACL in a situation in which dual diagnoses that involve depression also are considered, two groups of psychiatric patients completed DACL list E and independently were assigned psychiatric diagnoses via the Psychiatric Diagnostic Interview. Findings indicate that the DACL may be of considerable use in screening for depression. Sensitivity was high for both males and females (.84 and .80, respectively) with a cutting score of 12/13. Correct classification rates were also between 4 and 10% higher than base rates. PMID- 8682909 TI - The role of sensory and nonsensory factors in body size estimations of eating disorder subjects. AB - Body size distortion of anorectic and bulimic subjects was compared to controls via a video-distortion technique. Subjects judged the whole body, chest, hips and stomach regions. A adaptive probit estimation (APE) methodology examined separately the sensory and nonsensory components of body image distortion. Eating disorder subjects overestimated body size more than control subjects. There were no significant differences between eating disorder groups, although there was more variability in eating disorder subjects. Subjects overestimated more on whole body as compared to body regions. There were no differences in sensory sensitivity to detecting size differences between groups. Results indicate that differences in body size distortion between eating disorder and control subjects are due exclusively to affective, nonsensory factors. PMID- 8682910 TI - IQ loss and emotional dysfunctions after mild head injury incurred in a motor vehicle accident. AB - Intelligence and personality dysfunctions after minor traumatic brain injury (TBI) (whiplash; slight head impact) incurred in a motor vehicle accident (MVA) were studied in adults after an average interval of 20 months. There was a mean loss of 14 points of Full Scale IQ from estimated preinjury baseline IQ determined from the standardization group (WAIS-R) without evidence for recovery. Personality dysfunctions included cerebral personality disorder, psychiatric diagnosis (30 of 33 patients), post-traumatic stress disorder, persistent altered consciousness, and psychodynamic reactions to impairment. Cognitive loss is caused by interaction of brain injury with distractions such as pain and emotional distress. Unreported head impact and altered consciousness at the time of accident contribute to the underestimation of brain trauma after minor TBI. PMID- 8682911 TI - Event-related potentials during the Continuous Visual Memory Test. AB - The Continuous Visual Memory Test (CVMT; Trahan & Larrabee, 1988) is a recognition format assessment of figural memory. It includes 112 ambiguous designs presented sequentially, with a number of designs that recur through the 112 presentations. The patient's task is to identify the recurring figures by responding with the word "old" for recurring stimuli and "new" for non-recurring stimuli. This study examined cortical event-related potentials during discrimination of old vs. new stimuli. While no latency differences between stimuli were found, P300 amplitude was greater during recognition of old stimuli and increasingly prominent at anterior sites. A stimulus by electrode site interaction suggests greater functional involvement in the discrimination by the frontal areas. This points to a degree of psychophysiological validation of the CVMT and cortical specificity of the task. PMID- 8682912 TI - Therapists' attitudes about addressing the role of exercise in psychotherapy. AB - A questionnaire was mailed to 250 psychotherapists selected from the National Register of Health Providers in Psychology to assess attitudes regarding the discussion of exercise in psychotherapy. Responses were received from 110 (44%) of this group. The study focused on (1) reasons therapists do or do not address exercise in therapy; (2) beliefs about the efficacy of exercise; (3) the relationship between theoretical orientation and the likelihood of discussing exercise; and (4) the relationship between gender and the likelihood of discussing exercise. We found that exercising therapists are more likely to raise the issue and discuss exercise with their clients. In addition, male therapists are more likely to discuss exercise with their male clients than with their female clients. Although cognitive-behavioral therapists are more likely than psychodynamic therapists to use a cognitive-behavioral approach, no relationship was found between exercise variables and primary orientation. PMID- 8682913 TI - Prediction of adolescent aggression by childhood personality measures: a comparison of projective procedures, self-report tests, and behavior ratings. AB - Projective procedures, self-report measures, and teacher behavior ratings were compared as to which type of assessment best predicted adolescent aggressive behavior 6 years after they were administered. A questionnaire that assesses aggressive behavior was given to 125 adolescents in grades seven through twelve who had been administered a variety of projective, self-report, and teacher ratings of aggression 5 years earlier. Their parents were given the same questionnaire. Controlling for sex, age, and academic ability, the results indicated that children's scores on the projective measures predicted aggressive behaviors 5 years later. In addition, projective procedures were at least as valid as the other types of assessments in predicting aggressive behaviors. Results suggest that criticisms of projective procedures may be addressed with continued efforts to evaluate their validity. PMID- 8682914 TI - Intellectual evaluations of children using human figure drawings: an empirical investigation of two methods. AB - This study evaluated the scoring systems of Goodenough and Harris (1963) and Koppitz (1968) for using human figure drawings to assess the intellectual abilities of children. Drawing scores of 125 children, aged 5 to 15, were compared to their performance on the Wechsler Intelligence Scale for Children Revised (WISC-R), while the drawing scores of a separate group of 74 children, aged 5 to 12, were compared to their performance on the Stanford-Binet Intelligence Scale, Form L-M. While Both drawing systems correlated significantly with the WISC-R as well as the Stanford-Binet, the longer and more detailed Goodenough-Harris had a significantly higher correlation with Performance IQ on the WISC-R than did the Koppitz. Neither drawing system had a pattern of significantly different validity coefficients for children of varying ages or IQ levels. PMID- 8682915 TI - Profile patterns, consistency, and change in the Millon Clinical Multiaxial Inventory-II in cocaine abusers. AB - This study examined the MCMI-II in samples of cocaine-dependent subjects who were receiving treatment in three separate residential facilities. Profile characteristics, patterns of scale stability, and change are reported. MCMI-II elevations are found in all three samples on the Antisocial, Aggressive/Sadistic, Narcissistic, Passive-Aggressive, Borderline, Drug Dependence, and Alcohol Dependence scales at both intake into treatment and discharge. Moderate stability coefficients are found on Basic Personality, Pathological Personality, and Symptom scales. Although some statistically significant mean scale changes between intake and discharge are noted in each sample, few involve change from clinically elevated to below clinical levels. PMID- 8682916 TI - Essential and reactive alcoholism: a review. AB - Methodological characteristics and substantive findings of investigations of essential and reactive alcoholics were reviewed. The data base was comprised of approximately 12 studies published between 1951-1992, most of which employed small samples of hospitalized male alcoholics. Psychometric properties of the Essential-Reactive Alcoholism Questionnaire, the instrument generally used to assess the essential-reactive dimensions, rarely were examined. The weight of the evidence suggests that essential alcoholics have earlier onset and greater severity of alcoholism, lower levels of occupational and educational achievement, more interpersonal conflict, fewer long-term friendships, more antisocial attitudes and conduct, greater density of familial alcoholism, more impaired neuropsychological functioning, and lower resting blood pressure than do reactive alcoholics. Research is needed to assess the prognostic utility of the essential reactive typology and the degree to which the distinction may facilitate patient treatment matching. PMID- 8682917 TI - Correlations among maternal rejection, dropping out of school, and drug use in adolescents: a pilot study. AB - Rejection and hostility scores of mothers whose sons had dropped out of school and of mothers whose sons were in good standing academically formed non overlapping distributions. All mothers of drop-outs had higher hostility and rejection scores than mothers whose sons were doing well academically. Scores of mothers whose sons were still in school, but who were experiencing academic problems, fell midway between these two groups and were significantly different from both. Maternal rejection and hostility also correlated significantly with drug use. Possible causal linkages among these phenomena and clinical and preventive implications were discussed briefly. PMID- 8682918 TI - The influence of endodontic infection on progression of marginal bone loss in periodontitis. AB - The purpose of the present investigation was to determine magnitude and rate of proximal radiographic attachment loss in relation to endodontic infection in periodontally involved teeth. The investigation was conducted as a retrospective longitudinal study on a periodontitis-prone randomly selected referral population, including 175 single-rooted, root-filled teeth in 133 patients. An observation period of at least 3 years was required. Periapical conditions of the selected sample at baseline and re-examination were evaluated on radiographs, independently by 3 investigators. Each single-rooted, root-filled tooth of the sample was given a score according to the combined registrations. Radiographic attachment level was measured as the distance between the most coronal point of the alveolar bone and the apex at the mesial and distal sides of the tooth, and expressed as relative radiographic attachment level (RRAL) (radiographic attachment level at baseline/root length) at proximal sites for every tooth. Multiple regression analysis was used to study change in RRAL over time. Teeth in periodontitis-prone patients with progressing periapical pathology indicating a continuous root canal infection were found to lose comparatively more radiographic attachment than teeth with no signs of periapical pathology or teeth with an established periapical destruction which subsided during the observation period. An approximate 3-fold amplification of the rate of marginal proximal radiographic bone loss by endodontic infection in periodontitis-prone patients was found with an average 0.19 mm/year, while 0.06 mm/year was lost for teeth without endodontic infection or subsiding endodontic involvement. PMID- 8682919 TI - Compartmentalization of inflammatory cell phenotypes in normal gingiva and peri implant keratinized mucosa. AB - The interpretation of studies aimed at understanding the pathophysiology of periodontal breakdown has been hampered by an insufficient understanding of the physiology of host responses in clinically healthy gingiva. This investigation was aimed at the evaluation of the in situ phenotype and topographic distribution of the inflammatory cells in clinically normal gingiva and peri-implant keratinized mucosa (PIKM). Soft tissue biopsies were obtained from clinically healthy gingiva or PIKM in 14 patients. Acetone fixed, cryostat sections were stained with a panel of monoclonal antibodies with a three stage avidin-biotin immunoperoxidase technique. Numbers of positive cells/mm2 were determined with a calibrated image analysis system. The major findings of the study were: (i) the presence of significantly higher densities of phenotypically characterized mononuclear cells in the ICT than in the JE in both gingiva and PIKM; (ii) the absence of a significant difference in PMN densities between JE and ICT in both gingiva and PIKM; (iii) the absence of statistically significant differences in densities of phenotypically characterized leukocytes associated with gingiva and PIKM; (iv) the presence of regional differences in the relative proportions of immunocompetent cells in both the gingiva and PIKM. It is concluded that inflammatory cells are selectively distributed in gingiva and PIKM. Unique functional compartments could be identified. The observed compartmentalization requires selective regulatory mechanisms. PMID- 8682920 TI - Smoking and periodontal disease severity. AB - This study was performed to assess the influence of smoking on periodontal disease severity. Data concerning periodontal status and smoking habits were collected from 889 periodontal patients: 340 male and 549 female, 21 to 76 years of age, 47.4% being non smokers and 52.6% smokers. Periodontal parameters, recorded by the same examiner (PMC), were: gingival recession (GR), Pocket depth (PD), Probing attachment level (PAL), and mobility (M). The influence of age, sex and tobacco consumption on these periodontal parameters was statistically evaluated using an analysis of variance (ANOVA) with covariates. A non-linear effect model was also fitted by taking the natural logarithms of the response variables (GR, PD, PAL) closer to biomedical phenomena. Mobility was analyzed by a chi2-test. The effect of smoking on periodontitis showed no association with age or with sex. Smoking, age and sex were shown to be statistically significant for periodontitis, by performing both univariate (t-test for equal means) and multivariate tests. p-values for smoking and periodontitis were: GR (p=0.000), PD (p=0.000), PAL (p=0.000) and M (P=0.015). Smoking one cigarette per day, up to 10, and up to 20, increased PAL by 0.5%, 5% and 10%, respectively. The impact of tobacco is comparable to the impact resulting from the factor of age in this sample, increasing PAL by 0.7% for each year of life. Comparison between smokers of less than 10 cigarettes per day (PAL mean 3.72 mm +/-0.86) and non-smokers (PAL mean 3.84 +/- 0.89) showed no differences in PAL (p=0.216), while comparison for smokers from 11 to 20 cigarettes (PAL mean 4.36 +/- 1.23) and for more than 20 cigarettes (PAL mean 4.50 +/- 1.04) demonstrated significant differences (p=0.000). These findings suggest that: (1) tobacco increases periodontal disease severity; (2) this effect is clinically evident above consumption of a certain quantity of tobacco. PMID- 8682921 TI - The effect of oxidising mouthrinses compared with chlorhexidine on salivary bacterial counts and plaque regrowth. AB - For various clinical indications, oxidising agents have been used in dentistry for many years. Little is known, however, of their antibacterial activity and their ability to inhibit plaque formation. In this study, 2 mouthrinses containing peroxyborate (Bocasan) and peroxycarbonate (Kavosan) were compared alongside a negative control saline rinse and a positive control chlorhexidine rinse (Corsodyl) for their ability to inhibit plaque reformation. Employing a randomised four replicate 4 x 4 latin square cross over design and, whilst omitting all other oral hygiene, plaque was measured by area and index after rinsing for 4 days. In a second study, in vivo antibacterial effects of the rinses were assessed by measuring salivary bacterial counts following single rinses with the preparations at various time intervals over 7 h. Plaque inhibition by chlorhexidine was significantly greater than the other rinses. All rinses were significantly better than the saline rinse at inhibiting plaque. For plaque area, the peroxycarbonate rinse was significantly better than the peroxyborate rinse at inhibiting plaque. Salivary bacterial count reductions were significantly greater compared to saline with chlorhexidine at all time intervals up to 7 h. Whilst both peroxyborate and peroxycarbonate rinses produced greater reductions in bacterial counts than saline up to 3 h, at no time interval were the differences significant. The findings of these studies would suggest oxidising mouthrinses may inhibit plaque formation not by a direct antibacterial effect, but by some other mechanism. The magnitude of plaque reductions obtained with the peroxyborate and more so peroxycarbonate rinses would suggest a need for further study of these preparations when used as adjuncts to normal toothbrushing. PMID- 8682922 TI - Guided tissue regeneration in the treatment of degree II furcations in maxillary molars. AB - he present clinical trial was designed to evaluate the clinical effect of GTR in the treatment of degree II furcation defects in maxillary molars. 28 patients, 21 to 59 years of age, referred for treatment of advanced periodontal disease were included. They presented with similar periodontal lesions in the right and the left maxillary molar regions, but had only one surface which exhibited furcation involvement. A total of 28 pairs of contralateral furcation defects of degree II including 18 interproximal pairs (10 mesial, 8 distal) and 10 buccal pairs, were available for the study. After the completion of basic therapy, the furcation involved molars in the right and left quadrants in each patient were randomly assigned to either a test or a control treatment procedure. Following flap elevation, scaling, root planing and granulation tissue removal, an e-PTFE membrane at the test site was adjusted to cover the entrance to the furcation defect and adjacent bone and was retained in this position with sling sutures. The mucoperiostal flaps were subsequently adjusted and positioned to cover the entire surface of the membrane and were secured in this position. An identical surgical procedure was performed in the control tooth regions with the exception of the placement of a teflon membrane. No periodontal dressing was used. Starting the day before surgery and continuing for 7 days, the patients received 1 + 1 g of Amoxicillin per day; morning and evening. The sutures were removed after 10 days. At the test sites, the membranes were removed after 6 weeks of healing. The treated sites were examined and re-entry procedures performed 6 months after reconstructive surgery. Open flap debridement at maxillary furcations of degree II resulted in some gingival recession and probing depth reduction, but no change occurred in parameters describing probing attachment or bone levels. The addition of GTR at buccal furcations enhanced the treatment result by promoting probing attachment and bone gain and reduced the amount of soft tissue recession above what was accomplished by flap debridement alone. No such benefit of membrane therapy was observed at mesial and distal furcations. PMID- 8682923 TI - Reliability of single and double probing attachment level measurements. AB - Clarification of the reliability associated with probing attachment level measurements and with diagnostic rules derived from them is necessary to examine the potential of these measurements as reliable markers of the disease process and as an outcome measure in clinical treatment studies. The purpose of the present study was to describe and compare the longitudinal reliability of single and double probing attachment level measurable by estimating false positive and false negative rates. In 20 systemically healthy adults with untreated advanced adult periodontitis, probing attachment levels and probing depth were measured at 6 sites in all teeth at the start of the study, and every 30 days thereafter for 11 months. Attachment levels were double measured, using acrylic onlays providing reference points and an electronic pressure sensitive probe. Attachment loss from baseline of 2.5 mm or more was used to accept dynamic attachment loss. The statistical methods for the cross-sectional analysis included mean absolute differences between double measurements and cross-correlations. Longitudinal analyses, expressing estimates of diagnostic error rates were made using maximum likelihood methods. 5 measurement protocols were compared. The results showed that the mean absolute difference between replicate measurements was 0.095 mm in bicuspids and 0.107 mm in molars. The mean absolute differences decreased over time from 0. 128 mm in visit 3 to 0.08 mm in visit 7. Correlation coefficients for replicate measurements were higher than 0.98. In general, false positive rates were markedly lower (< or = 0.02) than false negative rates (< or = 0.31). The relative sample size required to obtain comparable statistical power, was minimized in premolars when using the first of 2 measurements or the mean of 2 measurements, and in molars when using the first of 2 measurements. The methodology used in the present study provides guidelines for designing clinical studies which maintain statistical power by balancing off examiner reliability and sample size. PMID- 8682924 TI - Periodontal ligament tissue reactions to trauma and gingival inflammation. An experimental study in the beagle dog. AB - The aims of the present study were to analyze (i) which tissue changes may occur in the zone of co-destruction to better understand why trauma from occlusion may induce additional attachment loss, and (ii) whether changes occur in the periodontal ligament tissue when an inflammatory lesion (ICT) approaches the periodontal ligament space. 16, 1-year-old beagle dogs, were selected and divided into 2 groups, group A and group B, consisting of 6 and 10 dogs, respectively. In group A, on day 0, a bucco-lingual jiggling type movement was induced resulting in increasing tooth mobility at P3 (test tooth) by the application of an orthodontic elastic which traversed the buccal surface of the crown of the test tooth. The elastic was exchanged either in a buccal or in a lingual position 2x a week during a 3-month period. 3P served as non-jiggled control tooth. Tooth mobility measurements were recorded on days 0, 30, 60, 90. A plaque control regimen was maintained until the end of the experiment (day 90). On day 90, biopsies including P3 and 3P were harvested. The dogs representing group B, were divided into 2 subgroups of 5 each, group BI and group BII. On day 0, a 4-month period of experimental periodontal tissue breakdown was initiated by placing cotton floss ligatures submarginally around the mandibular fourth premolars (4P4) in group BI and around the mandibular third premolars GP3) in group BII. All ligatures were exchanged, replaced 1x every month, and on day 120 permanently removed. On the same day, biopsies included 4P4 were harvested. Following supragingival debridement 3P3 were allowed to accumulate plaque until the end of the study (day 225). On this occasion, biopsies including 3P3 were harvested. The results of the histological measurements revealed that in the most coronal portion of the periodontal ligament of teeth exhibiting increasing mobility, there was an increased width, a reduced % tissue volume of collagen, and an increased volume of vascular structures and leukocytes. Furthermore, the number of osteoclasts bordering this portion of the alveolar bone was increased and the number of collagen fibers inserting into the root cementum and into the alveolar bone was reduced. It was also demonstrated that in teeth with normal mobility, the position of the gingival ICT failed to influence the composition of the tissue within the coronal portion of the periodontal ligament. PMID- 8682925 TI - Clinical and microbiological changes associated with an altered subgingival environment induced by periodontal pocket reduction. AB - The purpose of the present investigation was to study the effect of an altered subgingival environment, induced by changing the local soft tissue morphology, i.e., pocket depth reduction, on the subgingival microbiota and the clinical conditions. 7 patients aged 30-60 years with generalized marginal periodontitis were selected. Patients were instructed in proper oral hygiene and all teeth were cleaned supragingivally. Mucoperiosteal flaps were raised and the bone re contoured to eliminate angular bony defects. While the control teeth were carefully debrided and thoroughly root planed, no root instrumentation was performed on the test teeth. Calculus deposits visible to the naked eye were only chipped-off with the tip of a scaler. The flaps were apically repositioned and sutured at the level of the bone crest. Clinical parameters showed a similar pattern of response in the test and control sites over a one year observation period post therapy. Probing depths and probing attachment levels were significantly reduced one month after surgery and remained at a lower level. A significant decrease was also noted for total anaerobic viable bacterial counts. The proportion of the Gram-negative anaerobic rods decreased significantly in both groups. P. gingivalis, Fusobacterium sp., C rectus were detected significantly less often after treatment in both groups. Capnocytophaga and A. odontolyticus, on the other hand, were more frequently isolated after therapy. These findings corroborate the concept that the reduction of selected subgingival microorganisms is the key element for the success of periodontal therapy, rather than the removal of tooth substance and mineralized deposits by root instrumentation. PMID- 8682926 TI - Alveolar bone loss on neolithic man remains on 38 skulls of Khirokitia's (Cyprus) inhabitants. AB - 38 skulls, belonging to inhabitants of various age groups of the Neolithic settlement of Khirokitia in Cyprus (5800-3000 BC) were studied and the alveolar bone loss was evaluated in areas where teeth still existed. It was found that the alveolar bone loss increased with age. The differences deriving from the comparison of skulls belonging to older people (the mean life-span of the inhabitants was 35.2 years), with skulls belonging to younger people suggest that our findings are not due to postmortem weathering of bones through the centuries but represent a real fact. The results of this study indicate that periodontal disease has accompanied human beings since prehistoric time without being affected by civilization. PMID- 8682927 TI - A multicenter clinical trial of PerioGard in distinguishing between diseased and healthy periodontal sites. (I). Study design, methodology and therapeutic outcome. AB - We designed and performed a multicenter clinical trial to determine the relationship between measurements of the level of the enzyme aspartate aminotransferase (AST) in gingival crevicular fluid (GCF) to other measures used to detect periodontal disease and monitor outcome of treatment, including pocket depth and gingival inflammation. 32 periodontitis patients were enrolled at the University of Washington, Seattle, 30 at the University of Florida, Gainesville, and 34 at the University of Illinois, Chicago. 10 periodontally normal control subjects were enrolled at each location. 8 diseased and 4 healthy sites were designated for study in each patient and 8 healthy sites designated in each control subject. Measures of disease included pocket depth, severity of gingival inflammation, and GCF volume. AST levels were measured using the PerioGard test kit. Clinical measurements were made and GCF samples harvested and tested 2x before and 2x after therapy consisting of scaling and root planing under local anesthetic. Specific design and other issues are discussed, including selection of patients and control subjects, sample size, selection of experimental test sites, methods for assessment of diseased and therapeutic improvement, harvesting of GCF and selection of appropriate biostatistical methods for data analysis. Demographics of the patient populations at the 3 locations are reported. As expected, therapy induced only negligible changes in the measures of disease at healthy sites in control subjects, and relatively minor improvement in healthy sites in patients. In contrast, statistically significant improvement relative to pretreatment baseline status in all 3 measures of disease was observed for diseased sites at all 3 study locations with all p-values less than 0.0002. The magnitude of improvement was comparable to that reported previously by others. The % of PerioGard-positive sites decreased significantly between the screening baseline and both post-treatment visits for patients at all 3 locations, with p values of 0.0001 to <0.0008. PMID- 8682928 TI - Subgingival temperature as a gingival inflammatory indicator. AB - Elevated temperature is one of 4 cardinal inflammatory signs. Previous work indicates that subgingival temperature assessments are accurate and re- liable, and provide objective, quantitative information over a broad 10 degrees C range, in small 0.1 degrees C increments with a direct, immediate report on the inflammatory status at the pocket base. However, complicating the use and interpretation of subgingival temperature assessments are its 3 forms: actual subgingival temperature, sublingual temperature minus subgingival temperature (temperature differential), and a temperature indicator light. We reasoned that if one could determine which of the temperature assessments reflected the periodontal condition, and which were independent variables, they would provide new and unique information about the inflammatory status of the periodontium. We also reasoned that by providing objective, quantitative data over a broad range, subgingival temperature should reduce the sample size required to obtain significance in clinical trials. Therefore, the purpose of this study was 2-fold: (1) to determine whether the 3 subgingival temperature assessments could differentiate between clinically defined periodontal health and disease; (2) to determine whether the 3 assessments were dependent or independent clinical variables. The data indicated that all 3 subgingival temperature assessment methods differentiated between clinically-defined periodontal health and disease (all p<0.02). All 3 assessments also correlated significantly (all p<0.03), but modestly (all r>0.49), with bleeding on probing. Based on scatter-plot matrices and common factor analysis, the data indicated that only actual subgingival temperature and temperature differential were independent variables. Taken together, this data indicates that subgingival temperature and temperature differential provide unique information about the periodontal inflammatory state. Power calculations indicated that the temperature differential may significantly reduce the subject number required to achieve significance in clinical trials examining gingival inflammation. Because of the body's rapid temperature response, these assessments may also significantly reduce the time required for gingival inflammation trials. PMID- 8682929 TI - Guided tissue regeneration in the treatment of degree III furcation defects in maxillary molars. AB - 11 subjects with generalized periodontitis and advanced lesions in the maxillary molar regions, including bilateral mesial-distal, but not buccal, degree III furcation defects in the 1st and/or 2nd molars, were recruited for the present clinical trial. The patients were given oral hygiene instruction and full-mouth scaling and root planing. A re-examination was performed after 3 months of healing, after which the furcation involved molars were randomly selected for a GTR or conservative treatment modality. An informed consent form was signed by each participating patient. The GTR procedure involved the elevation of mucoperiostal flaps, root surface debridement, and the placement of an e-PFTE membrane at the 2 entrances of the furcation defect. The flaps were repositioned and secured. The contralateral molar was treated in an identical manner but without the placement of the teflon membrane. The patients received amoxicillin (1g x 2/day for 8 days), were placed on chlorhexidine mouth rinsing and were recalled for prophylaxis 1x every 2 weeks. The teflon membranes were removed at a 2nd stage procedure after 6 weeks. All subjects were re-examined 6 months after the regenerative procedure, and in addition, all sites were evaluated following a reentry procedure. The final examination and measurements made during the reentry procedure documented that, although some reduction in probing pocket depth and some gain in probing attachment had occurred at both test and control sites, none of the furcation defects had closed, but retained the characteristics of a degree III furcation involvement. PMID- 8682930 TI - Nucleus medialis-nucleus interpositus interface: its olivary and cerebellocortical projections in the rat. AB - The nuclear target of the X zone of the cerebellar cortex was identified in rats as clusters of neurons scattered at the interface between the nuclei medialis (NM) and interpositus (NI). In a previous study, we had outlined these target neurons and termed them "interstitial cell groups" (icg). In order to determine whether the icg should be considered as part of either the NM or the medial NI, we analyzed two efferent pathways from the icg: their nucleocortical and nucleoolivary projections. These were compared to their homologues from the NM and the NI. This analysis is based on mapping retrograde cell labeling and anterograde terminal labeling following microinjections of tracers in either the cerebellar cortex, the cerebellar nuclei, or the inferior olive. Nucleocortical projections originating from the icg are of the three types described previously: a "reciprocal" projection to the ipsilateral X zone, a "nonreciprocal" projection to the ipsilateral A zone, and a "symmetrical" projection to the contralateral X zone. These features can be considered as the summed characteristics of the nucleocortical projections from the NM and from the medial NI. Nucleoolivary projections from the icg target the lateral-rostral portion of the dorsal accessory olive as well as the centrocaudal part of the medial accessory olive. These pathways converge with the nucleoolivary projections from the medial NI and from the NM, respectively. The icg receives olivary afferents from both the regions of the dorsal and medial accessory olives to which it projects. On the basis of similarities shown here between the two types of efferents originating from the icg and those from the NM as well as the medial NI, the icg may be regarded as a "mosaic" of neuron clusters alternately belonging to the NM and the medial NI. Therefore, the icg would be reciprocally connected with the inferior olive. PMID- 8682931 TI - Ultrastructural basis for synaptic transmission between jaw-muscle spindle afferents and trigeminothalamic neurons in the rostral trigeminal sensory nuclei of the rat. AB - Trigeminothalamic neurons were retrogradely labeled by injection of horseradish peroxidase into the ventroposteromedial nucleus of the thalamus in rats. Jaw muscle spindle afferent axons were then physiologically identified and intracellularly stained with biotinamide. The ultrastructure of labeled spindle afferent boutons was then studied in the caudolateral supratrigeminal region (Vsup) and dorsomedial trigeminal principal sensory nucleus (Vpdm). A total of 418 stained spindle afferent boutons were identified in Vsup and Vpdm; approximately 75% of these synapsed with dendrites, 10% synapsed with somata, and 15% synapsed with axons. Most jaw-muscle spindle afferent boutons were postsynaptic to unlabeled P-type boutons. Reciprocal synapses between spindle afferent boutons and unlabeled boutons were occasionally observed. A few dendrites in Vsup and Vpdm received synapses from multiple spindle afferent boutons. Conversely, some large (from 3 x 6 to 4 x 8 microns) and giant (from > 4 x 8 to 5 x 10 microns) spindle afferent boutons simultaneously contacted two to five dendrites and/or somata. Jaw-muscle spindle afferent boutons also formed synapses with retrogradely labeled trigeminothalamic neurons in Vsup and Vpdm. Numerous unlabeled S-and F-type boutons converged onto the same trigeminothalamic dendrite or soma contacted by a spindle afferent bouton. A small number of synaptic triads consisting of an unlabeled P-type bouton, a spindle afferent bouton, and either a dendrite or soma were also encountered. These data indicate that sensory feedback from the masticatory muscles is subject to presynaptic inhibition and integration prior to reaching the thalamus. This pathway is likely to be important in the relay of proprioceptive and kinesthetic information from the muscles of mastication to the thalamus. PMID- 8682932 TI - An immunochemical, ultrastructural, and developmental characterization of the horizontal basal cells of rat olfactory epithelium. AB - The olfactory epithelium, which retains a capacity for neurogenesis throughout life, contains two categories of basal cells, dark/horizontal and light/globose, neither of which is fully characterized with respect to their function during the processes of neurogenesis and epithelial reconstitution after injury. The aim of this study was to define the potential biological role(s) of dark/horizontal basal cells (D/HBCs) in the epithelium by performing immunochemical, electron microscopic, and developmental analyses of this cell population. The D/HBCs express several specific immunochemical characteristics, which include the rat homologues of human cytokeratins 5 and 14, which were identified on the basis of staining with subunit-specific monoclonal antibodies and two-dimensional immunoblot analysis of the immunoreactive proteins. Indeed, the D/HBCs are the only cells in the olfactory mucosa that express these specific cytokeratins. The D/HBCs also express an alpha-galactose or alpha-N-acetyl galactosamine moiety to which the I beta 4 isolectin from Bandeiraea simplicifolia binds. Moreover, the D/HBCs are heavily labeled by two different antibodies against the EGF receptor and by a monoclonal antibody that binds to phosphotyrosine. These characteristics are also common to the basal cells of respiratory epithelium. The electron microscopic analysis of the basal region of the olfactory epithelium and the light microscopic immunofluorescence observations demonstrate that the D/HBCs provide a bridge between the basal processes of some sustentacular cells and the basal lamina. The most striking ultrastructural feature of the D/HBCs is their enfolding of virtually all bundles of olfactory axons within tunnels formed where D/HBCs arch over the basal lamina. The intimacy of the arrangement between D/HBCs and olfactory axons suggests that signals may pass from axons to D/HBCs or vice versa. With respect to the development of D/HBCs, cells that express cytokeratins 5 and 14 and the EGF receptor first appear near the boundary with respiratory epithelium late in development, but do not extend throughout the olfactory epithelium until the middle of the first postnatal week. Taken together, the present findings and previously published data suggest that D/HBCs help to maintain the structural integrity of the olfactory epithelium, participate in its recovery from injury, and may also function to signal the status of the neuronal population of the epithelium. PMID- 8682933 TI - Projection of individual axons from the pretectum to the dorsal lateral geniculate complex in the cat. AB - The dorsal lateral geniculate nucleus of the thalamus transmits visual signals from the retina to the cortex. Within the lateral geniculate nucleus, the ascending visual signals are modified by the actions of a number of afferent pathways. One such projection originates in the pretectum and appears to be active in association with oculomotor activity. Much remains unknown about the pretectal-geniculate projection. Our purpose was to examine for the first time individual axon arbors from the pretectum that project to the lateral geniculate nucleus, describing their topography and nuclear and laminar targets. We made injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin into the cat pretectum, targeting the nucleus of the optic tract. Serial 40 microns coronal sections were processed by using immunohistochemistry to reveal labeled axons that were then serially reconstructed using light microscopy. Pretectal geniculate axons appeared morphologically heterogeneous in terms of swelling size, branching patterns, and laminar target. Most axons innervated the geniculate A laminae. A separate, smaller population innervated the C laminae. All axons exhibited substantially greater spread medial-laterally than rostral caudally in the lateral geniculate nucleus, displaying a topographical organization for visual field elevation, but not azimuth. Many pretectal axons that projected to the LGN also innervated adjacent structures, including the medial interlaminar nucleus, the perigeniculate nucleus, and/or the pulvinar. These results indicate that the projection from the pretectum to the dorsal lateral geniculate nucleus is heterogeneous, is semitopographical, and may coordinate neural activity in the lateral geniculate nucleus and in neighboring visual thalamic structures in association with oculomotor events. PMID- 8682934 TI - In situ hybridization analysis of vasopressin gene transcription in the paraventricular and supraoptic nuclei of the rat: regulation by stress and glucocorticoids. AB - Hypothalamic arginine vasopressin-containing neurons are prime elements in central circuits regulating the hypothalamo-pituitary-adrenocortical stress response. It is known that release and synthesis of vasopressin are cued by stressful stimuli. The present study was designed to assess effects of stress on vasopressin transcription and mRNA expression in defined populations of vasopressin neurons in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Intron- and exon-directed in situ hybridization analyses were used to examine stress regulation of vasopressin heteronuclear (hn) gene transcription and mRNA levels. Actions of glucocorticoids on vasopressin induction were tested using adrenalectomized rats implanted with subcutaneous pellets delivering a constant, physiological dose of corticosterone. Pellet implantation into adrenalectomized rats allows for normal pituitary-adrenal tone in the absence of the ability to mount glucocorticoid stress responses. Elevation of vasopressin heteronuclear (hn) RNA in the medial parvicellular PVN was observed in both normal and adrenalectomized-corticosterone replaced rats as early as 30 minutes after stress initiation. In control rats, vasopressin hnRNA levels returned to baseline by 120 minutes. In contrast, vasopressin hnRNA remained elevated 120 minutes post-restraint in adrenalectomized-corticosterone replaced rats, indicating that the glucocorticoid stress response acts to rapidly inhibit vasopressin transcription. Significant changes in post-stress vasopressin mRNA levels were observed in the parvicellular PVN of control rats 90 minutes following restraint induction, returning to normal expression profiles by 120 minutes. Adrenalectomized-replaced rats showed elevated vasopressin mRNA expression at all time points examined. No changes were observed in magnocellular vasopressin-containing nuclei at any time point, suggesting that magnocellular vasopressin is not induced by this particular stress paradigm. Thus, in parvicellular paraventricular nucleus neurons the vasopressin gene is rapidly induced by stress. Restraint-induced up-regulation of vasopressin transcription is limited by glucocorticoid secretion, consistent with direct actions of glucocorticoid negative feedback on the vasopressin gene in parvicellular neurons. PMID- 8682935 TI - Nerve-mast cell interaction in normal guinea pig urinary bladder. AB - Urinary bladders of normal adult female guinea pigs were analyzed for anatomical evidence of nerve-mast cell interaction using light microscopy and electron microscopy. Nerves, ganglia, and individual nerve fibers were visualized on paraffin sections using immunohistochemistry with antisera against the neural antigens neurofilament protein and protein gene product 9.5, and sections were also immunoreacted with antisera against the neuropeptides substance P and calcitonin gene-related peptide. Separate mast cell populations were identified by counterstaining with toluidine blue and alcian blue. Mast cells of both types were found within nerves and intramural ganglia and were in close contact with individual nerve fibers displaying substance P- and calcitonin gene-related peptide-like immunoreactivity. Moreover, serotonin-immunoreactive mast cells were innervated with nerve fibers that reacted with antiserum against vasoactive intestinal polypeptide. At the ultrastructural level, these fibers were almost exclusively identified as unmyelinated primary sensory afferents. Mast cells contacted these fibers with lamellipodia that wrapped around and enclosed the fibers deeply within the cell. Close association between mast cells, nerves, and vessels was common. Ultrastructural evidence suggests that bidirectional communication occurs between nerve fibers and mast cells. These structures may participate in axon reflexes that regulate normal vascular and detrusor smooth muscle function and cause vasodilation, edema, inflammation, and bladder hyperreactivity. In summary, a close relationship exists between mast cells and peptidergic nerve fibers, including primary sensory afferents. Results suggest that bidirectional interaction could occur between nerves and mast cells. PMID- 8682936 TI - Relationships between the morphology and function of gastric- and intestine sensitive neurons in the nucleus of the solitary tract. AB - This study employed single cell recording and intracellular iontophoretic injection techniques to characterize and label gastric- and/or intestine sensitive neurons in the rat nucleus of the solitary tract (NST). It was possible to divide our sample of NST neurons into three broad groups based on their response to increased intra-gastric and intra-duodenal pressure. Group 1 cells (N = 14) were excited by duodenal distention but were not responsive to gastric stimulation. Most of these intestine-sensitive neurons exhibited a delayed tonic response to the stimulus. Group 2 neurons (N = 13) were excited by gastric distention but were not sensitive to distention of the duodenum. The typical Group 2 neuron evidenced a rapid, phasic response to the distention stimulus. Group 3 neurons (N = 29) responded to both gastric and duodenal stimulation. We found that the Group 2 neurons had greater dendritic length and more dendritic branch segments than the Group 1 or Group 3 neurons. Most of the Group 1 neurons were found in the subpostremal/commissural region of the NST, while the majority of the Group 2 neurons were in the gelatinous subnucleus and a disproportionate number of the Group 3 neurons were located in the medial subnucleus. The results of this investigation demonstrate that 1) there are relationships between the morphology and physiology of distention-sensitive neurons in the NST, and 2) there are distinct functional differences between the gelatinous, medial and commissural subnuclei of this nucleus. PMID- 8682937 TI - Development of microglial topography in human retina. AB - The development of microglial topography in wholemounts of human retina has been examined in the age range 10-25 weeks gestation (WG) using histochemistry and immunohistochemistry for CD45 and major histocompatibility complex class II antigens. Microglia were present in three planes corresponding to the developing nerve fibre layer/ganglion cell layer, the inner plexiform layer and the outer plexiform layer. Distribution patterns of cells through the retinal thickness and across the retinal surface area varied with gestational age. Microglia were elongated in superficial retina, large and ramified in the middle plane, and small, rounded and less ramified in deep retina. Intensely labeled, rounded profiles seen at the pars caeca of the ciliary processes, the retinal margin and at the optic disc may represent precursors of some retinal microglia. At 10 WG, the highest densities of microglia were present in middle and deep retina in the far periphery and at the retinal margin, with few superficial microglia evident centrally at the optic disc. At 14 WG, high densities of microglia were apparent superficially at the optic disc; microglia of middle and deep retina were distributed at more central locations although continuing to concentrate in the retinal periphery. Microglia appear to migrate into the developing human retina from two mains sources, the retinal margin and the optic disc, most likely originating from the blood vessels of the ciliary body and iris, and the retinal vasculature, respectively. The data suggest that the development of microglial topography occurs in two phases, an early phase occurring prior to vascularization, and a late phase associated with the development of the retinal vasculature. PMID- 8682938 TI - Peripheral projections of rat primary sensory neurons immunoreactive for neurotrophin 3. AB - Sensory neurons can be classified into subpopulations based on a variety of characteristics, including their morphology and physiological modalities. Whether any of these classifications correlates with neurotrophic sensitivities has not been determined. We have recently reported that a subpopulation of large diameter sensory neurons of the rat contain neurotrophin 3-like immunoreactivity (NT3-ir). In this study, we have further characterised NT3-ir sensory neurons by their size, segmental localization, and peripheral projections by combined techniques of retrograde tracing and immunohistochemistry. The size distribution showed that NT3-ir was localised to a subpopulation of large-diameter neurons ranging from 560 to 3,120 microns2. Greater numbers of NT3-ir neurons reside in trigeminal (43% of total), cervical (36%), and lumbar (39%) than in thoracic spinal ganglia (13-17%). In combination with Fluoro-Gold retrograde tracing, it was found that about 30% of sensory neurons projecting to the tibial muscle were NT3-ir, compared with 39% for tendon, 50% for whisker hair follicles, 17% for subdermis or epidermis, and only 1% for kidney or adrenal gland. These studies indicate that NT3-ir sensory neurons mainly project to skin and muscles but not viscera. Thus, the characterization of NT3-ir spinal sensory neurons suggests that large sensory neurons subserving proprioception and mechanoception require NT3 for the maintenance of normal function. PMID- 8682939 TI - Developmental changes in calretinin expression in GABAergic and nonGABAergic neurons in monkey striate cortex. AB - The development of the calcium-binding protein calretinin (CaR) and its co localization with GABA was studied in the striate cortex of Macaca monkeys from fetal day (Fd) 45 to adult. At Fd45, early neurons resembling Cajal-Retzius cells are stained in the marginal zone (MZ). At Fd55 the MZ is filled with CaR+ Cajal Retzius cells and their processes, and scattered CaR+ cells are also found in deep cortical plate (CP), intermediate zone (IZ), and subventricular zone (SVZ). At Fd66, a band of CaR+ fibers appears in the IZ, corresponding to the location of the geniculocortical axons. This fiber band labels heavily until Fd130 but then ceases to be immunoreactive by postnatal (P) 16 weeks. At Fd85-101, the number of CaR+ cells in the CP, SVZ, and ventricular zone (VZ) reaches its highest cell density. After Fd130, CaR+ cells are concentrated in layer II and upper layer III, and this distribution changes little into adulthood. After mid gestation, there is a progressive loss of CaR+ cell bodies and processes in the MZ, and these are rare in the adult cortex. Just before birth, a weakly stained CaR+ cell band appears in layer IVA at the border between layer IVA and IVB, but this band disappears immediately after birth. Another CaR+ cell band appears transiently in upper layer V just below the border with layers IV at P6 months. These results suggest that CaR is expressed early in fetal development in the cell populations that are immunoreactive for CaR in the adult. However, developmental events related to cortical maturation during late prenatal and early postnatal stages result in transient expression of CaR in neurons that are not immunoreactive for CaR in the adult. CaR-immunoreactivity is colocalized with GABA in almost all CaR+ cells with the exception of Cajal-Retzius cells in the MZ and some large cells observed at Fd70-101 in the VZ. The band of CaR+ fibers in the IZ is GABA-. At Fd90, almost all (> 96%) CaR+ cells are GABA+ in the CP and the first developed layers V/VI. This percentage declines later, so that on average 80% of CaR+ cells are GABA+ in adult cortex. At Fd135, 53% of GABA+ neurons located in layers II/III are CaR+; this percentage declines to 37% in the adult. These double-label patterns suggest that early in fetal development the majority of GABA+ cells stain for CaR and that expression of CaR may be related to the migration of these neurons into the cortical plate. Once they attain their final position in the cortex many GABA+ cells loose CaR-immunoreactivity, so that in postnatal life only a minority of GABA+ neurons contain this calcium-binding protein. PMID- 8682940 TI - Development of the spinocerebellar projection in the prenatal mouse. AB - An abundance of information is available concerning the spinocerebellar projection in adult mammals. However, only a few studies have attempted a developmental analysis of this important projection system in early postnatal and/or prenatal animals. The present study provides an analysis of the development of the projection from the spinal cord to the cerebellum in fetal mice using anterograde tracing techniques in an in vitro preparation. After applications of biocytin to the caudal cervical spinal cord, anterogradely labelled fibers were present in the brainstem of embryonic day 12 (E12/13) mice, however, there was no indication of label in the cerebellum. At E13/14, labelled fibers were evident in the rostrolateral portions of the cerebellum/isthmus region. By E15/16, labelled spinocerebellar fibers had progressed farther into the cerebellum and were seen crossing the midline in a very superficial position. At older ages, the number of crossing fibers increased, and they became more ventrally positioned within the cerebellum. At E17/18 and E18/19, labelled spinocerebellar fibers were observed to branch and invade deeper portions of the cerebellum including the cerebellar nuclei. However, at E18/19, there was no indication of the parasagittal organization characteristic of this projection in the adult animal. The results of this study indicate that spinocerebellar fibers are present within the cerebellum significantly earlier than the development and differentiation of their primary targets, the granule cells. Furthermore, these data suggest that spinocerebellar fibers may form associations with cerebellar nuclear cells during fetal development. PMID- 8682941 TI - Atopic dermatitis: an update. AB - This review focuses on recent literature regarding the following clinical features of atopic dermatitis (AD); diagnostic criteria, epidemiology and genetics, provocative factors, predictors of disease development and markers of disease severity, therapy, and prognosis. For example, the frequency of AD appears to be increasing, perhaps in response to provocative factors such as food allergens and house dust mites. Determination of reliable markers for disease development may identify susceptible newborns and facilitate avoidance of relevant triggers. Immunomodulating therapy holds promise in the treatment of refractory AD, and new investigation has led to refinements in conventional modalities such as antihistamines and phototherapy. PMID- 8682942 TI - Surgical pearl: Q-switched Nd:YAG laser removal of eyeliner tattoo. PMID- 8682943 TI - HIV-associated eosinophilic pustular folliculitis: The first case reported in a woman. PMID- 8682944 TI - Localized green pigmentation in a patient with hyperbilirubinemia. PMID- 8682945 TI - A double-blind, randomized comparison of itraconazole capsules and placebo in the treatment of onychomycosis of the toenail. PMID- 8682946 TI - Toxic epidermal necrolysis after mifepristone/gemeprost-induced abortion. PMID- 8682947 TI - Effects of a water-impermeable, non-silicone-based occlusive dressing on keloids. PMID- 8682948 TI - Therapeutic efficacy of terbinafine in the treatment of three children with tinea tonsurans. PMID- 8682949 TI - Perforating pilomatricoma. PMID- 8682950 TI - High-potency topical corticosteroid rapidly decreases histamine-induced itch but not thermal sensation and pain in human beings. PMID- 8682951 TI - Response of PUVA-induced keratoses to etretinate. PMID- 8682952 TI - Detection of anti-Fc gamma R antibodies and different cytokines in sera from patients with systemic sclerosis. PMID- 8682953 TI - Systemic antifungal drugs and drug interactions. PMID- 8682954 TI - Diagnosis of cutaneous tuberculosis. PMID- 8682955 TI - Nail abnormalities in nondermatologic patients. PMID- 8682957 TI - Acquired ichthyosis in bone marrow transplant recipients. AB - BACKGROUND: Acquired ichthyosis (AI) has been described in a variety of clinical situations. We have observed cases of ichthyosis in bone marrow transplant recipients. OBJECTIVE: Our purpose was to characterize these changes clinically and histologically and to compare them with other cases of acquired ichthyosis. METHODS: Skin biopsy specimens were taken before transplantation and from affected areas after transplantation. RESULTS: AI was observed in four patients who had received a bone marrow transplant for leukemia. None of the patients had a previous personal or family history of ichthyosis. In all patients graft-versus host disease developed after transplantation. The eruption clinically and histologically most closely resembled ichthyosis vulgaris. The ichthyotic changes appeared to be unrelated to specific drug therapy. CONCLUSION: AI is a previously unreported cutaneous complication of bone marrow transplantation. It may be related to graft-versus-host disease in these patients. PMID- 8682958 TI - Cytomegalovirus DNA identified in skin biopsy specimens of patients with vitiligo. AB - BACKGROUND: Viral infections have been implicated in the pathogenesis of a variety of autoimmune diseases. OBJECTIVE: This investigation was undertaken to determine the presence or absence of viral genomes in the depigmented and uninvolved skin of patients with vitiligo. METHODS: A polymerase chain reaction assay was used to detect viral genomes in paraffin-embedded skin biopsy specimens. Twenty-nine patients with vitiligo and 22 control subjects were included. Biopsy specimens were screened in a blinded fashion for a panel of DNA and RNA viruses including herpes simplex, varicella-zoster, cytomegalovirus (CMV), Epstein-Barr, HIV, and human T-cell lymphotropic virus. RESULTS: CMV DNA was identified in 38% of the patients studied. Twenty-one percent had indeterminate results. Results in all control subjects were negative. Polymerase chain reaction screening for identification of other viral genomes was negative. Although not statistically significant, data trends suggested a correlation between the presence of CMV DNA in biopsy specimens and active vitiligo of relatively brief duration. In addition, CMV-positive patients had a statistically significant increased frequency of other concurrent autoimmune diseases. CONCLUSION: CMV DNA in the depigmented and uninvolved skin of some patients with vitiligo and its absence in control subjects suggest that vitiligo may indeed be triggered by a viral infection in select patients. PMID- 8682959 TI - Effect of coadministration of corticosteroids on the development of contact sensitization. AB - BACKGROUND: Transdermal administration of drugs can increase patient compliance and reduce side effects, but it can also cause contact sensitization. Corticosteroids frequently are used to suppress the local immune response; however, their use as a pretreatment for transdermal system application sites is not practical. OBJECTIVE: Our purpose was to determine the feasibility of suppressing contact sensitization by delivering a corticosteroid with the transdermal delivery systems. METHODS: Materials were applied continuously for 3 weeks to the same (protocol SS) or different (protocol AS) skin sites. Skin flux and appearance of sensitization were determined. RESULTS: Coadministration of hydrocortisone reduced the incidence of sensitization by d-chlorpheniramine and benzoyl peroxide from 45% to 7.5% and from 20% to 2.3%, respectively, under protocol SS. Under protocol AS, sensitization by d-chlorpheniramine was reduced from 15% to 1%. Frequent exposure to the sensitizer plus corticosteroid induced tolerance to the sensitizer. CONCLUSION: Sensitization by moderately immunogenic drugs after any length of exposure may be reduced to acceptable levels by the coadministration of hydrocortisone. PMID- 8682960 TI - Silicone deposition in reconstruction scars of women with silicone breast implants. AB - BACKGROUND: The possible association of silicone breast implants and disease is a subject of continuous debate and concern. OBJECTIVE: Our purpose was to examine microscopically and ultrastructurally the periprosthetic fibrous capsules and reconstruction scars of women with silicone breast implants. METHODS: Representative samples from the periprosthetic capsules and reconstruction scars from six women with silicone breast implants were examined by a variety of light microscopy techniques, transmission electron microscopy, and electron probe microanalysis. RESULTS: Silicone globules of various sizes were identified in every periprosthetic capsule and reconstruction scar. CONCLUSION: Extrusion and seeding of the incision tract during surgery most likely accounts for the presence of silicone in the reconstruction scar specimens. This observation suggests that the identification of silicone in the reconstruction scars of women with silicone breast implants does not necessarily implicate rupture of the silicone breast implant with systemic dissemination of silicone gel. PMID- 8682961 TI - Localization of dermal edema in lipodermatosclerosis, lymphedema, and cardiac insufficiency. High-frequency ultrasound examination of intradermal echogenicity. AB - BACKGROUND: Chronic edema in venous insufficiency is associated with leg ulceration, whereas in lymphedema skin ulceration is less frequent and edema from cardiac failure does not cause major skin changes. The reason for these differences is unclear. OBJECTIVE: Our purpose was to investigate, by means of ultrasound, the distribution of intradermal fluid in patients with edema associated with lipodermatosclerosis, lymphedema, or cardiac insufficiency. METHODS: Sixteen patients with lipodermatosclerosis, 10 with lymphedema, 16 with leg edema from heart insufficiency, and 16 healthy control subjects were studied. Ultrasound images were obtained with a 20 MHz scanner. The echogenicity of the dermis was quantified by image analysis and the echogenicity of the upper (subepidermal) and lower portions of the dermis were measured. RESULTS: In any type of edema the dermal echogenicity was lower than that of the control group, indicating intradermal edema. In normal skin the upper dermis was only slightly less echogenic than the lower dermis. In patients with lipodermatosclerosis a low echogenic area was present in the upper dermis, which suggests the papillary dermis as a preferential site of edema formation. In contrast, in lymphedema dermal echogenicity was uniformly distributed, whereas in patients with heart failure the lower portion of the dermis was less echogenic than the upper dermis. CONCLUSION: This study demonstrates that intradermal echogenicity shows characteristic patterns in different types of edema, which indicates that localization of fluid varies in the dermis, from subepidermal (lipodermatosclerosis), uniform (lymphedema), to deep dermal (heart failure). These differences may help in understanding the origin of different skin sequelae of edema. PMID- 8682962 TI - False-positive polymerase chain reaction results for human papillomavirus in lichen planus. Potential laboratory pitfalls of this procedure. AB - BACKGROUND: The polymerase chain reaction (PCR) is a common tool in laboratory evaluation of tissue samples. It has been particularly useful in testing for nucleic acids of infectious organisms implicated in the pathogenesis of cutaneous diseases. OBJECTIVE: Our purpose was to evaluate archival biopsy material (paraffin-embedded) of lichen planus for human papillomavirus (HPV) DNA with PCR and in situ hybridization (ISH). METHODS: Tissue sections were obtained from 13 specimens of lichen planus and 10 control tissues. Standard methods for PCR and ISH were used to evaluate the presence of HPV DNA. RESULTS. Initial PCR results demonstrated HPV DNA in 11 of 13 specimens and in none of the control tissue. However, testing for specific HPV types revealed nucleic acid contamination. ISH was negative in all specimens. CONCLUSION: Accurate evaluation of tissue with PCR is difficult because of the procedure's profound sensitivity. Positive results reported in the literature should be viewed with caution. Potential causes for false-positive and false-negative results should be considered. PMID- 8682963 TI - Skin reactivity to sodium lauryl sulfate in patients with respiratory atopy. AB - BACKGROUND: No literature data are available on the skin reactivity of patients with respiratory atopy alone. OBJECTIVE: Our purpose was to assess skin reactivity to detergents in patients with allergic asthma, rhinitis, or both. METHODS: The skin of the volar aspect of the forearm of 19 subjects with allergic asthma or rhinitis (or both) was challenged with a single exposure to 0.5% sodium lauryl sulfate. The skin response was evaluated by transepidermal water loss (TEWL), capacitance, and echogenicity measurements. Results were compared with those obtained in 19 patients with atopic dermatitis (AD) and 20 healthy subjects. RESULTS: In patients with AD preexposure TEWL values were higher than in healthy subjects, whereas capacitance values were lower. In this patient group, postexposure TEWL, capacitance, and echogenicity values showed more pronounced variations than in healthy subjects. Conversely, in patients with allergic asthma or rhinitis (or both), both baseline and postexposure TEWL, capacitance, and echogenicity values were similar to those in healthy subjects. CONCLUSION: Patients with respiratory atopy without AD do not have the functional abnormalities characteristic of skin affected by AD, either under baseline conditions or after exposure to sodium lauryl sulfate. PMID- 8682964 TI - Erythroderma. A clinical and follow-up study of 102 patients, with special emphasis on survival. AB - BACKGROUND: Erythroderma may result from different causes. There have been no publications on this subject with special emphasis on survival. OBJECTIVE: The aim of the study was to determine the cause of the erythroderma and the prognosis of these patients. METHODS: Clinical and follow-up data from 102 patients with erythroderma were analyzed. We estimated survival of patients with erythroderma, from causes other than Sezary syndrome, mycosis fungoides, or leukemia cutis. The survival was compared with that of an age-matched control group of the general population. RESULTS: The main cause of erythroderma was exacerbation of a preexisting dermatosis (53%). Drug reactions were rarely the cause (5%). A high proportion of the patients had chronic actinic dermatitis/actinic reticuloid (12%). Survival of men with erythroderma was significantly lower than that of the general population. CONCLUSION: Men with erythroderma, from causes other than Sezary syndrome, mycosis fungoides, or leukemia cutis, have a lower survival than men in the general population. PMID- 8682965 TI - Fluorescence photography in the evaluation of acne. AB - BACKGROUND: Quantification of acne remains a challenge. It may be difficult to identify lesions by standard flash photography. Previous studies have shown that foci of light in fluorescence photographs correspond to high protoporphyrin IX production by Propionibacterium acnes in open comedones, follicles, and inflammatory lesions. OBJECTIVE: Our purpose was to study the utility of fluorescence photography for evaluation of acne. METHODS: Forty subjects with mild to moderate acne vulgaris were randomly selected to apply either clindamycin 1% topical solution or vehicle twice daily. Counts of acne lesions and flash and fluorescence photographs were obtained at baseline, and at 4, 8, and 12 weeks. RESULTS: At 12 weeks, the treatment group had a larger percentage change in open comedones, less fluorescence in all areas assessed, and a larger percent decrease in fluorescence than the vehicle group. CONCLUSION: Fluorescence photography appears to be a useful tool to chart the course of acne treatment. PMID- 8682966 TI - Clinical and histologic evaluation of psoriatic plaques treated with a flashlamp pulsed dye laser. AB - BACKGROUND: Psoriatic plaques can be cleared by destruction of the dermal papillae. Dilated vessels, the major component of psoriatic dermal papillae, can be selectively destroyed with yellow light lasers. Previous investigators have demonstrated partial clearing of psoriatic plaques after treatment with a pulsed dye laser (PDL) (585 nm). OBJECTIVE: This study was designed to examine the clinical and histologic events of psoriasis treated with the PDL. METHODS: Psoriatic plaques were treated with a short (450 microseconds) and long (1500 microseconds) pulse-width PDL. Photographs of the plaques were used for clinical assessment. Biopsy specimens were examined microscopically. RESULTS: Significant clinical improvement was seen, and no significant difference between the long and short pulse-width lasers was found. Patients responding to treatment with the PDL remained in remission for up to 13 months. Histologic normalization occurred after treatment. Two pretreatment vascular patterns were seen: vertically oriented vessels with few horizontal vessels and numerous tortuous vessels. Tortuous vessels were associated with poor clinical results. CONCLUSION: The PDL can induce prolonged remission in chronic plaque psoriasis. The vascular pattern may help to distinguish those patients likely to respond to this treatment. PMID- 8682967 TI - Additional courses of total skin electron beam therapy in the treatment of patients with recurrent cutaneous T-cell lymphoma. AB - BACKGROUND: Recurrent cutaneous T-cell lymphoma (CTCL) is managed with a variety of modalities. Repeat treatment with additional courses of total skin electron beam therapy (TSEBT) has not been formally evaluated. OBJECTIVE: Our purpose was to evaluate the efficacy and toxicity of additional TSEBT for recurrent CTCL. METHODS: A total of 14 patients were treated with TSEBT and received at least two courses, with five of those patients receiving a third course. Patients were offered additional TSEBT if they suffered recurrence despite other therapy if the extent of the recurrence precluded localized radiation. The median follow-up was 36 months. RESULTS: The median dose for the entire group was 57 Gy. Thirteen patients (93%) achieved a complete response (CR) after the initial course. After the second course, 12 patients (86%) had a CR; of the five patients who underwent a third course, three (60%) achieved a CR. The median disease-free interval after the first course of therapy for those with a CR was 20 months and 11.5 months after the second course. Median survival after the second course was 15 months. All patients had xerosis, pruritus, desquamation, mild erythema, epilation, and anhidrosis of the skin. CONCLUSION: Patients with recurrent CTCL recalcitrant to other forms of therapy or too diffuse for treatment with localized radiation fields are candidates for additional TSEBT. This therapy is effective and well tolerated with an acceptable risk profile. PMID- 8682968 TI - A randomized trial of minoxidil in chemotherapy-induced alopecia. AB - BACKGROUND: Hair loss is a side effect of many chemotherapeutic agents, and patients have even refused possibly palliative or lifesaving drugs because they could not accept temporary or prolonged baldness. Topical minoxidil has been shown to be effective for androgenetic alopecia and alopecia areata. OBJECTIVE: Our purpose was to investigate the value and safety of minoxidil in chemotherapy induced hair loss. METHODS: Twenty-two women who were facing adjuvant chemotherapy after breast surgery were registered in a protocol that used a 2% minoxidil topical solution or a placebo in a randomized double-blind trial. RESULTS: There was a statistically significant difference (favoring minoxidil) in the interval from maximal hair loss to first regrowth. Thus the period of baldness was shortened (mean, 50.2 days) in the minoxidil group. CONCLUSION: Minoxidil decreased the duration of alopecia caused by chemotherapy. There were no significant side effects. PMID- 8682969 TI - Improvement of facial acne scars by the 585 nm flashlamp-pumped pulsed dye laser. AB - BACKGROUND: Hypertrophic or erythematous scars (or both) have remained notoriously difficult to treat because of their persistence or recurrence after traditional therapies. Recently, the 585 nm flashlamp-pumped pulsed dye laser has been shown to be effective in treating similar traumatic and surgical scars. OBJECTIVE: Our purpose was to determine the effectiveness of the 585 nm flashlamp pumped pulsed dye laser in the specific treatment of facial acne scars. METHODS: Twenty-two patients with erythematous or hypertrophic facial acne scars were included in this Investigational Review Board-approved study. The 585 nm flashlamp-pumped pulsed-dye laser was used to treat scars on half of each patient's face, with the contralateral side used as control. Baseline, 6-week, and 6-month posttreatment photographs, erythema measurements made with reflectance spectrometry, and skin texture analyses were obtained from laser irradiated and untreated scars. Clinical analyses were performed independently by two "blinded" observers. RESULTS: Significant clinical improvement was observed in laser-irradiated acne scars compared with the untreated (control) scars after one or two 585 nm pulsed-dye laser treatments. Erythema measurements and skin texture analyses of laser-treated scars approximated those obtained in the adjacent normal skin. CONCLUSION: The 585 nm flashlamp-pumped pulsed-dye laser can significantly improve the clinical appearance of erythematous or hypertrophic facial acne scars. PMID- 8682970 TI - A comparison between Mohs micrographic surgery and wide surgical excision for the treatment of dermatofibrosarcoma protuberans. AB - BACKGROUND: There is growing evidence that Mohs micrographic surgery (MMS) is the treatment of choice for dermatofibrosarcoma protuberans (DFSP). OBJECTIVE: This study retrospectively compared the recurrence rates of DFSP after MMS with those after wide surgical excision; results at the Mayo Clinic and in the world literature were evaluated. In addition, preoperative tumor sizes and postoperative defect sizes after MMS were compared to determine whether MMS conserved more normal tissue than wide surgical excision. METHODS: The medical records of 84 patients with DFSP who had been treated at the Mayo Clinic were reviewed. They were categorized into two treatment groups: MMS and surgical excision. RESULTS: Fifteen patients with DFSP who underwent MMS had follow-up data available; one of these patients had local recurrence (recurrence rate, 6.6%; average duration of follow-up, 40 months). Thirty-nine patients had wide excision; four of these patients had local recurrences and one had pulmonary metastases (recurrence rate, 10%; average duration of follow-up, 36 months). A review of the world literature revealed neither local recurrences nor metastases in the 11 studies in which DFSP was treated with MMS. Overall, including our results, the average recurrence rate of DFSP after MMS was 0.6% (range, 0% to 6.6%) and the total recurrence rate was 1.6% (1 of 64). Including our series, DFSP was treated with wide excision in 15 studies; the average recurrence rate was 18% (range, 0% to 60%) and the total recurrence rate was 20% (100 of 489). In eight published studies, DFSP was surgically resected with undefined or conservative excisional margins; the average recurrence rate was 43% (range, 26% to 60%) and the total recurrence rate was 44% (140 of 317). A surgical margin of 2.5 cm to deep fascia was required for complete clearance of all tumors treated with MMS. Twenty-two percent of tumors were removed with a 0.5 cm margin, 50% with a 1.0 cm margin, 67% with a 1.5 cm margin, and 89% with a 2.0 cm margin. CONCLUSION: On the basis of our results and data compiled from the literature, MMS may be the treatment of choice for DFSP because of its high cure rate and maximal conservation of tissue. PMID- 8682972 TI - Camp Knutson: the first three years. PMID- 8682971 TI - Sign of Leser-Trelat. AB - The sign of Leser-Trelat is rare. It is defined as the sudden eruption of multiple seborrheic keratoses caused by a malignancy. Because both seborrheic keratoses and cancer are common in the elderly, it is not always easy to tell from the literature or in any given patient if this sign is present. In fact, its validity has been questioned. Its association with malignant acanthosis nigricans is one of several of its features that support its legitimacy as a true paraneoplastic disorder. PMID- 8682973 TI - Cognitive therapy of affective disorders: a review. AB - Cognitive therapy is the most extensively researched psychological treatment for nonpsychotic, unipolar outpatient depressive disorders. Careful analysis of published outcome studies suggests that its benefits in acute depression whilst very promising have not been proven, mainly because of inadequate methodology in treatment trials. However, cognitive therapy does appear to reduce the risk of depressive relapse and may have a more durable effect than pharmacotherapy alone. This paper explores short- and long-term outcome data and reviews clinical factors, including therapists competency, that may predict outcome. The development of cognitive approaches to individuals with bipolar disorders is examined. Future areas of research, particularly the need to detect which individuals may differentially respond to cognitive therapy, are identified. PMID- 8682974 TI - Dominance of the 'nondominant' hemisphere in depression. AB - We examined 36 patients with major depression diagnosed by DSM-III-R to find and qualify disturbances in brain oxygenation and hemodynamics during a psychological task. A group of 36 age- and sex-matched healthy volunteers were monitored as controls. Multichannel near-IR spectrophotometry (NIRS) was used to observe real time alterations in the oxygenation in corresponding areas of the hemispheres at the forehead during the mirror drawing task (MDT). Nearly half of the patients (12 of 24 males and 4 of 12 females) showed a 'nondominant hemisphere response pattern', which was never observed in normal volunteers during the MDT. The other half of the patients showed a 'bilateral response pattern'. There was no 'dominant hemisphere response pattern', the pattern observed in most normal males. When re-examined after recovery from depression, the response pattern of the two patients who had shown the 'nondominant hemisphere response pattern' during the course of the illness had changed to the 'bilateral response pattern'. The response pattern of the three patients with refractory depression who first showed the 'bilateral response pattern' changed to the 'nondominant response pattern' after several months. The nominally 'nondominant' hemisphere may become dominant during the course of depression. PMID- 8682975 TI - Mood-congruent versus mood-incongruent psychotic symptoms in first-admission patients with affective disorder. AB - The distribution of mood-congruent and mood-incongruent symptoms in 49 first admission DSM-III-R psychotic bipolar and 35 psychotic depressed patients is presented. Most patients had mood-incongruent symptoms (77.4%). 73% of mood incongruent bipolars and 32% of incongruent depressives had a combination of mood congruent and mood-incongruent symptoms. Demographic and clinical variables were unrelated to incongruence. The only 24-month clinical outcome predicted by mood incongruence was poorer GAF rating. 15 of the 16 patients whose diagnosis was changed at follow-up from affective to nonaffective psychosis had mood incongruent features initially. The findings raise questions about the general prognostic utility of mood congruence. PMID- 8682977 TI - The effect of alcohol and substance abuse on the course of bipolar affective disorder. AB - It has been found that > 60% of bipolar I and almost 50% of bipolar II patients have a history of substance abuse (Regier et al., 1990). While previous studies have examined comorbidity of bipolar disorder and substance abuse, little has been done to examine the effect of substance abuse on the course of bipolar disorder. There has also been little distinction made between bipolar disorder occurring prior to substance abuse and that occurring after the onset of substance abuse. Given the high prevalence of substance abuse in bipolar patients, it would be useful to determine more about the effect of substance abuse on demographic and clinical features and on the course of illness. We attempted to do this with a retrospective chart review of 188 bipolar patients seen by D.L. Dunner between January 1992 and December 1993. Demographic and clinical information as well as information about course of illness were systematically extracted from the charts. We compared the means and percentages of these variables and analysed them for significance. Preliminary results show differences in demographics, clinical features and course of illness between patient groups. These differences may illustrate the clinical effects of substance abuse on the course of bipolar disorder. Our results also indicate that there are differences between patients whose bipolar disorder began prior to and those whose disorder began after the onset of substance abuse. PMID- 8682976 TI - Amitriptyline in combination with repeated late sleep deprivation versus amitriptyline alone in major depression. A randomised study. AB - Only few systematic studies are available on the status of sleep deprivation therapy in the overall treatment regimen of depressive patients. 51 patients suffering from a major depressive episode (ICD-10) were randomly allocated to 4 weeks' treatment with amitriptyline (150 mg/day) or to a combination of amitriptyline with six partial-sleep-deprivation treatments late in the night (at 4-5 day intervals). According to observer rating (Hamilton Rating Scale for Depression, 21- and 10-item version), a highly significant amelioration was recorded in both groups until the 14th day of treatment. A further improvement occurred, however, only in those patients treated with both antidepressants and sleep deprivation. Hence the response rate ( > or = 50% HAMD reduction) after 4 weeks' treatment was distinctly more favourable in this group than in those patients under pharmacotherapy alone. The superiority of the combined therapy cannot be confirmed statistically by self-rating (Befindlichkeitsskala: von Zerssen; Visual Analogue Mood Scale). The immediate antidepressive effect of sleep deprivation diminished in the course of the sleep deprivation series. The response to the first sleep deprivation was a predictor neither for the response to further sleep deprivation treatments nor for the overall treatment outcome. PMID- 8682978 TI - The effect of a history of conduct disorder in adult major depression. AB - This paper examines the impact of a history of conduct disorder on major depression in adulthood, including its symptomatology, comorbidity and response to tricyclic antidepressants. 103 subjects with DSM-III-R major depression were assessed for DSM-III-R axis I and II comorbidity, severity of depression, social functioning, general psychiatric symptomatology, early familial environment and family psychiatric history. 18 patients (17%) had a history of conduct disorder, 32 (31%) were subthreshold, and 53 (51%) had no childhood symptoms of conduct disorder. Depressed adults with a history of conduct disorder had significantly higher lifetime alcohol and drug dependence and virtually all (17/18, 94%) met criteria for a personality disorder. Despite this, the current episode of depression did not differ in severity, symptoms or response to treatment except that those with a history of conduct disorder were more likely to be agitated when depressed. The authors conclude that a history of conduct disorder is depressed patients predicts the presence of adult personality disorders and psychoactive substance dependence. In most other ways, depressed subjects with a history of conduct disorder were similar to other subjects. PMID- 8682979 TI - Meaning is perception. PMID- 8682980 TI - Direct reimbursement. PMID- 8682981 TI - Invest now for the future. PMID- 8682982 TI - ADA/AGD. PMID- 8682983 TI - Dentistry as a business. PMID- 8682984 TI - Disability or contagious disease? PMID- 8682985 TI - More about AGD. PMID- 8682986 TI - Good news from annual session health screening. PMID- 8682987 TI - Biofilm and the dental office. AB - The author provides a brief overview of the basic processes involved in biofilm formation and explores the implications these biofilms have for health care facilities such as hospitals and dental offices. Included with this article are suggestions dentists may consider for improving water quality and a white paper on waterlines adopted by the ADA. PMID- 8682988 TI - Assessing the efficacy of three dentifrices in the treatment of dentinal hypersensitivity. AB - A multicenter clinical trial conducted by the authors compared the desensitizing efficacy of a new 5 percent potassium nitrate: 0.243 percent sodium fluoride dentifrice along with two clinically proven, commercially available desensitizing dentifrices to a placebo dentifrice. Sensitivity to cold air and tactile stimulation, along with patients' subjective assessments, were evaluated to assess the dentinal desensitizing efficacy of the test dentifrices. Results demonstrated that after four weeks, participants who used the new dentifrice formulation experienced significant decreases in dentinal sensitivity compared to the placebo group for all measured indexes. PMID- 8682989 TI - Repairing fractured porcelain: how surface preparation affects shear force resistance. AB - This article reports on a study of the shear bond strength of porcelain repaired with any of several currently available dentin bonding systems and composite resin. The authors describe the benefits of the use of silane and the decrease in shear bond strength values after thermocycling. The results should be helpful to any practitioner confronted with a restoration that is a candidate for intraoral repair of fractured porcelain. PMID- 8682990 TI - Dental considerations for the patient with renal disease receiving hemodialysis. AB - An increasing number of Americans are living with end-stage renal disease. This disease has many implications for dentistry, in terms of oral manifestations and management of afflicted patients. The authors present pertinent information to help dentists treat patients who exhibit the oral and systemic manifestations of renal disease, from the onset of renal impairment through hemodialysis. PMID- 8682991 TI - Orofacial phantom pain: theory and phenomenology. AB - Developing a treatment strategy for patients who are in chronic pain can be challenging for any health care professional, particularly when traditional measures to relieve pain are ineffective. Pain treatment can be further complicated by phenomena known as phantom pain--most often associated with limb amputation. The author describes three phantom syndromes experienced in the orofacial region: phantom tooth pain, phantom bite syndrome and intraoral stump pain. PMID- 8682992 TI - Treating the oral sequelae of an acoustic neuroma. AB - This article describes the treatment of oral complications that arose after surgery for the removal of an acoustic brain tumor. The authors contend that a thorough oral examination can pinpoint the cranial nerves that have been affected by the tumor or the surgery, and that dental appliances can offer special protection after surgery. PMID- 8682993 TI - Trouble-shooting dual arch impressions. AB - Dual arch impression techniques enable the dentist to capture an impression of the prepared tooth, the opposing teeth and the occlusal registration in one procedure. This saves chair time and impression material. PMID- 8682994 TI - Preventing factitious gingival injury in an autistic patient. AB - A 34-year-old man with a history of autism developed a deep gingival cleft. During clinical evaluation, the patient repeatedly scraped the affected area with his fingernail. The lesion's clinical features were consistent with focal inflammatory hyperplasia, periodontal disease and factitious stomatitis. This article describes the case and discusses diagnostic and behavioral issues important in treating any patient whose mental age is impaired. PMID- 8682995 TI - Provisional restorations for fixed prosthodontics. AB - Provisional restorations for crowns and fixed prostheses are often poorly made, contributing to inadequately fitting restrations, sensitive teeth and occlusally incorrect crowns and prostheses. Properly made resin temporary restorations are easy and inexpensive to make by qualified auxiliary staff, and they provide assurance that the final restorations will fit well with minimal clinical adjustments. PMID- 8682997 TI - Do dentists and physicians advise tobacco users to quit? AB - To examine dentists' and physicians' effectiveness in advising patients who use tobacco to quit, the authors estimated the percentages of smokers in the United States who visited a dentist or physician in the preceding year, the percentages of those who were advised by their health care provider to quit and the percentages of those who planned to quit smoking. They also estimated the percentage of smokeless tobacco users who were ever advised by their dentist or physician to quit. The results of the study indicate that dentists and physicians may not be maximizing their opportunities to advise their patients who use tobacco to quit, or they are not adequately communicating to their patients the importance of quitting. PMID- 8682996 TI - Predicting dentists' career choices using the Myers-Briggs type indicator. AB - The Myers-Briggs Type Indicator is a psychological measure designed to determine personality preferences, learning styles and management styles and to assist with career choices. The authors surveyed 1,117 practicing dentists to determine if the MBTI was useful in determining which respondents were most likely to be specialists. They found no significant differences between general practitioners and specialists. PMID- 8682998 TI - Understanding human genetics. PMID- 8682999 TI - What dentists need to know about employment law. PMID- 8683000 TI - Finding nutrition information on the Net. PMID- 8683001 TI - Food safety update. PMID- 8683002 TI - The Healthy Eating Index needs further work. PMID- 8683003 TI - ADA recommends reevaluation of WIC food package. PMID- 8683004 TI - New Dietary Reference Intakes proposed to replace the Recommended Dietary Allowances. PMID- 8683005 TI - Communications technology and the profession. PMID- 8683006 TI - Benefits of training dietetics students in preprofessional practice programs: a comparison with dietetic internships. AB - OBJECTIVE: To conduct a nationwide study on the opinions of dietitian preceptors regarding the intangible benefits to hospitals and medical centers of training dietetics students in approved preprofessional practice programs (AP4s) and to compare the findings with a similar survey of dietetic internships. DESIGN: A questionnaire was adapted from a 1990 study of preceptors in dietetic internships to investigate the benefits of training dietetics students in AP4s. SAMPLE: Program directors and dietitians who supervise and teach students in the 117 preprofessional programs approved by The American Dietetic Association were sent pretested questionnaires. Responses to the survey were received from 312 dietitians who supervise students in 74 practice programs. STATISTICAL ANALYSIS: Descriptive statistics were used to calculate frequency of response. t Tests were used to compare mean differences between the opinions of preceptors in AP4s and internships. Analysis of variance and Scheffe post-hoc test were used to determine the demographic characteristics related to the dietitians' opinions of benefits. RESULTS: Strongest agreement (agree to strongly agree) was found for three items: sense of satisfaction from seeing students develop as professionals (4.34); belief that teaching students makes the job more interesting (4.17); and real sense of achievement in working with students (4.05). Significant differences were found between the groups on six items and, in all but one instance, the internship preceptors were more in agreement with the statements on intangible benefits than the AP4 preceptors. APPLICATIONS/CONCLUSIONS: The preceptors generally agreed that intangible benefits exist for departments that are AP4 sites and the professionals that work in them. As programs develop from AP4s into accredited internships, examination of intangible and monetary benefits may affect the continuation of dietetics training programs. PMID- 8683007 TI - Order writing for parenteral nutrition by registered dietitians. AB - OBJECTIVES: The purpose of the study was to describe the involvement of registered dietitians in parenteral nutrition (PN) orders, to identify characteristics of those who write orders; and to rank education, training, and support elements that dietitians believe facilitate PN order-writing skills. DESIGN: Mail survey method. SUBJECTS: Usable returned questionnaires (n = 266) represented randomly sampled membership of the Dietitians in Nutrition Support (a dietetic practice group of The American Dietetic Association) and registered dietitian membership of the American Society of Parenteral and Enteral Nutrition. STATISTICAL ANALYSIS: Data were analyzed using basic frequency displays on all questionnaire items, Pearson correlations between the quantitative variables, and one-way analysis of variance with each of the categorical variables and the quantitative variables. Detail exploration among variables was done by chi(2) analyses and two-tailed t tests. RESULTS: "Recommend" was the most frequent response to a query about participation in PN orders. An average of 37% of respondents sometimes or always wrote orders for nutrients. Specialists were more likely to write orders than clinicians and managers. No relationship was found between those who wrote orders and educational level, and writers had been registered for a shorter length of time. Agreement on the training and support needed for order-writing skills was nearly unanimous. APPLICATIONS: The PN skills of respondents who were specialists distinguished them from managers and clinicians. Specialists did not fit criteria for advanced practice, and specialty practice in metabolic nutrition care may be too broad to define their practice. Educators must recognize the importance of including PN training in didactic and clinical training programs. Registered dietitians with PN skills will be well positioned to play an active role in the evolving health care system. PMID- 8683008 TI - Diet composition related to body fat in a multivariate study of 203 men. AB - OBJECTIVE: To assess whether usual diet (especially intake of dietary fat, carbohydrate, and fiber) was related to body fat percentage in healthy men. DESIGN: A written questionnaire provided data on demographic and lifestyle characteristics. Dietary fat, carbohydrate, protein, and fiber intakes were analyzed using the National Cancer Institute food frequency questionnaire. Percentage of body fat was determined using three-site skinfold measurements, and a submaximal treadmill test was used to estimate aerobic fitness. SUBJECTS: Subjects were 203 healthy men (14.0 +/- 5.3% mean body fat) aged 21 to 71 years. The subjects were chosen from randomly selected districts within Utah County and volunteered for free diet and fitness evaluations. STATISTICAL ANALYSIS: Multiple regression analysis determined the extent to which the individual diet components predicted body composition before and after controlling for energy intake, fitness level, body weight, and age. Multivariate analysis of variance was used to compare relative body fat groups in regard to dietary variables. RESULTS: Reported intakes of carbohydrate (P = .0085, R2 = .022), complex carbohydrate (P = .0127, R2 = .024), and fiber (P = .002, R2 = .03) were inversely associated with body fat after controlling for age, energy intake, and fitness level. Energy intake was positively related to body fat after controlling for age, fitness level, and body weight. When subjects were separated into low-, moderate-, and high-body-fat groups, the fattest subjects reported eating significantly more dietary fat (P = .05) and less carbohydrate (P = .01), complex carbohydrate (P = .01), and fiber (P = .005) than the leanest subjects. No significant difference in reported energy intake was noted across body fat groups. APPLICATIONS: Composition of the diet may play a role in obesity beyond energy intake in men over the long-term. Lifestyle changes for men should probably include modifications in diet composition, especially increased consumption of foods high in complex carbohydrate and fiber. PMID- 8683010 TI - Indexes of overall diet quality: a review. AB - This article reviews the published indexes of overall diet quality. Approaches used for measuring overall diet quality include those based on examination of the intake of nutrients, food groups, or a combination of both. A majority of the indexes have been examined in relation to nutrient adequacy only; few have been evaluated for assessment of quality according to current dietary guidelines, namely, a diet relatively low in fat that meets energy and nutrient needs. The indexes of overall diet quality were related to the risk of disease more strongly than individual nutrients or foods. PMID- 8683009 TI - Survey of the diet of Pima Indians using quantitative food frequency assessment and 24-hour recall. Diabetic Renal Disease Study. AB - OBJECTIVE: A dietary survey was conducted in the Gila River Indian Community in Arizona using two methods of dietary assessment--24-hour recall and quantitative food frequency (QFF) assessment--to determine the usual intake of the population. DESIGN: Interviews were conducted by Pima women who were trained and monitored by a research dietitian. Energy and nutrient intake were calculated using a computerized dietary database that included specific Pima foods. SUBJECTS: An age and sex-stratified sample of 575 Pima Indians (273 men, 302 women) aged 18 to 74 years participated in the study. STATISTICAL ANALYSES: Spearman correlations were used to compare the results of the two survey methods for energy and each nutrient. Intraclass correlations were used to measure reproducibility. RESULTS: According to the 24-hour recall, mean reported energy intakes within decades of age were 95% to 112% of those in the US population for Pima women, and 76% to 94% of those in the US population for Pima men. Total energy intake assessed using QFF was 30% higher in men and 33% higher in women than the intake assessed using the 24-hour recall method. CONCLUSIONS: A large dietary survey conducted using lay interviewers in a Native-American community was as reproducible as studies conducted in the general US population. The Pima diet was distributed among the major nutrients in a proportion similar to the US diet. PMID- 8683011 TI - Sensory acceptability is inversely related to development of fat rancidity in bread made from stored flour. PMID- 8683012 TI - Eating quality of banana nut muffins and oatmeal cookies made with ground flaxseed. PMID- 8683013 TI - Foodservice specialists exhibit lack of knowledge in identifying whole-grain products. PMID- 8683014 TI - Role of undergraduate dietetics programs in providing nutrition education to premedical students. PMID- 8683015 TI - Impact of preceptors on student attitudes toward supervised practice. PMID- 8683016 TI - Adolescent milk consumption, menarche, birth weight, and ethnicity influence height of women in Hawaii. PMID- 8683017 TI - Applying a new model, principles, and process in nutrition intervention partnerships. PMID- 8683018 TI - Domestic violence: legal issues for health care practitioners and institutions. AB - If health care practitioners and institutions became familiar with legal options available to survivors of domestic violence, they could better facilitate their patients' access to potentially life-saving recourses. Such options include calling the police and obtaining civil protection orders and bringing custody, divorce, and support actions. Provider awareness of legal obligations and other legal considerations that arise when handling domestic violence cases is important for patient care and the practice of good risk management. Examples of such issues include domestic violence protocol requirements, documentation of abuse, and repercussions of mandatory reporting laws. Health care providers should work in collaboration with community domestic violence programs in educating staff on issues pertaining to domestic violence and in crafting policies that promote patient safety and autonomy. PMID- 8683019 TI - Depression in battered women. AB - Sex differences in rates of depression and of battering by intimate partners are substantial: 3:1 and 10:1, respectively. The relationship between battering and depression has been documented for more than two decades, but has rarely been noted in the depression literature. This paper presents a brief summary of the major etiological theories of depression with a discussion of the evidence that links these theories with research on battered women. It seems clear that battering can be an important component of depression in battered women. Understanding the mechanisms involved in the relationship between depression and battering can result in a better approach to the diagnosis and treatment of depression in battered women. This discussion has particular ramifications for the primary health care system as well as the mental health care system. PMID- 8683020 TI - Abuse histories among newly incarcerated women in a New York City jail. AB - This article reports the findings from a study of women detained in the women's jail at Rikers Island Correctional Facility in New York City. Interviews were used to gather data on five variables: women's childhood physical and sexual abuse, victimization as adults, drug use, homelessness, and suicide. These findings were analyzed along with biological data on STDs. The conclusions suggest that an association exists between childhood physical and sexual abuse and drug use, suicide attempts, and homelessness in adulthood. The findings indicate that these experiences are common for the population under study, and that a positive association between the variables exists in a sample of incarcerated women. Implications and questions for further research are discussed. PMID- 8683021 TI - Alcohol, drugs, and domestic violence: confronting barriers to changing practice and policy. PMID- 8683022 TI - Homicide against women in the workplace. AB - OBJECTIVES: To examine the nature and magnitude of violence against women in the workplace. METHOD: Data from the National Traumatic Occupational Fatalities surveillance system were analyzed for the 13-year period, 1980 to 1992. Employment information was coded from industry and occupation narratives taken from the death certificates. Rates were calculated using annual average employment data published by the Bureau of Labor Statistics. RESULTS: From 1980 to 1992, 2,001 women and 7,935 men were victims of work-related homicides, for rates of 0.32 and 1.01 per 100,000 female and male workers, respectively. The majority of female homicide victims were employed in two industries-retail trade (46%) and services (22%). The highest risk industry was grocery stores (1.74 per 100,000 workers), followed by eating and drinking establishments, hotels and motels, and justice and public order. CONCLUSIONS: The findings presented here are consistent with previous research indicating that homicide is the leading cause of occupational injury death for women, but that women are at lower risk than their male counterparts. Homicide played a major role in sales and service, sectors that have increased over the last several decades and in which future growth is predicted. Feasible and effective prevention strategies to reduce the risk of work-related homicides must be developed and implemented. PMID- 8683023 TI - Health workers: potential allies in the battle against woman abuse in developing countries. PMID- 8683024 TI - Guidelines for doctors on identifying and helping their patients who batter. AB - While there are a growing number of medical guides for assisting physicians to identify and help victims of domestic violence, there has been scant attention to how physicians can best respond to perpetrators. The medical model's deficient grasp of violence, combined with the minimizing and excuse-making strategies employed by batterers hinder physicians' ability to detect batterers in their practices and to prescribe the right solutions. Earlier detection is possible, however, when doctors adopt routine diagnostic procedures for all patients and ask informed follow-up questions when there are indications of domestic violence. Finally, physicians should become aware of the effective batterer treatment programs in their areas and make this information easily available to their patients who batter. PMID- 8683025 TI - Synergy: violence prevention, intervention, and women's health. PMID- 8683026 TI - Prevalence of domestic violence in the United States. AB - This comprehensive review of the literature reports on the annual and life-time prevalence of domestic violence against women in the United States. Data on population-based samples, pregnant women, and women treated in emergency rooms are each presented separately, as are the effects of age, marital status, socioeconomic status, race and ethnicity, and alcohol and drug use. Prevalence reports vary across studies, due in part to definitional issues and differences in the populations studied, but this is primarily true for lifetime and not for current prevalence. Prevalence is 0.3% to 4% for severe violence and 8% to 17% for total violence in the past year. Lifetime occurrence is 9% for severe violence and 8% to 22% for total violence. When minor as well as severe acts of physical violence toward women in the general female population are included, prevalence appears to be between 10% and 15% and somewhat higher for some subgroups. PMID- 8683027 TI - CDC's family and intimate violence prevention team: basing programs on science. AB - Women are frequent targets of both physical and sexual assault not only by strangers, but by partners and acquaintances as well. The public health approach to violence, including violence against women, focuses on prevention rather than treatment and is science based. Its steps include defining the problem, identifying causes, developing and testing interventions, and then implementing interventions and measuring their effectiveness. The Family and Intimate Violence Prevention Team in the National Center for Injury Prevention and Control at the Centers for Disease Control and Prevention uses the public health approach to address the prevention of violence against women. We describe here some of the team's major activities and show how these activities will add to the scientific database on violence against women. PMID- 8683028 TI - Domestic violence: changing theory, changing practice. AB - Despite widespread recognition of domestic violence as a public health problem, many clinicians still have difficulty integrating routine intervention into their day-to-day practice. This is in part because domestic violence raises a distinct set of challenges for both providers and the institutions that shape clinical practice. Domestic violence is a complex social problem rather than a biomedical one; addressing it means asking clinicians to step beyond a traditional medical paradigm to confront the personal feelings and social beliefs that shape their responses to patients and to work in partnership with community groups committed to ending domestic violence. In addition, addressing domestic violence raises important challenges to the health care system itself-to its theoretical models, to the nature of medical training, and to the rapidly changing structure of clinical practice. If we truly want to play a role in preventing domestic violence, rather than just treating its consequences, we must work together to transform both the individual and social conditions that create and support this kind of violence in the first place. PMID- 8683029 TI - The emergency department as a violence prevention center. AB - No longer confined to the criminal justice system alone, violence is now regarded as a major health care issue in America. Changes are apparent not only in health care delivery, but also in medical school curricula, residency training board examinations, and accreditation. Although tertiary prevention demands the most acute attention, opportunities for secondary prevention are important and often neglected, especially when the immediate health care issue is not related to violence. This article describes the development of the Emergency Department as a Violence Prevention Center program, established at The George Washington University Medical Center. The program moves beyond responding to acute cases of violence only and considers the hospital emergency department as an active player in a community-wide effort to end violence. It does this through universal screening, assessment, treatment and other interventions, documentation, and patient and professional education. PMID- 8683030 TI - Woman abuse and pediatrics: expanding the web of detection. AB - Efforts to increase the medical care system's responsiveness to victims of domestic violence have been focused on emergency and obstetric/gynecologic care. This paper advocates for expanding the web of detection to include pediatric practitioners. In order to effectively address the issue of domestic violence, medical providers must be linked to community-based resources. Physicians need to understand the complexity of this issue and focus on the process (empowerment) rather than on an outcome (leaving). A broader conceptualization of the battering situation, appropriate medical system response, and specific suggestions for how pediatric providers can inquire about and respond to domestic violence are provided. PMID- 8683031 TI - Successful eradicating treatment of Helicobacter pylori in patients with chronic gastritis: gastric levels of cytokines, epidermal growth factor and polyamines before and after therapy. AB - In 10 patients with Helicobacter pylori (HP) positive chronic gastritis, gastric mucosal content of interleukin (IL)-1 beta, IL-8, Transforming Growth Factor (TGF)-beta 1, Epidermal Growth Factor (EGF) and Polyamines (putrescine, spermine and spermidine) was evaluated before and after eradicating treatment. Histologically, in all patients eradication of HP was accompanied by a marked reduction of the inflammatory infiltrate. At the same time, at the end of the therapeutical regimen, elevated levels of IL-1 beta, IL-8, TGF-beta 1, putrescine and spermidine/spermine ratio significantly dropped, while EGF mucosal content, significantly increased. Results are discussed in terms of the reciprocal role of inflammatory cytokines, growth factors and polyamines in the evolution of the HP associated chronic gastritis. PMID- 8683032 TI - Effects of Chinese herbs on macrophage functions in N-butyl-N-butanolnitrosoamine treated mice. AB - We investigated the effect of Chinese herbs Lithospermi radix, Astragali radix and Cnidii rhizoma on the functions of macrophages obtained from mice treated with the carcinogen N-butyl-N-butanolnitrosoamine (BBN). The chemotactic activity of murine macrophages was significantly decreased by 17 weeks of treatment with BBN compared with controls. Production of IL-1 and TNF was also markedly reduced. Treatment with Lithospermi radix, Astragali radix, and Cnidii rhizoma significantly inhibited BBN-induced suppression chemotactic activity and production of IL-1 and TNF-alpha by macrophages. Moreover, we found that Astragali radix treated macrophage chemotaxis, it or Cnidii rhizoma induced productions of TNF-alpha were in excess of control. PMID- 8683034 TI - Immunotoxic effects of copper and cadmium in the sea bass Dicentrarchus labrax. AB - Two phagocytes-mediated activities of the sea bass Dicentrarchus labrax were examined after exposure to sublethal concentrations of copper and cadmium: (a) phagocytosis (measured by phagocytotic index), and (b) the production of reactive oxygen intermediates (luminol-dependent chemiluminescence) in response to bacteria Aeromonas salmonicida. In vivo exposure for 48 h to each metal separately by intraperitoneal injection did not affect the quantity of phagocytes of pronephros and their viability but inhibited, in dose-dependent manner, phagocytosis and chemiluminescence of these cells. The half-inhibition value was 250 micrograms kg-1 for copper and 1 mg kg-1 for cadmium. In vitro exposure to copper for 30 min had the same immunomodulatory effect on macrophage chemiluminescence as that observed in vivo, whereas treatment with cadmium under the same conditions had a dose-dependent effect opposite to that observed in vivo. Assessment of these two macrophage-mediated functions could therefore be used as early bioindicators of the marine pollution. PMID- 8683033 TI - Influence of salbutamol and isoproterenol on the production of TNF and reactive oxygen species by bovine alveolar macrophages and calcitriol differentiated HL-60 cells. AB - The influence of the beta-adrenergic agonists Salbutamol and Isoproterenol on the release of reactive oxygen species and Tumor Necrosis Factor (TNF) was tested with bovine alveolar macrophages and HL-60 cells differentiated to macrophages by calcitriol. The production of reactive oxygen species was analyzed by a microplate assay using dichlorofluorescein-diacetate. It could be shown that this method almost exclusively measures superoxide anions. TNF was determined by a bioassay with WEHI cells. The superoxide anion production was stimulated by Zymosan, the TNF release by LPS. By incubation with 5 x 10(-6) and 5 x 10(-7) M Salbutamol or 5 x 10(-7) and 5 x 10(-8) M Isoproterenol prior to the stimulation, the production of superoxide anions as well as of TNF was inhibited to a significant degree. The inhibitory effects of the adrenergic agonists were completely or at least partially inhibited by the respective antagonists, ICI 118.551 and Propranolol, respectively. PMID- 8683035 TI - Distribution and localization of monophosphoryl lipid A in selected tissues of the rat. AB - The distribution and cellular localization of Monophosphoryl Lipid A in the kidney, liver, lung, spleen, and stomach of rat were investigated by immunohistochemistry on paraffin embedded tissue sections. Rats were sacrificed 24h or 48h following intraperitoneal administration of MPL at a dose of 5mg/Kg. The presence of MPL in selected tissues was indicated by a positive reaction to MPL antibody. In the kidneys, MPL was found in collecting tubules and distal convoluted tubules in the medulla, whereas the glomerulus was essentially free of it. Regarding liver, MPL was found to be abundant in hepatocytes but only occasionally present in Kupffer cells. In lungs, both alveolar and bronchiolar macrophages were positive, indicating the lung can also serve as a possible site for the elimination of MPL. In spleen, endothelial cells and macrophages were positive for MPL. In stomach, MPL was detected in the gastric mucosa and vascular endothelial cells. In all the tissues studied the intensity of the peroxidase reaction was significantly weaker in 48h samples as compared to corresponding 24h samples indicating possible elimination of MPL from these tissues. PMID- 8683036 TI - Tumor necrosis factor and interferon-gamma augment anticolon antibody- dependent cellular cytotoxicity in ulcerative colitis. AB - The effect of tumor necrosis factor (TNF) and interferon (IFN)-gamma on antibody dependent cellular cytotoxicity (ADCC) in patients with ulcerative colitis (UC) was investigated. ADCC activity was measured by the 51Cr release assay, using peripheral blood mononuclear cells of healthy subjects as effector cells and RPMI 4788 cells derived from human colon cancer as target cells. ADCC activity under sera from healty subjects remained low whether or not the effector cells were pretreated with TNF (100 U/ml, 16h). Under sera from UC patients, ADCC activity of 13.9%, compared to 9.6% when pretreatment was deleted. The effect of IFN pretreatment (100 U/ml, 16h) was also examined under sera from UC patients; in that experiment activity rose to 26.8%, in comparison to a 10.7% when IFN-gamma pretreatment was deleted. Finally, when the effector cells were pretreated with both TNF and IFN-gamma (100 U/ml of each, 16h) the ADCC activity under sera from UC patients was higher than when either TNF or IFN-gamma were used alone. These results suggest that TNF and IFN-gamma, by increasing ADCC activity in UC lesions, are involved in cell injury in the colonic epithelium. IFN-gamma appears to increase ADCC activity by increasing the number of high affinity monocyte Fc gamma RI receptors, while TNF increases ADCC activity by a different mechanism. PMID- 8683037 TI - PGE2-induced immunoregulation mediated by cytokine production from cultures of human peripheral T lymphocytes. AB - Prostaglandins (PGs) are generally known to exert inhibitory as well as some enhancing effects on the immune system. This study was performed to assess the influence of the exogenous PGs and cyclic adenosine monophosphate (cAMP) elevating agents on cytokine production by PWM-stimulated human T lymphocytes. Peripheral blood T lymphocytes from healthy donors were pretreated for 30 min at 25 degrees C with PGE2 (10(-4) to 10(-7) M) PGF1 alpha, IBMX or Forskolin (10(-4) to 10(-5) M) and cultured for 7 days in the presence of Pokeweed Mitogen (PWM), PGE2, IBMX and Forskolin, but not PGF1 alpha, significantly increased IL-6 production while inhibited IL-2, IL-3, IL-4, IFN-gamma, TNF-alpha and GM-CSF production. Our data indicate that cAMP-elevating agents can profoundly affect cytokine secretion by T cells in PWM-driven cultures and that this effect is dose dependent. The results reported here are compatible with the existence of separate pathways of gene induction for IL-2, IL-3, IL-4, IFN-gamma, TNF-alpha and GM-CSF on the one hand and IL-6 on the other one. PMID- 8683038 TI - Pretreatment of human peripheral blood lymphocytes with interleukin-2 or dexamethasone does not alter their response to Met-Enkephalin in a NK-cytotoxic assay. AB - The effect of Met-Enkephalin (MENK; 10(-12) - 10(-8) M) on NK-activity of peripheral blood lymphocytes (PBL) after in vitro treatment (18 h, 37 degrees C) was examined in 30 young, healthy male donors. In the group as a whole (n = 30), no significant effect of MENK was detected. At the individual level, 18 of 30 donors (60%) responded to MENK either by mild enhancement (up to 8%, 8 responders), or by mild attenuation (up to 12%, 10 responders) of the basal NK activity. The effect of MENK was donor-related regarding the dose-response, E/T ratio, and direction of MENK action. The influence of pretreatment of PBL (1 h) with either graded doses of interleukin-2 (IL-2; 3, 25, 50 U/ml) or dexamethasone (Dex; 2.5 x 10(-9), 2.5 x 10(-8), 2.5 x 10(-7) M), on the effect of MENK was also tested. The idea was that pretreatment of PBL would result in predictable, and/or stronger response to MENK. In the group as a whole again no significant effect of MENK was detected on the NK-activity of PBL prestimulated by IL-2 (n = 16), or inhibited by Dex (n = 12). Further, pretreatment of PBL with IL-2/Dex did not significantly alter the intensity of modulation by MENK, which was generally mild. The data obtained have shown that pretreatment of PBL with IL-2 or Dex, regardless of their concentrations, did not significantly alter the frequency of responders to MENK being 50%, 62.5% and 64.3% with 3, 25 or 50 U/ml IL-2, respectively, and 50% with all concentration of Dex used, as compared to that observed with resting PBL (60%). However, at the individual level physiological concentrations of MENK (10(-12) - 10(-9) M) induced enhancement or/and attenuation of the NK-activity pretreated with IL-2/Dex, respectively. The effect of MENK at the individual level was donor-related regarding the dose-response, E/T ratio, and direction of MENK action. Thus, pretreatment of PBL with graded concentrations of IL-2/Dex did not alter the effect of MENK on NK-activity, regarding the frequency and intensity, as well as the direction of modulation: it remained bidirectional, of low intensity, and independent of the grade of PBL preactivation/inhibition, therefore unpredictable. PMID- 8683039 TI - Thalidomide can be either agonistic or antagonistic to LPS evoked synthesis of TNF-alpha by mononuclear cells. AB - The effect if thalidomide on tumor necrosis factor alpha (TNF-alpha) produced in vitro by lipopolysaccharide (LPS) stimulated human cells was investigated. In cultures of LPS stimulated human mononuclear cells enriched for adherent cells and in cultures of LPS stimulated human monocytes of the cell line-THP-1, thalidomide enhanced the synthesis of TNF-alpha. When cultures of unfractionated peripheral blood mononuclear cells were stimulated with LPS, thalidomide decreased the synthesis of TNF-alpha. Depending on the type of cells stimulated with LPS in vitro, thalidomide, at concentrations achieved in vivo, can either enhance or suppress the synthesis of TNF-alpha. PMID- 8683040 TI - Protection of C3H/HE J mice from development of Candida albicans infection by oral administration of Juzen-taiho-to and its component, Ginseng radix: possible roles of macrophages in the host defense mechanisms. AB - Protective effect of a Japanese traditional herbal medicine, Juzen-taiho-to (TJ 48), which was recently reported to augment host-mediated antifungal actions, in Candida albicans-infected mice was further studied. TJ-48, given orally once daily for 5 consecutive days in a dose of 2 g/kg after intravenous infection of C. albicans, prolonged survival period of infected mice of a C3H/He J strain which is characteristic of functional deficiency of macrophages, but did not that of infected mice of a C3H/He N strain with normal macrophage function. Peritoneal macrophages obtained from C3H/He J mice showed a moderate inhibitory activity against Candida growth in vitro. The anti-Candida activity of the macrophages was augmented by the addition of TJ-48 or some component extracts of TJ-48 to the incubation medium. Among such active component extracts is an extract of Ginseng radix which was demonstrated to enhance the anti-Candida activity of macrophages in vitro and to prolong the survival time of C. albicans-infected C3H/He J mice without effect on C3H/He N mice. On the base of these findings, the mechanisms underlying the protective action of TJ-48 against systemic Candida infection was discussed in relation with its possible activity to activate the macrophage function. PMID- 8683041 TI - Effects of ethyl carbamate and its metabolites on the antibody response in splenocyte cultures from female Balb/C mice. AB - To investigate a possible role by cytochrome P450 (P450) in ethyl carbamate induced immunosuppression, an attempt to assess the ability of ethyl carbamate, its metabolites produced by P450 (i.e., ethyl N-hydroxycarbamate and vinyl carbamate), and methyl carbamate to suppress the polyclonal antibody response induced by bacterial lipopolysaccharide was made in splenocyte cultures isolated from female Balb/C mice. The results showed that vinyl carbamate and ethyl N hydroxycarbamate were more immunosuppressive compared to ethyl carbamate. A structurally related analogue, methyl carbamate, did not suppress the antibody response. These results indicate that metabolism of ethyl carbamate by P450 may produce more immunosuppressive metabolites as in ethyl carbamate-induced carcinogenicity. A pre-incubation study with phenobarbital-induced liver microsomes in the presence of NADPH-generating system showed that the antibody response was suppressed by ethyl carbamate when splenocytes were pre-incubated with ethyl carbamate and microsomes simultaneously. Moreover, the suppression was completely recovered by the addition of a P450 inhibitor, aminoacetonitrile, in the pre-incubation. Taken together, the present results indicate that metabolism of ethyl carbamate by P450 enzyme(s) may be an important pathway to cause immunosuppression. PMID- 8683042 TI - The gross and histologic anatomy of the scapholunate interosseous ligament. AB - The scapholunate interosseous ligament, which connects the carpal scaphoid and lunate bones, was evaluated by gross dissection and serial histologic sections in transverse, sagittal, and coronal planes in 21 fresh and 16 fixed adult cadaver wrists. The scapholunate interosseous ligament is consistently divisible into three anatomic regions: dorsal, proximal, and palmar. The dorsal region is thick and composed of short, transversely oriented collagen fibers. The proximal region is principally composed of fibrocartilage, with a few superficial, longitudinally oriented collagen fibers. The proximal region may extend distally a few millimeters into the scapholunate joint space, thus resembling a knee meniscus. The radioscapholunate ligament separates the proximal and palmar regions of the scapholunate interosseous ligament, often extending distally to cover the dorsal surface of the palmar region of the scapholunate interosseous ligament. The palmar region is thin and composed of obliquely oriented collagen fascicles, just dorsal to and separate from the long radiolunate ligament. PMID- 8683043 TI - Midcarpal arthrodesis. AB - This retrospective review of midcarpal arthrodesis was undertaken between July 1985 and March 1990. Fourteen patients were identified and 11 were available for follow-up evaluation. Mean follow-up time was 66 months (range, 48-102 months). Four patients eventually underwent total wrist arthrodesis due to continued pain. Seven patients improved and each returned to work between 3 and 4 months after surgery. Wrist motion was 50% and grip strength 65% of the normal side. Midcarpal arthrodesis has a predictable fusion rate; however, it does not reliably relieve pain. PMID- 8683044 TI - Displaced intra-articular fractures of the distal radius: the effect of fracture displacement on contact stresses in a cadaver model. AB - Contact stresses in the wrist were measured after simulating displaced fractures of the lunate fossa in the distal radius of eight human cadaver arms. Osteotomies created displaced lunate fossa fractures of 0, 1, 2, and 3 mm. Contact stresses were measured with Fuji pressure-sensitive film after loads of 100 N were applied to the wrist through wrist flexor and extensor tendons. Mean contact stresses were significantly increased with step-offs of 1 mm or more. Maximum stresses and overloaded areas were significantly increased with step-offs of 2 mm or more. As the magnitude of the fracture displacement increased, there was a shift in the focus of the maximum stresses toward the fracture line. In this model, simulated displaced die-punch fractures created alterations in both the magnitude and location of contact stresses in the wrist joint. PMID- 8683045 TI - Triangular fibrocartilage injury: a laboratory model. AB - A potential injury mechanism for triangular fibrocartilage tears and ulnar styloid fractures was investigated in cadaver specimens. The distal radioulnar joint was distracted to failure, thus applying a tensile force to the triangular fibrocartilage. During distraction, strains in the triangular fibrocartilage and the anatomic site of disruption were recorded with an image analysis system. Complete avulsion of the triangular fibrocartilage from the ulnar head occurred in 7 of 10 specimens. No ulnar styloid fractures occurred. Although strains were high in the radial portion of the disk (28%), no tears occurred in the substance of the disk or at its attachment to the radius. These findings suggest that distal radioulnar joint distraction can cause avulsion of the triangular fibrocartilage. However, ulnar styloid fractures and tears within the disk are more likely caused by injury mechanisms that include shear or compressive forces. Since complete avulsions of the triangular fibrocartilage occurred without a fracture, the absence of a fracture does not rule out a destabilizing injury to the distal radioulnar joint. PMID- 8683046 TI - Stabilized resection arthroplasty by an anterior approach in trapeziometacarpal arthritis: results and surgical technique. AB - Resection arthroplasties were performed through a carpal tunnel incision in 72 hands of 57 patients with trapeziometacarpal joint arthritis and coexistent pathology of the anterior hand or wrist. Sixty-nine hands were followed for an average of 44 (range, 12-74 months). Pain relief was excellent in 60 hands, good in 7, and fair in 2, and thumb motion was satisfactory in 64 hands. Mean strength increase was 30%. Scaphometacarpal space loss was 0.5 mm each year, and residual space averaged 3.1 mm at 60 months. There were two failures. The study corroborated the frequent coexistence of other pathology of the anterior area of the hand and wrist, specifically, carpal tunnel syndrome and flexor carpi radialis tenosynovitis. Furthermore it demonstrated the possibility of an anterior approach to treat these conditions via the same incision. After 5 years, functional results remained good despite progressive collapse of the scaphometacarpal space. PMID- 8683047 TI - Basal joint arthritis: trapeziectomy with ligament reconstruction and tendon interposition arthroplasty. AB - This article provides a qualitative and quantitative outcomes assessment of a consecutive series of 27 patients (30 thumbs) with basal joint arthritis of the thumb undergoing ligament reconstruction and tendon interposition arthroplasty. Outcome analysis revealed that 24 (89%) patients were satisfied with the relief of pain provided by the arthroplasty and 23 (87%) would undergo surgery again. Eighteen (67%) thumbs were noted to have improvement in the ability to perform activities of daily living. Significant improvements were noted in web space measurements and in grip and pinch strength determination. X-ray film assessment using the trapezial space ratio averaged 0.33 +/- 0.08 in preoperative x-ray films of thumbs with stage III and IV degenerative arthritis and 0.23 +/- 0.07 in thumbs following basal joint arthroplasty. This represents a total decrease of 51% in the trapezial space ratio following arthroplasty compared to the normal values obtained in previous studies and 33% compared to the preoperative values obtained in this study. Outcomes assessment at a mean of 42 months after surgery showed that there was no significant correlation between maintenance of trapezial height and both objective and subjective clinical outcomes. Although ligament reconstruction consistently failed to restore trapezial height, primary and secondary clinical outcomes following basal joint arthritis were almost uniformly satisfactory. PMID- 8683048 TI - The role of transforming growth factor beta in Dupuytren's disease. AB - This study was undertaken to mark immunologically intracellular and extracellular sites of two common transforming growth factor beta (TGF-beta) isoforms, TGF beta1 and TGF-beta2, in the proliferative, involutional, and residual stages of Dupuytren's disease. The effect of TGF-beta on myofibroblast proliferation was also studied using explant cultures from Dupuytren's nodules in the proliferative or involutional stage. TGF-beta1, TGF-beta2 and the combination of both isoforms were studied at low and high myofibroblast plating densities to simulate respectively proliferative or involutional disease stage conditions. Our results indicate that TGF-beta1 showed an intense intracellular marking pattern associated with fibroblasts, myofibroblasts, and capillary endothelial cells in all Dupuytren's samples, regardless of disease stage. TGF-beta2 showed an intense intracellular localization within myofibroblasts in the proliferative and involutional stages. Fibroblasts in the residual stage did not contain TGF-beta2. Neither isoform was present in the extracellular matrix. Results of cell culture indicate that compared with control myofibroblasts, the addition of TGF-beta1, TGF-beta2 and TGF-beta1 + beta2 had significant effects on myofibroblast proliferation, especially at higher plating densities. However, TGF-beta2 had the most significant proliferative effect. PMID- 8683049 TI - Osseointegrated thumb prostheses: a concept for fixation of digit prosthetic devices. AB - Three patients with traumatic amputation of the thumb at the metacarpophalangeal joint level underwent a two-stage reconstruction aimed at fixation of a thumb prosthesis to the first metacarpal bone via an osseointegrated titanium fixture. The first stage included insertion of the fixture into the medullary cavity of the first metacarpal bone in combination with transplantation of cancellous bone from the iliac crest. After 3 months, when the fixture was firmly osseointegrated into the bone, a skin-penetrating abutment was placed on top of the fixture, the surrounding skin being thinned to the thickness of a split-skin graft to minimize relative mobility. A thumb prosthesis could then be firmly attached to this fixture. At follow-up examinations between 18 months and 3 years; postoperatively perfect osseointegration of the implant persisted. There were no skin problems. Some extent of tactile discrimination was achieved in the prosthesis hypothetically based on transfer of tactile stimuli to endosteal nerves in the bone via the titanium fixture. PMID- 8683050 TI - Benefits and use of digital prostheses. AB - This study examines our clinical experience of fitting 136 digital prostheses in 90 patients. The careful selection of patients, especially concerning their expectations, is the single most important factor for successful prosthetic development for physically suitable candidates. Whether continued disability is due to physical loss or to its emotional impact, the socioeconomic consequences are similar, so attention to both is required. In a review of 30 patients fitted with digital prostheses after a minimum follow-up time of 2 years, it was found that 22 (73%) used their prostheses daily and another 7 (23%) used them intermittently according to the occasion. Thus, a total of 29 (97%) of those fitted with our digital prosthesis continued to use them after 2 years. Technical problems, such as loose fit and perspiration, resulted in 7 (23%) of the patients using the prostheses only occasionally. Fitting a prosthesis goes beyond aesthetics, and our study confirmed that digital prostheses, if of high quality, can alone or in conjunction with appropriate surgical reconstructions restore near normal appearance and form, substantially repair damaged body image, and simultaneously improve physical capability. PMID- 8683051 TI - Nail regeneration in digits replanted after amputation through the distal phalanx. AB - Nail regeneration was studied in 48 digits replanted after amputation through the distal phalanx. Twenty-seven were amputated through Tamai's zone I, at the nailbed level, and 21 digits were amputated through zone II, proximal to the nail. The nails of 9 digits in zone I and 14 in zone II showed almost normal nail regeneration. We observed that replantation after amputations distal to the lunula will show near normal nail regeneration if there is minimal postoperative circulatory disturbance. Amputations proximal to the lunula, however, have a greater chance of causing damage to the germinal matrix, which results in more problems with nail growth. PMID- 8683052 TI - Effect of peripheral suture depth on strength of tendon repairs. AB - The peripheral suture in flexor tendon repairs was originally introduced to "tidy up" the repair site and to improve gliding after core suture placement. More recently, it has been proposed that the peripheral suture can be an important structural component of tendon repair; yet, the effect of peripheral suture technique as an independent factor on the strength of the tendon repair has had little attention. We proceeded to determine whether differing levels of penetration of the tendon by the peripheral suture significantly affect the strength of the repair. We performed tensile tests on two groups of fresh frozen cadaver flexor digitorum superficialis tendons that had lacerations repaired by modified Kessler core sutures: one group had supplemental superficial peripheral sutures while the other group had supplemental deep (half the depth to the center of the tendon) peripheral sutures. The mean failure load of the deep peripheral suture group (38.96 N) was almost 80% greater than that of the superficial suture group (21.68 N). This increased strength may be due to an improved tendon-suture interface, with the deep peripheral suture acting as an auxiliary core suture. Our results with deep peripheral sutures, a simple technique based on a modification of commonly employed suture patterns, demonstrate substantially improved repair strength. This suture has the potential to be used in conjunction with early active finger motion rehabilitation program after flexor tendon repair. PMID- 8683053 TI - Mechanical analysis of the palmar aponeurosis pulley in human cadavers. AB - The anatomy of the palmar aponeurosis pulley has been well described, but its biomechanical function is not as well characterized. This study describes the functional importance of the palmar aponeurosis pulley by using efficiency parameters. We obtained data by generating load, excursion, and work efficiencies in the intact pulley system and compared these to the efficiencies obtained after sectioning the palmar aponeurosis pulley alone and in combination with the proximal annular pulleys. The variability associated with comparisons between different fingers and hands was therefore diminished. Sectioning the palmar aponeurosis pulley alone did not significantly change any of the efficiency parameters. When the palmar aponeurosis pulley was sectioned in combination with either or both of the proximal annular pulleys (A1, A2) there was a significant decrease in excursion efficiency. Only after all three proximal pulleys were sectioned did the load efficiency increase and the work efficiency decrease significantly. These findings prove that the palmar aponeurosis pulley in combination with the proximal annular pulleys acts to decrease the tendency to bowstringing around the metacarpophalangeal joint. The increased load efficiency is probably the result of a decrease in friction and counteractive forces generated by the integrated fibers of the intact palmar aponeurosis pulley. Change in work is due not only to an increase in excursion, but also to the increased resistance that results from the acute angulation that the tendon must endure as it follows behind the remaining pulleys during flexion. Intergroup comparisons show a significant contribution by the palmar aponeurosis pulley. This study demonstrates a significant biomechanical role for the palmar aponeurosis pulleys and suggests that it be considered similar to the annular and cruciate flexor tendon pulleys in importance. PMID- 8683054 TI - Diagnosis of digital pulley rupture by computed tomography. AB - Seven patients who presented with a rupture of the digital pulley were investigated by computed tomography. The rupture involved the A2 and A4 pulleys in four cases, the A2 pulley in two cases and, in the final case, the A4 pulley alone. A sagittal-plane CT scan gave a precise analysis of the rupture in all cases. Two cases were surgically repaired and CT scanning was used in their postoperative assessment. When performed by a radiologist with an interest in musculoskeletal pathology, we have found CT scanning to be an excellent imaging procedure in the investigation and diagnosis of digital pulley injury. This can be useful when the diagnosis of digital pulley rupture cannot be made by history and physical examination. PMID- 8683055 TI - Persistent post-traumatic fourth web space pain after rupture of the fourth lumbrical muscle: a case report. PMID- 8683056 TI - The Linburg Comstock anomaly: a case report. PMID- 8683057 TI - Extrusion of fracture fragment into flexor sheath following proximal interphalangeal joint fracture-dislocation: a case report. PMID- 8683058 TI - Hemangioma of the extensor pollicis brevis in the first dorsal compartment: an unusual cause of bilateral de Quervain's disease. PMID- 8683059 TI - Nerve coaptation studies with and without a gap in rabbits. AB - Appropriate matching of proximal and distal fibers is a major objective when suturing a lacerated nerve. Recent studies suggest that neurotropic factors may influence motor/sensory specificity and affect the functional outcome. This was studied in animal models by direct coaptation of cut nerve ends inside a 5-mm collagen tube with and without appropriate sensory/motor alignment, as well as in models where the cut nerve ends were placed in a 10-mm collagen tube with a 5-mm gap, with and without appropriate sensory/motor alignment. The radial nerve of 49 New Zealand white rabbits was chosen because it has distinct motor and sensory divisions. The animals were killed at 24 weeks and electrophysiologic, histologic, and muscle contraction studies were performed. Axon counts and diameters were measured from the distal motor and sensory stumps. Nerve conduction velocity, dry muscle weight, and motor axon counts were not statistically different between the groups. The malaligned group without a gap had better regeneration in sensory nerves than other groups. The muscle contraction force of the malaligned group without a gap was significantly less than the other groups. The malaligned group with a 5-mm gap had the same muscle contraction force as the aligned group without a gap. In this study, a short nerve gap lessened the misdirection of motor fibers after nerve-end coaptation. PMID- 8683060 TI - Spontaneous anterior interosseous nerve palsy with hourglass-like fascicular constriction within the main trunk of the median nerve. AB - Interfascicular neurolysis was performed in nine patients with spontaneous anterior interosseous nerve palsy. In eight of these patients, an hourglass-like constriction in the fascicles forming the anterior interosseous nerve was found within the main trunk of the median nerve at 2-7.5 cm above the medial epicondyle. The clinical signs and symptoms of these eight patients were similar to those that have been described to isolated neuritis. While the etiology remains unknown, when spontaneous anterior interosseous nerve palsy is suspected to be caused by isolated neuritis, interfascicular neurolysis should be performed to confirm the lesion and to discover whether fascicular constriction is present. PMID- 8683061 TI - Brachial plexus surgery through the infraclavicular approach using an interscalene block. PMID- 8683062 TI - Anatomic delineation of the ulnar nerve and ulnar artery in relation to the carpal tunnel by axial magnetic resonance imaging scanning. AB - In a number of publications the distal branches of both the ulnar artery and ulnar nerve have been identified as being positioned ulnar to the hook of the hamate. We undertook a magnetic resonance imaging project in patients who presented for carpal tunnel release to determine how far radially vital structures of Guyon's canal may be located and if they may overlap the carpal tunnel at the hook of the hamate. Cross-sectional magnetic resonance imaging scans of 20 patients were performed prior to carpal tunnel release with the wrist positioned in neutral, flexed, and extended positions. Linear measurements were made either radial or ulnar to the hook of the hamate taken as the reference point. In the neutral position, the ulnar nerve was found to be, on average, 3.6 mm ulnar to the hook of the hamate (range of 5.8 mm radial to 7.5 mm ulnar). The ulnar artery averaged 0.7 mm to the radial side of the hook of the hamate (range 7.8 mm radial to 2.8 mm ulnar). Guyon's canal extended 28% of the way across the carpal ligament (range 9 to 63%). With the wrist in flexion and extension, there was an ulnar displacement and a radial displacement, respectively, of these structures relative to the hook of the hamate. PMID- 8683063 TI - Ulnar nerve compression syndrome due to an anomalous arch of the ulnar nerve piercing the flexor carpi ulnaris: a case report. PMID- 8683064 TI - Supracondylar process syndrome: a case report. PMID- 8683065 TI - Carpal tunnel syndrome caused by a synovial nodule of the flexor digitorum profundus tendon of the index finger. PMID- 8683066 TI - Angiomyoma (vascular leiomyoma) of the median nerve. PMID- 8683067 TI - Bilateral forearm compartment syndromes resulting from neuroleptic malignant syndrome. PMID- 8683068 TI - Monostotic fibrous dysplasia in the hand: a case report. PMID- 8683069 TI - Chondromyxoid fibroma of a metacarpal: a case report and review of the literature. PMID- 8683070 TI - Turret exostosis of the metacarpal: a case report. PMID- 8683071 TI - Treatment of infected clench-fist human bite wounds in the area of metacarpophalangeal joints. AB - We reviewed the cases of 221 patients with infected clench-fist human bite wounds in the area of metacarpophalangeal joints. If the joint's capsule was not violated (79 patients), the wound was debrided and irrigated using an antiseptic solution. The would was drained with microirrigators and closed primarily. A second group of 53 patients in whom the joint had been violated but without osseous or articular involvement were treated with debridement, irrigation, drainage, and skin closure. A third group with articular and/or bone destruction (89 patients) was treated the same way as group 2 with the addition of a distraction device to fix and "unload" the joint. In the first group, 71 patients had excellent results and 2 had satisfactory results (6 were lost to follow-up examination). In the second group, 38 patients had excellent results, 7 patients had satisfactory results, and 2 had unsatisfactory results (six patients were lost to follow-up examination). In the third group, 39 patients had excellent results, 24 had satisfactory results, and 10 had unsatisfactory results (16 patients were lost to follow-up examination). PMID- 8683072 TI - Acute flexor tenosynovitis in association with Clostridium difficile infection: a case report. PMID- 8683073 TI - Bacillary angiomatosis mimicking pyogenic granuloma in the hand: a case report. PMID- 8683074 TI - An acute Nocardia brasiliensis infection of the hand: a case report. PMID- 8683075 TI - Symptomatic pisiform hamate synchondrosis: a case report and review of the literature. PMID- 8683076 TI - Congenital triquetral absence: a case report of an asymptomatic wrist. PMID- 8683077 TI - Buddy strapping of mismatched fingers: the offset buddy strap. PMID- 8683078 TI - A custom brace for treatment of angulated fifth metacarpal fractures. PMID- 8683079 TI - Hand surgery certification in the United States. PMID- 8683080 TI - Kirschner wire fixation through anatomic snuffbox. PMID- 8683081 TI - Intraneural ulnar nerve pressure in cubital tunnel decompression surgery. PMID- 8683082 TI - Diagnosis of reflex sympathetic dystrophy. PMID- 8683083 TI - Contaminated foods in healthcare facilities. PMID- 8683084 TI - Vancomycin-resistant enterococci: pervasive and persistent pathogens. PMID- 8683086 TI - Control of methicillin-resistant Staphylococcus aureus at a university hospital: one decade later. AB - OBJECTIVE: To investigate the cause of increasing rates of nosocomial methicillin resistant Staphylococcus aureus (MRSA) infection at a university hospital. DESIGN: Review of data collected by prospective hospital wide surveillance regarding rates of nosocomial MRSA colonization and infection. SETTING: A 700-bed university hospital providing primary and tertiary care. PATIENTS: Patients admitted to the hospital between 1986 and 1993 who were found to be infected or colonized with MRSA. MAIN OUTCOME MEASUREMENT: Rates of MRSA infection and colonization. RESULTS: MRSA infection or colonization was identified in 399 patients (0.18%) admitted during the 8-year study. There was no correlation between the annual rates of MRSA and methicillin-sensitive Staphylococcus aureus (MSSA) infections (P = .66). The frequency of both nosocomial and non-nosocomial cases increased significantly over the last 4 years of the study (P < .001 for trend). The ratio of patients who had acquired MRSA nosocomially to those admitted who already were infected or colonized decreased significantly during the study period (P = .002 for trend). There was a significant increase in the frequency of patients with MRSA being transferred from nursing homes and other chronic care facilities (P = .011). A cost-benefit analysis suggested that surveillance cultures of patients transferred from other healthcare facilities would save between $20,062 and $462,067 and prevent from 8 to 41 nosocomial infections. CONCLUSIONS: An increase in the incidence of nosocomial MRSA infection was associated with an increased frequency of transfer of colonized patients from nursing homes and other hospitals. The lack of correlation between rates of MRSA and MSSA infections suggested that MRSA infections significantly increased the overall rate of staphylococcal infection. Screening cultures of transfer patients from facilities with a high prevalence of MRSA may offer significant benefit by preventing nosocomial infections and reducing patient days spent in isolation. PMID- 8683085 TI - Natural history of colonization with vancomycin-resistant Enterococcus faecium. AB - OBJECTIVE: To determine the incidence, duration, and genetic diversity of colonization with vancomycin-resistant Enterococcus faecium (VREF). SETTING: Oncology unit of a 650-bed university hospital. METHODS: Surveillance perianal swab cultures were performed on admission and weekly. The molecular relatedness of VREF isolates was determined by pulsed-field gel electrophoresis and by the hybridization pattern of the vanA resistance determinant. RESULTS: During 8 months of surveillance, the VREF colonization rate was 16.6 patients per 1,000 patient-hospital days, which was 10.6 times greater than the VREF infection rate. Eighty-six patients with VREF colonization were identified. Colonization persisted for at least 7 weeks in the majority of patients. Of 36 colonized patients discharged from the hospital and then readmitted, an average of 2 1/2 weeks later, 22 (61%) patients still were colonized with VREF. Of the 14 patients who were VREF-negative at readmission, only three patients remained culture negative throughout hospitalizations. PFGE demonstrated that colonization with the same VREF isolate may persist for at least 1 year, and patients may be colonized with more than one strain of VREF. CONCLUSION: VREF colonization is at least 10-fold more prevalent than infection among oncology patients. Colonization often persists throughout lengthy hospitalizations and may continue for long periods following hospitalization. PMID- 8683087 TI - Recorded criteria as a "gold standard" for sensitivity and specificity estimates of surveillance of nosocomial infection: a novel method to measure job performance. AB - OBJECTIVES: To compare the accuracy of infection control practitioners' (ICPs') classifications of operative site infection in Florida Consortium for Infection Control (FCIC) hospitals, in two time periods, 1990 to 1991 and 1991 to 1992, and to estimate the effect of duration of surveillance experience on that accuracy. METHODS: Medical record reviewers examined records of all patients classified by an ICP as infected, to distinguish false-positives from true infections based on evidence of standard infection criteria and the ICP's contemporaneous clinical observations. Reviewers also examined a random sample of 100 records from patients classified as noninfected for evidence of undetected infections (false negatives). These observations permitted estimates of the sensitivity and specificity of each ICP's classification of infection status. SETTING: Fourteen FCIC community hospitals at which performance of 16 ICPs was monitored. RESULTS: There was a strong linear trend relating increasing sensitivity to numbers of years of ICP surveillance experience (P < .001). For ICPs with < 4 years of experience, satisfactory sensitivity (> or = 80%) was reached in only one of 10 ICP-years of observation. For ICPs with > or = 4 years' experience, satisfactory sensitivity was achieved for 14 of 18 person-years (P = .001). Estimated specificity was 97% to 100% for all ICP-years observed. CONCLUSIONS: ICPs with < 4 years of surveillance experience in FCIC community hospitals rarely achieved a satisfactory sensitivity estimate, whereas ICPs with > or = 4 years' experience generally did. Monitoring ICP surveillance accuracy through retrospective medical record audits offers an objective approach to evaluating ICP performance and to interpreting infection rates at different hospitals. PMID- 8683088 TI - Skin and mucous membrane contacts with blood during surgical procedures: risk and prevention. AB - OBJECTIVE: To study the epidemiology and preventability of blood contact with skin and mucous membranes during surgical procedures. DESIGN: Observers present at 1,382 surgical procedures recorded information about the procedure, the personnel present, and the contacts that occurred. SETTING: Four US teaching hospitals during 1990. PARTICIPANTS: Operating room personnel in five surgical specialties. MAIN OUTCOME MEASURES: Numbers and circumstances of contact between the patient's blood (or other infective fluids) and surgical personnel's mucous membranes (mucous membrane contacts) or skin (skin contacts, excluding percutaneous injuries). RESULTS: A total of 1,069 skin (including 620 hand, 258 body, and 172 face) and 32 mucous membrane (all affecting eyes) contacts were observed. Surgeons sustained most contacts (19% had > or = 1 skin contact and 0.5% had > or = 1 mucous membrane-eye contact). Hand contacts were 72% lower among surgeons who double gloved, and face contacts were prevented reliably by face shields. Mucous membrane-eye contacts were significantly less frequent in surgeons wearing eyeglasses and were absent in surgeons wearing goggles or face shields. Among surgeons, risk factors for skin contact depended on the area of contact: hand contacts were associated most closely with procedure duration (adjusted odds ratio [OR], 9.4; > or = 4 versus < 1 hour); body contacts (arms, legs, and torso) with estimated blood losses (adjusted OR, 8.4; > or = 1,000 versus < 100 mL); and face contacts, with orthopedic service (adjusted OR, 7.5 compared with general surgery). CONCLUSION: Skin and mucous membrane contacts are preventable by appropriate barrier precautions, yet occur commonly during surgery. Surgeons who perform procedures similar to those included in this study should strongly consider double gloving, changing gloves routinely during surgery, or both. PMID- 8683089 TI - An apparent excess of operative site infections: analyses to evaluate false positive diagnoses. AB - OBJECTIVE: To investigate an apparent excess of operative site infections (OSI) reported according to doctor's diagnosis (presumptive OSI) by applying objective criteria for classification (documented OSI). To examine potential consequences of habitual overdiagnosis of OSI. DESIGN: A case-control design was used to examine the clinical course of 18 case patients (12 presumptive OSI, six documented OSI) and 18 matched controls. Comparisons also were made between presumptive and documented OSI patients. SETTING: A nonteaching community hospital. PATIENTS: Thirty-six patients having laminectomies done by the same surgeon. INTERVENTION: Implementation of objective criteria for diagnosis of confirmed OSI and reclassification of presumptive OSI patients. RESULTS: Postoperatively, the frequency of specific adverse events within the operative site (including postoperative hematoma or bleeding; wound necrosis, dehiscence, or sinus tract; and dural tear) was 83% for documented OSI patients, contrasted with 16.7% for presumptive OSI patients (P < .01) and controls (P = .007). Median days of inpatient stay were 27 for documented OSI, contrasted with 9.5 for presumptive OSI (P = .01) and 7 for controls (P < .001). CONCLUSION: Documented OSI patients were found to have significantly more adverse findings and longer lengths of stay than presumptive OSI patients or controls. The similarity of findings for presumptive OSI patients and controls suggests that the apparent excess frequency of OSI was caused by incorrect diagnosis. Whereas doctor's diagnosis may be useful as an initial screen for OSI, use of objective criteria for confirming OSI may avert the consequences of overdiagnosis including excessive length of stay and unnecessary therapy, which lead to elevated healthcare costs and threaten a physician's practice. PMID- 8683090 TI - Ribotyping of nosocomial methicillin-resistant Staphylococcus aureus isolates from a Canadian hospital. AB - OBJECTIVE: To evaluate the clonality of methicillin-resistant Staphylococcus aureus (MRSA) strains among hospitalized patients. SETTING: University affiliated, 465-bed tertiary-care teaching hospital with adjacent cancer clinic in Hamilton, Ontario, Canada. DESIGN: Thirty-five colonized and 30 infected patients from January 2, 1992, through August 31, 1993, were investigated retrospectively. Analysis by restriction fragment-length polymorphisms of ribosomal RNA genes (ie, ribotyping) of 103 nosocomial isolates of MRSA from these 65 patients and of 25 selected unrelated strains was completed. Ribotyping results were compared with the phage typing data obtained prospectively during the course of prospective MRSA surveillance. RESULTS: HindIII ribotyping was more discriminating than phage typing when epidemiologically unrelated strains were differentiated by these methods (19 different ribotypes versus 14 page types; P < .005). Two early index cases were identified. Isolates from the index cases were two different strains, identified by ribotyping analysis as ribotype A (clonal group 1) and ribotype B (clonal group 2), respectively. These two ribotypes were not found when typing the unrelated control strains. Thirty-six colonized and infected patients (55%) had clonal group 1 isolates, and 20 (31%) had clonal group 2 isolates. These two clones emerged in the hospital in January and February 1992 and dominated the entire investigated period. There also were six patients with an additional clonal group (group 4) that emerged and disappeared in the second quarter of 1993. CONCLUSIONS: This study highlights the utility of ribotyping in investigating nosocomial MRSA. Three MRSA clones caused nosocomial colonization or infection in patients at this hospital. Two of these MRSA clones, once introduced, were maintained among our patients throughout the study period. PMID- 8683091 TI - The risk of infection associated with epidural analgesia. AB - Four infections were identified among 4,832 patients receiving epidural analgesia (an attack rate of 0.08%). The infections involved cesarean-section patients and occurred within a 9-month period. Findings suggest that the risk of infection is decreased by maintaining a closed system for the duration of the analgesia course. PMID- 8683092 TI - A pseudoepidemic of Rhodotorula rubra: a marker for microbial contamination of the bronchoscope. AB - Rhodotorula rubra was isolated from bronchoscopy specimens from 11 patients. An investigation of the bronchoscopy equipment and the bronchoscopy suite revealed contamination of the suction channel with R rubra, as well as potentially pathogenic bacteria. Disinfection control methods included gas sterilization of the bronchoscope and the institution of an alcohol and air flush through the suction channel to allow complete drying of the scope between each patient use. We have had no further isolates of R rubra from bronchoscopy specimens since these measures were instituted, and repeat cultures from the suction channel have been negative. PMID- 8683093 TI - The computer-based patient record: the role of the hospital epidemiologist. AB - Despite advances in computers and software for data analysis, hospital epidemiologists still must use manual methods for data collection. To automate infection control surveillance fully, healthcare institutions need computerized medical records; however, very few institutions currently have such a system. Healthcare institutions appreciate the need for automation, but frequently do not see a clear path to the desired outcome. In this article, we outline the important issues that hospital epidemiologists must understand if they wish to help their institutions to computerize their medical records. PMID- 8683094 TI - HIV transmitted by bite. PMID- 8683096 TI - Genomic distribution of P elements in Drosophila willistoni and a search for their relationship with chromosomal inversions. AB - According to the recent-invasion hypothesis, Drosophila melanogaster may have acquired its P elements in a fairly recent process of horizontal transmission between species. Drosophila willistoni has been identified as the potential donor species in that transfer process. A most remarkable feature of D. willistoni is its extensive chromosomal polymorphism due to inversions-the adaptiveness of which has been the subject of many classical studies on evolutionary genetics. In this article, we further extend the study of P elements in D. willistoni, focusing on the possible role they may play in the generation of chromosomal inversions. Our results may be summarized as follows. P-homologous sequences were detected in South American populations of D. willistoni. In two of them, a recently collected wild population and an old laboratory stock, the P insertion sites were located in the polytene chromosomes. Several hybridization sites were mapped in all major chromosome arms of the natural population, which was also chromosomally polymorphic; in the laboratory population, nearly devoid of inversions, hybridization sites were found to be confined to the chromocenter. In the wild population, 10 of the 24 P hybridized sites coincided with several inversions break points and another five sites located themselves very close to those points. The results are discussed within the context of evolutionary hypotheses. PMID- 8683095 TI - The Wilhelmine E. Key 1992 Invitational lecture. Phenotypic analysis of the Dopa decarboxylase gene cluster mutants in Drosophila melanogaster. AB - Mutations in a majority of the 18 loci of the Dopa decarboxylase (Ddc) gene cluster effect similar morphological defects of the cuticle and/or catecholamine related abnormalities. Mutations in 14 loci affect cuticle formation, cuticle sclerotization, or cuticle melanization, with mutations in 11 of these same loci (including Ddc and amd) producing melanotic psueudotumors, symptomatic, perhaps, of abnormal catecholamine metabolism. Mutations in seven of the genes perturb catecholamine pool levels during prepupal and pupal development, all of which also form melanotic pseudotumors, suggesting several of these genes may encode proteins involved in catecholamine metabolism. Thus, the Ddc gene cluster represents in higher eukaryotes an unusual example of a large cluster of functionally related genes involved in a common physiological process. PMID- 8683097 TI - A linkage map of sweet cherry based on RAPD analysis of a microspore-derived callus culture population. AB - A partial linkage map was constructed for the sweet cherry (Prunus avium L.) cultivar Emperor Francis from a population of 56 microspore-derived callus culture individuals. The callus cultures were genotyped for two allozymes and 90 random amplified polymorphic DNA (RAPD) markers using 79 random decanucleotide DNA primers and the polymerase chain reaction (PCR). Eighty-nine markers mapped to 10 linkage groups totaling 503.3 cM. DNA blot and hybridization analysis using five cloned RAPDs as probes demonstrated that one of the decanucleotide primers amplified a region of the Emperor Francis genome containing a unique sequence, whereas the other four decanucleotide primers amplified regions of the Emperor Francis genome containing repeated sequences. The five cloned RAPD probes also recognized putative homologous regions in ground cherry, P.fruticosa Pall., and sour cherry, P. cerasus L., a naturally occurring allopolyploid between P.fruticosa and P.avium. PMID- 8683098 TI - Chromosome extraction and revision of linkage group 2 in Tribolium castaneum. AB - We used a balancer chromosome to recover ethylmethanesulfonate-induced recessive mutations in a targeted region of the genome of the red flour beetle (Tribolium castaneum) by the technique of chromosome extraction. The experiments reported herein constitute the first successful application of this powerful technique in the order Coleoptera. Using the balancer chromosome maxillopedia-Dachs3 (mxpDch 3), we recovered seven recessive visible variants representing seven distinct loci and several dozen recessive lethal variants representing at least five distinct loci after screening 1,607 EMS-mutagenized chromosomes. A subset of the mxpDch-3-extracted mutations were positioned on the map of the second linkage group by a series of two-, three-, and four-point crosses. The orientation of the homeotic gene complex (HOM-C) on this linkage group was also determined. With the advent of better and more varied balancer chromosomes and the concomitant improvement of chromosome extraction procedures for genetic analysis of T. castaneum, saturation mutagenesis of targeted regions of the genome is now feasible in this species. PMID- 8683099 TI - Variation of repetitive DNA sequences in progenies of regenerated plants of Pisum sativum. AB - The frequency variation of highly repeated (HR) DNA sequences was studied in plants regenerated through in vitro culture of macerated vegetative apices of Pisum sativum and their progenies. Feulgen cytophotometry showed that regenerated plants (R1) have 6-7% more DNA per nucleus than control plants; this difference is maintained in the subsequent generation (R2). Slot-blot analyses using isolated highly repeated sequences as probe indicated that an increased frequency of these sequences occurs in regenerated plants and their progenies. These results were confirmed by a series of experiments: (a) metaphase chromosomes were longer in R2 than in control plants; (b) cytophotometric analyses of chromatin structure after Feulgen-staining showed that condensed chromatin is more represented in R2 than in control plants; and (c) thermal denaturation of isolated HR sequences indicated that a new HR family appears in R1 and is maintained in R2 plants. These results suggest that, in this species, the DNA extrasynthesized during in vitro culture is, at least in part, integrated in the chromosomes and transmitted to the progeny. PMID- 8683100 TI - Derivation and characterization of a somatic cell hybrid containing the portion of mouse chromosome 11 (MMU11) homologous to human chromosome 17q. AB - To contribute to the physical gene map of mouse chromosome 11 (MMU11) and to extend the mapping resources available for this chromosome, we have produced mouse x rat somatic cell hybrids containing only bands B5 to E of MMU11. Characterization of the hybrids by polymerase chain reaction (PCR) amplification and Southern blot analyses of MMU11 markers revealed two hybrids, T16Ad14B and T16Ad19A, that had selectively retained the 3(11) translocation product containing distal MMU11 (bands B5-E). Cytogenetic analysis of the hybrid T16Ad14B by fluorescence in situ hybridization (FISH) and conventional G-banding confirmed the presence of the 3(11) translocation chromosome. Mapping of markers in both the T16Ad14B and T16Ad19A hybrids localized the T16Ad translocation breakpoint between the proximal markers Atplb2 and Acrb and the more distal markers Scya2 and Mpo. Loci for D11Mit5, Rpo2-1, Trp53, Glut4, Acrb, and Atplb2 could all be localized proximal to the T16Ad breakpoint in band B5, between bands B1 and B5 on MMU11. PMID- 8683101 TI - Protective antibodies in murine Lyme disease arise independently of CD40 ligand. AB - Borrelia burgdorferi-infected mice develop acute arthritis that undergoes Ab mediated resolution. To further investigate the role of B. burgdorferi-specific Abs in Lyme borreliosis, CD40 ligand-deficient (CD40L-deficient) mice were infected with B. burgdorferi. The development and regression of arthritis were similar in CD40L-deficient and control mice. Although CD40L-deficient mice have defects in Ig class switching, infected CD40L-deficient mice developed B. burgdorferi-specific IgG2b Abs. Moreover, the transfer of serum from B. burgdorferi-infected CD40L-deficient animals prevented infection in severe combined immunodeficient mice. These data show that B. burgdorferi-infected CD40L deficient mice are capable of producing Abs that are protective, despite the inability of these mice to mediate T-dependent immune responses. PMID- 8683102 TI - CD45 monoclonal antibodies inhibit TCR-mediated calcium signals, calmodulin kinase IV/Gr activation, and oncoprotein 18 phosphorylation. AB - The effects of a pan-CD45 mAb (CD45.2) on TCR-mediated signaling pathways were investigated in Jurkat T cells. The simultaneous addition of CD45 mAb with an activating OKT3 mAb had little effect on TCR-stimulated signals. However, when Jurkat cells were exposed to the CD45 mAb for 10 to 20 min before the addition of OKT3, a partial uncoupling of the TCR from intracellular signals was observed. The maximal increase in intracellular calcium was inhibited 47 +/- 10% (n = 11, range 33-67%), whereas no inhibition of inositol trisphosphate production was detected. The transient TCR-mediated activation of the Ca2+/calmodulin-activated kinase IV/Gr was also inhibited by the CD45 mAb, and this was reflected in a 50 to 60% inhibition in the TCR-stimulated generation of the p21 and p23 phosphoisomers of oncoprotein 18, a Ca2+/calmodulin-activated kinase IV/Gr substrate recently implicated in cell cycle regulatory events. Oncoprotein 18 is also a substrate for mitogen- activated protein kinase, but no inhibition by the CD45 mAb of TCR-triggered mitogen-activated protein kinase activation was observed. The CD45 mAb was therefore selective in causing the uncoupling of the TCR from calcium signals and calcium-regulated events without promoting a general inhibition of all TCR-mediated signals. Confocal microscopy revealed that binding of the CD45 mAb caused patching of CD45 molecules at the cell surface and, unexpectedly, a marked redistribution of intracellular CD45. However, no change was observed in the total level of CD45 expressed at the cell surface. Aggregation of CD45 at the cell surface may result in its sequestration from its tyrosine kinase substrates, with a consequent selective uncoupling of the TCR from intracellular signaling pathways. PMID- 8683103 TI - Tyrosine-phosphorylated Cbl binds to Crk after T cell activation. AB - Crk is a Src homology 2 (SH2)/Src homology 3 (SH3)-containing adapter protein that has been implicated in intracellular signaling in fibroblasts and PC12 pheochromocytoma cells. Crk has been shown to bind to a tyrosine-phosphorylated protein of 116 kDa after TCR-mediated T cell activation. Here we demonstrate that the Crk-associated p116 phosphoprotein is not the Crk-associated substrate (Cas) but, rather, is a protein product of the c-cbl proto-oncogene. Whereas Cas was not tyrosine-phosphorylated after T cell activation, Cbl became highly phosphorylated. Crk immunoprecipitates from activated T cell lysates contain tyrosine-phosphorylated Cbl. This association is mediated by the SH2 domain of Crk, as evidenced by the interaction between Cbl and the fusion protein product of a glutathione S-transferase (GST) expression construct encoding the Crk-SH2 domain in vitro. Furthermore, phosphopeptide-binding studies revealed that the GST-Crk SH2 domain binds to a tyrosine-phosphorylated peptide corresponding to amino acids 770-781 of Cbl with high affinity. Cbl is a protein tyrosine kinase (PTK) substrate that becomes phosphorylated after engagement of numerous cell surface receptors including the TCR. Data revealed by genetic studies in the nematode, Caenorhabditis elegans, implicates a Cbl-like molecule, Sli-1, as a negative regulator of the Let-23-signaling pathway. Because the signal from the Let-23 pathway affects the activation status of the Let-60 (Ras homologue in C. elegans) pathway, the activation-dependent association between Crk and Cbl may represent another TCR-generated signal leading to Ras-related pathways. PMID- 8683104 TI - Suppression of murine allergic contact dermatitis by CTLA4Ig. Tolerance induction of Th2 responses requires additional blockade of CD40-ligand. AB - Blockade of costimulation through the B7-CD28 pathway by CTLA4Ig can lead to Ag specific T cell tolerance. Most models studied to date involve a Th1-dependent response. To investigate whether the tolerizing effects of CTLA4Ig might vary depending upon the cytokine nature of the immune response, we studied its effects on contact hypersensitivity (CHS) in response to two allergens. In BALB/c mice, both 2,4-dinitrofluorobenzene (DNFB) and FITC induce CHS. However, the DNFB response is Th1-predominant, while the FITC response is Th2 predominant. CTLA4Ig treatment during primary sensitization induced long-lasting unresponsiveness to DNFB, with 88% and 76% inhibition of primary (first challenge) and secondary (re sensitization and re-challenge) CHS, respectively. In contrast, CTLA4Ig inhibited primary CHS to FITC by over 82% but had little effect on secondary CHS. Consistent with its effects on CHS, the suppressive effect of CTLA4Ig on Th2 cells was short-lived in FITC-sensitized mice, while Th1-like cytokine-secreting cells remained reduced in DNFB-sensitized mice, even when the animals were rechallenged with DNFB. The addition of anti-CD40L Ab to CTLA4Ig was able to induce long-lasting unresponsiveness to FITC, indicating the ability of cells mounting this Th2 response to receive costimulatory signals through either pathway. In conclusion, CHS can be mediated by both Th1 and Th2 cells, and the ability of CTLA4Ig to lead to long-standing nonresponsiveness in this model depends on the nature (i.e., cytokine profile) of the immune response. PMID- 8683105 TI - IL-10 production is enhanced in human T cells by IL-12 and IL-6 and in monocytes by tumor necrosis factor-alpha. AB - IL-10, an immunoregulatory cytokine produced by T cells and monocytes, inhibits the expression of inflammatory and hemopoietic cytokines as well as its own expression. To evaluate the regulation of IL-10 production by T cells and monocytes, we measured IL-10 levels by ELISA in supernatants of PHA-stimulated PBMC following depletion of either T cells or monocytes. IL-10 production was significantly down-regulated in both T cell- and monocyte-depleted PBMC compared with undepleted PBMC, and IL-10 production could be restored by the addition of monocyte-conditioned medium (supernatant of PHA-stimulated, T cell-depleted PBMC), suggesting that IL-10 production by T cells is regulated by a monokine(s) produced by activated monocytes. To further clarify the monokine(s) responsible for IL-10 induction, we stimulated monocyte-depleted PBMC, purified CD4+, and CD8+ T cells with PHA and measured IL-10 production by ELISA and semiquantitative reverse transcriptase-PCR following monokine(s) addition. Addition of IL-6 and IL 12 enhanced IL-10 production in monocyte-depleted PBMC in a dose-dependent and additive manner. Furthermore, anti-IL-6 and anti-IL-12 Abs neutralized the IL-10 inductive effect of monocyte-conditioned medium. Similarly, IL-12 and IL-6 induced IL-10 production by purified CD4+ and CD8+ T cells. With respect to regulation of IL-10 produced by monocytes, TNF-alpha was found to induce IL-10 production by resting as well as by LPS-stimulated purified monocytes/macrophages. Taken together, these findings suggest that IL-10 production by human T cells and monocytes is differentially regulated. IL-12 and/or IL-6 can induce the expression of IL-10 by PHA-stimulated T cells, whereas TNF-alpha induces IL-10 production by monocytes. Since IL-10 inhibits the production of IL-6, IL-12, and TNF-alpha, these results may indicate a potential mechanism of negative feedback regulation of the immune response. PMID- 8683106 TI - Differential utilization of Janus kinase-signal transducer activator of transcription signaling pathways in the stimulation of human natural killer cells by IL-2, IL-12, and IFN-alpha. AB - IL-2-, IL-12-, and IFN-alpha-mediated signaling pathways were analyzed in primary NK cells and in the NK3.3 cell line. Gel mobility shift and immunoprecipitation analyses revealed that in addition to activating STAT3 (signal transducer and activator of transcription-3) and STAT5, IL-2 induced tyrosine and serine phosphorylation of STAT1 alpha, which formed IFN-gamma-activated sequence-binding complexes by itself and with STAT3. Although IL-2 and IFN-alpha activated STAT1 alpha and STAT5, IL-2 predominantly activated STAT5, while IFN-alpha predominantly activated STAT1 alpha. IL-2 induced less STAT1 alpha activation and IFN-alpha induced greater STAT5 activation in NK3.3 cells compared with preactivated primary NK cells. In NK3.3 cells, IL-2 induced comparable formation of c-fos promoter sis-inducible element IFN-gamma-activated sequence-binding complexes containing STAT3 alone with complexes containing STAT3 and STAT1 alpha, while in preactivated primary NK cells, it preferentially induced complexes containing STAT3 and STAT1 alpha. Thus, signaling in NK3.3 cells is not always identical with that in primary NK cells. In contrast to IL-2 and IFN-alpha, IL-12 induced strong tyrosine phosphorylation of STAT4 and variable weak phosphorylation of STAT3. However, supershift analyses using the c-fos promoter sis-inducible element probe showed that IL-12 activated STAT4, STAT1 alpha, and STAT3, and induced complexes containing STAT4 only, STAT4 with STAT1 alpha, STAT3 with STAT1 alpha, or STAT1 alpha only in preactivated primary NK cells. STAT1 alpha activation by IL-12 correlated with increased phosphorylation of serine, but not tyrosine. Finally, IL-2 induced tyrosine phosphorylation of JAK1 and JAK3, while IL-12 induced phosphorylation of JAK2 and TYK2 in both preactivated primary NK and NK3.3 cells. Differential phosphorylation and consequent differential activation of both separate and overlapping STAT proteins by IL-2, IL-12, and IFN-alpha may provide a molecular basis for the similarities and differences in the actions of these cytokines on NK cells. PMID- 8683107 TI - Distinct developmental patterns of short-term and long-term functioning lymphoid and myeloid precursors defined by competitive limiting dilution analysis in vivo. AB - Functional abilities of individual marrow precursor cells were defined by competitive limiting dilution without enrichment, tissue culture, or induced marking, manipulations that might affect cell functions. We directly measured long-term repopulating abilities in limiting doses (0.25-1.0 x 10(5)) of genetically marked congenic marrow cells. These were mixed with a standard dose of 4 or 5 x 10(5) competitor marrow cells, which contained a predictable distribution of precursor cells and allowed quantitative assays. Percentages of donor type T and B lymphocytes, granulocytes, platelets, and erythrocytes were measured in recipient blood. Applying the maximum likelihood statistic, concentrations (per 10(5)) of precursors repopulating at least one lineage were: 4.7 and 6.0 after 6 wk, 1.6 and 2.7 after 14 to 15 wk, and 1.2 and 1.9 after 30 to 32 wk; concentrations repopulating at least three lineages were 2.3 and 3.4 after 6 wk, 0.9 and 1.7 after 14 to 15 wk, and 0.9 and 1.3 after 32 wk. Almost all precursors functioning after 14 wk repopulated all lineages. At 6 wk, similar levels of donor cells were produced in recipients of both short- and long-term precursors. However, after 14 to 32 wk, contributions by short-term precursors (about two-thirds of the precursors) dropped to zero, while contributions by long term precursors (about one-quarter of the precursors) expanded severalfold. The latter permanently repopulated all lineages after 30 to 32 wk, functioning as the most primitive stem cells (PSC) in the immune and myeloid systems. Nearly all the variance in long-term repopulated recipients was explained using the Poisson distribution to calculate donor percentages in a model where each donor and competitor PSC contributed equally. PMID- 8683108 TI - Transcriptional regulation of the junB promoter in mature B lymphocytes. Activation through a cyclic adenosine 3',5'-monophosphate-like binding site. AB - The experiments presented herein were designed to understand the molecular mechanism(s) by which membrane Ig (mIg)-dependent signals are integrated at the level of the junB promoter to induce gene transcription. Functional studies using chloramphenicol acetyltransferase reporter gene constructs that contained deleted 5' flanking region junB sequences identified a region located between -194 and 87 that contains an Ets binding site and a putative cAMP response element binding site (CRE-like). Point mutagenesis of the CRE-like site blocked junB promoter activation in response to mIg cross-linking in mature Bal17 B cells. Nuclear extract binding activity to a synthetic oligonucleotide containing the junB CRE like site was detected in unstimulated B cells and was increased in response to mIg cross-linking. Binding activity was competed with unlabeled oligonucleotides that contained the junB CRE-like site or the somatostatin CRE consensus motif, the latter observation suggests that members of the activating transcription factor/CRE binding protein (CREB) family may mediate mIg-dependent junB transcription. Consistent with this interpretation, recombinant CREB and activating transcription factor proteins bound the junB CRE-like site, but did not interact with a mutant CRE-like site. Expression of a dominant negative CREB protein blocked mIg-mediated transcription from a junB CRE-like site chloramphenicol acetyltransferase reporter gene. CRE-like nucleoprotein complexes from Bal17 B cells contained constitutively bound CREB-1, which was phosphorylated on serine 133 in response to mIg cross-linking. Activating transcription factor-1 protein was also constitutively expressed in CRE-like nucleoprotein complexes. Collectively, these results suggest that components of the protein kinase A signaling pathway are recruited by mIg to induce junB transcription. PMID- 8683109 TI - Mutagenesis of the human IgA1 heavy chain tailpiece that prevents dimer assembly. AB - The structural features of the human IgA1 tailpiece required for interaction with J chain in IgA dimer assembly were investigated using a protein engineering approach. Wild-type and mutant forms of IgA1 were expressed in the mouse myeloma cell line, J558L, which endogenously expresses J chain. Wild-type IgA1 was secreted as a mixture of dimers and monomers. Deletion of the entire tailpiece by stop codon introduction completely prevented dimer formation. Similarly, substitution of the penultimate residue of the tailpiece, Cys471, with serine resulted in the secretion of IgA monomers alone. Substitution of Asn459 with alanine to prevent attachment of N-linked carbohydrate to the tailpiece also resulted in markedly reduced dimer assembly. These results indicate the critical role played by the tailpiece, and Cys471 in particular, in IgA dimerization. In addition, we found tailpiece-deleted IgA1 and the Cys to Ser471 mutant IgA1 were secreted as mixtures of covalently associated monomers (alpha 2L2) and alpha L half-molecules. The tailpiece may thus play some role in promoting the association of alpha-chains required for IgA monomer assembly. PMID- 8683110 TI - Sublethal levels of oxidative stress stimulate transcriptional activation of c jun and suppress IL-2 promoter activation in Jurkat T cells. AB - Sublethal levels of oxidative stress are well known to alter T cell functional responses, but the underlying mechanisms are unknown. The current study examined the effects of oxidative stress on transcriptional activities mediated by c-Fos/c Jun AP-1 and the nuclear factor of activated T cells (NF-AT). The present results show that Jurkat T cells acutely exposed to micromolar concentrations of H2O2 exhibit substantial increases in AP-1 binding activity and the expression of c jun but not c-fos mRNA. The preferential induction of c-jun by H2O2 did not represent redox stabilization of mRNA transcripts, and oxidative signals closely resembled PHA/PMA stimulation by effectively transactivating the full length c jun promoter via the proximal jun1 tumor promoter-responsive element (TRE)-like promoter element. Similarly, the complexes binding the consensus AP-1 TRE and jun TRE-like motifs in cells exposed to oxidative signals or PHA/PMA were indistinguishable, being composed of c-Fos, c-Jun, and JunD. However, PHA/PMA but not oxidative signals induced the coordinate activation of reporter constructs containing the AP-1-TRE, NF-AT, and IL-2 promoter regions along with IL-2 mRNA expression. Furthermore, sublethal levels of H2O2 actively suppressed the transcriptional activation of NF-AT and IL-2 reporters as well as the expression of IL-2 mRNA in cells stimulated with PHA/PMA. Gel shift analysis revealed that oxidative suppression of NF-AT represented inhibition in the early generation of NFAT complexes rather than the binding of preformed NF-AT complexes. These results suggest that oxidative signals can positively and negatively regulate T cell transcriptional events and that changes in cellular redox can uncouple AP-1 regulation of c-jun from transcriptional up-regulation of IL-2 via NF-AT. PMID- 8683111 TI - Molecular defects in TCRBV genes preclude thymic selection and limit the expressed TCR repertoire. AB - A prerequisite for the assembly of a functional TCR is the rearrangement of gene segments to result in in-frame transcripts that can vary in length across the CDR3 region. Selection for in-frame 3-bp spaced rearrangements is observed for functional TCRB genes in thymocyte DNA and mRNA transcripts from PBMC. Previous analyses of the expressed human TCRBV gene repertoire have suggested that BV10S1 and BV19S1 gene segments may be expressed at very low levels or not at all in some individuals. CDR3 size analysis for BV10 and BV19 transcripts and thymic DNA rearrangements revealed no such selection of in-frame 3-bp spaced rearrangements. Comparison of the BV19 leader intron sequence with consensus 5'-splice signal sequences suggested that the mature mRNA for this gene would contain the unspliced leader intron. Sequencing of BV19 transcripts from PBMC confirmed that the intron was not spliced, resulting in a predicted translation product that terminates prematurely. Both genomic DNA and mRNA were analyzed for the BV10 gene. The leader sequence contained a single extra base, which would result in a shift in the V region reading frame upon conventional mRNA splicing. This gene is predicted to be nonfunctional due to the presence of a stop codon in the V gene segment just after the splice signal. A splice variant that uses an alternative 3'-splice site further downstream in the V region was also detected. This variant is predicted to be nonfunctional due to the presence of an in-frame stop codon in the V region. These processing defects are sufficient to abrogate positive selection. Therefore, the conclusions drawn from previous studies of the expressed T cell repertoire in normal and disease states based on the presumed functional status of these two genes need to be reassessed. PMID- 8683112 TI - The gamma 1 heavy chain gene includes all of the cis-acting elements necessary for expression of properly regulated germ-line transcripts. AB - The regulation of heavy chain switch recombination and the production of germ line transcripts are highly correlated. IL-4 induces the production of murine gamma 1 germ-line transcripts, and much, if not all, of the regulation is transcriptional. We have investigated the cis-acting elements involved in the regulation of expression of germ-line transcripts by preparing transgenes with the gamma 1 locus. A construct that includes 5' flanking regions, I gamma 1, S gamma 1, and C gamma 1, is regulated like the endogenous gene. Deletion of either most of S gamma 1 or most of C gamma 1 does not alter the correctly regulated expression of the transgenes. An element common to these three different gamma 1 transgenes confers insertion-site independence and copy-number dependence on the transgenes. Finally, the absolute amount of gamma 1-line transcripts is regulated, as transgenic mice with more than 30 gamma 1 genes express no more germ-line transcripts than nontransgenic mice. PMID- 8683113 TI - Multiple interactive residues of recognition: elucidation of discontinuous epitopes with linear peptides. AB - The discontinuous epitopes of beta-factor XIIa for three mAbs were mapped by a linear peptide-based immunoblotting technique, referred to as multiple interactive residues of recognition. The Abs were incubated with a set of overlapping synthetic peptides, deduced from the cDNA sequences of beta-factor XIIa, on a polymer membrane, and the signal was amplified by an ECL assay. Several discrete sequences of the protein were recognized by each Ab. The recognized peptides were further characterized using alanine substitution analogues and peptides of different lengths. The discontinuous epitopes found for each Ab were formed by several peptides and were composed of 20 to 31 residues. The sequence FLQEA was recognized by all three Abs and was the immunodominant peptide. Abs 201/9 and 2/15 bound to very similar discontinuous sequences, but with subtle differences. The sequences 76RLHEAFSP83, 88HDLALLRLQE97, 178GFLEG182, 146FLQEA150, and 237IRE239 formed the epitope for mAb 201/9, whereas 76RLHEAFSP83, 90LALLRLQE97, 146FLQEA150, and 235AWIREHT241 formed the epitope for Ab 2/15. The third Ab 202/7 recognized the sequences 79EAFSP83, 93LRLQE97, 133WGHQF137, and 146FLQEA150. We suggest that these sequences represent the sites to which the Abs bind. This procedure provides a sensitive and convenient tool to elucidate discontinuous epitopes for the binding of Abs, receptor ligand-binding sites, or enzyme inhibitor binding sites. PMID- 8683114 TI - Identification, molecular cloning, biologic properties, and tissue distribution of a novel isoform of murine low-affinity IgG receptor homologous to human Fc gamma RIIB1. AB - A cryptic splice donor site in the first intracytoplasmic (IC) exon of the murine Fc gamma RIIB gene generates a previously unknown Fc gamma RIIB isoform. Three membrane Fc gamma RIIB polypeptides of 37, 32, and 30 kDa were immunoprecipitated by Fc gamma RIIB-specific Abs, and three Fc gamma RIIB cDNAs of 1071, 987, and 930 bp were amplified by reverse transcriptase-PCR with Fc gamma RIIB-specific oligonucleotides from the mastocytoma cells P815. The 1071-bp cDNA contains all sequences of IC exons and encodes the 37-kDa Fc gamma RIIB1 isoform. The 930-bp cDNA lacks sequences of the first IC exon and encodes the 30-kDa Fc gamma RIIB2 isoform. The 987-bp cDNA has an 84-nucleotide deletion of the first IC exon 3' sequences. When stably transfected in the lymphoma B cells IIA1.6, or in the mast cells RBL-2H3, this cDNA encoded 32-kDa Fc gamma RIIB whose biologic properties were undistinguishable from those of Fc gamma RIIB1: they inhibited B cell activation when coaggregated to B cell receptors and capped when aggregated at 37 degrees C, but failed to mediate endocytosis or phagocytosis. Sequences responsible for capping and inhibition of internalization, previously assigned to sequences encoded by the first IC exon, can thus be mapped in the 19 N-terminal residues. These residues are highly conserved in human Fc gamma RIIB1. The 87-bp first IC exon of the human gene ends by a single splice site in the downstream intron and encodes a 19-amino acid insertion. The 32-kDa Fc gamma RIIB is the murine homologue of human Fc gamma RIIB1. We propose to name it Fc gamma RIIB1'. Fc gamma RIIB1' was expressed in myeloid and lymphoid cell lines, in normal spleen cells, and in resting or LPS-activated B cells. PMID- 8683115 TI - Epitope mapping by mass spectrometry: determination of an epitope on HIV-1 IIIB p26 recognized by a monoclonal antibody. AB - Matrix-assisted laser desorption mass spectrometry in combination with proteolytic protection assays has been used to identify the functional epitope on HIV-1 IIIB p26 recognized by a mAb. In this procedure, the intact protein is affinity bound to an immobilized mAb under physiologic conditions. A combination of proteolytic enzymatic cleavages was then performed to remove unprotected residues. Protected residues were identified by matrix-assisted laser desorption mass spectrometry based on their m.w. With this approach, an 11-residue sequence was identified as the most tightly affinity-bound fragment. in addition, two less tightly bound segments were observed. These latter two residues may contain elements of a discontinuous epitope or may be residues involved in a wider contact area. The combination of matrix-assisted laser desorption and proteolytic epitope footprinting has been applied to the determination of the epitope on a recombinant protein recognized by a mAb but should be equally applicable to the definition of an epitope on a native protein in its natural folded conformation. PMID- 8683116 TI - Structure and diversity of the TCR alpha-chain in a teleost fish. AB - T cell receptor beta-chain genes are well characterized in representatives of most vertebrate phyla, from sharks to mammals, but the molecular structure of complete TCR alpha-chains has not yet been established in cold-blooded vertebrates. We used a PCR approach to isolate cDNAs encoding putative teleost fish (Oncorhynchus mykiss, rainbow trout) TCR alpha-chains. Eight V alpha segments were identified, belonging to six different families, and the best amino acid sequence identity scores for these trout V alpha were all provided by mammalian V alpha or V delta sequences. Twenty-four (60.1 %) of the 39 analyzed V alpha segments belong to the V alpha 2 family, which has limited homology with mammalian V alpha/delta sequences and with the human V pre-B sequence. A total of 32 different J alpha segments were identified from 40 J alpha regions sequenced, suggesting that a large repertoire of J alpha segments is a characteristic of most vertebrates. The structural properties of the TCR alpha-chain complementarity-determining region 3 loop are well conserved between trout and mammals, suggesting that this region has been under continuous selective pressure in jawed vertebrate evolution. The trout C alpha segment has conserved N-terminal and transmembrane domains, but the C alpha intercysteine distance contains only 40 residues, significantly smaller as compared with mammals (49-56 residues). The conserved features of teleost fish TCR beta- and alpha-chains with their mammalian equivalents suggest that TCR-alpha beta receptors were still present in the common Devonian ancestors of modern teleost fish and mammals, about 450 million years ago. PMID- 8683117 TI - Stimulation of phosphatidylinositol turnover is a key event for Fas-dependent, activation-induced apoptosis in human T lymphocytes. AB - We have analyzed the requirements for activation-induced apoptosis in Jurkat T cells expressing the heterologous human muscarinic type 1 receptor (HM1R; J-HM1 2.2 cells) that is coupled to phosphatidylinositol turnover through a protein tyrosine kinase-independent, G protein-regulated mechanism. Triggering of HM1R with the agonist carbachol is sufficient to induce apoptosis in J-HM1-2.2 cells. Apoptosis is also induced in J-HM1-2.2 cells by triggering of the TCR. Calcium influx, intracellular Ca2+ increase, calcineurin function, and de novo protein synthesis are necessary for receptor-controlled apoptosis. However, blocking protein kinase C with a specific inhibitor does not abrogate receptor-induced apoptosis. Furthermore, HM1R-induced apoptosis is inhibited by blocking Fas ligand/Fas interaction with an antagonist anti-Fas Ab, and Fas ligand mRNA and protein are expressed in J-HM1-2.2 cells stimulated through the HM1R. Therefore, protein tyrosine kinase activation is not an absolute requirement for receptor controlled Fas ligand expression. Taken together, the results demonstrate that stimulation of phosphatidylinositol turnover can induce apoptosis through a Fas dependent mechanism that requires calcineurin stimulation, but not protein kinase C activation. PMID- 8683118 TI - Selection and binding of peptides to human transporters associated with antigen processing and rat cim-a and -b. AB - Cytotoxic T lymphocytes recognize antigenic peptides presented by MHC class I molecules. The peptides are generated in the cytosol by proteasomes, and probably also other proteases, and are then translocated into the endoplasmic reticulum (ER) lumen. The transporters associated with Ag processing (TAP) are key molecules for transporting peptides from the cytosol to the lumen of the ER. Using semipermeabilized cells, TAP-dependent peptide translocation was demonstrated, and the selectivity of peptide translocation was based on the carboxyl-terminal amino acid of peptides. We have examined peptide binding proteins in the ER membrane and the selection of peptides for binding to TAP by using a panel of peptides of different sequences and carboxyl-termini as well as peptides containing D amino acids. Peptides bound to TAP molecules in the absence of ATP. The presence of ATP induced binding of peptides to two additional membrane proteins (58 and 43 kDa). The selection of peptides by TAP molecules was based on peptide sequence and the carboxyl-terminal amino acid. Peptides containing D amino acid did not bind to TAP molecules. Rat cim-a and -b selected peptides differently, and selection was not only dependent on the carboxyl terminal residue of the peptide, but included an influence of the peptide sequence. The different off-rates after peptide binding to TAP, indicated a dual binding step of peptide to TAP. ATP regulated the off-rate of peptides at a high affinity binding step. Our results demonstrate that the binding of peptides to TAP molecules is specific and most likely involves a multiple step pathway. PMID- 8683119 TI - High-affinity oligonucleotide ligands to human IgE inhibit binding to Fc epsilon receptor I. AB - Using the systematic evolution of ligands by exponential enrichment (SELEX) method, we have identified oligonucleotides that bind to human IgE with high affinities and high specificity. These ligands were isolated from three pools of oligonucleotides, each representing 10(15) molecules: two pools contained 2'-NH2 pyrimidine-modified RNA with either 40 or 60 randomized sequence positions, and the third pool contained ssDNA with 40 randomized sequence positions. Based on sequence and structure similarities, these oligonucleotide IgE ligands were grouped into three families: 2'-NH2 RNA group A ligands are represented by the 35 nucleotide truncate IGEL1.2 (Kd = 30 nM); 2'-NH2 RNA group B ligands by the 25 nucleotide truncate IGEL2.2 (Kd = 35 nM); and the ssDNA group ligands by the 37 nucleotide truncate DI 7.4 (Kd = 10nM). Secondary structure analysis suggests G quartets for the 2'-NH2 RNA ligands, whereas the ssDNA ligands appear to form stem-loop structures. Using rat basophilic leukemia cells transfected with the human high-affinity IgE receptor Fc epsilon RI, we demonstrate that ligands IGEL1.2 and D17.4 competitively inhibit the interaction of human IgE with Fc1 epsilon RI. Furthermore, this inhibition is sufficient to dose-dependently block IgE-mediated serotonin release from cells triggered with IgE-specific Ag or anti IgE Abs. Therefore, these oligonucleotide ligands represent a novel class of IgE inhibitors that may prove useful in the fight against allergic diseases. PMID- 8683121 TI - A synthetic peptide derived from the tumor-associated protein mdm2 can stimulate autoreactive, high avidity cytotoxic T lymphocytes that recognize naturally processed protein. AB - Studies in melanoma patients have shown that unaltered self proteins can function as targets for tumor-reactive CTL. Here, we have investigated in a murine model whether autoreactive CTL can be found against the widely expressed proteins cyclin D1, mdm2, and p53, which are frequently overexpressed in transformed cells. Sixteen MHC class I binding peptides were identified in these proteins, and seven of them consistently stimulated primary CTL in vitro. Avidity measurements revealed that the avidity of peptide-induced CTL differed by >1000 fold. The highest avidity CTL were induced by a peptide derived from mdm2. These CTL recognized target cells expressing mdm2 endogenously, while CTL generated against the remaining peptides were of lower avidity and did not recognize cells expressing relevant proteins endogenously. Generation of high avidity anti-mdm2 CTL required several cycles of peptide stimulation, suggesting that the CTL precursor frequency was low. The data show the normal T cell repertoire contains small numbers of potentially autoreactive CTL. Expansion of these CTL may lead to beneficial autoimmunity against tumors, but, equally, it may be the basis of detrimental autoimmune diseases. PMID- 8683120 TI - Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice. AB - Cellular IL-10 (cIL-10), the collective term for human and murine IL-10, has both stimulatory and inhibitory effects on diverse cell types, including costimulation of T cell proliferation, chemoattraction of CD8+ T cells, and stimulation of lymphokine-activated killer cell activity. Human IL-10 (hIL-10) differs from its EBV homolog viral IL-10 (vIL-10) by only 16% at the amino acid level; however, vIL-10 shares with cIL-10 predominantly inhibitory effects, such as macrophage deactivation. We administered cIL-10 systemically to mice bearing established (day 7) sarcomas, melanomas, or colorectal carcinomas. At high doses (20 to 60 micrograms/day x 7 days), cIL-10 induced rejection of tumors, delaying tumor outgrowth or resulting in complete cure. Sublethal irradiation (500 rad) of mice prior to tumor inoculation abrogated the IL-10 effect. Cured mice were immune to subsequent rechallenge with 10-fold higher inoculation with the same, but not a different, tumor. IL-12 also has potent antitumor activity and interacts with IL 10 in both complementary and antagonistic ways; co-administration of both cytokines resulted in additive antitumor activity. To compare cIL-10 vs vIL-10 effects in vivo, we engineered CL8-1 melanoma transfectants bearing the vIL-10 or the murine IL-10 (mIL-10) gene. Local secretion of mIL-10 induced rejection of tumors, while vIL-10 resulted in accelerated outgrowth. Subsequent systemic administration of cIL-10 to mice bearing vIL-10-transduced tumors completely reversed the local suppressive effects, leading to rejection, suggesting distinct pathways for cIL-10 and vIL-10 effects. That cIL-10 can stimulate the acquisition of an effective, specific, and long-lived antitumor immune response in murine models and can reverse the local immunosuppressive effects of vIL-10 indicates a potential role for cIL-10 administration in the biologic therapy of cancer and suggests a broader interpretation of IL-10 biology. PMID- 8683122 TI - The role of p56lck in the development of gamma delta T cells and their function during an infection by Listeria monocytogenes. AB - We investigated roles of p56lck tyrosine kinase (Lck) on the development and function of gamma delta T cells in adult mice using lck gene knockout (lck -/-) mice. The mature gamma delta T cells (heat-stable Ag negative) were generated significantly in the thymi of adult lck -/- mice. When Listeria monocytogenes was infected i.p., gamma delta T cells were induced in the peritoneal cavity of the lck -/- mice. Interestingly, the repertoire of gamma delta T cells was obviously different in the lck +/+ and lck -/- mice; i.e., the gamma delta T cells of the lck -/- mice induced by the listerial infection dominantly expressed V delta 1 while those of the lck +/+ mice dominantly expressed V delta 6. The V delta 1 + gamma delta T cells in the lck -/- mice were extrathymically generated, supported by their appearance in thymectomized irradiated mice reconstituted with bone marrow cells from the lck -/- mice. Furthermore, the gamma delta T cells of the lck +/+ mice were protective in the early stage of the listerial infection, while the gamma delta T cells in the lck -/- mice were not protective against the listerial infection because the depletion of the gamma delta T cells from the lck -/- mice did not influence the bacterial burden in the spleens. These observations thus suggest that 1) gamma delta T cells can develop in adult mice through the intrathymic and extrathymic pathways even in the absence of Lck, 2) Lck influences the expansion and the repertoire of gamma delta T cells, and 3) the gamma delta T cells raised in the absence of Lck are not protective against L. monocytogenes. PMID- 8683123 TI - Increased susceptibility of mice to Salmonella infection following in vivo treatment with the substance P antagonist, spantide II. AB - Successful resolution of salmonellosis in naive mice depends in large part upon IL-12-induced IFN-gamma production to eliminate this intracellular pathogen of macrophages. In the present study we questioned the contribution that expression of substance P receptors makes to the protective response following oral inoculation with a lethal dose of Salmonella. Such a relationship was suggested when oral inoculation with Salmonella induced rapid and dramatic increases in substance P receptor mRNA expression within Peyer's patches and mesenteric lymph nodes and subsequently in the spleen. The importance of substance P receptor expression in vivo was further suggested by pretreatment of mice with the substance P antagonist, spantide II, before oral inoculation with Salmonella. Mice pretreated with spantide II and then orally inoculated developed advanced salmonellosis and had significantly reduced survival rates compared with mice pretreated with a control peptide. Treatment with spantide II significantly reduced early Salmonella-induced IL-12p4O and IFN-gamma mRNA expression at mucosal sites, suggesting a mechanism for the reduced ability of spantide II treated mice to resist this pathogen. Increased susceptibility to salmonellosis was not due to 1) spantide II-induced alterations in the uptake of this pathogen from the gut, 2) global spantide II-mediated immune suppression, or 3) nonsubstance P receptor-mediated effects of spantide II on macrophages. The ability of Salmonella to induce substance P receptor expression on cultured macrophages suggested that one mechanism for resistance against this intracellular pathogen might be a direct effect of substance P on this cell population. PMID- 8683124 TI - T cell vasoactive intestinal peptide receptor subtype expression differs between granulomas and spleen of schistosome-infected mice. AB - Granulomas form in the liver and intestines of mice infected with the parasite Schistosoma mansoni. Vasoactive intestinal peptide (VIP) is a neurokine that can modulate aspects of the immune response by acting through receptors within the granuloma. Cloned are two novel VIP receptor (VIPR) mRNAs (VIPR1 and VIPR2) that also bind a second neurokine called pituitary adenylated cyclase-activating polypeptide (PACAP). The objective of this study was to determine if granulomas express either VIPR1 or VIPR2. Using a radioligand-binding assay, it was established that PACAP is as effective as VIP at displacing radiolabeled VIP from splenocytes and granuloma cells, and that most if not all VIPRs in the spleen and granulomas bind PACAP. PCR amplification of reverse transcribed RNA determined that granulomas express both VIPR1 and VIPR2 mRNAs. Gel electrophoresis and nucleotide sequencing confirmed the authenticity of the PCR products. Also, both receptor subtypes were amplified from several granuloma CD4+ T cell lines; yet reverse transcribed RNA from T cell-depleted, dispersed granuloma cells had only VIPR1 RNA. It is notable that reverse transcriptase-PCR detected only VIPR1 in the thymus and spleen, which are organs rich in T lymphocytes. Thus, the granulomas and spleens from mice with schistosomiasis contain cells that display authentic VIP/PACAP receptors. Moreover, these data suggest that T cells in different compartments vary in VIPR subtype expression. VIPR1 and VIPR2 may have different physiologic roles in inflammation. PMID- 8683125 TI - DNA double strand breaks in epidermal cells cause immune suppression in vivo and cytokine production in vitro. AB - UV irradiation of the skin causes immune suppression by a mechanism involving epidermal cytokines. To determine the role of epidermal DNA damage in immune suppression, we used HindIII restriction endonuclease encapsulated in liposomes to cause DNA strand breaks in epidermal cells in vivo and in vitro. Topical application of HindIII in liposomes to murine skin in vivo impaired the induction of contact hypersensitivity responses initiated either locally or at distant sites and impaired the function of APCs. Unlike UV-B radiation, however, treatment of mice with HindIII in liposomes before contact sensitization did not induce tolerance or transferable suppression. The liposome-encapsulated HindIII caused double strand breaks in DNA and induced IL-10 and TNF-alpha production when added to cells of a murine keratinocyte line in vitro. Topical application of liposomal HindIII also induced TNF-alpha in the epidermis of mice. Liposomes containing heat-inactivated HindIII or an endonuclease specific for pyrimidine dimers in DNA did not exhibit these effects. These results support the hypothesis that DNA damage is a trigger for the production of cytokines that modulate immune responses. They also suggest that immune suppression and suppressor cell induction are separate consequences of cutaneous injury that require different stimuli. PMID- 8683126 TI - B cell lymphoma-2 transfected P815 cells resist reactive nitrogen intermediate mediated macrophage-dependent cytotoxicity. AB - Activated murine peritoneal macrophage cytotoxicity against P815 tumor cells has been shown to be mediated by the reactive nitrogen intermediates (RNI) produced by macrophages from L-arginine through nitric oxide (NO) synthase. Previous results from this laboratory indicated that NO-dependent killing of P815 fulfilled the criteria for apoptotic death. Work by others, in turn, demonstrated that the product of the bcl-2 gene confers protection against various inducers of apoptosis, including reactive oxygen intermediates. Experiments were performed to determine whether Bcl-2 could equally protect sensitive cells from RNI-dependent apoptosis within the context of a relevant biologic system such as the delivery of such RNI by activated macrophages. Results demonstrated that transfection of P815 cells with the human bcl-2 gene confers immunity from RNI-dependent, macrophage-mediated cytotoxicity. In contrast with wild-type or mock-transfected P815 cells, which do not contain detectable Bcl-2, bcl-2-transfected cells showed minimal DNA fragmentation and cell membrane failure when cocultured with activated macrophages. Additional findings indicate that Bcl-2 affords the transfected cells almost complete resistance to the DNA-fragmenting effects of chemically generated NO or H202 and partial protection from their cytolytic effects. These findings are consistent with the hypothesis that tumor cells expressing bcl-2 may escape destruction by macrophage-dependent immune surveillance mechanisms. PMID- 8683127 TI - Complex of the soluble IL-11 receptor and IL-11 acts as IL-6-type cytokine in hepatic and nonhepatic cells. AB - The signaling functions of the membrane and soluble form of the mouse IL-11 receptor (mIL-11R) were compared in rat and human hepatoma cells, which have a low endogenous IL-11 response. The expression vectors encoding either the full length or a secretory form of the ligand binding subunit of mIL-11R together with IL-6-responsive reporter gene constructs were transiently transfected into the H 35 and HepG2 cells. An IL-11-specific stimulation of transcription was detected that was qualitatively similar to that mediated by the endogenous IL-6R. HepG2 cells were noted to synthesize constitutively IL-11, resulting in an autocrine stimulation of gene expression. Addition of COS cell-derived soluble mIL-11R to the hepatoma cell cultures prominently enhanced IL-11 regulation of transfected reporter gene constructs and expression of endogenous acute phase plasma protein genes. Similarly, the complex of soluble mIL-11R and IL-11 was capable of mediating an IL-6-type signaling in cells that are naturally deficient in IL-11 response as shown by the activation of STAT1 and STAT3 in mouse embryonal carcinoma cells and human T cells. The results indicate that the IL-11R can serve as a substitute to IL-6R in activating gene expression in target cells that are devoid of the appropriate ligand-binding receptor subunits. PMID- 8683128 TI - Analysis of the site of interaction of CD28 with its counter-receptors CD80 and CD86 and correlation with function. AB - CD28 and CTLA-4 are homologue members of the Ig superfamily of molecules, containing a single V-like domain, transmembrane, and cytoplasmic regions. Both receptors associate with the counter-receptors CD80 and CD86, but the avidity of interaction for CD28 is about 20-fold lower than for CTLA-4. The interaction between CD28 and its cognate receptors provides a costimulatory signal for optimal T cell activation. Our previous mutational analysis of CD28 defined the highly conserved "MYPPPY" motif in the CDR3-region of the V-like domain as a key site of common and selective recognition. We have extended our analysis to cover all residues in the membrane distal loops of the V region, examining their effect on association with CD80/CD86 in cell adhesion and novel protein-based binding assays, and determining correlation between binding and functional response. Conservative F substitutions at either Y residue in the MYPPPY motif selectively reduced binding to CD86, but mutation of the three amino acids immediately C terminal to Y 104 equivalently reduced binding to both co-receptors. The conservative F substitution of Y 26 in the CDR1-like region also reduced binding to CD80 and CD86. Other substitutions in the CDR1 loop and mutations spanning the CDR2 and DE loops had no effect. We conclude that the CDR1 and CDR3 regions contribute to a common binding site for CD80/CD86, and that the CDR3 region also carries determinants for selective recognition of these counter-receptors within the MYPPPY motif. Furthermore, for CD28, the strength of functional response, as measured by IL-2 production, directly correlates with binding avidity. PMID- 8683130 TI - Acidic sphingomyelinase-generated ceramide is needed but not sufficient for TNF induced apoptosis and nuclear factor-kappa B activation. AB - Previously we have shown that treatment of ML-1a cells with TNF in the presence of cycloheximide triggers apoptosis within 90 min. In the present report we used this system to investigate the role of ceramide in TNF action. We found that while maximum DNA fragmentation response was induced by 1 nM TNF, the synthetic membrane-permeable C-2, C-6, and C-8 ceramides had no effect even up to 40 microM concentration. To investigate the roles of ceramide in TNF action, we used ((2 isopropyl-1-(4-[3-N-methyl-N-(3,4-dimethoxy-phenethyl)amino] propyloxy)benzenesulfonyl))indolizine (SR33557), a potent inhibitor of acidic but not neutral sphingomyelinase (SMase). Even though ceramides by themselves did not mimic TNF, we found that SR33557 inhibited TNF-induced apoptosis and the addition of ceramide reversed this effect, indicating that ceramide generated by acidic SMase is involved in TNF action. The addition of SR33557 to cells at 0 or at 30 min after TNF treatment showed inhibition, but the addition 60 min later had no effect, indicating that an SR33557-sensitive step is located between 30 and 60 min of signal transduction. Since ceramide has been shown to play a role in TNF mediated activation of nuclear factor-kappa B (NF-kappa B), we examined the effect of SR33557 on this early cellular response of TNF. Surprisingly, this inhibitor of ceramide production was found to have no effect on TNF-mediated NF kappa B activation, thus suggesting that SR33557-sensitive acidic SMase is not involved in this process. From these results, we concluded that ceramide is needed for certain TNF-mediated cellular responses, but it alone may not be sufficient. PMID- 8683129 TI - Effect of endotoxin in IL-1 beta-deficient mice. AB - IL-1 plays an important role in the pathophysiologic responses to infection and inflammation, in part by mediating its own production and that of other proinflammatory cytokines. However, the relative contribution of IL-1 alpha and IL-1 beta to the inflammatory response has not been well clarified. Using IL-1 beta-deficient (IL-1 beta -/-) mice, we investigated the specific role of IL-1 beta in the in vivo and in vitro response to LPS. No differences between IL-1 beta +/+ and IL-1 beta -/- mice were observed in circulating levels for IL-1 alpha, IL-6, or TNF-alpha after the systemic administration of either a low (5 micrograms/kg) or high (5 mg/kg) dose of LPS. IL-1 beta -/- mice also had a normal response to LPS in terms of activation of the hypothalamus-pituitary adrenal axis, hypoglycemia, serum amyloid A production, and anorexia. IL-1 beta /- mice were normally sensitive to the lethal effect of LPS and were protected against LPS toxicity when pretreated with low-dose LPS. However, in vitro, peritoneal macrophages from IL-1 beta -/- mice stimulated with LPS produced significantly less IL-1 alpha than macrophages from IL-1 beta +/+ mice (p < 0.05). No differences in IL-6 or TNF-alpha synthesis were observed between macrophages from IL-1 beta +/+ and IL-1 beta -/- mice. In summary, our results suggest that either IL-1 beta is not essential for the in vivo systemic response to LPS or that its role can be fulfilled by other cytokines with overlapping activities. PMID- 8683131 TI - IFN-alpha beta reconstitutes the deficiency in lipid A-activated AKR macrophages for nitric oxide synthase. AB - AKR mouse peritoneal macrophages (PM) were previously found to have a defect in their response to lipid A for nitric oxide (NO)-mediated tumor cytotoxicity, which was related to a lower level of C1q synthesis and reconstituted by exogenous IFN-gamma or C1q. We used AKR-PM as a model to further define the role of IFN-alpha beta in modulation of induction of macrophage nitric oxide synthase (NOS) in response to lipid A. Studies have revealed that AKR-PM produced a significantly lower level of IFN-alpha beta than responsive C3H-PM in response to lipid A. AKR-PM failed to increase NOS mRNA synthesis and NO generation when exposed to lipid A, although they had normal levels of TNF-alpha bioactivity and mRNA expression. This partial deficiency of AKR-PM to lipid A stimulation was reconstituted completely by exogenous IFN-alpha beta for both synthesis of NOS mRNA and release of NO. The failure of AKR-PM to produce NOS to lipid A stimulation appears to be related to reduced secretion of IFN-alpha beta and the resultant failure to express TNF-alpha type II receptor (TNF-RII) mRNA, which in turn decreases TNF-alpha binding to its receptor for autocrine induction of NOS. Insufficient synthesis and secretion of endogenous IFN-alpha beta may be the primary reason for AKR-PM refractoriness to induction of NOS in response to lipid A. furthermore, the close correlation between lack of IFN-alpha beta secretion and decreased TNF-RII mRNA synthesis may implicate a critical role for IFN-alpha beta in the upregulation of macrophage TNF-RII receptor expression for autocrine induction of NOS during lipid A stimulation. PMID- 8683132 TI - Nerve growth factor and cytokines mediate lymphoid tissue-induced neurite outgrowth from mouse superior cervical ganglia in vitro. AB - Superior cervical ganglia (SCG) from neonatal mice were cultured with adult murine lymphoid tissue explants in Matrigel (Collaborative Biomedical, Bedford, MA). After 1 and 2 days in culture, many neurites grew toward thymus and spleen. Normal mesenteric lymph node (MLN) induced a smaller effect; however, activated MLN (isolated from mice 10 days after infection with Nippostrongylus brasiliensis; Nb-MLN-10d) caused significantly increased neurite outgrowth. To determine the roles of nerve growth factor (NGF) and cytokines in the promotion of neuritogenesis by lymphoid tissues, anti-NGF and various anti-cytokines were added to cocultures. Anti-NGF inhibited most of the neurite outgrowth toward thymus and spleen but only partially that toward Nb-MLN-10d. Anti-mouse IL-1 beta also significantly reduced the number of neurites growing toward thymus, spleen, and normal MLN. The number of neurites growing toward Nb-MLN-10d was significantly reduced by anti-IL-1 beta, anti-IL-3, anti-IL-6, or anti-GM-CSF. Exogenous IL-1 beta and IL-3 caused neurite outgrowth in single SCG cultures; and the IL-1 beta-, but not the IL-3-, mediated effect was completely blocked by anti NGF. In one-day thymus/SCG cocultures, endogenous IL-1 was not detectable at concentrations sufficient to cause nerve growth; however, ample NGF was present in the thymic tissues and culture supernatants, but not in SCG. These data suggest that IL-1 mediates NGF production in lymphoid tissues, which in turn induces the growth of sympathetic nerves. Moreover, IL-3, IL-6, or GM-CSF produced during inflammation might also play important roles in the stimulation of nerve growth in vivo. PMID- 8683133 TI - The cytoplasmic domains of E- and P-selectin do not constitutively interact with alpha-actinin and are not essential for leukocyte adhesion. AB - The selectins are a family of carbohydrate-binding adhesion molecules involved in the regulation of leukocyte migration. Although there is strong homology between different selectins in their extracellular regions, there is none in the cytoplasmic tails, suggesting selectin-specific functions for these domains. Our previous work showed that the cytoplasmic tail of L-selectin interacts with the actin cytoskeleton via alpha-actinin and vinculin, and that truncation of the cytoplasmic tail of L-selectin blocked both association with alpha-actinin and vinculin and leukocyte adhesion. In the present study, the effects of truncation of the cytoplasmic tails of E- or P-selectin on cell adhesion and cell surface expression were examined, and possible interactions between alpha-actinin and the E- and P-selectin cytoplasmic tails were assessed. In contrast to previous observations demonstrating a requirement for the L-selectin cytoplasmic tail, truncation of the E- or P-selectin cytoplasmic domains had no effect on cell adhesion, or on cell surface expression, when assessed in transiently transfected COS cells. This lack of effect on cell surface expression and adhesion was also observed when transfections were performed with lower amounts of cDNA, which led to submaximal levels of expression. In addition, no interaction between alpha actinin and the cytoplasmic tails of either E- or P-selectin could be detected under conditions in which binding of alpha-actinin to the L-selectin cytoplasmic tail could be readily demonstrated. Therefore, interactions between the cytoplasmic tail of E- or P-selectin and alpha-actinin or other cytoskeletal proteins are not necessary for leukocyte adhesion per se, but may facilitate downstream biologic events. PMID- 8683134 TI - L- and P-selectins, but not CD49d (VLA-4) integrins, mediate monocyte initial attachment to TNF-alpha-activated vascular endothelium under flow in vitro. AB - Monocyte adhesion to the vascular endothelium is a pivotal step during their egress to tissues at sites of inflammation and immune reactions, and during atherogenesis. In this study, an in vitro flow model and blocking mAb were used to define the role of adhesion molecules in monocyte interactions with activated HUVEC under flow conditions. By videomicroscopy, freely flowing monocytes abruptly halted (initial attachment) on 6-h TNF-alpha-activated HUVEC under flow via L- and P-selectin, whereas E-selectin was not involved. CD49d/CD29 integrin (VLA-4), which can mediate initial attachment of certain T cells to VCAM-1 under flow, did not support monocyte initial attachment. Once initially attached, a small number of monocytes began rolling at 9 microns/s through a mechanism involving L-selectin, as well as CD49d and CD11/CD18 integrins, while the remaining monocytes became firmly adherent, or released to the flow stream. Monocyte stable arrest and subsequent transendothelial migration occurred rapidly and efficiently through either CD49d or CD18 integrin adhesion pathways. Transendothelial passage was also dependent on PECAM-1 (CD31). These data reveal monocytes initially attach to activated endothelium via an L-selectin-dependent mechanism, with a smaller contribution from P-selectin and no contribution by CD49d. Subsequent monocyte rolling, arrest, and transmigration require overlapping functions between multiple members of the selectin, integrin, and Ig gene families. PMID- 8683135 TI - 5-Oxo-eicosatetraenoate is a broadly active, eosinophil-selective stimulus for human granulocytes. AB - 5-Oxo-eicosatetraenoate (5-oxoETE) is gaining recognition as a chemotactic factor for eosinophilic (Eo) as well as neutrophilic (Neu) polymorphonuclear leukocytes. We found that the eicosanoid was far stronger than C5a, platelet-activating factor (PAF), leukotriene B4 (LTB4), or FMLP in stimulating Eo chemotaxis. Moreover, it had weak intrinsic degranulating effects on otherwise unstimulated Eo, produced prominent degranulation responses in Eo primed by granulocyte macrophage CSF, and enhanced the Eo-degranulating potencies of PAF, C5a, LTB4, and FMLP by up to 10,000-fold. Low picomolar levels of 5-oxoETE also induced Eo to activate mitogen-activated protein kinases (MAPKs), as defined by shifts in the electrophoretic mobility and tyrosine phosphorylation of two immunodetectable proteins, p44 and p42. 5-OxoETE was > or = 100-fold weaker or unable to stimulate any of these responses in Neu. Finally, 5-oxo-15-hydroxy-ETE and 5-hydroxy-ETE activated both cell types, but were weaker than 5-oxoETE and had Eo/Neu potency ratios approaching unity. 5-OxoETE, thus, is uniquely potent and selective in promoting Eo not only to migrate, but also to release granule enzymes and activate MAPKs. By triggering MAPK activation, the eicosanoid may also influence the production of anaphylactoid lipids (e.g., PAF), arachidonic acid metabolites, and cytokines. 5-OxoETE therefore possesses a biologic profile well suited for mediating Eo-dominated allergic reactions in vivo. PMID- 8683137 TI - Human monocytes are unable to bind to or phagocytize IgA and IgG immune complexes formed with influenza virus in vitro. AB - An in vitro model system was used to investigate how human monocytes recognize influenza A/WSN(H1N1)-infected epithelial cells, and the role that anti-influenza IgA and IgG Abs play in this interaction. Pretreatment of the monocytes with neuraminidase or F(ab')2 fragments of a mAb against the Ca1 epitope on the hemagglutinin (HA) molecule inhibited monocyte adherence to the infected cells. This suggested that monocytes bound to the sialic acid binding site on the HA molecule and not to other viral or epithelial cell Ags. In the presence of neutralizing concentrations of intact Abs (human serum IgA, secretory IgA, IgG, or mouse anti-HA mAb), monocytes were unable to bind to influenza-infected epithelium or to phagocytize the IgA or IgG immune complexes formed with influenza virus, even though they could use these same Abs to attach to or phagocytize inert particles. Under conditions of Ag excess and low concentrations of Ab, monocytes bound primarily to the viral HA molecule, but showed some recognition of the viral immune complexes. This dual binding did not increase monocyte adherence to the infected epithelium above that observed with virus alone. These findings indicate that neutralizing concentrations of IgA or IgG Abs, the predominant Abs found in the upper and lower respiratory tract, respectively, do not augment and can prevent monocyte recognition of influenza virus. This suggests that in vivo monocytes must use a non-Fc-mediated mechanism to adhere to and phagocytize these immune complexes. PMID- 8683136 TI - Selective growth of human mast cells induced by Steel factor, IL-6, and prostaglandin E2 from cord blood mononuclear cells. AB - To establish the method for generating a large number of mature human mast cells, we cultured cord blood mononuclear cells (CBMC) in several conditions in the presence of Steel factor (SF). Among several cytokines tested, IL-6 enhanced SF dependent mast cell growth from purified CD34+ cells for more than 8 wk in culture. When CBMC were cultured instead of CD34+ cells, IL-6 enhanced the mast cell development in the presence but not in the absence of PGE2. PGE2 enhanced the SF- and IL-6-dependent development of mast cells from CBMC probably by blocking granulocyte-macrophage CSF (GM-CSF) secretion from accessory cells, because 1) PGE2, or anti-GM-CSF enhanced the mast cell development induced by SF and IL-6 from CBMC, but not from CD34+ cells; 2) GM-CSF inhibited the enhancing effect of IL-6 on the mast cell development from CD34+ cells; and 3) PGE2 inhibited GM-CSF secretion from CBMC. The mast cells cultured in the presence of SF, IL-6, and PGE2 for >10 wk were 99% pure, and seemed to be functionally mature, because 1) they contained 5.62 micrograms of histamine and 3.46 micrograms of tryptase per 10(6) cells; and 2) when sensitized with human IgE and then challenged with anti-human IgE, the cells released a variety of mediators such as histamine, and an increase in intracellular Ca2+ was found in advance of the activation of membrane movement by using a confocal laser-scanning microscope. Electron-microscopic analysis revealed that some of the cultured mast cells are morphologically mature since they filled with scroll granules and contained crystal granules. PMID- 8683138 TI - Transforming growth factor-beta 1 inhibits the production of IL-8 and the transmigration of neutrophils through activated endothelium. AB - A central mechanism of inflammation is the activation of vascular endothelium by the inflammatory cytokines TNF-alpha and IL-1. These cytokines induce the expression of adhesion molecules, the elaboration of chemokines, and the transendothelial migration of white cells. TGF-beta 1 has anti-inflammatory properties, is expressed in the vessel wall, and has previously been shown to inhibit leukocyte adhesiveness to the endothelium at least in part by inhibiting the expression of E-selectin. We now show that TGF-beta 1 also inhibits the migration of neutrophils through endothelial monolayers activated by TNF-alpha. At a dose of 10 U/ml TNF-alpha, the transmigration of neutrophils was inhibited 42.7 +/- 7.9% (n = 8) by 0.2 ng/ml TGF-beta 1. Furthermore, TGF-beta 1 inhibited, in a time- and dose-dependent fashion, the elaboration of IL-8 by TNF-activated endothelial cells by between 33 and 78% (TNF doses from 100 down to 0.1 U/ml) and the elaboration of mRNA for IL-8 by 69%. TGF-beta 1 treatment did not significantly alter the TNF-induced IL-8 mRNA stability, suggesting that the mechanism of action of TGF-beta 1 is on gene transcription. Neutrophil transmigration through cytokine-activated endothelium involves both IL-8 dependent and IL-8-independent mechanisms. Using an anti-IL-8 Ab, we show that TGF-beta 1 inhibits only the IL-8-dependent pathway, but does not affect the IL-8 independent transendothelial migration mechanism. These and our previous results show that TGF-beta1, achieves its anti-inflammatory properties by inhibiting the expression of at least two genes, E-selectin and IL-8, which are essential in the inflammatory pathway. PMID- 8683139 TI - Heat shock protein 65 induces CD62e, CD106, and CD54 on cultured human endothelial cells and increases their adhesiveness for monocytes and granulocytes. AB - Expression of members of the heat shock protein 60 (hsp60) family in tissues has been reported to coincide with leukocyte infiltration, but it is not known whether these proteins are directly involved in the extravasation of leukocytes. Extravasation of leukocytes requires their adhesion to endothelial cells (EC) via an interaction between adhesion molecules expressed on both cell types. The aim of the present study was to investigate the effect of recombinant mycobacterial hsp65 on the adhesive characteristics of EC for monocytes and granulocytes. Incubation of EC with hsp65 induces a concentration- and time-dependent increase in adhesiveness of these EC for monocytes and granulocytes. The effect was maximal after incubation of EC with hsp65 for 4 to 6 h. In addition, incubation of EC with hsp65 induced the expression of endothelial CD62E (E-selectin), CD106 (vascular cell adhesion molecule-1) and CD54 (intercellular adhesion molecule-1). The increased adhesion of granulocytes to hsp65-stimulated EC was inhibited completely by blocking Ab against CD62E. mAb against endothelial CD62E, CD106, or CD54 or against the monocyte adhesion molecules CD14 or CD49d (very late Ag-4) did not inhibit the increased adhesion of monocytes to hsp65-stimulated EC; however, mAb against the monocyte adhesion molecule CD18 (beta2-integrin) inhibited monocyte adhesion to hsp65-stimulated EC to the same extent as monocyte adhesion to nonstimulated EC. Hsp65 did not exert its effect in an autocrine or paracrine fashion via the endogenous production of IL-1, TNF-alpha, or other factors or via contaminating LPS. Together these results indicate that hsp65 can play an important role in the adhesion of monocytes and granulocytes to EC at sites of inflammation via modulation of the adhesive characteristics of EC and thus may facilitate extravasation of these phagocytes. PMID- 8683140 TI - Modulation by IL-10 of antigen-induced IL-5 generation, and CD4+ T lymphocyte and eosinophil infiltration into the mouse peritoneal cavity. AB - Sensitized BALB/c mice challenged i.p. with 1 microgram of OVA showed IL-5 release in the peritoneal lavage fluid, which peaked at 6 h and decreased thereafter. This was followed by a massive eosinophil accumulation, which started at 6 h and reached a plateau between 24 and 48 h. The i.p. injection of recombinant murine (rm) IL-10 (0.01-0.1 microgram/cavity) along with OVA reduced IL-5 release at 6 h and allergic eosinophilia at 6, 24, and 48 h. rmIL-10 also blocked in vitro IL-5 generation by sensitized peritoneal cells cultured in the presence of OVA. The inhibitory effect of rmIL-10 on Ag-induced eosinophilia and IL-5 release was suppressed by pretreatment of the animals with 1 mg/mouse of a neutralizing anti-mIL-10 mAb. Flow cytometric analysis revealed an increase in the number of CD4+ and CD8+ T lymphocytes and in the number of CD25+/CD4+ cells in the peritoneal lavage fluid collected 24 and 48 h after challenge, respectively; these numbers were reduced significantly by the administration of 0.1 microgram of rmIL-10. Finally, rmIL-10 failed to modify the anti-CD3-induced IL-5 release in vivo in the peritoneal cavity and in vitro from purified spleen CD4+ T lymphocytes. This suggests that rmIL-10 acts indirectly, by deactivating APC, rather than directly on T cell activation. These findings indicate that rmIL 10 displays anti-allergic activity in sensitized BALB/c mice by preventing Ag induced CD4+ T lymphocyte and eosinophil accumulation as well as IL-5 release in the peritoneal cavity. PMID- 8683141 TI - Prevention of experimental autoimmune myasthenia gravis by a monoclonal antibody to a complementary peptide for the main immunogenic region of the acetylcholine receptors. AB - We have previously reported that a complementary peptide (denoted RhCA 67-16), encoded by RNA complementary to that of the Torpedo acetylcholine receptor (AChR) main immunogenic region (MIR), AChR residues alpha 61-76, induces polyclonal and monoclonal Ab reactive with Ig against the AChR MIR. RhCA 67-16 vaccination also protected against the development of experimental autoimmune myasthenia gravis (EAMG) in Lewis rats. In the present report, we found that a mAb (denoted TCM 240, IgG1 kappa) against RhCA 67-16 recognized three different idiotypic Ab (mAb 6, mAb 35, and mAb 198), which were previously reported by others to recognize the AChR MIR and to cause EAMG. Based on these results, TCM 240 was tested for prophylactic effects in EAMG. EAMG induced passively by mAb 35 was inhibited by simultaneous injection with TCM 240. The disease severity was inversely paralleled by the ratio of mAb 35 to TCM 240. EAMG induced by immunization with purified native Torpedo AChR was also inhibited by TCM 240, but not a control mAb. The inhibitory effect of TCM 240 on actively induced EAMG occurred without significantly lowering the overall AChR Ab levels, which indicates a limited repertoire of disease-causing Ab in EAMG and perhaps MG. Such findings suggest the existence of an EAMG-associated Id and also support the concept of an MIR. In a more general sense, these results demonstrate that prophylactic and perhaps diagnostic mAb for autoimmune diseases can be produced by immunization with complementary peptides for disease-associated epitopes. PMID- 8683142 TI - Antigen-receptor engagement in B cells induces nuclear expression of STAT5 and STAT6 proteins that bind and transactivate an IFN-gamma activation site. AB - The signal transducer and activator of transcription (STAT) family of transcription factors is triggered by cytokine and growth factor receptors in a number of cell types, and binds to a consensus sequence defined in part by the IFN-gamma activation site (GAS). It is not known whether these transcription factors respond to other kinds of growth stimuli, and, with particular relevance to lymphocytes, it is not known whether STAT proteins participate in Ag-specific responses. To determine the role of STAT proteins, coupling between Ag-receptor cross-linking and nuclear expression of DNA-binding protein complexes that recognize GAS sequences was evaluated. Ag-receptor triggering in primary B lymphocytes stimulated nuclear expression of a complex that specifically binds the IFN response factor-1 (IRF-1) GAS sequence, and is distinguished by electrophoretic mobility and GAS preference from IRF-1 GAS-binding complexes induced by IFN-gamma. Activation of nuclear IRF-1 GAS-binding activity by sIg was inhibited by the tyrosine kinase inhibitor, herbimycin A, and binding activity was eliminated by tyrosine phosphatase treatment. Activation of IRF-1 GAS-binding activity was blocked by depletion of protein kinase C. The IRF-1 GAS-binding activity induced by sIg engagement in B cells was transcriptionally active, and was found to consist of immunoreactive STAT5 and STAT6 proteins. This work demonstrates that the STAT signaling pathway previously associated with cytokine signaling is triggered in B lymphocytes through Ag-receptor engagement in a protein kinase C-dependent fashion. This heretofore described cytokine signaling pathway may play a role in bringing about Ag-specific proliferative and differentiative responses. PMID- 8683143 TI - 5-Lipoxygenase metabolism in alveolar macrophages from subjects infected with the human immunodeficiency virus. AB - Pulmonary infection represents a major source of morbidity and mortality in AIDS. One important component of pulmonary host defense is the elaboration by resident alveolar macrophages (AM) of proinflammatory leukotrienes (LT) and other 5 lipoxygenase (5-LO) metabolites of arachidonic acid (AA). In this study, we compared the 5-LO metabolic capacity of AM isolated from normal controls with two groups of HIV-infected subjects: (1) patients with low CD4 counts undergoing diagnostic evaluation for pulmonary indications, and (2) volunteers without pulmonary complaints stratified into normal (> 500) and low (< 200) CD4 count groups. Compared with AM from control subjects, AM from HIV-infected subjects with normal and low CD4 counts demonstrated a marked reduction in LT synthesis. This reduced metabolic capacity could not be attributed to in vivo activation because there was no increase in lavage fluid LTB4 levels. However, there was a reduction (approximately twofold) in 5-LO protein expression in both the normal and the low CD4 subsets. 5-LO-activating protein (FLAP) expression was unchanged in cells from the normal CD4 HIV group, but was decreased threefold in the two groups with low CD4 counts. These observations indicate that there is a graded defect in the 5-LO metabolic capacity of AM from HIV-infected subjects, with decreased expression of only 5-LO in the normal CD4 group, and decreased expression of both 5-LO and FLAP in the low CD4 group. This defect would be expected to compound the immunosuppression seen in these subjects. PMID- 8683144 TI - Unstimulated peripheral blood mononuclear cells from patients with the hyper-IgD syndrome produce cytokines capable of potent induction of C-reactive protein and serum amyloid A in Hep3B cells. AB - The hyper-IgD and periodic fever syndrome (HIDS) and familial Mediterranean fever (FMF) are both characterized by attacks of periodic fever accompanied by acute phase responses that are substantially higher in HIDS than in FMF. To determine whether this difference could be due to differences in production of acute phase protein-inducing mediators, we studied PBMC from HIDS and FMF patients in the inactive phase of disease. Unstimulated PBMC from patients with inactive HIDS released significantly more IL-1 beta, IL-6, and TNF-alpha than did PBMC from patients with FMF, but unstimulated PBMC from the latter group released significantly more IL-1 beta and IL-6 compared with controls. Conditioned medium (CM) derived from PBMC of patients with inactive HIDS induced significantly greater CRP production and significantly higher mRNAs for CRP and SAA in Hep3B cells than did CM derived from the PBMC of patients with inactive FMF. Stimulation of PBMC with LPS led to further increases in cytokine production and in acute phase protein-inducing ability in both patient groups and in controls. These findings suggest that the greater acute phase response seen in HIDS compared with FMF reflects greater production of acute phase protein-inducing cytokines in the former patients and indicates that PBMC from inactive HIDS patients are already activated in vivo. Finally, the finding of both quantitative and qualitative differences in cytokine production by unstimulated PBMC from HIDS and FMF patients supports the likelihood of different pathogeneses of these diseases. PMID- 8683145 TI - Impaired production of both normal and mutant C1 inhibitor proteins in type I hereditary angioedema with a duplication in exon 8. AB - In the autosomal dominant disorder type I hereditary angioedema, reduced levels of C1 inhibitor may be due in part to increased turnover and decreased synthesis of normal C1 inhibitor protein. A type I hereditary angioedema patient was recently described in whom the C1 inhibitor mutation consisted of a 20-bp duplication of nucleotides 1414 to 1433 in exon 8 that introduced a frame shift predicting the loss of a normal stop codon and the translation of a protein 52 amino acids longer than normal. In this study, we analyzed the expression of C1 inhibitor in fibroblasts obtained from a skin biopsy of this patient. Two proteins of approximately 78 and 94 kDa were found intracellularly, corresponding to the products of normal and mutated alleles, respectively. Pulse-chase analysis showed a complete lack of secretion of the mutated form. In addition, there was decreased extracellular production of the normal C1 inhibitor, suggesting either decreased secretion or increased intracellular catabolism of the normal protein because of the presence of the mutant allele. The production of other complement proteins was normal. This study provides a model for further analysis of autosomal dominant genetic disorders in which production of the functional protein may be affected by the product of the mutated allele. PMID- 8683146 TI - Defective monocyte costimulation for IFN-gamma production in familial disseminated Mycobacterium avium complex infection: abnormal IL-12 regulation. AB - We have described previously a family in which several members have disseminated Mycobacterium avium complex infection. PBMC from affected members produced abnormally low amounts of IFN-gamma upon stimulation with PHA. Using PHA stimulated allogeneic cocultures of highly purified monocytes and T cells from familial patients and normal subjects, we have now demonstrated that familial patient monocytes are defective in accessory cell function for IFN-gamma production. Familial patient monocytes did not inhibit IFN-gamma production by normal cells, nor did inhibition of PG synthesis restore normal IFN-gamma production by familial patient cells. Familial patient cells responded to the addition of exogenous IL-12 by increasing IFN-gamma production, while addition of exogenous anti-IL-12 had an insignificant effect on their IFN-gamma production. IL-12 was undetectable in PHA-stimulated cocultures of familial patient monocytes with familial or normal T cells. In addition, IL-12 production by adherent cells from patients and their unaffected mothers was abnormally low following stimulation with fixed Staphylococcus aureus Cowan I strain. However, normal amounts of IL-12 were detected when adherent familial patient cells were stimulated with S. aureus Cowan I strain and IFN-gamma, suggesting abnormal regulation of IL-12 production by familial monocytes. This is the first report of defective IL-12 production associated with increased susceptibility to an infectious disease, a finding that supports the critical role of this cytokine in host defense. PMID- 8683147 TI - Autoimmune lpr/lpr mice deficient in CD40 ligand: spontaneous Ig class switching with dichotomy of autoantibody responses. AB - Fas-deficient MRL/Mp-lpr/lpr mice develop a syndrome that resembles human systemic lupus erythematosus, including production of IgG autoantibodies against small nuclear ribonucleoproteins (snRNPs), dsDNA, and self IgG (rheumatoid factor). To investigate the necessity for T-B cell contact in MRL autoimmunity, mice deficient in CD40 ligand (CD40L) were backcrossed onto this background, and Ab synthesis was assessed. In comparison to their CD40L-intact lpr/lpr counterparts, CD40L-deficient lpr/lpr mice had elevated levels of serum IgM and lower levels of IgG; however, a subset of animals had IgG2a, and to a lesser extent, IgG2b levels similar to those found in wild-type lpr/lpr mice. Levels of both isotypes in CD40L-deficient lpr/lpr mice were significantly greater than those found in nonautoimmune CD40L-deficient animals. IgG autoantibodies, including those directed against small nuclear ribonucleoproteins, also arose in CD40L-deficient lpr/lpr mice; however, they did not develop IgG rheumatoid factors or anti-dsDNA, and lacked histologic evidence of overt glomerulonephritis at age 3 mo, in contrast to CD40L-intact lpr/lpr animals. These results indicate that isotype switching occurs in lpr/lpr mice deficient in CD40L, and that production of IgG autoantibodies to ribonucleoproteins is at least partially preserved. They also suggest that different mechanisms may be responsible for eliciting autoantibody responses in lpr/lpr mice. PMID- 8683148 TI - TNF-alpha enhances colony-stimulating factor-1-induced macrophage accumulation in autoimmune renal disease. AB - The lpr mutation on the MRL background accelerates autoimmune nephritis in which macrophage (M phi) accumulation is prominent. Renal disease is absent in other strains with lpr. TNF-alpha and CSF-1 are increased in the kidney of MRL-lpr mice with loss of renal function. We have established that CSF-1 can incite renal injury in mice with the lpr mutation, and M phi from the MRL strain hyper-respond to this growth factor. We hypothesized that TNF-alpha enhanced the M phi response to CSF-1 in MRL-lpr mice. We now report that TNF-alpha enhanced CSF-1-induced bone marrow M phi proliferation in MRL-lpr mice, and not in congenic MRL +/+, normal C3H +/+, and BALB/c, or another strain with lpr (C3H-lpr). Using a gene transfer approach to deliver CSF-1 together with TNF-alpha into the kidney, we evaluated the impact on renal injury. Tubular epithelial cells genetically modified to produce CSF-1 (CSF-1-TEC) and TNF-alpha (TNF-TEC) placed under the renal capsule caused a greater accumulation of M phi in the implant site than CSF 1-TECs alone in MRL-lpr, but not MRL +/+ mice. We noted in tissues adjacent but not distal to the implanted TECs, an increase in M phi in the interstitium and surrounding glomeruli of MRL-lpr but not MRL +/+ mice. This indicated that CSF-1 and TNF-alpha released by TECs were responsible for promoting renal pathology. Taken together, these data suggest that the simultaneous expression of TNF-alpha and CSF-1 in the MRL-lpr kidney fosters M phi accumulation. We speculate that the increase in M phi in the kidney in response to CSF-1 and TNF-alpha is responsible for the rapid tempo of autoimmune renal injury in MRL-lpr mice. PMID- 8683149 TI - Enhanced response of macrophages to CSF-1 in autoimmune mice: a gene transfer strategy. AB - Mice with the MRL background have a genetic propensity for autoimmune lupus nephritis. The lpr mutation on the MRL, but not the C3H background, induces rapid and fatal renal injury in which macrophages (M phi) are prominent. We previously established that CSF-1 accompanies M phi accumulation in the kidney of MRL-lpr mice. Furthermore, CSF-1 introduced into the kidney incites renal injury in mice with the lpr mutation, but not congenic strains. Notably, CSF-1 induces more severe tissue injury in MRL-lpr than in C3H-lpr mice. We hypothesized that M phi from the MRL background respond more readily to CSF-1 than normal strains. We establish herein the following: 1) glomerular M phi and bone marrow M phi (BMM phi) from MRL-lpr mice proliferate similarly to CSF-1; 2) MRL BMM phi proliferate more vigorously to CSF-1 than normal strains (C3H, BALB/c) or another strain with lpr (C3H-lpr); and 3) modulation of CSF-1 receptor expression by CSF-1 is more rapid in MRL than C3H BMM phi. We used a gene transfer strategy to deliver CSF-1 into the kidney to evaluate M phi response to CSF-1. We genetically modified tubular epithelial cells to produce CSF-1 (CSF-1-TECs) and placed these cells with BMM phi under the renal capsule. CSF-1-TEC + BMM phi caused a greater accumulation of M phi in the implant site and interstitium of MRL +/+ than C3H +/+ mice. Furthermore, CSF-1-TEC + BMM phi caused a lesion consisting of M phi in MRL +/+ mice, extending from the implant into the adjacent cortex. We suggest that the response of MRL M phi to CSF-1 is responsible for the notable accumulation of M phi in the MRL-lpr kidney. PMID- 8683150 TI - Stimulation of IgE and IgA production by CD45RA T helper cells in atopic patients. AB - The role of CD45RA T cells on allergen-dependent lymphocyte functions was analyzed in atopic patients. As compared with age-matched nonatopic controls, atopic patients exhibited a significantly (p < 0.01) increased frequency of CD45RA T cells in peripheral blood. Concentration of serum IgE correlated with increases in this T cell subset. In contrast to nonatopic controls, not only CD45RO but also CD45RA T cells from atopic patients provide help for allergen stimulated IgE and IgA production, and they act in a synergistic fashion. Transwell coculture experiments revealed that optimal production of IgE and IgA required physical contact of CD45RA T cells with B cells. Freshly prepared and in vitro-activated CD45RO and CD45RA T cells from atopic patients showed an increased expression of CD40 ligand when compared with nonatopic individuals. In addition, CD45RA (and CD45RO) T cells from atopic individuals produced IL-4, IL 5, and IFN-gamma when stimulated with mitogens. Whereas stimulation of normal lymphocytes with tetanus Ag was followed by conversion of the CD45RA to the CD45RO phenotype, T cells from atopic donors did not acquire the CD45RO isoform to the same degree despite T cell activation. In atopic patients, addition of IL 4 to anti-CD3/anti-TCR stimulated CD45RA T cell prevented the shift towards the CD45RO phenotype. These data indicate that a subset of CD45RA T cells plays a unique role as effector T cells regulating IgE and IgA production in atopic patients. PMID- 8683151 TI - Peripheral V gamma 9/V delta 2 T cell deletion and anergy to nonpeptidic mycobacterial antigens in asymptomatic HIV-1-infected persons. AB - Gamma delta T cells represent a minor population of human peripheral lymphocytes, the majority of them expressing the V delta 2/V gamma 9 TCR. Their accumulation in infectious disease lesions and their reactivity toward mycobacterial Ags suggest that V gamma 9/V delta 2 T cells play a role during infectious diseases. We have shown previously a significant expansion of the V delta 1 subset parallel to a dramatic decrease of the V delta 2 subset in PBMC from HIV-infected persons. To understand the mechanisms involved in the deletion of V delta 2 T cells, we analyzed their ability to respond in vitro to several V gamma 9/V delta 2 t cell specific ligands. We observed that in 60% of asymptomatic HIV-infected persons, V delta 2 T cells exhibited a functional anergy to Daudi and to Mycobacterium tuberculosis stimulations. These observations were supported by the defective expansion of this subset to the recently described nonpeptidic phosphorylated Ag, TUBAg-1. Since V delta 2 responsiveness to mycobacterial Ags was shown to be normally dependent on IL-2 secretion by Th1-type CD4 T cells, the ability of IL-2 to restore V delta 2 T cells' responsiveness to TUBAg-1 was tested. V delta 2 T cell anergy persisted in spite of the presence of IL-2, and was frequently correlated with a defect in CD25 expression on stimulated V delta 2 T cells. Since V delta 2 anergy was associated with an in vivo depletion of this subset, we studied whether programmed cell death could be involved in this process, particularly because of their activated phenotype. Although peripheral V delta 2 T cells from some HIV-infected persons showed an increased susceptibility to spontaneous and activation-induced apoptosis, statistical comparison between HIV+ and HIV- donors indicated that there was no difference between both groups in the rate of V delta 2 apoptosis. Finally, V delta 2 complementarity-determining region 3 TCR analysis indicated that, in vivo, the remaining V delta 2 T cells were still polyclonal. All together these results suggest that the qualitative and quantitative alterations of the V delta 2 subset in the course of HIV infection are the consequence of a chronic antigenic stimulation, and raise the question of the contribution of a cellular ligand induced or modified by chronic HIV infection. PMID- 8683152 TI - Mucosal immunity to HIV-1: systemic and vaginal antibody responses after intranasal immunization with the HIV-1 C4/V3 peptide T1SP10 MN(A). AB - To optimize mucosal immune responses to the HIV-1 peptide vaccine candidate T1SP10 MN(A), we intranasally immunized BALB/c and C57BL/6 mice with C4/V3 HIV-1 peptide together with the mucosal adjuvant cholera toxin (CT). Four doses over a 4-wk period resulted in peak serum anti-peptide IgG titers of > 1:160,000 in BALB/c mice and > 1:520,000 in C57BL/6 mice, and significant levels (>1:30,000) persisted in both strains of mice for longer than 6 mo. Furthermore, intranasal immunization with peptide and CT induced serum IgG reactivity to HIV-1 gp120 and HIV-1(MN) neutralizing responses. The primary anti-peptide IgG subclass was IgG1, suggesting a predominant Th2-type response. In addition to elevated serum anti peptide A responses, intranasal immunization with T1SP10 MN(A) and CT induced both vaginal anti-peptide IgG and IgA responses, which persisted for 91 days in both strains of mice. Vaginal anti-HIV IgA was frequently associated with secretory component, suggesting transepithelial transport of IgA into vaginal secretions. Cervical lymph nodes contained the highest relative concentration of anti-T1SP10 MN(A) IgG-producing cells, while the spleen was the next major site of anti-T1SP10 MN(A) IgG-producing cells. Ag-specific proliferative responses were also detected in cervical lymph node and spleen cell populations after intranasal immunization with T1SP10 MN(A) and CT. In addition, intranasal immunization with T1SP10 MN(A) and CT was able to induce anti-HIV cell-mediated immunity in vivo as indicated by the induction of delayed-type hypersensitivity. Therefore, intranasal immunization with hybrid HIV peptides provides a noninvasive route of immunization that induces both long-lived systemic and mucosal Ab responses as well as cell-mediated immunity to HIV. PMID- 8683153 TI - CRP-mediated activation of complement in vivo: assessment by measuring circulating complement-C-reactive protein complexes. AB - The in vivo function of C-reactive protein (CRP) is unknown. Among the in vitro functions assigned to CRP is the ability to activate complement via the classical pathway. To date, there is no evidence supporting that CRP exerts this function in vivo. We here show a novel approach to assess CRP-mediated complement activation in vivo, which is based on the property that activated complement factors C3 and C4 fix to CRP during complement activation induced by this acute phase protein. We developed specific ELISAs for complexes between CRP and C4b, C4d, C3b, or C3d. We established that in vitro complement-CRP complexes were formed only during CRP-dependent activation, and not during activation by other activators, even in the presence of high CRP levels. Circulating levels of complement-CRP complexes were undetectable in normal donors, but significantly increased in nine patients following implantation of a renal allograft. Importantly, levels of complement-CRP complexes did not change in these patients upon a bolus infusion of mAb OKT3, which induces activation of the classical complement pathway, demonstrating in vivo that complement-CRP complexes are not formed during CRP-independent activation of complement, even when CRP is elevated. We conclude that measurement of complement-CRP complexes provides a suitable tool to study CRP-mediated activation of complement in vivo. Furthermore, increased levels of these complexes occur in clinical samples, indicating that CRP may induce activation of complement in vivo. PMID- 8683154 TI - The signaling activity of murine CD19 is regulated during cell development. AB - CD19, a B cell-specific transmembrane protein, is essential for murine B-1 cell development and T cell-dependent B cell immune responses. Whereas signaling by the human B cell Ag receptor can be modulated by CD19, less is known about the biochemical properties of murine CD19. We have used a novel rat mAb specific for murine CD19 to study the biochemical properties of the murine protein. We demonstrate that murine CD19 shares with human CD19 an association with complement receptor CD21 and CD81, tyrosine phosphorylation, binding of phosphatidylinositol-3 kinase, and synergistic signaling with membrane IgM. Murine CD19 is shown also to enhance signaling through the micro-surrogate light chain complex of primary pre-B cells. We found that although expressed in the earliest B cell precursors, CD19 ligation does not activate Ca2+ mobilization until the pre-B cell stage of development. In mature B cells, CD19 cross-linking activates Ca2+ flux in B-2 cells but not in B-1 cells, although it can synergize with surface IgM in both B-1 and B-2 cells. These biochemical properties of CD19 will be important for understanding its function in B cell development and the humoral immune response. PMID- 8683155 TI - Fc receptor off-signal in the B cell involves apoptosis. AB - By linking surface Ig to the FcR Fc gamma RII on the mouse B lymphocyte surface, whole anti-Ig has been shown to block cell cycle entry and subsequent Ab production, a phenomenon called the "Fc receptor off-signal." IL-4 or blocking Ab to Fc gamma RII, present with whole anti-Ig, restores cell cycle progress to the levels observed with F(ab')2 anti-Ig. The current study demonstrates that under "off-signal" conditions with whole anti-Ig, the early entry of B cells into apoptosis was accelerated relative to medium alone or equimolar F(ab')2 anti-Ig. All reagents tested which opposed the whole-anti-Ig-induced blockade of B cell cycle entry also protected B cells from apoptosis (IL-4, PMA, dextran sulfate, and the monoclonal anti-Fc gamma RII 2.4G2). This protective effect was most evident at 4 to 12 h, waning at later times. Low dose cycloheximide partially protected B cells from whole anti-Ig-induced apoptosis, but acted as a survival factor, failing to advance B cells from G0 phase or stimulate thymidine incorporation. Additive early apoptosis-associated membrane changes were transiently seen when whole anti-Ig was combined with other apoptosis accelerating agents (trifluoperazine, staurosporine, dexamethasone, ionomycin, high-dose cycloheximide), but hypodiploid nuclei did not show this effect. B cells from bcl-2 transgenic mice showed less apoptosis when cultured with whole anti-Ig, or with any of the other agents tested. At 4 h the bcl-2-associated reduction in hypodiploid nuclei was greater than the reduction in membrane unpacking, but by 16 h this difference was much less. These results suggest that acceleration of apoptosis contributes to the inhibition of proliferation induced by whole anti-Ig. PMID- 8683156 TI - Tenidap and other anion transport inhibitors disrupt cytolytic T lymphocyte mediated IL-1 beta post-translational processing. AB - LPS-activated murine peritoneal macrophages produce IL-1 beta but externalize little mature cytokine in the absence of a secondary stimulus, and CTLs previously were reported to serve this capacity. The release of 17-kDa IL-1 beta from LPS-activated BALB/c macrophages occurred rapidly after the addition of C57/B1-derived allogeneic CTLs; within 30 min of coculture, mature IL-1 beta was observed in the medium, and maximum release was achieved within 4 h. CTL-induced post-translational processing was efficient, and >80% of newly synthesized pro-IL 1 beta was released into the medium as the 17-kDa species. Externalization of IL 1 beta required active recognition of the macrophage target by the CTL preparation; C57/B1 CTLs promoted the release of mature IL-1 beta from allogeneic BALB/c macrophages, but not from syngeneic C57/B1 macrophages. In contrast, extracellular ATP promoted mature IL-1 beta release from both macrophage populations. CTL-induced cytokine post-translational processing was blocked by anion transport inhibitors, including 4,4'-diisothiocyanatostilbene-2,2' disulfonic acid, UK5099, and the anti-inflammatory agent tenidap. An analogue of tenidap, CP-100,829, was more effective as an inhibitor of both IL-1 beta post translational processing and anion transport. In contrast, the close structural analogue CP-236,492 inhibited neither process. Tenidap's activity was reversible and was not mimicked by cyclooxygenase inhibitors or by cycloheximide. Therefore, tenidap disrupted CTL-induced IL-1 beta post-translational processing by a mechanism dependent on anion transport inhibition. Multiple stimuli are likely to operate in vivo to promote IL-1 beta post-translational processing, and anion transport inhibitors such as tenidap that suppress cytokine processing independently of the initiating stimulus thus represent attractive candidates as therapeutic regulators of IL-1 production. PMID- 8683157 TI - Analysis of central B cell tolerance in autoimmune-prone MRL/lpr mice bearing autoantibody transgenes. AB - The effect of the autoimmune prone MRL/lpr (H-2k) genetic background on central B cell tolerance was studied in mice bearing 3-83 (anti-H-2Kk) Ig heavy and light chain transgenes. B cells bearing the dominant, transgene-encoded anti-H-2Kk specificity were tolerized appropriately on the MRL/lpr genetic background. Nevertheless, mice developed disease traits characteristic of the MRL/lpr strain, including lymphadenopathy and elevated levels of IgG dsDNA autoantibodies. Two transgenic lines were examined in this analysis: 3-83 mu delta, which expresses IgM and IgD forms of the 3-83 Ab, and Tol 1, which expresses only the IgM form of 3-83. The results obtained differed somewhat between the two transgenic lines. Crosses using 3-83 mu(delta) mice never demonstrated any defects in B cell self tolerance to H-2Kk. Similarly, no Kk autoantibody production was seen in Tol 1 mice that were backcrossed onto the MRL/lpr genetic background and maintained in a specific pathogen-free facility. However, a subset of Tol 1/MRL/lpr mice that were housed in a conventional mouse facility demonstrated significant transgene derived anti-Kk autoantibodies. Overall, these results suggest that there is no general defect in central B cell tolerance in MRL/lpr mice, despite their defect in the fas gene. These findings suggest similarities between the MRL/lpr T and B cell systems, because both fail to manifest clear central tolerance defects, but they nevertheless promote hyperplasia and autoimmunity in the peripheral immune system. PMID- 8683158 TI - B4B, a novel growth-arrest gene, is expressed by a subset of progenitor/pre-B lymphocytes negative for cytoplasmic mu-chain. AB - We subjected PBMC of normal adults to density fractionation to enrich for an immunoblast fraction that would include early immune lineage precursors. Differential display PCR experiments identified one transcript that is expressed specifically in this immunoblast fraction. This cDNA, designated B4B, encodes a novel gene product containing four putative transmembrane-spanning domains. B4B+ cells, detected with anti-B4B Ig, were found at very low frequency in PBMC (0.01%) and were enriched significantly in intermediate density fractions (0.1 1.0%). B4B+ cells were shown to be CD19+CD45+HLA-DR+ and negative for CD20, cytoplasmic mu-chain, CD3, CD16, CD56, CD34, and CD68 (monocyte), consistent with a progenitor/pre-B lymphocyte subset that does not express cytoplasmic mu-chain and thus may lack productive Ig rearrangement. This phenotypic description of the B4B+ subset agrees with our finding that the frequency of B4B+ cells was greatly increased in bone marrow (3-10%) as compared with PBMC (0.01%). The B4B polypeptide sequence exhibits significant homology to only one known protein, PMP 22/gas-3, a Schwann cell-specific protein that induces cell growth arrest. Transient expression of B4B specifically inhibited cellular proliferation by more than 50%. Based on its antiproliferative effect and pattern of expression restricted to a subpopulation of immature B cells, the B4B gene product may be involved in the elimination of B cells before productive VDJC rearrangement of Ig loci or, alternatively, in the growth arrest of transformed progenitor B cells. PMID- 8683159 TI - Maintenance of nuclear factor-kappa B/Rel and c-myc expression during CD40 ligand rescue of WEHI 231 early B cells from receptor-mediated apoptosis through modulation of I kappa B proteins. AB - Engagement of surface IgM (sIgM) on WEHI 231 murine B lymphoma cells leads to abortive activation and apoptosis, suggesting that this cell line may represent a model for tolerance. Loss of viability in these cells is preceded by an early increase in c-myc RNA levels followed by a decline below control values, implicating c-myc in the control of apoptosis. Costimulation with CD40 ligand (CD40L) has been shown to rescue WEHI 231 cells from anti-sIgM-induced apoptosis, and therefore, the effects of CD40L on c-myc RNA and protein levels were measured. Treatment of these cells with the combination of CD40L and anti-sIgM led to induction and maintenance of elevated levels of c-myc RNA and protein. Since transcriptional regulation of c-myc is mediated through two nuclear factor kappa B (NF-kappa B) sites in WEHI 231, the effects of CD40L on DNA binding by this family of transcription factors were evaluated. CD40L induced and sustained the levels of NF-kappa B binding to both of these sites, paralleling the changes in c-myc RNA levels. Elevated levels of NF-kappa B were partially achieved through a sustained decrease in the steady state amount of the NF-kappa B/Rel specific inhibitory protein, I kappa B alpha, and a transient decrease in I kappa B beta. These data lend support to the hypothesis that anti-sIgM-induced apoptosis is caused by a drop in c-myc expression and that an appropriate second signal, such as that provided by CD40L, is able to rescue these cells by inducing NF-kappa B and thereby maintaining c-myc RNA levels. PMID- 8683160 TI - Peptides corresponding to CD4-interacting regions of murine MHC class II molecules modulate immune responses of CD4+ T lymphocytes in vitro and in vivo. AB - Immune responses mediated by CD4+ T cells depend on Ag-specific alpha beta TCRs that recognize the specific antigenic peptide presented by MHC class II molecules. Interactions between CD4 coreceptors and monomorphic regions of MHC class II molecules contribute to these responses. To examine whether immune reactions could be modulated by specifically interfering with CD4-MHC class II interactions, we have used, in various in vitro and in vivo assays, peptides that correspond to a region of MHC class II molecules previously shown to control interaction with CD4. Depending on the chemical nature and concentration of these peptides, they modulated Ag-specific responses of CD4+ T cells. At high concentrations, these peptides inhibited T cell responses in vitro. However, under conditions that can cause Ag-induced unresponsiveness, the peptides enhanced T cell responses. Also, primary in vivo immune responses to systemically administered soluble protein Ag, keyhole limpet hemocyanin, were enhanced when mice were treated with peptides corresponding to the CD4-interacting region of MHC class II molecules but not when treated with control peptides. Lymphokine profiles suggested that the peptides may favor the differentiation of Th1 cells, because lymphocytes from peptide-treated mice secreted more IL-2 and IFN-gamma than lymphocytes from nontreated or control-peptide-treated mice upon restimulation with Ag in vitro. These results demonstrate that MHC class II derived peptides can directly interfere with interactions with CD4 and modulate T cell responses in vitro and in vivo. PMID- 8683161 TI - Use of RAPD analysis for in situ identification of Ascosphaera aggregata and Ascosphaera larvis in larval cadavers of the alfalfa leafcutting bee, Megachile rotundata. AB - Chalkbrood of the alfalfa leafcutting bee, Megachile rotundata, is caused by the fungus Ascosphaera aggregata. We used random amplified polymorphic DNA (RAPD) analysis for the in situ identification of A. aggregata and a related species, Ascosphaera larvis, in larval cadavers of M. rotundata. A simple DNA extraction method was developed to preferentially isolate DNA from fungal spores on the cadaver surface, or from ascocysts beneath the cuticle. Similar banding patterns were obtained in A. aggregata-infected larval cadavers from different sources and geographic areas. The RAPD banding pattern of cadavers infected with A. aggregata differed from that of healthy leafcutting bee prepupae. RAPD analyses of cadavers infected with A. aggregata and A. larvis resulted in similar banding profiles as those obtained from corresponding pure fungal cultures of the two species. This suggests that the RAPD bands of infected cadavers were amplified from fungal DNA, rather than from other DNA associated with the leafcutting bee cadaver. The banding patterns of "sporulating" and "non-sporulating" chalkbrood cadavers exhibited no differences; this provides the first definitive evidence that both forms of the disease result from infection with A. aggregata. PMID- 8683162 TI - [The protective effect of hypothermia in a new transient cerebral ischemic model of the rat--A 31P magnetic resonance spectroscopy in vivo study]. AB - The energy state and intracellular pH of the rat brain during and after transient cerebral ischemia was measured by the method of 31P magnetic resonance spectroscopy in vivo for the purpose of the evaluation of the protective effect of hypothermia. The rat's chest was opened and the bilateral subclavian arteries were ligated. The transient cerebral ischemia was induced by occlusion of the bilateral cerebral arteries using the balloon occluders. The rat's brain was cooled to 20 degrees C by the surface cooling using the ice bags and was heated to 37 degrees C in the control group, respectively. The animal's temperature was adjusted and regulated by a water blanket placed under the animal's body. After 30 min cerebral ischemia, the level of phosphocreatine (PC) was decreased to 58 +/- 4% versus to 36 +/- 4%, 20 degrees C versus 37 degrees C, respectively (p < 0.01). ATP was decreased to 73 +/- 5% versus 52 +/- 4% (< 0.01). Intracellular pH was decreased from 7.23 to 6.48 at 20 degrees C, from 7.22 to 6.08 at 37 degrees C (p < 0.01). After 60 min ischemia, PC was decreased to 52 +/- 5% versus to 33 +/- 6%, 20 degrees C versus 37 degrees C (p < 0.01). ATP was decreased to 62 +/- 6% versus 36 +/- 6% (p < 0.01). At 37 degrees C either PC or ATP was not recovered to the pre-ischemic level. Intracellular pH was decreased to 6.38 at 20 degrees C, to 5.80 at 37 degrees C (p < 0.01). It is concluded the hypothermia saved the high energy phosphates and keeps intracellular pH high and this beneficial effects contribute the brain protection during cerebral ischemia. PMID- 8683163 TI - [A case of mucoepidermoid carcinoma of the thymus]. AB - A 19-year-old man was admitted to our hospital with anterior mediastinal cystic tumor. Subtotal thymectomy with the tumor was performed. The tumor was localized inside the thymus without outer infiltration. It weighed 145 g and measured 9 x 8 x 5 cm. The cut surface was cystic and spongy, partially with a solid focus. Pathological findings of the solid area was compatible with mucoepidermoid carcinoma of the thymus. The histogenesis of mucoepidermoid carcinoma of the thymus was discussed. PMID- 8683164 TI - [Modified trapdoor thoracotomy for lung cancer invading the distal border of the innominate vein]. AB - A 62-year-old woman suffering from lung cancer of the left upper lobe has a tumor invaded the distal border of the left innominate vein. We resected the vein through trapdoor thoractomy combined with resection of the first rib, followed by a left upper lobectomy through posterolateral thoracotomy. Trapdoor thoracotomy combined with first rib resectioning thus proved useful to resect lung cancer invading the distal border of the innominate vein. PMID- 8683165 TI - [A case report of discordant lymphoma composing Hodgkin's disease and non Hodgkin's lymphoma occurring simultaneously in mediastinum]. AB - A 30-year-old man with discordant lymphoma, composing Hodgkin's disease and non Hodgkin's lymphoma occurring simultaneously in mediastinum, is described. The coexistence of these two diseases is very infrequent and difficult to be treated. It has classically been considered as coincidental. Nevertheless, recent researches have referred the relationship between these two disease and possibility of transformation with each other. PMID- 8683166 TI - [Evaluation of inferior epigastric arterial graft from the aspect of angiography]. AB - We evaluated inferior epigastric artery (IEA) from the aspect of preoperative and postoperative grafts angiography. Between January 1994 and february 1995, we could perform preoperative and postoperative graft-angiography for 12 patients in 27 patients who were undergone CABG using IEA graft. They were 7 males and 5 females. The age ranged from 56 to 76 years (mean, 66.2 years). We used 12 IEAs, 8 LITAs, 7 RGEAs and 2 RITAs as artrial grafts. We measured the diameter of arterial grafts in each angiography. The preoperative diameter of IEA was measured at three points; the proximal part (Prox), center (Cent) and bifurcation (Bif). The postoperative diameter of IEA was measured at two points; the proximal part of composite graft (Prox) and the distal part (Dist). The preoperative grafts diameters were IEA-Prox = 2.01 +/- 0.40 mm, IEA-Cent = 1.75 +/- 0.39 mm, IEA-Bif = 1.32 +/- 0.29 mm, LITA-Prox = 2.40 +/- 0.25 mm, LITA-Cent = 2.00 +/- 0.24 mm, LITA-Bif = 1.64 +/- 0.22 mm, RGEA-Prox = 2.72 +/- 0.49 mm, and RGEA-Cent = 2.29 +/- 0.34 mm. RGEA was the largest, the second was RITA, the third was LITA and IEA was the smallest of the four. The diameter of IEA-Prox was almost equal to LITA-Cent. The postoperative grafts diameter were IEA-Prox = 1.85 +/- 0.37 mm, IEA-Dist = 1.67 +/- 0.38 mm, LITA-Prox 2.57 +/- 0.11 mm, LITA-before Y = 2.01 +/- 0.22 mm, LITA-after Y = 1.83 +/- 0.14 mm, RGEA-Prox = 2.70 +/- 0.55 mm and RGEA Dist = 0.53 mm. RGEA was the largest and RGEA-Dist = 2.34 +/- 0.53 mm. RGEA was the largest and IEA was the smallest. The diameter of LITA was not significantly different between before-Y and after-Y. We conclude in view of the graft diameter, LITA-IEA Y composite graft is the best method for CABG using IEA but IEA graft should be used only to myocardial revascularization to the coronary lesion that does not require high blood flow. PMID- 8683167 TI - [Clinical experience with normothermic selective cerebral perfusion during graft replacement of ascending-arch-descending aortic aneurysms with annuloaortic ectasia]. AB - We treated three cases of ascending-arch-descending aortic aneurysm with annuloaortic ectasia by performing graft replacement. The patients included a 34 year old female, a 34 year old male and a 42 year old male. In one case the aneurysm was atherosclerotic and of type I and II + IIIb dissection in the other two cases. During the operation we were able to utilize normothermic selective cerebral perfusion during construction of the left common carotid artery. Specially, normothermic partial F-F bypass and normothermic selective cerebral perfusion to the left common carotid artery were used during graft replacement from the descending aorta to the left common carotid artery. This was followed by regular hypothermic total ECC and hypothermic cerebral selective perfusion during subsequent graft replacement of the innominate artery and a modified Bentall's operation. This new protocol in which normothermic cerebral perfusion is utilized during the procedure on the left common carotid artery and hypothermic perfusion is utilized only during the subsequent procedure on the innominate artery permits significant shortening of the cardiac arrest time and cerebral perfusion time compared with when only hypothermic perfusion is used. This significant shortening contains obvious benefits in the areas of cardiac and brain protection. PMID- 8683168 TI - [CABG operation with sequential bypass using arterial grafts]. AB - We evaluated 39 cases where sequential anastomoses had been performed using arterial graft (AG) in coronary artery bypass grafting (CABG). Fourty three AGs were used, and anastomosed to 87 coronary arterial branches. The details of these anastomoses were: 25 right gastroepiploic arteries (RGEA) to 51 branches; 10 left internal thoracic arteries (LITA) to 20 branches; 8 right internal thoracic arteries (RITA) to 16 branches. The interrupted suture was employed for all anastomoses. The proxymal site was initially anastomosed in the parallel way to a native coronary artery, and then, the distal anastomosis was done. In CABG using RGEA, the number of cases receiving anastomoses to RCA and LCX was the largest as in 13 cases, and the patent rate was favorable. There were also 8 cases of anastomoses to LAD and Dx and these GEA'S grafts were all patent. But, in the 2 cases of astomoses to RCA and LAD, the GEA's grafts between RCA and LAD were occluded. Therefore, this combination was thought to be inadequate for sequential hypass. On the other hand, in the 10 cases using LITA, these grafts were all anastomosed to LCA system, and were all patent. In the 8 cases using RITA, 4 in situ grafts and 4 free grafts were employed. There were 3 anastomoses to LAD and D1 in the former, and 2 cases each of anastomoses to LAD and D1, and LCx (segment 12) in the latter. The patency was excellent, 100%. Although there were 1 case of post-operative early death (renal failure) and 1 case of remote death (cerebral infarction), they were found not due to arterial sequential bypass. In the 37 cases of post-operative angiography, patency was recognized in 40 AGs out of the 41 (97.6%) and 78 anastomosed branches out of the 83 (94.0%). These satisfactory findings indicate that it is possible and effective to perform sequential bypass in multivessel GABG using AG. PMID- 8683169 TI - [Depression of cellular immunity after aortic arch replacement]. AB - Multiple organ failure due to infection is now one of the most serious postoperative complications following aortic arch replacement. We therefore evaluated the postoperative changes of cellular immunity using four parameters, 1) peripheral lymphocyte subsets 2) mitogen responsiveness 3) the activity of natural killer (NK) cells 4) interleukin-2 (IL-2) production. Patients were divided into two groups: group A (n = 5) with aortic arch replacement and group B (n = 10) with coronary artery bypass grafting. All variables were measured the day before, the day after, 3 days after, 7 days after, and 14 days after surgery. CD3 positive cells in group A were significantly lower than in group B throughout the postoperative course. CD4 positive cells in group A were significantly lower than in group B on the day after 3 days after the operation. IL-2 production in group A was markedly depressed the day after (all patients 0.8 U) and 3 days after (1.5 +/- 1.6 U) as compared to the preoperative level (7.7 +/- 4.4 U) and the levels on the same days in group B. The activity of NK cells in group A was significantly impaired the day after (10.6 +/- 6.7%) and 3 days after (10.0 +/- 6.7%) as compared to the preoperative level (28.6 +/- 16.7%) and the levels on the same days in group B. IL-2 production in group A was significantly correlated to CD3 and CD4 positive lymphocyte levels. These results clearly showed that patients who underwent aortic arch surgery suffered functional depression of cellular immunity, in particular IL-2 production and the activity of NK cells. These depressions may be a result of massive blood transfusion, tissue trauma under hypothermic cardiopulmonary bypass. PMID- 8683170 TI - [The study on the mechanism of brain damage due to high flow and pressure during selective cerebral perfusion]. AB - It has been reported that the high flow and pressure perfusion produced the brain damage during selective cerebral perfusion. This time we studied the mechanism of this brain damage with mock circulation. We made the mock circulation system of brain with the hard shell reservoir as cranium, and with the triple soft bags as brain tissue, involving into reservoir. We designed the control group that intracranial pressure (ICP) was 0 mmHg at pump off, and the increasing intracranial pressure (IICP) group that ICP was 10 mmHg at pump off. We measured the flow-pressure relationship in the control and IICP group, and then stenosis in outflow. In results, the flow and pressure in both the inflow and outflow side increased significantly (p < 0.001) in control groups, as pump flow increased. The changes of the flow and pressure in IICP group showed a same tendency to the control group. Moreover, both the inflow volume into bag and the outflow volume from bag decreased as pump flow increased stepwisely. The pressure in both inflow and outflow side increased significantly and the volume of the inflow side in IICP group showed a tendency to decrease, compared with the control. The stenosis in the outflow side produced the significant increase in the pressure of both inflow and outflow side, and intracranium, with the same pump flow as the control without stenosis. In conclusion, the high flow perfusion produced the increase of the several pressure in intracranial and extracranial vessels. Moreover, the high flow perfusion produced the decrease of the intracranial blood volume cerebral blood flow. The high flow perfusion does not necessarily contribute to the cerebral tissue perfusion. The stenosis at the side of venous return produced relative high perfusion. This result suggests that the venous return should be taken care of during the selective cerebral perfusion. PMID- 8683171 TI - [The evaluation of the bio-compatibility and the clinical usefulness of heparin coated cardiopulmonary bypass circuits]. AB - We studied the biocompatibility and the clinical usefulness of heparin-coated cardiopulmonary bypass circuits (Duraflow-II) compared with non-coated circuits. First study was done to clarify the biocompatibility of heparin coated circuit. 33 cases of elective coronary artery bypass grafting were randomized into two grops. Both group had full dose heparin in this study and laboratory tests were done such as blood cell count, free hemoglobin, AT-III, fibrinogen, FDP, and complement system. The use of heparin-coated circuits resulted in a reduction of C3a generation, and a reduction of fibrinogen consumption. The decline of AT-III may be due to bonding of coated heparin to AT-III, leading to effective anticoagulation. Next study was carried out in 26 cases. In heparin coated group, the amount of heparin was reduced to 200 IU/kg compared to 350 IU/kg in control group. ACT was maintained above 300 sec. and 400 sec. respectively. The amount of post operative bleeding was identical in both groups. There was no case which required autologous blood transfusion, re-operation for bleeding in both groups. Myocardial infarction and hospital mortality were not seen in this study. Concerning the fear of graft occlusion in low dose heparin surgery, there was no statistical difference of graft patency in both groups. In conclusion, heparin coated CPB circuits (Duraflo-II) are favorable in the meaning of biocompatibility and sefely used with low dose heparin. PMID- 8683172 TI - [Use of the omentum for infected sternal dehiscence after aortic valve replacement--a case report]. AB - A 68-year-old man had prosthetic valve replacement for aortic stenosis. Unfortunately, sternal dehiscence with osteomyelitis occurred on the fifth postoperative day. Implantation of the pedicled omentum to the wound was carried out three days later. The result was excellent. This is the worthy method to try to such wound of infected sternum with dehiscence. From the point of view of anatomy and physiology, the omentum has a great benefit to repair the infected space and promote the wound healing process. PMID- 8683173 TI - [A case report of pseudo-false aneurysm of the left ventricle perforated into the right ventricle]. AB - A 60-year-old diabetic women with acute inferior myocardial infarction was admitted to our hospital. An echocardiogram suggested a left ventricular false aneurysm. A left ventricular cineangiogram showed the communication between the left ventricle and the right ventricle through a false aneurysm. At operation one week after the infarction, the pericardial space was free from adhesions. A pseudo-false aneurysm communicating to both ventricle was revealed. The defects were closed with patches and pledgetted mattress sutures. The pseudo-false aneurysm was obliterated with pledgetted mattress and running sutures. The postoperative course was uneventful and the patient was discharged without complication. We emphasize the importance of preoperative morphological and hemodynamic evaluation using a left ventricular cineangiogram in the case of post myocardial infarction ventricular septal perforation. PMID- 8683174 TI - [A case of cardiac herniation following intrapericardial pneumonectomy after induction chemoradiotherapy]. AB - A case of cardiac herniation following left intrapericardial pneumonectomy after induction chemoradiotherapy has been presented. Curative resection after induction chemoradiotherapy for central bronchogenic cancer may require intrapericardial pneumonectomy. Cardiac herniation through the pericardial defect is a fatal complication after a pneumonectomy unless pericardial repair should be done immediately. Closure of the pericardial defect with prosthetic patch, regardless of defect size, is always necessary for the prevention of the cardiac herniation following intrapericardial pneumonectomy after induction chemoradiotherapy. PMID- 8683175 TI - [A case report of pulmonary blastoma--well differentiated fetal adenocarcinoma]. AB - We report a pulmonary blastoma lacking sarcomatous features in 33-year-old woman. Abnormal shadow was detected in the right upper field in a routine chest X-ray film. The preoperative imaging films showed a 4 x 4 cm, well-circumscribed solid tumor in S3 of the right lung. The preoperative clinical diagnosis of primary lung cancer was considered. The operative findings showed that an elastic hard tumor, 5 cm in diameter, was localized in S3 of the right lung and partially contacted the middle lobe. Right upper and middle lobe resection was performed with lymph node dissection. The postoperative diagnosis was pulmonary blastoma, well differentiated fetal lung (= WDFA). It is considered that the degree of the malignancy of WDFA is lower and the prognosis of WDFA is better than conventional pulmonary blastoma (= biphasic blastoma). There are not available treatments except for surgical resection. It is suggested that it necessary to collect as many cases as possible, to make definite classifications and to examine the clinical course and prognosis of pulmonary blastoma. PMID- 8683176 TI - [Graft replacement of a thoracic aneurysm and coronary artery bypass grafting using retrograde cerebral perfusion through left thoracotomy--a case report]. AB - A 67-year-old woman having descending thoracic aneurysm and 90% stenosis of the obtuse marginal artery underwent a concomitant operation of graft replacement of a thoracic aneurysm and coronary artery bypass grafting. The operation was performed through left posterolateral thoracotomy with total cardiopulmonary bypass using femoral artery, femoral vein and the pulmonary artery cannulation, deep hypothermia and retrograde cerebral perfusion (RGCP). RGCP was performed by high central venous pressure (17-18 mmHg) resulted from low flow perfusion of the lower body under clamping of the descending aorta. Distal coronary anastomosis was done during an initial 100ling period and proximal anastomosis was put on the replaced thoracic graft after coming off extracorporeal circulation (ECC). ECC time was 167 minutes, and RGCP time was 27 minutes. The patient did well after the operation. Postoperative coronary angiography showed the patent coronary bypass graft. We conclude that this method provides good exposure of the thoracic aorta and the coronary artery, and satisfactory brain protection. PMID- 8683177 TI - [Infarction exclusion technique for postinfarction ventricular septal defect]. AB - A new technique for post-infarction ventricular septal defect is accomplished by suturing a single patch to healthy endocardium excluding the infarcted area from the high left ventricular pressure. We have used this infarction exclusion technique for 3 cases since 1994. Three patients developed cardiogenic shock before operation and were managed initially with an intra-aortic balloon pump. All patients were urgently operated using this technique, at the same time, CABG operation was performed in 2 cases from the finding of preoperative coronary angiography. All of the patients survived. The first patient had a residual shunt (L-R; 30%), which spontaneously resolved in one month after the operation. In this method, a two-dimensional plane patch has to be sutured to healthy endocardium like a three-dimensional dome. Consequently the edge of the patch has wrinkles, which cause a residual shunt easily at the suture line. So from the second case, previously prepared circular conic patch, which had been made from a plane circular patch, was sutured to the left ventricular endocardium. At the suture line, this conic patch was well fitted to the endocardium, and the patients had no residual shunt. Though this method has the advantage to retain left ventricular function and volume, the technique must be improved to prevent residual shunt after operation. PMID- 8683178 TI - [A case of a univentricular heart developed subaortic stenosis after fontan operation]. AB - The patient was a seven-old-boy with univentricular heart of left ventricular morphology with transposition of the great arteries and coarctation of the Aorta. Pulmonary artery banding and coarctactomy (subclavian flap method) were performed as prior surgery during infancy and significant subaortic stenosis (SAS) was not identified before or immediately after Fontan operation. SAS was suspected in an ejection murmur that developed without symptoms two years and five months after Fontan operation. It became clear that the SAS was caused by both restrictive ventricular septal defect and narrowing of outlet chamber (right ventricle). Surgery was performed with myectomy in the outlet chamber, enlargement of ventricular septal defect and a patch enlargement of the right ventricle outflow tract for relief of the SAS. Postoperative pressure gradient across the subaortic component was decreased, however, valve regurgitation remained grade I to II. The mechanisms of SAS after Fontan operation are related to hypertrophy of the subaortic component that incorporates the infundibulum and trabeculae. Careful morphological investigation is essential in patients with risk factors for SAS Mild deterioration of the ventricular compliance due to progressive SAS may result in reduction of the cardiac function and patient's quality of life. Adequate surgical treatment to relieve the SAS is considered essential before and after Fontan operation. PMID- 8683179 TI - [Surgical treatment of esophageal cancer in four patients after gastrectomy for gastric cancer]. AB - The incidence of another cancer in subjects with esophageal cancer is high. Gastric cancer is the most common. We report surgical treatment for esophageal cancer in four patients who underwent gastrectomy for gastric cancer earlier. Extended lymphadenectomy of the neck, mediastinum, and abdomen was performed together with subtotal esophagectomy for three patients with thoracic esophageal cancer. In the two patients who had undergone subtotal gastrectomy and Billroth II reconstruction, the esophagus was reconstructed with part of the colon from the left side, perifused by the left colic artery. In a third patient, who had undergone total gastrectomy and jejunal interposition, reconstruction was done with part of the colon from the right side. In the remaining patient, who had cervical esophageal cancer and who had undergone total gastrectomy, cervical esophagectomy and total laryngectomy were done, followed by free jejunal interposition. One patient with thoracic esophageal cancer died of pulmonary metastasis of the esophageal cancer 24 months after surgery. The three other patients were not found to have recurrence in the most recent follow-up. Esophagectomy and reconstruction are more risky and complicated in patients who have already undergone gastrectomy for malignancy. However, in patients who have undergone curative surgery for gastric cancer, curative treatment for esophageal cancer such as esophagectomy together with extended lymphadenectomy is indicated. PMID- 8683180 TI - [Replacement of descending thoracic aorta using open proximal anastomosis under hypothermic circulatory arrest]. AB - Open proximal anastomosis under hypothermic circulatory arrest was applied to eleven consecutive patients with descending aortic diseases. These patients included five aortic dissections and six thoracic aortic aneurysms. Fourth and 7th intercostal spaces were opened by left posterolateral thoracotomy. Cardiopulmonary bypass was established by right atrial drainage via femoral vein and main pulmonary artery. Arterial blood was perfused via femoral artery. The descending aorta was opened under hypothermic circulatory arrest with anal temperature of 20 degrees C, and the anastomosis of the proximal site of the graft was performed with bloodless field. After the proximal anastomosis was finished, the main graft was clamped and perfused via the branch of the graft. The distal anastomosis was performed during circulatory arrest of the lower body. Mean circulatory arrest time of the upper body was 31 min, and that of the lower body was 37 min. Nine of the patients arrive without any major complications, but two of them died due to postoperative low cardiac output syndrome and postoperative pneumonia. Open proximal anastomosis under hypothermic circulatory arrest may be useful for the replacement of the diseased descending aorta due to dissection or aortic aneurysm with mural thrombi because of the advantage of non clamping anastomosis with bloodless surgical field. PMID- 8683181 TI - [A case report of Darling's classification Ib total anomalous pulmonary venous return with an unusual left pulmonary vein]. AB - A radical correction involving Vargas's method and a direct anastomosis between the left pulmonary vein (PV) and left atrium (LA) was performed in a 29 day-old infant with supracardiac type Ib total anomalous pulmonary venous return (TAPVR) and an unusual form of the left PV. the left upper and lower PVs drained into a left "common" PV that was just behind the LA, and then into the right pleural cavity. The left common PV was located cephalad to the normal course and received blood from the right lower and upper PVs and drained into the supra-vena cava (SVC). The junction of the SVC and the right PV was slightly stenotic. Vargas's method is a useful technique for Darling's classification Ib TAPVR even in cases without the common PV situated behind the LA. But this patient had a left common PV and it was possible either to anastomose the common PV and LA directly or to perform Vargas's technique. We performed both procedures to prevent left PV obstruction (PVO). Cineangiography performed 2 months after surgery showed that a large amount of blood from the right and left PV drained into the LA through the common PV-LA route. These procedures, which create a dual PV channel, reduce the risk of PVO, so they are useful for radical correction of Darling's Ib type TAPVR. PMID- 8683182 TI - 15th Joint meeting of the British Endocrine Societies. Dublin, 25-28 March 1996. Abstracts. PMID- 8683183 TI - Children's metamemory about the influence of conceptual relations on recall. AB - Developmental differences in children's metamemory about the influence of conceptual relations on free recall were examined. First, third, and fifth grade children memorized two lists of words, a two-category (items blocked by category) and an unrelated list. On both lists, four metamemory measures were obtained from each subject. These were estimates of recall performance, estimates of the cognitive effort associated with that recall performance, causal attributions about recall, and reports of strategy use. At each grade, subjects recalled more words on the related than the unrelated list and demonstrated reliable clustering at recall for the related words. Metamemory about the influence of conceptual relations was demonstrated at each grade level, but the nature of that metamemory changed with age. Even the youngest children realized that their recall performance would be superior on the related list but they did not understand how or why their recall was facilitated. With age, children attributed superior recall of the related material to the categorical relations in the stimuli, reported using categorical organization strategies, and demonstrated increasing awareness of the facilitative effects of conceptual relations on cognitive effort. Older children used their metamemory to direct their use of organizational strategies and to enhance recall on the related list. However, the four aspects of metamemory were not well coordinated at any grade level. The findings are discussed in terms of the importance of developing comprehensive, well-elaborated models of metamemory development. PMID- 8683184 TI - Kindergarten letter knowledge, phonological skills, and memory processes: relative effects on early literacy. AB - Kindergarten phonological awareness tasks are first compared as to their predictability of later literacy performance independent of letter knowledge for a group of German children. Results indicate that the phonological awareness tasks vary in their prediction of later literacy performance, which includes spelling and a variety of reading tasks in the first and second grades. A second concern was the relative influence of kindergarten phonological awareness compared with letter knowledge in the prediction of later literacy. The primacy of phonological awareness was demonstrated in predicting later literacy. However, evidence indicated that high letter knowledge in kindergarten may also reliably predict better later literacy skills. Results also suggest a developmental effect in the emergence of phonological processing skills in verbal memory between the ages of 4 and 8. Results of this study differ from those found in other (English speaking) populations most likely given differences in early literacy knowledge, age of beginning reading instruction, and differences in German and English orthography. PMID- 8683185 TI - The development of phonological rules and visual strategies in average and poor spellers. AB - To investigate the development of phonological and visual skills used in spelling, 420 children between the ages of 6 and 16 completed the spelling dictation test of the Wide Range Achievement Test-Revised. The misspellings were scored for phonological as well as visual accuracy using a constrained (inclusion of position cues) and an unconstrained system. Poor spellers made fewer phonologically accurate and fewer visual matches than age-matched average spellers. Poor spellers produced significantly more misspellings that were close visual matches to the target word and fewer phonologically unconstrained misspellings than spelling grade-matched average spellers. The groups did not differ in their production of phonologically constrained misspellings. Average spellers used a phonological approach more frequently than a visual approach, while the reverse pattern was true for poor spellers. When phonological rules are less well developed, then individuals are more likely to use orthographic skills. PMID- 8683186 TI - Age-related and intelligence-related differences in implicit memory: effects of generation on a word-fragment completion test. AB - In two experiments, subjects either read a bracketed word in a sentence or generated a word in response to its definition. A word-fragment completion test was then carried out. In Experiment 1, children's priming under the generate condition was substantial, as compared with baseline performance, but was significantly lower than that under the read condition, whereas there was no difference in adults' priming between these two conditions. Furthermore, prior generation induced an age-related increase in priming despite no age difference under the read condition. In Experiment 2, mentally retarded persons exhibited a profile similar to that of children. These results suggests that there are two different components in implicit memory, one that shows no developmental difference and heavily relies on perceptual processing and the other that shows an age-related or intelligence-related increase and heavily relies on conceptual processing. PMID- 8683187 TI - Children's performance on "animal tests" of oddity: implications for cognitive processes required for tests of oddity and delayed nonmatch to sample. AB - To investigate the ontogenesis of oddity learning, children (16 to 102 months of age) and adults were tested on two versions of the oddity task using non-verbal procedures originally developed for monkeys. On the standard, "one-part" or "simultaneous" oddity task (Experiment 1), young children (16 to 74 months of age) performed more poorly than older children (81-102 months of age) who were as proficient as adults. The delayed mastery of one-part oddity contrasts to mastery, at much younger ages (3 to 4 years of age) of a similar, but two-part task, delayed non-match to sample (DNMS) (Overman, 1990). In Experiment 2, those children from the first experiment who had difficulty in learning the one-part oddity task were tested on a two-part oddity task, and a subset of the subjects was retested on the one-part oddity task, and, finally, given verbal instructions for the one-part oddity task. The two-part oddity task was mastered significantly more rapidly than the previous one-part task; however, children's performance dropped significantly when tested on the one-part oddity task, and finally, children rapidly mastered the one-part oddity task when given verbal instructions. The data suggested that (a) children used different strategies to solve the different versions of the oddity task, (b) the solution for the two part-task appeared earlier in life than the solution for the one-part task and did not involve the use of the concept of "oddity relations", and (c) in tasks in which stimuli are shown twice, behavior may come under control of the absolute properties of the exemplar stimulus via a simple "win-shift" pattern of behavior. In contrast, in tasks in which all stimuli are presented simultaneously, behavior may be controlled by stimulus relations, the analysis of which has a protracted ontogenetic development. PMID- 8683188 TI - Induction of a memory retrieval strategy by young children. AB - This study examines children's modification of their own retrieval processes in a cued recall task. Each experiment had multiple study-test trails with triplets of categorically related words (Horse-Pig-Cow). Category-orienting questions were asked at acquisition, and each trial had different triplet stimuli. The last triplet word was the target, and the retrieval cues were the whole-context cue (Horse-Pig), a part context cue (Horse), or a noncontext associate (Goat). The measure of retrieval induction was recall increases across trials. Experiments 1 and 3 examined retrieval support for induction by 7- to 12-year olds by manipulating cue type. Experiments 2 and 4 manipulated acquisition variables that might effect retrieval induction. The results showed induction of an effective retrieval strategy in the situations of maximum retrieval support even by the 7 year olds, and developmental differences occurred in the situations where the retrieval cues provided few hints about the acquisition encoding operation. The results suggest that monitoring and modification of retrieval processes should be distinguished and that monitoring is necessary but not sufficient for induction of an effective retrieval strategy. The results have implications for understanding children's strategy-utilization deficiencies in memory tasks. PMID- 8683189 TI - Habituation of the orienting response to stimuli of different functional values in 4-month old infants. AB - In experiments on infant attention, the sudden presentation of a stimulus elicits an orienting response (OR). Its persisting presence then reinforces its visual exploration. When subsequently projected, this stimulus comes to signal the availability of something to look at. The aim of the present study was to sort out the effect of these three functional values of stimuli on OR elicitation. Fifty 4-month-old infants (M = 120 days) were randomly assigned to one of three experimental conditions. In Condition 1, they received 12 presentations of a 2-s visual stimulus. In Condition 2, the same 12 short stimuli presentations were accompanied by the projection of another event, visible after having the infant's gaze oriented toward the first stimulus. Condition 3 was a infant-control procedure: the same stimulus was repeatedly presented and remained on for as long as the infant looked at it. In each condition, half of the infants were shown a 4 x 4 checkerboard pattern, the others a 8 x 8 pattern. After this phase of repetitive presentation of one checkerboard pattern, the other was presented for two test trials, followed by two dishabituation trials with the initial first pattern. When the eliciting function of the stimulus (Condition 1) was isolated, orienting responses decreased over trials, and were of different latencies, according to stimulus complexity. On the other hand, the isolated function of the stimulus (Condition 2) raised its capacity to elicit ORs. Stimulus complexity was a determining factor in OR habituation, in attention recovery and in dishabituation for Conditions 1 and 3, but it was overshadowed by its signaling function in Condition 2. These results suggest the importance of taking into account the functional value of stimuli when analyzing infant attention. PMID- 8683190 TI - Intending to forget: the development of cognitive inhibition in directed forgetting. AB - The thesis of this research is that children's cognitive inhibition increases in efficiency with age over the middle childhood years, and this increasing efficiency contributes to developmental improvements in memory performance. To explore this thesis, the development of efficient retrieval inhibition, defined as the suppression of activation and retrieval paths to information stored in long-term memory, was investigated. In Experiment 1, first, third, and fifth graders and adults participated in a directed-forgetting experiment. Using a blocked-cuing procedure, subjects were given a "forget" or "remember" cue halfway through an unrelated free-recall list. At recall, subjects were asked either to remember all the words (even the ones they had been instructed to forget) or to remember only to-be-remembered words. The results suggested that the ability to intentionally inhibit the maintenance and recall of irrelevant information improves gradually over the elementary school years, but is not fully mature by fifth grade. Children were less able than adults to inhibit the to-be-forgotten words, and they were less able to withhold production of remembered to-be forgotten words than were adults. Experiment 2 replicated the development effects found in the first experiment and demonstrated that the developmental differences in performance were due to differences in mnemonic processing rather than differences in the ability to understand the instructions of the tasks. PMID- 8683191 TI - Vertical orienting control: evidence for attentional bias and "neglect" in the intact brain. AB - Unilateral neglect may be due to attentional bias: an exaggerated tendency to orient in an ipsilesional direction. Likewise, cases of vertical neglect suggest the existence of vertical attentional biases. This article reports evidence of upward biases in neurologically intact observers. In 5 experiments, observers performed a visual line-bisection task by judging the location of a gap along a tachistoscopically presented vertical line. The upward bias was influenced by attentional cues and was stronger in the right visual field than in the left visual field. Instructions designed to foster the use of an object-based, categorical encoding strategy were associated with an upward bias, whereas those fostering spatial, between-object comparisons were not. The results are discussed in terms of hemispheric differences in attention and specializations along the dorsal-ventral axis of the brain that influence directional orienting. PMID- 8683192 TI - The effects of divided attention on encoding and retrieval processes in human memory. AB - The authors examined the effects of divided attention (DA) at encoding and retrieval in free recall, cued recall, and recognition memory in 4 experiments. Lists of words or word pairs were presented auditorily and recalled orally; the secondary task was a visual continuous reaction-time (RT) task with manual responses. At encoding, DA was associated with large reductions in memory performance, but small increases in RT; trade-offs between memory and RT were under conscious control. In contrast, DA at retrieval resulted in small or no reductions in memory, but in comparatively larger increases in RT, especially in free recall. Memory performance was sensitive to changes in task emphasis at encoding but not at retrieval. The results are discussed in terms of controlled and automatic processes and speculatively linked to underlying neuropsychological mechanisms. PMID- 8683193 TI - Some problems with the process-dissociation approach to memory. AB - The process-dissociation framework (L. L. Jacoby, 1991) is a technique for deriving estimates of controlled (e.g., recollection) and automatic (e.g., familiarity) memory processes. The authors examined 3 assumptions of this framework. In Experiment 1, estimates of familiarity were affected by varying the proportion of old targets to old nontargets on the inclusion and exclusion tests and whether or not the tests were completed with full or divided attention, violating the assumption that familiarity's influence is automatic. In Experiment 2, the similarity of old targets and old nontargets was manipulated to show that source confusions (i.e., misrecollections) violate the assumption that the process of recollection is all-or-none. Source confusions also create an imbalance in the influence of recollection on the inclusion and exclusion tests, violating the consistency assumption. The source-monitoring framework is consistent with the present findings. PMID- 8683194 TI - Estimating unconscious processes: implications of a general class of models. AB - Jacoby and his colleagues (e.g., L. L. Jacoby, J. P. Toth, & A. P. Yonelinas, 1993) have shown how the mnemonic contributions of conscious recollection and unconscious familiarity can be separated using a process-dissociation procedure based on a comparison of tasks in which consciously recollected material is to be included in vs. excluded from the responses. However, the estimate of unconscious familiarity depends on the assumptions of the model. This article describes a more general class of models in which the ratio of overlap between conscious and unconscious processes remains fixed and shows that this class of models (which includes the redundancy and exclusivity models as extreme cases) yields improbable results. PMID- 8683195 TI - Differential expression in human cells from the p6 promoter of human parvovirus B19 following plasmid transfection and recombinant adeno-associated virus 2 (AAV) infection: human megakaryocytic leukaemia cells are non-permissive for AAV infection. AB - Expression from the human parvovirus B19p6 promoter fused to the firefly luciferase ('Luc') reporter gene was evaluated in a non-erythroid human nasopharyngeal carcinoma cell line, KB, and a human megakaryocytic leukaemia cell line, MB-02, known to become permissive for B19 replication following erythroid differentiation. The B19p6-Luc construct was introduced into KB and MB-02 cells, both in undifferentiated and differentiated states, either via DNA-mediated transfection, or via infection with recombinant adeno-associated virus 2 (AAV), a non-pathogenic human parvovirus known to possess a broad host-range. Although Luc activity was readily detected in KB cells following transfection of the B19p6-Luc plasmid DNA, no expression from the B19p6 promoter was observed following infection with recombinant virus. In addition, transfection of the reporter plasmid resulted in high-level expression of Luc in differentiated but not in undifferentiated MB-02 cells. However, no Luc activity was detected, even in differentiated MB-02 cells, following infection with recombinant virus. Further studies with an additional recombinant as well as wild-type (wt) AAV revealed that MB-02 cells were non-permissive for AAV infection. A second human megakaryocytic leukaemia cell line, M07e, was likewise resistant to infection by recombinant as well as wt AAV. Taken together, these studies identify the first human cell type that cannot be infected by AAV. They indicate that expression from the B19p6 promoter, in the context of an AAV genome, is restricted to primary human haematopoietic cells, perhaps because parvoviral DNA replication and transcription are intrinsically coupled. PMID- 8683196 TI - Translational stop codons in the precore sequence of hepatitis B virus pre-C RNA allow translation reinitiation at downstream AUGs. AB - Hepatitis B virus (HBV) wild-type pre-C RNA directs the synthesis of the HBeAg precursor but does not serve as mRNA for translation of the adjacent downstream C gene which encodes the core protein. Using bicistronic mRNA constructs that mimick pre-C RNA, we have demonstrated that this RNA likewise does not serve as messenger for translation of the P gene, which is located downstream of the C gene. However, when the pre-C RNA contains a translational stop codon at position 2 or 28 of the pre-C sequence (as in certain HBV mutants), it no longer directs synthesis of the HBeAg precursor but instead translation is initiated at downstream C and P gene AUGs. We propose that this occurs by a translation reinitiation mechanism. PMID- 8683197 TI - Novel pre-C/C gene mutants of hepatitis B virus in chronic active hepatitis: naturally occurring escape mutants. AB - We have analysed serum samples taken from hepatitis B virus (HBV) e antigen (HBeAg)-positive and HBeAg-negative chronic active hepatitis (CAH) patients by PCR using primers spanning the pre-core/core (C) and pre-S1/S2 ORFs. Nucleotide sequence analysis showed that among 18 HBV-infected CAH patients, 11 had virus with a G to A mutation (nucleotide 1896; leading to the formation of a stop codon) and one patient also had virus with an additional G to A mutation three nucleotides downstream (nucleotide 1899). HBV from three patients that were HBeAg negative showed a 1 bp deletion at nucleotide 1937, causing pre-termination of the C gene. Mutation frequencies in the sequences identified as coding for cytotoxic T lymphocyte epitopes, B cell epitopes, CD4+ helper T cell epitopes and arginine-rich regions of the HBV C peptide were investigated. Mutations were more frequently identified in these regions, suggesting that the mutations might have been selected as a result of immune responses. PMID- 8683198 TI - Human papillomavirus type 16 in infants: use of DNA sequence analyses to determine the source of infection. AB - Perinatal transmission of human papillomavirus type 16 (HPV-16) and persistence of virus DNA in infants until 6 months of age has been described. To confirm the origin of infant infections as maternal, we determined the nucleotide sequence of the upstream regulatory region (URR; bp 7540 to 157) of HPV-16 in samples from 13 HPV-16 DNA-positive mothers and their infants at 6 weeks and 2 years of age. Identical HPV-16 variant URR sequences were found in two mother/infant samples and similar variants were found in three sets. Four mothers with samples which contained prototypic HPV-16 sequences delivered infants who also had the prototypic sequence. Four mothers with variant URRs delivered infants who harboured either prototypic or different URR variants. Thus, concordant variants or prototypic sequences were detected in nine of 13 mother/infant samples, indicating that up to 69.2% of HPV-16-positive infants acquire virus from their mothers. PMID- 8683199 TI - Coincidental expression of E5a and c-jun in human papillomavirus type 6/11 infected condylomata. AB - Previously, we have shown that E5a can induce expression of the c-jun gene in human papillomavirus (HPV)-11 E5a transformed NIH 3T3 cells and human epidermal keratinocytes. In this study, we investigated the relationship between expression of the E5a gene and c-jun in pathologically confirmed condylomata specimens using mRNA hybridization in situ. The c-jun RNA concentration was significantly higher in condylomata specimens with E5a mRNA expression than in specimens without E5a mRNA expression, or in normal cervical specimens. The cells with c-jun expression were located predominantly in the basal and parabasal cell layers. These layers were also the primary location of E5a-expressing cells. This is the first demonstration of a strong correlation (74%) between expression of the E5a and c jun genes in condylomata specimens. This correlation might reflect regulation by HPV-11 E5a of c-jun gene expression in condyloma. PMID- 8683200 TI - Human cytomegalovirus pp65 lower matrix phosphoprotein harbours two transplantable nuclear localization signals. AB - Human cytomegalovirus phosphoprotein pp65 is targeted to the cell nucleus immediately after infection. Deletion and point mutation analysis of the pp65 gene expressed in insect cells showed that two hydrophilic regions (HP1 and HP2) within the pp65 C-terminal 40% each harboured an independent nuclear localization signal (NLS); strong association to the nuclear stroma also requires the N terminal domain. Either region, when fused to chloramphenicol acetyltransferase, localized the reporter protein to the nucleus in insect cells as well as in NIH 3T3 cells and human lung fibroblasts. In addition, HP1 was found to be the target of pp65 Ser/Thr phosphorylation in insect cells and a prokaryotically expressed HP1 was actively phosphorylated in vitro by casein kinase II, for which two site clusters map in HP1. These findings indicate that pp65 includes two NLSs, one of which has the potential to be modulated by phosphorylation. PMID- 8683201 TI - B cell-specific activation of the Epstein-Barr virus-encoded C promoter compared with the wide-range activation of the W promoter. AB - We have studied the activity of reporter plasmids, carrying the Epstein-Barr virus (EBV) nuclear antigen (EBNA) promoters Wp and Cp, in a group of somatic cell hybrids obtained by fusing EBV-positive lymphoblastoid cell lines or group II/III Burkitt's lymphoma cell lines with non-B cell lines. In B/non-B cell hybrids of this type, B cell markers are extinguished as a rule, in parallel with the inactivation of Cp or Wp and down-regulation of EBNA-2-6 expression. A Wp carrying reporter construct was active in non-B cell lines. Only cells with a B cell phenotype could support the activity of Cp-carrying plasmids. EBNA-2 transactivated Cp only in B cells. Our data suggest that while Wp can be used for EBNA transcription in B and non-B cells, Cp activity is restricted to B cells. The inability of EBNA-2 to transactivate Cp in non-B cells indicates that other factors present in B cells might be involved in Cp transactivation. PMID- 8683202 TI - Transcriptional analysis of the Epstein-Barr virus interleukin-10 homologue during the lytic cycle. AB - The Epstein-Barr virus (EBV) open reading frame (ORF) BCRF1, expressed in the late phase of the viral cycle, encodes a homologue of human interleukin-10 (hIL 10). Unspliced, 3' co-terminal transcripts of 0.8 and 1.6 kb from O tetradecanoylphorbol 13-acetate (TPA)-treated B95-8 cells have been described but other results indicated the existence of uncharacterized transcript(s) initiated upstream of the 1.6 kb BCRF1 mRNA. Here we describe two additional large transcripts of the BCRF1 ORF, a possibly spliced product of 3.5 kb and an unspliced product of 4.5 kb. The time course of the expression of BCRF1 transcripts and of the secreted protein from Akata cells were also determined. PMID- 8683203 TI - Transmission of donor Epstein-Barr virus (EBV) in transplanted organs causes lymphoproliferative disease in EBV-seronegative recipients. AB - Epstein-Barr virus (EBV) is associated with post-transplant lymphoproliferative disease (PTLD). To determine whether the donor EBV isolate is transmitted to the recipient via the allograft and causes PTLD, EBV isolates from four cases of PTLD in cadaveric heart and/or lung transplant recipients were compared with the donor isolates by PCR and DNA sequence analysis. Two recipients who were EBV seronegative at transplantation acquired an EBV isolate indistinguishable from that of the donor and developed PTLD. In contrast, in two patients who were seropositive before transplantation, the donor isolate differed from that present in PTLD of the recipient. The results suggest that the acquisition of donor EBV is a risk factor for PTLD development in a previously seronegative transplant recipient. PMID- 8683204 TI - Persistent Epstein-Barr virus infection in the common marmoset (Callithrix jacchus). AB - Epstein-Barr virus (EBV) infection of the common marmoset causes long-term infection, with production of antibodies to virus-induced antigens, without clinical illness. Attempts to show the presence of EBV DNA in saliva of infected animals by PCR were initially unsuccessful, although slot-blot hybridization analysis demonstrated that viral DNA was present. Further investigations showed that most samples of pilocarpine-induced saliva, and 33% of the samples of whole mouth fluids (WMF) tested, were inhibitory to PCR. Similar results were found using human WMF. A method of assessing samples of marmoset WMF for the presence of EBV, by PCR using an EBV BamHI W probe, and removing inhibition with Chelex 100, is described. A total of 202 samples from 21 EBV infected, and seven non infected animals was tested. Five seropositive animals shed virus on every occasion, and 15 intermittently. Two marmosets, infected as neonates, showed progressively increasing humoral responses to viral antigens, and shed virus on every occasion tested over 3 years. When mated with uninfected animals, the latter seroconverted 4 and 6 weeks later, respectively, and later shed virus into their WMF. The naturally infected animals were paired with naive marmosets, and were able to pass on infection. These results establish that long-term, permissive EBV infection occurs in the common marmoset, and demonstrate again the similarities in the response to EBV between marmoset and man. PMID- 8683205 TI - A retrovirus isolated from cell lines derived from neurofibromas in bicolor damselfish (Pomacentrus partitus). AB - Damselfish neurofibromatosis (DNF) is a naturally occurring, neoplastic disease affecting bicolor damselfish (Pomacentrus partitus) living on coral reefs in southern Florida, USA. The disease consists of multiple neurofibromas, neurofibrosarcomas and chromatophoromas and has been proposed as an animal model for neurofibromatosis type 1 in humans. DNF is transmissible by injection of crude tumour homogenates, cell-free filtrates of homogenates or cells from tumour cell lines. An analysis of tumorigenic cell lines derived from fish with spontaneous or experimentally induced DNF revealed virus particles budding from cells and present in conditioned media. The 90-110 nm particles resembled type C retroviruses. This virus exhibited a buoyant density of 1.14-1.17 g/cm2 in sucrose, at least six virus proteins of 15 to 80 kDa and reverse transcriptase (RT) activity. RT activity was maximized with a poly(rC).oligo(dG) template.primer combination and Mn2+ at a concentration of 0.5-1.0 mM. The optimum temperature for RT was determined to be 20 degrees C, a finding consistent with the ambient temperatures encountered by this species. This retrovirus, tentatively named damselfish neurofibromatosis virus (DNFV) may be the aetiological agent of DNF. Whether DNFV or another, as yet unidentified, virus is the cause of DNF, this agent may be unique in virus oncogenesis; neoplastic transformation of the cell types involved in DNF, Schwann cells and chromatophores, has not been documented in any other transmissible tumour. PMID- 8683206 TI - Influence of the transduced 3'UTR of the c-src oncogene on tumour growth induced by the v-src gene of avian sarcoma virus PR2257. AB - Avian sarcoma virus PR2257 contains 952 bp transduced from the left part of the 3'UTR of the chicken c-src oncogene. Deletion mutants were constructed to determine the effect of the 3'UTR on tumorigenicity in vivo and in vitro. In the presence of the 3'UTR, tumours were 3.4 times larger in vivo, and tumorigenicity was increased 2.5-fold in vitro. Several regulatory submotifs were also found within the 3'UTR. Parts of the 3'UTR were cloned into the LTR CAT plasmid and analysed for CAT expression. A 170 bp element was found to be responsible for the enhanced expression of the CAT gene. These results demonstrate the effect of the transduced 3'UTR sequence during long-term interaction between PR2257 virus and the chicken genome, and suggest a novel regulatory mechanism of the src oncogene. PMID- 8683207 TI - Complete nucleotide sequence of the Italian human T-cell lymphotropic virus type II isolate Gu and phylogenetic identification of a possible origin of South European epidemics. AB - The complete nucleotide sequence of a human T-cell lymphotropic virus type II isolate (HTLV-II-Gu) from an Italian injecting drug user was obtained, representing the first entire sequence of a European HTLV-II isolate. The HTLV-II Gu genome was more similar to the HTLV-IIb-NRA isolate (98.4%) and HTLV-IIb-G12 (98.2%) than to HTLV-IIa-Mo (95.2%). The classification of HTLV-II-Gu as subtype IIb was confirmed by restriction analysis. Just as for HTLV-IIa strain Mo, HTLV IIb-Gu cultured lymphocytes produce two additional mRNAs generated through alternative splicing in the pX region. A phylogenetic analysis was performed by using the methods of neighbour-joining and parsimony with bootstrapping, and maximum likelihood. The different gene regions were analysed separately, comparing Gu with all other HTLV-II strains presently available. In the LTR, as well as in other genome regions, a clear separation between IIa and IIb was evident, and within the IIb subtype three clusters were present of which two were well supported; one contained exclusively Amerindian strains and the other included all Italian and Spanish strains together with two strains obtained from New York drug users. All data clearly showed that HTLV-IIa and IIb subtypes are closely related and are equidistant from HTLV-I, suggesting that both groups evolved simultaneously. The results suggest that HTLV-II-Gu and other IIb South European isolates were probably derived from North American IIb isolates. The data also indicate that sequence analysis is necessary to further classify IIa and IIb subtypes. PMID- 8683208 TI - Evidence for the multimeric nature and cell binding ability of avian reovirus sigma 3 protein. AB - It has been suggested that avian reovirus sigma 3 protein is analogous to sigma 1 trimer, the mammalian reovirus attachment protein. We have investigated the multimeric nature and cell binding ability of sigma 3 protein. The data presented here demonstrate that sigma 3 protein is a multimer in its undisrupted form as determined by SDS-PAGE in non-dissociating conditions. However, virion-associated sigma 3 protein and COS-7 cell-expressed protein behaved differently in SDS-PAGE, suggesting a need for virus-associated factor(s) to control the multimerization of the protein. The data also show that Escherichia coli expressed sigma 3 fusion protein (sigma 3-MBP) in its multimeric form is capable of attaching to Vero cells. The binding was found to be specific and receptor mediated by the fact that it was inhibited by a monoclonal antibody specific for sigma 3 protein and by competition with avian reovirus particles. As determined by a reverse experiment, sigma 3-MBP was also able to reduce the virus p.f.u. in monolayer cell cultures, indicating the important role of sigma 3 protein in the initiation of virus infection. PMID- 8683209 TI - Full protection against African horsesickness (AHS) in horses induced by baculovirus-derived AHS virus serotype 4 VP2, VP5 and VP7. AB - African horsesickness virus serotype 4 (AHSV-4) outer capsid protein VP2, or VP2 and VP5 plus inner capsid protein VP7, derived from single or dual recombinant baculovirus expression vectors were used in different combinations to immunize horses. When the proteins were purified by affinity chromatography, the combination of all three proteins induced low levels of neutralizing antibodies and conferred protection against virulent virus challenge. However, purified VP2 or VP2 and VP5 in the absence of VP7 failed to induce neutralizing antibodies and protection. Immunization with non-purified proteins enhanced the titres of neutralizing antibodies. Again, the combination of the three proteins was able to confer total protection to immunized horses, which showed absence of viraemia. The antigenicity of recombinant VP2 was analysed with a collection of 30 MAbs. Both purified and unpurified recombinant VP2 proteins showed different antigenic patterns in comparison to that of VP2 on virions. An immunization experiment with four more horses confirmed these results. The vaccine described here would not only prevent the disease, but would drastically reduce the propagation of the virus by vectors. PMID- 8683211 TI - Susceptibility of chicken lymphoid cells to infectious bursal disease virus does not correlate with the presence of specific binding sites. AB - Pathogenic serotype 1 strains of infectious bursal disease virus (IBDV) replicate efficiently in lymphoid cells of the bursa of Fabricius of chicken. Lymphoid cells in other organs are not susceptible. Apathogenic serotype 2 strains do not replicate in lymphoid bursa cells or in other lymphoid cells. Chicken embryo fibroblasts (CEF), however, efficiently replicate strains of either serotype. Binding studies showed that strains of both IBDV serotypes bind to lymphoid cells isolated from the bursa, thymus or spleen, indicating that restriction of IBDV replication to lymphoid B cells is not determined by the presence of specific receptor sites. The specificity of binding was demonstrated by saturation and competition experiments. These revealed the presence of different receptors: CEF had receptors common to both serotypes and specific ones for each serotype. Receptor sites common to both serotypes were also present on lymphoid cells; however, additional serotype-specific sites were only demonstrated for the apathogenic serotype 2 strain. Strains of both serotypes specifically bound to proteins with molecular masses of 40 kDa and 46 kDa, exposed on the surface of CEF and lymphoid cells. Competition experiments indicated that these proteins might represent the common receptor sites of IBDV. PMID- 8683210 TI - Multiple-gene rotavirus reassortants responsible for an outbreak of gastroenteritis in central and northern Australia. AB - Two rotavirus strains, E210 and E212, implicated in epidemics of gastroenteritis in children in central and northern Australia during 1993-1994, exhibited the unusual combination of a 'short' RNA electrophoretic pattern and subgroup II specificity. The outer capsid protein VP7 was found by PCR typing and sequence analysis to be related to that of serotype G2 viruses. Both strains displayed a novel pattern of reactivity to G2-specific monoclonal antibodies that correlated with sequence variation in the antigenic regions of VP7. The VP4 serotype of E210 and E212 was determined as P1B in an enzyme immunoassay, consistent with other G2 viruses. Analysis of the VP6 gene indicated significant identity (98-99%) with other human subgroup II viruses. Northern hybridization analysis of E210 RNA using total genome probes derived from the prototype strains RV4 and RV5 indicated that E210 was derived from multiple gene reassortment between rotaviruses belonging to different genetic types. PMID- 8683212 TI - Mutant forms of the F protein of human respiratory syncytial (RS) virus induce a cytotoxic T lymphocyte response but not a neutralizing antibody response and only transient resistance to RS virus infection. AB - Vaccinia virus (vv) recombinants expressing either wild-type (VA-F) or mutant forms (VA-FT, VA-FR47, VA-FS1 to VA-FS6) of the fusion (F) protein of respiratory syncytial (RS) virus were examined for their ability to elicit antibody, cytotoxic T lymphocytes (CTL) and protection against RS virus infection in BALB/c mice. Cells infected with the VA-F and VA-FT recombinants expressed the F protein on their surface and mice vaccinated with these recombinants developed RS virus neutralizing antibodies. The VA-FR47 recombinant expressed a mutant form of the F protein (with six amino acid changes from the wild-type) in which both proteolytic processing of the F0 precursor and its transport to the cell surface were inhibited. These mutants induced transient protection against RS virus infection although they did not induce RS virus neutralizing antibodies, or antibodies detectable by ELISA. All the vv recombinants were able to induce an RS virus-specific, MHC class I restricted CTL response. Vaccination of mice with a second set of vv recombinants expressing mutant forms of the F protein showed that the replacement Phe to Ser at amino acid 237 either alone or in combination with others abolished the neutralizing antibody response but did not affect priming of CTLs. These results demonstrate that long-term protection against RS virus infection in mice vaccinated with recombinant vv expressing the F protein is more dependent upon the induction of an antibody rather than a CTL response. PMID- 8683213 TI - Proposed three-dimensional model for the attachment protein G of respiratory syncytial virus. AB - Protein G of respiratory syncytial virus (RSV) is an envelope glycoprotein that is structurally very different from its counterparts (haemagglutinin neuraminidase and haemagglutinin) in other paramyxoviruses. In this study, we put forward a model for this unique viral envelope protein. We propose that protein G of RSV contains several independently folding regions, with the ectodomain consisting of a conserved central hydrophobic region located between two polymeric mucin-like regions. The central conserved region is probably the only relatively fixed and folded part of the ectodomain of RSV-G. This central conserved region contains four conserved cysteine residues which can form two disulphide bridges. Analysis of the proteolytic digestion products of a peptide corresponding to the central conserved region showed that one of the three theoretically possible combinations of disulphide connections could be eliminated. The final disulphide bridge assignment was established by affinity measurements with peptide variants in which different disulphide connections were formed. Additionally, peptide binding studies were used to map the binding site, at the amino acid level, of a monoclonal antibody directed against the central conserved region. These studies indicated the level of surface exposure of the amino acid side-chains. The surface exposure agreed with the structural model. The proteolytic digestion, the peptide binding studies and the affinity measurements with structural peptide variants support a structural model with disulphide connections that correspond to a structural motif called a cystine noose. This model provides a structural explanation for the location and molecular details of important antigenic sites. PMID- 8683214 TI - Identification of the non-virion (NV) protein of fish rhabdoviruses viral haemorrhagic septicaemia virus and infectious haematopoietic necrosis virus. AB - Sequence analysis of a 795 nucleotide region of the fish rhabdovirus viral haemorrhagic septicaemia virus (VHSV) genome revealed one complete and one partial ORF of 369 and 153 nucleotides, respectively. The latter ORF probably encodes the amino-terminal part of the L (polymerase) protein. The former ORF potentially encodes a 122 amino acid protein. The location of this ORF as well as the size and deduced structure of the translation product indicate that it represents a homologue of the non-virion (NV) protein of the related infectious haematopoietic necrosis virus (IHNV). Antisera raised against prokaryotically expressed NV protein of VHSV and IHNV were used to detect NV expression in VHSV- and IHNV-infected cells by Western Blot and immunofluorescence analyses. We present here the sequence of the VHSV NV gene and demonstrate the presence of IHNV and VHSV NV proteins in virus-infected cells. PMID- 8683215 TI - A nested set of six or seven subgenomic mRNAs is formed in cells infected with different isolates of porcine reproductive and respiratory syndrome virus. AB - The subgenomic mRNAs (sg mRNA) of porcine reproductive and respiratory syndrome virus (PRRSV) were characterized. The number of sg mRNAs, which form a 3' coterminal nested set in PRRSV-infected cells, varied from six to seven among PRRSV isolates with differing virulence. The additional species of sg mRNA in some isolates of PRRSV was designated as sg mRNA 3-1. The leader-mRNA junction sequences of sg mRNAs 3, 3-1 and 4 were found to contain a similar six nucleotide sequence motif, U(G)UA(G/C)ACC. By comparing the 5'-terminal sequence of sg mRNA 3-1 with the genomic sequence of two isolates, ISU79 and ISU1894, it was found that a point mutation, from U in isolate ISU1894 to C in isolate ISU79, led to the acquisition of a new leader-mRNA junction sequence (UUGACC) in isolate ISU79, and therefore an additional species of sg mRNA 3-1. A small ORF (3-1) was identified at the 5' end of sg mRNA 3-1. PMID- 8683216 TI - Genetic variation in porcine reproductive and respiratory syndrome virus isolates in the midwestern United States. AB - The nucleotide sequence of a 3266 bp region encompassing open reading frames (ORFs) 2 through 7 of the porcine reproductive and respiratory syndrome virus (PRRSV) was determined for 10 isolates recovered from the midwestern United States. Pairwise comparisons showed that genetic distances between isolates ranged from 2.5% to 7.9% (mean 5.8% +/- 0.2%) whereas the Lelystad strain from Europe was, on average, 34.8% divergent from US clones. Thus, US and European PRRSV isolates represent genetically distinct clusters of the same virus. ORF 5, which encodes the envelope glycoprotein, was the most polymorphic [total nucleotide diversity (pi) = 0.097 +/- 0.007] and ORF 6, encoding the viral M protein, was the most conserved (pi = 0.038 +/- 0.003). The substantial differences in nucleotide diversity among ORFs suggests that the virus is evolving by processes other than simple accumulation of random neutral mutations. In support of this hypothesis, statistical analyses of the nucleotide sequence provided strong evidence for intragenic recombination or gene conversion in ORFs 2, 3, 4, 5 and 7, but not in ORF 6. An excess of synonymous (silent) substitutions was observed in all six ORFs, indicating an evolutionary pressure to conserve amino acid sequences. Taken together, the data indicate that despite intragenic recombination among extant PRRSV isolates, purifying selection has acted to maintain the primary structure of individual ORFs. PMID- 8683217 TI - Replication of yellow fever virus in the mouse central nervous system: comparison of neuroadapted and non-neuroadapted virus and partial sequence analysis of the neuroadapted strain. AB - Serial passage of yellow fever virus (YF17D) in mouse brain enhances neurovirulence, causing a reduction in survival time after intracerebral inoculation of adult mice. To study the biological and genetic basis for this phenomenon, we compared neurovirulence properties of the neuroadapted Porterfield strain (PYF) to a YF17D strain generated from a full-length YF cDNA template (YF5.2iv). Adult mice were infected by olfactory bulb inoculation, which results in widespread distribution of virus throughout the central nervous system. Although PYF and YF5.2iv spread rapidly throughout the neuraxis, maximal titres of PYF in the brain and spinal cord were 1000- to 10,000-fold higher than those of YF5.2iv. Paralysis and death occurred earlier with the PYF strain. Several cDNA clones of the E/NS1 region of the PYF strain were sequenced. Three predicted amino acid changes were consistently observed in the envelope protein of the PYF strain compared to YF5.2iv. Common substitutions were also identified in NS1 and NS2A. The potential contribution of these genetic differences to neurovirulence was evaluated by generating recombinant, intertypic PYF/YF5.2iv viruses. Physical signs of disease and mean spinal cord titres after inoculation of one recombinant were not different from the YF5.2iv parent. Our data indicate that PYF and YF5.2iv differ significantly in their virulence properties, however, common amino acid substitutions in the E/NS1 region of the PYF strain do not determine its enhanced neurovirulence. Other regions of the viral genome may contribute dominant effects on the virulence properties of the PYF strain. PMID- 8683218 TI - Protective immune responses to the E and NS1 proteins of Murray Valley encephalitis virus in hybrids of flavivirus-resistant mice. AB - The lack of an effective animal model has been a major obstacle in attempts to define the role of humoral and cellular immune responses in protection against flavivirus infection. We have used F1 hybrid mice (BALB/c x C3H/RV) that are heterozygous for the flavivirus resistance allele F1vr and show reduced virus replication in the brain after intracerebral inoculation. F1 hybrid mice challenged by intracerebral inoculation with Murray Valley encephalitis (MVE) virus developed encephalitis 2-3 days later than a genetically susceptible strain (BALB/c) but showed a similar mortality rate. This delay in the onset of disease provided more opportunity for virus clearance by primed immune responses. Using F1 hybrid mice we were able to demonstrate protective immunity induced by structural and non-structural proteins of MVE virus by immunization with pure NS1 protein or recombinant vaccinia viruses that expressed various regions of the MVE genome. These constructs included VV-STR (C-prM-E-NS1-NS2A), VV-delta C (prM-E Ns1-NS2A) and VV-NS1 (NS1-NS2A). VV-delta C vaccinated mice were completely protected (100% survival)from challenge with 1000 infectious units of MVE virus, while mice inoculated with VV-STR, VV-NS1 or pure NS1 were partially protected (40%, 47% and 85% respectively). Analysis of prechallenge sera and in vivo depletion studies revealed that the solid protection induced by VV-delta C was mediated by neutralizing antibody to the E protein and did not require a CD8+ T cell response. The partial protection provided by VV-STR, VV-NS1 and pure NS1 occurred after induction of antibody to NS1. However, depletion of CD8+ cells prior to virus challenge ablated the protection provided by VV-NS1 indicating some requirement for class I restricted cytotoxic T cells. PMID- 8683219 TI - Swine and ruminant pestiviruses require the same cellular factor to enter bovine cells. AB - Pestiviruses initiate infection of susceptible cells by receptor-mediated endocytosis. Cellular plasma membrane or endosomal molecules involved in translocation of these viruses into the cytosol have not been unequivocally identified. We reported previously that a mutant cell line derived from Madin Darby bovine kidney (MDBK) cells, termed CRIB-1, was resistant to infection with bovine viral diarrhoea virus. CRIB-1 cells were also resistant to infection with classical swine fever virus and border disease virus of sheep, suggesting that entry of these three different pestiviruses into bovine cells requires a common cell membrane function. The resistance is pestivirus-specific: CRIB-1 cells were as susceptible as the parental MDBK cells to 14 other viruses of cattle and swine belonging to unrelated families. The resistance of CRIB-1 cells to pestivirus infection involves a block in virus entry since transfection of virus RNA or virus inoculation in the presence of PEG resulted in productive infection. Furthermore, quantitative analyses of the outcome of PEG-mediated infection of CRIB-1 cells indicated that the intracellular milieu was fully permissive for pestivirus replication. Binding studies revealed that virus attachment to CRIB-1 cells was not completely abrogated. These results indicate that entry of pestiviruses into MDBK cells depends on a common plasma membrane or endosomal function, which is lacking in CRIB-1 cells. PMID- 8683220 TI - Three new cytotoxic T cell epitopes identified within the hepatitis C virus nucleoprotein. AB - Cytotoxic T lymphocytes (CTLs) may play a role in host defence against hepatitis C virus (HCV) infection, and HCV-specific CTL epitopes may be included in vaccines to induce protective CTLs. We identified three new epitopes within the HCV nucleoprotein recognized by CTLs. HCV nucleoprotein residues 28-37 are the minimal epitope recognized by CTLs in association with the class I human leukocyte antigen B60, and epitopes in HCV nucleoprotein residues 111-130 and 161 180 are both recognized by CTLs in association with the class II human leukocyte antigen DRBI*08032. PMID- 8683221 TI - Classical swine fever virus diversity and evolution. AB - By analysing the nucleotide sequence data generated from both the E2 (gp55) and the NS5B genes of classical swine fever virus (CSFV), in addition to previously published data from the 5'NCR, we were able to divide 115 CSFV isolates into two major groups, five subgroups and two disparate isolates. Further discrimination was possible by analysis of sequence data from the E2 region. The three sequencing based methods were compared to monoclonal antibody (MAb) typing and to limited restriction enzyme (RE) mapping. Although both MAb and RE methods confirmed the previous classification the resolution was inferior. We estimated an approximate evolution rate for CSFV from an analysis of the virus variation observed in a single geographical area over a 6 year period. Applying this proposed rate to each of our deduced CSFV subgroups enabled us to calculate the approximate dates of divergence for each subgroup. PMID- 8683222 TI - The translation-enhancing region of the Semliki Forest virus subgenome is only functional in the virus-infected cell. PMID- 8683224 TI - 11th meeting of the European Society for Neurochemistry. Groningen, The Netherlands, June 15-20, 1996. Abstract. PMID- 8683223 TI - Biological and molecular properties of a pathotype P-1 and a pathotype P-4 isolate of pea seed-borne mosaic virus. AB - Two isolates of pea seed-borne mosaic potyvirus, DPD1 and NY, were identified as pathotypes P-1 and P-4, respectively, by their infectivity on Pisum sativum L. lines homozygous for the recessive resistance genes sbm-1 and sbm-4. The two isolates differed in several biological characteristics. DPD1 induced transient vein clearing, downward rolling of leaflets and internode shortening on P. sativum, whereas NY only caused a slight growth reduction. DPD1 moved systemically in Chenopodium quinoa whereas NY was restricted to inoculated leaves. DPD1 was frequently transmitted by seeds whereas NY was rarely seed transmitted: 24% and 0.3%, respectively, in P. sativum '549'. Both DPD1 and NY were transmitted by aphids (Myzus persicae), though a DAG triplet was not present in the N terminus of the coat protein. The nucleotide sequence and deduced amino acid sequence of NY were determined and compared to the corresponding sequences of DPD1. PMID- 8683225 TI - International Clinical Epidemiology Network. INCLEN XIIIth Global Meeting. Victoria Falls, Zimbabwe. 1996. Abstracts. PMID- 8683226 TI - Cyclophosphamide, methotrexate, and fluorouracil: still the gold standard? PMID- 8683227 TI - Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma. AB - PURPOSE: The CD20 B-lymphocyte surface antigen expressed by B-cell lymphomas is an attractive target for radioimmunotherapy, treatment using radiolabeled antibodies. We conducted a phase I dose-escalation trial to assess the toxicity, tumor targeting, and efficacy of nonmyeloablative doses of an anti-CD20 monoclonal antibody (anti-B1) labeled with iodine-131 (131I) in 34 patients with B-cell lymphoma who had failed chemotherapy. PATIENTS AND METHODS: Patients were first given tracelabeled doses of 131I-labeled anti-B1 (15 to 20 mg, 5 mCi) to assess radiolabeled antibody biodistribution, and then a radioimmunotherapeutic dose (15 to 20 mg) labeled with a quantity of 131I that would deliver a specified centigray dose of whole-body radiation predicted by the tracer dose. Whole-body radiation doses were escalated from 25 to 85 cGy in sequential groups of patients in 10-cGy increments. To evaluate if radiolabeled antibody biodistribution could be optimized, initial patients were given one or two additional tracer doses on successive weeks, each dose preceded by an infusion of 135 mg of unlabeled anti B1 one week and 685 mg the next. The unlabeled antibody dose resulting in the most optimal tracer biodistribution was also given before the radioimmunotherapeutic dose. Later patients were given a single tracer dose and radioimmunotherapeutic dose preceded by infusion of 685 mg of unlabeled anti-B1. RESULTS: Treatment was well tolerated. Hematologic toxicity was dose-limiting, and 75 cGy was established as the maximally tolerated whole-body radiation dose. Twenty-eight patients received radioimmunotherapeutic doses of 34 to 161 mCi, resulting in complete remission in 14 patients and a partial response in eight. All 13 patients with low-grade lymphoma responded, and 10 achieved a complete remission. Six of eight patients with transformed lymphoma responded. Thirteen of 19 patients whose disease was resistant to their last course of chemotherapy and all patients with chemotherapy-sensitive disease responded. The median duration of complete remission exceeds 16.5 months. Six patients remain in complete remission 16 to 31 months after treatment. CONCLUSION: Nonmyeloablative radioimmunotherapy with 131I-anti-B1 is associated with a high rate of durable remissions in patients with B-cell lymphoma refractory to chemotherapy. PMID- 8683228 TI - Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. AB - PURPOSE: To compare sequential methotrexate (M) and fluorouracil (F) (M-->F) with surgery (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-13) and cyclophosphamide (C), M, and F with M-->F (NSABP B-19), in patients with estrogen receptor (ER)-negative tumors and negative axillary nodes. PATIENTS AND METHODS: A total of 760 patients were randomized to B-13; 1,095 patients with the same eligibility requirements were randomized to B-19. Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were determined using life table estimates. RESULTS: A significant benefit in overall DFS (74% v 59%; P < .001) was demonstrated at 8 years in all B-13 patients who received M-->F (69% v 56% [P = .006] in those or= 50 years). A survival advantage was evident in older patients (89% v 80%; P = .03). In B-19, through 5 years, an overall DFS advantage (82% v 73%; P < .001) and a borderline survival advantage (88% v 85%; P = .06) were evident with CMF. The DFS (84% v 72%; P < .001) and survival (89% v 84%; P = .04) benefits from CMF were greater in women aged F or CMF after lumpectomy and breast irradiation resulted in a low probability of ipsilateral breast tumor recurrence (IBTR). In B-13, the frequency of IBTR was 2.6% following M-->F versus 13.4% in women treated by lumpectomy; it was 0.6% following CMF in B-19. Toxicity >or= grade 3 was more frequent among CMF patients in B-19. The age-related difference in CMF benefit was not related to amount of drug received. CONCLUSION: M-->F and CMF are effective for node-negative patients with ER-negative tumors. The incidence of local-regional or distant metastases and IBTR decreased after either therapy. The benefit from either therapy was evident in all patients, but the CMF advantage was greater in those F may be used in patients with medical problems that would preclude CMF administration. PMID- 8683229 TI - Phase II trial of paclitaxel and cisplatin in women with advanced breast cancer: an active regimen with limiting neurotoxicity. AB - PURPOSE: A phase II study of paclitaxel and cisplatin in patients with advanced breast cancer was performed to determine the objective response rate and make further observations about the toxicity of this regimen. PATIENTS AND METHODS: Patients were required to have histologically proven adenocarcinoma of the breast with no more than one chemotherapeutic treatment for advanced disease. Treatment consisted of paclitaxel 200 mg/m2 administered as a 24-hour intravenous (i.v.) infusion followed by cisplatin 75 mg/m2 i.v. Patients received granulocyte colony stimulating factor (G-CSF) 5 micrograms/kg subcutaneously on day 3 until WBC recovery. Cycles were repeated every 21 days. Patients continued to receive therapy until disease progression or unacceptable toxicity. RESULTS: Forty-four patients entered the trial. Forty-two patients were assessable for response. Nineteen patients (43%) had no prior chemotherapy and 41 had no chemotherapy for metastatic disease. The median number of cycles administered per patient was five (range, one to seven). There were five complete responses (CRs) (11.9%) and 17 partial responses (PRs) (40.5%), with an overall response rate of 52.4% (95% confidence interval [CI], 36.4% to 68.0%). Nine patients had stage III disease. The response rate for this group was 66.7% (95% CI, 33.0% to 92.5%), with three CRs and three PRs. Among 35 patients with stage IV disease, there were two CRs and 14 PRs, with an overall response rate of 48.5% (95% CI, 30.8% to 66.5%). Overall, the median response duration was 10.6 months. Thirty patients (68%) developed transient grade 4 neutropenia. Cumulative neuropathy was the major dose limiting toxicity. After five cycles of chemotherapy, 96% of patients had at least grade 1 neurotoxicity and 52% had at least grade 2 neurotoxicity. One patient had a toxic death after cycle 1 of therapy. CONCLUSION: The combination of paclitaxel and cisplatin as first-line chemotherapy for women with advanced breast cancer is an active regimen. However, the cumulative neurotoxicity was significant and dose-limiting in the majority of patients. PMID- 8683231 TI - Limited-sampling models for irinotecan pharmacokinetics-pharmacodynamics: prediction of biliary index and intestinal toxicity. AB - PURPOSE: To construct limited-sampling models (LSMs) for irinotecan (CPT-11) pharmacokinetic (PK) measures. MATERIALS AND METHODS: The recommended phase II dose of weekly CPT-11 administered as a 90-minute infusion is 145 mg/m2 with granulocyte colony-stimulating factor (G-CSF) and maximal antidiarrheal support. Diarrhea is the dose-limiting toxicity. Previously, we demonstrated a highly significant correlation between severity of diarrhea and biliary index (BI), the estimated biliary exposure of SN-38. BI was the product of total CPT-11 area under the concentration-time curve (AUC) and the relative area ratio of SN-38 to SN-38 glucuronide (SN-38G). At 145 mg/m2, PK data were available for 40 patients; 36 were also assessable for intestinal toxicity. Total plasma concentrations of CPT-11, SN-38, and SN-38G from 1.0 to 11.5 hours from the start of the infusion were evaluated. CPT-11 concentration at each time point, t, is denoted by CPT 11t. LSMs were constructed by stepwise linear regression, on a training set (n = 25), and were validated on a test set (n = 15). RESULTS: LSMs for CPT-11, SN-38, and SN-38G AUCs displayed excellent fit to the training set (R2 = .87, 0.75, and .98, respectively). AUCCPT-11 = 5.25 x CPT-11(3.0) + 20.60 x CPT-11(11.5) + 1,520.53; AUCSN-38 = 5.38 x SN-38(3.5) + 33.61 x SN-38(11.5) - 7.73; and AUCSN 38G = 10.73 x SN-38G9.5 + 20.66 x SN-38G11.5 + 142.69. BI at each time point (denoted BIt) was calculated as CPT-11t x (SN-38t/SN-38Gt). Several promising LSMs were defined by BI3.5 paired with BI7.5 (R2 = .63) or BI9.5 (R2 = .76), or BI5.5 paired with BI9.5 (R2 = .76). Predicted BI from each model (categorized into low, intermediate, or high) accurately predicted observed intestinal toxicity grade (P < or = .005). CONCLUSION: These LSMs appear to accurately predict PK parameters of CPT-11. Notably, BI, predicted from several LSMs, accurately predicted intestinal toxicity and thus may be useful for future trials that use adaptive control with feedback. PMID- 8683230 TI - Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. Arimidex Study Group. AB - PURPOSE: To compare the efficacy and tolerability of anastrozole (1 and 10 mg once daily), a selective, oral, nonsteroidal aromatase inhibitor, and megestrol acetate (40 mg four times daily), in postmenopausal women who progressed following tamoxifen treatment. PATIENTS AND METHODS: Two randomized, double-blind for anastrozole, open-label for megestrol acetate, parallel-group, multicenter trials were conducted in 764 patients. Because both trials were identical in design, an analysis of the combined results was performed to strengthen interpretation of results from each trial. RESULTS: The median follow-up duration was approximately 6 months. The estimated progression hazards ratios were 0.97 (97.5% confidence interval [CI], 0.75 to 1.24) for anastrozole 1 mg versus megestrol acetate and 0.92 (97.5% CI, 0.71 to 1.19) for anastrozole 10 mg versus megestrol acetate. The overall median time to progression was approximately 21 weeks. Approximately one third of patients in each group benefited from treatment. Twenty-seven patients (10.3%) in the anastrozole 1-mg group, 22 (8.9%) in the anastrozole 10-mg group, and 20 (7.9%) in the megestrol acetate group had a complete or partial response, and 66 (25.1%), 56 (22.6%), and 66 (26.1%) patients, respectively, had stable disease for > or = 24 weeks. For all end points, individual trial results were similar to the results of the combined analysis. Anastrozole and megestrol acetate were well tolerated. Gastrointestinal disturbance was more common among patients in the anastrozole groups than the megestrol acetate group; the difference between the anastrozole 10 mg and megestrol acetate groups was significant (P = .005). Significantly fewer patients in the anastrozole 1-mg (P < .0001) and 10-mg (P < .002) groups had weight gain than in the megestrol acetate group. More than 30% of megestrol acetate-treated patients had weight gain > or = 5%, and 10% of patients had weight gain > or = 10%. Patients who received megestrol acetate continued to gain weight over time. CONCLUSION: Anastrozole, 1 and 10 mg once daily, is well tolerated and as effective as megestrol acetate in the treatment of postmenopausal women with advanced breast cancer who progressed following tamoxifen treatment. Moreover, anastrozole therapy avoids the weight gain associated with megestrol acetate treatment. PMID- 8683232 TI - Etoposide bioavailability after oral administration of the prodrug etoposide phosphate in cancer patients during a phase I study. AB - PURPOSE: The purpose of this study was to determine the bioavailability (F) of etoposide (E;VP-16) after oral administration of the water-soluble prodrug etoposide phosphate (EP;BMY-40481) during a phase I trial in cancer patients. PATIENTS AND METHODS: Twenty-nine patients received oral EP (capsules, 50 to 150 mg/m2/d of E equivalent) for 5 days in week 1 (course 1), followed every 3 weeks thereafter by a daily intravenous (i.v.) infusion for 5 days of E (80 mg/m2, 1 hour i.v. infusion; course 2); in three patients, the i.v. E course was given before oral EP. Plasma and urine E pharmacokinetics (high-performance liquid chromatography [HPLC]) were performed on the first day of oral EP administration and on the first day of i.v. E. RESULTS: Twenty-six of 29 patients completed two courses or more, whereas three patients received only one course due to toxicity. Myelosuppression was dose-dependent and dose-limiting, with grade 4 leukoneutropenia in four of 15 patients at 125 mg/m2 and in five of seven patients at 150 mg/m2. One patient died of meningeal hemorrhage related to grade 4 thrombocytopenia. Other toxicities were infrequent and/or manageable. No objective response was observed. The maximum-tolerated dose (MTD) is therefore 150 mg/m2, and the recommended oral dose of EP for phase II trials in this poor risk patient population is 125 mg/m2. Twenty-six patients had pharmacokinetic data for both oral EP and i.v. E, whereas three had pharmacokinetic data on the i.v. E course only. After oral administration of EP, the pharmacokinetics of E were as follows: mean absorption rate constant (Ka), 1.7 +/- 1.7 h-1 (mean +/- SD); lag time, 0.3 +/- 0.2 hours; time of maximum concentration (t(max)), 1.6 +/- 0.8 hours; and mean half-lives (t1/2), 1.6 +/- 0.2 (first) and 10.3 +/- 5.8 hours (terminal); the increase in the area under the plasma concentration-versus-time curve (AUC) of E was proportional to the EP dose. After the 1-hour i.v. infusion of E, maximum concentration (C(max)) was 15 +/- 3 micrograms/mL; mean AUC, 88.0 +/- 22.0 micrograms.h/mL; mean total-body clearance (CL), 0.97 +/- 0.24 L/h/m2 (16.2 mL/min/m2); and mean t1/2, 0.9 +/- 0.6 (first) and 8.1 +/- 4.1 hours (terminal). The 24-hour urinary excretion of E after i.v. E was significantly higher (33%) compared with that of oral EP (17%) (P < .001). Significant correlation was observed between the neutropenia at nadir and the AUC of E after oral EP administration (r = .58, P < .01, sigmoid maximum effect [E(max)] model). The mean F of E after oral administration of EP in 26 patients was 68.0 +/- 17.9% (coefficient of variation [CV], 26.3%; F range, 35.5% to 111.8%). In this study, tumor type, as well as EP dose, did not significantly influence the F in E. There was no difference in F of E, whether oral EP was administered before or after i.v. E. Compared with literature data on oral E, the percent F in E after oral prodrug EP administration was 19% higher at either low ( < or = 100 mg/m2) or high ( > 100 mg/m2) doses. CONCLUSION: Similarly to E, the main toxicity of the prodrug EP is dose-dependent leukoneutropenia, which is dose-limiting at the oral MTD of 150 mg/m2/d for 5 days. The recommended oral dose of EP is 125 mg/m2/d for 5 days every 3 weeks in poor-risk patients. Compared with literature data, oral EP has a 19% higher F value compared with oral E either at low or high doses. This higher F in E from oral prodrug EP appears to be a pharmacologic advantage that could be of potential pharmacodynamic importance for this drug. PMID- 8683233 TI - Systemic administration of recombinant interferon alfa in carcinoma patients upregulates the expression of the carcinoma-associated antigens tumor-associated glycoprotein-72 and carcinoembryonic antigen. AB - PURPOSE: The ability of interferons (IFNs) to enhance tumor-associated antigen expression may be an important approach to enhance the efficacy of some monoclonal antibody (MAb)-based protocols for tumor diagnosis and/or therapy. The present study was designed to determine whether systemic IFN alpha-2a administration (via the intramuscular [IM] route) could upregulate the expression of tumor-associated glycoprotein-72 (TAG-72) and/or carcinoembryonic antigen (CEA) at histologically confirmed sites of carcinoma. PATIENTS AND METHODS: Eighteen patients diagnosed with gastrointestinal (GI) carcinoma received systemic IFN alpha-2a according to four dose schedules. In cohorts I and II, patients received two injections of 3 or 6 x 10(6) U IFN alpha-2a per injection, respectively. Patients in cohorts III and IV received the same doses of IFN alpha 2a, 3 and 6 x 10(6) U, respectively, but three injections were given. Tumor and normal colonic mucosa biopsies were obtained from each patient by endoscopy before IFN alpha-2a and after IFN alpha-2a at surgery. The levels of TAG-72 and CEA expression were measured by (1) immunohistochemistry and reported as percent antigen-positive tumor cells, as well as the relative staining intensity, and (2) a quantitative radioimmunoassay. RESULTS: TAG-72 and CEA levels were consistently increased in tumor biopsies taken from patients in cohorts III and IV. For example, of 10 patients treated in cohorts III and IV, eight had enhanced TAG-72 expression when measured either as percentage TAG-72-positive tumor cells or as an increased MAb staining intensity following IFN alpha-2a. CEA expression in tumor biopsies from seven of 10 patients in cohorts III and IV was also elevated following IFN alpha-2a treatment. Quantitative analysis of TAG-72 and CEA levels in tumor biopsies confirmed higher tumor antigen levels following IFN alpha-2a administration. No such increases in TAG-72 or CEA levels were observed in tumor samples taken from patients in cohorts I and II. CEA or TAG-72 expression in samples of histologically confirmed normal colonic mucosa showed little or no change after IFN alpha-2a treatment. CONCLUSION: Systemic IFN alpha-2a administration can upregulate TAG-72 and CEA expression at distal tumor sites, which may play an important role in immunodiagnosis and therapy. PMID- 8683234 TI - Influence of inflammatory bowel disease on the ability of patients to tolerate systemic fluorouracil-based chemotherapy. AB - PURPOSE: To evaluate the safety of administering fluorouracil (5FU)-based chemotherapy to cancer patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS: We retrospectively reviewed all patients entered into the Memorial Sloan-Kettering Cancer Center clinical data base from 1985 through 1995 who had a diagnosis of IBD, had a gastrointestinal malignancy, and were treated with systemic 5FU-based chemotherapy. A total of 19 patient charts were identified and reviewed. RESULTS: Fifty-three percent of patients reviewed experienced severe (grade III/IV) diarrhea on treatment. Sixty percent of patients with a history of active IBD and 40% of patients with a history of inactive IBD experienced severe diarrhea on treatment. The incidence of severe diarrhea did not appear to be substantially influenced by age, schedule of 5FU administration, concurrent radiation, or type of IBD. CONCLUSION: While there does appear to be an increased risk of diarrhea exacerbation in IBD patients treated with 5FU, a substantial number of patients tolerate chemotherapy without increased difficulty. The degree of IBD activity or other clinical parameters can not be used to predict accurately the likelihood of toxicity. PMID- 8683235 TI - Surgery for lung metastases from colorectal cancer: analysis of prognostic factors. AB - PURPOSE: To identify prognostic factors of improved survival after resection of isolated pulmonary metastases (PM) from colorectal cancer. PATIENTS AND METHODS: A retrospective analysis of the records of all patients with PM from colorectal cancer who underwent thoracic surgery with curative intent before December 1992 at a single surgical center was performed. Univariate (log-rank) and multivariate (Cox's model) analyses of survival were used to identify significant prognostic factors. RESULTS: Eighty-six patients with PM from colon (n = 49) or rectal (n = 37) cancer underwent 102 thoracic operations, which included 21 bilateral and 10 incomplete resections. The 5- and 10-year probabilities of survival (Kaplan Meier) after the first thoracic operation were 24% (95% confidence interval [CI], 15% to 35%) and 20% (95% CI, 13% to 31%), respectively. Sex, age, site of the primary tumor (colon or rectum), disease-free interval (DFI), and previous resection of hepatic metastases were found not to be statistically significant prognostic factors. Complete resection, a limited number ( < two) of PM, and a normal prethoracotomy serum carcinoembryonic antigen (CEA) level were predictors of a longer survival duration by univariate analysis, but only complete resection (P = .024) and preoperative CEA level (P = .001) were identified as independent prognostic factors by multivariate analysis. The estimated 5-year survival rate of patients with a normal prethoracotomy CEA level was 60%, as compared with 4% in cases with elevated ( > 5 ng/mL) CEA level. CONCLUSION: Besides resectability, the prethoracotomy serum CEA level appears the most reliable predictor of survival in patients with isolated PM from colorectal cancer. PMID- 8683236 TI - Paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a phase II trial. AB - PURPOSE: Studies conducted by the Eastern Cooperative Oncology Group (ECOG) indicate both paclitaxel and carboplatin are associated with an improvement in 1 year survival in patients with stage IV non-small-cell lung cancer (NSCLC). Based on these findings, a phase II trial of these agents in combination was conducted in patients with advanced NSCLC. PATIENTS AND METHODS: Eligibility included previously untreated stage IIIB or IV NSCLC patients with a good performance status (PS). Paclitaxel (135 or 175 mg/m2) was administered by 24-hour infusion on day 1, followed by a 1-hour infusion of carboplatin on day 2 (300 mg/m2 or dosed to an area under the concentration-time curve [AUC] of 6 mg/mL.min). Treatment was repeated every 28 days for a total of six cycles. Hematopoietic growth factors were not routinely used. RESULTS: Among 51 eligible patients, there were no complete and 14 partial responses, for an overall response rate of 27% (95% confidence interval [CI], 17% to 41%). The median progression-free survival time was 23.8 weeks (range, 12.1 to 73.9) and median survival time, 38 weeks. The survival rate at 1 year was 32%. Grade 3 or 4 granulocytopenia and thrombocytopenia were observed in 47% and 3%, respectively, of the 184 treatment cycles administered. The most common nonhematologic toxicities included nausea and emesis, neuropathy, and arthralgia/myalgia. CONCLUSION: Paclitaxel plus carboplatin is a moderately active regimen in patients with advanced NSCLC and warrants comparison with existing cisplatin-based regimens in a prospective randomized trial. The toxicities of this regimen are well tolerated in patients with a good PS. PMID- 8683237 TI - Bilateral germ cell testicular tumors in New Zealand: experience in Auckland and Christchurch 1978-1994. AB - PURPOSE: The incidence of germ cell testicular tumors (GCTTs) is increasing world wide, and with effective treatment, the majority of patients are being cured. Thus, the clinical and social impact of a second testicular tumor is becoming more important. The frequency, cumulative risk, and relative risk of developing a second testicular cancer in New Zealand have been documented and compared with other reports. PATIENTS AND METHODS: The records of 741 men presenting with germ cell testicular cancer in Auckland and Christchurch between 1978 and 1994 have been reviewed, and these data have been compared with data from other published studies. Cumulative risk was assessed by the Kaplan-Meier method. RESULTS: Over 2% of the study population developed a second germ cell testicular cancer. The cumulative risk was 5.2% over 15 years. The relative risk of developing a contralateral testicular tumor is 27.5 times higher than age-matched New Zealand peers. These results match the only comparable report in the literature. Five of the 16 bilateral tumors (31%) were synchronous, which is a higher incidence than in any other reported series. There was no concordance of histology in the first and second tumors. Prior exposure to cisplatin combination chemotherapy did not prevent the development of a second tumor. CONCLUSION: Men who are cured of a germ cell testicular cancer have a greatly increased risk of developing a second testicular cancer. Such patients should be informed of this risk and ideally kept under long-term surveillance. PMID- 8683238 TI - Correlation between polysialic-neural cell adhesion molecule levels in CSF and medulloblastoma outcomes. AB - PURPOSE: To quantify CSF levels of polysialic-neural cell adhesion molecule (PSA NCAM) in patients with medulloblastoma (MB) metastasis, to assess the correlation with other diagnostic techniques (imaging and cytology) and clinical features, and to determine whether it is a suitable marker to monitor response to treatment and subsequent follow-up data. PATIENTS AND METHODS: PSA-NCAM levels were measured using a double-site enzyme-linked immunoadsorbant assay (ELISA) in 145 samples from 14 controls and 29 patients with MB. Clinical status of patients, imaging, and cytologic data were available at the time of each lumbar puncture. Medians and ranges for the 131 pooled PSA-NCAM concentrations were calculated for the MB versus the control groups, and for MB patients for normal versus abnormal groups at cytology or imaging, and for four clinical subgroups, respectively. For patients with MB, three PSA-NCAM measurements that corresponded to punctures performed during three time periods following surgery were selected. The kappa measure of agreement was calculated between normal and abnormal groups at cytology or imaging, and between groups of patients in remission and refractory, respectively. For the same phases, sensitivity and specificity of PSA-NCAM and cytology tests and their 95% confidence intervals (95% CIs) were computed. RESULTS: PSA-NCAM was never detected in control CSF. PSA-NCAM concentration medians were higher in CSF with metastatic cells or that corresponded to abnormal imaging than in the corresponding normal groups (P < .05). The PSA-NCAM concentration median was significantly higher (P < .05) in CSF from patients refractory to treatment or who relapsed than from patients in remission. Agreements between PSA-NCAM and clinical status and between PSA-NCAM and cytology were excellent during and after treatment. The sensitivity of PSA-NCAM test was always better than that of cytology, whereas its specificity was lower for phases that corresponded to more than 1 month following surgery. However, specificity was 100% for patients refractory to treatment or with relapse. CONCLUSION: PSA NCAM measurement appears to be a new biologic marker of possible use in the management of patients with MB. PMID- 8683239 TI - Disease course and late sequelae of Langerhans' cell histiocytosis: 25-year experience at the University of California, San Francisco. AB - PURPOSE: The purpose of our investigation was to correlate the extent and degree of organ involvement at presentation of Langerhans' cell histiocytosis (LCH) with subsequent disease course, survival, and late sequelae. MATERIALS AND METHODS: The medical records of 71 patients with a pathologic diagnosis of LCH, age 0 to 21 years, who presented between January 1, 1969 and June 30, 1994, were reviewed for organ involvement at diagnosis, treatment, disease course, and late sequelae. Supplementary data were obtained by mailed questionnaire. RESULTS: The median follow-up time from diagnosis for all patients was 8.1 years. Involvement at diagnosis included nine patients with skin-only disease, 22 with monostotic disease, 12 with polyostotic disease, and 28 with multisystem presentation. Treatment was surgery only in 17 and chemotherapy and/or radiotherapy in 54 patients. Recurrences were seen in 35 patients, with the highest rate in the polyostotic group. Ten patients died: seven with the multisystem presentation, two with monostotic disease, and one with skin-only disease. Causes included progressive LCH (n = 6) and late sequelae of either treatment (n = 3) or disease (n = 1). Late sequelae were seen in 64% of 51 patients with more than 3 years of follow-up data. The most common were skeletal defects in 42%, dental problems in 30%, diabetes insipidus in 25%, growth failure in 20%, sex hormone deficiency in 16%, hypothyroidism in 14%, hearing loss in 16%, and other CNS dysfunction in 14%. The overall estimated survival rates at 5, 15, and 20 years are 88%, 88%, and 77%, with an estimated event-free survival rate of only 30% at 15 years. CONCLUSION: Despite the favorable survival, more than half of LCH patients will have further dissemination of disease or late sequelae, including even some patients with single-system disease at diagnosis. Future treatment needs to be designed to prevent disease progression and late sequelae. PMID- 8683240 TI - Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. National Cancer Institute of Canada Clinical Trials Group. AB - PURPOSE: We designed and conducted a randomized, double-blind, placebo-controlled trial to compare the response rates and survival of patients with metastatic melanoma who received carmustine (BCNU), dacarbazine (DTIC), and cisplatin with tamoxifen, or the same chemotherapy with placebo. PATIENTS AND METHODS: Eligible patients with metastatic melanoma received either BCNU 150 mg/m2 intravenously (i.v.) on day 1, DTIC 220 mg/m2 i.v. daily on days 1 to 3 and on days 22 to 24, and cisplatin 25 mg/m2 i.v. daily on days 1 to 3 and on days 22 to 24 with placebo every 6 weeks, or the same chemotherapy with tamoxifen 160 mg orally daily for 7 days before chemotherapy and 40 mg orally daily throughout the remainder of the treatment cycle. Patients were treated on protocol for up to three cycles depending on the type of response. Assuming that a minimum increase in response rate of 20% would be necessary to conclude that tamoxifen conferred a clinically important benefit, we designed the study with an 80% chance of detecting that difference at the 5% level (two-sided). RESULTS: Between February 1992 and January 1995, 211 patients were accrued, 199 of whom were considered assessable for response and toxicity. The overall response rate was 21% in the placebo group and 30% in the tamoxifen group (P = .187). Complete and partial responses were 3% and 27%, respectively, for the tamoxifen group and 6% and 14%, respectively, for the placebo group. Poor performance status and liver involvement were associated with a reduced likelihood to respond to treatment. Major toxicities were similar in both groups with no statistically significant difference in the rates of deep vein thrombosis, pulmonary thromboembolus, grade 4 neutropenia, or grade 4 thrombocytopenia. CONCLUSION: These results demonstrate that the addition of high doses of tamoxifen to this chemotherapy regimen does not increase the response rate compared with chemotherapy alone in unselected patients with metastatic melanoma. PMID- 8683241 TI - Detection of circulating neoplastic cells by reverse-transcriptase polymerase chain reaction in malignant melanoma: association with clinical stage and prognosis. AB - PURPOSE: Circulating melanoma cells can be detected in peripheral blood by means of tyrosinase mRNA amplification by reverse-transcriptase polymerase chain reaction (RT-PCR). We conducted a prospective study to evaluate the clinical significance of the presence of circulating neoplastic cells in the blood of patients with malignant melanoma (MM). METHODS: A sensitive RT-PCR assay was used to detect tyrosinase mRNA in the peripheral blood of patients with stages I to IV melanoma. Healthy subjects or patients with other malignancies were used as negative controls. RESULTS: Ninety-one assessable patients were included in the study. There was a statistically significant association between RT-PCR positivity and clinical stage. Circulating melanoma cells were detected in 36% of patients with localized disease (stages I and II), in 45% of patients with regional nodal involvement (stage III), and in 94% of patients with metastatic disease (stage IV) (P < .001). In stage II-III patients who were RT-PCR-positive for mRNA tyrosinase in blood, the recurrence rate and disease-free survival were significantly worse than patients who were RT-PCR-negative. In multivariate analysis, RT-PCR was an independent prognostic factor for recurrence in patients with nonmetastatic disease (P = .002). CONCLUSION: The detection of circulating melanoma cells in peripheral blood by RT-PCR correlated with the clinical stage of patients with melanoma and was an independent prognostic factor for recurrence. Further studies are warranted to better assess the significance of this test in the evaluation of prognosis, early detection of relapse, and in monitoring the effectiveness of systemic therapy. PMID- 8683242 TI - Malignant mesothelioma following treatment for Hodgkin's disease. AB - PURPOSE: Asbestos exposure is the major known risk factor for mesothelioma, but several case reports have suggested a link between radiation therapy and subsequent development of malignant mesothelioma. This report explores a possible association between radiation therapy for Hodgkin's disease and mesothelioma. PATIENTS AND METHODS: Four cases of malignant mesothelioma were observed following Hodgkin's disease at the Mesothelioma Clinic of the Dana-Farber Cancer Institute. A fifth such patient was found after a review of the literature. RESULTS: In all five cases, the mesothelioma arose in the field of prior radiotherapy. No history of asbestos exposure was elicited by careful questioning or by review of chest radiographs. Examination of lung tissue in one patient showed 250 ferruginous bodies per gram of lung tissue, consistent with no significant prior exposure. The mean interval between radiation treatment for Hodgkin's disease and development of mesothelioma was 15 years, which emphasizes the need for continued follow-up and evaluation of these patients and supports a causal relationship. CONCLUSION: Mesothelioma may need to be added to the list of second malignancies that arise following radiation therapy for Hodgkin's disease. Further support is given to a causal link between radiation exposure and mesothelioma. PMID- 8683243 TI - Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. AB - PURPOSE: Serious cumulative toxicity is a well-recognized consequence of chemotherapy. Amifostine, an organic thiophosphate, has demonstrated the ability to protect selectively a broad range of normal, but not neoplastic, tissues from the cytotoxic effects of chemotherapy and radiotherapy. This study was designed to determine if amifostine could reduce the serious toxicities associated with cyclophosphamide and cisplatin (CP), without reducing antitumor efficacy in patients with ovarian cancer. PATIENTS AND METHODS: Two hundred forty-two patients with advanced ovarian cancer were randomized to receive six cycles of cyclophosphamide (1,000 mg/m2) and cisplatin (100 mg/m2) with or without amifostine (910 mg/m2) every 3 weeks for six cycles. The occurrence of hematologic, renal, neurologic, and ototoxicity was evaluated. Antitumor efficacy was assessed by pathologic tumor response and survival. RESULTS: Pretreatment with amifostine before each cycle of chemotherapy resulted in a reduction of cumulative toxicities. Hematologic toxicity consisted of grade 4 neutropenia associated with fever and/or infection that required antibiotic therapy (P = .005), days in hospital (P = .019), and days on antibiotics (P = .031). Platinum specific toxicities consisted of protracted serum creatinine elevations (P = 0.004), > or = 40% reduction from baseline in creatinine clearance (P = .001), and severity of neurologic toxicity (P = .029). Twenty-four percent of CP patients compared with 9% of amifostine plus CP patients discontinued therapy because of protocol-specified toxicity (P = .002). Pathologic tumor response rates were 37% with amifostine and 28% in controls, with comparable median survival times of 31 months. Amifostine was generally well tolerated; the principal side effects were emesis and a transient decrease in blood pressure. CONCLUSION: Pretreatment with amifostine reduces the cumulative hematologic, renal, and neurologic toxicities associated with the CP regimen, with no reduction in antitumor efficacy. PMID- 8683244 TI - Mature results of a randomized trial of two doses of cisplatin for the treatment of ovarian cancer. Scottish Gynecology Cancer Trials Group. AB - PURPOSE: In 1992, we reported the first results of a randomized study in ovarian cancer, comprising two doses of cisplatin and indicated a significant difference (P = .0008) in median survival. Four years later, we now describe the results of this trial. PATIENTS AND METHODS: After a median follow-up of 4 years and 9 months, 115 of 159 cases of advanced ovarian cancer, originally randomized to receive six cycles of cyclophosphamide 750 mg/m2 and either a high dose (HD) of 100 mg/m2 cisplatin or a low dose (LD) of 50 mg/m2 (LD) cisplatin, have now died. RESULTS: The overall survival for HD and LD patients is 32.4% and 26.6%, respectively, and the overall relative death rate is 0.68 (P = .043). This represents a reduction in overall benefit with longer follow-up compared with the first 2 years (relative death rate of 0.52). Toxicity, particularly neurotoxicity, is still evident in the fourth year (10/31 on HD compared with 1/24 on LD). CONCLUSION: Our recommended dose of cisplatin in combination schedule is therefore 75 mg/m2, representing the optimal balance between efficacy and toxicity. PMID- 8683245 TI - p53 and bcl-2 proteins as prognostic markers in human papillomavirus-associated cervical lesions. AB - PURPOSE: The present study was designed to analyze the expression of p53, mdm2, and bcl-2 proteins, with special emphasis on their association with the grade of squamous intraepithelial lesion (SIL), human papillomavirus (HPV) type, and clinical course of the disease. Special attention was focused on the value of individual protein expressions, as well as combined p53/mdm2 and p53/bcl-2 phenotypes, in predicting the clinical course of cervical lesions. MATERIALS AND METHODS: The expression of p53, mdm2, and bcl-2 was studied immunohistochemically in a series of 98 HPV lesions of the uterine cervix. RESULTS: Frequent expression of p53, mdm2, and bcl-2 proteins was found in the cervical lesions. However, only p53 expression independently provided information for prediction of the clinical course of HPV lesions. High levels of p53 expression were detected in most low grade SILs (LSILs) (83%) and HPV 6/11/42-associated lesions (86%). In high-grade SILs (HSILs) positive for high-risk HPV types, p53 expression was frequently either totally absent or it only occurred in a few scattered cells. These lesions were closely associated with disease progression. The evaluation of bcl-2 expression alone was not useful for predicting clinical outcome, although abnormal bcl-2 expression in suprabasal layers was more common in HSILs. By contrast, the combined p53/bcl-2 phenotype, which showed a low percentage of p53 positive cells with bcl-2 overexpression in upper epithelial layers, was found to be involved in the progression of HPV lesions. CONCLUSION: The present study showed that HPV lesions with a high percentage of cells that express p53 are more likely to regress than those with low or absent p53. p53 thus seems to hold promise as a molecular marker for the risk of the progression of HPV-associated SILs. In addition, the assessment of p53 and bcl-2 expression patterns may be useful to predict the clinical course of cervical HPV lesions. PMID- 8683246 TI - Clinical significance of bcl2 and p53 protein expression in diffuse large B-cell lymphoma: a population-based study. AB - PURPOSE: We studied the prognostic significance of bcl2 and p53 protein expression in relation to clinical and pathologic characteristics in patients with diffuse large B-cell lymphoma (LCL). PATIENTS AND METHODS: Three hundred seventy-two patients with LCL were retrieved from a population-based registry for non-Hodgkin's lymphoma (NHL). bcl2 and p53 protein expression was studied on paraffin-embedded tumor tissue by immunohistochemistry in relation to clinical factors. Response to therapy and survival were analyzed in 165 patients who were uniformly staged and treated and for whom all prognostic data were available according to the International Prognostic Index (IPI). RESULTS: Forty-five percent of tumors showed strong expression of the bcl2 protein (bcl2++), with a higher frequency in patients with primary nodal involvement. Disease-free survival (DFS) was significantly better in bcl2-negative/intermediate (bcl2-/+) cases as compared with bcl2++ cases (P = .0011). At 5 years, bcl2-/+ patients showed a DFS rate of 74%, in contrast to bcl2++ patients with a DFS rate of 41% (P = .002). Bcl2 was the strongest independent prognostic value in a multivariate analysis, with a relative risk (RR) of 3.0 in comparison to p53 expression and the clinical factors of the IPI. Overall survival (OS) was not significantly influenced by bcl2 protein expression. p53 protein expression was found in 13% of cases, with a higher frequency in patients with extensive disease. p53 expression did not influence the chance to achieve complete remission (CR) and survival. CONCLUSION: bcl2 protein is frequently expressed in LCL and is a strong independent prognostic factor for DFS. p53 expression is related with high tumor burden, but is not an independent risk factor for CR and survival. PMID- 8683247 TI - Cladribine and mitoxantrone dose escalation in indolent non-Hodgkin's lymphoma. AB - PURPOSE: Since cladribine (2-chlorodeoxyadenosine [2-CdA]) and mitoxantrone both exhibit major activity against indolent lymphoid malignancies and have different mechanisms of action, we performed a dose-escalation study of 2-CdA and mitoxantrone in patients with alkylator-failed indolent lymphoma to determine the maximum-tolerated dose (MTD) of this combination and to make preliminary observations about efficacy. PATIENTS AND METHODS: Twenty-three patients were treated every 28 to 35 days, in cohorts of at least three patients, with stepwise dose escalations until dose-limiting toxicities (DLTs) were encountered. The initial dose levels were 2-CdA 0.1 mg/kg/d by continuous infusion for 7 days, mitoxantrone 5 mg/m2 intravenously (i.v.) on day 1, and prednisone 100 mg/d on days 1 to 5. Mitoxantrone was dose-escalated in increments of 2.5 mg/m2 i.v. on day 1. RESULTS: The MTD of the combination was 2-CdA 0.1 mg/kg/d for 7 days, mitoxantrone 7.5 mg/m2 i.v. on day 1, and prednisone 100 mg/d on days 1 to 5. Myelosuppression and infection were the DLTs. The recommended phase II doses were 2-CdA 0.075 mg/kg/d for 7 days mitoxantrone 5 mg/m2 i.v. on day 1; prednisone was omitted to decrease the risk of opportunistic infections. The overall response rate was 70%, with 22% complete responses (CRs) and 48% partial responses (PRs). The median duration of CR was 15 months and PR 5 months. CONCLUSION: These results demonstrate the feasibility and safety of combining 2-CdA and mitoxantrone in the treatment of indolent lymphoma, and appear to confirm clinically the mechanistic synergism and rationale for this combination regimen. Prednisone exacerbated the risk of opportunistic infection and was omitted. The overall response rate was high, including durable CRs. Further studies of this combination regimen are warranted in untreated and alkylator-failed indolent lymphoma. PMID- 8683248 TI - Carboxypeptidase G2 rescue after high-dose methotrexate. AB - PURPOSE: This study was a pilot project to assess the safety and efficacy of carboxypeptidase G2 (CPG2) rescue from high-dose (HD) methotrexate (MTX) in patients with recurrent cerebral lymphoma. PATIENTS AND METHODS: Four patients with recurrent primary CNS lymphoma (PCNSL) were studied. Patients received 3.0 g/m2 MTX infused over 2 hours. Twelve hours after the start of MTX, 50 U/kg CPG2 was infused; a second dose of CPG2 was given 6 hours after the first. Blood and CSF were collected and assayed for levels of MTX, CPG2, and 2,4-diamino-N10 methylpteroic acid (DAMPA), a cleavage product of MTX after CPG2. Serum was collected for at least 2 weeks after administration of MTX-CPG2 to assess anti CPG2 activity antibodies. RESULTS: All patients had at least a 2-log decline in plasma MTX levels to the subtherapeutic range within 5 minutes of CPG2 administration. The second dose of CPG2 did not further diminish the already low plasma MTX level. DAMPA appeared and was detected as the plasma MTX concentration decreased. CSF MTX concentration remained elevated for 4 hours after CPG2, and its decline followed first-order kinetics. Anti-CPG2 activity antibodies were not detected in any patient. No MTX or CPG2 toxicity was observed. CONCLUSION: CPG2 rescue is a safe, effective alternative to leucovorin rescue after HD MTX and may prove particularly useful for the treatment of MTX-sensitive CNS tumors, as it does not affect CSF MTX levels. PMID- 8683249 TI - Granulocyte-macrophage colony-stimulating factor associated with induction treatment of acute myelogenous leukemia: a randomized trial by the European Organization for Research and Treatment of Cancer Leukemia Cooperative Group. AB - PURPOSE: To assess the value of granulocyte-macrophage colony-stimulating factor (GM-CSF) for induction treatment of acute myeloid leukemia (AML), both for priming of leukemic cells and for acceleration of hematopoietic recovery. PATIENTS AND METHODS: GM-CSF was administered 5 micrograms/kg/d by continuous intravenous (i.v.) infusion during induction therapy with daunorubicin (DNR) (days 1 to 3) and cytarabine (ARA-C) (days 1 to 7). A total of 102 patients were randomized onto four arms, as follows: (1) GM-CSF 24 hours before and during chemotherapy (arm +/-); (2) GM-CSF after chemotherapy until day 28 or recovery of polymorphonuclear leukocytes (PMNs) (arm -/+);(3) GM-CSF before, during, and after chemotherapy (arm +/+); or (4) no GM-CSF (arm -/-). Stopping rules were applied in case of an initial WBC count greater than 30 x 10(9)/L or a secondary increase of circulating blast cells. Analyses were performed according to the intention-to-treat principle. RESULTS: The complete remission (CR) rates were 77% (arm -/-), 72% (arm +/-), 48% (arm -/+), and 46% (arm +/+). Patients randomized to receive GM-CSF after induction (arms -/+ and +/+) had a significantly lower CR rate (P = .008) and a trend toward accelerated recovery of neutrophils, but no fewer infections or induction deaths. The lower CR rate appeared to be related to an increased resistance rate, with persistent leukemia. The main side effects of GM-CSF were fluid retention and hypotension. CONCLUSION: GM-CSF administered during induction treatment of AML with a DNR/Ara-C combination did not provide any clinical benefit. Furthermore, there was a significant decrease in the CR rate with more persistent leukemia when GM-CSF was administered during the hypoplastic phase after the chemotherapy courses. PMID- 8683250 TI - Oral cladribine as primary therapy for patients with B-cell chronic lymphocytic leukemia. AB - PURPOSE: Purine analogs have wide potential indications in the treatment of hematologic malignancies, but intravenous administration has been required. We previously established that the oral bioavailability of cladribine is 50%. Our aim was to evaluate the efficacy and toxicity of oral cladribine to previously untreated patients with chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Sixty-three patients with symptomatic but previously untreated CLL received cladribine solution 10 mg/m2/d orally for 5 consecutive days in monthly courses. RESULTS: Complete remission (CR) was achieved in 24 patients (38%), and 23 patients (37%) had a partial response (PR). Most patients, including those in whom there was no remission (NR) achieved normal blood lymphocyte counts. Failure to meet response criteria was mostly due to thrombocytopenia. The median response duration was not reached at 2 years. The median survival time among 13 deceased patients was 322 days, whereas the median observation time of surviving patients is 760 days. The overall survival rate at 2 years is 82%. Response rate was associated with clinical stage. Grade III to IV infectious toxicity occurred in one third of patients. CONCLUSION: Orally administered cladribine is an effective and feasible therapy for CLL, and produces durable remissions in three quarters of the patients. However, significant toxicity may occur and further studies are required to assess long-term effects and quality-of-life aspects. PMID- 8683251 TI - Survival of multiple myeloma patients who are potential candidates for early high dose therapy intensification/ autotransplantation and who were conventionally treated. AB - PURPOSE: To analyze the outcome of patients with multiple myeloma (MM) who were potential candidates for early high-dose therapy (HDT) intensification followed by autotransplantation from a series treated with conventional chemotherapy. PATIENTS AND METHODS: From January 1985 through December 1989, 487 patients with symptomatic MM were entered onto a randomized study to compare melphalan and prednisone (MP) versus vincristine, cyclophosphamide, melphalan, and prednisone (VCMP) /vincristine, carmustine (BCNU), doxorubicin, and prednisone (VBAP). The sub-group of 77 patients who could have been candidates for early intensification with HDT followed by stem-cell support (ie, < 65 years of age, stage II or III disease, performance status < 3, and objective or partial response to initial chemotherapy) are the subjects of this report. RESULTS: Seventy-seven of 487 patients could have been candidates for early intensification. The median age was 56 years (range, 27 to 64). At diagnosis, 12% had abnormal renal function, 16% hypercalcemia, and 42% serum beta 2-microglobulin level > or = 6 mg/L; 62% had stage III disease at diagnosis. Thirty-six patients were initially treated with MP and 41 with VCMP/VBAP. The median response duration to initial chemotherapy was 22 months, and the actuarial probability of being in continued first response at 5 years was 14%. After a median follow-up time of 58 months, 59 patients have died, one was lost to follow-up evaluation, and 17 are still alive 69 to 119 months after initial chemotherapy. The median survival time from initiation of treatment was 60 months and from the time when autotransplantation would be considered, 52 months. The only independent prognostic parameter for survival was renal function at diagnosis. CONCLUSION: The median survival time of patients with MM who are less than 65 years of age and who respond to initial chemotherapy is 5 years. This survival duration is similar to that reported in selected series of patients given early HDT and stresses the importance of ongoing randomized trials to determine the role of HDT in the treatment of younger myeloma patients. PMID- 8683252 TI - International neuroblastoma staging system stage 1 neuroblastoma: a prospective study and literature review. AB - PURPOSE: To gain insight into the management of non-metastatic neuroblastoma by examining clinical and biologic features of International Neuroblastoma Staging System (INSS) stage 1 tumors. METHODS: Patients were staged by both the INSS and the Evans staging system and were evaluated for biologic prognostic factors. Patients with INSS stage 1 received no cytotoxic therapy. The literature was reviewed for clinical and biologic data about INSS stage 1. RESULTS: We evaluated 10 consecutive patients (median age, 17.5 months) with INSS stage 1; all remain disease-free (median follow-up duration, > 5 years). Tumors were in the abdomen (n = 6), chest (n = 3), or pelvis (n = 1). Neuroblastoma involved margins of resection in six tumors. Poor-prognostic biologic findings included tumor-cell diploidy (n = 2) and unfavorable Shimada histopathology (n = 2). Two patients were to receive chemotherapy for, respectively, a tumor deemed unresectable and a tumor classified as Evans stage III; second opinions resulted in surgical management alone in each case. Published reports confirm that some INSS stage 1 patients (1) are at risk for overtreatment, and (2) have poor-prognostic biologic findings yet do well. CONCLUSION: Surgery alone suffices for INSS stage 1 neuroblastoma, even if biologic prognostic factors are unfavorable, microscopic disease remains after surgery, and tumor size is suggestive of "advanced-stage" status in other staging systems. Attempts to resect regionally confined neuroblastomas should take precedence over immediate use of cytotoxic therapy; otherwise, some patients may receive chemotherapy or radiotherapy unnecessarily. PMID- 8683253 TI - Challenges and opportunities of the Internet for medical oncology. AB - PURPOSE: The internet, and in particular the world wide web (www), has a rapidly increasing potential to provide information for oncologists and their patients about cancer biology and treatment. A brief overview of this environment is given along with examples of how easily the information is accessed as a means of introducing the web page of the American Society of Clinical Oncology (ASCO), ASCO OnLine. METHODS: Oncology information sources on the www were accessed from the author's home using a 14.4 kbs modem, Netscape browser (Netscape communications Corp, Mountain View, CA), and the locations recorded for tabulation and discussion. RESULTS: Overwhelming amounts of oncology-related information are now available via the Internet. CONCLUSION: Oncology as a subspecialty is ideally suited to apply the newest information technology to traditional needs in areas of education, research, and patient care. Oncologists will increasingly act as information guides rather than information resources for patients and their families with cancer. PMID- 8683254 TI - Adjuvant chemotherapy in pathologic Stage II nonseminomatous testicular cancer: are two cycles of etoposide-cisplatin a standard option? PMID- 8683255 TI - Cytogenetic findings in T-cell lymphoma of angioimmunoblastic lymphadenopathy. PMID- 8683256 TI - Safety profile of single-dose dexamethasone premedication for paclitaxel. PMID- 8683257 TI - Embryological basis of some aspects of cerebral vascular fistulas and malformations. AB - The literature on the formation of cerebral veins is reviewed to obtain a better understanding of some cerebrovascular anomalies. Clinical observations such as the entry of the superior ophthalmic vein into the cavernous sinus through the inferior rather than the superior orbital fissure, the relative infrequency of middle cerebral vein backflow in the presence of an extensive cavernous fistula, and the relative infrequency of hemorrhage in relation to the inferior petrosal fistula all relate to the persistence of an older venous pathway. The frequent occurrence of hemorrhage in association with the superior petrosal sinus fistula and the frequent failure of the superior petrosal sinus to connect to the cavernous sinus similarly have an embryological explanation. The frequent association of the vein of Galen aneurysm and an absent or deformed straight sinus probably relates to the time at which the paired internal cerebral veins fuse into one channel. It is speculated that the origins of cerebral venous malformations (CVMs) and arteriovenous malformations (AVMs) probably relate to sequential formation and absorption of surface veins, which occur in human embryonic development mainly in the 40- to 80-mm length interval, although persistent AVM growth is possible even after birth. The frequent absence or anomaly of the middle cerebral vein and its failure to communicate with the cavernous sinus in the presence of both CVMs and AVMs are linked to the late development of that vein and to its even later connection to the cavernous sinus. PMID- 8683258 TI - A use-dependent sodium channel antagonist, 619C89, in reduction of ischemic brain damage and glutamate release after acute subdural hematoma in the rat. AB - Acute subdural hematoma kills or disables more severely head injured patients than any other complication of cranial trauma. The main pathological factor involved is ischemic neuronal damage, which is caused by raised intracranial pressure and local effect. The authors have evaluated the hypothesis that a novel use-dependent sodium channel antagonist, 619C89, could reduce ischemic brain damage in the rat subdural hematoma model. Because previous studies have shown that focal neuronal damage may be mediated by "excitotoxic" mechanisms, and because excitatory amino acid levels have been shown to be markedly elevated after brain trauma in humans, the authors have measured levels of glutamate, aspartate, and threonine within the cortex underneath the hematoma, using in vivo microdialysis before and after induction of hematoma, in both vehicle- and drug treated rats. Postinjury treatment with 619C89 (30 mg/kg) significantly reduced the volume of hemispheric ischemic damage produced by subdural hematoma, from 99.77 +/- 7.51 mm3 in vehicle-treated control rats to 46.07 +/- 11.06 mm3 (p = 0.0007) in drug-treated animals. In the vehicle-treated animals, induction of subdural hematoma led to a fourfold increase in glutamate in the first 30 minutes after subdural hematoma occurred. The mean extracellular glutamate concentration in these animals remained 2- to 2.6-fold increased over the following 2.5 hours. In the 619C89-treated animals, the release of glutamate from the cortex underneath the hematoma was significantly attenuated. In these rats, induction of subdural hematoma led to a 2.7-fold increase in the first 30-minute sample, but extracellular glutamate concentration returned to near-basal levels thereafter, compared with vehicle-treated animals (p < 0.05). These results show that 619C89 is highly neuroprotective in this model and that its effects may, in part, be mediated by the inhibition of glutamate release from the ischemic cortex underneath the hematoma. PMID- 8683259 TI - Protective effect of the 5-lipoxygenase inhibitor AA-861 on cerebral edema after transient ischemia. AB - This study examined the effect of AA-861, a specific 5-lipoxygenase inhibitor, on brain levels of leukotriene C4 (LTC4) and correlated any changes with changes in edema formation and cerebral blood flow (CBF) after transient ischemia in gerbils. Brain levels of LTC4 were observed to be increased at 1, 2, and 6 hours of reperfusion following 20 minutes of occlusion. At 2 hours of reperfusion, a pretreatment dose of 1000 mg/kg of AA-861 was required to inhibit more than 90% of the reperfusion-induced increases in brain LTC4. At this dose, inhibition of LTC4 production was observed at 2 and 6 hours of reperfusion. The specific gravity of both the cortex and subcortex was decreased at 6 hours of reperfusion after 20 minutes of occlusion. At 2 hours of reperfusion, no significant difference was observed in the specific gravity of the cortex and subcortex regions of gerbils pretreated with AA-861 or with vehicle, but at 6 hours of reperfusion significant positive differences were observed. Cerebral blood flow decreased to approximately 10% of preocclusion values during occlusion and returned to near-preocclusion values after 10 minutes of reperfusion. No significant differences were observed in regional CBF in the AA-861- and vehicle pretreated gerbils during reperfusion. These findings indicate that LTC4 production after transient cerebral ischemia may be an important contributor to the development of cerebral edema and that CBF does not mediate the LTC4-involved development of edema. PMID- 8683260 TI - Neuroprotective effects of preischemia intraarterial magnesium sulfate in reversible focal cerebral ischemia. AB - The known cytoprotective properties of MgSO4 led the authors to study its effects on infarct size in rats when administered intraarterially before reversible focal ischemia. Following an intracarotid infusion of MgSO4 in the amount of 30 mg/kg (24 animals), 90 mg/kg (18 animals), or an equal volume of vehicle (23 animals), middle cerebral artery occlusion was produced in rats by means of an intraluminal suture technique. Reperfusion occurred after 1.5 (42 animals) or 2 hours (23 animals) of ischemia. Automated, volumetric measurements of 2',3',5'-triphenyl-2H tetrazolium chloride-stained coronal brain sections demonstrated a statistically significant decrease in infarct size for MgSO4 treatment groups compared to controls. Cytoprotection was greater in animals subjected to 1.5 hours of ischemia (28.4% reduction in infarct volume, p < 0.001, Student's t-test), than in those having 2 hours of ischemia (19.3% reduction, p < 0.05). Animals given 90 mg/kg MgSO4 prior to 1.5 hours of ischemia (12 animals) showed a 59.8% reduction in infarct volume compared to controls (11 animals, p < 0.001) and a 43.1% reduction compared to the 30 mg/kg group (11 animals, p < 0.001). Analysis of variance demonstrated the statistically significant effects of MgSO4 doses on infarct volume across all groups (F = 22.95, p < 0.0001). The neuroprotective effect of intraarterial MgSO4 in this model is robust, dose dependent, and related to the duration of ischemia. The compound may be valuable for limiting infarction if given intraarterially before induction of reversible ischemia during cerebrovascular surgery. PMID- 8683261 TI - Synthetic fibronectin peptides and ischemic brain injury after transient middle cerebral artery occlusion in rats. AB - Leukocytes play an important role in the development of ischemia-reperfusion injury. This study was conducted to ascertain whether synthetic peptides corresponding to the cell- and heparin-binding sequences of fibronectin that disturb leukocyte adhesion molecules were effective in neuronal protection after transient focal cerebral ischemia in rats. The authors evaluated the efficacy of peptides on infarction size, leukocyte infiltration in the ischemic tissue, and neurological outcome in rats subjected to 1 hour of cerebral ischemia and 48 hours of reperfusion. Twenty-one animals were divided into three groups: transient ischemia without treatment (Group I), transient ischemia with administration of vehicle (Group II), and transient ischemia with administration of fibronectin peptides (Group III). The mean myeloperoxidase activity (U/g wet wt) in the ischemic area was as follows: Group I, 0.19% +/- 0.05; Group II, 0.21% +/- 0.03; and Group III, 0.08% +/- 0.02. The mean size of the infarction as a percentage of the total hemispheric volume was as follows: Group I, 38.35% +/- 1.34%; Group II, 39.21% +/- 2.42%; and Group III, 25.81% +/- 4.87%. Group III showed a significant decrease in myeloperoxidase activity in the lesion and the infarction size was smaller when compared to Groups I and II (p < 0.05). The neurological grade in Group III was significantly better than in Groups I and II at 48 hours after reperfusion (p < 0.01). This study is the first to explore the therapeutic potential of synthetic fibronectin peptides in brain protection after transient focal ischemia, and the results also serve as a basis for studies of important cellular and molecular events that contribute to tissue damage. PMID- 8683262 TI - Effect of magnesium given 1 hour after head trauma on brain edema and neurological outcome. AB - Excitatory amino acids (EAA), mainly glutamate and aspartate, are released in excessive amounts from terminals of ischemic or traumatically injured neurons. These excessive levels of EAAs initiate a cascade of events believed to lead to secondary delayed damage to the surrounding brain. The N-methyl-D-aspartate receptor antagonists MK-801 and ketamine are reported to suppress excessive EAA release and to attenuate the development of focal brain edema following neuronal injury. Magnesium is also reported to work at the postsynaptic receptor to reduce the neurotoxic effect of glutamate. The present study was undertaken to examine the effect of postinjury treatment with Mg++ on brain edema and neurological outcome after traumatic brain injury. Sixty-nine rats that survived halothane anesthesia and closed head trauma (CHT) were randomly assigned to one of seven experimental groups: sham, CHT, and CHT with administration of Mg++ 1 hour postinjury. At 48 hours, brain tissue Mg++ concentration (calculated from optical density using a standard curve) was significantly increased compared to baseline levels (10.06 +/- 2.44 mg/g vs. 6.83 +/- 0.81 mg/g, p < 0.01 calculated by one way analysis of variance). Also at 48 hours postinjury, brain tissue specific gravity in the contused hemisphere of Mg(++)-treated rats was significantly greater than that in the contused hemisphere of untreated rats, indicating attenuation of brain edema formation by Mg++. The neurological severity score (NSS) of rats treated with Mg++ improved significantly at both 18 and 48 hours, compared to baseline values obtained 1 hour after CHT but prior to administration of Mg++ (11.2 +/- 2.5 vs. 15.2 +/- 4.1, p = 0.03; and 12.3 +/- 6.1 vs. 17.3 +/- 3.6, p = 0.004, respectively). In the untreated groups, the NSS at 18 and 48 hours was not significantly different from baseline values (that is, no neurological improvement). The present study indicates that postinjury treatment with Mg++ attenuates brain edema formation and improves neurological outcome after experimental CHT. PMID- 8683264 TI - Recurrent cerebral arteriovenous malformations after negative postoperative angiograms. AB - Angiography has been considered to be the gold standard to judge the success of treatment for cerebral arteriovenous malformations (AVMs). Patients without residual nidus or early draining veins on postoperative angiograms are considered cured, with the risk of hemorrhage eliminated. A series of five patients with recurrent AVMs after negative postoperative angiography is described. All patients had hemispheric AVMs, presented initially with hemorrhage, and were between 5 and 13 years of age. Recurrence was noted 1 to 9 years later (at 12-16 years of age); after a hemorrhage in three patients, seizures in one, and on follow-up magnetic resonance imaging in one. Four patients underwent angiography that showed recurrence of the AVM at or adjacent to the original site. Three years postsurgery, the fifth patient died from a large intracerebral and intraventricular hemorrhage originating in the previous location of the AVM; however, the patient did not undergo angiography at the time of recurrence. The initial negative angiograms obtained postoperatively in these patients may be explained by postoperative spasm or thrombosis of a small residual malformation. However, in the authors' cumulative experience with 808 patients who have undergone complete surgical removal of AVMs (of whom 667 were older than 18 years of age), no case of recurrent AVM has been observed in an adult. Therefore, actual regrowth of an AVM may occur in children and could be a consequence of their relatively immature cerebral vasculature and may involve active angiogenesis mediated by humoral factors. The present findings argue against the assumption that AVMs are strictly congenital lesions resulting from failure of capillary formation during early embryogenesis. It is concluded that delayed imaging studies should be considered in children at least 1 year after their initial negative postoperative arteriogram to exclude a recurrent AVM. PMID- 8683265 TI - Prognostic value of flow cytometry and correlation to some conventional prognostic factors: a retrospective study of archival specimens of 134 astrocytomas. AB - The S-phase fraction and the DNA ploidy type in 134 astrocytomas (18 Grade II, 46 Grade III, and 70 Grade IV astrocytomas) were studied using flow cytometry in a retrospective study of archival tumor specimens. A high grade of malignancy was associated with both a high S-phase fraction (p < 0.0001) and an aneuploid DNA pattern (p < 0.0001). There was no aneuploid DNA pattern found in the fibrillary astrocytomas (World Health Organization (WHO) Grade II); where-as the aneuploid pattern was observed in 80% of all the glioblastomas multiforme (WHO Grade IV). The age and gender of the patients were not significantly related to the flow cytometry parameters. The survival of patients with Grade II or III astrocytomas was significantly longer when their tumors exhibited a tetraploid DNA pattern or had a low S-phase fraction. In patients with Grade IV tumors, there was no correlation between length of survival and either the DNA ploidy or the S-phase fraction. In a multivariate Cox regression analysis of data obtained in patients with Grade II and III astrocytomas, age, grade of malignancy, DNA ploidy, and S phase fraction were independent prognostic factors. PMID- 8683263 TI - Induction of HSP70 in rat brain following subarachnoid hemorrhage produced by endovascular perforation. AB - Current experimental research on subarachnoid hemorrhage (SAH) has been limited by the lack of a small-animal model that physiologically resembles SAH and consistently demonstrates acute and delayed cellular injury. Recently, a model for inducing SAH by endovascular perforation of the internal carotid artery has been developed in the rat. This model physiologically resembles SAH. However, little histological data detailing cellular injury after SAH are available in this or other models. Using immunocytochemistry, the authors investigated the induction of the 70-kD heat shock protein, HSP70, a sensitive marker for cellular stress or injury in the brain, 1 and 5 days following endovascular SAH. The authors also used the conventional histological techniques of cresyl violet and hematoxylin and eosin staining to investigate cellular damage 1 and 5 days after the endovascular SAH. One day following the SAH, HSP70 was induced in all six animals examined in multiple anatomical regions, including the basal forebrain, thalamus, neocortex, striatum, and hippocampus. This HSP70 induction was observed in multiple vascular distributions bilaterally. Immunostaining with HSP70 occurred primarily in neurons but also was observed in glia and endothelium. Five days after the SAH, a similar but more intense pattern of HSP70 immunostaining was observed in all eight animals examined. Specifically, HSP70 immunoreactivity was observed in at least one region of the hippocampus more often at 5 days (six of eight animals) than at 1 day (one of six animals, p < 0.05, one-tailed Fisher's exact test). No HSP70 immunostaining was observed in control animals at 1 day or at 5 days. Conventional histology demonstrated foci of ischemic neuronal damage and cellular necrosis; however, HSP70 immunocytochemistry detailed cellular injury far better than conventional histology in all animals tested at both 1 day and 5 days. Our results demonstrate that HSP70 is induced in multiple regions and cell types 1 day and 5 days following endovascular SAH. Because ischemia is a known inducer of stress genes, the authors propose that acute and delayed ischemia are the processes responsible for the induction of HSP70 that was observed at 1 day and 5 days, respectively. Investigation of HSP70 induction following endovascular SAH may also serve as the basis for a new, inexpensive animal model to assess potential therapeutic interventions. PMID- 8683266 TI - Agenesis of the corpus callosum: female monozygotic triplets. Case report. AB - A case of identical (monozygotic) triplets, two of whom have agenesis of the corpus callosum, is presented. Prenatal ultrasonography and magnetic resonance imaging revealed two of the triplets to have agenesis of the corpus callosum and the third triplet to have an intact corpus callosum. No such case has been reported in the literature. Theories of the etiology and pathogenesis of corpus callosum agenesis are discussed. In this case, unequal X-inactivation as related to the twinning process is implicated as the cause of the agenesis. PMID- 8683267 TI - Monstrous, crablike hypertrophy of the cerebellar vermis and its relationship with Lhermitte-Duclos disease. Case report. AB - The case of an infant with a peculiar tumorous malformation of the cerebellum is described. The tumor apparently developed as an exophytic, hypertrophic sprout of the inferior vermis. It had a monstrous appearance resembling a crab, with a metameric body and multiple pairs of limbs attached to the folia of both cerebellar hemispheres. Histologically, the lesion was formed by poorly differentiated neuroepithelial cells without any evidence of organization into nuclei, cortex, or fascicles. Clinically, the tumor behaved in indolent manner and did not regrow after subtotal surgical resection. Because of its gross appearance and its biological behavior, this unusual hamartoblastomatous growth is readily distinguished from medulloblastoma. The morphology of the cerebellum in Lhermitte-Duclos disease is reviewed, and a new interpretation of its basic structure is proposed. This and other known types of cerebellar hypertrophy are different from the malformation in the present case. PMID- 8683268 TI - Primitive neuroectodermal tumor of the median nerve. Case report with cytogenetic analysis. AB - The authors describe a malignant peripheral primitive neuroectodermal tumor (PNET) that originated in the median nerve in an elderly adult. After the diagnosis was made by biopsy, the patient underwent radical local resection with interpositional vein grafting of the brachial artery. The tumor had the typical appearance of a primitive neural tumor with small, round cells forming rosettes. It stained positively for both the Ewing's sarcoma/peripheral PNET antigen (HBA 71) and neuron-specific enolase, confirming its neural origin. Ultrastructural examination revealed dense core granules and suggested neural differentiation of the neoplasm. Cytogenetic analysis suggested a chromosome (11;22) translocation typical of peripheral PNET. Early reports consisted of tumors arising solely in peripheral nerves, but recent series have focused mainly on tumors arising in the soft tissues other than nerves. There are no other cases of true PNET of peripheral nerve in the modern literature that have been fully characterized by immunohistochemical, ultrastructural, and cytogenetic criteria. Although peripheral PNETs occur more commonly in children, this unusual neoplasm should be considered in the differential diagnosis of peripheral nerve neoplasms in adults. Early diagnosis is desirable because of its aggressive nature and poor outcome. PMID- 8683269 TI - Aplasia cutis congenita. Case report. AB - The authors report the use of intraoperative tissue expansion in the treatment of a neonate with aplasia cutis congenita, a congenital defect of the scalp and skull. The case for immediate surgical intervention is presented, and intraoperative tissue expansion and cranioplasty are recommended as components of an effective surgical approach. PMID- 8683270 TI - Reconstruction of irreparable brachial plexus injuries with reinnervated free muscle transfer. Case report. AB - The complete avulsion of the brachial plexus is a severe injury usually caused by high-energy trauma. Even with the advent of modern microsurgical techniques, many patients have been rendered severely handicapped following this injury. The authors present a new reconstructive procedure that uses a microsurgical reinnervated free-muscle transfer to return prehensile function to an upper limb that is completely paralyzed. Although the procedure is still preliminary, a successful case is briefly described. PMID- 8683271 TI - Treatment of aneurysms by excision or trapping with arterial reimplantation or interpositional grafting. Report of three cases. AB - The authors report three cases of ruptured, large or giant aneurysms that were treated by excision or trapping, followed by revascularization of distal vessels by means of arterial reimplantation or superficial temporal artery interpositional grafting. In the first case, a large serpentine aneurysm arising from the anterior temporal branch of the right middle cerebral artery (MCA) was excised and the distal segment of the anterior temporal artery was reimplanted into one of the branches of the MCA. In the second case, a giant aneurysm, fusiform in shape, arose from the rolandic branch of the MCA. This aneurysm was totally excised and the M3 branch in which it had been contained was reconstructed with an arterial interpositional graft. In the third case the patient, who presented with a subarachnoid hemorrhage, had a dissecting aneurysm that involved the distal portion of the left vertebral artery. In this case the posterior inferior cerebellar artery (PICA) arose from the wall of the aneurysm and coursed onward to supply the brainstem. This aneurysm was managed by trapping and the PICA was reimplanted into the ipsilateral large anterior inferior cerebellar artery. None of the patients suffered a postoperative stroke and all recovered to a good or excellent postoperative condition. These techniques allowed complete isolation of the aneurysm from the normal blood circulation and preserved the blood flow through the distal vessel that came out of the aneurysm. These techniques should be considered as alternatives when traditional means of cerebral revascularization are not feasible. PMID- 8683272 TI - Thoracic disc. PMID- 8683273 TI - Thoracic disc. PMID- 8683275 TI - Cavernous sinus or lateral sellar compartment. PMID- 8683274 TI - Treatment of brain arteriovenous malformations by embolization and radiosurgery. AB - Embolization was used to reduce the size of brain arteriovenous malformations (AVMs) prior to radiosurgical treatment in 125 patients who were poor surgical candidates or had refused surgery. Of these patients, 81% had suffered hemorrhage, and 22.4% had undergone treatment at another institution. According to the Spetzler-Martin scale, the AVMs were Grade II in 9.6%, Grade III in 31.2%, Grade IV in 30.4%, and Grades V to VI in 28.8% of the cases. Most embolizations were performed using cyanoacrylate delivered by flow-guided microcatheters. Radiosurgery was performed using a linear accelerator in 62 patients treated by the authors, and 34 patients were treated at other institutions using various methods. Embolization produced total occlusion in 11.2% of AVMs and reduced 76% of AVMs enough to allow radiosurgery. Radiosurgery produced total occlusion in 65% of the partially embolized AVMs (79% when the residual nidus was < 2 cm in diameter). Embolizations resulted in a mortality rate of 1.6% and a morbidity rate of 12.8%. No complications were associated with radiosurgery. The hemorrhage rate for partially embolized AVMs was 3% per year. No patient with a completely occluded AVM experienced rehemorrhage. Angiographic follow-up review of AVMs embolized with cyanoacrylate demonstrated a 11.8% revascularization rate, occurring within 1 year. It is concluded that after partial embolization with cyanoacrylate, the risk of hemorrhage from the residual nidus is comparable to the natural history of AVMs and that the residual nidus can be irradiated with results almost as good as for a native AVM of the same size. PMID- 8683276 TI - Acquired Chiari I malformation and syringomyelia associated with bilateral chronic subdural hematoma. PMID- 8683277 TI - Spontaneous intracranial hypotension. PMID- 8683278 TI - Anterolateral decompression of the atlantoaxial vertebral artery. PMID- 8683279 TI - Frequency of intracranial hemorrhage as a presenting symptom and subtype analysis: a population-based study of intracranial vascular malformations in Olmsted Country, Minnesota. AB - The purpose of this study was to determine the symptoms at presentation and the incidence of intracranial hemorrhage (ICrH) caused by intracranial vascular malformations (IVMs) in a defined population. The authors used the Mayo Clinic medical records linkage system to detect all cases of IVM among residents of Olmsted County, Minnesota, during the period 1965 through 1992. Forty-eight IVMs were detected over the 27-year period. Twenty-nine of the 48 patients were symptomatic at presentation. The most common presenting symptom was ICrH, which was present in 20 patients, 69% of all symptomatic cases. Sixty-five percent of arteriovenous malformations (AVMs) presented with ICrH. The most common subtype of ICrH was intracerebral hemorrhage, which was found in nine of 20 patients; the second most common subtype was subarachnoid hemorrhage. The peak occurrence of hemorrhage was during the fifth decade of life. The age- and gender-adjusted occurrence of a first ICrH from an IVM among residents of Olmsted County, Minnesota was 0.82 per 100,000 person years (95% confidence interval 0.46-1.19). There was no increase in the detection of IVM-related ICrH throughout the study period. The 30-day mortality rate following ICrH was 17.6% for patients with an AVM and 25% for all patients with IVMs. This study provides unique data on symptoms at presentation and the incidence of ICrH and hemorrhage subtypes from IVMs on a population basis. PMID- 8683280 TI - Overall management outcome of ruptured posterior fossa aneurysms. AB - A study of the overall management of ruptured posterior fossa aneurysms was conducted over a 1-year period (1993) in five neurosurgical centers in Sweden, serving a population of 6.93 million people. Forty-nine cases were identified and treated. One-third of the patients were in the seventh or eighth decade of life. Good overall management outcomes at 6 months were achieved in 30 cases (61%). The overall mortality rate was 27%. Patients with Hunt and Hess Grades I and II had a good overall recovery rate of 87%. On admission, 69% of the patients were assigned Hunt and Hess Grades III to V. The impact on patient outcomes of the intraoperative difficulties encountered, especially in the basilar tip area, is stressed. The authors found that delayed operation is not warranted in most cases. Frequent devastating rebleeding was observed among patients not offered early aneurysm clipping and the operative results were not at significant variance between the early and late surgical groups. Only 50% of the patients scheduled for delayed surgery ultimately made a good recovery, whereas 72% of patients scheduled for early operation did so. The data demonstrate that overall management results with posterior fossa aneurysms, comparable to achievements with supratentorial lesions, are within the reach of modern strategies, even in centers not specializing in these problems. PMID- 8683281 TI - Predicting outcome in poor-grade patients with subarachnoid hemorrhage: a retrospective review of 159 aggressively managed cases. AB - To determine what factors predict outcome, the authors retrospectively reviewed the management of all 159 poor-grade patients admitted to Harborview Medical Center at the University of Washington who suffered aneurysmal subarachnoid hemorrhage between 1983 and 1993. Favorable outcome (assessed by the Glasgow Outcome Scale) occurred in 53.9% of Hunt and Hess Grade IV, and 24.1% of Grade V patients. Outcome was largely determined by the initial hemorrhage and subsequent development of intractable intracranial hypertension or cerebral infraction. Using multivariate analysis, the authors developed three models to predict outcome. It was found that predicting outcome based only on clinical and diagnostic criteria present at admission may have resulted in withholding treatment from 30% of the patients who subsequently experienced favorable outcomes. It is concluded that aggressive management including surgical aneurysm obliteration can benefit patients with poor neurological grades and should not be denied solely on the basis of the neurological condition on admission. PMID- 8683282 TI - Outcome analysis of 85 patients undergoing the pi procedure for correction of sagittal synostosis. AB - The authors present a retrospective review of their experience with 85 cases using the pi procedure to correct sagittal synostosis. A male preponderance of four to one was recognized in this group. Sixty-five infants underwent computerized tomography scanning of the head prior to surgery; these scans revealed unexpected intracranial pathology in 5% of cases. Surgical complications included three intraoperative dural lacerations. All children received blood transfusions with no complications. Cosmetic outcomes were excellent in 53%, good in 43%, and poor in 4% of cases. One patient required reoperation. All poor outcomes were in infants who were younger than 8 weeks of age at the time of surgery and who underwent a "reverse pi" procedure. Most of the excellent outcomes occurred in infants who were between 3 and 6 months of age at the time of surgery. Although more extensive than strip craniectomy, the pi procedure can be accomplished with minimal morbidity. In the authors' opinion, the pi procedure provides better immediate and long-term cosmetic results than synostectomy alone. PMID- 8683284 TI - Prognosis for mental function in Apert's syndrome. AB - The factors involved in the mental development of patients with Apert's syndrome were studied by the authors, focusing on the age of the patient at operation, associated brain malformations, and the quality of the family environment. Overall, 32% of patients with significant follow-up review had an intelligence quotient (IQ) greater than 70. Age at operation appeared to be the main factor associated with changes in mental development: final IQ was greater than 70 in 50% of patients operated on before 1 year of age versus only 7.1% in patients operated on later in life (p = 0.01). Malformations of the corpus callosum and size of the ventricles played no role in the final IQ, whereas anomalies of the septum pellucidum had a significant effect, with the proportion of patients with an IQ over 70 increasing more than twofold in patients with a normal septum compared with patients with septal anomalies (p < 0.04). Quality of the family environment was the third factor involved in intellectual achievement: only 12.5% of institutionalized children reached a normal IQ level compared to 39.3% of children from a normal family background. PMID- 8683283 TI - Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. AB - Clinical and pathological features of 52 infants and children with atypical teratoid/rhabdoid tumor (ATT/RhT) of the central nervous system are defined. This tumor is typically misdiagnosed as a primitive neuroectodermal tumor (PNET) primarily because 70% of ATT/RhTs contain fields indistinguishable from classic PNETs. Separation of these two tumor types is crucial because the prognosis for ATT/RhT is given even when treatment includes surgery with or without radio and/or chemotherapy. These tumors are most common in infants less than 2 years of age. The cases described in this study arose in intracranially in all but one instance, although one-third had already spread throughout the subarachnoid space at presentation. Clinical signs and symptoms and radiological features do not distinguish ATT/RhTs from PNETs. The tumors are composed entirely (13%) or partly (77%) or rhabdoid cells. Seventy percent contains fields of typical PNET alone or in combinations with mesenchymal and/r epithelial elements. The immunohistochemical profile is unique: epithelial membrane antigen, vimentin, and smooth-muscle actin are positive in the majority of tumors and markers for germ cell tumors are consistently negative. Abnormalities of chromosome 22 distinguish ATT/RhTs from PNETs, which typically display an i(17q) abnormality. PMID- 8683285 TI - Management of childhood craniopharyngioma: can the morbidity of radical surgery be predicted? AB - Seventy-five children treated for craniopharyngioma between 1973 and 1994 were studied to demonstrate which pre- and intraoperative factors were indicative of a poor outcome as defined by a quantitative assessment of morbidity. This involved a retrospective review of 65 patients and a prospective study of 10 patients focused on clinical details and cranial imaging and a follow-up "study assessment" of 66 survivors performed over the last 2 years. As part of the assessment, 63 patients underwent magnetic resonance imaging with a three dimensional volume acquisition sequence 1.5 to 19.2 years after initial surgery. Predictors of high morbidity included severe hydrocephalus, intraoperative adverse events, and young age ( < or = 5 years) at presentation. Predictors of increased hypothalamic morbidity included symptoms of hypothalamic disturbance already established at diagnosis, greater height ( > or = 3.5 cm) of the tumor in the midline, and attempts to remove adherent tumor from the region of the hypothalamus at operation. Large tumor size, young age, and severe hydrocephalus were predictors of tumor recurrence, whereas complete tumor resection (as determined by postoperative neuroimaging) and radiotherapy given electively after subtotal excision were less likely to be associated with recurrent disease. Based on these findings, the authors propose an individualized, more flexible treatment approach whereby surgical strategies may be modified to provide long-term tumor control with the lowest morbidity. PMID- 8683287 TI - Cerebral venous malformation-arteriovenous malformation transition forms. AB - Three cases of cerebral venous malformation (CVM) are presented to demonstrate the triad that characterizes CVM: abnormal surface venous drainage, a "star cluster" system of deep collecting veins, and a deep draining vein. Four other cases are introduced that illustrate this triad and show an additional feature, namely arterial fistulization; these cases represent arteriovenous malformations (AVMs). A final case demonstrates a CVM within an AVM. Both of these structures have a common draining vein and an identical venous core. On the basis of the cases described and of others less suitable for illustration, it is postulated that an AVM is a fistulized CVM and that both relate to a failure in the development of the cortical venous mantle. This proposition is based on the authors' observations and their assessment of the "best possible fit." PMID- 8683286 TI - Traumatic subarachnoid hemorrhage and its treatment with nimodipine. German tSAH Study Group. AB - A prospective, randomized, double-blind, placebo-controlled study of nimodipine used to treat traumatic subarachnoid hemorrhage (tSAH) was conducted in 21 German neurosurgical centers between January 1994 and April 1995. One hundred twenty three patients with tSAH appearing on initial computerized tomography (CT) scanning were entered into the study. Requirements for inclusion included age between 16 and 70 and admission into the study within 12 hours after head injury, regardless of the patient's level of consciousness. Eligible patients received either a sequential course of intravenous and oral nimodipine or placebo treatment for 3 weeks. Patients were closely monitored using clinical neurology, computerized tomography, laboratory, and transcranial Doppler ultrasound parameters. Patients treated with nimodipine had a significantly less unfavorable outcome (death, vegetative survival, or severe disability) at 6 months than placebo-treated patients (25% vs. 46%, p = 0.02). The relative reduction in unfavorable outcome in the nimodipine-treated group was even higher (55%, p = 0.002) when only patients who complied with the protocol were considered. PMID- 8683288 TI - Elevated transcranial Doppler flow velocities after severe head injury: cerebral vasospasm or hyperemia? AB - Sixty-seven patients (45 males and 22 females) aged 2 to 70 years (mean 36 years) who had suffered closed head injury were investigated with daily transcranial Doppler (TCD) recordings. A total of 470 TCD recordings (mean 7) were made during Days 1 to 14 after admission. Blood flow velocities were determined in the middle cerebral artery (MCA) and the extracranial internal carotid artery (ICA). Twenty seven (40%) of the 67 patients demonstrated traumatic subarachnoid hemorrhage (tSAH) on the first computerized tomography (CT) scan after the injury. Flow velocities exceeded 100 cm/second in 22 patients. Eleven (41%) of the 27 patients who showed tSAH on the first CT scan developed velocities greater than 100 cm/second, as compared to 11 (28%) of 40 patients without tSAH on CT. Two patients in whom a thick layer of tSAH was revealed on the first CT scan had MCA flow velocities exceeding 200 cm/second for several days. Measurements of cerebral blood flow (CBF) with single-photon emission CT (SPECT) were performed in six tSAH patients who showed TCD flow velocities exceeding 120 cm/second (uni- or bilaterally) to determine whether the increase in velocity reflected vasospasm or hyperemia. The SPECT studies verified ischemia in five patients but revealed general hyperemia in one. The bilateral increase in MCA flow velocities in the latter case was due to high-volume flow through the MCA secondary to elevated CBF rather than arterial narrowing. In one patient with a thick layer of subarachnoid blood on a CT scan obtained at admission, MCA flow velocities exceeded 220 cm/second bilaterally on Day 8 after the head injury. A SPECT measurement obtained on the same day reflected bilateral ischemia. In this patient flow velocities decreased, with a corresponding normalization of CBF, after 5 days of intravenous nimodipine administration. The MCA/ICA ratio correlated well with the distribution of CBF in the six patients studied using SPECT. This report suggests that vasospasm is an important secondary posttraumatic insult in patients suffering severe head injury and, in some cases, is probably treatable by administration of intravenous calcium channel blockers. PMID- 8683289 TI - Jugular bulb temperature: comparison with brain surface and core temperatures in neurosurgical patients during mild hypothermia. AB - Blood temperature at the jugular bulb was monitored in 10 patients undergoing neurovascular procedures that used induced mild hypothermia, and its correlation with surface brain, core, and peripheral temperatures was determined. The study was motivated by the difficulty encountered in directly measuring global brain temperature and the poor correlations between various core and peripheral sites temperatures and brain temperature, particularly during deep hypothermia. Although not statistically significant, previous studies have suggested a trend toward higher brain temperatures. Temperatures from the jugular bulb (collected using a No. 5 French Swan-Ganz catheter) as well as from subdural, pulmonary artery, esophagus, tympanic membrane, and bladder sites were analyzed during three surgical conditions: prior to incision, with the dura open, and after closure of the dura. No complications related to placement of the jugular bulb catheter, induced hypothermia, or temperature monitoring were seen. The authors found that jugular bulb temperature was similar to pulmonary artery and esophageal temperatures; although prior to incision it tended to be higher than that found at the pulmonary artery, most commonly by 0.2 degrees C. Surface brain temperature was cooler than all other temperatures (p < 0.05), except that of the tympanic membrane, and was particularly sensitive to environmental variations. Finally, as has been shown by others, bladder temperature lagged substantially behind core temperatures particularly during rapid cooling and rewarming of the patient. In summary, monitoring of jugular bulb temperature is a feasible technique, and temperatures measured in the jugular bulb are similar to core temperatures. PMID- 8683290 TI - Proceedings of the 43rd annual meeting of the Society of Nuclear Medicine. Denver, Colorado, June 3-5, 1996. Abstracts. PMID- 8683291 TI - Technetium-99m-sestamibi uptake in myeloma. AB - A number of reports describe how 99mTc-sestamibi detects benign and malignant primary and metastatic tumors. We report abnormal 99mTc-sestamibi uptake in nine sites in a 53-yr-old patient with histologically and biochemically proven IgG kappa-secreting myeloma. The 99mTc-sestamibi study was undertaken for an unrelated hyperparathyroidism. PMID- 8683292 TI - Tumor-selective radiopharmaceutical targeting via receptor-mediated endocytosis of gallium-67-deferoxamine-folate. AB - The receptor-mediated endocytosis uptake pathway for the vitamin folate was investigated as a target for tumor-selective radiopharmaceutical delivery. The molecular target for this delivery mechanism is a membrane-associated folate binding protein (FBP) that is overexpressed by a variety of malignant cell lines. METHODS: The ability of a 67Ga-labeled deferoxamine-folate conjugate (67Ga-DF folate) to target tumor cells in vivo was examined using an athymic mouse tumor model. Subcutaneous inoculation of approximately 4 X 10(6) folate-receptor positive KB (human nasopharyngeal carcinoma) cells into athymic mice yielded approximately 0.20 g tumors in 15 days, at which time either 67Ga-DF-folate, 67Ga deferoxamine (67Ga-DF) or 67Ga-citrate was administered by intravenous injection. RESULTS: The 67Ga-DF-folate conjugate showed marked tumor-specific deposition in vivo, with 1.0 +/- 0.3% of the injected dose (%ID) in tumor at 4 hr postinjection (equating to 5.2 +/- 1.5 %ID/g tumor; n = 3 mice). Corresponding tumor-to background ratios at 4 hr postinjection were: tumor/blood = 409 +/- 195; tumor/muscle = 124 +/- 47; tumor/liver = 11 +/- 3; and tumor/kidney = 2.6+/-0.9. Tumor uptake of 67Ga-DF-folate conjugate was effectively blocked by co-injection of 2.4+/-1.0 mg free folate. In control experiments, 67Ga-citrate exhibited tumor uptake of 2.2 +/- 0.4% of the injected dose (10.9 +/- 0.2 %ID/g tumor), but very poor target-to-background contrast (tumor/blood = 0.84 +/- 0.19; tumor/muscle = 5.4 +/- 0.7; tumor/liver = 2.3 +/- 0.2; and tumor/kidney = 2.4 +/- 0.3). Unconjugated 67Ga-deferoxamine showed no tumor affinity. CONCLUSION: Receptor mediated endocytosis of radiolabeled folate-conjugates may offer a suitable mechanism for selectively delivering radiopharmaceuticals to tumors for diagnostic imaging and/or radiation therapy. PMID- 8683293 TI - Preclinical evaluation of fluorine-18-labeled androgen receptor ligands in baboons. AB - A noninvasive method for detecting and quantifying androgen receptors (AR) in metastatic prostate cancer may be helpful in choosing the method of treatment and in better understanding the pathophysiology of this disease. Nine previously synthesized fluorinated androgens exhibited high affinity binding to AR and showed AR-mediated uptake in the ventral and dorsal prostate of the rat. Further evaluation of these agents for PET imaging is needed since sex hormone binding globulin (SHBG), a glycoprotein which binds androgens with high affinity, is absent in rat blood but is present at high levels in the blood of primates. We chose to study three of the nine fluoro-androgens by PET in the baboon. METHODS: In this study, 16beta-[18F]fluoro-5 alpha-dihydrotestosterone (I), 16beta [18F]fluoromibolerone (II) and 20-[18F]fluoromibolerone (III) were synthesized and studied in both a young and old male baboon using PET. Blood samples were withdrawn in three of the 10 studies and analyzed for total radioactivity and percent unmetabolized radioligand. Tissue radioactivity was evaluated semiquantitatively, using prostate absolute, standard and target to nontarget uptake values. RESULTS: Prostate uptake was observed with all three 18F androgens. At 60 min postinjection, compound I gave the highest prostate to soft tissue ratios in both baboons and prostate uptake was shown to be AR-mediated by blocking uptake through the coadministration of testosterone. Compound I gave the highest level of unmetabolized radioligand present in blood up to 45 min postinjection, and gave a 37-fold greater prostate-to-bone ratio at 2 hr postinjection in baboons compared to rats. The favorable behavior of this compound in the baboon may be related to its high affinity for SHBG. CONCLUSION: All three compounds can be used to determine AR-positive tissue in primates. Compound I was selected for the evaluation of AR in men with prostate cancer using PET. PMID- 8683294 TI - Preclinical evaluation of technetium-99m-labeled somatostatin receptor-binding peptides. AB - We report here the results of studies on the in vitro receptor binding affinity, in vivo tumor uptake and biodistribution of two 99m-Tc-labeled peptides. METHODS: Peptides P587 and P829 were synthesized by N-alpha-Fmoc peptide chemistry, purified by reversed-phase HPLC and characterized by fast-atom bombardment mass spectrometry. The peptides were labeled with 99mTc by ligand exchange from 99mTc glucoheptonate. In vitro somatostatin receptors (SSTR)-binding affinities of P587, P829 and their oxorhenium complexes, [DTPA]octreotide and In [DTPA]octreotide were determined in an inhibition assay using AR42J rat pancreatic tumor cell membranes and 125I-[Tyr3]somatostatin-14 as the probe. In vivo single- and dual-tracer studies of 99mTc peptides and 111In-[DTPA]octreotide were carried out using Lewis rats bearing CA20948 rat pancreatic tumor implants. RESULTS: Technetium-99m-P587 and 99mTc-P829 of high-specific activity (>60 Ci (2.2 TBq)/mmole) were prepared in >90% radiochemical yield. P587 and P829 had a Ki = 2.5 nM and 10 nM, respectively. [ReO]P587 and [ReO]P829, representing the 99mTc complexes, had Ki = 0.15 nM and 0.32 nM, respectively. In comparison, [DTPA]octreotide and In-[DTPA]octreotide had Ki = 1.6 and 1.2 nM, respectively. In vivo tumor uptake of 99mTc-P587 and 99mTc-P829 was high (4.1 and 4.9%ID/g at 90 min postinjection compared to 2.9% for 111In-[DTPA]octreotide). Tumor/blood and tumor/muscle ratios at 90 min postinjection were 6 and 33 for 99mTc-P587, 21 and 68 for 99mTcP829, and 22 and 64 for 111In-[DTPA]octreotide. CONCLUSION: The high SSTR-binding affinity and high receptor-specific and saturable in vivo tumor uptake indicate that 99mTc-P587 and 99mTc-P829 are promising radiotracers for the clinical detection of SSTR-expressing tumors and other tissues by 99mTc gamma scintigraphy. PMID- 8683295 TI - In vitro and in vivo evaluation of a technetium-99m-labeled 2-nitroimidazole (BMS181321) as a marker of tumor hypoxia. AB - The 99mTc-labeled 2-nitroimidazole derivative BMS181321, previously studied in experimental models of myocardial and cerebral ischemia, has been evaluated in single-cell and tumor models. METHODS: Accumulation of BMS181321 was studied in aerobic and hypoxic (<10 PPM O2) suspension cultures of Chinese hamster ovary (CHO) cells at 37 degrees C and the oxygen dependency and stability of the accumulated radioactivity determined. Biodistribution studies of the tracer after intravenous injection in C3H mice bearing three different murine solid tumors were performed noninvasively using a gamma camera, as well as invasively by determining blood and tissue levels of radioactivity from 10 min to 24 hr after injection. RESULTS: Accumulation of BMS181321 in aerobic cells in vitro equilibrated within 5 min at a approximately 10-fold level over the external medium. Hypoxic cells showed a linear increase in radioactivity up to 4 hr for cell densities < or = 1 x 10(6)/ml. At higher cell densities (2-4 x 10(6)/ml) there was substantial depletion of radioactivity from the growth medium and increased alteration in the chemical state of the tracer that remained. Low O2 levels (approximately 40 ppm) inhibited the maximal accumulation rate by 50%. Approximately 30% of radioactivity accumulated under hypoxic conditions remained cell-associated after 24 hr. Following intravenous injection, the tracer rapidly distributed throughout the mouse and was predominately cleared through the hepatobiliary system. Blood levels of radioactivity cleared quickly and plateaued at approximately 4% of the total dose from 2-24 hr. Absolute uptake in the tumors was highest 10 min after injection, and the tumor-to-muscle activity ratios increased and plateaued from 4-8 hr at values of 3.5-4.0. Two drugs which affect blood flow and increase hypoxic cell fraction in these tumors, hydralizine and nitro-L-arginine, significantly increased levels of BMS181321 radioactivity over control levels with minimal effects on normal tissue retention. CONCLUSION: These results suggest BMS181321 or an analog of it will be a useful agent to investigate the status of hypoxia in solid tumors experimentally and potentially in the clinic. PMID- 8683296 TI - Targeting of glucose transport proteins for tumor imaging: is it feasible? AB - If glucose transport proteins (Glut) are elevated in tumors they may be good targets for tumor imaging. For targeting, the overexpression of Glut should be a general characteristic of tumors. Moreover agents which bind to Glut should accumulate selectively in tumors. METHODS: To test this, we quantitated Glut in isolated membranes from three human tumor xenografts, two murine tumor models and normal murine tissues using direct binding studies. Additionally, the biodistribution of two compounds which bind to Glut, 7-[[(2-(3-(125I-p hydroxyphenyl)propionyl)aminoethyl)amino]carbonyl]-7-+ ++desacetyl forskolin([125I]HPP forskolin) and [3H]cytochalasin B, were studied in a tumor model which overexpressed Glut. RESULTS: There were multiple classes of binding sites for [3H]cytochalasin B and a percentage of these sites were competitive with D-glucose but not L-glucose. The rank potency and IC50 values for [3H]cytochalasin B binding were: 2-deoxy-D-glucose (4.5 mM) > or = D-glucose (7 mM) > mannose (25 mM) > galactose (35 mM) > rhamnose (1-3 mM) > sorbitol (1-3 mM) and were similar to reported values for transport. The average density of Glut in four tumor models and normal tissues was between 0.7 and 4 pmole/mg protein, but Kd values were not significantly different (69 nM). In LX-1 human lung tumor xenograft (LX-1) Glut were 10-to-20-fold higher than other tissues (21.6 +/- 0.6 pmole/mg protein, p<0.01). Immunostaining of Glut-1 was more prominent in LX-1 than other xenograft tumors, consistent with the binding data. Glut density was highest in poorly vascularized regions suggesting that Glut upregulation was related to a biofeedback mediated event. Iodine-125 HPP-forskolin and [3H]cytochalasin B did not localize in LX-1 tumors. CONCLUSION: Glut overexpression was not a common characteristic of the five tumors tested. Iodine 125 HPP-forskolin and [3H]cytochalasin B did not localize in LX-1 tumors, indicating that these agents did not target tumors with upregulated Glut. Results suggest that Glut are not a promising target for tumor imaging. PMID- 8683297 TI - Targeting glucose transporters for tumor imaging: "sweet" idea, "sour" result. PMID- 8683298 TI - Intratumoral distribution of tritiated-FDG in breast carcinoma: correlation between Glut-1 expression and FDG uptake. AB - Increased expression of glucose transporters is frequently associated with transformation and is often found in malignant tumors. To assess the relationship between cellular glucose transporter Glut-1 (brain/erythrocyte) and FDG uptake in malignant tumors we studied the expression of Glut-1 and 3H-FDG uptake in a syngeneic rat mammary cancer (RMC), an animal tumor model that closely mimics human breast carcinoma. METHODS: Tumors of 1-9 RMT cell line were grown in female Lewis rats and were studied by immunoperoxidase staining with anti-Glut-1 antibodies, macro- and microautoradiography and densitometry following intravenous injection of 3H-FDG. RESULTS: Most of the cancer cells contained Glut 1 positive cytoplasmic granules. Cells with strongly stained cell membrane were mainly observed in areas of intensive intraductal proliferation and high tumor cell density. No staining was observed in necrotic areas, connective tissue stroma or granulation tissue. FDG uptake in areas of high cancer cell density was consistently higher than average tumor uptake. Silver grain counts were 31 +/- 8/0.023 mm2 in regions of viable cancer cells, and were higher as compared to 10 +/-7 counted in necrotic or 8 +/- 8 in connective tissue areas (p = 0.0001). Densitometry of the autoradiograms and of the histochemically stained consecutive sections showed positive correlation between estimates of FDG uptake and the intensity of staining of the Glut-1 antigen (r=0.3-0.6; p=0.0001). CONCLUSION: Our results demonstrate significant positive correlation between the expression of the facilitative glucose transporter Glut-1 and FDG accumulation in viable cancer cells in the syngeneic rat breast cancer. They suggest that the regulation of FDG uptake may be mediated by Glut-1 and the heterogeneous expression of Glut 1 and tracer uptake may reflect localized variations in the metabolic conditions. PMID- 8683299 TI - [Methyl-carbon-11] thymidine for in vivo measurement of cell proliferation. AB - [Methyl-11C]thymidine and PET provide an in vivo, noninvasive, quantitative approach for studying nucleoside uptake in cells on condition that the fraction of metabolites in the total accumulated activity is known. METHODS: Using an animal model (Wistar rats), two independent approaches were followed. In the first approach, total accumulated activity in rapidly dividing tissue after intravenous injection of [methyl-11C]thymidine, respectively, [methyl-11C]thymine (first metabolite), was compared. In the second approach, the liver was surgically isolated to avoid thymidine catabolism. RESULTS: After injection of [methyl-11C]thymidine, tissue activity consists of both labeled thymidine and metabolites, while after injection of [methyl-11C]thymine, it consists only of metabolites. The fraction of metabolites ranged from 9% to 44%. Comparing the specific activity with and without liver function yielded similar results. The calculated amount of metabolites was about 10%. CONCLUSION: In spite of the intense in vivo catabolism, major activity in rapidly dividing tissue consists of [methyl-11C]thymidine. PMID- 8683300 TI - Enhancement of radiation dose to the nucleus by vesicular internalization of iodine-125-labeled A33 monoclonal antibody. AB - In radioimmunotherapy, the emission characteristics of the radioisotope is critical in determining the radiation dose to the tumor compared to normal organs. If antibodies internalize and transport low-energy electron emitting isotopes close to the tumor cell nucleus, an improved therapeutic advantage is achieved. METHODS: Using fluorescent microscopy, we studied the subcellular distribution of an internalizing antibody, A33, which detects a restricted determinant on colon cancer cells. We developed a physical model to assess the dose deposited on the nucleus by electrons emitted from radiolabeled A33 accumulated inside vesicles. This model is based on the energy-range relationship of electrons in water. Similarly, another model was developed to calculate the radiation dose to the nucleus from electrons emitted from extracellular space. The percentage of A33 bound to membrane and internalized was determined in vitro at various time points. Cytotoxicity experiments were performed with 125I- and 131I-labeled A33 at various concentrations and specific activities. RESULTS: A33 accumulates in cytoplasmic vesicles (40% of total bound) which transport the activity close to the nucleus. This increases the radiation dose to the cancer cell nucleus by a factor of 3 compared to the average dose calculated based on the assumption of a uniform distribution on the cell membrane. The cytoplasm of antigen-negative normal cells shields the nucleus from the electrons emitted from extracellular 125I. This shielding is 30 times less for 131I. Cytotoxicity data show 10% cell survival with 10 microCi/ml of 125I-A33, but 90% survival with up to 100 micro/Ci/ml of 125I-A33 in the presence of a blocking dose of 100-fold excess of cold A33. Similar experiments with 131I showed cytotoxicity in both cases. CONCLUSIONS: The results of the cytotoxicity experiment are in agreement with the physical model and suggest a basis for improved tumor-to-marrow radiation dose by clinical use of 125I-A33. PMID- 8683302 TI - New NRC rule spurred by radiation incidents. Motivated by two recent acts of suspected radiation sabotage, the Nuclear Regulatory Commission wants any future events to be reported within 24 hours. Will the new rule prevent international misadministrations or just cause unnecessary paperwork? PMID- 8683301 TI - Iodine-131-metaiodobenzylguanidine dosimetry in cancer therapy: risk versus benefit. AB - In the treatment of neural crest tumors, such as pheochromocytoma, with[131I]MIBG, bone marrow toxicity limits the amount of administered activity and, thus, a therapeutically useful tumor dose. METHODS: We calculated tumor doses in a series of diagnostic studies with [123I]MIBG using accurate quantification of SPECT and planar scintigraphy. By extrapolating diagnostic results to therapeutic activities of [131I]MIBG, we could compare the results with whole-body doses from a series of therapies. RESULTS: The tumor dose was DT = 2.2 mGy MBq(-1) (median value of 27 measurements, range 0.04 < or = DT < or = 20 mGy MBq(-1) and the whole-body dose in a series of 16 patients undergoing 50 therapies was DWB = 0.12 +/- 0.04 mGy MBq(-1) (mean +/- s.d.). The therapeutic ratio varied between 130 to below 10 in some patients. CONCLUSION: The results were compared with published data. We found clearly skewed distribution of tumor doses, with a majority of tumors receiving only a few mGy per MBq administered activity. In some patients, however, doses did reach 20 mGy MBq(-1). PMID- 8683303 TI - How to be an effective risk communicator--Part 1. PMID- 8683304 TI - Special issue: Nuclear oncology. PMID- 8683305 TI - Cost-effectiveness analysis of somatostatin receptor scintigraphy. AB - We analyzed the results of conventional imaging and somatostatin receptor scintigraphy in 150 patients with neuroendocrine tumors. METHODS: The outcomes of combinations of imaging modalities were compared in terms of tumor localization, effect on patient management and financial costs. RESULTS: In patients with carcinoids, a combination of somatostatin receptor scintigraphy, chest radiograph and ultrasound of the upper abdomen had a high sensitivity for tumor localization, and detected lesions in patients in whom no tumor was found with conventional imaging, justifying the greater cost. In patients with medullary thyroid carcinoma, somatostatin receptor scintigraphy adds little to the information obtained with conventional imaging and therefore should not be used as a screening method. In patients with paraganglioma, CT scanning of the region where a paraganglioma is suspected, followed by somatostatin receptor scintigraphy to detect multicentricity has the best cost effectiveness ratio. In patients with gastrinomas, the combination of somatostatin receptor scintigraphy and CT scanning of the upper abdomen had the highest sensitivity. The relatively high cost of this process is outweighed by its demonstrating a resectable tumor. In patients with insulinomas, the highest yield against the lowest cost is obtained if somatostatin receptor scintigraphy is only performed if CT scanning fails to demonstrate the tumor. CONCLUSIONS: Somatostatin receptor scintigraphy should be performed in patients with small-cell lung carcinoma because it can lead to a change of stage and may demonstrate otherwise undetected brain metastases. The cost increase is outweighed by the omission of unnecessary treatment for some of the patients and by the possibility of irradiating brain metastases at an early stage, which may lead to a better quality of life. PMID- 8683306 TI - Indium-111-pentetreotide scintigraphy in children with neuroblast-derived tumors. AB - The somatostatin analog 111In-pentetreotide was evaluated in 11 children with sympathetic embryonic cell-derived tumors. METHODS: Six neuroblastomas, four ganglioneuroblastomas and one ganglioneuroma (benign) were imaged 4 and 24 hr after injection of 111In-pentetreotide (5 MBq/kg) and 24 hr after administration of 123I-metaiodobenzylguanidine (MIBG) (3.7 MBq/kg). RESULTS: Primary tumor was detected with both tracers in four of the five patients studied before surgery (one Stage III neuroblastoma, one Stage IV neuroblastoma, one Stage IVs neuroblastoma, one ganglioneuroblastoma), but the ganglioneuroma was not localized. Detection of bone marrow metastases was clearly better with 111In pentetreotide in two patients, similar or slightly better with MIBG in six and (true) negative with both procedures in three. The positivity rate of 111In pentetreotide for imaging of metastases was higher in undifferentiated malignant tumors (six neuroblastomas: two very positive, three positive, one true-negative) than in histologically well-differentiated tumors (four ganglioneuroblastomas: three weakly positive, one true-negative). All patients with positive 111In pentetreotide imaging results had elevated urinary catecholamine levels, and the two most 111In-pentetreotide-positive metastases were found in neuroblastomas from children with an aneuploid primary tumor. The 111In-pentetreotide and MIBG results were only partly correlated with bone marrow status, as assessed by immunocytological and histological studies at the time of scanning. CONCLUSION: Abnormalities detected in 111In-pentetreotide uptake were slightly different from those seen with MIBG as a first-line routine method in neuroblast-derived tumors. However, some MIBG as a first-line routine method in neuroblast-derived tumors. However, some MIBG-negative tumor sites were detected by 111In-pentetreotide in patients with neuroblastomas. Thus, 111In-pentetreotide could provide novel information on the biology and prognosis of tumors whose clinical significance remains to be defined. PMID- 8683307 TI - Nodal spread of squamous cell carcinoma of the oral cavity detected with PET tyrosine, MRI and CT. AB - The uptake of L-1-[11C]-tyrosine (TYR) in cervical lymph nodes of eleven patients with squamous-cell carcinoma (SCC) of the oral cavity was studied with PET to detect lymphogenic metastases. METHODS: The TYR-PET results were compared with clinical, MRI, CT, histopathologic findings and historical data of patients studied with FDG. Sensitivity, specificity, accuracy and the positive and negative predictive values were calculated. RESULTS: TYR-PET had sensitivity of 83% and a specificity of 95%. In contrast, the sensitivity and specificity for MRI were 33% and 96%, respectively. The sensitivity and specificity for CT were 55% and 91%, respectively. TYR-PET results compared favorably with FDG. CONCLUSION: With TYR-PET, SCC metastases of the oral cavity can be visualized with high sensitivity and specificity. TYR-PET can be an additional tool for further evaluation of neck malignancies. PMID- 8683308 TI - Technetium-99m-sestamibi scintigraphy compared with thallium-201 in evaluation of thyroid tumors. AB - Technetium-99m methoxyisobutylisonitrile (MIBI) is a myocardial perfusion imaging agent that has been reported to effectively localize in various tumors (e.g., lung and thyroid carcinomas and osteogenic sarcoma). To determine its usefulness in thyroid tumors, we compared 99mTc-MIBI with 201TI imaging. METHOD: We evaluated 25 patients with thyroid tumors (papillary carcinoma in 11, follicular carcinoma in 2, follicular adenoma in 7, adenomatous goiter in 5). Fifteen metastatic lesions from differentiated thyroid carcinomas were also evaluated. Early (10 min after injection) and delayed images (120 min after injection) were obtained for both 99mTc-MIBI and 201TI scintigraphy. RESULTS: The early images showed very similar findings for both 99mTc-MIBI and 201TI. However, the delayed images showed that malignant tumors tended to retain more tracer agent than benign nodules. Marked retention was in 61.5% (8 of 13) of 201TI images and 53.8% (7 of 13) of 99mTc-MIBI images. For metastatic lesions from thyroid carcinomas, the findings for 99mTc-MIBI imaging were nearly identical to those for 201TI imaging. A slight difference in clarity was seen that may have been due to the effect of the 99mTc. CONCLUSION: Although 99mTc-MIBI scintigraphy does not have particularly good results in differentiating malignant from benign thyroid tumors, it may be useful in evaluating metastases or predicting recurrence because of its better imaging characteristics. PMID- 8683309 TI - Radioimmunotherapy of medullary thyroid cancer with iodine-131-labeled anti-CEA antibodies. AB - This study evaluates the pharmacokinetics, dosimetry, toxicity and therapeutic potential of radiolabeled NP-4 and MN-14 anti-CEA antibodies in medullary thyroid cancer (MTC). METHODS: Eighteen patients with advanced MTC entered exploratory clinical studies with therapeutic doses of 131I-labeled NP-4 and MN-14 murine monoclonal antibodies (MAbs) reactive with carcinoembryonic antigen (CEA). Doses administered ranged from 46 mCi for 131I-MN-14 lgG to 195 mCi for 131I-MN-14 F(ab)2 in patients negative for human anti-mouse antibodies (HAMA). RESULTS: The radioconjugate blood half-life (T1/2) for the whole lgG was 42.5+/-5.0 hr compared to 18.8+/- 4.1 hr for the bivalent fragments. Tumor doses of 17.5+/-11.0 and 11.4+/-6.3 cGy/mCi were estimated for 131I-MN-14 lgG and F(ab)2, respectively. Tumor/red marrow dose ratios exceeded 3:1 for most lesions. Red marrow doses of up to 350 cGy generally could be delivered with < grade 4 toxicity. Seven of 14 evaluable patients showed evidence of anti-tumor effects lasting up to 26 months, based on physical exam, tumor markers or computed tomography. CONCLUSION: This study demonstrates that anti-CEA MAbs may be suitable for radioimmunotherapy of metastatic or recurrent MTC. PMID- 8683310 TI - Comparison of octreotide scintigraphy and conventional imaging in medullary thyroid carcinoma. AB - We evaluated the clinical utility of positive somatostatin receptor scintigraphy in patients with medullary thyroid cancer (MTC). METHODS: Twenty-four MTC patients with increased calcitonin levels underwent somatostatin receptor scintigraphy using 111In-pentetreotide (120-200 MBq) with early (4 hr after injection) and delayed (24 hr) whole-body scans and liver SPECT imaging. In Group 1 (12 patients), conventional imaging modalities demonstrated the presence of tumor sites prior to somatostatin receptor scintigraphy; in Group 2 (12 patients), conventional imaging modalities were negative or inconclusive. RESULTS: Somatostatin receptor scintigraphy had positive results in 9 of 24 patients (37%): of Group 1 patients, 7 of 12 had positive somatostatin receptor scintigraphy results. Of these patients cases, somatostatin receptor scintigraphy demonstrated several involved organs and tumor sites either identical (two patients) or smaller (five patients) in size than conventional imaging modalities. Only two patients in Group 2 had positive somatostatin receptor scintigraphy results which demonstrated significant mediastinal uptake previously classified as indeterminate on conventional imaging modalities. No new tumor site was identified nor were therapeutic options modified by the somatostatin receptor scintigraphy results. CONCLUSION: Somatostatin receptor scintigraphy only demonstrates part of tumor sites and cannot visualize small tumor sites (< or = 1 cm). We believe that somatostatin receptor scintigraphy has a limited role in the management of MTC patients. PMID- 8683311 TI - Indium-111-pentetreotide uptake in endocrine tumors and lymphoma. AB - The biodistribution of 111In-pentetreotide was assessed in patients with gastroenteropancreatic (GEP) neuroendocrine tumors or lymphoma and in control patients and analyzed as a function of scanning time, presence or absence of tumor uptake, tumor type and previous octreotide treatment. METHODS: Patients underwent imaging 4 and 24 hr after injection of approximately 200 MBq 111In pentetreotide. The frequency of organ visualization was assessed on planar views. Total organ and tumor uptake (% injected dose [ID]) was determined using the geometric mean method and regional tissue uptake (% ID/100 ml) by semiquantitative SPECT. RESULTS: Liver, spleen, kidneys and urinary bladder were visualized in all patients. Thyroid, bowel and pituitary were more often visualized at 24 hr than at 4 hr. Activity in the gallbladder, breast, ureters and ascites was only occasionally observed. Total liver, spleen and thyroid uptake was stable over time, whereas kidney activity decreased slightly. At 24 hr, regional uptake was threefold lower in the liver than in the spleen or kidneys and was similar in the three groups. In patients with long-term octreotide therapy, a positive correlation was found between the duration of octreotide therapy and liver or spleen uptake. Total and regional tumor uptake showed high intraindividual and interindividual variations. Total tumor activity was stable over 24 hr in patients with GEP and decreased in those with lymphoma. The mean regional tumor uptake was 10-fold lower in patients with lymphoma than in those with GEP. Cold octreotide injected 24 hr after tracer administration did not result in any displacement of organ and tumor activity. CONCLUSION: Organ uptake seems not to be influenced by the presence of 111In-pentetreotide-positive lesions or by tumor type. Tumor uptake is highly variable among patients and clearly lower in patients with lymphoma than in those with GEP. The widespread of uptake values in tumors indicates that radiotherapy using radiolabeled somatostatin analogs may not be applicable to all patients with 111In pentetreotide-positive tumors. PMID- 8683313 TI - Mammoscintigraphy with technetium-99m-sestamibi in suspected breast cancer. AB - Our goal was to determine the clinical usefulness of 99mTc-sestamibi to identify breast cancer in patients prior to biopsy. METHODS: We studied 66 patients who received 20 mCi 99mTc-sestamibi intravenously. Lateral and anterior planar images were gathered within 30 min of the injection. Only focal increased uptake was interpreted as positive. Confirmatory pathologic diagnoses were obtained within 2 mo. The prevalence of breast cancer in our sample was 54%. RESULTS: We report an overall sensitivity of 83% and specificity of 93% for the diagnosis of breast cancer. In palpable lesions, the sensitivity was of 94% with a specificity of 91%, while in nonpalpable abnormalities the sensitivity was of 64% with a 100% specificity. Six patients with a malignancy had negative scans, four of these lesions were nonpalpable. Only two of 31 patients with benign lesions had an abnormal scan. CONCLUSION: Mammoscintigraphy with 99mTc-sestamibi has high specificity and adequate sensitivity for the noninvasive diagnosis of breast carcinomas. PMID- 8683312 TI - Technetium-99m-sestamibi uptake in breast tumor and associated lymph nodes. AB - The aim of this study was to measure the accumulation of 99mTc-sestamibi in breast tumors and their axillary lymph nodes in patients undergoing scintimammography. METHODS: Eighteen patients who were scheduled for breast surgery underwent scintimammography with 740 MBq of 99mTc-sestamibi on the day before the operation. The next morning, reinjection with 370 MBq was performed. Immediately after the surgical procedure, the 99mTc activity of the tumor samples and, when available, the related lymph nodes was measured in a gamma counter. The samples were weighed and prepared for histological analysis. The activity of each sample was normalized to the mean activity of normal tissue samples obtained from the same patient. RESULTS: Among the 198 samples analyzed, the relative uptake of sestamibi was increased in 111 containing normal lymph nodes (1.80+/-0.79 vs 1.00+/-0.22, p<0.05), as well as in the seven containing invaded lymph nodes (2.01+/-0.83, p<0.01) and more dramatically, in the 22 with a carcinoma (5.64+/ 3.06, p<0.001). In two patients with a benign lesion, both scintigraphy and counting demonstrated increased activity in the tumor. Four patients had negative scan results despite the presence of malignant tumor and a more than fourfold increase of sestamibi concentration in two of them. CONCLUSION: Technetium-99m sestamibi concentrates strongly in breast carcinoma, sometimes even when the scan results appear normal, and mildly in lymph nodes, especially when invaded; it also concentrates in some benign tumors, possibly in relation to the presence of epithelial hyperplasia. PMID- 8683314 TI - Evaluation of preoperative chemotherapy using PET with fluorine-18 fluorodeoxyglucose in breast cancer. AB - We retrospectively investigated the value of PET with fluorine-18 fluorodeoxyglucose (FDG) for preoperative chemotherapy response in patients with locally advanced breast cancer. METHODS: FDG-PET studies were performed on 16 consecutive patients. All patients had PET studies before chemotherapy, 13 patients between the end of the first cycle and at the midpoint of chemotherapy, and 14 patients before surgery. Visual diagnoses and the standardized uptake values (SUV) of PET scans were compared with pathology findings at surgery and with the results of mammography, ultrasonography (US) or both, which were performed before chemotherapy and before local surgery for residual disease. Each patient's clinical course was monitored for up to 3 yr. RESULTS: Sensitivity for detection of pathologically proven primary lesions was 100%, 62.5% and 87.5% with FDG-PET, mammography and US, respectively; and sensitivity for detection of initial nodal involvement was 77%, 70% and 87.5%, respectively. Sensitivity for detection of residual primary tumor was 75%, 71.4% and 87.5%, respectively; and sensitivity for detection of residual nodal involvement was 41.6%, 71.4% and 66.6%, respectively. The mean SUV value of primary lesions was 9.4 (range 2.0 20.7, n = 16), with only two lesions showing an SUV below 3. Clinical improvement of primary lesions was seen in all patients; improvement with smaller size and less FDG uptake was visible as early as the second study in 11 patients (69%). Mean SUV values obtained at the second and third studies decreased significantly from those obtained in the first study. In four patients, the disease recurred after breast surgery with high SUV values. The mammograms and sonograms obtained before surgery showed a decrease in the diameter of 6 and 12 primary lesions of the 13 and 14 patients examined, respectively. CONCLUSION: FDG-PET is valuable for monitoring the effects of preoperative chemotherapy in patients with locally advanced breast cancer with better sensitivity for primary tumor and better specificity for nodal metastasis in comparison with ultrasonography. PMID- 8683315 TI - Assessment of mediastinal involvement in lung cancer with technetium-99m sestamibi SPECT. AB - This study evaluated the clinical role of SPECT with sestamibi versus CT in the presurgical staging of lung cancer. METHODS: Forty-seven consecutive patients (44 men, 3 women; mean age 63.3 yr, range 49-82 yr) with clinical and radiological suspicion of lung cancer were enrolled in this study. Staging procedures including radiography, CT, fiberoptic bronchoscopy and sestamibi SPECT of the thorax. Radionuclide imaging was performed after intravenous injection of 740-925 MBq of sestamibi. In 36 patients a histological diagnosis was made, and these patients were evaluated for the study of mediastinal lymph node involvement. RESULTS: Mediastinal lymph node involvement was demonstrated in 11 of the 36 patients evaluated. Sestamibi SPECT correctly staged 10 of 11 patients with and 21 of 25 without mediastinal nodes, showing a diagnostic sensitivity of 91% and a specificity of 84%. Computed tomography gave 8 true-positive and 15 true-negative results, with a sensitivity of 73% and a specificity of 60%. Sestamibi SPECT results were also better than those of CT with regard to positive and negative predictive values and accuracy. CONCLUSION: The clinical role of sestamibi SPECT can be fully appreciated when the technique is used in selected patients, combined with CT or MRI, or both, to assess mediastinal involvement and avoid any invasive staging procedures. PMID- 8683317 TI - Is PET ready for prime time? PMID- 8683316 TI - Probability of malignancy in solitary pulmonary nodules using fluorine-18-FDG and PET. AB - Nearly one-third of solitary pulmonary nodules are radiographically indeterminate for the presence of malignancy. METHODS: FDG-PET imaging was used to differentiate benign and malignant solitary pulmonary nodules in 61 patients with radiographically indeterminate nodules. After confirmation of the histological diagnosis, the probability for cancer was established for positive and negative PET scans and compared to the risk estimates calculated using other patient variables. RESULTS: FDG-PET had a sensitivity, specificity and positive predictive value of 93%, 88% and 92%, respectively, for detecting malignancy in indeterminate solitary pulmonary nodules. The probability of malignancy with a positive PET scan is 83%, which increases with the patient's age (90% in >60 yr) and the size of the nodule. A negative PET scan is associated with only a 4.7% risk of malignancy. FDG-PET also accurately characterized hilar/mediastinal lymphadenopathy in 12 patients with associated lymph node lesions. CONCLUSION: FDG-PET imaging can be a useful noninvasive test to determine the risk estimate or probability of cancer as well as preoperative staging in patients with radiographically indeterminate solitary pulmonary nodules. PMID- 8683318 TI - Simplified measurement of deoxyglucose utilization rate. AB - The reliability of the dose uptake ratio (DUR), a widely used index of 18F-fluoro 2-deoxy-D-glucose (18FDG) metabolism in a variety of tumors, depends on the overall rate of removal of 18FDG from the circulation. Correcting for this factor is important if DUR is to be used quantitatively for pre- and post-treatment assessments of tumors. METHODS: We developed a simplified kinetic method (SKM), based on measured blood curves from a control group, which requires one venous blood sample. We compared the simplified method to the conventional kinetic method and the widely used DUR index in 13 patients with grade 3 or 4 non-small cell lung carcinoma. Studies were obtained before and after treatment. In all patients, dynamic PET imaging and blood activity measurement was performed for 80 min. The utilization rate of 18FDG (MRDGlc) was calculated by using a three compartment model and correlated with a 55-min measurement of DUR and with the simplified kinetic method. RESULTS: Coefficients of determination (R2) between MRDGlc and DUR before and after treatment were 0.53 and 0.71, respectively. Using the SKM, these values improved significantly (p < 0.0001) to 0.96 and 0.94, respectively. The pooled pre- and post-treatment coefficient of determination for DUR versus MRDGlc was 0.81; for SKM, it improved significantly (p < 0.001) to 0.98. CONCLUSION: These results indicate that the observed tumor tissue uptake of 18FDG, corrected for blood 18FDG activity and glucose concentration, can reliably predict glucose metabolic rate from a single static image acquired at between 45 min and 1 hr after injection. This has substantial implications for the quantitative use of 18FDG PET to diagnose and manage malignancy. PMID- 8683319 TI - Thallium-201 uptake, histopathological differentiation and Na-K ATPase in lung adenocarcinoma. AB - To clarify differences in accumulation in 201 Tl scintigraphy, we examined the relationship between uptake of 201 Tl, histopathological differentiation and Na-K ATPase. METHODS: Thallium-201 SPECT was performed twice: 15 min (early scan) and 120 min (delayed scan) after intravenous injection of 3 mCi 201 Tl-chloride. The uptake ratio of 201 Tl was calculated and compared with the grade of differentiation and the staining pattern of Na-K ATPase. RESULTS: The sensitivity of 201 Tl SPECT for well-differentiated adenocarcinomas was lower than that for moderately and poorly differentiated ones. The uptake ratio on the delayed scan was significantly lower in the well-differentiated group than that in the moderately and poorly differentiated groups. This parameter was also significantly higher in the Na-K ATPase-positive group than the -negative group. CONCLUSIONS: These results indicate that the uptake ratio of 201 Tl SPECT may be a noninvasive indicator of the grade of pathological differentiation of adenocarcinoma and provide insight into the relationship among 201 Tl SPECT, malignancy and Na-K ATPase. PMID- 8683320 TI - Ultrasound-guided internal radiotherapy using yttrium-90-glass microspheres for liver malignancies. AB - Treatment of liver malignancies, in particular hepatocellular carcinoma, remains a serious problem because of the difficulty of delivering adequate therapeutic agents to the lesions while sparing the surrounding normal tissue. In an attempt to overcome this obstacle, intratumoral injection of 90Y, a beta-emitter, was performed. METHODS: Twenty-seven hepatocellular carcinomas and six liver metastases were studied, most of which had failed other therapeutic modalities. Guided by ultrasound, 90Y-glass microspheres (GMS) were carefully injected into predetermined tumor sites. The procedure was repeated at 3--4-wk intervals where indicated. Echographic, clinical and laboratory follow-up was conducted at regular intervals. RESULTS: Twelve to 32 mo after treatment, 27 patients were still alive, with dramatic improvement of their clinical condition: 90.6% of the tumor foci became smaller, with echogenic or blood flow changes on liver sonograms. Serum titers of alpha-FP in 10 of 13 patients returned to normal levels. Repeat biopsy in nine patients showed complete tumor destruction in eight. Six patients died of either end-stage disease or wide dispersion of the tumor. CONCLUSION: The intratumoral administration of 90Y-GMS under ultrasound guidance yielded a higher cure rate for liver malignancy with no severe side effects. The higher radiation dosage delivered by injected 90Y to the periphery of the lesions (up to 28,215-75,720 cGy) was thought to account for the successful outcome. These results show that intratumoral radionuclide injection is feasible for treatment of malignant lesions inside the body. PMID- 8683321 TI - New treatment approaches to liver tumors. PMID- 8683322 TI - Lymphatic drainage to triangular intermuscular space lymph nodes in melanoma on the back. AB - METHODS: Lymphoscintigraphy with 99mTc-antimony sulphide colloid was performed on patients with cutaneous melanoma of the back to define draining node fields and sentinel nodes before surgery. RESULTS: One patient was found to have drainage from the back to sentinel lymph nodes in the triangular intermuscular spaces bilaterally, above and lateral to the scapula. Subsequently, drainage to this node field has been found in 26% of 42 consecutive patients who have had lymphoscintigraphy performed for melanoma on the back. CONCLUSION: When performing lymphoscintigraphy to locate draining node fields and sentinel nodes in patients with melanoma on the back, it is important to look for drainage to the triangular intermuscular space node field by obtaining posterior and lateral scans. Any sentinel lymph nodes found in this field should be marked prior to surgery in the same way as nodes in other node fields are delineated so that they may be removed at surgery. PMID- 8683323 TI - Quantitative comparison of direct antibody labeling and tumor pretargeting in uveal melanoma. AB - SPECT radioimmunoscintigraphy with 99mTc-labeled anti-melanoma monoclonal antibodies (MAbs) 225.28S is being used to detect uveal melanoma. Recently, pretargeting methods have been described to reduce background activity and perform imaging in a shorter time interval. METHODS: We compared the three-step pretargeting method with conventional radioimmunoscintigraphy in 15 patients with a clinical and laboratory diagnosis of uveal lesion. High-resolution SPECT radioimmunoscintigraphy was performed in all patients with directly labeled MAbs and, 1 wk later, with the three-step pretargeting technique. Eleven patients underwent eye enucleation and specimens of uveal melanoma were available for histology, whereas four patients underwent conservative therapy. The percent injected dose (%ID) delivered to the tumor and the tumor-to-background ratio were calculated. RESULTS: In all three-step radioimmunoscintigraphy studies, there was a reduction of nonspecific nasopharyngeal background. The three-step radioimmunoscintigraphy tumor-to-nontumor ratio was 3.1 +/- 1.3 versus 1.5 +/- 0.5 of conventional radioimmunoscintigraphy, while the percent injected dose on the tumor was similar for the two methods (4.4 +/- 3.0 versus 3.8 +/- 2.8) x 10( 3). CONCLUSION: Improved SPECT imaging with the three-step radioimmunoscintigraphy results from reduced background and from higher counting statistics due to reduction of time interval between radiotracer administration and imaging, whereas the absolute amount of tracer delivered to the tumor by the two methods is comparable. PMID- 8683324 TI - Reproducibility of lymphoscintigraphy for lymphatic mapping in cutaneous melanoma. AB - One of the indications for lymphoscintigraphy in patients with melanoma is to determine the lymphatic drainage pattern and position of the first draining lymph node--the sentinel node. Metastasis in the sentinel node indicates the need for therapeutic lymph node dissection. The purpose of the present study was to examine the reproducibility of lymphoscintigraphy in assessing the location and number of sentinel nodes. METHODS: Twenty-five patients with clinically localized melanoma were investigated. The same investigator performed two scintigraphic studies with a 2-4 wk interval in each patient, in an identical manner. A 60-MBq dose of 99mTc-nanocolloid was injected intradermally at the primary tumor site. The lymph flow was studied dynamically, complemented by lateral/oblique views. The images were evaluated by a panel of three observers. RESULTS: The sentinel node was visualized within 20 min in all patients. A difference in number of sentinel nodes depicted on the first and second study was noted in three patients (12%). The melanoma was situated on the head (two patients) and arm (one patient) in these patients. Otherwise, the images were identical for number and location of nodes. CONCLUSIONS: Reproducibility of lymphoscintigraphy with 99mTc nanocolloid was high in this study. However, some sentinel nodes may be missed in lymphoscintigraphy for melanoma. PMID- 8683325 TI - Does bone SPECT actually have lower sensitivity for detecting vertebral metastasis than MRI? AB - We compared the ability of bone SPECT and MRI to detect vertebral metastasis. METHODS: Skeletal scintigraphy, including planar and SPECT imaging, and spinal MRI examinations, were performed in 22 cancer patients in whom a total of 88 metastatic foci and 12 degenerative joint disease lesions were detected. Metastatic foci were defined as lesions that suggested metastasis on MRI and/or bone destruction on radiographs or CT and/or aggravation of increased tracer uptakes on serial bone scans. Image reconstruction of axial, coronal and sagittal sections was processed in a 128 X 128 matrix. MRI studies were performed with a 1.5 tesla signal scanner using fast spin-echo sequences. T1- and T2-weighted images were obtained in the sagittal plane. RESULTS: Twenty patients had at least one vertebral metastasis. MRI diagnosed 86 of the 88 (97.7%) metastatic foci; bone SPECT correctly diagnosed 81 of 88 (92.0%); and planar imaging detected 62 of 88 (70.4%). The two vertebrae with metastasis not detected by MRI were clearly seen by bone SPECT. Extra-vertebral body metastases (e.g. in the pedicle, lamina, transverse and spinous processes) were, however, most often detected by SPECT, followed by MRI and planar imaging (40 versus 32 versus 4). CONCLUSION: Vertebral SPECT, using high-resolution SPECT equipment, produced excellent results that were comparable to and complementary with MRI in detecting vertebral metastasis. Our data suggest that vertebral SPECT is superior to MRI in detecting extra vertebral body metastasis. PMID- 8683326 TI - Bone marrow scintigraphy using technetium-99m-antigranulocyte antibody in hematologic disorders. AB - Bone marrow is the primary site for many hematologic disorders. To date, however, no suitable bone marrow imaging method has been found. The present study investigates the usefulness of bone marrow immunoscintigraphy using 99mTc-labeled antigranulocyte antibody (anti-NCA-95) in 31 patients with hematologic disorders. METHODS: One milligram of antibody labeled with 259-370 MBq 99mTc was injected intravenously, and bone marrow images were taken 4 hr later. We also calculated the uptake ratios of lumbar bone marrow-to-background (L/B) and ilium-to background (I/B). RESULTS: Of 15 patients with aplastic anemia, 7 showed diffusely decreased antibody uptake (L/B = 2.3 +/- 0.8, I/B = 3.0 +/- 0.8) compared to control patients (n = 21, L/B = 8.2 +/- 2.5, I/B = 10.3 +/- 3.1) Six patients had both decreased and increased uptake areas and two had normal to slightly increased uptake. Of those patients receiving various types of therapy for aplastic anemia, all but one showed increased or irregular uptake. The degree of antibody uptake in the bone marrow correlated with peripheral blood analyses (hemoglobin, white blood cells, platelets). Of six patients with myelodysplastic syndrome, four had irregular uptake and two diffusely decreased uptake. Four patients with myelogenous leukemia showed normal uptake, whereas two with lymphocytic leukemia had decreased uptake. Patients with iron deficiency anemia, pure red cell aplasia or thalassemia minor exhibited normal uptake with bone marrow expansion. CONCLUSION: Immunoscintigraphy with antigranulocyte antibody is a useful method for evaluating the bone marrow status of patients with various hematologic disorders. PMID- 8683327 TI - Noninvasive evaluation of the bone marrow. PMID- 8683328 TI - FDG-PET to evaluate response to hyperthermic isolated limb perfusion for locally advanced soft-tissue sarcoma. AB - We investigated FDG-PET in patients undergoing hyperthermic isolated limb perfusion (HILP) with rTNF-alpha, rIFN-gamma and melphalan for locally advanced soft-tissue sarcoma of the extremities. METHODS: Twenty patients (11 women, 9 men; aged 18-80 yr, mean age 49 yr) were studied. FDG-PET studies were performed before, 2 and 8 wk after HILP. After the final PET study, the tumor was resected and pathologically graded. Patients with pathologically complete response (pCR) showed no viable tumor after treatment. Those with pathologically partial response (pPR) showed various amounts of viable tumor in the resected specimens. RESULTS: Seven patients showed a pCR (35%) and 12 patients showed a pPR (60%). In one patient, pathological examination was not performed (5%). The pre-perfusion glucose consumption in the pCR group was significantly higher than in the pPR group (p<0.05). Visual analysis of the PET images after perfusion showed a rim of increased FDG uptake around the core of absent FDG uptake in 12 patients. The rim signal contained a fibrous pseudocapsule with inflammatory tissue in the pCR group, viable tumor was seen in the pPR group. The glucose consumption in the pCR group at 2 and 8 wk after perfusion had decreased significantly (p<0.05) in comparison to the glucose consumption in the pPR. CONCLUSION: Based on the pretreatment glucose consumption in soft-tissue sarcomas, one could predict the probability of a patient achieving complete pathological response after HILP. FDG PET indicated the pathological tumor response to HILP, although the lack of specificity of FDG, in terms of differentiation between an inflammatory response and viable tumor tissue, hampered the discrimination between pCR and pPR. PMID- 8683329 TI - Thymic uptake of iodine-131 in the anterior mediastinum. AB - Two thyroidectomized patients with a history of differentiated thyroid carcinoma are presented who had nonmetastatic mediastinal 131I uptake following therapeutic doses of 131I. Chest CT scans in both patients demonstrated an anterior mediastinal mass. Surgical excision in one patient and a percutaneous CT-guided fine needle aspiration biopsy in the other disclosed normal thymus tissue. Iodine 131 uptake in the anterior mediastinum in patients thyroidectomized for follicular or papillary thyroid carcinoma may represent the thymus. PMID- 8683330 TI - Isolated porta hepatis metastasis of papillary thyroid cancer. AB - Metastases from differentiated thyroid cancer are usually seen in the cervical or mediastinal lymph nodes, lung or bone. We report a case of papillary thyroid cancer metastasizing to lymph nodes in the porta hepatis. No other site of metastasis was apparent on neck or abdominal exploration or on iodine whole-body scans. The primary tumor was a multifocal papillary thyroid cancer arising on a background of multinodular goiter. The metastasis was observed on a diagnostic radioiodine scan after surgical resection of the primary tumor despite significant (11%) radioiodine uptake by residual thyroid tissue in the neck and was proven by histologic examination and thyroglobulin immunohistochemistry. Although rare, metastasis to porta hepatis lymph nodes should be considered in the differential diagnosis of abdominal radioiodine uptake in patients with differentiated thyroid cancer. PMID- 8683332 TI - Focal accumulation of iodine-123-BMIPP in liposarcoma of the thigh. AB - Findings for focal accumulation of 123I-15-(p-iodophenyl)-3-R,S methylpentadecanoic acid ([123I]BMIPP) in a patient with liposarcoma of the thigh are presented. Iodine-123-BMIPP accumulated heterogeneously in the liposarcoma. The region with marked accumulation of [123I]BMIPP was diagnosed as mixoid liposarcoma. The region with little accumulation of [123I]BMIPP was diagnosed as well-differentiated liposarcoma. Differences in the accumulation of [123I]BMIPP may reflect differences in fatty acid metabolism between histopathological types of liposarcoma. PMID- 8683331 TI - Gallium-67 imaging of pericardial lymphoma in AIDS. AB - A 33-yr-old homosexual man with acquired immune deficiency syndrome (AIDS) and Mycobacterium avium intracellulare (MAI) infection presented with fever, sweats, lethargy and dyspnea. A chest radiograph showed cardiomegaly and an echocardiograph revealed a large pericardial effusion. After pericardial aspiration, which confirmed T cell non-Hodgkin's lymphoma, he remained dyspneic. Gallium-67 imaging was performed to determine whether the patient's residual dyspnea was related to pulmonary MAI infection or lymphomatous infiltration of the heart. Planar 67Ga scintigraphy revealed intense tracer uptake in two areas within the mediastinum and surrounding the entire heart shadow but no evidence of pulmonary MAI infection. SPECT 67Ga scintigraphy precisely localized the two mediastinal abnormalities and demonstrated the tracer uptake around the heart to be pericardial rather than myocardial. Gallium-67 scintigraphy suggested that pericardial lymphoma was the likely basis of the patient's dyspnea. PMID- 8683333 TI - Bone metastasis with superimposed osteomyelitis in prostate cancer. AB - The following case of a male patient with a history of prostate cancer suffering from pain and swelling in the right mandibular area illustrates the well-known diagnostic problem of a superinfected tumor. Orthopan tomography and CT showed no defects in bone structure or smooth tissue. Whole-body bone scanning showed increased tracer uptake in the mandibular bone and in several other locations in the skeletal system. Antigranulocyte immunoscintigraphy showed increased uptake over the right mandible, whereas the other metastatic sites were visualized as cold spots. A second CT scan depicted a sclerotic lesion with surrounding periostal reaction and soft-tissue swelling and was interpreted as osteomyelitis. Therefore, clinical symptoms, bone scanning, antigranulocyte immunoscintigraphy and follow-up CT resulted in a diagnosis of osteomyelitis, although open needle biopsy revealed the lesion to be prostate cancer metastasis with massive leukocytic invasion. PMID- 8683334 TI - Executive summary from the third report on nutrition monitoring in the United States. PMID- 8683335 TI - Ribonucleic acid nucleotides in maternal and fetal tissues derive almost exclusively from synthesis de novo in pregnant mice. AB - The contributions of dietary nucleotides and nucleotides synthesized de novo to ribonucleic acid synthesis in vivo were estimated by feeding, from d 13 to 18 of gestation, two groups of five pregnant mice a defined diet that contained either uniformly [U13C]-labeled nucleotides or [U13C]-algal amino acids isolated from algal biomass. Ribonucleic acid and protein were isolated from mucosa, liver and fetus. Nucleosides and amino acids were isolated and converted to their trimethylsilyl and n-propyl ester, heptaflurobutyramide derivatives, respectively. The isotopic enrichments of all isotopomers were determined by gas chromatography-mass spectrometry. In the mice that ingested [U13C]-nucleotides, the isotopic enrichment of [Ul3C]-purines (0.03-0.2 mol/100 mol) was significantly (P < 0.001) less than that of [U13C]-uridine (1.5-4.2 mol/100 mol). [13C5]-Purines (0.1-0.8 mol/100 mol) and [13C4]-uridine (0.2-0.5 mol/100 mol) were detected, showing that some dietary bases and ribose were incorporated via the salvage pathway. In mice that Ingested U13C-amino acids, the isotopic enrichment (2-4.6 mol/100 mol) of the [13C2]-purines, which derive from [Ul3C] glycine, was between 73 (liver) and 113% (fetus) of protein-bound 13C2-glycine. The isotopic enrichment (0.8-1.6 mol/100 mol) of [13C3]-uridine, an isotopomer that derives from [U13C]-aspartate, was 50 (liver) to 126% (mucosa) of [13C4] protein-bound aspartate. The results suggest that a large majority of the bases incorporated into maternal and fetal ribonucleic acids derive from synthesis de novo. PMID- 8683336 TI - A high cholesterol, (n-3) polyunsaturated fatty acid diet induces hypercholesterolemia more than a high cholesterol (n-6) polyunsaturated fatty acid diet in hamsters. AB - This study was designed to study the effects of (n-3) polyunsaturated fatty acids (PUFA) on plasma and liver lipids, particularly lipoprotein cholesterol concentrations, in hamsters. Diets rich in (n-3) PUFA (21 g/100 g fatty acid) or (n-6) PUFA (37.4 g/ 100 g fatty acid) with or without 5 g/kg cholesterol (C) supplements were given for 4 wk to male hamsters weighing 70-90 g. The VLDL- and (IDL + LDL)-cholesterol concentrations were 114 and 128% higher in hamsters fed the (n-3) PUFA + C diet than in those fed the (n-6) PUFA + C diet. However, these differences were not observed when cholesterol was not supplemented. Hamsters fed the (n-3) PUFA diet had significantly lower plasma and hepatic triglyceride concentrations than those fed the (n-6) PUFA diet. Concentrations were comparable in hamsters fed (n-6) PUFA + C and (n-3) PUFA + C. Hepatic cholesteryl esters were significantly lower, while hepatic microsomal acyl-CoA:cholesterol acyltransferase activity and VLDL cholesteryl esters were significantly higher in hamsters fed the (n-3) PUFA + C diet than in those fed the (n-6) PUFA + C diet. Our results demonstrate that elevation of VLDL- and (IDL + LDL)-cholesterol in hamsters by (n-3) PUFA, compared with (n-6) PUFA, is dependent on dietary cholesterol supplementation and may be due to decreased catabolism of these lipoproteins. PMID- 8683337 TI - Pectin feeding influences fecal bile acid excretion, hepatic bile acid and cholesterol synthesis and serum cholesterol in rats. AB - This study was designed to investigate the effects of pectin on cholesterol and bile acid metabolism and to elucidate the mechanisms involved in its hypolipidemic effect in rats. The key regulatory enzymes in cholesterol and bile acid metabolism, 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) and cholesterol 7alpha-hydroxylase, were determined. Circulating, hepatic, and biliary lipid concentrations and fecal bile acid excretion were also measured. Male Wistar rats were fed a fiber-free or a pectin-supplemented (7 g/100 g) diet for 4 wk. Bile flow and the biliary secretion of both bile acids and cholesterol were not significantly different than controls in pectin-fed rats. The addition of pectin to the diet resulted in lower serum and liver cholesterol concentrations (-27 and -17%, respectively). Fecal bile acid excretion (+168%) and the hepatic activity of cholesterol 7alpha-hydroxylase (+70%) were significantly higher in pectin-fed animals. HMG-CoA reductase activity was also significantly greater (+11%) in the presence of dietary pectin. Results of our study indicate that pectin, by enhancing fecal bile acid excretion, may cause increased hepatic synthesis of bile acids and liver depletion of cholesterol in rats, which results in a higher rate of cholesterol synthesis and reduced serum cholesterol concentrations. PMID- 8683338 TI - Enhanced expression of hepatic genes in copper-deficient rats detected by the messenger RNA differential display method. AB - The influence of copper (Cu) status on hepatic gene expression was examined by using the "messenger RNA differential display" technology. This method involves the distribution of mRNA in a two-dimensional array for the rapid identification and cloning of differentially expressed genes. Livers from male Sprague-Dawley rats that had been fed a Cu-deficient (CD) diet (9.4 micromol/kg) or a Cu adequate (CA) diet (103.9 micromol/kg) for 6 wk were used to supply cytosolic RNA. Cytosolic RNA were reverse-transcribed in the presence of anchor primers and then amplified by polymerase chain reaction with anchor and arbitrary primer sets. The amplified cDNA were then resolved by denaturing polyacrylamide gel electrophoresis. Differences in mRNA expression between the CD and CA rats were identified. DNA fragments were cloned, sequenced and used as probes for Northern blot analysis to confirm that the identified genes were differentially expressed. The analysis of cDNA sequences by computer searches against DNA and protein databases revealed that one cDNA fragment, whose mRNA abundance was enhanced 1.2 fold by copper deficiency, is novel. Four other cDNA fragments were found to have substantial homology with rat ferritin mRNA; rat fetuin mRNA; rat mitochondrial 12S and 16S rRNA, phenylalanine-, valine- and leucine-tRNA genes; rat mitochondrial genes for 16S rRNA, tRNA-leucine and tRNA-valine; and their mRNA abundance was 0.6- to 0.8-fold higher in Cu-deficient rats. Five additional cDNAs detected by this method appeared to represent novel genes because they exhibited no substantial homology to recorded gene and protein sequences deposited in DNA and protein databases. These results demonstrate the usefulness of this technology in the detection of genes which were differentially expressed as a result of the deprivation of a single nutrient, dietary copper, in this research project. PMID- 8683339 TI - Metallothionein I and II protect against zinc deficiency and zinc toxicity in mice. AB - Metallothionein (MT)-bound zinc accumulates when animals are exposed to excess zinc and is depleted under conditions of zinc deficiency, suggesting that MT serves as a means of sequestering excess zinc as well as a zinc reservoir that can be utilized when zinc is deficient. To examine the importance of MT for these processes, mice with null alleles of both MT I and MT II genes were created and the zinc concentration and histological appearance of multiple organs assessed. At birth, the hepatic zinc concentration of these MT-null mice was lower than that of wild-type controls (0.27 +/- 0.02 vs. 0.65 +/- 0.11 micromol zinc/g tissue, P < 0.05). During the next 3 wk of suckling zinc-replete (95 micrograms zinc/g diet) dams, the hepatic zinc concentration of controls fell to 0.42 +/- 0.04 micromol/g but was unchanged in the MT-null mice (0.28 +/- 0.04 micromol/g). The most prominent histological anomaly observed at 3 wk of age was the presence of swollen Bowman's capsules in the kidneys of MT-null mice. When nursing MT-null dams were fed a severely zinc-deficient (1.5 microg/g) diet, kidney development in the MT-null pups was retarded as indicated by the retention of the nephrogenic zone and incomplete tubule development. We suggest that the lack of a hepatic reservoir of zinc jeopardizes the developing kidney in the MT-null mice. In addition to being more sensitive to dietary zinc restriction, MT-null mice are more sensitive to zinc toxicity. When adult mice were challenged with a ramping dose of zinc up to a total of 3700 micromol zinc/kg body weight, MT-null mice had a greater incidence of pancreatic acinar cell degeneration compared with control mice despite accumulating less zinc (2.72 +/- 0.46 vs. 1.23 +/- 0.52 micromol zinc/g pancreas, control and MT-null, respectively, P < 0.05). The results of these experiments suggest that MT I and MT II can protect against both zinc deficiency and zinc toxicity. PMID- 8683340 TI - Thiamine pyrophosphate-requiring enzymes are altered during pyrithiamine-induced thiamine deficiency in cultured human lymphoblasts. AB - The most common of the severe complications of thiamine deficiency are beriberi and Wernicke-Korsakoff syndrome. To help clarify the biochemical basis for these disorders, a cell culture system has been established in which pyrithiamine, a potent thiamine transport inhibitor, was used to mimic different degrees of thiamine deficiency within human lymphoblasts. Activities of both transketolase and alpha-ketoglutarate dehydrogenase (alpha-KGDH) decreased at the same rate and to roughly the same levels in response to thiamine deficiency within a given cell line. However, variation in sensitivity to thiamine deficiency, as judged by the relative percentage of loss of enzymatic activities, was found when different cell lines were compared. When exogenous thiamine pyrophosphate was added to the activity assays, differences between transketolase and alpha-KGDH became readily apparent. Only 25% of the lost transketolase activity was present as apo-enzyme, whereas 70% of the lost alpha-KGDH activity was present in the apo-enzyme form. For transketolase, the non-recoverable activity was due mainly to a decrease in the synthesis rate of the protein during thiamine deficiency, suggesting that thiamine has a direct effect on the expression of the transketolase gene and/or protein. PMID- 8683341 TI - Very low protein diets induce a rapid decrease in hepatic cAMP-dependent protein kinase followed by a lower increase in adenylyl cyclase activity in rats. AB - Recent evidence indicates that cAMP-mediated responses are desensitized in liver during malnutrition. While receptor-stimulated production of cAMP is increased in hepatocytes from rats fed very low protein diets for 14 d, activity of cAMP dependent protein kinase (PKA) is decreased in liver cytosol. The present study investigated the time course for this desensitization. Weanling rats were fed either a 0.5 (malnourished) or 15% protein (control) diet for 1, 3, 7 or 14 d. Total PKA activity decreased after only 3 d of feeding the low protein diet. This decrease was confined to the cytosolic compartment and was associated with a lower quantity of immunoreactive RI regulatory subunit of PKA, with no difference in the quantity of immunoreactive RII regulatory subunit. In contrast, basal-, MnCl2- and guanine nucleotide regulatory protein-stimulated adenylyl cyclase activities were not greater in liver membranes of malnourished rats than in those of the control rats until the 2nd wk of feeding. Greater activity was paralleled by an increase in the quantity of the stimulatory guanine nucleotide regulatory protein at d 14. The inhibitory guanine nucleotide regulatory protein quantity did not differ between dietary groups. Greater cAMP production was not mediated by changes in PKA phosphorylation of adenylyl cyclase because preincubation of membranes with purified PKA catalytic subunit decreased MnCl2-stimulated cAMP production equally in liver membranes of both control and malnourished rats. Similarly, treatment with alkaline phosphatase decreased adenylyl cyclase activity but did not eliminate the difference in adenylyl cyclase activity between control and malnourished rats. These data demonstrate that loss of PKA activity is an early response to a low protein diet and that, subsequently, a number of molecular adaptations occur which increase cAMP production. These changes may be adaptive responses to malnutrition that maintain essential cAMP dependent functions. PMID- 8683342 TI - Active feeding behavior compensates for low interest in food among young Nicaraguan children. AB - The association of caregivers' feeding behavior with young children's anthropometric status was examined in 80 poor urban families from Nicaragua. Caregiver and child behaviors observed during eating were recorded for midday meals, snacks and bottle feeds. Two kinds of scales were constructed. The Active Feeding Scale measured the caregiver's attempts to encourage or promote the child's food ingestion through behaviors such as verbal encouragement, threatening, offering more food or demonstrating eating. The Child Demand Scale measured the child's interest and enthusiasm for food. Results suggested the following: 1) there were significant differences in caregiver encouragement of feeding by meal type (midday meal, snack or bottle-feed); 2) mothers were significantly more likely to encourage eating than were other caregivers; and 3) active feeding was not associated with child anthropometric status but often appeared to be associated with child disinterest in the meal. It is suggested that active feeding may be used to compensate for child disinterest in food rather than to enhance the child's growth and developmental trajectory. The importance of lack of child interest in food, probably related to poor appetite, needs to be recognized and incorporated into nutrition education programs. PMID- 8683343 TI - Vitamin A-deficient rats have only mild changes in jejunal structure and function. AB - This study investigated the effect of clinical and subclinical vitamin A deficiency on intestinal structure and function in rats. Weanling male rats fed a vitamin A-deficient diet (VA-) for 40-42 or 60-63 d were compared with rats either pair-fed (PF) or with free access to the same diet supplemented with vitamin A (VA+). A reference (REF) group was fed a standard rat diet. Weight began to plateau in VA- rats after 42 d, becoming significantly different from PF rats at 60-63 d (P < 0.02). Diarrhea did not develop in any study group. VA- rats had clinical signs of vitamin A deficiency in the 60-63 d study, but not in the 40-42 d study. However, serum and liver retinol concentrations were negligible in all VA- rats. VA- rats in the 60-63 d study had significantly reduced villus height (P < 0.02), and sucrase and maltase activities (P < 0.02) compared with PF rats. There were no differences between VA- and PF rats in mucosal wet weights, protein and DNA concentrations, thymidine kinase activity and glucose transport. No differences were detected in the 40-42 d study for any variable measured. Because clinical vitamin A deficiency in rats causes only mild changes in intestinal structure and function, it is unlikely that these alterations alone are responsible for the interactions observed in epidemiological studies between vitamin A deficiency and diarrheal disease. PMID- 8683344 TI - Relationship of protein synthesis to mRNA levels in the muscle of chicks under various nutritional conditions. AB - The relationship between the rate of protein synthesis and the level of messenger RNA (mRNA) in the breast muscle (pectoralis major) was studied to examine the mechanisms regulating muscle protein synthesis in chicks under various nutritional conditions. The fractional synthesis rate (FSR) of protein was measured by a large-dose injection of L-[4-3H]phenylalanine. Poly(U)-Sepharose 4B affinity chromatography was used to extract Poly(A)+ RNA as mRNA. The first study examined the effect of dietary protein levels (0-60%) on protein synthesis rate and the contents of mRNA and total RNA. The fractional synthesis rate increased with increasing dietary protein levels from 0 to 20%. When chicks were fed high protein diets (40 and 60% of dietary protein), both the FSR and absolute synthesis rate (ASR) of protein were reduced compared with the 20% protein group. Multiple regression analysis indicated that for graded dietary protein levels below the dietary protein requirement, the response of muscle protein synthesis is largely regulated by variation in the ASR per unit RNA (the efficiency of RNA in synthesizing protein). At dietary protein levels above 20%, synthesis rates are also related to changes in the RNA:mRNA ratio (ribosome number relative to mRNA), the mRNA:DNA ratio (mRNA availability) and the DNA:protein ratio (DNA concentration). When chicks were food deprived for 2 d, FSR was reduced to about half that of well-fed controls. Upon refeeding of these chicks with the control diet, the FSR returned to the normal level within 0.5 h. When food-deprived chicks were refed with protein, carbohydrate or fat alone, the FSR returned to the control level within 0.5 h after consumption of each nutrient. The increase in muscle protein synthesis of unfed chicks following refeeding of various nutrients was explained by an increased ASR per unit RNA. Our results suggest that nutrient intake can change muscle protein synthesis rates in chicks largely by altering the ASR per unit RNA, in some cases associated also with changes in the levels of RNA, mRNA and DNA. PMID- 8683345 TI - Alteration of glutathione and antioxidant status with exercise in unfed and refed rats. AB - The influences of food deprivation and refeeding on glutathione (GSH) status, antioxidant enzyme activity and lipid peroxidation in response to an acute bout of exercise were investigated in the liver and skeletal muscles of male Sprague Dawley rats randomly divided into three groups: starved for 48 h without refeeding; starved for 48 h and refed for 24 or 48 h. Half of each group of rats was exercised on a treadmill until exhaustion and killed immediately, whereas the other half group was killed at rest. Food-deprived rats had significantly lower liver GSH concentration and GSH:glutathione disulfide (GSSG) ratio. Malondialdehyde concentrations in the liver and skeletal muscle were both higher in the starved than in the refed rats (P < 0.05). Refed rats had significantly greater liver GSH level, gamma-glutamylcysteine synthetase and glucose 6 phosphate dehydrogenase activities and plasma insulin concentration than unfed rats. Exercised 24- and 48-h refed rats had 27% and 31 % lower liver GSH (P < 0.05), respectively, and a 21 % lower GSH:GSSG ratio (P < 0.05) than their rested counterparts. Plasma insulin concentrations were significantly lower, whereas glucagon concentrations were greater in the exercised than in the rested rats. Muscle GSH concentration was significantly lower in the food-deprived than in the refed rats (P < 0.05) but was unaffected by exercise. Exercised 24-h refed rats had significantly elevated muscle GSSG concentration compared with rested rats, along with a higher GSH peroxidase and a lower gamma-glutamyltranspeptidase activity (P < 0.05). These data indicate that both food deprivation-refeeding and exhaustive exercise influence liver and skeletal muscle glutathione status and that these changes may be controlled by hepatic glutathione synthesis and release due to hormonal stimulation. PMID- 8683346 TI - Maintenance requirement for valine and efficiency of its use above maintenance for accretion of whole body valine and protein in young chicks. AB - Experiments were conducted with chicks during the period 10-20 d posthatching to assess valine accretion and protein accretion as a function of incremental valine intakes between 5 and 95% of its ideal level (requirement for maximal growth). Chemically defined crystalline amino acid diets were fed, and amino acids other than valine were maintained at minimized excess levels as valine was increased. With dietary valine concentrations representing 5, 10, 40, 55, 70 and 95% of the ideal level, weight gain (r2 = 0.98), protein accretion (r2 = 0.98) and valine accretion (r2 = 0.99) increased linearly (P < 0.01) as a function of valine intake. Slope of the valine accretion curve was 0.73 +/- 0.02, and there was no indication of decreased valine utilization as valine intake increased to 95% of its required level for maximal growth. Using the linear regression equation, i.e., valine accretion (Y) regressed on valine intake (X), the maintenance valine requirement (X at Y zero) was 18.4 mg/d or 48.8 mg/d per kg body weight3/4. Whole body valine was 4.72 g/100 g whole body protein accreted and was constant at all levels of valine intake. At zero protein accretion, however, valine accretion was negative (-3.8 mg/d). Thus, the valine requirement for zero valine accretion (48.8 mg/d per kg(3/4) was higher than the valine requirement for zero protein accretion (32.4 mg/d per kg3/4). In a subsequent experiment, also involving whole body valine and protein accretion, valine doses of 40, 55 and 70% of ideal were compared using amino acid-balanced diets (amino acids other than valine at 55, 70 and 85% of ideal levels, respectively) or imbalanced diets (amino acids other than valine at a constant 100% of their ideal levels). Straight-line (P < 0.01) valine and protein accretion responses occurred, but slope of the response curves (accretion vs. valine intake) was lower in the imbalanced series than in the balanced series. The results of these studies suggest a constant utilization above maintenance of absorbed valine over a wide range of valine intake. PMID- 8683347 TI - The metabolite profile of radioisotope-labeled biotin in rats indicates that rat biotin metabolism is similar to that in humans. AB - The egg white-fed rat is the most commonly used animal model of human biotin deficiency. We sought to determine whether the urinary excretion rates of biotin and biotin metabolites in rats are similar to those reported in humans. D (Carbonyl-14C)biotin was injected intraperitoneally at physiologic doses in 6- to 10-wk-old rats; HPLC and radiometric flow detection were used to specifically identify and quantify biotin and metabolites in urine. Substantial amounts of bisnorbiotin and biotin sulfoxide, the two principal human metabolites, were detected. The excretion rates of biotin and metabolites were strikingly dependent on the dose of biotin. When the dose of [14C]biotin was 30% of the daily dietary intake (a physiologic dose), 50% of the administered 14C was excreted within 24 h; more than half of the excretion was the unchanged vitamin. After d 1, [14C]bisnorbiotin was the major form excreted. For the cumulative 5-d excretion, [14C]biotin accounted for 46 +/- 9%, [14C]bisnorbiotin accounted for 47 +/- 11 %, and [14C]biotin sulfoxide accounted for 8 +/- 4% of the total of biotin, bisnorbiotin, and biotin sulfoxide recovered radioactivity (mean +/- 1 SD, n = 6). These proportions are similar to those reported in humans: biotin = 52 +/- 12%, bisnorbiotin = 35 +/- 9%, and biotin sulfoxide = 13 +/- 4% of total biotin plus metabolites (mean +/- 1 SD, n = 10). Thus, these studies confirm the earlier identification of bisnorbiotin and biotin sulfoxide as the two principal biotin metabolites and provide evidence that the rat is an appropriate model for human biotin metabolism. PMID- 8683348 TI - Dietary iron levels and hypoxia independently affect iron absorption in mice. AB - The effect of dietary iron levels on the hypoxic response of iron absorption was investigated by feeding mice diets of different iron composition and determining iron absorption. Eight groups of mice were fed a purified diet consisting of casein, corn oil and sucrose with vitamins and iron-free mineral supplements. Groups A-D were fed a nonpurified diet until 6 wk old and then switched to purified diet for 4 d. Groups E-H were fed purified diet for 4 wk from weaning. Groups C, D, G and H were exposed to hypoxia (53.3 kPa) for the last 3 d of the study. Groups A, C, E and G received the low iron purified diet (<1 mg iron per kg); the other groups received the same diet supplemented with 62 mg/kg iron as FeCl3 x 6H2O. Hypoxic exposure raised iron absorption (P < 0.001) by a similar proportion (2.5- to 5.0-fold) in all mice but did not affect duodenal nonheme iron levels. Low iron diet feeding raised iron absorption but reduced duodenal and liver nonheme iron levels. In a second experiment, mice fed nonpurified diet were divided into four groups and exposed to normal atmosphere or hypoxia (53.3 kPa) with or without dosing with 100 microg iron by stomach tube 1 h before determining iron absorption. There was no effect of iron dosing on iron absorption at either pressure. The data suggest that the control of iron absorption by tissue oxygen acts through a mechanism independent of the control exerted by dietary or mucosal iron levels. PMID- 8683349 TI - Dietary xylitol, sorbitol and D-mannitol but not erythritol retard bone resorption in rats. AB - The aim of the present study was to compare the ability of four dietary polyols to reduce bone resorption. Urinary excretion of 3H radioactivity from [3H]tetracycline-prelabeled rats was used as a marker of bone resorption. After prelabeling, the rats were divided randomly into five groups of 10, and fed for 1 mo a nonpurified diet that was supplemented in four groups with either xylitol, sorbitol, D-mannitol or erythritol, respectively, to give a polyol concentration of 1 mol/kg. Xylitol (42%), sorbitol (44%) and to a lesser degree D-mannitol (23%) decreased the excretion of 3H relative to the basal diet. The erythritol group, however, did not differ from the controls. Sorbitol caused continuous diarrhea, whereas in the other groups, intestinal adaptation took place during the 1st wk of polyol feeding. In conclusion, dietary xylitol, sorbitol and to a lesser degree D-mannitol supplementations in rats retard bone resorption, whereas dietary erythritol has no effect. PMID- 8683350 TI - Pattern of amino acid requirements in humans: an interspecies comparison using published amino acid requirement recommendations. AB - We undertook an interspecies comparison of essential (indispensable) amino acid requirements, in relation to those for total protein, to examine whether the current, internationally proposed human amino acid requirement patterns are significantly different from those of other animals. Data were compiled in their original form and then expressed as mg amino acid/g total dietary protein (N X 6.25) required (amino acid requirement pattern). Patterns of requirements within the various species were organized according to four, arbitrary age-developmental groupings (very young, early growth, growth and mature), and these were compared with the requirements for (a) human infants, (b) 2-5 year old children, (c) 10-12 year old children and (c) adults, respectively. Statistical comparisons determined if significant differences existed between humans and other species, at apparently similar age-development stages, for both the total and for individual indispensable amino acids. The sum of the specific indispensable amino acid requirements for humans was significantly different than that for other species at infancy, growth and adulthood; the greatest differences, however, were for the amino acid requirement pattern in adulthood. The change between the very young and adult was the greatest for humans. Some of this difference might be due to experimental factors, including the biological status of a species within the arbitrary groupings described and the criteria used to determine "requirements." Nevertheless, it is difficult to escape the conclusion that the current international human amino acid requirements, for adults in particular, appear to be anomalous when judged against data for other animal species. PMID- 8683351 TI - Pectin with low molecular weight and high degree of esterification increases absorption of 58Fe in growing rats. AB - Effects of pectins with different degrees of esterification (DE) and molecular weights (MW) on iron bioavailability were investigated in healthy growing rats by following erythrocyte incorporation of a dose of 58Fe. Rats were fed a control diet for 8 d and then deprived of food for 16 h. Two hours after the start of feeding iron-deficient diets, with or without pectin (80 g/kg diet), a dose of FeSO4 rich in 58Fe (60.28%) was intubated into the stomach; rats were then allowed to feed for an additional 4 h before withdrawal of food for 10 h. Rats were then fed iron-adequate diets for 9 d. The pectins differed in DE and MW, respectively, as follows: P-A (73%, 860,000), P-B (75%, 89,000), P-C (22%, 1,260,000) and P-D (24%, 114,000). Rats fed pectin-free diet with free access to food or restricted to the same quantity consumed by a respective pectin group served as controls. Iron absorption was 48% in the control group and 57% in rats fed P-B. Rats fed P-B had higher (P 2 < or = 0.05) serum iron, transferrin saturation, hematocrit and liver and spleen iron than the control group or the group fed P-C. These indices, except for transferrin saturation, were also higher In rats fed P-A and P-D compared with those fed P-C and controls, but to a lesser extent than in rats fed P-B. The data indicate that bioavailability of dietary non-heme iron was enhanced when pectin of low MW and high DE was added to the diet. This improvement was not evident with pectins having high MW and/or low DE. PMID- 8683352 TI - Vitamin B-6 status of women with a constant intake of vitamin B-6 changes with three levels of dietary protein. AB - To determine the effect of varying levels of dietary protein with a constant intake of vitamin B-6 (B-6) on B-6 status, nine women were fed diets providing daily intakes of 1.25 mg B-6 and 0.5, 1.0 and 2.0 g protein/kg body weight. After an 8-d adjustment period, the women consumed each level of dietary protein for 14 d in a Latin-square design. Several direct and indirect B-6 status indicators were measured in blood and urine. Significant differences among protein levels were found for urinary 4-pyridoxic acid (4-PA) excretion (P < 0.01), plasma pyridoxal 5'-phosphate (PLP) concentration (P < 0.05), and urinary excretion of volatile amines (VA, kynurenine plus acetylkynurenine) after a 2-g L-tryptophan load (P < 0.05). Nitrogen intake was significantly negatively correlated with urinary 4-PA excretion (r = -0.619, P < 0.001) and plasma PLP concentration (r = 0.549, P < 0.01), and positively correlated with erythrocyte alanine aminotransferase percentage stimulation (r = 0.418, P < 0.05) and urinary post tryptophan load excretion of xanthurenic acid (r = 0.535, P < 0.05), kynurenic acid (r = 0.563, P < 0.05) and VA (r = 0.626, P < 0.01). Compared with men consuming diets with similar B-6 to protein ratios In a previous study, the women excreted a greater percentage of the B-6 intake as 4-PA, had lower plasma PLP concentrations and excreted greater amounts of postload urinary tryptophan metabolites at all three protein levels. If the Recommended Dietary Allowance (RDA) of vitamin B-6 is to be based on the dietary B-6 to protein ratio, gender differences in response to varying protein intakes should be considered. For the levels of protein intake used in this study and a B-6 intake of 1.25 mg/d, a B-6 to protein ratio of greater than 0.020 mg/g is required for adequate vitamin B-6 status in women. PMID- 8683353 TI - The rites of spring. PMID- 8683354 TI - Methotrexate for nonsurgical treatment of ectopic pregnancy: nursing implications. AB - Early diagnosis of ectopic pregnancy can provide women an alternative to surgical therapy. Nonsurgical treatment using methotrexate is cost-effective, restores subsequent fertility, and decreases the morbidity and morality intrinsic to traditional surgical procedures. This article reviews the risk factors, signs and symptoms, diagnostic techniques, and nursing care for medically treated ectopic pregnancy. PMID- 8683355 TI - Neonatal nutritional requirements and formula composition: a review. AB - Adequate neonatal nutrition is essential for appropriate growth and avoidance of complications associated with deficiencies. Neonatal nutritional requirements vary with metabolic states, degree of prematurity, and diseases affecting the gastrointestinal, pulmonary, and cardiac systems. Differences exist between formula brands for protein, fat, and carbohydrate sources. Differences also exist between formulas designed for preterm and full-term infants, as well as infants with special nutritional needs. Optimal nutrition should be a consistent goal for each infant, whether in a healthy newborn nursery, intensive-care unit, or home care setting. Nurses must be aware of the possibilities available to address the special needs of infants. PMID- 8683356 TI - Intrathecal narcotics: new approach for labor analgesia. AB - Injection of narcotics in the subarachnoid space is the most recent advancement in managing pain during childbirth. This article reviews the history of labor pain control and discusses the introduction of intrathecal narcotics (ITNs), including administration, side effects, and nursing care, in one birthing center. The responses of clients and nurses to ITNs are discussed. PMID- 8683357 TI - Colposcopy: sensory information for client education. AB - OBJECTIVE: To determine women's sensory experiences during colposcopy and to describe a model for developing sensory information. DESIGN: Four-stage survey design, which included standardizing the procedure, discovering the experience, validating the experience, and writing the message. SETTING: Ambulatory clinics in a large teaching hospital in New Brunswick, Canada. PARTICIPANTS: Sixty women undergoing colposcopy. RESULTS: A valid sensory information message for colposcopy was documented. A model for developing sensory information was derived from a critical appraisal of the four-stage process. The merits of validation interviews were reinforced. CONCLUSIONS: The step-by-step approach outlined in the developmental model provides nurses with precise guidelines for developing other sensory messages. Nurses using a prepared message, such as that provided for colposcopy, need to ensure that it is accurate for their practice setting. PMID- 8683358 TI - Behavioral characteristics of very-low-birth-weight infants of varying biologic risk at 6, 15, and 24 months of age. AB - OBJECTIVE: To explore the relationship between developmental outcome and behavior of very-low-birth-weight (VLBW) infants (< or = 1500 g) at high and low biologic risk. DESIGN: Descriptive, ex post facto. SETTING: Clinic for follow-up of infants at high risk. PARTICIPANTS: A convenience sample of 102 VLBW infants, free of major congenital anomalies, who completed 6-, 15-, and 24-month developmental testing and who were part of a larger study of 274 VLBW infants. MAIN OUTCOME MEASURE: Bayley Scales of Infant Development. RESULTS: Infants at high biologic risk, versus infants at low biologic risk, were less attentive and active through age 15 months and were less adept in gross and fine motor skills through age 24 months (p < or = 0.05-0.001). Infants with continuous delay were less attentive than infants with no delay or late delay through age 24 months, less active through age 15 months (p < or = 0.001-0.001), and less skilled in motor behaviors through age 24 months (p < or = 0.05-0.001). CONCLUSION: Infants at high biologic risk and infants with developmental delays are less attentive, less active, and less skilled in motor tasks during the first 15-24 months of life, suggesting an association between biologic risk and behavior and developmental delay and behavior. PMID- 8683359 TI - Breastfeeding conjoined twins. AB - The breastfeeding experience of a mother and her preterm conjoined twins is described. Assisting the mother in achieving her breastfeeding goal presented unusual nursing-care problems in securing, positioning, and comforting the twins. This case report emphasizes the individualized support provided to this mother and her infants, which was a critical factor in their breastfeeding success. PMID- 8683360 TI - The experience of maternity in a woman's life. AB - A woman's childbearing experience is deeply influenced by the culture of her society. Some of the significant historical events taking place in 20th century America and associated cultural perceptions of women and childbirth are explored. An examination of the long-term personal impact of childbirth on women reveals the importance of the attitudes of caregiving staff and the degree of emotional support they provide. PMID- 8683361 TI - Women, providers, and control. AB - Childbirth in America is dominated by a management perspective that emphasizes the efficient removal of a fetus from a woman's body. This article discusses the obvious and not so obvious ways that routine American management of childbirth systematically strips women of power and control. It is argued that, although providers may be well-meaning and nurturing in their care of childbearing women, their approach is most often nurturing to weakness, rather than strength. PMID- 8683362 TI - Nursing support of the laboring woman. AB - Labor support is one of the most important intrapartum nursing functions, with measurable effects on the outcomes of labor and birth. Supportive activities fall within five categories: emotional support, comfort measures, advocacy, supporting the husband/partner, and information/advice. Labor support is a repertoire of techniques the nurse can use to help women during one of the most memorable and personally challenging experiences of their lives. PMID- 8683363 TI - [Distribution of neuropeptides in the inferior nasal turbinate mucosa of patients with allergic rhinitis]. AB - An immunohistochemical study was made on the distribution of neuropeptides in 36 surgical specimens of the inferior nasal turbinate mucosa obtained from 32 patients with allergic rhinitis. Eleven patients (15 specimens) of the 32 underwent chemosurgery in which trichloracetic acid (TCA) was used before excision. In these patients a watery nasal discharge remained even after TCA application, although the nasal obstruction decreased. As a control, 6 specimens obtained from 6 patients with non-allergic rhinitis were also studied. In the present study, the distribution of Substance P (SP) was examined as an index of the parasympathetic nervous system. The distribution of nerve fibers showing a positive reaction specific to each of the two types of neuropeptides was examined in the frontal sections of the specimens at distances of 5 and 15 mm from the anterior tip of the inferior turbinate. In particular, the modes of the distribution in the superficial and deep layers of the mucosa were compared. It was found that, in the patients with allergic rhinitis who had not undergone TCA treatment, both SP-positive and VIP-positive fibers were abundant in the anterior portion of the turbinate immediately beneath the basement membrane. In those patients who underwent chemosurgery prior to excision, SP-positive fibers were very scarce in both superficial and deep layers, whereas VIP-positive fibers appeared to exist only in the deep layer around the remaining nasal glands. In the specimens obtained from patients with non-allergic rhinitis, there was no appreciable difference in the pattern of distribution of SP-and VIP-positive fibers among different sites of the specimens. The present study would indicate that chemosurgery using TCA inhibited the appearance of neuropeptides and resulted in improvement in clinical symptoms. However, in those patients having a continuous watery discharge even after TCA treatment, the function of the remaining nasal glands might be responsible for the symptom, although the contribution of VIP to the increase in vasopermeability should also be taken into consideration. Further studies are needed to determine the distribution of neuropeptides around the vessel walls. PMID- 8683364 TI - [Immunological determinants and the spread of viral infection in facial nerve paralysis induced by herpes simplex virus in mice]. AB - Herpes simplex virus type 1 (HSV-1) infection of the facial nerve has been strongly suggested as a cause of Bell's palsy. The author's group have produced a transient and homolateral facial paralysis in Balb/c mice by inoculating HSV-1 onto the auricle, simulating the symptoms of Bell's palsy. To clarify whether and how age and specific immunity against HSV-1 are involved in the pathogenesis of facial nerve paralysis, age dependent susceptibility to the virus and passive immunization with anti-HSV-1 antibody or immunized splenic T cells were investigated in a mouse model system. Following inoculation of HSV-1 into 3-week old mice, 80% of the animals died whereas only 13% of 4-to 5-week-old mice died, and 50% developed facial nerve paralysis 1 week after the inoculation. No 6-week old mice died and 6% developed facial nerve paralysis. Although all mice showed seroconversion of neutralizing antibody regardless of the presence of facial nerve paralysis, six-week-old mice and 4-week-old mice without facial nerve paralysis produce higher titers of anti-HSV-1 antibody than 4-week-old-mice with facial nerve paralysis. These results suggested that the age and the immunological potential of mice are closely related to the pathogenesis of facial nerve paralysis. Passive transfer of either anti-HSV-1 antibody or HSV-1 immunized splenic T cells into 4-week-old mice prevented development of facial nerve paralysis and death if they were transferred within 3 hours postinoculation. However, a similar transfer 48 or 96 hours after HSV-1 inoculation did not produce such protection. HSV-1 DNAs were detected in the facial nerve as early as 48 hours postinoculation by polymerase chain reaction (PCR). These results indicate that the passive immunization, providing both cellular and humoral immunity, is effective for preventing facial nerve paralysis if performed before virus infects the facial nerve. The nervous system has a blood-nerve barrier (BNB) which privileges it from the peripheral immune system. Therefore, once the virus infects the facial nerve, passive immunity transferred from peripheral vessel might be excluded from the virus or virus-infected cells unless the BNB is broken down. Bell's palsy is thought to occur during the course of HSV-1 latency in the geniculate ganglion. If we could reactivate latently infected virus and produce facial nerve paralysis again in the animal model, this might provide clues to clarify not only the pathological mechanism of Bell's palsy but also the interaction between immune system and virus reactivation. PMID- 8683365 TI - [Case reports of mucosal melanoma of the head and neck]. AB - Twelve patients with mucosal melanoma in the head and neck were treated at Yokohama city University from 1975 to 1994. The sex distribution was 5 male and 7 female, and the age ranged from 40 to 79 years-old. The highest number of patients were in their sixties. In 10 cases tumors arose in the nasal cavity, in one case in the maxillary sinus and in other case in the oral cavity. The treatment modality for this tumor consisted of various combination therapies including surgery, radiotherapy, chemotherapy and immunotherapy. Combination chemotherapy consisting of dimethyltriazeno imidazole carboxamide (DTIC, Dacarbazine), amino methyl pyrimidinyl methyl chlorethyl nitrorosourea hydrochloride (ACNU) and vincristine (VCR). Cisplatin (CDDP) was recently used for cases where other chemotherapy was not effective. Surgical treatment in the initial therapy was performed in 8 patients. In three of these 8 cases, the surgical margin was positive. One of them was dead after 9 months, another dead with complication after 1 year and the other survived free of any tumor. Immunotherapy using OK-432, interleukin-2, LAK therapy and low dose CPM was effective for some patients. The 5-year survival rate was 44%. Patients with surgical treatments in the initial therapy had longer survival than those without surgical treatments. PMID- 8683366 TI - [A longitudinal study of hearing level aggravation due to aging]. AB - It has been reported that hearing aggravation due to aging is predominantly in the high frequency range and that there are rapid and slow phase of aggravation in hearing level. In the present study, the pattern of aggravation of hearing level due to aging was investigated in 387 adults of over 35 years of age who had visited the Kitasato Health Science Center for a regular health check-up annually for more than 5 years, and were diagnosed as having neither external of middle ear diseases nor hearing impairment of obvious origin at their first visit. The subjects were divided into 8 groups according to their ages in increments of 5 years. Their audiograms were obtained annually, and the results were used to obtain the distribution of the hearing level at each test frequency. All of the subjects were examined for individual changes in audiograms and those who showed 20 dB or more aggravation of hearing in a 1-year period without subsequent improvement were defined as having a rapid phase of aggravation. There were clustering points in hearing distribution at around 30 dB and 60 dB at the test frequency of 8 kHz in those subjects showing a rapid phase of aggravation. Similar clustering points were also noted in those subjects who showed gradual aggravation of 20 dB or more in a 5-year period and who had 20 dB or more aggravation in one year but showed later improvement. As for the test frequencies lower than 4 kHz, there appeared to be a clustering point at around 30 dB. The incidence of the rapid phase of aggravation was then determined in each group, in order to investigate the relationship between aging and the appearance of the rapid phase of aggravation. The rapid phase was already noted in the youngest age group (range, 35-39 years), while the incidence gradually increased up to the 50 54-year group and stayed at a constant level in the 55-69-year groups. The incidence markedly decreased thereafter. The results suggest that hearing aggravation due to aging does not occur at any particular age. Rather, the hearing aggravation appeared to be closely related to the hearing level, and to manifest itself when the hearing level approaches 30 dB or 60 dB. PMID- 8683367 TI - [Neuroendocrine carcinomas of the head and neck]. AB - Neuroendocrine carcinomas (NECs) of the head and neck are rare. Between 1980 and 1995, only 163 cases of laryngeal and 30 cases of sinonasal NEC had been reported worldwide. We report two cases of sinonasal NEC. Case 1: A 49-year-old man complaining of left nasal obstruction was admitted to our hospital. A tumor with a tendency to bleed was seen in the left nasal cavity. CT scanning revealed an enhanced mass in the left nasal cavity and both maxillary and ethmoid sinuses. An open biopsy was performed to determine the diagnosis. The diagnosis of NEC was based on light microscopic and immunohistochemical findings. Chemotherapy and radiation were performed, but bone, liver and brain metastasis occurred 15 months after diagnosis and the patient died. Case 2: A 59-year-old man, complaining of right forehead swelling visited our department. CT scanning and MRI revealed that the right ethmoid sinus was filled by a tumor which had invaded the base of the skull. An open biopsy was performed. From the results of light microscopic and immunohistochemical investigations, NEC was highly suspected. Chemotherapy and radiation were performed, but the patient died 6 months after diagnosis. This study shows that there are aggressive types of nasal NEC, although these sinonasal carcinomas were reported in the literature to be not very lethal. The diagnosis, histopathological classification, treatment, and prognosis of sinonasal and laryngeal NECs were reviewed. PMID- 8683368 TI - [Comparison of speech perception with cochlear implant and hearing aid--analysis according to speech strategy and hearing level]. AB - This study was carried out to compare the speech perception ability of patients using hearing aids with hearing levels of 81dB or more (55 patients) and those with cochlear implants (67 patients). The patients with hearing aids were divided into group A (hearing levels 81-90dB, 7 patients), group B (91-100dB, 11 patients), group C (101-110dB, 19 patients), group D (111-120dB, 7 patients), and group E (121-130dB, 6 patients). The patients with cochlear implants were using the strategies of F0F1F2 (14 patients), MPEAK (32 patients) and SPEAK (21 patients). Speech perception tests of monosyllables, words, and sentences under conditions of auditory plus vision were administered. The means and standard deviations of percentages giving the correct answer in F0F1F2, MPEAK and SPEAK were 45.2 +/- 14.7%, 45.7 +/- 14.6% and 62.6 +/- 15.9% for monosyllables, 44.8 +/ 18.9%, 56.3 +/- 15.0% and 73.4 +/- 15.5% for words, and 64.0 +/- 26.4%, 60.5 +/- 15.9% and 84.7 +/- 13.8% for sentences. In comparison with the results for patients with hearing aids, and speech perception for F0F1F2 and MPEAK was equivalent to that of group C, and that for SPEAK was better than that of group B but poorer than that of group A. In other words, the speech perception ability in conventional cochlear implant strategies--F0F1F2 and MPEAK--corresponded to that of patients with hearing levels of 101-110dB, but that in the new strategy, SPEAK, gave better results than 91-100dB. PMID- 8683369 TI - [Assessment of cochlear functions of patients with acoustic neuromas]. AB - Electrocochleographic cochlear microphonics (ECochG-CM) and Evoked Otoacoustic Emissions (EOAE) were recorded for 17 patients with acoustic neuromas to assess their cochlear functions. ECochG-CM was recorded by a transtympanic needle electrode technique. The acoustic stimuli of EOAE were short tone bursts and thresholds of detection of the slow components were determined. In 13 of the 17 patients, elevated detection thresholds of ECochG-CM and/or abnormal interaural differences in detection thresholds of the slow components of EOAE were observed. The patients with hearing loss and an elevated thresholds of CM were believed to have cochlear impairments. Those with hearing loss and a relatively low detection threshold of CM were thought to have cochlear nerve damage and a smaller degree of cochlear impairment. The correlation of ECochG-CM and EAOE was 0.799. Both ECochG-CM and EOAE were useful in evaluating the cochlear functions of patients with acoustic neuromas. Although EOAE was easier to apply clinically, ECochG was indispensable when detailed examinations of cochlear functions were necessary. PMID- 8683370 TI - [Quantitative analysis of color of the nasal mucosa]. AB - The color of the nasal mucosa was quantitatively studied. Chromaticity of the nasal mucosa was indicated by two parameters, x (red component in RGB) and y (green in RGB) values, measured with a chromameter (MINOLTA Co., CS-100). According to preliminary studies in normal subjects, the following conditions were thought to make the method suitable for measuring the color of the nasal mucosa. 1) The chromameter can be held in the hand. 2) Brightness of the nasal mucosa should be kept as constant as possible. 3) The inferior turbinate mucosa is easier to measure than the septal one. In the preliminary study there was no significant difference in chromaticity measurements among the examiners. Chromaticity of the inferior turbinate was compared among patients with perennial nasal allergy (PNA, n = 19), with cedar pollinosis (CP, n = 11), and normal subjects serving as a control (n = 15). The x values in the PNA and CP groups were significantly lower than those in the control group (p < 0.01), and the y values were significantly higher (p < 0.02). The results agreed with the macroscopic observations made by trained rhinologists. The x values increased when azelastin was administered in five of the PNA group. This increase was related to improvement of their subjective symptoms. Quantitative analysis of the nasal mucosal color could be useful for objective evaluation of the clinical course of allergic rhinitis. PMID- 8683371 TI - [A fundamental study of relationships between rhinomanometry and acoustic rhinometry]. AB - A cylindrical model consisting of a single or plural acrylic plates with holes of various cross-sectional areas was ventilated by a Harvard pump. Pressure flow curves of the combinations were drawn and analyzed according to the percent expression method. The length of the cylinder through the same cross-sectional area did not influence the ventilatory resistance. Divergent flow toward the downstream part decreased the resistance, but convergent flow from the upstream part did not. Simultaneous setting of convergent flow from the upstream part and divergent flow to the downstream part decreased the resistance most effectively, as much as approximately 70% of the original resistance. Two separately positioned cross-sectional areas in a respiratory circuit increased the resistance about 1.4 times when the separation length was more than 3 cm, while the resistance remained between 1 and 1.4 times when the separation was shorter than 3 cm. The average values of the minimum areas measured by acoustic rhinometry were usually much larger than expected from the present study. One of the factors affecting this difference may be that the axis from the nostril to the choana is complicated enough to significantly modify the aerodynamics of the nasal cavity. PMID- 8683372 TI - [Diagnostic imaging and physiological function tests--cholesteatomatous otitis media]. PMID- 8683373 TI - Lymphomas of mucosa-associated lymphoid tissue and antigen drive. PMID- 8683374 TI - t(2;5) translocations in anaplastic large cell lymphomas and Hodgkin's disease. PMID- 8683375 TI - The molecular pathology of small round-cell tumours--relevance to diagnosis, prognosis, and classification. AB - Substantial improvements have been made in the treatment and survival of children with SRCT, resulting in an increased emphasis on precise histological diagnosis. Although diagnostic procedures such as electron microscopy and immunocytochemistry contribute in poorly differentiated cases, an accurate diagnosis can remain elusive in a proportion of SRCTs. The cytogenetic and molecular genetic abnormalities characteristic of the different SRCTs can now be consistently and rapidly identified from minimal quantities of tumour material, using the techniques of FISH and PCR. This, coupled with the identification of novel phenotypic characteristics, has had a major impact on SRCT diagnosis. The aim of a tumour classification is to identify disease entities which are biologically distinct and whose recognition is of clinical value. The recent advances described above demonstrate that the SRCTs are genotypically and phenotypically distinct tumour types and that the genetic abnormalities represent key alterations that influence both the morphology and the clinical behaviour of the tumour. This suggests that these advanced phenotypic and genotypic analyses should form an integral and complementary part of the laboratory assessment and clinical management of these forms of paediatric cancer. PMID- 8683376 TI - Helicobacter pylori-specific tumour-infiltrating T cells provide contact dependent help for the growth of malignant B cells in low-grade gastric lymphoma of mucosa-associated lymphoid tissue. AB - Previous studies have shown that tumour cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue (MALT) type proliferate in vitro in response to heat-killed whole cell preparations of Helicobacter pylori, but only in the presence of tumour-infiltrating T cells. This response is strain specific in that the tumours studied responded optimally to different strains of H. pylori. It was unclear from these studies, however, whether the ability to recognize the specific stimulating strains of H. pylori was a property of the tumour cells or the tumour-infiltrating T cells. This study shows that whereas the tumour cells do not respond to H. pylori, both freshly isolated tumour infiltrating T cells and a T cell line derived from these cells proliferate in response to stimulating strains of H. pylori. T cells from the spleen of one of the patients do not share this property. These results suggest that B-cell proliferation in cases of low-grade gastric lymphoma of MALT type in vitro in response to H. pylori is due to recognition of H. pylori by tumour-infiltrating T cells, which in turn provide help for tumour cell proliferation. The observations provide an explanation for properties of gastric MALT-type lymphoma, such as regression following eradication of H. pylori and the tendency of the tumour to remain localized to the primary site. PMID- 8683377 TI - Molecular analysis of the NPM-ALK rearrangement in Hodgkin's disease. AB - The fusion gene NPM-ALK occurs in a subset of anaplastic large cell lymphomas (ALCLs), as a result of a chromosomal translocation, t(2;5) (p23;q35). It has been suggested that Hodgkin's disease (HD) and ALCL share a common histogenesis because of pathological and phenotypical similarities. In order to check this hypothesis, reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to detect the hybrid NPM-ALK gene in 30 tumour samples, including 22 lymph node biopsies from HD and eight ALCL specimens. The threshold level of sensitivity was shown to reach at least 1/10(4) by dilution experiments using cell lines as positive and negative controls. The expected 177 bp product indicative of the NPM-ALK rearrangement was identified in Karpas 299 and SUDHL-1 cell lines and in two out of eight ALCLs. The 22 HD cases were negative, even after two successive tests. Thus, since the ALCL-specific genetic alteration was absent in our series of HD cases, the present study does not support the hypothesis that HD and ALCL are histogenetically related entities. PMID- 8683378 TI - Detection of p53 and bcl-2 protein in carcinoma of the renal pelvis and ureter including dysplasia. AB - Ninety-four patients with transitional cell carcinoma (TCC) of the renal pelvis and ureter, including dysplastic lesions, were studied for p53 and bcl-2 protein expression by immunohistochemistry. Twenty-one patients were also studied for p53 gene mutations by direct sequencing and for bcl-2 gene rearrangement by Southern blot analysis. Overexpressed p53 protein was detected in 26 cases (27.7 per cent). bcl-2 immunostaining was observed in 21 tumours (22.3 per cent), including four cases with labelling for p53. Furthermore, the dysplastic lesions surrounding 19 p53-positive tumours also stained for p53. bcl-2 expression was also detected frequently in dysplastic lesions adjacent to 14 bcl-2-positive TCCs. Positive reactions of dysplastic lesions were also found adjacent to 37 bcl 2-negative tumours. p53 point mutation was detected in 6 of 21 cases. Five of the six cases were positive for p53 protein. blc-2 positivity was detected in 3 of 21 tumours, without bcl-2 gene rearrangements in the major breakpoint region. Overexpressed p53 protein was frequently detected in both high-grade (P < 0.05) and invasive tumours (P < 0.05). In three cases of p53-positive non-papillary invasive tumours, bcl-2 was found in non-invasive portions, but was not present in invasive areas. These findings suggest that overexpression (mutation) of p53 and/or bcl-2 protein may be early events in tumourigenesis and that p53 alterations in particular are essential for the maintenance of a malignant phenotype in tumour development. PMID- 8683379 TI - Overexpression of different members of the type 1 growth factor receptor family and their association with cell proliferation in periampullary carcinoma. AB - The expression of epidermal growth factor receptor (EGFR), c-erbB-2, and c-erbB-3 was examined immunohistochemically in 57 cases of periampullary carcinoma. The percentage of Ki-67-positive cells was also examined in the same tissue, to determine the relationship between the expression of the members of the type I growth factor receptor family and cell proliferation. In carcinoma of the head of pancreas, the percentage of cases with overexpression of c-erbB-3 was significantly higher than with overexpression of c-erbB-2 and EGFR. In contrast, in lower bile duct carcinoma and carcinoma of the ampulla of Vater, the percentages of cases with overexpression of c-erbB-2 was greater than with overexpression of other growth factor receptors. A higher percentage of cases with overexpression of c-erbB-3 in pancreatic head carcinoma and overexpression of c-erbB-2 in carcinoma of the ampulla of Vater was found in Ki-67 antigen positive cases. Moreover, the overexpression of c-erb-3 in pancreatic head carcinoma, c-erb-2 in ampulla of Vater carcinoma, and Ki-67 in both carcinomas was found to be associated with poor patient outcome. These results demonstrate that different members of the type I growth factor receptor family are overexpressed in different carcinomas of the periampullary region. PMID- 8683380 TI - Expression of markers of differentiation in normal bronchial epithelium and bronchial dysplasia. AB - Bronchial epithelial dysplasia is a non-invasive cellular change often associated with physical or chemical injury and considered a pre-neoplastic lesion in the formation of lung cancer. A series of 39 bronchial dysplasias associated with both neoplastic and non-neoplastic lesions were assessed for expression of markers of differentiation by immunocytochemistry and compared with samples of normal bronchial epithelium. The normal bronchial epithelium studied expressed cytokeratins (CKs) 4, 6, 7, 8, 18, and 19 in all cases; CK 13 in 13 cases; and peanut agglutinin (PNA) in seven cases. Involucrin, CK 10, and CK 14 were not observed in the normal bronchial samples. In the dysplastic bronchial biopsies, epithelial staining was observed with epithelial CKs 7, 8, 18, and 19 in all cases; CK 13 was seen in 26 cases; CK 14 in 13 cases; CK 6 in 11 cases; and CK 10 in five cases. In 13 cases of dysplasia, only simple epithelial antigens were identified. Involucrin expression was observed in 17 dysplastic biopsies and PNA in 12. By Fisher's exact test, a significant association between non-severe histological grade of dysplasia and CK 6 expression (P = 0.018) was found. Comparison of the results using the same analysis showed significant correlations between the loss of CK 6 expression (P < 0.001) and the expression of CK 14 (P = 0.008) and involucrin (P = 0.0018) with bronchial dysplasia. These data show that the pattern of differentiation antigen expression in bronchial dysplasia is significantly different from that of the normal bronchial epithelium, but the phenotypic heterogeneity of these lesions is similar to that of bronchial carcinomas. PMID- 8683381 TI - Expression of platelet-derived growth factor (PDGF) and PDGF receptors in human malignant mesothelioma in vitro and in vivo. AB - The expression of platelet-derived growth factor (PDGF) and PDGF receptors was studied in human normal and malignant mesothelial cells in vitro and in vivo. Staining with anti-cytokeratin and ME1 antibodies and ultrastructural analysis confirmed the mesothelial nature of the cell lines used to study PDGF and PDGF receptor expression in vitro. Using antibodies, mesothelioma cell lines were found to express PDGF and both the PDGF alpha- and the PDGF beta-receptor, whereas cultured normal mesothelial cells expressed PDGF and PDGF alpha-receptor. This PDGF and PDGF receptor staining pattern largely reflects the earlier described mRNA expression in these cell lines. The only exception was the immunocytochemical detection of PDGF alpha-receptors in the mesothelioma cell lines, which is different from the inability to detect alpha-receptor transcripts on Northern blots. Expression was also investigated in mesothelial cells in vivo. Expression of PDGF was observed in malignant mesothelioma cells on frozen tissue sections. In pleural effusions, a double immunofluorescence staining procedure for PDGF and epithelial membrane antigen (EMA) revealed PDGF expression by EMA positive malignant mesothelioma cells. PDGF beta-receptors and occasionally PDGF alpha-receptors were detected in frozen tissue sections of malignant mesotheliomas, whereas mesothelioma cells in effusions showed faint expression of only the PDGF beta-receptor. In contrast, in effusions containing non-malignant mesothelial cells, only a very low level of PDGF alpha-receptor could be detected. Taken together, these results indicate that the pattern of PDGF and PDGF receptor expression in mesothelial cells in vivo largely corresponds to expression of PDGF and its receptors in vitro. Malignant mesothelioma cell lines thus constitute a good model system for studies on the role of PDGF in this malignancy. Furthermore, the data reported in this paper are consistent with the idea that an autocrine growth stimulatory effect of PDGF via PDGF receptors may play a role in the pathogenesis of malignant mesothelioma. PMID- 8683382 TI - Immunoreactive neuron-specific enolase (NSE) is expressed in testicular carcinoma in-situ. AB - Neuron-specific enolase (NSE) is a well-known marker of tumours that have neuroendocrine origin. High levels of NSE have also been described in various types of testicular germ cell neoplasms, particularly in seminomas. To evaluate the presence of NSE in testicular carcinoma-in situ (CIS), a preinvasive stage of testicular germ cell tumours, a panel of CIS tissue specimens was examined. Fifteen of 18 (83 per cent) CIS samples showed immunohistochemical staining with anti-NSE monoclonal antibody. Immunoreactivity has also been found in overt testicular germ cell tumours, including seminomas, non-seminomas, and a mixed germ cell tumour. As the co-existence of high NSE production and gene amplification of N-myc has been reported in some tumours, including germ cell tumours, the expression of the protein product of N-myc was also examined in this study, but only sporadic cases showed N-myc staining. These results are evidence against a relationship between NSE and N-myc in testicular germ cell tumours. The high expression of NSE in CIS and overt germ cell tumours may be due to the increased gene dosage effect associated with the overrepresentation of isochromosome 12p. PMID- 8683383 TI - Prolonged expression of the c-kit receptor in germ cells of intersex fetal testes. AB - Stem cell factor (SCF) and its receptor Kit encoded by the c-kit proto-oncogene are crucial for the development and migration of primordial germ cells in rodents. The expression of Kit has been examined immunohistochemically in gonads obtained from five specimens of fetal tissues with intersex conditions which included 45,X/46,XY mosaicism; androgen insensitivity syndrome; and 46,XY/iso(p)Y mosaicism. Individuals with such disorders of sexual differentiation and Y chromosome material carry a very high risk of developing testicular neoplasms. Fetal testicular germ cells of the intersex subjects expressed Kit at a later developmental age than controls, in which no Kit protein was detectable beyond the 15th week of gestation. This finding may indicate a disturbance of the chronology of germ cell development, or it may suggest a change of the regulation of c-kit expression in subjects with disorders of gonadal development. PMID- 8683384 TI - Detection of p53 in Hodgkin's disease using the monoclonal antibody PAb248. AB - The recent demonstration that the murine anti-p53 monoclonal antibody PAb248 can identify human p53 in a variety of normal tissues proves that immunohistochemical detection does not necessarily indicate the presence of mutations. PAb248 can detect p53 protein in a cytoplasmic-perinuclear localization, not previously described. The present study presents the expression of this antibody in a series of 34 cases of Hodgkin's disease, comparing it with the antibodies CM1, PAb1801, and PAb240. In all cases, PAb248 showed uniform cytoplasmic-perinuclear staining in small and medium-sized lymphocytes, while it was constantly negative in Hodgkin, Reed-Sternberg (R-S/H) cells, and variants. This pattern of staining was the opposite to that observed with the antibodies CM1, PAb1801, and PAb240, where the staining was nuclear and restricted to the R-S/H cells, with the small lymphocytes being negative. p53 can be found in different conformations and localizations, with the cytoplasmic-perinuclear localization mainly, although not exclusively, being found in normal and reactive tissues and the nuclear localization being mainly expressed by neoplastic cells. These results give further support to the theory that the R-S/H cells are the neoplastic population in Hodgkin's disease, while the surrounding lymphocytes are reactive. PMID- 8683385 TI - Absence of Epstein-Barr viral encoded RNA (EBER) in primary cutaneous t-cell lymphoma. AB - Epstein-Barr virus (EBV) has been associated with various extracutaneous lymphoproliferative diseases and it has been suggested that EBV may have a similar aetiological role in cutaneous T-cell lymphoma. In this study, in situ hybridization was used to investigate the presence of EBV encoded RNAs (EBER-1 and EBER-2) in 37 biopsies from 28 cases of primary cutaneous T-cell lymphoma originating from the U.K. The results showed that EBV had no demonstrable pathogenic role in the lymphomas studied, as EBER was not detected in any case. PMID- 8683386 TI - Beta-cell apoptosis is responsible for the development of IDDM in the multiple low-dose streptozotocin model. AB - Although insulin-dependent diabetes mellitus (IDDM) results from irreversible loss of beta cells, the mode of cell death responsible for this loss has not previously been categorized. In this study, the multiple low-dose streptozotocin (stz) model (intraperitoneal injection of stz at a concentration of 40 mg/kg body weight per day for five consecutive days) was used to investigate beta-cell death during the development of IDDM in male C57B1/6 mice. Apoptotic cells were evident by light microscopy within the islets of Langerhans of treated animals from day 2 (the day of the second stz injection) until day 17. Immunohistochemical localization of insulin to the dying cells confirmed the beta-cell origin of the apoptosis. Two peaks in the incidence of beta-cell apoptosis occurred: the first at day 5, which corresponded to an increase in blood glucose concentration, and the second at day 11, when lymphocytic infiltration of the islets (insulitis) was maximal. Insulitis did not begin until day 9, by which time treated animals had developed overt diabetes as revealed by blood glucose and pancreatic immunoreactive insulin (IRI) measurements. Beta-cell apoptosis preceded the appearance of T-cells in the islets and continued throughout the period of insulitis. Thus, whether induced by stz or a subsequent immune response, apoptosis is the mode of cell death responsible for beta-cell loss in the multiple low-dose stz model of IDDM. PMID- 8683387 TI - Assessment of the distribution of mitochondrial ribosomal RNA in melas and in thrombotic cerebral infarcts by in situ hybridization. AB - In situ hybridization to mitochondrial ribosomal RNA (rRNA) has been used to study the distribution of mitochondria in paraffin-embedded autopsy brain tissue from two patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and other organs from one of the patients. Comparison of in situ hybridization and electron microscopic findings in an antemortem biopsy specimen of pylorus from the latter patient showed a close correspondence between the distribution of hybridization signal on light microscopy and of mitochondria in ultrathin sections. Strong hybridization signal was present over smooth muscle fibres of the muscularis externa, which contained abnormal accumulations of mitochondria on electron microscopy. Hybridization to sections of skeletal muscle confirmed previous reports of 'ragged-red' fibres in this disorder and of mitochondrial accumulations in the walls of intramuscular blood vessels. To try to elucidate the role of vessel wall accumulation of mitochondria in the genesis of the stroke-like lesions, the distribution of mitochondrial rRNA was assessed in sections of brain from both of the cases of MFLAS and several cases of atherothrombotic cerebrovascular disease. Blood vessels in and adjacent to the cerebral lesions of MELAS showed strong hybridization signal with the mitochondrial probes, as was also seen in infarcts of various ages in the control brains. Only weak signal was present in the walls of blood vessels distant from the lesions, in both MELAS and control brains. These findings suggest that mitochondria accumulate in vascular endothelium and tunica media as a normal response to cerebral infarction or ischaemia. The accumulation of mitochondria in the cerebral lesions of MELAS may, at least in part, be a reaction to the destructive effects of the underlying metabolic dysfunction. PMID- 8683388 TI - Tissue plasminogen activator production by monocytes in venous thrombolysis. AB - Laminated occlusive thrombus was induced in the rat inferior vena cava (IVC) by a distal stenosis and injection of thrombin. Immunocytochemistry was performed on serial cryostat sections of the thrombus for tissue plasminogen activator (tPA) and a variety of phenotype markers for mononuclear cells. There was little tPA in 2-day-old thrombus. However, tPA was present in significant quantities in 1- and 2-week-old thrombus. Most of the staining for tPA was associated with monocytes, which had infiltrated the thrombus in large numbers. No caval endothelium was seen in these sections. By 4 weeks, the IVC had re-canalized and new endothelium had formed; tPA staining was weakly positive in the endothelium and smooth muscle. In situ hybridization with a digoxigenin-labelled RNA probe confirmed the monocytes as the main source of tPA. This study shows that large numbers of infiltrating monocytes are present in venous thrombosis and that they are the main source of tPA. PMID- 8683389 TI - Number and morphology of mechanoreceptors in the myotendinous junction of paralysed human muscle. AB - The mechanoreceptor system of the myotendinous junction (MTJ) of human palmaris longus muscle obtained at autopsy was studied histologically from six patients with flaccid paralysis (complete acute tetraplegia 4-6 weeks before the autopsy, due to a spinal cord injury), eight patients with spastic paralysis (chronic hemiplegia due to cerebral stroke) and ten neurologically normal controls. Four types of nerve endings, Ruffini and Pacini corpuscles, Golgi tendon organs, and free nerve endings, could be identified in the MTJs of the controls. In the MTJs of the patients with flaccid and spastic paralysis, the free nerve endings were not present and the mechanoreceptors that were found were few in number, degenerated, fibrotic, and atrophic. These mechanoreceptors had lost their connection with the muscle fibres and tendon bundles and were frequently located within pathological accumulations of fatty tissue in the myotendinous region. The number and distribution of mechanoreceptors in the MTJ were almost identical in patients with flaccid and spastic paralysis. PMID- 8683390 TI - Differential in situ expression of the genes encoding the chemokines MCP-1 and RANTES in human inflammatory bowel disease. AB - Two chemotactic cytokines, monocyte chemoattractant protein-1 (MCP-1) and RANTES, possibly contribute to the recruitment and activation of leukocytes in inflamed tissues. The expression of these cytokine genes was evaluated in tissue sections from resected bowel segments of 14 patients with inflammatory bowel disease (IBD) and seven control patients by use of 35S-labelled antisense RNA probes. MCP-1 and RANTES transcripts were generally increased in the intestinal mucosa of patients with IBD, compared with controls. Whereas MCP-1 gene expression in the mucosa was restricted to the lamina propria, the gene coding for RANTES was expressed in intraepithelial lymphocytes and in the subepithelial lamina propria. Furthermore, MCP-1 mRNA, but not RANTES mRNA, was abundant in vessel-associated cells, such as endothelial cells, medial smooth muscle cells, and intraluminal cells; in smooth muscle cells of the intestinal tunica muscularis; and in cells of the myenteric plexus. Compared with controls, a significant increase of MCP-1-expressing cells was observed in tissue specimens from patients with IBD, in endothelial cells of venules, and in cells present in the lumen of intestinal vessels. Conversely, the expression of MCP-1 mRNA in smooth muscle cells and myenteric plexus cells appeared to be comparable in control and diseased intestines. The increased number of MCP-1 and RANTES mRNA-expressing cells in mucosa from patients with IBD suggests that these cytokines play a role in the pathogenesis of mucosal inflammation. Furthermore, the expression of the MCP-1 gene in vessel-associated cells may indicate its involvement in mechanisms regulating the adhesion of blood monocytes to endothelial cells. PMID- 8683391 TI - AM-3K, a novel monoclonal antibody specific for tissue macrophages and its application to pathological investigation. AB - An anti-human macrophage monoclonal antibody, AM-3K, was produced using human alveolar macrophages as antigen. The molecular weights of the antigen recognized by AM-3K were 120 and 70 kD. Immunohistochemically, AM-3K reacted intensely with most macrophages in lymphoreticular organs and in many other organs and tissues. In the spleen, AM-3K reacted with red pulp macrophages, some white pulp macrophages, and tingible body macrophages in lymphoid follicles. In the lymph nodes, many macrophages distributed in the outer cortex, paracortical area, medulla, capsule, or within lymphoid follicles showed an intense reaction for AM 3K. Kupffer cells of the liver, macrophages in the connective tissues, and interstitial macrophages of the kidneys, pancreas, testis, and many other organs were also strongly labelled. AM-3K also reacted with macrophages in many pathological conditions. This antibody, however, did not react with dendritic cell populations, such as epidermal Langerhans cells, interdigitating cells in the paracortex of the lymph nodes, and follicular dendritic cells within the lymphoid follicles, nor with cells other than macrophages, including epithelial cells, vascular endothelial cells, lymphocytes, and granulocytes. Reaction products for AM-3K were found on the cytoplasmic membrane of macrophages by immunoelectron microscopy. In both cryostat sections and formalin-fixed paraffin sections, this monoclonal antibody recognized the antigen present on the cell surface membrane of tissue macrophages, but not monocytes or dendritic cells. PMID- 8683392 TI - The trypsin-induced leucostasis which leads to emphysema in the hamster is not due to contaminating endotoxins. AB - Intravenous injection of trypsin in the rat induces early lung leucostasis and emphysema of delayed onset. This report confirms that this emphysema is not rat specific and that the leucostasis is not related to the presence of contaminating endotoxin in the trypsin. In hamsters (n = 37), leucostasis did not occur when they were injected with heat-treated trypsin, but numerous granulocytes were sequestered in the vessels of hamsters receiving a fresh solution of trypsin. In these hamsters, the number of granulocytes harvested by lavage increased significantly (1.87 x 10(6) per ml, P < 0.001) compared with hamsters injected with either heat-denatured trypsin (0.89) or saline (0.86), or compared with controls (0.86). Emphysema was inconstantly observed in hamsters 6 or 12 weeks after injection with trypsin for 1 h. It was frequently (17/20) present and always (20/20) well developed (intercept + 180 per cent) in the 2-h perfused hamsters whose lungs were abnormally heterogeneous (index + 100 per cent) relative to the seven controls and to the nine saline-injected hamsters. The efficiency of trypsin in triggering emphysema (percentage of hamsters having abnormal values of intercept) was dependent on the time of perfusion. This form of experimental emphysema is thus considered to be due to an endotoxin independent leucostasis. PMID- 8683393 TI - Diagnostic value of different PCR assays for the detection of mycobacterial DNA in granulomatous lymphadenopathy. AB - Diagnosis of mycobacterial infection is made by assessment of characteristic histological features, staining of acid-fast bacilli, or agar culture. Recent advances in molecular biology have provided alternative approaches for the detection of mycobacteria, but only limited data are available dealing with the comparative evaluation of these methods. In order to determine the diagnostic applicability of polymerase chain reaction (PCR)-based assays, 20 formalin-fixed and paraffin-embedded lymph nodes with bacille Calmette-Guerin (BCG) lymphadenitis were investigated which in Lowenstein Jensen agar culture were either positive or negative (ten cases each); ten lymph nodes with non-specific lymphadenitis served as negative controls. Ziehl-Neelsen staining as well as three different PCR assays (including nested PCR), amplifying a specific sequence of the Mycobacterium tuberculosis complex or sequences of the 65 kD antigen gene, were performed. Positive culture was only obtained from lymph nodes which had been surgically removed within 20 weeks after vaccination (P < 0.001). In contrast to microscopic examination, which yielded no more information than agar culture, PCR detection of mycobacterial DNA was unrelated to culture findings. Combined use of different assays, as well as DNA extraction from at least three paraffin sections from each specimen, resulted in the detection of mycobacterial DNA in all lymph nodes with amplifiable DNA (18 out of 20 cases). Controls remained consistently negative. Thus, the combined use of different PCR assays is proposed as a rapid and sensitive technique for the detection of mycobacterial DNA in formalin-fixed and paraffin-embedded tissue. PMID- 8683394 TI - 14q+ chromosome marker in a T-cell-rich B-cell lymphoma. AB - Cytogenetic, in situ hybridization, and molecular studies were performed in a case of T-cell-rich B-cell lymphoma. Demonstration of Ig gene rearrangements for both heavy and light chains confirmed the B-lineage restriction of the neoplastic cell population. Moreover, as expected in B-cell malignancies, all abnormal karyotypes showed a 14q+ chromosome marker involving 14q32. The origin of the extra material on the derivative 14q+, as defined by chromosome painting with a library for chromosome 11, and Southern blotting for c-myc and bcl-2 rearrangements, remains unknown. PMID- 8683395 TI - Pathological Society of Great Britain and Ireland, 172nd meeting. London, 3-5 January 1996. Abstracts. PMID- 8683396 TI - Langmuir-Blodgett films of photosensitive proteins. AB - The striking properties of monolayers and multilayers of photosensitive proteins obtained by using the Langmuir-Blodgett technique are described. The close packing of the protein molecules, which preserve most of the properties found in solution, seems to be the main cause for their thermal stability, which in some cases reached a temperature of 200 degrees C without the loss of the protein secondary structure. The review is focused on three of the most intensively studied photosensitive proteins, namely photosynthetic reaction centres, bacteriorhodopsin and bovine rhodopsin, and on their possible applications as molecular optical devices. PMID- 8683397 TI - Apoptosis of mouse MS-2 fibrosarcoma cells induced by photodynamic therapy with Zn (II)-phthalocyanine. AB - The destructive process of mouse MS-2 fibrosarcoma induced by photodynamic therapy (PDT) with liposome-administered Zn(II)-phthalocyanine (ZnPc) was studied by electron microscopy. Pronounced ultrastructural changes characteristic of apoptosis were observed for several tumour cells, including early occurrence of condensation and margination of chromatin, disappearance of nuclear pores, karyopyknosis, karyorrhexis, protuberance formation at the cell surface and cell fragmentation. The findings indicate that apoptosis was involved in the process of tumour cell death induced by ZnPc-PDT. The detailed mechanism and pathways controlling this phenomenon need to be elucidated further. PMID- 8683398 TI - Formation of water-soluble porphyrins and protoporphyrin IX in 5-aminolevulinic acid-incubated carcinoma cells. AB - The bioconversion of 5-aminolevulinic acid (ALA) into hydrophobic protoporphyrin IX and other water-soluble porphyrins was investigated in Ehrlich ascite carcinoma (EAC) cells and in a myeloma cell line. The effects of irradiation (514 nm), temperature, incubation time and added glucose on the relative porphyrin concentrations (protoporphyrin vs. water-soluble porphyrins) were examined. Variations in these parameters induced a change in the amount of water-soluble porphyrins relative to protoporphyrin IX. The main component of the hydrophilic porphyrins was found to be uroporphyrin (Up), with minor components of coproporphyrin (Cp) and other carboxyporphyrins. The enhanced production of water soluble porphyrins appears to be associated with alterations in the activities of the various enzymes in the heme biosynthetic pathway, resulting, for example, in the reduction in the activity of mitochondrial enzymes. PMID- 8683399 TI - Alteration of lipoproteins of suction blister fluid by UV radiation. AB - Suction blister fluid is a good representative of the interstitial fluid feeding the epidermal cells. Lipoproteins contained in the suction blister fluid of healthy volunteers are readily photo-oxidized by UV radiation in the wavelength range 290-385 nm. Absorbed light doses equivalent to one minimal erythemal dose absorbed by skin exposed to UVB (e.g. 290-320 nm) are sufficient to induce lipid peroxidation and modification of apolipoproteins A-I, A-II and B. Albumin, which is known to protect serum fully from oxidative stresses, is not so effective against photo-oxidation. Although tryptophan (Trp) residues of proteins contained in the suction blister fluid are photo-oxidized, apolipoprotein A-II, which does not contain any chromophoric Trp residue, is also altered by the UV radiation. With regard to results obtained with a model reconstituted fluid, it is suggested that the radical chain reaction of the lipid peroxidation can transfer the initial photodamage at sites not directly susceptible to photo-oxidation. The biological implications of these results are discussed. PMID- 8683400 TI - Quantitative comparison of excited state properties and intensity- dependent photosensitization by rose bengal. AB - A quantitative (multistep) excitation-deactivation model of rose bengal (RB) has been developed which includes energy and electron transfer to oxygen and the possibility of photoproduct formation via higher excited triplet-singlet states. The model is based on previous measurements of non-linear absorption (NLA) and emission of RB with picosecond pulses at 532 nm and on NLA measurements with nanosecond pulses. A coupled rate equation and photon transport equation approach for non-linear light-matter interaction is used. The resulting term scheme with all relevant excited state parameters confirms that (i) in the first excited state of RB, relevant absorption at 532 nm takes place only in the triplet, and (ii) the previously reported intensity dependence of RB-sensitized enzyme inhibition is well modelled by the intensity-dependent RB-T1 population and (as the main process) subsequent energy transfer to form singlet oxygen. PMID- 8683401 TI - Open questions in photobiology. IV. Photoaging of the skin. PMID- 8683402 TI - Biodistribution of a Zn(II) phthalocyanine to plasma lipoproteins. PMID- 8683403 TI - Chromosome reorganization in Candida albicans 1001 strain. AB - The karotype of Candida albicans 1001, a pathogenic isolate, presents two additional chromosome bands when compared with C. albicans 1006 strain. These two bands were a 2600 kb chromosome located between chromosome group 1-R and chromosome 2 (named chromosome 2*) and a 710 kb small chromosome, called snc due to its similarity in size to the supernumerary chromosome in strain WO-1. A comparison of karyotypes of strains 1001, 1006 and WO-1 has enabled us to conclude that chromosomes 2 and 7 are involved in such a reorganization giving rise to the new chromosome bands of strain 1001. We describe a tentative physical map of C. albicans 1001 based on the previously outlined map of C. albicans strain 1006. PMID- 8683404 TI - Comparison of D0870 and fluconazole in the treatment of murine cryptococcal meningitis. AB - Cryptococcal meningitis is a common infection in patients with AIDS. Using a murine cryptococcosis model, we compared treatment with a new triazole, D0870, and fluconazole. Groups of ICR (Institute for Cancer Research) mice were infected intracerebrally with eight different isolates of Cryptococcus neoformans variety neoformans with different in vitro susceptibilities to fluconazole. For survival studies mice were challenged with two to four times LD(50) or six to nine times LD(50). Treatment was given for 10 days. Mice were observed through to day 30. To assess the effect of treatment on fungal tissue burden, mice received a three to five times LD(50) inoculum and treatment for 10 days. They were sacrificed on day 12 and serial dilutions of brain homogenates were cultured. Fluconazole prolonged survival primarily in isolates which were susceptible in vitro. D0870 prolonged survival in all isolates except one, which was also resistant in vitro to D0870 and fluconazole. Both drugs reduced colony counts of all isolates. D0870 warrants further development for use in cryptococcosis, and appears effective for isolates relatively resistant to fluconazole. There is a relative correlation of in vivo and in vitro susceptibility to D0870 as well as fluconazole. PMID- 8683405 TI - A comparison of miconazole, ketoconazole and fluconazole in their effects on temperature-dependent growth and thermal death in Candida albicans. AB - A strain of Candida albicans isolated from human sputum exhibited an associative temperature profile, with the initial maximum temperature = 42 degrees C, the final maximum temperature = 38 degrees C, and the minimum temperature of thermal death = 33 degrees C, showed a decrease in its cardinal temperatures and a reduction in the specific rates of growth and thermal death throughout the novel temperature ranges in the presence of either 25 microM of miconazole, ketoconazole or fluconazole. In the concentration range 0-30 microM, each drug concertedly depressed the kinetic and energetic parameters of growth, with lesser variation on the specific glucose transfer rate. The overall effect of miconazole was the greatest (up to one order of magnitude), while that of fluconazole was the least. PMID- 8683406 TI - Immunochemical study of a Paracoccidioides brasiliensis polysaccharide-like antigen. AB - The polysaccharide antigen from P. brasiliensis has been largely employed in serologic tests ,as well as in skin tests, to evaluate cellular immunity. SDS PAGE analysis of this antigen has revealed a variability in the number of bands exhibited by isolates SN, 265, 339, 113, and 18 (7 to 16 bands). The antigens obtained from isolates 2, PTL, 192 and Adel showed two or three bands. Glycoprotein analysis demonstrated a broad region between 50 and 90 kDa. Major bands of 48 and 30 kDa were present in almost all antigens. Optimal complement fixing dilution appears to be unaffected by the number of bands presented by different antigens. The immunoblot analysis revealed that the 90 and 30 kDa bands were mainly recognized by sera from paracoccidioidomycosis patients. Bands of high molecular weight were also recognized by most of the sera studied. Sera from histoplasmosis recognized the 94 kDa band. In conclusion, although the isolates exhibit quantitative variability in the number of fractions, it is possible to use only one or two samples given the greatest frequency of reactivity is seen in the 30 and 90 kDa fractions. PMID- 8683407 TI - Activation of murine resident peritoneal macrophages by a cell wall extract of Candida albicans. AB - Ethylenediamine extraction of the cell walls of Candida albicans yields an extract which possesses antigenic activity, and like other whole cell and cell wall preparations of Candida, has been shown previously to possess immunomodulatory activity. We report here results which show that non-elicited, resident peritoneal macrophages treated with the ethylenediamine cell wall extract exhibit morphological characteristics of activated macrophages. Treated cells also manifest an increased respiratory burst response and secrete elevated levels of IL-6. The treatment with the extract appears to provide a co-priming signal to the resting macrophages, since co-stimulation with interferon-gamma results in an increased level of IL-6 and IL-1. Our results also show that extract-treated cells manifest increased responsiveness to a lipopolysaccharide as measured by the production of tumour necrosis factor-alpha. These results provide an additional basis for our understanding of the immunomodulatory activity of components of the Candida cell wall. PMID- 8683408 TI - Ultrastructural alterations produced by sertaconazole on several opportunistic pathogenic fungi. AB - Sertaconazole is a new synthetic antifungal which has shown promising activity against numerous fungi. The morphological changes induced by the drug at two concentrations, the MIC and 10 times the MIC, during 24 and 48 h on the filamentous opportunistic fungi Aspergillus fumigatus, Chaetomium atrobrunneum and Scedosporium prolificans indicated that the intensity of the ultrastructural breakdown depended on the dose and not on the time of exposure. Common severe alterations of many fungal cells, which could be considered beyond repair, were seen at the cell wall, plasmalemma and cytoplasm levels. The results obtained underline the drug efficacy for those fungi and suggest its applicability as therapeutic agent in the human infections produced by them. PMID- 8683409 TI - Evaluation of the susceptibility of dermatophytes to antifungal drugs: a new technique. AB - The evaluation of the minimal inhibitory concentration (MIC) for pathogenic fungi is still a technically difficult assay. Insufficient standardization of the technique is often the basis of problems which appear. Culture characteristic of dermatophytes do not favour techniques usually used in bacteriology (Steers agar dilution method). A study was undertaken to compare the Steers agar dilution method and a new culture method to evaluate the minimal inhibitory concentration of antifungal compounds on several species of dermatophytes. The new method involves dilution of the antifungal drug in solid medium in a Petri dish. Standardized agar cylinders are cut from the plates and filled with inocula of the same size cut from plates of dermatophyte cultures. Such inocula facilitate analysis of the fungus in its natural growth conditions in vitro without being submitted to a disruptive preparative technique. The MIC values were similar for the two methods of evaluation in spite of important differences between the inocula. The new technique is reliable, quick, and highly reproducible. It is more efficient than the Steers agar dilution method because it enables assays to be run on several strains simultaneously and avoids labour-intensive procedures for the preparation of the inocula. PMID- 8683410 TI - Paracoccidioidomycosis in a renal transplant recipient. AB - Paracoccidioidomycosis is a fungal infection rarely described in immunodeficient patients. We report a severe case of pulmonary paracoccidioidomycosis in a renal transplant recipient and demonstrate deficiencies of in vitro lymphocytic transformation assays, skin hypersensitivity tests, as well as low levels of antibodies to Paracoccidioides brasiliensis. PMID- 8683411 TI - Subcutaneous abscess caused by Pleurophomopsis lignicola Petr: first case. AB - The dematiaceous coelomycete Pleurophomopsis lignicola Petr. was isolated repeatedly in pure culture from a subcutaneous abscess of the left leg in a farmer undergoing corticosteroid therapy for asthma gravis. To our knowledge, we report the first case involving this fungus as an aetiological agent of subcutaneous phaeohyphomycosis. PMID- 8683412 TI - Cryptococcus neoformans var. gattii can be separated from var. neoformans by its ability to assimilate D-tryptophan. AB - An additional test to differentiate the varieties of Cryptococcus neoformans is described. It is based on the assimilation of D-tryptophan by the variety gattii. PMID- 8683413 TI - CO2 lasers and temperature changes of titanium implants. AB - Lasers may be useful in uncovering submerged implants or in removing contaminants from "ailing" implants. The purposes of this study were to record temperature changes at the bone-titanium implant interface when using a CO2 laser to: 1) uncover the implant at second stage surgery; and 2) "decontaminate" exposed implant threads. Scanning electron microscopy (SEM) was used to characterize surface changes of lased implants, both uncontaminated or contaminated with blood or saliva. In part one, 28 titanium implants, measuring 3.75 mm by 7 to 20 mm, were placed into room temperature, fresh, resected pig mandibles and covered with a flap of gingiva. The overlying tissue was removed with a CO2 laser at different power levels. Bone-implant interface temperatures were measured with a thermocouple near the top of the implant, and 5 to 7 mm apical to the osseous crest. The effects of implant size, power level, tissue thickness, and operation time were evaluated. In part two, 5 mm by 4 mm bony dehiscences were created on 3 implants in one mandible and the exposed fixture threads lased at varying times and power levels. The results from part one showed temperature increases at the top thermocouple ranged from 4.2 to 16.8 degrees C and increases at the bottom thermocouple ranged from 2.0 to 11.5 degrees C. The results from part two showed temperature increases at the top thermocouple ranged from 1.2 to 11.7 degrees C and increases at the bottom thermocouple from 0.0 to 5.0 degrees C. If baseline ambient temperatures are 37 degrees C, then the temperature at the bone-implant interface might exceed 50 degrees C. SEM revealed no gross surface changes in lased uncontaminated implants, but laser treatment alone of contaminated implants failed to completely remove saliva or blood. Further study is needed regarding temperature increases and surface changes induced by lasers that may adversely affect osseointegration. PMID- 8683414 TI - Comparison of the characteristics of human gingival fibroblasts and periodontal ligament cells. AB - To elucidate the characteristics of human periodontal ligament cells, we compared these cells with gingival fibroblasts isolated from the periodontal tissues of female human subjects. Human periodontal ligament (HPDL) cells had a sharper spindle shape and exhibited a higher growth rate than human gingival fibroblasts (HGF). HPDL cells had a high level of alkaline phosphatase (ALPase) activity, whereas HGF had a low level of such activity. Northern blot analysis demonstrated that HPDL cells produced ALPase mRNA. Decorin and biglycan mRNA were detected in both HPDL cells and HGF, whereas osteocalcin and bone sialoprotein mRNA was not detected in either cells. Both HPDL cells and HGF responded to prostaglandin E2 (PGE2) and isoproterenol, and produced cyclic AMP (cAMP), but did not respond to human 1-34 parathyroid hormone (PTH). Intracellular Ca2+ ([Ca2+]i) was measured in HPDL cells and HGF, using Fura 2-AM. Bradykinin (BK) and histamine (HIS), which are major chemical mediators, caused a transient rise of [Ca2+]i in the presence of extracellular Ca2+. In HGF, but not HPDL cells, HIS induced a biphasic transient peak in [Ca2+]i. BK and HIS increased PGE2 release in both HPDL cells and HGF. However, HGF released a larger amount of PGE2 than HPDL cells. These results demonstrate that HPDL cells have quite different characteristics from HGF. HPDL cells proliferate at a higher rate than HGF, show higher levels of cAMP production and greater ALPase activity, and respond in a different fashion to chemical mediators (BK and HIS) compared with HGF. PMID- 8683415 TI - Effect of ND:YAG laser irradiation and root planing on the root surface: structural and thermal effects. AB - Effects of ND:YAG laser irradiation on untreated and root planed tooth roots were investigated to determine whether a cleaning effect and/or removal of smear layer could be achieved without concomitant microstructural or thermal damage. Sixty (60) healthy extracted teeth were either untreated, irradiated only, root planed only, or irradiated and root planed. Intra-pulpal and surface temperatures were monitored during irradiation, then SEM was performed. Smear layer elimination was achieved without inducing hard tissue microstructural damage at 5W, using pulse durations and intervals of 0.1 s, a fluence of 0.77 J/cm2, and a total energy density of approximately 700 J/cm2. However, these results were not consistent in all samples. At these parameters, intra-pulpal temperature increases of 9 to 22 degrees C and surface temperature increases of 18 to 36 degrees C were recorded. Thus, despite their effectiveness for smear layer removal, these parameters may not be appropriate for clinical use as an adjunct to conventional periodontal therapy. PMID- 8683416 TI - Periodontal files--a comparative study. AB - Periodontal files are used by many dentists for instrumentation of root surfaces as a part of periodontal treatment. The purposes of this study were: 1) to examine, evaluate, and compare several periodontal files in 3 different conditions: new, used, and used/sharpened and 2) to evaluate the efficacy of 5 sharpening devices. The main characteristics observed included: the number, shape, and interval of blades; the active, rake, and lip angles; changes induced by wear; the influence of sharpening; and the type of metal surfaces comprising the blades. There was a wide range of active angles on each individual file, from a high of 75 degrees to a low of 51 degrees. The range of active angles for all blades on all new files was even greater, from a high of 87 degrees to a low of 30 degrees. Wear, observed on some but not all blades, was not extensive and appeared either as abrasion or, occasionally, as fracture of the blade edge. Sharpness scores (5 = sharpest and 1 = dullest) for new file blades were also extremely variable and spanned the full range of values, with a majority of blades scoring 3.5 and below. Attempts to sharpen files with several devices produced inconsistent results. All 5 sharpening devices had significant shortcomings. It was concluded that the extreme ranges both in active angles and in sharpness scores probably have a significant influence on effectiveness of root instrumentation. PMID- 8683417 TI - Inhibition of neutrophil and monocyte defensive functions by nicotine. AB - To learn more about the effects of smokeless tobacco on the defensive functions of neutrophils, we studied the influence of nicotine on these cells in vitro, looking at their bactericidal activity against oral pathogens, and at their ability to produce microbicidal reactive oxygen species (oxygen radicals). Exposure of human blood neutrophils to nicotine (0.01% to 0.1%) inhibited their ability to kill Actinomyces naeslundii, Actinobacillus actinomycetemcomitans, and Fusobacterium nucleatum. Although these concentrations of nicotine are high, such concentrations are relevant to phagocytes in the gingival sulcus, because smokeless tobacco contains 0.5% to 3.5% nicotine by dry weight. Nicotine had no such inhibitory effect when the killing assay was performed in an anaerobic environment, implying that nicotine preferentially affected oxygen-dependent killing mechanisms. To further investigate the effects of nicotine on production of oxygen radicals, neutrophils were primed with lipopolysaccharide and triggered with f-met-leu-phe or phorbol ester in the presence of nicotine. Nicotine inhibited production of superoxide anion (measured by reduction of cytochrome c) and hydrogen peroxide (measured by oxidation of phenol red). Nicotine inhibition of superoxide production was reversible by washing away the nicotine. By observing that nicotine inhibited the reduction of cytochrome c by reagent potassium superoxide, we determined that nicotine directly absorbed superoxide. In addition, by examining nicotine inhibition of the uptake of oxygen by neutrophils, we determined that nicotine also interfered with the production of oxygen radicals by these cells. Nicotine also inhibited production of superoxide and interleukin-1 beta by monocytes. Nicotine did not affect the viability of neutrophils and monocytes, as determined by their ability to exclude trypan blue dye. Inhibition of the aerobic antimicrobial functions of neutrophils and monocytes by nicotine may alter the microbial ecology of the oral cavity, and this might be one mechanism by which nicotine compromises the oral health of users of tobacco products. PMID- 8683418 TI - Effects of nicotine on proliferation and extracellular matrix production of human gingival fibroblasts in vitro. AB - Normal function of gingival fibroblasts is essential for maintenance of the gingival extracellular matrix (ECM), but under inflammatory conditions in gingival tissue which may occur with tobacco use, they can also act in its destruction. The purpose of this study was to determine the effects of nicotine, a major component of tobacco, on gingival fibroblast proliferation, the production of fibronectin (FN), and the production and breakdown of type I collagen to elucidate its role in periodontal destruction associated with its use. A human gingival fibroblast strain derived from a healthy individual with non-inflamed gingiva was used in this study. Nicotine at concentrations > 0.075% caused cell death, and at 0.075% and 0.05% it caused transient vacuolization of the fibroblasts. At concentrations of 0.001% to 0.075%, nicotine significantly inhibited proliferation (P < or = 0.03), measured by the incorporation of [3H] thymidine into DNA. The production of FN and type I collagen was significantly inhibited by nicotine at > or = 0.05% (P < or = 0.001), measured using specific ELISAs. On the other hand, nicotine at > or = 0.025% significantly increased collagenase activity (P < or = 0.008), using [3H]-gly and [14C]-pro-labeled type I collagen gels as substrate. The results show that, in vitro, nicotine inhibits the growth of gingival fibroblasts and their production of FN and collagen, while also promoting collagen breakdown. This suggests that nicotine itself may augment the destruction of the gingival ECM occurring during periodontal inflammation associated with smokeless tobacco use. PMID- 8683419 TI - Peripheral ameloblastoma. AB - Peripheral ameloblastomas are rare odontogenic tumors presenting as tumoral masses, erythematous plaques, or papillary lesions on the attached gingiva. This study reviews the demographic, clinical, and microscopic features of 8 previously unreported cases. One patient had two separate peripheral ameloblastomas, one 7 years after the first in the opposite side and arch. The cases match those described previously with respect to age, gender, location, and radiographic and microscopic features. Because recurrence has been reported and second primary sites may be found, periodic follow-up is recommended after conservative surgical removal. PMID- 8683420 TI - Botryoid odontogenic cyst: analysis of 33 cases. AB - The botryoid odontogenic cyst is considered to be a multiloculated variant of the lateral periodontal cyst. Fewer than 40 of these lesions have been described, many of which have recurred. This paper describes the demographic, clinical, microscopic, and radiographic features of 33 unreported cases from the files of the Oral Pathology Biopsy Service at the University of North Carolina School of Dentistry. Our findings are in agreement with previously published cases for an average age of 57 years and the most common site for occurrence in the lower premolar area. Follow-up information on 12 patients determined that 2 had recurrences. PMID- 8683421 TI - MMPI-A profiles of adolescent boys with a history of firesetting. AB - Firesetting in childhood and adolescence is associated with the more severe end of the conduct-disorder continuum and is considered to be prognostic of later pathology. The literature provides limited understanding of the pathology underlying firesetting in juveniles. This study compared the Minnesota Multiphasic Personality Assessment-Adolescent profiles of 28 psychiatric inpatient adolescent boys with a history of firesetting with the profiles of 96 psychiatric inpatient adolescent boys who do not have a history of firesetting. Using multivariate analyses, the firesetting group appeared more pathological than did the nonfiresetting group as reflected by significantly higher scores on three clinical scales: Psychasthenia (Pt), Schizophrenia (Sc), and Mania (Ma). The firesetting group also scored significantly higher than did the nonfiresetting group on eight of the content scales: Adolescent-Depression, Adolescent-Alienation, Adolescent-Bizarre Mentation, Adolescent-Anger, Adolescent Conduct Problems, Adolescent-Family Problems, Adolescent-School Problems, and Adolescent-Negative Treatment Indicators. Taken together, these results suggest that the pathology associated with juvenile firesetting is more complex as well as more severe than that associated with nonfiresetting conduct disorder. The firesetting group's profiles suggest that their psychopathology is not merely a severe behavior disorder but rather is indicative of feelings of distress, alienation, depression, and thought disorder or poor reality testing. This degree of inner turmoil may be motivational impetus for the firesetting itself. PMID- 8683422 TI - Size, detail, and line heaviness in children's drawings as correlates of emotional distress: (more) negative evidence. AB - This study examined the reliability and validity of three commonly used indicators of emotional distress in children's projective drawings--size, detail, and line heaviness--and assessed their relation to established objective and projective measures of childhood depression and anxiety. Participants were 80 child and adolescent psychiatric inpatients (53 boys, 27 girls; ages 6 to 16; M = 10.69, SD = 2.94). Although the present results indicated that these drawing indices can be assessed with very high reliability, they were not significantly associated with self-report or thematic projective measures of depression and anxiety. Age and defensiveness did not moderate the relation between the drawing indices and the non-drawing measures of emotional distress. The patterning of the intercorrelations among and within the drawing indices, projective stories, and self-report measures indicated greater support for the self-report measures, in terms of convergent and discriminant validity. This study did not support the continued use of these three projective drawing indices of emotional distress. PMID- 8683423 TI - Measuring children's self-concept with a Dutch version of the "self-perception profile for children": factorial validity and invariance across a nonclinic and a clinic group. AB - Harter's (1985) Self-perception Profile for Children (SPPC) is used to investigate whether the pattern and size of relations among the subscales in a clinic group are equivalent to those in a nonclinic group of children, and whether the items are perceived in the same way and with the same degree of accuracy across both groups. The first aspect indicates equivalence of structure, the latter equivalent measurement. Both are aspects of between-group invariance. It is essential to show evidence of these aspects before content-based comparisons are made between these groups. Using restrictive factor analysis, support was found for equivalence of structure. Equivalence of measurement was partially found. The items were perceived in the same way, but not with the same degree of accuracy. The conclusion is that the SPPC has sufficient between-group invariance to be used in studies with children in a clinic group. PMID- 8683424 TI - Five-factor analysis of Buss-Durkee hostility inventory neurotic hostility and expressive hostility factors: implications for health psychology. AB - Neurotic and expressive hostility from the perspective of the five-factor model of personality. Sixty-five male and 105 female students (mean age = 25.0 years) at a public university completed the Buss-Durkee Hostility Inventory, the revised NEO Personality Inventory, and measures of stress and depression. Correlations were computed between the hostility measures and all personality domains and facets. Profiles of participants classified into neurotic and expressive hostility groups were also produced using T scores based on normative samples. The results suggest that neurotically hostile individuals view others as distrustful, the world as threatening, and themselves as unable to cope. They experience frequent negative affect, including unexpressed anger. Expressive hostility predicts direct and positive engagement of the environment and others, but also a readiness to express anger in response to conflict. The lack of association between neurotic hostility and objective health problems may be due, in part, to an absence of exaggerated behavioral and physiological responses to stressors, whereas the positive association between expressive hostility and heart disease may result partly from frequent and intense behavioral engagement and accompanying physiological arousal. PMID- 8683425 TI - Measuring adult attachment: are self-report instruments congruent? AB - To assess the association between several recently generated measures of adult attachment, a sample of 160 college students were administered the following 6 scales: Hazan-Shaver attachment self-report (Hazan & Shaver, 1987), Attachment Style Measure (Simpson, 1990), Adult Attachment Scale (Collins & Read, 1990), Attachment Style Inventory (Sperling & Berman, 1991), Reciprocal Attachment Questionnaire (West, Sheldon, & Reiffer, 1987), and Anxious Romantic Attachment Scale (Hindy, Schwarz, & Brodsky, 1989). Findings indicated that scale and subscale reliability and intercorrelations generally show sufficient evidence of expected consistencies. There is also indication for a primary distinction between the omnibus spheres of positive-affiliative attachment versus negative conflictual attachment, with secondary distinctions among the attachment styles within each sphere. Notwithstanding the overall consistencies, suggestions are offered for context-specific utilization of each of the measures reviewed. PMID- 8683426 TI - Effects of MMPI-2 and MMPI-A norms on T-score elevations for 18-year-olds. AB - This study examines the effects of scoring 18-year-old respondents on Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and Minnesota Multiphasic Personality Inventory for Adolescents (MMPI-A) norms in terms of T-score elevations and profile configuration. Results indicate that substantial differences can occur in T-score elevations for 18-year-olds as a function of norms, with MMPI-2 norms generally producing lower validity scale values and higher clinical scale values than MMPI-A norms. These differences can range as high as 15 T-score points and resulted in different single-scale and 2-point profiles in 34% of the cases examined in this study. PMID- 8683427 TI - Effects of maximum performance instructions on the sentence completion test of ego development. AB - This modified replication of Jurich and Holt's (1987) test-retest study investigated the stability of scores on the Washington University Sentence Completion Test (SCT; Loevinger, 1985; Loevinger & Wessler, 1970; Loevinger, Wessler & Redmore, 1970) across alternate instructional formats. Initially, 90 adult participants completed the SCT using standardized instructions. After a 1 week interval participants were readministered the SCT based on random assignment to either a standardized instruction (control) group, a role-play instructional set, or a best-effort instructional set. A repeated measures multivariate analysis of variance yielded statistically significant differences in ego level scores across the 3 instructional sets. The differences in ego level scores were approximately one-half level higher for the role-play and best-effort instructional sets. Effect sizes for the experimental instructional sets ranged from .23 using item sum scores to .45 using total protocol ratings. Results are supportive of Jurich and Holt's (1987) findings, indicating that the standardized instruction SCT may be susceptible to the motivational set of the test-taker. PMID- 8683428 TI - Factor analysis of the suicide intent scale with adolescent suicide attempters. AB - Examined the factor structure of the Suicide Intent Scale (SIS; Beck, Schuyler, & Herman, 1974) when used with adolescent suicide attempters as well as the validity of these factors. Participants consisted of 190 hospitalized adolescent suicide attempters evaluated within 36 hr of the attempt. They responded to multiple self-report measures as part of a standard battery administered in the hospital that included the Suicide Ideation Questionnaire (Reynolds, 1987b), Reynolds Adolescent Depression Scale (Reynolds, 1987a), and the Hopelessness Scale for Children (Kazdin, French, Unis, Esveldt-Dawson, & Sherrick, 1983). A clinician rated suicide intent on the SIS. A common factor analysis, using the items of the SIS, revealed a three-factor solution. Factors were labeled Isolation Behaviors, Expected Outcome, and Planning Activities. The latter two factors correlated modestly with measures of depression, hopelessness, and suicidal ideation. Isolation Behaviors did not correlate with these measures. Results suggest that the Expected Outcome and Planning Activities factors may be more useful with adolescent suicide attempters than the total score. PMID- 8683429 TI - [Late coronary artery aneurysm formation following directional coronary atherectomy]. AB - The most important factor to reduce late restenosis following directional coronary atherectomy is the technical provision of the largest luminal diameter as possible. However, the safety of deep arterial resection and the resulting arterial perforation or late aneurysm formation is questionable. This study examined the frequency of coronary artery aneurysm formation in patients treated by directional coronary atherectomy. Ninety-eight patients with 123 lesions were analyzed by quantitative angiographic and histologic data. Coronary aneurysms (ratio of dilated vessel segment to the adjacent reference segment > 1.2:1) occurred in seven patients (seven lesions: 5.7%). Specimens were categorized by the deepest layer retrieved. Forty lesions (32.5%) were treated by resection of the intima alone, 65 (52.8%) by resection of the medial tissues and 18 (14.6%) received resections of the adventitial tissues including fatty tissues in three lesions. Late coronary aneurysms occurred often in lesions with resection of adventitial tissue (38.9%) and occurred in all three lesions with resections of fatty tissues. Six coronary aneurysms occurred in the left anterior descending artery (six in segs. 6, 7), and one aneurysm in the left circumflex artery. Among the target lesions in which coronary artery aneurysms were formed, six lesions were primary lesions and one lesion was a restenotic lesion after percutaneous transluminal coronary angioplasty. Statistically, patients with coronary artery aneurysms frequently have associated hypertension (p = 0.02) but rarely diabetes mellitus (p = 0.05). Lesions with late aneurysms had significantly high specimen weight (p = 0.01) and a trend to lower postprocedure % diameter (p = 0.20). There was no significant preprocedural angiographic predictor of aneurysms such as minimal lumen diameter or reference vessel diameter. PMID- 8683430 TI - [Assessment of Japanese patients receiving heart transplants overseas]. AB - No heart transplants have been performed in Japan due to various obstacles since the only operation performed in 1968. Since 1981, a number of patients requiring heart transplants have been accepted by foreign transplantation centers in England, the U.S.A., and Germany. This report describes an investigation of the postoperative course of these Japanese heart transplant patients and discusses the problems regarding transplantation in Japan. Of the 21 transplant patients, the diagnosis was dilated cardiomyopathy in 17, restrictive cardiomyopathy in 1, hypertrophic cardiomyopathy in 2, and congenital muscle dystrophy in 1. All patients survived surgery but three died in the long-term period. The causes of death were acute rejection (after 3 months), chronic rejection (after 50 months) and infection (after 30 months). The actuarial survival curve of these patients was 95.0% for one-year survival and 86.4% for three-year survival. The postoperative functional class was NYHA classification I in all patients (100%). Ninety-three percent of patients returned to work. Immunosuppressive therapies included triple drug therapy in 14 patients (66.7%), double drug therapy in 4 (19.0%), ciclosporin alone in 2 (9.5%) and FK506 in 2 (5.0%). The incidence of acute rejection was 1.56 episodes per patient per year within 3 months and 2.9 episodes per patient per year within 1 year. The postoperative courses of Japanese patients who underwent heart transplantation at foreign transplantation centers were satisfactory. These results will encourage heart transplantation in Japan. PMID- 8683432 TI - Thermal vasodilation as a treatment of congestive heart failure: a novel approach. PMID- 8683431 TI - [Left cardiac output curve and pulmonary venous return curve in patients with various heart diseases]. AB - This study assessed the cardiac function of humans by drawing simultaneous left cardiac output and pulmonary venous return curves using radionuclide angiocardiography and right heart catheterization which allows recording of the pressure-flow relationship. Thirty-one subjects with various cardiac diseases were divided into two groups [18 patients with New York Heart Association (NYHA) functional class I and 13 patients with NYHA classes II or III]. Mean pulmonary filling pressure (Pmp) was calculated from the formula of Guyton, using pulmonary arterial compliance which was measured by Reuben's method and pulmonary venous compliance measured as reported previously. On the pressure-flow plane, the down slope of the pulmonary venous return curve was drawn by joining the points of (Pmp, 0) and (mean pulmonary capillary wedge pressure, cardiac output). To construct the cardiac output curve, two levels of lower body negative pressure were used to regulate the venous return to the heart. Pmp and the resistance to pulmonary venous return in NYHA II or III patients were significantly higher than those in NYHA I patients (Pmp: 16.3 +/- 1.5 vs 9.0 +/- 0.5 mmHg, p < 0.01; resistance to pulmonary venous return: 0.75 +/- 0.09 vs 0.43 +/- 0.04 mmHg/l/min, p < 0.01, respectively). The slope of pulmonary venous return curve in NYHA II or III patients was smaller than that in NYHA I patients and the pulmonary venous return curve in NYHA II or III patients shifted rightward. The slope of cardiac output curve in NYHA II or III patients was significantly smaller than that in NYHA I patients. This curve in NYHA II or III patients shifted downward and rightward. These results indicate that simultaneous cardiac output and pulmonary venous return curves may be a useful method for assessing the cardiac function in patients with various heart diseases. PMID- 8683433 TI - [Cardiovascular imaging]. PMID- 8683434 TI - [Value and limitations of valve resistance in assessing prosthetic aortic valve function: clinical study using dobutamine stress doppler echocardiography]. AB - Hemodynamic resistance may be a useful index for the severity of valvular aortic stenosis, but little is known about the utility of valve resistance in assessing the prosthetic aortic valve function. This study investigated whether valve resistance is useful in assessing prosthetic valve function in 13 patients with normally functioning CarboMedics prosthetic aortic valves. Transvalvular pressure gradient, effective orifice area and valve resistance derived from two dimensional and Doppler echocardiography were calculated before and after dobutamine infusion. Dobutamine was infused incrementally (3-12 micrograms/kg/min) under echocardiographic imaging. Transvalvular pressure gradient (24 +/- 7-->53 +/- 18 mmHg, p < 0.01) and valve resistance (102 +/- 32- >140 +/- 57 dynes.sec.cm-5, p < 0.01) significantly increased after dobutamine infusion. However, effective orifice area did not increase significantly (1.1 +/- 0.5-->1.2 +/- 0.5 cm2). These findings indicate that transvalvular pressure gradient and valve resistance are flow-dependent and should be treated with caution when assessing prosthetic valve function. PMID- 8683435 TI - Stabilization of tetanus toxoid in poly(DL-lactic-co-glycolic acid) microspheres for the controlled release of antigen. AB - Sustained release of antigenically active tetanus toxoid (TT) for several weeks from biodegradable poly (DL-lactic-co-glycolic acid) (PLGA) microspheres is very important for the development of a single dose vaccine. With a view to developing such a formulation, we evaluated in the vitro release of antigenic TT from TT containing PLGA films and microspheres stabilized with gelatin or human serum albumin. Without stabilizer, TT-containing PLGA films released low levels of antigenic TT whereas TT-containing PLGA microspheres (average size 50 microMs) released 18% of antigenic TT in 4 weeks. Inclusion of gelatin and human serum albumin increased the amount of antigenic TT released from PLGA films and microspheres. As the concentration of gelatin increased from 0.08% to 2.2% in PLGA films, release of antigenic TT also increased. Similar results were found with gelatin-stabilized TT-containing microspheres. But the significant increase by higher concentration of gelatin was on the initial burst during the first week. A concentration of 0.2% gelatin was found suitable for getting approximately 40% of antigenic TT in 4 weeks. The proportion of antigenic TT to total protein was higher during the first 2 weeks of the release studies (50% during the first week and 23% during the second week). After 2 weeks, the proportion of antigenic TT was approximately 10% for the next 2 weeks. TT containing microspheres stabilized with gelatin and human serum albumin showed stability of antigenic TT release when these microspheres were stored at 37 degrees C for 4 weeks. Gelatin appears to be a good stabilizer for TT-containing microspheres, but further studies are required to increase the proportion of antigenic TT beyond 2 weeks. PMID- 8683436 TI - Evaluation of blood clearance rates and biodistribution of poly(2-oxazoline) grafted liposomes. AB - Two amphipatic polymers of the poly(2-oxazoline) family, poly(2-methyl-2 oxazoline) (PMOZ) and poly(2-ethyl-2-oxazoline) (PEOZ), were synthesized with the carboxylic group positioned at either the initiation or termination ends of the polymer chains. Distearoylphosphatidylethanolamine was covalently linked to the carboxyl groups of the polymers, resulting in conjugates which incorporate readily into liposomes. Systematic evaluation of plasma clearance kinetics and biodistribution of liposomes containing hydrogenated soy phosphatidylcholine, cholesterol, and 5 mol % the polymer-lipid conjugates in mice revealed the following. Both polymers, PMOZ and PEOZ, exhibited long plasma lifetimes and low hepatosplenic uptake. PMOZ was more effective at decreasing blood clearance rates than PEOZ. The best results, which were quantitatively comparable to the results obtained with the optimized preparations of methoxypolyethylene glycol(PEG)-2000 grafted liposomes, were obtained with formulations containing PMOZ of molecular weight 3260. PMID- 8683437 TI - Preparation of microemulsions using polyglycerol fatty acid esters as surfactant for the delivery of protein drugs. AB - Phase diagrams containing the microemulsion region were constructed for pseudo ternary systems composed for polyglycerol fatty acid ester/cosurfactant/Captex 300/water. It was found necessary to add ethanol, 1-propanol, 1-butanol as cosurfactant to produce microemulsions. The results also demonstrated microemulsions were only able to form when employing polyglycerol fatty acid esters with hydrophile-lipophile balances (HLBs) between 8 and 13, such as MO500, MO750, SO750, and ML310. Most microemulsions were determined to be Winsor type IV by dilution and dye solubility tests. Microemulsions stored at ambient temperature maintained constant viscosity, indicating that the system was thermodynamically stable for long periods. Further, several microemulsion formulations were demonstrated to be promising for oral delivery of insulin based on the results of stability tests and acid-protection efficiency. PMID- 8683438 TI - Preparation and evaluation of sustained release AZT-loaded microspheres: optimization of the release characteristics using response surface methodology. AB - The purpose of the study was to prepare and optimize a sustained release formulation of zidovudine (AZT). Ethylcellulose microspheres containing AZT were prepared using an emulsification/solvent evaporation technique. The critical formulation variables were emulsifier concentration, drug to polymer ratio, and ethyl acetate concentration in the internal phase of the emulsion. The time to release 85% of the contents of the microspheres (t85) was used as a measure for the release time. A second-year polynomial equation was fitted to the release data to systemically investigate the effect of the formulation variables on the release rate. This equation was then used to predict t85 in the optimum region. The t85 was found to be dependent on the three formulation variables, with strong interactions observed between these variables. The microspheres were characterized in terms of their particle size and surface morphology. The study indicated no overall correlation between the mean diameter of the microspheres and the t85. PMID- 8683439 TI - Synthesis and in vitro transdermal penetration enhancing activity of lactam N acetic acid esters. AB - A homologous series of N-acetic acid esters of 2-pyrrolidinone and 2-piperidinone has been prepared and evaluated for its ability to enhance the skin content and flux of hydrocortisone 21-acetate in hairless mouse skin in vitro. Enhancement ratios (ER) were determined for flux (J), 24-hour diffusion cell receptor cell concentrations (Q24), and 24-h full-thickness mouse skin steroid content (SC) and compared to control values (no enhancer present). In addition, in an attempt to abrogate toxicity, these dermal penetration enhancers were designed to have the potential for biodegradation by dermal esterases. 2-Oxopyrrolidine-alpha acetic acid dodecyl ester (5) showed the highest enhancement ratios for J (ER 67.33) and Q24 (ER 180.66). 2-Oxopiperidine-alpha-acetic acid decyl ester (10) showed a high Q24 (ER 162.07) but a lower J (ER 12.67). 2-Oxopyrrolidine-alpha-acetic acid decyl ester (3) showed the highest enhancement ratio for SC (ER 8.7). The ER Q24 for 3, 5 and 10, as well as other lactam N-acetic acid esters in this work, were significantly higher than the ER found using Azone as enhancer. PMID- 8683440 TI - Quantitation of the area of overlap between second-derivative amide I infrared spectra to determine the structural similarity of a protein in different states. AB - Maintaining a native-like structure of protein pharmaceuticals during lyophilization is an important aspect of formulation. Infrared spectroscopy can be used to evaluate the effectiveness of formulations in protecting the secondary structural integrity of proteins in the dried solid. This necessitates making quantitative comparisons of the overall similarity of infrared spectra in the conformationally sensitive amide I region. We initially used the correlation coefficient r, as defined by Prestrelski et al. (Biophys. J. 1993, 65, 661-671), for this quantitation. Occasionally, we noticed that the r value did not agree with a visual assessment of the spectral similarity. In some cases this was due to an offset in baselines, which led artifactually to an unreasonably low r value. Conversely, if the spectra were baseline corrected and there existed a large similarity between peak positions, but differences in relative peak heights, the r value would be unreasonably high. Our approach to avoiding these problems is to use area-normalized second-derivative spectra. We have found that quantitating the area of overlap between area-normalized spectra provides a reliable, objective method to compare overall spectral similarity. In the current report, we demonstrate this method with selected protein spectra, which were taken from experiments where unfolding was induced by lyophilization or guanidine hydrochloride, and artificial data sets. With this analysis, we document how problems associated with calculation of the correlation coefficient, r, are avoided. PMID- 8683441 TI - Characterization of tepoxalin and its related compounds by high-performance liquid chromatography/mass spectrometry. AB - High-performance liquid chromatography/mass spectrometry (HPLC/MS) was used to identify and elucidate key structural characteristics of a novel dual cyclooxygenase/lipoxygenase inhibitor, tepoxalin (3-[5-(4-chlorophenyl)-1-(4 methoxyphenyl)-3-pyrazolyl]-N-hydroxy- N-methylpropanamide), its synthesis related byproducts in bulk drug substance, and degradation products stemming from probe stability studies. Such information is needed to assist in synthesis optimization and in the preparation of stable formulations for toxicity studies and clinical trials. High-performance liquid chromatography, in conjunction with mass spectrometry (HPLC/MS) and UV photodiode array detection, can often expedite the gathering of preliminary data that contribute to several aspects of the pharmaceutical development process. PMID- 8683442 TI - Flux measurements across Caco-2 monolayers may predict transport in human large intestinal tissue. AB - Confluent monolayers of Caco-2 cells, a human colonic carcinoma cell line, have been used extensively to predict intestinal absorption. A direct comparison of uptake characteristics, however, between cell monolayers and human tissue is missing in the literature. We have determined the flux for a series of small organic molecules, peptide and protein therapeutics, across Caco-2 monolayers and normal human colonic and rectal tissue in vitro to assess whether or not a predictive correlation of transport exists. Caco-2 cells were grown to confluency of Snapwells, and human tissue was obtained from patients undergoing surgery for localized tumors. Mucosa-serosa fluxes were measured by HPLC for small molecules and peptides, and proteins were analyzed by ELISA or RIA. Permeability coefficients were calculated from flux data and compared with previously published coefficients where possible. The permeability coefficients for the examined molecules were of a similar magnitude across Caco-2 cell monolayers and human tissues, ranging from 10(-7) to 10(-5) cm/s. A best-fit analysis of a log log plot of transport measurements obtained in these two systems gave a good correlation (R2 = 0.991). From this limited data set it appears that uptake characteristics for human colon and rectum are similar to those of Caco-2 cell monolayers. Thus, flux measurements across Caco-2 monolayers may be predictive for permeabilities of human colon and rectum for different classes of therapeutics. PMID- 8683443 TI - Zero-order release kinetics from a self-correcting floatable asymmetric configuration drug delivery system. AB - A new approach based on the three-layer matrix technology to control drug release for oral administration is presented. Polyethylene oxide polymers of various molecular weight together with theophylline as drug model and other excipients have been directly compressed into a three-layer asymmetric floatable system. The core layer contains the active drug while external layers with different thickness, composition, and erosion rates are designed to delay the hydration of the middle layer, restrict the early drug diffusion only through cylindrical side surfaces of the tablet, and provide controlled drug release. Results show that during a 16 h dissolution study drug is completely released following the zero order kinetics with no burst effect. The release rate remains around 0.1 mg min-1 throughout the dissolution study. The release kinetics is independent of changes in pH and compression force but dependent on layer thickness and formulation components. It appears that the operating release mechanism is based on the existence of a balance between the velocities of advancing glassy/rubbery front and erosion at the swollen polymer/dissolution front. PMID- 8683444 TI - Freeze crystallization of imipenem. AB - This work is a study of the freeze crystallization process developed for the production of a rapidly soluble and stable crystalline form of imipenem, an antibiotic. The objective is to understand the relationship between process conditions and the product crystallinity during the freeze crystallization. Solutions of imipenem and sodium bicarbonate, a drug stabilizer, were crystallized in acetone-water solvent systems at various ratios and temperatures. The degree of crystallinity of the resulting products was measured using an X-ray powder diffraction analysis technique. The acetone-water S-L phase diagram was used to correlate the resulting degrees of crystallinity of imipenem products and equilibrium properties of the system. It was discovered that the conversion of amorphous imipenem to crystalline products was directly related to the percentage of equilibrium liquid during the freeze crystallization. Solubility data indicated that imipenem is virtually insoluble in these equilibrium liquid phases. This suggests that the phase transition from the amorphous state to the crystalline state is mediated by the presence of the liquid phase. PMID- 8683445 TI - Partition coefficients by curve fitting: the use of two different octanol volumes in a dual-phase potentiometric titration. AB - It is shown that when two different volumes of the second phase are employed in a single dual-phase potentiometric titration, the partition coefficients of the most highly ionized species can be readily calculated by refinement of the parameters for the dual-purpose titration equations. Graphical comparison of the calculated titration curve with that obtained experimentally is helpful in making initial estimates of the parameters. PMID- 8683446 TI - An organic acid-induced sigmoidal release system for oral controlled-release preparations. 2. Permeability enhancement of Eudragit RS coating led by the physicochemical interactions with organic acid. AB - The drug release mechanism of the sigmoidal release system (SRS), which is a newly developed multiple-unit type time-controlled release system, was investigated. The drug release rate from the Eudragit RS-coated theophylline beads was considerably enhanced in succinic acid aqueous solution compared with the release rate in water. However, the drug release rate from the beads coated with Eudragit NE 30D, which has no quaternary ammonium groups in the polymer chain, was not affected by succinic acid, suggesting that the quaternary ammonium groups of Eudragit RS are essential to produce the unique drug release profile of the SRS. Ion-exchange experiments revealed that organic acids could interact with Eudragit RS by an ion exchanging mode to various extents depending on the acid species. To examine the individual effect of dissociated and undissociated forms of succinic acid on the drug release behavior of the Eudragit RS-coated theophylline beads, dissolution studies were performed in succinic acid or monosodium succinate aqueous solutions with various concentrations. The drug release rate was found to change depending on the concentration of either the dissociated or the undissociated form of succinic acid with different concentration dependency. From the glass transition temperature measurement using Eudragit RS cast film, it was assumed that the undissociated succinic acid was distributed to the hydrophobic segment of the polymer, resulting in the increase in mechanical flexibility of the film; whereas the dissociated succinic acid electrostatically interacted with the quaternary ammonium groups of the polymer to promote the distribution and to create new ionic circumstances: both effects of the organic acid can accelerate the hydration of Eudragit RS film. All these results suggest that the unique S-shaped drug release profile of SRS can be brought about by a drastic increase in the permeability through the hydration of Eudragit RS-based coating during the drug release process. PMID- 8683447 TI - Nonlinear pharmacokinetics of mibefradil in the dog. AB - The pharmacokinetics of mibefradil in the dog was evaluated in this study. Single intravenous (1 mg/kg) and three oral doses (1, 3, 6 mg/kg) of mibefradil were administered to three dogs according to a randomized complete block design, where dogs were blocks and treatments randomly assigned to each block. Systemic plasma clearance, volume of distribution at steady-state and half-life after intravenous administration were as follows: ClS = 18.4 +/- 1.2 mL/min/kg, VSS = 9.7 +/- 3.8 L/kg, and T1/2 = 9.5 +/- 3.4 h. Oral plasma clearance decreased with an increase in dose, from 101.8 +/- 18.8 mL/min/kg at 1 mg/kg to 21.7 +/- 4.3 mL/min/kg at a 6 mg/kg dose (p < 0.05). Half-life values did not change significantly with an increase in oral dose in all the animals studied (10.6 +/- 1.5 h at 1 mg/kg to vs 13.4 +/- 3.5 h at 6 mg/kg). Dose-normalized AUC ratios between the oral and intravenous treatments increased from 0.18 +/- 0.03 at 1 mg/kg to 0.87 +/- 0.21 at a 6 mg/kg dose (p < 0.05). The nonlinear kinetic behavior of mibefradil is consistent with an increase in gut absorption and/or reduction in elimination after higher oral doses. Although both dogs and humans exhibit nonlinear pharmacokinetics after oral administration, there are substantial differences in the clearance and volume of distribution values between these two species. Even though these differences can, in part, be accounted for by the difference in plasma protein binding, the use of the dog as an animal model for human mibefradil pharmacokinetics need to be qualified. PMID- 8683448 TI - Solubility behavior of lamivudine crystal forms in recrystallization solvents. AB - Lamivudine can be obtained as acicular crystals (form I, 0.2 hydrate) from water or methanol and as bipyramidal crystals (form II, nonsolvated) from many nonaqueous solvents. Form II is thermodynamically favored in the solid state (higher melting point and greater density than form I) at ambient relative humidities. Solubility measurements on both forms versus solvent and temperature was used to determine whether entropy or enthalpy was the driving force for solubility. Solution calorimetry data indicated that form I is favored (less soluble) in all solvents studied on the basis of enthalpy alone. In higher alcohols and other organic solvents, form I has a larger entropy of solution than form II, which compensates for the enthalpic factors and results in physical stability for form II in these systems. The metastable crystal form solubility at 25 degrees C was estimated to be 1.2-2.3 times as high as the equilibrium solubility of the stable form, depending on the temperature, solvent, and crystal form. Binary solvent studies showed that > 18-20% water must be present in ethanol to convert the excess solid to form I at equilibrium. PMID- 8683449 TI - Synthetic pyridopurines derived from food pyrolysis products: intercalation, interactions with membranes, cyclodextrin complexation, and biological mitogenic properties. AB - Crucial conditions for the pharmacological use of active compounds are their ability to cross the biological barriers and reach their intracellular target. In the case of two antiviral pyridopurine derivatives, 1 and 2, this included essentially the membranes and the nucleic acids. Thus the interactions of 1 and 2 with model membranes and oligonucleotides were studied using NMR spectroscopy. It was found that these hydrophobic molecules can be incorporated into the model membranes at the terminal methyl group level, inducing dynamic perturbations in the bilayer. In the presence of the synthetic oligonucleotide ACATGT, both molecules can intercalate aspecifically in AT and GC systems. Inclusion complexes of 1 and 2 beta-cyclodextrins with a 1:1 stoichiometry, were also prepared. This led to to propose two galenic forms 1 and 2, i.e. included in phospholipid vesicles in the form of a beta-cyclodextrin complex PMID- 8683450 TI - Application of central composite designs to the preparation of polycaprolactone nanoparticles by solvent displacement. AB - Cyclosporin A (CyA) is a good candidate for incorporation in colloidal carriers such as nanoparticles (NP) that would diminish the adverse effects associated with its use under conventional pharmaceutical dosage forms and improve bioavailability after oral administration. In this study a composite rotational experimental design was used to evaluate the joint influence of five formulation variables: temperature of the aqueous phase, needle gauge, volume of the organic phase, and the amounts of polymer and surfactant on the micromeritic characteristics of the CyA-loaded NP obtained by the method of Fessi et al. The percentage of drug encapsulated in the NP was also evaluated for each formulation, and the yield, which was expressed as the ratio between the experimentally measured quantity of drug in the formulation and the theoretical content, was determined because CyA undergoes surface absorption. Potential variables such as stirring speed (500 rpm), final drug concentration (100 micrograms/mL), or injection rates (GRi = 0.379 mL/s) were maintained constant. The ANOVA corresponding to the experimental design showed that the amounts of polymer and surfactant, and the diameter of the needle used in the preparation of NP, significantly affected the percentage of entrapped drug (I2 = 0.8916). The mean particle size was significantly affected by all the formulation variables tested except for the amount of surfactant dissolved in the external aqueous phase (r2 = 0.9518). Neither the yield (mean value of 99.61%) nor the size distribution parameters (polydispersity and coefficient of variation) presented good correlation coefficients for the equations obtained, although some variables showed statistical significance. A second study was carried out to investigate the effects on the drug-loaded NP characteristics of varying the global injection rates (GRi) for the organic phase into the aqueous medium. The results showed a dramatic decrease in both particle size and drug incorporation in the carrier as the rate of mixing increased. From the results of both the experimental design and the second study, a theoretical model for nanoparticle formation is proposed that considers the most significant variables, and an empirical relationship to predict mean particle size is presented. Thus, particle size can be controlled by the injection rates (GRi), the needle gauge, and the polymer concentration. PMID- 8683451 TI - Transdermal delivery of dideoxynucleoside-type anti-HIV drugs. 2. The effect of vehicle and enhancer on skin permeation. AB - The effects of vehicles and enhancers on the skin permeation of the dideoxynucleoside-type anti-HIV drugs Zalcitabine (DDC), Didanosine (DDI), and Zidovudine (AZT) were studied using hairless rat skin at 37 degrees C. After each drug was saturated in various volume fractions of ethanol (EtOH)/water or EtOH/tricaprylin (TCP) cosolvent system for 48 h at 37 degrees C, an in vitro skin permeation study was conducted using Valia-Chien permeation cells for 30 h. The skin permeation rates of DDC, DDI, and AZT from both EtOH/water and EtOH/TCP cosolvent systems increased as the volume fraction of ethanol was increased, reached maximum values at 50-60% (v/v) of ethanol, and then decreased with further increase of ethanol volume fraction. The EtOH/water cosolvent system seems to enhance the skin permeation of these drugs by increasing both the solubility of drug in the vehicles and partitioning of drug into the skin. The skin permeation enhancing effect of EtOH/TCP seems to be solely due to the increase in partitioning of drug into the skin. Addition of 1.0% (v/v) of permeation enhancers, such as oleic acid (OA) and N-methyl-2-pyrrolidone (NMP), in the EtOH/TCP (50:50) cosolvent system could not significantly increase the permeation rate of these drugs. Incorporation of viscous TCP into ethanol probably reduced the thermodynamic activity of enhancers to distribute from the vehicle to the skin. However, incorporation of 1.0% (v/v) of OA in the EtOH/water (60:40) cosolvent system dramatically enhanced the skin permeation of these drugs while reducing the lag time. The permeation rates of these drugs increased as OA concentration was increased up to 0.3% (v/v) in the EtOH/water (60:40) cosolvent system and reached a plateau with further addition of OA. Using a saturated solution in the EtOH/water (60:40) cosolvent system containing 1.0% (v/v) OA, DDC, and AZT reached the target permeation rate required to maintain a therapeutic system level across hairless rat skin. Although only DDC reached the target permeation rate across human cadaver skin, these results suggest that the mutual enhancement effect of ethanol and OA may make transdermal delivery of dideoxynucleoside-type anti-HIV drugs feasible. PMID- 8683452 TI - Confirmation of the Mukerjee term in an extended Corrin-Harkins relation using an anionic amphiphilic drug. AB - The amphiphilic behavior of the S-enantiomer of 3(S)-[(2-carboxyethyl)sulfanyl]-3 [2-(8-phenyloctyl)phenyl] propionic acid disodium salt (C26H32O4S.2Na) has been investigated as a function of the ionic strength, mu (buffer and simple electrolyte). The linearity predicted by the Corrin-Harkins relation (J. Am. Chem. Soc. 1947, 69, 683-688) is observed at low buffer concentrations, and it is verified that the nature of the buffer is of less importance than the concentration of the counterion. At high counterion concentrations, the salting out effect predicted by Mukerjee in 1965 (J. Phys. Chem. 1965, 69, 4038-4040) and 1967 (Adv. Coll. Interf. Sci. 1967, 1, 241-275) manifests itself, and a more complete equation resulting from attaching a salting-out term to the Corrin Harkins relation, as used recently by Mukerjee and Chan (ACS Abstracts of Papers 1993, 206, COLL 164; Ph.D. Thesis, University of Wisconsin, 1993), gives a better representation of the experimental data. It is shown that the parameter values obtained from this equation are reasonable and predict self-association in the form of micelles rather than as small aggregates. PMID- 8683453 TI - Paclitaxel partitioning into lipid bilayers. AB - Paclitaxel (taxol) is diterpenoid anticancer drug with a new mechanism of cytostatic action. It is under investigation in clinical trials for treatment of various types of human cancer. A major difficulty in developing paclitaxel as a chemotherapeutic agent in its poor water solubility. In order to improve the bioavailability of paclitaxel, novel vehicle systems such as mixed micelles or liposome-based formulations are being developed. In this study we determined the partition coefficient of paclitaxel partitioning into small unilamellar lipid vesicles composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine using two different methods, namely high-sensitivity titration calorimetry and fluorescence spectrometry. We measured a partition coefficient of Kp approximately equal to 9,500 M-1, a partition enthalpy of Delta H = -25 +/- 3 kcal mol-1 and a free energy of binding of Delta G = -7.9 kcal mol-1. The binding reaction is enthalpy driven, which can be explained by van der Waals interactions between the hydrophobic drug and the strong temperature dependence of the partition equilibrium. A temperature increase of 10 degrees C reduces the paclitaxel solubility in the lipid phase by a factor of 4. PMID- 8683454 TI - Is it possible to estimate the parameters of the sigmoid Emax model with truncated data typical of clinical studies? AB - Many drug concentration-effect relationships are described by the nonlinear sigmoid E(max) model. Clinical considerations frequently limit the magnitude of effect intensity that may be produced; the most pronounced effect intensity may be considerably below E(max). We have tested and quantified the influence of this limitation on the estimatability of the sigmoid E(max) model parameters. We have used the estimated parameter values to calculate data descriptors (drug concentrations required to produce certain effect intensities) and compared these with concentrations determined by using exact parameter values. We found that when the highest measured effect intensity was less than 95% of E(max), E(max) and EC50 were poorly estimated (high coefficient of variation and pronounced bias). Nevertheless, the fit to the data was quite good and the data descriptors were estimated with precision within the range for which data were available but not beyond. Baseline effect was estimated with good precision but the sigmoidicity parameter (gamma) was highly variable. Thus, where clinical considerations prevent determination of concentration-effect data near the maximum effect intensity, E(max) and EC50 estimations are unreliable. The use of estimable data descriptors is proposed to characterize the concentration-effect relationship under these conditions. PMID- 8683455 TI - A matrixed approach to long-term stability testing of pharmaceutical products. AB - A matrixed approach to long-term stability testing of pharmaceutical products is presented. The basic matrix design, suitable for testing three lots at one storage condition, may be extended to multiple product presentations or storage conditions. The design has full testing at the endpoints (0 and 36 months) and partial testing at the interim time points (3, 6, 9, 12, 18, and 24 months). The test points were selected with the assistance of a statistical search algorithm. The proposed matrix design provides a 37.5% reduction in analytical testing, while still permitting a reliable interim expiry estimate based on 12-month stability data. The expiration dating periods estimated using the matrixed approach are typically more conservative than estimates derived from a full testing approach. A comparison of expiration dating period estimates for a metered-dose inhaler and capsule drug product using the matrixed and full-testing approaches is presented. PMID- 8683456 TI - Effects of solid-state processing on water vapor sorption by aspirin. PMID- 8683457 TI - Comparative effects of inorganic phosphate and oxalate on uptake and release of Ca2+ by the sarcoplasmic reticulum in saponin skinned rat cardiac trabeculae. AB - 1. Ventricular trabeculae from the right ventricle of rat heart were suspended in a 6 microliters bath and "skinned' with saponin (50 mg ml-1). Preparations were perfused with solutions mimicking the intracellular milieu and the [Ca2+] within the bath was monitored continuously using fura-2. 2. Application of 20 mM caffeine released Ca2+ from the sarcoplasmic reticulum (SR), resulting in a transient increase in the fura-2 fluorescence ratio. Caffeine-induced Ca2+ transients were smaller in the presence of 30 or 60 mM inorganic phosphate (Pi). This depressive effect of Pi on SR function was reversed by 10 mM creatine phosphate (CP). Caffeine-induced Ca2+ transients were also reduced in the presence of 10 mM oxalate, although this effect was not reversed by CP. 3. When perfusion was stopped in the presence of 30 or 60 mM Pi, the [Ca2+] within the bath remained constant. However, when the flow was stopped in the presence of 60 mM Pi and 10 mM CP, a prolonged decrease in [Ca2+] occurred, consistent with precipitation of calcium phosphate within the SR. A similar decrease in [Ca2+] was observed when perfusion was stopped in the presence of 2 or 20 mM oxalate, in the absence or presence of CP. 4. The SR was Ca2+ depleted by withdrawal of ATP and exposure to 20 mM caffeine. Perfusion was then stopped and ATP reapplied, resulting in a maintained decrease in [Ca2+] within the bath, due to SR Ca2+ uptake. Net Ca2+ uptake was markedly reduced in the presence of 30 mM Pi. In contrast, 20 mM oxalate increased Ca2+ uptake and the [Ca2+] within the bath continued to fall over 2-3 min. 5. Introduction of Pi released Ca2+ from the SR. Ryanodine (100 microM) abolished caffeine-induced Ca2+ release while Pi-induced Ca2+ release was unaffected. Pi-induced Ca2+ release was reduced in the constant presence of 20 mM caffeine or 10 mM CP and was abolished completely by disruption of the SR membrane with Triton X-100. Pi-induced Ca2+ release occurred after abolition of SR Ca2+ uptake by ATP withdrawal. 6. These results suggest that the Pi-induced decrease in releasable Ca2+ does not result from precipitation of calcium phosphate within the SR lumen. Pi inhibits net SR Ca2+ uptake, but this appears to result from activation of a ryanodine-insensitive Ca2+ efflux pathway rather then inhibition of Ca2+ uptake. Possible mechanisms are considered, including reversal of the SR Ca2+ pump. PMID- 8683458 TI - Two different constituents of plasma increase cytosolic calcium selectively in neurons or glia of primary rat cerebellar cultures. AB - 1. The ability of several serum fractions to increase the cytosolic calcium concentration ([Ca2+]i) was tested in rat cerebellar cells maintained in primary culture. 2. Serum filtered through an ultrafiltration membrane with 3000 Da molecular mass cut-off (filtered serum, FS) selectively stimulated neurons whereas dialysed serum (DS) selectively stimulated glia. 3. The effects of FS were due to glutamate as they were reproduced by N-methyl-D-aspartate (NMDA), blocked by NMDA receptor antagonists and prevented by enzymatic removal of glutamate. 4. The effects of DS on glia were not reproduced by platelet activating factor, thrombin or bradykinin. They were not lost on heating or extraction with diethyl ether. They were reproduced by a methanol-chloroform-HCl extract from DS and by several commercial fraction V plasma albumins. 5. These [Ca2+]i-increasing factors present in blood could contribute to brain damage during ischaemia if they reached the brain interstitium on disruption of the blood-brain barrier. PMID- 8683459 TI - Calcium dependence of calcium extrusion and calcium uptake in mouse pancreatic acinar cells. AB - 1. The droplet technique was used to investigate the calcium dependence of calcium extrusion from pancreatic acinar cells with preserved intracellular environments. The calcium dependence of calcium extrusion indicated a strong co operativity (Hill coefficient, 3). The half-maximal rate of calcium extrusion occurred at an intracellular free calcium concentration ([Ca2+]i) of approximately 200 nM. At [Ca2+]i levels higher than 400 nM the calcium extrusion mechanism was almost completely saturated. 2. The rate of [Ca2+]i recovery was measured with the same cells under conditions where both calcium extrusion and calcium reuptake occurred simultaneously and under conditions when calcium reuptake was prevented and recovery depended entirely upon calcium extrusion. The rate of [Ca2+]i recovery due to calcium reuptake displayed a very sharp dependence on [Ca2+]i. The rate of [Ca2+]i recovery due to reuptake increased approximately 10 times (from 4.3 to 44.1 nM s-1) for an increase of [Ca2+]i of only 100 nM (from 120 to 220 nM). 3. With a decrease of [Ca2+]i the ratio of rate of calcium extrusion to rate of calcium uptake into internal stores increased, indicating that extrusion plays a more important role at low [Ca2+]i levels. Data for [Ca2+]i recovery rates due to extrusion and due to reuptake allowed us to evaluate the absolute rate of calcium translocation into the internal stores during the recovery process. When [Ca2+]i = 350 nM the total (i.e. bound and free) calcium concentration in the cytosol decreased by approximately 100 microM s-1 due to calcium uptake into internal stores. The rate of uptake was approximately 20 times slower when [Ca2+]i = 120 nM. PMID- 8683460 TI - Selective inhibition of high voltage-activated L-type and Q-type Ca2+ currents by serotonin in rat melanotrophs. AB - 1. Whole-cell Ca2+ currents (ICa) from cultured rat melanotrophs were identified by their sensitivity to Ca2+ channel blockers, and their modulation by serotonin (5-HT) was studied. All cells displayed high voltage-activated (HVA; > -30 mV) Ca2+ currents. A low voltage-activated (LVA; > -60 mV) Ca2+ current was detected in 92% of the cells. 2. The whole-cell ICa was insensitive to omega-conotoxin GVIA (0.5-1 microM) indicating the absence of N-type Ca2+ channels. 3. At a holding potential (Vh) of -70 mV, the L-type channel blocker nifedipine reduced ICa in a dose-dependent manner with a half-maximal effective concentration (IC50) of 28 nM. The L-type current represented 39% of the total ICa. 4. omega-Agatoxin IVA (omega-Aga IVA) produced a biphasic dose-dependent inhibition of ICa, with IC50 values of 0.4 and 91 nM, indicating the presence of P-type and Q-type Ca2+ channels, which accounted respectively for 16 and 45% of the total ICa. The P type current was also blocked by synthetic funnel-web spider toxin (sFTX 3.3; 1 10 microM) and was present only in a subpopulation (60-70%) of cells. 5. All cells possessed a Ca2+ current which was resistant to nifedipine (10 microM) and omega-Aga IVA (50 nM). This current was not affected by Ni2+ (40 microM) but was abolished by a low concentration of Cd2+ (10 microM) and by omega-conotoxin MVIIC (1 microM) indicating that it was a Q-type Ca2+ current. 6. 5-HT (10 microM) inhibited the whole-cell ICa in 70% of the cells tested (n = 120) by activating 5 HT1A and 5-HT2C receptors. 5-HT produced either a kinetic slowing of the activation phase (37% of the cells) or a scaling down (14% of the cells) of ICa. In the majority of cells (49%) both types of inhibition were found to coexist. 7. The effects of 5-HT were voltage dependent, rendered irreversible when GTP-gamma S (30 microM) was present in the pipette solution and abolished by pretreatment of the cells with pertussis toxin (PTX; 150 ng ml-1, 18 h). 8. Low concentrations of omega-Aga IVA (20 nM), which blocked mainly P-type channels, did not reduce the effect of 5-HT on ICa. The scaling down effect of 5-HT on ICa was eliminated in the presence of nifedipine (10 microM) and the kinetic slowing effect of 5-HT persisted after blockade of L- and P-type channels but was abolished by omega conotoxin MVIIC (1 microM). 9. We conclude that rat melanotrophs possess functional L-, P- and Q-type Ca2+ channels and that 5-HT inhibits selectively L type and Q-type Ca2+ currents with different modalities. These effects are voltage dependent and mediated by a PTX-sensitive G-protein. PMID- 8683461 TI - Direct influence of the sodium pump on the membrane potential of vomeronasal chemoreceptor neurones in frog. AB - 1. Whole-cell measurements were made from microvillous receptor neurones isolated from the frog vomeronasal organ. We examined the mechanisms that determined the value of the resting membrane potential. 2. Cells recorded in Ringer solution containing 4 mM K+ showed a resting membrane potential of -88 +/- 20 mV (mean +/- 1 S.D., n = 56). Sixty-six per cent of the cells had stable resting potentials more negative than the calculated equilibrium potentials for K+ (EK, -82 mV) indicating the presence of a hyperpolarizing outward pump current. 3. Cells recorded with an intracellular solution containing Na+ instead of K+, to set EK at 0 mV, presented stable membrane potentials in the range -65 to -119 mV when bathed in a normal Ringer solution. 4. Ouabain, a specific inhibitor of the Na+,K(+)-ATPase, blocked the outward sodium pump current (Ip) and depolarized the membrane. 5. The sodium pump current, measured as the current blocked by 0.5 mM dihydro-ouabain, was linearly related to the membrane potential in the range -60 to -120 mV. The reversal potential measured with a calculated free energy of ATP hydrolysis of -36.2 kJ mol-1 was estimated to be -143 mV. 6. Reduction of the external K+ concentration to 0 mM depolarized the membrane to less than -40 mV. Voltage-clamp observations in this condition indicated a reduction of Ip. Ouabain added to the bath reduced the blocking effect of low external K+. The addition of external K+ activated Ip and induced a rapid hyperpolarization of the cell membrane. 7. At membrane potentials more negative than -80 mV, an inward rectifying depolarizing current characterized as Ih was activated. When Ih was blocked by 5 mM external Cs+ the resting membrane potential increased. 8. These data indicate that the membrane potential of the vomeronasal receptor neurones is not generated by a passive diffusion of K+ ions but by the hyperpolarizing current created by the Na+,K(+)-ATPase. We propose that the resting potential is set by a balance between Ip and Ih. The physiological implications of these mechanisms for setting the resting potential are discussed. PMID- 8683462 TI - Regulation of renal Na+,K(+)-ATPase in rat thick ascending limb during K+ depletion: evidence for modulation of Na+ affinity. AB - 1. NaCl reabsorption along the loop of Henle is reduced in K(+)-depleted rats. Because Na+,K(+)-ATPase energizes this transport and because K+ depletion is known to induce an upregulation of Na+,K(+)-ATPase in most tissues, the regulation of this enzyme was investigated at the level of single thick ascending limbs of the loop of Henle freshly microdissected from rats fed either a normal (control rats) or a low-K+ diet (LK rats). 2. Within 2 weeks of K+ depletion, Na+,K(+)-ATPase activity and [3H]ouabain binding were increased by 30-50% in the medullary portion of the thick ascending limb (MTAL). 3. Despite this increase in the number of Na+,K(+)-ATPase units, the transport capacity of the Na+,K+ pump, determined by ouabain-sensitive Rb+ uptake in the presence of an extracellular concentration of Rb+ mimicking the kalaemia determined in control (4.0 mM Rb+) and LK rats (2.3 mM Rb+), was reduced in MTAL from LK rats. 4. Inhibition of the Na+,K+ pump was not accounted for by changes in either extracellular K+ or intracellular Na+ concentrations, but by a decrease in the pump affinity for Na+. 5. Because this change in the apparent affinity of the Na+,K+ pump for Na+ was detectable in intact but not in permeabilized MTAL cells, it is probably induced by a rapidly reversible cytosolic factor. PMID- 8683463 TI - A unique P-region residue is required for slow voltage-dependent gating of a G protein-activated inward rectifier K+ channel expressed in Xenopus oocytes. AB - 1. The structural determinants of a G protein-activated inwardly rectifying potassium channel, GIRK1 (KIR3.1), involved in voltage- and time-dependent gating properties were investigated by heterologous expression of chimeric constructs and point mutants in Xenopus oocytes. 2. Chimeras between GIRK1 and the weakly rectifying potassium channel, ROMK1 (KIR1.1), indicate that residues in the putative transmembrane segments TM1 and TM2 affect the steep inward rectification of GIRK1, while residues in the main pore-forming domain, the P-region segment, are critical for the manifestation of GIRK1 time-dependent activation. 3. Phenylalanine 137 in the P-region of GIRK1 is unique; in ROMK1, as in other inward rectifiers, there is a serine residue at this position. Mutation of the phenylalanine 137 to serine leads to expression of currents with nearly time independent activation. 4. An acidic residue (aspartate) in TM2 partially controls the time- and voltage-dependent gating in IRK1 (KIR2.1). Mutation of the equivalent aspartate 173 to glutamine in GIRK1 did not abolish the time-dependent activation but did decrease the degree of inward rectification. 5. These results reveal an important role for the P-region in controlling the time-dependent gating of an inwardly rectifying potassium channel and suggest a close relationship between permeation and gating in this family of K+ channels. PMID- 8683464 TI - Enhancement of delayed rectifier K+ current by P2-purinoceptor stimulation in guinea-pig atrial cells. AB - 1. We studied the effects of P2-purinoceptor stimulation on the delayed rectifier K+ current (IK) in guinea-pig atrial myocytes using a whole-cell voltage-clamp technique. 2. External application of ATP increased IK, evoked by a 500 ms depolarizing pulse from a holding potential of -40 mV, under conditions in which the L-type Ca2+ channel was blocked; the effect was dose dependent with a half maximal concentration (K1/2) of 0.95 microM. ATP (50 microM) produced a maximal increase of IK of about a factor of 2. 3. External ADP also enhanced IK in a dose dependent manner with a K1/2 of 3.65 microM, whereas adenosine (100 microM) failed to evoke this response. Theophylline (500 microM), a blocker of the Pi purinoceptor, did not antagonize the stimulating action of ATP on IK. These results indicate that IK was enhanced via P2-purinoceptors. 4. External ATP or ADP did not produce a significant change in the current kinetics of IK. 5. Pre incubation of the atrial myocytes with pertussis toxin (PTX, 5 micrograms ml-1) did not affect the stimulating action of ATP on IK, indicating that PTX-sensitive G proteins did not mediate the ATP action. 6. The enhancement of IK by ATP developed slowly; the effects usually reached a maximum approximately 30-60 s after the application of ATP. This suggests the involvement of a diffusible cytosolic second messenger(s) in the response. ATP could further increase IK after maximal enhancement by isoprenaline (0.5-1.0 microM), suggesting that the intermediate steps were independent of cyclic AMP-dependent protein kinase (protein kinase A). 7. Potentiation of IK by ATP was not attenuated by either (i) pretreatment of the cells with 5 microM 1-(5-isoquinolinylsulphonyl)-2 methylpiperazine dihydrochloride (H-7) or (ii) intracellular perfusion of 20 mM 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), suggesting that protein kinase C and intracellular Ca2+ did not mediate the response. 8. It is concluded that the activation of P2-purinoceptors increases IK through intracellular mechanisms independent of protein kinase A, protein kinase C or intracellular free Ca2+ in guinea-pig atrial myocytes. PMID- 8683466 TI - Patch-clamp characterization of nicotinic receptors in a subpopulation of lamina X neurones in rat spinal cord slices. AB - 1. Nicotinic acetylcholine receptors (nAChRs) on lamina X neurones in neonate (P1 P12) rat transverse thoracolumbar spinal cord slices were studied using the whole cell patch-clamp technique. These visually selected neurones are located dorsal to the central canal, mainly in the ventral half of the dorsal commissure. 2. Pressure application of the nicotinic agonist 1,1-dimethyl-4-phenyl-piperazinium (DMPP) (1 mM) induced a rapid depolarization on which action potentials are superimposed. 3. At -50 mV, DMPP (1 mM), pressure ejected for 100 ms, induced a fast inward current with a mean amplitude of -280 pA (n = 28) in 90% of the neurones recorded. Superfusion of tetrodotoxin (TTX), a solution containing 0 Ca(2+)-high Mg2+, CdCl2 or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) did not abolish the DMPP-induced current, which confirmed a direct postsynaptic effect of DMPP on recorded neurones. 3. The current-voltage (I-V) relationship for DMPP induced current exhibited a reversal potential of 0 mV (NaCl outside, potassium gluconate inside) and a strong inward rectification. 4. The DMPP-induced responses were blocked by mecamylamine, hexamethonium and d-tubocurarine (dTC) but were insensitive to alpha-bungarotoxin and methyllycaconitine (MLA). 5. We conclude that lamina X neurones located dorsally to the central canal possess nicotinic acetylcholine receptors. Activation of these nicotinic receptors results in depolarization and generation of action potentials. These receptors may be involved in the modulation of the somato- and viscerosensory transmission. PMID- 8683465 TI - Activation of the muscarinic K+ channel by P2-purinoceptors via pertussis toxin sensitive G proteins in guinea-pig atrial cells. AB - 1. Whole-cell voltage clamp and cell-attached patch-clamp techniques were applied to single atrial myocytes enzymatically dissociated from adult guinea-pig hearts. 2. In whole-cell clamp conditions, external applications, of ATP activated the muscarinic K+ (KACh) current, identified by its inward rectification, its reversal potential near the calculated K+ equilibrium potential (EK) and its relaxation properties during step changes of whole-cell membrane potential. Theophylline, an antagonist for Pi-purinoceptors, did not affect the action of ATP on the KACh current, indicating that the response was evoked through P2 purinoceptors. 3. The concentration-response relationship for ATP was well described by a Hill equation with a half-maximal concentration of 1.84 microM and a Hill coefficient of 0.94. ATP (100 microM) produced a maximal increase of the KACh current to 10.92 microA microF-1, which corresponds to 44.9 and 80.9% of the maximal increases evoked by ACh (10 microM) and adenosine (100 microM), respectively. 4. The activation of KACh current gradually declined to a steady level despite the continuous presence of ATP (desensitization). Recovery from the desensitization was relatively rapid with a half-time of approximately 1.5 min. 5. The activation of KACh current by ATP was completely abolished by pre incubating myocytes with pertussis toxin (PTX, 5 micrograms ml-1), indicating that P2-purinoceptors are coupled to PTX-sensitive G proteins to activate the KACh channel. 6. In the cell-attached patch recording, ATP (5 microM) applied to the pipette solution enhanced the activity of a channel with single-channel conductance of 52.7 +/- 0.9 pS (mean +/- S.E.M., n = 10), reversal potential near EK and mean open time of 1.1 +/- 0.1 ms. These conductance and kinetic properties are identical to those of the KACh channel in the heart. In contrast, ATP applied to the bath solution did not significantly affect the basal activity of KACh channel openings. These observations suggest that the mechanism coupling the P2 purinoceptor to the activation of the KACh channel involves membrane-delimited component(s) rather than soluble second messenger(s). 7. These results strongly suggest a direct coupling of the P2-purinoceptor to the KACh channel through PTX sensitive G proteins, analogous to the coupling mechanism of the muscarinic ACh receptor and Pi-purinoceptor to this channel. PMID- 8683467 TI - Electrophysiological consequences of ligand binding to the desensitized 5-HT3 receptor in mammalian NG108-15 cells. AB - 1. Using the whole-cell variation of the patch-clamp technique to record from mammalian NG108-15 cells, we have studied the ligand-gated ion channel current activated by a high concentration (100 microM) of local pressure-applied 5 hydroxytryptamine (5-HT). The response was induced at intervals of at least 90 120 s, which allowed the receptor to fully recover between activations. 2. The rapid inward current induced by pressure-applied 5-HT was reproducibly inhibited by the superfusion of low concentrations of 5-HT which evoked little or no detectable inward current alone (0.01-0.3 microM). This inhibitory effect was most likely to be due to a direct action on the 5-HT3 receptor as it could be recorded using intracellular solutions with or without adenosine triphosphate (ATP) and guanosine triphosphate (GTP). 3. The maximum inhibitory effect of a given concentration of 5-HT was not dependent on its superfusion time but on the number of activations of the receptor by pressure-applied 5-HT. This activation dependence was clearly evident, since the first inward current in the presence of 0.1 microM 5-HT was often unaffected in amplitude. 4. The inhibitory effect of 5 HT was evident at holding potentials of +60 and -60 mV; with the calcium chelator BAPTA in the recording pipette and with the nominal removal of extracellular calcium and magnesium ions. 5. The inhibitory effect was concentration dependent, with 50% inhibition of the inward current amplitude occurring at approximately 50 nM 5-HT. The slope factor of the inhibition curve was 1.3. The effect was mimicked by two other 5-HT3 receptor agonists, 2-methyl-5-HT and m chlorophenylbiguanide (mCPBG) which gave 50% inhibition at approximately 600 nM and approximately 20 nM, respectively. These values are similar to the affinity values for these ligands determined in radioligand binding assays. 6. The 5-HT3 receptor "antagonists' (+)-tubocurarine and quipazine (both at 3 nM) reduced the inward current amplitude by approximately 50%. The rate of onset of the inhibitory effect of bath-applied 5-HT was slowed in the presence of (+) tubocurarine but not in the presence of quipazine. This difference might be explained by the agonist properties seen only with quipazine. 7. The inhibition of the 5-HT3 receptor mediated inward current by low concentrations of bath applied 5-HT3 receptor agonists is compatible with the cyclic model of receptor activation and desensitization. We conclude that we have been studying the high affinity binding of agonists to the desensitized form of the 5-HT3 receptor. PMID- 8683468 TI - Sodium-dependent GABA-induced currents in GAT1-transfected HeLa cells. AB - 1. HeLa cells were infected with recombinant vaccinia virus containing the T7 RNA polymerase gene and transfected with the cDNA for a rat GABA transporter, GAT1, cloned downstream of a T7 RNA polymerase promoter. Six to sixteen hours after transfection, whole-cell recording with a voltage ramp in the range -90 to 50 mV revealed GABA-induced currents (approximately -100 pA at -60 mV in 100 microM GABA, 16 h after transfection at room temperature). No GABA-induced currents were observed in parental HeLa cells or in mock-transfected cells. 2. GABA-induced currents were suppressed by extracellular perfusion with GABA-free solutions or addition of GAT1 inhibitors SKF89976-A or SKF100330-A. At fixed voltage the GABA dependence of the inward current fitted the Michaelis-Menten equation with a Hill coefficient, n, near unity and an equilibrium constant, K(m), near 3 microM. The Na+ dependence of the inward currents fitted the Michaelis-Menten equation with n approximately equal to 2 and K(m) approximately equal to 10 mM. The constants n and K(m) for GABA and Na+ were independent of voltage in the range -90 to -30 mV. 3. GABA-induced currents reverse direction in the range 5-10 mV. The implication of this result is that GAT1 can mediate electrogenic (electrophoretic) influx or efflux of GABA depending on the membrane voltage. The presence of an outward current in our experiments is consistent with radioactive-labelled flux data from resealed vesicle studies. However, it is inconsistent with frog oocyte expression experiments using the sample clone. In oocytes, GAT1 generates no outward current in a similar voltage range. Smaller intracellular volume or higher turnover rates in the mammalian expression system may explain the outward currents. 4. External GABA induces inward current, and internal GABA induces outward current. However, in cells initially devoid of internal GABA, external GABA can also facilitate an outward current. This GAT1-mediated outward current occurs only after applying negative potentials to the cell. These data are consistent with the concept that negative potentials drive GABA and Na+ into the cell, which then leads to electrogenic efflux through GAT1 at positive voltages. 5. Assuming coupled transport, we estimate the number of transporters, N, times the turnover rate, r, to be Nr approximately 10(9) s-1 under nominal conditions (V = -60 mV, 30 microM GABA, 130 mM Na+ and room temperature). This indicates either very high levels of expression (approximately 10(4) microns-2), assuming published turnover rates (approximately 10 s-1), or turnover rates that are significantly greater than previously reported. As an alternative, a channel may exist in the GAT1 protein that is gated by GABA and Na+ and blocked by GAT1 antagonists. The channel mode of conduction would exist in addition to the coupled, fixed-stoichiometry transporter mode of conduction. PMID- 8683469 TI - Influence of actinomycin D, a RNA synthesis inhibitor, on long-term potentiation in rat hippocampal neurons in vivo and in vitro. AB - 1. Hippocampal long-term potentiation (LTP) may serve as an elementary process underlying certain forms of learning and memory in vertebrates. As is the case with behavioural memory, hippocampal LTP in the rat CA1 region and in the dentate gyrus occurs in stages, which can be separated by an inhibitor of RNA synthesis. 2. Experiments have been performed in two brain regions, in the hippocampal CA1 region in vitro and in the dentate gyrus in vivo. 3. Maintenance of hippocampal LTP in the CA1 region in vitro was influenced by the RNA synthesis inhibitor actinomycin D from 4 h onwards. 4. The effect of actinomycin D on the time course of the population spike potentiation was more pronounced than the effect on the time course of the EPSP component, suggesting different mechanisms for the two forms of potentiation. 5. Intrahippocampal and intracerebroventricular injection of actinomycin D into rats prevented a late stage of LTP in the dentate gyrus in vivo measured as the population spike amplitude. 6. Since actinomycin D was only effective in influencing the maintenance of LTP when applied before tetanization, the requirement for transcription during LTP may have a critical time window. 7. Actinomycin D influenced the maintenance of LTP specifically, since the drug did not alter any potentials in control experiments after its removal or when it was administered shortly after tetanization. A second, structurally different RNA synthesis inhibitor, 5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole, mimicked the effect of actinomycin D in vitro. PMID- 8683470 TI - Vasopressin-induced intracellular Ca2+ increase in isolated rat supraoptic cells. AB - 1. The intracellular Ca2+ concentration ([Ca2+]1) was monitored in single magnocellular neurones freshly isolated from rat supraoptic nucleus. Application of 100 nM vasopressin increased [Ca2+]1. Two types of [Ca2+]1 responses were observed: (i) a transient response, displayed by 86% of the vasopressin-sensitive neurones, and (ii) a sustained response displayed by 14% of the vasopressin sensitive neurones. 2. Among responding neurones, 52% were vasopressin sensitive, 44% were oxytocin sensitive and 4% were sensitive to both peptides. 3. Responses to vasopressin were dose dependent, showed a progressive desensitization after successive applications, were specifically blocked by the V1a vasopressin receptor antagonist, SR 49059, and were unaffected by the oxytocin receptor antagonist, d(CH2)5OVT. 4. Vasopressin responses were completely suppressed by the removal of external Ca2+. 5. The intracellular Ca2+ mobilizers, caffeine and tBuBHQ, did not affect resting or vasopressin-induced [Ca2+]1 changes. Thapsigargin (200 nM) on its own evoked an increase in [Ca2+]1, and reduced the [Ca2+]1 increase evoked by vasopressin by 52%, suggesting that thapsigargin sensitive Ca2+ stores are partially involved in the vasopressin response. 6. Immunocytochemical identification revealed that vasopressin-responding neurones synthesize vasopressin whereas oxytocin-responding neurones synthesize oxytocin. 7. In conclusion, vasopressin- (partially external Ca2+ dependent) and oxytocin (totally external Ca2+ independent)-induced [Ca2+]1 changes are mediated by specific receptors. In addition, vasopressin and oxytocin neurones are specifically autoregulated by their own peptides. PMID- 8683471 TI - Properties of presympathetic neurones in the rostral ventrolateral medulla in the rat: an intracellular study "in vivo'. AB - 1. Intracellular recordings were made in pentobarbitone-anaesthetized rats from sixty-eight neurones located in the rostral ventrolateral medulla (RVLM), which responded with inhibition (latency, 33.6 +/- 9.3 ms) after stimulation of the aortic depressor nerve with short bursts of pulses. This inhibition was due to chloride- and voltage-dependent IPSPs. 2. Seventeen neurones could be excited antidromically after stimulation in the T2 spinal segment (conduction velocity 1.9-8.5 m.s-1) and were classified as RVLM presympathetic vasomotor neurones. 3. "Spontaneously' active neurones (n = 29) displayed a largely irregular pattern of firing, with no clear relationship between the level of the membrane potential and cycles of phrenic nerve activity at end-tidal CO2 < 5.0%. Cardiac cycle related shifts of the membrane potential were not considered indicative of baroreceptor input as they could be due to movement artifacts. 4. All neurones displayed large synaptic activity (EPSPs and IPSPs, peak-to-peak amplitude > 5.0 mV). The depolarizing IPSPs observed during injection of chloride and/or negative current consisted of a phasic and a tonic component. 5. The on-going activity of these neurones resulted from synaptic inputs, with individual action potentials usually preceded by identifiable fast EPSPs. 6. No evidence was found for the presence of gradual depolarizations (autodepolarizations) between individual action potentials, and therefore under these experimental conditions the activity of RVLM presympathetic neurones did not depend on intrinsic pacemaker properties. 7. These results are consistent with the "network' hypothesis for the generation of sympathetic vasomotor tone. PMID- 8683472 TI - Behaviour of raphe cells projecting to the dorsomedial medulla during carbachol induced atonia in the cat. AB - 1. The activity of most brainstem serotonergic cells is suppressed during sleep, particularly the rapid eye movement (REM) phase. Thus, they may play a major role in state-dependent changes in CNS functioning. Our main goal was to search for medullary raphe cells having axonal branches in the region of the hypoglossal (XII) motor nucleus and assess their behaviour during the atonia produced by microinjections of a cholinergic agonist, carbachol, into the dorsal pontine tegmentum. In chronic animals, such microinjections evoke a desynchronized sleep like state similar to natural REM sleep; in decerebrate animals, they produce eye movements and a motor suppression similar to the postural atonia of REM sleep. 2. In decerebrate, paralysed, vagotomized and artificially ventilated cats, we recorded extracellularly from medullary raphe cells antidromically activated from the XII nucleus region. Forty-five cells recorded in the raphe obscurus and pallidus nuclei were antidromically activated with latencies characteristic of non-myelinated fibres (4.4-42.0 ms). For thirty-three of the forty-five cells, we found one or more axonal branches within or just below the XII nucleus. The remaining twelve cells, in addition to the XII nucleus, had axonal ramifications in the medial nucleus of the solitary tract (NTS) and/or the dorsal motor nucleus of the vagus (DMV). 3. A subset of fourteen spontaneously active cells with identified axonal projections were held long enough to be recorded during the carbachol-induced atonia, and eight of these also during the subsequent recovery and a systemic administration of the serotonergic 1A receptor agonist (+/-)8 hydroxy-2-(di-N-propylamino)tetrealin hydrobromide (8-OH-DPAT). All but one were suppressed during the atonia in parallel to the suppression of XII, phrenic and postural nerve activities (firing rate, 1.3 +/- 0.7 Hz before and 0.1 +/- 0.2 Hz after carbachol (means +/- S.D.)). Following the recovery from the atonia, the firing rates of the eight cells increased to the pre-carbachol level (1.6 +/- 1.0 Hz). Subsequently, all were silenced by 8-OH-DPAT. 4. These cells fulfil most physiological criteria for serotonergic cells and have the potential to modulate, in a state-dependent manner, activities in the motor XII nucleus, visceral sensory NTS, and DMV. The decrements in serotonergic neuronal activity that occur during the carbachol-induced atonia suggest that a similar withdrawal of serotonergic input may occur during REM sleep and contribute to the characteristic reductions in upper airway motor tone. PMID- 8683473 TI - Inhibition of a small-conductance cAMP-dependent Cl- channel in the mouse thick ascending limb at low internal pH. AB - 1. A small-conductance Cl- channel that is stimulated by ATP and protein kinase A has been identified in the basolateral membranes of cortical thick ascending limbs (CTALs) of the mouse nephron. The present study uses the cell-attached and inside-out variants of the patch-clamp technique to investigate the pH sensitivity of this channel. 2. The open-state probability (Po) was dependent upon the internal pH in inside-out patches. Expressed as a percentage of the Po value at pH 7.2, Po increased to about 180% at pH 7.6, and decreased to 25% at pH 6.8. Po was close to zero at pH 6.4. The internal pH had no effect on the channel unit conductance. 3. The effect of pH on the CTAL Cl- channel was assessed in intact cells using NH4Cl to acidify the intracellular compartment. Experiments with the pH-sensitive fluorescent dye 2',7'-(carboxyethyl)-5'(6')-carboxy fluorescein penta-acetoxymethyl ester (BCECF) indicated that 1 mmol l-1 NH4Cl acidified the cytoplasm by 0.15 pH units and 5 mmol l-1 NH4Cl by 0.34 pH units. These concentrations of NH4Cl reduced the activity of the CTAL Cl- channel by 24 and 82% in cell-attached patches, showing that moderate changes in internal pH substantially altered the activity of this channel. NH4+ had no direct effect on channel activity. 4. Inhibition at low pH is a newly discovered property of small conductance Cl- channels in epithelia, which might help discriminate between types of Cl- channel. PMID- 8683475 TI - Activation of L-arginine transport (system y+) and nitric oxide synthase by elevated glucose and insulin in human endothelial cells. AB - 1. Modulation of L-arginine transport (system y+) and release of nitric oxide (NO) and prostacyclin (PGI2) by elevated glucose and insulin were investigated in human cultured umbilical vein endothelial cells. 2. Elevated glucose induced a time- (6-12 h) and concentration-dependent stimulation of L-arginine transport, which was reversible and associated with a 3-fold increase in intracellular cGMP accumulation (index of NO synthesis) and 75% decrease in PGI2 production. 3. Elevated glucose had no effect on the initial transport rates for L-serine, L citrulline, L-leucine, L-cystine or 2-deoxyglucose. 4. Resting membrane potential was unaffected by elevated glucose whereas basal intracellular [Ca2+] increased from 65 +/- 5 nM to 136 +/- 16 nM. 5. Insulin induced a protein synthesis dependent stimulation of L-arginine transport and increased NO and PGI2 production in cells exposed to 5 mM glucose. 6. In cells exposed to high glucose, insulin downregulated elevated rates of L-arginine transport and cGMP accumulation but had no effect on the depressed PGI2 production. 7. Our findings suggest that insulin's normal stimulatory action on human endothelial cell vasodilator pathways may be impaired under conditions of sustained hyperglycaemia. PMID- 8683474 TI - Effect of a dynein inhibitor on vasopressin action in toad urinary bladder. AB - 1. The effect of the dynein inhibitor erythro-9-[3-(2-hydroxynonyl)] adenine (EHNA) on the osmotic water flow response to vasopressin or exogenous cAMP has been investigated in isolated toad urinary bladders. 2. Pretreatment with serosal EHNA had no effect on basal water flow, but inhibited the development and maintenance of the hydrosmotic response to vasopressin (20 mU ml-1) or 8-(4 parachlorophenylthio)-adenosine 3',5'-cyclic monophosphate (8 CPT-cAMP; 0.1 mM). 3. The inhibitory effect of EHNA on vasopressin-induced water flow was dose dependent. Inhibition occurred in the dose range in which EHNA inhibits the ATPase and motor activities of dynein in vitro. 4. EHNA also inhibited the maintenance of the high rate of water flow established by prior exposure to vasopressin. 5. The inhibitory effect of EHNA on the onset phase of the vasopressin response was attenuated after exposure of the tissue to the microtubule-disruptive drug nocodazole but was fully additive with that of cytochalasin B. 6. EHNA inhibited basal and vasopressin-stimulated transepithelial sodium transport. 7. The findings support the view that EHNA inhibits hormone-induced water flow through an action on a cytoplasmic dynein. The results are consistent with the hypothesis that dynein is involved in the microtubule-based delivery of water channel-containing vesicles to the apical membrane of the granular epithelial cells during both the onset and maintenance of the water permeability response to vasopressin. PMID- 8683476 TI - Mechanism of lactate-induced relaxation of isolated rat mesenteric resistance arteries. AB - 1. The effects of the sodium salt of the weak acid lactate on tension and intracellular pH (pH1) were studied in rat mesenteric small arteries mounted on a wire myograph. Sodium lactate was substituted iso-osmotically for sodium chloride. 2. At a concentration of 50 mM, both L- and D-stereoisomers of lactate markedly relaxed arteries preconstricted with noradrenaline (NA) within 10 min. The concentration-response relationship for L-lactate showed that the NA contracture was relaxed by 50% at approximately 26 mM. L-Lactate did not, however, relax arteries preconstricted with high-K+(45 mM) solution. 3. L-Lactate did not alter extracellular pH (pHo) but caused a small but significant decrease in pH1, measured using the pH-sensitive fluorochrome, 2',7'-bis(carboxyethyl)-5 (6)-carboxyfluorescein (BCECF). Relaxation to L-lactate was unaffected when this change in pHi was offset by the simultaneous addition of NH4Cl to the solution. 4. Sodium pyruvate (50 mM) caused a significant intracellular acidosis but did not relax arteries preconstricted with NA. 5. L-Lactate-induced relaxations were unaffected by removal of the endothelium or when the synthesis of nitric oxide (NO) was inhibited by 10(-4) M N omega-nitro-L-arginine methyl ester (L-NAME). 6. The potassium channel blockers glibenclamide (10 microM), 4-aminopyridine (3 mM) and tetraethylammonium chloride (10 mM) did not affect L-lactate-induced relaxation in arteries preconstricted with NA. Inhibition of guanylate cyclase with Methylene Blue, or cyclooxgenase with indomethacin, also did not affect relaxation to L-lactate. 7. The Rp stereoisomer of adenosine-3',5'-cyclic monophosphothioate (Rp-cAMPS), an analogue of cAMP which inhibits competitively stimulation of protein kinase A, reduced significantly L-lactate-induced relaxation at a concentration of 25 microM. Rp-cAMPS also significantly reduced forskolin-induced relaxation of the NA contracture. 8. It is concluded that L lactate-induced relaxation in this vascular bed is pHi-1 endothelium-, and nitric oxide-independent. It is not mediated by inhibition of voltage-gated Ca2+ channels, opening of K+ channels, prostacylin or cyclic GMP. cAMP may however play a role in L-lactate-induced relaxation. PMID- 8683477 TI - The role of adenosine in functional hyperaemia in the coronary circulation of anaesthetized dogs. AB - 1. The aim of this investigation was to determine the contribution of adenosine to coronary active hyperaemia in the dog denervated heart by using adenosine deaminase. 2. Beagles were anaesthetized with thiopentone sodium (500 mg, I.V.) and chloralose (100 mg kg-1, LV.) and artificially ventilated. The hearts were denervate by bilateral cervical vagotomy and cardiac sympathectomy. Blood samples were collected from the coronary sinus via a cannula passed through the right external jugular vein. The anterior descending or circumflex branch of the left coronary artery was cannulated and perfused with blood from the left subclavian artery under systemic blood pressure through an electromagnetic flow probe and a perfusion circuit. The heart was paced (3 V, 0.2 ms and a suitable frequency) via two electrodes attached to the right atrium from 109 +/- 7.3 to 170 +/- 9.8 beats min-4 (means +/- S.E.M.) for 3-4 min, first during an infusion of the solvent, and then during an infusion of a solution of adenosine deaminase (5 U kg-1 min-1) into the circuit. 3. In seventeen tests in eight dogs, infusion of adenosine deaminase did not cause a significant change in the basal coronary blood flow nor in the immediate increase (within 10s) in blood flow induced by pacing the heart from its basal rate to 170 beats min-1. However, adenosine deaminase did cause a significant attenuation by 58 +/- 5.2% (P < 0.05) of the increase in coronary blood flow induced at 3-4 min of pacing from 31 +/- 4.6 to 43 +/- 5.8 ml min-1 (100 g cardiac tissue)-1. Concomitantly, the pacing-induced increase in coronary vascular conductance (from 0.41 +/- 0.08 to 0.54 +/- 0.12 ml min-1 (100 g)-1 mmHg 1) was reduced by 75 +/- 6.6% (P < 0.02) and the increase in myocardial O2 consumption (from 13 +/- 3.5 to 21 +/- 4.2 ml min-1 (100 g)-1) was reduced by 50 +/- 12% (P < 0.05) but without significant changes in oxygen extraction or myocardial contractility. 4. The results show that although adenosine is unlikely to play a significant role in the regulation of the basal coronary blood flow, it can play a major role in the coronary active (functional) hyperaemia induced by atrial pacing to a high rate in the denervated heart of anaesthetized dogs. PMID- 8683478 TI - Ventilatory relief of the sensation of the urge to breathe in humans: are pulmonary receptors important? AB - 1. The sensation of an urge to breathe (air hunger) associated with a fixed level of hypercapnia is reduced when ventilation increases. The aim of the present study was to investigate whether pulmonary receptors are important in this mechanism. 2. Five heart-lung transplant (HLT) subjects and five control subjects were studied during periods of mechanical and spontaneous ventilation. End-tidal Pco2 (PET,CO2) was increased by altering the level of inspired CO2. Throughout, subjects rated sensations of air hunger. Air hunger was also monitored during and immediately following maximal periods of breath-holding. 3. When the level of mechanical ventilation was fixed, both groups experienced a high degree of air hunger when PET,CO2 was increased by about 10 mmHg. At similar levels of hypercapnia, both groups derived relief from approximately twofold increases in tidal volume, although relief was slightly less effective in HLT subjects. This was reversible, with decreases in the level of mechanical ventilation rapidly giving rise to increased ratings of air hunger. 4. With breath-holding, all subjects obtained some respiratory relief within 2 s of the break point; there was no significant difference between the groups. 5. The results suggest that sensations of an urge to breathe induced by hypercapnia can be modulated by changes in tidal volume in the presumed absence of afferent information from the lung. PMID- 8683480 TI - Gastrointestinal motility and disease in large animals. AB - An understanding of the relationship between gastrointestinal (GI) motility and disease is imperative for the proper treatment of large animal patients, especially as new therapeutic agents become available. However, the abundance of information that has become available in the last 2 decades makes gaining this understanding a formidable task. This article summarizes the changes in GI motility caused by some common diseases and conditions encountered in large animal practice, such as GI obstruction, postoperative ileus, resection and anastomosis, diarrhea, endotoxemia, GI parasitism, hypocalcemia, and pregnancy. PMID- 8683479 TI - A rate theory model for Mg2+ block of ATP-dependent potassium channels of rat skeletal muscle. AB - 1. We have studied the block by intracellular Mg2+ (0.08-4mM) of ATP-dependent potassium channels (KATP channels) from rat skeletal muscle using inside-out excised sarcolemmal patches. The block is voltage dependent, is relieved by extracellular potassium and has rapid kinetics, allowing the use of amplitude distribution analysis to estimate on and off rates. 2. To gain insight into the pore properties necessary to produce such a block, we have used an energy barrier model based on Eyring rate theory. The model has two energy wells and three barriers for K+ within the pore, while intracellular Mg2+ has access only to the inner well. We fitted the model to unitary current-voltage relations in different [Mg2+], to on and off rates, and to dissociation constants for Mg2+ block. 3. The voltage dependence of block was almost entirely due to the rate constant for unblocking. This implies that the inner energy barrier is asymmetrical, so that Mg2+ entry senses little of the voltage field, but Mg2+ exit senses about 20% of the voltage field. Best fits were obtained by placing the barrier and binding site 0.01 and 0.22, respectively, of the electrical distance through the pore from the inside. 4. The relief of block by [K+]o resulted from an increase in the unblocking rate for Mg2+, implying ionic repulsion between ions in the pore. PMID- 8683481 TI - Plasma von Willebrand factor antigen concentration and buccal mucosal bleeding time in dogs with experimental hypothyroidism. AB - This study was undertaken to investigate the effects of hypothyroidism on buccal mucosal bleeding time and von Willebrand factor antigen (vWf:Ag) concentrations. Hypothyroidism was induced in 8 adult dogs by administration of iodine 131. Four healthy dogs acted as controls. Measurement of plasma vWf:Ag and serum thyroxine and triiodothyronine concentrations, and buccal mucosal bleeding time were made before induction of hypothyroidism, for 23 weeks after 131I administration, and during 5 weeks of levothyroxine supplementation. No significant changes in buccal mucosal bleeding times were noted during the study. After an insignificant increase in vWf:Ag concentration in hypothyroid dogs, levothyroxine treatment was associated with a significant decrease in vWf:Ag concentration in hypothyroid dogs when compared with controls. Results of this study suggest that hypothyroidism does not induce acquired von Willebrand's disease or significant defects in primary hemostasis. PMID- 8683482 TI - A retrospective study of cavernous sinus syndrome in 4 dogs and 8 cats. AB - Cavernous sinus syndrome (CSS) is characterized by deficits in more than one of the cranial nerves (CN) that traverse the cavernous sinus at the base of the cranial vault: CN III (oculomotor), IV (trochlear), VI (abducens), and the first two branches of CN V (trigeminal). Records from 4 dogs and 8 cats with CSS diagnosed over a 14-year period were reviewed. The most common clinical signs were ophthalmoparesis or ophthalmoplegia, mydriasis with no direct or consensual pupillary light reflexes, ptosis, decreased corneal sensation, and decreased retractor oculi reflex. All cats had initial signs referable to a left CSS lesion (one had bilateral CSS), whereas in all dogs the lesions were localized to the right cavernous sinus. Median ages at diagnosis were 9 and 10 years of age for dogs and cats, respectively. Cerebel lomedullary cisternae cerebrospinal fluid analysis in 6 animals was useful as a sensitivebut nonspecific diagnostic test of an intracranial inflammatory or neoplastic lesion. Magnetic resonance imaging scans provided a more definitive diagnostic test in all dogs, revealing a contrast-enhancing mass on T1 weighted scans in the region of the cavernous sinus. A definitive pathological diagnosis was obtained in 2 dogs: a primary intracranial neoplasm and a metastatic intracranial neoplasm. A definitive diagnosis was obtained in 6 cats: metastatic neoplasm (n = 1), primary intracranial neoplasm (n = 1), primary intracranial infectious disease (n = 2), and associated systemic infectious disease (n = 2). The prognosis associated with CSS in dogs and cats was considered guarded to poor. PMID- 8683483 TI - Cystic meningiomas in 2 dogs. AB - Two dogs with signs of forebrain disease had hypodense lesions on computed tomography evaluation. Magnetic resonance imaging of the first dog showed a hypointense lesion on the T1-weighted scan and a hyperintense lesion on T2 weighted scanning. At surgery, both dogs had a primary cystic intracranial lesion, and the abnormal tissue adjacent to the cyst had histological features of meningioma. Each dog underwent whole brain irradiation after surgery, and 1 dog lived for 3 years after treatment. While uncommon, meningioma should be considered as a differential diagnosis in dogs with cystic intracranial lesions. PMID- 8683484 TI - Amputation and carboplatin for treatment of dogs with osteosarcoma: 48 cases (1991 to 1993). AB - Forty-eight dogs with histologically confirmed appendicular osteosarcoma (OSA) entered a prospective clinical trial evaluating treatment with amputation and up to 4 doses of carboplatin given every 21 days. The median disease-free interval (DFI) was 257 days, with 31.2% of the dogs disease-free at 1 year. The median survival time was 321 days, with 35.4% of the dogs alive at 1 year. Dogs with proximal humeral OSA had shorter DFI (P = .016) and survival (P = .037) times than dogs with OSA at other locations. Dogs with lower body weights ( < 40 kg) had longer DFI (P = .0056) and survival (P = .007) times than larger dogs. Survival times for dogs that received carboplatin were statistically longer than those previously reported for amputation alone (P < .001). DFI and survival times are similar to those previously reported for 2 to 4 doses of cisplatin. Carboplatin appears to be a well-tolerated chemotherapeutic drug that can be given safely every 21 days at a dose of 300 mg/m2. Neutropenia was the dose limiting toxicity in this study. PMID- 8683485 TI - Evaluation of a whole blood glutaraldehyde coagulation test for the detection of failure of passive transfer in calves. AB - The accuracy of a commercially available whole blood glutaraldehyde clot test in the detection of failure of passive transfer (serum immunoglobulin [Ig]G1 < 1,000 mg/dL) in neonatal calves was evaluated. Serum samples were obtained from 242 calves ranging in age from 1 to 8 days, and comparisons were made with serum IgG1 concentrations determined by radial immunodiffusion. Both the sensitivity and specificity of the currently marketed whole blood glutaraldehyde clot test are inadequate for routine diagnostic use. Concerns regarding test sensitivity are the most problematic. Sensitivity varied from 0.41 to 0.00, depending on the choice of test endpoint. Specificity varied from 0.85 to 1.00, depending on the choice of test endpoint. Regression analysis demonstrated that the relationship between serum IgG1 concentration and the glutaraldehyde clot results, although significant (P < .10), was of negligible biological relevance (r2 = .034). PMID- 8683486 TI - Effects of enalapril on exercise tolerance and longevity in dogs with heart failure produced by iatrogenic mitral regurgitation. AB - This study was conducted to evaluate the effects of enalapril on exercise capacity and longevity in dogs with left-sided heart failure produced by iatrogenic mitral regurgitation. After surgical creation of mitral regurgitation, 18 dogs were allocated into replicates according to exercise capacities. One dog in each replicate received placebo, and the other received 0.5 mg/kg of enalapril sid for 9 days and bid thereafter. Exercise tolerance was studied after 10, 19, 52 to 53, and 80 to 81 days, respectively. Finally, the percentage of dogs in each group that survived 357 days was compared. The duration of exercise for dogs in the placebo and enalapril groups did not differ at baseline (P > .1) or after 19 days (P > .1). Dogs that received enalapril had significantly reduced (P < .001) exercise tolerance at day 10, and significantly increased (P = .002) exercise tolerance at days 52 to 53 and 80 to 81 when compared with controls. At 357 days, 22% of dogs receiving placebo were alive, compared with 67% of dogs receiving enalapril; however, these differences were not statistically significant (P = .124). This study shows that enalapril increases exercise tolerance in dogs with left-sided heart failure induced by iatrogenic mitral regurgitation. PMID- 8683487 TI - Bradycardia-associated episodic weakness, syncope, and aborted sudden death in cardiomyopathic Doberman Pinschers. AB - Paradoxical sinus bradycardia and cardiac asystole resulted in episodic weakness, syncope, or aborted sudden cardiac death during exertion in 8 cardiomyopathic Doberman Pinschers. Bradycardias persisted for 1 to 2 minutes in 5 of 8 dogs, and were often followed by sinus tachycardia. Syncope was prolonged on multiple occasions in 5 dogs, and was accompanied by white, then cyanotic mucous membranes, mydriasis, and apparent sudden death. PMID- 8683489 TI - Progression of subaortic stenosis detected by continuous wave Doppler echocardiography in a dog. PMID- 8683488 TI - Clostridial myonecrosis, hepatitis, and nephritis in a llama with vegetative endocarditis. PMID- 8683490 TI - Use of dual-energy x-ray absorptiometry (DEXA) to measure lean body mass, body fat, and bone mineral content (BMC) in dogs and cats. PMID- 8683492 TI - Recurrent panniculitis as the first clinical manifestation of recurrent acute pancreatitis secondary to cholelithiasis. AB - A case of recurrent panniculitis in the legs as the first clinical manifestation of recurrent acute pancreatitis secondary to cholelithiasis is described in a 59 year-old Caucasian woman. PMID- 8683491 TI - Evaluation of the effect of colloid (Haemaccel) on the bleeding time in the trauma patient. PMID- 8683493 TI - Consequences of lymphatic malformations in the Klippel-Trenaunay syndrome. PMID- 8683495 TI - A case of malignant rectoduodenal fistula: an unusual form of duodenum to large bowel fistula. PMID- 8683494 TI - Major vascular injury during lumbar laminectomy. AB - Major vascular injury during lumbar laminectomy is an extremely rare complication of one of the commonest surgical procedures performed in orthopaedic and neurosurgical units. Its occurrence may be associated with high morbidity and mortality, particularly if it is not diagnosed in the early stages. Early diagnosis and repair is associated with an improved prognosis in the long term. We illustrate these points with a description of two cases, and discuss the anatomical factors predisposing to these injuries and the importance of angiography in the management and early diagnosis of suspected cases. PMID- 8683496 TI - Primary adenocarcinoma of the appendix. PMID- 8683497 TI - Secondary amenorrhoea after total body irradiation in pre-puberty. AB - Bone marrow transplant (BMT) has been used as part of the overall treatment of refractory malignant diseases. High dose cyclophosphamide and total body irradiation (TBI) are frequently used as conditioning for BMT. Initial regimens included a single fraction of TBI, with doses varying from 7.5-10 Gy, but this was associated with a high incidence of late sequelae including multiple endocrinopathies. A fractionated irradiation course over 3-4 days of a higher total dose, 12-15 Gy, of TBI is now used. Successfully treated patients with childhood cancer have an increased risk, of developing second tumours. We describe a patient successfully treated for AML who developed multiple endocrine dysfunction and a second benign ovarian tumour. PMID- 8683498 TI - The consequences of toxic shock syndrome in an 18-month-old boy with 20% scalds. AB - Toxic shock syndrome may complicate burns and scalds in young children. However, it can occur in the district general hospital setting, where early recognition of the prodromal features to facilitate early therapy will depend on the knowledge and training of paediatricians and casualty staff. PMID- 8683500 TI - Get some research under your belt. PMID- 8683499 TI - Anticardiolipin antibodies and cardiovascular disease. PMID- 8683501 TI - Euthanasia: going Dutch? AB - My experience in 25 years as a hospice doctor have reinforced my belief that when everything is taken into account--physical, psychological, social and spiritual- euthanasia is not the answer. This belief is enhanced by what I see happening in the Netherlands. However, lest it be thought that I have become hardened and indifferent to suffering let me add that, although firmly opposed to euthanasia, I consider that: (i) a doctor who has never been tempted to kill a patient probably has had limited clinical experience or is not able to empathize with those who suffer (ii) a doctor who leaves a patient to suffer intolerably is morally more reprehensible than the doctor who performs euthanasia A doctor has twin obligations to preserve life and to relieve suffering. Preserving life is increasingly meaningless when a terminally ill patient is close to death, and the emphasis on relieving suffering becomes paramount. Even here, however, the doctor is obliged to achieve his objective with minimum risk to the patient's life. This means that treatment to relieve pain and suffering which coincidentally might bring forward the moment of death by a few hours or days is acceptable (the principle of double effect), but administering a drug such as potassium or curare, with the primary intention of causing death, is not. PMID- 8683502 TI - Physical activity, the compression of morbidity, and the health of the elderly. AB - The Compression of Morbidity hypothesis envisions a potential reduction of overall morbidity, and of health care costs, now heavily concentrated in the senior years, by compression of morbidity between an increasing age of onset of disability and the age of death, increasing perhaps more slowly. For this scenario to be able to be widely achieved, largely through prevention of disease and disability, we need to identify variables which predict future ill health, modify these variables, and document the improvements in health that result. Physical activity is perhaps the most obvious of the variables which might reduce overall lifetime morbidity. PMID- 8683503 TI - Aggression against doctors: a review. AB - Although the number of doctors abused is comparatively small, the perceived risk of violence presents a major issue for the whole profession since the consequences extend to all doctors through the intimidation reports in the medical press and newspapers engender. PMID- 8683504 TI - Near-death experiences. AB - Reactions to claims of near-death experiences (NDE) range from the popular view that this must be evidence for life after death, to outright rejection of the experiences as, at best, drug induced hallucinations or, at worse, pure invention. Twenty years, and much research, later, it is clear that neither extreme is correct. PMID- 8683505 TI - Pitcairne's disease: an historical presentation of oro-facial granulomatosis. PMID- 8683506 TI - Characteristics of referrals to an inpatient hospice and a survey of general practitioner perceptions of palliative care. AB - In order to determine symptoms, drug prescribing and physical problems of patients referred to an inpatient hospice, case notes from 130 consecutive first admissions (95 general practitioner (GP) referrals, 35 consultant referrals) were analysed. GP referrals were more likely to be constipated, require care and be discharged to home. Consultant referrals were more gravely ill, dependent and more likely to die in the hospice. On admission 76 (58%) patients were receiving opiates with co-prescription of opiate and laxative occurring in 41% (31/76) of the cases. The prescription of laxatives with the symptoms of constipation occurred in 62% (26/42) of the cases on admission. A telephone survey of 79 referring GPs revealed that 37% had attended neither a course nor a lecture relevant to palliative care in the past 3 years. GPs experienced difficulties frequently or always in: (a) managing pain (8/79); (b) managing other symptoms (25/79); (c) helping patients and relatives cope with their emotional distress (18/79); and (d) coping with their own emotional responses to death and dying (5/79). In conclusion, the differences demonstrated between the GP and consultant referrals have implications for purchasers. The high incidence of possible opiate induced side-effects and the difficulties with symptom control expressed by some GPs indicate a continuing need for effective educational input. PMID- 8683507 TI - A winter survey of domestic heating among elderly patients. AB - Elderly people have a greater need for domestic heating given the time they spend at home and the decline in the body thermoregulation that occurs with ageing. The use of domestic heating by 200 mentally competent newly admitted elderly in patients was evaluated by means of a questionnaire survey. Most patients (69%) were aware of the addition of value added tax (VAT) to their fuel bill and 31% said they had reduced the amount of heating they use because of this. A third of patients (29.5%) said they had difficulty keeping warm prior to this admission. The majority of patients said they could not manage to keep warm in the winter without financial hardship. In addition, 29% said they had reduced the amount spent on food in order to pay for fuel bills. This study suggests that cold may contribute to hospital admissions in elderly patients. This should have implications for government spending and taxation policy on domestic heating. PMID- 8683508 TI - Can a lecture influence attitudes to suicide prevention? AB - Attitudes held by various groups of healthcare professionals with regard to suicide prevention were assessed using an attitude inventory before and after they attended a formal lecture. The lecture presented basic facts and statistics, discussed clinical techniques and challenged negative attitudes. Evidence is presented to suggest that a reduction in the proportion of expressed attitudes which were equivocal or negative towards the feasibility of suicide prevention in clinical practice, can be achieved by a lecture of this kind. PMID- 8683509 TI - Non-convulsive status epilepticus presenting as a psychiatric condition. AB - Non-convulsive status epilepticus may present as confusion, behavioural disturbances and psychiatric conditions. We present the case of a 17-year-old man who had episodes of non-convulsive status epilepticus as his only manifestation of epilepsy which was mis-diagnosed as a psychiatric condition for over 10 years. He has had almost complete resolution of his symptoms with the introduction of carbamazepine. Non-convulsive status epilepticus is probably commoner than previously thought, and should be considered as a possible diagnosis in all patients presenting with prolonged episodes of altered consciousness even without other manifestations of epilepsy. PMID- 8683510 TI - The clinical section--a special case for case reports. PMID- 8683511 TI - The delayed arrival: from Davy (1800) to Morton (1846). AB - Dr Adams was previously consultant anaesthetist to Addenbrooke's Hospital, Cambridge, with a special interest in ophthalmic and neuroanaesthesia, and Associate Lecturer in Cambridge University. She was Dean of the Faculty of Anaesthetists of the Royal College of Surgeons of England in 1985, now the Royal College of Anaesthetists, of which she is currently Honorary Archivist/Curator. She was Hunterian Professor in the Royal College of Surgeons in 1993, and is a past president of the History of Anaesthesia Society. Within the RSM she was president of the Section of Anaesthetics in 1985-1986 and of the Section of the History of Medicine in 1994-1995, having served as Honorary Secretary of each. She is now an Honorary Treasurer of the Society. PMID- 8683512 TI - Medical textbooks and journals for Afghanistan? A visiting doctor's perspective. PMID- 8683513 TI - Ought low alcohol intake to be promoted for health reasons? AB - There is increasingly widespread acceptance that alcohol taken in moderation by the population aged 35 years or older reduces the risks of ischaemic heart disease and all-cause mortality. Ten causal criteria are used to evaluate the scientific evidence for a protective effect of low alcohol intake on ischaemic heart disease. Inferences for public policy are then assessed using the principles of beneficence, non-maleficence, justice and autonomy to support a framework of nine ethical considerations: intervention versus causation; effect modification by gender, smoking, biogenetic and other factors; inappropriate adoption of recommendations; competing hazards between atherosclerotic disease and cancer; opportunity cost; equity of access; the value system used to judge outcomes; the degree of social influence warranted; and consent and responsibility. We conclude that in the absence of more adequate scientific knowledge and informed community debate it is unethical to promote low alcohol intake as a preventive health measure. PMID- 8683514 TI - Prenatal screening vouchers. PMID- 8683515 TI - The management of childhood otitis media with effusion. PMID- 8683516 TI - Diseases of Babylon: an examination of selected texts. PMID- 8683517 TI - How can acute mountain sickness be quantified at moderate altitude? AB - Reports of acute mountain sickness (AMS) at moderate altitude show a wide variability, possibly because of different investigation methods. The aim of our study was to investigate the impact of investigation methods on AMS incidence. Hackett's established AMS score (a structured interview and physical examination), the new Lake Louise AMS score (a self-reported questionnaire) and oxygen saturation were determined in 99 alpinists after ascent to 2.94 km altitude. AMS incidence was 8% in Hackett's AMS score and 25% in the Lake Louise AMS score. Oxygen saturation correlated inversely with Hackett's AMS score with no significant correlation with the Lake Louise AMS score. At moderate altitude, the new Lake Louise AMS score overestimates AMS incidence considerably. Hackett's AMS score remains the gold standard for evaluating AMS incidence. PMID- 8683518 TI - Three simple methods of detecting malnutrition on medical wards. AB - Malnutrition in hospital is often unrecognized. A nutrition team aims to teach simple methods of detecting malnutrition. On a single day all medical in-patients underwent a nutritional assessment. Eighty-four patients (43 men), median age 71 years (range 28-97), were assessed. The most common diagnoses were cardiac disease (26), stroke/dementia (12), non-malignant lung disease (9) and malignancy (6). A weight loss of more than 10% (%WL) was found in 17/65 (26%) and a body mass index (BMI) of less than 19 kg/m2 in 13/69 (19%). A mid-arm muscle circumference (MAMC) less than the fifth percentile occurred in 16/83 (19%) patients. Percentage weight loss alone detected seven patients of whom four were overweight (BMI > 25 kg/m2), BMI alone detected three patients, and MAMC alone eight patients of whom three could not be weighed and three had fluid retention. There was fluid retention in 35/84 (42%) patients of whom nine were malnourished (six detected by BMI and/or %WL, and three by MAMC alone). All three measurements were made in 64 patients, six (9%) of whom were detected as malnourished by all three methods. Combining the three measurements 29/84 (35%) of patients were malnourished and only 28% of these patients had been assessed by a dietitian. BMI and %WL detect most patients but fluid retention may limit their accuracy. MAMC is useful in those who cannot be weighed or who have fluid retention. PMID- 8683520 TI - The Canadian Familial Adenomatous Polyposis Registry: past, present and future. AB - The advent of the molecular world opening up for familial adenomatous polyposis and other genetically predisposed cancers has now provided us with wonderful tools to study these diseases. The challenges, however, clearly remain to transfer discoveries in the laboratory to improvements in the care of these patients. PMID- 8683519 TI - Preventing the admission of difficult psychiatric patients--a questionnaire survey. AB - By means of a postal survey of all consultant psychiatrists (n = 143) in the South East Thames Region, the authors examined factors associated with psychiatrists' decisions to impose restrictions on certain patients' access to admission. Twenty-two per cent of respondents reported the use of admission restrictions. Usage of this measure was associated with a local absence of psychotherapy services (OR 0.34; 95% CI 0.17-0.63) which might suggest that there is a need for more equal access to specialist psychiatric services across health districts. PMID- 8683521 TI - Antenatal diagnosis of renal tract anomalies: has it increased the sum of human happiness? AB - When used as a screening procedure, ultrasound examination of the fetal urinary tract seldom leads to beneficial interventions. There is also a cost in terms of parental anxiety and unnecessary investigation and treatment. A formal screening programme would therefore be unjustified. However, screening of women for obstetric purposes will continue to reveal fetal abnormalities, and a strategy for dealing with these is needed. Antenatal treatments remain experimental; for most of the common conditions postnatal treatment has no urgency; and, in cases of minor abnormality detected by ultrasound, the best course may be to do nothing. PMID- 8683522 TI - A survey of the current methods used in the UK to assess pituitary function. AB - A national survey of the current methods used by specialists to evaluate pituitary function in the UK was performed by postal questionnaire. Seventy-three respondents, of whom 89% were consultants and 80% clinical endocrinologists, returned the questionnaire. Fifty per cent routinely used the insulin stress test (IST) to evaluate the hypothalamo-pituitary-adrenal (HPA) axis, while 50% routinely used tetracosactrin stimulation, there being little overlap between the two groups. This represents a significant change in clinical practice since the last survey in 1988. In those who used ACTH stimulation there was almost an equal split into those who administered the tetracosactrin intramuscularly (45%) or intravenously (47%). Furthermore, either the peak or 60 min cortisol value was used by 71% when interpreting the result of the test, despite the fact that in previous studies only the 30 min cortisol value has been shown to correlate with the IST result. The IST remains the most frequently used method to assess growth hormone reserve in adult subjects. The thyrotrophin-releasing-hormone and gonadotrophin-releasing-hormone tests are still used routinely by approximately a quarter of clinicians. These results provide data that could be used to develop guide-lines for the use of tests to investigate pituitary function. PMID- 8683523 TI - Recurrent aspergilloma of the frontoethmoid sinus in a non-immunocompromised patient. AB - Management of invasive aspergillosis of the paranasal sinuses requires sufficient experience to initiate appropriate investigations and then utilize the correct treatment protocol. Computed tomography (CT) or magnetic resonance imaging (MRI) is essential to show the extent of the disease and diagnosis is confirmed by histological analysis. Aspergillus flavus is a ubiquitous soil saprophyte in the Sudan and is responsible for many cases originating from this area. The literature is reviewed and treatment options discussed. PMID- 8683524 TI - Successful outcome of severe unilateral pulmonary interstitial emphysema after bi lobectomy in a very low birthweight infant. AB - Extubation of ventilated infants with severe unilateral pulmonary interstitial emphysema is difficult because the function of normal lung tissue is impaired. Continued positive pressure ventilation worsens hyperinflation on the side with interstitial emphysema, leading to cardiorespiratory compromise. Resection of affected single lobes is well described, but there are no reported cases of multiple lobectomies in very low birthweight infants. We describe a case where resection of both right upper and middle lobes was successful, allowing extubation within a few days of surgery. Computed tomography (CT) of the chest was helpful in making the decision to treat this infant by surgery. PMID- 8683525 TI - Uretric obstruction in Gardener's syndrome. AB - Desmoid tumours in Gardener's syndrome are a rare cause of ureteric obstruction. We report two cases of ureteric obstruction caused by desmoids, in a mother and daughter. PMID- 8683526 TI - Munchausen's syndrome--masquerading as necrotizing fasciitis. AB - We would like to present a novel form of Munchausen's syndrome which presented us with a difficult problem in the midst of the recent media hysteria regarding flesh eating bacteria. This condition, first described by Richard Asher in 1951, is often very difficult to diagnose and it is not, therefore, surprising that the victims have been through several episodes of treatment before the suspicions of staff are raised. It owes its name to a fictitious character, Baron Karl Friedrich Hieronymus Freihess von Munchausen, who recounted extraordinary and wildly exaggerated exploits of adventure and daring, not unlike patients who present with this condition. Our enquiries revealed that the laid down procedure when faced with a patient with this condition is that the regional medical officer (RMO) should be contacted. It is then his responsibility to contact other RMOs, who in turn pass the information on to accident and emergency consultants in their area. PMID- 8683527 TI - Severe small airways disease resistant to medical treatment in a child with cystic fibrosis. AB - At the age of 12, a child with cystic fibrosis developed severe small airways obstruction of unknown aetiology, in the absence of significant bronchiectasis. He remained resistant to medical treatment until, following an exacerbation of allergic bronchopulmonary aspergillosis 18 months later, he responded to high dose oral steroids. He now remains steroid-dependent, and suffering from multiple side-effects. Possible aetiology and further therapeutic strategies are discussed. PMID- 8683528 TI - William Harvey and the circulation of the blood. PMID- 8683529 TI - Get some research under your belt. PMID- 8683530 TI - Population strategy for preventive medicine. PMID- 8683531 TI - Understanding American health-care and health-care reform. PMID- 8683532 TI - Ocular and renal sarcoidosis. PMID- 8683533 TI - Risk factors for HIV infection overlooked in routine antenatal care. PMID- 8683534 TI - Unexplained illness. PMID- 8683535 TI - Antioxidants and lupus erythematosis. PMID- 8683537 TI - The role of UK tobacco advertising: no effect on the nation's health? Part III: Government influence on cigarette advertising. PMID- 8683536 TI - Iodine in the diet: perspectives for vegans. PMID- 8683538 TI - Typing of proteus from patients with bacteriuria. AB - Forty-five strains of Proteus mirabilis isolated from hospital in-patients, out patients and community patients with significant bacteriuria, were investigated to determine whether a predominant type was present using the Dienes test. Antimicrobial susceptibility patterns of the 45 strains of Proteus mirabilis were also determined. There were 38 different Dienes types which shows that there is no predominant type of Proteus amongst the isolates examined in this study. This suggests that there is no predominant type of Proteus mirabilis in the community and hospital acquired bacteriuria. The antimicrobial susceptibility pattern of an isolate was not a useful marker for typing because susceptibility patterns between different Dienes types were so similar. PMID- 8683539 TI - Obesity in Bahraini adults. AB - In this study the prevalence of obesity and the demographic factors associated with it were analysed on 290 adult Bahraini individuals, of whom 137 were males and 153 were females. The overweight and obesity prevalence rates, using the Body Mass Index (BMI) as a criterion, were 26% and 16% in males and 29% and 31% in females, respectively. The prevalence of underweight (BMI < 20) was 16.8% and 11.8% in the males and females respectively. The mean body fat percentage of females, calculated from the skinfold measurements, was 35%; the fat percentage of males was 18.6%. Bahraini women had greater fat deposition in the subscapular region than the amount reported for American women. Females and males living in urban areas had a greater tendency to be obese than those residing in rural areas. Marriage, ownership of a car as well as a large family ( > 7 members) were positively associated with obesity; unmarried women were more likely to be underweight than married women. The educational level was not associated with obesity in either the males or females. The age of adult females was not found to be associated with obesity, whereas in males the incidence of obesity was more frequent among those who were 50 years of age and above than under 50 years of age. Family monthly income was not associated with the incidence of obesity. The high prevalence of overweight and obesity in the women reported in this study and the difference in the distribution of body fat suggest that genetics may be a determinant factor of this disorder in Bahrainis but certainly social factors are also important. PMID- 8683540 TI - Apolipoprotein E and Alzheimer's disease. PMID- 8683541 TI - The future of community health trusts. AB - In summary therefore, I believe Community/Mental Health Trusts must: Work closely with purchasers/contracts in context. Focus local services in GP surgeries or own homes. Dispose of unnecessary estate. Concentrate on what they do best. Meet customer needs, improve customers' perceptions and market and publicise services. Cut out restrictive professional practices and increase staff flexibility, information systems etc. Develop customer relations, contracting, business planning. Identify ?niche' (minority/specialist) markets (including social care). Develop active Quality Assurance, Clinical Audit, outcomes, research programmes. Create effective organisation and management style (Empowerment, delivery). Minimise costs (Value For Money, minimise internal expenditure, rationalise estate, streamline management). Maximise income. Build alliances. Develop user empowerment, advocacy etc. Finally, whatever the future holds we must keep our eye on the ball - the patient - and ensure their needs are paramount over professions and organisations. PMID- 8683542 TI - The nursing profession--a changing role in a changing world. PMID- 8683543 TI - Achieving excellence in care: inspection and standard setting in homes for older people. PMID- 8683544 TI - Exercise and mental health: a review. AB - With the advent of programmes to raise the level of fitness in the general population, and alliances between primary health care and community leisure services, the potential of exercise in promoting mental as well as physical health deserves investigation. In contrast to USA and continental Europe, there is a paucity of British research studies systematically exploring the mental health benefits of exercise. The recent rapid growth of exercise prescription among general practitioners presents an opportunity for future research. This review of eleven randomised control trials (RCTs) suggests a causal relationship between exercise and mental health based upon studies in various settings. The methodological difficulties associated with randomised control trials of psycho social interventions are discussed. The value of future randomised control trials which incorporate examination of perceived acceptability and health economics is indicated. PMID- 8683545 TI - Persistent infection with virulent but not avirulent Mycobacterium tuberculosis in the lungs of mice causes progressive pathology. AB - A strain of Mycobacterium tuberculosis (H37Rv) considered virulent for mice and a strain (R1Rv) considered relatively avirulent were compared for their ability to survive host immunity in the lungs and to induce lung pathology. Although both strains of M. tuberculosis were capable of causing a slowly progressive infection in the lungs of immunocompetent mice, only the H37Rv strain was capable of inducing progressive destructive pathology and of causing loss of lung function over a 300-day period. Therefore, the ability to survive host immunity in the lungs and the ability to cause lung pathology are separate manifestations of mycobacterial virulence. PMID- 8683546 TI - The high amino-acid content of sputum from cystic fibrosis patients promotes growth of auxotrophic Pseudomonas aeruginosa. AB - Many isolates of Pseudomonas aeruginosa from cystic fibrosis (CF) patients are auxotrophic and require amino acids for growth. A quantitative assay was used to determine the total content of free amino acids of sputum sol-phase extracts from CF and non-CF patients to assess the presence of amino acids in the airway. CF patients colonised with auxotrophic P. aeruginosa had a higher sputum amino-acid content (mean 6.77 mg/ml) than those colonised with prototrophs (mean 3.77 mg/ml); overall, CF specimens (mean 5.70 mg/ml) had a higher amino-acid content than non-CF samples (2.52 mg/ml). The amino-acid profile of sputum extracts was assessed by one-dimensional thin layer chromatography (TLC). Several amino acids were identified in the extracts, in particular, leucine, isoleucine, phenylalanine, tyrosine, alanine, serine and methionine or valine or both. All sputum specimens except two (which contained < 1.5 mg of amino acids/ml), promoted the growth, of 34 auxotrophic strains of P. aeruginosa from CF patients in a minimal medium. These results indicate, therefore, that amino acids are plentiful in the sputum of CF patients and are able to supply the requirements of auxotrophic strains. It is suggested that the increased amino-acid content in the airways of CF patients plays a significant role in the selection and maintenance of nutritionally deficient P. aeruginosa. PMID- 8683547 TI - Bacterial vaginosis in pregnancy: distribution of bacterial species in different gram-stain categories of the vaginal flora. AB - Vaginal swabs for microbiological culture were taken from 174 pregnant women whose vaginal flora had been evaluated by Gram's stain; 50 had grade III flora (bacterial vaginosis, BV), 50 grade II (intermediate), 41 had vaginal flora graded as abnormal which then reverted to grade I (revertants) and 33 had normal flora (controls). The aim was to determine whether bacterial species isolated from women with grade II flora differed from those with grade III flora. Isolation of Lactobacillus spp. decreased from grade I to grade III and that of other aerobic and anaerobic bacterial species increased. There was little difference in the species isolated from women with grade II and grade III flora, but there was a distinct order in which organisms in different species increased in numbers. The vaginal flora of revertants was intermediate between that of healthy controls and those with grade II flora. Coagulase-negative Staphylococcus spp. were isolated from a greater number of revertants than grade I controls but the incidence did not increase in grade II or grade III. Bifidobacterium spp. were isolated from a greater number of revertants than grade I controls and increased further in grade II and grade III. However, Gardnerella vaginalis and Mycoplasma hominis were isolated from a much larger number of women with grade III flora than the other groups. The conclusion is that grade II is a transitional phase between grade I and grade III and that some organisms such as G. vaginalis and M. hominis only reach large numbers in the late stage. The sequence of appearance of the various bacterial species may be a result of the pathophysiological alteration of the vaginal ecosystem associated with BV. PMID- 8683548 TI - An examination of the clonal variants of Serratia marcescens that infect the eye during contact lens wear. AB - Serratia marcescens colonises contact lenses during wear, although the frequency of isolation is generally low (0.6% contamination rate). A method for typing the S. marcescens colonising the eye or contact lens was developed, based upon ribotyping, serotyping and biotyping. Twelve different types of S. marcescens were isolated from the eyes, contact lenses, contact lens cases and fingers of contact lens wearers in the Sydney area over a 2-year period. There was no evidence of a specific type being more readily able to colonise the contact lenses than other types. Indeed, eight S. marcescens strains were isolated from the lenses and these belonged to seven types. The diversity of types isolated from the eye indicates that there is probably not a subset of S. marcescens that can colonise the eye, although the results suggest that the types of strains isolated from contact lenses are different from those isolated from nosocomial infections. PMID- 8683549 TI - The distribution of Clostridium difficile in the environment of South Wales. AB - A large study of the distribution of Clostridium difficile in the environment of the Cardiff area of South Wales was performed with a methodology designed to maximise recovery. A total of 2580 samples was taken, with 184 (7.1%) yielding isolates. The highest yield for C. difficile was obtained from river waters, with 14 (87.5%) of 16 samples from four rivers positive, and from sea water samples with 7 (44%) of 15 positive from six beaches on the Bristol Channel. In addition, 7 (46.7%) of 15 samples of lake water were also positive. Twenty-two (21%) of 104 soil samples, taken from random sites in Cardiff, were positive, as were 20% of environmental samples from four Cardiff hospitals. C. difficile was also isolated from 50% of eight swimming pool waters examined and 1 (5.5%) of 18 of mains tap water. Carriage of C. difficile in 524 faecal samples of assorted farm animals was c. 1%, and was 10% in dogs and 2% in cats. In private residences, the organism was present in 12 (2.2%) of 550 samples. While 2.4% of 300 raw vegetable samples were positive, none of 107 assorted fish gut contents was. These findings indicate that C. difficile may be more widely distributed in the general environment, particularly water, than was previously thought. PMID- 8683550 TI - Langerhans cell density and serological changes following intradermal immunisation of mice with dengue 2 virus. AB - After the introduction of the dengue-2 (16681) virus by intradermal (i.d.) injection into the footpads of mice, Langerhans cells (LCs) increased in numbers within 24 h at the site of injection and neutralising antibody developed. On comparing the i.d. and intramuscular (i.m.) routes, antibody was produced more rapidly and at higher levels when the virus was injected by the i.d. route. Subsequent re-challenge by the i.d. route produced an even more rapid serological response with all mice producing significant neutralising titres within 12 h. Numbers of ATPase-positive LCs varied with time. A significant sharp drop in LC densities in the early post-injection phase directly correlated with the increased numbers of dendritic cells in the superficial dermis and interfollicular sinuses of draining lymph nodes (LN). Immunofluorescence showed the presence of viral antigen in the footpad epidermis and draining LN within minutes or within 2 h of challenge, respectively. PMID- 8683551 TI - Imbalance between Pneumocystis carinii cysts and trophozoites in bronchoalveolar lavage fluid from patients with pneumocystosis receiving prophylaxis. AB - Detection and quantification of different Pneumocystis carinii (PC) life cycle forms were performed by polymerase chain reaction (PCR) and by morphological stains on bronchoalveolar lavage fluids (BALF) from HIV-infected patients with P. carinii pneumonia (PCP). The number of PC trophozoites was higher in patients with PCP who were receiving prophylaxis than in those not receiving prophylaxis. Also the cyst: trophozoite ratio was lower in the first group. No difference was observed between patients receiving different prophylactic medications. The imbalance between PC forms in BALF from patients with PCP receiving anti-PC prophylaxis may hamper the sensitivity of cyst stains. Multiple stains or PCR examination should be performed on BALF from patients with clinically suspected PCP who are receiving prophylaxis. PMID- 8683552 TI - Cytomegalovirus in bronchoalveolar lavage specimens from patients with AIDS: comparison with antigenaemia and viraemia. AB - Pulmonary infection with cytomegalovirus (CMV) is a well recognised complication of AIDS. It is often possible to detect CMV-infected cells in bronchoalveolar lavage (BAL) specimens with monoclonal antibodies, but the clinical significance of their presence remains unclear. To investigate this, 24 AIDS patients were tested for CMV antigenaemia and viraemia, in addition to CMV detection in BAL. CMV was detected in the BAL of nine patients (38%), five with clinical and laboratory evidence of pulmonary infection and four without pulmonary involvement. Blood samples positive for CMV antigen were observed in two patients with CMV-positive BAL specimens and, in both cases, antigenaemia resolved without therapy. No case of viraemia was detected. Pneumocystis carinii was detected concomitantly with CMV in the BAL of four of the patients with pulmonary involvement and in one without signs of pulmonary infection. These data suggest that CMV-positive BAL results are of limited significance in the diagnosis of CMV pneumonia in AIDS patients, unless associated with high levels of antigenaemia or viraemia and compatible clinical symptoms. PMID- 8683554 TI - Health issues for the 21st century: infection, antimicrobial drug resistance, distance learning and technology. PMID- 8683553 TI - A novel simple method for quantifying bacteria from endotracheal aspirates. AB - A convenient dipstrip method (Bacteruritest; Mast Diagnostics) for bacterial quantification was evaluated with 42 endotracheal aspirates. For 31 specimens, the dipstrip method yielded counts within a 10-fold range of surface plate counts. Two specimens yielded counts by the dipstrip within a 100-fold range of plate counts. Six specimens yielded confluent growth at the greatest dilution tested by the dipstrip method, and counts > 10(10) cfu/ml in the surface plate method. Three specimens yielded no detectable growth by the dipstrip and surface plate counts < 10(2) cfu/ml. Dipstrips provide a cheap, convenient method for the routine quantification of the bacterial load in endotracheal aspirates. PMID- 8683555 TI - Therapeutic vaccines. PMID- 8683557 TI - A low molecular weight outer-membrane protein of Escherichia coli O157:H7 associated with adherence to INT407 cells and chicken caeca. AB - Enterohaemorrhagic Escherichia coli (EHEC) O157:H7 and O26:H11 have been shown to produce a low mol.wt outer-membrane protein (OMP) that is unique to a few serotypes of E. coli. A mutant (A10) of E. coli O157:H7 strain HA1 deficient in the OMP was constructed by TnphoA mutagenesis and assayed for its adherent ability. Adherence of A10 to intestinal epithelial cells (INT407) was significantly less than that of its parent strain (HA1). Adherence of HA1 to INT407 cells was significantly decreased by treatment with a monoclonal antibody (4E8C12) that specifically binds to the OMP. When chickens were infected experimentally with E. coli O157:H7 strains, the average number of cfu of strain A10 recovered from chicken caeca was significantly less than those of strain HA1 and wild-type strain 932 at 14 and 21 days after peroral inoculation. These data suggest that the OMP of EHEC is associated with adherence of E. coli O157:H7 to epithelial cells in vitro and chicken caeca in vivo. PMID- 8683556 TI - The vacuolar ATPase proton pump is present on intracellular vacuoles induced by Helicobacter pylori. AB - Cytotoxic strains of Helicobacter pylori cause an intense vacuolar degeneration of cells, due to the enlargement of late endosomes in the presence of membrane permeant weak bases. Bafilomycins, specific inhibitors of the vacuolar-type (V-) ATPase proton pump, prevent vacuole formation. The presence of the V-ATPase on vacuolar membranes was demonstrated by immunofluorescence with a monoclonal antibody (MAb) specific for the human 116-kDa regulatory subunit. The V-ATPase co localised with the late endosomal marker rab7 on vacuolar membranes. In contrast, the early recycling endosomal compartment was not altered by the VacA cytotoxin, although it was endowed with the V-ATPase. Endocytosis of a MAb against the 116 kDa regulatory subunit of V-ATPase blocked endosomal acidification in HeLa cells and prevented VacA action. These results indicate that selective swelling of late endosomes, due to accumulation of osmotically active weak bases driven by the V ATPase, is essential for vacuole formation. PMID- 8683558 TI - Induction of nitric oxide production in mouse macrophages by Shiga toxin. AB - Host mediators play an important role in the pathogenesis of shigellosis and Shiga toxin toxicity. Nitric oxide (NO) production in mouse peritoneal macrophages and in the macrophage J744 cell line in response to purified Shiga toxin and lipopolysaccharide (LPS) from Shigella flexneri were studied. Shiga toxin induced NO production in a dose-dependent manner up to 800 ng/ml. Detectable levels of NO were present as early as 4 h after induction and continued to increase during 72 h; Shiga toxin induced greater NO production with time than did LPS. Pre-treatment of Shiga toxin (400 ng/ml) or LPS (10 ng/ml) with polymyxin B, which inactivates LPS, reduced their ability to induce NO by 28% and 96%, respectively. Induction in the presence of anti-TNF alpha antibodies did not reduce the amount of NO in the supernate. These studies showed that Shiga toxin induces NO production in murine macrophages. PMID- 8683559 TI - The effect of deformation on the lateral resolution of atomic force microscopy. AB - A computer model based on the elastic properties of rubber is introduced for the evaluation of the lateral resolution in atomic force microscopy of deformable specimens. The computational results show that, if the full width at half-height can be defined as the lateral resolution, it is continuously improved at greater probe forces, at the expense of a reduced molecular height, In fact, even for a probe that is bigger than the molecule, the real size of the molecule can be 'recovered' at about 25% compression. This result demonstrates that for a better lateral resolution, a greater probe force can be beneficial, provided that the molecule is not moved or damaged and the response remains elastic. Measurements on isolated low-density lipoproteins (LDL) show that with 26% vertical compression, the lateral size measured in atomic force microscopy is only 72% of the value predicted by a simple convolution, and is only slightly larger (approximately 13%) than the known size of LDL. Therefore, the results on LDL provide a direct support for the conclusions of the computational model. PMID- 8683560 TI - Membrane deformation of living glial cells using atomic force microscopy. AB - Using atomic force microscopy (AFM) it has been possible to detect actin filaments that are beneath the cell membrane of living cells despite the fact that the AFM tip is applied to the surface of the cell. To determine whether the AFM tip actually penetrates or deforms the cell membrane we determined whether an intracellularly trapped fluorescent indicator was lost from cells during AFM. Using epifluorescence illumination to monitor the presence of fluo-3 in the cell, we found that AFM did not cause dye leakage from the cell. Further, force distance curves indicated that standard tips did not penetrate the membrane while sharper Supertips TM did. In addition, the physiology of cells was found to be unaffected by AFM with standard tips since volume regulatory signal transduction mechanisms were intact in such studies. Thus, traditional AFM tips deform the cell membrane in order to reveal the presence of subcellular structures. PMID- 8683561 TI - Elimination of the effects of stray light in measurements by total internal reflection aqueous fluorescence (TIRAF). AB - Total internal reflection aqueous fluorescence has been shown to be capable of achieving spatial resolution in surface contours of about 1 nm. When used with highly structured objects, errors in measurements can arise from light scattered either by the object or within the body of the microscope. We describe how these errors can be eliminated when studying surface contours of human platelets. PMID- 8683562 TI - Cryofixing single cells and multicellular specimens enhances structure and immunocytochemistry for light microscopy. AB - Cryofixation is widely held to be superior to chemical fixation for preserving cell structure; however, the use of cryofixation has been limited chiefly to electron microscopy. To see if cryofixation would improve sample structure or antigenicity as observed through the light microscope, we cryofixed Nicotiana alata and Lilium longiflorum pollen tubes and Tradescantia virginina stamen hairs by plunge freezing. After freeze-substitution, and embedding in butylmethylmethacrylate, we found using the light microscope that the superiority of cryofixation over chemical fixation was obvious. Cryofixation, unlike chemical fixation, did not distort cell morphology and preserved microtubule and actin arrays in a form closely resembling that of living cells. Additionally, to test further the usefulness of cryofixation for light microscopy, we studied the appearance of cells and the retention of antigenicity in plunge-frozen multicellular organ. Roots of Arabidopsis thaliana were either chemically fixed or plunge frozen, and then embedded in the removable methacrylate resin used above. We found that plunge freezing preserved cell morphology far better than did chemical fixation, and likewise improved the appearance of both actin and microtubule arrays. Plunge-frozen roots also had cells with more life-like cytoplasm than those of chemically fixed roots, as assessed with toluidine-blue staining or high-resolution Nomarski optics. Damage from ice crystal formation could not be resolved through the light microscope, even in the interior of the root, 40-75 microns from the surface. We suggest that plunge freezing would enhance many investigations at the light microscope level, including those of multicellular organs, where damage from ice crystals may be less severe than artefacts from chemical fixation. PMID- 8683563 TI - Soft-X-ray damage to biological samples. AB - X-ray damage to biological samples was investigated in the wavelength region of 2.7-5 nm, which overlaps the so-called 'water-window', the wavelength range of 2.4-4.3 nm usually used in X-ray microscopy. Yeast cells and myofibrils were chosen as representatives of whole cell samples and motile protein systems, respectively. The samples were exposed to X-rays using an apparatus composed mainly of a laser-plasma X-ray source, a Wolter mirror condenser, and a sample cell. The yeast cells lost their dye exclusion ability when the X-ray flux was higher than 1 x 10(6) photons micron-2, while the myofibrils lost contractility when the X-ray flux was higher than 4 x 10(5) photons micron-2. These X-ray fluxes are lower than the flux required for the X-ray microscope observation of biological samples at a resolution higher than that of light microscopes. PMID- 8683564 TI - Visualization of proteoglycans and link protein in embryonic chick limb cartilage via cryofixation, freeze-substitution and immunochemical techniques. AB - Chick embryo limb bud cartilage contains a family of proteoglycans, a few of which have been identified ultrastructurally by antibody labelling. Limb bud cartilage from stage 30-34 chick embryos was high-pressure frozen, freeze substituted and embedded in Lowicryl resin. Sections were treated with polyclonal antibodies for core protein and monoclonal antibodies for chondroitin-6-sulphate and link protein. Label for core protein was demonstrated on both structural matrix and free within the compartmental space. Quantitative analysis indicates that core protein is preferentially localized on electron-dense structural matrix, and that this distribution is uniform between stages 30 and 34. The association of protein epitopes on electron-dense lattice is strongly influenced, rather than a chance observation. Significant quantities of core protein are also located in the free compartments of the cartilaginous lattice. Chondroitin-6 sulphate and link protein were localized predominantly within the compartments of the embryonic lattice. Our data provide convincing evidence that the proteoglycans were immobilized within a microcrystalline matrix of the embryonic compartments. A role for core protein as a stabilizer within the lattice and in the free space where it serves to aggregate polymeric proteoglycans is suggested from our results. PMID- 8683565 TI - Interaction between cAMP-dependent protein kinase catalytic subunit and peptide inhibitors analyzed with lambda repressor fusions. AB - The lambda phage repressor is currently used as a genetic tool to analyze homodimeric interactions in Escherichia coli. We have applied this system to detect the interaction that takes place within an enzyme-protein inhibitor complex. The sequences encoding the catalytic subunit of the cAMP-dependent protein kinase and the active portion of the natural thermostable protein kinase inhibitor have been fused to the carboxy terminus of the repressor DNA binding domain and introduced into compatible plasmids. Co-expression of the two gene fusions in E. coli lead to the formation of heterodimers that confer a high level of protection from lambda phage infection. The level of lambda immunity depends specifically upon the amino acid sequence of the interacting proteins, as a single amino acid substitution in the inhibitor peptide (Phe10-Ala) restores the sensitivity phenotype. PMID- 8683566 TI - Short-range order in two eukaryotic genomes: relation to chromosome structure. AB - Fourier transform techniques have been used to analyze the distributions of all ten independent DNA dinucleotide steps in two eukaryotic genomes and one prokaryotic genome, for periodicities of approximately 2 to 500 bp. The results reveal systematic deviations from random expectation for certain dinucleotide steps over this entire range of periodicities, together with striking peaks at certain spatial periodicities for particular dinucleotide steps. Several dinucleotides yield peaks at a periodicity of approximately 10.2 bp that are unique to the eukaryotic genomes. Certain members of this set of dinucleotide signals were previously identified as involved in nucleosome positioning, while others were previously unrecognized. In real-space, these dinucleotides are uncorrelated or even anticorrelated (relative to random expectation) at distances of 10 and 11 bp, despite having greater than random spectral power at the corresponding periodicity. Real-space correlations of these dinucleotides at distances of 10 and 11 bp are suppressed by another spectral component, a 3 bp periodicity attributed to codons, which has a local minimum probability at approximately 10.5 bp. When the two eukaryotic genomes are encoded for the signal "AA or TT", the peak at approximately 10.2 bp periodicity is strengthened, whereas for the prokaryotic genome such a peak remains absent. For the Caenorhabditis elegans genome, this peak becomes the dominant feature in the transform, surpassing a peak owing to the existence of codons in both height and integrated intensity. These results suggest that the requirements of chromosome structure place significant constraints on eukaryotic genome organization; they reveal additional signals that may be related to nucleosome positioning; and they reveal a wealth of additional new non-random aspects of genome sequence organization. PMID- 8683567 TI - Salmonella typhimurium apparently perceives external nitrogen limitation as internal glutamine limitation. AB - Assimilation of nitrogen requires the synthesis of only two central intermediates, glutamate and glutamine, from which other compounds derive nitrogen by secondary transfers. We measured the internal pool sizes of glutamate and glutamine in Salmonella typhimurium under conditions of external nitrogen limitation or sufficiency. When growth was slowed by nitrogen limitation, the glutamine pool was lower by a factor of up to 10, whereas the glutamate pool remained high. The decrease in the glutamine pool was general in nature, being seen with various limiting nitrogen sources in batch culture and with ammonia, the optimal nitrogen source, as the limiting nutrient in continuous culture. The only nitrogen source that gave discordant results was alanine, and we present evidence that alanine has inhibitory effects which extend beyond simple nitrogen limitation. Studies with mutant strains having altered nitrogen assimilation indicated that the decreases in the glutamine pool observed in the wild-type strain under nitrogen-limiting conditions were probably sufficient to account for slow growth and were likely to be responsible for slow growth. Hence we postulate that external nitrogen limitation is first perceived by Salmonella as a drop in its internal glutamine pool. PMID- 8683568 TI - Separation of scrapie prion infectivity from PrP amyloid polymers. AB - The prion protein (PrP) undergoes a profound conformational change when the cellular isoform (PrPC) is converted into the scrapie form (PrPSc). Limited proteolysis of PrPsc produces PrP 27-30 which readily polymerizes into amyloid. To study the structure of PrP amyloid, we employed organic solvents that perturb protein conformation. Hexafluoro-2-propanol (HFIP), which promotes alpha-helix formation, modified the ultrastructure of rod-shaped PrP amyloids; flattened ribbons with a more regular substructure were found. As the concentration of HFIP was increased, the beta-sheet content and proteinase K resistance of PrP 27-30 as well as prion infectivity diminished. HFIP reversibly decreased the binding of Congo red dye to the rods while inactivation of prion infectivity was irreversible. In contrast to 10% HFIP, 1,1,1-trifluoro-2-propanol (TFIP) did not inactivate prion infectivity but like HFIP, TFIP did alter the morphology of the rods and abolish Congo red binding. This study separates prion infectivity from the amyloid properties of PrP 27-30 and underscores the dependence of prion infectivity on PrPSc conformation. The results also demonstrate that the specific beta-sheet-rich structures required for prion infectivity can be differentiated from those needed for amyloid formation as determined by Congo red binding. PMID- 8683569 TI - Bacteriophage T4 strand transfer protein UvsX tolerates symmetric and asymmetric heterologies in short double-stranded oligonucleotides. AB - The UvsX protein of bacteriophage T4 catalyzes strand transfer from double stranded DNA to homologous single-stranded DNA to generate both paranemic and plectonemic joints. We demonstrate here that UvsX mediates strand transfer efficiently from synthetic double-stranded donor oligonucleotides of 30 to 117 bp in length to circular single-stranded recipient M13mp19 DNA. Recovery of a diagnostic BamHI-restriction site, activated in the recipient after strand transfer, demonstrates that recipient and donated strands are perfectly base paired after the exchange reaction has taken place. The transfer reaction progresses with greatest efficiency using donor DNA with a 3' overhang. Use of donor DNA having recessed 3' ends or blunt ends reduces the transfer efficiency by half. Single-stranded heterologies, centrally located in either strand of the donor DNA and forming either heteroduplex loops or a bulge in the donor are transferred with 80 to 100% efficiency. Also, a centrally located C/C-mismatch in the donor does not affect the transfer efficiency. Double-stranded heterologies are tolerated by the UvsX-catalyzed reaction but have different effects on the transfer efficiencies, depending on length and location in the molecule. A heterology of 24 bp located at the proximal end (start of transfer), the distal end (termination of transfer) and at each end of the donor molecule results in transfer efficiencies of 100%, 50% and 50 to 60%, respectively. Strand transfer efficiency is markedly reduced to about 15% if the 24 bp heterology is at a central location. However, insertion of a 4 bp heterology at this position yields a transfer efficiency of about 30%. Also, large double-stranded heterologies of 187 bp at the proximal end or 590 bp at the distal end of control-donor DNAs derived from plasmid digests did not impair the transfer activity of UvsX. This result differs from published results obtained with strand transfer reactions with large distally located heterologies catalyzed by RecA of Escherichia coli in vitro. PMID- 8683570 TI - Kinetic selectivity of complementary nucleic acids: bcr-abl-directed antisense RNA and ribozymes. AB - Efficacy and sequence specificity are two major requirements in the use of antisense nucleic acids and ribozymes. For long-chain complementary RNA sequences (>30 nt), effects in living cells are correlated with the association rate of the complementary RNA in vitro, but not with the stability of the formed double strand. Thus, sequence selectivity of complementary RNA has to be defined as fast versus slow annealing with the appropriate target or non-target sequences, respectively. In this work, we performed a systematic kinetic analysis to evaluate the selectivity of bcr-abl-directed antisense RNA and hammerhead ribozymes with a length of the complementary sequences of between 20 and 80 bases. By kinetic in vitro selection, we identified oligomeric as well as long chain complementary RNA that annealed at least tenfold faster with the bcr-abl sequence in comparison with either of the wild-type sequences bcr or abl, respectively. In the presence of selected oligodeoxynucleotide sequences and RNase H, the bcr-abl transcript was specifically hydrolysed out of a mixture containing abl and bcr sequences as well. Hammerhead ribozymes were designed such that binding with their target was facilitated either via helix I or helix III forming antisense arms but not both. Further, cleavage and binding occurred on opposite sides of the bcr-abl fusion point. Target selectivity was found for a ribozyme that annealed fast via abl sequences and cleaved within the bcr portion of bcr-abl RNA. Kinetic probing and calculations of the local folding potential indicate that the bcr-abl fusion point sequences are not easily accessible for complementary nucleic acids. This study supports the need for more detailed structural investigations of the bcr-abl fusion sequence and forms a more rational basis for the therapeutic use of nucleic acid inhibitors of the aberrant bcr-abl gene expression in Philadelphia chromosome-positive cells. PMID- 8683571 TI - Functional base-pairing interaction between highly conserved elements of U3 small nucleolar RNA and the small ribosomal subunit RNA. AB - The U3 nucleolar RNA has a remarkably wide phyletic distribution extending from the Eukarya to the Archaea. It functions in maturation of the small subunit (SSU) rRNA through a mechanism which is as yet unknown but which involves base-pairing with pre-rRNA. The most conserved part of U3 is within 30 nucleotides of the 5' end, but as yet no function for this domain has been proposed. Elements within this domain are complementary to highly conserved sequences in the SSU rRNA which, in the mature form, fold into a universally conserved pseudoknot. The nature of the complementarity suggests a novel mechanism for U3 function whereby U3 facilitates correct folding of the pseudoknot. Wide phylogenetic comparison provides compelling evidence in support of the interaction in that significant complementary changes have taken place, particularly in the archaeon Sulfolobus, which maintain the base-pairing. Base-substitution mutations in yeast U3 designed to disrupt the base-pairing indicate that the interaction is probably essential. These include cold-sensitivity mutations which exhibit phenotypes similar to U3 depletion, but without impairment of the AO processing step, which occurs within the 5' ETS. These phenotypes are consistent with the destabilization of SSU precursors and partial impairment of the processing steps A1, at the 5' ETS/18 S boundary, and A2, within the ITS1. PMID- 8683572 TI - Isolation, characterization and evolution of nine pufferfish (Fugu rubripes) actin genes. AB - The Japanese pufferfish Fugu rubripes (Fugu) has a small genome of about 400 Mb. Nine different actin genes have been isolated and sequenced from a genomic library constructed from this teleost. The six muscle-type actin genes include two alpha-skeletal actins, three alpha-cardiac actins and an alpha-anomalous (testis type) actin, and the three cytoplasmic actins include two beta cytoplasmic actins and a beta-cytoplasmic (vascular type) actin. The two skeletal muscle actin genes have identical genomic organization, but differ by five amino acid residues. The three cardiac actin genes code for the same protein but differ in their nucleotide sequences and genomic organization. beta-Cytoplasmic actin1 differs by three amino acids from beta-cytoplasmic actin2. The alpha-anomalous (testis type) and beta-cytoplasmic (vascular type) actins are novel vertebrate actins. The amino acid sequence of alpha-anomalous (testis type) actin is the most divergent of all the known vertebrate actins and transcripts of this gene are abundant in the testis. The beta-cytoplasmic (vascular type) actin gene has eight introns, similar to mammalian smooth muscle actins, and is expressed in vascular tissues such as the gills, kidney and skin. Several known regulatory elements are found in the 5' flanking sequences and the first intron of various Fugu actin genes. The intron patterns of the various Fugu actins seem to be the result of loss of certain introns from a common ancestral gene. PMID- 8683574 TI - Self-assembly of the filament capping protein, FliD, of bacterial flagella into an annular structure. AB - A bacterial flagellum has a cap structure at the tip of the external filament. The cap is composed of the FliD protein (Mr, 49 x 10(3)), and plays an essential role in the polymerization of the filament protein, flagellin, which is believed to be transported through a central channel in the flagellum. A fliD-deficient mutant becomes non-motile because it lacks flagellar filaments and leaks flagellin monomer out into the medium. We have constructed a FliD-overproducing plasmid and purified the protein. The purified FliD at high concentration formed a large complex (Mr, ca. 600 x 10(3)) under physiological conditions. The complex was found by electron microscopy to be ring shaped. Image analysis revealed that the complex consisted of five substructures arranged in a pentagonal shape. Its outer diameter, approximately 10 nm, was about the same as that of the cap at the tip of the wild-type flagella. When the annular structure was added to the culture medium of a Salmonella fliD mutant, almost all of the cells became able to swim. Overall, about ten molecules of FliD self-assemble into an annular structure in vitro, forming the functional capping structure by incorporating flagellin at the tip of the flagellar filament in vivo. PMID- 8683573 TI - Rate constants of sugar transport through two LamB mutants of Escherichia coli: comparison with wild-type maltoporin and LamB of Salmonella typhimurium. AB - Two LamB (maltoporin) point mutants of Escherichia coli (R8H and Y118F) and wild type LamB of Salmonella typhimurium were reconstituted into artificial lipid bilayer membranes. Ion transport through wild-type LamB of S. typhimurium and the LamB mutants was inhibited by the addition of carbohydrates of maltose and maltooligosaccharide type in a dose-dependent fashion. The sugar-induced block of the channel function could be used for the study of current noise through the different wild-type and mutant LamB-channels. The analysis of the power density spectra allowed the evaluation of the on and off-reactions (k1 and k-1) of sugar binding to the binding site inside the channels. Wild-type LamB of S. typhimurium had approximately the same sugar-binding kinetics as has been observed for LamB of E. coli. The results suggest that the binding site inside the channel interacts with a maximum of three glucose residues within the maltooligosaccharides. The LamB mutants R8H and Y118F showed kinetics for sugar binding substantially different from that of wild-type LamB. In particular, the on-rate, k1, for the binding of different sugars of the maltooligosaccharide series to the mutant R8H was approximately 500-times smaller than for wild-type LamB, which resulted in substantially smaller stability constant of sugar binding to the channel. Similarly, the off-rate constant, k-1, for sugar binding to the mutant Y118F decreased about 20-fold, which led to a strong increase of the affinity of carbohydrates to the site. The role of the amino residues acid R8 and Y118 in the transport of maltose and maltooligosaccharides through LamB-channels is discussed on the basis of the net flux of sugars through the channels. PMID- 8683575 TI - Rotational fluctuation of the sodium-driven flagellar motor of Vibrio alginolyticus induced by binding of inhibitors. AB - Rotation of the Na(+)-driven flagellar motor of Vibrio alginolyticus was investigated under the influence of inhibitors specific to the motor, amiloride and phenamil. The rotation rate of a single flagellum on a cell stuck to a glass slide was examined using laser dark-field microscopy. In the presence of 50 mM NaCl, the average rotation rate (omega) was about 600 r.p.s. with a standard deviation (sigma omega) of 9% of omega. When omega was decreased to about 200 r.p.s. by the presence of 1.5 mM amiloride, sigma omega increased to 15% of omega. On the other hand, when omega was decreased to about 200 r.p.s. by the addition of 0.6 microM phenamil, a large increase in sigma omega up to 50% of omega, was observed. Similarly large fluctuations were observed at other concentrations of phenamil. These observations suggest that dissociation of phenamil from the motor was much slower than that of amiloride. A very low concentration of phenamil caused a transient but substantial reduction in rotation rate. This might suggest that binding of only a single molecule of phenamil strongly inhibits the torque generation in the flagellar motor. PMID- 8683576 TI - Sequence variation as a strategy for crystallizing RNA motifs. AB - The determination of RNA structures by X-ray crystallography is an exciting and developing field. At present, the crystallographic characterization of RNA is limited by the difficulty in obtaining large, high quality crystals. This paper outlines several techniques for improving the likelihood of obtaining RNA crystals, for improving the size of those crystals, and for extending the limit of the diffraction maxima. Sequence variations have proven to be more effective in changing the quality of the crystals than variations in crystallization conditions, often making the difference between obtaining true single crystals and multiply twinned crystalline material. PMID- 8683577 TI - Crystal structure of a bacterial lipase from Chromobacterium viscosum ATCC 6918 refined at 1.6 angstroms resolution. AB - The crystal structure of a lipase from the bacterium Chromobacterium viscosum ATCC 6918 (CVL) has been determined by isomorphous replacement and refined at 1.6 angstroms resolution to an R-factor of 17.8%. The lipase has the overall topology of an alpha/beta type protein, which was also found for previously determined lipase structures. The catalytic triad of the active center consists of the residues Ser87, Asp263 and His285. These residues are not exposed to the solvent, but a narrow channel connects them with the molecular surface. This conformation is very similar to the previously reported closed conformation of Pseudomonas glumae lipase (PGL), but superposition of the two lipase structures reveals several conformational differences. r.m.s. deviations greater than 2 angstroms are found for the C alpha-atoms of the polypeptide chains from His15 to Asp28, from Leu49 to Ser54 and from Lys128 to Gln158. Compared to the PGL structure in the CVL structure, three alpha-helical fragments are shorter, one beta-strand is longer and an additional antiparallel beta-sheet is found. In contrast to PGL, CVL displays an oxyanion hole, which is stabilized by the amide nitrogen atoms of Leu17 and Gln88, and a cis-peptide bond between Gln291 and Leu292. CVL contains a Ca2+, like the PGL, which is coordinated by four oxygen atoms from the protein and two water molecules. PMID- 8683578 TI - Extended glycoprotein structure of the seven domains in human carcinoembryonic antigen by X-ray and neutron solution scattering and an automated curve fitting procedure: implications for cellular adhesion. AB - Carcinoembryonic antigen (CEA) is one of the most widely used cell-surface tumour markers for tumour monitoring and for targeting by antibodies. It is heavily glycosylated (50% carbohydrate) and a monomer is constructed from one V-type and six C2-type fold domains of the immunoglobulin superfamily. The solution arrangement at low resolution of the seven domains in CEA cleaved from its membrane anchor was determined by X-ray and neutron scattering. Guinier analyses showed that the X-ray radius of gyration RG of CEA was 8.0 nm. The length of CEA was 27 to 33 nm, and is consistent with an extended arrangement of seven domains. The X-ray cross-sectional radius of gyration RXS was 2.1 nm, and is consistent with extended carbohydrate structures in CEA. The neutron data gave CEA a relative molecular mass of 150,000, in agreement with a value of 152,500 from composition data, and validated the X-ray analyses. The CEA scattering curves were analysed using an automated computer modelling procedure based on the crystal structure of CD2. The V-type and C2-type domains in CD2 were separated, and the C2-type domain was duplicated five times to create a linear seven-domain starting model for CEA. A total of 28 complex-type oligosaccharide chains in extended conformations were added to this model. By fixing the six interdomain orientations to be the same, three-parameter searches of the rotational orientations between the seven domains gave 4056 possible CEA models. The best curve fits from these corresponded to a family of zig-zag models. The long axis of each domain was set at 160(+/-25) degrees relative to its neighbour, and the two perpendicular axes were orientated at 10(+/-30) degrees and -5(+/-35) degrees. Interestingly, the curve fit from this model is within error of that calculated from a CEA model generated directly from the CD2 crystal structure by the superposition of adjacent domains. Zig-zag models of this type imply that the protein face of the GFCC' beta-sheet in neighbouring CEA domains lie on alternate sides of the CEA structure. Such a model has implications for the adhesion interactions between CEA molecules on adjacent cells or for the antibody targeting of CEA. PMID- 8683580 TI - The crystal structures of trout Hb I in the deoxy and carbonmonoxy forms. AB - We have determined the X-ray crystallographic structure of trout Hb I in both the deoxy and carbonmonoxy forms to resolution limits of 2.3 angstroms and 2.5 angstroms, respectively. The overall fold of the molecule is highly similar to that of human HbA despite the low level of sequence identity between these proteins. Trout Hb I is unusual in displaying almost no pH dependence of oxygen binding affinity, and (at most) very weak interactions with heterotropic effector ligands such as organic phosphates. Comparison of the two quaternary states of the protein indicates how such effects are minimised and how the low-affinity T state of the protein is stabilised in the absence of heterotropic interactions. PMID- 8683579 TI - Mechanism of Fe(III)-Zn(II) purple acid phosphatase based on crystal structures. AB - Purple acid phosphatase is a widely distributed non-specific phosphomonoesterase. X-ray structures of the dimeric 111-kDa Fe(III)-Zn(II) kidney bean purple acid phosphatase (kbPAP) complexed with phosphate, the product of the reaction, and with tungstate, a strong inhibitor of the phosphatase activity, were determined at 2.7 and 3.0 angstroms resolution, respectively. Furthermore the resolution of the unligated enzyme, recently solved at 2.9 angstroms could be extended to 2.65 angstroms with completely new data. The binding of both oxoanions is not accompanied by larger conformational changes in the enzyme structure. Small movements with a maximal coordinate shift of 1 angstroms are only observed for the active site residues His295 and His296. In the inhibitor complex as well as in the product complex, the oxoanion binds in a bidentate bridging mode to the two metal ions, replacing two of the presumed solvent ligands present in the unligated enzyme form. As also proposed for the unligated structure a bridging hydroxide ion completes the coordination spheres of both metal ions to octahedral arrangements. All three structures reported herein support a mechanism of phosphate ester hydrolysis involving interaction of the substrate with Zn(II) followed by a nucleophilic attack on the phosphorus by an Fe(III)-coordinated hydroxide ion. The negative charge evolving at the pentacoordinated transition state is probably stabilized by interactions with the divalent zinc and the imidazole groups of His202, His295, and His296, the latter protonating the leaving alcohol group. PMID- 8683581 TI - Refined structure of lac repressor headpiece (1-56) determined by relaxation matrix calculations from 2D and 3D NOE data: change of tertiary structure upon binding to the lac operator. AB - The solution structure of the DNA binding domain of lac repressor (headpiece 1 56; HP56) has been refined using data from 2D and 3D NMR spectroscopy. The structure was derived from 1546 restraints (giving an average of 27.6 per residue), comprising 389 intraresidual, 402 sequential, 385 medium range and 325 long range distance restraints and also 30 phi and 15 chi 1 dihedral angle restraints. The structures were determined by the method of direct refinement against nuclear Overhauser enhancement peak volumes with the program DINOSAUR. The final set of 32 selected structures displayed an r.m.s. deviation from the average of 0.43(+/-0.08) A angstroms (backbone) and 0.95(+/-0.08) angstroms (all heavy atoms) for the best defined region of the protein (residues 3 to 49). The ensemble R-factor was 0.35, which indicates close correspondence with the experimental data. The structures revealed good stereochemical qualities. The conformations of the NMR structures of free and DNA complexed lac repressor headpiece were compared. The regions comprising the secondary structure elements show close correspondence for both conformations. However, the conformation of the loop between helix II and III changes considerably upon complexation of the headpiece. This change in the conformation of the loop in lac HP56 is essential for binding of the side-chains of residues Asn25 and His29 to the lac operator DNA. Finally, the lac headpiece residues that are intolerant to mutations were analysed. Most of these mutation-sensitive residues are important for a correct folding of the headpiece region, and a number of these residues are also involved in contacting the operator DNA. PMID- 8683582 TI - Predictions of secondary structure using statistical analyses of electronic and vibrational circular dichroism and Fourier transform infrared spectra of proteins in H2O. AB - Vibrational circular dichroism (VCD) and Fourier transform IR (FTIR) methods for prediction of protein secondary structure are systematically compared using selective regression analysis. VCD and FTIR spectra over the amide I and II bands of 23 proteins dissolved in H2O were analyzed using the principal component method of factor analysis (PC/FA) and regression fits to fractional components (FC) of secondary structure. Predictive capability was determined by computing structures for proteins sequentially left out of the regression. All possible combinations of PC/FA spectral parameters (coefficients) were used to form a full set of restricted multiple regressions (RMR) of PC/FA coefficients with FC values, both independently for each spectral data set as well as for the VCD and FTIR sets grouped together and with similarly obtained electronic CD (ECD) data. The distribution of predictive error for a set of the best RMR relationships that use a given number of spectral coefficients was used to select the optimal prediction algorithm. Minimum predictive error resulted for a small subset (three to six) of spectral coefficients, which is consistent with our earlier findings using VCD measured for proteins in 2H2O and ECD data. Subtracting the average absorption spectrum from all the training set FTIR spectra before analysis yields more variance in the FTIR band shape and improves the predictive ability of the best PC/FA RMR to near that for the VCD. Both methods (FTIR and VCD) using data for proteins in H2O are somewhat better predictors than amide I' (in 2H2O) VCD alone and, for helix, worse than ECD alone. Combining FTIR and VCD data did not dramatically change the prediction results. Predictions are improved by combining both with ECD data, indicating that the improvement is due to using their very different structural sensitivities. The coupled H2O-based spectral analyses and the mixed amide I' + II VCD plus ECD analysis are comparable for the helix and sheet components, indicating that partial deuteration is not a major source of prediction error. PMID- 8683583 TI - 1H, 15N resonance assignment and three-dimensional structure of CYP1 (HAP1) DNA binding domain. AB - CYP1(HAP1) is a transcriptional activator involved in the aerobic metabolism of the yeast Saccharomyces cerevisiae. The amino acid sequence of its DNA-binding domain suggests that it belongs to the "zinc cluster" class. This region is indeed characterized by a pattern known to form a bimetal thiolate cluster where two zinc ions are coordinated by six cysteine residues. Structures of two such domains, those from GAL4 and PPR1, have been solved as complexes with DNA. These domains consist of the zinc cluster connected to a dimerization helix by a linker peptide. They recognize, as a dimer, an inverted repeat of a CGG motif that is separated by a specific number of bases. Interestingly, the specificity of that interaction seems not to be due to the interaction between the cluster region and the DNA but rather to a fine tune between the structure of the linker peptide and the number of base-pairs separating the two CGGs. However, the CYP1 target sites fail to display such a consensus sequence. One of the two CGG sites is poorly conserved and some experiments suggest a direct rather than an inverted repeat. Using 1H, 15N and 113Cd NMR spectroscopy, we have undertaken the analysis of the structural properties of the CYP1(56-126) fragment that consists of the zinc cluster region, the linker peptide and a part of the dimerization helix. We have demonstrated that the six cysteine residues of the peptide chelate two cadmium ions as in GAL4 and PPR1. Fifteen structures of the zinc-cluster region (residues 60 to 100) were calculated, the linker peptide and the dimerization helix being unstructured under the conditions of our study. This region possesses the same overall fold as in GAL4 and PPR1, and most of the side-chains involved in the interaction with DNA are structurally conserved. This suggests that the CYP1 zinc cluster region recognizes a CGG triplet in the same way as GAL4 and PPR1. In this case, the particular properties of CYP1 seem to be due to the structure of the linker peptide and/or of the dimerization helix. PMID- 8683585 TI - Selection of chymotrypsin inhibitors from a conformationally-constrained combinatorial peptide library. AB - A synthetic library of cyclic peptides was constructed utilizing the anti-tryptic loop region of the Bowman-Birk inhibitor, D4 from Macrotyloma axillare, as a template. The loop region of this proteinase inhibitor was reproduced by an 11 residue sequence, conformationally constrained by the presence of a disulfide bridge, to act as a mimetic of the functional reactive site region of this protein. This sequence, plus a pentaglycine spacer arm, was used to create a "one bead, one peptide" combinatorial library after on-resin deprotection and cyclization. Randomization at three positions considered to be important for proteinase specificity (P2, P1 and P'2) with the genetically coded amino acids (minus cysteine) plus norleucine generated 8000 permutations. Screening this library with biotinylated alpha-chymotrypsin under appropriate conditions revealed a small number (<0.05%) of beads that selectively bound the labeled proteinase. The sequences present on these active beads were determined, and found to have a well-defined consensus. Analysis of chymotrypsin inhibition in solution using re-synthesized peptides reveals that the sequences identified are potent inhibitors with Ki values in the nanomolar range. These results show that directed randomization of the canonical loop is a powerful way of generating proteinase inhibitors with targeted specificities. Incorporation of selective random changes within a defined structural framework is found to be an effective means of generating variation in large synthetic systems. The functional basis for inhibition by the identified sequences is discussed. PMID- 8683584 TI - Cold denaturation of barstar: 1H, 15N and 13C NMR assignment and characterisation of residual structure. AB - Detection of residual structure in denatured proteins is of interest because fleetingly structured regions may be initiation points of the folding pathway. Residual structure in this context is not the definition of one stable conformation but a population phenomenon. Acid, thermal and solvent-denatured states have recently been examined by NMR spectroscopy, but cold-denatured states have not been characterised to date. Cold denaturation is a general phenomenon of globular proteins, which provides a convenient route for studying early events in protein folding: such states can be induced to fold and be monitored on a submillisecond time scale by temperature-jump methods. Here, we use NMR spectroscopy to define residual structure in cold-denatured barstar. The cold denatured state becomes significantly populated in the presence of increasing concentrations of urea and lower temperature. In the presence of 3 M urea, the double mutant of barstar in which Cys40 and Cys82 are both mutated to Ala (C40/82A) is completely and reversibly denatured at 278 K, a temperature that is accessible to NMR experiments. This cold-denatured state of barstar was assigned by heteronuclear NMR experiments and structural parameters such as NOE, coupling constants and chemical shifts were derived. Based on the excellent dispersion in a HSQC-NOESY-HSQC experiment, dNN(i,i+1) NOEs were observed for almost all residues. This allowed us to normalise NOE intensities as the NOE: diagonal ratio dNN(i,i+1) NOE (sigma NN) and the NOE ratio of d(alpha N(i+1,i+1)):d(alpha N(i,i+1)) (sigma N alpha/sigma alpha N). This approach reveals residual structure populating the alpha-region of the (phi, psi) conformational space in the regions corresponding to the first and the second helices and near the end of the second beta-strand of native barstar, whereas the C-terminal region that corresponds to the fourth helix and the third beta-strand is in a random coil conformation. The results suggest that the first and the second helices are potential initiation sites for the folding of barstar. The details presented here provide the starting point for the study of rapid folding of cold-denatured barstar. PMID- 8683586 TI - Measurement and modelling of sequence-specific pKa values of lysine residues in calbindin D9k. AB - A pH titration study of calbindin D9k was performed using heteronuclear 1H-13C two-dimensional NMR spectroscopy. The protein was produced with carbon-13 label in the side-chain of lysine residues, next to the titrating group. The site specific pKa values of these lysine residues, ranging from 10.1 to 12.1, were obtained from the analysis of pH-dependent chemical shifts of 13C and 1H resonances. Ionization constants for both the Ca(2+)-free (apo) and Ca(2+)-loaded forms of the protein were determined. The proton uptake by lysine residues in the apo form was shifted up to 1.7 units towards high pH as compared to that for the model compound. The binding of calcium affected the pKa values of all lysine residues. The largest reduction of one pK unit was observed for Lys55, which is also the closest to the calcium binding sites. A threefold increase in protein concentration, from 0.5 to 1.5 mM, reduced the pKa values by 0.1 to 0.4 pK unit in agreement with the screening concept of ionic interactions. All the observed pKa shifts were site-specific, depending on the local electrostatic environment and were reproduced in Monte Carlo simulations based on the three-dimensional structure of calbindin D9k and a dielectric continuum model for the electrostatic interactions. PMID- 8683587 TI - FASTA-SWAP and FASTA-PAT: pattern database searches using combinations of aligned amino acids, and a novel scoring theory. AB - We introduce two new pattern database search tools that utilize statistical significance and information theory to improve protein function identification. Both the general pattern scoring theory with the specific matrices introduced here and the low redundancy of pattern databases increase search sensitivity and selectivity. Pattern scoring preferentially rewards matches at conserved positions in a pattern with higher scores than matches at variable positions, and assigns more negative scores to mismatches at conserved positions than to mismatches at variable positions. The theory of pattern scoring can be used to create log-odds pattern scores for patterns derived from any set of multiple alignments. This theoretical framework can be used to adapt existing sequence database search tools to pattern analysis. Our FASTA-SWAP and FASTA-PAT tools are extensions of the FASTA program that search a sequence query against a pattern database. In the first step, FASTA-SWAP searches the diagonals of the query sequence and the library pattern for high-scoring segments, while FASTA-PAT performs an extended version of hashing. In the second step, both methods refine the alignments and the scores using dynamic programming. The tools utilize an extremely compact binary representation of all possible combinations of amino acid residues in aligned positions. Our FASTA-SWAP and FASTA-PAT tools are well suited for functional identification of distant relatives that may be missed by sequence database search methods. FASTA-SWAP and FASTA-PAT searches can be performed using our World-Wide Web Server (http://dot.imgen.bcm.tmc.edu:9331/seq search/Op tions/fastapat.html). PMID- 8683588 TI - A global taxonomy of loops in globular proteins. AB - A bank of loops from three to eight amino acid residues long has been constituted. On the basis of statistical analysis of occurrences of conformations and residue, loops could be divided into two parts: the side residues directly bonded to the secondary structure flanking element, and the inner part. The conformations of the side residues are correlated to the nature of their neighboring flanks, while the inner residues adopt conformations uncorrelated from one residue to the next; thus they are unrelated to the flanks. Two zones in the Ramachandran plot are important: alpha L and beta P. In particular, the high occurrence of alpha L, mainly occupied by glycine residues, is necessary to induce flexibility and thus allow loops to comply with the geometrical constraints of the flanks. An algorithm of clustering has been used to aggregate loops of the same length within families of similar 3D structures. At each position in each cluster, sequence and conformational signatures have been deduced if the occurrence of a residue (or a conformation) is higher than an equiprobable distribution over all clusters. The result is that some positions favor particular amino acids and conformations, which are typical of a cluster although not unique. This is an indication of a relation between structure and sequence in loops. A taxonomy is proposed that classifies the various clusters. It relies on two terms: the mean distance between the first and last C alpha in one cluster and, perpendicular to this line, the distance to the center of gravity of the cluster. It is noteworthy that the differently populated clusters represented in such 2D plots can be separated. Thus, although the conformations of loops in globular proteins could cover a continuum, it has been possible to cluster them into a limited number of well populated families and superfamilies. This basic feature of protein architecture could be further exploited to better predict their geometry. PMID- 8683589 TI - Free energy determinants of secondary structure formation: III. beta-turns and their role in protein folding. AB - The stability of beta-turns is calculated as a function of sequence and turn type with a Monte Carlo sampling technique. The conformational energy of four internal hydrogen-bonded turn types, I, I', II and II', is obtained by evaluating their gas phase energy with the CHARMM force field and accounting for solvation effects with the Finite Difference Poisson-Boltzmann (FDPB) method. All four turn types are found to be less stable than the coil state, independent of the sequence in the turn. The free-energy penalties associated with turn formation vary between 1.6 kcal/mol and 7.7 kcal/mol, depending on the sequence and turn type. Differences in turn stability arise mainly from intraresidue interactions within the two central residues of the turn. For each combination of the two central residues, except for -Gly-Gly-, the most stable beta-turn type is always found to occur most commonly in native proteins. The fact that a model based on local interactions accounts for the observed preference of specific sequences suggests that long-range tertiary interactions tend to play a secondary role in determining turn conformation. In contrast, for beta-hairpins, long-range interactions appear to dominate. Specifically, due to the right-handed twist of beta-strands, type I' turns for -Gly-Gly- are found to occur with high frequency, even when local energetics would dictate otherwise. The fact that any combination of two residues is found able to adopt a relatively low-energy turn structure explains why the amino acid sequence in turns is highly variable. The calculated free-energy cost of turn formation, when combined with related numbers obtained for alpha-helices and beta-sheets, suggests a model for the initiation of protein folding based on metastable fragments of secondary structure. PMID- 8683590 TI - RNA editing in Drosophila 4f-rnp gene nuclear transcripts by multiple A-to-G conversions. AB - Pre-mRNA editing results in production of transcripts having nucleotide sequences differing from that of the DNA template. We describe the first example of RNA editing in the fruitfly Drosophila melanogaster. This editing occurs in an alternatively spliced adult head transcript arising from the single-copy nuclear 4f-rnp gene via numerous A to G conversions. Editing sites were identified from comparisons of the genomic DNA sequence with that of corresponding cDNAs prepared from various developmental stages. We show that only the non-edited sequence is present in wild-type fly chromosomes, and have conducted a genetic rescue experiment that suggests that the edited cDNA is expressed in a protein that partially complements a lethal 4f-rnp mutation. The extensive editing observed is predicted to significantly alter the amino acid sequence of the encoded protein, and thus could provide a novel mechanism for the modulation of gene expression in Drosophila. The true significance of our discovery is that it was made in Drosophila, and the advantages of using Drosophila as a genetic model to further study RNA editing in the 4f-rnp gene are discussed. PMID- 8683591 TI - Autophosphorylation of a bacterial protein at tyrosine. AB - Autophosphorylation at tyrosine is a common process in eukaryotic kinases, which is generally modulated by regulatory ligands and affects the properties of these enzymes. We report that this type of modification occurs also in bacteria, namely in an 81 kDa protein from Acinetobacter johnsonii. This protein is phosphorylated at the expense of ATP exclusively at tyrosine residues. It is located in the inner-membrane fraction of cells and can be totally solubilized by detergents. It has been purified to homogeneity by antiphosphotyrosine immunochromatography. Analysis of the peptides released under trypsin proteolysis of the protein has shown that it autophosphorylates at several tyrosine residues. The discovery of protein autophosphorylation in bacteria seems of special interest for studying the regulatory aspects of this modification when considering the relative simplicity of the bacterial systems, as compared with most eukaryotic systems, namely in terms of physiology and genetics. PMID- 8683592 TI - Titin domain patterns correlate with the axial disposition of myosin at the end of the thick filament. AB - Titin has been suggested to act as a molecular ruler for the precise assembly of thick filaments in vertebrate striated muscle. To investigate the correlation of titin domain patterns with the architecture of the thick filament at its end, we have investigated the axial position of titin epitopes at the thick-filament/I band junction. Antibodies against immunoglobin (Ig) domains N and C-terminal to the unique block of six fibronectin-3 (fn3) domains in this region were used. The distance between these epitopes confirms the idea that titin is laid out linearly along the thick filament with each domain measuring about 4 nm in length. Our data demonstrate that the gap of myosin crossbridges near the end of the thick filament closely correlates with the stretch of six fn3 domains, and that the last two crossbridges are at the level of the first two groups of fn3 domains which were previously assigned to the I-band. We conclude that the pattern of groups of fn3 domains reflects the arrangement of the myosin heads, at least at the end of the A-band. It seems likely that an alteration in the interaction between myosin and the titin fn3 domains towards the end of the thick filament is important for the formation of the crossbridge gap and thus the termination of the thick filament. PMID- 8683594 TI - Inhibition of the self-cleavage reaction of the human hepatitis delta virus ribozyme by antibiotics. AB - Human hepatitis delta virus (HDV) poses a health threat in populations where chronic hepatitis B is endemic. It is a single-stranded RNA virus of 1700 nucleotides and both genomic and antigenomic sequences contain ribozymes which are important for viral replication. Using ribozyme constructs we show that several classes of antibiotics inhibit the self-cleavage reaction of the HDV ribozyme. Antibiotics of the aminoglycoside, peptide and tetracycline classes all inhibit HDV cleavage in vitro at micromolar concentrations. Neomycin (an aminoglycoside) inhibits HDV self-cleavage with a Ki value of 28 (+/- 10) microM. Neomycin inhibition can be reversed by increasing magnesium ion concentration in a competitive manner. Lead acetate cleaves positions G76, A42 and G28, which surround the ribozyme cleavage site. Both Mg2+ and neomycin prevent lead cleavage. Footprinting experiments using base-specific chemical probes revealed enhanced modifications of a set of bases by neomycin, overlapping with the above mentioned lead cleavages. These observations may indicate that neomycin directly displaces divalent metal ions essential for catalysis. PMID- 8683593 TI - A Xenopus laevis homologue of the La autoantigen binds the pyrimidine tract of the 5' UTR of ribosomal protein mRNAs in vitro: implication of a protein factor in complex formation. AB - In Xenopus and other vertebrates, ribosomal protein mRNAs share a common sequence in the 5' untranslated region (5' UTR), in particular a pyrimidine tract at the 5' end, which has been demonstrated to be involved in the translational regulation of this class of mRNAs. In previous studies, carried out in the Xenopus system, we demonstrated the specific binding of two proteins (57 kDa and 47 kDa) to the pyrimidine tract of the mRNAs for three different ribosomal proteins. Here, we show that the two binding proteins are in fact one; one being the cleavage product of the other. By immunoprecipitation and protein purification, this binding protein has been identified as the Xenopus homologue of the human La autoantigen, an RNA-binding protein previously reported to be implicated in RNA polymerase III transcription termination and in translation initiation of poliovirus and immunodeficiency virus type 1 RNAs. We show that the specific interaction of La with the 5' pyrimidine tract of ribosomal protein mRNA is mediated by a protease-sensitive factor, which, after assisting La-RNA binding, dissociates from the complex and becomes again available to promote further binding. We show that mutations in the 5' UTR pyrimidine tract, known to disrupt the translational control of ribosomal protein mRNA, severely impair La binding. Although a direct relationship between ribosomal protein mRNA translation and La binding is not yet available, the properties of the interaction suggest that La protein, possibly together with other components, might be involved in translational regulation. PMID- 8683595 TI - Multiple gene copies for bombyxin, an insulin-related peptide of the silkmoth Bombyx mori: structural signs for gene rearrangement and duplication responsible for generation of multiple molecular forms of bombyxin. AB - Thirty-eight genes that encode bombyxin, the insulin-related brain secretory peptide of the silkmoth Bombyx mori, have been cloned and characterized. These genes have been classified into four families, A, B, C and D, according to their sequence similarity. All the bombyxin genes lack introns. Five of them have structural features of pseudogenes. The 38 genes cluster in the three DNA segments of Bombyx in unique distribution patterns. Their arrangement has been classified into three categories: gene pairs, gene triplets and single genes. In the pairs, two bombyxin genes belonging to families B and A (B/A) or to families B and C (B/C) are apposed with opposite transcriptional orientation. All triplets are arranged in the order of the family-B, family-C and family-A genes, and the transcriptional directions of the family-C and family-A genes are opposite to the direction of the family-B gene. The bombyxin gene triplets may have been generated by an unequal crossing-over between two gene pairs, B/A and B/C. Crossing-over may have occurred in the bombyxin family-B genes to increase their structural diversity. Duplications may have served to multiply the bombyxin gene triplets. These genomic rearrangements are thought to have led to the generation of multiple bombyxin gene copies and their diversity in structure and genomic organization. PMID- 8683596 TI - X-ray structure of the uncomplexed anti-tumor antibody BR96 and comparison with its antigen-bound form. AB - The X-ray structure of the uncomplexed human chimeric Fab' of the anti-tumor antibody BR96 has been determined at 2.6 A resolution. The structure has been compared with Lewis Y antigen-complexed structures of BR96 which were determined previously. The comparison reveals segmental motions and/or conformational rearrangements of three CDR loops (L1, L3, and H2), whereas CDR H3 does not undergo changes upon complexation despite its significant main-chain contacts to the carbohydrate antigen. In light of the uncomplexed chimeric Fab' structure reported here, the previously observed high mobility of the CL:CH1 domains of the complexed chimeric BR96 Fab is rationalized as a "swinging" motion approximately about the axis of the elbow bend. PMID- 8683597 TI - A study of the mechanisms of slow religation to sickle cell hemoglobin polymers following laser photolysis. AB - Time-resolved linear dichroism (TRLD) measurements are conducted on gels of sickle cell hemoglobin following laser photolysis of the carbonyl adduct to monitor religation kinetics to hemoglobin S polymers. The return of the polymer phase to its equilibrium ligation state has been found to be about 1000 times slower than that of the solution phase hemoglobin tetramers. Several mechanisms describing this slow religation to the polymer were proposed: (1) religation occurs through a biomolecular process involving all polymer hemes, (2) religation occurs through a bimolecular process in which only hemoglobin molecules at the polymer ends can participate, and (3) religation occurs through the exchange of ligated hemoglobin molecules in the monomer phase with unligated ones in the polymer phase. To test these mechanisms, measurements are performed on gels having different domain sizes. The results show no relation between domain size and religation kinetics. The independence of religation kinetics and domain size is most consistent with the first of the three mechanisms described above (bimolecular recombination involving all polymer hemes). This result is discussed in terms of a model in which diffusion of the ligand is inhibited in the polymer phase. An understanding of the ligand binding kinetics of sickle hemoglobin polymers could have pathophysiological significance in its relevance to polymer formation and melting during red blood cell circulation. PMID- 8683598 TI - Rearrangement of the former VL interface in the solution structure of a camelised, single antibody VH domain. AB - The solution structure of the isolated antibody heavy chain variable domain (VH) P8 was determined by NMR spectroscopy. The VH had previously been modified (camelised) at three positions in its former antibody light chain variable domain (VL) interface to reduce hydrophobicity by mimicking camelid heavy chains naturally devoid of light chains. The architecture of two pleated beta-sheets and the conformation of the H1 and H2 loops in VH-P8 are very similar to those in non camelised, VL-associated VH domains. Major differences concern the H3 loop, which no longer points towards the now absent VL, and three residues in the former VL interface. The side-chains of Val37 and Trp103 are buried and the Arg38 side chain exposed in VH-P8. In non-camelised, VL-associated VH domains the side chains of Val37 and Trp103 are in contact with the VL while the Arg38 side-chain is buried within the VH. Reorientation of Trp103 is due to the local structure in the beta-bulge of strand G. Reorientation of Val37 and Arg38 is caused by a disruption of regular beta-structure in strand C opposite the beta-bulge in strand C'. These changes, combined with the more hydrophilic side-chains of the camelised residues, reduce hydrophobicity and prevent non-specific binding of camelised VH domains, which proved critical for their use as small recognition units. The VH-P8 structure also indicates structural reasons for two other mutations specific for light-chain-lacking camel immunoglobins. Absence of the VH typical Arg94/Asp101 salt bridge at the base of the H3 loop in VH-P8 may explain why a positively charged residue at position 94 is not conserved in camels. Reorientation of Val37 suggests a function of the camel-specific phenylalanine residue at this position in the hydrophobic core of light-chain-lacking camel heavy chains. PMID- 8683599 TI - Solution structure of the granular starch binding domain of glucoamylase from Aspergillus niger by nuclear magnetic resonance spectroscopy. AB - The solution structure of the granular starch binding domain (SBD) of glucoamylase 1 from Aspergillus niger has been determined by heteronuclear multidimensional nuclear magnetic resonance spectroscopy and simulated annealing. A total of 1092 nuclear Overhauser enhancement-derived 1H-1H distance constraints, 137 dihedral constraints and 86 hydrogen bond constraints were incorporated into an X-PLOR simulated annealing and refinement protocol. The family of calculated structures shows a well defined beta-sheet structure consisting of one parallel and six antiparallel pairs of beta-strands which forms an open-sided beta-barrel. The root-mean-square deviation (rmsd) of 53 individual structures to the calculated average structure for the backbone atoms of residues excluding the N terminus and two mobile loops is 0.57(+/-0.10) A while the rmsd for backbone atoms in beta-strands is 0.45(+/-0.08) A. Structural features of the SBD in solution are compared to the X-ray crystal structure of a homologous domain of cyclodextrin glycosyltransferase (CGTase) in the free and bound forms. Titration studies with two ligands, maltoheptaose and beta-cyclodextrin, show the existence of two binding sites. Examination of the tertiary structures shows these two sites to be at one end of the molecule on opposite faces. The majority of residues showing the largest 1H and 15N chemical shift changes are located in loop regions. Many residues implicated in binding, based on these changes, are similar in location to previously identified binding site residues in the crystal structures of CGTase. Overall, the shift changes are small indicating that the SBD does not undergo large conformational changes upon ligand binding. PMID- 8683600 TI - Local interactions dominate folding in a simple protein model. AB - Recent computational studies of simple models of protein folding have concluded that a pronounced energy minimum (i.e. large gap in energy between low-energy states of the model) is a necessary and sufficient condition to ensure folding of a sequence to its lowest-energy conformation. Here, we show that this conclusion strongly depends on the particular temperature scheme selected to govern the simulations. On the other hand, we show that there is a dominant factor determining if a sequence is foldable. That is, the strength of possible interactions between residues close in the sequence. We show that sequences with many possible strong local interactions (either favorable or, more surprisingly, a mixture of strong favorable and unfavorable ones) are easy to fold. Progressively increasing the strength of such local interactions makes sequences easier and easier to fold. These results support the idea that initial formation of local substructures is important to the foldability of real proteins. PMID- 8683601 TI - Crystal structure of human trypsin 1: unexpected phosphorylation of Tyr151. AB - The X-ray structure of human trypsin 1 has been determined in the presence of diisopropyl-phosphofluoridate by the molecular replacement method and refined at a resolution of 2.2 A to an R-factor of 18%. Crystals belong to the space group P4, with two independent molecules in the asymmetric unit packing as crystallographic tetramers. This study was performed in order to seek possible structural peculiarities of human trypsin 1, suggested by some striking differences in its biochemical behavior as compared to other trypsins of mammalian species. Its fold is, in fact, very similar to those of the bovine, rat and porcine trypsins, with root-mean-square differences in the 0.4 to 0.6 A range for all 223 C alpha positions. The most unexpected feature of the human trypsin 1 structure is in the phosphorylated state of tyrosine residue 151 in the present X ray study. This feature was confirmed by mass spectrometry on the same inhibited sample and also on the native enzyme. This phosphorylation strengthens the outstanding clustering of highly negative or highly positive electrostatic surface potentials. The peculiar inhibitory behaviour of pancreatic secretory trypsin inhibitors of the Kazal type on this enzyme is discussed as a possible consequence of these properties. A charged surface loop has also been interpreted as an epitope site recognised by a monoclonal antibody specific to human trypsin 1. PMID- 8683602 TI - Monitoring the impact of traumatic brain injury: a review and update. PMID- 8683603 TI - Long-term consequences of head injury. AB - This study was undertaken to determine the long-term consequences of head injury resulting from police reported tow-away motor vehicle crashes in the U.S. in 1993. The results are presented in terms of the Functional Capacity Index (FCI), which quantifies the relative functional capacity of a previously healthy adult 1 year postinjury, and Life-years Lost to Injury (LLI), defined as the FCI value times the injured person's life expectancy. FCI values vary from 0 for no effect to 1.0 for complete loss of function. Total LLI is indicative of the effect on society, and average LLI represents the effect of an injury on an "average" individual in the injured population. The results show that 1.7 times as many people with a brain injury resulting from a motor vehicle crash die than survive, and the Life-years Lost to Death are 1.8 times greater for these fatalities than the Life-years Lost to Injury for the surviving population. The injuries with the greatest FCI for survivors were unconsciousness, brain stem, and cerebrum injuries, all with FCI values at or near 1.0. The average LLI for these injury categories were 44.4, 45.1, and 42.8 years, respectively. The total LLI for these injuries were 57,843, 18,364, and 11,725 years, respectively. The principal conclusion is that motor vehicle related head injuries continue to have major consequences on the injured individuals, and considerable effect on society as a whole. PMID- 8683604 TI - Head injury mechanisms and the concept of preventive management: a review and critical synthesis. AB - Recent advances in head injury research have produced a plethora of useful data coupled with a paucity of conceptual integration across the four ways in which this research is pursued. These research orientations are the epidemiological, biomechanical, basic neuroscientific, and clinicopathologic/therapeutic (including rehabilitation). This overview of the history and current state of the art assumes that biomechanics is the basic science of causation in head injury research and when fully integrated with its counterparts, physiology and pathology, it can serve to overcome our conceptual handicaps. A paradigm integrating biomechanics; into the sequence of preventive, protective, acute therapeutic, and rehabilitative interventions will be described as the concept of preventive management. From this we derive the hypothesized claim that the exact biomechanics and the physiopathologic response at the time of injury (at the macroscopic and microscopic levels) determine the sequence of so-called secondary effects that are conceived as the inexorable delayed manifestations of the primary events and concomitant boundary conditions. Knowledge of these events will enable accurate predictions of the natural history and outcome of head injuries from observations carried out in the early acute phase. Examples to test this claim will be given with particular reference to the two types of traumatic brain injury (TBI) phenomenologically associated with disturbances of consciousness, the onset of which can be either immediate or delayed. The current economics and availability of computational power provide a significant opportunity for the development of selected experimental, physical, and simulated models of head injury on the basis of which the complex neurovascular and nonneural cellular and fluid elements of the nervous system may be accurately modeled. This approach will significantly improve the efficiency and quality of the essential biological and clinical observations and model experiments required to validate the theoretical methods and their predictions. PMID- 8683605 TI - The role of excitatory amino acids in severe brain trauma: opportunities for therapy: a review. AB - Severe brain trauma remains poorly understood, because of its pathophysiological complexity, and this has so far thwarted our attempts to improve outcome by means of drug therapy, although better understanding of the role of ischemic events has led to improved mortality rates, in some centers. With regard to excitatory amino acid antagonists, new mechanistic insights from both animal models, and human monitoring has enabled better trial design, which may allow the tremendous laboratory neuroprotective potency of this group of compounds to be translated to clinical benefit. PMID- 8683606 TI - The pathobiology of traumatically induced axonal injury in animals and humans: a review of current thoughts. AB - This manuscript provides a review of those factors involved in the pathogenesis of traumatically induced axonal injury in both animals and man. The review comments on the issue of primary versus secondary, or delayed, axotomy, pointing to the fact that in cases of experimental traumatic brain injury, secondary, or delayed, axotomy predominates. This review links the process of secondary axotomy to an impairment of axoplasmic transport which is initiated, depending upon the severity of the injury, by either focal cytoskeletal. misalignment or axolemmal permeability change with concomitant cytoskeletal. collapse. Data are provided to show that these focal axonal changes are related to the focal impairment of axoplasmic transport which, in turn, triggers the progression of reactive axonal change, leading to disconnection. In the context of experimental studies, evidence is also provided to explain the damaging consequences of diffuse axonal injury. The implications of diffuse axonal injury and its attendant deafferentation are considered by noting that with mild injury such deafferentation may lead to an adaptive neuroplastic recovery, whereas in more severe injury a disordered and/or maladaptive neuroplastic re-organization occurs, consistent with the enduring morbidity associated with severe injury. In closing, the review focuses on the implications of the findings made in experimental animals for our understanding of those events ongoing in traumatically brain-injured humans. It is noted that the findings made in experimental animals have been confirmed, in large part, in humans, suggesting the relevance of animal models for continued study of human traumatically induced axonal injury. PMID- 8683607 TI - Topography of axonal injury as defined by amyloid precursor protein and the sector scoring method in mild and severe closed head injury. AB - Axonal injury (AI), as defined by amyloid precursor protein (APP) positive axonal swellings, was recorded on a series of line diagrams of standard brain sections divided into 116 sectors to provide an Axonal Injury Sector Score (AISS) ranging from 0 to 116. This sector scoring method of recording axonal damage and providing a topographic overview of AI was applied to a series of 6 mild head injury cases [Glasgow Coma Scale (GCS) 13-15] and six severe head injury cases (GCS 3-8). The AISS ranged from 4 to 107 overall and varied from 4 to 88 in the mildly injured group and 76 to 107 in the severe head injury group, supporting the concept that there is a spectrum of AI in traumatic head injury and that the AISS is a measure of the extent of AI. APP immunostaining demonstrated positive axonal swellings 1.75 h after head injury and analysis of the pattern of AI in the mild and severe head injury groups showed that axons were more vulnerable than blood vessels and that the axons in the corpus callosum and fornices were the most vulnerable of all. PMID- 8683608 TI - New magnetic resonance imaging techniques for the evaluation of traumatic brain injury. AB - Although current computerized tomography (CT) and magnetic resonance imaging (MRI) techniques have shown great utility in diagnosing various aspects traumatic brain injury, damage resulting from mild diffuse brain injury often goes undetected with these procedures. Newly developed MRI techniques, including magnetization transfer imaging (MTI) and diffusion-weighted imaging (DWI), have been proposed to have enhanced sensitivities for identifying damage induced by both diffuse and focal brain injury. Results from recent initial studies with experimental models of brain injury suggest that MTI may be useful for evaluating diffuse white matter damage, while DWI may demonstrate regions of focal contusion more acutely and with greater accuracy than conventional MRI procedures. PMID- 8683609 TI - The effect of associated injuries, blood loss, and oxygen debt on death and disability in blunt traumatic brain injury: the need for early physiologic predictors of severity. AB - Studies of 4590 patients with blunt trauma injuries admitted to a Level I Trauma Center, have shown that 37% had a blunt traumatic brain injury (BTBI). Of these brain injured patients 60% has an associated other injury. Examination of mortality has shown that those with an isolated brain injury had an 11% mortality compared with 21.8% in those with an associated systemic injury. Further investigation demonstrated that the cause of the increased mortality was related to the blood loss associated with the injuries and that when hypovolemic shock resulted, mortality rose from 12.8 to 62%. The severity of the associated injuries effect on the brain injured patient could be estimated by a parameter of oxygen debt, the base deficit and this allowed for a quantitative estimate of the probability of death as an index of severity. A combined linear logistic model using the admission Glasgow Coma Score (GCS) as a measure of brain injury and the base deficit as a measure of physiologic injury provides such a predictive score. The effect of associated injuries in patients with moderate brain injury (AIS 2,3) was to increase the average total cost of medical care in the first year of injury by three-fold ($12,489 to $36,177) and for severe brain injury (AIS 4,5) to increase average cost from $59,000 in isolated BTBI to $90,000 in BTBI with associated injury. The high incidence of brain injuries in motor vehicle crashes (MVC) caused by lateral impacts and their association with other side-impact injuries (lungs, spleen, kidney, and pelvic fractures) in which large blood volume losses are common, focuses attention on the need for side impact protection standards that simultaneously protect brain, thoracoabdominal viscera, and pelvis as a means of reducing the severity and cost of lateral impact MVCs. PMID- 8683610 TI - A new application for near-infrared spectroscopy: detection of delayed intracranial hematomas after head injury. AB - Clinical studies have documented the importance of secondary brain insults in determining neurologic outcome after head injury. Delayed intracranial hematomas are one of the most easily remediable causes of secondary injury if identified early, but can cause significant disability or death if not promptly recognized and treated. Early identification and treatment of these lesions that appear or enlarge after the initial CT scan may improve neurological outcome. Serial examinations using near-infrared spectroscopy (NIRS) to detect the development of delayed hematomas were obtained in 167 patients. The difference in absorbance of light (deltaOD) at 760 nm between the normal and the hematoma side was measured serially during the first 3 days after injury. Twenty-seven (16%) of the patients developed some type of late hematoma: an intracerebral hematoma in 8 patients, an extracerebral hematoma in 6 patients, and a postoperative hematoma in 13 patients. Eighteen of the delayed hematomas caused significant mass effect and required surgical evacuation. The hematomas appeared between 2 and 72 h after admission. In 24 of the 27 patients, a significant increase (>0.3) in the deltaOD occurred prior to an increase in intracranial pressure or a change in the neurological examination, or a change on CT scan. Early diagnosis using MRS may allow early treatment and reduce secondary injury caused by delayed hematomas. PMID- 8683611 TI - Neurobehavioral outcome of closed head injury: implications for clinical trials. AB - This review encompasses the neurobehavioral sequelae of moderate to severe closed head injury (CHI). Following a discussion of posttraumatic amnesia and its measurement, the paper discusses assessment of the global outcome of CHI using the Glasgow Outcome Scale. Domains of residual neurobehavioral sequelae that are reviewed include attention/information processing speed, memory, language, intellectual ability, executive functions, and motor speed. The contribution of behavioral disturbance and psychosocial maladjustment to overall outcome is reviewed, as is the impact on the family. Finally, the neurobehavioral outcome measures for clinical trials involving moderate to severe head-injured patients are presented. Caveats for completing clinical trials that involve assessment of neurobehavioral functioning are provided. PMID- 8683612 TI - Comparison of three measures of injury severity in children with traumatic brain injury. AB - Eighty-six traumatically brain-injured children aged 6 to 15 years who were consecutively admitted to a pediatric Level I trauma center were recruited for participation in the study. A comprehensive battery of behavioral, cognitive, communicative, social, motoric, and neurological tests was administered to the children from 12 to 36 months postinjury. The performance of three severity indices, the Glasgow Coma Scale (GCS), the ASCOT probability of survival, and the head injury component of the Anatomic Profile, was compared with respect to their association with long-term outcomes in five neurological domains, as assessed by linear regression models. The ASCOT probability of survival was correlated to test scores in all five domains. The GCS and the head injury component of the Anatomic Profile were each correlated to outcome in only one domain. The ASCOT probability of survival, which includes coded variables for the GCS, systolic blood pressure, and respiratory rates on admission, as well as a measure of multisystem anatomic injury, was the most sensitive indicator of head injury severity and was associated with outcomes beyond survival and death in this population. Probability of survival is a promising brain injury severity index that may be useful in efforts to assess new medical and rehabilitative therapies for children with traumatic brain injury. PMID- 8683613 TI - Brain injury without head impact? AB - The proposition that acceleration of the brain without direct impact to the head can result in brain injury is examined by reviewing a series of 414 road users who were fatally injured in the vicinity of Adelaide, South Australia. The series comprises 170 pedestrians, 10 pedal cyclists, 143 motorcyclists, and 91 vehicle occupants. In each case a member of the research team attended the autopsy to look for evidence of impact on the body, particularly to the head or face. The brain was examined by a neuropathologist and the type and pattern of injury was recorded. The circumstances of the crash were investigated, including an examination of the crash site and the vehicles involved and, where relevant, interviews with witnesses. In cases involving a motorcyclist the helmet worn was retrieved by the police and assigned to the research unit for examination. Particular attention was paid to the identification of objects causing injury to the head or face and also to objects impacted by a helmet. Brain injury was recorded as a cause of death in 55% of the 403 cases for which there was a clear classification of cause of death. Brain injury, at any level of severity, was identified by a neuropathologist in 86 percent of the 414 fatally injured road users in the sample, including 24 cases that were examined microscopically. There were no cases in which there was an injury to the brain in the absence of evidence of an impact to the head. PMID- 8683614 TI - Field and analytic observations of impact brain injury in fatally injured pedestrians. AB - To develop more effective head protection against impact injury, maximum levels of mechanical impact or injury tolerance criteria, or both, should be specified for particular levels of injury and for particular structures of the brain. By using a development of an existing very simplified model of the head-vehicle impact for pedestrians we were able to make estimates of the peak angular acceleration and change in angular velocity of head impacts for fatally injured pedestrians. This model also enabled us to examine the relationship between the parameters of the impact, and the critical strain curves for brain injury proposed by Margulies and Thibault (1992). It was found that the offset of the impact from the center of mass of the head was a major influence, and, in addition, in impacts with a combined head/vehicle stiffness above 130 kN/m, the head impact velocity and change in head angular velocity were important, whereas for impacts with lower stiffness, the stiffness of the impact structure and hence, peak angular acceleration, were the major influences. Transformed into the frequency domain, the 130 kN/m region corresponds roughly to a harmonic of the natural frequency of the brain and skull, and the change in behavior may be related to decoupling of the skull and brain at impact. In 12 cases of lateral head impact, all but one case with visible injury in the corpus callosum were found to lie close to or above the 10% critical strain curve. Despite the very wide error limits around each data point, there is sufficient consistency between the field observations of brain injury and the analytic findings to suggest that the 10% critical strain curve represents a threshold for brain injury, expressed in terms of peak angular acceleration and change in angular velocity. PMID- 8683615 TI - On the mechanics of impact neurotrauma: a review and critical synthesis. AB - A computational modeling technique for the simulation of head impact mechanics is proposed as a tool for the study of traumatic brain injury (TBI). The capabilities, limitations, and consequently the utilities of this technique are discussed in light of the current computing and imaging technologies and their prospective advancement. A significant portion of the mechanics, relevant to head impact simulation, has been incorporated into this computational technique resulting in automated devices that ease the technical burden of biomechanical analysis of TBI mechanisms. A brief exposition of the concepts utilized in these devices is given and their basis in experiment is discussed. PMID- 8683616 TI - Recent advances in biomechanics of brain injury research: a review. AB - Biomechanics of cerebral trauma attempts to delineate the dynamic response of the cranial vault contents to a direct or indirect impact to the head. Consequently, brain injury mechanisms and associated tolerance to impact can be deduced by establishing a relationship between neurological deficit and mechanical dosage. The resulting information is invaluable to brain injury prevention and diagnosis. This paper presents an overview of our recent research on head injury focusing on establishing brain injury biomechanics by developing a comprehensive and validated mathematical model. To achieve our goal, we developed a comprehensive three-dimensional finite element human head model, finite element porcine head models, and sensors to monitor head kinematics and brain strains by neutral density accelerometers. The information obtained from this research thus far provided a predictive and somewhat validated mathematical model of the head, which clearly shows a correspondence between brain mechanical response and experimentally observed injuries. PMID- 8683617 TI - Biomechanics of skull fracture. AB - This study was conducted to determine the biomechanics of the human head under quasistatic and dynamic loads. Twelve unembalmed intact human cadaver heads were tested to failure using an electrohydraulic testing device. Quasistatic loading was done at a rate of 2.5 mm/s. Impact loading tests were conducted at a rate of 7.1 to 8.0 m/s. Vertex, parietal, temporal, frontal, and occipital regions were selected as the loading sites. Pathological alterations were determined by pretest and posttest radiography, close-up computed tomography (CT) images, macroscopic evaluation, and defleshing techniques. Biomechanical force-deflection response, stiffness, and energy-absorbing characteristics were obtained. Results indicated the skull to have nonlinear structural response. The failure loads, deflections, stiffness, and energies ranged from 4.5 to 14.1 kN, 3.4 to 16.6 mm, 467 to 5867 N/mm, and 14.1 to 68.5 J, respectively. The overall mean values of these parameters for quasistatic and dynamic loads were 6.4 kN (+/- 1.1), 12.0 mm (+/- 1.6), 812 N/mm (+/- 139), 33.5 J (+/- 8.5), and 11.9 kN (+/-0.9), 5.8 mm (+/ 1.0), 4023 N/mm (+/- 541), 28.0 J (+/- 5.1), respectively. It should be emphasized that these values do not account for the individual variations in the anatomical locations on the cranium of the specimens. While the X-rays and CT scans identified the fracture, the precise direction and location of the impact on the skull were not apparent in these images. Fracture widths were consistently wider at sites remote from the loading region. Consequently, based on retrospective images, it may not be appropriate to extrapolate the anatomical region that sustained the impact forces. The quantified biomechanical response parameters will assist in the development and validation of finite element models of head injury. PMID- 8683618 TI - Mechanisms of basilar skull fracture. AB - Basilar skull fractures comprise a broad category of injuries that have been attributed to a variety of causal mechanisms. The objective of this work is to develop an understanding of the biomechanical mechanisms that result in basilar skull fractures, specifically focusing on mandibular impact and neck loading as potential mechanisms. In the characterization of the injury mechanisms, three experimental studies have been performed. The first study evaluated the response of the base of the skull to midsymphysis loading on the mental protuberance (chin) of the mandible. Five dynamic impacts using a vertical drop track and one quasi-static test in a servohydraulic test frame have been performed. In each test, clinically relevant mandibular fractures were produced but no basilar skull fractures were observed. The second study assessed the fracture tolerance of the base of the skull subject to direct loading on the temporomandibular joint in conjunction with tensile loading imposed locally around the foramen magnum to simulate the effect of the ligaments and musculature of the neck. Among four specimens that sustained either complete or incomplete basilar skull ring fractures remote from the sites of load application, the mean load at fracture was 4300 +/- 350 N. Energy to fracture was computed in three of those tests and averaged 13.0 +/- 1.7 J. Injuries produced were consistent with clinical observations that have attributed basilar skull ring fractures to mandibular impacts. In the third series of experimental tests, loading responses resulting from cranial vault impacts were investigated using unembalmed human cadaver heads and ligamentous cervical spines. Multiaxis load cells and accelerometers, coupled with high-speed digital video, were used to quantify impact dynamics. The results of these experiments suggest that while there is a greater probability of cervical spine injury, basilar skull ring fractures can result when the head is constrained on the impact surface and the inertia of the torso drives the vertebral column onto the occiput. PMID- 8683619 TI - An imaging-based computational and experimental study of skull fracture: finite element model development. AB - The development of a three-dimensional finite element model of the human skull is presented as a part of a novel imaging-based experimental and computational approach to study skull fracture. The rationale for this approach and its potential utility are presented. Mathematical model development, using computed tomography (CT) imaging data as a basis for collecting geometric characteristics of the skull, is given. The model includes anatomical detail of the cranial structure, accurate thickness distributions of the bone and soft tissue components, and density information that can be related to the elastic moduli of the various constituent materials. A procedure for generating the model from CT scan image data is presented. This procedure segments the head into cranial bone, facial, and scalp structures, and the brain. PMID- 8683620 TI - Biomechanical analysis of experimental diffuse axonal injury. AB - The purpose of this paper is to present results from methodologies used in our laboratory that are targeted toward identifying specific brain injury thresholds. Results from studying one form of brain injury, diffuse axonal injury, are presented in this report. Physical models, or surrogates, of the skull-brain complex are used to estimate the relationship between inertial loading and brain deformation. A porcine model of diffuse axonal injury, developed with information from these physical models and earlier in vitro tissue modeling studies, is used to correlate histologic and radiologic evidence of axonal injury to predicted regions of injury from the experimental and theoretical analysis. These results form the basis for developing improved diffuse brain injury tolerance levels, as well as identifying new means of diagnostic and treatment techniques for diffuse axonal injury. PMID- 8683621 TI - Development of tissue level brain injury criteria by finite element analysis. AB - A three-dimensional finite element model of the direct cortical impact experiment was built and a preliminary validation against mechanical response was completed. The motion of the impactor was enforced in the model by applying the same acceleration history as that of the experimental impactor. A nonlinear contact surface algorithm was used for impactor-brain interface with the ABAQUS general purpose finite element program. The resulting motion of the impactor and the contacting node in the brain model confirmed that the impactor moved realistically and contacted the brain surface. The pressure generated in the model compared favorably with that measured by a pressure transducer in the experiment. The pattern of high shear deformation generated at the impact site in the model was similar to the pattern of contusion hemorrhage seen in the experiment. The pressure generated at the impact site propagated to the skull brain boundary, especially, at the posterior margin of the cerebellum. Analysis of experimental data using a biomechanically validated finite element model will enable determination of tissue-level injury criteria for application in human brain models to predict head injury potential in contact, noncontact, or side impact situations. PMID- 8683622 TI - Internal cavitation in simple head impact model. AB - A two-dimensional computational model is used to evaluate the potential for cavitation to occur inside the brain material during head impact. The model represents a simple water-filled 14-cm-diameter, 5-cm-deep cylinder. For the purpose of our study, this cylinder represents the skull while the water inside the cylinder represents the brain material. To ensure that the stress predicted by the model is realistic, it has been calibrated against experimental data. When the cylinder is struck by a free-flying mass cavitation is initiated at the boundary opposite impact. Significant vaporous regions may develop at the boundary, while only limited vaporization occurs internally. Higher accelerations, or an additional loading of the domain by a constant acceleration perpendicular to impact, adds to the likelihood and to the severity of internal cavitation. This indicates that preexisting conditions or complex loading conditions of the head during an impact event may affect the cavitation response. Such conditions could be the result of angular velocity, angular accelerations, or head accelerations as a result of neck loading. PMID- 8683623 TI - The influence of different boundary conditions on the response of the head to impact: a two-dimensional finite element study. AB - The objective of the present study is to gain a better understanding of the possible importance of skull-brain interface conditions, boundary conditions at the head-neck junction, and brain material properties when modeling the response of the human head to transient loadings. To that end, a two-dimensional plane strain finite element model of a para-sagittal section of a human head has been developed. The model comprises the brain and the skull, with the foramen magnum represented by a force-free opening. The model geometry was obtained from MRI data. The material properties used were adopted from the literature and are homogeneous and isotropic. In all analyses the skull bone was modeled as a linearly elastic material. First, to enable a comparison between simulation results and experiments reported in the literature, the loading conditions, realized in experiments reported in literature, were used as input to the completely linearly elastic model without a kinematic constraint at the head-neck junction. This was done for both rigid coupling and no coupling at the skull brain interface. Next, various versions of the model were constructed by using different combinations of the following features: linear elastic or viscoelastic brain material properties, different contact conditions at the skull-brain interface, and incorporation of a neck constraint. The results show that both coup and contrecoup pressures are much more sensitive to the type of skull-brain interface condition than to the presence or absence of a force-free foramen magnum. A neck constraint proves to be an important modeling assumption, because of its effect upon the deformation of the brain. The use of different time dependent deviatoric material parameters for the brain did not significantly change the head's response. PMID- 8683624 TI - Coupling of a finite element human head model with a lumped parameter Hybrid III dummy model: preliminary results. AB - A skull-brain finite element model of the human head has been coupled with a multilink rigid body model of the Hybrid III dummy. The experimental coupled model is intended to represent anatomically a 50th percentile human to the extent the dummy and the skull-brain model represent a human. It has been verified by simulating several human cadaver head impact tests as well as dummy head 'impacts" during barrier crashes in an automotive environment. Skull-isostress and brain-isostrain response curves were established based on model calibration of experimental human cadaver tolerance data. The skull-isostress response curve agrees with the JARI Human Head Impact Tolerance Curve for skull fracture. The brain-isostrain response curve predicts a higher G level for concussion than does the JARI concussion curve and the Wayne State Tolerance Curve at the longer time duration range. Barrier crash simulations consist of belted dummies impacting an airbag, a hard and soft steering wheel hub, and no head contact with vehicle interior components. Head impact force, intracranial pressures and strains, skull stress, and head center-of-gravity acceleration were investigated as injury parameters. Head injury criterion (HIC) was also calculated along with these parameters. Preliminary results of the model simulations in those impact conditions are discussed. PMID- 8683625 TI - Development of a finite element model of the human skull. AB - Head injury is the most frequent injury resulting from traffic accidents. Head injury mechanisms are difficult to study experimentally due to the variety of impact conditions involved, as well as ethical issues, such as the use of human cadavers and animals. Finite element modeling is a comprehensive technique through which human head impact tolerance can be studied. A finite element human head model would ideally allow for the assessment of the injurious effects of different impact conditions and enable the development of enhanced head injury and protection criteria. The paper describes the development of a three dimensional finite element model based on the anatomical features of the adult human cranium. The complex cranial geometry was measured from a series of two dimensional computer tomography images. The CT scans were transformed with a self developed preprocessor into a finite element mesh. To model the skull's impact responses, valid material properties are required. The mechanical characteristics of cranial bone were investigated experimentally at Heidelberg University's Institute for Forensic Medicine. To create a sample of material properties for use in the human head model, statistical analyses of the experimental results were undertaken. The tests were modeled with the finite element method and a numerical material model representing the mechanical properties of the human skull bone was developed. The first approach to validate the model and to investigate different boundary conditions by using experimental data is shown. PMID- 8683626 TI - Modal and temporal analysis of head mathematical models. AB - The basic hypotheses used during these investigations were based on the vibration analysis of the head, which demonstrated that the head is not a solid nondeformable body, but a complex structure including deformable elements. Laboratoire des Systemes Biomecanique (LSBM) has recently proposed three mathematical models: a lumped model, a finite element model of the head in its sagittal plane, and a three-dimensional finite element model. These models were validated by their modal behavior and enabled the lesion mechanisms to be distinguished as a function of the spectral characteristics of the shock. The objective of this study is to complete these modal results by temporal analysis of the models by calculating the evolution of the intracranian mechanical parameters under shock conditions. To describe the head's dynamic behavior in the temporal domain, constant energy shocks of variable duration were simulated to evaluate their influence on different quantities as the intracerebral stresses in terms of compression, tensile, and shearing stresses, the relative brain-skull displacement, and the skull deformation. The importance of modal behavior of the head is illustrated by analyzing its temporal response to variable duration impacts, thus exciting very different frequencies. For a triangular shock, the critical duration times are between 10 and 15 x 10(-3) s, which correspond to impacts that excite the first resonance frequency of the head. Taking modal behavior into consideration in developing the finite element model leads to a harmonization of the calculated intracerebral stresses, even for short duration shocks. So, when the head is considered as a complex structure made up of several deformable elements, risk limitation is conditioned by an impact energy reduction for frequencies close to the natural frequencies of the structure. In the time field, the objective will be to avoid a number of impact shapes and durations. Therefore, the aim will not be to dampen the impact at any cost, but to damper it in an "intelligent" manner. In the future, this will allow the reduction of an injury mechanism-related risk, without increasing the risk of an injury generated by another mechanism. PMID- 8683627 TI - Mechanical characteristics of vascular tissue and their role in brain injury modeling: a review. AB - A review of the mechanical characterization of vascular tissue is presented in the context of its relevance to the computational modeling of traumatic brain injury (TBI). Mathematical representations of experimentally observed vascular behavior are described. Several material models, for large vessels, and their applicability to blood vessels in the brain are discussed. Integration of vascular tissue behavior into an existing computational model of the brain, to account for the anisotropic effects they produce, is discussed. PMID- 8683628 TI - Loss of p53-immunostaining intensity in breast cancer. PMID- 8683629 TI - Serving those for whom cure is no longer feasible (2) PMID- 8683630 TI - Researchers debate clinical role of telomerase. PMID- 8683631 TI - Prostatic intraepithelial neoplasia: will it help doctors pinpoint early prostate cancer? PMID- 8683632 TI - Memorial Sloan-Kettering goes electronic to manage patient care. PMID- 8683633 TI - Determinants of survival in older cancer patients. AB - BACKGROUND: We and others have previously described a number of characteristics that are associated with delays in diagnosis and increased risk for inadequate treatment of older women and men with cancer. These characteristics include poor social support, limited access to transportation, and impaired cognition. However, there is little information on how these factors influence survival of older cancer patients. PURPOSE: The purpose of the study was to determine which patient characteristics predicted survival up to 10 years after the diagnosis of cancer. METHODS: In 1984, we initiated a population-based study of men and women who were 65 years of age or older, living in a six-county area of New Mexico, and newly diagnosed with cancer. For 646 individuals with cancer of the breast (n = 188), prostate (n = 247), or colon or rectum (n = 211), we assessed patient baseline characteristics, disease stage at diagnosis, and adequacy of treatment (definitive or nondefinitive) as determinants of survival for up to 10 years following diagnosis. Multivariate survival models were used to analyze the data; all P values were two-sided. RESULTS: In multivariate analyses, we first included all patient characteristics, except the stage at diagnosis and the adequacy of treatment. In this initial analysis, the following were among variables that were significantly associated with patient survival: age, education, cancer knowledge, ethnic group, and cognitive status. When stage at diagnosis and adequacy of treatment were added to the model, both advanced stage at diagnosis (hazard ratio = 1.7 [95% confidence interval ?CI? = 1.3-2.1] for diagnosis at regional stage versus local stage; hazard ratio = 3.0 [95% CI = 2.0-4.7] for distant stage versus local stage) and inadequate treatment (hazard ratio = 1.6 [95% CI = 1.1 2.3]) were associated with poor survival. However, adding stage at diagnosis and adequacy of treatment to the analysis had little influence on the magnitude of the effect of patient characteristics on survival. In separate analyses of patient data by cancer site, receipt of nondefinitive therapy was associated with increased mortality among patients with colon/rectal cancer (hazard ratio = 7.8 [95% CI = 2.8-21.4]) and breast cancer (hazard ratio = 2.2 [95% CI = 1.1-4.3]) but not among patients with prostate cancer (hazard ratio = 1.0 [95% CI = 0.6 1.9]). CONCLUSIONS: Advanced stage at diagnosis and inadequate treatment of older cancer patients are associated with poor survival. Impaired cognition and inadequate education in elderly patients are also associated with poor survival. This decreased survival does not appear to be a consequence of known barriers to health care that are responsible for delays in diagnosis and for inadequate treatment. IMPLICATIONS: Efforts to facilitate early diagnosis and receipt of definitive treatment for cancer in older individuals may improve their survival. PMID- 8683634 TI - A quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis of adjuvant radiation therapy and chemotherapy for resectable rectal cancer. AB - BACKGROUND: Combined radiation therapy and chemotherapy after surgery, compared with postsurgical radiation therapy alone, has been shown to improve disease-free survival and overall survival significantly among patients with poor-prognosis (i.e., advanced stage disease or metastasis to regional lymph nodes) resectable rectal cancer. However, the combined therapy is associated with more toxic effects, raising the question of whether the benefits of the treatment justify its quality-of-life costs for the individual patient. PURPOSE: To assess the trade-offs between improved survival and increased treatment toxicity, we reanalyzed data from a randomized clinical trial that compared the efficacy of combined adjuvant chemotherapy and radiation therapy with adjuvant radiation therapy alone in the treatment of patients with poor-prognosis resectable rectal cancer. METHODS: The data were from a North Central Cancer Treatment Group trial in which 204 patients with poor-prognosis rectal cancer were randomly assigned to receive either postoperative radiation therapy alone or radiation therapy plus fluorouracil-based chemotherapy. A quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis was used to account for freedom from symptomatic disease and from early and late side effects of treatment. All reported P values are two-sided. RESULTS: As reported previously, the combined therapy reduced the risk of relapse by 34% (95% confidence interval [CI] = 12%-50%; P = .0016) and reduced the overall death rate by 29% (95% CI = 7%-45%; P = .025) in comparison with adjuvant radiation therapy alone. In the 5 years following assignment to treatment, patients who received the combined therapy had more time with toxicity (3.1 months; 95% CI = 2.0-4.1 months), shorter survival after relapse (3.6 months less; 95% CI = 0.9-6.3 months less), and more TWiST (6.1 months; 95% CI = 0.2 12.0 months) than patients who received adjuvant radiation therapy alone. Despite an increase in the amount of time that individuals spent with early and late toxic effects, the Q-TWiST analysis indicated that the combined therapy conferred significantly greater benefit for a wide range of patient preferences about living with the toxicity of treatment or the symptoms of overt disease. CONCLUSIONS AND IMPLICATIONS: Use of combined chemotherapy and radiation therapy as an adjuvant to surgery for patients with poor-prognosis resectable rectal cancer is justified, since the improved outcome in terms of delayed recurrence and increased survival balances the time spent with early and late toxic effects. The Q-TWiST method is an excellent way to compare treatment outcomes that include quality-of-life considerations. PMID- 8683635 TI - Monitoring of aromatic amine exposures in workers at a chemical plant with a known bladder cancer excess. AB - BACKGROUND: In April 1991, an excess of bladder cancer cases among workers employed at a chemical manufacturing facility in Niagara Falls, NY, was reported. This excess was primarily confined to 708 workers who had ever been employed in the rubber chemicals manufacturing area of the plant, where the aromatic amines aniline and o-toluidine have historically been used. PURPOSE: An environmental and biological monitoring survey was conducted to evaluate current exposures to aniline and o-toluidine in the rubber chemicals department. METHODS: Personal air sampling for aniline and o-toluidine was conducted with the use of a modified Occupational Safety and Health Administration (OSHA) 73 method. Urine samples were collected before and after work (i.e., pre-shift and post-shift, respectively) and stored at -70 degrees C. Base hydrolysis was used to convert acetanilide and N-acetyl-o-toluidine, metabolites of aniline and o-toluidine present in the urine, to the parent compounds. The parent compounds were extracted from the alkaline urine into butyl chloride and then back-extracted from the butyl chloride into aqueous hydrochloric acid. An aliquot of each acidic extract was subjected to ion-interaction reversed-phase liquid chromatography with coulometric electrochemical detection. Hemoglobin (Hb) was extracted from blood and stored at -70 degrees C. For the measurement of adducts of aniline, o toluidine, and 4-aminobiphenyl (4-ABP), precipitated Hb was dissolved in 0.1 M sodium hydroxide in the presence of recovery standards, and the hydrolysate was extracted with hexane, derivatized with pentafluoropropionic anhydride, and analyzed by gas chromatography-mass spectrometry with negative chemical ionization. RESULTS: A total of 73 workers, including 46 of 64 exposed workers who were employed in the rubber chemicals department and had the potential for exposure to aniline and o-toluidine and 27 of 52 unexposed workers employed in other departments where aniline and o-toluidine were not used or produced, had data available for both aniline and o-toluidine and Hb adducts; 28 of the workers in the former group also had personal air-sampling data. Personal air sample measurements showed that airborne concentrations of aniline and o-toluidine were well within the limits allowed in the workplace by OSHA. Urinary aniline and o toluidine levels, however, were substantially higher among exposed workers than among unexposed control subjects. The most striking differential was for post shift urinary o-toluidine levels, which averaged (+/- standard deviation) 2.8 micrograms/L (+/- 1.4 micrograms/L) in unexposed subjects and 98.7 micrograms/L (+/- 119.4 micrograms/L) in exposed subjects (P = .0001). Average aniline-Hb and o-toluidine-Hb adduct levels were also significantly higher (P = .0001) among exposed workers than among unexposed control subjects. Average levels of adducts to 4-ABP, a potential contaminant of process chemicals, were not significantly different (P = .48), although three exposed workers had 4-ABP levels above the range in unexposed workers. CONCLUSIONS: The adduct data suggest that, among current workers, o-toluidine exposure substantially exceeds aniline exposure and that 4-ABP exposure, if it occurs at all, is not widespread. These data support the conclusion that occupational exposure to o-toluidine is the most likely causal agent of the bladder cancer excess observed among workers in the rubber chemicals department of the plant under study, although exposures to aniline and 4-ABP cannot be ruled out. PMID- 8683636 TI - Loss of tumor marker-immunostaining intensity on stored paraffin slides of breast cancer. AB - BACKGROUND: We previously observed decreased p53 immunostaining over time in paraffin-embedded sections of ductal carcinoma in situ of the breast of women; these sections had been stored on slides at room temperature. This observation suggests that slide storage adversely affects p53-immuno-staining intensity and could result in spurious negative staining for p53 in patient samples. PURPOSE: The goals of this study were to determine the time course and factors influencing loss of p53 immunoreactivity and to investigate whether a similar loss of reactivity occurs with other antigens commonly used to study breast cancer. METHODS: Serial sections cut from 12 formalin-fixed, paraffin-embedded, p53 positive invasive ductal carcinomas of the breast were stored on slides at room temperature or at 4 degrees C, with or without an additional paraffin coating, for 2, 4, 8, or 12 weeks. For each case, freshly cut slides from the same block (day 0) and stored slides were simultaneously stained for p53 by use of an automated immunostainer. Slides cut from formalin-fixed, paraffin-embedded breast carcinomas and stored for 12 weeks were also stained for factor VIII-related antigen (n = 12), estrogen receptor (ER) (n = 9), and Bcl-2 protein (n = 9). The staining intensity of all slides was assessed by visual microscopic examination and was also quantified by image analysis. Quantitative results were expressed as a percentage (mean +/- standard error) of the staining intensity on day 0. Data were analyzed by the Friedman Repeated Measures Analysis of Variance on Ranks, with statistical significance set at two-sided P < .05. RESULTS: The intensity of p53 staining decreased over time in nine (75%) of the 12 cases studied. In three (or 25% of all cases studied) of the nine cases that showed decreased p53 staining, slides stored for 12 weeks were scored as p53 negative. Antigen loss on slides stored at 4 degrees C was significantly less than that on slides stored at room temperature at all time points (all P < .05). At 12 weeks, the average staining intensity of slides stored at 4 degrees C was 33.2% +/- 9% of that on day 0 compared with 8.4% +/- 3% of that on day 0 for slides stored at room temperature (P < .001). Paraffin coating of the sections did not significantly diminish antigen loss at either room temperature or 4 degrees C, except for slides stored at room temperature for 12 weeks. The intensity of factor VIII staining decreased in nine of 12 cases (average staining intensity, 37.3% +/- 6% of that on day 0 at 12 weeks; P = .0001). The intensity of ER and Bcl-2 staining decreased in all nine cases studied at 12 weeks (average staining intensity, 14.0% +/- 6% and 21.0% +/- 4% of that on day 0, respectively; P = .0001 for each). CONCLUSIONS AND IMPLICATIONS: Slide storage, particularly at room temperature, results in substantial loss of p53 reactivity, with some p53 positive cases becoming p53 negative after 12 weeks of storage. Substantial loss of immunoreactivity for factor VIII, ER, and Bcl-2 occurs on slides stored at room temperature for 12 weeks. Storage of unstained slides for up to 12 weeks may lead to false-negative immunostaining for p53 and other antigens. PMID- 8683637 TI - Male sexual behavior and human papillomavirus DNA: key risk factors for cervical cancer in Spain. AB - BACKGROUND: It is now established that certain types of human papillomaviruses (HPVs) are the sexually transmitted agents etiologically linked to cervical cancer. Studies assessing the contribution of the male's sexual behavior and genital HPV DNA status to the risk of development of cervical neoplasia in sexual partners have yielded inconsistent results. PURPOSE: This study evaluates the role of men's sexual behavior and the presence of HPV DNA in the penis on the development of cervical cancer in their sexual partners in Spain, a low-risk area for cervical neoplasia. METHODS: Husbands (n = 633) of women participating in two case-control studies of cervical neoplasia were interviewed to obtain information on lifestyle habits, including sexual practices. Cytologic samples were taken from the distal urethra and the surface of the glans penis of 183 husbands of case women and of 171 husbands of control women. These samples were analyzed by a polymerase chain reaction-based system using a generic probe and 25 type-specific probes for the detection and typing of HPV DNA. Serologic specimens were also obtained and analyzed for antibodies to Chlamydia trachomatis, Treponema pallidum, herpes simplex virus type II, and Neisseria gonorrhoeae. RESULTS: The presence of HPV DNA in the husbands' penis conveyed a fivefold risk of cervical cancer to their wives (adjusted odds ratio [OR] for HPV DNA positivity = 4.9; 95% confidence interval [CI] = 1.9-12.6). The risk of cervical cancer was strongly related to HPV type (adjusted OR for HPV type 16 = 9.0; 95% CI = 1.1-77.5), to the husbands' number of extramarital partners (adjusted OR = 11.0; 95% CI = 3.0 40.0; for > or = 21 women versus one), and to the number of prostitutes as extramarital sexual partners (adjusted OR = 8.0; 95% CI = 2.9-22.2; for > or = 10 women versus none). Presence of antibodies to C. trachomatis (adjusted OR = 2.6; 95% CI = 1.4-4.6) and an early age at first sexual intercourse of the husband (adjusted OR = 3.2; 95% CI = 1.7-5.9; for < or = 15 years versus > or = 21 years) were also associated with cervical neoplasia in the wife. After adjustment for these variables and for the wife's pack-years of smoking, the husband's smoking was moderately associated with cervical cancer in his wife (adjusted OR = 2.5; 95% CI = 1.4-4.4; for > or = 26.2 pack-years versus none). CONCLUSIONS: The study supports the role of men as vectors of the HPV types that are related to cervical cancer. Life-time number of female sexual partners, number of female prostitutes as sexual partners, and detection of HPV DNA in the penis of husbands are all surrogate markers of exposure to HPV during marriage. IMPLICATIONS: Men who report multiple sexual partners or who are carriers of HPV DNA may be vectors of high-risk HPV types and may place their wives at high risk of developing cervical cancer. Prostitutes are an important reservoir of high-risk HPVs. PMID- 8683638 TI - Difficulty in elucidating the male role in cervical cancer in Colombia, a high risk area for the disease. AB - BACKGROUND: Epidemiologic evidence has been inconclusive in linking men's sexual behavior and genital human papillomaviruses (HPVs) with cervical cancer risk in their sexual partners in areas with a high incidence of cervical cancer. PURPOSE: This study assesses the role of men's sexual behavior and the presence of penile HPV DNA on the risk of their wives' developing cervical neoplasia in an area in Colombia with a high incidence of cervical cancer. METHODS: A total of 210 husbands of women with cervical intraepithelial neoplasia grade III (n = 118) or invasive squamous cell carcinoma of the cervix (n = 92) and a total of 262 husbands of women recruited as control subjects (173 and 89, respectively) were interviewed. Questionnaires included detailed information on sexual behavior. Exfoliated cells were obtained from the glans penis and from the distal urethra of the penis. The specimens were analyzed for HPV DNA by use of a polymerase chain reaction-based assay that included a generic probe and 25 type-specific probes. Serum specimens were collected and analyzed for antibodies to Chlamydia trachomatis, Treponema pallidum, herpes simplex virus type II, and Neisseria gonorrhoeae. RESULTS: Limited education (adjusted odds ratio [OR] = 4.4; 95% confidence interval [CI] = 1.9-9.8; for no schooling versus secondary or higher education) and presence of antibodies to C. trachomatis (adjusted OR = 2.5; 95% CI = 1.5-4.4) in husbands were the only identified risk factors for cervical neoplasia in their wives. The prevalence of HPV DNA in the penis was 25.7% among husbands of case women and 18.9% among husbands of control women (adjusted OR = 1.2; 95% CI = 0.6-2.3). Neither the lifetime number of female sexual partners (adjusted OR = 1.0; 95% CI = 0.4-2.6; for > 50 partners versus one to five) nor the lifetime number of female prostitutes as sexual partners (adjusted OR = 1.2; 95% CI = 0.7-2.0; for > or = 21 prostitutes versus one to five) was associated with the risk of cervical cancer. CONCLUSIONS: Our results are compatible with the hypothesis that in the population of Cali, whose women are at high risk of developing cervical cancer, exposure to HPV among young men is a common occurrence and is mediated by contacts with large numbers of female sexual partners and prostitutes. These widespread sexual practices limit the power of case-control studies to detect significant associations between men's sexual behavior and the cervical cancer risk in their sexual partners. HPV DNA detection in the penis of adult men is a poor reflection of lifetime exposure or of etiologically relevant exposure to HPV. The role of C. trachomatis in cervical carcinogenesis deserves further investigation. IMPLICATIONS: Further research is needed to elucidate the male's role in cervical carcinogenesis in populations at high risk for cervical cancer. HPV DNA prevalence surveys and studies of the natural history of HPV in young men will be of great value. PMID- 8683639 TI - Typhlitis associated with docetaxel treatment. PMID- 8683640 TI - Severe neurotoxicity from vinorelbine-paclitaxel combinations. PMID- 8683641 TI - A multidimensional model of the antecedents of stress and coping appraisals: an approach to studying patients' perceptions of post cardiac surgery pain and their coping strategies. AB - Lazarus' stress and coping theory has been recognized as a valued conceptual framework for nursing scholars who are interested in studying their client's experiences of stress and coping. However, little data provide in-depth critiques in concepts, availability and limitations of employing Lazarus' theory in nursing phenomena in Taiwan, nor did data provide culturally sensitive propositions for Taiwanese nursing scholars to better understand their clients' stress experience such as post cardiac surgery pain. In order to help Taiwanese critical care nurses better understand the process of theoretical development while assessing their clients' perceptions of post cardiac surgery pain, the historical perspective of the concept of stress and the core components of Lazarus' theory are examined. Following is a critical critique of Lazarus' theory as a conceptual framework with which to study how patients perceive post cardiac surgery pain as a stressor. A multidimensional model of the antecedents of stress and coping appraisals for nurses to assess their clients' perceptions of pain and the resulting coping behaviors is further developed based on the aforementioned critiques. Finally, suggestions for testing theoretical propositions related to this phenomenon, as well as implications for nursing practice, research, as theory are delineated and discussed. PMID- 8683642 TI - Major causes of diabetic death at one hospital. AB - Death certificates filed between 1987 and 1990 at the Kaohsiung Medical College Hospital (KMCH) were reviewed to investigate causes of diabetic death. During this period, 1,383 patients expired at KMCH, of which 151 had diabetes mellitus. The major causes of death in these 151 diabetic patients were infection in 25.8%, cardiovascular disease in 18.5%, cerebrovascular disease in 11.3%, uremia in 8.6% and diabetic ketoacidosis in 1.3%, while diabetes was reported as the contributory or underlying cause of death. Malignancy in 12.0%, liver disease in 5.3%, trauma in 1.3% and upper gastroenteral bleeding in 0.7%, likewise, were among the leading causes of death irrespective of underlying diabetes. However, cause of death in 15.2% of these diabetic patients was undetermined. Our analysis revealed that infection and cardiocerebrovascular disease were the leading problems contributing to diabetic death. Therefore, reducing the risk of infection by strict glycemic control, intensive medical intervention in infection and the proper prevention of diabetic angiopathy-related risk factors and complications are imperative for the reduction of diabetic mortality in our patients. PMID- 8683643 TI - Hypercholesterolemia in undiagnosed non-insulin-dependent diabetes in southern Taiwan. AB - The purpose of this study was to investigate the prevalence of hypercholesterolemia among subjects having diabetes and glucose intolerance, according to the guidelines of the National Cholesterol Education Program (Adult Treatment Panel II, ATP II). This survey consisted of 2090 subjects (856 men, 1234 women) aged 30 years or more from the Sun-Ming district of Kaohsiung city. Glucose tolerance status was ascertained for both medical history and a 75-g oral glucose tolerance test according to World Health Organization criteria. Frequency of elevated total cholesterol in female subjects with abnormal glucose tolerance is significantly greater than in those with normal glucose tolerance (NGT). However, only male subjects with undiagnosed NIDDM (UDDM) had a statistically higher rate of hypercholesterolemia than those with NGT. Of UDDM individuals, 68% have total cholesterol level between 200 and 239 mg/dl and two or more risk factors for heart disease or evidence of coronary heart disease or total cholesterol > or = 240 mg/dl or high-density lipoprotein (HDL) cholesterol < or = 35 mg/dl. Such individuals should have their low-density lipoprotein (LDL) cholesterol measured. Using the ATP II, LDL cholesterol levels warranting dietary treatment for hypercholesterolemia would be expected in 76% of UDDM. Due to the high prevalence of coronary heart disease in diabetic patients, investigation of blood lipid levels and coronary heart disease risk factors should be routine in these patients, and treatment strategies should include management of lipid disorders and the many other risk factors. A high frequency of dyslipidemia was found among UDDM group in our study. Early detection of undiagnosed diabetic patients is also very important in decreasing the prevalence of coronary heart disease. PMID- 8683644 TI - Patterns of distant metastases in nasopharyngeal carcinoma. AB - The distant metastasis in nasopharyngeal carcinoma has remained the major cause of mortality and treatment failure despite better locoregional control of the disease in the past decades. Between 1987 and 1992, 125 out of 629 cases of nasopharyngeal carcinoma were found to have distant metastasis. The location of metastatic site, the timing and median survival were analyzed. The diagnosis of distant metastasis in the retrospective study was based on radiography, computed tomography, skeletal scintigraphy, abdominal sonography and pathology reports. The results showed that the frequencies of metastases were as follows: bone (75% of total metastatic patients), lung (46%), liver (38%), retroperitoneal lymph nodes (10%). Multiple organ involvement was high (57%). Most of the distant metastases (95%) occurred within 3 years after completion of radiotherapy, the first year (52%), the second year (23%) and the third year (20%). The median survival time from the discovery of distant metastasis was 11.2 months for bone metastasis, 16.3 months for pulmonary metastasis, and 3.2 months for hepatic metastasis. The results revealed that the skeletal system was the most common site of distant metastasis, followed by lung and liver. The incidence of retroperitoneal lymphadenopathy is higher than previous reports. PMID- 8683645 TI - Early diagnosis of necrotizing fasciitis by utilization of ultrasonography. AB - Necrotizing fasciitis is a rare and rapid progression soft tissue infection. The only identifiable feature is tissue necrosis along a single fascia plane. Because the skin is initially spared, it is difficult for early recognition prior to extensive tissue destruction. Ultrasonography was used for early diagnosis of this infection in five cases. All 5 patients presented with severe cellulitis. Under the suspicion of necrotizing fasciitis, ultrasonography was performed before surgical debridement. Tissue biopsy was done for histological confirmation of the diagnosis. Three patients were proven to have necrotizing fasciitis and two cellulitis only. The ultrasonographic findings of necrotizing fasciitis included: 1) irregularity of the fascia; 2) abnormal fluid collections along the fascia plane; and 3) diffuse thickening of the fascia when compared with the control site in the normal limb. However, in severe infectious cellulitis, the above mentioned findings were not observed. Our results indicate the usefulness of the ultrasonography for early diagnosis of necrotizing fasciitis. PMID- 8683646 TI - Risk factors of hepatitis C virus infection in a Taiwanese aboriginal community. AB - The aim of this study is to identify the risk factors associated with anti-HCV positive status in a Bunun aboriginal community in Taiwan. In a door-to-door survey we collected 712 blood samples, and employed an enzyme immunoassay for anti-HCV to detect the recombinant antigen of viral genome including one structural and two nonstructural proteins. The prevalence of anti-HCV was 16.9% for the whole community covering an age range of five years to 84 years, but it was 48% in individuals older than 45 years. The calculated annual incidence rate was 1.25%. Information about possible risk factors was obtained from questionnaires completed in 1992. Age, sex, village of residence, educational level, and the extraneous factor of having been iatrogenic injected during a period one or two years before the survey, showed a significant association with positive anti-HCV status. A dose response relationship between the rate of positive anti-HCV status and frequency of injections was found statistically significant (P < 0.001). Accordingly, a second visit was made to find the possible infection source, and according to information obtained from the recall of 211 interviewees, an illegal medical service was suspected of spreading the recent infection. PMID- 8683647 TI - The effect of child-birth class on first-time fathers' psychological responses. AB - The purpose of this study was to examine fathers' psychological responses to labor/delivery over time and to evaluate the effect of child-birth class on the father. A quasi-experimental and exploratory study was conducted with data collected at the 36th and the 39th weeks of pregnancy, and the first day of the postpartum period. 100 married, first-time expectant fathers in both the experimental and control groups were drawn from one medical center in southern Taiwan as a convenient sample. Three two-hour sessions of childbirth class, each lasting for one day, were conducted consecutively following the first data point for the experimental group. The "Chinese Health Questionnaire" and Zung's Self rating Anxiety and Self-rating Depression Scales were used to obtain the first time fathers' health status, anxiety, and depression scores at each data point. The two-way ANOVA with repeated measures was used to compare the means of psychological responses between experimental and control groups at each point in time. The main effect of classes on paternal health status, anxiety, and depression of the experimental group was not found and the limitations of the study were discussed. PMID- 8683648 TI - Nasal septal cyst--a case report. AB - The usual complications of submucous resection of the nasal septum (SMR) are septal hematoma, infection, hemorrhage, septal perforation, and nasal deformity. We present a case of nasal septal cyst which may be a rare complication of SMR. Entrapment of free nasal mucosal remnants or inward folding of incised septal mucosa is thought to be the cause. The patient underwent deroofment of the left cystic wall by lateral rhinotomy. There was no recurrence after one year. PMID- 8683649 TI - Anatomic and hemodynamic study of the vascularized pig fibula bone flap model. AB - Despite much interest in studying the pathophysiology of experimental skin and muscle flaps to better understand the pathobiology of flap failure, relatively little has been published in the investigation of vascularized bone flaps. The aim of this study was to develop a suitable vascularized bone flap model in the pig in the hope that this model may prove useful in studying the pathophysiology of vascularized bone tissue transfer. Yorkshire pigs (17-26 kg) were used for all experiments. Anatomic studies revealed that the fibula in the hindlimb was the most suitable bone for investigation as a flap model. Anatomic dissections, radiologic investigations (plain x-rays, angiograms), and morphometric analyses of the fibulae in both hindlimbs of five animals were carried out. In a separate group of pigs (n = 6), the fibula was elevated as a vascularized flap and then blood flow was measured using the 15-microns radioactive microsphere technique. The fibula in the pig is supplied by a branch of the cranial tibial artery, running along an intermuscular septum between the posterior and anterior compartments of the hindlimb accompanied by one or two vena commitans. The bone flap is raised with a cuff of flexor hallucis longus with a length of 9.2 +/- 0.2 cm (mean +/- SEM). Blood flow measurement confirmed that the entire fibula was well vascularized when elevated on its pedicle. Gradient blood flow showed a bimodal distribution, with regions of highest blood flow noted at the proximal and distal ends of the bone flap, in areas where there were greater percentages of cancellous bone. The results of these experiments suggest that the pig fibula may be a suitable model for the study of vascularized bone flap pathophysiology. PMID- 8683650 TI - [The excision of branchial parapharyngeal cysts by transbuccal or l cervical approach]. AB - Branchial cysts located in the parapharyngeal space are extremely rare; only seven cases were described in the literature between 1927 and today. In Quebec City, two cases were operated on during the last 3 years. Often, many antibiotic and surgical treatments have been inefficiently used, before getting to the correct diagnosis and final curative treatment. We stress the importance of a detailed evaluation of the lesion and of a noninvasive surgery. Magnetic resonance imaging is the primary imaging modality for parapharyngeal space masses, and surgical excision using the transoral approach is advantageous in selected cases. PMID- 8683651 TI - Development of a standardized proforma for reporting computerized tomographic images of the paranasal sinuses. AB - The complex regional anatomy of the paranasal sinuses has only recently been elucidated through the use of modern imaging techniques. The advent of computerized tomography in the delineation of sinonasal pathology and anatomic variation has proven invaluable to the otolaryngologist in preoperative planning for functional endoscopic sinus surgery (FESS). Frequently, the radiologic reporting schemes for these studies are not standardized, and in many respects have been found to be inadequate. This study attempts to develop a simple reporting proforma that the head and neck radiologist can routinely use in order to facilitate the presentation of CT scan findings in evaluating sinus, nasal, or upper airway pathology. Over 100 CT sinus reports that had previously been reported were re-read according to this reporting scheme and were analyzed in order to determine whether any significant discrepancies existed. These differences were then classified according to their incidental, minor, and major surgical significance. It is hoped that through the development of a standardized proforma, the complementary relationship between preoperative imaging and endoscopic intervention can be consolidated and further enhanced. PMID- 8683652 TI - Post-treatment instructions in the nonsurgical management of benign paroxysmal positional vertigo. AB - Benign paroxysmal positional vertigo (BPPV) is the commonest peripheral vestibular disorder seen in dizziness clinics. It was long believed that the condition was caused by inorganic particles in the cupula of the posterior semicircular canal (PSC). More recently it has been suggested that BPPV may result from free-floating densities in the endolymph of the long arm of the PSC. Among the various treatment modalities used, two maneuvers, each based on a different theory of pathogenesis, have reported equally high success in the control of this disorder. These maneuvers are customarily followed by strict post treatment instructions. We studied patients with BPPV prospectively by comparing the therapeutic effectiveness of these two modalities and studying the importance of post-treatment instructions in affecting the final outcome in each modality. We showed that both maneuvers were equally successful in controlling the symptoms and that post-treatment instructions were not necessary. PMID- 8683653 TI - Imaging and surgery in hyperparathyroidism: a 10-year review. AB - A 10-year review (1984-1994) of patients undergoing surgical treatment for hyperparathyroidism at St. Joseph's Health Centre in London, Ontario, is presented. The role of preoperative localization is discussed. We review our experience with the various imaging modalities and their usefulness in the surgical decision-making process. Our experiences with the surgical management of both primary and secondary hyperparathyroidism are evaluated. Controversies in parathyroid surgery, unilateral versus bilateral neck exploration for parathyroid adenomas, and autotransplantation versus total parathyroidectomy for secondary hyperparathyroidism are discussed and our approach is explained. PMID- 8683654 TI - History of otolaryngology in Canada, McGill University: Part 2. PMID- 8683655 TI - Prospective study of patients' subjective responses to botulinum toxin injection for spasmodic dysphonia. AB - Adductor spasmodic dysphonia (SD) is a speech disorder resulting from involuntary contractions of the laryngeal muscles. Botulinum toxin (BT) injection of the thyroarytenoid muscle is an effective, though temporary, treatment for most SD patients. Though there are reports of objective improvements in voice quality, there are no large studies of patients' subjective responses to treatment over time. In the present study, patients were given voice diaries to rate vocal spasms, hoarseness, breathiness, volume problems, and dysphagia before and the after treatment. Analysis of these diaries revealed that: (1) most side effects had resolved 4 to 6 weeks after injection, whereas vocal spasm relief persisted; (2) vocal spasm relief and severity of side effects peaked within 1 week; and (3) unilateral injections, though as effective in relieving vocal spasms, caused less volume and swallowing problems than did bilateral injections. PMID- 8683656 TI - Functional results in oral cavity reconstruction using reinnervated versus nonreinnervated free fasciocutaneous grafts. AB - Recent advances in free-tissue transfer have given the otolaryngologist--head and neck surgeon a number of reliable options for reconstruction of the oral cavity following ablative procedures. One recent modification has been the transfer of free reinnervated fasciocutaneous grafts in the hope of enhancing oral rehabilitation following surgery. To assess the efficacy of this modification, a protocol was established to retrospectively evaluate patients that received either reinnervated or non-reinnervated free-tissue transfers. Factors including site, surgical resection, type of tissue transfer, and follow-up period were controlled. Evaluation of free-graft sensory return and quality of life was carried out through physical examination and patient interview. Speech assessment was carried out using standardized tests of intelligibility administered by a speech pathologist. Swallowing assessment was carried out with videocinefluoroscopic and scintigraphic techniques, and the oropharyngeal swallow efficiency was calculated. Sensory return in the reinnervate free grafts was superior; however, there was not statistical difference between groups in the speech and swallowing tests. Quality of life was judged to be good in both groups. Sensory return and functional outcome in intraoral reconstruction after tumour ablation was reviewed and discussed PMID- 8683657 TI - Transforming growth factor-beta 1 in a guanidine-extracted demineralized bone matrix carrier rapidly closes a rabbit critical calvarial defect. AB - Transforming growth factor beta 1 (TGF-beta 1) is a polyfunctional regulatory cytokine that has been shown to have roles in extracellular matrix interactions, soft tissue healing, and osteogenesis. Twenty-five microL of recombinant human TGF-beta 1 was added to guanidine-extracted demineralized bone matrix carrier and the implants were used to fill a 14-mm osteoperiosteal critical calvarial defect in New Zealand white rabbit model. The defects were allowed to heal over 4 weeks and the degree of new bone formation was assess by radiodensitometry and undecalcified bone histomorphometry techniques. Implants with TGF-beta 1 showed complete bridging of the gap with new bone in all cases, while the controls showed fibrous tissue repair of the gap with little or no new bone formation. These results demonstrate the ability of TGF-beta 1 to induce new bone in a brief time period in an inactive carrier. PMID- 8683658 TI - Tobacco, alcohol, and oral cancer: the patient's perspective. AB - It is well known that smoking, chewing tobacco, and alcohol play a significant role in the etiology of oral cancer. Although this is common knowledge in the medical community, it appears that patients are not aware of this association. We performed a prospective study on all patients newly diagnosed with oral cancer and a control group without any head and neck cancer. Patients completed a questionnaire assessing their awareness of these causative factors. Other parameters measured as possible influences of patient perception included patient age, sex, smoking status, education level, occupation, and place of residence. Patients were also questioned about their knowledge of the causes of lung cancer to allow for comparison. A total of 134 patients were questioned, with 22 of the patients assigned to the oral cancer group and the second group being comprised of 112 patients without head and neck cancer. Only 20 patients (14.9%) were aware of the causative factors of oral cancer. There was no significant difference in the knowledge of causation when comparing the cancer and control group. The patient age, sex, smoking status, or place of residence did not affect their knowledge of the causes of oral cancer. There was a highly significant difference between patients of different education levels and occupations, with the more educated and higher level occupations being better informed about the causes of oral cancer. In contrast, the majority of patients were aware of smoking as a causative factor in the development of lung cancer. The results from this study demonstrate a serious lack of knowledge in the general population of known causes of oral cancer. The relevant issues are discussed and recommendations are made. PMID- 8683659 TI - Schwann cell differentiation of modified myoepithelial cells within adenoid cystic carcinomas and polymorphous low-grade adenocarcinomas: clinicopathologic assessment of immunohistochemical staining. AB - Adenoid cystic carcinomas and polymorphous low-grade adenocarcinomas have a known propensity for perineural invasion. Although modified myoepithelial cells have been shown to possess characteristics of a variety of cell types, they have not yet been found to mimic nerve tissue. Histologic evidence of Schwann cell differentiation would suggest the pathophysiologic mechanism by which these tumours exhibit neurotropism. An archival study of 41 specimens was performed to evaluate the Schwann cell staining properties of adenoid cystic and polymorphous low-grade adenocarcinomas using antibodies to S-100 protein, GFAP, neuron specific enolase, and using a solochrome stain. Charts were reviewed to assess correlations between immunohistochemical and histochemical staining properties and various clinical parameters. The findings strongly suggest that neuronal differentiation does occur within these tumours. Furthermore, it was determined that solochrome positivity confers a significantly less favourable disease-free interval in these neoplasms. This new finding was highly statistically significant and has potential implications in the determination of prognosis for patients with these tumours. PMID- 8683660 TI - Ultrasonography of hepatic arteries in the portacaval space: celiac versus superior mesenteric artery origin. AB - A hepatic artery coursing within the portacaval space was seen in 30 (18.3%) of 164 consecutive patients in whom this region was seen with ultrasonography. In 12 subjects (40%) this vessel represented the right hepatic artery arising from the proximal celiac artery. In the other 18 subjects (60%) this vessel arose from the superior mesenteric artery. It should not be assumed that a hepatic artery traversing the portacaval space arises from the superior mesenteric artery until its origin is clearly documented. PMID- 8683661 TI - 13 MHz high-frequency sonography of the lateral ankle joint ligaments and the tibiofibular syndesmosis in anatomic specimens. AB - In this study, the ligaments of the ankle joint and the tibiofibular syndesmosis were examined in formalin-fixed anatomic specimens using a 13 MHz sonographic scanner. For this purpose, 48 specimens of the ankle joint were examined, and the anterior tibiofibular, anterior talofibular, and calcaneofibular ligaments were marked by sonographically guided dye injection. The markings were checked during the subsequent dissection. The number of identifications reached 89.6% for the anterior tibiofibular and talofibular ligaments and 87% for the calcaneofibular ligament. The results show that the most frequently injured ligaments of the ankle joint can be visualized reliably by use of 13 MHz high-frequency sonography. PMID- 8683662 TI - Sensitivity and specificity of sonohysterography for the evaluation of the uterine cavity in perimenopausal patients. AB - Sonohysterography is a technique for evaluating the uterine cavity by the instillation of sterile saline solution through an 8 Fr Foley catheter, before performing an ultrasonographic evaluation. The sensitivity and specificity of the procedure were evaluated in comparison to hysteroscopy. In a prospective double blind study, 47 postmenopausal patients were evaluated first by sonohysterography, and within 1 week by hysteroscopy. After comparing the hysteroscopic and sonohysterographic results, sonohysterography showed a sensitivity of 86% and specificity of 100%. Sonohysterography is an accurate mode of diagnosis for pathologic intrauterine processes in perimenopausal patients. PMID- 8683663 TI - Laparoscopic liver sonography: preliminary experience in liver metastases compared with CT portography. AB - This study evaluated the ability of laparoscopic ultrasonography to detect, localize, and characterize focal liver masses. Laparoscopic ultrasonography and CT portography of the liver were performed in 13 patients with known or suspected malignancy. Laparoscopic ultrasonography directly influenced surgical management in four (31%) cases; three by detection of small focal masses and one by exclusion of masses suspected on CT portography. Laparoscopic ultrasonography provided guidance for biopsy or added important anatomic information in three cases. Laparoscopic ultrasonography was complementary to CT portography but added no additional information in three cases, and it failed to provide any information in two cases. Laparoscopic ultrasonography was falsely negative in one case. In this preliminary series, laparoscopic ultrasonography assisted surgeons in critical decision-making by either providing important new information, clarifying questionable areas, or complementing CT portography. PMID- 8683664 TI - Sonographically guided aspiration of ovarian cyst with simple appearance. AB - The objective of this study was to evaluate the role of sonographically guided aspiration of simple ovarian cysts. During the period from 1985 through 1992, 107 ultrasonographically guided punctures of apparently simple ovarian cysts were performed. The group included 76 premenopausal and 31 postmenopausal women who were followed for 1 to 6 years (mean, 2.7 years) after initial cyst puncture. In 42 cases, cyst aspiration constituted the definitive therapy. In 65 cases the cyst recurred and in this group, 38 women (with complete recurrence) were operated on whereas 27 women with a cyst less than 5 cm (incomplete recurrence) were allocated to a follow-up group. Overall, in 69 cases (65%) surgery was avoided. No major complications were encountered. In our experience, aspiration of simple ovarian cysts is a suitable alternative in the management of this problem. Close follow-up is necessary to detect recurrence and perform surgical intervention when indicated. PMID- 8683665 TI - Comparison of umbilical Doppler velocimetry, nonstress testing, and biophysical profile in pregnancies complicated by diabetes. AB - The purpose of this study was to determine which test is best for predicting adverse outcomes in pregnancies complicated by diabetes: the nonstress test, biophysical profile, or umbilical artery velocimetry. We evaluated 207 singleton pregnancies complicated by diabetes within 1 week of delivery using the afore mentioned pregnancy surveillance tests. Adverse pregnancy outcome was defined as delivery before 37 weeks of gestation or the occurrence of fetal growth restriction, hypocalcemia, hypoglycemia, hyperbilirubinemia, respiratory distress syndrome, or fetal risk requiring cesarean delivery. The prognostic value of each of the three tests was assessed, after controlling for the mothers' White classification and third trimester glycosylated hemoglobin value. Among the 207 pregnancies, 75 (36.2%) had an adverse outcome. In pregnancies in which the umbilical artery systolic to diastolic ratio was > or = 3.0, the relative risk of adverse outcome was 2.6 (95% confidence interval: 1.9-3.5, P < 0.001). For those with a biophysical profile < or = 6 the relative risk was 1.7 (95% confidence interval: 0.9-2.9, P = 0.109). Patients with a nonreactive nonstress test had a relative risk of 1.7 (95% confidence interval: 1.2-2.5, P = 0.009). Umbilical artery Doppler velocimetry was superior to either the nonstress test or the biophysical profile in identifying the subgroup of pregnancies complicated by diabetes that resulted in an adverse outcome. PMID- 8683666 TI - Multigate spectral Doppler velocimetry for fast assessment of intraplacental fetal circulation: a preliminary study. AB - The aim of this preliminary study was to investigate the assessment of the intraplacental fetal circulation with a new multigate Doppler system. Doppler velocimetry of the umbilical artery is widely used for assessment of fetal well being, but its sensitivity is too low for prediction and early detection of pathologic placental processes. Intraplacental velocimetry is more accurate and detects pathologic conditions of the placenta earlier. Color Doppler imaging of intraplacental circulations is a difficult process, and the multigate system was developed to enhance the assessment of intraplacental circulation. This study shows that the multigate system is accurate and is a successful means of fast evaluation of the intraplacental circulation. PMID- 8683667 TI - Focal hepatic vein stenoses in diffuse liver disease. AB - To determine the frequency of focal hepatic vein stenosis in diffuse liver disease and to study the relationship of stenosis to abnormal hepatic venous Doppler waveforms, 92 patients being evaluated for liver transplantation or transjugular intrahepatic portosystemic shunt were prospectively studied with color flow and pulsed Doppler sonography for the presence of focal hepatic vein stenoses and waveform abnormalities. Thirty-six patients had no focal stenoses with normal curves, 26 of 38 patients with Bolondi type I curves had focal stenoses, and 10 of 18 patients with damped type II curves had focal stenoses. Damped hepatic venous velocity curves associated with liver disease probably are caused by increased resistance in the hepatic venous circulation produced by focal stenoses. PMID- 8683668 TI - Doppler velocimetry of the fetal middle cerebral and renal arteries: interobserver reliability. AB - Using color and pulsed Doppler ultrasonography, the interobserver reliability of measurements in the fetal circulation was evaluated in 41 pregnancies of 25 to 39 weeks' gestation. Two observers recorded flow velocity waveforms from the middle cerebral and renal arteries for measurement of peak systolic, minimum diastolic, and mean velocities, pulsatility index, and resistive index. Intraclass correlation coefficient of reliability was calculated by analysis of variance. Substantial interobserver agreement was found for pulsatility index and minimum diastolic velocity in both arteries. Therefore, these measurements have the greatest clinical applicability. PMID- 8683669 TI - Acute intestinal ischemia due to occlusion of the superior mesenteric artery: detection with Doppler sonography. AB - The aim of our study was to assess the feasibility of using Doppler sonography for the detection of acute intestinal ischemia due to occlusion of the superior mesenteric artery. Between September 1993 and March 1995, abdominal sonography with Doppler imaging of the mesenteric vessels was performed in 770 patients with emergency admissions for acute abdominal pain. In six cases, the diagnosis, based on surgery or arteriography and computed tomography, was acute intestinal ischemia due to complete or localized occlusion of the superior mesenteric artery. Five cases of occlusion of the superior mesenteric artery were correctly detected by Doppler sonography. These results suggest that Doppler sonography may be a feasible method for detecting acute intestinal ischemia due to proximal superior mesenteric artery occlusion. PMID- 8683670 TI - Congenital left ventricular aneurysm causing hydrops fetalis: prenatal diagnosis with color Doppler ultrasonography. PMID- 8683671 TI - Thoracoabdominal duplication cyst: prenatal and postnatal imaging. PMID- 8683672 TI - Angiomyolipoma: ultrasonographic signs of lipomatous hepatic tumors. PMID- 8683673 TI - Ultrasonographic diagnosis of seminal vesicle cysts in polycystic kidney disease. PMID- 8683674 TI - American Urological Association 91st annual meeting. Orlando, Florida, May 4-9, 1996. Abstracts. PMID- 8683675 TI - This month in investigative urology: Commentary on the replacement of urologic associated mucosa. PMID- 8683676 TI - Protozoan infections in the male genital tract. AB - PURPOSE: We reviewed the literature on protozoan infections in the male genital tract, with special reference to histopathological findings and their repercussions on different andrological functions. MATERIALS AND METHODS: A literature search of the MEDLINE data base from 1966 to May 1995 was done and related articles were identified. The considered terms were parasitology and the male genital organs. Additional searches on infertility, semen and sexually transmitted diseases were performed. RESULTS: Protozoan infections of the male genital tract are rare and only a few species of parasites are involved. Trichomonas vaginalis, Trypanosoma species, Leishmania donovani, Entamoeba histolytica, Acanthamoeba species, Toxoplasma gondii and Plasmodium falciparum have been described in the male genital tract as producing testicular damage or secondary hypogonadism via hypothalamic-hypophyseal axis alterations. CONCLUSIONS: Topics of interest were the role of sexual transmission by some parasites, principally T. vaginalis, relationship with subfertility or infertility in the male subject, clinical significance in differential diagnosis with other inflammatory processes, and for some parasites the relationship with opportunistic behavior and immunodeficiency syndromes, including the acquired immunodeficiency syndrome. PMID- 8683677 TI - A comparison of the free fraction of serum prostate specific antigen in men with benign and cancerous prostates: the best case scenario. AB - PURPOSE: In most previous studies of free-to-total serum prostate specific antigen (PSA) ratios, the specimens from patients with prostate cancer or those with benign prostatic hyperplasia (BPH) have not been highly characterized. We compared preoperative sera from post-radical prostatectomy patients with clinically significant cancers of at least 2 cm.3 to sera from those with BPH and large, biopsy negative prostates. MATERIALS AND METHODS: We used 2 different time resolved immunofluorometric assays for free and total PSA, and a combination of a chemoluminescent immunoassay for free PSA detection with an immunoradiometric assay for total PSA to measure free and total PSA. The serum ratios of free-to total PSA in these assays were compared to those obtained previously from gel filtration studies. Sera from 51 men with prostate cancer volumes of 2 to 18 cm.3 were compared to those from 48 men with BPH and a mean prostate volume of 78 +/- 7 cm.3. The respective mean serum PSA levels plus or minus standard deviation were 10.0 +/- 6.3 and 8.9 +/- 7.2 ng./ml. RESULTS: Monoclonal assays for free PSA confirmed the previous study with gel filtration. For PSA 4 to 10 ng./ml., 94 to 95% of the men with prostate cancer were correctly diagnosed, with a cutoff of less than 15% for free-to-total PSA on immunofluorometric assay and less than 14% for chemoluminescent immunoassay with immunoradiometric assay. However, 46% (immunofluorometric assay) and 36% (chemoluminescent immunoassay and immunoradiometric assay) of men with BPH did not have enough free PSA for diagnosis of BPH (that is 36 to 46% false-positive rate). CONCLUSIONS: For total PSA 4 to 10 ng./ml., the sensitivity of approximately 15% free-to-total PSA for prostate cancer is high (94 to 95%) but 36 to 46% of men with BPH and a large gland will not be correctly identified. For PSA 2 to 4 ng./ml., no ratio of percent free-to-total PSA discriminated BPH from prostate cancer. PMID- 8683678 TI - Bone demineralization following urinary intestinal diversion assessed by urinary pyridinium cross-links and dual energy x-ray absorptiometry. AB - PURPOSE: We investigated the acid-base balance and bone mineral status in patients with 3 types of urinary intestinal diversion. MATERIALS AND METHODS: Of 46 men with urinary intestinal diversions 20 had a Kock pouch, 15 had an Indiana pouch and 11 had an ileal conduit. Acid-base balance was assessed by arterial blood gas analysis. Bone mineral status was measured by urinary pyridinium cross links and dual energy x-ray absorptiometry. In addition, urinary deoxypyridinoline was measured in 79 patients. RESULTS: Of the 46 patients 7 (15%) with the Kock pouch (1), Indiana pouch (5) and ileal conduit (1) had metabolic acidosis associated with significantly lower bone mineral densities (p < 0.05) and higher urinary pyridinium cross-links (p < 0.005) than did those with normal acid-base status. No difference was found in metabolic acidosis and bone demineralization among the 3 groups. Additionally, in 79 patients urinary deoxypyridinoline reached the highest level immediately postoperatively and then gradually decreased to the stable level within 1 or 2 years. CONCLUSIONS: Metabolic acidosis following urinary intestinal diversion results in bone demineralization. The types of diversion did not cause differences in metabolic acidosis and bone resorption. Bone has a major role in buffering acid overload in the early postoperative period. PMID- 8683679 TI - Endoscopic ureteroneocystostomy for complete obstruction at the ureterovesical junction. AB - PURPOSE: We evaluated the technical and long-term success of endoscopic ureteroneocystostomy in patients with complete obstruction of the distal ureter. MATERIALS AND METHODS: We treated 7 patients with complete obstruction at the ureterovesical junction via a combined antegrade and retrograde endoscopic approach (endoscopic ureteroneocystostomy). The etiology of obstruction included ureteroscopy for ureteral calculi in 3 patients and previous resection of bladder tumors or the prostate in 4. Six patients had proximal drainage with a percutaneous nephrostomy catheter at referral. An antegrade approach was used for localization, and a retrograde approach was used for direct visual ureteral meatotomy or ureterotomy with the endoscopic scissors or a cold-knife urethrotome. RESULTS: Continuity at the ureterovesical junction was restored in all 7 patients, and 6 are currently stricture-free with followup of 14 to 64 months. The sole failure in this series was due to recurrent invasive transitional cell carcinoma. CONCLUSIONS: Endoscopic ureteroneocystostomy is a safe and effective treatment of complete obstruction of the ureterovesical junction. PMID- 8683680 TI - Use of a new tumor marker, urinary NMP22, in the detection of occult or rapidly recurring transitional cell carcinoma of the urinary tract following surgical treatment. AB - PURPOSE: We evaluated the ability of an immunoassay for nuclear matrix protein 22 (NMP22 test kit) to predict the subsequent disease status of patients with transitional cell carcinoma of the urinary tract at approximately 10 days after transurethral resection of bladder tumor. MATERIALS AND METHODS: A total of 90 patients with transitional cell carcinoma provided voided urine samples at least 5 days postoperatively. NMP22 was determined using a commercial test kit. At initial cystoscopic examination 3 to 6 months later the disease status was recorded, and the NMP22 values before and after transurethral resection of bladder tumor were compared. RESULTS: Of 125 followup cystoscopic examinations (60 patients had 1, 26 had 2, 3 had 3 and 1 had 4 recurrences) transitional cell carcinoma was pathologically confirmed in 33. No malignancy was present at 79 examinations (if tumor was seen endoscopically, pathological evaluation indicated atypia, dysplasia or no abnormality). NMP22 values in these 2 populations were significantly different (malignancy median 20.81 units per ml. and no malignancy median 5.72 units per ml., Mann-Whitney U test for differences between 2 medians p = 0.00005). Of the 33 recurrences 23 (70%) had NMP22 values greater than the reference range (10 units per ml.). Additionally, NMP22 identified all 6 subjects (100%) who had invasive disease 3 to 6 months later. Of 72 patients with NMP22 less than 10 units per ml. 62 (86%) had no malignancy at subsequent cystoscopy. CONCLUSIONS: NMP22 was highly predictive of tumor status at followup cystoscopy. This quantitative, noninvasive assay, with high negative predictive value (86%) and sensitivity to detect malignancy (100% for invasive disease and 70% overall), may be a helpful adjunct to cytology and endoscopy for monitoring disease status after endoscopic tumor resection. PMID- 8683681 TI - Methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy and cystectomy for unresectable bladder cancer. AB - PURPOSE: We combined chemotherapy and surgery to improve local control and survival of patients with unresectable bladder cancer. MATERIALS AND METHODS: A total of 41 patients with unresectable bladder cancer (T4bNX/N + M0) received methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) chemotherapy followed by radical cystectomy when possible. End points were response to M-VAC, local control and survival. RESULTS: Minimum followup was 4 years (range 4 to 7). Of the 41 patients 14 (34%) achieved a complete (T0) and 27 (66%) achieved an incomplete (T+) clinical response to M-VAC, including 29 who underwent exploration and 24 who underwent cystectomy. Definitive surgery was not done in 17 patients due to lack of response to M-VAC with local or systemic tumor progression, or refusal. Nine patients (22%) are alive, including all but 1 after cystectomy for T0 disease, and 2 had T+ tumor confined to the bladder for longer than 5 years. None of the patients with no response or tumor progression on M-VAC survived. Resection of extravesical disease after M-VAC in 16 patients did not prolong survival or improve local tumor control. Six patients required laparotomy for palliation of tumor related complications. CONCLUSIONS: Our results suggest that patients who present with unresectable bladder cancer may benefit from M-VAC and definitive surgery, especially when disease is T0 and P0 status. Surgery may salvage select cases of advanced pelvic tumor down staged by chemotherapy to tumors pathologically confined to the bladder. Alternative treatment strategies are needed for the majority of patients with locally advanced bladder cancer. PMID- 8683682 TI - A randomized prospective study comparing long-term intravesical instillations of mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. AB - PURPOSE: We compared the efficacy and toxicity of long-term mitomycin C versus bacillus Calmette-Guerin (BCG) instillation in patients at high risk for recurrence and progression of superficial bladder carcinoma. MATERIALS AND METHODS: Our randomized comparison study included 261 patients with primary dysplasia, or stage Tis, stage T1, grade 3 and multiple recurrent stage Ta/T1, grade 1 or 2 disease. Mitomycin C (40 mg.) or Pasteur strain BCG (120 mg.) was instilled weekly for 6 weeks, then monthly for up to 1 year and every 3 months during year 2. RESULTS: After a median followup of 39 months 49% of the patients given BCG and 34% given mitomycin C were disease-free (p < 0.03), compared to 48 and 35%, respectively, of those with stage Ta or T1 disease, and 54 and 33%, respectively, of those with dysplasia or stage Tis tumor. Tumor progressed in 13% of patients, with no statistically significant difference observed regarding progression between the mitomycin C and BCG groups. Side effects were more common after BCG instillation, with 5 cases of severe side effects compared to 1 in the mitomycin C group. Treatment was stopped due to toxicity in 10% of the patients. CONCLUSIONS: The majority of patients tolerated long-term intravesical therapy well. BCG instillation was hampered by more frequent side effects. BCG was superior regarding recurrence prophylaxis, since patients given BCG had fewer recurrences and a significantly longer time to treatment failure compared to those treated with mitomycin C. No statistically significant difference was observed regarding progression. PMID- 8683683 TI - Endourological treatment of upper tract urothelial carcinomas: analysis of a series of 59 tumors. AB - PURPOSE: We analyzed a series of 59 reno-ureteral units with upper tract urothelial carcinoma treated endourologically at our institution. MATERIALS AND METHODS: Between January 1980 and January 1995, 54 of 185 patients with a clinically diagnosed upper tract tumor were considered candidates for endourological treatment. Of the patients 14 had either bilateral disease or a solitary kidney. The primary approach was ureteroscopy in 39 reno-ureteral units and percutaneous nephroscopy in 20. Superficial stage pTa, T1 or Tis disease was noted in 48 cases, infiltrating stage pT2 cancer in 4 and inverted papilloma in 4, while the tumor was impossible to classify in 3. A total of 32 patients received adjuvant supplemental therapy. RESULTS: Ureteroscopy failed in 11 cases (28.2%), with salvage by nephroureterectomy in 6 and percutaneous nephroscopy in 5. Primary nephroscopy failed in 3 cases (15%) that were salvaged by open surgery. Two patients died of unrelated causes postoperatively and 14 (26%) had intraoperative or late complications that were treated conservatively in 12. After a mean followup of 30.6 months (range 2 to 119), 2 patients died of progressive upper tract tumor, 2 died of concurrent bladder cancer and 2 died of a second cancer. Of 42 upper tracts treated solely by endourological means 10 (23.8%) had recurrences, which were treated endourologically in 6. Bacillus Calmette-Guerin and mitomycin C seemed to be effective at preventing recurrences, with recurrence rates of 12.5 and 14.2%, respectively, compared to 60% for thiotepa, and 40% for oral combination 5-fluorouracil and uracil. CONCLUSIONS: Endourological treatment of low grade, small, noninvasive tumors of the upper urinary tract is a feasible and safe alternative even in patients with a normal contralateral kidney. PMID- 8683684 TI - Fever following intracavitary bacillus Calmette-Guerin therapy for upper tract transitional cell carcinoma. AB - PURPOSE: We attempted to identify the source of fever during intracavitary upper tract instillation of bacillus Calmette-Guerin (BCG). MATERIALS AND METHODS: Of 34 patients who had previously undergone percutaneous resection of upper tract transitional cell carcinoma 18 received weekly intracavitary BCG through the nephrostomy tubes for 6 consecutive weeks. After treatment 6 all patients underwent nephroscopy and biopsy, and all cases were retrospectively reviewed. Parameters analyzed were BCG related symptoms, maximum temperature during treatment, maximum renal pelvic pressure during treatment, culture results, chest x-ray findings, pretreatment serum creatinine concentration, serum liver enzyme values, untoward events and treatments performed for BCG related complications. RESULTS: No obvious pattern in appearance of fever occurred. During 88 treatment episodes evaluated there were 14 temperature elevations to more than 100F in 7 patients (39%). Positive urine cultures were associated with fever in only 4 cases and none was positive for Mycobacterium. There was no correlation between greater renal pelvic pressures and fever. All chest radiographs and serum creatinine levels were unchanged, and liver enzymes were normal in all but 1 patient. Two patients had prolonged fever with elevations to greater than 104F following treatment: 1 died in a motor vehicle accident and 1 died after the third BCG infusion led to overwhelming sepsis. No source of fever was identified in either patient. CONCLUSIONS: Patients with low grade fever coincident with upper tract BCG may be treated conservatively simply by withholding the infusion. Fever greater than 103F should be considered an emergency condition with high potential for mortality. Immediate and aggressive attempts at identifying a source along with institution of antituberculous therapy are priorities. PMID- 8683685 TI - Transitional cell carcinoma. PMID- 8683686 TI - Penile thermal sensation. AB - PURPOSE: To our knowledge no direct measurement of autonomic failure in the penis is currently available. Indirect techniques in clinical use, such as bulbocavernosus reflex, genital somatosensory evoked potentials and biothesiometry, all rely on large nerve fiber function. Since micturition and potency depend on small fibers of the peripheral system, tests of these fibers might be more relevant in the clinical diagnostic evaluation. We provide upper normal limits and demonstrate repeatability of small fiber mediated sensations of warm and cold sensory thresholds on penile skin. MATERIALS AND METHODS: Penile warm and cold sensory thresholds were measured in 35 healthy volunteers (at 2 sessions in 27) via 2 methods. RESULTS: Upper normal values, expressed as 95% confidence limits for warm and cold thresholds, through methods of limits and levels as well as inter-session repeatability are given. CONCLUSIONS: Penile thermal thresholds are repeatable and can be used as a valid diagnostic tool to assess somatic small fiber function in patients with lower urinary tract disorders. PMID- 8683687 TI - Treatment of penile fibrosis with prosthetic implantation and flap advancement with tissue debulking. AB - PURPOSE: Even after successful penile prosthesis implantation in patients with extensive penile fibrosis, a subset will have insufficient penile length for satisfactory sexual intercourse. We report a combined surgical approach to gain additional functional length in these patients. MATERIALS AND METHODS: During the last 18 months 11 patients with extensive cavernous fibrosis underwent penile prosthesis implantation with a modified suprapubic V-Y advancement flap and lower abdominal tissue debulking. RESULTS: After prosthesis implantation the accompanying procedures allowed these patients to gain an additional 3.5 to 6.5 cm. in functional length. All patients had a functional device after a mean followup of 12 months. No prosthesis became infected and no patient required an additional flap procedure. CONCLUSIONS: This surgical approach allows patients to gain additional functional length for satisfactory intercourse after treatment of extensive penile fibrosis. PMID- 8683688 TI - Penile curvatures and aneurysmal defects with the Ultrex penile prosthesis corrected with insertion of the AMS700CX. AB - PURPOSE: We reviewed our series of patients with an AMS700 Ultrex penile prosthesis whose erectile deformities were corrected by replacement with AMS700CX cylinders. MATERIALS AND METHODS: Ultrex cylinders were replaced by AMS700CX cylinders in 7 men with erectile deformities. RESULTS: Deformities were corrected successfully in all 7 patients. The penis is completely straight in 6 patients, while a mild 30-degree ventral curvature is present in 1. CONCLUSIONS: Erectile deformities with the AMS700 Ultrex penile prosthesis can be repaired successfully by replacement with the AMS700CX cylinders. PMID- 8683689 TI - Risk factors for penile prosthetic infection. AB - PURPOSE: We determined the risk factors for penile prosthesis infections. MATERIALS AND METHODS: The records of 156 men undergoing 167 procedures for insertion of a penile prosthesis were reviewed. The device was implanted during a primary uncomplicated procedure in 114 cases. Simultaneous penile reconstruction was performed in 23 cases. A malfunctioning penile prosthesis was replaced or repaired immediately following removal in 30 cases. Minimum followup was 1 year. RESULTS: The infection rate was 1.8% after insertion of a penile prosthesis in 114 men without previous penile surgery compared to 21.7% for procedures requiring reconstruction of the corpora, which was significantly different (p < 0.01). The infection rate after revision of a penile prosthesis was 13.3%, which was significantly greater than that following primary uncomplicated implantation (p < 0.05) but not different from that for patients requiring reconstruction (p = 0.5). There was no difference in patient age, etiology of impotence or associated medical disorders among the 3 groups. Operative time was significantly longer for patients requiring penile reconstruction than for the other 2 groups (p < 0.01). CONCLUSIONS: The risk of infection is significantly greater when penile reconstruction is required, and appears to be related to increased duration of surgery. The increased risk of infection associated with revision of a penile prosthesis cannot be explained by patient characteristics or operative time. PMID- 8683690 TI - Endocrine screening for sexual dysfunction using free testosterone determinations. AB - PURPOSE: Controversy exists concerning the need for routine endocrine screening in impotent men. Debate also continues as to what hormonal studies are necessary, the role of the free fraction of testosterone and whether a history of decreased libido or testicular atrophy can predict these endocrinopathies. MATERIALS AND METHODS: We reviewed 508 consecutive men who presented with sexual dysfunction within a 22-month period. Testosterone data were available for 268 patients (53%) and prolactin data were available for 170 (33%). RESULTS: Hypogonadism, defined as 2 abnormal total testosterone levels, was found in 42 of our 268 patients (15.6%). A history of decreased libido by patient questionnaire and/or testicular atrophy on physical examination could not predict these cases. A normal free fraction of testosterone saved further unnecessary endocrine evaluation in 50% of patients with hypogonadism. Hypoprolactinemia was noted in 3 of 170 patients (1.8%). CONCLUSIONS: Routine endocrine screening remains a necessary part of the evaluation for sexual dysfunction. A history of decreased libido and/or testicular atrophy on physical examination cannot predict hypogonadism. Measurement of free fraction of testosterone will further lessen unnecessary endocrine evaluations by 50% and should become standard practice in screening for hypogonadism. Prolactin levels are necessary only in patients with hypogonadism and/or a history of decreased libido. PMID- 8683691 TI - Ultrasonographic evidence of abnormal lymphatic vessels in young men with adult Wuchereria bancrofti infection in the scrotal area. AB - PURPOSE: We determined the prevalence and magnitude of dilatation of the lymphatic vessels of the spermatic cord in men infected with Wuchereria bancrofti, which is known major cause of hydrocele in the tropics. MATERIALS AND METHODS: Scrotal ultrasound was performed with a 7.5 MHz, transducer in 78 men from Recife, Brazil (endemic for filariasis) and in 15 from a nonendemic area. RESULTS: Among men from Recife the lymphatic vessels were dilated (1.3 to 15.0 mm., mean 3.8) at the location of the adult worm. Vessel diameter was not associated with hydrocele. CONCLUSIONS: Lymphatic dilation was observed in all men with ultrasonographically detectable W. bancrofti infection, even those who were asymptomatic. PMID- 8683692 TI - Transurethral needle ablation of the prostate: report of initial United States clinical trial. AB - PURPOSE: We studied the efficacy and safety of transurethral needle ablation of the prostate for treatment of symptomatic benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A total of 12 patients with symptomatic BPH underwent transurethral needle ablation of the prostate. Voiding outcomes, including American Urological Association symptom scores, bother scores, bother scores, quality of life scores, peak urinary flow rates, residual urine volumes and urodynamic pressure flows, were measured with time, and immediate and short-term (6 months) complications were assessed. RESULTS: Transurethral needle ablation of the prostate was performed with local intraurethral lidocaine anesthesia in 11 patients and general anesthesia in 1. At 6 months there was a 61.7% improvement in American Urological Association symptom score (25.6 to 9.8, p = 0.0001), 61.1% improvement in bother score (18.8 to 7.3, p = 0.0002), 70.0% improvement in quality of life score (13.7 to 4.1, p = 0.0001), 73.0% increase in peak flow rate (7.8 to 13.5 cc per second, p < 0.0001) and 54.9% decrease in the post-void residual (111 to 50 cc, p = 0.0457). Prostate volumes, maximum detrusor pressures and detrusor opening pressures decreased significantly. There were no intraoperative complications. Postoperatively, all 12 patients had mild dysuria for 1 to 7 days, 5 had transient urinary retention for 1 to 4 days, 3 had hematuria for 1 to 2 days and 1 had retrograde ejaculation. CONCLUSIONS. This initial United States trial confirms previous experience, and shows that transurethral needle ablation of the prostate appears to be a simple, safe and efficacious procedure for treatment of symptomatic BPH. In addition, it can be performed in the majority of patients using topical urethral anesthesia. PMID- 8683693 TI - Laser treatment of the prostate using the Urolase fiber: the Dutch experience. AB - PURPOSE: Subjective and objective results were assessed after laser prostatectomy with the Urolase fiber at 5 different centers in The Netherlands. MATERIALS AND METHODS: Patients were evaluated with the international prostatic symptom score questionnaire, uroflowmetry and post-void residual volume measurements. Urodynamic investigations with pressure-flow analysis were performed at 2 centers. RESULTS: Data for 233 patients were evaluated. Overall significant improvement in mean international prostatic symptom score, maximum flow, post void residual and urodynamic parameters was noted. Differences in outcome among the centers may be due to variation of technique or different selection criteria. Postoperative morbidity was significant, with irritative voiding complaints for 4 to 6 weeks in up to 50% of all patients and urinary tract infections in 21.1%. CONCLUSIONS: Laser prostatectomy results in subjective and objective improvement, which is operator independent. Despite the observation that perioperative (intraoperative and immediate postoperative) morbidity seems less severe compared to transurethral resection of the prostate, there is a shift toward greater postoperative morbidity. PMID- 8683694 TI - Benign prostatic hyperplasia--are we too "hot" on new therapies? PMID- 8683695 TI - Prostate specific antigen density versus prostate specific antigen slope as predictors of prostate cancer in men with initially negative prostatic biopsies. AB - PURPOSE: We determined if prostate specific antigen (PSA) density and PSA slope alone or in combination could be used to predict which men with persistently elevated serum PSA and prior negative prostate biopsies will have prostate cancer on repeat evaluation. MATERIALS AND METHODS: In our PSA-1 data base we identified 327 men 50 years old or older with an initially negative prostate biopsy who had persistent PSA elevation, and compared those who did and did not have prostate cancer on subsequent serial prostatic biopsy. RESULTS: Of 70 men with a PSA density of 0.15 or more and PSA slope of 0.75 ng./ml. or more annually compared to 83 with a PSA density of less than 0.15 and PSA slope of less than 0.75 ng./ml. annually 32 (46%) and only 11 (13%), respectively, had prostate cancer on subsequent prostate biopsies (p < 0.0001). In a hierarchical logistic regression analysis PSA density and PSA slope were predictive of prostate cancer on subsequent biopsy (p = 0.001 and 0.03, respectively). PSA density of 0.15 or more alone or PSA slope of 0.75 ng./ml. or more annually alone as the indicator for repeat biopsy would have missed 35 and 40% of cancers, respectively. CONCLUSIONS: In men with persistently elevated serum PSA after an initially negative prostate biopsy, PSA density and PSA slope alone or in combination provide useful predictive information about the results of repeat prostate biopsies. However, these parameters are not sufficiently sensitive to identify all patients with detectable prostate cancer. PMID- 8683696 TI - Comparative analysis of prostate specific antigen and its indexes in the detection of prostate cancer. AB - PURPOSE: Prostate specific antigen (PSA) density and age referenced PSA have been proposed in an attempt to improve the power of PSA in the detection of early prostate cancer. Reported results have been controversial and disappointing. Because the association of gland volume with PSA is stronger than that of age we developed a new index, volume referenced PSA, and compared it to PSA density and other indexes. MATERIALS AND METHODS: Volume referenced PSA was developed from a control group of 408 men without clinical evidence of prostate cancer using a standardized Z score. A retrospective analysis was performed comparing PSA and all its indexes in 580 men who underwent prostate biopsy. In addition to overall analysis, PSA and its indexes were evaluated with receiver operating characteristic curves by age and volume subcategories. RESULTS: Cancer was identified in 35% of the 580 men. The number of missed cancers using established thresholds significantly favored volume referenced PSA clinically and statistically compared to all other indexes but it was equivalent to PSA alone clinically. Age referenced PSA prevented more biopsies from being done than did volume referenced PSA (39% versus 31%) but resulted in the diagnosis of 48% fewer cancers. Receiver operating characteristic curve analysis demonstrated a significantly better performance for volume referenced PSA and PSA density compared to PSA alone and age referenced PSA. CONCLUSIONS: Volume based PSA indexes are superior to PSA and age referenced PSA statistically. However, clinically volume referenced PSA is comparable to PSA, and both are superior to age referenced PSA and PSA density in the detection of prostate cancer. PMID- 8683697 TI - The effect of exogenous testosterone on total and free prostate specific antigen levels in healthy young men. AB - PURPOSE: We evaluated the effect of exogenous testosterone administration on serum total and free prostate specific antigen (PSA) in healthy young men. MATERIALS AND METHODS: Nine volunteers received either 100, 250 or 500 mg. testosterone by intramuscular injection each week for 15 weeks. Blood was drawn every other week for 28 weeks and at week 40. Serum total and free PSA, and total and free testosterone were measured and compared to baseline values. RESULTS: Significant elevations in total and free testosterone occurred but no significant change in serum total and free PSA was detected. CONCLUSIONS: Serum PSA is not responsive to elevated serum testosterone levels in healthy young men. PSA metabolism in the normal prostate is unclear but our findings may have implications for differentiation of pathological conditions of the human prostate. PMID- 8683698 TI - Can prostate specific antigen derivatives reduce the frequency of unnecessary prostate biopsies? PMID- 8683699 TI - Radical prostatectomy with preservation of urinary continence. AB - PURPOSE: In an effort to improve postoperative urinary continence after radical retropubic prostatectomy, a new operation to preserve the bladder neck and a significant portion of the prostatic urethra has been developed. MATERIALS AND METHODS: The prostatic urethra is dissected in continuity with the bladder away from the lumen of the prostate, which allows for a true urethra-to-urethra anastomosis. RESULTS: A total of 24 patients who underwent the new continence sparing radical retropubic prostatectomy was compared retrospectively to 80 who previously underwent a nerve sparing procedure. Total continence was noted immediately in 11 patients, within 9 days in 15 and within 7 weeks in 21 of 24 who underwent the new operation, compared to 1, 5 and 33, respectively, of 80 who underwent the standard operation. Microscopic positive margins were noted in 2 of 24 patients with the new continence sparing operation. Early results of cancer control were good. CONCLUSIONS: Early followup of this new technique of radical retropubic prostatectomy suggest that preservation of the continence mechanism at the level of the bladder neck and prostatic urethra results in significantly improved postoperative urinary continence without adversely affecting cancer control. PMID- 8683700 TI - Prostate specific antigen nadir following external beam radiation therapy for clinically localized prostate cancer: the relationship between nadir level and disease-free survival. AB - PURPOSE: We determined whether the prostate specific antigen (PSA) nadir achieved following external beam radiation therapy alone predicts biochemical disease-free survival in a large cohort of men with clinically localized prostate cancer. MATERIALS AND METHODS: Between January 1986 and October 1993, 364 men with clinically localized, stages T1 to T3 adenocarcinoma of the prostate received definitive external beam radiation therapy with no prior, concomitant or adjuvant endocrine therapy. PSA was measured before treatment in 326 men (90%) and serial PSA was measured following treatment in all patients. All men were followed continuously for at least 24 months (median 44 months, range 24 to 90, mean 46). Biochemical failure after irradiation was defined as PSA of 1.5 ng./ml. or more and 2 consecutive serum PSA elevations. RESULTS: The 5-year overall biochemical disease-free survival rate for the entire group was 56%. PSA nadir was predictive of subsequent biochemical disease-free survival. The biochemical disease-free survival rate at 3 years was 93, 49 and 16% for PSA nadirs of 0 to 0.99, 1 to 1.99 and 2 or more ng./ml., respectively (p = 0.0001). In a multivariate analysis PSA nadir (0 to 0.99 versus 1.0 to 1.99 versus 2 or more ng./ml.) was an independent predictor of biochemical disease-free survival along with pretreatment PSA, central axis dose, Gleason grade and T stage. CONCLUSIONS: PSA nadir after radiation therapy is an indicator of subsequent biochemical disease free survival. Patients who achieve a nadir of less than 1 ng./ml. following external beam radiation therapy have a favorable biochemical disease-free survival rate, while those with a nadir of greater than 1 ng./ml. have a high subsequent failure rate. Strategies to improve results should focus on techniques to increase the likelihood of achieving a PSA nadir of less than 1 ng./ml. PMID- 8683701 TI - Extended followup of the influence of wide excision of the neurovascular bundle(s) on prognosis in men with clinically localized prostate cancer and extensive capsular perforation. AB - PURPOSE: The effect of wide excision of the neurovascular bundles on disease-free survival was determined in men with clinically localized prostate cancer and pathological evidence of extensive capsular perforation in the region of the neurovascular bundle. MATERIALS AND METHODS: We previously analyzed 107 men with clinically localized prostate cancer and pathological evidence of extensive capsular perforation in the region of the neurovascular bundles. Wide excision of the neurovascular bundle on the sides of palpable induration resulted in negative surgical margins in 58% of patients compared to only 45% in whom the neurovascular bundles were left intact (p = 0.03). At a mean followup of 20 months, median interval to disease recurrence as defined by a measurable PSA level was 33 months in patients whose neurovascular bundle(s) were widely excised versus 22 months in those whose neurovascular bundle(s) were left intact (p = 0.03). However, by 43 months 75% of the patients in both groups had a detectable prostate specific antigen and the Kaplan-Meier curves had converged, suggesting that wide excision of the neurovascular bundle(s) did not confer a sustained survival advantage. RESULTS: With an additional followup of 28 months, the probability of having an undetectable prostate specific antigen level at 5 years was 47% in patients with negative versus 6% with positive surgical margins (p < 0.001). CONCLUSIONS: Our extended followup suggests that some patients with extensive capsular perforation can be rendered free of disease with wide excision of the neurovascular bundle(s). PMID- 8683702 TI - Prostate cancer. PMID- 8683703 TI - Repeat biopsy strategy in men with isolated prostatic intraepithelial neoplasia on prostate needle biopsy. AB - PURPOSE: Isolated high grade prostatic intraepithelial neoplasia on needle biopsy of the prostate is a strong predictor of malignancy on repeat biopsy. However, the optimal repeat biopsy technique for these patients has not been defined. MATERIALS AND METHODS: We reviewed the records of 66 men in whom isolated prostatic intraepithelial neoplasia was found on needle biopsy of the prostate. We evaluated the side and/or quadrant and grade of prostatic intraepithelial neoplasia on initial biopsy, and compared the findings to the location of cancer on repeat biopsy. RESULTS: Of 66 men 31 (47%) had cancer on repeat biopsy, with disease on the same side of the prostate as prostatic intraepithelial neoplasia in 20 (64%). The quadrant locations of prostatic intraepithelial neoplasia and cancer matched in 6 of 12 cases (50%). Low and high grade prostatic intraepithelial neoplasia predicted the side of cancer on repeat biopsy in 3 of 5 (60%) and 17 of 26 (65%) cases, respectively. CONCLUSIONS: Directing repeat biopsy solely to the side with prostatic intraepithelial neoplasia will miss cancer in approximately 35% of cases. The optimal repeat biopsy technique for patients with high grade prostatic intraepithelial neoplasia should include systematic biopsy of the prostate. PMID- 8683704 TI - Detection of prostate specific antigen in pancreas and salivary glands: a potential impact on prostate cancer overestimation. AB - PURPOSE: We explored the immunohistochemical expression of prostate specific antigen (PSA) in pancreas and salivary glands. MATERIALS AND METHODS: We investigated 62 specimens from male and female subjects, representing normal cases and several pathological conditions of pancreas and salivary glands. Two commercially available monoclonal antisera for PSA and 1 for prostatic acid phosphatase were used. RESULTS: A consistently positive reaction for PSA and prostatic acid phosphatase, independent of patient sex, was noted in ductal cells of normal pancreas and normal salivary glands, as well as pleomorphic adenoma, adenocarcinoma and all oncocytic epithelial cells of Warthin's tumor. Reaction was absent in normal stromal and acinar cells, and squamous carcinoma. CONCLUSIONS: PSA is detectable in normal and cancer tissues far from the prostate. Therefore, we may not entirely rely on specificity of PSA alone to diagnose metastatic prostate cancer. PMID- 8683705 TI - Complications of urological laparoscopy: a standardized 1 institution experience. AB - PURPOSE: Urological laparoscopy has a significant and steep learning curve plus its own unique set of complications. Our retrospective study documents the success at 1 institution of maintaining a low number of complications during urological laparoscopy using a standardized approach plus clinicians with significant laparoscopic experience. MATERIALS AND METHODS: We evaluated 282 consecutive adults who underwent urological laparoscopic procedures at our institution. Of the procedures 241 (85%) were performed for pelvic lymph node dissection, and 41 (15%) for renal and other miscellaneous conditions. The common factor in all of these laparoscopic procedures was a single team approach, thus standardization for the entire series of procedures. RESULTS: Of 12 complications (4.2%) 5 were noted intraoperatively and 7 were discovered in the postoperative period. Five patients (1.8%) required open surgical intervention, including 3 intraoperative repairs of vascular (1), ureteral (1) and bladder (1) injuries. Procedures were aborted because of technical difficulties in 7 patients (2.8%) and because of hemorrhage during adrenalectomy in 1. Delayed complications included ureteral injury in 1 patient, seroma at the trocar site in 2, exacerbation of bowel diverticulitis requiring surgical intervention in 1, prolonged endotracheal intubation for hypercapnia in 1 and transient brachial nerve palsy in 2. CONCLUSIONS: Along with appropriate patient selection and adequate instrumentation, the benefit of significant laparoscopic experience and standardization cannot be overemphasized. The success of this combined approach is reflected in the low rate of major (2%) and minor (2.5%) complications experienced at 1 institution. PMID- 8683706 TI - Neodymium:YAG laser removal of stone formed on nonabsorbable suture used previously in colposuspension. PMID- 8683707 TI - Evaluation of detrusor activity during micturition in patients with benign prostatic enlargement with a clinical nomogram. AB - PURPOSE: We investigated the accuracy of analysis of detrusor contraction during micturition with a simple to use pressure-flow nomogram (linear passive urethral resistance relation). The computer derived maximum detrusor contraction parameter was used as a reference. The correlation with bladder emptying capability was used as a control. MATERIALS AND METHODS: Advanced pressure-flow analysis was performed in 224 elderly men with lower urinary tract symptoms. RESULTS: All patients with a contraction classified as normal on the nomogram had good maximum detrusor contractions. However, 50% of the patients with a weak classification on the nomogram showed good maximum detrusor contractions. CONCLUSIONS: The nomogram is useful in the selection of patients with a good detrusor contraction. PMID- 8683708 TI - Re: Psoas abscess: case report and review of the literature. PMID- 8683709 TI - Re: Nephron sparing surgery for renal cell carcinoma in von Hippel-Lindau disease. PMID- 8683710 TI - Re: Continuous epidural anesthesia after ureteroneocystostomy in children. PMID- 8683711 TI - Re: Continuous epidural anesthesia after ureteroneocystostomy in children. PMID- 8683712 TI - Re: Biofeedback for the treatment of stress and urge incontinence. PMID- 8683713 TI - Re: Intracorporeal phenylephrine in the treatment of priapism. PMID- 8683714 TI - Re: Testicular seminoma: clinical significance of nuclear deoxyribonucleic acid ploidy pattern as studied by flow cytometry. PMID- 8683715 TI - Re: Editorial: the central role of prostate specific antigen in diagnosis and progression of prostate cancer. PMID- 8683716 TI - Re: The clinical implications of procedural deviations during orchiectomy for nonseminomatous testis cancer. PMID- 8683717 TI - Re: Cutaneous metastasis following laparoscopic pelvic lymphadenectomy for prostatic carcinoma. PMID- 8683718 TI - Re: Continuous versus intermittent bladder irrigation of amphotericin B for the treatment of candiduria. PMID- 8683719 TI - Re: Should renal ultrasound be performed in the patient with microscopic hematuria and a normal excretory urogram? PMID- 8683720 TI - Re: Should renal ultrasound be performed in the patient with microscopic hematuria and a normal excretory urogram? PMID- 8683721 TI - Re: Snail-headed catheter retriever: a simple way to remove catheters from female patients. PMID- 8683722 TI - Pediatric urology manpower report 1995. Ellen Shapiro on behalf of the American Association of Pediatric Urologists. AB - PURPOSE: The quality and efficiency of any health care system depend on an appropriate level of manpower. The manpower issues of tomorrow will be influenced by the number of physicians and specialists trained today. The objectives of this manpower survey of pediatric urologists in the United States were to determine anticipated manpower requirements and provide caveats related to the practice of pediatric urology. MATERIALS AND METHODS: A manpower questionnaire was distributed to pediatric urologists at the American Urological Association meeting in Las Vegas, Nevada in April 1995. Of the 234 distributed questionnaires 204 (87%) were completed and entered into a computer program. RESULTS: Of responding pediatric urologists 70% were younger than 50 years, 81% practiced full-time pediatric urology and 45% were university based. The rates of respondents indicating that their present workload was too busy, appropriate or not busy enough were 10, 70 and 20%, respectively. A total of 71% of respondents indicated that they would discourage a newly trained individual from setting up a practice in their area. Of practicing pediatric urologists 26% intended to retire within the next 10 years. In April 1995, 80 respondents (39%) representing 67 practices were considering adding an associate within the next 10 years. By the end of 1995 only 56 practices will remain that will add an associate within the next 10 years. A total of 82% of respondents believed that there was an excess number of pediatric urology training programs. CONCLUSIONS: The pediatric urology community presently trains 10 to 15 pediatric fellows per year. Based on the 1995 manpower survey, if this trend continues an excess of 40 to 90 pediatric urologists will be trained in the next 10 years. The conclusion that there is an overabundance of pediatric urologists in training is supported by the general consensus of practicing pediatric urologists. Policies related to the training of pediatric urology fellows and urology residents should depend, not on the manpower needs at individual medical centers, but on the collective needs of our specialty and the patients whom we serve. PMID- 8683723 TI - Too much of a good thing?-Part II. PMID- 8683724 TI - Total replacement of urethral mucosa with oral mucosa in dogs. AB - PURPOSE: If the urethral mucosa is replaced by another mucosa, urethral recurrence might decrease in patients who undergo neobladder construction for bladder cancer. We determined whether such replacement is possible. MATERIALS AND METHODS: Six dogs underwent an operation consisting of a longitudinal urethral incision at its full length and immediate closure. In 6 other dogs, after the urethral mucosa was totally removed, a tubularized sublingual mucosa was closely set inside the urethral lumen. Postoperatively, the urinary stream and external meatus were observed every day. To measure urine leakage, a 10-minute pad test was performed once a month. All dogs were sacrificed 3 to 12 weeks after the operation for histological examination of the urethra. The excised urethras were examined with a 12F catheter for urethral patency. RESULTS: All dogs were continent postoperatively. The results of the 10-minute pad test showed no significant difference in the weight increase of the pad among the control, sham operated and mucosa-replaced dogs. Urethral stricture developed in 1 mucosa replaced dog. Histological examination revealed that all of the grafted oral mucosa survived in the urethra. CONCLUSION: These results indicate that the urethral mucosa can be replaced by oral mucosa without damaging the continence mechanism in female dogs. PMID- 8683725 TI - Testosterone enhances whereas estrogen inhibits calcium oxalate stone formation in ethylene glycol treated rats. AB - PURPOSE: The present study was conducted to extend our earlier study on the role of testosterone in the pathogenesis of urolithiasis and to further investigate the influence of sex hormone on the pathogenesis of calcium oxalate stone. MATERIALS AND METHODS: Adult Sprague-Dawley rats were divided into 9 groups, each containing 10 rats. Two groups of rats were left untreated and served as male and female controls. Another 7 groups of rats were fed a 0.5% ethylene glycol (EG) lithogenic diet for 4 weeks. Among them, 2 groups were male and female rats, 2 groups were castrated, 2 groups were castrated and then were subcutaneously implanted with testosterone, and 1 group of intact female rats was also subcutaneously implanted with testosterone. The stone and crystal deposits were examined by infrared spectrometer and polarizing and scanning electron microscope, respectively. Serum testosterone, creatinine and electrolytes and the renal excretion of, oxalate, citrate and creatinine were determined. RESULTS: Subcutaneous implantation of exogenous testosterone restored calcium oxalate stone formation in castrated, EG-treated male rats (80%) and enhanced urolithiasis in castrated female rats receiving EG (40%). However, the testosterone effect was less striking in intact female rats fed EG (10%). CONCLUSIONS: These data suggest that testosterone can promote and estrogen may inhibit calcium oxalate stone formation in EG-treated rats. PMID- 8683726 TI - Expression patterns of multidrug-resistance (MDR1), multidrug resistance associated protein (MRP),glutathione-S-transferase-pi (GST-pi) and DNA topoisomerase II (Topo II) genes in renal cell carcinomas and normal kidney. AB - PURPOSE: Expression levels of the multidrug-resistance (mdr1), multidrug resistance-associated protein (MRP), glutathione-S-transferase-pi (GST-pi) and DNA topoisomerase II (Topo II) genes in normal kidney and renal cell carcinomas were analyzed to study the complexity of the roles of these genes. MATERIALS AND METHODS: The reverse transcription-polymerase chain reaction (RT-PCR) assay was used with beta 2 microglobulin (beta 2 m) as the internal control. RESULTS: In normal kidneys, the expression levels of the 4 genes in individual normal kidney samples correlated significantly with one another. Comparisons of the expression levels between normal kidneys and renal cell carcinomas showed that only the mean MRP gene expression level was higher in renal cell carcinomas than in normal kidneys (p = 0.018). The expression patterns of the 4 genes in renal cell carcinomas differed markedly for nonpapillary and papillary tumors. The mean MRP/beta 2 m ratio for the papillary type was significantly lower than that for the nonpapillary alveolar type carcinoma (p = 0.004). The 4 genes showed moderate positive correlations with one another in alveolar type renal carcinoma similar to the correlations observed in normal kidneys. In contrast, in papillary type, MRP expression was inversely correlated with mdr1 and Topo II expression. CONCLUSION: Differences in cytogenetic changes, origins and natural histories between papillary and nonpapillary carcinoma may be associated with these distinct expression patterns of the resistance-related genes. Further study is required to clarify whether the differences in the expression patterns between these 2 structural types of carcinoma affect their chemosensitivities and clinical outcomes. PMID- 8683727 TI - Hypermethylation of chromosome 17P locus D17S5 in human prostate tissue. AB - PURPOSE: Under normal conditions genomic CpG islands are not methylated. Hypermethylation of a CpG island in the 5' regulatory region of a gene has the capacity to silence gene transcription. Recently, hypermethylation of a CpG island at D17S5 on chromosome 17P13.3 has been shown to be a frequent tumor specific event. When it has been observed, hypermethylation of D17S5 occurs solely in neoplastic tissues. Consequently, it has been hypothesized that hypermethylation of D17S5 may be an important carcinogenic event in the organs in which it occurs (colon, kidney, and brain). In this study we examine D17S5 hypermethylation in DNA from the prostate, a gland which is unique in that it undergoes hyperplastic or neoplastic growth or both in virtually all aging men. MATERIALS AND METHODS: The methylation sensitive restriction enzyme Notl, a cDNA probe specific for the D17S5 locus, and Southern blotting were used to assay for hypermethylation of D17S5 in DNA derived from normal, benign hyperplastic and malignant prostate tissues. RESULTS: We find that methylation of Notl restriction sites at D17S5 is a very common occurrence in prostate cancers (25 of 26 cases examined). Surprisingly, we found that methylation of these sites at D17S5 also occurred in histologically normal prostate and benign hyperplastic (BPH) tissue from glands which both did and did not contain cancer. In contrast, seminal vesicle, an androgen-dependent male sex accessory tissue that rarely undergoes pathological overgrowth, was devoid of hypermethylation at this locus. CONCLUSIONS. These data demonstrate that hypermethylation of D17S5 is a tissue specific event in prostate DNA, and we hypothesize that methylation of this and/or related loci may play a role in the extreme predilection of this gland to neoplastic growth. PMID- 8683728 TI - Exposure to vinorelbine inhibits in vitro proliferation and invasiveness of transitional cell bladder carcinoma. AB - PURPOSE: To study the effect of vinorelbine (VNR) on in vitro cell proliferation, invasiveness, cell adhesion to substrate, cell motility and metalloproteinase secretion of MB-49, a murine transitional cell carcinoma of the bladder (TCC). MATERIALS AND METHODS: The colorimetric MTS assay, which depends upon viable versus nonviable mitochondria, was used to evaluate the effect of graded concentrations of VNR on in vitro MB-49 cell growth. Chemoinvasion and cell motility were studied in TCC cells exposed for 24 hours to a noncytotoxic dose of VNR, through their ability to migrate across Matrigel-coated or Type IV collagen coated 8-microns. pore filters. Zymographic studies in gelatin-embedded polyacrylamide gels were done to investigate gelatinolytic activity in conditioned media from treated and untreated MB-49 cells. RESULTS: Vinorelbine inhibited MB-49 cell growth in a dose-dependent manner (IC(50)40 ng./ml.). In vitro cell invasive capacity of MB-49 cells pretreated for 24 hours with VNR at noncytotoxic doses (1 and 10 ng./ml.) was significantly lower than that of untreated cells. The decreased invasion of VNR-treated cells was not accompanied by a diminished adhesion to Matrigel or type IV collagen nor by a significant reduced secretion of gelatinolytic metalloproteinases. Instead, motility of MB-49 cells exposed to noncytotoxic concentrations of VNR was inhibited in a dose response fashion similar to that of invasion. CONCLUSION: Vinorelbine proved to be an effective drug to inhibit tumor cell growth and invasion in a transitional cell bladder carcinoma model. The results obtained would justify preclinical studies to evaluate the effectiveness of VNR as a potential treatment of TCC. PMID- 8683729 TI - In vitro contraction of the canine corpus cavernosum penis by direct perfusion with prolactin or growth hormone. AB - PURPOSE: It is well established that hyperprolactinemia, most typically seen in prolactinoma patients, causes hypogonadism and impotence. There seems to be a good possibility that hyperprolactinemia causes impotence, at least partially via some intrinsic property of prolactin (PRL), rather than through its suppressive effects on the hypothalamic-pituitary-gonadal testosterone dynamics. In the present investigation, we used an in vitro canine model to attempt to clarify whether direct action of PRL on the corpus cavernosum penis may lead to erectile insufficiency. Growth hormone (GH) and placental lactogen (PL), both having close structural and functional homologies to PRL, were also studied. MATERIALS AND METHODS: Isometric tension measurement with cavernous strips was performed in the presence or absence of 10(-5) to 10(-9) M. PRL, GH, or PL in the perfusion medium. The tension change induced by the test substances was normalized relative to that induced by 120 mEq KCl. RESULTS: Both PRL and GH produced dose-related elevations (p < 0.01) of the cavernous tension, whereas PL and thiol-cleaved PRL in comparable doses were without effect (p > 0.05). When the tension rise produced by 120 mEq KCl was taken as 100%, the maximum contractions produced by PRL and GH were 80% and 110%. The minimum effective concentration was 10(-8) to 10(-7) M. for both PRL and GH. Pretreatment with indomethacin (10(-5) M.), but not tetrodotoxin (10(-5) M., partially suppressed (p < 0.05) the effects of PRL. CONCLUSION: These results suggest that PRL and GH directly and specifically produced contraction of the corpus cavernosum penis, resulting in erectile insufficiency, and that the effect of PRL is partially mediated by prostaglandin. PMID- 8683730 TI - Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH like domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts. AB - PURPOSE: To determine whether parathyroid hormone-related protein (PTHrP) is a substrate of prostate-specific antigen (PSA) and how the biological activity of PTHrP may be altered by cleavage with PSA. MATERIALS AND METHODS: Prostate specific antigen cleavage of recombinant human PTHrP 1-141 was conducted in vitro at 37C and analyzed by SDS-PAGE. Five rounds of automated amino-terminal amino acid sequence analysis were performed on blotted PSA-cleaved PTHrP peptide fragments to determine the PSA cleavage sites. The mouse osteoblast cell line MC3T3-E1 was used to test whether PSA cleavage of PTHrP 1-141 altered its ability to stimulate cAMP production. RESULTS: Prostate-specific antigen was found to specifically cleave PTHrP 1-141 in a time- and dose-dependent manner. Cleavage of PTHrP 1-141 by PSA generated fragments on Coomassie-stained acrylamide gels that migrated with mobilities that corresponded to 19.5, 17, 15 and < 7 kd. The preferred PSA cleavage site of PTHrP 1-141 was determined to be at the carboxyl terminus of phenylalanine 23, consistent with chymotryptic-like enzymatic activity of PSA. Cleavage of PTHrP by PSA completely abolished the ability of PTHrP to stimulate cAMP production. CONCLUSIONS: Cleavage of PTHrP 1-141 by PSA carboxyl-terminal to phenylalanine 23 represents a unique pattern of PTHrP processing that may be specific to the prostate. Prostate-specific antigen inactivation of the cAMP-inducing activity of PTHrP 1-141 demonstrates that PSA cleavage regulates the biological activity of PTHrP. These results have implications for the role of PTHrP in prostate cancer metastasis to bone and its subsequent regulation of bone remodeling. Study of the biological activities of the PSA-generated PTHrP peptides identified in this study merits further investigation. PMID- 8683731 TI - Potentiation by bradykinin and substance P of purinergic neurotransmission in urinary bladder. AB - PURPOSE: The higher than normal levels of substance P (SP) and the kinins in patients suffering from interstitial cystitis suggest that they may contribute to the complex symptoms of the condition. The purpose of our experiments was to determine whether SP and bradykinin (BK) influence the excitatory motor innervation of the urinary bladder. MATERIALS AND METHODS: Strips of guinea pig urinary bladder were placed in isolated tissue baths, and the influence of SP and BK on contractions induced by transmural electrical stimulation and cholinergic and purinergic agonists was evaluated. RESULTS: Substance P and BK potentiated responses to the purinergic component of the neurogenic stimulation (that part of the contractile response that remains after treatment with atropine) and potentiated responses to exogenously applied adenosine triphosphate (ATP). The peptides did not potentiate the response to the cholinergic component of the nerve-induced contraction (that part of the neurogenic response that remains after desensitization of purinoceptors with alpha, beta-methylene ATP) nor responses to carbachol. The potentiating actions of SP and BK were reduced but not abolished by treatment with meclofenamic acid. CONCLUSIONS: Substance P and BK potentiate the neurogenic response of the bladder by influencing the purinergic component of the excitatory motor innervation, apparently at a postjunctional site. Prostaglandins may be involved in mediating some of the actions of these peptides. PMID- 8683732 TI - Localization of IL-1, IL-2, IL-4, IL-8 and TNF in superficial bladder tumors treated with intravesical bacillus Calmette-Guerin. AB - PURPOSE: Cytokines have been detected in the urine during the first hours after intravesical Bacillus Calmette Guerin (BCG) treatment against superficial bladder cancer. To investigate the long-lasting mucosal inflammatory response, we analyzed intracellular cytokines by immunohistochemistry in biopsies taken 2 weeks after BCG treatment. MATERIALS AND METHODS: Tumor biopsies were obtained from 8 patients with noninvasive, papillary transitional cell carcinoma (TCC), and intracellular cytokines were visualized by immunohistochemistry using cytokine-specific monoclonal antibodies. RESULTS: Interleukin (IL)-1 beta+ or tumor necrosis factor (TNF)-alpha+ cells were abundant in tumor and stroma. Interleukin-1 alpha, IL-2, IL-4, IL-8 and TNF-beta were variably expressed, while IL-10+ and interferon (IFN)-gamma+ cells were not detected. Among the few patients studied (5 responders and 3 nonresponders to BCG treatment) no single cytokine or cytokine profile was associated with clinical response to BCG therapy. CONCLUSION: We conclude that the in situ cytokine response after BCG treatment is highly complex, since cytokine profiles differed among the 8 patients investigated and between tumor and surrounding tumor-free mucosa. Further studies, investigating larger numbers of patients, is required to clarify whether cytokine profiles correlate with the clinical response to BCG. PMID- 8683733 TI - Human cytomegalovirus is not implicated in benign prostatic hyperplasia: a study using immunohistochemistry and the polymerase chain reaction. AB - PURPOSE: To evaluate whether human cytomegalovirus (CMV) may play a role in the pathogenesis of benign prostatic hyperplasia. MATERIALS AND METHODS: We used immunohistochemistry and the polymerase chain reaction (PCR) to evaluate the presence of CMV in normal prostatic tissue (n = 12) and BPH tissue (n = 21). RESULTS: Immunostaining for CMV in prostatic tissue was negative; however, staining was evident in mononuclear cells seen in the tissues of both groups. With nested PCR, CMV genomic material was demonstrated in 1 tissue specimen from each group (p > 0.1). CONCLUSIONS: These data suggest that CMV is unlikely to be a significant factor in the pathogenesis of BPH. PMID- 8683734 TI - Developmental regulation of collagen differential expression in the rabbit bladder. AB - PURPOSE: It has been suggested that the amount and relative ratios of different types of collagen influence bladder compliance. To understand the mechanisms regulating collagen synthesis and degradation in the bladder we investigated the gene expression of collagen types I and III in the rabbit bladder during normal development. MATERIALS AND METHODS: New Zealand white rabbits ages fetus to adult were used for this study. The mid portion of the bladder wall was harvested. Northern blot hybridization was performed to analyze quantitatively collagen types I and III messenger (m) ribonucleic acid (RNA), and in situ hybridization was done to localize the messages. Corresponding protein distributions were obtained by immunohistochemical staining. RESULTS: Types I and III collagen are developmentally regulated at the level of gene expression. The temporal and spatial distribution of the mRNA transcripts of alpha 1(I) and alpha 1(III) correlates with extracellular protein deposition. Differential distribution of the mRNA transcripts is also developmentally regulated. CONCLUSIONS: This study characterizes the relationship between collagen gene expression and normal rabbit bladder development. The expression of alpha 1(I) and alpha 1(III) alters as the bladder grows. High levels and nonconcordant up and down regulation of different types of collagen mRNA during early development demonstrate the complexity of the extracellular matrix in a young bladder. This observation may be important in our understanding of the injury response in a developing versus mature bladder. PMID- 8683735 TI - Papers presented at the annual meeting of the section on urology, American Academy of Pediatrics. San Francisco, California, October 14-16, 1995. PMID- 8683736 TI - Regeneration of bladder urothelium, smooth muscle, blood vessels and nerves into an acellular tissue matrix. AB - PURPOSE: To study the cellular events occurring during bladder development and regeneration we developed an in vivo model of bladder augmentation with an acellular tissue graft. We propose that the extracellular matrix orchestrates the regenerative capacity of host bladder cells (urothelium, smooth muscle, blood vessels and nerve cells) after bladder augmentation with acellular tissue matrix. MATERIALS AND METHODS: A total of 40 adult rats underwent partial cystectomy and augmentation with a patch of extracellular matrix representing the full thickness of rat gastric or bladder tissue. Sections were examined histologically to assess urothelial, smooth muscle and neuronal invasion of the graft. RESULTS: A total of 32 rats was evaluated 1 day to 26 weeks after grafting. Epithelialization occurred by day 4, accompanied by granulocytic infiltration. Smooth muscle regenerated 2 weeks after grafting in juxtaposition to epithelial surfaces and it matured into normal sized bundles by 26 weeks. Neovascularity was noted 2 weeks postoperatively. Neural elements formed around developing smooth muscle bundles as early as 4 weeks after grafting. CONCLUSIONS: We demonstrated the regeneration of urothelium, smooth muscle, blood vessels and nerves within a full thickness grafted acellular tissue matrix scaffold in the rat. The spatial orientation of these elements suggests that mesenchymal-epithelial interactions occur during phenotypic regeneration of the bladder. Urothelium appears to regulate the early forming smooth muscle. This in vivo model provides a suitable method to study cellular events during regeneration. PMID- 8683737 TI - The decompensated detrusor I: the effects of bladder outlet obstruction on the use of intracellular calcium stores. AB - PURPOSE: As in other smooth muscle groups, extracellular calcium influx as well as the release of calcium from intracellular storage sites or sarcoplasmic reticulum occur in response to receptor stimulation. The relative participation of extracellular influx versus intracellular release has recently been shown to be influenced by developmental stage and obstruction. Partial bladder outlet obstruction results in marked hypertrophy of the bladder and produces alterations in contractile function. To understand better how this contractile dysfunction after outlet obstruction is influenced by intracellular calcium handling we tested the effects of 2 drugs with known effects on the sarcoplasmic reticulum. MATERIALS AND METHODS: We evaluated ryanodine, which blocks the release of calcium from the sarcoplasmic reticulum, and thapsigargin, which blocks the ability of the sarcoplasmic reticulum to pump cytosolic calcium back into the storage sites. Rabbit bladders were obstructed for different periods, after which detrusor muscle strips were harvested and contractile performance was evaluated in the absence and presence of ryanodine and thapsigargin. RESULTS: In the early phases of outlet obstruction the release of intracellular calcium increased significantly. With prolonged obstruction and detrusor decompensation the intracellular storage sites lost the ability to contribute to the generation of contractile force. CONCLUSIONS: Alterations in the calcium handling ability of the smooth muscle cell appear to have an important role in the process of decompensation of bladder function in infravesical obstruction. PMID- 8683738 TI - Collagen types I and III localization by in situ hybridization and immunohistochemistry in the partially obstructed young rabbit bladder. AB - PURPOSE: The objective of the study was to investigate the alteration of collagen expression patterns at the transcription and translation levels during partial outlet obstruction and to compare changes in collagen types I and III gene expression, and protein deposition during early and subacute phases of obstruction. MATERIALS AND METHODS: Following 1, 2, 7, 14 and 21 days of partial bladder obstruction in 2-week-old rabbits bladder tissues were evaluated for collagen types I and III messenger ribonucleic acid localization by in situ hybridization and for protein localization by immunohistochemical study. RESULTS: There is up regulation of collagen types I and III gene expression after obstruction. Up regulation of collagen gene expression immediately after obstruction is within the lamina propria and the message moves into the muscular layer as obstruction progresses. Protein deposition for both collagen types is analogous to that of gene expression. CONCLUSIONS: Up regulation of collagen types I and III gene expression, and increased protein deposition after partial obstruction demonstrate that the alteration in collagen synthesis is at least partially transcription regulated. This alteration starts from superficial layers of the bladder wall and becomes deeper as the pathological process progresses. PMID- 8683739 TI - The decompensated detrusor II: evidence for loss of sarcoplasmic reticulum function after bladder outlet obstruction in the rabbit. AB - PURPOSE: While it may lack the classic morphological pattern in striated muscle systems, there is ample evidence that smooth muscle also contains sarcoplasmic reticulum. These intracellular storage sites release calcium into the cytosol to generate contractile force in response to various stimuli. A major component of the sarcoplasmic reticulum is an adenosine triphosphate dependent ion pump, which serves to drive free calcium out of the cytosol back into this intracellular reservoir. This ion pump serves to maintain the intracellular calcium storage sites, and also as a marker of the sarcoplasmic reticulum. MATERIALS AND METHODS: Muscle strip studies were performed to stratify the data into 3 major groups (controls, and compensated and decompensated obstructions) based on physiological performance. These were correlated with biochemical and molecular determinations of sarcoplasmic endoplasmic reticulum calcium, magnesium-adenosinetriphosphatase expression. RESULTS: Our results demonstrate a remarkable loss of sarcoplasmic endoplasmic reticulum calcium-adenosinetriphosphatase activity in the decompensated group and a moderate loss in the compensated group. CONCLUSIONS: These data provide molecular support for our previous physiological studies in which we demonstrated an important role for intracellular calcium storage and release with normal bladder smooth muscle function. These data strongly support our contention that contractile dysfunction in bladder smooth muscle following outlet obstruction is partially mediated by changes in the mechanisms of intracellular calcium homeostasis. PMID- 8683740 TI - Angiotensin II and basic fibroblast growth factor induce neonatal bladder stromal cell mitogenesis. AB - PURPOSE: Our aims were to establish primary stromal cell cultures from the neonatal rabbit bladder and investigate the potential mitogenic effects of angiotensin II and basic fibroblast growth factor on these cells. MATERIALS AND METHODS: Primary bladder stromal cell cultures were obtained from 3-day-old rabbits, plated at a density of 3 x 10(4) cells per ml. and allowed to grow for 24 hours. Subconfluent cells were growth arrested in serum deficient (0.25% newborn calf serum) or serum-free media for 24 hours and then stimulated with 10( 7) M. angiotensin II or 10 ng./ml. basic fibroblast growth factor for an additional 48 hours. Cell counts and [3H] thymidine incorporation were done to measure cellular proliferation and deoxyribonucleic acid synthesis. RESULTS: Angiotensin II and basic fibroblast growth factor each stimulated neonatal bladder stromal cell proliferation and [3H] thymidine incorporation under serum deficient conditions. Angiotensin II provoked an average 26% increase in cell number (p < 0.01) and 35% increase in [3H] thymidine incorporation (p < 0.01) compared to control values. Basic fibroblast growth factor was an even more potent mitogen with a 47% increase in cell number (p < 0.01) and 180% increase in [3H] thymidine incorporation (p < 0.01) compared to controls. In contrast, angiotensin II and basic fibroblast growth factor each failed to have significant stimulatory effects under serum-free conditions. CONCLUSIONS: Angiotensin II and basic fibroblast growth factor induce a mitogenic response to neonatal bladder stromal cells in vitro. These mitogenic effects require the presence of serum factors. Whether angiotensin II and basic fibroblast growth factor are involved in the in vivo regulation of bladder growth associated with obstructive uropathy requires further investigation. PMID- 8683741 TI - Characterization of small intestinal submucosa regenerated canine detrusor: assessment of reinnervation, in vitro compliance and contractility. AB - PURPOSE: We characterized small intestinal submucosa regenerated canine bladder. MATERIALS AND METHODS: We subjected 15-month small intestinal submucosa regenerated canine bladder strips to in vitro muscle bath compliance, contractility testing and immunohistochemical staining. RESULTS: Compliance studies demonstrated no significant difference between small intestinal submucosa regenerated and control bladders, which were 30-fold more compliant than native small intestinal submucosal graft material. Contractility studies demonstrated contractile responses and innervation similar to those of normal canine bladder. Afferent nerves were demonstrated through immunohistochemical techniques. CONCLUSIONS: These characteristics further support the regenerative capacity of small intestinal submucosa and its potential use as a bladder augmentation material. PMID- 8683742 TI - Augmentation cystoplasty using pedicled and de-epithelialized gastric patches in the mini-pig model. AB - PURPOSE: The most common methods of bladder augmentation are gastrocystoplasty and enterocystoplasty. Gastrocystoplasty is advantageous due to minimal mucous secretion and a well developed muscular wall as well as good urodynamic properties of the patch. However, the permanent contact of urine with the gastric mucosa is not free of complications. We report the urodynamic, macroscopic and histological outcomes of a pedicled de-epithelialized gastric patch incorporated in the bladder. We compared the results to those of our previous study, which sought to analyze these techniques of patch coverage using sigmoid patches. MATERIALS AND METHODS: We performed 20 augmentation cystoplasties in the mini-pig model using a pedicled de-epithelialized gastric patch and 5 techniques of patch coverage. RESULTS: Three months after surgery all bladders had an increase in volume except those in which the auto-augmentation technique was used. However, all gastric patches were smaller compared to preoperative size. Many had irregular fibrosed inner surfaces and histological evaluation revealed a fibrosed newly formed submucosal layer with a complete urothelial coverage in every patch. No gastric mucosal remnant was found. CONCLUSIONS: De-epithelialized gastrocystoplasty is an attractive procedure that can increase bladder capacity as well as provide a complete urothelial lining without mucosal remnants. However, the success of this procedure seems to be limited by increased morbidity and fibrotic changes, and decreased surface of the patch. PMID- 8683743 TI - Pediatric continent reservoirs and colocystoplasty created with absorbable staples. AB - PURPOSE: For patients undergoing continent urinary diversion or bladder augmentation the process of detubularization and refashioning bowel into a spherical configuration is often tedious and time-consuming, and may cause undesirable blood loss. We sought to determine whether using absorbable staples in a pediatric population was safe, effective and economical. MATERIALS AND METHODS: We performed our technique of rapid right colon pouch construction in 18 children (average age 12.3 years) undergoing continent urinary diversion (8) or colocystoplasty (10). We evaluated the cost of performing the procedure relative to conventional suturing as well as the results of up to 3 years of followup. RESULTS: In all cases pouch construction using absorbable staples was performed easily and rapidly, and resulted in minimal blood loss. Using the staples decreased operative time by approximately 1 hour and saved nearly $350 per case. Only 1 significant complication requiring surgical intervention developed during extended followup (delayed pouch rupture) and in that case the use of absorbable staples did not contribute to morbidity. None of the patients had reservoir stones. CONCLUSIONS: The use of devices applying absorbable staples in conjunction with a 1-step method of colonic reservoir construction proves to be effective and economically sound for continent urinary diversion and bladder augmentation. PMID- 8683744 TI - New application of the gastrostomy button for clinical and urodynamic evaluation before vesicostomy closure. AB - PURPOSE: We report use of the Bard gastrostomy button to occlude vesicostomy and provide access for intermittent catheterization before closure in children with vesicostomy. Evaluation of bladder function in such children usually relies on radiographic and urodynamic studies, which may fail to predict bladder compliance, emptying and continence after closure. MATERIALS AND METHODS: Buttons were placed before vesicostomy closure in 1 boy with the prune-belly syndrome and 2 girls with cloacal anomalies 2.5 to 10 years old. The patients had undergone vesicostomy using the Blocksom technique soon after birth because of urinary infection, and impairment of bladder emptying and renal function. RESULTS: With the button in place bladder emptying, compliance, continence and possible upper tract changes could be evaluated during several weeks. Button coaptation to the vesicostomy was complete with no urine leakage around the device, allowing easy intermittent drainage through its channel. After 4 weeks the buttons did not have any encrustation or lithiasis and patients were free of urinary infection. Vesicostomy was closed in each patient and the period of temporary closure provided by the button was predictive of future bladder behavior. CONCLUSIONS: This new and original application of the gastrostomy button as a temporary vesicostomy closure may be useful to predict the clinical and urodynamic responses of a defunctionalized bladder in patients with vesicostomy who are candidates for urinary undiversion. PMID- 8683745 TI - Combined use of enterocystoplasty and a new type of artificial sphincter in the treatment of urinary incontinence. AB - PURPOSE: We report the results of the combination of enterocystoplasty and a periurethral expander, a simplified type of artificial sphincter, in the treatment of urinary incontinence. MATERIALS AND METHODS: The new 1-piece device has an adjustable cuff connected to a port positioned at the subcutaneous space in the abdomen. The cuff is adjusted to the bladder neck and the pins are fixed according to the diameter of the urethra. The port is punctured percutaneously and saline is injected until continence is achieved. Eight boys and 3 girls underwent nonsecretory sigmoid cystoplasty and placement of the device at a single operation. Nine patients had neurogenic bladder and in 2 exstrophy reconstruction had failed. Followup ranged from 4 to 26 months. RESULTS: All patients were continent with improved bladder compliance 6 to 8 weeks after the operation, when the device was activated. In 1 case the device was extracted after 2 months due to frequent episodes of hematuria and edema at the port site. Two patients had erosion of the skin at the port site. Urodynamics were repeated at the time of activation. Maximal urethral closing pressure increased from 16.27 to 157.44%. Two patients needed a second injection to achieve continence. The patients with exstrophy void spontaneously and those with neurogenic bladder are on clean intermittent catheterization. CONCLUSIONS: Although more followup is needed, the combination of these procedures seems to offer a new option for the treatment of urinary incontinence in children. PMID- 8683746 TI - Ten-year experience with the artificial urinary sphincter in children. AB - PURPOSE: To assess the efficacy of the artificial urinary sphincter survival and continence were first evaluated 5 years ago. We now evaluated the effects of the artificial urinary sphincter more than a decade after implantation. MATERIALS AND METHODS: Before 1985 an artificial urinary sphincter was implanted in 22 male and 14 female consecutive patients 4 to 30 years old (median age 12). In addition, between 1985 and 1990, 18 other children underwent artificial urinary sphincter implantation. Results of both series were compared. RESULTS: Of the 25 sphincters in the original series that were functioning after 5 years 1 was removed and 2 patients were lost to followup, resulting in 22 functioning implants (61% of the patients). Mean survival time of the prostheses was 12.1 years and average followup for functioning sphincters was 13.7 years. There was no statistically significant difference in artificial urinary sphincter survival between the original group at 5 years and the second group treated after 1985. Of the patients in both groups with sphincters in place 32 of 39 (82%) were dry. Augmentation cystoplasty was performed in 9 of 18 patients (50%) in the second series (5 preoperatively and 4 postoperatively) compared to 10 of 36 (28%) in the original series at 5 years (3 preoperatively and 7 postoperatively). Renal failure developed in 6 patients from both series. CONCLUSIONS: The artificial urinary sphincter is a durable long-term solution for children with intractable incontinence. Long-term surveillance of the urinary tract is mandatory because of the potential for renal failure in patients who have bladder hypertonicity after placement of the device. PMID- 8683747 TI - Bladder neck reconstruction: long-term followup of reconstruction with omentum and silicone sheath. AB - PURPOSE: In 1986 we reported the placement of a silicone sheath sandwiched between layers of omentum around a newly reconstructed bladder neck. We now present long-term followup of 94 cases of silicone sheath bladder neck reconstruction. MATERIALS AND METHODS: A total of 94 silicone sheaths was placed in 84 patients between August 1983 and October 1992. We retrospectively reviewed our results and divided the reconstructions into 3 groups according to modifications in surgical technique. We report the results of each modification and current recommendations for use. RESULTS: Each sequential modification of silicone sheath bladder neck reconstruction significantly reduced the risk of erosion from 100%, 32% and 7%, respectively (p < 0.05). Erosion was independent of patient age, sex, pathological condition or whether bladder neck reconstruction was a repeat procedure. Patients who had silicone sheath erosion did not have different continence or loss of urethral continuity than those with no erosion. In 13 patients (16%) artificial sphincter placement was clearly facilitated by the silicone sheath. CONCLUSIONS: Modifications in the surgical technique of silicone sheath placement around a reconstructed bladder neck have resulted in a decrease in the erosion rate to 7%. The primary benefit of silicone sheath placement is ease of subsequent sphincter placement. Currently we reserve silicone sheath placement for a small subset of patients who are most likely to benefit from subsequent artificial sphincter placement. PMID- 8683748 TI - Submucosal bladder neck injection of bovine dermal collagen for stress urinary incontinence in the pediatric population. AB - PURPOSE: The surgical management of stress urinary incontinence in the pediatric population includes various surgical techniques of which the simplest is outpatient transurethral or periurethral injection of a bulking agent. Currently purified bovine dermal collagen cross-linked with glutaraldehyde (Contigen) is the only Food and Drug Administration approved bulking agent available. Patients with stable detrusor function are ideal candidates. We review our initial experience with children. MATERIALS AND METHODS: Between January 1994 and June 1995, 23 boys and 9 girls 4 to 17 years old (mean age 9) consecutively underwent submucosal bladder neck injection with cross-linked bovine dermal collagen. Incontinence was secondary to spinal dysraphism in 24 patients, complete epispadias in 4, classic bladder exstrophy in 3 and neurogenic bladder secondary to a sacral teratoma in 1. Preoperative video urodynamics documented intrinsic sphincteric deficiency in all patients with leak point pressure of 15 to 60 cm. water (mean 37). Injection volumes ranged from 2.5 to 17 cc (mean 10). Continence results were defined as dry-requiring no protection while on a 4-hour clean intermittent catheterization program, good-improved but requiring 1 to 5 pads daily and failure-no postoperative improvement or still requiring diapers. RESULTS: Of the children with neurogenic bladder 20% became dry following the first injection and an additional 28% had a good result. Furthermore, of the 6 children with exstrophy or epispadias who underwent a Young-Dees-Leadbetter procedure 50% were dry and 17% had a good result after the first injection. Complications were limited to a febrile urinary tract infection associated with urinary retention in 1 patient and transiently worse continence in 2. CONCLUSIONS: Despite the limited success rate, we believe that transurethral collagen injection therapy has a viable role in the treatment of intrinsic sphincteric deficiency in select pediatric patients, particularly since the procedure has low morbidity and can be performed on an outpatient basis. Preoperative counseling should be given with realistic expectations. PMID- 8683749 TI - Treatment of urinary incontinence in children by endoscopically directed bladder neck injection of collagen. AB - PURPOSE: We assessed optimal selection criteria for and expected outcome of bladder neck injection of collagen in children with intrinsic sphincteric deficiency. MATERIALS AND METHODS: We retrospectively reviewed the charts of children with intrinsic sphincteric deficiency treated with bladder neck injection of collagen at 3 pediatric urology centers. RESULTS: We reviewed the records of 12 boys and 6 girls 6 to 18 years old (median age 10.5). The underlying etiology of incontinence was neurogenic bladder in 10 patients, the epispadias-exstrophy complex in 6, ureterocele in 1 and trauma in 1. Previous surgery included bladder augmentation in 4 cases, bladder neck plasty in 7 and epispadias repair in 4, and concurrent medical management comprised anticholinergics in 8, alpha-agonists in 1 and intermittent catheterization in 9. Skin tests in all patients were negative for collagen. Seven patients had 1 injection, 9 had 2 and 2 had 3. The volume of collagen injected ranged from 2.4 to 13 cc (median 5) per treatment and 3 to 28 cc (median 7) per patient. Followup ranged from 5 to 21 months (median 15). Of the 14 patients evaluated 5 are dry, 4 are improved, 1 is unchanged and 4 underwent further continence surgery. No treatment related morbidity was seen. CONCLUSIONS: Endoscopically directed injection of collagen around the bladder neck is successful in 64% of children with intrinsic sphincteric deficiency. It is an outpatient treatment with no significant morbidity. Further continence surgery is not precluded when necessary. Patients with adequate capacity and compliant neurogenic bladders, and those with the exstrophy-epispadias complex and failed bladder neck plasty seem to be optimal candidates for collagen injection. PMID- 8683750 TI - Outcome of sling cystourethropexy in the pediatric population: a critical review. AB - PURPOSE: We performed a critical retrospective analysis of the records of all consecutive children who underwent sling cystourethropexy at our institutions. We particularly assessed the incidence and outcome in children who underwent enterocystoplasty in addition to a sling procedure. MATERIALS AND METHODS: Between May 1992 and August 1994, 24 girls and 15 boys 4 to 17 years old (mean age 9) consecutively underwent 1 of 4 techniques of sling cystourethropexy for stress urinary incontinence using rectus fascia via an abdominal approach. Diagnoses included spinal dysraphism in 34 patients, spinal trauma in 2, cecoureterocele in 1, epispadias in 1 and classic bladder exstrophy in 1. All children underwent preoperative video urodynamics. In 4 patients only a sling procedure was performed (group 1), while in 9 others a sling procedure was performed after enterocystoplasty (group 2). In 26 patients a sling procedure and concomitant enterocystoplasty were performed (group 3). RESULTS: Patients who underwent concomitant enterocystoplasty had more hyperactive preoperative urodynamics than those who did not. Postoperative continence was subcategorized in terms of patient age, sex, diagnosis (neurogenic versus nonneurogenic), preoperative video-urodynamics, surgeon technique, group (that is with or without cystoplasty) and type of enterocystoplasty (that is stomach versus ileum). Of these factors only concomitant enterocystoplasty was predictive of postoperative dry continence (73% of group 3, 33% of group 2 and 25% of group 1). In most patients who were not dry postoperative video urodynamics suggested suboptimal outlet resistance overcome by a hyperactive detrusor. No patient had postoperative upper tract deterioration. CONCLUSIONS: These results suggest that concomitant enterocystoplasty should be critically considered for pediatric patients undergoing sling cystourethropexy. PMID- 8683751 TI - Preservation of continence after posterior sagittal surgery. AB - PURPOSE: An animal study was performed to evaluate the effect of posterior sagittal pararectal mobilization on anorectal sphincter function. MATERIALS AND METHODS: We initially divided 11 juvenile pigs into 3 groups: group 1-anesthesia alone (3), group 2-posterior sagittal incision alone (4) and group 3-posterior sagittal incision with unilateral pararectal dissection (4). Two animals in group 1 subsequently underwent posterior sagittal incision with circumferential pararectal dissection (group 4). The anal canal was preserved intact in all animals. Anorectal sphincter manometry was performed preoperatively, and 2, 4, 8 and 12 weeks postoperatively. Electromyography was performed 12 weeks postoperatively. Anorectal sphincter muscle complexes were harvested for histological examination. RESULTS: All animals had postoperative bowel continence. Postoperatively manometry revealed no difference from preoperative measurements in all study groups (p = 0.90). Electromyography and histological examination of the anorectal sphincters were normal in all but 2 animals. Denervation injury and histological atrophy were detected after repair of inadvertent enterotomy in 1 animal following unilateral pararectal dissection, and polyphasic motor unit potentials implying reinnervation were detected in another after circumferential pararectal mobilization. CONCLUSIONS: These results indicate that posterior sagittal incision and unilateral pararectal mobilization cause no permanent injury to the anorectal sphincter. However circumferential pararectal dissection or repair of a rectal injury may cause measurable changes in sphincter function. PMID- 8683752 TI - The influence of small functional bladder capacity and other predictors on the response to desmopressin in the management of monosymptomatic nocturnal enuresis. AB - PURPOSE: The relationship of functional bladder capacity as well as other variables to the responsiveness to desmopressin in children with monosymptomatic nocturnal enuresis was investigated. MATERIALS AND METHODS: A total of 95 children 8 to 14 years old with monosymptomatic nocturnal enuresis (6 or more of 14 nights wet) were evaluated in a double-blind study followed by open label crossover extension using 20 to 40 mcg. desmopressin. Evaluated predictors of response included patient age, gender, race, family history, number of baseline wet nights, urine osmolality parameters and maximum functional bladder capacity (as a percent of predicted bladder capacity based on the formula, patient age + 2 x 30 = cc). Responders to desmopressin were classified as excellent (2 or less of 14 nights wet) or good (50% or greater decrease but more than 2 of 14 nights wet) and nonresponders were defined by a less than 50% decrease in wet nights. RESULTS: Of the 95 patients 25 (29.5%) achieved an excellent response to desmopressin and 18 (18.9%) had a good response for a cumulative response rate of 45.3%. The remaining 52 patients (54.7%) were nonresponders. There were no significant differences between responders and nonresponders in regard to gender, race, positive family history or baseline urine osmolality parameters. Response to desmopressin was associated with older age, fewer baseline wet nights and larger bladder capacity. Patients with a functional bladder capacity greater than 70% predicted bladder capacity were 2 times more likely to respond to desmopressin. CONCLUSIONS: The responsiveness of children with nocturnal enuresis to desmopressin is adversely affected by reduced functional bladder capacity. The results of this study have implications regarding the potential use of combination pharmacotherapy with desmopressin and an anticholinergic for enuretic patients who are nonresponsive to single drug therapy. PMID- 8683753 TI - Successful treatment of giggle incontinence with methylphenidate. AB - PURPOSE: Giggle incontinence, the second most common type of childhood enuresis unrelated to disease, is notoriously difficult to treat. However, the association of laughter or emotion precipitated alteration of muscle tone is suggestive of a functional relationship to cataplexy, a part of the narcoleptic syndrome complex that may respond to stimulant medication. MATERIALS AND METHODS: Two boys and 5 girls (mean age 10.9 years) with giggle incontinence, a positive family history of giggle incontinence (4 patients) and no evidence of urological disease were treated with methylphenidate for 1 to 5 years. RESULTS: All patients responded positively with complete cessation of enuresis to varying dose schedules of methylphenidate. CONCLUSIONS: These results suggest that giggle incontinence is a centrally mediated and likely hereditary disorder that may share a common pathophysiological basis with the narcolepsy/cataplexy syndrome. PMID- 8683754 TI - Percutaneous endoscopic trigonoplasty: a minimally invasive approach to correct vesicoureteral reflux. AB - PURPOSE: A procedure was designed to correct vesicoureteral reflux with minimally invasive technology. MATERIALS AND METHODS: A total of 22 children 14 months to 18 years old underwent percutaneous endoscopic trigonoplasty between January and June 1995. Followup ranges from 4 to 11 months. In 32 ureters reflux was grade 2 in 13, grade 3 in 13, grade 4 in 5 and grade 5 in 1. RESULTS: All patients had normal sonography of the kidneys after surgery. On followup voiding cystourethrography at 2 or 6 months there was resolution of reflux in 20 of the 32 ureters (62.5%). The probability of resolution was unrelated to patient age, laterality of reflux, initial grade, operative sequence or preoperative bladder instability. The 3 major complications were vesicovaginal fistula, hyponatremia and perivesical fluid collection. CONCLUSIONS: Percutaneous endoscopic trigonoplasty is technically feasible but it involves a distinct learning curve. It offers significant advantages related to more rapid recovery with less discomfort. The success rate is modest at present. If it were to be improved with technical modifications, percutaneous endoscopic trigonoplasty may change the basic approach to treating children with vesicoureteral reflux. PMID- 8683755 TI - The mechanism of new onset contralateral reflux following unilateral ureteroneocystostomy. AB - PURPOSE: We studied a population of patients undergoing unilateral antireflux surgery to determine the mechanism of new onset contralateral reflux postoperatively. MATERIALS AND METHODS: A total of 141 patients underwent unilateral antireflux surgery via the Cohen, Glenn-Anderson or extravesical technique. The 18% of patients who had new onset contralateral vesicoureteral reflux were analyzed according to grade of initial reflux, presence of a Hutch diverticulum or duplex system and surgical technique. RESULTS: Surgical technique did not influence the development of contralateral reflux. As grade of corrected reflux increased, a significant trend toward development of contralateral reflux was noted. A Hutch diverticulum was not a risk factor for contralateral reflux but reflux into a duplicated system was a distinct risk factor (26 versus 12% in single system reflux). CONCLUSIONS: Our study supports the concept that new onset contralateral reflux may result from elimination of a pop-off mechanism. Surgical distortion of the contralateral hemi-trigone appears not to be responsible. Correction of severe (grade V) reflux and reflux into duplex systems put patients at particular risk for development of contralateral reflux postoperatively. PMID- 8683756 TI - An analysis of social and economic factors associated with followup of patients with vesicoureteral reflux. AB - PURPOSE: Nonsurgical treatment of vesicoureteral reflux requires antibiotic prophylaxis and long-term surveillance. We examined factors that affect followup compliance and influence quality of care in these children. MATERIALS AND METHODS: We retrospectively reviewed the records of 288 boys and 742 girls with vesicoureteral reflux. RESULTS: Of the children treated nonsurgically for vesicoureteral reflux 34% were lost to followup and the majority (80%) were not monitored beyond the 1-year followup appointment. Older maternal age (36 years or older) was significantly associated with improved followup compliance. Paternal age, primary physician type, medical insurance type, income, education level and environment (urban, suburban or rural) were not significant. CONCLUSIONS: Approximately a third of children treated nonsurgically for vesicoureteral reflux will be lost to followup. Only older maternal age predicts for good compliance. Preconceptions about compliance on the basis of other factors, such as socioeconomic status and primary physician type, may be incorrect. Furthermore, the notion that certain forms of medical insurance plans may help to promote followup may also be unsupported. These children would benefit from efforts to improve compliance with a medical regimen or early correction of reflux. PMID- 8683757 TI - Comparative urodynamic findings after primary valve ablation, vesicostomy or proximal diversion. AB - PURPOSE: There is little known about the effect of urinary diversion on the bladder of children with posterior urethral valves. There is a fear that diversion may result in contracted noncompliant bladders. We wished to compare urodynamic parameters in patients who underwent primary ablation of posterior urethral valves and in those who underwent diversion in the form of vesicostomy or pyelostomy. MATERIALS AND METHODS: Urodynamics were done in 32 boys with a history of posterior urethral valves divided into 3 groups based on initial treatment: 1) transurethral valve ablation; 2) cutaneous vesicostomy, subsequent closure and valve ablation, and 3) proximal cutaneous pyelostomy, subsequent reconstitution and valve ablation. RESULTS: Patients who underwent initial diversion with vesicostomy or pyelostomy had bladders with larger functional capacity, better compliance and less instability. Chronic renal failure developed in 25% of the patients who underwent primary valve ablation and 33% of those who underwent diversion. Average period of diversion in vesicostomy and pyelostomy patients was 25 months. CONCLUSIONS: Based on our findings temporary diversion does not seem to damage bladders. On the contrary, placing a damaged bladder at rest may help to improve bladder function. Bladder function following reconstitution correlated poorly with ultimate outcome and progression to renal failure. While we do not recommend temporary diversion as the treatment of choice for patients with posterior urethral valves, we believe that when chosen as treatment, it can be safely performed with little risk of further damage to the bladder. PMID- 8683758 TI - Sibling reflux: a dual center retrospective study. AB - PURPOSE: Siblings of index patients with vesicoureteral reflux are known to have an increased incidence of reflux. Previous reports may be biased due to significantly more female siblings undergoing screening. In addition, it has been suggested that screening is unnecessary in older children. MATERIALS AND METHODS: We retrospectively reviewed the records of probands with vesicoureteral reflux. A total of 422 families comprising 622 siblings was identified at our centers from 1985 to 1994. Of the 255 boys and 277 girls newborn to 16 years old (mean age 6.2 years) 85% were evaluated. Almost 43% of the probands (225) were older than 7 years. RESULTS: Vesicoureteral reflux was noted in 144 siblings (52 boys and 92 girls, 27%). The majority had low grade reflux but in 111 (77%) maximum reflux grade was II or III. Reflux nephropathy was demonstrated on a nuclear renal scan in 18 of the 132 tested siblings (13.6%). In all of these children reflux was grades II to IV and 27% were older than 10 years. CONCLUSIONS: When vesicoureteral reflux is discovered, all siblings should be considered for screening. The evaluation of older siblings remains controversial, since they comprise only a small fraction of all siblings with reflux but may have a significant portion of reflux nephropathy. There was a 27% overall incidence with a 33% rate in girls. The incidence of reflux in siblings decreased after age 7 years but reflux nephropathy was identified even in the older children. PMID- 8683759 TI - Endoscopic correction of vesicoureteral reflux secondary to posterior urethral valves. AB - PURPOSE: We review our experience with children with high grade vesicoureteral reflux secondary to posterior urethral valves treated endoscopically with subureteral polytetrafluoroethylene (Teflon) injection. MATERIALS AND METHODS: Between 1985 and 1994, 54 infants and children were diagnosed with posterior urethral valves of whom 38 (70%) had vesicoureteral reflux. In 9 patients reflux resolved after valve ablation. Seven patients underwent nephroureterectomy for nonfunctioning kidneys and in 2 reflux was treated with continuous chemoprophylaxis. The remaining 20 patients underwent an antireflux procedure, including reimplantation of the ureters in 5 and subureteral polytetrafluoroethylene injection in 15. Of the 15 patients who underwent injection 6 had unilateral and 9 had bilateral vesicoureteral reflux. According to the international classification reflux was grade IV in 6 ureters and grade V in 18. Patient age at injection ranged from 8 months to 6 years (mean 2.2 years). RESULTS: Reflux was eliminated in 17 ureters after a single subureteral polytetrafluoroethylene injection. Five ureters required 2 injections and 2 ureters required 3 to correct reflux. Followup of the 15 patients ranges from 1 to 10 years. Followup voiding cystography in the 15 patients (24 ureters) showed no evidence of recurrence of reflux. No clinically untoward effects were noted in these children from the use of polytetrafluoroethylene as an injectable material. CONCLUSIONS: Subureteral polytetrafluoroethylene injection is a simple and effective endoscopic alternative to open surgery for the management of high grade vesicoureteral reflux secondary to posterior urethral valves. PMID- 8683760 TI - Lower pole heminephrectomy: its role in treating nonfunctioning lower pole segments. AB - PURPOSE: We assessed the role and long-term outcome of lower pole heminephrectomy in the treatment of nonfunctioning lower renal moieties in children with duplex kidneys. MATERIALS AND METHODS: Between 1979 and 1994, 54 lower pole heminephrectomies were performed in 53 patients 1 to 192 months old (mean age 54) with duplex systems. A total of 15 patients was prenatally diagnosed, while the others presented with a urinary tract infection (36), orchiepididymitis (1) and failure to thrive (1). The surgical technique was essentially similar to that of upper pole heminephrectomy. RESULTS: Operative course was uneventful except for intraoperative bleeding in 5 cases, which necessitated blood transfusion, and a postoperative urinary tract infection in 1. Followup ranged from 3 to 168 months (mean 56.9). Postoperative renograms available in 34 cases showed unchanged differential function in 12 and an ipsilateral 2 to 14% decrease (mean 5.65%) in 22. No late complications were detected except in 1 patient, who had postoperative urinary tract infections and subsequently underwent removal of the ureteral stump. Our series includes 4 patients with solitary ipsilateral upper poles (after the contralateral kidney was removed or nonfunctioning) who had good renal function at long-term followup despite the reduced parenchymal mass. CONCLUSIONS: Based on our experience it seems that lower pole heminephrectomy is the treatment of choice in cases of nonfunctioning dilated lower segments of duplicated kidneys. PMID- 8683761 TI - Unilateral nephrectomy induces the expression of the Wilms tumor gene in the contralateral kidney of the adult rat. AB - PURPOSE: The tumor suppressor gene WT-1 encodes a nuclear deoxyribonucleic acid binding protein that is a transcriptional regulator. This gene is commonly deleted or defective in Wilms tumors and the Denys-Drash syndrome. Recently WT-1 was demonstrated to be essential for the development of the urogenital tract. We determined whether we could induce WT-1 expression in mature kidneys induced to grow by performing contralateral nephrectomy in mature rats. MATERIALS AND METHODS: Northern analysis with a 32phosphorus-labeled antisense riboprobe synthesized by in vitro transcription of a 731 bp complementary deoxyribonucleic acid insert spanning exons 1 to 7 of the rat WT-1 in a pT7 Blue vector was used to demonstrate the expression of WT-1 in the developing and adult Sprague-Dawley rat kidney. RESULTS: Transcript levels of WT-1 in the rat kidney decreased from day 0 (day of birth) to day 16, after which WT-1 transcripts were undetectable in the normal rat kidney. Unilateral nephrectomy in the adult male Sprague-Dawley rat (250 to 300 gm.) induced the expression of WT-1 ribonucleic acid in the contralateral kidney to detectable levels by Northern analysis 0.25 hours after nephrectomy. Subsequently levels of WT-1 ribonucleic acid decreased progressively to undetectable by 3 hours after nephrectomy. Expression of this gene was not detected in the normal kidneys of adult rats or sham operated adult rats. CONCLUSIONS: These data suggest that the WT-1 gene product is involved in normal renal growth in the adult and developing rat kidney. PMID- 8683762 TI - Is contralateral exploration of the kidney necessary in patients with Wilms tumor? AB - PURPOSE: Surgical exploration of the contralateral kidney in patients with Wilms tumor is standard practice. The introduction of modern imaging techniques (ultrasound, computerized tomography and magnetic resonance imaging) in place of excretory urography has led to a more accurate definition of intrarenal pathology. Is contralateral kidney exploration still necessary in patients with Wilms tumor? MATERIALS AND METHODS: We reviewed the records of 75 patients from 3 medical centers who were evaluated and treated for Wilms tumor in the last 14 years. All children underwent preoperative excretory urography, computerized tomography, ultrasound and/or magnetic resonance imaging. RESULTS: Seven bilateral Wilms tumors were diagnosed preoperatively and confirmed surgically, whereas extensive operative exploration of the contralateral kidney in the other 69 patients revealed no additional pathological condition. This concurred with preoperative radiological findings with 100% sensitivity and specificity. Furthermore, 1 month to 12 years of followup (mean 4.3 years) revealed no tumor in the contralateral kidney. The major postoperative complication was small bowel obstruction in 5 patients 15 to 180 days (mean 77.2) after explorative laparotomy. CONCLUSIONS: In all patients preoperative radiological investigation was accurate in excluding bilaterality. With modern imaging techniques and effective chemotherapy extensive contralateral renal exploration may no longer be mandatory for managing Wilms tumor. PMID- 8683763 TI - Early characterization of a novel metastatic disease model of murine neuroblastoma. AB - PURPOSE: We developed a measurable metastatic disease model of murine neuroblastoma. MATERIALS AND METHODS: Murine neuroblastoma cells (C1300) were cotransfected with plasmids encoding for neomycin resistance and beta galactosidase. Transfected cells were selected by culture in media containing gentamicin. Monoclonal and polyclonal transfected cell lines were selected from surviving colonies. Three cell lines (M1, P1 and P2) were cultured and inoculated into female A/J mice. A control group was included for analysis. Animals were sacrificed on day 18 after injection, and primary tumors and organs were assayed for beta-galactosidase activity by chemoluminescence assay. Animal livers were stained with hematoxylin and eosin for histological assessment. RESULTS: Transfected primary tumor tissue demonstrated beta-galactosidase activity. Livers from control mice had no beta-galactosidase activity. Of the 3 cell lines tested M1 showed the highest levels of beta-galactosidase activity in liver and lung, suggesting homology with human disease. Kidneys from all experimental groups had elevated beta-galactosidase activity, suggesting that the kidney is a common metastatic site for murine neuroblastoma. Hematoxylin and eosin sections demonstrated normal livers in control mice and micrometastases in the livers of all experimental animals. CONCLUSIONS: A novel metastatic disease model for murine neuroblastoma has been developed. By transfecting tumor cells with genetic material encoding 2 marker proteins distant metastases may be detected by assay for beta-galactosidase or cells can be selected for neomycin resistance, even at a stage when they are difficult to identify by standard histological techniques. PMID- 8683764 TI - Treatment of pediatric urolithiasis between 1984 and 1994. AB - PURPOSE: We report our experience with the management of pediatric urolithiasis during a 10-year period. Our aim was to assess the impact of new technology in the treatment of pediatric urolithiasis. MATERIALS AND METHODS: We retrospectively reviewed the records of all patients up to age 18 years in whom urolithiasis was treated from 1984 to 1994. In 37 cases 24-hour urine collections were available for metabolic evaluation. RESULTS: A total of 100 pediatric patients was treated for urolithiasis. Mean followup was 36 months. A total of 79 patients underwent 115 procedures for symptomatic urolithiasis and 21 were treated nonoperatively. In 42 patients structural anomalies of the urinary tract required additional management. Metabolic abnormalities in 48 patients included hypercalciuria in 19, defined as greater than 4 mg./kg./24 hours calcium by 24 hour urine collection. Only 24 of the 100 patients had no identifiable predisposing factors. Procedures included shock wave lithotripsy in 42 cases, basket extraction with or without ureteroscopy in 20, percutaneous nephrostolithotomy in 11 and litholapaxy in 12. Open surgery included cystolithotomy in 10 cases and other forms of open lithotomy in 15. Thus, open surgical removal was necessary in 1 of 5 cases. CONCLUSIONS: Compared to the traditional mode of stone treatment, fewer patients required open surgery. Our results indicate that a comprehensive approach to the care of pediatric patients with urolithiasis requires attention to metabolic and structural abnormalities. PMID- 8683765 TI - Percutaneous vacuum vesicolithotomy under direct vision: a new technique. AB - PURPOSE: The number of vesical calculi is increasing as the number of patients with intestinocystoplasty increases. We describe our technique for easily removing vesical calculi in children via an atraumatic percutaneous endoscopic approach. MATERIALS AND METHODS: The procedure involves percutaneous suprapubic puncture and direct visualization of the calculi via cystoscopy through the urethra or via a second suprapubic puncture when the bladder neck is closed. The stones are vacuumed up 1 at a time with suction tubing through the suprapubic working sheath in a controlled manner with no urethral trauma. Ten patients 3 to 16 years old (mean age 8) with vesicolithiasis underwent percutaneous vacuum vesicolithotomy under direct vision in 1993 to 1995. RESULTS: Two to 12 bladder calculi were extracted (mean 7). All calculi less than 1 cm. were removed by this procedure. All bladder calculi between 1 and 1.5 cm. were also removed but they required simultaneous electrohydraulic lithotripsy. There were no complications at a mean 1-year followup. Mean hospitalization was less than 24 hours (range 0 to 3 days). CONCLUSIONS: Percutaneous vacuum vesicolithotomy is highly successful, easy to perform and safe for extracting vesical calculi. Since the procedure is done through a percutaneous sheath, it is particularly suited to the individual with an absent, small caliber, sensitive or surgically reconstructed urethra. PMID- 8683766 TI - The natural history of nephrocalcinosis in premature infants treated with loop diuretics. AB - PURPOSE: We investigated the natural history of nephrocalcinosis in premature infants treated with furosemide and attempted to identify factors to predict infants most at risk. MATERIALS AND METHODS: We evaluated 13 preterm infants in this longitudinal pilot study. During hospitalization and while receiving a loop diuretic nephrocalcinosis developed in each patient. Patients were divided into groups based on resolution (6) and nonresolution (7) according to spontaneous resolution of nephrocalcinosis at any point during followup. The 2 groups were compared to each other and to a control group. RESULTS: Mean followup after discontinuation of furosemide in the resolution versus nonresolution groups was 10.3 and 7.7 months, respectively. Between the 2 groups there was no significant difference in average gestational age, birth weight, number of days hospitalized or on furosemide, or total furosemide dose. Mean calcium-to-creatinine ratio while receiving furosemide at the time nephrocalcinosis developed was 0.38 in the resolution group but 2.23 in the nonresolution group (p < 0.005). Initial calcium to-creatinine ratio in age matched infants who did not have nephrocalcinosis was 0.4. Frank renal stones developed in 2 of the 7 patients without resolution and 0 of the 6 with resolution. When nephrocalcinosis resolved, it was at a mean of 5.2 months following discontinuation of the diuretic. CONCLUSIONS: Early data indicate that nephrocalcinosis resolves in approximately 50% of premature infants 5 to 6 months after discontinuation of furosemide. The only factor that appears to be predictive of the infants who will have resolution is the calcium-to creatinine ratio when nephrocalcinosis is diagnosed. In patients without resolution this ratio is much higher than in age adjusted normal controls, while in those with resolution it appears normal for age. PMID- 8683767 TI - Developmental renal physiology of the low birth weight pre-term newborn. AB - PURPOSE: The remarkable growth of the kidney and the rapid changes in renal function in the second half of gestation and early postnatal period are discussed. MATERIALS AND METHODS: Adaptation to the extrauterine environment involves immediate postnatal natriuresis that is prolonged in the pre-term neonate, followed by the sodium retention necessary for growth. Glomerular filtration rate increases throughout the postnatal period, and it is modulated by the renin-angiotensin system and prostaglandins. Because of this, the fetus and neonate are particularly susceptible to renal injury following the administration of angiotensin converting enzyme inhibitors or nonsteroidal anti-inflammatory drugs. Renal tubular function in the neonate is characterized by reduced renal concentration and acidification ability, which can be further compromised by obstructive uropathy. Urine calcium excretion is high in the neonate, which can be aggravated by calciuric drugs, such as furosemide and glucocorticoids. RESULTS: Reduced renal mass results in compensatory renal growth even in the fetus, a response that could prove maladaptive later in life through excessive glomerular hyperfiltration and progressive interstitial fibrosis. CONCLUSIONS: These factors underscore the importance of attempting to maximize functional renal mass in the neonate or infant with renal impairment of any etiology. PMID- 8683768 TI - Fetal therapy for obstructive uropathy: diagnosis specific outcomes [corrected]. AB - PURPOSE: Attempts to evaluate prenatal vesico-amniotic shunt therapy have been hampered by inconsistencies in patient selection, treatment and termination criteria, and outcomes measurement. Outcomes have generally been measured against those of patients with postnatally detected posterior urethral valves. The purpose of this report was to evaluate the influence of the underlying diagnosis on the clinical outcomes of fetuses undergoing evaluation for prenatal intervention for suspected obstructive uropathy. Furthermore, specific outcomes diagnosis was compared to the published natural history of these disorders to begin to establish a basis for measuring the efficacy of prenatal intervention. MATERIALS AND METHODS: We retrospectively reviewed the outcomes of 55 consecutive patients undergoing prenatal evaluation using structured outcome measures stratified by specific diagnoses to provide a comparison to the reported natural history for each underlying disorder. RESULTS: All fetuses had early onset of oligohydramnios/anhydramnios representing the worst end of the spectrum. Compared to postnatally diagnosed patients, prenatally diagnosed patients with posterior urethral valves had lower survival (60 versus 93%) but similar postnatal renal failure rates (31 versus 33%). Cases of prenatally detected but untreated posterior urethral valves had a 44% renal failure rate. In fetuses with the prune belly syndrome survival (86 versus 72%) and renal function rates (17 versus 27% renal failure) compared favorably with the postnatal experience, although 55% of the cases had significant urethral obstruction. All patients with urethral atresia died. CONCLUSIONS: The underlying etiology of obstruction appears to have a marked influence on clinical outcome independently of treatment. When evaluated by specific diagnosis, intervention appears to provide outcomes in these high risk fetuses that are comparable to those for disease detected postnatally. Interpretation of series that do not distinguish cases by onset, severity and specific pathological process is problematic. Greater standardization of patient selection, treatment and outcome measurement, including the use of specific diagnoses, is necessary to allow an accurate assessment of the efficacy and proper role of fetal therapy. PMID- 8683769 TI - Sonographic renal parenchymal and pelvicaliceal areas: new quantitative parameters for renal sonographic followup. AB - PURPOSE: We determined better quantitative parameters for renal sonography and applied these parameters to the evaluation and followup of prenatal hydronephrosis. MATERIALS AND METHODS: We retrospectively reviewed normal renal ultrasound studies of 120 children and serial ultrasound studies of 40 with prenatal hydronephrosis. Renal length, bipolar parenchymal thickness and anteroposterior pelvic diameter were measured from serial sonograms of patients with hydronephrosis. Renal longitudinal parenchymal area and renal longitudinal pelvicaliceal area were determined from the sonograms of normal children and from serial studies of patients with hydronephrosis using computer planimetry. Data from normal children were plotted to construct a renal parenchymal area growth chart. Length and area measurements were compared using regression analysis. The ability of these parameters to predict patients who would require pyeloplasty was examined. RESULTS: Normal parenchymal area correlated well with normal renal length (r2 = 0.92). Differential parenchymal area correlated with differential function (r2 = 0.75), while differential length and bipolar thickness correlated poorly with function (r2 = 0.01 and 0.42, respectively). The ratio of parenchymal to-pelvicaliceal area differentiated patients with unilateral hydronephrosis requiring pyeloplasty from those treated conservatively. The ratio was less than 1.6 in all patients requiring pyeloplasty and greater than 1.6 in those followed conservatively. CONCLUSIONS: Renal parenchymal area provides a more accurate estimate of renal size and function in the hydronephrotic kidney than traditional 1-dimensional measurements. In our limited series the ratio of renal parenchymal to-pelvicaliceal area allowed the prediction of patients who required pyeloplasty. PMID- 8683770 TI - The value of Doppler resistive index and peak systolic velocity in the evaluation of porcine renal obstruction. AB - PURPOSE: We evaluated the use of Doppler resistive indexes and systolic velocities as diagnostic tools in a partially obstructed animal model. MATERIALS AND METHODS: We studied 12 normal pigs by Doppler sonography, which served as control units. In 9 subjects partial ureteral obstruction was then created surgically, and 3 continued as controls. The presence or absence of obstruction was confirmed by ultrasound, antegrade nephrostography and intrapelvic pressure monitoring. Doppler parameters were measured 1 hour to 21 days postoperatively. Resistive index, and angle corrected peak and mean systolic velocities were measured bilaterally from samplings of interlobar and arcuate arteries. An average of 4 samplings per kidney was obtained at each session. Data from the control and obstruction groups were compared for statistical differences. RESULTS: In controls mean resistive index was 0.53, and peak and mean systolic velocities were 0.38 and 0.26 m. per second, respectively. In the subacute period after obstruction (defined as days 4 to 21) mean resistive index was 0.54, and peak and mean systolic velocities were 0.33 and 0.22 m. per second, respectively. Compared to control data there was no significant change in resistive index after obstruction (p = 0.6). However, peak and mean systolic velocities showed significant downward trends (p < 0.05). CONCLUSIONS: Known small sequential changes in renal blood flow after ureteral obstruction are reflected in flow velocities, as measured by duplex Doppler sonography. However, resistive indexes are not useful in assessing these changes in renal blood flow, and they do not correlate with the presence or absence of obstruction in this animal model. PMID- 8683771 TI - Efficacy of retrograde endopyelotomy in children. AB - PURPOSE: Endopyelotomy has been performed extensively in adults for the treatment of ureteropelvic junction obstruction. To determine its applicability to the pediatric population we reviewed our experience with retrograde endopyelotomy in children. MATERIALS AND METHODS: Eight children 4 to 15 years old were treated with retrograde endopyelotomy and results were compared to those of a concurrent group of 8 treated with open pyeloureteroplasty. RESULTS: Retrograde endopyelotomy was done in all of our patients with lower ureteral dilatation (as an adjunct measure in 5). Seven patients had symptomatic and radiographic improvement. The patient in whom the procedure failed had a crossing lower pole vessel. Postoperative analgesia, length of hospitalization and cost were lower in the endopyelotomy group. CONCLUSIONS: Retrograde endopyelotomy is feasible in children older than age 4 years and it results in reduced morbidity. The success rate is high but open surgery remains the standard, particularly when a crossing lower pole vessel is identified preoperatively. PMID- 8683772 TI - Management of the failed pyeloplasty. AB - PURPOSE: We present our experience with repeat surgery for persistent ureteropelvic junction obstruction. MATERIALS AND METHODS: We retrospectively reviewed the records of patients who underwent pyeloplasty for ureteropelvic junction obstruction between 1984 and 1994, focusing on those who underwent repeat surgery for persistent ureteropelvic junction obstruction after initial pyeloplasty. RESULTS: During the 10-year period 127 pyeloplasties were done by a single surgeon (R. D. W.). Three cases of persistent ureteropelvic junction obstruction occurred in this primary pyeloplasty series (success rate 97.6%). During the same period 9 other patients were referred to us from elsewhere for persistent ureteropelvic junction obstruction after initial pyeloplasty (total 12 patients). Ten patients underwent repeat pyeloplasty with a postoperative stent in place. Two patients needed nephrectomy at the initial repeat procedure and 1 of the 10 repeat pyeloplasty patients ultimately underwent nephrectomy. Six patients who had recurrent ureteropelvic junction obstruction were younger than 6 months at the time of the original pyeloplasty. Excessive urinary drainage was noted in 2 of our 3 cases of failed pyeloplasty. Thus, in 9 patients satisfactory resolution of obstruction was achieved by repeat pyeloplasty (salvage rate 75%). CONCLUSIONS: Persistent ureteropelvic junction obstruction is an uncommon complication after pyeloplasty. Infants who undergo pyeloplasty may be more prone to persistent obstruction after pyeloplasty. Prolonged urinary drainage seems to be a harbinger of persistent ureteropelvic junction obstruction. Careful repeat pyeloplasty with attention to preservation of the blood supply and meticulous watertight anastomosis led to satisfactory resolution of ureteropelvic junction obstruction in 75% of the cases. PMID- 8683773 TI - Ureteropelvic junction obstruction with concurrent renal pelvic calculi in the pediatric patient: a long-term followup. AB - PURPOSE: We determined the long-term prognosis of the pediatric patient presenting with simultaneous ureteropelvic junction obstruction and a renal calculus. MATERIALS AND METHODS: We retrospectively reviewed all individuals younger than 17 years who presented to our institutions with simultaneous ureteropelvic junction obstruction and an ipsilateral renal calculus. RESULTS: Simultaneous ureteropelvic junction obstruction with nonstruvite calculi was present in 22 patients, while 6 had struvite calculi. Median age at diagnosis was 11 years (range 5 to 16). During a median followup of 9 years (range 2 to 38) renal calculi recurred in 19 patients (68%), including 10 (36%) with 1 and 9 (32%) with 2 or more recurrences. Median time to first stone recurrence was 11 years (range 2 to 38). Of the 22 patients with nonstruvite calculi 15 (68%) had recurrence. An identifiable metabolic etiology for renal lithiasis was found in 13 of these patients (87%). In contrast, only 2 of the 7 patients (29%) with nonstruvite calculi and no recurrent stones had an identifiable abnormality. This finding suggests that the presence of an identifiable metabolic abnormality significantly predisposes to recurrent nonstruvite renal lithiasis (p < 0.01). CONCLUSIONS: Of the pediatric patients presenting with simultaneous ureteropelvic junction obstruction and a renal calculus 68% will have recurrent renal lithiasis. It remains to be determined whether active treatment of coexisting metabolic abnormalities could prevent or reduce the incidence of recurrent stone disease. PMID- 8683774 TI - Is there a best alternative to treating the obstructed upper pole? AB - PURPOSE: We addressed whether salvage of upper pole renal units in comparison to partial nephrectomy affects differential renal function in patients with a duplicated obstructed upper pole. MATERIALS AND METHODS: We retrospectively reviewed the records of all children who underwent surgery for a unilateral obstructed duplicated kidney at our institution from 1988 to 1995. Patients were evaluated with respect to postoperative complications, reoperation rate and percent change in differential renal function of the obstructed duplicated kidney, as determined by nuclear renography. RESULTS: We identified 46 patients with a unilateral obstructed upper pole of a duplicated kidney who were divided into 2 groups. Group 1 (12 patients) underwent an upper pole salvage procedure, that is ureteropyelostomy or ureteroureterostomy, and group 2 (31 patients) underwent partial nephrectomy. Three reoperations (25%) were performed in group 1 and 1 (4%) was done in group 2. Postoperative symptomatic urinary tract infections were diagnosed in 3 group 1 patients (25%) and in 2 (8%) in group 2. Average change in ipsilateral renal function in the 8 patients who underwent upper pole salvage procedures was 2.25 +/- 2.34% (range -6 to 12). In the 8 patients who underwent upper pole nephrectomy and who also had postoperative renal scans average change in function was -1.25 +/- 4.51% (range -23 to +16). CONCLUSIONS: There was no statistically significant loss of relative renal function in patients treated with partial nephrectomy and no significant gain in relative renal function in those treated with an upper pole salvage procedure. The reoperation rate was higher in the upper pole salvage than in the partial nephrectomy group (25 versus 4%). While not statistically significant, we believe that this rate is clinically important. We think that partial nephrectomy should remain the preferred treatment for most patients with obstructed duplicated kidneys. PMID- 8683775 TI - Use of bladder stimulation in high risk patients. AB - PURPOSE: We evaluated whether intravesical bladder stimulation therapy is effective in improving bladder compliance in patients with myelomeningocele, neurogenic bladder and high risk urodynamic parameters. MATERIALS AND METHODS: We reviewed the charts of all patients treated with bladder stimulation therapy at our institution since 1984, and identified 7 with pretreatment high risk urodynamic findings (percent expected bladder capacity 60% or less and bladder capacity pressure 50 cm. water or greater). Urodynamic and clinical data were reviewed before and after therapy. RESULTS: Following bladder stimulation in 4 of the 7 patients percent expected bladder capacity substantially increased and bladder capacity pressure decreased to safe levels. Two patients had minimal increases in percent expected bladder capacity but bladder capacity pressure decreased to 50 cm. water or less. Overall percent expected bladder capacity increased from an average pretreatment value of 44% before to 65% after bladder stimulation (p < 0.05). Average bladder capacity pressure improved from 63.9 cm. water before to 32.3 cm. water after treatment (p < 0.05). Also, bladder compliance improved in all 7 patients to the point that bladder augmentation was not performed. CONCLUSIONS: Bladder stimulation is effective in improving bladder compliance in high risk patients and it may be a viable alternative to enterocystoplasty. Further long-term followup will be necessary to establish the longevity of this response. PMID- 8683777 TI - A new technique for assessing detrusor leak point pressure in patients with spina bifida. AB - PURPOSE: We report a new modification of the technique used to measure detrusor leak point pressure in patients with myelodysplasia and discuss its clinical implications. MATERIALS AND METHODS: We assessed detrusor leak point pressure during standard multichannel urodynamics in 77 patients with spina bifida. At leakage and in the absence of a detrusor contraction detrusor pressure is noted and the catheter is removed. With the cessation of leakage the catheter is reinserted and detrusor pressure is again noted. This cycle is repeated several times and the average difference is noted. In 23 patients there was no identifiable detrusor leak point pressure. The remaining 54 patients with a detrusor leak point pressure are included in this report. Also reviewed were renal ultrasound studies and voiding cystourethrograms for each patient. RESULTS: Three groups of patients were identified: 1 (20 patients)-detrusor leak point pressure greater than 40 and less than 40 cm. water with the catheter in and out, respectively; 2 (29)-detrusor leak point pressure consistently less than 40 cm. water with the catheter in and out, and 3 (5)-detrusor leak point pressure consistently greater than 40 cm. water with the catheter in and out. There was a 5% incidence of upper tract changes in group 1 and a 40% incidence in group 3. All patients in group 2 had normal upper tracts. CONCLUSIONS: A difference in upper tract changes was noted between groups 1 and 3, although in both groups detrusor leak point pressure was greater than 40 cm. water using standard measurement techniques and similar rates of upper tract changes would have been expected. Our modification may be a more accurate measurement of detrusor leak point pressure. It provides a better means of identifying patients at increased risk for renal deterioration and assessing outlet resistance. PMID- 8683776 TI - Expanded followup of intravesical oxybutynin chloride use in children with neurogenic bladder. AB - PURPOSE: We evaluated the long-term results of intravesical oxybutynin chloride use in children with neurogenic bladders who could not tolerate or whose conditions were refractory to oral therapy. MATERIALS AND METHODS: We reviewed our experience with 28 children (myelomeningocele in 27 and imperforate anus in 1) who presented with urinary incontinence and/or elevated bladder pressures refractory to intermittent catheterization and oral anticholinergic medication. Intravesical oxybutynin was administered to each child by instillation of 5 mg. crushed oxybutynin chloride in 10 cc sterile saline 2 times daily during catheterization. RESULTS: Seven patients (25%) could not tolerate intravesical oxybutynin secondary to anticholinergic side effects. The remaining 21 children have been followed on intravesical oxybutynin for a mean of 35 months (range 3 to 67). Of these 21 children 12 (57%) became completely dry day and night, 5 (24%) achieved daytime continence between catheterizations and 4 (19%) remained clinically unchanged with 2 in diapers. On urodynamics these 21 patients had increased bladder capacity of up to 1,150% (mean 237%, p < 0.0001) and decreased mean maximum filling pressures of -31% (p = 0.002). CONCLUSIONS: Although a number of patients continued to have anticholinergic side effects, a majority had significant improvement in urodynamic parameters and continence. The response appears to be durable, and it spares many of these children from undergoing bladder augmentation. PMID- 8683778 TI - Bladder stimulation therapy improves bladder compliance: results from a multi institutional trial. AB - PURPOSE: We examined data from multiple institutions to determine whether intravesical bladder stimulation therapy is effective in improving bladder compliance by increasing bladder capacity and lowering bladder storage pressures. MATERIALS AND METHODS: The charts of 568 patients from 11 institutions were evaluated. Of the 568 patients 335 had adequate and accurate pretreatment and posttreatment urodynamic studies, and were included in this study. A total of 155 patients was from Children's Memorial Hospital, while the remaining 180 were from 10 other institutions. Bladder capacity and bladder capacity pressure were determined for each patient before and after therapy. RESULTS: Overall, 53% of patients had increased bladder capacity of 20% or greater after treatment (average increase 105 cc), which represents a 63% increase from pretreatment values. This increase occurred in an average of 1.9 years. Further analysis of this subset of patients revealed that in 90% intravesical storage pressures were decreased or maintained within a safe range (less than 40 cm. water). Evaluation of patients who did not respond to bladder stimulation with a 20% or greater increase in bladder capacity revealed that they had nearly normal bladder capacity before therapy. When the data on bladder capacity and bladder capacity pressure from Children's Memorial Hospital were compared to results from the 10 other institutions, there were no appreciable differences. CONCLUSIONS: Bladder stimulation is effective in increasing bladder capacity without significantly elevating storage pressure in a majority of patients. We conclude that this technique is safe and effective in improving bladder compliance, and that it is reproducible elsewhere. PMID- 8683779 TI - Lack of feminization of the cremaster nucleus by prenatal flutamide administration in the rat and pig. AB - PURPOSE: The sexually dimorphic cremaster nucleus contains motoneurons that project via the genitofemoral nerve and theoretically direct androgen dependent testicular descent. The effects of flutamide on descent and masculinization of the cremaster nucleus were studied in the rat and pig. MATERIALS AND METHODS: Flutamide was given to pregnant rats and pigs on days 16 to 22 and 65 to 113 of gestation, respectively. Tissues were perfused and examined at birth (pigs) or at age 30 days (rats). Spinal cords were removed, sectioned and immunohistochemically stained for serotonin (rats) or substance P (pigs) to demarcate the position of the cremaster nucleus and allow the determination of cremaster motoneuron number. RESULTS: After exposure to flutamide testes were undescended in 6 of 9 rats and 7 of 10 pigs. Cremaster motoneuron number per nucleus were 288 +/- 22 in control versus 250 +/- 27 in flutamide treated rats, and 165 +/- 28 in control versus 148 +/- 24 in flutamide treated pigs. The decrease in motoneuron number by flutamide was significant in both species (p < 0.02) but it did not approach the levels in female rats (93 +/- 11) and pigs (57 +/- 12). Cremaster motoneuron number did not correlate with testicular position. Porcine undescended testes were associated with a significant increase in mean gubernacular volume. CONCLUSIONS: Unlike other sexually dimorphic spinal cord nuclei masculinization of the cremaster nucleus appears to be largely androgen independent and it does not correlate with ipsilateral testicular descent. These data suggest that androgens do not mediate descent of the testes via the efferent limb of the genitofemoral nerve. PMID- 8683780 TI - Laparoscopically assisted testicular autotransplantation for management of the intraabdominal undescended testis. AB - PURPOSE: The intra-abdominal testis continues to present a considerable urological challenge and the approach to its management continues to evolve. We report our initial experience with laparoscopically assisted testicular autotransplantation. MATERIALS AND METHODS: An intra-abdominal testicle was identified laparoscopically in 5 patients who subsequently underwent testicular autotransplantation. RESULTS: The success rate was 100% and median operative time was 5 hours. All patients were discharged home the day after surgery with no complications and a good result. CONCLUSIONS: Because of success with this technique, this procedure offers significant advantages (decreased hospital stay and lower morbidity) than an open or 2-stage Fowler-Stephens approach. PMID- 8683781 TI - The effects of androgen administration on phallic androgen receptor expression. AB - PURPOSE: Whether androgens down regulate the androgen receptor during penile development is controversial. We investigated the effects of androgens on penile androgen receptor expression. MATERIALS AND METHODS: We injected prepubertal hypogonadotropic hypogonadal microphallic rats with testosterone or dihydrotestosterone. Specimens were obtained at 3 (prepuberty), 9 (puberty to early postpuberty) and 12 weeks (late postpuberty). At necropsy we compared penile size and androgen receptor expression of these animals to those of age matched nontreated hypogonadotropic hypogonadal and normal controls. RESULTS: At age 3 weeks prepubertal androgens up regulated androgen receptor expression and significantly increased penile size compared to normal and untreated hypogonadotropic hypogonadal controls. By 9 weeks the normal down regulation of androgen receptor that occurs with maturation was present. Prepubertal androgens failed to accelerate or exaggerate the normal maturational loss of the androgen receptor. At 9 weeks penile size of normal controls and prepubertal androgen treated animals was identical. Interestingly despite down regulation of the penile androgen receptor, normal animals continued to have increases in penile size between 9 and 12 weeks, while the prepubertal androgen treated animals had no penile growth. CONCLUSIONS: Prepubertal androgen administration in hypogonadotropic hypogonadal animals resulted in diminutive penises in adulthood. However, the decrease in penile size was not associated with an accelerated or exaggerated down regulation of the androgen receptor. This finding coupled with continued growth of the normal control penises after androgen receptor down regulation suggests that cessation of penile growth may not be solely related to down regulation of the penile androgen receptor. PMID- 8683782 TI - Congenital adrenal hyperplasia: is there an effect on penile growth? AB - PURPOSE: Experimental evidence in rodents suggests that prepubertal exposure to excess androgens may prematurely down regulate the penile androgen receptor and cause micropenis in adulthood. To evaluate the effect of prepubertal androgens on human penile growth we reviewed phallic development in male patients with congenital adrenal hyperplasia. MATERIALS AND METHODS: We retrospectively reviewed the records of 12 patients with 21-hydroxylase deficiency. Stretched penile length was recorded at diagnosis and at last followup. Bone age, height and weight were recorded at each visit. RESULTS: At diagnosis mean z-score for stretched penile length (z-score equals the number of standard deviations above or below the mean, that is z-score for micropenis equals -2.5) was 2.95 (1.23 to 4.88). Final mean z-score for stretched penile length in adulthood was -1.70 ( 2.96 to 1.87). Mean decrease in z-score for diagnosis until the last followup was -4.68 (-1.08 to -6.82). Only 2 of the 12 patients (17%) had micropenis in adulthood. Notably excessive adrenal androgen production resulted in diminutive stature with median height in adulthood in the 10th percentile. CONCLUSIONS: These findings suggest that excessive prepubertal androgen exposure due to congenital adrenal hyperplasia is associated with a reduction in adult somatic height but it does not routinely result in micropenis. PMID- 8683783 TI - The effect of prepubertal androgen exposure on adult penile length. AB - PURPOSE: Recent studies in the rat suggest that early exposure to exogenous testosterone accelerates the loss of androgen receptors and compromises eventual penile length. To determine whether this is true in men we measured adult penile length of patients treated in childhood for sexual precocity. MATERIALS AND METHODS: We examined 21 men with sexual precocity due to true precocious puberty (12) or congenital adrenal hyperplasia (9) who had been followed at our institution since childhood. Penile lengths were compared with data from normal men. RESULTS: Mean stretched penile length plus or minus standard deviation was 12.7 +/- 2.6 cm. in all patients, 12.1 +/- 2.6 cm. in those with true precocious puberty and 13.6 +/- 1.6 cm. in those with congenital adrenal hyperplasia. These lengths were not significantly different from those of normal men (12.4 +/- 2.7 cm.). CONCLUSIONS: In contrast to findings in rats, exposure to endogenous testosterone during gestation and/or childhood does not reduce adult penile length in men. Thus, the use of testosterone to treat childhood genitourinary anomalies would likely not compromise mature penile size. PMID- 8683784 TI - Semen analysis in young men with varicocele: preliminary study. AB - PURPOSE: Our aim was to determine whether the deleterious effect of varicocele on spermatogenesis, as reflected by semen analysis, occurs in boys as young as 17 to 19 years. Data analysis was done of semen variables of select boys attending randomly chosen schools. MATERIALS AND METHODS: A total of 36 healthy boys without a pathological condition detected by history, physical examination and scrotal ultrasound served as controls, and 38 with profound varicocele who were otherwise healthy served as an experimental group. All boys were followed as outpatients 2 times during the last year. We performed semen and clinical examinations, Doppler ultrasound assessment of venous reflux, and ultrasound measurement of testicular and pampiniform vein diameters. RESULTS: No significant differences were found in sperm concentration, volume, presence of spontaneous agglutination and pH between the 2 groups. There were significant differences in total and progressive sperm motility and vitality, which were lower in boys with varicocele, as were the number of normal sperm forms. There was a statistically and clinically significant linear negative relationship between sperm motility, and maximal and basal blood flow velocities as well as pampiniform vein diameter. CONCLUSIONS: Varicocele can affect spermatogenesis in boys as young as 17 to 19 years, as shown by the decrease in motility, vitality and number of normal forms of spermatozoons. The clinically significant correlations between semen analysis parameters and ultrasound findings allow the prediction of testicular function using ultrasound alone. PMID- 8683785 TI - Scrotal-inguinal ultrasonography: a technique for identifying the nonpalpable inguinal testis without laparoscopy. AB - PURPOSE: Treatment of the patient with a nonpalpable testis is controversial, since a high percent will have an inguinal testis or testicular remnant at exploration. While laparoscopy is an effective modality for localizing the intra abdominal testis, diagnostic laparoscopy is of limited value for patients with nonpalpable (normal or atrophic) inguinal testes. In an effort to identify preoperatively impalpable inguinal testes, we performed scrotal-inguinal ultrasound. MATERIALS AND METHODS: We evaluated 64 patients (74 nonpalpable testes) in the last 4 years, representing 20% of all those presenting with cryptorchidism. Average patient age was 4.5 years (range 6 months to 17 years). All patients underwent preoperative scrotal-inguinal ultrasound and surgical exploration. Diagnostic laparoscopy was reserved for patients with negative ultrasound and no palpable tissue in the scrotum or groin on a preoperative examination. RESULTS: Scrotal-inguinal ultrasound correctly identified 40 of the 42 inguinal testes (95% sensitivity), 7 of the 21 atrophic inguinal testes (33% sensitivity) and 1 of the 11 intra-abdominal testes (9% sensitivity). Therefore, scrotal-inguinal ultrasound correctly identified an inguinal testis or remnant for 47 of the 74 nonpalpable testes (64%), eliminating the need for diagnostic laparoscopy in those cases. For 26 of 74 nonpalpable testes with negative ultrasound 13 had an associated palpable inguinal or scrotal nubbin of tissue, and inguinal exploration only was performed, resulting in 9 orchiectomies, 2 inguinal orchiopexies and 2, 2-stage orchiopexies. Of the 13 nonpalpable testes without palpable nubbins and negative scrotal-inguinal ultrasound 8 were intra abdominal and 5 were atrophic inguinal testes. CONCLUSIONS: Scrotal-inguinal ultrasound identifies patients with nonpalpable testes who will maximally benefit from diagnostic laparoscopy. When diagnostic laparoscopy was limited to nonpalpable testes without palpable nubbins and negative scrotal-inguinal ultrasound, only 13 of 74 (18%) required laparoscopy. Inguinal exploration without further diagnostic studies is appropriate for boys with nonpalpable testes and palpable nubbins. PMID- 8683786 TI - Benefits and afterthoughts of laparoscopy for the nonpalpable testis. AB - PURPOSE: Recent reports in the literature indicate that laparoscopy tends to be seen as the most appropriate approach to the nonpalpable testis for diagnosis and therapy. The aim of our study was to evaluate the real benefits of laparoscopy in terms of diagnostic accuracy, safety, costs and validity of the chosen treatment. MATERIALS AND METHODS: We compared anatomical findings and results of the treatment of impalpable testes in 2 pediatric surgical groups, including 47 children treated laparoscopically during a 2 1/2-year period and 296 treated with open surgery (classic orchiopexy) in a 6 1/2-year period. RESULTS: There was no significant difference in the diagnosis of abdominal testes (51 versus 50%), whereas a difference was noted in inguinal (4 versus 15%) and absent testes (45 versus 35%). Differences in treatment were more striking. In the laparoscopic group standard orchiopexy was performed in 62.5% of cases versus 83% in the open group. Conversely the rate of Fowler-Stephens repairs increased from 5.5% of open surgery cases to 37.5% of laparoscopic cases. There have been no serious complications in the laparoscopic procedures. To date 6 of the 9 patients who underwent a staged Fowler-Stephens procedure have undergone complete repair (open second stage). A review of the literature revealed a similar but lower tendency to over perform the Fowler-Stephens operation in laparoscopic cases (34%) versus open surgery (8%). Also, in previous series there was a 29% orchiectomy rate during laparoscopy compared to only 5% in classic open surgery. In Italy under current public health programs overall costs of the laparoscopic approach to the nonpalpable testis become noncompetitive when the procedure is extended from only diagnostic to interventional use due to the need for additional trocars and other special instruments. In contrast, private health insurers provide an additional 30% for laparoscopic cases over the cost of open orchiopexy. CONCLUSIONS: Laparoscopy is definitively accurate in establishing the differential diagnosis of impalpable testis. The number of Fowler-Stephens repairs in the laparoscopic group seems inordinately high, probably due to a lack of definite standards in the proper assessment of the length of the internal spermatic vessel pedicle and the potential scrotal displacement of the testis. This reason may explain the higher number of orchiectomies reported in the literature. PMID- 8683787 TI - Treatment of high undescended testes by low spermatic vessel ligation: an alternative to the Fowler-Stephens technique. AB - PURPOSE: We determined whether testis viability after a Fowler-Stephens orchiopexy depends on ligating the spermatic vessels high and far proximal to the undescended testis. MATERIALS AND METHODS: Based on studies of testicular vascular anatomy we developed a technique of low spermatic vessel ligation and performed it on 39 high undescended testes in 33 patients. RESULTS: Testis viability was 97% at 1 month and 93% (25 of 27) at 1 year. CONCLUSIONS: Ligation of the spermatic vessels does not need to be performed high to ensure testis viability. Testicular vascular anatomy supports low spermatic vessel ligation and by decreasing tension on the testis low spermatic vessel ligation may enhance viability. A 2-stage laparoscopic approach to the high undescended testis is difficult to justify on the basis of cost or outcome analysis. PMID- 8683788 TI - Reappraisal of the role of human chorionic gonadotropin in the diagnosis and treatment of the nonpalpable testis: a 10-year experience. AB - PURPOSE: We retrospectively evaluated the ability of human chorionic gonadotropin (HCG) to make the nonpalpable cryptorchid testis become palpable and promote testicular descent. MATERIALS AND METHODS: Through surgical bookings we identified 94 patients younger than 11 years who received HCG between 1984 and 1994 for the diagnosis or treatment of a nonpalpable undescended testis. The dose of HCG was 1,500 IU/m.2 intramuscularly 2 times weekly for 4 weeks. Testis location was determined by physical examination before and after hormone administration, and confirmed at surgical exploration. RESULTS: Of the 99 nonpalpable testes identified in 94 patients 39 (39%) became palpable following HCG administration and only 2 (2%) completely descended. A total of 60 testes remained nonpalpable with the most common reason being an absent or severely atrophic testis (40, 67%). Of the testes remaining nonpalpable after hormonal stimulation 73% were surgically located at or distal to the internal ring. CONCLUSIONS: HCG is preoperatively efficacious in causing the nonpalpable undescended testis to become palpable. For patients failing to respond to hormonal stimulation we recommend preliminary inguinal exploration, since most testes or testicular remnants are located within the inguinal canal or immediately below the internal ring. PMID- 8683789 TI - Pediatric Urology Medal. Victor A. Politano. PMID- 8683790 TI - Bilateral anterior pubic osteotomy in bladder exstrophy closure. AB - PURPOSE: We report our clinical experience with anterior pelvic osteotomy in 16 patients who underwent surgery for bladder exstrophy. The technique and its difficulties are discussed. MATERIALS AND METHODS: Anterior pelvic osteotomy of the superior ramus of the public bone is a simple and efficient method to facilitate symphyseal approximation and abdominal wall closure without or with low tension on the suture lines in neonates who undergo surgery for bladder exstrophy. Older children in whom surgery has been delayed can also benefit from this method. Compared to other methods of osteotomy in exstrophy surgery it does not require additional incisions, nor does the patient need to be repositioned on the operating table. A successful operation does not depend on any particular orthopedic skills and it can easily be done by the pediatric urologist. RESULTS: Immediate postoperative results regarding abdominal wall closure were excellent in all 16 patients. However, major postoperative complications developed in 2 patients. Despite antibiotic prophylaxis a severe soft tissue infection developed in 1 child, resulting in complete bladder dehiscence. In another patient an obturator nerve injury resulted in transient palsy, which resolved completely. While the first complication was not related to osteotomy, the second was osteotomy related. CONCLUSIONS: Bilateral superior ramotomy of the pubic bones is a new alternative, easily performed technique to optimize bladder exstrophy surgery in children. PMID- 8683791 TI - Creation of a model of bladder exstrophy in the fetal lamb. AB - PURPOSE: To our knowledge we describe the first reproducible large animal model to mimic the congenital birth defect of classic bladder exstrophy. MATERIALS AND METHODS: Eight male and 15 female fetal sheep underwent in utero surgical creation of classic bladder exstrophy. The fetus was then replaced within the amniotic sac and allowed to come to term. A sham procedure was performed on 16 male fetuses. RESULTS: After the creation of bladder exstrophy 53% of the female and 62% of the male fetuses survived to full term and through delivery. Of the male fetuses that underwent sham surgery 62% also survived through delivery. Lambs with exstrophy were born with the bladder wall in continuity with the abdominal wall and exposed to the environment. The sham operated male lambs had a well healed abdominal scar. CONCLUSIONS. To our knowledge we have devised the first reproducible large animal:model of bladder exstrophy. This model will be useful in studying bladder development and composition in the patient with exstrophy. It may also serve as a useful tool in developing innovative forms of surgical treatment for such patients. PMID- 8683792 TI - Morphometric analysis of smooth muscle in the exstrophy-epispadias complex. AB - PURPOSE: In bladder exstrophy and to a lesser extent in epispadias the muscular tissue in the bladder wall may often be replaced by collagen. The aim of our study was to assess the relative changes of smooth muscle versus connective tissue in patients with the exstrophy-epispadias complex. MATERIALS AND METHODS: Nine full thickness detrusor biopsies from children with the exstrophy-epispadias complex were analyzed. Biopsies were stained with the Masson trichrome method to differentiate muscular tissue from collagen. At x50 magnification using image software for computerized morphometry the areas of smooth muscle and collagen were measured and expressed as a percent. As controls, detrusor biopsies from 8 children with unilateral obstructive megaureter or ectopic ureter were analyzed using the same method. RESULTS: The average rates of smooth muscle in children with the exstrophy-epispadias complex were 7, 19.3 and 31.5%, respectively, in newborns, and before and after bladder neck reconstruction. In controls the rate averaged 56.5%. CONCLUSIONS: The ratio of smooth muscle-to-connective tissue increases from the newborn period to puberty in the exstrophy-epispadias complex. After staged reconstruction is completed this ratio remains below normal, although it is increased. Such a change may represent a histological marker of the inadequate volume increase of some of these bladders. PMID- 8683793 TI - The long-term outcome in men with exstrophy/epispadias: sexual function and social integration. AB - PURPOSE: We evaluated the long-term outcome of social integration and sexual function in 29 men with bladder exstrophy and epispadias. MATERIALS AND METHODS: Four men with epispadias and 25 with bladder exstrophy were available for long term followup. Patients were interviewed by telephone regarding sexual history and social integration. Semen analyses were obtained in 8 cases. RESULTS: Patient assessment of genital appearance was good or fair in 71%. Potency was present in all patients, and erections were straight in 66% and curved in 34% with no curvature so severe as to prevent sexual intercourse. Semen analysis showed a normal sperm count in 63% of the men and no azoospermia. Social integration was satisfactory: 100% of the men attended high school, 55% have a college education and all who are not attending school have full-time jobs. CONCLUSIONS: Our long term review demonstrates that despite what appears to be a significant sexual handicap, patients with exstrophy/epispadias can have adequate sexual function and overall successful social integration. PMID- 8683794 TI - Androgen receptor gene mutations are rarely associated with isolated penile hypospadias. AB - PURPOSE: Hypospadias has no known single etiology but it has been linked to androgen insensitivity caused by mutations of the androgen receptor gene. The purpose of this study was to search for such mutations in cases of various degrees of isolated hypospadias to determine whether such an association exists and, if so, with any particular anatomical subgroup. MATERIALS AND METHODS: Isolated deoxyribonucleic acid from the penile tissue of 40 patients undergoing reconstructive surgery was screened for mutations of the coding regions of the androgen receptor gene using single strand conformational polymorphism analysis. In cases with abnormal single strand conformational polymorphism findings sequence analysis of the deoxyribonucleic acid was performed to define the mutation. RESULTS: A missense mutation of exon 2 of the androgen receptor gene was noted in 1 patient with isolated distal penile shaft hypospadias. Sequence analysis revealed that the mutation changed amino acid residue 546 from proline to serine. No abnormalities were detected in the other 39 patients. CONCLUSIONS: Isolated distal shaft hypospadias is associated with mutations of the androgen receptor gene but these mutations appear to be a rare cause of hypospadias. PMID- 8683795 TI - Double onlay preputial flap for proximal hypospadias repair. AB - PURPOSE: We describe a new technique for primary repair of proximal hypospadias. The double onlay preputial flap combines the principles of onlay urethroplasty and the double face preputial flap, namely preservation of the urethral plate and use of a total preputial flap. MATERIALS AND METHODS: Common problems of classic onlay urethroplasty, including rotation and asymmetry of the penile shaft when the preputial flap is brought laterally around the shaft and the viability of the Byars flaps after dissecting the pedicle for the onlay flap, are avoided with this technique by passing the penis through a buttonhole incision in the pedicle of the total preputial flap. Onlay urethroplasty is performed using a secondary flap outlined from the total preputial flap. The remainder of the total preputial flap tissue is used to cover the ventral skin defect. RESULTS: Since June 1994, 18 patients 6 months to 9 years old (median age 10 months) underwent primary hypospadias repair with the double onlay preputial flap technique, representing 15% of all repairs performed. Complications included a urethrocutaneous fistula, persistent chordee, a recessed meatus and a urethral diverticulum in 1 patient each. In all cases complications were corrected surgically with minor procedures. No patient had urethral stricture. Functional and cosmetic results were satisfactory in all patients. CONCLUSIONS: This technique yields good functional and cosmetic results for proximal hypospadias repair. PMID- 8683796 TI - Outcome analysis of the modified Mathieu hypospadias repair: comparison of stented and unstented repairs. AB - PURPOSE: We compared surgical outcomes of stented and unstented Mathieu repairs in boys with primary distal hypospadias, and evaluated the efficacy and safety of caudal analgesia relative to other forms of analgesia (penile block and epidural analgesia). MATERIALS AND METHODS: We retrospectively reviewed the records of 336 consecutive boys who underwent the modified Mathieu repair for primary distal hypospadias. A urethral stent was placed in 114 patients and nonstented repair was performed in 222. Adjunct caudal analgesia was given in 136 cases, a penile block in 158 and continuous epidural analgesia in 42. RESULTS: None of the unstented cases had urinary retention. Analysis of surgical outcomes revealed no difference in fistula formation between patients with and without stents (2.63 versus 2.70%, respectively, p > 0.999). Overall complication rates in the stented and unstented groups were not significantly different (2.63 versus 3.60%, respectively, p = 0.756). The fistula rate in patients who received adjunct caudal analgesia was no different than in those who received other forms of adjunct analgesia (2.21 versus 3.0%, respectively, p > 0.999). CONCLUSIONS: These data suggest that successful Mathieu hypospadias repair is independent of the use of a stent. Caudal analgesia, a penile block and epidural analgesia provided effective postoperative pain control with no difference in complication rates. To our knowledge our report represents the largest observational study reported to date comparing stented and unstented repairs. However, because of the small number of complications in each group, a much larger study is required to determine statistically significant differences among these groups. PMID- 8683797 TI - Tubularized incised plate hypospadias repair: results of a multicenter experience. AB - PURPOSE: We report a multicenter experience using tubularized incised plate urethroplasty to correct distal hypospadias. MATERIALS AND METHODS: A total of 148 patients underwent repair by 6 pediatric urologists at different institutions in the United States and Europe. RESULTS: Tubularized incised plate repair created a functional neourethra with a vertically oriented meatus. Complications, including meatal stenoses and fistulas, occurred in 10 patients (7%). CONCLUSIONS: Tubularized incised plate urethroplasty can be performed in most cases of distal hypospadias. Cosmetic results are superior to those of other popular techniques. PMID- 8683798 TI - Circumcision: successful glanular reconstruction and survival following traumatic amputation. AB - PURPOSE: Circumcision remains the most common operation performed on male individuals in the United States. Unfortunately various complications may occur during circumcision ranging from trivial to tragic. We report 7 cases of traumatic amputation of the glans penis and/or urethra during circumcision. In addition, errors in circumcision technique as probable mechanisms of injury, principles of repair and limits of tissue viability are discussed. MATERIALS AND METHODS: The medical records of 7 patients who underwent traumatic circumcision amputation of the glans penis and/or urethra were reviewed. Glanular amputation occurred in 6, 8-day-old neonates during ritual circumcision and in 1, 5-month old infant circumcised by a physician. RESULTS: Excised glanular tissue remained viable up to 8 hours after injury. Followup ranged from 8.5 to 108 months. All patients had an acceptable cosmetic result. No long-term complications developed in the 8-day-old group but a distal urethral fistula formed in the 5-month-old patient. CONCLUSIONS: Careful selection of technique and device as well as strict attention to detail at circumcision should eliminate most injuries. On the basis of our results we recommend reanastomosis of the glans and/or urethra following distal amputation even when there is a delay in surgical repair of up to 8 hours. PMID- 8683799 TI - Exogenous endothelin-1 causes renal vasodilation in the fetal lamb. AB - PURPOSE: Endothelin-1 is known to be a potent vasoconstrictor. We investigated the effects and mechanisms of action of endothelin-1 and its receptors in regulating renal vascular tone in the fetal lamb. MATERIALS AND METHODS: We observed the in vivo effects of endothelin-1, an endothelin-b receptor agonist (4 alanine-endothelin-1), endothelin-a receptor antagonists (BQ-610 and BQ-123), and the inhibition of prostaglandin and nitric oxide synthesis on the response of the renal circulation to endothelin-1 in a chronic preparation in third trimester fetal lambs. RESULTS: After injection of 250 ng./kg. endothelin-1 into the descending aorta proximal to the renal arteries in 8 fetal animals, renal blood flow increased (4.4 +/- 0.7 ml. per minute per kg., p < 0.001 versus vehicle), as did mean arterial blood pressure (3.0 +/- 0.3 mm. Hg,p < 0.001 versus vehicle). Calculated renal vascular resistance decreased (-1.1 +/- 0.2 mm. Hg per minute per kg./ml., p < 0.001 versus vehicle). After injection of 1,725 ng./kg. 4 alanine-endothelin-1 in 5 animals renal blood flow increased (3.8 +/- 0.4 ml. per minute per kg., p < 0.05 versus vehicle) and mean arterial blood pressure was unchanged (1.6 +/- 1.7 mm. Hg). Calculated renal vascular resistance decreased ( 0.8 +/- 0.2 mm. Hg per minute per kg./ml., p < 0.05 versus vehicle). After injection of 0.5 mg./kg. BQ-610 in 6 animals renal blood flow increased (2.3 +/- 0.7 ml. per minute per kg., p < 0.05) and mean arterial blood pressure decreased (-2.7 +/- 0.3 mm. Hg, p < 0.05 versus vehicle). Calculated renal vascular resistance decreased but this difference was not statistically significant (-0.7 +/- 0.3 mm. Hg per minute per kg./ml., p < 0.07). A dose of 1 mg./kg. BQ-123 in 2 animals decreased renal vascular resistance markedly. Infusion of a prostaglandin synthesis inhibitor (1 mg./kg. per minute meclofenamic acid) did not alter the decrease in renal vascular resistance after endothelin-1 (-0.7 +/- 0.4 mm. Hg per minute per kg./ml). In contrast, during infusion of a nitric oxide synthesis inhibitor (1.5 mg./kg. per minute N-omega-nitro-L-arginine) endothelin-1 increased renal vascular resistance (1.2 +/- 0.2 mm. Hg per minute per kg./ml., p < 0.001). CONCLUSIONS: Endothelin-1 is a vasodilator in the fetal renal circulation, which acts primarily via endothelin-b receptors. Ongoing activity of endothelin-a receptors contributes to renal vascular tone in fetal lambs. The vasodilatory effects of endothelin-1 in the fetal lamb renal circulation are mediated via the nitric oxide system and not via prostanoids. PMID- 8683800 TI - Splenogonadal fusion. AB - PURPOSE: We report on 7 patients with splenogonadal fusion and review the literature on this unusual condition. MATERIALS AND METHODS: The medical records of patients diagnosed with splenogonadal fusion between 1989 and 1994 at 4 institutions were retrospectively reviewed. RESULTS: All 7 patients were properly diagnosed at surgery and the testes were salvaged in 5. In 1 intersex patient gonadectomy was appropriate. CONCLUSIONS: Splenogonadal fusion is a rare condition. Familiarity with this lesion allows for intraoperative diagnosis and testicular salvage. PMID- 8683801 TI - Urethral meatotomy in the office using topical EMLA cream for anesthesia. AB - PURPOSE: We determined the effectiveness of lidocaine and prilocaine (EMLA) topical cream for anesthesia during urethral meatotomy performed in an office setting. MATERIALS AND METHODS: Meatotomy was performed in 58 patients 1 hour after topical application of EMLA cream to the glans. RESULTS: Of the 58 patients 55 had no pain, while early in our experience 3 had limited discomfort because EMLA cream was applied in too small a volume or it became dislodged. Results have been good in 57 patients, while partial restenosis developed in 1. CONCLUSIONS: Urethral meatotomy in an office setting with EMLA cream for anesthesia is generally painless, well tolerated, successful and cost-effective versus operative meatotomy. PMID- 8683802 TI - Interstitial cystitis in children. AB - PURPOSE: Interstitial cystitis has been rarely reported in children. We present our experience with 16 children in whom clinical symptomatology and cystoscopic findings were consistent with the diagnosis of interstitial cystitis. MATERIALS AND METHODS: We retrospectively reviewed the charts of 20 children referred for chronic sensory urgency, frequency and bladder pain who underwent cystoscopy and hydrodistension. Four patients were excluded from study because of infection identified at cystoscopy or lack of cystoscopic changes with hydro-distension. RESULTS: Patient age at onset of first symptoms ranged from 2 to 11 years (median 4.5) and age at diagnosis ranged from 3 to 16 years (mean 8.2). Of the 16 children 14 (88%) presented with symptoms of urinary frequency and sensory urgency, and in 13 (81%) lower abdominal pain was relieved by voiding. None of the children had motor urgency. Urodynamic evaluation in 8 cases revealed early bladder sensation with no evidence of involuntary bladder contractions. Diffuse glomerulations and terminal hematuria were demonstrated in all patients after hydro-distension. Followup was available for 14 patients. Relief of symptoms occurred after hydro-distension in all children except 1. Seven children (50%) required repeat hydro-distension. CONCLUSIONS: Children with symptoms of bladder pain, urinary frequency and sensory urgency have bladder changes on cystoscopy consistent with interstitial cystitis. Although rare, this condition is recognizable and it should not be confused with dysfunctional voiding in which complaints are secondary to involuntary bladder contractions. PMID- 8683804 TI - Human rights, torture, terrorism. PMID- 8683805 TI - Confronting a biological Armageddon: experts tackle prospect of bioterrorism. PMID- 8683803 TI - Risk of operative site bleeding with parenteral ketorolac. PMID- 8683806 TI - Healing the Hiroshima maidens: a historic lesson in international cooperation. PMID- 8683807 TI - Hanford Health Information Archives offers unique history of exposure to radiation in US Northwest. PMID- 8683808 TI - Physician service opportunities abroad. PMID- 8683809 TI - Medical supplies donated to hospitals in Bosnia and Croatia, 1994-1995. Report of a survey evaluating humanitarian aid in war. AB - OBJECTIVE: To evaluate access to and distribution and quality of medical supplies donated by humanitarian aid organizations to hospitals and health services during the war in Bosnia and Croatia. DESIGN: Retrospective survey of 68 representatives of hospitals and field hospitals regularly caring for inpatients between May 1994 and April 1995. SETTING: Three study areas: the Republic and Federation of Bosnia Herzegovina, Republika Srpska (part of Bosnia-Herzegovina controlled by Bosnian Serbs), and Republika Srpska Krajina (part of Croatia controlled by Croatian Serbs during the study period). PARTICIPANTS: Of 68 hospital representatives, 44 completed the survey (65% response rate). Respondents did not include representatives from 11 hospitals and field hospitals that could not be contacted because of operational obstacles resulting from the ongoing war. RESULTS: Lack of supplies was reported as an important limitation by 62% (26/42) of respondents, followed by lack of staff and security, physical isolation, and lack of infrastructure. Antibiotics were mentioned by 76% (32/42) of respondents as the unavailable drug or item most urgently needed. The majority of drug and medical supplies used to treat patients had been supplied by 5 humanitarian aid organizations. The frequency with which respondents mentioned their ?own means? (eg, from the ministry of health or respective municipalities) was relatively low (9%), reflecting the high degree of dependency on humanitarian aid. All respondents rated the quality of donated supplies and the working relationship with the donating organization as ?very good? or ?satisfactory?; 93% 41/44) of respondents indicated that the donated supplies were appropriate. Six of 44 respondents preferred to receive supplies as part of assembled kits; 70% (31/44) preferred to receive such assistance as loose supplies according to demand. CONCLUSION: During war, access and security are beyond the control of humanitarian agencies. Assistance coordination, however, must be provided. Although a consensus on policies and objectives between different humanitarian organizations is difficult to reach, satisfactory complementarity can be achieved. The systematic and continuous gathering of information at the recipient and user level, beginning at the early phase of the conflict, is recommended to maintain appropriate assistance. PMID- 8683810 TI - Breast cancer among radiologic technologists. PMID- 8683811 TI - Effects of war on the health care of Bosnian children. PMID- 8683812 TI - Use of over-the-counter nicotine patch for smoking cessation: prudent or premature? PMID- 8683813 TI - Global climate controversy. PMID- 8683814 TI - Global climate controversy. PMID- 8683815 TI - Long-term health outcomes and medical effects of torture among US Navy prisoners of war in Vietnam. AB - OBJECTIVE: To characterize incidence of illnesses and injuries from 1979 to 1993 in former naval aviator prisoners of war (POWs) from the Vietnam War and a comparison group of naval aviators from the same war. DESIGN: Cohort analytic study. SETTING: A US Navy primary care clinic. PARTICIPANTS: Volunteer sample consisting of 70 former naval aviator POWs (white men, aged 47 to 69 years in 1993) and a comparison group of 55 naval aviators who served in Vietnam but were not POWs, matched on race, age, marital status, education, rank, year of entry into the navy, and pilot status. Subjects participated in an annual health screening program. This study reports data sampled on a biennial basis from subjects screening both in 1979 and 1993. MAIN OUTCOME MEASURE: Medically diagnosed incidence of illness and injury based on a standard protocol. RESULTS: POWs had higher incidence rates than the comparison group did of disorders of the peripheral nervous system (relative risk [RR], 8.4; 95% confidence interval [CI], 2.7-25.9; P<.001), joints (RR, 1.5; 95% CI, 1.2-2.0; P<.006), and back RR, 1.8; 5% CI, 1.0-3.0; P<.037). These findings also were statistically significant according to Kaplan-Meier survival analyses that included 131 (95%) of 138 POWs and 115 (83%) of the 138 members of the comparison group. Survival analyses revealed that, in addition to these disorders, POWs had higher hazard rates of peptic ulcer (P<.01). CONCLUSIONS: During captivity, ropes, ratchet handcuffs, leg irons, or stocks were used to put tightly constrictive pressure around the extremities of POWs as a means of torture, resulting in painful ischemia and subsequent neuropathies. Being a former POW was associated with increased cumulative incidence rates of chronic disorders of the peripheral nervous system, joints, and back and an increased hazard rate of peptic ulcer. PMID- 8683816 TI - Physical injuries and fatalities resulting from the Oklahoma City bombing. AB - OBJECTIVE: To provide an epidemiologic description of physical injuries and fatalities resulting from the April 19, 1995, bombing of the Alfred P. Murrah Federal Building in Oklahoma City. DESIGN AND SETTING: Descriptive epidemiologic study of all persons injured by the bombing and of all at-risk occupants of the federal building and 4 adjacent buildings. Data were gathered from hospital emergency and medical records departments, medical examiner records, and surveys of area physicians, building occupants, and survivors. STUDY POPULATION: All persons known to have been exposed to the blast. MAIN OUTCOME MEASURES: Characteristics of fatalities and injuries, injury maps, and injury rates by building location. RESULTS: A total of 759 persons sustained injuries, 167 persons died, 83 survivors were hospitalized, and 509 persons were treated as outpatients. Of the 361 persons who were in the federal building, 319 (88%) were injured, of whom 163 (45%) died, including 19 children. Persons in the collapsed part of the federal building were significantly more likely to die (153/175, 87%) than those in other parts of the building (10/186, 5%) (risk ratio [RR], 16.3; 95% confidence interval [CI], 8.9-29.8). In 4 adjacent buildings, injury rates varied from 38% to 100%; 3 persons in these buildings and 1 person in an outdoor location died. The most frequent cause of death was multiple injuries. Among survivors, soft tissue injuries, fractures, sprains, strains, and head injuries were most common; these injuries were most often caused by flying glass and other debris and collapsed ceilings. CONCLUSIONS: The Oklahoma City bombing resulted in the largest number of fatalities of any terrorist act in the United States, and there were 4 times as many nonfatal injuries as fatalities. Disaster management plans should include the possibility of terrorist bombing, and medical preparedness should anticipate that most injuries will be nonfatal. The role of building collapse in fatal injuries should be considered in the design of buildings at high risk of being bombed so as to reduce injuries. PMID- 8683818 TI - Using middle upper arm circumference to assess severe adult malnutrition during famine. AB - OBJECTIVES: To examine the use of middle upper arm circumference measurement (MUAC [cm]) and body mass index measurement (BMI [kg/m2]) in the screening of severely malnourished adults during famine. DESIGN: Nonrandomized cohort study, correlating measurements of MUAC and BMI. SETTING: The Concern Worldwide adult feeding center in the village of Ayod in south Sudan. The area has experienced several years of war, leading to severe famine during early 1993. PARTICIPANTS: A total of 98 adult inpatients belonging to the Nuer tribe. Criteria for entry into the study were prior admission to the feeding center and the ability to stand and have a BMI measured. MAIN OUTCOME MEASURES: A comparison of the ease of use of MUAC and BMI assessments, and a correlation of MUAC and BMI measurements. RESULTS: An MUAC measurement was easier to perform on severely malnourished adults than BMI assessment. For MUAC, the patient could be standing, sitting, or, in extreme cases, lying. For BMI, patients were required to stand. Measuring BMI requires a height board, weighing scales, and mathematical calculations; to measure MUAC, only a tape measure is required. A correlation between measurements of MUAC and BMI was demonstrated (r=0.88; 95% confidence interval, 0.82-0.92 P<.001). The proportions of the population and the actual individuals identified as malnourished by the 2 indicators were similar. CONCLUSIONS: The MUAC measurement reflects adult nutritional status as defined by BMI. During famine, MUAC may be better suited to screening admissions to adult feeding centers than BMI. Studies to assess the capacity of MUAC cutoffs to predict mortality in severe adult malnutrition are needed. PMID- 8683817 TI - Stab wounds associated with terrorist activities in Israel. AB - OBJECTIVE: To describe injuries resulting from terrorist-associated knife stabbings. DESIGN: Retrospective case series. SETTING: Israel (population 5.5 million). SUBJECTS: Israeli victims (N=154) of knife stabbings on nationalistic basis (the intifada) between July 1987 and April 1994. RESULTS: A total of 125 men and 29 women sustained stab wounds associated with terrorist activities. The median age was 28 years (range, 12-92 years), and 99 victims were aged 18 to 35 years. Seventy percent (108 patients) of the stabbing events occurred between 7 AM and 11 AM. The 154 victims sustained a total of 327 stab wounds, the median number of injuries was 2 per person (range, 1-28), and 68 individuals (44%) sustained more than 1 stab wound. The chest was the most commonly involved site (146 wounds), with the right posterior chest stabbed in 71 patients. The knife penetrated the heart in 20 patients and penetrated the peritoneal cavity in 29 patients. Overall, 29 patients (19%) had superficial injuries, 86 (56%) had internal organ injuries that mandated operative interventions, and 39 died (overall mortality, 25.3%). CONCLUSIONS: Unlike other civilian stabbings, wounds resulting from terrorist-associated stabbings represent severe and highly lethal injuries. PMID- 8683819 TI - Physician complicity in misrepresentation and omission of evidence of torture in postdetention medical examinations in Turkey. AB - Between June 1994 and October 1995, representatives of Physicians for Human Rights studied the problem of physician complicity in torture (ie, misrepresentation and omission of medical evidence in postdetention examinations of detainees) in Turkey. The research consisted of a survey of forensic documentation of torture, interviews with individual physicians who examine detainees, analyses of official medical reports of detainees, and interviews with survivors of torture. Results from the survey, interviews, and medical report analyses provide evidence that torture of political and criminal detainees continues to occur in Turkey and that Turkish physicians are coerced to ignore, misrepresent, and omit evidence of torture in their examinations of detainees to certify that there are no physical signs of torture. PMID- 8683820 TI - Research ethics and the medical profession. Report of the Advisory Committee on Human Radiation Experiments. AB - The Advisory Committee on Human Radiation Experiments was convened by President Clinton in January 1994 in response to allegations of unethical practices in radiation experiments involving human subjects that were sponsored by the US government between 1944 and 1974. The committee's Final Report was released in October 1995. In addition to analyzing the history of the ethics of medical research involving human subjects, the committee reviewed current federal policies and procedures for protection of human subjects. In this article, the committee's findings are discussed as they relate to the patient-physician relationship, the issue of trust, and the specific role of the physician investigator in all types of human experimentation. The committee found evidence of discussion of the conduct of human research at the highest levels of the government and within the medical profession, particularly with regard to risk, during the 1940s and 1950s. However, in both federal policy and professional practice, requirements for consent were more likely to apply to "healthy volunteers" than to patient-subjects (ie, those with disease or illness). Today, consensus exists that duties to obtain informed consent apply to all human subjects, whether healthy or sick, regardless of the risk or potential for medical benefit from participation in the research and regardless of the nature of sponsorship or funding (eg, federal, military, or private). Based on a finding of serious deficiencies in the current system of protections for human subjects, the committee offers a number of recommendations, including changes in institutional review boards; in the interpretation of ethics rules and policies; in oversight, accountability, and sanctions for ethics violations; and in compensation for research injuries. More than public policy changes, however, the committee recommends that the medical profession intensify its commitment to the ethics of research involving human subjects. PMID- 8683821 TI - Ethical considerations in the management of asylum seekers on hunger strike. AB - Hunger strikes have confronted physicians with complex ethical dilemmas throughout history. Asylum seekers under threat of forced repatriation have emerged as a new category of hunger strikers, posing novel challenges for management. The management of 3 Cambodian asylum seekers on hunger strike admitted to a hospital in Sydney, New South Wales, Australia, posted important ethical dilemmas for the physicians and mental health experts involved in their care. Several factors confounded the task of assessment and decision making, including language and cultural barriers, the patients' past exposure to persecution by authorities, and the complexities of the legal procedures being pursued. Different rules appeared to govern the actions of the hunger strikers, the medical team, and the immigration authorities, creating a ?malignant triangle? of mounting confrontation. Recent recommendations for the management of asylum-seeking hunger strikers include the appointment of an external physician of confidence and the writing of a confidential advance directive specifying the hunger striker's wishes about resuscitation in the event of collapse. In addition, we consider the value of constituting an ad hoc ethics committee to advise the responsible physician on points of conflict in managing the hunger strike. The advantages and limitations of these proposals in relation to the particular cultural, historical, and contextual issues relevant to asylum seekers are examined herein. PMID- 8683823 TI - Infectious disease--a threat to global health and security. PMID- 8683822 TI - Compromise, complicity, and torture. PMID- 8683824 TI - The threat of biological weapons--prophylaxis and mitigation. PMID- 8683825 TI - A piece of my mind. The way to Jerusalem. PMID- 8683826 TI - Ethical issues in renal transplantation in developing countries. PMID- 8683827 TI - Neonatal disease profile in Larkana before and after establishment of neonatal ward. AB - This is a study of 2050 neonatal admissions excluding neonatal tetanus in children hospital CMC Larkana from December, 1988 to July, 1993. Six hundred and eighty-nine cases were admitted in General Paediatrics Ward before establishment of neonatal unit and 1361 cases were admitted in neonatal ward. The aime of study was to compare the disease pattern and mortality rates before and after establishment of a neonatal unit in the same hospital. Number of admissions significantly increased after the establishment of neonatal unit but there was no decline in the mortality. Changes in disease pattern were observed particularly for Gastroenteritis and miscellaneous (undetermined) category. Seventy percent of admissions were males in Ist week of their life. Commonest cause of admission and mortality was birth anoxia. PMID- 8683828 TI - Glucose intolerance in pulmonary tuberculosis. AB - The frequency of glucose intolerance was studied in 106 patients with pulmonary tuberculosis attending Nazimabad Chest Clinic. Diagnosis was based on X-ray and a positive sputum smear. An oral glucose tolerance test (OGTT) was performed and evaluated according to the WHO criteria. Glucose intolerance was detected in 52 (49%) patients, 31 Impaired Glucose Tolerance (IGT), 21 Diabetes Mellitus (DM). After adequate antitubercular therapy and sputum conversion, the OGTT was repeated in 23 cases. Of these 13 (56.5%) patients had a normal glucose tolerance indicating that glucose intolerance observed during active pulmonary tuberculosis improves or normalizes after adequate therapy. PMID- 8683829 TI - Evaluation of oral midazolam as pre-medication in day care surgery in adult Pakistani patients. AB - A placebo controlled randomized double blind study was designed to assess the suitability of oral Midazolam as a premedication in day care surgery in adult Pakistani patients. Fifty ASA I and II patients aged between 20-60 years received either Midazolam 7.5 mg or a placebo approximately one hour prior to surgery. Midazolam 7.5 mg produced significant anxiolysis and sedation (p < 0.001) in comparison to placebo after one hour of premedication. There was a significant difference (p < 0.001) in the mean heart rate and blood pressure in both groups after 1 hour of premedication with a lesser rise in blood pressure and heart rate in the Midazolam group. Psychomotor performance assessed by 'n' deletion test was impaired by Midazolam (p < 0.001) and recall of pictures revealed differences (p < 0.05) in the groups at one hour after premedication. However, at four hours after surgery there were no differences in both groups. These findings indicate that rapidly acting oral Midazolam in doses of 7.5 mg provided safe and effective premedication in terms of anxiolysis, sedation, amnesia and psychomotor performance and is suitable for day surgery. PMID- 8683830 TI - Famotidine 40mg B.I.D. in the treatment of reflux oesophagitis. AB - To assess the efficacy of famotidine in the healing of reflux oesophagitis, 25 endoscopically proven cases were treated with famotidine 40 mg B.I.D. for 6 to 12 weeks. Six patients were lost to follow-up, of the 19 cases analysed, 16 (84.2%) healed at 6 weeks and 17 (89.5%) at 12 weeks. Twelve cases (63%) became asymptomatic within six weeks of treatment. In conclusion famotidine 40 mg B.I.D. is effective in the healing of reflux oesophagitis. PMID- 8683832 TI - Genetic variants of serum alpha 1 antitrypsin. AB - Complete absence of data on alpha 1 antitrypsin in this country prompted us to determine serum levels using radial immunodiffusion (RID) and phenotypes by isoelectric focusing (IEF) in 100 healthy adults (52 males and 48 females). Mean serum alpha 1 antitrypsin concentration in healthy subjects was 2.47 +/- 0.08 g/l and the main phenotypes MM (70%), M1 M2 (28%) and FM 3 (2%) are infrequent in our population. PMID- 8683831 TI - Are non-specific reactions to tuberculin common? AB - Three thousand four hundred eighty-five BCG scar negative school children were given tuberculin test. Results showed very little non-specific reactions, suggesting BCG should produce high levels of protection in our population. PMID- 8683834 TI - Necrotizing crepitant fasciitis of abdominal wall following caesarean section. PMID- 8683833 TI - Oligospermia and its relation with hormonal profile. AB - Serum of 161 oligospermic men was analysed for pituitary hormones LH and FSH and the androgen testosterone. The hormonal analysis indicated normal levels of LH and testosterone, while the FSH levels showed negative correlation to the sperm concentration. PMID- 8683836 TI - Basic medical research as a means of solving national health problems. PMID- 8683835 TI - Relapsing polychondritis associated with rheumatoid arthritis. PMID- 8683837 TI - Severe thrombocytopenia in a man with prostatic cancer. PMID- 8683838 TI - Immunofluorescent titers in H. pylori. PMID- 8683839 TI - Immediate haemorrhoidectomy for thrombosed fourth degree haemorrhoids. PMID- 8683840 TI - Pattern of malignant bone tumour in northern areas of Pakistan. PMID- 8683841 TI - Primary carcinoma of the gall bladder-a 5 year experience. PMID- 8683842 TI - Management of ARI. PMID- 8683843 TI - Analysis of factors causing acute renal failure. AB - Factors leading to acute renal failure (ARF) were analysed in 376 consecutive patients between January 1993 and December, 1994 in a Karachi centre. Two hundred and sixteen (57%) had medical conditions, 86 (24%) obstetrical, 28 (7%) obstructive, 18 (5%) surgical and in 28 (7%) the causes were uncertain. Within the medical group, the causes were diarrhoea 30%, drugs 23%, malaria 15% and liver disease 5%. In the obstetrical group majority of the patients had multiple etiologies. Sixty percent of patients had ante-partum haemorrhage, 33% post partum haemorrhage, intrauterine deaths were seen in 31%, septic abortions in 20% and pre-eclamptic toxemia in 22% cases. In the obstructive group, most of the patients had stone disease, where bilateral ureteric calculi constituted 57% of the cases. In surgical group, 11 (61%) had ARF due to post-operative complications. This data confirms the pattern of ARF from other third world countries where obstetrical and obstructive causes are high as compared to western countries. PMID- 8683844 TI - The use of GnRH agonists in the treatment of endometriomas with or without drainage. AB - To assess the efficacy of GnRH-agonist therapy in the treatment of endometriomas with or without surgical intervention, 26 women with laparoscopically proven endometriomas larger than 3 cm were recruited to the study. Fourteen women with 19 endometriomas (5 bilateral), had drainage of endometrioma at initial laparoscopy. After the procedure, ovarian suppression was done with GnRH-a therapy for 6 months. The second group which consisted of 12 women, had 17 endometriomas. No surgical procedure was performed. They received only GnRH-a therapy for 6 months. On repeat laparoscopy, in the first group, the rates of decrease in ovarian AFS scores of endometriomas and complete resolution were found as 100% and 37% respectively. In the second group the response was only 18% (p < 0.0001). It was concluded that drainage of the cyst (surgical therapy) combined with postoperative GnRH-a suppression is a better treatment modality than the use of GnRH-a (medical therapy) alone for endometriomas. PMID- 8683845 TI - Management of chronic subdural haematoma--a review of 23 cases. AB - Twenty-three cases of chronic subdural hematoma were admitted and treated at the neurosurgery department of Allied Hospital, Faisalabad, from 1991 to 1993. All these patients were treated with simple burr holes and drainage. Six patients developed post-operative complications; infection in one, cerebral oedema in two, haematoma recurrence in two. There was no mortality. Follow-up revealed that 18 patients recovered completely, one still had neurological or mental deficit and four suffered epileptic seizures. PMID- 8683846 TI - Hematologic effect of vitamin A supplementation in anemic Pakistani children. AB - To assess the prevalence of vitamin A deficiency in anemic Pakistani children and investigate the hematologic response to vitamin A supplementation, 4-8 year old primary school children from the slum areas of Karachi were surveyed for anemia. Of 101 anemic children selected, 16% had low level of vitamin A ( < 20 micrograms/dl) and an additional 2% had deficient level ( < 10 micrograms/dl). Serum Retinol level showed positive associated with serum iron, ferritin, hemoglobin, hematocrit and Mean cell hemoglobin concentration. A non-randomized control trial was then carried out. Oral vitamin A capsules were given to 42 children and 53 children served as controls. After 6 weeks, there were significant differences between the two groups for Retinol, Retinol-Binding Protein and Hematocrit. However, no significant difference could be found for Hemoglobin, RBC count, Mean Corpuscular Volume, Mean Corpuscular Hemoglobin, Mean Corpuscular Hemoglobin Concentration, Serum iron, ferritin or transferrin. A single vitamin A supplement improved the hematocrit in 6 weeks. Long-term studies are needed to find if the WHO recommended periodic massive doses of vitamin A besides improving the morbidity and mortality will also improve the overall picture of anemia in children. PMID- 8683848 TI - Serum immunoglobulin levels in giardiasis. PMID- 8683847 TI - Evaluation of dipstrips, direct gram stain and pyuria as screening tests for the detection of bacteriuria. AB - Two hundred and fifty cases of clinically suspected urinary tract infection were analysed for the detection of bacteriuria. Parameters studied included direct Gram staining, pyuria on microscopic examination of uncentrifuged urine and dip strip method for the detection of blood, protein, nitrite and leucocyte esterase. Significant bacteriuria (colony count 10(5) per ml) was found in 112 cases with a positivity ranging from 65 to 83% for the presence of blood, protein, nitrite and leucocyte esterase. Highest positive predictive values were obtained with the presence of nitrite and leucocyte esterase (98%), blood, protein and nitrite (94%) as well as with blood, protein, nitrite and leucocyte esterase (98%). Both pyuria and direct Gram staining were positive in 85% cases. The combined presence of both these parameters gave 100% positive predictive value. Gram staining combined with pyuria was more effective and economical as compared to the dipstrips for the detection of bacteriuria. PMID- 8683849 TI - Neonatal sepsis and meningitis due to Staphylococcus cohnii. PMID- 8683850 TI - Myelomegakaryoblastic transformation of essential thrombocythemia. PMID- 8683851 TI - Priapism associated with fluoxetine therapy: a case report. PMID- 8683852 TI - Angiographic assessment of the stretch-recoil-gain relation after balloon coarctation angioplasty and its relation to late restenosis. AB - The effects of stretch and immediate recoil after balloon angioplasty were evaluated in 21 patients with coarctation of the aorta who underwent balloon coarctation angioplasty. A total of 28 procedures were performed in these patients, who ranged in age from 1 month to 17 years with a mean of 4.3 years. The systolic pressure gradient and coarcted diameter changed significantly from 42 +/- 22 to 14 +/- 9 mmHg (P < 0.0001) and from 4.0 +/- 1.7 to 6.1 +/- 2.0 mm (P < 0.001), respectively. Immediate recoil was responsible for the loss of 33% of the potentially achievable coarcted dimension. Recoil was determined mainly by the degree of arterial stretch. Gain increased exponentially with an increase in stretch. There was a narrow range of % stretch (60-80%) within which an effective diameter gain could be obtained. Both gain and stretch were the best predictors for late restenosis: patients with a larger immediate gain and stretch developed more restenosis. These results suggest that the stretch-recoil-gain relationship may be clinically important for evaluating the best predictor of late restenosis after balloon coarctation angioplasty. PMID- 8683853 TI - Sequential changes in laminin and type IV collagen in the infarct zone- immunohistochemical study in rat myocardial infarction. AB - BACKGROUND: The healing process, which affects ventricular remodeling, is an important factor in the prognosis of myocardial infarction. We hypothesized that laminin and type IV collagen contribute to extracellular matrix assembly in healing after myocardial infarction. We examined sequential changes in these two components after experimental myocardial infarction in rats. MATERIALS AND METHODS: Hearts were excised from 1 day to 10 weeks after permanent left coronary ligation in rats. Immunohistochemical staining with a polyclonal antibody to laminin and type IV collagen was performed by the avidin-biotin-peroxidase method. RESULTS: Laminin: On day 3, laminin initially appeared in a wavy fashion in the granulation tissue of the infarct peripheral zone and was not restricted to the cell membrane; the staining distribution in the peripheral zone then gradually increased, reaching a maximum on days 7-11. The distribution progressed from the peripheral zone to the outer lesion of the central zone of the infarct for 1-2 days, and reached the center point after 2 weeks. The extent of the staining distribution gradually decreased after reaching this maximum, but the staining did not completely disappear. Type IV Collagen: Changes in type IV collagen were essentially the same as those in laminin. A wavy staining pattern of type IV collagen appeared in the infarct peripheral zone from day 3, reached its maximum extent on days 7-11, and decreased gradually thereafter. The distribution progressed from the peripheral zone to the outer lesion of the central zone for 1-2 days, reaching the center point after 2 weeks. CONCLUSIONS: Laminin and type IV collagen contribute to extracellular matrix formation in the infarct zone relatively early after myocardial infarction. PMID- 8683854 TI - Assessment of pulmonary venous and transmitral flow in closed-chest dogs under various loading conditions by transesophageal Doppler echocardiography. AB - Pulmonary venous flow velocity (PVFVe), pulmonary venous dimension (PVD) and transmitral flow (TMF) velocity were examined under various loading conditions in 15 anesthetized closed-chest dogs by transesophageal Doppler echocardiography (TEE). We also compared PVFVe with pulmonary venous flow volume (PVFVo) simultaneously in open-chest dogs using an ultrasonic flow probe. PVFVo decreased by more than 50% and PVD also decreased significantly during preload reduction, while there was no change in PVFVe. This discrepancy between PVFVo and PVFVe was apparently due to the collapse of pulmonary veins. TMF consisted of both rapid filling flow velocity and atrial flow velocity components (R and A), while PVF consisted of systolic and diastolic forward flow velocity components (S and D). The peak values of R,A,S and D and the time-velocity integrals of each wave (RI, AI, SI and DI, respectively) were measured. There was a significant correlation between the changes in RI and SI/DI during preload reduction (r = 0.82, p < 0.001) and during after-load increase (r = -0.59, p < 0.05). These results suggest that changes in RI with different loading conditions might be attributable to changes in atrial reservoir volume and conduit volume. PMID- 8683855 TI - Vasospastic angina in patients with systemic triglyceride storage disease with Jordans' anomaly and cardiomyopathy. AB - Vasospastic angina was demonstrated clinically and angiographically in a 54-year old patient with systemic triglyceride storage disease and cardiomyopathy. He and his younger sister had been diagnosed in 1985 as having systemic triglyceride storage with Jordans' anomaly. In 1993, he began complaining of rest and effort chest pain in the morning, which was accompanied by ST depression by ECG. Sublingual nitroglycerine was effective for treating this pain. Intracoronary injection of acetylcholine induced severe coronary vasoconstriction in the left anterior descending artery. Left ventricular contraction was diffusely impaired. Deposits of numerous triglyceride droplets and a decrease in the density of myofibrils in cardiocytes were found in the specimens obtained by endomyocardial biopsy. The impaired left ventricular contraction may have been due to the changes in myocardial cells. His sister complained of a similar chest pain that was completely controlled by calcium channel antagonis. Thus, our cases demonstrated vasospastic angina associated with cardiomyopathy secondary to systemic triglyceride storage disease with Jordans' anomaly, though the causal relationship between these conditions remains unclear. PMID- 8683856 TI - Recurrent left atrial myxoma in a patient with a twin fetus pregnancy. AB - We experienced a case of a recurrent left atrial myxoma in a pregnant woman with twin fetuses. Normal healthy twins weighing 1430 and 1190 gm were delivered by cesarean section performed under epidural anesthesia at 32 weeks gestation. Neither cardiac failure nor embolisms were observed during pregnancy or delivery. The left atrial myxoma was removed surgically one week after delivery. The infants and mother remain in good health. According to previous reports and our present observations, the decision for cardiac surgery during pregnancy should be based on the maternal and fetal status. PMID- 8683857 TI - Sudden death in a patient with apparent idiopathic ventricular tachycardia. AB - Idiopathic ventricular tachycardia is widely believed to carry a favorable prognosis, although there have also been reports of sudden cardiac deaths. We present a case of sudden death in a patient with apparent idiopathic right ventricular tachycardia. This patient had long-standing and exercise-related symptoms, an essentially negative non-invasive cardiac evaluation, and spontaneous and inducible ventricular tachycardia of left bundle branch block and inferior axis morphology, that was treated with propranolol. After an uneventful 5-year course, the patient died suddenly. Postmortem examination revealed a severely dilated right ventricle and significant replacement of the right ventricular wall with adipose tissue. Interstitial fibrosis was also seen, but only to a very slight degree. PMID- 8683858 TI - Thrombogenic and lipid risk factors in hypertension and coronary artery disease. AB - Hypertension is not solely a phenomenon of elevation of systemic blood pressure. It frequently occurs in association with a great deal of metabolic derangement's and should never be regarded as coincidental only. Furthermore, a knowledge of these metabolic derangements may provide a clue to unveil the underlying mechanisms how essential hypertension and its associated complications arise. Therefore we devoted our attention to platelet dysfunction and dyslipidemia which are closely associated with atherosclerosis-the commonest complication of hypertension. We found there exists enhanced platelet aggregation in essential hypertension and a variety of its associated atherosclerotic diseases. Such an aberration in platelet function may be modified after administration of antihypertensive medications such as angiotensin converting enzyme (ACE) inhibitors, calcium channel blockades, beta blockades and dietary manipulation. We also demonstrated the close association between hypertension and its associated atherosclerotic complications and abnormal lipids profile. Hypertriglyceridemia which was initially regarded unimportant in the pathogenesis of atherosclerosis is found to be closely related to hypertension. In an intensive review, we found that people in Taiwan has experienced a huge increase in dietary calories and total fat consumption. In order to solve this emerging problem, a national guideline for diagnosis and management of lipid disorders in Taiwan was developed and announced. Through these efforts, we hope we can reduce the cardiovascular morbidity and mortality in Taiwan and even extend our experience to other countries. PMID- 8683859 TI - Measurement of left ventricular volume by dual-field conductance catheter in humans--comparison with single-field conductance catheter. AB - The single-field conductance (SF) method for continuous measurement of left ventricular (LV) volume has achieved widespread use. However, it has been shown theoretically that the ratio between the measured conductance and the actual volume varies between the different interelectrode segments of the catheter due to the convex shape of the equipotential planes at the apex and base. The dual field conductance (DF) method has recently been introduced and reportedly provides a flatter equipotential plane within the LV. In 11 patients, we compared LV volume measured by biplane cineangiography with conductance volume by the SF and DF methods. Strong correlations were found for both the SF method (r = 0.98) and the DF method (r = 0.99). However, in comparison with the SF method, the DF method gave a regression line with a slope factor, alpha, that was closer to unity, and the intercept of the regression line was small (p < 0.01). The DF method gave a significantly greater segmental stroke volume (SV) in the apex and base than the SF method. The ratio of the DF segmental SV to the SF segmental SV in the apex increased in proportion to the end-diastolic volume (p < 0.05). In conclusion, the DF method may facilitate the accurate measurement of LV volume in the human heart. PMID- 8683860 TI - Right ventricular systolic performance before and after surgery for tricuspid regurgitation associated with mitral stenosis. AB - The reversibility of right ventricular function in patients with mitral stenosis associated with secondary tricuspid regurgitation (TR) is as yet undetermined. We assessed the right ventricular systolic performance by cardiac catheterization before and 19 months after surgery in 18 patients who underwent DeVega's tricuspid annuloplasty plus mitral valve replacement (MS plus TR group) and in 9 with mitral valve replacement for isolated mitral stenosis (MS group). After surgery, the right ventricular systolic pressure decreased significantly in both groups (both p < 0.01). In the MS plus TR group, the postoperative right ventricular end-diastolic and end-systolic volume indices (RVEDVI and RVESVI, respectively) were significantly decreased compared with the respective preoperative values (both p < 0.001). No significant difference was noted between the groups with regard to the right ventricular peak-systolic pressure/end systolic volume index ratio (RVPSP/ESVI) either before or after surgery. Various left ventricular indices were comparable between the groups both before and after surgery. Linear regression analysis revealed significant correlations between RVEDVI and the RVPSP/ESVI, and between RVPSP and the RVPSP/ESVI both before and after surgery. These results indicate that right ventricular systolic performance in patients with MS plus secondary TR became comparable to those that in patients with isolated MS after surgery, and that this was probably due to nearly equivalent right ventricular contractility before surgery. PMID- 8683861 TI - [Cloning of thrombopoietin and its physiologic role in megakaryocytopoiesis and thrombopoiesis]. PMID- 8683862 TI - [Ganciclovir prophylaxis for cytomegalovirus interstitial pneumonitis after allogeneic bone marrow transplantation]. AB - We evaluated the efficacy of ganciclovir to prevent the development of cytomegalovirus interstitial pneumonitis (CMV-IP) in patients with bone marrow transplants. Of 35 patients enrolled in this study, 33 were seropositive for CMV or had seropositive donors, and two were seronegative before transplant but were positive for CMV examined by polymerase chain reaction (PCR) on days 30-37. Ganciclovir was given at a dose of 250 mg/body daily from day 30-37 to day 70. Blood, throat swabs, urine and bronchoalveolar-lavage fluid (BALF) were screened for CMV by PCR on days 30-37, 70 and 100. CVM-IP developed in two of 35 patients (5.7%) who received ganciclovir for prophylaxis, as compared with six of 39 historical controls who did not receive ganciclovir. A significant reduction of CMV detection by PCR in blood, throat swabs, and BALF was observed after administration of ganciclovir, on day 70. The incidence of neutropenia, thrombopenia and renal impairment in the study period showed no difference between the study group and the historical control. Early prophylactic use of ganciclovir appears to reduce the risk of CMV disease in allogeneic transplant recipients with positive serology or positive CMV-PCR. PMID- 8683863 TI - [Interleukin-3 therapy in patients with aplastic anemia refractory to prior therapies]. AB - A therapeutic trial of interleukin-3 (IL-3) was carried out in four patients with aplastic anemia refractory to the prior therapies. Daily subcutaneous doses of 2.5, 5.0 or 7.5 micrograms/kg was given for 7 or 14 days. In a patient who had co and immediate boost-administration of granulocyte colony-stimulating factor (G CSF) and/or erythropoietin (Epo) and another who had sequential administration of G-CSF and Epo two weeks after IL-3, definite hematological response was obtained during the course after IL-3. In one patient, moderate to severe side effects consisting of facial edema, conjunctival bleeding, chills and fever, were observed after two days' administration of IL-3. Co- or sequential administration of other hemopoietic factor(s) may be essential in IL-3 therapy for aplastic anemia. PMID- 8683864 TI - [Acute lymphoblastic leukemia with marked morphologic abnormalities after chemotherapy for gastric cancer]. AB - A 76-year-old man was admitted to our hospital in February, 1994 because of fever and general fatigue. The patient had received radical gastrectomy for gastric cancer in August, 1987 and was subsequently treated with adjuvant chemotherapy using UFT for 25 months. On admission, the leukocyte count was 57,700/microliters with 74% blasts. Bone marrow aspiration revealed proliferation of blasts with marked giant cells and polynucleolar cells. The diagnosis of T-lineage of acute lymphoblastic leukemia (ALL) was then made by analysis of surface markers and T cell receptor rearrangement. Although combination chemotherapy was initially effective, blasts rapidly reappeared in the peripheral blood, and the patient died of pneumonia in August, 1994. In the presented case, blasts showed marked morphologic abnormalities. It is well known that most cases of therapy-related leukemia deviate from the myeloid lineage, and rarely from the lymphoid lineage. In addition, morphologic abnormalities are rare in de novo ALL. Since such abnormalities were demonstrated in our patient, and UFT was administered for a long period, it is possible that this leukemia occurred as a second malignancy related to UFT treatment. PMID- 8683865 TI - [Resolution of psoriasis vulgaris following allogeneic bone marrow transplantation for aplastic anemia]. AB - A 36 year-old man had suffered from psoriasis vulgaris for about 25 years. He had received corticosteroids ointment and PUVA therapy with partial response. In 1987, he was diagnosed as having aplastic anemia (AA) and treated with various medications, but failed to respond. He received an allogeneic bone marrow transplantation (BMT) from his histocompatible sister in 1993. Conditioning regimen of BMT consisted of total lymphoid irradiation (7.5 Gy) and cyclophosphamide (200 mg/kg). Cyclosporin A and methotrexate were given for prophylaxis of graft-versus-host disease. On day 24, bone marrow examination disclosed normocellular marrow and karyotypic analysis completely confirmed the donor's origin. Before BMT, he had systemic psoriatic plaques with scales, together with nail involvement. After BMT, psoriatic plaques disappeared and nail deformity improved. He has remained in remission of his AA and completely free of psoriasis in the absence of immunosuppressive or other treatments. The cause of psoriasis is thought to be an immune-mediated disorder. Our case supports the observation that changing the host's immune system through allogeneic BMT can achieve remission of psoriasis. It is suggested that allogeneic BMT may be one strategy for the treatment of intractable immune-mediated disorders. PMID- 8683866 TI - [A case of virus-associated hemophagocytic syndrome (VAHS) complicated by rhabdomyolysis which were associated with herpes-simplex virus infection]. AB - A 60-year-old male was admitted to our hospital complaining abdominal pain and fatigue. Complete blood count showed as follows; WBC 3,900/microliters (48% of monocytes), Hb 11.5 g/dl, Plt 0.9 x 10(4)/microliters. Marrow smears showed the presence of phagocytic histiocytes that consist 22.4% of total nuclear cells. Laboratory findings showed as follows; BUN 109.5 mg/dl, Creatinine 7.4 mg/dl, CPK 1,259 IU/l, Aldolase 195 IU/l, Myoglobin 4,200 mg/dl. Serological studies showed a 16-fold increase in herpes-simplex virus (HSV) antibody titers 4 weeks after admission. So we diagnosed his illness as virus-associated hemophagocytic syndrome (VAHS) and rhabdomyolysis that were associated with HSV. We performed three times of hemodialysis for acute renal failure and used prednisolone for VAHS. These treatments were successful, and he made a complete recovery from illness. VAHS complicated by rhabdomyolysis is very rare, and we think this case is full of suggestions. PMID- 8683867 TI - [Chronic myelocytic leukemia associated with cytomegalovirus induced sialoadenitis after unrelated allogeneic bone marrow transplantation]. AB - A 26-year-old male with chronic myelocytic leukemia was admitted for unrelated allogeneic bone marrow transplantation (BMT). After BMT, he developed swelling of biateral submandibular glands accompanied with pneumonitis possibly due to cytomegalovirus (CMV). Biopsy from the left submandibular gland showed giant cells with nuclear inclusion bodies that were positive for anti-CMV-IE monoclonal antibody, there fore cytomegalic sialoadenitis was diagnosed. The administration of ganciclovir resulted in resolution of the pnumonitis and submandibular gland swelling. Although cytomegalic sialoadenitis is not a life-threating complication in BMT patients, it should be noted that biopsy is very useful for the diagnosis of systemic cytomegalovirus infection. PMID- 8683868 TI - [Two cases of therapy-related myelodysplastic syndrome]. AB - Myelodysplastic syndrome (MDS) was sorted out two types; primary type and secondary type caused by irradiation or several drugs. Clinical features and chromosomal analysis were investigated in two patients with secondary MDS, caused by cyclophosphamide (CPM) or rifampicin (RFP) respectively, and fourteen cases of primary MDS hospitalized from 1988 to 1993. Two cases of secondary MDS progressed refractory anemia with excess of blasts (RAEB), however two of 14 patients with primary MDS progressed to acute leukemia. Median survival was similar in two groups. In cytogenitic analysis, complex abnormalities including -5/5q- and/or 7/7q- have two cases of secondary MDS and nine out of 14 cases of primary MDS. Complex chromosomal abnormalities did not improve following chemotherapy. In this study, clinical features and cytogenetic analysis demonstrated no significant difference between primary and secondary MDS. PMID- 8683869 TI - [Refractory anemia with excess of blasts (RAEB) with a high level of HbF that preceded apparent pancytopenia]. AB - A 76-year-old male was kept under observation for idiopathic interstitial peumonitis in our hospital from August 1992. Laboratory data revealed a slightly high level of HbF (2.7%) but normal values of other hematological examination. The level of HbF increased slowly, and in April 1994, pancytopenia appeared for the first time. Bone marrow was normocellular with myelodysplasia and 9% blasts. Cytogenetic analysis revealed 46, XY, del (20) (q11;q13). He was diagnosed as having myelodysplastic syndrome (MDS), refractory anemia with excess of blasts. At diagnosis of MDS, the level of HbF was 20.0%. He developed acute myelocytic leukemia 3 months later. It has been reported that approximately 40% of patients with MDS have higher HbF levels than normal, which is considered to be functional abnormality of the MDS clone. It is suggested that the MDS clone had already increased in this patient at presentation, 32 months before pancytopenia appeared. PMID- 8683870 TI - [Successful combination chemotherapy including deoxycoformycin in a case of cutaneous T cell lymphoma]. AB - A 44-year-old woman was admitted to our department because of fever and skin eruptions on August, 1991. Physical examination revealed superficial lymph node swelling, hepatosplenomegaly and generalized erythroderma. Laboratory findings were as follows; WBC 21,490/microliters with 67% lymphocytes including flower cells. The surface phenotype of lymphocytes was positive for CD2, CD4, CD25, CD29 suggesting helper-inducer T cell. Skin and lymph node biopsies revealed the infiltration of T cells with indented nuclei. Anti-HTLV-1 antibodies in the serum and HTLV-1 proviral DNA analysis by PCR method were negative. She was diagnosed as CTCL, and she was treated with prednisolone. However, her erythroderma deteriorated gradually, in spite of well-controlled lymphocyte counts. Combination chemotherapy, utilizing vincristine, etoposide and cyclophosphamide, was effective against organomegaly but not against generalized erythroderma. After DCF was initiated at a weekly dose of 7.5 mg, her erythroderma improved rapidly and markedly with the disappearance of severe itching, and she achieved complete remission. Our results suggest that DCF is beneficial for chemotherapy resistant generalized erythroderma in CTCL. PMID- 8683871 TI - [Retrospective analysis on 21 patients with follicular lymphoma]. AB - We retrospectively analyzed the clinical data of the 21 patients with follicular lymphoma admitted to our institution from 1977 to 1994. The frequency of follicular lymphoma was 9.1% in the 231 patients with non-Hodgkin's lymphoma. Overall survival rates at 1 year, 3 years, and 5 years were 90.2%, 78.2%, and 52.1%, respectively. The median follow-up of surviving patients and time to treatment failure (TTF) was 43 months and 30 months, respectively. The median time from disease progression to death was 171 days. In univariate analysis, factors associated with poor survival were stage IV (Ann Arbor staging system), anemia (hemoglobin level less than 10g/dl), bone marrow involvement, two or more extranodal sites, and failure in induction of complete remission (CR) in the entire course. Factors associated with short TTF were anemia, bone marrow involvement, and failure in induction of CR. In multivariate analysis, induction of CR affected survival and TTF independently. PMID- 8683872 TI - [Urgent allogeneic bone marrow transplantation using a preparative regimen of cyclophosphamide anti-human thymocytes rabbit globulin in a patient with severe aplastic anemia with pneumonia]. AB - A 16-year-old girl was diagnosed as having severe aplastic anemia (SAA) had received emergency complicated by sever pneumonia. She had an HLA-identical younger brother and been urgently transplantation with her brother's marrow following a preparative regimen of CY+rabbit antithymocyte globulin (ATG). Granulocyte transfusions carried out before and after the transplant prevented exacerbation of the pneumonia. The pneumonia was cured in association with the hematopoietic recovery after BMT. No signs or symptoms of acute or chronic graft versus-host disease were recognized and her hematological data are normal. The rabbit ATG was thought to be effective in preventing rejection and could be used in the preparative regimen instead of total body irradiation. PMID- 8683873 TI - [Mixed warm and cold antibody type autoimmune hemolytic anemia associated with systemic lupus erythematosus]. AB - A 56-year-old woman developed mixed warm and cold antibody type autoimmune hemolytic anemia (mixed AIHA) associated with systemic lupus erythematosus. The patient was admitted to our hospital for acrocyanosis and shortness of breath. High fever and jaundice were observed. Urinalysis revealed protein and hemoglobin, and the sediment contained granular and hyaline casts. Her erythrocytes agglutinated markedly at room temperature. Her hemoglobin was 5.6 g/dl and reticulocyts were 19.3%. Total bilirubin, GOT and LDH were elevated, while haptoglobin and complements were abnormally reduced. Polyclonal increase of immunoglobulin, ANA and anti-Sm antibody were detected. The direct antiglobulin test was positive; IgG1, IgG3 and C3d were detected on the red cell surface. The cold agglutinin (CA) titer was 4096, showing anti-I blood group specificity, and was still active at 30 degrees C. Upon administration of prednisolone gradual increase of hemoglobin and decrease of reticulocytes were observed, indicating the healing of hemolysis. CA disappeared but the direct antiglobulin test remained positive. Mixed AIHA has been defined as the presence of both warm and cold antibodies. In addition, the presence of symptoms of cold agglutinin disease, or low-titer and high thermal amplitude CA might be necessary for the diagnosis of mixed AIHA. PMID- 8683874 TI - [Gaucher disease type 1, incidentally found on a periodic physical examination]. AB - A 33-year-old man was admitted to our hospital because of thrombocytopenia found on a periodic physical examination. Splenomegaly was recognized Peripheral blood showed WBC 4,510/microliters, Hb 12.5 g/dl, and Plt 40,000/microliters. Increased serum levels of acid phosphatase and angiotensin converting enzyme were observed on laboratory tests. Bone marrow aspirate revealed Gaucher cells. Decreased beta glucosidase activity was demonstrated in blood leukocytes, cultured blood lymphocytes, and cultured bone marrow fubroblasts from the patient. His glucocerebrosidase genotype was T1448C/C1504T (L444P/R463C). Since neurological examination and skeletal X ray results were normal, Gaucher disease type 1 was diagnosed. PMID- 8683875 TI - [Cancer detection with whole-body FDG PET images without attenuation correction]. AB - Whole-body positron emission tomography (PET) using 2-deoxy-2-[18F]fluoro-D glucose (FDG) has been applied successfully for the detection of cancer. In PET studies, transmission scans for attenuation correction are usually performed. In whole-body PET studies, however, the transmission scans lengthen the acquisition time and are not practical for routine clinical use. Thirty-two patients underwent whole-body PET studies with transmission scans. A total of 106 lesions were true positive on corrected images. At the same time that the corrected images were being reconstructed, uncorrected images were also reconstructed and visually inspected. In a patient with a large breast cancer (11 cm in diameter), the parasternal metastatic lymph node was not identified on the uncorrected image because of image artifacts produced by high FDG accumulation in the breast cancer. In a patient with recurrent colonic cancer, paraaortic metastatic lymph nodes were not well visualized because of attenuation effects. However, 104 out of 106 (98.1%) lesions were recognizable on uncorrected images as well as corrected images. This suggests that uncorrected images can be used for the detection of cancers. PMID- 8683876 TI - [Effect of reconstruction arc in myocardial SPECT imaging--comparison between 180 degrees and 360 degrees arc--]. AB - A series of thallium-201 (201Tl) and technetium-99m (99mTc) myocardial perfusion images with or without perfusion defects were acquired by 360 degrees arc using a triple-head camera. The vertical long, horizontal long, and short axis images of 201Tl and 99mTc with 360 degrees, 180 degrees, and opposite 180 degrees were identically reconstructed and reoriented without attenuation correction. In order to detect the detailed differences between 360 degrees (30 degrees - 390 degrees) and 180 degrees (30 degrees - 210 degrees) images, the opposite 180 degrees (210 degrees - 30 degrees) images were utilized. Opposite 180 degrees images revealed the contribution of those to the 360 degrees images. In the normal perfusion images, the CV (coefficient of variation) of the counts in 360 degrees images with 201Tl by the segments was larger than 180 degrees images. On the contrary, the CV of the counts in 360 degrees images with 99mTc was smaller than 180 degrees images. This difference, caused by the difference of photon energy, were detected mainly as the extent of counts decreasing in the deep segments in the opposite 180 degrees images. Lesion contrasts of the opposite 180 degrees images were lower than those of 180 degrees images due to distance related collimator response (the detector response of the collimated gamma camera varies with source to-detector distance) and scatter. Therefore, lesion contrasts were more decreased in the 360 degrees images compared with those of 180 degrees images, especially in the segments of lateral and anterior walls. The differences in lesion contrasts between 201Tl and 99mTc images were mainly in the segments of inferior and posterior walls (p < 0.05). Lesion contrast was dependent on the location of the perfusion defects, reconstruction arc, and photon energy. PMID- 8683877 TI - [Diagnosis of lung cancer using functional image of 201Tl SPECT with parameter of 201Tl retention--evaluation of its applicability to post irradiated lung cancer]. AB - Thallium-201 (201Tl) SPECT is a useful method for detecting lung cancer. Moreover, the 201Tl Retention Index (R.I.) reported by Tonami et al is now available for differentiating pulmonary lung cancer from benign lesions. The diagnosis of recurrent tumors is, however, difficult to establish as they are often shaded by radiation pneumonitis or fibrosis. Therefore, we employed functional images (F.I.) obtained using as parameter a modified version of the R.I. First we indicated the statistical value of untreated solitary lung tumor as follows: sensitivity 84.6%, specificity 80.0%, and accuracy 83.3%. In our assessment, the lesions with tumor size over 2.0 cm and R.I. by Tonami et al over 12.7 were detected as positive images. Secondly in assessment of 22 cases (23 lesions) of post irradiated lung cancer, the results obtained were: sensitivity 80.0%, specificity 92.3%, and accuracy 87.0%. 201Tl SPECT functional images seem to be useful for the diagnosis of recurrent lung cancer by shaded radiation pneumonitis and fibrosis. PMID- 8683878 TI - [Impairment of benzodiazepine receptor in Parkinson's disease evaluated by 123I iomazenil SPECT]. AB - 123I-iomazenil is a partial inverse agonist of central-type benzodiazepine receptor (BZR). Single photon emission tomography (SPECT) using 123I-iomazenil was performed in 15 patients with Parkinson's disease (PD). SPECT images were obtained 3 hours after intravenous injection of 167 MBq of 123I-iomazenil. The ratio of 123I-iomazenil SPECT count in the cerebral cortex to that in the cerebellum was calculated as the binding potential index (BPI). The BPIs in the lower frontal, temporal, parietal and occipital cortices correlated with the motor disability evaluated by Yahr's stage. The BPI in the upper frontal cortex showed the same tendency as in the other regions but did not reach a significant level. These results suggest that BZR in the cerebral cortex of patients with PD may be impaired in proportion to the severity of the disease and that 123I iomazenil SPECT is useful for evaluating the pathophysiological condition in PD. PMID- 8683879 TI - [Usefulness of change ratio map in 99mTc-HMPAO SPECT with acetazolamide enhancement]. AB - Although a sequential 99mTc-HMPAO SPECT technique with Diamox test (seq-SPECT) is a simple and time-saving procedure to assess brain perfusion reserve, the influence of the first dose of the tracer on the second one is not negligible. Therefore, a subtraction of the rest-SPECT from the 2nd SPECT is widely-used. However, subtracted SPECT images not only need to be corrected for the injected dose and the radiochemical purity due to inherent instability of HMPAO but also are usually degraded in quality. This study was undertaken to resolve these problems utilizing a change ratio (CR) map. The CR map was obtained by dividing 2nd SPECT by rest-SPECT. Prior to subtraction, the 2nd SPECT was normalized with the ratio of the mean whole brain counts between both SPECTs. To validate CR map, 7 patients were studied with both seq-SPECT and 133Xe inhalation CBF measurement (Xe-CBF). The right to left count ratio obtained from the ROIs placed on MCA territory of CR map correlated well with that from Xe-CBF (r = 0.89, p < 0.01). Fifty-three patients with stroke underwent the seq-SPECT which was compared with the cerebral angiography (CAG) and classified into 4 groups according to the CR map. In 25 patients, all of the rest-, the subtracted-SPECT and the CR map did not show any difference between the affected side and the contralateral normal side. Seven patients with normal rest-SPECT showed decreased subtracted-SPECT counts and CR on the affected side. Three of them showed more than 75% stenosis on CAG. Four patients with the decreased counts both at the rest- and the subtracted-SPECT revealed no difference on the CR map suggesting the matched decrease of both blood flow and metabolism in the affected side. In conclusion, the CR map was a simple and useful method to evaluate the brain perfusion reserve with the seq-SPECT. PMID- 8683880 TI - [Evaluation of left ventricular diastolic function using gated SPECT with 99mTc MIBI]. AB - Development of 3 head SPECT system and 99mTc-labeled radiopharmaceuticals enable us to evaluate left ventricular systolic function on the basis of once gated SPECT routine. This study was focused on assessment of left ventricular diastolic function using 99mTc-MIBI gated SPECT data. Twenty nine patients with ischemic heart diseases underwent 99mTc-MIBI gated SPECT and 99mTc-HSAD ventriculographic assessment of left ventricular diastolic function within 1 month. Region of interests (ROI), simultaneously calculating counts per pixel within ROI, were placed over whole myocardium of 16 serial phasic images reconstructed from gated SPECT data, following selection of the central slice within short axial images. Then, 29 patients were classified into 3 patterns of phase count curve (normal, mixed, and delayed relaxation = diastolic dysfunction). Moreover, 1/3 Count Decreasing Fraction (1/3 CDF) was calculated on the same concept as 1/3 FF. The curve pattern showed significant differences between normal and abnormal group divided on the basis of established indices such as 1/3 FF and PFR, and 1/3 CDF has correlations with 1/3 FF (r = 0.61) and PFR (r = 0.58). We concluded that the new parameters drawn from 99mTc-MIBI gated SPECT data might be feasible for evaluation of diastolic function. PMID- 8683881 TI - [Application of laser spectroscopy for 13C-breath tests]. AB - A new device Tunable Diode Laser Spectroscopy (LS) was developed for the analysis of isotope ratios of 13CO2/12CO2. Its applicability for breath tests was validated. The exhaled breath is collected in a 2 l aluminum bag, of which CO2 is separated by cryogenic system and introduced into LS. Repeat measurements (8 times) of two kinds of gases (delta 13C:-2.62 and - 1.14%) revealed 0.045% and 0.065% variation (IS.D.), from which precision of measurement was estimated as 0.2% (3S.D.). Seven healthy volunteers were given orally different dose of 13C glycine (50 mg-200 mg in 5 subjects) and 13C-methacetin (30 mg and 150 mg in 2 subjects). One patient with gastric ulcer with helicobacter pylori (HP) infection was given 100 mg of 13C-urea. Serial breath samples (9-15) were taken and measured both by LS and mass spectrometer (MS) thereafter. Appreciable peaks were obtained at 30-50 min. after glycine and methacetin ingestions. The height of the peaks were dose dependent. Increased excretion of 13CO2 characteristics to HP infection was obtained in 13C-urea breath test. Measured values with LS were identical with those measured with MS (60 samples) with the range of difference within 0.2% (3S.D.). [Y (LS) = 1.02X (MS) + 0.55, r = 0.996] We conclude the LS is suitable for various 13C-breath tests. PMID- 8683882 TI - [Detection of bone metastasis by serial measurement of C-terminal telopeptide of type I collagen in patients with malignancy]. AB - Measurements of biochemical markers specific to bone resorption are known to be useful in evaluation of skeletal metastasis. However, most of previous studies were performed cross-sectionally and sensitivity for detection of early bone metastasis was not satisfactory. Since basal levels of bone markers differ significantly individually, longitudinal studies would be preferable to evaluate small metabolic changes such as in early skeletal metastasis. Thus, we performed serial measurements of serum c-terminal telopeptide of type I collagen (ICTP), a bone resorption marker, in patients with malignancy and evaluated its clinical significances for detection of bone metastasis, comparing with measurements of propeptide of type I procollagen (PICP) and tumor markers. In total, 43 patients (41 of them are breast cancer), serial serum samples were obtained during 0.5 to 2.4 years (mean 1.4 years). In all of nine patients, who developed bone metastasis, serum ICTP level increased, and by successful treatment to the metastatic lesions, ICTP level decreased, while in some cases, tumor markers remained to be elevated. PICP was less sensitive and specific for detection of bone metastasis. Thus, serial measurement of ICTP is suggested to be useful for detection and evaluation of therapeutic responses in patients with bone metastasis. PMID- 8683883 TI - [Fast and accurate numerical method for principal components analysis dealing with large image data sets]. AB - The principal components analysis has been applied to various imaging studies in nuclear medicine. This technical report describes a fast and accurate numerical method of calculating eigenvalues and eigenvectors in the principal components analysis dealing with larger image data sets. The method employs both data transformation and matrix transpose of original data sets to calculate a variance covariance or correlation matrix. The method was tested on actual image data sets using a common workstation, confirming faster execution time and efficient accuracy in comparison to a standard method. PMID- 8683884 TI - [Observation of relation between object size or length and count rate for 3D PET]. AB - We obtained the concentration range of better S/N in 3D than 2D acquisition by measuring count rate for phantoms of different size and length. We used noise equivalent count rate (NECR) for evaluation of S/N of images. For 20 cm diameter 15 cm length cylindrical phantom, NECR of 2D was higher than that of 3D more than 1.2 microCi/ml. For 30 cm diameter 15 cm length cylindrical phantom, NECR of 2D was higher than that of 3D more than 0.7 microCi/ml. For 14 cm diameter 25 cm length cylindrical phantom, NECR of 3D was lower than that of 25 cm length phantom. With these results, though 3D is useful when administered dose is small, image quality of 2D becomes better than 3D more than a certain concentration. For the larger diameter or longer object, the advantage of 3D is diminished at lower concentration. PMID- 8683885 TI - [Contamination levels to room air arising from the use of 99mTc-gas and prevention from the contamination]. AB - 99mTc-gas (TECHNEGAS) is a 99mTc-labeled micro-aerosol which is considered to have different behavior from 133Xe or 81mKr gas. In order to estimate contamination levels to room air arising from the use of 99mTc-gas, filtered expired air during administration and 1, 2, 3, 5, 10 min after the administration were collected in each polyethylene bag. Radioactivities of the polyethylene bags, used filter and the lung were measured with 3-head scintillation camera. The activity of the expired air diminished within 6-10 min and about 5% of whole discharged 99mTc-gas was released to room air. The activity of the used filter was two times of the lung. According to these results, it is recommended that the 99mTc-gas may be administrated in a exclusive room. The administrated patient and used filter must be remain in the exclusive room. PMID- 8683887 TI - [Invasion, metastasis and angiogenesis of renal cell carcinoma]. PMID- 8683886 TI - [Imaging of somatostatin receptor using 111In-pentetreotide]. AB - Recently radiolabeled somatostatin analog, [111In]pentetreotide, was developed and its usefulness for the diagnosis and localization of neuroendocrine tumors has been described. In this paper, we reported the results of [111In]pentetreotide scintigraphy in four patients with gastroenteropancreatic endocrine tumors. Two patients with metastatic gastrinoma, one patient with gastric carcinoid, and one patient suspected with gastrinoma, were injected with 119-156 MBq of [111In]pentetreotide. Planar and SPECT images were obtained 4, 24, and 48 hours postinjection. Both primary and metastatic tumors were well visualized in patients with metastatic gastrinoma. Especially in one patient small liver metastases which were not detected by CT or MRI were imaged. We could not obtain positive images in the other two patients. Four-hour or 24-hr images were better than 48-hr images because of higher count density and lower gut activity. No significant adverse effect were seen in any patient. [111In]pentetreotide scintigraphy is a useful procedure for the localization of gastroenteropancreatic endocrine tumors. PMID- 8683888 TI - [Retroperitoneal laparoscopic nephrectomy: initial 2 cases]. AB - Two patients with nonfunctioning kidney were treated with retroperitoneal laparoscopic nephrectomy. The working space in the retroperitoneum was created by balloon dissector consisted of surgical glove and rigid nephroscope. The balloon dissector inserted to retroperitoneal space was inflated with 500-600 ml normal saline. After removal of the balloon dissector, 4 trocars were inserted to the retroperitoneal space. In these two cases, the kidney were removed successfully without any complication. The operating time was 165 min and 219 min, respectively. PMID- 8683889 TI - [Study on the lower urinary tract function in experimental diabetic rats]. AB - BACKGROUND: Diabetic lower urinary tract disfunction is well known, however, precise mechanism of the lower urinary tract disfunction remains to be solved. The present study is to clarify the lower urinary tract disfunction of diabetic rats by simultaneously measuring bladder and urethral pressures. METHODS: Female wistar rats were administered with streptozotocin (STZ 65 mg/kg, i.p.) to induce diabetes mellitus. Bladder and urethral pressures during rhythmic bladder contractions were compared under urethane anesthesia (1.0 g/kg, i.v.) between the control rats, diabetic rats, and diuretic rats. RESULTS: The bladder contraction pressures of diabetic rats were decreased initially, but returned to the control values at 8 weeks. Atropine (2.5 mg/kg, i.a.) produced a marked reduction of bladder contraction pressure in the 8 weeks diabetic rats. The diabetic rats showed an increase of urethral pressure simultaneously with an increase of bladder pressure in the initial phase of rhythmic bladder contraction which is totally blocked by striated muscle relaxant. This phenomenon was not observed in the control or diuretic rats. Both group showed an initial decrease of urethral pressure followed by bladder contraction and rhythmic contractions of the urethra. CONCLUSION: Our results suggest that bladder muscarinic receptors of the 8 weeks diabetic rats are more dominant than those of the other groups, and Mahoney's 4th reflex (urethrosphincteric guarding reflex) is facilitated but Mahoney's 6th reflex (detruthodetrusor facilitative reflex) is suppressed in the diabetic rats. We think that in the diabetic rats, sensory inputs by bladder distension were weak and could not induce Mahoney's 6th reflex until certain threshold values. Diabetic rats might develop changes in the mode of spinal neuronal transmission. PMID- 8683890 TI - [Trial of bladder sparing for patients with invasive bladder cancer by transurethral resection and intra-arterial chemotherapy]. AB - BACKGROUND: We reviewed our experience with bladder conservative treatment for invasive bladder cancer in 20 patients to investigate which type of tumor was suitable for organ conservation. METHODS: We performed radical transurethral resection with dissection to deep layer of the muscle plus intra-arterial chemoinfusion of the cis-platinum at a dose of 80-100 mg/body twice at least, and the recurrent tumor was treated by the same procedure. There were 13 cases of stage T2 and 7 cases of stage T3a. All patients were pathologically diagnosed transitional cell carcinoma with 9 cases of grade 2 and 11 cases of grade 3. RESULTS: With a follow-up of 36 months (range 18 to 82), 15 (75%) of 20 patients were survived and 10 (50%) of 20 patients were free of tumor. Of 5 patients with residual or recurrent tumor, 2 patient underwent cystectomy and the others were required transurethral resection. Of 5 patients died, 4 patients died of cancer all with distant metastasis (lung meta: 2 cases, liver meta: 2 cases). In reference to tumor characteristics, all 4 patients had over 3 cm diameter tumors with non-papillary surface and 3 of 4 patients had invasive tumors extended to bladder neck and prostatic urethra. Of 15 patients alive, 7 (47%) patients had non-papillary tumors, 9 (60%) had grade 3 tumors, 5 (33%) had T3a tumors, but invasion of the prostate urethra was recognized in only 3 patients (20%). CONCLUSION: We had possibility of doing organ prevention therapy for the patients with invasive bladder cancer, even though it was non-papillary or grade 3 tumor. On the other hand, it was thought that a conservative approach should not be considered in patients with large non-papillary tumors that extended to bladder neck and prostatic urethra. PMID- 8683892 TI - [The effects of cyclosporin azathioprine and mizoribine on male reproduction in rats]. AB - BACKGROUND: The effects of cyclosporin (Cs), azathioprine (AZP) and mizoribine (MZR) on male reproduction in rats were examined. METHODS: Each drug was orally administered every day for 14 days at the following doses; Cs, 10, 20, 40, or 80 mg/kg body weight; AZP, 5, 10, or 20 mg; and MZR, 2.5, 5, 10, or 20 mg. RESULTS: In the sperm count in the cauda epididymis, two weeks after the discontinuation of administration, a significant decrease was observed only in the 80 mg/kg dose group among the Cs-treated groups and in the 5 mg/kg and 20 mg/kg dose groups among the AZP-treated groups. At the end of the administration, a significant dose-dependent decrease was observed in the MZR-treated groups. The degree of the decrease was smaller after Cs administration compared with the other 2 drugs. Sperm motility was significantly decreased in each Cs-treated group immediately after the oral administration of Cs and improved gradually, but was not changed in AZP- and MZR-treated groups. Significant dose-dependent damage of the seminiferous tubules was noted 6 weeks after administration of Cs, AZP and MZR. The serum levels of luteinizing hormone and follicle-stimulating hormone remained the same throughout the experiment. The serum level of testosterone was significantly low immediately after the oral administration of AZP, but was not changed by that of Cs and MZR. CONCLUSION: Cs, AZP and MZR injured the spermatogenesis in rat. However, changes in the sperm count in the cauda epididymis suggested that the degree of impairment by Cs is relatively small, but only Cs injured epididymal function as well. PMID- 8683891 TI - [Treatment of advanced testis cancer with a high dose chemotherapy regimen (PVeBV)]. AB - BACKGROUND: The prognosis of patients with testis cancer classified as being in the advanced extent according to the Indiana University staging system is still poor even when treated with cisplatin based chemotherapy. METHODS: Attempting to increase the efficacy of chemotherapy in this high risk group, we have adopted PVeBV chemotherapy (high dose CDDP+VBL+VP-16+BLM) for recent 8 patients with such advanced conditions. In this study, we analized the treatment outcome of those patients retrospectively. RESULTS: Two patients died during the first course of PVeBV chemotherapy due to cancer progression, while 6 patients treated with 3 to 4 cycles of PVeBv were eligible and assessable for response, survival, and toxicity. Five of those 6 achieved pathological CR (pCR) following surgical resection of residual masses after 3 cycles of PVeBV. The other case was saved by salvage chemotherapy with autologous BMT. All 6 patients were long-term disease free survivors in median follow up of 46 months. With the rG-CSF application and vigorous hydration, acute phase toxic effects (myelosuppression, pulmonary fibrosis and nephrotoxicity) were manageable in this intensive regimen. Long term toxic effects such as peripheral neuropathy and ototoxicity were also tolerable and quality of life in such advanced cancer patients was preserved well. CONCLUSION: To improve a cure rate of high risk testis cancer, the dose escalation of induction chemotherapy should be considered. PMID- 8683893 TI - [Clinical study of pediatric kidney transplantation at Kansai]. AB - BACKGROUND: The clinical study of pediatric kidney transplantation in Kansai area is reported in this paper. METHODS: Seventy six children, 0-15 years old, received renal transplants at 8 transplant centers of Kansai area up to December, 1993. Clinical study was carried out about the etiology of renal failure causes, the graft survival and the complications. RESULTS: End-stage renal failure was due to a variety of diseases. The 3 most common causes were chronic glomerulonephritis, chronic pyelonephritis including of reflux nephropathy and focal segmental glomerulosclerosis (FSGS). The graft rates at 3, 5 and 8 years were 75%, 71% and 53% for children receiving azathioprine (AZ), compared to 77%, 59% and 52% for ones receiving ciclosporin (Cs). Cs has led no improvement of the graft survival. Adult had the better graft survival rate than children in Cs immunosuppressive protocol. In 12 children transplanted kidneys for FSGS, only 3 cases had recurrent FSGS. Neoplasia was found in two case. They were acute leukemia and liposarcoma. CONCLUSION: Kidney transplantation is recommended as the treatment for end-stage FSGS. Even the children should be carefully followed up after transplantation for malignant tumors. PMID- 8683894 TI - [One-stage urethroplasty with the modified OUPF IV for proximal hypospadias]. AB - BACKGROUND: We previously performed one-stage urethroplasy with OUPF IV in 17 patients with proximal hypospadias and experienced meatal stenosis in 3 and meatal regression in 2. METHODS: Because these complications seemed to be caused by diminished vascularity, we modified the technique to preserve the vascularity to the peripheral site of the neourethra. The modified OUPF IV (Koyanagi) was used to treat 6 patients with proximal hypospadias during the last 3 months. RESULTS: Urethrocutaneous fistulas developed in 2 patients but meatal stenosis and meatal regression did not occur. CONCLUSION: We think this modification is suitable for severe proximal hypospadias. PMID- 8683895 TI - [Random biopsy and recurrence risk in patients with bladder cancer]. AB - BACKGROUND: We studied the relationship between the recurrence rate of primary superficial bladder cancer and random biopsy. METHODS: We performed transurethral resection of primary superficial bladder cancer in 144 patients, and in 55 of those cases a random biopsy was also performed. The non-recurrence rate was examined in many recurrence facters. RESULTS: The non-recurrence rate in the group with random biopsy was not significantly different from that observed in the group (100 patients) without random biopsy (chi 2 test, Generalized Wilcoxon test and multivariate analysis). Because the intravesical instillation therapy is an important inhibition factor in the recurrence rate of the primary superficial bladder cancer, we further analysed the recurrence rate in two non treated groups with or without random biopsy (13 and 35 patients respectively). No significant difference in the rate of recurrence between the two groups was observed. However, we noted recurrence of bladder cancer at biopsy positions in 8/13 patients. CONCLUSION: It appears that random biopsy may have an effect on the recurrence or the implantation of tumor cells. Further studies are needed to clarify whether random biopsy is a risk factor in the recurrence rate of primary superficial bladder cancer. PMID- 8683896 TI - [Indications of parathyroidectomy for bone disease associated with secondary hyperparathyroidism]. AB - BACKGROUND: The indications and suitable operative time of parathyroidectomy for secondary hyperparathyroidism were discussed. METHODS: From October 1978 to September 1994 parathyroidectomy was performed for 71 patients who had bone and/or joint pain due to secondary hyperparathyroidism. There were 37 men and 34 women (mean age 48.4 years). The duration of dialysis treatment before parathyroidectomy was 0.8 to 19 years, with a mean of 10.9 years. RESULTS: Postoperative subjective improvement was noted in 69% of the patients. No significant difference was observed between the improved and non-improved groups regarding age and the duration of dialysis treatment. But the improvement rate in female patients was significantly lower than that in male patients. CONCLUSION: Patients with high carboxyl-terminal PTH level and generalized fibrous osteitis were good suitable objects for parathyroidectomy. But, those with high serum aluminum level were unsuitable objects for it. Furthermore, 99mTc-Pyrophosphate bone scintigraphy and bone mineral determination using dual photon absorptiometry (DPA) or dual energy X-ray absorptiometry (DEXA) were proved to be valuable for patient selection for parathyroidectomy. PMID- 8683897 TI - [A case report of renal leiomyoma and its DNA ploidy pattern]. AB - We experienced a case of renal leiomyoma. A 51-year-old woman was referred to the Department of Urology, Tochigi Cancer Center with a complaint of right renal incidentaloma pointed out on CT scan. The renal mass was removed by enucleation. Histological examination revealed the tumor composed of monotonous proliferation of spindle shaped cells without atypia. Thus, the diagnosis of leiomyoma was confirmed. DNA flow cytometric analysis of this tumor was performed and diploid pattern was shown. PMID- 8683898 TI - [A case of mucinous adenocarcinoma of the prostate]. AB - We experienced a case of mucin producing prostate carcinoma, which occurred 46 year-old male patient. Serum tumor markers of prostate carcinoma were all in normal levels, and physical findings were similar to those of benign prostate hypertrophy. Histopathological study showed poorly differentiated mucinous adenocarcinoma occupying more than 30% of specimen. In literatures there seemed two types of mucin producing prostate carcinoma, the one is different from usual prostate carcinoma as our case and the other is a subtype of usual one, and so it was suggested that we must respect to this point on diagnosis and therapy of it. PMID- 8683899 TI - Human melanoma antigens recognized by T lymphocytes. AB - Human melanoma antigens and their epitopes recognized by T cells have been identified using a variety of methods. These antigens are classified as 1) melanocyte specific melanosomal proteins (MART-1, gp100, tyrosinase and TRP-1), 2) proteins expressed in testis and a variety of cancers (MAGE-1, MAGE-3, BAGE and GAGE), 3) tumor specific mutated proteins (beta-catenin, MUM-1 and CDK4), and 4) others (p15). Some of the HLA-A2 binding non-mutated melanoma epitopes contained non-dominant anchor amino acids and have relatively low HLA-A2 binding affinity, suggesting that these epitopes were likely to be subdominant or cryptic self determinants. The significant correlation observed between vitiligo development and IL2 based immunotherapy suggested that autoreactive T cells specific for these self peptides were involved in melanoma regression in vivo. In addition, since adoptive transfer into patients of CTL recognizing these epitopes resulted in tumor regression, these epitopes may be tumor rejection antigens. Melanoma reactive CTL were efficiently induced from PBL of patients by in vitro stimulation with PBMC pulsed with these melanoma epitopes and may be useful in adoptive transfer protocols for the treatment of patients with metastatic melanoma. An immunization trial using the MART-1 and gp100 peptides in conjunction with incomplete Freund's adjuvant is in progress. These identified antigens may be useful for the development of new immunotherapies for the treatment of melanoma patients as well as for understanding the mechanisms of anti-tumor immune responses and autoimmune disorders against melanocytes. PMID- 8683900 TI - Alpha 1 antitrypsin defective Lewis rats injected with heparin: comparison of the glomerular changes with those of Lewis rats produced anti BSA antibody. AB - Heparin effects were studied on Lewis rats with alpha 1 antitrypsin (AT) defect. Among 8 rats that were born at the same birth, three rats were shown to have mild defect of alpha 1 AT. Heparin was injected repeatedly into all the 8 rats. Interstitial pneumonia and localized periodic acid-Schiff (PAS) stain of hepatocytes were found in alpha 1 AT defective male. One of the three alpha 1 AT defective rats had about a half of normal alpha 1 AT level. Antithrombin (AT) III level was slightly low in the alpha 1 AT defective female with splenomegaly. Lung electron micrograph of the other alpha 1 AT defective female showed edematous changes of capillaries and alveolar basement membranes and also proliferated collagen fibers. In the lung of alpha 1 AT defective male, many thrombocytes adhered to alveolar degenerated smooth muscles that were recognized as Masson bodies. Extracted platelet-activating factor (PAF) in the plasma of the alpha 1 AT defective male was shown to trigger T lymphocyte chemotaxis. Five normal Lewis rats were immunized with bovine serum albumin (BSA). IgG1 antibody to BSA was produced in all the rats. The rats with high titers of IgG1 anti BSA antibody showed more strongly atrophic changes of glomerulus than those of the mild alpha 1 AT defective rats treated with heparin. PMID- 8683901 TI - CD7 positive acute lymphoblastic leukemia successfully treated with high dose cytosine arabinoside and mitoxantrone: a case report. AB - A 45-year-old woman with acute lymphoblastic leukemia (ALL) who failed to achieve complete remission (CR) after one course of induction chemotherapy with vincristine, daunorubicin, prednisolone and l-asparaginase was successfully treated with a high dose of cytosine arabinoside (Ara-C) and mitoxantrone. The leukemic blasts were CD7, 19, 33, and 38 antigens positive, and had a rearrangement in the T-cell receptor delta chain gene. The karyotype was normal. Primary induction failure and positivity for myeloid antigens are both reported to be poor prognostic factors for ALL. Nevertheless, this patient was successfully treated with the high dose Ara-C and mitoxantrone, and she remains in CR for over 20 months. Combination chemotherapy with high dose Ara-C and mitoxantrone may be of benefit for refractory ALL with both CD7 and myeloid antigens. PMID- 8683902 TI - Clinical application of flow cytometry to urological malignancies. AB - Flow cytometric DNA analysis provides rapid, quantitative objective information regarding the biological behavior of urological malignancies. Moreover, clinical applications of the many recent advances made the flow cytometry are expected to materialize soon. For instance, flow cytometric DNA ploidy analysis for human bladder cancers may provide a significant diagnostic and prognostic potential. Also, flow cytometric DNA analysis of irrigation specimens produces a higher sensitivity than conventional cytology for detecting bladder cancer. However, there are obvious pitfalls with this approach since diploid or near-diploid tumors cannot always be recognized by DNA analysis alone. One of the most significant advantages possible with flow cytometry is its capability of analyzing simultaneously multiple parameter on single cells. The integration of the DNA content with proliferative activity should yield important information significant to the biological behavior of individual tumors. Flow cytometric DNA/bromodeoxyuridine bivariate analysis can be used as an effective adjunct to histological examination for prognostication and decision-making in treatment of bladder cancer patients. Therefore, multiparameteric flow cytometric analysis can be used to isolate specific tumor cells from mixed cell populations, and should receive even increased attention as a valuable diagnostic technique and prognostic factor. In the present review, the efficacy of flow cytometric DNA ploidy analysis integrated with cell proliferation markers is discussed. PMID- 8683903 TI - Grafting of genetically manipulated cells into adult brain: toward graft-gene therapy. AB - Accumulating evidence has shown that functional recoveries in various kinds of animal models of neurodegenerative diseases can be achieved by grafting fetal neurons into the brain. On the basis of these successful results, clinical trials are under way to determine whether human fetal mesencephalic tissue can ameliorate motor functions in patients with Parkinson's disease. Recent autopsy findings of parkinsonian patient implanted with human fetal mesencephalic tissue clearly revealed that the fetal neuronal graft can survive for extended period of time in the human brain and densely reinnervate the surrounding host striatal tissue. It is, however, still important to obtain more practical, effective and ethically justifiable donor material for the future clinical application of the procedures. Desirable properties for the donor cells include long-term survival in the host brain, neuronal cell type for the reconstruction of damaged neural circuits, and susceptibility to genetic manipulation for the practical use. With the development of molecular biology techniques, genetic modification and transplantation of the donor neuronal cells might be a feasible way to cure many kinds of central nervous system diseases toward a "graft-gene therapy". PMID- 8683904 TI - Beyond oxidized LDL: the initiation and progression of atherosclerosis. AB - Oxidized-low density lipoprotein (ox-LDL) exhibits various atherogenic properties, such as the formation of foam cells, the recruitment of macrophages into arteries, the promotion of cell growth, the formation of thrombi, and the development of vasoconstriction. Antioxidants inhibit atherosclerosis in cholesterol-fed animals by preventing the recruitment of macrophages into the arteries suggesting that oxidation is important for such recruitment of macrophages, and that it is responsible for early development of atherosclerosis. Calcification and an increase in extracellular matrix (ECM) are frequently observed in advanced atherosclerosis. These processes are active and regulated, not passive and degenerative, and do not appear to be controlled by ox-LDL. The control of calcifications and ECM increase will provide new directions in the treatment of atherosclerosis especially in the advanced stages. Future treatment should include strategies to inhibit the calcification and the increase in ECM. PMID- 8683905 TI - Current topics in neuroleptic-induced extrapyramidal symptoms in Japan. AB - This article reviews current topics in neuroleptic-induced extrapyramidal symptoms in Japan, focusing especially on the clinical features of akathisia and dystonia. Akathisia is a common side effect associated with antipsychotic drugs. It is most commonly characterized by subjective inner restlessness and objective motor signs, especially in the lower extremities. The mechanisms underlying akathisia remain unclear and controversial; however, an increase in the activity of beta-adrenergic systems relative to dopaminergic systems has been hypothesized, based on clinical therapeutic observations that beta-blocking agents are effective in this condition. A Japanese version of the Barnes Akathisia Scale has recently been established and uses a standardized videotape method for its precise evaluation. Various acute and chronic manifestations of neuroleptic-induced dystonia have been reported in Japan, including blepharospasm, difficulty in opening the eye lids, torticollis, retrocollis, oculogyric crisis, and Pisa syndrome. This review also introduces several other topics related to drug-induced extrapyramidal symptoms in Japan. These include; 1) the Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS), which has recently been established, 2) studies on the discontinuation of anticholinergic drugs, and 3) a summary of extrapyramidal symptoms induced by drugs other than neuroleptics. PMID- 8683906 TI - [Clinical evaluation on causes of death in patients with active pulmonary tuberculosis]. AB - Seventy one patients with active pulmonary tuberculosis who died during the past 5 years (1989 to 1993) were evaluated on their causes of death. Twenty two patients (31%) died directly of tuberculosis, and among them, 18 patients (81%) of 22 patients who died of tuberculosis) had very advanced tuberculosis. The majority of them (64%) were old age over 70 years and were bedridden due mostly to cerebrovascular injuries. The serum level of albumin was low in all 17 patients in whom it was measured. Establishment of diagnosis of tuberculosis was delayed over one month after the onset of symptoms in 59% of patients who died of severe disease. Sixty one percent (11/18) of patients died within the first month after the initiation of chemotherapy and about 90% (16/18) died within 3 months. Two patients died from massive hemoptysis and other patients died of either respiratory failure or tuberculosis meningitis. From these observations it was found that very advanced tuberculosis was the major cause of death in patients who died of tuberculosis and that the advanced disease was chiefly caused by the delay on the establishment of diagnosis, and it was most important to detect tuberculosis as early as possible, with regular check up of chest X-ray and frequent examination for AFB (acid-fast bacilli) for tuberculosis suspected patients. On the other hand, the majority of patients (49/71) died of complicating medical problem unrelated to tuberculosis. Seventeen patients died from malignancy (seven lung cancer, four lymphoma, two laryngeal cancer, etc). Ten deaths were the result of bacterial superinfection. Other patients died from respiratory failure due to COPD, arteiosclerotic heart disease, or cerebrovascular injuries, etc. Two patients of old age died of hepatic failure possibly caused by adverse reaction of TB chemotherapy. It was found that diseases unrelated to tuberculosis were the cause of death in approximately 70% of patients with active tuberculosis, and it should be emphasized to detect early and to treat these diseases, in particular malignancy. And it is also imperative that the chemotherapy for TB must be instituted very carefully with frequent monitoring of liver function in patients with old age. PMID- 8683907 TI - [Patient's delay and doctor's delay in the pulmonary tuberculosis--the experience of the National Chiba Higashi Hospital]. AB - Out of 1628 tuberculosis patient discharged from the to National Chiba Higashi Hospital, 537 previously untreated pulmonary tuberculosis patients were selected for the study to examine the delay in case-defection. Patient's delay were longer but doctor's delay were shorter in male than in female. The main reasons for doctor's delay were the delay in taking chest X-ray, and the error in the interpretation of initial chest X-ray findings. In 88 patients who were detected in the advanced stage, the total delay were longer than the others common cases and the doctor's delay was found in 13 cases. To avoid such an unnecessary delay, the importance of sputum examinations must be re-emphasized in all patients who show respiratory symptoms and/or abnormal chest X-ray findings. PMID- 8683908 TI - [Four cases of pulmonary tuberculosis resembling pulmonary abscess with a so called niveau-like shadow in a medical school hospital: discussion concerning the formation mechanism of niveau-like shadows]. AB - Four cases of pulmonary tuberculosis resembling pulmonary abscess radiographically were reviewed from their clinical features, chest X-ray and chest CT, and the mechanism of formation of so-called niveau-like shadows was discussed. Only one case showed a newly formed tuberculous cavity with air fluid level on chest X-ray, however, even in this case, the possibility of the infection with tubercle bacilli of an emphysematous bulla of the lung could not be completely excluded as several bulla were found on chest CT. The remaining three cases showed a slightly different mechanism of the formation of niveau-like shadows. Namely, mycobacterium tuberculosis spread into an existed bulla and a tubercle bacilli infected bulla was formed. Regarding the clinical features, no remarkable findings were detected and we could find no differences with common tuberculosis. Based on these experiences, the presence of pulmonary tuberculosis resembling the shadow of pulmonary abscess should be emphasized. PMID- 8683909 TI - [Changes in the working status of pulmonary tuberculosis patients after the admission]. AB - We reported changes in the working status of pulmonary tuberculosis patients after the admission to our hospital. The age of patients ranged from 20 to 69 years old, and they were admitted to the 18th ward of our hospital from April 1991 to March 1993. We sent out the questionnaire to 198 patients, and the reply was sent back from 116 patients (Male 74, Female 42). Out of the 116 patients, we excluded the unemployed, the government employees, and self-employed workers. The remaining 76 patients were examined about their working status after admission, and the results were as follows: 2 patients lost their work, 11 patients retired from the work, 2 patients faced the drop of their position, and 3 patients had their salary reduced. PMID- 8683910 TI - [Tuberculosis as a global emergency]. PMID- 8683911 TI - [Prognostic factors in the surgical treatment of lung cancer]. AB - Some prognostic signs of surgical treatment of carcinoma of the lung are analysed. The stability and paramount importance of the integral clinical factor "extension of the tumor" is shown. The ultrastructural features of adenocarcinoma and squamous-cell carcinoma of the lungs influencing the disease prognosis were revealed. It is shown that electron microscopy allows differentiation of the tumor cells to be profoundly and precisely assessed. The results of the study unable a differentiated approach to the problems of postoperative therapy. PMID- 8683912 TI - [Diagnosis and treatment of malignant melanoma of the skin (a lecture)]. AB - The authors analyse specific features of the diagnosis and treatment of malignant melanoma of the skin in individuals follaved up in 1985-1990. A program of active diagnosis of skin melanoma has been developed and introduced into practice which allowed detection of the tumor at the first stage of its development in 83% of patients and to limit the radical management to a quite economical resection (by 2-5 cm from the border of the tumor) in 72% of patients. Five-year survival was 92%. PMID- 8683913 TI - [Diagnosis and surgical treatment of recurrences of rectal cancer]. AB - The authors present the analysis of the results of surgical treatment of 145 patients with recurrent rectal carcinoma in 1960-1990 at the State Scientific Centre of Proctology. A group of 304 patients who underwent radical operation for carcinoma of the rectum was also studied to determine the frequency of recurrences after radical surgery. It was found to be 30.9% (in 94 out of 304 patients). More than half of carcinoma recurrences (63.8%) were revealed in the first postoperative year and 85.1% in the first two years. The average term of their appearance was 13.4 months. A radical operation may be performed for a second time in only 22.3% of cases of recurrences. The study of factors considerably influencing the frequency of the recurrence made it possible to determine three groups of patients with various risks of the development and create a scheme of their regular medical examination. Repeated radical operations on the cavities were carried out in 90 patients with recurrences, in 55 patients local resection of recurrrent tumor was performed. The indications for repeated operations were elaborated. More than half repeated operations on the cavity (53.3%) were combined, extensive, and concomitant. The incidence of intraoperative (52.2%) and postoperative (62.2%) complications was significantly higher than in primary operations. The use of a complex of therapeutic and preventive measures usulted in relatively low postoperative lethality (6.7%). Five-year survival after repeated operations on the cavity was 29 +/- 5.5%, the frequency of repeated recurrences was 34.5 +/- 5.2%; the respective figures after local excision were 14.6 +/- 5.5 and 40.8 +/- 7%. PMID- 8683914 TI - [Current possibilities in the diagnosis and treatment of appendiceal mucocele]. AB - The authors present an original experience of using an ultrasonography and a computer scan for a preoperative diagnosis of VP mucocele. The laparoscopy has been used as a method for the final diagnosis as for an appendectomy. The authors also describe their understanding of VP mucocele pathogenesis and their opinion about diagnosis and treatment of such kind of a case. PMID- 8683915 TI - [Drainage operations in acute pancreatitis]. PMID- 8683916 TI - [Iron metabolism in patients with portal hypertension]. AB - Ninety-four patients with portal hypertension (48 with cirrhosis of the liver and 46 with pathological changes of the portal vein trunk) were examined. The main parameters of iron metabolism were determined by the radioimmunoassay and the iron deports in the liver and spleen biopsy material were revealed. Tissue iron deficiency was found in all patients. The results of the tests were marked by essential peculiarities. In sharp reduction of the level of serum iron and ferritin the parameters of total and latent iron-binding capacity were decreased. PMID- 8683917 TI - [Perspectives for minimally invasive surgery]. PMID- 8683918 TI - [Endoscopic surgery: sources and present status]. PMID- 8683919 TI - [The functional results of distal subtotal gastric resections in cancer patients]. AB - It was clinically proven that a gastrojejunostomy with Rue-type anastomosis, following the subtotal gastric resection has better functional results. This method does not cause as many late postoperative disorders as Billroth I and Billroth II operations. So, it is better to use the Rue-type anastomosis for treatment of distal stomach cancer stage I-III. PMID- 8683920 TI - [Stimulation of tissue lymphatic drainage in the treatment of patients with arterial diseases]. AB - The results of treatment of 17 patients with endarteritis obliteran and 44 patients with atherosclerosis obliteran of the lower limbs were analysed. The complex of therapeutic measures included direct and indirect stimulation of lymphatic drainage in the tissues. The effect of lymphostimulation on regional hemodynamics, microcirculation, and metabolism in the tissues of the ischemic lower limb are appraised. Changes in the lymphatic system resorption capacity, in microcirculation, in the composition and properties of the peripheral lymph in the limb in stimulation of lymphatic drainage of tissues are analysed. Indirect lymphostimulation contributed to the improvement of the indices under study in patients with IIb and IIIa stages of ischemia. Direct stimulation of lymphatic drainage caused a more pronounced effect in cases of stage IIIa ischemia of the limb and may be applied in preoperative and postoperative management of patients with stage IIIb ischemia. PMID- 8683921 TI - [Surgical treatment of ischemia of the stump of the lower extremity]. AB - The authors observed 22 patients who had obliteration of leg arteries and stage III-IV leg stump ischemia. The reconstruction of the stump circulation by using a deep artery of the thigh allowed to stop the ischemia and make the stump more functional or gave an opportunity to make Gritty operation. PMID- 8683922 TI - [Treatment of trophic ulcers of the lower extremities with Trental-400]. AB - Thirty-two patients with arterial and venous trophic ulcers were treated by Trental-400 in a dose of 1200 mg a day within 6 months. The full success has been achieved in 65.6% of all cases. Significant progress was in 9.4% of all patients. There were several reasons for no success in other cases. The mains of them are: aterial insufficiency in a complex with an old age, other severe problems, unadequate local therapy. PMID- 8683923 TI - [New antiseptics and disinfectants in surgery (2)]. AB - Various forms of plivasept, an agent produced by Pliva (Croatia), were studied in the laboratory and clinic and found to be highly effective. For the prevention of intrahospital infections the use of 0.02% and 0.05% water solutions of plivasept without PAV is advisable as an antiseptec for inyracavitary administration, 0.05% water solution of plivasept for disinfection of surfaces and equipment, 0.5% alcohol plivasept solution for disinfection of instruments, a plivasept tincture for surgical treatment of the skin on the hands and the injection and operative fields, and foam-forming plivasept for hygienic treatment of the hands. PMID- 8683924 TI - [Preparation of suppurative wounds for autodermatoplasty with electrochemially activated solutions]. AB - The article analyses 37 cases of autodermatoplasty. The purulent wound was prepared for grafting by electrochemically activated solutions (ECAS) in 25 and by salve dressings in 12 patients. The duration of the preparation was three times schorter with the use of ECAS than in treatment with salve dressings. Skin grafts treated by ECAS "took" in 100% of cases, those preparated by salve dressings--in 75%. PMID- 8683925 TI - [Restoration of the burn-damaged face with a split-thickness skin-fatty tissue flap from the neck]. AB - The article deals with experience in the treatment of 94 patients with a split thickness cellulocutaneous flap taken from the neck. It has been established that the skin on the neck has an axial blood supply which allows it to be mobilized extensively without including the platysma of the neck and chest wall and transfer it to the face, avoiding necrosis. Four main types of cicatricial damage to the face are distinguished, which determine the peculiarities of transfer of the mobilized skin. Maintenance of the platysma in situ and vacuum drainage of the space under flap retain the contours of the neck and face. In total affection of the face the tissues must be mobilized again in 6 to 12 months and moved so to restore the skin to the orbits. The skin of the neck, when transferred to the face, maintains its natural properties and is best plastic material. The method is indicated in all cases in which the skin of the neck and anterior surface of the chest is not damaged. PMID- 8683926 TI - [Thoracoscopic sympathectomy in the surgical treatment of axillary and palmar hyperhidrosis]. AB - 47 patients with axillary palmar hyperhydrosis underwent this surgery. There were 36 women (76.6%) and 11 men (23.4%) among them. The sympathetic trunk has been coagulated on the level between 2d and 4th ribs on both sides. There were no surgical mortality in this group. Nine patients (9.1%) had a pneumothorax, one patient (2.1%) had a subcutaneous emphysema, the other one had pneumonia and one had wound pyosis. In 43 cases the result of the surgery was very good. In 2 cases bilateral relapse and in 2 cases marked compensatory hyperhydrosis were resistered. PMID- 8683927 TI - [Relaparotomy: determination of the indications and results]. AB - The indications for relaparotomy in cases of bleeding, peritonitis, acute ileus and abdominal abscess were determined. Using the indications gave a possibility to perform the relaparotomy on 1-st postoperative day right after first signs of those complications. The mortality dropped from 46% to 20.5%. PMID- 8683928 TI - [Anaerobic bacteremia in the suppurative-septic complications of trauma and surgery patients]. AB - Modern technology plays a very important role in bacteriemia identification. The new bottles for anaerob extraction from a blood were developed and tested in a Central Institute of Traumatology, Moscow. The blood from 110 patients was examined. There were 37 blood culture in a group and 24 strains of them were anaerobic. PMID- 8683929 TI - [Diagnosis and treatment of local forms of surgical anaerobic non-clostridial infection]. AB - 145 patients with such kind of surgical infection have been taken to clarify the cause of it. Aerobic agents were the cause in 16.6% and anaerobic nonclostridial agents--in 33.1% of all cases. The mixed flora was the cause in 44.1%. The most important place among anaerobic nonclostridial infections belongs to bacteroids (38.3%), peptostreptococcus (27.3%) and the peptococcus (17.2%). One must use wide-spectrum antibiotic for a treatment of a such kind of infection tiel the usults of microbiological test are known and only then one can use group-specific antibiotics. PMID- 8683930 TI - [Ultrasound in the study of the adrenal glands]. PMID- 8683931 TI - [New aspects of the pathogenesis of peritonitis]. PMID- 8683932 TI - [Autotransplantation of splenic tissue]. PMID- 8683933 TI - [Autotransplantation of a double-bone-muscle-skin flap in the one-step segmental resection and plastic repair of distal segments of the extremities in cancer patients]. AB - This article describes a biosteodermomuscular flap formation. The flap contains parts of VIII-IXribs, the broadest muscle of the back and a musculus serratus anterior. This method has been successfully used for a one-step segmental resection and microsurgical plastic operations on distal parts of extremities in five patients with malignant tumors of soft tissues. PMID- 8683934 TI - Changes in the expression of matrix proteases and of the transcription factor c Ets-1 during progression of precancerous bronchial lesions. AB - Matrix proteases and the transcription factor c-Ets-1, which regulates in vitro stromelysin 1, collagenase 1, and urokinase type plasminogen activator gene promoters, are frequently expressed in invasive carcinomas. Using in situ hybridization and immunohistochemistry, we analyzed collagenase 1, stromelysins 1 and 3, matrilysin, urokinase type plasminogen activator, and c-Ets-1 gene expression on serial frozen sections of 39 intraepithelial bronchial lesions, including areas of hyperplasia, metaplasia, dysplasia, carcinoma in situ, and corresponding lung carcinomas in 13 patients. In intraepithelial lesions, expression of all matrix proteases was detected in epithelial cells. Conversely, in microinvasive or invasive lesions, a fibroblastic expression was observed. Collagenase 1 and matrilysin were expressed seldomly in intraepithelial lesions and frequently in carcinomas (p = 0.0016 and p < 0.0001, respectively). Stromelysin 1 was expressed inconsistently in 31% of intraepithelial lesions of all grades and in 50% of carcinomas. Stromelysin 3 and urokinase type plasminogen activator were expressed only, but frequently, in preinvasive lesions (dysplasia, carcinoma in situ) and in carcinomas. The expression of stromelysin 3 in fibroblasts started with dysplasia and carcinoma in situ, but was more frequent in invasive than preinvasive lesions (p = 0.0012). c-Ets-1 was more often expressed in carcinomas than in intraepithelial lesions (p < 0.0001) and was always expressed in fibroblasts. Comparing preinvasive lesions adjacent to or at a distance from squamous lung carcinoma, stromelysin 3 epithelial expression was more frequent in preinvasive lesions adjacent to invasive foci than in others (p = 0.036). We conclude that (a) both epithelial expression of matrix proteases in intraepithelial bronchial lesions and their stromal expression in microinvasive and invasive lesions suggest their role in lung tumor development; (b) c-Ets-1 does not act as a transcriptional activator for matrix proteases genes in preinvasion, although it might regulate collagenase 1 gene during lung tumor progression; and (c) matrix proteases might offer new therapeutic targets for chemoprevention of lung cancer. PMID- 8683935 TI - Multiple sclerosis: a protective or a pathogenic role for heat shock protein 60 in the central nervous system? AB - The stress proteins belonging to the heat shock protein 60 (hsp6O) family of molecular chaperones with known immunogenic properties are expressed at increased levels in a number of autoimmune conditions. Because previous studies from this laboratory suggested that hsp6O may be involved in the pathogenesis of the chronic multiple sclerosis (MS) plaque, we have examined autopsied central nervous system tissue from 10 cases of MS, ranging in clinical history from acute to chronic inactive. MS lesions ranged from acute, actively demyelinating and edematous, to fibrous astrogliotic and chronically demyelinated. As controls, central nervous system tissue from other neurologic diseases and nonneurologic conditions was used. Frozen, paraffin, and epoxy-embedded sections were studied immunocytochemically with the ML30 mAb to hsp6O. Acute MS lesions displayed the greatest reactivity, with particularly prominent staining of hypertrophic astrocytes, reactive macrophages, and hyperplastic oligodendrocytes. In all these cells, elevated expression occurred in the constitutive site for hsp6O (mitochondria) and within the cytosol, which is suggestive of a shift in expression. The hsp6O-reactive oligodendrocytes were structurally intact. Chronic active MS lesions also revealed the highest levels of hsp6O in hypertrophic astrocytes and oligodendrocytes. Chronic silent MS lesions displayed elevated hsp6O in hypertrophic astrocytes only while constitutive expression occurred elsewhere in the central nervous system at levels slightly higher than normal. Other neurologic disease tissue displayed expression elevated above that found in nonneurologic cases, but this was considerably less than that seen in acute MS. Of the other neurologic diseases, AIDS encephalitis revealed the greatest activity for hsp6O, with both mitochondrial and cytosolic staining of astrocytes. It is proposed that the high levels of hsp6O in hyperplastic, structurally intact oligodendrocytes in acute MS lesions may bespeak a protective mechanism, whereas hsp6O in chronic active lesions may serve a pathogenic role in the later depletion of these cells. PMID- 8683936 TI - Expression of leukemia inhibitory factor and its receptor during liver regeneration in the adult rat. AB - Leukemia inhibitory factor (LIF) is a polyfunctional cytokine that was discovered in the conditioned medium from Buffalo rat liver cells. In the liver, LIF is known to induce acute phase proteins in the hepatocytes. No comprehensive study has yet been performed on the physiological role of this cytokine during liver regeneration. Thus, we studied the level of expression and cellular distribution of transcripts for LIF, its receptor (LIFR), and signal transducing subunit gp13O during rat liver regeneration after both simple partial hepatectomy (PH) and the oval cell activation induced by the combination of 2-acetylaminofluorene and PH. In addition, the expression of an acute phase protein alpha1-acidglycoprotein was examined. The level of transcripts for LIF and its receptor subunits increased and remained elevated during oval cell expansion. In contrast, after PH, the transcripts were induced only transiently, showing a peak 24 hours after the operation. LIF and receptor subunits were expressed in both parenchymal and nonparenchymal fractions in the 2-acetylaminofluorene/PH model, but the level of expression was most pronounced in the nonparenchymal fraction. In situ hybridization clearly revealed a strong expression of LIF, LIFR, and gp13O in the oval cells and demonstrated only a weak expression in the parenchyma. Interestingly, transcripts of alpha1-acidglycoprotein were exclusively detected in the parenchyma. These results suggest a phenotypic difference between oval cells and hepatocytes in their signaling through gp130. We hypothesize that the LIF/LIFR gp130 system may be involved in the expansion and differentiation of the liver stem cell compartment. PMID- 8683937 TI - Conserved expression of intestinal trefoil factor in the human colonic adenoma carcinoma sequence. AB - Human intestinal trefoil factor (ITF), a mucosa-associated trefoil peptide, has been implicated in maintenance of mucosal integrity and may denote commitment to goblet cell differentiation. We have quantitated and localized ITF expression in normal and neoplastic colons, determined the molecular forms present, and examined the relationships among ITF expression and mucin production and increasing dysplasia. Normal and neoplastic human colonic mucosa (n = 30) were extracted for quantitation by ITF radioimmunoassay and size determination by gel filtration and immunoblotting. Paraffin sections of normal bowel, hyperplastic polyps, adenomatous polyps, and adenocarcinoma were examined for ITF immunohistochemistry and mucin histochemistry. The predominant molecular species in both normal and neoplastic colon was a 7-kd monomer. Staining was localized to goblet and Paneth cells and the luminal surface in normal colon and in most adenomatous polyps but not hyperplastic polyps; this colocalized with periodic acid-Schiff histochemistry. ITF staining of undifferentiated cells was seen with increasing dysplasia, and Golgi region immunoreactivity was highly conserved in adenocarcinoma, independent of the presence of periodic acid-Schiff-positive mucin. ITF concentration in colonic extracts was 10 to 200 pmol/g. Levels in normal (88.1 +/- 15.1 pmol/g) and malignant (90.1 +/- 12.7 pmol/g) tissue were comparable. In carcinomas, there were significant associations among ITF expression and degree of differentiation and mucin presence. Loss of expression was associated with tumor necrosis and advanced Duke's stage. ITF is uniformly processed in normal and neoplastic colons. Goblet cell-derived ITF is associated with stainable mucin production. ITF synthesis by non-goblet colonocytes, however, is highly conserved in neoplastic differentiation. PMID- 8683938 TI - Interleukin-11 prevents apoptosis and accelerates recovery of small intestinal mucosa in mice treated with combined chemotherapy and radiation. AB - Previous studies have shown that acute injury to rodent small intestinal mucosa as a result of either chemotherapy or radiation is caused by a combination of high-frequency cell death caused by apoptosis, continued migration of epithelial cells from the intestinal crypts toward the villi, and absence of adequate compensatory mitotic activity in the crypt bases. Recently, we have shown that IL 11, a novel multifunctional bone marrow stromal-derived growth factor, could stimulate rapid repair of small intestinal villous structures in mice treated with combined radiation and chemotherapy by increasing the mitotic index of crypt cells. To further clarify the biological mechanism responsible for its protective action, we used a similar experimental model to evaluate whether IL-11 could reduce the high frequency of apoptosis observed after cytoablative treatment. In the present study, 78 C3H/HeJ mice received 5-fluorouracil at 150 mg/kg body weight intraperitoneal injection 3 days before 7.0-Gy total body irradiation. The animals received IL-11 250 microg/kg body weight/day divided into two equal doses or vehicle control by subcutaneous injections beginning on the same day of irradiation within 1 hour of the end of the dose. The mice killed on Days 1, 2, and 5 after cytoablative treatment were autopsied, the small intestine was processed for histologic examination, and the mitotic index and other parameters were measured, including the expression of the proliferating cell nuclear antigen and of the p53 protein. Apoptosis was detected by a nonisotopic in situ DNA end labeling technique applied to the same histologic sections. The cytoablative treatment caused marked degenerative changes in the small intestinal mucosa, including shortening of the villi and damage to the crypt cells. The degenerative changes, which included nuclear fragmentation with formation of apoptotic bodies, increased expression of proliferating cell nuclear antigen, and strong expression of p53 was seen in mice killed on Days 1 and 2 after cytotoxic treatment. IL-11 administration resulted in a partial suppression of apoptosis, as shown by a reduced number of crypt cells stained with in situ DNA end-labeling for fragmented DNA. In addition, IL-11 treatment was associated with an increase in the frequency of mitosis and proliferating cell nuclear antigen expression in crypt cells as compared with the vehicle treated mice. Morphometric analysis of intestinal villi and crypt depth showed increased villus length and decreased crypt to villus ratio after IL-11 treatment. These results indicate that IL-11 can exert a potent effect on the recovery of the small intestinal mucosa of mice by its combined effects on proliferation and apoptosis of crypt cells. IL-11 may thus have potential clinical applications in limiting the intestinal toxicity that is associated with cytotoxic therapies. PMID- 8683939 TI - Development of intralobular bile ductules after spontaneous hepatitis in Long Evans mutant rats. AB - Oval cell proliferation occurs during spontaneous hepatitis in Long-Evans cinnamon (LEC) rats. It has been reported that oval cells undergo differentiation into mature hepatocytes via small hepatocytes during carcinogenesis. This study was designed to demonstrate in vivo differentiation of oval cells into typical bile ductular cells in the liver lobule and the characteristic feature of intralobular bile ductule formation in LEC rats. We have examined kinetics, intralobular distribution, and morphology of oval cells, small hepatocytes, and bile ductular cells in LEC rat livers at prehepatitic, acute hepatitic, chronic hepatitic, and precancerous stages by conventional light and electron microscopy, immunostaining for cytokeratin, and 3-dimensional reconstruction analysis. Our results indicate that oval cells proliferated and extended into the periportal zone of the liver lobule during acute hepatitis at 20 to 23 weeks after birth. They exhibited tubular structures with a poorly defined lumen and incomplete basement membrane. After remission of the jaundice, small hepatocytes proliferated in association with oval cells and predominated in the periportal zone at 26 weeks. In a chronic hepatitic stage at 28 to 30 weeks, tubular structures were transformed into typical bile ductules, which had a well defined lumen and complete basement membrane, and small hepatocytes became a normal size. Intralobular bile ductules originated from the interlobular bile ducts, ran in the space of Disse, giving rise to several branches in the course, and were terminated at the hepatocytes. The present results indicate that oval cells that proliferate in the liver lobule of LEC rats after spontaneous hepatitis not only differentiate into small hepatocytes but also into typical bile ductular cells. This study suggests that intralobular bile ductules may play roles in maintaining the bile excretion during and after the disorganized proliferation of oval cells and small hepatocytes. PMID- 8683940 TI - Expression of type VI collagen in uveal melanoma: its role in pattern formation and tumor progression. AB - Choroidal and ciliary body melanomas disseminate exclusively by a hematogenous route because there are no lymphatics inside the eye. Although angiogenesis is an absolute precondition for metastasis in this tumor system, not all morphologic expressions of tumor angiogenesis are associated with metastasis from choroidal and ciliary body melanomas. Specifically, the remodeling of the microcirculation to form vascular networks is very strongly associated with metastasis. Type VI collagen is upregulated in tissue remodeling and the generation of tissue patterns and is either not present in the normal choroid or present at very low levels. This study was designed to investigate the possible expression of type VI collagen in the stroma of choroidal and ciliary body melanomas. Type VI collagen was detected in tissue sections from five primary choroidal melanomas and three melanomas involving the choroid and ciliary body in the subendothelial compartment of the microcirculation and in avascular areas by immunohistochemistry. Melanoma cell lines were established from each of these tumors. Cultured melanoma cells invaded into type I collagen gels and expressed type VI collagen by immunohistochemistry. Using specific primers for human type VI collagen, the expected band size (413 base pairs) was isolated from one of the cell lines by reverse transcriptase PCR. The presence of type VI collagen in the melanoma tumor stroma reflects active remodeling of the uveal extracellular matrix microenvironment by the melanoma cells themselves. Before the formation of the microvasculature, the expression of type VI collagen and of the other matrix components, such as hyaluronan, to which it binds, may erect a scaffold permitting the formation of higher order stromal patterns such as vascular networks. These stromal patterns, which are markers of tumor progression, may be detectable clinically by a specialized form of ultrasonography that detects backscatterers of the same dimension as tissue compartments encircled by vascular loops in networks. PMID- 8683941 TI - Immunophenotypic characterization of Epstein-Barr virus-associated gastric carcinoma: massive infiltration by proliferating CD8+ T-lymphocytes. AB - A subset of gastric carcinoma carries Epstein-Barr virus (EBV). The immunophenotypic features of EBV-associated (EBV+) gastric carcinoma, which we have analyzed using 25 EBV+ cases, remain unclear. Frozen tissue samples were stained with antibodies to various immune cell markers. To evaluate the proliferative activity of CD8+ cells, we performed CD8/Ki-67 double staining on paraffin-embedded sections. The results were compared with those in EBV-negative (EBV-) gastric carcinomas. All EBV+ and EBV- gastric carcinoma cells expressed major histocompatibility complex class I, whereas major histocompatibility complex class II expression in tumor cells was more prominent in EBV+ cases. Intercellular adhesion molecule-1 and Fas/APO-1 expression was largely restricted to EBV+ cases. The lymphocytes that infiltrated EBV+ tumor nests were predominantly CD8+ T cells, many of which expressed perforin. Immunoelectron microscopy confirmed a close cell to cell contact between these CD8+ cells and carcinoma cells. CD8+ cells were CD11a+ and CD11b- by flow cytometry performed in one case. The labeling index of Ki-67, the proliferation-associated antigen, in CD8+ cells was 4 times higher in EBV+ cases than in EBV- cases. Our data suggest that these CD8+ cells, which bear a cytotoxic phenotype, are actively proliferating in close contact with EBV+ tumor cells and that the specificity of the CD8+ cells may be directed to EBV and/or cellular antigens expressed by the tumor. This is consistent with a generally favorable prognosis of EBV+ gastric carcinoma. Because the observed T-cell infiltration is insufficient to eradicate the tumor cells, certain immunosuppressive factors were speculated to allow the essentially immunogenic carcinoma cells to establish a macroscopic lesion. PMID- 8683942 TI - Inducible nitric oxide synthase is present within human atherosclerotic lesions and promotes the formation and activity of peroxynitrite. AB - Inflammatory cytokines associated with atherosclerosis may be capable of stimulating the synthesis and activity of inducible nitric oxide synthase (iNOS), which could further influence the pathologic features associated with the disease. Although there is a certain amount of indirect evidence to support the presence of iNOS in atherosclerosis, there has been no definitive study to confirm this. This study has assessed the localization of iNOS within human normal and atherosclerotic vessels by immunocytochemistry, Western blotting, and in situ hybridization. Further, activity of NO synthase has been assessed by detection of nitrotyrosine, which is a marker indicative of the formation and activity of the nitric oxide-derived oxidant, peroxynitrite. In Western blots of crude homogenates of atherosclerotic aorta, the iNOS antiserum reacted with a band of approximately 130 kd (the known molecular weight for iNOS), but no such band was seen in normal aorta. Immunostaining and in situ hybridization confirmed the presence of iNOS in atherosclerotic vessels, in which it was specifically localized to (CD68-positive) macrophages, foam cells, and the vascular smooth muscle. The antiserum to nitrotyrosine reacted with a wide range of protein bands (approximately 180 to 30 kd) in Western blots of atherosclerotic aorta. The distribution of immunostaining for nitrotyrosine was virtually identical to that seen for iNOS and was present in macrophages, foam cells, and the vascular smooth muscle. In conclusion, these studies have demonstrated that stimulated expression of iNOS is associated with atherosclerosis and that the activity of this enzyme under such conditions preferentially promotes the formation and activity of peroxynitrite. This may be important in the pathology of atherosclerosis, which contributes to lipid peroxidation and to vascular damage. PMID- 8683943 TI - Ocular pathology in bovine Marfan's syndrome with demonstration of altered fibrillin immunoreactivity in explanted ciliary body cells. AB - Cattle affected by bovine Marfan's syndrome demonstrate most clinical features of the human disease, which is caused by mutations in the fibrillin-1 gene. Immunohistochemical and metabolic labeling studies in affected cattle have demonstrated abnormalities in fibrillin metabolism. Clinically identified ocular features of the bovine disease, which are similar to human Marfan's syndrome, are ectopia lentis, microspherophakia, and myopia. The purpose of this study was to compare the ocular pathology of the human and bovine diseases and to evaluate fibrillin-1 immunoreactivity in the extracellular matrix of explanted ciliary body cells from affected cattle. Eyes from affected cattle and unrelated normal cattle were examined grossly, and portions of the anterior uvea and ciliary zonule were examined by light and scanning electron microscopy. Portions of the ciliary zonular fibers were examined by transmission electron microscopy. The results were compared between affected animals and normal controls. Explanted ciliary body cells from two affected cattle and one unaffected cow were grown on chambered microscope slides, and expression of fibrillin-1 in the extracellular matrix was compared. Eyes of affected cattle were characterized by megaloglobus, increased circumlental distance, asymmetrical ciliary processes, intact but fragile zonular fibers, and ectopia lentis. Affected animals had moderately hypoplastic ciliary bodies, compact filtration angles, and long thin irises with decreased fibrous stroma. As shown by scanning electron microscopy, the zonular fibers of affected animals were wavy and loosely arranged, with abnormal sites of insertion on the lens capsule. The ciliary processes of affected animals had flattened or smooth surfaces. Explanted ciliary body cells from affected animals demonstrated decreased fibrillin immunoreactivity when compared with a normal control. The ocular pathology observed in bovine Marfan's syndrome is, in most respects, similar to that described for the human disease and will be a useful model for studies of in vivo evaluation of abnormal microfibrillar aggregation within ocular structures. PMID- 8683944 TI - AAMP, a conserved protein with immunoglobulin and WD40 domains, regulates endothelial tube formation in vitro. AB - Angio-associated migratory cell protein (AAMP) is a newly discovered protein that is widely distributed with strong expression in endothelial cells and others with migratory potential (cytotrophoblasts, carcinoma cells, etc). AAMP is 52 kd with an isoelectric point of 5.2. Its sequence contains immunoglobulin type domains, WD40 repeats, a large acidic region with an acid box, a potential transmembrane region, potential serine/threonine phosphorylation sites, and a positively charged amino-terminal region with strong heparin binding potential (Kd = 14 pmol). Human umbilical vein endothelial cells cultured on Matrigel, a basement membrane material, form endothelial tubes (capillary-like structures). Anti recombinant AAMP (anti-rAAMP) (1 to 10 microg/ml) inhibits this process under conditions that favor cross-linking of its ligand (AAMP). Immunofluorescent staining has shown that AAMP is distributed both intracellularly and extracellularly in cultures of endothelial cells and tubes. Molecular analysis of AAMP's protein sequence shows a striking evolutionary relationship with the YCR072c protein in Saccharomyces cerevisiae. Both the human and yeast proteins show an unusual and almost identical arrangement of immunoglobulin type domains, WD40 repeats, a protein kinase C phosphorylation consensus site in the carboxyl region, and a positively charged amino-terminal region that in AAMP has heparin binding potential. Detection of YCR072c's immunoglobulin type domains is new. Thus, AAMP is a protein that has been highly conserved in evolution and may function in the regulation of endothelial tube formation. PMID- 8683945 TI - A school-based clinic for elementary schools in Phoenix, Arizona. AB - A community hospital, a school district, and a private pediatrician's office collaborated to ensure all children enrolled in five elementary schools had access to health care services. The school nurse at each school identified children needing health care services and obtained parental consent. The school nurse referred children to a nurse practitioner who visited one school each day. School nurses and space in the nurse's office were provided by the school district. The hospital provided a nurse practitioner as well as pharmacy, radiology, laboratory, and emergency department services. The pediatrician as medical director for the program provided vision, training, and community connections, and served as collaborating physician for the nurse practitioner. PMID- 8683946 TI - Using focus group interviews to understand school meal choices. AB - Focus groups were used to examine adolescents' participation in school nutrition programs, their opinions about the meals served in these programs, and their suggestions for improving the meals. A pilot and four focus group interviews were conducted with ninth grade students in five geographically distinct regions of Florida. Male students and those from rural areas were more likely to participate in school meal programs than were females and those from suburban and urban areas. Students expressed intense dislike and distrust of school meals. School meals were criticized for taste, appearance, small serving sizes, and cost. Students overwhelmingly favored commercial food vendors serving lunch at school. Suggestions for improving school meals included improving the taste and appearance of food, offering a wider variety of foods, serving more fresh fruit and vegetables, lowering the price, increasing the serving sizes, teaching food service workers how to cook, and offering more condiments. PMID- 8683947 TI - The Dartmouth Health Promotion Study: a failed quest for synergy in school health promotion. AB - The Dartmouth Health Promotion Study was a longitudinal, quasi-experimental field study with a qualitative research arm, designed to learn whether coordinating school health instruction, health services, and a healthful environment enhanced the program's effect on the heart health and mental health of children. The research strategy-the Coordinated Approach-was applied to approximately 300 children in each of two cohorts in grades four to six attending nine trial schools; a further 600 children attended 10 comparison schools in Dartmouth and nine distal comparison schools. Although the qualitative analysis demonstrated that positive feelings were engendered in most areas of the study, when either the classroom or the individual was used as the unit of analysis, the Coordinated Approach did not have a more favorable effect on the heart or mental health of children than did the standard school health program. Thus, the effect of an existing school health program was not directly enhanced through coordinating its components. PMID- 8683948 TI - Teachers' receptiveness and comfort teaching sexuality education and using non traditional teaching strategies. AB - This article reports on the comfort level of 97 eighth grade teachers using non traditional teaching strategies in sexuality education classes. Most were comfortable teaching sexuality education and undeterred by external factors such as students' religious beliefs, lack of administrative support, or parental protest. However, a quarter to a third of teachers reported never or rarely using activities such as roleplays, small-group discussions, and problem-solving exercises. Multiple regression indicated that only gender was a significant predictor of such usage. The greatest perceived barriers to teaching sexuality education and using alternative teaching strategies were lack of materials, lack of time, and difficulty with facilitation under traditional classroom structure. Although more research is needed to better understand barriers to using alternative strategies, teachers in two focus groups (n = 19) suggested 1) restructuring classroom settings to match the demands of new teaching strategies, and 2) "experience appropriate" curricula. PMID- 8683949 TI - Gender differences in physical activity and determinants of physical activity in rural fifth grade children. AB - This study determined if gender differences in physical activity could be accounted for by differences in selected social-cognitive determinants of activity behavior. Some 334 fifth grade, predominantly African-American students provided information regarding after-school physical activity and the hypothesized determinants of activity behavior. Boys reported significantly greater participation in vigorous ( > or = 6 METs) and in moderate to vigorous ( > or = 4 METs). Relative to girls, boys demonstrated higher levels of physical fitness, greater self-efficacy in overcoming barriers to physical activity, greater amounts of television watching, and higher levels of participation in community sports and physical activity organizations. When mean physical activity scores for girls and boys were adjusted for the effects of these determinant variables, the significant gender difference in physical activity remained. However, adjustment for self-efficacy in overcoming barriers and community sports reduced the gender gap by 5% and 7%, respectively. In contrast, adjustment for television watching increased the gender gap by about 8%. Results indicated perceived confidence in overcoming barriers to physical activity and participation in community physical activity programs are factors related to the gender difference in physical activity. PMID- 8683950 TI - Sexual health for America's adolescents. PMID- 8683951 TI - Applying the K-W-L reading strategy in health education. AB - The K-W-L strategy provides students with structure to guide them when reading textbooks or other resource materials, and enables them to take responsibility for their own learning. The process incorporates the teacher's guidance with student input allowing both to feel ownership in the learning process. K-W-L lends itself well to a health curriculum that promotes student decision-making, problem-solving, and active participation. PMID- 8683952 TI - Factors associated with elevated cutaneous Malassezia pachydermatis populations in dogs with pruritic skin disease. AB - The prevalences of breeds and concurrent diseases in a group of 40 dogs with pruritic skin disease associated with elevated cutaneous Malassezia pachydermatis populations were compared with samples of a dermatological hospital population. The ages and genders of the affected dogs were comparable to those of the dermatology population. Basset hounds, cocker spaniels and West Highland white terriers were significantly overrepresented. Concurrent diseases were diagnosed in 27 dogs, of which 15 were atopic. However, the prevalences of atopic disease, primary keratinisation defects and endocrinopathies in dogs with elevated cutaneous M pachydermatis populations were comparable to those in the dermatology population as a whole. These results indicate that certain breeds are predisposed to the development of elevated cutaneous M pachydermatis populations and that concurrent skin diseases can frequently be identified in affected dogs. However, the relationship between these concurrent diseases and abnormal M pachydermatis populations remains unclear. PMID- 8683953 TI - Systemic use of pentosan polysulphate in the treatment of osteoarthritis. AB - Forty dogs diagnosed as having chronic osteoarthritis took part in a double-blind clinical dose-response study using the antiarthritic agent pentosan polysulphate (PPS). After complete physical examination to ensure good general health, dogs received four subcutaneous injections at intervals of one week 0, 1, 3 or 5 mg/kg PPS from code-numbered bottles. At weekly intervals and four weeks after the last injection, weakness, stiffness, pain on joint manipulation, willingness to exercise, body condition and overall response were scored. There were no differences between groups in baseline data, but dogs receiving PPS had a favourable response compared to dogs receiving a placebo for lameness, body condition, pain on joint manipulation and willingness to exercise. The 3 mg/kg dose rate gave the best improvement, the 1 mg/kg dose was partially effective and the 5 mg/kg group was least effective. The use of PPS at a dose rate of 3 mg/kg for the treatment of clinical osteoarthritis in dogs is indicated by our study. PMID- 8683954 TI - Epidemiological study of blood pressure in domestic dogs. AB - Previous experience has shown that a non-invasive (indirect) technique using an oscillometric monitor in conjunction with a tail cuff makes routine clinical blood pressure measurement practicable in dogs. The relationship between indirect and direct readings has been evaluated in both anaesthetised and conscious dogs (Bodey and others 1994, 1996). In this study, more than 2000 pressure measurements were taken from 1903 dogs. It was found that systolic is the most variable pressure parameter and that it depends on age, breed, sex, temperament, disease state, exercise regime and, to a minor extent, diet. Diet was not a significant determinant of diastolic and mean arterial pressure. Age and breed were the major predictors for all parameters. Heart rate was primarily affected by the temperament of the animal, though other factors also play a part in prediction. The distribution of systolic, diastolic, mean arterial pressure and heart rate across the dog population approximates to a log normal distribution. On the basis of these results it is possible to describe normal ranges for canine blood pressure; definition of hypertension, though, demands attention to age and breed normal values. The existence of statistically defined hypertension in an individual or breed does not imply adverse effects justifying therapy. Among the secondary causes of hypertension, such as diabetes, obesity and hyperadrenocorticism, hepatic disease was a new addition also undocumented in humans. The hypothesis that dogs, though classic model animals for hypertension, are resistant to its development found support from the modest increase in mean pressure values observed among dogs with renal disease, notably those with substantial reduction of glomerular filtration rate. The existence of breeds such as deerhounds with average pressures in the borderline range for hypertension in humans (and many individuals, therefore, well above) suggests that dogs may also be resistant to some of the adverse effects of high blood pressure. PMID- 8683955 TI - Investigation of possible leptospiral infection in cats in Scotland. AB - Eighty-seven cats from the Glasgow area were investigated to determine the prevalence of leptospiral infection and possible resultant disease. Eight (9.2 per cent) of the cats reacted serologically with the antigens of three serovars. Five of the cats were seropositive to Leptospira hardjo, two to L autumnalis and one cat seroconverted to L icterohaemorrhagiae. A paired serum sample indicated a recent infection in one of the cats. The major clinical sign shown by this cat was ascites. Four of the cats were from rural areas. This appears to be the first report of a serological survey of leptospiral infection in cats in the Glasgow area. PMID- 8683956 TI - Osteochondromatosis of the cervical spine causing compressive myelopathy in a dog. AB - A 10-month-old Alaskan malamute presented with cervical pain and hindlimb proprioceptive deficits. Plain and myelographic radiographic studies of the cervical spine demonstrated extradural compression of the spinal cord at the level of C7 and C5. Computed tomography assisted presurgical characterisation of the lesions as osteochondromatosis. Laminectomy permitted successful removal of the lesions. PMID- 8683957 TI - Diagnosis and clinical course of canine oral papillomavirus infection. AB - A six-month-old intact male rottweiler presented with papillomatous growths protruding from the oral mucous membranes. A tentative diagnosis of canine oral papillomavirus (COPV) infection was made based on the gross appearance of the numerous lesions and the young age of the patient. Two warts from the oral mucosa were removed surgically for further diagnostic investigations. The viral aetiology of the diseases was confirmed by histopathological and electron microscopic findings, and by the identification of specific COPV DNA is removed oral papillomatous tissue. The patient was followed clinically and complete regression of the oral lesions occurred after four weeks. Neither the route of transmission nor the source of infection was found. Immunodeficiency as a contributing aetiological factor to the development of COPV-induced lesions as discussed. PMID- 8683958 TI - Use of external skeletal fixators in the repair of femoral fractures in cats. AB - This paper reports the results of fixation of 35 femoral fractures in cats using an external skeletal fixator alone or in combination with supplementary devices. All the fractures healed. The average time to fixator removal was eight weeks and two days. The external skeletal fixator offers a method of repairing many types of femoral fractures in cats allowing sound orthopaedic principles to be maintained and producing a successful outcome. PMID- 8683959 TI - Alcohol and older American Indians. PMID- 8683960 TI - Alcohol consumption among older urban American Indians. AB - OBJECTIVE: To describe the pattern of alcohol consumption by older urban American Indians in Los Angeles, California, in 1987-89. METHOD: Data come from a cross sectional community health survey with a convenience sample of 282 nonhomeless American Indians, both male and female. The sample matched the age and sex distribution reported by the U.S. Census. During the face-to-face structured interview self-reports of alcohol consumption were gathered for American Indians recognized by their community as elders (mean [+/-SD] age 61.1 +/- 11.1 years). RESULTS: Most elders (73%) did not drink alcohol. More women than men, and more individuals aged 60+ than people under 60 years, abstained. Elders in single generation households tended to consume more alcohol than those in multigeneration households. Among the 76 people we reported drinking, significantly more people under age 60 than over age 60 consumed four or more drinks per sitting (p < .01), and those who lived alone were more likely than drinkers living with others to consume alcohol at least once a week (p < .04). CONCLUSIONS: Age seemed to be a salient marker with respect to alcohol consumption, with fewer people 60+ years of age drinking as much or as often as people under this age. Abstainers are not necessarily lifetime teetotalers, but may be former drinkers who have quit, and may still on occasion go on short-term binges. Results of this survey replicate findings from surveys of the general elderly population, suggesting that older urban American Indians are not different from other older people with respect to consumption of alcohol. PMID- 8683961 TI - The effect of heavy social drinking on recall and event-related potentials. AB - OBJECTIVE: It has been suggested that alcohol-related brain impairments progress on a continuum from subtle deficits in social drinkers through to end-state Korsakoff syndrome. The aim of the present study was to investigate whether heavy levels of social drinking have an adverse effect on sober cognitive functioning in young nonalcoholic adults. METHOD: Event-related potentials (ERPs) were recorded from heavy ( > 200 gm/week) and light ( < 20 gm/week) male social drinkers under the effects of a pharmacological challenge (lorazepam-ATIVAN) and a placebo. The heavy (n = 14) and light (n = 14) social drinkers completed a free recall task with a rare word probability of .30. RESULTS: Analysis of the P300 component of the ERP to recalled and not-recalled words found that P300 amplitude in heavy social drinkers (HSDs) was reduced following placebo compared to the light social drinkers (LSDs). Lorazepam produced a distinctive pattern of anterograde memory deficits in both groups and reduced P300 amplitude to rare words in the LSDs compared to both the placebo treatment and the HSDs. CONCLUSIONS: The differences in central nervous system functioning evident between HSDs and LSDs were reflected in ERP deviations in both the presence and absence of lorazepam. Even though no definite statements can be made because of the small sample size, the results appear to indicate that HSDs have an impairment in their information-processing ability in the absence of an acute inhibitory agent (e.g., alcohol or a benzodiazepine) as well as a differential response to the depressant effects of lorazepam. PMID- 8683962 TI - Visuospatial perception, construction and memory in alcoholism. AB - OBJECTIVE: To analyze visuospatial cognition in recently detoxified alcoholics from the perspectives of three ways of conceptualizing spatial information processing: egocentric versus allocentric orientation, featural versus configural analysis, and categorical versus coordinate spatial judgements. METHOD: Twenty eight chronic alcoholics (19 men, 9 women) were compared to 20 (10 men, 10 women) controls of comparable age and education on a battery of tests of visuospatial scanning, construction, mental imagery, and anterograde and remote spatial memory. Tests were administered 21-40 days after alcoholics entered treatment. RESULTS: Alcoholics displayed impairment in visuospatial scanning, construction, utilizing and manipulating information from visual images and on three tests of anterograde spatial memory, but remote spatial memory was not significantly affected. Their deficits were evident on some measures of allocentric orientation, featural and configural analysis, but consistent deficits on egocentric orientation or categorical or coordinate spatial judgments were not seen. CONCLUSIONS: Deficits in spatial cognition exhibited by alcoholics do not seem to arise from dysfunction in any localized brain region. Small but potentially important impairments in fundamental aspects of spatial information processing such as scanning and use of visual imagery were found. The empirical basis and clinical significance of these deficits requires further study. PMID- 8683963 TI - Visual laterality patterns for the perception of emotional words in alcoholic and aging individuals. AB - OBJECTIVE: This study evaluated hypotheses concerning alcohol-related cerebral dysfunction: (1) alcoholism, like normal chronological aging, has a more detrimental effect upon functions controlled by the right hemisphere of the brain than functions controlled by the left hemisphere; (2) interhemispheric transfer dysfunction is associated with alcoholism and aging; and (3) alcoholism and aging act synergistically. METHOD: The participants were 61 right-handed men: 18 young (ages 30 to 49 years) and 14 older (50 to 69 years) detoxified abstinent alcoholics and 14 young and 15 older healthy nonalcoholic controls. In a perceptual laterality paradigm, emotional and nonemotional words were presented to the left or right visual fields, followed by a visual masking stimulus. The participants were asked to judge the emotional valence of each word (positive, negative or neutral) and to respond verbally or manually (button presses). The dependent variable was the Critical Interstimulus Interval needed to escape the backward-masking effect. RESULTS: The alcoholics showed a significant right visual field advantage in both response mode conditions, whereas the controls did not. In addition, older alcoholics showed a selective impairment in processing negative words. CONCLUSIONS: The findings support the suggestion that alcoholics may have deficient right-hemisphere functioning. Since both the young and older alcoholic groups showed similar right visual field advantages, the idea of synergism between alcoholism and aging with respect to perceptual asymmetries was not supported. PMID- 8683964 TI - Personality disorders according to DSM-III-R and thrombocyte monoamine oxidase activity in type 1 and type 2 alcoholics. AB - OBJECTIVE: Several criteria used to distinguish type 2 alcoholics from Type 1 alcoholics, as well as the incidence of lower platelet monoamine oxidase (MAO) activity in the former group, would indicate that personality disorders might be more common in Type 2 alcoholics. The purpose of the present study was to investigate the relation between personality disorders, according to DSM-III-R, platelet MAO activity and Type 1/Type 2 alcoholism. METHOD: The occurrence of personality disorders, according to DSM-III-R, was studied in a series of 34 male inpatients with alcohol dependence, subclassified into Type 1 (n = 18) and Type 2 (n = 16). Platelet MAO activity was studied in the same series of patients. RESULTS: Patients with Type 2 alcoholism had significantly higher frequencies of self-defeating, schizotypal, antisocial and borderline personality disorders than Type 1 alcoholics. Patients with Type 2 alcoholism had significantly lower mean activity of platelet MAO than Type 1 alcoholics. No correlation was found between platelet MAO activity and personality disorders according to DSM-III-R. CONCLUSIONS: Disorders of the antisocial personality and borderline personality types as well as low platelet MAO can all predict the occurrence of Type 2 alcoholism with rather high specificity but with a comparatively low degree of sensitivity. PMID- 8683965 TI - Role of estradiol in alcohol intake and alcohol-related behaviors. AB - OBJECTIVE: Gonadal hormone estrogen affects many alcohol-related behaviors, including aggression and depression. Alcohol, on the other hand, alters circulating gonadal hormone levels. The present study investigated whether estrogen influences voluntary alcohol intake in male and female mice. METHOD: Alcohol-related behaviors of outbred CD-1 mice, which were implanted with pellets that released over a 60-day period either 0.1 or 0.25 mg 17 beta-estradiol (E2) or 1.5 or 5 mg anti-estrogen tamoxifen, were studied. RESULTS: Male mice treated with E2 exhibited significantly higher levels of voluntary alcohol consumption than the tamoxifen-treated males. In contrast, tamoxifen-treated ovariectomized female mice consumed significantly more alcohol than the E2-treated ovariectomized females. Immobility in the swim test model of depressive behavior was not altered by treatment with E2 or tamoxifen. However, E2 reversed the gonadectomy-induced lengthening in immobility in the swim test both in males and females. E2 increased aggression in the resident-intruder test in males, but failed to affect females. Tamoxifen or gonadectomy did not affect aggressive behavior in either sex. CONCLUSIONS: These findings suggest that E2 stimulates alcohol consumption and aggression in male mice, but it is not required to maintain baseline levels of these behaviors. Thus, elevated serum levels of E2 may link alcohol abuse and aggression in males. In female mice, low E2 levels are associated with increased immobility in the swim test and possibly with increased alcohol intake. PMID- 8683966 TI - Heeding the alcoholic beverage warning label during pregnancy: multiparae versus nulliparae. AB - OBJECTIVE: We compared the impact of the Federal Alcoholic Beverage Warning Label on multiparae (women with at least one previous live birth) and nulliparae (women with no previous live births). The label, implemented on November 18, 1989, urges women not to drink during pregnancy because of the risk of birth defects. If multiparae drank during prior pregnancies, delivering apparently normal babies, we hypothesized that the warning might be less salient for them. METHOD: We studied 17,456 inner city black gravidas seen between September 1986 and September 1993 at one antenatal clinic. Time series analysis (ARIMA) examined trends in monthly means of antenatal drinking scores (alcohol consumption adjusted for weeks' gestation, age, parity and periconceptional drinking). RESULTS: For nulliparae (n = 7,349), reported drinking began to show a significant decline in June 1990, 7 months after the implementation of the warning label (t = 2.00, p < .04). In contrast, multiparae (n = 10,107) showed no change in reported drinking (t = 1.23) postlabel. CONCLUSIONS: Given previous results that multiparae drink more and that heavier drinkers are ignoring the warning label, these data are very distressing and suggests the importance of targeting multiparae for intensive prevention efforts. PMID- 8683967 TI - The effects of alcohol on the aggressive responding of women. AB - OBJECTIVE: The purpose of this study was to determine the effects of a range of alcohol doses on the aggressive responding of women. METHOD: The Point Subtraction Aggression Paradigm was used. It has two response options available to the subject: (1) point-maintained responding, emitting 100 responses on one button earned the subject 10 cents; and (2) aggressive responding, emitting 10 responses on an alternative button ostensibly subtracted 10 cents from another person also working to earn money. Aggressive responses were engendered by a random-time schedule of point loss (every 6 sec. to 120 sec.), and instructions attributed these point losses to button presses made by another fictitious subject. Ten female subjects participated, and each experienced placebos and three alcohol doses, 0.25, 0.50, and 1.00 g of 95% alcohol per kg of body weight. RESULTS: The most important finding was that the 1.00 g/kg alcohol dose produced statistically significant increases in aggressive responding relative to placebo. There was, however, a small subset of individuals whose greatest increase in aggressive responding occurred after consuming the 0.25 g/kg alcohol dose. Rates of point-maintained responding were unaffected by the 0.25 and 0.50 g/kg alcohol doses and slightly suppressed by the 1.00 g/kg alcohol dose. CONCLUSIONS: These results are important because the handful of previous studies with women have provided little evidence for increased aggression after alcohol consumption in women. These observed inconsistencies between this study and previous studies may be attributed to procedural differences, which have varied considerably across studies. PMID- 8683968 TI - Drinking by police officers, general drivers and late-night drivers. AB - OBJECTIVE: This study compares police officers' reported alcohol use with similar reports from age- and gender-matched samples from the general driving population (GDP) and drivers recruited at high-risk hours who are most likely to drink and drive (roadside drivers). METHOD: Data were derived from interviews with 239 police officers who spent at least 5% of their time on alcohol or traffic enforcement; 243 subjects from the GDP, selected by random-digit dialing; and 249 drivers recruited at roadside on Friday and Saturday nights between 10:00 PM and 3:00 AM. RESULTS: Officers report drinking less frequently and in smaller quantities than either of the driver samples. Differences between police and general drivers are modest: e.g., usual frequency of drinking (1 to < 3 vs 3 or 4 times/month; p < or = .001) and number of days/average month with > or = 2 drinks/day (mean = 2.5 [+/- 3.4] vs 4.9 [+/- 6.5]; p < or = .001). There are greater differences between police officers and roadside drivers: e.g., 14.2% and 2.4%, respectively, abstain (vs 15.6% of general drivers; police vs general drivers; NS; police and general drivers vs roadside drivers, p < or = .001). CONCLUSIONS: The data suggest that officers' drinking differs significantly from that of drivers most likely to be driving under the influence of alcohol (DUI). If this is so, police training programs pertaining to DUI and other alcohol related offenses should pay explicit attention to the effects of alcohol and not assume that all officers have experienced them. PMID- 8683969 TI - The Driving Expectancy Questionnaire: development, psychometric assessment and predictive utility among young drink-drivers. AB - OBJECTIVE: The primary objective of this research was to develop a Driving Expectancy Questionnaire (DEQ) that reflects a model in which a distinction is made between driving skill and driving style. The second objective was to study young drivers across the spectrum of drink-driving practices, from non-drivers to convicted drink-drivers, and to examine the relationship between their expectancies about driving and their drink-driving practices. METHOD: The data from two separate samples, recruited through availability sampling, were used for the purpose of exploratory (n = 224; 122 men) and confirmatory factor analyses (n = 191; 101 men), respectively. RESULTS: The results revealed two factors of expectancies, driving skill and driving style, supporting the proposed model. The reliability, internal validity and relative independence of the factors were largely confirmed. Furthermore, criterion-related validity was demonstrated: expectancies about driving varied with drink-driving practices. Expectancies also contributed additional predictive power in relation to drink-driving practices beyond that afforded by several well-validated variables. CONCLUSIONS: The results are encouraging in terms of the ability of the DEQ to identify individual differences in expectancies about driving skill and driving style that are closely related to variations in drink-driving practices. The practical implications of these findings, as well as the potential research possibilities, are discussed. PMID- 8683970 TI - Patient factors influencing variation in the use of preventive interventions for alcohol abuse by primary care physicians. AB - OBJECTIVE: To identify patient factors associated with primary care physicians asking about alcohol consumption, warning of harmful ethanol effects, and advising modification of alcohol use in their patients. METHOD: A cross-sectional design was used, with a probability sample of 1,333 adult family medicine patients, stratified by sex and racial/ethnic background, drawn from a university based, family medicine clinic. Patients completed self-report screens for alcohol related problems (including the CAGE) and questionnaires on their experiences with the primary care provider. RESULTS: Over 64% of male and female patients indicated their physician had asked them at some time about their alcohol consumption. Logistic regression models indicated that male patients were 1.5 times as likely to have been warned about alcohol and three times as likely to have been told to stop or modify their consumption compared to female patients. Patients with lower educational attainment were more likely to have been warned, while the likelihood of ever being told to stop or modify consumption increased with age. These associations were significant after controlling for patient race/ethnicity, cigarette use and CAGE scores. CONCLUSIONS: Patient factors including sex, educational attainment, age, cigarette use and problem alcohol use appear to explain some of the variation in the use of preventive interventions for alcohol abuse by primary care providers. Yet, different patient factors appear to be related to the use of different preventive interventions. The role of patient factors, and in particular sex of patient, in the use of preventive intervention strategies for alcohol abuse by primary care physicians should be further explored. PMID- 8683971 TI - Reality monitoring in recovering alcoholics. AB - OBJECTIVE: The major aim of this study was to provide confirmation of the lack of metamemory deficits found in previous research, and we chose reality monitoring as our empirical arena. Reality monitoring is defined as the ability to distinguish between memories for events that have actually occurred and memories for imagined events, with actual events characterized by higher levels of sensory perceptual information. Further, since detoxified alcoholics have demonstrated perceptual, especially visual, deficits, this study examined whether that would have an adverse effect on reality-monitoring performance. METHOD: Young adult, male, detoxified alcoholics (n = 60) and appropriate controls (n = 29) participated in reality-monitoring tasks using, primarily, either visual or verbal information. RESULTS: There were no significant differences between the two subject groups on either of the reality-monitoring tasks, and no significant contributions from descriptive, background or educational variables on these tasks. CONCLUSIONS: Convergent validation of the previous finding of no metamemory deficits with young, male, recovering alcoholics was obtained. The results also were discussed briefly in the context of alcoholics' quality of memory in therapeutic situations. PMID- 8683972 TI - Gilles de la Tourette's syndrome in a girl with fetal alcohol syndrome. PMID- 8683973 TI - "A battle not man's but God's". PMID- 8683974 TI - Trisomy 12 is a rare cytogenetic finding in typical chronic lymphocytic leukemia. AB - We have studied 61 cases of B-chronic lymphocytic leukemia (CLL), combining cytological features, conventional cytogenetics and in situ hybridization (ISH). The comparison of these results constitutes the main subject of this study. The patients were cytologically classified according to the FAB criteria as: chronic lymphocytic leukemia (CLL) typical type (48 cases) and CLL atypical types (13 cases). Chromosome analysis was carried out on lymphoid cells from peripheral blood. The following mitogens were used: phytohemagglutinin (PHA) 5%, pokeweed (PWM) and lipopolysaccharide from E. coli. The ISH was performed with a biotin labeled, chromosome 12-specific alpha satellite DNA probe, pSP12-1. Trisomy 12 was not found in any of the 48 patients with the typical type of CLL and in contradistinction it was present in some patients with atypical types. This study emphasizes the great importance of a closer link between hematological morphology and the cytogenetic approach. PMID- 8683975 TI - Trisomy 12 in chronic lymphocytic leukaemia. PMID- 8683976 TI - Treatment of leukemia with fibroblast-mediated interferon-alpha gene therapy alone or in combination with doxorubicin. AB - The therapeutic effects of fibroblast-mediated human interferon-alpha (IFN-alpha) gene therapy, alone or in combination with Doxorubicin (Dox), a chemotherapeutic agent, on the human leukemia-bearing nude mice were investigated. An NIH3T3 fibroblast clone (NIH3T3-IFN-alpha +) secreting the highest level of human IFN alpha was obtained from the human IFN-alpha gene-transfected fibroblasts. Three days after i.p. Implantation of NIH3T3-IFN-alpha + cells, a certain level of human IFN-alpha could be detected in the sera from the implanted mice. After the NIH3T3-IFN-alpha + cells were implanted intraperitoneally into leukemia-bearing nude mice, the growth of leukemia was inhibited and the survival time of the leukemia-bearing mice was prolonged. The growth of leukemia was inhibited more obviously and the survival rate of the mice increased significantly when NIH3T3 IFN-alpha + cells were implanted in combination with Dox. These results demonstrate that fibroblast-mediated human IFN-alpha gene therapy is effective in treating leukemia and may achieve a better therapeutic effect when combined with Dox. PMID- 8683977 TI - Treatment of high risk myelodysplastic syndromes with idarubicin and cytosine arabinoside supported by granulocyte-macrophage colony-stimulating factor. (GM CSF). AB - In this prospective study, patients with "high risk' primary MDS, namely RAEB or RAEBt, were treated with combination chemotherapy (CT) supported by GM-CSF. The induction CT consisted of idarubicin 6 mg/m2 days 1-3 and cytosine-arabinoside 200 mg/m2 in 12 h infusion, days 1-5. The GM-CSF 3 micrograms/kg s.c. was given on day 6 until the neutrophil count was 1 x 10(9)/l. Postremission CT consisted of two similar courses. Patients not in remission after two courses of CT were considered as treatment failures. Twenty-two patients with a median age of 64 years, range 50-79 years (11 RAEB and 11 RAEBt) were evaluable. Twelve out of 22 patients (54.5%) achieved complete remission (CR) and four, partial remission. Six patients were resistant to treatment; there were two toxic deaths; seven patients achieved CR after the first course and five after two courses. The median time of neutrophil recovery to 1 x 10(9)/l was day 15 (range 3-22) after the first course of treatment and day 14 (range 4-21) after the second. Thirteen out of 22 patients developed febrile episodes after the first course of treatment and nine after the second. The median duration of CR was 12 months. The median survival for CR patients was 24 months, for non-CR patients, 12 months; while survival for the whole population was 18 months. In conclusion, the results of this study indicate that the administration of moderately intensive CT supported by GM-CSF in "poor risk' MDS gives promising results; the response rate is high for this disease, while the incidence of toxic death is low. GM-CSF appears to accelerate neutrophil recovery and probably reduces the incidence of infection. PMID- 8683978 TI - A comparison of the effect of bcr/abl breakpoint specific phosphothiorate oligodeoxynucleotides on colony formation by bcr/abl positive and negative, CD34 enriched mononuclear cell populations. AB - In chronic myeloid leukaemia, the expression by clonal cells, of a leukaemia specific bcr/abl chimeric mRNA, makes the condition suitable for the application of "antisense" strategies. Furthermore, the origin of the condition in a pluripotential progenitor allows enrichment of leukaemic clonogenic cells by selection for CD34 expression, together with a useful reduction in contaminating accessory cells. In a methylcellulose clonogenic assay system we incubated bcr/abl expressing (n = 9) and bcr/abl negative (n = 8), CD34 enriched progenitors with phosphothiorate oligodeoxynucleotides (PS oligomers), antisense and sense to the b3a2 and b2a2 chimeric bcr/abl junctional sequences. All samples were cloned in the presence of both antisense, and sense PS oligomers to provide appropriate controls. For bcr/abl positive progenitors, the mean number of colonies formed was reduced by 21 (39%) (P < 0.05) in the presence of the specific antisense oligomer, 11 (20%) (P < 0.05) with the antisense oligomer directed to the alternative junctional breakpoint, and colony formation was not significantly altered by either sense PS oligomer. Colony formation by bcr/abl negative progenitors was not reproducibly reduced by any of the PS oligomers. These results confirm that PS oligomers can have a sequence dependent inhibitory effect on a CD34 enriched progenitor population from patients with chronic myeloid leukaemia. PMID- 8683979 TI - Effect of methylglyoxal on human leukaemia 60 cell growth: modification of DNA G1 growth arrest and induction of apoptosis. AB - Methylglyoxal induced growth arrest in the G1 phase of the cell cycle and toxicity in human leukaemia 60 cells in vitro. Inhibition of DNA synthesis but not inhibition of RNA synthesis, protein synthesis or inhibition of glyceraldehyde-3-phosphate dehydrogenase activity correlated with cytotoxicity. Incubation of human leukaemia 60 cells with methylglyoxal led to the rapid accumulation of adducts of methylglyoxal with DNA, and a lower accumulation of methylglyoxal adducts with RNA and protein in the initial hour of culture; fragmentation of nuclear DNA characteristic of apoptosis developed in the second hour of culture. Methylglyoxal induced apoptosis in human leukaemia 60 cells but did not affect the growth and viability of concanavalin A-stimulated human peripheral lymphocytes in vitro. These effects confirm and further substantiate the anti-proliferative anti-tumour activity of methylglyoxal in vitro, which may mediate the anti-tumour activity of glyoxalase I inhibitors in vivo. PMID- 8683980 TI - An in vitro study of blast cell metabolism in acute myeloid leukaemia using the MTT assay. AB - We have utilized the MTT assay to measure the metabolic activity of cells from the bone marrow of 55 patients with acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS) and non-clonal disease. Doubling dilutions of cells were exposed to MTT for 3-4 h. The mean optical density of the formazan produced by each cell dilution was plotted and the gradient of the line produced was calculated, higher gradients indicating more metabolically active cells. Results showed that the median activity of mononuclear cells from seven patients with non-clonal disease was 0.202 (range 0.175-0.253); blast cells from 27 patients with de novo AML had a median activity of 0.187 (range 0.079-0.345) and 13 patients with MDS a median of 0.155 (range 0.062-0.311). Seven assays on mononuclear cells from five patients in remission had a median activity of 0.203 (range 0.190-0.248), indicating no significant difference between these and normal patients. There was no correlation between the metabolic activity of cells when compared with their proliferative capacity, cell size and expression of P glycoprotein. Following exposure of the AML patients' blast cells to the anthracyclines, cytosine arabinoside, 6-thioguanine and etoposide, cell survival was measured using the MTT assay. While there was no correlation between the in vitro sensitivity of these cells to the anthracyclines or etoposide, less metabolically active cells showed significantly greater sensitivity to 6 thioguanine. Conversely, the more active cells appeared to be more sensitive to cytosine arabinoside. Patients whose blasts cells showed higher metabolic activity appeared to achieve remission and had a longer mean survival time. Therefore, by using a simple technique we were able to establish that some patients were more likely to respond to certain cytotoxic regimes. Our preliminary study reflected the multifactorial nature of clinical response in AML and MDS, so providing further information on the relationship between cellular metabolic activity and treatment failure. PMID- 8683981 TI - Inhibitory effect of a nucleoside analog, acyclovir, on leukemia cells. AB - Acyclovir (ACV), a nucleoside analog, has been demonstrated previously to suppress selectively the proliferation of NIH3T3 fibroblastic cells transformed by either v-abl or bcr-abl gene transfection. From a viewpoint of clinical application of ACV, we investigated whether ACV inhibited the growth of leukemia cells expressing either p210 BCR-ABL or p185BCR-ABL. Acyclovir exerted an inhibitory effect on OM9;22 cells, p185BCR-ABL expressing cells, in a dose dependent manner. Despite no down-modulation of a BCR-ABL tyrosine kinase activity or its expression was observed after treatment with ACV, cell cycle analysis demonstrated synchronization of OM9;22 cells at the G0/G1 phase. This suggests that, although ACV does not directly act on BCR-ABL tyrosine kinase, ACV may exert its inhibitory effect on some leukemia cell lines via alterations of the cell cycle. Although selective inhibition of Philadelphia chromosome-positive leukemia cell growth was not apparent, our data provides a therapeutic possibility for ACV in the treatment for leukemia. PMID- 8683982 TI - Association of repeat sequences with integrated retroviruses in a murine leukaemia cell line. AB - An analysis was made of the retroviral integration sites for retroviruses in a murine lymphoid precursor cell line, C1-V13D, derived following in vitro infection with RadLV, an ecotropic murine retrovirus. A genomic library was constructed and lambda clones were selected for their capacity to hybridize with the specific RadLV gp70 ecotropic env probe. Analysis of these clones by a combination of approaches, including subcloning, partial restriction mapping and sequencing, has confirmed the existence of multiple recombinant and defective viruses in C1-V13D. To check for the presence of coding sequences in flanking genomic DNA, 32P-labelled cDNA from C1-V13D was used to probe HindIII- and Psti digested virus-positive lambda clones by Southern analysis. Regions hybridizing specifically with 32P-labelled C1-V13D cDNA were subcloned and analysed. A notable feature of these cDNA+ regions was the frequent presence of B1, B2 and simple repeats. These repeat elements were found to be present in high frequency in the genomic regions flanking the proviruses, in numbers higher than expected for the genome as a whole. All full-length viruses isolated appeared to represent integration events into regions rich in repeat elements. Some B1 and B2 repeats have been shown to code for functional proteins and to play regulatory roles. Viral integration in the vicinity of these genetic elements could contribute to oncogenesis if the integration event were to disrupt normal gene function. PMID- 8683983 TI - c-myb intron I protein binding and association with transcriptional activity in leukemic cells. AB - Specific binding of nuclear proteins to the region of transcriptional attenuation has been shown to modulate the expression of c-myb, a nuclear proto-oncogene preferentially expressed in lympho-hematopoietic cells. Here, it plays an important role in processes of differentiation and proliferation. The mechanism that regulates c-myb expression is not yet fully understood. The block of transcriptional elongation which has been mapped to a 1 kb region within murine intron 1 may represent one regulatory pathway. The DNA sequences containing the transcriptional pause site are well conserved between murine and human species, thus Implying similar transcription-control strategies. We compared the binding potential of nuclear extracts (from human fibroblasts and MOLT4 as well as murine NIH3T3- and 70Z/3B- cell lines) to oligonucleotide sequences previously shown to be target binding sites in the murine system. One complex containing a 70 D protein was found to be associated specifically with transcriptionally active leukemia cells. We performed transient expression studies with a CAT reporter construct containing this putative enhancer sequence and yielded significant CAT activity. We identified further a putative 20 kD repressor protein in transcriptionally silent cells and demonstrated that c-Jun is part of an ubiquitously present complex. Our results confirm the participation of intron 1 in transcriptional regulation of the c-myb gene (in mouse and human) and implicate multiple and complex regulatory mechanisms of activation during myelomonocytic differentiation and leukemic cell growth control. PMID- 8683984 TI - Persistence of E2A/PBX1 transcripts in t(1;19) childhood acute lymphoblastic leukemia: correlation with chemotherapy intensity and clinical outcome. AB - The occurrence of t(1;19) translocation was investigated by reverse transcriptase polymerase chain reaction (RT-PCR) for the E2A/PBX1 hybrid message in a panel of 37 consecutive childhood acute lymphoblastic leukemias (ALLs). Three patients with B-precursor ALL were found to be positive at diagnosis and were re-tested during follow-up to assess the presence of minimal residual disease (MRD). Two of them became PCR-negative during treatment, whereas one remains positive 3 years after diagnosis. Since all three patients are presently in clinical and hematological complete remission, PCR detection of persistent E2A/ PBX1 transcript does not seem to affect significantly the DFS at 3 years. However, the predictivity for an eventual late relapse still remains to be assessed. PMID- 8683985 TI - B cell malignancy and hepatitis C virus infection. PMID- 8683986 TI - Cis-elements in the promoter region of the human myeloperoxidase (MPO) gene. AB - We recently reported the identification and initial characterization of the human myeloperoxidase (MPO) promoter. The minimal or basic MPO promoter lies within the proximal 128 bp of the 5'-flanking region of the MPO gene. Plasmids containing progressively larger segments of the 5'-flanking region show correspondingly greater MPO promoter activity and increased tissue specificity compared with smaller promoter fragments. These findings suggested the presence of a multiple important regulatory cis-elements in the 5'-flanking region of the MPO gene. We now report results of studies which reveal the presence of seven discrete nuclear protein binding sites (DP1-DP7) within the proximal 600 bp of 5'-flanking MPO DNA. DNase I footprinting and gel shift analyses indicate tissue-specific and/or maturation-specific differences in nuclear protein binding to most of these sites, suggesting that they play a role in transcriptional regulation. Mutation of site DP7 stimulates the activity of a 594-bp MPO promoter construct in transfection studies, whereas mutation of any of the six other sites (DP1-DP6) reduces promoter activity. These results indicate that oligonucleotides DP1-DP7 constitute cis-elements which contribute to the activity of the human MPO promoter. PMID- 8683987 TI - Homozygous deletions of p16/MTS1 and p15/MTS2 genes are frequent in t(1;19) negative but not in t(1;19)-positive B precursor acute lymphoblastic leukemia in childhood. AB - We analyzed 60 B precursor acute lymphoblastic leukemia (ALL) primary samples and 15 cell lines for homozygous deletions of p16 and p15 genes and mutations of p16 gene. These included five cell lines and 13 primary samples with the t(1;19)(q23;pl3), and eight primary samples with the t(9;22)(q34;qll). Of 10 cell lines without t(1;19), homozygous deletion of both p16 and p15 genes was found in eight cell lines (80%), and a rearrangement of p16 in one cell line (10%). In contrast, only one (20%) of the five cell lines with t(1;19) showed homozygous deletion or rearrangement of p16/p15 gene. Thirteen of 60 (22%) primary samples demonstrated p16 gene homozygous deletion. No case with t(1;19) showed homozygous deletion of p16 gene (0/13, 0%), while cases without t(1;19) showed considerable incidence of p16 gene homozygous deletion (13/47, 28%). These results suggest that the incidence of deletions of p16 gene differs according to the subtypes of B precursor ALL. We also compared the frequency of p16 gene homozygous deletion between the patients at diagnosis and at relapse. Nine of 45 (20%) samples at diagnosis and four of 22 (18%) samples at relapse showed p16 homozygous deletions. The similarity of the rate in these two groups raises the question of the role of p16 gene in progression of B precursor ALL. Mutations were found in three of the primary cases (5%); the mutations included two nonsense mutations at codon 72 and one missense mutation at codon 98. All the mutations found in this study were heterozygous, and the clinical relevance of p16 gene mutation is yet to be determined in these case PMID- 8683988 TI - Do G-CSF and GM-CSF contribute to the management of acute lymphoblastic leukemia? PMID- 8683990 TI - Expression of the LH2 gene in chronic myeloid leukaemia cells. AB - The LH2 gene encodes a putative transcription factor containing two N-terminal LIM and one C-terminal HOX domains. The LH2 locus was mapped to 9q33-34.1, centromeric to the ABL gene. In a recent report, it was suggested that high levels of LH2 expression are consistently observed in chronic myeloid leukemia (CML) patients, whereas no transcription is detected in normal individuals. This led to the hypothesis that aberrant expression of LH2 may represent an additional mechanism for malignant cell proliferation in CML. We have studied the expression of LH2 in leucocytes from patients with CML or with other chronic myeloproliferative disorders (CMD), and from normal individuals, using an optimised reverse-transcription and polymerase chain reaction (PCR) technique. Twenty-seven out of 29 cDNA samples from normal individuals (93%), 49 out of 51 samples from CML patients (96%) and 20 out of 20 from Philadelphia chromosome negative CMD showed evidence of LH2 expression. Similarly, LH2 transcription was also detected in leucocytes from CML patients in complete cytogenetic remission after treatment with interferon-alpha. Furthermore, all 36 EBV-induced lymphoblastoid cell lines established from six chronic phase CML patients showed unequivocal LH2 expression, regardless of the BCR-ABL status of the line (9 BCR ABL positive, 27 BCR-ABL negative). We conclude that LH2 expression is not confined to CML cells, and that the t(9;22)(q34;qll) does not promote 'de novo' transcriptional activation of this gene. PMID- 8683989 TI - Expression of G alpha 16, a G-protein alpha subunit specific for hematopoiesis in acute leukemia. AB - G-proteins are essential in signal transduction pathways. A G-protein alpha subunit termed G alpha 16 was found to be exclusively expressed in hematopoietic cell lines. In cells derived from patients, G alpha 16 expression has been detected in progenitor- and pre-B ALL cells and also in peripheral blood stem cells (PBSC). In this study, we analyzed G alpha 16 expression using a RT-PCR technique by testing elutriated blood cells from normal donors, PBSC from breast cancer patients and bone marrow or peripheral blood cells from acute leukemia patients. Both of two ALL patients and 15/16 AML patients expressed G alpha 16. In elutriation experiments, G alpha 16 expression was found in fractions containing the highest number of precursor cells but was absent in mature T and B cell fractions. In addition, CD34-enriched PBSC were positive for G alpha 16 expression. Further in vitro experiments using the cell line KG1 showed that G alpha 16 expression was not affected by the growth inhibiting hemoregulatory peptide pEEDCK which has a sequence homology present within G alpha 16. Taken together, these data demonstrate that G alpha 16 is expressed in various normal and malignant hematopietic progenitors but not in their differentiated counterparts. G alpha 16 could play a vital role in signal transduction pathways controlling proliferation in early normal and malignant hematopoiesis. PMID- 8683991 TI - Expression pattern of WT1 and GATA-1 in AML with chromosome 16q22 abnormalities. AB - WT1 is a tumor suppressor gene that can repress transcription of many growth factor and growth-factor receptor genes. We quantitated WT1 expression levels in 62 acute myelogenous leukemia (AML) samples and found that 82% strongly expressed WT1. WT1 expression levels are highest in the undifferentiated and granulocytic French-American-British (FAB) subclasses and lower in the monocytic subclasses. WT1 was strongly expressed in normal CD34+ bone marrow (BM) stem cells but only weakly or not expressed in normal mature blood cells. This suggests that WT1 gene expression is associated with immature cells, which have high proliferative capacities. Previous studies of WT1 gene regulation showed that GATA-1 may regulate WT1 expression. To understand the relationship between WT1 and GATA-1 expression in leukemia, we examined the expression pattern of GATA-1 in the cells described above. Overall, AML samples expressed significant amounts of both WT1 and GATA-1. However, AML samples with 16q22 abnormalities, presumably interrupting the core binding factor (CBF) beta gene expressed lower than normal levels of GATA-1 but high levels of WT1. Our data suggest that the transcription factor CBF beta may be important for GATA-1 gene regulation. Thus, WT1 expression varied in different FAB subclasses, and GATA-1 expression was strongly affected by the presence of chromosome 16q22 abnormalities. PMID- 8683992 TI - Abberant cytogenetic evolution pattern of Philadelphia-positive chronic myeloid leukemia treated with interferon-alpha. AB - The cytogenetic evolution of 32 Philadelphia (Ph)-positive chronic myeloid leukemias (CML) receiving interferon-alpha (IFN-alpha) therapy was compared to the patterns in untreated CML and cases treated with busulfan (Bu), hydroxyurea (Hy), and allogeneic bone marrow transplantation (BMT). Half of the CML receiving IFN-alpha had at least one of the well-known major or minor route aberrations whereas 16 cases displayed unusual secondary abnormalities, of which only del(7p) and del(13q) were recurrent; a frequency significantly higher than in CML without therapy or after Bu and Hy treatment (P < 0.001) but similar to the one found post-BMT. The incidence of cases with cytogenetically divergent subclones, ie cell populations with unrelated aberrations in addition to the t(9;22), was also higher in the IFN-alpha group compared to the untreated, Bu and Hy groups (P < 0.01) but similar to the post-BMT group. Finally, 14 of the 32 IFN-alpha-treated CML displayed cytogenetic evolution already during the chronic phase; again a higher incidence than in the untreated, Bu and Hy groups (P < 0.001) but not different from the post-BMT group. These findings strongly indicate that IFN alpha, directly or indirectly, can induce clones with aberrant chromosomal evolution patterns to evolve and proliferate, but the mechanisms underlying these cytogenetic peculiarities remain to be elucidated. PMID- 8683993 TI - Expression of diverse AML1/MTG8 transcripts is a consistent feature in acute myeloid leukemia with t(8;21) irrespective of disease phase. AB - The (8;21) chromosomal translocation occurs in 20% of adult patients with AML M2. This translocation interrupts two genes, AML1 on chromosome 21q and MTG8 (ETO) on 8q to form a chimeric gene AML1/MTG8 on the der(8) chromosome. Recent reports have shown the presence of diverse forms of transcript for this chimeric gene. Three alternative out-of-frame transcripts have been previously demonstrated (types II, III, IV) all of which have a stop codon 3' of the runt box encoding a truncated runt polypeptide. We have characterized a novel transcript (V) which is in-frame and has a stop codon 3' to the runt box. We have examined transcript diversity in 10 AML patients with t(8;21) in remission of their disease following chemotherapy or bone marrow transplantation. Specific transcripts detected at presentation in six patients were similarly expressed during remission and at relapse in two patients; thus expression of transcript diversity was unaffected by the disease phase. Alternative transcripts were unhelpful as a marker of remission quality or predictor of relapse. The significance of these diverse transcripts in leukemogenesis remains unknown. PMID- 8683994 TI - Generation of reactive oxygen intermediates after treatment of blasts of acute myeloblastic leukemia with cytosine arabinoside: role of bcl-2. AB - Cytosine arabinoside is usually considered to be lethal by incorporation into DNA followed by chain termination. Recently, we have reported that the radical scavenger N-acetyl-cysteine (NAC) protects cultured clonogenic AML blast cells from the lethal affects of Ara-C if given before the drug. This observation provides indirect evidence that toxic reactive oxygen intermediates (ROI) are generated in AML blast cells following Ara-C-induced damage to DNA. In the present paper we present evidence in support of this hypothesis. Using flow cytometry and multiple fluorescent probes for live cell function, we have mapped a sequence of discrete stages that occur during Ara-C cytotoxicity. An early event was the increased generation of ROI. Initially this oxidative stress was countered by an increase in the cellular content of reduced glutathione (GSH), but cells then underwent an abrupt transition to a state characterized by low GSH and very high ROI generation indicative of collapse of cellular redox balance. Next, the capacity to maintain low intracellular ionized calcium was lost, probably due to lipid peroxidation at membrane sites of calcium regulation. Finally, surface membrane integrity was lost. Concurrent measurements of clonogenic cell survival insured the relevance of these flow cytometry measurements to the stem cell population. We used OCI/AML-2 cells transfected with bcl-2 to look for the place in this sequence where bcl-2 protein protects cells against apoptosis; bcl-2 transfectants showed an increase in ROI generation similar to controls, but were able to maintain GSH levels in the face of this oxidative stress. We conclude that oxidative stress plays a major role in Ara-C toxicity, and that bcl-2 protein protects cells by maintaining cellular redox balance in a reducing state. These studies complement previous work showing how regulators of AML growth affect the sensitivity of blast cells to Ara-C by changing the concentration or stability of bcl-2 protein. PMID- 8683995 TI - Effect of AS101 on bryostatin 1-mediated differentiation induction, cell cycle arrest, and modulation of drug-induced apoptosis in human myeloid leukemia cells. AB - Based upon earlier reports of synergism in cells of lymphoid origin, we have examined interactions between the organotellurium compound AS101 and the protein kinase C (PKC) activator bryostatin 1 with respect to differentiation and Ara-C induced apoptosis in human myeloid leukemia cells (HL-60). Although preincubation with bryostatin 1 (10 nM) for 24 h significantly increased DNA fragmentation and apoptosis in cells subsequently treated with 10 microM Ara-C for 6 h, this effect was not enhanced by co-administration of AS101 (1.5 microM). However, while exposure of cells to AS101 or bryostatin 1 alone for 72 h was ineffective in inducing cellular maturation, combined treatment resulted in the induction of differentiated features in a subset of cells, manifested by an increase in cell adherence, CD11b expression, cytoplasmic granularity and cell spreading. In addition, cells exposed to the combination of AS101 and bryostatin 1, in contrast to cells incubated with these agents individually, displayed a significant decline in the S-phase and a corresponding increase in the G0/G1 cell populations. These events were accompanied by an increase in protein expression of the cyclin-dependent kinase inhibitor, p21 (WAF1/CIP1/MDA6), and a decline in expression of the c-myc protein. AS101 failed to increase intracellular free Ca2+ ([Ca2+]i) in HL-60 cells, or reverse the profound PKC down-regulation induced by bryostatin 1. Whereas treatment of cells with 1.5 microM AS101 or 10 nM bryostatin 1 for 24 h exerted minimal growth inhibitory effects, combined exposure to these agents reduced colony formation by over 70%. Finally, although addition of AS101 did not potentiate apoptosis induced by the bryostatin 1/Ara-C combination, it did lead to a further reduction in clonogenicity. Together, these findings demonstrate that AS101 partially restores the ability of bryostatin 1 to trigger a differentiation program in an otherwise unresponsive HL-60 cell line, possibly by facilitating bryostatin 1-mediated G1 arrest. They also indicate that AS101 potentiates the antiproliferative effects of bryostatin 1 administered alone or in combination with Ara-C through a mechanism other than, or in addition to, induction of apoptosis. PMID- 8683996 TI - Coexpression of cell-surface immunoglobulin (sIg), terminal deoxynucleotidyl transferase (TdT) and recombination activating gene 1 (RAG-1): two cases and derived cell lines. AB - While it is generally agreed that in the lymphoid differentiation of B lineage cells there is no stage in which cell-surface immunoglobulin (sIg) and terminal deoxynucleotidyl transferase (TdT) are expressed simultaneously, a few B cell acute lymphoblastic leukemia (B-ALL) cases with this phenotype have been reported. Two such cases and the derived cell lines are reported here, in which the expression of recombination activating gene-1 (RAG-1) was also detected. One case was a CD19+ CD22+ HLA-DR+ sIg+ (gamma, kappa) B-ALL. The cell line (Bay9I) also expressed CD10. Karyotypic analysis revealed t(14;18)(q32;q21) and additional aberrations. In the other case, the fresh leukemia cells expressed CD19, CD24 and HLA-DR antigen. The derived cell line (Tree92) also expressed CD22 and sIg (mu, lambda). The karyotype of the Tree92 cells was t(8;14)(q24;q32) with additional aberrations. Tree92 is the first established cell line having both t(8;14)(q24;q32) and TdT. TdT was detected by Northern blotting as well as indirect immunofluorescence analysis. In addition, both Bay9I and Tree92 expressed RAG-1, as detected by Northern blot analysis. Cross-linking of sIg on Tree92 cells with anti-mu antibody led to significant down-regulation of RAG-1 expression. It seems that there is a sIg+ TdT+ RAG-1+ B lineage differentiation stage, and that signaling through sIg can modulate RAG-1 expression. PMID- 8683997 TI - All-trans retinoic acid in adult chronic myelomonocytic leukemia: results of a pilot study. AB - Retinoids can inhibit the spontaneous in vitro growth of CFU-GM observed in juvenile chronic myeloid leukemia (JCML) and, when administered in vivo, have shown some clinical benefit in this disease. Because adult chronic myelomonocytic leukemia (CMML) has many features in common with JCML, we treated 10 cases of advanced adult CMML with ATRA (45 mg/m2/day). Five of them were also tested in vitro. After two patients had a rapid increase in WBC counts and clinical signs reminiscent of the 'ATRA syndrome' seen in acute promyelocytic leukemia, with fatal outcome in one of them, it was decided to add hydroxyurea (HY) to ATRA to patients with high WBC at inclusion or during ATRA treatment, and no more cases of ATRA syndrome were seen. Overall, six patients received ATRA + HY and four ATRA alone. Four patients had a minor but significant response with reduction of transfusion requirement (two cases) or increase in platelet counts (two cases). Apart from the ATRA syndrome, no other side-effect of ATRA was seen. Bone marrow mononuclear cells showed spontaneous growth of CFU-C in methylcellulose in the five patients tested in vitro, with a predominance of CFU-M. ATRA (10(-7) M) inhibited CFU-M growth in all cases, but increased CFU-G growth in one patient who developed the ATRA syndrome. No differentiation of bone marrow myeloid cells after short-term liquid culture with ATRA was observed. A decrease of CFU-C growth was observed in the four patients reevaluated during follow-up. In some cases of CMML, ATRA can improve anemia or thrombocytopenia but not other parameters. Furthermore, it can also induce hyperleukocytosis and ATRA syndrome in some patients, requiring the rapid addition of cytoreductive agents such as HY. PMID- 8683998 TI - Expression of costimulatory molecules in human leukemias. AB - In order to determine the indication of B7 (B7-1 and B7-2) molecules-mediated immuno-gene therapy for human leukemias, we investigated 94 human leukemic samples for the expression of MHC molecules required for tumor antigen-specific signals and of B7-1, B7-2, and ICAM-1 molecules required for non-specific costimulatory signals. All samples were strongly positive for MHC class I and 84% for class II antigen. B7-1, B7-2 and ICAM-1 were expressed in 5%, 22% and 16% of the total cases, respectively. Especially in 54 AML samples, B7-1 was only expressed in one case, while B7-2 was detected in as many as 15 cases (28%). We have also examined 13 human myelo/monocytic cell lines for the expression of class II and costimulatory molecules and found that significant expression of costimulatory molecules was induced in human leukemic cells by some suitable drugs, among which interferon-gamma (IFN-gamma) was the most potent inducer. Our results indicate that when the B7-mediated immuno-gene therapy was applied to human leukemias, especially to AML, B7-1 was rather preferable to B7-2 in that the latter was more widely expressed on human leukemic cells. Furthermore, since gene-transfer systems occasionally accompany serious problems, it should be taken into account that costimulatory molecules on human myelo/monocytic leukemic cells could be induced ex vivo without the introduction of exogenous genes. PMID- 8683999 TI - Topoisomerase II activities in AML and their correlation with cellular sensitivity to anthracyclines and epipodophyllotoxines. AB - We have developed a method to quantify topoisomerase (topo) II activities in partially purified nuclear extracts from human leukemia cells. By virtue of their different pH optima in the reaction buffer, two different topo II activities were found with activity optima at pH 7.9 and at pH 8.9 under high stringency conditions. The activities could be identified as topo II beta activity (pH 7.9) and topo II alpha activity (pH 8.9) by their different sensitivities to topo II alpha inhibitors, dephosphorylation experiments and immunoprecipitation with polyclonal antibodies. Seventy-two bone marrow or blood samples from patients with acute myeloid leukemias have been examined and their in vitro sensitivities to anthracyclines and epipodophyllotoxines correlated to the activities of topo II alpha and topo II beta. Although the topo II alpha activity could be directly inhibited by incubation of the cells with the mentioned drugs, no correlation between the topo II alpha activity and the sensitivity of the cells could be found. In contrast, the topo II beta activity which was not substantially inhibited by the drugs inversely correlated with the sensitivity of the cells. These findings were statistically significant for idarubicin (P= 0.017) and daunorubicin (P = 0.006). Vice versa, resistant cells (IC50 > median) had a higher topo II beta activity. Clinical relevance might be indicated by the finding that cells from patients that relapsed after initial treatment with anthracyclin-containing regiments had a significantly higher topo II alpha/beta activity ratio (P=0.0276). Obviously, the sensitivity of AML cells is substantially influenced by the activity of the resistant topo II (topo II beta) which gives evidence that the remaining topo II activity after treatment helps the cell to survive the DNA repair phase. PMID- 8684001 TI - Ongoing mutation in MALT lymphoma immunoglobulin gene suggests that antigen stimulation plays a role in the clonal expansion. AB - Indirect antigenic stimulation by H. pylori-specific T cells is implicated in the development of low-grade gastric lymphoma of mucosa-associated lymphoid tissue (MALT), however, the role of direct antigen stimulation is unknown. To study the role of direct antigen stimulation in MALT lymphomagenesis and its relationship with the pathogenesis of distinct pathological lesions, which represent different stages of the tumour progression, we cloned and sequenced the rearranged immunoglobulin (Ig) heavy chain gene in three low-grade (two from the lung, one from the stomach) and one high-grade (from the stomach) cases. In the low-grade gastric case, we studied the Ig sequence in primary as well as its disseminated and recurrent tumours. In the high-grade gastric case, we analysed the Ig sequence in tumour cell populations microdissected from the residual diffuse low grade lesions, diffuse high-grade areas from follicles colonized by high-grade blasts. Compared with the published germline sequences, the heavy chain variable (VH) genes of three MALT lymphomas, in which the putative germline was identified, contained frequent somatic mutations, showing a much higher ratio of replacement/silent mutations in the complementarity determining regions (CDRs) than the framework regions (FRs). Ongoing mutation as indicated by intraclonal variation of the Ig sequence clearly existed in low-grade tumour including its dissemination and recurrence, but was not evident in high-grade tumour cell populations including those microdissected from independent colonized follicles. In addition, the germlines of VH genes used by the three MALT lymphomas are frequently found in autoreactive antibodies. Our results suggest that MALT lymphoma derives from postgerminal centre memory B cells, possibly autoreactive B cell clones, and that direct antigen stimulation may play an important role in the clonal expansion of low-grade MALT lymphoma. PMID- 8684000 TI - In vitro effects of IL-2 on NK-activity, clonogenic potential, blast cell proliferation and cytokine release of MDS bone marrow patients. AB - To evaluate the clinical usefulness of IL-2 in myelodysplastic syndromes (MDS) the in vitro effects of interleukin-2 (IL-2) on blast cell proliferation, clonogenic activity, cytokine release and cell mediated cytotoxicity were examined in 49 MDS patients. Morphological analyses of bone marrow (BM) cytospin preparations showed a significant decrease in the number of blast cells in MDS after incubation with IL-2. Incubation of bone marrow mononuclear cells (BMMNCs) with IL-2 induced a significant increase in the number of CFU-GM in comparison with untreated controls. gamma-IFN and GM-CSF, but not alpha-TNF were found to be released in significant amounts by the BMMNCs cultured with IL-2. No significant differences in the surface phenotypes of fresh lymphocytes were observed between the normal and MDS subjects. After incubation with IL-2, we observed a significant increase in the number of CD3-/CD56+ cells in both normal and MDS subjects. Peripheral blood (PB) and BM NK activity against K562 was significantly greater in MDS after stimulation with IL-2. These data suggest the clinical usefulness of IL-2 in a large subgroup of patients as it may reduce the percentage of blasts and increase clonogenic capacity and cell-mediated cytotoxicity. PMID- 8684002 TI - Concurrent activation of MYC and BCL2 in B cell non-Hodgkin lymphoma cell lines by translocation of both oncogenes to the same immunoglobulin heavy chain locus. AB - Concurrent activation of BCL2 and MYC usually occurs in B cell non-Hodgkin lymphoma (B-NHL) by translocation of both oncogenes to both immunoglobulin heavy chain (IGH) alleles: this abrogates immunoglobulin synthesis. We have studied three B-NHL cell lines (DoHH2, VAL and ROS 50) and show that concurrent activation of BCL2 and MYC may follow translocation of both oncogenes to the same IGH allele. Conventional cytogenetics of DoHH2 suggested the presence of a t(14;18)(q32;q21) translocation. However, fluorescent in situ hybridization (FISH) studies using whole chromosome paints, alpha satellite probes and flow sorted chromosomes as probes revealed an unexpected complexity of rearrangements involving chromosomes 8, 14 and 18, namely t(8;14;18)(q24;q32;q21). DNA blot and previous PCR analysis confirmed the juxtaposition of BCL2 major breakpoint region (mbr) with IGJH6, but also demonstrated a rearrangement within the first exon of MYC. The centromeric (5') MYC rearranged fragment comigrated with the BCL2-JH6 rearranged fragment in BamHI, EcoRI and Bg/II restriction digests. The der(8)t(8;14;18) therefore comprised 5' MYC (exon I)-Sgamma4-JH6-BCL2 mbr. Similar rearrangements were observed in both ROS 50 and VAL cell lines which contained two and three copies of the der(8)t(8;14;18) respectively. Quantitative flow cytometry for BCL2 and MYC expression showed abundant expression of both proteins in all three lines. These data indicate the der(14)t(14;18)(q32;q21) may itself be the target for any second translocation. The presence of the intact BCL2-JH fusion gene on the der(8)t(8;14;18) allowed concurrent activation of both BCL2 and MYC with no loss of immunoglobulin expression. PMID- 8684003 TI - Hepatitis C virus infection and monoclonal gammopathies not associated with cryoglobulinemia. AB - A pathogenetic role of HCV has been recently postulated in some lymphoproliferative disorders and in particular in essential mixed cryoglobulinemia. To assess the relevance of HCV infection in multiple myeloma, Waldenstrom's macroglobulinemia and monoclonal gammopathy of undetermined significance in the absence of cryoglobulinemia (cryo-ve MG), 102 patients were evaluated for antiHCV, HCVRNA and HCV genotypes. A control group of 466 patients referring for acute trauma to the Orthopedic Division of our hospital was also studied. The overall prevalence of HCV was 15.6% in MG patients and 5.4% in the control group (P= < 0.001). Since only patients with MG older than 50 years had HCV infection, we compared the prevalence rate of infection in patients aged 50 and older: in cryo-ve MG HCV prevalence was 17.9%, while in patients with an acute trauma it was 10%; the difference was not statistically significant. In addition, occurrence of cryo-ve MG was investigated in 614 antiHCV+ patients with chronic liver disease and was found in 1.9%. Comparing all the 28 cryo-ve MG patients HCV+ with an appropriately matched control group of HCV+ patients without MG, no difference in severity of liver disease and genotype distribution was detected. These findings show that: (1) among cryo-ve MG, HCV infection is frequent as shown in the appropriately matched control population; (2) prevalence of cryo-ve MG in antiHCV patients with chronic liver disease is similar to the rate found in the general population; and (3) HCV infection and disease do not differ in patients with and without cryo-ve MG. PMID- 8684004 TI - Improved rapid detection of the PML/RARalpha fusion gene in acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) is a medical emergency which requires rapid diagnosis and tailored treatment. Detection of the PML/RARalpha fusion gene in APL blasts is critical to start promptly the specific therapy with all-trans retinoic acid (ATRA). APL lacking this genetic lesion have been reported as being ATRA resistant. Reverse-transcription polymerase chain reaction (RT-PCR) has been extensively used to detect the PML/RARalpha cDNA. The reported PML/RARalpha amplification techniques are laborious and time consuming, and include conventional RNA extraction, cDNA synthesis and a two-round (nested) PCR. We hereby describe a few variations of the commonly adopted RNA extraction and PML/RARalpha RT-PCR protocols which allow a molecular diagnosis of APL to be carried out in less than 5 h. Processing of small volumes of leukemic cell lysate (0.5 ml) in a microfuge allows extraction of good quality RNA in 1 h. After reverse transcription to obtain cDNA, a 'hot start' PCR procedure was adopted which enabled us to amplify clearly visible and specific products after a single (not nested) amplification round. The PML/RARalpha fusion gene was detected in the blasts of six consecutive APL at diagnosis, and an APL-tailored protocol including ATRA was started in each case within 6 h of admission. On repeated experiments, the assay proved highly specific and sensitive for the rapid detection of all PML/RARalpha transcript types. Our data should encourage the use of this rapid procedure for the diagnosis of both typical APL and, particularly, less typical cases awaiting urgent therapeutic intervention. PMID- 8684005 TI - Reverse transcription/polymerase chain reaction (RT/PCR) amplification of very small numbers of transcripts: the risk in misinterpreting negative results. AB - Technical modifications of the reverse-transcription/polymerase chain reaction (RT/PCR) amplification method now permit its use to detect amplified products from as few as one abnormal cell, either isolated or mixed with a larger number of normal cells. We studied the reproducibility of such results using as targets low numbers of cells from chronic myeloid leukaemia (CML) patients and CML cell lines in quintuplicate two-step RT/PCR designed to amplify BCR-ABL sequences. When one K562 or KYO1 cell was diluted in 10(3) non-CML HL60 cells, an amplification product was obtained in each test; at greater dilutions BCR-ABL transcripts were detected erratically. Titration of cDNA synthesised from 5 x 10(7) cells from four CML patients showed that whereas positive BCR-ABL sequences could be amplified in some tests starting with as little as a 1 in 10(7) dilution of cDNA template (corresponding to 5-10 cells), the dilution threshold for reproducible amplification was around 1 to 5 in 10(5) (100-500 cells). Quantitative PCR analysis revealed that reactions from 1 in 10(7) diluted cDNA contained less than 10 BCR-ABL transcripts as the starting template. The stochastic nature of the amplification from such small numbers of transcripts was illustrated by results of 10 replicate PCR tests on cDNA from a patient expressing both b3a2 and b2a2 transcripts: dilutions of cDNA up to 1 in 10(5) yielded dual transcript amplification in all 10 tests, but the 1 in 10(7) cDNA dilution resulted in b3a2 and b2a2 products in three tests, b3a2 only in three, b2a2 only in one and no amplification in three tests. We conclude that this 'sampling effect' may yield false-negative results and thus misinterpretation of data regarding assessment of gene expression when the quantity of target material available for study is very small. PMID- 8684006 TI - Detection of minimal residual disease B cell lymphoma by a PCR-mediated RNase protection assay. AB - To detect and monitor tumor cells in the bone marrow (BM) or peripheral blood (PB) of patients with B cell lymphoma, we used the PCR-mediated RNase protection assay to identify the complementarity determining regions (CDR)-III gene rearrangement. This method required neither determination of nucleotide sequences nor construction of tumor-specific oligonucleotide probes or primers. The sensitivity of this assay using B cell lines as well as clinical samples revealed one tumor cell in a background of 10(4)-10(5) normal cells. Using this assay we examined 31 patients with B cell lymphoma in whom an IgH rearrangement of initial tumor tissues was confirmed by Southern blot analysis. Twenty of 31 (65%) patients were able to be analyzed using this assay. Tumor cells in the BM and PB evident on routine morphological examination or surface marker analysis were confirmed by this assay in all the evaluable samples. Moreover, we detected tumor cells in the BM or PB of five patients in whom no tumor cells were identified by conventional methods. The PCR-mediated RNase protection assay is useful to detect minimal residual disease (MRD) in B cell lymphoma because it is highly sensitive, rapid and simple. PMID- 8684007 TI - Improving chimaerism quantification in bone marrow transplant recipients by image processing and analysis after restriction endonuclease in situ digestion (IPA REISD). AB - Restriction endonuclease in situ digestion (REISD) with Sau3A of human metaphase chromosomes and interphase nuclei produces a conspicuous banding pattern involving pericentromeric regions of chromosomes 9 and 3. Constitutive heterochromatin of chromosome 9 is never digested by this enzyme while that of chromosome 3 is polymorphic, giving rise to three possible karyotypes: homozygous digested (3--), homozygous undigested (3++) or heterozygous individuals (3+-). Discrimination of this polymorphism between donor and recipient cells constitutes a rapid sex-independent method to monitor quantitatively the chimaerism achieved after bone marrow transplantation. An image processing and analysis (IPA) assisted procedure which resolves residual fluorescent regions in metaphase chromosomes or interphase nuclei after REISD has been developed. IPA-REISD has interesting advantages over the basic REISD method by allowing a rapid, objective and precise discrimination of the polymorphism in large cell samples. PMID- 8684008 TI - Establishment of AIDS-related lymphoma cell lines from lymphomatous effusions. AB - AIDS-related non-Hodgkin lymphomas (AIDS-NHL) are most frequently derived from B cells and include small non-cleaved cell lymphoma (SNCCL) and diffuse large cell lymphoma (DLCL) and less frequently anaplastic large cell lymphoma (ALCL) or body cavity-based lymphoma (BCBL). AIDS-NHL cell lines have proved useful to study AIDS-NHL pathogenesis. In this report, we describe the establishment and molecular characterization of two novel AIDS-NHL cell lines (HBL-4 and HBL-6) derived from lymphomatous effusions. HBL-4 was derived from a patient with SNCCL, whereas HBL-6 was derived from a patient with BCBL. The identity of the cell lines with the original tumor clone was established by immunoglobulin gene rearrangement analysis. Both HBL-4 and HBL-6 carry a monoclonal EBV infection and do not contain HIV. In addition, HBL-6 harbors DNA sequences of the recently identified Kaposi's sarcoma-associated herpesvirus (KSHV), now formally called human herpesvirus 8 (HHV8). Finally, HBL-4, but not HBL-6, harbors a rearranged c MYC allele, while the BCL-6 gene displayed a germline configurations in both cell lines. These AIDS-NHL cell lines may prove useful in understanding the biologic events contributing to AIDS-NHL development. PMID- 8684009 TI - Chronic myeloid leukemia of thrombocythemic onset: a CML subtype with distinct hematological and molecular features? AB - Among 84 consecutive patients with chronic phase Ph-positive chronic myeloid leukemia (CML) who were investigated for the hybrid BCR/ABL mRNA, in six cases (7%) the disease mimicked essential thrombocythemia (ET) at presentation, because of marked thrombocytosis (platelet counts ranging from 1003 x 10(9)/l to 2800 x 10(9)/l) and moderate leukocytosis (WBC counts from 10 x 10(9)/l to 19 x 10(9)/l). At initial examination, four of the six patients showed a few (4-9%) immature myeloid cells in the peripheral blood, and two had blood basophilia. All six patients later developed increasing leukocytosis, and two subsequently died from blast crisis and accelerated CML, respectively. In the overall series, 38 patients (45%) expressed the b2a2 type of BCR/ABL mRNA, and 46 (55%) either the b3a2 or both mRNAs. By contrast, only one of the six patients with CML of thrombocythemic onset expressed the b2a2 mRNA vs five with either b3a2 (n = 4) or both mRNA types (n = 1). The above results, in conjunction with similar data from a few previously published cases, suggest an association between the above form of CML and b3a2 type of BCR/ABL transcript. PMID- 8684011 TI - Angiocentric T cell lymphoma with prominent cutaneous ulceration. PMID- 8684010 TI - An adolescent with HTLV-I-associated adult T cell leukemia treated with interferon-alfa and zidovudine. PMID- 8684012 TI - A young child with acquired t(8;9)(p11;q34): additional proof that 8p11 is involved in mixed myeloid/T lymphoid malignancies. PMID- 8684013 TI - 2-Chlorodeoxyadenosine (2-CdA) in chronic lymphocytic leukemia refractory to fludarabine? PMID- 8684014 TI - [Food and nutrient consumption in Spain in the period 1940-1988. Analysis of its consistency with the Mediterranean diet]. AB - BACKGROUND: Not enough information is available regarding Spanish alimentation from the Civil War up to the present. Furthermore, there are some evidence that the Spaniards are leaving behind their traditional, healthy Mediterranean diet. The aim of this study was therefore to describe the food and nutrient intake trends of the Spanish population from 1940-1988 and establish to what extent the pattern of the Mediterranean diet has been maintained. METHODS: New food balance sheets for the Spanish population have been elaborated using all the information available and consistently applying the methodology of the European Union over the period from 1940-1988. RESULTS: Total caloric intake and that of all the macronutrients increased over the study period although this increase was greater after 1960. The contribution of lipids to total caloric intake has increased (30% in 1960-1968 and 42% from 1980-1988), protein contribution has remained the same (13% 1960-1968 and 13% 1980-1988) and carbohydrate intake has decreased (58% from 1960-1968 to 45% from 1980-1988). These changes are the result of an important increase in the consumption of meat, eggs, milk and derivatives. Nonetheless the high intake of fruit and vegetables, fish and olive and seed oils has been maintained. Thus, from 1980-1988 the ingestion of monounsaturated/saturated fatty acids and polyunsaturated/saturated fatty acids was 1.3 and 0.5, respectively. CONCLUSIONS: The first systematic reconstruction of the alimentary and nutritional history of the Spanish population over the last fifty years has been carried out. The Spanish diet has undergone typical changes associated with economic development but continues to be consistent with the pattern of the Mediterranean diet. These changes in diet are, however, of worry because of their deviation from optimum nutritional patterns. PMID- 8684016 TI - [Consumption, dietary habits and nutritional status of the Reus (IX) population. Evolution of food consumption, energy and nutrient intake and relationship with the socioeconomic and cultural level, 1983-1993]. AB - BACKGROUND: Mediterranean diet (a greater intake of olive oil, cereals, legumes, fruits and vegetables), is related to a lower prevalence of some associated diseases. The aim of the study was to observe in a Spanish population the evolution of dietary intake, whether there could be changes in the contribution of different kinds of food in energy intake, and the importance of socioeconomic and cultural factors which could influence this phenomenon. METHODS: Dietary intake was evaluated using the 24 hours recall method in a representative sample (n = 941, age range = 10-69) of a Reus population (Spain). This longitudinal study consisted of 70% of the sample studied in 1983 using identical methodology. RESULTS: From 1983 to 1993, we observed a significant increment of lactic derivatives (50.0%), vegetables (12.5%) and fruit intake (10.6%), and a significant decrease in tubercles (-56%), eggs (-15.6%), sugars (-13.0%), milk ( 9.2%), and cereal (-7.6%) intake. Meat, fish, and visible fat intake remained unchanged. The intake of the 9 groups of food was different for men and women along this time period. We observed an increment in animal sources to our diet, primarily because of an increment in lactic derivative intake and a decrease in tubercles intake. Differences observed in 1983 between social classes related to different kinds of nutrients had nearly disappeared in 1993. Medium and high social classes followed very similar diets. However, the group of population with lowest socioeconomic status had a lower intake of energy and nutrients. CONCLUSIONS: Our diet consisted of the main characteristics of the typical mediterranean diet, although we observed a decrease in cereal intake and an increase in food of animal origin. Differences observed in 1983 related to dietary habits and nutritional profile between medium and high social classes, disappeared in 1993. However, there exists a small group of people of low social class which had a lower intake of energy and other nutrients. PMID- 8684015 TI - [Immunologic reconstitution of peripheral blood lymphocytes in patients treated by bone marrow transplantation]. AB - BACKGROUND: Lymphocyte subset reconstitution was studied in 65 patients undergoing allogeneic and autologus bone marrow transplantation (BMT). PATIENTS AND METHODS: The expression of molecules on the membrane of lymphocyte subsets was assessed by two-colour flow cytometry and a direct immunofluorescence assay. The functional capacity of the patient's T lymphocytes following transplantation was identified by stimulation whit peripheral blood lymphocytes; B cells from BMT recipients were tested for their ability to respond, in vitro, to pokeweed (PWD) mitogen. RESULTS: 1) The proportion of CD8+ T lymphocytes was higher than the CD4+ T lymphocytes until 1 1/2 year after-BMT, with high percentage of immature T cells (CD3+, CD8+, HLA-DR+, CD25-) in the first nine months post-transplant. Moreover, a large proportion of T lymphocytes lacked CD5 expression in the first year following BMT. 2) T-cell proliferative response to PHA was low with subsequent recovery until normality. 3) Low numbers of B cells in the first two months with a significant increase since then until 1 1/2 year after-BMT; the phenotype of these B cells was mainly CD19+, CD5+. 4) High in vitro spontaneous immunoglobulin production by peripheral blood B lymphocytes and an impaired response to PWM was observed. 5) Increased percentage of cells with natural killer (CD56) cell phenotype was seen during the 2nd and 3rd months after the graft infusion. After 1 1/2 year postgrafting, this percentage returned to normal level. CONCLUSIONS: Taken together, these data indicate the existence of numerous abnormalities in several subsets of peripheral blood lymphocytes after BMT and suggest a slow kinetics of immune recovery after human marrow transplantation being complete between 18 and 24 months following BMT. PMID- 8684017 TI - [Lumbar pain and bone gammagraphy]. PMID- 8684018 TI - [Health care management: coordination of health care assistance levels]. PMID- 8684020 TI - [Abdominal pain, loss of strength in upper limbs and microcytic anemia in a 58 year-old man]. PMID- 8684019 TI - [Vertebral hemangioma and quiescent myeloma: association of therapeutic significance]. AB - Smouldering myeloma is a monoclonal gammopathy in which the M component is higher than 30 g/l and the proportion of plasma cells in the bone marrow is higher than 10% with no anemia, renal failure, hypercalcemia, osteolysis or other features due to the monoclonal gammopathy. The recognition of this clinical variant of myeloma resides in the fact that treatment should be deferred until there are clinical or biologic data indicating evident disease progression. Vertebral hemangioma is a relatively frequent benign tumor in the general population which, although usually asymptomatic, may cause local or radicular bone pain. A patient who fulfilled the criteria of myeloma and who complained of localized bone pain in the spinal column is herein presented. Following a study of the dorsolumbar column by computerized tomography and magnetic resonance, bone lesions with radiologic images characteristic of vertebral hemangioma, clearly different from those observed in myelomatous lesions, were identified. This finding conditioned the treatment, which included radiotherapy for the vertebral hemangioma and no treatment for the smouldering myeloma. PMID- 8684021 TI - [Absence of relationship between Behcet's disease and hepatitis B and C virus infection]. PMID- 8684022 TI - [Cardiac arrhythmias and ionic hypomagnesemia during liver transplantation]. PMID- 8684023 TI - [Anaphylactoid reaction caused by intravenous gadopentetate dimeglumine in magnetic resonance]. PMID- 8684024 TI - [Cardiac failure secondary to factitious thyrotoxicosis]. PMID- 8684025 TI - [Aspecific chorioretinitis as initial manifestation of HIV infection and diffuse Toxoplasma encephalitis]. PMID- 8684026 TI - [Brown-Sequard syndrome secondary to intramedullary metastasis as the initial symptom of microcytic lung tumor]. PMID- 8684027 TI - [France: increasing morbidity differences in spite of a democratic health care system]. PMID- 8684028 TI - [Mona Britton has had enough, she quits as the physician in charge. Health services must have a more flexible system--and stable rules of the game]. PMID- 8684029 TI - [British NHS plan a national computer network. BMA is worried because of the deficient computer security]. PMID- 8684030 TI - [Who will choose patients' medication in the future? Independent information must be strengthened II]. PMID- 8684031 TI - [Should primary health care be highly specified?]. PMID- 8684032 TI - [Bone density measurement--SBU follows the development?]. PMID- 8684033 TI - [Critical scrutiny is no threat to loyalty]. PMID- 8684034 TI - [Lung collapse. A common phenomenon during anesthesia]. PMID- 8684035 TI - [A model system in cell culture shows pathogenic processes. Biochemical diagnosis in Alzheimer dementia]. PMID- 8684036 TI - [Check-ups via telephone after day surgery. An effective part of quality assurance work]. PMID- 8684037 TI - [Even children may be affected by malignant abdominal tumors. Far too long diagnostic delay in many cases]. PMID- 8684038 TI - [Surgery of hypophyseal tumors via lateral rhinotomy. Reduced risk of recurrence and the impact on vision]. PMID- 8684039 TI - [The absorbable knot is smaller and stronger. An easy and safe method for continuous suture technique]. PMID- 8684041 TI - [A family-therapeutic method for the national disease of obesity. Start the treatment already when the children are about 10 years old!]. PMID- 8684040 TI - [Unnecessary admissions to departments of internal medicine. The contact with primary health care must be improved]. PMID- 8684042 TI - [Sugar potentiates the taste of fat: sweetness alone does not cause fatness]. PMID- 8684043 TI - [The 4th frame program of the EEC. Time for Biomed 2 application]. PMID- 8684044 TI - [Penicillin resistant pneumococci. Do not close the day care centers for healthy children]. PMID- 8684045 TI - [What do health services know about waiting lists? A questionnaire shows that few clinics do follow-ups]. PMID- 8684047 TI - [A comment to the discussion on drug utilization. Pharmacies owned by county councils should reduce drug costs]. PMID- 8684046 TI - [Supervisory groups for better treatment of patients]. PMID- 8684048 TI - [Child health services are for the children's best]. PMID- 8684049 TI - [Child health services in the USA respective Sweden. A comparison does not support cost savings in Sweden]. PMID- 8684050 TI - [Doubtful value of postpartum ultrasound]. PMID- 8684051 TI - [Hand fatigue? An alternative compression method in pseudoaneurysm]. PMID- 8684052 TI - [Care adapted to persons with psychoses]. PMID- 8684053 TI - [Unscientific criticism supports grave-diggers of welfare]. PMID- 8684054 TI - [Training in clinical medicine. An activity without distinct goals?]. PMID- 8684055 TI - [Many premature infants do not receive optimal nutrition. Importance of improving the feeding system!]. PMID- 8684056 TI - [Training in clinical medicine. A profession or a side-line occupation?]. PMID- 8684057 TI - [Easy to misunderstand patients with "white fingers". Vibrating tools may cause sensory disorders]. PMID- 8684058 TI - [Communication by way of a computer in intensive care]. PMID- 8684059 TI - [Einar Wallquist was born 100 years ago. A physician of Lapland who became king in his county]. PMID- 8684060 TI - [Childhood cancer and chickenpox. Principles of management]. PMID- 8684061 TI - [Olfactory perception of newborn infants is well-developed. Does the scent in the environment have any clinical significance?]. PMID- 8684062 TI - [Too varying practices in the care of Chlamydia infections. Is a care program a solution?]. PMID- 8684063 TI - [Compensation to a patient with cerebral hemorrhage. He was injured after thrombolysis in suspected myocardial infarction]. PMID- 8684064 TI - [Obstructive lung disease. Oxygen inhalation therapy does carry a risk of carbon dioxide narcosis]. PMID- 8684065 TI - [Systemic cholesterol embolism. A severe and often overlooked diagnosis]. PMID- 8684066 TI - [The committee on quality in health care introduces: a strategy for quality development at emergency departments]. PMID- 8684067 TI - [The physician and the computer]. PMID- 8684068 TI - [The role in the society of physicians employed by insurance authorities. Extended information as a basis for assessment]. PMID- 8684069 TI - [Meeting patients and help them find themselves]. PMID- 8684070 TI - [Who is responsible for autopsy?]. PMID- 8684071 TI - [Are steroid injections in allergic rhinitis without risk?]. PMID- 8684073 TI - [A nurse reported for human and professional behavior]. PMID- 8684072 TI - [Shorter immobilization with plaster of Paris in distal radius fractures]. PMID- 8684074 TI - [Mammography screening of women aged 50-69: now only two controversies!]. PMID- 8684075 TI - [Tape recorded consultations are a good support]. PMID- 8684076 TI - [Rapid progression of allergy must be prevented]. PMID- 8684077 TI - [Symptomatic prostatic cancer must be treated!]. PMID- 8684078 TI - [Women, arise from the delivery bed and protest!]. PMID- 8684079 TI - ["Heredity:0?" Human genes on the examination table]. PMID- 8684080 TI - [Antithrombotic treatment in connection with PTCA. New substances and regimes are coming]. PMID- 8684081 TI - [Tuberculosis--a ticking bomb. A new group of vaccines slows down the increasing threat]. PMID- 8684082 TI - [Epilepsy is difficult to treat during an attack of porphyria]. PMID- 8684083 TI - [Surgical alternatives in hysterectomy]. PMID- 8684084 TI - [Anorexia nervosa--a severe somatic and psychiatric diagnosis! One does not die of anxiety but of caloric deficiency]. PMID- 8684085 TI - [Intranasal steroids and perforation of the septum. An overlooked complication?]. PMID- 8684086 TI - [Indication for gastroscopy is not the problem. It may prevent medication without previous diagnosis!]. PMID- 8684087 TI - [Dyspepsia--is the anamnesis enough? Let general practitioners perform gastroscopy!]. PMID- 8684088 TI - [More penalties without reason by the disciplinary board. Criticism against the handling of appendicitis]. PMID- 8684089 TI - [An injury caused by diagnostic biopsy performed " for safety's sake only". A man received compensation from the Patient Insurance]. PMID- 8684090 TI - [Deficient examination and erroneous interpretation of X-rays. Missed diagnosis of femoral neck fracture is still a common problem]. PMID- 8684091 TI - [Science watchers watched in vain]. PMID- 8684092 TI - [Do false memories help victims of incest? The National Board of Health and Welfare approves of the much criticized psychotherapy]. PMID- 8684093 TI - Biotech's uncertain present. PMID- 8684094 TI - Papillomavirus oncoproteins as vaccine candidates. PMID- 8684095 TI - Antibiotics for the uncommon cold. PMID- 8684096 TI - Why arts courses for medical curricula. PMID- 8684097 TI - Value of direct amplified test for diagnosis of tuberculosis. PMID- 8684098 TI - Tackling environmental endocrine disrupters. PMID- 8684099 TI - Piltdown: another suspect. PMID- 8684100 TI - History of migraine and risk of cerebral ischaemia in young adults. The Italian National Research Council Study Group on Stroke in the Young. AB - BACKGROUND: A history of migraine has been proposed as a risk factor for cerebral ischaemia in women under 45. METHODS: To investigate the association between history of migraine and cerebral ischaemia, we performed a case-control study of 308 patients aged 15-44, with either transient ischaemic attack (TIA) or stroke, and of 591 age- and sex-matched controls prospectively recruited in seven university hospitals. Crude and adjusted odds ratios were calculated using logistic regression analysis. FINDINGS: A history of migraine was more frequent in patients than in controls (14.9% vs 9.1%; adjusted odds ratio 1.9, 95% confidence interval 1.1-3.1). In the prospectively designed subgroup analyses, a history of migraine reached the highest odds ratio (3.7, 95% CI 1.5-9) and was the only significant risk factor in women below age 35 (p=0.003); atherogenic risk factors were more relevant in men and in patients older than 35; previous migraine attacks with aura were more frequent in stroke patients (odds ratio 8.6, 95% CI 1-75). INTERPRETATION: Our findings indicated that the rare association between migraine and cerebral ischaemia is limited to women below age 35, and suggest a need for careful clinical evaluation of comorbidity in the presence of migraine with aura. PMID- 8684101 TI - Effects of antibiotic treatment in the subset of common-cold patients who have bacteria in nasopharyngeal secretions. AB - BACKGROUND: Upper-respiratory-tract infection is one of the main causes of overuse of antibiotics. We have found previously that bacteria such as Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae can be isolated from the nasopharyngeal secretions of a substantial proportion of adults with upper-respiratory-tract infections. We have assessed the efficacy of co-amoxiclav in patients with common colds but no clinical signs of sinusitis or other indications for antibiotics. METHODS: Between January, 1992 and March, 1994, 314 patients who presented to our outpatient clinic with common colds were enrolled in the double-blind, placebo-controlled study. They were randomly assigned 5 days' treatment with co-amoxiclav (375 mg three times daily) or identical placebo. Clinical examinations were done at enrolment and on day 5-7 to assess outcome (cured, persistent symptoms, worse symptoms). Seven patients were excluded after randomisation, seven did not have nasopharyngeal aspiration, and 12 did not return for followup assessment. FINDINGS: Of 300 patients with nasopharyngeal aspirates, 72 had negative bacterial cultures, 167 had cultures positive only for bacteria unrelated to respiratory infections, and 61 had cultures positive for H influenzae, M catarrhalis, or S pneumoniae. At 5-day follow-up of these culture-positive patients, the distribution of outcome was significantly better among co-amoxiclav-treated (n=30) than placebo-treated (n=28) patients (cured 27 vs 4%; persistent symptoms 70 vs 60%; worse symptoms 3 vs 36%; p=0.001). Patients on co-amoxiclav also scored their symptoms significantly lower than patients on placebo (p=0.008). Among culture-negative patients (n=230), the outcome distribution did not differ between the treatment groups (p=0.392). INTERPRETATION: The majority of patients with upper-respiratory tract infection do not benefit from antibiotics and side-effects are frequent. However, for the subgroup whose nasopharyngeal secretions contain H influenzae, M catarrhalis, or S pneumoniae, antibiotics are clinically beneficial. PMID- 8684102 TI - Atovaquone and proguanil for Plasmodium falciparum malaria. AB - BACKGROUND: The increasing spread of multidrug-resistant Plasmodium falciparum malaria emphasises the urgent need for alternative treatment regimens. The objective of the study was to establish the efficacy of a novel drug combination. We compared a combination of atovaquone and proguanil with amodiaquine in the treatment of acute uncomplicated P falciparum malaria in Lambarene, Gabon. METHODS: 142 adults were randomly allocated either a combination treatment of atovaquone 1000 mg daily and proguanil 400 mg daily for 3 days or treatment with amodiaquine 600 mg on admission, 600 mg 24 h later, and 300 mg after a further 24 h. Symptoms and clinical signs were recorded and giemsa-stained thick blood smears were done every 12 h until patients had been symptom-free and aparasitaemic for 24 h. 126 patients were followed up for 28 days or until recrudescence. FINDINGS: In the atovaquone plus proguanil group 62 (87%) of 71 patients were cured and only one had recrudescent infection. By contrast, the cure rate was significantly lower (p=0.022) with amodiaquine (51 [72%] of 71; there were 12 recrudescences in the amodiaquine group). Eight patients in each group were lost to follow-up. Patients treated with atovaquone plus proguanil complained of nausea (33%) and vomiting (29%), and the most commonly reported adverse effects of amodiaquine were pruritus (43%) and insomnia (27%). INTERPRETATION: Atovaquone and proguanil was a highly effective and safe drug combination in patients with acute uncomplicated P falciparum malaria in Gabon. PMID- 8684103 TI - Clinical usefulness of serum 1,5-anhydroglucitol in monitoring glycaemic control. AB - BACKGROUND: To evaluate prospectively the clinical value of measuring serum concentrations of 1,5-anhydroglucitol (1,5AG) in monitoring glycaemia in patients with newly diagnosed non-insulin-dependent diabetes mellitus (NIDDM), we measured serum 1,5AG in 56 such patients. METHODS: 28 patients (group A) were started on, and continuously received, an oral hypoglycaemic agent for at least 6 weeks. The other 28 patients (group B) were given such agents for 4 weeks, and then stopped taking them for at least 2 weeks. All patients were then followed for an additional 10 weeks. Serum 1,5AG, fructosamine, glycated haemoglobin (HbA1c), and self-monitoring of blood glucose were monitored every 14 days for 16 weeks. FINDINGS: When sudden worsening of glycaemia occurred within 2 weeks, entailing withdrawal of oral treatment, 1,5AG accurately detected the slight change in glycaemia whereas HbA1c and fructosamine both failed to detect it. Although the change was detected by measurement of fasting plasma glucose (FPG) concentrations, FPG was less sensitive than 1,5AG. In patients with "near normoglycaemia" (HbA1c about 6.5%) in the preceding 8 weeks, those who showed a lower concentration of 1,5AG (<10.0 micrograms/mL) manifested a higher mean daily plasma glucose concentration even though HbA1c measurement suggested good control of glycaemia. Results of 1,5AG were correlated more strongly with the FPG (r=0.790) and mean daily plasma glucose (r=-0.835) estimated on the same day than those estimaoffted in the preceding 2, 4 and 8 weeks, and with a fall in the Spearman correlation coefficient at any preceding time interval. INTERPRETATION: Because 1,5AG accurately detected a slight change in glycaemia without delay, it is suitable for use in monitoring for strict control of glycaemia, an important clinical goal. PMID- 8684104 TI - Decreased fertility in Britain compared with Finland. AB - BACKGROUND: There has been much interest in the apparent decrease in semen quality. Because the evidence for such a decrease is open to criticism, a different type of evidence is needed. Finland seems to have escaped this decrease, as well as other disorders of the male reproductive tract, notably testicular cancer. If there has been a true decrease, the implications for fertility are unknown. METHODS: The most sensitive functional measure of fertility is time to pregnancy (TTP); this can be studied retrospectively at group level with a high degree of validity. To test the hypothesis that Finnish men are more fertile than British men, TTP distributions from published Finnish studies and data from Britain were compared. Two comparisons were made: a pair of antenatal studies, and a pair of cross-sectional studies. FINDINGS: In both comparisons, fertility was statistically significantly greater in Finland than in Britain. The findings did not seem to be due to methodological problems; in particular, the results could not be attributed to differences in frequency of intercourse, since this would have had the opposite effect on sperm concentration and on TTP. INTERPRETATION: The previously reported difference in sperm counts between Finland and elsewhere in northwest Europe (including Britain) is probably not artefactual, suggesting that the reported world-wide decline in semen quality is also real. Reasons for the "Finnish exception" may include maternal smoking, which used to be lower in Finnish women than elsewhere, and which might affect developing make offspring. PMID- 8684105 TI - A recombinant vaccinia virus encoding human papillomavirus types 16 and 18, E6 and E7 proteins as immunotherapy for cervical cancer. AB - BACKGROUND: Human papillomavirus (HPV) infection, especially with type 16 or 18, is associated with cervical cancer. Two HPV proteins, E6 and E7, are consistently expressed in tumour cells. The objectives of the study were to examine the clinical and environmental safety and immunogenicity in the first clinical trial of a live recombinant vaccinia virus expressing the E6 and E7 proteins of HPV 16 and 18 (TA-HPV). METHODS: The study was an open label phase I/II trial in eight patients with late stage cervical cancer. The patients were vaccinated with a single dose of TA-HPV and kept in strict isolation to monitor local and systemic side-effects, environmental spread, and anti-E6/E7 immune responses. FINDINGS: Vaccination resulted in no significant clinical side-effects and there was no environmental contamination by live TA-HPV. Each patient mounted an antivaccinia antibody response and three of the eight patients developed an HPV-specific antibody response that could be ascribed to the vaccination. HPV-specific cytotoxic T lymphocytes, the effector mechanism most likely to be of therapeutic benefit, were detected in one of three evaluable patients. INTERPRETATION: Further studies to investigate the use ot TA-HPV for immunotherapy of cervical cancer are warranted. PMID- 8684106 TI - Knot Crohn's disease. PMID- 8684107 TI - Population policies and reproductive patterns in Vietnam. AB - BACKGROUND: Vietnam's population policy since the 1980s had stipulated a limit on family size to two children, born 3-5 years apart, and recommends a minimum age of 19 for the mother of a first child. We analysed trends in the timing of marriages and births, and in fertility and abortion rates, among women born between 1945 and 1970, to assess the impact of these policies on reproductive patterns. METHODS: Reproductive histories were recorded in a random sample of 1432 married women aged 15-49 in a rural province in northern Vietnam. Mean age at marriage and at birth of the first child, birth intervals, fertility, and abortion rates were examined in relation to the woman's year of birth. FINDINGS: Later-born women married and had their first child at a younger age than women born earlier. Birth intervals had increased among later-born women but 25% still had only a 1-year interval between first and second child. Fertility had gradually decreased while abortion ratios had increased rapidly. Childbearing patterns had become "earlier, longer, and fewer" rather than "later, longer, and fewer" as stipulated by the policies. The results also show that women with more schooling married and had their first child later. Women involved in farming had shorter spacing between children. INTERPRETATION: There are signs that Vietnam's population policy has focused too strongly on contraception and abortion while ignoring the connection between fertility and women's opportunities for education and employment. In these respects, rural women are at particular risk. PMID- 8684108 TI - Influence and power of the media. AB - People tend to get most of their information beyond work and family horizons from the press, radio, and television. So, do they really believe media stories that suggest, for example, there is no link between HIV and AIDS? This is unlikely, but there is a curious paradox--namely, that the same time, people to varying degrees are open minded about such stories as unidentified flying objects, astrology, reincarnation, and alien abduction. Yet, people are discerning and seem able to spot the dangerous rubbish, happy to be entertained and unlikely to be misled by the things that will really alter their lives. PMID- 8684109 TI - Reform of the World Health Organization. PMID- 8684110 TI - UK panics over phthalates in babymilk formulae. PMID- 8684111 TI - Two spinal fusion devices recommended for US approval. PMID- 8684112 TI - Old hopes and new horizons for treating cystic fibrosis. PMID- 8684113 TI - Not what the UK health ministers ordered. PMID- 8684114 TI - FDA warns Pfizer on failure to report drug problems. PMID- 8684115 TI - Immunochromatographic test for malaria diagnosis. PMID- 8684116 TI - Cerebral malaria or Plasmodium falciparum malaria with hypoglycaemia. PMID- 8684117 TI - Endocytosis by mature muscle cells of aggregates of parasitised erythrocytes and macrophages in severe malaria. PMID- 8684118 TI - Follow-up time bias and Crohn's disease. PMID- 8684120 TI - Follow-up time bias and Crohn's disease. PMID- 8684119 TI - Follow-up time bias and Crohn's disease. PMID- 8684121 TI - GBV-C virus and fulminant hepatic failure. PMID- 8684122 TI - Myocardial infarction in pre-war Leeds. PMID- 8684123 TI - Computer software programs and Down's syndrome risk calculations. PMID- 8684124 TI - Computer software programs and Down's syndrome risk calculations. PMID- 8684125 TI - Combined loss of BRCA1/BRCA2 in grade 3 breast carcinomas. PMID- 8684126 TI - Mycoplasmas and oncogenesis. PMID- 8684127 TI - Posterior leucoencephalopathy syndrome. PMID- 8684128 TI - Posterior leucoencephalopathy syndrome. PMID- 8684129 TI - European guidelines on resuscitation. PMID- 8684130 TI - Media distortion of dangers of diagnostic radiology. PMID- 8684131 TI - Medical advice for sick physicians. PMID- 8684132 TI - Ethics committees. PMID- 8684133 TI - Low rates of Paget's disease of bone and osteosarcoma in elderly Japanese. PMID- 8684134 TI - Medical advice for sick physicians. PMID- 8684135 TI - Incomplete penetrance of familial Alzheimer's disease in a pedigree with a novel presenilin-1 gene mutation. PMID- 8684136 TI - Presenilin-1 polymorphism and Alzheimer's disease. PMID- 8684137 TI - Presenilin-1 polymorphism and Alzheimer's disease. The Alzheimer's Study Group. PMID- 8684138 TI - Botulism and Gulf War syndrome. PMID- 8684139 TI - Hirudin CGP 39393 as thromboprophylaxis. PMID- 8684140 TI - Bronchoalveolar lavage in rapid diagnosis of leptospirosis. PMID- 8684141 TI - Human parvovirus B19 infection and hepatitis. PMID- 8684142 TI - Dural venous sinus thrombosis due to cranial trauma. PMID- 8684143 TI - Melioidosis causing a mycotic aneurysm. PMID- 8684144 TI - Melioidosis in India. PMID- 8684145 TI - Lady Mary Wortley Montague's contribution to the eradication of smallpox. PMID- 8684146 TI - Greening our health. PMID- 8684147 TI - Leptin and leptinomania. PMID- 8684148 TI - Economic evaluations to aid decision to conduct a trial. PMID- 8684149 TI - Epidemiological surveillance for detecting typical Lyme disease. PMID- 8684150 TI - HLA and natural history of HIV infection. PMID- 8684151 TI - Is it "urban" or is it "asthma"? PMID- 8684152 TI - Read before you cite. PMID- 8684153 TI - Fall-related factors and risk of hip fracture: the EPIDOS prospective study. AB - BACKGROUND: Most hip fractures result from falls. However, the role of fall related factors has seldom been examined. Comparison of the predictive value of these factors with that of bone mineral density (BMD) has important implications for the prevention of hip fractures. METHODS: We assessed femoral-neck BMD by dual-photon X-ray absorptiometry and potential fall-related risk factors, which included self-reported physical capacity, neuromuscular function, mobility, visual function, and use of medication in 7575 women, aged 75 years or older, with no history of hip fracture recruited at five centres in France. We followed up these women every 4 months to record incident hip fractures. During an average of 1.9 years of follow-up 154 women suffered a first hip fracture. FINDINGS: In age-adjusted multivariate analyses, we found four independent fall-related predictors of hip fracture: slower gait speed (relative risk = 1 . 4 for 1 SD decrease [95% Cl 1.1-1.6)]; difficulty in doing a tandem (heel-to-toe) walk (1.2 for 1 point on the difficulty score [1.0-1.5]); reduced visual acuity (2.0 for acuity < or = 2/10 [1.1-3.7]); and small calf circumference (1.5 [1.0-2.2]). After adjustment for femoral-neck BMD, neuromuscular impairment--gait speed, tandem walk--and poor vision remained significantly associated with an increased risk of subsequent hip fracture. With high risk defined as the top quartile of risk, the rate of hip fracture among women classified as high risk based on both a high fall-risk status and low BMD was 29 per 1000 women-years, compared with 11 per 1000 for women classified as high risk by either a high fall-risk status or low BMD; for women classified as low risk based on both criteria the rate was five per 1000. INTERPRETATION: We conclude that neuromuscular and visual impairments, as well as femoral-neck BMD, are significant and independent predictors of the risk of hip fracture in elderly mobile women, and that their combined assessment improves the prediction of hip fractures. PMID- 8684154 TI - Modelling cost-effectiveness of Helicobacter pylori screening to prevent gastric cancer: a mandate for clinical trials. AB - BACKGROUND: It is unknown whether eradication of Helicobacter pylori infection prevents development of gastric adenocarcinoma. To determine whether screening and treatment trials are warranted, we conducted a cost-effectiveness analysis to estimate the costs and benefits associated with screening for H pylori at age 50 and treating those individuals infected with antibiotics. METHODS: We compared two interventions: (1) screen for H pylori and treat those with a positive test, and (2) do not screen and do not treat. Estimates of risks and costs were obtained by review of published reports. Since the efficacy of H pylori therapy in cancer prevention is unknown, we did sensitivity analyses, varying this estimate widely. In our base-case analysis, we assumed that H pylori treatment prevented 30% of attributable gastric cancers. FINDINGS: In the base-case analysis, 11,646,000 persons in the US would be screened and 4,658,400 treated, at a cost of $996 million. Cost-effectiveness was $25,000 per year of life saved. Cost-effectiveness was sensitive to the efficacy of the cancer prevention strategy. At low efficacy rates (< 10%), the screening programme was more expensive (> $75,000 per year of life saved). In a high-risk group such as Japanese-Americans, however, screening and treatment required less than $50,000 per year of life saved, even at 5% treatment efficacy. INTERPRETATION: Screening and treatment for H pylori infection is potentially cost-effective in the prevention of gastric cancer, particularly in high-risk populations. Cancer prevention trials are strongly recommended. PMID- 8684155 TI - Double-blind placebo-controlled study of the hyperventilation provocation test and the validity of the hyperventilation syndrome. AB - BACKGROUND: Hyperventilation syndrome (HVS) describes a set of somatic and psychological symptoms thought to result from episodic or chronic hyperventilation. Recognition of symptoms during the hyperventilation provocation test (HVPT) is the most widely used criterion for diagnosis of HVS. We have investigated the validity of the HVPT and of the concept of HVS. METHODS: In a randomised, double-blind, crossover design, the ability of 115 patients with suspected HVS to recognise symptoms during the HVPT was compared with the ability to recognise symptoms during a placebo test (isocapnic overbreathing, with carbon dioxide levels maintained by manual titration). 30 patients who had positive results on the HVPT underwent ambulatory transcutaneous monitoring of pCO2 to ascertain whether they hyperventilated during spontaneous symptom attacks. FINDINGS: Of the 115 patients who underwent the HVPT and the placebo test, 85 (74%) reported symptom recognition during the HVPT (positive diagnosis HVS). Of that subset, 56 were also positive on the placebo test (false-positive), and 29 were negative on the placebo test (true-positive). False-positive and true positive patients did not differ in symptom profile or in physiological variables. During ambulatory monitoring (15 true-positive, 15 false-positive) 22 attacks were registered. Transcutaneous end-tidal, pCO2 decreased during only seven. The decreases were slight and apparently followed the onset of the attack, which suggests that hyperventilation is a consequence rather than a cause of the attack. There were no apparent differences between false-positive and true positive patients. INTERPRETATION: The HVPT is invalid as a diagnostic test for HVS. Hyperventilation seems a negligible factor in the experience of spontaneous symptoms. The term HVS should be avoided. PMID- 8684157 TI - A new Borrelia species isolated from patients with relapsing fever in Spain. AB - BACKGROUND: Lyme disease and tick-borne relapsing fever are worldwide systemic borrelioses caused by several Borrelia species transmitted by hard ticks (family Ixodidae) and soft ticks (family Argasidae), respectively. A previous seroepidemiological study of Lyme borreliosis showed several serologically reactive patients with clinically atypical presentations, and this discovery led to the hypothesis that some of the cases of Lyme borreliosis had been caused by another borrelia organism. METHODS: Blood from patients in southern Spain who had suspected Lyme disease or relapsing-fever borreliosis was cultured before treatment began. Isolates of Borrelia spp were inoculated into several strains of mice of different ages. The 16S rRNA and flagellin in genes of Borrelia spp were sequenced by PCR and assessed by phylogenetic analyses. FINDINGS: We isolated a species of Borrelia from three patients with relapsing fever and from Ornithodorus spp ticks in southern Spain. This organism (refractory to in-vitro cultivation) caused a relapsing spirochaetaemia with multiple organ involvement in laboratory mice that recreated the human disease. Phylogenetic analysis showed that this organism is a previously unrecognised species. INTERPRETATION: We have discovered a new borrelia pathogen that is closely related to the other tick borne agents of relapsing fever in Europe and Africa, and which causes a relapsing systemic disease with serological similarities to Lyme borreliosis. PMID- 8684156 TI - Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. AB - BACKGROUND: A receptor for leptin has been cloned from the choroid plexus, the site of cerebrospinal-fluid (CSF) production and the location of the blood/cerebrospinal-fluid barrier. Thus, this receptor might serve as a transporter for leptin. We have studied leptin concentrations in serum and (CSF). METHODS AND FINDINGS: We demonstrated by radioimmunoassay and western blot the presence of leptin in human CSF. We then measured leptin in CSF and serum in 31 individuals with a wide range of bodyweight. Mean serum leptin was 318% higher in 8 obese (40.2 [SE 8.6] ng/mL) than in 23 lean individuals (9.6 [1.5] ng/mL, p < 0.0005). However, the CSF leptin concentration in obese individuals (0.337 [0.04] ng/mL) was only 30% higher than in lean people (0.259 [0.26] ng/mL, p < 0.1). Consequently, the leptin CSF/serum ratio in lean individuals (0.047 [0.010]) was 4.3-fold higher than that in obese individuals (0.011 [0.002], p < 0.05). The relation between CSF leptin and serum leptin was best described by a logarithmic function (r = 0 x 52, p < 0.01). INTERPRETATION: Our data suggest that leptin enters the brain by a saturable transport system. The capacity of leptin transport is lower in obese individuals, and may provide a mechanism for leptin resistance. PMID- 8684158 TI - An emaciated man with eosinophilic pneumonia. PMID- 8684159 TI - Health services: an Italian market. AB - One of the glories of Italy is its capacity to surprise. In out-of-the-way places extraordinary things are suddenly encountered; and this is hardly less true of science than of architecture or music or painting. Italian medicine can boast excellence in many quiet spots. Yet Italy's record in medical science and practice is perceived to be below par, and one reason may be a lack of central coordination--forgivable in a country that had fifty governments in half a century. The latest administration offers a rare chance of political stability and the prospect of reforms. In this profile of Italian medicine The Lancet's guide was Dr Giuseppe Remuzzi, whose central coordination was exemplary. PMID- 8684160 TI - Difficulties and strategies of HIV diagnosis. AB - HIV infection is commonly diagnosed by detection of antibodies (anti-HIV) by ELISA or agglutination. Reactive results are confirmed by western blot (immunoblot) or further specific tests such as competitive ELISA, which, when evaluated quantitatively, allow the differentiation of HIV types and partially subtypes. Detection of infection of newborn babies, characterisation of individual strains for subtyping and forensic identification, and therapeutic monitoring are the domain of nucleic-acid-based assays. Nucleic-acid-based assays narrow the serological diagnostic window period in early HIV infection and, when quantified, give some indication of clinical status. PMID- 8684161 TI - Vancouver conference marks viral-load era of AIDS. PMID- 8684162 TI - Structure of HIV p24 capsid protein revealed. PMID- 8684163 TI - Norwegian health chief angers Africans. PMID- 8684164 TI - Fetoscopic cord ligation to prevent neurological injury in monozygous twins. PMID- 8684165 TI - Use of CA 125 in follow-up of ovarian cancer. PMID- 8684166 TI - Association of BRCA1 expression with gonadotropin-responsive cells. PMID- 8684167 TI - Body temperature and outcome in stroke patients. PMID- 8684168 TI - Efficacy of rice-based oral rehydration. PMID- 8684169 TI - Allocation of kidneys for renal transplantation. PMID- 8684170 TI - Botulism and pregnancy. PMID- 8684171 TI - Lymphadenectomy and pancreatico-splenectomy in gastric cancer surgery. PMID- 8684172 TI - Red fingers syndrome in patients with HIV and hepatitis C infection. PMID- 8684173 TI - Collection of urine from washed-up potties. PMID- 8684175 TI - What to do with spare embryos. PMID- 8684174 TI - Hyperbaric oxygen therapy in a woman who declined colostomy. PMID- 8684176 TI - Withdrawal of medical research council funding for intercalated BSc students. PMID- 8684177 TI - Preimplantation gender determination and X-linked diseases: ethical controversy. PMID- 8684179 TI - Descriptions of correlation. PMID- 8684178 TI - Meta-analysis: the final answer, or even more confusion? PMID- 8684180 TI - Salmonella durban in an infant. PMID- 8684181 TI - Comparison of non-chlorofluorocarbon-containing salbutamol and conventional inhaler. PMID- 8684182 TI - Acute upper gastrointestinal haemorrhage. PMID- 8684183 TI - Acute upper gastrointestinal haemorrhage. PMID- 8684184 TI - Superantigens in the aetiology of Kawasaki disease. PMID- 8684185 TI - Neurological complications and Japanese encephalitis vaccination. PMID- 8684186 TI - 1-year follow-up of the use of hydroxycarbamide and didanosine in HIV infection. PMID- 8684187 TI - Ischaemic preconditioning. PMID- 8684188 TI - Which cyclosporin formulation? PMID- 8684189 TI - Heparin prophylaxis in bedridden patients. PMID- 8684190 TI - Myocardial infarction in pre-war Leeds. PMID- 8684191 TI - The challenge of asthma: Lancet conference 1997. PMID- 8684192 TI - Midwife-managed care. PMID- 8684193 TI - Prevention of brain haemorrhage and ischaemic injury in premature babies. PMID- 8684194 TI - Major orthopaedic surgery and post-discharge DVT. PMID- 8684195 TI - New technology and recurrent varicose veins. PMID- 8684196 TI - What do you do, partner? PMID- 8684197 TI - Randomised, controlled trial of efficacy of midwife-managed care. AB - BACKGROUND: Midwife-managed programmes of care are being widely implemented although there has been little investigation of their efficacy. We have compared midwife-managed care with shared care (ie, care divided among midwives, hospital doctors, and general practitioners) in terms of clinical efficacy and women's satisfaction. METHODS: We carried out a randomised controlled trial of 1299 pregnant women who had no adverse characteristics at booking (consent rate 81.9%). 648 women were assigned midwife-managed care and 651 shared care. The research hypothesis was that compared with shared care, midwife-managed care would produce fewer interventions, similar (or more favourable) outcomes, similar complications, and greater satisfaction with care. Data were collected by retrospective review of case records and self-report questionnaires. Analysis was by intention to treat. FINDINGS: Interventions were similar in the two groups or lower with midwife-managed care. For example, women in the midwife-managed group were less likely than women in shared care to have induction of labour (146 [23.9%] vs 199 [33.3%]; 95% CI for difference 4.4-14.5). Women in the midwife managed group were more likely to have an intact perineum and less likely to have had an episiotomy (p = 0.02), with no significant difference in perineal tears. Complication rates were similar. Overall, 32.8% of women were permanently transferred from midwife-managed care (28.7% for clinical reasons, 3.7% for non clinical reasons). Women in both groups reported satisfaction with their care but the midwife-managed group were significantly more satisfied with their antenatal (difference in mean scores 0.48 [95% CI 0.41-0.55]), intrapartum (0.28 [0.18 0.37]), hospital-based postnatal care (0.57 [0.45-0.70]), and home-based postnatal care (0.33 [0.25-0.42]). INTERPRETATION: We conclude that midwife managed care for healthy women, integrated within existing services, is clinically effective and enhances women's satisfaction with maternity care. PMID- 8684198 TI - The effects of dopamine and adrenaline infusions on acid-base balance and systemic haemodynamics in severe infection. AB - BACKGROUND: Adrenaline is used increasingly in the management of septic shock, but its efficacy and safety are uncertain. METHODS: In an open, randomised, crossover study we compared the effects of stepped doses of adrenaline 0.1 to 0.5 microgram/kg per min and dopamine 2.5 to 10 micrograms/kg per min on the haemodynamic and acid-base status of 23 patients critically ill with severe sepsis (n = 10) or severe malaria (n = 13). FINDINGS: All patients completed the dopamine study whereas in 16 (84%) patients the adrenaline infusion had to be terminated before reaching, or during, the maximum dose because of lactic acidosis (p < 0.0002). Adrenaline was associated with a mean (95% CI) increase in plasma lactate of 3.2 (2.6 to 3.8) mmol/L, and mean falls in arterial pH of 0.052 (0.035-0.068) pH units and base excess of 3.8 (2.8-4.7) mmol/L. The geometric mean (95% CI) lactate increment per unit adrenaline dose was 8.2 (5.8-10.5) mmol/L per microgram/kg per min. In contrast dopamine was associated with a fall in lactate of 1.0 (0.4-1.5) mmol/L, a rise in base excess of 1.4 (0.7 to 2.0) mmol/L (p < 0.0001 in each case), and no effect on arterial pH. Both drugs induced significant increases in cardiac index and oxygen delivery with smaller increases in oxygen consumption and falls in systemic vascular resistance which were similar in severe malaria and severe sepsis (p > 0.1 in each case) [corrected]. INTERPRETATION: Infusion of inotropic doses of adrenaline in severe infections causes lactic acidosis. PMID- 8684199 TI - Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomised comparison of enoxaparin versus placebo. AB - BACKGROUND: The risk of deep-vein thrombosis (DVT) and pulmonary embolism after total hip replacement (THR) surgery may persist after hospital discharge, but the extent of the risk is not known. We carried out a single-centre, prospective, randomised, double-blind trial with the aims of quantifying this risk and assessing the efficacy of continued prophylactic treatment. METHODS: At hospital discharge 13-15 days after surgery, we recruited 179 consecutive THR patients who had no DVT visible on bilateral ascending venography of the legs. The patients were randomly assigned subcutaneous enoxaparin (40 mg, once daily; n = 90) or placebo (n = 89) for 21 (19-23) days. The primary endpoint was the occurrence of DVT or pulmonary embolism. Venography was repeated at the end of 21 days' treatment or earlier if necessary. FINDINGS: There were no deaths and no symptomatic pulmonary embolisms during the study or follow-up periods. Of 173 patients with evaluable venograms, intention-to-treat analysis of efficacy showed that the rate of DVT at day 21 after discharge was significantly lower in the enoxaparin group than in the placebo group (6 [7.1%] vs 17 [19.3%], p = 0.018). Distal DVT was detected in one (1.2%) patient in the enoxaparin group and in ten (11.4%) patients in the placebo group (p = 0.006). Proximal DVT was observed in five (5.9%) patients in the enoxaparin group and in seven (7.9%) patients in the placebo group (p = 0.592). A perprotocol analysis of efficacy in 155 patients confirmed these findings. Safety was good; three minor bleeding episodes occurred in the enoxaparin group and one in the placebo group, but none of these episodes necessitated withdrawal from the study. INTERPRETATION: In patients who have undergone THR surgery, are without venogram-proven DVT at hospital discharge, and do not receive antithrombotic prophylaxis after discharge, the risk of late occurring DVT remains high at least until day 35 after surgery. Continued prophylaxis with enoxaparin is effective and safe in reducing this risk. PMID- 8684200 TI - Randomised trial of prophylactic early fresh-frozen plasma or gelatin or glucose in preterm babies: outcome at 2 years. Northern Neonatal Nursing Initiative Trial Group. AB - BACKGROUND: Preterm babies are at risk of haemorrhagic and ischaemic brain injury. One controlled trial suggested that prophylactic fresh-frozen plasma (FFP) may reduce that risk but did not clarify whether the reduction in periventricular haemorrhage seen on ultrasonography was due to a haemostatic effect or stabilisation of intravascular volume by FFP. We undertook a trial of 776 babies of gestational age at birth less than 32 weeks to look at the short term and long-term outcome after early prophylactic FFP. METHODS: The defined primary trial outcome was survival without identifiable major disability 2 years after birth. The babies were randomly allocated, within 2 h of birth, 20 mL/kg FFP followed by a further 10 mL/kg after 24 h; or the same volumes of a gelatin based plasma substitute; or maintenance infusion of glucose (control). The three groups were similar at trial entry. Outcome at discharge from hospital after birth (reported elsewhere) was similar in the three groups. FINDINGS: No child was lost to follow-up, and all the surviving children underwent neurological and developmental assessment at the age of 2 years. The proportions dying (21.0%, 24.9%, 20.5%), and the proportions of survivors with a severe disability (11.3%, 11.2%, 14.1%) did not differ significantly between the randomised groups. The survivors had similar mean developmental quotients at age 2 (Griffiths' quotients 94, 97, and 95). INTERPRETATION: This trial provides no evidence that the routine early use of FFP, or some other form of intravascular volume expansion, affects the risk of death or disability in babies born more than 8 weeks before term. PMID- 8684201 TI - Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. AB - BACKGROUND: Lesion and neuroimaging studies suggest that left prefrontal lobe dysfunction is pathophysiologically linked to depression. Rapid-rate transcranial magnetic stimulation (rTMS) to prefrontal structures has a lateralised effect on mood in normal volunteers, and several preliminary studies suggest a beneficial effect of rTMS on depression. However, adequately controlled studies have not been conducted. METHODS: We have studied the effects of focal rTMS on the depressive symptoms in 17 patients with medication-resistant depression of psychotic subtype. The study was designed as a multiple cross-over, randomised placebo-controlled trial. Sham rTMS and stimulation of different cortical areas were used as controls. FINDINGS: Left dorsolateral prefrontal cortex rTMS resulted in a significant decrease in scores on the Hamilton depression rating scale HDRS (from 25.2 to 13.8) and the self-rated Beck questionnaire BQ (from 47.9 to 25.7). 11 of the 17 patients showed pronounced improvement that lasted for about 2 weeks after 5 days of daily rTMS sessions. No patient experienced any significant undesirable side-effects. INTERPRETATION: Our findings emphasise the role of the left dorsolateral prefrontal cortex in depression, and suggest that rTMS of the left dorsolateral prefrontal cortex might become a safe, non convulsive alternative to electroconvulsive treatment in depression. PMID- 8684202 TI - Yelling attacks and wasted hands. PMID- 8684203 TI - Changing the natural history of HIV disease. AB - Our understanding of the pathogenesis of AIDS has advanced considerably since the disease was first reported 15 years ago. We now know that the primary damage inflicted by HIV-1 is mainly brought about by active virus replication. With the advent of sensitive tools for monitoring HIV replication in vivo, an individual's risk of disease progression can be assessed early in the course of the infection and the efficacy of antiviral therapies can now be determined accurately and expeditiously. When used appropriately, potent combinations of antiviral drugs seem to be able to circumvent the inherent tendency of HIV-1 to generate drug resistant viruses, the main reason for failure of all antiviral therapies, and are significantly more effective than earlier approaches. For the first time, rational approaches to contain and perhaps eliminate HIV-1 infection can be pursued. PMID- 8684204 TI - HIV and the paediatrician as the child's advocate. PMID- 8684205 TI - Salt--more adverse effects. PMID- 8684206 TI - Think fungus in HIV-infection. PMID- 8684207 TI - Coronary stents--open choices for closed arteries. PMID- 8684208 TI - UK human growth-hormone cover up. PMID- 8684209 TI - Tumour marker levels during marimastat therapy. PMID- 8684210 TI - Endoscopic sphincterotomy with gallbladder left in situ versus open surgery for common bileduct calculi. PMID- 8684211 TI - Endoscopic sphincterotomy with gallbladder left in situ versus open surgery for common bileduct calculi. PMID- 8684212 TI - Endoscopic sphincterotomy with gallbladder left in situ versus open surgery for common bileduct calculi. PMID- 8684213 TI - Whole-body metabolic map with positron emission tomography of a man after running. PMID- 8684214 TI - CD44 variants in ulcerative colitis and Crohn's disease. PMID- 8684215 TI - Ginseng as cause of Stevens-Johnson syndrome? PMID- 8684216 TI - Prevention of rubella. PMID- 8684217 TI - Mucosa-associated lymphoid tissue lymphoma of the oesophagus. PMID- 8684218 TI - Regression of salivary gland MALT lymphoma after treatment for Helicobacter pylori. PMID- 8684219 TI - The causes of diabetes. PMID- 8684220 TI - Medicine and the media. PMID- 8684221 TI - Medicine and the media. PMID- 8684222 TI - Medical evacuation in war-torn countries. PMID- 8684223 TI - Arts courses for students and clinicians. PMID- 8684224 TI - Defining "enzyme unit" correctly. PMID- 8684225 TI - Carriage of pneumococci after pneumococcal vaccination. PMID- 8684226 TI - Thrombolysis for acute MI. PMID- 8684227 TI - Blastocystis hominis infection. PMID- 8684228 TI - Metronidazole to clear intestinal parasites. PMID- 8684229 TI - Ticlopidine and renal function. PMID- 8684230 TI - Birthing pools and infection control. PMID- 8684231 TI - Birthing pools and infection control. PMID- 8684232 TI - Birthing pools and infection control. PMID- 8684233 TI - HCV and lymphomagenesis. PMID- 8684234 TI - Long-term tacrine treatment in patients with Alzheimer's disease. PMID- 8684235 TI - All is not what it seems. PMID- 8684236 TI - Laser tissue welding: a comprehensive review of current and future clinical applications. AB - Laser techniques for joining tissue, in combination with other surgical technologies, will be a hallmark of surgery in the next century. At present, there are many clinical applications of tissue welding and soldering which are beginning to achieve wide spread acceptance. These exciting clinical developments are the result of many advances which have been made in the past few years in our understanding of the mechanism of laser tissue welding. Also contributing to this progress are many important technical refinements such as tissue solders and feedback control of the laser device. In this article, we describe in depth the history and development of laser tissue welding including key theoretical concepts as well as crucial experiments which have added to our insight into this phenomenon. We also review the evolving concepts of its clinical application and indicate clinical applications which are likely to become more important in the future. PMID- 8684237 TI - Spectroscopic diagnosis of bladder cancer with elastic light scattering. AB - BACKGROUND AND OBJECTIVES: Recently, significant progress has been made toward the development of optical, noninvasive medical diagnostics. The goal of this study was to evaluate elastic scatter measurements as a tool for diagnosing bladder cancer. STUDY DESIGN/MATERIALS AND METHODS: In vivo measurements on 10 patients with suspected bladder cancer were made with the optical biopsy system (OBS) developed at Los Alamos National Laboratory. Elastic-scatter spectra over the wavelength range 250-800 nm were obtained using a fiber-optic probe through one of the lumens of a urological cystoscope. Measurements were made on putatively normal areas and areas of uncertain abnormality, as well as those suspected to be cancerous. After measurements were made with the OBS, biopsy samples were taken at the measurement sites. Comparisons of the histopathology and the optical spectra were then made. RESULTS AND CONCLUSIONS: A diagnostic algorithm for distinguishing malignant from nonmalignant tissue based on the values of the slopes over the wavelength range 330-370 nm has a sensitivity of 100% and specificity of 97% for the limited number of patients in this study. PMID- 8684238 TI - Transurethral balloon laser prostatectomy in the canine: medium-term, follow-up results. AB - BACKGROUND AND OBJECTIVE: To demonstrate surgical complications in transurethral balloon laser prostatectomy by medium-term, follow-up observation. STUDY DESIGN/MATERIALS AND METHODS: Three dogs were treated with transurethral laser irradiation using 15 watts for 20 minutes at 60 degrees C at a 5 mm depth of the prostate, one dog was for 5 minutes with same parameters, and one dog was with only laser balloon probe as a control. All animals were followed for 24 weeks. RESULTS: A large cavity in the prostatic urethra was formed in laser-treated animals 4 weeks later, whereas the cavity in the balloon-treated animals was not shown. Cavity volume did not significantly change for 6 months, and there was no bladder neck stricture or urethral stenosis observed in any case. An increase in collagen fibers in the periurethral tissue was barely observed by Mallory staining. CONCLUSION: The risk of bladder neck stricture and urethral stenosis was estimated to be low for transurethral balloon laser prostatectomy. PMID- 8684239 TI - Transurethral Nd:YAG laser prostatectomy with a laterally firing fiber: local effects on tissue associated with erectile dysfunction. AB - BACKGROUND AND OBJECTIVES: Transurethral laser prostatectomy is anticipated to become a recognized alternative to conventional transurethral resection of the prostate. However, the effects of this procedure on the nerves of the pelvic plexus and erectile dysfunction remain unaddressed. The objective of this study was to evaluate the effects of laser energy on extent of prostatic damage as well as injury to periprostatic cavernosal nerves and erectile dysfunction in a canine model. STUDY DESIGN/MATERIALS AND METHODS: Six adult male mongrel dogs underwent transurethral laser prostatectomy at 30 (n = 3) and 40 (n = 3) watt power settings. Total laser energy delivered varied between 6,000 and 13,800 joules. Erectile function was evaluated by pelvic nerve stimulation at 2, 4, and 8 weeks. Animals were then sacrificed to assess histopathology of the prostate at each time point. RESULTS: Histopathologic changes were noted in the prostate in a dose dependent manner and did not vary with different laser power settings. In dogs that received approximately 10,000 J, substantial prostate ablation confined within the capsule was achieved in every prostate gland. Adequate erectile responses were noted in five of six animals; all received < 10,000 J. In one animal that received a total dose of 13,800 J, an erectile response was not obtained, and histology revealed both prostatic capsule perforation in close proximity to the cavernous nerves and thermal neural damage. CONCLUSIONS: We conclude that cavernous nerve damage may result from excessive doses of laser energy during transurethral laser treatment of the prostate gland. In canines, the upper limit for periprostatic injury is between 10 and 14,000 joules. PMID- 8684240 TI - Reduced in vivo local recurrence with contact neodymium: Yttrium-Aluminium-Garnet (Nd:YAG) laser scalpels. AB - BACKGROUND AND OBJECTIVE: Local recurrence after surgical resection for breast cancer is a significant problem and is often not controlled by radiation or chemotherapy treatments. Local recurrence is thought to be, at least in part, due to residual disease, and/or due to the contamination of the surgical field during resection. STUDY DESIGN MATERIALS AND METHODS: To address this later concern, we defined a model system using the mouse mammary cell line, EMT6. Using this model system, we have directly compared the rate of local recurrence of two different surgical approaches. One approach employed the use of traditional surgical instruments, and the other used a comparatively new contact Nd:YAG laser system. Tumor-bearing animals (242) were randomized into three groups. One group consisted of 50 animals that were not treated; 103 animals were randomized into a treatment group that received surgical resection using traditional instruments; 89 animals were resected using the contact laser system. In both surgical procedures, an intentional incision was made through the tumor and then through an uninvolved portion of the surgical field in an attempt to "seed" the incision using the contaminated surgical instrument. RESULTS: Twenty-one of the 103 scalpel-treated animals had local recurrence; only seven of the 89 laser-treated animal had local recurrence. The untreated group died of disease within 8 weeks. In the treatment groups, recurrences were palpable within 1 week. At the time of death for all groups, no metastatic lesions were noted. CONCLUSION: These findings support the conclusions that the EMT6 cell line is a useful model to study local recurrence and that contact laser surgery provides about a 50% improvement in the control of local disease in vivo (P < 0.05). PMID- 8684241 TI - Laser-assisted removal of a foreign body in the bronchial system of an infant. AB - BACKGROUND AND OBJECTIVE: Foreign body aspiration is an important cause of acute respiratory distress in children. Removal by use of rigid tracheobronchoscopy under general anesthesia is usually the treatment of choice, but this technique is sometimes unsuccessful. Thoracotomy in these instances often cannot be avoided. STUDY DESIGN/PATIENTS AND METHODS: Case report with review of the literature. The patient was 19 months old with an aspirated foreign body. A Neodym:YAG laser with a special small-size delivery system was inserted into the rigid "baby" bronchoscope. The Neodymium:YAG laser with a wave-length of 1,064 nm and a Helium-Neon 630 nm light guide provided an aiming beam to weaken and cut the aspirated chicken bone. RESULTS: The foreign body could be easily removed with a regular biopsy forceps. CONCLUSION: We discuss a patient in whom laser assisted rigid tracheobronchoscopy obviated the need for thoracotomy. PMID- 8684242 TI - [Leiomyosarcoma of the stomach]. AB - A 35-year old woman showed gastrointestinal bleeding right after normal pregnancy. With endoscopy of the GI-tract with biopsy, ultrasound, conventional radiology of the stomach and computed tomography a gastric leiomyoma was diagnosed. After en-bloc resection of tumor, part of the stomach and spleen, histologic examination and size of tumor changed diagnosis in gastric leiomyosarcoma. Patient died 15 month postoperatively on systemic metastasis. Case report and review of the literature show difficulties in diagnosis and prognosis of gastric leiomyosarcoma. PMID- 8684243 TI - [Acute abdomen in abdominal actinomycosis]. AB - The case of a female patient aged 34 suffering from abdominal actinomycosis is reported. She underwent emergency surgery for an abscess-forming tumour infiltrating the lateral abdominal wall and giving rise to the clinical picture of acute abdomen. The casuistry is complemented by two further case histories of actinomyces infections in patients with fistulas of the anal region and pilonidal sinus respectively. Abdominal actinomycosis presents itself as a rare chronic bacterial inflammation, usually located in the right lower abdomen, with local abscess or fistula formation as well as tumour-like infiltration of the surrounding tissues. Exceptionally, the diagnosis is ascertained prior to surgery. Postoperative antibiotic therapy with penicillin for several months ist essential. PMID- 8684244 TI - [Expert consultation. Prolonged elevation of transaminase concentration]. PMID- 8684245 TI - [Bleeding peptic ulcers--concept for acute therapy]. PMID- 8684246 TI - ["Deficient" grade for quality of gastrointestinal diagnosis in Germany?]. PMID- 8684247 TI - [Differential surgical procedure in curative therapy of stomach carcinoma]. AB - The principle of histology-and stage-oriented cancer treatment generally adopted in modern oncology is realizable and desirable also in surgery for stomach carcinoma. Instead of a single standard operation for all gastric carcinomas surgical procedure should be individualized. Curative local therapy as endoscopic polypectomy or mucosal resection or laparoscopic intraluminal surgery is possible only in a limited number of patients. In all other patients radical resection is indicated, either as subtotal distal gastrectomy or as total gastrectomy, if necessary with extension to adjacent organs. The radical resection includes a radical lymphadenectomy (D2 dissection). Its extent should be adapted to the individual situation by consideration at least of tumor site. Preferable is the use of a pretherapeutic computer model which calculates the probability of metastasis to the various lymph node groups considering additional factors with influence on lymphatic spread. PMID- 8684248 TI - [Adenocarcinoma of the esophagogastric junction: association with Barrett esophagus and gastroesophageal reflux--surgical results in 122 patients]. AB - OBJECTIVE: To investigate the surgical results of adenocarcinoma of the esophagus and esophagogastric junction and its relationship with gastroesophageal reflux disease (GERD) and Barrett's esophagus. BACKGROUND: The incidence of adenocarcinoma of the cardia is continuously rising. Specialized intestinal metaplasia in Barrett's esophagus seems to be the source of these tumors. Barrett's esophagus is end stage GERD. In experimental studies alkaline reflux give rise of Barrett's esophagus and adenocarcinoma. PATIENTS: 122 patients with adenocarcinoma of the cardia and 121 patients with squamous cell tumor of the esophagus. METHODS: All esophageal resections between 11/85 and 2/95 were retrospectively analyzed. The relationship of gastroesophageal reflux disease, Barrett's esophagus and malignancy was compared between both groups using parameters of case history and histological sections. Survival was analyzed for tumorstage, T-and N-stage and R-classification. RESULTS: 5.9% of the adenocarcinomas were stage I, 44.1% stage II, 41. 5% stage III and 8.5% stage IV. Heartburn, regurgitation, consumption of H2 blockers or Barrett's mucosa were significantly more frequent for adenocarcinomas. A 5 year survival of 100% was seen for stage I tumors. Invasion of t he muscular layer reduced survival to 50%, lymph node invasion to 20%. R0-resection had a survival of 40%. CONCLUSIONS: A relationship of GERD and adenocarcinoma of the cardia seems to be likely in our cases. Most patients had advanced malignancy. Survival is good only for early cases. Prevention of tumor genesis with effective antireflux surgery in case of alkaline reflux seem to be the best therapeutic decision. PMID- 8684249 TI - [Gastroesophageal reflux--surgical indications, laparoscopic surgical technique, results]. AB - OBJECTIVE: To investigate criteria for indication to surgery and results of laparoscopic fundoplication. BACKGROUND: Gastroesophageal reflux is a common problem in well developed countries. Beside clinical symptoms of heartburn and regurgitation complications may occur like esophagitis, bleeding, ulceration, mucosal metaplasia and loss of motility. A connection of reflux disease, Barrett's esophagus and adenocarcinoma of motility. A connection of reflux disease, Barrett's esophagus and adenocarcinoma of the esophagogastric junction is discussed. In some patients medical treatment is complicated by relapse, persistent or progressive disease. For these patients laparoscopic antireflux surgery may be an effective alternative. PATIENTS: 22 patients with chronic gastroesophageal reflux disease. METHODS: Since 9-2-1922 patients with gastroesophageal reflux disease were prospectively evaluated and treated by laparoscopic Nissen fundoplication. RESULTS: 11 patients had frequent recurrent disease, 9 persistent reflux and 2 a stricture while on medical treatment. All had pathologic reflux on 24 hour pH monitoring and defective sphincter on standard manometry. Beside an intraoperative pneumothorax there was no intraoperative complication. Postoperative 2 patients had a temporary and 1 mild persisted dysphagia. None had recurrent reflux. 10 patients were reevaluated one year after surgery. None had an esophagitis, abnormal reflux or an insufficient or hypercontinent sphincter. CONCLUSIONS: Patients with recurrent or persistent reflux while on medical treatment with abnormal reflux on pH monitoring and defective sphincter on manometry can be treated by laparoscopic Nissen fundoplication with good results. PMID- 8684250 TI - [Does chronic alcohol drinking modify digestive gastrobiliary motility?]. AB - In 23 chronic alcoholics and 23 controls gastric emptying, antral motility, fasting gallbladder volume and gallbladder emptying after a standardized, liquid fatty meal were investigated ultrasonically in order to assess the effect of chronic alcoholism on postprandial gastrobiliary motility. Only a subgroup of the alcoholics with signs of autonomic cardiovascular neuropathy (21.7%) exhibited a significant antral hypomotility and a tendency towards higher fasting gallbladder volumes. No significant differences between the study groups could be obtained for the other parameters. The duration and daily amounts of alcohol consumption were not significant different between patients with autonomic neuropathy and patients without autonomic neuropathy. Within the whole group of alcohol consumers the only significant correlation that was observed occurred between the fat induced gallbladder residual volumes and the amounts of daily alcohol consumption (r = 0.62, p < 0.05). However 19 of these 23 relative gallbladder residual volumes were within the normal range (95. percentile of the control group), indicating no major clinical relevance of this phenomenon. None of the motility parameters exhibited a significant correlation to the duration of alcohol consumption. From these results chronic alcohol consumption has no irreversible effects of clinical relevance on the postprandial gastrobiliary motility in the majority of patients in contrast to well documented reversible effects of acute alcohol consumption on gastric motility. PMID- 8684251 TI - Nerve function impairment in leprosy: an epidemiological and clinical study--Part 2: Results of steroid treatment. AB - This retrospective cohort study aimed to determine the progress of sensory and motor function during and after steroid treatment, and to identify any prognostic factors for the outcome of treatment. The study used one hundred and sixty-eight leprosy patients registered at Green Pastures Hospital, Pokhara, West Nepal, who were treated with one of four different corticosteroid regimens for impairment of nerve function. The function of the main peripheral nerve trunks affected in leprosy was assessed with a nylon filament to test touch thresholds (TST) and a manual voluntary muscle test (VMT) to quantify muscle strength. The TST and VMT scores at 3 months after initiation of steroid treatment served as the main outcome measure. The significance of potential prognostic factors was evaluated with logistic regression. At 3 months, the sensory and motor function of the majority of patients with 'recent' impairment ( = less than 6 months duration) had improved significantly (p < 0.01, Wilcoxon matched pairs signed-ranks test). The likelihood of 'good' recovery (prognosis) for both sensibility and motor function was directly related to the severity of the nerve damage at the beginning of treatment. Although nerve function improved in 30-84% (depending on the type of nerve) of patients, an active search for better methods of treatment and improved regimens is justified. The need for early assessment and treatment is stressed. PMID- 8684252 TI - Correlation of skin and nerve histopathology in leprosy. AB - Discrepancies have been noted in the histopathological findings between skin and nerve lesions of leprosy patients in some recent works. We studied concurrent skin and nerve biopsies in 27 randomly selected leprosy patients to correlate the histopathological features of skin and nerve lesions, and to assess the importance of neural histology in the classification of leprosy. Skin and nerve biopsies were diagnostic of leprosy in 23 and 26 patients, respectively. A discrepancy was found between the two in 15 cases. Neural histology was helpful in the classification of determinate forms in 24 cases while dermal histology was significant only in 16 patients. A multibacillary nerve and paucibacillary skin picture was observed in 3 patients. It was concluded that nerve biopsy is more informative and specific than skin biopsy in the diagnosis of leprosy and further helps to classify the patients when the skin histology is indeterminate or nonspecific. PMID- 8684253 TI - Long-term follow-up of joint stabilization procedures in the treatment of fixed deformities of feet in leprosy. AB - This retrospective study of 52 patients, who underwent joint stabilization procedures for static deformities of the feet in leprosy between 1971 and 1985, was undertaken to asses the long-term results of joint stabilization of feet for fixed deformities in leprosy. The main purpose of joint stabilization is to make the feet plantigrade for weight bearing and to make the wearing of footwear possible. Deformities corrected include varus, equinus and equinovarus. Chronic ulceration occurs repeatedly if these deformities are not corrected and leads to inevitable bone destruction and eventual amputation. PMID- 8684254 TI - Active surveillance in leprosy: how useful is it? AB - In this paper, active surveillance is compared with self-reporting as a method of detecting new nerve function loss in leprosy patients who have completed multidrug therapy (MDT). Five hundred and three patients were selected according to new surveillance guidelines in one part of the Danish-Bangladesh Leprosy Mission leprosy control project working area. Surveillance coverage of 71% was achieved in a 7-month period. During this time, 10 released-from-treatment (RFT) patients from among the study group were found to have acute nerve damage requiring prednisolone treatment. Out of the 10, only 2 were detected actively; the remaining 8 self-reported. It is concluded that health education given at RFT time is effective in motivating patients to self-report with acute nerve damage, and that the time spent on active surveillance could have been better used in other activities, i.e., case detection. As a result of these findings, active surveillance has been abandoned in the leprosy control project. PMID- 8684255 TI - Dry skin lesions with marked hair loss in a case of BL leprosy. A case report. AB - Skin lesions of leprosy that are anaesthetic, well defined, limited in number and dry with significant hair loss generally fit into the paucibacillary (PB) spectrum. The bacteriological index (BI) is expected to be negative or low. We have reported a case who presented with such findings but whose BI readings were high. Together with the biopsy findings the patient was classified as having borderline (BL) leprosy. The role of the skin smear examination and the misleading nature of some clinical features are highlighted. The authors feel that skin smear examinations should be performed on all leprosy patients at the time of diagnosis. PMID- 8684256 TI - Case report: cutaneous lymphoma and borderline leprosy simulating lepromatous leprosy. PMID- 8684257 TI - Comment: training in leprosy: the training needs for Africa, and the role of large training institutions. PMID- 8684258 TI - Diagnosis and management of single lesions in leprosy. PMID- 8684259 TI - Antisphingolipid antibodies in the sera of leprosy patients. AB - Earlier we reported the presence of significant levels of antigalactocerebroside (GalC) antibodies in the sera of leprosy patients. This study corroborates the above result and also gives evidence for the presence of antibodies to the nonpolar ceramide (Cer) moiety of GalC. AntiCer antibody titres were higher as compared to antiGalC antibodies in all categories of leprosy. The specificity of antibodies directed to the Cer moiety was confirmed using Lactosyl-BSA and neutralization assays. Statistically significant and positive correlations were observed between antiGalC and antiCer antibodies. Responsiveness factors were computed using natural logarithmic transformation of the variables. PMID- 8684260 TI - [MPR14]-rADM(14-50), a novel analog of adrenomedullin, possesses potent vasodilator activity in the hindlimb vascular bed of the cat. AB - Responses to [Mpr14]-ADM(14-50), a novel analog of adrenomedullin, were investigated in the hindlimb vascular bed of the cat under conditions of controlled blood flow. Intraarterial injections of [Mpr14]-rADM(14-50) in doses of 0.003-1 nmol caused dose-related decreases in hindlimb perfusion pressure. In terms of relative vasodilator activity, [Mpr14]-rADM(14-50) was more potent than human synthetic adrenomedullin (hADM) in doses of 0.003-0.1 nmol. The recovery half-times (T 1/2) for the vasodilator response to [Mpr14]-rADM(14-50) were significantly greater than the recovery half-times for hADM in all doses studied. Decreases in hindlimb perfusion pressure in response to [Mpr14]-rADM(14-50) were not altered by the calcitonin gene-related peptide receptor antagonist rCGRP(8 37) at the same time vasodilator responses to calcitonin gene-related peptide were significantly reduced. The present data demonstrate that [Mpr14]-(14-50) has potent and long-lasting vasodilator activity when compared to hADM, and that vasodilator responses to [Mpr14]-rADM(14-50) are not dependent on the activation of CGRP receptors in the hindlimb vascular bed of the cat. PMID- 8684261 TI - Resveratrol promotes atherosclerosis in hypercholesterolemic rabbits. AB - The hypothesis was tested that resveratrol, a compound in red wine, would inhibit atherosclerotic development in rabbits fed 0.5% cholesterol for 60 days. Rabbits were supplemented with or without oral resveratrol. During the study, body weights and food consumption were similar for the two groups. The lack of differences between liver weights and a series of serum parameters indicative of liver disease suggest that liver function was similar in the two groups. The diet produced hypercholesterolemia in both groups, but no differences in lipoprotein cholesterol concentrations. The electrophoretic mobility of plasma low-density lipoprotein (LDL) and plasma LDL after induced oxidation also was not different between the groups. Staining of atherosclerotic lesions in the control and resveratrol-treated groups revealed that the resveratrol-treated rabbits had significantly more aortic surface area covered by atherosclerotic lesions (P < 0.02). Therefore, resveratrol promoted atherosclerotic development, rather than protect against it, by a mechanism that is independent of observed differences in gross animal health, liver function, plasma cholesterol concentrations, or LDL oxidative status. PMID- 8684262 TI - Orphanin FQ: receptor binding and analog structure activity relationships in rat brain. AB - A tritiated form of orphanin FQ (a heptadecapeptide also known as Nociceptin) has been prepared. This radioligand (33 Ci/mmole) was used to develop a radioreceptor assay using rat brain homogenates. Binding was observed to be saturable, and analyses of the binding data indicate the presence of a single binding site with a dissociation constant of 5 +/- 1.1 nM and Bmax of 535 +/- 85 fmoles/mg protein. Thirty-four analogues of orphanin FQ, including a complete alanine "scan" of orphanin FQ, and truncation analogues from both the N- and C- terminals were synthesized and tested. The data obtained indicate that the N-terminus plays a more critical role in binding than the C-terminus and that residues 1, 2, 4, and 8 are essential for binding. PMID- 8684263 TI - Age associated decrements in dopamine D2 receptors in thalamus and in temporal insula of human subjects. AB - This study evaluates the effects of age on DA D2 receptors in extrastriatal regions. DA D2 receptor availability was evaluated in 42 healthy male subjects (mean age 41 +/- 16, range 21 - 86 year old) with positron emission tomography (PET) and [11C]raclopride. Estimates of Bmax/Kd were obtained using the ratio of the distribution volume in the region of interest (caudate, putamen, thalamus, frontal, occipital cortices, temporal insula, cingulate and orbitofrontal gyri) to that in cerebellum. Correlations between age and D2 receptors were significant in putamen (r = -0.58, p < or = 0.0001), caudate (r = -0.54, p < or = 0.0002), thalamus (r = -0.33, p < or = 0.03) and temporal insula (r = -0.39, p < or = 0.01) but not in any of the frontal regions. The decrease in DA D2 receptor availability was 6.6% per decade in caudate, 8.2% in putamen, 7.6% in thalamus and 13% in temporal insula. This study indicates that D2 losses with age are not limited to striatum and involve also thalamic as well as temporal cortical regions. PMID- 8684264 TI - Methylprednisolone and isoproterenol inhibit airway smooth muscle proliferation by separate and additive mechanisms. AB - To determine whether glucocorticoids and beta-adrenoceptor agonists act independently to inhibit airway smooth muscle (ASM) proliferation, the present study investigated the effects of methylprednisolone (MP) and isoproterenol (ISO) alone and in combination on leukotriene D4-induced ASM proliferation. MP and ISO had no effect on unstimulated ASM cell growth. In contrast, MP and ISO demonstrated dose-dependent inhibition of LTD4-induced proliferation, and the inhibitory effect was additive for combinations of MP and ISO. The competitive cAMP receptor antagonist, Rp-cAMPS, ablated the ISO-induced inhibition but had no affect on the inhibitory response to MP. In cells exposed to both ISO and MP, Rp cAMPS attenuated the growth inhibition to levels achieved by MP alone. Accordingly, these findings demonstrate that glucocorticoids and beta-adrenergic agonists inhibit LTD4-induced ASM proliferation, and that their inhibitory effects are mediated by different signaling pathways. PMID- 8684265 TI - Sex steroid hormones and macrophage function. AB - Macrophages are versatile cells whose activities are programmed by environmental signals. In this review, we discuss the potential impact of sex steroid hormones on macrophage activation and production of various effector molecules. The evidence accumulated to date supports the postulate that estrogens, progesterone, androgens and testosterone profoundly influence host defense by controlling the ability of macrophages to participate in immune responses. PMID- 8684266 TI - Alpha 1-antitrypsin activity in subarachnoid hemorrhage. AB - An altered equilibrium of protease/protease-inhibitor factors may be involved in the pathogenesis of aneurysm rupture: alpha 1-antitrypsin (alpha 1-AT) represents the most relevant inhibitor of elastase, a proteolytic enzyme enhancing catabolic processes of collagen metabolism. In the present study we test the hypothesis whether the activity of alpha 1-AT is altered in SAH patients; 5 cases with unruptured intracranial aneurysm and 27 patients with diagnosis of aneurysm SAH were included in the study. Blood samples were obtained immediately at admission. As control samples we consider the 5 cases of unruptured aneurysm, 15 cases of unruptured aortic aneurysms and 10 patients with non-vascular CNS diseases. Measurement of alpha 1-AT level was determined by immunoturbidimetric method. Serum levels of alpha 1-AT are significantly lower in patients admitted within 72 hours after SAH, if compared to patients admitted in a delayed phase. The linear relationship between alpha 1-AT and collagenase inhibitory percentage capacity (CIC) was shown to be different in the 4 subgroups considered, and so were the mean % CIC values in the between-groups comparison, except for unruptured aneurysm vs controls. The alpha 1-AT CIC in patients with SAH is shown to be the lowest when compared to controls and unruptured aneurysms (p = 0.0001). PMID- 8684267 TI - Progesterone induces vascular endothelial growth factor on retinal pigment epithelial cells in culture. AB - Diabetic retinopathy is known to frequently deteriorate during pregnancy but the cause remains obscure. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a potent vascular endothelial cell mitogen which is mainly up-regulated by hypoxia, and is closely associated with the development and progression of diabetic retinopathy. To examine the influence of the drastic hormonal alterations during pregnancy on the worsening of diabetic retinopathy, we examined the effects of estradiol (E2) and progesterone (P4) on the production of VEGF/VPF in bovine retinal pigment epithelial cells in culture. The VEGF/VPF production was significantly elevated (214.5 +/- 28.3 ng/g protein, P < 0.01) by 48 h of exposure to a high concentration of P4(10 microM), which is still within the physiological range during pregnancy, compared to that of the control group (147.7 +/- 17.9 ng/g protein). However, E2 significantly stimulated the production of VEGF/VPF only at concentrations (100 microM) much higher than normally encountered during pregnancy. These two hormones were not observed to have a synergistic effect, at least at physiological concentrations. As the increase in serum P4 levels during pregnancy is reported to be greater in pregnant diabetic patients with progressive retinopathy, our findings suggest that P4 may contribute to the worsening of diabetic retinopathy during pregnancy by up-regulating intraocular VEGF levels. PMID- 8684268 TI - Gonadotroph function in 3-week-old gilts reared in a warm or cool thermal environment. AB - The present study evaluated the effect of a warm (cycling 27-32 degrees C, 50-70% RH) or cool (21 degrees C, 55% RH) thermal environment (TE) on gonadotroph function in 3-week-old gilts (females). Pituitary cells from twelve gilts reared in each TE were cultured at a density of 250,000 cells/1 ml well and exposed to vehicle (culture medium); 1,1, and 10 nM gonadotropin-releasing hormone (GnRH); 2 mM 8-Br-cAMP (cAMP); and 100 nM phorbol myristate acetate (PMA). Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion in culture were stimulated by GnRH and by pharmacological compounds (p < .0001). In vitro LH secretion was approximately three-fold higher in the warm, compared to the cool, TE group (p < .0001). Similarly, cellular LH content in the warm TE exceeded that in the cool TE (p < .005). The in vitro secretion of FSH and cellular FSH content were significantly elevated in the warm TE (p < .02). Serum LH concentrations in the warm and cool TE were 7.01 +/- 1.75 and 2.13 +/- .44 ng/ml, respectively (p < .02). Serum FSH concentrations were 6.38 +/- .53 and 4.59 +/- .28 ng/ml in the warm and cool TE, respectively (p < .01). The results of this study demonstrate that secretory responses of gonadotrophs in early postweaning pigs are influenced by chronic TE exposure. These differences in secretory activity may reflect levels of cellular gonadotropin available for release. PMID- 8684269 TI - An attenuated alpha-1 potentiation of beta adrenoceptor-stimulated cyclic AMP formation after repeated saline injections in Fischer 344 strain rats. AB - We investigated the behavioral and neurochemical features of Fischer 344 strain rats in which a depressive state was induced by repeated handling and saline injections as a mild stressor. The repeated intraperitoneal injections of saline (2 ml/kg, twice a day for 14 days) elicited a moderate suppression of body weight gain, a decrease in their open field activity and a prolonged immobility in the tail suspension test. In the stress-exposed rats, the tissue content of norepinephrine (NE) was increased in the cerebral cortex and hypothalamus, whereas that of dopamine or serotonin was not affected. Although the stress exposure did not affect the binding properties of either the alpha-1 or beta adrenoceptors, it suppressed cAMP formation stimulated by NE, but not by isoproterenol or forskolin, in the cerebral cortical slices. In the presence of prazosin or phorbol ester, the difference in NE-stimulated cAMP formation between the control and the stress groups was totally abolished. Phenylephrine enhanced isoproterenol-stimulated cAMP formation in the control but not in the stress group. From these results, it is postulated that the alpha-1 potentiation of beta adrenoceptor- stimulated cAMP formation was attenuated in the stress group. These findings suggest that the manipulation of mild stressor with repeated handling and saline injections to Fischer 344 rats elicits a depressive state characterized by the behavioral changes and the attenuated alpha-1 potentiation in the cerebral cortex, and that this manipulation might be available for the study of the stress-induced depressive state as a generally acceptable mild stress model. PMID- 8684270 TI - Glycosylated hemoglobin and fructosamines: does their determination really reflect the glycemic control in diabetic patients? AB - The present experiment was designed to determine whether scavenging capacity of serum, in addition to glucose level, influences hemoglobin and serum protein glycosylation in non-insulin dependent diabetic patients. For this purpose forty seven patients homogeneous for age, disease duration, therapy and glyco-metabolic control were selected. Fasting and post-prandial glycemia and insulinemia as well as glycosuria were weekly analysed during the sixty days preceding glycosylated hemoglobin (HbA1c), fructosamines and serum scavenging capacity determination. This last parameter has been evaluated by a method based on the property of beta phycoerythrin (beta-PE) to loss its fluorescence when damaged by oxygen radicals, that were produced by Cu++ and H2O2. The oxygen radical absorbance capacity (ORACOH) of serum was assayed as the ability of serum to delay the loss of beta PE fluorescence. As expected, a statistically significant positive correlation was found comparing both fructosamines and HbA1c levels with mean fasting glycemia measured over twenty and sixty days, respectively. The key result of this study is represented by the finding that both HbAlc and fructosamines levels show a statistically significant negative correlation with ORACOH values. This correlation can explain a large percent of the data dispersion occurring when ORACOH is not taken into account. In order to better describe the role of ORACOH, patients were separated into two sub-groups with an ORACOH lower (L-ORACOH) and greater (H-ORACOH) than 100 U/ml. Examining the correlation between mean fasting glycemia and the two glycosylated proteins considered in these two sub-groups, curves with different slopes were obtained, supporting that the rate of glycosylation of both proteins was higher in L-ORACOH patients as compared to those with H-ORACOH. Present data suggest that for a proper interpretation of the HbA1c and fructosamines data in diabetic patients, the scavenging capacity level of serum should be taken into account. PMID- 8684271 TI - The influence of ethanol exposure on insulin-like growth factor (IGF) type II receptors in fetal rat tissues. AB - The effect of ethanol (ETOH) exposure on the IGF type II receptor concentration was examined in 18 and 20 day fetal rat tissues. Pregnant dams were fed an ETOH (36% of calories derived from ETOH; 6.6% v/v) liquid diet. Control fetuses were offspring of dams either pair-fed a control liquid diet or ad libitum-fed a standard pelleted lab chow. Fetal brain, heart, kidney, liver, lung and skeletal muscle were removed and whole homogenates from individual animals were analyzed. Results of immunoquantification of IGF type II receptors in whole tissue homogenates show that there is a trend towards increased receptor concentration between 18 and 20 days in all tissue and this trend is significant for lung, liver and muscle. There were no significant differences in receptor concentration between treatment groups. These studies suggest that during the later stages of fetal development, there is an increase in total IGF type II receptors and this increase is undisturbed by ETOH exposure. PMID- 8684272 TI - A Brazilian issue. PMID- 8684273 TI - Keeve Brodman and the Cornell Medical Index. PMID- 8684274 TI - Roster maker. PMID- 8684275 TI - Synthesizing Shewhart and Shannon. Part 2. Reducing uncertainty. PMID- 8684276 TI - A microcomputer-based transplantation registry. AB - We describe a microcomputer-based program developed for the Brazilian Kidney Transplant Registry. The system can construct life tables and survival curves online, without the need to export the database. From 1987 through 1993, 6069 kidney transplants were reported; 3485 (57.4%) were from living donors and 2584 from cadavers. The proportion of cadaveric transplants increased from 28.5% in 1987 to 58.1% in 1993. Overall kidney transplantation activity was 8.1 patients per million population per year. Sixty-four percent of the patients were male, and 71% were white. The mean age was 33.4 years. The primary renal diseases most frequently reported were glomerulonephritis (43.6%) and hypertensive renal disease (13.6%). Only 3.6% of the recipients were diabetic. Patient and graft survival rates have improved in recent years. We expect that cadaveric organ procurement programs will continue to develop in our country, increasing the number of organ transplantations and creating a more equal distribution of cadaveric organs. PMID- 8684277 TI - Mathematical and computer models in epidemiology. PMID- 8684279 TI - Hycones: a hybrid approach to designing decision support systems. AB - Hycones II is a tool that facilitates the construction of hybrid connectionist expert systems to solve problems in classification. Hycones II provides a hybrid system that integrates frames with three types of neural network: the "combinatorial" neural model (CNM), the "Fuzzy ARTMAP" model, and the "Semantic ART" (SMART) model, a combination of the CNM and Fuzzy ART-MAP. We will compare the ability of these three models to solve diagnostic problems in two medical domains. PMID- 8684278 TI - Lossy compression techniques, medical images, and the clinician. AB - There has been increasing interest in the storage and retrieval of medical images in hospitals and clinics here in Brazil and elsewhere. At the Heart Institute of Sao Paulo, with thousands of image-based procedures performed each month, the pursuit of optimal transmission and storage methods for digital images is a major concern. The use of data-compression techniques can reduce the enormous amount of imaging data to be stored or transmitted across a computer network, so that the efficiency of the computing system is preserved. The techniques for image compression can be categorized as "lossless" or "lossy," with "lossy" techniques being those in which some, supposedly irrelevant information is lost. Lossy techniques are much more efficient than lossless ones, achieving data-compression ratios as high as 100:1. PMID- 8684280 TI - Using neural networks for processing biologic signals. AB - Artificial neural networks can represent and handle information by means of interconnected processing elements, in a manner similar to that of biologic neurons. Artificial neural networks are useful in processing time-patterned biologic signals, such as electrocardiograms and electroencephalograms, particularly in tasks involving pattern classification and recognition. They do not need to be programmed, since they are capable of learning. Using artificial neural networks to build associative memories and perform true parallel processing permits "intelligent" biomedical instrumentation. PMID- 8684281 TI - Interpretation of symptoms with a data-processing machine. 1959. AB - Recognizing that machines in the practice of medicine are here to stay, physicians have the obligation to learn as much of their advantages and limitations as they can comprehend. The machine described here merely correlates symptoms set down by the patient and draws conclusions on the basis of what it has "learned" from physicians. Hence it makes the same errors as the human brain which "taught" it plus others that are inherent in its inability to initiate the thinking process. One reviewer of the paper presented below asked this important question, "What is the character of the error when a diagnosis is made which is not correct? If a patient with flat feet is simply not so diagnosed, this is one type of error, but if the machine reads, ?respiratory tuberculosis inactive,' it's another." This and many other questions properly may arise. At the same time, the device is an extremely ingenious one and does eliminate the factors of emotional bias and fatigue, which may confuse the issue when a physician tries to analyze the complex of subjective complaints which the patient serves up to him. Whether the machine described here will have a place in the internists' armamentarium cannot be determined until more of them know about it. PMID- 8684282 TI - Guidelines from the consumer: improving consumer involvement in research and training for persons with mental retardation. AB - Consumer involvement of individuals with mental retardation in research and training was assessed. Twenty-two subjects with experience in research and/or training were interviewed to determine how professionals can encourage meaningful participation of persons with mental retardation in research and training activities. Results suggest that persons with mental retardation have participated in various roles in research and training but that there are many barriers to meaningful consumer involvement that have not been adequately addressed. Guidelines for professionals to foster meaningful consumer involvement in research and training activities were provided. PMID- 8684283 TI - The Community Living Attitudes Scale, Mental Retardation Form: development and psychometric properties. AB - We described the development and psychometric properties of the Community Living Attitudes Scale, Mental Retardation Form (CLAS-MR), a 40-item measure based on the input of self-advocates and focused on contemporary community living philosophies. The CLAS-MR, which consists of four subscales that tap attitudes about people with mental retardation, demonstrated acceptable internal consistency, retest reliability, and construct validity with samples of 104 college students and 283 community members. Using data from a sample of 355 staff members from community agencies, we confirmed the factor structure of the measure. Given the importance of attitudes toward persons with mental retardation in policy making and community inclusion, the CLAS-MR can help chronicle the diffusion of the new paradigm of empowered community living for persons with mental retardation. PMID- 8684284 TI - "This is your meeting": a qualitative study of person-centered planning. AB - Participant observation and in-depth interviews were conducted to determine processes involved in person-centered planning. Initial planning meetings of 6 individuals were studied in connection with a project to assist young adults in transition from school to adult life. The organization and structure, facilitation process, participation of families, professionals, friends, and the focal individual were described. Although the major goal of the project was to assure that this was the individual's own meeting, implementation of this principle was constrained in several ways, including facilitators' tendency to behave according to prior roles and training. Six months following initiation, several positive outcomes could be attributed to the planning process. Further, many unplanned positive outcomes appeared to result from person-centered planning. PMID- 8684286 TI - Preventable fraction of mental retardation: analysis based on individuals with severe mental retardation. AB - Reduction in the prevalence of mental retardation has been identified as a national goal since 1971. President Nixon proposed the year 2000 as a benchmark, by which time the prevalence of severe mental retardation should be reduced by as much as 50%. An analysis to determine the fraction of severe mental retardation that could be prevented with strategies currently available indicates that the goal will not be met. Knowledge of the causes of severe mental retardation is fundamental to developing prevention strategies. Increased diagnostic capability clinical and laboratory-must be dramatically increased if a 50% reduction in the prevalence of severe mental retardation is to be achieved in the foreseeable future. PMID- 8684285 TI - Psychoeducational support groups for aging parents: development and preliminary outcomes. AB - A psychoeducational support group program for aging parents (mean age = 65.3) of adult offspring with developmental disabilities was established with assistance from a focus group of practitioners and parents. We reported on the program's development, parents' self-reported objectives for participating in the program, as well as appraisals made by the parents and professional group leaders regarding process and outcome issues. We were also interested in whether parents who resided with their offspring (n = 17) experienced support groups differently than did parents with offspring who lived away (n = 13). Implications for developing and evaluating future interventions with this target population were discussed. PMID- 8684288 TI - Updating the epidemiology of asbestos disease. Symposium proceedings. Carpi, Italy, October 30, 1994. PMID- 8684287 TI - Beware the managed health-care companies. PMID- 8684289 TI - Mesothelioma as a risk indicator of asbestos exposure: the role of the pathologist. AB - Malignant mesothelioma is an uncommon tumour, which has become an important epidemiological marker for exposure to asbestos. This tumour is characterised by a wide range of microscopic features which may be classified in three histologic patterns: epithelial, mesenchimal and mixed or biphasic. Histochemical staining is often necessary to distinguish mesothelioma from carcinoma. As regards immunohistochemistry, only the use of a combination of antibodies significantly decreases the risk of false-negative results. Analytic electron microscopy techniques may also be useful, permitting the evaluation of the cumulative fiber burden in the target organ. PMID- 8684290 TI - Recent data on cancer due to asbestos in the U.S.A. and Denmark. AB - The Authors present data, from the USA and Denmark, dealing with the carcinogenicity of chrysotile. This review considers epidemiological studies on the incidence of bronchogenic carcinoma and mesothelioma in populations exposed to commercial chrysotile and to mixtures of chrysotile and commercial amphiboles, with which the chrysotile is often contaminated. The analyses demonstrate that the risk of lung cancer is similar for chrysotile, amosite and crocidolite on a fiber exposure basis. Chrysotile and amosite appear to produce equal mesothelioma risks. The risk of mesothelioma is four to ten times greater for crocidolite. PMID- 8684291 TI - Asbestos related disease in the United States. AB - In the United States workers are still exposed to asbestos, and particularly to chyrsotile, mainly in mines, in manufacturing of asbestos-containing products, and in construction, with the extent of exposure widely varying according to the job; familial exposure must also be taken into account. It is quite difficult to evaluate the entity of previous exposures, which have sometimes occurred 30-40 years ago. The risk furthermore varies according to the intensity of exposure and smoking habits. As far as allowed exposure levels are concerned, there is not homogeneity among the laws of different countries; above all it is no longer justifiable to regulate chrysotile differently than the amphiboles. PMID- 8684292 TI - Asbestos and cancer in Finland. AB - Primary prevention carried out today can reduce the disease incidence in the future decades. The present disease panorama is the consequence of past asbestos exposure mainly before the 1970s. The peak incidence of asbestos-induced diseases will be reached around 2010 in Finland. The number of asbestos-related premature deaths is at present annually about 150 which exceeds the figure of fatal work accidents. Asbestos-related cancer will increase still for 15-20 years and reach its maximum, about 300 cases, in 2010, and will start to decrease after that. More than 20,000 asbestos-exposed workers have participated in the medical screening and follow-up. The termination of exposure, antismoking campaigns, improved diagnostics and careful attention to compensation issues, as well as other potentials for prevention, were the central issue of the Asbestos Program of the Finnish Institute of Occupational Health. An important objective of research work is to improve early diagnostics, and thereby treatment prospects, in case of asbestos-induced cancers. PMID- 8684293 TI - Recent data on cancer due to asbestos in Sweden. AB - Asbestos exposure in Sweden rapidly grew in the '50s and '60s, and then began to drop at the beginning of the '70s. The number of pleural mesotheliomas due to this exposure increased to some 80 a year during the second half of the '80s, and is rapidly increasing. The jobs with the highest risk are the wood and pulp industry, plumbing, shipbuilding, and, most of all, railroad manufacturing and sugar refineries. Data dealing with peritoneal mesotheliomas are more uncertain, and possibly misleading. As far as lung cancer incidence is concerned, it remains high in plumbers and insulators, while it declined to the expected levels in the other categories of exposed workers. PMID- 8684294 TI - Recent data on cancer due to asbestos in Germany. AB - The Authors evaluate the risk of lung cancer and mesothelioma among asbestos workers in Germany. 3,988 workers (3,372 male and 616 female) were included in the study, which took into consideration the branch of the asbestos industry in which they had worked, the duration of their employment and also their smoking habits. At the end of the 12 year follow-up, 3,315 workers were alive and 673 dead. The analysis of cause of death showed an increased risk of dying from lung cancer and pleural and peritoneal mesothelioma, in men as well as in women. The risk was shown to be greatest among workers in the asbestos textile industry and among insulators. A probable multiplicative effect of asbestos exposure and smoking on lung cancer causation was noted. PMID- 8684295 TI - Chrysotile and crocidolite asbestos in Israel: uses, exposures and risks. AB - Importation of raw asbestos (90% chrysotile; 10% crocidolite) for manufacture of cement products and other uses, including friction materials and spraying, had dropped to under 3000 tons by 1993 from a peak of 10,000 tons per annum in the late 1970s. Drops in use, manufacture, persons exposed in manufacture and measured exposure levels followed heightened public concern over the carcinogenic effects of asbestos products, despite a relatively high worker exposure standard of 400,000 f/m3. The atypically low ratio of reported deaths from lung cancer compared to mesothelioma in asbestos cement workers up to 1992 (1:2.5) is suggested to be a consequence of low baseline risks for lung cancer mortality in Israel and dropping smoking levels. Exposure to asbestos use and asbestos in place remain, but total risk should drop after 2010 if imports continue to drop. These projections may be altered by trade between Israel and its neighbors following peace agreements. Reductions in risk will have resulted from reduction in exposure brought about by reductions in manufacture and use. PMID- 8684296 TI - The use of asbestos in Japan and China and malignancy related findings. AB - Asbestos use in industrialized countries is generally being curtailed, with the exception of Japan which, even if it is not a major producer, is now the world's largest user, and this use is still increasing. On the contrary, China is one of the major producers at world levels. The author refers data from the literature dealing with epidemiological, and also experimental, studies performed in these two countries, which confirm that asbestos produces mesotheliomas in man and laboratory animals. The author underlines the possibility of demonstrating, through epidemiological studies, differences with respect to western countries, possibly related to different life styles and genetic and racial influences, and proposes some categories at risk, for either environmental or occupational reasons, which are particularly interesting for this type of study. PMID- 8684297 TI - Mesotheliomas following exposure to asbestos used in railroads: 130 Italian cases. AB - The available knowledge on the oncogenic risks of asbestos, the data on the uses of asbestos in railroads, with particular regard to the Italian State Railroads (Ferrovie dello Stato = FS), and the groups at risk due to the exposure to asbestos used in railroads were briefly reviewed. The available data on the pathological effects of such exposure, and particularly on the onset of mesotheliomas among machinists and other railroad workers, were also summarized. One hundred and thirty cases of mesothelioma (122 pleural, 1 pericardial, 6 peritoneal and 1 pleuro-peritoneal), related to the exposure to asbestos used in railroads, observed in various Italian regions, were reported. Fifty-three of these cases (among which 49 reported in the Emilia Romagna Region) were submitted to a detailed study at the Bologna Institute of Oncology. Seventy-seven cases of mesothelioma occurred among occupationally exposed FS workers, in particular machinists; 45 cases occurred among rolling-stock machinists and workers engaged in the repair and demolition of the rails of workshops not belonging to the FS; 3 cases occurred among travelling workers of rolling-stock, not belonging to the FS; and 5 cases were found in family members (1 daughter, 3 wives and 1 sister) of railroad workers. This series of cases, together with similar data from the literature, proves the existence of an actual health risk due to asbestos used in railroads, and indicates its gravity. On the basis of the available data, the following steps are considered necessary: the promotion of systematic epidemiological investigations, the adoption of preventive measures, the performance of medical oncological surveillance, and the automatic compensation for tumours following the exposure to the asbestos used in railroads. PMID- 8684298 TI - Mesotheliomas following exposure to asbestos used in sugar refineries: report of 12 Italian cases. AB - Twelve Italian cases of mesothelioma (all the cases but one from the Emilia Romagna Region), following exposure to asbestos used in sugar refinery plants, are reported. Eleven cases arose in workers occupationally exposed, and one in the daughter of an exposed worker, following family contact. Eleven of the cases were pleural and one peritoneal. In the 11 cases following occupational exposure the average latency time was 36.0 (range 23-48) years, and the average age at onset was 63.4 years. In the case which followed family contact, the latency time and the age of the onset were 37 years. This represents the largest series of cases of mesothelioma due to the asbestos present in sugar refinery plants reported to date in the scientific literature. While these cases demonstrate the risk of asbestos mesothelioma in the sugar refinery industry, they in no way give the dimension of the pathological effects of asbestos (and man-made mineral fibres) used in this industry. To assess this risk further research is suggested. PMID- 8684299 TI - Ignored occupational risks of asbestos mesotheliomas. AB - Nine cases of asbestos mesothelioma following usually ignored asbestos exposure were reported. In these cases the asbestos exposure has been traced following a thorough medical inquiry within the hospital. Such a type of inquiry would reduce the number of mesotheliomas due to unknown causes or considered spontaneous. The role of the hospitals as a primary source of epidemiological information is stressed. PMID- 8684300 TI - Asbestos mineralogic analysis as indicator of carcinogenic risk. AB - Asbestos fibers can be found in several tissues and fluids, by different techniques, but up to now there is not a standardised approach. Chrysotile seems to be removed from the lung with greater ease than the amphiboles, but it is more frequently found in pleural tissues. Human and animal studies agree in documenting that chrysotile and amphiboles produce mesotheliomas, even if these studies rarely add much to the understanding of mechanisms of asbestos-related diseases. Further of asbestos-related diseases. Further studies are needed with standardized materials and techniques to better understand these mechanisms and to determine which individuals may be at highest risk for the development of disease. PMID- 8684301 TI - European multicentric case control study on risk for mesothelioma after non occupational (domestic and environmental) exposure to asbestos. AB - The paper presents the European multicentric case-control study on risk for mesothelioma after non-occupational (domestic and environmental) exposure to asbestos. The study includes eight centres in seven European countries (Belgium, Denmark, Greece, Italy, Spain, Sweden and Switzerland). It is focused on the measurement of mesothelioma risk in relation to low intensity exposure to asbestos and to exposure to MMMF and other agents. It includes incident cases of pleural malignant mesothelioma (histologically diagnosed and verified) and a random sample of the population. PMID- 8684302 TI - [Sleep disorders--diagnosis and treatment. Recommendations of the German Society of Sleep Research and Sleep Medicine]. PMID- 8684304 TI - [To the Interpharm in Stuttgart in April]. PMID- 8684303 TI - [Paracetamol and metoclopramide in fixed combination?]. PMID- 8684305 TI - [Control of gene expression. Cell specialization and adaptation of gene expression to current need]. PMID- 8684306 TI - [Fecal incontinence. Etiology and therapeutic possibilities]. PMID- 8684307 TI - [New therapeutic possibilities in AIDS]. PMID- 8684308 TI - [Phospholipase D. New pathways of signal transduction]. PMID- 8684309 TI - [Drug therapy in advanced age]. PMID- 8684310 TI - [Guidelines for therapy of obesity. Position of the German Society of Obesity Research]. PMID- 8684311 TI - [Recommendations for patient education in poor prognosis. Australian Consensus Document]. PMID- 8684312 TI - [Gamma-linolenic acid in atopic patients?]. PMID- 8684313 TI - [Intermittent self-ventilation--burden or relief?]. PMID- 8684314 TI - [Home Care and Respirator Weaning. Congress report from the 3rd session of the working group on home and longterm care. Bad Wildungen-Reinhardshausen, 4-6 May 1995. Proceedings]. PMID- 8684315 TI - [Intermittent nasal ventilation in primary pulmonary disease]. PMID- 8684316 TI - [Noninvasive intermittent ventilation. A prospective data collection in patients with hypoventilation syndrome]. AB - INTRODUCTION: Noninvasive intermittent ventilation is usually performed in patients with severe ventilatory pump disorder. From 1988 to 3/1995 we treated 163 patients with the aim of home mechanical ventilation (HMV). PATIENTS AND RESULTS: In March 1993 115 of these 163 patients practiced HMV, 22 had already died and 26 had rejected or broken off ventilation therapy. The 115 patients were classified in three main diagnostic groups: Scoliosis or chest wall disease (n = 76), COPD (n = 11) and neuromuscular disease (n = 28). The mean pCO2 at rest of all patients before ventilation therapy was 56 (+/- 12) Torr and fell to 46 (+/- 5) Torr in the course of therapy. The maximum statical inspiration pressure PImax rose from average 3, 8 (+/- 2, 3) to 4, 9 (+/- 2, 0) kPa. There was a probability of surviving two years after onset of ventilation therapy of 85% in the scoliosis group, of 60% in the neuromuscular group and of 30% in the COPD group. CONCLUSIONS: According to results of others home ventilation therapy was very successful in patients with chest wall disease. In some patients with neuromuscular disorder quality of life could be improved and life prolonged. Only half of the COPD patients could be treated successfully, whereas the other half had no benefit from noninvasive ventilation therapy. PMID- 8684317 TI - [Quality of life and long-term survival with intermittent self-ventilation in respiratory insufficiency caused by thoracic restrictive diseases]. AB - BACKGROUND: Mortality and quality of life are to be assessed in patients with respiratory failure due to restrictive chest wall disease. Neither specific questionnaires, nor perspective studies are available. PATIENTS AND METHOD: In a retrospective analysis records of mortality and morbidity, physical and social activity, and duration of IPPV are reviewed. RESULTS: The group consists of 35 patients (mean age 56 +/- 12 years; 22 female, 13 male; 11 post tuberculosis, 24 kyphoskoliosis; IPPV duration 28.5 +/- 20.7 months). Five patients died, 3 of which during the first 4 months: In 3 death is related to respiratory symptoms, 1 is due to pulmonary embolism, 1 to disruption of aortic aneurysm. Hospitalisation is required by 12 patients in 20 instances with a mean duration of 14.2 days. Respiratory symptoms are the cause in 13 instances, special difficulties are met with occlusion of tracheostoma in 3 patients. Professional activity is performed by 14 of the 21 patients < 60 years old. Physical activity is severely reduced in 4 patients, while it is mildly to moderately compromised in 26. Seven of all patients need supplemental oxygen. CONCLUSION: In respiratory failure due to restrictive chest wall disease treatment with IPPV seems to improve long-term survival and to enhance quality of life. PMID- 8684318 TI - [Intermittent self-ventilation in chronic obstructive lung disease]. PMID- 8684319 TI - [Intermittent self-ventilation in torsion scoliosis. Possibilities and limits]. AB - BACKGROUND: In patients with hypercapnic respiratory failure due to restrictive lung diseases home mechanical ventilation leads to improvement of daytime blood gases and symptoms. In this paper we regard the possible pitfalls and complications associated with intermittent mechanical ventilation in patients with kyphoscoliosis. PATIENTS AND METHODS: From 1990 to 1994 we treated 30 patients suffering from severe kyphoscoliosis with home mechanical ventilation. RESULTS AND CONCLUSIONS: 1. As our cases show in the prehospital phase before initiating home mechanical ventilation there is still room for the outpatient pneumologists to improve their knowledge and awareness of symptoms and treatment of chronic respiratory failure. 2. In the subsequent inpatient phase and specialised center must be aware and experienced in regarding possible problems inherent with home mechanical ventilation. 3. After discharge during chronic home mechanical ventilation a good cooperation between the center, patient, relatives, general services and general pulmolgists is necessary. The centers should offer training courses for the caring persons and general pneumologists. PMID- 8684320 TI - [Intermittent self-ventilation after respirator weaning]. AB - BACKGROUND: Weaning from the mechanical ventilator often proves to be difficult after prolonged ventilation due to excessive load or decreased capacity of the respiratory muscles. In the present retrospective study we examined the impact of the nocturnal mechanical ventilation during the "post-weaning-period" of long term ventilated patients. PATIENTS AND METHODS: We studied 43 patients (23 men, 59.1 +/- 14.6 years) with chronic respiratory failure who were transmitted from external ICUs after a mechanical ventilation period of 57.5 +/- 60.3 days. The weaning regime consisted of an individually adapted volume-cycled ventilation. If the patients were hypercapnic (pCO2 > 48 mm Hg) after the first 24-hour-period of spontaneous breathing without supplemental oxygen nocturnal mechanical ventilation was initiated. RESULTS AND CONCLUSIONS: In a retrospective study we could show that the decision to initiate invasive or noninvasive nocturnal mechanical ventilation after successful weaning primarily depends on the question whether a chronic hypercapnic respiratory failure persisted also after weaning from long-term mechanical ventilation. In about 40% of unselected patients nocturnal mechanical ventilation stabilized the weaning success whereas 60% of the patients did not need any further nocturnal mechanical ventilation. PMID- 8684321 TI - [Noninvasive nocturnal nasal mask ventilation (NIPPV) in childhood and adolescence. Dresden experiences with 11 patients]. AB - BACKGROUND: There are only small experiences with mechanical ventilation via nasal mask in childhood. PATIENTS AND METHODS: Eleven patients using NIPPV (9 patients aged 4 to 18 years and 2 patients with cystic fibrosis aged 20 and 25 years). RESULTS: NIPPV was effective in all 11 patients. Seven patients needed supplemental oxygen. Theophyllin, Almitrin and Salbutamol could support the nasal ventilation in special conditions. CONCLUSION: Intermittent ventilation via nasal mask is a noninvasive and effective treatment of chronic respiratory failure in childhood. Monitoring with continuous pulse-oximetry is necessary. PMID- 8684322 TI - [Preoperative risk assessment of children with Duchenne muscular dystrophy and relevance for anesthesia and intra- and postoperative course]. AB - BACKGROUND: Patients suffering from muscle disorders have an elevated anesthetic risk, i.e. to develop malignant hyperthermia or rhabdomyolysis. In addition serious cardial and pulmonal complications are imminent during anesthesia for surgery. PATIENTS AND METHODS: We investigated retrospectively the preoperative risk factors of 81 Duchenne patients undergoing 101 anesthesia (79 for muscle releasement operations and 23 for spine surgery) and the relation to possible complications due to the anesthesia and the intra- and postoperative course. RESULTS AND DISCUSSION: 83% of the patients showed pathologic ECG, 26% cardiac insufficiency in echocardiography, 31% pathologic X-rays of the thorax and 73% serious pulmonary restriction. Consequently avoiding of anesthetic agents with a high trigger potential for developing malignant hyperthermia (i.e. halothane or muscle relaxants type succinylcholine) prevented severest complications as malignant hyperthermia, rhabdomyolysis or cardiac arrest. Nevertheless other complications (i.e. arrhythmia, cardiac insufficiency) occurred due to the cardiac and pulmonary limitations more pronounced in the older patients of the spine surgery group. PMID- 8684324 TI - [Intermittent self-ventilation in neuromuscular diseases. Comparison of lung function parameters in ventilated and non-ventilated patients]. AB - BACKGROUND: Based on neuromuscular-disease patients in our case, we investigate the possibility of elaborating criteria by which to judge when home intermittent mechanical ventilation should be commenced and to access its consequences over an extended period. PATIENTS AND METHODS: Out of 24 patients with neuromuscular diseases (6 female, 18 male, mean age 32 years), 14 were treated with IPPV. They were suffering from hypercapnic respiratory failure with heavy sleep disruption and corresponding daily symptoms. RESULTS: The aim was to calculate significant examination parameters to facilitate indication for IPPV. The clinical situation of patients dependent on respiratory support improved under IPPV. We witnessed a "ventilation-saving effect" and--despite progression of the basic disease within the monitoring period--no deterioration of the blood-gas situation. CONCLUSIONS: It is possible to elaborate criteria for the indication of IPPV based on our group of neuromuscular-disease patients. PMID- 8684325 TI - [Home ventilation in neuromuscular diseases in adults. Presentation of recommendations of the Bavarian Muscle Centers of the DGM]. PMID- 8684323 TI - [Perioperative use of noninvasive ventilation]. AB - BACKGROUND AND AIM: Noninvasive mask ventilation is in some cases of respiratory failure the treatment of choice. It is used in cases of acute respiratory failure. We report about perioperative application of noninvasive mask ventilation. PATIENTS AND METHODS: We treated 25 patients with respiratory failure pre- and/or postoperative with noninvasive mask ventilation. RESULTS: The success rate in all patients was 68%, but it was very different in respect to the varying causes of respiratory failure. CONCLUSION: With noninvasive mask ventilation it is possible to avoid in some patients with acute postoperative respiratory failure complications who are referred to intubation. In patients with postoperative decompensation of chronic respiratory failure postoperative treatment becomes easier, in extraordinary cases the method makes surgery possible. PMID- 8684326 TI - [Possibilities and limits of ventilation in amyotrophic lateral sclerosis]. PMID- 8684327 TI - [Discontinuing ventilation of patients with amyotrophic lateral sclerosis. Medical, legal and ethical aspects]. PMID- 8684329 TI - [Ventilation in nursing homes. Management of ventilator-dependent patients in inpatient facilities for handicapped--a report of experiences]. PMID- 8684328 TI - [Growing up on the intensive care unit. Results of a survey on quality of life of long-term ventilated children on intensive care units]. AB - BACKGROUND: The situation of children treated with long-term ventilator assistance after tracheostomy and living in intensive-care units for an indefinite period of time has still been neglected in spite of its complex nature. PATIENTS AND METHODS: Already in 1988 the Ministry for Employment, Public Health and Social Welfare of Nordrhein-Westfalen ascertained 51 children living in hospitals in Nordrhein-Westfalen for a long time. An inquiry of our hospital in 1994 comprising 32 children's hospitals in Westphalen-Lippe showed 14 patients at the age from 6 months to 16 years 9 months with mechanically ventilation and intensive care unit as their "living-space". Due the modern medico-technical development increasing of this form of life is expected. RESULTS: The survey shows that beyond medical care public assistance is insufficient. There are serious deficiencies in pedagogics and therapeutic accompaniment. The children's social contacts outwards are greatly reduced so that they neither get an adequate help during pre-school times nor at school age. CONCLUSIONS: Considering the problems, physicians and educationalists of various hospitals in Datteln established the study group "Children and adolescents exposed to ventilation". This group is engaged in developing alternatives towards the accommodation in intensive care units. Major intensions are first to support parents in integrating their child within the family; second to create flat-sharing groups for children, whose parents are not able to integrate their child within the family. PMID- 8684330 TI - [Legal problems in management of home ventilation patients]. AB - To prevent financial problems caused of homecare for patients with artificial respiration the prescription has to include the extent and the necessity of medical care which is much more than the care for the basic requirements. It has to be explained, that the lost of special homecare entails even intensive care in a hospital. Only in this way the health insurance has to pay for homecare of patients with artificial respiration without recourse to income and property. PMID- 8684331 TI - [Disadvantages of health care financing by social organizations. A patient report]. PMID- 8684332 TI - [Respiratory insufficiency caused by early summer meningoencephalitis with polyradiculitis. 2 case reports]. PMID- 8684333 TI - [Advantages and disadvantages of invasive and noninvasive artificial respiration exemplified by a patient with postpolio syndrome]. PMID- 8684334 TI - [Proportional assisted ventilation--clinical use of a new ventilation mode]. AB - BACKGROUND: Proportional assist ventilation (PAV), a new mode for assist ventilation, allows the patient not only to trigger the ventilator but enables him to keep his breathing pattern. The basis of PAV is a positive feed back between patient and ventilator. PATIENTS AND METHOD: PAV was applied in 6 patients, who were under long-term ventilation and who were stable. The ventilator was adjusted to compensate for the endotracheal tube, different parts between 90 and 40% of resistance and elastance were assisted. Airway pressure, flow and tidal volume were measured. PAV was compared with pressure support ventilation (PSV). RESULT: No difference in blood gases were found in PAV as compared to PSV. Airway pressure were lower in PAV than in PSV (10.4 +/- 3.3 cm H2O vs. 18.8 +/- 5.9 cm H2O in PSV). Breathing frequency was higher (22.4 +/- 8.1 vs. 15.8 +/- 5.9 in PSV). CONCLUSION: The higher breathing frequencies in PAV were associated with the underlying diseases and resulted in a better synchronisation with the respiratory center output. PMID- 8684336 TI - [Technical evaluation of ventilation filters]. PMID- 8684335 TI - [Reproducibility of computer-assisted mouth occlusion pressure measurements]. AB - BACKGROUND: The measurement of mouth occlusion pressure is an easy method to assess respiratory drive and muscle function. Lately there is a variety of computer assisted programmes, but their precision is discussed controversially. In this study we analysed the repeatability of measurements of mouth occlusion pressures performed by a computer assisted measurement unit. PATIENTS AND METHODS: We examined maximal inspiratory mouth occlusion pressure (PI(max)), mouth occlusion pressure 100 ms after onset of inspiration (PO.1) and PI(max) after 100 ms (PO.1(max)) of 32 patients with COPD. Subjects were divided into group A (normal blood gas pressures) and group B (hypercapnia due to alveolar hypoventilation). Controls (K) consisted of 22 healthy men. Criteria for repeatability were analysis of variance, intraindividual standard deviation of the mean and the variation coefficient of 5 consecutive measurements. RESULTS: Controls produced the highest values for PI(max) and the lowest ones for PO, 1. Intraindividual standard deviation was small as well as the variation coefficient; we found no statistically significant differences. Compared with controls in group A PI(max) values were markedly reduced with elevated PO.1 values. Intraindividual standard deviation and variation coefficient were low, differences not significant. We observed similar results for group B, variance analysis showed no significant differences, deviation around the mean was small. CONCLUSION: Our data suggest a high repeatability of measurements of mouth occlusion pressures. Especially patients with severe COPD and alveolar hyperventilation are able to produce valid and reliable test results. PMID- 8684337 TI - [Mechanical ventilation in acute exacerbation of COPD--indicated in every case?]. PMID- 8684339 TI - [Monitoring and prevention of hospital infections in neonatal intensive care]. AB - The authors monitored newborns in the Intensive Care Unit and the equipment with culture exams for a period of 6 months in order to evaluate the incidence of microbic infections and eventual clinical manifestations in relation to risk factors and to test the efficacy of the prophylactic and therapeutic measurements adopted. The results evidenced a positivity in the culture exams of 24.4% at the 1st control, 14.3% at the 2nd and no positive results at the 3rd. Only two newborns presented sepsis that was resolved without any consequences. Aimed antimicrobic therapy was begun at the 1st clinical and/or haematochemical sign that could suspect the onset of infection. A careful control of the microbic flora, the use of aimed antibiotic therapy and respect of the hygienic conditions permitted us to obtain an excellent control of the infections the morbidity, mortality, the days of hospitalization and the onset of bacterial resistance. PMID- 8684340 TI - [To what extent is breast feeding practiced in Italy today?]. AB - OBJECTIVES: During a survey regarding infant health in 7 regions, diffusion and length of time of breast-feeding nowadays in Italy were studied. MATERIALS AND METHODS: By OMS Epi methodology, 210 children sampled from each area of study and specialized health workers carried out the interviews at home using a specific questionnaire. The mothers were questioned about the length of time they breast fed their child. RESULTS: 76% of mothers said they breastfed, 32% said they did it for less than 3 months and 44% for more. In each area, the percentage of breastfeeding was 70% or more. This percentage changed only if the birth weight was very low or the mothers' instruction was high, but this is probably because the most cultured mothers answered easier they breast fed longer. DISCUSSION: It seems that mothers are pro-breastfeeding and, in each region, just a quarter of them don't practise it. Besides, about half women breastfed for more than 3 months. This study doesn't permit us to know why some women don't breastfeed or why they wean their children too early. For this reason, we need to curry out further studies. PMID- 8684338 TI - [Hepatitis A vaccine]. PMID- 8684341 TI - [Neoadjuvant treatment of Ewing's sarcoma: results obtained in 122 patients treated with a 6-drug chemotherapeutic protocol (vincristine, adriamycin, cyclophosphamide, dactinomycin, ifosfamide and etoposide)]. AB - From January 1988 to October 1991, one hundred and twelve patients with non metastatic Ewing's sarcoma of bone were treated with a 6 drugs neoadjuvant chemotherapy protocol (IOR/Ew2) in which, to the four drugs usually used in the treatment of this tumor (vincristine, adriamycin, cyclophosphamide and dactinomycin), Ifosfamide and VP-16 were added. The local treatment consisted of radiation therapy in 52 cases, a surgical treatment was performed in 27 cases and in the remaining 33 cases both the previous treatments were used. At a mean follow-up of 4.5 years (3-6.5), 62 patients (55.3%) remained continuously free of disease and 50 relapsed: 41 with metastases, 8 with mestastases and local recurrence and 1 with local recurrence alone. These results do not differ from the ones obtained in our Institution in 98 patients treated between 1983 and 1988 with a neoadjuvant protocol (IOR/Ew1) in which only VCR, ADM, CTX and actD were used (3 year CDFS: IOR/Ew2 = 60.7%-IOR/Ew1 = 55.1%). In IOR/Ew2 a higher DFS rate was observed in the patients with tumor located in the axile bones in comparison with that obtained in the previous study (IOR/Ew2 = 48.6%, IOR Ew1 = 25.6%). Despite the fact that these results came from a not-randomized study, the authors conclude that the addition of Ifosfamide and VP-16 to the four drugs standard regimen do not improve the outcome of patients with Ewing's sarcoma of bone, with the possible exception of the patients with tumor located in the axile bones. This data should be confirmed in further and larger studies. PMID- 8684342 TI - [Congenital adrenal hypoplasia and hearing loss. A case report]. AB - We report on the diagnostics, the therapeutics and the follow-up (to 3 years and 5 months) of a newborn affected by X-linked congenital adrenal hypoplasia. After the beginning of substitute hormonal therapy, the patient underwent periodical clinical examinations, with particular attention to the growth, and laboratory tests, which monitored the hormonal pattern. This experience points out the diagnostic role of low maternal levels of urinary estriol during pregnancy and the importance of a prolonged follow-up, so as to discover associated pathologies as early as possible. In our case, in fact, the study of auditory brainstem responses enabled us to recognize a mild transmission hearing loss at the early age of 8 months. PMID- 8684343 TI - [A case of Caffey-De Toni-Silvermann disease with mandibular localization]. AB - Report of a case of infantile cortical hyperostosis with localitation in the jaw bone in a female child five month old. Spontaneous resolution, not relapse. There weren't other affected subjects in the same family. Unknown etiology. Discussion about the differential diagnosis and the therapeutic ways described in literature. PMID- 8684344 TI - [Idiopathic scrotal hemorrhage: a rare cause of acute scrotum in the newborn]. AB - Spontaneous hemorrhage of the scrotum in the newborn is an entity very rarely encountered in clinical practice and characterized by scrotal mass and slightly bluish discoloration. We present two cases of spontaneous idiopathic hemorrhage of the scrotum and review the literature. The difficulty in establishing the diagnosis and ruling out testicular torsion is outlined. The importance of ultrasounds in distinguishing between testicular and scrotal acute disease is stressed. Indications for surgery are: the important scrotal hematoma and the patent processus vaginalis. PMID- 8684345 TI - [The human tail. Report of a case of coccygeal retroposition in childhood]. AB - The authors explain a little patient's case of coccydynia by back-position of the coccyx; the patient underwent an operation of partial resection with favourable clinical outcome. According to classification, the treated case corresponds to vestigial tail. PMID- 8684346 TI - Strangers in a strange land. PMID- 8684347 TI - Screening and diagnosis for gestational diabetes mellitus among Chippewa women in northern Minnesota. AB - We reviewed prenatal records of Chippewa women residing on two Minnesota reservations to define the incidence of gestational diabetes mellitus (GDM) and to describe the screening and diagnosis practices for GDM according to National Diabetes Data Group Criteria. Of the 554 pregnancies included in the study, six (1%) involved women with preexisting diabetes mellitus and 32 (5.8%) with GDM. In 24 (4.3%) of the pregnancies, the women were misclassified as having GDM. Women completed screening and/or testing during 450 (82%) of the pregnancies-by 32 weeks gestation for 401 (73%). This is of 548 pregnancies that could potentially have involved GDM. Women with incomplete screening and/or testing were older and of higher parity than those who completed negative screening and/or testing (p<0.05). Chippewa Indian women in northern Minnesota experienced GDM at rates higher than most other U.S. populations. Screening rates for GDM were high, but some high-risk women were not screened. Programs targeting high-risk women for timely and accurate diagnosis of GDM are needed in this primary care setting. PMID- 8684348 TI - Cultural barriers to health care for refugees and immigrants. Providers' perceptions. AB - What are the barriers to good health care for immigrants who have come to the Minneapolis-St. Paul metropolitan area since the early 1980s? Why do immigrants often delay or avoid seeking mainstream health care services? The research described here examines these questions from the perspective of nonimmigrant health care providers in the Twin Cities. The 24 metropolitan health care providers interviewed in our study confirmed the existence of significant barriers to health care-barriers that probably differ from those experienced by nonimmigrant patients. Refugees and immigrants from other cultures had varying culturally based reactions to Western-style, allopathic medicine-some positive and many negative. Providers and administrators must consider these barriers when serving a growing population of immigrant patients. PMID- 8684349 TI - Integrating culture and healing. Meeting the health care needs of a multicultural community. AB - Delivering health care to culturally diverse patients is fast becoming an integral part of patient care-a change driven by shifting demographics in Minnesota and especially in the Twin Cities metro area. At United Hospital and Children's Health Care-St. Paul, ethnographic research is being used to create cross-cultural health care information systems that address the needs of providers and patients. These include an easy-to-use computer-based information system, brown bag seminars, and cross-cultural skills training. This article discusses that hospitals' efforts to identify provider needs, collect cultural information, and disseminate that information in a manner that supports quality and cost-effective health care delivery. PMID- 8684351 TI - Providing culturally competent health care to Hmong patients. PMID- 8684350 TI - Developing preventive health programs for recent immigrants. A case study of cancer screening for Vietnamese women in Olmsted County, Minnesota. PMID- 8684352 TI - Trading places. PMID- 8684353 TI - [Sleep and intra-ictal epileptic electroencephalographic activities]. AB - From this review it appears that the slow wave sleep (SWS) increases the mean density of electroencephalographic paroxysmal activities (PA) whatever the epileptic syndrome. This pattern is not marked according to a bell curve among the epileptic population: about half the patients exhibit few or no PA during SWS, 20% show an increase during waking and another 20% during SWS. Begnin epilepsy with centro-temporal spikes is associated with an important sleep PA increase. In partial epilepsy, stage 3 and 4 sleep should increase the PA transmission. In children, a large increase in PA during SWS defines the continuous spike-wave during sleep syndrome, which is also observed in the syndrome of acquired aphasia with epilepsy of Landau-Kleffner; both conditions raise the issue of the neuropsychological consequences of the sleep PA. The sleep effect on the various epileptic models is analysed, showing a mean increase in PA during SWS and during transition between sleep and waking. This evidence is in agreement with the fact that during light sleep thalamocortical loops are functioning with an oscillatory pattern which facilitates PA expression. More hypothetic is the effect of sleep on the discharge rate of epileptic focus and on the cortical diffusion of the epileptic discharges. Gaba certainly participates in the thalamic influence, but its role on PA by the cortical and brain stem inhibition is speculative. Noradrenaline and acetylcholine, implicated in waking, reduce PA activity. Interindividual variations suggest that each epileptic has his own pathological neuronal organisation in which cortex and thalamocortical connexions are variously sensitive to the neurotransmitters implicated in sleep and waking. PMID- 8684354 TI - [Misleading aspects of the standard electroencephalogram in juvenile myoclonic epilepsy: a retrospective study of 56 consecutive cases]. AB - Atypical clinical and/or EEG presentation may complicate the diagnosis of juvenile myoclonic epilepsy (JME). To assess the sensitivity of a standard EEG recording, we retrospectively evaluated the EEG performed at their first referral in 56 consecutive JME patients first seen between 1986 and 1992 (26 M, 30 F, aged 12-53, mean 24.4, with onset of JME at age 10-33, mean 14.3). The diagnosis had been made in none of these patients prior to referral, and was often confirmed only during follow-up. A 20-minute standard EEG was recorded, including hyperventilation (HV) and intermittent light stimulation (ILS). This EEG was normal in 15 cases (27%), showing aspecific or misleading changes in 11 cases (20%) and typical changes in only 30 cases (54%). The baseline EEG was normal in 25 (45%), atypical in 11 (20%), and typical for JME in only 20 (35%). HV and ILS yielded 37 and 39 normal, 10 and 7 aspecific and 9 and 10 specific findings, respectively. A single standard EEG without activation may thus be inconclusive or misleading for the diagnosis of JME in more than 50% of newly referred patients. PMID- 8684355 TI - [The influence of suicide risk and despondency on the amplitude of P300 in major depression]. AB - P300 amplitude represents a useful tool to assess information processing in normal and psychopathological subjects. In depressive disorders, many studies have shown a decrease of P300 amplitude and an increase of its latency. However, functional significance of the P300 modifications remain unclear. The aim of the study was to assess the influence of suicidal risk and hopelessness on P300 amplitude among 40 depressive inpatients. The results showed significant relationships between P300 amplitude and suicidal risk (r = -0.68, p < 0.001) and with hopelessness (r = -0.76, p < 0.001). From a clinical point of view, P300 amplitude should be considered as a psychophysiological index of suicidal risk in major depressive disorder. PMID- 8684357 TI - The Research Assessment Exercise (RAE): criteria and issues. PMID- 8684356 TI - [Classification of epileptic seizures. Comparison of two systems]. AB - In spite of its universal acceptance, the international classification of epileptic seizures suffers from certain limitations. The fundamental divisions between partial and generalized seizures on the one hand, and between partial simple and complex seizures on the other, are not always practical, nor useful. The terminology is often cumbersome, and does not contain essential localizing information. Finally, the seizure classification is sometimes dependent on ancillary testing, particularly the EEG. We propose a different seizure classification, which answers the above shortcomings of the international classification, and which has been used for years in major epilepsy centers. In this system, the seizure classification is based exclusively on seizure symptomatology. The terms are generally more concise than those of the international classification, and yet convey more precise information. For example, the term left visual aura-->automotor seizure-->generalized tonic clonic seizure would be equivalent to simple partial seizure with visual symptom evolving into complex partial seizure evolving into generalized tonic clonic seizure. The international classification is longer and omits essential later alizing information. This classification is easy to apply, and can be an extremely useful complement to the international seizure classification, especially for centers whose emphasis is on surgical treatment of epilepsy. PMID- 8684359 TI - Training and education in practice nursing: the perspectives of the practice nurse, employing general practitioner and Family Health Service Authority. AB - Continuing training and education, although fundamental to the development of practice nursing, is subject to considerable debate. This paper, by drawing on material from a national qualitative study funded by the Department of Health and Welsh Office, explores the role of continuing training and education from the perspectives of practice nurses, general practitioners, representatives from Family Health Service Authorities (FHSAs), commissioners of community nursing services and managers of community nursing provider units. The paper demonstrates how practice nurses make use of a variety of education and training opportunities and do not seem particularly disadvantaged in their training pathways. Problems, however, have began to emerge. The informal arrangements covering training and education have been felt by many practice nurses, to leave them in a potentially needs might not be so easily accommodated. More generally, the paper concludes that debates about training and education cannot take place without referring to the type of work it is appropriate for a practice nurse to perform. The role expected of general medical services and the general development of primary health care provision, therefore, will influence practice nurses' training and educational needs. PMID- 8684358 TI - Deciding to pursue nurse education: sources of information, influence and encouragement. AB - Current concerns about a shortage of nurses means attention may again be focusing on recruitment strategies. This paper presents findings on aspects of the decision to take nurse training, and contributes to available information upon which recruitment strategies can be formulated. Questionnaires were sent to 1164 registered general nurses shortly after qualification; this represented the first phase of a longitudinal study of these nurses' careers. Participants were asked about the effect of the following on their decision to take nurse training: written information about nursing; discussions with staff of educational institutions; personal involvement in health care work or caring activities, and having relatives qualified in health care. Findings for the 87% who returned the questionnaire, showed that respondents were more likely to report that these events had a positive than a negative effect on their decision. Participants were also asked how encouraging educational staff, careers staff, family and friends had been about their decision to take nurse training. The implications of the findings for those responsible for nurse recruitment are discussed. PMID- 8684360 TI - Towards a philosophical understanding of mentoring. AB - This paper commences with a brief introduction during which the foundations are laid for the ensuing discussion, in which learning, practical knowledge and expertise, and reflective practice are briefly analysed. Thereafter, it is argued that mentorship is best understood as relationship and function, neither of which is necessarily the same as that of the teacher-practitioner. PMID- 8684361 TI - Experiential learning and teaching--a critical evaluation of an enquiry which used phenomenological method. AB - Experiential teaching methods have been recommended as the most effective medium for students to acquire the interpersonal skills and self-awareness required for the mental health nurse. This enquiry developed from the premise that there is potential for students to learn effectively in experiential teaching sessions. The authors experience of teaching in mental health gave focus to the question as to whether nurse teachers consider, and then use, a particular experiential learning framework when facilitating experiential teaching methods. The enquiry was an individual case study of one nurse teacher, and the data were collected through non-participant observation and focussed, non-directive interviewing. The philosophical perspective and methodology was phenomenological with the data analysed using phenomenological guidelines. This was used as it concentrated on the nurse teachers understanding of experiential learning as a phenomenon. The results concluded that the nurse teacher had a clear understanding of experiential learning and aspects of her interpretation manifested themselves within the classroom as part of experiential teaching. When compared with the literature there were commonalities with the meaning of experiential learning held by the nurse teacher studied. The focus of this paper is to report briefly on the enquiry, and then offer a detailed critical description and evaluation of the methodological approach used. PMID- 8684362 TI - Developing the sociology of health in nurse education: towards a more critical curriculum--part I: andragogy and sociology in Project 2000. AB - This paper examines the potential for developing a more critical and reflexive curriculum around the sociology of health in nurse education. In Part One a review of the literature on Project 2000 to date suggests that insufficient attention has been paid to the scope for linking methodological and epistemological issues. it is argued that the status of 'andragogy' as a strategy of teaching and learning is ill-defined and that the nature of sociological theory in nurse education remains too crude and dichotomous to produce the 'knowledgeable doer', a qualitatively different kind of professional nurse practitioner. PMID- 8684363 TI - Developing the sociology of health in nurse education: towards a more critical curriculum--Part 2: Linking methodology and epistemology. AB - In Part Two of the paper a model for curriculum development is proposed which derives from the teaching experience of the authors. This is intended to provide a methodological and conceptual framework for studying the problem of human consciousness and action in relation to health in a way that is consistent with both the values and purposes of student-centered learning and the claims of critical theory. It is suggested that such a critical curriculum of health is needed in order to ensure that the 'knowledgeable doer' Project 2000 aims to produce is indeed a qualitatively different kind of professional nurse practitioner. PMID- 8684364 TI - Establishing priorities for research in education within one college of nursing and midwifery. AB - The educational provision for nurses and midwives is currently undergoing immense change. These innovations encompass the organizational structure, the process of delivery and the projected outcomes for professional education within the UK. There is, however, a dearth of published research evidence designed to evaluate these educational changes. Nevertheless, anecdotal evidence suggests that within individual institutions small-scale, educationally-focused research is currently being conducted. These are usually 'one off' studies which address questions of personal interest to individual researchers rather than issues of importance to the organization or to the professions as a whole. the net result is a diverse research portfolio which, by its very nature, is wasteful in terms of lost opportunity to commission larger-scale research which might influence educational practice and in failing to direct effectively the energies and skills of researchers. In an attempt to address these issues and to set an agenda for research priorities within one college of nursing and midwifery, a four-round Delphi survey was conducted. This is the first of its kind to be reported in the UK literature. Fifty six of the teaching staff (77% of the total number of teaching staff) initially identified 213 issues which were grouped into 14 categories. The interrater reliability of the categorization process was checked on three separate occasions. In successive rounds, high response rates were maintained. To test for the manipulative effect of providing respondents with controlled feedback of their score in round 2, the third questionnaire was completed "blind' to previous scores. In the final round, participants were provided with feedback and invited to re-score and rank the items. The final round yielded 28 prioritized items. It was notable that the top ten issues primarily focused upon the pre-registration (Project 2000) provision encompassing both the preparation of students for professional practice and the changing role of the nurse/midwife teacher. This paper explores the implications of these findings for setting a research agenda within the organization. PMID- 8684365 TI - The portfolio workbook as a strategy for student-centred learning. AB - This paper described the portfolio workbook as a strategy to support student centred learning in nurse education. The portfolio workbook combines the use of reflection on prior experiences, forward planning to meet identified course outcomes, critical incident analysis and a reflective journal to ensure the integration of theory with practice. This enables the student, rather than the teacher, to control the educative process, and thus develops the skills of autonomy and decision-making envisaged in the development of Project 2000 courses. In using a weekly add-on format, the workbook provides a comprehensive record of the student's learning, whilst at the same time monitoring progress and facilitating the acquisition of knowledge and skills. The use of reflective practice from the beginning of the course, and reinforced throughout, enables the student to internalize the process as a way of identifying and managing their own learning needs. The author concludes that this strategy would be appropriate for all types of nurse learners; however, a precondition for this is an espousal and commitment by teachers to student-centered philosophies and methods of learning. PMID- 8684366 TI - Reflection and learning in student nurses. AB - One aim of the reforms in nurse education is to produce reflective practitioners. The researcher teaches in a diploma programme and decided to see if there was any evidence that students, one year into a Common Foundation Programme, were developing reflective skills or if they were learning through reflection. Students in this study value reflection as a means of learning and it seems that reflection has led to behaviour change, problem-solving and personal and professional awareness as well as improved patient care. They value debriefing following experience and there is evidence that they would benefit from training in mental previewing techniques prior to embarking on new experience. PMID- 8684367 TI - Preparing for Post-Registration Education and Practice (PREP): the support role of the library. AB - A survey of 5% of trained nursing staff in the Plymouth area provided indications of the impact of changes in post-registration education and practice on the library service of the Tor & South West College of Health in Plymouth. The survey comprised, first, a structured interview to obtain details of professional development plans and preferences, number of courses attended recently, learning styles, use made of ward/unit resources (particularly journals) and optimum periods for library opening. The second part of the survey was a vignette information problem. The responses (written by the participants) provided an indication of information-seeking skills and perceptions of various information sources, both formal (publications) and informal (colleagues and organizations). Analysis indicated that the most popular method of learning was attending a study day, and the most popular combination of learning styles was study day combined with further reading. Reading or journals was selective. Most staff would have to rely on a library for journal literature, particularly the new journals. One third of the sample appeared lacking in information-seeking skills. One third appeared confident in information-seeking skills, and this group was associated with the use of more than two sources of information and use of a library. No single library in Plymouth would be adequate for the sources of information required, indicating the need for better networking and/or integration. PMID- 8684368 TI - Radiology quiz #4. Subdural hematoma. PMID- 8684369 TI - Estate planner primer. PMID- 8684370 TI - Seasonal allergic rhinitis. AB - Seasonal allergic rhinitis is the most well understood of the types of allergic rhinitides. The disease is characterized by sneezing, itching, rhinorrhea, and nasal congestion upon exposure to pollen allergens in susceptible individuals. These symptoms can cause considerable misery in affected patients. Recent advances in the diagnosis and treatment of this disorder as well as new insights into the pathophysiology of allergic rhinitis enable practitioners to provide more effective therapy. PMID- 8684371 TI - Evaluation of inhA gene and catalase-peroxidase gene among isoniazid-sensitive and resistant Mycobacterium tuberculosis isolates. AB - The katG gene and the inhA gene of 30 INH-resistant (INH-R) and 28 INH-sensitive (INH-S) isolates of M. tuberculosis from Haiti and Maryland were analysed by PCR to establish the presence and frequency of two postulated mechanisms of INH resistance, total katG gene deletion and inhA Ser94 to Ala94 amino acid substitution. Only two of 30 INH-R isolates (3%) appear to have total katG gene deletions. All 28 INH-S isolates (100%) produced a PCR product at both the 5' and the 3' ends of the katG gene. Gene deletion of katG is a rare mechanism of INH resistance. Allele specific oligonucleotide hybridisation analysis of the inhA PCR products from the same 58 isolates revealed no mutation at amino acid 94 or directly surrounding it. Other inhA gene mutations may be responsible for INH resistance in M. tuberculosis. Diagnostic strategies using katG gene deletion or inhA Ser94 mutations would fail to detect almost all INH-R isolates. PMID- 8684372 TI - Polymerase chain reaction for Mycoplasma hyopneumoniae detection in tracheobronchiolar washings from pigs. AB - We have used the polymerase chain reaction (PCR) to detect Mycoplasma hyopneumoniae in tracheobronchiolar washings collected from experimentally infected piglets. On the basis of the published nucleotide sequence of M. hyopneumoniae I141 probe (accession number U02537), primers were chosen to produce an amplified fragment of 1561 bp. All the M. hyopneumoniae strains tested could be detected by the PCR test. DNA from other mycoplasmal and bacterial species currently isolated from respiratory tract of piglets gave negative result. The detection limit was estimated to be 500 fg of purified DNA corresponding to 4.10(2) organisms. The sensitivity of PCR reaction was also evaluated on microorganisms in culture, the limit sensitivity was 2.5 10(3) organisms. In the present study, a total of 143 tracheobronchiolar washings collected from experimentally infected piglets were submitted to PCR. For each tracheobronchiolar washing, PCR was performed on crude extracts treated with lysis buffer and on extracted DNA. The PCR results obtained with the two kinds of samples were compared to the immunofluorescence (IF) results. This comparison indicates a good correlation between PCR and IF test in 121/143 cases. The presence of M. hyopneumoniae is revealed in 19/143 of the washing samples only by PCR. In our hand, PCR appears to be the more sensitive test to detect M. hyopneumoniae in experimentally infected piglets. PMID- 8684373 TI - Specific detection of Mycoplasma iowae using polymerase chain reaction. AB - A polymerase chain reaction assay was developed for the specific detection of Mycoplasma iowae, a poultry pathogen. Two primers were chosen in the DNA region located immediately 5' of the ribosomal genes operon. Under our PCR conditions, specific amplification of all M. iowae strains tested was achieved, and none of 17 other Mycoplasma species isolated from birds gave an amplification product. We obtained amplification from culture medium samples of M. iowae by using Tth DNA polymerase instead of Taq DNA polymerase, and we were able to detect as few as 10 organisms. Finally, we described a dot blot hybridization test, using cold labelling and chemiluminescence, which is very convenient for routine detection of M. iowae. PMID- 8684374 TI - Quantification of polymerase chain reaction products: enzyme immunoassay based systems for digoxigenin- and biotin-labelled products that quantify either total or specific amplicons. AB - Enzyme immunoassays were developed for quantification of polymerase chain reaction (PCR) products, referred to as amplicons. Amplicons were dual labelled simultaneously by enzymatic incorporation of digoxigenin and biotin during PCR. For total amplicon quantification, Microfluor B polystyrene wells, compatible with chemiluminescent detection, were coated with streptavidin. Dual labelled amplicons were bound, treated with anti-digoxigenin antibody conjugated to alkaline phosphatase to complete the two-site sandwich immunoassay configuration, and detected by the chemiluminescence generated upon hydrolysis of a phosphate substituted dioxetane substrate, AMPPD. For specific amplicon quantification, the Microfluor B wells were coated with an unlabelled DNA probe complementary to the labelled amplicon target. Subsequent steps were performed as described above. This assay detects 2 pg of specifically amplified DNA. Chemiluminescent detection provides a linear range of four orders of magnitude for amplicon quantification. The non-radioactive labels are safe and stable. PCR as described here obviates the need for labelled primers and constitutes the initial report of concurrent dual non-radioactive labelling of DNA by a DNA polymerase. PMID- 8684375 TI - PCR detection of the two 'Candidatus' Liberobacter species associated with greening disease of citrus. AB - Greening is a severe and widespread disease of citrus in two main citrus growing areas of the world, Asia and Africa. It is caused by an uncultured phloem restricted bacterium that we have recently characterized from the sequence of its 16S ribosomal DNA. The bacterium is a new "Candidatus' genus, Liberobacter, in the alpha subdivision of the proteobacteria, and two 'Candidatus species' have been recognized: Liberobacter asiaticum and Liberobacter africanum. In this paper we describe a PCR method to detect the two liberobacter species in citrus trees by amplification of a 1160 bp fragment of their 16S rDNA. Distinction between the two species has also been achieved by Xbal digestion of the amplicons. PMID- 8684376 TI - A rapid and convenient method to prepare DIG-labelled RNA probes for use in non radioactive in situ hybridization. AB - We describe here the use of PCR-generated templates incorporating T3 polymerase sites in order to prepare digoxigenin (DIG)-labelled cRNA probes against any gene of known sequence. This method was applied to the preparation of probes specific for chicken glyceraldehyde-3-phosphate dehydrogenase messenger RNAs and we demonstrate that such probes can be used for in situ hybridization (ISH). This technique therefore represents a rapid and convenient means to prepare DIG labelled cRNA probes for use in a non-radioactive ISH. It adds speed and convenience of probe preparation to the previously described advantages of non radioactive detection techniques. PMID- 8684377 TI - Detection of four mutations in six unrelated South African patients with acute intermittent porphyria. AB - We have screened the hydroxymethylbilane synthase cDNA from six South African patients with acute intermittent porphyria, using a combination of chemical cleavage mismatch analysis and direct sequencing of asymmetrically amplified PCR products. Four mutations were detected, a novel T insertion (771insT) and three missense mutations (R26H, R116W and R173Q). The 771insT mutation produces a stop codon, thirty-three codons downstream and a loss of approximately 20% of the protein is predicted. The R116W mutation, which was found to have a high prevalence in the Dutch population, was detected in three unrelated South African patients. PMID- 8684378 TI - An improved procedure for in situ RTPCR. AB - Direct in situ RTPCR has been successfully applied to paraffin-embedded human placental specimens. The expression of stem cell factor (SCF) mRNA visualized in cytotrophoblast and stromal cells is validated by the lack of any specific signal in parallel specimens where reverse transcription is omitted. PMID- 8684379 TI - Development of an amplification and hybridization assay for the specific and sensitive detection of Mycoplasma fermentans DNA. AB - A polymerase-chain-reaction-based detection system for Mycoplasma fermentans was established. The highly conserved tuf gene, which encodes elongation factor Tu of prokaryotes, served as target sequence for the PCR. With two PCR oligodeoxynucleotides, which were selected from M. fermentans specific sequences of the tuf gene, we amplified a 850 base pair DNA fragment. Via the biotin-moiety of one primer the PCR fragments were immobilized on streptavidin-coated microtitre plates. After alkaline denaturation a digoxigenin-labelled M. fermentans specific DNA probe was hybridized to the single stranded immobilized PCR fragment. Detection was performed by addition of an alkaline phosphatase conjugated anti-digoxigenin antibody. 4-methyl-umbelliferyl-phosphate was used as a fluorogenic substrate. Amplification of 10 fg chromosomal target DNA was detected by this 'DNA enzyme immuno assay (DEIA)' technique, corresponding to seven genome copies. Our study supports the presumption that the tuf gene proves to be a suitable target sequence for the PCR based detection of any bacterial species. Furthermore, hybridization of PCR fragments with radio-labelled DNA probes should no longer be necessary, because a very sensitive non-radioactive test system can easily be established with the 'DEIA' technique. PMID- 8684380 TI - Essential myoclonus and myoclonic dystonia. AB - This review explores the history and use of the terms essential myoclonus and myoclonic dystonia. In addition, the review proposes that hereditary essential myoclonus and dominantly inherited myoclonic dystonia, with lightning jerks and dramatic response to alcohol, are the same disease, although proof of this hypothesis must come from ongoing genetic studies. PMID- 8684381 TI - An appraisal of the antiparkinsonian activity of piribedil in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine-treated common marmosets. AB - The D2 dopamine agonist piribedil is not widely used in the treatment of Parkinson's disease because it was thought to be effective mainly on parkinsonian tremor and to produce a high incidence of peripheral side effects, particular nausea. In this study, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates to reevaluate the antiparkinsonian ability of piribedil after its oral administration in the presence or absence of domperidone pretreatment. Adult common marmosets (Callithrix jacchus) were treated with the nigral toxin MPTP to induce a parkinsonian syndrome characterised primarily by bradykinesia and other motor deficits. Oral administration of a solution of piribedil [1-(3,4-methylenedioxybenzyl)-4-(2-pyrimidinyl)piperazine] produced a dose-related reversal of all MPTP locomotor and behavioural deficits. However, this effect was short lived and associated with unwanted effects, particular nausea and retching, which clearly hindered locomotion. In contrast, after pretreatment with the peripheral dopamine antagonist domperidone, administration of piribedil did not induce nausea or retching in MPTP-treated marmosets. In these animals, piribedil caused a more marked and longer lasting enhancement of locomotor activity and a further reduction in behavioural deficits than that observed after administration of piribedil alone. In addition, piribedil induced increased vigilance and awareness. These data show that piribedil can reverse akinesia and rigidity in MPTP-treated primates. In addition, they show the drug to be effective without peripheral side effects when used in conjunction with domperidone. These data indicate that piribedil should be an effective monotherapy for Parkinson's disease. PMID- 8684382 TI - Unified Huntington's Disease Rating Scale: reliability and consistency. Huntington Study Group. AB - The Unified Huntington's Disease Rating Scale (UHDRS) was developed as a clinical rating scale to assess four domains of clinical performance and capacity in HD: motor function, cognitive function, behavioral abnormalities, and functional capacity. We assessed the internal consistency and the intercorrelations for the four domains and examined changes in ratings over time. We also performed an interrater reliability study of the motor assessment. We found there was a high degree of internal consistency within each of the domains of the UHDRS and that there were significant intercorrelations between the domains of the UHDRS, with the exception of the total behavioral score. There was an excellent degree of interrater reliability for the motor scores. Our limited longitudinal database indicates that the UHDRS may be useful for tracking changes in the clinical features of HD over time. The UHDRS assesses relevant clinical features of HD and appears to be appropriate for repeated administration during clinical studies. PMID- 8684383 TI - Core Assessment Program for Intracerebral Transplantation in Huntington's Disease (CAPIT-HD). AB - Studies in Parkinson's disease using the Core Assessment Program for Intracerebral Transplantation (CAPIT) protocol have demonstrated that grafts of embryonic mesencephalic cells into striatum can survive, grow, and exert useful clinical effects. Attention in now being directed toward neural grafting in other conditions, such as Huntington's disease. As a precondition for grafting of embryonic striatal cells into diseased striatum in this complex motor and psychiatric disorder, not only is further basic research needed, but also a thorough and wide-ranging assessment protocol is essential. This article presents such a CAPIT-HD assessment protocol. PMID- 8684384 TI - Variable phenotype of rapid-onset dystonia-parkinsonism. AB - Rapid-onset dystonia-parkinsonism (RDP) is an autosomal dominant disorder characterized by the rapid onset of dystonic spasms and parkinsonism over a period of a few hours to weeks after their onset. We have seen two additional members of this previously reported family with RDP who present with a more gradual progression of their disorder over 6-18 months. One of these individuals experienced the rapid progression of symptoms 2 years after an initial stabilization of his condition. The RDP phenotype is variable, and presentation may be gradual in some cases. Cerebrospinal fluid neurotransmitter levels in these two and other family members suggest involvement of the dopaminergic pathways in RDP. PMID- 8684385 TI - Olivopontocerebellar pathology in multiple system atrophy. AB - Olivopontocerebellar atrophy (OPCA) is widely accepted as part of the neuropathological spectrum of multiple system atrophy (MSA). The distribution of affected sites in the olivopontocerebellar (OPC) system and their interrelationship remain poorly understood due to lack of quantitative studies. To further investigate the OPC pathology in MSA, we performed a morphometric analysis of 20 MSA cases and eight healthy controls. In the MSA cases, mean neuronal cell densities were significantly reduced in (medial and dorsal) accessory and principal inferior olives, pontine nuclei, cerebellar vermis (except nodulus), and hemispheres. Inferior olives and pontine nuclei were more severely affected than cerebellar Purkinje cells in most cases. Cerebellar Purkinje cells were more severely depleted in vermis rather than in hemisphere. There was a poor topographic correlation between neuronal cell loss in inferior olives and cerebellar cortex. These results suggest a primary degeneration of olivopontine nuclei and cerebellar Purkinje cells in OPCA. Inferior olives, pontine nuclei and cerebellar cortex were all significantly more severely affected in cases with a pure or predominating cerebellar syndrome (OPCA type, n = 4) compared to those with pure or predominating parkinsonism (SND type, n = 14). However, although cerebellar signs had been noted in life in only six cases, morphometry revealed OPCA in 17 of the 20 MSA brains. PMID- 8684386 TI - Haplotype analysis at the DYT1 locus in Ashkenazi Jewish patients with occupational hand dystonia. AB - Genetic haplotypes at five marker loci that are closely linked to the DYT1 gene on chromosome 9q were determined in 10 Ashkenazi Jewish patients with focal hand dystonia (eight with musician's cramp, two with writer's cramp). The founder haplotype associated with > 90% of cases generalized dystonia in the Ashkenazi Jewish population could not be constructed from any of the twenty chromosomes. Potential haplotypes were determined, and no common haplotype was discerned in these patients. These findings argue against a role for the founder mutation in the DYT1 gene in the etiology of occupational hand dystonia in this ethnic group. Further, if the DYT1 gene is involved in these later onset dystonias, there is no evidence for a common mutation in the Ashkenazic Jewish population. It appears that excessive, repetitive use, possibly in combination with ulnar neuropathy, may serve as the inciting cause of some focal dystonias. PMID- 8684388 TI - Dominantly inherited cerebello-olivary atrophy is not due to a mutation at the spinocerebellar ataxia-I, Machado-Joseph disease, or Dentato-Rubro-Pallido Luysian atrophy locus. AB - The dominantly inherited ataxias are characterized both by phenotypic variability (phenotypic heterogeneity) within the same genotype and overlapping phenotypes from different genotypes (genotypic heterogeneity). Therefore it is important to characterize specific clinical-neuropathologic phenotypes as precisely as possible at the genetic level. We describe a family with dominantly inherited ataxia of late adult onset with relatively "pure" cerebellar signs. Neuropathologic examination in two individuals from this family revealed findings consistent with cerebello-olivary atrophy, suggesting that this neuropathologic phenotype many run true within f families. Mutations at the spinocerebellar ataxia-I, Machado-Joseph disease, and dentatorubropallidoluysian atrophy loci were excluded by direct DNA analysis on the leukocytes of one living affected member. Thus we provide evidence that these mutations are not responsible for this particular phenotype of dominantly inherited ataxia. PMID- 8684387 TI - Proton magnetic resonance spectroscopy in Huntington's disease: evidence in favour of the glutamate excitotoxic theory. AB - The gene responsible for Huntington's disease (HD) has been located, but its action and the pathophysiology of HD remain unclear. Glutamate excitotoxicity may contribute to the striatal neurodegeneration seen in HD. We used localised proton magnetic resonance spectroscopy (MRS) of the brain to investigate five patients with early HD, one symptom-free gene carrier, and 14 healthy volunteers. Peak area ratios of choline-containing compounds (Cho), glutamine and glutamate (Glx), and N-acetyl moieties including N-acetylaspartate (NAx), relative to creatine (Cr), were calculated. Spectra were analysed from the striatum and the occipital and the temporal cortex. The HD patients all had an elevated Glx/Cr in spectra localised to the striatum, compared with healthy controls, and one patient also had an elevated thalamic Glx/Cr. The mean Glx/Cr was unaltered in the cortical spectra of HD patients. The asymptomatic gene carrier displayed no spectral abnormalities. Our findings suggest disordered striatal glutamate metabolism and may support the theory of glutamate excitotoxicity in HD. PMID- 8684389 TI - Response to botulinum toxin F in seronegative botulinum toxin A--resistant patients. AB - Botulinum toxin type A (btx A) injections are the most effective treatment for most patients with focal dystonia. Some patients who improve after btx A injections and later lose response have serologic evidence of antibodies to btx A with the mouse neutralization assay (seropositive patients). Another group of patients who lose response to btx A do not have detectable antibodies (seronegative patients). Seropositive patients may improve after injections of botulinum toxin type F (btx F), an alternative serotype of botulinum toxin. We treated nine seronegative resistant patients with btx F. None of these patients had muscle atrophy after injection with btx A. Five of the nine had improvement after btx F injection that was sustained for at least three consecutive btx F injections. This observation is consistent with the hypothesis that btx resistance in seronegative patients is caused by undetected antibodies to btx A. If this be the case, then there may be techniques for preventing or reversing btx resistance, as in the case of resistance of factor VIII in the treatment of hemophilia A. PMID- 8684390 TI - Reliability of patient completion of the historical section of the Unified Parkinson's Disease Rating Scale. AB - Evaluating the reliability of self-assessed disability in patients with Parkinson's disease (PD) is important for therapeutic trials epidemiologic surveys. This is the first study to examine the interrater reliability between physician and patient in the historical section of the Unified Parkinson's Disease Rating Scale (UPDRS). Thirty consecutive subjects with idiopathic PD self administered the historical section of a modified UPDRS. This instrument was then readministered to these 30 subjects by a neurologist. Interobserver reliability was assessed with the weighted kappa statistic (kw). The kw for each of the 17 items in the historical section of the UPDRS ranged from 0.63 to 1.0 (moderate to excellent agreement). Total kw = 0.83 (95% confidence interval = 0.79-0.87). There were no correlations between kw and age, disease duration, dose of levodopa, Hoehn and Yahr score, Schwab and England score, or modified Mini-Mental State score. Nondemented subjects with PD may reliably assess their level of disability by self-administering the historical section of the UPDRS. This has important implications for the reliable use of self-administered disability instruments for clinical research. PMID- 8684391 TI - Rhythmic auditory stimulation in gait training for Parkinson's disease patients. AB - Rhythmic auditory stimulation (RAS) was used as a pacemaker during a 3-week home based gait-training program for Parkinson's disease (PD) patients (n = 15). Electromyogram (EMG) patterns and stride parameters were assessed before and after the test without RAS to evaluate changes in gait patterns. Data were compared with those of two control groups (n = 11), who either did not participate in any gait training or who participated in an internally self-paced training program. RAS consisted of audiotapes with metronome-pulse patterns embedded into the on/off beat structure of rhythmically accentuated instrumental music. Patients who trained with RAS significantly (p < 0.05) improved their gait velocity by 25%, stride length by 12%, and step cadence by 10% more than self paced subjects who improved their velocity by 7% and no-training subjects whose velocity decreased by 7%. In the RAS-group, timing of EMG patterns changed significantly (p < 0.05) in the anterior tibialis and vastus lateralis muscles. Evidence for rhythmic entrainment of gait patterns was shown by the ability of the RAS group to reproduce the speed of the last training tape within a 2% margin of error without RAS. PMID- 8684392 TI - Occupation, education, and Parkinson's disease: a case-control study in an Italian population. AB - Current epidemiologic data on the association between occupational exposures and Parkinson's disease (PD) are inconsistent. In a case-control study, we investigated the associations between occupation and PD and between education and PD. The cases (n = 62) were those identified in a prevalence survey (door-to door, two-phase) of three Sicilian municipalities, as a November 1, 1987. We then randomly selected from the general population two controls for each case, matched for age ( +/- year), sex, and municipality (n = 124). Information on current and past occupations and education for cases and controls was obtained during the survey. Subjects who worked for most of their lives as farmers were not at increased risk of PD (OR = 0.6; 95% CI = 0.3-1.3). Neither were subjects who worked for most of their lives in other occupations (e.g., housewives, fishermen, factory workers, salesmen, craftsmen, clerks). PD was not associated with low education. Our findings suggest that farming, as a broad occupational category, does not play a major role in the causation of PD. PMID- 8684393 TI - DC60: an example of one of the 450 cases that compose the Denny-Brown collection of primate lesion material. AB - The Denny-Brown collection consists of films depicting the behavioral responses of approximately 450 monkeys after central nervous system lesions; operative, behavioral, and neuropathologic descriptions; and histologic slides. This collection is available for use by interested investigators. This report describes one case, DC60, to provide an example of the types of material that are available and how these materials might be used better to understand the nervous system. To demonstrate how precisely the actual lesions can be defined and compared with the planned ablations, this report also includes a detailed evaluation of the extent of the lesions made in this case, based on the histologic slides and on photographs of the brain taken before histologic processing. PMID- 8684394 TI - Rapid eye movement sleep behavior disorder preceding Parkinson's disease with therapeutic response to levodopa. AB - Rapid eye movement (REM) sleep behavior disorder (RBD) involves complex behavior and a loss of muscle atonia occurring during REM sleep. Half of these patients with RBD have an underlying neurologic disorder including dementia, olivopontocerebellar atrophy, subarachnoid hemorrhage, and cerebrovascular disease. Clonazepam is the drug of choice for RBD. RBD has been rarely reported to precede the onset of Parkinson's disease (PD). Three patients are presented here whose RBD preceded the onset of PD by several years, and both the symptoms of PD and RBD improved with levodopa treatment. It is postulated that levodopa ameliorates RBD by suppressing REM sleep, and it remains to be seen whether levodopa can be an alternative to clonazepam in idiopathic RBD without PD. PMID- 8684395 TI - Ataxia without telangiectasia masquerading as benign hereditary chorea. AB - We report a nonconsanguineous family in whom two (of three) sons developed isolated chorea in early childhood, suggesting a diagnosis of benign hereditary chorea (BHC). However, cerebellar ataxia and oculomotor apraxia, without telangiectasia, subsequently developed. Chromosome analysis showed increased radiosensitivity in both brothers and translocations in the younger one. We conclude that ataxia with chromosomal instability may masquerade as BHC in some patients. PMID- 8684396 TI - Delayed-onset dystonia secondary to unilateral schizencephaly. PMID- 8684397 TI - Action myoclonus as an early clinical sign of carcinomatous meningitis. PMID- 8684398 TI - The effect of dancing on dystonia. PMID- 8684399 TI - Induction of microsomal enzymes in liver of rats treated with cyclohexanol. AB - The S9 fraction obtained from rats orally pretreated for 3 days with cyclohexanol was able to activate the pro-mutagen N-nitrosodimethylamine (NDMA) into highly mutagenic metabolite(s) detected in the TA100 strain of Salmonella typhimurium. NDMA was not mutagenic when uninduced S9 was used as metabolic source but was approximately twice more mutagenic with cyclohexanol-induced S9 compared to ethanol-induced S9. Separation of microsomal proteins by sodium dodecylsulfate gel electrophoresis, displayed protein bands situated in the range of 50,000 to 52,000 molecular weight induced by both, ethanol and cyclohexanol. These results are evidence of the induction properties of cyclohexanol. PMID- 8684400 TI - Studies on the genotoxicity of tamoxifen citrate in mouse bone marrow cells. AB - The genotoxic effects of tamoxifen citrate, an anti-oestrogenic drug, were studied using mouse bone marrow chromosome aberration assay (CA) and micronucleus (MN) test. The dose and time yield effects of the drug were investigated after repeated administration of various doses of the drug for 10 days. The doses used were, 0.1, 0.2, 0.4 and 0.8 mg/kg/day. Bone marrow preparations were made at 24, 48, 72 and 96 h after the last administration. The anticancer drug cyclophosphamide (CP) at a dose of 100 mg/kg was used as positive control. A statistically significant chromosomal aberration and MN induced by tamoxifen revealed its clastogenic potency. PMID- 8684401 TI - Selective induction of micronuclei in the rat/mouse colon and liver by 1,2 dimethylhydrazine: a seven-tissue comparative study. AB - 1,2-Dimethylhydrazine (DMH) was administered to both genders of mice and rats by oral gavage for 3 days. Twenty-four hours later, an assessment of the incidence of micronucleated cells was made in the bone marrow and sections of the gastrointestinal tract. An increase in micronucleated cells was observed in the colon of both genders of both species of rodent. Negative responses were observed in the forestomach, stomach, duodenum, intestine of both species. The bone marrow micronucleus assays were essentially negative, but the absence of a precise definition of the MTD precludes a definitive conclusion from being drawn. These results are consistent with the selective carcinogenicity of DMH to the colon of the rodent GI-tract. DMH is also known to be carcinogenic to rat and mouse liver and, although it is known to induce micronuclei in the hepatocytes of rats, no such data exist for the mouse. Consequently, mice were administered DMH on 13 successive days, followed by 2/3 partial hepatectomy and assessment of micronucleated hepatocytes. A strong positive liver micronucleus assay response was observed. Thus, DMH selectively induces micronuclei in the colon and liver of rats and mice, consistent with its carcinogenicity to these two tissues. No qualitative differences between the genders was observed in any of the assays. These results indicate that the assessment of genetic toxicity in rodents should not rely solely on assays made in bone marrow. PMID- 8684402 TI - Biochemical changes associated with the adaptive response of human keratinocytes to N-methyl-N'-nitro-N-nitrosoguanidine. AB - Exposure of cells to low doses of radiation or chemicals renders them more resistant to higher doses of these agents. This phenomenon, termed adaptive response, was studied in quiescent human keratinocytes exposed to the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The cells were adapted with 2.5 nM MNNG for 60 min and challenged immediately thereafter with 2.5 microM MNNG for 30, 45 or 60 min. Clonogenic survival studies revealed that adapted cells were more resistant to the subsequent challenge treatment (up to 30% higher survival) than unadapted cells. In addition, formation of DNA strand breaks was lower in adapted cells. We monitored poly-ADP-ribosylation activity during expression of the adaptive response both at the substrate as well as the product level. NAD+ utilization in adapted and non-adapted cells exposed to the high dose of MNNG was similar, but recovery from NAD+ depletion was faster in low-dose pretreated cells. Induction of poly(ADP-ribose) formation was more than 2 times higher in low-dose adapted cells and this was associated with the formation of a distinct class of ADP-ribose polymers, i.e., branched polymers. These polymers exhibit a very high binding affinity for histones and can displace them from DNA. Elevated levels of poly(ADP-ribose) and, particularly, synthesis of branched polymers may play a critical role in low-dose adaptation. PMID- 8684403 TI - Suppressive effects of retinoids, carotenoids and antioxidant vitamins on heterocyclic amine-induced umu C gene expression in Salmonella typhimurium (TA 1535/pSK 1002). AB - Effects of retinoids, carotenoids and antioxidant vitamins were studied by mutagen-induced umu C gene expression system in Salmonella typhimurium (TA 1535/pSK 1002). Retinol (vitamin A), retinol acetate and retinoic acid showed remarkable inhibitory activities, whereas retinol palmitate exhibited significant but weak activity for umu C gene expression in tester bacteria induced by 3-amino 3,4-dimethyl-5H-pyrido[4.3-b]indol (Trp-P-1) in the presence of hepatic metabolizing enzymes (S9 mixture). Carotenoids having provitamin A activity (beta carotene and canthaxanthin) exhibited moderate suppressive effects on the same experimental system. The ranks of suppressive activities were retinol > retinol acetate > retinoic acid > canthaxanthin > beta-carotene > retinol palmitate and their doses for inhibition by 50% (ID50) were estimated to be 1.2 x 10(-7), 3.0 x 10(-7), 5.4 x 10(-7), 1.5 x 10(-6), 4.0 x 10(-5) and 6.0 x 10(-5) M, respectively. However, they did not cause significant inhibition on umu C gene expression induced by direct-acting mutagen (adriamycin or mitomycin C) in the absence of S9 mixture. Inhibition of umu gene expression appears to be due to inhibition of P450-mediated metabolic activation of the heterocyclic amine Trp-P 1. Ascorbic acid (vitamin C) showed weak but significant suppressive activity at high-dose concentrations (3 x 10(-6) - 10(-4)M). However, alpha-tocopherol did not exhibit significant suppression at all dose concentrations. The significance of the experimental results is discussed from the viewpoint of the chemoprevention against genotoxicity associated with carcinogenesis. PMID- 8684405 TI - In vitro studies on the genotoxicity of 2,4-dichloro-6-nitrophenol ammonium (DCNPA) and its major metabolite. AB - 2,4-dichloro-6-nitrophenol ammonium (DCNPA) is used as a herbicide. However, information on the potential health hazards of DCNPA is limited. In a previous study, we found that DCNPA is genotoxic to Bacillus subtilis and yeast. Further studies were performed to determine whether DCNPA and its major metabolite, 2,4 dichloro-6-aminophenol (DCAP), can induce reverse mutations in Salmonella, gene mutations at the HPRT locus, sister chromatid exchanges (SCEs) and micronuclei (MN) in V79 cells. Results show that DCNPA does not produce a positive response for any endpoint at concentrations tested. However, treatment of V79 cultures with DCAP caused a significant increase in SCEs and MN in a concentration dependent manner. These results indicate that DCAP damages DNA and causes chromosomal aberrations in V79 cells. Therefore, DCNPA could pose potential health hazards to populations exposed to this herbicide. PMID- 8684404 TI - Urinary promutagens of smokers: comparison of concentration methods and relation to cigarette consumption. AB - Different extraction techniques can be used to concentrate the promutagens of cigarette smokers' urine before evaluation of their mutagenic potency by Ames test. In this study, three solid adsorbents, C18, XAD2 and CN were compared for their ability to concentrate the promutagens of smokers' urine prior to acetone elution. C18 extracts were observed to have a higher promutagenicity than XAD2 and CN extracts. The mutagenicity of smokers' urine depended on the smoking habits, and a strong correlation was observed between urinary promutagenicity, daily cigarette consumption, and the tobacco type (black or blond). Smokers of black tobacco had a higher urinary genotoxicity than smokers of blond tobacco, after taking into account the level of tobacco consumption. Urinary promutagenicity did not appear to depend on the tar level of cigarettes. PMID- 8684406 TI - Revalidation of the in vitro alkaline elution/rat hepatocyte assay for DNA damage: improved criteria for assessment of cytotoxicity and genotoxicity and results for 81 compounds. AB - The in vitro alkaline elution/rat hepatocyte assay is a sensitive assay for genotoxicity, measured as DNA strand breaks induced in primary cultures of rat hepatocytes after 3-h treatments with test compounds. Since DNA degradation can be rapid and extensive in dead and/or dying cells, the original criteria for a positive result in the assay were that a compound induce a 3.0-fold or greater increase in the elution slope (for the terminal phase of alkaline elution from 3 to 9 h) in the absence of significant cytotoxicity (defined as relative cell viability of less than 70% by trypan blue dye exclusion; TBDE). Recently we have shown that false-positive results can still be obtained due to cytotoxicity when loss of membrane integrity is a late event in toxic cell death relative to the induction of endonucleolytic DNA degradation. To improve the ability of the assay to discriminate between genotoxic vs. cytotoxic effects of chemicals, we have evaluated additional assays of cytotoxicity including cell adenosine triphosphate (ATP) and potassium (K+) content, tetrazolium dye reduction (MTT), TBDE after a further 3-h recovery incubation without test chemicals (delayed toxicity), cell blebbing and endonucleolytic DNA degradation (double-strand breaks; DSBs) assessed by pulsed-field gel electrophoresis (PFGE). We have also evaluated 2 parameters derived from the elution data which can indicate extensive, cytotoxicity-induced DNA degradation: the fraction of the DNA recovered in the neutral lysis/rinse fraction and the gamma-intercept of the extrapolation of the 3-9-h segment of the elution curve. Twenty-eight rodent non-carcinogens that are negative (or inconclusive) in the Ames assay with no, or limited, other evidence of genotoxicity, and 33 genotoxins, most of which are also carcinogens, were evaluated. The results showed that DNA degradation as measured by a 1-h PACE (Programmed Autonomously Controlled Electrodes)/PFGE assay was a sensitive indicator of cytotoxicity which correlated well with results of the other cytotoxicity indicators. The delayed TBDE (after a 3-h recovery), intracellular potassium and ATP assays as well as the gamma-intercept parameter were also shown to be sensitive and in some cases complementary measures of cytotoxicity. Using new criteria based on these data of an induced slope (treatment slope-negative control slope) of 0.020 for the 3- to 9-h elution period and cytotoxicity limits of 70% relative viability for the delayed TBDE assay and 50% for intracellular ATP content, the assay scores the genotoxicity of these 61 reference compounds with an overall accuracy of 92%. Test results using these new criteria are provided for an additional 20 compounds (5 non-genotoxic carcinogens and 15 compounds whose genotoxic and carcinogenic potential are unknown or equivocal). PMID- 8684407 TI - The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. AB - BACKGROUND: Men with benign prostatic hyperplasia can be treated with alpha 1 adrenergic-antagonist drugs that relax prostatic smooth muscle or with drugs that inhibit 5 alpha-reductase and therefore reduce tissue androgen concentrations. However, the effects of the two types of drugs have not been compared. METHODS: We compared the safety and efficacy of placebo, terazosin (10 mg daily), finasteride (5 mg daily), and the combination of both drugs in 1229 men with benign prostatic hyperplasia. American Urological Association symptom scores and peak urinary-flow rates were determined at base line and periodically for one year. RESULTS: The mean changes from base line in the symptom scores in the placebo, finasteride, terazosin, and combination-therapy groups at one year were decreases of 2.6, 3.2, 6.1, and 6.2 points, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). The mean changes at one year in the peak urinary-flow rates were increases of 1.4, 1.6, 2.7, and 3.2 ml per second, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). Finasteride had no more effect on either measure than placebo. In the placebo group, 1.6 percent of the men discontinued the study because of adverse effects, as did 4.8 to 7.8 percent of the men in the other three groups. CONCLUSIONS: In men with benign prostatic hyperplasia, terazosin was effective therapy, whereas finasteride was not, and the combination of terazosin and finasteride was no more effective than terazosin alone. PMID- 8684409 TI - Images in clinical medicine. Rabies. PMID- 8684408 TI - Invasive group A streptococcal infections in Ontario, Canada. Ontario Group A Streptococcal Study Group. AB - BACKGROUND: Several reports suggest that the incidence of invasive group A streptococcal infections, including streptococcal toxic shock syndrome and necrotizing fasciitis, is increasing. METHODS: During 1992 and 1993 we conducted prospective, population-based surveillance of invasive group A streptococcal disease in Ontario, Canada. We reviewed clinical and laboratory records, searched for secondary cases of invasive disease, and cultured specimens from household contacts. RESULTS: We identified 323 patients with invasive group A streptococcal infections, for an annual incidence of 1.5 cases per 100,000 population. The rates were highest in young children and the elderly. Fifty-six percent of the patients had underlying chronic illness. Risk factors for disease included infection with the human immunodeficiency virus, cancer, diabetes, alcohol abuse, and chickenpox. The most common clinical presentations were soft-tissue infection (48 percent), bacteremia with no septic focus (14 percent), and pneumonia (11 percent). Necrotizing fasciitis occurred in 6 percent of patients, and toxic shock in 13 percent. The mortality rate was 15 percent overall, but it was 29 percent among those over 64 years of age (P<0.001) and 81 percent among those with toxic shock (P<0.001). Fourteen percent of the cases were nosocomial, and 4 percent occurred in nursing home residents, often in association with disease outbreaks. Invasive disease occurred in 2 household contacts of patients with infection, for an estimated risk of 3.2 per 1000 household contacts (95 percent confidence interval, 0.39 to 12 per 1000). CONCLUSIONS: The elderly and those with underlying medical conditions are at greatest risk for invasive group A streptococcal disease, toxic shock, and necrotizing fasciitis. Invasive steptococcal infection is associated with a substantial risk of transmission in households and health care institutions. PMID- 8684410 TI - Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 26-1996. A seven-year-old boy with fever, lymphadenopathy, hepatosplenomegaly, and prominent eosinophilia. PMID- 8684411 TI - Management of acute mesenteric ischemia. PMID- 8684412 TI - Management of acute mesenteric ischemia. PMID- 8684413 TI - Management of acute mesenteric ischemia. PMID- 8684414 TI - Management of acute mesenteric ischemia. PMID- 8684415 TI - Management of acute mesenteric ischemia. PMID- 8684416 TI - Management of acute mesenteric ischemia. PMID- 8684417 TI - Effect of benazepril in chronic renal insufficiency. PMID- 8684418 TI - Effect of benazepril in chronic renal insufficiency. PMID- 8684419 TI - The physician work force in the United States. PMID- 8684420 TI - The physician work force in the United States. PMID- 8684421 TI - The physician work force in the United States. PMID- 8684422 TI - Primary care physicians and health promotion. PMID- 8684423 TI - Primary care physicians and health promotion. PMID- 8684424 TI - Prozac or prilosec for gastric ulcer? PMID- 8684425 TI - Synergy of fluconazole with macrophages for antifungal activity against Candida albicans. AB - The possible between macrophages and fluconazole for antifungal activity against different isolates of C. albicans was studied. The susceptibility of C. albicans isolates to fluconazole (FCZ), when incubated in RPMI-1640 with 10% fetal bovine serum (FBS) and 10% fresh mouse serum (test medium, TM) was determined by using a quantitative culture methodology, Multiplication of isolate Sh27 was strongly inhibited by FCZ, even at 1.0 microgram/ml. However, FCZ even at 100 microgram/ml was not fungicidal. Resident murine peritoneal macrophages (MP) incubated for 48 h in RPMI-1640 + 10% FBS (tissue culture medium, TCM), then challenged with Sh27 in TM for 24 h, were fungistatic (20 +/ 9%, n = 4). Cultured macrophages synergized with FCZ (10 micrograms/ml) for fungicidal activity when co-cultured with sh27 in TM for 24 h (46 +/ 8%) and for 48 h (74 +/ 5%), n = 3. Macrophages and FCZ (10 micrograms/ml) could not synergize for significant killing of a less FCZ-sensitive C. albicans isolate 94-164. Multiplication of a FCZ-resistant isolate (94-20) was not inhibited by FCZ at 10 micrograms/ml TM; however, macrophages and FCZ (10 micrograms/ml) could synergize for fungistatic (64%), but not fungicidal, activity. PMID- 8684426 TI - Extracellular enzymatic activity of Microsporum canis isolates. AB - The enzymatic activity of 70 feline and canine Microsporum canis isolates was determined by the Api-Zym test. The liquid phase of cultures, inoculated into Tryptic Soy Broth, was used to examine 19 enzymes. Considerable differences were observed among the extracellular enzymatic patterns. All the isolates produced alkaline phosphatase and beta-glucosidase, while lipase (C14), trypsin, chymotrypsin, beta-glucuronidase, and alpha-fucosidase activity was never revealed. Esterase (C4) activity was present in 57 samples (81%), esterase lipase (C8) in 31 (44%), leucine arylamidase in 35 (50%), valine arylamidase and cystine arylamidase in 7 (10%), acid phosphatase in 64 (91%), naphthol-AS-BI phosphohydrolase in 60 (86%), alpha-galactosidase in 5 (7%), beta-galactosidase in 6 (8%), alpha-glucosidase in 25 (36%), N-acetyl-beta-glucosaminidase in 41 (58%), and alpha-mannosidase in 51 (73%). The beta-galactosidase activity of M. canis has not been reported previously. Remarkable variations of intensity for each enzymatic activity were also detected. It is believed that these results could provide basic data for further investigations on the pathogenic role of enzymes secreted by M. canis. PMID- 8684427 TI - Deactivation of macrophage oxidative burst in vitro by different strains of Histoplasma capsulatum. AB - It was previously reported that Histoplasma capsulatum (Hc) yeast not only failed to stimulate a murine macrophage oxidative burst (OB), but they also blunted or abolished OB stimulation by a subsequent encounter with potent stimuli such as zymosan or phorbol 12-myristate 13-acetate (PMA). The present studies show that macrophage deactivation is proportional to the time of incubation and the dose of Hc yeast that induce the deactivated state. Hc yeast derived from a virulent strain (G217B) are more efficient inducers of macrophage deactivation than similar preparations derived from the avirulent Downs Hc strain. Yeast cells of two other pathogenic fungi, Candida albicans and Cryptococcus neoformans are shown to stimulate rather than deactivate a macrophage OB. PMID- 8684428 TI - Skin colonization by Malassezia furfur in healthy children up to 15 years old. AB - The prevalence of M. furfur, a lipodependent fungus, in the skin of 0 to 15-year old healthy children was studied. Sterilized carpet was used to collect skin samples which were cultured in Oxgall medium (Difco) with 1% olive oil and incubated for 10 days at 37 degrees C M. furfur was recovered in 17.8% of infants, with similar findings in both sexes. The highest prevalence of M. furfur colonization was found among children of 0 to 18 months and 11 to 15-year-olds, with 23.3% and 26.7% respectively. PMID- 8684429 TI - Mycoflora and aflatoxin production in pigeon pea stored in jute sacks and iron bins. AB - The mycoflora, moisture content and aflatoxin contamination of pigeon pea (Cajanus cajan (L.) Millisp) stored in jute sacks and iron bins were determined at monthly intervals for a year. The predominant fungi on freshly harvested seeds were Alternaria spp., Botryodiplodia theobromae, Fusarium spp. and Phoma spp. These fungi gradually disappeared from stored seeds with time and by 5-6 months, most were not isolated. The fungi that succeeded the initially dominant ones were mainly members of the general Aspergillus, Penicillium and Rhizopus. Population of these fungi increased up to the end of one year storage. Higher incidence of mycoflora and Aspergillus flavus were recorded in jute-sack samples throughout the storage period. The moisture content of stored seeds was found to fluctuate with the prevailing weather conditions, being low during the dry season and slightly high during the wet season. The stored seeds were free of aflatoxins for 3 and 5 months in jute sacks and iron bins respectively. The level of aflatoxins detected in jute-sack storage system was considerably higher than that occurring in the iron bin system. Of 196 isolates of A. flavus screened, 48% were toxigenic in liquid culture (54% from jute sacks and 41% from iron bins). PMID- 8684430 TI - Influence of dietary rice culture material containing cyclopiazonic acid on certain serum biochemical parameters of broiler chickens. AB - Three hundred and forty-eight Vencob broiler chickens were fed diets containing Penicillium griseofulvum rice culture material with 0, 12.5, 25 and 50 ppm of the mycotoxin cyclopiazonic acid (CPA) for 28 days. Serum samples were collected from 9 birds in each group at weekly intervals to study the effect of sublethal doses of CPA on certain serum biochemical parameters. Significant reductions in weight gains (p < 0.01) and feed consumptions (p < 0.05) were observed at 25 and 50 ppm. Exocrine pancreas showed degenerative and necrotic changes in CPA fed chickens. The CPA had significant (p < 0.05) influence on serum total protein, albumin, cholesterol, amylase and lipase levels. CPA did not affect serum glucose levels. There was a decline in levels of total serum protein and albumin in CPA fed groups. But serum cholesterol, amylase and lipase showed dose-dependent increases. PMID- 8684432 TI - Qualitative Methods in Drug Abuse and HIV Research. Proceedings of a meeting. July 19-20, 1994. PMID- 8684433 TI - The daily life of heroin-addicted persons: the biography of specific methodology. PMID- 8684431 TI - Mycotoxin producing potential of Fusarium graminearum isolates from Uruguayan barley. AB - Twelve isolates of Fusarium graminearum were obtained from barely grains collected from different Uruguayan regions (harvest 1993-94). This was the predominant fungal species contaminating the crop due to a particular humid and warm season with cold nights conductive to toxin production The isolates were grown on moist, sterile rice, extracted with aqueous methanol, and examined for mycotoxin production. Zearalenone (ZEA) and the trichothecenes deoxynivalenol (DON), 3- and 15-acetyl-DON (AcDON), nivalenol (NIV), nivalenol (NIV), fusarenon X (FX) and T-2 toxin (T-2) were analyzed by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) and confirmed by gas chromatography mass spectrometry (GC-MS). Eleven of the 12 strains were DON and/or ZEA producers and 9 were AcDON positive. No NIV, or FX were detected. One strain produced T-2. The predominant acetyl-DON isomer was 15-AcDON. Mass-spectral analysis yielded detectable levels of other mycotoxins, 13-OH-apotrichothecenes, 11 epiapotrichothecenes, culmorin, sambucinol, and isotrichodermol being the most numerous. From the metabolic profiles it is suggested that Uruguayan F. graminearum strains belong to the chemotype IB (DON/15-AcDON). The predominance of this chemotype is in accordance with data from Canada, United States, Mexico and Argentina which have similar climatic conditions that would favor F. graminearum growth and mycotoxin production. PMID- 8684434 TI - Hitting a moving target: the use of ethnographic methods in the development of sampling strategies for the evaluation of AIDS outreach programs for homeless youth in New York City. PMID- 8684435 TI - Using focus groups in drug abuse and HIV/AIDS research. PMID- 8684436 TI - Qualitative research considerations and other issues in the study of methamphetamine use among men who have sex with other men. PMID- 8684437 TI - Team research methods for studying intranasal heroin use and its HIV risks. AB - Nineteen years ago Douglas (1976), a sociologist, vigorously recommended team field research. As Douglas noted, most ethnography is carried out using the "Lone Ranger" approach, which--while producing a number of excellent studies--generally limits the researcher to small groups or parts of large groups. In the few cases where field research teams were assembled (e.g., Becker et al. 1961), they tended to be homogeneous and to simply divide the group being studied between them and then essentially perform identical investigations (Douglas 1976). Douglas had a different vision. He saw the optimal field research group as heterogeneous, able to take on large projects, and able to take multiple perspectives. Such a team would have a variety of talents, experiences, and inclinations to call upon and would be more able to connect with the people being studied (e.g., by including indigenous members noted for their sociability). Douglas argued for giving greater consideration in designing research to society's conflictory nature and the desire and need for people to misinform, evade, construct false fronts, lie, and deceive themselves. According to Douglas, field research teams were an excellent means of coping with these problems. With various members using their array of talents to study a problem from multiple perspectives and through numerous webs of social cliques and networks, research teams would be particularly able to get behind people's facades and produce valid data. Though Douglas presented a compelling argument, there is little evidence of an increase in team field research, with one exception: research groups studying HIV/AIDS. The NADR program, funded by NIDA, created a number of field research teams across the United States that combined ethnographers with indigenous staff who, whatever their principal duties, could be used to assist in the research. These field research teams were also part of a survey research effort, and, in this fashion, quantitative and qualitative methods were combined to a degree uncommon in social science research. While many of these research groups have since disbanded, COIP was fortunate enough to remain in operation. The authors have described how they assembled a field research team composed of COIP members that combined ethnographers with selected indigenous staff to address a particular problem--new heroin use and its implications for HIV/AIDS. The goals the researchers set for the study would have been impossible for a single ethnographer or for a survey research team acting alone: to discern potential trends in new heroin use (though researchers were limited to studying mostly poor people); to develop fairly deep understandings regarding the study's central concerns (e.g., factors likely to influence the decision to inject heroin); and to quickly and economically collect data that were useful and valid. The authors note that all members of the research team had a host of other responsibilities; thus, this study was conducted as a sort of side job, that is, researchers had to fit it in when time and circumstances allowed. Altogether, the team field research method as applied to new heroin use in Chicago has enabled the research team to quickly and economically generate data that can be used to inform public policy on this issue (Ouellet et al. 1993; Ouellet et al., submitted). The authors believe that they can make a reasonably strong case for the following: New heroin use deserves greater study--the prevalence and incidence of use are probably sufficient to form a new cohort of potentially longtime users. New users are most likely to be found where major heroin street drug markets operate. Among youth there is a need for education about heroin--current users often report being surprised by heroin's addictiveness. Intranasal use is the predominant form of heroin administration among young, new users, and there is strong peer pressure against injection. Experimentation with injection, how PMID- 8684438 TI - Multimethod research from targeted sampling to HIV risk environments. PMID- 8684439 TI - Ethnography and the evaluation of needle exchange in the prevention of HIV transmission. PMID- 8684440 TI - The role of qualitative research in the Global Programme on AIDS at the World Health Organization. PMID- 8684441 TI - Drug use, AIDS, and ethnography: advanced ethnographic research methods exploring the HIV epidemic. AB - This chapter identifies and explores a small number of recently developed advanced ethnographic research methods. There are other techniques that provide an excellent adjunct to standard prevention research efforts, as well. These include the cultural models approach (Price 1987; Quinn and Holland 1987), anthropological decision modeling (Gladwin 1980, 1989; Plattner 1984; Young 1980), the advances in focus group techniques (Morgan 1989), the processes for using ethnographic interviews to create culturally competent survey questionnaires (Converse and Presser 1986), and the uses of systematic direct observations of public behavior. Some of these issues are explored in the references cited above, as well as in other recent articles (e.g., Trotter 1991; Trotter et al. 1995). The number of tools available to ethnographers is growing rapidly, and they promise to greatly increase the capacity to make important contributions to reducing the spread of HIV in human populations. PMID- 8684442 TI - Qualitative research methods in drug abuse and AIDS prevention research: an overview. PMID- 8684443 TI - Determining drug use patterns among women: the value of qualitative research methods. PMID- 8684444 TI - Applying the methodology of participant observation to the study of injection related HIV risks. PMID- 8684445 TI - AIDS myths that need eradicating. PMID- 8684447 TI - Rights issue take-up for British Biotech 'disappointing'. PMID- 8684448 TI - Brazilian researchers took first bite at 'new muscle'. PMID- 8684446 TI - Rival Parkinson's bills focus US debate on fetal tissue. PMID- 8684449 TI - Outbreak of E. coli infection in Japan renews concerns. PMID- 8684450 TI - Japanese AIDS expert files law suits for damages. PMID- 8684451 TI - The best athletes are better. PMID- 8684452 TI - Under arrest at atomic resolution. PMID- 8684453 TI - Evolutionary biology. Endless forms, several powers. PMID- 8684454 TI - Simple worms, complex genes. PMID- 8684455 TI - Links in childhood leukaemia. PMID- 8684456 TI - Organization of the visual cortex. PMID- 8684457 TI - Feeding inhibition by neuropeptide Y. PMID- 8684458 TI - Function of 14-3-3 proteins. PMID- 8684459 TI - A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. AB - The adenoviral oncoprotein E1A induces progression through the cell cycle by binding to the products of the p300/CBP and retinoblastoma gene families. A new cellular p300/CBP-associated factor (P/CAF) having intrinsic histone acetylase activity has been identified that competes with E1A. Exogenous expression of P/CAF in HeLa cells inhibits cell-cycle progression and counteracts the mitogenic activity of E1A. E1A disturbs the normal cellular interaction between p300/CBP and its associated histone acetylase. PMID- 8684460 TI - Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. AB - The crystal structure of the human p27Kip1 kinase inhibitory domain bound to the phosphorylated cyclin A-cyclin-dependent kinase 2 (Cdk2) complex has been determined at 2.3 angstrom. p27Kip1 binds the complex as an extended structure interacting with both cyclin A and Cdk2. On cyclin A, it binds in a groove formed by conserved cyclin box residues. On Cdk2, it binds and rearranges the amino terminal lobe and also inserts into the catalytic cleft, mimicking ATP. PMID- 8684461 TI - Using antibodies to perturb the coordination sphere of a transition metal complex. AB - Metal ions in the active sites of many metalloenzymes exhibit distinctive spectral and chemical features which are different from those of small inorganic complexes. These features are the result of the unusual geometric and electronic constraints that are imposed on the metal ion within the protein environment. Much effort has been invested to try to mimic this feature of metalloenzymes in synthetic systems, but this remains a formidable task. Here we show that one of the key lessons learned from the science of catalytic antibodies--that binding energy can be converted into chemical energy--can be exploited to 'fine-tune' the physicochemical properties of a metal complex. We show that an antibody's binding site can reversibly perturb the coordination geometry of a metal ion, and can stabilize a high-energy coordinated species. Specifically, antibodies designed to bind the organosilicon compound 1 also bind the geometrically similar Cu(I) complex 2. However, the antibody binds a slightly compressed form of 2, which is closer in size to 1. This distortion is manifested by a spectral shift--an 'immunochromic' effect. PMID- 8684462 TI - A new specimen of Ankarapithecus meteai from the Sinap Formation of central Anatolia. AB - Hominoid fossils from the Middle and Late Miocene are exceedingly rare, yet such material is necessary for determining hominoid phylogeny. We report here the discovery of a fossil hominoid partial skull from the Upper Miocene Sinap Formation of central Turkey that is the most complete known from the period of 18 to 3 Myr. Our fieldwork places the hominoid locality within a precisely dated geochronological and biostratigraphical framework that permits detailed comparisons with other fossil hominoids. Earlier discoveries of more fragmentary remains of Ankarapithecus meteai suggested affinities with the Asian hominoids Sivapithecus and Pongo. This new and nearly complete specimen reveals a combination of facial, mandibular, and dental features including a relatively narrow interorbital region, extensive frontal and maxillary sinuses, moderately developed supraorbital tori, square orbits, robust mandibular corpus, and incisor heteromorphy that is not matched in any extant or fossil hominoid. This configuration of features seems to support its placement as a stem member of the great ape and human clade. PMID- 8684463 TI - Infant leukaemia after in utero exposure to radiation from Chernobyl. AB - There has been no documented increase in childhood leukaemia following the Chernobyl accident. However, different forms of childhood leukaemia may not be equally susceptible to radiation carcinogenesis. Infant leukaemia is a distinct form associated with a specific genetic abnormality. Outside the former Soviet Union, contamination resulting from the Chernobyl accident has been highest in Greece and Austria and high also in the Scandinavian countries. All childhood leukaemia cases diagnosed throughout Greece since 1 January 1980 have been recorded. Here we report that infants exposed in utero to ionizing radiation from the Chernobyl accident had 2.6 times the incidence of leukaemia compared to unexposed children (95% confidence interval, 1.4 to 5.1; P approximately 0.003), and those born to mothers residing in regions with high radioactive fallout were at higher risk of developing infant leukaemia. No significant difference in leukaemia incidence was found among children aged 12 to 47 months. Preconceptional irradiation had no demonstrable effect on leukaemia risk at any of the studied age groups. PMID- 8684464 TI - Correct Hox gene expression established independently of position in Caenorhabditis elegans. AB - The Hox genes are expressed in a conserved sequence of spatial domains along the anteroposterior (A/P) body axes of many organisms. In Drosophila, position specific signals located along the A/P axis establish the pattern of Hox gene expression. In the nematode Caenorhabditis elegans, it is not known how the pattern of Hox gene expression is established. C. elegans uses lineal control mechanisms and local cell interactions to specify early blastomere identities. However, many cells expressing the same Hox gene are unrelated by lineage, suggesting that, as in Drosophila, domains of Hox gene expression may be defined by cell-extrinsic A/P positional signals. To test this, we have investigated whether posterior mesodermal and ectodermal cells will express their normal posterior Hox gene when they are mispositioned in the anterior. Surprisingly, we find that correct Hox gene expression does not depend on cell position, but is highly correlated with cell lineage. Thus, although the most striking feature of Hox gene expression is its positional specificity, in C. elegans the pattern is achieved, at least in part, by a lineage-specific control system that operates without regard to A/P position. PMID- 8684465 TI - BMP-4-responsive regulation of dorsal-ventral patterning by the homeobox protein Mix.1. AB - In an expression screen for factors that pattern or induce ventral mesoderm, we isolated a complementary DNA encoding Mix.1, a paired class homeobox gene with no previously known function. Injection of Mix.1 messenger RNA results in extensive blood formation in the whole embryo and transforms dorsal mesoderm to a ventral fate. Mix.1 expression is induced by bone morphogenetic protein-4 (BMP-4), and a dominant inhibitory mutant of Mix.1 can restore a dorsal axis in embryos ventralized by ectopic BMP-4 expression. Mix.1 can form heterodimers with the dorsalizing gene siamois, which encodes a homeodomain protein that is structurally similar to Mix.1. Furthermore, Mix.1 blocks the duplicated axis induced by ectopic siamois expression. Our findings indicate that Mix.1 participates in a BMP-4 signalling pathway to pattern ventral mesoderm, and suggest a model whereby dimerization of homeodomain proteins regulates dorsal ventral patterning. PMID- 8684466 TI - The mouse Engrailed-1 gene and ventral limb patterning. AB - During vertebrate limb development, positional information must be specified along three distinct axes. Although much progress has been made in our understanding of the molecular interactions involved in anterior-posterior and proximal-distal limb patterning, less is known about dorsal-ventral patterning. The genes Wnt-7a and Lmx-1, which are expressed in dorsal limb ectoderm and mesoderm, respectively, are thought to be important regulators of dorsal limb differentiation. Whether a complementary set of molecules controls ventral limb development has not been clear. Here we report that Engrailed-1, a homeodomain containing transcription factor expressed in embryonic ventral limb ectoderm, is essential for ventral limb patterning. Loss of Engrailed-1 function in mice results in dorsal transformations of ventral paw structures, and in subtle alterations along the proximal-distal limb axis. Engrailed-1 seems to act in part by repressing dorsal differentiation induced by Wnt-7a, and is essential for proper formation of the apical ectodermal ridge. PMID- 8684467 TI - Influence of dendritic structure on firing pattern in model neocortical neurons. AB - Neocortical neurons display a wide range of dendritic morphologies, ranging from compact arborizations to highly elaborate branching patterns. In vitro electrical recordings from these neurons have revealed a correspondingly diverse range of intrinsic firing patterns, including non-adapting, adapting and bursting types. This heterogeneity of electrical responsivity has generally been attributed to variability in the types and densities of ionic channels. We show here, using compartmental models of reconstructed cortical neurons, that an entire spectrum of firing patterns can be reproduced in a set of neurons that share a common distribution of ion channels and differ only in their dendritic geometry. The essential behaviour of the model depends on partial electrical coupling of fast active conductances localized to the soma and axon and slow active currents located throughout the dendrites, and can be reproduced in a two-compartment model. The results suggest a causal relationship for the observed correlations between dendritic structure and firing properties and emphasize the importance of active dendritic conductances in neuronal function. PMID- 8684468 TI - Critical role for beta7 integrins in formation of the gut-associated lymphoid tissue. AB - Immune defence against pathogens entering the gut is accomplished by lymphocytes in the gut-associated lymphoid tissue (GALT), a major compartment of the immune system. The GALT, comprising Peyer's patches, lamina propria lymphocytes and intra-epithelial lymphocytes of the intestine, is populated by lymphocytes that migrate there from the vasculature. Here we report that, in mice deficient for the beta7 integrin subfamily of adhesion molecules, the formation of the GALT is severely impaired. This is probably due to a failure of beta7-/- lymphocytes to arrest and adhere to the vasculature at the site of transmigration into the GALT. PMID- 8684469 TI - Role of kinases and the phosphatase calcineurin in the nuclear shuttling of transcription factor NF-AT4. AB - A new facet of calcium signalling involves the nuclear import of the NF-AT transcription factors from their dormant position in the cytoplasm. The protein phosphatase calcineurin appears to play an essential role in activating NF-AT nuclear import, as the calcineurin inhibitors cyclosporin A and FK506 block dephosphorylation and nuclear import of NF-AT (refs 4-7). Here we show that calcium signalling induces an association between NF-AT4 and calcineurin, and that these molecules are transported, as a complex, to the nucleus, where calcineurin continues to dephosphorylate NF-AT4. We propose that a nuclear complex of NF-AT4 and calcineurin maintains calcium signalling by counteracting a vigorous nuclear NF-AT kinase. PMID- 8684470 TI - RNA-catalysed RNA polymerization using nucleoside triphosphates. AB - The hypothesis that certain RNA molecules may be able to catalyse RNA replication is central to current theories of the early evolution of life. In support of this idea, we describe here an RNA that synthesizes RNA using the same reaction as that employed by protein enzymes that catalyse RNA polymerization. In the presence of the appropriate template RNA and nucleoside triphosphates, the ribozyme extends an RNA primer by successive addition of up to six mononucleotides. The added nucleotides are joined to the growing RNA chain by 3',5'-phosphodiester linkages. The ribozyme shows marked template fidelity: extension by nucleotides complementary to the template is up to 1,000 times more efficient than is extension by mismatched nucleotides. PMID- 8684471 TI - BSE transmission data cause confusion. PMID- 8684472 TI - Indian budget boosts AIDS research. PMID- 8684473 TI - Liability clause blocks talks on biosafety protocol. PMID- 8684474 TI - Medical developments get small investors' backing in Canada. PMID- 8684475 TI - Hot biology papers. PMID- 8684476 TI - Genetic testing and insurance. PMID- 8684477 TI - Look ma, no chromosomes! PMID- 8684478 TI - George D. Snell (1903-96) PMID- 8684479 TI - Genome analysis. PMID- 8684481 TI - Self-organization of microtubules into bipolar spindles around artificial chromosomes in Xenopus egg extracts. AB - Functional nuclei and mitotic spindles are shown to assemble around DNA-coated beads incubated in Xenopus egg extracts. Bipolar spindles assemble in the absence of centrosomes and kinetochores, indicating that bipolarity is an intrinsic property of microtubules assembling around chromatin in a mitotic cytoplasm. Microtubules nucleated at dispersed sites with random polarity rearrange into two arrays of uniform polarity. Spindle-pole formation requires cytoplasmic dynein dependent translocation of microtubules across one another. It is proposed that spindles form in the absence of centrosomes by motor-dependent sorting of microtubules according to their polarity. PMID- 8684480 TI - Cyclin encoded by KS herpesvirus. PMID- 8684482 TI - Detection of molecular gas in the quasar BR1202 - 0725 at redshift z = 4.69. AB - Although great efforts have been made to locate molecular gas--the material out of which stars form--in the early Universe, there have been only two firm detections at high redshift. Both are gravitationally lensed objects at redshift z approximately = 2.5 (refs 9-14). Here we report the detection of CO emission from the radio-quiet quasar BR1202 - 0725, which is at redshift z = 4.69. From the observed CO luminosity, we estimate that almost 10(11) solar masses of molecular hydrogen are associated with the quasar; this is comparable to the stellar mass of a present-day luminous galaxy. Our results suggest that BR1202 - 0725 is a massive galaxy, in which the gas is largely concentrated in the central region, and that is currently undergoing a large burst of star formation. PMID- 8684483 TI - Molecular gas and dust around a radio-quiet quasar at redshift 4.69. AB - Galaxies are believed to have formed a large proportion of their stars in giant bursts of star formation early in their lives, but when and how this took place are still very uncertain. The presence of large amounts of dust in quasars and radio galaxies at redshifts z > 4 shows that some synthesis of heavy elements had already occurred at this time. This implies that molecular gas--the building material of stars--should also be present, as it is in galaxies at lower redshifts (z approximately = 2.5, refs 7-10). Here we report the detection of emission from dust and carbon monoxide in the radio-quiet quasar BR1202 - 0725, at redshift z = 4.69. Maps of these emissions reveal two objects, separated by a few arc seconds, which could indicated either the presence of a companion to the quasar or gravitational lensing of the quasar itself. Regardless of the precise interpretation of the maps, the detection of carbon monoxide confirms the presence of a large mass of molecular gas in one of the most distant galaxies known, and shows that conditions conducive to huge bursts of star formation existed in the very early Universe. PMID- 8684484 TI - Increased bone formation in osteocalcin-deficient mice. AB - Vertebrates constantly remodel bone. The resorption of preexisting bone by osteoclasts and the formation of new bone by osteoblasts is strictly coordinated to maintain bone mass within defined limits. A few molecular determinants of bone remodelling that affect osteoclast activity have been characterized, but the molecular determinants of osteoblast activity are unknown. To investigate the role of osteocalcin, the most abundant osteoblast-specific non-collagenous protein, we have generated osteocalcin-deficient mice. These mice develop a phenotype marked by higher bone mass and bones of improved functional quality. Histomorphometric studies done before and after ovariectomy showed that the absence of osteocalcin leads to an increase in bone formation without impairing bone resorption. To our knowledge, this study provides the first evidence that osteocalcin is a determinant of bone formation. PMID- 8684485 TI - Induction of a specific muscle cell type by a hedgehog-like protein in zebrafish. AB - The notochord plays a central role in vertebrate development, acting as a signalling source that patterns the neural tube and somites. In in vitro assays, the secreted protein Sonic hedgehog mimics the inducing effects of notochord on both presomitic mesoderm and neural plate explants of amniote embryos, suggesting that both patterning activities of the notochord may be mediated by this protein in vivo. In zebrafish, however, mutants with disrupted notochord development lack a specific muscle cell type, the muscle pioneers, although they retain the ability to induce neural differentiation, raising the possibility that neural tube and somite patterning may be mediated by distinct signals. Here we describe a new member of the hedgehog family, echidna hedgehog, that is expressed exclusively in the notochord and has the ability to rescue the differentiation of muscle pioneer cells in mutants with no notochord. Moreover, we show that a combination of ectopic echidna hedgehog and sonic hedgehog expression induces supernumary muscle pioneers in wild-type embryos, suggesting that both signals act sequentially to pattern the developing somites. PMID- 8684486 TI - A non-muscle myosin required for embryonic polarity in Caenorhabditis elegans. AB - Daughter cells with distinct fates can arise through intrinsically asymmetrical divisions. Before such divisions, factors crucial for determining cell fates become asymmetrically localized in the mother cell. In Caenorhabditis elegans, PAR proteins are required for the early asymmetrical divisions that establish embryonic polarity, and are asymmetrically localized in early blastomeres, although the mechanism of their distribution is not known. Here we report the identification in C. elegans of nonmuscle myosin II heavy chain (designated NMY 2) by means of its interaction with the PAR-1 protein, a putative Ser/Thr protein kinase. Furthermore, injections of nmy-2 antisense RNA into ovaries of adult worms cause embryonic partitioning defects and lead to mislocalization of PAR proteins. We therefore conclude the NMY-2 is required for establishing cellular polarity in C. elegans embryos. PMID- 8684487 TI - Affinity maturation without germinal centres in lymphotoxin-alpha-deficient mice. AB - Affinity maturation by somatic hypermutation is thought to occur within germinal centres. Mice deficient in lymphotoxin-alpha (LT alpha-/- mice) have no lymph nodes or Peyer's patches, and fail to form germinal centres in the spleen. We tested whether germinal centres are essential for maturation of antibody responses to T-cell-dependent antigens. LT alpha-/- mice immunized with low doses of (4-hydroxy-3-nitrophenyl)acetyl-ovalbumin (NP-OVA) showed dramatically impaired production of high-affinity anti-NP IgG1. However, LT alpha-/- mice immunized with high doses of NP-OVA, even though they failed to produce germinal centres, manifested a high-affinity anti-NP IgG1 response similar to wild-type mice. Furthermore, when LT alpha-/- mice were multiply immunized with high doses of NP-OVA, the predominantly expressed anti-NP VH gene segment VH186.2 showed somatic mutations typical of affinity maturation. Thus, B-cell memory and affinity maturation are not absolutely dependent on the presence of germinal centres. PMID- 8684488 TI - 'Anaphase' and cytokinesis in the absence of chromosomes. AB - Anaphase and cytokinesis are key processes in the segregation of replicated chromosomes to the daughter cells: in anaphase, chromosomes move apart; in cytokinesis, a cleavage furrow forms midway between the separated chromosomes. Some evidence suggests that chromosomes may be involved both in controlling the timing of anaphase onset and in dictating the position of the cleavage furrow. Other evidence indicates that the controlling mechanisms are intrinsic to the spindle and the cell. Here we test these possibilities in grasshopper spermatocytes by observing spindles and cells after removal of chromosomes. We found that both anaphase and cytokinesis occur independently of chromosomes: stage-specific changes occur at an appropriate time and in the correct way, despite the absence of chromosomes. This finding is particularly noteworthy because chromosomes have an important impact on spindle microtubule assembly and the timing of anaphase onset in these cells. PMID- 8684489 TI - Autocatalytic processing of the 20S proteasome. AB - The Ntn (N-terminal nucleophile) hydrolases are enzymes with an unusual four layer alpha + beta fold. The amino-terminal residue (cysteine, serine or threonine) of the mature protein is the catalytic nucleophile, and its side chain is activated for nucleophilic attack by transfer of its proton to the free N terminus, although other active-site residues may also be involved. The four currently known Ntn hydrolases (glutamine PRPP amidotransferase, penicillin acylase, the 20S proteasome and aspartylglucosaminidase) are encoded as inactive precursors, and are activated by cleavage of the peptide bond preceding the catalytic residue. It has been suggested that autocatalytic processing is a common feature of Ntn hydrolases, and proceeds by an intramolecular mechanism determined by their common fold. Here we show that propeptide processing in the proteasome from Thermoplasma acidophilum is indeed autocatalytic, but is probably intermolecular. Processing is not required for assembly, is largely unaffected by propeptide length and sequence, and occurs before beta-subunit folding is completed. Although serine is an acceptable active-site nucleophile for proteolysis, and cysteine for processing, only threonine is fully functional in both. This explains why threonine is universally conserved in active proteasome subunits. PMID- 8684490 TI - Visualization of ordered genomic RNA and localization of transcriptional complexes in rotavirus. AB - In double-stranded-RNA (dsRNA) viruses found in animals, bacteria and yeast, the genome is transcribed within the structurally intact core of the virion with extraordinary efficiency. The structural organization of the genome and the enzymes involved in the transcription inside any of these viruses, critical for understanding this process, is not known. Here we report what we believe is the first three-dimensional characterization of the viral genome and the transcription complex in a prototypical dsRNA virus. Rotavirus is a large (diameter 1,000 A) icosahedral virus composed of three capsid protein layers and 11 dsRNA segments. It is the most important cause of gastroenteritis in children, accounting for over a million deaths annually. We show that viral dsRNA forms a dodecahedral structure in which the RNA double helices, interacting closely with the inner capsid layer, are packed around the enzyme complex located at the icosahedral 5-fold axes. The ordered RNA accounts for about 4,500 out of a total 18,525 base pairs in the genome, the largest amount of icosahedrally ordered RNA observed in any virus structure to date. We propose that the observed organization of the dsRNA is conducive for an orchestrated movement of the RNA relative to the enzyme complex during transcription. PMID- 8684491 TI - [Referral necessary in suspected foreign body aspiration]. PMID- 8684492 TI - [The treatment of Gaucher's disease in The Netherlands using enzyme substitution therapy]. PMID- 8684493 TI - [Xanthelasma palpebrarum]. PMID- 8684494 TI - [Guidelines for endocarditis prophylaxis; revision 1996. Commission Endocarditis Prophylaxis of the Netherland Heart Foundation]. PMID- 8684495 TI - [Fungi and yeasts isolated in mycological studies in skin and nail infections in The Netherlands, 1992-1993]. AB - OBJECTIVE: To describe fungi and yeasts isolated from skin and nail infections in the Netherlands. DESIGN: Retrospective. SETTING: Centraalbureau voor Schimmelcultures (CBS), Baarn, the Netherlands. METHOD: Results of mycological investigation of skin and nail samples in the period 1992-1993 were analysed. After a clinical diagnosis of mycosis, performed by dermatologists and general practitioners, material was sent to the CBS for mycological research. RESULTS: The clinical diagnosis of onychomycosis was rather accurate, especially if made performed by dermatologists. Mycoses of the skin were sometimes confused with other skin diseases. When microscopical observation showed a positive result, 93% of the cultures were positive as well. The main agent of onychomycosis was Trichophyton rubrum; T. mentagrophytes was more frequently isolated from tinea manuum/pedis and T. tonsurans from tinea corporis/cruris. Epidermophyton floccosum was only isolated from skin lesions and Microsporum canis, T. soudanense and T. verrucosum only from tinea corporis/cruris. The most important yeasts isolated were Trichosporon mucoides, Candida guilliermondii, C. parapsilosis, C. famata and Malassezia furfur. Other fungi isolated were either pigmented (melanin, carotene), thermophilic or belonged to the order of the Onygenales. CONCLUSION: Mycological research to confirm the clinical diagnosis of a skin mycosis is advisable. Species isolated differed in their predilection for different parts of the human body. Yeasts were mainly isolated as double infections. Apart from the dermatophytes there is a special group of fungi which can cause mycoses. PMID- 8684496 TI - [Cornea protection in ptosis induced by botulinum injection]. AB - Two patients, men aged 82 and 53 years, with weakness of the facial muscles after surgery in the posterior fossa had keratitis caused by the inability to blink and to close the eye. Botulinum toxin type A was injected into the levator palpebrae superioris muscle under electromyographic control. A selective, reversible paralysis of this muscle was induced without weakness of the anatomically related rectus superior muscle. This botulinum toxin-induced protective ptosis appeared to be effective and safe in the treatment and prevention of keratitis in patients with a temporary weakness of the facial muscles. PMID- 8684497 TI - [Introduction of exotic HIV-1 variants in The Netherlands]. PMID- 8684498 TI - [Travel experiences in Central and Eastern Europe: Latvia en route to the 26th floor]. PMID- 8684499 TI - [Opportunistic lung infections in patients with chronic obstructive pulmonary disease; a side effect of inhalation corticosteroids?]. PMID- 8684500 TI - [Pulmonary infection caused by Coccidioides immitis]. PMID- 8684501 TI - [Electroconvulsive therapy in therapy-resistant depression]. PMID- 8684502 TI - [ACE-inhibitors increase the risk of hypoglycemia in diabetics]. PMID- 8684503 TI - [Therapeutic (im)possibilities in Raynaud's phenomenon]. PMID- 8684504 TI - [Therapy of idiopathic and uremic restless legs syndrome]. AB - Sensory and motor symptoms of the limbs, motor restlessness and an urge to move only at rest are the characteristics of the restless legs syndrome (RLS), which often leads to severe sleep disturbances. The clinical diagnosis can be made on the basis of the typical history, normal neurological findings and, in some cases, a positive family history, and can be confirmed by polysomnography. The indication for treatment depends on the patient's discomfort and the severity of the sleep disturbances. L-DOPA is the treatment of first choice both in idiopathic and uremic RLS. A bedtime dose of 100-200 mg L-DOPA standard plus decarboxylase inhibitor is effective against mild and moderate sleep disturbances in RLS. Titration of the dosage and additional treatment with sustained-release preparations of L-DOPA should be applied individually. Opioids and dopamine agonists are effective alternative treatments in idiopathic RLS. Benzodiazepines are indicated only in individual cases. Besides L-DOPA, uremic RLS patients can be treated with opioids and benzodiazepines. Various approaches in the treatment of idiopathic and uremic RLS are reviewed and the practical management of therapy is outlined. PMID- 8684505 TI - [EDMUS--a new European databank for multiple sclerosis. A brief introduction of ongoing and planned multicenter studies within the scope of the "European Concentrated Action for Multiple Sclerosis"]. AB - EDMUS, the European Database for Multiple Sclerosis (MS), was established on the occasion of the first European Concerted Action for MS under the auspices of the European Community. The system is user-friendly and makes it possible to record and retrieve data relevant to MS. Within the framework of another European Concerted Action, several international multicenter trials are currently in progress. EVALUED, a validation of the EDMUS system, assesses the interrater variability; PRIMS examines the influence of pregnancy and the post-partum period on the course of MS; and PRESTIMUS investigates predictive factors in suspected MS. Further, planned studies include ERAZMUS (early azathioprine and interferon beta treatment in MS) and AZASTOP, which is designed to evaluate the effect of stopping azathioprine treatment. PMID- 8684506 TI - [Intracranial blood flow parameters in cerebral functional changes and cognitive cerebral performance]. AB - Extensive studies have revealed a close relationship between neuronal activity and regional cerebral blood flow. However, SPECT and PET, the technologies most commonly used in these studies, are of limited value for assessment of the dynamics of cerebral blood flow changes at different states of functional brain activity. The introduction of transcranial Doppler sonography and the extended application of stimuli presentation and perception have now been added to the investigator's armamentarium. Simple sensory stimulation (visual, acoustic and tactile) and complex mental tasks (viewing of complex pictures, tactile differentiation of objects) changed the blood flow velocity in the basal intracranial arteries. These changes corresponded to the current concepts of functional cortical organization. The magnitude of the flow velocity increases upon visual stimulation was dependent on the complexity of the stimuli used, and was up to 38% in our studies. The introduction of continuous and bilateral simultaneous Doppler recordings, the calculation of mean flow velocity from cardiac cycle to cardiac cycle and a specially designed averaging method for data analysis allowed effective elimination of non-specific influences and made it possible to demonstrate rapid changes of perfusion in both middle cerebral artery territories in direct response to hemisphere-specific tasks. These changes were correlated with known functional cerebral asymmetries. A language task, for instance, was associated with a significantly larger flow velocity increase in the middle cerebral artery of the dominant hemisphere than in the corresponding artery of the non-dominant hemisphere (5.2 +/- 1,8% vs 3.0 +/- 1.8%, p < 0.001). The excellent time resolution of this technology made it possible to record hemodynamic changes taking place in response to modifications of neuronal activity within less than 1 s. The shortest time interval between stimulus presentation and the first significant increase in flow velocity was on average 717 +/- 191 ms. The latency of less than 1 s suggest that the coupling between alterations of neuronal activity and the regional cerebral blood flow response is mediated by an remarkably rapid mechanism. PMID- 8684507 TI - [Germinoma of the pineal area. Long-term follow-up after stereotaxic biopsy]. AB - The current study analyses the long-term clinical course of 12 patients with pineal germinomas. The histological diagnosis was established by stereotactic biopsy in all cases. In 11 of the 12 cases the diagnosis was correct. There was no operative mortality or morbidity. All patients were treated by external radiotherapy. The median follow-up period for the surviving patients is 5.9 years (range 4.5-8.8 years). After radiotherapy, CT and MRI follow-up examinations showed complete tumor remissions with no local tumor recurrences in all cases. Two patients died of other, unrelated, illnesses 1.4 and 5.8 years after diagnosis of the pineal germinoma. Since long-term survival and morbidity do not document any superiority of operative resection of germinomas, the minimally invasive approach with stereotactic biopsy and radiotherapy is strongly advocated. There is no longer any justification for irradiating pineal tumors to check the diagnosis now that stereotactic biopsy is available. PMID- 8684508 TI - [Cavernoma. Indications for surgical removal and outcome]. AB - Between July 1990 and October 1994 26 patients were operated on for 26 intracranial and 2 intraorbital cavernous hemangiomas. We found seizures in 62% of our patients, focal neurological deficits and unspecific complains (like headache or dizziness) in 19% each. The average follow-up period was 12 months, 24 patients could be included in this study. 12/14 patients of the seizure group improved, 10/14 reported a complete relieve of their epilepsy. All 5 patients with focal deficits improved, among them 2 with no residual deficit. Finally 3/5 patients with unspecific complains improved, 2/5 remained unchanged. The functional morbidity was 4% (one slight aphasic syndrome), we did not have any mortality. Therefore we conclude that a neurosurgical treatment is indicated in any case of cavernous hemangioma with focal deficits or intractable epilepsy. The operation should also be considered in patients with supressed seizures by anti convulsants, if the malformation is not located in an eloquent area. Due to the risk of spontaneous bleeding (comparable to incidental aneurysms), the indication for a neurosurgical treatment mainly depends on the location of the cavernoma in cases of its accidental discovery. PMID- 8684509 TI - ["Tailoring" resections in drug refractory temporal lobe epilepsy]. AB - On the basis of results obtained from extensive pre- and intraoperative diagnostic investigations of 69 patients, minimalisation of epileptogenic brain tissue resection was strived for. The extent of resection ranged from selective amygdalohippocampectomy up to "en bloc" standard resections, and in rare cases even beyond these. In the majority of cases however, tailoring allowed smaller resections than the standard "en bloc" resections. The outcome of tailoring in regard to seizure control as well as verbal memory and visual performance show that this method should be favoured in epilepsy surgery of temporal lobe epilepsies. PMID- 8684510 TI - [Physostigmine in treatment of cerebellar ataxia]. AB - Cerebellar ataxias are still a challenging problem for neurologists, and to this day there exists no medical, physiotherapeutic, psychot-erapeutic or surgical therapy which constantly leads to a reduction of ataxic symptoms. In the pathophysiology of cerebellar ataxia a cholinergic defect has often been described. In a double-blind, cross-over study with 14 patients with cerebellar ataxia and an open follow-up, long-term study with 21 patients, the clinical effects of physostigmine capsules in doses up to 10 mg per day were studied. Moreover, a transdermal application (physostigmine patch) was developed, achieving constant physostigmine plasma levels for 24 h. Of 14 patients treated with physostigmine during the double-blind, cross-over study, nine could correctly distinguish between verum and placebo. They all showed small but constant improvements, clearly experienced by the patients. With the physostigmine patch, 12 of 14 patients improved. Thirteen of 14 patients decided to take part in open follow-up studies with physostigmine, and most of them preferred the physostigmine patch as long-term medication. To date, 21 patients with cerebellar ataxia have been treated with physostigmine. As far as we can judge at the end of a treatment period of at least 2 years, the progression of the disease could be stopped in 17 of 21 patients. These patients reported small but constant effects, and none wants to live without the physostigmine patch. PMID- 8684511 TI - [Reversible exogenous psychosis in thiazide-induced hyponatremia of 97 mmol/l]. AB - Severe hyponatraemia may be cause unconsciousness, vomiting, seizures or exogenous psychosis and is associated with a high mortality. We report on a 44 year-old woman who presented with somnolence and psychomotor unrest. After rousing stimuli she showed no verbal response and did not follow any instructions. For three days she suffered from nausea and vomiting. Laboratory values included a natrium serum level of 97 mmol/l. CT scan demonstrated no abnormal findings. Because of severe arterial hypertonia she received for 12 days intensive diuretic therapy with 50 mg hydrochlorothiazide and 100 mg triamterene. Retrospectively, we proved that as a result of saluretic therapy, chronic hyponatremia had already existed before admission. Serum sodium was corrected slowly (< 12 mmol/l) with fluid restriction and normal saline solution. This is considered to be the first case report of a complete restitution after hyponatremia less than 100 mmol/l. We suggest that the preexisting chronic hyponatremia and the slow correction of serum sodium level are responsible for the favorable outcome of this case of severe hyponatremia. PMID- 8684512 TI - [Drug-induced asterixis amplified by relative hypoglycemia]. AB - A 58-year-old man with chronic paranoid-hallucinatoric psychosis had transient episodes with marked paranoid delusions, auditory hallucinations without confusion, shakiness of both upper extremities, tachycardia and sweating. EMG performed with surface electrodes revealed many silent periods in postural active muscles with maximum duration of 120 ms; blood glucose was 65-75 mg/dl. At other times, blood glucose was 135-140 mg/dl, EMG revealed few silent periods in postural active muscles with maximal duration of 50 ms and the patient noted some vibration in his outstretched hands only. Drug-induced asterixis (clozapine, benperidol) amplified by relative hypoglycemia was therefore assumed, and symptoms disappeared after oral antidiabetics were reduced. PMID- 8684513 TI - [Long-term treatment with 7S immunoglobulins in myasthenia gravis. Preliminary clinical results]. AB - After initial high-dose intravenous 7S immunoglobulin therapy, six patients with seropositive myasthenia gravis received intermittent low-dose 7S immunoglobulins for at least 4-12 months. This treatment was started in five cases following an acute exacerbation of myasthenic symptoms (Oosterhuis class 3-4) and in one case because of marked clinical fluctuations (Oosterhuis class 3). In five of the six patients, there was a clinical response to the immunoglobulin therapy within 2 weeks, followed by marked long-standing improvement and stability of the clinical outcome. In four cases a decrease in the titer of acetylcholine receptor antibodies was noted in parallel. Our observations suggest an additional positive therapeutic effect of long-term, low-dose intravenous immunoglobulin therapy following the acute management of myasthenic exacerbations. PMID- 8684514 TI - [Cerebral infarct in chronic acetylsalicylic acid poisoning]. AB - Salicylates increase the risk of hemorrhage. An ischemic brain infarct has not previously been described following intoxication with salicylates. Case report. A 58-year-old comatose patient was admitted with symptoms of a basilar artery thrombosis. A diagnostic angiography was impossible because laboratory results showed a prothrombin time (Quick) of 9% and a toxic salicylate level of 528 mg/l. During the next few days CCT and MRI scans revealed ischemic infarctions within the brain stem. Discussion. Salicylates can induce hemorrhage both by inhibiting platelet aggregation and - especially in higher doses - by vitamin K antagonism, leading to severe coagulopathy. The occurrence of an ischemic infarction, as presented in this case report, can be explained by a reduction of the vitamin K dependent protein C level. PMID- 8684515 TI - Microscopic hematuria diagnosis and management. PMID- 8684516 TI - Increased plasma lipoprotein(a) in continuous ambulatory peritoneal dialysis is related to peritoneal transport of proteins and glucose. AB - Markedly increased plasma lipoprotein(a) [Lp(a)] levels have recently been reported in continuous ambulatory peritoneal dialysis (CAPD) patients but the genesis is obscure. Lp(a) levels in CAPD are in general higher than in hemodialysis (HD) patients, suggesting that the dialysis procedure might be of importance. In the present study, we investigated relationships between Lp(a) and parameters related to the dialysis procedure per se (dialysis dose, peritoneal glucose absorption, protein losses and protein clearances) in 32 adult CAPD patients. Uremic patients treated with HD (n = 73) as well as a group of 43 healthy subjects served as control groups. The plasma level of Lp(a) was significantly higher in the CAPD patients (median 28.2 mg/dl) than in the HD patients (median 9.2 mg/dl) and the healthy controls (median 7.0 mg/dl), whereas Lp(a) levels in the HD patients did not differ from the healthy controls. In the CAPD patients, significant correlations were found between Lp(a) and 24-hour peritoneal and total clearance for albumin (r = 0.472 and r = 0.368, p < 0.01 and p < 0.05, respectively), and between Lp(a) and 24-hour peritoneal clearance for beta(2)-microglobulin (r = 0.421; p < 0.05). Similar correlations were found between Lp(a) and 24-hour peritoneal albumin excretion, total albumin excretion and peritoneal beta(2)-microglobulin excretion. Furthermore, a significant correlation was found between Lp(a) and peritoneal glucose absorption (r = 0.352; p < 0.05). Serum cholesterol showed significant correlations with 24-hour .peritoneal albumin loss and 24-hour peritoneal beta(2)-microglobulin clearance, whereas LDL cholesterol showed a significant correlation with 24-hour peritoneal beta(2)-microglobulin clearance. In a longitudinal study of 12 CAPD patients, Lp(a) levels increased significantly between the start of CAPD and at follow-up 3 5 months later. The correlation of the markedly increased levels of Lp(a) with peritoneal albumin and beta(2)-microglobulin clearance suggests that the mechanism behind the increased Lp(a) levels may be related to the large protein losses in CAPD, perhaps via an increased synthesis rate of apolipoprotein (a) in the liver or via decreased Lp(a) catabolism in CAPD patients. Finally, the correlation between Lp(a) and peritoneal glucose absorption also indicates that the increased plasma Lp(a) levels in CAPD are related to the dialysis procedure, in particular peritoneal transport of proteins and glucose. PMID- 8684517 TI - Lipoprotein(a) and vascular access survival in patients on chronic hemodialysis. AB - Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic and cardiovascular complications in the general population and in hemodialysis patients. Increased Lp(a) levels have been also described as a possible predictor of vascular access occlusion in patients on chronic hemodialysis. We have studied prospectively the relationship between vascular access survival and Lp(a) levels in 40 hemodialysis patients. The Lp(a) plasma concentrations were measured by enzyme-linked immunosorbent assay in all patients in April 1993. Throughout the following year, evolution and survival of their vascular accesses were analyzed. Failure of vascular access was established when there were complications requiring surgical repair or transluminal angioplasty. Fourteen patients showed failure of vascular access, and the cumulative survival of vascular accesses after 1 year of follow-up was 63.8%. The Lp(a) levels were higher in patients with failure of vascular access than in the others (35.2 +/- 31 vs. 22.4 +/- 25 md/dl), but this difference did not reach statistical significance (p = 0.064). The vascular access survival in patients with Lp(a) levels > 75th percentile (52.5 mg/dl) was significantly lower than in the remaining patients (40 vs. 72%; p = 0.045). This difference increased when we analyzed the patients with Lp(a) levels > 90th percentile (76 md/dl; 25 vs. 68%; p = 0.002). Our results suggest that patients with the highest levels of Lp(a) are at risk of developing complications in their vascular accesses, and they also have lower vascular access survival. PMID- 8684518 TI - Successful treatment of secondary hyperparathyroidism in hemodialysis patients with oral pulse 1-alpha-hydroxy-cholecalciferol therapy. AB - We have used high-dose oral pulse therapy with 1 alpha-hydroxycholecalciferol (1 alpha-OH-D3) to treat 40 hemodialysis patients suffering form secondary hyperparathyroidism. Forty patients with intact parathyroid hormone (PTH) levels of > 150 pg/ml were treated with 4 micrograms oral 1 alpha-OH-D3 twice weekly for 1 year. The mean PTH level was 515 +/- 50 pg/ml prior to treatment, which fell to 191 +/- 42 pg/ml after 6 months of treatment (p < 0.00001), and to 164 +/- 39 pg/ml after 12 months of treatment. Patients with very high PTH levels (> 800 pg/ml) suppressed less well than patients with lower levels (150-300 pg/ml). The therapeutic end point of PTH < 100 pg/ml was achieved in 23 patients (58%). The main side effect of the treatment was hypercalcemia, but this was symptomatic in only 3 patients, all above the age of 70 years. In summary, oral high-dose pulse therapy with 1 alpha-OH-D3 was highly effective in suppressing PTH levels in hyperparathyroid hemodialysis patients, and side effects were relatively few. PMID- 8684519 TI - Long-term performance of hemofilters in continuous hemofiltration. AB - We measured the filter performance of six polyamide hemofilters with a running time exceeding 72 h applied for continuous hemofiltration in intensive care patients. The sieving coefficients for urea and creatinine were close to unity and remained constant. The sieving coefficient of polyfructosan (mean molecular weight 3 kD) was around 0.75 and did not change with running time. The hydraulic permeability remained also unchanged. The relationships between blood pressure and blood flow and between blood flow and filtration rate remained linear, and the gradient did not change with time. We conclude that a daily routine change of polyamide hemofilters applied in continuous arteriovenous hemofiltration and presumably in continuous venovenous hemofiltration is not necessary within the first 72 h of treatment, unless a major decrease in the filtration rate occurs. PMID- 8684520 TI - Continuous venovenous haemodialysis: a three-pump system. AB - A simple three-pump-based system for the performance of continuous venovenous haemodialysis is described. The method employs access to the circulation via a double-lumen catheter, and by means of a standard extracorporeal peristaltic pump the blood is circulated through a haemofiltration filter. Standard solutions for peritoneal dialysis are administered in a single-pass manner countercurrent to the blood flow. To control the dialysate flow through the filter, two separate pumps designed for intravenous infusion are used. Anticoagulation is achieved by means of continuous heparin infusion. This three-pump system is effective in controlling the fluid balance and the level of azotemia. Furthermore, this system makes haemodialysis possible in spite of severe haemodynamic instability. The system is easy to use and inexpensive. 3 patients participated in the study. PMID- 8684521 TI - Transperitoneal absorption and kinetics of chromium in the continuous ambulatory peritoneal dialysis patient--an experimental and mathematical analysis. AB - The functional model of Cr kinetics and metabolism described by Lim et al. [Am J Physiol 1983; 224:R445-R454] for healthy people was adapted to the specific situation of the continuous ambulatory peritoneal dialysis (CAPD) patient. For this purpose 3 CAPD patients were submitted to an acute 51Cr-labelled dialysis dwell of 6 h. The rate of uptake of Cr in the plasma appeared to be equal to its disappearance rate from the peritoneal fluid. The plasma levels increased to a constant value in the first 2 h after the start of the dialysis session. The amount of Cr cumulatively excreted in the urine over the follow-up period of 10 12 days was 10-15% of the amount absorbed during the acute dwell. The experimental pharmacokinetic data were in close agreement with the values predicted by the modified functional model for Cr(III) kinetics and metabolism. According to this model, the effect of long-term CAPD treatment (10 years) should result in an accumulation of Cr with a factor of 100 in those organs, especially liver and spleen, known to have a slow exchange of Cr with the central plasma compartment. This predicted and dramatic increase was in close agreement with the Cr concentrations found in liver tissue of 3 patients who died after a variable time on CAPD. PMID- 8684522 TI - Morphological changes in the peritoneal vasculature of patients on CAPD with ultrafiltration failure. AB - Vascular changes in the peritoneum were histochemically assessed in patients on continuous ambulatory peritoneal dialysis (CAPD) with ultrafiltration failure. Light microscopy showed extensive interstitial fibrosis, mesothelial denudation and vascular changes. Morphological changes in the vasculature were observed at different levels. The specific changes in the vasculature in these patients were characterized by severe fibrosis and hyalinization of the media of venules. Immunofluorescence microscopy revealed extensive deposition of such extracellular matrices as type IV collagen and laminin in the vascular wall. Electron microscopy revealed a significant increase in collagenous fibers and degeneration of smooth muscle cells in the media. However, the endothelial cells at the levels of vasculature affected were relatively well preserved. These pathological alterations in the vasculature in CAPD patients with ultrafiltration failure suggest that certain toxic factors, such as a high osmolar dialysate or low pH of dialysate, had affected the peritoneal vasculature from the adventitial side rather than the endothelial side. These vascular changes in the peritoneum are thought to be irreversible, associated with deterioration of peritoneal function, and to cause ultrafiltration failure in the patients on long-term CAPD therapy. PMID- 8684523 TI - No direct evidence of increased lipid peroxidation in hemodialysis patients. AB - Lipid peroxidation, as measured by the thiobarbituric acid test, has been reported to have increased in hemodialysis (HD) patients, even though the test has low specificity in vivo. Conjugated diene fatty acid (CDFA) hydroperoxides are formed during lipid peroxidation, but not all conjugated dienes (CD) detected in humans originate from lipid peroxidation: octadeca-9,11-dienoic acid, a nonhydroperoxide CD derivative of linoleic acid (CDLA), has a dietary origin. We evaluated CDFA hydroperoxides, CDLA and linoleic acid, using high-performance liquid chromatography, in lipids extracted from plasma, adipose tissue and RBC membranes obtained from 25 patients treated with HD, 16 patients treated with hemodiafiltration (HDF) and 29 controls. No differences in the levels of CDFA hydroperoxides and linoleic acid were seen in any of the groups. Concentrations of CDLA were found to be significantly high in the adipose tissue and low in the RBC membranes of HD patients. HDF-treated patients showed the same results as HD patients. No direct evidence of increased lipid peroxidation was found in HD patients. This does not exclude the possibility that lipid peroxidation is increased and escapes direct detection due to the body's homeostatic control eliminating the increased production of hydroperoxides. Both HD- and HDF-treated patients showed a significant change in CDLA concentrations, either in the adipose tissue, or in the RBC membranes. These dietary CD may be mistaken for markers of lipid peroxidation by conventional methodologies. PMID- 8684524 TI - Thiol group control of sodium-lithium countertransport kinetics in uraemia: evidence of a membrane abnormality affected by haemodialysis. AB - Uraemia affects erythrocyte metabolism and membrane function but no consistent effect on Na/Li countertransport (CT) has been reported. We report only small differences in Na/Li CT at 150 mmol/l Na over haemodialysis, but major differences in other properties of Na/Li CT. The Km for external sodium and Vmax both increased during haemodialysis but the Vmax/Km ratio, which was greater than normal, was not affected. The thiol reagent, N-ethylmaleimide (NEM), which causes a decrease in Km and Vmax in normal subjects, had no effect on Km in the predialysis erythrocytes. After haemodialysis, the sensitivity of Na/Li CT to NEM was improved. The changes in Na/Li CT kinetics were not related to changes in membrane lipid fluidity or plasma lipids. These observations suggest that uraemia affects a thiol group that controls Na/Li CT kinetics and that haemodialysis temporarily improves this aspect of membrane function. PMID- 8684525 TI - Changes in serum type I and III procollagen levels in children with chronic renal failure. AB - Serum levels of carboxyterminal propeptide of type I procollagen (PICP) and aminoterminal propeptide of type III procollagen (PIIINP) can be used as markers of bone formation and the evaluation of children with growth disorders. We measured the serum levels of these collagens with radioimmunoassay in 24 children aged between 4 and 14 years with chronic renal failure (CRF; n = 12 dialysis, n = 12 nondialysis) and 12 age-matched healthy controls, to find out whether these parameters have a prognostic or therapeutic value in monitoring the growth retardation in CRF. Mean serum PIIINP levels in the dialysis patients were higher than in the control group; the difference between the groups was statistically significant (p < 0.05). It seemed that the pubertal stage of the patients did not affect the levels of PICP and PIIINP. There was no significant correlation between PICP and PIIINP in any patients. Neither PICP nor PIIINP correlated with the height z-score or bone age. It was concluded that the increased serum PIIINP levels in renal patients might be accepted as a poor prognostic factor leading to progressive renal failure and end-stage renal disease. Further investigations into the effects of these collagens on growth failure associated with CRF are needed. PMID- 8684526 TI - Low-dose intradermal versus intramuscular hepatitis B vaccination in patients with end-stage renal failure. A preliminary study. AB - Patients with end-stage renal disease (ESRD) are at high risk of hepatitis B infection. Only 50-60% of the patients respond adequately to the routinely performed intramuscular (i.m.) hepatitis B vaccination. We examined whether low dose intradermal (i.d.) application of the vaccine is equivalent to regular i.m. administration. Thirty-two patients with ESRD of different etiologies were investigated at the onset of dialysis treatment [11 patients on continuous ambulatory peritoneal dialysis (CAPD) and 21 patients on hemodialysis (HD)]. Patients were vaccinated at month 0, 1, 3 and 6 with either 40 micrograms HBs Ag (2 ml Engerix B, 14 patients) i.m. or with 10 micrograms HBsAg (0.5 ml Engerix B, 18 patients) i.d. The i.m. vaccination was applied in the deltoid muscle, while for i.d. vaccination the vaccine was injected into the skin of the deltoid region. Six weeks after the last vaccination anti-HBs titers were measured. 61% (11 patients) of the patients vaccinated i.d. and 64% (9 patients) of the patients vaccinated i.m. developed protective titers. Neither the height of the titers nor the proportion of patients responding to the vaccination differed significantly between the two vaccination schedules. No difference regarding the height of titers achieved or the rate of seroconversion could be found when CAPD and HD patients were analyzed separately. Only minor side effects have been observed. According to these preliminary data i.d. hepatitis B vaccination in patients with ESRD may be equivalent to i.m. administration of the vaccine. Given equivalency i.d. vaccination may be a cost-saving alternative to i.m. vaccination (only a quarter of the dose of i.m. administered vaccine is needed) with a good practicability (vaccination can be performed during HD) and a low rate of side effects. PMID- 8684527 TI - Geographic factors and plasma selenium in uremia and dialysis. AB - The importance of selenium (Se) as an essential trace element for man has been increasingly recognized. Blood Se levels in chronic uremic patients are frequently reported to be lower than in controls. Definitive determination of the Se status in uremic patients, however, is hampered by the wide range of blood Se content in humans from different parts of the world. The present study was designed to assess and compare the Se status in two European populations from Rostock (Germany) and Chieti (Italy). Plasma Se levels were evaluated in healthy controls, chronic renal failure nondialyzed patients (CRF) and hemodialysis patients (HD). All Se determinations were performed in a single laboratory. The Se concentration was significantly higher (p < 0.005) in Italian healthy controls than in German healthy controls. In contrast, Se levels were similar in both CRF and HD patients from both cities. In both countries, the Se concentration in CRF and HD patients was significantly lower (p < 0.001) than in their corresponding controls, but no difference between CRF and HD was found. CRF and HD patients from the two countries showed quite similar laboratory and anthropometric data. In CRF patients in Chieti, a significant (p < 0.05) negative correlation between plasma Se and serum creatinine was found. In both HD groups, the length of time on HD and type of membrane dialyzer used did not influence the Se status. A significant positive correlation (p < 0.01) between Se levels and the protein catabolic rate was found in both HD groups. Uremia seems to be a strong factor which overrules the difference in Se levels that is present in healthy adults from different European countries. Uremia in itself may influence and level the Se concentration in patients with geographic diversity. PMID- 8684528 TI - Importance of donor/recipient body weight ratio as a cause of kidney graft loss in the short to medium term. AB - The importance of the donor/recipient body weight ratio (DRBWR) as a cause of kidney graft loss was evaluated in 112 non-diabetic, ciclosporin-treated, first cadaver kidney transplant recipients. According to the DRBWR, the patients were divided into three groups: 'low' (< or = 0.80), 'medium' (0.81-1.20), and 'high' (> 1.20). The three groups did not differ in patient or graft survival, and the DRBWR was not a predictor of graft failure at multivariate analysis (Cox models), even after only patients with graft survivals > 1 year were considered. The three groups did not differ in glomerular filtration rate (GFR) and proteinuria 6-60 months after renal transplantation. When the 55 patients with a follow-up period > 4 years were considered, no differences between groups were found in GFR or GFR evolution over time. Hypertension was significantly less frequent in group 'high' (Mantel-Cox p = 0.04), but very likely as a consequence of uneven recipient gender (an independent predictor of hypertension at multivariate analysis) distribution between groups, the significance being lost when survival curves were rebuilt by stratifying for recipient gender. DRBWR never resulted as a significant predictor of GFR at multivariate analysis when GFR values 6-60 months after transplantation were analyzed. We conclude that the DRBWR has no major effects on kidney graft function and survival in the short to medium term. PMID- 8684529 TI - Gadodiamide in renal transplant patients: effects on renal function and usefulness as a glomerular filtration rate marker. AB - Gadodiamide at a dose of 0.1 mmol/kg was administered intravenously to 10 renal transplanted patients with stable, impaired, or slowly deteriorating renal function (serum creatinine 194-362 mumol/l). The patients were referred for contrast medium enhanced magnetic resonance imaging to rule out possible graft circulation abnormalities. The excretion of gadodiamide in urine was prolonged as compared with healthy controls. After 120 h 92% of the injected dose was excreted in urine and only 0.4% in faeces. The plasma clearance of gadodiamide was 28.6 +/ (SD) 5.5 ml/min (n = 10), and the renal clearance (0-72 h) was 26.3 ml/min. The renal clearance of 125I-iothalamate for the same time period was 27.9 +/- 5.3 ml/min. Thus, gadodiamide is eliminated by glomerular filtration also in renal transplant patients with moderately to severe impaired renal function, and gadodiamide clearance may serve as an alternative marker for the determination of the glomerular filtration rate. Serum values of creatinine and beta(2) microglobulin and creatinine clearance were unchanged by gadodiamide and neither was the urinary enzyme excretion significantly changed. These results suggest that the renal tolerance to gadodiamide is good also in renal transplant patients with impaired renal function. PMID- 8684531 TI - Influence of hypertension on early renal insufficiency in autosomal dominant polycystic kidney disease. AB - To determine the potential effect of hypertension on early renal function deterioration, 30 patients (13 normotensive and 17 hypertensive) with autosomal dominant polycystic kidney disease and initially normal renal function were retrospectively analyzed. The decline in renal function was estimated by the slope of the linear regression of creatinine clearance versus time. Analysis was made in terms of standardized slope (slope divided by its standard deviation, i.e., measured in standard deviation units). In the hypertensive group the mean standardized slope was significantly higher than in the normotensive group ( 10.89 and -4.98, respectively; p < 0.001). The average mean arterial pressure was significantly lower in the normotensive group with respect to the hypertensive one (95 and 109 mm Hg, respectively; p < 0.0001). There was a significant negative linear relationship between the average values of systolic, diastolic, and mean arterial pressures and standardized slopes. The best prediction equation for renal function deterioration was obtained using a multiple linear regression model in which independent variables were maximum and average diastolic pressures. Therefore, prior to renal insufficiency, a high arterial pressure had a significant contribution to renal function deterioration. PMID- 8684530 TI - Estimation of statistical moments for desferrioxamine and its iron and aluminum chelates: contribution to optimisation of therapy in uremic patients. AB - We investigated the best time of administration of desferrioxamine (DFO) with respect to the dialysis session, using the approach of the stochastic dynamic system, integrated with the classical pharmacokinetic models. In the 6 patients studied, the mean arrival times of DFO, aluminoxamine (AlO) and ferrioxamine (FO) were, respectively, 193, 1,350 and 126 min, the mean residence times were 1,048, infinite, 1,190 min, respectively. AlO serum levels reach steady state in a mean time of 7 h and 22 min and remain stable in the interdialytic period. FO achieves a peak at the end of DFO infusion and declines during the interdialytic period. DFO, AlO and FO persist a very long time in the body of the uremic patient, thus the dialysis session should be administered when AlO and FO reach steady state. With a dose of 5-10 mg/kg b.w. of DFO, we propose to start the dialysis 8-12 h after the infusion if the main purpose is to treat Al overload or 2-3 h after the infusion if the main purpose is the treatment of hemosiderosis. PMID- 8684532 TI - Increased activity of plasma cholesteryl ester transfer protein in children with end-stage renal disease receiving continuous ambulatory peritoneal dialysis. AB - The activity of cholesteryl ester transfer protein (CETP) was assayed in sera of children and adolescents on continuous ambulatory peritoneal dialysis (CAPD) by coincubating lipoprotein-deficient samples with exogenous donor and acceptor lipoproteins. Serum levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B and apolipoprotein B/apolipoprotein A1 ratio were increased, while the high-density lipoprotein cholesterol level was decreased. The CETP activity in children on CAPD exceeded that in either adults or control children, and was correlated with low-density lipoprotein cholesterol, apolipoprotein B, and total cholesterol/high-density lipoprotein cholesterol, low density lipoprotein cholesterol/high-density lipoprotein cholesterol, and apolipoprotein B/apolipoprotein A1 ratios. The CETP activity in CAPD patients may be due to increased synthesis in response to a protein loss in the dialysis fluid and may exacerbate atherosclerosis. PMID- 8684533 TI - Steroid therapy during the early stage of progressive IgA nephropathy. A 10-year follow-up study. AB - This study was undertaken to clarify the effect of corticosteroids on the long term clinical course of the early stage of progressive IgA nephropathy. The early stage of progressive IgA nephropathy was defined as having moderate proteinuria between 1 and 2 g/day, creatinine clearance values of 70 ml/min or more, and a histological severity score of 7 or more. The number of patients who fulfilled these three conditions during 12 years from 1972 and then were continuously followed up for 10 years or more in our renal unit was 46. Twenty of them received steroid treatment for an average period of 18 months, and the remaining 26 patients had no steroid treatment. The initial data of proteinuria, creatinine clearance values, frequency of hypertensive cases, and histological scores of 7 or more were not different between the two groups: 1.4 +/- 0.4 vs. 1.3 +/- 0.3 g/day, 85 +/- 14 vs. 88 +/- 13 ml/min, 25 vs. 38%, and 10.7 +/- 2.5 vs. 11.0 +/- 3.0, respectively. During the follow-up period of 10 years, the renal survival rate was significantly different between the two groups (100 vs. 84% 5 years after starting therapy and 80 vs. 34% 10 years later; p < 0.001). The final creatinine clearance values were significantly different between the two groups (54 +/- 35 vs. 20 +/- 29 ml/min; p < 0.005). On the other hand, the patient groups with mild histological changes or decreased renal function due to moderate proteinuria showed no significant differences in the final outcome. These results indicate that corticosteroids are beneficial in stabilizing the renal function for a long time during the early stage of progressive IgA nephropathy, although this study was not a randomized one. PMID- 8684534 TI - Characteristics of renal tubular atrophy in experimental renovascular hypertension: a model of kidney hibernation. AB - The inability to separate irreversible lesions of tubular epithelia from reversible tubular atrophy constitutes a major problem in histopathology and in decisions for revascularization of shrunken kidneys with renal artery stenosis. In order to characterize reversible tubular atrophy ('kidney hibernation') we studied the physiological and biochemical parameters and morphology including histochemistry in rat kidneys made atrophic by renal artery stenosis and treatment with the angiotensin-converting enzyme inhibitor, enalapril. Renal artery stenosis was induced by a 0.2-mm clip around the left renal artery. Following 7 weeks of clipping and 2 concomitant weeks of enalapril treatment, the kidney length decreased from 17.8 +/- 0.3 to 13.7 +/- 0.7 mm (mean +/- SEM). Renal blood flow and glomerular filtration rate decreased to 39 +/- 3% and to approximately 3% of control values, respectively. The activities of the intracellular proteolytic enzymes cathepsin B and L and of Na-K-ATPase in microdissected proximal tubular segments decreased to values below 50 and 10%, respectively. All changes were significant (p < 0.05). Histochemical staining for ATPase activity in the distal tubule segments remained unchanged. Tubular cells were atrophic but not necrotic. Histochemical staining of alkaline phosphatase in the tubular brush border and of acid phosphatase and peroxidase in lysosomes was greatly reduced. All observed changes were reversible within 2-3 weeks following removal of the clip and withdrawal of enalapril either with or without contralateral nephrectomy. Thus, a form of kidney hibernation with readily reversible tubular atrophy has been described. Based on this description it may be possible in consecutive experiments to differentiate between reversible and irreversible tubular atrophy. PMID- 8684535 TI - Effect of parathyroid hormone on rat skeletal muscle in vivo. AB - The secondary hyperparathyroidism of chronic renal failure has been implicated in the pathogenesis of metabolic abnormalities in skeletal muscle. We studied the muscle metabolism in a model of hyperparathyroidism (Wistar rats injected with parathyroid hormone or saline for 4 days). 31P magnetic resonance spectroscopy allowed measurements of the concentration of cytosolic metabolically active inorganic phosphate [Pi] at rest and the rates of oxidative and anaerobic adenosine triphosphate turnover during exercise and recovery. Parathyroid hormone caused significant reductions in plasma [Pi] and intracellular [Pi], but had no effect upon oxidative or glycogenolytic adenosine triphosphate turnover. PMID- 8684536 TI - Role of cadmium-induced lipid peroxidation in the kidney response to atrial natriuretic hormone. AB - In order to investigate the role of increased lipid peroxidation in the development of cadmium-induced hypertension, 30 male albino rats were exposed to drinking water containing 15 micrograms/ml cadmium for 30 days, and the results were compared with those of 30 controls. Water containing high cadmium concentrations caused a significant accumulation of the element in blood and kidneys, associated with an obvious elevation in blood pressure. The systolic and diastolic blood pressures rose from 102.8 +/- 7.0 and 81.2 +/- 3.8 mm Hg to 128.1 +/- 4.6 and 107.9 +/- 7.4 mm Hg, respectively, in cadmium-treated rats (p < 0.01). A decreased glomerular filtration rate and increased serum creatinine levels were accompanied by elevated levels of cortical and medullary thiobarbituric acid reactive substances in cadmium-induced hypertensive rats. The mean thiobarbituric acid reactive substance level rose from a control value of 211.5 +/- 64.1 to 303.3 +/- 46.3 nmol/g protein (p < 0.01) in the renal cortex due to the high intake of cadmium. Despite its obvious diuretic and natriuretic action in control animals, the bolus injection of 1.2 and 2.4 micrograms/kg atrial natriuretic peptide corrected neither elevated blood pressure nor the reduced glomerular filtration rate in rats exposed to cadmium. However, the tubular response to atrial natriuretic peptide remained unaltered. These data suggest that a lack of vascular response to atrial natriuretic peptide is one of the many putative causes of cadmium-induced hypertension, and cadmium-mediated increased lipid peroxidation may be involved in this unresponsiveness. PMID- 8684537 TI - Mesangial cell DNA synthesis induced by hydrogen peroxide, interleukin-6, and platelet-derived growth factor: effects of indomethacin and dazmegrel. AB - This study indirectly examined the role of prostanoids (PG) in mediating rat mesangial cell (MC) DNA synthesis induced by hydrogen peroxide (H2O2), interleukin 6 (IL-6), and platelet-derived growth factor (PDGF). MC were exposed to three daily pulses of 10(-6) mol/l H2O2 alone or in combination with IL-6 (5 ng/ml) or PDGF (10 ng/ml). In order to examine (indirectly) the role of PG in mediating changes in MC DNA synthesis, indomethacin (1.5 x 10(-5) mol/l) or the thromboxane A2 synthetase inhibitor Dazmegrel (10(-5) mol/l) was added to the medium and DNA synthesis assessed after 72 h using 3H-thymidine incorporation (3H TdR). Stimulation of MC by H2O2 alone resulted in an increase in 3H-TdR of 34.7 +/- 5.5% (p < 0.01). H2O2 enhanced the mitogenic effects of IL-6 and PDGF, 3H-TdR increasing by 52 +/- 12.1% (p < 0.01) and 100 +/- 21% (p < 0.001), respectively. Indomethacin suppressed the DNA synthesis induced by H2O2 alone, 3H-TdR decreasing by 33 +/- 12% (p < 0.05). Indomethacin also reduced the mitogenic response to H2O2 plus IL-6 and H2O2 plus PDGF by 91 +/- 17 and 97 +/- 12%, respectively (p < 0.05). Dazmegrel reduced 3H-TdR when MC were exposed to H2O2 alone by 31.8 +/- 16% (p < 0.05) and when combined with IL-6 or PDGF by 80 +/- 26 and 120 +/- 13%, respectively (p < 0.05). These data suggest that the pathways through which H2O2-induced growth of MC is mediated appear, at least in part, to involve PG, particularly thromboxane A2. PMID- 8684538 TI - Reduced enzymatic antioxidant defense mechanism in kidney tissues from gentamicin treated guinea pigs: effects of vitamins E and C. AB - In this study, the activities of major enzymes participating in free radical metabolism (xanthine oxidase, XO; Cu,Zn and Mn superoxide dismutases, SOD; glutathione peroxidase, GSH-Px; catalase, CAT) were measured in kidney tissues from guinea pigs treated with gentamicin alone (200 mg/kg/day), gentamicin plus vitamin C (600 mg/kg/day), gentamicin plus vitamin E (400 mg/kg/day), and gentamicin plus vitamins C and E together for 10 days, and from animals treated with physiological saline solution alone during this period. We found no significant differences between control and gentamicin groups with respect to XO and Cu,Zn-SOD activities. However, the activities of Mn-SOD, GSH-Px, and CAT were found to be significantly depressed in the gentamicin-treated group relative to controls. In the gentamicin plus vitamin C group, the renal tissue Mn-SOD activity was found to be higher as compared with control and gentamicin groups. In this group, XO, GSH-Px and CAT activities were also higher than in the gentamicin-treated group, but no statistically significant differences existed between the values of this group and controls. Similar results were also observed in the gentamicin plus vitamin E group for Mn-SOD, GSH-Px, CAT, and XO. In this group, the Cu,Zn-SOD activity was found to be decreased as compared with control and gentamicin groups. In the gentamicin plus vitamins C and E group, the Cu,Zn SOD activity was found to be decreased, the XO activity to be unchanged, and Mn SOD, GSH-Px, and CAT activities to be increased as compared with the gentamicin and control groups. The results suggest that the enzymatic antioxidant defense system was significantly disturbed because of the suppressed activities of Mn SOD, GSH-Px, and CAT in the kidney tissues from animals treated with gentamicin. However, vitamins C and E given concurrently with gentamicin completely abrogated this enzymatic suppression. PMID- 8684539 TI - Effects of hypoxia on the extracellular matrix production of cultured rat mesangial cells. AB - Glomerular changes in patients with cyanotic congenital heart and chronic lung diseases and in persons living at a high altitude might be related to hypoxemia. This study was carried out to examine the effects of hypoxia on the extracellular matrix production by cultured rat mesangial cells (CRMC). Subconfluent CRMC monolayers were grown with 10% oxygen (hypoxia) and 20% oxygen (control) for 1, 3, and 5 days. The production of type IV collagen (CIV), fibronectin (FN), and laminin (LN) by CRMC was evaluated by flow cytometry and immunofluorescent microscopy. Total RNA was extracted and Northern blotting and hybridization were performed with cDNAs for CIV, FN, and LN. The surface expression of CIV on FC was higher in hypoxia than under control conditions at day 5 (158% of control). The surface expression of FN was also higher in hypoxia at day 3 (303%) and at day 5 (332%). The surface expression of LN was lower at day 1 (71%). Immunofluorescent microscopy showed similar changes with flow cytometry. The mRNA level for CIV and FN was maximal at day 5 with 206 and 305% of control, respectively. Hypoxia had little effect on LN mRNA expression. These results show that hypoxia stimulates the synthesis of extracellular matrix of cultured rat mesangial cells. Hypoxia may contribute to the development of glomerular changes in cyanotic congenital heart diseases, chronic lung diseases, and in persons living at a high altitude. PMID- 8684540 TI - Autoradiographic localization and age-related changes in vasopressin receptors in spontaneously hypertensive rats. AB - To understand the regulation of vasopressin receptors in an animal model of hypertension, localization and age-related changes in renal arginine vasopressin (AVP) receptors in spontaneously hypertensive rats (SHR) were investigated using in vitro (macro) autoradiography and a radiolabeled receptor assay. Autoradiography localized renal AVP V2 receptors to the distal tubules and collecting ducts in the medulla. We also found small numbers of AVP-binding sites within glomeruli, possibly representing V1 receptors in the mesangium. The radiolabeled receptor assay of the medulla membrane fraction revealed that the binding affinity of renal V2 receptors did not differ significantly between SHR and control Wistar-Kyoto rats in any age group. However, the binding capacity (Bmax) for V2 receptors in 12-week-old SHR was significantly increased (p < 0.025) as compared with that of age-matched control rats. The Bmax values for V2 receptors in 3- and 7-week-old SHR were not significantly different from those of age-matched controls. There was no significant change in urine volume between SHR and control rats at the age of 12 weeks. The mean plasma AVP concentration in SHR increased at 7 and 12 weeks of age. These findings suggest that SHR have different developmental changes in kidney AVP receptors and that renal V2 receptors play a role in maintaining fluid homeostasis in SHR with established hypertension. PMID- 8684541 TI - Diffuse mesangial sclerosis: a unique type of congenital and infantile nephrotic syndrome. AB - Clinical and pathological findings in four Turkish infants with isolated diffuse mesangial sclerosis (DMS) are presented. All the patients were offsprings of consanguineous marriages and two had similarly affected sibs indicating an autosomal recessive inheritance. The onset of the nephrotic syndrome was at 7, 17, 11 and 3 months of age. They all died in a state of renal failure complicated by infections at the ages of 11, 33, 13 and 5 months. DMS was diagnosed at postmortem examination in all. Fluorescence-microscopical studies in all and an electron-microscopical study in one revealed nonspecific findings. The shorter survival in three of the cases was thought to be due to intervening infections. The variation of the clinical features along with the fluorescence and electron microscopical findings are consistent with the previously mentioned heterogeneous aspect of DMS. PMID- 8684542 TI - Successful renal transplantation in a patient with large granular lymphocytic leukemia with natural killer cell proliferation. AB - A patient with advancing renal failure attributed to focal segmental glomerulosclerosis was found to have marked NK (CD56+) cell expansion and large granular lymphocytic leukemia. Subsequent living-related renal transplantation was accomplished with two early bouts of acute cellular rejection requiring therapy with methylprednisolone and monoclonal antibody OKT3. Chronic triple drug immunosuppressive therapy has substantially reduced the marked NK (CD56+) proliferation. The renal transplantation remains successful after 15 months despite persistent but reduced numbers of circulating NK cells, the potential role of which in the pathogenesis of the underlying nephropathy or the cellular rejection process remains speculative. PMID- 8684543 TI - Renal infarction in a severely hypertensive patient with lupus erythematosus and antiphospholipid antibodies. AB - Systemic lupus erythematosus (SLE) patients, specially those with antiphospholipid antibodies, have a high incidence of arterial and venous thrombotic manifestations. However, renal infarction has been rarely reported in these patients. The case of a young female with renal infarction, diagnosed by renal arteriography and scintigraphy, and arterial hypertension (AH) is described. In subsequent years she also suffered several cerebrovascular accidents with important neurological sequelae. No evidence of systemic disease was observed at this time. Fourteen years after the renal infarction a diagnosis of SLE was established. Despite therapy with prednisone, acetylsalicylic acid, azathioprine and antihypertensive drugs the progression of the neurological disease led to death. The sudden appearance of severe AH in a young woman with a renal infarction should alert the clinician about a possible underlying renal artery thrombosis in association with SLE and antiphospholipid antibodies. PMID- 8684544 TI - Transplant renal artery stenosis presenting with recurrent acute pulmonary edema. AB - Renal artery stenosis of the transplant kidney occurs in approximately 6% of renal allograft recipients. Severe bilateral renal artery stenosis and unilateral renal artery stenosis to a single functioning kidney have been described as causes of recurrent pulmonary edema in nontransplant patients with normal cardiac function. We report 2 patients with severe transplant renal artery stenosis who presented with recurrent episodes of acute pulmonary edema. Successful revascularization in 1 patient prevented the recurrence of pulmonary edema. In renal allograft recipients who present with unexplained recurrent episodes of acute pulmonary edema, who do not have an obvious cardiac cause, transplant renal artery stenosis should be considered as a possible etiology. PMID- 8684546 TI - Sodium thiosulfate in the treatment of tumoral calcifications in a hemodialysis patient without hyperparathyroidism. AB - Extraskeletal tumoral calcifications (TC) may occur in patients with end-stage renal disease. The TC usually develop in the presence of secondary hyperparathyroidism or a high calcium x phosphate product, while other factors have been also occasionally implicated in their development. At present, no uniformly accepted effective treatment has been described for this condition. We describe a 58-year-old female patient with end-stage renal disease who 7 years after the onset of dialysis presented with pain and movement restriction of various joints. A skeletal X-ray showed huge amounts of periarticular TC. The TC occurred in the absence of hyperparathyroidism or a high calcium x phosphate product as evidenced by hormonal and biochemical examination as well as by a bone biopsy specimen that revealed an adynamic bone disease with significant aluminum staining. Sodium thiosulfate, an inorganic salt that has been claimed to inhibit the formation and to favor the solubility and the mobilization of calcified masses, was administered to the patient, and after a long period of treatment considerable radiological regression of the TC with concurrent clinical recovery was noticed. Aluminum intoxication, along with other factors, was considered to be the cause of TC development. The use of sodium thiosulfate seemed to be a reasonable nonspecific therapeutic approach for the management of TC in this case. PMID- 8684545 TI - Chronic granulomatous interstitial nephritis: unusual complication of acute pyelonephritis. AB - We describe an unusual complication of acute pyelonephritis in a 45-year-old diabetic female. She was admitted to our hospital due to fever and flank pain which had developed 10 days earlier. Urinalysis showed many WBC and urine culture revealed Escherichia coli. After adequate antibiotic treatment, clinical symptoms abated but renal failure and leukocyturia persisted. Abdominal CT showed bilateral focal bacterial nephritis and renal biopsy disclosed chronic granulomatous interstitial nephritis. On the 80th hospital day she was discharged with a serum creatinine of 299 mumol/l. In the outpatient clinic, renal dysfunction and leukocyturia persisted up to 1 year. In conclusion, this case raises the possibility of a chronic interstitial process of acute pyelonephritis. PMID- 8684547 TI - Deliberate overdose of uranium: toxicity and treatment. AB - A case is described of deliberate ingestion of 15 g of uranium acetate which resulted in acute renal failure requiring dialytic therapy for 2 weeks, refractory anaemia, rhabdomyolysis, myocarditis, liver dysfunction with a disproportionate coagulopathy and paralytic ileus. Despite significant elevations in plasma uranium levels, treatment with both calcium EDTA and calcium DTPA were ineffective in promoting uranium excretion. Six months later the initial significant renal impairment exists with a persistent incomplete Fanconi syndrome. Future options for management of this unusual cause of acute renal failure are discussed. PMID- 8684548 TI - Complete remission of the nephrotic syndrome due to focal glomerular sclerosis achieved with low density lipoprotein adsorption alone. PMID- 8684549 TI - Red blood cell Na(+)-K+ pump activity and arterial hypertension in autosomal dominant polycystic kidney disease. PMID- 8684550 TI - A patient with amyloidosis, vesicoureteral reflux and renal cell adenoma complicated by intrarenal calcification and acquired cystic renal disease. PMID- 8684551 TI - Norwegian scabies complicated by fatal brain abscess in a renal transplant patient. PMID- 8684552 TI - Elevated bile acid serum concentrations in uremics. PMID- 8684553 TI - Acute renal failure and nephrotic syndrome in a patient with T-cell lymphoma. PMID- 8684554 TI - Immunologically mediated chronic tubulo-interstitial nephritis caused by valproate therapy. PMID- 8684555 TI - Severe hypoglycemia in a patient with chronic renal failure due to amyloidosis. PMID- 8684556 TI - Ciclosporin A in lupus nephritis. PMID- 8684557 TI - Effect of low-protein diet on glomerular changes in ddY mice: a spontaneous animal model of IgA nephropathy. PMID- 8684558 TI - L-arginine and salt sensitivity. PMID- 8684559 TI - Correlation between serotonin concentration and blood pressure in kidney transplant recipients treated with cyclosporine. PMID- 8684560 TI - Is AIDS a predisposing factor to urinary tract infection? PMID- 8684562 TI - Effects of nutritional status and oral essential amino acid replacement on serum L-carnitine levels of chronically hemodialyzed patients. PMID- 8684561 TI - Wegener's granulomatosis complicated by pericardial tamponade and renal failure. PMID- 8684563 TI - Anti-hepatitis E virus markers in hemodialysis patients. PMID- 8684564 TI - Esophageal motor dysfunction in chronic renal failure. PMID- 8684565 TI - End-stage renal failure in a solitary kidney from emphysematous pyelonephritis. PMID- 8684566 TI - Car safety seat belts as a risk factor after percutaneous renal biopsy. PMID- 8684567 TI - Membranous glomerulonephropathy associated with psoriasis vulgaris. PMID- 8684568 TI - Is analgesic nephropathy a problem in the south-west region of Poland? PMID- 8684569 TI - Second attack of acute tubulointerstitionephritis induced by cefataxim and pregnancy. PMID- 8684570 TI - Multiple organ failure associated with dimethylsulfoxide and hydroxyethyl starch in autologous blood stem cell transplantation. PMID- 8684571 TI - Acute pneumoperitoneum in a patient on nocturnal intermittent peritoneal dialysis. PMID- 8684572 TI - Which factors account for increased serum laminin levels in patients with chronic renal diseases? PMID- 8684573 TI - Non-dysmorphic haematuria in a case of Berger's disease (focal segmental glomerulosclerosis) associated with acute renal failure. PMID- 8684574 TI - Inversed diurnal rhythm of urinary prostaglandins E2 and F2 alpha excretion in kidney graft recipients. PMID- 8684575 TI - Renal tubular dysfunction of vitamin-D deficiency rickets. PMID- 8684576 TI - Occurrence rate of polyarteritis nodosa in chronic renal diseases. PMID- 8684577 TI - Transient 'milky urine' after cardiac catheterization: another unreported cause of non-parasitic chyluria. PMID- 8684578 TI - Quantitation of proteinuria in patients with IgA nephropathy and membranous nephropathy in early morning and spot urine specimens. PMID- 8684579 TI - Plasma terminal complement complex concentrations in renal allograft recipients. PMID- 8684580 TI - Is isolation needed for anti-HCV-positive hemodialysis patients? PMID- 8684581 TI - Relation between blood pressure and hematocrit in anephric patients treated by means of recombinant DNA human erythropoietin. PMID- 8684582 TI - Primary brain tumor incidence rates in four United States regions, 1985-1989: a pilot study. AB - There has been controversy in the last decade over whether the reported increase in brain tumors reflects a real increase in incidence rates. Incidence data on the full spectrum of brain tumors is lacking in the discussion since current cancer reports in the United States are restricted to malignant tumors. Data on tumors from four population-based cancer registries in the United States were compiled to provide incidence rates of benign and malignant brain tumors and to assess the feasibility of providing these data on a larger scale. A total of 8,070 primary tumors diagnosed from 1985 to 1989 in Connecticut, Massachusetts, Missouri and Utah were obtained. Brain tumors were defined using the International Classification of Diseases for Oncology codes 191.0-191.9, 192.0 192.3, 192.8-192.9 and 194.3-194.4. Stratum-specific incidence rates by location and histology were estimated by sex, age and region. Age-adjusted rates were standardized to the 1970 United States population. An age-adjusted incidence rate of 9.4/10(5) was observed, which reflects a 36% increase in males and a 68% increase in females over the rate based on malignant tumors alone from the Surveillance, Epidemiology and End Results cancer reporting system. Incorporating benign tumors into cancer registry data would increase the reported incidence rates primarily in females and for meningiomas and nerve sheath tumors. This expanded incidence rate represents a substantial improvement in the ability to describe the occurrence of these complex tumors by subtype with a modest increase in overall case registrations for cancer registries. Centralization of data on all brain tumors appears feasible. Variations in histology-specific rates across regions raises questions that need to be addressed about the ascertainment and accuracy of tumor classification. Use of the cancer registration system to improve the reporting of brain tumors in the United States is important to our understanding of the occurrence of these complex tumors and to our ability to conduct large-scale epidemiologic investigations. PMID- 8684583 TI - Latent periods in multiple sclerosis. PMID- 8684584 TI - Methodologic issues in clinical research: the example of Guillain-Barre syndrome. PMID- 8684585 TI - Effects of blood lead levels on cognitive function of older women. AB - Elevated blood lead concentrations are known to have detrimental effects on neuropsychological function in both children and occupational cohorts of men and women. Although it is generally accepted that lead exposure at low levels is more dangerous for infants and children than for adults, the issue of the lowest level of exposure at which lead causes deleterious health effects in adults is yet to be solved. There is no available data on the role of lead exposure in cognitive dysfunction in nonoccupational cohorts of older persons. In the current study, we examined the cross-sectional relationship between blood lead levels and a variety of measures of neuropsychological function in a large cohort of elderly women recruited at both urban and rural sites. This study of elderly women demonstrates that blood lead levels as low as 8 micrograms/dl were significantly associated with poorer cognitive function as measured by certain neuropsychological tests. Even a slight decrement in cognition would have a large public health impact due to the large number of elderly at risk. PMID- 8684586 TI - Neurological disease in a defined population: the results of a pilot study in two general practices. AB - A pilot study was set up to ascertain incident neurological disorders occurring in 25,000 people attending two general-practice surgeries for a period of 1 year. To achieve completeness of ascertainment and diagnostic validity poses considerable logistical and theoretical difficulties, and these are discussed. The commonest disorders (incidence in parentheses) were headaches (210/100,000), back syndromes (319/100,000), acute cerebrovascular disease (128/100,000), and migraine (64/100,000), with non-specific symptoms the most common problem overall (514/100,000). The incidence of Parkinson's disease was 26/100,000 and that of epilepsy 23/100,000. The pilot study will form the basis for a more comprehensive linkage scheme between the National Hospital for Neurology and Neurosurgery in London and surrounding general practices with a total base population of 100,000. PMID- 8684587 TI - Epidemiological study of lathyrism in northwestern districts of Bangladesh. AB - Two northwestern districts of Bangladesh with a population of 629,752 were surveyed from June 1991 to March 1993 to detect and follow up lathyrism patients. Out of 2,567 neurological patients, 882 were diagnosed as having lathyrism, giving a prevalence rate of 14.0/10,000. This prevalence was higher among young males: only 12.9% of the patients were female, and only 19.3% of the patients were over 30 years of age at onset of the disease. The average family size was 4.6 members. In the surveyed area, 730 families were evaluated: 622 families had only 1 affected member, and 108 families had 2-8 affected members. Most of the patients were working, while only 4% were not. The majority of the patients had a very low intake of animal protein. A few cases of human T-lymphotropic virus infection and osteolathyrism were found during this study. PMID- 8684588 TI - Prevalence of stroke: a door-to-door survey in three Sicilian municipalities. Sicilian Neuroepidemiologic Study (SNES) Group. AB - As part of a door-to-door survey, we screened for stroke among the inhabitants of three Sicilian municipalities (n = 24,496 as of November 1, 1987). Neurologists then investigated those subjects suspected to have had a stroke. Diagnoses of first-ever strokes were based on specified criteria and were reviewed by an adjudication panel. We found 189 subjects who had experienced at least one completed stroke (180 definite, 9 possible); 15 strokes were hemorrhagic, 71 ischemic, and 103 uncertain. The prevalence (cases/100,000) was 771.6 in the total population and 1,893.6 in those aged 40 years or over. The prevalence increased steeply with age, was higher in men between 60 and 79 years, but was higher in women thereafter. Age-specific figures were similar in the three study municipalities. Although all first-ever strokes had been previously diagnosed, 40% of the subjects had not been hospitalized for this condition. PMID- 8684589 TI - Differential inhibition of Ca2+ channels in mature rat cerebellar Purkinje cells by sFTX-3.3 and FTX-3.3. AB - Synthetic funnel web spider toxin (sFTX-3.3) is a polyamine amide analogue of FTX, a toxin fraction isolated from the venom of the funnel web spider, Agelenopsis aperta, that blocks P-type Ca2+ channels. The structures of these polyamine containing compounds are not identical: sFTX-3.3 contains an amide carbonyl oxygen that is absent from the predicted structure of native FTX. Recently, a compound called FTX-3.3 was synthesized with the structure predicted for native FTX. We have compared the effects of polyamine amide sFTX-3.3 and polyamine FTX-3.3, on Ca2+ channel currents in the soma of mature rat cerebellar Purkinje neurons, in which the predominant Ca2+ channels are defined as P-type. Differential inhibition by sFTX-3.3 and FTX-3.3 revealed three populations of Ca2+ channels. One group, mediating approximately 66% of the current, was blocked by sFTX-3.3 with an IC50 (concentration producing half maximal inhibition) of 33 nM or by FTX-3.3 with an IC50 of 55 pM. A second population (5-25% of the total current) was inhibited by sFTX-3.3 with an IC50 of 33 nM, but was insensitive to FTX-3.3, while a third (10-30%) was blocked by FTX-3.3 with an IC50 of 125 nM and was resistant to sFTX-3.3. These channels also showed distinctive current-voltage relationships. Our results suggest that P-type Ca2+ channels in mature rat cerebellar Purkinje cells may be subdivided according to pharmacological and biophysical properties. PMID- 8684590 TI - Abnormalities in 5-HT1A and 5-HT1B receptor binding in severe-seizure genetically epilepsy-prone rats (GEPR-9s). AB - The present study was designed to determine whether abnormalities in serotonin receptor binding co-exist with the presynaptic serotonergic deficits that have previously been identified in the genetically epilepsy-prone rat (GEPR) brain. In vitro binding of [3H]8-OH-DPAT (0.16-10.3 nM) to 5-HT1A receptor sites was found to be decreased in the hippocampus of severe seizure GEPRs (GEPR-9s) when compared to nonepileptic control rats, while no difference in [3H]8-OH-DPAT binding was observed in the GEPR-9 corpora quadrigemina or midbrain tegmentum. The decreased binding of [3H]8-OH-DPAT to hippocampal membranes was due to a decrease in Bmax (P < 0.001), rather than to a change in the Kd. Conversely, in vitro binding of [125I]cyanopindolol (2-400 pM) to 5-HT1B receptor sites was increased in the GEPR-9 hippocampus, corpora quadrigemina and midbrain tegmentum when compared to nonepileptic control rats. The increased binding of [125I]cyanopindolol in all three regions resulted from an increase in the Bmax (P < 0.05), rather than a change in the Kd. These finding suggest that in addition to the innate reduction in 5-HT presynaptic markers, GEPR-9s also exhibit abnormalities in the density of 5-HT1A and 5-HT1B receptors in some regions of the brain. Inasmuch as serotonin acts to attenuate audiogenic seizures in GEPRs, these abnormalities in 5-HT receptor binding may contribute to the seizure susceptibility exhibited by these animals. PMID- 8684591 TI - Clozapine is a partial agonist at cloned, human serotonin 5-HT1A receptors. AB - Clozapine exhibited 10-fold higher affinity than haloperidol for human 5-HT1A receptors expressed in Chinese Hamster Ovary cells (CHO-h5-HT1A) (Kis = 160 and 1910 nM respectively). Whereas haloperidol did not alter the basal binding of [35S]GTP gama S to CHO-h5HT1A membranes, clozapine stimulated it with an EC50 of 2320 nM and an efficacy of 49% (compared to 5-HT). The stimulation was antagonized by the selective 5-HT1A receptor antagonist, WAY 100635 (1 nM). PMID- 8684592 TI - Electrophysiological effects of aconitine in rat hippocampal slices. AB - The electrophysiological effects of aconitine were investigated in the rat hippocampal slice and compared with those of veratridine. Both alkaloids are known to bind at site 2 of sodium channels and to block its inactivation. Extracellular recordings revealed that aconitine and veratridine exert inhibitory effects on neuronal excitability. Aconitine slowly and reversibly decreased the population spike recorded in the CA1 pyramidal cell layer. The reduction of the spike amplitude was similar whether orthodromically or antidromically activated. The aconitine-induced inhibition did not differ from that of veratridine. However, following washout of aconitine, the amplitude of the antidromic spike was increased compared to the control amplitude. The veratridine-induced inhibition was only partially reversible. This inhibition was also observed during suppression of synaptic transmission by a low Ca2+/high Mg2+-medium, indicating an inhibition of axonal conductance. The results show that in the absence of synaptic transmission the antidromic (alvear) spike is more sensitive to the inhibitory action of aconitine than the presynaptic fiber spike elicited by stimulation of the Schaffer collaterals. Furthermore, it is shown that aconitine acts in an activity-dependent manner, in that the latency of onset of the inhibition is prolonged when the stimulation frequency is decreased. Field excitatory postsynaptic potentials were also suppressed by aconitine, whereas excitatory postsynaptic currents recorded by the patch clamp technique were not influenced by aconitine when cells were held at -60 mV. PMID- 8684593 TI - Systemic DL-kynurenine and probenecid pretreatment attenuates quinolinic acid induced neurotoxicity in rats. AB - Kynurenine (KYN) is the precursor of kynurenic acid (KYNA), an endogenous antagonist of the glycine site of the NMDA (N-methyl-D-aspartate) receptor. Probenecid (PROB), blocks the excretion of KYNA from the extracellular fluid. KYNA antagonizes the toxic action of quinolinic acid (QUIN), an endogenous NMDA receptor agonist. In this study, we tested the effect of the systemic administration of KYN and PROB, either alone or in combination, on QUIN-induced circling behavior and gamma-aminobutyric acid (GABA) depletion in rats. Circling behavior and GABA depletion induced by QUIN were both partially prevented by PROB (200 and 300 mg/kg) and KYN (300 and 450 mg/kg) treatments. Lower doses of drugs administered separately were nonprotective. However, when administered in combination, doses of 150 or 300 mg/kg KYN plus 100 mg/kg PROB significantly protected animals against QUIN neurotoxicity. These findings suggest a role of KYN and PROB as promoters of KYNA-mediated NMDA receptor antagonism, via an increase of kynurenate in brain extracellular spaces. PMID- 8684594 TI - Effect of protein kinase-C activation on the Mg(2+)-sensitivity of cloned NMDA receptors. AB - The mechanisms responsible for protein kinase-c (PKC) mediated potentiation of NMDA receptors are poorly understood. One hypothesis is that PKC-activation reduces the receptor's characteristic voltage-dependent Mg(2+)-blockade. Experiments performed on Xenopus oocytes expressing cloned NMDA receptors demonstrated that PKC-activation induced no change in the sensitivity of zeta 1/epsilon 3 and zeta 1/epsilon 4 receptors to Mg(2+)-blockade and, even though PKC-activation did induce a small shift in Mg2+ sensitivity for the zeta 1/epsilon 1 and zeta 1/epsilon 2 receptors, the change seen was not large enough to account for an appreciable increase in NMDA receptor activity. Baseline Mg(2+) sensitivities and levels of PKC-mediated potentiation were also quantified for each of the di-heteromeric NMDA receptors. The order of Mg(2+)-sensitivity is zeta 1/epsilon 1 (most sensitive) > zeta 1/epsilon 2 > zeta 1/epsilon 4 > zeta 1/epsilon 3 (least sensitive). PKC-activation caused a 2-fold increase in zeta 1/epsilon 1 currents, a 4-fold increase in zeta 1/epsilon 2 currents and no change in either zeta 1/epsilon 3 or zeta 1/epsilon 4 currents. These data suggest that PKC-potentiation of the cloned di-heteromeric NMDA receptors does not involve a reduction in Mg(2+)-blockade. The di-heteromeric receptors possess varied properties in regard to PKC-potentiation and Mg(2+)-blockade which have been quantified here. PMID- 8684595 TI - Characterization of taurine transport in human glioma GL15 cell line: regulation by protein kinase C. AB - Data describing characteristics of taurine transport system in human brain cells are not currently available. We have used GL15 cells, a cell line of human brain origin that keeps some properties of normal glial cells, to investigate these characteristics. The human glioma cell line GL15 was found to take up taurine. The uptake was strictly sodium-dependent. Replacement of NaCl with choline chloride almost totally abolished the uptake. There was also an anion requirement for the uptake system, and Cl- was the most potent among several monovalent anions tested. The uptake process was specific for beta-amino acids such as taurine, hypotaurine and beta-alanine. The kinetics of uptake were studied. Apparently, a single transport system with a K(m) of 8.95 +/- 0.26 microM was responsible for the uptake. A maximal velocity of 1.32 +/- 0.03 nmol/mg of protein/10 min was found. Stoichiometric analysis revealed that two Na+ and one Cl- ions were involved in the translocation of one taurine molecule. Phorbol 12 myristate 13-acetate (PMA), a potent stimulator of protein kinase C (PKC), inhibited taurine uptake. Maximal inhibition was obtained at 50 nM after 1 hr of treatment. This effect was prevented by pretreatment of the cells with chelerythrine, a potent and selective inhibitor of PKC. The transport of beta alanine was inhibited to a comparative extent. The mechanism of this inhibition was not investigated, but it was found that this inhibitory effect was not prevented by cycloheximide, actinomycin D, colchicine or cytochalasin D, indicating that neither protein synthesis, nor microfilament function were involved. The effect of PMA was associated with an impairment of kinetic constants. It is concluded that human GL15 cells have a taurine transporter similar to that expressed in rodent glial cells, and that the activation of PKC can modulate the activity of this transporter. PMID- 8684596 TI - gamma-Butyrolactone-induced absence-like seizures increase nuclear CRE- and AP-1 DNA-binding activities in mouse brain. AB - We examined the involvement of the GABAB receptor and the coordinated induction of nuclear transcriptional factors in experimental generalized absence seizures induced by gamma-butyrolactone (GBL) in mice. Although administration of GBL 50 mg/kg did not show any effects on behavior or ECoG pattern, higher doses of GBL (70 and 100 mg/kg, i.p.) induced behavioral changes associated with 3-6-Hz spike and wave discharges in the mice. CGP 35348, a GABAB receptor antagonist, suppressed both the GBL-induced absence seizures and the spike and wave discharges. The antiepileptic effects of CGP 35348 (200 mg/kg, i.p.) were stronger than those of ethosuximide (200 mg/kg, i.p.). Sodium valproate (100 mg/kg, i.p.) attenuated the early phase but not the late phase of the GBL-induced absence seizures. Gel-mobility assay demonstrated that administration of an effective dose of GBL for eliciting spike and wave discharges dose-dependently increased nuclear cyclic AMP-responsive element (CRE)- and activator protein 1 (AP-1) DNA-binding activities in mouse whole brain. The increases in nuclear CRE- and AP-1 DNA-binding were antagonized by CGP 35348 in a dose-dependent fashion. In addition, GABAB receptor binding assay revealed that GBL or antiepileptic drugs did not displace [3H]baclofen binding in cerebral cortical membranes. In contrast, gamma-hydroxybutyrate (GHB), an active metabolite of GBL, inhibited [3H]baclofen binding in a concentration-dependent manner. These results suggest that GABAB receptor-mediated synaptic responses are involved in GBL-induced generalized absence seizures and that the increases in nuclear CRE- and AP-1 DNA binding activities are correlated with the GBL-induced generalized absence seizures. PMID- 8684597 TI - Glutamic acid decarboxylase activity of the olfactory bulb in male rats is influenced by olfactory stimuli and hormonal status. AB - Changes is glutamate decarboxylase activity (GAD) in the main (MOB) and accessory (AOB) olfactory bulbs were determined at 11:00 hr and 17:00 hr in intact odor deprived (IOD) male rats exposed to female olfactory stimuli, and in castrated odor deprived males (COD) either injected with testosterone (T), exposed to female pheromone or injected with T and exposed to pheromone. Grouping IOD males by female olfactory stimulus and time of the day. MOB and AOB-GAD activity changed in the morning and not in the afternoon. In COD males, T injection induced an increased response in MOB-GAD activity 24 hr later either in the morning or in the afternoon, while no changes were seen at 11:00 or 17:00 hr exposure to female odor. In the AOB of COD males, both T administration or exposure to female pheromone, only induced an increase of enzyme activity in the morning. The association of T and female pheromone, decreased morning GAD activity both in the MOB and in the AOB compared with the values of COD males treated with T. In the afternoon this association had no effect compared with MOB, AOB-GAD activity of COD males injected with testosterone. These results indicate that hormonal and olfactory inputs in IOD and COD males are effective in changing olfactory bulb-GAD activity mainly in the morning. PMID- 8684598 TI - [3H]nisoxetine--a radioligand for noradrenaline reuptake sites: correlation with inhibition of [3H]noradrenaline uptake and effect of DSP-4 lesioning and antidepressant treatments. AB - Nisoxetine is a potent and selective inhibitor of noradrenaline uptake into noradrenergic neurones. [3H]Nisoxetine binding to rat frontal cortical membranes was of high affinity. The binding data of both competition and saturation studies fitted a single site binding model. [3H]Nisoxetine binding was potently inhibited by the selective noradrenaline uptake inhibitors desipramine and protriptyline. In addition, a very good correlation was obtained between the ability of 25 monoamine reuptake inhibitors and related compounds both to inhibit [3H]nisoxetine binding and to inhibit [3H]noradrenaline uptake in rat frontal cortex. DSP-4 (10-100 mg/kg, i.p.) dose-dependently depleted cortical noradrenaline concentrations (51-100%), with no significant effects on 5-HT and dopamine. These depletions, which were used as a marker of loss of noradrenergic nerve terminals, were associated with a dose-dependent decrease in the number of [3H]nisoxetine binding sites (20-97%) with no change in binding affinity. Furthermore, a good correlation was obtained between cortical noradrenaline concentrations and the number of [3H]nisoxetine binding sites. These data support the view that [3H]nisoxetine binds to a single population of homogeneous sites associated with the noradrenaline transporter complex. Using this ligand, the effects of repeated administration of both antidepressant drugs with a range of pharmacological actions and of electroconvulsive shock on noradrenaline reuptake sites were examined. The number and affinity of [3H]nisoxetine binding sites were unaltered by all treatments. It is unlikely, therefore, that antidepressant therapy would produce adaptive changes in noradrenaline uptake sites. PMID- 8684599 TI - Prenatal exposure to cocaine selectively disrupts motor responding to D amphetamine in young and mature rabbits. AB - Acute administration of D-amphetamine probed the functional effects of prenatal exposure to cocaine on the integrity of monoaminergic systems in preweanling (48 56 days old) and adult (> or = 140 days old) Dutch belted rabbits. D-Amphetamine sulfate (0, 0.3, 1.0, 3.3 and 6.0 mg/kg, s.c.) produced equivalent dose-related reductions in food intake in 180 day-old rabbits that had been exposed in utero on gestational days 8-29 to cocaine or saline. Intrauterine exposure to cocaine also did not alter the incidence of exploratory behaviors stimulated by D amphetamine during the anorexia test. In contrast, however, prenatal cocaine virtually eliminated stereotyped head bobbing elicited by the highest dose of D amphetamine. When responses to 5.0 mg/kg D-amphetamine were measured during a 90 min open field test, prenatal cocaine prevented head bobbing in preweanling rabbits and reduced this behavior by 92% in 140 day-old adults. Prenatal cocaine also diminished the intensity of other motor responses in the open field in the adults but not in preweanlings. In normal rabbits, the D1 antagonist R(+)-SCH 23390 (0.01 mg/kg, s.c.) blocked D-amphetamine-induced head bobbing. Thus, prenatal exposure to cocaine produces an early and persistent deficit in behavioral responding to a high dose of D-amphetamine. The deficit is especially selective at the time of weaning, broadens to affect more motor behaviors with maturation and may reveal impaired D,-mediated dopaminergic neurotransmission in the brain. PMID- 8684600 TI - Adenosine A1 and A2A receptors and nitrobenzylthioinosine-sensitive transporters in gerbil brain: no changes following long-term treatment with the adenosine transport inhibitor propentofylline. AB - There is evidence that adenosine is an endogenous neuroprotective substance in the gerbil and that propentofylline, a novel xanthine derivative that acts as a transport inhibitor, exerts part of its neuroprotective activity in this species by enhancing adenosine actions. Using autoradiography we have examined the distribution of adenosine A1 and A2A receptors and of equilibrative adenosine transporters in gerbil brain as well as the possible changes induced by repeated treatment with propentofylline. Nucleoside transporters, studied by [3H]NBMPR binding, were found to be widely distributed in the gerbil brain, with no clear relationship to the distribution of adenosine receptors. Adenosine A2A receptors, studied by [3H]CGS 21680 binding and by in situ hybridization, were found to be present in intrinsic neurons in the caudate putamen, nucleus accumbens and tuberculum olfactorium. Adenosine A1 receptors were studied by examining the binding of [3H]CHA, an agonist, and [3H]DPCPX, an antagonist. There was an overall similarity in the distribution of binding sites for these two ligands, and a similarity with the distribution in the rat. However, the antagonist was found to label certain structures, especially white matter structures, more than the agonist. It is argued that these binding sites for antagonists represent receptors that are in transit from the site of synthesis in the perikaryon to the destination in the nerve terminal, and are not coupled to G proteins. There were no differences in the binding of any of these ligands or in A2A mRNA following 2 weeks' treatment with propentofylline, indicating that the drug has minimal effects on adenosine mechanisms under basal physiological conditions. This also suggests that tolerance to adenosine-related effects of the drug is less likely to occur. PMID- 8684601 TI - The interaction of dexamethasone with ondansetron on drug-induced emesis in the ferret. AB - The potential of dexamethasone (0.5-20 mg/kg i.p.) to antagonize the emesis induced by cisplatin (10 mg/kg i.v.), apomorphine (0.25 mg/kg s.c.), morphine (0.5 mg/kg s.c.) and copper sulphate (100 mg/kg intragastric) was investigated alone and in combination with ondansetron in the ferret. There was a trend for dexamethasone 0.1-5 mg/kg to reduce cisplatin-induced emesis and for 0.05-2.5 mg/kg to delay the onset of apomorphine-induced emesis but doses of dexamethasone up to 20 mg/kg were without effect to modify morphine- or copper sulphate-induced emesis. The combination of dexamethasone 2.5 mg/kg with ondansetron 0.1 mg/kg did not have additive effects to reduce cisplatin-induced emesis but did reduce significantly the total numbers of episodes recorded. Ondansetron 1 mg/kg was without effect to modify apomorphine-, morphine- or copper sulphate-induced emesis but the combination pretreatment of ondansetron 1 mg/kg with dexamethasone 2.5 and 5 mg/kg reduced significantly apomorphine-induced retching. Data are discussed in terms of the antiemetic effectiveness of dexamethasone to antagonize chemotherapy-induced emesis in man. PMID- 8684602 TI - Activation of 5-HT2A receptors potentiates pain produced by inflammatory mediators. AB - Previous results from our laboratory indicate that serotonin (5-HT) potentiates pain produced by other inflammatory mediators. To characterize the receptor subtype(s) mediating this synergistic effect of 5-HT, selective 5-HT agonists were injected, alone or with noradrenaline (NA) or prostaglandin E2 (PGE2), into the plantar surface of the paws of rats. The behavioural response (favouring, elevation and licking the paw) was recorded using the rating scale developed to quantify formalin-induced pain. The 5-HT1A and 5-HT3 agonists, 8-OH-DPAT and 2 methyl-5-HT, respectively, produced only transient responses by themselves and did not interact with PGE2 or NA. The 5-HT2 agonists, alpha-methyl-5-HT and DOI, also produced transient responses alone, but induced lifting and licking of the injected paw lasting more than 30 min when combined with PGE2 or NA. The lifting and licking response produced by 5-HT plus PGE2 was not altered by intraplantar pretreatment with the 5-HT1A and 5-HT3 antagonists, BMY 7378 and tropisetron, but was attenuated by the 5-HT2A/2C antagonist ketanserin. The pain response produced by alpha-methyl-5-HT plus PGE2 was blocked by pretreatment with the 5-HT2A/2C antagonists ketanserin and ritanserin, and the 5-HT2A antagonist spiperone (MPE50 values 1.4, 7.7 and 0.06 nmol, respectively). The second phase of the response to intraplantar formalin was also attenuated by ketanserin, ritanserin and spiperone (MPE50 values 11.3, 21.8 and 0.23 nmol, respectively). These data imply that 5 HT2A antagonists may be effective peripherally acting analgesics or analgesic adjuncts in pain associated with 5-HT release from platelets, such acute injury and, perhaps, some chronic pain states. PMID- 8684603 TI - Morphological plasticity in dendritic spines of cultured hippocampal neurons. AB - Rat hippocampal neurons, grown in dissociated culture for about 18 days, were exposed for 6 h to three days to stimuli which cause either an increase (GABAA antagonists, bicuculline or picrotoxin), or decrease (tetrodotoxin) in spontaneous neuronal activity. Individual neurons were stained with 1,1' dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate and visualized with a confocal laser scanning microscope. GABA antagonists caused a marked, up to 60%, increase in spine density on secondary dendrites of cultured hippocampal neurons. This was associated with a small decrease in spine length. The rise in spine density was partially prevented by treatment with the calcium chelator 1,2 bis(2-aminophenoxy)ethane-N,N,N,N-tetra-acetate, or by blockade of protein synthesis with cycloheximide. Tetrodotoxin caused a marked elongation of dendritic spines (but did not cause a decrease in spine density comparable to the increase caused by picrotoxin). This effect was seen primarily but not exclusively in spines with no distinct head. Both treatments were most effective within 24 h of exposure. There were no other systematic effects of the drugs on the morphology of the dendritic spines. These results indicate that dendritic spines in cultured neurons depend on ongoing synaptic activity to maintain their shape, and that neurons respond to an increase in synaptic demand by an increase in spine density. Thus, dendritic spines are likely to have a role in short-term synaptic interaction rather than to constitute a long-term memory storage device. PMID- 8684604 TI - Distribution of alpha 1A, alpha 1B and alpha 1E voltage-dependent calcium channel subunits in the human hippocampus and parahippocampal gyrus. AB - The distribution of voltage-dependent calcium channel subunits in the central nervous system may provide information about the function of these channels. The present study examined the distribution of three alpha-1 subunits, alpha 1A, alpha 1B and alpha 1E, in the normal human hippocampal formation and parahippocampal gyrus using the techniques of in situ hybridization and immunocytochemistry. All three subunit mRNAs appeared to be similarly localized, with high levels of expression in the dentate granule and CA pyramidal layer. At the protein level, alpha 1A, alpha 1B and alpha 1E subunits were differentially localized. In general, alpha 1A-immunoreactivity was most intense in cell bodies and dendritic processes, including dentate granule cells, CA3 pyramidal cells and entorhinal cortex pre-alpha and pri-alpha cells. The alpha 1B antibody exhibited relatively weak staining of cell bodies but stronger staining of neuropil, especially in certain regions of high synaptic density such as the polymorphic layer of the dentate gyrus and the stratum lucidum and radiatum of the CA regions. The alpha 1E staining pattern shared features in common with both alpha 1A and alpha 1B, with strong immunoreactivity in dentate granule, CA3 pyramidal and entorhinal cortex pri-alpha cells, as well as staining of the CA3 stratum lucidum. These findings suggest regions in which particular subunits may be involved in synaptic communication. For example, comparison of alpha 1B and alpha 1E staining in the CA3 stratum lucidum with calbindin-immuno-reactivity suggested that these two calcium channels subunits may be localized presynaptically in mossy fibre terminals and therefore may be involved in neurotransmitter release from these terminals. PMID- 8684605 TI - Mutant vasopressin precursors in the human hypothalamus: evidence for neuronal somatic mutations in man. AB - We report here the expression of mutant proteins displaying the +1 reading frame of the vasopressin and oxytocin precursors in magnocellular neurons of the human hypothalamus. Our data demonstrate a high frequency of frameshift mutations in these neurons and thus provide the first evidence of somatic mutations in neurons of the human brain. The results imply that other neuronal populations and specific genes may also undergo similar mutational events with possible consequences for neuronal functioning and pathology. PMID- 8684606 TI - Opposite regulation by the beta-adrenoceptor-cyclic AMP system of synaptic plasticity in the medial and lateral amygdala in vitro. AB - The effects of beta-adrenoceptor activation on short-term potentiation in the medial and lateral amygdala were investigated using rat brain slice preparations in vitro. Application of tetanic stimulation (100 pulses at 100 Hz) induced only short-term potentiation under normal recording conditions. In the medial amygdala, when the same tetanic stimulation was applied in the presence of a beta adrenoceptor agonist, isoproterenol, short-term potentiation was significantly enhanced and long-term potentiation was induced. Phenylephrine, an alpha adrenoceptor agonist, did not affect short-term potentiation. The short-term potentiation-enhancing effect of isoproterenol was mimicked by forskolin, an adenylate cyclase activator, and was blocked by Rp-adenosine-3',5'-cyclic monophosphothioate, an inhibitor of cyclic AMP-dependent protein kinase. On the other hand, in the lateral amygdala, isoproterenol suppressed short-term potentiation. The short-term potentiation-suppressing effect of isoproterenol was mimicked by forskolin, and was blocked by Rp-adenosine-3',5'-cyclic monophosphothioate. These results suggest that the beta-adrenoceptor-cyclic AMP system plays a role in facilitating the induction of long-term potentiation in the medial amygdala, but suppresses synaptic plasticity in the lateral amygdala. PMID- 8684607 TI - Regional expression and subcellular localization of the tyrosine-specific phosphatase SH-PTP2 in the adult human nervous system. AB - The protein tyrosine phosphatase SH-PTP2 has been implicated in a variety of cell signaling cascades, including those mediating neuronal survival. We therefore investigated the expression of SH-PTP2 in the adult human nervous system using Western blotting, immunohistochemistry and immunoelectron microscopy. SH-PTP2 immunoreactivity was noted only in neurons, but was not restricted to a specific neuronal type or location. Immunohistochemistry showed perikaryal staining, whereas Western blotting and ultrastructural analysis suggested that SH-PTP2 is present in axons as well. While immunohistochemistry showed a Nissl-like pattern in large motor neurons, immunoelectron microscopy demonstrated a diffuse pattern of cytoplasmic staining, without apparent preferential localization. The presence of the SH2 domain-containing tyrosine-specific phosphatase SH-PTP2 in diverse neurons in the adult nervous system suggests that SH-PTP2 may play a role in a broad spectrum of neuronal responses. PMID- 8684608 TI - Neuroprotective strategies for treatment of lesions produced by mitochondrial toxins: implications for neurodegenerative diseases. AB - Neuronal death in neurodegenerative diseases may involve energy impairment leading to secondary excitotoxicity, and free radical generation. Potential therapies for the treatment of neurodegenerative diseases therefore include glutamate release blockers, excitatory amino acid receptor antagonists, agents that improve mitochondrial function, and free radical scavengers. In the present study we examined whether these strategies either alone or in combination had neuroprotective effects against striatal lesions produced by mitochondrial toxins. The glutamate release blockers lamotrigine and BW1003C87 significantly attenuated lesions produced by intrastriatal administration of 1-methyl-4 phenylpyridinium. Lamotrigine significantly attenuated lesions produced by systemic administration of 3-nitropropionic acid. Memantine, an N-methyl-D aspartate antagonist, protected against malonate induced striatal lesions. We previously found that coenzyme Q10 and nicotinamide, and the free radical spin trap n-tert-butyl-alpha-(2-sulfophenyl)-nitrone (S-PBN) dose-dependently protect against lesions produced by intrastriatal injection of malonate. In the present study we found that the combination of MK-801 (dizocipiline) with coenzyme Q10 exerted additive neuroprotective effects against malonate. Lamotrigine with coenzyme Q10 was more effective than coenzyme Q10 alone. The combination of nicotinamide with S-PBN was more effective than nicotinamide alone. These results provide further evidence that glutamate release inhibitors and N-acetyl-D aspartate antagonists can protect against secondary excitotoxic lesions in vivo. Furthermore, they show that combinations of agents which act at sequential steps in the neurodegenerative process can produce additive neuroprotective effects. These findings suggest that combinations of therapies to improve mitochondrial function, to block excitotoxicity and to scavenge free radicals may be useful in treating neurodegenerative diseases. PMID- 8684609 TI - Behavioural, autonomic and endocrine responses associated with C-fos expression in the forebrain and brainstem after intracerebroventricular infusions of endothelins. AB - Endothelins are a range of peptides (endothelin-1, endothelin-2, and endothelin 3) well known to act peripherally as powerful cardiovascular-regulating agents. Recently, they have been shown to be localized in CSN, where they may act as central neurotransmitters. A variety of putative roles has been ascribed to them in the CNS. To identify those regions of the brain capable of responding to these peptides, the expression of c-fos (an immediate-early gene), has been used to map patterns of activation following intracerebroventricular (i.c.v.) infusions of endothelins in Lister-hooded rats. This has been correlated with changes in heart rate, core temperature and plasma corticosterone levels. Endothelin-3 i.c.v. (50 pmol) decreased both heart rate and core temperature (both recorded by telemetry). This effect lasted for about 30-45 min. Endothelin-1 (10 pmol) or endothelin-3 (50 pmol) i.c.v. induced c-fos expression in the specific regions in the forebrain and brainstem. Strong expression was found in the septum, bed nucleus of the stria terminalis, parvicellular paraventricular nucleus, the central nucleus of the amygdala, dorsal motor nucleus of the vagus and solitary nucleus. There was less marked c-fos expression in other areas of the basal forebrain, such as the organum vasculosum of the lamina terminals, median preoptic nucleus, supraoptic nucleus and the magnocellular. There are two classes of endothelin receptor (A and B). An endothelin-A receptor antagonist, BQ-123, abolished c-fos expression in all structures in the forebrain and brainstem following endothelin-1 infusions. However, an endothelin-B agonist (TetraAla endothelin-1) did not induce discernible c-fos expression in the forebrain or brainstem. These results suggest that the endothelin-A receptor is responsible for endothelin-dependent c-fos induction in the brain. Interactions between endothelins and angiotensin II were also studied. The pattern of c-fos induced by endothelin-3 and angiotensin II was different (particularly in the anteroventral region of the third ventricle). Furthermore, prior infusions of endothelin-3 interfered with the expression of c-fos induced by subsequent angiotensin II, and also suppressed the latter's dipsogenic effect. These results show that endothelin-3 and angiotensin II interact at both behavioural and cellular levels, and that endothelins may play significant roles in the central control of fluid balance and autonomic activity. PMID- 8684610 TI - Sex comparison of neuronal Fos immunoreactivity in the rat vomeronasal projection circuit after chemosensory stimulation. AB - In rodents, reproductively relevant pheromonal cues are detected by receptors in the vomeronasal organ, which in turn transmit this information centrally via the accessory olfactory bulb, the medial nucleus of the amygdala, the posterior medial bed nucleus of the stria terminalis and the medial preoptic area. In the rat, more neurons are present in males than in females at virtually every relay in this vomeronasal projection circuit. Using Fos immunoreactivity as a marker of neuronal activation, we compared the ability of pheromonal cues derived from the urine and feces of estrous or anestrous female rats to activate neurons in this vomeronasal projection circuit in sexually experienced, gonadectomized male and female rats which were chronically treated in adulthood with a high dose of testosterone propionate (5 mg/kg). When compared with rats killed after 2 h of exposure to clean bedding, male and female subjects exposed for 2 h to bedding from estrous females had similar and significant increments in the number of Fos immunoreactive neurons at each level of the vomeronasal projection circuit, including the granular layer of the accessory olfactory bulb, the posterior dorsal portion of the medial amygdaloid nucleus, the posterior medial portion of the bed nucleus of the stria terminalis and the medial preoptic area. Exposure to bedding from anestrous females stimulated similar and significant increments in Fos immunoreactivity in most of these same brain regions. Chemosensory stimulation failed to augment Fos immunoreactivity in neurons located in the ventrolateral subregion of the ventromedial nucleus of the hypothalamus or in the midbrain central tegmental field, sites at which mating has previously been shown to augment Fos immunoreactivity in both sexes. Finally, chemosensory stimulation augmented Fos immunoreactivity in the nucleus accumbens shell and core, two regions receiving dopaminergic afferents which have been implicated in sexual reward. On two occasions all subjects were given simultaneous access to bowls containing bedding from estrous versus anestrous females. Both males and females spent significantly more time investigating the estrous bedding, although the total time spent investigating either type of bedding was significantly greater in males. The results suggest that the previously established sexual dimorphism in the morphology of the rat's vomeronasal projection circuit is not reflected in the functional responsiveness of neurons in this circuit to chemosensory cues emitted by female conspecifics. PMID- 8684611 TI - Somatostatin receptor subtypes SSTR2 and SSTR5 couple negatively to an L-type Ca2+ current in the pituitary cell line AtT-20. AB - The somatostatin receptor subtypes SSTR2 and SSTR5 mediate distinct endocrine and exocrine functions of somatostatin and may also be involved in mediating the neuromodulatory actions of somatostatin in the brain. To investigate whether these receptors couple to voltage-sensitive Ca2+ channels, SSTR2 and SSTR5 selective agonists were tested for their effects on AtT-20 cells using whole cell patch clamp techniques. The SSTR2 selective agonist MK 678 inhibited Ca2+ currents in AtT-20 cells. The effects of MK 678 were reversible and blocked by pertussis toxin pretreatment, suggesting that SSTR2 couples to the L-type Ca2+ channels via G proteins. Other SSTR2-selective agonists, including BIM 23027 and NC8-12, were able to inhibit the Ca2+ currents in these cells. The SSTR5 selective agonist BIM 23052 also inhibited the Ca2+ currents in these cells and this effect was reversible and blocked by pertussis toxin treatment. The ability of SSTR5 to mediate inhibition of the Ca2+ current was greatly attenuated by pretreatment with the SSTR5-selective agonist BIM 23052, whereas SSTR2-mediated inhibition of the Ca2+ current was not altered by pretreatment with the SSTR2 selective agonist MK 678. Thus, the SSTR2 and SSTR5 couplings to the Ca2+ current are differentially regulated. The peptide L362,855, which we previously have shown to have high affinity for the cloned SSTR5, had minimal effects on Ca2+ currents in AtT-20 cells at concentrations up to 100 nM and did not alter the ability of MK 678 to inhibit Ca2+ currents. However, it completely antagonized the effects of the SSTR5-selective agonist BIM 23052 on the Ca2+ currents. L362,855 is an antagonist/partial agonist at SSTR5 since it can reduce Ca2+ currents in these cells at concentrations above 100 nM. L362,855 is also an antagonist/partial agonist at the cloned rat SSTR5 expressed in CHO cells since it is able to block the inhibition of cAMP accumulation induced by somatostatin at concentrations below 100 nM but at higher concentrations can inhibit cAMP formation itself. Structural analysis of L362,855 reveals that only a single hydroxyl group at residue seven in the peptide is needed to convert the compound from an antagonist/partial agonist to a full agonist at SSTR5. These studies reveal that two different somatostatin receptor subtypes, SSTR2 and SSTR5, can mediate the inhibition of an L-type Ca2+ channel in AtT-20 cells by somatostatin. The receptor subtype responses can be distinguished by selective agonists and antagonists and are regulated differently by agonist pretreatment. The inhibition of Ca2+ influx into endocrine cells and neurons may be a major cellular mechanism by which somatostatin modulates hormone and neurotransmitter release. Our results reveal that at least two receptor subtypes can mediate this cellular response. PMID- 8684612 TI - Delayed sympathectomy after a prolonged hyperalgesia results in a subsequent enhanced acute hyperalgesic response. AB - We report on the ability of a delayed sympathectomy after a prolonged hyperalgesia to result in a subsequent enhanced hyperalgesic response. Sympathectomy was performed one day after injection of prostaglandin E2 plus rolipram, which induces a prolonged sympathetically-maintained hyperalgesia [Aley K. O. and Levine J. D. (1995) Eur. J. Pharmac. 273, 107-112]. The duration of hyperalgesia produced by a subsequent injection of prostaglandin E2 or prostaglandin E2 plus rolipram was then assessed. Lumbar surgical sympathectomy, done on day 2 or 3, prevented prostaglandin E2 plus rolipram-induced prolonged hyperalgesia from developing when they were injected five days after surgery, similar to the previous report of the effect of prior sympathectomy to block the rolipram enhancement [Aley K. O. and Levine J. D. (1995) Eur. J. Pharmac. 273, 107-112]. Sympathectomy done five days after injection of prostaglandin E2 plus rolipram, however, paradoxically prolonged (at least 10 days) hyperalgesia induced by a subsequent prostaglandin E2 plus rolipram injection, a duration much greater than that seen after prostaglandin E2 plus rolipram in naive animals. To determine the roles of prostaglandin E2 and rolipram in the prolongation of hyperalgesic response after delayed sympathectomy, rats were treated with either prostaglandin E2 or rolipram prior to sympathectomy. Prostaglandin E2 or rolipram alone were also administered five days after the sympathectomy. It was found that sympathectomy done five days after first injecting either prostaglandin E2 or rolipram alone did not produce enhanced hyperalgesic response. These data suggest that induction of a prolonged state of mechanical hyperalgesia causes time dependent alterations in the sympathetic control of peripheral nociceptive mechanisms such that sympathectomy can lead to enhanced hyperalgesic response. These findings may be relevant to post-sympathectomy pain, a clinical entity for which there has been no available animal models. PMID- 8684613 TI - Leukemia inhibitory factor induces mechanical allodynia but not thermal hyperalgesia in the juvenile rat. AB - Systemic administration or local injection to the rat hindpaw of leukemia inhibitory factor induced a prolonged, dose dependent, mechanical hypersensitivity of the hindpaw flexion withdrawal reflex. Mechanical stimuli which were innocuous prior to leukemia inhibitory factor administration, evoked a rapid hindpaw withdrawal reflex indicative of mechanical allodynia. Pre administration of anti-leukemia inhibitory factor antibodies prevented this behavioural hypersensitivity. Hindpaw sensitivity to a noxious thermal stimulus was unaffected by leukemia inhibitory factor administration. Anti-leukemia inhibitory factor had no effect upon hindpaw withdrawal thresholds when injected alone nor influenced the mechanical hypersensitivity produced by a subcutaneous injection of nerve growth factor. Injection of the closely related cytokine ciliary neurotrophic factor did not affect mechanical or thermal reflex withdrawal thresholds. Elevation of the neuroactive cytokine leukemia inhibitory factor following peripheral nerve injury may be a contributory factor to the pathogenesis of neuropathic pain. PMID- 8684614 TI - Calcitonin gene-related peptide is involved in the spinal processing of mechanosensory input from the rat's knee joint and in the generation and maintenance of hyperexcitability of dorsal horn-neurons during development of acute inflammation. AB - In an electrophysiological study in anaesthetized rats, the involvement of calcitonin gene-related peptide in the spinal processing of mechanosensory information from the normal and inflamed knee joint was investigated. Calcitonin gene-related peptide(8-37), a specific antagonist at calcitonin gene-related peptide 1 receptors was administered ionophoretically close to nociceptive neurons with input from the knee joint before, during, and after development of acute inflammation in the knee induced by the intra-articular injections of kaolin and carrageenan. Calcitonin gene-related peptide (8-37) selectively antagonized the effects of ionophoretically applied calcitonin gene-related peptide but not those of ionophoretically applied substance P, neurokinin A, and (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid. Before inflammation, calcitonin gene-related peptide (8-37) reduced the responses to noxious pressure applied to the knee in 22 of 23 neurons; in 14 of 22 neurons, the responses to innocuous pressure were also reduced. In eight neurons calcitonin gene-related peptide (8-37) was administered during induction and in three periods within the first 90 min of inflammation. In these neurons the developing inflammation evoked a significantly smaller increase of the responses to innocuous and noxious pressure applied to the injected knee than in 13 control neurons which were not treated by the antagonist during induction of inflammation. In 16 of 16 neurons, calcitonin gene-related peptide (8-37) reduced the responses to innocuous and noxious pressure once inflammation and hyperexcitability of the spinal cord neurons were established. These data show that calcitonin gene-related peptide is involved in the spinal processing of mechanosensory input from the normal joint. Furthermore, this peptide and its spinal receptors significantly contribute to the generation and expression of inflammation-evoked hyperexcitability of spinal cord neurons during the development of inflammation. Finally, calcitonin gene-related peptide is involved in the maintenance of inflammation-evoked hyperexcitability. By these effects calcitonin gene-related peptide receptors may significantly contribute to the neuronal basis of hyperalgesia and allodynia associated with inflammation. PMID- 8684615 TI - Time course of axotomy-induced apoptotic cell death in facial motoneurons of neonatal wild type and bcl-2 transgenic mice. AB - In neonatal animals, axotomy of facial motoneurons induces cell death. Using the TUNEL technique, which labelled apoptotic DNA breaks in situ, the kinetics of motoneuron death were studied. Lesion of the right facial nerve were performed on two-day-old mice. Then, animals were perfused 8, 12, 16, 20, 24, 28, 32, 48, 72 and 120 h after the lesion. Our results provide direct evidence that, following an axotomy, facial motoneurons die through an apoptotic process. We showed that apoptotic neurons can be detected as early as 16 h after the lesion. Facial motoneurons die within 120 h, with a peak observed 28 h after the lesion. The kinetics of appearance of apoptotic cells were correlated with the loss of Cresyl Violet-stained motoneurons. Furthermore, labelled cells were observed in the contralateral side of the lesion, suggesting that spontaneous apoptotic cell death occurs during the postnatal period. The same study was performed on transgenic mice overexpressing the proto-oncogene bcl-2, a gene repressor of cell death. In these mice, no TUNEL-labelled cells were detected on the lesioned and unlesioned sides. In vivo, Bcl-2 may protect motoneurons from apoptotic death following axotomy and during naturally occurring cell death. These results suggest that these two types of cell death may occur via the same mechanism. PMID- 8684616 TI - Nodal swelling produced by ciguatoxin-induced selective activation of sodium channels in myelinated nerve fibers. AB - Ciguatoxin-1b, the major toxin involved in ciguatera fish poisoning, and D mannitol were examined on frog nodes of Ranvier using confocal laser scanning microscopy and conventional current- and voltage-clamp techniques. During the action of 10 nM ciguatoxin-1b, an increase in nodal volume was observed as determined by digital image processing and three-dimensional reconstruction of axons. The increase was prevented by blocking Na+ channels with tetrodotoxin. Ciguatoxin-1b (10 nM) induced high frequency action potential discharges up to 70 100 Hz. Analysis of Na+ current revealed that the toxin modified a current fraction which was activated at resting membrane potential and failed to inactivate. Increasing the osmolality of the external solution by about 50% with D-mannitol restored the nodal volume to its control value and suppressed spontaneous action potentials. In addition, D-mannitol affected unmodified and ciguatoxin-1b-treated Na+ currents in a similar manner causing a reduction of maximum conductance, negative shifts of current reversal potential and modification of the voltage-dependence of current activation and inactivation. In conclusion, ciguatoxin-1b induced a tetrodotoxin-sensitive swelling of nodes of Ranvier and selectively affected the Na+ current of myelinated axons. It is proposed that ciguatoxin-1b, by modifying Na+ current, increased intracellular Na+ concentration which caused water influx and nodal swelling. This may explain some of the reported symptoms of ciguatera fish poisoning. D-mannitol, an agent used for ciguatera treatment, was found to reverse the effects of ciguatoxin-1b by reducing Na+ entry and increasing the efflux of water through its osmotic action. It is the first time that osmotic changes produced by the selective activation of ionic channels, i.e. Na+ channels, are reported. PMID- 8684617 TI - Centripetal transport of herpes simplex virus in human retinal pigment epithelial cells in vitro. AB - Herpes simplex virus displays tropism for neurons and other polarized epithelial cells. We have grown human retinal pigment epithelial cells in culture to study potential mechanisms whereby herpes simplex virus (type I) is transported from the plasma membrane of the cell to the nucleus. The cells were highly polarized as determined by a variety of criteria. They were tightly coupled by junctional complexes, as determined by electron microscopy, immunofluorescent staining of tight junctions and measurements of transepithelial electrical resistances > 200 omega cm2. Immunofluorescence and confocal microscopy were used to visualize microtubule orientation. The microtubules were arranged (i) in a single apical cilium, (ii) in a meshwork beneath the apical membrane and (iii) in longitudinally arranged bundles near the lateral membranes and nucleus. The latter microtubules were primarily oriented with their plus ends directed toward the basal surface of the cells. We infected retinal pigment epithelial cells at the apical surface with virus and assayed the uptake and transport of virus to the nucleus by quantitative immunoblot and immunocytochemical staining for the viral immediate early gene product, infected cell protein 4. The antigen first appeared in retinal pigment epithelial cells 2 h after infection. Treatment of the cells with 33 microM nocodazole, a microtubule-destabilizing drug, delayed the appearance of the viral antigen by 1 h. The effect of nocodazole treatment on microtubule integrity was confirmed by immunofluorescent staining and immunoblots of tubulin. Both cytoplasmic dynein and the ubiquitous form of kinesin were identified in the cells using immunoblots. These novel data indicate that human retinal pigment epithelial cells, like neurons, are susceptible to infection by herpes simplex virus and that the centripetal transport of virus to the nucleus in both cell types is facilitated by microtubules. The orientation of microtubules in retinal pigment epithelial cells suggests that the transport of herpes simplex virus from the apical surface is mediated by a microtubule activated motor enzyme, possibly kinesin. PMID- 8684618 TI - A chromaffin cell-derived protein induces the NADPH-diaphorase phenotype in cultured rat spinal cord neurons. AB - We have recently demonstrated that neurotrophins induce reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase activity in cultured spinal cord neurons. One prominent neuron population of the spinal cord expressing NADPH diaphorase activity in vivo are preganglionic sympathetic neurons, including those innervating the adrenal medulla. These neurons receive trophic support from their target. We have shown previously that chromaffin cells contain as yet unidentified neurotrophic molecules, which may include releasable factors relevant for the survival and differentiation of developing preganglionic sympathetic neurons. We have studied the influence of proteins derived from bovine chromaffin cells and released by nicotine on NADPH-diaphorase expression in spinal cord cultures established from 16-day-old rat embryos. At this embryonic age, NADPH-diaphorase activity becomes apparent in the spinal cord and predominantly expressed in sympathetic nuclei. Similar to brain-derived neurotrophic factor and neurotrophin-4, a heat- and trypsin-sensitive component from chromaffin cells contained in granule preparations up-regulated the number of NADPH-diaphorase-positive neurons in spinal cord cultures. Combined application of this activity and neurotrophin-4 resulted in an additive effect, indicating that the effect of the chromaffin cell-derived active component is not mediated by one of the trk B ligands. This was confirmed by co-treatment studies with the trk-signalling pathway inhibitor K252b, which did not inhibit the effect of the chromaffin cell-derived protein(s). Further studies revealed that NADPH diaphorase reactivity is inducible in spinal cord neurons at any time point throughout the entire culture period of six days, suggesting de novo induction of the enzyme rather than a survival-promoting effect of the activity from chromaffin cells. Culture supernatants from nicotine-stimulated bovine chromaffin cells induced NADPH-diaphorase-positive neurons at the same magnitude as the material obtained from chromaffin granule preparations. Our data suggest that chromaffin cell-derived proteins are capable of up-regulating NADPH-diaphorase activity or to induce de novo this transmitter phenotype in neuron populations of the spinal cord, which may include preganglionic sympathetic neurons. PMID- 8684619 TI - Laminin alpha 2 is a component of brain capillary basement membrane: reduced expression in dystrophic dy mice. AB - In the present study we demonstrate low level expression of the laminin alpha 2 chain in brain and localize the alpha 2 protein to the capillary basement membrane. While in peripheral basement membranes the laminin alpha 1 and alpha 2 chains have an almost mutually exclusive distribution, the present results suggest both alpha 1 and alpha 2 in the cerebral capillary basement membrane. Towards elucidating the function of alpha 2 in brain, we have performed ultrastructural analysis of the capillary basement membrane in dystrophic dy mice, which show a 70-90% and > 95% reduction of alpha 2 messenger RNA compared to heterozygous and wild-type mice, respectively, and show a nearly total absence of the alpha 2 protein by immunofluorescence. In contrast to the muscle and Schwann cell basement membrane, where alpha 2 deficiency causes structural basement membrane abnormalities, the present results show that the lack of the alpha 2 subunit in the cerebral capillary basement membrane is not detrimental to its structure. This observation might be explained by the fact that the cerebral capillary basement membrane expresses both alpha chains and therefore exhibits structural redundancy. PMID- 8684620 TI - Mast cell mediators excite the afferents of cat small intestine. AB - The influence of intra-arterial injections of 5-hydroxytryptamine, histamine and prostaglandin E2 on afferent impulse activity of mesenteric nerves of small intestine was studied. In anaesthetized cats 5-hydroxytryptamine (10(-5)-10(-4) M) and histamine (10(-5)-10(-3) M) were shown to increase the impulse activity in a dose-dependent manner. Metergolin, 5-hydroxytryptamine antagonist, suppressed the effect of 5-hydroxytryptamine. Clemastine and cimetidine, antagonists of H1 and H2 histamine receptors respectively, distinctly diminished excitatory histamine effects. Prostaglandin E2 (10-30 micrograms/kg) enhanced the afferent impulse activity. The results suggest that afferents of the small intestine may be involved in reception of inflammatory and immune responses. PMID- 8684621 TI - Metabolic activity of the basal ganglia in parkinsonian syndromes in human and non-human primates: a cytochrome oxidase histochemistry study. AB - In order to examine the consequences of nigrostriatal denervation on metabolic and functional activity of the basal ganglia, we analysed the distribution of cytochrome oxidase, a metabolic marker for neuronal functional activity, throughout the different basal ganglia structures in parkinsonian syndromes. The study was performed using enzyme histochemistry and densitometric measurements in patients with Parkinson's disease and in monkeys rendered parkinsonian by 1 methyl-4-phenyl-1,2,3,6-tetrahydropyrydine (MPTP) intoxication. In MPTP intoxicated monkeys compared to control animals, enzyme activity was significantly increased in the subthalamic nucleus and in the output nuclei of the basal ganglia, e.g. the internal segment of the globus pallidus and the substantia nigra pars reticulata, but remained unchanged in the external segment of the globus pallidus and the striatum. L-DOPA treatment reversed the increased enzyme activity in all of the affected structures studied. In contrast, in parkinsonian patients, who had all been chronically treated with L-DOPA, no changes in enzyme activity were detected compared to control subjects. The results in MPTP-intoxicated monkeys are in agreement with the accepted model of basal ganglia organization, in which the output nuclei of the basal ganglia are considered to be overactive after nigrostriatal denervation, partly due to increased activity of excitatory afferents from the subthalamic nucleus. Since the increased enzyme activity in MPTP-intoxicated monkeys was reversed by L-DOPA therapy, the unchanged cytochrome oxidase activity observed in parkinsonian patients might result from L-DOPA treatment, combined with the chronicity of nigrostriatal denervation. PMID- 8684622 TI - Functional and anatomical reconstruction of the 6-hydroxydopamine lesioned nigrostriatal system of the adult rat. AB - In an attempt to reconstruct the 6-hydroxydopamine lesioned nigrostriatal system of the adult rat we have combined homotopic grafting of embryonic ventral mesencephalon suspensions with the implantation of long oblique "bridge" grafts of fibroblast growth factor-4-transfected RN-22 schwannoma cells stretching from the site of the neuronal grafts to the striatum. At seven weeks after receiving both grafts, animals were killed and processed for immunohistochemistry against tyrosine hydroxylase. Tyrosine hydroxylase-immunoreactive axons were seen to extend from the nigral grafts, along the bridge graft to the striatum where terminal arborizations could be seen. The retrograde tracer Fluoro-gold was injected intrastriatally in some of the experimental animals and was taken up by grafted neurons confirming their projection to the striatum. In parallel to the anatomical reconstruction of the system, a decrease in amphetamine-induced rotation was demonstrated in those animals receiving both grafts which had received > 98% complete lesions. This decrease was greatest in those animals with the most tyrosine hydroxylase-immunoreactive axons in their bridge grafts. The presence of the bridge graft also led to an increase in neuronal graft survival with twice as many tyrosine hydroxylase-immunoreactive neurons being found in the grafts of those animals that had received both grafts compared to those that had received a neuronal graft but no bridge graft. PMID- 8684623 TI - Quantitative autoradiography reveals regionally selective changes in dopamine D1 and D2 receptor binding in the genetically dystonic hamster. AB - Dystonia has been proposed to be caused by abnormal input from thalamus to premotor cortex due to altered activity of the striatum projecting by way of the globus pallidus and substantia nigra pars reticulata to the thalamus. However, in the case of idiopathic dystonia, i.e. the most common form of dystonia in humans, there is only limited evidence to support such a neuroanatomic concept. In view of the problems of studying the pathophysiology of idiopathic dystonia in patients, genetically determined animal models of idiopathic dystonia may be used as a practical means of studying brain dysfunctions involved in this movement disorder. The genetically dystonic hamster is an animal model of idiopathic dystonia that displays sustained abnormal movements and postures either spontaneously or in response to mild environmental stimuli. Autoradiographic analysis of dopamine D1 receptor density, using the ligand [3H]SCH 23390, revealed significant decreases of D1 binding in several parts of the striatum and substantia nigra pars reticulata of dystonic hamsters. Binding of the D2 ligand [3H]YM-09151-2 was decreased in the dorsomedial caudate-putamen, but increased in nucleus accumbens. In most other sites studied, no significant changes were found in either [3H]SCH 23390 or [3H]YM-09151-2 binding. By studying groups of dystonic hamsters in the absence and presence of dystonic attacks, it was shown that most changes in D1 and D2 binding were not secondary to abnormal movement but rather due to the dystonic condition of the animals. The study provides evidence of altered dopamine receptor binding in dystonia and confirms the concept that basal ganglia dysfunction may be a primary component of dystonia. PMID- 8684624 TI - Ultrastructural characterization of the acetylcholine innervation in adult rat neostriatum. AB - The ultrastructural features of acetylcholine axon terminals (varicosities) in adult rat neostriatum were characterized by electron microscopy after immunostaining with a sensitive monoclonal antibody against rat choline acetyltransferase. Several hundred single sections from these varicosities were analysed for shape, size and content, presence of a synaptic membrane specialization, and composition of the microenvironment. An equivalent number of unlabeled varicosities selected at random from the same micrographs were similarly examined. The immunostained varicosity profiles were relatively small and seldom showed a junctional membrane specialization. Stereological extrapolation to the whole volume of these varicosities indicated that less than 10% were synaptic. Far fewer dendritic spines were juxtaposed to these predominantly asynaptic profiles than to their unlabeled counterparts. This difference seemed imputable to the low synaptic incidence of the acetylcholine varicosities and was consistent with the view that these are randomly distributed in relation to surrounding elements. The bulk of the data was suggestive of volume transmission. This raised the possibility that, in such a densely innervated area, a basal level of acetylcholine is permanently maintained around all cellular elements, contributing to the modulatory properties of this transmitter. This basal level of acetylcholine could also serve as a regulatory signal controlling the expression of different receptor subtypes in neurons, glia and blood vessels. PMID- 8684625 TI - The metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations. AB - Glutamate neurotransmission involves numerous ionotropic and metabotropic glutamate receptor types in postsynaptic, presynaptic and glial locations. Distribution of the metabotropic glutamate receptors mGluR2 and mGluR3 was studied with an affinity-purified, characterized polyclonal antibody made from a C-terminus peptide. This antibody, mGluR2/3, recognized both mGluR2 and mGluR3, but did not cross-react with any other type of metabotropic glutamate receptor except for a very slight recognition of mGluR5. Light microscope distribution of the antibody binding sites in the nervous system matched the combined distributions of messenger RNA for mGluR2 and mGluR3. For example, dense staining seen in the accessory olfactory bulb and cerebellar Golgi cells matched high levels of mGluR2 messenger RNA in these structures, while moderately dense staining in the reticular nucleus of the thalamus and light to moderate staining in glia throughout the brain matched significant levels of mGluR3 messenger RNA in these structures. In the rostral olfactory structures, the densest stained neurons belonged to presumptive "necklace olfactory glomeruli." In the hippocampus, staining was densest in the neuropil of the stratum lucidum/pyramidale, stratum lacunosum/moleculare, hilus and middle third of the molecular layer of the dentate gyrus. Ultrastructural studies of the cerebral cortex, hippocampus and caudate-putamen revealed significant staining in postsynaptic and presynaptic structures and glial wrappings of presumptive excitatory synapses; frequently, this staining was concentrated in discrete patches at or near active zones. In the hippocampus, presynaptic staining appeared to be concentrated in terminals of two populations of presumptive glutamatergic axons: mossy fibers originating from granule cells and perforant path fibers originating from the entorhinal cortex. These data suggest that populations of mGluR2 and/or mGluR3 receptors are localized differentially in synapses, i.e. those in and near the postsynaptic and presynaptic membranes and in glial wrappings of synapses, in several regions of the brain. In addition, we provide immunocytochemical evidence of mGluR2 or mGluR3 receptors in presynaptic terminals of glutamatergic synapses. Thus, mGluR2 and mGluR3 are found in various combinations of presynaptic, postsynaptic and glial localizations that may reflect differential modulation of excitatory amino acid transmission. PMID- 8684626 TI - Differential effects of sigma ligands on the N-methyl-D-aspartate response in the CA1 and CA3 regions of the dorsal hippocampus: effect of mossy fiber lesioning. AB - In the CA3 region of rat dorsal hippocampus, several sigma ligands, such as 1,3 di(2-tolyl)guanidine (DTG), (+)-pentazocine and (+)-N-cyclopropylmethyl-N-methyl 1, 4-diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride (JO-1784), administered intravenously at low doses, potentiate selectively the pyramidal neuron firing activity induced by microiontophoretic applications of N-methyl-D-aspartate, without affecting those induced by quisqualate, kainate or acetylcholine. A similar potentiation of the N-methyl-D-aspartate response has also been found with microiontophoretic applications of neuropeptide Y, an effect exerted via delta receptors. The present experiments were carried out to determine the effects of these sigma ligands and of neuropeptide Y; in the CA1 and CA3 regions following unilateral destruction by a local injection of colchicine of the mossy fiber system, which is a major afference to CA3 pyramidal neurons. In the CA1 region, DTG, JO-1784 and neuropeptide Y did not potentiate the activation induced by microiontophoretic applications of N-methyl-D-aspartate. However, (+) pentazocine potentiated the N-methyl-D-aspartate response, similarly to its effect in the CA3 region on the intact side. In the CA3 region, on the intact side, (+)-pentazocine, DTG, JO-1784 and neuropeptide Y induced a selective potentiation of N-methyl-D-aspartate-induced activation, in keeping with previous reports. On the lesioned side, the effect of (+)-pentazocine on the N-methyl-D aspartate response was still present, but those of DTG, JO-1784 and neuropeptide Y were abolished. These results suggest that (+)-pentazocine, on the one hand, and DTG, JO-1784 and neuropeptide Y, on the other, are not acting on the same subtype of sigma receptors. Since (+)-pentazocine, JO-1784 and neuropeptide Y have been suggested to act on the sigma 1 subtype of receptors, these data suggest the existence of two subtypes of sigma 1 receptors. They also suggest that the receptors on which DTG, JO-1784 and neuropeptide Y are acting are located on the mossy fiber terminals in the CA3 region and are absent in the CA1 region. PMID- 8684627 TI - Expression of the glutamate transporter GLT1 in neural cells of the rat central nervous system: non-radioactive in situ hybridization and comparative immunocytochemistry. AB - Non-radioactive in situ hybridization using complementary RNA and oligonucleotide probes was applied in order to clearly identify the cell types expressing GLT1 and to show their regional distribution in the central nervous system of the rat. The results were compared with immunocytochemical data achieved using an antibody against a synthetic GLT1 peptide. The study showed that GLT1 was expressed in astrocytes and Bergmann glia which were identified by the detection of an astrocytic marker protein. Additionally, subsets of neurons in different brain regions (e.g., CA3/4 pyramidal cells of the hippocampus, endopiriform nucleus) were labelled by in situ hybridization. In other cell types of the central nervous system (oligodendrocytes, ependymal cells, epithelal cells of the choroid plexus, tanycytes), GLT1 expression was not detectable. The generally dense astrocytic immunolabelling of the gray matter of the brain showed an even higher intensity in regions reported to show high glutamatergic activity and astrocytic glutamate metabolism (e.g., the termination field of the glutamatergic perforant path in the hippocampus). On the basis of the cellular regional distribution of the GLT1 messenger RNA and protein demonstrated in the present study, it is reasonable to assume that this high affinity transporter is of importance for the maintenance of adequate extraneuronal glutamate levels. PMID- 8684628 TI - [Surgical treatment of rectal cancer: comparison of anterior resection and abdominoperineal excision]. AB - From 1987 to 1992, 91 rectal neoplasms were operated in the Istituto di Patologia Speciale Chirurgica of the University of Bologna: 50 anterior resections and 41 abdomino-perineal amputations. The local recurrence rate shows no significant difference between the two groups. The mortality rate is 7.6% in anterior resections and 14.2% in abdomino-perineal amputations. Our results and literature review show that local recurrence and mortality rates depend more from the tumor stage than from the surgical procedure. PMID- 8684629 TI - [Malignant tumors of the pancreas and periampullary area. Our experience]. AB - The authors analyse and evaluate the clinical records of 45 patients treated in the last 4 years for pancreatic cancer and neoplasm of the bilioduodenapancreatic area, comparing the results with data available in the literature. In the group of patients treated with resection (12 cases), postoperative morbidity and mortality were respectively 28% and 6%, and three-years survival was 22%. The authors discuss particularly about reconstruction ways after duodenopancreatectomy, showing good results after reconstruction by Y loop sec. Roux and pancreato-jejunal anastomosis. PMID- 8684630 TI - Prevention and treatment of complications after endoscopic prostheses placement in tumors of the upper gastrointestinal tract. AB - Endoscopic intubation is a popular palliative method to resolve immediately malignant dysphagia. However, the complication rate is still high. Between 1978 and 1993, at the Division of Diagnostic and Surgical Endoscopy of Istituto Nazionale Tumori in Milan, 305 patients suffering from malignant dysphagia, were endoscopically treated by insertion of an endoprosthesis. We report the analysis of data regarding our complication rate, compared with the literature, and our experience in preventing managing complications related to this endoscopic procedure. PMID- 8684631 TI - [Pulmonary carcinoma and solitary intracranial metastasis: results of the combined surgical treatment]. AB - Previous reports have shown the utility of combined lung and brain surgery in patients with a primary non small cell lung cancer (-NSCLC) and solitary brain metastasis. This paper reports our recent data with the aim to rationalize the indication of this surgical approach. Over a period of eighteen years (1975 1992), 50 patients with NSCLC and solitary brain metastasis underwent combined lung and brain surgery. Fifteen of these patients had a synchronous presentation while the remaining 35 had a metachronous presentation of lung cancer and single brain metastasis. There were no operative deaths and complete remission of neurological symptoms was obtained in 46 patients (92%). Actuarial overall five year survival was 16% with a median survival of 21 months. Age, gender, histology, T status, size and site of NSCLC, site and location of brain metastasis and the association with adjuvant therapy did not significantly affect survival. The variables that were associated with a significantly prolonged survival were type of lung surgery, N status and interval between the two operations. Patients with synchronous presentation had a five-year survival of 6.6%. By contrast the actuarial five-year survival of those patients with the diagnosis of brain metastasis after the removal of NSCLC was 19%. In this subset of patients those with N0 status and a median interval between lung and brain surgery longer than 14.5 months had a significantly longer survival. We may conclude that combined lung and brain surgery is recommended both for relieving neurological symptoms and for prolonging survival. This is particularly true in those patients with limited loco-regional involvement and a late single brain metastasis. PMID- 8684632 TI - [Laparoscopic surgery in abdominal emergencies]. AB - The authors report their experience in the use of laparoscopy in the treatment of abdominal surgical emergency; the advantages in the diagnosis and in the correct surgical approach in many cases are underlined. They note furthermore that the laparoscopic exploration of peritoneal cavity can lead to an ideal laparotomy. PMID- 8684633 TI - [Laparoscopic cholecystectomy: evaluation of intraoperative complications with respect to 2 different kinds of anesthesia]. AB - Two anaesthetic managements for elective laparoscopic cholecystectomy were compared in 64 patients in order to investigate some perioperative complications: 1) bowel distension during surgery. 2) recovery from anaesthesia. 3) post-surgery incidence of emesis and pain. In addition, the quality of postoperative peristalsis as well as the time of dimissal were recorded. Group I (n = 30) was treated with NLA in N2O-O2 and Group II (n = 34) received propofol plus fentanyl in air-O2. Bowel distension, evaluated by surgeon at 15 min intervals throughout the operation was similar in both the groups as well as postoperative peristalsis recuperation. During the first 12 hours after laparoscopy no differences were found at any times of observation in the incidence or severity of emesis and pain between the two different anaesthesia patients. In subjects which were given propofol the psychomotor recovery was more rapid than after NLA, particularly during the first 6 hours after surgery. The patients were discharged between 36 48 hours following the operation independently from anaesthetic management. It is concluded that both the anaesthetic techniques provide similar intra/postoperative conditions, except the early recovery that is more rapid for the propofol patients. The overall frequency of emesis and pain was rather high in both the groups, suggesting a routine medication with analgesics and antiemetics. PMID- 8684634 TI - [Epidemiological behavior of perforated peptic ulcer before and after the introduction of the antisecretory drug therapy. Our experience]. AB - The diagnostic iter and treatment of peptic ulcer have evolved considerably over the past 20 years. The capillary spread of endoscopy has permitted secure and precise diagnoses to be made, in terms of both the site and size of the anatomic lesion, on the one hand, and on the other, the introduction of antisecretory drugs has led to the resolution of the majority of ulcers, so much so that the ulcer is no longer managed using strictly surgical methods but is now treated medically and only emergency cases, such as perforations, undergo surgery. Complications, such as digestive hemorrhage, penetration and stenosis, may lead to the need for surgery. In particular, perforation seems to be the only complication which has not been significantly influenced by the introduction of antisecretory therapy, the point that its status as a "complication" has been questioned leading to the suspicion of its nosological autonomy. The authors review the series of ulcer patients admitted to hospital during the period 1968 to 1991, paying special attention to the correlation with the use of antisecretory drugs which were introduced during the period 1978-1981, the trend of ulcer complications over the entire period, the duration of symptoms and the epidemiology of peptic and perforated ulcers. PMID- 8684635 TI - [Immediate reocclusion of the infrapopliteal segment after thrombolysis in acute ischemia of the lower limb of the thrombotic nature]. AB - Early reocclusion of below knee segment after fibrinolytic therapy is mainly due to thrombo-embolism, coagulopathy or to the arterial wall condition. 42 patients facing acute lower limb ischaemia because of iliofemoral thrombosis (prosthesis 19, native artery 23) underwent locoregional thrombolysis. UK was given in 33 cases while the others received rt-PA. The early reocclusion after fibrinolysis leads to a serious worsening in these patients; thrombosis in distal vessels and in microvasculature make any surgical approach unserviceable. Major amputation was required in 3 cases. We believe that fibrinolytic treatment has taken on great importance in making accurate diagnosing of thromboembolism and, once restored patency of distal vessels, allows to perform revascularization procedures. PMID- 8684636 TI - [Femoro-popliteal bypass with reversed saphenous vein. Experience in a General Surgery Department]. AB - Femoro popliteal bypass with reversed saphenous vein are "the gold standard" for revascularization of lower extremities with femoro popliteal occlusion. This form of therapy is usually performed in a Vascular Surgery Department. We report the experience of a General Surgery Department, with patency of 90% at two years. PMID- 8684637 TI - [Pseudoaneurysms after carotid endarterectomy]. AB - Pseudoaneurysms after TEA of the internal carotid artery are one of the rarest and most severe complications of this form of surgery. Their etiology appears to depend on 3 causes: a suturing defect due to technical errors made by the surgeon or to the incorrect choice of threads; an infections, and lastly the arterial wall weakened by TEA. The patch increases the risk of false aneurysm approximately four fold. We therefore agree with other authors that, in spite of the undoubted value of the patch in the prevention of restenosis, it must only be used in the presence of an internal carotid of small diameter (less than 4 mm). Contrary to what is reported in the literature we performed both these operations under loco-regional anesthesia and a detailed knowledge of this method allows is to be performed on the carotid axis. Only through a careful follow-up of all the carotids operated can the small dilations which often do not require surgical treatmente identified. The two cases reported here were treated by the removal of the pseudoaneurysms and its replacement with a prosthesis in one case and with the vena saphena in the other. Both were monitored with clinical examination and echo-Doppler and no recidivation has been reported to date. PMID- 8684638 TI - [Injuries of the nasal bone in boxing]. AB - Nose fractures in boxers ar clamfied and their pathogenesis described. Therapy is related to boxer's activity; in fact in boxers in activity the respiratory tract was reinstated; in that one retired over respiratory tract, nose aesthetics was treated too. PMID- 8684639 TI - [Castleman's disease with abdominal localization. Report of an unusual case]. AB - Castleman's disease is an unusual condition characterized by uncontrolled growth of lymphoid tissue. The first case was recorded by Castleman in 1956. In this paper a case of the above-mentioned disease is reported with regard to its unusual clinica-histologic aspect (localized form of plasmacellular type) and surgical therapeutic strategies. PMID- 8684640 TI - [The reappearance of gastrointestinal tuberculosis in general surgery]. AB - Gastro-intestinal tuberculosis (TB) continues to give rise to diagnostic and therapeutic challenges. Its increasing incidence and multiple and non-specificity of symptoms and signs require special attention to establish a prompt diagnosis and not to delay treatment. The authors describe on case of colonic TB presenting with multiple episodes of subocclusion suggesting a stenosing neoplasm of the caecum. PMID- 8684641 TI - [A case of perforated diverticulum of the right colon]. AB - Diverticulum of the right colon is a rare disease which is often wrongly diagnosed and asymptomatic. It affects young individuals and is manifested by symptoms similar to appendicitis. The paper reports a case of a young man with an isolated perforated diverticulum of the right colon which was clinically manifested as acute appendicitis with peritoneal reaction. It is extremely difficult to make a preoperative diagnosis of cecal diverticulitis. Even the anatomosurgical appearance sometimes makes it difficult to distinguish from neoplasia. For this reason the most frequent operation is right hemicolectomy which is however well tolerated by young patients. PMID- 8684642 TI - [Intestinal obstruction caused by ischemic colitis: description of 3 surgically treated cases]. AB - The diagnosis of ischemic colitis is challenging and still based upon a high index of suspicion. We report here, three patients affected by ischemic colitis causing stenosis and intestinal obstruction who required surgical treatment. Results of surgery in the three cases were not fair reflecting the high mortality and morbidity rate of ischemic colitis. However, the three cases showed peculiar features allowing us to make a few speculative considerations. Better results in the treatment of ischemic colitis might be achieved by means of a prompt recognition of the initial picture and through a better control of the many associated diseases, that represent the main risk factor for the development of ischemic colitis itself and for the bad prognosis of surgical treatment. PMID- 8684643 TI - [Sclerosing hemangioma of the lung: a case report]. AB - The authors present a case of sclerosing hemangioma, a rare benign neoplasm of the lung. The patient presented coughing, blood-tinded spuntum and thoracic pain; chest x-ray showed an irregular shadow close to right hilum. A right superior lobectomy was performed. Immunohistochemical and electronic microscopy studies of the lesion supported its origin from respiratory epithelium. PMID- 8684644 TI - [Inflammatory pseudotumor of the lung]. AB - An inflammatory pseudotumour of the lung was occasionally observed at radiology and is reported. Such lesions account for 1% of all lung tumours and are frequently asymptomatic; the findings on physical and laboratory examinations are usually nonspecific. Radiographic findings and invasive diagnostic procedures- including bronchoscopy and transthoracic fine needle biopsy--may be not sufficient for histological diagnosis. Surgery is then important for both diagnostic and therapeutic reasons; the treatment of choice is complete but non extensive excision. Radiotherapy should be considered in patients who had incomplete surgical resection or postoperative recurrences and in patients non resectable due to associated medical conditions. PMID- 8684645 TI - [Adrenal cysts: therapeutic indications]. AB - Adrenal cysts are relatively rare and usually discovered only if large and associated with clinical manifestations. Asymptomatic cysts are diagnosed with increasing frequency because of their incidental finding on ultrasonography or computed tomography, but surgical treatment is indicated when the cysts are large, symptomatic or rapidly expanding. A case of adrenal cyst is reported. The clinical, pathologic and therapeutic implications of this disease are briefly discussed. PMID- 8684646 TI - [Clinical evaluation and therapeutic strategy in necrotizing fasciitis or Fournier's syndrome. 2 case reports]. AB - Fournier's syndrome or necrotizing fasciitis is a rare infection with high mortality rate. Old patients especially with diabetes mellitus, liver and renal failure are more affected. This disease requires prompt treatment: early diagnosis, antibiotic therapy, nutritional support and immediate extensive surgical debridement are necessary. Two clinical cases are presented. PMID- 8684647 TI - [Surgery of the external saphenous vein]. AB - The authors report their experience of external saphena surgery and they explain the results obtained for the treatment of varicose lower limb disease. They emphasize the importance of the global treatment of the superficial venous circle in preventing relapses; moreover, they point out the technical execution difficulties of the posterior stripping as a consequence of the strict connections of proximity among venous vessels and nerves of the posterior region of the leg. They offer as well some notes on surgical technique. PMID- 8684648 TI - [Efficacy of continuous intercostal analgesia versus epidural analgesia on post thoracotomy pain]. AB - The authors compare the efficacy of epidural morphine analgesia with continuous intercostal extrapleural block using bupivacaine 0.5% after thoracotomy. They affirm that antalgic treatment in thoracotomised patients is the most important factor in preventing the onset of major complications that may negatively influence the results of surgery. The efficacy of the analgesic techniques examined was evaluated using El-Baz's visual analogic scale of pain, through the analysis of spirometric values and on the incidence of postoperative complications. The authors demonstrate that the extrapleural continuous nerve block is a reliable method of post-thoracotomic analgesia. PMID- 8684650 TI - [Clinical approach to hydatid disease in uremic patients]. AB - Uremic patients in hemodialytic treatment have the same opportunity to be affected with hydatid disease as healthy people. However, because these patients usually have an immunodeficiency syndrome, it is always necessary to evaluate correctly the most common immune diagnostic procedures; furthermore the clinical approach and successive surgical treatment must evaluate carefully electrolyte and acid-base balances, the cardiovascular system, hemostasis and energy intake. Authors, in this paper, report 8 cases of hydatid disease in as many patients during a period of 27 years. At the beginning they describe diagnostic and therapeutic management; later they emphasize the necessity of a careful immunological diagnostic evaluation (which is often falsely negative), and of radiological, ultrasonographic and scintigraphic diagnosis. They conclude by emphasizing that uremic patients with hemodialytic treatment survive with disease and although a surgical approach of hydatid disease is not really different from others it could be insidious not to consider the peculiar immunological and clinical metabolic state of uremic patients also to perform a correct treatment. PMID- 8684649 TI - [Features and evolution of postoperative pain in patients undergoing thoracotomy]. AB - We examined in this perspective study 30 patients (15 males and 15 females) who undergone classic thoracotomy for lung or mediastinal diseases, without postoperative complications. Intensity and different qualitative components of postoperative pain have been evaluated in the 1st, 3rd, 5th, the day after last pleural drainage removal and 2 months after the operation. All patients answered a schedule adherent to Questionario Italiano del Dolore (QUID). Pain became less intense chiefly with drainage removal with the same time trend for both sex (parallel curves). Pain is probably stronger in women. From a qualitative point of view, the sensorial component is the same in both sexes. Affective and evaluative component is greater in women: in other words, women realize more than men the painful stimulus and are more troubled. A computerized analysis of answers to a questionnaire like QUID or, better, its evolution, may be helpful for a more effective pharmacological choice between pure analgesics, sedative analgesics and ataractic drugs. PMID- 8684651 TI - [New evolution of the technique in trasaxillary augmentation mammaplasty: subpectoral-subglandular implant]. AB - Transaxillary subpectoral augmentation mammaplasty combines the advantages of an axillary located scar with those of a submuscular pocket. However, according to the classical technique, the caudal extension of the pectoral fascia prevents the prosthesis from filling completely the inferior breast pole, thus creating a double submammary fold and/or an excessive fullness of the superior quadrants. In order to overcome this limit Barnett (1990) proposed to disrupt the caudal extension of the pectoral fascia along with its insertions to the submammary fold, thus allowing the implant to lie in a submuscular plane superiorly and in a subglandular/subcutaneous one inferiorly. In this paper the authors present their clinical experience with this new surgical technique. PMID- 8684653 TI - [Gastric injury by caustics: a case report]. AB - The authors get the idea from the observation of a case of ingestion of muriatic acid, recently happened by Clinical Surgery II of the IRCCS Polyclinic "San Matteo" of Pavia in order to examine carefully the matter. The rareness of the shown case is given by the whole involvement of only the stomach, without damages for the oropharynx and the esophagus. The total gastrectomy executed 6 months after the ingestion of the acid has given to the patient the whole recovery. The follow-up checked for a periodical time of 6 months for a period of about five years, permits to observe the normal intestinal canalization without stenitical symptoms or zonas with degenerative risk. PMID- 8684652 TI - [Preoperative serum levels of CEA and CA19-9 in patients with gastric cancer]. AB - The serum level determination of tumor markers in gastric cancer, more than other neoplasia, presents, many difficulties for the impossibility to identify specific molecules released during neoplastic growth. In this research the authors report their experience on the preoperative determination of two tumor markers diffusely used in gastrointestinal neoplasia: CEA and CA19-9. The study has been done in order to establish relations between the expression of markers and some considered variables. The values have been studied on 113 patients. A total of 24% sensibility was reported for CEA while 48% for CA19-9 applying cut-off levels of 10 mg/ml and 37 U/ml respectively. The results have shown a better sensibility of CA19-9 with a statistical significance between the expression of this marker and stage of disease (from 21% to 66%), lymph nodal involvement (from 31% to 59%), histologic grading (from 39% to 48%) and surgical purpose (from 37% to 78%) (p < 0.001). PMID- 8684654 TI - [Ischemic colitis: a report of 2 cases of ischemic gangrene of the colon]. AB - Two personal cases of ischaemic gangrene of the colon required emergency surgery. The two cases provide the basis for a discussion of the aetiopathogenetic, anatomo-pathological and clinical aspects of this pathology. Stress is laid on the fact that ischaemic colitis in its various anatomo-pathological signs is not easy to diagnose and needs early treatment of conservative or emergency surgery type depending on its anatomo-pathological expression. PMID- 8684655 TI - [Cystic lymphangioma: a case report of abdominal location]. AB - A case of cystic lymphangioma is reported, located on the mesentery of the jejunum in a fifty-seven year old patient. The lymphangioma is an extremely rare disease and it is often located in the neck and arm pit. An intra abdominal and mediastinal location takes place in just 5% of the examined cases. Pre operative exams are taken into account; computerized (Axial) tomography and echo tomography have made diagnosis possible. The surgical therapy is the preferred treatment; no therapeutic options exist. The radical extirpation of the mass becomes necessary to avoid relapses. PMID- 8684656 TI - [Medullar breast cancer, occult papillary carcinoma, pulmonary metastases: a case report]. AB - The authors have carried out their study on a woman who previously underwent QU.A.R.T. because of a medullar breast cancer. She also had pulmonary metastases resistant to chemotherapy which were then resected by mini-invasive video assisted thoracic surgery: it was so discovered that such lesions came from an occult papillary carcinoma of the thyroid gland originated in a multinodular goitre. This study has allowed the accomplishment of a right aetiologic and therapeutic classification of the patient. PMID- 8684657 TI - [An unusual association: Jaffe-Linchtenstein syndrome, arcuate ligament syndrome and hepatic adenoma]. AB - A case of a woman affected by an unusual association of rare diseases, is presented. The patient was referred to our department for acute anaemia. Preoperative investigations revealed that the patient was affected by fibrous polyostotic dysplasia, so called Jaffe-Lichtenstein syndrome. The presence of skin brown spot and endocrine disorders requiring pill administration, allows to classify the patient as carrier of Albright syndrome. Moreover, the angiography pointed out a celiac trunc stenosis (Dunbar syndrome). The long-standing administration of the pill could be the cause of bleeding adenoma. The patient underwent hepatic resection. We did not treat the Dunbar syndrome because of poor symptoms. From literature, we review some opinions on the fibrous dysplasia of the bone. PMID- 8684658 TI - [Toward the ideal bag: a clinical evaluation of a new aid for ostomized patients]. AB - The authors report the results of a multicentre trial to evaluate the characteristics of a new bag for ostomised patients (Coloplast Alterna). While affirming that a correct technique is essential to avoid complications and to achieve good stoma function, the authors emphasise that the bag also pays an important role in giving confidence to patients and enabling them to enjoy a social life which is as similar as possible to that before surgery. In the search for the ideal bag the trial evaluated adhesive, filter and the bag and a whole. 85% of the 92 patients who tested the new bag for four weeks considered it good or excellent. Although it cannot yet be considered ideal, Alterna represents a further step towards this aim. PMID- 8684659 TI - [Results of endoscopic Nd-Yag laser treatment of inoperable colorectal carcinoma]. AB - Between November 1986 and December 1993, 94 patients underwent endoscopic laser therapy for inoperable colo-rectal cancers. According to the main clinical symptoms, tumors were divided into obstructing and bleeding; A Nd-YAG non contact laser was used at power setting of 70 to 100 watt. In 28 cases laser therapy was carried out after electrorection of the tumor and in 22 cases after dilation; in 41 cases it was associated with radiation therapy. In 90% of bleeding tumors and in 70% of obstructing tumors we achieved a good result in the short term. In 50% of bleeding tumors and in 65% of obstructing tumors the symptoms recurred after an interval of 8.2 and 6.1 weeks. The main survival period was 11.2 months for bleeding tumors and 7.4 months for obstructing tumors. Two patients with a small rectal cancer are free to neoplasia at 19 and 26 months after laser therapy. PMID- 8684660 TI - [Surgical treatment of radiation enteritis]. AB - Abdomen and pelvic radiation therapy, as a complement to medical and surgery therapy in malignancies, may determine acute and chronic intestinal injuries. The acute intestinal effects of ionizing radiation are the necrosis of crypt epithelial cells and the cessation of the intestinal epithelium; late radiation injury is the result of a progressive vasculitis and diffuse collagen deposition and fibrosis. In this paper we report a clinical case of radiation enteritis and examine different surgical managements, above all complications such as fistulas, stenosis and fibrinous adhesions. As the literature reports, the treatment of choice is a wide resection of the stenotic bowel and occasionally by-pass. In our case we have performed a wide resection. It is extremely important to emphasize the high morbidity and mortality of every surgical approach. We conclude by affirming the important role of physicians and oncologists to perform a correct radiotherapy to avoid the radiation injuries to the intestine; this considering also that the sites of intestinal injuries may not seem readily apparent. PMID- 8684661 TI - ["N2" carcinoma of the lung. Therapeutic considerations]. AB - The follow-up of 240 N2 lung cancer cases operated in Thoracic and Cardiovascular Surgery Department of Florence is examined. The analysis is performed in compliance with global survival, "T", histology, therapeutic choices. Global survival is 81% after 6 months, 60% after 1 year, 37% after 2 years, 26% after 3 years, 23% after 4 years, 23% after 5 years. Significative difference on survival does not exist between principal histologic types (squamous, adenocarcinoma, adenosquamous). Raising the "T" survival decreases, but only for adenocarcinoma. Different therapeutic options (only surgery, surgery+radiotherapy, surgery+chemotherapy, surgery+radio and chemotherapy) do not influence the survival in a way statistically significative. From the literature, any certainty about radiotherapy and chemotherapy associated to surgery for N2 lung cancer treatment does not exist at the moment. Thus radical surgery is essential. PMID- 8684662 TI - Expectations for and precursors to leaving home in young women. PMID- 8684663 TI - Geographical distance from parents and adjustment during adolescence and young adulthood. PMID- 8684664 TI - Adolescent-parent relationships and leaving home in young adulthood. PMID- 8684665 TI - Leaving home at an early age among females. PMID- 8684666 TI - Leaving the parental home: predictors for young adults raised in former East and West Germany. PMID- 8684667 TI - Timing of childhood events early-adult household formation. PMID- 8684668 TI - [Prognosis in iatrogenic gas embolism]. AB - Prognosis of iatrogenic air embolism is various according to previous studies. The purpose of this study was to determine the risks factors associated with the prognosis of iatrogenic air embolism. We conducted a retrospective analysis of 113 patients treated with HBO therapy in our hyperbaric center from 1979 to 1993. Initial symptomatology consisted in neurological disorders (71% of cases), respiratory disorders (43% of cases) and hemodynamic disorders (33% of cases). When neurological disorders were observed, HBO therapy included immediate compression to 6 atm abs for 10 to 15 mn with air followed by decompression to 2 atm abs where the patients received 100% oxygen during 1 hour. When no neurological disorders was observed, HBO therapy consisted in an oxygenation for 1 h, 2 atm abs, FiO2 = 1. Overall outcome was: recovery: 69 per cent of cases, sequelae: 26 per cent of cases, death: 5 per cent of cases. Prognosis was very different according to etiologies and existence of neurological disorders. Venous emboli had a better improvement than arterial emboli. In conclusion, patterns of air embolism can be divided clinically into two major categories, cerebral and pulmonary air embolism, which should be individualised in clinical studies. The studies must also individualised etiologies. PMID- 8684669 TI - [Parma Stroke Data Bank: embolic stroke]. AB - Cerebral infarction is one of the three main causes of death in most countries. It is very frequent and, since it is more often disabiliting rather than fatal, it is of high social impact. The correct classification of patients and the accurate diagnostic definition of the various subtypes of stroke is of great prognostic and therapeutic importance since cerebral infarction is not a single entity. In this study we report our findings concerning 244 patients with embolic infarction recorded in the Parma Stroke Data Bank hospital register. Clinical features were studied (risk factors, symptomatology of the onset, degree of severity within 3 days of the onset, post-stroke complications) as were instruments readings (TAC) and evolution (outcome, mortality, personal performance and environmental integration, both 4 weeks after the clinical onset and after one year). PMID- 8684670 TI - [A syndrome caused by separating rags in textile industry: a new clinical entity?]. AB - A group of 104 workers were examined. They were employed in selecting rags and separating the lining from wollen fabrics to be used again as thread waste in the textile industry. The aim of the study was to point out tendon and joint related disorders of the upper limb due to repetitive and forced movements. Twenty-eight (26.9%) workers complained of hand and wrist echography and thermography. In 19 patients (67.8%) clinical carpal tunnel syndrome was diagnosed. Eight workers (28.5%) had Dupuytren's contracture. Swelling of the fingers was found in 23 (82.1%). 14.2% and 28.5% of the workers showed respectively acro-osteolysis and acrosclerosis. The textile industry of Prato shows peculiar characters: the workers employed in selecting rags out a manual job which causes soft tissues and skeletal disorders in a great number of them. The acro-osteolytic and acrosclerotic changes of the fingers seem alike the bone disorders of chronic inflammatory rheumatic diseases as seronegative spondyloarthritis. PMID- 8684671 TI - [Digoxin-like immunoreactive factors. Review of the literature]. AB - It is confirmed by several studies that in normal subjects a substance recognized by antibodies anti digoxin exists. Such a substance can be found at increased concentration in pregnant women, neonates, in liver or kidney diseases. A limited increase in concentration has been also registered in patients with essential hypertension and in normotensive patients with a family history of hypertension. Serum or urines rich in such a substance show an increased capacity of inhibiting in vitro the sodium-potassium pump and therefore in reducing also in vivo the capacity of reabsorption of sodium and with it, of water. The investigators interest for this substance has two main reasons: 1) the interference that such a substance has in dosages of digitalis in therapeutic monitorizing; 2) the possibility that such a substance has an important physiological role in hydroelectrolytic metabolism. PMID- 8684672 TI - [European regulations concerning medical devices]. AB - The employment in clinical practice and prosthetic surgery of a number of medical devices implies a great responsibility to the operators so as to make the knowledge of existing regulations mandatory. The authors illustrate the problems concerning the free circulation of medical devices within the European market. They describe the new strategy of EEC which led to the definition of the directives which apply to all medical devices and of the harmonized standards for inspecting their biological effects. The appointment of certification bodies and the accreditation of Testing Laboratories are described. Finally, particular attention is given to product certification, which is compulsory for the pre market approval of medical devices. PMID- 8684673 TI - Eosinophilic fasciitis: report of a case diagnosed 14 years after its onset. AB - The authors describe a case of eosinophilic fasciitis diagnosed 14 years after the onset of the clinical and laboratory manifestations of the disease. Failure to carry out an adeguate histopathological examination during this period played a role in delaying diagnosis. PMID- 8684674 TI - [Listeria monocytogenes meningitis. Description of a clinically significant case]. AB - Meningitis caused by Listeria monocytogenes is a rare affection: it develops from close contagion as professional illness (veterinarians, butchers) or in newborns by infected mothers; in indirect way for ingestion of contaminated food in subjects at high risk: elderly, immunosuppressed patients, alcoholics, diabetics. Clinically it is not diversified from the other bacterial meningitises. In this paper we present a case of Listeria monocytogenes meningitis in an adult female, without a sure occasion of infection and in absence of the factors of typical risk. PMID- 8684675 TI - [Radiologic and skeletal-anatomical study of mummies at the Tourin Egyptian Museum]. AB - The authors present a study performed on three Egyptian mummies, coming from the same inviolate grave belonging to the Necropolis of Gebelin. The grave bore no indications on the occupiers' identity and for that reason Schiaparelli identified it as "Tomb of the Unknown". The mummies and their funerary furniture are now exposed at the Egyptian Museum of Turin. Standard radiographies of the mummies have been taken in situ by means of a portable radiological equipment. It has also been possible to examine directly the anatomic aspect of one unbandaged skeletal mummy. The procedure was simple, reliable, not expensive and did not expose the mummies to damages due to an eventual transfer. Reliable data on the findings have been taken in that way: the three burials, one of them is likely a reburial, belong to three grown-up subjects, whose sex was male for two and probably female for the third. No bone pathology has been found. One of the cadavers seems to be dead due to a serious cranic injury, probably the effect of a heavy bladed weapon. PMID- 8684676 TI - [Blood rheology and fibrinogenemia: two independent parameters in the assessment of cerebral vascular damage]. AB - The increase in fibrinogen level is consequent on several hurtful events: inflammatory, traumatic, stress reaction. Traumatic event, during cerebral vasculopathies, often causes an inflammatory reaction, certainly in the acute phase, inducing fibrinogen synthesis. There are also other inflammatory changes as the increase in WBC and PLT counts and in other hematic components, both in increase and in decrease. Patients with cerebral vasculopathies were divided in two groups according to the clinic picture seriousness. Haemorheologic characteristics were measured with a double filtering method I (with 5 and 12 mu filters) and under a filtering pressure of 15 cm H2O, eliminating WBC interference even if using native blood. In this way we have determined whole blood, plasma, and plasma-erythrocyte viscosities. From these measures we have obtained corpuscular viscosity and erythrocyte deformability. Fibrinogen concentration is increased in all patients with acute vasculopathies, but there is not a difference in relation to the clinic pictures seriousness. Also other inflammatory parameters, namely: total protein, gamma-globulins, ESR, are increased in a significant way without difference in relation the clinic seriousness. The WBC count is more increased in the group with Stroke than in the other one with TIA. The corpuscular viscosity is almost doubled with consequent decrease in deformability; plasma-erythrocyte viscosity, measured with both methods, is quite increased. These parameters show the same behaviour in both groups. Only plasma viscosity increased in the group with Stroke. Haemorheology alteration is not statistically correlated to the fibrinogen level. The decrease in deformability can be related to the viscouselastic membrane properties, and the fibrinogen, because of its adhesive properties, can contribute to such a decrease. PMID- 8684677 TI - [The motility of the biliary tract studied with 99mTc-Br-IDA in patients with type-2 diabetes mellitus]. AB - Autonomic neuropathy in diabetes mellitus can cause alterations of the motor function of various segments of the gastroenteric apparatus. With hepatocholangio cholecystiscintigraphy-HIDA we have studied the motility of the biliary system in patients with diabetes mellitus type II. The research has been carried out in 29 patients with diabetic autonomic neuropathy; 12 healthy volunteers have been studied to compare the results obtained. The results showed a delay in the appearance of radionucleotide in the small intestine of diabetic subjects compared to controls with statistical significance. Moreover the diabetic subjects with a serious neuropathic injury showed increased intestinal transit time. These results match those obtained by other authors that have studied the cholecystic emptying in diabetic subjects with other methods. Consequently the biliary system is also affected by the diabetic autonomic neuropathy that can be in its turn the cause of other pathologies such as biliary lithiasis. PMID- 8684678 TI - [The parietal cell mass and acid secretion: Helicobacter pylori does not induce changes in the course of a duodenal ulcer]. AB - Some studies have postulated that Helicobacter pylori (HP) itself might be responsible for hypergastrinemia and acid secretion in duodenal ulcer (DU). In each DU patient parietal cell mass (expressed by a parietal index) and stimulated acid secretion (expressed by maximal acid output) were evaluated. The study has been conducted grouping DU patients in relation to HP infection in antral mucosa. HP infection does not modify parietal cell mass and stimulated acid secretion. Therefore, mild chronic hypergastrinemia induced by HP infection is not sufficient to justify any increase of parietal index and acid secretion. In fact, parietal cells and acid secretion remain higher in DU subjects independently from HP infection. PMID- 8684679 TI - [The use of ambulatory pressure monitoring for evaluating antihypertensive treatment in clinical practice]. AB - OBJECTIVE: To describe the clinical experience of our Centre in the assessment of antihypertensive therapy with 24-hour ambulatory blood pressure monitoring (ABPM). DESIGN AND PATIENTS: We retrospectively studied all the 241 out-patients on antihypertensive therapy submitted to ABPM (SpaceLabs 90207, USA) between March 1992 and March 1993 for clinical purposes. We evaluated: 1) the clinical indications for the test; 2) the modifications of drug treatment suggested by the ABPM results; 3) the referring physicians' acceptance of these suggestions; 4) the changes of office BP measured before and 3-6 months after ABPM. RESULTS: 1) The indications for ABPM were: resistant or poorly controlled hypertension (n = 170-71%); suspected "white coat effect" (n = 51-21%); assessment of symptoms (n = 20-8%). 2) The analysis of ABPM suggested to modify drug treatment in 51% of the patients; a "white-coat effect" was found in 18% of the patients. 3) The ABPM suggestions about treatment were accepted by the referring physicians in 89% of the patients. 4) Office BP decreased from 163 +/- 18/99 +/- 9 mm Hg (before ABPM) to 151 +/- 13/91 +/- 7 (3-6 months after ABPM), (p < 0.001). CONCLUSIONS: The use of ABPM in our Centre, which is based on specific clinical indications, provided indications to modify the drug treatment in a high percentage of patients. PMID- 8684680 TI - [Anorexia nervosa: a follow-up of nutritional, hormonal and psychiatric parameters]. AB - Well known is the need to treat "acute onset" Anorexia Nervosa in care units. Nevertheless even the "successfully treated" patients show a very high percentage of relapse. The aim of our study has been to revalue different clinical, nutritional (hemoglobin, transferrin, IGF1), hormonal (thyroid function, gonadotropins) and psychiatric (EDI: Eating Disorder Inventory Test) parameters in a group of nineteen women aged 20-34 years (median 27 years) admitted to our department 1-11 years (median 6 years) before for anorexia nervosa treatment. On admission their weight loss was -33% +/- 10% according to Ideal Body Weight (IBW); a "low T3 syndrome" was present and all the patients not treated with estro-progestins were amenorrhoic. After a long hospitalization (median 51 days) the patients showed a significant decrease in weight loss (25% +/- 6%; p < 0.01). At follow-up seventeen patients had a weight better than at discharge (13% +/- 12%; p < 0.01) and 9/17 patients non treated with estro-progestins had spontaneous menses. Nutritional (hemoglobin*: 13 +/- 0.2 g%, transferrin*: 313 +/ 57 mg%, IGF-1: 187 +/- 15 ng/ml) and hormonal (LH*: 9.4 +/- 1 mUI/ml, FSH*: 15 +/- 1.3 mUI/ml, T3: 1 +/- 1 ng/ml) parameters were significantly improved (*p < 0.01, p < 0.05) compared to those at admission (hemoglobin: 12 +/- 0.2 g%, transferrin: 218 +/- 58 mg%, IGF-1: 154 +/- 21 ng/ml, LH: 5.6 +/- 0.8 mUI/ml, FSH: 9.5 +/- 1 mUI/ml, T3: 0.8 +/- 1 ng/ml). The EDI test has shown a persistence of anorexic condition ("overt" or latent) in 2/3 of patients. This study confirms the endocrine and nutritional modifications of anorexia nervosa and underlines the persistence of psychiatric ones in a great number of patients including the "clinically cured", justifying long-term follow-up and the high percentage of disease relapse. PMID- 8684681 TI - [Susceptibility to multiple sclerosis and T-lymphocyte receptor genes. A synthetic review]. AB - The immunogenetics of multiple sclerosis is reviewed: particular attention is drawn to genes of T-cell receptor variable regions, both in animal models for human demyelinating diseases and in linkage studies on multiple sclerosis. PMID- 8684682 TI - [An atypical presentation of a case of Horton's giant-cell arteritis]. AB - Horton giant cell arteritis can present with an atypical clinical picture that often resembles other diseases. In the case described below, the patient initially demonstrated clinical and laboratory evidence of a Candida albicans sepsis, and therefore we started antimycotic treatment with amphotericin B. Because of an adverse reaction to that drug, we added parenteral steroids before every administration of the antimycotic which led to an unexpected improvement of symptoms. This result caused us to reconsider some clinical aspects that could have been interpreted also as vasculitis, in particular for a giant cell arteritis: throbbing temporal headache, diffuse weakness, important rise in ESR, myoarthralgias. We performed a biopsy of the temporal artery that confirmed our diagnosis. PMID- 8684683 TI - [Extrapulmonary tuberculosis. An unusual case]. AB - Skeletal tuberculosis with extravertebral location is rare. We report a case of tuberculous osteomyelitis simultaneously affecting two right ribs and the left ulna. We emphasize the diagnostic problems (failure or delay in diagnosis) in extrapulmonary tuberculosis interesting uncommon sites and having relatively indolent presenting symptoms. PMID- 8684684 TI - [Preclinical lymph node metastasis in ovarian cancer. Report of a case]. AB - The involvement of inguinal lymph nodes in the spread and metastatic process of ovarian cancer is not common and has been reported in a very small percentage of cases (1-3%) and at relatively advanced stages. This paper examines the case of a patient in whom lymph node metastasis at inguinal level became manifest at quite an early stage in the form of a swelling, initially mistaken for a crural hernia, and preceding by about one year the onset of papilliferous serous cystoadenocarcinoma which subsequently developed in the right ovary. This case, which to the authors' knowledge represents the second observation of this kind reported in the literature, aims to draw attention to the need to examine and monitor these patients more carefully and accurately (at both instrumental and biochemical levels) in order to intervene as rapidly and appropriately as possible. PMID- 8684685 TI - [Association of interleukin 2 and interferon alpha in the management of cervical condylomatosis]. AB - At present the therapy of cervical condylomatosis is based on the use of interferon because the HPV types responsable for condyloma inhibit the immunitary system. But many A. studying the effects of IFN have found that at high concentration it has an immunosuppressive action. The aim of the present study was to evaluate if interleukin-2 associated with IFN is useful in avoiding this negative effect by improving the efficacy of cervical condylomatosis therapy. We treated 25 women suffering from cervical condyloma with increasing doses of IL-2 injected intralesionally and associated with natural alpha-IFN injected intramuscularly. The duration of the whole therapy was six weeks. We evaluated the percentage of inflammatory cells in peripheral blood before and after treatment. The per-cent number of lymphocytes, eosinophils and lymphoblasts was increased by 27%, 88% and 40%, respectively. The clinical response to the therapy was total in 14 cases, partial in 9 cases and unsuccessful in 2 cases. These data suggested that combination therapy with interleukin-2 and alpha-IFN for the treatment of patients with cervix condylomatous is successful. PMID- 8684687 TI - [The role of heparin sulfate in the treatment of pregnant women with circulatory deficiency syndrome]. AB - The syndrome from circulatory maternal, precocious and belated deficit could influence the appearance of a vast range of obstetric incluted pathology: recurrent abortions, delays of increase, pre-eclampsia, fetal and neonatal dead. The principal biochemical implicated mechanism has represented from alteration of equilibrium trombossano prostaciclina with adjunct vasoconstriction and uterum placental hypoperfusion. In this study the authors have estimated the efficacy and the compliance of the heparan sulfate in 30 pregnant patients to risk for vascular pathology. In all these cases, the rational to the use the heparan sulfate had represented from the necessity to associate a therapy anteplatelet with associate an fibrinolitic activity. The percent of pregnancies with alive and vital fetuses was of the 90%; the collateral effects have been inconsiderable. The authors retain useful effect randomize checked studies to evaluate further the real results this therapy. PMID- 8684686 TI - [Human recombinant erythropoietin in the treatment of anemia in obstetric gynecologic patients. Evaluation of such treatment as an alternative to blood transfusion]. AB - The authors introduce the subject with physiological comments regarding the ability of r-HuEP to stimulate erythropoietic bone marrow, underlining the need for other molecules to backup the therapy (vitamin B12, folic acid and iron). Subsequently, and in the light of this introduction, they outline the indications for r-HuEPO treatment in specialist fields and the relative contraindications. They then report the results obtained in a group of 24 patients with the relevant indications receiving subcutaneous treatment on alterate days with r-HuEPO in fials of 4000 IU/ml. Basal hemoglobin levels were 6-8 g and treatment was continued until levels of around 10-11 g were reached; tolerance was good in both gynecological and obstetric patients. PMID- 8684688 TI - [Vulvo-vaginal HPV infection: immunological aspects]. AB - All phases of HPV infection are under the control of the immunitary system which is probably inhibited by the virus itself. We studied 65 patients (range 22-55 year). They presented an HPV vulvovaginal infection not healed after common therapy. The aim of our study was to verify the changes occurring in the immune system during HPV vulvo-vaginal infection. Using the immunohistochemical method we evaluated the number of T4,T8 and NK lymphocytes inside the lesion. Moreover we measured the immunitary cells of the hematic compartment. Inside the lesion we noted a reduction of the immune system in 69.23% of cases, while in the hematic compartment it was reduced only in 6.15% of cases. These data strongly suggested that the evaluation of the immunitary state, before starting therapy, is important in deciding when it would be useful to associate immunostimulating substances at the common treatment of vulvo-vaginal infection. PMID- 8684689 TI - [Quantitative evaluation of endocervical cells in women with human papillomavirus infection]. AB - Human papilloma virus (HPV) DNA in cells of endocervical origin has been demonstrated by in situ hybridization and Polimerase Chain Reaction (PCR). Similarly, the presence of HPV DNA has been shown in many cases of endocervical Adenocarcinoma. Morphological changes in squamous cells, specific for HPV infection, have already been described in previous reports, but similar specific alterations in the endocervical elements have not yet been reported. In this retrospective study we analyzed 30 endocervical smears from women with HPV infection, ascertained colposcopically, cytologically and/or histologically. Thirty endocervical samples have been taken from healthy women of the same age and hormonal status, as a control group. We evaluated maximum and minimum nuclear diameters, anisocariosis, chromatin pattern and cytoplasmic characteristics of at least 60 endocervical cells selected from each specimen. RESULTS: In the cases with HPV infection, the mean nuclear diameter of endocervical cells was increased and anisonucleosis was more evident. However, the most significant parameter was the chromatin distribution with a granular pattern in almost 90% of the cilindrical cells in more than 80% of the cases. The cytoplasm does not show any peculiar alteration of endocervical cells except for an unconspicous "alo" in some elements, but this pattern is not frequent. In conclusion, some of the parameters studied seem to have a diagnostic relevance in confirming HPV infection. This may suggest that this infection could be present even at endocervical site, and should be confirmed by molecular techniques or by microcolpohysteroscopy. PMID- 8684690 TI - [Infants born to hypertensive mothers: a clinical-epidemiological study]. AB - The aim of this prospective study was to evaluate the frequency of the hypertensive disorders of pregnancy and their effects on the newborn infants. The study was performed between January 1992 and December 1994 on the 4793 infants born at the Obstetric Divisions of the University of Messina. These 123 infants were born of hypertensive women and 4670 were control infants. Between the two groups of infants there were significant differences with regard to the incidence of nulliparity, prematurity, low Apgar scores at birth and low birth weight. The blood pressure and the haematic parameters were not different between the two groups of infants. Five of the infants born to hypertensive women were referred to the Division of Neonatal Pathology. The low frequency of infants born to hypertensive women observed by us suggests that in our population the hypertensive disorders of pregnancy are understimated. Moreover, the high incidence of preterm and LBW infants confirms that in infants born to hypertensive women the neonatal risks are consequent to fetal growth retardation. PMID- 8684691 TI - [Surgical treatment of ovarian cysts: economic analysis as a means for the evaluation of alternative technics. Results of a biennial study]. AB - The large use of new gynaecological technologies such as the operative laparoscopy, requires both efficacy and efficiency evaluation. The aim of this work is to compare costs of the surgical treatment of ovarian cysts between two groups of patients--35 patients undergone to laparotomic cystectomy (age: mean 27.5) and 34 operated by laparoscopic technique (age: mean 27). The analysis of the costs, related to three steps of health care (pre-operative, operative, post operative) shows that the laparoscopic cystectomy results the more efficient intervention (L. 6,244,808 vs L. 8,310,002). This economic analysis may offer a planning tool for health care to hospital managers and represent an efficiency evaluation criterion of surgical techniques employed by the gynaecologists. PMID- 8684692 TI - [Retrospective study of postoperative infectious morbidity following cesarean section]. AB - The increase of cesarean sections produced more postoperative infections. Several authors assessed the effectiveness of chemioantibiotic prophylaxis to reduce the postoperative infective morbidity. Although the family of antibiotics more frequently used is that of cephalosporin, the best single agent has not been found yet. The aim of our study, made in the Department of Obstetrics and Gynecology of University of Naples "Federico II", is to propose a retrospective analysis concerning the incidence of cesarean section (CS), the postoperative infective morbidity and the employment of antibiotic prophylaxis. Our sample is a group of 13285 pregnant women, 3171 (23.9%) of these patients underwent to CS from 1st January 1985 to 31st December 1994. The group of 3171 women was divided in two subgroups, the first of 2748 patients un-derwent to antibiotic prophylaxis, the second of 423 was untreated due to their previous experience of allergy towards antibiotics or because there was no evidence of risk factors. The women we treated with antibiotics underwent a three days prophylactic therapy with cefazolin or ampicillin soon after the CS. The incidence of infective complications had a 21.2% rate over a total of 3171 women. Endometritis was the most common infectious complication following cesarean delivery. The rate was 53.3% in the case of primary cesarean section and 52.3% in the case of iterative cesarean section. The use of antibiotic prophylaxis gave us the opportunity to reduce the postoperative morbidity in the primary CS (23.4%) as well in the iterative CS (16.6%). On the contrary the untreated group had an infective incidence with a 33.8% rate in the case of primary CS and with a 27.4% rate in the case of iterative CS. Our opinion is that the administration of antibiotics as cefazolin and ampicillin is able to reduce in a significant way the incidence of postoperative infective morbidity as well the period of hospitalization. PMID- 8684693 TI - [Colpocytology in patients on hormonal contraceptives]. AB - In this paper, the authors analyse retrospectively 737 colpocytologic examinations done on patients on hormonal contraception, on IUD contraception and in a control group. A careful examination of data revealed no statistically relevant differences among the various groups. PMID- 8684694 TI - Term and postterm low-risk pregnancies: management schemes for the reduction of high rates of cesarean section. AB - BACKGROUND: We compare trends and current levels of cesarean section delivery by indication in some industrialized countries to help us understand factors underlying national differences in obstetric delivery practice and identify pathways to lower cesarean rates. STUDY DESIGN: In this report we describe the schemes employed at our Department for the management of low-risk at term and postterm pregnancies and list the most important motivations for increased cesarean section rate and remedies suggested to reduce high cesarean section rate. Moreover a randomized trial to assess the role of labor induction with PGE2 gel vs i.v. Oxytocin+Amniotomy in the management of prolonged pregnancy is being evaluated presently at our center. METHODS: To date, 75 postterm pregnancies have been followed. Patients are enrolled at > or = 287 days (41 weeks). Intracervical PGE2 gel (0.5 mg) is used for cervical ripening. Induction of labor is randomly performed using intravaginal PGE2 gel (2 mg) or i.v. Oxytocin+Amniotomy. RESULTS: Overall rates of 75% for spontaneous delivery, and 25% for cesarean section have been observed in our study group of prolonged pregnancies. CONCLUSIONS: The accurate labelling of low- and high-risk pregnancy and the appropriate management of term and postterm pregnancy are two important steps for the reduction of a high rate of cesarean section. PMID- 8684696 TI - Administering intradermal injections. PMID- 8684697 TI - Fluoroquinolone antibiotics: tied to tendon ruptures. PMID- 8684695 TI - [Gynecologic problems in female athletes]. AB - More than 6 million women now compete in strenous exercis, worldwide. The sports participation is a sage experience for the teenage athlete. But intense exercise had been reported to delay menarche when the sports activity was begun before puberty. Is has been shown to increase beta-endorphins and catecholamine in women. Menstrual cyclicity is influenced by prior and concomitant exercise intensity and/or duration in long-distance runners, gymnasts, ballet dancers, fencers, rowers. Altered menstrual cyclicity can approach 70% in strenuously exercising women. Menstrual dysfunction has been associated with significant weight loss, decreased body fat, previous history od menstrual dysfunction, stress and intensity of athletic training. A complication of amenorrhea is the loss of bone mineral content and bone density. Urinary incontinence during physical stresses is common in young nulliparous women. Some female athletes to increase their sports performance artificially take illegal steroid substances. Perineo-sphincter exercise must be started very early during the post-partum, before the start of sports. Most of the athletes of all ages resulted to prefer the oral contraceptive method. PMID- 8684698 TI - Protecting against tetanus. PMID- 8684699 TI - Myths & facts ... about acute compartment syndrome. PMID- 8684700 TI - Actionstat. Blunt chest trauma. PMID- 8684701 TI - Labor laws: working to protect you. PMID- 8684702 TI - Putting clinical practice guidelines to work. PMID- 8684703 TI - When things go wrong. PMID- 8684704 TI - What you should know about coronary artery bypass graft surgery. PMID- 8684705 TI - Do's and don'ts for using sharps containers. PMID- 8684706 TI - Searching for Tim's shoes. PMID- 8684707 TI - Assessing normal heart sounds. PMID- 8684708 TI - Listen up! Don't trust tympanic thermometers? PMID- 8684709 TI - A lesson in the science of uncertainty. PMID- 8684710 TI - Understanding edema. PMID- 8684711 TI - Bertha's final wish. PMID- 8684712 TI - Teaching your patients about PSA and CA-125. PMID- 8684713 TI - "This can't be our Stacy". PMID- 8684714 TI - Antipsychotics and neuropeptides: the atypical profile of CI-943 and its relationship to neurotensin. AB - CI-943 is a new drug candidate with antipsychotic-like activity in a variety of behavioural tests in rodents and primates, but without any affinity for brain dopamine receptors. CI-943 does not cause dystonia in monkeys, a predictive symptom of extrapyramidal side effects (EPS). Its mechanism of action remains unclear. Neurotensin (NT) concentration in nucleus accumbens and caudate is increased by CI-943; this may be associated with its antipsychotic effect. Indeed various observations suggest that the clinical action of antipsychotic drugs may at least be partially mediated by some neuropeptides. Various actions of neurotensin are reviewed. The hypothesis on the role of neurotensin represents a new strategy in the development of pharmacological tools for the treatment of schizophrenia. PMID- 8684715 TI - Long-term potentiation and N-methyl-D-aspartate receptors: foundations of memory and neurologic disease? AB - Understanding the physiology of learning and memory is one of the great challenges of neuroscience. The discovery in recent years of long-term potentiation (LTP) of synaptic transmission and the elaboration of the mechanisms involved, in particular the NMDA receptor, offers the prospect not only of improving our understanding of normal memory storage and retrieval, but may also yield insights about various neurological and psychiatric clinical disorders. In this review, we begin by examining the different forms, properties, and methods of inducing LTP, followed by a description of molecular mechanisms thought to underlie the phenomenon. Molecular structure of the receptor is discussed, along with the roles of Ca2+ second messenger systems, synaptic morphology changes, and retrograde messengers in LTP. Finally, implications of the NMDA receptor and LTP in learning, memory, and certain clinical conditions such as epilepsy, Alzheimer's disease, and schizophrenia are discussed. PMID- 8684716 TI - Changes in circadian rhythms and sleep quality with aging: mechanisms and interventions. AB - Literature is reviewed indicating that aging is characterized by changes in circadian rhythms and sleep quality. The most marked change is an attenuation of amplitude. An advance of phase, a shortening of period, and a desynchronization of rhythms are also evident. The mechanisms underlying these changes are unknown. However, age-related changes in the retina, suprachiasmatic nucleus, and pineal gland seem relevant along with behavioral changes such as a reduction in physical activity and exposure to photic stimulation. Changes in circadian rhythms are frequently associated with a reduction in nighttime sleep quality, a decrease in daytime alertness, and an attenuation in cognitive performance; reversing such changes could enhance the quality of life for a large and rapidly increasing percentage of the population. Reversal appears possible by increasing melatonin levels with either appropriately timed exposure to photic stimulation and/or appropriately timed administration of exogenous melatonin. These interventions may increase aspects of genetic expression that have changed with aging. A hypothesis concerning the potential benefits of enhanced circadian amplitude is also offered. PMID- 8684717 TI - Functional significance of mesolimbic dopamine. AB - Although a large body of neuropharmacological evidence suggests that the mesolimbic dopamine system (ML DA) is critical for goal-directed behaviors, exactly which aspects of behavior are mediated or modulated by this system remains a matter of conjecture. By measuring changes in DA cell firing patterns and extracellular DA concentrations in target areas of ML DA cells during the development and performance of goal-directed behavior, it is possible to directly examine the relationship between ML DA transmission and various stages and components of behavior. This permits tests of hypotheses concerned with the functional significance of ML DA. This review will discuss recent electrophysiological, microdialysis and electrochemical data on behavior associated changes in firing activity of ML DA cells and fluctuations in DA concentrations in target areas of these cells. Although application of an electrochemical technique to study behavior-associated changes in DA transmission is an area of hot debates, a close correlation between DA-dependent electrochemical signal changes and separate behavioral components, with a generally similar pattern of rapid signal fluctuations found in trained animals during operant lever-pressing behavior maintained by palatable food, cocaine or heroin, suggests that extrasynaptic DA may have some important functions in regulating behavior. This review will discuss possible mechanisms underlying phasic and tonic changes in ML DA transmission accompanying development and performance of positively-reinforced behavior, the contribution of learning, behavioral and pharmacological variables in the mediation of these changes, and their relevance for the organization and regulation of goal-directed behavior. PMID- 8684718 TI - Biochemical background for an analysis of cost-benefit interrelations in aggression. AB - Aggression consumes important amounts of energy (e.g., in fish the effort of "routine" social life may be as costly as life-long forced swimming at moderate speeds). In fish the amount of energy spent and the metabolic compartment mobilized seem to depend on the length of cohabitation, the number of contestants and the result of the fight. In mammals, metabolic preparations for fights were shown. The fights cause elevations of both body temperature and metabolic rate, as well as important changes in carbohydrate and lipid metabolism. There are evidences which show that the energetic aspects of aggressive behavior have a significant impact on the behavioral tactics and survival chances in free living animals. The relevance of these studies to game theoretical analyses and to practical aspects of the aggression-energy metabolism interrelationship are also outlined. Although many details of the phenomenon are known, important issues have to be clarified, among them the possible neuroendocrinologic co-regulation of this behavior and of its energetic background. PMID- 8684719 TI - Again: what is nursing? PMID- 8684720 TI - About all those paradigms: many in the universe, two in nursing. PMID- 8684721 TI - Can researchers transcend bad science? PMID- 8684722 TI - Replanting: pot-bound nursing revisited. PMID- 8684723 TI - The lived experience of aging in community-dwelling elders in Valencia, Spain: a phenomenological study. AB - The purpose of this qualitative research study was to explore the lived experience of aging in community-dwelling elders in Valencia, Spain. A bilingual, bicultural endeavor, this research was a collaborative project conducted by nurse educators in New York City and Valencia. Parse's theory of human becoming guided the research, and van Kaam's phenomenological method of analysis was used to identify common elements and major themes of experience. Findings revealed the meaning of aging to be confirming triumphs through the forceful enlivening of bridled potency. These findings were conceptually consistent with Parse's major themes of meaning, rhythmicity, and cotranscendence. Implications for practice and research are discussed. PMID- 8684724 TI - Grief responses, coping processes, and social support of widows: research with Roy's model. AB - This ex post facto descriptive correlational design study of widows during their second year of bereavement utilizes Roy's adaptation model as a guiding framework. Contextual stimuli (social support, social network, income/education, spiritual beliefs) were related to the cognator function (coping process), which was related to adaptation outcome (grief response). Significant moderate positive relationships were found between social support and coping process, and between social network and coping process. A significant relationship was also found between coping process and grief response. The path model accounted for 18% explained variance. PMID- 8684725 TI - Orem's nursing theory and positive mental health: practical considerations. AB - The impetus for the authors' development of this article was their growing awareness of the failure of some nurses to recognize positive mental health behaviors of patients. The authors also were aware of the absence of readily applicable criterion measures of positive mental health. This awareness led to the formulation and investigation of two questions: What human behaviors constitute adequate criterion measures of positive mental health of adults? Do adult persons in health care, including nursing situations, reveal evidence of positive mental health? PMID- 8684726 TI - Hermeneutics: philosophical traditions and nursing practice research. AB - This analysis begins with the premise that nursing practice research has often ignored or suppressed the fact that nurses participate in and benefit from the same American illness care nonsystem that leaves 40 million citizens without health care. This collective denial has its historical roots in philosophic foundationalism, health care authoritarianism, and nursing's disciplinary isolation. Philosophical hermeneutics offers perspectives that emphasize the inescapability of nursing's history. This article traces some of the main themes in philosophical hermeneutics and their potential significance for nursing practice research. The relationship between hermeneutic philosophy and research methods employed in interpretive traditions (for example, grounded theory) and the role of experimental design in addressing hermeneutic questions are discussed. PMID- 8684727 TI - Nutrition and HIV/AIDS. Edinburgh, 23-25 September 1994. Conference report. PMID- 8684728 TI - Interactions between nutrients and the immune system. PMID- 8684729 TI - Looking at dietary effects on weight loss and diarrhea in HIV seropositive patients: a pilot project. AB - This was a pilot study and therefore only gives us information as to the direction that we can continue looking towards. There were two factors that could have skewed the results. One is the small size of the sample group and the other is that in the Nutritionist III program, not every nutrient, especially in the case of a trace mineral such as selenium, is listed in all foods. Further research is certainly warranted in this area to advance the study of the long term effects of a nutritional intervention on long-term survival of HIV/AIDS persons. A theory was published by the Journal of Medicinal Chemistry (Aug. 1994) that the HIV virus slowly depletes the body of the trace mineral selenium, which it uses to erupt into uninfected cells. The theory proposes that the HIV virus needs selenium, which preserves the elasticity of body tissue and slows the aging process, to trigger its growth. Once the virus uses up all the selenium in one cell, then it breaks out in search of more, spreading the infection to new cells. The researchers at the University of Georgia suggested that the latency period may be attributed to the period of time it takes to deplete the body of selenium storage. (NY Times, Aug. 20, 1994) PMID- 8684730 TI - Lothian's Community Drug Problem Service--a brief history of sex, drugs & HIV. PMID- 8684731 TI - Positively healthy. PMID- 8684732 TI - A fertility diet for planning pregnancy. PMID- 8684733 TI - Infant weaning practises of some Idoma women in Makurdi, Nigeria. AB - The weaning practices in infants aged 4-9 months of two hundred Idoma women resident in Makurdi were examined. A pre-tested standard questionnaire was used to collect data from mothers who regularly visited the post-natal health clinics in Makurdi. The results showed that better educated mothers breast fed for a shorter time or planned to cease breast feeding after a shorter period than mothers who had little education or no formal training. Most mothers (97%) fed milk formula which they claimed was used to supplement breast milk and was good for their babies. The most influential factors were the hospital and the husband. The majority of the mothers fed pap; 73% using corn in its preparation, with 91% of them storing such paps in flask. More than half of the mothers used a bottle in feeding the paper or gruel to their infants while a similar proportion (65.5%) fed legumes to their infants in addition to fruits. The implications of these practices in comparison with other ethnic groups is discussed. PMID- 8684734 TI - Nutrition and health practices of diabetic and nondiabetic men and women from two southeastern New England communities. AB - Diabetes occurs in at least 13 million persons in the United States and is a major cause of morbidity and premature mortality. Diet is the cornerstone of diabetes management, and the purpose of this investigation was to examine dietary intakes and health practices among diabetic and nondiabetic individuals from a recently surveyed population-based sample from two communities in southeastern New England. Data were collected during cross-sectional home health surveys conducted in random population samples of two New England communities during 1987 1988, 1989-1990, and 1992-1993. A food frequency questionnaire was completed by 1,897 of 2,077 eligible respondents who made up our study sample. Statistical analyses suggest that diabetic individuals do not appear to be adhering to measures known to improve metabolic control (i.e., weight reduction and physical activity). Furthermore, both diabetic and nondiabetic individuals alike should be targeted for educational programs aimed at improving dietary intakes which lead to a reduction in consumption of total and saturated fatty acid. PMID- 8684735 TI - Effect of wilting and processing on the nitrate and nitrite contents of some Nigerian leaf vegetables. AB - Nitrate and nitrite contents of seven varieties of commonly consumed leaf vegetables were determined. Effect of cooking and wilting on the contents of these factors were investigated. Nitrate ranged from 48.10 in ewuro to 270.0 ppm ogunmo (mean 116.43+/- 78.31) while nitrite ranged from 0.024 ppm in tete to 0.064 in ogunmo (mean 0.044+/-0.018). Cooking reduced the nitrate levels in all the samples but nitrite levels inexplicably increased in all sample. On wilting nitrate levels decrease while nitrite levels increased up to 83% in tete. The nitrate and nitrite levels were not considered hazardous but toxicological implications of high consumption of these factors is briefly highlighted. PMID- 8684736 TI - A criticism of a report on the Scottish diet. PMID- 8684737 TI - Sir Alister Hardy's paradigm (AAT) PMID- 8684738 TI - Outcome of twin gestations complicated by a single anomalous fetus. AB - OBJECTIVE: To compare the outcome of twin gestations complicated by a single anomalous fetus with twin gestations with no fetal anomalies. METHODS: The study included all patients with twin gestations diagnosed with a fetal anomaly in one fetus during 1990-1994, and excluded twin gestations with anomalies in both fetuses. The control twin group was composed of all other normal twin pregnancies followed and delivered at our center in the preceding 2 years. RESULTS: We reviewed 24 twin gestations with at least one anomalous fetus. Five cases were excluded because of anomalies in both fetuses, and a further five pregnancies had selective termination or termination of the entire pregnancy. There were 14 ongoing twin pregnancies with one anomalous fetus, and their median gestational age at diagnosis was 18 weeks (range 16-20). All twin anomalies were correctly diagnosed antenatally. Gestational age at delivery and birth weight were significantly lower for twins complicated by an anomaly compared with control twins (P = .008 and P = .001, respectively). The cesarean delivery and perinatal mortality rates of twin pregnancies with anomalies were significantly higher than those of normal twins (P = .01 and P < .001, respectively). CONCLUSION: The presence of a single anomalous fetus in a twin gestation significantly increases the risk of preterm delivery compared with nonanomalous twin gestations. PMID- 8684739 TI - Sonographic prediction of shoulder dystocia in infants of diabetic mothers. AB - OBJECTIVE: To determine if the difference between the abdominal diameter and biparietal diameter (AD-BPD difference), as measured by ultrasound examination, predicts shoulder dystocia in borderline macrosomic infants of diabetic mothers. METHODS: A retrospective study was performed of births occurring from January 1990 through June 1995. Eligibility requirements included diabetic pregnancy, ultrasound examination within 2 weeks of delivery, estimated fetal weight of 3800 4200 g, and vaginal delivery. The mean AD-BPD difference was compared in normal deliveries and those complicated by shoulder dystocia, using the Student t test and by multiple regression analysis. A receiver operating characteristic curve was generated to determine if an AD-BPD cutoff value could be used clinically to predict shoulder dystocia. RESULTS: Thirty-one patients, six with dystocia, were eligible for the study. The mean AD-BPD differences for those with and without shoulder dystocia were 3.1 and 2.6 cm, respectively, a statistically significant difference (P = .05). Comparing the groups with and without shoulder dystocia, no significant differences could be found in mean age, parity, weight, birth weight, or gestational age. Shoulder dystocia occurred in six of 20 patients (30%) in whom the AD-BPD difference was at least 2.6 cm but in none of 11 patients in whom it was less than 2.6 cm, also a statistically significant difference (P = .05). CONCLUSION: The AD-BPD difference was greater in borderline macrosomic fetuses of diabetic mothers who experienced shoulder dystocia than in those who had uncomplicated vaginal deliveries. Applying an AD-BPD cutoff value of 2.6 cm to this population prospectively would have provided excellent sensitivity, specificity, and predictive value in identifying those fetuses at high risk for birth injury. PMID- 8684740 TI - Cerebral artery blood flow in relation to age and menopausal status. AB - OBJECTIVE: To investigate vascular reactivity in women's cerebral arteries from reproductive age to postmenopause. METHODS: The pulsatility index (PI) was measured cross-sectionally in the internal carotid and middle cerebral arteries of 120 women, using a Doppler ultrasound system. Fifteen women were enrolled in each of eight 5-year intervals, spanning ages 20-59 years. RESULTS: In the population as a whole, there was a slight but statistically significant correlation between age and the PI in both arteries, but not after excluding postmenopausal subjects. A significant correlation was found between PI and months since menopause (but not chronologic age) in the postmenopausal women. There was also a statistically significant difference in the PI values for both arteries between pre- and postmenopausal women of similar age. CONCLUSION: Menopause causes a significant increase in the PI of women's cerebral arteries. In postmenopausal women, there is a significant correlation between the PI of the internal carotid and middle cerebral arteries and menopausal but not chronologic age. This effect may be one of the mechanisms by which menopause is associated with the known higher risk for coronary heart disease observed in women. PMID- 8684741 TI - Concentrated oxytocin plus low-dose prostaglandin E2 compared with prostaglandin E2 vaginal suppositories for second-trimester pregnancy termination. AB - OBJECTIVE: To examine the efficacy and side effects of concentrated oxytocin plus low-dose prostaglandin (PG) E2 compared with a standard dose of vaginal PGE2 for second-trimester pregnancy termination. METHODS: Patients with obstetric or fetal complications were randomly assigned to receive either a 20-mg PGE2 vaginal suppository every 4 hours (n = 81) or a concentrated oxytocin infusion plus a 10 mg PGE2 vaginal suppository every 6 hours (n = 73). Treatment success was defined as delivery (or imminent delivery) within 24 hours of therapy. Women who failed their assigned regimen were crossed to the alternate method. RESULTS: Indications for delivery were similar in the two groups. The success rate with oxytocin was 89%, compared with 81% with vaginal PGE2 (relative risk 0.92, 95% confidence interval 0.8-1.04; P = .2). Maternal fever (P < .001), nausea (P = .02), and vomiting (P = .003) occurred significantly more often in women who received a 20 mg PGE2 vaginal suppository every 4 hours. CONCLUSION: Concentrated oxytocin plus low-dose PGE2 should be considered as an alternative to vaginal PGE2 for indicated second-trimester pregnancy termination. PMID- 8684742 TI - Pregnancy outcome following genetic amniocentesis at 11-14 versus 16-19 weeks' gestation. AB - OBJECTIVE: To compare pregnancy complications in women having genetic amniocentesis at 11-14 weeks versus those undergoing amniocentesis at 16-19 weeks' gestation. METHODS: A genetics data base was used to identify patients retrospectively, those who had genetic amniocenteses by three experienced operators during a 4-year period. The study group consisted of women who had amniocenteses at 11-14 weeks' gestation. For each study patient (early amniocentesis), two controls (amniocentesis at 16-19 weeks) were identified and matched for maternal age, race, and the number of prior spontaneous abortions. An immediate post-procedure complication was defined as any vaginal bleeding, rupture of membranes, or fetal loss occurring up to 30 days after the amniocentesis. A later complication was defined as any fetal death longer than 30 days after the amniocentesis, any preterm delivery, any infant weighing less than the tenth percentile for gestational age, and any neonatal death. Immediate and later complications were compared between the study and control groups. RESULTS. The study group consisted of 314 patients who were matched to 628 controls. Women who had a genetic amniocentesis performed at 11-14 weeks were significantly more likely to have post-procedure amniotic fluid leakage (2.9 versus 0.2%), post procedure vaginal bleeding (1.9 versus 0.2%), and a fetal loss within 30 days of the amniocentesis (2.2 versus 0.2%) than women undergoing genetic amniocentesis at 16-19 weeks' gestation. Four of the seven patients (57%) with a fetal loss within 30 days of an early amniocentesis had procedure-related complications, such as amniotic fluid leakage, bleeding, and infection, that caused the pregnancy to be lost. No differences were noted between the two groups in the number of preterm deliveries, later fetal deaths, neonatal deaths, or newborns weighing less than the tenth percentile for gestational age. CONCLUSION: Genetic amniocentesis at 11-14 weeks is associated with more post-procedure complications and a higher fetal loss rate within 30 days of the procedure than a genetic amniocentesis performed at 16-19 weeks' gestation. PMID- 8684743 TI - Postpartum tubal ligation after pregnancy complicated by preeclampsia or gestational hypertension. AB - OBJECTIVE: To determine the anesthetic and surgical morbidity associated with postpartum tubal ligation after pregnancy complicated by pregnancy-induced hypertension. METHODS: Preoperative hemodynamic measurements, laboratory results, choice of anesthetic technique, intraoperative hemodynamic changes, and postoperative morbidity were compared in 53 women with pregnancy-induced hypertension (hypertensive group) and 53 controls who underwent postpartum tubal ligation between October 1992 and November 1995. We used a retrospective case control design. RESULTS: Preoperative mean blood pressure (BP) measurements ( +/- standard deviation) were greater in hypertensive women than in controls (158 +/- 22/91 +/- 12 versus 126 +/- 13/71 +/- 10 mmHg; P < .001). Among women given spinal anesthetics for tubal ligation, the minimum intraoperative systolic BP was significantly lower in controls than in hypertensive women (P < .05). However, the maximum percentage decrease in systolic BP was greater in hypertensive women than in controls (33 +/- 14 versus 22 +/- 10%; P < .05). Only one patient in each group developed intraoperative hypertension. The percentage of patients discharged later than the first postoperative day was greater in hypertensive women than in controls (23 versus 8%; P < .05). CONCLUSION: The lack of profound hemodynamic responses during spinal or general anesthesia for postpartum tubal ligation supports the continued use of this procedure in selected women with pregnancy-induced hypertension. PMID- 8684744 TI - Treatment of the small unruptured ectopic pregnancy: a cost analysis of methotrexate versus laparoscopy. AB - OBJECTIVE: To compare the economic costs between two strategies for management of the small unruptured ectopic pregnancy: initial treatment with methotrexate versus initial treatment with laparoscopic salpingostomy. METHODS: We assumed that both treatment strategies would result in identical clinical outcomes: resolution of the ectopic pregnancy without maternal mortality or long-term morbidity. Based on a literature review, estimates were derived for the likely clinical outcomes of a single injection of methotrexate (50 mg/m2) and for the likely clinical outcomes of the laparoscopy strategy. A range of values was evaluated for the initial success rate of each strategy and varying assumptions made about the type of treatment modality used for initial treatment failures. Direct medical costs of each strategy were estimated based on actual reimbursement rates of a third-party payer for the components of each strategy. The treatment strategies were compared in best-case/worst-case scenarios to determine the potential range of differences in costs between the two strategies. RESULTS: The cost of the methotrexate strategy ranged from $438 to $1390, and the cost of laparoscopic salpingostomy ranged from $2506 to $2974; therefore, the methotrexate strategy was less costly than laparoscopy, with a cost difference ranging from $1124 (best-case laparoscopy-worst-case methotrexate scenario) to $2536 (worst-case laparoscopy-best-case methotrexate scenario). Sensitivity analyses demonstrated that initial therapy with methotrexate was less costly over a wide range of probability and cost estimates. CONCLUSION: Initial methotrexate is a cost-effective alternative to laparoscopic salpingostomy in the treatment of the small unruptured ectopic pregnancy. PMID- 8684745 TI - The empty supine stress test as a predictor of intrinsic urethral sphincter dysfunction. AB - OBJECTIVE: To assess the usefulness of a proposed test for intrinsic urethral sphincter dysfunction. METHODS: Subjects were included in the study if they had complaints of incontinence, did not have substantial pelvic prolapse, and had undergone multichannel urodynamic testing. The initial evaluation involved uroflowmetry, catheterized residual urine, history, urogenital examination, and a cough stress test within 20 minutes after catheterization. Standardized multichannel urodynamic testing was performed at a follow-up appointment. Test indices were calculated based on the result of the empty supine stress test, the presence of genuine stress incontinence, and maximum urethral closure pressures. RESULTS: Three hundred four women met the inclusion criteria; 124 had a positive empty supine stress test and 180 had a negative test. Genuine stress incontinence was diagnosed in 238 subjects. A positive empty supine stress test was found to have 70% sensitivity and 90% negative predictive value for detecting very low urethral closure pressures, and 98% positive predictive value for genuine stress incontinence; in low-risk populations, the test had 95% negative predictive value for excluding urethral dysfunction. CONCLUSION: The empty supine stress test is easy to perform, inexpensive, and without significant risk. By itself, a positive empty supine stress test is essentially diagnostic for genuine stress incontinence, and in combination with a fixed urethra, it is diagnostic for intrinsic urethral sphincter dysfunction. In low-prevalence populations, a negative test reliably excludes the presence of intrinsic urethral sphincter dysfunction. However, for high-prevalence and referral populations, the low predictive values of the test limit its usefulness. PMID- 8684746 TI - Answers to applicant selection from a directory of residency programs in obstetrics and gynecology. AB - OBJECTIVE: To answer six questions applicants commonly ask of programs, using the data base of a directory of residency programs in obstetrics and gynecology. METHODS: We analyzed data from a directory of 258 civilian residency programs in the United States compiled from a 1994-1995 survey. We expanded the analysis to compare small and large residency programs on the six questions. RESULTS: The average-size program of four residents per year received 50 applications for each position, offered interviews to less than a third of its applicants, and interviewed 15 applicants for each position. An interview gives an applicant a 7% chance of matching with a program. Small programs (fewer than four residents per year) interviewed more of their applicants than did large programs. Programs reported that their residents' scores on part I ranged from the 25th to the 90th percentile, and on part II from the 38th to the 92nd percentile. In general, residents in large programs scored better on these tests than did residents in small programs. Most programs (74%) considered electives beneficial in obtaining a residency position and reported a higher percentage of elective takers than programs without this policy. One in four residents in a program either took a senior elective there, graduated from the same institution, or both. Residents from programs offering fellowship training were twice as likely to pursue fellowship training than residents from programs with no fellowships. Large programs were four times more likely to sponsor fellowships than were small programs. CONCLUSION: Getting an interview in a residency program is a major accomplishment, whereas becoming known in a program may improve the applicant's odds of matching there. Applicants should review a program's policy on electives and selection record. Those considering fellowships should probably apply to programs that offer them. The directory offers a valuable data source for comparing residency programs in obstetrics and gynecology. PMID- 8684747 TI - Fetal transfusion for red blood cell alloimmunization in pregnancy. AB - OBJECTIVE: To present an up-to-date review of the literature encompassing all important aspects of fetal transfusion for red blood cell alloimmunization in pregnancy. DATA SOURCES: A MEDLINE computer data base search was conducted for pertinent articles through August 1995. Additional publications were identified by cross-referencing. METHODS OF STUDY SELECTION: All pertinent references were reviewed by the authors, and their clinical significance in the fetal treatment of red blood cell alloimmunization was summarized. TABULATION, INTEGRATION, AND RESULTS: Fetal intraperitoneal transfusion in the treatment of severe red blood cell alloimmunization was first reported by Liley in 1963. Since then, major advancements have included intravascular techniques and fetal paralysis. A total of seven different approaches have been used. Case series describing fetal intravascular transfusion were reviewed, and outcomes were analyzed for all pregnancies and, separately, for those presenting with and without hydrops fetalis. Eighty-four percent of 411 fetuses that underwent intravascular transfusion had good outcomes. Ninety-four percent of nonhydropic fetuses and 74% of hydropic fetuses survived. Those with severe anemia but no hydrops at transfusion were five times more likely to survive than fetuses already hydropic. CONCLUSION: For pregnant patients presenting with severe red blood cell alloimmunization remote from term, fetal transfusion remains the best available therapeutic option. It is a safe procedure with a perinatal loss rate of approximately 1-3%, and overall neonatal survival exceeds 80%. It is the best available option until red blood cell alloimmunization can be prevented altogether. PMID- 8684748 TI - The effects of S-nitrosoglutathione on platelet activation, hypertension, and uterine and fetal Doppler in severe preeclampsia. AB - OBJECTIVE: To determine the effects of the platelet-specific nitric oxide donor S nitrosoglutathione on women with severe preeclampsia. METHODS: Ten women with severe preeclampsia or preeclampsia with severe fetal compromise at 21-33 weeks' gestation each received a 60-90-minute intravenous infusion of 50-250 micrograms/minute of S-nitrosoglutathione. Each was hypertensive, despite conventional oral antihypertensive therapy in eight. Maternal blood pressure, heart rate, platelet activation, uterine artery, and fetal Doppler indices were measured during the infusion. RESULTS: A dose-dependent reduction in mean arterial pressure from 125 mmHg (95% confidence interval [CI] 117-133) to 103.5 (95% CI 97-111) (P < .005) and an increase in pulse rate from 73.7 beats per minute (95% CI 64.3-84.5) to 89.1 (95% CI 81.2-97.8) (P < .02) was observed during the infusion. Mean uterine artery resistance index fell from 0.76 (95% CI 0.73-0.81) to 0.70 (95% CI 0.65-0.75) (P < .009). Platelet activation measured by P-selectin expression was reduced from 3.02% (95% CI 2.09-4.36) to 1.22% (95% CI 0.94-1.58) (P < .01). Fetal Doppler indices (umbilical artery, middle cerebral artery, and thoracic aorta) showed no significant changes during the infusion. CONCLUSION: S-nitrosoglutathione infusion reduced material mean arterial pressure, platelet activation, and uterine artery resistance without further compromising fetal Doppler indices. This study suggests that platelet-specific nitric oxide donors may prove beneficial in the management of severe preeclampsia. PMID- 8684749 TI - The Yuzpe regimen of emergency contraception: how long after the morning after? AB - OBJECTIVE: To determine whether failure of the Yuzpe method of emergency contraception (which involves taking a higher than usual dose of ordinary combined oral contraceptives within 72 hours after unprotected intercourse, with a second dose taken 12 hours later) depends on the interval between intercourse and treatment. DATA SOURCES: We searched the literature for studies in which investigators separately reported both the number of women treated with the Yuzpe regimen and the resulting pregnancies when treatment was started on the first, second, and third days after unprotected intercourse. Searches of the electronic data bases MEDLINE, POPLINE, EMBASE, and BIOSIS were supplemented by scrutiny of the bibliographies of all papers identified through the electronic search. METHODS OF STUDY SELECTION: We identified nine published studies that present the number of women treated and outcome of treatment by time since unprotected intercourse. We included all nine studies in our analysis. TABULATION, INTEGRATION, AND RESULTS: Differences in failure rates by time of treatment adjusted for study-site effects were analyzed using logistic regression. We found no significant differences in failure rates when therapy was started on the first, second, or third day after unprotected intercourse. The large sample size ensured a power of 76% to reject the null hypothesis of equal failure rates when the odds of failure on the third day are twice those on the first and second days. CONCLUSION: Our results have two clinical implications. First, insistence on taking the first dose as soon as possible may be counterproductive in circumstances when taking the second dose 12 hours later would be difficult. Second, clinical protocols that deny treatment after 72 hours may be excessively restrictive, particularly if the alternative of emergency insertion of a copper intrauterine device is not immediately available or appropriate. PMID- 8684750 TI - A technique for laparoscopic completion of vaginal hysterectomy. PMID- 8684751 TI - Diagnosing gestational diabetes mellitus: use of a glucose screen without administering the glucose tolerance test. PMID- 8684752 TI - An ethically justified algorithm for offering, recommending, and performing cesarean delivery and its application in managed care practice. PMID- 8684753 TI - Underreimbursement of obstetric and gynecologic invasive services by the resource based relative value scale. PMID- 8684754 TI - Use of the Centers for Disease Control and Prevention childhood lead poisoning risk questionnaire to predict blood lead elevations in pregnant women. PMID- 8684755 TI - Transvaginal ultrasound and preterm prelabor: a nonrandomized intervention study. AB - OBJECTIVE: To characterize the continuum between normal and preterm labor to prevent spontaneous preterm birth and low birth weight. METHODS: Between August 1, 1992, and November 30, 1993, obstetric patients from a large managed care medical group were assigned in rotation to five private practice offices for pregnancy care. In the study office (374 births), a systematic approach of visit by-visit screening, patient education, selective office evaluation of cervical change by transvaginal ultrasound examination, outpatient modification of activity, and graded oral or subcutaneous tocolysis was used; inpatient tocolysis was used only when outpatient management failed. In the comparison offices (1391 births), transvaginal ultrasound was not used and conventional methods were used at the discretion of the attending physicians. RESULTS: Birth weights below 1500 g (P = .008; odds ratio [OR] 0.08, 95% confidence interval [CI] 0.05-1.32), 2000 g (P = .21; OR 0.21, 95% CI 0.05-0.88), and 2500 g (P = .008; OR 0.44, 95% CI 0.23-0.83) occurred significantly less often in the study group than in the comparison group. The difference in spontaneous preterm births under 2500 g was also significant (P < .001; OR 0.08, 95% CI 0.01-0.58). CONCLUSION: By emphasizing transvaginal ultrasound and graded outpatient tocolysis, the diagnosis and management of preterm prelabor was associated with a reduction in the rate of spontaneous preterm birth and low birth weight infants. PMID- 8684756 TI - Second-trimester amniotic fluid or maternal serum interleukin-10 levels and small for gestational age neonates. AB - OBJECTIVE: To evaluate if interleukin-10 levels in either early second-trimester amniotic fluid (AF) or maternal serum can be utilized as a predictor of the subsequent occurrence of small for gestational age (SGA) infants after controlling for gestational age at delivery. METHODS: We identified patients who underwent genetic amniocentesis for standard genetic indications or maternal blood sampling for maternal serum alpha-fetoprotein (MSAFP)/triple screen between January 1992 and February 1995 with available follow-up delivery data. Small for gestational age was defined as birth weight less than the tenth percentile for gestational age. Control patients were matched for gestational age at delivery, maternal age, race, and parity with at least two controls for each study patient. We excluded patients with maternal immune disease, chronic hypertension, diabetes, asthma, congenital heart disease, multiple gestation, and fetuses with structural or chromosomal anomalies. Second-trimester AF and serum samples were assayed for interleukin-10. Potential confounding variables considered were MSAFP level, smoking history, pregnancy-induced hypertension, and neonatal gender. The interleukin-10 levels were normalized using natural log transformation for statistical analysis. Statistical analysis included chi 2, Fisher exact test, and analysis of variance, with P < .05 considered significant. RESULTS. From the AF data base, 18 patients (6%) delivered SGA neonates and were matched with 46 controls. From the maternal serum data base, 13 patients (7%) delivered SGA neonates and were matched with 45 controls. Neither AF nor maternal serum interleukin-10 levels were significantly different in patients subsequently delivering SGA neonates compared with controls (AF: median 21.0 pg/mL. [range 13.8-27.6] versus 17.5 pg/mL. [range 8.9-362.12], P = .18; serum: median 15.7 pg/mL [range 9.9-73.5] versus 18.7 pg/mL [range 9.7-71.7], P = .60, respectively). No significant differences were identified in gestational age at sampling, maternal smoking history, pregnancy-induced hypertension, or elevated MSAFP in patients delivering SGA neonates compared with controls (P > .05 for each). As expected, birth weight was significantly lower in patients delivering SGA neonates compared with controls (P < .001). CONCLUSION: Second-trimester AF or maternal serum interleukin-10 levels are not predictive of subsequent delivery of SGA infants. PMID- 8684757 TI - Postoperative management of cesarean patients: the effect of immediate feeding on the incidence of ileus. AB - OBJECTIVE: To evaluate the effect of immediate feeding on gastrointestinal function in patients undergoing cesarean delivery. METHODS: A prospective study was conducted in which patients were randomized to one of two groups, either early feeding or delayed feeding, ie, feeding according to the institution's current protocol. Questionnaires were filled out by the subjects on the day of discharge. Fisher exact test was used to compare the two groups with respect to the type of anesthetic used and to compare the incidence of gastrointestinal symptoms. A one-sided exact binomial confidence interval was used to determine the upper bound of the likelihood of paralytic ileus. Logistic regression analysis was used to evaluate the presence of ileus symptoms when controlling for the type of anesthetic used. RESULTS: There were no significant differences between the control and study groups. There was no significant difference in the number of gastrointestinal symptoms between the two groups. The incidence of postoperative paralytic ileus was zero in both the study and control groups. CONCLUSION: Routine early feeding of subjects undergoing cesarean delivery can be implemented without an increase in gastrointestinal symptoms or paralytic ileus. PMID- 8684758 TI - Serial hematologic changes and pregnancy outcome. AB - OBJECTIVE: To reevaluate the concept that poor maternal hematologic changes relate to increased placental protein hormones, increased birth weight, and placenta to birth weight ratio. METHODS: Sixty-nine normal women were studied prospectively. On several occasions, pre-pregnancy, during pregnancy, and post delivery, plasma volume was measured together with maternal hematologic indices and placental protein hormone levels. Birth weight and placental weight were measured at delivery. RESULTS: The decrements in hemoglobin concentration and hematocrit were apparent by 7 weeks' gestation. By 12 weeks, these progressive changes resulted mostly from the increase in plasma volume, and both hemoglobin concentration and hematocrit continued to decrease until near term. Increments in red cell and hemoglobin mass were maximal at 12-28 weeks of pregnancy. Concentrations of the placental hormones hCG and human placental lactogen at 12 weeks showed a lack of correlation with hemoglobin concentration or any other hematologic index. The correlations of birth weight with hemoglobin concentration and hematocrit at 36 weeks were not significant when we controlled for the effect of plasma volume. Neither hemoglobin mass at 36 weeks nor the change in hemoglobin concentration, hematocrit, and mean cell volume from the pre-pregnancy value to that at 36 weeks were significantly related to birth weight, placental weight, or the placenta to birth weight ratio. CONCLUSION: Low hemoglobin in late pregnancy reflects plasma volume changes, rather than poor maternal nutrition or adaptation, and is not linked to discordant placenta to birth weight ratio. PMID- 8684759 TI - A longitudinal study of maternal hemodynamics during normal pregnancy. AB - OBJECTIVE: To investigate the maternal hemodynamic changes that occur during normal pregnancy. METHODS: Serial hemodynamic investigations were performed throughout normal pregnancy by thoracic electrical bioimpedance monitoring in 50 healthy women. Analysis of variance with repeated measurements was used to evaluate the time course of a number of hemodynamic indies. RESULTS: The mean heart rate (+/- standard error [SE]) increased gradually from 87 +/- 2 beats per minute at 10-18 weeks' gestation to 92 +/- 1 beats per minute at 34-42 weeks' gestation. Mean arterial pressure decreased significantly after 14 weeks' gestation and increased significantly after 29 weeks' gestation. During the third trimester, mean cardiac output and mean stroke volume decreased, and mean systemic vascular resistance increased significantly. The course of cardiac output during the third trimester was not uniform in all women; it increased in nine and decreased in 41 women. A significantly higher mean cardiac output was found in nulliparous women compared with multiparous women (mean difference +/- SE 0.76 +/- 0.33 L/minute). The mean (+/- SE) cardiac output increased significantly from 6 (5.49 +/- 0.16 L/minute) to 12 weeks' postpartum (5.91 +/- 0.19 L/minute). CONCLUSION: Mean cardiac output and mean stroke volume decreased in late pregnancy. A significant difference in mean cardiac output was observed between nulliparous and multiparous women. Cardiac output usually, but not invariably, declined during the third trimester. PMID- 8684760 TI - Decreased plasma tryptophan in pregnancy. AB - OBJECTIVE: To examine levels of serum tryptophan and its degradation product kynurenine in uncomplicated pregnancy, according to the week of pregnancy and the concentrations of neopterin. METHODS: Plasma was analyzed from 45 healthy pregnant women (15 in each trimester), 15 healthy puerperas, and 20 nonpregnant controls. Tryptophan and kynurenine were measured by reverse-phase, high performance liquid chromatography, and neopterin by radioimmunoassay. RESULTS: In healthy pregnant women, tryptophan values decreased (median first trimester: 72 mumol/L; second trimester: 51 mumol/L; third trimester: 46 mumol/L; P < .001) in a manner correlated with the duration of pregnancy (Spearman rank correlation coefficient ra = -0.771, P < .001) and normalized in the puerperium (median 60 mumol/L). No change in kynurenine, a tryptophan degradation product, was observed, but the ratio of kynurenine to tryptophan increased during pregnancy and correlated positively with gestational age (ra = 0.714, P < .001). In addition, an inverse correlation existed between neopterin and tryptophan concentrations (ra = -0.566, P < .001), as well as a positive one between neopterin and the kynurenine to tryptophan ratio (ra = 0.660, P < .001). CONCLUSION: Tryptophan levels decrease during normal pregnancy and the decrease may be related to immune activation phenomena. PMID- 8684761 TI - Inadequacy of rapid immunoassays for intrapartum detection of group B streptococcal carriers. AB - OBJECTIVE: To determine the accuracy of two currently used immunoassays and a newly developed optical immunoassay for rapid intrapartum detection of group B streptococcal colonization compared with culture methods. METHODS: Rayon-tipped swabs were used to collect specimens from the distal vagina of 502 women at admission for labor or rupture of membranes. Four tests were performed on specimens from the first 197 patients: culture in selective broth medium, semiquantitative culture on blood agar medium, and ICON Strep B and Quidel Group B Strep Test enzyme immunoassays. For the remaining 305 women, a fifth test, Strep B OIA, a newly developed optical immunoassay, was also performed. RESULTS: The prevalence of group B streptococcal vaginal colonization was 25.1% by selective broth medium and 17.3% when swabs were plated directly onto blood agar medium, giving the latter method a sensitivity of 69%. When compared with selective broth medium results, the sensitivities of the rapid immunoassays were 12% (Quidel), 15% (ICON), and 37% (Strep B OIA). These values rose to 16% (Quidel), 21% (ICON), and 53% (Strep B OIA) when compared with nonselective blood agar medium results. For women with heavy group B streptococcal colonization (more than 10(6) colony forming units/mL), the sensitivities were 36% (Quidel), 46% (ICON), and 100% (Strep B OIA). Specificities for all assays were high (98 100%), but variability was found in positive (79-100%) and negative (77-85%) predictive values. CONCLUSION: Although Strep B OIA reliably detects women with heavy group B streptococcal colonization and is more sensitive than either the ICON or Quidel enzyme immunoassays, none of these rapid assays is sufficiently accurate for routine use in the intrapartum detection of women colonized with group B streptococcus. PMID- 8684762 TI - Maternal serum dehydroepiandrosterone sulfate levels and the efficiency of labor in young nulliparas. AB - OBJECTIVE: To evaluate the maternal serum dehydroepiandrosterone (DHEA) sulfate level as a factor influencing labor "efficiency" at term. METHODS: On admission to the labor and delivery unit, blood was collected from 55 term nulliparous women up to 25 years of age in active labor. Following delivery, umbilical venous cord blood was also collected. Pregnancies complicated by diabetes mellitus, hypertension, fetal growth restriction, tobacco use, corticosteroid use, or chorioamnionitis were excluded. Serum DHEA sulfate levels were measured by radioimmunoassay. Dehydroepiandrosterone sulfate levels and other obstetric variables were correlated retrospectively with the clinically determined requirement for oxytocin augmentation of labor. The unpaired Student t test, Mann Whitney test, and linear correlation were used for statistical analysis. P < .05 was considered statistically significant. RESULTS: Oxytocin augmentation followed standard indications in 29 of the 55 patients. The mean (+/- standard error) maternal serum DHEA sulfate level was significantly lower in these patients than in the remaining 26 who progressed spontaneously through labor (99.31 +/- 8.92 versus 135.05 +/- 12.30 micrograms/dL, respectively; P = .02). With the exception of cervical dilation on admission, no significant demographic differences were identified between the two groups. The maternal serum DHEA sulfate level did not correlate significantly with cervical dilation on admission (r = 0.03, P = .81). CONCLUSION: Among term nulliparous women, maternal serum levels of DHEA sulfate are significantly lower in those clinically requiring pharmacologic augmentation than in those progressing spontaneously through labor. Dehydroepiandrosterone sulfate may be an important factor in efficient labor. PMID- 8684763 TI - Evaluation of the twin peak or lambda sign in determining chorionicity in multiple pregnancy. AB - OBJECTIVE: To assess prospectively the diagnostic capabilities of ultrasound assessment, using the twin peak or lambda sign, in determining chorionicity in multiple pregnancy. METHODS: Fifty-five cases of multiple pregnancy were assessed. Real-time ultrasound scans of the origin of the inter-twin membrane for the presence or absence of the twin peak/lambda sign were performed and permanent images recorded. Chorionicity was determined by placental pathologic analysis. RESULTS: Presence or absence of the twin peak/lambda sign as determined by real time ultrasound correctly predicted chorionicity in 34 of 36 dichorionic and seven of eight monochorionic twin pregnancies: sensitivity for dichorionicity 94%, specificity 88%, positive predictive value 97%, and negative predictive value 78%. Real-time assessment was superior to analysis of permanent films. CONCLUSION: Ultrasound assessment of chorionicity using the twin peak/lambda sign has high sensitivity and specificity, but accuracy may not be sufficient to guide clinical management in all cases. PMID- 8684764 TI - Cesarean delivery for intrapartum fetal heart rate abnormalities: incorporating survey data into clinical judgment. AB - OBJECTIVE: To identify the descriptive clinical practice of maternal-fetal medicine specialists when faced with severe intrapartum fetal heart rate (FHR) abnormalities (as determined by continuous electronic fetal monitoring). METHODS: All regular members of the Society of Perinatal Obstetricians (maternal-fetal medicine specialists) were sent a survey questionnaire on the topic of cesarean delivery for intrapartum FHR abnormalities. The time from observation of FHR abnormalities to making the decision to proceed to cesarean delivery was the main outcome measure. Time was allowed for intrauterine resuscitative maneuvers to alleviate the abnormal pattern. Legislative definitions of consensus and strong consensus were applied to the data. Analysis of covariance was performed to determine the effect of physician demographic factors on the times reported. RESULTS: Four hundred thirty-one of 704 (61.2%) questionnaires were returned. Consensus was identified for deciding on cesarean delivery (after intrauterine resuscitation) 1) after 30 minutes for cases of repetitive late and severe variable decelerations, 2) after 10 minutes in cases of fetal bradycardia, and 3) in all scenarios with decreased beat-to-beat variability of the FHR. Consensus was identified for deciding on cesarean delivery in five of eight intrapartum FHR pattern abnormalities. CONCLUSION: The descriptive clinical practice of maternal fetal medicine specialists demonstrated in this study should be considered in prudential clinical judgment. PMID- 8684765 TI - Psychologic profiles of and sexual function in women with vulvar vestibulitis and their partners. AB - OBJECTIVE: To compare psychologic profiles of women with vulvar vestibulitis and their partners with a normal population, and to identify sexual dysfunction in women and their partners. METHODS: Forty-three women with vulvar vestibulitis and 38 partners, recruited from a gynecology outpatient clinic, completed the Symptom Check List-90, the Short Dutch Version of the Minnesota Multiphasic Personality Inventory, the Maudsley Marital Questionnaire, and the Questionnaire for Screening Sexual Dysfunctions. RESULTS: The women with vulvar vestibulitis scored significantly higher on the somatization and shyness subscales than a normal population. They didn't differ in respect to their current level of psychologic distress, extraversion, risk of psychopathology, and marital satisfaction. Their partners had significantly lower scores for psychopathology than a normal population. They didn't differ from a normal population in respect to their level of psychologic distress, extraversion, shyness, somatization, and marital satisfaction. Women with vulvar vestibulitis reported more frequent problems and higher distress with genital pain, lubrication, sexual arousal, and negative emotions in the sexual interaction with the partner. During masturbation, however, they reported less frequent problems and distress. The partners of these women reported nearly no problems or distress in either sexual situation. CONCLUSION: Women with vulvar vestibulitis and their partners seem in general to be psychologically healthy, although vulvar vestibulitis may be associated with a situationally defined sexual dysfunction for the women. PMID- 8684766 TI - Medium-term follow-up of women with menorrhagia treated by rollerball endometrial ablation. AB - OBJECTIVE: To assess the medium-term efficacy of rollerball endometrial ablation. METHODS: From January 1990 to December 1993, 142 women underwent rollerball endometrial ablation for menorrhagia, most with ovulatory dysfunctional uterine bleeding. Each was sent a detailed questionnaire 12-52 months later and then followed-up, with an overall 93% response rate. Thirty-two had uterine myomas (13 with hysteroscopic myoma resection) and 11 had a large endometrial polyp (four with both). Most of the women were pretreated with danazol. RESULTS: Thirty-two of 128 (25%) achieved long-term, complete amenorrhea and only three eventually resumed their periods after prolonged amenorrhea. Four women experienced late amenorrhea, which was probably due to menopause. The percentage of satisfactory outcomes decreased gradually with time (95.5, 85.5, and 75% for 13-24, 25-36 and more than 36 months respectively; P = .051); this was not statistically significant. One hundred twenty-one patients (85.2%) did not need further surgical treatment. The incidence of repeat ablation (8.5%) and hysterectomy (8.5%) increased gradually with time over the first 3 years but not thereafter, although total numbers are still small. Cyclic pelvic pain and premenstrual symptoms were much improved in both short and long term. Most women remained satisfied with the operation (84%) and would recommend it to others (89%). CONCLUSION: Rollerball endometrial ablation is a simple, effective, and acceptable procedure for the management of intractable menorrhagia due to ovulatory dysfunctional uterine bleeding. However, with the findings of slightly less satisfactory results with time, longer-term follow-up is still needed to establish the ultimate effectiveness of the procedure using different techniques. PMID- 8684767 TI - Microcolposcopic topographic endocervical assessment before excisional treatment of cervical intraepithelial neoplasia. AB - OBJECTIVE: To evaluate whether microcolposcopic topographic endocervical assessment reduces the failures of excisional treatment of cervical intraepithelial neoplasia (CIN). METHODS: Three hundred fifty patients with colposcopic and histopathologic findings of endocervical CIN were recruited for excisional treatment. Three hundred forty-eight of these were randomized to have or not have microcolposcopy before excisional treatment. Measurement of endocervical lesion was the only aim of microcolposcopic evaluation. When an endocervical extension was available, the cone biopsy was cut according to microcolposcopic measurement. Excision status was evaluated and related to presurgical management on operative specimens. After excision, patients were followed-up for at least 5 years after treatment. Three hundred thirty (171 and 159 with and without preoperative microcolposcopy, respectively) patients completed the study. Disease persistences were defined by cytologic, colposcopic, and histologic results. Microcolposcopic value was defined as completeness of excision and/or lack of persistent disease. RESULTS. On surgical specimens, involved margins were detected in 19 (5.4%) cases. Presurgical microcolposcopy was performed in only one of these cases. The difference of incomplete excision between cases with or without microcolposcopy was statistically significant (P < .001). In patients who were followed-up, persistent disease was detected in one (0.6%) woman in the microcolposcopy group and in 16 (10%) women in the control group. Comparison between the two groups showed a significantly lower risk of persistent disease when presurgical microcolposcopy was performed (P < .001). CONCLUSION: By measuring endocervical extension of the lesion, preoperative microcolposcopy allows individualized cones, thus improving the prognosis after excisional treatment of CIN. PMID- 8684768 TI - Adenocarcinoma in situ of the cervix: significance of cone biopsy margins. AB - OBJECTIVE: To evaluate the treatment and outcome of patients with adenocarcinoma in situ of the cervix, with special emphasis on cone biopsy margins. METHODS: Sixty-one women with adenocarcinoma in situ of the cervix treated between April 1984 and December 1993 were identified. Medical records and histologic material were reviewed. Mixed lesions with both adenocarcinoma in situ and squamous cervical intraepithelial neoplasia (CIN) were included. RESULTS: The mean age of the patients was 35.9 years. Fifty-five of the 61 (90%) patients had cone biopsies, and 44 of these 55 (80%) subsequently had hysterectomies. Eight women (13%) had associated invasive cancer. Among 50 patients in whom the status of the margins was confirmed, 23 (46%) had positive margins and 27 (54%) had negative margins. Of 23 women with positive margins, 19 had hysterectomies and ten of the 19 (53%) had residual disease in the uterus. Of 27 patients with negative cone margins, 21 had hysterectomies, and seven of the 21 (33%) had residual disease in the uterus. Two women with negative margins who did not have hysterectomies developed recurrent disease. Fifty-five of the total series of 61 patients followed-up for a median of 57 months (range 17-132) had no evidence of disease at last follow-up. CONCLUSION: Women with adenocarcinoma in situ of the cervix often have residual disease in the uterus, regardless of whether the margins on cone biopsy are positive or negative. PMID- 8684769 TI - 2500 Outpatient diagnostic hysteroscopies. AB - OBJECTIVE: To evaluate the feasibility and acceptability of outpatient diagnostic hysteroscopy. METHODS: The outcome of 2500 consecutive outpatient hysteroscopies was analyzed. Cervical dilation was performed when necessary and local anesthesia was not administered routinely. Endometrial biopsy and minor hysteroscopic procedures were carried out when indicated. Findings and outcome were compared according to patient characteristics. RESULTS: The most common indication for hysteroscopy was abnormal uterine bleeding (87%). Hysteroscopy was performed successfully in 96.4%, and a complete view of the uterine cavity was obtained in 88.9%. Local anesthesia was used in 29.8% and was associated with the need for cervical dilation; both local anesthetic use and cervical dilation were significantly more often required in nulligravid, nulliparous, and postmenopausal women. Intrauterine pathology was diagnosed in 48%, the highest incidence being found in those 50-60 years old (53.7%). The presence of fibroids was the most common abnormality (24.3%) but was seen in only 6.8% of women older than 60 years. Conversely, the incidence of endometrial polyps increased with age, up to 20.5% in women over 60 years. Endometrial biopsy was performed in 68% and produced adequate tissue for histologic examination in 83.7%. Endometrial hyperplasia or carcinoma was detected in 1%. One hundred sixteen women (4.6%) underwent a minor hysteroscopic procedure. CONCLUSION: Outpatient diagnostic hysteroscopy is both feasible and acceptable in the overwhelming majority of cases, with a high detection rate for intrauterine pathology. This procedure may become as routine in the 21st century as D&C has been in the 20th. PMID- 8684770 TI - Effect of age on intrauterine insemination with frozen donor sperm. AB - OBJECTIVE: To assess the effect of variables that influence the pregnancy outcome of intrauterine insemination with frozen donor sperm. METHODS: A retrospective analysis of 408 cycles of frozen donor sperm inseminations were studied. Cycle fecundity and cumulative probability of pregnancy were compared according to several variables. RESULTS: The pregnancy rate was 13.5% per treatment cycle and 57.3% per patient. By life-table analysis, the cumulative probability of pregnancy was 75.6% after 12 cycle attempts, but there was a plateau after seven cycles. The cycle fecundity after the seventh cycle was 0.05, compared with 0.16 during the first seven cycles. Age had a profound impact on cycle fecundity. The cycle fecundity for women age 35 or less, 35-40, and over 40 years old were 0.2, 0.12, and 0.06, respectively. The cumulative probability of pregnancy after seven cycles for women 35 years or younger was 88%, compared with 65 and 42% in women 35-40 and over 40 years old, respectively. The number of motile sperm inseminated for pregnant cycles was higher than that for nonpregnant cycles. The fecundity rates for cycles with five or fewer, five to ten, greater than ten to 20, and over 20 million motile sperm inseminated were 5, 11, 16, and 20%, respectively. CONCLUSION: The most significant predictors of the fertility of intrauterine insemination with frozen donor sperm were the women's age and the total number of motile sperm inseminated. Fecundity dropped after seven cycles of treatment. PMID- 8684771 TI - Hysterectomy in Danish women: weight-related factors, psychologic factors, and life-style variables. AB - OBJECTIVE: To assess weight-related risk factors, psychologic factors, and life styles of importance for hysterectomy performed for benign conditions. METHODS: In a prevalence study, 2301 Danish women aged 30, 40, 50, or 60 years were selected at random in 1982, and self-report questionnaires were collected from 77%. Information about weight and dieting history, life-style, psychologic factors, gynecologic history, and social background were recorded. Weight, height, and plasma lipids were measured. In an incidence study, the cohort was followed during 1982-1990 via central registers to assess the incidence of hysterectomy. Logistic and Cox regression were used to analyze the data. RESULTS: In the prevalence study, weight cycling (recurrent weight loss and weight gain of more than 5 kg) was associated with hysterectomy for benign disease (odds ratio 1.77, 95% confidence interval [CI]1.05-2.99) by multivariate analysis independent of overweight, smoking, psychologic factors, social factors, and gynecologic characteristics. In the incidence study, all the weight-related factors except slimming diets were significant risk factors for hysterectomy performed recently for benign disease in women under age 50. In the multivariate analysis, weight cycling was the only significant weight-related factor (relative risk 2.49, 95% CI 1.10-5.60), explaining the relation between hysterectomy and psychologic factors. Coffee, tea, alcohol, smoking, and plasma lipids were not related to hysterectomy in either study. CONCLUSION: Weight cycling might be an important risk factor for premenopausal hysterectomy performed for benign conditions. Whether weight cycling causes menstrual irregularities and leiomyomas, these results give us a better understanding of the pathways to hysterectomy. PMID- 8684772 TI - Fuel metabolism in pregnancy and in gestational diabetes mellitus. AB - Fuel metabolism during pregnancy and in gestational diabetes mellitus (GDM) is reviewed with emphasis on carbohydrate and fat metabolism. In early pregnancy, insulin secretion in response to glucose is increased, peripheral insulin sensitivity is normal or increased, glucose tolerance is normal or slightly enhanced. In addition, there is maternal fat accumulation. During late pregnancy, there is increased fetal growth and increased fetal demand for nutrients. Maternal responses to these demands consist of an accelerated switch from carbohydrate to fat utilization that is facilitated by peripheral insulin resistance and by high blood levels of lipolytic hormones. In patients with GDM, insulin resistance is either comparable or greater than in nondiabetic pregnancy whereas insulin secretion appears to be compromised. Important short term consequences of GDM are perinatal complications, whereas long term complications include an increased rate of development of maternal non-insulin-dependent diabetes mellitus. PMID- 8684773 TI - Fetal surveillance and timing of delivery in pregnancy complicated by diabetes mellitus. AB - Protocols for antepartum fetal assessment in pregnancies complicated by diabetes mellitus are an important part of a care program that allows most of these pregnancies to reach term, ensuring fetal maturation. Maternal assessment of fetal activity serves as an efficient screening test in most surveillance programs. These programs have used primarily biophysical testing consisting of the nonstress test, cardiac stress test, or biophysical profile. Doppler studies have been investigated as an adjunct for identifying fetal compromise. These studies may prove most valuable in cases of maternal vascular disease. The success of these protocols continues to be predicated on careful regulation of maternal glycemia through aggressive therapy with insulin and diet. Reassuring tests of fetal condition are present in most diabetic women and, therefore, permit fetal maturation to occur prior to delivery. PMID- 8684774 TI - Prenatal diagnosis and prevention of diabetic embryopathy. AB - This article emphasizes the need for early biochemical and sonographic evaluation of pregnancies complicated by diabetes mellitus. Methods available for the prenatal diagnosis and prevention of diabetes-associated malformations are described. PMID- 8684775 TI - Screening and testing for gestational diabetes mellitus. AB - Gestational diabetes mellitus is defined as carbohydrate intolerance of variable severity first diagnosed during pregnancy. Although universal screening for gestational diabetes mellitus is practiced by more than 75% of obstetricians in the United States, agreement is lacking worldwide regarding the appropriateness of this approach. This article discusses the assumption that some type of screening program is desirable and considers how best to conduct screening and diagnostic testing for gestational diabetes mellitus. PMID- 8684776 TI - Management of gestational diabetes mellitus. AB - This article addresses management of gestational diabetes in a two part fashion. It discusses the pathophysiology and pathogenesis of diabetes and outlines the contemporary management approach for gestational diabetes in the 1990s. PMID- 8684777 TI - Diabetic retinopathy in pregnancy. AB - Diabetic retinopathy is the most common chronic complication associated with diabetes mellitus. It affects 20% to 30% of diabetic women in the reproductive age group. This article reviews the course and treatment of pregnancy complicated by diabetic retinopathy. PMID- 8684778 TI - Diabetic nephropathy and pregnancy. AB - Knowledge of the pathogenic mechanisms of diabetic nephropathy (by which hyperglycemia, hyperfiltration, and hypertension cause the gradual development of microproteinuria, mesangial expansion, and eventual glomerular closure) provides the basis for effective treatment. Intensified glycemic control and antihypertensive therapy that is safe for the fetus are crucial for success during pregnancy. Considered outcome measures include perinatal survival, size at birth, child development, and long-term maternal renal function. PMID- 8684779 TI - Management of diabetic pregnancy complicated by coronary artery disease and neuropathy. AB - Various manifestations of diabetic neuropathy may complicate pregnancies of young diabetic patients. Of all forms of diabetic neuropathy, autonomic neuropathy, and, in particular, gastropathy, may cause the most devastating complications. Because neuropathy is a common abnormality in young asymptomatic diabetic women, screening for this disorder may be advisable and can be accomplished by relatively simple and noninvasive tests. Screening is best performed before conception or early in pregnancy, because pregnancy itself and its possible complications later modify the autonomic nervous function tests and make testing unreliable. Practitioners and obstetricians who provide care and counseling to young diabetic patients should be familiar with the risks and consequences to maternal and fetal health that may be imposed by the different forms of neuropathy. Moderate-to-severe autonomic dysfunction may be considered a relative contraindication to pregnancy, especially if gastropathy is part of the clinical presentation. The management dilemmas and high mortality and morbidity associated with symptomatic diabetic neuropathy may justify the addition of a new independent class, class N (neuropathy), to the current classification systems for diabetes in pregnancy. PMID- 8684780 TI - The infant of the diabetic mother. AB - The history of the medical success in treatment of the pregnant diabetic woman and her infant in the twentieth century illustrates how the combined efforts of dedicated clinicians and researchers have resulted in dramatic improvements in outcome for this patient group. This article discusses fetal growth, metabolic complications of the infant of the diabetic mother, risk of respiratory distress syndrome, hypertrophic cardiomyopathy, and congenital anomalies. PMID- 8684781 TI - Contraception in diabetic women. AB - Contraceptive prescription in diabetic women with current diabetic mellitus (type I or type II) or in prediabetic women with previous gestational diabetes mellitus must consider the specific metabolic effects and risks in diabetic women. This article addresses these issues, enabling the practitioner to develop individually tailored contraceptive programs to meet the changing needs and demands of the reproductive-aged diabetic woman. If focuses on the most efficacious, reversible option available--hormonal methods and intrauterine devices--both of which have been controversial for diabetic women. PMID- 8684782 TI - Fuel metabolism in deviant fetal growth in offspring of diabetic women. AB - Fetal growth and development from its very first stages of intrauterine life is significantly influenced by the metabolic environment in which the conceptus develops. Maternal disease states such as gestational diabetes and hypertensive pregnancy, representing maternal conditions involved in extremes of impaired fetal growth (macrosomia versus growth restriction), can serve as excellent examples of the various factors that are involved in intrauterine growth. PMID- 8684783 TI - The pathogenesis of diabetes-associated congenital malformations. AB - Congenital malformations convey a major financial and social burden to society. Epidemiologic, clinical, and animal studies indicate that these malformations occur in early pregnancy, are influenced by an aberrant metabolic fuel milieu, and seem to result from a combination of more than one factor acting synchronously. Unfortunately, during the critical period of organogenesis, the pregnancy is hardly recognizable, making evaluation and study of relevant maternal embryonic parameters extremely difficult. Additionally, there are obvious limitations to human study for technical and ethical reasons. Animal experimentation, however, has demonstrated that these malformations can be produced in many vertebrates and are similar to those seen in humans. The mechanism for induction of dysmorphogenesis in experimental diabetic pregnancy has been shown to include generation of free oxygen radicals and are associated with alterations in the embryonic levels of arachidonic acid, prostaglandins, and myo-inositol. Most of the earlier experimental studies focused on defects at the level of the embryo excluding the extraembryonic membranes. Current investigations provide evidence that the yolk sac has an integral role in diabetic embryopathy. The experimental use of several different compounds, such as arachidonic acid, myo-inositol, and antioxidants, offers significant promise for the future in possibly serving as a pharmacologic prophylaxis against diabetic embryopathy. PMID- 8684784 TI - Glucose monitoring and insulin therapy during pregnancy. AB - Excellent blood glucose control is necessary to reduce the excess fetal morbidity and mortality associated with the diabetic pregnancy. This article outlines the roles of glucose monitoring and insulin therapy in intensive treatment regimens during gestation. The discussion includes recommended monitoring frequency, glycemic standards, types of insulin and mechanism of action, goals and timing of insulin therapy, as well as the complications of insulin therapy. PMID- 8684785 TI - Exercise and the nutritional management of diabetes during pregnancy. AB - Although exercise is widely accepted as an important component in programs of maintaining a healthy lifestyle, the question of safety and utility of an exercise program for pregnant diabetic women is still controversial. Pregnant women who have diabetes want some direction as to what their possibilities are regarding exercise programs, as there is accumulating evidence that exercise during pregnancy has some advantages for them. In addition, there is now a consensus of thought that the ideal nutritional therapy for the gestational diabetic woman is a diet that facilitates normoglycemia. This article outlines a program that not only improves metabolic control through dietary principles and exercise prescriptions to achieve and maintain normoglycemia, but also will be safe for the mother and her baby, is enjoyable, and also has physical benefits for the mother. PMID- 8684786 TI - Management of hypoglycemia and diabetic ketoacidosis in pregnancy. AB - The article discusses the incidence and management of hypoglycemia and diabetic ketoacidosis (DKA) in pregnancy. Additional topics addressed are the incidence of hypoglycemia, pathophysiology, diagnosis and management of hypoglycemia in pregnancy, fetal monitoring with short- and long-term fetal sequelae, and prevention of hypoglycemic recurrences. Subsequently, attention is focused on the diagnosis and management of hyperglycemia and DKA in pregnancy. PMID- 8684787 TI - The effects of multiple doses of ivermectin on ocular onchocerciasis. A six-year follow-up. AB - BACKGROUND: Ivermectin has been shown to be a safe treatment for onchocerciasis and is now being distributed through mass treatment programs. Previous studies of up to 3 years of treatment have demonstrated that ivermectin improves anterior segment lesions and reduces the incidence of optic atrophy. The benefit of multiple doses of ivermectin on visual acuity and chorioretinitis has yet to be shown. METHODS: A community-based, double-blind, randomized, controlled trial of ivermectin was started in Bo, Sierra Leone, in 1987. Two cohorts are reported in this study: (1) 214 subjects had received four 6-month doses of ivermectin followed by up to six additional 6-month treatments. The second cohort, with 185 subjects, had received four 6-month doses of placebo followed by up to four annual doses of ivermectin. All subjects received a full ophthalmic examination in 1989 and again in 1994. For both cohorts, there was an 18-month gap between the fifth and sixth rounds of treatment. RESULTS: There was no significant difference in the prevalences of any ocular lesion nor of visual acuity categories between the cohorts at the second examination. Comparisons of the prevalences of anterior segment lesions for both cohorts combined between the first and second examinations show highly significant improvement (P < 0.001) for all lesions. Posterior segment lesions show a more variable pattern, with chorioretinitis showing highly significant deterioration (P < 0.001) and the emergence of new lesions in both groups. CONCLUSION: The authors conclude that annual treatment with ivermectin is effective in controlling ocular onchocerciasis apart from chorioretinal lesions and that a 6-month treatment gives no additional benefit. PMID- 8684788 TI - Glaucoma care and conformance with preferred practice patterns. Examination of the private, community-based ophthalmologist. AB - BACKGROUND: Practice guidelines are becoming more prominent in the provision of medical care. A previous study demonstrated a high rate of conformance with recommended patterns of care for patients with open-angle glaucoma in an academic, public clinic setting. This study seeks to examine conformance within the private, community-based setting in which the vast majority of healthcare is delivered. METHODS: One-hundred ninety-three charts (average, 24 charts each from 8 different practices) of patients who received diagnoses for at least 2 years of open-angle glaucoma were evaluated retrospectively for conformance with recommendations from the American Academy of Ophthalmology's Preferred Practice Pattern (PPP) for primary open-angle glaucoma. The criteria were evaluated in three areas: (1) the performance of specified examination steps at the initial visit; (2) the performance of specified examination steps at follow-up; and (3) the time interval between follow-up visits. RESULTS: In 56.4% of patients who had stable moderate to severe glaucomatous damage, documentation of examination findings on the initial visit ranged from 39.4% for a pupil examination to 100% for intraocular pressure. At the initial visit, visual fields were obtained or scheduled in 90.2% of eyes, gonioscopy was performed in 51.3%, and the disc/nerve fiber layer status was noted in 97.9%. On follow-up, 44% of patients had documentation concerning the status of their glaucoma, but only 23.3% of patients had an optic nerve head drawing or photograph within 15 months of the most recent visit. In addition, the authors found that 37.8% of patient charts had neither an optic nerve head drawing nor a photograph documented after the initial visit. Finally, although 92.2% of patients with glaucoma were scheduled for follow-up within the time intervals recommended by the PPP, patients with uncontrolled or unstable glaucoma were the least likely to be followed up within PPP-recommended time intervals. CONCLUSIONS: Chart reviews from private, community-based ophthalmologists show that some initial examination steps such as gonioscopy and pupil examination are performed to widely varying degrees. While patients are generally likely to be scheduled for follow-up within PPP-recommended intervals, patients with unstable glaucoma are the least likely to be so scheduled. In addition, the visual appearance of the optic nerve is recorded for a relatively low percentage of patients. Additional data are needed from other geographic areas and other practice settings and for other patterns of care to more fully assess provider behavior relative to PPPs. PMID- 8684789 TI - Optic disc hemorrhages and progression of glaucoma. AB - PURPOSE: To assess progressive changes of the optic nerve head and visual fields in patients with glaucoma and ocular hypertension after optic disc hemorrhage. METHODS: The authors reviewed the charts of 91 patients with 121 disc hemorrhages who had a mean follow-up of 41.9 +/- 3.6 months. The frequency of visual field and optic nerve head changes in these patients was studied. RESULTS: The mean intraocular pressure at the examination when the disc hemorrhage was noted was 18.9 +/- 0.5 mmHg. Overall, 64 (63%) of 101 eyes showed progressive changes of visual fields after disc hemorrhage, compared with 24 (24%) of 101 control eyes (P < 0.0005). Similarly, 56 (79%) of 71 eyes showed progressive changes of optic nerve head contour by masked evaluation of stereophotographs, compared with 16 (22%) of 71 control eyes (P < 0.0005). Eyes with disc hemorrhage showed significantly greater progression of visual field defects in patients with open angle glaucoma (P < 0.001), low-tension glaucoma (P < 0.05), and ocular hypertension (P = 0.0067) compared with control eyes matched by age, follow-up time, and diagnosis. Similarly, progressive changes of optic nerve head contour were observed more often in eyes after disc hemorrhage in patients with open angle glaucoma (P < 0.0005), low-tension glaucoma (P < 0.025), and ocular hypertension (P < 0.005), compared with controls. The mean time interval to progression after disc hemorrhage was observed was 16.8 +/- 2.0 months for visual field changes and 23.8 +/- 2.9 months for optic nerve head changes. In eyes with disc hemorrhage, 27 (22%) of 121 had recurrent hemorrhages at a mean interval of 21.5 +/- 2.9 months after previous hemorrhage. The most common site of disc hemorrhage was the inferotemporal quadrant. Eyes with disc hemorrhage that occurred on the temporal side of the optic nerve head had a significantly lower intraocular pressure (P < 0.02) and greater progressive changes of the optic discs (P < 0.001) compared with eyes with hemorrhage on the nasal side. CONCLUSION: The authors' results indicate that disc hemorrhages in eyes with glaucoma or ocular hypertension often are associated with progressive changes of the optic nerve head and visual fields. PMID- 8684790 TI - Combined cataract extraction with intraocular lens implant and mitomycin augmented trabeculectomy. AB - PURPOSE: Cataract and glaucoma commonly coexist in elderly patients and present complex treatment options. This study investigates the results of simultaneous treatment of both conditions using phacoemulsification with posterior chamber lens implant and mitomycin-augmented trabeculectomy (combined surgery). METHODS: A retrospective analysis was performed of 56 consecutive patients who had undergone combined surgery. Fifty-one (91%) of 56 patients had fornix-based conjunctival flaps resutured at the limbus. A variety of postoperative interventional techniques (mechanical and pharmacologic) were used to encourage the achievement of successful filtering blebs. RESULTS: All patients had follow up of at least 12 months. The mean preoperative intraocular pressure (IOP) was 20.2 mmHg (range, 14-43 mmHg) and the mean postoperative IOP was 10.7 mmHg (range, 4-17 mmHg). Fifty-three (95%) of 56 patients had IOPs of 15 mmHg or less at the completion of follow-up. All except two patients (96%) were able to discontinue all glaucoma medications. The filtering blebs that resulted from the fornix-based conjunctival flap procedures were predominantly large, diffuse, and noncystic. Best-corrected visual acuity was 20/40 or better in 47 (84%) of 56 of patients. CONCLUSION: Control of IOP and improvement of visual acuity can be achieved in a high percentage of patients with coexisting cataract and glaucoma by performing combined surgery using intraoperative mitomycin and fornix-based conjunctival flaps resutured to the limbus. The filtering blebs illustrated a distinctive morphology compared with blebs resulting from limbus-based conjunctival flap procedures. PMID- 8684791 TI - Probable exclusion of GLC1A as a candidate glaucoma gene in a family with middle age-onset primary open-angle glaucoma. AB - PURPOSE: To determine whether an adult-onset variety of primary open-angle glaucoma in family UM:POAG1 is linked to the previously mapped GLC1A juvenile onset primary open-angle glaucoma locus on chromosome 1q or whether linkage can be excluded. METHODS: Microsatellite repeat markers from the 9 cM D1S196 to D1S218 interval containing the GLC1A gene were amplified by polymerase chain reaction from DNA samples collected from 11 members of one sibship in family UM:POAG1. Haplotype analysis was carried out, including calculation of the probability that the observed data would have been obtained if the underlying cause of primary open-angle glaucoma in this family were a defect in a gene located in the tested interval. Linkage analysis was carried out under an autosomal dominant model for GLC1A glaucoma. RESULTS: In family UM:POAG1, primary open-angle glaucoma was diagnosed in six surviving and one deceased member of a sibship of 13 individuals during the fifth or sixth decade of life. Glaucoma in this family has a later average age at diagnosis and significantly less elevation in intraocular pressure than GLC1A glaucoma so far described. Haplotype analysis, using a population prevalence up to 0.9%, shows that it is unlikely that the reported data would have been observed if primary open-angle glaucoma in this pedigree were due to the GLC1A locus on chromosome 1q21-q31. Linkage analysis under the juvenile glaucoma autosomal dominant model allowed exclusion of linkage across the entire GLC1A genetic inclusion interval, with a maximum lod score in the interval of -3.28. CONCLUSION: The most likely interpretation of these observations is that a defect in the GLC1A glaucoma gene is not responsible for adult-onset primary open-angle glaucoma in family UM:POAG1. This suggests the existence of at least two primary open-angle glaucoma genes, the previously reported GLC1A gene on chromosome 1q and another gene located elsewhere in the genome. Diagnosis of UM:POAG1 glaucoma between 42 and 57 years of age also raises questions regarding the relation of the glaucoma present in this family to the common later-age-onset form of the disease. PMID- 8684792 TI - Ciliary body endophotocoagulation during pars plana vitrectomy in eyes with vitreoretinal disorders and concomitant uncontrolled glaucoma. AB - PURPOSE: To investigate the efficacy of ciliary body endophotocoagulation during pars plana vitrectomy in eyes with medically uncontrolled glaucoma and concomitant vitreoretinal disorders. METHODS: The authors compared preoperative and postoperative intraocular pressure (IOP) and visual acuity in 21 eyes of 21 patients undergoing ciliary body endophotocoagulation with pars plana vitrectomy. RESULTS: Preoperative IOPs ranged from 22 to 59 mmHg (median, 46 mmHg). Visual acuity ranged from 20/200 to light perception (median, hand motions). Follow-up ranged from 3 to 18 months (median, 10 months). Postoperative IOPs ranged from 11 to 19 mmHg (median, 16 mmHg) at 6 weeks, 4 to 20 mmHg (median, 14 mmHg) at 3 months, 1 to 26 mmHg (median, 12 mmHg) at 6 months, and 0 to 48 mmHg (median, 12 mmHg) at 12 months. Postoperative visual acuity was statistically improved from preoperative visual acuity by 6 weeks. CONCLUSION: Ciliary body endophotocoagulation combined with pars plana vitrectomy can effectively treat concomitant glaucoma and vitreoretinal disorders. PMID- 8684793 TI - Optical coherence tomography of macular lesions associated with optic nerve head pits. AB - PURPOSE: Although optic pits were described more than a century ago, the pathogenesis and pathologic nature of the associated macular lesions remain controversial. The authors used the technique of optical coherence tomography (OCT) to further define the anatomic relation that exists between optic pits, macular schisis-like spaces, and macular detachments. METHODS: Four eyes of three consecutive patients with optic pit-related macular pathology were evaluated. Cross-sectional OCT images were correlated with findings from slit-lamp biomicroscopy and stereo fundus photography. All eyes previously had undergone unsuccessful photocoagulation to the temporal juxtapapillary retina. One eye had undergone vitrectomy and intraocular gas tamponade, resulting in partial resorption and displacement of the submacular fluid. RESULTS: Retinal edema and cystic degeneration were present, overlying macular neurosensory detachments in all four eyes. The most prominent edema was present in the outer retina at the level of the outer plexiform layer. This mimicked a true retinoschisis cavity, although bridging retinal elements were identifiable. A lesser degree of edema was present in the inner retina, predominantly located between the disc and fovea. In one eye, a lamellar hole was shown to be a defect in the outer neurosensory retina. In another eye, a macular detachment developed under a pre existing schisis-like cavity. The schisis-like cavity or edematous retina communicated with the optic disc in all eyes, whereas none of the eyes demonstrated a direct connection between the macular detachment and optic pit. CONCLUSION: These findings support the concept of a bilaminar structure in which a macular detachment develops secondarily to a pre-existing schisis-like lesion consisting of severe outer retinal edema. Fluid may enter from the optic pit into the retinal stroma and not directly into the subretinal space, explaining the prolonged recovery and frequency of treatment failure after photocoagulation to the juxtapapillary retina. PMID- 8684794 TI - A randomized, masked, cross-over trial of acetazolamide for cystoid macular edema in patients with uveitis. AB - PURPOSE: To study the effect of acetazolamide on cystoid macular edema in patients with uveitis. METHODS: Forty patients with chronic intermediate, posterior, or panuveitis associated cystoid macular edema were randomized into a masked, cross-over trial comparing acetazolamide versus placebo. Patients received an initial 4-week course of either acetazolamide or placebo (course A) followed by a 4-week washout period. They then received a 4-week course of the opposite study medication (course B). Primary endpoints included area of cystoid macular edema measured on late-phase views of fluorescein angiography and visual acuity. RESULTS: Thirty-seven patients completed the trial and were available for analysis; 17 (46%) were randomized to receive acetazolamide and 20 (54%) to receive placebo during course A. Acetazolamide resulted in a 0.5-disc area (25%) decrease in cystoid macular edema over that of placebo (P = 0.01; estimated treatment effect = -0.5 disc areas; 95% confidence interval, -0.9 to -0.1). However, there was no statistically significant effect of acetazolamide on visual acuity (P = 0.61; estimated treatment effect = 0.6 letters; 95% confidence interval, -2 to 3). CONCLUSIONS: A 4-week course of acetazolamide therapy results in a statistically significant but small decrease in cystoid macular edema in patients with chronic uveitis, and does not improve visual acuity. In contrast to previous studies in the literature, acetazolamide may have a more limited clinical benefit in patients with long-standing cystoid macular edema associated with chronic uveitis. PMID- 8684795 TI - Managing recurrent neovascularization after subfoveal surgery in presumed ocular histoplasmosis syndrome. AB - PURPOSE: To report the authors' experience with recurrent neovascularization after subfoveal surgery in the presumed ocular histoplasmosis syndrome (POHS). METHODS: One-hundred seventeen patients with POHS and subfoveal choroidal neovascularization were followed a median of 13 months after submacular surgery. RESULTS: Recurrent neovascularization developed in 51 eyes (44%). The median time to recurrence was 3 months (range, 0.5-28 months). Recurrence location was extrafoveal in 16%, juxtafoveal in 18%, and subfoveal in 66%. Sixteen eyes were treated with laser photocoagulation, 17 eyes underwent repeat submacular surgery, and 18 eyes were observed. The visual outcome for patients with recurrences amenable to laser was better than that for patients who were observed or who underwent surgery. CONCLUSION: Recurrent neovascularization after surgery is common; prompt recognition may allow laser photocoagulation. PMID- 8684796 TI - Visual field loss after macular hole surgery. AB - BACKGROUND: Vitrectomy has been successfully used for treating idiopathic macular holes. Although macular hole surgery has been successful and is generally regarded as a safe procedure, various complications have been reported. The authors report eight patients with symptomatic peripheral visual field loss occurring after vitrectomy for macular holes. METHODS: Over a 3-year period, vitrectomy with removal of the posterior cortical vitreous and fluid-gas exchange was performed on 50 eyes of 47 patients with idiopathic macular holes. Eight patients reported visual field loss postoperatively, and Goldmann visual fields were obtained. The clinical characteristics and outcomes of the group of patients with visual field loss were compared with the group of patients without visual field loss. RESULTS: Postoperatively, significant peripheral visual field loss was documented in eight patients. The macular holes were anatomically closed in seven eyes (87.5%) of these patients compared with 37 (88.1%) of 42 eyes in the group of patients with no symptomatic visual field loss. The visual field loss was not associated with age, sex, macular hole stage, postoperative intraocular pressure, or history of hypertension or coronary artery disease. The etiology of visual field loss was unclear in six patients. CONCLUSION: Vitrectomy for idiopathic macular holes can result in significant peripheral visual field loss. The etiology of this complication usually is unknown. PMID- 8684798 TI - Ophthalmic manifestations of Smith-Magenis syndrome. AB - PURPOSE: The Smith-Magenis syndrome (SMS) is a multiple-anomaly, mental retardation syndrome associated with deletions of a contiguous region of chromosome 17p11.2. Prior reports have described ophthalmic anomalies with SMS, including telecanthus, ptosis, strabismus, myopia, iris anomalies, cataracts, optic nerve hypoplasia, and retinal detachment. This report defines the ophthalmic spectrum in 28 individuals with SMS subjected to a multidisciplinary clinical and molecular survey. METHODS: Individuals with deletion of chromosome 17p11.2 detected by high-resolution cytogenetic analysis underwent complete ophthalmologic evaluation comprised of ophthalmic history, visual acuity, cycloplegic refraction, motility, and biomicroscopic and ophthalmoscopic examination. RESULTS: Among the 28 subjects, ranging in age from 0.8 to 29.3 years, the most frequent ocular findings were iris anomalies (68%), microcornea (50%), myopia (42%), and strabismus (32%). Bilateral microphthalmos with uveal and retinal coloboma was observed in one individual. No subject had cataract or retinal detachment. CONCLUSIONS: This is the largest single-center series of subjects with SMS that includes ophthalmic evaluation. As in prior reports, iris anomalies and strabismus were observed, but microcornea had not been noted previously. The absolute refractive error was hypermetropic in half of these subjects. Cataract, ptosis, and retinal pathology, including detachment, were not observed in any subject. All individuals with SMS should be evaluated by an ophthalmologist, with special attention to strabismus, microcornea, iris anomalies, and refractive errors. PMID- 8684797 TI - Intravitreal cidofovir for the maintenance treatment of cytomegalovirus retinitis. AB - PURPOSE: To evaluate the efficacy and safety of multiple intravitreal cidofovir (HPMPC) injections given every 5 to 6 weeks for the maintenance treatment of cytomegalovirus (CMV) retinitis. METHODS: A prospective consecutive case series of 53 eyes in 35 patients with acquired immune deficiency syndrome and CMV retinitis was treated with maintenance intravitreal injections of cidofovir (20 micrograms) at one referral center between April 1994 and September 1995. Twenty four eyes received intravitreal cidofovir as their initial treatment for CMV retinitis (group A), and 29 eyes previously had received systemic therapy (group B). None of the patients in either group received systemic anti-CMV therapy at any time during the study period. Progression of retinitis was the primary end point. RESULTS: All eyes with active retinitis healed in response to treatment. None of the 24 eyes in group A demonstrated any progression during the study period. Four (14%) of the 29 eyes in group B had one episode each of retinitis progression (mean follow-up, 15 weeks; range, 0-58 weeks). In 1 (1.9%) of the 53 eyes, a retinal detachment developed. A mild iritis was observed after 14% of injections, which were prophylaxed with oral probenecid. Irreversible visually significant hypotony developed in two eyes (3.8%). CONCLUSION: Treatment and subsequent maintenance therapy of CMV retinitis with 20 micrograms intravitreally injected cidofovir, given at 5- to 6-week intervals, is highly effective, with only rare episodes of re-activation and progression. PMID- 8684799 TI - Anterior proliferative vitreoretinopathy in the silicone study. Silicone Study Report Number 10. AB - BACKGROUND: As part of the design of the Silicone Study, a new classification of proliferative vitreoretinopathy (PVR) was developed that distinguishes the different types of contraction found in PVR. In contrast to the original Retina Society system that emphasized the post-equatorial retinal pathology (posterior PVR), the Silicone Study classification system included the characteristic types of contraction found in both the equatorial region and the pre-equatorial retina and vitreous base (anterior PVR). METHODS: The authors contrast (1) preoperative and intraoperative findings and (2) vision and anatomic outcomes in the cohort of anterior PVR eyes with the cohort of posterior-only PVR eyes. For the cohort of eyes randomized to perfluoropropane gas (C3F8) or silicone oil, the authors carry out univariate and multivariate analyses to assess the predictive value of baseline and intraoperative parameters on vision and anatomic outcome. RESULTS: Anterior PVR was present in 321 eyes (79%) and was more prevalent in eyes that had undergone an unsuccessful vitrectomy before study entry than in eyes that underwent a primary vitrectomy for PVR (88% versus 73%; P < 0.001). Compared with eyes that had posterior PVR at the preoperative examination, eyes that had anterior PVR tended to (1) be graded (Retina Society classification system) as D 1 or worse (86% versus 49%; P < 0.0001), (2) have worse (< 2/200) visual acuity (93% versus 86%; P = 0.003), (3) have more hypotony (24% versus 11%; P = 0.03), more edema (8% versus 2%; P = 0.04), more aqueous flare (P = 0.02), more macular pucker (69% versus 52%; P = 0.005), and more intravitreal contraction (21% versus 6%; P = 0.002). When compared with eyes that had anterior PVR, eyes with posterior PVR had a better outcome at the 6-month postoperative examination: complete attachment of the retina (76% versus 62%; P = 0.04), visual acuity of 5/200 or better (64% versus 45%; P = 0.006), and normal intraocular pressure (86% versus 71%; P = 0.04). For eyes with anterior PVR, significant predictors of poor (< 5/200) visual acuity were a preoperative PVR grade D-1 or worse and the use of C3F8 gas as the intraocular tamponade. CONCLUSION: The Silicone Study classification of anterior PVR permits greater specificity in characterizing PVR and is prognostic of anatomic and vision outcome. Eyes with anterior PVR and clinically significant posterior PVR changes had a better visual prognosis if silicone oil was used. With the current understanding of the pathoanatomy of anterior PVR and the recent development of new surgical techniques, the incidence of anterior PVR in eyes that previously underwent vitrectomy may decline, and the prognosis in eyes with anterior PVR may improve. PMID- 8684800 TI - Visual prognosis of multifocal choroiditis, punctate inner choroidopathy, and the diffuse subretinal fibrosis syndrome. AB - PURPOSE: To characterize the visual prognosis of patients with multifocal choroiditis and panuveitis (MCP), punctate inner choroidopathy (PIC), and the diffuse subretinal fibrosis (DSF) syndrome. METHODS: Forty-one patients with MCP, 16 with PIC, and 5 with DSF syndrome were evaluated. The mean follow-up was approximately 39 months for patients with MCP, 51 months for patients with PIC, and 59 months for patients with DSF syndrome. Complete ophthalmic examinations were performed, and photofiles were reviewed. RESULTS: The final average visual acuity for patients with MCP was 20/50. Forty-five of the 68 involved eyes (66%) had 20/40 visual acuity or better. Choroidal neovascularization (CNV) developed within choroiditis lesions in 22 (19 patients) of 68 eyes, causing visual acuity poorer than 20/50 in 14 eyes. The final average visual acuity in patients with PIC was 20/39; 23 (77%) of the 30 involved eyes had visual acuity of 20/40 or better. Six of the seven eyes with 20/50 or poorer vision had CNV. Six other eyes had CNV within the macula that regressed spontaneously with good resultant vision. Seven of the ten involved eyes with DSF syndrome had 20/200 or poorer vision. Poor vision was due to fibrosis and atrophy within the macula. CONCLUSION: Most patients with MCP and PIC retained visual acuity of 20/40 or better. In nearly one third of patients with MCP and PIC, CNV developed. Severe visual loss in these diseases was usually due to subfoveal CNV. Patients with DSF syndrome had a poor prognosis due to fibrosis and atrophy involving the macula. PMID- 8684801 TI - Lattice corneal dystrophy type II associated with familial amyloid polyneuropathy type IV. AB - BACKGROUND: Finnish-type familial amyloidosis (FAP-IV) is an autosomal, dominantly inherited disorder characterized by progressive polyneuropathy and lattice corneal dystrophy type II. The vast majority of families with this disorder originated from Finland. Only two families, in neighboring districts, have been reported in Japan previously. METHODS: The authors report two additional Japanese patients with FAF-IV. The proband, a 70-year-old man, had decreased perspiration and abnormal facial muscle movement. Results of neurologic examination showed bilateral facial and hypoglossal nerve palsies, and an autonomic disturbance, including orthostatic hypotension and dysfunction of perspiration. Histochemical, immunohistological, and DNA studies confirmed the diagnosis of FAP-IV. RESULTS: Results of ophthalmologic examination showed asymptomatic lattice corneal dystrophy of both eyes, but the appearance of the cornea was different from that described in the patients from Finland. Lattice lines in the authors' patient were very fine, short, and glassy and could be observed with indirect retroillumination, but might be missed with direct illumination by the slit-lamp microscope. The proband's younger half-sister, a 68 year-old woman, showed clinical findings and laboratory data similar to those of the proband. CONCLUSION: The authors report two Japanese patients with lattice corneal dystrophy type II related to FAP-IV. This is the third Japanese family with this disorder, and there is no familial relationship to the two previously reported families in Japan. PMID- 8684803 TI - Achieving emmetropia in extremely short eyes with two piggyback posterior chamber intraocular lenses. AB - PURPOSE: To examine the refractive results and limitations of current intraocular lens power formulas when implanting two posterior chamber lenses in-the-bag to achieve emmetropia in extremely short eyes. METHODS: Preoperative measurements (corneal diameter, axial length, keratometry, anterior chamber depth, and lens thickness) and postoperative measurements (refraction, corneal vertex to iris depth, and iris to front anterior lens surface) were taken in six eyes from three patients, with axial lengths ranging from 15.09 to 19.95 mm. These data were used to calculate the prediction error for three current third-generation formulas (Holladay, Hoffer Q, SRK/T) and two older formulas (SRK2 and SRK1). RESULTS: None of the formulas accurately predicted the refractions using the optimized lens constants for normal eyes. The third-generation formulas were not different (P > or = 0.602) and averaged 5 diopters (D) of absolute error (Hoffer Q = 4.64 +/- 1.57 D; Holladay = 5.07 +/- 1.28 D; SRK/T = 5.12 +/- 1.43 D). The older formulas were significantly worse (P = 0.0006), with average mean absolute errors of 10.93 +/- 5.09 D for the SRK2 and 13.33 +/- 5.09 D for the SRK1. When the formulas were optimized for these six eyes, the mean absolute errors were Holladay = 1.33 +/- 1.25 D; SRK/T = 2.10 +/- 1.31 D; Hoffer Q = 4.54 +/- 2.00 D; SRK2 = 4.71 +/- 1.94 D; and SRK1 = 4.71 +/- 1.94 D. The Holladay and SRK/T formulas were statistically better (P = 0.0068) than the Hoffer Q and the two older formulas. CONCLUSION: Current third-generation formulas are better than older formulas for extremely short eyes, but still are not acceptable for the desired clinical accuracy. Newer formulas that will use additional anterior segment measurements (corneal diameter, anterior chamber depth, and lens thickness) will be required for improved accuracy, because the anterior segment often is not proportional to the axial length. PMID- 8684802 TI - Macular corneal dystrophy in Iceland. A clinical, genealogic, and immunohistochemical study of 28 patients. AB - BACKGROUND: The frequency of different types of macular corneal dystrophy (MCD) was determined in Iceland where MCD accounts for one third of every penetrating keratoplasty. METHODS: The authors determined the serum levels of antigenic keratan sulfate (aKS) in 27 patients with MCD and 53 unaffected family members by an enzyme-linked immunosorbent assay that uses an anti-KS monoclonal antibody (5 D-4). The authors also stained sections from 37 corneal buttons (including 2 regrafts) from 23 patients with MCD by the avidin-biotin complex method using the same anti-KS monoclonal antibody. RESULTS: Based on the serum analyses, 22 patients had MCD type I and 5 had MCD type II. The corneas from patients without detectable KS in the serum lacked immunohistochemical reactivity to the anti-KS antibody. Every MCD cornea examined from individuals with normal serum KS levels showed KS reactivity. All 53 unaffected siblings and parents carrying the recessive gene had normal serum KS levels. CONCLUSIONS: Macular corneal dystrophy types I (78.6%) and II (21.4%) both occur in Iceland. Members of affected sibships had only one of these types, not both. Nine patients with MCD type I and four persons with MCD type II belonged to a large pedigree in which individuals have been traced as far back as the beginning of the 16th century. The linking of patients with MCD types I and II in an inbred pedigree suggests that both types may be manifestations of the same abnormal gene rather than independent entities. The serum KS levels were not helpful in detecting heterozygous MCD carriers. PMID- 8684804 TI - Scanning electron microscopic characteristics of small-incision intraocular lenses. AB - PURPOSE: To evaluate the surface characteristics of commonly used, small incision, intraocular lenses (IOLs). METHODS: Representative samples of five groups of foldable IOLs (4 silicone and 1 acrylic) underwent surface and edge finish examination using a slit lamp. The IOLs were folded using a folding block and forceps. All the IOLs then were examined using a scanning electron microscope. A one-piece polymethylmethacrylate IOL was used for comparing surface finish characteristics. The IOLs were examined for optic surface quality, edge finish, haptic, haptic/optic junction, and possible post-folding modifications. RESULTS: Slit-lamp evaluation of the surface quality of all of the silicone lenses demonstrated a smooth finish of the optic surface, edge, and haptics. Scanning electron microscopic analysis of the IOLs demonstrated adequately finished haptics or footplates and optics. Excess molding flash was seen on the edges of the some of the silicone IOLs, and no molding flash was observed on others. The acrylic IOL had a somewhat sharper optic edge. Irregular finish of the haptic/optic junctions of some of the IOLs (both silicone and acrylic) was noted. CONCLUSIONS: Currently available foldable IOLs have demonstrated adequate lens finish. However, irregularities of the haptic/optic junctions and molding flash are present on most IOLs evaluated, indicating room for improvement in the finish of foldable IOLs. Phacoemulsification with capsular bag IOL placement may decrease the clinical significance of these relatively subtle lens finish irregularities. PMID- 8684806 TI - Anisometropia and binocularity. AB - PURPOSE: To determine the effects of experimentally induced anisometropia on binocular function in healthy adults as a means of assessing the potentially detrimental effects of uncorrected anisometropia on binocular development in childhood. METHODS: Nineteen adults with normal binocularity, ranging in age from 26 to 59 years, were studied. Unilateral myopia, hyperopia, or astigmatism (at 90 degrees or 45 degrees) was induced in each subject using trial lenses. Sensory status then was assessed by measuring stereoacuity, Worth four-dot fusion, and Bagolini lens response. RESULTS: All subjects showed a decline in binocular function with increasing levels of anisometropia. Foveal suppression was evident on the Worth four-dot test, and increased in proportion to the anisometropia. Stereoacuity was similarly degraded by the induced anisometropia, with some subjects showing significant loss of stereoacuity with as little as 1 diopter of spherical anisometropia. Bagolini lens responses were binocular in almost all patients, although occasional abnormalities were found. CONCLUSIONS: Relatively low degrees of anisometropia may cause significant abnormalities in high-grade binocular visual functions in adults. The potential effects of uncorrected anisometropia on binocularity in children require further investigation, but should be considered in developing guidelines for the empiric correction of refractive errors. PMID- 8684805 TI - Refractive outcome and corneal topographic studies after photorefractive keratectomy with different-sized ablation zones. AB - BACKGROUND: Discrepancies may still occur between planned and actual refractive correction in eyes undergoing photorefractive keratectomy (PRK). The authors have evaluated the use of an enlarged ablation zone. METHOD: A computerized corneal analysis system has been used to compare the changes of the anterior surface of the cornea and the refractive changes before and 1, 6, and 12 months after PRK in 113 patients (119 eyes) treated with an excimer laser. The patients were divided into two groups: those treated with a mask with a 5-mm window (59 eyes), and those with a new mask with different window openings according to the degree of refraction at the corneal apex, starting from 5 mm in diameter for treatments less than 6.5 diopters (D) and from 7 mm in diameter for higher treatments (60 eyes). In the first group, treatment ranged from -2.5 to -16 D (mean +/- standard deviation. -8.5 +/- 3.24 D); in the second group, it ranged from -1 to -14 D ( 7.8 +/- 3.06 D). Treatments were evaluated with a chi-square test. RESULTS: In the first group of eyes, 46% were within +/-1 D at 1 month, 37% at 6 months, and 39% at 12 months. In the second group of eyes, 73% were within +/-1 D at 1 month, 60% at 6 months, and 58% at 12 months. The comparison between these data and corneal topographic changes shows that both are more stable and predictable with the new mask compared with the 5-mm mask (P = 0.002, 0.02, 0.04, at 1, 6, and 12 months, respectively). CONCLUSIONS: The use of larger ablation zones improves the predictability and stability of refractive changes. PMID- 8684807 TI - Automated perimetry. American Academy of Ophthalmology. AB - Automated perimetry is one product of the computer revolution that has had a dramatic impact on the practice of ophthalmology, affecting the quality of both the perimetric test (perimetric technique) and the interpretation of the test results. Before automation, the quality of visual field technique in many practices was poor, partly because perimetrists lacked the volume of patients requiring the test to provide training sufficient to maintain a high level of experience and expertise. At first, automated perimetry was developed simply to make available to all practitioners visual field testing that was nearly as good as the most skilled manual perimetry. The data provided by first-generation automated perimeters lacked the accuracy, sensitivity, and reproducibility obtainable from a highly skilled manual perimetrist. As automated perimeters evolved, perimetric techniques and the software that analyzes data for clinical significance were improved. The use of automated perimetry to evaluate routinely various visual disorders that require testing of the visual field has increased significantly. Statistical analysis of the test results aids interpretation, both to determine if the field is abnormal and if there is change in the field from one occasion to another, especially in the context of glaucoma. The test is excellent; it is now standardized, with better test algorithms, and in many cases it achieves better results than the best manual perimetrist. However, attention to detail and skill in administering the automated test are still essential. The future will hold further improvements. Nevertheless, as each manufacturer enhances computerized perimetry, it may become more difficult to compare the test results among instruments or even between two test algorithms on the same instrument. In addition, clinical knowledge and experience will still be necessary to reach accurate diagnostic conclusions. PMID- 8684808 TI - White paper on cataract surgery. American Academy of Ophthalmology and American Society of Cataract and Refractive Surgery. PMID- 8684810 TI - Standardized measurements of visual acuity for clinical research. PMID- 8684809 TI - CDI of ophthalmic artery blood flow in patients with TIAs. PMID- 8684811 TI - Hypertropia and the posterior blowout fracture. PMID- 8684812 TI - Ocular injuries in battered women. PMID- 8684813 TI - New developments in the treatment of CMV retinitis. PMID- 8684814 TI - [Results of a study on structural quality]. PMID- 8684815 TI - [Implementation of nursing standard with quality assurance on the ward]. PMID- 8684816 TI - [Problems in the determination of patient satisfaction concerning their care]. PMID- 8684818 TI - [Personalized care at the rehabilitation center "Weisser Hof"]. PMID- 8684817 TI - [Quality development in the care of the elderly]. PMID- 8684819 TI - [Nursing visits as an instrument for quality assurance]. PMID- 8684820 TI - [Counseling of nursing personnel integrated with the nursing service]. PMID- 8684821 TI - [Quality management in hospital hygiene]. PMID- 8684822 TI - [Does quality improvement work in health and nursing?]. PMID- 8684823 TI - [Nursing documentation: a condition for quality improvement in the care of the well and the sick]. PMID- 8684824 TI - Annual meeting of the American Academy of Otolaryngology Head and Neck Surgery Foundation, Inc. Washington, D.C., September 29-October 2, 1996. Instructional course program. PMID- 8684825 TI - Reversal of hypoglycaemia in murine malaria by drugs that inhibit insulin secretion. AB - We have investigated the metabolic disturbances in 2 murine models of blood-stage malaria, Plasmodium chabaudi and Plasmodium yoelii. Blood glucose, plasma insulin and parasitaemia were measured in normal and infected mice before and after treatment with diazoxide, adrenaline, Sandostatin and quinine. Severe hypoglycaemia and marked hyperinsulinaemia developed during both infections. A single injection of diazoxide (25 mg/kg i.p.) or adrenaline (0.03 mg s.c.) lowered insulin concentrations in normal mice, reversed the hypoglycaemia in both infections and significantly reduced the hyperinsulinaemia in P. chabaudi infected mice (P < 0.0001). Higher doses of Sandostatin (500 micrograms/kg s.c.) were required to reverse hypoglycaemia. Quinine (25 mg/kg i.p.) significantly increased blood glucose in normal and infected mice (P < 0.0010 and no hypoglycaemia was observed in mice with normal blood glucose for more than 3 h. This study shows that the major cause of hypoglycaemia in murine malaria is hyperinsulinaemia rather than high consumption of glucose by host and parasites or chemotherapy with quinine, and that hypoglycaemia can be reversed by correcting the hyperinsulinaemia. PMID- 8684826 TI - Eimeria tenella: infection with a single sporocyst gives a clonal population. AB - Two genetically defined parents of Eimeria tenella, each characterized by a selectable phenotype, were mated to provide "recombinant' oocysts for an analysis of the inheritance of DNA markers into the sporocyst stage of the life-cycle. A total of 23 populations was established from infection with a putative single sporocyst and their inheritance of DNA markers provided compelling evidence that the 2 sporozoites within each sporocyst are genetically identical. EAch of the 5 polymorphic DNA markers used segregated independently within the "recombinant' parasites and only 1 of the parental forms was inherited in 22 of the populations aimed to have been established from a single sporocyst. PMID- 8684827 TI - Characterization of fractionated Schistosoma mansoni soluble adult worm antigens that elicit human cell proliferation and granuloma formation in vitro. AB - Soluble adult worm antigens (SWAP) of Schistosoma mansoni were fractionated by fast protein liquid chromatography (FPLC) system, using Q-Sepharose anion exchange resin, in order to characterize antigenic fractions that may elicit cell responses in human schistosomiasis. SWAP fractions were eluted by 20 nM Tris-HCl solution (pH 9.6) with an increasing gradient of 1 M NaCl. The FPLC system was able to resolve 6 fractions, enumerated I to VI, according to the NaCl gradient. The analysis of each fraction on SDS-PAGE showed that fractions I to IV were constituted by multiple protein bands with M, ranging from 21 to > 200 kDa. Large amounts of nucleic acids were evidenced in fractions V and VI, as revealed by ethidium bromide staining of agarose electrophoresis gels. Using ELISA, it was shown that sera from chronic schistosomiasis patients contained antibodies that recognized antigens in practically all fractions. Studies were designed to investigate the capacity of these fractions to induce cell proliferation and granuloma formation. It was demonstrated that fraction III stimulated significant proliferative response of peripheral blood mononuclear cells (PBMC) from chronic schistosomiasis patients. However, fraction III coupled to polyacrylamide beads induced small granuloma formation in vitro, whereas beads coated with fractions I, II and V were able to induce significant granuloma reactions. PMID- 8684828 TI - Immunohistochemical and ultrastructural localization of Schistosoma mansoni soluble egg antigens processed by the infected host. AB - The detection of egg-derived antigens in the serum and urine of Schistosoma mansoni-infected individuals and experimental animals would provide an alternative method to assess the tissue egg burden. The detected levels are, however, not only a function of the amounts of antigen produced, but also of the processing or clearance by the host. In the present study the immunolocalization pattern of antigens using 2 recently described monoclonal antibodies to repetitive carbohydrate epitopes of S. mansoni soluble egg antigen (114-5B1-A and 114-4D12-A) in various organs of the host was investigated. In the liver strong immunoreactivity could be detected around the entrapped eggs and in egg-shells, as well as in Kupffer cells accumulating both antigen and schistosomal pigment. In the spleen, immunohistochemistry revealed antigen in the plasma as well as in secondary lysosomes of macrophages. Strong labelling was found in the vesicles of the eosinophilic granulocytes: indirect evidence perhaps for the presence of antigen-antibody complexes. In conclusion, the secreted egg antigens were sequestered in the reticulo-endothelial macrophages of the liver and the spleen as already partly described for worm-derived antigens. The presence of large quantities of antigenic material in the spleen could suggest an important role of this organ in the clearance of antigen and might even provide an additional explanation for the hepatosplenomegaly mainly present in S. mansoni-infected children. PMID- 8684829 TI - Ecology of anti-microbials produced by bacterial associates of Steinernema carpocapsae and Heterorhabditis bacteriophora. AB - Based on the ability of bacterial associates of entomopathogenic nematodes to produce antibiotic compounds on artificial media, it has been commonly accepted that Xenorhabdus sp. and Photorhabdus sp. inhibit a wide range of invading microorganisms in insects infected with Steinernema spp. or Heterorhabditis spp. Therefore, the question of whether antibiotic compounds produced by the primary form of bacterial symbionts associated mutualistically with S. carpocapsae and H. bacteriophora explain why insect carcasses do not putrefy but provide nutritional requirements for insect parasitic rhabditoid nematodes to complete their life cycle was examined. Laboratory bioassays of anti-bacterial activity on nutrient agar and during parasitism in larvae of Galleria mellonella have confirmed earlier observations that in virto colonies of the primary form of X. nematophilus and P. luminescens produced agar-diffusible antibiotic compounds of a broad spectrum of anti-bacterial activity; their role in parasitism seems doubtful, however. This hypothesis is supported by a low antibiotic potency of a limited spectrum of anti-bacterial activity throughout the life-cycle of the parasites, principally in Galleria infected with S. carpocapsae. Since the lack of putrefaction cannot be explained simply by antibiotic inhibition of contaminating bacterial microflora, other competition mechanisms must be operating in parasitized insects. I postulated that a rapid and massive colonization of the insect body by nematophilic bacteria creates unfavorable conditions for the growth and multiplication of bacterial (proteolytic) contaminators making the insect carcass decay-resistant. In the case of H. bacteriophora, low antibiotic activity at an early stage of parasitism could support the colonization by P. luminescens of the host. PMID- 8684830 TI - Mice infected with the larvae of Taenia crassiceps exhibit a Th2-like immune response with concomitant anergy and downregulation of Th1-associated phenomena. AB - Infection of intermediate hosts with eggs of taeniid parasites results in a larval infestation known as cysticercosis. A number of studies have indicated that cysticercosis is associated with immunosuppression, although little is known about the mechanisms involved. In the present study, mice infected with the larvae of Taenia crassiceps were found to exhibit a pronounced energy, which preferentially affected T-cells located anatomically close to the parasite. This anergy was linked to late events in the T cell activation pathway; that is, stimulation through the T cell receptor(TCR)/CD3 complex by Concanavalin-A, or plate-bound monoclonal antibodies (mAb) to TCR alpha beta or CD3 epsilon, or combinations of phorbol ester and ionomycin (all of which can bypass early membrane-related events), failed to fully activate T lymphocytes. The relative proximity of T cells to the parasite was directly related to upregulation of IL-4 and downregulation of IL-2 production. In addition, the profiles of parasite specific Abs showed an exclusive increase of serum IgG1 during infection. Taken together, the data suggest that infection of mice with larvae of T. crassiceps alters the balance of CD4+ Th cells by upregulating Th2 and downregulating Th1 cells located in close proximity to the parasite. PMID- 8684831 TI - The activity periods and life-cycle of the tick Ixodes uriae (Acari: Ixodidae) in relation to host breeding strategies. AB - We investigated the timing of seasonal activity of the seabird tick Ixodes uriae by examining engorgement rates of off-host ticks and the prevalence of infested common guillemots (Uria aalge) and kittiwakes (Rissa tridactyla) on the Isle of May, Scotland. More than 99% of I. uriae fed during the period late April to early August which coincided with the seabird breeding season. No ticks fed in the autumn and winter, and none over-wintered in the engorged state. Peak tick feeding activity was during the hosts' incubation period in May and early June, when over 70% of birds were parasitized. Few ticks were active when guillemot chicks were being brooded, or during the early part of kittiwake chick-rearing. Adult female tick feeding peaked in the first week of June, while nymphal and larval activity peaked in the third week of May. Adult female ticks fed later than nymphs on guillemots and larvae on both guillemots and kittiwakes; however, there was considerable temporal overlap in the feeding periods of the 3 stages of both hosts. All larvae and nymphs fed in May and early June, but up to 18% of adult females remained unengorged at this time, and probably deferred feeding by 1 year. A small proportion of individuals which fed as larvae in May appeared to feed again as nymphs in July of the same season, thereby shortening their life cycle by 1 year. The duration of the life-cycle of I. uriae on the Isle of May is typically 3 years but varies from 2 to 4 years. Ticks feeding on guillemots did so significantly earlier than those feeding on kittiwakes, possibly because guillemots start breeding earlier in the year. Breeding of both guillemots and kittiwakes was later in 1994 than in 1993. This delayed the activity of all tick stages on kittiwakes and adult female ticks on guillemots, but did not affect the timing of activity of nymphs or larvae feeding on guillemots. PMID- 8684832 TI - Genetics of host and parasite--implications for immunity, epidemiology and evolution. PMID- 8684833 TI - Host genetics and infectious disease. AB - Recent work on the inheritance of susceptibility of malaria suggests that, over what may have been a relatively short evolutionary period, a remarkably diverse series of gene families have been modified in response to the selective drive of this single infection. The phenotype consequences are not confined to the red cell, but involve the immune system, cytokines and many other systems. It seems likely that the mechanisms of variation in genetic susceptibility to other infective agents will reflect at least a similar degree of complexity and, if the selective pressures have been present for longer periods of our evolutionary history, may be even more diverse. This may have important implications for work directed at trying to define susceptibility loci for current infectious and non infectious diseases. PMID- 8684834 TI - T cell and cytokine basis of host variability in response to intestinal nematode infections. AB - Infection by a variety of species of intestinal nematode infection gives rise to a wide variation in parasite load within a host population. There has been much investigation into the basis of this variation and is thought to involve several factors. Studies of infections of gut dwelling nematodes in laboratory rodents has clearly demonstrated that this variation may be due to the production of cytokines produced as part of the host immune response to infection. More specifically, activation of distinct T helper cell subsets leads to the generation of effective or ineffective responses resulting in clearance of the parasite load or maintenance of chronic infection. The induction of differential responses remains to be determined but is likely to be influenced at a number of levels including involvement of accessory cells and activation of co-stimulatory molecules on antigen presenting cells. Moreover, it appears that these parasites may actively interfere with the host cytokine response to promote their own survival. This review concentrates on recent findings of cytokine mediated control of intestinal nematodes highlighting a central role for the immune system in regulating both acute and chronic infection by these parasites. PMID- 8684835 TI - The role of MHC- and non-MHC-associated genes in determining the human immune response to malaria antigens. AB - Individual susceptibility to malaria infection, disease and death is influenced by host genotype, parasite virulence and a number of environmental factors including malaria-specific immunity. Immune responses are themselves determined by a combination of host genes and environmental effects. The extent to which host genotype limits the spectrum of possible immune responses may influence the outcome of infection and has consequences for vaccine design. Associations have been observed between human major histocompatibility complex (MHC) genotype and susceptibility to severe malaria, but no similar associations have been observed for mild malarial disease or for specific antibody responses to defined malaria antigens. Epidemiological studies have shown that, in practice, neither T helper cell nor antibody responses to malaria parasite are limited by host MHC genotype, but have revealed that genes lying outside the MHC may influence T cell proliferative responses. These genes have yet to be identified, but possible candidates include T cell receptor (TcR) genes, and genes involved in TcR gene rearrangements. More importantly, perhaps, longitudinal epidemiological studies have shown that the anti-malarial antibody repertoire is selective and becomes fixed in malaria-immune individuals, but is independent of host genotype. These findings suggest that the antibody repertoire may be determined, at least in part, by stochastic events. The first of these is the generation of the T and B cell repertoire, which results from random gene recombinations and somatic mutation and is thus partially independent of germline genes. Secondly, of the profusion of immunogenic peptides which are processed and presented by antigen presenting cells, a few will, by chance, interact with T and B cell surface antigen receptors of particularly high affinity. These T and B cell clones will be selected, will expand and may come to dominate the immune response, preventing the recognition of variant epitopes presented by subsequent infections-a process known as original antigenic sin or clonal imprinting. The immune response of an individual thus reflects the balance between genetic and stochastic effects. This may have important consequences for subunit vaccine development. PMID- 8684836 TI - Influence of host and parasite genotypes on immunological control of Theileria parasites. AB - Infections with Theileria parva in the African buffalo are invariably asymptomatic, whereas infections in cattle usually result in clinical disease, the severity of which varies in different populations of cattle. The parasite exhibits antigenic heterogeneity, which in cattle manifests as differences between parasite strains in their cross-protective properties. A series of studies on T cell responses to T. parva in cattle have demonstrated that class I MHC-restricted cytotoxic T lymphocytes (CTL), specific for parasitized lymphoblasts, are important mediators of immunity. Cytotoxic T cell responses frequently display parasite strain-restricted specificities which appear to correlate with the capacity of strains to cross-protect. The strain specificity of CTL responses varies in animals immunized with the same parasite strain and is influenced by both host and parasite genotype. Recent studies have provided evidence that there is competition between epitopes for induction of CTL responses, which can result in a bias to strain-specific epitopes. These properties of the CTL response have important implications for vaccination. Thus, in designing a vaccine, it may be possible, by selecting parasite proteins containing appropriate CTL epitopes, to generate CTL responses that protect against a wide range of parasite strains. Although there are no comparable data on CTL responses in the buffalo, it is considered that the features of the immune response described for cattle would be advantageous for survival of parasite populations in the buffalo. Specifically, a bias in the immune responses to strain-specific determinants should favor establishment of infection in buffalo already carrying the parasite and allow fluctuation in the levels of different parasite strains during the course of persistent infection. PMID- 8684837 TI - Genetic susceptibility to leishmanial infections: studies in mice and man. AB - Two important recent advances in Leishmania immunology are: (i) the demonstration of a dramatic dichotomy in T helper 1 versus T helper 2 subset expansion leading to protection versus disease exacerbation; and (ii) analysis of the macrophage activation pathways leading to enhanced intracellular killing of parasites, in particular the tumour necrosis factor alpha (TNF alpha)-dependent sustained induction of the inducible nitric oxide synthase gene (Nos2) leading to the generation of large amounts of nitric oxide (NO). Given the broad spectrum of disease phenotypes in human leishmaniasis, one might predict that a genetic defect at any key point in this macrophage activation pathway and/or in pathways leading to activation of different T cell subsets, and the latter may be a pleiotropic effect of the former, will contribute to disease susceptibility. By studying disease in genetically-defined inbred mouse strains, it has been possible to identify 5 regions of the murine genome carrying leishmanial susceptibility genes. The genes include: (i) Scl-2 (mouse chromosome 4/human chromosome 9p; candidate Janus tyrosine kinase 1) controlling a unique no lesion growth resistance phenotype to Leishmania mexicana; (ii) Scl-1 (distal mouse chromosome 11/human 17q; candidates Nos2, Sigje, MIP1 alpha, MIP1 beta) controlling healing versus non-healing responses to L. major; (iii) the 'T helper 2' cytokine gene cluster (proximal murine chromosome 11/human 5p; candidates IL4,5,9) controlling later phases of L. major infection; (iv) the major histocompatibility complex (MHC: H-2 in mouse, HLA in man: mouse chromosome 17/human 6p; candidates class II and class III including TNF alpha/beta genes); and (v) Nramp1, the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (mouse chromosome 1/human 2q35). This review examines these 5 regions and the candidate genes within them, reflecting on their current status as candidates for human disease susceptibility genes. PMID- 8684838 TI - Genetic variability in parasites and host-parasite interactions. AB - We have examined genetic variability in parasites in the context of ecological interactions with the host. Recent research on Echinococcus, Giardia and Cryptosporidium has been used to illustrate: (i) the problems that parasite variability and species recognition pose for understanding the complex and often controversial relationship between parasite and host occurrence; (ii) the need for accurate parasite characterization and the application of appropriate molecular techniques to studies on parasite transmission if fundamental questions about zoonotic relationships and risk factors are to be answered; (iii) our lack of understanding about within-host interactions between genetically heterogeneous parasites at the inter- and intraspecific levels, and the significance of such interactions with respect to evolutionary considerations and the clinical outcome of parasite infections. If advances in molecular biology and mathematical ecology are to be realized, we need to give serious consideration to the development of appropriate species concepts and in vivo systems for testing the predictions and assumptions of theoretical models. PMID- 8684839 TI - Genetic susceptibility to malaria and other infectious diseases: from the MHC to the whole genome. AB - There is substantial evidence that host genetic factors play a major role in determining the outcome of infection with many pathogens. Detailed analysis of malaria has identified twelve genes that affect susceptibility in various human populations. However, less attention has been paid to other major infectious diseases where twin studies have identified an important host genetic component to susceptibility. Recent progress in the analysis of the human genome offers exciting prospects for the mapping and identification of new susceptibility and resistance genes for common infectious diseases. Screening of the whole genome in affected sibling pair studies is now feasible by employing highly informative microsatellite markers. In addition, many polymorphic candidate genes have become available for analysis in case-control studies. It is proposed that these new genetic tools offer a powerful approach to the epidemiological analysis of many infectious diseases in humans and supersede traditional genetic approaches to identifying susceptibility genes in mouse models. Progress in characterizing the role of major histocompatibility genes in susceptibility to malaria and other infectious diseases is reviewed before outlining the methodologies for and progress in identifying non-MHC susceptibility genes. PMID- 8684840 TI - Developing a sensible newborn discharge policy. PMID- 8684841 TI - Learning from stories: parents' accounts of the pathway to diagnosis. AB - Although the diagnosis of a child's chronic illness is typically a stressful time for parents, the events leading up to it vary considerably across families. As part of a larger study that addressed the experience of living with chronic illness, an analysis was undertaken to identify major themes in parental reports of the events preceding their child's diagnosis of chronic illness. Data are based on accounts given by parents in 63 families from three health science centers in the midwestern United States. Narrative analysis techniques were used to identify 5 major pathways to diagnosis (direct, delay, detour, quest, ordeal) and to explore parents' perceptions of the nature and quality of their interactions with health care providers. Results are discussed in terms of their implications for initiating positive working relationships between parents and health care providers. PMID- 8684842 TI - The family systems approach and pediatric nursing care. AB - The pediatric nurse is increasingly called upon to function as a family specialist, yet many nurses have assumed this role with little or no training in family systems theory. The family systems approach to pediatric nursing care maximizes family strengths. The nurse and family collaborate to identify important family needs and to match needs with resources. The primary goal is family empowerment. A basic understanding of the family systems approach to assessment and intervention can help pediatric nurses function more effectively in this role. PMID- 8684843 TI - Parental needs following the discharge of a hospitalized child. AB - Many studies have addressed parents' needs when their child is hospitalized, yet few studies have identified the needs of parents after their child is discharged. An exploratory-descriptive study of families (N = 16) at a large acute care general hospital in Canada examined parents' needs following their child's discharge and parents' perceptions of the effectiveness of a discharge follow-up program. Parents described needs in two areas: (a) the need for detailed information about their child, and (b) the need for support regarding multiple stresses that their families were facing. Parents reported high levels of satisfaction with the discharge follow-up program, and all of the families recommended its continuance. PMID- 8684844 TI - Divorce mediation and children's adjustment to parental divorce. AB - Divorce can have marked negative effects on children, particularly when parental conflict is sustained and intense. A review of literature demonstrated that parents' participation in divorce mediation counseling resulted in positive outcomes including decreased parental conflict and children's healthier emotional and psychosocial adaptation to divorce. As family advocates, nurses are well positioned to educate families about divorce mediation counseling. PMID- 8684845 TI - Education for the menarche. AB - Young girls reach menarche, the first menstruation, with misinformation and conflicted attitudes. Education for the menarche for many young women has not been adequate because of inaccurate information, uncomfortable teachers, and cognitive and developmental issues of young girls. When presenting information about the menarche the nurse should pay careful attention to the timing, context, content, and methodology of menarcheal information. PMID- 8684847 TI - Health care reform: the industrial revolution revisited. PMID- 8684846 TI - Genetics and cystic fibrosis: a focus on carrier testing. AB - Identification of mutations in the cystic fibrosis (CF) gene makes it possible to offer carrier testing for family members of people with CF. However, this may also be used for more controversial purposes such as the carrier testing of minors, inclusion of CF testing in newborn screening, and screening for the CF gene in adults in the general public. Pediatric nurses provide information, advocacy, referral, and psychosocial support for people who want to learn more about the genetic aspects of cystic fibrosis. PMID- 8684848 TI - Inpatient immunization program: eliminating a missed opportunity. AB - In response to the nation's low immunization rates among preschool-aged children, health care providers need to consider alternate sites as potential opportunities to administer vaccinations. One hospital established a Childhood Immunization Group designed to identify and provide immunizations to hospitalized children, 0 2 years of age. Sixty percent of the over 1,600 children evaluated have required immunizations in which 70% of these were immunized prior to discharge. The integration of primary care with "hospital care" can contribute to improving the immunization rate of preschool-aged children. PMID- 8684849 TI - Nursing perceptions of using physical restraints on hospitalized children. AB - PURPOSE: To describe the perceptions of pediatric nurses about restraint use in children. METHOD: A descriptive survey using a questionnaire collected data from nurses working in four types of pediatric facilities. Nurses were asked to rate reasons for using restraints and alternatives to restraints on a Likert Scale. Analysis of variance analyzed the nurses' responses according to type of institution and age of the child. An open-ended question asked nurses to list reasons for using restraints. RESULTS: Responses were collected from 60 nurses. There were significant differences in responses according to age of the child and according to the type of hospital. There were no interaction effects. The perceived need for restraints was highest between 1 and 6 years of age. Reasons for using restraints differed among types of facility. CONCLUSIONS: Restraint policies may need to vary according to the type of institution. Intervention and outcome studies are needed regarding the use of physical restraints in children. PMID- 8684850 TI - Parent-professional collaboration when hospital visits are infrequent. AB - Parents and family members may be unable to visit a hospitalized child frequently for any number of logistical or emotional reasons. Strategies to promote parent professional collaboration when parents visit infrequently include: reaching out to both establish a relationship with family members and encourage their relationship with the hospitalized child; providing logistical support to facilitate visiting; and providing training and support for staff in family centered care, including accepting diversity in family styles and choices. PMID- 8684851 TI - Pegaspargase. AB - L-asparaginase is an antineoplastic agent proven to be effective in depleting the amino acid L-asparagine in patients with childhood and adult acute lymphoblastic leukemia. It has become a significant part of most chemotherapy protocols, however, its use is sometimes limited by the development of hypersensitivity reactions. Pegaspargase offers leukemia patients adequate asparagine depletion with a reduced incidence of hypersensitivity. Other advantages include a longer circulating half-life, increased solubility, and increased resistance to proteolysis, which allows administration of smaller dosages at less-frequent intervals. PMID- 8684852 TI - Pediatric management problems. Physiologic gynecomastia. PMID- 8684853 TI - Keeping secrets: the ethical and legal challenges. AB - Blatant examples of breeches of confidentiality are less common in comparison to the daily indiscretions that occur by members of the health care team or support staff. Yet such breeches of confidentiality are rarely identified as ethical or legal problems and therefore remain unaddressed. To uphold their moral and legal obligation to protect private information, nurses must examine the nature of their obligations and devise strategies to create and maintain a culture that holds health care professionals accountable for their actions. PMID- 8684854 TI - Workup of febrile urinary tract infections. PMID- 8684855 TI - Two "old" bone diseases. PMID- 8684856 TI - [Infant formula follow-up: an update]. AB - The work presents and comments on, the recommendations of the European Society of Pediatric Gastroenterology and Nutrition, European Communities Commission and FAO/WHO regarding the composition of infant formulae and follow-up formulae. The survey is aimed at facilitating selection of adequate formula's out of their abundance on the Polish market. PMID- 8684857 TI - [An evaluation of vitamin A status based on the measurement of retinol in the serum of children and infants]. AB - A statistical comparison of serum vitamin A content among groups of children of various age ranges, revealed a much lower vitamin A level in infants (p < 0.001). The possibility of vitamin A deficiency among ill infants points to the necessity of supplementation with this vitamin. PMID- 8684858 TI - [Food allergy in pathogenesis of chronic abdominal pain in children]. AB - Food allergy has been implicated lately in the etiopathogenesis of abdominal pain in children, with particular attention pain to gastritis and/or duodenitis. The aim of the study was to analyse the cause-and-effect relationship between chronic abdominal pain in children, endoscopic and histopatological picture, and food allergy, as well as to evaluate the applied elimination diet and/or antiallergic treatment on the improvement of both the clinical status and endoscopic picture. In 71 children gastrofiberoscopic examinations, food skin tests, and specific and total IgE allergen serum tests were performed. In the majority of examined children one could observe an improvement of clinical status and of the endoscopic-histopatological picture of the stomach mucous membrane after application an elimination diet and/or treatment with sodium cromoglycate. PMID- 8684859 TI - [Selenium, glutathione peroxidase and TBARS in plasma of children with malignant diseases of the hematopoietic system]. AB - The selenium and TBARS concentrations and glutathione peroxidase activity were measured in the plasma of children with leukemia, lymphoma and histiocytosis X. A group of fifty-four children aged 1 to 16 years was divided into the following age groups: 1-3, 3-7, 7-16 years. In the patients aged 3-7 and 7-16 years, plasma selenium concentration and glutathione peroxidase activity were significantly lower than in age-matched healthy children. PMID- 8684860 TI - [Comparison of skin prick test and specific bronchial challenge results in asthmatic children]. PMID- 8684861 TI - [Broncho-pulmonary complications due to aspiration of foreign bodies by children]. AB - The paper describes 239 children with bronchopulmonary disease due to foreign body (f.b.) aspiration treated in our center during between 1980-1992. Twenty eight percent of the cases had been referred to hospital without any suspicion of f.b. aspiration. Almost half of the children (49.7%) were below the age of 2 years. Boys were affected more often (61.5%) than girls. In 61.1% the cases the f.b. had been aspirated into the right bronchial tree. Pieces of nuts were the most common f.b. - 35.1%. The most common chest X-ray symptoms were disturbances of bronchial patency (74.1%). Non-metalic, but potential shadowing f.b. like bones and teeth gave the clear signs only in 17.6% of the cases. After f.b. aspiration chronic irreversible lesions such as bronchiectasis and lung fibrosis were observed in 18.8% of the children. The prevalence of bronchiectasis was proportional to the duration of deposition. If the f.b. had been removed within the first month after aspiration we observed no complications. After aspiration of ears of grain, bronchiectasis was present in 80% of cases. Aspiration of f.b. into the left bronchial tree very often caused ventilation disturbations. Such cases were diagnosed and treated earlier than cases of right side f.b. aspirations. As a consequence bronchiectasis in the left lung was observed 2.7 less frequently. PMID- 8684862 TI - [Respiratory function in myasthenic children]. AB - Results of lung function testing in myasthenic children to be thymectomized were compared with the results in healthy children. Data of adult myasthenic patients were also included for comparison. Lung function was within normal range. It seems reasonable to widen functional diagnostics in myasthenic children by occlusion pressure and minute voluntary ventilation measurements. PMID- 8684863 TI - [Evaluation of serum cortisol concentration in neonates with infections complicated by acute respiratory failure]. AB - In 84 newborns with acute respiratory failure serum cortisol and its changes were evaluated in relation to the cause of the disease, maturity of the neonate and severity of the respiratory insufficiency. Thirty-nine out of the 84 newborns were born prematurely, 51 were suffering from pneumonia, 23 had sepsis. In all the neonates, serum cortisol concentrations were measured three times: on admission, on the fourth day of treatment and during convalescence. During the acute stage of the disease serum cortisol was raised in all newborns, irrespective of their maturity. The level of cortisol declined to normal values during convalescence. PMID- 8684864 TI - [Body mass coefficient: a proposal of a new method of nutritional assessment]. AB - A new method of nutritional assessment was developed on the basis of Quetelet's equation. The equation for the Body Mass Coefficient: BMC = M1,425 x 71.84/L1,275 (M - body mass in kg; L - height in cm) made it possible to draw a curve and to compile a table of normal values for boys and girls aged 4-18 years. Population data for children and adolescents from Warsaw were used. The sensitivity of the method is very high for detecting weight deficiences below the 10th percentile but the method should also be suitable as a screening test for obesity. PMID- 8684865 TI - [A case of campomelic dysplasia]. PMID- 8684866 TI - [Chronic subdural hematoma in a 7-year-old boy]. PMID- 8684867 TI - [A vascular ring as a rare cause of recurrent obstructive bronchitis in children]. AB - The authors have described two cases of vascular ring in small children. Recurrent obstructive bronchitis and pneumonitis with severe dyspnoea, stridor and wheezing predominated in clinical manifestation. Early diagnosis and proper surgical treatment were the most important for the prognosis of the children. PMID- 8684868 TI - Helicobacter pylori infection and peptic ulcer disease in children. PMID- 8684869 TI - Measles vaccination in Korea. PMID- 8684870 TI - Randomized, double blind comparison of brand and generic antibiotic suspensions: I. A study of taste in adults. AB - BACKGROUND: A belief that brand oral liquid medications taste better than their generic counterparts may influence prescribing habits among pediatricians. METHODS: We undertook a prospective, randomized, double blinded, comparative evaluation of the taste of brand and generic erythromycin ethylsuccinate, cephalexin monohydrate, erythromycin ethylsuccinate/sulfisoxazole, penicillin V potassium and trimethoprim-sulfamethoxazole in 42 adult volunteers. Subjects tasted one class of brand and generic antibiotics and rated them according to smell, texture, taste and aftertaste. RESULTS: At least one generic preparation of cephalexin, erythromycin ethylsuccinate/sulfisoxazole and penicillin V potassium was rated equal in taste to the respective brand name products. However, brand erythromycin estolate and trimethoprim-sulfamethoxazole name brand suspensions rated significantly higher than the other products tested. CONCLUSIONS: Based on our results brand name oral antibiotic formulations do not necessarily taste better than their generic counterparts. PMID- 8684871 TI - Randomized, double blind comparison of brand and generic antibiotic suspensions: II. A study of taste and compliance in children. AB - BACKGROUND: The taste of oral liquid medications influences compliance in children. Generic preparations are prescribed to reduce cost and may taste worse than brand name products. METHODS: This was a prospective, randomized, double blind, crossover trial of the differences in taste and compliance between brand and generic antibiotic suspensions in children 3 to 14 years of age. Verbal and visual assessment methods were used to assess taste, and compliance was measured by the amount of drug returned after use. RESULTS: Ten children in each of the cephalexin and erythromycin-sulfisoxazole groups did not report that the brand and generic formulations tasted differently. Fifteen children thought that brand trimethoprim-sulfamethoxazole tasted better than the generic preparation. CONCLUSIONS: Brand name oral liquid antibiotics do not necessarily taste better than their generic counterparts. Despite preference for the taste of brand trimethoprim-sulfamethoxazole, all of the children in this study were compliant with both brand and generic medications. PMID- 8684872 TI - Purified fusion protein vaccine protects against lower respiratory tract illness during respiratory syncytial virus season in children with cystic fibrosis. AB - OBJECTIVE: To test in a double blind, placebo-controlled study a purified fusion protein (PFP-2) vaccine against respiratory syncytial virus (RSV) in RSV seropositive children with cystic fibrosis (CF). METHODS: Seventeen CF children, mean age 4.5 years, received PFP-2 vaccine and 17 CF children, mean age 5.8 years, received a saline vaccine. At enrollment the Shwachman clinical score, Brasfield radiographic score, oxygen saturation (SpO2), anthropometric indices and other variables were recorded. After vaccination the reactions were assessed daily for 7 days. During the RSV season weekly telephone interviews were performed and children with an acute respiratory illness were evaluated and cultured for RSV. Serum was drawn before vaccination, 1 month after vaccination and at the end of the RSV season and tested for antibodies to RSV. RESULTS: Other than age the baseline measurements at enrollment were similar between groups. The PFP-2 vaccine produced mild local reactions and induced a significant neutralizing antibody response in two-thirds of the vaccinees and a significant enzyme-linked immunosorbent assay-fusion glycoprotein antibody response in nearly all the PFP-2 vaccinees. Vaccine-enhanced disease was not observed in PFP-2 vaccines infected with RSV. Protection against RSV infection was not observed; however, a significant reduction (t test, P < 0.01) in mean number of lower respiratory tract illnesses (0.8 vs. 2.1), antibiotic courses (2.2 vs 4.5) and days ill (30.5 vs. 67) occurred among RSV-infected PFP-2 vaccinees. CONCLUSIONS: Efficacy of the PFP-2 vaccine against lower respiratory tract illness during the RSV season was shown in RSV-seropositive children with CF. PMID- 8684873 TI - Measles outbreaks in the United States, 1987 through 1990. AB - BACKGROUND: During 1989 and 1990 reported measles cases in the United States increased 6- to 9-fold over the annual mean of 3000 between 1985 and 1988. To evaluate recent epidemiology we summarized measles outbreaks. METHODS: Confirmed measles cases reported to the National Notifiable Disease Surveillance System during 1987 through 1990 were analyzed. An outbreak was defined as > or = 5 epidemiologically linked cases. RESULTS: There were 815 outbreaks, accounting for 94% of the 52,846 cases reported. Similar to 1985 and 1986, 3 patterns of measles transmission during outbreaks were identified: (1) predominantly among unvaccinated pre-school age children < 5 years of age (38% of outbreaks); (2) predominantly among vaccinated school age children 5 to 17 years of age (40%); and (3) predominantly among unvaccinated and vaccinated post-school age persons > or = 18 years of age (22%). Most outbreaks were small (median, 12 cases), but very large outbreaks occurred (maximum size, 10,670). Although school age outbreaks (58%) predominated during 1987 and 1988, preschool age (40%) and post school age (23%) outbreaks were more important during 1989 and 1990. CONCLUSIONS: Recent epidemiology suggests that to achieve elimination of measles, ACIP recommendations must be fully implemented, including (1) routine administration of the first dose of measles vaccine from 12 to 15 months of age and (2) use of a routine two-dose schedule to prevent school age and post-school age outbreaks. PMID- 8684874 TI - No persistent T lymphocyte immunosuppression or increased mortality after measles infection: a community study from Guinea-Bissau. AB - BACKGROUND: Because measles immunization is reducing overall childhood mortality in addition to mortality from acute measles infection, it has been suggested that postmeasles cases have excess mortality, possibly related to persistent immunosuppression after measles infection. After an epidemic in 1988 in Guinea Bissau, we therefore examined T lymphocyte subsets and long term survival among measles cases and controls. METHODS: We examined 69 children < 3 years of age with a median delay of 2 months after measles infection and 71 controls who did not contract measles. The immunoalkaline method was used to determine T lymphocyte subsets. The children were followed for 5 years. RESULTS: Compared with controls, there were no significant differences in white blood cell count, absolute lymphocyte count, CD4 percentage, CD8 percentage, total CD4 count and total CD8 count, although measles cases examined > 2 months after infection had slightly higher CD4 counts than controls (P = 0.06). Adjusted for age, sex and immunization status, postmeasles cases had a mortality rate ratio of 0.50 (95% confidence interval, 0.22 to 1.16) (P = 0.11) compared with controls. CONCLUSIONS: There is no indication of persistent suppression of T cell subsets after measles infection, and postmeasles cases did not have higher mortality than uninfected community controls. PMID- 8684875 TI - Thrombocytopenic purpura after measles, mumps and rubella vaccination: a retrospective survey by the French regional pharmacovigilance centres and pasteur merieux serums et vaccins. AB - BACKGROUND: Thrombocytopenic purpura (TP) after vaccination with measles, mumps and rubella has occasionally been reported. OBJECTIVES: To evaluate the incidence and characteristics of thrombocytopenic purpura reported in France after measles, mumps or rubella vaccination with monovalent or multivalent vaccines. METHODS: A retrospective epidemiologic survey was conducted. All confirmed cases of TP reported spontaneously either to the French Regional Pharmacovigilance Centres or to the manufacturer (Pasteur-Merieux Serums et Vaccins) between 1984 and June 30, 1992, were reviewed. RESULTS: Sixty cases of TP in children between 1 and 11 years of age occurred 2 to 45 days after administration of 1 of 7 vaccines. The reported incidence of TP varied from 0.17 and 0.23/100,000 doses of measles or rubella vaccines, respectively, given alone to 0.87/100,000 doses of combined measles-rubella vaccines and 0.95/100,000 doses of the measles-mumps-rubella vaccine. The mean platelet count was 8000 +/- 6000/mm3 and was lower than 10,000/mm3 in 58% of cases. The immediate outcome was favorable in 89.5% of cases. CONCLUSIONS: According to the clinical course and biologic findings, vaccine-associated TP appears to be similar to that occurring after natural measles or rubella infections and is not distinguishable from acute childhood idiopathic thrombocytopenic purpura not associated with vaccination. Such observations, combined with a clear temporal relationship between measles-mumps rubella vaccination and the occurrence of TP, make a causal relationship highly plausible. Nevertheless the incidence of these events remains relatively low with a favorable immediate outcome. PMID- 8684876 TI - Safety and immunogenicity of one vs. two injections of Oka/Merck varicella vaccine in healthy children. AB - OBJECTIVE: To compare the safety and immunogenicity of a one- vs. two-dose regimen of Oka/Merck varicella vaccine in approximately 2000 healthy children 12 months to 12 years of age. METHODOLOGY: Subjects with a negative history of varicella were randomized to receive either one or two injections of the vaccine given 3 months apart and were followed for clinical reactions and serologic response (glycoprotein-based enzyme-linked immunosorbent assay). RESULTS: Both one- and two-dose vaccine regimens were generally well-tolerated. The incidences of varicelliform rash and fever were less frequent after the second injection. However, a slight increase in the incidence of injection site reactions was noted after the second injection; these were generally mild. Seroconversion rates by glycoprotein-based enzyme-linked immunosorbent assay were 98.2% (1700 of 1731) after one injection and 99.9% (717 of 718) after two injections. A significant (P < 0.001) boost in geometric mean titers was observed in children who received a second injection of vaccine 3 months after the first injection. Of the children who seroconverted at 6 weeks postregimen (one or two doses as assigned), 99.8% (528 of 529) of the one-dose group and 99.8% (473 of 474) of the two-dose group maintained antibody to varicella at 1 year with geometric mean titers of 19.5 and 31.2, respectively. CONCLUSIONS: Administration of a one- or two-dose regimen of the live Oka/Merck varicella vaccine (VARIVAX) is immunogenic and is generally well-tolerated in healthy children 1 to 12 years old. Antibody to varicella persists in > 99% of vaccinees 1 year after vaccination regardless of a one- or two-dose regimen. Long-term follow-up studies of this cohort of children may determine whether a two-dose regimen offers superior protection against chickenpox. PMID- 8684877 TI - Detection of Bordetella pertussis by polymerase chain reaction and culture in the nasopharynx of erythromycin-treated infants with pertussis. AB - BACKGROUND: Pertussis is a highly contagious respiratory disease and the most serious effects occur in young infants. Recently it has been shown that rapid and highly specific PCR can be a useful diagnostic tool for detection of pertussis infection. To our knowledge there are no previous studies concerning the disappearance of Bordetella pertussis DNA from the nasopharynx during antimicrobial treatment. METHODS: We studied prospectively how rapidly live B. pertussis organisms and DNA of these bacteria disappear from the nasopharynx during erythromycin therapy in unvaccinated infants. Eighty-five nasopharyngeal swabs obtained from nine erythromycin-treated infants with pertussis on consecutive days during hospitalization were tested by PCR and culture. The PCR products were further analyzed by Southern hybridization. RESULTS: On the fourth day of treatment 56% of the samples were positive by culture and 89% by PCR, whereas after 7 days the rates were 0 and 56%, respectively. In seven of nine patients PCR remained positive for 1 to 7 days longer than culture. The follow-up study also showed the semiquantitative nature of the PCR assay. The intensity of the PCR products in agarose gel usually weakened with time during erythromycin therapy. CONCLUSIONS: The results of this study show that PCR assay can achieve the specific diagnosis of pertussis infection in a large proportion of infants even when antimicrobial treatment has killed the organisms and culture is no longer positive. PMID- 8684878 TI - Etiology of acute otitis media in human immunodeficiency virus-infected children. AB - BACKGROUND: Acute otitis media (AOM) is one of the most common infections that are implicated as significant contributors to morbidity in HIV-infected children. To establish the optimal antibiotic therapy tympanocentesis is indicated as the first line diagnostic procedure, because unusual pathogens may play a role in advanced stages of deficient humoral or cellular immunity. METHODS: The microbiology of 60 episodes of AOM diagnosed in 21 symptomatic HIV-infected children (ages 9 months to 12 years) was compared with that of 121 episodes of AOM occurring in 113 immunocompetent HIV-negative children (ages 6 months to 12 years) in the last 5 years. RESULTS: The prevalence of the three most common pathogens (Streptococcus pneumoniae, Haemophilus influenzae and group A beta hemolytic Streptococcus) was similar in HIV-infected and in normal children (56.5% vs. 54.9% of the ears). Staphylococcus aureus was significantly more frequent in AOM diagnosed in severely immunosuppressed stages. A significantly lower proportion of middle ear effusions obtained in HIV-infected children yielded no bacteria compared with normal children. Beta-lactamase production among isolates of H. influenzae was a rare phenomenon, both in HIV-infected and in normal children. No penicillin-resistant S. pneumoniae was found. CONCLUSIONS: In HIV-infected children with absent or moderate immunosuppression empiric antibiotic therapy should be based on the recommendations given for immunocompetent children of the same geographic area. In severe immunosuppressed stages, given the possible role of Staph. aureus, extended spectrum antibiotics should be considered. PMID- 8684879 TI - Secondary failure rates of measles vaccines: a metaanalysis of published studies. AB - BACKGROUND: Recent measles outbreaks in highly vaccinated populations have highlighted the role of vaccine failure as a barrier to the elimination of measles. We sought to estimate the rate of secondary failure (clinical measles after vaccine-induced seroconversion) of measles vaccines using metaanalysis. METHODS: We identified 1411 studies of which 125 were relevant. From these we found 10 original studies of healthy subjects with sufficient details to calculate a pooled secondary failure rate. We performed a test for homogeneity before any pooling. RESULTS: Although significant heterogeneity prevented their pooling as a single group, the studies fell into three homogeneous groups suitable for pooling. Group A studies used killed vaccine whereas the other two groups (Groups B and C) of studies used live vaccine. These latter groups differ in that the studies in Group B share higher failure rates and are difficult to interpret with respect to the lack of verification of vaccination, immunization before 12 months of age and a non-North American study site and vaccine manufacturer. Those studies in Group C, in which US subjects were older than 12 months at vaccination and received a live US-manufactured vaccine that was documented in a medical record, had a failure rate of 0 of 2031 with a 95% confidence interval of 0.0 to 0.147%. CONCLUSIONS: Although reports of measles related to secondary failure exist, studies that permit the calculation of the rate of secondary failure demonstrate that the rate appears to be < 0.2%. PMID- 8684880 TI - Nonpolio enteroviruses and the febrile young infant: epidemiologic, clinical and diagnostic aspects. PMID- 8684881 TI - Children with hyperimmunoglobulinemia D and periodic fever syndrome. PMID- 8684883 TI - Multilocular thymic cyst in a child with acquired immunodeficiency syndrome. PMID- 8684882 TI - Septic arthritis and osteomyelitis caused by penicillin and cephalosporin resistant Streptococcus pneumoniae in a children's hospital. PMID- 8684884 TI - Cryptosporidium testing practices among clinical laboratories in the United States. PMID- 8684885 TI - Thrombocytopenia after immunization with measles vaccines: review of the vaccine adverse events reporting system (1990 to 1994). PMID- 8684886 TI - Poor validity of parent reading of skin test induration in a high risk population. PMID- 8684887 TI - Atypical streptococcal nephritis. PMID- 8684888 TI - Systemic cat-scratch disease presenting as leukocytoclastic vasculitis. PMID- 8684889 TI - Group B Streptococcal epiglottitis. PMID- 8684891 TI - Fever, aseptic meningitis and rash in a twenty-one-month-old male. PMID- 8684892 TI - Physicians and schools: a matter of communication. PMID- 8684890 TI - Thymic abscess caused by methicillin-resistant Staphylococcus aureus. PMID- 8684893 TI - Glycerol treatment in bacterial meningitis. PMID- 8684894 TI - Trait and state anxiety before and after competitive performance. AB - 33 subjects were tested on competitive trait and state anxiety immediately before and after a competitive motor task of short duration (average performance time of 25 seconds). It required precise coordination of correct muscular activity, timing as well as speed, and physical strength that included explosive shifts in direction of movement. Two types of performance measures were employed, (a) number of errors during the performance and (b) the time it took to complete the motor task. Analysis showed a positive relation between trait anxiety and performance errors when a linear model was applied; however, when a curvilinear model was used, a strong significant U-relationship between errors and precompetition state anxiety emerged. Further, a strong positive linear relation between poststate anxiety and number of performance errors was observed. The results indicate that making errors in performance situations is a critical factor in producing postcompetition state anxiety. PMID- 8684895 TI - Metals and school learning: a review of investigative techniques. AB - A growing body of literature suggests a relationship between metals and a threatened health status among children, adolescents, and adults. Recently, several investigators have reported a direct link between exposure to metal and diminished affective, behavioral, and cognitive performance of school children. The purpose of the present study was to review and analyze methods and procedures used to understand the relationship between exposure to metals and cognitive, social, and motor functioning of school children. PMID- 8684896 TI - An event-related potential study of the effects of semantic deviations: an application of a method of sequential-part presentation. AB - The present study was designed to evaluate the effects of semantic deviations of picture stimuli by applying a method of sequential-part presentations. S1 stimuli were 10 pictures of animals which were divided into 7 x 7 portions and successively presented in random order. S2 stimuli were three types of pictures (A, the same as S1; B, semantically the same but physically different from S1; and C, both semantically and physically different from S1). Subjects were required to name S1 verbally after seeing S2. The largest N400 components of the event-related potential were elicited for Category C of S2, whereas large LPCs were elicited for Categories B and C. This suggests that a method of sequential part presentations is effective for eliciting the N400 component of the event related potential for picture stimuli. PMID- 8684897 TI - Youth sport participation and associated sex differences on a measure of spatial ability. AB - Sex-related differences on measures of spatial ability favoring males are commonly found in psychological studies. This study investigated the possible association of differential participation in organized youth sport with scores on a measure of spatial ability among a sample of 167 college students. Such participation was not significantly related to spatial scores of men or women nor did it reduce sex differences. PMID- 8684898 TI - The moral acceptability of suicide. AB - Four studies (Ns of 50, 148, 201, and 63) examined personality correlates of people's opinions about the morality of suicide. The more depressed and suicidal college students viewed suicide as less morally wrong. PMID- 8684899 TI - Relations of goal orientations and expectations on multidimensional state anxiety. AB - This study examined the relationships among task and ego orientation, expectations for success, and multidimensional state anxiety in a competitive sport situation. Subjects (N = 107) enrolled in a tennis skills class were gender and ability-matched and asked to play an eight game pro-set. One week prior to the match goal orientations were assessed. Immediately prior to competition multidimensional state anxiety and performance expectations were measured. Multiple regression analyses predicting multidimensional state anxiety revealed that somatic and cognitive state anxiety were only predicted by performance expectations. Also, lower ego orientation and positive match expectations were predictive of state self-confidence. Results are interpreted in light of goal perspective theory. PMID- 8684900 TI - Internal consistency of dynamometer measurements in healthy subjects and stroke patients. AB - Measurements of strength from six muscle groups described in two previously completed reports were analyzed further using Cronbach alpha. The coefficients were greater than .948 for a small sample of stroke patients and a larger sample of healthy individuals. This finding shows in diverse samples that the measures possess internal consistency and are measuring the same underlying construct. PMID- 8684901 TI - Lower-limb speed and foot preference in children. AB - Foot preference and performance characteristics of gross-motor lower-limb speed of tapping were examined in 606 4- to 6-yr.-olds. Analysis indicated no effect for gender; however, speed of foot tapping increased significantly across the three ages, suggesting an association with selected developmental (neuromuscular) processes. Contrary to earlier reports on handedness, there was no statistical evidence that mixed- or left-footers were at a performance disadvantage compared to right-footers. All groups performed best with the right foot, limb differentiation (right versus left) being significant for the right- and mixed footed groups. Speculation about maturational and environmental influences is given. PMID- 8684902 TI - Effects of taboo words on color-naming performance on a stroop test. AB - The effect of irrelevant taboo and control words on performance on the Stroop task was examined. The mean response time for taboo words was higher than that for control words. Single stimulus presentation made it possible to estimate internal consistency for interference of taboo words, which was acceptable (Cronbach alpha = .80). PMID- 8684903 TI - Sensorimotor learning in ideomotor apraxia. AB - Sensorimotor learning ability in patients with ideomotor apraxia was investigated, using as subjects, eight patients with ideomotor apraxia, 8 with aphasia without ideomotor apraxia, and 8 normal controls. The aphasia, apraxia, and normal control groups were matched for age, sex, and education. The aphasia and apraxia groups were chosen to control for lesion size and scores on Kimura's recurring figure test, the Token test, and intelligence. The mirror-aiming test was performed and the learning effect in terms of decreases in total time, the number of errors, and the times for errors were examined. There was no statistically significant difference between the learning effect of the apraxic group and that of the aphasic group for total time, the number of errors, and the times for errors; however, there were group differences on each trial for number of errors and the times for errors. These results suggest that patients with ideomotor apraxia have some difficulties in motor performance rather than disturbance of learning. PMID- 8684904 TI - Are two hearing aids better than one? AB - The use of hearing aids in 114 persons fitted with one or two hearing aids was compared. Those with two hearing aids registered significantly more daily use of their hearing aids. PMID- 8684905 TI - Developmental trends in pursuit eye movements among preschool children. AB - The purpose of this study was to investigate the developmental differences in pursuit eye movements among preschool children. The subjects were 28 children aged 3 to 6 years old and 5 adults aged 22 to 37 years. The target was moved sinusoidally on the horizontal plane at 0.3-, 0.5-, and 0.7-Hz stimulus frequency. The power ratio which represented the smoothness of eye movements and the phase difference between eye movements and target movement was calculated. The power ratio decreased with increased stimulus frequency for all subjects, indicating that eye movements became less smooth. At all stimulus frequencies, the power ratio was higher for adults than for children. Among the three age groups of children, there was no statistically significant difference on this parameter. The phase shifted from a small amount of lead for no lag to the lag with faster stimulus frequency in adults, but the gap was not statistically significant. For children, there was a statistically significant difference across age groups on change in the phase difference. These findings may suggest that the developmental differences in pursuit eye movements of children across ages 3 to 6 years were clear in what related to the phase difference. PMID- 8684906 TI - Base rate of "10 to 11" clocks among patients referred for neuropsychological evaluation. AB - Of 655 neuropsychological referrals who were asked to draw a clock and set the hands at "10 after 11," 9% set the hands at "10 to 11." This low base rate of occurrence suggests the error was not highly sensitive to neurological impairment or diagnostically specific. PMID- 8684907 TI - Coping processes in competitive gymnasts: gender differences. AB - The Ways of Coping with Sport questionnaire was used to investigate coping with performance problems in a sample of 115 adolescent gymnasts. The coping processes reported most frequently by the total sample of gymnasts were Increased Effort and Resolve, Wishful Thinking, Seeking Social Support, and Problem-focused Coping. Analysis of gender differences by multivariate analysis of variance indicated that, compared with males, the female gymnasts were more likely to use Seeking Social Support to cope with slumps in performance. The findings were consistent with previous research on coping in sporting and nonsporting populations. PMID- 8684908 TI - Suicide rates in birth cohorts in england and wales. AB - In an analysis of birth cohorts in England and Wales, no support was found for the hypothesis that birth cohorts with high suicide rates at one point in their lives would have lower suicide rates at times 20 years or more distant. PMID- 8684909 TI - Retest reliability of the woodcock language proficiency battery. AB - The Woodcock Language Proficiency Battery: English Form was administered to 152 of the 478 students beginning medical studies at an Australian university in 1990 and 1991. Two years after admission 147 of the students were available for retest. Test-retest reliability coefficients ranged from .70 to .85 for the 8 subtests, .83 to .91 for the three cluster scores, and the coefficient for the Broad Language Cluster score was .95. The sample had deliberately over represented students low in English language proficiency but the reliability coefficients were only slightly reduced when this bias was corrected by forming a representative sample of 72 students. The mean incremental gain on the Broad Language Cluster of 1.8 was statistically significant and corresponded closely to the 2.0 predicted from the test norms for a 2-year developmental period. These results support previous reports of the excellent psychometric properties of this instrument. PMID- 8684910 TI - Cross-validation of the alternative impairment index. AB - The Alternative Impairment Index, a new composite measure of neuropsychological deficit, was cross-validated by comparison with an established measure of neuropsychological impairment, the Halstead Impairment Index. An initial study gave agreement of 60% (15/25) between the Halstead Impairment Index and the Alternative Impairment Index. Analysis of a cross-validation sample of 50 brain damaged patients with complete Halstead-Reitan Neuropsychological Test scores yielded agreement of 66% (33/50) on severity for the Alternative Impairment Index and Halstead Impairment Index. PMID- 8684912 TI - Selected health-fitness rankings of low-income youth. AB - Two parameters, tricep skinfold and one-mile walk/run, from the American Alliance for Health, Physical Education, Recreation and Dance health-related fitness test were assessed in 226 low-income children, ages 10 through 14 years. Group means by age and sex were compared with state and national norms. As a whole, on both fitness parameters, this low-income sample fell in the bottom quartile for the state of Maine. The group's national ranking was even lower. Not only are low income families burdened financially, it appears from this study that the children are also at health risk. PMID- 8684911 TI - Stimulus-response compatibility effects in a manual tracking task. AB - The purpose of this study was to determine whether there are stimulus-response (S R) compatibility effects in a manual tracking task for male and female subjects of different ages. 20 healthy men and 20 healthy women in each of three different age groups (20 to 39, 40 to 59, and 60 to 79 years) participated (total N = 120). Subjects performed extension and flexion movements of the index finger metacarpophalangeal joint to track a computer-screen cursor along a target sine wave. The hand and forearm were positioned so that the finger movement was either vertical or horizontal, and the computer monitor was positioned so that the voluntary cursor movement was either vertical or horizontal. Each subject performed four different tracking tests corresponding to the four different ensembles of hand-forearm position and monitor position. There were significant differences in tracking performance between test ensembles in both women and men aged 60 to 79 years, and the compatible ensembles showed the superior performance. The results suggest that S-R compatibility effects exist in elderly women and elderly men performing a finger-movement tracking task, and these effects are consistent with impaired information processing in elderly persons. More research is needed on how S-R compatibility affects performance in persons with cerebral lesions. PMID- 8684913 TI - Relationships between scores on the motor activity anxiety test and the fear survey schedule. AB - Relationships between the Motor Activity Test and the Fear Survey Schedule scales were assessed in a research involving 120 subjects ages 13 to 21 years. Correlations ranged from low (r = .27) to moderate (r = .49). These results confirm the specificity of fearful situations in motor activity compared to events not related to physical activity and they also confirm the opportunity to use the Motor Activity Anxiety Test in an educational context. PMID- 8684914 TI - An investigation of the relationship between color choice and depression measured by the Beck Depression Inventory. AB - The relationship between self-reported depression and color preference was investigated. It was proposed that a cognitive schema would be activated affecting negatively that part of the environment selected for cognitive preference. When requested to select a series of preferred colors, the 72 undergraduates scoring above 10 on the Beck Depression Inventory tended to choose black or brown. It is believed that internal schema represented in 3 questions may be reflected in color choice(s). PMID- 8684915 TI - A preliminary investigation of the relationship between language and gross motor skills in preschool children. AB - This study was undertaken to explore the relationship between language skills and gross-motor skills of 28 preschool children from two private preschools in New York City. Pearson product-moment correlation coefficients were calculated for language (revised Preschool Language Scale) and gross motor (Test of Gross Motor Development) scores. Locomotor skills were significantly related to both auditory comprehension and verbal ability while object control scores did not correlate significantly with either language score. These results were discussed in terms of previous research and with reference to dynamical systems theory. Suggestions for research were made. PMID- 8684916 TI - Analysis of eyeblink activity during self-referent information processing in mild depression. AB - This study was designed to assess characteristics of self-referent information processing in mildly depressed persons using the eyeblink response measured in a discrete-trial paradigm. 7 mildly depressed and 9 nondepressed subjects (classified by scores on Beck's inventory) performed a self-reference task for positive and negative trait adjectives. The eyeblink was suppressed before and during presentation of stimuli and a burst pattern of the eyeblink was observed just after exposure. The pattern of the eyeblink burst after trait adjectives could be interpreted to reflect cognitive effort, cognitive load, or amount of attentional resource. Present results suggested that depressed individuals should have less cognitive load or allocate less attentional resource to negative stimuli than to positive ones during self-referent information processing. PMID- 8684917 TI - Suicide rates in Canadian prisons. AB - In Canada from 1960 to 1985, the male federal prisoners' suicide rate was associated with the general Canadian male suicide rate and predicted by measures of domestic social integration. PMID- 8684918 TI - Specificity in the relationship between training and performance in triathlons. AB - The present study examines whether swim, cycle, and run performance during a triathlon are predicted best by training in the same sport, as suggested by the theory of specificity for the relationship between sport training and performance. Using behavioral measures of training (pace, mileage, workouts), multiple regression analyses of questionnaire responses from 624 triathletes (443 men, 181 women) showed pace of training in the same sport to be the best predictor of swim and run performance for both sprint and endurance triathlons. No clear patterns were seen for cycle performance. Thus, specificity in the relationship between training and performance appears supported, especially for sports that rely more on the body (swim, run) and less on equipment (cycle). PMID- 8684919 TI - Magnitude of stress reported by basketball referees. AB - 723 basketball referees responded to a survey that assessed stress related to officiating. Mean reported ratings were between "very little" and "moderate amount"; only 4% reported high stress. Results are consistent with other accounts, suggesting that most sport officials experience low occupational stress. PMID- 8684921 TI - Differing results in research on preference for music tempo. AB - Iwanaga's research procedure was quite different from ordinary life and from the methodology used in traditional research on musical preference. This might explain the difference in the results he obtained. PMID- 8684920 TI - Attention-deficit hyperactivity disorder: a longitudinal case study of handwriting characteristics. AB - This longitudinal case study focuses on handwriting samples of a female diagnosed with Attention-Deficit/Hyperactivity Disorder from 12 years of age to 21 years of age. Diaries and journals produced for class assignments and later for this research yielded 293 handwriting samples. 15 characteristics of handwriting were measured and statistically analyzed to follow changes in handwriting across time. At seven years of age while in elementary school the subject was diagnosed with ADHD and placed on Ritalin (methylphenidate). At puberty the drug was discontinued. During two summers she visited grandparents, once alone and once with two sisters with whom she was in conflict. Her handwriting deviated from its pattern of general decrease in size and increase in uniformity during these visits. The changes over time of three handwriting characteristics (slant of "l," heights and areas of the lower loop of the "g," and area of the left loop of the "I") also deviated from the general pattern of her handwriting change. PMID- 8684922 TI - Path analysis examining relationships among antecedents of anxiety, multidimensional state anxiety, and triathlon performance. AB - The study explored predictive paths for antecedents of anxiety, state anxiety responses, and performance. Male triathletes (N = 175) completed a modified Competitive State Anxiety Inventory-2 which included the original intensity scale and a direction scale of Jones and Swain. They also completed a 23-item Prerace Questionnaire which measured antecedents of anxiety among triathletes. Factor analysis of intercorrelations for the Prerace Questionnaire identified six factors similar to those found in 1995 by the present authors. Path analysis to predict state anxiety from antecedents of anxiety indicated that rated intensity of anxiety was predicted by the perceived difficulty of race goals and by perceived readiness. Direction of anxiety was predicted by coach's influence, recent form, and perceived readiness. Path analysis to predict performance from state-anxiety scores and antecedents of anxiety indicated that recent form predicted performance directly without mediation of anxiety responses. Anxiety scores did not predict performance. The findings support the notion that intensity and direction of anxiety responses have different antecedents. PMID- 8684923 TI - Covert speech behavior during video-viewing tasks with and without an overt speech soundtrack. AB - This pilot study tested the prediction that covert speech activity measured by lip EMG(mu v) is significantly greater during the presentation of prerecorded speech than in a 'speechless' video-viewing test condition and conditions of rest. A single-subject multiple-baseline design was used and nondominant forearm EMG(mu v) activity was also measured for comparison purposes. Analysis showed a significant increase in lip EMG(mu v) activity in 1 out of 2 rest-to-test conditions involving the presentation of prerecorded overt speech. There was no significant difference in the subjects' mean lip EMG(mu v) values across 3 test conditions, however. PMID- 8684924 TI - A review of the clinical and research use of the Bender-Gestalt Test. AB - The Bender Visual-motor Gestalt test has been an integral part of the standard test battery for the past 50 years. However, the test has been extensively critiqued on issues of inappropriate administration, scoring schemes, and clinical interpretation. In an analysis of recent surveys on test use, the Bender Gestalt remains quite popular in a variety of clinical settings across all age groups. Secondly, the test has a respectable level of research interest, based on a citation analysis of the Psychological Abstracts database. PMID- 8684925 TI - Practice variability and transfer of a racket skill. AB - This study used a forehand hitting task to explore the effect of racket variability on 'out of range' transfer. 48 11-yr.-old girls were randomly assigned to four treatment groups of Random Variability, Blocked Variability, Specific, and Control. The experimental groups had 32 trials for 4 successive days after which all groups were tested on 4 transfer conditions. Retention tests were given after 1, 4, and 8 days and the data were examined for treatment, range, and occasion effects. Analysis showed the superiority of practice over no practice, variable over specific practice, and random over blocked variability for transfer with two 'out of range' dimensions. Accuracy decayed between the transfer tests. These results are consistent with schema theory, and it is recommended that physical education teachers should focus variable practice on task dimensions that are new to their classes. PMID- 8684926 TI - Suicide rates in Canadian aboriginals and size of population. AB - There was no association between the proportion of aboriginals in the nine major Canadian regions and the aboriginal suicide rate of motor vehicle death rate. PMID- 8684927 TI - Clinical neurological indicators are only moderately correlated with quantitative neuropsychological test scores in patients who display mild-moderate brain impairment following closed-head injuries. AB - Quantitative comparisons were completed between mean scores for standardized neuropsychological tests (requiring 6 hr.), numbers of neurological signs (tests requiring 15 min.), anomalies within the electroencephalogram, subjective symptoms during a structured interview (requiring 20 min.), and an indicator of an organic brain syndrome for 81 patients who had sustained significant mechanical impacts to their skulls. The composite of neuropsychological scores was correlated 0.70 with a composite of neurological indicators and EEG anomalies. There were no significant correlations between neuropsychological or neurological scores and the numbers of subjective complaints, abnormal personality indicators, duration of coma or the interval of posttraumatic dysmnesia. However, the scores for the severity of the organic brain syndrome, partial complex epileptic symptoms, and subjective complaints were inversely correlated (rho = -0.35) with the duration of coma, the period of posttraumatic amnesia, and the numbers of qualitative electroencephalographic anomalies. PMID- 8684928 TI - Comments to dr. LeBlanc's report. AB - Acknowledging LeBlanc's evaluation of my recent work in this journal, three comments are provided. PMID- 8684929 TI - Reliability of the stroop test with single-stimulus presentation. AB - Different versions of the Stroop test are used; however, for most versions of the Stroop test, there are no estimations of reliability. In the present study, stimuli were presented singly on a computer screen. 55 Swiss German subjects were tested. Test-retest reliabilities of 'XXXX' strings and conflicting color words were evaluated. Response latencies and Stroop interference were quite reliable. Single-stimulus presentation made it possible also to estimate internal consistency, which was high for classical Stroop interference in this format. PMID- 8684930 TI - Apparent horizontal and vertical extents of patterns with and without a surround. AB - Following earlier informal observations, the first of two experiments confirmed that, whereas the vertical and horizontal extents of a printed passage are more or less veridically perceived when the passage is surrounded by margins as is usual on a page, they appear reduced when the margins are removed by cropping them close to the edges of the passage. In Exp. 2 with a horizontal-line grating a similar reduction occurred vertically but not horizontally, suggesting that the effect occurs for patterned regions but less or not at all for unpatterned, i.e., uniform, regions. The possible relationship between this effect and the Delboeuf illusion of size is discussed. PMID- 8684931 TI - Size of the visual field in collegiate fast-pitch softball players and nonathletes. AB - The purpose of this study was to examine whether visual-field size differed between female Division I collegiate fast-pitch softball players and female college students who were nonathletes. The relationship between visual-field size and batting performance among the softball players was also examined. 24 female undergraduate students (12 varsity fast-pitch softball players and 12 nonathletes) participated. The size of the visual field was measured via manual kinetic perimetry, and batting performance was assessed using a batting-skill test as well as batting averages for an entire competitive season. Analyses indicated that the mean visual-field size of softball players was significantly larger than that of nonathletes. However, there was no relationship between visual-field size and batting performance among the softball players. Results are discussed with respect to the origin of the superiority of visual-field size of softball players. PMID- 8684932 TI - Alcoholics anonymous and rational recovery: readability of the "big book" vs the small book. AB - Readability of the Big Book used in Alcoholics Anonymous confirmed Mills' finding of an 8th- or 9th-grade reading level, but readability of the Small Book for Rational Recovery required college level reading. PMID- 8684933 TI - Visual perception of area and hypnotic susceptibility. AB - The visual perception of area of geometrical figures was compared for subjects of high and low hypnotizability in experiments with direct comparison of two different geometrical figures. The Stanford Hypnotic Susceptibility Scale (Form C) was used to assess subjects' hypnotizability. No differences between 17 highly hypnotizable and 10 low hypnotizable subjects were found. Present results were also compared with those previously obtained for subjects of unknown hypnotizability. The model based on the Image Function Theory proposed earlier to explain the errors in area estimation committed by subjects of unknown hypnotizability was confirmed as a general rule. PMID- 8684934 TI - Spatial information and temporal representation in memory. AB - This study examined the effect of spatial cues on memory for temporal order. Improved performance for temporal order with added spatial cues was found only for certain directions and orientations. Dependent measures included memory for items, order, and response latency. The presence of a spatial cue had a significant effect on memory for order but not on memory for an item. For response latency, there were significant main effects for visual field and direction. There were also several significant interactions of visual field, direction, and orientation. The implications of these findings for the understanding of the relationship of spatial and temporal information in memory are discussed. PMID- 8684935 TI - A case study of improved performance in archery using hypnosis. AB - Active-alert hypnosis and traditional hypnosis procedures can be combined and applied in sport following the lines of an isomorphic model. A case study of improved shooting performance in an adult expert archer after 20 weeks of mental training is reported. PMID- 8684936 TI - Effects of batting performance feedback on motivational factors and batting performance in youth baseball. AB - The effects of batting feedback on motivational factors and batting of young baseball players were investigated. Hypotheses were that, compared to participants receiving feedback or no feedback on their batting average, those receiving contact average would exhibit (a) a greater increase in batting efficacy, (b) more enjoyment, satisfaction, and persistence, and (c) superior batting performance. Participants were 78 children from nine teams. Although analyses did not support the hypotheses, performance-to-efficacy correlations as well as other data provided tentative evidence for the premise that contact average may be more appropriate feedback for young players because (compared to batting average) it is less ambiguous and is based on a more realistic definition of success. Limitations and implications for coaches were discussed. PMID- 8684937 TI - An experimental test of "the mozart effect": does listening to his music improve spatial ability? AB - This experiment was designed as a test of the 1993 findings of Rauscher, Shaw, and Ky who reported a positive effect of listening to classical music on spatial reasoning. Present results do not demonstrate the "Mozart effect." In our study, 114 students were pretested on items from the Raven's Progressive Matrices- Advanced Form, then instructed to listen to either 8 min. of Mozart's music, relaxation instructions, or silence. Then subjects were posttested on an equivalent set of Raven's items. The subjects were also asked to provide information about their musical background and preferences. All instructions and treatments were audiotaped and played to individual subjects through earphones in the university language laboratory, ensuring standardization of procedures. Subjects in all 3 treatment groups showed a practice effect, but this improvement in Raven's scores was not dependent on the type of treatment received. There were no differences in Raven's scores among groups before or after treatment so our results do not confirm the prior ones. There was no evidence that the brief music had a different effect on subsequent problem solving according to listeners' musical background and training. PMID- 8684938 TI - Professional development. Parkinson's disease: knowledge for practice (continuing education credit). PMID- 8684939 TI - Admitting solutions. PMID- 8684940 TI - Problem power. PMID- 8684941 TI - Nurse-led clinics. Nurse practitioners managing anticoagulant clinics. AB - A combination of factors resulted in the reconsideration of how the anticoagulant therapy service was offered at Frimley Park Hospital in Camberley. The reduction in available staff led to the introduction of a nurse managed service. This has improved the service by cutting waiting times. Anecdotal evidence suggests that patients value the service. Objective measures of blood results suggest that the nurse-led service manages the patients as well as the previous medically led service. PMID- 8684942 TI - Nurse-led clinics. Care in pre-admission clinics. AB - This paper is essentially an evaluation of a newly established nurse-led orthopaedic pre-admission clinic. It centres around three key elements, namely patient satisfaction, length of in-patient stay and waiting list management. It is hoped that this evaluation will demonstrate the importance and the benefits of having an orthopaedic nurse co-ordinate the clinic so that patient education is given the priority it deserves. PMID- 8684943 TI - Nurse-led clinics. The growth of nurse-led care. AB - All four main winners in this year's NT/3M National Nursing Awards were from units which were either nurse or midwife-led. What is more, the winners all came from units providing services for out-patients. This article examines some of the reasons why nurse-led initiatives in out-patient settings seem to be a growth area for practice development. It will also examine issues around the function and effectiveness of such units. PMID- 8684944 TI - Fish-odour syndrome: dealing with offensive body odour. AB - This article is aimed at nursing professionals who may have been, or may be confronted with, patients who complain of fish-smelling body odour. The individual may be suffering from intermittent symptoms of the fish-odour syndrome. Recent contact with sufferers of such symptoms has highlighted the need to raise awareness among nurses about this syndrome. Sufferers expressed disappointment with regard to the advice they received from primary health-care professionals with respect to their problem. In content, the advice was variable but commonly centred around methods of increasing personal hygiene. Thus, the purpose of this article is to provide factual information about the fish-odour syndrome to increase awareness among nurses who could potentially aid the management of the syndrome and relieve some of the distress of its sufferers. PMID- 8684945 TI - Health promotion in general practice: the views of staff. AB - Since July 1993 general practices have been offered the responsibility for health promotion programmes to reduce coronary heart disease and strokes. This paper reports on a study which examined the views of GPs and practice nurses on the new arrangements for health promotion. It concludes that there has been an increase in paperwork as result of the changes. It also suggests that practices may have been over-ambitious in the level of health promotion they were trying to provide. PMID- 8684946 TI - Making sense of pulse oximetry and oxygen dissociation curve. AB - It is important to maintain oxygen supply to the tissues. The article reviews the physiology of oxygen transport and highlights the use of pulse oximetry as a versatile tool for monitoring the adequacy of patient oxygenation in various nursing situations. The practicalities of using a pulse oximeter are discussed. PMID- 8684947 TI - Fast action. PMID- 8684948 TI - Keys to the ideal home. PMID- 8684949 TI - An alternative vision. PMID- 8684950 TI - Analgesia: under patient control. PMID- 8684951 TI - New for old. PMID- 8684952 TI - Education. Practical conflicts. PMID- 8684953 TI - Education. The pitfalls of Project 2000. PMID- 8684954 TI - Myocardial infarction. Knowledge for practice. Part 1. PMID- 8684955 TI - On the bed-line. PMID- 8684956 TI - Why staffing has gone critical. PMID- 8684957 TI - Desperately seeking nurses ... PMID- 8684958 TI - Beastly dilemma. PMID- 8684959 TI - A case of priorities.... PMID- 8684960 TI - Animal experimentation ... or an abomination? PMID- 8684961 TI - The central issue. PMID- 8684962 TI - Lymphocytic leukaemia: classification and treatment. PMID- 8684963 TI - Individualised patient care: a framework for guidelines. AB - It is assumed that individualised patient care (IPC) benefits both patients and nurses. This study set out to clarify what IPC means to nurses and how they practise it, as well as how it is experienced by patients. With some exceptions, IPC was not practised widely in the seven wards used as case studies. Even in the wards where it was more common, there were some examples of bad practice. Factors that facilitated IPC were: the personal qualities of the nurses; a shared understanding among the ward team of the goals of nursing care and what constitutes good practice; levels of staffing and skill mix; effective leadership and management of nursing work. PMID- 8684964 TI - A student survey of older people in the Western Isles. AB - A group of six students nearing the end of the Project 2000 Common Foundation Programme became involved in a health and social assessment of the over-75s at a geographically remote GP practice in the Western Isles of Scotland. The aim was to provide a database of the island's population so that care in the community could be implemented more effectively. The methods used included a questionnaire and interviews. The collation of data and some of the interpretation were carried out by the students with support from teaching staff. This is an account of their experience and findings. PMID- 8684965 TI - Counselling: how should it be defined and evaluated? AB - Counselling is becoming an increasingly popular approach among nurses working with people with mental health problems. This paper explores some basic questions about counselling. What is it? How does it differ from other conversations and from psychotherapy? Does it actually work? If counselling is to become widely used in the nursing profession, these issues need to be addressed. PMID- 8684966 TI - A true complement? PMID- 8684967 TI - Self-catheterisation: A guide to this underused technique. PMID- 8684968 TI - Harriet's hassles. PMID- 8684969 TI - The placement dilemma. PMID- 8684970 TI - High anxiety. PMID- 8684971 TI - The race card. PMID- 8684972 TI - Flying high in America. Interview by Jane Cassidy. PMID- 8684973 TI - A vital consideration. PMID- 8684974 TI - When shareholders come before service. PMID- 8684975 TI - The full treatment. PMID- 8684976 TI - The causes of meningitis and meningococcal disease. AB - This article looks at the different causes of viral and bacterial meningitis, and gives a brief overview of these conditions. Meningococcal disease, including the incidence, signs and treatment, is described PMID- 8684977 TI - Meningitis: public health issues. AB - This paper describes a case-note review of 25 cases of meningococcal disease which occurred in the six months following distribution of pre-admission antibiotic treatment packs and prophylaxis advice packs. The data showed that while these interventions had improved some aspects of public health, and management of cases and their contacts, further action was needed PMID- 8684978 TI - Extra work but little respect. PMID- 8684979 TI - Making sense of arterial blood gases and their interpretation. AB - The measurement of arterial blood gases provides insight into the clinical condition of patients with acute illness. This article discusses the theory and terminology used, introduces the analysis of results and gives an overview of how samples are taken PMID- 8684980 TI - Nurse-led management of minor illness in a GP surgery. AB - This study reports on an intervention in which a practice nurse saw patients with acute minor illnesses presenting to one general practice. Three hundred and forty three patients were seen, of whom 328 (96%) were managed by the nurse alone and 145 (42%) were given prescriptions. In a time of increasing pressure on all members of the primary health-care team, interventions such as this need careful consideration and require a review of the relative roles of nurses and general practitioners PMID- 8684981 TI - Using health promotion to support volunteer workers. AB - Volunteers face the same potential stresses and anxiety at work as paid workers, but may not have access to sources of support. This paper describes how one hospice approached meeting the mental health needs of its volunteers PMID- 8684982 TI - Complementary medicine. Safe practices. PMID- 8684983 TI - Sensory delights. PMID- 8684984 TI - The legacy of Nightingale. PMID- 8684985 TI - Flotation beds. PMID- 8684986 TI - Myocardial infarction. The role of the nurse. Part 2. PMID- 8684987 TI - New traditionalist. PMID- 8684988 TI - Publicly investigated. PMID- 8684989 TI - Service under scrutiny. PMID- 8684990 TI - The three professors. PMID- 8684991 TI - [Genomic imprinting and human pathology. 2]. AB - Genetic imprinting does occur in humans. This is manifest at the level of the genome, the individual chromosome or subcromosomal region, and the single locus. Genomic imprinting is manifest in the developmental defects of hydatiform mole, teratoma and triploidy. Chromosomal imprinting effects are revealed when uniparental disomy or deletion occur as costitutional aberration or in tumural tissues. Evidence at the single gene level comes from an increasing number of autosomal dominant genetic diseases. This part of the paper will briefly review the importance of imprinting in the contest of human genetic diseases. PMID- 8684992 TI - [Magnetic resonance imaging and hypothalamo-hypophyseal disorders in children: morpho-functional and etiologic aspects]. AB - In recent years magnetic resonance (MR) has improved the diagnostic accuracy of the study of the sellar area. In patients with growth hormone deficiency, particularly when associated with other hormonal defects, MR has identified the picture characterized by posterior lobe ectopia, non-visible stalk, hypoplasia of the anterior lobe and presence of intrasellar CSF (empty sella). The latter is not exclusive of growth hormone deficient patients, but can be found also in children with disorders of puberty. Although a certain relationship between pituitary height and growth hormone secretion has been described, it is usually difficult to find a clear association between pituitary dimensions and function of the gland. The theory supporting the congenital origin of the above mentioned abnormalities, which may be part of midline abnormalities, is currently sustained by most Authors. In diabetes insipidus the posterior lobe may or may not be visible and a thickened stalk has been found in patients with disease duration of less than 2 years. In disorders of puberty morphological abnormalities of the sellar area are rare. In girls with precocious puberty the pathological findings described are hamartoma of the tuber cinereum, empty sella and pituitary height increased for age. There seems to be a certain relationship between gonadotropin secretion and pituitary dimensions. PMID- 8684993 TI - [Calcium-phosphorus metabolism in celiac disease in children]. AB - The Authors studied the changes of the main parameters of calcium-phosphate metabolism in twenty four untreated celiac children (mean age: 23.7 +/- 14.4 months) and in eleven control subjects (mean age: 28.5 +/- 21.2 months). 16 patients were checked again one and three months after treatment was begun. Compared with controls patients show at diagnosis a significant increase of serum phosphate (P = 0.025) and a decrease of calcitonin levels (P = 0.02), whereas serum calcium is slightly lower and parathyroid hormone higher with serum levels above normal range in 5 of the coeliac patients (20.8%). During the three months of gluten free diet we find a significant increase of calcemia values (ANOVA: P = 0.025) together with a decrease of serum phosphate (ANOVA: P = 0.009) and of parathyroid hormone levels (ANOVA: P = 0.042). No significant change was found in vitamin D metabolites levels. The Authors conclude that coeliac disease affect clearly mineral metabolism. Actually the tendency to hypocalcemia, due to abnormalities of the intestinal mucosa, and the comparative iperphosphatemia, cause in some patients a compensatory increase of PTH levels. This increase seems to be the cause of the osteoporotic lesions described in current literature. Rickets due to the lack of vitamin D does not occur. PMID- 8684994 TI - [Computerized stabilometry in the monitoring of antiepileptic therapy in children]. AB - Computerized stabilometry is an useful test to monitor postural effects of anticonvulsant therapy in adults. Our study was carried out on 65 epileptic children: 51 were treated with CBZ or PHT or VPA or PB in monotherapy, and 14 were not on therapy, in the aim to observe abnormalities of postural control in pediatric population. Computerized stabilometry has to be considered auxiliary monitoring to evaluate toxic effect of anticonvulsant therapy in children. PMID- 8684995 TI - [A morphological study of ciliary abnormalities in patients with immotile cilia syndrome]. AB - The present study has the aim of studying the morphological aspects of ciliary abnormalities in patients affected by immotile-dyskinetik cilia syndrome. Five patients affected by primary ciliary dyskinesia have been studied, examining by TEM the cells obtained by bronchial brushing during fiberoptic bronchoscopy. Many types of anomalies have been observed, and a morphologic classification was proposed. The frequency of abnormal cilia appears to be correlated to the severity of respiratory pathology. The morphological anomalies are not specific for this pathology. PMID- 8684996 TI - [Limits in the evaluation of bronchial reactivity in children with asthma]. AB - Bronchial hyperresponsiveness (BHR) reflects an exaggerated sensitivity of airways to pharmacologic and/or physical stimuli. Patients with symptomatic asthma often have a higher degree of BHR than nonasthmatics, even though BHR shows a variable relationship with the clinical expression of the disease and with medication requirements. Methods of bronchial challenge, initially developed in adults, are increasingly employed also in children. The Authors discuss the clinical significance of the evaluation of bronchial responsiveness in the diagnostic approach and follow-up of children with asthma. Some methodological aspects and limits of bronchial challenging in childhood are expecially addressed. PMID- 8684997 TI - [Correlations of the response to the prick test and blood levels of specific IgE in children]. AB - A good correlation between intensity of prick test result and haematic levels of specific IgE is a fundamental presupposition to affirm that both diagnostic methods are equivalent to demonstrate a condition of IgE-mediate hypersensitivity. Using a retrospective analysis of our data, we intended to examine the degree of this correlation for the most common food and inhalant allergens. The comparison between prick test results and specific IgE haematic levels for all considered allergens-shows a good concordance of F.A.S.T. for prick negative results and a sharp discordance of F.A.S.T. for prick positive results. Both food and inhalant allergens are equally involved in the discordance between the tests. Therefore, we cannot exclude the possibility of clashing results between prick test reaction and specific IgE haematic levels, even in further analysis would be necessary to obtain more reliable verifications. PMID- 8684998 TI - [Early neonatal manifestations of group B Streptococcus infection: case series and preventive strategy]. AB - Group B Streptococcus (GBS) is, so far, one of the most important causes of neonatal morbidity and mortality. In order to elucidate the extent of this problem a screening for GBS has been performed on a group of pregnant women and their neonates. Maternal vaginal and rectal swabs were obtained on admission to the labor area. In these infants throat swabs at birth and throat and rectal swabs on day 4th and 6th were obtained. In the 14,248 pairs mother/infant examined, the rate of colonization was, respectively, 9 (7%) and 4 (1%). 6 among 569 colonized newborn show evidence of the early onset type infection (respiratory form: 2 cases; meningitic form: 4 cases). Fatal outcome and severe neurologic impairment were observed respectively in 3 and 1 patient. Risk factors (prematurity) were present only in two patients. In all cases clinic evidence was observed before that laboratory findings were disposable. The Authors remark the importance of the bacteriological screening in pregnancy, and of antibiotic therapy intrapartum in women with risk factors and in colonized newborn in the first hour of life when acute phase reactants are positive. PMID- 8684999 TI - [Results of specific neonatal screening for congenital dysplasia of the hip at the Vicenza Hospital. A prospective study of subjects at risk]. AB - The aim of the study was to evaluate the incidence of pathological neonatal hips in the community served by the central Vicenza local health authority and to establish a protocol to minimize demands on available equipment, staff and the family. From May 1992 to May 1993 all neonates at San Bortolo Hospital in Vicenza were subjected to specific clinical examination of the hip by staff experienced in neonatal care. Neonates then underwent ultrasound examination--catalogued according to Graf--if they presented risk factors (dynamic ultrasound test was omitted). The orthopaedic examination was carried out in all cases. The total number of neonates involved was 1939 (994 m., 945 f.). Of these, 142 (7.3%) underwent ultrasonography (60 m., 82 f.). Family history and breech delivery were the most frequent anamnestic risk factors justifying ultrasound examination while among objective risk factors the most frequent being a clicking sound. Considering the clinical and ultrasound findings the resulting overall incidence of pathological hips is 0.25%. So far, there have been no late cases of c.d.h. A screening protocol such as ours cannot realistically aim to identify all pathological hips, however the great majority can be diagnosed at this early stage. Resources comparable to those used for our study are available to many other local health authorities. Higher diagnostic standard depend closely on local health policy. PMID- 8685000 TI - [Fungal infections in pediatric oncology]. AB - The clinical charts of cancer patients with documented fungal infections hospitalized at G. Gaslini Children's Hospital, Italy, from 1980 to 1990 were reviewed. Thirty-seven episodes developing in 37 patients were identified, based on microbiological and/or histological documentation. Patients' age ranged from 3 months to 18 years (median 7 years). Twenty patients were treated for hematological malignancy and 17 had solid tumor. Seven patients (3 with leukemia and 4 with solid tumours), developed mycosis after bone marrow transplantation procedure. A history of neutropenia in the month preceding the documentation of fungal infection was present in 76% of cases (28 of 37). However, only 16 of 28 (55%) of these patients were still neutropenic at time of diagnosis. In 40% of the cases the fungal infection developed as primary infection not preceded by any febrile and/or infectious episode. Fungemias without evident organ localization accounted for the 40% of episodes with a mortality rate of 20%. The other 22 cases (60%) were classified as invasive mycoses; 9 of these patients died (41%). Mortality was higher among patients with mold infection (5 of 7, 72%), than in those with yeast infection (7 of 29.24%). Molds infections and invasive mycoses were virtually absent in the first part of our period of observation (1980-84), but emerged in the second period (1985-90) when also the incidence rate of fungal disease increased (from 2.67/10,000 person/day to 5.93), probably in relation with extensive construction works and with the implementation of a bone marrow transplantation program. PMID- 8685001 TI - [Systemic lupus erythematosus: description of a pediatric series]. AB - We describe 11 cases of Systemic Lupus Erythematosus (SLE) with pediatric onset (10 females and 1 male). Mean age at onset was 10.9 years (range 3 to 16 years). Initial manifestations: cutaneous involvement in 7 cases, articular symptoms in 7 cases, renal involvement in 5 cases (proteinuria and/or microhematuria, or renal failure), pancytopenia in 3 cases. In 3 cases the onset of the disease was extremely sudden and severe: one patient had an intestinal infarct following mesenteric thrombosis associated with glomerulonephritis; another started with encephalopathy (deep coma, stage III); a third patient presented renal failure due to acute glomerulonephritis. At diagnosis all patients received systemic steroid therapy with the exception of one who had only a cutaneous involvement. The course of the disease is described. We underline that, in our series, it was rare for organs and systems, apart from the central nervous system, to be involved in exacerbations after initial onset of the disease. Six patients are presently asymptomatic or have only minor cutaneous and/or articular manifestations which are well controlled with low-dose cortisone therapy. Laboratory indices did not return to normal in any of the patients. In fact, in our series the disease doesn't appear to reach a complete remission, even many years after onset and no patient seems to be able to withdrawal the therapy at all. Our data confirm, according to other Authors, that the course of LES with paediatric onset is more severe than in adults. PMID- 8685002 TI - [Retroperitoneal nodular fasciitis: analysis of a case]. AB - A case of nodular fasciitis occurring in a 14-year-old girl is described and the clinical-pathological profile and the diagnostic problems are analyzed. The Authors believe this report useful to be reported for the relative rarity of the disease, especially in children, the very great dimension and the unusual retroperitoneal localization. PMID- 8685003 TI - [Antiphospholipid antibody syndrome as a possible cause of paresis in a child]. AB - The Authors report on the case of a 4-year-old boy, admitted to the pediatric department for left hemiplegia. CT scan of the brain was negative on the day of admission but, on the following day, showed 3 small hypodense focal lesions in the posterior branch of the internal capsule, in the knee of the internal capsule and in the posterior parietal region of the cortex. The acute phase almost completely resolved in 10 days. Twenty days after presentation, cerebral angiography showed a thrombosis of an anterior, right perforating vessel, together with the hypoplasia of the horizontal portion of the cerebral anterior artery. The determination of anti-cardiolipin antibodies, even though performed far from the acute phase of the disease, showed a low IgG positivity. Two months after the onset the neurological symptoms completely resolved. In the presence of hypoplasia, narrowing and other lesions of cerebral vessel, it is possible to hypotesize that the occurrence of thrombotic fenomen, ascribable to anti phaspholipid antibodies, is responsible for the neurological symptoms. The association of thrombosis and anti-phospholipid antibodies suggest that the assessment of anti-phospholipid antibodies should be routinely performed in the presence of thrombotic phenomena. PMID- 8685004 TI - [A case of chronic progressive external ophthalmoplegia with severe scoliosis]. AB - The Authors reports a case of myopathy with severe scoliosis which can be classified within the context of chronic progressive external ophthalmoplegia (CPEO) and discusses the complex etiopathogenetic, histological and clinical aspects of this mitochondrial myopathy. In particular, they underlines the severity of the scoliosis and muscular, bone and respiratory symptoms in this case and the important role played by histological, histochemical and biochemical aspects in the diagnosis. PMID- 8685005 TI - [A case of slowly resolving enteritis caused by Clostridium difficile]. AB - Clostridium difficile is considered as the most important cause of severe antibiotic-associated diarrhea and pseudomembranous colitis. We describe the case of an one year old boy presenting C. difficile chronic diarrhea without previous antibiotic treatments. PMID- 8685006 TI - [Recurrent facial paralysis in a child with renovascular hypertension]. AB - Hypertension is rarely observed in childhood. The renal diseases are the most common causes of this condition. Headache, seizures, cranial nerve palsy and hemiplegia are the most frequent neurological manifestations. The Authors report on a patient with a severe involvement of central nervous system due to renal hypertension. The main clinical features were recurrent episodes of facial nerve palsy. PMID- 8685007 TI - [Tuberculous meningitis. A case with severe ocular complications]. AB - Tuberculosis in the world is the mean cause of death from single infectious agent. It is reported increase not only in underdeveloped countries but in developed too. Tuberculosis meningitis is a very serious form of tuberculosis. Outcome in tuberculosis meningitis is associated with the stage of the disease at presentation. When the child at presentation is extremely ill with coma the completely recovery is seen only in about 20% of cases. In our case patient had severe ocular complications: optochiasmatic tuberculomas. It is difficult recognize the two forms of tuberculomas intra- and perichiasmatic even with RNM. The good response at intrathecal therapy with recovery of the visus proves the perichiamsatic localitation of tuberculomas. PMID- 8685008 TI - [A case of reflex sympathetic dystrophy in childhood]. AB - Reflex sympathetic dystrophy, a well-described clinical entity that is frequently encountered in adults, is uncommonly reported in children. We report a case of reflex sympathetic dystrophy in a little girl aging 8 years. The main symptom was the acute pain referred to the right lower extremity. We underline once more the difficult of diagnosis and the contribution of 3-phase bone scan. PMID- 8685009 TI - [Gardner syndrome]. AB - The observation of Gardner's syndrome case, in a six year old girl, referred to the hospital for seizures, provides the Authors with the opportunity of reviewing that important subject of the medical and surgical clinical pathology. The diagnostic features and differential diagnosis are described. The current criteria for diagnosis and surveillance of the affected or at risk subjects are outlined. Today the molecular, and, thereafter, the prenatal, neonatal and preclinical diagnosis of the disease, is possible. PMID- 8685010 TI - [Peutz-Jeghers syndrome]. AB - An observation of Peutz-Jeghers syndrome, in a 13 year old girl, provides the Authors with the opportunity of reviewing the clinical features, the natural history and the complications of the disease, mainly the malignancies. In recent reviews the occurrence of cancer was further on investigated: gastrointestinal and non gastrointestinal tumors occurred in 22-48% of the patients examined. The surveillance protocols of the subjects at risk and genetic counseling are discussed. PMID- 8685011 TI - [Catering services in schools for children (critique and operative proposals)]. AB - Several protests by pupils' parents against bad-quality of food given in school meal--widely and minutely reported by local press--advised Autors to give due emphasis on some deficiencies in school-meal administration, rightly denounced by relatives. To cut down health troubles, Authors suggest to commit school-meal's management to catering firms for their great experience in field of collective meal. In fact they have implements and competence to check properly: -education and skill of staff attached to school-meal and distribution; -places, structures, tools used to get meals; -victualling, carriage, storage and condition of food maintenance; -the fancy diets, appropriately diversified by age. Authors think that each school should have places, structures and tools to prepare and take meals and should engage a sole firm both for cooking and serving school-meal. PMID- 8685012 TI - [Therapeutic obstinacy: knowledge of limits]. PMID- 8685013 TI - [Pathology of sexual development]. PMID- 8685014 TI - [A case of type II achondrogenesis]. AB - We describe a rare case of type II achondrogenesis (gestational age = thirty-two weeks) dead forty-five minutes after birth. This congenital skeletal dysplasia is classified among the lethal osteochondrodysplasias. Clinical features were enough for diagnosis and autopsy added nothing to our clinical knowledges. PMID- 8685015 TI - [Pertussis. Critical revision of its physiopathology. Implications]. AB - The re-examination of Bordetella pathogenic power and of the mechanisms which regulate relations between these bacteria and men make us conclude that in pertussis and with intramuscular vaccines an antihistaminic "coverage" is needed and antipertussis vaccinations is to be made by natural way. Via aerosol, minor intrinsic toxicity of acellular vaccines will be determinant. PMID- 8685016 TI - [Normal pubertal development]. AB - Puberty, the period of transition between childhood and adulthood, is the result of sequential changes in endocrine activity determined largely by genetic factors. The process is controlled by a number of complex neuroendocrine factors for its onset as well as its progression to full sexual maturity. The Authors summarize the morphological, biometric and hormonal changes and the factors of neuroendocrine control of puberty. PMID- 8685017 TI - [Acceleration of pubertal development]. AB - Sexual precocity is defined as the appearance of physical signs of puberty at a time -3 SD before the mean age for the population, that is before 8 years for girls and 8.5-9.0 years for boys. The Authors discuss about etiology, therapeutic approach, indications for treatment, results and still open problems in this condition. From the pathogenetic point of view disorders that induce sexual precocity can be classified as gonadotropin-releasing hormone (Gn-RH) dependent or Gn-RH independent. Premature activation of the hypothalamic Gn-RH pulse generator may be induced by malformations, tumours and other neurogenic lesions of the CNS, while in more than 70% of patients the primary factor is not identifiable (idiopathic form). Idiopathic true precocious puberty is more frequent in females, whereas in males CNS lesions, especially neoplasms, are more prevalent. The main aims of therapy in precocious puberty are to inhibit puberty, to stop and possibly reverse the progression of secondary sex characteristics and particularly menses, to slow down skeletal maturation, to delay epiphyseas closure and consequently to improve final height, to preserve fertility, to improve psycho social well-being and naturally to treat the underlying cause, when known. Gonadotropin-releasing hormone agonists (Gn-RHa) are now the therapy of choice when the disease is Gn-RH dependent. They are effective both in arresting pubertal development and in improving final adult height. In selected cases with a great reduction of growth velocity an association with hGH therapy is possible. We must pay special attention to bone mineralization with this kind of treatment at this very delicate age. PMID- 8685018 TI - [Delayed puberty]. AB - Delayed puberty can be defined as the absence of any signs of puberty in subjects that have attained an age at the upper limit (+2DS) for the onset of puberty, that means 13 years in girls and 14 years in boys. The causes of delayed puberty can be classified into three groups, functional temporary impairment in gonadotropin and sex steroid secretion (most frequently constitutional delay of puberty), hypothalamo-pituitary failure with deficiency in gonadotropin secretion, primary gonadal failure with increased gonadotropin levels. The Authors discuss about etiology, diagnostic testing and therapeutic approach in these conditions. The majority of children with delayed puberty are males that have only a constitutional delay of growth and puberty. It is difficult, in teenage years, to distinguish this common and benign condition from true gonadotropin deficiency, in spite of the variety of endocrine tests developed for this purpose. Individuals with constitutional delayed puberty with a bone age greater than 11.5 years, show after triptorelin stimulation an increase in LH capable of distinguishing them from patients with gonadotropin deficiency. In our opinion this could be an important screening test to exclude gonadotropin deficiency in boys with delayed puberty. PMID- 8685019 TI - [Sex differentiation and its anomalies]. AB - Sex determination and differentiation is a sequential process that involves genetic, gonadal, phenotypic and psychological sex. Sex determination is primarily testis determination. The primary event is differentiation of the gonad; all subsequent sexual differentiation is hormonally controlled. The Authors present a classification of abnormal sexual development and consider the errors of primary sex differentiation (anomalies of sex chromosomes and of gonadogenesis) and the errors of sexual differentiation (inadequate masculinization of genetic male and virilization of genetic female). At the end the clinical approach to disorders of sexual differentiation is briefly considered. PMID- 8685020 TI - [Variations in renal hemodynamics during acute renal insufficiency in anoxic neonates]. AB - The purpose of this study is to verify if the increase of renal resistance, along with the consequent reduction of glomerular filtrate, and the activation of renina-angiotensin system, could be attributed to not only neonatal acute hypoxia but to other factors as well. These factors could provoke an increase in renal vascular resistance (R.V.R.), a reduction of renal blood flow (R.B.F.) and renal glomerular filtrate (R.G.F.) condition. These components are present in angiotensin as well as in endothelin (ET1), a potent peptide from vascular endothel with vasoconstricting action and whose secretion increases during hypoxia. The Authors have studied and compared two groups of newborns. The first group of newborns was affected by perinatal asphyxia or hypoxia of variable seriousness. It included 24 newborns with gestational age between 37 and 41 weeks and with a birth weight between 3.200 gms and 3.500 gms. The second, control group, was made of an identical number of newborns of the same gestational age with a weight adequate to the birth age. The dosage of the ET1 was evaluated on the plasma, using the RIA method. The diagnostic criteria for this evaluation included clinical and biohumoral evidence (tab. 1). Between the two groups, group 1 with anoxic syndrome showed the more intense increase of ET1. This increased is due to either an increase value of plasmatic creatinine that is present in normal situations or in physiopathologic role played by the ET1 in course of acute renal failure after asphyxia. PMID- 8685021 TI - [Neonatal ultrasonic screening and follow up of urinary tract malformations]. AB - 1881 consecutive healthy newborn babies underwent abdominal ultrasonography on day 4-6. 228 subjects presented an echographic abnormality. Renal abnormalities were diagnosed in 213 newborn. Of those, 134 had dilatative uropathy with a pelvic diameter greater than 5 mm, 73 renal medulla hyperechogenicity, 3 ectopics, 2 unilateral renal agenesis and one horseshoe kidney. Extrarenal findings were present in 15 neonates: 11 with surrenal gland haemorrhage and 4 with hepatic ultrasonographic alterations. Grignon classification was used for evaluation of the dilatative urinary tract abnormalities. In 173 renal pelvis (134 neonates) the anteroposterior diameter was found > 5 mm: 97 were classified as GI (5-10 mm), 45 as GII (10-15 mm), 13 as GIII ( > 15 mm), 11 as GIV (moderate dilatation of the calyces with easily identified residual renal cortex) and 7 as GV (severe dilatation of the calyces with atrophic cortex). The follow-up of 72.3% of these abnormalities showed a spontaneous normalization in 90% of GI, 73% of GII and 58% of GIII. Only one patient with GIII demonstrated progressive dilatation and he underwent corrective surgery. 15 of the 17 newborn with severe uropathy (GIV-GV), had regular follow-up. 8 underwent surgery and 7 showed a progressive spontaneous recovery and in 4 of these cases a complete resolution. The ultrasound follow-up of all cases of renal medulla hyperechogenicity and surrenal gland haemorrhage shows a spontaneous resolution without any clinical or biochemical complication. PMID- 8685022 TI - [Prevalence of HCV antibodies and vertical transmission of hepatitis C virus]. AB - HCV infection is one of the most frequent causes of hepatitis in man. There are numerous means of infection, not all of which can be documented. In infancy HCV infection occurs particularly in children that have been multitransfused or are on dialysis. Vertical transmission of HCV infection is rare, and the times and means of occurrence are not as yet well defined. The present study sets out to establish the prevalence of HCV-Ab carriers within a population of 4,242 pregnant women in Verona (Italy). It also aims to assess the incidence of vertical transmission of HCV infection in a sample of newborns examined over a 15-months follow-up. Of the 4,242 pregnant women subjected to screening, 45 (1.06%) were HCV-Ab positive. In only 74% of the cases it was possible to identify an HCV infection risk factor. On the 45 children of the HCV positive mothers, at present 25 have completed the 15 months follow-up. Only one of these children has contracted the infection: the incidence of transmission is therefore 4%. PMID- 8685023 TI - [Interactions between drugs and food in pediatric age]. AB - Interactions between food and drugs represent a very interesting chapter even in paediatric field, although this subject has not been very treated so far. We have tried to locate common points between pharmacology and elementary metabolism, in order to divide drug-food interactions into five great categories, according to the scheme suggested by Vannucci and Capriati. This scheme is based on the phases in which the interactions take place: 1) before gastroenteric absorption; 2) during gastroenteric absorption; 3) during distribution and storage in tissues; 4) during process of bio-transformation; 5) during excretion. If we want rationally to give a drug, we must exactly know its pharmacokinetic, particularly in paediatrics. In fact, we can avoid detrimental interactions drug-food merely adjusting the pharmacologic dosage to the particular diet of the considered child and vice versa. PMID- 8685024 TI - [Diagnosis of food allergy and IgG4]. AB - We compared specific IgG4 levels in a group of children with food allergy and in an healthy control group. The results show no significant differences in the values of specific IgG4 levels between the two groups of children. PMID- 8685025 TI - [Liver damage and obesity in pediatric age]. AB - In adult obese patients both an increase of aminotranspherase values and hepatic steatosis have been frequently showed. Conversely in childhood the existence of a liver's damage is often not investigated. To assess the prevalence of hepatic alterations in obese children, we studied 135 subjects, all affected by simple obesity, showing in a 20% of them the presence of ultrasonographic evidence of hepatic steatosis and/or hyperaminotransferasemia. Our study demonstrates the existence of silent hepatic alterations also in obese children and suggests to improve the treatment of obesity in childhood to prevent the progression of liver's damage. PMID- 8685026 TI - [Evaluation of a rapid and simple ambulatory method for the determination of HbA1c in diabetic children]. AB - The aim of this study was to compare a simply and quick outpatient method for the determination of HbA1c (DCA 2000 Bayer) to a laboratory immunoturbidimetric method (B M Hitachi 911). We have determined HbA1c in 139 subjects (120 diabetics and 19 healthy controls, 81 males and 58 females, mean age ( +/- DS) 14.4 +/- 6.41 years, range 2-40) with the two methods at the same time. The HbA1c normal range, determined by DCA 2000 and by laboratory method, were 4-5.2% and 4.5-6% respectively. The HbA1c values determined with both methods were significantly correlated (r = 0.91; p < 0.001). In 16 diabetic patients, chosen for their reliability, the HbA1c values determined by DCA 2000 were significantly correlated to the last two month mean glycemic level preceding the test. In 14 healthy subjects HbA1c was determined simultaneously by DCA 2000 in capillary and venous blood samples. The values were similar. The DCA 2000 method showed to be reliable, simply to use, no traumatic and ideal for pediatric outpatient use. PMID- 8685027 TI - [Abdominal pain syndrome recurring after 40 years: critical revision]. AB - Recurrent abdominal pain (RAP) syndrome is described by Apley 40 years ago. The definition of condition, still generally accepted, is at least three episodes of abdominal pain over a period of three months, with pain of intensity which affects the behaviour of the child. The prevalence of condition among school children is 10-15%. Apley's classic studies demonstrated organic disease in only 10% of the children. Apley's conclusions have dominated pediatric writing through present era. In recent years, however, a number of reports have appeared in the medical literature that have suggested that careful investigation of children with RAP may reveal previously unsuspected functional or morphologic abnormalities of the gastrointestinal tract. These have included reports of peptic disease and Helicobacter Pylori infection, abnormal antro-duodenal motility, lactase malabsorption, gastro-esophageal reflux. Nevertheless these abnormalities cannot be correlated always with specific complaints. Therefore pathogenetic background is not clarified. Despite greater understanding of these disorders the enigme remains. There is a need for controlled studies in non selected patients. PMID- 8685028 TI - [Oral rehydration in infants with acute diarrhea: using a new preparation of reduced osmolarity]. AB - Oral rehydration solutions (ORS) are widely employed in the treatment of acute diarrhea in children. Although several studies in the recent literature prove the efficacy and safety of newly formulated, reduced-osmolarity solutions, and a specific working group of the European Society for Pediatric Gastroenterology and Nutrition (ESPGAN) has made similar recommendations, such evidence in our Country is lacking. To this aim, we enrolled 38 children (age from 3 to 24 months, average: 8.2) with acute diarrhea lasting from no more than 5 days (average: 2.5). At observation, dehydration was found to be: absent in 12 (31.6%), mild in 19 (50%), moderate in 5 (13.2%), severe in 2 (5.2%). The last 2 patients were admitted and treated i.v., thus excluded from the study. In the 36 remaining children, a pathogen was identified in 25 (69.4%): Rotavirus in 18, Salmonella in 4, EPEC in 2, Cryptosporidium in 1. Stool Clinitest was positive in 7/31 children, all with Rotavirus infection. All the patients received ad libitum for the first 4-6 hours exclusively a reduced-osmolarity ORS formulated according to the ESPGAN criteria. Afterwards, they were fully re-fed and were also given the same ORS until diarrhea stopped. Most of the children accepted the ORS; those who refused it were either not dehydrated and/or older than 15 months. Thirty-three out of 36 children were fully rehydrated after 12 hours, without any side effects. We conclude that such an ORS is safe and effective in the treatment of children with acute diarrhea in our settings. PMID- 8685029 TI - [Mutation analysis in Hunter patients]. AB - Mutations of the iduronate-2-sulfatase gene have been identified as responsible of Hunter syndrome or mucopolysaccharidosis type II. About 20% of the patients have deletions of the whole gene or other major structural alterations. The mutations found so far include: 34 missense, 8 nonsense, 11 small deletions from 1 to 3 bp, 2 deletions of 8 pb, 2 insertions of 1 bp and 2 insertions of 14 bp, with most leading to a frameshift and premature chain termination. Also 8 different splice-site mutations leading to insertions or deletions in the mRNA have been tabulated. Knowledge of the primary genetic defect allows insight into genotype-phenotype correlation and allows a better understanding of the structure and function of iduronate-2-sulfatase. PMID- 8685030 TI - [Intracranial arachnoid cyst in pediatric age]. AB - Arachnoid cysts are a pathological condition in which an arachnoid-lined cavity is filled with a CSF-like fluid, often creating a disturbance in intracranial dynamics, due to shift and displacement of surrounding structures, and intracranial hypertension. Primary or congenital arachnoid cysts are maldevelopmental anomalies and contain clear CSF-like fluid. Acquired cysts may result from a variety of aethiologies such as traumas and infections. In these cases the intracystic fluid may be emosiderin-stained or may contain inflammatory cells. A general survey of this peculiar pathological finding in the pediatric age group is reported by the Authors in this paper. PMID- 8685031 TI - [Mucopolysaccharidosis II (Hunter syndrome): identification of the carrier state of the disease by means of mutation analysis]. AB - Identification of iduronate-2-sulfatase (IDS) gene mutations in patients with mucopolysaccharidosis type II (MPS II, Hunter syndrome) allows fast and reliable carrier detection in females, relatives of the patients. We describe here a study on a Hunter family where, after the identification of the primary genetic defect in the patients, we identified carriers unambiguously among at-risk female relatives and excluded such status in other subjects. This is an example of direct, DNA based diagnosis. PMID- 8685032 TI - [Malignant sacrococcygeal teratoma: report of a case of "explosive" intrauterine growth]. AB - An exceptional case of fetal sacrococcygeal teratoma with an exclusive abdominopelvic growth is described. The tumor was not detected on a "routine" ultrasound study obtained at 31 weeks of gestation showing findings of a severe congenital uropathy. It remained unrecognized until the 34 weeks of gestation when the mass began an explosive growth causing a rectouretral fistula. Despite appropriate obstetrical and surgical management the baby died 24 hours later because inadequate pulmonary maturity. The istological findings showing malignant elements such as embryonal carcinomas. PMID- 8685033 TI - [Marinesco-Sjogren syndrome with chronic progressive ophthalmoplegia caused by presumed defective oxidative phosphorylation]. AB - A case of Marinesco-Sjogren syndrome (ataxia, cataracts, retarded somatic and mental maturation, spasticity) with myopathy, hyperlactacidaemia, hypopyruvicaemia, chronic progressive external ophthalmoplegia was reported and relationships with the cerebellar ataxias of unknown aetiology discussed. In the personal case of Marinesco-Sjogren syndrome with hyperlactacidaemia and hypopyruvicaemia a defective oxidative phosphorylation in mitochondria is supposed. PMID- 8685034 TI - Injury-specific cytotoxic response of tumor cells and endothelial cells. AB - Cytotoxicity indicated by increased release of prelabeled 51chromium (51Cr) and lactate dehydrogenase (LDH) was studied in human prostate cancer and melanoma cells in cell culture following irradiation or exposure to several injurious substances. These changes were compared to those observed in bovine aortic endothelial cells (BAEC) subjected to identical treatments. Further, the effect of irradiation on plasminogen activator (PA) secretion from prostate cancer cells, and the effect of glycine on radiation-induced cytotoxicity in BAEC were also investigated. Radiation, lipopolysaccharide and xanthine/xanthine oxidase stimulated no release of 51Cr or LDH from tumor cells, while these treatments induced a dose- and time-related loss of those cytotoxic indicators from BAEC. Protease, elastase and Triton X-100 incited loss of 51Cr and LDH from all three cell types. Radiation, lipopolysaccharide and xanthine/xanthine oxidase have been shown to cause cell injury via a common pathogenic pathway of oxidant generation. Tumor cells appear quite resistant to oxidant stress. Cell damage precipitated by protease, elastase and Triton probably involves hydrolysis of proteins and phospholipids in the cell membrane, leading to an increased leakage of intracellular proteins such as LDH and those bound with 51Cr. Radiation caused a dose- and time-related reduction in the secretion of PA from prostate cancer cells. PA is alleged to play a role in tumor metastasis; the reduced secretion could be another beneficial effect of radiation, in addition to interruption of cell proliferation, in the impediment of tumor growth and spread. Glycine diminished cytotoxic injury of BAEC inflicted by radiation. This amino acid may prove useful in offering a degree of protection of normal tissue against radiation associated side-effects. PMID- 8685035 TI - Stereological evaluation of malignant mesothelioma versus benign pleural hyperplasia. AB - The differential diagnosis between malignant mesothelioma and benign pleural hyperplasia constitutes a well-known problem. In the present study we examined unbiased stereological techniques to assess the mean nuclear volume (MNV) using the point-sampled intercepts (PSI) in 37 cases of malignant mesothelioma and in 28 cases of benign pleural hyperplasia. Neither the use of different fixatives nor the histological type of malignant mesothelioma produced any significant difference on the measured nuclear volume. The differences observed between the MNV data obtained from benign pleural hyperplasia and those from any of the three types of malignant mesothelioma were found to be highly significant. All lesions with an MNV larger than 250 microns3 were found in our study to correspond to the malignant mesothelioma type, while an MNV that was smaller than 200 microns3 could only be detected in benign specimens. These observations lead us to propose the MNV measurement using PSI as an additional tool to enhance the differential diagnosis of malignant mesothelioma versus benign pleural hyperplasia. PMID- 8685036 TI - Parathyroid hormone-related peptide: immunolocalisation in normal salivary glands and in pleomorphic adenomas. AB - Parathyroid hormone-related peptide (PTHrP) has been shown to be produced as an early step in the differentiation sequence and is considered to be a marker of some progenitor cells. We investigated the presence and distribution of PTHrP in 7 normal parotid glands and in 18 salivary pleomorphic adenomas (PA). Localisation of PTHrP was studied by immunohistochemistry with a three-step unlabelled peroxidase-antiperoxidase method. In the normal glands PTHrP is found mainly in the basal and dark cells, and to a lesser extent in the light cells of the ducts. In PA the inner layer of tubulo-ductal structures and all cells of the cyst-like structures show strong positivity for PTHrP. Scattered cells in the dense clusters also stain strongly. Virtually all tumour cells in myxoid and chondroid areas are devoid of staining. In clusters of squamous metaplasia, most cells are slightly positive and scattered cells are stained strongly. PTHrP contributes to cellular differentiation and is also related to keratinisation. We suggest that the PTHrP-positive inner layer cells in pleomorphic adenomas represent a step in the squamous differentiation and in the further elaboration of the tubulo-ductal structures. PMID- 8685037 TI - Expression of MMP-1 in the capsule of thyroid cancer--relationship with invasiveness. AB - To investigate the invasive activity of thyroid cancer, an in situ hybridization study was carried out in 19 thyroid tumors, including nine papillary carcinomas, five follicular carcinomas and five follicular adenomas, by using a 35S-labeled MMP-1 (matrix metalloproteinase-1) cDNA probe. The MMP-1 gene was expressed not in the cancer cells but in the fibrous capsules of papillary carcinoma. Thyroid cancer is generally circumscribed by a fibrous capsule. We found that types I and III collagen constitute the fibrous capsule, and that the MMP-1 gene was expressed in the outer border of these sites. These findings suggest that MMP-1 plays an important role in the invasion of thyroid cancer. PMID- 8685038 TI - Estrogen and progesterone receptors, c-erbB-2, p53, and Bcl-2 in thirty-three invasive micropapillary breast carcinomas. AB - Tests for estrogen (ER) and progesterone (PR) receptors, c-erbB-2, p53 and Bcl-2 were made on paraffin sections of thirty-three cases of invasive micropapillary carcinoma (MPCa) of the breast. The relations between these proteins and general parameters and the patients' evolution, were analyzed and their statistical significance determined by Fisher's exact test. Follow up was available on twenty one patients of whom thirteen were alive after a mean of sixty months. Tumor size, metastatic nodes, c-erbB-2 and Bcl-2 all showed higher values in the dead patient group, but only nuclear grade and extensive lymphatic vessel invasion (LVI) were statistically significant prognostic factors. Hormone receptors and oncogenes were positive in quite similar figures to those of common breast cancers (NOSCa) and offered supplementary information about differentiation and cell atypia of individual cancers. Accordingly, ER (72.7%), PR (45.4%) and Bcl-2 (69.6%) were directly interrelated and inversely related with nuclear grade, mitotic grade, c-erbB-2 (36.3%) and p53 (12.1%). In conclusion, MPCa is a lymphotropic cancer phenotype whose prognosis can be influenced by known prognostic factors, including molecular. The lack of discriminative power between MPCa and NOSCa of ER, PR, c-erbB-2, p53, and Bcl-2 reinforces the importance of recognizing this particular type of cancer. PMID- 8685039 TI - Unusual endometrial stromal cell changes mimicking metastatic carcinoma. AB - We report an unusual histopathologic finding in the endometrium from six premenopausal or perimenopausal patients who underwent biopsy for abnormal uterine bleeding. In each case the endometrial stromal cells focally exhibited a pronounced epithelioid appearance; some showed a cord-like trabecular pattern and others a signet-ring-like cell change. All raised the possibility of a metastatic malignancy, particularly from the breast. The epithelioid appearance of the stromal cells appears to be an unusual artifact occurring in a background of secretory change and predecidualization with nonmenstrual breakdown. PMID- 8685040 TI - Primary diffuse large B-cell lymphoma of the breast. A clinicopathologic study of 31 cases. AB - Primary non-Hodgkin's lymphoma of the breast is a rare neoplasm for which survival data vary among the reported studies. Thirty-one cases of diffuse large B-cell lymphoma of the breast, which had been seen in consultation from 1973 to 1985 at our institution, were reviewed. This represents the largest number of lymphomas of this histologic subtype reported to date in the English literature. Histologic examination and immunophenotypic analysis were performed and the results were correlated with clinicopathologic data. The patient population consisted of 29 females and 2 males with a mean patient age of 58.2 years. At the time of diagnosis, 26 patients had unilateral involvement (16 left, 10 right), and 5 had bilateral disease. Mean tumor size was 3.8 cm. Histologically, all cases showed a diffuse large B-cell lymphoma as classified by the Revised European-American Classification of Lymphoid Neoplasms (R.E.A.L Classification). Immunophenotypic studies on paraffin sections confirmed a B-cell lineage in every case. The majority of patients received chemotherapy and/or radiation therapy. The median survival was 36 months, confirming that this neoplasm has a poor prognosis. PMID- 8685041 TI - Expression of bcl-2 oncogene product in primary non-Hodgkin's malignant lymphoma of the oral cavity. AB - The B-cell leukemia/lymphoma-2 (bcl-2) proto-oncogene is peculiar, as its product appears to provide survival advantage to B cells by blocking apoptosis. Expression of bcl-2 protein was analyzed in 54 cases of primary non-Hodgkin's malignant lymphomas of the oral cavity by immunohistologic staining of paraffin embedded tissue. The immunophenotype of each tumor was established with the use of a panel of monoclonal and polyclonal antibodies to lymphoid cell differentiation antigens. The cases in the present study were 42 B-cell lymphomas, 7 T-cell lymphomas and 5-lymphomas revealing histiocytic markers. Sixteen of the 42 B-cell lymphomas were positive for bcl-2 protein, and were composed of 7 low-grade B-cell lymphomas and 9 high-grade B-cell lymphomas. Seven low-grade B-cell lymphomas were composed of one mucosa-associated lymphoid tissue type, three centrocytic types and three centroblastic-centrocytic types. Nine high-grade B-cell lymphomas comprised four centroblastic types, one immunoblastic type and four lymphoblastic types. Enhanced expression of the bcl-2 oncogenic protein was detectable in lymphoma cells in 2 cases for the T-cell lymphoma, and one case for the true histiocytic lymphoma. In contrast to the previous reports of American node-based lymphomas, Japanese primary oral lymphomas in our series expressed a lower frequency of bcl-2 protein. Furthermore, the present study indicated that bcl-2 protein was expressed on a wide variety of B-cell lymphomas, T-cell lymphomas and true histiocytic lymphoma, and that differences in bcl-2 protein expression may be useful in the diagnostic separation of lymphoblastic lymphoma with B-cell marker from Burkitt's lymphoma. PMID- 8685042 TI - Atrio-ventricular nodal tumor associated with polyendocrine anomalies. AB - We report the clinical and autopsy findings of a young female suffering of complete heart block since the age of 11 and who suddenly died at the age of 32 because of a polycystic atrio-ventricular node tumor. In association with this tumor, we observed a hyperplasia of the islets of Langherans, a true thymic hyperplasia, bilateral multicystic ovaries, adrenal tissue heterotopia and clear cell adenomatosis in the right kidney. We suggest that the polycystic atrio ventricular node tumor may be part of a complex syndrome with endocrine disorders and heterotopias. PMID- 8685043 TI - Adrenal cortical adenoma with extensive fat cell metaplasia. AB - This report describes a large adrenal cortical tumor with a significant component of mature adipose tissue in a 40 year old woman. No bone marrow elements were identified in multiple sections. This lesion, representing most likely an adrenal cortical adenoma with extensive fat cell metaplasia, has not been previously reported and must be differentiated from adrenal myelolipoma. PMID- 8685044 TI - Encapsulated follicular thyroid carcinoma exhibiting glandular and spindle cell components. A case report. AB - We describe an unusual case of a thyroid carcinoma exhibiting glandular and sarcomatous features. The tumor occurred in a 16-year-old girl. Histologic study of the resected thyroid gland revealed an encapsulated tumor composed predominantly of glandular structures and some solid areas. In the glandular areas, the tumor cells showed a cribriform growth pattern, and neither colloid secretion into the lumen nor clear-cut cytologic features suggestive of papillary or follicular thyroid carcinoma were observed. In the solid areas, tumor cells became spindled and showed a sarcomatous arrangement with occasional whorl formation. A transition from the glandular areas to the solid ones was observed. Immunohistochemical study revealed that tumor cells were positive focally for epithelial membrane antigen, cytokeratin and secretory component. Thyroglobulin was positive only in a few and limited areas of the glandular component. Calcitonin was negative throughout the tumor. The histologic and immunohistochemical evidence indicates that this tumor is of thyroid origin and is probably derived from thyroid follicular cells. The histology of this tumor is unique, so we report this case briefly. PMID- 8685045 TI - Osteogenic sarcoma of the tongue. Case report and review of the literature. AB - A case of osteosarcoma of the tongue with lymph node metastasis is reported. The patient, 81 years old, underwent hemiglossectomy and neck dissection. The rarity of this tumor is emphasized and the treatment, differential diagnosis and etiology of osteosarcomas of the tongue are discussed. Osteogenic sarcoma of the extraskeletal soft tissues and organs is itself a rare event. To the best of our knowledge only three previous cases of primary osteogenic sarcoma of the tongue have been described. The aim of this report is to present a further case. PMID- 8685046 TI - Primary adenocarcinoma of the ureter. Case report with immunohistochemical characterization. AB - Genuine adenocarcinomas of the ureter are rare tumors and have to be distinguished from other gland-forming malignancies arising from the transitional epithelium, due to the poor clinical outcome. The histopathological features of a tumor combined with intestinal metaplasia of the adjacent urothelium are described. The tumor has to be distinguished from transitional cell cancer with glandular metaplasia, muco-urothelial cancer, microcystic transitional cell cancer and transitional cell cancer with mucoid cytoplasmatic inclusions. Immunohistochemical analysis of the cancer shows positivity for carcinoembryonic antigen and a staining pattern characteristic for adenocarcinomas. The expression of keratin types 7 and 13, which is typically found in transitional cell carcinomas, is lost. PMID- 8685047 TI - Coexistence of an unusual form of scabies and lepromatous leprosy. A case report. AB - A case of unusual crusted (Norwegian) scabies involving the entire skin of a 26 year old Brazilian patient with lepromatous leprosy is reported. The more prominent histopathological findings were acanthosis, hyperkeratosis and crusting with many mites of Sarcoptes scabiei. In the dermis, numerous foamy histiocytes filled with abundant acid-fast bacilli were seen. PMID- 8685048 TI - Regarding Schmidt, D., von Hochstetter A.R., "The use of CD31 and collagen IV as vascular markers". PMID- 8685049 TI - Influence of diethylstilbestrol, Leuprolelin (a luteinizing hormone-releasing hormone analog), Finasteride (a 5 alpha-reductase inhibitor), and castration on the lobar subdivisions of the rat prostate. AB - The effects of various means of interfering with androgen action on rat coagulating gland, ventral prostate, lateral type 1 prostate, lateral type 2 prostate, and dorsal prostate were examined morphologically and quantitatively by assessing DNA content, wet weight, protein content, and zinc concentrations. Adult male Sprague-Dawley rats were subjected to 2 weeks of interfering with androgen action by treatment with Leuprolelin (a luteinizing hormone-releasing hormone analog), Finasteride (a 5 alpha-reductase inhibitor), or diethylstilbestrol (DES), or by physical castration. For all prostatic lobes, inhibition of 5 alpha-reductase elicited the smallest reduction in prostatic wet weight, DNA and protein contents, and zinc concentration. The most profound reductions in all parameters were elicited by castration. Treatments with DES and Leuprolelin gave intermediate effects with DES being the more effective in reducing all parameters in all prostatic lobes. Morphological changes elicited by all forms of androgen blockade were reduction of epithelial height, relative increase of connective tissue, reduction in ductal diameter, length, and number. The order of effectiveness of the various treatments on morphological features was as described above. While all forms of androgen blockade elicited similar effects throughout the prostate, differences in response to all forms of interference with androgen action were observed in different lobes of the prostate with regard to wet weight, DNA and protein contents, and zinc concentration as well as morphological effects. Regressive changes at the morphological level were particularly striking in the coagulating gland and ventral prostate, and indistinct in the lateral type 2 prostate. Prostatic zinc concentration in both normal and androgen-deprived rats was the highest in the lateral type 2 prostate and was reduced by interfering with androgen action to the greatest extent in the dorsolateral prostate (lateral type 1 and type 2, and dorsal prostate). The distribution of zinc correlated with the expression of metallothionein, which was detected by immunocytochemistry only in the lateral type 2 prostate of both normal and androgen deprived rats. Intraprostatic heterogeneity of zinc and metallothionein expression emphasizes interlobar differences in biological function within the rat prostate. The mechanism of development of regional heterogeneity within the prostate may shed light on the pathogenesis of prostatic proliferative diseases (prostatic hyperplasia and prostatic cancer) that initially owe their development to focal changes within large cell populations. PMID- 8685050 TI - Deoxythymidine kinase in the staging of prostatic adenocarcinoma. AB - The role of prostate-specific antigen in the management of prostatic adenocarcinoma is still not fully ascertained. Its place in the monitoring of patients who have undergone radical treatment is without question but its role in the primary assessment of a lesion is a point of continuous discussion. This study reports the analysis of prostate-specific antigen (PSA) in 92 patients with different stages of prostatic adenocarcinoma prior to treatment; in the case of the localized lesions, this was based to a great extent on the findings at lymphadenectomy. Apart from PSA analysis, deoxythymidine kinase (dTK) analyses were also performed in an attempt to discover whether the latter could provide additional information about the tumor load in the different patient categories, viz. those with lymph node involvement (group 1), those with lymph node involvement but without distant metastases (group 2), and those with disseminated disease (group 3). The median PSA and dTK values in groups 1-3 were 6.5 micrograms/L and 2.7 U/microliter, 16 micrograms/L and 2.6 U/microL, and 90 micrograms/L and 7.8 U/microL, respectively. If the two analyses were used concomitantly, they could differentiate true localized disease from metastatic in approximately 92% of cases. The combination should prove of value in the primary assessment of a patient with a newly diagnosed prostatic adenocarcinoma. PMID- 8685051 TI - Parathyroid hormone--related protein (PTHrP) is an epidermal growth factor regulated secretory product of human prostatic epithelial cells. AB - Parathyroid hormone-related protein (PTHrP) has previously been shown to be expressed in human prostatic tissue and in prostatic cancer cell lines. In the present study, PTHrP immunoreactivity was detected in the glandular epithelium of normal prostate and benign prostatic hyperplasia (BPH), as well as in prostatic adenocarcinoma (CaP). Epithelial cell cultures derived from normal, BPH, and CaP tissues were also stained by antibodies against PTHrP, and northern analysis revealed multiple transcripts of PTHrP in the cellular RNA. PTHrP (1-34) was measurable by radioimmunoassay (RIA) in media conditioned by the prostatic epithelial cell cultures, and PTHrP accumulated in conditioned media during a 72 hr time course. Addition of complete growth medium to starved cells resulted in increased PTHrP mRNA levels by 1 hr, with maximal stimulation at 8-24 hr. Several individual factors contained in the complete growth medium were tested for their ability to regulate PTHrP expression. Epidermal growth factor (EGF) was the major inducer of PTHrP expression, while cholera toxin, bovine pituitary extract, hydrocortisone, and insulin had minimal or no effect on PTHrP transcript levels. Since each of these factors is growth stimulatory, the unique ability of EGF to induce PTHrP is apparently unrelated to mitogenicity. 1,25-Dihydroxyvitamin D3[1,25(OH)2D3], an inhibitor of PTHrP expression in several other cell types, had no effect on steady-state levels of PTHrP mRNA expressed by epithelial cells in complete growth medium, although prostate cells have vitamin D receptors and are responsive to 1,25(OH)2D3 in other ways. Our results indicate that PTHrP expression is not confined to the neuroendocrine cells of the human prostate and that our culture system can be used as a model to investigate the role of PTHrP in the prostate. PMID- 8685052 TI - Influence of hormone treatment on prostate growth and micturition characteristics of the rat. AB - The influence of dihydrotestosterone propionate (DHT) and estradiol (E) on prostate growth and micturition was evaluated. Complete studies were carried out on 49 Sprague-Dawley rats over a 14-day period. Rats were divided into three groups: (1) controls, (2) DHT, and (3) DHT + E. All groups were injected daily with 0.1 ml of sesame oil, together with 1.25 mg/kg of DHT for group 2 and 1.25 DHT + 0.125 mg/kg E for group 3. Physiological measurements of micturition were done weekly by subcutaneously administering a fluid loading dose consisting of 10 mg/kg furosemide + 5 ml saline. Parameters of micturition frequency, volume, and prostate weight were calculated. Prostate weight values for controls were 0.89 +/ 0.06 g while those treated with DHT increased significantly to 1.26 +/- 0.10 g (P < 0.05) and those treated with DHT + E also increased significantly to 1.24 +/ 0.09 g (P < 0.05). There was no significant difference in prostate weight between the DHT and DHT + E groups. Analysis of micturition data shows that the mean volume voided per micturition decreases in both the DHT and DHT + E treated rats. At between 7 and 14 days of DHT and DHT + E treatment, rats micturated at significantly reduced mean volumes. The lowest mean volume per micturition was detected on the 14th day of DHT treatment, showing a significant reduction from control values of 3.05 +/- 0.27 to 1.68 +/- 0.05 ml. The corresponding value of the mean micturated volume in the DHT + E groups was 1.86 +/- 0.31 ml. Control values for frequency of micturition was 3.25 +/- 0.52/hr, while for rats treated with DHT it was 3.62 +/- 0.38/hr and for DHT + E it was 4.0 +/- 0.54/hr. Evidence is provided to demonstrate that 14 day DHT, and particularly DHT + E, stimulation produces significant alterations in prostate weight and micturition characteristics of unanesthetized rats. On the basis of these observations it is proposed that the hormonally enlarged prostate promotes stimuli to trigger the spinal micturition reflex, thereby producing increased frequency of micturition. PMID- 8685053 TI - Analysis of the oxidative catabolism of retinoic acid in rat Dunning R3327G prostate tumors. AB - We studied the enzymatic characteristics of the oxidative catabolism of retinoic acid (RA) and its inhibition by liarozole-fumarate in homogenates of rat Dunning R3327G prostate tumors. Homogenates of rat liver were used as reference material. Both tumor and liver homogenates were able to catabolize retinoic acid. HPLC analysis revealed only very polar metabolites in tumors, while in the liver both metabolites with intermediate polarity and more polar metabolites were found. Kinetic analysis of retinoic acid catabolism showed a K(m) of 1.7 +/- 0.7 microM and a Vmax of 4.2 +/- 4.4 pmol polar RA metabolites/mg protein/hr for Dunning G tumor homogenates. In liver homogenates a K(m) value of 4.3 +/- 0.5 microM and a Vmax value of 290 +/- 120 pmol polar RA metabolites/mg protein/hr were obtained. Liarozole-fumarate inhibited retinoic acid catabolism in Dunning tumors and liver with IC50 values of 0.26 +/- 0.16 microM and 0.14 +/- 0.05, respectively. The results suggest that rat Dunning R3327G tumors are able to metabolize retinoic acid in a manner similar to that found in rat liver but with a lower metabolizing capacity. PMID- 8685054 TI - Is there an association between cigarette smoking and gland size in benign prostatic hyperplasia? AB - Several studies have implied a potential inhibitory effect of smoking on the development of clinical benign prostatic hypertrophy (BPH). None of these studies compared gland size and smoking habits. We prospectively test the hypothesis that the identified "negative risk factor" that cigarette smoke has on the development of clinical BPH is mediated through inhibition of gland growth. One hundred and ninety-five men underwent transrectal ultrasonography with prostate volume calculations. A self-administered questionnaire detailing smoking habits was completed by the subjects. Correlations were looked for between various smoking habit parameters and gland size. Prostate gland size did not differ between current smokers, ex-smokers, and never smokers. Prostate volume did not correlate with smoking years (duration of exposure), nor with intensity of exposure (cigarette packyears). Smoke-mediated changes in enzymatic and endocrine pathways that regulate prostatic growth have been well documented. However, whatever "protective" effects smoke may have on BPH, they are not mediated via direct inhibition on gland growth. Alternatively, cigarette smoke may be involved in changing the dynamic component of BPH. Further testing, with special emphasis on irritative and obstructive symptoms, may help elucidate this possibility. PMID- 8685055 TI - Comparative analysis of prognostic factors in men undergoing radical prostatectomy for adenocarcinoma of the prostate, including DNA ploidy, surgical tumor stage, prostatic specific antigen, Gleason grade, and age. AB - One hundred consecutive men with adenocarcinoma of the prostate, treated by modified pelvic lymphadenectomy and radical retropubic prostatectomy, were evaluated, comparing DNA ploidy as determined by flow cytometry to surgical tumor stage (pT), preoperative prostatic specific antigen (PSA), Gleason grade, and age at presentation, in an effort to assess the prognostic ability of DNA ploidy. There were 71 (71%) men found to have diploid tumors and 29 (29%) with nondiploid tumors. There was no statistical difference in surgical pathologic stage between these two groups (P = 0.2369). There was no statistical difference when comparing preoperative PSA between these two groups (P = 0.0925). There was no statistical difference when comparing Gleason grade between these two groups (P = 0.5807). Age at presentation was similar in both groups. Based on these findings, it is apparent that longitudinal studies of patient outcome will be necessary to fully assess the prognostic ability of DNA ploidy determined by flow cytometry in men undergoing radical prostatectomy for treatment of adenocarcinoma of the prostate gland. PMID- 8685056 TI - Characterization of prostatic basal cell hyperplasia and neoplasia in aged macaques: comparative pathology in human and nonhuman primates. AB - There are very few reports of proliferative prostatic lesions occurring spontaneously in nonhuman primates. We found that 15 of 19 glands in aged macaques contained one or more epithelial lesions in the cranial lobe. These originated in the basal cell compartment and were characterized as hyperplasia and benign neoplasia. The adenomas contained variable gland formation, with morphologic and immunohistochemical evidence of secretory, mucigenous, neuroendocrine, transitional, and squamous cell differentiation. These cell types are resident in the normal prostate or appear in metaplastic lesions, and their presence in the macaque tumors is consistent with differentiation of a stem cell along multiple phenotypic pathways. The macaque growths are similar to human prostatic basal cell lesions and could provide insights into their pathogenesis as well as cellular ontogeny and general mechanisms of carcinogenesis in this organ. PMID- 8685057 TI - Development of a high-efficiency method for gene marking of Dunning prostate cancer cell lines with the enzyme beta-galactosidase. AB - Although the bacterial enzyme beta-galactosidase has been used as a reporter gene in a variety of mammalian systems; the variability and instability of its expression has limited its use. Transfection of Dunning rat prostatic cell lines with beta-galactosidase expression plasmids resulted in 5-10% of cells expressing the enzyme transiently, and < 5% of G418-resistant clones showing any level of expression. To address this problem, we developed a labeling protocol using a replication defective retrovirus containing a beta-galactosidase expression cassette. Between 30-50% of cells transduced expressed high levels of this enzyme. Homogeneous cell populations were isolated by subsequent fluorescence activated cell sorting, using a fluorescent beta-galactosidase substrate. Using a modification of standard staining procedures, small metastatic foci of cells expressing beta-galactosidase in mouse lung tissue were detected with high sensitivity. This method has several advantages over standard transfection protocols, including the expedient and efficient transfer of the beta galactosidase gene and the stability of its expression in a variety of Dunning sublines. PMID- 8685058 TI - Isoforms of prostate-specific antigen in serum: a result of the glycosylation process in dysplastic prostatic cells? PMID- 8685059 TI - Diaphragmatic hernia. PMID- 8685060 TI - Beta2-adrenergic agents in asthma. PMID- 8685061 TI - Hypotonia in infants. PMID- 8685062 TI - Hyperkalemia. PMID- 8685063 TI - The biological aspects of puberty. PMID- 8685064 TI - Sleep problems among infants and young children. PMID- 8685065 TI - Evaluation of hypercholesterolemia in childhood. AB - For many adults, the risk of atherosclerosis can be reduced by intervention and treatment of known risk factors. Direct proof that similar intervention will be effective in children is not available. However, evidence suggests that prevention beginning in childhood will lead to a decrease in incidence of heart disease later in life. The majority of families are eager to take steps to prevent heart disease in their children, especially if there is a family history of early heart disease. It is the role of the pediatrician to identify those children at risk for early heart disease and to initiate advice on reducing risk factors. PMID- 8685066 TI - Index of suspicion. Case 1. Diagnosis: Kawasaki syndrome. PMID- 8685067 TI - Index of suspicion. Case 2. Diagnosis: Meckel diverticulum. PMID- 8685068 TI - Index of suspicion. Case 3. Diagnosis: trichobezoar. PMID- 8685069 TI - A comparison of the activity of a heparan sulphate of defined molecular weight range (7500-15,000 Da) with heparin and dermatan sulphate. AB - The fibrinolytic and anticoagulant activities of heparan sulphate (HS) and dermatan sulphate (DS) were compared with those of heparin using in vitro tests. Our results demonstrate that HS has higher profibrinolytic activity than heparin and DS. Although 50 times less potent than heparin in inhibiting factor IIa, HS is three times more active than DS. The action of HS resides in HCH-mediated factor IIa inhibition combined with an ATIII-mediated inhibition. DS has no action on ATIII-mediated inhibition of factor IIa. The comparison of the anticoagulant activities of the three compounds confirmed the very limited anticoagulant effect of both HS and DS in comparison with heparin. PMID- 8685070 TI - Ketamine may modify intestinal motility by acting at GABAA-receptor complex; an in vitro study on the guinea pig intestine. AB - In the present study the effect of ketamine, a dissociative anaesthetic, on the GABA- and on the specific GABAA-agonist muscimol-induced responses of the isolated guinea pig ileum was investigated. GABA as well as muscimol produce a concentration-dependent contractile effect on the duodenum, jejunum and ileum. The sensitivity of the intestinal parts to both the above substances increases from the duodenum to the ileum. Ketamine produces a non-competitive inhibition of the GABA- and muscimol-induced contractions of the ileum, while it does not influence the ileal cholinergic contractions induced by exogenous acetylcholine. These results suggest that ketamine may modify intestinal motility through its antagonistic action at the GABAA-receptor complex. PMID- 8685071 TI - Capsaicin and its analogue resiniferatoxin inhibit gastric acid secretion in pylorus-ligated rats. AB - The effect of capsaicin and its analogue resiniferatoxin on gastric acid secretion was studied in conscious pylorus-ligated rats. Capsaicin administered intragastrically (i.g.) in very low concentrations inhibited gastric acid secretion (GAS) in a dose-dependent manner. The effect was most pronounced in the first hour. Resiniferatoxin administered in low concentrations like capsaicin produced a similar dose-dependent inhibition of GAS. The antisecretory action of both compounds was not present in rats desensitized with capsaicin applied i.g. in high concentration or in rats depleted of somatostatin by pretreatment with cysteamine. The results suggest that stimulation of capsaicin-sensitive primary afferents inhibits gastric acid secretion in rats and this effect is likely to be mediated by the release of neuropeptides. PMID- 8685072 TI - Fluvoxamine and fluoxetine: interaction studies with amitriptyline, clomipramine and neuroleptics in phenotyped patients. AB - The in vivo pharmacokinetic interaction between two selective serotonin reuptake inhibitors (SSRI) (fluvoxamine, fluoxetine) and tricyclic antidepressants (TCAs) (amitriptyline, clomipramine) or neuroleptics (haloperidol, cyamemazine, levomepromazine, propericiazine) was assessed in 29 in-patients. They were phenotyped twice with dextromethorphan and mephenytoin: first in steady state conditions while under treatment with TCAs or neuroleptics; and also 10 days after an associated treatment with fluvoxamine (150 mg day(-1)) or fluoxetine (20 mg day(-1)). A clear and statistically significant increase in the mean urinary metabolic ratio (MR) of dextromethorphan/dextrorphan and in the mean mephenytoin S/R ratio (S/R) was seen with the fluvoxamine and fluoxetine treatment. The mean MR increased from 0.13 to 0.27 (P<0.01) with fluoxetine and from 0.34 to 0.84 with fluvoxamine (P<0.05). The (dextromethorphan) 'extensive metabolizer' phenotype switched to the 'poor metabolizer' phenotype in six patients by the 10 day fluoxetine treatment, and in two patients by the fluvoxamine treatment. The mean S/R increased from 0.24 to 0.34 (P<0.05) with fluoxetine, and from 0.33 to 0.58 (P<0.002) with fluvoxamine. These results are in agreement with the observed modification of TCA plasma levels after the SSRI association. During fluvoxamine treatment, amitriptyline and clomipramine plasma levels (P<0.06 both) tendentially increased, and those of demethylclomiprarnine decreased (P<0.06). Fluoxetine addition lead to a significant increase (P<0.02) of the desmethylclomipramine plasma levels. Fluvoxamine induced a moderate augmentation of the plasma levels of haloperidol and its reduced metabolite and no change in the plasma levels of cyamemazine and levomepromazine. But patients treated with neuroleptics are to few to draw any firm conclusion. This study suggests, that fluoxetine and fluvoxamine differ in their interaction with the metabolism of some other basic psychotropic drugs, by a mechanism which implies CYP2D6 and CYPmeph and possibly other isoformes of cytochrome P-450. Moreover, the interactions produced varied with the TCA prescribed. PMID- 8685073 TI - Sustained decrease of blood pressure in psoriatic patients during treatment at the Dead Sea. AB - The diastolic and systolic blood pressure of 1366 psoriatic patients, treated at the Dead Sea for a period of 4 weeks, was monitored from the day following their arrival. The patients were divided into three categories: (a) psoriatics on antihypertensive medication; (b) psoriatics not receiving antihypertensive medication, but whose initial diastolic blood pressure equaled or exceeded 90 mmHg, and (c) psoriatics with normal blood pressure (diastolic pressure lower than 90 mmHg). A paired t-test revealed that the systolic blood pressure of the two hypertensive groups (a and b) dropped by an average of 22 mmHg, and the diastolic blood pressure dropped by 11 and 16 mmHg, respectively. The drop was evident 2 days after their arrival, and leveled off only after 2 weeks. A similar drop in systolic blood pressure was observed in normotensive psoriatics. On the basis of this study it may be concluded that high blood pressure is not a contraindication for the treatment of psoriasis at the Dead Sea. PMID- 8685074 TI - Biochemical evaluations in skeletal muscles of primates with MPTP Parkinson-like syndrome. AB - The toxic effects of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine) in primates can be exploited for investigating the physiopathology of Parkinson's disease which may also cause functional alterations of skeletal muscles, whose biochemical modifications have been studied very little. Some enzyme activities related to energy transduction in skeletal muscles were evaluated (gastrocnemius, soleus and biceps) from MPTP treated monkeys. Systemically administered MPTP altered the enzyme activities related to: (i) the anaerobic glycolytic pathway (decrease in hexokinase and phosphofructokinase activities; increase in lactate dehydrogenase activity); (ii) the tricarboxylic acid cycle (decrease in malate dehydrogenase activity); (iii) the electron transfer chain (decrease in cytochrome oxidase activity related to complex IV). No alteration in mitochondrial Complex I was observed. Treatment with an ergot alkaloid derivative (dihydroergocryptine) modified some alterations in the muscle enzyme activities and reduced the rigidity and some autonomic dysfunction. PMID- 8685075 TI - Hormonal regulation of the mRNA level of male-dominant cytochrome P450 (CYP2C27) in hamster livers. AB - Hormonal regulation in the expression of CYP2C27, a male-predominant form of cytochrome P450 in the hamster, was investigated. The mRNA level of CYP2C27 was five-fold higher in male than in female livers. The mRNA level was suppressed by both gonadectomy and hypophysectomy in male, while the mRNA level was increased by the same treatment in female, resulting in the disappearance of sex difference. In both sexes, treatment of the gonadectomized animals with testosterone induced the cytochrome over the level of sham- operated males. Treatment of the hypophysectomized animals with testosterone elevated the level in females. On the other hand, oestradiol did not show any effects on either the gonadectomized or the hypophysectomized animals of both sexes. Twice-daily injection of growth hormone to hypophysectomized animals restored the level in males. Continuous infusion of growth hormone to hypophysectomized animals suppressed the level in both sexes. These results indicate that the expression of CYP2C27 in hamsters is under the control of endocrine factors and suggest that the gonadal-pituitary axis pathway is a control mechanism as proposed in rats and mice. PMID- 8685076 TI - Left ventricular hypertrophy in spontaneously hypertensive rat: effects of ACE inhibition on myocardiocyte ultrastructure. AB - The aim of this study is to investigate the effects of two ACE-inhibitors with different chemical formulae, cilazapril (CLZ) and captopril (CPT), on left ventricular myocardiocytes from spontaneously hypertensive rats (SHR), characterized by ultrastructural alterations associated with left ventricular hypertrophy, and from Wistar-Kyoto (WKY) rats, considered as controls. After CLZ treatment, not remarkable changes are observed in WKY myocardiocytes, whereas SHR ones show a considerable reduction in their original alterations in ultrastructure. After CPT-treatment, both SHR and WKY myocardiocytes are altered in ultrastructure. The morphometric investigation confirms that CPT and CLZ produce different effects. Even if the drugs induce a similar decrease in blood pressure and left ventricular mass index, CLZ unlike CPT seems to improve the ultrastructural abnormalities associated with left ventricular hypertrophy. These changes could be related to the different chemical structure of CLZ and CPT, or to a different affinity of the two drugs for the local renin-angiotensin system. PMID- 8685077 TI - Evidence for a role of inhibition of sympathetic neurotransmission in the cardiovascular effects of intravenously administered verapamil. AB - The effects of intravenous administration of verapamil, nifedipine and diltiazem on sympathetic stimulation-induced increase in heart rate (HR) and blood pressure (BP) have been investigated in chloralose-anaesthetized and artificially ventilated cats. Verapamil (300 micrograms kg(-1) i.v.) produced a significant inhibition of sympathetically-induced tachycardia and pressor responses. The same dose of verapamil did not significantly alter adrenaline (2 micrograms kg(-1) i.v.) induced increase in HR and BP. In contrast, neither the sympathetically induced nor the adrenaline-induced pressor and tachycardiac responses were significantly affected by nifedipine or diltiazem. These results demonstrate that peripherally administered verapamil but not nifedipine and diltiazem can inhibit cardiovascular sympathetic neurotransmission and this can possibly contribute to its effects on HR and BP. PMID- 8685078 TI - Effectiveness of carbocysteine lysine salt monohydrate on models of airway inflammation and hyperresponsiveness. AB - We investigated the possible effects of the mucoactive drug Carbocysteine lysine salt monohydrate (CLS.H2O) on experimentally-induced airway inflammation and hyperresponsiveness. CLS.H2O given by the oral route (300 mg kg(-1)) significantly reduced neutrophil infiltration into the airway lumen induced by intratracheal injection of IL-1 beta in rats. In addition, CLS.H2O inhibited dose dependently (100-300 mg kg(-1) p.o.) the formation of pleural exudate and leukocyte recruitment induced by intrapleural injection of carrageenan in rats. Because of the close interaction between the inflammatory process and the development of airway hyperresponsiveness we also tested CLS.H2O on cigarette smoke-induced inflammation and hyperreactivity in anaesthetized guinea-pigs. The drug, given either by oral (300 mg kg(-1)) or aerosol route (30-100 mg ml(-1)), was able to reduce the increase in airway responsiveness induced by smoke and the associated cell recruitment detected in the bronchoalveolar lavage (BAL) fluids. These results suggest that CLS.H2O can exert an anti-inflammatory action in addition to its mucoregulatory activity. The anti-inflammatory and anti hyperreactivity effect of the drug within the airways may be of advantage in the treatment of inflammatory lung diseases where mucus secretion together with airway inflammation and hyperreactivity contribute to airway obstruction. PMID- 8685079 TI - Calculating predictive performance: a user's note. AB - The method proposed by Sheiner and Beal plays a cornerstone role in the evaluation of the predictive performance. Recently, the Sheiner and Beal's method has been intensively used in pharmacokinetic studies, however, this method has been used in a somewhat confusing way by several authors. Therefore, if one wants to use this method, one might find different examples to follow in the pharmacokinetic literature. Meanwhile, several detailed points were not given by Sheiner and Beal in their original paper. Clearly, the principles suggested by Sheiner and Beal are simple, but the practical application is something of an art. In this work we addressed these detailed points and indicated the confusion in using the Sheiner and Beal's method. PMID- 8685080 TI - Pharmacological treatment of central nervous system trauma. AB - Traumatic injuries to the brain or spinal cord cause tissue damage, in part by initiating reactive biochemical changes. Pharmacological approaches aim to modify this delayed injury response by blocking one or more components of the reactive biochemical/metabolic cascade. This minireview summarizes both historical and recent developments in experimental and clinical treatment of CNS trauma. Potential treatments include: corticosteroids, antioxidants or free radical scavengers; drugs that modify arachidonic acid metabolism, platelet-activating factor antagonists; gangliosides; modulators of monoamine actions; opioid receptor antagonists; thyrotropin-releasing hormone and thyrotropin-releasing hormone analogues; glutamase receptor antagonists; calcium channel blockers; agents that modify the inflammatory/immune response; and trophic factors. Understanding the mechanisms of action for these compounds can permit rational drug development/application, delineation of the therapeutic window, and laying of the ground-work for evaluating potential synergistic effects of combination treatment strategies. PMID- 8685081 TI - Effects of exposure to lead on selected biochemical and haematological variables. AB - Blood and urine samples were taken from 34 persons occupationally exposed to lead and from 56 non-exposed control persons and blood lead and haemoglobin concentrations, red blood cell count, erythrocyte glutathione peroxidase (GSH peroxidase) and acetylcholinesterase (AChE), and urinary delta-aminolevulinic acid were determined. Blood lead concentrations of the lead-exposed subjects were within the range of generally accepted as safe for occupationally-exposed adults in many countries (i.e. below 50 micrograms Pb/dl blood). Yet, significant dose dependent elevations were found in erythrocyte GSH-peroxidase and urinary delta aminolevulinic acid. The urinary delta-aminolevulinic acid concentration of lead exposed smokers was significantly elevated over that of lead-exposed non-smokers. Smoking did not effect the urinary delta-aminolevulinic acid concentration of control persons. In addition, a statistically significantly lower red blood cell count was observed in the lead-exposed group. Our results indicate that the above described safety standard for blood lead concentrations in occupationally exposed adults, although generally accepted, needs revision. PMID- 8685082 TI - BB-882 is a potent antagonist of the haemodynamic changes induced by platelet activating factor in pigs. AB - The effects of bolus doses (0.2-2 micrograms) of platelet-activating factor (PAF) on systemic and pulmonary arterial pressures were tested in five juvenile pigs, and were demonstrated to have a biphasic effect. There was an initial drop in the mean systemic arterial pressure within seconds, followed by an increase within 1 2 min., whereas mean pulmonary arterial pressure only rose. The response was dose related and did not include tachyphylaxis. The pressures returned to baseline within 10 min. After confirming these results a novel specific PAF receptor antagonist (BB-882) was given as a 1 mg/kg bolus followed by a continuous infusion of 2 mg/kg/hr, and a third dose response curve was repeated with ten fold higher PAF doses (2-20 micrograms). BB-882 effectively counteracted these effects. Six pigs were given a continuous infusion of BB-882 33 mg/kg/hr for 5 hr and were compared with another group of five pigs given vehicle only. In this high dose BB-882 did not affect the intravascular pressures. These results indicate that BB-882 is a potent PAF receptor antagonist in juvenile pigs. PMID- 8685083 TI - Stable guanosine 5'-triphosphate-analogues inhibit specific (+)-[3H]isradipine binding in rat hearts by a Ca(2+)-lowering, G protein-independent mechanism. AB - We investigated if and how stable guanosine 5'-triphosphate-analogues affect (+) [3H]isradipine binding in rat hearts. Gpp(NH)p and GTP-gamma-S inhibit specific (+)-[3H]isradipine binding in membranes and cell-homogenates by reducing the binding density without changing the Kd of the k-1. Inhibition by Gpp(NH)p was less in crude tissue homogenates than in membranes apparently due to a soluble factor. Pretreatment of cardiomyocytes with cholera toxin or the presence of the protein kinase A inhibitor, PKI6-22, did not influence the effect of 10(-3) M Gpp(NH)p on binding. The inhibitory effect of 10(-3) M Gpp(NH)p was not significantly altered in membranes from in vivo pertussis toxin treated rats. The addition of 10(-3) M Ca2+ or Mg2+ abolished the inhibitions. Gpp(NH)p in the concentration that inhibits binding, reduced the free concentration of Ca2+. The Ca(2+)-lowering effect of 10(-3) M Gpp(NH)p produced 70%, 60% and 100% of the inhibition in membranes, sonicated and unsonicated cell homogenates. Thus, Gpp(NH)p inhibited specific (+)-[3H] isradipine binding mainly by lowering the free concentration of Ca2+ by chelation and not by activation of cholera toxin or pertussis toxin-sensitive G proteins or protein kinase A. PMID- 8685084 TI - The use of beta 2-adrenoceptor agonists in the treatment of bronchial asthma. AB - All guidelines recommend short-acting inhaled beta 2-adrenoceptor agonists as the first-line drugs in acute asthma attacks and inhaled corticosteroids as the drugs of choice when regular daily treatment is needed. Short-acting inhaled beta 2 adrenoceptor agonists are not effective in reducing nocturnal awakenings because of their short duration of action. In addition there has been an intense debate about the regular use of these drugs. This debate is reviewed. They should only be used on "as needed basis". The Swedish guidelines for the treatment of asthma were the first to recommend the new long-acting inhaled beta 2-adrenoceptor agonists at relatively early stage of the illness (800 micrograms daily of inhaled corticosteroids). Two recently completed large multicentre studies with salmeterol in asthmatics support this opinion. Both studies showed a better asthma control with a combination of a low inhaled steroid dose and salmeterol compared to a doubling of the steroid dose. In most asthmatic patients, still symptomatic on inhaled steroids doses 400 to 800 micrograms daily, a test of the addition of inhaled salmeterol is recommended. The steroid dose can be kept low and safe. However, asthmatic patients with either frequent or severe exacerbations should primarily have their steroid dose increased. PMID- 8685085 TI - Demonstration of benzo(a)pyrene-induced DNA damage in mice by alkaline single cell gel electrophoresis: evidence for strand breaks in liver but not in lymphocytes and bone marrow. AB - Alkaline single cell gel electrophoresis (also known as the 'comet assay') was used to measure DNA strand breaks and alkali-labile sites in peripheral lymphocytes, bone marrow and liver cells of C57BL/6 mice orally exposed to benzo(a)pyrene. Although this polycyclic aromatic hydrocarbon is a well-known genotoxic agent, little is known about to what extent it actually induces DNA strand breaks in peripheral lymphocytes and other tissues after in vivo exposure. Significant and dose-related damage was observed in liver cells after three days of exposure (lowest observed effect level being 3 x 100 mg benzo(a)pyrene/kg b.wt. No such damage could be observed in the lymphocytes and bone marrow cells even after administration of 3 x 150 mg benzo(a)pyrene/kg b.wt. The reference substance cyclophosphamide produced pronounced DNA damage in lymphocytes and bone marrow cells already in a single dose of 100 mg/kg b.wt. The present mouse study questions the usability of DNA strand breaks in peripheral lymphocytes as an indicator of benzo(a)pyrene-induced genotoxicity. PMID- 8685086 TI - The toxicity of repeated exposures to rolipram, a type IV phosphodiesterase inhibitor, in rats. AB - Rolipram is a selective inhibitor of Type IV phosphodiesterase isozymes (PDE IV) which is often used as a baseline comparator for compounds in this class. To document the toxicological effects of rolipram, it was administered to female rats at 0, 10, 30 or 100 mg/kg/day orally for up to 2 weeks. One treatment related death in the 100 mg/kg/day dose group was observed on day 3, and all rats at this dose level were considered moribund and euthanatized on day 5. Several clinical signs were observed in treated rats, including increased salivation, slight distention of the abdomen, emaciated appearance, and ataxia. After 14 days of treatment, the rats were necropsied and tissues examined microscopically. A number of compound-related histopathological changes were observed in rats receiving 30 or 100 mg/kg/day. Myocardial degeneration and necrosis, endocardial fibrosis, epicarditis, and arteritis/periarteritis of intramural and extramural coronary arteries were observed in the heart. A necrotizing vasculitis and inflammation were observed in the mesentery and interstitial areas of the liver, affecting medium-sized portal arteries and veins. Focal necrosis was also observed in the glandular mucosa of the stomach at these 2 dose levels. Other treatment-related effects included squamous hyperplasia and hyperkeratosis with or without ulceration in the nonglandular stomach of at least one animal from all treatment groups. Enlarged salivary glands were noted at necropsy in animals treated with 100 mg/kg/day, and this finding correlated microscopically with dilatation and degeneration of ducts and acini in the sublingual gland with secondary inflammation and edema. The results of this study demonstrate that rolipram, a selective inhibitor of the type IV class of PDE, can cause effects on the heart and vasculature of rats which heretofore have been ascribed only to selective inhibitors of the PDE III class of isozymes. Therefore, these organs should be closely examined in studies with other PDE IV inhibitors. In addition, the gastrointestinal tract and salivary glands were sites for rolipram-induced toxicity and may be targets of other PDE IV inhibitors. PMID- 8685087 TI - Characteristics of contractile 5-HT receptors in isolated human omental arteries: presence of 5-HT1 and 5-HT2 receptors. AB - 5-Hydroxytryptamine (5-HT) has a variety of biological effects, e.g. it induces and modulates vascular smooth muscle activity. The effects are mainly mediated via a hetergenous group of 5-HT receptor subtypes. In order to elucidate the 5-HT receptor mechanisms in the human splanchnic circulation, in vitro studies were carried out on omental arteries obtained from patients undergoing abdominal surgery. Four 5-HT receptor agonists with different selectivity all induced concentration-dependent contraction (potency and order of potency indicated): 5 HT (non-selective; 6.12 +/- 0.14)=sumatriptan (5-HT1; 6.32 +/- 0.07) > alpha methyl-5-HT (5-HT2; 5.41 +/- 0.05) > 2-methyl-5-HT (5-HT3; < or =4.46+/-0.05). The 5-HT1/5-HT2 receptor antagonist methiothepin antagonised the contraction induced by 5-HT, sumatriptan, alpha-methyl-5-HT and 2-methyl-5-HT. The 5-HT2 receptor antagonist ketanserin antagonised the contraction induced by 5-HT, alpha methyl-5-HT and 2-methyl-5-HT. The 5-HT3 receptor antagonist tropisetron did not antagonise the contraction elicited by 2-methyl-5-HT. The results suggest that 5 HT-induced conataction in human omental arteries involves both 5-HT1 and 5-HT2, but maybe not 5-HT3-receptors. PMID- 8685088 TI - Ex vivo time-dependent cell DNA-degradation shown by single cell gel electrophoresis. PMID- 8685090 TI - [Special diagnostic problems in osteopathies and bone tumors]. PMID- 8685089 TI - [Pitfalls and typical false interpretations in bone tumors. From the viewpoint of long-term consultation]. AB - Problems in diagnosis of bone tumors in routine laboratories concern very rare tumors, differentiation between chondroma and low grade chondrosarcoma, the recognition of lesions containing multinucleated giant cells, lesions with secondary cysts simulating iuvenile or aneurysmal bone cyst and sometimes the discrimination of callus from osteosarcoma. Real misdiagnoses are done in ossifying pseudotumors interpreted as osteosarcoma, metaphyseal fibrous defect confound with giant cell tumor and chondroblastoma misdiagnosed as giant cell tumor or osteosarcoma. All these mistakes are avoidable if the clinical and radiological features, especially age and exact site in bone studied on the x rays, are taken into consideration. PMID- 8685091 TI - [Report of experiences with rapid reading]. PMID- 8685092 TI - [Histologic grading of chondrosarcoma. A qualitative and quantitative analysis of 74 cases of the Hamburg bone tumor register]. AB - Chondrosarcomas are frequent malignant bone tumors. Aside from different subtypes, such as dedifferentiated, mesenchymal and clear-cell chondrosarcoma, chondrosarcomas (classical chondrosarcoma) show different grades of differentiation. The borderline between chondroma and classical chondrosarcoma is not clearly defined. The same chondrosarcoma can be graded differently at different institutes. Standardized therapy concepts are currently in preparation. As the Hamburg Bone Tumor Registry is often consulted for chondrogenic tumors, the histological criteria are based on a series of 74 chondrosarcomas recorded there. The emphasis has been laid on a classification which can be used in daily routine and which is reproducible and in agreement with the classifications of other international groups. Grade I chondrosarcomas (50%) can be distinguished only by growth criteria. The nuclei are small and show high chromatin density. Grade II chondrosarcomas (42%) have medium-sized, regular nuclei with loose chromatin structure. The chondrocytes of grade III cases (8%) show polymorphic nuclei. Binucleas forms, the number of mitoses and cellularity all show considerable overlap for all three grades. So far there are no immunohistological and molecular biological methods for reliable differentiation. The therapeutic consequences of the classification into grades are thorough curettage, in the case of grade I tumors, or complete resection, for grade II and III cases. The long-term results, however, need to be confirmed by a larger number of cases. From 1991 to 1995 the method was applied and proved to be easily practicable in daily diagnostic routine. Some 104 cases of classical chondrosarcomas (grade I 53%, grade II 39%, grade III 8%) were analyzed. Two pathologists both assigned the same grade in 90% of cases. PMID- 8685093 TI - [Morphologic characteristics of chondroblastoma. A retrospective study of 56 cases of the Hamburg bone tumor register]. AB - Representing only about 1% of all primary bone tumors, chondroblastoma constitutes a very rare bone tumor entity. 56 cases of chondroblastoma, that had been collected by the Hamburg Bone Tumor Registry from 1972 to 1995, were examined histologically together with the radiological and clinical findings. In addition immunohistochemistry with antibodies against S 100, PGM1, LCA and the proliferationmarker MIB 1 was performed. The mean age was 20.4 years and male patients being the majority with a gender ratio of 2.7:1. Predominant localisation was the epiphyses of the long bones, although almost 40% of the tumors were located at untypical sites. Usually a well-circumscribed lysis could be seen on plain X-Ray examination, however partial cortical destruction could be observed in one third of the cases. Histologically characteristic was a polygonal cell component with a weblike chonroid matrix, sometimes with a plane-like appearance. 5 cases showed a distinct nuclear polymorphism making a distinction from osteosarcoma difficult. Using immunohistochemistry all tumors except for one showed positive reaction for S 100 protein. Although the histogenesis of chondroblastoma is not completely understood, morphological findings as well as the observed reactivity with the S 100 protein indicate the chondroid origin. No reactivity for PGM 1 (CD 68) or LCA could be detected. All chondroblastoma showed a low rate of proliferation, thereby being distinguishable from high malignant bone tumors. In general chondroblastoma show a benign biological behavior. Different behavior was observed in 2 cases. One relapse located in the pelvis revealed local aggressive growth while in another case in the humerus a malignant transformation had taken place. PMID- 8685094 TI - [Therapy-induced changes in osteosarcoma after neoadjuvant chemotherapy (COSS 86 Therapy Study). Correlation between morphologic findings and clinical follow-up]. AB - 207 osteosarcomas were examined morphologically after neoadjuvant chemotherapy according to the COSS-86 protocol using representative slides of one whole tumor plane. The rate of responders 63%. In relapse-free patients both the whole tumors and the vital areas there of were smaller than in patients with relapse during a follow-up period of 5 years. Within the subgroup of osteoblastic osteosarcomas, metastases were observed following smaller tumors than in chondroblastic osteosarcomas. Therefore, in addition to degree of regression, histological subtype and tumor size should be considered in the prognostic evaluation of osteosarcomas. PMID- 8685095 TI - [DNA cytometry of solitary and aneurysmal bone cysts and low malignancy and high malignancy central osteosarcomas. Current significance within the scope of morphologic diagnosis of intraosseous cystic and osteoblastic lesions]. AB - DNA cytometric investigations of intraosseous cystic lesions and osteoblastic tumors may be helpful in morphological diagnosis. The detection of a DNA aneuploid stemline supports the diagnosis of a high-grade malignant bone neoplasm, even in small biopsies. Solitary and aneurysmal bone cysts have DNA diploid cell populations. Low-grade central osteosarcomas may show single-cell aneuploidies of varying extent as well as a DNA-diploid stemline. Their presence may be a sign of genetic instability within the population of neoplastic cells before a DNA-aneuploid stemline is established and should prompt careful postoperative observation. PMID- 8685096 TI - [P-glycoprotein expression in osteosarcoma]. AB - One of the mechanisms by which multidrug resistance is mediated, is the mdr1 gene product, P-glycooprotein. Immunohistochemistry was performed for 63 osteosarcomas of 54 patients to investigate P-glycoprotein expression using the monoclonal antibody JSB-1. Most of the patients were children or adolescents who had received treatment under the framework of the Cooperative Osteosarcoma Study Group. In addition P-glycoprotein expression was assayed in five growth plates. Of all cases 68.5% stained positive for P-glycoprotein. Cases that had received chemotherapy showed a higher incidence (80.9%) of positive P-glycoprotein immunostaining than cases that had not received chemotherapy (66.6%). No relation could be established between P-glycoprotein expression and the response to chemotherapy, since the majority of P-glycoprotein positive biopsies showed a good response in the surgical specimen after chemotherapy. Furthermore, 42.9% of P-glycoprotein negative biopsies were classified as non-responders in the later surgical specimen. In addition to P-glycoprotein expression in osteosarcomas positive immunostaining was also detected in osteoblasts, osteocytes, osteoclasts as well as in some chondroblasts. The results indicate that P-glycoprotein expression in osteosarcomas also exists prior to chemotherapy and resembles the phenotype of normal bone tissue. However, the determination of P-glycoprotein by using immunohistochemistry in biopsies of osteosarcomas cannot predict the response to chemotherapy. PMID- 8685097 TI - [Cell proliferation in bone tumors. Immunohistologic study of Ki-67 protein expression]. AB - Bone tumors represent a group of tumors of various dignity. In spite of this single tumor entities may display strong morphological resemblance to each other which can in turn result in profound difficulties in differential diagnosis. The biological behaviour of a tumor is mainly determined by its rate of proliferation. In this study the rate of proliferation of 64 bone tumors (30 high grade central osteosarcomas, 6 low-grade osteosarcomas, 8 giant cell tumors, 8 aneurysmatic bone cysts, 5 osteoidosteomas/osteoblastomas, 7 fibrous dysplasias and 5 cases of a myositis ossificans) were analysed. Immunohistochemistry was performed on paraffin-embedded tissue sections using the MIB-1 monoclonal antibody. MIB-1 recognizes the proliferation-associated Ki-67 protein which is expressed during the active phases of the cell cycle but cannot be detected in senescent cells. Among high-grade central osteosarcomas a significantly higher rate of proliferation (average value 30%) was found in comparison with low-grade osteosarcomas and other benign intraosseous bone tumors. This approach proved to be very useful in the distinction between high-grade and low-grade osteosarcomas as well as bone-forming intraosseous tumors. However distinguishing low-grade osteosarcomas from benign bone tumors by determining only the rate of proliferation was not possible, although interestingly, the proliferative rate of myositis ossificans, a purely reactive lesion, was in the range of the values determined for high-grade osteosarcoma. PMID- 8685098 TI - [Pathology of Ewing sarcoma]. AB - Ewing's sarcoma is a very rare tumor which has, however, attracted much oncological interest since the dramatic improvement of its prognosis under chemotherapy. Its histogenesis has been discussed controversially for a long time, including a possible origin in immature reticulum, myogenous, endothelial and undifferentiated mesenchymal cells. Repeated reports have also suggested a possible neuroectodermal genesis. Convincing arguments, however, have only been brought forward during recent years, since it was found that Ewing's sarcoma and malignant peripheral neuroectodermal tumor share a common chromosome translocation 11;22. In the meantime this hypothesis has been strengthened by numerous cell biological analyses. There seems to be no clear border between Ewing's sarcoma and malignant peripheral neuroectodermal tumors with definite neural differentiation. Histological differential diagnosis of Ewing's sarcoma has been improved by immunohistological methods. In most cases, they can be distinguished from lymphoma (leucocyte common antigen, B and T markers) and embryonal rhabdomyosarcoma (muscle specific actin, desmin) without problems. Apart from that, it is possible nowadays to obtain antibodies against the MIC 2 protein, which is preferably expressed in Ewing sarcoma. The diagnostics of Ewing's sarcoma and the malignant peripheral neuroectodermal tumor have considerably been enriched by the fact that the specific chromosome translocation t(11;22) can be proved molecular biologically. In contrast to the cytogenetic evidence, it is not necessary to establish cell cultures. PMID- 8685099 TI - [Solitary bone cysts. Morphologic variation, site, incidence and differential diagnosis]. AB - Analysis of 402 solitary bone cysts demonstrates the wide morphological variation of this cystic lesion with regard to histology and radiology. Aside from metaphyseal location in femur (33%) and humerus (23%), solitary bone cysts are also often located in calcaneus (11%), tibia (11%) and pelvis (10%). Most patients are in the second decade of life. Differentiation between this benign lesion and malignant bone tumors is very important in daily clinical routine. The diagnosis cannot be based solely on radiological findings because of the variation of solitary bone cysts and the special forms, such as calcifying solitary bone cyst. Therefore, exact histological diagnosis is of particular importance. PMID- 8685100 TI - [Spongiosa structure and polyostotic heterogeneity in osteoporosis. Mechanism of bone transformation, morphology, clinical significance]. AB - Osteoporosis is the most frequent generalized bone disease. The clinical expression of postmenopausal osteoporosis is characterized by spontaneous fractures of the vertebral bodies which affect mainly the trabecular bone structure. Thus the morphological bone transformation in osteoporosis is of clinical relevance. The object of this study was to analyze quantitatively and qualitatively the distribution of three-dimensional structure of cancellous bone in the human spine in osteoporosis. Therefore the complete anterior column of the spine and bone biopsies of the iliac crest of 11 autopsy cases with proven osteoporosis and 26 autopsy cases without primary or secondary bone disease were removed. A 1-mm-thick prepared sagittal section through the center of all vertebral bodies was embedded undecalcified in plastic and stained on the surface using a modification of the von Kossa method. This technique allowed combined two and three-dimensional measurements simultaneously; these included evaluation of trabecular bone volume, trabecular interconnection, trabecular thickness, and trabecular number. The quantitative spine deformity index and qualitative analysis of the trabecular bone structure completed the investigation. The bone loss in osteoporosis is a loss of structure and the loss of whole trabeculae caused by perforations. The age-related decrease of trabecular bone mass is due to the transformation from plates to rods. Patient with osteoporosis show pathologically diminished trabecular bone volume and apparently reduced trabecular interconnection, while trabecular thickness and trabecular number show age-dependent change. The polyostotic heterogeneity in osteoporosis is immense. Neighboring vertebral bodies show differences of up to 100% in bone volume and bone structure. Due to this fact it is impossible to define a threshold for osteoporotic fractures. At the moment the transformation and loss of trabecular bone structure in osteoporosis is assumed to be irreversible; therefore, early prophylaxis is necessary to prevent clinical manifestations of these changes of bone. PMID- 8685101 TI - [Friedrich Daniel von Recklinghausen. Biography and significance of his osteopathologic work after more than 100 years]. AB - Even today the name of F.D. von Recklinghausen is often mentioned in connection with primary and secondary hyperparathyroidism. He was one of the first physicians and scientists to render outstanding services to the classification of structural changes of bones, and in many aspects his work remains valid today. He succeeded through precise and comparative studies in making the disease and symptoms of primary hyperparathyroidism known and thus distinguishing it from other known structural bone diseases. He also described the phenomenon of "bone remodeling" which has become relevant today again. Although his written macroscopic and microscopic observations include meticulously precise differentiations which make it difficult to study them today, they are still of interest in order to follow his basic ideas. This article does not constitute a comprehensive biography, but it contains a description of F.D. von Recklinghausen's important work on bone pathology against the background of the main stages of his life. PMID- 8685102 TI - [Archiving of pathologic-anatomic findings in bone diseases and bone neoplasms in individual databanks. Experiences of a new enterprise with applicable outcome]. AB - In this paper my experience with a databank for cases with bone diseases is reported. All cases which had been diagnosed in the newly formed Department of Bone Pathology of the University of Hamburg since 1970 were registered in uniform fashion. Adapting the system to state-of-the-art network structures required a lot of personal and financial investment. This could not be accomplished by university resources alone, but only in cooperation with other research funds. Now 76,000 cases can be routinely accessed and scientifically analysed. PMID- 8685103 TI - [Periosteal osteosarcoma. Histologic characteristics, preparation technique, growth pattern and differential diagnosis]. AB - Periosteal osteosarcoma is a distinct bone tumor entity with characteristic morphological features within the group of juxtacortical osteosarcoma. Periosteal osteosarcoma is predominantly located in the long tubular bones, especially in the tibia and femur and is situated on the outer circumference of the tumor bearing bone (saucerization phenomenon). In contrast to parosteal osteosarcoma, periosteal osteosarcoma is less differentiated and is believed to have a worse prognosis. In this work the histological features are described with predominantly chondroblastic differentiation of 14 cases with periosteal osteosarcoma. A horizontal preparation technique of periosteal osteosarcoma specimens allows comparison with computed tomography and is the optimal method to detect an invasion of the medullary cavity. Further studies are necessary to clarify if neoadjuvant chemotherapy could improve the prognosis of certain patients. PMID- 8685104 TI - [Diseases of the breast]. PMID- 8685105 TI - [Problem cases in lung pathology]. PMID- 8685106 TI - [New medical treatment of epilepsy]. AB - Nearly three-fourths of all newly diagnosed cases of epilepsy are easily controlled with our current drug armamentarium. Further progress will undoubtedly come with use of three new drugs, gabapentin, lamotrigine, and vigabatrin now in diverse stages of clinical trials. Gabapentin is a gamma-aminobutyric acid (GABA) analog which passes the blood-brain barrier. Its mode of action is unknown. The anti-convultion effect of lamotrigine apparently results from its capacity to stabilize voltage-dependent sodium channels and thus limit release of the excitory neuromediator glutamate. Vigabatrin produces irreversible inhibition of GABA transaminase, increasing the concentration of this neurotransmittor inhibitor in the brain. The pharmacokinetic properties of these three anti epileptics are more favorable than those of earlier drugs. Renal excretion is proportional to creatinine clearance allowing better dose adjustment and all three can be associated with oral contraception. They are as effective as the classical agents although indications may vary. There are fewer adverse effects and no teratogenic effect has been observed in animal studies. Clinical surveillance is usually sufficient without laboratory tests. One handicap is the increased cost although it has been demonstrated that the overall cost for the society for a patient with well controlled epilepsy is less. The prescription of a third-generation anti-epileptic drug is justified immediately whenever treatment with one of the classical drugs has been unsuccessful; however, in case of failure the new drug should not be continued. PMID- 8685107 TI - [Pulmonary toxoplasmosis in patients with human immunodeficiency virus infection. 21 cases]. AB - OBJECTIVES: Assess expression of pulmonary toxoplasmosis, the second most frequent localization after brain, in patients infected with the human immunodeficiency virus (HIV). METHODS: Twenty-one HIV-infected patients (18M, 3F) were admitted for pulmonary toxoplasmosis between September 1987 and February 1995. Mode of HIV transmission was unprotected homosexual sexual activity (n = 16), intravenous drug abuse (n = 3) and transfusion (n = 2). RESULTS: Isolated pulmonary toxoplasmosis was found in 11 patients. In 10 patients pulmonary toxoplasmosis was associated with cerebral (n = 4), bone marrow (n = 2), ocular (n = 1) and multifocal (n = 3) localizations. Seven patients were admitted for acute pulmonary distress. Fever (reported for 20 patients) and nonproductive cough (reported for 16 patients) were the most common clinical symptoms. Chest roentgenogram revealed bilateral pulmonary infiltrates in 16 (76%) patients. Mean absolute CD4 count was 25 +/- 57 (range 0-110). Serologic evidence of past infection was observed in 18 patients. Serology tests were not done for two patients and negative for one. Two patients presented co-infection with Pneumocystis carinii. Fourteen patients had elevated serum lactic dehydrogenase (LDH) concentration. Among those, 4 patients whose LDH concentration was elevated more than ten fold died of respiratory distress. Patients received pyrimethamine and sulfadiazine (n = 13) or clindamycin (n = 8). Seven patients died during the first month after diagnosis was made. For the other patients, mean survival was 8 months. No relapse of toxoplasmosis was observed. All the patients took a secondary prophylaxis. CONCLUSION: No difference between patient with isolated pulmonary toxoplasmosis and patients with associated extra-pulmonary localization was noted for clinical, biological, radiological presentations and outcome. PMID- 8685108 TI - [Neurological complications in adults following rabies vaccine prepared from animal brains]. AB - OBJECTIVES: Despite well-known neurological complications, post-exposure semple type rabies vaccine is still used in Tunisia. We retrospectively studied neurological manifestations following post-exposure rabies vaccine. METHODS: Over a 3-year period, semple-type phenol inactivated lamb nerve tissue vaccine (Pasteur Institute, Tunis) was given to 1392 adults after exposure to rabies. RESULTS: The frequency of neurological complications was 1/200. Seven patients presented complications 4 to 14 days after the first vaccine injection (median 11 days). Central nervous system manifestations occurred in all 7 patients with peripheral neuropathy in 5. Manifestations were meningoradiculitis (n = 3), meningomyeloradiculitis (n = 2), meningomyelitis (n = 1) and myelitis (n = 1). No vaccine-associated death occurred, but one patient suffered persistant paraplegia. CONCLUSION: Semple-type adult animal nerve tissue vaccine produces an unacceptable rate of severe post-vaccinal neurological complications in adults. Human diploid cell rabies vaccine should be used for post-exposure rabies vaccination. PMID- 8685109 TI - [Excision of a parathyroid adenoma of the aorto-pulmonary window under thoracoscopy]. AB - OBJECTIVES: Neck exploration is usually required in all cases of primary hyperparathyroidism. Without a precise localization preoperatively cervicotomy may be unsuccessful, especially in case of an ectopic adenoma. CASE REPORT: A patient with primary hyperparathyroidism due to a solitary adenoma localized in the middle mediastinum was identified on preoperative computed tomography and technetium-99m-sestamibi radionuclide scan. The tumor was successfully removed at thoracoscopy without neck exploration. DISCUSSION: Preoperative localization of primary hyperparathyroid tumors is not indicated in all patients. In some selected cases (acute hypercalcemia, reoperation, serious illness) prior neck exploration would be useful in guiding the surgeon. PMID- 8685110 TI - [Portal hypertension caused by intra-hepatic block in chronic lymphoid leukemia]. AB - A 83-year-old woman with chronic lymphoid leukemia--well controlled for 14 years with chemotherapy--was admitted for ascitis due to portal hypertension. Liver biopsy showed major portal infiltration with monomorphic little lymphocytes. Portal hypertension during chronic lymphoid leukemia might be caused by this periportal lymphoid infiltration or by intraportal venous thrombosis due to thrombophilia or by increasing of hepatic blood flow. Our observation showed that hepatic localizations of the disease may induce acute symptoms even when the lymphoid leukemia seems to be under control both in terms of blood parameters and lymphadenopathy. PMID- 8685111 TI - [Surveillance of patients treated with tamoxifen]. AB - Tamoxifen is a nonsteroidal anti-estrogen frequently used in breast cancer therapy. Side effects to tamoxifen are uncommon (2%) but should be recognized and detected early by careful follow-up. Tamoxifen adjuvant therapy is absolutely indicated in postmenopausal breast cancer with estrogen-receptor--positive nodes. Recently, this indication has been extended to negative-node postmenopausal breast cancer. Mild acute side effects are the most frequent: hot flushes, menstrual irregularity, nausea, headache, vertigo, minimal modifications in blood cell counts. However, more serious accidents can occur. Increased risk of thromboembolism is linked to a fall in the level of antithrombin III. Ocular toxicity can occur. If such ocular lesions are diagnosed early enough, they can be cured by promptly withdrawing treatment. For patients given tamoxifen, there appears to be a small increase in risk of endometrial carcinoma, especially if the daily dose is > 30 mg. This over-risk requires adequate detection based on sufficient knowledge of the usual tamoxifen-related modifications in the endometrium. Physicians should also be aware of two favorable effects. Tamoxifen therapy leads to decreased cardiovascular morbidity and mortality in postmenopausal women and is associated with a significant increase in lumbar bone density. Risk of interaction with oral anticoagulants has been reported. We discuss here practical steps in the follow-up of women treated with tamoxifen. PMID- 8685112 TI - [Cat scratch disease. Atypical forms]. AB - First described by Robert Debre in 1950, cat scratch disease, usually observed in children and young adults (80% of the case occur in subjects under 18), is the principal cause of chronic benign lymph node enlargement. The Centers for Disease Control at Atlanta currently recognize Afipia felis and Rochalimaea henselae as the causal agents of cat scratch disease. Cats transmit the disease to humans by skin scratches or by licking open wounds. The bacilli can also be transmitted by dogs, monkeys, squirels or inert objects. The contaminating cats are usually young. There is no interhuman transmission. There are several uncommon manifestations of cat scratch disease which may misguide diagnosis. In atypical forms, the positive diagnosis of this benign disease can only be confirmed by serology or molecular biology techniques. In order to reduce the duration of the disease, antibiotic treatment is recommended in forms with systemic involvement and in atypical forms although there has been no proof of efficacy. PMID- 8685113 TI - [Effect of intravenous naloxone on bladder hypofunctions]. PMID- 8685114 TI - [Ingestion of raw fish: a cause of eosinophilic meningitis caused by Angiostrongylus cantonensis after a trip to Tahiti]. PMID- 8685115 TI - [Maintenance treatment of cerebral toxoplasmosis in AIDS: role of clarithromycin minocycline combination]. PMID- 8685116 TI - [Encephalitis caused by ticks in Central Europe, an imported disease]. PMID- 8685117 TI - [Apropos of partial properdin deficiency disclosed by Neisseria meningitidis septicemia]. PMID- 8685119 TI - [What does remain about bronchopulmonary dysplasia?]. AB - Bronchopulmonary dysplasia is defined as prolonged respiratory failure resulting from sequellae after neonatal intensive care in premature infants. Functional impairment continues into adult life. There are two main causal factors: the initial respiratory disease and pulmonary immaturity. Up through the nineties, bronchopulmonary dysplasia was a major problem in neonatal intensive care units; mortality reached 20% of infants requiring artificial ventilation for 1 or 2 months. Despite the rising rate of premature births (currently 2%) considerable progress has been made in the treatment of bronchopulmonary dysplasia. The question is whether the infants in the current generation with still suffer into adult life. Advances in preventive therapy have included antenatal corticosteroid therapy, use of exogenous surfactants and progressive improvement in ventilatory assistance techniques. Improved neonatal care to relieve pain and maintain nutrition have also had an important effect. Specific treatments include the use of salbutamol spray to reduce bronchospasme and improve respiratory compliance. The initial hopes placed in inhaled corticosteroids were unfortunately recently shown to be unfounded. Due to the large number of premature infants it appears difficult to predict the future situation of bronchopulmonary dysplasia, but current data show a clear tendancy towards regression of the disease. Three preventive measures could further reduce the incidence: better coordination between obstetricians and pediatricians, extension of antenatal corticosteroid therapy and the development and improvement of continuous positive pressure ventilation. PMID- 8685118 TI - [Medical treatment of osteoarthritis]. AB - Immediate symptom relief, long-term symptom relief and chondroprotection comprise the basis of medical treatment of degenerative joint disease. Nonsteroid anti inflammatory agents, antalgics and intra-articular infiltrations with corticosteroids provide rapid relief. A more delayed long-term effect can be obtained with a large number of drugs. Chondroprotectors are currently the focus of therapeutic research. Advances in our knowledge of the pathophysiological processes involved in the development of the degenerative process, a critical analysis of current medical therapies and rigorous methodology in clinical trials will soon provide a better range of treatments for patients suffering from degenerative joint disease. PMID- 8685121 TI - [Behavior assessment in Alzheimer type dementia using the disruptive behavior questionnaire]. AB - OBJECTIVES: We developed a disruptive behavior questionnaire designed for persons living close to the patient in order to assess behavior disorders in Alzheimer type dementia. METHODS: The study included 111 patients with criteria for diagnosis of Alzheimer type dementia. The questionnaire was used to assess the patients 15 days after withdrawal of psychotropic drugs. A partially-structured interview was also conducted by a psychiatrist in 20 cases. RESULTS: There was no relationship between the different behavior disorders and the mini-mental-state score or the social and cultural situation. Answers to the questionnaire and responses given during the interview were nearly identical. CONCLUSION: There has been little effort to assess behavior disorders compared with cognitive disorders in patients with Alzheimer type dementia. Behavior assessment should be an integral part of patient evaluation since cognitive and non-cognitive disorders are independent and certain therapeutics may be effective in behavior disorders. PMID- 8685120 TI - [Glycoforms of alpha-1 antichymotrypsin in infectious process. Diagnostic value and follow-up]. AB - OBJECTIVES: Three alpha 1-antichymotrypsin (alpha 1-ACT) glycans have been identified. We followed their levels during the septic processes in 24 patients in order to determine their diagnostic value in correlation with C-reactive peptide in patients with infection. METHODS: Sera were collected for assay on days 0, 3 and 6 after starting antibiotics. Erythrocyte sedimentation rate, alpha 1-ACT and C-reactive protein were determined. RESULTS: Erythrocyte sedimentation rate changed little while C-reactive protein fell sharply as in other inflammatory processes. Crossed immunoaffinoelectrophoresis showed a decreased formation of the Con-A non reactive fraction which disappeared rapidly after initiating antibiotics. Glycan microheterogeneity returned to normal at 6 days while C-reactive protein and alpha 1-ACT were still elevated. CONCLUSION: Synthesis and glycosylation of alpha 1-ACT are independent. Study of alpha 1-ACT glycan microheterogeneity may provide a useful test in the diagnosis of inflammatory processes of unknown origin and may be helpful in following-up patients with sepsis. PMID- 8685122 TI - [Yersinia enterocolitica: a cause of acute intestinal intussusception]. AB - OBJECTIVES: Yersinia enterocolitica infection is a rare cause of intestinal intussusception, especially in adults. We report here a case in a 29-year-old man and review the literature on diagnosis and therapy. CASE REPORT: A 29-year-old man presented with a 2-week history of diarrhea and weight loss. Ultrasonography revealed acute intestinal intussusception localized at the site of enlarged mesenteric nodes. At laparostomy, intestinal resection was not required. Histology examination of the mesenteric nodes showed follicular hyperplasia. Serology was positive for Yersinia enterocolitica. Outcome was favorable after treatment with tetracycline for 15 days. DISCUSSION: Yersinia enterocolitica are Gram negative bacilli that grow at low temperature. Food contamination is the most frequent source of infection in man, usually in children. Clinical manifestations include gastroenteritis or pseudoappendicular syndrome. Intestinal intussusception is rare. Operative reduction by taxis is generally sufficient. Histology examination of the lymph nodes excludes lymphoma. The diagnosis is confirmed by serology. A 10 to 15-day antibiotic regimen is needed. PMID- 8685123 TI - [Basedow disease following metastatic thyroid cancer]. AB - OBJECTIVES: Metastatic thyroid carcinoma rarely provokes hyperthyroidism. We describe here the main characteristics of this association observed in a 48-year old woman. CASE REPORT: The patient had presented signs of hyperthyroidism for one year. Clinical examination revealed severe Graves' disease with nodular goiter. Presurgery investigations demonstrated thyroid carcinoma and lung metastasis. Thyroid stimulating immunoglobulins were elevated. After total thyroidectomy, hyperthyroidism persisted, indicating the functional nature of the lung metastases. DISCUSSION: The effect of thyroid stimulating immunoglobulins on the clinical course of thyroid carcinoma and distant metastases remains unknown. PMID- 8685124 TI - [Antral exclusion. A complement to palliative gastrojejunal shunt in pancreatic cancer]. AB - OBJECTIVES: Prophylactic gastrojejunostomy remains a controversial issue in the management of unresectable pancreatic cancer. The main disadvantage of the gastrojejunostomy being the postoperative delayed gastric emptying (gastroparesia and circulus vitiosus through the nonobstructed duodenum). In the aim to reduce the effects of delayed gastric emptying we advocated the adjunct of an antral exclusion to simplify antrectomy by eliminating antral dysfunction and duodenal circulus vitiosus. METHODS: The procedure of antral exclusion was performed using a 4-row linear stapler. The gastrojejunostomy was immediately proximal to the staples row. RESULTS: Preliminary results in 6 patients, evaluated by clinical follow up, radiologic and radionucleide studies, showed no delayed gastric emptying nor other postoperative complications related to this technique. CONCLUSION: These preliminary results are encouraging and suggest that this procedure could improve the functional results of the prophylactic gastrojejunostomy. PMID- 8685125 TI - [Detection of endocrine tumors of the digestive tract. Value and limitations of scintigraphy of somatostatin receptors]. AB - Most neuroendocrin tumors (excepting insulinomas) carry a high density of somatostatin receptors which readily bind somatostatin analogs, allowing tumor and metastasis imaging with indium-labeled somatostasin analogs. For primary tumors (gastrinomas, carcinoid tumors), detection sensitivity is about 80%. The scintiscan adds complementary information to other imaging techniques including echoendoscopy. By combining indium-scan with echoendoscopy we have been able to detect 90% of the tumors in the upper duodenopancreatic area. In addition, scintigraphy detects tumors in about half of the patients with characteristic laboratory tests but negative imaging with other techniques. Metastases can also be detected; sensibility for liver is > 90%. The indium-scan is also positive in up to 20-30% of the patients after other imaging methods failed to identify metastasis. Finally, tumors found to be receptor-positive would respond better to treatment with somatostatin analogs. PMID- 8685126 TI - [Medical treatment of aortic abdominal aneurysms. Outstanding questions]. AB - The low mortality of programmed surgical treatment of aortic abdominal aneurysms (2-4%) contrasts with a high mortality of surgical treatment in case of rupture (70-90%). These data underline the benefit of a "prophylactic" surgical treatment of aortic abdominal aneurysms, even those of small size or in older patients. Recently, experimental models and results of a few clinical studies suggest that medical treatment with beta-adrenergic blocking agents may reduce the expansion rate of aortic abdominal aneurysms and thus lower the risk of rupture. Several questions remains open. Should beta-blocking agents be reserved for aneurysms more than 5 cm in diameter in patients with a contraindication for surgery, or on the contrary proposed for aneurysms less than 4 cm in diameter in patients still free of contraindications? What is the mode and delay of action for beta blockers, their effect on modulating blood pressure and their contribution to the use of endoluminal prostheses? Controlled prospective trials enrolling a large number of patients are required to answer these questions. PMID- 8685128 TI - [Ischemic accidents of the sylvian and tibial arteries in the course of severe extracellular dehydration]. PMID- 8685127 TI - [Bilateral C8 meningoradiculitis in infectious mononucleosis]. PMID- 8685129 TI - [Hashimoto's encephalopathy. A new case]. PMID- 8685130 TI - [Laparoscopic cholecystectomy in patients with severe obesity]. PMID- 8685131 TI - [Painful experience of urodynamic and neurophysiological examinations]. PMID- 8685132 TI - [Pseudo-hypertriglyceridemia in children. A possibly underestimated entity?]. PMID- 8685133 TI - [Prospects in video-assisted spinal surgery]. AB - Advances in spinal surgery for both posterior procedures on herniated discs and anterior procedures involving the vertebral body have been greatly affected by developments in video-assisted techniques. Many of the procedures mentioned here are still in the development stage, others have proven their efficacy. Discoscopy, achieved by introducing the endoscope via a posterolateral route into the intervertebral disc, can be used for diagnosis and treatment of the disc and the end plates. Other techniques exploring the spinal canal are also being developed. With miniaturization, these techniques will undoubtedly be predominant in the near future. The anterior route is facilitated at the thoracic level by the pleural cavity. Current indications for anterior endoscopic spinal surgery are limited to cord compression syndromes, but perspectives for trauma or tumor surgery as well as reconstruction surgery for malformations in children are quite promising. On the lumbar level, surgery involving the lombo-sacral disc is the main indication for transperitoneal endoscopy. The risks (sepsis, occlusion, gas emboli) cannot be overlooked, but few complications have been observed to date. The retroperitoneal route can be used to approach the anterolateral aspect of the spine, particularly useful for the upper lumbar bodies. A third possibility is the extraperitoneal anterior route for video-assisted procedures from L2-L3 to L5 S1. Although video-assisted procedures have not yet been shown to improve long term outcome after spinal surgery, the immediate post-operative period is greatly simplified, a point which may be of particular importance depending on the patient's general status. PMID- 8685134 TI - [Legionnaires' disease with acute respiratory insufficiency. Clinical and biological characteristics, comparison with pneumococcal pneumonia]. AB - OBJECTIVES: Legionnaires' disease is one of the main etiologies of bacterial pneumonias because of its frequency as well as its potential severity. The therapeutic choice implies the need to look for distinctive clinical, biological or radiological signs, due to the unreliability of rapid immunological criteria. Pneumococcus is the first cause of bacterial pneumopathy. Thus, identifying the distinctive signs between these two etiologies may be necessary. METHODS: In our restrospective study, nine Legionnaires' disease-related pneumonias were compared with nine pneumococcus-related pneumonias with acute respiratory failure and comparable level of severity. Patients were recruited over a two year period in a medical intensive care unit. RESULTS: Four criteria were found more frequently in pneumonia related to Legionnaires' disease: high-grade fever at the time of admission, elevated transminases, presence of Miller's criteria (converging clinical and biological signs) and increasing creatine kinase. CONCLUSION: In patients with severe pneumonia, both Pneumococcus and Legionella should be entertained as possible diagnoses before starting treatment. A prospective analysis of precise diagnostic criteria is needed to distinguish between these two bacterial diseases. PMID- 8685135 TI - [Acute appendicitis in patients over 70 years of age]. AB - OBJECTIVES: We assessed preoperative diagnosis of appendicitis and perforations in elderly patients in our unit to determine whether the overall higher rate of appendectomy in France (3 to 4 times higher than in anglo-saxon countries) has an effect. METHODS: We analyzed retrospectively the cases of all patients over 70 years of age who undervent appendectomy for histologically confirmed appendicitis between February 1, 1990 and 31 January 1995. RESULTS: There were 20 patients (15 women 5 men) in the study group (age range 70-89 years). The site of abdominal pain was atypical in 10 cases (50%) and acute bowel occlusion occurred in 9 (45%). The diagnosis of appendicitis was made before surgery in 10 patients; surgery was performed within 24 hours of admission in only 8. The high rate of perforations (70%) was not correlated with age. Complications occurred in 70% of the cases and were related to perforation (p < 0.02) and an American Society of Anesthesia (ASA) score > 2 (p < 0.05). CONCLUSION: Acute appendicitis in the elderly patient is a serious condition. The atypical nature of the clinical presentation in half of the patients often requires computed tomography or laparoscopy for diagnosis. PMID- 8685136 TI - [Planned pregnancy program in systemic lupus erythematosus]. AB - OBJECTIVES: Maternal and fetal risk is high during pregnancy for young women with systemic lupus erythematosus. We analyzed outcome after a planned pregnancy program for these patients. METHODS: Between 1982 and 1994, 58 pregnancy were planned in 34 women with systemic lupus. Nine of them had renal and 5 central nervous system involvement; antiphospholipid syndrome was present in 8; steroid therapy was given in 24, immunosuppressors in 2 and plasma exchange in 1. At diagnosis of pregnancy, prednisone was prescribed (at least 10 mg/d), associated with aspirin in all non-symptomatic patients with antiphospholipid antibodies followed by heparin at pre partum. Heparin was used in case of antiphospholipid syndrome. Women with anti-SSA or B antibodies and no past history of congenital atrioventricular block were not given any specific treatment. RESULTS: An acute lupus flare-up occurred in 27% of the cases including 6% in post partum. The flare-up was mild in all cases and treatment had to be changed in half of the cases. There were 9 early abortions, 1 induced abortion for congenital malformation, 2 fetal deaths, 28 premature deliveries and 18 term deliveries. Cesarean section was indicated in 8 cases. Severe neonatal infection occurred in 2 premature infants and 1 other was growth retarded. Cutaneous neonatal lupus was observed in 2 infants. No atrioventricular blocks occurred. CONCLUSION: Fetal death or very premature birth were more frequent in patients with antiphospholipid syndrome. When pregnancy is planned in women with systemic lupus erythematosus, live birth rate reaches 96% after exclusion of early and therapeutic abortions. This rate is close to the rate in the general population. The high rate of premature birth is the main risk, but there were no maternal nor neonatal deaths. PMID- 8685137 TI - [Osteoporosis in ankylosing spondylitis]. AB - Bone formation is classically observed in ankylosing spondylitis, but osteoporosis can also occur. This condition has been recognized for years on radiographs. Compared with controls, osteoporosis in ankylosing spondylitis is responsible for increasing the incidence of vertebral compression fractures and also explains spinal fractures after trauma, mainly observed at the cervical level. Measurement of bone mass is useful in diagnosing osteoporosis commonly observed in the lumbar spine and the femoral neck but not in the appendicular skeleton. Osteoporosis is seen early in the disease whereas increased bone mass is observed later or due to syndesmophyte formation. Osteoporosis in ankylosing spondylitis is probably a multi-factorial condition. Contributing factors are spine immobility secondary to ankylosis, inflammatory cytokines which enhance bone resorption, prolonged use of nonsteroidal antiinflammatory drugs and a deficit in sex hormone secretion. Furthermore, there is no alteration in calcium or phosphorus metabolism in ankylosing spondylitis. Finally, a study of bone morphometrics in the iliac crest region is required to better explain osteoporosis in ankylosing spondylitis. PMID- 8685138 TI - [Non-surgical treatments of renal artery stenoses]. AB - Management of patients with renal artery stenoses is aimed at normalizing or reducing blood pressure and correcting or preventing reduced glomerular filtration. The results of renal revascularization have been documented mainly in retrospective, uncontrolled reports in which blood pressure improvement was overestimated due to the placebo effect and optimization of drug treatment, the latter being frequently required despite adequate revascularization. In an overview of 10 series reporting blood pressure outcome following percutaneous angioplasty, cure rates were 50% in patients with fibrodysplastic stenosis but only 19% in those with atherosclerotic stenosis. The literature on revascularization of atherosclerotic stenosis with progressive renal failure shows that 55% of patients have improved renal function following surgery and 41% following angioplasty. Mortality is 6 and 5% respectively. The first controlled trials comparing revascularization to medical treatment in renal artery stenosis have recently been published. In a prospective randomized trial, Weibull et al. compared percutaneous angioplasty and surgery in 58 patients with unilateral atherosclerotic stenosis. Although 17% of the patients initially treated with angioplasty required subsequent surgery, blood pressure, renal function and renal artery patency rate did not differ between angioplasty and surgery 24 months after treatment. A Scottish group reported a prospective randomized trial of percutaneous angioplasty vs. medical therapy in patients with bilateral or unilateral atherosclerotic stenosis. In the bilateral group (n = 28), the drop in systolic pressure was significantly larger following angioplasty than following medical therapy, but diastolic pressure and creatinine did not differ after 24 months. In the unilateral group (n = 27), there were no differences in blood pressure or creatinine levels following angioplasty or medical therapy. Several randomized trials comparing angioplasty and conservative treatment or angioplasty and stent placement in patients with renal artery stenosis and normal or reduced renal function are currently underway. They should provide additional information regarding the risk/benefit ratio of these procedures. PMID- 8685139 TI - [Incidence of AIDS in the mortality of young women in the UHC (University Hospital Center) of Nice]. PMID- 8685140 TI - [Plurimicrobial meningitis in adults associated with asymptomatic spondylodiscitis. An uncommon manifestation of sigmoid tumor]. PMID- 8685142 TI - [Cholangiocarcinoma in genetic hemochromatosis]. PMID- 8685141 TI - [Bladder metastasis of breast cancer]. PMID- 8685143 TI - [Macrophage activation syndrome following bone metastases of prostatic cancer]. PMID- 8685144 TI - [True popliteal venous aneurysm. 2 cases]. PMID- 8685145 TI - [Combination regimens in rheumatoid arthritis]. AB - The objective of combination regimens in the treatment of rheumatoid arthritis is to improve effectiveness (additive or synergistic effect) and reduce the rate of side effects. Many combinations have been tried. In general, compared with single drug regimens, combination therapy does not increase toxicity but clinical improvement has not been proven. In addition, there is no evidence concerning the long-term effects of combination regimens. Despite these drawbacks, combining drugs known to be effective in rheumatoid arthritis alone may be an interesting alternative for patients who have responded incompletely to single drugs, particularly methotrexate. However, for both single-drug and combination regimens we are still lacking proof of a real beneficial effect in terms of reducing functional impairment, improving quality of life, lengthening life expectancy, or reducing overmortality resulting from rheumatoid arthritis. Long-term outcome may provide some answers. Finally, there are still several combinations to be studied including methotrexate with "targeted" drugs such as anti-CD4 and anti-TNF alpha antibodies or the soluble TNF alpha receptor. PMID- 8685146 TI - [Treatment of moderate arterial hypertension with physical exercise]. AB - OBJECTIVE: To compare the anti-hypertensive effect of physical exercise programs with that of usual therapeutic regimens. METHODS: Blood pressure measurements at rest and during exercise were compared in two groups of patients with moderately high blood pressure treated either medically or with physical exercise. Outcome was evaluated at 5 years. RESULTS: In the first group there were 28 patients who were given drug treatment (excepting beta blockers). In the second group, 53 patients performed regular physical exercises specifically prescribed. After 5 years, the analysis of variance confirmed that physical exercise had a real anti hypertensive effect. CONCLUSION: Physical exercise can be an effective mean of treating moderately high blood pressure with a more prolonged effect than drug regimens. PMID- 8685147 TI - [Value of endorectal ultrasonography in the treatment of rectal tumors]. AB - OBJECTIVES: To determine the diagnostic accuracy of endosonography and to appreciate its influence on the therapeutic strategy. METHODS: Sixty-two patients referred to the gastroenterology unit between April 1990 and February 1995 for a rectal tumor. Thirty-two patients did not receive any preoperative treatment (group A) and 30 were treated by radiotherapy or chemoradiotherapy before surgery (group B). Transrectal ultrasonography was performed with a Bruel and Kjaer device. RESULTS: Diagnostic accuracy for parietal infiltration was 84% for the entire series, 94% for group A and 73% for group B. Diagnostic accuracy of lymph node invasion was 71% for the entire series, 81% and 60% for groups A and B, respectively. It is highly probable that a histopathologic down-staging due to preoperative treatment explained the results in the group B. Using a pragmatic approach which combined the results for parietal infiltration and for lymph node invasion, transrectal ultrasonography would have correctly selected 20 among the 25 patients who could have been treated by local excision. The use of this same pragmatic approach in patients with high risk of local recurrence enabled correct selection of 26 among the 32 exposed patients. CONCLUSION: We conclude that transrectal ultrasonography: 1. is a reliable technique for the pretherapeutic staging of rectal cancer, especially for the assessment of parietal infiltration. Progress is needed for the diagnosis of lymph node invasion; 2. selects well the patients who can be treated by local excision; 3. is a reliable technique for the selection of patients who need preoperative treatment. PMID- 8685148 TI - [Transanal excision of rectal tumors. New applications of the endo-GIA forceps]. AB - Two new applications of the endo-GIA technique are presented for endoluminal intrarectal resection of benign or malignant tumors of the lower or middle part of the rectum. These procedures allow resection of sessile lesions with a large implantation base. Depending on the pathology and the type of implantation, resection can either be total or via the musculosa. Results have been good with this simple procedure which allows total tumor resection and an uneventful post operative period. PMID- 8685149 TI - [Use of related live donors in renal transplantation]. AB - Collecting pertinent information is first step in assessing the use of living related kidneys for transplantation. Current bioethics legislation in France limits kidney donation to first-degree family members and spouses in emergency situations. Severe penalties are inflicted for use of other donors or sale of organs. Further valuable information can be obtained from reports in the literature on complications in donors and on the advantages of living donor organs. The proportion of live donors in France is small (3.5% from 1984 through 1993) indicating that transplantation teams prefer cadaver organs except in pediatric cases. The proportion of live donor organs transplanted in northern Europe and North America is much higher. A quick survey of French teams show that opinions and practices vary. Questions still under debate include how to guarantee freedom to refuse or accept, a freedom directly related to correct information. Several propositions have been made in an attempt to harmonize management. First, an information sheet could be distributed during the early discussions, outlining the advantages and disadvantages of live organ donation. A list of complementary examinations could also be established to identify possible contraindications for nephrectomy and define exclusion criteria. A similar procedure adopted by all transplantation teams could be based on these propositions presented in the appendix. Potential donors could then benefit from uniform protection. PMID- 8685150 TI - [Intraglomerular hypertension. Physiopathology and therapeutic implications]. AB - It is now well-established in experimental models in rodents that increased glomerular pressure results in the development of focal and segmental glomerulosclerosis, proteinuria and progressive renal functional deterioration. In humans, direct measurement of glomerular capillary pressure is impossible. However, it is widely accepted that glomerular hypertension is present in different clinical situations, like diabetic nephropathy, chronic renal failure associated with glomerulonephritides, some forms of essential hypertension and cadaveric kidney transplantation. Many studies were performed on the effects of protein-restricted died and/or angiotensin converting enzyme inhibition on the rate of progression of renal failure in these renal diseases. Although controversial, the overall results suggest that these therapeutic strategies may reduce the rate of progression, particularly in diabetic nephropathy. PMID- 8685152 TI - [Symptomatic respiratory involvement in Crohn disease]. PMID- 8685151 TI - [Myocardial infarction caused by probable paradoxical embolism and aneurysm of the interatrial septum]. PMID- 8685153 TI - [Digestive tuberculosis is not uncommon in surgery]. PMID- 8685154 TI - [Follicle freezing and autografting. A new method of medically assisted procreation?]. AB - Although frozen human follicles were shown to be viable after thawing, more than forty years, the low yield of primordial follicles after cryopreservation has greatly limited research in this area. The aim of freezing follicles is to stock a patient's ovocytes before potentially destructive therapy for cancer then to reimplant the follicular tissue after successful treatment. The patient's ovulatory capacity would then theoretically be restored, allowing natural or possibly in vitro fertilization. As have other teams, we recently renewed work in cryopreservation of follicles in experimental models in search for a better cryopreservation agent and have had encouraging results suggesting that primordial human follicles or ovarian fragments can be grafted successfully after cryopreservation. Questions still under study include the optimal site for implantation, the survival time for grafts and the quantity of follicles needed to achieve pregnancy. Work on large animal models or xenografts of human tissues on immunotolerant animals may provide further insight. The possibilities of grafting primordial follicles, either alone or within ovarian tissue, may raise hope for many women, although new questions such as an age limit for reimplantation and use of allografts requiring preparation with major immunosuppressive therapy require further debate. PMID- 8685155 TI - [Clinical, biological and developmental aspects of alcoholic ketoacidosis]. AB - OBJECTIVES: To review cases of alcoholic ketoacidosis in order to better ascertain therapeutic management. METHODS: The medical files of 32 alcoholic patients with ketoacidosis hospitalized in the Saint-Pierre general hospital of the Reunion island from January 1, 1991 through 31 August 1994 were analyzed. RESULTS: There were 18 women and 14 men, mean age 47 years. The first clinical signs were predominated by digestive (n = 22) or neurological disorders (n = 10). Acidosis was severe (mean pH = 7.12) and always associated with a wide anion gap (mean anion gap = 35). There were 3 types of glycemic status: hypoglycemia 10 cases, normal or subnormal glycemia in 19 cases (mean glycemia = 9.3 mmol/l) and hyperglycemia above 20 mmol/l in 3 cases. Hypophosphatemia, elevated serum lactate levels and cytolytic hepatitis were the main abnormalities associated. CONCLUSION: Short-term outcome was favorable in all cases after rehydration. The use of insulin may be dangerous and needs to be avoided. PMID- 8685156 TI - [Swyer-James or Macleod syndrome or unilateral translucent lung]. AB - The syndrome, described by Swyer and James in 1953 and by Macleod in 1954 is a specific entity within a much larger group of radiological conditions brought together under the term of unilateral translucent lung. Generally acquired in childhood subsequent to viral bronchopulmonary infections, the syndrome is caused by predominantly unilateral obliteration of the distal bronchi. The lung is usually small as the infection during childhood inhibited the normal growth pattern. Two elements found in all patients are trapped air and distal bronchiol obstruction. Pulmonary vascularization is greatly reduced leading to radiological translucency. Clinical signs are usually absent. We report two cases illustrating late diagnosis in adults and focus on the novel aspects of this syndrome as well as recent pathogenic hypotheses and diagnostic approach. PMID- 8685158 TI - [Pseudocysts of the pancreas. Diagnosis, course and principles of treatment]. AB - Pseudocysts of the pancreas are collections of liquid more or less completely composed of pancreatic secretions. Patients with acute pancreatitis without underlying chronic pancreatitis may develop necrotic pseudocysts while those with chronic pancreatitis may develop either necrotic or retention pseudocysts. The prevalence and localization are largely dictated by the cause of the pancreatitis. Ultrasonography and computed tomography give the diagnosis and reveal the size, localization and relations of the pseudocyst. Some pseudocysts may regress spontaneously, usually within a few weeks, especially necrotic pseudocysts measuring less than 6 cm. In others, complications include acute infection, intracystic bleeding, rupture, fistulization and compression of neighboring organs. Surgery was classically proposed for all pseudocysts, but puncture-evacuation and percutaneous or endoscopic drainage have also been successful. The risk of recurrence is higher with puncture-evacuation. Today, complicated forms and unsuccessful medical treatment are good indications for surgery. Cystodigestive drainage is preferred although exeresis may be required in specific cases. PMID- 8685157 TI - [Lymphocytic hypophysitis: a reality]. AB - Lymphocytic hypophysitis is a rare entity; we report here three cases. This condition usually occurs in women during pregnancy or in the post-partum period. Pituitary enlargement is associated with complete or partial hypopituitarism. The difficulty in diagnosis is well illustrated by our cases and results from the similarity between the clinical and biological signs of adenoma and hypophysitis. Circulating antipituitary antibodies are not constantly found and are nonspecific, evidence only of the autoimmune nature of hypophysitis. Thus the diagnosis has to be undertaken in all suspected cases in pregnant women or during the post-partum period. The clinical course may be very long, emphasizing the need for rigorous long-term observation. The pituitary gland is commonly enlarged and homogenous in lymphocytic hypophysitis, but in our third case the enlargement was heterogeneous with associated cyst formation. We suggest that the inflammatory process could have been maintained by the presence of cysts. Finally, corticosteroids are the therapy of choice in the inflammatory stage and should be undertaken as soon as the diagnosis has been established. Regular surveillance is required. PMID- 8685159 TI - [Nosocomial pneumonia]. AB - Second cause of nosocomial infections and certainly the most serious, pneumonia concerns nearly 1% of all hospitalized patients. The need for intensive care, especially mechanical ventilation, is the leading risk factor for acquiring nosocomial pneumonia. Clinical and radiological data are contributive but insufficient for diagnosis and correct selection of antibiotics. Many germs are potentially accountable for these diseases, especially Pseudomonas and Staphylococcus. The endobronchial protected brush has been considered as the gold standard for diagnosis by the fifth consensus report of SRDLF (Societe de Reanimation de Langue Francaise). Other methods are currently proposed which are less traumatic, cheaper, easier to use and give quicker results, but their sensitivity and specificity are debated. The bacteriological results of these searches are precious guides to choose curative antibiotics. The prevention of nosocomial pneumonia has become an accepted priority for public health. PMID- 8685161 TI - [Esophageal bezoars: late complication of mediastinal radiotherapy]. PMID- 8685160 TI - [Difficulties for interpreting the serology of the Parvovirus B 19]. PMID- 8685162 TI - [Does gastroesophageal reflux exist in newborn infants?]. PMID- 8685163 TI - [Pseudomonas aeruginosa mediastinitis after transesophageal echocardiography]. PMID- 8685164 TI - [Detection of prostatic cancer in symptomatic patients with serum levels of prostate-specific antigen between 4 and 10 ng/ml]. AB - OBJECTIVES: Determine the incidence of prostate cancer in patients consulting for common miction disorders and serum prostatic specific antigen (PSA) between 4 and 10 ng/ml. METHODS: A total of 153 patients consulted for miction disorders. In 107 of them, the digital examination was abnormal and PSA was between 4 and 10 ng/ml. Transrectal sonography and prostatic biopsies were performed in these 107 patients. We determined the number of cancers detected and assessed the contribution of PSA density (PSAD) to diagnosis. In patients undergoing radical prostatectomy, invasion of the capsule (C+) and positive exeresis section (M+) were recorded. RESULTS: Cancer of the prostate was diagnosed in 29.4% of the patients on the basis of at least 1 of the 6 biopsies. This rate was 47.8% in patients with an abnormal and 21.5% with a normal digital examination. Radical prostatectomy was performed in 32 patients: 50% of them were C+ and 33% M+. CONCLUSION: Biopsy of the prostate is indicated in patients with an abnormal prostate at digital examination when PSA is between 4 and 10 ng/ml. When the prostate appears to be normal, PSAD may be helpful in determining when to perform a biopsy. Intermediary serum PSA levels do not guarantee favorable pathological characteristics. PMID- 8685165 TI - [Vertebral bone loss in perimenopause. Results of a 7-year longitudinal study]. AB - OBJECTIVES: Rapid bone loss after menopause is generally recognized although the exact chronology of the events, particularly in relation to onset of amenorrhea, remains poorly understood. We assessed bone loss in perimenopausal women over a 7 year period. METHODS: Twenty-one women with an uneventful past history were enrolled before menopause and followed until menopause had been completely established. Vertebral bone density was measured by biphotonic absorptiometry annually over two 2-year periods. Individual variations in bone density were calculated according to onset of menopause. RESULTS: Bone loss in the vertebral body increased during the two years preceding menopause (-1.6 +/- 1.5% per year), reached a peak during the first three post-menopausal years (-2.4 +/- 1.6% per year), and then fell off (-1.2 +/- 1.4% per year). CONCLUSION: Bone loss was independent of calcium intake and appeared to be related mainly to characteristic hormone changes during the perimenopausal period. These findings raise the question as to the need and means of prevention. PMID- 8685166 TI - [Hemostatic embolization of hepatocellular carcinoma with portal vein thrombosis complicated by hemoperitoneum]. AB - A 59-year-old chronic drinker (120 g alcohol/day) was hospitalized for sudden increase in abdominal volume found to be caused by a hemoperitonoff resulting from ruptured hepatocellular carcinoma with thrombosis of the portal vein. Emergency arterial embolization with gelatin sponge successfully stopped intraperitoneal bleeding. No surgical treatment could be attempted due the severity of the cirrhosis. This patient survived for 4.5 month. Based on this observation and a review of the literature, it can be suggested that hemostatic embolization is an effective treatment for spontaneous hemorrhage of hepatocellular carcinoma even in cases with portal vein thrombosis. PMID- 8685167 TI - [Acute myopathy in an asthmatic patient treated with corticoids and muscle relaxants in the intensive care unit]. AB - Acute myopathy occurred in a 49-year-old woman hospitalized in the intensive care unit for status asthmaticus. She was given high-dose intravenous steroid therapy and intubated. Pancuronium bromide was used for prolonged curarization. Flaccid quadriplegia developed with preservation of the deep tendon reflexes. Muscle biopsy showed a myogenic process with disorganized myofibrils and selective loss of thick myosin filaments. This mainly myogenic process would result from the toxic effect of corticosteroids favored by prolonged curarization although the effect of other factors still remains unknown. PMID- 8685168 TI - [Thymus hyperplasia following chemotherapy]. AB - Hyperplasia of the thymus, an uncommon development following chemotherapy, raises doubt concerning possible tumor recurrence. We report a case of thymic hyperplasia in a 12-year-old girl who was given chemotherapy for a cervicomediastinal lymphoma. Three months after treatment end, dry cough and an enlargered mediastinum suggested recurrence, but histological examination of tissue biopsy demonstrated benign reactive hyperplasia. Outcome was favorable without recurrence after corticosteroid therapy. According to the literature, thymic hyperplasia is neither tumor nor treatment specific. It generally occurs in children but may be observed in young adults. Hyperplasia of the thymus following chemotherapy would appear to be a good prognosis factor. PMID- 8685169 TI - [Congenital and acquired neutropenia in children]. AB - Neutropenia is a common feature in pediatric pratice. Besides the particular etiological aspects in the newborn, neutropenia in a child may be acquired, part of a more complex genetic disease, or an isolated inborn disorder. Primary acquired neutropenia, also called benign chronic neutropenia, is the most frequent cause of chronic neutropenia in children. Infantile agranulocytosis is the main primary congenital neutropenia. Its underlying mechanisms are still unknown. Prevention of repeated infections is the main issue in the management of such patients. This implies careful individual assessment for each patient. Management includes first prophylactic antibiotherapy using trimethoprim sulfamethoxazole and secondly hematological growth factors (mainly G-CSF). Long term G-CSF therapy results in a rise in the absolute neutrophil count, a reduction in the rate of infection and an improvement in the patient's quality of life. Severe side effects, including osteoporosis, vasculitis, myelodysplasia or leukemia have been occasionally reported in certain subsets of patients. These features are currently being prospectively assessed in an international register. Use of hematological growth factors must be evaluated for each individual case. PMID- 8685170 TI - [Congenital diabetes insipidus. Recent advances in molecular genetics]. AB - Hereditary diabetes insipidus can occur in two forms: the first, referred to as central diabetes insipidus, is responsive to vasopressin whereas the second, termed nephrogenic diabetes insipidus, is resistant to treatment. Recent advances in molecular genetics have contributed to elucidate the pathogenesis of these affections. Familial central diabetes insipidus depicts two unsimilar illnesses. The first, characterized by an autosomal dominant transmission, is of delayed onset and worsens progressively all through life. It is related to a heterozygous mutation of the vasopressin precursor gene mainly involving either the sequence encoding for the signal peptide or the one encoding for neurophysin II, the hormone carrier protein. Mutations described to date are responsible for impairment of vasopressin precursor transportation and processing. Therefore mutant protein accumulates in the posterior pituitary which is involved in the persistant bright spot seen on magnetic resonance imaging. The second illness or Wolfram syndrome, autosomal recessive, associates obligatory features: insulin dependant diabetes, bilateral optic atrophy and more inconstantly: diabetes insipidus, deafness, genito-urinary and neuropsychiatric disturbances. The cause of this syndrome, still unknown, may involve mitochondrial ADN mutations. Familial nephrogenic diabetes insipidus, of neonatal onset, are mainly X-linked and associated to mutations in the V2 receptor gene. About 60 mutations have been described until now. Some rare cases, transmission of which is autosomal recessive, result from homozygous mutations of aquaporin 2 gene, a water channel involved in the water reabsorption in the renal collecting duct. Other mutations will be probably discovered in future. In conclusion, familial diabetes insipidus constitutes an interesting pathogenic model because it may be explained by impairment of vasopressin gene precursor as well as by abnormalities of renal receptor or post receptor mechanisms of the hormone. PMID- 8685171 TI - [Acute voluntary poisoning by inhalation of "poppers"]. PMID- 8685172 TI - [Meningoradiculitis related to Lyme disease. Course and prognosis]. PMID- 8685174 TI - [Laparoscopic cholecystectomy and endoscopic sphincterotomy. Analysis of a homogeneous series of 500 patients]. PMID- 8685173 TI - [Effects of naltrexone on automutilation behavior in autistic psychosis]. PMID- 8685175 TI - [Alcaligenes denitrificans subsp. xylosoxidans infection in a patient with corticodependent chronic respiratory insufficiency]. PMID- 8685176 TI - [Diphtheria: apropos of an epidemic]. AB - Since Ramon developed the anti-diphtheria anatoxin in 1924 widespread vaccination has almost eliminated diphtheria, but since the acquired immunity is anatoxic and not anti-bacterial, carriage of the causal agent Corynebacterium diphteriae remains possible. In 1990, 1214 declared cases of diphtheria inaugurated an epidemic which spread through Russia, Ukraine and neighboring countries and even reached a few subjects in Europe and North America. Mortality in Russia was 10.15 per 100000 cases in 1993. Higher rates were observed in children. The question is raised as to the level of protection in Western countries despite generalized vaccination programs. In France, a recent survey showed that only 49.3% of the 1004 subjects evaluated had complete protection and 20.4% had no protection at all. While 95% of young adults in the 15 to 24 age range were protected, the rate of protection was below one-third in subjects over 65. These results emphasize the importance of anti-diphtheria vaccination programs and continued surveillance in adult populations. Current French legislation requires vaccination before the age of 18 months but without any requirement for re-vaccination in adults. The current situation clearly demonstrates that the risk of a diphtheria epidemic still exists, even in our Western countries. To completely protect the population, the present vaccination policy should include re-vaccinations of the adult population every 10 years, as for tetanus. Use of a preparation containing a reduced dose of vaccine, given with the tetanus and polio booster shots, is to be recommended. Re-vaccination with DT or the reduced dose dT would also be indicated after injury instead of tetanus alone. Surveillance and typing of C. diphteriae strains isolated from clinical cases should also be maintained. PMID- 8685177 TI - [Pneumocystis carinii pneumonia: an opportunistic infectious risk associated with systemic diseases and their treatment]. AB - Pneumocystis carinii, an opportunistic pathogen, often causes pneumonia in persons with human immunodeficiency virus (HIV) infection. In patients free of HIV infection, the risk is clearly associated with certain diseases and immunosuppressive therapy. Pneumocystis carinii pneumonia can complicate solid or hematologic malignancies, organ transplantation and connective tissue diseases. Recent therapeutic strategies based on aggressive immunosuppression have increased the risk of opportunistic infection with Pneumocystis carinii, particularly in patients with Wegener's syndrome and systemic lupus erythematosus. The risk of interhuman nosocomial transmission of Pneumocystis carinii in units caring for HIV-infected patients and patients with immunosuppressive diseases should also be considered. The undeniable progress in therapeutic immunosuppression has increased the risk of opportunistic infections. The gravity of Pneumocystis carinii pneumonia demonstrates the importance of optimizing treatment choice in order to strike the right balance between beneficial effect and risk of opportunistic infection. PMID- 8685178 TI - [Hepatitis viruses: from the old ones to the new ones. Will the alphabet be enough to list them all?]. AB - Viral infection is by far the most frequent cause of hepatitis. Search for the causal virus is however difficult since they cannot be cultured on most cell lines in vitro and because regulatory factors required for viral expression are found only in the human hepatocytes which cannot be maintained in vitro sufficiently long for experiments. To date, viruses A, B, C and E have been well documented. Virus D, a defective virus which only develops in association with virus B has also been identified. As have others, we have also found evidence of the existence of a non-A, non-B, non-C, non-E virus (non A-E). Currently, the diagnosis of non A-E hepatitis can only be made by elimination. Our personal experience suggests that non A-E hepatitis could be incriminated in less than 10% of the acute cases requiring hospitalization. Other viruses have been isolated. We were unable to confirm the pathogenic nature of a virus isolated in India in 1994 and assigned the letter F. Virus G has been identified in a patient with post-transfusion hepatitis and corresponding serology has been found positive in 46% of a population of drug abusers and 1.7% of blood donors in the United States. Isolates of the virus GB were first recognized in 1967. There are three viruses: Ga, Gb and Gc, belonging to the Flavivirus or Pestivirus, analogous to the hepatitic C virus. Virus G appears to be identical with virus Gc. The exact pathogenic nature of all these viruses remains to be determined. Search for new viruses would suggest that there are few new pathological situations indicating the presence of unknown viruses. This observation might mean that the alphabet will be, thankfully, largely sufficient to enumerate the hepatitis viruses. PMID- 8685179 TI - [New antibacterial vaccinal strategies]. AB - The prevalence of bacterial diseases and bacterial resistance is currently increasing, emphasizing the need for alternative vaccines. The body of knowledge on molecular determinants of bacterial virulence has tremendously increased during the recent years, and new molecular targets are available for immunization. Intramuscular injection of plasmid DNA containing bacterial genes with a suitable appropriate promotor is followed by transfection of host cells which will produce bacterial proteins, and elicit humoral and cytotoxic lymphocyte-mediated responses. Mucosal vaccines induce local immune response, both by type 1 and type 2 dependent pathways. Living bacterial vectors can provide conditional delivery of foreign antigens in selected host sites. A series of new substances allows us to steer the immune response in a way that optimizes immune protection. All this impressive progress will undoubtedly lead to the development of novel vaccines enabling us to ensure improved protection against bacterial diseases. PMID- 8685180 TI - [Bacteria isolated in 1994-1995 in female upper genitalia infections and in male urethritis. Distribution and sensitivity to antibiotics]. AB - OBJECTIVE: Classify antibiotics according to their individual activity so as to identify those suitable for empiric therapy. METHODS: We studied bacterial strains isolated from patients with urethritis (n = 189) and upper genital tract infections (n = 163) between June 1994 and February 1995 in 3 hospital and 4 community laboratories. Upper genital tract infections were divided into two groups: proven infection on laparoscopy specimen (n = 79) and suspected infection with isolation of pathogen in cervical samples (n = 84). Pathogens isolated were: Chlamydia trachomatis in 36/12/15 cases respectively, Mycoplasma hominis in 12/20/13, Ureaplasma urealyticum in 55/30/15, Neisseria gonorrhoeae in 40/2/0, Haemophilus spp in 20/2/1, group B streptococci in 7/1/8, E. coli in 8/1/17 and miscellaneous in 11/8/15. The minimal inhibitory concentrations for all strains were determined in 4 laboratories for ofloxacin, erythromycin and doxycyclin against C. trachomatis, M. hominis and U. urealyticum, and for ofloxacin, erythromycin, doxycyclin, amoxicillin+clavulanate, cefotaxime and gentamicin against the other strains. The activity score (% susceptibility to each antibiotic weighted by the frequencies of each isolate in urethritis and upper genital tract infection based on recent French epidemiologic data) was calculated for each antibiotic. CONCLUSION: The antibiotics with the best empiric activity scores in urethritis were, in decreasing order: doxycyclin (90.4%), ofloxacin (88.1%), and erythromycin (50.2%). The most active combinations in upper genital tract infections were ofloxacin+amoxicillin (100%), doxycyclin+cefotaxime+metronidazole (95.9%) and doxycyclin+amoxicillin (95.3%). PMID- 8685181 TI - [Hepatitis C virus infection in internal medicine and infectious diseases departments in France. Preliminary results of a national epidemiological survey]. AB - OBJECTIVES: In order to know the number and the main clinical features of patients with hepatitis C virus (HCV) infection, we conducted a national epidemiological study of patients followed in Internal Medicine and in Infectious Diseases departments in France. METHODS: For each patient with HCV infection seen between 13/03 and 13/04/1995 (in- or out-patients), a chart was completed. RESULTS: The response rate was about 30% with 2002 charts being analyzed. There were 59% males and 39% females, with a peak of frequency between 25 and 40 years, including 1241/2002 (62%) patients. Most patients were of French origin (85.7%). We found that 1436/2002 (72%) patients came from provinces of southern France and Paris. In 10% of cases the diagnosis was made during the study period. A route of transmission was identified in 86.4%, mainly drug abuse 60.4% and blood product transfusion 19.3%. At the time of diagnosis, main clinical features were: no symptom 47%, liver biological abnormalities 52%, cirrhosis 7.4%, cryoglobulinemia 2.7%, auto-immune disease 3%, hepatocellular carcinoma 0.85%. We frequently found a viral co-infection: HIV 56.1%; HBV 22.2%. A confirmation RIBA test was done in 67.8%, measurement of viremia in 33.4%, genotyping in 6.7% and liver biopsy in 28.7% of cases. Finally, 407 (20.3%) patients received a specific anti-HCV treatment. CONCLUSION: These preliminary results underscore: 1) the large percentage of the population with HCV infection followed outside of hepatogastroenterology departments in France. 2) the high probability that the HCV epidemic is underestimated as we noted 10% of new diagnosis during the study period. 3) the requirement for a multidisciplinary approach for these HCV patients. PMID- 8685182 TI - [Bacterial meningitis in adults in the intensive care unit. Clinical analysis and study of prognostic factors]. AB - OBJECTIVES: Bacterial meningitis frequently leads to hospitalization in the intensive care unit. Despite progress in antibiotics, prognosis remains poor. METHODS: We analyzed the clinical manifestations and complications which occurred in 41 patients admitted to the intensive care unit for bacterial meningitis. A case-control survey was used to determine prognosis factors. RESULTS: All patients required ventilatory assistance and 83% were in a state of coma at admission. Causal germs isolated were: Pneumococci 34%, Listeria 22%, Staphylococcus aureus 17%, and Gram-positive bacilli 12%. Overall mortality was 56%. The main prognosis factors after univariate analysis were age, delay to treatment, presence of septic shock, bacteriemia at admission, low cell count in first lumbar tap, high urea level and low protein level. After multivariate analysis, the following risk factors were retained: low number of leukocytes at first lumbar tap and high urea level. CONCLUSION: The gravity of bacterial meningitis in the intensive care unit appears to be related to the patient's overwhelmed defense system and especially to hemodynamic disorders with acute renal failure and capillary hyperpermeability leading to insufficient cerebral perfusion. PMID- 8685183 TI - [Non-nucleoside antiretroviral agents]. AB - Antiviral agents, other than nucleoside reverse transcriptase inhibitors, are currently being developed. Some have been marketed. Most of these new drugs are protease inhibitors which inhibit the formation and release of new infecting virions at the end of the intracellular cycle of the human immunodeficiency virus. Saquivanir, ritonavir, and indinavir are among the most widely studied. Non-nucleoside reverse transcriptase inhibitors (nevirapine is the leading product) include several components called TIBO or TIBO-like. These drugs have the advantage of good tolerance but resistance may develop early when they are given alone. Clinical trials aimed at preventing virus-cell fusion have not been successful in vivo. Other therapeutic approaches, including antisense oligonucleotids, ribozymes, and TAT or REV gene inhibitors are being explored. Several trials focusing on therapeutic strategy are being conducted using combinations of drugs. The objective is to use both non-nucleoside and nucleoside reverse transcriptase inhibitors together with antiproteases. Certain combination protocols using 3 or more antiviral agents have shown a synergetic effect and reduced or delayed resistance. Finally, the role of immunomodulation and immunotherapy is under investigation. PMID- 8685184 TI - [Systemic diseases and infections: current questions]. AB - Infections are a major cause of morbidity and mortality in patients with connective tissue diseases. Infectious consequences are caused by systemic disorders by themselves and the immunosuppressive treatments. Systemic lupus erythematosus and Wegener's granulomatosis are associated with the higher risk of infection. Primary prophylaxis of Pneumocystis carinii pneumonia has to be systematically given in patients with Wegener's granulomatosis and in other patients with connective tissue diseases if their CD4-cell count is lower than 200/mm3. Intensitification of immunosuppression during the course of systemic disorders can not be performed before any infection has been eliminated. PMID- 8685185 TI - [Cofactors in the course of HIV infection]. AB - Cohorts of patients infected with the human immunodeficiency virus (HIV), and followed-up since their infection, have identified risk factors of progression to acquired immunodeficiency syndrome (AIDS). The risk of progression increases with the subject's age at contamination by 40% for each decade. Other host factors such as certain HLA subtypes would be related to progression. Virus-related factors have also been described. Sexual or transfusional transmission from a highly immunodepressed subject increases the risk of progression in the infected subject. Progression is more rapid in male homosexuals than in heterosexuals, even after exclusion of Kaposi's syndrome. There has been little success in isolating co-infections which might explain this finding. The more rapid progression in homosexuals could be due to infection with particularly virulent strains or particular subtypes. Finally, progresion is more rapid when signs of primary infection are major or prolonged, an observation which probably results from a complex host-virus interaction. Behavioral factors occurring after contamination (pregnancy, continued intravenous drug abuse, tobacco, alcohol) have not been demonstrated until now to play a role in progression. PMID- 8685186 TI - [Epidemiology of Clostridium difficile nosocomial infections]. AB - Clostridium difficile accounts for 15-25% of cases of antibiotic-associated diarrhea (AAD) and for virtually all cases of antibiotic-associated pseudo membranous colitis (PMC). This anaerobic bacterium is also carried in the gastro intestinal tract of less than 3% of the normal adult population and can be isolated from the feces of 50-70% asymptomatic neonates. Since recent years, C. difficile has been identified as the leading cause of nosocomial diarrhea in adults. Pathogenesis relies on a disruption of the normal bacteria flora of the colon, a colonization with C. difficile and the release of toxins that cause mucosal damage and inflammation. Incidence of C. difficile intestinal disorders varies between 1 to 30 per thousand patient admissions. Risk factors for C. difficile-associated diarrhea include antimicrobial therapy, older age (> 65 years), intensive care, nasogastric tube, anti-acid use, and length of hospital stay. Nosocomial transmission of C. difficile via orofecal route occurs in 3-30% of total patient admissions but it often remains asymptomatic. Environmental contamination and carriage of the organism on the hands of hospital staff are common. Measures that are recommended to reduce cross-infection rely on an accurate and rapid diagnosis, implementation of enteric isolation, use of disposable gloves, hand washing with a suitable disinfectant (e.g. chlorhexidine) and daily environmental disinfection. C. difficile is a common cause of infectious diarrhea and should be therefore systematically investigated in patients with nosocomial diarrhea. PMID- 8685187 TI - [Multidrug-resistant tuberculosis]. AB - The quality of diagnosis and therapeutic management affects the frequency of multiresistant tuberculosis observed in a given country. In 1991, physicians in the United States were faced with a large number of cases of multiresistant tuberculosis in patients with acquired immune deficiency syndrome, leading to international public health measures designed to prevent the development of resistant strains. At the present time there are only a limited number of resistant strains in France. Continuous surveillance of multiresistant strains by the 33 University Hospitals in Paris and 300 bacteriology laboratories throughout France has shown that the rate of multiresistance is 0.7%. Six of the 8 cases of primary resistance observed in Paris from 1992 to 1994 were associated with human immunodeficiency virus infection. Approximately half of the cases with secondary multiresistance occurred in subjects born outside France. Patients with multiresistant tuberculosis must be placed in strict isolation and given long term treatment combining antibiotics and toxic products requiring careful handling in a specialized unit. PMID- 8685188 TI - [Tissue pharmacokinetics of antibiotics. Theoretical bases and new pharmacological approaches]. AB - Tissue pharmacokinetics has become an important feature of our knowledge of antibiotic behavior in the human body. Serum pharmacokinetic parameters are well established for all available antimicrobial agents but do not provide a means of assessing concentrations to be achieved at the site of infection nor an evaluation of intracellular penetration and bioactivity. Studies of tissue concentrations in animal or human models would be of more clinical significance if they took into account several in vivo microbial parameters such as the intracellular location of the pathogens, their state of growth, and size of the inoculum at the infection site. When minimal inhibitory concentrations are established, there could be a significant difference between in vitro results and the in vivo conditions. Pharmacodynamic parameters offer a new approach to antibiotic bioactivity in the patient. In addition to physicochemical characteristics of antibiotics governing tissue distribution, particularly liposolubility and degree of ionisation, patient conditions should also be considered as major factors interfering with in vivo antibiotic behavior. These concerns are of particular relevance for infections involving lung tissues, cerebrospinal fluid, bones and several other sites of infection. Newer approaches in tissue pharmacology of antibiotics are in progress. PMID- 8685189 TI - [Therapeutic applications of tissue pharmacokinetics of antibiotics]. AB - Antibiotic therapy is constantly changing. Among the criteria used to choose the right antibiotic, tissue pharmacokinetics provides useful, though controversial, information on drug distribution in organs and body fluids at potential sites of infection. Various study models have established i) the high rate of penetration of third-generation cephalosporins, aminoglycosides and fluoroquinolones into cerebrospinal fluid when meninges are inflamed; and ii) high levels of macrolides and fluoroquinolones in lung parenchyma and other respiratory sites of infection. These data should be analyzed in terms of pharmacodynamic activities in sites in the cerebrospinal fluid where the minimum inhibitory concentration and the minimum bactericidal concentration have been determined for the pathogen. In other situations, the criteria with the most clinical significance is the correlation between tissue concentrations and clinical outcome. There has been much progress in targeted (liposomes) antibiotic therapy with promising advances toward better tissue distribution of drugs. PMID- 8685190 TI - [Tick-borne encephalitis in Central and Eastern Europe]. AB - The tick-borne encephalitis virus, a major arbovirus, is endemic in Central and Eastern Europe. Since the first case of tick-borne encephalitis observed in Alsace in 1968, there have been approximately 30 cases reported in eastern France. The tick Ixodes persulcatus (and the western subtype I. ricinus) is both the main reservoir and vector of the disease. Early clinical signs of infection are followed by a second phase complicated with meningoencephalitis. The geographical distribution of the different viral subtypes would explain the variable severity of tick-borne encephalitis. Outcome may be fatal or leave major neurological sequellae. Currently, only symptomatic treatment is available, underlining the importance of prevention with anti-tick-borne virus vaccine for populations at risk living in endemic areas. PMID- 8685191 TI - [Asthma and corticotherapy]. AB - There has been a considerable amount of progress in the treatment of asthma providing a highly acceptable quality of life for the majority of patients. Cortisone remains the main medication in severe asthma. But despite the effective reduction in bronchial inflammation provided by cortisone, it is somewhat disappointing that nothing better has been found after a half-century of use. Actually, we have done better. Inhaled cortisone allows application of the active substance in situ, avoiding the inconvenience of systemic administration. In addition, doses can be given in micrograms instead of milligrams. Corticodependency and corticoresistance are the two main problems encountered. Corticodependency is a very heterogeneous highly individual phenomenon. In some corticodependent patients, respiratory function is nearly normal and stable while in others, respiratory function cannot be controlled readily and frequent hospitalizations in the intensive care unit are required. Weaning is a long-term process which must be planned as part of an overall management program. Corticoresistance, in our experience a rather rare condition, involves abnormal cell response to corticoids with abnormal or impaired production of cytokins, interleukin 4 and interleukin 5. A decrease in the number and binding capacity of corticosteroid receptors may also be involved. Cytoplasmic regulation rather than the receptor gene itself would be implicated. By modifying the corticosteroid receptors it would theoretically be possible to override corticorestistance and, by targeting the bronchial epithelium, disassociate the local anti-inflammatory effects of cortisone and the deleterious systemic effects. Understanding the mechanism of action of corticosteroids in patients with severe asthma is one of the challenges facing medicine in the 21st century. PMID- 8685192 TI - [Acquired toxoplasmosis of ocular or neurologic site: 49 cases]. AB - OBJECTIVES: Over a period of 13 years (1982-1995), 49 cases of acquired toxoplasmosis complicated with ocular and/or neurologic or meningeal involvement were observed in our toxoplasmosis laboratory. This series includes 43 cases of isolated ocular lesions, 3 cases of meningoencephalitis (associated with retinochoroiditis in 1 case), 1 case of meningitis with uveitis, 1 case of polyradiculoneuritis and 1 case of facial nerve palsy. METHODS: The patients were aged 1 to 62 years. None had either spontaneous or iatrogenic immunodeficiency. There were two steps in the diagnosis. First congenital infection was eliminated on one or several of the following criteria: any possibility of maternal infection during pregnancy ruled out in 26 cases, evidence of recent acquired infection (i.e. clinical and/or serological evidence of recent acquired toxoplasmosis in 17 cases, retinochoroiditis in non-twin siblings in 3 cases). The second step was to confirm the diagnosis of toxoplasma infection. Apart from serological evidence of recent infection, confirmation included specific local antibody synthesis in the aqueous humor of the eye and/or in cerebro-spinal fluid or ocular lesions characteristic of toxoplasmosis and absence of other etiology. RESULTS: Ocular lesions were unilateral in 43 cases among 45. A mean follow-up of 37.9 months revealed relapses in 14 among 36 patients (39%). As routine serological examination for toxoplasmosis is compulsory in France since 1978, it was possible to document retrospectively the immune status of the mothers of many of the patients of the present series during pregnancy and to rule out congenital toxoplasmosis in a number of cases. This might explain the discrepancy between the relatively large number of cases in the present series and the fact that complicated acquired toxoplasmosis has been considered hitherto as relatively rare in immunocompetent patients. CONCLUSION: Based on the epidemiology of ocular toxoplasmosis and the data obtained here, it is suggested that the acquired pattern of ocular toxoplasmosis might be more frequent than estimated up to now. PMID- 8685193 TI - [Prognostic factors of Pneumocystis carinii pneumonia in AIDS]. AB - OBJECTIVES: Identify prognosis factors in Pneumocystis carinii pneumonia at diagnosis and construct a model to predict mortality according to these prognosis factors. METHODS: Seventy-seven consecutive cases of proven AIDS-related Pneumocystis carinii pneumonia (67 men, 10 women, mean age 37.2 years) were reviewed to determine the most accurate initial prognostic factors and estimate an individual prediction of death. A stepwise logistic regression analysis was performed. Three kinds of data were entered into the logistic model: historical data, clinical and laboratory data obtained within the first 24 hours of diagnosis, and specific data related to chest X-ray and bronchoalveolar lavage results. RESULTS: The sum of arterial partial pressure of oxygen and carbon dioxide (PaO2 + PaCO2) and serum albumin level best predicted a fatal outcome in multivariate analysis. CONCLUSION: The logistic equation provided by the model might be used to accurately and quickly identify the patients with severe Pneumocystis carinii pneumonia who might benefit from supportive intensive care. PMID- 8685194 TI - [Hemodynamic profile and serum cytokines in crush syndrome. Analogy with severe burns]. AB - A 71-year-old woman remained under the rubble of her house for 4 hours after an accidental gas explosion. She suffered from a crush syndrome associating fractures, minor skin burns (< 10% body surface area), inhalation lung injury and moderate hypothermia (34 degrees C). In addition to local signs of compression of the lower limbs, the patient presented with hypovolemic shock and developed acute renal failure on day 3. We describe here the variations in hemodynamic and oxymetric parameters and cytokine response during the first post-injury week. A vasoplegic state resulting from low systemic vascular resistances with progressively increasing cardiac index, oxygen delivery and oxygen consumption closely followed the brief hypovolemic shock. Tumor necrosis factor-alpha remained below normal levels while interleukin-6 increased markedly with a major peak on day 2, in parallel with the drop in systemic vascular resistances. Interleukin-6 is a mediator of impairment in cell membrane function and a vasoconstriction inhibitor. Isolated increased interleukin-6 has been previously reported in severely burned patients suggesting a pathophysiological and hemodynamic similarity between crush syndrome and burn injury. PMID- 8685195 TI - [Magnetic resonance imaging of the fetus. Contribution to antenatal diagnosis]. AB - Magnetic resonance imaging (MRI) of the fetus has been developed over the last 10 to 15 years. This new imaging technique cannot remplace ultrasonography which remains the key examination for antenatal diagnosis but can add further improvements over ultrasonographic findings, particularly in evaluating the fetal brain. MRI of the fetus has thus been focused in this area, the main studies aiming at analyzing brain malformations and at searching for ischemic or hemorrhagic lesions and possible gyration anomalies. Advances in data processing software and volume acquisition and the development of the echo-planar technique and T2-weighted sequences are currently under study. MRI of the fetus has thus progressed rapidly. It is however a long costly examination which may not be well tolerated by pregnant women. Currently, routine MRI of the fetus is not possible, because of the requirement for specialized facilities. This new technique, still in the evaluation phase, should be studied using strict protocols reserved for centers specialized in antenatal diagnosis. PMID- 8685196 TI - [HDL breakdown in an athlete taking anabolic steroids]. PMID- 8685197 TI - [Sub-adventitial cystic degeneration of the radial artery. Report of a case]. PMID- 8685198 TI - [Bronchial actinomycosis of pseudo-tumor form]. PMID- 8685199 TI - [Vidarabine-interferon combination in patients with chronic viral hepatitis B of mutant form. Efficiency and tolerability during a pilot study]. PMID- 8685200 TI - [1691 G to A mutation of the factor V gene: no association with thrombosis of the central retinal vein]. PMID- 8685201 TI - [Major depressive episodes in patients over 70 years of age. Evaluation of the efficiency and acceptability of tianeptine and mianserin]. AB - OBJECTIVES: The aim of this multicenter study was to compare the efficacy, acceptability and impact on quality of life of tianeptine (T) and mianserine (M) in patients over 70 years of age with major depression. METHODS: Fulfilment of the DSM IIIR criteria for major depression with a total Montgomery and Asberg depression rating scale (MADRS) of at least 25 and a Hamilton anxiety rating scale (HARS) of at least 18 were required for inclusion. The 315 men and women enrolled in the study were given, by double blind assignment, either T: 37.5 mg/day, T: 25 mg/day or M: 30 mg/day. Treatment duration was 6 months in all three groups and follow-up continued for 3 months after withdrawal of tianeptine or mianserine. The main efficacy criterion was the MADRS score evaluated at each of 6 visits at day 15 (D15) and month 1 (M1), M2, M4, M4.5 and M6. The HARS score was another efficacy criterion. Overall assessment of efficacy and acceptability was done at each visit by the patient and the investigator. Both the patient and the physician estimated global effectiveness on a quality of life scale at M1, M3, M6 and M9. RESULTS: In the intention-to-treat population (n = 299), the antidepressant efficacy of tianeptine and mianserine was not significantly different, whether assessed as effect on anxiety or on quality of life. Scores however tended to be better in the T: 37.5 mg group. Acceptability was good as shown by the low number of adverse events in all 3 groups, but at D15, the incidence of impaired vigilance or equilibrium was significantly lower in the T: 25 mg group than in the M: 30 mg group, emphasizing the advantage of tianeptine in decreasing the risk of falling. Physician-assessed tolerance and acceptability was significantly different at M3 (p = 0.014) and at M6 (p = 0.028) in favor of T: 37.5 mg, indicating that though increasing dosage does not improve efficacy, there is no risk of poorer acceptability. CONCLUSION: These findings reconfirm the antidepressive efficacy, acceptability and safety of tianeptine. They also confirm the anxiolytic aspect associated with the antidepressive effect of tianeptine without any sedative effect. Tianeptine is particularly well indicated in the treatment of depression in elderly or very elderly subjects. PMID- 8685202 TI - [Sleep apnea and chronic obstructive respiratory tract disease (COPD): diagnostic and therapeutic consequences]. PMID- 8685203 TI - [Incidence of chronic obstructive respiratory tract disease in patients with obstructive sleep apnea]. AB - Data concerning the occurrence of chronic-obstructive pulmonary disease (COPD) in patients with obstructive sleep apnea syndrome (OSAS) vary between 11 and 20% due to the underlying definition of COPD. We investigated the frequency of COPD in 202 patients with OSAS. The obstructive pattern was defined by bodyplethysmography (Rt > 0.35 kPa x 1(-1) x s(-1)), flow-volume-curve (MEF50 < 50% pred.), Tiffeneau-index (FEV1/IVC < 70% pred.) and anamnesis (cough and/or sputum). Prevalence of COPD in our 202 patients with OSAS was 16.3%. Patients with OSAS and COPD had a higher body-mass-index (BMI), lower PaO2 and spent more time in an oxygen saturation < or = 90% in relation to total recording time (t90). Polysomnographically there was no difference between the two groups with regard to the ventilatory parameters apnea-index (AI) and apnea-hypopnea-index (AHI). As there is a high risk of developing hypercapnia, pulmonary arterial hypertension and cor pulmonale in patients with OSAS and COPD there is need for early diagnosis of the combination of both diseases. PMID- 8685204 TI - [Tumor necrosis factor--friend and enemy]. PMID- 8685206 TI - [New developments in non-tuberculoid mycobacterioses. 1: Diseases in patients without HIV infection]. PMID- 8685205 TI - [Characterization of structural and cellular components in pulmonary sarcoidosis granuloma]. AB - Granulomas occurring in sarcoidosis with lung involvement are mostly located in the paravasal interstitium, pleura, bronchial mucosa and stroma. The phases and the activity of the disease process are characterised by different patterns from multicellular epitheloidcellular granulomas to marked hyalinisations and scarifications. For the purpose of histochemical characterisation of the composition of the cells and matrix of pulmonary granulomas in open and transbronchial lung biopsies of 15 patients suffering from sarcoidosis in different clinical stages, antibodies were employed against macrophages, neutrophil elastase, collagen types I and III, fibronectin, laminin, PCNA and against the tumour suppressor gene product P53. Identification was subsequently performed either by means of indirect immunofluorescence or the PAP technique. Multicellular granulomas showed, especially centrally, a specific fluorescence for macrophages involving also giant cells, whereas antibodies against neutrophil elastase could be mainly identified peripherally. PCNA and P53 protein were identified in the cytoplasm and partly also in the nuclei of giant cells. Collagen types I and III were mainly expressed pericentrally. Fibronectin was found in numerous multicellular epitheloid cellular granulomas not only in the peripheral collagen network but also centripetally oriented. The scarifying granulomas showed initially increased centripetal deposition of fibronectin followed by an addition of collagen types I and III. Laminin was always present in very small quantities only. The results obtained demonstrate a variable expression of matrix structures in sarcoidosis, dependent on the developmental stages of pulmonary granulomas, this expression being capable of control to some extent with the proportions of epitheloid cells, lymphocytes and macrophages that are present. Tumour suppressor gene p53 positive macrophage giant cells and adhesion molecules such as fibronectin participate in granuloma production to a varying extent. PMID- 8685207 TI - [Current status and diagnostic value of nucleic acid amplification and conventional methods in laboratory diagnosis of tuberculosis]. PMID- 8685208 TI - Molecular genetic fingerprints: clues to monoclonal origin of multifocal disease. PMID- 8685209 TI - Ovarian, peritoneal, and endometrial serous carcinoma: clonal origin of multifocal disease. AB - The clonality of disseminated serous carcinoma involving the ovary, peritoneum, and, occasionally, the endometrium is controversial. Histopathologic examination alone cannot unequivocally distinguish between a monoclonal origin and a multicentric origin. Two patients with peritoneal serous carcinoma with minimal ovarian involvement (one with endometrial serous carcinoma), nine patients with stage III bilateral ovarian carcinoma, and one patient with stage III bilateral carcinosarcoma were studied for clonality. One patient with ovarian carcinoma that recurred after chemotherapy was also studied. Previous analyses of single frozen tumor specimens from these patients had identified different p53 gene mutations in each patient. To test the hypothesis that the disseminated cancers had a monoclonal origin, we assayed DNA from numerous foci from each patient to determine whether the known p53 mutation was present in each specimen. Identical mutations were detected in the tumor foci from each patient with peritoneal dissemination and minimal ovarian involvement, including one patient with an endometrial serous carcinoma as well. In all the patients with bilateral ovarian cancer, the genetic change in p53 was identical in both ovarian tumors. Genetic progression was observed in two patients, one of whom showed a loss of heterozygosity involving the p53 gene in a recurrent tumor. In the second patient, a p53 mutation not present in either ovarian tumor was detected in a metastatic tumor from the omentum. These results strongly suggest that disseminated serous carcinomas, whether primary in the ovary, endometrium, or peritoneum, are of monoclonal rather than multicentric origin; that bilateral stage III ovarian cancers are typically of monoclonal origin; and that additional genetic events involving p53 might occur during progression of these tumors. PMID- 8685210 TI - Self-similarity and fractal irregularity in pathologic tissues. AB - The irregularity and self-similarity under scale changes are the main attributes of the morphologic complexity of cells and tissues, either normal or pathologic. In other words, the shape of a self-similar object does not change when scales of measure change because any part of it might be similar to the original object. Size and geometric parameters of an irregular object, however, differ when inspected at increasing resolution, which reveals more details. Significant progress has been made over the past three decades in understanding how to analyze irregular shapes and structures in the physical and biologic sciences. Dominant influences have been the discovery by B.B. Mandelbrot of a new, practical geometry of nature, now called fractal geometry, and the continuous improvements in computational capabilities. The application of the principles of fractal geometry, unlike the conventional Euclidean geometry developed for describing regular and ideal geometric shapes practically unknown in nature, enables one to measure the fractal dimension, contour length, surface area, and other dimensional parameters of almost all irregular and complex biologic tissues. During the past decade, a large amount of experimental evidence has accumulated showing that even in biomedical sciences fractal patterns could be observed. Through several examples borrowed from the recent literature, we focus on the application of the fractal approach to measuring irregular and complex features of pathologic cells and tissues and also on its potential role in the understanding of tumor biology. PMID- 8685211 TI - Rapid identification of patient specimens with microsatellite DNA markers. AB - Despite the use of standardized clerical and processing procedures in surgical pathology, questions might arise regarding the proper identification of specimens with respect to patient source. Genotypic analysis of microsatellite DNA polymorphisms was used to identify the patient source of two surgical pathology specimens showing carcinoma. Four highly polymorphic microsatellite loci were evaluated in DNA extracted from various formalin-fixed, paraffin-embedded tissues. Using this technique, we determined that the diagnosis of poorly differentiated adenocarcinoma arising from a background of colitis had been assigned to the correct patient, despite the fact that multiple repeat endoscopic examinations, with biopsy specimens, were negative. In the second case, a suspected processing error involving the exchange of specimen accession numbers was resolved when a lymph node containing a microscopic focus of metastatic carcinoma was assigned to the appropriate patient. A multitude (approximately 50,000 to 100,000) of microsatellite loci are distributed throughout the human genome, and many are highly polymorphic. Hence, genotypic analysis using microsatellite loci has a significantly higher power of discrimination than other commonly used methods. The technique is rapid and is particularly well suited to the analysis of small, fixed-tissue specimens. PMID- 8685212 TI - Estrogen and progesterone receptors and pS2 and ERD5 antigens in gastric carcinomas from the European population. AB - We examined immunohistochemically 50 gastric carcinomas from European patients for estrogen receptors, progesterone receptors, and hormone-receptor-related proteins pS2 and ERD5. Unlike gastric carcinomas from non-Europeans reported previously, the carcinomas of the present series were all negative for estrogen and progesterone receptors. One-half of them, however, expressed pS2, and three fourths were positive for ERD5. pS2 expression was significantly more frequent in carcinomas of the diffuse type than in those of the intestinal type and in advanced carcinomas compared with early ones. Our results indicate that pS2 and ERD5 are estrogen independent in the stomach. The possibility that estrogen and progesterone receptor status could be different in gastric carcinomas from Occidental and non-Occidental patients is discussed. PMID- 8685213 TI - Gallbladder adenocarcinoma and acalculous chronic lymphoplasmacytic cholecystitis associated with ulcerative colitis [corrected]. AB - Patients with ulcerative colitis, particularly long-standing ulcerative pancolitis, have an increased risk of developing carcinoma of the hepatobiliary tract. However, only 14 cases of carcinomas localized to the gallbladder have been associated with ulcerative colitis. Of 57 cases of gallbladder carcinomas seen at this institution, we found 3 cases in patients with ulcerative colitis, all of whom had undergone total proctocolectomy. All three patients had pancolitis, two with high-grade dysplasia, and one with low-grade dysplasia. All three gallbladders harbored an invasive adenocarcinoma. The nonneoplastic gallbladder mucosa showed a background of acalculous chronic lymphoplasmacytic cholecystitis in two cases. One of these patients also had a liver biopsy which showed changes of primary sclerosing cholangitis. Because cholecystectomy adds little to the operative morbidity and mortality of total proctocolectomy, it might be advisable to perform both operations when the latter is indicated for high-grade dysplasia in ulcerative colitis. PMID- 8685214 TI - K-ras-2 and p53 genotyping of intestinal-type adenocarcinoma of the nasal cavity and paranasal sinuses. AB - Intestinal-type adenocarcinoma (ITAC) of the nasal cavity and paranasal sinuses is an uncommon neoplasm manifesting a variety of histologic growth patterns, most of which are reminiscent of colorectal adenocarcinoma. To determine whether this morphologic resemblance is mirrored in equivalent genetic alterations, a series of ITAC was genotyped using archival, formalin-fixed tissues for point mutational damage in K-ras-2 oncogene and p53 tumor suppressor gene, forms of DNA damage frequently found in colorectal adenocarcinoma. In contrast to colorectal adenocarcinoma, which demonstrates K-ras-2 mutation in about 50% of cases, ITAC showed no evidence of K-ras-2 mutation. p53 mutations were present in 18% of ITAC (2 of 11) compared to more than 75% incidence of p53 mutation seen in colorectal adenocarcinoma. Fifty-eight percent of ITAC demonstrated scattered positive p53 immunohistochemical nuclear staining, but no mutations were identified in exon-5 through exon-8 by genotyping. There was no specific p53 alterations with respect to histologic subtype of ITAC. Although ITAC and colorectal adenocarcinoma are histologically similar, there are important differences at the genetic level based on expression of K-ras-2 and p53 abnormalities. PMID- 8685215 TI - Cell proliferation and apoptosis in prostate cancer--correlation with pathologic stage? AB - Gleason grade, especially at low and high ends of the spectrum, is a known predictor of pathologic stage. What are needed are predictors of stage with Gleason sum 5 to 7 tumors, which encompasses the majority of clinically organ confined tumors. In this study, we analyzed whether cell proliferation and apoptosis (programmed cell death) were correlated with stage in men with clinically organ-confined Gleason sum 6 to 7 cancer. We studied 98 radical prostatectomies with the following pathologic stages: organ-confined disease (n = 28); capsular penetration (n = 28); seminal vesicle invasion (n = 21); and pelvic lymph node metastases (n = 21). Histological sections from the radical prostatectomies were stained for cell proliferation using MIBI antibody (Ki-67) and for apoptosis using the TUNEL technique. The extent of staining was recorded as the number of positive cells per 1000 cells. Overall daily growth (kp) was calculated as: kp = (ki/2) - (apoptosis/0.5), based on the time of prostate cancer to undergo mitosis and apoptosis per day. Using logistic regression analysis, pathologic stage did not correlate with cell proliferation, apoptosis, or overall daily growth. These parameters also did not distinguish between Gleason sum 6 and Gleason sum 7 tumors. We supplemented these cases with examples of Gleason sum < or = 4 and Gleason sum > or = 8 to study cell proliferation and cell death in the full spectrum of Gleason grades. There was a significant difference (P = 0.005) in cell proliferation between Gleason sum > or = 6 and Gleason sum < or = 4 tumors, but apoptosis and daily growth were not significant. We conclude that cell proliferation and apoptosis do not correlate with pathological stage in clinically organ-confined cancer with Gleason sum 6 or 7, but that cell proliferation can distinguish between high (Gleason sum > or = 6) and low (Gleason sum < or = 4) grade tumors. PMID- 8685216 TI - A pancreatic cyst of the anterior mediastinum. AB - Although heterotopia of pancreatic tissue is a developmental anomaly found in approximately 2% of all autopsies, pancreatic tissue within the thorax and mediastinum is uncommon. In most of these instances, the pancreatic acini and islets are components of gastroenteric duplication cysts, intralobar pulmonary sequestrations, or teratomas. We describe the clinicopathologic features and hormonal profile of a patient with an anterior mediastinal cyst formed entirely by pancreatic tissue. To our knowledge, the English literature reveals only two previous examples of this lesion. The patient, a previously healthy 16-year-old girl, was found to have a cystic lesion in the anterior mediastinum during investigation of an asymptomatic heart murmur. The lesion measured 12 cm in maximal diameter and contained dark, turbid fluid. The wall was fibrotic and contained a haphazard mixture of ducts, exocrine acini, and islets. In many areas, the ducts and islets formed ductuloinsular complexes resembling those seen in diffuse nesidioblastosis. Immunohistochemical examination showed that the islets contained an increased number of B and PP cells, recapitulating the hormonal profile of the ventral anlage of the fetal pancreas. The similarity between this lesion and a fetal pancreas was further supported by the presence of a significant number of islet cells containing gastrin. The histogenesis of this lesion is unclear; we think that this lesion represents a derivative of the ventral (anterior) primitive foregut, but unidirectional differentiation of a benign cystic teratoma cannot be excluded. PMID- 8685217 TI - Proliferative activity and p53 expression in adenoid cystic carcinoma of the breast. AB - Adenoid cystic carcinoma is a rare type of invasive breast carcinoma that has a good prognosis. We studied a series of four cases of adenoid cystic carcinoma in which we correlated the clinical and pathological features. The pathological features examined included light microscopy; electron microscopy; immunohistochemistry using antibodies to keratin, vimentin, S100 protein, actin, estrogen and progesterone receptors, and proliferation marker MiB-1, and p53 suppressor protein; image cytometric analysis for measurement of DNA ploidy; and molecular analysis using polymerase chain reaction single strand conformation polymorphism to assess point mutation of the p53 gene. All of the cases had a low nuclear grade, were negative for estrogen and progesterone receptors, and were DNA diploid. Three of the cases showed no evidence of metastases and had small primary tumors with low proliferative activity and absence of p53 protein expression. In contrast, one of the cases showed axillary lymph node metastases and in this case the primary tumor was large with a higher proliferative activity and expression of p53 protein, suggesting that these factors might play a role in the biological behavior of adenoid cystic carcinoma. PMID- 8685218 TI - Adenomyomas of the uterine cervix of of endocervical type: a report of ten cases of a benign cervical tumor that may be confused with adenoma malignum [corrected]. AB - Ten benign biphasic cervical tumors that we have designated "adenomyomas of endocervical type" are reported because they might be confused with adenocarcinoma. The patients ranged from 21 to 55 years of age (mean, 40 yr). Two presented with abnormal vaginal bleeding, but, in most patients, the cervical tumors did not cause symptoms. On physical examination or at operation, eight patients were found to have tumors ranging from 1.3 to 8.0 cm in greatest dimension growing into the endocervical canal and, in three cases, prolapsing through the external os. The remaining two patients had mural tumors measuring 11.0 and 23.0 cm in greatest dimension, which projected into the pelvis from the outer aspect of the cervix, without mucosal involvement. The tumors were well circumscribed and grey-white or tawny, and five contained multiple mucin-filled cysts up to 3.0 cm in diameter. One tumor was focally hemorrhagic. On microscopic examination, the tumors were composed of glands and cysts lined by a single layer of endocervical-type mucinous epithelium admixed with smooth muscle. The epithelial component was typically composed of large irregularly shaped glands with papillary epithelial infolding, surrounded by smaller simple glands, frequently resulting in a lobular arrangement. Tubal-type epithelium was present focally in six tumors and endometrial-type glands surrounded by endometrial stroma were present in one case. Both the epithelium and smooth muscle were uniformly bland, without significant mitotic activity. Five patients were treated initially by "polypectomy." Hysterectomy 1 month and 1 year later in two of the cases revealed residual adenomyoma; a "recurrence" 3 years after polypectomy in another patient was treated by hysterectomy. In no case has there been evidence of spread beyond the cervix. The finding of a cervical tumor composed of bland, irregularly shaped, mucinous glands surrounded by smooth muscle caused significant problems in differential diagnosis and a diagnosis of adenoma malignum was either favored or raised as a possibility by the initial pathologist in five of the cases. The gross circumscription of the adenomyomas, their polypoid appearance, the frequent lobular arrangement of glands, the absence of invasive glands with a desmoplastic stromal reaction, and lack of even focal atypia were the most helpful findings in differentiating these tumors from adenoma malignum. PMID- 8685219 TI - Low-grade transitional cell carcinoma of the urinary bladder: application of select cytologic criteria to improve diagnostic accuracy [corrected]. AB - The cytologic diagnosis of low-grade transitional cell carcinoma of the bladder is difficult, and the reported sensitivity of a positive diagnosis ranges from 0 to 73%. Using regression analysis, our laboratory previously reported the criteria of increased nuclear/cytoplasmic ratios, irregular nuclear membranes, and cytoplasmic homogeneity as indicative of low-grade transitional cell carcinoma. To examine the validity of these criteria, six observers examined 88 bladder-wash specimens (39 transitional cell carcinomas and 49 benign) and, using the selected criteria, graded each wash for the probability of malignancy. Diagnostic accuracy was measured using the receiver operating characteristic curve and the likelihood ratio. Overall observer accuracy was 76%, the sensitivity of a definitive negative diagnosis was 82%, and the specificity of a definitive positive diagnosis was 96%. We conclude that key cytologic criteria can be learned and effectively applied with high accuracy. Observer variation in diagnostic categories might reflect different confidence levels and probabilities of transitional cell carcinoma. PMID- 8685220 TI - The hepatic von Meyenburg complex: prevalence and association with hepatic and renal cysts among 2843 autopsies [corrected]. AB - von Meyenburg complexes (VMC) are dilated small bile ducts surrounded by fibrous stroma. These lesions are frequently seen at autopsy, especially in association with polycystic disease of the kidney and/or liver. The purpose of this study was to quantitate the prevalence of VMC and associated lesions, with a view to clarifying the nature of VMC. We examined the liver slides from 2843 autopsies and found 157 patients having VMC or cysts in the liver. For each of the 157 patients, and age- and gender-matched controls, VMC, hepatic cysts, and gross and microscopic renal cysts were counted and measured and autopsy reports were reviewed. VMC were found in 5.6% of adults and in 0.9% of children. Macroscopic hepatic cysts were found in 16.9% of livers that also had VMC. Of livers with hepatic cysts, 73.5% also had VMC. Adult polycystic kidney disease (APKD) was found in 11% of adults with at least one VMC and in 40% of those with four or more VMC. Among adults with APKD, VMC were found in 97% and hepatic cysts in 88%. Because APKD could account for only 11% of the patients with VMC, we suggest that VMC, in the absence of APKD, are a manifestation of a different disease, which could be genetic or secondary to inflammation or ischemia. PMID- 8685221 TI - Immunophenotype, mRNA expression, and gene structure of p53 in Wilms' tumors. AB - The anaplastic variant of Wilms' tumor is regarded as the result of tumor progression of the more common classic Wilms' tumor. Anaplasia is rare and occurs in only 4.5% of tumors. Three anaplastic Wilms' tumors in our collection were examined in comparison with 10 classic Wilms' tumors for p53 expression by immunohistochemical techniques and Northern blot analysis, and their p53 gene structure was determined by single-stranded conformation polymorphism and sequence analysis. All classic tumors contained a wild-type p53 gene and expressed marginal levels of protein as expected for normal p53. In contrast, three out of three anaplastic tumors demonstrated evidence of p53 alterations consistent with a role of p53 in tumor progression. One of the anaplastic mutants (W4) did not express protein or p53 mRNA. Its apparently normal immunophenotype would have disguised the mutated nature of p53, which was detected only by mRNA and sequence analysis. The second anaplastic mutant (W16) contained normal levels of p53 mRNA, but overexpressed the protein in a fashion typical of mutated p53. The same immunophenotype was displayed by fixed primary tissue of the third anaplastic tumor (W17), but p53 mutation could not be confirmed for lack of frozen primary material. The present study emphasizes the importance of p53 function in the anaplastic progression of Wilms' tumor and the risk of error in assessing normal p53 function using a single methodology. PMID- 8685222 TI - p53 in lymphomas of mucosal-associated lymphoid tissues. AB - Lymphomas of mucosal-associated lymphoid tissues (MALT) constitute a distinct clinicopathologic entity comprised of centrocyte-like cells with a characteristic morphologic appearance and immunophenotype. The origin of these cells is still undetermined, although evidence suggests that they might derive from marginal zone lymphocytes present in normal lymph nodes and spleens. Recently, marginal zone lymphomas have been shown to have a high rate of p53 mutation. To determine whether p53 mutations were also present in MALT lymphoma, we evaluated specimens from eight patients (six gastric specimens, one parotid, and one from the small bowel) for p53 mutations using polymerase chain reaction and single strand conformational polymorphism analysis. Exon-4 through exon-8 were evaluated, because these are common sites of p53 mutation. In addition, tissues from 15 patients with MALT (including seven studied by single strand conformational polymorphism analysis) were examined for expression of p53 gene protein product by immunohistochemical techniques. All specimens were negative for p53 mutations, suggesting that mechanisms of lymphomagenesis are different for MALT than for splenic marginal zone lymphomas. Despite the absence of p53 point mutations, p53 gene product was localized in tissues from three of 15 patients with MALT. Staining was restricted to nuclei of neoplastic cells and was present in less than 10% of the cells. In summary, low-grade MALT lymphomas differ from marginal zone lymphomas in lacking p53 point mutations, although some patients express low levels of p53 gene product. PMID- 8685223 TI - Myxoid liposarcoma with cartilaginous differentiation. AB - Common histologic variants of liposarcoma are readily recognized. Histologic classification might be difficult, however, when liposarcoma demonstrates cartilaginous differentiation. Although this phenomenon has previously been noted, it has not, to our knowledge, been reported as a specific pathologic entity. All three patients in the present study were men, ages 37, 42, and 63 years. Each presented with a solitary, enlarging mass of the thigh that was surgically excised. The tumors ranged in size from 8 to 13 cm. Microscopically, each lesion displayed characteristic features of myxoid liposarcoma; in addition, all possessed discrete, rounded foci of mature-appearing hyaline cartilage. One case displayed small foci showing chondrocyte atypia. No other patterns of mesenchymal differentiation were present. All patients received postoperative radiation therapy. No recurrences or metastases have been identified (mean duration, 39 mo). Myxoid liposarcomas with cartilaginous differentiation are of importance because they might be misdiagnosed as malignant mesenchymoma. The latter, if not qualified as to histologic grade, might be presumed to be a biologically more aggressive lesion. In addition, these lesions must be distinguished from two benign processes: chondroid lipoma and extraskeletal chondroma with lipoblast-like cells. Additional studies of this uncommon variant of liposarcoma will be necessary to document further its status as a low-grade sarcoma. PMID- 8685224 TI - The prognostic importance of nuclear morphometry and the MIB-1 index in rhabdomyosarcoma [corrected]. AB - Both nuclear morphometry and an evaluation of the cell proliferative activity have been reported to be useful tools in predicting prognosis in malignant tumors. There have been few reports, however, on rhabdomyosarcoma regarding these evaluative techniques. We performed nuclear morphometry on 51 tumor specimens obtained either by biopsy or by resection of primary and untreated rhabdomyosarcomas, and we then evaluated MIB-1 staining on 25 of the 51 specimens. The morphometric analysis was semiautomatically performed on hematoxylin- and eosin-stained sections by using a personal computer. The areas, perimeters, and lengths of the major and minor axes of the best fitting ellipse of the nuclei were all measured. In addition, the Form Ell (nuclear ellipsoidity score: minor axis/major axis) was calculated. Using the monoclonal MIB-1 antibody, which detects Ki-67 antigen in formalin-fixed, paraffin-embedded tissue, immunohistochemical studies were performed. The values of the major and minor axes and the Form Ell showed significant differences between each histologic subtype whereas the values of nuclear areas did not. We defined the nucleus whose Form ELL was smaller than 0.25 as spindle-shaped nuclei and then divided all cases into two groups on the basis of the ratio of the spindle-shaped nuclei to the total number of nuclei of the tumor cells. The group with the higher ratio showed a significantly better prognosis (P < 0.05). The same trends were also found in the specimens with an embryonal subtype. Nuclear morphometry was a useful tool in predicting prognosis. In particular, the appearance of spindle tumor cells in rhabdomyosarcoma correlated with a better prognosis. PMID- 8685225 TI - Epstein-Barr virus and lymphoproliferation in methotrexate-treated rheumatoid arthritis. AB - Generalized lymphadenopathy developed in a 60-year-old female receiving methotrexate and prednisone for treatment of rheumatoid arthritis. Histologic examination of an enlarged right axillary lymph node revealed effacement of normal architecture by a polymorphic population of lymphocytes. The recognition that the patient was medically immunosuppressed and the similarity of lymph node histology to that of a polymorphic post-transplantation lymphoid proliferation led to suspicion that the adenopathy might represent an immunosuppression-related lymphoid proliferation. This possibility was supported by regression of the adenopathy on discontinuation of methotrexate, despite continued corticosteroid therapy, which is an outcome reminiscent of the remissions observed with reduction of immunosuppressive therapy in post-transplantation lymphoproliferative disorders. Subsequent ancillary laboratory studies of lymph node tissue included genetic probe analysis, which revealed a monoclonal population of B-lymphocytes containing clonal Epstein-Barr virus DNA. In situ hybridization studies performed on lymph node tissue revealed expression of Epstein-Barr virus-encoded RNA 1 transcripts, and immunohistochemical studies revealed expression of Epstein-Barr virus latent membrane protein 1. These ancillary studies confirmed the similarity to post-transplantation lymphoproliferative disorder. Although immunosuppression-related lymphoproliferative disorders share features with malignant lymphoma, the possibility of resolution in situations in which immunosuppression can be reversed provides a distinction from true malignancy and is of profound importance in therapeutic decision making. PMID- 8685226 TI - p53 oncoprotein overexpression in choroidal melanoma. AB - This study immunohistochemically demonstrates p53 oncoprotein overexpression on routinely processed choroidal melanomas by means of four different anti-p53 antibodies after high-temperature antigen retrieval. The results were correlated both with morphologic and clinical parameters. Routinely formalin-fixed and paraffin-embedded tumor tissues from 43 choroidal melanomas were immunohistochemically investigated with four different anti-p53 antibodies directed against four different epitopes (CM-1, DO-7, PAb1801, PAb240) after wet autoclave antigen retrieval. The application of this technique is of outstanding importance for the demonstration of p53 protein on routinely processed tissues. Five patients (11.6%) of 43 showed more than 10% p53-positive tumor cell nuclei, which was regarded as p53 overexpression; these five patients underwent preoperative telecobalt or ruthenium irradiation. An additional 18 patients (41.9%) showed a few positively stained nuclei with at least one of the antibodies applied. p53 expression was more often found in epithelioid cell tumors; there was no statistical correlation between p53 overexpression and the clinical outcome. Our results suggest that p53 oncoprotein overexpression in choroidal melanomas indicates a late event in the progression rather than a crucial step in the development of these tumors. This conclusion is supported by the finding that all tumors with immunohistochemical p53 overexpression underwent preoperative irradiation, which might have caused p53 alteration(s) and thus enabled its immunohistochemical demonstration. PMID- 8685227 TI - Fibrosarcomatous dermatofibrosarcoma protuberans with myofibroblastic differentiaion: a histologically distinctive variant [corrected]. AB - We report two examples of dermatofibrosarcoma protuberans with fibrosarcomatous change, in which the fibrosarcomatous component of the tumor demonstrated focal myofibroblastic differentiation. This was recognized by light microscopy as plump myoid cells associated with abundant extracellular collagen production, immunohistochemically by positive staining for smooth muscle and muscle specific actin, and ultrastructurally by subplasmalemmal filament aggregates and micropinocytotic vesicles. Myofibroblastic differentiation has not been described before in dermatofibrosarcoma protuberans with fibrosarcomatous change and because of a lack of information concerning the immunohistochemical profile of this variant of DFSP its incidence is unknown. Focal myofibroblastic differentiation, as demonstrated in the fibrosarcomatous regions of these two tumors, might support the proposed dermal fibroblastic origin for dermatofibrosarcoma protuberans with fibrosarcomatous change. PMID- 8685228 TI - Juxtacortical dedifferentiated chondrosarcoma from a primary periosteal chondrosarcoma. AB - In this report, we describe dedifferentiation in a primary periosteal chondrosarcoma in the proximal tibia of a 73-year-old man. The diagnosis of primary periosteal chondrosarcoma was made by the characteristic radiographic, gross, and microscopic features of the tumor. The presence of dedifferentiation, however, in the form of malignant fibrous histiocytoma, was an unexpected histologic finding. Although rare, dedifferentiation is a well-recognized occurrence in secondary chondrosarcomas arising from precursor osteochondromas. This event has not been previously documented in the setting of primary periosteal chondrosarcoma. PMID- 8685229 TI - Angiomyofibroblastoma of the vulva and vagina. AB - Nine vulvar and three vaginal angiomyofibroblastomas from patients 23 to 71 years of age (mean, 46 yr) were analyzed. The tumors were well circumscribed and ranged from 0.9 to 11 cm (average, 4.7 cm) in maximal dimension. On microscopic examination, they had hypercellular and hypocellular areas. The neoplastic cells were spindle-shaped, plasmacytoid, or epithelioid; a variable number were binucleated or multinucleated cells. A focal storiform pattern was present in one tumor, and, in one tumor, the neoplastic cells formed a collar around a central area of dense collagen. There was no significant nuclear atypia, and there was less than one mitotic figure per 10 high-power fields. The tumors contained small to medium-sized blood vessels, which were characteristically thin walled and, occasionally, ectatic and branching. The stroma was edematous, separated collagen fibers and contained a variable number of inflammatory cells, especially lymphocytes and mast cells. Three vulvar tumors contained a variable amount of fat. Ultrastructural study of three tumors showed intracytoplasmic, dilated, rough endoplasmic reticulum, moderate numbers of pinocytotic vesicles, and numerous filaments without dense bodies; rare intercellular rudimentary junctions were identified. Eleven of 11 tumors were immunoreactive for vimentin, 11 of 12 for desmin, three of 11 for muscle actin, one of 12 for smooth muscle actin, and four of 12 for CD34. There was no staining for factor XIIIa, keratin, S100 protein, Leu-7, glial fibrillary acidic protein, or CD68. Follow-up revealed no recurrences or metastases. Angiomyofibroblastoma is a distinctive benign tumor that arises most commonly in the vulva and vagina and has a diverse histologic and immunohistochemical profile. PMID- 8685230 TI - Growth factors and oncogene products in transitional cell carcinoma. AB - Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) stimulate cellular proliferation, whereas epidermal growth factor receptor (EGFR) and c-erb-B-2 oncoprotein are involved in the regulation of cellular growth. Although the immunoreactivity for growth factors and oncogene products in transitional cell carcinoma (TCC) of the urinary bladder has been shown to correlate with clinicopathologic findings and prognoses, there have been no such reports on TCC of the upper urinary tract (TCC-UUT). The present study investigated the prognostic value of these growth factors (EGF and TGF-alpha) and oncogene products (EGFR and c-erb-B-2) in TCC-UUT. Formalin-fixed, paraffin embedded tumor tissues from 133 patients with TCC-UUT were analyzed using immunohistochemical staining. Immunohistochemically, EGF was recognized as positive in 50.4% of the samples, TGF-alpha in 27.8%, EGFR in 41.3%, and c-erb-B 2 oncoprotein in 6.8%. The immunoreactivity for EGF and c-erb-B-2 oncoprotein was significantly (P < 0.05) correlated with both stage and grade, whereas TGF-alpha correlated only with stage and EGFR only with grade. The 5-year survival rate for all cases taken together was 66.7%. Univariate analysis revealed that patients with EGF- and c-erb-B-2 oncoprotein-positive tumors had a worse clinical course than patients with EGF- and c-erb-B-2 oncoprotein-negative tumors, whereas in the final models of multivariate analysis, stage was found to be the only prognostic factor. Detection of immunoreactivity for growth factors and oncogene products does not appear to be of any real value in deciding the prognosis of TCC-UUT. PMID- 8685231 TI - Epstein-Barr virus reactivation in hairy leukoplakia. AB - Hairy leukoplakia, often seen in patients with acquired immunodeficiency syndrome, is strongly associated with Epstein-Barr virus (EBV) infection and questionably associated with human papillomavirus (HPV) infection. To date, most in situ hybridization (ISH) studies suggest that the EBV is localized only to the superficial squamous layers, favoring the theory of lingual infection by saliva rather than by reactivation of latent lingual infection. We describe 11 formalin fixed, paraffin-embedded specimens from patients with lingual hairy leukoplakia that we examined for the presence of the EBV, HPV, cytomegalovirus, and human immunodeficiency virus. We used standard DNA ISH for the EBV and cytomegalovirus and polymerase chain reaction ISH for the EBV, HPV, and human immunodeficiency virus. The EBV was present in all 11 specimens according to polymerase chain reaction ISH studies but in only seven specimens according to conventional DNA ISH. Polymerase chain reaction ISH localized the EBV to the basal and parabasal layers in addition to the strong localization in the upper epithelial layers. No evidence for HPV or cytomegalovirus DNA was found. The human immunodeficiency virus was focally localized to rare superficial squamous cells in seven specimens. The presence of EBV DNA in basal and parabasal lingual cells, as well as localization of latency-associated proteins in these layers, suggests that hairy leukoplakia in patients with acquired immunodeficiency syndrome might represent a reactivation of latent lingual infection accompanied by a dramatic increase in viral copy number in the more mature, superficial, squamous cells. The human immunodeficiency virus was also found in seven specimens, but the significance of this new finding is uncertain and requires further study. There is no evidence to suggest that the HPV is involved in the development of hairy leukoplakia. PMID- 8685232 TI - Immunocytochemical staining on ThinPrep processed smears. AB - This study reports our first-year experience in the immunocytochemical staining of specimens prepared by the ThinPrep processor. The avidin-biotin-complex technique was applied to smears of 70 cytological specimens, including fine needle aspiration samples from various sites (56 specimens), body fluids (13 specimens) and urine (one specimen). The specimens were collected in CytoLyt solution to lyse red blood cells and then resuspended in the processing solution. The smears were made by the processor and fixed in 95% alcohol. The panel of antibodies used included alpha-fetoprotein, carcinoembryonic antigen, cytokeratin, chromogranin A, HMB-45, beta-human chorionic gonadotropin (beta HCG), Kappa, Lambda, Ki-1, leucocyte common antigen, L26, neuron-specific enolase, 013, prostatic acid phosphatase, prostatic-specific antigen, S100, thyroglobulin, UCHL-1, and vimentin. The various antigens could be easily demonstrated in the ThinPrep smears, except for some lymphoma markers. Nonspecific background staining caused by blood and proteinaceous debris was virtually absent. In general, the monolayer preparation made the interpretation easier than conventional preparations. The only problem with this technique was in the classification of lymphomas where immunotyping was inconclusive. Our preliminary results indicate that ThinPrep smears are suitable for immunocytochemical studies, except for the classification of lymphomas. PMID- 8685233 TI - Ovarian granulosa cell tumors with bizarre nuclei: an immunohistochemical analysis with fluorescence in situ hybridization documenting trisomy 12 in the bizarre component [corrected]. AB - Granulosa cell tumors with bizarre nuclei (GCT-BN) are rare lesions with a prognosis apparently similar to that of conventional granulosa cell tumors (GCT NOS). The immunohistochemical features of GCT-BN have not been described, and the exact nature of the bizarre nuclei (BN) is unclear. Thirteen GCT-BN were studied with antibodies to cytokeratin, vimentin, epithelial membrane antigen, muscle specific actin, alpha smooth muscle actin, desmin, and S-100 protein. Six cases were also examined by fluorescence in situ hybridization for trisomy 12, a nonrandom chromosomal aberration found in a proportion of ovarian sex-cord stromal tumors. Histologically, 12 tumors (86%) contained BN areas interspersed with large areas of GCT-NOS. The remaining tumor contained only microscopic foci of GCT-NOS. Immunohistochemically, the tumors stained for vimentin (13 tumors), S 100 protein (11 tumors), muscle-specific actin (10 tumors), cytokeratin (eight tumors), alpha smooth muscle actin (eight tumors), and desmin (one tumor), but none stained for epithelial membrane antigen. Immunostaining results for the BN and GCT-NOS areas were concordant in eight (73%) of the 11 tumors in which both areas could be independently assessed. The remaining three tumors (27%) showed discordant results for only one of the eight markers used. In five patients, trisomy 12 was detected by fluorescence in situ hybridization in areas of BN but not in areas of GCT-NOS present in the same tumor. Trisomy 12 was also present in another BN tumor in which the foci of GCT-NOS were too small to be evaluated. We conclude that within GCT-BN, areas with BN are immunohistochemically similar to areas of GCT-NOS present in the same tumor. The finding of trisomy 12 in areas with BN but not GCT-NOS in the same tumor, however, suggests that cells with BN represent a genetically distinct clone of tumor cells arising within GCT-NOS. PMID- 8685234 TI - Microglioma, a histiocytic neoplasm of the central nervous system. AB - Neuropathologists have long suspected the existence of a tumor derived from the microglia, which are the resident immunocompetent cells of the central nervous system. Previously, definitive characterization of this rare putative tumor was hampered by the lack of precise immunohistochemical reagents. We herein report on a patient with microglioma, and we define the immunohistochemical characteristics of the tumor. The patient was a 50-year-old white woman who presented with a 1 year history of progressive paresthesia, visual difficulties, and cranial nerve abnormalities. The patient died in June 1972. At autopsy, the brain weighed 1540 grams and was remarkable for a diffusely infiltrating periventricular tumor, which extended from the rostral tip of the lateral ventricles through the spinal cord. Microscopically, the tumor cells had extremely long, slender, twisted nuclei, and the cells diffusely infiltrated the brain parenchyma so that the extent of the tumor was difficult to determine. Formalin-fixed, paraffin-embedded tissue blocks from the neuropathology archives were studied. The neoplastic cells stained intensely with CD68 (KP1) and Ricinus communis agglutinin-120 markers for microglia and also with HAM-56, a marker for macrophages. The tumor cells stained negative for glial fibrillary acidic protein. The recent availability of precise immunohistochemical reagents has clearly defined this rare neoplasm and has facilitated reliable distinction from lymphoma and gliomatosis cerebri. PMID- 8685235 TI - Bronchiolar basement membrane changes associated with bronchiolitis obliterans in lung allografts: a retrospective study of serial transbronchial biopsies with immunohistochemistry [corrected]. AB - Lung transplantation is an accepted mode of therapy for selected patients with end-stage lung disease. Their long-term survival is mainly limited by chronic rejection, i.e., bronchiolitis obliterans (BO), which represents a fibrosing inflammatory process of the terminal and respiratory bronchioles, leading to progressive small airway obstruction. To evaluate its development, and associated irreversible allograft dysfunction, we retrospectively studied the histological and clinical data from nine patients who developed BO, and nine matched control patients. A total of 152 serial transbronchial biopsies (87 from patients with BO; 65 from the control group) were studied using immunohistochemical stains, with antibodies to laminin, desmin, fibronectin, collagen IV, collagen III, and vimentin. The staining with anti-collagen IV antibody was the most productive and in eight of the nine patients with BO demonstrated early focal bronchiolar basement membrane damage, manifested by thickening and subsequent splitting and duplication. This was seen in association with the second episode and onward of clinically significant episodes of acute cellular rejection which occurred 7 to 12 months posttransplant. The larger airways were unaffected. The histological onset of BO exhibited varying degrees of obstruction of the bronchioles with no detectable basement membrane staining. The control patients failed to demonstrate these findings. The other immunohistochemical stains used were found to be noncontributory. We conclude that the usage of anti-collagen IV on lung allograft biopsies demonstrates the sequential changes of bronchiolar basement membrane disruption in lung allograft recipients who have multiple episodes of clinically significant acute cellular rejection and later develop BO. PMID- 8685236 TI - Metanephric adenoma: histology, immunophenotype, cytogenetics, ultrastructure. AB - Metanephric adenoma is a rare renal neoplasm that is histologically and clinically unique. We found this neoplasm in a 54-year-old woman. This large, well-circumscribed, solid, tan tumor showed histologic similarity to developing metanephric tubular epithelium. It is composed of uniformly small epithelial cells forming tubules. Immunohistochemical evaluation showed that the tumor cells express proximal tubule marker URO-2 and wt1 gene protein product, commonly expressed in Wilms' tumors. Ultrastructurally, the epithelial cells were characterized by the presence of cilia on the luminal side and were resting on an abundant basement membrane. Cytogenetic analysis showed normal female karyotype. The unique features of metanephric adenoma should be clinically and pathologically recognized because of its invariably benign course. PMID- 8685237 TI - Light-chain mRNA in lymphocyte-predominant and mixed-cellularity Hodgkin's disease. AB - There is growing evidence for a B-cell lineage of lymphocyte-predominant Hodgkin's disease (1). To support this assumption, in situ hybridization techniques were used to detect immunoglobulin light-chain mRNA in 44 formalin fixed specimens of Hodgkin's lymphoma (22 of lymphocyte-predominant Hodgkin's disease; 22 of mixed-cellularity Hodgkin's disease). In addition, immunoglobulin light chains were evaluated by polyclonal antisera. All specimens had been unequivocally diagnosed histologically by the referees of the German Hodgkin Trial and been immunophenotyped by monoclonal antibodies against CD15, CD20, CD30, and CD45. Light-chain mRNA coding either for kappa or for lambda could be detected by an enhanced in situ hybridization protocol using microwave heating in the lymphocytic and histiocytic cells of 14 (64%) of 22 specimens of lymphocyte predominant Hodgkin's disease tested. None of the specimens, however, belonging to one of the classic subtypes of Hodgkin's disease (mixed-cellularity Hodgkin's disease) showed positivity for mRNA in the giant tumor cells. Our results support the idea that lymphocyte-predominant Hodgkin's disease represents a B-cell malignancy that is a entity separate from classic Hodgkin's disease. Diverging results of former studies in assessing light-chain mRNA in lymphocytic and histiocytic cells probably reflect problems with the detection threshold, i.e., the sensitivity of the techniques applied. PMID- 8685238 TI - Wild-type and mutant retinoblastoma protein in paraffin sections. AB - Inactivation of the retinoblastoma susceptibility (RB) gene plays a role in the pathogenesis of a variety of human malignancies. Recently, it has become feasible to study RB expression in archival tissues, and it is expected that immunohistochemical studies on routinely processed tumors will further elucidate the biologic and clinical significance of RB mutations. Our study was designed to address two issues that are critical for the interpretation of such studies, i.e., whether mutant RB protein (pRB) can reliably be distinguished from normal pRB and whether there are significant differences in the performance characteristics of various anti-RB antibodies. We studied cell blocks of 26 mutant RB cell lines (11 lines without any RB expression, nine lines expressing truncated mRNA/pRB, six lines carrying missense mutations) with five different anti-RB monoclonal antibodies, using a recently described procedure that includes an antigen retrieval step. The specific staining pattern for pRB was nuclear. Cytoplasmic staining was found to be nonspecific and could be strong. Some truncated and all full-length mutant pRBs localized to the nucleus, creating positive nuclear staining that might be indistinguishable from the staining pattern of cells carrying wild-type RB. The five antibodies tested showed significant differences in sensitivity, specificity, and background reactivity. Our data suggest that a significant subset of mutant pRB has preserved nuclear translocation capacity, that not all anti-RB antibodies are equally suitable for immunohistochemical analysis of RB expression, and that any such analysis is bound to include a certain, albeit probably small, number of positive stains, despite the absence of functional pRB. PMID- 8685239 TI - Fatty acid composition of adipose tissue in humans. Implications for the dietary fat-serum cholesterol-CHD issue. AB - Interest in studies of the fatty acid composition of adipose tissue has arised from the dietary fat-serum cholesterol-CHD issue. The fatty acid composition of depot fat reflects that of the diet. Gas chromatography analysis of subcutaneous adipose tissue yield objective and reliable information of the fatty acid composition of the habitual diet of individuals. A relative linoleic acid deficiency, as depicted by low adipose tissue linoleate levels, has not convincingly been demonstrated to be of importance in the aetiology of atherosclerosis or related disorders. Inverse correlation between n-3 fatty acids and coronary artery disease has been reported. Dietary supplementation of n-3 fatty acids may be of relevance, however the risk of hazardous side-effects do exist. In conclusion, a simple reduction of the total fat content of the diet still seems to be the most important strategy for prevention of atherosclerosis. PMID- 8685240 TI - Xenobiotic lipids: the inclusion of xenobiotic compounds in pathways of lipid biosynthesis. PMID- 8685241 TI - Postprandial triacylglycerolaemia--nutritional implications. PMID- 8685242 TI - beta-oxidation of fatty acids in mitochondria, peroxisomes, and bacteria: a century of continued progress. PMID- 8685243 TI - Glycerolipid biosynthesis in peroxisomes (microbodies). PMID- 8685244 TI - X. International Union of Pharmacology recommendations for nomenclature of new receptor subtypes. PMID- 8685245 TI - Pharmacology of cotransmission in the autonomic nervous system: integrative aspects on amines, neuropeptides, adenosine triphosphate, amino acids and nitric oxide. PMID- 8685246 TI - Pharmacological modulation of voltage-gated Na+ channels: a rational and effective strategy against ischemic brain damage. PMID- 8685247 TI - Effects of oxidized low-density lipoprotein on vascular contraction and relaxation: clinical and pharmacological implications in atherosclerosis. AB - Oxidized LDL exerts profound effects on the vasomotor response of isolated blood vessels to various stimuli that closely mimic the vascular dysfunction associated with hypercholesterolemia and atherosclerosis in humans. The beneficial effect of lipid-lowering therapy in normalizing vascular function and greatly decreasing the frequency of clinical events associated with atherosclerosis, combined with the ability of antioxidants to alleviate vasomotor disturbances in hypercholesterolemia and slow the progression of atherosclerosis, strongly support a causative role of oxidized LDL in mediating vascular dysfunction in vivo and contributing to the clinical sequalae of coronary artery disease. Further research to understand more fully the mechanisms of oxidized LDL formation and actions in vivo may reveal novel strategies to inhibit these events, and may prove beneficial in the therapeutic management of atherosclerotic disease. PMID- 8685248 TI - Effects of experimental diabetes and insulin on smooth muscle functions. PMID- 8685249 TI - Water calorimetry for radiation dosimetry. AB - Calorimetry has a long history as a technique for establishing the absorbed dose, and graphite calorimetry has often been used to establish absorbed dose standards for use in radiation therapy. However, a conversion process is necessary to convert from dose to graphite to dose to water, which is the quantity of clinical interest. In order to more directly measure the dose to water, considerable effort has been devoted in the last fifteen years to the development of water calorimetry. This article reviews these developments and summarizes the present status of water calorimetry. Absorbed dose standards based on water calorimetry and with a relative standard uncertainty of 0.5-1% now seem achievable. PMID- 8685250 TI - The calibration of CT Hounsfield units for radiotherapy treatment planning. AB - Computer tomographic (CT) scans are used to correct for tissue inhomogeneities in radiotherapy treatment planning. In order to guarantee a precise treatment, it is important to obtain the relationship between CT Hounsfield units and electron densities (or proton stopping powers for proton radiotherapy), which is the basic input for radiotherapy planning systems which consider tissue heterogeneities. A method is described to determine improved CT calibrations for biological tissue (a stoichiometric calibration) based on measurements using tissue equivalent materials. The precision of this stoichiometric calibration and the more usual tissue substitute calibration is determined by a comparison of calculated proton radiographic images based on these calibrations and measured radiographs of a biological sample. It has been found that the stoichiometric calibration is more precise than the tissue substitute calibration. PMID- 8685251 TI - A two-dimensional Kolmorogov-Smirnov test for binned data. AB - A new two-dimensional version of the Kolmorogov-Smirnov test has been developed for the testing of data which has been placed in a two-dimensional array of bins. Monte Carlo testing has been used to derive the test statistics for 8 x 8, 16 x 16 and 32 x 32 arrays. The predicted probabilities for non-square arrays and arrays with intermediate numbers of elements are compared to the probabilities derived from Monte Carlo testing. The new test is applied to two-dimensional histograms of movement vectors derived from electrical impedance images of the stomach. PMID- 8685252 TI - The UK primary standard calorimeter for photon-beam absorbed dose measurement. AB - A description is given of the UK primary standard graphite calorimeter system. The calorimeter measures absorbed dose to graphite for photon radiations from 60Co to 19 MV x-rays, and is the basis of the NPL therapy-level absorbed dose to water calibration service. Absorbed dose to graphite from the photon calorimeter has been compared with three other standards: an ionization chamber and cavity theory, for 60Co gamma radiation; the NPL electron calorimeter, for 12-14 MeV electron beams; and the BIPM 60Co absorbed dose standard. The three standards agreed within 0.5% which is similar to the measurement uncertainties. PMID- 8685253 TI - Model-based scatter correction for fully 3D PET. AB - A method is presented that directly calculates the mean number of scattered coincidences in data acquired with fully 3D positron emission tomography (PET). This method uses a transmission scan, an emission scan, the physics of Compton scatter, and a mathematical model of the scanner in a forward calculation of the number of events for which one photon has undergone a single Compton interaction. The distribution of events for which multiple Compton interactions have occurred is modelled as a linear transformation of the single-scatter distribution. Computational efficiency is achieved by sampling at rates no higher than those required by the scatter distribution and by implementing the algorithm using look up tables. Evaluation studies in phantoms with large scatter fractions show that the method yields images with quantitative accuracy equivalent to that of slice collimated PET in clinically useful times. PMID- 8685254 TI - Proton dose monitoring with PET: quantitative studies in Lucite. AB - The feasibility of using PET for proton dose monitoring is examined here in detail. First experimental studies in a Lucite phantom have been performed at the medical TRIUMF proton beamline for proton energies of 62 MeV and 110 MeV. The proton dose delivered to the phantom ranged from 16 Gy up to 317 Gy. The induced activity was analysed 20-40 min after the irradiation with a PET scanner. The obtained depth activity profiles were compared to our calculation based on a model using available isotope production cross-section data. Both the observed absolute count rates and the activity profiles were found to agree very well with this model. Effects such as proton range straggling, inelastic nuclear interactions and the energy spectrum of the emitted positrons were studied in detail and found to change the activities by 5-10%. The lateral deposition of dose in the phantom could be very well localized by the induced activity. However, the spatial correlation between dose depth profiles and depth activity profiles was found to be poor, hence the extraction of isodose profiles from activity profiles seems to be very difficult. PMID- 8685255 TI - Broadband ultrasound attenuation value dependence on bone width in vitro. AB - The purpose of this study was to examine the dependence of broadband ultrasound attenuation (BUA) on bone width using 16 samples of dense bovine cancellous bone. Both BUA and density were measured simultaneously so that a dependence of BUA on bone width independent of density could be found. BUA was found to increase significantly with bone width (3.6 dB MHz-1 mm-1, r = 0.92, p < 0.0001) and this increase could not be explained by associated changes in density. PMID- 8685256 TI - Imaging laser heated subsurface chromophores in biological materials: determination of lateral physical dimensions. AB - We describe a non-contact method using infrared radiometry to determine lateral physical dimensions of laser heated subsurface chromophores in biological materials. An imaging equation is derived that relates measured radiometric temperature change to the reduced two-dimensional temperature increase of laser heated chromophores. From measured images of radiometric temperature change, the lateral physical dimensions of chromophores positioned in an in vitro model of human skin are determined by deconvolution of the derived imaging equation using a non-negative constrained conjugate gradient algorithm. Conditions for optimum spatial resolution are found by analysis of a derived radiometric transfer function and correspond to superficial chromophores and/or weak infrared absorption in a laser irradiated biological material. Analysis indicates that if the infrared attenuation coefficient is sufficiently small (i.e., less than 10mm 1), infrared radiometry in combination with a deconvolution algorithm allows estimation of lateral physical dimensions of laser heated subsurface chromophores in human skin. PMID- 8685257 TI - Time-domain reflectometry studies on Halobacterium halobium and Halobacterium marismortui. AB - The dielectric properties of Halobacterium halobium and Halobacterium marismortui measured over the frequency range 1 MHz to 1 GHz are compared with a single-shell model for interfacial polarization. In the case of Halobacterium halobium, the model shows excellent agreement with the experimental data for reasonable values of membrane and cytoplasmic conductivity and permittivity. For Halobacterium marismortui however, an acceptable fit to the data can only be achieved by invoking a plasma membrane conductivity some three orders of magnitude larger than that of Halobacterium halobium and adding a second high-frequency dielectric dispersion. These observations confirm the findings of a previous study and are consistent with a scheme for Halobacterium marismortui involving thermodynamic compartmentalization of Na and K ions and the existence of a conductive plasma membrane. PMID- 8685258 TI - An estimation of the relative biological effectiveness of 50 MV bremsstrahlung beams by microdosimetric techniques. AB - An efficient algorithm has been developed to estimate the relative biological effectiveness (RBE) from experimental RBE data and measured single-event energy deposition spectra. As benchmarks for the calculations well established RBE data for crypt cell survival and associated microdosimetric distributions from a number of therapeutic high- and low-LET beams was used. As a by-product of the calculations the RBE for this system was determined for the lineal energy range 0.1-5000 keV microns-1 in very good agreement with experimental data. These data have been applied to estimate the biological effectiveness of therapeutic high energy bremsstrahlung beams characterized by microdosimetric measurements with a wall-less proportional counter. The absorbed dose component due to photoneutrons and charged particles from photonuclear reactions in scanned 50 MV bremsstrahlung beams was measured to be about 2% of the total absorbed dose. The RBE of 50 MV scanned bremsstrahlung beams was estimated to be 1.09 for jejunum crypt cell survival as the biological endpoint at absorbed doses of the order of 10 Gy, in fair agreement with reported results based on radiobiological experiments. The RBE is fairly independent of the bremsstrahlung target used. Using the estimated increase in the RBE of neutrons compared to photons for absorbed dose levels applied in clinical fractionation schedules increases the RBE further to 1.13 at absorbed doses per fraction of the order of 2 Gy. PMID- 8685259 TI - Domestic magnetic field exposures in Avon. AB - To define a protocol for surrogate measurement of magnetic field exposure by questionnaire, a series of spot and 24-hour measurements was made at 50 houses in Avon, UK. Measurements were made with Emdex II equipment in the centres of rooms with the house power encountered at the start of the visit, and then with all power to the house isolated at the main switch. The mean spot magnetic field averaged over the 50 homes for each room varied between 0.011 and 0.023 microT with an overall mean (0.017 +/- 0.003) microT with the power 'on', and between 0.008 and 0.015 microT, giving an overall mean (0.012 +/- 0.002) microT with power 'off'. Measurements over 24 h in the three main occupancy rooms showed a distinct diurnal variation in the overall mean magnetic field of the 50 homes by a factor of three, giving a 24-hour mean of (0.044 +/- 0.06) microT; at the same time mean recorded personal exposure for the occupants monitored was (0.067 +/- 0.08) microT. These values appear low compared with, for example, USA domestic levels of magnetic field exposure demonstrated in several studies, but also show a wide variation in individual values, which could not be predicted from spot measurements. PMID- 8685260 TI - Respiration gated radiotherapy treatment: a technical study. AB - In order to optimize external-beam conformal radiotherapy, patient movement during treatment must be minimized. For treatment on the upper torso, the target organs are known to move substantially due to patient respiration. This paper deals with the technical aspects of gating the radiotherapy beam synchronously with respiration: the optimal respiration monitoring system, measurements of organ displacement and linear accelerator gating. Several respiration sensors including a thermistor, a thermocouple, a strain gauge and a pneumotachograph were examined to find the optimal sensor. The magnitude of breast, chest wall and lung motion were determined using playback of fluoroscopic x-ray images recorded on a VCR during routine radiotherapy simulation. Total dose, beam symmetry and beam uniformity were examined to determine any effects on the Varian 2100C linear accelerator due to gating. PMID- 8685261 TI - A comparison of dosimetry techniques in stereotactic radiosurgery. AB - Accurate dosimetry of small-field photon beams used in stereotactic radiosurgery (SRS) can be made difficult because of the presence of lateral electronic disequilibrium and steep dose gradients. In the published literature, data acquisition for radiosurgery is mainly based on diode and film dosimetry, and sometimes on small ionization chamber or thermolominescence dosimetry. These techniques generally do not provide the required precision because of their energy dependence and/or poor resolution. In this work PTW diamond detectors and Monte Carlo (EGS4) techniques have been added to the above tools to measure and calculate SRS treatment planning requirements. The validity of the EGS4 generated data has been confirmed by comparing results to those obtained with an ionization chamber, where the field size is large enough for electronic equilibrium to be established at the central axis. Using EGS4 calculations, the beam characteristics under the experimental conditions have also been quantified. It was shown that diamond detectors are potentially ideal for SRS and yield more accurate results than the above traditional modes of dosimetry. PMID- 8685262 TI - The Arabidopsis profilin gene family. Evidence for an ancient split between constitutive and pollen-specific profilin genes. AB - Profilin is a ubiquitous eukaryotic protein that regulates the actin cytoskeleton and recently has been identified as a potent allergen in pollen. We examined the profilin gene family in the model plant, Arabidopsis thaliana, and found that it contained approximately 8 to 10 members. Four distinct profilin sequences, three cDNAs, PRF1, PRF2, and PRF3, and two genomic clones, PRF1 and PRF4, were isolated and characterized. These genes encoded four distinct profilin isoforms of 131 to 134 amino acids. Northern and reverse-transcriptase polymerase chain reaction analyses demonstrated that Arabidopsis PRF1 was expressed in all major plant organs, whereas PRF4 was specifically expressed in mature pollen. Gene trees constructed from amino acid sequence data revealed the presence of two ancient, distinct profilin gene classes in plants. PRF4 was in a class with previously identified pollen-specific profilins from monocot and dicot species. PRF1, PRF2, PRF3, and a distant dicot sequence formed a separate novel class, suggesting an ancient separation of plant profilins based on regulation and perhaps function. The coevolution of plant actin and profilin classes with similar patterns of expression is discussed. The similarity of plant, fungal, protist, insect, and nematode profilins and their extreme divergence from the vertebrate profilins has striking implications for the evolution of fungal-spore- and plant-pollen profilins as allergens. PMID- 8685264 TI - Functional expression of the extraplastidial Arabidopsis thaliana oleate desaturase gene (FAD2) in Saccharomyces cerevisiae. AB - The functional expression in yeast of the Arabidopsis thaliana FAD2 gene, encoding the extraplastidial oleate desaturase (1-acyl-2-oleoyl-sn-glycero-3 phosphocholine delta 12-desaturase) is reported. Dienoic fatty acids constituted up to 11% (w/w) of the total fatty acids in transformed Saccharomyces cerevisiae cells and were confirmed to be linoleic acid and delta 9, delta 12 hexadecadienoic acid by gas chromatography-mass spectrometry. PMID- 8685263 TI - A thiol protease and an anionic peroxidase are induced by lowering cytokinins during callus growth in Petunia. AB - We previously identified a group of proteins that increase early in Petunia hybrida calli subcultured on a low-cytokinin medium, unlike the calli subcultured on a high-cytokinin medium. The calli on the low-cytokinin medium do not regenerate (J.-P. Renaudin, C. Tournaire, B, Teyssendier de la Serve [1991] Physiol Plant 82: 48-56). Two of these proteins, P21 and P17, have been identified by peptide sequencing and cloned. P21 is highly homologous to a group of thiol proteases, including barely aleurain, rice oryzain gamma, Arabidopsis SAG2, and mammalian cathepsin H. P17 is highly homologous to a group of anionic peroxidases from potato and tomato. A study of their expression in two P. hybrida lines, PC6 and St40 which differ in their ability to regenerate, showed that the genes for P21 and P17 are differentially expressed depending on the type and the age of the organ, with the highest expression in senescing leaves and in aged calli. The data are in favor of these genes being associated with an early step of senescence, which may be due, in part, to a reduction in total cytokinin. The two Petunia lines are, thus, functionally different concerning the action of cytokinin in two developmental phenomena: in vitro organogenesis and senescence. PMID- 8685266 TI - A cherry protein and its gene, abundantly expressed in ripening fruit, have been identified as thaumatin-like. AB - A 29-kD polypeptide is the most abundant soluble protein in ripe cherry fruit (Prunus avium L); accumulation begins at the onset of ripening as the fruit turns from yellow to red. This protein was extracted from ripe cherries and purified by size-exclusion and ion-exchange chromatography. Antibodies to the purified protein were used to screen a cDNA library from ripe cherries. Numerous recombinant plaques reacted positively with the antibodies; the DNA sequence of representative clones encoded a polypeptide of 245 amino acid residues. A signal peptide was indicated, and the predicted mature protein corresponded to the purified protein in size (23.3 kD, by mass spectrometry) and isoelectric point (4.2). A search of known protein sequences revealed a strong similarity between this polypeptide and the thaumatin family of pathogenesis-related proteins. The cherry thaumatin-like protein does not have a sweet taste, and no antifungal activity was seen in preliminary assays. Expression of the protein appears to be regulated at the gene level, with mRNA levels at their highest in the ripe fruit. PMID- 8685265 TI - Transgenic AEQUORIN reveals organ-specific cytosolic Ca2+ responses to anoxia and Arabidopsis thaliana seedlings. AB - Using the transgenic AEQUORIN system, we showed that the cotyledons and leaves of Arabidopsis thaliana seedlings developed a biphasic luminescence response to anoxia, indicating changes in cytosolic Ca2+ levels. A fast and transient luminescence peak occurred within minutes of anoxia, followed by a second, prolonged luminescence response that lasted 1.5 to 4 h. The Ca2+ channel blockers Gd3+, La3+, and ruthenium red (RR) partially inhibited the first response and promoted a larger and earlier second response, suggesting different origins for these responses. Both Gd3+ and RR also partially inhibited anaerobic induction of alcohol dehydrogenase gene expression. However, although anaerobic alcohol dehydrogenase gene induction occurred in seedlings exposed to water-agar medium and in roots, related luminescence responses were absent. Upon return to normoxia, the luminescence of cotyledons, leaves, and roots dropped quickly, before increasing again in a Gd3+, La3+, ethyleneglycol-bis(beta-aminoethyl ether)-N,N'-tetraacetic acid-, and RR-sensitive fashion. PMID- 8685267 TI - Sugar accumulation in grape berries. Cloning of two putative vacuolar invertase cDNAs and their expression in grapevine tissues. AB - During grape berry (Vitis vinifera L.) ripening, sucrose transported from the leaves is accumulated in the berry vacuoles as glucose and fructose. To study the involvement of invertase in grape berry ripening, we have cloned two cDNAs (GIN1 and GIN2) from berries. The cDNAs encode translation products that are 62% identical to each other and both appear to be vacuolar forms of invertase. Both genes are expressed in a variety of tissues, including berries, leaves, roots, seeds, and flowers, but the two genes have distinct patterns of expression. In grape berries, hexose accumulation began 8 weeks postflowering and continued until the fruit was ripe at 16 weeks. Invertase activity increased from flowering, was maximal 8 weeks postflowering, and remained constant on a per berry basis throughout ripening. Expression of GIN1 and GIN2 in berries, which was high early in berry development, declined greatly at the commencement of hexose accumulation. The results suggest that although vacuolar invertases are involved in hexose accumulation in grape berries, the expression of the genes and the synthesis of the enzymes precedes the onset of hexose accumulation by some weeks, so other mechanisms must be involved in regulating this process. PMID- 8685268 TI - Inhibitors of serine/threonine phosphoprotein phosphatases alter circadian properties in Gonyaulax polyedra. AB - Protein serine/threonine phosphatases were implicated in the regulation of circadian rhythmicity in the marine dinoflagellate Gonyaulax polyedra based on the effects of three inhibitors specific for protein phosphatases 1 and 2A (okadaic acid, calyculin A, and cantharidin). Chronic exposure to okadaic acid resulted in a significant period lengthening, as measured by the bioluminescent glow rhythm, whereas cantharidin and calyculin A caused large phase delays but no persistent effect on period. Short pulses of the phosphatase inhibitors resulted in phase delays that were greatest near subjective dawn. Unlike 6 dimethylaminopurine, a protein kinase inhibitor, okadaic acid, calyculin A, and cantharidin did not block light-induced phase shifts. The inhibitors tested also increased radiolabeled phosphate incorporation into Gonyaulax proteins in vivo and blocked protein phosphatase 1 and 2A activities in Gonyaulax extracts. This study indicates that protein dephosphorylation catalyzed by protein serine/threonine phosphatases is necessary for proper functioning of the circadian system. PMID- 8685269 TI - Purification and properties of Arabidopsis thaliana COR (cold-regulated) gene polypeptides COR15am and COR6.6 expressed in Escherichia coli. AB - Arabidopsis thaliana cold-regulated genes COR15a and COR6.6 encode 15- and 6.6-kD polypeptides, respectively. The COR15a polypeptide is known to be targeted to chloroplasts and, during import, to be processed to a 9.4-kD polypeptide designated COR15am. The COR6.6 polypeptide is thought to be located in the cytosol. The coding sequences for COR15am and COR6.6 were fused to the bacteriophage T7 promoter and expressed in Escherichia coli. The recombinant polypeptides COR15amr and COR6.6r were purified to near homogeneity using a combination of ammonium sulfate fractionation, ion-exchange chromatography, and adsorption chromatography on hydroxyapatite. COR15amr and the major species of COR15am in chloroplasts co-migrated on both two-dimensional O'Farrell gels and nondenaturing polyacrylamide gels. These data corroborate the site of COR15a processing and indicate no difference in charge or quaternary structure between COR15amr and the major species of COR15am in plants. In contrast, the migration patterns of COR6.6r and COR6.6 on two-dimensional gels suggest that a considerable portion of the COR6.6 population in plants is modified. In the accompanying papers (M.S. Webb, S.J. Gilmour, M.F. Thomashow, P.L. Steponkus [1996] Plant Physiology 111: 301-312; M. Uemura, S.J. Gilmour, M.F. Thomashow, P.L. Steponkus [1996] Plant Physiology 111: 313-327), the effects of COR15amr and COR6.6r on the cryostability and lyotropic phase behavior of liposomes are examined. PMID- 8685270 TI - Effects of COR6.6 and COR15am polypeptides encoded by COR (cold-regulated) genes of Arabidopsis thaliana on dehydration-induced phase transitions of phospholipid membranes. AB - Cold acclimation of Arabidopsis thaliana includes the expression of cold regulated (COR) genes and the accumulation of COR polypeptides. The hydration characteristics of two COR polypeptides, COR6.6 and COR15am, have been determined and their effects on the dehydration-induced liquid crystalline-to-gel and lamellar-to-hexagonal II phase transitions in phospholipid mixtures have been examined. After dehydration at osmotic pressures between 8 and 150 MPa, the water content of the COR polypeptides was less than that of bovine serum albumin, with COr15am the least hydrated: bovine serum albumin > COR6.6 > COR15am. Neither COR6.6 nor COR15am altered the dehydration-induced gel lamellar --> fluid lamellar phase transition temperature of either dipalmitoylphosphatidylcholine or dioleoylphosphatidylcholine (DOPC). In multilamellar vesicles of dioleoylphosphatidylethanolamine:DOPC (1:1, mol:mol) prepared by either freeze thaw or reverse-phase evaporation methods, neither COR6.6, COR15am, nor bovine serum albumin altered the incidence of the dehydration-induced formation of the inverted hexagonal phase as a function of osmotic pressure. However, a specific ultrastructural alteration--the formation of a striated surface morphology in the lamellar domains--was observed in mixtures of dioleoylphosphatidylethanolamine:DOPC that were dehydrated in the presence of COR15am. Nevertheless, neither COR6.6 nor COR15am appears to participate in a specific protein-phospholipid interaction that alters the dehydration-induced phase behavior of phospholipid vesicles. PMID- 8685271 TI - Effects of COR6.6 and COR15am polypeptides encoded by COR (cold-regulated) genes of Arabidopsis thaliana on the freeze-induced fusion and leakage of liposomes. AB - Several cold-regulated (COR) polypeptides, which have little or no amino acid sequence identity with known proteins, are synthesized during cold acclimation of Arabidopsis thaliana. However, the function of the polypeptides has yet to be elucidated. The objective of this study was to determine if COR6.6 and COR15am influence the incidence of either freeze-induced fusion or freeze-induced leakage of small unilamellar vesicles (SUVs) composed of either a single species of phosphatidylcholine (either 1-palmitoyl-2-oleoyl-,dioleoyl-, or dilinoleoylphosphatidylcholine), a mixture of dioleoylphosphatidylcholine, dioleoylphosphatidylethanolamine, and free sterols (1:1:1, mol:mol), or the total lipid extract of the plasma membrane of either nonacclimated or cold-acclimated rye leaves. When the SUVs were suspended in a dilute tris(hydroxymethyl) aminomethane/2-(N-morpholino) ethanesulfonic acid buffer, both COR6.6 and COR15am invariably decreased the incidence of freeze-induced fusion regardless of the lipid composition. However, if the SUVs were suspended in a dilute solution of either sucrose or NaCl, the COR polypeptides had little or no effect on the incidence of freeze-induced fusion. Moreover, the COR polypeptides did not decrease the incidence of freeze-induced leakage--regardless of whether the SUVs were suspended in either the dilute buffer alone or with added sucrose or NaCl. In fact, with SUVs composed of a single species of phosphatidylcholine suspended in the dilute buffer, the COR polypeptides resulted in an anomalous increase in freeze-induced leakage. When considered collectively, these results suggest that neither COR6.6 nor COR15am has a direct cryoprotective effect on SUVs frozen in vitro. PMID- 8685273 TI - The electronic Plant Gene Register. PMID- 8685272 TI - Analysis of flavanone 3-hydroxylase in Arabidopsis seedlings. Coordinate regulation with chalcone synthase and chalcone isomerase. AB - A genomic clone encoding flavanone 3-hydroxylase (F3H) was isolated from Arabidopsis thaliana. The deduced amino acid sequence is 72 to 94% identical to all previously reported F3H proteins. Low-stringency DNA blot analysis indicated that F3H is encoded by a single gene in Arabidopsis. The F3H locus was mapped to the bottom of chromosome 3 and therefore does not correspond to any of the 13 flavonoid-deficient transparent testa mutants for which a map position is known. Analysis of gene expression in etiolated seedlings exposed to white light and in two putative regulatory mutants, ttg and tt8, demonstrated that the Arabidopsis F3H gene is coordinately expressed with chalcone synthase and chalcone isomerases is seedlings, whereas dihydroflavonol reductase expression is controlled by distinct regulatory mechanisms. The F3H gene may represent a pivotal point in the regulation of flavonoid biosynthesis because its expression is coordinated with different subsets of genes in different plant species. PMID- 8685274 TI - Developmental stage-specific and nitrate-independent regulation of nitrate reductase gene expression in rapeseed. AB - cDNA clones for two isogenes of nitrate reductase (NR) have been isolated from rapeseed (Brassica napus L.) androgenetic haploid embryos induced by microspore culture. NR mRNA accumulation can be detected by northern hybridization at 14 d after culture initiation when embryos develop to the heart/torpedo-shaped stage. Whole-mount in situ hybridization experiments demonstrate that the mRNA accumulation is developmental stage specific. In addition, even when cultured in media containing no nitrate, embryos accumulated NR mRNA to almost the same level as the control. This indicates the unique regulation of NR in embryogenesis in which NR mRNA transcription is activated in a developmental stage-specific manner that is independent of nitrate induction. In zygotic embryogenesis, a stage specific accumulation of NR mRNA was also observed. By contrast, the obvious effect of nitrate on NR expression that has been reported in many plant species was also confirmed in rapeseed leaf. Quantitative combined reverse transcription polymerase chain reaction analysis suggests that the flexible and variable regulation of NR expression, which is organ specific, nitrogen metabolite specific, and developmental stage specific, is caused principally by regulation of one major structural gene. PMID- 8685275 TI - Identification of a new pea gene, PsNlec1, encoding a lectin-like glycoprotein isolated from the symbiosomes of root nodules. AB - A 27-kD glycoprotein antigen recognized by monoclonal antibody MAC266 was purified from isolated symbiosomes derived from pea (Pisum sativum) root nodules containing Rhizobium. The N-terminal amino acid sequence was obtained, and the corresponding cDNA clone was isolated by a polymerase chain reaction-based strategy. The clone contained a single open reading frame, and the gene was termed PsNlec1. Phylogenetic analysis of 31 legume sequences showed that the PsNlec1 protein is related to the legume lectin family but belongs to a subgroup that is very different from pea seed lectin. Expression of the PsNlec1 transcript was much stronger in nodules than in other parts of the plant. It was found in both infected and uninfected cells in the central tissue of the nodule and in the stele of the root near the attachment point of the nodule. When uninfected pea seedlings were grown on medium containing nitrate, weak transcription of PsNlec1 was observed in the root system. The identification of PsNlec1 inside the symbiosome is consistent with the observation that legume lectins are generally vacuolar proteins that may serve as transient storage components. PMID- 8685276 TI - A putative Mg chelatase subunit from Arabidopsis thaliana cv C24. Sequence and transcript analysis of the gene, import of the protein into chloroplasts, and in situ localization of the transcript and protein. AB - We have isolated and sequenced a cDNA from Arabidopsis thaliana cv C24 that encodes a putative Mg chelatase subunit. The deduced amino acid sequence shows a very high level of identity to a gene previously characterized from Antirrhinum majus (olive and also high similarity to bchH, a bacterial gene involved in the Mg chelatase reaction of bacteriochlorophyll biosynthesis. We suggest that this gene be called CHL H. Northern blot analyses were used to investigate the expression of CHL H, another putative Mg chelatase gene, ch-42, and ferrochelatase. The CHL H transcript was observed to undergo a dramatic diurnal variation, rising almost to its maximum level by the end of the dark period, then increasing slightly at the onset of the light and declining steadily to a minimum by the end of the light period; in contrast, transcripts for ch-42 and ferrochelatase remained constant. A model is proposed in which the CHL H protein plays a role in regulating the levels of chlorophyll during this cycle. In situ hybridization revealed that the transcripts are located over the surface of the chloroplasts, a feature in common with transcripts for the ch-42 gene. The CHL H protein was imported into the stromal compartment of the chloroplast and processed in an in vitro assay. Immunoblotting showed that the distribution of CHL H protein between the stroma and chloroplast membranes varies depending on the concentration of Mg+. In situ immunofluorescence was used to establish that the CHL H and CH-42 proteins are localized within the chloroplast in vivo. PMID- 8685278 TI - The dopamine D4 receptor in schizophrenia: an update. PMID- 8685279 TI - Measuring the need for psychiatric treatment in the general population: the community version of the MRC Needs for Care Assessment. AB - The community version of the MRC Needs for Care Assessment Schedule (NFCAS-C) is a new instrument designed for the psychiatric conditions seen in general populations. Its principles are based on the original Needs for Care Assessment, although that was developed for the very different population of those with long standing mental illness (Brewin et al. 1987). The NFCAS-C is designed to reproduce, in an itemized and systematic manner, the functioning of well organized primary care and psychiatric services. It is primarily intended for research purposes, in particular, the comparison of treatment needs and services in different populations. In this paper we describe the problems of assessing the need for psychiatric care in general populations and the rationale and development of the instrument, while in its companion we present the results of a reliability study (Lesage et al. 1995). PMID- 8685277 TI - Early genes and auxin action. PMID- 8685280 TI - The reliability of the community version of the MRC Needs for Care Assessment. AB - One hundred and nine adults were screened in the community using the abridged version of the CIDI (CIDIS). The subjects comprised DSM-III-R current cases (N = 48), lifetime cases (N = 31) and non-cases (N = 30). The interviews with the 109 subjects were conducted by one of two pairs of clinicians and videotaped. Each interviewer-pair included a psychiatrist and a clinical psychologist. They rated the community version of the Needs for Care (NFCAS-C) by consensus. The other pair of judges then viewed the video and rated the NFCAS-C independently. The agreement on overall needs was excellent (kappa = 0.75), and very good for four of the seven specific sections (from kappa = 0.61 to 0.81). One section could not be rated because of low prevalence, and agreement was less good for the remaining two sections. Agreement was good on specific interventions (medication, kappa = 0.60; specific psychotherapy, kappa = 0.55), but poor on non-specific interventions. The majority of disagreements were due to differences in clinical judgement rather than to technical errors. A new instruction manual has been produced and should help training as well as stabilizing reliability. In devising reliable and valid instruments based on clinical judgement, a balance must be achieved between enhancing reliability with more precise rules and constraining clinical judgement so tightly that validity is lost. PMID- 8685282 TI - Adrenal secretion and major depression in 8- to 16-year-olds, II. Influence of co morbidity at presentation. AB - The association between high evening cortisol and low morning DHEA and the pattern of co-morbid diagnoses in 82 cases of major depressive disorder in 8- to 16-year-olds has been analysed. There was a significant association between the presence of high evening cortisol and co-morbid dysthymia. This was independent of age or sex. No positive association was found between the presence of low morning DHEA and any co-morbid diagnosis. However, co-morbid panic or phobic disorder was significantly associated with the absence of this endocrine abnormality. These findings suggest that specific endocrine disturbances may be associated with different patterns of co-morbidity during an episode of major depression in this age group. PMID- 8685281 TI - Adrenal secretion during major depression in 8- to 16-year-olds, I. Altered diurnal rhythms in salivary cortisol and dehydroepiandrosterone (DHEA) at presentation. AB - The association between basal cortisol, dehydroepiandrosterone (DHEA), its sulphate (DHEAS) and major depression was investigated in 8- to 16-year-olds. Eighty-two subjects with major depression, 25 non-depressed psychiatric cases and 40 community controls were systematically assessed for current mental state and hormone levels at 08.00, 12.00 and 20.00 h, assayed from salivary samples collected over a 48 h period. The average mean of the two time points was compared between the three groups. Evening cortisol hypersecretion and morning DHEA hyposecretion were significantly, and independently, associated with major depression. High evening cortisol (> 0.594 ng/mL) and low morning DHEA (< 0.200 ng/mL) identified subgroups of depressives with different types of adrenal hormone dysregulation. The association between high evening cortisol or low morning DHEA and MDD was not affected by either age or gender. PMID- 8685283 TI - Abnormal saccadic distractibility in patients with schizophrenia: a 99mTc-HMPAO SPET study. AB - Recent research has shown that some patients with schizophrenia have a severe impairment in the suppression of reflexive saccadic eye movements in the ANTI saccade task. This saccadic distractibility has previously been found in patients with lesions of dorsolateral prefrontal cortex, implicating an abnormality of prefrontal cortex. The objective of the present study was to determine the contribution of these and other areas to the ANTI-saccadic abnormality in schizophrenia by functional neuroimaging. Using 99mtechnetium-HMPAO high resolution multidetector single-photon emission tomography, regional cerebral blood flow (rCBF) during performance of the ANTI-saccade eye-movement task was compared, by statistical parametric mapping, in ten male schizophrenic patients on stable antipsychotic medication who had a high distractibility error rate on the task, and eight similar patients who had normal distractibility error rates. Compared with the normal error group, the patients with high error rates showed significantly decreased rCBF bilaterally, in the anterior cingulate, insula, and in left striatum. These same patients also had increased perseverative errors on the Wisconsin Card Sort Test. PMID- 8685284 TI - Obstetric complications in children born to parents with schizophrenia: a meta analysis of case-control studies. AB - On the basis of previous findings, we used meta-analyses to consider whether births to parents with schizophrenia have an increased risk of obstetric complications. Meta-analyses were based on published studies satisfying the following selection criteria. The schizophrenic diagnosis could apply to either parent: parents with non-schizophrenic psychoses were not included: only normal controls were accepted. In all, 14 studies provided effect sizes or data from which these could be derived. Studies were identified by data searches through MEDLINE, PSYCLIT and through references of papers relating to the subject. Births to individuals with schizophrenia incur an increased risk of pregnancy and birth complications, low birthweight and poor neonatal condition. However, in each case the effect size is small (mean r = 0.155; 95% CI = 0.057). The risk is greater for mothers with schizophrenia and is not confined to mothers with onset pre delivery or to the births of the children who become schizophrenic themselves. PMID- 8685285 TI - Abnormal eating attitudes and behaviours in two ethnic groups from a female British urban population. AB - African-Caribbean (N = 136) and White British (N = 192) female family planning clinic attenders were administered the Bulimic Investigatory Test, Edinburgh (BITE) and the General Health Questionnaire (GHQ-28). A proportion of the participants were subsequently interviewed. The African-Caribbeans were found to have both significantly more disordered eating attitudes and a significantly higher level of abnormal eating behaviour than the White British. Although the African-Caribbean group had a significantly higher mean Body Mass Index this did not mediate the difference in levels of eating attitudes. When compared with the White British group more African-Caribbean women reported feelings of failure, guilt, abnormality and self-consciousness concerning their eating habits. The results indicate that eating problems may be highly prevalent in this ethnic minority population and suggest that there may be differences in the nature of eating disorder psychopathology between ethnic groups. PMID- 8685286 TI - Growth hormone response to growth hormone releasing hormone in non-delusional and delusional depression and healthy controls. AB - Growth hormone (GH) responses to growth hormone releasing hormone (GHRH) of 53 in patients meeting DSM-III-R criteria for major depressive episode with melancholia (24 non-delusional and 23 delusional depression) were compared with those of 19 healthy controls. No significant differences in basal GH were found between the control and either the non-delusional or the delusional groups. The whole group of depressed patients showed a significantly lower response than the control patients at all points of the GH response to GHRH curve as well as a lower area under curve. When the three groups (control, delusional, and non-delusional depressed) were compared, it was found that only the non-delusional depressed patients had a significantly lower area under curve and lower values at +60, +90 and +120 min than the controls. The only significant difference between the two groups of depressed patients was that the delusional group showed a delayed appearance of the maximum response peak and a more prolonged response. PMID- 8685287 TI - Situational versus pervasive hyperactivity in a community sample. AB - Groups of home and school situational hyperactive primary schoolboys identified from the community were compared with pervasive hyperactive and non-hyperactive controls on a wide range of measures. The hyperactive groups tended to persist in the same category over a half-year period. Both situational hyperactive groups had lower measured activity levels than the pervasive hyperactive group and only the latter differed from non-hyperactive controls. Home hyperactivity was characterized by poor family relationships and was not distinguishable from non hyperactive home-antisocial controls. School hyperactive boys had specific correlates of low intelligence, motor clumsiness, poor reading and academic abilities. Pervasive hyperactive subjects differed from both situational groups in showing a higher percentage of delayed language development. While home hyperactivity has dubious identity, the distinct pattern of external correlates in school and pervasive hyperactivity speak for the need to regard these as separate entities. PMID- 8685289 TI - Treatment, expressed emotion and relapse in recent onset schizophrenic disorders. AB - The effect of in-patient and individual orientated psychosocial intervention (IPI) and in-patient and individual and family orientated intervention (IPFI) across levels of expressed emotion (EE) on relapse was compared in a group of patients with recent onset schizophrenic disorders. Patients were randomly assigned to an individual orientated psychosocial intervention programme or to an identical psychosocial programme plus a behavioural family intervention. Seventy six patients were studied during a 12 month out-patient treatment period after an in-patient treatment programme in which parents followed a psychoeducational programme. Overall relapse rates during the out-patient interventions were low (16%). Adding family intervention to the psychosocial intervention did not affect the relapse rate. Patients in low EE families relapsed slightly more often during the psychosocial plus family intervention. In-patient treatment with psychoeducation for parents, followed by an out-patient psychosocial intervention programme, has a favourable impact on relapse. Additional family intervention may increase stress in low EE families, thus affecting relapse in their children. PMID- 8685288 TI - Aggression and personality: association with amino acids and monoamine metabolites. AB - Associations in 52 normal individuals were examined between plasma and cerebrospinal fluid (CSF) concentrations of tryptophan (Trp) and tyrosine, and concentrations of monoamine metabolites in the CSF, and scores on an aggression questionnaire, the Kinsey Institute Reaction List II, and the Eysenck Personality Questionnaire. There was a significantly positive correlation between CSF 5 hydroxyindoleacetic acid (5-HIAA) levels and extroverted aggression scores, and a significantly negative correlation between CSF 5-HIAA levels and introverted aggression scores. Males showed higher plasma Trp concentrations than females, and significantly positive correlations between plasma Trp concentrations and scores on extroverted aggression and the Eysenck E scale. Males, furthermore, showed a significantly negative correlation between CSF Trp levels and scores on the Eysenck P scale, and a significantly positive correlation between concentrations of 3-methoxy-4-hydroxy-phenylglycol in CSF and scores on moral aggression. These results suggest that central serotonin influences aggression in normal individuals through effects on personality. PMID- 8685290 TI - The role of drug and alcohol abuse in recent increases in depression in the US. AB - Previous studies have reported an increase in depression among recent birth cohorts. Concurrent with the increase in rates of depression, there have been increases in rates of drug and alcohol abuse and dependence. This study sought to determine if the recent increase in rates of depression could be attributed to co morbid alcohol and drug abuse. The data derived from two studies: (1) a sample of relatives of probands with affective disorder; and (2) a community survey of the US population. The piecewise exponential statistical model was applied to evaluate the association of gender, age, period and birth cohort with rates of major depressive disorder (MDD) separately for those with, and without, diagnoses of alcohol or drug abuse. Elevated rates of MDD occurred among those with co morbid drug and alcohol abuse in both the family and community samples. However, there were also temporal increases in rates of MDD in those with no such co morbidity. Specifically there were effects of age and gender for both studies; in addition, there was a period effect in the family study and a birth cohort effect in the community sample. The recent increases in depression in the US cannot be accounted for solely by concurrent increases in co-morbid drug and alcohol abuse. Temporal (period and cohort) effects on rates of depression occur in addition to the contribution of co-morbid drug and alcohol abuse or dependence. PMID- 8685291 TI - Serotonin activity in anorexia nervosa after long-term weight restoration: response to D-fenfluramine challenge. AB - Abnormalities in central serotonin function have been implicated in the pathogenesis of anorexia nervosa. It is difficult, however, to separate neuroendocrine abnormalities induced by weight loss and malnutrition from those related primarily to the disorder itself. To minimize these influences, this study assessed long-term weight restored anorexics. A correlation between persistent eating-related psychopathology, co-morbid illness and serotonin dysfunction was sought. Nine female weight-restored out-patients who had previously fulfilled DSM-III-R criteria for anorexia nervosa and nine healthy controls participated. Following baseline estimation, prolactin and cortisol responses to 30 mg p.o. of D-fenfluramine were measured over a 5 h period. Eating related psychopathology was assessed using the Eating Disorders Inventory and Eating Attitudes Test. Depressive and obsessional symptoms were measured using the Beck Depressive and Maudsley Obsessive-Compulsive Inventories respectively. The Tridimensional Personality Questionnaire assessed impulsivity. The weight restored anorexic group exhibited persistent eating-related psychopathology and significant co-morbid symptomatology. There was no difference between long-term weight-restored anorexics and controls in their endocrine response to D fenfluramine. Long-term weight-recovered anorexic subjects continued to exhibit behavioural and attitudinal disturbances characteristic of anorexia nervosa. The results suggest that abnormalities in 5HT activity do not contribute significantly to trait status in anorexia nervosa. PMID- 8685292 TI - The nature of 'transient' and 'partial' psychoses: findings from the Northwick Park 'Functional' Psychosis Study. AB - Three hundred and twenty-six consecutively admitted patients with definite or possible functional psychotic illnesses to which no diagnostic classification had been applied were followed up after 2.5 years. In 86 cases symptomatology had been inadequate for the patients to enter the functional psychosis study, and in 75 cases this was because the symptoms were partial or transient. These patients were compared at follow-up with those who fulfilled operational criteria for schizophrenic, affective or schizoaffective psychoses. Differences between the 'partial' cases and those fulfilling specific diagnostic criteria were few, but the transient cases fared significantly better. Although the transient illnesses were recurrent, at follow-up at 2.5 years they appeared to have a good outcome in terms of social variables and symptomatology. PMID- 8685293 TI - A cognitive science perspective on kindling and episode sensitization in recurrent affective disorder. AB - A cognitive science analysis of the interaction between psychological stress and the neurobiology of affective illness highlights a number of mechanisms relevant to the study of recurrence in major depressive disorder. It builds on observations previously offered by Post (1992) regarding the importance of kindling and sensitization effects in determining activation of neural structures, and proposes a model of knowledge structure activation that follows similar parameters. Vulnerability to depressive relapse/recurrence is determined by the increased risk of particular negative patterns of information processing being activated in depressed states. As is found in studies of kindling and behavioural sensitization, the likelihood of cognitive patterns being activated is dependent on the frequency of past usage, and increased reliance on these patterns of processing makes it easier for their future activation to be achieved on the basis of increasingly minimal cues. This model suggests that the processes related to relapse/recurrence and episode onset may not be isomorphic and, as such, treatments that emphasize relapse prevention strategies should take this distinction into account. PMID- 8685294 TI - Reversibility of brain tissue loss in anorexia nervosa assessed with a computerized Talairach 3-D proportional grid. AB - We describe the results of our follow-up magnetic resonance imaging (MRI) study of underweight patients with anorexia nervosa, using rigorous methodology to control for head position across time. All subjects first underwent an initial scan and rescan to verify that our computerized three-dimensional co-planar grid method for volume measurement was reliable and accurate, regardless of head positioning. After a period of several months, subjects had a follow-up scan to assess for changes that may have occurred following significant weight gain. Ventricular and total brain volume measurements from the initial scans were compared with the scans from an age- and sex-matched normal control group to determine whether we could replicate previous findings of ventricular enlargement compared with controls and whether brain volume is reduced compared with controls. Anorexic subjects had significantly larger ventricles when compared with normal controls but did not differ significantly in total brain volume. Using a repeated measures analysis of variance, a priori contrasts compared the initial/rescan pair volumes with each other and the initial/rescan pair volumes with the follow-up volume. These analyses showed that ventricular and total brain volumes derived from the initial/rescan pair were nearly identical, but that at follow-up ventricular volume decreased significantly and total brain volume increased significantly after weight gain. PMID- 8685295 TI - Confabulation in schizophrenia: evidence of a new form? AB - This study is an attempt to demonstrate confabulation in schizophrenia. Twelve patients who met DSM-III-R criteria for schizophrenia were matched for age, sex and pre-morbid IQ with 12 volunteers, 9 of whom were normal healthy subjects, with the remainder being depressed patients. To elicit confabulation, subjects were asked to recall narratives. In addition, subjects were examined on a number of neuropsychological tests. Confabulation was defined as recall of information not present in the narrative. Variable amounts of confabulation were observed in all schizophrenics, while only one control subject confabulated. The content and structure of their productions differed from previously reported forms of confabulation in that schizophrenic patients spontaneously rearranged the original narratives to produce new ideas. The amount of confabulation was found to be related to difficulties in suppressing inappropriate responses (Hayling test) and formal thought disorder, but unrelated to understanding of the gist or moral of the narratives. Tentative mechanisms for the process of confabulation are proposed, based on specific difficulties with comprehension, response monitoring and response suppression. PMID- 8685297 TI - Early development and progression of dementing illness in the elderly: a general practice based study. AB - In a study carried out in 21 general practices in Mannheim, Germany, a stratified random sample (N = 507) of patients over the age of 65 years was drawn from the total of nearly 4000 who were medically documented. Eighty per cent of the sample were examined, using the Hierarchic Dementia Scale to test cognitive functioning and the CAMDEX criteria to assess global clinical severity. Repeat assessment after a mean interval of 27 months showed that all new cases of clinical dementia had arisen in persons with mild deficits initially and represented one-fifth of this group. The first-assessment ratings of cognitive function proved to be strongly predictive of risks for age-corrected mortality, admission to long-term care and dependency at follow-up, as well as of further progressive cognitive decline. PMID- 8685296 TI - Diagnostic accuracy and confusability analyses: an application to the Diagnostic Interview for Genetic Studies. AB - The dominant, contemporary paradigm for developing and refining diagnoses relies heavily on assessing reliability with kappa coefficients and virtually ignores a core component of psychometric practice: the theory of latent structures. This article describes a psychometric approach to psychiatric nosology that emphasizes the diagnostic accuracy and confusability of diagnostic categories. We apply these methods to the Diagnostic Interview for Genetic Studies (DIGS), a structured psychiatric interview designed by the NIMH Genetics Initiative for genetic studies of schizophrenia and bipolar disorder. Our results show that sensitivity and specificity were excellent for both DSM-III-R and RDC diagnoses of major depression, bipolar disorder, and schizophrenia. In contrast, diagnostic accuracy was substantially lower for subtypes of schizoaffective disorder especially for the DSM-III-R definitions. Both the bipolar and depressed subtypes of DSM-III-R schizoaffective disorder had excellent specificity but poor sensitivity. The RDC definitions also had excellent specificity but were more sensitive than the DSM-III-R schizoaffective diagnoses. The source of low sensitivity for schizoaffective subtypes differed for the two diagnostic systems. For RDC criteria, the schizoaffective subtypes were frequently confused with one another; they were less frequently confused with other diagnoses. In contrast, the DSM-III-R subtypes were often confused with schizophrenia, but not with each other. PMID- 8685298 TI - Severe global amnesia presenting as Wernicke-Korsakoff syndrome but resulting from atypical lesions. AB - A female alcoholic presented with Wernicke's encephalopathy subsequent to administration of diazepam and glucose (without thiamine) for treatment of withdrawal seizures. Nystagmus and cerebellar ataxia quickly resolved when administered thiamine, although severe global amnesia consistent with Korsakoff's syndrome persisted. Magnetic resonance imaging (MRI) revealed infarction of the right temporal lobe with hippocampal atrophy, but no lesions of thalamus or atrophy of mammillary bodies. Positron emission tomography (PET) confirmed decreased cerebral metabolic rates for glucose (CMRglu) in the right temporal lobe corresponding to MRI findings, but also significant metabolic asymmetry of dorsal thalamus, i.e. reduced CMRglu in left versus right. This patient is unique in that neuroradiological findings revealed intact mammillary bodies and suggest asymmetrical dysfunctions (structural right temporal and functional left diencephalic) to produce her profound amnesia. PMID- 8685299 TI - Brief cognitive screening of the elderly: a comparison of the Mini-Mental State Examination (MMSE), Abbreviated Mental Test (AMT) and Mental Status Questionnaire (MSQ). AB - One hundred and fifty unselected elderly community subjects were assessed by Mini Mental State Examination (MMSE), Abbreviated Mental Test (AMT) and Mental Status Questionnaire (MSQ). The effects on cognitive test scores of potential confounding (non-cognitive) variables were evaluated. Sensitivities and specificities were: MMSE 80% and 98%; AMT 77% and 90%; and MSQ 70% and 89%. The MMSE identified significantly fewer false positives than the AMT and MSQ. The major effect of intelligence on cognitive test scores has previously been underestimated. Age, social class, sensitivity of hearing and history of stroke were also significantly correlated with cognitive test scores. Years of full time education and depression only affected the longer MMSE and CAMCOG. The MMSE (cut off 20/21) can be recommended for routine screening. However, as scores are affected by variables other than cognitive function, particularly intelligence, further assessment of identified cases may fail to reveal significant functional impairment. PMID- 8685300 TI - Prevalence of cavum septum pellucidum detected by MRI in patients with bipolar disorder, major depression and schizophrenia. AB - The incidence of cavum septum pellucidum (CSP), which has been widely regarded as a developmental anomaly of little clinical importance in neuropathology, was examined in 113 patients with affective disorders (69 with bipolar disorder and 44 with major depression), 40 schizophrenic patients, and 92 control subjects by magnetic resonance imaging (MRI). Significantly higher incidence of Grade 3-4 CSP (moderate to large) compared with the controls was found only in the schizophrenics. When a broader interpretation of CSP, including indeterminant (Grade 1) and small (Grade 2) CSP was used, three additional patients with bipolar disorder were found to have Grade 1-2 CSP, and the total prevalence of Grade 1-4 CSP in the patients with bipolar disorder was significantly higher than that in the control subjects but slightly lower than that in the schizophrenic patients. CSP was not observed in any patient with major depression. There were no differences between the patients with and without CSP in age, sex, education, or the duration of illness. These findings are consistent with the hypothesis that neurodevelopmental abnormality may be present in schizophrenia, and such an abnormality may also be present in some patients with bipolar disorder. PMID- 8685301 TI - Protopithecus: rediscovering the first fossil primate. AB - The earliest discoveries of extinct primates and humans profoundly affected the course of evolutionary theory as a scientific model for explaining life and its diversity through time. The absence of such fossils in the early nineteenth century provided important negative evidence to the competing French intellectual schools of Lamarckian evolutionism and Cuvierian catastrophism. Indeed, the first recognition of extinct primates fell serendipitously between the death of Cuvier in 1832 and the revolutionary writings of Darwin in 1859. Largely unknown to history, however, is that four different European scholars, working on three continents, independently discovered and recognized extinct primates within a few months of each other in 1836. The first of these to be formally named, Protopithecus, is ironically the least well known despite being the largest monkey ever discovered in the western hemisphere. The reasons for this forgotten first discovery reflect a general unawareness of South American mammals, and propagation of misinterpretation at a critical time in the history of primatology. PMID- 8685302 TI - Variation in purchasing for the invasive management of coronary heart disease. AB - This paper reports the results of a postal questionnaire survey of Directors of Public Health in all health authorities in the United Kingdom (as at March 1994). Our aim was to examine variations in the purchasing of coronary artery bypass grafting, percutaneous transluminal coronary angioplasty and coronary angiography. Information on planned service developments in cardiology was also sought. The response rate was 62%. The mean rate of CABG was 374 per million total population (range 162-710); PTCA 183 (range: 18-648); and coronary angiography 1,010 (range 581-2,334). The mean ratio of invasive treatment to angiography was 1:2 Variations in provision were not related to mortality from coronary heart disease or the availability of a local provider. Those districts purchasing higher levels of CABG tended to purchase higher levels of PTCA (Spearman's r = 0.52). Observed variations in purchasing of invasive treatments and investigation for coronary heart disease do not relate to population "need' as defined by mortality rates from CHD. The greatest variations are seen in the purchasing of PTCA, an intervention whose place in the management of CHD is as yet not fully defined. Consensus guidelines on the appropriate use of these interventions and on population needs are required. PMID- 8685303 TI - Essential skills for purchasing--the views of directors of public health and health authority chief executives. AB - Since the NHS reforms, health authorities have been purchasing health care and have been advised that public health considerations must inform all NHS activities, and that the Director of Public Health must be supported by a team of qualified support staff. This survey of directors of public health and health authority chief executives in England shows the skills currently available to support health authority purchasing, and the perceived importance of this wide range of skills to the purchasing process. Future models of purchasing will need to ensure access by purchasers to public health and multi-disciplinary advice. PMID- 8685304 TI - An "early warning system' for health needs: surveillance of the quality of clinical services by audit of extra-contractual referrals (ECRs). AB - Extra-contractual referrals (ECRs) can be a cause of considerable anxiety to purchasing authorities, mainly because of their potential to generate unexpected expenditure. But ECRs can also be used as a tool for monitoring the demand for, and quality of, clinical services. ECRs were studied in the Darlington Health Authority district using a variety of methods including inter-disciplinary meetings, a series of interviews with local GPs, and a questionnaire to general practitioners on 230 consecutive ECRs. The methods and results of the questionnaire study are presented. The commonest reasons for making ECRs included the mistaken belief that a contract existed with the ECR provider, patient dissatisfaction with the local provider, and referral to benefit from shorter waiting lists. ECRs for bone-mass densitometry, orthopaedics, and ear nose and throat services were over-represented. Questionnaire results were validated by comparison with an interview study of all GPs in the district. We conclude that trends in ECRs can be monitored as a convenient "early warning system' to alert purchasing authorities to changes in demand or perceived problems with local provider units. ECR data must be interpreted in the context of further local background information from sources such as GPs and public health physicians. In the case of Darlington, scrutiny of ECRs has led to changes in services and contracts. PMID- 8685305 TI - Perceived usefulness of the Director of Public Health Annual Report: a consumer survey. AB - The Annual Report of the Director of Public Health for Forth Valley was evaluated in terms of its usefulness as perceived by recipients. Six months after publication, more than half had retained their copy and a similar proportion had made use of it or anticipated using it in the coming year. Its main use was as a reference. The Report had least impact upon Consultants and General Practitioners. PMID- 8685306 TI - Environmental health and public health: are they compatible? AB - Since the beginnings of public health were rooted in environmental issues the question posed might seem absurd. However, there is a point because the approaches to the two are slightly different in most countries and increasingly different in the United Kingdom. PMID- 8685307 TI - Peer education: a strategy for improving health education in disadvantaged areas in Belfast. AB - The paper reports on the initial phase of an evaluation of a multi-agency project designed to deliver social and health education to 16-18-year-old trainees attending four community workshops in North and West Belfast. A survey of the first year of the project was carried out using quantitative and qualitative methodologies which included a questionnaire survey of those trainees attending the programme and structured interviews with a representative sample of trainees. The first stage of the research involved a baseline measure (time 0) which provided valuable insights into the behaviours, attitudes and values of the trainees regarding a range of health issues, including smoking and alcohol behaviours, and substance abuse. Some changes in behaviour, during the first year of the project, were noted, such as reported reductions in substance abuse and increased awareness of sources of advice relating to health issues. PMID- 8685308 TI - Child protection in schools: an evaluation of a training course for Fife schools' co-ordinators of child protection. AB - The incidence of reported episodes of child abuse has risen in recent years in Scotland and the importance of multi-agency collaboration is widely recognised in achieving an effective response to this problem. We have identified that school teachers are the single largest professional group which refer children with a history of suspected abuse to child protection units in Fife. Priority was therefore given to the training of coordinators of child protection within all Fife schools. An evaluation of this training carried out approximately 12 months after the training course showed that the child protection training course for coordinators of child protection in Fife schools has been well received. Coordinators attending the training reported a number of positive outcomes both in terms of their own personal confidence in dealing with child protection issues and also on progress made with developing school policies on child protection. However, the follow-up survey suggested that the course has not generally had a major impact on teachers from the same schools who had not attended the training course. This is in turn due to the low level of effective dissemination of the course to other teachers. It is recommended that a session on how to disseminate information, knowledge and skills gained during the course be incorporated into the training course and that a further follow-up evaluation of a sample of teachers who did not attend the training course be carried out. Our experience suggests that if the training courses are based on a knowledge of the training needs of school teachers and are run by professionals from all of the various agencies involved in child protection then these courses can be successful in improving the performance of coordinators of child protection in primary and secondary schools. This can then lead to better support for classroom teachers and promote the development and implementation of school child protection policies. In addition these courses helped develop inter-agency links and facilitate a true team approach in response to episodes of disclosure of child abuse. Regional child protection committees and education departments should consider giving priority to training coordinators of child protection in schools within their region as an important element in the response to the growing problem of child protection in their region. PMID- 8685309 TI - Morbidity and injury recurrence in victims of firearm injuries. AB - Civilian violence has become an increasing problem in the industrial world. Gunshot wounds, fatal or non-fatal, are often considered as acute trauma episodes. However, our previous study, based on 820 firearm injuries, showed that this group of patients was characterized by a high mortality rate and a pronounced involvement in criminality when compared to a control group. The aim of this study was to determine the general morbidity in the same group of firearm victims. Our hypotheses were that these patients consume a considerable amount of hospital care due to recurring trauma episodes and that their general morbidity is raised. Information was collected concerning all episodes of in-patient care for victims of firearm injuries from 1972-1992 in Stockholm, Sweden. The victims were compared with a sex- and age-matched control group. During the study period, 69.9% of the 820 firearm victims were treated for other reasons than gunshot injuries, compared to 45.5% of the 820 controls. The former group was hospitalized 3,703 times and the latter on 1,512 occasions. The firearm injury group showed an higher morbidity in almost all diagnostic subgroups according to ICD-9. The trauma recurrence rate was high and suicide, homicide and assault were relatively more common in this group. We suggest that the gunshot episode may be regarded as one expression of a "chronic trauma syndrome'. Patients exhibiting this "syndrome' are characterized by recurrent episodes of trauma, a risk-taking and destructive behavior, high morbidity and mortality as well as anti-social traits. Medical, social and legal complications are common making these patients extremely costly for society and their identification a matter of concern. It is probable that this "syndrome' also exists in other groups of trauma patients. Since hospitalization affords a unique opportunity of reaching patients who have a "chronic trauma syndrome' risk profile, we believe, that these patients should not only be treated for their acute injuries, but that they should be offered help in order to change their destructive life-style. Research should be undertaken to evaluate whether an intervention program, such as counseling, could have an effect on morbidity and injury recurrence for these patients. PMID- 8685310 TI - Role of primary care physicians in the care of epileptic patients. AB - OBJECTIVES: To assess the utilization and efficiency of the primary health care (PHC) centres in the delivery of care to epileptic patients. DESIGN: Sixty health centres were randomly selected to represent various socioeconomic classes and urban/ rural population in Riyadh. The study was conducted during August 1993. A predesigned data form was used to ascertain socio-demographic characteristics of patients, clinical features, health centre profile and health care resources available to epileptic patients. PHC doctors completed these forms for all epileptic patients found in their health centre register which entered in PC computer for analysis. RESULTS: At the end of the study, 131 epileptic patients were found in the health centre register which accounted for 0.05% (0.03% in urban and 0.1% in rural). The majority of patients 80.2% were 30 years old or below. Out of all patients 77.1% attended health centres for up to six times. At least one referral to hospital or admission were recorded in 53.4% and 20.6% of patients respectively. PHC doctors thought that 31.3% were not compliant. Family history of epilepsy was positive in 12.9% of patients. CONCLUSION: The number of epileptic patients registered as epileptic at health centres were too low. There is a need to design a policy for detection of cases, training of PHC doctors and cost effective mobilization of resources to PHC centres so to attract more epileptic patients to use the health centres. PMID- 8685311 TI - Comparison of cancer deaths in England and Wales and the developed world by age and gender 1973-92, and, new malignancies in England and Wales 1971-88. AB - Cancer deaths in England and Wales and the developed world were examined by age and gender between 1973-1992. Whilst over-all mortality levels increased, this was mainly linked to extended longevity, as the rate fell substantially for people under 55 in the majority of countries, possibly as a result of improved treatment and prevention outcomes. Whilst England and Wales had above average reductions in cancer deaths, especially for children, there were considerable rises in new malignancies, 1971-88, particularly amongst women under 35 years, and in certain selected sites. These over-all changes do not appear to be the result of improved diagnosis, thus, despite evidence of more effective therapeutic and preventative measures the incidence of new malignancies is increasing. The possible implications are briefly discussed, in the context of "medical audit', which increasing uses mortality rates as "indicators of effectiveness'. PMID- 8685312 TI - Has general practice fundholding been good for patients? AB - This article discusses some of the advantages and drawbacks of GP fundholding from both the patient's and a population point of view. An equitable division of resources should be a major priority of the health service. Evidence to date suggests that there are problems with fundholding. These require evaluation in order to build on the successes and improve in areas of controversy. PMID- 8685313 TI - Dissemination of the work of public health medicine trainees in peer-reviewed publications: an unfulfilled potential. AB - OBJECTIVE: To assess the extent to which work undertaken during training in public health medicine was formally disseminated in peer-reviewed publications. SETTING: An English Health Region. METHODS: A postal questionnaire survey of former and current senior trainees. RESULTS: The response rate was 75% (38/51). Thirty per cent (11/37) had no publications arising from any work undertaken during training and specifically 49% (18/37) had no publications arising from submissions made for the Part II examination for Membership of the Faculty of Public Health Medicine. Major perceived barriers to publication were: lack of priority accorded to publication by the training department; lack of time and lack of a supervisor or mentor to facilitate preparation of material. CONCLUSIONS: Overcoming these perceived barriers will require action at trainee, trainer and organisational level. Skills training in writing could be included in academic courses and publication could be identified as a training goal for appropriate pieces of work. Health authorities could be more active in encouraging publication of work undertaken by trainees on their behalf. PMID- 8685314 TI - Age and sex differences in the management of ischaemic heart disease. AB - OBJECTIVE: To investigate age and sex differences in the utilisation of hospital services for ischaemic heart disease. DESIGN: Analysis of routine mortality data and hospital activity data. SETTING: South West Thames Regional Health Authority. SUBJECTS: Residents of the South West Thames Regional Health Authority who in 1991 either died from ischaemic heart disease or were admitted to an NHS hospital in England and Wales with a main diagnosis of ischaemic heart disease. MAIN OUTCOME MEASURES: Ratio of consultant episodes to deaths from ischaemic heart disease (as a proxy measure of the utilisation of hospital care), and the percentages of consultant episodes in which further investigation (angiography or catheterisation) or revascularisation treatment (coronary artery bypass grafting or angioplasty) were carried out. RESULTS: The ratio of episodes to deaths was similar in men and women (odds ratio for men vs. women 0.96, 95% confidence intervals 0.90 to 1.03). The percentage of episodes in which further investigation was carried out was higher in men than women (odds ratio for men vs. women 1.46, 95% confidence intervals 1.25 to 1.70) as was the percentage of episodes in which revascularisation treatment was carried out (odds ratio for men vs. women 1.46, 95% confidence intervals 1.20 to 1.77). The ratio of episodes to deaths, the percentage of episodes in which further investigation was carried out, and the percentage of episodes in which revascularisation treatment was carried out all declined with age (all p values < 0.001). CONCLUSIONS: Women with ischaemic heart disease are as likely as men to be admitted to hospital, but after admission are less likely to undergo further investigation and revascularisation treatment. Elderly patients with ischaemic heart disease are less likely than younger patients to be admitted to hospital; after admission, they are also less likely to undergo further investigation and revascularisation treatment. Further research is needed to determine whether these age and sex differences in the use of hospital services are clinically justified. PMID- 8685315 TI - Selective use of radiographic low-osmolality contrast media in the 1990s. PMID- 8685316 TI - Volumetric analysis of volumetric data: achieving a paradigm shift. PMID- 8685317 TI - Tethered cord and associated anomalies in children and infants with imperforate anus: evaluation with MR imaging and plain radiography. PMID- 8685318 TI - Whither thou goest, magnetization transfer? PMID- 8685319 TI - Deep venous thrombosis: one leg or both legs? PMID- 8685320 TI - Role of the imaging specialist in the detection of opportunistic infection after lung transplantation: are we out of the loop? PMID- 8685321 TI - Glossary of terms for CT of the lungs: recommendations of the Nomenclature Committee of the Fleischner Society. PMID- 8685323 TI - Diffuse lung disease: assessment with helical CT--preliminary observations of the role of maximum and minimum intensity projection images. AB - PURPOSE: To evaluate assessment of diffuse lung disease with helical computed tomography (CT) and maximum intensity projection (MIP) and minimum intensity projection images. MATERIALS AND METHODS: Six patients with suspected lung disease (the control group) and 20 patients with documented disease underwent axial helical CT through the upper and lower lung fields. Findings on the MIP and minimum intensity projection images of each helical data set were compared with findings on the thin-section scan obtained at the midplane of the series. RESULTS: Owing to markedly improved visualization of peripheral pulmonary vessels (n = 26) and improved spatial orientation, MIP images were superior to helical scans to help identify pulmonary nodules and characterize them as peribronchovascular (n = 2) or centrilobular (n = 7). Minimum intensity projection images were more accurate than thin-section scans to help identify lumina of central airways (n = 23) and define abnormal low (n = 15) and high (ground-glass) (n = 8) lung attenuation. Conventional thin-section scans depicted fine linear structures more clearly than either MIP or minimum intensity projection images, including the walls of peripheral, dilated airways (n = 3) and interlobular septa (n = 3). MIP and minimum intensity projection images added additional diagnostic findings to those on thin-section scans in 13 (65%) of 20 cases. CONCLUSION: MIP and minimum intensity projection images of helical data sets may help diagnosis of a wide spectrum of diffuse lung diseases. PMID- 8685322 TI - Diffuse infiltrative lung disease: clinical value of sliding-thin-slab maximum intensity projection CT scans in the detection of mild micronodular patterns. AB - PURPOSE: To evaluate sliding-thin-slab maximum intensity projection (MIP) reconstructions in the assessment of micronodular patterns of low profusion in diffuse infiltrative lung disease. MATERIALS AND METHODS: Eighty-one adult patients (mean age, 48 years) with suspicion of pneumo-coniosis (n = 25), sarcoidosis (n = 19), smoker bronchiolitis (n = 17), and bronchiolitis of miscellaneous causes (n = 20) underwent 1- and 8-mm-thick conventional computed tomography (CT) and focal spiral CT with generation of 3-, 5- and 8-mm-thick MIP reconstructions. The presence and characterization of micronodular infiltration were analyzed on the two sets of conventional CT scans and on the three sets of MIPs. RESULTS: When conventional CT findings were normal (n = 18 [22%]), MIPs did not demonstrate additional abnormalities. When conventional CT findings were inconclusive (n = 17 [21%]), MIPs enabled detection of micronodules that involved less than 25% of the lung surface. When conventional CT scans depicted micronodules (n = 46 [57%]), MIPs showed the profusion and distribution of micronodules and associated bronchiolar abnormalities better. The sensitivity of MIP (3-mm-thick MIP, 94%; 5-mm-thick MIP, 100%; 8-mm-thick MIP, 92%) was significantly higher than that of conventional CT (8 mm thick, 57%; 1 mm thick, 73%) in the detection of micronodules (P < .001). CONCLUSION: Sliding-thin-slab MIP helps detect mild forms of micronodular infiltration and should be considered a valuable additional tool in the evaluation of diffuse infiltrative lung diseases. PMID- 8685324 TI - Opportunistic bronchopulmonary infections after lung transplantation: clinical and radiographic findings. AB - PURPOSE: To assess clinical and radiographic findings in opportunistic bronchopulmonary infections after lung transplantation. MATERIALS AND METHODS: Forty-five episodes of opportunistic bronchopulmonary infection occurred in 27 (35%) of 77 lung transplant recipients during a 4-year period. Causative organisms, radiographic patterns, and mortality were reviewed. RESULTS: Cytomegalovirus (CMV) was the most common pathogen (25 episodes), followed by Aspergillus species (seven episodes), Pneumocystis carinii (six episodes), herpes simplex virus (four episodes), Mycobacterium avium complex (two episodes), and M tuberculosis (one episode). Eighteen of the 25 episodes (72%) of CMV pneumonitis occurred in the first 4 months after transplantation; 24 (96%) occurred within the 1st year. Radiographic patterns of symptomatic CMV pneumonitis were diffuse haziness (60%), focal haziness (33%), and focal consolidation (7%). Aspergillus species locally invaded a necrotic bronchial anastomosis in three patients, each within 4 months of transplantation. P carinii was seen as focal haziness and caused no symptoms. Radiographic findings, when present, were seen almost exclusively in the transplanted lung. Despite three deaths attributable to opportunistic bronchopulmonary infection, the difference between the survival rates of patients with and those of patients without bronchopulmonary infection was not statistically significant (82% and 81%, respectively, 1 year after transplantation). CONCLUSION: Opportunistic bronchopulmonary infections are common after lung transplantation. The most common pathogen is CMV, which causes diverse chest radiographic patterns. Opportunistic bronchopulmonary infections do not adversely affect overall mortality. PMID- 8685325 TI - Positive predictive value of breast biopsy performed as a result of mammography: there is no abrupt change at age 50 years. AB - PURPOSE: To determine if the positive predictive value (PPV) of a biopsy initiated because of an abnormal mammogram changes abruptly at age 50 years. MATERIALS AND METHODS: The PPV and its variation with age was analyzed for 4,778 women who underwent biopsy for a clinically occult abnormality detected at mammography. The relationship of the results to the patient's age was analyzed with age represented as a continuous and two-categorized (< 50, > 50) measure. The latter measure represented an abrupt change, which distinguished those aged 49 years and younger from those aged 50 years and over. With this measure, the patients in each of the two age groups were statistically indistinguishable. RESULTS: The results were consistent with a steady increase in PPV and the yield of cancers with age, and there was no abrupt change at age 50 years. The modeled PPV for all cancers for these 4,778 patients was approximately 12% for women aged 40 years and increased to 46% by age 79 years. CONCLUSION: The PPV did not change abruptly at any age for women aged 40-79 years but increased steadily, which reflects the prior probability of breast cancer at each age. Inappropriate grouping of data can lead to misinterpretation of results. Screening guidelines should not be predicated on the false assumption that this variable changes at age 50 years. PMID- 8685326 TI - Microcalcifications in breast core biopsy specimens: disappearance at radiography after storage in formaldehyde. AB - PURPOSE: To determine whether radiographically proved calcifications in core biopsy specimens are better preserved in a nonaqueous fixative than in aqueous solutions. MATERIALS AND METHODS: One hundred fifty core biopsy specimens were taken from two female breast specimens that had been preserved in ethanol. Forty one of the specimens with radiographically proved microcalcifications were divided into four groups and deposited in four different solutions: 10% formaldehyde, 0.9% sodium chloride, electrolyte solution, and 74.1% ethanol with 10% 2-propanol. The core specimens were radiographed again after 1 and 3 days. Five ethanol-preserved specimens were also reexamined radiographically after 2 weeks. RESULTS: Within 3 days, total radiographic disappearance of microcalcifications was observed in all core biopsy specimens that were immersed in solutions with high water content. In those core specimens preserved in ethanol, microcalcifications showed no change. CONCLUSION: A nonaqueous fixative, such as ethanol, is a better preservative of microcalcifications in breast core biopsy specimens than various aqueous solutions, possibly because calcium compounds are water-soluble. PMID- 8685327 TI - Large-core biopsy guns: comparison for yield of breast tissue. AB - PURPOSE: To compare seven large-core, long-throw, 14-gauge biopsy guns for yield and quality of breast tissue obtained. MATERIALS AND METHODS: A two-phase, randomized and blinded study was performed. In the first phase, four fully automated 14-gauge biopsy guns (BIP, Manan, Biopsy, and ASAP) and one semiautomated device (Temno) were used to obtain breast cores from a cadaver. Samples were assessed for volume, number of fragments, and crush artifact. In the second phase, seven biopsy guns (previously mentioned guns plus Monopty and Ultra Cut guns) were used to obtain cores from a breast parenchyma model. These cores were then evaluated for weight, volume, and number of fragments. RESULTS: The mean specimen volume of cadaveric breast tissue obtained was 17.9 mm3 for the BIP gun, 17.8 for the Manan gun, 14.9 for the Biopsy gun, 14.1 for the ASAP gun, and 9.9 for the Temno gun. The Temno gun obtained statistically significantly smaller volumes than all other guns. For the breast parenchyma model, mean obtained volumes were 24.5, 24.1, 16.2, 21.7, 17.5, 20.0, and 15.2 mm3, respectively. The BIP and Manan guns yielded statistically significantly larger cores than all other guns except the ASAP. CONCLUSION: Yields of breast tissue provided by each biopsy device differed statistically significantly. BIP and Manan biopsy guns yielded the greatest volume of core tissue, which may facilitate histopathologic diagnosis from breast biopsies performed with imaging guidance. PMID- 8685328 TI - Spin lock and magnetization transfer imaging of head and neck tumors. AB - PURPOSE: To evaluate and compare the spin lock and magnetization transfer techniques in the differentiation of benign and malignant head and neck tumors at magnetic resonance (MR) imaging. MATERIALS AND METHODS: Forty consecutive patients with histologically verified head and neck tumors (20 malignant and 20 benign tumors, including five infections) were studied with a 0.1-T MR unit. The spin lock and magnetization transfer effects were defined as 1-(signal intensity with stronger preparation pulse/signal intensity with weaker preparation pulse). RESULTS: A strong correlation between the spin lock and magnetization transfer effects was found (r = 85, P < .001). With a spin lock effect of 0.48 and a magnetization transfer effect of 0.32 as the thresholds, sensitivity for detecting a malignant tumor was 95% and 94%, respectively, and specificity was 60% and 65%. CONCLUSION: Low spin lock and magnetization transfer effects are characteristic of benign tumors. High spin lock and magnetization transfer effects were associated with malignancy, but there were overlapping values for salivary gland infections, some benign tumors, and malignancies. The spin lock technique seems to be an effective method for generating magnetization transfer based contrast in the head and neck tumors. PMID- 8685329 TI - Tethered cord and associated vertebral anomalies in children and infants with imperforate anus: evaluation with MR imaging and plain radiography. AB - PURPOSE: To evaluate in children and infants with imperforate anus the prevalence and types of occult myelodysplasia that may result in tethered cord and the association of these lesions with vertebral anomalies. MATERIALS AND METHODS: Records and images were retrospectively reviewed in 86 patients who underwent spine magnetic resonance imaging and had either low-level imperforate anus (n = 30), intermediate-level imperforate anus (n = 15), or high-level imperforate anus (n = 41). RESULTS: Thirty-one of 86 patients (36%) had occult myelodysplasia suggestive of tethered cord (27% of all patients with low-, 33% of all patients with intermediate-, and 44% of all patients with high-level lesions). Of these 31 patients, 16(52%) were asymptomatic, 24, (77%) had a thickened fatty filum, 13 (42%) had normal conus position, and 23 (74%) had vertebral anomalies. Twenty four of the 31 patients (77%) underwent surgical untethering. CONCLUSION: A substantial number of patients with all types of imperforate anus have occult myelodysplasia that may necessitate surgical intervention, including those patients with normal spine radiographs. PMID- 8685330 TI - Diagnostic value of spinal US: comparative study with MR imaging in pediatric patients. AB - PURPOSE: To assess the diagnostic value of spinal ultrasonography (US) in pediatric patients. MATERIALS AND METHODS: The findings on 38 spinal US scans in 30 patients (mean age, 5.5 months) were compared with those of corresponding magnetic resonance (MR) images. RESULTS: MR imaging showed a normal spinal canal in 14 of 38 examinations, a congenital anomaly in 22, and a neoplasm in two. In 32 of 38 examinations, US allowed exactly the same diagnosis as MR imaging. In five examinations, US depicted the main abnormality, but MR imaging revealed additional findings. In one examination, no consensus was achieved. Whenever US scans were normal, MR images also did not depict any spinal disorder. In all 24 examinations with abnormal MR findings, US enabled detection of the abnormality. CONCLUSION: Spinal US seems to represent a valuable diagnostic tool for congenital anomalies of the lower spine in infants and is recommended as the primary imaging modality in those patients. PMID- 8685331 TI - Normal gyration and sulcation in preterm and term neonates: appearance on MR images. AB - PURPOSE: To provide a practical standard for normal development of gyri and sulci in preterm and term neonates. MATERIALS AND METHODS: Thirty-nine living preterm infants without substantial neurologic problems underwent magnetic resonance (MR) imaging of the brain. Five infants who were born at term but died of a nonneurologic disorder within 1 week and who underwent autopsy were examined after death with MR imaging. Seven cerebral surface areas were defined, and the development of gyri and sulci in each area was assigned a score between 1 and 5. RESULTS: The postconceptional age (PCA) range of the newborns was 30-42 weeks. When the gyral development scores were assessed as a function of PCA, four transition points could be discerned for the brain as a whole; these transitions occurred at PCAs of 32, 34, 37, and 40 1/2-41 weeks. These four transition points allowed the general gyral development to be divided into five stages. Development of gyri and sulci was most advanced in the area of the central sulcus and the medical occipital area. Development was latest in the frontobasal and frontopolar areas and the anterior part of the temporal lobe. CONCLUSION: A simple staging system allows easy assessment of the progress of cerebral gyration and sulcation in preterm and term infants. PMID- 8685332 TI - Dacron-covered stent-grafts for the percutaneous treatment of carotid aneurysms: effectiveness and biocompatibility--experimental study in swine. AB - PURPOSE: To evaluate the short-term effectiveness and biocompatibility of Dacron covered stent-grafts for percutaneous treatment of carotid aneurysms. MATERIALS AND METHODS: In eight swine, nine aneurysms were created surgically in the common carotid artery. Percutaneous treatment was performed with Dacron-covered stent grafts. Seven of eight swine underwent follow-up angiography at 2, 3, 4, and 5 weeks after stent implantation. Histologic examinations of tissue from the site of stent implantation were performed at the same intervals. RESULTS: Initial closing off of the aneurysm was possible in all swine. Angiographic follow-up revealed patency of only one Dacron-covered stent-graft after 2 weeks. In six of seven swine, the stent was occluded on the follow-up angiogram. One of the swine died of unclear cause after 1 week. The stent-graft of this swine was not occluded. In all Dacron-covered stent-grafts, inflammatory reaction with granulocyte infiltration was found next to the Dacron material. CONCLUSION: Primary treatment of carotid aneurysms with Dacron-covered stent-grafts is effective. However, the short-term patency rate is poor, which probably can be attributed to the limited biocompatibility of the Dacron cover. An acute inflammatory reaction against Dacron seems responsible for the poor patency rate. PMID- 8685333 TI - Optimization of parameters for the detection of cerebral aneurysms: CT angiography of a model. AB - PURPOSE: To optimize parameters with computed tomographic angiography for the detection of cerebral aneurysms. MATERIALS AND METHODS: Model aneurysms were placed randomly at various branch points and scanned multiple times with spiral technique. The final analysis included 63 branch points and 22 aneurysms. Each spiral scan used a different parameter combination. Collimation ranged from 1.5 to 4.0 mm and pitch ranged from 1:1 to 1.5:1. Images were constructed with shaded surface display (SSD) and maximum intensity projection (MIP) algorithms and were interpreted by three readers for the presence or absence of aneurysm. RESULTS: The receiver operating characteristic (ROC) curve area for 1.5-mm collimation was greater than those of 3- or 4-mm collimation (P < .01 and P < .001, respectively). There was no statistically significant difference in the ROC curve areas between 3- and 4-mm collimation (P = .37). There was no statistically significant decrease in ROC curve area when increasing pitch from 1:1 to 1.5:1 for any value of collimation (P = .96). For all parameter combinations the ROC curve areas for SSD images was greater than that of MIP images (P < .0001). CONCLUSION: For cerebral aneurysm detection, narrow collimation is superior to wider collimation. Mild increases in pitch do not substantially degrade diagnostic accuracy. SSD offers improved diagnostic accuracy over MIP display in this model. PMID- 8685334 TI - Do iodinated contrast media increase serum potassium levels? AB - PURPOSE: To test the hypothesis that iodinated contrast media may induce an elevation in serum potassium level. MATERIALS AND METHODS: Protocol A: After intravenous infusion of contrast media into six rabbits, alterations of potassium ion concentrations were measured. Protocol B: Fresh rabbit blood was mixed in vitro with contrast media, and the fluctuations in potassium were monitored over a 30-minute period. Protocol C: Similar to protocol B, except that blood from humans with no reaction to contrast media was used. RESULTS: For protocol A, blood potassium levels increased above baseline levels. The elevations were statistically significant (P < .05). For protocol B, diatrizoate and ioxaglate caused a gradual increase in blood potassium levels, but iopamidol did not. In protocol C, all three contrast media caused statistically significant elevation in potassium levels. The release of potassium was statistically significant at 5 minutes (P < .05 for diatrizoate and ioxaglate, and P < .01 for iopamidol). The mean release rates (+/- standard deviation) by means of linear regression analysis were 0.0190 mmol/min +/- 0.0112 with diatrizoate, 0.0159 mmol/min +/- 0.0057 with iopamidol, and 0.0088 mmol/min +/- 0.0033 with ioxaglate. CONCLUSION: Iodinated contrast media increase blood potassium levels causing release of potassium into intravascular spaces. This potassium release may play some role in contrast medium-induced adverse reactions. PMID- 8685335 TI - Traumatic aortic injury: diagnosis with contrast-enhanced thoracic CT--five-year experience at a major trauma center. AB - PURPOSE: To review the literature and the authors' experience with admission contrast material-enhanced computed tomography (CT) in patients admitted after blunt trauma. MATERIALS AND METHODS: From January 1990 to December 1994, thoracic CT was performed to evaluate traumatic aortic injury in 677 patients with positive or equivocal findings at chest radiography. CT scans positive for mediastinal hemorrhage or aortic injury were retrospectively reviewed and interpreted by consensus, with angiographic and surgical confirmation. RESULTS: CT findings were negative for TAI in 570 (84%) of the 677 patients. Mediastinal hemorrhage was reported in 100 patients and was the only abnormality in 79 of them. Findings at angiography were negative for traumatic aortic injury in 77 (97%). CT signs of traumatic aortic injury in 21 patients included contour abnormality or pseudoaneurysm (n = 19), intimal flap(s) (n = 8), and pseudocoarctation (n = 3). Findings at angiography were positive for traumatic aortic injury in 19 (90%). For aortic injury and mediastinal hemorrhage, respectively, specificity for traumatic aortic injury was 99% and 87% and sensitivity was 90% and 100%; at meta-analysis of data from the authors and the literature, sensitivity was 97.0% and 99.3% and specificity was 99.8% and 87.1%. Reliance on findings at admission CT rather than radiography to indicate suspicion for traumatic aortic injury before angiography resulted in savings of more than $365,000. CONCLUSION: The CT finding of mediastinal hemorrhage alone is sensitive for traumatic aortic injury, but the finding of aortic injury is more specific. PMID- 8685336 TI - Deep venous thrombosis of the lower extremity: efficacy of spiral CT venography compared with conventional venography in diagnosis. AB - PURPOSE: To compare the efficacy of spiral computed tomographic (CT) venography with conventional venography in the diagnosis of suspected deep venous thrombosis (DVT). MATERIALS AND METHODS: In a prospective study, 52 consecutive patients with clinically suspected unilateral or bilateral DVT were studied with CT venography and conventional venography. In cases in which conventional venographic findings were inconclusive, color-coded duplex sonography and follow up examinations were performed to make a final diagnosis. CT venography of both extremities covered a 100-cm section from the ankle to the inferior vena cava (IVC). Contrast material diluted with saline was injected in a dorsal vein of each foot. CT and conventional venography (including color-coded duplex sonography and follow-up findings) were correlated for three venous regions for each patient. RESULTS: Correlation was excellent between CT and conventional venographic findings in the detection of DVT. The sensitivity of CT venography was 100% (confidence interval: 0.92, 1.00), specificity was 96% (confidence interval: 0.84, 0.98), positive predictive value was 91%, and negative predictive value was 100%. CT venography more clearly demonstrated thrombus extension of DVT into the pelvic veins and IVC than conventional venography alone. CONCLUSION: CT venography is a valuable tool in the diagnosis of DVT. Compared with conventional venography, CT requires use of 80% less contrast material. PMID- 8685337 TI - Suspected deep venous thrombosis: is US of both legs necessary? [ comment]. AB - PURPOSE: The first purpose was to test the assumption that ultrasound (US) examination of the asymptomatic leg was unnecessary. The second was to confirm the absence of deep venous thrombosis (DVT) in patients with bilateral symptoms. MATERIALS AND METHODS: Four hundred eighty-eight patients were evaluated at a peripheral vascular laboratory for signs and symptoms of DVT. All patients then underwent bilateral color Doppler US of their leg veins. RESULTS: Ninety-four patients had no lower extremity symptoms. Of these, 73 had no DVT, 11 had unilateral DVT, and 10 had bilateral DVT. Of 245 patients with unilateral symptoms, 180 had no DVT, 44 had ipsilateral DVT, three had contralateral DVT, and 18 had bilateral DVT. Of 149 patients with bilateral symptoms, 114 had no DVT, 10 had unilateral DVT, and 25 had bilateral DVT. CONCLUSION: The frequent finding of bilateral DVT and unsuspected contralateral DVT in patients with unilateral symptoms, and the even more frequent finding of DVT in patients with bilateral symptoms, clearly indicates that both categories of patients need to be evaluated with bilateral US. PMID- 8685338 TI - Recurrent angina pectoris in patients with internal mammary artery to coronary artery bypass: treatment with coil embolization of unligated side branches. AB - PURPOSE: The purpose of the study was to evaluate the effect on the symptoms of transcatheter coil embolization of branches of the internal mammary artery. MATERIALS AND METHODS: In five patients with coronary steal syndrome that was caused by preferential flow in large unligated side branches of the internal mammary artery, coil embolization of the side branches was performed with use of a coaxial microcatheter. RESULTS: Anginal symptoms disappeared in three patients and were substantially reduced in one patient following the radiologic intervention. In the fifth patient, who had concomitant stenoses of other coronary vessels, only a moderate change in symptoms was noted. No complications occurred. CONCLUSION: In patients with internal mammary artery to coronary artery bypass who experience recurrent angina pectoris caused by preferential flow in large, unligated side branches of the internal mammary artery, repeat surgery may be circumvented or simplified by transcatheter coil embolization, which can help treat the angina. PMID- 8685339 TI - Benign biliary obstruction: is treatment with the Wallstent advisable? AB - PURPOSE: To evaluate the effectiveness of the self-expanding Wallstent in the treatment of benign biliary strictures. MATERIALS AND METHODS: Twenty patients with benign biliary strictures were included in this retrospective study. Seven patients had chronic pancreatitis, two had fibrous papillary stenosis, one had primary sclerosing cholangitis, and 10 had postsurgical strictures, including four who had a stenosed bilidigestive anastomosis. Primary and secondary patency of the stents and clinical outcome after stent insertion were evaluated. RESULTS: Stent placement was successful in all patients. At the end of the observation period, which lasted 3-78 months (mean, 31.2 months +/- 4.5 [standard error]), 10 patients were alive. Median primary patency was 32 months +/- 8.7. In 10 patients, patency was preserved during the observation period (two with secondary patency). Six patients had a good clinical result. Among the other four patients, one had recurrent cholangitis, one had a biliary abscess, and two had stent revisions. In the other patients, stents became occluded after 3-55 months. The reason for stent occlusion was a stone in one patient; in the others, the causes were not proved. CONCLUSION: Results of stent placement for treatment of benign biliary strictures are not encouraging. However, the patient population is too limited to allow final conclusions. PMID- 8685340 TI - CT and MR imaging in the staging of colorectal carcinoma: report of the Radiology Diagnostic Oncology Group II. AB - PURPOSE: To prospectively evaluate the relative accuracy of computed tomography (CT) and magnetic resonance (MR) imaging in the staging of colorectal carcinoma. MATERIALS AND METHODS: CT and MR studies were independently interpreted in a group of 478 patients with colorectal carcinoma in a study conducted from 1989 to 1993. The accuracy of each modality was assessed in a subset of 365 patients with primary tumors with respect to staging of local extent of tumor, status of local regional lymph nodes, and the presence of liver metastases. RESULTS: In the staging of local extent of tumor, CT is more accurate than MR imaging, particularly in the definition of penetration of the muscularis propria by rectal cancer (74% vs 58%). Accuracies of CT and MR imaging were equivalent in depiction of transmural extent in colon cancers. CT and MR imaging exhibited accuracies of 62% and 64% in assessment of lymph node involvement with sensitivities of 48% and 22%, respectively. The accuracy of MR imaging and of CT (85% for each) are better for evaluation of liver metastases; lower sensitivities (62% and 70%, respectively) than specificities (97% and 94%, respectively) were demonstrated for both modalities. CONCLUSION: CT was more accurate than MR imaging in detection and characterization of transmural penetration of rectal tumors. Recent technologic advances in MR imaging may affect these results. PMID- 8685341 TI - Dynamic contrast-enhanced subtraction versus T2-weighted spin-echo MR imaging in the follow-up of colorectal neoplasm: a prospective study of 41 patients. AB - PURPOSE: To compare dynamic contrast-enhanced subtraction (DCES) and T2-weighted spin-echo (SE) magnetic resonance (MR) imaging in the differentiation of fibrosis from recurrence during the follow-up of treated colorectal neoplasms. MATERIALS AND METHODS: Forty-one patients with 39 malignant and 16 benign lesions confirmed by means of surgery (n = 23), biopsy (n = 24), or 12-month follow-up examination (n = 8) underwent DCES MR imaging and T2-weighted SE MR imaging. Enhancement of an abnormal pelvic structure within the first 90 seconds on DCES images or high signal intensity on T2-weighted SE images was considered indicative of malignancy. RESULTS: Sensitivity, specificity, and positive and negative predictive values were, respectively, 97%, 81%, 93%, and 100% for DCES MR imaging and 77%, 56%, 81%, and 56% for T2-weighted MR imaging. The number of correctly classified lesions was significantly higher with DCES imaging compared with T2 weighted imaging (P < or = .006). CONCLUSION: DCES imaging is more accurate than T2-weighted SE imaging for differentiating fibrosis from recurrence during the follow-up of treated colorectal neoplasms. PMID- 8685342 TI - Liver masses: replacement of conventional T2-weighted spin-echo MR imaging with breath-hold MR imaging. AB - PURPOSE: To evaluate breath-hold magnetic resonance (MR) imaging with single-shot and multishot T2-weighted fast spin-echo (SE) and inversion-recovery (IR) SE echo planar (EP) SE (IR-SE-EP) sequences compared with conventional T2-weighted SE imaging for detection of liver masses. MATERIALS AND METHODS: Imaging with all sequences was performed in 32 patients on a 1.5-T whole-body system. Images were compared on the basis of lesion-to-liver contrast-to-noise ratio (C/N), lesion conspicuity, and image quality. Image analysis was performed by two experienced radiologists in consensus. RESULTS: Lesion-to-liver C/Ns were highest on fat suppressed-half-Fourier-single-shot-fast-SE images. For solid lesions, the lesion to-liver C/Ns were highest with IR-fast-SE, which was significantly better (P < .05) than IR-SE-EP and conventional SE techniques and also produced the best image quality. Sensitivity with IR-fast-SE was 96%; with fat-suppressed-half Fourier-single-shot-fast-SE, 92%; with fat-suppressed-fast-SE, 89%; with IR-SE EP, 83%; and with conventional SE, 78%. CONCLUSION: T2-weighted breath-hold imaging, particularly IR-fast-SE imaging, was more sensitive for hepatic masses than conventional SE imaging, with a substantial reduction in acquisition time. Half-Fourier-single-shot-fast-SE imaging was especially useful in patients who were unable to hold their breath. PMID- 8685343 TI - Focal liver disease: comparison of breath-hold T1-weighted MP-GRE MR imaging and contrast-enhanced CT--lesion detection, localization, and characterization. AB - PURPOSE: To compare breath-hold T1-weighted magnetization-prepared gradient-echo (MP-GRE) magnetic resonance (MR) imaging with contrast material-enhanced computed tomography (CT) in the assessment of focal liver disease. MATERIALS AND METHODS: The MR and CT images obtained in 64 patients with focal liver disease were reviewed by six independent reviewers in a randomized, blinded fashion. Sets of axial T1-weighted MP-GRE images, three-plane (a compilation of axial, sagittal, and coronal) T1-weighted MP-GRE images, and contrast-enhanced CT scans were analyzed. T2-weighted spin-echo (SE) MR images were also compared with CT scans. RESULTS: Lesions were detected, localized, and characterized more accurately and generally with greater confidence with three-plane T1-weighted MP-GRE imaging than with CT (P < .01). Axial T1-weighted MP-GRE imaging was also superior (P < .05) to CT (although slightly less superior than three-plane imaging) except in the characterization of specific lesions, where both techniques were equal. T2 weighted SE MR imaging and CT were about equal. CONCLUSION: Lesion detection, localization, and characterization are performed more accurately and confidently with breath-hold T1-weighted MP-GRE imaging than with contrast-enhanced CT, particularly when breath-hold images are obtained in three planes. PMID- 8685344 TI - Fistula in ano: endoanal sonography versus endoanal MR imaging in classification. AB - PURPOSE: To assess agreement between endoanal sonography, endoanal magnetic resonance (MR) imaging, and surgery in depiction and classification of fistula in ano. MATERIALS AND METHODS: Twenty-eight consecutive patients with nonspecific, cryptoglandular fistula in ano were studied. The fistulas were classified with endoanal sonography, endoanal MR imaging, and surgery. Agreement between the modalities was also evaluated. RESULTS: Classification of fistulas was possible in 17 of 28 patients (61%) with sonography, in 25 of 28 (89%) with MR imaging, and in 26 of 28 (93%) with surgery. Concordance between endoanal sonography and MR imaging occurred in 46% of the cases (kappa = 0.27, poor agreement); between sonography and surgery in 36% (kappa = 0.09, no agreement); and between MR imaging and surgery in 64% (kappa = 0.43, moderate agreement). CONCLUSION: Endoanal MR imaging more accurately allows depiction and classification of fistula in ano than endoanal sonography. PMID- 8685345 TI - Benign and malignant gynecologic disease: clinical importance of fluid and peritoneal enhancement in the pelvis at MR imaging. AB - PURPOSE: To correlate magnetic resonance (MR) imaging findings of pelvic fluid, peritoneal enhancement, and peritoneal nodules with the presence of benign or malignant pelvic disease. MATERIALS AND METHODS: Pelvic MR imaging findings in 87 women (mean age, 46 years) who subsequently underwent surgery were retrospectively reviewed. Phased-array multicoil, axial spin-echo T1-weighted MR images and axial fast spin-echo T2-weighted images were obtained. The largest pelvic fluid pocket was measured on the T2-weighted images in three orthogonal dimensions. Peritoneal enhancement and nodules were evaluated on gadolinium enhanced MR images in 54 women. RESULTS: Pelvic fluid was shown in 21 of 25 patients with malignant neoplasms and 48 of 62 patients with benign disorders. Larger fluid pockets were associated with malignancy rather than with benign disorders, but there was substantial overlap. Use of peritoneal enhancement to diagnose peritoneal spread of tumor had a sensitivity, specificity, accuracy, and positive predictive value of 92% (11 of 12), 86% (36 of 42), 87% (47 of 54), and 65% (11 of 17), respectively. Use of peritoneal nodules for peritoneal spread had a higher specificity (90% [38 of 42]) and positive predictive value (69% [nine of 13]), although the sensitivity was lower (75% [nine of 12]). CONCLUSION: Large peritoneal fluid pockets are moderately predictive of malignancy or peritoneal spread of tumor. Peritoneal enhancement and enhancing peritoneal nodules are more sensitive and more specific. PMID- 8685346 TI - Prostate cancer: metabolic response to cryosurgery as detected with 3D H-1 MR spectroscopic imaging. AB - PURPOSE: To determine, in patients with prostate cancer treated with cryosurgery, whether levels of choline and citrate measured at magnetic resonance (MR) spectroscopy can help discriminate regions of residual tumor from other prostatic tissues and necrosis. MATERIALS AND METHODS: Combined MR imaging and three dimensional proton spectroscopic imaging were performed in 25 patients (mean age, 69 years) with prostate cancer who underwent cryosurgery. Volume imaging and spectroscopic data were analytically corrected for the reception profile of the endorectal and pelvic phased-array coils. Spectral data were aligned with the MR imaging data and compared with serum prostate-specific antigen levels and biopsy results. RESULTS: Histologically confirmed necrotic tissue (432 voxels) did not demonstrate any observable choline or citrate. The (choline + creatine)/ citrate values in regions of histologically confirmed benign prostatic hyperplasia (0.61 +/- 0.21 [standard deviation], 52 voxels) and cancer (2.4 +/- 1.0, 65 voxels) after cryosurgery were not statistically significantly different from those before therapy but were statistically significantly different from the ratio in necrotic tissue and from each other. The (choline + creatine)/citrate images threshold and overlaid in color on T2-weighted images yielded an estimate of the spatial extent of prostate cancer and benign prostatic hyperplasia. CONCLUSION: Volume MR imaging with MR spectroscopic imaging provided a noninvasive assessment of the presence and location of residual cancer after unsuccessful therapy and helped identify successful cryosurgery in patients who still had an elevated prostate-specific antigen level. PMID- 8685347 TI - Transvaginal uterine cervical dilation with fluoroscopic guidance: preliminary results in patients with infertility. AB - PURPOSE: To assess efficacy of uterine cervical dilation performed with fluoroscopic guidance to treat patients with infertility who have cervical stenosis, false channels within the endocervical canal, or both. MATERIALS AND METHODS: Fifteen patients in whom infertility was diagnosed were referred because the uterine lumen could not be accessed. Three of the patients had endometriosis. With fluoroscopic guidance, the cervix was cannulated and the endocervical canal was dilated with an angioplasty balloon or with dilators. Five patients underwent simultaneous fallopian tube recanalization. Five of 15 patients who underwent dilation subsequently underwent in vitro fertilization for embryo transfer (IVF ET) or intrauterine insemination. RESULTS: Four patients became pregnant. Of those four, one underwent IVF-ET and one underwent intrauterine insemination. Two patients became pregnant spontaneously. In the five patients who underwent IVF-ET or intrauterine insemination and in the remaining eight patients, the cervix could be easily cannulated up to 7 months after dilation. CONCLUSION: Dilation of the uterine cervix may provide options for treatment in selected patients with infertility. The effect of dilation on patients with other sequelae of cervical obstruction such as endometriosis remains uncertain. PMID- 8685348 TI - Quantitating regrowth delay of prostate cancers after failure of radiation therapy. AB - PURPOSE: To evaluate the benefit of radiation therapy as determined by regrowth delay of prostate tumors and to identify tumor and patient characteristics associated with prolonged regrowth delay. MATERIALS AND METHODS: The records of 113 patients with prostate cancer were studied retrospectively after radiation therapy failed. Pretreatment prostate-specific antigen (PSA) levels and three or more post-failure PSA levels were obtained. The post-failure PSA doubling time was used to estimate the time until the pretreatment PSA level would be reached. The difference in time between the initiation of treatment and the return to pretreatment PSA levels is the regrowth delay. RESULTS: Regrowth delay ranged from 1 to 584 months in the 133 patients: 0-12 months (14 patients); 13-24 months (22 patients); 24-59 months (39 patients); and 60 months or more (38 patients). Gleason score was significantly correlated with interval to failure, PSA doubling time, and regrowth delay (P = .01, .04, and .02 respectively). Pretreatment PSA and clinical T stage were not statistically significantly related to regrowth delay. CONCLUSION: Regrowth delay is a clear quantitative benefit of radiation therapy to patients with incurable prostate cancer. Nearly 70% of patients realize a 2 year or greater delay in tumor progression, with 34% having a delay greater than 5 years. This observation supports continuing use of radiation therapy in prostate cancer. PMID- 8685349 TI - Imaging of osseous and cartilaginous intraarticular bodies in the knee: comparison of MR imaging and MR arthrography with CT and CT arthrography in cadavers. AB - PURPOSE: To compare magnetic resonance (MR) imaging and MR arthrography with computed tomography (CT) and CT arthrography in the detection of intraarticular bodies in the knee. MATERIALS AND METHODS: Cuboid (3- or 6-mm-long sides) osseous and cartilaginous bodies were implanted in 16 cadaveric knee specimens. MR imaging was performed with T1-weighted spin-echo (SE), T2-weighted SE, proton density-weighted SE, gradient recalled acquisition in the steady state (GRASS), and spoiled GRASS sequences. MR arthrography was performed in two phases with saline and 2 mmol/L gadopentetate dimeglumine. CT and CT arthrography were performed in the transaxial plane. RESULTS: MR arthrography yielded the highest accuracy for the detection of osseous and cartilaginous bodies combined (92%) and was significantly (P < .01) better than MR imaging (57%-70%), CT arthrography (80%), and CT (74%). Accuracy of CT arthrography was significantly better than that of MR imaging and that of CT. Accuracy of saline-enhanced MR arthrography was significantly inferior (P < .001) to that of gadolinium-enhanced MR arthrography. CONCLUSION: MR arthrography is the best imaging technique for detection of individual intraarticular bodies. CT arthrography is the second most accurate method. Spoiled GRASS and T2-weighted SE sequences are the most accurate at MR imaging. The presence of intraarticular fluid and performance of saline enhanced MR arthrography improve detectability of intraarticular bodies. PMID- 8685350 TI - Labral injuries: accuracy of detection with unenhanced MR imaging of the shoulder. AB - PURPOSE: To prospectively assess the accuracy of unenhanced magnetic resonance (MR) imaging in the detection and localization of labral injuries. MATERIALS AND METHODS: One hundred three patients with clinically suspected shoulder injuries were prospectively examined with unenhanced MR imaging. A combination of gradient echo and high-resolution fast-spin-echo axial pulse sequences were used. Surgical correlation was obtained in all patients. RESULTS: At surgery, 37 torn anterior, 36 torn superior, and 19 torn posterior labral were identified. The sensitivity for detection of these tears with MR imaging was 100%, 86%, and 74%, respectively; the specificity was 95%, 100%, and 95%, respectively. Overall, unenhanced MR imaging was 95% accurate in the detection of labral injuries. CONCLUSION: With appropriate pulse sequences, unenhanced MR imaging of the shoulder is an accurate technique for the detection and localization of labral injuries. PMID- 8685351 TI - Percutaneous vertebroplasty for osteolytic metastases and myeloma: effects of the percentage of lesion filling and the leakage of methyl methacrylate at clinical follow-up. AB - PURPOSE: To determine whether the percentage of vertebral lesion filling and the leakage of methyl methacrylate have any clinical significance at follow-up. MATERIALS AND METHODS: Forty percutaneous vertebroplasties were performed for metastases (30 cases) and myeloma (10 cases) in 37 patients. A computed tomographic scan was obtained 1-8 hours after methyl methacrylate injection and was used to assess the percentage of lesion filling by methyl methacrylate and the leakage of methyl methacrylate into the epidural tissues, neural foramina, intervertebral disks, venous plexus, and paravertebral tissue. The results were correlated with those obtained at clinical follow-up. RESULTS: Partial or complete pain relief was sustained in 36 of 37 patients. Pain relief was not proportional to the percentage of lesion filling. Clinical improvement was maintained in most patients. The 15 epidural leaks, eight intradiskal leaks, and two venous leaks of methyl methacrylate had no clinical importance. Two of eight foraminal leaks produced nerve root compression that required decompressive surgery. One of 21 paravertebral leaks produced transitory femoral neuropathy. CONCLUSION: Pain relief can occur despite insufficient lesion filling. In most patients, intradiskal and paravertebral leaks of cement had no clinical importance. PMID- 8685352 TI - MR imaging of digital mucoid cysts. AB - PURPOSE: To assess the usefulness of magnetic resonance (MR) imaging in the diagnosis and clarification of the physiopathology of digital mucoid cysts. MATERIALS AND METHODS: Twenty-three patients (14 women, nine men; aged 52-75 years) with mucoid cysts underwent MR imaging at 1.5 T with a local surface gradient coil. The pixel size was 117 microns in one direction. T2 relaxation times were measured. Contrast material was intravenously administered in 15 patients. RESULTS: All mucoid cysts had high signal intensity and sharp borders on T2-weighted images. Intracystic septa were present in nine patients (39%). Most cysts were solitary (n = 13) and/or in the proximal nail fold (n = 16). Satellite cysts were present in five patients. Nineteen patients (83%) had cysts with pedicles that extended to the joint. Osteoarthritis of the distal interphalangeal joint was present in 16 patients (70%). Five patients (22%) had multiple flattened cysts that were usually independent of the joint. In seven patients (30%), MR images showed cysts beneath the nail plate. CONCLUSION: Digital mucoid cysts may be polymorphic. MR imaging is helpful when cysts are in the nail bed. PMID- 8685354 TI - The role of radiology in the Oklahoma City bombing. AB - PURPOSE: To evaluate the role of radiologic services in the assessment of injuries and identification of deceased victims of the bombing of the Alfred P. Murrah Federal Building in Oklahoma City, Okla. MATERIALS AND METHODS: In cooperation with the Oklahoma University Health Sciences Center Disaster Studies Group, all victims of the Oklahoma City bombing who were treated in hospitals were evaluated. All radiologic studies performed in these patients during a 4 week period after the bombing were recorded. Major injuries incurred by the victims were noted but were not documented. In addition, assistance provided by radiologic services to the medical examiner's office for identification of deceased victims was assessed. RESULTS: On the day of the bombing, 99% (480 of 485) of the imaging studies performed were either plain radiography, primarily of the extremities and chest, or computed tomography (CT), half of which were of the head. Six deceased victims were identified solely by means of characteristics on radiographs. CONCLUSION: Almost all bombing-related radiologic studies were either plain radiography or CT. Other modalities had only limited roles. In deceased victims, plain radiography aided identification, and in many other victims it allowed localization of materials that were potential pieces of evidence. PMID- 8685353 TI - First-trimester nuchal translucency: a risk analysis on fetal chromosome abnormality. AB - PURPOSE: To investigate the importance of nuchal translucencies in the first trimester of pregnancy as an ultrasonographic marker for fetal chromosome abnormalities. MATERIALS AND METHODS: One hundred two first-trimester fetuses with a nuchal translucency of 3 mm or more were karyotyped. Multiple logistic regression analysis was performed to estimate the risk of fetal chromosomal abnormalities related to nuchal translucencies. RESULTS: Fifty-five (54%) of the fetuses had a normal karyotype. Forty-seven (46%) had an abnormal karyotype. The risk of chromosome abnormality was strongly increased in fetuses with a septated nuchal translucency compared with fetuses with a nonseptated nuchal translucency. CONCLUSION: First-trimester nuchal translucency is an important ultrasonographic marker for chromosomal abnormalities in the fetus. The presence of a normal karyotype in a fetus is a strong indication that detailed ultrasonographic examination for associated anomalies should be undertaken. PMID- 8685355 TI - Too many radiologists? Update. AB - In light of the growing concern that a large surplus of diagnostic radiologists is pending, the authors (a) reviewed the major projections of the surplus shortage situation made during the past quarter century and (b) semiquantitatively analyzed factors widely expected to have a substantial effect on the future situation. Projections uniformly were seriously mistaken. Some factors expected to affect the future, such as the increasing percentage of women among radiologists, are foreseeable and have small effects. However, other factors, most notably new technology, cannot be predicted, although their effects may be very large. The authors conclude that the long-term future situation is not predictable. The authors also examined steps that might be taken to reduce the supply of radiologists if a large surplus were known to be pending and antitrust prohibitions against coordinated responses were eliminated. At first, there appear to be multiple actions possible that would reduce the number of graduates of residency programs while preserving, or even enhancing, quality and equity. Closer examination, however, shows that these actions are often conflicting, sometimes not actually desirable, and generally troubled by questions of effectiveness and feasibility of implementation. Thus, even with changes in the law, the authors find no ready solutions to a possible large oversupply of radiologists. PMID- 8685356 TI - Human lung air spaces: potential for MR imaging with hyperpolarized He-3. AB - Two healthy volunteers who had inhaled approximately 0.75 L of laser-polarized helium-3 gas underwent magnetic resonance imaging at 1.5 T with fast gradient echo pulse sequences and small flip angles ( < 10 degrees). Thick-section (20 mm) coronal images, time-course data (30 images collected every 1.8 seconds), and thin-section (6 mm) images were acquired. Subjects were able to breathe the gas (12% polarization) without difficulty. Thick-section images were of good quality and had a signal-to-noise ratio (S/N) of 32:1 near the surface coil and 16:1 farther away. The time images showed regional differences, which indicated potential value for quantitation. High-resolution images showed greater detail and a S/N of approximately 6:1. PMID- 8685357 TI - Selective percutaneous transhepatic embolization of the portal vein in preparation for extensive liver resection: the ipsilateral approach. AB - The ipsilateral approach was used at preoperative portal vein embolization in 38 patients with hepatobiliary malignancy. The right anterior portal branch was punctured. Two different 5.5-F triple-lumen balloon catheters were used, and fibrin glue and iodized oil were injected. Portal vein embolization was successful in all cases (right lobe, 24 patients; left lobe and right anterior segment, six; right lobe and left medial segment, three; right posterior segment, two; right anterior segment, one; left lobe, one; and right and caudate lobes, one). PMID- 8685358 TI - CT angiography with volume rendering: advantages and applications in splanchnic vascular imaging. AB - The authors compared volume rendering with maximum intensity projection (MIP) and shaded surface display as a technique for generating three-dimensional (3D) images of the vasculature from spiral computed tomography (CT) data sets. In four patients with pathologic splanchnic vasculature, the advantages of volume rendered display are illustrated for depiction of 3D vascular anatomy, vascular and visceral interrelationships, variant vasculature, tumor encasement, and hepatic tumor localization for presurgical planning. PMID- 8685359 TI - Breath-hold, contrast-enhanced, three-dimensional MR angiography. AB - Breath-hold gadolinium-enhanced three-dimensional magnetic resonance (MR) angiography was performed with a high-performance gradient MR imaging system in 10 volunteers with no history of vascular abnormalities (breath-hold interval, 28 seconds; repetition time, 4.0 msec; echo time, 1.9 msec; 0.4 mmol gadoterate meglumin per kilogram of body weight). High-resolution three-dimensional time-of flight angiograms of the aorta, renal arteries, pulmonary arteries, pelvic arteries, and portal venous system were successfully acquired in all cases. PMID- 8685360 TI - Unusual burns of the lower extremities caused by a closed conducting loop in a patient at MR imaging. AB - An extremely rare occurrence of third-degree burns was induced in the medial calves of a male patient with unusual anatomy (after resection and radiation therapy of a liposarcoma) during conventional magnetic resonance (MR) imaging on a clinical 1.5-T MR system that operated without any external conductor present and within safe limits. A closed conducting loop was inadvertently created, which caused focal increased temperature at the junction of his calves. PMID- 8685361 TI - Aneurysm clip testing for ferromagnetic properties: clip variability issues. AB - To assess ferromagnetic properties of intracranial aneurysm clips reported to be nonferromagnetic, 1,765 Yasargil, 11 Sugita, and 15 Perneczky aneurysm clips were studied for rotation or translation on plate glass in a 1.5-T MR imager. Sixty three clips (52 Yasargil, 11 Perneczky) weakly reoriented along the static magnetic resonance (MR) field. These results confirm the need for standardized testing for ferromagnetic properties for implantable metallic devices. PMID- 8685362 TI - Pelvic abscesses: transvaginal US-guided drainage with the trocar method. AB - The effectiveness of the trocar technique of catheter placement for transvaginal sonographically guided drainage of pelvic abscess was assessed in seven women who presented with pelvic pain, fever, and presumed pelvic abscess. Endovaginal ultrasound was performed to document fluid collection before drainage. All procedures were performed in less than 1 hour, without complications. Catheters were left in place for 1-3 days. Catheter placement was curative in six of seven patients (86%). PMID- 8685363 TI - Capitated contracting in radiology. PMID- 8685364 TI - Managed care: the reality must be controlled. PMID- 8685365 TI - Future of radiology. PMID- 8685366 TI - Obtaining previous mammograms for comparison. PMID- 8685367 TI - Residual metal shavings and fragments associated with large-core breast biopsy. PMID- 8685368 TI - Cost of performing a radiologic percutaneous gastrostomy. PMID- 8685369 TI - CT evaluation of pulmonary nodule enhancement. PMID- 8685370 TI - Hepatic artery thrombosis. PMID- 8685371 TI - "Whistleblower" termination: statute of limitations. PMID- 8685372 TI - Senior Vice-President for patient care an "at-will" employee. Case in point: Duncan v. St. Joseph's Hosp. & Med. Cent. 903 P. 2d 1107--AZ (1995). PMID- 8685373 TI - Legal briefs for nurses. PA: expert testimony on care standard--OK: testimony on causation & diagnosis--NG; MO: failure to recognize complications: admissibility of nursing staff meeting minutes. PMID- 8685374 TI - 02 disconnected, pt. misplaced, notes altered & missing. Case in point: Gordon v. Willis Knighton Medical Center 661 So. 2d 991--LA (1995). PMID- 8685375 TI - [Stereochemical basis of DNA super-structure formation by transcription factors]. PMID- 8685376 TI - [On the novel differentiation-apoptosis inducers in tumor cells]. PMID- 8685377 TI - [Regulation of apoptosis by products of the bcl-2 gene family]. PMID- 8685378 TI - [Chlorophyll biogenesis]. PMID- 8685379 TI - [Bacterial chemotactic transducer-type protein family]. PMID- 8685380 TI - [Directed molecular evolution of oligonucleotides]. PMID- 8685381 TI - [High resolutional two-dimension electrophoresis of DNA: a refinement of RLGS method]. PMID- 8685383 TI - [Appropriate distance in the relationship between supervisor and candidate]. PMID- 8685382 TI - [Questions on Freudian psychoanalysis: dream interpretation, reality, fantasy]. PMID- 8685384 TI - [Evenly floating attention, models and theories of the cognitive process of the psychoanalyst]. AB - The perception process taking place in the mind of the analyst in the psycho analytic situation is a constant oscillation between the temptation to be guided too much by theory and the dangers of trusting to feelings and intuition alone. In order to avoid the pitfalls of this Scylla and Charybdis situation and with a view to reconciling empathy and knowledge in such a way as to provide optimal access to the patient's unconscious, the author draws upon a model devised by W.R. Bion. The author claims that Bion's model, an intermedium between affect and cognition, achieves the integration of evenly suspended attention and theory guided perception by taking account of patient's experiential objects while at the same time allowing scope for cognitive activity, a process which Bion calls "intervening phase" Konig then briefly recounts a case study illustrating the possibility of achieving interpretations that combine both empathy and knowledge. PMID- 8685385 TI - Dissociating face processing skills: decision about lip-read speech, expression, and identity. AB - The separability of different subcomponents of face processing has been regularly affirmed, but not always so clearly demonstrated. In particular, the ability to extract speech from faces (lip-reading) has been shown to dissociate doubly from face identification in neurological but not in other populations. In this series of experiments with undergraduates, the classification of speech sound (lip reading) from personally familiar and unfamiliar face photographs was explored using speeded manual responses. The independence of lip-reading from identity based processing was confirmed. Furthermore, the established pattern of independence of expression-matching from, and dependence of identity-matching on, face familiarity was extended to personally familiar faces and "difficult" emotion decisions. The implications of these findings are discussed. PMID- 8685387 TI - To forget or not to forget: the effect of probability of test on directed forgetting. AB - Two experiments investigated how individuals use explicit memory cues that designate different probabilities of test. As in typical directed forgetting studies, subjects received words explicitly cued as having either a 0% or a 100% chance of being on a subsequent memory test (i.e. forget and remember cues, respectively). In addition, some words were explicitly cued as having the potential to be either forgotten or remembered (i.e. a 50% cue). Recall of 50% words was between that of 0% and 100% words. In addition, the presence of 50% words lowered recall of the 100% words compared to that of a control group that did not receive 50% words, but received the same number of 100% words. A think aloud task indicated that these results were due to 50% words being treated like either 100% of 0% words at encoding. The results are discussed in terms of the effect of different probabilities of test on the strategic processing and representation of information. PMID- 8685386 TI - Recency effect in Alzheimer's disease: a reappraisal. AB - This study investigated the hypothesis that discrepant results regarding the recency effect in Alzheimer's disease (AD) patients are due to the different scoring procedures used by various authors and/or to the different number of terminal items attributed to the recency part of the curve. Our results indicate that the last two processed words are available to AD patients for recall, just as they are to controls. Words processed slightly earlier are less available to AD patients than to controls, presumably because of the accelerated forgetting rate in demented patients. PMID- 8685388 TI - An analysis of errors in the learning, overlearning, and forgetting of sequences. AB - This paper investigates the effects upon delayed recall of errors made during learning. Subjects learn a sequence of wagons in a model train over repeated presentation and test cycles. The recall of the same sequence is unexpectedly tested one week later. The results show that the errors subjects make during learning are a significant factor in predicting which elements of the sequence are forgotten. Learning is modelled by a population of discrete traces, accumulated during learning, which has two characteristics: First, many of the traces duplicate information encoded in other traces; and second, representations of the correct sequence coexist with traces containing incorrect information about the same elements of the sequence. Forgetting is modelled by the accretion of null traces that compete with correct traces of retrieval and the increasing inability with time to discriminate correct representations in memory from erroneous records. This model is shown to provide a good fit to the experimental results and suggests a strong link between the complete history of learning new material (including errors) and its subsequent likelihood of forgetting. PMID- 8685389 TI - Skilled motor performance and working memory in rowers: body patterns and spatial positions. AB - Previous studies using unfamiliar laboratory tasks (e.g. Smyth & Pendleton, 1990) have shown that working memory for movements to targets external to the body (positional movements) is dissociable from working memory for movements made to recreate specific configurations of body parts (patterned movements). In Experiment 1 this dissociation is replicated using tasks that were adapted for use in Experiment 2. In Experiment 2 the timing of experienced rowers performance of patterned and positional elements of the rowing stroke was selectively disrupted by concurrent performance of patterned and positional memory tasks, respectively. These results suggest that patterned and positional elements of well-practised everyday motor tasks, which involve a complex interaction of the two types of movement, are controlled separately and place dissociable demands on working memory. PMID- 8685390 TI - Distribution of programming in a rapid aimed sequential movement. AB - Studies indicate that rapid sequential movements are preprogrammed and that preprogramming increases with complexity, but more complex sequences that require on-line programming have been seldom been studied. The purpose of this investigation was to determine whether on-line programming occurs in a 7-target sequence in which there is a unique target constraint and if so, to determine how different task constraints affect the distribution of additional programming. Subjects contacted seven targets with a hand-held stylus as quickly as possible while maintaining a 90% hit rate. Initiation-band execution-timing patterns and movement kinematics were measured to determine when the additional programming took place. Results indicated that additional programming occurred before initiation and during movement to the first target when the constraint required more spatial accuracy (small target). A different type of unique target (a triple hit of one target) caused the additional programming to occur on-line one or two segments before its execution. Different positions of the unique target also affected timing patterns. Results were discussed in terms of: (1) capacity of processing; (2) control of movement variance; and (3) mean velocity as a programmed parameter in sequential aiming movements. PMID- 8685391 TI - Effects of irrelevant sounds on phonological coding in reading comprehension and short-term memory. AB - The effects of irrelevant sounds on reading comprehension and short-term memory were studied in two experiments. In Experiment 1, adults judged the acceptability of written sentences during irrelevant speech, accompanied and unaccompanied singing, instrumental music, and in silence. Sentences varied in syntactic complexity: Simple sentences contained a right-branching relative clause (The applause pleased the woman that gave the speech) and syntactically complex sentences included a centre-embedded relative clause (The hay that the farmer stored fed the hungry animals). Unacceptable sentences either sounded acceptable (The dog chased the cat that eight up all his food) or did not (The man praised the child that sight up his spinach). Decision accuracy was impaired by syntactic complexity but not by irrelevant sounds. Phonological coding was indicated by increased errors on unacceptable sentences that sounded correct. These errors rates were unaffected by irrelevant sounds. Experiment 2 examined effects of irrelevant sounds on ordered recall of phonologically similar and dissimilar word lists. Phonological similarity impaired recall. Irrelevant speech reduced recall but did not interact with phonological similarity. The results of these experiments question assumptions about the relationship between speech input and phonological coding in reading and the short-term store. PMID- 8685392 TI - Response biases in oral reading: an account of the co-occurrence of surface dyslexia and semantic dementia. AB - This paper reports a case study of a subject (EP) with a progressive impairment of semantic memory and a coincident surface dyslexia. These two disorders frequently occur together, but their association is not readily explained within current models of reading. This study investigated two theories that offer different principled accounts of this association, the "semantic glue hypothesis" (Patterson & Hodges, 1992) and the "summation hypothesis" (Hillis & Caramazza, 1991) and found both hypotheses wanting. Instead it was shown that when vestiges of word meaning remained, a lexical response was preferred, but when meaning was lost entirely, the evidence derived from sublexical processing appeared to bias selection of the response towards the regularized form. PMID- 8685393 TI - Spatial orienting controlled without awareness: a semantically based implicit learning effect. AB - Three experiments tested whether spatial attention can be influenced by a predictive relation between incidental information and the location of target events. Subjects performed a simple dot detection task; 600 msec prior to each target a word was presented briefly 5 degrees to the left or right of fixation. There was a predictive relationship between the semantic category (living or non living) of the words and target location. However, subjects were instructed to ignore the words, and a post-experiment questionnaire confirmed that they remained unaware of the word-target relationship. In all three experiments, given some practice on the task, response times were faster when target appeared at likely ( p = 0.8 ), compared to unlikely ( p = 0.2 ) locations, in relation to lateral word category. Experiments 2 and 3 confirmed that this effect was driven by semantic encoding of the irrelevant words, and not by repetition of individual stimuli. Theoretical implications of this finding are discussed. PMID- 8685394 TI - Effects of limitations on the use of some visual and kinaesthetic information in spatial mapping during exploration in the rat. AB - The purpose of this experiment was to study the effects of limiting visual and/or locomotor access to a part of the environment in the building up of a spatial representation of the whole space. During five sessions, rats were allowed to explore separately and successively the two halves (subspaces) of a circular open field containing four objects. During exploration of each half, continuous or discontinuous locomotor and/or visual access to the other half was provided by using opaque or transparent partitions, with or without doors. Once habituation was complete, the partition was removed for some subjects but remained for others. The locomotor and exploratory reactions to this removal were recorded. Whatever their locomotor experience (continuous or discontinuous), rats that had a discontinuous visual experience between the subspaces displayed a renewal of exploratory activity, whereas the rats that had received a continuous visual experience did not re-explore the objects. This result suggests that continuous visual access to the whole space is necessary for the construction of an overall representation. Furthermore, continuous locomotor activity does not seem to compensate for the discontinuity of visual information. PMID- 8685395 TI - Rats' memory for serially presented novel flavours: evidence for non-spatial primacy effects. AB - Four experiments examined the effects of serially presenting a number of novel flavours to rats on their subsequent consumption of those flavours. In Experiments 1-4, rats were orally infused with 0.5 ml of flavour over 30 sec for each of five flavours in the exposure phase of the experiment. In these studies, primacy and recency effects emerged, the size of the primacy effect being related to the length of the retention interval, which varied from zero to twenty-four hours. Thus, both primacy and recency effects can be generated using non-spatial stimuli with rats. PMID- 8685397 TI - Architecture of health information systems. State of the art and new perspectives. AB - In last years, requirements for health information systems have markedly increased. From essentially sectorial requirements limited to the single operational units, the need has emerged for the interaction and integration of the various components of the health care structure, within the service and over the territory. A major role in this evolutionary process is played by the architectural features of the information system. They must respond to precise requirements of standardization, modularity and openness so as to allow the integration and interaction of different, even if preexisting, applications and of different suppliers. In this article, some fundamental aspects of the architecture of health information systems are discussed based on actual experiences as well as on results of the principal approaches to standardization in Italy and Europe. PMID- 8685396 TI - Computerization of a diagnostic imaging department: a way of managing the health care complexity. AB - Today, while the potentialities for communication networks and an increasingly sophisticated and widespread technology, have made social participation in the planet's events (global village) simultaneous, at the same time the human language is undergoing an ever increasing fragmentation and differences are not communicable. In medicine, the impossible communication of fragmentation has created a gap between society and science, health care service and patients, primary people's needs and superspecializations etc., that cannot be bridged. In this alarming situation, which poses economic, ethical and philosophical problems, difficulties in the organization and management have become even more pressing in an economic and administrative system which requires effectiveness and efficiency of the health care system. Departmental automation, in our case of the department of "Diagnostic imaging" and of the hospital system as a whole, may supply an adequate tool to "users-operators-administrators" for the management of the patient and of his/her illness through the integration and correlation between information, complementary resources, interaction between health operators and administrators. Diagnostic imaging is undoubtedly a complex and important crossroads for the patient and for the disease and computerization can markedly contribute in terms of "service efficiency", "intervention effectiveness" "quality assurance". In health care services, especially in a university setting, "information and knowledge packages" for education and research should be available. This "feasible dream" can come true only if dreamt by all. This means that operators responsible for the patient and the illness must be involved in a radical change of environment and behavior. PMID- 8685398 TI - Radiology information systems (RISs): state of the art and new perspectives. AB - The Diagnostic Imaging Department plays a crucial role in the hospital structure, essentially due to the critical importance of its activities at the clinical as well as the organizational level. Moreover, its structure is complex and susceptible of changes in the course of time. Thus Radiology Information Systems (RISs) have acquired a specific relevance within Hospital Information Systems (HISs). The major requirements of a Diagnostic Imaging Department and the developmental course, RISs have followed in time to meet them effectively and efficiently, are reported. The main problems of the present situation and the trend of the future development of RISs are considered. PMID- 8685399 TI - Radiation therapy information systems (RTISs): state of the art and new perspectives. AB - Information technology in radiotherapy finds three separate fields of application: direct computerization is essentially aimed at the conformation of target volume. It is present in devices used for treatment planning and execution. Indirect computerization is essentially aimed at the acquisition of patient's data relevant to the routine and clinical management and at the ready access to the acquired information. Communication networks are intended to facilitate the definition of the patient's integrated reporting, to optimize available resources and multicentric research. Present information technology in radiotherapy is based on the need for a radiation therapy information system (RTIS). It should be designed as a transverse access between the various subsystems, unified in planning, even if implemented at different times and with different technologies, ready to work on a geographic scale, now feasible with the international communication networks. PMID- 8685400 TI - Digitization of radiologic images. AB - Information technology is at present an integrating part of the department of radiology. The applications to radiology involve the new imaging procedures as CT and MRI as well as exams which to-date are performed with analog methods. Besides off-line digital conversion of images by video camera or scanner, on-line systems are available with which conventional images are directly converted to digital images. Digital radiography using photostimulable phosphors is based on the capability of barium fluorohaldeide plates to emit light when stimulated by a laser beam. Digital spot fluorography is a dedicated system which enables the digital acquisition of dynamic images. The diffusion and evolution of digital systems dedicated to conventional exams will permit in a near future a fully digital radiology department. PMID- 8685401 TI - Standardization of digital radiologic images. AB - The need for uniform digital formats of radiologic images obtained from the human body by the various methods (CT, MRI, DF, DSA, NM) is felt by both the manufacturers and the radiologists since a long time. The ACR-NEMA standard was initially established to overcome this problem, however it was not fully satisfactory. Its up-dated version, DICOM 3 seems a more successful approach to the solution of the problem. The rationale on which DICOM 3 is based, the main guidelines with some reference to the various parts of the new standard, are analyzed. Its advantages as well as disadvantages are considered in view of a future complete integration of data and images of a radiology department within a hospital information system. In the appendix, a list of DICOM components and addresses where to find the original documentation are supplied. PMID- 8685402 TI - Implementation of a management information system for hospital use at the Policlinico Universitario A. Gemelli. AB - First, the experience with the implementation of HISs at the "Policlinico Gemelli", is reported. They were adopted since long for management support. In fact, they are playing an increasingly relevant role in health care facilities. Subsequently, operational applications are described with particular reference to the most recent ones, implemented within European projects with partial EEC financing. They are very useful to the medical and nursing personnel and for patient data management during treatment. Finally, the accounting system for cost centers, using, processing and integrating data of all used information systems, is described. It affords a low cost aggregation of all information about costs and services required for the management of four-hundred elementary operating units which constitute the structure. This system is representative of all managerial information of the "Policlinico" which is included in monthly reports, also described. They are sent to the Direction and managers of the organizational units. The system is a strategic tool of the utmost importance for rapid and effective management. PMID- 8685403 TI - Radiology Information Systems: DREAM. patient management. AB - Until recently Radiology Information Systems (RISs) were considered a set of separate, often heterogeneous applications at the functional, technological and architectural level. In last years, the need for an integrated methodological approach and an engineering vision of the system design has become the most important aspect in the implementation of RISs. Based on this approach, the fundamental organizational, operational and clinical objectives of an advanced RIS together with the major critical factors of success, are presented. Such objectives and requirements have constituted the starting basis for the implementation of the DREAM (Distributed radiological environment advanced and multimedia) system, the result of the collaboration of the "Universita Cattolica del S. Cuore, Policlinico A. Gemelli" of Rome and "GESI-Gestione Sistemi per l'Informatica". An overview of the main functional characteristics, the most qualifying aspects of the system and the methodological approach followed in its implementation, are reported. PMID- 8685404 TI - Diagnostic Imaging Information Systems: DREAM. Reporting management. AB - From the clinical standpoint, the report represents the synthesis of the diagnostic process and it is the central activity of radiology. However, reporting cannot be separated from the entire organizational cycle inside the Diagnostic Imaging Department as well as within the structure as a whole. The effectiveness of the contribution an information system can give to the radiologist is related to the information and functional integration of the various applications operating in the hospital and over the territory. Based on these considerations, the main types of support the information tool can offer, are reported together with the primary objectives which were basic to the development of the reporting module within the DREAM system and the major solutions adopted to facilitate the attainment of these objectives. PMID- 8685405 TI - DREAM: integrated image and traditional data management. AB - Main objectives and characteristics of computerized radiological image handling in a radiology department, homogeneously integrated with other information typologies, are discussed. The extension of the present DREAM system to image handling functionalities is in progress. The activities are based on the collaboration between the "Universita Cattolica del Sacro Cuore (UCSC), Istituto di Radiologia". Hopital Cantonal Universitaire de Geneve-Centre d'Informatique Hospitalier (HCUG) and Gesi aiming at the integration of "Osiris", image handling information system implemented by HCUG with DHE middleware implemented by Gesi and UCSC which represents the functional and information core of the entire information system. The initiative is part of "Synapses" project, partially supported by the European Union DG XIII within the program of information technology applications in health care. PMID- 8685406 TI - START: an advanced radiation therapy information system. AB - START is an advanced radiation therapy information system (RTIS) which connects direct information technology present in the devices with indirect information technology for clinical, administrative, information management integrated with the hospital information system (HIS). The following objectives are pursued: to support decision making in treatment planning and functional and information integration with the rest of the hospital; to enhance organizational efficiency of a Radiation Therapy Department; to facilitate the statistical evaluation of clinical data and managerial performance assessment; to ensure the safety and confidentiality of used data. For its development a working method based on the involvement of all operators of the Radiation Therapy Department, was applied. Its introduction in the work activity was gradual, trying to reuse and integrate the existing information applications. The START information flow identifies four major phases: admission, visit of admission, planning, therapy. The system main functionalities available to the radiotherapist are: clinical history/medical report linking function; folder function; planning function; tracking function; electronic mail and banner function; statistical function; management function. Functions available to the radiotherapy technician are: the room daily list function; management function: to the nurse the following functions are available: patient directing function; management function. START is a departmental client (pc-windows)-server (unix) developed on an integrated database of all information of interest (clinical, organizational and administrative) coherent with the standard and with a modular architecture which can evolve with additional functionalities in subsequent times. For a more thorough evaluation of its impact on the daily activity of a radiation therapy facility, a prolonged clinical validation is in progress. PMID- 8685407 TI - Telecommunications and multimedia systems in education: what developments for radiology? AB - What are the new perspectives for the radiologist with the development of new technologies of telecommunications? At present, when digitization of most biomedical images has become a reality, problems of remote transmission are simplified. However, telematic literacy is necessary to the radiologist. It is already possible through multimedia supports, as CD-ROM and Internet "navigation". Which are the modalities to access "the network of networks"? Through Internet, hypertexs can be consulted, databases can be accessed, programs and printings can be retrieved, electronic mail can be exchanged. The CD-ROM is a further source of knowledge, especially effective in education due to multimedia and hypertext technology. In this context in the education of the radiologist, the hypertext version of a radiology text, finds its place. It is conceived to offer to each user an individualized approach to learning. PMID- 8685409 TI - [Teaching, research, profession and the new image of the radiologist. Presentation and introduction of the topic]. PMID- 8685408 TI - [Italian radiology celebrates the centennial of the discovery of X-rays]. PMID- 8685410 TI - [Teaching in graduate education]. PMID- 8685411 TI - [Teaching in specialization schools: radiotherapy]. PMID- 8685412 TI - [Teaching in the school of specialization in nuclear medicine]. PMID- 8685413 TI - [Teaching in schools of specialization in diagnostic radiology]. PMID- 8685414 TI - [Hypothesis of subspecialty]. PMID- 8685415 TI - [Post-university teaching and continuing professional updating]. PMID- 8685416 TI - [Cultural and professional profile of the radiologist]. PMID- 8685417 TI - [Technicians in the area of radiology]. PMID- 8685418 TI - [Role of the physicist in radiology]. PMID- 8685419 TI - [Research in radiology: quality of life of tomorrow is tied to the scientific research of today]. PMID- 8685420 TI - [Role of the university radiology in the future development of the discipline]. PMID- 8685421 TI - [Role of editor's activities in the professional training]. PMID- 8685422 TI - [The role of hospital radiology in the future development of the discipline]. PMID- 8685423 TI - [Radiology area as a federal reality. I]. PMID- 8685424 TI - [Radiology area as a federal reality. II]. PMID- 8685425 TI - [Celebration of the centennial of the discovery of X-rays. Centennial address]. PMID- 8685426 TI - [Presentation of the volume "Images and marks of man--story of the Italian radiology"]. PMID- 8685427 TI - [The why of "Postal Radiations", a book of scientific and philatelic disclosure]. PMID- 8685428 TI - ["A new kind of rays": epistemology and ideology of the discovery]. PMID- 8685429 TI - [Traditional radiology]. PMID- 8685430 TI - [State of the art and ways of progress in computerized tomography]. PMID- 8685431 TI - [State of the art and ways of progress in different sectors of the radiologic discipline: echography]. PMID- 8685432 TI - [Magnetic resonance. State of the art and ways of progress]. PMID- 8685433 TI - [Nuclear medicine: state of the art]. PMID- 8685434 TI - [Oncologic radiotherapy: state of the art]. PMID- 8685435 TI - [Informatics and radiology]. PMID- 8685436 TI - [State of the art and ways of progress: neuroradiology]. PMID- 8685437 TI - [State of the art and ways of progress in radiology of the head and neck]. PMID- 8685438 TI - [State of the art and ways of progress in odontostomatology]. PMID- 8685439 TI - [The respiratory system]. PMID- 8685440 TI - [The cardiovascular system]. PMID- 8685441 TI - [State of the art and ways of progress in interventional radiology]. PMID- 8685442 TI - [Interventional radiology: what future?]. PMID- 8685443 TI - [State of the art and ways of progress in senology]. PMID- 8685444 TI - [Radiology of the musculoskeletal system]. PMID- 8685445 TI - [State of the art and ways of progress concerning the digestive system]. PMID- 8685446 TI - [State of the art and ways of progress concerning the urogenital system]. PMID- 8685447 TI - [State of the art and ways of progress in pediatric radiology]. PMID- 8685448 TI - [Current state and prospects of the use of uro-angiographic, ultrasonographic and magnetic resonance contrast media]. PMID- 8685450 TI - [The Museum of Radiology]. PMID- 8685449 TI - [Relations between radiodiagnosis and legal medicine: a centenary history]. PMID- 8685451 TI - [Monoarthritis]. AB - By definition, monoarticular arthritis means one-joint involvement, even though, in fact, such a condition is often an oligoarthritis because as many as two or three separate joints will be involved. Arthritis is often limited and may regress, so that it is frequently misdiagnosed. Sometimes, a monoarticular condition may be a polyarthritis onset (i.e., rheumatoid arthritis). Monoarticular arthritis can be caused by many factors, such as infections (septic arthritis), nonspecific inflammatory processes (reactive arthritis), crystals deposition (gout, CPPD crystal deposition disease), trauma, neoplasm (pigmented villonodular synovitis), immunologic conditions (amyloidosis) and hormonal changes (parathyroid disease). Its onset is usually acute and sometimes dramatic, with fever, pain and joint swelling, so that a decision must be made promptly to stop rapid illness evolution and to prevent the irreversible destruction of cartilage and bone (especially in septic arthritis). Diagnostic studies are performed with mono-bilateral radiographs of the joint. Radiographic findings (i.e., soft tissue swelling, joint effusion, widening and thinning of joint spaces, bone erosions and destruction of bone surface) are typical of the disease, but some findings (e.g., type of evolution and progression), laboratory tests, synovial biopsy and arthroscopy can differentiate infectious from inflammatory forms. Scintigraphy can depict isotopic joint uptake, before articular abnormalities are demonstrated with radiography, thanks to its high sensitivity; nevertheless, because of its low specificity, scintigraphy may miss some kinds of lesions (including osteoarthritis) and cannot easily differentiate osteomyelitis from septic arthritis. CT and MRI play a secondary, though not negligible, role, especially to study such deep infections as psoas abscesses, which may mimic arthritides. PMID- 8685452 TI - [Classification, significance and sequelae of posttraumatic "occult" bone and cartilage fractures of the knee. The role of magnetic resonance]. AB - Magnetic Resonance Imaging (MRI) shows, in the post-traumatic knee, a fairly high number of bone and cartilage injuries missed by conventional radiography and therefore called occult. Our aim is to classify these injuries, to correlate their site and distribution with associated menisco-ligamentous injuries and with trauma mechanisms. Thirty-eight patients with a history of acute knee trauma and negative X-ray findings were examined with MRI within 15 days of trauma. 1.5- and 0.5-T units and SE T1-weighted GE T2*-weighted and SE T2-weighted sequences were used. The injuries were classified as intraosseous and osteochondral bruises or fractures. Twenty-three patients with menisco-ligamentous injuries were submitted to therapeutic arthroscopy; the sites of bone and cartilage injuries depicted with MRI were studied with arthroscopy. Seven patients were followed-up with MRI at 6-12 months to investigate subchondral injury evolution: 5 of 7 patients were also submitted to arthroscopy. MRI showed a statistically significant correlation between site and distribution of bone and cartilage injuries and between internal derangement and trauma mechanisms, i.e., contusion, distortion, stress. In our experience, MRI could identify and characterize occult subchondral injuries, thus allowing appropriate treatment. PMID- 8685453 TI - [Biomechanics and semeiotics of traumatic lesions of the posterior cruciate ligament using magnetic resonance]. AB - The authors reviewed 458 MR examinations of the knee to assess the potentials of this technique in the study of traumatic injuries of the posterior cruciate ligament (PCL) and to investigate the frequency of their association with injuries of other knee joints. MR images were acquired with an 0.5-T super conductive unit with an extremity coil. T1-weighted spin-echo (SE) and T2* weighted gradient-echo (GE) sequences were used on sagittal, coronal and, in some cases, axial planes, with 3-mm slice thickness and 0-1 mm slice gap. The following parameters were studied to diagnose partial or complete PCL tears: PCL thickness and outline, disruption of ligamentous fasci and signal intensity features. The injuries were classified as proximal, intermediate and distal according to their site. Thirteen PCL tears were detected, 5 of them complete and 8 partial. Complete tears were found in 4/5 patients in the middle third and one patient had a distal intersection tear with tibial bone avulsion. Partial tears were found in the distal tract in 5/8 patients, in the proximal tract in one patient and in the middle third in 2 patients. In 12/13 patients capsuloligamentous knee tears were associated. Overall MR rate of PCL tears was 2.8%; of them, 92.3% were associated with other capsuloligamentous injuries. MR diagnosis was confirmed at arthroscopy in 12/13 patients. The sagittal plane was best in optimally demonstrating the whole PCL and its injuries. GE T2* sagittal sequences demonstrated the site of PCL tears better than SE sagittal ones. Relative to other authors, we found MRI an extremely reliable method to distinguish partial from complete PCL tears. This was probably due to the thinner slices (3 mm) we used. MRI can accurately assess the extent of traumatic injuries of the PCL and of other capsuloligamentous parts of the knee, which is relevant from the clinical point of view. Indeed, MRI allows useless diagnostic arthroscopy to be avoided and yields major indications to choose the correct treatment. PMID- 8685454 TI - [Nonpalpable lesions of the breast. Diagnostic potentials of the stereotaxic guided radiogram]. AB - PURPOSE: To investigate the diagnostic capabilities of the stereotaxic technique in characterizing suspicious mammographic findings for which stereotaxic FNAB is indicated. METHOD: January, 1990, through December, 1992, 871 patients underwent stereotaxic mammograms preliminary to FNAB; in 12 of them (1.4%) mammography could rule out the malignant nature of the lesions, thus making FNAB useless. MATERIAL: Stereotaxic images were acquired with a conventional mammographic unit (Senographe 500 or 600T CGR-GE). An average 34 months' mammographic follow-up confirmed the absence of malignancy in the above patients. The most common glandular structure in these patients was investigated, together with the type of nonpalpable lesions found on conventional mammograms (opacity, local distortion or scar, microcalcification without a mass) and the reasons why FNAB was unfeasible, or useless. In our patients FNAB was unfeasible mostly in fatty breasts (9/12), while lesion type was not relevant for screening. The lesions were 5/12 distortion, 5/12 small opacities and 2/12 clusters of small microcalcifications. In 9/12 patients FNAB was not performed because the image observed on conventional exams had disappeared, in 2/12 patients with microcalcifications because they were scattered on a large glandular area and in 1/12 patients because vascular sinuosity was diagnosed. PMID- 8685455 TI - [Diagnostic pitfalls in magnetic resonance angiography]. AB - The authors report on their clinical experience with Magnetic Resonance angiography (MRA) pitfalls. January, 1989, to February, 1995, six hundred MRA examinations were performed in different vascular districts, with a 1.5-T superconductive magnet, the time-of-flight (TOF) technique and 2D and 3D acquisitions. Intracranial arteries, epiaortic vessels and renal arteries were studied with FISP 3D sequences; intracranial veins, thoracic vessels, vena cava and pelvic vessels were studied with FISP 2D sequences. Pitfalls were observed in 56 of 600 MRA exams (9.3%). Of 56 pitfalls, 26 (46.4%) were in epiaortic vessels, 15 (26.7%) in intracranial vessels, 6 (10.7%) in renal arteries, 6 (10.7%) in thoracic vessels, 1 (1.7%) in the inferior vena cava and 2 (3.5%) in iliac vessels. Stenoses were overestimated in 21 patients and underestimated in three; 16 patients were misdiagnosed and 16 were false positives. As for cerebral vascular lesions, 5 aneurysms and 7 transverse sinus thromboses were false positives, while 3 lesions were misdiagnosed as venous angiomas. As for 26 MRA exams of thoracic vessels, stenoses were overestimated in 16 patients and underestimated in 10 patients with subclavian steal syndrome, where the left vertebral artery was misinterpreted as occluded. In 6 MRA exams of thoracic vessels, 1 patient was misdiagnosed as having an aneurysm and 5 patients were misdiagnosed as having lung cancer infiltrating aorta and superior vena cava. As for renal vessels, 2 normal renal arteries were misdiagnosed as false positives and 4 stenoses were overestimated. In the inferior vena cava, a partial agenesis was misinterpreted as thrombosis. In 2 MRA exams of iliac vessels, a stenosis and a thrombosis were misinterpreted as false positives. Our experience suggests that MRA pitfalls are caused by the incorrect use of the various techniques. The pitfalls we observed can be classified as caused by three types of artifacts: saturation, turbulence and paramagnetic substance artifacts. PMID- 8685456 TI - [Spiral computed tomography with arteriography in the diagnosis of digestive system hemorrhages of obscure origin]. AB - Some 5-20% of gastrointestinal (GI) bleeding cases are of obscure origin because bleeding is difficult to diagnose or locate with conventional imaging methods. The authors suggest arterial spiral CT (ASCT) of the abdomen as an original tool to study GI bleeding of obscure origin. This diagnostic method consists of two subsequent phases: first, after abdominal aorta catheterization, the catheter is positioned in the celiac artery; then, CT of the abdomen is performed before and after intra-arterial contrast agent injection. In 6 of 10 patients with GI bleeding of obscure origin, ASCT depicted small high-intensity areas in the intestinal lumen, which indicate a source of bleeding. The site of bleeding was studied only with topographic criteria according to scanning planes, and the morphological features of the intestinal segments were investigated. All patients were submitted to surgery: when ASCT identified a bleeding site, angiography was limited to the involved arterial district. Angiography alone could locate the source of bleeding in 5 patients; angiography and ASCT were in agreement in 4 patients. The combined techniques located the source of bleeding in 7/10 patients and the nature of bleeding was diagnosed in 3/10 patients (angiodysplasia). Even though their experience is limited, the authors believe that ASCT can be useful in locating GI bleeding of obscure origin, as well as in guiding subsequent selective angiography. PMID- 8685457 TI - [Identification of pancreatic insulinomas. The role of magnetic resonance]. AB - Insulinomas are the most common endocrine tumors of the pancreas. Although their clinical and biochemical diagnosis is extremely accurate, these lesions must be correctly located preoperatively to plan the best possible treatment. Many different noninvasive diagnostic techniques have been proposed, with only partially satisfying results. For many years such non-invasive modalities as arteriography have been considered the most reliable and accurate diagnostic tools. Recently, however, MRI has been proposed for best pancreas imaging, especially for tumor detection, and its results have been excellent especially thanks to its optimal contrast resolution. Fat-suppressed and turbo-spin-echo (TSE) sequences now yield even better results. In our study we examined 21 patients, whose symptoms were typical of insulinoma, using two different 0.5T magnets, one of which with 15 mT/m gradients. We used T1-weighted spin-echo (SE) sequences with and without respiratory compensation, SE ad TSE T2-weighted and fat-suppressed T1-weighted SE sequences. In 16 patients the lesions were correctly diagnosed and located, as confirmed at surgery. In the other 5 patients, MRI failed to locate the insulinomas. Three of these 5 patients were submitted to surgery, during which palpation and intraoperative US findings were also negative for a solid mass. The remaining 2 patients underwent clinical follow-up. Our study demonstrated that MRI, especially with fat-suppressed and T2 weighted TSE sequences, is a very accurate modality to detect pancreatic insulinomas and can therefore be proposed as the only preoperative technique. PMID- 8685458 TI - [Carcinoma of the pancreas. Typical and atypical aspects using midfield-strength magnetic resonance]. AB - Until few years ago, MR assessment of pancreatic carcinoma was thought to be feasible only with high-strength equipment, but today also low- and midfield units allow pancreatic lesion detection, thanks to parameter optimization. The authors retrospectively analyzed the MR findings of 57 patients examined with a midfield MR unit; all the patients had clinically suspected pancreatic carcinoma, which was confirmed in 54 cases. The lesions were more easily detected using T1 weighted sequences, thanks to their high intrinsic contrast, while T2-weighted sequences often confirmed the glandular changes already depicted by T1-weighted sequences. MRI correctly depicted vascular and lymph node involvement and detected liver metastases with no i.v. contrast agent injection. The only limitations of this technique are the unfeasibility of MR exams of diagnostic value in uncooperative patients (5% of cases) and the very similar MR features of parenchymal scars, due to previous acute pancreatitis, to those of pancreatic carcinoma. In conclusion, CT remains the gold standard in the study of pancreatic cancers, but midfield strength MRI, if correctly performed, can be proposed as a complementary tool to CT, especially in questionable cases and in the patients with known reactions to iodinated contrast agents. PMID- 8685459 TI - [Preoperative imaging in the detection of parathyroid tumefaction in patients with primary hyperparathyroidism. The authors' own experience]. AB - The authors report their 3-year experience with the diagnosis of parathyroid lesions in primary hyperparathyroidism patients in a geographic area where the occurrence of endemic goiter is medium. Our study was aimed at prospectively assessing preoperative imaging results in these patients. The following imaging methods were used: high-definition and color-Doppler ultrasonography (US), double tracer 201Thallium-99mTechnetium (T1/Tc) subtraction scintigraphy, Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and US-guided fine-needle aspiration of the suspected parathyroid lesions. Preoperative US and scintigraphy were performed in 50 patients with primary hyperparathyroidism; in addition, color-Doppler US studies were performed in 33 patients for vascular characterization of the lesions. In 19 patients, the suspected lesions were punctured under US guidance to measure parathormone (PTHa) and thyroglobulin (TGa) levels in the aspirated material. CT and MRI were performed in 9 patients, to identify a possible ectopic parathyroid gland. Surgery demonstrated 48 solitary parathyroid lesions and one double parathyroid adenoma. In one patient no abnormal parathyroid gland was found. Overall sensitivity rates of US and scintigraphy were 85.7% and 61.2%, respectively. In multinodular goiter patients, the sensitivity rates of US and scintigraphy were 71.4% and 47.6%, respectively. At color-Doppler US the presence of parenchymal vascularization was specific of parathyroid nodules and the method helped differentiate parathyroid lesions from thyroid nodules in 14 multinodular goiter patients. Overall PTHa sensitivity was 72.2% and its specificity 100%. Overall TGa sensitivity was 100% and specificity 94.7%. CT and MRI allowed the detection of 8 ectopic parathyroid lesions. In conclusion, in our personal experience, US should be preferred to double-tracer T1/Tc subtraction scintigraphy in the early examination of primary hyperparathyroidism patients. When US detects a suspected parathyroid lesion, color-Doppler US and PTH and TG sampling can make useful diagnostic tools for reducing false-positive results, especially when thyroid disease is associated. PMID- 8685460 TI - [Scintigraphic characterization of expansive lesions located in the adrenals. Comparison with magnetic resonance imaging]. AB - In this study, 35 patients (11 men and 24 women, mean age 47 +/- 16 years) with unilateral adrenal masses underwent nor-cholesterol (nor-Chol) (n = 11), metaiodobenzylguanidine (MIBG) (n = 15) or nor-Chol and MIBG (n = 9) radionuclide studies. In all patients Magnetic Resonance (MR) adrenal imaging was also performed. In 19 (54%) patients, no laboratory abnormalities of adrenal function were observed. In the other 16 (46%) patients, adrenal hyperfunction was found. In 21 lesions, histology showed 10 pheochromocytomas (Pheos), 6 adenomas, 3 metastases, 1 cyst and 1 nodular focal liver hyperplasia. In the remaining 14 lesions, increased cortisol (n = 4) or aldosterone (n = 2) levels and/or intense nor-Chol uptake (n = 14) were considered suggestive of adenoma. Diagnostic accuracy of both nor-Chol and MIBG radionuclide studies in correctly identifying adenoma or Pheos was 100%. Conversely, qualitative MR signal intensity (SI) analysis on T2-weighted images did not allow to accurately distinguish lesions of different nature. In particular, 10 Pheos, 8 adenomas, 3 mestastasis and 1 cyst clearly showed on T2-weighted images higher SI than the liver; 5 adenomas had a slight higher SI; the remaining lesions (7 adenomas and 1 liver hyperplasia) exhibited low SI. In conclusion, adrenal scintigraphy using nor-Chol or MIBG allows to identify adenomas and Pheos, respectively. Conversely, qualitative MR SI analysis cannot differentiate different adrenal lesion (Pheos, adenoma, metastasis and cyst) and yields heterogeneous results in adenomas. PMID- 8685461 TI - [Long-term survival of patients with inoperable hepatocarcinoma, treated with interventional radiology]. AB - Survival rates in untreated patients with unresectable HCC are rather disappointing. Our study was aimed at assessing long-term survival in the patients submitted to combined transarterial chemoembolization (TACE) and percutaneous ethanol injection (PEI). We treated 223 patients, but long-term follow-up is available in 143 of them only. Eighty-seven of 143 patients had Child's A liver cirrhosis, 45 had Child's B and 6 Child's C. Five patients did not have cirrhosis. Eighty-seven patients had single lesions--45 of them < 5 cm and 42 > 5 cm. Fifty-six patients had multiple/diffuse lesions. All patients underwent TACE while PEI was performed in selected patients with single or double lesions. Survival rates were calculated with the life-table analysis by Kaplan and Meyer. Follow-up was 1-72 months (median: 28 months). At 1, 3 and 5 years, the overall survival rates were 72%, 34.5% and 16.4%, respectively. The survival rates at 1, 3 and 5 years in single lesions < 5 cm were 90.4%, 52.1% and 34.8%, respectively, vs. 69.4%, 37.4% and 18.7% in lesions > 5 cm and 58.8%, 12.5% and 0% in multiple/diffuse lesions. In conclusion, the long-term results of the radiologic treatment of unresectable HCC are comparable with surgical results obtained in selected cases. PMID- 8685462 TI - [Percutaneous transluminal angioplasty in the treatment of iliac stenosis. The authors' new guideline for 100 patients]. AB - This retrospective study was carried out from January, 1990, to September, 1994, after reviewing a series of 100 patients submitted to 143 percutaneous maneuvers (PTA) for aortoiliac revascularization (PTA, PTA and stenting, PTA and bypass). This study was aimed at conforming as much as possible our patients selection criteria and the analysis of the results to the current standards adopted by the major interventional radiology and vascular surgery departments. The Fontaine and the SCVIR classification methods were used for patients selection. Long-term patency was analyzed with clinical and noninvasive diagnostic exams. The results were studied with the Life-table analysis statistical method. The patients were divided into 3 groups: the patients treated only with PTA, those treated with PTA and stenting and finally those submitted to PTA before or after a surgical bypass. The results were analyzed separately. In 95/100 patients the maneuver was technically successful and immediate clinical success was not achieved only in one of them. At the first follow-up we collected data on 87 patients; at 3 years we followed-up 30 patients, but only 5 of them had to be resubmitted to PTA (3 PTA and stenting and 2 PTA alone) because of restenosis. Secondary patency was obtained in 91% and 84% of patients at 1 year and 3 years, respectively. With the Life-table analysis, the cumulative patency rate was 95.44% at 36 months. Few complications were observed (11/100 patients), especially considering that they were classified as "severe" in 3 cases only. To conclude, our results prove PTA to be a highly effective tool in the aortoiliac arteries, whose low mortality and complication rates suggest the use of this percutaneous procedure. PMID- 8685463 TI - [Percutaneous transluminal angioplasty of the iliac arteries: methodological and technical innovation and the need for standard guidelines]. PMID- 8685464 TI - [Quality control in radiotherapy. Computerized management of the "total" oncologic follow-up]. AB - Since 1992, in the Rovigo Radiotherapy Department, we have computerized the management of oncologic follow-up to minimize all "non-medical" times during the different phases. System efficiency was analyzed and the results follow: 1) the absolute number of follow-up visits, compared with the standard reference year (1991), shows that we were able to double our "performance" within the time unit, with the same "resources"; 2) the average number of follow-up visits per malignancy within 6 months of the diagnosis and then every seventh month, approximated to the number of scheduled visits; 3) the number of cancer relapses in the patients who could not be submitted to a specific antiblastic treatment (a reversed efficacy indicators) progressively reduced from 13.7% to 12.6% and 10.4% respectively, in 1992, 1993 and 1994; 4) secondary lesion diagnosis, an indirect efficacy parameter, was found to be accurate; 5) the cost of follow-up per malignancy reduced, in 6 months' periods, especially in the cancers with easier clinical diagnosis (-32% for breast cancer, -50% for head and neck cancer), by as much as 43,639,000 Italian liras in 1994 (relative to 1993); 6) the scheduled visits began only 12 minutes late, as studied on 2,346 visits. To conclude, the computed management of medical records improves our Department's efficiency, with no additional cost for the patients. PMID- 8685465 TI - [Analysis of recurrences following conservative treatment of breast carcinoma]. AB - In the conservative treatment of early breast cancer, great attention must be paid to define the prognostic factors correlated with the local recurrence rate. The goal is to customize surgery, radiotherapy and chemotherapy to the risk predicted in every single patient. To investigate the impact of some prognostic factors in a group of patients treated with homogeneous treatment schedules, 251 women with UICC stage I or II breast cancer were examined in the Padua Radiotherapy Department from 1988 to 1990. All patients underwent conservative surgery consisting in quadrantectomy, axillary node dissection and radiotherapy. During a median follow-up period of 49.2 months, 12 patients presented a breast relapse (4.8%). In 4 patients the relapse occurred in the same quandrant as the primary lesion, whereas a different quadrant was involved in the other 8 patients. The relapse rate in women under 60 was 5% and 4.7% in older patients, with p = 0.73. In pT1 patients, the relapse rate was 4.5% and in pT2 patients it was 7.9% (p = 0.37). No significant difference was observed between pN- and pN+ patients (4.5% vs. 6.25%, p = 0.37). In our series, none of the studied factors significantly influenced breast relapse rates. The number of patients may be too little relative to the low rate of relapses. However, an unfavorable trend was observed in the patients under 60, in pT2 or pN+ patients, or in the patients with positive or unknown surgical margins. PMID- 8685466 TI - [Assessment of residual mediastinal tumor in patients with Hodgkin's lymphoma using computed tomography, magnetic resonance and 67Ga scintigraphy]. AB - 594 patients with Hodgkin's disease were treated from 1983 to 1993 at the Department of Radiotherapy and Institute of Hematology, "La Sapienza" University, Rome, Italy. 385 patients presented mediastinal involvement; CT and/or chest radiography showed residual mediastinal masses in 96 of them (25%). In this study we included only the patients treated after 1986; they were examined with MRI of the chest (24 patients) and 67Gallium scintigraphy of the mediastinum (44 patients) with or without SPECT, combined with high-dose 67Ga in some cases. Eighteen patients underwent both MRI and 67Gallium scintigraphy. MR accuracy, sensitivity and specificity were respectively 75%, 86% and 86%; gallium scintigraphy had 86%, 77% and 93%. These data were confirmed by the results fo the subgroup of 18 patients submitted to both exams; MRI had higher sensitivity (80% vs. 75%) and lower specificity and accuracy (83% vs. 80% and 72% vs. 67, respectively) than 67Gallium scintigraphy. The predictive value of MR scintigraphy agreement is high: indeed, no false negatives or false positives were observed when MR and scintigraphy results were in agreement. PMID- 8685467 TI - [Radiotherapy of T1N0 neoplasms of the glottis. Analysis of the parameters that influence local control]. AB - Treatment and tumor-related parameters were reviewed in 176 patients with T1N0 carcinoma of the glottic larynx submitted to primary radiation therapy from 1980 to 1992. Our aim was to analyze local control and treatment-related toxicity. Over-all local control rates at 10 years were 88.3% with irradiation alone and 94.5% after salvage surgery (larynx preservation: 91%). Verrucous histology was a negative factor affecting local control and anterior commissure involvement exhibited only a negative trend but had no statistical significance. Among treatment-related factors, local control was 76.5% after split-course and 91.1% after continuous-course irradiation (p < 0.05). With continuous-course irradiation, the total dose influenced local control only for single of 2 Gy (local control rates were 69% with 60 Gy and 93% at > or = 64 Gy; p < 0.05), but not for single doses of 2.25 Gy and total doses ranging 56.25-65.25 Gy (local control failed in 55 patients). Early and late complications did not increase with single doses > or = 2.25 Gy. Our current policy in T1N0 nonverrucous glottic carcinoma is to use a single fraction of 2.25 Gy and a total dose ranging 56.25 63 Gy according to tumor size, with a continuous course. PMID- 8685468 TI - [Single-dose palliative radiotherapy in inoperable non-small-cell lung carcinoma]. AB - The treatment of choice for advanced inoperable non-small cell lung cancer (NSCLC) is radiation therapy. Palliative radiotherapy schedules vary considerably in different centers, but a 30-Gy dose given in ten fractions over two weeks is a typical standard schedule. Our study was aimed at investigating whether a shorter course of only one 10-Gy fraction allows good palliation in the treatment of inoperable NSCLC patients whose main symptoms are related to an intrathoracic lesion. Patients of both sexes and any age, untreated with radiotherapy, with inoperable and histologically or cytologically proved NSCLC were examined. Seventeen patients, too advanced for radical "curative" radiotherapy and whose main symptoms were related to primary intrathoracic lesions, entered the study even though they had metastases. On admission, 76% (13/17) of patients had cough 76% (13/17) dyspnea, 70.7% (12/17) chest pain and 23.6% (4/17) hemoptysis. They received a single dose of 10 Gy, delivered with an 18-Mv linear accelerator via anteroposteriorly opposing portals without spinal cord shielding. Treatment volume usually included the macroscopically detected lesion identified with a CT simulator. Palliation of symptoms was achieved in high rates of patients: 46% for cough, 69% for dyspnea, 83% for pain and 75% for hemoptysis. These results were obtained within one month of treatment. Unfortunately, palliation of symptoms did not last long, decreasing to 42% within two months of the end of treatment and to 32% at three months. Four patients were retreated, one patient three months and three patients two months after the end of radiotherapy. Ten Gy to the target volume were administered as retreatment with spinal cord shielding. Side-effects were mild: nausea in 3 patients (17%), vomiting in one patient (5%) and grade-II dysphagia in two patients were observed and classified according to WHO criteria. Pain increased 24 hours after radiotherapy in five patients. We can conclude that single dose radiotherapy yields good, but short, palliation of symptoms with acceptable side-effects. PMID- 8685469 TI - [Imaging of thromboembolism by scintigraphy with the 99m-technetium-labelled synthetic peptide P280]. AB - P280, a synthetic peptide composed of 26 aminoacids, has high affinity (Kd = 100 nM) and specificity for the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor expressed on activated platelets. In this study we investigated the potential usefulness of imaging deep vein thrombosis (DVT) and pulmonary embolism (PE) in humans with 99mTc-P280. In 15 patients (9 men and 6 women; mean age +/- s.d.: 49.2 +/- 14.1) with known DVT and/or PE, serial images were acquired within 24 hours of the injection of approximately 200 micrograms of P280 radiolabelled with 10-23 mCi of 99mTc. P280 was labelled with the ligand exchange method using 99mTc glucoheptonate. Rapid blood clearance (< or = 5% ID was still circulating in 1 hour) enabled identification of thrombi as early as 60 minutes after the injection, with significant thrombi-to-background ratios (range: 2-4) in 11/15 patients (73%), in 7/9 with DVT, in 2/3 with PE and in 2/3 patients with both DVT and PE. Radiotracer uptake was clearly detectable also in late scans, which confirms that 99mTc-P280 specifically binds to the thrombi through a receptor mediated mechanism. PE localizations were detectable 3-4 hours after peptide injection, and in 2 cases SPECT enabled the detection of thrombi missed on planar views. Conversely, the test was negative in 4 patients who had the onset of clinical symptoms and the diagnosis of DVT and/or PE more than 40 days before scintigraphy. The lack of 99mTc-P280 uptake in the latter patients suggested that the peptide does not bind to thrombi when thrombogenesis is not active. These preliminary results clearly indicate scintigraphy with 99mTc-P280 to be a suitable, noninvasive and highly specific tool to image fresh clots causing DVT and/or PE. Thus, this technique might overcome the limitations of the imaging procedures currently in use. PMID- 8685470 TI - [Echinococcosis of the paravertebral space. Report of a case]. PMID- 8685471 TI - [Giant intracranial aneurysms: a case history assessment of the correlation between etiopathogenetic hypothesis and magnetic resonance imaging]. PMID- 8685472 TI - [Perforation of a duodenal diverticulum. Report of a case with CT diagnosis]. PMID- 8685473 TI - External abdominal hernia of mucocele of the appendix in drain-tube removal site. PMID- 8685474 TI - [Appendiceal mucocele: diagnosis by echography, spiral computed tomography and magnetic resonance]. PMID- 8685475 TI - [A rare anatomical variant of the left hepatic lobe. Report of a case]. PMID- 8685476 TI - [Aneurysm of the right hepatic artery. Diagnosis by color Doppler echography]. PMID- 8685477 TI - [Polysplenia syndrome in adults. Report of an atypical case]. PMID- 8685478 TI - [Hemospermia associated with a urogenital sinus cyst: diagnostic contribution of MRI. Report a case]. PMID- 8685479 TI - [Giant myelolipoma of the adrenals. A report of 3 cases studied by CT and a review of the literature]. PMID- 8685480 TI - [A nephropathic patient with lung problems ...]. PMID- 8685482 TI - [Usefulness of biological markers in pleural effusion]. PMID- 8685481 TI - [Bronchiolitis obliterans organizing pneumonia. Review of six cases]. AB - BACKGROUND: Bronchiolitis obliterans with organizing pneumonia (BOOP) is recently described clinicopathological entity, with only a few series of patients reported. Terminology is unclear, which together with its rarity lead to a poor understanding of the entity. OBJECTIVE: To review the clinical, radiological, and laboratory features and the response to therapy in cases of BOOP in our environment. MATERIALS AND METHODS: A total of 463 lung biopsies were obtained at Mostoles Hospital, Madrid, from 1992 to 1994. In six cases the anatomo pathological diagnosis was BOOP. Clinical histories of these patients were reviewed. RESULTS: Six patients were diagnosed with BOOP. From these six patients, four (66%) were female, with a mean age of 59 years (45-74 years). Three patients (50%) were smokers. BOOP was idiopathic in four cases (66%) and secondary to rheumatoid arthritis in one (17%) and Legionella pneumonia in another patient (17%). Patients presented with cough and dyspnea (100%), chest pain and constitutional syndrome (66%) and fever (34%) of one to eight weeks evolution. Laboratory data included: increased ESR (100%), abnormal levels of liver enzymes (83%), hypoxemia (83%) and abnormal spirometry (50%). Radiological studies demonstrated alveolar infiltrates in 83%, predominantly in lower lobes, which were of a migratory nature in 33%. CT, performed in five patients, demonstrated alveolar infiltrates in all patients, which were bilateral and peripheric in two. Transbronchial biopsy was diagnostic in five cases, and in one patient thoracotomy had to be performed. One patient died (17%); the remaining patients (83%) improved with steroids, although 34% relapsed. Mean follow-up time was eleven months (5-24 months). CONCLUSIONS: BOOP observed in our environment is a rare entity, usually of an idiopathic nature, which presents with characteristic clinical course and laboratory findings. Transbronchial biopsy is diagnostic in many patients. The clinical course is good with steroids in most patients, although relapses are common. PMID- 8685483 TI - [Neurotoxicity of excitatory amino acids and the central nervous system]. PMID- 8685484 TI - [Anti-5-HT-3: a new group of antiemetics]. PMID- 8685485 TI - [Edema of the left lower limb]. PMID- 8685486 TI - [Pseudocystic pulmonary images]. PMID- 8685487 TI - [Severe cellulitis in an immunocompetent patient]. PMID- 8685488 TI - [Chronic thrombosis of the pulmonary artery]. PMID- 8685489 TI - [Chronic eosinophilic pneumonia or Churg-Strauss syndrome?]. PMID- 8685490 TI - [Use of magnetic fields in medicine]. PMID- 8685491 TI - [Usefulness of electromagnetic fields in the treatment of hip avascular necrosis: a prospective study of 30 cases]. AB - A series is here reported of 30 hips from 21 patients with the diagnosis of avascular necrosis in different stages (Ficat 0 = 1, I = 4, II = 13, III = 10, IV = 2). Patients underwent external electro-stimulation by means of a electromagnetic field generator, and results were evaluated by NMR at three-month intervals. Lesions were categorized by NMR: < 25%, 25%-50%, and > 50% of involved head volume. The grading of lesions yielded the following distribution: grade 1 = 12, grade 2 = 10, and grade 3 = 7. Results were categorized in "clinical success", "NMR success" and "combined success" when symptoms decreased or disappeared, the lesion stabilized by NMR, or both, respectively. Overall, the corresponding figures were 80%, 76.6%, and 63.3%, and were remarkably influenced by the NMR grading of the lesion. PMID- 8685492 TI - [A case control study of the relationship between diet and breast cancer in a sample from 3 Spanish hospital populations. Effects of food, energy and nutrient intake]. AB - A case-control study was conducted to analyze the possible role of diet on the incidence of breast cancer in a group of 275 women (139 cases and 136 controls) recruited from three hospital populations (Madrid, Merida, and Santiago de Compostela). The retrospective intake of foods was studied by a modified dietary history; from this the intake of energy, nutrients, fiber, and alcohol was derived. Intake of oils and fats was significantly higher among cases, which translates into a higher intake of lipids and vitamin E. In contrast, intake of vitamin D and legumes was significantly lower. No differences were observed regarding other foods and nutrients between cases and controls. The estimate of the odds ratio as a relative risk measure for breast cancer, adjusted and unadjusted for total energy, indicates that intake of cereals and legumes, proteins, carbohydrates and fiber is apparently a protective factor, whereas an excessive intake of meat, oils and fats and a lipid intake higher than 46% of the total caloric intake or poly-unsaturated fatty acids higher than 15 g would be a risk factor for this pathology. PMID- 8685494 TI - [Lipoprotein(a) concentrations in type I diabetes mellitus]. AB - OBJECTIVES: To determine the distribution of lipoprotein(a) levels and prevalence of hyperLp(a) in diabetes mellitus type I (IDDM). To analyze the effect of glycemic control and microalbuminuria on Lp(a) levels. METHODS: Cross-sectional study of 263 subjects with IDDM with a mean age of 19.2 +/- 11.6 years and an evolutive course of 6.3 +/- 6.5 years. Apart from Lp(a), measurements were obtained from serum levels of lipids, apolipoproteins AI and B, fructosamine, glycosilated hemoglobin (HbA1c), and albuminuria in all patients. RESULTS: Mean serum concentrations of Lp(a) were 16.5 +/- 18.1 mg/dl and 18.5% of patients had Lp(a) levels > 30 mg/dl [hyperLp(a)]. With a multivariate regression analysis, the only variable correlated with Lp(a) levels was cholesterol LDL (p < 0.001). Patients with hyperLp(a) did not differ from the other patients in any of the other variables analyzed, and patients with HbA1c higher and lower than 8% had similar mean serum Lp(a) concentrations (14.0 +/- 16 vs. 17.9 +/- 20). Lp(a) concentration was also similar among patients with albuminuria higher and lower than 20 micrograms/min (16.6 +/- 20 vs. 17.7 +/- 16). CONCLUSIONS: Control of glycemia and microalbuminuria have no effect on Lp(a) concentrations in diabetes mellitus type I. HyperLp(a) is not indicative of a poor glycemic control. PMID- 8685493 TI - [Etiology of acute respiratory infections in 87 hospitalized children]. AB - OBJECTIVE: The aim of this study was to assess the effectiveness of two microbiologic methods: viral culture and serology for the etiologic study of acute respiratory infections in children under 14 years of age admitted to our hospital. PATIENTS: From January 1992 to December 1993, a prospective study was carried out in 87 patients with a mean age of two years with the following diagnosis: upper respiratory tract infections (URTI) 19, laryngitis 3, bronchitis 18, bronchiolitis 18, and pneumonia 29. METHOD: Nasopharyngeal aspirates were collected for virologic culture on cell monolayers in 87 patients. Serologic studies by complement fixation test were carried out in 42 patients older than six months. RESULTS: The etiologic agent was detected in 54 (62%) of the 87 patients, being the most frequent the respiratory sincitial virus (VRS) with 18 cases (20%), followed by adenovirus (ADV) in 17 (19%) and Mycoplasma pneumoniae in 9 cases (11%). Viral culture was positive in 32 (37%), being ADV in 14 (41%), and RSV in 9 (26%). Significative serologic studies were obtained in 25 (60%) of the 42 studied patients, with VRS in 9 (32%) and M. pneumoniae in 9 (32%). Concerning clinical diagnosis, the major effectiveness corresponded to serology in pneumonia (76%), and to viral culture in URTI (63%). CONCLUSION: Viral culture and serology are useful methods for the detection of etiologic agents in acute respiratory infections. The serology effectiveness increases with age (p < 0.01) and the severity of the clinical diagnosis. Both methods have limited usefulness from clinical point of view. PMID- 8685495 TI - [Medullary carcinoma of the thyroid gland. Prognostic factors]. AB - OBJECTIVE: To analyze the clinical features and possible prognostic factors involved in the clinical course of a series of 26 patients with the diagnosis of thyroid medullar carcinoma (TMC). MATERIALS AND METHODS: An analysis was made of the variables age, sex, clinical course to diagnosis, paraneoplastic manifestations (flush, diarrhoea), clinical type (sporadic, non-associated, familial MEN IIa associated TMC, familial MEN IIb associated TMC), histologic uni or multicentricity, and stage of disease as possible predictive factors for the evolution. RESULTS: The most remarkable prognostic factor was tumoral stage. The likelihood of a patient diagnosed with stage I or II being free of metastatic disease was 1, 0.66 and 0.33 at 15, 16 and 17 years, respectively. In contrast, those patients in stage III at diagnosis had a likelihood of being free from metastasis 5 years after diagnosis and therapy of 0. With regard to sex, a better clinical course was observed among males than among females, statistically significant at 3 and 5, but not at 10 years. No statistical significance was reached with the other possible prognostic factors investigated. CONCLUSION: Given the obvious influence of tumoral stage of disease on prognosis, an early access to medical attention is desirable for diagnosis and treatment of TMC, as well as an early detection of family cases by a screening test. PMID- 8685496 TI - [Bronchiolitis obliterans organizing pneumonia. Clinical and evolutive features]. AB - A series is here reported of eleven patients with the histological diagnosis of bronchiolitis obliterans with organized pneumonia (BOOP) and the clinical course after one year of corticosteroid therapy. Four patients had idiopathic BOOP, one patient BOOP secondary to bone marrow transplantation and the other six patients had BOOP secondary to inhalation of toxic substances (Ardystil syndrome). The most common radiological feature at the onset of the disease was the presence of bilateral patchy infiltrates; the most common functional finding was a decreased diffusion capacity for carbon monoxide. After one year of follow-up, seven out of the ten patients still alive had a normal radiology and all showed a significant improvement in ventilatory and gasometric parameters. PMID- 8685498 TI - [Action plan for prevention of coronary disease in Europe]. PMID- 8685497 TI - [Prevention of coronary disease in clinical practice. Recommendations of the Task Force of the European Society of Cardiology (ESC), European Atherosclerosis Society (EAS) and European Society of Hypertension (ESH)]. PMID- 8685499 TI - [Registry of activities of the Hemodynamics and Interventional Cardiology Section in 1994]. AB - Results of the Spanish Registry for Hemodynamic and Interventional Cardiology are presented. As previous years, has been done by the Chapter of Hemodyamics and Interventional Cardiology of the Spanish Society of Cardiology. Seventy seven cardiac catheterization laboratories have collaborated, which represents 100% of those who had any activity in 1994. Sixty nine performed cardiac catheterization in adults, in 90% of the cases performing coronary intervention, and 22 performed both adult and pediatric studies. Eight laboratories exclusively performed pediatric cardiac catheterizations. Fifty five thousand one hundred sixty nine diagnostic procedures were performed, the majority of them being coronariographies (41,887), representing an increase of 10% from 1993. Ten thousand four hundred thirty three angioplasty procedures were performed in 1994. This represents 274 PTCA per million people (an increase of 21% compared to 1993). Eighty seven per cent of these procedures were done with conventional balloon, 1,361 stents were implanted (724 electivily), and 308 directional and 305 rotational atherectomies were performed. The overall results are similar to those of 1993, except for a marked reduction in complications of stents procedures (mainly in those implanted in a rescue situation). PTCA success was 91% with a complication rate of 3.4% and a mortality of 0.69%. The number of mitral valvuloplasties decreased 16% (694 vs 825 in 1993), and the pediatric interventional procedures were 7% less than those of 1993. PMID- 8685500 TI - [National Registry of Heart Transplantation. 6th Report (1984-1994)]. AB - As in previous years, the results of the Spanish Registry for Heart Transplantation are presented by the Section of Heart Transplantation of the Spanish Society of Cardiology. There are 12 participating Hospitals with Heart Transplantation Program. The activity of the different centres depends on the geographic situation and the years of activity. In 1994, 292 procedures were performed, all orthotopics, which represents a 2% increase from 1993. The early mortality was 12%. The actuarial survival is 53% at 8 years, similar to the International Society for Heart and Lung Transplantation (ISHLT). The survival depends on donor age, receptor age, receptor sex, ischemic time, etiology of cardiac dysfunction and period of time of intervention. PMID- 8685501 TI - [Coronary angioscopy: initial experience during coronary interventions]. AB - BACKGROUND AND OBJECTIVE: Percutaneous coronary angioscopy (CAG) provides in vivo visual information about the luminal aspect of the vessel. In this report we describe our initial experience with CAG during coronary angioplasty (PTCA). METHODS: Fifty-five patients (age 60 +/- 9 years), 8 female, were included. Most patients, 42 (76%) were treated for unstable angina. RESULTS: In 49 patients (89%) CAG was performed prior to PTCA, and in all cases the intraluminal material responsible of the stenosis was recognized. This included plaque associated to thrombus in 29 patients (59%), isolated plaque in 15 (31%) and isolated thrombus in 5 (10%). Of these plaques, 25 (57%) were yellow, 14 (32%) were yellow and white and 5 (11%) were white. Of the 34 thrombi, 23 (68%) were mural and 11 (32%) protruding. CAG post-PTCA was performed in 43 patients (78%). CAG visualized residual plaque in 41 patients (95%) and residual thrombus in 34 (79%). In addition, CAG recognized dissections in 30 patients (70%). CAG was more sensitive than angiography for the detection of thrombus (pre-PTCA 34 [69%] vs 11 [22%]; p < 0.05, and post-PTCA 34 [79%] vs 5 [12%]; p < 0.05]) and coronary dissections (post-PTCA 30 [70%] vs 19 [44%]; p < 0.05). CAG before intervention caused angina in 39 patients (80%), ventricular fibrillation (successfully managed with DC cardioversion) in 1, and AV block in another patient. The angiographic result deteriorated in 4 patients (9%) immediately after the CAG performed following PTCA. A repeat balloon PTCA was required in these patients. CONCLUSIONS: CAG provides unique information on coronary lumen surface that complements angiographic data. As compared with angiography, CAG is more sensitive in the detection of intracoronary thrombi and dissections. Further studies are required to determine whether the additional information provided by CAG may be used, to select coronary interventions according to specific lesion characteristics, to optimize dilation results and, eventually, to improve the clinical outcome of these patients. PMID- 8685502 TI - [Usefulness of nuclear magnetic resonance in the diagnosis of aortic coarctation and recoarctation]. AB - OBJECTIVE: To assess nuclear magnetic resonance (NMR) usefulness in aortic coarctation and recoarctation diagnosis. MATERIAL: 46 NMR performed on 43 patients: aortic coarctation was suspected in 30 patients and recoarctation in 13 by means of clinical, echocardiographic and Doppler examination. METHOD: Comparison of the NMR observations with the previous diagnosis and the surgical and therapeutic catheterism findings. RESULTS: 41 patients were diagnosed of aortic coarctation or recoarctation by NMR, although a second examination was needed in 3 cases. This diagnosis was confirmed in the 26 treated children (surgical treatment or by angioplasty). CONCLUSIONS: NMR offers excellent aortic images; positive diagnoses have a high safety level, but patients with negative diagnoses must be clinically followed; children suffering from native coarctation can be operated without previous angiographic examination. PMID- 8685503 TI - [Technical innovations in total extracardiac cavo-pulmonary connection in Fontan type operation. An experimental study and first 2 operated clinical cases with excellent immediate results]. AB - INTRODUCTION: Three technical modalities are presented with total extracardiac cava-pulmonary connection, with bidirectional Glenn, as coverage of this type of extracardiac connection for all types of cardiopathies suitable for Fontan type correction. METHODS: Development of an experimental protocol for the perfecting of the three technical variants tested: "Tunnel from inferior cava to right pulmonary artery by means of right atrial wall and vascularized pericardium", "Tunnel from inferior cava to the trunk of the pulmonary artery with or without pulmonary valve with P.T.F.E. hemiconduit" and "Tunnel from inferior cava to the pulmonary graft as a artery with P.T.F.E. graft as a hemiconduit". RESULTS: The first two clinical cases operated on using the third technical variant are presented. Both cases evolved during immediate postoperative period with a very favourable hemodynamic response, with pressures at conduit and P.A. level of 10 12 mmHg, normal cardiac output and sinus rhythm. The later clinical evolution in both cases is very satisfactory. The five cases published by Laschinger with this same technique showed a very favourable evolution during the immediate postoperative period and later. CONCLUSION: The technical facility of its performance, the slight traumatism of this surgery, the important technical advantages with respect to the total cava-pulmonary intraauricular connection and the good initial hemodynamic results make us consider the total extracardiac cava pulmonary connection as an important contribution in this type of surgery. It is clear that time and greater clinical experience with this type of connection is required for the correct evaluation of all and each one of the numerous theoretical advantages shown and in order to detect possible disadvantages. PMID- 8685505 TI - [Role of noninvasive techniques (electrocardiogram, Holter, tilt-table test, nuclear magnetic resonance, isotopes) in the evaluation of patients with hypertrophic cardiomyopathies]. AB - In most patients with hypertrophic cardiomyopathy the electrocardiogram is abnormal (left ventricular hypertrophy, abnormal Q waves, giant T waves, ST segment elevation). Occasionally, the localization of ventricular hypertrophy may be suggested by the electrocardiogram. Holter monitoring should always be performed in these patients as it permits to assess one of the leading prognostic factors, i.e. nonsustained ventricular tachycardia. Head-up tilt test may point to the mechanism of syncope, and thus be helpful in patients with this symptom. In patients with poor acoustic window, magnetic resonance imaging and perfusion single-photon emission tomography may give useful additional morphological information. Recent studies indicate that patients with perfusion defects have poorer prognosis, but this suggestion should be validated in wider series. Finally, radionuclide ventriculography is the most reproducible technique for the follow up of ventricular systolic and diastolic function and response to therapy. PMID- 8685504 TI - [Radiofrequency treatment of tachyarrhythmias in children and adolescents]. AB - INTRODUCTION: Radiofrequency ablation has been extensively used in adults to treat supraventricular and ventricular tachycardia. In children and adolescents few data are available on its safety and efficacy. METHODS: 28 patients (mean age 12.8) with symptomatic tachyarrhythmias underwent catheter ablation; 21 children had atrioventricular accessory pathways (11 right connections, 9 lef connections and one midseptal pathway), 3 had intranodal tachycardia, 2 had ventricular tachycardia and 2 had atrial tachycardia. Only four patients had associated structural anomalies. RESULTS: Success rate was 71.4% (20 patients). The success per cents in each group were: in intranodal tachycardias 100%; we failed in the two patients with ventricular tachycardias; in accessory pathways 76.1% and 50% in atrial tachycardia. There were no recurrences of arrhythmia in a mean chase period of 24 months (12-46). Major complications were only observed in one patient who developed a Wallenberg syndrome after ablation. CONCLUSIONS: Radiofrequency catheter ablation appears to be a safe and effective method to treat arrhythmias in children and adolescents, which in most cases can supersede surgery. Alow incidence of complications is reported, although long term damage on endocardial structures remains yet to be determined. PMID- 8685506 TI - [Silent myocardial ischemia. Arguments in favor of treatment]. PMID- 8685508 TI - [Adverse effects of dobutamine stress echocardiography]. AB - OBJECTIVES: To study the side effects of dobutamine echocardiography and to define the protocol with less side effects. PATIENTS AND METHODS: Since June 1992 to November 1994 dobutamine echocardiography was performed on two different groups of patients. In the first, the test was preoperatively done to evaluate the surgical risk. The remaining were patients with angina. Dobutamine was started at a dose of 5 micrograms/kg/min and increased up to a total dose of 40 micrograms/kg/min. Since March 1993 atropine was added if the heart rate was under 90 beats/min. RESULTS: One hundred and forty one patients were included (76 for a preoperatory appraisal and 65 with angina). Echocardiography test was not performed on 3 patients (2 with pulmonary disease and 1 with a therapeutic neumothorax). Among the remaining 138 patients, side effects appeared in 53 patients (38%) and test had to be prematurely interrupted in 11 (8%) of them. Side effects presented during the test in 9 (7%) although it could be finished and at the end of the test in 33 (24%). The most frequent side effects were arrhythmias that appeared in 28 patients (20%) and were considered significant in 17: 7 with supraventricular tachycardia, 7 with more than 6 ventricular premature systoles per minute, 2 with ventricular tachycardia and 1 with multifocal supraventricular premature systoles. These arrhythmias were observed when the dose of dobutamine was 20 micrograms/kg/min or more (p < 0.05). Hypotension developed in 11 patients (8%) and noncardiac effects in 13 (9%). The dobutamine test was interrupted for arrhythmias in 4% of cases, noncardiac side effects in 2% and poor image quality in 3%. A steady increment of heart rate 5 minutes after infusion of atropine was detected in 12 patients (maximal: 93 +/- 23 beats per minute; after five minutes: 94 +/- 19) and side effects were encountered in only one of these patients (hypotension). CONCLUSIONS: Intravenous administration of dobutamine during echocardiography can be finished in the majority of patients with good tolerance in spite of its side effects. Arrhythmias with dose over 20 micrograms/kg/min, poor image quality and chronotropic insufficiency are the most frequently encountered limitations. PMID- 8685507 TI - [Morphological and quantitative analysis of the mechanism of balloon angioplasty. An intravascular ultrasonic study]. AB - BACKGROUND AND OBJECTIVES: Intracoronary ultrasound allows to study in vivo the morphology of the arterial wall, the presence and composition of atheroma and the associated lumen encroachment. The objective of our study was to assess the value of intravascular ultrasound to determine the dilatation mechanism after a conventional balloon angioplasty. PATIENTS AND METHODS: Sixteen patients were examined with intravascular ultrasound before and after they had undergone percutaneous transluminal coronary angioplasty. A mechanical intravascular ultrasound system was used. Two different types of imaging catheters were used in this study: a 20 MHz, 4.8 F catheter in 5 patients and a 30 MHz, 3.5 F in 11 patients. RESULTS: Quantitative and qualitative assessments were made from the angiograms and the ultrasound images. Seven out of 16 patients had a calcified plaque, in 8 patients the plaque was fibrotic and in 1 patient soft. Rupture of the plaque was the most common dilatation pattern. Post-PTCA the cross-sectional arterial area was increased from 15.3 +/- 5.2 mm2 to 17.3 +/- 6.2 mm2, the intraluminal area was increased from 2.7 +/- 2.5 mm2 to 7.3 +/- 3.4 mm2, and the plaque area was reduced from 12.3 +/- 4.8 mm2 to 9.7 +/- 3.4 mm2. The quantitative analysis showed that the "most frequent dilatation mechanism" found was the reduction of size plaque, an increase in cross-sectional arterial area was present in only 4 patients (25%). The incidence of depth rupture of the plaque was greater in patients with a calcified plaque than in those without (NS). CONCLUSIONS: 1). Intracoronary ultrasound provides a complete description of plaque composition and geometry before and after coronary balloon angioplasty; 2) several morphologic dilatation patterns were found, and plaque tearing was the most common, and 3) increase in luminal area was most frequently due to a reduction in plaque area. Nevertheless an increase in the cross-sectional arterial area was also common, but less important. PMID- 8685509 TI - [Study of heart rate variability in acute myocardial infarction and its relationship with ventricular function and other clinical variables]. AB - BACKGROUND: The influence of ventricular function (VF) on prognosis in acute myocardial infarction (AMI) is well known. Heart rate variability (HRV), as a neurohumoral parameter could predict VF after discharge in AMI patients. Our goal is to investigate the possible relation among HRV, VF and another clinical variables in AMI. PATIENTS AND METHODS: We studied 37 patients with AMI after hospital discharge. Age, AMI type, location, enzymes, treatment (thrombolysis versus no thrombolysis) were evaluated. The left ventricular ejection fraction (LVEF) was assessed by radionuclide ventriculography in 27 subjects. Twenty nine subjects without cardiopathy were the control group. Twenty four hour electrocardiographic recordings were obtained and a proper software was used to measure HRV. This was evaluated with time domain measures: RR interval, standard deviation of the mean RR interval (SDNN), standard deviation of the average of the RR intervals measured every 5 minutes during 24 hours (SDANN) and number of two consecutive RR intervals with a variability > 50 ms (pNN50). We considered a decreased variability if SDANN was less than 100 ms. Two groups were established: 1) low heart rate variability (LHRV) if SDANN was less than 100 ms, and 2) normal heart rate variability (NHRV) if SDANN was larger than 100 ms. Continuous variables were examined by the t-test, chi square for discrete ones and linear regression analysis was used to assess the relation among variables. A p < 0.05 was considered significant. RESULTS: The percentage of infarcted patients in the group of LHRV is 75%, whereas it is 14% in the control group (p < 0.05). SDANN, SDNN and pNN50 values are significantly lower (p < 0.05) in the AMI than in the control group. LHRV was more frequent in patients with complicated AMI with congestive heart failure. LVEF was significantly lower (35% vs 56%) in the LHRV than in the NHRV group. No significant differences were found among: site, type infarct, treatment or ventricular ectopy in the Holter before discharge. There is good correlation (r = 0.635; p < 0.05) between LVEF and HRV measures. No correlation was found between HRV and age, or the enzymatic size of infarction. CONCLUSIONS: 1) LHRV is frequent in the late phase of AMI, and 2) LHRV can be an indirect index of left ventricular failure. PMID- 8685510 TI - [Value of a short (7 days) prophylactic course of ganciclovir in the prevention of cytomegalovirus disease after heart transplantation]. AB - BACKGROUND: The incidence of cytomegalovirus disease remains important after heart transplantation, mainly in the first months after transplantation. We undertook a study to evaluate a short (7 days) prophylactic administration of ganciclovir to prevent cytomegalovirus disease after heart transplantation. PATIENTS AND METHODS: There were two groups of patients: patients transplanted in 1993 (37) and patients transplanted in 1992 (38). In the first group, ganciclovir was given intravenously at a dose of 10 mg per kilogram of body weight every day from postoperative day 1 through day 7. In the second group, ganciclovir was not given. Similar regimens of immunosuppression (ATG, deflazacort, azathioprine and cyclosporine) were given. RESULTS: Age, sex, serology in recipients and donors and incidence of acute rejection were comparable between both groups. Mortality was slightly higher in ganciclovir group (35%) than in control group (26%), although this difference was not statistically significant. There were two cases of cytomegalovirus disease in the ganciclovir group (6%) and nine cases in the control group (27%) (p < 0.05), all of them treated successfully. Cytomegalovirus disease in ganciclovir group occurred in two children, who were seronegative before transplantation. The incidence of cytomegalovirus disease in the pediatric recipients of ganciclovir group were 50% (2 of 4) and 100% in the control group (1 of 1). The incidence of cytomegalovirus disease were therefore 0% in the adult subgroup of ganciclovir group and 24% in the adult subgroup of control group. CONCLUSIONS: A short (7 days) prophylactic administration of ganciclovir reduces the incidence of cytomegalovirus disease. In the pediatric group, the effectiveness is lower. PMID- 8685511 TI - [Percutaneous extraction of intravascular foreign bodies: a series of 38 cases]. AB - BACKGROUND AND OBJECTIVES: Retained foreign bodies or embolization in cardiac chambers is a relatively common clinical problem. As experience was acquired, it became apparent that failure to remove such fragments could result in morbility or mortality. In the past, surgical removal was the only method available. We present our experience of percutaneous extractions of embolized foreign bodies. The technical aspects are discussed. PATIENTS AND METHODS: Twenty eight cases (age between 1 and 80 years) of cardiac and intravascular foreign bodies seen in two hospitals are reported. Seventeen were plastic catheters or fragments (two were radiotransparent), 5 guide wires in vena cava, right atrial and ventricle, pulmonary artery and abdominal aorta, 4 patients had pacemaker electrodes in the right atrium or ventricle. Stent embolization was observed in two patients. The stents were stripped from the delivery catheter and removed from iliac artery. A pigtail catheter was sometimes used to remove the fragment found in the right ventricle. In 8 cases the capture and extraction was made using a loop snare with a 0.025 inch guide J-wire device folded in half at its midsection and inserted through a long introducer, and in another 20 cases a Dormia basket system was used. In all four patients with pacemaker electrodes, simple counteraction was used with a 10 F left coronary directional atherectomy guide catheter. RESULTS: In two patients removal was impossible--in one the pacemaker electrode was caught but not retrieved because was densely adhered to the endocardium for several years; in another a guide wire was found in a child one year old--. In the other 26 patients, foreign body extraction was performed percutaneously without any complication with a basket or snare; only in one case (a radiotransparent catheter) both systems were used. CONCLUSIONS: Percutaneous removal of centrally embolized foreign bodies, cardiac or vascular, is a safe and successful procedure. The basket system needs to be used more carefully. PMID- 8685512 TI - [Radiofrequency catheter ablation in permanent atrioventricular junctional reciprocating tachycardia in children]. AB - BACKGROUND: The permanent form of junctional reciprocating tachycardia occurs predominantly in childhood and is frequently refractory to pharmacologic treatment. These patients are at high risk for developing tachycardia-induced cardiomyopathy. Radiofrequency transcatheter ablation appears promising as safe and effective therapy in children. PATIENTS, METHODS AND RESULTS: Six patients ranged in age from 3 months to 20 years who had the permanent form of junctional reciprocating tachycardia underwent radiofrequency catheter ablation. Five patients had been treated with 3.4 +/- 1.1 antiarrhythmic drugs and one patient did not receive treatment before ablation. Three accessory pathways were located in the right posteroseptal area, two in the left posteroseptal area and one in the left posterior free wall. The six patients had seven successful procedures performed including one after tachycardia recurrence in one patient six weeks after the first ablation session. Five ablation procedures were performed with temperature-guided catheter ablation. The temperature reached during successful radiofrequency applications was 55-60 degrees C at a power output from 24 to 47 W. In the other two procedures 25 W were given. No complications were observed. After a mean follow up of 11.6 months all patients are asymptomatic including a 3 months old patient with tachycardia-induced cardiomyopathy. CONCLUSIONS: Radiofrequency transcatheter ablation is an important option of therapy in children with the permanent form of junctional reciprocating tachycardia, including patients with tachycardia-induced cardiomyopathy. PMID- 8685513 TI - [Hemodynamic and electrophysiologic changes in hypertrophic cardiomyopathy]. AB - Hypertrophic cardiomyopathy is characterized by abnormalities of the myocardium, and the activation and conduction tissues, that may have separate manifestations, but often occur together in complex clinical pictures. The subaortic gradient, although not always present, is the most classical manifestation of the disease, with its typical dynamic behavior, changing with preload, afterload and contractility. In most cases it is due to systolic motion of the mitral valve against the septum in systole, but in a few it is caused by midventricular "constriction". Alteration of diastolic ventricular function is important, and probably the main cause of heart failure, that is usually accompanied by normal systolic function. Mitral insufficiency is common in the obstructive forms, due to the abnormal mitral valve motion, but in some cases it may be due to structural abnormalities of the valve. There may be systolic constriction, or nonatherosclerotic occlusion of the intramyocardial coronary arteries, causing myocardial infarction and ventricular aneurysms, that may lead to systolic dysfunction. The electrocardiogram is rarely normal. Hypertrophy patterns, deeply inverted T waves, deep Q waves, QRS slurring suggestive of WPW syndrome without true preexcitation are the most common manifestations. Rhythm disturbances are common and include sinus node dysfunction, superconductor atrioventricular node or heart block. Atrial fibrillation is frequent and may have catastrophic consequences, including systemic embolism. Non-sustained ventricular arrhythmias are often present, but its predictive value for sudden death is unclear. Monomorphic ventricular tachycardia is infrequent, and programmed stimulation is more likely to precipitate polymorphic ventricular tachycardia of difficult clinical interpretation. Sudden death may be due to multiple mechanisms, and it is difficult to predict and prevent. PMID- 8685514 TI - [Silent myocardial ischemia. Arguments against treatment]. PMID- 8685515 TI - [A case of corrected transposition of great vessels in an adult. Value of magnetic resonance]. AB - Corrected transposition of the great arteries is an unusual congenital heart defect, particularly in adults. Echocardiography and angiography are still cornerstones for its diagnosis. However, other techniques, as magnetic resonance imaging, may constitute a noinvasive diagnostic alternative to cardiac catheterization. We present one case of corrected transposition of the great arteries in an adult patient in which this method was used. PMID- 8685516 TI - [Pheochromocytoma, acute myocardial infarction and silent postprandial ischemia]. AB - We report the case of a 70 years-old patient admitted for an acute anterior myocardial infarction and who subsequently presented postprandial episodes of astenia, dyaphoresis and arterial hypertension associated with re-elevation of the ST segment and positivization of T waves in the precordial leads, without chest pain. These episodes were interpreted as silent postprandial myocardial ischemia. A coronary angiography demonstrated a single vessel disease with a severe and proximal stenosis of the left descending coronary artery which was successfully dilated during angioplasty. However, the postprandial episodes persisted and re-estenosis was ruled out in a repeated coronary angiogram. A stress thallium myocardial scintigraphy was negative. Complementary tests documented the existence of a pheochromocyctoma and the refered postprandial symptoms did not recur after removal of the tumor. Thus, the persistence of postprandial episodes of myocardial ischemia associated with severe hypertension and dyaphoresis in the absence of a significant coronary stenosis, may possibly be related to a concomitant coronary and systemic vasoconstriction secondary to the adrenal tumor. PMID- 8685517 TI - [Persistence of the left superior vena cava associated with aortic insufficiency: diagnostic and therapeutic considerations]. AB - In the course of the routine evaluation of a 26-years-old male for acquired aortic valve disease the persistence of a left superior vena cava draining into the coronary sinus was detected. This is a frequent congenital malformation of the systemic venous system that has no hemodynamic consequences in itself, though it may be associated to other congenital or acquired cardiac malformations that may require surgery. The preoperatory detection of the anomaly prevents unexpected problems when connecting the cardiopulmonary bypass. We emphasize the importance of procedures that suggest the diagnosis and characterize the anatomo functional nature of the condition--including transthoracic and transesophageal echocardiography using echocardiographic contrast, and cardiac catheterization with cardiac and vascular angiography. PMID- 8685518 TI - [Stratification of arrhythmia risk and therapeutic options in survivors of acute myocardial infarction]. AB - A significant improvement in late survival of post-myocardial infarction patients has been observed during the last few years, even before the beginning of the thrombolytic era. However, about half of the fatality rate in these patients is related to arrhythmic sudden death. So, a discussion of the value of different diagnostic and therapeutic tools available for reducing arrhythmic risk seems pertinent. Several features are considered risk markers for sudden arrhythmic death: symptomatic ventricular arrhythmias, left ventricular disfunction, myocardial ischemia, frequent or complex premature ventricular contractions, late ventricular potentials in high-resolution ECG and autonomous nervous system disturbances. It seems reasonable to state that the risk markers whose value was established before the thrombolytic era maintain most of their clinical applicability to the present, but none of them has specificity enough as a sudden death predictor to warrant a general systematic strategy to trace such risk arrhythmic factors. Prophylactic administration of Type I antiarrhythmic drugs to patients with frequent or complex premature ventricular contractions can no longer be justified. There is probably a place for betablockers, mainly in patients with mild to moderate depression in left ventricular function. The final results of several trials currently in progress should contribute to establish the potential role of low dose amiodarone. There is not enough evidence to determine which post-myocardial infarction patients will be candidates for an Implantable Cardioverter Defibrillator Device. Patients with risk factors for sudden death, in particular those who have a severe impairment of left ventricular function and/or severe ischemia in the stress test, would be able to take advantage of a revascularization procedure when the culprit vessel remains occluded. In the intermediate risk patients (20-40% of the total population), tests attempting to more precisely evaluate the arrhythmic risk would be warranted, always in an individualized, sequential schedule. In some cases, like the high-resolution ECG or the heart rate variability indices, more clinical investigation is necessary to adequately establish their value in routine clinical practice. PMID- 8685519 TI - [Changes in mean serum lipid levels in pediatric and adolescent population of Navarra between 1987 and 1993]. AB - INTRODUCTION AND OBJECTIVES: Atherosclerosis originates during childhood and serum lipid levels are a key factor of the process. The aim of this study is to assess the evolution in the mean serum lipid levels found in children and teenagers in Navarra, Spain, in 1987 and 1993 and to compare them with the overall Spanish standard levels. METHODS: Two cross-sectional surveys on cardiovascular risk factors in the population aged 4 to 17-years in the Navarra region, carried out in 1987 and 1993. Both studies used comparable procedures, and covered school-children between the above-mentioned ages of 4 and 17 years. The lipid levels were assayed by enzymatic methods from blood samples, using an autoanalyzer. Statistical methods to compare means and proportions were used. RESULTS: The sample size was 5,829 in 1987 and 3,256 in 1993. Among males, the average cholesterolemia was 177.3 mg/dl in 1987 and 174 mg/dl in 1993. Among females it was 179.8 mg/dl in 1987 and 174.9 mg/dl in 1993. The percentage of males with cholesterolemia over 200 mg/dl was 20.4% in 1987 and 16.8% in 1993. Among females this percentage was 21.9% in 1987 and 17.8% in 1993. The percentage of males showing hyperlipidemia (LDL/HDL > 2.2) was 15.1% in 1987 and 12.5% in 1993. For females this percentage went from 16.8% in 1987 to 13% in 1993. CONCLUSIONS: Between 1987 and 1993 a decrease in the average levels of serum cholesterol and LDL-cholesterol among the infant-to-young population of Navarra has been assessed. No changes in the HDL or serum tryglicerides were detected. Some effects in the results, due to differences in the pre-analytical and analytical phases of both surveys, cannot be excluded. PMID- 8685520 TI - [Electrocardiographic differentiation between lesions of the right coronary artery and circumflex artery in acute inferior myocardial infarction]. AB - INTRODUCTION AND OBJECTIVES: The objective of this prospective study is to analyze the value of the standard electrocardiogram in the identification of the lesioned coronary artery in the inferior acute myocardial infarction. METHODS: One-hundred consecutive patients with inferior acute myocardial infarction were studied, 67 with lesion in the right coronary artery and 33 in the circumflex artery. The ST segment changes in inferior, lateral and precordial leads were analized, as was the ST segment relation between the DII and DIII. The arithmetic sum of the ST segment in the inferior and V2 leads (II+V2, III+V2 and aVF+V2). RESULTS: This study shows that the most useful parameters to predict the lesioned coronary artery in the inferior acute myocardial infarction, with specificity and positive predictive value of 100% are: a) the arithmetic sum of the ST segment: aVF+V2 > 0, with a sensibility of 86.5%, for the right coronary artery; b) the arithmetic sum of the ST segment: III+V2 < 0, with a sensibility of 90.9%, for the circumflex artery, and c) the arithmetic sum of the ST segment: aVF+V2 > 1, with a sensibility of 97.6%, for the proximal right coronary artery. Other useful predicting parameters, with specificity of 100%, although with a lower sensibility, are: a) ST segment elevation in I and ST segment in II > III, for the circumflex artery, and b) ST segment elevation in V1-V3 for the lesion in the proximal right coronary artery. CONCLUSIONS: These findings demonstrate that the standard electrocardiogram represents an important tool in predicting the lesioned coronary artery, right coronary and circumflex artery, in the acute myocardial infarction, with a sensibility and specificity between 86.5% and 100%, respectively, which are within the published range of the traditionally used right thoracic leads. PMID- 8685521 TI - [Survival in patients with sick sinus syndrome and artificial pacemaker. Determining clinical factors]. AB - INTRODUCTION AND OBJECTIVE: The hypothesis that ventricular pacing is the most important factor in the survival of patients with Sick Sinus Syndrome remains controversial. The aim of this report was to determine independent clinical variables to predict survival in paced SSS patients. METHODS: Retrospective, nonrandomized study of 153 patients with a mean age of 69 +/- 11 years, who received an initial pacemaker for Sick Sinus Syndrome between 1980 and 1994: 65 physiologic pacing (32 dual chamber, 33 atrial) and 88 ventricular pacing mode. After a maximum follow up of 177 months (median 57 months) the end point was total mortality. RESULTS: Total mortality was 21%. Using univariate analysis, single chamber ventricular pacing, age > or = 70 years and NYHA > or = 2, was associated with a higher risk for total mortality (4 times increased risk for ventricular pacing compared to other pacing modalities). Independent predictors using multivariate analysis were: 1) NYHA > or = 2 (p < 0.05). 2) Coronary artery disease (p < 0.01). 3) Chronic obstructive pulmonary disease (p < 0.05) and 4) Gender (p < 0.05). CONCLUSIONS: Mortality in patients with the Sick Sinus Syndrome is strongly predicted by preimplant baseline clinical variables. Our data indicate that the role of ventricular pacing mode remains inconclusive. A large, randomized study is necessary to confirm these results. PMID- 8685522 TI - [Normal values of valvular flow velocities determined by Doppler echocardiography: relations with heart rate and age]. AB - INTRODUCTION AND OBJECTIVES: The velocity-time integral (VTI) and the mean velocity of valvular flow are widely-used variables in Doppler-echocardiography. The aim of the present work was to determine normal VTI and mean velocity values of valvular flow and their relation to age, sex, heart rate and body surface area. METHODS: One hundred and fifty-six patients (84 men, 72 women; age range: 6 86 y; mean: 37 +/- 20) without cardiovascular disease were studied by Doppler echocardiography. VTI and the mean velocity of left and right ventricular outflow tract, and mitral and tricuspid valvular flow were determined by pulsed-wave Doppler. Aortic and pulmonary valvular flow were assessed by continuous wave Doppler. RESULTS: Mean value of aortic valvular flow VTI (22 +/- 4 cm) was slightly higher than that of pulmonary valvular flow (20 +/- 4 cm). Mean VTI values of left and right ventricular outflow tract and mitral valvular flow were similar (16 +/- 3, 15 +/- 3 and 15 +/- 3 cm, respectively) with an acceptable correlation (r = 0.76-0.83). VTI of tricuspid valvular flow was clearly lower than the rest (10 +/- 3 cm; p < 0.001). Linear regression analysis showed the VTI to be inversely related to heart rate and age, and mean velocity positively related to heart rate and inversely to age. While VTI remained relatively stable up to the age of 60 and decreased sharply thereafter, mean velocity decreased progressively with age. VTI values were identical for both sexes; however, mean velocity was higher in women up to the age of 60. CONCLUSIONS: VTI is a Doppler parameter independent of body surface area, inversely related to heart rate, not sex-related and remains stable up to the age of 60. Normal mean velocity values should be defined in relation to heart rate and age. Normal values of these Doppler parameters should be borne in mind for non-invasive assessment of cardiovascular function. PMID- 8685523 TI - [Identification of intramural aortic hematoma by transesophageal echocardiography]. AB - BACKGROUND AND AIM: The usefulness of transesophageal echocardiography in the diagnosis and assessment of patients with aortic dissection has been widely demonstrated. The aim of this study was to evaluate the role of this technique in the detection of intramural aortic hematoma and in the follow-up of these patients. METHODS: The records of 51 patients with aortic dissection by transesophageal echocardiography diagnosed between May 1990 and May 1994 were reviewed. RESULTS: The diagnosis of intramural aortic hematoma was established in 6 patients by transesophageal echocardiography (11%). This diagnosis was confirmed either anatomically (3 patients) or with an additional diagnostic technique (computed tomography or magnetic resonance imaging) and on the basis of echocardiographic follow-up changes (3 patients). CONCLUSIONS: Intramural aortic hematoma represents an infrequent variant of aortic dissection that can be detected by transesophageal echocardiography and is usually unrecognized by aortography. PMID- 8685524 TI - [Clinical usefulness of stored electrograms in implantable defibrillators]. AB - BACKGROUND AND PURPOSE: The storage of intracavitary electrograms by the automatic implantable defibrillators is one of the latest advantages. The objective of this study was to determine the clinical utility and limitations of electrograms stored by the new generation of defibrillators. MATERIAL AND METHODS: We have implanted at our institution 43 generators with the facility of storing electrograms; 8 Ventak P2, 17 PRxII, and 1 PRxIII from CPI, 14 Jewel, from Medtronic and 3 Guardian ATP 4215, from Telectronics. All were implanted with an endocavitary system lead, an only one patient needed a subcutaneous patch. Mean age was 57 +/- 16 years, 36 were males and 7 women. The mean left ventricular ejection fraction was 44 +/- 23%. The mean follow up was 6 +/- 8 months (limits 1-20 months). RESULTS: We registered and analyzed a total of 268 episodes in 20 patients. Fourteen (82%) received what was considered appropriate therapy. Three patients (from 17 with any treatment delivered by the defibrillator) presented an inappropriate therapy. The parameters, "onset" and "stability", were differentiated in each arrhythmia, the "onset" is useful to differentiate sinus tachycardia, but not atrial fibrillation, from ventricular tachycardia. Programming a stability value between 30-40 mseg eliminates 88% of inappropriate therapies due to atrial fibrillation. In all patients, the identification of the event, facilitated by the stored electrograms, allowed us to resolve the problem. CONCLUSIONS: The programmable features "onset" and "stability" allowed us to eliminate a significant number of inappropriate therapies. The stored electrograms facilitate the identification of the events, leading to treatment by the generator, and were very useful in guiding the clinical management of the patient. PMID- 8685525 TI - [Cardiomyopathies (VII). Natural history of hypertrophic cardiomyopathy]. AB - After a short historic review of conceptual developments in hypertrophic cardiomyopathy, the natural history of the disease is analyzed according to each of its morphologic and functional abnormalities. The lack of association between hypertrophic morphology and sudden death is considered. Diastolic dysfunction and LV obstruction, although a frequent cause of dyspnea and heart failure, is not a risk factor for sudden death. Something similar occurs with the infrequent appearance in this disease of contractile failure. Myocardial ischemia is frequent in hypertrophic cardiomyopathy and general prognostic information about it is still lacking. Nevertheless, in young patients with family history of sudden death, a positive Thallium effort test may be a marker of sudden death (without an arrhythmogenic substrate), and may respond to verapamil. Finally, the new knowledge about genetic mutations in hypertrophic cardiomyopathy are analized. We conclude with some futuristic comments about hypertrophic cardiomyopathy. PMID- 8685526 TI - [Chylopericardium after acute pericarditis]. AB - We present an 18 year-old man with chylopericardium after acute pericarditis with severe pericardial effusion and cardiac tamponade secondary to Mycoplasma pneumoniae infection. We review the etiology, diagnostic procedures and therapeutic possibilities for chylopericardium. PMID- 8685527 TI - [Palliative arterial switch]. AB - We report the first case published in Spain of a palliative anatomic correction associated with aortic arch repair in a neonate with (S,D,L)-transposition of the great arteries, multiple ventricular septal defects, and severe hypoplasia of the right ventricle with subaortic obstruction and hypoplasic aortic arch with coarctation. A one stage palliative surgery on cardiopulmonary bypass was performed with reconstruction of the aortic arch and an arterial switch procedure which obtained a satisfactory result. The principle of this operation is to switch the subaortic obstruction into a subpulmonary obstruction and reconstruct a large natural aortic root from the principal ventricle. The right ventricle pulmonary artery continuity may promote growth of the right ventricle with the possibility of a future biventricular repair. We conclude that this operation, when used by surgical teams experienced with arterial switch surgery, is the best treatment for the complex newborn group with single ventricles or severe ventricular disbalance, ventriculoarterial discordance and stablished subaortic stenosis. PMID- 8685528 TI - [Rupture of type A aortic dissection into right cardiac cavities]. AB - We present three cases of communication between the false channel of an ascending aortic dissection and a right cardiac chamber in three patients that had previously been operated on for aortic valve replacement. In two cases there already was a degree of aortic dissection at the moment of surgery. Diagnosis was confirmed by transesophageal echocardiography and/or aortography. Two patients developed severe cardiac failure and underwent surgery, while the other one is surviving with medical treatment. PMID- 8685529 TI - Biotin-avidin amplified enzyme-linked immunosorbent assay (ELISA) for the measurement of canine serum IgA, IgG and IgM. AB - An amplified capture enzyme-linked immunosorbent assay (ELISA) has been developed by the use of the biotin-avidin detection system, for the measurement of canine plasma immunoglobulins (Ig) A, G and M. Test responses of dilutions of both the Ig standards and test plasma samples were consistently linear (r > 0.987) for the three Ig classes. The within-assay variation was 3.53 per cent for IgG, 5.84 per cent for IgM and 6.34 per cent for IgA. The analytical recoveries were 95 per cent for IgA, 97 per cent for IgG and 98 per cent for IgM. The lower detection limits of the assay were 38.4 ng ml-1 for IgG, 20.3 ng ml-1 for IgM and 41.2 ng ml-1 for IgA. The results indicate that this ELISA has a much higher sensitivity than the single radial immunodiffusion assay or the non-amplified ELISA for measurements of canine Igs, but has a comparable specificity and precision. PMID- 8685530 TI - Identification of soyabean allergens and immune mechanisms of dietary sensitivities in preruminant calves. AB - The allergenicity of soya proteins was assessed by direct skin testing and by in vitro lymphoproliferation tests in calves fed milk substitutes containing skim milk powder (SMP) or an antigenic heated soya flour (HSF). During the last three weeks of treatment, the calves were injected intradermally with raw soya flour (RSF), HSF, hydrolysed soya protein isolate (HSPI), SMP or purified soya proteins, after being premedicated with anti-histamine or not. Peripheral blood leucocytes (PBL) were grown over five days with various mitogens or dietary antigens, and the incorporation of tritiated thymidine was measured. Strong skin oedema reactions to RSF, HSF and all the purified proteins were observed in the calves fed HSF at various times up to 24 hours after injection. The skin oedema was largely prevented by premedication with anti-histamine. A strong delayed skin thickening was observed in the calves fed HSF for up to five days with beta conglycinin. PBL from the calves fed HSF proliferated in vitro with HSF, HSPI and beta-conglycinin, but not with glycinin. Thus, most proteins from soyabean were implicated in the immediate and semi-delayed immune reactions, whereas beta conglycinin was strongly involved in a delayed type hypersensitivity in calves. PMID- 8685531 TI - Evaluation of iohexol as a marker for the clinical measurement of glomerular filtration rate in dogs. AB - The contrast medium iohexol can be used as a marker for the measurement of glomerular filtration rate. It has the advantages of sample stability and the availability of a simple, automated (though expensive) analyser. The clearance of iohexol was compared with the clearance of Tc-DTPA in 24 dogs with known or suspected renal impairment. The results were comparable but fractionally lower with iohexol. The correction factors developed for human beings were found to be satisfactory in the dogs, thus validating the software routines used in the automated analyser with the canine samples. PMID- 8685532 TI - Stereological estimation of the absolute number of glomeruli in the kidneys of lambs. AB - An association between the arrest of renal development and intra-uterine growth retardation (IUGR) has been demonstrated in human beings and it has been suggested that the same defect may occur in the kidneys of lambs affected by IUGR. Using design-based stereological methods, the physical disector and Cavalieri's principle, smaller absolute numbers of glomeruli were found in all six IUGR lambs studied with a low birthweight and in two of six control lambs studied with a normal birthweight than in other lambs with a normal birthweight. There was no difference in absolute numbers of glomeruli between twin births and singletons. The absolute numbers of glomeruli in three stillborn lambs were distributed among results obtained from the normal and IUGR lambs in accordance with their individual bodyweights. IUGR had a profound detrimental effect on the renal development of the lambs. PMID- 8685533 TI - Further observations on the primary and anamnestic humoral responses to Dichelobacter nodosus in sheep in relation to the diagnosis of footrot. AB - An anamnestic serological test for ovine footrot was evaluated. Footrot-free lambs were infected with Dichelobacter nodosus and treated four, six or eight weeks later. There were strong linear correlations between the severity of the lesions and both the primary response and the anamnestic response evoked by the subcutaneous injection of an antigen from D nodosus 16 weeks after the treatment of the lambs; the latter correlation was stronger than the correlations reported elsewhere in mature sheep. Similar anamnestic responses were elicited six and 12 months after the treatment of mature sheep which had had severe lesions. Natural anamnestic responses were demonstrable in sheep which had had recurrent clinical episodes of virulent footrot. The non-specific humoral responses after the anamnestic challenge of footrot-free sheep increased with age and did not depend on the dose of the antigen between 10 and 200 micrograms. Using the pooled data from sheep of all ages and a positive-negative cut-off which was selected to obtain a sensitivity of 75 per cent, the specificity of the anamnestic test was 90 per cent, similar to that reported for the primary response when it was used to diagnose footrot. The anamnestic test can be applied to determine the presence and severity of footrot in young sheep. PMID- 8685534 TI - Ventricular arrhythmogenic dose of adrenaline during sevoflurane, isoflurane, and halothane anaesthesia either with or without ketamine or thiopentone in cats. AB - The doses of adrenaline required to induce ventricular arrhythmia during sevoflurane, isoflurane and halothane anaesthesia, either with or without infusions of ketamine (76 micrograms kg-1 min-1) or thiopentone (0.5 mg kg-1 min 1), were determined in cats. Groups of six to eight cats were maintained at end tidal concentrations equivalent to 1.25 times the minimal alveolar concentration of each anaesthetic. The mean dose of adrenaline required to induce arrhythmia during sevoflurane anaesthesia (19.0 micrograms kg-1) was approximately 11 times higher than that required during halothane anaesthesia (1.66 micrograms kg-1) and the same as that required during isoflurane anaesthesia (19.0 micrograms kg-1). Ketamine tended to decrease the requirement of adrenaline during halothane anaesthesia, but not significantly, and did not change the requirement during isoflurane or sevoflurane anaesthesia. Thiopentone did not change the requirement for adrenaline during halothane, isoflurane or sevoflurane anaesthesia. It was concluded that either with or without ketamine or thiopentone, the effect of sevoflurane on the sensitisation of the feline myocardium to the arrhythmogenic effects of adrenaline was significantly less than that of halothane and not different from that of isoflurane. PMID- 8685535 TI - Influence of soyabean meal supplementation on the resistance of Scottish blackface lambs to haemonchosis. AB - Protein supplementation improves the resistance of sheep to haemonchosis. This experiment investigated the Scottish blackface breed to establish whether dietary protein supplementation is still beneficial in a genetically resistant breed. Lambs were given either a basal diet or a diet supplemented with soyabean meal to give an additional 80 g crude protein kg dry matter-1. The lambs were given an initial loading dose of Haemonchus contortus, followed by a trickle infection for 10 weeks. The weight gains of the lambs given the supplemented diet were greater and their carcases were leaner, irrespective of infection status. Infected animals on the basal diet were more anaemic and hypoalbuminaemic than animals receiving the supplemented diet, although there were no statistically significant differences in mean worm burdens or faecal egg counts. PMID- 8685536 TI - Pharmacodynamics and enantioselective pharmacokinetics of carprofen in the cat. AB - The pharmacodynamics and enantioselective pharmacokinetics of the arylpropionic acid non-steroidal anti-inflammatory drug, carprofen, were investigated in cats after administration of the racemic mixture (rac-carprofen) at dose rates ranging from 0.7 to 4.0 mg kg-1 intravenously and subcutaneously. A low dose of rac carprofen (0.7 mg kg-1) partially inhibited the rise in skin temperature at a site of acute inflammation but had no effect on the ex vivo synthesis of serum thromboxane (Tx) B2. A higher dose (4.0 mg kg-1) inhibited oedematous swelling, although the response was statistically significant at only one time, and also reduced the ex vivo synthesis of serum TxB2 for 12 hours after intravenous injection or 24 hours after subcutaneous injection. The main features of carprofen pharmacokinetics were a low distribution volume, a relatively long elimination half-life, the predominance of the R(-) enantiomer and a bioavailability (after subcutaneous dosing) of 100 per cent and 92 per cent, respectively, after doses of 0.7 and 4.0 mg kg-1. On the basis of these data, it is suggested that a dose of 4.0 mg kg-1 by both intravenous and subcutaneous routes should be evaluated in clinical subjects. PMID- 8685537 TI - Plasma disposition kinetics of albendazole metabolites in pigs fed different diets. AB - The influence of diet on the disposition kinetics of albendazole (ABZ) and its metabolites in pigs was investigated. ABZ was administered orally at 10 mg kg-1 to pigs fed either a commercially produced 35 per cent protein/grain concentrate diet (concentrate group), a whey-based diet supplemented with corn grain (whey/grain group) or grazed on pasture (pasture group). Blood samples were taken serially for 96 hours and plasma was analysed by high performance liquid chromatography (HPLC) for ABZ, ABZ sulphoxide (ABZSO), ABZ sulphone (ABZSO2) and amino-ABZSO2 (NH2ABZSO2). ABZ was not detected in plasma at any time after the treatment, and ABZSO and ABZSO2 were the main metabolites detected between 0.5 and 30 to 48 hours after treatment in all the experimental animals. Low concentrations of the NH2ABZSO2 metabolite were found in plasma between 18 and 36 hours after the administration of ABZ to all the groups of pigs. The pharmacokinetic behaviour of the ABZ metabolites in pigs fed either the concentrate of the whey/concentrate diet was substantially different from that observed in pigs grazing on pasture. The peak concentration (C(max)) and areas under the concentration-time curves (AUC) for ABZSO and ABZSO2 were significantly higher (P < 0.01) in the pigs fed on pasture, and were correlated with significantly longer elimination half-lives and mean residence times for both metabolites. PMID- 8685538 TI - Presence of antigen and antibodies in serum and genital discharges of heifers after experimental intrauterine inoculation with Leptospira interrogans serovar hardjo. AB - The excretion of Leptospira interrogans serovar hardjo in cervico-vaginal mucus (CVM) or urine and the local and systemic immune responses to the organism were monitored in eight susceptible heifers after intrauterine inoculation while six similar heifers served as controls. All the heifers were inseminated at the subsequent oestrous periods. The overall percentage pregnancy rate (the number of pregnancies divided by the total number of inseminations) was lower in the infected heifers than in the controls though not significantly (33.3 v 50.0 per cent). Leptospires were detected, in either the urine or the CVM of six of the eight infected heifers during the study period of 15 weeks, either by direct immunofluorescence or dark ground microscopy; the bacteria did not grow in culture from any of the CVM samples. The control heifers remained free from evidence of infection. In the infected heifers, mean titres of at least 1:100 in a microscopic agglutination test were maintained for one to two weeks before declining to 1:10 to 1:30, whereas in serum IgG-ELISA tests (developed by using either protein or carbohydrate antigens), antibody titres of at least 1:100 were maintained throughout the study. During oestrous periods, IgA antibodies were detected more frequently in CVM with titres which were usually higher than the titres of IgG. PMID- 8685539 TI - Presence of antigen and antibodies in serum and genital discharges of cows from dairy herds naturally infected with Leptospira interrogans serovar hardjo. AB - Samples of cervico-vaginal mucus from 163 bulling cows (group 1) and post calving discharges from 59 newly calved cows (group 2) in five dairy herds naturally infected with Leptospira interrogans serovar hardjo were examined for the presence of antigen and IgG and IgA antibodies by using two ELISA systems which were protein or carbohydrate based. Corresponding serum samples were examined for systemic immune responses by using a microscopic agglutination test (MAT) and IgG ELISA tests. Antigen was detected by direct immunofluorescence in six of the 163 samples of cervico-vaginal mucus. Both IgG and IgA antibodies were detected by ELISA in the genital discharges with a prevalence much higher than that obtained by the MAT but lower than that observed with the serum IgG-ELISA. Combining both groups, none of the MAT-positive cattle was negative by serum-ELISA. By using the protein or carbohydrate fraction serum IgG-ELISA assays, respectively, 29 or 41 per cent of the MAT-negative cows were positive at a titre of at least 1:40. Similarly, eight or 23 samples (10 or 27 per cent) had titres of at least 1:20 in the genital discharge ELISA for IgG and IgA antibodies, respectively. The serum IgG-ELISA was the most efficient in detecting hardjo antibodies, but in group 2 the IgG- and IgA-ELISA of the post calving discharge proved to be equally effective. PMID- 8685540 TI - Restriction fragment length polymorphism of polymerase chain reaction products applied to the differentiation of poultry campylobacters for epidemiological investigations. AB - A technique for subtyping Campylobacter jejuni isolates has been developed by using the restriction fragment length polymorphism (RFLP) of polymerase chain reaction (PCR) products of the flaA and flaB genes. The technique was validated by using strains representing 28 serotypes of C jejuni and it may also be applied to C coli. From these strains 12 distinct RFLP profiles were observed but there was no direct relationship between the RFLP profile and the serotype. One hundred and thirty-five campylobacter isolates from 15 geographically distinct broiler flocks were investigated. All the isolates could be subtyped by using the RFLP method. Isolates from most of the flocks had a single RFLP profile despite data indicating that several serotypes were involved. Although it is possible that further restriction analysis may have demonstrated profile variations in these strains, it is more likely that antigenic variation can occur within genotypically related campylobacters. As a result, serotyping may give conflicting information for veterinary epidemiological purposes. This RFLP typing scheme appears to provide a suitable tool for the investigation of the sources and routes of transmission of campylobacters in chickens. PMID- 8685542 TI - Detection of antibodies to Staphylococcus aureus in water buffalo milk by flow cytometry. AB - An assay has been developed to detect antibodies to Staphylococcus aureus in water buffalo milk by flow cytometry. The method was the protein A-deficient strain Wood 46 of S aureus incubated with milk samples and fluorescein-labelled rabbit anti-water buffalo antiserum. The assay can detect antibodies when the pathogen is not detectable by bacterial tests and can determine the antibody titre directly on undiluted samples. PMID- 8685541 TI - Sequential studies of endochondral ossification and serum 1,25 dihydroxycholecalciferol in broiler chickens between one and 21 days of age. AB - Two commercial broiler flocks of two distinct strains (A and B) were studied at weekly intervals from day old to 21 days, to assess the progressive endochondral ossification of the proximal tibiotarsus and the serum concentration of 1,25 dihydroxycholecalciferol (1,25(OH)2D3). The incidence of defects of endochondral ossification was different in the two strains, strain B having an incidence of tibial dyschondroplasia (TD) of 10 to 70 per cent and strain A an incidence of 10 to 20 per cent. In strain B, 40 per cent of the bone samples collected at 14 days of age also had lesions of calcium deficiency rickets. The concentration of 1,25(OH)2D3 in the two flocks was similar in the day-old chicks, but was 40 to 50 per cent lower at seven, 14 and 21 days of age in strain B, during the development of the rachitic and dyschondroplastic lesions. These results suggest that TD in some broiler strains is related to an inherent predisposition to rickets and to lower serum concentrations of 1,25(OH)2D3. PMID- 8685543 TI - Immunohistochemical detection of rinderpest virus: effects of autolysis and period of fixation. AB - Samples of eyelid, tongue, soft palate and palatine tonsil were collected from calves infected experimentally with rinderpest virus. The tissues were fixed in 10 per cent neutral buffered formalin immediately, 24 or 48 hours post mortem. Then, after three days, 10 days, 28 days or three months in formalin, they were processed into paraffin blocks and examined immunohistochemically for rinderpest viral antigen. The tonsil was the best of the four tissues in providing a consistently positive immunohistochemical signal for the presence of virus, despite autolytic changes and/or prolonged fixation. PMID- 8685544 TI - Density and breaking strength of bones of mortalities among caged layers. AB - The incidence of deaths attributable to cage layer osteoporosis (CLO) and the associated parameters of bone strength were studied in a flock of 5000 commercial laying hens over one laying cycle. Of the 9.7 per cent mortality rate, 35 per cent were attributed to CLO, and the mean age of death of the CLO hens (45.5 weeks) was significantly earlier than that of the non-CLO hens (51.6 weeks). There was a significant linear relationship between the density and breaking strength of whole bones with no difference between the CLO and non-CLO hens. However, the density and breaking strength of the bones of the non-CLO hens were consistently greater than those of the CLO hens. The density and breaking strength of the bones of both groups of birds increased with age. PMID- 8685545 TI - Isolation and subgrouping of rotaviruses from buffalo calves in Sri Lanka. AB - Twenty-eight faecal specimens from Sri Lankan buffalo calves shown to be positive for rotavirus group A antigen were subgrouped by an enzyme-linked immunosorbent assay, by using monoclonal antibodies prepared against subgroup I and II antigens. The 13 of the 28 specimens which were classified as strongly positive belonged to subgroup I. Three of five faecal specimens inoculated on to roller cultures of MA104 cells yielded group A subgroup I rotavirus. As with other group A rotaviruses isolated from human beings and young animals, the buffalo isolates required pre-treatment with trypsin and to have trypsin incorporated in the maintenance medium, and the inoculated cell cultures had to be rolled; at least six serial passages were required before distinct rotavirus cytopathic effects were produced in the MA104 cells. PMID- 8685546 TI - Induction of L-arginine-dependent production of nitric oxide in bovine monocytes by interferon gamma and lipopolysaccharide. AB - Bovine monocytes freshly isolated from peripheral blood were induced to produce nitric oxide by exposing them to recombinant bovine interferon gamma (rbIFN-y) and Escherichia coli lipopolysaccharide (LPS) in vitro. Moderate amounts of nitric oxide were induced by rbIFN-gamma alone, but larger amounts were induced by rbIFN-gamma and LPS together, the amount being dependent on the quantity of rbIFN-gamma added. Reactive nitrogen intermediates (RNI) were produced within six hours, their concentration peaked at four days and they were detectable for at least eight days after the cells had been stimulated with rbIFN-gamma and LPS. The production of RNI was diminished by the addition of NG-monomethyl-L-arginine. The data suggest that bovine monocytes can produce RNI via a pathway involving an inducible nitric oxide synthase. PMID- 8685547 TI - Effects of selenium and vitamin E on the immune responses of domestic animals. AB - The gross effects of selenium and vitamin E deficiency on animal production and the potential benefits of supplementation are recognised, and the influence of these micronutrients on the resistance of animals to a variety of infections has also been reported. As a result, deficiencies could compromise the immune system and result in a decline in production and performance before gross effects become apparent. Data obtained by laboratories studying different animal species indicate that the responses of domestic animals, particularly ruminants, differ from those of human beings and laboratory animals as well as differing among themselves. This paper provides a comprehensive review of the effects of selenium and vitamin E on the immune responses of domestic animals and discusses their effects with respect to the differences in the basal nutritional status of the animals concerned, the type of supplements used, the route and timing of their administration and the different agents which have been used to stimulate an immune response. PMID- 8685548 TI - ["Malignant Kent" arrhythmia, clinical case and literature review]. AB - The Wolff-Parkinson-White syndrome is considered as benign disorder. However, some electrophysiological properties of the accessory pathway may lead to a life threatening affection due to rapid anterograde conduction over the accessory pathway. We report on four young patients admitted to our hospital in a haemodynamic shock. We strongly recommend to perform to all patients with preexcitation or suspected to have one, a 24 hour ambulatory ECG, an exercise stress testing and if necessary a transoesophageal electrophysiological study or an invasive electrophysiological study in order to detect patients at high risk of sudden death. PMID- 8685549 TI - [Alzheimer's disease in 1995]. AB - Alzheimer's disease is the most common cause of dementia in our society. Recent progress in the understanding of the mechanisms leading to the central nervous system abnormalities produced by this disease will lead soon to new strategies of treatment and new diagnostic approaches. PMID- 8685550 TI - [Contribution of enteroscopy in the diagnosis of digestive hemorrhages of unknown origin]. AB - In this work we report our experience with enteroscopy and its contribution in the diagnosis of anaemia of unknown digestive origin. 90 enteroscopies had been performed in 83 anaemic patients with positive blood stool. 37 of the patients experienced episodes of melena. Preliminary minimal routine investigations including gastroscopy and coloscopy were not contributive. Potentially haemorrhagic lesions were diagnosed in 49 patients (59%), and 7 of these lesions were located in the small bowel. A small bowel lesion has been found in 17 patients with melena and in 19 patients without melena (p > 0.10). The most frequent lesions were angiodysplasias (AD). The mean age of patients with AD was 71.4 years old, vs. 57.2 years (p < 0.00001). Endoscopic bipolar electrocoagulation was performed in 22 patients. Enteroscopy is an efficient technique in the evaluation of patients suffering from obscure digestive bleeding, regardless the presence or absence of melena. PMID- 8685551 TI - [Primary hyperoxaluria]. AB - Primary hyperoxaluria is a rare hereditary disease. Two types have been identified. Type 1 is due to the deficiency of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase/serine: pyruvate amino-transferase whereas, in type 2, the deficiency concerns the glyoxylate reductase/D-glycerate dehydrogenase, a cytosolic enzyme present in the leucocytes and hepatocytes. In the elapsed decade, important progress in molecular biology led to the introduction of new strategies in the diagnosis and treatment of type 1 primary hyperoxaluria. However, the greater rarity of type 2 has so far prevented similar development. The present review recalls the normal metabolism of oxalic acid, details its deviations and their clinical consequences, and describes the methods of diagnosis and treatment to be presently recommended in primary hyperoxaluria. PMID- 8685552 TI - [Exposure to ionizing radiation: radiobiological and pathogenic effects (2)]. AB - The present paper describes the radiobiological effects induced by an exposure to ionizing radiation and their pathogenesis. The different skin reactions are described in detail because of their importance and frequency. Thus the acute skin lesions after high doses and the late effects resulting, either from high doses, or from accumulation of chronic irradiation, are studied. The main early syndromes are then characterized: neurological, gastro-intestinal, bone-marrow and prodromic. As far as the complex problem of radiocarcinogenesis is concerned, the main results derived from studies by international organizations such as the ICRP and the UNSCEAR are reported: risk coefficient of 5% per gray, for lethal radioinduced cancer, after total body irradiation, at low dose of low-LET radiation. The effects of irradiation in utero are then considered: risk of malformation after irradiation during the two first months of pregnancy and risk of mental retardation after irradiation during the third and the fourth months. Finally, the genetic risk is presented as being equal to one fourth of the risk of carcinogenesis at low doses. The effects of irradiation on the gonads are also described. PMID- 8685553 TI - [Contribution of curietherapy in the treatment of ENT tumors]. AB - Considerable improvement has been made in head and neck brachytherapy since the historical radium era. This technique now allows a conservative treatment for buccal cavity and oropharynx tumors with a local control similar to surgery. When combined with external beam radiotherapy, brachytherapy allows to give a lesser dose to the critical organs. We review the brachytherapy techniques and results for various head and neck location. PMID- 8685554 TI - [Anatomo-clinical conference: bronchial cancer and massive hemoptysis]. PMID- 8685555 TI - [What is your diagnosis? Idiopathic thrombocytopenic purpura]. PMID- 8685557 TI - [Implantable cardioverter-defibrillator]. AB - In 1980, therapy with implantable cardioverter-defibrillators in survivors of cardiac arrest was introduced by Michael Mirowski. Over the last 15 years technology in these devices has dramatically improved. In this overview we give a short historical perspective and discuss, briefly aspects of generators, lead systems, sensing and detection algorithms as well as the main therapies of the ICD. Several studies have demonstrated that ICD therapy nearly eliminates sudden cardiac death and that device- and procedure-related mortality has become very low. Despite these impressive results, the overall benefit in terms of mortality has to be assessed; therefore, several randomized studies comparing ICD and competing pharmacological therapies have been started. Because of the rapid growth in popularity of these devices, guidelines for their use have been developed. PMID- 8685556 TI - [Ventricular arrhythmias: diagnosis and drug therapy]. AB - After a brief classification of antiarrhythmic drugs and their mode of action, ventricular dysrhythmias are defined and characterized with respect to underlying causes. A short chapter is dedicated to the treatment of acute ventricular tachycardia, a longer one to the prophylaxis of ventricular dysrhythmias, based on our knowledge in the "post CAST Study era' (CAST = Cardiac Arrhythmia Suppression Trial). A special interest is dedicated to patients commonly encountered in daily practise: patients with coronary artery disease, patients with chronic heart failure, and patients without underlying heart disease. Then a separate assessment is made of the proarrhythmic effects of antiarrhythmic drugs. PMID- 8685558 TI - [Current pacemaker treatment and technology]. AB - The increasing use of microprocessor technology in pacemaker devices results, by multiple programmability, in a more reliable follow-up of pacemaker systems and accounts for individual patient program settings. Rate-adaptive and AV-sequential pacing allows physiologic pacing. The implantation of dual-chamber pacemakers is no longer precluded in patients with atrial tachyarrhythmias with the availability of pacemakers with automatic mode switching (DDD[R] to DDI[R]). The actual vast variability of pacemaker treatment modalities requires a careful evaluation of the indication for pacemaker implantation, with international guidelines being helpful in decision-making. Besides frequent pacemaker indications, the occasional patient with hypersensitive carotid sinus syndrome, neurocardiogenic syncope and hypertrophic cardiomyopathy may benefit from pacemaker treatment. Temporary pacemaker functions with programmable stimulation extend the diagnostic and therapeutic horizon of various arrhythmia treatments. PMID- 8685559 TI - [A case from practice (349). Calcium-pyrophosphate arthropathy with acute pseudogout and involvement of the large joints with bilateral preference of wrist joint and knee joint]. PMID- 8685560 TI - [What is your diagnosis? Ventricular tachycardia]. PMID- 8685561 TI - [Snoring--a sociocultural phenomenon with medical significance]. PMID- 8685562 TI - [Uvulo-palatopharyngioplasty: indication, technique and results in relation to ronchopathy and sleep apnea syndrome]. AB - 56 patients with habitual snoring (n = 43) or with complicated snoring accompanied by sleep apnea syndrome (n = 13) under went uvulopalatopharyngoplasty. The patients were observed for a period of 2 to 84 months (average: 20,8 months). Postoperatively, 80 % showed a disappearance or great reduction of snoring intensity. Other symptoms of obstructive sleep apnea syndrome such as apneas, tiredness during the day and deterioration of sleep quality also improved markedly. In ten out of 13 patients with a demonstrated sleep apnea syndrome, the apneas disappeared or became noticeably reduced (in seven patients shown by means of a polysomnographic check-up). Two patients developed velopharyngeal stenosis, which was subsequently corrected. Other operative side effects were temporary (from days to weeks) and only minor (transient speaking problems, nasal regurgitation, rhinopharyngitis sicca, taste disturbances). PMID- 8685563 TI - [History of the treatment of snoring]. AB - The history of snoring can be divided into three major periods. First, there was a prehistoric phase during which everything was ignored and in which there was no interest in knowing anything. We call this "le repos du guerrier'. Sleep was regarded mainly as a phase of recovery, and there was no question of related problems. A second period began about the beginning of this century: they still did not know anything, but it was felt that something needed to be done. Multiple types of therapy were attempted. This was a time in which research extended in all directions. Modern times began in the middle of this century with the first serious work of medical scientists who discovered and defined the sleep apnea syndrome, the UPPP, the CPAP, etc. PMID- 8685564 TI - [Medical treatment of snoring and obstructive sleep apnea syndrome]. AB - Although snoring may have deleterious effects by itself, its only clearly identified hazard is that of a social nuisance; therefore, treatment of snoring should before all make no harm. Conversely, the potential hazards of obstructive sleep apnea are well established, and it is clearly important to eliminiate sleep apneas. The medical treatments which may improve snoring and obstructive sleep apneas are basically the same. They include avoidance of risk factors such as obesity, alcohol and hypnotics as well as active treatments such as positional treatment, dental appliances and by nasal continuous positive airway pressure. Nasal continuous positive airway pressure has become the treatment of choice for obstructive sleep apnoea, since it is both efficient and safe. Its only limitation is related to variable acceptance by patients. PMID- 8685565 TI - [Aggressive behavior, increasing loss of independence in mentally retarded patient]. AB - Morbus Wilson is a rare autosomal recessive inborn error of metabolism which leads to an excessive deposition of copper many tissues. There are three types of presentation, an asymptomatic, a hepatic and a neurologic one. In this case report we present a 24-year-old man with mental retardation who showed changes in behaviour and slowness. Clinical and laboratory investigations confirmed the diagnosis of Morbus Wilson. We briefly review typical aspects of this rare disease. PMID- 8685566 TI - [A case from practice (350). Mesangioproliferative glomerulonephritis (IgA nephritis)--nephrotic syndrome. Type II diabetes mellitus. Arterial hypertension (WHO-stage II)--grade II fundus hypertension. Chronic bronchitis following long term nicotine abuse]. PMID- 8685567 TI - [A case from practice (351). Acute myeloid leukemia FAB-type M2]. PMID- 8685568 TI - [What is your diagnosis? Atrial septal defect]. PMID- 8685569 TI - [Palliative pain therapy in terminally ill tumor patients]. AB - The treatment of cancer-associated pain in the terminally ill patient requires a vast knowledge of the available treatment modalities, but we also have to be aware of the fact that the continuous education of patients, nurses and doctors about the proper usage of these modalities is of paramount importance. The 3-step ladder proposed by the World Health Organization (WHO) remains the backbone of pain treatment. Adjuvant drugs may add to the analgesic effect, and medications to relief opioid side effects should routinely be prescribed. Local irradiation remains one of the mainstays in painful bone metastasis. Newer systemic modalities to treat skeletal pain such as the bisphosphonates or radionuclides may in the future change some of our current approaches. The treatment of pain in the terminally ill remains a continuous challenge. PMID- 8685570 TI - [Palliative pain therapy--medico-ethical arguments]. AB - The phenomenon pain expressed on an imaginary scale stretches from one end to the other between an event localized anywhere in the body to a condition menacing human existence as a whole, threatening i.e. the confidence in the sense of survival and wishes and goals for life. Whenever healing in the sense of a restitutio ad integrum is no longer possible, palliative strategies for pain relief have to be contemplated and questions about the right moment to abandon causal treatment, about what it means to orientate life on illness to be answered. Focus of discussion is on pain relief: 1. superior to all other therapeutic goals, 2. supporting human identity, 3. as key for the discovery of the meaningful present moment. PMID- 8685571 TI - [Magnetic resonance angiography in vertebro-basilar ischemic accidents]. AB - This study evaluates the use of MR angiography in the diagnosis of vertebrobasilar stroke. The MRI/MR angiography and clinical presentation of 50 unselected adult patients who presented with ischemic symptoms in the vertebrobasilar territory (10 TIAs, 40 strokes) were prospectively evaluated. Conventional T1 and T2-spin echo sequences were obtained for evaluation of the brain parenchyma, with gadolinium injection in 41 cases and 3D time-of-flight MR angiography in all patients. Data were reconstructed with a maximal intensity projection algorithm and displayed in 3D. Arterial and parenchymal lesions and clinical data were correlated. MR angiography showed intracranial vertebrobasilar lesions in 30 patients (5 stenosis or occlusion of a vertebral artery, 17 stenosis or occlusion of the basilar artery, 6 stenosis of arterial branches of the basilar artery, 10 dolichoectasia of the basilar artery). 7 patients had multiple lesions. Recognized etiologies of the strokes were: 23 vertebrobasilar lesions, 16 nonvertebrobasilar causes, 6 mixed (vertebrobasilar and associated alternative causes) cases, while 5 cases had no recognized cause of stroke. Our study demonstrates a high incidence of intracranial arterial lesions in patients suffering from vertebrobasilar stroke and suggests that MRA can help in a noninvasive way to determine the origin of vertebrobasilar strokes. PMID- 8685572 TI - [Frontal lobe dementia: a case report]. AB - Frontal lobe dementia (FDL) is a disorder that has only been described in recent years. It is mainly characterized by language disturbances and personality changes. We describe the problems and the possible therapeutic approaches to FLD, using a single case which has been well documented for several years. PMID- 8685573 TI - [Increasing vision disorder]. AB - A 62-year-old patient complained about slowly increasing, intermittent vision disorders. Ophthalmologic investigation revealed choked disks in both eyes. A neurologic investigation performed thereafter disclosed increased cerebrospinal fluid pressure without recognizable cause. Internistic investigation was inconspicious; in particular, there were no indications for a systemic disease. The distinct findings of choked disks on both sides and increased cerebrospinal fluid pressure without detectable organic causes finally lead to the diagnosis of benign intracranial hypertension or pseudotumor cerebri. Not until the nerve sheath of the right optic nerve was split did the visual field defects in the right eye diminish. Splitting of the left optic nerve sheath is planned. PMID- 8685574 TI - [A case from practice (343). Chronic fatigue syndrome following Lyme borreliosis]. PMID- 8685575 TI - Laparoscopic extirpation of renal cell cancer: feasibility, questions, and concerns. AB - Laparoscopic nephrectomy for benign disease has become an increasingly popular alternative to open surgery as more urologists gain confidence in their laparoscopic skills. However, the idea of laparoscopic extirpation of renal cell cancer caused significant concerns over the adequacy of surgical resection margins, trocar site seeding, and potential tumor spillage. The present chapter is the result of 5 year's experience with laparoscopic nephrectomy for renal tumor. To date, total and radical nephrectomies have been performed at Washington University in 20 patients; in each case, the appropriate surgical margins were obtained. Moreover, there have been, as yet, no instances of tumor spillage or delayed trocar seeding in our or others' experience. Furthermore, the immediate effectiveness of the procedure equals that of open radical nephrectomy; yet the hospital stay, patient discomfort, and convalescence are all markedly decreased. Only two drawbacks to the laparoscopic approach remain: 1) lengthy operative time, and 2) the increased cost associated with the prolonged operating room time. These problems will only be overcome by increased surgeon experience and further technological advances. Lastly, given the newness of the procedure, follow-up of these patients is still brief; however, results to date substantiate the hypothesis that laparoscopic radical nephrectomy is an effective, minimally invasive, long-term therapy for patients with localized renal cell cancer. PMID- 8685576 TI - Laparoscopic approaches to transitional cell carcinomas of the upper urinary tract. AB - Traditionally transitional cell tumors of the upper urinary tract are treated by nephroureterectomy. In circumstances where low functional renal reserve necessitates renal parenchymal preservation, endoscopic or percutaneous treatment may be an option for low grade and stage lesions. In this article, the role of laparoscopic surgery as an alternative modality to open surgery is discussed. Techniques of laparoscopic nephroureterctomy are described and different approaches (transperitoneal, retroperitoneal, and gasless hand-assisted) are contrasted. The limitations imposed on laparoscopic treatment by the requirement of adherence to oncological principles of tumor containment and excision of the intramural ureter, are outlined. Laparoscopic nephroureterectomy, although technically demanding, has been shown to be a feasible procedure. Benefits of the laparoscopic approach include shortened hospital stay and early return to daily activities. It is unclear at this time whether these immediate advantages over open surgery will yield comparatively efficacious long term outcomes. PMID- 8685577 TI - Laparoscopic approach to retroperitoneal lymph node dissection. AB - Laparoscopic retroperitoneal lymph node dissection is a new surgical procedure used to enhance staging in men with clinical stage I nonseminomatous germ cell tumors of the testis. The procedure has been performed in a limited number of patients at several centers with extensive laparoscopic experience. Laparoscopic retroperitoneal lymphadenectomy is a technically demanding procedure which can be successfully completed in the majority of patients. However, the risk of complications is greater than in patients who undergo standard open retroperitoneal lymph node dissection. The primary advantage of a laparoscopic approach is shortened hospitalization and rapid return to normal activity. The role of laparoscopy in the management of patients with testis malignancy has not been defined. The use of this staging procedure may help minimize the need for surveillance studies following surgery and may be best utilized in men with a lower likelihood of nodal metastases. Ultimately, prospective study in large groups of patients will be necessary to determine the role of laparoscopic retroperitoneal lymph node dissection in patients with testis cancer. PMID- 8685578 TI - Laparoscopic pelvic lymphadenectomy: transperitoneal approach. AB - Laparoscopic pelvic lymph node dissection (PLND) is the most commonly performed laparoscopic procedure in urology today. Indications for laparoscopic PLND are being refined to selectively identify patients who are at high risk for lymphatic metastases. From a technical standpoint, the anatomic detail and number of lymph nodes retrieved by the laparoscopic approach are comparable to open PLND. Laparoscopic PLND is associated with a steep learning curve and increased operative time; however, the decreased postoperative discomfort, shortened hospital stay, rapid resumption of normal activities, and enhanced cosmesis are clear advantages over open PLND. PMID- 8685579 TI - Laparoscopic staging pelvic lymphadenectomy: extraperitoneal approach. AB - Comparative studies have proven the feasibility as well as reduced morbidity of endoscopic pelvic lymph node dissection when compared to open pelvic lymphadenectomy. Transperitoneal laparoscopic pelvic lymphadenectomy, however, has been associated with complications related to transperitoneal access and intraperitoneal dissection. We, therefore, developed the extraperitoneal laparoscopic staging pelvis lymph node dissection which combines the anatomic principles of open pelvic lymphadenectomy with the minimally invasive endoscopic technique. Exploration of the area of our endoscopic lymphadenectomy during radical retropubic prostatectomy proved the feasibility of our dissection. In patients selected for laparoscopic lymphadenectomy, we now prefer the extraperitoneal approach. PMID- 8685580 TI - Role of laparoscopy in the diagnosis and treatment of prostate cancer. AB - Laparoscopic surgical techniques were originally applied to the staging of prostate cancer in the form of laparoscopic pelvic lymph node dissection. The efficiency of laparoscopic pelvic lymph node dissection has proven to be comparable to open lymphadenectomy in tissue yield and also shows a considerable decrease in postoperative morbidity. Subsequently, laparoscopy has been used as an adjuvant to perineal prostatectomy for preliminary dissection of the seminal vesicles. Laparoscopic radical prostatectomy has been performed but the long-term efficacy of this treatment is unknown at this point. Future clinical applications of laparoscopic surgical techniques in the diagnosis and treatment of prostate cancer include harvesting of primary and metastatic prostatic tissue for adjuvant gene therapies for prostate cancer. PMID- 8685581 TI - Laparoscopic surgery for bladder carcinoma. AB - Recent utilization of laparoscopy in urology has led to the performance of several pelvic procedures. The successful performance of laparoscopic diverticulectomies and cystectomies for benign pathology has led to speculation about, and utilization of, the laparoscopic approach in the treatment of bladder cancer. Herein, we relay our experience with the laparoscopic approach for bladder surgery and discuss the pros and cons of its current status in the treatment of bladder cancer. PMID- 8685582 TI - Pathophysiologic effects of prolonged laparoscopic operation. AB - Laparoscopy may have significant effects on homeostasis, particularly on the cardiovascular and pulmonary systems. The surgeon needs to appreciate the complex interactions of increased intra-abdominal pressure, changes in patient position, and gas absorption in order to appropriately select patients for laparoscopic procedures. Practical guidelines for the avoidance and management of complications due to pathophysiologic derangement during laparoscopy are included. PMID- 8685583 TI - Laparoscopic surgery for adrenal lesions. AB - Laparoscopy has become an important tool in the urologist's armamentarium. The optimal utilization of this technology is still in evolution; however, it offers assistance in diagnosis and treatment for a variety of conditions. As experience with laparoscopy increases, more procedures that have traditionally been done with an open surgical approach will be adapted to use with the laparoscope. In this article, we review current applications of laparoscopic adrenalectomy. PMID- 8685584 TI - [Supplementation of DL-alpha-tocopherol acetate in children with chronic cholestasis and vitamin E deficiency]. AB - OBJECTIVE: To determine the oral supplement doses of dl-alpha-tocopheryl-acetate to maintain normal serum alpha-tocopherol concentrations in children with chronic cholestasis and vitamin-E deficient. BACKGROUND: Malabsorption and deficiency of vitamin E in children with chronic cholestasis causes a progressive, neuromuscular degeneration at approximately 18-24 months of life, if left untreated. Using prompt treatment, it can be completely prevented and reversed to normal. METHOD: Longitudinal, prospective and comparative study was performed on consecutive sixty vitamin E deficient children with chronic cholestasis divided in three groups. After initial evaluation, therapy was started for 15 days in each group with 100 IU, 200 IU and 400 IU/day of oral dl-alpha-tocopheryl acetate, respectively; alpha-tocopherol-status, neurological function and biochemical parameters were monitored during therapy. RESULTS: Any oral supplement does administrated for 15 days of dl-alpha-tocopheryl-acetate were enough to maintain the normalization of alpha-tocopherol status (p > 0.06). Neurological function, which had not deteriorated before entry in the trial, stabilized in all after 15 days of therapy. No adverse effects were observed. CONCLUSIONS: Oral supplement of dl-alpha-tocopheryl-acetate for 15 days with 100 IU, 200 IU, and 400 IU, in spite of safety, weren't enough to maintain the alpha tocopherol serum concentration in children with chronic cholestasis and vitamin-E deficient. PMID- 8685585 TI - [Extraction of foreign bodies in the esophagus. Experience in 215 cases]. AB - OBJECTIVE: To analyze our experience in management of foreign bodies in esophagus. BACKGROUND: At present, the flexible endoscope is usually the instrument of choice for foreign bodies of the esophagus. The rigid endoscope is less expensive, but the advantages of the flexible endoscope are numerous. MATERIAL, METHODS: Management of 215 foreign bodies of esophagus are reported. The flexible endoscope was used to manage these foreign bodies. The patients comprised 151 children and 64 adults. RESULTS: In children, coins were the commonest foreign bodies (119 cases), whereas in adults, the commonest cause was impacted meat (35 cases). Two hundred fourteen foreign bodies (99.5%) were successfully managed endoscopically. The surgery rate was 0.5%. There was no morbidity or mortality. In fifteen adults we diagnosed significant associated medical conditions: benign esophageal stricture in eleven, esophago-gastric junction carcinoma in one, two patients with esophageal motility disorders and remaining with Plummer-Vinson Syndrome. CONCLUSIONS: The forward-viewing flexible endoscope has became the instrument of choice in diagnosis and management of esophageal foreign bodies. PMID- 8685586 TI - [Early detection of adenomas in asymptomatic subjects: flexible sigmoidoscopy or colonoscopy]. AB - OBJECTIVE: The aim of this study was to determine the frequency of adenomas as well as sensitivity, specificity, positive and negative predictive values of FS for polyp screening in two groups of asymptomatic individuals using colonoscopy (CP) as the gold standard. BACKGROUND: Flexible sigmoidoscopy (FS) is the screening procedure of choice for polyps and colorectal carcinoma (CRC) in asymptomatic individuals. However, the validity of this approach has been questioned, specially in subjects with a family history of CRC. METHODS: A total of 92 asymptomatic individuals were included in two groups: group A: with a family history (1st or 2nd degree relatives) of polyps or CRC (fifty-eight), and group B: without a family history and > 50 years (thirty-four). FS was simulated with the videocolonoscope until 60 cm, and was continued into the cecum. The number, type and localization of polyps were noted for each, FS and CP. The values mentioned previously were calculated according to established formulas. Comparisons were performed using Chi square test. RESULTS: Adenomas were found in twenty individuals in group A (34.4%) and 7 in group B (20.5%), p = NS. Sensitivity for FS in group A was 42% vs 71% in group B, with a negative predictive value of 44.5 and 93%, respectively. CONCLUSION: Colonoscopy is probably the screening procedure of choice in individuals with a family history of polyps or CRC. The utility of FS for screening purposes in asymptomatic individuals without a family history seems adequate, although more studies are required in different populations in our country. PMID- 8685587 TI - [Incidence of peptic ulcer at the Instituto Nacional de la Nutricion "Salvador Zubiran": study of localization, associated factors and temporal trends]. AB - OBJECTIVE: To know the frequency, trends and associated factors of peptic ulcer disease in our Institute. BACKGROUND: Peptic ulcer is an important disease; about 5-10% of the population can expect to develop this disease during lifetime. MATERIAL AND METHODS: We reviewed 1,123 patients with peptic ulcer in five years. Sex, age, habits (tobacco and alcohol consumption), non-steroidal anti inflammatory drugs use, ulcer location and complications were analyzed. To evaluate temporal trends, our results were compared with previous studies made in our Institute. RESULTS: The male-female ratio was 1:1, with a mean age of 52.2 years. Forty percent of the patients had duodenal ulcer, 42% had gastric ulcer, and 19% had esophageal, anastomotic or multiple ulcers. The most common complication was bleeding, which occurred more frequently in gastric (37%) than duodenal ulcer (24%) (P < 0.005). Gastric ulcer occurred in older patients when compared to duodenal ulcer (P < 0.02). Non-steroidal anti-inflammatory drugs consumption was more frequent in patients with gastric (14%) than duodenal ulcer (10%) (P < 0.04). The frequency of tobacco and alcohol consumption was higher in multiple ulcers. CONCLUSIONS: A tendency toward a decreased frequency of duodenal ulcer and increased frequency of gastric ulcer was observed in our Institute during the last 30 years. In the same period, bleeding has been the leading complication, suggesting a higher referral of complicated peptic ulcer. PMID- 8685588 TI - [Chronic unspecified ulcerative colitis]. PMID- 8685589 TI - [Primary sclerosing cholangitis]. PMID- 8685590 TI - [Unusual ingestion of a nasogastric tube by Ascaris lumbricoides]. AB - We present the unusual ingestion of a Levin's tube by Ascaris lumbricoides found in the stomach of a 60 year old woman who died with the clinical diagnosis of cerebral vascular disease. MATERIAL AND METHODS: The parasite was studied in serial histological sections with hematoxylin-eosin stain, to observe the tube in situ. RESULTS: Cross sections showed loss of the intestinal lumen with distension of the internal border and the identification of structures through uterus and ovaries and the effects of compression by the Levin's tube. CONCLUSIONS: Considering the muscular tissue of the esophagus, this condition tolerates in the utmost degree the passage of the catheter to reach the anus. This finding, plus the lytic effects of enzymes in the parasite's mouth, contributes partially to explain the variety of pathology observed in literature. PMID- 8685591 TI - [Magnetic resonance diagnosis of insulinoma]. AB - OBJECTIVE: The purpose of this report is to highlight the use of the magnetic resonance imaging in the detection of very small tumors of the pancreas. BACKGROUND: The computed axial tomography and angiography have been the traditional methods in the detection of neoplasms of the pancreas, mostly vascular lesions, both lacking the tissue characterization and contrast; the magnetic resonance scan was performed to rule out a pancreatic tumor in a 37 year old female patient with hypoglycemia, previously treated for seizures. RESULTS: A 1.0 cm nodular hypointense lesion was seen in the union of the body and the tail of the pancreas, confirmed by surgery and pathology as an insular cell tumor. CONCLUSION: Given its axial and tissue contrast resolution, as demonstrated in our case, the magnetic resonance imaging has became the gold standard in the identification of very small tumors of the pancreas. PMID- 8685593 TI - [Endoscopy and ethics]. PMID- 8685592 TI - [Giant biliary lithiasis and nasobiliary drainage. Is it history?]. PMID- 8685594 TI - [Homage to Dr. Miguel Delgado Marquez]. PMID- 8685595 TI - [Words of gratitude]. PMID- 8685596 TI - [Homage to Dr. Norberto Trevino Garcia Manzo]. PMID- 8685597 TI - [Homage to Dr. Raul Bolio Vales]. PMID- 8685598 TI - [Closing Presidential Address, Mexican Association of Gastroenterology, Merida, Yucatan, 7 December 1995]. PMID- 8685599 TI - [Opening Presidential Address, Mexican Association of Gastroenterology]. PMID- 8685600 TI - The scope of perspectives for research in oncodevelopmental biology and medicine. PMID- 8685601 TI - Specificity and affinity of 26 monoclonal antibodies against the CA 125 antigen: first report from the ISOBM TD-1 workshop. International Society for Oncodevelopmental Biology and Medicine. AB - The specificity of 26 monoclonal antibodies against the CA 125 antigen was investigated in two phases of the ISOBM TD-1 workshop. The binding specificity was studied using CA 125 immunoextracted by specific antibodies immobilized on various solid phases, or on the surface of human cell lines. Immunometric assays using all possible antibody combinations were used to study the topography of antibody binding sites on the antigen. We conclude that the CA 125 antigen carries only two major antigenic domains, which classifies the antibodies as OC125-like (group A) or M11-like (group B). One antibody, OV 197, showed binding specificity related to some of the OC125-like antibodies, but was classified into a separate group C. The OC125-like group of antibodies has four subgroups with different binding specificities. These are A1 = OC 125 and K 95, A2 = K 93, A3 = B43.13, and A4 = ZS 33, B27.1 and CCD 247. Binding of nonlabelled OC 125 or K 95 to CA 125 caused a marked increase in binding of labelled OV 197 to the complex. This conformational change was not observed with any other antibody combinations. Antibody B43.13 could form immunometric assay combinations particularly with antibodies of subgroup A4, indicating that the B43.13 epitope is in the periphery of the binding area of OC125-like antibodies. The M11-like group of antibodies is more homogenous with strong cross-inhibition between most antibodies. Only one antibody, ZR 38, would form an immunoassay combination with other M11-like antibodies and thus represents a distinct subgroup. The main group of M11-like antibodies are M 11, ZR 45, MA602-6, K 91, OV 185, K 101, K 90, K 96, K 97, K 102, CCD 242, 145-9, and 130-22. Antibody OV 197 binds to a domain designated C and is unique, as stated above. Antibody pairs from any two of the three groups may be used in immunometric assays. Three antibodies were not studied by complete cross-inhibition due to low affinity (OV 198 and K 100) or lack of material (MA602-1). OV 198 and K 100 are most likely OC125-like and MA602-1 is M11-like. Antibody affinity was estimated with labelled antigen in solution or with antigen absorbed on microtiter wells. Western blot analysis showed staining both in the stacking gel and corresponding to a molecule of 200 kDa. There was a marked difference between the antibodies in their ability to bind to CA 125 immobilized on a membrane. Strongest binding was observed with the M11-like antibodies, particularly M 11, K 96, K 97, MA602-6, 145-9. Antibodies belonging to the subgroup A4 were the only OC 125-like antibodies which reacted well with CA 125 in Western analysis. Digestion of CA 125 with proteolytic enzymes showed it to be particularly sensitive to trypsin cleavage. However, no low molecular weight fragments with preserved immunoreactivity were found. PMID- 8685602 TI - Evidence for S stage quiescence in regeneration blastema cells. AB - Working on the temporal structure of the S stage of regeneration blastema cells we have discovered that some blastema cells, containing a 3C quantity of DNA, do not incorporate radioactive thymidine, or that they proceed through the synthetic phase with a speed undetectable by a radioactive pulse. We report the identification of several short-term periods of quiescence for regeneration blastema cells in vivo, operating during the S stage of the cell cycle. Blastema cell smears from regenerating urodele forelimbs were used in this study. Combined microdensitometric scanning of Feulgen-stained nuclei and microradioautographic labelling of the same nuclei have been exploited to assess DNA replication. A total of 3,600 blastema cell nuclei were scanned, mapped on photographic film and subsequently processed for radioautography. It was found that 49.7% of the cells with a DNA content ranging between 2C and 4C were unlabelled after 1 h exposure to tritiated thymidine. PMID- 8685603 TI - Expressions of the fibroblast growth factor family (FGF-1, -2 and -4) mRNA in endometrial cancers. AB - To investigate whether growth, invasion and metastasis of endometrial cancer cells is associated with neovascularization, the expressions of fibroblast growth factor-1 (acidic FGF), -2 (basic FGF) and -4 (hst-1) mRNAs and FGF-2 in endometrial cancers and normal endometria as controls were determined by reverse transcription-polymerase chain reaction-Southern blot and ELISA, respectively, and the relationships between their expressions and histological grades, grades of myometrial invasion or clinical stages of endometrial cancers were analyzed. The levels of FGF-1 mRNA and FGF-2 and its mRNA tended to increase with dedifferentiation (especially grade G3), myometrial invasion (especially grade C) and staging (especially stages III and IV) in endometrial cancers were significantly (p < 0.05) higher than those in normal endometria. However, the levels of FGF-4 mRNA expression were significantly (p < 0.05) lower than those of FGF-1 and -2 mRNAs in both endometrial cancers and normal endometria. Therefore, endometrial cancers might mainly secrete FGF-1 and -2, which leads to neovascularization to provide nutrition, resulting in accelerated growth, invasion and metastasis. Apparently, the increased secretion parallels the progressive malignancy of endometrial cancers. PMID- 8685604 TI - Drug targeting and metabolic investigations of cryoprepared tumor cells with analytical electron energy loss spectroscopy. AB - Analytical electron microscopy is an ideal tool for holistic data acquisition on biological systems. The use of analytical electron microscopy for both, the investigation of micropharmacokinetic problems and metabolic studies, is becoming more and more important. Depending on the mode of investigation, it is possible to localize drugs and xenobiotics precisely in situ under optical control or to quantify their uptake and distribution in the corresponding target cells without disintegrating the cell or tissue material. In this paper, we present instructive examples for the application of analytical electron energy loss spectroscopy in transmission electron microscopy in order to investigate the cellular uptake and distribution of cisplatin and cyclophosphamide and the metabolic changes induced by an alteration in the extracellular calcium concentration in a holistic manner. PMID- 8685606 TI - Maximize your patient teaching potential. PMID- 8685605 TI - Alpha-fetoprotein binding and uptake by primary cultures of human skeletal muscle. AB - alpha-Fetoprotein (AFP), a serum alpha-globulin mainly synthesized by the fetal liver and the yolk sac, is the major carrier of polyunsaturated fatty acids during embryo-fetal development. One property characteristic of fetal cells undergoing growth and differentiation is their ability to bind and internalize AFP. In the present work, we have studied the binding and endocytosis of AFP by human muscular cells developing in vitro. Primary cultures of human skeletal muscle, obtained from biopsies and examined at two stages of differentiation (myoblasts and myotubes), were incubated for different times, at 0 and 37 degrees C, with a colloidal-gold-conjugated human AFP probe and studied by light and electron microscopy, as well as by laser scanning confocal microscopy in the reflection mode. The results obtained show that (a) human myoblasts in primary culture bind and internalize the protein, probably through specific AFP receptors, (b) this property is strongly reduced or lost in well-differentiated myotubes, and (c) AFP is also bound, throughout culture development, to the extracellular matrix of fusing myoblasts and differentiated myotubes. The physiological significance of AFP uptake by human myoblasts undergoing growth and differentiation may be based on the ability of AFP to carry and deliver fatty acids to fetal cells. PMID- 8685607 TI - Waging war on HIV wasting. PMID- 8685608 TI - Managing heart failure. PMID- 8685610 TI - Remembering Ricky. PMID- 8685609 TI - The ABCs of TPN. PMID- 8685611 TI - Chemo quick guide: alkylating agents. PMID- 8685612 TI - Reiki: an ancient touch therapy. PMID- 8685613 TI - If you're sexually harassed. PMID- 8685614 TI - Low back pain is a major cause of workers' disability. PMID- 8685615 TI - A valentine. PMID- 8685616 TI - [Mutilation of the lower lip. Repair using the Karapandjic technic. Apropos of 2 cases]. AB - Many processes of repairing concerning the mutilation of the lower lip were described with their advantages and drawbacks. The Karapandjic process which has been described since 1974 is simple to realize, leaving no after-effects provided the loss of the substance is not very important. This process is illustrated regarding two cases. PMID- 8685617 TI - [Dental rehabilitation using osseointegrated implants: treatment of oro-maxillo facial cancer. A preliminary study of 7 cases]. AB - Edentulism is often reported after treatment for malignancy of oral cavity. The resulting deformities from loss of teeth and bone create a "social invalid" with difficulties in articulation and mastication. Prosthetic rehabilitation was difficult because of two problems: the risk of osteoradionecrosis development and local anatomic modifications. The introduction of osseointegrated implants improved results of oromandibular reconstruction. A preliminary report of nineteen Branemark implants of seven patients is reported here. Implants have been in place and functioning for a period of one to four years. No major complication occurred and osseointegration permitted good oral rehabilitation. Placement of osseointegrated implants in osteomyocutaneous flaps and in irradiated bone is discussed. PMID- 8685618 TI - [Myxoma of the upper jaw. Apropos of a case]. AB - We report a patient with odontogenic myxoma of the upper maxillary. The authors underline for this particular case, that there are no clinical features specific of the tumor; the diagnosis can be only histological. The evolution of this tumor is always benign. PMID- 8685619 TI - [Transmission of infection in oral medicine. Evaluation of the risk of transmission in the office surgery]. AB - The present study was designed to estimate the risk of transmission of infectious diseases by dental equipment in stomatology. The protocol was carried out on 30 patients. The three following samples were collected from each patient: (a) oral flora before any treatment, (b) aerosol produced by the hand-piece before internal decontamination, (c) aerosol produced by the hand-piece after internal decontamination. The results of this study indicate there was a risk of transmission of infectious diseases in 3 cases (10%) with dental equipment, even if there were no consequences for healthy individuals. We have to improve the security in stomatology, with internal and external decontamination after each patient. PMID- 8685620 TI - [Proposal of a new topographic classification of mandibular fractures]. AB - There has been a certain amount of confusion in publications concerning fractures of the mandible due to the lack of consensus on classification. Starting with the embryological, anatomic, biomechanical, pathogenic and epidemiological features of these fractures, we propose a new terminology and a new distribution of the units and subunits of the mandible in traumatology. The main point is to incorporate the angle subunit into the ramus unit. PMID- 8685621 TI - [The value of an osteosynthesis arch-plate combination in the application zone in the treatment of fractures of the body of the mandible]. AB - Fractures of the tooth-bearing part of the mandibular body require both orthopedic stabilization of the maxillomandibular joint and surgical fixation. From an evaluation of the anatomic and biomechanical features of the mandible, we propose the notion of a useful zone for fixation. The useful zone is basically submitted to traction forces and includes both the teeth and the teeth-bearing bone situated above the mandibular canal in the body and the entire symphysis. Applying an arch-plate on the useful zone has the advantage of providing initial stability, progressive loading and reduction in risk of displacement or secondary infection. This therapeutic approach gives better results than simple plate fixation. PMID- 8685622 TI - [Treatment of fractures of the mandibular angle using miniplates attached through the transjugal approach]. AB - We present 114 cases of mandibular angle fractures treated by screwed miniplates placed through a transbuccal incision with transbuccal trochar instrumentation. Usually patients were young men who suffered traffic accidents. The mean hospitalization time was 7 days. 94.5% of the patients healed without incident, no malocclusion complication was observed. Two postoperative hematomas required surgical drainage without healing complication. One non union required removal of the miniplate and maxillo-mandibular immobilization. 2 temporary postoperative hypoaesthesiae were observed. One patient presented a pericoronary infection of a third impacted molar, four months after surgery, but the fracture was healed. The comparison of the results with the others in the literature confirms the reliability of this technique. PMID- 8685623 TI - [A rapid intermaxillary fixation technic]. AB - The authors describe a new intermaxillary fixation (IMF) technique. This technique is particularly easy and quick. It needs usual 4/10 or 5/10 steel wire with a small pearl fixed at one extremity. Four wires are used, passed from lingual side to vestibular side, between premolars. Wires are then linked and intermaxillary fixation is performed. Osteosynthesis is realised by intraoral approach. This technique does not allow to maintain IMF during a long postoperative period. Therefore, it should be reserved for cases where miniplate osteosynthesis will be sufficient. It seems interesting to use this technique for monofocal mandibular fractures, in association with rigid miniplate osteosynthesis. PMID- 8685624 TI - [The Abbe-Estlander flap: anatomic basis, surgical technic and indications for lip repair]. AB - The Abbe-Estlander flap is a full-thickness lip-switch flap rotated from mid lower lip to fill defects of the upper lip. In 1872, Estlander emphasized the importance of this flap. Abbe, in 1898, was the first to switch a lower lip flap into the upper lip for a cleft deformity. The lip-switch flap is an arterialized flap, based on the constant inferior labial artery. This flap is widely used to repair the defects from cancer and traumatism or in repair of the cleft lip deformities. PMID- 8685625 TI - Migraine--a haematological disorder? AB - We analysed 22 patients suffering from migraine to evaluate the possible activation of platelet function utilizing the following methods: platelet factor 4, thromboxane B2 and 6 - keto prostaglandin F 1 alpha levels in platelet poor plasma. Laboratory tests were performed on all patients during headache-free period and the results obtained were compared with those of a normal healthy individuals. The mean results obtained in the patients group during pain-free period indicated a significant activation of platelet function when compared with the normal group. PMID- 8685626 TI - Immunohistochemical detection of proliferative cells. AB - The cell proliferation represents one of the most relevant cellular functions. There are many approaches to assess the proliferative activity in tissues. Immunohistochemical methods offer a high sensitivity and specificity. They use monoclonal antibodies raised against specific antigens associated with the cell proliferation. Anti-BrdU immunohistochemistry detects bromodeoxyuridine (BrdU) which as an exogenous proliferation marker has been incorporated into the newly synthesized DNA of dividing cells. The best known endogenous proliferation markers are PCNA and Ki-67 that may be detected with specific commercially available antibodies. Here we describe our experience with an immunohistochemical detection of these proliferation markers. Anti-bromodeoxyuridine (BrdU) antibody binds BrdU that was exogenously introduced into the synthesizing DNA during the S phase of the cell cycle. The precise timing and dosage of BrdU enable tissue kinetics studies. A long-time administration of BrdU may be used for labelling tissues with a low proliferative activity. BrdU incorporated into the cell nucleus is still a very stable antigen which gives a strong and reliable signal regardless the kind of fixation and further tissue processing. The proliferating cell nuclear antigen (PCNA) as an auxillary protein for DNA polymerase gamma is an evolutionarily conserved molecule that may be detected in human and animal frozen or paraffin-embedded tissues. In spite of the fact that anti-PCNA immunohistochemistry may weakly stain non-proliferating cells, PCNA is the most frequently detected proliferation marker. The staining intensity may be influenced by the kind of fixation and the length of microwave pretreatment. Ki 67 is another endogenous antigen detectable in proliferating cells. Its detection in paraffin-embedded sections requires also exposition to microwaves. Both Ki-67 and PCNA may be revealed in archival specimens that means these techniques do not require any prelabelling. Ki-67 labelling index (LI) correlates better with BrdU LI than PCNA LI as the Ki-67 antigen has a shorter half-life than PCNA. PMID- 8685627 TI - Changes in microvascularization of some rat organs following soman poisoning. AB - Vascularization of some organs of rat following soman (O-pinacolyl methylphosphonofluoridate) intoxication was studied using scanning electron microscopy. Corrosion casts were prepared with commercially available methyl metacrylate monomer which was partly polymerized, supplemented with catalyst and accelerator and injected into the prewashed and fixed vascular bed. The obtained corrosion casts were sectioned and trimmed using a stereoscopic light microscope. Microvascular casts of normal organs', bed pattern were studied under scanning electron microscope and compared with vascularization patterns after soman poisoning. Changes in the vascular bed architecture of kidneys, brain, adrenal glands and thymus were described. PMID- 8685628 TI - Histoautoradiographical detection of DNA repair synthesis in different organs of mice after methylnitrosourea "in situ". AB - Methylnitrosourea (MNU) was applied by gavage into the stomach in a dose of 123.1 mg/kg. Hydroxyurea (250 mg/kg) and 6 (3)H thymidine (dTh - 2 MBq/g) were injected intraperitoneally. DNA repair synthesis as the labelling of non-proliferating cells was most reliably established in the testicles, bronchi, duodenum, kidney, liver and pancreas after 3 months to 3 years exposure of the histoautoradiograms. The findings in the stomach and rectum are near to this group. Less reliable positivity was found in the adrenals, urinary vesicle, spleen and heart, while in the musculature of the abdominal wall and in the thymus the results were negative. There is some correlation of these results with literary data about organ specific development of tumors after orally applied MNU to mice. This suggests wide applicability of this autoradiographical method. The possibility of increasing the dose of 3H thymidine is also discussed. PMID- 8685629 TI - A Czech version of the inventory of learning processes. AB - A Czech version of the Schmeck's ILP inventory was administered to 1898 university and college students from Bohemia, Moravia and Slovakia. Factor analysis identified six factors which explained 73% of data variance. The Czech version is shorter as compared to the original and includes 49 items; its reliability is satisfactory. Our experience showed that ILP-CZ inventory could be used in senior classes of secondary (high) schools, and in both undergraduate and graduate studies. The inventory can be used both for screening at the beginning of university and/or college studies and counselling services offered during the study. PMID- 8685630 TI - Hepatitis E virus infections in patients with acute hepatitis non-A-D in Sweden. AB - A total of 12 patients previously treated for acute hepatitis of unknown aetiology were retrospectively found to be anti-hepatitis E virus (HEV) IgG positive. Four patients were anti-HEV IgM- and IgG-positive consistent with an acute HEV infection. All 4 had travelled to or were immigrants from HEV-endemic countries. One anti-HEV IgM-negative patient seroconverted from anti-HEV IgG negative to positive and 3 from anti-HEV IgG-positive to negative in 2 consecutive serum samples. Of the remaining 4 patients without anti-HEV IgM, 3 had a history of recent travel to an HEV-endemic country. Most patients were young adults and all but 1 recovered from the hepatitis. One patient with a fulminant hepatitis was anti-HEV IgG-positive when tested 4 months after a journey to Turkey. She died from her fulminant hepatitis shortly after admission. All the other patients but 1 normalized their serum liver enzymes within 1-2 months after the onset of disease. PMID- 8685631 TI - HTLV infections among Swedish intravenous drug users in 1992. AB - Serum samples collected in 1992 from 1158 intravenous drug users (IVDUs) in Stockholm, Sweden, were tested retrospectively for antibodies to human T lymphotropic virus type I and II (HTLV-I and II). The overall prevalence rate of HTLV infections was 2.4% (28/1158). A majority of the HTLV infections were caused by HTLV-II (27/28). A significant association between HTLV-II and HIV-1 seropositivity was found, the prevalence of HTLV-II infection being 11.4% (11/96) in HIV-seropositive individuals compared with 1.5% (16/1062) in HIV-seronegative persons (p < 0.001). All the HTLV-infected individuals were of Scandinavian origin. No significant differences in age and sex distribution were observed in HTLV-infected persons compared to seronegative individuals. This study confirms that HTLV-II infection is present in the Swedish IVDU population and the findings provide baseline information for future epidemiological studies. PMID- 8685632 TI - Parvovirus B19 infection--persistence and genetic variation. AB - 53 patients with acute B19 infection were studied; symptoms at acute infection were rash and arthralgia (n = 26), rash (n = 7), arthralgia (n = 16), aplastic crisis (n = 3), and intrauterine fetal death (n = 1). These patients were followed for 26-85 months (mean 57 months) and re-assessed for persistent symptoms, anti-B19 antibodies, and B19 DNA. At follow-up, 7 individuals were positive for serum B19 DNA, compared with none of the controls (2-tailed p value = 0.016). All 7 of those persistently infected were women, 3 of whom had symptoms; 1 had a chronic haemolytic anaemia (initial presentation was aplastic crisis); 1 had persistent arthralgia in both knees (initial presentation was bilateral knee arthralgia); and 1 had arthralgia in one knee and chronic fatigue syndrome (initial presentation was bilateral arthralgia in knees and shoulders). For the 7 persistently infected patients, serum from the time of diagnosis of acute B19 infection was available for 4, all of which contained B19 DNA. With single-stranded conformational polymorphism (SSCP) assay of these 11 PCR products, identical SSCP types were demonstrated in 5 of 7 follow-up isolates. In 2 of the 4 cases for which both acute and follow-up PCR product was available, the SSCP type of the follow-up product was different from that of the acute product. Two B19 virus types were demonstrated in one patient (with persistent arthralgia and chronic fatigue syndrome) at follow-up assessment. PMID- 8685633 TI - Quantitation of human cytomegalovirus (HCMV) DNA in cerebrospinal fluid by competitive PCR in AIDS patients with different HCMV central nervous system diseases. AB - The current study was designed to quantitate human cytomegalovirus (HCMV) DNA in cerebrospinal fluid (CSF) of persons with AIDS with specific HCMV-related CNS disease. DNA present in CSF obtained from AIDS patients was initially detected by a qualitative PCR procedure and then quantitated using a competitive PCR assay. In a group of 21 AIDS patients with HCMV-related CNS disease, 12 patients with HCMV polyradiculopathy had a mean +/- SEM of 11,982 +/- 4,480 copies/microliters in their CSF compared to 1,747 +/- 929 for 9 patients with HCMV encephalitis p = 0.017). Of the 14 patients with > 1,000 copies/microliters of HCMV DNA in CSF, 11(79%) had HCMV polyradiculopathy including all 3 with > 10,000 copies/microliters. Ganciclovir treatment of 3 patients with HCMV-related CNS disease was associated with a decline in HCMV DNA detectable within CSF. These data indicate that quantities of HCMV DNA in CSF are higher in persons with HCMV related polyradiculopathy than encephalitis, and that quantitation of HCMV DNA can be useful in monitoring antiviral therapy. PMID- 8685635 TI - Staphylococcus aureus meningitis: a review of 28 consecutive community-acquired cases. AB - From 1966 to 1989 a total of 1,830 cases of bacterial meningitis were recorded at the Department of Infectious Diseases, Rigshospitalet, Denmark. Staphylococcus aureus meningitis accounted for 44 (2.4%) of these cases. Among these, 28 cases were classified as community-acquired S. aureus meningitis. The mortality rate for these cases was 43%. A retrospective study of clinical features and parameters in these community-acquired cases showed the following conditions to be associated with a high mortality risk: advanced age, an underlying condition requiring artificial ventilation, cardiovascular disease and immune deficiencies. At admission, more than 75% of the patients had fever, nuchal rigidity and decreased consciousness. In 57% of cases the focus for the S. aureus infection was endocarditis, pneumonia or skin infections. All the patients had complications due to the meningitis, the major one being insufficient respiration. Autopsy performed in 9 of the 12 fatalities showed endocarditis in 5, pneumonia in 4, and pyelonephritis in 2. All of the brains examined at autopsy showed cerebral and subarachnoid hemorrhage. PMID- 8685634 TI - Staphylococcus aureus bacteremia: a 14-year nationwide study in hematological patients with malignant disease or agranulocytosis. AB - This retrospective nationwide study of 756 cases of S. aureus bacteremia in hematological patients, between 1977-1990, confirms that S. aureus bacteremia is disproportionately prevalent among, and a major cause of morbidity and mortality in, hematological patients. The case mortality rate attributable to S. aureus bacteremia (44%) was significantly higher than the rate (29%) found in patients without hematological disease. A decreasing mortality was, however, observed from the first to the last part of the study period (53 and 37% respectively). A logistic regression analysis showed that mortality was further dependent on age, the type of hematological disease and origin of infection/primary focus of infection. Analysis of clinical features confirmed that in comparison with other patients, S. aureus bacteremia in hematological patients more often was hospital acquired, acquired without known portal of infection/primary focus of infection and much less frequently resulted in osteomyelitis or endocarditis. From phage typing and antibiotic susceptibility patterns no specific types of S. aureus were associated with hematological patients. PMID- 8685636 TI - Molecular epidemiology of Staphylococcus epidermidis isolates in a hematological unit during a 4-month survey. AB - In order to study the strain variety, clonal stability and epidemiology of Staphylococcus epidermidis, isolates from all bacterial cultures taken when clinically indicated in 2 wards of the hematological unit of Helsinki University Hospital, during a 4-month period, were characterized by 3 typing methods: antibiogram, plasmid profile and ribotype. A total of 141 distinct S. epidermidis colonies, from 28 blood cultures and 37 cultures from other sources in 32 patients were studied. Plasmid profiles and ribopatterns revealed 47 different strains of which 16 were bacteremic. One of these strains caused bacteremia in 4 different patients over a 3-month period and it was isolated from blood on 7 different sampling occasions. The occurrence of this clone was constant; it was usually found in both of 2 blood culture bottles inoculated (6/7 pairs) and dominated among the 17 distinct S. epidermidis colonies studied from the positive bottles (94% of the total). The clones causing bacteremias in the 2 wards were distinct. These findings indicate that certain clones of S. epidermidis can predominate in hematological wards and that nosocomial transmission of S. epidermidis strains may occur among patients, particularly within the same ward. PMID- 8685637 TI - Corynebacterium CDC group JK (Corynebacterium jeikeium) sepsis in haematological patients: a report of three cases and a systematic literature review. AB - We describe 3 patients with Corynebacterium jeikeium sepsis in neutropenic phase during treatment for acute myeloid leukaemia. Fever was the first symptom. All had a central venous catheter which was removed. Two patients developed subcutaneous nodules containing pus when the neutrophil count recovered; 1 had intracutaneous and pulmonary lesions. They were treated with vancomycin and recovered when the neutrophil count started to rise. A review of 80 neutropenic patients with C. jeikeium sepsis reported in the literature, together with our 3 cases indicates that risk factors for infection are the presence of a central venous catheter, being an adult male or postmenopausal female, profound and prolonged neutropenia and exposure to multiple antibiotics. Skin lesions are reported in 48% and pulmonary lesions in 36% of the patients. The overall mortality is 34% but in patients with recovery of the bone marrow only 5%. Therefore haematopoietic growth factors should be considered in neutropenic patients with C. jeikeium infection. PMID- 8685638 TI - Restriction fragment length polymorphisms (RFLP) of cholera toxin genes in Vibrio cholerae O139 recovered from patients in Thailand, India and Bangladesh. AB - Since its first appearance in 1992, Vibrio cholerae O139 has caused large epidemics of a cholera-like disease in India and Bangladesh and has subsequently spread to several neighboring countries. We characterized and compared 56 V. cholerae O139 isolates recovered from patients in Thailand, India and Bangladesh by analyzing restriction fragment length polymorphisms (RFLP) of their ctx genes. The strains comprised 9 different BglI cleavage patterns of ctx genes (CT genotypes) and contained 1-4 gene copies. A total of 6 different CT genotypes were found among the 52 Thai isolates studied whereas the 2 Indian isolates and 1 isolate from Bangladesh all showed unique CT genotypes. The molecular analysis of ctx genes appeared superior to ribotyping for subspecies differentiation of O139 strains since ribotyping revealed 3 different BgII ribotypes. In addition, no correlation was found between the two methods. The molecular analysis of virulence determinants such as ctx genes in combination with other molecular techniques appears to be promising for the study of genetic changes within V. cholerae O139. PMID- 8685639 TI - Campylobacter jejuni/coli and enterotoxigenic Escherichia coli (ETEC) in faeces from children and adults in Tanzania. AB - The occurrence of Campylobacter and enterotoxigenic E. coli (ETEC) was studied in faecal samples from Tanzanian children (< 5 years of age), adolescents and adults (only Campylobacter) with and without diarrhoea. The Campylobacter strains isolated were tested for subspecies, enterotoxigenicity and serotype. Out of 394 children with diarrhoea 18% were infected with Campylobacter and 20% with ETEC. In 278 samples tested for Campylobacter and 136 tested for ETEC from asymptomatic children the corresponding numbers were 12 and 5%, respectively. In children < 18 months with diarrhoea Campylobacter was noted in 22% and ETEC in 18%, whereas the figures were 11 and 4% respectively in asymptomatic children. In the age group 18 months to 5 years Campylobacter was demonstrated in 2% of the children with diarrhoea and 27% had ETEC, while the figures were 15 and 8% for asymptomatic children. Among adults the prevalence of Campylobacter-positive samples was 1% both for symptomatic and asymptomatic individuals. There were no seasonal differences in the prevalences of both Campylobacter and ETEC either in the symptomatic or the asymptomatic group. Campylobacter jejuni was the dominating Campylobacter species among both symptomatic and asymptomatic individuals. C. jejuni strains from patients with diarrhoea were significantly more often enterotoxigenic than were C. coli strains. The serotype pattern regarding Campylobacter was in general similar for symptomatic and asymptomatic individuals. We conclude that Campylobacter and ETEC are common causes of bacterial diarrhoea in Tanzanian children, and that Campylobacter infections are more important in children younger than 18 months, than in older ones. PMID- 8685640 TI - Prevalence of Borrelia burgdorferi sensu lato infection in Ixodes ricinus in Sweden. AB - Between 1988-1991, a total of 3,141 Ixodes ricinus ticks, 2,740 adults and 401 nymphs, was collected from different localities in 23 of the 25 provinces of Sweden. The ticks were identified, dissected and examined for the presence of Borrelia spirochetes. Indirect immunofluorescence was performed, using an antiserum obtained from rabbits, immunized with sonicated, whole Borrelia burgdorferi spirochetes isolated from Swedish Ixodes ricinus ticks. Borrelia positive I. ricinus were found in all 23 provinces. The prevalence of infection in adults ranged from 3% in Jamtland to 23% in Sodermanland. In nymphs, the infection prevalence ranged from 0% in 9 provinces to 15% in Sodermanland. A significantly greater proportion of the adult ticks were found to be positive for Borrelia in the southern and central parts of Sweden as compared to the northern part (Norrland). No significant difference in prevalence could be demonstrated between the western and eastern parts of Sweden. On average, 10% of the nymphs and 15% of the adult I. ricinus were positive for Borrelia. Of 41 non-I. ricinus ticks, none was positive for Borrelia. This study shows that Borrelia burgdorferi sensu lato is present throughout the distributional area of I. ricinus in Sweden. This should lead to increased awareness of signs and symptoms compatible with Lyme borreliosis in persons living in or visiting areas where I. ricinus is present. PMID- 8685641 TI - Dipslide culture in colonic surgery: a tool for assessment of surgical performance and a guide to antibiotic use. AB - We evaluated a bacterial culture system for the assessment of surgical performance during colorectal operations, and for assessing the impact of selective postoperative antibiotics in contaminated cases. Surgically related infections were recorded and their risk factors were estimated, using univariate and multivariate methods, in 1079 patients undergoing elective colorectal operations. (Study period 1 was prospective, controlled and randomized, and study period 2 was prospective and open). All the patients were given metronidazole, 1 g i.v., at induction of anaesthesia and 12 h postoperatively. The number of colony-forming units (CFU) on an intraoperative dipslide culture was classified as 0, 1-4 or > or = 5 (n = 591, 183 and 305). Patients with > or = 5 CFU were randomized to receive either no further antibiotics or cefuroxime (1.5 g, i.v. every 8 h for 2 days) during the first study period (30 months). During the second period (84 months), all patients with > or = 5 CFU were to be given cefuroxime. Increasing age (p = 0.014), postoperative transfusion of packed red blood cells (p < 0.001), and high bacterial numbers (p < 0.001) were independently associated with infection. Surgeon-related rates of operative bacterial contamination varied between 12 and 50% (p < 0.001). In patients given only metronidazole, the likelihood of infection rose as the density of bacteria in the wound increased according to a sigmoid dose-response curve (5.1, 9.8 and 47.5% with CFU 0, 1-4 and > or = 5, respectively). In the category with > or = 5 CFU, 265 patients were treated with cefuroxime and 23 (8.7%) subsequently had infections [corrected]. Of 40 patients with > or = 5 CFU who did not receive cefuroxime postoperatively, 19 developed infections (p < 0.001, relative risk 5.47; 95% confidence interval 3.29-9.10). In conclusion, dipslide culture can identify patients at high risk of infection after colonic operations. It can be used to assess surgical performance. The addition of postoperative antibiotic cover for aerobic bacteria, detected by the dipslide, reduced the risk of infection more than 5-fold and almost eliminated the risk of contamination. PMID- 8685643 TI - Pneumonia in mechanically ventilated children. AB - The quantitative aerobic and anaerobic microbiology of bronchial aspirates, obtained using protective brush catheters, from 10 children with ventilator associated pneumonia, is presented. Aerobic or faculative organisms only were isolated in 1 child, anaerobic bacteria only in 3, and aerobic mixed with anaerobic bacteria in 6. There were 10 aerobic or faculative and 17 anaerobic isolates. The predominant aerobes were Pseudomonas aeruginosa (2 isolates) and Klebsiella sp. (2). The predominant anaerobes were pigmented Prevotella and Porphyromonas species (5), Peptostreptococcus sp. (4), Fusobacterium sp. and B. fragilis group (2). A total of 10 beta-lactamase-producing aerobic and anaerobic bacteria were isolated in 8 patients. All patients except 1 responded to antimicrobial therapy directed against the recovered isolates. These data highlight the polymicrobial aerobic-anaerobic flora isolated from pulmonary specimens of patients with ventilator-associated pneumonia. PMID- 8685642 TI - Fluconazole compared with itraconazole in the treatment of esophageal candidiasis in AIDS patients: a double-blind, randomized, controlled clinical study. AB - The aim of this study was to assess the role and the therapeutic efficacy of 2 azole antifungal drugs, fluconazole and itraconazole, in the treatment of endoscopically diagnosed Candida esophagitis in patients with acquired immunodeficiency syndrome (AIDS). The study involved 123 human immunodeficiency virus (HIV)-positive patients (70 males and 53 females, mean age 27 years) at their first episode of esophageal candidiasis diagnosed by endoscopy. The patients were randomized in a double-blind design to receive either fluconazole (100 mb b.i.d. per os) or itraconazole (100 mg b.i.d. per os). In order to evaluate the efficacy of treatment, clinical examinations were performed every week up to the end of follow-up (2 months); endoscopic examination was performed at baseline, at the end of treatment (3 weeks) and at the end of follow-up. At the end of the treatment, cure, as judged by endoscopy, was observed in 74% of fluconazole-treated patients and in 47.2% of itraconazole-treated patients (p < 0.01); at the end of follow-up, cure was observed endoscopically in 71.7% of fluconazole-treated patients and in 43.2% of the itraconazole-treated patients (p <0.05). As regards clinical cure, no statistically significant difference was observed between the groups, at the end of pharmacological treatment and at the end of follow-up. The results of this study demonstrate that both fluconazole and itraconazole are efficacious in the treatment of Candida esophagitis in AIDS patients; fluconazole is associated with higher rate of endoscopic cure than is itraconazole. PMID- 8685644 TI - Chronic ulcerating acyclovir-resistant varicella zoster lesions in an AIDS patient. AB - We describe a 28-year-old HIV-infected woman with AIDS, defined by cerebral toxoplasmosis and a CD4-count of less than 10 x 10(6) cells/I, who, after several eruptions of genital herpes and typical dermatomal herpes zoster, all successfully treated with acyclovir, developed chronic cutaneous ulcerating lesions on a finger and on the tibia. The lesions were found to contain varicella zoster virus antigen but repeated treatment courses with acyclovir were unsuccessful. After a course of intravenous foscarnet the lesions resolved. They recurred after discontinuation of foscarnet but finally responded to a second course of treatment. PMID- 8685645 TI - Liver failure due to disseminated HSV-1 infection in a newborn twin. AB - Most cases of neonatal herpes simplex virus (HSV) infection result from contact with maternal genital tract secretions and are caused by infections with HSV type 2. We report on a fatal HSV-1 infection in a newborn twin presenting with liver failure. The infection was acquired by single contact with an aunt. The route of transmission was proven by PCR followed by restriction endonuclease fingerprinting and DNA sequencing. This report demonstrates that liver failure may be an early and single symptom in life-threatening neonatal HSV-1 infection. PMID- 8685646 TI - Parvovirus B19 infection associated with encephalitis in a patient suffering from malignant lymphoma. AB - A parvovirus B19 infection was established in a 58-year-old woman undergoing treatment for malignant lymphoma. Clinically, the patient displayed a variety of neurologic symptoms that could not readily be explained by the mere presence of lymphoblastic cells within the central nervous system. This is the first time parvovirus B19 DNA has been detected in the cerebrospinal fluid of a patient suffering from encephalitis. PMID- 8685647 TI - Total knee arthroplasty complicated by Corynebacterium jeikeium infection. AB - Corynebacterium jeikeium is a slow-growing multiresistant micro-organism. It causes serious opportunistic infections in patients with long hospital stays who receive broad-spectrum antibiotics. It can be isolated from blood and other sites in neutropenic, immunosuppressed bone marrow recipients and in patients with indwelling catheters. Cases of infection related to bone and joint replacements are rare. This case is the first where Corynebacterium jeikeium has been isolated from an infected knee following total knee arthroplasty. PMID- 8685648 TI - Corynebacterium afermentans subsp. lipophilum: multiple abscess formation in brain and liver. AB - Corynebacterium afermentans, a species recently identified, has previously been isolated from human blood cultures. We report the case of a previously healthy 39 year-old man who developed a brain abscess and a liver abscess due to Corynebacterium afermentans subsp. lipophilum. The liver abscess penetrated through the diaphragm to cause pleural effusion and periostitis of the ribs. We believe this is the first reported case of disseminated infection with abscess formation due to this organism. PMID- 8685649 TI - A case of Brucella melitensis endocarditis successfully treated by a combination of surgical resection and antibiotics. AB - Endocarditis is a rare complication of brucellosis, often fatal, and the treatment is controversial. We present a case of Brucella melitensis endocarditis successfully treated by a combination of surgical resection and antibiotics. PMID- 8685650 TI - Overwhelming myocarditis due to Fusarium oxysporum following bone marrow transplantation. AB - Disseminated infection by Fusarium is being increasingly reported in immunocompromised patients. We report the first case of Fusarium oxysporum disseminated infection with well-documented fungal myocarditis. Despite antifungal therapy and hematologic recovery, the patient died in cardiogenic shock, myocardial involvement clearly contributing to the fatal outcome. PMID- 8685651 TI - Acute clonorchiasis. AB - A 42-year-old Chinese woman developed 3 weeks of swinging fever, rash, malaise, and discomfort at the right upper quadrant of the abdomen. Acute Clonorchis sinensis infection eventually became evident and the patient responded to praziquantel. Although acute infestation is usually asymptomatic, occasional cases suffer severe symptoms and present difficulties in clinical diagnosis. Clonorchiasis is endemic in South East Asia. With the increasing popularity of travel to these countries and the global migration of Asians, physicians need to be aware of the condition. Treatment with praziquantel is effective and prevents the serious sequelae of chronic infection. PMID- 8685652 TI - Schizophrenia, Alzheimer's disease, and anti-inflammatory agents. AB - Some recent postmortem reports raise the possibility that Alzheimer-type pathology may be 6 to 12 times higher in elderly schizophrenia patients than in general population. One study indicates that neuroleptic treatment may be an important contributor. Other reports, however, suggest that cognitive impairment in elderly schizophrenia patients is seldom due to Alzheimer-type pathology, indicating that more detailed follow-up studies are needed. Since multiple epidemiological studies show that Alzheimer's disease is less prevalent in patients with medical conditions requiring anti-inflammatory drugs than in the general population, anti-inflammatory medication might be considered as an adjuvant to chronic neuroleptic treatment in elderly schizophrenia patients showing early signs of Alzheimer-type memory deficits. PMID- 8685653 TI - Pathogenesis of schizophrenic delusions and hallucinations: a neural model. AB - We implement and study a computational model of Stevens' theory of the pathogenesis of schizophrenia. This theory hypothesizes that the onset of schizophrenia is associated with reactive synaptic regeneration in brain regions that receive degenerating temporal lobe projections. Concentrating on one such area, the frontal cortex, we model a frontal module as an associative memory neural network whose input synapses represent incoming temporal projections. Modeling Stevens' hypothesized pathological synaptic changes in this framework results in adverse side effects similar to hallucinations and delusions seen in schizophrenia: spontaneous, stimulus-independent retrieval of stored memories focused on just a few of the stored patterns. These could account for the delusions and hallucinations that occur in schizophrenia without any apparent external trigger and for their tendency to concentrate on a few central cognitive and perceptual themes. The model explains why the positive symptoms of schizophrenia tend to wane as the disease progresses, why delayed therapeutic intervention leads to a much slower response, and why delusions and hallucinations may persist for a long time when they do occur. PMID- 8685654 TI - Occupations, factors, and schizophrenia. PMID- 8685655 TI - Frontal/executive impairments in schizophrenia. AB - A study of frontal/executive impairments in schizophrenia is reported. Schizophrenia patients and controls were not significantly different with respect to age, sex, and premorbid IQ. The schizophrenia group demonstrated significant impairments in cognitive flexibility and forward planning, replicating results from a 1990 study by Morice. Impairment prevalence figures of 65 and 76 percent for cognitive flexibility and forward planning, respectively, were demonstrated. Several tests for short-term memory were administered. Schizophrenia patients were not found to be impaired on tests of simple, or primary, short-term memory as measured by Digits Span Forward and Words Span Forward, but they were found to be significantly impaired compared with controls on two tests of working memory, Alphabet Span and Sentence Span. Using a cutoff derived from the mean score for the controls, 65 percent of schizophrenia patients proved to be impaired on Sentence Span. A total of 16 (94%) were impaired on one or more of the three tests of executive functioning used. The effects of IQ on test results were examined, and impairment of cognitive flexibility and forward planning seemed to occur regardless of whether premorbid IQ had been preserved or had deteriorated. However, working memory impairments occurred in the subgroup of schizophrenia patients demonstrating a substantial fall in IQ from premorbid levels. The ability to process increasingly complex information was addressed by a more detailed examination of the Tower of London results. There were no differences in performance between groups for the first three levels of complexity (1-3 moves), but significant, and increasing, differences emerged for the last three levels (4 6 moves). These results were taken to support the hypothesis that schizophrenia represents a loss of, or a failure to acquire, the ability to process complex information. Impairments of executive functions that could affect complex information processing could have implications for schizophrenia rehabilitation. PMID- 8685656 TI - Cognitive inhibition and schizophrenic symptom subgroups. AB - Subgroups of patients with schizophrenia were examined in relation to repetition and semantic priming under conditions in which the prime stimulus was to be either attended to or ignored (unattended). Attended conditions normally would produce positive priming; and unattended conditions, negative priming (i.e., a delayed reaction resulting from inhibition of target information previously presented as to-be-ignored stimulus). Cluster analysis of participants' ratings on the Schedule for the Assessment of Positive Symptoms and the Schedule for the Assessment of Negative Symptoms revealed three subgroups that aligned broadly previous research citing with disorganization, reality distortion, and psychomotor poverty syndromes, and a fourth episodic subgroup. The Disorganization, Reality Distortion, and Episodic subgroups were associated with reduced, indeed reversed, negative priming in unattended priming conditions, whereas the Psychomotor Poverty subgroup exhibited the usual negative priming effect. Participants in the former three subgroups also exhibited reversed positive priming for the repetition condition, while the Psychomotor Poverty group displayed the expected positive priming effect. These results indicate that weakening of inhibitory processes may underlie both the reality distortion and disorganization dimensions of positive schizophrenic symptomatology, including the latent presence of these symptoms. In contrast, negative symptoms contributing to the psychomotor poverty dimension of schizophrenia are not linked to reduced inhibition. The association of positive symptom subgroups with reversed positive priming suggested that, for these participants, stimuli and task differences have an impact on the preattentive activation of information underlying such priming. It is proposed that a "reduced inhibition" model of schizophrenic symptomatology may need to be extended to account for influences on preattentive processing. PMID- 8685657 TI - Clozapine eligibility among state hospital patients. AB - Connecticut State Hospital's entire resident population (n = 1,300) was screened on an arbitrary target day to determine eligibility for clozapine. Sixty percent of 803 patients with schizophrenia or schizoaffective disorder diagnoses met Food and Drug Administration (FDA)- approved criteria for clozapine use as judged by review of past medication trial records and by the responsible physicians. Eighty eight percent of these patients were medically cleared, and of those cleared, 63 percent agreed to clozapine treatment. Of the patients who began a clozapine trial, 76 percent were still taking the drug 12 months later. Preliminary findings from a randomized trial of clozapine versus usual care (n = 227) indicate that discharge rates associated with clozapine and usual care do not differ. Once discharged, however, patients assigned to clozapine are less likely to be readmitted. Hence, clozapine may be more cost-effective than usual care. However, before savings can be realized, State governments will have to make up front investments of approximately $140 million simply to give patients hospitalized on a single day a year's access to clozapine. PMID- 8685658 TI - Situational familiarity and feature recognition in schizophrenia. AB - Research has shown that schizophrenia patients are less able to identify a situation's abstract features (goals) than its concrete features (actions). However, it has been unclear whether this differential deficit represents a cognitive dysfunction or a lack of familiarity with many situations because of impoverished social experiences. Twenty-nine inpatients with DSM-III-R diagnosis of schizophrenia completed the Situational Feature Recognition Test, Version 2 (SFRT-2). The SFRT-2 included familiar and unfamiliar situations of which subjects were asked to identify characteristic goals and actions. A 2 x 2 x 2 analysis of variance (group by feature abstraction by situational familiarity) found a significant three-way interaction. Post-hoc analyses suggested that patients were better able to recognize concrete features in familiar situations. Differences in discriminating power of the four conditions of the SFRT-2 had been diminished on standardization and cross-validation groups. Therefore, the differential deficits shown by the patient sample probably do not represent psychometric confound. Implications for remediation of social cognitive deficits are discussed. PMID- 8685659 TI - Regional cerebral blood flow in schizophrenia and the local circuit neurons hypothesis. AB - It has been suggested that nitric oxide, a nonconventional intra- and intercellular messenger involved in various biological and nervous system functions, may play a crucial role in a sophisticated cerebral microvascular system that regulates cerebral blood flow (CBF) under resting and activated conditions. A review of regional cerebral blood flow (rCBF) studies is schizophrenia shows that in schizophrenia patients this microvascular regulatory system may be deficient, failing to selectively raise rCBF in areas of the frontal and temporal lobes to respond to the physiological load placed on brain cells in these areas during certain neuropsychological tasks. A hypothesis about the more general role of local circuit neurons (LCNs) in the pathophysiology of schizophrenia is revised in light of recent information about both the characterization of LCN subpopulations and the interactions of multiple neuro transmitter systems in midbrain, striatum, and cortex. This revision helps explain the subtle rCBF regulatory failure, as well as other failures in information processing, in schizophrenia patients and points to interneurons as likely sites for the action of both typical and atypical antipsychotic drugs. PMID- 8685660 TI - First person account: social, economic, and medical effects of schizophrenia. PMID- 8685661 TI - Convulsive therapy in schizophrenia? AB - Schizophrenia is a clinical syndrome of extraordinary importance and complexity. Its early identification is difficult, and our concepts of its main characteristics have undergone many changes in the past century. Electroconvulsive therapy (ECT) was introduced as a treatment for dementia praecox. The initial reports were salutary, and the treatment was widely applied until it was replaced by psychoactive drugs. ECT was reintroduced in the 1970s in the treatment of therapy-resistant disorders. The initial reviews argued that ECT was not applicable in patients with schizophrenia, a conclusion based mainly on experience with chronic forms of the disorder. This article assesses the role of ECT in schizophrenia today. We find it to be an effective treatment for psychosis. ECT is particularly applicable in patients with first-break episodes, especially those marked by excitement, overactivity, delusions, or delirium; in young patients, to avoid debilitating effects of chronic illness; and in patients with syndromes characterized by catatonia, positive symptoms of psychosis, or schizoaffective features. PMID- 8685662 TI - Impact of brief family psychoeducation on self-efficacy. AB - One hundred eighty-three relatives of people with serious mental illnesses were randomly assigned to receive individualized consultation or group psychoeducation or were placed on a 9-month wait list. Analysis of variance and multiple regression revealed that the individualized consultation increased the family members' sense of self-efficacy regarding mentally ill relatives. Group psychoeducation was helpful in increasing self-efficacy of family members who had never participated in a support or advocacy group for relatives of psychiatrically disabled individuals. PMID- 8685663 TI - Cognitive impairment in elderly schizophrenia: a dementia (still) lacking distinctive histopathology. AB - Recent clinical and neuropsychological studies have shown that severe deterioration in cognitive and functional capacities is prevalent in elderly, chronically hospitalized patients with schizophrenia. Postmortem studies of tissue from patients who were clinically well characterized have found notably little neurodegenerative or other pathology to explain the dementia. In contrast, several large studies using archival material have reported an unexpectedly high occurrence of Alzheimer's disease pathology in patients with schizophrenia irrespective of clinical status. Reasons for conflicting results likely include inaccuracies in psychiatric diagnoses but also could be due to differences in sample selection, treatment histories, and environmental influences. Thus, the neurobiological substrates for dementia in late-life schizophrenia remain uncertain. Further studies should incorporate standard diagnostic procedures with community-based and institutionalized schizophrenia patients as well as psychiatric control patients with similar treatment histories. These should apply sensitive neuropathological methods to assess disease-specific and nonspecific markers of neurodegeneration and dementia. PMID- 8685664 TI - Clinical benefits of paid work activity in schizophrenia. AB - Although indirect support can be found for the clinical benefits of work, it has not been studied in randomized designs, nor have critical variables been manipulated. One such variable is pay incentive. The authors present a study of 150 subjects with schizophrenia or schizoaffective disorder who were randomized into Pay ($3.40/hour) and No-Pay conditions and offered 6-month work placements within a Department of Veterans Affairs medical center. Subjects participated in a work-related support group and were evaluated weekly on symptom measures. Results indicated that Pay subjects worked more hours and earned more money than No-Pay subjects. Pay subjects showed more total symptom improvement at followup, and more improvement, particularly on positive and emotional discomfort symptoms. They also had a significant lower rate of rehospitalization than No-Pay subjects. Participation in work activity was closely associated with symptom improvement. Participators showed more total symptom improvement at followup than partial participators or nonparticipators, and more improvement, particularly on positive, hostility, and emotional discomfort symptoms. We concluded that pay increased participation and that, in this study, participation in work activity was primarily responsible for symptom reduction. PMID- 8685665 TI - Mental disorder and criminality: male schizophrenia. AB - This study investigated lifetime prevalence of criminal behavior in a population of male schizophrenia patients. A total of 282 schizophrenia patients was divided into three subgroups (representing schizophreniform disorder, acute schizophrenia, and chronic schizophrenia). The same number of control subjects was drawn from the general population and matched with the patients for sex, age, marital status, occupational level, and community size. The full account of conviction records in the criminal register was used as a measure of criminal behavior. Patients were 5 times more likely to have been convicted of violent crimes, 2 1/2 times more likely to have been convicted of crimes against property, and almost 3 times more likely to have violated drug laws. Criminality rates in schizophrenia depended, however, not only on the type of offense but also on the type or stage of the illness, which contributed to criminal behavior to some extent independently of sociodemographic factors. PMID- 8685666 TI - Schizophrenia and homicidal behavior. AB - It is generally thought that schizophrenia does not predispose subjects to homicidal behavior. However, many previous studies have suffered from notable methodological weaknesses. In particular, obtaining comprehensive study groups of violent offenders has been difficult. Finnish police have been able to solve about 97 percent of homicides during the last few decades. Because most homicide offenders are subjected to intensive forensic psychiatric examination, we were able to obtain data for 93 homicide offenders with schizophrenia among 1,423 arrested during a 12-year period. Calculations of the odds ratios revealed that the risk of committing a homicide was about 10 times greater for schizophrenia patients of both genders than it was for the general population. Schizophrenia without alcoholism increased the odds ratio more than 7 times; schizophrenia with coexisting alcoholism more than 17 times males. PMID- 8685667 TI - Psychosis and violence: the case for a content analysis of psychotic experience. AB - There has been a great deal of debate about the dangers psychiatric patients pose to the general population. Recent studies appear to confirm a moderate but reliable association between mental illness and violence. The nature of this association, however, is unresolved. Considerable evidence suggests that much of the violent behavior observed in the mentally ill is not random but is motivated and directed by psychotic symptoms. In many cases, the behavior appears to be a predictable and in some ways rational response to irrational beliefs (delusions) and perceptions (hallucinations). The content and themes of a psychotic patient's delusion or hallucination often imply a specific course of violent action. Unlike studies of associations between violence and broad categories of subject characteristics (e.g., mental illness), an analysis of the association between violence and the content and themes of psychotic symptoms could be much more informative. Conceivably, such an analysis could identify not only psychiatric patients at risk for committing violence but also those individuals who are at risk for becoming targets of their violence. PMID- 8685668 TI - Buildings with moisture problems--a new challenge to occupational health care. PMID- 8685669 TI - Incidence and risk factors of cancer among men and women in Norwegian agriculture. AB - OBJECTIVES: The objective of the study was to examine cancer incidence and identify risk factors among subjects born in 1925-1971 and engaged in agricultural activities in Norway. METHODS: A cohort was established through linkage between agricultural censuses in 1969-1989 and the Central Population Register, which identifies farm holders and their spouses. Available census information on the activity of the farm provided the exposure indicators. Incident cancer in 1969-1991 was identified in the Cancer Register. In an analysis for standardized incidence ratios (SIR), the cohort was compared with the total rural population of Norway. Associations with exposure indicators were investigated in a Poisson regression analysis. RESULTS: In the follow-up of 136,463 men for 1.5 million person-years and 109,641 women for 0.6 million person years, 3333 and 2145 cancer cases were identified, respectively. The subset defined as farmers had an SIR of 77 [95% confidence interval (95% CI) 73-81] for the men and 92 (95% CI 85-99) for the women, with particularly low SIR values for lung cancer and other sites linked to life-style. The several positive associations found confirmed the a priori hypothesis of an association between dairy farming and acute leukemia among men [rate ratio 1.76, 95% CI 1.02-3.05]. Multiple myeloma was associated with pesticide indicators for both genders, mainly for subjects cultivating potatoes. CONCLUSIONS: The results support the hypothesis of a relationship between acute leukemia and animal contact and between multiple myeloma and pesticides in potato cultivation. Other exposure associations, especially for cancer among women, warrant further investigation. PMID- 8685670 TI - Mortality in a cohort of Russian fertilizer workers. AB - OBJECTIVES: The study evaluated the mortality of workers exposed to precursors of N-nitroso compounds in a Russian fertilizer plant. METHODS: Workers employed at least two years between 1945 and 1985 in production departments or other services were included in the cohort, which comprised 2039 men and 2957 women followed from 1965 to 1990. The standardized mortality ratios (SMR) were calculated using cause-specific death rates for the Moscow region as reference. An internal comparison was carried out using Poisson regression modeling. Exposure to arsenic, nitrogen oxides, and sulfur dioxide was estimated from an industrial hygiene survey. RESULTS: The production and other workers had no excess of mortality from all causes or all neoplasms. However the male production workers had excess mortality from all cancers combined (SMR 143) and lung cancer (SMR 186) after a latency period of > or = 20 years. Men with the highest exposure to nitrogen oxides had a twofold increase in mortality from stomach cancer, with a marginally significant increasing trend between stomach cancer and cumulative exposure to nitrogen oxides for both genders. Excess mortality from all cancers and stomach cancer was found for the worker with the highest average exposure to arsenic, and excess lung cancer mortality could be attributed to exposure to arsenic. CONCLUSIONS: The investigation showed a weak association between employment in a fertilizer production plant and increased mortality from cancer. The results somewhat support the hypothesis that occupational exposure to precursors of N-nitroso compounds increases the risk of stomach cancer mortality, as does exposure to arsenic. PMID- 8685671 TI - Pulmonary asbestos bodies and asbestos fibers as indicators of exposure. AB - OBJECTIVES: The aim of the study was to analyze the correlation between pulmonary concentrations of asbestos bodies and asbestos fibers and to characterize asbestos body counts from lung tissue of Finnish patients occupationally exposed and unexposed to asbestos. METHODS: Ninety-nine surgically treated lung cancer patients were investigated. The number of asbestos bodies in iron-stained 5 micrometers histological lung tissue sections was determined by optical microscopy, and the pulmonary concentration of asbestos fibers was assessed by scanning electron microscopy. The correlation between asbestos body and asbestos fiber counts was calculated with linear regression. The asbestos body and asbestos fiber concentrations were also compared with exposure history according to a personal interview of the patients. RESULTS: The average number of asbestos bodies ranged from < 0.1 to 750 asbestos bodies per tissue section. All the cases with definite exposure showed an average of at least one asbestos body per tissue section. An average of at least one asbestos body per section was, however, detected in 34% of the patients with unlikely exposure. The regression equation log (AF) = -0.429 + 0.600.log (AB) was found to predict the concentration of asbestos fibers (AF, 10(6) fibers.g-1) corresponding to a given number of asbestos bodies (AB) in a section of lung tissue. CONCLUSIONS: The background level of asbestos bodies in the lungs of patients with no specific asbestos exposure seems to be higher in Finland than in other countries. In medicolegal cases, the methodological variation involved in asbestos fiber and asbestos body counting must be recognized and all available exposure data should be used to produce the best possible estimate of the exposure. PMID- 8685672 TI - Exposure to high-frequency transient electromagnetic fields. AB - OBJECTIVES: The purpose of this study was to assess exposure to high-frequency transient (HFT) electromagnetic fields in occupational and residential environments. METHODS: Exposure to HFT electromagnetic fields was measured with personal dosimeters for 301 volunteers (396 measurements) in periods of 24 h in both occupational and residential environments. The study included electrical utility workers (generation, transmission, distribution, substation), office and industrial workers, and people living near high-power transmission lines. The measure of exposure to HFT fields was specified as the proportion of time (parts per million) in which the electric field exceeds a nominal threshold level of 200 V.m-1 at 5-20 MHz. Recently the specification of the HFT channel of the dosimeter has been found to be incomplete; therefore a testing of the threshold level and the sensitivity to electromagnetic fields from radio-telephones was carried out. RESULTS: The percentage of measurements with a mean workday exposure above 0.1 ppm was 6.5-9.4% for the utility groups and 0.9% for all the nonwork measurements. It is likely that the use of radio-telephones has contributed significantly to the number of HFT events in some of the measurements, especially for the generation workers. The nominal threshold level of the dosimeter was found to vary considerably depending on the polarization of the field (20-400 V.m 1 at 13.56 MHz for one instrument). CONCLUSIONS: Generally speaking, HFT fields appeared infrequently. The workday exposure to HFT fields and 50 Hz magnetic fields ranked the groups differently. There is a need for developing instrumentation for HFT field measurements further. PMID- 8685673 TI - Work conditions and mental health among prison staff in France. AB - OBJECTIVES: A cross-sectional epidemiologic survey was conducted among prison staff in France to investigate the relationships between work conditions and mental health. METHODS: The sample included men and women 20 to 64 years of age belonging to all categories of prison personnel (prison guards, administrative staff, socioeducational workers, technicians, health care workers, and managers). A postal self-administered questionnaire was used to assess sociodemographic factors, work conditions, and physical and mental disorders. Multiple logistic regression analyses were conducted to determine the effects of work conditions and social relationships on the mental health of prison staff. RESULTS: The results presented in this report only concern depressive symptomatology (measured by the French version of the Center for Epidemiologic Studies Depression Scale), anxiety (measured by the state version of the State-Trait Anxiety Inventory), and sleep disorders. The percentage of mental disorders was higher among prison staff than that determined for other occupational samples. Guards comprised the prison staff least affected by these symptoms. CONCLUSIONS: The results show that, in our sample, the factors concerning the subjective evaluation of work conditions and social support were more closely related to mental disorders than work conditions. In addition, seniority was associated with depressive symptoms and anxiety among the men. PMID- 8685674 TI - Health effects of indoor-air microorganisms. AB - The review provides a summary and discussion of current data on exposure to indoor-air microorganisms and their health effects, for example, respiratory irritation and nonspecific symptoms, respiratory infections, asthma and allergy, alveolitis and organic dust toxic syndrome, and chronic bronchitis, as well as a summary and discussion of the health effects of mycotoxins. PMID- 8685675 TI - Underreporting of occupational cancers in Denmark. AB - OBJECTIVES: The goal of the study was to investigate whether the reporting of occupational cancers has improved in Denmark since 1987 and whether medical records currently have better information on occupational exposures. METHODS: All cases of pleural mesothelioma and sinonasal adenocarcinoma and 766 randomly selected adenocarcinomas of the lung diagnosed between 1983 and 1990 were identified from the Cancer Register. These cases were traced in the Register of Reported Occupational Diseases and in the records of the National Board of Industrial Injuries. Medical records for patients not reported to the Register of Reported Occupational Diseases were requested from hospitals and the data on work related exposure were retrieved. RESULTS: For pleural mesotheliomas the frequency of reporting increased from 43% in 1983-1987 to 53% in 1988-1990. The frequency of reporting of sinonasal adenocarcinomas decreased from 34 to 20% in these periods. Of the adenocarcinomas of the lung, 1% had been reported. CONCLUSION: Overall the reporting of occupational cancer has not improved in Denmark since 1987. PMID- 8685676 TI - Clonal chromosome aberrations in myeloid leukemia after styrene exposure. AB - OBJECTIVES: The purpose of the study was to determine the risk of myeloid leukemia subclassified according to clonal chromosome aberrations in styrene exposed workers. METHODS: A nested case-referent study was carried out on 19 myeloid leukemia patients, of which 12 showed clonal chromosome aberrations, and 57 referents ascertained within the Danish reinforced plastics industry and similar industries with no styrene exposure. RESULTS: A 2.5-fold increased risk for myeloid leukemia with clonal chromosome aberrations (95% confidence interval 0.2-25.0) was found among workers of companies with styrene exposure. CONCLUSIONS: The results suggest that styrene may cause leukemia through a clastogenic effect. But similar findings could also have been found if the exposure was associated with a specific subtype of leukemia prone to develop the chromosome aberrations in question. Due to the few observations and the lack of detailed exposure data, additional studies are needed to corroborate or refute the present suggestive findings. PMID- 8685677 TI - A fatal case of hard-metal disease. AB - OBJECTIVES: The purpose of this report is to present a case of hard-metal disease in which the symptoms and findings were minimal early in the disease, but further exposure rapidly led to a fatal outcome. HISTORY: A 22-year-old nonsmoking white male, employed for over four years in hard-metal tool grinding, started experiencing a dry cough and shortness of breath during exercise. Preliminary investigations did not reveal any cause for these symptoms, and the patient continued to work. Several months later he developed clinically apparent alveolitis with recurrent pneumothorax. Pulmonary infiltrates in chest radiographs did not disappear during corticosteroid treatment. Soon it was evident that the patient had irreversible pulmonary failure, and a bilateral lung transplantation was performed. No signs of rejection were seen in the resected lungs. The patient died of pneumonia five months later, but no signs of hard metal disease were found in the transplanted lung. CONCLUSIONS: This fatal case of hard-metal lung disease demonstrates that symptoms and findings in pulmonary function tests or chest radiographs may be minimal or misleading in the early stages of the disease. Cobalt-exposed workers with inexplicable respiratory symptoms should be closely monitored and the exposure should be suspended. PMID- 8685678 TI - Testicular cancer in pesticide applicators in Swedish agriculture. PMID- 8685679 TI - Mesothelioma in oil refinery workers. PMID- 8685680 TI - Second international scientific conference on the prevention of work-related musculoskeletal disorders, PREMUS 95, 24-28 September 1995, Montreal (Canada). PMID- 8685681 TI - [Fluorescent in-situ hybridization technique (FISH) in the diagnosis of Philadelphia translocation in chronic myeloid leukemia]. AB - The Philadelphia chromosome (Ph) resulting from translocation t(9;22)(q34;q11) is observed in more than 90% of patients with chronic myeloid leukemia (CML). Its molecular consequence is the genesis of a fusion gene BCR-ABL between the 5' sequences of the BCR gene (chromosome 22) and the 3' end of the ABL gene (chromosome 9). Fluorescence in situ hybridization (FISH) using specific DNA probes provides a useful tool for the detection of t(9;22) and BCR-ABL rearrangement. We report our results using the FISH technique for t(9;22) assessment in the hematopoietic cells of patients with Ph-positive CML. The DNA libraries pBS 9 and pBS 22 containing multiple sequences derived from chromosomes 9 and 22 have been used to identify t(9;22) in metaphase cells. The cos bcr-51 and cos abl-18 probes that hybridize to unique sequences specific to the BCR and ABL genes have the ability to detect the BCR-ABL rearrangement in metaphase cells as well as in interphase nuclei. FISH is a sensitive and specific technique that represents a valuable complement to conventional cytogenetics. The BCR-ABL rearrangement can be detected in metaphase spreads of insufficient quality or from interphase nuclei in the case of terminally differentiated cells or of cells which do not divide in vitro. When the efficiency of hybridization and detection is good, a large number of cells can be analyzed. This is of major significance in assessment of response to treatment and definition of a cytogenetic remission. However, interphase cytogenetics may be difficult due to variations in signal resolution and background level. The FISH technique can also be used to detect the BCR-ABL rearrangement in cases of Ph negative BCR-ABL positive CML. PMID- 8685682 TI - [Patient satisfaction in the ambulatory setting: validation of a scale and identification of associated factors]. AB - BACKGROUND: Patient satisfaction is increasingly used to evaluate the performance of health services. Validated French-language instruments to measure satisfaction are currently lacking. This study was designed to validate a questionnaire of this kind and to identify factors associated with patient satisfaction. METHODS: Mail survey of 1027 patients who consulted at 4 different ambulatory health care settings in Geneva, Switzerland. The participation rate was 81%. The questionnaire measured 7 dimensions of satisfaction using 16 items adapted from other sources. RESULTS: The questionnaire was easy to respond to (scores were available for 95 to 99% of respondents, depending on the scale). The internal consistency of the scales was satisfactory (Cronbach alpha between 0.65 and 0.82) for 5 of 6 multi-item scales; it was lower for the scale which measures satisfaction with access to care. Factor analysis identified two principal components corresponding roughly to the "process" and to the "organization" of care. Open comments also confirmed the validity of the multi-item scales. Several patient or visit characteristics were independently associated with the level of satisfaction: older patients, those who were born in Switzerland, who had a visit appointment, who consulted a specialist, and those who saw the same physician as at their previous visit were more satisfied than other patients. CONCLUSIONS: The brief satisfaction questionnaire described in this paper is easy to use, and its reliability and validity are good. Its use can be recommended in ambulatory health care settings. Several variables associated with the level of satisfaction were identified; they should be measured in satisfaction surveys to allow correct appraisal of the results. PMID- 8685683 TI - [Chemotherapy of gastrointestinal carcinomas and non-small-cell pulmonary carcinoma: a controversy]. AB - Patients with metastatic gastrointestinal cancers and metastatic non-small cell lung cancer present an important challenge in medical oncology and palliative care. Symptoms caused by tumor progression should undoubtedly be treated. The management of asymptomatic patients, however, is still controversial. A clinical decision on whether an asymptomatic patient should be treated with chemotherapy at an early or at a late stage in the evolution of the disease must often be reached on an individual basis. Ongoing clinical research to improve treatment results is still urgently needed. Research programs should aim at (a) evaluating new drugs and (b) testing new multi-modal treatment strategies. PMID- 8685684 TI - [Ventilation in the prone position in acute respiratory distress syndrome (ARDS)]. AB - Prone position mechanical ventilation (PPV) secures an improvement in gas exchange in approximately two-thirds of ARDS patients. Recent experimental and clinical data suggest that PPV acts mainly by recruiting alveoli situated in the dorsal dependent regions which are collapsed under the superimposed weight of the overlying edema-laden lungs. The purpose of this article is to provide an overview of the basic pathophysiological mechanisms underlying PPV as well as to underscore the promising clinical results so far obtained with this technique. In spite of these results the place of PPV among the other ventilatory and pharmacological approaches in the supportive treatment of ARDS, and the possible beneficial or deleterious consequences of associating PPV with one or more of these therapeutic modalities, remains to be determined. PMID- 8685685 TI - [Effectiveness of triple therapy to eradicate H. pylori in patients after failed therapy with omeprazole/amoxicillin]. AB - Helicobacter pylori (H. pylori) eradication rates with omeperazole/amoxicillin range from 0-90%. The best regimen for retreatment after failure of omeprazole/amoxicillin has not been established so far. The aim of this prospective study was to evaluate the efficacy of triple therapy with bismuth, tetracycline and ornidazole in eradicating H. pylori after failure of omeprazole/amoxicillin. 79 duodenal ulcer patients with H. pylori infection were treated with oral omeprazole (40 mg bid) and amoxicillin solute (750 mg tid) for 10 days. Eradication rate was 28/79 (35%) and was distinctly lower in smokers (> 10 cigarettes/day) vs nonsmokers (10/49 [20%] vs 18/30 [60%], p < 0.001). 37 patients with persistent H. pylori infection in whom omeprazole/amoxicillin had failed agreed to retreatment with triple therapy. Persistence of H. pylori was confirmed by histology (3 antral and 2 gastric body biopsies; H&E, Giemsa), urease test (CLO) and/or H. pylori culture. Patients smoking > 10 cigarettes/day were classified as smokers. Retreatment consisted of oral bismuth-subcitrate 4 x 120 mg/d for 28 days (day 1-28), tetracycline 4 x 500 mg/d and ornidazole 3 x 500 mg/d for 10 days (day 1-10). Control endoscopy was done 30 days after the end of treatment. Criteria for H. pylori eradication was negative urease test, culture and histology. 34/37 patients (6 females/28 males; 39 [23-64] years) completed the study (24/34 smokers, 10/34 nonsmokers). 3/37 patients dropped out because of side effects (n = 1) or incompliance (n = 2). H. pylori subcultures for resistance testing were possible in 32/34 patients: H. pylori was metronidazole sensitive in 11/32 (1 female, 10 males; 38 [24-55] years; 9 smokers, 2 nonsmokers) and metronidazole-resistant (minimal inhibitory concentration for metronidazole > 8 mg/ml) in 21/32 (5 females, 16 males; 40 [23-64] years; 13 smokers, 8 nonsmokers). The overall H. pylori eradication rate of the triple therapy was 27/34 (79%). H. pylori was eradicated in 19/24 (79%) smokers and in 8/10 (80%) nonsmokers. Eradication rate for metronidazole-sensitive H. pylori was 11/11 (100%) vs 14/21 (67%) for metronidazole-resistant H. pylori (p = 0.012). Triple therapy is effective and safe in eradicating H. pylori in patients after failure of omeprazole/amoxicillin. Smoking had no negative effect on the eradication rate of the triple therapy after failure of omeprazole/amoxicillin. Eradication failures were due to metronidazole-resistance. PMID- 8685686 TI - [Evaluation of bones using quantitative ultrasonography]. AB - The evaluation of bone by ultrasound is a new, transportable and non-irradiating method. It measures attenuation of ultrasound (BUA), as well as velocity (SOS) of ultrasound in a given tissue. For the measurement of bone, the most frequently used bone is the calcaneus. We have used this technique (Achilles, Lunar) to evaluate the reproducibility of measurements in healthy volunteers and to determine the correlations between the results of ultrasound measurements and those of conventional densitometry (DXA) in a population of postmenopausal females who consulted for screening or diagnosis of osteoporosis. Although several publications have already dealt with the same questions, it is important to reexamine them locally before the technique is uncritically used even in unspecialized centers. The coefficients of variation corresponded to that reported by others: 1.8% for BUA and 0.3% for SOS. The correlations between the ultrasound measurements and the results of DXA at lumbar spine, femoral neck and calcaneus in 57 postmenopausal women aged +/- 59 (43-78) years and in part osteoporotic (DXA results below 2.5 SD-T-score) (Hologic QDR 2000) were all significant (p < 0.001). The best correlation between the two techniques (DEXA and ultrasound) is found when applied to the same site, i.e. the calcaneus (r > 0.8). These results also agree with the literature. Low ultrasound values (BUA < 100 dB/MHz, SOS < 1495 m/s) are highly suggestive of osteoporosis, while high ultrasound values are almost exclusively found in non-osteoporotic women. This information provides the basis for further investigations, such as correlation with fracture risk, in cross-sectional and longitudinal studies. PMID- 8685687 TI - [Therapeutic measures following acute myocardial infarct: differential use of PTCA, surgery and drugs]. AB - Myocardial infarction represents a crossroads in the natural history of coronary artery disease. The prognosis is determined by the severity of coronary artery disease, infarct size (and hence ejection fraction), and age of the patient. After infarction, patients may remain symptomless, or suffer angina, silent ischemia, reinfarction, heart failure or sudden death. Hence patient management after infarction includes (1) estimation of risk, (2) the use of stress tests to detect ischemia and rhythm disorders, (3) PTCA or bypass if required and (4) medical therapy. Cardiac catheterization is indicated in patients with angina or silent ischemia, non-Q wave infarction or large infarctus; its use is less well established in patients without ischemia and left ventricular dysfunction, but this indication is nevertheless increasingly accepted. PTCA is primarily utilized in patients with single or two vessel disease, while coronary bypass surgery is indicated in patients with left main or three vessel disease. All these measures are designed to improve symptoms and prognosis. For secondary prevention medical therapy should be used to treat cardiovascular risk factors (antihypertensive drugs, lipid-lowering drugs etc.), to inhibit platelets (aspirin, ticlopidine) or coagulation (coumarins), to block neurohumoral activation (betablocker, ACE inhibitors), for vasoconstriction (calcium channel blockers, nitrates) and to suppress arrhythmias. The large number of drugs requires reasoned use depending on the risk profile of the individual patient. Cardiovascular risk factors should be treated appropriately. Platelet inhibitors should be given to all patients except those with atrial fibrillation or large ventricles (coumarins). Betablockers reduce mortality, reinfarction and sudden death after infarction and hence should be used if no contraindications exist. ACE-inhibitors are particularly effective in improving symptoms and prognosis in patients with impaired left ventricular function. Calcium antagonists should be used with caution and only in patients with normal left ventricular function. Nitrates are primarily effective in improving symptoms in patients with angina or heart failure. Antiarrhythmic drugs (amiodarone) are only useful in patients with complex arrhythmias. Digitalis has been shown to improve symptoms in patients with heart failure, while other inotropic drugs are virtually no longer used. These guidelines allow reasoned differential therapy after myocardial infarction to the maximum benefit of the patient and at minimum cost. PMID- 8685688 TI - [Folic acid in the prevention of neural tube defects]. AB - Neural tube defects (spina bifida) imply a severe limitation of quality of life. 70 to 100% of these defects are preventable by additional intake of folic acid during the periconceptional period. In accordance with the recommendations of Anglo-Saxon and other authorities prevention of this grave malformation should be attempted not only after a first-affected child, but primarily in a general manner in Switzerland, too. All women of childbearing age not under contraceptives should be advised to consume a diet rich in folic acid and to take an additional daily dose of 0.4 mg folic acid as a monosubstance or with a multivitamin preparation. A supplement of folic acid to cereal grain products, mainly bread flours, is recommended. A generally elevated folic acid intake may have further beneficial effects, such as risk reduction for the occurrence of carcinoma and atherosclerosis. PMID- 8685689 TI - The treatment of tardive dyskinesia. AB - The causes and the pathogenesis of tardive dyskinesia are not well understood. There is no therapy currently available that has been shown to alter the overall course. However, it is possible to influence the development or the progression of this disorder. A decision tree of feasible therapeutic choices is presented here, to prevent or treat tardive dyskinesia in patients who need long term neuroleptic therapy. PMID- 8685690 TI - [Opinion and attitude of physicians regarding organization and participation on a multidisciplinary alcoholism unit]. AB - The inaccuracy of physicians in the diagnosis, evaluation and treatment referral of alcoholic patients has prompted us to set a Multidisciplinary Alcohol Unit (Unit). Its aims are to set coordinated and individualized treatment proposals and to train medical staff in dealing with alcohol problems. After six months of activity we performed an investigation by all physicians who delt with the Unit including residents and practitioners. We sent 78 questionnaires investigating training in alcohol problems, addictive diseases and psycho-social medicine, subjective usefulness of the Unit for the patient as well as for the medical staff, subjective effectiveness of treatments for alcoholics and reasons for patients' referral. 87% of the physicians completed the questionnaire. According to groups, 12 to 20% of the physicians reported that their training in addictive problems was sufficient. Half of practitioners and 20% of hospital residents reported that their training in psychosocial medicine was satisfactory. All the physicians who answered the questionnaire considered the Unit to be usefull for themselves, mainly because of the Unit's teaching abilities and 89% considered the Unit useful for the patients. In term of effectiveness, alcoholism treatment is percieved by residents to be more efficient when mediated by a specialized unit rather than by practitioners or by themselves. Practitioners percieved that the treatment is more efficient when handled by themselves or by a specialized social unit. Principal reasons to seek help from the Unit were a main diagnosis of alcohol-related disease, the need to complete the psycho-social evaluation and subjective insufficient skills in the field. In conclusion the Unit seems to meet the need of medical doctors despite the limited number of referred cases and is said to be usefull for their patients as well as for themselves. PMID- 8685692 TI - [Madness(es). Social psychiatric-affective-chaos theory observations]. PMID- 8685691 TI - [Theory and practice of psychodynamic supervision in psychiatry]. AB - Supervision has become a canonical part of psychotherapeutic training. Supervision has been increasingly introduced into general psychiatric treatment, especially where the team is subjected to increased psychological stress. Some psychodynamic models of the functioning of team supervision in psychiatry are presented, esp. support of the team's "synthetic functions" and the use of "mirror phenomena". Case vignettes drawn from supervisory sessions may help to illustrate the models. Finally the institutional prerequisites for establishing team supervision are pointed out. PMID- 8685693 TI - [Acoustic and optical perceptual disorders in depressive diseases--an overview of results from experimental studies]. AB - This literature review concentrates on a disregarded part of depressive disorders' symptomatology (especially concerning present-day classifications of mental disorders) that can be approached with a great number of experimental procedures. From the acoustical field the following findings are demonstrated and discussed: elevated click thresholds in auditory signal detection, changed ear asymmetry in dichotic click detection and differences in dichotic listening asymmetries according to symptomatology. The most important results from the so far investigated optical perceptual disturbances in depressive disorders are: breakdown of perceptual defence in the form of greater access to emotionally unpleasant stimuli referring to the tachistoscopic recognition of neutral/unpleasant words, impairments at near-distance assessments, disturbances in recognition and discrimination of facial emotions-especially concerning the perception of emotional chimeric faces. Interpretational attempts for these acoustical and optical disturbances of perception reach from developmental psychology to biological psychiatry. Changes in hemisphere functions hold the dominating position in this discussion. Up to now it remains open to what extent the reported results correlate with the clinical phenomenology of depressive disorders, of what diagnostic specifity they are and if the can be viewed with sufficient reliability as state marker and indicators for theraopeutical effects. PMID- 8685694 TI - [Transcranial Doppler and color duplex ultrasound. Familiar and new uses]. AB - Transcranial Doppler and color-coded duplex sonography provide reliable information on cross-flow through the circle of Willis, stenoses, occlusions and vasospasm of the major basal cerebral arteries. The CO2 and acetazolamide tests allow quantitative evaluation of the hemodynamic impact of obstructive cerebrovascular disease. Furthermore, transcranial Doppler sonography is used for detection of enhanced intracranial pressure, confirmation of brain death, detection of cerebral microemboli ("high intensity transient signals" = "HITS"), and patent foramen ovale. In the future, cerebral microemboli may become a marker for embolic activity of both occlusive carotid artery and cardiac disease. Transcranial color-coded duplex sonography identifies intracranial hemorrhage, cerebrovascular malformations, and hydrocephalus, but is inferior to neuroradiological techniques. Transpulmonary contrast agents make the examination of patients with inadequate insonation windows feasible, and increase diagnostic confidence in transcranial ultrasonography. Transcranial power-based color-coded duplex sonography ("power Doppler") may further improve transcranial ultrasonography, and visualize flow in smaller vessels. PMID- 8685695 TI - [Dissection of the extracranial vertebral artery. Color duplex ultrasound findings and follow-up of 20 patients]. AB - AIM: To assess the diagnostic potential of duplex color-flow imaging in the evaluation of extracranial vertebral artery dissection. In 15 of 20 patients (75%), the dissection was related to trauma. METHOD: Over the last six years, we evaluated 20 consecutive patients aged 18 to 59 years with 24 extracranial vertebral artery dissections (four occurring bilaterally). The examinations were performed with a color Doppler imaging system using a 7 MHz transducer. Angiography was done in 18 patients, confirming the diagnosis. RESULTS: In 15 patients, the diagnosis was primarily established with ultrasonography. Six vertebral arteries were dissected at the origin or in the proximal V1 segment, one in the distal V2 segment and one at the atlas loop. Most dissections occurred in the region between the V1 and V2 segments (n = 16), most often at the entrance of the artery into the transverse foramen of the C6 vertebra (n = 11). Typical ultrasonographic findings were irregular stenosis, dissecting membrane with true and false lumen, localized increase in diameter of the artery, pseudoaneurysm, intramural hematoma and tapering stenosis with distal occlusion. The diagnosis of dissection in the V3 segment was based on indirect signs such as high resistance flow pattern and decreased diastolic flow velocity. In follow-up examinations, marked resolution of pathological findings were found in 17 cases (70.8%). Two occlusions were completely recanalized. CONCLUSION: Duplex color-flow imaging is a valuable noninvasive method for early diagnosis of extracranial vertebral artery dissection and for follow-up examinations. PMID- 8685696 TI - [Transcranial Doppler examination on effect of hemodynamics on cerebral autoregulation in acute cerebral infarct]. AB - AIM: We treated 24 patients suffering from an acute ischemic stroke of the middle cerebral artery, with a hypervolemic hemodilution combined with dopamine/dobutamine. METHOD: The influence of blood pressure and cardiac output on the blood flow velocity in the middle cerebral artery was measured using transcranial Doppler sonography (TCD). RESULTS: Under the hypervolemic hemodilution supported with dopamine/dobutamine a dosage-dependent increase of 12% in blood pressure and a 53% increase in cardiac output was observed. In the affected hemisphere, flow velocity was one fourth lower (significance p < 0.05) than in the unaffected hemisphere. With therapy, the systolic flow velocity was increased in the unaffected hemisphere by 27%, on the side of the lesion only 11%. Mean flow velocity remained nearly constant. The pulsatility index (PI) increased simultaneously by 46% in the affected and 47% in the unaffected hemisphere. CONCLUSION: Similar effects on TCD-flow velocity and PI under comparable slight increases in blood pressure are not known. The increase in cerebrovascular resistance can be ascribed to a counter-regulation of the cerebral autoregulation, triggered by an increase of cardiac output. PMID- 8685697 TI - [Measuring basilar artery blood flow velocity with transcranial Doppler and and transcranial Doppler color ultrasound]. AB - GOAL: The aim of the present study was to clarify, by means of transcranial colour-coded duplex sonography of the basilar artery, whether there are changes in basilar artery blood flow in patients with acute inner ear disturbances and whether the flow in the basilar artery is affected by acoustic stimuli in such patients and in normal, healthy controls. METHOD: Basilar artery blood flow velocity was measured in 52 patients with severe inner ear impairment over a period of two weeks by means of conventional transcranial Doppler sonography and transcranial colour-coded duplex sonography. The same measurements were carried out in 45 healthy control subjects. At the end of the two week period, both patients and controls were exposed to 70-dB noise, with basilar artery flow evaluated before and during exposure. The basilar artery Doppler curves were analysed for systolic flow velocity, end-diastolic flow velocity, resistance index (Pourcelot) and pulsatility index (Gosling). RESULTS: During the first two days of the study, the basilar artery resistance index and pulsatility index were significantly (p < 0.001) higher in patients than in controls. During noise exposure, both patients and controls showed significant (p < 0.01) increases in these indices. CONCLUSION: This study shows that temporary increases in the basilar artery resistance index and pulsatility index are found both in the acute phase of inner ear disease and during exposure to noise. PMID- 8685698 TI - [Evaluating the measuring accuracy of intravascular ultrasound]. AB - AIM: Intravascular ultrasound investigations are new tomographic imaging methods for evaluation of artery dimensions and wall morphology. The present study was performed to test accuracy and observer variability. METHOD: 3 plastic phantoms and 1 iliacan artery were assessed. The quantitative measurements were made by computerised 3D reconstruction. RESULTS: The plastic phantoms showed ultrasonically three layers of echogenic structures. An intimal fibrous thickening was seen in the iliac artery. The cross sectional diameters were ultrasonically overestimated by 12.6 +/- 5.6%. Due to the lower velocity of sound in water than in blood there were no significant differences to the true diameters. The intra- and interobserved variabilities were determined to 1.4 +/- 0.8% and 2.6 +/- 1.2%. CONCLUSIONS: Intravascular ultrasound provides a reproducible method for measuring vessel lumen diameters with excellent intraobserver and interobserver variabilities. For in vitro examinations the different velocities of sound in different media have to be taken into account. PMID- 8685699 TI - [Diagnostic value of portal duplex ultrasound in liver cirrhosis]. AB - AIM: In a prospective study we investigated if the endoscopical evaluation of the bleeding risk of esophageal varices in cirrhotics could be improved by additional duplex sonography of the portal vein. METHOD: The trial involved 41 patients with endoscopically diagnosed esophageal varices (27 male, 14 female) who were followed up over a period of 30 months (mean of 13 +/- 3). According to the Child Pugh-Turcotte -classification, 14 patients were classified as grade A, another 14 as grade B, and 13 as grade C. The cause of the cirrhosis included virus infection (n = 14), alcohol (n = 17) and miscellaneous disorders (n = 9, primary biliary = 3, autoimmune = 2, idiopathic = 4). RESULTS: During the observation time, 17 patients who developed an acute esophageal variceal hemorrhage were put in the bleeding group (mean portal flow velocity Vm = 9.29 +/- 3.31 cm/s, mean flow volume Fm = 371 +/- 173 ml/min), while the remaining 24 patients formed the non-bleeding group (Vm = 13.29 +/- 5.12 cm/s, FV = 500 +/- 200 ml/min). The bleeding group had significantly lower mean portal flow velocities (p < 0.017) and mean flow volumes (p < 0.05) than the non-bleeding group. By adopting cut-off values of 12 cm/s for Vm and 420 ml/min for FV we obtained a diagnostic sensitivity for predicting esophageal variceal hemorrhage of 0.88 and 0.65 respectively. CONCLUSION: Portal duplex sonography may improve the evaluation of bleeding risk in patients wit endoscopically diagnosed esophageal varices and could influence the decision for prophylactic treatment. PMID- 8685700 TI - [Phantom studies of ultrasound equipment for quality improvement in breast diagnosis]. AB - AIM: According to the German guidelines for quality control of ultrasonic equipment, the following conditions are required for breast ultrasound: A transducer frequency between 5-7.5 MHz and a minimum field of view of 5 cm. Satisfactory images must be obtained in a depth between 0.5 and 4 cm with a wide tolerance of the focal zones. This allows the use of poor quality equipment which does not produce satisfactory image quality and it excludes a number of high frequency and high resolution transducers with a field of view below 5 cm. This study with a test phantom was performed to define image quality objectively. METHOD: Sixteen ultrasound instruments in different price categories were used to perform standardized examinations on a breast phantom model 550 (ATS Laboratories, Bridgeport, USA). Contrast and spatial resolution in different penetration depths were investigated on cyst phantoms from 1-4 mm diameter and wire targets with defined distances between 0.5-3 mm 4 investigations reported the images. RESULTS: A positive correlation was seen between price category and image quality. CONCLUSION: This study demonstrates that transducer frequency and image geometry do not allow sufficient quality control. An improvement of ultrasound diagnosis is only possible if equipment guidelines are based on standard examinations with test phantoms. PMID- 8685701 TI - Marine mammals and the marine environment. Proceedings of a conference. Lerwick, Shetland, 20-21 April 1995. PMID- 8685702 TI - Hepatocyte vacuolation and autolytic changes in the liver of pilot whales, Globicephala melas, stranded on Cape Cod, MA, USA. AB - Most cetacea available for internal sampling in recent times have died through mass or single stranding events. It is important to know how the time elapsed between death and sampling affect quality of tissues. This study evaluated histological quality in the liver of long-finned pilot whales that either died or were euthanased after mass stranding events. Histological detection of significant autolysis was found in animals when 2 or more hours elapsed between death and sampling. In addition, hepatocytes often had marked idiopathic cytoplasmic vacuolation that did not stain with hematoxylin and eosin. The extent of this vacuolation did not show any correlation with time between death and sampling, but did appear more often in animals of greater total length. These observations suggest that when animals die or are euthanased at a single or mass stranding, every effort should be made to obtain samples as soon as possible, although meaningful histological observations can still be made in the presence of significant autolysis. These data also suggest that a multi-disciplinary study should be conducted to determine whether increasing autolysis is associated with changes in the organic chemical residues, molecular biology, histopathology and microbiology of those tissues. PMID- 8685703 TI - An overview of exposure to, and effects of, petroleum oil and organochlorine pollution in grey seals (Halichoerus grypus). AB - Most incidences involving oil pollution of grey seals (Halichoerus grypus) seem to have occurred at the breeding sites. Because of the high concentration of animals at this time, even small oil spills will pollute many animals. As a result of chronic low-level pollution from coastal ship traffic and discharges from offshore petroleum activity in the North Sea, approximately 50% of the grey seal pups at the largest breeding colony in Norway are polluted each year by oil. In this case, as well as in other similar cases of spills at breeding colonies, oil has produced little visible disturbance to the seals behaviour and there has been little mortality. The effects and mortality may, however, be more serious following a spill of crude oil, where animals may be affected by inhalation of toxic volatile compounds. High body burdens of PCBs and DDTs seem to have caused skull-bone lesions and occlusions of the uteri in grey seals in the Baltic Sea. Exposure to these persistent compounds has also been suspected to be the cause of reduction in the population of Baltic grey seals. There are indications that thyroid hormone and vitamin A status of grey seal pups are affected by the low exposure concentrations experienced at the Norwegian coast (approximately 1/20 of the concentration detected in grey seal pups from the Baltic Sea). This gives serious cause for concern about the effects that chronic low-level exposure to persistent organochlorine pollutants may have on individuals and on populations of grey seals. PMID- 8685704 TI - The impact of the 1993 Braer oil spill on grey seals in Shetland. AB - Signs of acute respiratory distress were reported in moulting grey seals (Halichoerus grypus) hauled out on Lady's Holm, Shetland, following the Braer oil spill in January, 1993. Behavioural observations carried out between 16 January and 13 February 1993 showed that the proportion of animals exhibiting a discharge of nasal mucus was significantly higher than the proportion at a control site in the north (Papa Stour). The proportion of animals affected on Lady's Holm increased for up to one month following the spill. However, the time lag between exposure and peak response was approximately 30 days, longer than may be expected for an acute effect. The proportion of non-specific signs of respiratory distress in unexposed Shetland seals was assessed from observations made between 16 January and 25 January 1994. Symptoms similar to those seen in 1993 were also reported during this period, but the proportion of affected animals was higher in 1993. Symptoms were not observed at a grey seal moult site on the east coast of England in March 1993 and 1994. Grey seals moulting in Shetland during the time of the oil spill may have been acutely affected by exposure to hydrocarbons, but without sufficient baseline data on the occurrence of respiratory distress in grey seals it is difficult to determine the proportion attributable to other causes. PMID- 8685705 TI - Exposure of Greenlandic Inuit to organochlorines and heavy metals through the marine food-chain: an international study. PMID- 8685706 TI - Health implications for Faroe islanders of heavy metals and PCBs from pilot whales. AB - In the Faroe Islands marine food constitutes a considerable part of the diet. In addition to fish, both meat and blubber from pilot whales are included in the diet. Muscle tissue of pilot whales caught in the Faroe Islands contains an average mercury concentration of 3.3 micrograms/g (16 nmol/g), about half of which is methylmercury. In some years an evenly distributed annual catch of pilot whales would make the average dietary intake of mercury close to an excess of the Provisional Temporary Weekly Intake of 0.3 mg recommended by WHO. In one out of eight consecutive births, the mercury concentration in maternal hair exceeded a limit of 10 micrograms/g where a risk of neurobehavioral dysfunction in the child may occur; the maximum was 39.1 micrograms/g. Mercury concentrations in umbilical cord blood showed a similar distribution with a maximum of 351 micrograms/l. The large variation in mercury exposure is associated with differences in the frequency of whale dinners. The average PCB concentration in pilot whale blubber is very high, i.e. about 30 micrograms/g. With an estimated daily consumption of 7 g of blubber, the average daily PCB intake could therefore exceed 200 micrograms, i.e. close to the Acceptable Daily Intake. In Scandinavia, the average daily PCB intake is about 15-20 micrograms. To obtain an improved scientific basis for public health action, two major prospective studies have been initiated. A birth cohort of 1000 children has been examined at approximately 7 years of age for neurobehavioral dysfunctions associated with prenatal exposure to mercury and PCB. Preliminary analyses of the data show that several neurobehavioral tests are associated with mercury exposure parameters. With emphasis on prenatal exposures to PCB, another cohort has been generated during 1994-95, and this cohort will be followed closely during the next years. PMID- 8685707 TI - Environmental pollutants in marine mammals from the Norwegian coast and Arctic. PMID- 8685708 TI - Organochlorine residues in marine mammals from the northern hemisphere--a consideration of the composition of organochlorine residues in the blubber of marine mammals. AB - Levels of organochlorines (PCBs, sigma DDT, lindane and its isomers, HCB, chlordane, and toxaphene) were determined in blubber of marine mammals from the northern hemisphere. Differences in both levels and ratios of organochlorine compounds were detected in different species of marine mammals living in the same region, e.g. blubber of harbour seals (Phoca vitulina) accumulated significantly lower levels of lindane, HCB, toxaphene, and DDT and its metabolites than harbour porpoises (Phocoena phocoena). Compared to such elementary differences in the organochlorine pattern in different marine mammals, the influence of age and sex on the results was only minimal. Varying ratios of contaminants in individual harbour porpoises were explained by migration. Constant PCB/DDT ratios were measured in harbour seals. Due to the sedentariness of harbour seals, even local sources of contaminants could be recognized. Careful evaluation of the organochlorine levels and ratios in marine mammals made it possible to monitor the transport of PCBs from the European continent to European Arctic regions. PMID- 8685709 TI - Overview and regional and temporal differences of heavy metals in Arctic whales and ringed seals in the Canadian Arctic. AB - Concentrations of mercury, cadmium, and other heavy metals in tissues of belugas (Delphinapterus leucas), narwhal (Monodon monoceros) and ringed seals (Phoca hispida) from across the Canadian Arctic are reported. Published and new information is used to provide an overview of metals in tissues of these animals, to delineate the existence of a spatial trend of mercury and cadmium in belugas and ringed seals, and to show a temporal trend is superimposed on the geochemical trend. Mercury concentrations in tissues of Arctic whales and ringed seals were high relative to the Canadian guideline of 0.5 micrograms/g wet wt., for mercury in fish, except in the skin of belugas (0.59-0.78 micrograms/g wet wt.) and flesh of ringed seals (0.39-0.41 micrograms/g wet wt.). In the flesh of belugas (0.94 1.34 micrograms/g wet wt.), and in the liver of ringed seals, tissues that are also consumed by Native people in the Arctic (8.34-27.5 micrograms/g wet wt.), the guideline value was significantly exceeded. Mean lead concentrations in tissues of belugas, narwhal and ringed seals were generally low (0.002-0.028 micrograms/g wet wt.), except in tissues of belugas in the St. Lawrence River (0.10-0.15 micrograms/g wet wt.). The concentration of zinc in the skin of whales was two to three times higher than in other tissues. The concentration of cadmium in organs was highest in narwhal. There was a positive correlation between mercury and selenium in the liver of all three species. The concentration of mercury in tissues of belugas and ringed seals was higher in the western than the eastern Arctic. This was attributed to different natural background concentrations in the western and eastern Arctic of Canada dictated by different geological formations in the two regions. Cadmium concentrations in tissues of belugas and ringed seals were higher in the eastern than the western Arctic. Zinc and copper in some tissues of belugas and ringed seals were also higher in the eastern than the western Arctic. Mercury in the liver of belugas was found to have increased in the western and eastern Arctic over 10-12 years. Mercury in the liver of ringed seals in the western Arctic and narwhal in the eastern Arctic showed similar increases. In recently collected belugas, the rate of accumulation of mercury in the liver was approximately twice that in belugas collected 10-12 years ago. In ringed seals, the rate was three times higher in recent samples compared to 15-20 years ago. There was no temporal change in cadmium levels in tissues of belugas, ringed seals or narwhal. PMID- 8685710 TI - Lead, cadmium, mercury and selenium in Greenland marine animals. AB - Baseline concentrations of lead, cadmium, mercury and selenium are reported from different tissues in marine organisms from Greenland. Overall, lead levels in marine organisms from Greenland are low, whereas cadmium, mercury and selenium levels are high. Tissue differences are not very distinct for lead, whereas the opposite is the case for cadmium and mercury. Selenium shows an intermediate behaviour in this respect. In general, lead concentrations do not correlate with the age/size of animals, whereas cadmium, mercury and selenium increase with age/size of most species and tissues analysed. No clear conclusions can be drawn in relation to geographical differences in lead, mercury and selenium concentration in Greenland. In general, cadmium levels are higher in Northwest Greenland compared to southern areas. Local differences with increasing cadmium levels from inner fjords to the open sea in stationary species may be of the same order of magnitude as those observed over long distances in Greenland. There is no indication that lead and selenium levels increase in higher trophic levels, although this is clearly the case for cadmium and mercury. In almost all cases lead levels in marine organisms from Greenland are well below the Danish food standard limits, however, a substantial proportion of marine mammals and seabirds in Greenland have cadmium and mercury levels exceeding the Danish standard limits. No food standard limits are given for selenium in food, but in some cases human intake of selenium is estimated to be high. PMID- 8685711 TI - Mercury in pilot whales: possible limits to the detoxification process. AB - The ability of pilot whales (Globicephala melas) to concentrate cadmium and mercury is well established. The levels of these metals were generally higher than those encountered in other species of marine mammals. The biological data have not revealed a major toxic problem in the population, and this suggests a remarkable tolerance of this species to heavy metals. Cellular distribution of mercury was carried out in liver samples. The presence of metallothionein-like proteins in the soluble fraction has been demonstrated, but 95% of mercury was mainly bound to the insoluble fraction, showing that these proteins had no role in this metal detoxification. The molar ratio between mercury and selenium suggests that the major mechanism of detoxification is through the formation of a complex Hg-Se which leads to the demethylation of mercury. The site of this process is the liver in which mercury mainly appeared as inorganic, whereas in the muscle the percentage of organic to total mercury was much higher. Nevertheless, this detoxification is limited in lactating females and in all the individuals of one school. This could be the result of changes in the diet and could constitute a toxicological risk for the species. PMID- 8685712 TI - Biotech finds a growth industry. PMID- 8685714 TI - '97 budget. Congress targets fusion, favors NIH. PMID- 8685713 TI - AIDS conference. Chemokines share center stage with drug therapies. PMID- 8685715 TI - Xenotransplants. IOM backs cautious experimentation. PMID- 8685716 TI - Developmental biology. Receptor for vital protein finally found. PMID- 8685717 TI - Psychiatric drug development in Japan. PMID- 8685718 TI - Mechanosensation and the DEG/ENaC ion channels. PMID- 8685719 TI - [Pelvic injuries: low incidence but unsatisfactory outcome]. PMID- 8685720 TI - [Pelvic fractures: epidemiology, therapy and long-term outcome. Overview of the multicenter study of the Pelvis Study Group]. AB - Pelvic fractures are rare injuries (3-8%) when compared to fractures in other body regions. They are accompanied by high mortality (5-20%), and the survivors suffer from severe pain and pelvic-related handicaps. The German Pelvic Group (German Chapter of the AO-International & German Trauma Society) started a prospective multicenter study, including ten major trauma centers for collecting a high number of data in a short period of time (1991-1993). All pelvic injuries were documented consecutively using a special set of evaluation sheets. The study closed with 1,722 patients. A 2-year follow-up was completed for 486 patients injured in 1991 and 1992 after type B and C injuries, complex pelvic trauma, acetabulum fractures and a random 25% of A-type injuries (overall follow-up rate 73%). The follow-up included special "out-come" criteria. Of the pelvic ring injuries without significant peripelvic soft tissue involvement, 63.6% were A type fractures, 21.0% B-type injuries and 15.5% C-type injuries. The rate of operative stabilization was 3.9% after A-type injuries, 37.3% after B-type injuries and 54.3% after C-type injuries. In isolated acetabular fractures ORIF was performed in 38.6%. The total lethality was 7.9% with a significant difference between "complex" pelvic trauma (21.3%) and patients without concomitant peripelvic injuries (7.2%). In 0.9% the pelvic injury was reported as the main cause of death. Pain at follow-up was observed in every classification group, the rate of completely "pain-free" patients being 55% after A-type, 41% after B-type and 27% after C-type fractures. Malfunction of micturia was reported by 7.6% of all patients, sexual malfunction by 11.6% of the males ("erectile dysfunction") and 2.2% of the female ("dysparneuria"). Scaled by the recently developed "outcome score", the radiological result showed anatomical healing after 90.8% of the B-type and 74.6% of the C-type injuries. On the other hand, the clinical result was rated as good or excellent in only 70% of the B-type and 54% of the C-type injuries. Although progress in indications and treatment techniques has shown improved radiological results after unstable pelvic ring injuries when compared to earlier studies, the clinical result still remains unsatisfactory. Further analyses and studies must be conducted to identify the prognostic factors for the late sequelae. Whether it is possible influence these factors by additional surgical intervention cannot be answered at present. PMID- 8685721 TI - [Isolated hip dislocation of traumatic origin]. AB - The final outcome following isolated traumatic dislocation of the hip that is reduced within 6 h is generally believed to be excellent. Forty-nine patients with an isolated dislocation of the hip were treated between 1974 and 1989 at the Department of Traumatology of the Hannover Medical School. The majority of patients were involved in traffic accidents, and 42 had associated injuries. All dislocations primarily treated at our hospital were reduced by closed methods within 3 h, (average 85 min, range 10-180 min), followed by early mobilisation with partial weight-bearing for 2-3 weeks. 42 patients were evaluated after an average follow-up period of 7.7 years. Radiological signs of partial necrosis were seen in two patients. Mild arthrosis was found in seven patients, moderate degeneration in two and heterotopic ossifications in four patients (two Brooker II, one Brooker III, one hip ankylosed). Twenty-nine of 33 MRI examinations were normal. Despite early reduction only 9/12 anterior and 14/30 posterior dislocations revealed excellent and good results according to the Thompson and Epstein classification. According to the present study the important prognostic factors are the direction of dislocation, the overall injury severity and the age at the time of injury. PMID- 8685722 TI - [Recurrent fracture of the pediatric forearm]. AB - In a retrospective multicenter study 28 relapse fractures of the forearm in children were reviewed. The male to female ratio was 23:5. Six children were younger than 6 years, 12 were between 6 and 10 years, and 10 were between 10 and 14 years old. The primary fracture was treated by cast fixation of 3-7 weeks duration. The refracture occurred on a average 14 weeks (4-32 weeks) after the primary fracture by a simple fall (n = 14) or a fall from height (n = 4), or during school (n = 6) or leisure-time (n = 3) sporting activities. In 84% of the patients partial consolidation, i.e. incomplete healing of one cortex of one or both forearm bones, preceded the refracture. In the majority of patients this was observed after a green stick fracture due to permanent angulation. Six patients were operated upon for irreducibility of the relapse fracture; the others were treated by conservative means. In two patients a second refracture occurred. Fifteen patients were available for a 2 year result. Definitive angulation of more than 10 degrees caused a clinically relevant limitation of pro-supination in five of six patients. To prevent relapse fractures of the forearm in children, complete circular consolidation of the original fracture has to be guaranteed. It remains unclear whether this is best achieved by special plaster techniques or by converting a greenstick fracture into a complete, unstable fracture. PMID- 8685723 TI - [Morphologic aspects of alloplastic augmentation in replacement of the posterior cruciate ligament. An experimental study on the sheep]. AB - The treatment of injuries to the posterior cruciate ligament (PCL) remains controversial. Various problems have prevented PCL reconstruction from consistently producing the knee stability desired. Biological graft tissue undergoes a remarkable healing process comprising different phases. The strength of autogenous graft material decreases soon after the operation. During this early healing phase synthetic augmentation could protect the graft tissue from overloading or overstretching, supporting the tissue restoration process. In order to evaluate the morphological effects of the ligament augmentation device (LAD) on a free patellar tendon autograft in PCL reconstruction a comparative study in sheep was conducted. In 24 mature sheep the PCL was replaced with either a patellar tendon autograft alone or a patellar tendon autograft augmented by the LAD. The LAD was fixed at both ends. The animals were not immobilized after the operation. Tibial fixation was released 8 weeks after the operation. The autografts of both groups were histologically evaluated after 2, 6, 16, 26, 52 and 104 weeks. In addition to necrotic and degenerative alterations a pronounced inflammatory reaction could be seen in the LAD-augmented autografts soon after the operation. Compared with the non-augmented autograft, tissue formation and remodeling was delayed in the augmented group. After 1 and 2 years, the morphology of the autograft tissue was similar in the augmented and the non augmented group and was different from that of a normal PCL. The LAD was surrounded by a chronic inflammatory reaction, and collagen fiber ingrowth into the LAD was not observed. Transmission electron microscopy showed that small diameter collagen fibrils were predominant in the graft tissue of both groups. Thus, better remodeling of the autograft tissue in the presence of the LAD was not demonstrable in this particular study. The value of synthetic augmentation of biological grafts of PCL reconstruction seems to be questionable at present. PMID- 8685724 TI - [The pivot-shift test in relation to hip position and lower leg rotation. A clinical analysis]. AB - In a prospective clinical study conducted on 50 patients with isolated insufficiency of the anterior cruciate ligament (ACL), we investigated the triggering of pivot shift as a function of the position of the hip joint and the rotational position of lower leg; the results were compared with those yielded by the Lachman test. The pivot shift phenomenon was found to be more readily triggered when the hip was abducted, and especially when the investigator had specified external rotation of the lower leg at the same time. Our results show that this modification of the classic pivot shift test can fill a diagnostic gap in the clinical investigation. The pivot shift test with hip abduction and external rotation of the lower leg is a valuable alternative test for the diagnosis of ACL insufficiency. PMID- 8685725 TI - [Surgical outcome in subtrochanteric fractures. A study over 15 years]. AB - During the past 15 years new methods for the surgical approach to subtrochanteric fractures have been developed, e.g. the dynamic hip screw (DHS) and the gamma nail (GN). Reviewing the results of this change in methods, we report on 102 patients after subtrochanteric fractures of the femur. We divided them into three groups according to the time of operation (1980-1984, period I; 1986-1989, period II; 1991-1993, period III). During period I, 74% of the fractures were stabilized using angle plates. During period III, more than 30% were operated on using the DHS and nearly 50% using the GN. The total hospital stay (department of surgery as well as geriatric hospital) decreased from 107.5 +/- 46.5 days to 78.9 +/- 24.3 days (P < 0.001). During period I, 86.2% of patients could be discharged home, during period III, 100%. Serious complications decreased during these 15 years. In conclusion, as observed in pertrochanteric fractures, the introduction of new operative techniques for the treatment of subtrochanteric fractures in the elderly was followed by a shortened hospital stay, a decreased complication rate and an increased rate of discharge home. PMID- 8685726 TI - [Craniocerebral trauma in fall from bicycles--what is the effect of a protective helmet?]. AB - A prospective study was performed to analyze the particular injuries of 76 cyclists who required in-patient treatment in our department in 1994. There were 50 male and 26 female cyclists, with a median age of 33 years (range: 4-87 years). The most frequent diagnosis, in 50% (n = 38), was head injury. The series included 63 cyclist (83%) who had not been wearing helmets, and 33 of these sustained a head injury; in the helmet group head injury was found in only 38% (5 out of 13). It is remarkable that more serious head injuries did not occur in the helmet group. In 24 of these 33 head-injured patients (73%) without helmets additional intra- and extracranial diagnoses were made: pathologic EEG in 18 patients (55%), skull fracture in 13 patients (39%), intracerebral haemorrhagic contusion in 4 patients (12%) and an increase in intracerebral pressure (edema) in 3 patients (9%). In contrast to these findings, only 2 of the 5 head-injured patients (40%) in the helmet group showed slight changes in the EEG. In our opinion the bicycle helmet can reduce the incidence and the grade severity of head injuries significantly, particularly as we had 2 deaths in the non-helmet group and none in the helmet group. The use of a bicycle helmet is therefore strongly advocated. PMID- 8685727 TI - [Pathophysiology of shock]. PMID- 8685728 TI - [Acute isolated ventral dislocation of the head of the fibula]. AB - We present the case of a 19-year-old soccer player who had sustained a valgus, external rotation trauma to the flexed knee with traumatic anterolateral dislocation of the proximal tibiofibular joint and concomitant partial peroneal nerve palsy, which went away within a few days. We discuss the clinical features and treatment by temporary screw fixation of the proximal tibiofibular joint, as well as the results in the literature where predominantly conservative treatment is reported. PMID- 8685729 TI - [Isolated ossicle of the dens axis. Case reports and differential diagnosis]. AB - Two patients with an incidental finding of isolated ossicles adjacent to the dens axis are presented. One case was thought to be based on an isolated part of the dens axis, possibly due to trauma; the second case could be a true ossiculum terminale. Such ossicles can be confused with acute fractures, initiating treatment that is not indicated. PMID- 8685730 TI - [Bone substitutes. State of the art and: what lies ahead?]. AB - For the treatment of bony defects in the skeleton, today there are five different options. Filling a defect by the application of autogenous bone is one of them. Autogenous cancellous bone is still considered to be the gold standard, but numerous shortcomings of this material, described in detail in this paper, are not taken into account. Besides, we are still unable to influence bone healing by the transplantation of autogenous bone with reference to quality, quantity of newly forming bone and the time period, in which bone healing occurs. Investigation into the different kinds of biomaterial developed to replace autogenous bone as a transplant, and their implantation into experimental animals did not result in the production of a synthetic material that was as active as autogenous or even allogeneic cancellous bone. This was therefore not a solution to the problem. The reasons for this are multiple and are discussed in this paper. We developed a classification for bone replacement materials that differentiates between biological, synthetic, and composed materials, i.e., composite biomaterials made for bone replacement. In reference to the literature, as well as our own results, based on the implantation of more than 1200 rats, dogs, and sheep with distinct materials, the plus/minus effects of the different classes, groups and subgroups of bone replacement materials are summarized and discussed. The most recent knowledge about the mechanisms of bone formation and how it is influenced by different growth factors, as well as bioactive ceramics, indicates that in the future an applicable bone replacement material will be a composite of a carrier material combined with chemotactic, inductive, morphogenetic and proliferative, chemically pure, recombinant factors, with a mainly local action. Unfortunately, the road to get there is long. PMID- 8685731 TI - Traditional reaction to modern stress. PMID- 8685732 TI - Quality of care: a comparison of preferences between medical specialists and patients with chronic diseases. AB - In this study, we have looked for differences between medical specialists and patients with chronic diseases (COPD, rheumatoid arthritis and diabetes mellitus) in preferences of aspects of care in relation to the quality of care. Firstly, to enumerate relevant aspects for chronic diseases, open interviews and a concept mapping were conducted among patients with chronic disease, and medical specialists treating them. Here, the respondents have been asked to evaluate statements in relation to the quality of care. Secondly, a final questionnaire, including statements of nine relevant aspects of care, was presented to patients and medical specialists. The response rate among patients was 96% (N = 260) and among medical specialists 67% (N = 340). Both study populations ranked 'effectiveness of care' the highest. However, the difference in opinion between the two populations was significant, mainly due to the patient's giving a higher ranking to 'continuity of care' and a lower ranking to 'efficiency'. Significant differences were also found between the three patient groups on the aspects 'knowledge' and 'waiting time for treatment'. Patients with rheumatoid arthritis ranked 'knowledge' higher and 'waiting time for treatment' lower than did the other two patient groups. A lower level of education, having state-regulated health insurance and being older were associated with a higher preference for 'continuity'. Between the three groups of the medical specialists, no significant differences were found regarding to the profession, age, and sex. IN CONCLUSION: the patients and medical specialists researched did not show wide differences of opinion on preferences of care in relation to quality. The only exception to this concerned 'continuity of care' which was ranked higher by patients. PMID- 8685733 TI - The significance of children's age in estimating the effect of maternal time use on children's well-being. AB - The women's initiative launched by the United Nations Decade for Women has sparked unresolved controversy over the consequences of mothers' increased participation in economically productive activities on children's well-being. Clearly, in many developing countries, poor mothers face stringent time constraints requiring trade-offs in time allocated to various activities, including child caregiving. However, the impact of these trade-offs on children's well-being remains unclear. The effect of maternal time use on children's nutrition and health status requires more rigorous examination. In particular, the role of children's age in this relationship is critical. Although children's requirement for maternal care varies with factors such as their age (a proxy for stage of psychobiological and sociocultural development), season of year and family size and structure, children's age has not been highlighted in the debate or in the relevant research. This paper documents children's age as a critical factor in the relationship between maternal patterns of time use and the well being of children 18-30 months of age in peri-urban Egypt. It describes differences in maternal patterns of daily time use according to children's age and illustrates the differential associations between maternal daily activity patterns and children's well-being by children's age. Quantitative data collected on 161 mother-toddler pairs included information on maternal daily time allocation, children's dietary energy intake and diarrheal morbidity, maternal hemoglobin, and household and individual sociodemographics. Data were stratified by children's age at 24 months and were analyzed cross-sectionally using multiple linear and logistic regression. Results indicated that the age of two is critical in Kalama. At this age, toddlers begin to receive less time-intensive care freeing mothers for economic and self production. With respect to children's well being prior to age two, frequency of feeding was positively related to their energy intake and more time spent in household sanitation activities reduced children's risk of diarrhea (during the diarrhea season). After two years of age, the maternal behaviors measured did not affect children's energy intake; however, children's diarrheal risk was reduced (during the diarrhea season) when mothers held them more and allocated more time to household sanitation year-round. We recommend that other investigators carefully examine the relationships between children's well-being according to developmentally-defined child age intervals and maternal patterns of time use. Results will help to resolve concern over the effect of maternal participation in economically productive activities on children's well-being. PMID- 8685734 TI - Regulatory effects of health examination programs on medical expenditures for the elderly in Japan. AB - In order to evaluate if there is any correlation between the use of general medical examination programs organized by each community under the Health Service Law for the Elderly, and the medical expenditures for the elderly, an analysis was conducted based on 97 communal data of Fukuoka prefecture, Japan in 1991. According to the results, the use of health examinations showed a statistically significant negative correlation with the medical expenditures for the elderly both for in- and outpatient services. The analysis of the medical expenditure components has clarified that this negative correlation is mainly due to the low utilization rate of services at medical facilities among the communities with a high participation rate in the examination. A part of this low utilization rate could be explained by the complementary effect of the examination program as an alternative for the elderly instead of going to a medical facility for consultation. The present result suggests that a community health service program could decrease the demand for medical services of the elderly. PMID- 8685735 TI - Which resources pay for treatment? A model for estimating the informal economy of health. AB - The model proposed is a means for (i) documenting the resources a woman deploys to choose, seek, find, get and pay for treatment; (ii) comparing what she has/does with a neighbour facing similar symptoms and problems, and (iii) understanding which difference between them makes most difference to the way they manage illness. In a narrow economic perspective, only tangible items with easily enumerated values are called resources, and only the formal economy counts. This model allows assessment of the value of both formal and informal resources in the household system. It will not establish the absolute or market worth of households in the sample, but does offer a framework for comparing households which have the same access to a given set of treatment options when faced with the same symptoms. Its application improves the possibility of understanding which resources, or combinations of resources, make most difference to a household's capacity to seek and get the treatment it has decided it needs. The paper is one element of a multi-layered and multi-disciplinary study of 'The Informal Economy of Health in African Cities'. The overall project aims are (i) to map the cultural, infrastructural and clinical factors affecting the treatment seeking behaviour of women in low-income urban areas; (ii) to compare their effect(s) on the management of symptoms of adult venereal infection (STD) and crisis symptoms in children under five. The project mapped the social context of illness management in a district of Kampala. Important dimensions of that context are: the infrastructure of the area, and the treatment options available in or around it; women's assessments of how good/kind/shameful/private/feasible/ appropriate those options are, and the social and physical signs which trigger the conclusion that a symptom is 'serious enough' to need treatment outside the home in the first place. The focus here is the value of resources mobilized after the 'serious enough' assessment has been made. PMID- 8685736 TI - Self-rated health and mortality in a Lithuanian and a Dutch population. AB - The hypothesis that the evaluation of one's health as poor is associated with mortality, independent of the results of a standardized medical examination, was tested in the Kaunas-Rotterdam Follow-Up Study. In this study two cohorts, one consisting of 2452 Lithuanian males and one of 3365 Dutch males, aged 45-60, were screened for cardiovascular risk factors in 1973, using identical protocols, and were followed for about ten years. Self-rated health was assessed by two direct questions: 'How would you assess your own health?' and 'What do you think of your own health compared to that of other men of your age?' as well as by a Semantic Differential Test of 'My Health'. In both cohorts a negative evaluation of one's health was associated with mortality, controlling for past or present heart disease, cardiovascular risk factors, parental life span, socio-economic and marital status. Especially the data with regard to the comparative question indicate that self-rated health is associated with mortality in men living in two different socio-cultural systems. The date suggest that a weak sense of mastery may explain the association between health perception and mortality. PMID- 8685737 TI - Syringe-mediated drug sharing among injecting drug users: patterns, social context and implications for transmission of blood-borne pathogens. AB - Drug injectors are at risk for infection with human immunodeficiency virus (HIV) and other blood-borne pathogens through the exchange of (infected) blood resulting from unhygienic injecting practices. Research attention and public discussion have focused primarily on the sharing of syringes and needles. While the focus on syringe sharing has sparked important interventions (bleach distribution, syringe exchange) it may have obscured the social relationship in which injecting equipment is used. Drug sharing plays a crucial role in the social organization of the drug using subculture. In this paper, various drug sharing practices and other distinguishable aspects of the injecting process collectively termed Syringe-Mediated Drug Sharing (SMDS)-are described. All of these behaviors may put injecting drug users (IDUs) at risk for infection. The purpose of this paper is to stimulate scientific inquiry into SMDS behaviors and the social contexts which shape them. Descriptions are based primarily on field studies in Rotterdam and New York City. Recommendations for safer injecting training and education are proposed, as are directions for future research. PMID- 8685738 TI - Variation in diagnoses: influence of specialists' training on selecting and ranking relevant information in geriatric case vignettes. AB - Variation in aspects of medical practice such as diagnosis, has been studied at different levels of aggregation. At the inter-practitioner aggregation level, attention is increasingly being paid to factors explaining medical variation which are attributed to 'professional uncertainty'. The concept of 'professional uncertainty' refers to variability that is considered to be inherent to the nature and structure of medical knowledge which depend on the epistemological characteristics of medical science. In this study the relationship between specialty training and variation in diagnostic practice was examined at the inter practitioner aggregation level. Determination of a direct relationship would support the thesis that specialization is a structuring factor in the inherent variability of medical practice. Three groups of medical specialists participated in the study: geriatricians, geriatric-psychiatrists and internists. Four case scenarios were submitted to the specialists. The cases used involved elderly patients presenting with problems in domains common to all the participating specialists. For each case the specialists were requested to select those facts they considered important for reaching diagnoses and to rank these facts in order of perceived salience. Subsequently they were asked to provide (tentative) diagnoses, ranked in order of perceived significance. The occurrence of variability in diagnostic practice due to 'professional uncertainty' and the influence of specialist specific factors and shared knowledge, respectively, are demonstrated. The results clearly show that these three groups of specialists focused on different elements of information, and formulated different diagnoses in the same case, but expressed similar ranking patterns. PMID- 8685739 TI - Health and a residential care population. AB - This article describes the health status of 234 severely mentally ill (SMI) persons residing in California's supervised residential care facilities in 1973. Relocated in 1983, 63.2% reported their health as good to excellent. Over the follow-up period 80.8% maintained their SSI benefits, insuring them of health insurance coverage. Surprisingly the follow-up sample, believed to be at high risk of increased physical morbidity, compared quite favorably to low income subsamples of the National Health Interview Survey (NHIS). The SMI reported better health, access to and utilization of health services. Differences were particularly striking in the poor health category with NHIS respondents reporting poor health 3.5 times more frequently than SMI sample numbers. These results offer some support for the contribution of health insurance benefits and supervised residential settings to positive health outcomes of this vulnerable population. PMID- 8685740 TI - Determinants of informal caregivers' satisfaction with services for dying cancer patients. AB - The association between bereaved informal caregivers' satisfaction with services delivered by district nurses, general practitioners and hospital doctors, and various service and non-service variables was examined to assess whether satisfaction is a reflection of service characteristics, non-service related factors, or attributable to both. Secondary analysis was undertaken on a sub sample from the "Regional Study of Care for the Dying" (RSCD) in which bereaved relatives or friends of a random sample of deaths in 1990 in 20 health districts across England were interviewed some ten months after the death. 1858 relatives or close friends/neighbours of people who died from cancer were included in this analysis. Using multiple logistic regression, larger odds ratio were found in association with service than non-service variables. For example, high satisfaction with district nurses was strongly associated with visiting the patient very frequently (OR = 10.8, 95% CI = 4.5 - 25.9), while the GP visiting 20 times or more (OR = 5.5, 95% CI = 3.6 - 8.5), and informing the informal caregiver of the diagnosis (OR = 3.3, 95% CI = 2.3 - 4.7) were associated with high satisfaction with GPs. However, some non-service variables were significantly associated with satisfaction. For instance, having no bereavement related psychological problems was positively associated with high satisfaction with district nurses (OR = 2.3, 95% CI = 1.6 - 3.4) and GPs (OR = 2.0, 95% CI = 1.4 - 2.8), while the informal caregiver perceiving caring as rewarding as opposed to a burden was positively associated with high satisfaction with district nurses (OR = 3.7, 95% CI = 1.8 - 7.5) and negatively associated with high satisfaction with hospital doctors (OR = 0.46, 95% CI = 0.24 - 0.86). The findings indicate that, in post-bereavement surveys evaluating services delivered to dying cancer patients, informal caregivers' satisfaction is mainly determined by service characteristics. However, attributes of both patients and informal caregivers also play an important role. PMID- 8685741 TI - A review of research on the nature and quality of HIV testing services: a proposal for process-based studies. AB - Considerable research has been conducted on various issues associated with HIV testing. However, rather than conceptualizing HIV testing as a dynamic process which consists of interrelated elements, this body of work has focused on discrete aspects of the HIV testing process. As an example of such research, studies which have examined HIV testing in terms of various behavioural and psychological outcomes are critically reviewed. Their limitations are attributed to their failure to account for all the elements involved in the HIV testing process that-singly and in dynamic combination-could have produced the measured outcomes. It is contended that if research on HIV testing is to be of use in the development and improvement of HIV testing services, it should be able to identify and describe in detail the factors that might lead to various outcomes of testing. This requires an in-depth examination of all aspects of the HIV testing process and their interrelationships from the perspectives of those undergoing testing and those providing testing services. The principal process elements in HIV testing are described; existing research on these topics is critically reviewed; and recommendations are made for future research. The process elements of HIV testing are identified as making a decision to be tested; accessing testing services; test counseling; and waiting for the test result. Of these, most consideration is accorded to the HIV test counselling process. It is contended that research is needed which examines both clients' and counsellors' expectations, experiences of and satisfaction with HIV test counselling. Specific issues that could usefully be addressed by future research include the process of obtaining clients' informed consent for testing; the ways in which test results are conveyed to clients; the strategies used in HIV counselling to help clients avoid or reduce behaviours in the future; partner notification; and which professional groups are best placed to conduct HIV test counselling. Finally, the question of which research methods might be suitable for process-based studies is considered. It is concluded that qualitative methods could be particularly appropriate as they are well-placed to chart in detail the varied aspects of the HIV testing process and their interrelationships. PMID- 8685742 TI - New directions for health: towards a knowledge base for public health action. AB - The need for new types of solutions to respond to community health needs, along with the poor fit between research and the knowledge needed for improving the health of populations, have stimulated a renewal process in the field of public health. Growing out of this movement, an international workshop held at the Nuffield Institute for Health, University of Leeds in 1993 took up issues related to the role and limitations of epidemiology as generally practiced today. Concern for creating a relevant and sound knowledge base for public health action was the impetus guiding this project. Some of the major topics taken up in the deliberations of the workshop are reflected in the selection of papers that follow. They are highlighted and supplemented with an overview of other issues taken up by the conferees in this introduction. PMID- 8685743 TI - Collecting retrospective data: development of a reliable method and a pilot study of its use. AB - The present paper argues that a need will remain for data which have been collected retrospectively. Recent developments in oral history and sociology are described to suggest a method of collecting retrospective data which may minimize recall bias. Pilot work is reported on the adaptation of the method for a study of chronic respiratory disease. The results of the pilot study proved promising. The technical properties of the measures appeared adequate. The results of the substantive analysis were consistent with existing knowledge and went beyond existing knowledge to suggest new areas of research. Ways of further validating the method are identified and its wider application discussed. PMID- 8685744 TI - Public health research and lay knowledge. AB - Social science research into the social patterning of health and illness is extensive. One important aspect of this has been work on lay knowledge about health and illness. In this paper we develop three main arguments. First, we suggest that recent developments in social science understanding of the nature and significance of lay knowledge should be more widely recognized within the social sciences themselves. Second, we argue that if public health research, whatever the disciplinary perspective, is to provide an understanding of contemporary health problems that is simultaneously more robust and more holistic, it must incorporate and develop the theoretical and conceptual insights offered by this recent work on lay knowledge and with lay people. Finally, we argue that in order to accomplish this it will be necessary to construct research questions in such a way that the conventional distinctions between science and non-science, and the methodological wrangles associated with this distinction, become marginal to the research process. This will inevitably involve conflicts between members of different professional groups. These conflicts provide the opportunity for open debate on the science and politics of public health research and represent a challenge for the many disciplines involved in this field. PMID- 8685745 TI - Non-medical influences on medical decision-making. AB - BACKGROUND: The influence of non-medical factors on physicians' decision-making has been documented in many observational studies, but rarely in an experimental setting capable of demonstrating cause and effect. We conducted a controlled factorial experiment to assess the influence of non-medical factors on the diagnostic and treatment decisions made by practitioners of internal medicine in two common medical situations. METHOD: One hundred and ninety-two white male internists individually viewed professionally produced video scenarios in which the actor-patient, presenting with either chest pain or dyspnea, possessed various balanced combinations of sex, race, age, socioeconomic status, and health insurance coverage. Physician subjects were randomly drawn from lists of internists in private practice, hospital-based practice, and HMO's, at two levels of experience. RESULTS: The most frequent diagnoses for both chest pain and dyspnea were psychogenic origin and cardiac problems. Smoking cessation was the most frequent treatment recommendation for both conditions. Younger patients (all other factors being the same) were significantly more likely to receive the psychogenic diagnosis. Older patients were more likely to receive the cardiac diagnosis for chest pain, particularly if they were insured. HMO-based physicians were more likely to recommend a follow-up visit for chest pain. Several interactions of patient and physician factors were significant in addition to the main effects. CONCLUSIONS: The variability in decision-making evidenced by physicians in this experiment was not entirely accounted for by strictly rational Bayesian inference (the common prescriptive model for medical decision-making), in-as-much as non-medical factors significantly affected the decisions that they made. There is a need to supplement idealized medical schemata with considerations of social behavior in any comprehensive theory of medical decision making. PMID- 8685746 TI - Public health medicine in a new era. AB - The health service reforms in the United Kingdom have posed significant problems for the carrying out of the public health function. The increasing size of populations for which health authorities are responsible makes the formation and maintenance of strong community links difficult. An attempt to broaden the membership of the Faculty of Public Health Medicine beyond members of the medical profession has failed to achieve consensus support, and academic departments are highly variable in their working links with the NHS. The creation of a separate public health service for the country has become a possibility. Behind these structural problems lies the lack of a commonly understood and agreed theoretical basis within the specialty. It is argued that an understanding of the role and functioning of the specialty as well as the real determinants of health is important to the achievement of improvement in the health of the population. The NHS reforms have created an opportunity for public health practitioners that if not seized may not be recreated for some time. PMID- 8685747 TI - A better way of approaching adolescent pregnancy. PMID- 8685748 TI - Hansen's Disease. AB - Physicians in the United States may encounter Hansen's disease in immigrants and areas such as Texas, Louisiana, Hawaii, and California. Exposure to infected armadillos may be one means of acquiring the disease. The Mycobacterium leprae bacillus has a predilection for nerves and skin in the cooler areas of the body. The limited tuberculoid form of the disease is characterized by one or a few hypoesthetic skin lesions and palpably enlarged nerves. The more extensive lepromatous form of the disease appears as multiple nodular skin lesions, sometimes with involvement of the nasal structures and eye. Current recommended regimens for treatment of Hansen's disease are based on combinations of dapsone, rifampin, and clofazimine. Recent advances in treatment have resulted in a significant decline in the worldwide prevalence of the disease. PMID- 8685749 TI - Surgical management of malignant tumors of the adult bony spine. AB - Modern diagnostic imaging techniques and new methods for anterior and posterior decompression and reconstruction of the bony spinal column have dramatically improved the surgeon's ability to treat malignant tumors of the adult bony spine. The day of the laminectomy and Harrington rod reconstruction has passed, and an aggressive surgical approach is now justified for many primary and secondary malignant lesions of the spine. This article addresses the diagnosis and therapy of malignant tumors of the bony spine, emphasizing the common primary tumors of the spine and even more common metastatic lesions. Specific tumor types and therapeutic approaches at different levels of the spine are addressed, and newer techniques available to the treating clinician are reviewed. Current specific approaches to myeloma/plasmacytoma, breast carcinoma, prostate carcinoma, lung carcinoma, renal cell carcinoma, and chordoma and primary rectal carcinoma of the sacrum are reviewed in detail. PMID- 8685750 TI - Normal sinus heart rate: appropriate rate thresholds for sinus tachycardia and bradycardia. AB - Conventional rate limits for sinus rhythm--100/min as the tachycardia threshold and 60/min as the bradycardia threshold--were established by consensus and never formally examined. Because clinical experience indicated that both figures were too high, we investigated this formally in 500 normal individuals. Results were consistent with normal data from the Framingham Study 5,000-subject cohort and the EPICORE Center cohort of more than 18,000 normal persons. Therefore, rounded tachycardia and bradycardia thresholds of 90/min and 50/min for normal sinus rhythm should improve the sensitivity of tachycardia detection and the specificity of bradycardia detection. The appropriate rate range (rounded) for sinus rhythm is 50/min to 90/min. PMID- 8685751 TI - Laparoscopic versus open appendectomy. AB - This prospective clinical study was done because our initial retrospective review suggested that laparoscopic appendectomy (LA) offers no significant advantages over open appendectomy (OA) yet is significantly more expensive. From July 1992 to August 1993, 57 patients were approached preoperatively for randomization to either LA (n = 19) or OA (n = 18). There were no statistically significant differences between the LA and OA groups in operative risk: mean age, 28 +/- 2 vs 26 +/- 2 years; percent female, 26% vs 22%; body mass index, 24 +/- 0.8 vs 26 +/- 1.2 kg/m2. All patients were either ASA class I or class II, 78% in each group being class II. The differences between the LA and OA groups in mean operating time required (93 +/- 12 vs 87 +/- 8 minutes), postoperative intramuscular narcotic analgesic usage (24 +/- 6 vs 26 +/- 6 hours), postoperative hospital stay (57 +/- 12 vs 66 +/- 10 hours), and return to normal activity (20 +/- 6 vs 14 +/- 3 days) were also not significant. However, LA was much more expensive because of higher operating room charges. The mean total hospital bill was $4,600 +/- $160 for the LA group and $1,700 +/- $70 for the OA group. This prospective study corroborated our previous analysis. Laparoscopic appendectomy is safe, effective, and expensive and overall has no greatly significant advantages over open appendectomy. PMID- 8685752 TI - Postoperative pulmonary changes after laparoscopic cholecystectomy. AB - Laparoscopic cholecystectomy (LC) has been widely used in recent years because of short postoperative hospital stays and low morbidity. In this study, 24 patients were prospectively evaluated with preoperative and postoperative spirometry, arterial blood gas determinations, and chest radiographs to quantitate the magnitude of postoperative pulmonary changes after LC. Statistically significant reductions were noted in forced vital capacity (FVC) (mean decrease, 810 mL) and forced expired volume in 1 second (FEV1) (mean decrease, 420 mL). Clinically important changes in arterial blood gas values did not occur. Of 20 postoperative chest films, 7 showed the development of atelectasis or effusion and 9 showed persistence of subdiaphragmatic free air 24 hours after LC. In summary, LC caused mean decreases of 23% in FVC and 16% in FEV1 24 hours after surgery. The physiologic derangements that follow LC are sufficiently small that all but the most severely impaired patients with pulmonary disease should be able to tolerate this operation. PMID- 8685753 TI - Prediction of cure of hypertension in atherosclerotic renal artery stenosis. AB - We analysed the outcome of 63 consecutive, adequate interventions for atherosclerotic renal artery stenosis and hypertension: 34 patients had percutaneous transluminal renal angioplasty, and 29 had surgical correction. Hypertension was cured in 21% of patients and improved in 47%, but 32% failed to respond. We analyzed clinical variables predictive of cure. Duration of hypertension, level of diastolic blood pressure, and sex were found to be predictive of cure. The highest probability of cure was found in men with a duration of hypertension of less than 10 years and an initial diastolic blood pressure of greater than 80 mm Hg. Use of these clinical variables in a tree based model correctly classified 80% of cases, with a sensitivity of 92% and a specificity of 77%. We conclude that a tree-based clinical algorithm based on only three clinical criteria correctly predicted cure of hypertension in most patients with renal artery stenosis and may be useful in decision making. A prospective analysis will be required to evaluate the clinical validity of the algorithm. PMID- 8685754 TI - Attitudes and knowledge regarding breast-feeding: a survey of obstetric residents in metropolitan areas of South Korea. AB - A 15-minute, 6-page questionnaire on breast-feeding was administered to the obstetric residents in four metropolitan academic training programs in Korea to assess their attitudes toward and knowledge about breast-feeding and their confidence in managing breast-feeding problems. The questionnaires were self administered and confidential, and the participation rate was 84% (n=76). Overall, the study participants indicated a neutral attitude toward breast feeding (2.9 on a 6-point scale, where 1 equals the most positive attitude and 6 equals the most negative attitude). Their self-confidence was inappropriately high, with 49% of the total sample describing themselves as "confident" or "very confident" to manage common breast-feeding problems. Female residents had a higher confidence level than male residents. Although high in self-confidence about breast-feeding, the residents in this study were not knowledgeable about breast-feeding management, answering only 38% of the questions correctly. To be truly supportive of breast-feeding, obstetricians should receive didactic and clinical training in breast-feeding management. PMID- 8685755 TI - Improvement in oxygenation after large volume paracentesis. AB - Seventeen patients with biopsy-confirmed hepatic cirrhosis and tense ascites performed reproducible pulmonary functions and had arterial blood gas analysis before and after having a therapeutic large volume paracentesis. Each patient showed significant improvement in the static lung volumes as determined by helium dilution techniques. Dynamic airflow also improved as expressed by the FVC and the FEV1. The FEV1/FVC ratio remained unchanged. Each patient showed a significant improvement in oxygenation 120 minutes after LVP. Alveolar ventilation as expressed by PaCO2 did not change. The pathophysiology that explains the improvement in oxygenation remains speculative. Large volume paracentesis appears to have a salutary effect on oxygenation, as well as on pulmonary function. PMID- 8685756 TI - Persistent neurotoxicity from a battery fire: is cadmium the culprit? AB - Two train conductors had chest tightness, painful breathing, muscle cramps, and nausea after fighting a fire in a battery box under a passenger coach. Shortly thereafter, they became anosmic and had excessive fatigue, persistent headaches, sleep disturbances, irritability, unstable moods, and hypertension. Urinary cadmium and nickel levels were elevated. Neurobehavioral testing showed, in comparison to referents, prolonged reaction times, abnormal balance, prolonged blink reflex latency, severely constricted visual fields, and decreased vibration sense. Test scores showed that immediate verbal and visual recall were normal but delayed recall was reduced. Scores on overlearned information were normal. Tests measuring dexterity, coordination, decision making, and peripheral sensation and discrimination revealed abnormalities. Repeat testing 6 and 12 months after exposure showed persistent abnormalities. Cadmium and vinyl chloride are the most plausible causes of the neurotoxicity, but fumes from the fire may have contained other neurotoxic chemicals. PMID- 8685757 TI - Changes in employee smoking behavior after implementation of restrictive smoking policies. AB - How do restrictive smoking policies affect the smoking behavior of employees? At two federal hospitals, 2,700 employees completed written surveys after implementation of restrictive smoking policies. At one hospital, smokers reported less smoking at work (down 2.0 cigarettes a day at 6 months, 1.7 at 12) without compensatory smoking. At the other, no significant changes in smoking behavior were reported. However, at both hospitals, some baseline smokers quit smoking. At 6 months, 9% had quit at one hospital and 8% at the other. Analyses were done using these two studies and 17 published studies. In 11 of 11 studies, consumption at work decreased, and in 12 of 14, total daily consumption decreased. Regression analysis indicated that the number of smokers who quit smoking after policy implementation increases over time at rates exceeding those normally expected in the population. Smoking policies appear to effect a reduction in total cigarette consumption and an increase in the number of smokers who quit. PMID- 8685758 TI - Marjolin's ulcer of the foot caused by nonburn trauma. AB - Marjolin's ulcers are malignancies that arise from previously traumatized, chronically inflamed, or scarred skin. We report a case of squamous cell carcinoma arising in a foot wound 42 years after the time of injury. The historical background, epidemiology, pathophysiology, diagnosis, treatment, and prognosis of Marjolin's ulcer are reviewed. Diagnosis is best accomplished by punch biopsy or excision of suggestive lesions. Wide local excision is required and amputation may be necessary to achieve an adequate margin. Regional lymph node dissection should be done if regional nodes are palpable. Elective lymph node dissection is controversial but should be considered if the tumor is poorly differentiated. Lymph node metastases and high tumor grade indicate a poor prognosis. Clinicians should be diligent in the long-term surveillance of all significant scars or areas of chronic inflammation. PMID- 8685759 TI - Apical hypertrophic cardiomyopathy. AB - We report the case of a patient with recurrent admissions for congestive heart failure who was subsequently diagnosed with apical hypertrophic cardiomyopathy. The major physiologic characteristic of patients with apical hypertrophic cardiomyopathy is diastolic dysfunction due to abnormal stiffness of the left ventricle during diastole, with resultant impaired ventricular filling. In these patients, as in all patients with hypertrophic cardiomyopathy, the main pathology is inadequate relaxation of the ventricle; therefore, a regimen of diuretics and inotropic agents can actually worsen the clinical picture. We emphasize the need to consider hypertrophic cardiomyopathy in evaluating cases of congestive heart failure. PMID- 8685760 TI - Management of catheter emboli. AB - Catheter emboli are a significant risk to patient well-being. With a 49% complication rate for indwelling catheter emboli, the consensus is that these foreign bodies should be removed. Preferably, the emboli are removed by percutaneous extraction; however, if the emboli are in the heart or central vasculature and percutaneous extraction fails, then thoracotomy with operative removal is necessary. We analyze the literature on catheter emboli and present a case showing that extraction of embolized fragments is not always possible. PMID- 8685761 TI - Disseminated epidemic Kaposi's sarcoma treated with radiation and chemotherapy. AB - When a 40-year-old patient with end-stage acquired immunodeficiency syndrome (AIDS) had bloating and abdominal pain, a large epidemic Kaposi's sarcoma (EKS) lesion was found obstructing the pylorus. Treatment consisted of single-agent chemotherapy for the disseminated lesions and external beam irradiation to the obstructing lesion. Within days of radiation therapy, symptoms began to resolve, and by completion of therapy, the patient was virtually asymptomatic. Although EKS is common in homosexual men infected with the AIDS virus, these patients usually succumb to overwhelming opportunistic infections. Nevertheless, palliative courses of radiation, which can produce a complete response in 50% to 100% of treated KS lesions, can substantially improve the quality of life in these patients. PMID- 8685762 TI - Periorbital varicella gangrenosa necessitating orbital exenteration in a previously healthy adult. AB - A previously healthy 31-year-old man had profound neurologic compromise and necrotizing periorbital infection due to a complication of varicella infection. Despite aggressive treatment, he required orbital exenteration and radical debridement of the involved tissues. He survived in a vegetative state for almost 1 year before succumbing to progressive neurologic deterioration. We present and discuss this complicated case of varicella gangrenosa to show the devastating nature of complications that can occur from varicella infection in the unsensitized adult. PMID- 8685763 TI - Fatal Cytomegalovirus pneumonia in a patient receiving corticosteroids and methotrexate for mixed connective tissue disease. AB - Cytomegalovirus (CMV) pneumonia is a serious illness that may occur in severely immunocompromised patients such as those with bone marrow transplants. A strong association between this condition and immunosuppressive therapy for collagen vascular diseases has not been described. We describe a patient who had CMV pneumonia while receiving methotrexate and corticosteroids for mixed connective tissue disease. PMID- 8685764 TI - Infant diabetic ketoacidosis in the emergency department. AB - We present the case of an infant brought to the emergency department with complaints commonly associated with a typical childhood illness. Surprisingly, he was found to have diabetes mellitus with ketoacidosis. The usual symptoms of polyuria, polydipsia, and weight loss attributed to diabetes mellitus were not observed. A fruity smell on his breath led to appropriate laboratory tests and ultimately to the correct diagnosis. We review appropriate management of infantile diabetic ketoacidosis, emphasizing the importance of considering diabetes mellitus and ketoacidosis in infants admitted to the emergency department with common complaints such as vomiting and irritability. As in our case, the clinical finding of a fruity breath smell can be an important factor in diagnosis. PMID- 8685765 TI - Fatal disseminated herpes simplex in pregnancy with maternal and neonatal death. AB - Disseminated herpes is rare in the adult and usually occurs in the immunocompromised. Twenty-one cases have been reported in which healthy women contracted life-threatening disseminated herpes simplex virus (HSV) infections in the third trimester of pregnancy. Most of these patients had nonspecific symptoms, and many did not have mucocutaneous lesions. On physical examination, they were usually febrile and anicteric and had markedly elevated aminotransferase values, without a corresponding elevation in bilirubin level. In our review of the literature, we found that prompt acyclovir therapy resulted in 100% survival. Those patients not receiving treatment or treated late in the terminal stages of their disease had a 63% mortality rate. We report a case of maternal disseminated HSV with subsequent maternal death at an estimated 31 weeks' gestation in which the diagnosis was made at the time of necropsy. The infant was started on acyclovir therapy but died of disseminated HSV. PMID- 8685766 TI - Thyrotoxic periodic paralysis in a black man. AB - We report a case of thyrotoxic hypokalemic periodic paralysis occurring in a black man. This previously healthy 41-year-old man had a 3-year history of recurrent paroxysmal episodes of paresis in the upper and lower extremities proximally, often occurring after heavy exercise. The patient had no history of hyperthyroidism, nor family history of periodic paralysis. This case reveals a particularly rare characteristic of this disorder in which periodic paralysis is the presenting symptom of hyperthyroidism. This condition has been reported most commonly among Asians and is extremely rare in black men, only five cases having been described during the past 30 years. PMID- 8685767 TI - Antiphospholipid syndrome associated with seizures. AB - Antiphospholipid antibodies have been associated with thrombosis, fetal wasting, and thrombocytopenia. We discuss a case of antiphospholipid syndrome with the rarely recognized presentation of generalized tonic-clonic seizure during pregnancy. This case emphasizes the need for evaluation of possible hypercoagulable states in young adults with cerebrovascular events or newly diagnosed seizures. PMID- 8685768 TI - Maternal serum amylase and lipase profiles in pregnancy. PMID- 8685769 TI - Pulmonary Strongyloidiasis. PMID- 8685770 TI - Coming the Cubans. PMID- 8685771 TI - Action for women and health. PMID- 8685772 TI - Caring for survivors of torture. PMID- 8685773 TI - Ebola questions still unanswered. PMID- 8685774 TI - Health policy. PMID- 8685775 TI - HIV/AIDS in South Africa--a relentless progression? PMID- 8685776 TI - Antibiotic-resistant pneumococcal pneumonia. PMID- 8685777 TI - Tuberculosis research--the way forward. PMID- 8685778 TI - Tuberculosis control in South Africa--time for a new paradigm? PMID- 8685779 TI - What is the potential for future outbreaks of chikungunya, dengue and yellow fever in southern Africa? PMID- 8685780 TI - The use of a geographical information system (GIS) to evaluate the distribution of tuberculosis in a high-incidence community. AB - OBJECTIVE: To determine the geographical distribution of tuberculosis in the two Western Cape suburbs with the highest reported incidence of tuberculosis. DESIGN: Descriptive illustrative study. SETTING: Two adjacent Western Cape suburbs covering 2.42 km2 with a population of 34,294 and a reported tuberculosis incidence of > 1,000/100,000. SUBJECTS: All patients notified as having tuberculosis over a 10-year period (1985-1994). INTERVENTIONS: None OUTCOME MEASURE: The geographical distribution of the cases was determined using a geographical information system (GIS) and the National Population Census (1991). RESULTS: One thousand eight hundred and thirty-five of the 5,345 dwelling units (34.3%) housed at least 1 case of tuberculosis during the past decade and in 483 houses 3 or more cases occurred. These cases were distributed unevenly through the community, with the tuberculosis incidence per enumerator subdistrict (ESD) varying from 78 to 3,150/100,000 population. CONCLUSION: In a small area with a high incidence of tuberculosis, the cases are spread unevenly through the community and there are certain houses where tuberculosis occurs repeatedly. This information should be used to direct health services to concentrate on certain high-risk areas. PMID- 8685781 TI - Unexpectedly high strain diversity of Mycobacterium tuberculosis in a high incidence community. AB - OBJECTIVE: To characterise Mycobacterium tuberculosis strains present in a community experiencing an epidemic, in order to establish whether a high rate of transmission results in low strain diversity. DESIGN: Sputum specimens collected for 18 months; IS6110-based DNA fingerprinting. SETTING: The communities of Ravensmead and Uitsig, Cape Town, South Africa. PARTICIPANTS: Three hundred and thirty-four pulmonary tuberculosis patients attending the Local Authority Health Care Clinic. MAIN OUTCOME MEASURE: DNA fingerprinting. RESULTS: A total of 334 M. tuberculosis isolates were characterised by IS6110-based DNA fingerprinting; 209 strains were identified, 199 having 5 or more insertions. Forty of these strains were present in 2 or more patients (clustering--126 patients in total), which indicates a recent transmission rate of 30%. The 163 unique strains suggest reactivation of latent infections. Computer analysis showed a high degree of strain diversity, and a common progenitor could only be linked to 33% of the strains. Clustering was shown in 50% of drug-resistant isolates. CONCLUSIONS: The low rate of transmission (30%) and the high degree of strain diversity (209 strains) was unexpected and unexplained, given the high burden of disease in this community. The clustering of drug-resistant strains suggests that transmission, rather than lack of compliance, drives the spread of antibiotic resistance in this community. Preliminary indications are that BCG vaccination, while having little effect on the incidence of tuberculosis in this community, may have altered the strain dynamics. PMID- 8685782 TI - Rifampicin resistance in Mycobacterium tuberculosis--rapid detection and implications in chemotherapy. AB - OBJECTIVES: Tuberculosis treatment and susceptibility testing are cumbersome, especially in the case of multidrug-resistant (MDR) Mycobacterium tuberculosis. It is known that mutations in the rpoB gene of M. tuberculosis lead to resistance to rifampicin (RMP). In this study, an attempt was made to apply molecular techniques for rapid detection of antibiotic resistance in clinical isolates of M. tuberculosis. DESIGN, SETTINGS AND SUBJECTS: RMP-resistant clinical isolates of M. tuberculosis from South Africa (N = 120) with unique resistant patterns were selected for calculation of resistance frequencies, and 74 MDR isolates of M. tuberculosis from different geographical origins were used for microbiological and molecular analysis. The polymerase chain reaction (PCR) technique was applied for amplification of a previously described region around a cluster of mutations in the rpoB gene, and single-stranded conformational polymorphism (SSCP) analysis was optimised to screen for mutations in the amplified region. RESULTS: The results showed that an optimised PCR-SSCP procedure could detect a cluster of mutations in the rpoB gene (for RMP resistance) in 95% of RMP-resistant isolates. This procedure could therefore be used in the prediction of RMP resistance. Evidence was obtained that these mutations can be screened for directly from BACTEC cultures or even directly from Ziehl-Neelsen-positive sputum samples. Statistical analysis also showed that this locus can be used to predict the presence of an MDR isolate, which may have important implications in decisions concerning chemotherapy. CONCLUSION: It is currently not feasible to test all tuberculosis cases, but application of the PCR-SSCP technology in the prediction of multidrug resistance in M. tuberculosis isolates may be important in patients, especially where frequencies are high for drug-resistant isolates This methodology could reduce the time required for sensitivity testing from approximately 6-12 weeks to a few days. PMID- 8685783 TI - Academic research and HIV/AIDS in South Africa. PMID- 8685784 TI - Demographic modelling of the HIV/AIDS epidemic on the Soweto population--results and health policy implications. AB - In this paper we present the results of a local HIV/AIDS demographic modelling exercise for Soweto, Johannesburg. The Doyle model was used to project the growth of the HIV/AIDS epidemic in Soweto until the year 2010. High, medium and low AIDS scenarios are projected; these depend on reduction in the average number of sexual partners, increased condom use and effective treatment of sexually transmitted diseases. In 1993 the HIV prevalence was estimated to be 3% for all three of the low, medium and high AIDS scenarios, but differences emerge rapidly after this. By 2010 the projected HIV seroprevalences in the high, medium and low AIDS scenarios are 24%, 15% and 8% respectively, corresponding with 343,000, 222,000 and 118,000 HIV-infected people. By the year 2010, AIDS will have caused 135,000-270,000 deaths and during that year will account for 28-52% of all deaths. The total population will continue to increase in size, even in the high AIDS scenario, with the population growth rate ranging from 1.8% (low AIDS scenario) to 1% (high AIDS scenario) by the year 2010. This modelling exercise has demonstrated the enormous potential impact of timeous and effective implementation of currently available prevention strategies. The need to institute prevention programmes in the short term is therefore stressed. Recommendations are also made about the care of people with HIV/AIDS. Other areas are encouraged to attempt similar exercises in order to stimulate local and regional planning of HIV/AIDS prevention and care. PMID- 8685785 TI - HIV-related tuberculosis in South Africa--clinical features and outcome. AB - OBJECTIVE: To assess the difference between human immunodeficiency virus (HIV) infected and non-infected tuberculosis patients with regard to demographic characteristics, clinical features, case fatality rates and, particularly, compliance with therapy. DESIGN: Cohort study. SETTING: Hlabisa Hospital, KwaZulu Natal, a 450-bed hospital serving a rural district containing 180,000 people. PATIENTS: Two hundred and ninety-seven consecutive adult patients ( > 15 years) diagnosed with tuberculosis. MAIN OUTCOME MEASURES: Age, sex, type of tuberculosis, case fatality rate and compliance with therapy. RESULTS: A total of 107 out of 297 (36%) adults tested HIV-positive (95% confidence interval (CI) 31 42%). Prevalence of HIV infection was higher in women than men (46% v. 29%, relative risk (RR) 1.6, 95% CI 1.2-2.2). HIV-positive patients were significantly younger than HIV-negative patients (mean age 31.2 years v. 38.7 years; P < 0.001). Extrapulmonary tuberculosis (EPTB) was more common in HIV-positive patients (41% v. 11%, RR 3.7, 95% CI 2.3-5.9). The case fatality rate was higher in HIV-positive patients (13% v. 9%, RR 1.5, 95% CI 0.7-3.0). Many more HIV positive patients failed to complete treatment (21% v. 7%, RR 3.0, 95% CI 1.5 6.0). CONCLUSIONS: We found that HIV-positive patients with tuberculosis were three times more likely to fail to complete treatment than HIV-negative patients. HIV infection is clearly altering the epidemiological profile of tuberculosis in rural South Africa and poses an additional challenge to tuberculosis control programmes to maintain high case-holding rates among HIV-infected tuberculosis patients. PMID- 8685786 TI - A blood-result turn-around time survey to improve congenital syphilis prevention in a rural area. AB - The results of a turn-around time study of blood specimens for syphilis serology in antenatal clinic attenders between 19 rural clinics and their base hospital, including a follow-up survey to assess the impact of interventions, are described. The objective of the study was to determine how long blood samples took to get from the clinic to the laboratory and back again. The time between each phase was recorded by inclusion of a dating system on the documentation that routinely accompanies the blood samples. The longest delay was the time at the laboratory. The results were reported to the various sectors involved in the handling of the blood samples. The solution was to make all divisions of the health service aware of the needs of the clinic staff and clinic service users, and to change laboratory routine. PMID- 8685787 TI - A sero-epidemiological cross-sectional study of hepatitis B virus in Zimbabwe. AB - OBJECTIVE: To estimate the prevalence of hepatitis B viral markers. DESIGN: A sero-epidemiological community-based cross-sectional study. SETTING: All nine provinces of Zimbabwe. PARTICIPANTS: From April 1989 to December 1991 serum samples were collected from 1,461 males and 1,933 females in the age group 10-61 years, the majority in the younger age groups. MAIN OUTCOME MEASURES: Sera were tested for hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), antibody to HBs-Ag (anti-HBs), antibody to hepatitis B core antigen (anti-HBc) and antibody to hepatitis B e antigen (anti-HBe). All sera were tested for HBsAg, anti-HBs and anti-HBc but for the detection of HBeAg and anti-HBe, only samples positive for HBsAg were examined. MAIN RESULTS: The male-to-female ratio in rural and urban settings was 0.82 and 0.66 respectively. The median age for males and females in rural areas was 21 and 22 years and 28 and 26 years respectively in urban areas. The overall prevalence of HBsAg was 15.4% (males 16.8%, females 14.3%). The difference between sexes was consistent in all age groups and statistically significant (P < 0.05). The prevalences in urban and rural areas were almost identical (15.7% v. 15.3%). However, the prevalence was significantly higher among males in the age group 40-49 years in urban areas compared with rural areas (P < 0.0001). Using the case-referent approach, with HbsAg-positive patients as cases and HBsAg-negative ones as referents, the crude odds ratio for rural areas compared with urban areas was 0,97. However, standardisation for year of data collection and province resulted in a relative risk of 2.0, i.e. the risk of being HBsAg-positive in rural areas is twice as high as in urban areas. Similarly, the crude odds ratio for females compared with males was 0.83, and was reduced significantly to 0.7 when standardised for year of data collection and province. The prevalences of HBeAg, anti-HBe, anti-HBs and anti-HBc were 25%, 25%, 45% and 36% respectively. The prevalences of anti-HBs and anti-HBc increased continuously with age and were about 70% higher in the age group 50 years and above compared with those under 20 years. The prevalence of any of the HBV markers-HBsAg, or anti-HBc -was 66% in males and 61% in females. CONCLUSIONS: The results indicate that hepatitis B is hyperendemic in both rural and urban areas of Zimbabwe. PMID- 8685788 TI - Prevalence and intensity of Schistosoma haematobium urinary schistosomiasis in the Port St Johns district. AB - A urinary schistosomiasis survey undertaken in the Port St Johns district of the former Transkei showed the parasite to be endemic and noted an increase in overall infection rates in the region compared with previous studies. There was a general stability in infection over the sampling period 1987-1989. Prevalence rates were low to moderate with an overall prevalence of 42%. These ranged from approximately 10% in the low-prevalence settlement to 89.9% in the settlement with the highest prevalence. Infection rates were found to decrease nearer the coast, and settlements closest to the sea had the lowest prevalence rates. The intensity of infection was low, with the majority of patients having fewer than 200 eggs per 10 ml urine. Very few sufferers were treated with Ambilhar at clinics and hospitals. PMID- 8685789 TI - Hepatitis C virus infection in chronic liver disease in Natal. AB - The aim of this cross-sectional seroprevalence study was to determine the prevalence of antibodies to hepatitis C virus (HCV) (anti-HCV) in patients with cirrhosis, hepatocellular carcinoma (HCC) and chronic active hepatitis (CAH) attending a referral hospital in a hepatitis B virus (HBV)-endemic area in South Africa. One hundred and ten patients with suspected cirrhosis, 44 with suspected HCC and 6 with chronic hepatitis were initially included. The diagnoses were confirmed in 77 patients with cirrhosis (histologically or macroscopically at peritoneoscopy), 33 patients with HCC (histologically or elevated alpha fetoprotein levels plus focal lesion on hepatic imaging) and 6 patients with CAH (histologically) without antinuclear antibodies. All patients were tested for anti-HCV with the Abbott second-generation enzyme immunoassay combined with a supplemental neutralisation assay, and hepatitis B surface antigen (HBsAg). Anti HCV seroprevalence for cirrhosis, HCC and CAH were 18/77 (23%), 8/33 (24%) and 2/6 (33%) respectively. HBsAg was detected in serum in 16 (21%), 15 (46%) and 1 (17%) patient respectively. Only 1 patient (with cirrhosis) was positive for both anti-HCV and HBsAg. Of those who were anti-HCV-positive, 4/18 (22.2%) cirrhotics, none with HCC and 1/2 (50%) with CAH, had previously received blood transfusions, resulting in a cumulative frequency of 5/28 (18%). Our results indicate that HCV is an important aetiological agent in the pathogenesis of chronic liver disease in our patients. In the majority of patients (82%), the infection was not transfusion-related. Thus, screening of blood donors for anti-HCV would not prevent the majority of cases of chronic liver disease secondary to HCV. It appears as if HCV and HBV have different modes of transmission in southern Africa. PMID- 8685790 TI - Malaria in South Africa--the past, the present and selected implications for the future. PMID- 8685791 TI - Cardiobacterium hominis as a cause of bacterial endocarditis. PMID- 8685792 TI - HIV and tuberculosis. PMID- 8685793 TI - Shigella sonnei meningitis. PMID- 8685795 TI - Gauteng Eye Bank. PMID- 8685794 TI - HIV-1 infection in patients with tuberculous lymphadenitis. PMID- 8685796 TI - Nalidixic acid-resistant Shigella dysenteriae type I in KwaZulu-Natal. PMID- 8685797 TI - An outbreak of dysentery in Zambia. PMID- 8685798 TI - Exposure of cats in southern Africa to Coxiella burnetii, the agent of Q fever. PMID- 8685799 TI - Bacillary angiomatosis--another South African case. PMID- 8685800 TI - Of HIV infection, condoms and sexuality education. PMID- 8685801 TI - Rifampicin for ulcerative colitis. PMID- 8685802 TI - Counselling and the HIV test. PMID- 8685803 TI - At the heart: Sir Terence English. Interview by Jonathan Spencer Jones. PMID- 8685804 TI - The arterial blood supply of the pancreas: a review. II. The posterior superior pancreaticoduodenal artery. An anatomical and radiological study. AB - The present paper is the second part of a comprehensive review of the arterial blood supply of the pancreas and deals with the posterior superior pancreaticoduodenal artery. The aim of this review is to summarise the anatomical studies, starting from Haller's reports, and to supply as far as possible, with original material, angiographic evidences for the classic anatomical notions. For this purpose, the overall research was carried out by picking out and studying 1015 selective angiographies (celiac trunk and its branches, superior mesenteric a.) taken from the angiographic archives of the Institutes of Radiology of Siena, Rome (University of Sacro Cuore, Catholic University), and Perugia. Angiographically, many possible different sources of the posterior superior pancreaticoduodenal a. (superior pancreaticoduodenal a., proper hepatic a., right hepatic a., left hepatic a., superior mesenteric a., accessory and replaced right hepatic a. coming from the superior mesenteric a.) have been demonstrated, as have rare variations of the course and a small number of collateral branches (retroduodenal a. and ventral commissural a.). Moreover, the authors underline the discordant opinions still existing regarding the incidence of the different ways the posterior superior pancreaticoduodenal a. arises. PMID- 8685805 TI - Anatomic basis of mesenteric elongation for ileo-anal anastomosis with J-shaped reservoir: comparison of two techniques of vascular section. AB - Total proctocolectomy followed by ileo-anal anastomosis with a reservoir is the operation of choice for the treatment of familial adenomatous polyposis and of certain forms of hemorrhagic proctocolitis. Vascular section is sometimes necessary to enable the extremity of the reservoir to reach the anal sphincter without traction. The aim of this study was to compare the gain in length obtained by two different techniques of vascular section and to assess in terms of the vascular anatomy of the last small intestinal loop which technique best preserved the vascularisation of the reservoir as a whole. Twenty-two fresh cadavers had an ileal J-shaped reservoir of 18 cm fashioned from the last loop of small intestinal loop after section of the root of the mesentery. The gains in length so obtained were measured after section of the ileocolic a. at its origin (group A) or section between the two vascular arches of the last small intestinal loop (group B); the superior mesenteric vessels were then injected with colored resin. The gain in length obtained by these two methods was identical (2.3 +/- 1.1 cm for group A as against 2.18 +/- 0.9 cm for group B), but only if the section of the ileocolic a. was accompanied by section of the mesenteric peritoneum up to the vascular arch formed by the anastomosis between the terminal branch of the superior mesenteric a. and the ileocolic a. The constancy of this anastomosis always allowed section of the ileocolic a. while preserving good vascular distribution to the entirety of the reservoir. Section between the two arches was difficult when the distance separating them was small. PMID- 8685806 TI - Functional gliding spaces of the dorsal side of the human finger. AB - Although the clinical and functional importance of gliding and connective tissue spaces has been repeatedly emphasized (e.g. their role in the spreading of suppurative phlegmonic inflammation) only few literary findings can be presented dealing with the connective tissue spaces in the finger in the metacarpo phalangeal transition region. Three separate gliding spaces of the finger above the dorsal aponeurosis and their various regional connections can be displayed by means of a plastic injection technique followed by plastination and production of sectional series. These gliding spaces were also examined on fixed and unfixed hands using plastic injection and subsequent dissection. A space was depicted between the proximal interphalangeal joint and the insertion of the dorsal aponeurosis on the distal phalanx of the finger, as well as a further bursa-like space over the proximal interphalangeal joint. A third space was also depicted between the metacarpophalangeal joint and the proximal interphalangeal joint, which displays a variable connection to the gliding canal of the respective extensor tendons. Methodical, functional and clinical aspects will be discussed. PMID- 8685807 TI - The pterygoid venous plexuses. AB - The pterygoid venous plexuses are closely adjacent to the lateral pterygoid m. and occupy a considerable part of the infratemporal fossa (ITF). We have conducted a study after injection of colored latex in 10 unemblamed subjects in order to define the arrangement of the venous network and to assess the frequency of the different types of plexuses found. In all the subjects symmetry was noted between the right and left plexuses, with predominance of the venous layer in the upper part of the ITF. The pattern most often encountered was plexiform and complex. The development of these plexuses follows that of the masticatory muscles, whose contraction promotes drainage and represents an alternative venous pathway for drainage of the cranial cavity. PMID- 8685808 TI - Measurement and relationship of the inclination angle, Alsberg angle and the angle between the anatomical and mechanical axes of the femur in males. AB - The present study was undertaken to determine whether there is a constant difference between the angle of inclination and the Alsberg angle and to evaluate statistical relationships between the inclination angle, Alsberg angle and the angle between the anatomical and mechanical axes of the femur. Measurements were taken from 50 male femurs (25 right and 25 left, aged 30-40 years) from the Anatomy Department, Cukurova University: inclination angle was determined between the neck and the shaft of the femur; Alsberg angle, between a line drawn through the base of the epiphyseal plate and shaft of the femur, and the angle between the anatomical and mechanical axes. The results showed that, for the right and left femurs respectively, the average inclination angle was 123.72 degrees and 125.96 degrees; the angle between the anatomical and mechanical axes was 6.24 degrees and 5.96 degrees; and the average Alsberg angle was 39.92 degrees and 40.61 degrees. The difference between the angle of inclination and the Alsberg angle in this study was 83.80 degrees and 85.36 degrees for the right and left femurs respectively. The correlation, coefficient between the angle of inclination and Alsberg angle was 0.96 and 0.93 for the right and left femurs respectively, while those between the angle between the anatomical and mechanical axes and inclination angle were -0.89 and -0.91 for the right and left femurs respectively. Furthermore, the correlation coefficient between the angle between the anatomical and mechanical axes and Alsberg angle were -0.88 and -0.90 for the right and left femurs respectively. PMID- 8685809 TI - Subacromial fat pad. AB - The subacromial fat was studied using cadaver dissections and Magnetic Resonance Imaging (MRI). We found that the subacromial fat is not loose connective tissue, but a fat pad surrounded by a fascia. The measurements of this fat pad are presented and the clinical relevance for orthopedics and radiology particularly for the impingement syndrome of the shoulder is discussed. PMID- 8685810 TI - MRI of anatomical variants of the wrist in women. AB - In the analysis of magnetic resonance (MR) images of the wrist joint, some structural variations may lead to misinterpretation. Our aim was to search for different anatomical variants and their MR characteristics on axial images. Two groups of patients with rheumatoid arthritis (thirty one) and carpal tunnel syndrome (sixty two), and a group of asymptomatic controls (fifty four) underwent bilateral MR axial wrist imaging from the metacarpal bases to the distal radiocarpal joint. The imaging techniques included spin echo (SE), turbo spin echo (TSE) and fast field echo (FFE) sequences, using 3 mm-slice thickness. Different anatomical variants including hypoplasia of the hamulus or hook of the hamate bone (4 cases), anomalous muscles (lumbricals) inside the carpal tunnel (2 cases), unusual location (5 cases) and double branching of the median nerve (14 cases), and aberrant median artery (one case) were detected. These variants, if unfamiliar to MR readers, may be misinterpreted as pathological features. PMID- 8685811 TI - Relationship between intrahepatic vessels and computer-generated hepatic scissurae: an in vitro assay. AB - Liver segmentation is a matter of increasing importance for radiologists, in particular with respect to accurate preoperative localisation of focal hepatic lesions. Procedures for delineating the segmental anatomy from CT or MR images are therefore much in demand. In this context, a convenient technique for generating the intersegmental scissurae by computer has recently been proposed [9]. The procedure, however, seemed questionable from an anatomical point of view. We therefore checked its relevance using anatomical vascular casts of post mortem livers and comparing the computer-generated scissurae with the actual course of the intrahepatic vessels. The results presented in this paper confirm that a rigid application of flat scissural planes is not able to render the real intrahepatic compartmentation. Only techniques considering the effective individual vascular anatomy can provide a correct determination of the hepatic segments. PMID- 8685812 TI - Assessment of normal clivus related to age with magnetic resonance imaging. AB - The signal intensity pattern cf normal clivus bone marrow related to age was studied on T1-weighted sagittal plain magnetic resonance images. Bone marrow in the clivus had a uniformly low signal intensity (grade 1) in 100% of the patients at 0-5 years and 96% of patients in the first decade (0-9 years). In the second decade there was a sharp decrease in the number of patients (43%) showing grade 1 clivus. Patients having mixed clivus signal intensity (grade 2) were mostly seen in the second decade (28.5%). Uniform high signal intensity (grade 3) was not observed under the age of 10. Grade 3 clivus pattern increased with age from the second decade, while grades 1 and 2 clivus bone marrow showed a marked decrease. PMID- 8685813 TI - The position of the aorta in relation to the vertebra in patients with idiopathic thoracic scoliosis. AB - One CT-scan at the central part of the vertebral body of the apical vertebra of 32 patients with right convex thoracic idiopathic scoliosis and one CT-scan of either T8 or T9 of 22 normal subjects are included in this study. The position of the aorta in relation to the apical vertebra of the scoliotic patients and the corresponding vertebra of the normal subjects was determined at the horizontal plane. The mean lateral translation of the aorta in relation to the mid axis of the vertebral body increased from 19.7 +/- 4.3 mm in the normal group to 26.4 +/- 4.1 mm in the scoliotic group (p = 0.0001). In the normal group the aorta was located 41.7 +/- 8.6 mm in front of a perpendicular line to the mid axis of the vertebral body and in the scoliotic group this distance was reduced to 30.0 +/- 9.0 mm making the position of the aorta more posterior in the scoliotic group (p = 0.0001). This was in accordance with a decreased mean kyphosis-lordosis index from 0.53 +/- 0.06 in the normal group to 0.46 +/- 0.07 in the scoliotic group (p = 0.01). The position of the aorta, also expressed as the angle formed between the aorta and the vertebral body, the "aorto-vertebral angle", was increased from 24.4 degrees +/- 6.9 degrees in the normal group to 41.4 degrees +/- 8.4 degrees the scoliotic patients, (p = 0.0001). The aorto-vertebral angle did not change significantly with increasing Cobb angle (p = 0.26) but was positively correlated to the vertebral rotation (p = 0.0001). An estimation of the length of the intercostal arteries revealed a significantly greater R (right)/L (left) index in the scoliotic patients 1.18 +/- 0.11 than in the normal subjects 1.08 +/- 0.06 (p = 0.0003). It is concluded that the rotation and the anterior displacement of the vertebral body in scoliosis result in a deviation of the aorta along the left (concave) side of the vertebral body to a more posterior position relative to the vertebral body with a possible increased length of the intercostal artery on the right (convex) side. PMID- 8685814 TI - An accessory mylohyoid muscle. AB - During dissection of the submandibular region of a forty year old male a unilateral left accessory mylohyoid muscle was revealed. This muscle was located between the left anterior belly of the digastric and left mylohyoid muscles. It arose from the left mylohyoid line of the mandible and was inserted into the lower portion of the mylohyoid raphe and hyoid bone. This unilateral accessory mylohyoid muscle is a rare anomaly, which is thought to contribute to the functional support of the floor of the mouth. PMID- 8685815 TI - An anomalous course of the interazygos vein. AB - During an anatomic dissection of the posterior mediastinum, an unusual course of the interazygos v. was noted. The hemiazygos v. ascended to the 8th thoracic vertebra, in front of the vertebral column. It left the column, ascending obliquely, and passing in front of the aorta and behind the oesophagus. This transverse segment, crossing the midline, is called the interazygos v. It may be confused with different lesions situated at this level: aneurysm, tumour or lymph node hypertrophy, during CT or MRI studies. Secondly, the surgeon must be aware of this azygos variation as a possible cause of haemorrhage during a procedure in this region. PMID- 8685816 TI - Variant high-origin radial artery: a bilateral case. AB - During a dissection of both upper extremities, an abnormally high origin of the radial a. was found on each side. However, the arterial patterns were not the same. On the right side, the radial a. arose 2 cm above the junction of the two roots of the median n. On the left side, the radial a. arose from the brachial a. 3 cm distal to the origin of the profunda brachii a. The course of these arteries in the forearm were normal. However, in the hand, on the right side, the contributions of the radial and ulnar aa. to the superficial and deep palmar arches were, unusually, equal. On the left side, the superficial palmar arch was formed as usual mainly by the ulnar a. and the deep palmar arch was formed mainly by the radial a. The high origin of the radial aa. in this case is explained on the basis of the embryologic development and is distinguished from the other common arterial variations in the upper limb. PMID- 8685817 TI - Temporal lobe arteriovenous malformations: surgical management and outcome. AB - BACKGROUND: Temporal lobe arteriovenous malformations (AVMs) represent a subgroup of intracranial AVMs with particular characteristics and management issues. METHODS: We performed a retrospective analysis of 24 consecutive patients with temporal lobe AVMs treated with surgical excision. Factors such as location, size, arterial feeders, venous drainage, and clinical follow-up were recorded for each. Results were compared with those of 132 patients with nontemporal lobe AVMs surgically treated over the same time period. RESULTS: Sixteen of the temporal AVMs were located in the convexity, six in the mesotemporal region, and two were predominantly intraventricular. The mode of presentation was seizure in 11 patients, hemorrhage in 7, headache in 4, and 2 were asymptomatic. Patients with convexity AVMs more commonly presented with seizures, whereas patients with mesotemporal or intraventricular AVMs were more likely to present with hemorrhage. One patient with subarachnoid hemorrhage from a basilar artery aneurysm died. Postoperatively, 2 patients (8.3%) had a new hemiparesis and dysphasia, 1 (4%) had a new dysphasia and hemianopsia, and 3 others (13%) were left with an isolated superior quadrant field deficit. Lasting surgical morbidity other than isolated field deficit was 13% for patients with temporal AVMs and 15% for those with nontemporal AVMs. CONCLUSIONS: Temporal lobe AVMs may be successfully resected using a direct microsurgical approach with limited morbidity and excellent prognosis for recovery. Most of the deficits relating to AVM hemorrhage and those of the immediate postoperative period improved significantly over the subsequent few months. PMID- 8685818 TI - Successful removal of cryptic arteriovenous malformation located at the upper ventral pons via subtemporal transtentorial approach. AB - BACKGROUND: Lesions located at the ventral portion of the brain stem are still difficult to access surgically. We report herein a case of ventral pontine cryptic arteriovenous malformation that was successfully removed via a subtemporal-transtentorial approach. CASE REPORT: An 18-year-old female patient experienced repetitive hemorrhagic attacks leading to a massive pontine hemorrhage with several neurologic deficits. Since angiography and magnetic resonance imaging failed to delineate the hemorrhagic origin, a combination of multiple approaches was initially attempted. The subtemporal-transtentorial approach made it possible to obtain an adequate operative view in this case. An angioma observed at the septum of the multilocular hematoma was totally removed. Pathologic examination of the resected specimen revealed it to be an arteriovenous malformation. Postoperatively, the patient showed unexpectedly good recovery despite the original massive pontine hemorrhage. CONCLUSIONS: Several surgical approaches to the ventral pons have been proposed in the literature. While the subtemporal-transtentorial approach was useful in our patient, multiple routes should be considered to access a massive lesion of unknown extent at the ventral pons. The unexpected recovery observed in our patient suggests that surgery is an option in the treatment of this type of lesion. PMID- 8685819 TI - Large diffuse arteriovenous malformation affecting the right cerebral and cerebellar hemispheres: case report. AB - A cerebral vascular malformation was triggered in a 24-year-old man by left hemiparesis resembling transient ischemic attack. Cerebral angiography revealed slight dilation of the right anterior cerebral artery, middle cerebral artery, superior cerebellar artery, and posterior inferior cerebellar artery, as well as marked capillary blush and dilation of medullary veins involving the right cerebral hemisphere, especially the frontal lobe and cerebellar hemispheres. This vascular malformation, a clinical rarity, seemed to be in the same family as diffuse arteriovenous malformation or "medullary venous malformation." Single photon emission computed tomography showed a decline in cerebral blood flow in the right cerebral hemisphere, which was the probable cause of the left hemiparesis. PMID- 8685820 TI - Transverse sinus dural fistula: combined surgical and endovascular approach: a case report. AB - BACKGROUND: The treatment of a large dural sinus fistula can be very difficult and complicated. The very extensive and complex nature of these malformations may require a combination therapy in the form of surgery and multistaged embolization. The transverse sinus fistula in our patient was fed by multiple large high-flow feeders and was draining retrograde into the superior sagittal sinus (SSS) and the cortical veins. The SSS did not fill in the late venous phase of the carotid angiogram, suggesting increased venous pressure. METHODS: A case of transverse sinus dural fistula is described that was managed by a combination of surgery and embolization. The complex nature of this malformation encouraged us to adopt a combination of multistaged embolization and surgery for the management and clinical control. The patient underwent embolization of multiple feeders from the branches of the external carotid artery. After this procedure, the patient underwent endovascular occlusion of the transverse sinus via the SSS. Throughout the endovascular treatment, the patient had concomitant intracranial pressure monitoring and SSS pressure monitoring, along with transcranial cerebral oximetry (TCCO). Despite this aggressive endovascular intervention, the fistula could not be completely closed. The patient then underwent surgical excision of the transverse sinus along with duraplasty and cranioplasty. RESULTS: The patient had a good recovery and posttreatment angiogram revealed normal antegrade flow in the SSS with no evidence of the fistula. The combined surgical and endovascular techniques are described and their use in clinical practice is discussed. CONCLUSIONS: The complexity of certain large dural sinus fistulae should not be underestimated. They may require a prolonged multistaged treatment for their total obliteration. Also, despite the large size and complexity of the disease, complete cure can be achieved. PMID- 8685821 TI - Evaluation of time-dependent thresholds of cerebral blood flow and transit time during the acute stage of cerebral embolism: a retrospective study. AB - BACKGROUND: Neurons within the ischemic penumbra are thought to be in a potentially reversible state of ischemic challenge. One therapeutic approach that is being actively explored is the recovery of function of cells within the ischemic penumbra through endovascular recanalization of cerebral arteries occluded with embolus. The purpose of this study was to determine the time dependent hemodynamic threshold for the prevention of irreversible ischemia in patients with acutely symptomatic internal and middle cerebral artery (MCA) embolism. METHODS: Thirty-six patients admitted within 6 hours of the onset of symptoms of acute cerebral ischemia, due to embolic occlusion of the major trunk of one of the arteries of the anterior cerebral circulation, were studied. On admission, both cerebral blood flow (CBF) and mean transit time (MTT) measurements were obtained following plain computed tomography (CT). All patients were treated by intraarterial administration of urokinase. MTT in the territory of the affected MCA divided by that in the territory of the unaffected MCA was defined as %MTT. RESULTS: A significant negative correlation was found between MTT and CBF. In patients with at least 19 mL/100 g/minute CBF and a maximum of 1.6 %MTT, no cortical infarction occurred whether or not recanalization was obtained. Cortical infarction did not appear in patients with 9 mL/100 g/minute residual CBF and infinite %MTT in whom recanalization was achieved within 2 hours of onset, in patients with 13 mL/100 g/minute residual CBF and 3.7 %MTT in whom recanalization was achieved within 2.5 hours of onset, and in patients with 14 mL/100 g/minute residual CBF and 2.8 %MTT in whom recanalization could be achieved within 3.5 hours of onset. CONCLUSIONS: CBF and MTT thresholds for conversion of reversible to irreversible ischemia can be rapidly determined by CT based technologies. This type of information should be clinically relevant to guiding the management of patients with cerebral embolism. PMID- 8685822 TI - Occult intrasacral meningocele associated with spina bifida: a case report. AB - We present a rare case of occult intrasacral meningocele associated with spina bifida and tethered cord syndrome in a 13-year-old female. The etiology is thought to be due to a dysraphic disorder. The pertinent literature is reviewed. PMID- 8685823 TI - Hair-braiding closure for superficial wounds. AB - A superficial scalp wound can be approximated by tying the hair on each edge of the wound, without shaving or using suture material. This technique is useful in selected patients with lacerated scalp wounds, and its technical details and indications are described. PMID- 8685824 TI - How neurotrophic factors protect brain against excitotoxicity. PMID- 8685825 TI - Cerebellopontine-angle lesion. PMID- 8685826 TI - Encephalopathy following heart-lung transplantation. PMID- 8685827 TI - Back to the roots of modern neurosurgery: neurosurgical pioneers in Halle an der Saale. AB - At the end of the 19th and the beginning of the 20th centuries, German surgeons played a large role in the development of neurologic surgery. Many of them, however, have not been fully appreciated by the neurosurgical community until now. Pioneering personalities like F. Krause and F. von Bramann have contributed considerably to the early establishment of standard neurosurgical principles and operative techniques. Alexander Stieda was their successor and kept alive the neurosurgical tradition in Halle until the end of World War II. This middle-sized city in Central Germany, with an old university where Martin Luther once taught, was especially privileged to be one of the places where some of the best qualified and restless surgeons have practiced neurologic surgery and done work in progress. This paper traces the biographies of the great old masters of German neurosurgery in search of the "Halle connection" to the progress of our field. PMID- 8685828 TI - The need for neurological surgery programs to be departments. AB - The Decade of the Brain has brought recognition of the contributions neurological surgery has made to modern medicine, and neurological surgery training programs are a cornerstone of these achievements. While neurosurgeons are celebrating their achievements, however, a number of social, political, and administrative issues threaten to undermine the future of these programs. We discuss the ramifications of departmental status to the future of neurological surgery. These include the implications for operative experience-for example, carotid endarterectomy, spine instrumentation, acoustic tumors-the economic impact of a department versus a division, the ability to direct research, administrative input at the institutional level, and self-determination. We discuss the requirements for programmatic change and recommendations for national support. PMID- 8685829 TI - Work force requirements for neurosurgery. PMID- 8685830 TI - "The strike that failed" Canadian physician strike, 1987. PMID- 8685831 TI - Cavernous sinus meningiomas. PMID- 8685832 TI - Subgaleal preservation of calvarial flaps. PMID- 8685833 TI - Angiographic workup of a CCF. PMID- 8685834 TI - [Tendon injuries/diseases of the shoulder joint]. PMID- 8685835 TI - [Shoulder injuries in sports. Interview by Christiane Wesloh]. PMID- 8685836 TI - [Critical considerations in arthroscopic stabilization of the unstable shoulder joint]. AB - There is increasing interest in arthroscopic techniques for stabilisation of unstable glenohumeral joints. Consequently, plenty of new surgical techniques are developed over the last few years. However, most of the authors just report on short term results. In the presented paper, the current indications for surgical treatment in shoulder instability are discussed. The different arthroscopic techniques are described in detail. The advantages and disadvantages in relation to the conventional open Bankart-operation are presented, and the technique related risks are discussed in detail. Considering the recent information in the literature and the personal experience, the open Bankart-procedure still serves as the golden standard. PMID- 8685837 TI - [Differential indications for so-called "lateral release" in treatment of chondropathia patellae]. AB - The success rate of the operation of lateral release for pain caused by the patella is reported as being between 14% and 99%. The choice between arthroscopic or open procedures does not seem to affect the results. The wide ranges of results probably reflects differences in patients selection or the method and investigations of follow up. The early term outcome usually show better results than long term follow up. This study evaluates the indications for the operation of lateral releases and discusses the result of 36 out of a total of 42 patients who were follow up for 3 years later surgery. We found that an insufficiency of dysplasia of the vastus medialis, the laxity of the capsule and soft ligaments, and a strong lateral retinaculum were important factors in the indication for this procedure. The quadriceps angle was also of prime importance, but the minor forms of patellar dysplasia played only a minor role. In the so-called hyperpression syndrome, where the patella has a strong tendency to move laterally, the simple lateral release is the single most successful operation. The indication for procedures additionally to the lateral release is examined. We found that in a case with an insufficiently guided patella, a weak capsule and ligaments, an additional capsule roughing should be performed. The presence of early degenerative changes in the joint predisposes to poor results in operations such as abrasion and pride drilling. The results in our study were assessed using the Lysholm score. Our results show that the most successful technique was the combination of an arthroscopy and an extraarticular open operation controlled by arthroscopic means. This technique was not associated with major complications such as haemarthrosis and consecutive prolonged postoperative rehabilitation. Overall we achieved a rate of 83% of good or satisfactory results at more than 3 years using the indications and techniques described above. PMID- 8685838 TI - [Stress fractures in childhood and adolescence]. AB - Etiology, epidemiology and topographic findings of stress fractures in children are shown in our retrospective study (1976-1994). Signs and symptoms may be misdiagnosed as malignant tumors or osteomyelitis. Stress fractures in children may result from normal activities and are located mostly at the proximal tibia. Conventional X-ray and -tomography are the goal in diagnostic. Typical radiological findings are demonstrated by case reports. PMID- 8685839 TI - [Frequency and intensity of spinal syndromes in sailing. A comparative study at Bodensee and in the normal population]. PMID- 8685840 TI - Reporting of pediatric lead toxicity a good idea. PMID- 8685841 TI - Hope for antitrust relief. PMID- 8685842 TI - Who's the boss? PMID- 8685843 TI - Diversity dilemmas. PMID- 8685844 TI - MBAs for MDs. PMID- 8685845 TI - Consider implications of handgun prohibition. PMID- 8685846 TI - Physicians should tell patients about plan limits. PMID- 8685847 TI - Physicians should temper managed care rhetoric. PMID- 8685848 TI - [The pancreas will occupy us increasingly. Interview by Klaus Reinhardt]. PMID- 8685849 TI - [Etiology and pathophysiology of acute pancreatitis]. AB - The pathophysiology of acute pancreatitis can be divided into four different pathogenetic principles. 1. Ductular: The ductular pathogenesis is characterized by the frequent association between migrating gallstones and acute pancreatitis. The causative mechanism consists of an intraductal pressure and permeability increase with consecutive premature enzyme activation. 2. Acinar: The acinar pathogenesis is based on autoactivation of pancreatic enzymes after misdirected basolateral secretion into the interstitium of the pancreas and/or by colocalization of lysosomes and proenzyme-rich zymogen granules inside the acinar cell. 3. Mixed ductular-acinar: The main entity of this pathophysiological concept is the acute alcohol pancreatitis. An increase of intraductal pressure, of duct permeability and a possible direct toxic effect seem to be responsible. 4. Microcirculation disturbance: An impairment of pancreatic microcirculation appears to play a key role in the progression of edematous to necrotizing pancreatitis and was demonstrated in all models of necrotizing pancreatitis examined so far. Causative factors are poor blood fluidity by hemoconcentration, intravascular hypercoagulability, an impairment of arteriolar inflow by vasospasms, of capillary flow by direct endothelial injury and edema, of venous outflow by thrombosis, leukocyteendothelium interaction and direct toxic injury by activated enzymes, kinins and other mediators. A specific and therapeutically successful approach represents the administration of dextran which antagonizes both systemic and local causes of microcirculatory impairment. PMID- 8685850 TI - [Acute pancreatitis: diagnosis]. AB - In the differential diagnosis of abdominal pain, acute pancreatitis may be diagnosed by its clinical features together with blood determinations and ultrasonographic findings. The primary diagnostic steps include the differentiation between biliary or non-biliary etiology of the disease. In biliary acute pancreatitis, ERCP with endoscopic sphincterotomy is recommended, although the benefit of this procedure has only been shown in patients with severe clinical courses. An early discrimination between edematous-interstitial pancreatitis [mild clinical course] and necrotizing pancreatitis [severe clinical course associated with local and systemic complications] is possible by daily CRP monitoring. In necrotizing pancreatitis, contrast-enhanced computed tomography is the next diagnostic step, and the patient should be transferred to an intensive care unit. To differentiate between severe sterile pancreatitis and infected pancreatic necrosis, ultrasonographic or CT-guided fine needle aspiration of the pancreatic inflammatory mass is suggested. Infected pancreatic necroses are associated with systemic septic complications, which are the main mortality factor and the major reason for operative treatment of necrotizing pancreatitis. PMID- 8685851 TI - [Acute pancreatitis: conservative therapy)]. AB - Conservative treatment of acute pancreatitis is symptomatic and depends on the severity of the disease. For treatment of mild pancreatitis, fasting and intravenous application of fluids and analgetics is usually sufficient. Patients with severe pancreatitis should be monitored in an Intensive Care Unit and may require antibiotics. For treatment of acute pancreatitis, a large number of interventions has been suggested. They include nasogastric tubes, drugs which reduce pancreatic and gastric secretion, and treatments which inhibit activated proteases. Controlled studies have shown that most of these measures are ineffective. The value of early ERCP in acute pancreatitis is still under debate. ERCP appears to be helpful in biliary pancreatitis, especially if choledocholithiasis is present. Surgery should be reserved to those patients who do not respond to conservative treatment. PMID- 8685852 TI - [Technique and outcome of surgical therapy in acute pancreatitis]. AB - The most important diagnostic step in the management of patients with acute pancreatitis is to discriminate between interstitial edematous and necrotizing pancreatitis. Measurement of necroses indicating parameters in the serum, like CRP and PMN-elastase are useful in detecting the necrotizing course of acute pancreatitis. While patients with acute edematous pancreatitis can be treated on a regular ward, patients with a necrotizing course of disease should be treated in the intensive-care unit. Patients with biliary acute pancreatitis should be examined by ERCP with the performance of a papillotomy with stone removal in case of impacted ampullary stones within 24 hours. Surgical decision-making in patients with necrotizing pancreatitis should be based on the development of septic signs due to infected pancreatic necrosis. The information about infected pancreatic necrosis can be easily obtained by a bedside ultrasound-guided fine needle aspiration and bacteriological examination of the aspirate [gram stain plus culture]. Patients without organ complications and with focal necroses should be treated conservatively while patients with persisting organ insufficiencies or progressive multiple organ failure despite maximum intensive care measures are candidates for surgical therapy. The procedure of choice in necrotizing pancreatitis is the careful removal of necrotic tissue [necrosectomy] followed and supplemented by a postoperative regimen for the continuous evacuation of further necrotic debris. For this postoperative therapeutical concept three comparable procedures are available today, the closed continuous lavage, the 'open packing technique' and the management by planned, staged re laparotomies. Hospital mortality in severe acute pancreatitis has been reduced to less than 15% by these procedures in experienced hands. PMID- 8685853 TI - [Chronic pancreatitis: diagnosis]. AB - Chronic pancreatitis is a chronic, inflammatory process leading to destruction of the exocrine tissue, filorosis, and in some patients a loss of endocrine function. Because chronic pancreatitis results in a permanent destruction of pancreatic tissue, exocrine and/or endocrine pancreatic insufficiency may follow. However, owing to the tremendous reserve of pancreatic function, insufficiency may be subclinical at least in the beginning of the disease. The diagnosis of chronic pancreatitis is not difficult; it is based on a typical medical history, specific imaging procedures, and pancreatic function testing. The main differential diagnosis is to separate chronic pancreatitis form pancreatic carcinoma. In the present summary, the different imaging procedures and pancreatic function tests are discussed. PMID- 8685854 TI - [Chronic pancreatitis: conservative therapy]. AB - Chronic pancreatitis is mainly due to longstanding alcoholism. In general treatment is based on drug therapy. The clinical appearance is determined by chronic pain, steatorrhoea and eventually by the onset of diabetes mellitus. Beyond other measures total avoidance of alcohol ingestion provides a condition of a more benign course of the disease. Treatment of pain consists of symptomatic therapy and prescription of pancreatic enzymes in order to lessen pancreatic stimulation by inhibition of feedback mechanisms. The same principle applies to the prescription of octreotide which is used only in selected cases since it has failed to prove general effectiveness. Symptoms of exocrine insufficiency are alleviated by substitution of pancreatic enzymes. Attention must be directed on dose and preparation of pancreatic enzymes being used. Treatment of pancreatogenic diabetes resembles therapy of type I diabetes mellitus. In principle treatment of chronic pancreatitis should be adjusted to the highly variable clinical appearance of the disease and requires a systematic approach. It has to be kept in mind that some complications of chronic pancreatitis [e.g. pseudocysts] may require surgical intervention. PMID- 8685855 TI - [Surgical therapy in chronic pancreatitis]. AB - In patients with chronic pancreatitis, surgical treatment is required when conservative approaches are unsuccessful in treating symptoms and complications of the disease. The indications for surgery are 1) recurrent abdominal pain which does not respond to analgesics and 2) duodenal, common bile duct and/or main pancreatic duct obstruction or stenosis. In addition, obstruction of the retropancreatic vessels with subsequent portal hypertension is an indication to operate. Over the last decades the surgical standards in the treatment of chronic pancreatitis have changed. Due to disappointing long-term results, pancreatic left resection and drainage procedures of the main pancreatic duct are limited only to a small number of patients. In a number of patients with chronic pancreatitis, inflammatory enlargement of the pancreatic head causes complications which require surgical treatment. In the past, the classical Whipple resection has served as the standard operation in these patients. However, the classical Whipple resection was initially inaugurated for pancreatic head malignancies, and in addition to resection of the pancreatic head it includes resection of the complete duodenum, the extra hepatic bile system and 2/3 of the stomach. The Whipple procedure's disappointing long-term results and especially its disappointing quality of life have led to the development of newer organ-preserving procedures designed to treat complications caused by chronic pancreatitis. The pylorus-preserving Whipple resection is a modification of the classical Whipple resection which avoids the resection of the stomach. Since its initial publication by Watson in 1945 and Traverso and Longmire in 1978, pylorus preserving Whipple resection has been performed by many surgeons for the treatment of chronic pancreatitis. However, the high incidence of postoperative diabetes mellitus following this operation is a major drawback that has limited its use. The duodenum-preserving pancreatic head resection was developed to selectively remove the pancreatic head subtotally by preserving the body and tail of the pancreas as well as the pylorus, the duodenum, and the extrahepatic biliary tract. With this organ-preserving operation all the pancreatic head related complications of chronic pancreatitis can be abolished without inducing diabetes mellitus. Excellent short- and long-term follow-up results prove the superiority of the duodenum-preserving pancreatic head resection over the classical and the pylorus-preserving Whipple resections in patients with chronic pancreatitis. Therefore, the duodenum-preserving pancreatic head resection should be adopted as a new standard operation in patients with chronic pancreatitis and pancreatic head-related complications. PMID- 8685856 TI - [Pancreatic carcinoma: diagnosis]. AB - Early detection, tumor diagnosis with histological proof and tumor-staging are the principle aims of diagnostic approaches in patients suffering from pancreatic cancer. Asymptomatic and small cancers are often missed since they produce no or no typical symptoms and no reliable screening methods are available. Symptomatic pancreatic cancers are often so advanced that only about 20-30% of patients qualify for curative treatment. The diagnosis of pancreatic cancer with histological characterization occurs by imaging techniques [sonography and CT scan with guided fine needle punction, MRI, ERCP with biopsy or aspiration cytology, endoscopic sonography] and in some cases by laparoscopy or laparotomy. The combined use of tumor markers [CA 19-9, CEA, elastase-1] support the diagnosis of pancreatic cancer. The same methods used for diagnosis are also used for the preoperative tumor staging. Unfortunately the accuracy of these methods is smaller than 77%. The involvement of lymph nodes, encasement of large vessels and small liver metastases or a peritoneal spread of the tumor may be difficult to visualize and the real extent of the disease may only be observed during laparotomy. PMID- 8685857 TI - [Pancreatic carcinoma: conservative and adjuvant therapy]. AB - Patient with pancreatic have a median age of 78 years and without treatment an average survival of only a few months. Tumor stage and patient will determine the therapy. Patients with metastases or a high surgical risk are treated symptomatically. Jaundice, nausea, pain, and anorexia are the most relevant symptoms. The main symptom requiring treatment are jaundice and pruritus due to extrahepatic biliary obstruction which can be relieved in most cases by endoscopic placement of a biliary endoprosthesis. Pancreatic cancer may be a highly painful disease. Therapeutic modalities include, in addition to antitumoral treatment, narcotic and nonnarcotic analgesics, neurolytic celiac blockage, psychological support, and the treatment of associated symptoms such as emesis and constipation. Although radio- or chemotherapy show positive responses in a subgroup of patients, average survival remains unchanged with monotherapy. In contrast, improved median survival following combined radio-and chemotherapy has been demonstrated both in patients with locally unresectable pancreatic cancer and in patients after curative tumor resection. PMID- 8685858 TI - [Pancreatic carcinoma: surgical therapy]. AB - The incidence of pancreatic diseases has increased over the last years. Low morbidity and mortality rates after pancreatic resection procedures and an increasing 5-years survival rate allow more liberal indications for operation. These better results are due to careful preoperative investigations, perfect surgical techniques and the use of Octreotide perioperatively to reduce morbidity and leakage rate. Therefore resections for cancer of the pancreas should be carried out whenever possible, as well in curative as in palliative attempt. We discuss the indications and contraindications of pancreatic resection. At last, the decision to perform a resection depends of the tumor extension found at the operation and of the surgeon's skill. Infiltration of the wall of portal or superior mesenteric vein and retroperitoneum are not always definitive criteria of non-resectability, as there is still the possibility of vessel resection or partial excision of the retroperitoneum followed by locoregional chemotherapy. Today encouraging results of pancreatic resections allow the surgeon to carry out pancreatic resections whenever possible in patients fit for the operation. These resections should be carried out by experienced surgeons who carry out more than 10 pancreas resections per year and achieve a mortality rate below 5%. PMID- 8685859 TI - [Prognosis in pancreatic carcinoma]. AB - Pancreatic cancer is one of the most frequent carcinomas of the human gastrointestinal tract. despite considerable progress in diagnosis, its prognosis has remained unchanged during the last years. Up to now, there is no possibility to screen patients for pancreatic carcinomas, and the symptoms of the disease are uncharacteristic and often misleading. Surgical treatment, with resection of the tumor is the only chance for cure, but for experienced pancreatic surgeons, an advanced tumor stage at the time of operation is a common finding. Large studies reveal the poor prognosis of the disease. Only 20-30% of all patients suffering from pancreatic cancer can be operated with curative intention. In 80-85% of all cases, the tumor has spread into peripancreatic lymph nodes. Thus, mean 5-years survival rates of 3 to 5% are commonly reported, and the median survival time after establishment of diagnosis is 4-6 months. Improvements in surgical technique and postoperative patient's care have led to an impressive decrease in the formerly considerable morbidity and mortality after pancreatic resection. If the tumor can be resected at an early stage and the regional lymph nodes are not involved, median 5-years survival rates of 20-40% are commonly reported. Further approaches include more radical surgical procedures with dissection of the entire peripancreatic region and resection of the upper abdominal blood vessels. Whether this new technique or a combination of operation, radiation and chemotherapy will improve the prognosis of the disease remains unclear. Large clinical trials are necessary to prove these assumptions. PMID- 8685860 TI - [Endocrine pancreatic tumors]. AB - Endocrine active islet cell tumors of the pancreas are rare and become clinically evident mainly by symptoms of hormone over-production (hypoglycemia, gastric ulcer disease, diarrhea etc.). The tumors may occur sporadically or in connection with the familial MEN-I syndrome. Diagnosis is verified biochemically and does not need further localization studies. Localization studies are important, however, intraoperatively and in detecting persistent or recurrent tumor disease. Principally endocrine pancreatic tumors are excised selectively with exception of MEN-I patients and patients suffering from "Nesidioblastosis", where subtotal resections of the pancreas are indicated. In case of malignant metastatic endocrine pancreatic tumors palliative therapies (surgery, embolization, chemotherapy, therapy of hormone excess etc.) are demanded to improve the quality of life in these patients, since they may survive for years despite their tumor burden. PMID- 8685861 TI - [Pancreas transplantation--indication, technique and results]. AB - Pancreas transplantation is the only therapeutic measure currently available to achieve long term normoglycemia and normal HbA1 levels in diabetic patients. A live long immunosuppression with it's side effects is the price payed for that treatment. Like in renal transplantation an alternative treatment is available for potential pancreas transplant recipients so that most transplant centers are willing to perform pancreas transplantation as a combined kidney pancreas transplantation in patients with diabetic nephropathy only. This article reviews indications, technique, results and complications of simultaneous kidney pancreas transplantation and pancreas after kidney transplantation. PMID- 8685862 TI - [Vitamin D deficiency. From "the English disease" to a disease among immigrants in Norway]. PMID- 8685863 TI - [Cervical cytology--still demands on quality improvement]. PMID- 8685864 TI - [Can heart failure be diagnosed by hormone tests?]. PMID- 8685865 TI - [Pro-atrial natriuretic factor is predictive for the clinical status of patients with heart failure]. AB - This study was undertaken in order to evaluate the relationship between N terminal proatrial natriuretic factor [1-98] and routinely available measures of clinical status. Odds ratio estimates demonstrated a much higher risk of presence of left ventricular dysfunction and dilatation, pulmonary hypertension, and New York Heart Association function class III or IV with increasing proANF values. Analysis is simple and can be of practical value as a supplement in the assessment of cardiac status in this heterogeneous population. PMID- 8685866 TI - [Anal cancer. A review]. AB - The article contains a brief review of anal carcinoma. Biopsy and histopathological examinations are extremely important to ensure correct diagnosis, as there is a great therapeutic difference between squamous cell carcinoma and adenocarcinoma in this region. Primary treatment for squamous cell carcinoma is chemoradiotherapy, while surgery is second line treatment. This regimen gives excellent locoregional tumour control with 70% long-time survival. The most serious problem now is the the development of distant metastases. The main diagnostic procedure, both for primary tumours and local relapses, is well performed digital anal palpitation. A Norwegian standard protocol for anal carcinoma has been prepared to ensure good quality diagnostic procedures, therapy and follow-up in these patients. PMID- 8685867 TI - [Ischemic colitis in young patients]. AB - Ischaemic colitis is an established clinical entity in the elderly, characterized by acute onset of abdominal pain, diarrhoea and rectal bleeding. Six women 20-49 years old have been admitted to our hospital with ischaemic colitis during the last seven years. One of the cases in described, followed by a discussion of associated factors and clinical aspects. We emphasize that ischaemic colitis is an important differential diagnosis of colitis even in younger patients. PMID- 8685868 TI - [Measurements of serum activity of creatine kinase and creatine kinase isoenzyme MB in suspected myocardial infarction. Experiences from a hospital material]. AB - Total creatine kinase and the creatine kinase isoenzyme MB activities were measured simultaneously in 767 serum samples from 592 patients with suspected myocardial infarction. The main and obligate finding was that in the 89 patients with verified infarction the fraction of MB-activity related to the total creatine kinase activity lay between 4 and 25%. In 72 patients diagnosed as not having an infarction this fraction tended to lie below 4%. However, false positives frequently occurred within the lower total creatine kinase activity range. PMID- 8685869 TI - [Treatment of uncomplicated gonorrhea in adults. New guidelines from the working group against gonorrhea]. AB - Only 229 cases of gonococcal infection were recorded in Norway in 1994 (population 4.3 million), as against more than 14,000 cases two decades before. Up to now aminopenicillins with probenecid have been the standard treatment. In 1994, 29% of the reported cases of gonococcal infection were caused by a betalactamase-producing strain. We now recommend treating uncomplicated gonococcal infections with a single oral dose of ciprofloxacin 500 mg, or ofloxacin 400 mg. Pregnant or lactating women should receive intramuscular injections of cefotaxim 500 mg, or spectinomycin 2 g. Test-of-cure is essential. Its main purpose is to discover resistant strains and reinfections. Thorough contact tracing is more important than ever. Culture verification, susceptibility testing and test-of-cure in all cases will influence the continuous reevaluation of these guidelines. PMID- 8685870 TI - [Nutritional rickets. An old disease with new relevance]. AB - Rickets caused by poor nutrition was widespread in Norway at the beginning of this century. Today it is a very rare disease among Norwegian children. During the last 20 years, however, it has become quite common among immigrant children who have come from developing countries to live in Norway. This is probably due to a combination of different factors such as maternal vitamin D deficiency, lack of vitamin D supplementation, long-lasting breast feeding, latitude (therefore little sunshine in winter) and lack of exposure to sunshine during the summer. The paper reviews the disease, with a special emphasis on clinical findings, diagnosis, treatment and prevention. PMID- 8685871 TI - [Vitamin D deficiency among pregnant women from Pakistan. How best to prevent it?]. AB - Vitamin D deficiency is common among pregnant Pakistani women now living in Norway. This study was carried out to evaluate a health programme consisting of free samples of vitamin D (10 micrograms/day) combined with information about vitamin D deficiency. 38 pregnant women were included in the 18th week of pregnancy (study group) and blood samples were taken both at inclusion and after delivery. In addition, 18 other Pakistani women (control group) were included after giving birth at the same hospitals during the same period. 83% (30/36) of the pregnant women (study group) were vitamin D deficient (calcidiol < 30 nmol/l) at inclusion. Only 33% (11/33) of the women took more vitamin D than 5 micrograms/day. 19 of the women agreed to having a new blood sample taken after delivery, and 56% (10/18) of these women were still vitamin D deficient. 76% (13/17) of the women in the control group were vitamin D deficient at delivery. In conclusion the study demonstrates that it can be difficult to prevent vitamin D deficiency in the Norwegian immigrant population just by providing information and free samples of vitamin D. PMID- 8685872 TI - [Physicians' view on drug therapy for hypertension. A questionnaire in the county of Hordaland]. AB - A questionnaire survey was conducted in Hordaland county to discover opinions on drug therapy for uncomplicated hypertensives with no other risk factors. The response rate was 66%; 179 general practitioners and 31 hospital doctors. The doctors were well informed about the documentation of the clinical benefit of various drugs. As regards the minimum blood pressure that was considered as warranting drug treatment, the majority of the doctors followed the recently issued national guidelines. For young patients the first choice drugs were beta blockers (27%), ACE-inhibitors (25%) or calcium-blockers (20%). For older patients 65% of the doctors preferred diuretics or beta-blockers. The majority (80%) based their choice of drug primarily on documentation of clinical value or absence of side effects. The doctors underestimated the cost of the newer antihypertensive drugs. PMID- 8685873 TI - [Birthing institutions and births in Norwegian counties in the early 1990s]. AB - Between 1972 and 1993 the number of hospitals and maternity homes providing obstetric help in Norway fell from 158 to 67. Most of the decline is explained by the closing down of maternity homes and obstetrical units in small hospitals, partly due to a reduction in number of births and partly to a deliberate drive towards giving birth in larger units. 16 of the 19 counties of Norway contained four or fewer obstetric institutions in 1993. Nevertheless, most of the 60,000 births took place in institutions with between 500 and 2,999 births annually. Births at home accounted for 0.3%, and births during transport for 0.2% of the total in 1990 and 1993. PMID- 8685874 TI - [Chronic fatigue syndrome and cognitive therapy]. PMID- 8685875 TI - [Mortality trends in Norway--an international perspective]. PMID- 8685876 TI - [Woman decide themselves whether they want guidelines]. PMID- 8685877 TI - [Do tough men and women tolerate the sight of blood?]. PMID- 8685878 TI - [Regional hospitals deteriorate as university clinics]. PMID- 8685879 TI - [Patients' experiences may yield valuable information on quality assurance]. PMID- 8685880 TI - [Rotation crossing, an attractive system for preventing introduction of disease]. PMID- 8685881 TI - [Streptococci or slurry pit ventilation?]. AB - This article describes a case of disturbed behaviour in weaners resulting in mutilation. The mutilations mainly consisted of ear biting and ear necrosis. During some periods all weaners were affected. Deaths occurred as a result of sepsis and meningitis, caused by Streptococcus suis type 1. There were many runts. The stable was as follows: the sections contained 160 weaners; the floor consisted of plastic slats with a 1-metre-deep slurry pit. The weaners were medicated extensively for the Streptococci, to little effect. A ventilation expert was called in and the diagnosis was 'variable air distribution patterns resulting in slurry pit ventilation'. To solve the problem a number of modifications were made to the ventilation system. The solution was found in attaching flaps under the floor, hanging down into the slurry at every pen partition and in the middle across the entire length of each section. In this manner all air circulation in the slurry pit was effectively ended. Thus in conclusion, mutilative behaviour, eg. ear biting and ear necrosis, can be caused by draught. Medication can provide temporary relief, but does not solve the problem. Only ending the air circulation in the slurry pit provided a lasting solution. PMID- 8685882 TI - [50-year anniversary Group Poultry Sciences. Poultry practice at the turn of the century]. PMID- 8685883 TI - [Spring symposium Group Horse Medicine on 6 March 1996 in Amersfoort. Top sport without doping is (not) possible!]. PMID- 8685884 TI - [Celebrations of 50, 100, 125 and 150 years veterinary medicine education in The Netherlands]. PMID- 8685886 TI - [Flumequine in rainbow trout: not so difficult]. PMID- 8685885 TI - [Pharmaceutical quality of amoxicillin-containing tablets for veterinary use]. AB - Before a veterinary drug is licensed for the Dutch market it has to comply to basic pharmaceutical standards. From the results of this study, carried out in the Spring of 1995, it appeared that many amoxicillin-containing tablets marketed in Holland do not fulfil these requirements. Only one third of the preparations complied with all criteria set by us. The preparations investigated originated from eight licence holders. The preparations from two licence holders satisfied our criteria. When choosing a veterinary drug, veterinarians should be aware of the considerable differences in pharmaceutical quality. PMID- 8685887 TI - [Pioneers: veterinarians from earlier times (14): Philippe-Etienne Lafosse]. PMID- 8685888 TI - [What is your diagnosis? Ectopic cilia]. PMID- 8685889 TI - ['Weaving' in horses]. PMID- 8685890 TI - Lymphocyte beta2-adrenergic receptors and plasma catecholamine levels in lead exposed workers. AB - The effect of lead exposure on beta2-adrenoceptor density and catecholamine response was studied in 26 male workers and 1 female worker, exposed to lead on average for 6 years. The systolic blood pressure in lead workers (101-160 mmHg, 124.4 +/- 14.7 mmHg) was found to be significantly higher than in controls (97 134 mmHg, 115.4 +/- 10.4 mmHg, p < 0.01) as was plasma norepinephrine (0.51 +/- 0.1 microg/liter vs 0.24 +/- 0.05 microg/liter, p < 0.01). The density of lymphocyte beta2-adrenergic receptors (Bmax) in lead-exposed workers was 86% lower than that in controls (0.15 +/- 0.08 vs 1.08 +/- 0.29 fmol/0.1 x 10(6) cells; p < 0.01). The dissociation constants (Kd) of [125I]iodocyanopindolol were 93.6 +/- 42.6 and 87.9 +/- 42.7 pM in lead-exposed workers and controls, respectively. Multiple linear regression analysis showed that elevation of systolic pressure was closely related to (a) blood lead levels, (b) decreased beta2-adrenergic receptor density, and (c) increased plasma catecholamine levels in lead-exposed workers. Linear regression analysis revealed that both plasma norepinephrine levels and beta2-adrenoceptor density (Bmax) were highly correlated with both systolic blood pressures and blood lead levels in lead exposed workers, and a highly significant negative correlation was found to exist between Bmax and plasma norepinephrine levels (r = -0.82, p < 0.001). These data therefore demonstrate that there is a close relationship between elevated plasma catecholamine levels, decreased beta2-adrenergic receptors, and elevated blood pressure in lead-exposed workers. PMID- 8685891 TI - Disulfiram and diethyldithiocarbamate intoxication affects the storage and release of striatal dopamine. AB - Acute intoxication and chronic therapy with the alcohol consumption deterrent dithiocarbamate disulfiram have been associated with several neurological complications perhaps involving the impairment of neurotransmitter pathways. In this study we have tested the hypothesis that dopaminergic malfunction is a critical component in disulfiram-evoked neurotoxicity. Disulfiram antagonized the in vitro striatal binding of [3H]tyramine, a putative marker of the vesicular transporter for dopamine, and the uptake of [3H]dopamine into striatal synaptic vesicles, with inhibitory constants (Ki) in the range of reported blood dithiocarbamate levels in treated alcoholics. Furthermore, disulfiram provoked a loss of radioactivity from [3H]dopamine-preloaded striatal vesicles, when added directly to the incubation mixture. Several metal-containing fungicide analogs were also potent displacers of specifically bound [3H]tyramine. Diethyldithiocarbamate (DDC), the major metabolite of disulfiram, had none of these effects. The intraperitoneal injection of a high dose of disulfiram and DDC into rats, mimicking acute intoxication, induced in vivo overflow of striatal dopamine from both a reserpine-sensitive (vesicular) and an alpha-methyl-p tyrosine-sensitive (cytoplasmic) pool. The vesicular component of in vivo dopamine release resulted mainly from a direct activity of disulfiram, on the organelles (interaction with the carrier for dopamine plus membrane permeabilization) and indirectly through the mediation of serotonergic 5-HT3 receptors. DDC acted poorly at the vesicle membrane, and the in vivo releasing effect of dopamine was only partially prevented by the inhibition of 5-HT3 receptors, thus suggesting the role of additional mechanisms. It is concluded that disulfiram intoxication may acutely disrupt dopamine balance, an effect probably underlying some of the central neurotoxic, extrapyramidal symptoms associated with dithiocarbamate overdose. PMID- 8685892 TI - Effects of the antihypoxic and neuroprotective drug, lubeluzole, on repolarization phase of canine heart assessed by monophasic action potential recording. AB - The cardiovascular effects of the antihypoxic and neuroprotective drug, lubeluzole, were investigated using beagle dogs anesthetized with halothane. Endocardial-contact electrode catheter was used for continuous monitoring of monophasic action potential (MAP), which could provide a precise information of repolarization phase. Intravenous administration of an efficacious dose of lubeluzole (0.63 mg/kg, n = 6) slightly decreased both the heart rate and the blood pressure. It did not change PQ interval and QRS width, while it significantly prolonged QT interval, corrected QT (QTc) and the duration of the MAP during the observation period over 60 min. The effects of drug on repolarization phase were late-onset and long-lasting compared with the time course of plasma drug concentrations, which changed as predicted by the two compartment theory of pharmacokinetics. Additional injection of lubeluzole (2.5 mg/kg, n = 6) showed qualitatively similar changes to those of lower dose, and did not induce the cardiovascular collapse in any dog. Neither afterdepolarization nor ventricular escaped beat was detected during the observation period. The drug concentration in cardiac tissue was correlated linearly with the plasma drug concentration at 60 min after the second drug administration. These results indicate that lubeluzole exerts only minor cardiovascular effects except the prolongation of the repolarization period. The monitoring of plasma drug concentration may be helpful to estimate the steady state distribution of drug to the heart, but less helpful to predict the QT prolongation. In future clinical trials, care must be taken with patients, especially those at risk to have prolonged repolarization. PMID- 8685893 TI - Cellular factors mediate cadmium-dependent actin depolymerization. AB - Cadmium exposure produces depolymerization of the actin cytoskeleton in several cultured cell lines, and we have previously shown that in renal mesangial cells this effect is caused by picomolar concentrations of cytosolic Cd2+. The present study was undertaken to explore further the basis of this action of Cd2+. Skeletal muscle actin was labeled with pyrene and rates of polymerization and depolymerization were followed in vitro by changes in fluorescence. Concentrations of 100 microM or higher Cd2+ increased the rate of polymerization while lower concentrations stabilized actin filaments. Because this is in contrast to the observation that Cd2+ favors depolymerization in cultured mesangial cells, we examined the role of cellular factors in modifying the actions of Cd2+ on the polymerization/depolymerization equilibrium. Inclusion in the in vitro polymerization assay of cytosol from mesangial cells pre-treated with 5 microM CdCl2 caused a decrease in the rate of polymerization and an increase in the rate of depolymerization, relative to cytosol from control cells. EGTA normalized these rates, indicating involvement of Ca2+-dependent factors. Likewise, cytoskeleton from Cd2+-treated cells caused a Ca2+-dependent decrease in actin polymerization. Ligand blotting with [125I]actin revealed loss of binding of a 93-kDa protein from the cytosol and an increase in binding of a 49 kDa protein in the cytoskeletal fraction upon treatment of mesangial cells with Cd2+. Based on their electrophoretic mobility and Ca2+ dependence of actin binding these are tentatively identified as members of the gelsolin and severin families, respectively. Thus, Cd2+ may exert its effect on the mesangial cell cytoskeleton by altering the levels or actin-binding activity of actin-associated proteins. PMID- 8685894 TI - Calcium channel blockers induce thymic apoptosis in vivo in rats. AB - We investigated the in vivo effect of structurally different calcium channel blockers (CCB) on rat thymus. Administration of verapamil (40 mg/kg ip), diltiazem (90 mg/kg ip), nifedipine (15 mg/kg ip), or nicardipine (10 mg/kg ip) induced apoptotic indices of 4.3, 4.0, 2.0, and 6.5, respectively, compared to 0.5 in the saline-treated control rats. Apoptosis was assessed by morphology and the apoptotic index was calculated using a computer-assisted image analyzer. Diltiazem had a rapid and substantial effect as evidenced by apoptosis at 1.5 hr and a 36% decrease in thymus weight by 24 hr. We were uncertain about the mechanisms by which CCB induced thymic apoptosis in vivo since in vitro studies have shown that increases in intracellular calcium cause apoptosis and that CCB prevent apoptosis. We sought insight into the mechanism by evaluating potential and known in vivo effects of these drugs. Neither verapamil nor diltiazem was found to elevate serum cortisol levels, a known trigger for apoptosis. Hypotension, a known response to CCB, does not appear to be causal factor since the potent hypotensive agent sodium nitroprusside (10 microg/kg, iv) did not cause a significant increase in thymic apoptosis. Calcium signaling may be important since the calmodulin antagonist chlorpromazine (60 mg/kg ip) was found to induce a 15-fold increase in apoptosis. Our observations suggest that calcium signaling is necessary for the survival of the T lymphocytes in the thymus. PMID- 8685895 TI - Different mechanism of saturation of acetaminophen sulfate conjugation in mice and rats. AB - Sulfation of acetaminophen is a high-affinity and low-capacity conjugation pathway in rats. It is thought that sulfation becomes saturated in rats at high doses of acetaminophen because of limited availability of the active sulfate donor, 3'-phosphoadenosine 5'-phosphosulfate (PAPS), the supply of which is, in turn, limited by the availability of its precursor, inorganic sulfate. The present study was designed to determine whether a similar mechanism is responsible for capacity-limited sulfation in mice. Saturation of acetaminophen sulfation occurs in both species; however, at the maximal rate of sulfation, sulfate and PAPS concentrations were markedly decreased in rats but not in mice. Administration of sodium sulfate and the sulfate precursor N-acetylcysteine enhanced the formation of acetaminophen sulfate in rats, but not in mice. Mice exhibited lower activities of hepatic PAPS synthetic enzymes (i.e., ATP sulfurylase and APS kinase) and sulfotransferase than rats, which may in part be responsible for their lower capacity to sulfate acetaminophen. In addition, administration of acetaminophen further decreased phenolsulfotransferase activity in mice. In rats, administration of acetaminophen did not influence hepatic sulfotransferase activity. These observations suggest that while the capacity of rats to sulfate acetaminophen is limited by the availability of PAPS, in mice it is limited by sulfotransferase activity. PMID- 8685896 TI - 4-Hydroxynonenal-induced cell death in murine alveolar macrophages. AB - Oxidative stress is known to cause apoptosis in many cell types, yet the mechanism of oxidative stress-induced apoptosis is not clear. Oxidative stress has been described to cause peroxidation of polyunsaturated fatty acids. 4 Hydroxynonenal (HNE) is a diffusible product of lipid peroxidation and has been shown to be toxic to cells. In this study, the effects of HNE on isolated alveolar macrophages (AM) from two murine strains (C3H/HeJ and C57BL/6J) were examined. HNE induced the formation of protein adducts in AMs from both strains of mice in a dose-dependent manner, and the amounts of HNE-protein adducts formed in cells from both strains were very similar. In the HNE dose range from 1 to 100 microM, AMs from both strains had very little necrosis as shown by trypan blue staining. However, AMs from both C3H/HeJ and C57BL/6J mice had extensive apoptosis at 100 microM HNE, but little or no apoptosis at 25 microM HNE. Furthermore, AMs from C57BL/6J mice had significant apoptosis at 50 microM HNE while AMs from C3H/HeJ mice had no significant apoptosis at this dose. At low doses of HNE (10 to 25 microM), there was induction of heme oxygenase 1. The data indicated that HNE induces apoptosis in murine macrophages, and cells from different strains of mice have different sensitivities to the HNE-induced apoptosis. The cause of the difference in susceptibility is not known, but it is possible that different stress response and/or apoptosis-regulating proteins may be in part responsible. Our observation that a product of lipid peroxidation causes apoptosis suggested that it might be a mediator for oxidative stress induced apoptosis. PMID- 8685897 TI - Fluoranthene-induced apoptosis in murine T cell hybridomas is independent of the aromatic hydrocarbon receptor. AB - Recent studies suggest that environmental chemicals such as polycyclic aromatic hydrocarbons (PAH) compromise the immune system in part through the induction of programmed cell death (apoptosis). Nevertheless, mechanisms through which PAH induce apoptosis remain elusive. In particular, the role of the 8S AhR remains controversial and the nature of intracellular signal transduction in PAH-induced apoptosis remains largely undefined. To extend previous studies to the T cell compartment and to develop a clonal system in which intracellular signals leading to PAH-induced apoptosis can be dissected, the ability of fluoranthene, a ubiquitous, but less well-studied PAH, to induce apoptosis in murine T cell hybridomas was evaluated. Particular emphasis was placed on the role of the 8S AhR. The data indicate that (1) three of four hybridomas studied undergo apoptosis within 8 hr of fluoranthene exposure; (2) fluoranthene induces growth arrest concurrent with apoptosis; (3) at doses sufficient to induce lymphocyte apoptosis, fluoranthene does not induce AhR nuclear translocation in cells expressing high AhR levels; (4) fluoranthene-responsive hybridomas do not express AhR mRNA or protein; (5) the Ca2+ chelating agent EGTA partially inhibits fluoranthene-induced apoptosis. These results (1) indicate the immunosuppressive potential of fluoranthene; (2) support a role for apoptosis in PAH immunotoxicity; (3) demonstrate that fluoranthene-mediated T cell death and growth arrest are AhR independent; and (4) illustrate similarities between PAH- and antigen-specific receptor-mediated apoptosis. These findings encourage consideration of AhR- independent events in PAH risk assessment. PMID- 8685898 TI - The effects of 2,5-hexanedione and acrylamide on myosin heavy chain isoforms of slow and fast skeletal muscles of the rat. AB - We examined the effects of 2,5-hexanedione (2,5-HD) and acrylamide (ACR) on the muscle fiber types and myosin heavy chain (MHC) isoform composition of the slow twitch soleus and fast-twitch plantaris muscles of rats. We employed two differently designed experiments with respect to the dosage levels and treatment periods for developing clinical neuropathies. When male Wistar rats were subcutaneously injected with 4.5 mmol of 2,5-HD/kg or 0.4 mmol of ACR/kg, 5 days a week, they developed paralysis of the hindlimbs in 4 weeks (high-dosage experiment). When they were subcutaneously injected with 3.5 mmol of 2,5-HD/kg or 0.35 mmol of ACR/kg, 5 days a week, paralysis of the hindlimbs did not develop until 6 weeks (low-dosage experiment). We examined mainly the rats treated with the neurotoxicants for 4 and 8 weeks in the high-and low-dosage experiments, respectively. Significant decreases in the maximum motor conduction velocity of the sciatic nerves were observed in the hindlimbs of the rats in both experiments. The weights of the soleus and plantaris muscles were significantly reduced in the 2,5-HD-treated rats in both experiments, while in the ACR-treated rats, the weights of both muscles decreased only in the low-dosage experiment. We could not detect any changes in the fiber type composition of the muscles by any of the treatments. However, biochemical analysis revealed decreases in the values (percentage) of the relative amounts of fast-type MHC IIa and IIb isoforms to total MHC isoforms in the 2,5-HD-treated rats, but not in the ACR-treated rats in the high-dosage experiment. In contrast, significant differences in the relative amounts of MHC isoforms were not observed after administration of the low dosage of 2,5-HD. These results suggest that 2,5-HD preferentially disorders the muscle fibers which contain the MHC II isoform. These effects may occur only after the relatively acute intoxication of 2,5-HD at a high dosage. PMID- 8685899 TI - Role of glucocorticoids in ethanol-induced decreases in expression of MHC class II molecules on B cells and selective decreases in spleen cell number. AB - Glucocorticoids have been implicated in some of the immunosuppressive effects associated with acute ethanol (EtOH) intoxication, but other neuroendocrine mediators that are induced by EtOH can also be immunosuppressive. The possibility that glucocorticoids may act additively or synergistically with other mediators to produce immunosuppression has not been fully investigated. In the present study, complementary methods were used to address this issue. EtOH dose responsively decreased the following parameters in the spleen in B6C3F1 mice: total cell number, mature B cell (IgM+IgD+) number, and expression of MHC class II molecules on B cells. These effects were most pronounced 12 hr after administration of EtOH. The glucocorticoid antagonist, RU 486, completely or partially blocked these effects. Thus, glucocorticoids seem necessary for full expression of these immunological changes in EtOH-treated mice. To determine if glucocorticoids are also sufficient to cause these effects, corticosterone was administered to achieve serum levels and kinetics comparable to those in EtOH treated mice. This decreased the expression of MHC class II molecules on B cells to the same extent as treatment with EtOH. However, the other parameters were not affected by administration of corticosterone. Thus, corticosterone is necessary and sufficient to decrease expression of MHC class II molecules on splenic B cells, but other mediators in addition to corticosterone are required to decrease total spleen cell number and the number of mature B cells in the spleen. PMID- 8685900 TI - The impact of dose rate on the neurotoxicity of acrylamide: the interaction of administered dose, target tissue concentrations, tissue damage, and functional effects. AB - Health agencies are often required to predict the effects of long term low level exposure in humans based on annual data involving short-term high-level exposures. Uncertainties in extrapolation can be, in part, based on potentially different mechanism associated with different exposure scenarios. This study evaluated the adequacy of short-term exposures to acrylamide for predicting neurotoxicity produced by long-term exposures. The neurotoxic effects of acrylamide (ip) were assessed in rats after acute (0-150 mg/kg), 10-day (0-30 mg/kg), 30-day (0-20 mg/kg), and 90-day (0-10 mg/kg) exposures. Behavioral endpoints included motor activity, grip strength, and the acoustic startle response. Histological examination of sciatic nerve and spinal cord was also performed. Internal and target tissue doses were estimated by measurement of the concentration of acrylamide in serum and sciatic nerve. Functional and pathological results demonstrated that the effects of acrylamide depended on the dose rate and that the neurotoxicity of acrylamide was less than that predicted by a strict dose x time relationship. Behavioral endpoints showed both qualitative and quantitative changes as a function of dose rate. Recovery of behavioral function in these studies was independent of the duration of dosing. Because duration of dosing had no impact on the kinetics of acrylamide, these data indicate that the toxicity of acrylamide is not due to an accumulation of acrylamide in the target tissue. The less than strict cumulative toxicity of acrylamide may result from an interaction between administered dose, tissue damage, and repair processes. PMID- 8685901 TI - Assessment of the role of glutathione conjugation in the protection afforded by anethol dithiolthione against hexachloro-1,3-butadiene-induced nephrotoxicity. AB - Administration of anethol dithiolthione (ADT) to rodents can afford protection against some chemically induced toxicities. The aim of the present study was to assess the effects of ADT on hexachloro-1,3-butadiene (HCBD)-induced nephrotoxicity in the rat and to determine the mechanism of its action. Renal integrity was evaluated by measuring urinary excretion of glucose, protein, and gamma-glutamyl transpeptidase and by histological evaluation. A 3-day pretreatment with ADT (300 mg/kg/day) protected against the toxicity of various doses of HCBD (ranging from 15.6 to 62.5 mg/kg). The pretreatment increased (1.4 fold) the nonprotein sulfhydryl content (NPSH) of the liver. However, it did not modify the biliary excretion of radiolabeled materials in [14C]HCBD- treated (20 mg/kg) rats, nor that of the bioactivated HCBD metabolite, S-(1,2,3,4,4 pentachloro-1,3-butadienyl)-glutathione (PCBG). Moreover, ADT pretreatment protected rats against the nephrotoxicity induced by PCBG (20 mg/kg) itself. The extent of covalent binding to kidney proteins of [14C]HCBD-derived metabolites was not modified by pretreatment with ADT. Incubation of rat kidney cortical slices in a medium containing 0.1 mM of the nephrotoxic glutathione (PCBG) or cysteine (PCBC, S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine) conjugates of HCBD for 30 min resulted in a 75% reduction in the slice/medium ratio of p aminohipurate (PAH) compared to that seen in controls. When the cortical slices were incubated with ADT (30 min, 0.2 mM) prior to incubation with the nephrotoxic conjugates, the reduction was only 33%. Neither the in vitro nor the in vivo treatments did modify the activity of renal cytosolic beta-lyase; however, the latter treatment caused an increase in NPSH content. A 15-min incubation of kidney cortical slices with glutathione (10 mM) resulted in a 5-fold increase of NPSH, but failed to prevent the reduction in PAH uptake caused by PCBG and PCBC. Altogether, the in vivo and renal slice data suggest that ADT protects rats against HCBD-induced nephrotoxicity by a mechanism that does not involve the modulation of HCBD conjugation with liver GSH, nor the modulation of the kidney NPSH level and beta-lyase activity. The mechanism of protection conferred to rats by an ADT pretreatment against HCBD-induced nephrotoxicity appears to take place in the kidney at a step beyond the generation of ultimate toxic metabolites derived from PCBC. PMID- 8685902 TI - Acute and chronic toxicity of aromatic amines studied in the isolated perfused rat liver. AB - Isolated perfused livers from male Wistar rats were used to study acute and chronic toxic effects of carcinogenic aromatic amines. We investigated the hypothesis that aromatic amines can generate reactive oxygen species as part of their metabolism. Concentrations of 200-400 microM of 2-acetylaminofluorene (AAF), N-hydroxy-AAF, trans-4-acetylaminostilbene (AAS), N-hydroxy-AAS, and N hydroxy-2-acetylaminophenanthrene in the recirculating perfusate were not toxic in a 2-hr exposure time as assessed by LDH efflux into the perfusate, glutathione excretion into bile, and changes of the beta-hydroxybutyrate/acetoacetate ratio in the perfusate. N-Acetoxy-AAF, however, was severely toxic. Menadione served as a positive control. It is concluded that exposures likely to occur in carcinogenicity studies with these aromatic amines will not be acutely toxic. In additional experiments the isolated perfused liver system was used to demonstrate chronic effects generated by feeding the carcinogenic dose of 0.02% AAF for up to 12 weeks. The following alterations were observed in livers from AAF-fed animals. excretion of glutathione into bile is drastically reduced after 5 or more weeks, increasingly less glucose is released into the perfusate, and oxygen consumption is constantly increased by 20% after 3 and more weeks of AAF feeding. Whereas the total glutathione level increased with time in homogenates of such livers, it decreased in the mitochondrial fraction. The results are interpreted as adaptive responses to chronic toxic effects of AAF which may be related to the promoting properties of this carcinogen. PMID- 8685903 TI - Subacute neurotoxicity induced in mice by potent organophosphorus neuropathy target esterase inhibitors. AB - The mouse is considered to be insensitive and the hen sensitive to clinical expression of organophosphorus-induced delayed neuropathy (OPIDN) which is associated with inhibition of neuropathy target esterase (NTE). This species difference is reevaluated with two optimized inhibitors of hen brain NTE by examining them for potential neurotoxic effects in mice. 2-Octyl-4H-1,3,2 benzodioxaphosphorin 2-oxide (OBDPO) and ethyl octylphosphonofluoridate (EOPF) inhibit mouse brain NTE in vitro by 50% at 0.12 and 0.02 nM and induce neurotoxic signs in mice at 10 and 5 mg/kg, respectively. The action of these compounds in both l- and 6-month-old mice, sometimes after early transient cholinergic signs, involves ataxia, paralysis, and death in 1 to 3 days and is accordingly referred to as subacute neurotoxicity. The neurotoxic signs are associated with brain edema and severe vacuolation in the grey matter of the brain and spinal cord, particularly the neuropile. Subacute neurotoxic signs are always associated with at least 80% inhibition of brain NTE activity 16-24 hr after treatment. Acetylcholinesterase and butyrylcholinesterase are much less sensitive than NTE to inhibition by OBDPO and EOPF both in vitro and in vivo. Selected carbamates, thiocarbamates, phosphinates, and sulfanyl fluorides are prophylactic agents and dipentyl 2,2-dichlorovinyl phosphate is a promoter for OBDPO-induced subacute neurotoxicity. Although this type of neurotoxicity in mice is similar to OPIDN in the correlation with NTE inhibition and the prophylactic action of reversible NTE inhibitors, it differs from OPIDN in the delay time prior to onset, the sensitivity of both young and old animals, and the high incidence of fatality. A full neuropathological study is desirable to further characterize this subacute neurotoxicity. PMID- 8685904 TI - Interaction with the aromatic hydrocarbon receptor, CYP1A induction, and mutagenicity of a series of diaminotoluenes: implications for their carcinogenicity. AB - The present study was undertaken to provide a rationale for the marked difference in carcinogenic potential among isomeric diaminotoluenes, in relation to their ability to induce their own bioactivation through CYP1A induction, their genotoxic potential, and their ability to bind to the cytosolic aromatic hydrocarbon (Ah) receptor. Of the four possible diaminotoluenes only the 2,3- and, to a lesser extent, the 2,4-isomer induced CYP1A activity. Similarly, only these two isomers could displace [3H]T-CDD from the hepatic cytosolic Ah receptor. In the presence of Aroclor 1254- induced microsomes, 2,4- and 2,6 diaminotoluene were potent mutagens in the Ames test. Only 2,4-diaminotoluene could autoinduce its activation. Of the four isomers only 2,4-diaminotoluene is an established carcinogen and this is compatible with the present observations that it is the only isomer that stimulates its own activation through CYP1A induction, is metabolically converted to genotoxic intermediates, and binds to the Ah receptor. 2,6-Diaminotoluene is recognized as a mutagenic noncarcinogen and in the present studies it elicited a positive mutagenic response in the Ames test but failed to induce CYP1A activity and its own activation, and could not bind to the Ah receptor even at concentrations as high as 5 x 10(-4) M. The present findings demonstrate that in vitro studies are very useful tools in predicting the carcinogenic potency of isomeric chemicals. PMID- 8685905 TI - Toxicokinetic modeling of dose-dependent formate elimination in rats: in vivo-in vitro correlations using the perfused rat liver. AB - The dose-dependent elimination of formate was investigated in the rat using both in vitro and in vivo systems. The in situ perfused liver was used to define the kinetics of hepatic metabolism and obtain initial in vitro estimates of the hepatic metabolism kinetic parameters. Formate was eliminated from the perfused rat liver following Michaelis-Menten kinetics. Estimates of the Michaelis-Menten parameters obtained from the perfused liver studies were used in a two compartment pharmacokinetic model of the dose-dependent elimination of formate in vivo. This model consisted of a central, well-mixed compartment and a urine compartment. Other features of the model included (1) endogenous production of formate, (2) Michaelis-Menten hepatic metabolism of formate, and (3) renal excretion consisting primarily of glomerular filtration and saturable tubular reabsorption. A good fit of the model to the observed in vivo data was obtained (overall r2 = 0.978). AR dose dependencies of the data could be adequately fitted using a single set of model parameters. Initial estimates of the Michaelis-Menten parameters, Vmax and Km, obtained from the perfused liver system, were within 40% of the final fitted values of these parameters in the in vivo model, indicating the utility of the perfused liver system for performing in vitro-in vivo correlations. PMID- 8685906 TI - The regulation by gender, strain, dose, and feeding status of the induction of multiple forms of cytochrome P450 isozymes in rat hepatic microsomes by 2,4,5,2',4',5'-hexachlorobiphenyl. AB - 2,4,5,2',4',5'-hexachlorobiphenyl (HCB) induces hepatic microsomal cytochromes P450 with a similar selectivity for responsive genes to phenobarbital (PB). CYP2Bl, CYP2B2, CYP2C6, CYP3Al, and CYP2Al each showed large strain differences in induction by HCB Fisher F344 >> Wistar Furth (WF) that were much more evident in female rats, paralleling previous observations with PB. These five P450s and epoxide hydrolase were, however, induced more effectively by HCB than by PB and strain differences were even larger. With HCB, strain differences in male rats were much more apparent than with PB. This change was not due to the greater HCB induction since a 2-fold lower induction was maintained even with a 10-fold lower dose of HCB. The sex and strain differences were seen both by immunoblot analysis and by form-selective enzyme activity assays. induction of CYP2B1, CYP2B2, and CYP3A1 by HCB was decreased 3-fold when starvation during the final 24 hr was replaced by continuous feeding. This effect was similar in each strain and therefore independent of the regulatory processes associated with the differential suppression of induction in WF rats. This modulation of induction by feeding was also seen with PB which caused only a 30% lowering of induction in continuously fed F344 rats. A 52-kDa microsomal protein (p52) was prominently induced by both HCB and PB after starvation, while minor induction of a 50-kDa microsomal protein (p50) also occurred after the same treatment. Furthermore, a 100-kDa microsomal protein (p100) was induced by HCB but not by PB and only in rats that were continuously fed. These results suggest that the induction of multiple forms of P450 following HCB treatment functions through the same PB stimulated pathway that shows a strain-dependent endocrine (GH/T3/testosterone) sensitive suppression mechanism. The induction of p5O, p52, and plOO by HCB suggests the presence of at least two additional hepatic response mechanisms for HCB. PMID- 8685907 TI - CYP2E1-dependent bioactivation of 1,1-dichloroethylene in murine lung: formation of reactive intermediates and glutathione conjugates. AB - We investigated the cytochrome P450-dependent metabolism of 1,1-dichloroethylene (DCE) in murine lung microsomal incubations. The metabolites were identified as their glutathione conjugates or hydrolyzed products, analyzed by HPLC and quantified with [14C]DCE. We determined the relative quantities of DICE metabolites formed in lung microsomal incubations and compared them to those produced in liver. Furthermore, we used antibody inhibition experiments to investigate the CYP2E1-dependent metabolism of DCE in lung. Our results demonstrated that reactive intermediates were generated from DCE in the lung microsomal incubations. The DCE epoxide (12.6 +/- 1.4 pmol/mg protein/min) was the major metabolite formed and was identified as two glutathione conjugates, 2 (S-glutathionyl) acetyl glutathione and 2-S-glutathionyl acetate. Lower levels of the acetal of 2,2-dichloroacetaldehyde (3.6 +/- 0.25 pmol/mg protein/min) were detected. The ratio of acetal to DCE epoxide was higher in lung (0.30 +/- 0.04) than in liver (0.12 +/- 0.02). Preincubation of microsomes with a CYP2E1 inhibitory monoclonal antibody resulted in a maximum inhibition of 50% in the formation of both the acetal and the glutathione conjugates derived from the DCE epoxide. These data demonstrated that lung CYP2E1 metabolizes DCE to reactive intermediates of which the DCE epoxide is both the major metabolite formed and an efficient scavenger of glutathione, implicating it as an important toxic species mediating DCE-induced lung cytotoxicity. PMID- 8685908 TI - Interindividual differences in 2H8-toluene toxicokinetics assessed by semiempirical physiologically based model. AB - Recent applications of physiologically band toxicokinetic (PBTK) models have used animal to human scaling, the hypothetical average man, and Monte Carlo techniques to estimate human exposure to toxicants. Our study built a PBTK model suitable for person-specific dosimetry. Individual measurements of age, ventilation rate, blood/air partition coefficient, body weight, and adipose tissue fraction were made on 26 male subjects exposed to 50 ppm 2H8-toluene and 50 ppm toluene for 2 hr at rest, with collection of venous blood samples for 120 hr postexposure. Fitted lung metabolism was a novel feature of the PBTK model, used to explain a systemic clearance of 2H8-toluene well in excess of hepatic blood flow. A 10-fold interindividual range in venous concentrations was found. Subject-specific modeling explained 91% of the observed data variability, compared to 53% using literature values for model parameters. Body weight, adipose tissue fraction, and blood/air partition coefficient were correlated with terminal half-life, steady state volume of distribution, and terminal volume of distribution. Lung metabolism was correlated with systemic clearance and terminal half-life. Interindividual differences in lung metabolism resulted in divergent predicted fractions of 2H8-toluene in the body at 2 and 100 hr. An increased adipose fraction led to lower blood concentrations up to 8 hr postexposure, and simulations showed that at 98 hr, adipose tissue contained 97-99% of 2H8-toluene in the body. Use of subject-specific model parameters greatly improved model fit and demonstrated interindividual differences in toxicokinetics. PMID- 8685909 TI - Nonprotective effects of extracellular metallothionein. AB - Metallothionein (MT) is a small, cysteine-rich protein that is readily induced by exposure to heavy metal cations. In previous work, we have demonstrated that MT has several significant immunomodulatory properties. MT decreases antigen specific humoral responses in vivo and inhibits the ability of T cells to proliferate in response to antigen presented in vitro. To further characterize the mechanism by which this protein inhibits responsiveness to antigen, we have examined the effects of MT on cell viability in an antigen-presentation assay. MT (20 microM) caused substantial death to both lymphocytes and monocytes after 3 days of culture. The observed toxicity cannot be attributed to either increased superoxide radical generation or to production of tumor necrosis factor by MT treated macrophages. Fractionation of supernatants from MT-treated cells suggests that the agent responsible for causing cytotoxicity is a soluble factor of at least 30 kDa. These results counter the perception that metallothionein uniformly plays a protective role in metal-stressed individuals. PMID- 8685910 TI - Increased neutrophil adherence to endothelial cells exposed to asbestos. AB - Inhalation of asbestos may activate the pulmonary endothelium to promote an inflammatory cell phenotype that participates in the development of pulmonary fibrosis. However, little is known about the effects of asbestos on endothelial cell function. Therefore, endothelial cells were exposed to chrysotile and crocidolite asbestos for up to 72 hr to investigate the effects of noncytotoxic concentrations of asbestos on cell function. Noncytolytic concentrations of chrysotile and crocidolite caused localized changes in cell morphology, resulting in activation of endothelial cells to a vacuolated, "spindle-shaped" morphology at sites of fiber deposition. The adherence of neutrophils (PMN) to control and asbestos-treated cultures was examined to determine the functional significance of this altered morphology. Chrysotile asbestos caused a time-dependent, 2- to 4 fold increase in PMN adherence that was localized to spindled endothelial cells in close contact with fibers. Monoclonal antibodies against intercellular adhesion molecule-1 (ICAM-1) inhibited this asbestos-induced PMN adherence. Solution hybridization demonstrated a 2.5-fold increase in steady-state levels of ICAM-1 mRNA in cells exposed to chrysotile asbestos for 8 hr. Exposure to crocidolite asbestos resulted in similar alteration in cell morphology and increase in PMN binding to endothelial cells, while a physically similar nonasbestos fiber, refractory ceramic fiber-1 did not cause morphologic change or increased PMN binding. These data suggest that asbestos fibers can specifically and directly activate endothelial cells, resulting in an activated cell morphology, increased ICAM-1 expression, and enhanced PMN adherence. PMID- 8685911 TI - Influence of the halogen-substituent pattern of fluoronitrobenzenes on their biotransformation and capacity to induce methemoglobinemia. AB - In the present study both the biotransformation patterns and the capacity to induce methemoglobinemia of a series of fluoronitrobenzenes were investigated. This was done to investigate to what extent variation in the number and position of the halogen substituents influence the metabolic fate of the fluoronitrobenzenes, thereby influencing their capacity to induce methemoglobinemia. The results obtained were compared to the effect of the fluorine substituent patterns on the calculated electronic characteristics and, thus, on the chemical reactivity of the fluoronitrobenzenes. Analysis of the in vivo metabolic profiles demonstrates a dependence of the extent of nitroreduction, of glutathione conjugation, and of aromatic hydroxylation with the pattern of halogen substitution. With an increasing number of fluorine substituents at electrophilic carbon centers, 24-hr urine recovery values decreased and fluoride anion elimination increased, due to increased reactivity of the fluoronitrobenzenes with cellular nucleophiles. In vitro studies even demonstrated a clear correlation between calculated parameters for the electrophilicity of the fluoronitrobenzenes and the natural logarithm of their rate of reaction with glutathione or with bovine serum albumin, taken as a model for cellular nucleophiles (r = 0.97 and r = 0.98, respectively). Increased possibilities for the conjugation of the fluoronitrobenzenes to cellular nucleophiles were accompanied by decreased contributions of nitroreduction and aromatic hydroxylation to the overall in vivo metabolite patterns, as well as by a decreased capacity of the fluoronitrobenzenes to induce methemoglobinemia. In vitro studies on the rates of nitroreduction of the various fluoronitrobenzenes by cecal microflora and rat liver microsomes revealed that the changes in the capacity of the fluoronitrobenzenes to induce methemoglobinemia were not due to differences in their intrinsic reactivity in the pathway of nitroreduction, leading to methemoglobinemia-inducing metabolites. Thus, the results of the present study clearly demonstrate that the number and position of fluorine substituents in the fluoronitrobenzenes influence the capacity of the fluoronitrobenzenes to induce methemoglobinemia, not because their intrinsic chemical reactivity for entering the nitroreduction pathway is influenced. The different methemoglobinemic capacity must rather result from differences in the inherent direct methemoglobinemic capacity and/or reactivity of the various toxic metabolites and/or from the fact that the halogen substituent pattern influences the electrophilic reactivity, thereby changing the possibilities for reactions of the nitrobenzenes with glutathione and, especially, other cellular nucleophiles. When the number of fluorine substituents increases, the electrophilicity of the fluoronitrobenzenes can become so high that glutathione conjugation is no longer able to compete efficiently with covalent binding of the fluoronitrobenzenes to cellular macromolecules. As a consequence, it can be suggested that with an increasing number of fluorine substituents at electrophilic carbon centers in a nitrobenzene derivative, a toxic end point of the nitrobenzene other than formation of methemoglobinemia can be foreseen. PMID- 8685912 TI - Lead-induced alterations of glial fibrillary acidic protein (GFAP) in the developing rat brain. AB - The developing nervous system is preferentially vulnerable to lead exposure with alterations in neuronal and glial cells of the brain. The present study examined early lead-induced alterations in the developing astrocyte population by examination of the developmentally regulated astrocyte specific protein, glial fibrillary acidic protein (GFAP). A developmental profile (Postnatal Day (PND) 6, 9, 12, 15, 20, and 25) for GFAP mRNA was generated for the cortex and hippocampus of developing Long-Evans hooded male rats under various lead exposure conditions: (1) prenatal (Gestational Day 13 to birth), (2) postnatal (Postnatal Day 1 to Postnatal Day 20), or (3) perinatal (Gestational Day 13 to Postnatal Day 20) exposure to lead acetate (0.2% in the drinking water of the dam). Control GFAP mRNA levels displayed a developmentally regulated profile of expression. In the cortex this was characterized by a transient elevation in peak level between PND 9 and PND 15 followed by a decline to within adult levels by PND 25. Under all lead acetate exposure conditions, the cortex showed an increase in the peak level of expression and extended the time of elevation of GFAP mRNA until PND 20. Levels of GFAP were elevated at PND 60 but not as early as PND 28. In the control hippocampus, levels of GFAP mRNA gradually increased until PND 20 followed by a sharp decline at PND 25. Postnatal and perinatal lead exposure followed a similar pattern; however, levels declined earlier at PND 20. Following prenatal lead exposure, levels of GFAP mRNA showed an earlier peak at PND 12 and a decrease as early as PND 15. By PND 60 protein level for GFAP was elevated in the postnatal lead exposure group only. As demonstrated by GFAP immunoreactivity, these lead induced elevations were not associated with astrocyte hypertrophy. Following a physical injury in the cortex, astrocyte reactivity was similar between lead exposed and control rats. These data suggest an alteration in the timing of astrocyte differentiation and maturation in the brain following developmental lead exposure. PMID- 8685913 TI - An in vitro study of m-dinitrobenzene toxicity on the cellular components of the blood-brain barrier, astrocytes and endothelial cells. AB - We have studied the effects of an industrial compound, m-dinitrobenzene (DNB), on cultured astrocytes and brain capillary endothelial cells in an in vitro blood brain barrier (BBB) model. In single cultures, the threshold DNB concentration that induced cell death, as assessed by morphology and lactose dehydrogenase leakage into the culture medium, was 1 mM for both cell types after 1 day of incubation. In cocultures, astrocytes showed a dose-response curve similar to that obtained in single cultures, while endothelial cells showed an increased sensitivity to DNB cytotoxicity. DNB induced a dose-dependent increase in glucose consumption and lactate production in both cell types in single cultures, although astrocytes appeared to be more sensitive than endothelial cells. The role of oxidative stress was also studied using the reduction of nitroblue tetrazolium as an index of generation of active oxygen species. A dose-dependent increase was observed for both cell types in single cultures, although this could not be prevented by the addition of superoxide dismutase to the culture medium. Addition of 0.3 mM carmustine to the culture medium increased the cytotoxicity of 0.5 mM DNB in both astrocytes and endothelial cells, indicating a role of oxidative stress in DNB-induced damage. Desferrioxamine (20 mm) completely protected endothelial cells from damage by 1 mM DNB, suggesting that hydroxyl radicals mediated at least part of the DNB neurotoxicity. However, astrocytic damage by 2 mM DNB was only partially prevented by desferrioxamine. We conclude that our in vitro model is suitable for studying interactions between astrocytes and endothelial cells in toxicological situations. PMID- 8685914 TI - Perfluorodecanoic acid, a peroxisome proliferator, activates phospholipase C, inhibits CTP:phosphocholine cytidylyltransferase, and elevates diacylglycerol in rat liver. AB - Perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) are peroxisome proliferators that cause hepatotoxicity in rodents. This study shows that PFDA activates liver phospholipase C (PLC) and inhibits CTP:phosphocholine cytidylyltransferase (CT). PLC cytosolic and microsomal activities were increased 1.4- and 1.7-fold, respectively. CT activates were decreased to 58% (cytosol) and 36% (microsome) of control values. PFDA also caused a threefold increase in liver diacylglycerol (DAG) concentration. PFOA had no effect on the enzyme activities or DAG concentration. Together with previous results, these data suggest that PFDA activates a phosphatidylcholine-specific PLC causing an increase in liver phosphocholine and DAG. These effects are discussed in relation to cellular signalling processes that may provide a mechanism for PFDA-induced hepatotoxicity. PMID- 8685915 TI - The effects of inhibitors of cyclo-oxygenase, lipoxygenase and nitric oxide synthase pathways on the toxicity of hydroxyurea in adrenalectomized rats. AB - Our previous observations on the toxic effects of hydroxyurea (HU) in adrenalectomized (ADX) rats prompted us to suggest that these effects might be mediated by an increased synthesis of proinflammatory cytokines, which display similar toxicological profiles (e.g. increased lethality in adrenal-ablated animals). The present study was aimed at investigating whether some of the mediators of the biological effects of pro-inflammatory cytokines (i.e. prostaglandins, leukotrienes, and nitric oxide) are involved in the severe HU toxicity seen in ADX rats. The latter were treated over a 5-day period with HU alone or HU plus specific inhibitors of prostaglandin, leukotriene and nitric oxide synthetic pathways. Mortality was recorded throughout the experiments. Results showed that, while corticosterone and dexamethasone afford significant protection against HU toxicity, the latter is not reduced and may even be aggravated by treatments with specific inhibitors of cyclo-oxygenase, lipoxygenase or nitric oxide synthase. PMID- 8685916 TI - Developmental toxicity of mono-n-benzyl phthalate, one of the major metabolites of the plasticizer n-butyl benzyl phthalate, in rats. AB - Mono-n-benzyl phthalate (MBeP), one of the major metabolites of the plasticizer n butyl benzyl phthalate, was evaluated for developmental toxicity in Wistar rats. Rats were given MBeP by gastric intubation at 0, 250, 313, 375, 438 or 500 mg/kg from day 7 through day 15 of pregnancy. Significant decreases in the maternal body weight gains and food consumption during administration period were observed at 313 mg/kg and above and at 250 mg/kg and above, respectively. Significant increase in the incidence of postimplantation loss per litter was found at 438 and 500 mg/kg. The incidences of fetuses with external malformations at 438 mg/kg, of fetuses with skeletal malformations at 313 mg/kg and above and of fetuses with internal malformations at 375 mg/kg and above were higher than those in the control group. Defects in the cervical and thoracic vertebrae, ribs and kidney were frequently observed. PMID- 8685917 TI - Biomonitoring of diesel exhaust-exposed workers. DNA and hemoglobin adducts and urinary 1-hydroxypyrene as markers of exposure. AB - Diesel exhaust-exposed workers have been shown to have an increased risk of lung cancer. A battery of biomarkers were evaluated for their ability to assess differences in exposure to genotoxic compounds in bus garage workers and mechanics and controls. Lymphocyte DNA adducts were analyzed using the 32P postlabelling method with butanol and P1 enrichment procedures. Hydroxyethylvaline (HOEtVal) adducts in hemoglobin were measured by gas chromatography-mass spectrometry (GC-MS) and 1-hydroxypyrene (HPU) in urine determined using HPLC analysis. The exposed workers had significantly higher levels of all three biomarkers compared to the controls. Total DNA adduct levels were 0.84 fmol/micrograms DNA vs 0.26 in controls (butanol) and 0.65 fmol/micrograms DNA vs. 0.08 (P1 nuclease). Median HOEtVal adduct level in exposed workers was 33.3 pmol/g hemoglobin vs. 22.1 in controls. HOEtVal adducts correlated with HPU but not with DNA adducts. The levels of HPU in urine were 0.11 micromol/mol creatinine compared to 0.05 in controls. All three assays applied were sensitive enough to evaluate a low level of exposure to environmental pollutants, with postlabelling and GC-MS as the most sensitive assays. The study indicated that skin absorption of polycyclic aromatic hydrocarbons (PAH) might be an important factor to consider when studying PAH exposure from air pollution sources. PMID- 8685918 TI - Cadmium ions influence the chemiluminescence activity of murine splenocytes both in vitro and in vivo. AB - The luminol-enhanced chemiluminescence (CL) activity of splenocytes of mice of the strain (CBA x C57B1)F1 was monitored after treatment with Cd2+ (cadmium chloride) in both in vitro and in vivo experiments. Cd2+ (at concentrations of 1 microM-1 mM) increased the CL reaction of the splenocytes (2 x 10(6) cells/ml) in vitro in a dose-dependent manner, both instantaneously and after incubation for 1 h. In in vivo experiments, Cd2+ was administered in two ways. Following a 14-day administration of cadmium to mice in drinking water (300 mg Cd2+/l), the CL reaction of the splenocytes was significantly reduced. On the other hand, after i.p. administration of CdCl2 dissolved in PBS (2 mg/kg body mass, repeated seven times during 14 days), the metabolic activity of the phagocytes was increased. From the results it follows that cadmium affects the immune system. However, its toxicity is dependent on the route of administration. PMID- 8685919 TI - Mechanism of the formation of megamitochondria in the mouse liver induced by chloramphenicol. AB - Correlation between chloramphenicol-induced formation of megamitochondria in the mouse liver and oxidative stress was studied by lipid peroxidation analysis and electron microscopic technique. Chloramphenicol suppressed increases in the body weight and liver weight of experimental animals and at the same time induced a remarkable increase in lipid peroxidation in the liver during the formation of megamitochondria. A spin trapping agent, 4-hydroxy-2,2,6,6-tetramethyl-piperidine 1-oxyl, abolished all these changes induced by chloramphenicol. Namely, both the body weight and liver weight of chloramphenicol-treated animals stayed at the same levels as those of the control, and the formation of megamitochondria was completely suppressed. Allopurinol, a xanthine oxidase (EC 1.2.3.2) inhibitor, partly inhibited the changes induced by chloramphenicol, as described above. These results suggest that chloramphenicol-induced formation of megamitochondria is not simply ascribed to the suppression of the dividing process of mitochondria due to lowered protein synthesis in mitochondria but is intimately related to oxidative stress. Furthermore, the results obtained with allopurinol may indicate that enhanced levels of lipid peroxidation observed in chloramphenicol-treated animals are partly due to enhanced rate of the degradation of purine nucleotides catalyzed by xanthine oxidase. PMID- 8685920 TI - Immune reactions associated with cerebral amyloid angiopathy. AB - BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy (CAA) occasionally coexists with cerebral vasculitis. An immune system may influence deposition or degradation of the amyloid in cerebral blood vessels. The purpose of this study was to elucidate immune reactions associated with CAA. METHODS: In 11 elderly patients with sporadic CAA, 2 patients with Icelandic familial CAA, and 2 patients with CAA and granulomatous angiitis, the cerebrovascular amyloid proteins and infiltrating inflammatory cells were analyzed immunohistochemically. RESULTS: In both sporadic CAA (beta-protein amyloid angiopathy) and Icelandic familial CAA (cystatin C amyloid angiopathy), leptomeningeal and cortical vessels were associated with an increase or activation of monocyte/macrophage lineage cells. In the cases of CAA with granulomatous angiitis, the vascular amyloid was of beta-protein and associated with infiltration of many monocyte/macrophage lineage cells, which included multinucleated giant cells containing the amyloid in the cytoplasm as well as T cells composed of CD4+ and CD8+ subsets. Amyloid P component, which was reported to be a common component of amyloid deposits and to prevent phagocytic proteolysis of amyloid fibrils of beta-protein, was negative for the vascular amyloid in a case of CAA with granulomatous angiitis but positive in the others. CONCLUSIONS: In both the beta-protein and cystatin C amyloid angiopathies, cerebrovascular amyloid deposition was associated with an increase or activation of monocyte/macrophage lineage cells. Prominent reactions of monocyte/macrophage lineage cells admixed with CD4+ and CD8+ T cells (granulomatous angiitis) were occasionally associated with beta-protein angiopathy. In some of these cases, the absence of amyloid P component might be related to pathogenesis of the granulomatous reaction. PMID- 8685921 TI - Activated protein C resistance in ischemic stroke not due to factor V arginine506 ->glutamine mutation. AB - BACKGROUND AND PURPOSE: Resistance to activated protein C (APC), a natural plasma anticoagulant, is the most common identifiable risk factor for venous thromboembolic disease. One point mutation in coagulation factor V that renders it APC-resistant is found in >90% of APC-resistant venous thrombosis patients. To determine the prevalence of APC resistance and of this factor V mutation in stroke, we screened a group of ischemic stroke patients. METHODS: Hispanic ischemic stroke patients were screened using two different activated partial thromboplastin time-based assays. One assay using neat patient plasma determined APC resistance, and the other assay using patient plasma diluted into factor V deficient plasma determined APC-resistant factor V, including the Arg506-->Gln mutation. Results were compared with those in 31 Hispanic control subjects of similar ages. RESULTS: Six of 63 (9.5%) stroke patients had APC resistance compared with none of 31 (0%) control subjects. No patient or control subject had APC-resistant factor V, ie, the factor V Arg506-->Gln mutation. CONCLUSIONS: In Hispanic patients with ischemic stroke, the incidence (approximately 10%) of APC resistance is not caused by the factor V Arg506-->Gln mutation. APC resistance not caused by this factor V mutation may be a risk factor for ischemic stroke in this population. PMID- 8685922 TI - Five-year follow-up of patients after thromboendarterectomy of the internal carotid artery: Relevance of baroreceptor sensitivity. AB - BACKGROUND AND PURPOSE: In patients after myocardial infarction, baroreceptor sensitivity has been identified as a factor of prognostic relevance. This study was designed to assess the effects of an increased baroreceptor sensitivity in patients after surgery in the area of the internal carotid artery with respect to blood pressure variability, therapeutic interventions, and vascular events during a 5-year follow-up. METHODS: Receptor sensitivity before and immediately after carotid surgery was measured in 84 patients. Blood pressure variability, carotid artery status, and echocardiographic findings were assessed before and after surgery and at the end of follow-up. Vascular events as well as changes in blood pressure therapy during the follow-up period were evaluated. RESULTS: Significant negative correlations between an increase of baroreceptor sensitivity after surgery and the range of systolic (r=-.47; P<.001) and diastolic (r=-.33; P<.01) blood pressure were found for the immediate postoperative period. For the range of systolic blood pressure, this relation persisted (4.3 to 7 years after surgery) at the end of the observation period (r=-.38; P<.001). An inverse relation to the increase in baroreceptor function was also found for the average annual number of therapeutic interventions during follow-up (r=-.38; P<.001). Furthermore, the subgroup of patients without a postoperative increase of receptor sensitivity was characterized by a significantly higher risk of major vascular events (log-rank test, P<.018). CONCLUSIONS: Because an improvement of receptor sensitivity after carotid surgery is related to a long-lasting reduction of blood pressure levels and variability, baroreceptor function may be considered an indirect indicator for the later postoperative course. PMID- 8685923 TI - Importance of cerebrovascular disease in studies of myocardial infarction. AB - BACKGROUND AND PURPOSE: Myocardial infarction and stroke are both predominantly manifestations of atherosclerosis, yet stroke is commonly ignored in prognostic studies and therapeutic trials of ischemic heart disease. Our objective was to assess, in a community setting, the relative importance of stroke among patients at high risk for myocardial infarction. METHODS: We analyzed 1985 survey data from the National Academy of Science Twin Registry of white male veterans. To minimize confounding by genetic and environmental factors, we restricted our analysis to the rates of stroke and myocardial infarction among monozygotic twins counted as individuals or as twin pairs. RESULTS: Among 2764 monozygotic twins aged 58 to 68 years, the overall rate of myocardial infarction was 10% and stroke 3.1%. Among 2632 individual monozygotic twins (95%) with complete responses, the rate of stroke among men with a history of myocardial infarction was 7.5% (17/228) compared with 2.4% (58/2404) among those without myocardial infarction (odds ratio = 3.3, chi square 2 = 19.1, P<.001). A strong association between stroke and myocardial infarction was also found when the data were analyzed for twin pairs (chi square 2 = 135, P<.0005). CONCLUSIONS: Our results suggest that stroke, in addition to myocardial infarction, should be considered as an outcome in clinical investigations of ischemic heart disease. PMID- 8685924 TI - Evaluation of impaired cerebral autoregulation by the Valsalva maneuver. AB - BACKGROUND AND PURPOSE: Transcranial Doppler sonography has recently been used to describe cerebral hemodynamics during the Valsalva maneuver in normal human subjects. Since some changes in flow velocity during the Valsalva maneuver seem to reflect the brain's autoregulatory response to a decrease in cerebral perfusion pressure during the strain, we hypothesized that this method could identify vascular territories with impaired autoregulatory capacity. METHODS: Eight patients with unilateral (n=7) or bilateral (n=1) severe obstruction of the internal carotid artery and impaired vascular responses to the CO2 reactivity test and to dynamic autoregulation testing were studied. We compared changes in flow velocities and blood pressures during defined phases of the Valsalva maneuver in the patients with the results in a group of 17 normal volunteers. We defined two indices to evaluate autoregulatory capacity based on the response to the Valsalva maneuver. RESULTS: During the Valsalva maneuver, changes in flow velocity in the middle cerebral arteries ipsilateral to the lesions showed characteristic abnormalities compared with the normal pattern. Autoregulatory indices of these vessels as defined by the Valsalva maneuver were significantly different from those with normal vascular reactivity to CO2 (P<.0001). There were good correlations between an index based on the changes in flow velocity and blood pressure in phase II and the results of the CO2 test (r=.78; P<.0001) or those of dynamic autoregulatory testing (r=.6; P<.0001). CONCLUSIONS: Vascular territories with severely impaired vasomotor reactivity due to carotid obstruction can be identified by transcranial Doppler sonography by their pattern of flow velocity changes if their autoregulatory capacity is challenged during the Valsalva maneuver. PMID- 8685925 TI - Mitral valve strands in patients with focal cerebral ischemia. AB - BACKGROUND AND PURPOSE: Filamentous strands attached to the mitral valve are a recently described finding in occasional patients undergoing transesophageal echocardiography (TEE), but the frequency and clinical significance of these strands remain poorly defined. The purpose of the present study was to review the prevalence of mitral valve strands in patients undergoing TEE examination and to explore the relation of these strands to cardioembolic cerebral ischemia. METHODS: All patients with native mitral valves referred for clinically indicated TEE over a 2-year period at our institution were evaluated for the presence of mitral valve strands (defined as highly mobile filamentous masses <1 mm thick attached to the atrial surface of mitral leaflets). RESULTS: Of 968 study patients, mitral valve strands were identified in 22 individuals (2.3%). Mitral valve strands were significantly more common in patients referred for TEE as a result of a recent ischemic cerebrovascular event compared with patients referred for other study indications (6.3% versus 0.3%, respectively; P<.00001). Among patients < or = 50 years of age with likely cardioembolic stroke or transient ischemic attack, 16% were found to have mitral valve strands on TEE examination. In 9% of these young patients, no other TEE finding associated with cardioembolic risk was present. CONCLUSIONS: Filamentous strands attached to the mitral valve appear to represent another risk factor for embolic cerebral ischemia, particularly in patients < or = 50 years of age. PMID- 8685926 TI - Fluid-attenuated inversion recovery (FLAIR) for assessment of cerebral infarction. Initial clinical experience in 50 patients. AB - BACKGROUND AND PURPOSE: Our aim was to evaluate fluid-attenuated inversion recovery (FLAIR) sequence in the diagnosis of cerebral infarction with MRI. METHODS: A retrospective review was undertaken of 50 consecutive MRI studies ordered for suspected cerebrovascular accident. All studies included FLAIR and rapid acquisition with relaxation enhancement (RARE) T2-weighted spin-echo sequences. The two sequences were compared independently by four observers at two different institutions. Detectability of lesions and image quality were scored. RESULTS: Overall, FLAIR sequences proved superior in 10 patients, detecting acute cortical infarcts missed with RARE spin-echo technique in five patients. In five additional patients, improved characterization of chronic infarction and improved detection of microangiopathic deep hemispheric changes were observed. One brain stem infarct was missed with the FLAIR sequence. CONCLUSIONS: FLAIR offers advantages in detection of acute infarcts affecting the cortical ribbon, is a useful, rapid adjunct to conventional T2-weighted spin-echo sequences, and has the potential to replace these in the future. PMID- 8685927 TI - Do changes in oxygen metabolism in the unaffected cerebral hemisphere underlie early neurological recovery after stroke? A positron emission tomography study. AB - BACKGROUND AND PURPOSE: Whether an initial depression of function in the unaffected hemisphere ("transcallosal diaschisis") plays a role in early neurological recovery after acute stroke remains controversial. Previous studies were confounded by lack of acute-stage assessment with follow-up and by the problem of defining a suitable control group, since preexisting stroke risk factors may influence prestroke cerebral metabolism. We evaluated with positron emission tomography (PET) the relationships between unaffected-hemisphere (ie, contralateral) oxygen consumption (cCMRO2) and quantitative neurological assessments (and their respective evolution over time) after ischemic stroke. METHODS: Among 30 consecutive patients with first-ever middle cerebral artery ischemic stroke studied with the (15)O equilibrium method, we selected all survivors (n=19; mean age, 74.6 years) who were investigated both within the first 18 hours after stroke onset (PET1; mean, 11 +/- 4 hours) and 15 to 30 days later (PET2; mean, 24 +/- 10 days), with each patient serving as his/her own control. Neurological deficits were quantified using Orgogozo's middle cerebral artery scale (N score) at each PET session. Neurological changes were calculated as changes in the N score. A late CT scan coregistered with PET provided infarct topography and volume index. RESULTS: At PET2, we observed the overall expected neurological recovery. There was a nearly significant trend for a decrease in cCMRO2 from PET1 to PET2, especially for the neocortex (P=.08, F test); in a subgroup of eight patients with large infarcts, this CMRO2 decline was significant (P<.05) in the mirror region to the infarct. There was no significant correlation (Spearman's tests) between acute-stage cCMRO2 and same-day N scores or between changes in cCMRO2 versus changes in N score from PET1 to PET2 (any region). There was a nearly significant trend for lower PET2 cCMRO2 in the subgroup of eight patients with large compared with small infarcts (P=.06). CONCLUSIONS: We found no evidence for an influence of cCMRO2 on acute-stage neurological deficit or for a role of the unaffected hemisphere in early recovery after acute MCA ischemic stroke. The decline in unaffected-hemisphere metabolism from the acute to the subacute stage in the face of overall clinical recovery appears clinically irrelevant. The fact that the neocortical cCMRO2 at PET2 tended to be lower, and declined significantly from PET1 to PET2 in the mirror region in the subgroup of patients with large infarcts, suggests that this delayed effect represents transcallosal fiber degeneration. PMID- 8685928 TI - Complications and outcome after acute stroke. Does dysphagia matter? AB - BACKGROUND AND PURPOSE: The published data on the relationship between dysphagia and both outcome and complications after acute stroke have been inconclusive. We examined the relationship between these, using bedside assessment and videofluoroscopic examination. METHODS: We prospectively studied 121 consecutive patients admitted with acute stroke. A standardized bedside assessment was performed by a physician. We performed videofluoroscopy blinded to this assessment within 3 days of stroke onset and within a median time of 24 hours of the bedside evaluations. The presence of aspiration was recorded. Mortality, functional outcome, lengthy of stay, place of discharge, occurrence of chest infection, nutritional status, and hydration were the main outcome measures. RESULTS: Patients with an abnormal swallow (dysphagia) on bedside assessment had a higher risk of chest infection (P=.05) and a poor nutritional state (P=.001). The presence of dysphagia was associated with an increased risk of death (P=.001), disability (P=.02), length of hospital stay (P<.001), and institutional care (P<.05). When other factors were taken into account, dysphagia remained as an independent predictor of outcome only with regard to mortality. The use of videofluoroscopy in detecting aspiration did not add to the value of bedside assessment. CONCLUSIONS: Bedside assessment of swallowing is of use in identifying patients at risk of developing complications. The value of routine screening with videofluoroscopy to detect aspiration is questioned. PMID- 8685929 TI - Dementia after first stroke. AB - BACKGROUND AND PURPOSE: Cognitive deficits may significantly worsen the quality of life after stroke. Our aim was to determine the frequency of dementia in a consecutive series of previously nondemented patients between the ages of 40 and 79 years at 3 months after a first ischemic stroke. METHODS: All patients admitted to our department during an 18-month period who met the above criteria were visited and tested and underwent a CT scan 3 months after their stroke. Dementia was diagnosed according to criteria of the National Institute of Neurological Disorders and Stroke and AIREN, but cases with aphasia were not excluded. RESULTS: Of 304 patients admitted for stroke, 146 were eligible for study. Eleven refused to participate, 25 were dead at 3 months, and 110 were tested. Fifteen patients were demented (13.6%; 95% confidence interval [CI], 7.8% to 21.5%), and six had severe isolated aphasia, neglect, or memory deficit (5.4%). Excluding patients with aphasia, 5.0% of cases showed dementia (95% CI, 1.6% to 11.3%). The frequency of dementia was 24.6% (95% CI, 14.5% to 37.3%), considering only patients with supratentorial lesions and with residual deficits of elementary functions (paresis, sensory deficits) at the time of examination. Demented patients had significantly more diabetes (P<.029), atrial fibrillation (P=.032), aphasia at entry (P<.001), large middle cerebral artery infarctions (P=.001), and a more severe neurological deficit at entry (P=.003) and at 3 months (P=.001). At CT scan, demented patients had a larger mean volume of the recent lesion (P<.001) and more lesions in the frontal lobe (P=.041). An exploratory multivariate analysis selected age between 60 and 69 years (odds ratio [OR], 45.8; 95% CI, 2.9 to 726.0), diabetes (OR 59.4; 95% CI, 4.3 to 821.0), aphasia (OR, 14.8; 95% CI, 2.0 to 111.0), a large middle cerebral artery infarction (OR, 30.0; 95% CI, 2.7 to 334.0), and lesions of the frontal lobe (OR, 9.8; 95% CI, 1.3 to 72.8) as significant independent correlates of poststroke dementia. CONCLUSIONS: Dementia is relatively frequent after a clinical first stroke in persons younger than 80 years, and aphasia is very often associated with poststroke dementia. If aphasic patients are not considered, it may be necessary to screen a very large number of subjects to collect an adequate sample of demented cases. PMID- 8685930 TI - Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy. AB - BACKGROUND AND PURPOSE: In animals, drugs that increase brain amine concentrations influence the rate and degree of recovery from cortical lesions. It is therefore conceivable that antidepressants may influence outcome after ischemic brain injury in humans. We evaluated the effects of the norepinephrine reuptake blocker maprotiline and the serotonin reuptake blocker fluoxetine on the motor/functional capacities of poststroke patients undergoing physical therapy. METHODS: Fifty-two severely disabled hemiplegic subjects were randomly assigned to three treatment groups; during 3 months of physical therapy, patients were treated with placebo, maprotiline (150 mg/d), or fluoxetine (20 mg/d). Before and at the end of the observation period, we assessed activities of daily living by the Barthel Index, degree of neurological deficit by a neurological scale for hemiplegic subjects, and depressive symptomatology by the Hamilton Depression Rating Scale. RESULTS: The diverse treatments ameliorated walking and activities of daily living capacities to different extents. The greatest improvements were observed in the fluoxetine-treated group and the lowest in the maprotiline treated group. Furthermore, fluoxetine yielded a significantly larger number of patients with good recovery compared with maprotiline or placebo. These effects of the drugs were not related to their efficacy in treating depressive symptoms. CONCLUSIONS: Fluoxetine may facilitate or, alternatively, maprotiline may hinder recovery in poststroke patients undergoing rehabilitation. The effects of fluoxetine as an adjunct to physical therapy warrant further investigation, since treatment with fluoxetine may result in a better functional outcome from stroke than physical therapy alone. PMID- 8685931 TI - Hospitalization and case-fatality rates for stroke in Canada from 1982 through 1991. The Canadian Collaborative Study Group of Stroke Hospitalizations. AB - BACKGROUND AND PURPOSE: The purpose of this study was to estimate rates of hospitalization and in-hospital case-fatality for cerebral infarction and intracerebral hemorrhage in Canada and to describe variation in rates by age, sex, and calendar period. METHODS: Data were obtained from hospitalization databases for each of Canada's 10 provinces for the 10 fiscal years of 1982 through 1991. All hospitalizations of persons 15 years of age or older with a primary diagnosis at discharge coded 431, 434, or 436 according to the International Classification of Disease, 9th Revision, were included. Rates per 100,000 population were calculated for intracerebral hemorrhage and cerebral infarction, for men and women, and for five age groups. Annual age- and sex specific, 30-day, in-hospital case-fatality rates were also calculated. RESULTS: A total of 335,283 discharges for stroke were enumerated over the 10-year period (309,631 cerebral infarctions and 25 652 intracerebral hemorrhages). A significant decline of approximately 1% per year was observed for the rate of cerebral infarctions. For hemorrhages, the reverse was seen. For men there was a 44% increase over the 10-year period, and for women there was a 34% increase. In hospital case-fatality rates for cerebral infarctions increased with age but did not differ by sex when age was considered. For the five age groups of 15 to 54, 55 to 64, 65 to 74, 75 to 84 and > or = 85 years, rates were 6%, 8%, 12%, 18% and 27%, respectively. For intracerebral hemorrhage, the in-hospital case-fatality rates declined significantly over time from approximately 36% to 29%, 55% to 37%, 49% to 41%, 66% to 45%, and 72% to 59% for the five age groups, respectively. CONCLUSIONS: The possibility that these changes are artifactual could not be ruled out, but because there is no obvious risk in assuming that they are not, it would be prudent to investigate their causes further. PMID- 8685932 TI - Assessment of normal flow velocity in basal cerebral veins. A transcranial doppler ultrasound study. AB - BACKGROUND AND PURPOSE: Transcranial Doppler ultrasound has not yet been applied systematically to the analysis of the venous system and cerebrovenous disorders. Assessment of the intracranial venous system, however, would contribute to the understanding of cerebral hemodynamics and thus allow new possibilities for clinical application of the Doppler technique. Therefore, we demonstrated the validity of the transcranial Doppler technique in analyzing the basal cerebral veins. METHODS: Venous transcranial Doppler ultrasound was performed with a range gated 2-MHz transducer in 60 healthy volunteers in patients without central nervous disorders ranging in age from 10 to 71 years (mean +/- SD, 41.9 +/- 15 years). RESULTS: A venous signal away from the probe and adjacent to the posterior cerebral artery, considered to correspond to the basal vein of Rosenthal, was found in all subjects on at least one side. Mean blood flow velocity ranged from 4 to 17 cm/s (mean +/- SD, 10.1 +/- 2.3 cm/s). Analysis for age dependency revealed a trend of decreasing values with increasing age, exclusively caused by a significant reduction of velocity in men aged 40 years or older. No significant intraindividual side-to-side differences were found. A venous signal away from the probe and paralleling the middle cerebral artery, interpreted as corresponding to the deep middle cerebral vein, was found in 21.7% of the subjects with similar velocities. CONCLUSIONS: We have shown that transcranial Doppler methods can also be used for evaluation of the basal cerebral veins in both sexes, in differing age groups, and without major difficulty. The cerebral basal veins could be identified on the basis of their anatomic relation to specific arteries. PMID- 8685933 TI - Transcranial Doppler in the evaluation of internal carotid artery dissection. AB - BACKGROUND AND PURPOSE: A subject with dissection of the internal carotid artery (ICA) may present with a variety of symptoms, from headache to stroke. Thus far, it has not been possible to identify the subset of patients at risk for cerebral ischemia. Because the majority of these ischemic events are secondary to embolic phenomena, we used transcranial Doppler (TCD) evaluation with emboli monitoring to study 17 consecutive patients with ICA dissection treated at Harborview Medical Center, Seattle, Wash, during a 2-year period from 1992 until 1994. METHODS: Ten patients with ICA dissection secondary to trauma and seven with spontaneous ICA dissection were diagnosed by carotid angiography and studied by TCD from the time of diagnosis through initiation of therapy. Emboli monitoring was performed in the middle cerebral artery (MCA) ipsilateral to the dissection at the initial evaluation and intermittently thereafter to ensure that the emboli stopped with treatment. RESULTS: Emboli were detected in the MCA distal to the dissection in 10 of 17 patients (59%). Patients with microemboli detected by TCD presented with a stroke (70%) much more frequently than those without emboli (14%) (P=.0498). The presence of a pseudoaneurysm did not increase the risk of either microemboli or stroke. CONCLUSIONS: We have demonstrated a high incidence of intracranial microemboli in the MCA distal to carotid dissections and a significant correlation between the presence of emboli and stroke. TCD can therefore be used as an adjunctive tool to manage patients with suspected carotid dissection and may prove useful in evaluating the efficacy of treatment in reducing microemboli and subsequent stroke. PMID- 8685934 TI - Lipoprotein(a) in patients with acute cerebral ischemia. AB - BACKGROUND AND PURPOSE: In several cross-sectional studies, a high serum lipoprotein(a) [Lp(a)] level was found to be an independent risk factor for cerebral infarction. In a recent prospective study, however, no association was found between Lp(a) levels at baseline and future risk of stroke. Whether Lp(a) is a prognostic factor in a high-risk population of patients with acute ischemic stroke remains unclear. METHODS: We assessed Lp(a) level on admission to study its relationship with cardiovascular risk profile, stroke severity, and prognosis in 151 consecutive patients with acute cerebral ischemia. The mean follow-up period was 2.5 +/- 1.2 years. Lp(a) was measured by means of a solid-phase two site immunoradiometric assay. RESULTS: Increased Lp(a) levels were found in 53 (35%) of the patients with cerebral ischemia. Median (5th and 95th percentile) values of Lp(a) were 191 (12 and 1539) mg/L and 197 (10 and 1255) mg/L for patients with transient ischemic attack and patients with ischemic stroke, respectively. No relationship was found between Lp(a) levels and stroke severity (P=.68) or the occurrence of vascular events during follow-up (P log rank=0.81). CONCLUSIONS: We conclude that Lp(a) is increased in about one third of patients with acute cerebral ischemia, but it does not appear to be associated with the cardiovascular risk profile, stroke characteristics, or the prognosis of such patients. PMID- 8685935 TI - Felbamate protects CA1 neurons from apoptosis in a gerbil model of global ischemia. AB - BACKGROUND AND PURPOSE: Felbamate, a novel anticonvulsant that binds to the glycine site of the N-methyl-D-aspartate receptor, has been shown to have neuroprotective properties in vitro and in vivo. In a rat pup model of hypoxia ischemia, felbamate selectively reduced delayed death in hippocampal granule cells. The present study explores its neuroprotective potential in a gerbil model of global ischemia, in which good evidence exists that ischemia triggers apoptosis of CA1. METHODS: Gerbils were subjected to bilateral carotid occlusion for 5 minutes and then treated with felbamate (100 or 200 mg/kg IV) or vehicle. They were killed 3 days later, and the numbers of live and dead neurons in the CA1 sector of the hippocampus were counted at sterotaxically defined levels. RESULTS: Felbamate (200 mg/kg IV) administered after the release of carotid clamping did not change brain temperature but reduced neuronal death in CA1 from 332 +/- 60 cells per section of dorsal hippocampus in unmedicated gerbils to 62 +/- 12 cells in felbamate-treated animals (P<.001). A lower dose of felbamate (100 mg/kg post hoc) showed only a nonsignificant reduction of neuronal death. In the 200-mg/kg group, felbamate serum concentrations peaked at 162 microg/mL and were above 100 microg/mL for at least 3 hours, and brain levels reached 150 microg/mL at 1 hour. In the 100-mg/kg group, blood serum levels were well below 100 microg/mL. CONCLUSIONS: These results suggest that felbamate given post hoc is remarkably effective in preventing delayed apoptosis secondary to global ischemia but that effective neuroprotection requires doses higher than those used for anticonvulsant treatment. PMID- 8685936 TI - Cerebral oxygenation during cardiopulmonary resuscitation with epinephrine and vasopressin in pigs. AB - BACKGROUND AND PURPOSE: Administration of vasopressin during cardiopulmonary resuscitation (CPR) improves vital organ blood flow compared with epinephrine, but the effect of vasopressin on cerebral oxygenation and cerebral venous hypercarbia during CPR has not previously been studied. METHODS: Fourteen pigs were allocated to receive either epinephrine (0.2 mg/kg) or vasopressin (0.4 U/kg) after 4 minutes of ventricular fibrillation and 3 minutes of CPR. Cerebral blood flow was determined by radiolabeled microspheres, and arterial and cerebral venous blood gases were measured. RESULTS: Cerebral blood flow, measured before and 90 seconds and 5 minutes after drug administration, was 9 (3; 12), 25 (19; 27), and 18 (10; 23) mL/min per 100 g (median and 25th and 75th percentiles, respectively) in the epinephrine group and 12 (5; 16), 51 (48; 70), and 53 (45; 63) mL/min per 100 g in the vasopressin group (P<.05 at 90 seconds, P<.01 at 5 minutes between groups). Five minutes after drug administration, cerebral venous Pco2 was 63 (59; 68) mm Hg in the epinephrine group and 47 (43; 55) mm Hg in the vasopressin group (P<.01); at the same time cerebral venous pH was 7.18 (7.17; 7.20) and 7.26 (7.22; 7.36) (P<.01) in the epinephrine and vasopressin groups, respectively. Cerebral oxygen extraction ratio, calculated before and 90 seconds and 5 minutes after drug administration, was 0.42 (0.32; 0.57), 0.47 (0.41; 0.57), and 0.56 (0.56; 0.64) in the epinephrine group and 0.43 (0.38; 0.45), 0.38 (0.25; 0.44), and 0.35 (0.33; 0.49) in the vasopressin group (P<.05 at 90 seconds and 5 minutes). CONCLUSIONS: Compared with epinephrine, vasopressin not only increases cerebral blood flow but also improves cerebral oxygenation and decreases cerebral venous hypercarbia when administered during CPR in pigs. PMID- 8685937 TI - How good is intercenter agreement in the identification of embolic signals in carotid artery disease? AB - BACKGROUND AND PURPOSE: There has been concern regarding the reproducibility of the detection of embolic signals, particularly in patients with carotid artery stenosis in whom the signals are of low intensity. No published studies have examined inter-center agreement in reporting specific embolic signals or the factors responsible for any lack of agreement. We examined reproducibility between two centers in which widely differing proportions of embolic signals have previously been reported in patients with carotid artery stenosis. METHODS: Recordings from the middle cerebral artery of eight patients with ipsilateral carotid artery stenosis in whom embolic signals had been detected during a previously study were independently examined by three experienced observers in one center and by one experienced observer in another center. We calculated agreement within and between centers by estimating the probability that one observer would identify a specific embolic signal if other observers had identified it (a probability of 1 indicates complete agreement). The influence of different characteristics of the embolic signal on the probability of its detection as an embolic signal was determined. RESULTS: A high level of agreement in the identification of specific embolic signals was found. This was similar between all observers (.90), between the three observers in one center (.89), and between observers in the two different centers (.94). The probability of detection was independently related to the relative intensity of the embolic signal (P<.0001). It was less (although significantly) independently related to the position of the embolic signal in the cardiac cycle (P=.02), with signals in systole being more reliably detected. There was no independent relationship between the probability of detection and either the duration of the embolic signal or the velocity at the maximum intensity increase. The use of threshold intensity as a criterion for embolic signal detection increased interobserver agreement but reduced the sensitivity in detecting signals. CONCLUSIONS: The high level of interobserver agreement suggests that the technique is sufficiently reproducible for clinical use. PMID- 8685938 TI - SPECT using 99mTc-HMPAO versus neurological scales to predict outcome of acute cerebral infarction. PMID- 8685939 TI - Fish consumption and stroke incidence. PMID- 8685940 TI - Time course of diffusion imaging abnormalities in human stroke. PMID- 8685941 TI - Comparison of saccharides as osmotic impermeants during hypothermic lung graft preservation. AB - We have previously shown that the trisaccharide raffinose is largely responsible for the superior lung graft performance seen after storage in University of Wisconsin solution. To investigate the use of osmotic agents in perfusates for hypothermic lung graft storage, we compared saccharides of various molecular weights in an isolated rat lung model. Grafts were flushed with 1 of 6 preservation solutions (n=5 each group) containing either a monosaccharide (glucose [G] or fructose [F]), disaccharide (trehalose [T] or sucrose [S]), or trisaccharide (raffinose [R] or melezitose [M]. Grafts were stored for 6 hours at 4 degrees C, reperfused by a veno-venous circuit from an anesthetized support animal for 60 min, and ventilated with room air. The best graft function was seen when trisaccharides were used (PO2; R 126 +/- 3 mm Hg, M 129 +/- 3 mm Hg, blood flows: R 10.2 +/- 0.42 ml/min, M 10.3 +/- 0.22 ml/min). Disaccharides produced similar oxygenation (T 133 +/- 3 mm Hg, S 129 +/- 3 mm Hg) and flows (T 10.3 +/- 0.29 ml/min, S 9.7 +/- 0.4 ml/min) at 60 min, but initial flows were reduced. Monosaccharides produced the least satisfactory graft function, with impaired oxygenation (F 110 +/- 14 mm Hg, P<0.05; G 69 +/- 10 mm Hg, P<0.01) and blood flows (G 6.5 +/- 0.6 ml/min, F 9.1 +/- 0.6 ml/min, P<0.01 each). Only glucose stored lungs demonstrated a significant decrease in compliance (P<0.01) and weight gain (P<0.01). The worst results were seen with glucose, which is the osmotic agent most commonly used for clinical lung storage. A solution containing a trisaccharide or disaccharide may be more appropriate for this purpose. PMID- 8685942 TI - Local inflammatory response around diffusion chambers containing xenografts. Nonspecific destruction of tissues and decreased local vascularization. AB - Immunoisolation of xenogeneic pancreatic islets within membrane-bound devices has been proposed as an approach to cure diabetes. We examined the local response to implanted xenografts and allografts in comparison with isografts in diffusion chambers with 0.4-microm pore membranes when implanted into epididymal fat pads of rats. These membranes prevented host cell entry into the device but did not prevent passage of large molecules such as IgG and IgM. Well-differentiated allogeneic tissues (Sprague-Dawley rat embryonic lung implanted into Lewis rats) survived for 1 year when implanted in intact devices, but similar tissues were destroyed within 3 weeks when implanted within devices with holes poked in the membrane to allow host cell contact. In contrast, xenografts (CF1 mouse embryonic lung implanted into Lewis rats) were destroyed within 3 weeks even when implanted in devices with intact membranes. The death of the xenogeneic tissues was accompanied by a severe local accumulation of inflammatory cells and a decrease in local vascularization. When isogeneic tissues (Lewis rat embryonic lung implanted in Lewis rats) were mixed with xenogeneic tissues, a local inflammatory response occurred and both iso- and xenogeneic tissues were destroyed within 5 weeks. These results suggest the possibility that xenografts are killed by local accumulation of inflammatory cells, perhaps mediated by the release of antigens from the tissues within the device and presentation by an indirect pathway. The observation that the local response to xenografts is sufficient to kill isografts complicates issues of immunoprotection, suggesting that successful immunoisolation will require membranes that not only provide protection of the encapsulated tissues from the host immune system but also have properties that diminish the release of xenogeneic antigens. PMID- 8685943 TI - CD4+ T cell mediated destruction of xenografts within cell-impermeable membranes in the absence of CD8+ T cells and B cells. AB - Xenogeneic cells encapsulated in cell-impermeable diffusion chambers die within 3 weeks when implanted into immunocompetent animals but not when implanted into immunodeficient animals. To determine which cells are necessary for this observation, we depleted normal mice in vivo of either CD4+ or CD8+ T cells using monoclonal antibodies. We also reconstituted the immune system of athymic CBA mice (T-lymphocyte deficient) and C.B17 SCID mice (T- and B-lymphocyte deficient) with different cell subsets from normal CBA and BALB/C mice, respectively. Depleted or reconstituted mice were implanted with a diffusion chamber containing COS (monkey kidney) cells. Membrane enclosed xenografts survived in CD4+ T cell depleted mice but not in CD8+ T cell depleted or nondepleted control mice. Encapsulated xenografts survived when implanted into either athymic or SCID mice but were destroyed in reconstituted athymic and SCID mice. Furthermore, encapsulated xenogeneic cells were destroyed in athymic or SCID mice reconstituted with CD4+ cell preparations depleted of CD8+ cells and/or B cells. In contrast, encapsulated xenogeneic cells were not destroyed in athymic or SCID mice reconstituted with CD8+ cell preparations depleted of CD4+ cells. These studies highlight the critical role of CD4+ T cells, in the absence of CD8+ cells and B cells, in the processes leading to the ultimate destruction of encapsulated xenografts. Because of the use of cell-impermeable membranes in these studies, the most likely involvement of CD4+ T cells is in the indirect antigen recognition by these cells and subsequent stimulation of inflammatory cells. PMID- 8685944 TI - Combined transplantation of small and large bowel. FK506 versus cyclosporine A in a porcine model. AB - Clinically, FK506 is superior to CsA after solitary small bowel transplantation (SBTx). Development of diarrhea after SBTx has been the rationale for adding the colon to small bowel grafts. However, the additional lymphoid and bacterial content transferred with total small plus large bowel transplants (TBTx) might aggravate the alloimmune response-rejection and graft-versus-host disease (GVHD) and increase the risk of infection. We studied the incidence of rejection, GVHD, and infection after TBTx and the impact of CsA versus FK506. We performed orthotopic TBTx with portal drainage after total enterectomy in outbred Yorkshire Landrace pigs, divided into 3 groups: control pigs (n=6) received no immunosuppression; CsA pigs (n= 14) received CsA (5 mg/kg), antilymphocyte globulin (10 mg/kg for 10 days), prednisone (2 mg/kg), and AZA (2.5 mgtkg); and FK506 pigs (n=9) received FK506 (0.2 mg/kg) and prednisone (2 mg/kg). Trough CsA whole blood levels were >400 ng/ml for the first 7 days and >200 ng/ml thereafter. FK506 levels were > 15 ng/ml. We excluded from further analysis 5 early deaths (<3 days) due to anesthesiologic (n=2) or technical reasons (n=3). Median survival of control pigs was 9.5 days (range, 4-13). Cyclosporine did not extend survival: median, 9 days (range, 5-31) (P=0.6). FK506 prolonged survival: median, 37 days (range, 21-49) (P<0.001 vs. control and CsA pigs). Of FK506 pigs, 60% gained weight (+75 g/day), whereas 100% of controls and 75% of CsA pigs lost weight (-550 g/day and -300 g/day, respectively). All control pigs died of rejection within 2 weeks versus none of the FK506 pigs. However, 36% of CsA pigs died of rejection. Groupwise comparison showed less rejection in FK506 versus control pigs (P<0.001) and in FK506 versus CsA pigs (P<0.03), but no difference between CsA and control pigs. None of the control pigs died of GVHD versus 18% of CsA pigs (by day 31) and 37% of FK506 pigs (by day 49). Groupwise comparison showed increased GVHD in FK506 versus control pigs (P<0.001) and a tendency toward increased GVHD in FK506 versus CsA pigs (P=0.08). None of the control pigs died of infection alone versus 22% of CsA pigs (by day 31) and 67% of FK506 pigs (by day 49). Groupwise comparison showed increased infection in FK506 versus control pigs (P<0.001). We detected significant endotoxemia early and late postoperatively. But we saw no specific correlation between endotoxemia, rejection, GVHD, or infection. Based on this study, we have drawn several conclusions: (1) In untreated pigs, TBTx provokes a severe rejection response, but no lethal GVHD. (2) Cyclosporine and particularly FK506 pigs have a high incidence of infection and lethal GVHD, a complication that we had not seen after solitary SBTx. (3) FK506 is superior to CsA in controlling rejection and in prolonging graft and recipient survival; FK506, however, does not reduce GVHD, but rather tends to augment it. (4) TBTx causes endotoxemia. As with solitary SBTx, FK506 is superior to CsA after TBTx. However, longterm survival is difficult to achieve on FK506 recipients because of the development of GVHD and infection. PMID- 8685945 TI - Retransplantation reverses mononuclear infiltration but not myointimal proliferation in a rat model of chronic cardiac allograft rejection. AB - Episodes of acute rejection seem to play an important role in the development of chronic allograft failure. Whereas acute rejection appears to be fully reversible, at least at early stages, reversibility of chronic graft alterations is still unclear. Male Fisher F344 rat hearts were heterotopically transplanted into Lewis recipients (n=8/group). Minimal immunosuppression (rapamycin 0.5 mg/kg for 14 days) guaranteed allograft survival during the observation period (group 1). Allografted hearts were retransplanted into syngeneic recipients after 14 days (group 2) and 50 days (group 3) and compared with F344 isografts undergoing retransplantation after 4 days (group 4) and with F344 isografts without a second procedure (group 5). All organs were removed after 100 days and morphologically and immunohistologically assessed. Allografts of group 1 developed concentric myointimal proliferation with dense intramural and perivascular mononuclear infiltration and intravascular thrombosis in 59 +/- 7% of coronary arteries. Retransplantation into syngeneic recipients almost completely abolished mononuclear infiltration, but did not affect the development of myointimal proliferation (groups 2/3: 46 +/- 7%/31 +/- 24%, NS). Isograft retransplantation resulted in a similar incidence of coronary lotions (group 4: 37 +/- 9%, NS), whereas coronary arteries of isografts without a second transplant procedure (group 5) remained normal (0%, P<0.001). In conclusion, syngeneic retransplantation of allografts reverses mononuclear infiltration but not myointimal proliferation. The development of coronary lesions in retransplanted isografts underlines the participation of antigen-independent stimuli in the development of myointimal proliferation. These experiments further support the hypothesis of an interaction of antigen-dependent and antigen-independent factors for the development of coronary myointimal proliferation. PMID- 8685946 TI - Reversal of cyclosporine malabsorption in diabetic recipients of simultaneous pancreas and kidney transplant using a microemulsion formulation. AB - In view of the known problems that diabetic recipients have with drug absorption and of the potential advantages of the microemulsion formulation of cyclosporine (Neoral), 17 previously diabetic recipients of simultaneous pancreas and kidney allografts were studied before and after conversion from Sandimmune (SIM) to Neoral (NEO) formulations of cyclosporine a mean of 4.75 +/- 2.0 years after transplantation. The aims of this study were to determine whether there were changes in the absorption profiles using the 2 formulations and to analyze the safety of conversion from SIM to NEO on a 1:1 ratio. Pharmacokinetic, clinical, and renal function parameters were measured 2 weeks before, and 2 and 4 weeks after conversion. Pharmacokinetics demonstrated that, when taking SIM, only 5 patients had "good absorption" (maximal concentration >500 ng/ml and time to maximal concentration < / = 2 hr), but after conversion to NEO, 14 at week +2, and 13 at week +4 were good absorbers (P<0.02 and <0.01, respectively). There was a 50% reduction in the time to maximal blood concentration (from 3.2 +/- 1.9 hr with SIM, to 1.8 +/- 1.3 hr on NEO [P<0.007]) and a 36% increase in trough and a 143% increase (P<0.01) in maximal blood concentrations, although the 9-hr cyclosporine AUC showed an 89% increase (P<0.01). There was an 18% mean reduction in dose per kilogram prescribed 4 weeks after conversion. Renal function, measured by serum creatinine and technecium-99m diethylenetriamine pentaacetic acid glomerular filtration rate, was not altered and no adverse events were attributed to NEO. This study confirmed that previously diabetic recipients of simultaneous renal pancreas allografts had variable and poor absorption of cyclosporine using conventional Sandimmune and that this absorption was improved by conversion to Neoral. PMID- 8685947 TI - Clinical determinants of glucose homeostasis after pancreas transplantation. AB - Although successful simultaneous pancreas and kidney transplantation (SPK) achieves normoglycemia in the majority of diabetic recipients with end-stage renal disease, little is known about the factors that influence long-term endocrine function. In this prospective study of 48 bladder-drained SPK patients, 209 oral glucose tolerance tests were performed between 3 months and 6 years after transplantation. Normal fasting glucose levels and systemic hyperinsulinemia were stable for up to 6 years after SPK. Multivariate analysis revealed that increased area-under-curve (AUC) levels of C-peptide 3 months after transplantation were predicted by short surgical pancreas anastomosis time, greater recipient body weight, and total HLA mismatch score. Episodes of acute pancreas rejection were not associated with reduced allograft insulin output in the long term. Insulin output, stimulated by oral glucose tolerance tests and assessed by the ratio of AUC insulin to AUC glucose, fell gradually after transplantation and was decreased by an elevated serum calcium level and high cyclosporine dose. The ratio of fasting insulin to glucose, which acts as a marker of peripheral insulin resistance, fell with time after transplantation and was increased by greater body weight, higher prednisolone dose, and lower cyclosporine dose. The inhibitory effect of cyclosporine on both fasting and postprandial insulin output was, however, minor when quantified by multivariate analysis. Endocrine function of the transplanted pancreas was not correlated with its exocrine function measured by urinary amylase excretion, nor was there a correlation with change in renal function measured by isotopic glomerular filtration rate. In summary, simultaneous pancreas and kidney transplantation leads to excellent long-term glucose homeostasis maintained at the expense of systemic hyperinsulinemia. The key factors adversely affecting peripheral resistance in SPK were corticosteroid therapy, body weight, and time after transplantation. The susceptibility of islets to ischemia-reperfusion injury, as quantitated by surgical anastomosis time, may have implications for islet transplantation programs, as may the relative resistance of islets to allograft rejection. Glucose homeostasis after SPK, while remaining abnormal, may be used as the standard against which islet transplantation must be measured. PMID- 8685948 TI - The correlation of Banff scoring with reversibility of first and recurrent rejection episodes. AB - Recurrent acute rejection remains a significant problem for recipients of renal allografts, with a large proportion of patients progressing to graft loss. The newly introduced Banff schema was used to determine whether the histologic pattern of acute rejection (severity and renal compartment scoring) could discriminate recurring from nonrecurring rejections and to examine whether objective rejection scoring had predictive value for rejection reversal and outcome. A total of 67 biopsies obtained from 50 patients with acute rejection were examined for the occurrence of recurrent allograft rejection. All patients were maintained on a cyclosporine-based triple immunosuppressive protocol and had biopsy-proven acute rejection without chronic changes. Rejection recurred in 13 patients (26%), of whom 4 further developed a third rejection. The majority of the patients developed this first rejection within 2 months posttransplantation. Demographics, prebiopsy renal function, immunosuppression, and peak serum creatinine level at the time of biopsy were similar in patients with multiple and single rejection. Peak levels of reactivity to panel of lymphocytes seemed higher in the group of patients with recurrent rejection, whereas HLA matching was similar for all patients. Banff scores for acute rejection did not discriminate patients at risk of rejection recurrence who had lower vascular (0.6 vs. 1.2), tubular (0.6 vs. 1.1), and lower cumulative SUM (3.0 vs. 4.5) scores on their first rejection when compared with patients with one rejection. Histological scoring was, however, significantly different when first and third episodes were compared in the same patient, indicating increased rejection severity with recurrence. Moreover, the rate of reversal of recurrent rejection by anti lymphocyte therapy was significantly less than that of first rejection (P<0.05). In conclusion, these data demonstrate that Banff scoring correlated with rejection reversal and steroid responsiveness, yet rejection recurrence was independent of histological score of the first rejection. Furthermore, Banff schema provided an objective histological correlation to the poor clinical outcome seen with recurrent rejection. The data also suggest that patients with early mild rejection continue to be at risk for recurrence and graft loss. PMID- 8685949 TI - Incidence and predictors of cytomegalovirus pneumonia in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG Study Group. AB - The incidence, predictors, and outcome of cytomegalovirus pneumonia in OLT recipients have not been well defined. We conducted an analysis of prospectively collected data from 141 OLT recipients who were included as part of a randomized, placebo-controlled trial of CMV immune globulin prophylaxis. Cytomegalovirus pneumonia was diagnosed in 13 of 141 (9.2%) OLT recipients during the first year posttransplant and was associated with a higher 1-year mortality compared with those recipients without CMV pneumonia (84.6 vs. 17.2%, P=0.0001). Univariate analysis demonstrated that CMV viremia (P=0.001), invasive fungal disease (P=0.0001), donor(+)/pretransplant recipient(-) CMV serologic status (P=0.013), abdominal operation (excluding retransplantation) after liver transplantation (P=0.0027), bacteremia (P=0.0105), and advanced United Network of Organ Sharing status (P=0.023) were associated with CMV pneumonia. Cytomegalovirus viremia was diagnosed in 11 of 13 patients with CMV pneumonia at a median of 11 days (range 1 66 days) before diagnosis of CMV pneumonia. In a multivariate analysis using a time-dependent, Cox proportional hazards model, CMV viremia (RR=8.6, 95% CI 1.8 39.7, P=0.0012), invasive fungal disease (RR=6.5, 95% CI 2.1-20.3, P=0.0001), and abdominal reoperation (RR=4.4, 95% CI 1.4-13.1, P=0.0043) were found to be independent predictors of CMV pneumonia. The attributable mortality associated with CMV pneumonia within the first year after liver transplantation for the patients with CMV pneumonia was 67.4%. Intensified measures for prevention of CMV should be considered for patients at high risk of developing CMV pneumonia. PMID- 8685950 TI - Immunoblastic lymphoma of donor origin in the allograft after lung transplantation. AB - Posttransplant lymphoproliferative disorders (PTLD) are EBV-associated lymphoid neoplasms that are caused by the uncontrolled growth of EBV-infected B lymphocytes. The clinical presentation of PTLD can range from benign polygonal lymphoproliferative disorders to aggressive monoclonal immunoblastic lymphomas. In this report, we describe a seronegative lung transplant recipient who developed an immunoblastic lymphoma 4 months after lung transplantation from a seropositive donor. The neoplastic cells expressed B lymphocyte markers (CD19+, CD20+, sIgM+, kappa+) as well as the EBV antigen EBNA-2. A cell line with similar cytologic features spontaneously grew from in vitro cultures of the patient's peripheral blood mononuclear cells. The cell line and the lymphoma were EBV+, expressed a similar spectrum of B cell surface proteins, and had the donor's HLA haplotype. Analysis of immunoglobulin gene rearrangements and viral terminal repeat sequences revealed that the cell line and the tumor represented distinct B cell clones. Cultured peripheral blood mononuclear cells were restimulated in vitro with the EBV transformed cell line and tested for cytolytic activity. The host T cells demonstrated high levels of cytolytic activity against the tumor cell line that was abrogated by the addition of a anti-monomorphic HLA class I monoclonal antibody (mAb) (W6/32). These studies indicate that cells of donor origin can persist in the transplanted organ and may lead to an EBV-associated posttransplant lymphoma. PMID- 8685951 TI - Adenovirus-mediated gene transfer into rat cardiac allografts. Comparison of direct injection and perfusion. AB - With the ultimate goal of modulating the host immune response in organ transplantation, gene therapy studies have demonstrated that direct plasmid DNA injection into transplanted myocardium can result in detectable levels of transgene expression. However, the restricted distribution and low level of transgene expression evident in these studies have limited its application. Recently, replication-defective adenovirus vectors have been shown to be an efficient gene-transfer vehicle in vivo whose infection does not require target cell proliferation. In the present study, adenovirus vectors encoding reporter genes were delivered into transplanted hearts by either direct injection into the myocardium or perfusion via aorta of the donor hearts. The efficacy and stability of the transgene expression by perfusion and by direct injection were examined and compared. Using the adenovirus vector encoding the firefly luciferase gene, we found that a higher level of transgene expression was achieved by direct injection, but that more evenly distributed transgene expression was observed in hearts perfused with viral vector. These results were further confirmed by 5 bromo-4-chloro-3-indolyl-beta-d-galactoside histochemical staining of another adenoviral vector encoding beta-galactosidase. The transgene expression was not stable and decreased within 1 month with either delivery method. Nevertheless, these results indicate that adenovirus-mediated gene transfer can result in short term expression of the gene throughout the heart and may be useful as a gene vector in organ transplantation. PMID- 8685953 TI - Additional inhibitory effects of intravenous immunoglobulins in combination with cyclosporine A on human T lymphocyte alloproliferative response in vitro. AB - Intravenous immunoglobulins (IvIgG) are often used in patients receiving a basic immunosuppressive therapy with CsA either for prevention of infectious complications or as an additional prophylaxis of graft versus host disease in clinical bone marrow transplantation. As far as we know, the combined in vitro immunosuppressive effects of these 2 drugs have not been investigated yet. In this study, we compared the effect of CsA, IvIgG, and CsA combined with IvIgG on the proliferative capacity of peripheral blood mononuclear cells in a mixed lymphocyte culture system. The concentration-dependent inhibition of peripheral blood mononuclear cell proliferation in the mixed lymphocyte culture system by CsA is a well established phenomenon. By adding IvIgG to the cultures (n=20) containing CsA, we were able to show a significantly (P<0.0002) higher inhibition compared with the inhibitory capacity of CsA alone. Cyclosporine A was added to the cultures at concentrations ranging from 25 to 400 ng/ml, and IvIgG was added in 3 different fixed concentrations: 1.25, 2.5, and 5 mg/ml. These are all concentrations which one usually obtains in patients during therapy with these drugs. Even with a minimal concentration of CsA (25 ng/ml) plus IvIgG (1.25 mg/ml), we achieved a mean inhibition of 77.7 +/- 7.9%, which is in the range of the mean inhibition (84.3 +/- 4.7%) with the highest concentration of CsA (400 ng/ml tested. Our in vitro results could suggest that the additional therapy with IvIgG in patients receiving CsA might cause a CsA sparing effect. This might lead to a combined therapeutic regimen with a good immunosuppressive efficacy and minimal drug associated adverse effects. PMID- 8685952 TI - Tacrolimus pretreatment attenuates preexisting xenospecific immunity and abrogates hyperacute rejection in a presensitized hamster to rat liver transplant model. AB - In the hamster to rat liver transplant model, we determined the efficacy of tacrolimus in attenuating natural xenospecific humoral immunity and in abrogating the hyperacute liver rejection that is produced by presensitizing the Lewis rat recipient. Hamster livers, transplanted orthotopically into naive rats (controls), were rejected with animal death after 6.4.+/- 0.5 (SD) days. The infusion on (day -6) of 1.5 x 10(7) hamster hepatocytes, or of 1.5 x 10(8) nonparenchymal cells (NPC), resulted in hyperacute rejection and death in < or = 1.9 days. However, when the rats were pretreated with 1 mg/kg/day tacrolimus from days -6 to -1, survival of non-presensitized animals was prolonged to 25 +/- 20 days and that of recipients presensitized with hamster hepatocytes to 36 +/- l6 days or with NPC to 32 +/- 1.7 days. The tacrolimus pretreatment significantly reduced the hamster-specific complement-dependent cytotoxic antibodies response directed to liver NPC but not to lymph node cell targets. These observations suggest that the prolongation of survival by appropriately timed treatment with this T cell directed drug model is caused by the inhibition of humoral as well as cellular xenograft rejection. PMID- 8685954 TI - Nitric oxide mediates early dysfunction of rat and mouse islets after transplantation. AB - Evidence presented in this paper indicates that nitric oxide (NO), generated by a nonspecific "wound"-type of inflammation, is an important mediator of the early dysfunction of transplanted islets in rodents. Although allogeneic islets stimulate NO production to a greater degree than syngeneic islets, the amounts of NO produced after either are significantly elevated above baseline. Inhibition of NO production by N(G)-monomethyl-L-arginine (NMA), markedly decreases the time needed to restore euglycemia after intraportal transplantation of syngeneic islets in diabetic rats. The dose of NMA used was not observably toxic, with no significant changes in blood pressure, hepatic artery blood flow, serum hepatic enzyme levels, or in weight compared with control animals. In rat recipients of intraportal syngeneic transplants, evidence that NO is produced at the site of implantation includes (1) an early and transient increase in posttransplant hepatic vein nitrate levels (pretransplant, 90 microM; 24 hr, 230 microM; 48 hr, 250 microM; 72 hr, 170 microM; and 96 hr, 140 microM), (2) concurrent appearance of inducible NO synthase mRNA in liver extracts, and (3) immunohistochemical localization of inducible NO synthase within the transplanted islets. Suppression of NO production or inhibition of NO activity is a potential strategy to increase the early function and engraftment transplanted islets in the clinical setting. PMID- 8685955 TI - Induction of chemokine gene expression during allogeneic skin graft rejection. AB - The factors mediating trafficking of alloantigen-primed T cells and mononuclear phagocytes to the site of an allograft during the graft rejection process remain largely undefined. Based upon their demonstrated chemoattractant properties, chemokines may play a role in directing inflammatory cells to graft sites and initiate rejection. To begin to investigate the role of chemokines in graft rejection, we used Northern blot analysis to examine the temporal expression of 6 chemokine genes in murine allogeneic skin grafts disparate at the entire MHC and minor antigens and grafts with a disparity at either single class I or class II MHC determinants. Two general patterns of chemokine gene expression in each of the allografts were observed. Intragraft expression of 1 group of chemokine genes, including macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, JE, and KC was observed at peak levels 3 days posttransplant in each of the 3 different allograft models. Expression of these genes in control isografts was at low levels, with the exception of JE, which was expressed at equivalent levels in all iso- and allografts for the first 4-5 days posttransplant, and KC, which was expressed at equivalent levels in C57BL/6 isografts and bm1 and bm12 allografts. A second group of chemokine genes, including RANTES (regulated upon activation normal T cell expressed and secreted) and IP-10 (interferon-gamma inducible protein), was expressed at low levels at early times after transplantation but at high levels 3-4 days before rejection of the allografts was complete. Isograft expression of RANTES and IP-10 was undetectable at the late time points. The results suggest that these 2 patterns of chemoattractant cytokine gene expression may be representative of the early inflammatory and the late T cell-mediated phases of the allograft rejection process, respectively. PMID- 8685956 TI - Intrapulmonary production of RANTES during rejection and CMV pneumonitis after lung transplantation. AB - RANTES (regulated upon activation, normally T expressed and secreted) is a chemoattractant for macrophages, memory T lymphocytes, and eosinophils. We investigated whether intrapulmonary production of the chemokine RANTES contributes to the recruitment of immune cells during lung transplantation complications. RANTES concentration was measured in bronchoalveolar lavage (BAL) fluids using an ELISA assay. It was significantly higher during CMV pneumonitis (36.2 +/- l6 pg/ml, n=12, P=0.031) and allograft rejection (31.1 +/- 8.5 pg/ml, n=27, P=0.013) than in patients without complications (9.1 +/- 2.3 pg/ml, n=22). At least some of the RANTES was produced by lung macrophages: BAL macrophages cultured for 24 hr spontaneously released larger amount of RANTES during CMV pneumonitis (140 +/- 53 pg/ml, n=8, P=0.002) and allograft rejection (84 +/- 44 pg/ml, n=11, P=0.037) than in control patients (15.2 +/- 6.5 pg/ml, n=21). Moreover, macrophages in transbronchial biopsies were labeled by an anti-RANTES mAb. RANTES production by BAL macrophages was followed in 2 patients with CMV pneumonitis. It remained high as long as CMV-induced cytopathic effects or clinical symptoms were present, but it returned to baseline as the infection was controlled. These results suggest that the intrapulmonary production of the chemokine RANTES by activated macrophages contributes to the intrapulmonary accumulation of immune cells during complications of lung transplantation. PMID- 8685957 TI - Impact of oxidative stress on human cytomegalovirus replication and on cytokine mediated stimulation of endothelial cells. AB - Transplantation-related pathogenic factors such as ischemia or allograft-directed inflammation are associated with oxidative changes that might lead to cellular oxidative stress. The aim of this study was to investigate the impact of oxidative stress on: (1) CMV replication in cultured human endothelial cells and (2) the stimulation of endothelial cells by proinfiammatory cytokines. Both pathomechanisms are known to contribute to graft rejection crises in vivo. Oxidative stress was induced in endothelial cell cultures with 10-200 microM buthionine sulfoximine. Western blotting showed a significant increase in the production of CMV-specific immediate early and late proteins in buthionine sulfoximine-treated cultures. Immunocytochemical staining suggested that this effect was caused by increased numbers of CMV antigen expressing cells (66% immediate early; 78%, late). Quantitative polymerase chain reaction for CMV specific DNA and virus titration revealed that enhanced viral replication levels correlated with increased virion production. As a measure for the endothelial cell activation status, the surface expression of HLA-ABC and HLA-DR and adhesion molecules (ICAM-1, ELAM-1, VCAM-1) was quantified by fluorometric methods. Whereas oxidative stress alone did not modulate any surface molecule expression, the IFN-gamma-mediated expression of HLA-ABC and HLA-DR and the IL-1-mediated expression of ICAM-1, but not of ELAM-1 and VCAM-1 (IL-1 + TNF-alpha), was amplified. Interestingly, the amplification of HLA molecule expression was even higher in CMV-infected endothelial cells. This study provides evidence that oxidative stress contributes to the regulation of CMV replication, virus shedding, and the activation of endothelial cells by proinflammatory cytokines as it is observed in transplant recipients. PMID- 8685958 TI - Successfully treated invasive pulmonary aspergillosis associated with smoking marijuana in a renal transplant recipient. AB - Invasive pulmonary aspergillosis (IPA) is often a lethal entity in transplant recipients (up to 90%). We report the successful treatment of a case of IPA in a renal transplant recipient whose only risk for exposure was habitual marijuana smoking. Although marijuana smoking has been linked to the development of IPA in patients immunosuppressed for a variety of reasons, this case is the first report involving a solid organ transplant recipient. The patient's clinical course and treatment are described and the literature is reviewed with respect to environmental and patient risk factors. In this case, IPA was associated with the patient's heavy usage of marijuana during the immediate posttransplant period. Treatment was successful and included the experimental amphotericin product amphotericin B colloidal dispersion. Contemporaneous exposure to a large amount of inocula of Aspergillus within 30 days of receiving high doses of steroids appeared to be the most important factor that predisposed this patient to IPA. Transplant recipients should be specifically proscribed from marijuana use during periods of high steroid administration. PMID- 8685959 TI - Azathioprine hepatitis in kidney transplant recipients. A predisposing role of chronic viral hepatitis. AB - Influence of viral liver diseases on the occurrence of azathioprine hepatitis was evaluated in 21 kidney transplant recipients. Diagnosis of azathioprine hepatitis was always based on jaundice, which disappeared after azathioprine withdrawal in 18 patients and after azathioprine dose reduction in 3 patients. Histopathological diagnosis of azathioprine toxicity was ascertained in 14 patients. Rechallenge with azathioprine performed in 4 patients, within 2-4 months after the first jaundice episode, resulted in relapse of jaundice in all cases. Viral hepatitis B virus and hepatitis C markers were present in all 20 tested patients (serum hepatitis B surface antigen in 6 patients and anti-HCV antibodies in 17 patients). Biopsy-proven chronic hepatitis was observed in 18 patients, including 14 chronic active hepatitis, 3 chronic persistent hepatitis and cirrhosis in 1. In kidney transplant recipients, azathioprine hepatitis seems to be facilitated or induced by hepatitis B virus or hepatitis C virus chronic hepatitis. Azathioprine reduction or withdrawal should therefore be combined with the diagnostic evaluation and the treatment of viral liver diseases. PMID- 8685960 TI - Massive pseudolymphomatous pericardial effusion in the posttransplant setting mimicking posttransplant lymphoproliferative disease. AB - We report an unusual case of massive pseudolymphomatous pericardial effusion in a cardiac transplant recipient. The near-coincidental development of the lymphocytic effusion and an EBV-associated tonsillar lymphoproliferative disorder suggested that the effusion was a manifestation of a posttransplant B cell lymphoproliferative disorder (PTLD). Although benign pericardial effusion is frequently seen in the post-cardiac transplant setting, EBV-related PTLD may also present as a malignant lymphocytic effusion. We present detailed histologic, virologic, and immunophenotypic data that proved useful in distinguishing between these 2 processes. Whereas the tonsillar process was a potentially malignant EBV positive B cell predominant process requiring immunosuppressant withdrawal, the pericardial effusion was a benign EBV-negative T cell predominant process that, given its association with rejection, might require the diametrically opposite therapy of increased immunosuppression. Our approach to the proper diagnostic distinction between these 2 different post-cardiac transplant processes should prove useful to cardiac transplant teams. PMID- 8685961 TI - Kaposi's sarcoma developing in a liver graft. AB - The case reported herein involved a patient who developed Kaposi's sarcoma (KS) in the liver graft, with severe liver disfunction and eventually the patient's death. This patient is our only KS case among the 7 neoplasias arising de novo (6 lymphoproliferative syndromes) in a series of 402 liver transplants (382 immunosuppressed with cyclosporine and prednisolone and 20 with FK-506 and prednisolone). The anatomic distribution of the KS in the autopsy study, and the HLA haplotypes typed in the donor and in the recipient, suggest that the KS arose in the stromal endothelial cells of the donor liver. PMID- 8685962 TI - Combined liver/small bowel transplantation using a blood group compatible but nonidentical donor. AB - A successful liver/small intestinal transplantation with a blood group O donor to a blood type A recipient is described. Mild graft versus host disease developed, manifested by hemolysis, but did not result in graft loss or patient mortality. This suggests that minor ABO incompatibility may be tolerated with intestinal transplantation, despite the transplantation of large amounts of lymphoid tissue. PMID- 8685963 TI - The element of surprise. PMID- 8685964 TI - Maternal mortality in Kwazulu/Natal: need for an information database system and confidential enquiry into maternal deaths in developing countries. AB - In a 2-year retrospective analysis of 147 maternal deaths in South African urban and rural hospitals, the maternal mortality rate (MMR) was estimated to be 144 per 100,000 live births. MMR was significantly higher (P = 0.025) in urban hospitals (160 per 100,000) and the main causes of death were hypertensive disease in pregnancy (33%), of which eclampsia contributed to 70% of deaths and haemorrhage (18%). Only 49.7% of women who died, attended an antenatal clinic. The MMR in South Africa is lower than sub-Saharan countries but unacceptably high for a country with a mix of private and public medicine. Disparities have been noted in maternal mortality rates within the country due to different study rates within the country due to different study designs and poor documentation, Structural changes in the health care system would only be possible if a common information database system were established and confidential enquiries held into maternal deaths. PMID- 8685965 TI - DEC treatment of non-nematodal infections. PMID- 8685966 TI - The increased burden of tuberculous lymphadenitis in central Africa: lymph node biopsies in Lusaka, Zambia, 1981 and and 1990. AB - In order to assess the effect of the HIV epidemic on lymph node biopsies in Central Africa, HIV-1 serology was tested on a cohort of patients undergoing node biopsy in Lusaka in 1990, and the histology of all lymph nodes biopsied in Lusaka in 1981 and 1990 was reviewed. One hundred and eighteen lymph nodes were biopsied in 1981 and 351 in 1990. Cases of tuberculous lymphadenitis increased from 52 (31 children and 21 adults) in 1981 to 186 (22 children, 160 adults, four patients unknown age) in 1990. Sixty-eight of 77 adults (88%) with tuberculous lymphadenitis in 1990 tested HIV-positive. Cases of histology suspicious of primary HIV lymphadenopathy and nodal Kaposi's disease also increased. Cases of malignant lymphadenopathy and overall number of surgical biopsies remained equivalent for 1981 and 1990. The study concludes that the HIV epidemic has led to a large increase in diagnostic lymph node biopsies in Lusaka, mostly through an increase in HIV-related adult tuberculous lymphadenitis. PMID- 8685967 TI - Early diagnosis of septicaemia in infants with respiratory distress in the tropics. AB - A prospective study of buffy coat microscopy of 108 infants with respiratory distress during the first 48 h of life was undertaken. Thirty-two infants (29.6%)had positive blood cultures. The buffy coat was stained with methylene blue and with Gram's stain. Using methylene blue staining, 94% shared organisms in the buffy coat. Whereas using Gram's stain only 50% were positive--all of which were also positive with methylene blue. Twenty-four infants with negative blood cultures had radiological signs of pneumonia. Of these, 83% showed organisms in the buffy coat with both methylene blue and Gram staining. We conclude that buffy coat microscopy provides a simple and reliable guide in the early diagnosis of neonatal septicaemia or lung infection in infants with respiratory distress. PMID- 8685968 TI - Pharmaceutical inventory control software: Bhandari 2.2 (1995). AB - This article describes specialized software to manage pharmaceutical logistics and medicine inventories in hospitals and central/regional stores. It has been written especially for application in the developing world to support the administration of such departments. Features include ordering, inventory control, supplying, reporting and accounting. PMID- 8685969 TI - Pattern of rheumatic heart disease in adults in Maiduguri--north east Nigeria. AB - The pattern of rheumatic heart disease in 84 adolescent and adult patients seen over a 9 year period (1982-1990) at the University of Maiduguri Teaching Hospital (UMTH) is presented. Over 70% were in second and third decades of life. Pure mitral incompetence and mixed mitral valve disease were the commonest valvular lesions. This pattern appears similar to those in other developing countries. Congestive cardiac failure was the commonest complication. Declining economic fortunes of the developing countries, over crowding, malnutrition and inadequate medical facilities may further perpetuate the condition. Early recognition and the management of rheumatic carditis and early valvular lesions will reduce the morbidity and mortality. PMID- 8685970 TI - Antibiotic resistance of Shigella in Monrovia. AB - Twenty Shigella strains were isolated from bloody stools, of which 10 had been collected from children. Eighty per cent of the Shigella isolates were serogrouped as S. flexneri. All 20 Shigella strains were susceptible to gentamicin, nalidixic acid and ciprofloxacin. More than 80% were resistant to ampicillin, cotrimoxazole and tetracycline and 65% were resistant to chloramphenicol. Ten of 20 Shigella isolates showed a quadruple resistance to all four antibiotics. The usefulness of nalidixic acid for the treatment of multiresistant Shigella infections is discussed. PMID- 8685971 TI - AIDS in Africa: what drugs do the carers want or need? AB - Our objectives were: (1) to discover requirements for treatment of patients with AIDS (PWAs) for health-care workers in eight English-speaking African countries; (2) to establish policies for supply of drugs, and develop a method for determining the contents of parcels (PWA-BOXes) for the relief of PWAs. Fifty seven questionnaires were sent to non-government medical units treating PWAs, supplied by the charity Inter Care. Of these 37 units replied, two had no known PWAs, three were swamped by refugees; therefore, the total number analysed was 32. Only 24 units had access to HIV testing and the mean number of PWAs per unit was 58. The reported complications of AIDS were: diarrhoea 28 units; tuberculosis 27 units; pneumonia 28 units; sexually transmitted diseases 26; candidiasis 28 units; and herpes zoster 20. Lists of drug requirements were received. We present a protocol for calculation of contents of PWA-BOXes in the hope that this will provide guidelines for other workers in this field. PMID- 8685972 TI - Non-immunologic hydrops fetalis: study of 86 autopsies. PMID- 8685973 TI - Ecthyma gangrenosum. PMID- 8685974 TI - Presentation of parasites and the radiology of parasitic diseases. PMID- 8685975 TI - Northern Nigeria. Fertility. PMID- 8685976 TI - Intravenous chloramphenicol plus penicillin versus intramuscular ceftriaxone for the treatment of pyogenic meningitis in Nepalese children. PMID- 8685977 TI - Role of ovarian ablation for premenopausal patients in adjuvant systemic therapy of breast cancer. PMID- 8685978 TI - Hypoglycaemia in convalescent tuberculous children. PMID- 8685979 TI - Bradycardia in severely dehydrated patients. PMID- 8685980 TI - A wonderful dog-master story. PMID- 8685981 TI - Abnormal localization of visceral leishmaniasis in Turkey. PMID- 8685982 TI - Hepatitis B surface antigen (HBsAg) carrier rate among blood donors in Monrovia, Liberia. PMID- 8685983 TI - Field research, relief work and war: does chloroquine-resistance occur in displaced populations of southern Sudan? PMID- 8685984 TI - Triage management in Third World health ministries. PMID- 8685985 TI - Bacterial meningitis in developing countries. PMID- 8685986 TI - [Psychological stress and pregnancy outcome]. PMID- 8685987 TI - [Laparoscopy in acute abdomen]. PMID- 8685988 TI - [The significance of psychosocial stress for pregnancy course and fetal development]. AB - In a population-based study, 3021 women in a central Copenhagen district received a questionnaire on environmental and psychological factors during mid-gestation. Of these, 70 women were selected consecutively on the basis of moderate to severe stressful life-events (DSM-III-R categories 3 to 5), in combination with an inadequate social network. They were compared with 50 non-stressed women with an intact social network. Stress and smoking significantly affected birthweight and head circumference. When birthweight was corrected, stress remained a significant determinant of small head circumference, indicating a specific effect on brain development. Stress also led to a suboptimal Prechtl neonatal neurological score. These findings suggest the existence of a fetal stress syndrome with adverse effects on fetal development, including deficient brain development. PMID- 8685989 TI - [Violence towards pregnant women]. AB - The current literature concerning violence against pregnant women is reviewed. The prevalence of battering during pregnancy is estimated to be between one and ten percent, and the problem is most often hidden from the medical staff. In one fourth of the cases, violence increases during pregnancy, and usually the violent episodes are a continuation of the couple's habitual way of life. An episode of battering per se is only in extreme situations dangerous for the pregnancy, but serves as a marker of negative social events, e.g. unemployment, smoking, emotional instability etc., which increases the risk of an adverse pregnancy outcome. Furthermore, the violent husband may extend the battering to the child after delivery. It is concluded, that all medical personnel dealing with pregnant women should be aware of the high prevalence of battering during pregnancy. If battering is detected, the pregnancy may be at risk, but the main problem is the social issue and the later consequences for the child. The general practitioner is central in the long-term approach to these cases. PMID- 8685991 TI - [The effect of suxamethonium on intracranial pressure]. AB - The literature concerning the effect of suxamethonium on intracranial pressure in animals and in humans is presented. The studies have not provided firm indications that suxamethonium per se increases the intracranial pressure. Patients with increased intracranial pressure who are to receive suxamethonium should first be deeply anaesthetized and given a defasciculating dose of a non depolarizing blocker. PMID- 8685990 TI - [Laparoscopy in suspected acute appendicitis. Experiences with the first 233 laparoscopies at a university hospital department]. AB - In an initial stage of introducing laparoscopic appendicectomy, 233 patients with indication for surgical treatment were evaluated in an open prospective trial. Surgery was done by a total of 39 trainees on duty. The procedure was started as a diagnostic laparoscopy followed by laparoscopic appendicectomy if the appendix was macroscopically inflamed. If the appendix was normal, it was left in place. There were 51 patients with a macroscopically normal appendix. Subsequently, none of them suffered from appendicitis or any other disorder requiring surgery. In 182 patients with laparoscopically assessed inflamed appendix, laparoscopic appendicectomy was attempted. One hundred and forty-eight proved successful, whereas 34 were converted to an open operation, mainly because of limited experience with the laparoscopic technique. Wound infection occurred in two and intraperitoneal abscess in four patients (0.9% and 1.7%), respectively. There was only one complication (0.4%) directly related to the laparoscopic procedure, namely a coecal leak. In conclusion, in a teaching hospital, laparoscopic appendicectomy can be safely offered to patients where surgery is indicated due to suspicion of appendicitis. PMID- 8685992 TI - [Smoking as social heritage. Children whose mothers are smokers are more likely to become smokers as adults]. AB - Effective prevention of smoking depends on the identification of factors that determine smoking onset. We examined the influence of family factors during childhood (household income, parent education and smoking behaviour) on the subsequent risk of smoking in young adults. In 1979, 1300 children aged 6-18 years, whose parents were randomly selected for participation in the Copenhagen City Heart Study were invited to a health examination. Information about health and smoking behaviour was obtained from 73% of the children. A random sample of 579 of the children were invited to a follow-up examination 13 years later. Four hundred and eighty-six (84%) participated in the follow-up. The influence of household income, parent smoking behaviour and education on the child's risk of becoming a smoker in young adulthood was estimated. Household income and parent education did not significantly affect the risk of adult smoking. Maternal smoking during childhood increased the risk in comparison with the mother being a non-smoker (Adjusted Odds Ratio 1.95 (95% CI 1.07-3.58). Maternal smoking during childhood increases children's risk of becoming young adult smokers, independent of age and smoking behaviour in childhood, gender and social background. In Denmark 28% of smoking in young adults could be attributed to maternal smoking. PMID- 8685993 TI - [Diabetes regulation and oral contraceptives. Lipoporotein metabolism in women with insulin dependent diabetes mellitus using oral contraceptives]. AB - In an open prospective study we evaluated the glycaemic control and lipoprotein metabolism in 22 women with uncomplicated insulin dependent diabetes mellitus during one year of oral contraception with ethinyl oestradiol and gestodene. Twenty women of comparable diabetic status using non hormonal contraception served as controls. No changes in glycaemic control were observed in any of the groups. In the oral contraceptive group decreased serum levels of low-density lipoprotein cholesterol and increased levels of triglycerides and lipoprotein A were noted whereas total cholesterol and high-density lipoprotein cholesterol levels were unchanged. In the control group a decrease of low-density lipoprotein cholesterol was observed. No effect of tobacco smoking on glycometabolic control or lipoprotein metabolism could be demonstrated during hormonal intake. In conclusion, we found no evidence of impaired glycometabolic control or adverse changes in serum levels of lipoproteins known to be associated to atherosclerosis in diabetic women during one year of oral contraception with ethinyl oestradiol and gestodene. PMID- 8685994 TI - [Randomized trial and meta-analysis of somatostatin versus placebo in bleeding esophageal varices]. AB - We studied whether somatostatin or its derivative, octreotide, is more effective than placebo in the treatment of bleeding oesophageal varices in a randomised, double-blind trial and a meta-analysis with blinded data analysis and manuscript writing. Patients suspected of bleeding from oesophageal varices and of having cirrhosis of the liver were eligible. Eighty-six patients were randomised; 16 died in each group within six weeks (95% confidence interval (CI) for difference in mortality -19% to 22%). There were no differences between somatostatin and placebo in median number of blood transfusions (8 vs 5, p = 0.07, CI 0 to 4 transfusions) or in numbers of patients who needed balloon tamponade (16 vs 13, p = 0.54, CI -11% to 28%). In a meta-analysis of three trials, involving 290 patients, somatostatin had no effect on survival compared with placebo (p = 0.59, odds ratio 1.16, CI 0.67 to 2.01). For blood transfusions and use of balloon tamponade there was heterogeneity between the trials with no convincing evidence in favour of somatostatin. PMID- 8685995 TI - [Capnocytophaga canimorsus bacteremia]. AB - A case of bacteraemia in a 54-year-old previously healthy man caused by the gram negative rod Capnocytophaga canimorsus is presented. The patient developed severe ischaemia in both feet, thrombocytopenic purpura and renal failure. The bacteraemia was apparently caused by saliva from the patient's dog who had licked ulcers on the patient's legs. The patient regained full health but had a minor inferior myocardial infarction seven weeks after start of the infection. PMID- 8685996 TI - [Early onset of Huntington disease]. AB - The case of a childhood form of Huntington's disease in a 12-years-old girl is reported. The patient suffered from severe psychosis, progressive difficulties in speaking, and mental deterioration. Her father committed suicide due to Huntington's disease when the patient was eight years old. Neurological examination revealed nothing but speaking difficulties. She had no signs or symptoms of involuntary movements, muscular rigidity or ataxia. SPECT-scanning showed a picture similar to that seen in adult patients with Huntington's disease. The difficulties in diagnosing Huntington's disease in children are discussed, and the necessity of the child psychiatric expertise is emphasized. PMID- 8685997 TI - [Pharmacological prevention of late complications of diabetes]. PMID- 8685998 TI - [Modern gene technology]. PMID- 8686000 TI - [User guidelines on drug packages--written for whom, approved by whom?]. PMID- 8685999 TI - [A clearing report of the Danish society of hypertension]. PMID- 8686001 TI - [Kidney calculi--modern investigation and treatment]. PMID- 8686002 TI - [Primary HIV infection]. PMID- 8686003 TI - [Evaluation and treatment of patients with kidney calculi]. AB - Renal stone disease is a common disorder causing much discomfort and high rates of sick-leave. Surgical treatment has improved dramatically with extracorporeal shock wave lithotripsy, but the recurrence rate is high, and it would be desirable to be able to offer the patients effective steps in prevention of further stone formation. The biochemical abnormalities associated with stone formation are complex and not fully elucidated. It should, however, be possible to reduce the recurrence rate with a relatively simple programme for investigation of the patients. The pathogenesis of renal stones is, therefore, reviewed with reference to a plan for the practical approach to the prevention and management of nephrolithiasis, that has recently been recommended by The National Kidney Foundation, USA. PMID- 8686004 TI - [Primary HIV infection]. AB - Up to 70% of individuals with primary HIV infection will develop symptoms of an acute illness. The most common symptoms reported are fever, generalized lymphadenopathy, arthralgia and myalgia, headache, pharyngitis, enanthema, skin rash, diarrhoea, and mucocutaneous ulcerations. More rarely, oesophageal candidiasis, meningoencephalitis, rhabdomyolysis and epiglottitis have been reported. The diagnosis of the acute HIV infection syndrome can be established by demonstrating antibodies to HIV or by demonstration of HIV antigen positivity. Detection of virus through culture or PCR may prove to be more sensitive, but are not yet used as routine methods. The course of the primary infection has prognostic importance for the subsequent course of HIV infection. This probably reflects the importance of both the viral phenotype and of the initial immune response to HIV. Primary HIV infection should be considered in any patient with possible exposure to HIV presenting with fever of unknown cause. PMID- 8686005 TI - [Primary HIV infection. Case histories]. AB - More than 50% of individuals with primary HIV infection have a symptomatic febrile illness associated with seroconversion. The most common clinical picture is a mononucleosis-like or influenza-like illness but almost any organ system may be involved, and primary HIV infection is often an imitator of other acute diseases. Six cases of symptomatic primary infection are described, one with a characteristic presentation, and five cases respectively presenting with colitis, rhabdomyolysis, epiglottitis, cold agglutination haemolysis and meningitis as marked symptoms. PMID- 8686006 TI - [Peritonitis in continuous ambulatory peritoneal dialysis. An evaluation of the empiric initial antibiotic treatment]. AB - Retrospectively, the clinical outcome and the initial empiric antibiotic treatment of peritonitis in 106 patients on continuous ambulatory peritoneal dialysis (CAPD) were evaluated during a two-year period. A mean frequency of 0.89 episodes of peritonitis per year of dialysis was found. There was a tendency towards an increased frequency of peritonitis in older patients. Diabetic patients constituted a younger age group and had a tendency towards having a lower risk of peritonitis. Patients with polycystic renal disease had a significantly increased risk. The risk of episodes with coagulase-negative staphylococci increased significantly with age. Repeated peritonitis episodes with coagulase-negative staphylococci was associated with a significant increase in the appearance of methicillin drug resistance. Carriers of Staphylococcus aureus had a significantly increased risk of Staphylococcus aureus peritonitis. Microorganisms were cultured in 94% of the episodes. The initial antibiotic therapy was only sufficient in 66% due to antimicrobial drug resistance. The initial antibiotic treatment was changed in 58% of the episodes. The treatment could have been changed to antibiotics with a narrower antimicrobial spectrum in 51% of the episodes. Relapse was seen in 11% of culture positive episodes. In 16% of the episodes (29% of patients with peritonitis) it was necessary to remove the dialysis catheter and transfer the patient to haemodialysis to clear the infection. Only 15% of these patients returned to CAPD again. We found that an initial empiric antibiotic regime of vancomycin combined with an aminoglycoside is to be recommended as achieving an antibiotic coverage of 88%, and this is now the standard regime in the department. PMID- 8686007 TI - [Peritonitis in continuous ambulatory peritoneal dialysis. Culture of peritoneal dialysate fluid]. AB - Conventional aerobic and anaerobic culture of peritoneal dialysate effluent from patients in continuous peritoneal dialysis (CAPD) was compared to culture in a semiautomated blood culture system. During a two-year period 78 of 79 consecutive episodes of peritonitis among 45 Danish CAPD patients were cultured and the etiology of the infection found in 73 (94%). The sensitivity of the blood culture system was 88%, whereas the sensitivity of the conventional culture of the dialysate effluent was 81%. This difference is not significant (McNemar test; 0.5 > p > 0.3). The majority of isolates were Gram-positive bacteria dominated by coagulase-negative staphylococci (38%). In comparison, only 2% of the cultures of peritoneal dialysate effluent taken within the same period from patients without clinical signs of peritonitis were positive. All the Gram-positive aerobic bacteria were sensitive to vancomycin whereas 97% of the Gram-negative aerobic bacteria were sensitive to gentamicin. An initial empiric treatment of peritonitis with a combination of vancomycin and gentamicin is recommended. PMID- 8686008 TI - [Acquired coagulation factor VIII deficiency. A 4-year survey of patients at the East Danish Hemophilia Center]. AB - An East Danish population of acquired haemophilia A (factor VIII inhibitors) patients are described in a retrospective survey. Fifteen patients attended the centre during the period 1981-1994. The epidemiology, clinical presentation, time from debut until diagnosis and response to treatment are presented. Acquired factor VIII inhibitors are rare and without treatment the disease has a high mortality and morbidity. Inhibitors mostly develop among the elderly, independent of sex and almost half have no known underlying disease. When the diagnosis is clear, bleedings may be controlled and the patient may be cured by treatment that eliminates the inhibitor. Time until diagnosis varies a lot, for some patients it takes years. It is therefore important to be aware of the disease, so that time with risk of fatal bleeding is shortened as much as possible. PMID- 8686009 TI - [Autologous stem cell transplantation. From bone marrow to selected blood stem cells: 100 consecutive procedures at a single center]. AB - One hundred consecutive autologous stem cell transplants are reported: Non Hodgkin's lymphoma 51 cases, Hodgkin's disease 27 cases, acute leukaemia 14 cases, multiple myeloma seven cases and chronic myeloid leukaemia one case. Most patients were in their second or later remission. The overall three-year survival for all patients was 60% and the three-year disease-free survival was 50% for lymphoma patients and 30% for acute leukaemia patients. The dominant source of stem cells was bone marrow during 1993, but from 1994 it has been peripheral blood, now totalling 33 cases. There were 12 toxic deaths, all among patients who were heavily treated before bone marrow harvest and transplantation. The patients transplanted with blood stem cells had significantly shorter duration of pancytopenia, and hospital stay, but their disease-free survival was not longer than that of a comparable group of bone marrow transplanted patients. Six patients were transplanted with purified CD34+ cells (selected by avidity column (Ceprate (R)), and had duration of thrombocytopenia and hospital stay similar to the patients transplanted with unmanipulated blood stem cells, but slightly longer duration of neutropenia. We conclude that high-dose therapy with autologous stem cell transplantation in not too heavily pretreated patients is a safe procedure irrespective of the source of stem cells. PMID- 8686011 TI - [Portal hypertension]. PMID- 8686010 TI - [Cesarean section in severe double valvular disease]. AB - During pregnancy haemodynamic changes are a stress to the cardiovascular system. Women with previously asymptomatic cardiovascular disease may develop life threatening cardiac failure because of the extra demands of pregnancy. Early diagnosis, close control and treatment during pregnancy, delivery and the postpartum period are essential. We report a case where a woman with a mitral stenosis and insufficiency of the mitral and aortic valves gave birth to a child by caesarian section. PMID- 8686012 TI - [Zocor lobby?]. PMID- 8686013 TI - [The scientific editorial of the Ugeskrift on prevention of Chlamydia trachomatis complications is not scientific]. PMID- 8686014 TI - [Chlamydia trachomatis]. PMID- 8686015 TI - [Gestagen therapy and reactive psychosis]. PMID- 8686017 TI - [Cryptorchidism--any news on pathogenesis and treatment?]. PMID- 8686016 TI - [Acarbose, a glucosidase inhibitor: a new therapeutic principle in diabetes mellitus]. PMID- 8686018 TI - [100 years with Starling's hypothesis]. PMID- 8686019 TI - [Cryptorchidism in boys with anal atresia]. AB - In a retrospective study of the case reports of 136 boys who were operated on for an imperforate anus and who survived at least 18 months, cryptorchidism was the most common associated anomaly, involving 26 cases (19%). The higher the level of the anorectal malformations, the higher was the incidence of cryptorchidism. The incidence of renal and ureteric malformations and dysplasias showed a parallel tendency. The incidence of vertebral malformations and dysplasias in the T10-S5 area was low among patients with a covered anus or a perineal fistula. Cryptorchidism was found to be associated with urological and with T10-S5 vertebral malformations and dysplasias. Recognition of this association is probably new. The histopathological findings of testicular biopsy specimens and the location of the undescended testes in patients with an imperforate anus showed the same pattern as seen in undescended testes from patients with cryptorchidism only. These findings, together with the existing literature on the subject, indicate that further studies on the association of cryptorchidism, urological, and T10-S5 vertebral malformations and dysplasias may be important for a better understanding of cryptorchidism in general. PMID- 8686021 TI - [Evaluation of symptoms in patients with benign prostatic hyperplasia]. AB - Benign prostatic hyperplasia (BPH) is the most common cause of voiding dysfunction in elderly men. With the age related demographic changes in the western world, the epidemiological and economical burden of BPH is anticipated to increase. BPH is clinically diagnosed on a variety of more or less well defined symptomatic, macroscopical, and physiological criteria, whereas the histological diagnosis is straightforward. Yet, no symptom is specific for BPH and numerous other diseases have to be considered when a patient presents with symptoms of bladder outlet obstruction. A BPH questionnaire is useful when weighing the pros and cons for intervention. Furthermore, a symptom index represents a valuable indicator for the quality of care provided. Through the last decades a number of BPH questionnaires have been introduced. This article scrutinizes various BPH indices and provides an introduction to the prerequisites of clinical questionnaires. PMID- 8686020 TI - [Laparoscopy in 100 consecutive patients with 128 impalpable testes]. AB - A cohort of 100 patients underwent laparoscopy for 128 impalpable testes. They ranged in age from 2.7 to 19.3 years (median 10.8 years). There were no complications associated with laparoscopy. In 50% of the cases either blindending cord structures above the internal inguinal ring or intra-abdominal testes were identified; in the remainder, cord structures could be seen passing through the ring, indicating an intracanalicular testis. The impalpable testis was absent in 77% of patients with a contralateral scrotal testis. A seminoma was found in one 18.6-year-old patient with bilateral cryptorchidism. No intratubular germ cell neoplasia (carcinoma in situ) was proved. Germ cell hypoplasia or aplasia was demonstrated in 95% of cases with testicular parenchyma. We recommend laparoscopy as a safe procedure which leads to a diagnosis in patients with impalpable testes; the advent of laparoscopic procedure makes definitive treatment possible in about 50% of such cases. PMID- 8686023 TI - [Screening for lung cancer]. PMID- 8686022 TI - [Autonomous hyperreflexia and labor]. AB - Autonomic hyperreflexia is a serious complication for tetraplegic patients, especially during labour and delivery. The symptoms are piloerection, facial flushing, anxiety, headache, serious blood pressure crises and cerebrovascular accidents. A 30 year-old woman who was tetraplegic following a high cervical spinal cord lesion, showed signs of autonomic hyperreflexia. In early labour epidural analgesia was established and the vaginal delivery was successful without associated fluctuation of the blood pressure or other signs of autonomic hyperreflexia. PMID- 8686024 TI - [Fibroblast growth factors, their receptors and congenital diseases]. PMID- 8686025 TI - [Service for persons with hearing disorders]. PMID- 8686026 TI - [Active labor management--the best way to Rome goes via Dublin]. PMID- 8686027 TI - [My experiences with Zovir herpes tablets]. PMID- 8686028 TI - [Clarithromycin]. PMID- 8686029 TI - [Hereditary colorectal cancer]. PMID- 8686030 TI - [Myasthenia gravis and thymectomy]. PMID- 8686031 TI - [Thymectomy in myasthenia gravis]. AB - Thymectomy is in most cases the treatment of choice in myasthenia gravis (MG). In order to evaluate the Danish results, we investigated the outcome and patient satisfaction following thymectomy in Odense University Hospital from 1980 to 1994. Thirty-three patients were operated. Five (16%) were completely without symptoms or medication and 14 (44%) received less medication and had fewer symptoms than preoperatively. Sex, age, degree of illness, duration of symptoms, histology of the thymus and surgical approach had no significant (p > 0.05) influence on the result. Four patients died 2-29 months after surgery, three because of aggravation of MG and one of causes unrelated to the operation. Of the 29 patients still alive none had serious complications, 11 had minor complications and 23 were satisfied with the operation. Thymectomy is recommended for patients with symptomatic MG, but the effect of surgery should be evaluated in a prospective clinically controlled study. PMID- 8686032 TI - [Incidence of multiple sclerosis in Scandinavia and Finland]. AB - Review of studies of incidence of multiple sclerosis (MS) over several decades in seven geographical areas scattered over Scandinavia and Finland have shown that incidence rates fluctuate significantly with time in most of the areas, but in an inconsistent pattern. The incidence appeared to be the lowest in the northernmost parts of Norway showing that the well-known north-south gradient for risk of MS does not hold true for high latitudes. The time-space variation in incidence rates supports the view that local non-persistent environmental factors may play a role in the aetiology of the disease. PMID- 8686033 TI - [Prognosis of the onset of postpartum psychosis. Demographic, obstetric and psychiatric factors]. AB - The aim of the present study was to investigate women who had first-episode psychosis within the first year after parturition. The investigation was carried out by linking the Danish Psychiatric Case register and The Danish Medical Birth register to identify all women admitted for the first time to a psychiatric department in the county of Arhus with a psychotic episode. Fifty cases were found, giving a frequency of 1 per 1000 births. First-episode psychotic disorder within the first month postpartum occurred in 1 case per 2000 deliveries. Compared to the background population the cases were more often primiparous than would be expected. Birth complications did not occur more frequently than expected, but the probands had a higher incidence of preterm delivery than the controls. The follow-up, seven to 14 years later, was carried out by interviewing the patients' general practitioners. Forty percent of the women had not retained full working capacity due to mental disorder and recurrences were very common (60%), especially of the nonpuerperal type. The prognosis thus seems rather gloomy. PMID- 8686034 TI - [Nutritional and fluid supplementation for neonates. Types and use of supplementation in maternity wards]. AB - The objective of the study was to evaluate the practice of giving supplementary feeding to newborns on maternity wards according to type of supplement, use and choice of supplement in different clinical settings, recommended frequency of breast-feeding, recommended types of infant formula and finally the influence of paediatric department and geographic site on the use of different types and use of supplements at the wards. Sixty maternity wards (95%) in Denmark filled in and returned the questionnaire. The maternity wards offered six different kinds of supplements and 36% of the maternity wards offered human milk. The study gave the impression of a large consumption of supplements on the maternity wards. Most of the maternity wards (83%) would recommend hydrolysed infant formula for infants with a family history of allergy, and almost the same number (88%) would recommend traditional infant formula for infants without a family history of allergy. Mothers' request for hydrolysed infant formula for infants without a family history of allergy was refused in 20% of the maternity wards. There were no differences between the recommended frequencies of breast-feeding. Maternity wards in hospitals with paediatric departments would significantly more frequently offer the infants supplements than maternity wards in hospitals without paediatric departments. The same maternity wards would significantly more often use water and human milk and more rarely water with glucose than maternity wards in hospitals without paediatric departments. In the western part of Denmark the maternity wards significantly more often used traditional infant formula and water with glucose than in the eastern part of Denmark. In conclusion, the investigation showed a considerable variation in the different types of supplements used in the maternity wards. The variation was influenced by the presence of a paediatric department in the hospital as well as by the geographic site. To ensure a higher and more uniform quality in this area it would be desirable if The National Board of Health in collaboration with the Allergy committee in the Danish Society of Paediatricians would publish recommendations to all who work professionally with mothers and infants. PMID- 8686036 TI - [Atypical cervix uteri smears--consequences?]. AB - Among 37,992 cervical smears (725 (1.9%)) were found to be atypical. All atypial smears were referred for colposcopically guided biopsies and cervical abrasio within three months. This is an expensive and cumbersome procedure. In order to obtain a more differentiated follow-up procedure the atypical smears were divided into two groups without knowledge of the later histological diagnosis on biopsy: "Atypia, probably reactive" and "atypia, probably CIN (cervical intraepithelial neoplasia)". In the latter group the subsequent biopsies showed significantly more CIN than in the former (60.4% against 15.7%). We find it useful to divide the atypical smears into two groups in our daily routine work with a different follow-up procedure: "Atypia, probably reactive" to be followed by a repeat smear and "atypia, probably CIN" to be followed by colposcopically guided biopsies and cervical abrasio. PMID- 8686035 TI - [Plasma calprotectin. A new prognostic marker of survival in alcoholic liver cirrhosis]. AB - The purpose of this study was to determine plasma concentrations of calprotectin in patients with different severity of alcoholic cirrhosis. Additionally, the prognostic value of calprotectin for recurrent infections and for survival was investigated after a median observation period of 19 months. No difference was found in calprotectin levels when comparing healthy controls (n = 16), compensated (n = 50) and decompensated cirrhotics (n = 34). However, high calprotectin concentrations (> median) was a significant prognostic marker of poor survival (p = 0.001, Log-rank test). Calprotectin levels (> median) showed an independent and much higher prognostic value than variables of liver disease (multivariate Cox model). During follow-up calprotectin levels (> median) were also a predictor of recurrent infection (p = 0.009, Log-rank test). Thus, in patients with alcoholic cirrhosis, plasma calprotectin appears to be a new prognostic marker of survival, which seems independent of severity of liver disease. Furthermore, high plasma calprotectin levels may characterize a group of cirrhotics with recurring bacterial infections. PMID- 8686037 TI - [Characterization of "non-attenders" in an organized screening against cancer of cervix uteri]. AB - The aim of the study was to present social and other characteristics of non attenders in an organized cervical screening programme. It was conducted a case control study in a cohort. The cohort consists of women in the age group 23-60 years who were invited to the organized cervical screening programme in Aarhus county, Denmark, between 1.10.1990 and 1.4.1994, totalling 133,500 women. The case group included 694 "non-attenders" and the control group 1131 women who had had at least one smear performed during the previous 42 months. The results showed that non-attenders, compared to attenders, had less frequent contact to their general practitioner. The non-attender group did not have an over representation of markers for special risk of cervical cancer. PMID- 8686038 TI - [Hereditary nonpolyposis colorectal cancer]. AB - Hereditary non polypous colon cancer (HNPCC) is inherited in a dominant fashion, and accounts for 29-39% of all colon and rectum carcinomas occurring in people under 50 years of age. We present a case of a young male with a short history of fluctuating diarrhoea and bleeding per rectum. Family records showed a high incidence of colon and rectum cancer. Coloscopy showed a colon tumour that was treated by total colectomy. To obtain the correct diagnosis a thorough family history is crucial. Having found a sick individual in a family it is now possible to identify genotype-carriers among family members. PMID- 8686039 TI - [HELLP syndrome]. AB - A case of HELLP syndrome (Haemolysis, Elevated Liverenzymes, Low Platelets) (HS) a severe form of preeclampsia is presented. The case demonstrates that the syndrome is unpredictable, refers to differential diagnoses and pregnancy-induced abnormalities in the blood picture, and this points out the need for knowledge and awareness of the symptoms, clinical and laboratory signs of beginning HELLP syndrome. PMID- 8686040 TI - [Recompounding of intravesical Bacillus Calmette-Guerin]. PMID- 8686041 TI - [Supplementation of estrogen and progesterone to postmenopausal women]. PMID- 8686042 TI - [Molecular genetic diagnosis of severe colorectal cancer]. PMID- 8686043 TI - [Problems with urination?]. PMID- 8686044 TI - [Is it possible to measure the educational value of the work of interns?]. PMID- 8686045 TI - [Treatment of psoriasis: medical and surgical]. PMID- 8686046 TI - [Kidney function problems in rheumatoid arthritis]. AB - Rheumatoid arthritis is a systemic, disabling disease with significant excess mortality which is partly caused by renal disease, infection and renal insufficiency being the main contributors. The bulk of renal problems in reumatoid arthritis are related to complications such as vasculitis and amyloidosis, and complications to the medical treatment of the disease, the main offenders being gold salts, penicillamine and cyclosporine. Also, there is increasing evidence that reumatoid arthritis per se can cause subclinical renal dysfunction with microalbuminuria as well as clinical disease, caused by immune complex mediated glomerulonephritis and interstitial tubular fibrosis. In reumatoid arthritis serum creatinine can overestimate renal function by as much as 30% and it is suggested that more sensitive methods such as measuring urinary albumin excretion and glomerular filtration rate should be used for monitoring renal function. PMID- 8686048 TI - [Junior physicians educate themselves. Educational value of trainees' work at a department of surgery]. AB - In order to investigate the educational value of trainee surgeons' work, all work done by trainees at a Department of Surgery was recorded in a prospective and consecutive way for four weeks. It was recorded as fixed categories divided into intervals of 15 minutes. The work could be classified in three dimensions: Character, educational value and geography. The youngest trainees performed routine work without educational value. They had some practical jobs which could be done by other personnel. The work did not fulfil the educational claims for a trainee surgeon in phase I. The second group of trainees performed much routine work without educational value. They had no practical jobs that could have been performed by non-doctors. They had some work with educational value but not enough to fulfil the goals of a trainee surgeon in phase II. CONCLUSION: Doctors' clinical education could be improved by giving them work with educational value and supervision. Supervision should be performed by specialists who should also contribute to the routine work without educational value. PMID- 8686047 TI - [Microalbuminuria in rheumatoid arthritis]. AB - To assess the prevalence of microalbuminuria in patients with rheumatoid arthritis and its correlation with disease activity and drug treatment, we studied 65 patients with rheumatoid arthritis and 51 sex and age matched control persons. Microalbuminuria was significantly increased in patients with rheumatoid arthritis (27.7%) as compared to 7.8% in the control group. Patients with microalbuminuria had a significantly greater median duration of disease (11.2 v 7.8 years; p < 0.001). We found a significant correlation to C-reactive protein as a marker for disease activity. Also, a significant association to treatment with gold and penicillamine was found. The measurement of microalbuminuria by immunochemical methods represents a simple and sensitive test to detect subclinical renal damage and may be a sensitive indicator of disease activity in patients with rheumatoid arthritis. We suggest its use in the monitoring of patients with rheumatoid arthritis to detect early subclinical renal dysfunction and drug induced renal damage. PMID- 8686049 TI - [Femoral head necrosis treated with total hip alloplasty]. AB - One hundred and three patients with non-traumatic osteonecrosis of the femoral head had 144 primary total hip replacements performed. Average age was 47 (22-73) years. In 85 cases a cemented prosthesis, and in 45 cases an uncemented prosthesis was used, while 14 cases had a cemented femoral stem and an uncemented cup. At follow up, 25 patients had died, 13 patients had had a revision of the prosthesis, and two patients were lost to follow-up, leaving 63 patients (92 hips) for clinical and radiological evaluation. Kaplan-Meier plots for survival of the prosthesis were constructed, showing a total risk of failure of 8% at five years, increasing to 16% at seven years. In 89% of the patients without concomitant diseases, the clinical result was excellent or good. There was no difference in the clinical or radiological result in patients with cemented and uncemented prostheses. It is concluded, that the result after total hip replacement due to non-traumatic osteonecrosis of the femoral head is comparable to that of total hip replacement due to osteoarthrosis, and that an uncemented prosthesis can be expected to yield a result comparable to a cemented prosthesis. PMID- 8686050 TI - [Carcinoid tumors in Denmark 1978-1989 and the risk of development of new cancers]. AB - Previous studies have suggested an excess cancer risk in patients with carcinoid tumours. We re-examined this association by the use of truly population-based data from the Danish Cancer Register. One thousand and twenty-nine patients with carcinoid tumours diagnosed in Denmark 1978-89 were identified and followed for the occurrence of subsequent cancers. The ratio of observed to expected cancers calculated from population rates served as a measure of the relative cancer risk (RR). The annual age-adjusted incidence rate for carcinoid tumours was 1.1 per 100,000 person-years (world standardized). The overall relative risk of subsequent cancers was 1.1 (95% CI 0.8-1.6). Thyroid cancer, tumours of the brain and nervous system and non-Hodgkin's lymphomas were in excess. Overall, this study does not support previous findings of a general excess cancer risk in patients with carcinoid tumors. Significantly increased risks of cancer were observed at some sites, but these findings were based on small numbers, and consequently need further confirmation. PMID- 8686052 TI - [Ambulatory treatment of alcoholics. A prospective study]. AB - The present study covers 130 consecutive patients referred to the two outpatient clinics for alcoholism in Odense over a ten-month period from January to October 1993. The aim of the study was to describe the process of treatment over 12 months and assess the condition of the patients 12 months after the admission for treatment. All patients were assessed by means of the Addiction Severity Index at admission and after 12 months. While female alcoholics typically had psychiatric complaints, the drinking pattern was, however, alike for both sexes. Patients who themselves terminated their treatment had a significantly worse drinking pattern than those who completed treatment. Twelve months after the admission there was a significant decrease in the alcohol abuse and an improvement in psycho-social function for both sexes. PMID- 8686051 TI - [Clinical criteria for acute maxillary sinusitis in general practice]. AB - The purpose of the investigation was to examine the diagnostic value of various symptoms, clinical findings, erythrocyte sedimentation rate (ESR) and serum C reactive protein (CRP) in acute maxillary sinusitis using the aspiration of purulent or mucopurulent from the sinus of a patient with a pathological CT scanning as the golden standard. Of 174 patients with suspected acute maxillary sinusitis seen in general practice we found 70% to have a pathological CT scanning and 53% to have pus or mucous pus in the sinus aspirate. Only the ESR and CRP level were found to be significantly and independently associated with a positive diagnosis as defined by the golden standard. A clinical criterion based on either an elevated ESR and/or CRP level in a patient with pain related to the maxillary sinus region had sensitivity of 0.82, a specificity of 0.57, a positive predictive value of 0.68 and a negative predictive value of 0.75, and was diagnostically superior to the clinical examination. The investigation also confirms that this disease is most likely overdiagnosed in general practice. PMID- 8686053 TI - [Ordering and use of blood in elective surgery in Denmark. SANGUIS--a quality assurance project]. PMID- 8686054 TI - [Treatment of non-small-cell lung cancer and solitary adrenal gland metastasis]. AB - A patient with non-small-cell lung cancer and a solitary adrenal metastasis was treated with right subsegmental pulmonary resection and right adrenalectomy. Four months later an upper right lobectomy was performed because of local recurrence. Forty-one months following the initial operation the patient is doing fine without signs or symptoms of recurrence. Adrenalectomy because of a solitary adrenal metastasis in patients with non-small-cell lung cancer may offer the opportunity of prolonged survival, when a radical thoracotomy can be performed. PMID- 8686056 TI - [What is the best method for the examination of the deep biliary tract?]. PMID- 8686055 TI - [Vitamin A in pregnancy]. PMID- 8686057 TI - [Primary care and transportation of patients with neural trauma]. AB - It is well-known that it is difficult for the inexperienced doctor to estimate the need for treatment regarding patients with acute brain trauma. Brain ischaemia developing after a brain trauma (secondary cerebral ischaemia) is known to severely worsen the prognosis of the patient. This article gives a review of the most important pathophysiological changes occurring during the acute phase of severe brain trauma. The principles of prevention and management of cerebral ischaemia after brain trauma and during transportation of the patient are discussed. PMID- 8686058 TI - [The value of intravenous cholangiography prior to elective laparoscopic cholecystectomy]. AB - Thirty-eight patients admitted for elective cholecystectomy were preoperatively evaluated by means of liver function tests, ultrasonographic examination and intravenous cholangiography (IVC). Common bile duct stones (CBS) were found in four patients (11%, 95% confidence limits 3-25%). Due to a history of jaundice and/or elevated liver function tests, CBS were suspected in three of these patients, and unexpected in one. Totally, CBS were suspected in eight patients, either because of their history and/or elevated liver function tests. No side effects were observed during or after the IVC procedure. It can be concluded that IVC is a lenient procedure for radiological assessment of the common bile duct prior to elective laparoscopic cholecystectomy. It can be recommended as an alternative to diagnostic endoscopic retrograde cholangiography in patients in whom CBS are suspected. PMID- 8686059 TI - [Deliveries at a department of surgery during a 10-year period]. AB - In order to see whether the pattern of referral of pregnant women, intervention during labour and transport of neonates had changed over a 10-year period, we investigated these variables in the women who gave birth at our department of surgery in 1978, 1981 and 1988. The numbers of women were 790, 630 and 697 respectively for the three years, and the corresponding numbers of neonates transferred to the neonatal unit were 56, 44 and 53 respectively. The frequencies of risk pregnancies increased from 20% in 1978 to 37.7% in 1999, (p < 10(-6) and the frequency of primiparity increased from 43% to 51.2% over the same period (p < 10(-5)). More women underwent elective caesarean section due to an increased number of breech presentation in nulliparous women (p < 10(-3)). The frequency of induction of labour decreased from 21.7% to 16.5% (p < 10(-6)). The perinatal mortality ranges between 0% to 0.48% during the 10 years, and the rates of transfer of neonates to the neonatal unit were unchanged (7.1-7.6%). It is concluded that changes in referral and composition of the population had no influence on the incidence of acute intervention in labour or rate of neonatal transfer. PMID- 8686060 TI - [The Danish Pacemaker Registry. A database for quality assurance]. AB - The Danish Pacemaker Register was established in 1982 and since then all Danish pacemaker and lead implantations have been registered on a prospective basis by use of the European Pacemaker Patient Identification Card. The Register contains data on 17,002 patients with an implanted pacemaker. In 1994 the implantation rate was 314 per million inhabitants. The ECG indication was atrioventricular conduction disturbances in 46%, sick sinus syndrome in 37% and atrial fibrillation with bradycardia in 13%. Fifteen percent received a single atrial system and 41%, a dual chamber system. In 62% a rate adaptive pacemaker was used. Overall, the international recommendations for choice of pacing mode were met in 64% of the implantations. As the 11 implanting centres in Denmark report to the Register with a few days delay from the intervention, the Register is able to detect any irregularity in pacemaker or lead function within a very short period of time. PMID- 8686061 TI - [Drug induced fatal anaphylactic shock in Denmark 1968-1990]. AB - Based on notifications to the Danish Committee on Adverse Drug Reactions and to the Central Death Register, 30 cases of fatal drug-induced anaphylactic shock were identified during the period 1968-1990. The most frequent causes were contrast media for X-ray examinations, antibiotics, and extracts of allergens. Nine cases occurred outside hospital; they were mainly caused by the use of allergen extracts of moulds for desensitization in general practice. Fatal drug induced anaphylactic shock is rare, estimated in the present study at 0.3 cases per million inhabitants per year. PMID- 8686062 TI - [Esophagoscopy in patients with angina pectoris and normal coronary arteriography]. AB - The clinical value of oesophago-gastro-duodenoscopy and distal oesophageal biopsies was investigated in 49 patients with angina pectoris and normal coronary angiograms. The results were compared to 24 hour oesophageal pH-monitoring of the patients and of a control group of 22 healthy sons. Macroscopic esophagitis- mainly grade I was found in 31% of the patients and microscopic oesophagitis in 25%. The only major abnormalities were the identification of three peptic ulcers (6%). Median (range) reflux index was 1.3 (0.0-13.4) in the patient group and 2.1 (0.0-9.9) in the controls (p = 0.49). There were no differences with respect to endoscopical findings or reflux index between patients with a positive and patients with a normal exercise electrocardiogram. At a median 36 months post study 38% of the patients had undergone acid secretion inhibitor treatment with an effect on symptoms in only 4%. The study provides evidence that routine oesophago-gastro-duodenoscopy is of limited value in this patient group. PMID- 8686063 TI - [Ectopic thyroid gland in the submandibular region]. AB - A case of an ectopic thyroid gland in the submandibular region is presented. The embryological aspects are discussed. PMID- 8686064 TI - [Large epiglottic lipoma. Intubation method for large tumors in the pharynx and larynx]. AB - Large benign tumours in the aperture of the larynx are uncommon, and they are especially rare on the epiglottis. They are, however, important as they may cause fatal airway obstruction particularly at induction of general anaesthesia. We present a patient with a large lipoma originating in the vallecula epiglottica and the lingual surface of the epiglottis. The difficulties involved in tracheal intubation and possible solutions are discussed. In this case intubation was performed under local anaesthesia with the patient fully awake. A commissure laryngoscope was used for visualisation of the laryngeal inlet and a flexible bougie was inserted into the trachea. After removal of the laryngoscope a 7 mm ID endotracheal tube was advanced over the bougie into the trachea. After securing the airway in this way general anaesthesia was induced and the table tennis ball sized lipoma was uneventfully removed. PMID- 8686065 TI - [Renorenal reflexes]. PMID- 8686066 TI - [Screening for breast cancer]. PMID- 8686067 TI - [The concept of depression and evaluation of the effect of antidepressive agents]. PMID- 8686068 TI - [Active treatment of terminal uremia in Denmark]. PMID- 8686069 TI - [Active treatment of uremia in the study county of Vejle. Epidemiology 1979-1994 and future perspectives]. AB - We studied 275 renal replacement therapy (RRT) patients in a Danish county (population 329,000) from January 1st 1979 to June 30th 1994. Incidence, prevalence and age of new patients increased. The fraction of patients with diabetic nephropathy also increased. Patient survival remained constant (five year survival 62% for patients observed for more than 90 days). The total number of new patients entering haemodialysis and peritoneal dialysis seemed to be reaching a constant level, that could be calculated using a logistic function. The fraction of patients leaving therapy remained constant over the years and was higher for peritoneal dialysis than for haemodialysis (32 vs. 20% per year). The future prevalence can be estimated by combining these two last findings. PMID- 8686070 TI - [Transmyocardial laser revascularization. A new possible method for treatment of ischemic heart disease]. AB - Transmyocardial laser revascularization (TMR) using a CO2 laser or a holmium YAG laser represents a novel approach to treating coronary artery disease. Through a left thoracotomy, 15-30 transmural channels approximately 1 mm in diameter, are created with the laser through reperfusable areas of the left ventricular free wall of the beating heart. This allows blood to flow directly from the left ventricle into the myocardial vascular network. The epicardial holes seal within few minutes. More than 1000 patients have had TMR worldwide. Indications are not fully established. Preliminary results suggest that TMR may be of value either as an adjunct to coronary bypass surgery, or in patients in whom another invasive treatment is not an option. Results from randomized, controlled studies are not yet available. PMID- 8686071 TI - [Characteristics of mortality among patients waiting for coronary arteriographic evaluation or heart surgery]. AB - It was the aim to reduce deaths among future patients queuing for heart catheterization or surgery. All the patients who died, after they were referred for heart catheterization or surgery because of coronary heart and heart valve disease, were registered over a three year period (July 1, 1990 to June 30, 1993). The total number of deaths was 98. Ninety-two (94%) died of cardiac disease. Seventyfour (80%) only had symptoms of cardiac disease; ten (11%) had competitive disease and eight (9%) had received revascularizing treatment previously. The number of catheterizations increased from 968 to 1312 per year, while the number of operations remained constant at about 600 per year. The death rate for patients referred to heart catheterization was 2.5% for patients with aortic valve disease and 1.7% for patients with coronary heart disease. For patients referred for coronary artery bypass grafting the death-rate was 2.6% and for heart valve surgery 3.9%. The survival-time for patients waiting for catheterization was 4.2 months (0.3-16) and 4 months (1-16) for patients waiting for surgery. Half of the deaths in patients queuing for cardiac catheterization occurred within one month of waiting while half of the deaths in patients waiting for heart surgery appeared within 1.3 months. In the early deaths among patients queuing for cardiac catheterization there was a tendency towards prolonged doctor's delay and a surplus of patients with aortic valve disease. Deaths among patients awaiting heart catheterization or surgery can hardly be avoided. However, in the present study the death-rates for patients referred to surgery was 1.8 to 7.7 times higher compared to the conditions in other Western countries. The waiting-time was long and cardiac deaths frequent, reflecting the low capacity for invasive procedures as well as operations during this period. PMID- 8686072 TI - [Lesions of the ureter in radical hysterectomy for cervical cancer]. AB - Eight ureter lesions of the ureter occurred among 100 consecutive patients undergoing radical hysterectomy for cancer of the uterine cervix. The management of this problem is discussed, and treatment guidelines for the most commonly seen lesions are proposed. It is concluded that a more liberal use of ureteric stents or catheters should be considered so as to reduce the number of ureteric lesions occurring in connection with radical hysterectomy. Urological assistance should be sought for urological lesions recognized during or after such operations. PMID- 8686073 TI - [Late abortions in the county of Northern Jutland]. AB - Applications for termination of pregnancy beyond 12 weeks have been evaluated for the period 1992-1993 in the County of Northern Jutland. During this period the number of abortions performed later than 12 weeks of pregnancy has been reduced compared to the findings in 1986, while the total number of abortions performed in the county is unchanged. Abortions allowed on genetic indications have increased by 100% a year. Young women below 20 years of age still represent one third of late applicants for abortion. The amount of errors committed by doctors contributing to late applications shows a decreasing tendency. The use of ultrasonic scanning is increasing. PMID- 8686074 TI - [Isolated systolic hypertension: a significant risk factor of cerebral apoplexy and acute myocardial infarction. A prospective population based study]. AB - The aim of this prospective population based study was to determine the prevalence of isolated systolic hypertension (ISH) and associated cardiovascular risk. ISH was defined as systolic blood pressure > or = 160 mmHg and diastolic blood pressure < 90 mmHg. The associated risk of stroke and myocardial infarction (MI) was assessed using a multivariate Cox regression model. Subjects (n = 6621) were included if aged 50 or older, without antihypertensive or cardiac medicine, and without a previous stroke or MI. The prevalence of ISH increased from 3% among fifty-year olds to 13% among seventy-year olds. No sex difference was found. Adjusted relative risk of stroke was 3.0 (95% CI 1.6-5.3) for women and 2.7 (1.8-4.3) for men when compared to normotensives. Adjusted relative risk of MI was 0.8 (0.3-2.0) for women and 1.6 (1.0-2.5) for men. Population attributable risk percent for stroke associated with ISH is up to 30%. PMID- 8686075 TI - [Smoking among pregnant women and the significance of sociodemographic factors on smoking cessation]. AB - In order to describe smoking habits among pregnant women and predictors of smoking cessation all pregnant women attending routine antenatal care from 1989 to 1991 at the Department of Obstetrics, Aarhus University Hospital, were asked to fill in questionnaires. Information about smoking habits from 8806 women revealed that 44% smoked prior to pregnancy. One fifth of the smokers stopped smoking early in pregnancy, leaving 33% women smoking during pregnancy. The strongest predictor of smoking cessation was the number of cigarettes smoked prior to pregnancy, where those that smoked the least were most likely to give up smoking. Caffeine intake, parity, years of education, and partner's smoking habits were also associated with smoking cessation whereas social status, alcohol intake, marital status, and age of the women had no influence on smoking cessation. Thus, a strategy for a smoking cessation campaign among pregnant women could be directed towards women who smoke heavily prior to pregnancy and women with a high daily intake of caffeine. PMID- 8686076 TI - [Leiomyosarcoma of the spermatic cord]. AB - Sarcoma of the spermatic cord is a rare disease with less than 300 cases reported in the literature. A case of leiomyosarcoma is presented, and an analysis of the therapeutic approaches of radical orchidectomy, and in some cases retroperitoneal lymph node dissection, chemotherapy and radiation is given. The total numbers of different types of sarcomas in the spermatic cord, reported to The Danish Department of Cancer Registration are briefly presented as well. PMID- 8686077 TI - [Copper-induced green hair. Treatment with a penicillamine containing shampoo]. AB - A male patient with green hair is described. The cause was exogenous deposition of copper from domestic tap water which contained an increased copper concentration. The discolouration disappeared promptly following the use of a penicillamine containing shampoo. PMID- 8686078 TI - [More stringent guidelines for tympanostomy tubes in secretory otitis media in the USA]. PMID- 8686079 TI - [Beta-carotene--problems in health studies of simple antioxidants]. PMID- 8686080 TI - [Losartan. The first non-peptide angiotensin II receptor antagonist for treatment of hypertension]. PMID- 8686081 TI - [Traumatic dislocations of the cranial cervical spine in childhood]. PMID- 8686082 TI - [Possibilities and limits of interpretation of muscle sonograms. An experimental study of standardized muscle injuries]. AB - After sonographical examination we performed surgically an experimental muscle injury of known size and location on 28 New Zealand white rabbits by a stab with a scalpel into the supraspinatic muscle. The changes in the healing process were sonographically followed and documented for 2 months in short periods of time. The sonographically detectable changes during the healing process underlie a regularity. The changes in sonography can be explained by histopathology with respect to the theoretics of ultrasound physics. The development of a hematoma and of fibrous scars can be followed up by sonography with respect to some limits. Sonography is shown to be a supporting method of high value in the diagnosis of muscle injuries and with respect to certain limits in the follow-up of the healing process, too. PMID- 8686083 TI - [Electromyography studies of surgically managed knee ligament ruptures. A retrospective analysis of defined injury patterns]. AB - In 52 patients (5 groups, average age 32.8 years) with operative treatment of knee ligament injuries cutaneous electromyograms (EMG) under dynamic and isometric conditions (100 N, 200 N, 300 N) were performed in an average of 61.2 weeks postoperatively. The subgroups consisted of 13 patients with operative reconstruction of the anterior cruciate ligament (ACL), 12 after reconstruction of the medial collateral ligament (MCL), 21 after combined ACL and MCL reconstruction and 6 patients with autologous or alloplastic ligament replacement, respectively. The control group consisted of seventeen young adults without a history of knee joint injuries. The intensified and filtered analogous signals of 8 investigated thigh muscles were digitalized and analysed with help of a specially developed computer program. In summary, group specific EMG criteria reveal distinct ligamentomuscular inhibitory reflexes and, vice versa, EMG activities of thigh muscles may indicate tendencies for group specific criterion after operatively treated knee ligament injuries. PMID- 8686085 TI - [Value of ultrasound examination in injuries of the symphysis]. AB - Lesions of the symphisis are usually diagnosed by a pelvis X-ray. The use of ultrasound examination is not very common. The application of the ultrasonic head in a suprasymphyseal manner will result in good images of the anterior pelvis. The outcome of diastasis as well as of the edge of the symphysis measurements taken by ultrasound were comparable to the X-ray picture. Therefore ultrasound investigation is usefull for primary diagnosis and follow-up examination in injuries of the symphysis. Accompanying fractures of the pelvic ring stay in this case undetected. PMID- 8686084 TI - [Detection of the tendon of the musculus plantaris longus--diagnostic imaging and anatomic correlate]. AB - Using ultrasound as well as magnetic resonance imaging (MRI) and computed tomography (CT), the plantaris tendon can be identified between the top of the calcaneus and the upper third of the lower leg in cross sections. Due to the surrounding fat tissue, the best proof of plantaris tendon existence and diameter can be obtained on sections at the level of syndesmosis and ankle joint. This allows to avoid unnecessary incisions during plastic and reconstructive surgery using this tendon as an autologeous transplant. For the experienced examiner ultrasound seems to be the easiest way to show plantaris tendon existence; in case of doubt, MRI or CT will give further information. PMID- 8686086 TI - [Morphology of the carpal tunnel. Movement studies in patients with constriction symptoms and healthy probands using MR tomography]. AB - The morphological correlation of the phenomenon of increased pressure in the carpal tunnel during wrist flexion and extension--as has been proved though measurements using wick-catheters--was studied in healthy subjects (n = 15) and symptomatic patients with carpal tunnel syndrome (n = 15). Our own measurements using magnetic resonance imaging (MRI) showed that there is a significant reproducible decrease in carpal tunnel diameter when the wrist is held in position of either flexion or extension. During flexion the diameter is decreased at the pisiformes and hamate level as well as it is lowered during extension at the pisiformes level. This might explain the rise in carpal tunnel pressure and thus the consecutive negative influence on the median nerve. Proximal swelling, distal flattening and increased signal intensity of the median nerve as well as the palmar bulging of the flexor retinaculum at the level of the hook of the hamate and at the level of the pisiformes were significantly higher in patients with carpal tunnel syndrome than in normal volunteers (from p < 0.05 to p < 0.001). In post-operative follow-up examinations of 13 patients with no clinic symptoms the distal flattening of the median nerve normalized in 94% within 3 months. The increased signal of the median nerve on T2-weighted images decreased postoperatively in 2/3 of the patients, whereas the motor latency of the median nerve recovered only in 39% of our patients who had 100% partial or complete clinical benefit. These findings imply that postoperative imaging may be helpful for evaluating the success or failure of surgical treatment. PMID- 8686087 TI - [Functional anatomy of the posterior cruciate ligament]. AB - The human posterior cruciate ligament (7 unselected specimens) consists of 2 different bundles with a common tibial attachment: 1. a thin, flat and slightly twisted posterior bundle running to the posterior medial condyle taut in extension and lax in flexion of the knee, 2. a thick oval anterior bundle with parallel fibers running to the roof of the notch lax in extension and taut in flexion. This contra-tensile function explains the different posterior instability in extension or flexion of the knee in case of an isolated rupture of only 1 of these bundles. PMID- 8686090 TI - [Placement of anti-rotation screw using a fixed parallel bore guide device in dynamic hip screw management of hip para-articular femoral fractures]. AB - We implanted in case of hip-near fractures of the femur after DHS the anti rotation screw with help of a special parallel drill guide. It was possible to position the anti-rotation screw in a parallel fashion in all patients so that the dynamic effect of the DHS was not impaired and a faulty penetration of the screw into the hip by a badly positioned anti-rotation screw could be avoided. The radiological follow up shows us no sign of impaired healing. PMID- 8686088 TI - [Clinical relevance of fat embolism. Review of the literature]. AB - Fat embolism is since many decades a known and feared complication of fracture of long bones, polytrauma and also in endoprosthetic surgery. During this literature study old and actual experiences about fat embolism, in reference to pathophysiology and diagnosis, were summarized, the actual state of knowledge defined and also different possibilities of reducing fat embolism risks presented and evaluated. In order to estimate the clinical importance of fat embolism, 106 cases of fat embolism (51 clinical and 55 death cases) after hip and knee endoprosthesis were obtained from the literature and retrospectively compared with the results obtained by our own patients. Within a period of 10 years there were in Kantonsspital Liestal 834 primary hip prosthesis and 235 revisions, with 3 deaths. In none of the cases, fat embolism could be shown. Seven patients had respiratory complications after operation, but in only 2 cases the suspicion of fat embolism could not be excluded with certainty. Only 1 case out of 6 patients who had to stay in the intensive care unit after the operation could possibly be connected with intraoperative liberation of fat. At the end of this study simple and clinical proven methods are suggested, which can be helpful to reduce the risks of fat embolism. PMID- 8686089 TI - [Risk and prognosis of hip para-articular fractures. A comparison of treatment results of femoral neck and pertrochanteric femoral fractures]. AB - Fractures of the femoral neck and the intertrochanteric region account for 7.2% of our surgically treated trauma-patients. Thanks to gentle anaesthetic methods, pre- and postoperative intensive care, and using dynamic hip screws for stabilizing intertrochanteric fractures or total hip replacement in hybrid technique for fractures of the femoral neck, hospital mortality has decreased to 4.8%. A rate of 8.5% local complications, 5% of them needing revisional surgery, did not influence the final outcome. However, success of rehabilitation of the elderly patients is limited by pre-existing multimorbidity. Despite of achieved weight bearing strength of reconstruction, the number of people confined to bed increases from preoperative 4.9% to postoperative 11.5% at the end of 4 weeks hospitalization and up to 22.6% after 1 year. The need for permanent help in daily life activities, provided by the family or nursing homes increases from 50% to 80% after hospital discharge, usually with an increasing need for care. In the future--besides more and better organized out-patient physiotherapy--only more possibilities to look after the patients in their own families or the supply with an increasing number of places in nursing homes will give a chance, to provide a maximum of rehabilitation for these patients. PMID- 8686092 TI - [Emergency medical care in rescue work in the Hessen area]. PMID- 8686091 TI - [Recurrent hemarthrosis after cruciate ligament refixation by wire suture. A case report]. AB - Recurrent haemarthros is described as consequence of cruciate ligament repair. The main cause of haemarthros is described after unisometric fixation of the ligaments which leads to the rupture of the synovia membrane. This is a case report of a young man, who suffered from recurrent haemarthros for several years although he has intensively examined by radiological and arthroscopical means. It was falsely presumed to be a muscular arthrophy. The cause, however, was found in a wire suture, which was used to fix the anterior cruciate ligament in the femoral bone. This suture was laying under the synovia within the ligament and there fore could be seen and taken away arthroscopically only after total synovialectomy. PMID- 8686093 TI - Mesotheliomas all: long before their time. PMID- 8686094 TI - How to organise a year abroad. PMID- 8686096 TI - The thirtieth anniversary of pre-hospital coronary care in Belfast. PMID- 8686095 TI - The incidence and distribution of leukaemia and lymphoma within Northern Ireland in the period 1989-1993. AB - This is the first attempt to systematically record haematological malignancies in Northern Ireland. The methods are identical to a similar effort in other parts of the UK, except that an independent cross check with a cancer registry source was not possible. In addition problems with the census may create differences. Generally, the rates for the leukaemias are slightly lower than in England and Wales, except for acute lymphoblastic leukaemia whilst non-Hodgkin's lymphoma rates are higher. It remains to be seen how stable this situation is as further data are accumulated. PMID- 8686097 TI - Audit of surgical delay in relationship to outcome after proximal femoral fracture. AB - To ascertain the influence of surgical delay on outcome after proximal femoral fracture in elderly females, a cohort study of patients presenting in 1987 was compared to 1989/90. Organisational changes in the intervening period were introduced to reduce delay to surgical intervention. Two hundred and eighty females aged 65 years and over presenting from the local catchment area of an acute inner-city teaching hospital were enrolled in the study. Seventy-nine patients received surgery in 1987 and 186 in 1989/90. The one year mortality was 34% and 26% respectively. The proportion receiving surgery within 24 hours rose from 34% in 1987 to 57% in 1989/90. The relative hazard of the group receiving surgery on day 2 in comparison to day 1 was 1.7 (95% CI 1.0 to 2.9) when adjusted for co-variance of age and mental score. Medically fit elderly patients presenting with proximal femoral fracture have improved survival with early surgery within 24 hours of admission. Improvements in the organisation of hospital care will result in important benefits for the increasing number of elderly females presenting with proximal femoral fracture. PMID- 8686098 TI - The provision of adult intensive care in Northern Ireland with reference to the role of high dependency care. AB - In 1991 an audit of Intensive Care Services was carried out by the Northern Ireland Intensive Care Group. In conjunction with this regional overview, all patients in the Regional Intensive Care Unit, (RICU) in the Royal Victoria Hospital were assessed daily, over a 10 month period in 1990-91 and classified as conforming to either intensive care or high dependency status. These data were then used to compare adult intensive care service in Northern Ireland with recent national and international recommendations on intensive care. Ten units in Northern Ireland were surveyed. In regard to national or international guidelines, all ten were deficient to some degree. Four units had significant deficiencies; small patient numbers, lack of 'dedicated' 24 hr medical cover and or deficiencies in the provision of appropriate monitoring and or equipment. There was a large diversity in casemix among the ten units surveyed which suggested differing admission criteria. The bed occupancy of RICU was 100%. Refused admissions constituted a further 13% of unresourced workload. The lack of physically separate, dedicated high dependency unit facilities meant that 26% of bed days were devoted to HDU care (usually for "improved" intensive care unit patients not yet ready for discharge to a general ward. Achieving nationally recommended intensive care standards (on a regional basis) is probably only possible if a number of the smaller intensive care units are redesignated as high dependency units, and patients requiring intensive care are concentrated in a smaller number of larger ICUs. This will increase the frequency of interhospital transfer of critically ill patients. PMID- 8686099 TI - Home ventilation in Northern Ireland. AB - Thirteen patients were identified as receiving assisted ventilation at home in Northern Ireland in 1994. Two patients have since died. An increasing number of patients are starting home ventilation, especially by nasal mask. Recognition of the needs of these patients and provision of care require further consideration. PMID- 8686100 TI - Disease oriented medicine: the metabolic model. PMID- 8686101 TI - A comparison of the effect of intramuscular diclofenac, ketorolac or piroxicam on postoperative pain following laparoscopy. AB - Sixty patients presenting for in-patient gynaecological laparoscopic surgery were randomly allocated to receive either diclofenac 75 mg (n = 20), ketorolac 30 mg (n = 20) or piroxicam 20 mg (n = 20) as an intra-muscular injection immediately after induction of anaesthesia. Postoperative visual analogue scores over the first 24 hours, using a 10 cm scale, ranged from 3.2-0.5 in the diclofenac group, 2.7-0.85 in the ketorolac group and 2.8-0.5 in the piroxicam group. The scores did not differ significantly between the three groups (p > 0.05). Mean time (SD) to first analgesia was 27(94) minutes in the piroxicam group, 16 (30) minutes in the diclofenac group and 62 (120) minutes in the piroxicam group. Six out of twenty patients in the diclofenac group required further analgesia compared to nine out of twenty in the other two drug groups. This difference was not significant. There were no reports of increased bleeding, bronchoconstriction, bleeding from the upper gastrointestinal tract, renal impairment or pain from the intra-muscular injection site in any of the groups. The administration of a non steroidal anti-inflammatory drug to patients presenting for laparoscopic surgery reduces postoperative pain. There were no obvious differences between the agents used. PMID- 8686102 TI - Antineutrophil cytoplasmic antibodies in myelodysplasia. AB - Antibodies to neutrophil cytoplasmic antigens (ANCA) are good serological markers for patients with mainly vasculitic conditions. Two main types of ANCAs have been detected, the first termed cytoplasmic antineutrophil cytoplasmic antibody (cANCA) are mainly associated with patients with Wegener's granulomatosis, the other termed perinuclear antineutrophil cytoplasmic antibody (pANCA) are mainly associated with patients with renal vasculitis, rheumatic and collagen disorders. These antibodies are against various constituents of neutrophil granules. In patients with myelodysplasia, defects in normal granulocyte development are seen. We report a series of twelve patients with myelodysplasia of whom at least four showed a low titre and one a high titre of pANCA. Two of these patients also had demonstrable activity against myeloperoxidase (MPO). None of these patients had any evidence of systemic or cutaneous vasculitis or of any autoimmune disorder. There was no pANCA positivity in an age matched control group. PMID- 8686103 TI - Coccygodynia. AB - Ten coccygectomies were performed. Patients were all females (aged 26-74, average 46). All patients expressed satisfaction after the operation (one was deceased at the time of follow up). The material is too small for definitive conclusions, but it shows clearly that carefully selected cases with traumatic or idiopathic coccygodynia could benefit from coccygectomy. PMID- 8686104 TI - The Clinician Scientist--an endangered species? Annual oration--Royal Victoria Hospital--5th October 1995. PMID- 8686105 TI - A history of prehospital coronary care. PMID- 8686106 TI - 36 years of renal services at the Belfast City Hospital: looking back. PMID- 8686107 TI - MRI findings in a rare cause of bladder outlet obstruction. PMID- 8686108 TI - Idiopathic spontaneous pneumoperitoneum--avoiding laparotomy--a case report. PMID- 8686109 TI - Oral phentolamine mesylate in the treatment of complex regional pain syndrome. PMID- 8686110 TI - Necrotizing fasciitis: two cases in a single family. PMID- 8686111 TI - Transverse myelitis: a complication of systemic lupus erythematosus that is associated with the antiphospholipid syndrome. PMID- 8686112 TI - Synovial chondromatosis of the cubometatarsal joint. PMID- 8686113 TI - [Surgical treatment of kidney cancer with tumor thrombus invasion of the inferior vena cava]. AB - The paper presents original experience in the examination and surgical treatment of 61 patients with renal carcinoma thrombing the inferior vena cava. The thrombi are classified as floating (8) and occlusive (53). Subhepatic, retrohepatic, supradiaphragmatic and intracardial thrombi are distinguished by location of the thrombus top. The staging and the scope of cavatomy in respect to the thrombus occlusion site in the vena is specified. It turned out that the higher thrombic invasion is, the more serious is surgical invasion and worse are long-term outcomes. The conclusion on feasibility of effective treatment of the above condition is made. PMID- 8686114 TI - [Conservative surgery in tumors of the renal parenchyma]. AB - Policy in diagnosis and conservative therapy of renal parenchyma tumors is considered for bilateral lesion, single kidney, combination of renal tumor with renal failure, small-size tumors in normal renal function. The authors advocate all kinds of renal resection. Enucleation is feasible in the single kidney having encapsulated tumor of 3 and less cm in size. PMID- 8686115 TI - [The treatment procedure in patients with a combination of kidney tumor and urolithiasis]. AB - Renal carcinoma and urolithiasis combine rather rarely. Postnephrectomy patients often consult the urologist when the condition is serious because of complications resultant from uroliths in the contralateral kedney. In view of solitary kidney, progressive chronic pyelonephritis, associated chronic renal failure surgical treatment of the condition becomes risky and necessitates individual approach to choice of therapeutic policy and definition of indications to urolithiasis treatment in patients after nephrectomy for renal carcinoma. This includes the decision whether to perform nephrolithiasis before or after nephrectomy and whether to attempt any surgery in the absence of urolithiasis clinical symptoms. PMID- 8686116 TI - [Statistics on oncological urologic diseases in Russia]. AB - Incidence rate of male urogenital cancer has increased for 1975-1993 by 138.7% reaching 27,700. The disease-specific trends in prevalence, morbidity and mortality are outlined. The rise in urogenital cancer incidence is attributed to higher risk to develop the disease rather than to growing percentage of the elderly among overall population. Mean lifespan of Russian population due to urological cancer mortality is cut by 2 months. Fatal cases live by 11-19 years less than healthy subjects. Economical losses because of deaths of urological cancer make up 187.3 million rubles in 1990 prices. PMID- 8686117 TI - [Wilms' tumor in adults]. AB - 4 rare cases are reported of adult Wilms' tumor in females aged 35-65. It had been developing subclinically for a long time and was detected at palpation or at abdominal ultrasonography. In the 35-year-old woman the weight of the removed tumor reached 3.5 kg. Wilms' tumor in the adults seems to run asymptomatically and, consequently, is likely to be diagnosed late. PMID- 8686118 TI - [Management of nephroblastoma in children: current approaches and outlook]. AB - Nephroblastoma or Wilms' tumor occurs most frequently in children. New approaches to diagnosis and treatment of this malignancy introduced for the last 15 years are reviewed. Current approaches are characterized by advances in computer noninvasive diagnostic techniques and more aggressive chemotherapy. The first line treatment is polychemotherapy (1 or 2 courses) followed by surgical intervention and postoperative drug or drug+radiation treatment. As shown by follow-up, 40% of patients with nephroblastoma stage III and IV are now free of recurrences and metastases for at least five years. Special investigations are needed to elucidate these children's quality of life, physical, social and mental fitness. Serious problems still remain in perfection of programmed treatment of children with prognostically unfavourable factors. PMID- 8686119 TI - [Nephroblastoma in infants in the 1st year of life]. PMID- 8686120 TI - [Second primary tumors in children after treatment for nephroblastoma]. PMID- 8686121 TI - [Anatomical validation for selecting a segment of large intestine for creating urinary reservoirs]. PMID- 8686123 TI - [Effect of the spread of the process and treatment on the phenotype of peripheral blood lymphocytes in patients with prostatic cancer]. AB - A wide panel of monoclonal antibodies to differentiation antigens has been originally used to determine phenotype of peripheral blood lymphocytes in patients with prostatic cancer (PC). Patients with local PC exhibited marked lymphocytopenia existent in vertually all populations and subpopulations. In generalized PC the above changes are more pronounced. Treatment of PC adds to immunodepression observed in this disease. Thus, immunotherapy as an adjuvant modality of PC treatment is quite appropriate. PMID- 8686122 TI - [Cyproterone acetate (Androcur-depo) in the treatment of inoperable prostatic cancer]. AB - The authors consider fundamentals of hormone therapy in prostate cancer, mechanism of long-term androgenic stimulation, detail mechanism of action of antiandrogen (ciproteron acetate-androcur) on the basis of discovered key role of cellular receptor in endocrine regulation of physiological functions in metabolism. Monotherapy with androcur-depo (300 mg once a week) was given to 24 patients with prostatic cancer stage T2-T4. Eight patients had metastases to the bones. The age of the patients ranged from 58 to 80 years. Alleviation of pain, reduction of the prostate size and density, positive uroflowmetric changes (maximal urination rate increased from 2-5 to 10-15 ml/s), residual urine fall occurred as early as treatment week 5-7. There was also a decrease in the activity of acid phosphotase from 5-10 to 0.3-0.8 units according to Bodansky. Serum level of prostate-specific antigen (PSA) dropped from 388-23 to 116-4 ng/ml. Androcur-depo monotherapy demonstrated high efficacy in the treatment of local prostatic cancer. PMID- 8686124 TI - [Infrared telethermography in the diagnosis of testicular tumors]. AB - Diagnostic potential of infrared extracorporeal thermography (IET) was studied in 334 males: 167 with testicular tumors, 42 with acute or chronic epididimitis, 33 with orchitis, 17 with hydrocele and 75 controls. To assess thermography more objectively in large-size testicular tumors and bilateral lesions, a new thermographic criterium T3 was used. IET sensitivity, specificity and efficacy in testicular cancer made up 92.9%, 89.8% and 91.4%, respectively. In view of its safety, high efficacy, noninvasiveness and simplicity this method has perspectives in diagnosis of testicular diseases. PMID- 8686125 TI - [Current procedure for treating testicular germ-cell tumors]. AB - The treatment of testicular cancer has undergone considerable evolution since the introduction of cisplatin and widespread recognition of its curative potentials in any stage of this disease. The authors provide a review of today's therapeutic approaches to testicular cancer with special emphasis on the disease stage and tumor histology. PMID- 8686126 TI - [Organ-preserving treatment in cancer of the penis]. AB - Of 322 patients with squamous cell carcinoma of the penis, conservative therapy was conducted in 162 (50.3%) untreated patients free of metastases to regional lymph nodes. 125, 14 and 23 patients received radiation, drug and drug+radiation treatment, respectively. The efficacy of conservative treatment reached 74.6%, complete regression of the tumor was achieved in 61.1% of the cases. 8 patients with partial response (reduction of the tumor to 1 cm in size) were exposed to cryodestruction of the residual tumor. Thus, in 111 of 162 patients the penis was not amputated. Follow-up results show that within the period 4.5-14 years the disease relapsed in 20 of 111 patients, 4 patients throughout follow-up month 3-6 developed metastases to regional lymph nodes in the absence of recurrent tumor. It is concluded that amputation of the penis in early cancer should be made only in uneffective sparing therapy. PMID- 8686127 TI - [Late results of local transrectal hyperthermia in patients with benign prostatic hyperplasia and its complications]. AB - LTH on Yakhta-4M unit was used in benign prostatic hyperplasia (BPH). The prostate was heated transrectally by directional radiation. The course of treatment comprised 5 sessions for 60 min twice a week. The efficacy of the treatment was assessed 3 years later in 78 patients which were divided into 4 groups: 31 patients with BPH, 30 patients with BPH in combination with chronic prostatitis, 9 patients with acute urine retention and 8 patients with cystostomy fistula. 5 patients underwent surgery. LTH is safe in relation to side effects, may be used both at early stage of the disease and in risk of operative intervention. PMID- 8686128 TI - [Transurethral radiofrequency thermotherapy using the Thermex unit in benign prostatic hyperplasia]. PMID- 8686129 TI - [The All-Russian Conference with the participation of CIS Nations on Current Treatment Problems in Oncological Urologic Diseases]. PMID- 8686130 TI - [Symposium on Edex (alprostadil) in the diagnosis and treatment of erectile dysfunction]. PMID- 8686131 TI - [Management of patients with kidney cancer without distant metastases]. AB - The paper provides the analysis of treatment outcomes in 199 patients with local renal carcinoma. The highest effects were achieved in radical surgery followed by general hyperthermia with hyperglycemia and adriamycin chemotherapy. This approach allows to prolong the survival to 5 years in 94.3 +/- 5.5% of patients with renal carcinoma and tumor occlusion in the veins as well as in 60.9 +/- 10.4% of patients with metastases to the regional lymph nodes. These results are significantly better than in surgical and combined treatment including radiation. Preoperative large-fraction radiotherapy (14 Gy) significantly increases 5-year survival of renal cancer patients with tumor thrombus in the renal vein or inferior vena cava from 26.9 +/- 12.0 to 63.5 +/- 13.5% (p < 0.05). Additional postoperative radiotherapy in 2Gy fractions to total dose 40 Gy fails to affect survival of the above patients. Combined treatment using preoperative large fraction (14 Gy) and postoperative radiation in routine fractions (40 Gy) significantly improves 5-year survival against surgical treatment (22.2 +/- 7.1 and 5.4 +/- 3.8%, respectively) in patients with renal carcinoma metastasizing to regional lymph nodes. Large-fraction preoperative radiotherapy only in these patients adds little to the treatment efficacy. PMID- 8686132 TI - [The effect of experimental metabolic stress on ovulation and blood progesterone levels in cows]. AB - The effect of a long run subclinic metabolic stress of acidotic and alkalotic nature was examined with respect to the course of cloprostenol induced estrus, ovulation and progesterone levels in blood and milk. The stress of acidotic nature was induced by widening the ratio of digestible crude protein to total dietary energy to the value 1:8.1 in 11 cows, while the alkalotic stress was due to narrowing the nutrient ratio to 1:2.81 in eight cows. Control group with the nutrient ratio 1:4.5-5 comprised 11 cows. The stress of acidotic nature was accompanied by ovulation disorders in 4 out of 11 cows (36.4%), in the group with the stress of alkalotic type it was in 2 out of 8 animals (25%). No ovulation disorders were observed in control group. Within 7 days after estrus, the average progesterone levels were 1.26 +/- 0.84 ng/ml in the blood of cows with stress of acidotic type, 3.48 +/- 2.99 in cows with stress of alkalotic type and 3.12 +/- 1.98 ng/ml in control cows. The differences between acidotic stress and control were statistically significant (P < 0.05). During the whole pregnancy (18 to 276 days), average progesterone levels were lowest in the group subjected to stress of acidotic nature. They ranged from 1.9 to 3.8 ng/ml with the average value 2.65 +/- 1.40 ng/ml. In the group with stress of alkalotic type they ranged from 2.55 to 5.43 ng/ml with the average value 3.67 +2- 2.29 ng/ml. In this control group, they ranged from 4.00 to 8.68 ng/ml with the average value 5.62 +2- 2.24 ng/ml. Variations in cortisol concentrations indicated a certain stressing effect of feeding rations on the internal environment of dairy cow organisms and activation of compensatory mechanisms. PMID- 8686133 TI - [The effect of vitamin E on cortisol and lactate levels and on the acid-base equilibrium in calves exposed to transportation stress]. AB - The objective of this study was to examine the effect of vitamin E administration on plasma levels of cortisol and lactate, and on acid base balance in transported calves. In the study, eight calves, aged approx. ten days, divided into two groups, were used. 20 mg of tocopherol-acetate per kg body weight were administered orally to each of the four experimental calves 24 hours before loading. The calves were transported by road for 3 hours. Blood samples collected before and after the transportation were examined for acid base balance, lactate, and plasma vitamin E and cortisol levels. The administration of vitamin E led to a decrease of cortisol levels in 24 hours (from 7.6 +/- 9.5 to 4.2 +/- 0.2 nmol/l) as well as to a significant increase (p < 0.05) of plasma vitamin E levels 26 h after administration (from 2.52 +/- 1.36 to 12.28 +/- 6.14 mumol/l). There was no difference between the groups in cortisol response due to transportation stress (Tab. III). The transportation caused typical stress changes in lactate levels and acid base balance (lactacidaemia and the tendency to acidosis, Tab. III, IV). There was approx. threefold increase in plasma lactate concentrations due to transportation (from 2.49 +/- 0.69 to 6.35 +/- 3.75 mmol/l). The results of the present study demonstrated metabolic changes which has been reported to be typical of mild physiological stress reaction. In the present study, vitamin E had no significant effect on plasma levels of cortisol, and lactate, and acid-base balance. PMID- 8686134 TI - Vibriosis in rainbow trout cultured in the Krka estuary, Croatia: occurrence and comments. AB - The frequency of vibriosis in cultured rainbow trout, maintained under different rearing conditions in the Krka estuary, was examined over a 6 yr period. Annual studies commenced regularly in October and ended in June of the following year. Every month during study periods, 37-75 trouts were randomly taken from each of 4 farm sites for routine examination. Twenty fish from these samples were subsequently employed for bacteriological analyses. Based on morphological and biochemical properties, the bacterial isolates were identified as Vibrio anguillarum, (biotype I). The findings demonstrate high occurrence of vibriosis in trout cultivated in the Krka estuary. Furthermore, there was a direct relationship between water quality parameters and the severity of vibriosis epizootics. Moreover, the causative agent has been isolated from free-living species, fish, notably eel and mullet, which are abundant to the Krka aquatorium. The findings from these long-term studies will be considered with reference to the developing salmon farming industry of Croatia. PMID- 8686135 TI - [IgG antibodies to Borrelia in dogs in the area of Kosice]. AB - An ELISA investigation showed that 26.9% of dogs in Kosice region were positive for anti-borrelia IgG antibodies. A significantly higher seroprevalence was detected only in hunting dogs (40.0%) compared with service dogs (11.8%; p < 0.05). An analysis of seroprevalence by age showed a significant difference only between dogs in the categories 1-3 years (37.8%) and under 1 year of age (8.3%; p < 0.05). In other age groups no significant differences in seroprevalence were observed. No significant difference in seroprevalence was detected between sex either. A high correlation was determined to exist between the seroprevalence and the number of engorged ticks (R = 0.8) and the frequency of the exposure of dogs to the tick-infested wooded areas with the focal occurrence of boreliae (R = 1). The analysis of results suggests that seroprevalence of Lyme borreliosis in dogs of the Kosice region is not negligible. The breed, age and sex do not influence the seroprevalence of the disease. The decisive role is, however, played by the time of the exposure of dogs to the environment infested by Borrelia-contaminated ticks. PMID- 8686136 TI - High-voltage electrophoretic identification of residual antibiotics in milk. AB - Residual antibiotics in milk were identified by high-voltage electrophoresis in 1% agarose gel and bioautographic detection. The test strain Bacillus subtilis BGA was used for the detection, pH of the culture medium was 8.0. An electrophoretic identification map of 13 selected antibiotics has been set up and the following minimal inhibition concentrations (MIC), expressed in microgram per 1 g, have been established: benzylpenicillin 0.06; ampicillin 0.25; streptomycin 0.5; dihydrostreptomycin 0.2; spectinomycin 40; gentamycin 0.06; neomycin 0.15; oxytetracycline 5; tetracycline 2.5; chlortetracycline 1; erythromycin 0.01; tylosin 1; chloramphenicol 20. The established values of MIC were compared with the Maximum Residue Limits (MRL) as defined currently in the legislation of the European Union. The condensation of samples by freeze-drying increased the sensitivity of the method which was used for the identification of residual antibiotics detected by microbiological screening techniques in milk. PMID- 8686137 TI - Detection of antibodies to Salmonella enteritidis in sera and yolks from experimentally and naturally infected chickens. AB - An indirect enzyme-linked immunosorbent assay (ELISA) based on the lipopolysaccharide (LPS) of Salmonella enteritidis phage type 4, was developed for the detection of antibodies to salmonella. Sera and yolks from chickens infected experimentally with S enteritidis showed strong positive reactions. Cross-reactions occurred with sera from chickens inoculated with S typhimurium or S gallinarum. Cross-reactions were weak with sera from chickens infected with five strains of other Enterobacteriaceae. The ELISA was tested with sera and yolks from commercial poultry flocks which were bacteriologically negative for salmonella or infected with salmonella serotypes belonging to serogroup D or to other serogroups. The serological reactions were strong in most flocks infected with S enteritidis and were weaker in flocks infected with S typhimurium. In some flocks infected with these serotypes no antibodies were detected. The correct setting of the cut-off value of the optical density in the ELISA makes it possible to discriminate between chickens which are infected with S enteritidis and chickens which are not infected with S enteritidis. PMID- 8686138 TI - Effect of post-coital intrauterine inoculation of porcine reproductive and respiratory syndrome virus on conception in gilts. AB - The effect of porcine reproductive and respiratory syndrome virus (PRRSV) on early gestation was investigated by exposing susceptible gilts to the virus shortly after they had been bred naturally. Sixteen gilts were exposed intrauterinely to PRRSV and 23 gilts received a sham inoculum. One day after exposure, and on or about seven, 14, and 30 days after exposure, the gilts were bled and the serum was tested for PRRSV and homologous antibody. The pregnancy status of each gilt was determined on day 30 by ultrasound, and near or at term either by necropsy or by allowing the gilts to farrow naturally. All 16 gilts exposed to PRRSV became infected, as evidenced by the detection of PRRSV in seven of the gilts and homologous antibody in the serum of all of them, whereas all the 23 gilts exposed to a sham inoculum remained free of both virus and antibody. Ten of the 16 infected gilts conceived, and 19 of the 23 uninfected gilts conceived, but the difference in conception rate was not statistically significant. Moreover, the mean numbers of live fetuses or pigs per litter of the infected and uninfected gilts were similar (9.7 and 9.3). These results suggest that the intrauterine infection of susceptible pigs with PRRSV at or near the time of conception may have little or no effect on their reproductive performance. PMID- 8686139 TI - Estimation of the liveweight and body condition of working donkeys in Morocco. AB - The age, sex, liveweight and body measurements (heart girth, umbilical girth, height, length from elbow to tuber ischii and circumference of the foreleg cannon bone) of 516 donkeys used to transport goods in Morocco were recorded. There were few donkeys over 12 years of age. For adult donkeys weighing from 74 to 252 kg, the best equation with only one variable for predicting liveweight was: liveweight (kg) = heart girth (cm)2.65/2188. The inclusion of two variables improved the prediction marginally, but the addition of further variables gave little further improvement. The best prediction equation for adult donkeys was: liveweight (kg) = (heart girth [cm]2.12 x length [cm]0.688)/380. For donkeys under three years of age, weighing from 52 to 128 kg, the best prediction equation was: liveweight (kg) = (umbilical girth [cm]1.41 x length [cm]1.09)/1000. Other liveweight prediction equations for donkeys and horses were tested on the data and tended to overestimate the weight of these working donkeys. A subjective method for assessing the body condition of the donkeys was developed, using a scale from 1 (emaciated) to 9 (obese). PMID- 8686140 TI - Behavioural and cortisol response of pigs and sheep during transport. PMID- 8686141 TI - Cryosurgical dehorning of calves: a preliminary study. PMID- 8686142 TI - Eradication programme for caseous lymphadenitis in goats in The Netherlands. PMID- 8686143 TI - Companion animal diets. PMID- 8686144 TI - Companion animal diets. PMID- 8686145 TI - Government and the cascade. PMID- 8686146 TI - Reviews of state veterinary services. PMID- 8686147 TI - Bovine embryo transfer. PMID- 8686148 TI - Calf deaths. PMID- 8686149 TI - Endocarditis in broiler breeder rearers due to Enterococcus hirae. PMID- 8686150 TI - Elimination of transmissible gastroenteritis virus from a pig farm by culling and serological surveillance. AB - The first and only outbreak of transmissible gastroenteritis in pigs in Ireland occurred in 1984 in a 650-sow unit which was one of three such units owned by one enterprise which supplied pigs to a 12,000 head fattening unit in the same ownership. The depopulation of the clinically infected unit and extensive serological monitoring of pigs in the other units and in pig farms throughout the country has proved successful in the elimination of transmissible gastroenteritis infections from pigs in Ireland. PMID- 8686151 TI - Computer-aided veterinary learning at the University of Cambridge. AB - An approach of computer-assisted learning in veterinary education at the University of Cambridge, involving the development of four types of learning module, is outlined. A tutorial on regional perineural anaesthesia in the horse, based on the familiar tape-slide format but with significant improvements, is described. A question and answer self-assessment package and a computer-based 'digital lecture' are also discussed, together with a case simulation involving the investigation of a polydipsic dog. All the tutorials were developed using standard software packages and image digitising processes. The philosophy behind the development of these computer-assisted learning packages is discussed. PMID- 8686152 TI - Haematological and biochemical values of 10 green iguanas (Iguana iguana). AB - Ten clinically healthy green iguanas (Iguana iguana) imported from South America were examined, and haematological and biochemical measurements were made on samples of blood. This paper describes the methods of blood sampling, handling and laboratory analysis, and presents the results as a set of normal blood ranges for the green iguana. PMID- 8686153 TI - Bacterial pneumonia associated with corticosteroid therapy in three horses. AB - Three horses developed severe pulmonary infections while being treated with systemic corticosteroids for other diseases. Two of them had an immune-mediated skin disease, compatible with a diagnosis of pemphigus foliaceus, and one had severe chronic obstructive pulmonary disease. Case 1 developed diffuse pneumonia from which Streptococcus zooepidemicus and Bacteroides melaninogenicus were isolated, and it responded to antibiotic therapy. Case 2 developed septicaemia, pulmonary thrombosis and pneumonia associated with Escherichia coli, and died during a peracute illness with signs of disseminated intravascular coagulation. Case 3 developed focal pneumonia from which S zooepidemicus was isolated. This horse was destroyed at the owner's request and no treatment was attempted. PMID- 8686154 TI - Detection of Cryptosporidium muris oocysts in the faeces of adult dairy cattle in Scotland. PMID- 8686155 TI - Isolation and identification of infectious bronchitis virus from pheasants. PMID- 8686157 TI - Wildlife rehabilitation. PMID- 8686156 TI - Isolation of the gram-negative bacterium, Serratia marcescens, from the sheep scab mite, Psoroptes ovis. PMID- 8686158 TI - Wildlife rehabilitation. PMID- 8686159 TI - Scrapie genotyping for Suffolk sheep. PMID- 8686161 TI - Neurological syndrome in Italian spinones. PMID- 8686160 TI - Intestinal obstruction with hemp bedding. PMID- 8686162 TI - Veterinary Practice Management Association. PMID- 8686163 TI - The prevalence of anthelmintic resistance in nematode parasites of sheep in southern Latin America: general overview. AB - South America has a large population of small ruminants. Currents estimates are approximately 100 million sheep and 23 million goats. A large percentage of these flocks are raised in the humid tropics/sub-tropics. Nematode parasitism is singly the most important disease of these animals and typically farmers resort to frequent anthelmintic treatment in attempts to control this problem. Because of this reliance on drugs, price consideration is an important determinant in a farmer's choice of anthelmintic. In some circumstances, this has led to unethical practices of drug adulteration and substitution, or the offering to farmers of cheap, sub-standard generic products. The prevalence of anthelmintic resistance has not been investigated in any widespread sense in South America, although some of the first reports of resistance were made in southern Brazil almost 30 years ago. The following series of papers outline surveys conducted in the humid topics/sub-tropics of southern Latin America to assess the significance of resistance to the broad-spectrum anthelmintic groups in nematode parasites of sheep flocks. PMID- 8686164 TI - The prevalence of anthelmintic resistance in nematode parasites of sheep in southern Latin America: Argentina. AB - Sixty-five sheep farms in the northern provinces of Buenos Aires, Entre Rios, Corrientes, Cordoba and Sante Fe were used in this survey on anthelmintic resistance. Anthelmintic groups tested were the benzimidazoles, levamisole, the combination levamisole + benzimidazole product and the avermectins. The overall level of resistance was 46% of properties, with resistance to the individual drug groups being 40%, 22%, 11% and 6%, respectively. On a large proportion of farms the resistance recorded was to two, or more, anthelmintic groups. Haemonchus contortus, Ostertagia spp. and Trichostrongylus spp. were the most abundant parasite species recorded. Resistance was greatest in the province of Corrientes where the frequency of treatment is generally high due to the endemic nature of H. contortus. Management practices were also important with resistance greatest on farms where frequent drenching is carried out and on farms carrying only sheep. PMID- 8686165 TI - The prevalence of anthelmintic resistance in nematode parasites of sheep in southern Latin America: Brazil. AB - This survey was conducted in the southern Brazilian state of Rio Grande do Sul and involved 182 farms located in 26 counties. In addition to the three major broad-spectrum anthelmintic groups (viz. benzimidazole, levamisole and ivermectin) the combination benzimidazole and levamisole and the H. contortus specific anthelmintic, closantel, were tested by the faecal egg count reduction method for the prevalence of anthelmintic resistance. Resistance was found to be 90%, 84%, 13%, 73% and 20%, respectively. This is a crisis situation. Immediate, drastic action needs to be implemented, otherwise the sheep industry in this region (approx. 10 million head) will soon face a lack of any effective anthelmintics with the inevitable consequences of major restructuring or abandonment. PMID- 8686166 TI - The prevalence of anthelmintic resistance in nematode parasites of sheep in southern Latin America: Paraguay. AB - This survey to detect anthelmintic resistance in nematode parasites of sheep was conducted on 11 farms in the Occidental and 26 farms in the Oriental Regions of Paraguay using the faecal egg count reduction test (FECRT). The anthelmintic groups tested were the benzimidazoles, levamisole and avermectins (both oral and injectable). Overall the levels of resistance were 73%, 68%, 73% and 47%, respectively. Levels of resistance were similar for all three important nematode genera, viz. Haemonchus contortus, Ostertagia and Trichostrongylus. This survey clearly indicates that a large, and ever increasing, proportion of sheep farmers are rapidly approaching the time when they will have exhausted all chemotherapeutic options to control parasites. Unless they face having to abandon their sheep farming operations, radical changes will need to be implemented with urgency. PMID- 8686167 TI - The prevalence of anthelmintic resistance in nematode parasites of sheep in southern Latin America: Uruguay. AB - This survey was conducted on 252 farms randomly distributed over all the sheep raising areas in Uruguay. The study involved farms with more than 600 sheep, which represented 80% of the total sheep population of the country. Three anthelmintic groups were assessed, namely, benzimidazoles, levamisole and avermectins. Overall, the results showed 80% of sheep flocks had benzimidazole resistance, 71% had resistance to levamisole, and 1.2% of flocks showed resistance to avermectins. Approximately 28% of farms had resistance to one anthelmintic group, 64% to two anthelmintic groups, and 1% resistance to all three groups. Only 7.5% of farms had no detectable levels of anthelmintic resistance. More than 80% of farms had Trichostrongylus populations resistant to both benzimidazoles and levamisole. Resistance was recorded in all three anthelmintic groups for Haemonchus and resistance also occurred to benzimidazoles and levamisole in Ostertagia. PMID- 8686168 TI - Effect of Mycobacterium phlei on the development of immunity to Babesia bigemina. AB - The immunomodulatory role of Mycobacterium phlei against intracellular blood protozoan Babesia bigemina was demonstrated following experimental immunisation and challenge in bovine calves. A lysate of erythrocytes infected (6 x 10(9)) with B. bigemina was used as a source of dead antigen either with Freund's complete adjuvant (FCA) or with a trypsinised culture of M. phlei as a non specific immunomodulation (NSI) agent with appropriate controls. Following virulent challenge with B. bigemina infected erythrocytes (1 x 10(7)), the NSI printed calves showed 100% protection, while the dead antigen alone with FCA afforded 75% protection. The protective status of the immunising regimes was studied by clinicopathological parameters and assessment of humoral and cell mediated immune responses. The role of babesial dead antigen and the effects of M. phlei on the development of immunity to B. bigemina is discussed. PMID- 8686169 TI - The ultrastructure of bradyzoites and tissue cysts of Neospora caninum in dogs: absence of distinguishing morphological features between parasites of canine and bovine origin. AB - The fine structure of bradyzoites and tissue cysts of Neospora caninum in dogs is described. Original findings consisting of branching, septa-like structures of the cyst wall and peculiar, lipid-like inclusions in the cyst ground substance were described. Tubulo-vesicular structures in the cyst ground substance and distinctive, vesicular organelles containing short, membranous segments and smaller vesicles, described in Neospora parasites of bovine origin and previously undescribed in parasites of canine origin, were also observed. The findings in this study indicate that there are no distinct ultrastructural morphological criteria differentiating N. caninum in dogs and the Neospora-like protozoan of cattle. The previously reported morphological distinction between parasites of canine and bovine origin may be attributed to the relatively small numbers of tissue cysts examined, differences in tissue fixation and processing, and variation in developmental stage of the parasites examined. PMID- 8686170 TI - Prevalence of Sarcocystis in camels (Camelus dromedarius) from Al-Ahsa, Saudi Arabia. AB - The oesophagus, diaphragm and heart of 103 camels slaughtered at Al-Ahsa abattoir were investigated for infection with sarcocysts. Sarcocystis cysts were found in 91 camels (88.35%): in the diaphragm of 79.6%, oesophagus of 72.8% and heart of 71.8%. Two morphologically distinct sarcocysts were found. Thin-walled cysts (141 400 x 70.5-188 microns) were in all the three indicator organs while the thick walled cysts (170-194 x 117.5-188 microns) were only found in the oesophagus. Experimental feeding of four cats and two dogs with sarcocysts-infected meat showed that cats were refractory to the infection while dogs excreted Sarcocystis sp. sporocysts (10.7-14.3 x 8.3-10.7 microns mean, 13.2 +/- 0.32 x 9.4 +/- 0.20 microns) after a prepatent period of 9-10 days. It was concluded that dogs may be the final host of both types of sarcocysts or that one of these cysts develops in dogs while the other one uses other carnivores living in the desert as the final host. PMID- 8686171 TI - Detection of antibodies of Fasciola hepatica excretory--secretory antigens in experimentally infected goats by enzyme immunosorbent assay. AB - An ELISA with excretory-secretory (ES) antigens has been evaluated as a technique for the early detection of specific antibodies in Fasciola hepatica infections in goats. Goats were experimentally infected with 100 or 200 metacercariae of bovine origin and serum samples were taken periodically over 365 days. The ELISA test was performed with ES antigens (10 micrograms mL-1), a single dilution of sera (1:800) and anti-goat IgG conjugate (1:1000). ES specific antigens were detected in all infected goats between 15 and 30 days postinfection (PI) and maximum antibody levels were reached at 90 days PI. Positive antibody levels (significantly different from those of controls) were still found at 365 days PI. No significant differences were observed between goats infected with 100 or 200 metacercariae. In all infected goats, eggs appeared in faeces between 60 and 90 days PI. ELISA with ES antigens could be a feasible method for the early diagnosis of goat fasciolosis. PMID- 8686172 TI - The effect of faecally excreted ivermectin and fenbendazole on the insect colonisation of cattle dung following the oral administration of sustained release boluses. AB - The effects of faecal drug residues following the administration of anthelmintics in the form of sustained-release boluses, on dung-colonising Coleoptera and Diptera are reported. In blind field trials, pats of standard weight and size were prepared from the dung of cattle treated with an ivermectin (Ivomec SR Bolus, MSD Agvet) or a fenbendazole (Panacur Bolus, Hoechst) sustained-release bolus, and from a third control group of cattle that received no treatment. Pats were recovered after 7, 14, 21 and 42 days in the field and searched for invertebrates. There were no differences in the numbers of adult beetles found in the pats from the three treatment groups. Pats made from the dung of ivermectin treated animals contained no larval Diptera Cyclorrhapha and significantly fewer larval Scarabaeidae than pats made from the dung of the other two groups. Furthermore, larval Scarabaeidae in the ivermectin pats were inhibited in their development. The pats from fenbendazole-treated animals contained similar numbers of larval Scarabaeidae and Diptera to the pats from untreated animals throughout the trial. At 42 days, the solid matter of the control and fenbendazole containing cow pats were reduced to a crumbling, granular texture, while the pats from the ivermectin-treated animals were solid and compacted. Pitfall trapping, using traps baited with dung from the three groups, showed no significant difference between the numbers of adult Scarabaeidae attracted, though a trend towards higher numbers attracted to the dung of both anthelmintic-treated groups was evident. The results provide evidence of the toxic effects of excreted ivermectin on key dung-colonising families of insects, and show that fenbendazole lacks such toxic effects. PMID- 8686173 TI - Potential for misinterpretation of the faecal egg count reduction test for levamisole resistance in gastrointestinal nematodes of sheep. AB - The faecal egg count reduction test (FECRT) is widely used to assess the presence or absence of levamisole resistance in gastrointestinal nematodes in sheep flocks. However, in a recent study the FECRT appeared to falsely indicate the presence of levamisole resistance. One possible explanation for this result could have been that the anthelmintic failed to completely remove all immature stages of levamisole-susceptible strains, which then developed into egg laying adults and gave misleading results in the FECRT. Artificial infection of lambs with levamisole-susceptible, benzimidazole-resistant strains of Ostertagia circumcincta, Haemonchus contortus and Trichostrongylus colubriformis was followed by treatment with levamisole when the infections were between 2 and 10 days old. Levamisole was 84%, 88% and 98% effective against these immature stages of three species, respectively. The positive control, ivermectin, was more than 99% effective against all three species. The percentage faecal egg count reduction on samples taken 11 and 20 days post-treatment with levamisole was 80% and 78%, respectively. These results demonstrate that, due to the maturation of immature stages, the FECRT based on faecal eggs counts taken 11 or more days after treatment may give results indicative of levamisole resistance despite the absence of levamisole resistant strains of gastrointestinal nematodes. PMID- 8686174 TI - Control of gastrointestinal parasitism in calves with albendazole delivered via an intraruminal controlled-release device. AB - The efficacy of albendazole in an intraruminal controlled-release device against gastrointestinal nematodes in calves was evaluated under field conditions. Calf productivity was monitored during the first and second grazing seasons. Two groups of parasite-naive Holstein Friesian heifer calves were grazed from May to October on adjacent, similarly contaminated paddocks. One group was given a Captec bolus at turnout, the group was left untreated. Pasture larval counts peaked on the paddock grazed by the untreated calves at 23,000 1 kg-1 dry matter in October. This precipitated clinical parasitic gastro-enteritis in the untreated calves with a mean peak faecal egg count of 335 epg, high blood pepsinogen and gastrin concentrations and a mean worm burden of 79,614 at 100 days post-turnout. Pasture larval counts on the paddock grazed by the treated calves remained less than 3000 1 kg-1 DM and the mean faecal egg count was zero until mid-August, peaking at 146 eggs per gram of faeces (epg) in October. The treated calves had body liveweight advantage of 19 kg at the end of September. During the second grazing season the first season untreated calves were refractory to infection. The first season treated calves showed signs of parasitic gastro-enteritis, although not to the extent exhibited by a group of first season parasite-naive tracer calves which were grazed on the same paddock. PMID- 8686175 TI - Characterization of excretory-secretory products from larval stages of Haemonchus contortus cultured in vitro. AB - To determine biochemical changes associated with early parasite development, Haemonchus contortus larvae were cultured in vitro to the fourth stage (L4). Infective larvae developed from third to fourth stage in 48-96 h. Metabolic activity increased following stimulus of infective stages by CO2 secretion/excretion of significant amounts of protein into cultures and larval feeding did not occur until larvae had molted to the fourth stage. Larval feeding, as monitored by the ability of larvae to ingest fluorescein-labeled albumin, correlated with molting to the fourth stage and only fourth stage larvae were observed to feed. Fourth stage larvae secreted/excreted several enzymes into culture media including a metalloprotease, an acid phosphohydrolase, a cathepsin C-like enzyme, a phospholipase C-like enzyme and an N-acetyl-beta-D glucosaminidase. Excretory-secretory (ES) products produced by L4 had antigenic homologies with parasite products produced during the second molt and with proteins and glycoproteins extracted from third and fourth stage larvae. ES products were recognized by sera from sheep infected with H. contortus. The enzymes identified here serve as markers for maturation to the fourth larval stage as well as the initiation of feeding and are likely to be involved in extracorporeal digestion. Further, they might serve as potential targets for immune or chemical control of trichostrongyle infections. PMID- 8686176 TI - Comparison of methods for counting third stage larvae of gastrointestinal nematodes of small ruminants in tropical pastures. AB - The accuracy and the precision of a simple and reliable technique for the extraction and the counting of third stage larvae densities of gastro-intestinal strongyles of ruminants from pasture samples are assessed in tropical conditions, i.e. for pangola pastures and for the genera of Haemonchus and Trichostrongylus. To separate the larvae from herbage samples, water washings obtained by a centrifuge spin-dryer were put to sediment in disposable plastic bags. The extraction and counting of larvae from sediments were achieved by exhaustion of sediments with repeated sucrose/water interface procedures. The recovery rate of third stage infective larvae (L3) added to the sediment was 79.1% (+/- 9.49%). The accuracy, estimated as recovery rate of L3 added to herbage samples, was 76.5 (+/- 11.31%). The recovery by the sedimentation method was 3.5 times higher than that of a filtering method through a 20 microns sieve. The detection limit was estimated to be 130 L3 kg-1 dry matter. Precision, estimated as the residual standard deviation of duplicate assays, was 1857 L3 kg-1 dry matter (mean 9164 L3 kg-1 dry matter). Results obtained in routine epidemiological surveys of gastro intestinal strongylosis of small ruminants in West Africa and in the West Indies demonstrated the usefulness of the technique. PMID- 8686177 TI - Acquisition of resistance to the tick Amblyomma variegatum in Boran cattle, Bos indicus and the effects of Trypanosoma congolense and Babesia bigemina on host resistance. AB - Resistance was induced in cattle to the tick Amblyomma variegatum by five consecutive infestations with nymphs and adults. Using the principal component analysis (PCA), it was found that percentage of adults engorged, percentage of adults which died, percentage of nymphs which engorged, percentage of nymphs which moulted and percentage of nymphs which died, were the main indicators of resistance against A. variegatum. The percentages of nymphs which engorged or moulted after the third infestation were significantly (P < 0.01) reduced while the percentage of nymphs which died increased significantly (P < 0.01) after the third infestation. Percentages of adults which engorged or died started to decrease significantly (P < 0.01) from the fourth infestation after an initial increase during this period. The acquisition of resistance by cattle to the adult ticks was slower than to the nymphs. Infection of cattle with Trypanosoma congolense and Babesia bigemina after the fifth infestation enhanced the acquired immunity as revealed by the significantly (P < 0.01) increased feeding period of the adult ticks and changes in other parameters. PMID- 8686178 TI - The first isolation, in vitro propagation, and genetic characterization of Ehrlichia canis in Israel. AB - Ehrlichia canis, the etiologic agent of canine ehrlichiosis, was isolated in Israel from a naturally infected dog with acute signs of the disease. The organism designated E. canis 611, was passaged experimentally to a beagle, from which it was propagated in primary canine monocytes. The organism was then grown in vitro in a continuous canine cell line, DH82. Nine beagles subsequently injected with whole E. canis-infected blood all developed typical symptoms of ehrlichiosis. An indirect immunofluorescence antibody test to E. canis was developed and compared with a commercial kit, revealing a good correlation between the two assays. Transmission electron microscopy of DH82 cells infected with the Israeli strain of E. canis (611), revealed organisms similar to those described in the literature: two different forms of morulae appeared, one tightly, the other loosely, packed. The 16S rRNA gene sequence obtained from the Israeli Ehrlichia isolate was compared with other isolates, E. canis Oklahoma and E. canis Florida. The Israeli strain 16S rRNA had three nucleotide differences from the Oklahoma isolate, and four nucleotide differences from the Florida isolate, in addition to one nucleotide gap in each. The Israeli isolate was found to be 0.54% different from the Oklahoma strain, and 0.61% different from the Florida strain. There are the same magnitudes of differences displayed by the other most closely related group in the phylogenetic tree, namely Ehrlichia equi, Ehrlichia phagocytophilia and the human granulocytic ehrlichia. PMID- 8686179 TI - Ctenocephalides felis flea infestation in horses. AB - The horses were in two stables: in the first stable they were kept together with sheep and in the second stable they were kept together with goats. All horses in both stables were diagnosed as being infested with the cat flea Ctenocephalides felis felis. Foals were severely infested, whereas adult horses were only moderately infested. PMID- 8686180 TI - Some epidemiologic features of canine neosporosis in Denmark. AB - From a serological survey of 98 dogs, the overall prevalence of subclinical neosporosis among dogs in Denmark was estimated as 15.3%. From a questionnaire completed at the time of blood sampling in 87 dogs, it was found that exposure to cats could be a risk factor for the infection in dogs (odds ratio 3.46; 95% confidence limit 1.1-11.4). Further, it was shown that the antibody response in a pregnant dog increased markedly during gestation, suggesting that the parasite may be reactivated during pregnancy in a manner resembling that of Toxocara canis. PMID- 8686181 TI - [Evaluation of the effectiveness of antihypertensive therapy. Is the trough-peak ratio the determining factor?]. AB - The author describes the assessment of the effectiveness of antihypertensive drugs according to the T-P (Trough-Peak) ratio, i.e. the effect at the end of the dosage period to the effect during its peak after subtraction of the placebo effect. He draws attention to methodological difficulties which make it so far difficult to compare data from the literature. It is, however, advisable in clinical practice of the treatment of hypertension to assess the blood pressure at the end of the dosage period rather than during the peak of effectiveness, as frequently practiced. Drugs with a long biological half-life are particularly useful. The most important criterion of effectiveness of antihypertensives is, however, their effect on the cardiovascular and cerebrovascular mortality and morbidity. Only on diuretics and beta-blockers extensive data are available indicating that they lead to a decline of the morbidity and mortality. Therefore they should be the drugs of first choice, in particular in elderly hypertonics. Data on calcium channel blockers, in particular nifedipine are controversial. ACE inhibitors are suitable in heart failure, asymptomatic dysfunction after acute myocardial infarction and in type 1 diabetes mellitus. Only at present investigations are under way to assess whether the effect of new and more expensive antihypertensives on mortality and morbidity is greater than the effect of diuretics and beta-blockers and whether they will be suitable drugs of first choice. PMID- 8686182 TI - [Diuretics in the treatment of hypertension]. AB - Diuretics are basic antihypertensives indicated in essential and secondary hypertension. Their pharmacodynamics is well known, their therapeutic spectrum is wide, their tolerance is excellent, the cost/benefit is lowest among all contemporary antihypertensives and after re-evaluation of the safety of small doses, diuretics have come to their revival. PMID- 8686183 TI - [Angiotensin-converting enzyme inhibitors in the treatment of arterial hypertension]. PMID- 8686184 TI - [Ulfamid Krka (famotidine) in monotherapy of peptic ulcer]. PMID- 8686185 TI - [Antibiotics in the treatment of acute pancreatitis]. PMID- 8686186 TI - [Aminosalicylates in the treatment of idiopathic inflammatory bowel disease]. PMID- 8686187 TI - [Cholelithiasis--introduction to its problems]. PMID- 8686188 TI - [Conservative treatment of cholelithiasis]. PMID- 8686189 TI - [Present status of shock wave lithotripsy and dissolution in the treatment of cholecystolithasis and choledocholithiasis]. PMID- 8686190 TI - [Endoscopic therapy of choledocholithiasis]. PMID- 8686191 TI - [Osteomalacia]. AB - Osteomalacia is a metabolic bone disease caused by deficiency of vitamin D or its active metabolites. Despite a very typical X-ray picture and laboratory finding, it is very poorly diagnosed in the field and thus not treated. This may be due to its atypical clinical picture and also because this disease is frequently omitted in diagnostic considerations. After assessment of the diagnosis the vitamin D treatment or treatment with its metabolites is rapid and successful moreover these substances have also an immunomodulating and anabolic effect. PMID- 8686192 TI - [Empirical antimicrobial therapy of respiratory infections]. AB - Respiratory infections cause a significant morbidity and mortality. Ideally, the treatment should be directed against the identified pathogen and its sensitivity to antibiotics. In many situations, however, the pathogen is unknown and the infections are treated empirically. Author briefly reviews the current empirical therapeutical recommendations based on the age of patient, comorbidity and the type of infection (acute bronchitis, exacerbations of chronic bronchitis, community acquired pneumonia, nosocomial pneumonia and pneumonia in immunocompromised patients. PMID- 8686193 TI - [Antianginal therapy '95]. AB - The submitted review deals with contemporary possibilities of antianginal treatment. After a brief account of pathophysiological and morphological data in different types of cardiac ischaemia and angina pectoris the author submits algorithms which should be the basis for therapeutic decisions. It is a question of proper timing of invasive examinations leading to revascularization operations in relation to medicamentous treatment. The latter is supplementary treatment before or after revascularization, or is the main approach in case of minimal complaints, in case of contraindicated invasive treatment or in case of an inoperable finding. The author discusses the action, indications, contraindications, undesirable effects, and average dosage of nitrates, beta blockers, calcium channel inhibitors and antithrombotics. The author mentions also the use of angiotensin converting enzyme inhibitors. View on treatment will change with advancing knowledge. PMID- 8686194 TI - [Anticoagulation therapy in patients with valve defects]. AB - Thromboembolic episodes are the most frequent complication in patients with valvular defects or valvular prostheses. Introduction of anticoagulant treatment led to a marked drop of these complications, while haemorrhage became a serious problem in their care. When deciding on anticoagulant treatment it is important to evaluate not only the basic disease but also risk factors of thromboembolism in individual patients. The authors emphasize also procedures during operations, pregnancy, embolization or haemorrhage in patients treated with anticoagulants. PMID- 8686195 TI - [Corotenol, its effectiveness and tolerance in light of new studies]. AB - The effectiveness and tolerance of Corotenol of Mepha Co. was investigated in two studies under conditions of common ambulatory practice of specialists in internal medicine and general practitioners in patients suffering from mild to moderate hypertension and/or ischaemic heart disease. A surprising finding was a high percentage of patients with an inadequately controlled blood pressure before enlistment into the study. During regular check-up examinations already after two weeks a marked reduction or normalization of the blood pressure, was recorded, in the majority of patients. The author assumes that in addition to the effectiveness of the administered drug the marked improvement of the patients is due to better collaboration of the patients and adherence to the prescribed dosage and lifestyle. PMID- 8686196 TI - [Therapeutic approaches in patients after myocardial infarct]. PMID- 8686197 TI - [Pharmacodynamics of angiotensin-converting enzyme inhibitors]. AB - ACEI form a group of antihypertensives which inhibit the angiotensin II (A II) production and thus not only reduce the blood pressure but exert also a positive metabolic and antiproliferative effect (A II is a proliferative hormone). They are therefore indicated nowadays in the treatment of essential and secondary hypertension, left-ventricular hypertrophy, chronic heart failure, acute myocardial infarction, insulin resistance and other disorders. Despite intensive studies we still do not know many, in particular mediated effects, of ACEI but these drugs have become one of the key groups in therapy. PMID- 8686199 TI - [Prevention of polymorphous ventricular tachycardia in patients with congenital long QT interval syndrome]. AB - Patients with the Romano-Ward long QT interval syndrome run a high risk of sudden cardiac death. Beta-blockers of the sympathetic nerve are effective treatment. Some patients die suddenly despite this treatment. The treatment of choice is a combination of beta-blockers of the sympathetic nerve and cardiostimulation. The authors describe a group of their own five patients from three families with the Romano-Ward syndrome. The course was favourable. The stimulation rate needed for normalization of the QT interval and a favourable clinical development was 78 +/- 6 imp./min. Based on data in the literature and their own experience the authors recommended combined treatment with beta-blockers and cardiostimulation in patients with the Romano-Ward syndrome, if monotherapy with beta-blockers is not effective. PMID- 8686198 TI - [24-hour ambulatory monitoring of blood pressure in patients with essential hypertension: the effectiveness of enalapril therapy]. AB - The aim of the present paper was to study 24-h blood pressure profile in twenty patients with essential hypertension (mild to moderate) before and after treatment with ACE inhibitor enalapril in one day dose in the morning (15.6 +/- 6.1 mg). 24-h ambulatory blood pressure monitoring was examined after 14 days of placebo administration and after one month of enalapril therapy. Enalapril treatment decreased systolic blood pressure of 11.3 mmHg during daytime and of 9.4 mmHg at night, diastolic blood pressure of 6.1 mmHg during daytime and 5.8 mmHg at night, all differences were significant in comparison to placebo (p < 0.01). The through-peak ratios were 63.2% for systolic blood pressure and 54.0% for diastolic blood pressure. We can conclude that enalapril treatment in one day morning dose is efficient to decrease blood pressure during 24-h span without altering the diurnal profile. PMID- 8686200 TI - [Is antibiotic prophylaxis necessary in patients on chronic dialysis and with recurrent endocarditis?]. AB - The authors present a group of 77 patients with chronic dialysis treatment during the period from 1/92 to 4/95 with regard to the prevalence of infectious endocarditis. This disease was detected in 8 instances in 6 patients whereby one patient had three relapses. In 75% staphylococci were the infectious agent. The main risks of the disease are according to the authors impaired immunity, repeated cannulation, degenerative valvular changes. In the conclusion the authors state that the risk of developing infectious endocarditis and relapses of the disease can be reduced by careful diagnosis and antibiotic therapy. The authors do not consider lifelong antibiotic prophylaxis of these patients necessary. PMID- 8686201 TI - [Personal clinical experience in the treatment of arterial hypertension using amlodipine]. AB - In 15 centres of the Czech Republic the antihypertensive effect of Amlodipine Norvasc of Pfizer Co. was tested in 155 patients with mild or medium severe hypertension. The patients were treated by monotherapy, using doses of 5 mg (92%) and 10 mg (8%) per day. In all investigated hypertensive subjects a statistically significant decline of the systolic and diastolic blood pressure occurred in the course of the 12-week investigation (P smaller than 0.01) without affecting the heart rate. The rate of undesirable effects of treatment was very low: only three patients (1.9%) discontinued treatment on account of undesirable effects. The most frequent ones included perimalleolar oedema, the sensation of fullness, headache, cardiac palpitations, vertigo and insomnia. Evaluation of the antihypertensive effectiveness and tolerance of the preparation by the physician and patient is positive, and Amlodipine-Norvasc of Pfizer Co. holds therefore, because of its pharmacokinetic and pharmacodynamic properties, an important place among calcium channel inhibitors of the second generation. PMID- 8686202 TI - [A protein-restricted diet combined with ACE inhibitors does not improve insulin sensitivity in renal hypertension]. AB - Hypertension is one of the most important accelerating factors for progression of nephropathies. Its prevalence is about 35% in patients with nephropathies, even in minor or medium severe functional impairment. This is evidence that it is essential to select an optimal therapeutic regimen as soon as possible. A group of 38 patients (14 hypertensive patients) with a minor or medium severe functional impairment were included in a controlled trial. The patients were served a low-protein diet--0.6-0.7 g/kg/day and 2-10mg enalapril/day divided into two doses. The amount of enalapril depended on the blood pressure and enalapril was given also to normotensive patients. The investigation lasted 8 months. In the course of 8 months the authors did not reveal progression of the renal disease, as apparent from results of assessment of the creatinine level and clearance, assessment of uric acid and urea. The authors did not find deterioration of metabolic acidosis, nor of nephrogenic anaemia. Hypertensive patients had a tendency to deteriorating of insulin sensitivity while in normotensive patients a decline of triacylglycerols, VLDL and rise of HDL was recorded. The total cholesterol and LDL cholesterol level did not change. The authors conclude that the combination of a low-protein diet with ACEI in hypertensive and normotensive patients with mild to medium severe functional disorders inhibits the progression of nephropathies, but in hypertensive patients it does not prevent deterioration of insulin sensitivity. PMID- 8686203 TI - [The clinical picture of latent hypothyroidism in women]. AB - The authors investigated the most frequent clinical symptoms in a group of 132 women with latent hypothyroidism (mean age 40.2 years, incl. 102 women younger than 45 years). They assessed the diagnosis on the basis of an excessive TSH response after administration of 0.2 mg thyreoliberin by the i.v. route (TRH test), while the thyroxine values were normal (TSH 0 min.: 4.93 +/- 3.55, TSH after 20 min. following TRH: 39.27 +/- 18.28 mIU/ml, T4: 102.0 +/- 25.02 nmol/l). Forty-one patients (31%) had goitrectomy in the case-history. USG examination of 70 patients revealed goitre in 13 (18.6%) reduced echogenity of the thyroid gland in 20 (28.6%) and microcysts in 31 (44.2%) of the patients. Analysis of the clinical symptoms revealed manifestations of a depressive symptomatology in 56 patients (40.3%), benign mammary dysplasia in 39 patients (29%). In the subgroup of women younger than 45 years an impaired menstrual cycle was recorded in 49 (48%) and galactorrhoea in 10 patients (9.8%). After thyroid substitution (L thyroxine 50 micrograms/day) they observed in the majority normalization of the menstrual cycle and partial improvement of depressive manifestations. PMID- 8686204 TI - [Treatment of autonomous thyroid gland nodules using percutaneous injections of ethanol under ultrasonography control--initial experience]. AB - The authors treated nine women with autonomous adenomas of the thyroid gland by repeated ethanol injections under ultrasonographic control. In all patients clinical and laboratory characteristics of hyperthyroidism were present. After treatment is seven patients euthyroidism was induced, in two patients subclinical hypothyroidism which persisted also during the 6-month follow-up period. In all patients ultrasonographic changes in the nodes were recorded: a reduced echogenity the development of "halo"--hypoechogenic outlines--a change of the shape and on average a 37% reduction of the volume. Treatment was feasible also under out-patient conditions: it was well tolerated by the patients, undesirable effects were not serious and only transient and receded spontaneously. PMID- 8686205 TI - [Cystic fibrosis--a serious disease affecting the nutritional status and energy requirements in adult patients]. AB - At the Department for TB and Respiratory Diseases of the Faculty Hospital in Prague Motol at present half the patients with cystic fibrosis who in the Czech Republic reached adult age are being followed-up. The objective of the present work was to evaluate the nutritional profile of these adult patients with cystic fibrosis. The authors examined 15 patients, mean age 22.9 +/- 3.2 years. The examination included assessment of height, body weight, skinfold thickness above the triceps, brachii, the energy output transferrin, blood gases. Functional examination of the lungs was made by the method of the flow-volume curve. The body mass index (BMI) was 18.04 +/- 4.17, albumin 32.75 +/- 4.57. The resting energy expenditure was 112.1 +/- 20.8% of the basal energy output calculated according to the Harris-Benedict formula. The mean value of pO2 was 8,081 +/- 1,145 kPa, pCO2 5,841 +/- 1,197 kPa. The results indicate malnutrition of the examined patients: in general the findings can be considered as a sign of severe protein-energy malnutrition. The baseline study confirmed the assumption of a high prevalence of nutritional disorders in adult patients with cystic fibrosis. The next essential step must be to ensure comprehensive and individualized nutritional intervention. PMID- 8686206 TI - [Treatment of inoperable non-small cell bronchogenic carcinoma with a combination of cisplatin and vinorelbine--preliminary evaluation]. AB - The optimal therapeutic approach to patients with inoperable non-small-cell carcinoma is still a matter of discussion. The reason is that chemotherapy improves the quality of life only in some patients. It prolongs their life only by several weeks. In recent years in this indication a new cytostatic is tested- vinorelbine which when used in monotherapy achieves a therapeutic response in 16- 30%. In clinical trials of phase 2 a combination of vinorelbine and cisplatinum was most effective and therefore it was selected for the third phase of clinical trials. In the Czech Republic a clinical investigation was made with the objective to verify published data on the success of treatment, evaluate undesirable effects and consider whether it is suitable for routine use. Cisplatinum (Platidiam Lachema) was administered--80 mg/m2 on the first day, vinorelbine (Navelbine Pierre Fabre)--30 mg/m2 on the first and eighth day. The cycle was repeated on the 22nd day. All patients were treated for 12 weeks. Then followed the first evaluation and treatment was continued only in patients with regression or stabilization of the disease. In the group of 126 patients in 44 (35%) partial and in 3 (2.3%) complete therapeutic responses were obtained. In 35 (27%) the disease was evaluated during treatment as stabilized, in 38 (30%) of the patients the disease progressed despite treatment. The tolerance of treatment was, when effective antiemetic treatment was used (ondansetrone or granisetrone), relatively satisfactory. PMID- 8686207 TI - [Basic indicators characterizing the acid-base equilibrium and its disorders]. AB - The author describes and evaluates basic parameters used for evaluation of the acid-base balance: pH, pCO2, BE, BBS, (Na + K)/Cl, (AG) and RA. He compares the theories of two basic schools, the Copenhagen and Boston school and synthesizes the different views of various authors. A combination of modern theories permits to evaluate simple and combined disorders of the acid-base balance, disorders which can potentiate each other but also mask their effect. The author mentions also the importance of oxygen parameters and of other substances essential for obtaining energy, the importance of assessment of the patient's clinical condition, the necessity of retrospective evaluation based on the trend of changes of the acid-base balance in the course of time. In the article mathematical logical terminology of acid-base balance disorders is used, the attached figures and calculations facilitate the understanding of this pretentious problem. PMID- 8686208 TI - [Use of molecular genetics in the early diagnosis of familial adenomatous polyposis]. AB - Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary precancerous condition manifested by hundreds to thousands of polyps in the colon and rectum. Practically, with a 100% certainty, patients with FAP develop carcinoma of the colon or rectum. FAP is this the most dangerous sign of a precancerous condition. So far the only possibility of early diagnosis of this disease was rectoscopy or colonoscopy of risk subjects after annual intervals up to advanced age, After localization of the gene responsible for the development of FAP and discovery of its internal structure, possibilities for revealing FAP, decades before the first clinical symptoms appear, were disclosed. PMID- 8686209 TI - [Lipid risk factors and their role in the pathogenesis of atherosclerosis]. AB - The author presents an account on the main lipid risk factors of ischaemic heart disease. She emphasizes the causal role of cholesterol and low density lipoproteins (LDL), incl. the VLDL subclass and oxidized LDL in the pathogenesis of atherosclerosis. The atherogenic action of elevated concentrations of triacylglycerols is discussed (the importance of heterogenity of lipoproteins rich in triacyglycerols, postprandial hypertriacylglycerolaemia, combination with low concentrations of high density lipoproteins (HDL) and prothrombogenic changes). The protective role of HDL is mediated not only by their participation in the reverse cholesterol transport but also other antiatherogenic changes (antioxidant, increased prostacycline secretion, effect on the vascular tonus). Low HDL cholesterol concentrations in subjects with ischaemic heart disease indicate not only loss of these protective properties but also a pathological metabolism of lipoproteins rich in triacylglycerols with which they are metabolically associated. The author emphasizes the antiatherogenic importance of the sub-population HDL2 and of lipoprotein particles Lp AI. Lipoprotein (a) is another independent risk factor of ischaemic heart disease. The genetic determination and ratio of factors of the external environment in the variability of concentrations of all these lipid risk factors in the population is discussed. PMID- 8686210 TI - [Erythropoietin in the treatment of anemias]. AB - Recombinant erythropoietin (r-HuEPO) was the first growth factor introduced into clinical practice. The main indication for its therapeutic use remains treatment of anaemias during chronic renal failure. In Czech Republic it is at present administered to 55% of patients included in a regular haemodialyzation program and in the pre-dialyzation stage of the disease, consistent with European practice. In addition to a marked improvement of the quality of life, during r HuEPO treatment also the prevalence of some cardiovascular complications is reduced and immune functions improve. The list of diseases where r-HuEPO therapy is indicated has been, however, extended nowadays. A very favourable effect was recorded in some haematological malignicies and solid tumours. The best results were observed so far in the treatment of anaemia associated with multiple myeloma and chronic lymphatic leukaemia, and also in malignant lymphomas, carcinoma of the breast and ovary. It is used also in the treatment of suppressed erythropoiesis resulting from cytoreducing therapy. Other indications include anaemia after transplantations of bone marrow, preparation before autologous transfusions and some cases of myelodysplastic syndrome. The authors mention also other contemporary possibilities of r-HuEPO use. PMID- 8686212 TI - [The beginnings of extracorporeal hemodialysis at the 2nd Internal Medicine Clinic of the Charles University Medical School in Prague]. PMID- 8686211 TI - [Insulin resistance and pathogenesis of non-insulin-dependent diabetes mellitus (part II)]. AB - A review of the existing views is given, focused on the role of insulin resistance (IR), impaired insulin secretion and reduced suppression of hepatic glucose output and in the pathogenesis of noninsulin dependent diabetes mellitus (NIDDM). Currently, there are two basic theories on the sequence of these defects. Most of the authors suggest that NIDDM is caused primarily by insulin resistance (IR) (which is also considered an earliest detectable defect) with subsequent inability of the pancreas sufficiently compensate for IR. However, some authors suggest that NIDDM results from the abnormal pancreatic beta-cell function (disturbed pulsatility and first-phase of stimulated insulin secretion). These authors consider IR a secondary defect. It seems, that both these theories are well founded. Actually NIDDM is not a single disorder but is rather a syndrome of diverse etiology and pathogenesis. In case of NIDDM with obesity the primary etiopathogenetic role can be rather ascribed to IR. while in non-obese NIDDM subjects the secretory defect is more probable as a primary cause. PMID- 8686213 TI - [Ludwig Hirszfeld (1884-1954), a Polish physician and scientist]. PMID- 8686214 TI - [The use of EHF therapy in the rehabilitation of patients with chronic bronchitis at a moderate altitude]. AB - Patients treated in mid-altitude conditions for chronic bronchitis were exposed to EHF radiation. As shown by positive changes in external respiration, systemic and pulmonary hemodynamics, immune status, surface activity of lung surfactant, EHF therapy is effective in chronic bronchitis with ventilation disorders. The more severe these disorders were, the more marked the benefit was. PMID- 8686215 TI - [The effect of the massage of different areas of the body on the cerebral hemodynamics in patients with a history of acute disorders of the cerebral circulation]. AB - A definite effect is shown of massage conducted in different areas of the body on hemodynamics in 119 patients who have suffered an acute episode of reversible brain ischemia. The techniques of the massage for such patients are detailed. PMID- 8686216 TI - [Multilevel stimulation in the treatment of patients with paralysis and paresis]. PMID- 8686218 TI - [Tubal pregnancy: the experience of early rehabilitative treatment]. AB - The surgical treatment for tubal pregnancy including laparoscopy and antibacterial therapy were combined in 30 females with early start (on postoperative day 1) of rehabilitation: psychotherapy, diet, therapeutic exercise, low-frequency magnetotherapy. Hysterosalpingography and dynamic dopplerography assessed the effect as good. PMID- 8686217 TI - [The combined use of cryogenic exposure and ultrasound in patients with arthrosis of the joints of the legs]. AB - The authors propose special programs of rehabilitation for patients with arthritis-affected knee and ankle joints complicated with synovitis. The program includes combined use of cryoeffects, ultrasound and therapeutic exercise. These therapeutic complexes proved to be analgetic, effective against local inflammation in the joints, to relax muscular tension and pain contractures, to enhance functional activity of the affected joints. These programs may be introduced in any rehabilitation centers and departments. The complex of cryotherapy plus exercise can be practiced outpatiently under control of the physician. PMID- 8686219 TI - [The effect of the internal intake of carbonate mineral waters on lipid and carbohydrate metabolism in the development of experimental obesity]. AB - Experimental alimentary obesity was treated with hydrocarbonate magnesium-calcium water from Shmakovskoe deposit and hydrocarbonate-chloride sodium arsenous boric iodine-bromine water from springs in Sinegorsk. The study of lipid and carbohydrate metabolism proved the ability of the waters to prevent complex metabolic disorders typical for obesity. PMID- 8686220 TI - [The action of sulfate mineral water in experimental whole-body irradiation]. AB - The authors' experiments have shown that a course intake of sulfate mineral water after total radiation (1 and 5 Gy) can prevent and minimize dystrophic and necrobiotic changes in the liver, stimulate intracellular regeneration, reduce pathological mitoses in the small intestine. The response depended on radiation dose and time of crenotherapy start after radiation. Sulfate mineral water is also a weak radioprotector. PMID- 8686221 TI - [The dependence of the radioprotective effect of iodine-containing waters on the concentration and form of the iodine]. AB - Preradiation intragastric injection of iodine-containing waters during 21 days increased mean survival and decreased the mortality of rats exposed to gamma radiation (whole-body dose 5.4 and 6.4 Gy, dose rate 1.053 Gy/min). The highest radioprotective effect was reached in use of waters containing 49 and 100 mg/1 positive iodine ions in radiation dose 5.4 Gy. In the whole-body radiation 6.4 Gy, intragastric injection of water with 49 mg/1 positive ions resulted in 100% survival. PMID- 8686222 TI - [The effect of radon on the hormonal regulation of carbohydrate metabolism]. AB - Wistar rat experiments provided evidence for marked inhibition of early insulin secretion after a single dose of radon water (radon concentration 200 nCi/1). Hepatocytes and activity of transaminase remained unchanged. Miners in long contact with radon in mines (radon concentration in the air of mines 1.5 nCi/1) develop long-term adaptation of the hormonal systems associated with hyperadaptosis in the system of hormonal regulation of glycohomeostasis. PMID- 8686223 TI - [The transcerebral use of an impulse current in experimental alimentary hypercholesterolemia]. AB - 25 rats with alimentary hypercholesterolemia induced by diet rich in cholesterol and mercazoline were exposed to frontomastoid impulse current (1000 Hz, 0.75 mA). The treatment promoted normalization of lipid and protein metabolism in the myocardium and liver, of thyroid hormones and antiproteinase activity of the serum. Positive trends were noted in the activity of thymocyte nuclei and lipid peroxidation in the cerebral cortex. PMID- 8686224 TI - [New natural resources in the development of the sanatorium-health resort service of the Altai]. PMID- 8686225 TI - [The scope of rehabilitative measures for disabled children at sanatorium-health resort institutions for children with their parents]. PMID- 8686226 TI - [The dynamic interactions of the level of blood plasma and erythrocyte membrane cholesterol under the influence of the laser irradiation of patients with ischemic heart disease]. PMID- 8686227 TI - [Changes in the biophysical indices of the erythrocytes in osteoarthrosis patients being treated with Tskhaltubo mineral baths]. PMID- 8686229 TI - [Demyelinating diseases and physical treatment methods]. PMID- 8686228 TI - [The use of magnetic fields in the combined rehabilitation of children with a history of acute pneumonia]. PMID- 8686230 TI - [The combined exposure to physical factors at the sanatorium-health resort stage of patient rehabilitation in ischemic heart disease]. PMID- 8686231 TI - [The correction of hypoxic damage to the pulmonary surfactant system of rats with extremely high-frequency electromagnetic fields]. AB - 54 white rats were studied physically, histochemically and morphometrically for the effect of EHF electromagnetic field on repair of the lung surfactant system. The damage was inflicted by acute hypoxia existing at the altitude of 9000 m above the sea level simulated in the chamber. For the period studied natural repair was unable to secure the return to normal structure and function of the surfactant system, whereas daily 20-minute exposures to millimetric waves on the chest stimulated repair on after-exposure day 1-5 and provided normalization of all the physical and morphometric parameters. PMID- 8686232 TI - [Results of pulsed laser therapy of stage-I melanoma of the skin subjected to incisional biopsy]. PMID- 8686233 TI - [Combined operations for non-organ retroperitoneal tumors]. AB - Incision biopsy of skin melanoma is performed after forming a circular blocking barrier by means of a laser beam. Once tumor proper is subsequently irradiated, this prevents dissemination of tumor process. Skin melanomas, degree I-IV invasion (Clark), and 4.5 mm thick (Breslow) are effectively treated by pulsed laser radiation. PMID- 8686234 TI - [Predictive value of a questionnaire for epidemiologic studies]. AB - Combined surgical treatment was carried out in 29 cases of non-organ retroperitoneal tumors due to extensive involvement of adjacent organs. Postoperative mortality was 3.4 +/- 3.3%. Three-year survival was 51.2 +/- 10.3% and 5-year survival-47.1 +/- 10.10%. PMID- 8686235 TI - [A case of histiocytosis X with extensive changes]. AB - A procedure of epidemiological "case-control" study is presented. The structure and composition of a questionnaire are discussed. The predictive value of 82 +/- 7.3% is considered the basic criterion. The predictive value should be assessed at the stage of planning a study. The paper deals with certain basic characteristics of modern statistical analysis for evaluation of yearly consumption of different foodstuffs and some biochemical components of food. PMID- 8686236 TI - [Cancer of the bladder (analysis of autopsy data)]. PMID- 8686237 TI - [Creation of post-duodenal digestive pouch after gastrectomy]. PMID- 8686238 TI - [Kinetics of the growth of breast tumors and its role in early detection]. PMID- 8686239 TI - [Fjord-region polycyclic aromatic hydrocarbons: carcinogenic properties and mechanism of action]. PMID- 8686240 TI - [Evaluation of the proliferative potential of residual tumor. Verification of parametric methods by computer simulation]. PMID- 8686241 TI - [Microsurgery in the treatment and rehabilitation of cancer patients]. PMID- 8686242 TI - [Effect of radiation and other factors on the pathogenesis of various histologic types of lung cancer in workers of radiochemical plants]. AB - Adenocarcinoma frequency in Pu incorporation-related lung cancer patients among plutonium workers was found to be 74% versus 33% in control. Each histological pattern of lung cancer appeared to be related to several etiological factors but in varying degree. Incorporated Pu proved the strongest factor in adenocarcinoma development. Its odds ratio (OR) was 6.9, while that for smoking-4.3. However, smoking appeared to be the most significant factor in squamous cell carcinoma genesis (OR-6.8). Among other factors were chronic obstructive pathology of the lung (OR-3.9) and reduced body weight (OR-2.1). The OR for Pu incorporation was 3.9. Squamous cell carcinomas were traced to reduced body weight (OR-2.9), heavy smoking (smoking index more than 500) (OR-3.5). However, no significant relationship has been established between carcinogenesis and Pu incorporation. PMID- 8686244 TI - [The use of a mathematical method for the prognostication of the selected operative procedure in laryngeal neoplasms]. AB - The study was concerned with selection of the 12 most informative features, each presented on a scale of numerical values from zero to 20. Statistical evaluation of clinical data on 500 cases of laryngeal cancer was carried out on a computer. On the basis of 250 cases, two major procedures of treatment--K1 (functional organ-saving) and K2 (laryngotomy) were established. The method of mathematical analysis was based on evaluation of significance of relevant diagnostic features using distance function metrics. The three most informative features were identified following an evaluation of the results of standard specimen computation. Two programs for computing the extent of surgical intervention in cases of laryngeal cancer, stage III-IV, were developed for use in the MK-52 type microcalculators. Said programs were tested in 50 cases of laryngeal cancer, stage III-IV; they proved effective in 75.6 +/- 1.8%. More information was needed in 20 +/- 1.7%, while likelihood of error was 4.4 +/- 0.8%. These programs may be used by medical personnel who are not proficient in dealing with such problems. PMID- 8686243 TI - [The "dose-response" mechanism of tumorigenesis in workers of radiochemical plants]. AB - The "dose-response" mechanism has been studied for three main histological types of tumor in a cohort of 500 workers occupationally exposed to different doses of radiation (162 patients with lung cancer and 338 practically healthy persons) using the "case-control" method and multifactorial logic regression procedure. A non-linear threshold dependence was established for incorporated plutonium, with the threshold being at 8 kBq to correspond to 80 kGy. This relationship has been particularly distinct in cases of adenocarcinoma. No significant results have been obtained for the "dose-response" relationship in chronic external exposure to gamma irradiation. Said dependence for tobacco smoking appeared to be linear. Most pronounced variations were recorded for squamous cell carcinoma. PMID- 8686245 TI - [Effectiveness of adjuvant hormone therapy in breast cancer]. AB - A third series of randomized tests was undertaken to evaluate the efficacy of postoperative adjuvant hormone therapy (tamoxifen, diethylstilbestrol, orimethen amino glutethymide) in breast cancer patients. Tamoxifen was studied in 176 patients with T1-2N0M0 tumors. Five-year recurrence-free survival was registered in 85.2% of menopausal patients treated with tamoxifen versus 71.1% in control (P < 0.05). Five-year recurrence-free survival in menopausal females with breast tumors, stage IIb, was 71.1% among those treated with diethylstilbestrol and as low as 57.4% in the tamoxifen group (P < 0.05). Untoward side-effect incidence was much higher in the diethylstilbestrol group (30.4%) as compared with tamoxifen (3.5%). No significant difference was found for the relationship between orimethen and tamoxifen treatment with respect to 5-year survival and recurrence-free survival. PMID- 8686246 TI - [Lysosomal enzyme activity in white blood cells in leukemias]. AB - Total enzyme activity of acidic hydrolases and total neutral proteinase were compared in the post-nuclear fraction of leukocytes from healthy subjects and leukemia patients. The levels of acidic phosphotase and neutral proteinase in lymphoid cells of healthy donors were 11 and 7 times lower than those in myeloid cells, respectively. Patients suffering chronic myeloid leukemia revealed enhanced levels of beta-glucuronidase and neutral proteinases whereas B-chronic lymphoid leukemia involved acidic hydrolase concentrations lower than normal. As chronic myeloid leukemia advanced, neutral proteinase activity dropped dramatically (2.5 times); an aggressive course of B-chronic lymphoid leukemia was accompanied by a 3-fold decrease in acidic hydrolase level. The results may be used as indirect evidence of differences in the role of lysosomal enzymes in the mechanism of protein processing involved in myeloid and lymphoid proliferative pathologies. PMID- 8686247 TI - [Evaluation of immunotherapy in breast cancer (stage III-IV) and in cancer of the corpus uteri (stage I-III)]. AB - A new clinically-tested procedure of adjuvant immunotherapy carried out in conjunction with anticoagulant treatment is discussed. Application of said method has significantly improved the short-term and end results of treatment of inoperable cases of breast cancer, stage III-IV, receiving chemotherapy and patients with cancer of corpus uteri, stage I-III, receiving combined therapy plus radiation. PMID- 8686248 TI - [A.I.Serebrov--organizer of cancer control (birthday centenary)]. PMID- 8686249 TI - [Cysteine cathepsins secreted into the blood as markers of tumor growth]. AB - Cathepsin H was secreted into the blood plasma of cancer patients before and after surgery. In the mandibular osteoradionecrosis group, there was a tendency for cathepsin H level to decrease, although only in cases free from recurrent tumor growth. Constant levels of cathepsin H were maintained after specific treatment, even in tumor recurrence-free cases. Secretion of such enzymes may be considered a characteristic of tumor-bearing organism. Biochemical assay of cathepsin H level may be used as another procedure for diagnosing different patterns of malignant growth. PMID- 8686250 TI - [Effect of radiation emitted from personal computer terminal on urethan-induced lung tumors in mice]. AB - Female SHR mice were injected intraperitoneally 0.2 ml of 1% solution of urethan on days 1, 8, 54 and 61 of the experiment. Beginning from day 1, they were exposed to radiation emitted from the video terminal of the EGA/PC/AT-286 (personal computer), for 1 hr, 5 times a week. The exposure was conducted with or without the Ergostar G-14 protective filter. The distance between the PC screen and the cage bottom was 38 cm. It was found during the 12 months of the experiment that the lifespan of urethan-injected animals was somewhat shorter as a result of the exposure. A significantly higher frequency of all or only malignant tumors of the lung and uterine polyps was recorded in urethan- and irradiation-treated mice than in non-irradiated controls. However, irradiation of urethan-treated animals from a filter-protected screen was followed by a significant decrease in frequency of incidence of all neoplasms and multiple tumors of the lung, as compared with those exposed to unfiltered radiation. It is suggested that long-term exposure to PC-emitted irradiation may cause slight stimulation of urethan-induced carcinogenesis of the lung. The Ergostare filter was found to make no contribution to carcinogenesis. It is also thought that the urethan dose was too large and the entire model--too rigid to adequately assess the PC influence on neoplastic formation. PMID- 8686251 TI - [Skin carcinogenesis induced be neonatal administration of 5-bromo-2' deoxyuridine and subsequent treatment with 12-O-tetradecanoylphorbol-13-acetate in mice]. AB - Male and female SHR mice were injected, subcutaneously, 1 mg of 5-bromo-2' deoxyuridine (BrdUrd) or 0.05 ml of distilled water on days 1, 3 and 7 after birth and painted with 6.15 mkg of TPA dissolved in 0.1 ml of acetone, or acetone alone, twice a week, for 24 weeks, starting at the age of 15 weeks. The animals were followed up for 20 weeks after stopping TPA painting. Skin tumors emerged in TPA-treated animals only. TPA painting was followed by skin papilloma development in 20.9% of males and 36.6% females injected distilled water neonatally, tumors regressing in 88.4% of males and 85.4% of females by the end of the experiment. With combined treatments with BrdUrd and TPA, skin papilloma incidence was 56.5% in males and 52.6% in females, tumors persisting in 52.2% and 39.6%, respectively, until the end of the experiment. PMID- 8686252 TI - [The modifying effect of long-term administration of ascorbic acid with drinking water on asbestos-induced pleural carcinogenesis in Wistar rats]. AB - Ascorbic acid administered with drinking water, in a concentration of 2.5%, together with sucrose (1%) was found to significantly inhibit the development of mesothelial and pleural tumors induced in Wistar rats by asbestos treatment. Said agents, however, failed to influence spontaneous carcinogenesis. PMID- 8686253 TI - [Combined surgical treatment of malignant lung tumors]. AB - Two hundred-sixty four radical combined surgical operations (237 pneumonectomies and 27 lobectomies) were performed in 1981-1994. Two hundred-fifty four patients were operated on for cancer, 7-carcinoid and 3 patients for sarcoma. In 159 cases, tumors were identified as T3 and in 70 cases--as T4. Metastases into lymph nodes of the root and mediastinum--another 121 patients. Surgery alone was received by 90.5%. Mortality for the first 30 days was 1.9%. Twenty-six percent of patients with non-small cell carcinoma survived 5 years, small cell carcinoma 12.5% and carcinoid-100%. No significant difference in survival time was registered for T3 and T4 process. PMID- 8686255 TI - [Complications in patients with non-operated lung cancer]. AB - Autopsy-based data on complications involved in lung cancer untreated by surgery are presented. PMID- 8686254 TI - [Multiple primary tumors of the lung (autopsy reports)]. AB - Primary multiple malignancies were identified in 67 cases (3.55%) as a result of evaluation of 2,000 autopsy reports on deaths from lung cancer filed in Petrozavodsk and St. Petersburg. Eighty eight cases of primary multiple malignancies of the lung are discussed. A second tumor was found to be localized most frequently in the organs of respiration and digestion. PMID- 8686256 TI - [Comparative evaluation of the effectiveness of surgical treatment and pulsed laser therapy for malignant skin melanoma, stage I]. AB - The report deals with a comparison of the effectiveness of surgical (300 cases) and pulsed laser treatment (wavelength of 1,060 nm, pulse duration-1 ms) (230 cases) for skin melanoma, stage I, degree I-IV invasion (Clark). All patients were followed up for 5 years and longer. Following laser therapy, local recurrencies were detected in 0.75% while regional and distant metastases were identified in 24.8%; in 45.6%, they were detected within the first 12 months of follow-up. Treatment by radiation from a powerful pulse source proved effective for cutaneous melanoma, stage I, degree I-IV invasion (Clark). Total 5-year survival was 83.2%. All patients with degree I invasion have survived 5 years, and are still alive, degree II-92.3%, degree III-85.7% and degree IV-80.5%. For surgical treatment, total 5-year survival was 78.7%. All patients with degree I invasion have survived 5 years and are still alive, degree II-85.5%, degree III 78.9% and degree IV-68.4%. PMID- 8686257 TI - [Basic results of studies on AIDS from 1994]. PMID- 8686258 TI - [Expression of human immunodeficiency virus gag antigens and formation of virus like particles in a cell culture, infected with recombinant vaccinia virus strains (an electron-microscopic study)]. AB - The synthesis of gag antigens of human immunodeficiency virus (HIV) by recombinant vaccinia virus strains containing the expressed genes gag and gag-pol and the capacity of these proteins to formation of virus-like particles during infection of various cell cultures were studied. The recombinant strain containing the truncated gag gene (p48gag) was shown to effectively synthesize gag polypeptides and to form immature virus-like particles during infection of all the cell cultures tested (CV-1, Hep-2, HT-29). The morphogenesis of mature virus-like particles was detected by electron microscopy only in infection of Hep 2 cells with a strain containing a complete gag-pol sequence of HIV. PMID- 8686259 TI - [Prevalence of genotypes of the hepatitis C virus, circulating in northwestern and central parts of Russia]. AB - Testing of 90 sera for antibodies to hepatitis C virus (HCV) by genotyping methods resulted in determination of the genotype in 83 cases: 47 cases with 1b genotype, 27 with 1a, 7 with 3a, 1 with 2a, and 1 with 2b genotype. Hence, preliminary data indicate the predominance of HCV genotype 1b among patients with hepatitis C in these regions of Russia. PMID- 8686260 TI - [Comparative testing of live measles vaccines manufactured in France, Japan, and Russia]. AB - Live measles vaccines prepared from different strains in France, Japan, and Russia were compared at the L. A. Tarasevich State Institute for Standardization and Control of Viral Preparations. Clinical reactions to the tested vaccines were studied in 181 children seronegative before vaccination. Vaccinal reactions to French, Japanese, and Russian were observed in 24.2, 26.5, and 5.9% vaccinees, respectively. The French and Russian vaccines virtually did not differ by the level of seroconversion (96 and 98.1%, respectively). For the Japanese vaccine the level of sero-conversion was lower: 91.6%. The mean titers of antibodies in vaccinees immunized with the French, Japanese, and Russian vaccines were, respectively, 7.36 +/- 0.91, 2.07 +/- 0.42, and 4.40 +/- 0.42 IU. PMID- 8686262 TI - [Vergina-like strains of tick-borne encephalitis in Russia]. AB - The Greek strain Vergina representing an individual third serotype of tick-borne encephalitis (TBE) virus has been compared with 13 TBE strains isolated on the territory of Russia and Central Asia (in Kirghizia). A kit of deoxyoligonucleotide probes complementary to genome sites of Neudorfle strain of the TBE Central European subtype (protein C and prM genes) and of strain Sofyin of the Eastern subtype (protein E, C, M, prM, ns 1, ns 2b, ns 4b genes) was used in molecular hybridization of nucleic acids. Vergina strain was referred to the genetic variant VI prevalent in the western part of the East European plain, in Udmurtia, in the Altai mountains, and in West Siberia. By its antigenic properties Vergina strain is most close to strain Yar-90 isolated in the Yaroslavl district from Ixodes persulcatus ticks. PMID- 8686261 TI - [Attempts to develop a vaccine against Ebola fever]. AB - Data on the immunopathogenesis of Ebola fever in laboratory animals are presented and the efficacy of some methods of vaccine prophylaxis discussed. Antiviral immunity induced in guinea pigs by injection of inactivated viral agents did not protect them from infection, whereas injections of a nonlethal strain of the virus in ascending doses led to the formation of immunity preventing the development of disease upon inoculation with a lethal strain in high doses. The role of some viral peptides in the development of immune response is shown and variants of recombinant constructions for the prevention of Ebola fever are offered. PMID- 8686263 TI - [A highly-productive attenuated variant of Japanese encephalitis virus]. AB - Attenuated strain of Japanese encephalitis virus (JEV), clone 3, has been isolated from suckling mouse brain cell cultures chronically infected with JEV Nakayama strain, clone 33. Clone 3 actively replicates in 9-day chicken fibroblast cultures and possessed an uncommon for a JE agent capacity of causing cytodestruction of 1-2-day monolayer of chicken embryo cells, accumulates in these cultures in high titers (9.0 lg PFU/ml and higher), and is characterized by a high antigenic activity and a wide spectrum of antigenic relationships. New biologic properties acquired by JEV over the course of its persistence were retained after 10 and more passages through suckling mouse brain. PMID- 8686264 TI - [Comparative study of the immunogenicity of the inactivated hepatitis A vaccine Hep-A-in-vac from experimental and clinical data]. AB - Comparative analysis of the specific activities of various batches of Hep-A-in Vac vaccine showed that the immunologic efficacy of the agent directly depended on the content of hepatitis A virus antigen in the vaccine dose. The results of studying the immunogenicity of the agent on volunteers are compatible with the results of experimental studies and indicate that the test of guinea pigs adequately assesses this characteristic. Assessment of the immunogenic properties of Hep-A-in-Vac prepared using improved technology indicates that Russian vaccine injected three times in a dose containing at least 40 U EIA ensures 87.5% seroconversion in adult seronegative volunteers with the mean geometrical titer of antibodies to hepatitis A virus equal to 683 mIU/ml. PMID- 8686265 TI - [Development and study of the properties of immunoglobulin against Ebola fever]. AB - Immunoglobulin to Ebola fever has been for the first time prepared from hyperimmune equine blood sera by alcohol fractionation after Cohn. Preclinical study of the physicochemical and immunobiological properties of immunoglobulin showed that it protects up to 100% Papio hamadryas infected intramuscularly at doses of 110 to 29 LD50 Ebola virus. Scheme for the use of Ebola immunoglobulin has been experimentally validated. PMID- 8686266 TI - [A thermodynamic analysis of oxidative inactivation of influenza virus and lipid peroxidation of viral envelope lipids]. AB - The "activation energy" values for virus inactivation (22.2 kcal/mol) calculated using Arrenius formula and the levels of accumulation of the final product of lipid peroxidation, fluorescent pigment (21.2 kcal/mol), in virus envelopes were found to be in good correlation for purified influenza A/PR8/34 virus suspensions stored at temperatures from 6 to 37 degrees C. A "lipid" mechanism of inactivation of enveloped viruses is proposed, permitting, together with the "nucleic" and "protein" mechanisms, a satisfactory interpretation of the relationship between the stability of viral material and the medium composition, lipid composition of virus envelopes, and other factors. PMID- 8686267 TI - [Antiviral properties of recombinant human lymphotoxin]. AB - Study of the antiviral properties of recombinant human lymphotoxin obtained from Escherichia coli SG20050/pLT21 strain by microbiological synthesis showed this lymphotoxin to inhibit vesicular stomatitis virus on M-19 cells and exert a synergistic effect with recombinant human gamma-interferon. The drug exhibited no anti-HIV1 activity in experiments with MT4 cells pretreated with the virus or the drug itself; on the contrary, HIV1 reproduction in these cells was enhanced at low concentrations of the recombinant lymphotoxin. PMID- 8686268 TI - [Detection of bovine infectious rhinotracheitis virus by hybridization using nonradioactive DNA-probes]. AB - Biotin-labeled DNA probes for infectious bovine rhinotracheitis virus also known as bovine herpesvirus-1 (BHV-1) have been developed. The procedure is based on dot-blot hybridization using biotin-labeled bacteriophage M13 and plasmid probes containing cloned PstI and EcoRI-PstI restriction fragments of viral genome. The probes obtained were used to detect viral nucleic acids in specimens of bovine spermatic fluid or nasal swabs of calves. The method is simple and rapid, taking less than 24 h, and is highly specific and sensitive, this recommending it for practical veterinary. PMID- 8686270 TI - [Successes in global eradication of poliomyelitis: 1985-1994]. PMID- 8686269 TI - [Detection of viral-bacterial factors responsible for infertility in couples]. AB - A high prevalence of genital infections was revealed in patients suffering for a long time from sterility. The inflammatory process was found to predominate in tubal sterility. In other forms of sterility with asymptomatic urogenital infections the couples are frequently unaware of the disease and are not properly examined. Genital inflammations not diagnosed for many years augment the endocrine disorders and stimulate the development of autoimmune states. Today, a mixed viral/bacterial urogenital infection is the principal cause of reproductive disorders. PMID- 8686271 TI - [Preparation and study of properties of anti-idiotypic antibodies, carrying hemagglutinating paratopes of tick-borne encephalitis virus on their surface]. AB - Rabbit polyclonal and rat monoclonal anti-idiotypical antibodies (AIA) against two hemagglutinating murine monoclonal antibodies to glycoprotein E of tick-borne encephalitis virus (TBE) have been obtained, purified, and studied. All AIA reacted with murine monoclonal antibodies to TBE protein E and did not react with normal murine immunoglobulins in enzyme immunoassay (EIA). Polyclonal AIA to monoclonal E6B and 10H10 antibodies specifically reacted with RH, SPEV, and goose red cells. In addition, polyclonal AIA were capable of agglutinating goose erythrocytes. Mice immunized with purified polyclonal and monoclonal AIA produced antiviral sera, which reacted in EIA with purified TBE virions. These results indicate that AIA carry the TBE virus image and mimic the hemagglutination activity epitopes on glycoprotein E. Interactions of AIA with cell membranes indicates that they fix the cellular receptor needed for adsorption and penetration of TBE virus into the cells. PMID- 8686272 TI - [Reticuloendothelial system and persistence of influenza virus in the body]. AB - The method of in situ transcription was used to detect influenza virus genome in the organs of infected mice. Virus-specific RNA was found in the alveolar macrophages 5 months after infection, this confirming the capacity of the virus to persist in vivo in these cells for a long time. Evidence in favor of influenza virus modification in an infected host body is presented, which fact dramatically affects virus interactions with macrophages. Problems in the development of acute and persistent infections and influenza virus persistence in reticuloendothelial cells are discussed. PMID- 8686273 TI - [Adaptation of hepatitis A virus to nonprimate cells]. AB - Hepatitis A virus (HAV) was adapted to nonprimate BHK-21 cell line (Syrian hamster kidney). Enzyme immunoassay, immunoblotting, and slot hybridization demonstrated the capacity of HM175 culture strain to stable reproduction in this cell line. More than 50 passages of adapted HAV were carried out, which showed no changes in the basic cultural characteristics of the virus. The data permit a conclusion on the possibility of HAV reproduction in nonprimate cells. PMID- 8686274 TI - [Comparative characteristics of a test system for detecting antibodies to hepatitis C virus]. AB - The sensitivities and specificities of enzyme immunoassay (EIA) kits for the detection of antibodies to hepatitis C virus (HCV) were compared in donor blood screening. A total of 3308 donors were examined using Akvapast immunodiagnosticum (St. Petersburg), lot 12. Anti-HCV antibodies were detected in 43 (1.3%) subjects. Blood sera of these donors were additionally investigated using other lots of Akvapast, Hepascan (Bioservice, Moscow), Blot-0.5 (Bioservice, Moscow), and immunoComb (France). The studies demonstrated that none of the agents used can be acknowledged as ideally sensitive and specific for the detection of anti HCV antibodies. Maximally sensitive diagnostic kits should be preferred for the screening of donors of blood components and for other mass surveys. Highly specific test systems are advisable for profound examinations and diagnostic monitoring. The creation of a system of reference and expert diagnosis of hepatitis C remains a pressing task. PMID- 8686275 TI - [Genotype of hepatitis C virus in hemophiliacs]. AB - Testing of blood sera of 63 hemophiliacs revealed markers of hepatitides B and C in 97 and 98% cases, respectively. Polymerase chain reaction confirmed the presence of hepatitis C virus (HCV) RNA in 31 (94%) out of 33 sera tested which contained antibodies to HCV. Gene typing of the isolated strains revealed the presence of three types of HCV: 1b (94%), 2a (3%), and 3a (3%). Similar distribution of HCV genotypes was revealed in the blood sera of 39 patients with chronic hepatitis C. PMID- 8686276 TI - [Treatment of experimental herpesvirus infection with nonsteroidal anti inflammatory agents]. AB - The therapeutic effect of nonsteroid antiinflammatory drugs (pyrazolone and salicylate derivatives) and their combinations with acyclovir was assessed in experimental herpesvirus infection in cell culture and in mice. A combination of 4-iodoantipyrine and acyclovir protected mice from herpesvirus encephalitis. This effect was associated with a decrease of the level of the virus in mouse brain and an increase of the titers of serum interferon and virus neutralizing antibodies. PMID- 8686277 TI - [The genetics of the measles virus]. PMID- 8686279 TI - [Persistence of the measles virus]. PMID- 8686278 TI - [Measles virus proteins, their function and antigenic variability]. PMID- 8686280 TI - [Live measles vaccines]. PMID- 8686281 TI - [Measles vaccines: new directions, new strategies]. PMID- 8686282 TI - [Cellular and humoral immunity in measles]. PMID- 8686283 TI - [A noninjection method of using live measles vaccine]. PMID- 8686284 TI - [Modern serological methods of monitoring measles eradication pro grams]. PMID- 8686286 TI - Studying multidimensional constructs through cluster analysis. AB - The analysis of multidimensional constructs presents a challenge. The challenge is to combine the information from the dimensions relating to the construct in a meaningful way. This article examines a complex construct known as the nursing practice environment and describes the use of cluster analysis to combine information from three dimensional measurements to operationalize the construct. PMID- 8686285 TI - [WHO strategy for total eradication of measles]. PMID- 8686287 TI - Promoting research consumerism in B.S.N. students . PMID- 8686288 TI - A family's coming to terms with Alzheimer's disease. AB - Findings of a qualitative analysis of several members of a family in which one member has Alzheimer's Disease (AD) support the notion that differences in how each family member defines and makes meaning of the situation have consequences for the family as a unit. Ten in-depth individual and dyadic interviews of five available family members were conducted during a period of 18 months. Data support the finding that each member of the family experienced a similar process of coming to terms with changes in the person who has AD. This process consisted of three stages: identifying how the person with AD was the same as he was before, as well as how he was different, prior to disease onset; redefining the identity of the person with AD; and rewriting one's relationship with the person with AD. This study supports both Knafl's and Deatrick's concept of family management and Patterson's concept of family meaning. PMID- 8686289 TI - Homeless women's perceptions about their families of origin. AB - The purpose of this study was to examine descriptively the families of origin of women who are, or who had been, homeless. The research was done using a descriptive qualitative research design; specifically, intensive interviewing. A feminist framework guided the research process. Lofland and Lofland's (1984) conceptualization of units of social settings was used as the basis for analysis of the data. The sample consisted of 20 women who had been homeless. Twelve of the women were interviewed individually. Six of those 12 women and an additional 8 women were later interviewed as part of two focus groups. Themes within each social unit included: meanings--homelesness, home, family of origin, lack of connectedness, and being without; practices--male privilege, transiency, and abuse issues; episodes--loss of family and being homeless; roles--traditional female-male, scapegoating, and little adult; and relationships--mother/daughter, father/daughter, and sibling. Within the mother/daughter relationships, the dominant themes were betrayal, devaluation of self, enmeshment, emotional void, longing for, emotional cutoff, and destructive coalitions. The themes from the father/daughter relationships social unit were abuse issues, differential treatment, idealized father figure, and banished daughter. Criteria for transferability and adequacy were used to determine scientific rigor. PMID- 8686290 TI - Elder care recipients' care-seeking process. AB - The care-seeking process used by elders residing in a continuing-care retirement community to elicit care from caregivers and engage caregivers in care interactions is described. Generated from 8 months of ethnographic field research that incorporated semistructured interviewing, participant observation, and focus group interviewing data collection strategies with 47 elders, the care-seeking process emerged as the sequential phases and stages that evolved over time in elders' interactions with their formal and informal caregivers. The findings extend what is currently known about the active and thoughtful role elders assume in their care interactions. An understanding of the ways elders elicit care and engage caregivers may assist nurses to maximize their care interactions with elders. PMID- 8686291 TI - Overcoming national and cultural differences within collaborative international nursing research. PMID- 8686293 TI - Professionalism behaviors of hospital nurse executives and middle managers in 10 western states. AB - What is the level of professionalism of nurse managers? These leaders of nurses are expected to establish a climate in which professional practice can flourish. In this study, the authors used the Professionalism Inventory to determine professional behaviors of 144 nurse executives and 135 middle managers. Nurse executives performed at consistently higher levels except for the categories concerning autonomy and knowledge of the Code for Nurses. PMID- 8686292 TI - Long-term care nurses' ethical convictions about tube feeding. AB - Moral certainty, uncertainty, or both have an impact on every ethical decision confronted by the nurse. This article describes a qualitative study of the moral certainty and uncertainty experienced by long-term care nurses who are faced with the issue of withholding or withdrawing artificial nutrition and hydration from elders in the end stages of life. Moral certainty and uncertainty are analyzed as universal concepts, and the analysis is supported by the words of the study participants. Morally certain participants view tube feeding negatively and are likely to take some action when confronted with elders being tube-fed. The most common action is to educate families about tube feeding. Morally uncertain participants see the tube feeding as neutral or benign and are likely to take no action, but to maintain a strong belief that the elder should not suffer. Moral certainty and uncertainty are compared and contrasted and the findings discussed. PMID- 8686294 TI - A historical review of the depiction of women in cardiovascular literature. AB - A historical review of the literature demonstrates that women have long been acknowledged as suffering from cardiac disease and disorder. Until recently, women's experience with cardiac disease was investigated primarily as the cardiac disease impinged on pregnancy or women's ability to carry out home-related duties. Only in the last decade has a more appropriate and more holistic view of women's unique experience with cardiac disease been undertaken. The authors attribute this new perspective in health literature, in large part, to the advancement of feminist approach and critique. PMID- 8686295 TI - Clinical sequelae of hepatitis C acquired from injection drug use. AB - We determined the course of hepatitis C infection in 125 patients with a history of injection drug use. The mean age at presentation was 43.5 years, and the mean age of initiating injection drug use was 23.1 years. Fatigue and hepatomegaly were present in as many as 60% of patients. All had antibodies to the hepatitis C recombinant protein C25, and 99% were positive for hepatitis C virus RNA. After the initial workup, 33 (26%) patients had chronic hepatitis, 46 (37%) had chronic active hepatitis, 45 (36%) had cirrhosis, and 1 (0.8%) presented hepatocellular carcinoma. During follow-up, hepatocellular carcinoma developed in 2 other patients. In 74 patients with a 1-year history of injection drug use, the mean number of years to the development of chronic hepatitis, chronic active hepatitis, cirrhosis, and hepatocellular carcinoma were 15.6, 17.6, 19.4, and 26.3 years, respectively. In this subgroup of patients, heavy alcohol abuse did not appear to influence the progression of liver disease. The 2-year case fatality rate was 2%. Our findings indicate that hepatitis C is a progressive disease, but only a few died during the average 20.4 years after the initiation of injection drug use. Antiviral treatment to eradicate the virus and halt the progression of disease is indicated in this group of patients. PMID- 8686296 TI - Differing beliefs about breast cancer among Latinas and Anglo women. AB - To improve breast cancer control among Latinas, it is important to understand culturally based beliefs that many influence the way women view this disease. We did a telephone survey of randomly selected Latinas and non-Hispanic white (Anglo) women in Orange County, California, to explore such beliefs using questions from previous national surveys and an ethnographic study of breast cancer. Respondents included 803 Latinas and 422 Anglo women. Latinas were more likely than Anglo women to believe that factors such as breast trauma (71% versus 39%) and breast fondling (27% versus 6%) increased the risk of breast cancer, less likely to know that symptoms such as breast lumps (89% versus 98%) and bloody breast discharge (69% versus 88%) could indicate breast cancer, and more likely to believe that mammograms were necessary only to evaluate breast lumps (35% versus 11%) (P < .01 for each). After adjusting for age, education, employment status, insurance status, and income, logistic regression analysis confirmed that Latino ethnicity and acculturation levels were significant predictors of these beliefs. We conclude that Latinas' beliefs about cancer differ in important ways from those of Anglo women and that these beliefs may reflect the moral framework within which Latinas interpret diseases. These findings are important for the development of culturally sensitive breast cancer control programs and for practicing physicians. PMID- 8686297 TI - Use of risk-adjusted outcome data for quality improvement by public hospitals. AB - In 1993 the California Office of Statewide Health Planning and Development (OSHPD) began public release of risk-adjusted monitoring of outcomes (RAMO) under the California Hospital Outcomes Project. We studied how 17 acute are public hospitals in California used these RAMO data for quality improvement purposes following their initial distribution, first by analyzing the outcome data for San Francisco General Hospital Medical Center as recommended by OSHPD and, second, by querying the departments at the other 16 public hospitals to determine how their own analyses compared. We found that the hospitals generally did minimal analyses of the OSHPD RAMO data and considered the data of little value to them. Only 3 hospitals initiated quality improvement activities based on their data review. The major reasons given by the hospitals for not using the RAMO data were that their outcomes were adequate, as verified by a comparison of their observed outcomes and those expected after risk-adjustment; that the hospitals had too few patients in the diagnostic categories; that they had too few resources; and that they were not concerned with the data's public release. Other possible explanations were that awareness of the California Hospital Outcomes Project was not widespread at the time of the study, that the RAMO data were not distributed in a way that encouraged their use, and that public hospitals were not inclined to use the outcome data because the project was imposed on them. Whatever the explanation, our study suggests that the California Hospital Outcomes Project has had little effect on quality improvement in public hospitals. PMID- 8686298 TI - AIDS-related experiences of primary care physicians in rural California, 1995. AB - A telephone survey was conducted of primary care physicians in nonmetropolitan counties of California. In a random sample of those counties reporting fewer than 30 cases of the acquired immunodeficiency syndrome (AIDS) as of December 1994, all physicians in practice were called; in counties reporting from 31 to 150 cases of AIDS as of the same date, a 30% random sample was selected for interviewing. Completion rates were 82% in the smallest counties and 70% in the larger counties (overall 72%). Two thirds of physicians reported that they had seen a patient positive for the human immunodeficiency virus and were providing continuing care for the disease. In all, 60% of physicians had seen a patient with AIDS. In these counties, there were 653 primary care physicians and 873 patients living with AIDS. The proportion of physicians providing care to persons with AIDS was twice that reported in previous surveys done in Los Angeles, California. In the interval (1985-1994), there was a 20-fold increase in the number of AIDS cases in California. In the nonmetropolitan areas, the number of AIDS cases in late 1994 was 290 times that reported in 1985. PMID- 8686299 TI - Role of nitric oxide in progression and regression of atherosclerosis. AB - Endothelium-derived nitric oxide is a potent endogenous vasodilator that is derived from the metabolism of L-arginine. This endothelial factor inhibits circulating blood elements from interacting with the vessel wall. Platelet adherence and aggregation as well as monocyte adherence and infiltration are opposed by this paracrine substance. By virtue of these characteristics, endothelium-derived nitric oxide inhibits atherogenesis in animal models and may even induce regression. PMID- 8686301 TI - Female urethral syndrome. A female prostatitis? AB - The cause of the female urethral syndrome has previously been obscure, as it has been associated by definition with a lack of objective findings but a plethora of subjective complaints of retropubic pressure, dyspareunia, urinary frequency, and dysuria. There is now strong evidence that the microscopic paraurethral glands connected to the distal third of the urethra in the prevaginal space are homologous to the prostate. They stain histologically for prostate-specific antigen and, like the prostate, are subject to both infection and cancer. The most important aspect of recognizing this microscopic "female prostate" as an anatomic feature is that its infections may completely explain many cases of the urethral syndrome. Further, the diagnosis is not elusive if trained clinicians palpate for localized and objective paraurethral tenderness through the anterior vagina wall to one or both sides of the urethra. Treatment parallel to that for male prostatitis is usually rewarded by the elimination of symptoms and the objective finding of the loss of tenderness of the paraurethral glands. As with prostatitis, the localized problem often recurs. It is time to alert primary care physicians to this disorder and to eliminate the widespread practice of treating affected women with either invasive urethral dilation or tranquilizers. PMID- 8686302 TI - Advances in lung transplantation. PMID- 8686300 TI - Atrial fibrillation pearls and perils of management. AB - Atrial fibrillation, a common arrhythmia, is responsible for considerable cardiovascular morbidity. Its management demands more than antiarrhythmic therapy alone, but must address the causes and consequences of the arrhythmia. Although remediable causes are infrequently found, a thorough search for associated heart disease or its risk factors results in better-informed patient management. Controlling the ventricular response and protecting from thromboembolic complications are important initial goals of therapy and may include the administration of aspirin in younger, low-risk patients. Older patients and those with risk factors for systemic embolism are not adequately protected from stroke complications by aspirin therapy alone. It remains controversial whether all high risk patients should receive warfarin and at what intensity. Whether and how sinus rhythm should be restored and maintained poses the greatest therapeutic controversy for atrial fibrillation. The mortal risk of antiarrhythmic therapy is substantially greater in patients with evidence of heart failure. In such persons, the risks and benefits of maintaining normal sinus rhythm with antiarrhythmic medications should be weighted carefully. A definitive cure for atrial fibrillation remains elusive, but promising surgical and catheter ablation therapies are being developed. PMID- 8686303 TI - Clinical uses for low-molecular-weight heparins. PMID- 8686304 TI - Exercise-induced asthma. PMID- 8686305 TI - Osteoporosis--new techniques for screening, diagnosis, and clinical monitoring. PMID- 8686306 TI - Renal complications of hepatitis C virus infection. PMID- 8686307 TI - New treatments of sickle cell disease. PMID- 8686308 TI - Thrombotic thrombo-cytopenic purpura associated with histamine H2-receptor antagonist therapy. PMID- 8686309 TI - Anorectal melanoma. Successful palliation in a 59-year-old woman. PMID- 8686310 TI - Pulsus irregularis perpetus--100 years of progress, but many issues still unresolved. PMID- 8686311 TI - Evolution of form and circumstance in medical oaths. PMID- 8686312 TI - Terry and the fly. PMID- 8686313 TI - [Effectiveness of fixed analgesic combinations exemplified by thomapyrin]. AB - Thomapyrin has been on the German market as analgesic for the past 50 years. It is the prescription-free preparation with the highest sales there. This is an occasion to survey current state of scientific knowledge concerning combination analgesics with acetyl salicylic acid, paracetamol and caffeine. For the assessment and registration of fixed preparations authorities of different European countries and also USA have defined special criteria. Analgesic preparations must agree with these defined criteria. The importance of these combination analgesics in pain therapy is described with the respect to the latest scientific results. Combination analgesics represent an important area of self-medication by the patient. The properties of the active substances alone and in combination are set forth, with respect to pharmacokinetics and efficacy. The experimental and especially clinical results clearly show a broader spectrum of action in consequence of the different modes of action of the individual active substances. Analgesic action is 1.4 fold higher owing to added caffeine. The fixed combination of active substances does not change the profile of side effects. The conclusion is that combination analgesics such as Thomapyrine show a positive benefit/risk ratio. Furthermore such combination analgesics are appropriate for self-medications and suited to combat pain of different kinds. PMID- 8686314 TI - Cost effectiveness of cholesterol-lowering drugs: a review of the evidence. AB - Four studies of the cost per life year saved through lipid lowering with lovastatin or simvastatin showed considerable variation in the results. For example, the cost per life year saved on administration of simvastatin 20 mg/day for primary prevention in men 42 years old at the start of therapy and with an initial cholesterol level of 8 mmol/L, was 19,000 1994-US dollars according to one study, and 55,000 according to another. Both when the differences were due to different cost estimates and when they were due to different estimates of the number of life years saved, plausible explanations for the discrepancies between the cost-effectiveness ratios were generally found. The cost per life year saved through primary prevention was about three times greater among women than men at age 40, twice greater at age 60, an 1.3 times greater at age 70. The accordance between the studies was not good regarding how cost per life year saved varies with age at the start of drug therapy. According to one study, the cost per life year saved for secondary prevention is generally low. We also compared the estimates for statins with estimates for several other life-extending health interventions. Given current guidelines for the prescription of cholesterol lowering drugs, primary prevention with statins seems generally to be one of the less cost-effective life extending health interventions, especially for women. The cost effectiveness of statins is likely to become more favorable, though, when the patients on these drugs expire. PMID- 8686315 TI - Control mechanisms of cell-mediated reactions. AB - One of the most relevant aspects of tumor adoptive immunotherapy is provided by clinical trails on transfer of cytotoxic cells (LAK and TIL). However, LAK cell therapy is effective in a small number (16-22%) of only certain tumors, while therapy with TIL cells is efficient in about 40% of melanomas. Several possibilities have been raised to explain the low efficacy of cytotoxic cells in tumor therapy, amongst which are the poor immunogenicity of tumor and tumor induced immunodepression. Furthermore, the possibility that cytotoxic cells do not reach the tumor site in adequate numbers has to be considered. We have developed an experimental system to study the ability of antigen-specific T cells to reach the target antigen in the tissues. The results obtained demonstrate that gamma delta cells and IL-4 are required to allow tissue localization of antigen specific alpha beta cells, thus indicating that their ability to exert certain effect or functions requires cooperation by other cells types. These results may be relevant to the understanding of the mechanisms leading to localization of immunologically active cells at a tumor site. PMID- 8686316 TI - [Psoas abscess]. AB - Psoas abscess is a rare infection, which can present a diagnostic challenge. The classical symptoms are fever, rigor and pain in the loin, lower abdomen, groin or hip, as well as a characteristic limp, but these symptoms can vary. The general health can deteriorate with delayed diagnosis and anemia, weight loss and anorexia can develop. CT is the best diagnostic method to demonstrate the localization and extent of the abscess and also possible sources of infection in the neighbourhood. 14 cases of psoas abscess, which were largely diagnosed and treated in the urological department, are presented and the clinical spectrum of this infection is discussed. PMID- 8686317 TI - [Current treatment strategy in malignant pleural effusion]. AB - Malignant pleural effusions are a grave consequence of advanced cancer disease. The successful suppression of pleural fluid reaccumulation can make a major contribution to the management and palliative care of patients with disseminated cancer. Many treatment concepts have been reported in the literature. The recommended therapy in malignant pleural effusions consists of intrapleural instillation of a sclerotic agent to produce pleurodesis. Different substances have been used, including tetracyclines, cytostatic agents, fibrin, talc, Corynebacterium parvum, cytokines and others. We reviewed the most frequently used techniques of pleurodesis in order to define the most effective treatment concept. In 15 prospective randomized trials the success rates varied from 13% with bleomycin to 100% with talc or Corynebacterium parvum. Talc was superior to other agents in 6 of 6, Corynebacterium parvum in 3 of 4 and bleomycin or tetracycline only in 3 of 8 studies. Adverse effects were frequently observed with cytostatic agents, but were very rare in the case of talc or fibrin instillation. Comparing the recently published data pleurodesis with talc appears to be the most effective treatment strategy, followed by Corynebacterium parvum, bleomycin and tetracycline. PMID- 8686318 TI - Laparoscopic technique of proximal selective vagotomy. AB - Proximal selective vagotomy (PSV) is an effective, definitive therapy for peptic ulcer disease of the duodenum. Long-term studies have shown that ulcer recurrence occurs in less than 10% of patients if the operation is performed by an experienced surgeon. Since PSV does not influence gastric emptying, side effects such as diarrhea, gastric stasis or the dumping syndrome are rare. Due to this favorable experience, PSV is our preferred technique for the laparoscopic approach to peptic ulcer disease. We have performed this operation in 13 patients. Indications were chronic duodenal ulceration unresponsive to medical therapy, chronic duodenal ulceration combined with reflux esophagitis, and reflux esophagitis due to gastric acid hypersecretion. In patients with reflux esophagitis PSV was performed in addition to an antireflux procedure. Laparoscopic PSV can be performed more accurately than the open procedure since it allows for better visualization with less possibility of missing small vagal connections to the parietal cells such as the 'criminal nerve'. The median duration of operation was 3 hours. There were no serious peri- or postoperative complications. The median time of postoperative hospital stay was 3 days. During the median follow-up of 27 months no recurrence of duodenal or esophageal ulceration was encountered and none of the patients complained of epigastric pain, diarrhea or dumping symptoms. PMID- 8686319 TI - Peptic esophageal stricture: is surgery still necessary? AB - Gastroesophageal reflux disease is frequently complicated by peptic esophageal stricture formation. Treatment of choice over the past 25 years has changed from resection of the stenotic esophagus towards fundoplication, or conservative treatment combined with dilatation. Reports on the long-term results of the clinical course of such patients are still rare. Between 1965 and 1990 200 patients were treated for peptic esophageal stricture by surgery or bougienage with antisecretory medication. Retrospective analysis of the clinical outcome according to the primary therapeutic strategy was performed after a follow-up period of 1.5 to 267 months. 139 patients (group A) primarily received bougienage and medical treatment. After 71 months 36% of the patients were symptom-free, 52% had received further dilatation and 11% had undergone surgery. One fatal complication occurred. 61 patients (group B) underwent primary surgical treatment. Fundoplication was performed in 72% of the cases, resection in 18% and other procedures in 10%. After a median period of 84 months following standard fundoplication (n = 43) 44% were free of symptoms, 39% had received further dilatations and 12% had to be reoperated. Fatal complications occurred in 2 patients (5%). The risk of undergoing surgery after primary dilatation was 16% after 2 years, remaining on this level throughout follow-up time. We conclude that resection of peptic strictures of the esophagus is rarely indicated any more. Treatment of choice consists of primary bougienage combined with antisecretory medication. If conservative treatment fails or patient compliance is low we recommend fundoplication with intraoperative dilatation within the first 2 years after diagnosis of symptomatic stricture. PMID- 8686321 TI - [Extracorporeal Treatment Method in Intensive Care. Wien, 22-24 February 1996. Proceedings and abstracts]. PMID- 8686320 TI - Psychiatric prognostic factors in patients with alcohol-related end-stage liver disease before liver transplantation. AB - Discussion of selection criteria for liver transplantation in alcoholics has been controversial. The concern that there might be a return to alcohol misuse after transplantation which would cause non-compliance with post-transplantation management is not supported by recent reports. Six months of abstinence have been required generally as exclusion criterion, no other psychiatric prognostic factors have been evaluated up to now. METHODS: In 39 consecutive patients with alcohol-related end-stage liver disease who were referred to the Surgical University Clinic of Vienna for transplantation the psychiatric prognostic factors abstinence for at least six months, motivation (defined as combination of insight into the necessity of abstinence and readiness for alcohol dependence treatment) and compliance (which was stated to be positive if the psychiatric counselling dates were kept by the patients) were evaluated regarding survival for at least one year. RESULTS: Abstinence of at least six months failed to prove to be a positive influence on survival. In contrast, motivation and compliance proved to be good psychiatric prognosis parameters. PMID- 8686322 TI - [Pulmonary (side)effects of extracorporeal therapy procedures]. PMID- 8686323 TI - [Clinical aspects of biocompatibility]. PMID- 8686324 TI - [Activation of blood coagulation in extracorporeal circulation]. PMID- 8686325 TI - [Serum uric acid level in type 1 and type 2 diabetic patients]. AB - In 50 type-1 and 50 type-2 diabetic patients serum uric acid levels were measured. Type-1 diabetics showed significantly lower serum uric acid levels in comparison to type-2 diabetics (p < 0.02). This significant difference has been observed in both women (p < 0.001) and men (p < 0.01). Serum uric acid level was lower in type-1 diabetics than in healthy controls but only in diabetic men the difference was statistically significant (p < 0.001). Male type-2 diabetic patients showed serum uric acid levels similar to the controls, but levels were higher in women with type-2 diabetes (p < 0.001). The results of this study show that in type-1 diabetic patients the serum uric acid levels are lower in normal (creatinine clearance > or = 80 ml/min) as well as in slightly decreased (creatinine clearance < 80 ml/min) glomerular filtration rate. But in type-2 diabetic patients the serum uric acid levels were significantly higher when glomerular filtration rate was below 80 ml/min in contrast to normal renal function (p < 0.05). PMID- 8686326 TI - Age, time, entropy, and biological optimality--some remarks on the general problem of biological optimization. AB - The purpose of this paper is to look from a very general viewpoint to the interaction of factors which contribute to the process of aging. Life time is the most significant period for an individual. Several theories try to explain the process of aging by genetic determinants, by genetic or metabolic defects, by immunologic failure or by other reasons. It is noteworthy that the duration of life is correlated to the size of the body of different animals. This fact indicates a close relation to metabolism. It can be assumed that under optimal conditions of life, defects in function or structure are repaired by special maintenance functions. During the process of aging these functions lose effectuality. PMID- 8686327 TI - [Free love, wild marriage--on the gradual dissolution of marriage by love"]. AB - Within the different cultural epochs there exist different concepts of what is to be meant by 'love', 'marriage', 'human communication'. Maybe we are presently in the process of a paradigmatic change. However certain basic laws within human relations will always persist, such as: erotics, attraction, strive to social security, necessity to combine positive and negative within longer lasting human relations etc. Above all there is a great individual variability. There exist no one-way solutions. The more it is important that not only psychotherapists should be aware of the problems and include them in their daily work. But it counts for every doctor, who intends to operate humanistic medicine (not only a mechanistic one). This means a holistic approach towards a "partner"-patient. PMID- 8686328 TI - [Results of a double-blind, randomized comparative study of Wobenzym-placebo in patients with cervical syndrome]. AB - The results of this study are based on 30 patients per treatment group. The primary objective of this trial was evidence of a superior analgesic effect of the verum group under concomitant treatment with physicotherapeutic measures. This objective was achieved and showed a small, but statistically significant and beneficial effect of Wobenzym in the pain self ratings of the patients. The results of erythrocyte sedimentation rates (Westergreen), leukocyte counts and lymphocyte counts as secondary study parameters indicate, that the antiphlogistic effects of Wobenzym provide an additional beneficial effect for the patients suffering from cervical syndrome compared to placebo. In combination with the available safety data of this study, the final interpretation of the authors of this study leads to a superior benefit/risk ratio judgement for Wobenzym compared to placebo. PMID- 8686329 TI - [Beta receptor blockade in heart failure: a new look at an old topic]. PMID- 8686330 TI - [Serum digoxin level in patients with dilated cardiomyopathy]. AB - To investigate whether measuring levels of digoxin in patients with idiopathic dilated cardiomyopathy (IDC) is helpful in dose adjustment of digoxin we did the following study. In 77 patients (63 male, 14 female) with invasively verified IDC serum-digoxin levels were measured after a treatment period with beta acetyldigoxin of at least 6 months. All patients received digoxin, 76 had ACE inhibitors and 69 used diuretics. Mean serum-levels of digoxin were 0.96 ng/ml while using a mean daily dose of digoxin of 0.24 mg. Those who showed a serum level of digoxin within the recommended range took a slightly higher daily dose of digoxin when compared to those with low levels of digoxin (0.26 vs. 0.23 mg/day, p < 0.05). Therefore, we conclude that low serum-levels of digoxin are mainly caused by low intake of digoxin and it is justified to measure digoxin levels in IDC-patients even if it increases costs. PMID- 8686331 TI - Nursing practice. Report of a WHO expert committee. AB - Nursing is remarkable for the scope of activities that it includes. Nursing practice involves so many things in so many places that finding a definition that includes everything and applies everywhere is no easy task. This report by the WHO Expert Committee on Nursing Practice describes the basic functions of nursing practice and how they are manifested in different socioeconomic situations. Whatever the environment, the report concludes, there are certain core elements that are the responsibility of nurses the world over. The influence that social attitudes and political and economic policies have on nursing practice is examined. The report is honest in its admission that the situation in many places is far from ideal and that in most there is clear room for improvement. Policy makers, legislators, managers, educators, researchers, other professionals and nurses themselves have important roles to play in a comprehensive approach to the development of nursing practice proposed by the Expert Committee. The report emphasizes the importance of a well educated and highly skilled nursing workforce that is consistent in maintaining quality of care but is also responsive to change. It points the way to international standards in nursing practice and lays the foundation for new strategies to ensure that nurses will be fully equipped to meet future challenges in the delivery of health care. PMID- 8686332 TI - [The mistletoe myth--claims, reality and provable perspectives]. AB - Intuition guided R. Steiner to refer to mistletoe as the future remedy for cancer. He proposed that its spiritual qualities support re-establishment of the harmonious integration of the alleged four different entities of human existence in a patient. The assumption of potency without chemical basis is derived from the dogmatic system of anthroposophic reasoning. It explains the evidently similar claim of clinical efficiency for the proprietary mistletoe extracts despite the lack of information on the actual contents of the complex mixtures and despite the conspicuous diversity of methods of manufacture for these products. Thorough scientific analysis of the published clinical experience does not justify this claim. Due to the increasing reference to defined substances in advertisements for commercial extracts, they should no longer avoid rigorous testing according to common quality standards. Interdisciplinary research efforts on the immunomodulatory galactoside-binding lectin illustrate how to yield a clinically testable substance from an ill-defined extract, thereby providing a notable example for rational investigation of unconventional treatment modalities. PMID- 8686333 TI - [Echinacea drugs--effects and active ingredients]. AB - Echinacea-containing drugs have to be classified according to the used plant species (Echinacea purpurea, E. pallida or E. angustifolia), the processed part of the plant (root, upper parts or whole plant), and the mode of processing. Significant pharmacological effects have been found in vitro and in vivo for the expressed juice of the upper parts of E. purpurea and for alcoholic extracts of the roots of E. pallida, E. angustifolia and E. purpurea. The activity is mainly directed towards the nonspecific cellular immune system. Several active constituents are discussed: polysaccharides, glycoproteins, caffeic acid derivatives (cichoric acid) and alkamides. PMID- 8686334 TI - [Clinical application of extracts of Echinacea purpurea or Echinacea pallida. Critical evaluation of controlled clinical studies]. AB - The phytotherapy should be understood as being integrated into the rational pharmacotherapy. The modern phytotherapy tries hard to proof effects with pharmacological and clinical studies. The task force E of the federal bureau of health of Germany has made a statement regarding this problem. This article reviews only controlled clinical trials about the application of extracts of echinacea purpura or echinacea pallida. PMID- 8686335 TI - [Special treatment methods in general practice--legal medicine viewpoint]. AB - There is only one common medical law which is valid for all physicians. No therapy method can claim a special status or special rights. However, due to the considerable differences in training and qualification, the jurisdiction grants special rights to a healer without medical exam (non-medical practitioner) in comparison to a physician. Additionally, a physician has to take into account the limitations by the social legislation when he uses "special treatment methods" to avoid claims for compensation. PMID- 8686336 TI - [Principles of pain therapy with local anesthesia]. AB - The treatment of chronic pain consists of four basic concepts: Drugs (analgetic drugs, TAD, etc.), treatment by physicians (chiropraxis, massage, TENS, etc.), injection with local anesthetics and autosuggestion. Necessary for diagnosis and treatment of chronical pain is the knowledge of pathophysiology and anatomy of nerves, ligaments, muscles and the sympathetic nervous system. Diagnosis of chronical pain rarely includes roentgenograms or other technical procedures, mainly to exclude tumors, fractures or specific infections. The knowledge of pathophysiology means the knowledge of sympathetic and motoric efferences on one side and the functional examination of the anatomic structures on the other side. PMID- 8686337 TI - [Sleep disorders in neurologic diseases]. AB - Sleep disorders in central or peripheral nervous system diseases frequently occur, but they often are neglected in diagnosis and therapy. During the last 20 years, sleep medicine has obtained more and more importance. It is possible to draw conclusions about the topical organization of sleep-wake-regulation by investigating of certain diseases. In the following survey the most important clinical pictures in neurology are described in consideration of an affected sleep. Typical symptoms and polysomnographic findings as well as recommendations for therapy are demonstrated. PMID- 8686338 TI - [Diabetic cardiovascular neuropathy]. AB - Impairment of the autonomic nervous system is frequently detectable in diabetic patients. Symptoms and signs are less often observed but if present may be very important with regard to quality of life, metabolic control, and prognosis. Currently used methods to detect disturbances of the autonomic innervation of the cardiovascular system are easily performed, noninvasive, reliable and reproducible. They are not very time consuming and require only standard technical equipment allowing the quick identification of patients at risk. Damage of the cardiovascular autonomic nerve function may explain apparently disparate complaints and signs, i.e. orthostatic hypotension, painless myocardial ischemia, complications during anesthesia, postprandial hypotension and development of the diabetic food syndrome. The diagnosis of asymptomatic cardiovascular neuropathy should always induce attempts to intensify diabetes treatment because better metabolic control may improve or at least stop deterioration of nerve function. PMID- 8686339 TI - [Prevention, standards and future developments in medical specialty fields- developments, deficits and outdated methods in medical specialties]. PMID- 8686340 TI - [The role of general practice within the public health care system]. AB - A comparison of general medicine in a de jure (Germany) and de facto (Netherlands, Great Britain) existing structured primary care model describes the present state as well as the pro and contra of the strengthening of the general practitioner (GP) within the primary health care system. For the patient, the better continuity and comprehensiveness of care has to be emphasized. For the patients, who choose to inscribe on a list of a GP, a reduction of health insurance fees is proposed for the German out-patient care system. Another option would be to reimburse a specialist's service with 80% when he has been consulted directly but with 100% after referral from a GP. The patient care must be strengthened by a modification of the fee system and the task description of a GP has to be defined and delineated from specialist medicine. PMID- 8686341 TI - [Quality assurance in acupuncture therapy]. AB - Quality assurance for acupuncture therapy requires a good basic and on-going training in both conventional western medicine as well as in the theory and practice of acupuncture, the ability to synthesize the patient's objective findings and subjective feelings, and honesty with the patient and towards oneself. Thus, based on the continuous critical evaluation of the objective and subjective parameters, the question of acupunture as the optimal form of therapy for this specific case is honestly answered and one has the courage to admit failures. With regard to the theory, surveys of the acupuncture literature show that a considerable improvement in quality and honesty is necessary. There is a lack of standardised experimental methods (e.g. 28 different placebos in 28 different studies!). Especially German acupuncture journals have a disturbed relation to failures. To hide or deny failures is of no benefit neither to acupuncture, science to the relationship between the physician and the patient since the practitioner must be able to rely on the information in the literature. Furthermore, one should be open minded to alternative methods even if this means to refer a patient to a colleague. PMID- 8686342 TI - [Occupational medicine in public health service--evaluation results of an continuing education symposium]. AB - The demand for a quality controlled and quality proved continuing medical education (CME) has grown in the past. Especially the German "Bundesarztekammer" (society of physicians of Germany) has developed new models for CME and it's evaluation. This paper presents the background, methodology and results of two evaluations of CME for occupational physicians in health care institutions. The two symposia in 1994 and 1995 were evaluated using the same questionnaire. The comparative analysis of the results indicates the feasibility of the instrument and the validity of the results when used together with the results on an open discussion at the end of the symposium. It also demonstrates the value of the evaluation for future planning of comparable programs. PMID- 8686343 TI - [History of "special therapeutic directions": the example of homeopathy]. AB - As for generally accepted therapeutic methods, the "special methods" may appear to be effective due to spontaneous recovery provided by nature. A great number of sceptical physicians are aware of this fact. The pharmacologist works continuously to differentiate effects directly caused by medical treatments - mainly drugs - from effects resulting from spontaneous recovery. This is one of the most difficult problems in medical treatment. As a representative example of all "special methods", we concentrate here on the history of homeopathy. As is generally known, there is no conformity in homeopathy, for example monotherapy versus therapy with complex homeopathic products; refusing the simile-rule; treatment with high potencies versus treatment with low potencies; classic versus scholastic homeopathy. The number of homeopathies really equals the number of homeopathic physicians. For this reason, instruction in homeopathy on the academic level is impossible. In addition, we have to forget all natural laws only to prove that "potentiation" may be true. Therapeutic success due purely to chance may be explained rationally and is occasionally seen in all other "special methods". The theories of homeopaths for the action with homeopathic products are neither in accordance with our natural laws nor comply with a rational philosophy. PMID- 8686344 TI - [Homeopathy from the viewpoint of the clinical pharmacologist]. AB - The homeopathy is a therapeutic line developed about 170 years ago which is based on the sciences of the late 18th century. The homeopathy is founded (1) on the vitalism of Aristoteles, (2) on the examination of remedy reactions in healthy subjects as basis of the therapy of patients, (3) on the "simile" rule, that means the treatment of symptoms with remedies which produce similar symptoms of a mild intoxication in healthy subjects, (4) on the principle of potentiation with the opinion that low doses provoke stronger therapeutic effects, (5) on the individual finding of a remedy due to an extensive anamnesis and (6) on the principle of nosodes, that means the use of diluted body secretion due to infectious diseases for therapy. The therapeutic principles of homeopathy are based on insecure hypotheses and on the patient's information of improved behaviour. Thus, homeopathy does not agree with the present natural science. PMID- 8686345 TI - [Screening for hereditary neuroendocrine tumors of the gastrointestinal pancreatic system]. PMID- 8686346 TI - [Comment on the Stolte/Domschke letter-discussion]. PMID- 8686347 TI - [Risk of liver biopsy]. PMID- 8686348 TI - Local cellular immune response in Helicobacter pylori associated type B gastritis -selective increase of CD4+ but not gamma delta T-cells in the immune response to H. pylori antigens. AB - During recent years the infectious etiology of the majority of cases of chronic active type B gastritis and peptic ulcers has become increasingly evident. The chronicity of clinical symptoms and histopathological features such as numerous mucosal lymphocytic aggregates have implied a role of the specific cellular immune system. Whereas in Type A chronic active gastritis a pathogenetic role of lymphocytes and their target structures have been amply documented, in chronic active type B gastritis particularly that associated with Helicobacter pylori infection the nature of a specific immune response and its role in the pathogenesis of the epithelial and mucosal lesion has remained obscure. Here we report that CD4+ mucosal lymphocytes appear to selectively accumulate in Helicobacter pylori associated chronically active antral gastritis. Moreover, lamina propria gamma delta T lymphocytes were found to be more frequent in chronic active type B gastritis irrespective of the presence of absence of Helicobacter pylori. PMID- 8686349 TI - Systemic uptake of 5-aminosalicylic acid from olsalazine and eudragit L coated mesalazine in patients with ulcerative colitis in remission. AB - Aminosalicylates are used to maintain remission in patients with ulcerative colitis. Since there are potential systemic side effects of 5-aminosalicylic acid (5-ASA) and long term treatment is necessary for maintenance therapy preparations with low rates of absorption in the small intestine would be optimal for this indication. In this trial olsalazine (Dipentum), a 5-ASA dimer, and an eudragit L coated mesalazine preparation (Salofalk) were compared. PATIENTS AND METHODS: Fifteen patients with ulcerative colitis in clinical and endoscopical remission were randomized in a cross over design. They either received a 2 x 2 capsules of olsalazine 250 mg or 3 x 2 tablets mesalazine 250 mg, these being the doses recommended for maintenance therapy. After a five days equilibration period morning pre-dose serum samples and 24 hour urine were collected on two consecutive days and analyzed for 5-ASA and acetylated 5-ASA. Subsequently, patients were crossed over to receive the alternative preparation and were evaluated after five days correspondingly. RESULTS: Uptake of 5-ASA from mesalazine was significantly higher than from olsalazine (p < 0.0001). Plasma concentrations of 5-ASA were 3.4 times and of acetyl-5-ASA 3.2 times higher after mesalazine administration than after olsalazine. The same applies to the 24 hour 5-ASA and acetyl-5-ASA urinary excretion (median: 3.2 versus 1.0 mmol/24 hr) as well as to the percentage of administered dose (32.4 versus 17.7%). All patients finished the trial and no major systemic side effects occured with either preparation. CONCLUSION: Systemic uptake of 5-ASA from olsalazine was significantly lower than from eudragit L coated mesalazine. Therefore, olsalazine is less likely to produce side effects and seems to be especially suited for maintenance therapy in ulcerative colitis. PMID- 8686350 TI - Long-term follow-up of patients with chronic hepatitis B after interferon treatment. AB - We investigated the long-term effect of interferon-alpha treatment in patients with chronic hepatitis B with regard to the response status during treatment. 97 patients with chronic hepatitis B, including 18 patients with active cirrhosis Child A, were followed for 12-110 months (mean: 40.5 months) after interferon alpha treatment. At the end of treatment complete response with loss of HBeAg and HBV-DNA was observed in 32 patients, partial response with loss of HBV-DNA in 30 patients and non-response with persistence of HBeAg and HBV-DNA in 35 patients. Overall, delayed virological improvement was observed in 43% of the 97 patients during follow-up. Delayed clearance of HBsAg occurred more frequently in complete responders (25%) than in partial responders (13%, P = n. s.) and non-responders (3% p = 0.0217). 39% of the partial and non-responders lost HBeAg during the follow-up period. HBsAg and HBeAg clearance rates were increased in female patients compared to males (HBsAg: 21% vs. 12%, p = n. s.; HBeAg: 47% vs. 32%, p = 0.0045). Reactivation of the disease was seen in 28% of the complete responders. In the 18 patients with active cirrhosis, short- and long-term response rates were impaired. Only, 4/18 patients had a complete response during treatment and two of these patients suffered reactivation during follow-up. One patient underwent liver transplantation and five patients died due to complications of cirrhosis. Thus, in patients without apparent cirrhosis interferon-alpha treatment has a considerable long-term effect with regard to the enhanced rate of HBsAg and HBeAg clearance during prolonged follow-up. PMID- 8686351 TI - Giardiasis in travellers: evaluation of an antigen-capture ELISA for the detection of Giardia lamblia-antigen in stool. AB - Diagnosis of giardiasis relies largely on the microscopical detection of trophozoites or cysts in feces. However, this method is labour- and time intensive and depends highly on the skill of an experienced microscopist. In order to identify the prevalence of Giardia lamblia in travellers returning from overseas, we evaluated sensitivity and specificity of a commercially available ELISA kit for the detection of Giardia-lamblia-antigen in stool. Nine hundred seventy-eight stool samples from 795 patients were examined by microscopy (iron hematoxyilin-stain, SAF-concentration) and ELISA. Altogether, Giardia infection could be detected in 74 subjects. On evaluation of all samples, the ELISA turned out to be more sensitive than microscopy (95.5% vs. 81.8%) and 99.7% specific for Giardia lamblia. Especially with microscopy, the examination of more than one stool specimen did improve diagnostic sensitivity. It seems therefore advisable to retain the practise of examining at least three stool samples before considering a patient as not infected. The coproantigen-ELISA is especially advantageous in situations where only a single stool sample can be examined. It should not, however, replace microscopical examination of stool specimens for ova and parasites since other potential pathogens would otherwise escape detection. PMID- 8686352 TI - Endoscopic band ligation for treatment of post-polypectomy bleeding. AB - Endoscopic band ligation is a newly developed technique that has been proved to be an effective treatment of bleeding esophageal varices. Meanwhile, this technique also has been shown to be a successful method of controlling non variceal upper gastrointestinal hemorrhage. Moreover, there are scattered reports about endoscopic band ligation for treatment of post-polypectomy hemorrhage. In this report, we describe the successful application of colonoscopic band ligation to control severe post-polypectomy colonic bleeding not responding to standard techniques. PMID- 8686353 TI - Diarrhea, massive ascites, and portal hypertension: rare case of a splenic arterio-venous fistula. AB - Portal hypertension is a result of chronic liver disease in the majority of cases. Rare, potentially curable causes of portal hypertension include vascular conditions such as hepatic or portal venous thrombosis and arterio-portal fistulas. We present the rare case of a spontaneous splenic arterio-venous fistula in a 40 year old multiparous woman. The young woman presented with massive diarrhea, ascites, abdominal pain, and an abdominal machinery type bruit and represents the second ever reported case with diarrhea as presenting symptom of splenic arterio-venous fistula. The diagnosis was confirmed by color Doppler ultrasound. Transfemoral aortography was performed to assess the possibility of catheter embolization. Surgical intervention was initially complicated by collateral arterial tributaries of the fistula and finally resulted in a dramatic recovery with persistent resolution of all symptoms. This case report demonstrates a curable form of portal hypertension that must be considered in acute onset portal hypertension in multiparous women and in the absence of liver disease. A machinery type bruit in the upper left abdominal quadrant represents an important and simple diagnostic symptom found by auscultation. Color Doppler ultrasound represents a non invasive, universally applicable and fast method of establishing the diagnosis. The literature and management of splenic arterio venous fistulas are reviewed. PMID- 8686354 TI - [Recent psychosomatic contributions to the pathogenesis and therapy of irritable colon (irritable bowel syndrome)]. AB - Epidemiological studies indicate that irritable bowel syndrome represents the most frequent somatoforme disorder. Current pathogenetic concepts as well as newer results in pathophysiology, neurobiology and psychoendocrinology are described. As an example of the "brain-gut-link", the role of cholecystokinin (CCK) is discussed. The positive results of psychotherapeutic intervention studies are described in more detail. An intensified cooperation between the gastroenterologist and the psychotherapist is recommended. PMID- 8686355 TI - [Quality control in gastroenterology: caution is advised!]. PMID- 8686356 TI - [Role of zinc in treatment of acute diarrhea]. PMID- 8686357 TI - [Are proton pump inhibitors superior to H2 receptor antagonists within the scope of H. pylori eradication therapy? Meta analysis of current parallel group comparisons]. AB - The combined treatment with acid lowering drugs and antibiotics is widely accepted for H. pylori-eradication therapy. There are, however, controversies regarding the influence of the acid lowering drug on H. pylori-eradication rates. Therefore, this meta-analysis aimed to assess the available parallel-group eradication studies with proton pump inhibitors and H2-receptor antagonists and to compare H. pylori-eradication rates for both classes of acid lowering drugs. METHODS. We performed a broad based medline search to retrieve all published treatment trails for H. pylori-infection. In addition, a manual search of the abstracts of major national and international meetings was conducted. In total seven publications of eight comparisons with a parallel group design comparing H2 receptor antagonists and proton pump inhibitors plus antibiotics with a total of 538 patients were identified. Non parametric tests were utilized to assess the influence of the acid lowering drug on eradication rates. Furthermore, logistic regression adjusting for duration of antibiotic treatment and the number of antibiotics was used to compare the different acid lowering drugs. RESULTS. All studies utilized omeprazole as the proton pump inhibitor with doses ranging from 20 mg/die to 2 x 20 mg/die. Ranitidine (with doses ranging from 2 x 150 mg/die to 2 x 300 mg/die) was used in six trials and nizatidine (2 x 300 mg/die) in one trial. H. pylori was successfully eradicated in 78.6% (95% 73.6-83.5) with the proton pump inhibitor and in 76.5% (95% Cl 71.4-81.5) in patients treated with the H2-receptor antagonists. Utilizing two antibiotics instead of one antibiotic significantly increased eradication rates by 16.1% (95% Cl 9.3-22.8, p < 0.001). However, neither in protocols with one nor in protocols with two antibiotics the eradication rates significantly differed for regimens using H2-receptor antagonists or proton pump inhibitors. CONCLUSION. H. pylori-eradication rates for treatment protocols with one or two antibiotics in combination with an acid lowering drug are not different for the proton pump inhibitors or h2-receptor antagonists. Therefore, the question whether H2-receptor antagonists or proton pump inhibitors should be used in combination with antibiotics for H. pylori eradication therapy is without clinical relevance. PMID- 8686358 TI - Functional diagnostic work-up in patients with irritable bowel syndrome. AB - The first aim of the study was to find a cause of symptoms in patients suffering from "irritable bowel syndrome" using diagnostic tests aimed at functional disorders of lower gut. A second aim was to test, whether the presence of irritable bowel syndrome (or, synonymously, absence of classic organic disease) can be predicted by specific symptoms. 134 consecutive patients (50 +/- 16 SD years, range 17 to 88, 94 women) presenting in our gastroenterological outpatient department with abdominal pain and altered bowel habits were included. A conventional diagnostic work-up aimed at classic organic diseases and, if negative, a functional diagnostic work-up aimed at gastrointestinal malfunction such as dietary fibre trial, functional proctoscopy, defecography, colonic transit of radiopaque markers, anorectal manometry, and lactose tolerance test were done. A classic organic disease was found in only 15 of 134 patients by conventional diagnostic tests. Functional diagnostic work-up yielded a diagnosis in 70 of the remaining 119 patients that else would have been labeled to suffer from IBS (25 slow transit constipation, 20 disordered defecation, nine low fibre intake, and nine lactose intolerance among them). When symptoms were evaluated with a standardized questionnaire, "constipation" and the "necessity of straining to open bowels" were very specific for functional bowel disorder (92% and 100%), but sensitivity of both symptoms was only about 60%. The so-called "Manning criteria" had a very low prevalence in our sample and so were not discriminatory. Since in more than half of the patients with "irritable bowel syndrome" a specific diagnosis can be reached, functional tests should be considered in such patients. The symptom "constipation" in patients with lower gut complaints predicted a functional disorder rather than a classic organic disease with a high specificity. PMID- 8686360 TI - Intrahepatic high-grade malignant non-Hodgkin lymphoma in a patient with chronic hepatitis C infection. AB - A 61-year-old white female with chronic hepatitis C virus (HCV) infection first diagnosed in 1994 was admitted with two newly discovered lesions in the liver suspected to represent hepatocellular carcinoma. The alpha-1-fetoprotein (AFP) level was within normal limits and there was neither clinical nor sonographic evidence of liver cirrhosis. Fine needle aspiration, however, showed an high grade malignant centroblastic non-Hodgkin lymphoma (NHL). Staging failed to confirm extrahepatic involvement. Both a cryoglobulinemia and HIV infection were ruled out. Although the coincidence of HCV infection and NHL is not well recognized, recent studies have indicated an increased incidence of NHL and hepatitis C in up to 38% of patients with cryoglobulinemia. In these patients, the diagnosis is always one of a low-grade lymphoma. Based on its lymphoproliferative characteristics, an etiologic role for HCV in the development of NHL has been discussed, though the exact pathogenesis remains unclear. PMID- 8686359 TI - [A rare cause of recurrent upper gastrointestinal hemorrhage: aortoesophageal fistula in aneurysma spurium of the descending aorta]. AB - An aneurysma of the distal thoracic aorta developed in an 65 year old man. Several weeks later, the man was admitted to hospital because of upper gastrointestinal bleeding. The diagnosis of an aortoesophageal fistula was made not until several endoscopic investigations. The patient died from a major bleeding soon after. The aneurysm proved to be an aneurysma spurium. PMID- 8686361 TI - [Inflammatory esophageal diseases caused by herpes simplex virus infections- overview and report of 15 personal cases]. AB - Frequency of herpes simplex virus(HSV)-induced esophagitis was reported to range from 0.5% to 6% in non-selected patients according to autopsy and clinical studies. In case of gastrointestinal involvement, affinity of herpes simplex virus to squamous epithelia predisposes the esophagus to be affected. Typically, patients complain about acute onset of odynophagia, retrosternal pain, or symptoms of gastrointestinal blood loss, while systemic signs of inflammation are often absent. Endoscopic examination usually reveals disseminated, roundish mucosal defects with distinct borders preferably in the distal part of the esophagus. If suspected clinically and by endoscopy, a histological and/or cytological diagnosis should be achieved by carefully taking multiple biopsies from the edge of the suspicious lesions. Antiviral therapy is not obligatory, since HSV esophagitis often resolves spontaneously. In the presence of preexisting immunodeficiency, marked clinical symptoms, or complicated course, however, the guanosine analogue aciclovir is the treatment of choice. In view of a comparably low sensitivity of macroscopic assessment and an expected increase in incidence of this viral infection, a high index of suspicion for this disorder appears to be necessary for all clinicians working in the field of endoscopy. Based on 15 personal observations recorded from 1983 to 1995, epidemiological, pathogenetic, morphological, and clinical features of HSV esophagitis will be summarized and discussed in the light of the pending literature on this subject. PMID- 8686362 TI - [Expression of the MRP gene coded conjugate transporter in human liver and its selective defect in canalicular membrane transport deficient rat hepatocytes]. PMID- 8686363 TI - [Somatostatin receptors: a new pathway into the tumor?]. PMID- 8686364 TI - [Causal "cancer personality" attribution--an expression of maladaptive coping with illness?]. AB - In psycho-oncology, the concept of a "cancer-prone personality" has gained some attention. This notion means that persons who try to stay pseudo-normal in spite of severe life stress, suppress negative emotions, particularly anger, and sacrifice themselves for other people without uttering any personal demands, are at a high risk to develop cancer. However, it has been demonstrated by previous research that features of the cancer-prone personality could only be found if the ill person was convinced to suffer from cancer, irrespective of what the factual diagnosis was. Thus it can be concluded that at least some aspects of the so called cancer personality might be the results of coping with the belief of having cancer. The present study had the objective to describe causal attributions to psychosocial factors in cancer patients, and to find out if these were connected with emotional state and coping. N = 120 newly diagnosed lung cancer patients were included in the study. The instruments consisted of a semi structured interview, a check-list of subjective causal factors, self-reports and interviewer ratings on emotional state and standardised questionnaires about depression and coping. Patients who made a psychosocial causal attribution proved to suffer from greater emotional distress, to be more depressed and less hopeful than other patients. This difference seemed to be mediated by a depressive way of coping with the illness (brooding, wrangling). Thus, an attribution of the illness to psychological factors seems indicative of a maladaptive way of coping with illness. This result is supported by similar findings of previous research. The question is put up to discussion if the psychosomatic concept of a cancer personality may reflect patients' subjective theories which in turn may be the expression of their depressive coping modes. PMID- 8686365 TI - [Measuring scales for assessment of coping behavior: a critical evaluation]. AB - In the present report, assessment problems in the area of coping research are discussed. On the basis of some objective criterion, assessment procedures with theoretical background, development and areas of uses, are chosen to make clear the current status of the instrument for evaluating illness coping strategies. A comprehensive review allows an evaluation of the presented assessment instruments. The development, psychometric properties, testing, advantages and disadvantages of the procedures are briefly discussed to enable the selection of appropriate assessment procedures to answer specific questions and for specific target groups. PMID- 8686366 TI - [The Brodsky & Brodsky risk factor model of schizophrenia--an empirical contribution]. AB - In the year 1981 the Canadian psychologists Patricia & Marvin Brodsky published an article about a model integrating risk variables involved in the development of Schizophrenia which is very important but not very well known in the German speaking countries. This model which describes essentially the interaction of four risk variables, such as mental health of the mother, neonatal status, temperament and mothering style, shall be published for the interested reader on the one hand. On the other hand the consequences of the risk variable "mothering style" should be empirically examined in a retrospective study. With a standardized interview containing all essential variables of Brodsky's risk model 73 patients suffering in schizophrenia and being inpatient in the Rheinische Landesklinik Bonn were examined and the interview data were evaluated with regard to the contents in contrast to a control group of 26 healthy persons. With regard to the "schizophrenia spectrum" the portion of so called "superphrenics" (defined as "artistically and muscially gifted offspring with a schziophrenic mother" was not significantly increased in the schizophrenic sample (17.8% vs 7.7%) but the comparison of mothering style (empathic contingent vs. non-empathic and non contingent) revealed a statistically significant difference between the groups. Finally the data of the risk variable "mothering style" are discussed in the light of the Brodsky-model and it is pointed at the special problems in reliable and valid opertionalisation and assessment of the risk variables. PMID- 8686367 TI - [Coping strategies of children and adolescents with diabetes mellitus: the German language version of KIDCOPE]. AB - Coping with disease-related and everyday problems in chronically ill children and adolescents have not yet been studied with a standardized instrument in German speaking countries. Thus we have translated the KIDCOPE (Spirito et al. 1988) into German and conducted a cross-sectional study on coping behaviours of children and adolescents with diabetes mellitus. 43 children and adolescents aged 8 to 18 years have been tested; metabolic control has been identified by HbA1c values. The internal consistency of the KIDCOPE (German Version) is sufficient. Children most frequently use wishful thinking, social support and problem solving. Adolescents rely on resignation (especially with disease-related stressors), but also wishful thinking, social support, problem-solving and cognitive restructuring. Self-criticism and blaming others were used only rarely by both age-groups. Children and adolescents rate social support as the most efficient coping strategy. Whereas almost no gender differences occurred, significant situational differences could be found, which confirm the person situation-transactions-model of Lazarus. The quality of metabolic control showed no effect on frequencies of coping strategies. The KIDCOPE is a brief self-report test for school aged children and adolescents. It can be easily applied in clinical settings to assess coping with disease-related and everyday problems. PMID- 8686368 TI - [Goal attaining scale. Reliability and practical experiences in 397 psychiatric treatment courses. 2: Practical experiences with a simplified version of Goal Attainment Scaling in clinical practice and intermediate length rehabilitational treatment]. AB - Goal attainment scaling (GAS) measures outcome dependent on the degree, to which patients attain, what was thought to be their potential. Can this method be simplified by giving up to detail in advance, what would be "much more" and "much less" than the expected outcome? In 339 psychiatric treatment courses of inpatients, GAS was compared with a traditional clining rating. The patients did least agree to goals, their therapists wrote down concerning "social contacts" and "coping". The simplified form of GAS turned out to be more vulnerable to wrong prognoses. The influence of the vocational experience of those, who constructed the scales was tested as well. Despite methodological shortcomings GAS has evident therapeutic qualities: how else can we evaluate, how much of their potential our patients realize? PMID- 8686369 TI - ["I am but mad north-north-west"--Hamlet's portrayed delusion]. AB - Whereas science refers to the real world existing independently and conditioned by cause and effect, the world of literature is fictitious, created by the artist in our imagination by means of language, an artefact conditioned by aesthetic laws, a world sui generis. Accordingly, Hamlet is no person, but a literary figure, doing, saying, thinking and feeling only what the poet dictated him word for word. The essential difference between the two worlds is often overlooked. That "blind spot" has a long-standing tradition in European intellectual history and goes back i.a. to the German "Hamlet experience" in the eighteenth, the "Hamlet fever" and the felt spiritual kinship (Seelenverwandtschaft) in the nineteenth century. Teleological literary criticism, centering around Hamlet's "character" and isolating his psychologically evaluated monologues (e.g. Bradley), refrained from Hamlet's fictionality and role-play and led to blurring beyond recognition the boundaries between real person and literary figure (e.g. Freud, Jones) and assisted in reducing a dramatic role to a medical case history. Speaking of Hamlet, one has to start from Shakespeare's text, our subject matter. A dramatic play being a plot turned into dialogue, the poet's vocabulary used (but indirectly also the vocabulary not used) is particularly informative. When referring to Hamlet's "antic disposition", Shakespeare uses a wide range of over 20 different terms, the most frequented being mad/madness (44 times). Evidence of primary importance are the five occasions after the apparition of his father's ghost, when Hamlet speaks of hist "madness" as an assumed role. In Act I "madness occurs first as a mere possibility when Hamlet informs his friends, he might "put an antic disposition on"; in Act II vis-a-vis Rosencrantz and Guildenstern ("I am but mad north-north-west") it is his deliberate action under certain conditions; in Act III it occurs thrice, first in his declaration of intent ("They are coming to the play, I must be idle" (i.e. "mad"), next in answering the king ("I fare of the chamaeleon's dish"), and once again in a particularly explicit distinction for his mother ("I am essentially not in madness, but mad in craft"). The evidence of all other instances of mad/madness represented here corroborates these findings: madness as an adopted role and not as a character trait. - It should also be noted that Shakespeare's main source (Belleforests adaptation of the Amleth-story from Saxo Grammaticus) already knew of the motive of stimulated madness as a cover for revenge. Hamlet assumes the role of a "madman" in order to have full scope for action, first, to test by help of the "play in the play" the truth of his father's apparition as a ghost demanding revenge as well as the actual guilt of Claudius and, when that is established, for preparing and executing his revenge. By acting himself, Hamlet becomes guilty and (Shakespeare having chosen the dramatic genre of tragedy) pays for his success with his life. Considering the constant border-crossings between the spheres of real persons and fictive literary figures in psychological approaches to Hamlet, we stressed the essential difference of a literary work of art from real life. At the same time, the inherent limitations of that difference must be shown as well. Although the world of belles lettres is fictive and non-existent in reality, it does not play in a vacuum. It is fed, in many ways, by the poet's experience of his own days as well as by the work's position within the realm of literary tradition (genre, sources, etc.). It is perhaps easy, to insist on the self-contained nature of literature, making literary criticism an arcane activity of a few elected professionals. The price to pay would be, as Laurence Lerner points out, that great literature will no longer tell us anything about life, and the poet's subtle insights, his wisdom, his understanding of the soul and of the world cease to enrich the general read PMID- 8686370 TI - [Louis Pasteur (1822-1895). A century later]. AB - An overview of the amazing series of successive and diverse items worked on by the chemist and physicist Pasteur starts with the asymmetry of paratartrates, switches over to the fermentations and ends in the fight against diseases of invertebrates and vertebrates, including man. It is the wonderful story of an exceptional contribution to the advancement of knowledge, which was made possible by his keen observation skill, his rigorous and innovative methods and his careful judgement. A retrospective analysis of the inner man may impair somewhat the fame of Pasteur. He was a lonely man, in need of solitude to be able to make full use of his thinking capacity, foreboding secretiveness and shrewdness , which are contradictory to his careful writing down day after day of all the details of his thinking and research in his notebooks by now available to the scientific community. He was furthermore selfish, domineering, inflexible, impulsive and inclined to engage in endless controversies. But on the contrary his motivation to accept new assignments was subordinate to their public welfare value and as a rule he endeavoured to work on the problems in the field and in association with those concerned. He was courageous when struck by a cerebral hemorrhage at middle age, so that its aftermath hardly hampered his research activities. The dimness cast on his personality is not up to his pioneer role within a general conservative climate among the medical and even scientific profession, antagonistic to innovation. Pasteur has been a founder of stereochemistry, microbiology and its applications, immunology, bacterial vaccines, pasteurisation and a promotor of prevention and hygiene. These overwhelming achievements justify to keep alive the recognition of the outstanding stature of Pasteur. PMID- 8686371 TI - Low-level lead exposure, renal function and blood pressure. AB - The possible influence of low-level lead exposure on public health remains a matter of concern. The purpose of this article was to review the evidence that renal function and blood pressure may be affected at exposure levels encountered in the Belgian population. Moreover a meta-analysis explored whether the available studies in man would support a positive association between low-level lead exposure and hypertension. Renal function and lead exposures were studied in Belgium in a random population sample of 965 men and 1016 women (age range: 20 to 88 years). The mean (+/- standard deviation) creatinine clearance was 99 +/- 30 ml/min in men and 80 +/- 25 ml/min in women. In men the geometric mean blood lead concentration was 0.55 mumol/l with range from 0.11 to 3.5 mumol/l and in women 0.36 mumol/l with range from 0.08 to 2.9 mumol/l; the zinc protoporphyrin values in blood averaged 1.0 and 1.1 microgram/g haemoglobin, respectively. The creatinine clearance was negatively correlated with blood lead as well as zinc protoporphyrin values in men and women both before and after adjustments for age, body mass index and diuretic treatment. A tenfold rise in blood lead concentration was associated with a 10 to 13 ml/min reduction in the creatinine clearance. Serum beta 2-micro-globulin and zinc protopohyrin in both sexes, and serum creatinine and zinc protopohyrin in men were also significantly and positively correlated. Blood pressure was also measured in the Belgian population study. The sample, from which patients on antihypertensive treatment had been excluded, included 827 men and 821 women. Systolic/diastolic pressure averaged 131/77 mm Hg in men, and 124/74 mm Hg in women. After adjustment for significant covariates (age, body mass index, pulse rate, serum creatinine and serum calcium, and in women also contraceptive pill intake and menopause), systolic pressure was negatively correlated with blood lead in man (P < 0.05); the partial correlations with blood lead were not significant for systolic pressure in women, nor for diastolic pressure in both sexes. After excluding men exposed at work, the partial correlations between systolic and diastolic pressure and blood lead were negative (P < 0.05). In neither men nor women, there was a significant relation between blood pressure and the zinc protoporphyrin level in blood. A meta analysis of 23 human studies included 33141 subjects, recruited from the general population in 13 surveys and from occupational groups in 10 studies. In all but 4 studies the results had been adjusted for age, and most studies also considered additional confounders. The association between blood pressure and blood lead was similar in the 2 sexes. In all 23 studies combined, a twofold increase in the blood lead concentration was associated with a 1.0 mm Hg rise in the systolic pressure (95% confidence interval [CI]: 0.4 to 1.6 mm Hg; P = 0.002) and with a 0.6 mm Hg increase in the diastolic pressure (CI: 0.2 to 1.0 mm Hg; P = 0.02). In conclusion, lead exposure may impair renal function in the population at large. However, the alternative hypothesis that renal impairment may lead to an increase in the blood lead concentration cannot yet be excluded with absolute certainty. On balance, the available evidence suggests that there can only be a weak positive association between blood pressure and lead exposure. The latter relationship, which is barely visible at the horizon of epidemiological observation, may not be causal in nature, and is likely to entail any public health implication in terms of hypertension-related complications. PMID- 8686372 TI - Novel concepts in the treatment of human immunodeficiency virus type 1 (HIV-1) infections by HIV-1-specific reverse transcriptase inhibitors. AB - Reverse transcriptase (RT) is an appropriate target for anti-HIV chemotherapy. In recent years several entirely new leads for the design of different structural classes of HIV-1-specific RT inhibitors were provided (also called non-nucleoside RT inhibitors or NNRTI). We performed profound studies on (i) the structure antiviral activity relationship of TSAO (a prototype NNRTI compound), (ii) the biochemical and molecular mechanism of anti-viral action of TSAO and other NNRTI's, (iii) metabolism and antimetabolic effects of TSAO's in cell culture, and (iv) the pharmacokinetic properties of TSAO in mice. In addition, the molecular basis of resistance development of HIV-1 RT against other NNRTI's have also been profoundly studied. A mapping of the resistance mutations in the binding pocket of the RT and the sensitivity/resistance spectrum of the most important NNRTI's that are subject of clinical trials have been determined. Based on the information that became evident from these studies, a molecular model of interaction of the NNRTI inhibitor TSAO with the binding pocket in the HIV-1 reverse transcriptase has been proposed, and now provide the rational basis for the development of second generation TSAO molecules that may become suppressive to mutant HIV-1 strains. Also, resistance development could be markedly delayed, modulated, attenuated, or even fully suppressed by at least two different original approaches: (i) the knock-out drug concentration principle that exploits the limited capacity of mutant HIV-1 reverse transcriptases to respond to high NNRTI drug concentrations and (ii) the rational paired drug combination therapy that exploits the mutually exclusive sensitivity/resistance properties of NNRTI drugs against the different NNRTI-specific resistance mutations in the RT. Our findings have provided us with several powerful tools to have a more efficient chemotherapeutic impact on the HIV-1 infection and to better control the emergence of viral resistance. PMID- 8686373 TI - [Structure-activity relation study of anti-herpes associations with a 2' deoxyuridine basic structure]. AB - Structure-based drug design is still a difficult achievable goal because many parameters describing non-covalent intermolecular interactions are known with insufficient accuracy. Here, we describe an example of a structural analysis of 5 substituted 2'-deoxyuridines and investigate if this analysis can be used to predict new molecules with antiviral activity. The target enzyme is the thymidine kinase of herpes simplex virus type. The physicochemical analysis of the 5 substituent demonstrate where substituents may be introduced and how the electrostatic potential isocontour maps have to look like, in order to obtain a compound with high affinity for the target enzyme. Taking into account these considerations, a new compound was synthesized which is recognized by substrate by the herpes simplex virus thymidine kinase. This demonstrates the predictability of the proposed theory. PMID- 8686374 TI - Systematic mapping of autonomously replicating sequences on chromosome V of Saccharomyces cerevisiae using a novel strategy. AB - We have developed a new procedure for easy and rapid identification of autonomously replicating sequences (ARSs) and have applied it to the analysis of chromosome V of Saccharomyces cerevisiae. The procedure makes use of the ordered lambda phage clone bank of this chromosome that we have constructed, and includes transposition of a mini-transposon and selection of transposon-containing derivatives, isolation of their DNA and circularization at their cos-ends, transformation of yeast cells with the circularized DNA, and scoring transformation frequency. The transposon used was derived from Tn5supF, contained the yeast LEU2 gene, and was placed, together with the hyperactive transposase gene, on a mini-F plasmid for stable maintenance in Escherichia coli K-12. Sixteen regions of chromosome V showing ARS activity were identified, of which 12 were newly found in this work. Thus, the procedure will be useful for systematic genomic scale analysis of ARSs in yeast and related organisms in which ordered clone banks have been established. The average distance between adjacent ARS containing regions was approximately 40 kb. Two-dimensional gel electrophoretic analysis of chromosome replication indicated that one of the newly identified ARSs was functional as an actual in situ replication origin, at least under the conditions employed. PMID- 8686375 TI - Structure and regulation of the Candida albicans ADH1 gene encoding an immunogenic alcohol dehydrogenase. AB - The Candida albicans ADH1 gene encodes an alcohol dehydrogenase which is immunogenic during infections in humans. The ADH1 gene was isolated and sequenced, and the 5'- and 3'-ends of its mRNA were mapped. The gene encodes a 350 amino acid polypeptide with strong homology (70.5-85.2% identity) to alcohol dehydrogenases from Saccharomyces cerevisiae, Kluyveromyces lactis and Schizosaccharomyces pombe. The cloned C. albicans ADH1 gene was shown to be functional through complementation of adh mutations and efficient production of active alcohol dehydrogenase in S. cerevisiae. Northern analysis of C. albicans RNA revealed that ADH1 mRNA levels were regulated in response to carbon source and during batch growth. During growth on glucose, ADH1 mRNA levels rose to maximum levels during late exponential growth phase and declined to low levels in stationary phase. The ADH1 mRNA was relatively abundant during growth on galactose, glycerol, pyruvate, lactate or succinate, and less abundant during growth on glucose or ethanol. Alcohol dehydrogenase levels did not correlate closely with ADH1 mRNA levels under the growth conditions studied, suggesting either that this locus is controlled at both transcriptional and post transcriptional levels, or that other differentially regulated ADH loci exist in C. albicans. PMID- 8686376 TI - pMPY-ZAP: a reusable polymerase chain reaction-directed gene disruption cassette for Saccharomyces cerevisiae. AB - Gene disruption is an important method for genetic analysis in Saccharomyces cerevisiae. We have designed a polymerase chain reaction-directed gene disruption cassette that allows rapid disruption of genes in S. cerevisiae without previously cloning them. In addition, this cassette allows recycling of URA3, generating gene disruptions without the permanent loss of the ura3 marker. An indefinite number of disruptions can therefore be made in the same strain. PMID- 8686377 TI - Independent regulation of full-length and 5'-truncated PAS5 mRNAs in Saccharomyces cerevisiae. AB - Peroxisome assembly in Saccharomyces cerevisiae requires the products of several genes. In this report, the PAS5 gene has been characterized. The gene is on the left arm of chromosome X and encodes a polypeptide with similarity to the mammalian peroxisome assembly factor-1 (PAF-1). Two different length transcripts are produced from the yeast PAS5 gene. The longer mRNAs encompass an open reading frame, while the shorter transcripts initiate 46-110 base pairs downstream of the first in-frame AUG. The longer transcripts are induced four-fold on medium containing fatty acids as the sole carbon source, while the shorter transcripts are induced up to ten-fold on medium containing glycerol as a carbon source. The full-length coding sequence encodes a protein with a calculated molecular weight of 30.7 kDa. A protein of 25 kDa could be translated from the shorter transcripts and would lack a very acidic domain found in the amino-terminal extension of the longer protein. The common portion of the proteins is very basic; the calculated pI of the longer polypeptide is 9.02 and that of the shorter protein is 10.06. PMID- 8686378 TI - Sequence analysis of a 10 kb DNA fragment from yeast chromosome VII reveals a novel member of the DnaJ family. AB - We report the sequence analysis of a 10 kb DNA fragment of Saccharomyces cerevisiae chromosome VII. This sequence contains four complete open reading frames (ORFs) of greater than 100 amino acids. There are also two incomplete ORFs flanking the extremes: one of these, G2868, is the 5' part of the SCS3 gene (Hosaka et al., 1994). ORFs G2853 and G2856 correspond to the genes CEG1, coding for the alfa subunit of the mRNA guanylyl transferase and a 3' gene of unknown function previously sequenced (Shibagaki et al., 1992). G2864 is identical to SOH1 also reported (Fan and Klein, 1994). PMID- 8686379 TI - Analysis of a 36.2 kb DNA sequence including the right telomere of chromosome VI from Saccharomyces cerevisiae. AB - The nucleotide sequence of a 36.2-kb distal region containing the right telomere of chromosome VI was determined. Both strands of DNA cloned into cosmid clone 9965 and plasmid clone pEL174P2 were sequenced with an average redundancy of 7.9 per base pair, by both dye primer and dye terminator cycle sequencing methods. The G+C content of the sequence was found to be 37.9%. Eighteen open reading frames (ORFs) longer than 100 amino acids were detected. Four of these ORFs (9965orfR017, 9965orfF016, 9965orfR009 and 9965orfF003) were found to encode previously identified genes (YMR31, PRE4, NIN1 and HXK1, respectively). Six ORFs (9965orfR013, 9965orfF018, 9965orfF006, 9965orfR014, 9965orfF013 and 9965orfR020) were found to be homologous to hypothetical 121.4-kDa protein in the BCK 5' region, Bacillus subtilis DnaJ protein, hypothetical Trp-Asp repeats containing protein in DBP3-MRPL27, putative mitochondrial carrier YBR291C protein, Salmonella typhimurium nicotinate-nucleotide pyrophosphorylase, and Escherichia coli cystathionine beta-lyase, respectively. The putative proteins encoded by 9965orfF018, 9965orfR014 and 9965orfR020 were found to be, respectively, a new member of the family of DnaJ-like proteins, the mitochondrial carrier protein and cystathionine lyase. PMID- 8686380 TI - The sequence of 36.8 kb from the left arm of chromosome XIV reveals 24 complete open reading frames: 18 correspond to new genes, one of which encodes a protein similar to the human myotonic dystrophy kinase. AB - We have determined the complete nucleotide sequence of a 36.8 kb segment from the left arm of chromosome XIV carried by the cosmid 14-11. The sequence encodes the 5' coding region of the PSD1 gene, the 3' coding region of an unknown gene and 24 complete open reading frames, of which 18 correspond to new genes and six (SKO1, SCL41A, YGP1, YCK2, RPC31 and MFA2) have been sequenced previously. Of the 24 new genes, five show significant similarities to sequences present in the databanks. These include elongation factors 2 and the human myotonic dystrophy kinase. PMID- 8686381 TI - Fifteen open reading frames in a 30.8 kb region of the right arm of chromosome VI from Saccharomyces cerevisiae. AB - The nucleotide sequence of cosmid clone 9765, which contains 30.8 kb of the right arm of chromosome VI, was determined. Both strands were sequenced, with an average redundancy of 8.17 per base pair by both dye primer and dye terminator cycle sequencing methods. The G+C content of the sequence was found to be 40.3%. Fifteen open reading frames (ORFs) greater than 100 amino acids and one tRNA-Tyr gene (SUP6) were detected. Seven of the ORFs were found to encode previously identified genes (HIS2, CDC14, MET10, SMC2, QCR6, PH04 and CDC26). One ORF, 9765orfF010, was found to encode a new member of the Snf2/Rad54 helicase family. Three ORFs (9765orfR002, 9765orfR011 and 9765orfR013) were found to be homologous with Schizosaccharomyces pombe polyadenylate binding protein, Escherichia coli hypothetical 38.1-kDa protein in the BCR 5' region, and transcription regulatory protein Swi3, respectively. PMID- 8686382 TI - Current awareness on yeast. PMID- 8686383 TI - [Socio-professional aspects of ankylosing spondylitis in Switzerland]. AB - In this study, using a questionnaire, data were collected about the disease, the working conditions and problems, the working ability, the unemployment and the invalidity of 1134 patients suffering from ankylosing spondylitis (Bechterew's disease). In 739 cases (65.2%) a statistical evaluation could be made. 62.2% had pain when working; the reasons were most often the long working time, the position at work, and the climatic factors at the workplace. The solutions to working problems were often applied too late or they did not correspond to the needs of the patients with ankylosing spondylitis. Generally the working ability was with 97.3% high and the invalidity with 2.7% low. PMID- 8686384 TI - [Calcifying tendinitis of the femur--diagnosis and differential diagnosis exemplified by 5 cases]. AB - Five cases of calcifying tendinitis of the femur are presented. Diagnosis were proved histologically or catamnestically. The calcifying tendinitis occurred secondary to localized regressive changes in 3 patients; in 2 cases systemic inflammatory disease had to be assumed. In patients with unclear femoral pain and radiologically visible calcifications, especially at the linea aspera, one should include a calcifying tendinitis in the differential diagnosis besides juxtacortical osteosarcoma and myositis ossificans. This entity can sometimes be a symptom of systemic disease such as psoriasis and palmoplantar pustulosis. PMID- 8686385 TI - Nodular nonsuppurative panniculitis in association with primary biliary cirrhosis and Hashimoto's thyroiditis. AB - Recurrent episodes of livid, painful, subcutaneous nodules on both lower extremities with consecutive soft tissue atrophy developed in a 57-year-old woman with previously undiagnosed primary biliary cirrhosis (PBC) and Hashimoto's thyroiditis. Histological examination of a biopsy taken from an active area of the skin showed nodular nonsuppurative panniculitis. Immunosuppressive therapy with prednisone was necessary to control disease activity. The etiology and pathogenesis of nodular nonsuppurative panniculitis is still unknown. Frequently, the disease occurs in patients with autoimmune disorders. The association with PBC and Hashimoto's disease as described herein reinforces the view that nodular nonsuppurative panniculitis may be the response of the subcutaneous adipose tissue to an unknown autoimmune stimulus. PMID- 8686386 TI - [Successful therapeutic management of risk pregnancy in primary Sjogren syndrome with plasmapheresis and dexamethasone]. AB - We describe a 28-year-old woman with primary Sjogren's syndrome who had a miscarriage in the 10th week of gestation in December 1993. In her second pregnancy plasma hyperviscosity and high antibody reactivities to 52/60 kD Ro(SS A) and La(SS-B) represented elevated risk factors for abortion and fetal congenital heart block. Therefore, we performed plasmapheresis and administered dexamethason. At the end of 37th week of gestation a healthy boy was born by caesarean operation. Interestingly, antibody levels to the anti-Ro(SS-A)/La(SS-B) complex showed an increase during both pregnancies with a decline after the abortion as well as the partus. The combined therapy led to a decrease in both the autoantibody reactivities to 52 kD Ro(SS-A) and La(SS-B) and the plasmaviscosity. Plasmapheresis and dexamethason are safe treatment modalities in identified high risk pregnancies for the birth of a child with CHB. PMID- 8686387 TI - [Plasma- and lymphapheresis in autoimmune diseases]. AB - More than 25 years ago, first experiences were made using extracorporeal therapy in systemic rheumatic diseases. Since that time, several studies have documented the effect of plasmapheresis and immunoadsorption in eliminating circulating pathogenic antibodies and immune complexes, but these therapies are still not accepted as general options. This may be due not only to resource intensity, but also to controlled studies failing to confirm any obvious benefit because of inappropriate indication criteria and patient numbers. Today, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura and cryoglobulinemia also during the course of systemic rheumatic diseases and Goodpasture syndrome are classical indications for extracorporeal therapy. In other acute situations and in severe organ manifestations they may be helpful in addition to or probably even better in synchronization with immunosuppressive therapy. The new therapeutic options given by immunoadsorbers-a continuous application in acute disease states or chronic use instead of immunosuppressive drugs-have still to be evaluated in systemic rheumatic diseases. The efficacy of leukapheresis has long been proven in rheumatoid arthritis and systemic connective tissue diseases and may be increased by new technical equipment allowing peripheral elimination by specific leukocyte filters. The efficacy of photopheresis in systemic sclerosis and other systemic rheumatic diseases cannot be estimated by the available results. In general, the limited number of patients suitable for the different extracorporeal methods necessitates multicentric cooperation to reconsider definitively the efficacy of these therapeutic options in systemic rheumatic diseases. PMID- 8686388 TI - [Prognosis of ischemic complications following early surgical treatment of cerebral aneurysms]. AB - A summarized severity index has been defined on the basis of 11 preoperative findings from clinical and neurological studies, cerebral angiography, computerized tomography of the brain, and electroencephalography in 71 patients operated on for early aneurysmal rupture. The value of the summary severity index has a closely linear negative correlation with the likelihood of favourable postoperative outcomes: with a high summarized index, a risk for postoperative ischemic events and deaths increases. The paper shows it advisable to predict postoperative ischemic complications while defining indications for early aneurysmal surgical treatment. PMID- 8686389 TI - [Characteristics of adaptive reactions of the body's immune system following operations for vascular anomalies]. AB - Analysing the body's responses in 32 patients operated on for cerebral vascular aneurysms has shown that preoperatively there is activation of the peripheral blood antiprotease system, which appears to be associated with the impaired permeability of the vascular wall and with the activation of the hemostatic system and that their liquores contain sensitizing substances which are products of hemorrhages and cerebral detritus. On the whole, the immune responses of this group of patients are common to those of other groups of neurosurgical patients: acute-phase blood reaction, synthesizing-antibody binding of antigens, sanitating and brain tissue-transient neurosensitization. The use of mildronate contributes to the activation of the humoral link of the immune system on post-operative days 5-7, increases the serum antiprotease potential, by intensifying the body's responses, levels stress immunodeficiency and prolongs the time of neurosensitization. PMID- 8686390 TI - [Surgical treatment of migrainous neuralgia]. AB - The paper gives the results of surgical management in 18 patients with migrainous neuralgia who underwent 20 surgical interventions. High-frequency transcutaneous trigeminal rhizotomy eliminated pain in 2 of 6 patients. Microsurgical radicular exploration of the trigeminal nerve (1 case) and the intermediate facial nerve (2 cases) revealed no vascular compression of nerve fibers. Vertical ultrasonic destructions of the trigeminal caudal subnucleus and the descending upper spinal segment CII tract in 12 patients. The upper border of nucleotractomy varied from the obex level of the fourth ventricle to as long as 5 mm below. Complete removal of migrainous neuralgia was achieved in 11 patients followed for 12-81 months and in 1 patient with recurrent facial pain successfully treated with repeated trigeminal nucleotractotomy. Sensory sequelae of destruction and somatotopic organization of the trigeminal caudal subnucleus are also dealt with in the paper. PMID- 8686391 TI - [Neurosonography in the diagnosis of brain pathology in severe cranio-cerebral trauma]. AB - The paper analyzes neurosonographic studies of 66 patients with severe brain injury, which were carried out through the diagnostic cutting opening in 19 patients, intraoperatively in 26 and postoperatively in 21. They provided evidence for tomographic characteristics of various types of brain injuries and their dynamics were followed up in acute and subacute brain injuries. Neurosonographic signs of ventricular hemorrhage and temporotentorial wedging are described. The paper also indicates the informative value of dynamic neurosonographic monitoring in patients with severe brain injury in order to define treatment policy. PMID- 8686392 TI - [Microsurgical anatomy of the area of the superior orbital fissure]. AB - The microsurgical anatomy of the upper rima palpebrarum region was studied in 7 specimens of the base of the skull. The basic indicators in preparing specimens of the upper rime palpebrarum region are the upper and lower tendons of the lateral rectus, the upper orbital vein, the frontal and trochlear nerves. These indicators allow one to dissect cavernous sinusal formations to the rear and orbital formations to the front. PMID- 8686393 TI - [Intracranial cysts of different etiologies--the correlations between data from ultralow-field magnetic resonance tomography and results from biochemical analysis]. AB - The paper presents the results of comprehensive examination of 7 patients with intracranial cysts of various etiology and 1 with cholesteatoma. In addition to magnetic resonance imaging with an ultralow magnetic field intensity of 0.4 T, a biochemical assessment of the content of cysts was made. The cystic contrast range on T1 and T2 tomograms was evaluated. The levels of protein, total iron, and percentage of total solids of the cystic content were measured in the biochemical study. On T2 tomographs, the intensity of a signal from cysts on T2 tomographs was significant and differed in each case to a lesser extent. On T1 tomographs, the intensity of a signal was different in each case and increased virtually linearly as the concentration of protein increased up to 10%. The presence of paramagnetic active iron ions (reduced hemoglobin) in the cysts resulted in a much greater elevation of a signal on T1 tomograms. The findings are given as plots that associate the relative intensity of a signal with the concentration of protein. The total solids in the cysts examined predominantly showed protein. PMID- 8686394 TI - [Diagnosis of spinal cord diseases using myeloscintigraphy]. AB - Ninety-eight patients with a suspected spinal volumetric process were examined and treated. In addition to the routine examinations, modified myeloscintigraphy was performed in 48 patients in order to make an accurate diagnosis and to define process sites. Filling defect was the most common myeloscintigraphic symptom. This symptom was detected in 31 patients with spinal tumors and in 10 patients with another abnormality of the vertebral canal. Myeloscintigraphy was found to be of particular value in the diagnosis of spinal tumors. The technique allows minimum-size formations to be diagnosed even when there are no evidence for subarachnoidal space block. PMID- 8686395 TI - [Characteristics of the level of lipid-bound sialic acids in the blood of patients with brain tumors]. AB - In hemispheric tumors, the highest blood levels of lipid-conjugated acid were found in patients with malignant tumors despite their histology. In the blood of patients with benign tumors of the same site, the content of lipid-conjugated acids was the same as the control ones. However, the blood of patients with chiasmal-cellar tumors did not show these features. The blood level of lipid conjugated acids in these patients did not depend on tumor histogenesis, but it was generally high. In patients with benign tumours of the chiasmal-cellar region, the levels of lipid-conjugated acids were the same as in patients with malignant hemispheric tumors. This is suggested by the fact that patients with meningiomas or gliomas of the chiasmal-cellar site without anaplastic signs exhibit much higher blood levels of lipid-conjugated acids than those with the similar tumors of the hemispheric site. PMID- 8686396 TI - [Stereotaxic resection of intracerebral tumors]. AB - Stereotactic computerized technology providing a goal-oriented and low-traumatic access to small intracerebral tumors and their precision microsurgical removal has been developed. A specialized programme implemented on an IBM PC/AT makes a whole set of stereotactic calculations based on computerized tomography (CT). With this, a three-dimensional volumetric tumor reconstruction is conducted by interpolating the tumor outlines which can be seen on consecutive stereotactic CT sections. The system provides laminar visualization of the tumor outlines in the distal aperture plane of an original tubular retractor which makes an access to the tumor and its removal and coincides these sections with the aperture projection. Thus, each discrete unit of tumor volume (minimum 1 cubic mm) proves to be stereotactically oriented against the retractor both in the plane of its aperture and along its trajectory. Examining the images prio and during surgery simulates an operational field, thus computerally supporting the resection of a tumor strictly in the range of CT-defined outlines. A total of 15 patients aged 3 to 52 years who had hemispheric tumors were treated. Five patients presented with cancer metastases (one of them had multiple ones), 7 had gliomas and 1 displayed a radiation necrotic focus at the site of the irradiated glial tumor that was verified by stereotactic biopsy, 2 cases had cavernous angiomas. The use of stereotactic techniques for tumor removal in these patients was determined by their location and small sizes. Eight cases presented with in-depth tumors located in the area of subcortical ganglions, the visual tuber, and the internal bursa. In 7 patients there were a comparatively superficial tumors afflicting the cortex and substantia alba in the projection of central gyri or temporoparietal regions in the predominant hemisphere. The maximum dimensions of tumors varied 10 to 35 mm without exceeding 25 mm in most (14) patients. A small circulatory trephination with a crown cutter, 35 mm in diameter, was employed in the majority of cases (in 13 patients). In 3 cases, there was a slight and transient aggravation of the existing focal symptomatology followed by regression and return to the preoperative values during 5-6 days. Following surgery, 10 had either improved status or no additional iatrogenic defect or they underwent outpatient treatment within 6-7 days after intervention. In 2 cases, a steady state aggravation of focal symptoms was associated with surgery. Control studies by CT and MRT provided evidence for no residual tumor tissue in all cases except one. PMID- 8686397 TI - [Current principles of surgery of the base of the skull]. PMID- 8686398 TI - [Air embolism in neurosurgical interventions]. PMID- 8686399 TI - [Diastematomyelia in a 6-month-old child]. PMID- 8686400 TI - The Royal Society for Surgery. PMID- 8686401 TI - What is audit and how to start it? AB - The verb "to audit" dates from the sixteenth century when it meant "to make an official systematic examination of accounts". If we substitute "diseases and medical interventions" for "accounts", that is what clinical audit means. It is more than merely quality assurance, although that comes into it. It embraces also a great deal of clinical research. It certainly entails the complete, accurate, and honest recording of a doctor's practice. How to start it? That depends on whether you are going to audit the work of your own unit only, or whether you are going to include the work of the whole hospital, region, or country. Whatever you do you must compare the results that you find with those that have been published. Many departments find it impossible to record the outcome of every intervention in a way that allows sensible conclusions to be drawn. To these departments the reporting of critical incidents is a most welcome substitute. Whatever way you go, remember that audit must be interesting and it must produce results that help you to improve your practice. PMID- 8686402 TI - The containment of cost of health care. AB - The cost of health care services has become increasingly important to society. Although hospital physicians are traditionally not involved in cost calculation and cost containment, they bear the consequences of budget restrictions. Since 1987, the reimbursement for clinical laboratories in Belgian hospitals has changed towards an envelope based system. Clinical biologists became aware that new resources can only be obtained mainly through cost reductions. But to contain cost, one must understand how it is generated. Activity based costing (ABC) is a new technique developed for strategic management in the industry. By analyzing the cost of all activities involved in the production process, this technique is very well suited to calculate cost in service organizations like medical departments. Using the principles of ABC, we performed a detailed analysis of the cost of a microbiology laboratory, determining the full cost as well as the proportion of each cost sorts (materials, labor, ...) for each laboratory test. This analysis illustrates that cost can effectively be calculated in a hospital department and guide doctors in the evaluation of alternative medical techniques, investments in automation, and the decision on medical priorities. In our opinion, cost containment of hospital care must start from within each medical department. Responsibility and participation of physicians in the discussion on budget allocation are essential in the process of cost containment of the hospital health care. PMID- 8686403 TI - Adjuvant treatment in gastric cancer. Possibilities to take or to leave it. AB - The primary mode of management of gastric carcinoma is surgical resection with 5 year survival rate following curative resection of about 30 to 40%. This article reviews the results of randomized clinical trials including adjuvant chemotherapy, radiation treatment and chemoimmunotherapy after curative surgical resection. Randomized trials done to date largely do not support the use of adjuvant chemotherapy in resected gastric cancer. Mitomycin C or FAM association have demonstrated the best efficiency with increase of median survival in treated patients. Mitomycin C demonstrated a significant advantage by reduction of the incidence of hematogenous metastases. Encouraging perspectives come from the association between chemotherapy and biochemical modulators. PMID- 8686404 TI - Heller-Dor procedure for achalasia: from conventional to video-endoscopic surgery. AB - A Heller-Dor procedure was performed by laparotomy (group A: n = 8) or by laparoscopy (group B: n = 12) after failure of one to 17 sessions of intraluminal dilatations (n = 13) or as a primary treatment of oesophageal achalasia (n = 7). The oesophagomyotomy was extended over the thoracic oesophagus by thoracoscopy in two patients having vigorous achalasia. Injury to the oesophageal mucosa occurred in two group A patients who had previously been dilated. At follow-up (range: 1 to 113 months), 6 patients of group A (75%) and 10 of group B(83.3%) had no residual dysphagia. The four patients (group A: n = 2; group B: n = 2) who complained of heartburn prior to the operation were asymptomatic, only one group A patient developed symptoms of reflux, and oesophageal pH-monitoring was normal in the 6 group B patients investigated at follow-up. The laparoscopic approach reduces the magnitude of the operation, and the magnified overview permits precise dissection of the intraparietal adhesions which may develop after numerous sessions of dilatation. PMID- 8686405 TI - Exfoliated tumour cells and locally recurrent colorectal cancer. AB - The presence of intraluminal viable exfoliated tumour cells has been demonstrated in patients with colorectal cancer. Several non-randomised studies found a significant reduction of the recurrence rate after the intraoperative luminal instillation of cytotoxic agents, as compared with "historical" patient series. Antiseptic solutions, e.g. sodium hypochlorite and povidone-iodine, were reported to be "cancericidal" for exfoliated cancer cells in vitro. A survey held among Belgian surgeons practising colorectal cancer surgery revealed that 78% of them never use any agent during surgery. Only a minority performs pre-resectional luminal instillation-mostly to treat the distal (low) anastomotic level: 14% in patients with rectal cancer and 7% in patients with colon cancer. About 8% of the surgeons only perform peritoneal/pelvic lavage at the end of the procedure. This is in strong contrast with surgical practice in the UK. It seems reasonable to advocate intra-operative pre-resectional bowel washouts with cytotoxic agents besides other measures to avoid recurrence, e.g. the no touch isolation technique with early division of the vascular supply, wide excision of the mesenterium, avoidance of iatrogenic tumour perforation, "en bloc" resection if adjacent organs are invaded, adjuvant radio- and chemotherapy. PMID- 8686406 TI - Carotid surgery in octogenarians: is it worthwhile? AB - Controversy surrounds the role of carotid endarterectomy in octogenarians. Although the prognosis of severe degree carotid stenosis is more ominous in the elderly, operative risk seems more important in the aged. To evaluate the presumed detrimental effect of advanced age on the mortality-morbidity of carotid endarterectomy, the authors reviewed their common experience with carotid surgery in patients aged 80 years or more. From 1980 to 1994, 129 octogenarians were operated on for occlusive carotid artery disease in two university hospitals. The data for these patients, 80 years of age and older (group 1) are compared to these for a large middle age group (less than 80 years) (group 2) operated by the same surgeons during that period. The baseline characteristics of both groups were similar, except for smoking, diabetes and previous myocardial revascularization, more prevalent in the younger age group. In the elderly group prophylactic surgery for asymptomatic stenosis was done in 36%, versus 40% of the middle aged patients, and for stroke in evolution in 8% versus 4% (p < 0.05). The perioperative stroke rate was 0.8% in the group older than 80 years, compared to 1.2% for non octogenarians (NS). The operative mortality was similar for both age groups (2.3 and 1.5 respectively). The long-term results gave a similar outlook for both age groups. The 5-year stroke-free rate reached 89% for group 1 versus 91% for group 2. The 5-year survival rate, however, was less for the elderly patients (47% versus 77%, mean follow-up periods of 30 and 49 months). These results suggest that carotid endarterectomy can be safely done in elderly patients, with a similar risk/benefit ratio as for the younger patients. Advanced age, by itself, is not to be considered as contraindication to carotid surgery. PMID- 8686407 TI - Pelvic ring injuries: a challenge for the trauma surgeon. AB - A consecutive series of 105 patients with type B or type C pelvic ring lesions, which were treated operatively between 1987 and 1991, was reviewed retrospectively. 76 patients were also reviewed clinically and radiologically after a mean time of 20,7 months. The average ISS of all patients was 32,8, the peri-operative mortality was 12,4%. Eight deaths (7,6%) were pelvic trauma related deaths. 9,3% of patients with B-type lesions had associated neurological injuries and 24,2% of patients with C-type lesions. A second operative procedure was performed in 13,9% of B-type lesions and in 42,4% of C-type lesions. 79,1% of the patients with B-type fractures had excellent or good functional results and 57,6% of the patients with C-type fractures. The actual guidelines for primary and secondary operative management of patients with unstable pelvic ring injuries are exposed. An overview of possible concomitant intrapelvic lesions with their primary treatment is also presented. PMID- 8686408 TI - Therapeutic strategy in pilon fractures type C2 and C3: soft tissue damage changes treatment protocol. AB - The medical charts of 28 patients with type C2 and C3 fractures of the pilon tibial, who were operated between 1980 and 1990, were reviewed. All patients were evaluated clinically and radiologically after a mean time of 50 months. In 17 patients (60,7%) the pilon fracture was combined with severe soft tissue damage. In half of the cases (50%), a plate osteosynthesis was carried out. In six patients (21,4%) one or more reinterventions on the soft tissues were necessary, in eight patients (28,5%) one or more reinterventions on the bone. Eighteen patients (64,2%) had an excellent or good subjective end result in accordance to Ovadia and 15 patients (53,5%) an excellent or good objective end result. The high amount of secondary procedures in patients, treated primarily with plate and screw osteosynthesis, indicates that the standard protocol has to be changed in case of complex pilon fractures and severe soft tissue damage. We can avoid soft tissue problems with a step-wise reconstruction of the pilon: primarily a bridging external fixator and secondarily an internal fixation, when the situation of the soft tissues is stable. PMID- 8686409 TI - Hemobilia: a rare complication of cholecystitis and cholecystolithiasis. Case report. AB - Hemobilia, although not uncommon, is usually inconsequential and most of the times not even diagnosed. It is known that hemobilia is a rare complication of cholecystitis and cholecystolithiasis. We report the case of a patient who presented with a life-threatening upper gastro-intestinal bleeding due to erosion of the cystic artery by cholecystolithiasis and cholecystitis. PMID- 8686410 TI - The laparoscopic approach of a torsion of a benign mature ovarian teratoma: a case report and review of the literature. AB - Benign mature teratomas account for approximately 10-15% of all ovarian neoplasms. Many patients with these dermoid cysts are asymptomatic. The most frequent complication is torsion of the teratoma (in 3,5% of the cases). In a 26 year female patient admitted for severe, acute abdominal pain, a computerized abdominal tomography in accordance with the clinical characteristics of the abdominal examination, was highly suggestive for a torsion of a teratoma. The diagnose was confirmed by a celioscopic operative approach and the teratoma with the left tubo-ovarian complex was successfully removed laparoscopically. PMID- 8686411 TI - Fat-soluble vitamins in patients with chronic pancreatitis (pancreatic insufficiency). AB - The fat-soluble vitamin contents in the blood (vitamins A, D, E, and K) were determined in 12 patients with chronic pancreatitis (exocrine pancreatic insufficiency) and in 20 healthy adults by the HPLC and CPBA methods. In addition, 9 g (3 g x 3 times) of high potency pancreatin was given to 11 patients with chronic pancreatitis (CP) for approximately 1 month and changes in the blood fat-soluble vitamin levels were evaluated before and after the treatment. The major component of vitamin E was alpha-tocopherol. The mean alpha-tocopherol level in normal individuals was 0.97 mg/dl, while it was significantly reduced in CP patients (p < 0.01). The vitamin A, D, and K levels had also been reduced in patients with CP, but the differences were not significant (although some patients in this group exhibited significant reductions from the levels of normal individuals). Only the blood vitamin E level showed a significant correlation with the fecal fat excretion or the fat absorption rate. None of the patients with CP exhibited an overt fat-soluble vitamin deficiency (i.e., the deficiency of fat-soluble vitamins was at a subclinical level). These results indicated that CP patients suffer from a latent fat-soluble vitamin deficiency and that the vitamin E level is closely related to a dysfunction of fat digestion. It was suggested that the dietary intake of each fat-soluble vitamin should be evaluated further. PMID- 8686412 TI - Intestinal permeability in Crohn's disease. AB - We summarize the anatomical and physiological basis and the ways of measuring the intestinal permeability. We review the studies of the intestinal permeability in Crohn's disease. We analyse the involvement of an abnormal intestinal permeability in the pathogenesis of Crohn's disease, as a primary or secondary defect. We discuss the potential usefulness of the measure of intestinal permeability in Crohn's disease activity assessment, relapse prediction and efficacy of treatment. PMID- 8686413 TI - Epidemiology of inflammatory bowel disease: is there a "Belgian-French exception?". PMID- 8686414 TI - Incidence of inflammatory bowel disease in the province of Liege (Belgium). La Societe de Gastroenterologie Liegeoise. AB - Up to now, as there is no national registry of patients with inflammatory bowel disease (IBD) in Belgium, the study of IBD epidemiology in our country is only possible through institutional or regional series. Therefore we conducted a prospective epidemiologic study of IBD in the Province of Liege (1 million inhabitants). METHODS: 29 (out of 47) private and public gastroenterologists completed a standard questionnaire for each patient consulting for the first time with clinical symptoms compatible with IBD between 1/06/1993 and 31/05/1994. RESULTS: During that period 104 cases of IBD were recorded: 56 (54%) Crohn's disease (CD), 36 (35%) ulcerative colitis (UC) including 7 proctitis (19% of UC) and 12 (11%) unclassified colitis. The annual incidence was 5.5 per 100.000 for CD and 3.5 for UC. The sex ratio F/M was 1.7 for CD and 0.7 for UC. The median age at the time of diagnosis was 33.5 yrs for CD and 40 yrs for UC. The highest age specific incidence rate for CD and UC was between 20 and 29 yrs : 13.6 and 6.1, respectively. CONCLUSIONS: This first Belgian prospective study has shown an incidence rate for CD comparable with that seen in north European studies but lower than that seen for UC. These results were similar to those observed in the northern part of France. Belgium appears to be a privileged country to undertake a national register and to study epidemiological aspects of IBD. PMID- 8686415 TI - Epidemiology of inflammatory bowel disease in Brussels' area (1992-1993). AB - A prospective epidemiological study on inflammatory bowel diseases (IBD) patients was performed in Brussels' area from April 1st, 1992 to 30th March, 1993. The mean annual incidence for Crohn's diseases (CD) was 4.1/10(5) inhabitants/year among native Belgian people and 6.4/10(5) inhabitants/year for subjects issued from Moroccan families. For ulcerative colitis, the incidence was 3.7/10(5) inhabitants/year for native Belgian people and only 1.2/10(5) inhabitants/year for Moroccan subjects. The male/female sex ratio was 0.4 for CD and 1.9 for UC. At the time of diagnosis, the mean age was 34 years for CD and 38 years for UC. For both diseases, the age peak was between 20 and 29 years. Cigarette smoking was significantly higher in CD (48%) than in UC patients (12%). Family history was about 10% for both diseases. PMID- 8686416 TI - [Cranial morphology of modern kyongsangnam-do Koreans]. PMID- 8686417 TI - [Histocytochemical and functional aspects on the "brain-vascular peptides"]. AB - The vasoactive peptides, endothelins (ET-1, ET-2 and ET-3: ETs), natriuretic peptide family (ANP, BNP and CNP:NPs) and angiotensins (I, II, III and IV), exist in not only cardiovascular organs but also in the central nervous system. In the central nervous system, these peptides play important roles to maintain the water balance, electrolyte metabolism and blood pressure control as neural messengers. For this reason, we proposed that these peptides are "brain-vascular peptides" after the model of the "brain-gut peptides." Recent reports showed that these peptides also have the other common character to play significant roles for cell differentiation and/or proliferation or morphogenesis in various peripheral organs as cytokine/growth factors. We have consecutively studied the endogenous digitalis-like substance (sodium transport inhibitor), NPs and ETs by histocytochemical analysis. This article reviews (1) newly developed histological procedure for analyzing the biochemical and functional basis of brain-vascular peptides, e.g., a new technique for raising polyclonal antibody to distinguish their molecular form; c-fos expression analysis; TUNEL staining; culture-in-oculo chamber; and preparation of transgenic mice; (2) the synthesis and secretion of endothelins, their distributions, target sites, signal transduction and physiological actions; (3) histocytochemical studies on ETs, NPs and angiotensins in the central nervous system as the neural messengers; (4) histocytochemical and pharmacophysiological studies on ETs, NPs and angiotensins as the cytokine/growth factors. PMID- 8686418 TI - [The brain of the Agnatha]. AB - The brain of the Agnatha, especially of the hagfish, is discussed from the viewpoint of the telencephalon and the olfactory, visual, trigeminal, and vestibulolateral sensory systems. Myxiniformes and Petromyzontiformes, which were an independent group in the Ordovician, are thought to represent some parallels of ancestral vertebrate brains. It is interesting to study the brain of the Agnatha to investigate the process of the evolution of the vertebrate brain. In comparison with the lamprey, the hagfish has subcutaneous eyes under an unpigmented patch of skin, 4 paired tentacles at the rostral tip of the head, one semicircular canal on each side, a regressed ventricular system, a "primordium hippocampi" of unresolved homology in the telencephalon, no pineal body, fusion of the habenula of both sides, a tectum opticum with unclear laminations, no macroscopical cerebellum, and optic decussation within the hypothalamus. The arrangements of the trigeminal subnuclei of the descending tract are different from each other, unlike those of other gnathosomata. In the hagfish, the distribution of fibers carrying input of the vestibulum and lateral line system within the area vestibulo-lateralis differs from that of the lamprey, which resembles the teleosts and cartilaginous fish in this respect. These differences may be caused by an independent origin within the Agnatha. The basic organization of the brain of the Agnatha, such as the prosencephalon, mesencephalon, and rhombencephalon are common to the gnathostomata, although some variations in development are included in the sensory centers and higher centers of information processing. The sensory neurons within the brain are found in the medulla oblongata in the Agnatha, whereas in the gnathostomata the mesencephalic nucleus of the trigeminal nerve has been formed in connection with the development of the mandibula. PMID- 8686420 TI - [Actual example of microanatomy education in Kyorin university medical school]. PMID- 8686419 TI - [Histochemistry of the organs--application of histochemistry to anatomy]. AB - Histochemistry has been developed as a science to localize chemical components of cells and tissues on histological sections by using chemical, physical and biological techniques. Many textbooks are available dealing with the methodology of histochemistry, consisting of fixation of tissues, demonstration of biochemical components such as nucleic acids, proteins, sugars, lipids, enzymes, pigments, inorganic substances and amines by means of chemical reactions (Fig. 5) or application of physical (Figs. 1-3, 6-13) and biological (Fig. 4) methods such as spectrophotometry, X-ray microanalysis, radioautography and immunohistochemistry. The methodology has been well developed to form a new science which should be given a designation "general histochemistry" as similar to general histology. On the other hand, these techniques should be applied to all the organ systems, i.e. the skeletal, muscular, circulatory, digestive (Figs. 1-6), respiratory (Figs. 7, 8), urinary (Fig. 9), genital (Fig. 10), endocrine (Fig. 11), nervous (Fig. 12), and sensory organs (Fig. 13). The results of these applications to all the organs should be collected and construct a new field of histochemistry of the organs like "histology of the organs". These results now form a new field of science which should be designated as "special histochemistry". Since the present author started the career as an anatomist and histologist in 1955, the author first aimed at the study of histochemistry by developing new chemical, physical and biological techniques such as enzyme histochemistry (Fig. 5), microspectrophotometry, autoradiography (Figs. 1-3, 6 13), cryo-techniques, immunohistochemistry (Fig. 4) and lectins in the 1950s, 1960s and 1970s. However, the author and coworkers made efforts to apply these techniques to various organ systems of humans and animals since the 1970s to the present time and collected data from all the organs including the aging process from embryos, neonates, sucklings, weanlings, adults and to senescence. The data include not only 3-dimensional structures of the organs but also the 4 dimensional features taking the time dimension into account using the radioautographic techniques by labeling cells and tissues in connection with the time lapse. The original papers published from our laboratory during these 40 years were reviewed and compiled to form a new field of science, which should be designated as histochemistry of the organs or, alternatively, special histochemistry. It is hoped that this new prospect would be well developed to form a novel system in medical science. PMID- 8686421 TI - [Report on computer demonstration in Human-Body Plastination Exhibit]. PMID- 8686422 TI - SPECT in Clinical Neurology and Psychiatry. Antwerp, Belgium, August 31-September 2, 1995. Abstracts. PMID- 8686423 TI - 3rd International Conference on Xenon/CT CBF. 25-28 June, 1995. PMID- 8686424 TI - Comparison of measurement between Xe/CT CBF and PET in cerebrovascular disease and brain tumor. PMID- 8686425 TI - Xenon/CT CBF measurements as valuable diagnostic tool in a case of bilateral occlusive cerebrovascular disease associated with intracranial aneurysm. AB - A patient with the coincidental occurrence of a right internal carotid artery (ICA) stenosis and asymptomatic ipsilateral infraclinoidal ICA aneurysm is presented. CBF measurements including testing of the cerebrovascular reserve capacity (CRC) demonstrated a compromise of cerebral blood flow (CBF) within the anterior circulation of the affected side. We treated the patient in one operation by aneurysm clipping and subsequent carotid endarterectomy (CEA). 10 months later she presented with an occlusion of the contralateral ICA. CBF measurements showed sufficient resting flow and CRC on both sides. One year later repeat measurements disclosed a lowered resting CBF and diminished CRC on the affected side. Extracranial/Intracranial (EC/IC) artery bypass improved both symptoms and CBF/CRC values. The authors propose to treat symptomatic ICA stenosis and concurrent silent ipsilateral intracranial aneurysms at once if the patient is eligible for aneurysm surgery. CBF measurements should be performed before surgery. In a medically compromised patient carotid endarterectomy alone appears to be justifiable. In cases of symptomatic aneurysm and concurrent ICA stenosis a CEA can be added to aneurysm clipping to improve the hemodynamic situation for a better postoperative management. Xenon/CT investigations are suitable to provide important cerebral blood flow information. Together with angiography and clinical judgment it allows to identify patients with hemodynamic insufficiency. These are suitable candidates for an operative procedure to augment cerebral blood flow and to improve symptoms. PMID- 8686426 TI - Assessment of patients with intracranial hematomas. PMID- 8686427 TI - Cerebral hemodynamics in patients with traumatic subarachnoid hemorrhage sequential studies with TCD. PMID- 8686428 TI - Comparative study of regional cerebral blood flow values measured by Xe CT and Xe SPECT. AB - The regional cerebral blood flow (rBCF) values measured by stable xenon-enhanced computed tomography (Xe XT) and by radioactive xenon-133 single photon emission computed tomography (Xe SPECT) were compared in 16 patients with cerebral infarct. On the non-lesion side Xe SPECT recorded 10.7% higher rCBF values than Xe CT in the anterior cerebral artery territory, while Xe CT recorded 9.6% higher values than Xe SPECT in the middle cerebral artery territory. These differences were not statistically significant. Although the rCBF values were almost the same, no correlation was found between the two methods in the posterior cerebral artery territory and the basal ganglia. Only hemispheric CBF on the non-lesion side showed the same value and a good correlation between the Xe CT and the Xe SPECT. There was a good correlation in the hemispheric CBF values on the lesion side, too. The difference of rCBF between the non-lesion side and the lesion side was expressed smaller in the Xe SPECT than in the Xe CT. This is in agreement with the previous reports that Xe SPECT overestimates the flow in the low flow areas. The higher rCBF values in the anterior cerebral artery territory measured by the Xe SPECT was ascribed to the artifact from the radioactivities in the inhalation mask and the air passages as reported previously. In conclusion, there is no good correlation between the rCBF values measured by the Xe CT and by the Xe SPECT. Only hemispheric CBF shows a good correlation between the two methods. PMID- 8686429 TI - Early cerebral blood flow and vascular reactivity to acetazolamide in predicting the outcome after ruptured cerebral aneurysm. AB - The sequential cerebral blood flow (CBF) and CBF response to acetazolamide (AZ; 1 g i.v.) within 4 days after initial subarachnoid hemorrhage (SAH) were monitored in 50 patients by stable xenon-enhanced computed tomography (xenon CT). The mean global CBF of the subjects declined with the neurological grading (Hunt & Kosnik), and it was impossible to predict the occurrence of vasospasm from the value of the plain CBF at the acute phase of SAH. However, the CBF response to AZ at the acute phase of SAH among patients resulting in a poor outcome was significantly diminished compared to that among patients resulting in a good outcome. The usefulness of the CBF response to AZ in the acute phase of SAH is discussed. PMID- 8686430 TI - Presence and removal of arteriovenous malformation: Impact of regional cerebral blood flow, as assessed with xenon/CT. AB - In 26 patients with supratentorial AVMs and 1 patient with a dural arteriovenous fistula, the regional cerebral blood flow (rCBF) was assessed by means of xenon enhanced computed tomography (Xe/CT) before and after complete resective surgery. Each assessment comprised an acetazolamide challenge in order to check the cerebrovascular reserve capacity. While scanning through the AVM was purposely avoided, a single brain slice at the level of the basal ganglia was examined. Five regions of interest (ROIs) in gray matter of the AVM-bearing hemisphere were compared to the contralateral ROIs and categorized into 7 CBF groups. Interhemispherical differences exceeding 20% of the contralateral value in either direction were considered to the significant. AVM-related (AVM-R) and AVM-non related (AVM-NR) ROIs were looked at separately. Before surgery, all possible rCBF patterns were found, including a normal rCBF as well as a reduced or an increased rCBF, either in AVM-R, AVM-NR, or both. After AVM removal, a rCBF increase in AVM-R is relatively rare, whereas a rCBF decrease is twice as frequent. A rCBF drop to a level of impaired reserve capacity correlates with the occurrence of post-operative neurological deficit. PMID- 8686431 TI - Hemodynamics of hypertensive putaminal hemorrhage evaluated by Xenon-enhanced computed tomography and acetazolamide test. AB - Cerebral blood flow (CBF) is usually decreased in patients with hypertensive putaminal hemorrhage (HPH). However, there are few reports concerning cerebrovascular reserve capacity (CRC) in these cases. This study evaluated cerebral hemodynamics in patients with HPH by measuring CBF and CRC. CBF and CRC were measured by stable xenon enhanced computed tomography (Xe-CT) in 11 patients with HPH (HPH group) and 11 patients with essential hypertension without intracerebral hematoma (non-HPH group). CBFs of the hemisphere and thalamus in the HPH group were lower than those in the non-HPH group. And the CBF of the hemisphere was increased transiently after the surgical evacuation of the hematoma. Thereafter, it fell gradually. The CRCs were also lower in acute stage of the HPH group. The CRC recovered during the chronic stage. Hemodynamics in patients with HPH can be modulated by surgical removal of hematoma. However, some adjunct therapies are necessary to prevent delayed neuronal inactivity, Stable Xe CT with acetazolamide test is useful to evaluate hemodynamics in the HPH patients. PMID- 8686432 TI - The CBF distribution in Xenon-CT CBF study. PMID- 8686433 TI - Xe/CT CBF measurements during migraine and cluster headache. PMID- 8686434 TI - Alteration of rCBF in skull base lesions. AB - Cerebral functional imaging methods provide complementary information on brain function and large vessels regulatory controls which are compromised in cranial base lesions. The presence of a skull base tumor can alter regional cerebral blood flow (rCBF) in adjacent and remote brain tissue. This report presents the results of 104 CBF studies in 66 patients with skull base lesions (aged 17-75 years). The lesions included 36 meningiomas, 21 neurinomas and 9 other tumors. Regional CBF in tumor and brain tissue was measured prior to treatment using stable xenon enhanced computed tomography (Xenon(/T). For the quantitative analysis, regions of interest were delineated on tumor regions, cerebral and cerebellar hemispheres including peritumoral regions. In order to assess the remote effect of cerebellopontine angle (CPA) tumors, the brainstem, cerebellar, and cerebral blood flow were measured in 26 cases. The average brainstem CBF for patients with good outcome was higher than the average brainstem CBF for patients with poor outcome. This indicates that CBF studies in posterior fossa can be useful in predicting the prognosis of CPA tumor patients. We report a series of 16 patients with cavernous sinus tumors in whom the internal carotid artery was affected by the tumor. In nearly all cases Xenon/CT CBF studies with acetazolamide test showed no significant difference in hemispheric perfusion and a sufficient cerebrovascular reserve capacity. Interhemispheric asymmetry was present only in one patient. These results possibly indicate that i.v. administration of acetazolamide might contribute in selecting patients with higher risk for ischemic deficits after cavernous sinus surgery. Skull base meningiomas showed very high blood flow with a wide range. Local CBF in the peripheral region of meningiomas was higher than in the central region. Blood flow values in the peritumoral areas are about 30% lower than those of the ipsilateral hemisphere. In individual cases, blood flow values in the peritumoral low-density area on CT were extremely low. It is concluded that CBF studies in skull base tumors are valuable in treatment planning. Xenon/CT can be useful additional diagnostic procedure in the evaluation of skull base surgery candidates. PMID- 8686435 TI - Correlation between cerebral blood flow values obtained by Xenon/CT and Kety Schmidt (N2O) methods. AB - The means of the cerebral blood flow (CBF) values obtained by the stable xenon enhanced CT (Xe/CT) method using two different CT scanners were compared with global CBF value obtained by the Kety-Schmidt (N2O) method as a reference. Xe/CT CBF values were obtained using a GE CT9200 (31 patients, 2 flow maps, 120 kV, absorption constant of 0.040) as well as a GE ProSeed Accell (38 patients, 4 flow maps, 80 kV, absorption constant of 0.028). The protocol of inhalation in the Xe/XT method consisted of 4 min wash-in and 4-min wash-out of 35% stable xenon. In the Kety-Schmidt method, 15% N2O gas was inhaled for 10 min. The N2O content of blood samples was measured using a van Slyke-Neill blood gas analyzer. We corrected all obtained CBF values for a PaCO2 of 34 mmHG (CBF34). The global CBF34 values obtained by the Kety-Schmidt method were linearly correlated with the CBF34 values obtained using the CT9200 and with those obtained using the ProSeed Accell, and the regression line equations were, respectively, Y = 0.64X + 13.7 (X: CT9200, Y: Kety-Schmidt, r = 0.666, p < 0.01) and Y = 0.99X + 11.2 (X: ProSeed Accell, Y: Kety Schmidt, r = 0.756, p < 0.01). Since the CBF values obtained by the Xe/CT method using different CT scanners are not always the same as the global CBF values obtained by the Kety-Schmidt method, CBF values obtained by the Xe/CT method should be corrected referring to the regression line obtained by applying both methods for each patient. PMID- 8686436 TI - Regional cerebral blood flow measurements with Xenon-CT in the prediction of delayed encephalopathy after carbon monoxide intoxication. AB - Reported evaluations of CBF with Xe/CT were performed in 11 patients during the lucid interval following CO intoxication. Results were compared with clinical and SPECT data. Two patients developed neuropsychiatric behavior (delayed encephalopathy) one month following the initial recovery. The symptoms persisted in one of them 15 months later. Their CBF values as well as those in most of the other patients, monitored at the basal ganglia and white matter areas, were in relation with the clinical outcome, However, further studies with a larger number of patients, are needed to confirm the predictive significance of Xe/CT measurements for the long term sequelae of CO poisoning. PMID- 8686437 TI - A method of regional cerebral blood perfusion measurement using dynamic CT with an iodinated contrast medium. PMID- 8686438 TI - PET criteria of cerebral tissue viability in ischemia. PMID- 8686439 TI - Coronal flow mapping with Xe/helical CT. PMID- 8686440 TI - Effect of Xenon. PMID- 8686441 TI - Blood flow velocities in middle cerebral artery during inhalation of 30% stable xenon. PMID- 8686442 TI - Current status and controversies in the inhalation protocols for the Xenon CT CBF method. AB - The historical background and current status of the inhalation protocols for the xenon CT CBF method are reviewed. A wash-in method has been established and widely accepted as a standard protocol. A wash-in/washout method is a useful alternative for a practical CBF study. The effect of flow activation with xenon gas can be minimized by shortening the inhalation time. Xe CT CBF method remains to be an indispensable technology for the clinical decision-making in various brain disorders. PMID- 8686443 TI - Correction method for end-tidal Xenon concentration. PMID- 8686444 TI - Confidence analysis of Xe/CT CBF Technology. PMID- 8686446 TI - Xe-CT in cerebrovascular disease and moyamoya disease. AB - (1) Negative response to acetazolamide challenge test using Xe-CT is a reliable indicator for identifying the hemodynamic compromise. (2) The hemodynamic compromise may be a cause of TIAs in some patients with chronic cerebrovascular occlusive diseases. (3) The brain suffering from hemodynamic compromise actively works to induce collateral blood channels. PMID- 8686445 TI - Comparison of Xe-CT/CBF and quantitative ECD-SPECT. AB - We compared stable xenon enhanced X-ray computed tomography (Xe-CT) with Technetium-99m ethylsteinate dimer single-photon emission computed tomography (ECD-SPECT) in 12 patients. We evaluated the cerebral blood flow (CBF) values in the territory of the anterior, middle and posterior cerebral artery, and in the thalamus. The CBF values were higher in ECD-SPECT than in Xe-CT except for the values of the thalamus. The posterior cerebral artery territory showed a lower correlation and the thalamus had no correlation between two methods. We discussed causes of these differences. PMID- 8686447 TI - Surgical modulation of the natural course of collateral circulation in chronic ischemic patients. AB - The purpose of this study was to evaluate hemodynamic compromise in terms of baseline CBF and CRC in patients with chronic cerebral occlusive lesions and its modulation by a superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis. The study subjects were 10 healthy volunteers and 49 chronic ischemic patients with stenosis or occlusion of the internal carotid artery (ICA) or middle cerebral artery (MCA). The hemodynamics were measured using stable xenon enhanced computed tomographic CBF measurement with the acetazolamide challenge. The compromised hemodynamics in patients with chronic steno-occlusive lesions did not improve during their natural course after two months. STA-MCA bypass modulated hemodynamic compromise in the ischemic patients. We recommend STA-MCA bypass for patients with reduced CRC, regardless of whether baseline CBF is reduced or normal. Hemodynamic classification using a combination of baseline CBF values and CRC values is useful for evaluating cerebral hemodynamics and for choosing the best treatment for cerebral ischemia with occlusive lesions. PMID- 8686448 TI - EC-IC bypass in patients with chronic hemodynamic insufficiency. PMID- 8686449 TI - Modulation of cerebral hemodynamics by surgical revascularization in patients with moyamoya disease. AB - The purpose of this study was to evaluate hemodynamic compromise in the patients with moyamoya disease and surgical modulation of the hemodynamics using stable xenon enhanced computed tomographic CBF measurement with the acetazolamide challenge. The study group consisted of 15 preoperative cases and 17 postoperative cases. In the preoperative group, regional resting cerebral blood flow (rCBF) and regional cerebrovascular reserve capacity (rCRC) were reduced. The reduction was more prominent in the anterior circulation than in the posterior circulation. In the postoperative group, rCBF and rCRC were still low in the anterior circulation. Revascularization increased the resting CBF but did not change the CRC. Postoperative CBF did not increase in adults but increased in children. These findings suggest that the misery perfusion state may be present only in the child's brain. Measurement of CBF and CRC is useful to evaluate the hemodynamics of moyamoya disease. PMID- 8686450 TI - Regression of moyamoya vessels and hemodynamic changes after successful revascularization in childhood moyamoya disease. AB - Successful revascularization improves ischemic symptoms in the pediatric patients with moyamoya disease. However, it is not clear whether the revascularization prevents future intracranial hemorrhage from the residual moyamoya vessels. The purpose of this study is to investigate perioperative morphological and hemodynamic changes in the moyamoya vessels. Four pediatric patients (age < 15 years old) with bilateral moyamoya disease were selected for this study. To quantify the number of moyamoya vessels, T1-weighted transverse images at the level of the basal ganglia and the thalamus were selected and characteristic flow voids in the lentiform nucleus were counted. Resting CBF and cerebrovascular reserve capacity (CRC) were measured pre- and 1 year after surgery using Xenon-CT CBF method with acetazolamide test. The ratio of deep CBF/cortical CBF was calculated as an index of hemodynamic stress distribution. The one-year follow-up studies showed that 1) the number of moyamoya vessels decreased on the operative side, but did not change on the non-operative sides in all cases; 2) the ratio of deep CBF/cortical CBF decreased on the operative sides, but did not change in the non-operative sides; and 3) the CRC increased on both sides. This observation suggests the possibility that revascularization surgery may be effective for preventing the future risk intracranial hemorrhage. PMID- 8686451 TI - Cerebral blood flow and cerebrovascular reactivity capacity in patients with bilateral high-grade carotid artery stenosis. PMID- 8686453 TI - The effect of sodium bicarbonate on CBF and intracellular pH in man: stable Xe-CT and 31P-MRS. AB - The effects of sodium bicarbonate on cerebral blood flow (CBF) and intracellular pH were studied in five normal volunteers. CBF and intracellular pH were measured by stable xenon computed tomography and phosphorus-31 magnetic resonance spectroscopy (31P-MRS) respectively. Each patient received 7% sodium bicarbonate (3.5 ml/kg body weight) infused intravenously for 15 minutes. Before and after this injection, CBF intracellular pH and physiological parameters were measured. CBF and PaCO2 were significantly increased. On the other hand, hematocrit and intracellular pH were decreased. These result suggests that three factors are thought to contribute to increase CBF during administration of sodium bicarbonate in humans: 1) arterial dilatation in response to carbon dioxide 2) an decrease of hematocrit 3) intracellular acidosis. PMID- 8686452 TI - Effect of angiotensin converting enzyme inhibitor on chronic ischemic patients. AB - Most of patients with cerebrovascular disease are associated with hypertension. Hypertension induces progressive atheromatous changes in cerebral arteries, and often causes steno-occlusive lesions of cerebral arteries. Angiotensin converting enzyme (ACE) inhibitor cilazapril is one of the antihypertensive drugs. It was reported that cilazapril improved resting cerebral blood flow (CBF) and cerebrovascular reserve capacity (CRC) in experimental studies. In this clinical study, the authors investigated whether long-term treatment with cilazapril could improve CBF and CRC in patients with steno-occlusive lesions of the major cerebral arterial trunk, measured by stable xenon computerized tomography (Xe-CT) with acetazolamide challenge. On the other hand, CBF and CRC in the calcium blocker-treated patients were measured in the same way. CBF did not change after long-term treatment with both cilazapril and calcium blocker. In the cilazapril treated group, CRC was increased significantly (p < 0.05). However, CRC did not change in the calcium blocker-treated group. It was recognized that long-term treatment with cilazapril did not decrease CBF and improved CRC in patients with occlusive lesions of the major cerebral arterial trunk. PMID- 8686455 TI - 30th Congress of the Federation of Scandinavian Societies of Obstetrics and Gynecology. Stockholm, Sweden, 19-22 May 1996. Abstracts. PMID- 8686454 TI - Effects of acute percutaneous transluminal recanalization on cerebral embolism. AB - The effects of percutaneous transluminal recanalization (PTR) on critical hemodynamics of cerebral embolism were studied using stable xenon-enhanced computed tomography in patients within 6 hours after onset. PTR was conducted in 10 cases (PTR group) and not conducted 8 cases (non-PTR group). The development of infarction was followed by CT scan. In the cortical arterial regions, the lowest cerebral blood flow (CBF) value in regions of interests (ROIs) without development of infarction was 12.9 ml/100 g/min in the PTR group and 17.0 ml/100 g/min in the non-PTR group. In ROIs with a cerebrovascular reserve capacity (CRC) less than 0 ml/100 g/min, even with a CBF greater than 12.9 ml/100 g/min, 3 of 4 ROIs underwent cerebral infarction. PTR conducted within 6 hours after onset of cerebral embolism would prevent the cortical regions with a CBF greater than 12.9 ml/100 g/min and with a CRC greater than 0 ml/100 g/min from undergoing cerebral infarction. PMID- 8686456 TI - Sensory nerve ingrowth during bone graft incorporation in the rat. AB - We studied nerve ingrowth into a cancellous bone graft in a bone conduction chamber model in the rat. Before implantation of the chamber bilaterally in the proximal tibiae of 8 Sprague-Dawley rats, a defatted cancellous bone graft from separate donor rats was fitted snugly into each chamber. After 6 weeks, the animals were perfused with Zamboni's fixative and the chambers were harvested. Immunohistochemical detection of nerve fibers was performed in cryostat sections, using antisera to protein gene product 9.5 (PGP 9.5), neural growth-associated protein GAP-43/B-50, calcitonin gene-related peptide (CGRP), substance P and C- flanking peptide of neuropeptide Y (CPON). Nerve fibers were found in 10 out of 16 samples in the newly formed bone, and also in the fibrous tissue which had penetrated deeper into the graft. The nerve fibers were mainly of sensory origin, as they showed immunoreactivity for CGRP and GAP-43/B-50. We speculate that the nerve fibers may act as transmitters of nociceptive impulses from the graft, and as transport pathways for neuropeptides that are actively involved in angiogenesis and in the recruitment and activity of osteogenic cell populations from the graft recipient. PMID- 8686457 TI - Bisphosphonate inhibition of bone resorption induced by particulate biomaterial associated macrophages. AB - Aseptic loosening of total joint replacements is associated with bone resorption. A heavy infiltrate of foreign body macrophages in response to biomaterial wear particles is commonly found in the fibrous membrane surrounding loose components. It has recently been shown that foreign body macrophages can differentiate into osteoclastic cells. To determine whether pharmacological inhibitors of bone resorption have a role to play in controlling the osteolysis of aseptic loosening, we analyzed the effect of a bisphosphonate, disodium ethane-1, 1 diphosphonate (EHDP) on this process. Murine monocytes and foreign body macrophages (derived from granulomas formed by subcutaneous implantation of particles of prosthetic biomaterials) were co-cultured with UMR106 osteoblast like cells in the presence of 1,25 dihydroxyvitamin D3 for 14 days on glass coverslips and bone slices. EHDP significantly inhibited bone resorption in these co-cultures. There was little or no expression of the osteoclast-associated enzyme, tartrate-resistant acid phosphatase (TRAP) in EHDP-treated co-cultures. Addition of EHDP to monocyte-UMR106 co-cultures after the appearance of TRAP positive cells did not abolish bone resorption, indicating that EHDP, in addition to its known inhibitory effect on osteoclast function, suppresses differentiation of osteoclast precursors. EHDP inhibition of the osteolysis induced by particulate biomaterial-associated macrophages shows that pharmacological inhibition of bone resorption might be used to control the osteolysis of aseptic loosening. PMID- 8686458 TI - Basic fibroblast growth factor infused at different times during bone graft incorporation. Titanium chamber study in rats. AB - We investigated the effect of applying basic fibroblast growth factor (bFGF) to a bone graft during different stages of incorporation in an infusion bone chamber model. Bone chambers were implanted bilaterally into rat tibiae. Both chambers were connected to an implanted osmotic minipump. Ingrowing bone could enter the cylindrical interior of the chamber only at one end. The distance which ingrowing bone had reached into the bone graft was then measured on histological slides. Specimens were also analyzed by 99mTc-MDP scintimetry. The infusion of buffer during 2 weeks from implantation had no effects on tissue ingrowth distance or quality. bFGF was infused during 2 weeks from implantation in a dose of either 1.2 or 12 ng/day. Bone ingrowth was measured 6 weeks after implantation. The higher dose had a more marked effect and was used for studying the effect of application at different times. The maximum stimulation of bFGF as measured at 6 weeks postimplantation was found after infusion during the first postimplantation week. Infusion during the third and fourth weeks had no effect at 6 weeks, but tended to increase the bone ingrowth distance at 8 weeks postimplantation. These findings suggest that bFGF infusion increases bone ingrowth into bone grafts when infused at both an early and a later stage, but the effect can be measured only several weeks later. PMID- 8686460 TI - Measurement of limb length inequality. Comparison of clinical methods with orthoradiography in 190 children. AB - We studied the agreement in measuring limb length inequality with orthoradiograms and clinical methods. In 190 children attending our Limb Length Clinic for the first time, 95% of the measurements with wooden boards was within -1.4 and +1.6 cm of the results of the orthoradiograms. A tape measure had significantly less agreement. The predictive value of a localization of the main limb length inequality above the knee, as found with a tape measure, was 64% and for a localization of the main limb length inequality below the knee 75%. A Wooden Board Reliability Graph is presented, which can be helpful in the decision to perform orthoradiographic measurements of limb length inequality in, e.g., evaluation of impairment. PMID- 8686459 TI - Periosteal insulin-like growth factor I and bone formation. Changes during tibial lengthening in rabbits. AB - We investigated changes in periosteal insulin-like growth factor I (IGF-I) during tibial lengthening. In 37 rabbits, an osteotomy of the right middle tibia was made and fixed by a unilateral external fixator. The rabbits were randomized into 6 groups: the tibiae were distracted at 0.5 mm/day up to 4 weeks and the animals killed after 2 weeks, 4 weeks or 6 weeks, for each period there was a control group with no distraction. Periosteal IGF-I was measured by radioimmunoassay and bone formation was quantified by CT scanning. During bone lengthening, CT showed moderate bone formation, while IGF-I was increased. When lengthening was stopped, IGF-I returned to a basal level, and CT scanning showed considerable bone formation. Our study suggests that IGF-I plays a role in an early stage of bone formation. PMID- 8686461 TI - Unpredictable progression of osteolysis following cementless hip arthroplasty. 24 femoral components followed for 6-10 years. AB - We reviewed 24 hips that developed femoral osteolytic lesions following cementless total hip replacement with a Porous-Coated Anatomic prosthesis after a mean of 8 (6-10) years. 15 of the hips showed hardly any radiographic deterioration in the osteolysis. 2 became much worse with dramatic loss of bone stock. Both of these hips required revision of the acetabular component as well as bone grafting of the otherwise well-fixed femoral component. The remaining 7 hips showed mild-to-moderate enlargement of the lesions. All 24 hips were asymptomatic. Blood tests and bone scintigraphy were of no predictive value in assessing the probable progression of the lesions. Serial radiography remains the cornerstone of the monitoring of osteolysis, following cementless hip replacement, the extent of bone loss being usually far greater than indicated by radiographic examination. PMID- 8686462 TI - Posttraumatic osteonecrosis in a swine model. Correlation of blood cell flux, MRI and histology. AB - We used a miniature swine femoral neck fracture model to demonstrate the effects of the fracture on blood flow, histologic appearance, MRI signal and the development of posttraumatic osteonecrosis. The fracture was created and internally fixed in the right hip of 11 swine, with the left hip serving as the control. Femoral head blood flow via Laser Doppler Flowmetry and MRI data was examined for the experimental hip preoperatively, postoperatively and at 1, 2, 4 and 8 weeks postfracture. At 8 weeks, the animals were killed and the femoral heads were evaluated. Femoral head blood flow decreased immediately postfracture and continued to diminish with time. MRI signal intensities in the femoral head at 4 and 8 weeks were significantly less when the fixation failed than when it was intact. Histologic grades (0-14 points) and bone densities were 7.6 and 49%, respectively, on the experimental side, compared to 1.6 and 56% on the control side. Histologic grading, bone density values and blood flow data had no relation to changes in MRI signal intensity. PMID- 8686463 TI - Cryotherapy after cruciate knee surgery. Skin, subcutaneous and articular temperatures in 8 patients. AB - We recorded temperature changes on the skin surface, subcutaneously and intra articularly during cryotherapy after knee surgery by using Cryo-cuff compression dressings. Subcutaneous recordings on the contralateral knee were used as reference. 8 patients were examined. There was a reproducible decrease in skin temperature and subcutaneous temperature. Skin temperature had to be lowered to about 20 degrees C to obtain demonstrable intraarticular temperature changes. PMID- 8686464 TI - Shoulder destruction in rheumatoid arthritis. Classification and prognostic signs in 83 patients followed 5-23 years. AB - We studied the natural course and the possibility of making prognoses about shoulder joint destructions in 83 patients with rheumatoid arthritis (RA) (166 shoulder joints). For this purpose, we used radiographic patterns and 2 indices (upward migration and medial displacement). The patterns of joint destruction were classified into 5 groups: 1) non-progressive type (n 74) with normal radiographs, only osteopenia or small erosions even after 15-20 years of RA; 2) erosive type (n 22) showing marginal erosions but no collapse; 3) collapse type (n 34) showing subchondral cysts, followed by collapse; 4) arthrosis-like type (n 12) showing arthrotic features; 5) mutilating type (n 14) showing mutilating bone destructions. From the radiographic findings and the 2 indices determined at 5-10 years, we could predict the prognosis of shoulder joint destruction after 15-20 years of RA. Our findings may be of value for selecting treatment, including surgery, for the rheumatoid shoulder. PMID- 8686465 TI - Atrophy of the supraspinatus belly. Assessment by MRI in 55 patients with rotator cuff pathology. AB - A study of 5 fresh cadaveric shoulders demonstrated that an oblique-sagittal plane which crosses the scapula through the medial border of the coracoid process offers a view of the supraspinatus fossa mostly limited by bone. This view could easily be reproduced by MRI and we called it the Y-shaped view. It allowed a reliable measurement of supraspinatus muscle atrophy by the calculation of the occupation ratio (R) which is the ratio between the surface of the cross-section of the muscle belly and that of the fossa. This ratio was calculated in a prospective study based on 55 shoulders divided into 3 groups with different rotator cuff status: group I, 15 controls; group II, 10 degenerative cuffs, without tears; group III, 30 operated tears. There was no difference between groups I (mean ratio 0.7) and II (mean ratio 0.62), but the ratio was decreased in group III (mean ratio 0.44), in which the extent of the tear in both the sagittal and coronal planes aggravated the muscle atrophy. We propose a three stage classification to improve indications for rotator cuff tear treatment. PMID- 8686466 TI - Bone loss of the radius in rheumatoid arthritis. Comparison between 34 patients and 40 controls. AB - We measured bone mineral density (BMD) in the radius by dual energy X-ray absorptiometry in 34 patients with rheumatoid arthritis (RA) and in 40 healthy controls. The BMD in RA patients in their fifties and sixties, but not in their forties and seventies, was significantly lower than that in the control subjects. The decrease in total radial BMD correlated with grip strength, RA activity and RA stage. The decrease in distal radial BMD correlated with RA activity, but not with grip strength. The levels of serum parathyroid hormone, alkaline phosphatase, and urinary hydroxyproline/creatinine were significantly higher in the patients. From these findings, we suggest that the bone loss in RA patients is affected by severity of inflammation, disuse, postmenopausal osteoporosis and secondary hyperparathyroidism. PMID- 8686467 TI - Radiographic staging of Kienbock's disease. Poor reproducibility of Stahl's and Lichtman's staging systems. AB - We assessed the precision of 2 widely used radiographic classification systems for patients with Kienbock's disease by repeated staging of 76 radiographic examinations by 3 independent observers. The intraobserver reproducibility was strong but the interobserver reliability was fair or moderate. PMID- 8686468 TI - Incidence of Achilles tendon rupture. AB - We determined the incidence of a total Achilles tendon rupture in the city of Oulu and changes over the 16-year period 1979-1994. During this time, 110 ruptures occurred. The incidence increased from 2 ruptures/10(5) inhabitants in 1979-1986 to 12 in 1987-1994, with a mean of 7. The peak annual incidence, 18, was recorded in 1994. The incidence was highest in the age group 30-39 years. Male dominance was 5.5:1, and 81% of the ruptures were related to sports, with 88% occurring in ball games. The mean age was significantly lower for the sports injuries. PMID- 8686469 TI - Transposed skin graft for wound closure after Cincinnati incision. Experience in 7 patients with severe foot deformities. AB - I report a technique of wound closure by a transposed skin graft after operative treatment of foot deformities, using a Cincinnati incision. Three-dimensional correction of severe foot deformities (congenital talipes equinovarus, congenital vertical talus, etc.) results in skin excess on one side of the foot and lack of this on the opposite side. The skin excess can be cut out and used as a full thickness skin graft for wound closure on the opposite side of the foot. PMID- 8686470 TI - Correction of persistent clubfoot deformities with the Ilizarov external fixator. Experience in 10 previously operated feet followed for 2-5 years. AB - We reviewed the outcome in 10 idiopathic clubfeet in 7 patients treated with the Ilizarov external fixator (IEF) for persistent foot deformities after previous surgery. After follow-up of a median of 40 (25-56) months, 6 patients/parents were satisfied with the results and most of them reported better walking capacity and fewer problems finding shoes that fit. Severe equinus deformity was seen in 9/10 feet prior to treatment in the IEF and in no foot at follow-up. However, persistent reduction of ankle joint motion, limited walking capacity and intermittent pain were commonly found. PMID- 8686471 TI - Simple bone cysts treated by multiple drill-holes. 23 cysts followed 2-10 years. AB - We treated 23 simple bone cysts by the multiple drill-hole method and reviewed them a mean of 5 (2-10) years later. 11 cysts were located in the humerus, 9 in the femur, 2 in the tibia, and 1 in the pubis. The cysts recurred in 15 cases after the initial operation. 12 recurrent cysts were treated with reoperations. At the follow-up, good bone formation with no sign of recurrence was seen in 15 cases. A residual cyst was found in 8 cases, but further treatment was not considered necessary. PMID- 8686472 TI - Giant cell tumors with intraarticular fracture. Two-stage local excision, cryosurgery and cementation in 5 patients with distal femoral tumor followed for 2-4 years. AB - We describe a two-stage operation for intraarticular fracture through a giant cell tumor of the bone. The first stage aims at accurate reduction and fracture union, including curettage, open reduction and minimal internal fixation, autologous bone grafting and temporary bone cement filling. Following bone union, the second operation aims at tumor eradication, including meticulous recurettage, cryosurgery, cementing and stable internal fixation. We report our preliminary results in 5 patients, who were followed 2-4 years. All fractures united, there were no early complications or local recurrences and good function was achieved. PMID- 8686473 TI - A femoral fracture with an extruded 14-cm fragment treated by secondary locked nailing--a case report. PMID- 8686474 TI - Tuberculous infection superimposed on tophyceous flexor tenosynovitis in the wrist--a report on 2 cases. PMID- 8686475 TI - Idiopathic avascular necrosis of the scaphoid--a case of early diagnosis by MRI. PMID- 8686476 TI - Pantalar fusion for correction of painful equinus after traumatic Chopart's amputation--a report of 2 cases. PMID- 8686477 TI - Asymptomatic big toe changes in diabetic patients with early Charcot knees--a report of 2 cases. PMID- 8686478 TI - Congenital clubfoot. PMID- 8686479 TI - Familial vulnerability factors to post-traumatic stress disorder in male military veterans. AB - The question has been frequently raised about whether there are emotional disorders that predispose to post-traumatic stress disorder (PTSD). We do know that those with PTSD do have many comorbid disorders, but due to the difficulty in performing prospective studies it is hard to tell what is cause and what is effect. This study bypassed the problem caused by comorbidity by examining family history of four proband groups: PTSD, mixed anxiety disorders, coexisting anxiety and depressive disorders, and screened normal controls. Two questions were examined. First, whether family history predicted who experienced combat situations and second, whether the proband groups could be distinguished by family history. Logistic regression identified two variables that predicted the experience of combat: major depression (odds ratio 2.17) and the DSM-III dramatic personality disorder cluster (odds ratio 1.36). Although there was considerable overlap, family history variables distinguished PTSD from other proband groups. Overall, the pattern of psychopathology in the families of the PTSD probands most closely resembled that in the families of the coexisting anxiety and depressive disorders probands. We conclude that family history methods may be an addition to possible variables that predict who will be exposed to combat and also that family history variables may be able to distinguish a PTSD population from some other types of emotional disorders. PMID- 8686480 TI - The Reactivity of Psychosis Rating Form (RPRF): background, development and psychometrics. AB - The ICD-10 and DSM-IV classifications have both given low priority to "reactivity" to acute stress as a classificatory principle for functional psychoses. In Scandinavia, reactivity is still considered an important factor in the development of such psychoses. Reactivity is a complex concept, and its various components are historically examined. The Reactivity of Psychosis Rating Form (RPRF) was developed in order to operationalize reactivity. Seven of the 10 elements of RPRF can be rated reliably. Factor analysis of the RPRF yields three factors: stressor, onset and change, that also show high interrater reliability. Our results indicate that RPRF has both construct and discriminant validity. Further studies with the RPRF may elucidate the true status of reactivity in functional psychoses. PMID- 8686481 TI - Treatment of manic episodes: zuclopenthixol and clonazepam versus lithium and clonazepam. AB - For the treatment of acute mania, no single drug is sufficiently effective in daily clinical routine for all patients. Drug combinations are often prescribed but poorly investigated. The present study examined whether a treatment with a neuroleptic drug (zuclopenthixol) combined with a benzodiazepine (clonazepam) was superior to a treatment with lithium and the same benzodiazepine (lithium citrate and clonazepam). Twenty-eight hospitalized patients with a DSM-III-R manic episode were included, randomized to fixed drug doses and observed up to 28 days. Degree of mania, side effects and patients satisfaction with the treatment were registered. Approximately two thirds of the patients improved fully or partially on both drug combinations. Furthermore no statistically significant differences were found regarding acceptance and tolerance of the two drug combinations. The present drug combination are only two among several which deserve a thorough examination in order to prevent a random polypharmacy for treatment of mania. PMID- 8686482 TI - Routine evaluation of mental health: reliable information or worthless "guesstimates'? AB - Routine evaluation of mental health care systems necessitates a quick assessment of progress and outcome. This study was designed to determine the value of the GAF-scale in such applications. We allowed 104 raters from six therapeutic centres to rate five clinical case-vignettes. Interrater reliability was almost equal for raters within different professional categories. The highest and the lowest scores for each of the case-vignettes differed by between 39 and 45 points. The raters' biases ranged from -23 to +30 points, and random deviations were between 1 and 20 points. Systematic differences between centres were up to 6 points. Our main finding is that the reliability of GAF scores in routine settings proved unsatisfactory with entrained raters. PMID- 8686483 TI - Catatonia. I. Rating scale and standardized examination. AB - To facilitate the systematic description of catatonic signs, we developed a catatonia rating examination, rating scale and screening instrument. We constructed a 23-item rating scale and a truncated 14-item screening instrument using operationalized definitions of signs ascribed to catatonia in published sources. Inter-rater reliability was tested in 44 simultaneous ratings of 28 cases defined by the presence of > or = 2 signs on the 14-item screen. Inter rater reliability for total score on the rating scale was 0.93, and mean agreement of items was 88.2% (SD 9.9). Inter-rater reliability for total score on the screening instrument was 0.95, and mean agreement of items was 92.7% (SD 4.9). Diagnostic agreement was high based on criteria for catatonia put forth by other authors. Seven per cent (15/215) of consecutively admitted patients to an academic psychiatric in-patient facility met criteria for catatonia. It is concluded that catatonia is a distinct, moderately prevalent neuropsychiatric syndrome. The rating scale and screening instrument are reliable and valid. Their use facilitates diagnosis, treatment protocols, and cross-study comparisons. PMID- 8686484 TI - Catatonia. II. Treatment with lorazepam and electroconvulsive therapy. AB - Case material and retrospective studies support the use of both lorazepam and ECT in treating catatonia, but few prospective investigations exist and none employ quantitative monitoring of response. In this study we test their efficacy in an open, prospective protocol, and define a "lorazepam test' with predictive value for treatment. Twenty-eight patients with catatonia were treated systematically with parenteral and/or oral lorazepam for up to 5 days, and with ECT if lorazepam failed. Outcome was monitored quantitatively during the treatment phase with the Bush-Francis Catatonia Rating Scale (BFCRS). In 16 of 21 patients (76%) who received a complete trial of lorazepam (11 with initial intravenous challenge), catatonic signs resolved. A positive response to an initial parenteral challenge predicted final lorazepam response, as did length of catatonic symptoms prior to treatment. Neither demographic variables nor severity of catatonia predicted response to lorazepam. Four patients failing lorazepam responded promptly to ECT. It is concluded that lorazepam and ECT are effective treatments for catatonia. The rating scale has predictive value and displays sensitivity to change in clinical status. PMID- 8686485 TI - Prefrontal neuropsychological impairment and illness duration in schizophrenia: a study of 204 patients in Hong Kong. AB - Previous studies investigating the progression of neuropsychological impairment in schizophrenia have yielded conflicting results. We compared prefrontal neuropsychological function and other cognitive performance in a larger sample of schizophrenic patients with different duration of illness. The inclusion of a normal control group also allowed the effect of age to be taken into account. Performance in the Wisconsin Card Sorting Test (WCST) and semantic fluency were both impaired at an early stage in the illness and did not significantly deteriorate as the illness duration increased. Against this background there was preliminary evidence for deterioration in verbal memory function. The data support a lack of progression in prefrontal dysfunction and in most other cognitive domains. PMID- 8686486 TI - Antidepressants and drug-metabolizing enzymes--expert group report. AB - Antidepressant drugs are extensively metabolized. Consequently, the biotransformation pattern of antidepressants has an important influence on their clinical properties, i.e., pharmacokinetics, toxicity, drug-drug interactions, side-effect profile and last but not least therapeutic efficacy. It was against this background that a multidisciplinary group of experts discussed the clinical relevance of the rapidly increasing body of knowledge of antidepressant metabolizing enzymes. The variability of the response of a given individual to an antidepressant is determined genetically and by the environment. Genetic polymorphism of drug-metabolizing enzymes and inhibition by other substrates may affect the enzymatic biotransformation of antidepressants. In vitro assay techniques allow an estimation of the potential variability in clinical response to antidepressants and a reasonable prediction of the drug-drug interaction patterns. The results of in vitro tests should therefore be considered early in the development of an antidepressant as a background for designing clinical studies (treatment schedules and dosing). Physicians should have an understanding of the relevance of genetic polymorphism for clinical practice. Education is needed in order to fill the existing gaps in knowledge about antidepressant enzyme interactions and their application in daily treatment practice. The information on potential drug interactions determined by genetic polymorphism and based on studies with enzymes should be increasingly contained in drug compendia. PMID- 8686487 TI - The symptom structure of panic disorder: a trial using factor and cluster analysis. AB - Using cluster analysis of 207 patients with panic disorder (PD), we investigated the relationships between several panic symptoms at the time of panic attacks, which included anticipatory anxiety, agoraphobia, and 13 clinical symptoms based on the Diagnostic and Statistics Manual-III-Revised. Cluster analysis revealed three panic symptom clusters: cluster A (dyspnea, choking, sweating, nausea, flushes/chills); cluster B (dizziness, palpitations, trembling or shaking, depersonalization, agoraphobia, and anticipatory anxiety); and cluster C (fear of dying, fear of going crazy, paresthesias, and chest pain or discomfort). Generally, cluster A was comprised exclusively of physiological symptoms, among which respiratory symptoms were prominent, cluster B included both panic and non panic symptoms such as agoraphobia and anticipatory anxiety, and cluster C was comprised chiefly of fear symptoms. PMID- 8686488 TI - To what extent is female alcohol dependence and abuse known in the health care system? The use of multi-source information in a Swedish population survey. AB - In a multi-purpose two-phase general population survey of female alcoholism/alcohol problems, unknown alcohol dependence and abuse (ADA) was estimated with interviews and by search of medical and National Insurance Office records. Firstly, 3130 subjects received a screening questionnaire and, secondly, a stratified selection of 399 women were interviewed. A total of 56 subjects received a diagnosis of ADA in interview and four due to other information. Lifetime prevalence of ADA was 3.3%. A total of 63.6% of the diagnosed women 45 65 years of age, and 25.9% of the women 25-35 years of age, were known in these records. Corresponding rates for women with alcohol dependence were 71.4% and 30.8%, respectively. Record information reveals a lack of attention to ADA from several physicians. PMID- 8686489 TI - A factor analytic study of symptoms in acute schizophrenia. AB - The three-syndrome model of schizophrenic phenomenology has been well established in chronic illness. We report an attempt to replicate this concept in a sample of acutely unwell schizophrenic patients. Factor analysis was performed using PSE data collected within a week of admission from 114 patients who met DSMIII(R) diagnostic criteria for schizophrenia. Four main factors accounted for 58% of the variance. The first two factors closely resembled Liddle's disorganisation and psychomotor poverty syndromes. Hallucinations and delusions loaded separately under the third and fourth factors. To examine the validity of these four syndromes, the relationships between factor scores and other clinical data were examined. The disorganisation syndrome was associated with a history of multiple past admissions and a longer lifetime duration of in-patient treatment. PMID- 8686490 TI - Towards an understanding of defense style in terms of temperament and character. AB - The aim was to investigate the relationships between a model of personality based on the concept of defense mechanisms, as articulated by Vaillant, with the psychobiological model of personality, as developed by Cloninger. A total of 128 adults from 11 family pedigrees with at least two alcohol-dependent members completed the self-report Defense Style Questionnaire and the Temperament and Character Inventory. Immature defenses were largely explained by low character scores, while neurotic defenses were part temperament and part character. Cluster A, B and C defenses were related to low reward dependence, high novelty-seeking and high harm avoidance respectively. In a regression analysis, cluster B and C defenses were more related to low character scores than to temperament but, for cluster A defenses, temperament and character both contributed. The results suggest that it is possible to integrate an ego defense model of personality with a psychobiological model of personality, thereby enriching both approaches. PMID- 8686491 TI - Human interaction with technology: the accidental user. AB - Information technology is part of a growing number of applications in work and everyday life. It seems inevitable that the average person soon will have to interact with information technology in many ways, even when there is no desire to do so. Examples include finding a book in a library, personal financial transactions, the health sector, traffic and transportation, process control, etc. People who in this way are forced to interact with information technology shall be called accidental users. The accidental users poses a particular challenge to the design of technological artefacts because the disciplines of dealing with human-machine interaction are predicated on the assumption that users are motivated and have a minimum level of knowledge and skills. In particular, models of 'human error' and human reliability implicitly assume that users are benign and only fail as anticipated by designers. In this paper we investigate the extent to which current models of human erroneous actions and cognitive reliability can be used to account for interactions between accidental users and technology. PMID- 8686492 TI - Effect of enhancers on the pyridopyridazine-peroxide-HRP reaction. AB - 4-Substituted phenyl boronic acids (e.g., 4-iodo, 4-bromo, 4-phenyl) are effective enhancers of the horseradish peroxidase (Type VIA) catalysed chemiluminescent oxidation of various pyrido[3,4-d]pyridazine-1,4(2H,3H)dione derivatives. The most effective combination was 4-biphenylboronic acid and 8 amino-5-chloro-7-phenylpyrido[3,4-d]- pyridazine-1,4(2H,3H)dione. Generally, the intensity of light emission in the presence of peroxidase was higher with the pyridopyridazines than with sodium luminol. However, the blank light emission was much lower with sodium luminol than with the pyridopyridazines. A synergistic enhancement phenomenon was demonstrated for the combination of a 4-iodophenol and a 4-biphenylboronic acid enhancer with 8-amino-5-chloro-7-phenylpyrido[3,4 d]pyridazine-1,4(2H,3H) dione. The combination of these two enhancers produced a light emission intensity in an assay for 5 fmol of peroxidase that was 25% higher than expected from the sum of the individual light intensities. PMID- 8686493 TI - Competitive chemiluminescent immunoassay for estradiol using an N-functionalized acridinium ester. AB - We have compared three competitive chemiluminescent immunoassays (CLIA) for estradiol (E2) using an N-functionalized acridinium ester (AE). The assays were a standard competitive assay using immobilized antibody and directly labeled antigen (type A), an immobilized antibody and indirectly labeled antigen (type B), and an immobilized antigen and labeled antibody (type C). In an antibody immobilized system, the assay using both AE- and E2-labeled thyroglobulin as a tracer (type B) was more sensitive than that using AE directly coupled with E2 (type A). Subsequently, a comparison of the antibody-immobilized system (type B) and an antigen-immobilized system (type C) showed that the latter was slightly more sensitive than the former. The sensitivity of the CLIA (type C) was similar or superior to commercially available CLIA or radioimmunoassays for E2. Thus, the N-functionalized AE proved to be a useful labeling reagent for a competitive CLIA with high sensitivity. PMID- 8686494 TI - Expression of the Renilla reniformis luciferase gene in mammalian cells. AB - A cDNA encoding the Renilla reniformis luciferase was expressed in similan and murine cells in a transient and stable manner, respectively. Light emission catalyzed by luciferase was detected from transfected cells both in vitro and in vivo. This work establishes the Renilla luciferase gene as a new efficient marker of gene expression in mammalian cells. PMID- 8686495 TI - Bioluminescence and chemiluminescence literature. The 1995 literature. Part 2. PMID- 8686496 TI - Chemiluminescence emission during reactions between superoxide and selected aliphatic and aromatic halocarbons in aprotic media. AB - The reactions between superoxide free radical anion (.O2-) with the halocarbons CCl4. CHCl3, BrCH2CH2Br(EDB), decachlora-biphenyl (DCBP), and 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) in dimethyl sulphoxide (DMSO) results in the emission of chemiluminescence (CL). The chemiluminescence reactions are characterized as having biphasic second order kinetics, CL wavelengths between 350 nm and 650 nm, and exhibiting perturbation by chemicals reactive with singlet oxygen. These data suggest that singlet oxygen species are the excited state responsible for the light emissions. Polarographic studies confirm .O2- consumption and halide release in the reactions, while gas liquid chromatography and NBT reduction demonstrate the decomposition of the halocarbons into products. A chemiluminescent reaction mechanism is proposed involving reductive dehalogenation of the halocarbons and the generation of singlet oxygen. The significance of singlet oxygen generation is discussed with respect to a general mechanism for explaining the rapid initiation of lipid peroxidative membrane damage in halocarbon toxigenicity in animal and plant tissues. PMID- 8686497 TI - The skeleton as an ion exchange system: implications for the role of acid-base imbalance in the genesis of osteoporosis. PMID- 8686498 TI - Energy-shunting external hip protector attenuates the peak femoral impact force below the theoretical fracture threshold: an in vitro biomechanical study under falling conditions of the elderly. AB - The first objective of this study was to design a hip protector that would effectively attenuate and shunt away from the greater trochanter the impact energies created in typical falls of the elderly. As the shock absorption material, the protector included the 12 mm-thick Plastazote, which was found to be the most efficient energy-absorbing material in our previous in vitro biomechanical tests. With an anatomically designed semiflexible outer shield of the protector (high density polyethylene), the impact surface was increased and the impact energy shunted away from the greater trochanter. In the second phase of the study, we determined the force attenuation capacity of this device in realistic (in vitro) falling conditions of the elderly. With the impact force of 6940 N used (a typical hip impact force measured in in vitro falling tests), the trochanteric soft tissue (25 mm-thick polyethylene foam) attenuated the peak femoral impact force to 5590 N and the tested protector to 1040 N. In the second series of this experiment, the peak femoral impact force was set to be so high (13,130 N) that the protector, if effective, should prevent the hip fracture in almost all cases. The trochanteric soft tissue attenuated this peak impact force to 10,400 N and the tested protector to 1810 N. Thus, the force received by the proximal femur still remained clearly below 4170 N, the average force required to fracture in vitro the proximal femur of the elderly in a fall loading configuration. In conclusion, our test results suggest that an anatomically designed energy-shunting and energy-absorbing hip protector can provide an effective impact force attenuation in typical falling conditions of the elderly. However, the efficacy of the protector in the prevention of hip fractures can only be evaluated in randomized clinical trials. PMID- 8686499 TI - Regulation of COL1A1 expression in type I collagen producing tissues: identification of a 49 base pair region which is required for transgene expression in bone of transgenic mice. AB - Previous deletion studies using a series of COL1A1-CAT fusion genes have indicated that the 625 bp region of the COL1A1 upstream promoter between -2295 and -1670 bp is required for high levels of expression in bone, tendon, and skin of transgenic mice. To further define the important sequences within this region, a new series of deletion constructs extending to -1997, -1794, -1763, and -1719 bp has been analyzed in transgenic mice. Transgene activity, determined by measuring CAT activity in tissue extracts of 6- to 8-day-old transgenic mouse calvariae, remains high for all the new deletion constructs and drops to undetectable levels in calvariae containing the -1670 bp construct. These results indicate that the 49 bp region of the COL1A1 promoter between -1719 and -1670 bp is required for high COL1A1 expression in bone. Although deletion of the same region caused a substantial reduction of promoter activity in tail tendon, the construct extending to -1670 bp is still expressed in this tissue. However, further deletion of the promoter to -944 bp abolished activity in tendon. Gel mobility shift studies identified a protein in calvarial nuclear extracts that is not found in tendon nuclear extracts, which binds within this 49 bp region. Our study has delineated sequences in the COL1A1 promoter required for expression of the COL1A1 gene in high type I collagen-producing tissues, and suggests that different cis elements control expression of the COL1A1 gene in bone and tendon. PMID- 8686500 TI - Three-dimensional nuclear magnetic resonance microimaging of trabecular bone. AB - The conventional approach to measuring structural parameters in trabecular bone rests on stereology from optical images, derived from sections of embedded bone. In order to provide data that are statistically representative of a sufficiently large volume, multiple sections need to be analyzed in each of the three orthogonal planes. In this work, an alternative technique is presented which is based on three-dimensional (3D) volumetric proton nuclear magnetic resonance (NMR) microimaging. The method presented provides from 9 x 9 x 4 mm3 volumes of defatted bone specimens in 15-20 minutes scan time at isotropic resolution corresponding to (78 microm)3 voxel size. Surface-rendered images of bovine and human trabecular bone are shown and an algorithm was developed and implemented for determining the orientation and magnitude of the principle axes of the mean intercept length tensor. PMID- 8686501 TI - Osteoblasts are regulated by the cellular adhesion through ICAM-1 and VCAM-1. AB - The two major processes of bone metabolism--bone formation and resorption--are regulated by cellular interactions. Osteoblasts and osteoclasts play a significant role in bone metabolism, which is known to be regulated by local soluble factors and systemic hormones. Although bone is a heterogeneous tissue comprised of osteogenic and hematopoietic cells, cellular adhesion of osteoblasts and its regulation remains to be understood. We first demonstrate that cellular adhesion by which osteoblasts communicate with opposing cells in bone milieu is involved in the osteoblast activation: (a) purified human osteoblasts obtained from osteoarthritis patients expressed particular adhesion molecules, ICAM-1, VCAM-1, and LFA-3; (b) toe osteoblasts adhered to T cells which were used as representative adhesive partners, since T cells possess all the receptors to these adhesion molecules; (c) mRNA transcription and secretion of IL-1beta and IL 6 were induced in the osteoblasts by the cellular adhesion to T cells and they were reduced by interrupting the adhesion; (d) cross-linking of ICAM-1 and VCAM-1 on the osteoblasts induced IL-6 secretion from the osteoblasts. These results indicate that osteoblasts adhere to opposing cells through particular adhesion molecules on their surface and that the adhesion molecules on the osteoblasts not only function as glue with opposing partners but transduce activation signals that facilitate the production of bone-resorbing cytokines. We propose that cellular adhesion of osteoblasts as well as soluble factors is significant for the regulation of bone metabolism. PMID- 8686502 TI - Intermittent treatment with human parathyroid hormone (hPTH[1-34]) increased trabecular bone volume but not connectivity in osteopenic rats. AB - Previous studies have determined that intermittent parathyroid hormone (PTH) therapy increases bone mass and improves biomechanical strength in osteopenic animal models. The purpose of this investigation was to determine if intermittent human parathyroid hormone (hPTH[1-34]) therapy increased trabecular bone volume and connectivity in a rat model of established osteopenia using three-dimensional (3D) ex vivo in situ morphometry by X-ray tomographic methods (XTM). Six-month old retired Sprague-Dawley breeder rats were used. Thirty animals were ovariectomized (OVX) and six were Sham operated. On day 56, post-OVX, a prePTH treatment OVX groups was sacrificed. The remaining OVX animals were randomized into four groups of six animals each, given injections 5 out of every 7 days for 28 days of either vehicle or hPTH(1-34) at 4, 40, or 400 microg/kg of body weight (BW)/day and were sacrificed on day 84 post-OVX. At sacrifice, the left proximal tibias were harvested for XTM scans. hPTH(1-34) at medium and high doses significantly increased trabecular bone volume and trabecular thickness compared with ovariectomized animals treated with vehicle (p<0.05). The trabecular bone volume was equal to or greater than the Sham-operated animals in both hPTH(1-34) 40 and 400 microg/kg of BW treatment groups. Trabecular bone connectivity decreased by nearly 50% compared to the S ham-operated group at day 84 post-OVX and did not increase with any of the hPTH(1-34) treatments. Intermittent hPTH(1 34) treatment is osteopenic OVX rats increased trabecular bone volume to control levels or higher by thickening existing trabeculae. Human PTH(1-34) did not re establish connectivity when therapy was started after 50% of the trabecular connectivity was lost. We hypothesize that to re-establish trabecular connectivity, a therapeutic intervention would have to be given before a significant distance between trabeculae has developed. Further studies will need to be done to refute or confirm our hypothesis. PMID- 8686503 TI - Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. AB - Bisphosphonates inhibit bone resorption and are therapeutically effective in diseases of increased bone turnover, such as Paget's disease and hypercalcemia of malignancy. The mechanisms by which they act remain unclear. Proposed mechanisms include inhibition of osteoclast formation from precursors and inhibitory or toxic effect on mature osteoclasts. We have developed a new in vitro model to study osteoclast survival and in this paper present in vitro and in vivo evidence that may explain both the observed reduction in osteoclast numbers and in bone resorption by mature osteoclasts, namely that bisphosphonates induce programmed cell death (apoptosis). Three bisphosphonates (risedronate, pamidronate, and clodronate) caused a 4- to 24-fold increase in the proportion of osteoclasts showing the characteristic morphology of apoptosis in vitro. This observation was confirmed in vivo in normal mice, in mice with increased bone resorption, and in nude mice with osteolytic cancer metastases, with similar-fold increases to those observed in vitro. Of the three compounds, risedronate, the most potent inhibitor of bone resorption in vivo, was the strongest inducer of osteoclast apoptosis in vitro. Osteoclast apoptosis may therefore be a major mechanism whereby bisphosphonates reduce osteoclast numbers and activity, and induction of apoptosis could be a therapeutic goal for new antiosteoclast drugs. PMID- 8686504 TI - Short-term effect of testosterone treatment on reduced bone density in boys with constitutional delay of puberty. AB - We studied bone mineral content (BMC), bone mineral density (BMD), cortical thickness/total width (CT/TW) ratio and cortical area/total area (CA/TA) ratio in boys with constitutional delay of puberty and the effect of short-term testosterone treatment on bone mass. Seventeen boys (age 13.1-15.8 years) who met the family history and the clinical criteria of constitutional delay of puberty were selected and enrolled in the study. All subjects were eating a diet assuring an adequate intake of calories and calcium. A subset of 8 boys (group A) was treated with testosterone depot (100 mg/month x 6 months) while 9 boys (group B) were not. At inclusion, BMC and BMD were reduced in the patients according to their chronological age (BMC -4.04 +/- 1.34 standard deviation scores [SDS]; BMD 2.95 +/- 0.56 SDS), statural age (BMC -1.75 +/- 0.79 SDS; BMD -1.69 +/- 0.78 SDS), and bone age (BMC -1.80 +/- 0.65 SDS; BMD -1.86 +/- 0.68 SDS). No significant differences between the groups were found (group A: BMC 0.480 +/- 0.57 g/cm, BMD 0.488 +/- 0.037 g/cm2, CT/TW ratio 0.43 +/- 0.4, CA/TA ratio 0.68 +/- 0.04; group B: BMC 0.476 +/- 0.060, p = NS vs. group A; BMD 0.491 +/- 0.036 g/cm2, p = NS vs. group A). At 12 months of follow-up, BMC, BMD, CT/TW ratio, and CA/TA ratio significantly increased in group A (BMC 0.70 +/- 0.13 g/cm, delta +41.1 +/- 28.8%, p < 0.003 vs. 0 month; BMD 0.617 +/- 0.082 g/cm2, delta +26.2 +/ 13.6%, p < 0.005 vs. 0 month; CT/TW ratio 0.52 +/- 0.05, delta +20.59 +/- 10.65%, p < 0.001 vs. 0 month; CA/TA ratio 0.77 +/- 0.05 vs. 0 month; CT/TW ratio 13.60 +/- 6.65%, p < 0.004 vs 0 month), but not in group B (BMC: 0.48 +/- 0.05 g/cm; delta +5.1 7.8%, p = NS vs. 00 month; BMD: 0.492 +/- 0.037 g/cm2; delta +0.54 +/- 8.7%, p = NS vs. 0 month; CT/TW ratio 0.44 +/- 0.04, delta +4.04 +/- 6.75%, p = NS vs. 0 month; CA/TA ratio 0.68 +/- 0.05, delta +2.39 +/- 5.90%, p = NS vs. 0 month). We conclude that boys with constitutional delay of puberty have reduced BMC and BMD. The delay in statural and bone ages did not totally account for the decreased bone mass. Testosterone treatment for 6 months significantly increased BMC, BMD, CT/TW ratio, and CA/TA ratio in these patients, but definitive conclusions on the efficacy of the treatment in improving adult bone mass can be drawn only when our patients reach early childhood. PMID- 8686505 TI - Monoclonal antibodies recognize antigen expressed by osteoblasts. AB - A marrow stromal osteogenic cell line (MBA-15) was used to create monoclonal antibodies (MoAbs). In this study, we describe a series of MoAbs for mouse marrow stroma (MMS) (MMS-25/17, MMS-85/12, MMS-302/40, and MMS-319/4) that recognized antigens expressed by stromal cells including osteoblastic cells. The MoAbs were screened against various cell and tissue types. MMS-85/12 was positive in detecting an antigen that was highly abundant in osteoblastic cells and primary adherent bone marrow cultures (BMC) but was negative for the marrow adipocytes copartner. The MMS-85/12 MoAb is an IgGl immunoglobulin. The immunohistochemical staining pattern is suggestive of the antigen being associated with the osteoblasts' plasma membrane and with the extracellular matrix constituent secreted by these cells. Western blotting and immunoprecipitation indicated that the antigen that was recognized by MMS-85/12 apparently had a molecular weight of 84 dD. PMID- 8686506 TI - Inhomogeneity in body fat distribution may result in inaccuracy in the measurement of vertebral bone mass. AB - When bone mineral content (BMC) is measured by dual X-ray absorptiometry (DXA), the X-ray beam is attenuated by bone and soft tissue. Since the component of the attenuation caused by the soft tissue overlying bone cannot be measured, the attenuation caused by soft tissue adjacent to bone is measured and is used in the calculation of BMC. the assumption underlying this approach is that the amount and composition of this adjacent soft tissue is the same as overlying bone. The aim of this study was to examine the validity of this assumption by determining whether fat distribution over and adjacent to bone differ and whether this introduces accuracy errors in the measurement of BMC by postero-anterior (PA) and lateral scanning. BMC (posterior processes plus vertebral body, g) of the third lumbar vertebra was 17.3 +/- 0.7 by PA and 17. +/- 0.7 by lateral scanning in 27 premenopausal women (p = NS), but 2.7 g or 20% higher by PA than scanning in 27 postmenopausal women (14.4 +/- 0.7, 11.7 +/- 0.5, p<0.01). Thus, the respective diminutions across age by PA scanning was about half that by lateral scanning (16.8 +/- 3.9%, 31.2 +/- 3.0%, p<0.01). Percent fat in the soft tissue baseline (anterior to bone, ST-ant) used to derive BMC by lateral scanning by 2.6 +/- 0.7% in premenopausal women and 7.5 +/- 1.0% in postmenopausal women (both p<0.01). After adjusting for these differences in percent fat, BMC by PA and lateral scanning no longer differed. PMID- 8686507 TI - Pretreatment with low doses of norethindrone potentiates the osteogenic effects of fluoride on human osteosarcoma cells. AB - We recently reported that picomolar doses of norethindrone (NET), a synthetic analog of 19-nortestosterone, significantly stimulated human TE85 osteosarcoma cell proliferation, differentiation, and activity in vitro. In the present study, we investigated the possibility that NET interacts with another osteogenic agent, i.e., fluoride, to stimulate human TE85 osteosarcoma cell proliferation, differentiation, and activities. Bone cell proliferation was measured by the stimulation in [3H]thymidine incorporation. Differentiation was monitored by the increase in alkaline phosphatase-specific activity. Osteoblastic activity was assessed by the stimulations in collagen synthesis and in osteocalcin secretion (in the presence of 1 nM 1,25-dihydroxyvitamin D3). When the human TE85 cells were incubated with mitogenic doses of NET and fluoride concurrently, the stimulatory effects of the two agents on these parameters exhibited no significant interaction. The enhancing effect of NET on the osteogenic effect of fluoride was not due to a shift of the fluoride dose response curve. Pretreatment with NET for 24 h followed by a treatment with a mitogenic dose (i.e., 100 microM) of fluoride for an additional 24 h significantly and synergistically potentiated the effects of fluoride on the [3H]thymidine incorporation, alkaline phosphatase-specific activity, collagen synthesis, and osteocalcin secretion, compared with those with the subsequent vehicle (0.05% ethanol) treatments. In contrast, pretreatment with fluoride for 24 h before the addition of NET for 24 h did not produce significant synergistic stimulations in the test parameters. Pretreatment of TE85 cells with the same doses of dihydrotestosterone or progesterone prior to treatment with fluoride under the same conditions did not induce synergistic potentiation of fluoride in [3H]thymidine incorporation, suggesting that the synergistic interaction with fluoride is probably not a common property of anabolic sex steroids. In summary, we found that: (1) the osteogenic effects of fluoride and NET were additive when cells were treated with both agents concurrently; (2) a 24-h pretreatment with picomolar doses of NET potentiated the osteogenic actions of fluoride in human TE85 osteosarcoma cells; and (3) pretreatment with NET produced a subsequent fluoride response that was synergistic. In conclusion, these findings led us to speculate that the osteogenic actions of NET and fluoride act through different mechanisms, and that NET at low doses has a permissive effect on the osteogenic effects of fluoride, and as such NET may be used in concert with fluoride to increase osteoblast proliferation, differentiation, and activity. PMID- 8686508 TI - In vitro and ex vivo evidence that estrogens suppress increased bone resorption induced by ovariectomy or PTH stimulation through an effect on osteoclastogenesis. AB - The mechanism of bone loss following cessation of ovarian function is still unclear. Several studies have shown an increase in bone turnover following natural or surgical menopause which could be prevented by estrogen administration. However, a direct effect of estrogen on osteoclast-mediated bone resorption has been difficult to demonstrate in vitro. Recent evidence suggested that estrogen withdrawal stimulates the production of bone resorbing cytokines, (e.g., interleukin-6, IL-6), which regulate osteoclast formation in the bone marrow microenvironment. We studied the effects of 17beta-estradiol on osteoclastic resorption, measured as 45calcium release, in vitro using cultures of fetal mouse long bone explants in which different stages of osteoclast development and activity are represented. 17beta-estradiol (10(-12)-10(-8) M) had no effect on basal or parathyroid hormone (PTH)-stimulated resorption of bone explants in which mature osteoclasts (radii/ulnae) or osteoclast precursors/progenitors (metacarpals) are present. 17beta-estradiol, however, inhibited significantly the PTH-stimulated resorption of osteoclast-free metacarpals cultured together with mouse fetal liver as a source of early osteoclast progenitors; basal resorption was also not inhibited in this system. In ex vivo studies we further examined the effects of culturing bone marrow cells from ovariectomized (OVX) or sham-operated mice as an osteoclastic source together with osteoclast-free metacarpals on 45calcium release and bone histology. Cocultures of the bone marrow cells from OVX mice with osteoclast-free metacarpals increased significantly the osteoclast formation and subsequent osteoclastic resorption compared with control cocultures. This increase in resorption was prevented by either treatment of the OVX animals with estrogen for 1 week starting immediately after OVX or injection of the OVX animals with an IL 6 neutralizing antibody. We conclude that estrogens suppress the increased osteoclastic resorption induced by PTH or OVX through an effect on hematopoietic progenitor cells of the osteoclast lineage. Furthermore our data suggest that IL 6 is involved in the increase in osteoclastic resorption following OVX. PMID- 8686509 TI - Effect of menopause on femoral and vertebral bone loss. AB - The aim of this study was to investigate the effect of menopause on bone loss in the proximal femur and the lumbar spine. The rates of change in bone mineral density (BMD) were measured longitudinally by dual X-ray absorptiometry (DXA) at the femoral neck (FN), Ward's triangle (WT), and trochanter (TR) together with the lumbar spine in 81 healthy postmenopausal women (45-65 years of age) who had passed a natural menopause, 6 months to 12 years before. A significant correlation between the rate of change and interval since menopause was evidenced. The best fit of the data was a binomial function of interval since menopause at the spine, FN, and WT and a simple linear regression at TR level. At each skeletal site, the rate of bone loss (mean +/- SD) was significantly different (p<0.05) and twice as high in women who were between 6 months and 2 years postmenopausal at enrollment (FN, -1.82 +/- 1.1%; WT, -2.43 +/- 1.7%; TR, 1.12 +/- 1.7%) than in those who were beyond 5 years of menopause (FN, -0.48 +/- 0.8%; WT, -0.68 +/- 2.1% TR, 0.41 +/- 1.2%). A poor correlation (r = 0.39 - 0.42, p<0.001) was found between the rate of vertebral and that of femoral postmenopausal bone loss. This study demonstrates that menopause is associated with a rapid and transient bone loss in BMD of the proximal femur, which declines with time after 3 years. These data suggest that therapy should be initiated as early as possible after menopause to prevent bone loss. PMID- 8686510 TI - Evidence for interrupted bone resorption in human iliac cancellous bone. AB - Bone resorption and formation are coupled both in time and space and may occur simultaneously in the same remodeling unit. A number of studies have shown that the formative phase of the remodeling sequence may undergo temporary interruptions prior to completion and it is possible that bone resorption may be subject to similar interruptions. We have investigated this hypothesis by studying the distribution of eroded depth in resorption cavities in human cancellous bone. Eroded depth was assessed in iliac crest cancellous bone from 41 normal healthy subjects using a cubic spline curve fitting technique. The distribution of mean eroded depths was skewed to the right. Comparison of the observed distribution with an expected distribution, which was calculated from previously published data and assumes resorption begins rapidly and slows as it approaches completion, showed a significantly greater proportion of shallower cavities than expected (p<0001). Similarly, comparison of observed and uniform distributions, which assumes a constant rate of resorption throughout the erosion period, also showed a significantly greater proportion of smaller cavities (p<0.01). In subjects aged less than 39 years, there were fewer small cavities than in those aged 40-59 years. In addition, there was some evidence that females of 40-59 years had a proportionately greater number of smaller cavities than males; however, there were no differences in other age groups. Our results demonstrate a significantly greater proportion of smaller resorption cavities than would be expected from current models of bone remodeling and are consistent with the hypothesis that resorption undergoes temporary interruptions and/or permanent arrest during the process of bone remodeling. PMID- 8686511 TI - Aging changes mechanical loading thresholds for bone formation in rats. AB - The effect of aging on the mechanical loading thresholds for osteogenesis was investigated in rats. We applied mechanical loads varying from 30 to 64 N to the tibiae of 43 19-month-old rats using a four-point bending apparatus. Bone formation rates were measured on the periosteal and endocortical surfaces of the tibial midshaft using double-label histomorphometry. Bone formation rates from the old rats were compared with results from adult (9-month-old) rats that we reported earlier.(4) Bone formation on the periosteal surface of the old rats was predominantly woven-fibered. Periosteal bone formation was observed in a lower percentage of the old rats compared with the younger adult rats for applied loads of 40 N and greater (59% old, 100% adult). However, in the old rats that formed woven bone there were no significant differences in woven bone area (p=0.1) or surface (p=0.24) compared with younger adults. Therefore, the periosteum of old rats had a higher threshold for activation by mechanical loading, but after activation occurred, the cells had the same capacity to form woven bone as younger adult animals. On the endocortical surface, relative bone formation rates in old rats showed a marginal (p=0.06) increase in response to an applied load of 64 N but was not increased at lower loads. The relative bone formation rate in the old rats was over 16-fold less than that reported for the younger adult rats at an applied load of 64 N and the relative bone forming surface in old rats in this study was 5-fold less than it was younger rats under similar loading conditions. In the younger adult rats, a mechanical threshold for lamellar bone formation of 1050 microstrain was calculated for the endocortical bone surface. The old rats required over 1700 microstrain on the endocortical surface before bone formation was increased. The data suggest that both the periosteal and endocortical surfaces of the tibiae of older rats are less responsive to mechanical stimuli. PMID- 8686512 TI - The bone mineral status of patients with Marfan syndrome. AB - Osteopenia at the hip and low total body calcium content have been reported in women with Marfan syndrome. Using dual X-ray absorptiometry (DXA), we evaluated the lumbar spine L2-L4 and proximal femur bone mineral density (BMD,/cm2) in 32 women and 16 children with Marfan syndrome. The women were 38 +/- 10 (SD) years old (23-58 years); their mean height was 178.7 +/- 8 cm. The children (9 boys and girls were 9.9-17.5 years old. Children were tall for their ages but of normal weight. All subjects were moderately active, without previous nontraumatic fracture. In the women, BMD was reduced at L2-L4, femoral neck (fnk), trochanter (tr), and intertrochanter (intr) (p < 0.0001-0.006), compared with age-predicted values. Z scores for L2-L4 and for the fnk, tr, and intr, were -0.59 +/- 1.06, 1.25 +/- 0.99,-1.03 +/- 0.91, respectively. The average hip axis length (HAL) of 11.5 +/- 0.093 cm was at the 80th percentile for women. No significant change was observed in 1 year follow-up BMD measurements in 13 women (fnk = -0.23 +/- 2.3%/year; L2-L4 = -0.43 +/- 1.57%/year). In Marfan children, BMD correlated with age, height, and pubertal development. Femoral neck BMG was reduced (Z = -0.74 +/ 1.22,p < 0.05) with a nonsignificant trend toward decreased BMD at L2-L4 (Z = 33 +/- 1.48). Resorption markers in Marfan women were normal and did not correlate with bone status. We conclude that women with Marfan syndrome have both axial and peripheral osteopenia as well as an increased HAL. This combination of findings likely increases substantially their long-term risk for hip fracture. Presence of osteopenia in Marfan children indicates that the skeletal deficits of Marfan syndrome may reflect inadequate bone acquisition. PMID- 8686513 TI - Bone mineral metabolism in T lymphocyte-deficient and -replete strains of rat. AB - The immune and skeletal systems are known to interact. We have repeatedly shown that in contrast to in vitro data, the administration of T lymphocyte immunosuppressants, such as cyclosporin A, leads to an increase in bone resorption and a high turnover osteopenia. The purpose of this study was to characterize the bone metabolism of the T lymphocyte deficient Rowett athymic homozygous (rnu/rnu) nude rat. We wished to determine whether these rats share the bone abnormalities of cyclosporin A-treated rats. Eleven 10-week-old Sprague Dawley rats and 12 similarly aged nude rats were studied over a 4-week period. Metaphyseal cancellous bone histomorphometry was similar in the two groups of rats and only differed with regard to percentage eroded perimeter (lower in nude rats, p = 0.0008) and longitudinal growth rate (49% lower in nude rats, p < 0.001). The nude rats had less body mass (p < 0.001) but nevertheless gained the same percentage of their body weight over the study period. The athymic rats had lower levels of serum, 1,25-dihydroxyvitamin D (p < 0.014) and serum osteocalcin(p < 0.009), and at the age of 14 weeks the nude rats had lower concentrations of serum creatinine (p = 0.001) and blood ionized calcium (p = 0.0002), yet serum PTH was similar throughout. RNA isolated from the contralateral tibias revealed that the nude group had lower steady-state levels of osteocalcin mRNA despite similar rates of bone formation. In its entirety, the data suggest that T cell deficiency per se is not necessarily associated with high turnover osteopenia. PMID- 8686514 TI - Assessment of the skeletal status by peripheral quantitative computed tomography of the forearm: short-term precision in vivo and comparison to dual X-ray absorptiometry. AB - In order to assess precision of peripheral quantitative computed tomography (pQCT), duplicate bone mineral density (BMD) measurements at the radius were performed in 20 healthy premenopausal, 20 healthy postmenopausal, and 20 osteoporotic postmenopausal women using a Stratec XCT-960 system. The short-term reproductibility in vivo for the total, trabecular, and cortical regions of interest (ROI) was expressed as the absolute precision error (standard deviation, SD) and as the relative precision error (SD/mean x 100, or coefficient of variation, CV, in %). Reproducibility in vivo was good in all volunteers but was influenced by the study group and the ROI. The precision error for trabecular BMD was 3 mg/cm3, or about 1.6%. This is large relative to the aging decrease of 0.22%/year, or to the difference (12 mg/cm3, or 7%) between osteoporotic women and postmenopausal controls. In order to compare pQCT to dual X-ray absorptiometry (DXA) at the forearm and at the lumbar spine (L1-L4), 40 premenopausal healthy controls, 40 postmenopausal healthy controls, and 35 postmenopausal osteoporotic women were assessed. DXA measurements performed at the ultradistal, middistal, 1/3, and total ROI of the radius showed only moderate correlations between r = 0.38--0.75, r = 0.27--0.64, and r = 0.38--0.53 for the comparison versus pQCT total BMD, versus pQCT trabecular BMD, and versus pQCT cortical BMD, respectively. Correlations of DXA at the lumbar spine and pQCT were between r = 0.18 and 0.44. DXA at radius and spine was able to discriminate between post- menopausal controls and osteoporotic women (p = 0.001--.004),but BMD measurements by pQCT did not show this ability (p = 0.15--0.52). However, two nonstandard pQCT parameters, namely the surface area of the cortical bone and the cortical BMC were factors that discriminated well between these two groups (p = 0.002, p = 0.005, respectively). These pQCT parameters also yielded the highest relative annual changes in pre- and post-menopausal control subjects. The measurement of cortical bone in the distal radius proved to be a good predictor of vertebral fracture status and was a good indicator of age-related skeletal change. Our data emphasize the importance of cortical measurements when using pQCT of the radius to assess osteoporosis. PMID- 8686515 TI - Structural and chemical characteristics and maturation of the calcium-phosphate crystals formed during the calcification of the organic matrix synthesized by chicken osteoblasts in cell culture. AB - The calcium-phosphate (CA-P) crystals formed in the extracellular organic matrix synthesized by chicken osteoblasts in cell culture were examined after 30, 40, and 60 days of culture by a number of physical and chemical techniques including chemical analyses, X-ray diffraction, transmission electron microscopy of isolated crystals, and resolution-enhanced Fourier transform infrared spectroscopy. The data reveal that the solid inorganic calcium-phosphate phase consists of a very poorly crystalline apatite, having a low carbonate content and containing acid phosphate groups. The chemical and structural characteristics are generally similar to the apatite crystals found in young newly synthesized bone but there were small but significant differences found. The major significant differences noted were the rate at which maturational changes occurred in the crystals formed in cell culture compared with those noted in vivo and in synthetic carbonate apatite crystals equilibrated with the same cell culture medium, and the persistence of labile groups, especially HPO4(-2) ions during a relatively long period of incubation. Despite extensive chemical efforts to degrade the organic constituents and to disperse the individual crystals isolated from the organic matrix constituents, a large proportion of the crystals were found to be organized in both loosely and densely packed relatively large roughly spherical aggregates. A few of the aggregates were organized in the form of fibrils with the crystals oriented with their c-axes roughly parallel to the long axes of the crystal aggregate. With briefer periods of chemical treatment, larger aggregates of crystals were occasionally observed in which there was a distinct axial periodicity of approximately 70 nm. In such collagen-crystal fragments, the crystals were well-oriented with their c-axis roughly parallel to the long axes of the aggregate similar to the organization and relationships between crystals and collagen fibrils in native bone. Isolated crystals were in the shape of thin plates. At the end of 30 days of culture, many of the crystals were clearly larger than those observed in native chick bone, except for those in the very youngest (7- to 8-day-old) embryos. At the end of 40 and 60 days of culture, the crystal habit remained as thin plates but the crystals were predominantly smaller, similar to those found in older embryo and postnatal chicken bone. The marked tendency of the crystals to form relatively large aggregates that resist dispersion by techniques that readily disperse the crystals of bone, and the presence of a significant number of larger crystals has also been observed in studies of calcified cartilage. Resolution enhanced FTIR spectroscopy revealed the presence of a high concentration of labile phosphate groups, especially after 30 days of culture and just after the plateau of mineralization is reached. PMID- 8686516 TI - Isolation of calcium-phosphate crystals of bone by non-aqueous methods at low temperature. AB - We have developed low temperature nonaqueous solution methods as well as low power plasma ashing for the degradation of the organic matrix of bone power which have permitted us to obtain bone crystals essentially free of organic matrix constituents without any significant change in their composition, overall structure, or internal short-range order. We have also been able to disperse the crystals, which has made it possible to examine the isolated crystals by X-ray diffraction and resolution-enhanced Fourier transform infrared (FTIR) spectroscopy and isolated single crystals by high resolution transmission electron microscopy (TEM) and electron diffraction. TEM of isolated single crystals of fish, chicken, mouse and bovine bone have clearly demonstrated that the crystals are very thin plates. No rod or needle-like crystals were observed in any of the bone samples in the four species studied including the earliest crystals deposited. Although there were variations in the size distribution of the crystals in the different species studied, in general the average crystal dimensions were very similar. PMID- 8686517 TI - Standardization of spine BMD measurements. PMID- 8686518 TI - Anatomical and technical aspects of the contralateral approach for multiple aneurysms. AB - Microsurgery of multiple aneurysms is still a controversial subject. In order to avoid the risk of rebleeding and the consequent increase in morbidity in such cases all aneurysms or at least as many aneurysms as possible should be treated in the first operative procedure. To reach that goal aneurysms located on the contralateral side should also be considered for clipping during the first operation. Between 1984 and 1994 a series of 51 patients harboring multiple aneurysms of which 55 aneurysms were located on the contralateral side of the craniotomy were operated at our institution. No mortality or morbidity could be directly ascribed to the aneurysm that was clipped contralaterally. Based on that series we have described the anatomical features, technical aspects and surgical difficulties of approaching bilateral aneurysms through the same craniotomy. PMID- 8686519 TI - Study on early re-rupture of intracranial aneurysms. AB - The prognosis of patients with early re-ruptured intracranial aneurysms is discouraging. We compared the data on patients suffering re-rupture before the onset of late vasospasm (Early-Re) with those suffering rebleeding thereafter (Late-Re). The operability in the Early-Re group was lower (p < 0.05) and the outcome less satisfactory than that of Late-Re group. Of the Early-Re patients, 83% had a re-rupture within 24 hours of the initial subarachnoid haemorrhage; moreover 46% of these experienced rebleeding within three hours of the initial bleeding. Cases in the Early-Re group tended to belong to Hunt-Hess grade III or IV on admission, of wide spread subarachnoid haemorrhage on CT and of "bump" type aneurysms on angiograms. Based on our experience we propose that early re-rupture may be attributable to the following factors: a gradual and progressive thinning of the wall of bump type aneurysms results in such a large laceration through the fundus of the aneurysm. Re-rupture may occur within a short period after the first rupture because the fibrin net covering the wide laceration cannot tolerate the slight increase in internal pressure within the aneurysmal dome. Therefore, in the patients of Hunt-Hess grade III or IV, conventional angiography, tight holding during CT examination and lumbar puncture, should be avoided during the first three hours after the first bleed. Although early direct operations on patients with high Hunt-Hess grades tend to produce an unsatisfactory outcome, we cannot help these patients with Early-Re without surgical treatment. Not only early direct operation but also first conservative treatment to control systolic blood pressure are very important in patients with Early-Re. PMID- 8686520 TI - Intra-operative monitoring by facial electromyographic responses during microvascular decompressive surgery for hemifacial spasm. AB - The facial electromyographic response was monitored intraoperatively in 40 patients with hemifacial spasm who were operated on by microvascular decompression of the facial nerve. All 40 patients showed an abnormal facial electromyographic response (lateral spread response) with a latency of about 10 msec after stimulation. The abnormal response resolved before decompression in 22, resolved immediately with decompression in 16, and failed to resolve in two. Of the 38 patients in whom the abnormal response disappeared during surgery, 36 were postoperatively free from hemifacial spasm and two had mild hemifacial spasm. The two patients in whom the lateral spread response did not disappear during surgery showed persistent hemifacial spasm. In conclusion. Disappearance of the lateral spread response during surgery correlated with the absence of hemifacial spasm in the early postoperative period. The prognosis of hemifacial spasm was good in cases in whom the lateral spread response disappeared. Therefore, the authors think that intra-operative facial electromyography is very useful in assessing the efficacy of microvascular decompression and in predicting the prognosis of hemifacial spasm. PMID- 8686521 TI - Electrophysiological investigation of hemifacial spasm: F-waves of the facial muscles. AB - In patients with hemifacial spasm (HFS), the spasm is due to cross-compression of the facial nerve by a blood vessel. There are currently two hypotheses for the mechanism of HFS: 1) the spasm is caused by ephaptic transmission and an increase in excitability at the site of compression; and 2) the spasm is caused by hyperexcitability in the facial nerve nucleus. In peripheral nerves, F-waves, which result from the backfiring of antidromically activated anterior horn cells, have been proposed as indices of proximal motoneuron conduction and anterior horn cell excitability. Enhancement of the F-waves indicates increased anterior horn cell excitability. We have therefore measured F-waves in the facial muscle of HFS patients in order to investigate the excitability of the facial nerve nucleus. The authors obtained facial nerve evoked responses from 20 HFS patients before microvascular decompression (MVD), 10 HFS patients after MVD and 10 healthy controls. The F-waves, obtained with surface electrodes from the mentalis muscle, were the second response after the M-wave. On the patient's spasm side, the F wave duration, F/M amplitude ratio and frequency of F-wave appearance significantly increased compared with those of the normal side or healthy controls; minimum latency and chronodispersion did not significantly differ between these groups. In patients whose spasm disappeared completely following MVD, the abnormal muscle response (lateral spread), which is a characteristic sign of HFS, and the enhancement of the F-wave eventually also disappeared. Because of the correlation between HFS and F-waves, the authors' study supports the hypothesis that the cause of HFS is hyperexcitability of the facial motonucleus. PMID- 8686522 TI - Intra-operative epidural morphine, fentanyl, and droperidol for control of pain after spinal surgery. A prospective, randomized, placebo-controlled, and double blind trial. AB - The present study was conducted to investigate the analgesic effects of intra operatively administered epidural morphine in patients undergoing surgery for lumbar disc disease. Three treatment groups were constituted: one with 5.0 mg morphine and 2.5 mg dehydrobenzperidol (DHB) in 10 ml physiological saline, one with 5.0 mg morphine and 0.1 mg fentanyl in the same amount of saline, and one placebo group with saline only. The test solution was injected epidurally via catheter after haemostasis and before closure of the wound. Sixty eight patients were randomly assigned to each of the three groups and subjected to a double blind evaluation. In the morphine/fentanyl and morphine/droperidol groups, significantly better analgesia was found as compared to the placebo group. No significant difference was found between the morphine/fentanyl and morphine/droperidol groups considering side effects of therapy, as well as duration and quality of analgesia. The side effects in the treatment groups were only slight and not significantly different from the placebo group. It was shown that additional epidural fentanyl offers no significant improvement of postoperative analgesia. No significant reduction of adverse effects could be found in the morphine/droperidol group compared to the morphine/fentanyl group. In conclusion, the intra-operative epidural application of morphine is a safe, effective and simple method for achieving sufficient analgesia in the first 24 hours after lumbar spinal surgery for disc disease. PMID- 8686523 TI - A critical assessment of clinical diagnosis of disc herniation in patients with monoradicular sciatica. AB - The diagnostic power or clinical parameters in the diagnosis of lumbar disc herniation in patients with monoradicular pain was evaluated in a prospective study with a 100% verification of the diagnosis. Eighty patients with monoradicular pain corresponding to the fifth lumbar or the first sacral nerve root were included. Pre-operatively a number of clinical parameters were recorded and compared to the intra-operative finding of a disc herniation. The parameters were analysed by receiver operating characteristic (ROC) curves. Results from the available literature were analysed by ROC curves for comparison. In 76% of the cases a disc herniation was discovered. The level of the disc herniation was correctly predicted in 93% of these cases by the location of the pain alone or supplemented by neurological signs. Apart from radicularly distributed pain, all parameters in the present study and in the literature had no or low diagnostic accuracy. Thus, in patients with monoradicular sciatica further clinical parameters do not add to the diagnosis of lumbar disc herniation. PMID- 8686524 TI - Colloid cyst of the third ventricle. Evaluation of 28 cases of colloid cyst of the third ventricle operated on by transcortical transventricular (25 cases) and transcallosal/transventricular (3 cases) approaches. AB - The clinical and x-ray features of 28 cases of colloid cyst of the third ventricle are described. Colloid cyst is one of the most favourable space occupying lesions of the brain for successful surgical removal, because an exact pre-operative diagnosis is possible. The surgical approach for colloid cyst of the third ventricle is discussed and the frequency of postoperative seizure is reviewed in 28 cases and compared with the literature. PMID- 8686525 TI - Immune infiltrates and cytokines in gliomas. AB - Frozen sections of 21 gliomas were analysed to characterize inflammatory infiltrating cells, HLA-DR antigen expression and cytokine secretion. Mononuclear cells infiltrating the tumours were mostly macrophages, which were detected in 100% of cases, and expressed HLA-DR antigens. Lymphocytes were less frequently seen and expressed the CD8 phenotype. Interleukin-1 beta (IL-1 beta) and Interleukin-6 (IL-6), two cytokines mainly produced by activated cells of the macrophage lineage, were demonstrated especially in neoplastic astrocytes. IL-1 beta immunoreactivity was detected in all tumours, and was prevalent in more anaplastic gliomas; IL-6 was found in anaplastic gliomas and in glioblastomas. IL 1 receptors were expressed by both infiltrating macrophages and neoplastic astrocytes in the gliomas analysed. These findings suggest that cytokine production in gliomas seems not related to immune reactions against the tumour and their synthesis by anaplastic astrocytes could follow an unregulated activation of many metabolic processes after neoplastic transformation. PMID- 8686526 TI - CSF neurotransmitter metabolites in comatose head injury patients during changes in their clinical state. AB - The main metabolites of noradrenaline, serotonin, and dopamine, methoxyhydroxyphenylglycol (MHPG), 5-hydroxyindole-acetic acid (5HIAA), and homovanillic acid (HVA), respectively, were assessed in CSF samples of patients in coma after severe head injury, the first days after the accident and again after an improvement (13 patients) or deterioration (7 patients) in their clinical state, evaluated by the score on the Glasgow Coma Scale. Improvement was accompanied by significant decreases in HVA and 5HIAA. In the patients who deteriorated, the levels of the three metabolites remained high. The results show that the increased turnover of CNS neurotransmitters in severe head injury normalizes during recovery. The use of noradrenaline, dopamine, and serotonin antagonists in brain injury experimental models may clarify the role of the increased biogenic amine turnover in the processes that lead to recovery. We propose relevant pharmacological intervention influencing neurotransmission in severe head injury. PMID- 8686527 TI - Application of transcranial Doppler sonography in surgical aspects of hypertensive putaminal haemorrhage. AB - From May 1992 to February 1993, 22 cases of hypertensive putaminal haemorrhage (HPH) treated at our hospital were serially measured with transcranial Doppler (TCD) sonography. Among them, 13 patients underwent surgical intervention (3 stereotaxic surgery and 10 craniotomies), and 9 were conservatively treated. Most of the patients of the two operative groups had larger haematomas and developed clinical and/or neurological deterioration, which was the indication for subsequent surgery. Therefore the groups represent different clinical and physiological entities. On admission, the peak MCA velocities (Vs) in the surgical group (stereotaxic and craniotomy) were significantly lower than those in the conservative group (mean +/- S.E.M.: 38.33 +/- 4.26 and 42.00 +/- 2.62 cm/sec vs. 57.22 +/- 3.23 cm/sec; p < 0.005, respectively). The surgical group also had significantly lower diastolic (Vd) and mean (Vm) velocities than those of the conservative group (p < 0.001). Rather, the admission pulsatility indices (PI = (Vs-Vd)/Vm) in the surgical group were significantly higher than those of the conservative group (mean +/- S.E.M.: 1.42 +/- 0.04 and 1.31 +/- 0.09 vs. 0.95 +/- 0.01; p < 0.005, respectively). Time course velocity curves reached a peak around the 3rd hospital day in all the 3 groups. The Glasgow coma scale (GCS) scores positively correlated with the mean MCA velocities (n = 22; r = 0.63, p < 0.005; y = 2.04 x + 8.74), but negatively with PI values on admission (n = 22; r = -0.53, p < 0.05; y = 1.68-0.053 x). On the 7th hospital day, 2 patients with peak MCA velocities below 50 cm/sec had an unfavourable outcome. All the 3 patients in the stereotaxic group had higher peripheral resistance, as compared with those in conservative craniotomy groups (mean +/- S.E.M.: 1.28 +/- 0.13 vs. 0.99 +/- 0.07 and 0.87 +/- 0.06; p < 0.05, respectively). Our study supports TCD as a safe and valid monitoring method in patients with HPH. "Compromised cerebral haemodynamic status" (Vs < 50 cm/sec, Vd < 15 cm/sec, Vm < 25 cm/sec, PI > 1.15) may offer an aid in the decision for surgical intervention in HPH. Postoperatively, patients who made a favourable recovery had a significant increment in the MCA velocities in contrast to those severely disabled, whose MCA velocities remained low. PMID- 8686528 TI - Cerebral haemodynamic considerations in obstructive carotid artery disease. AB - 46 subjects with obstructive carotid artery disease were investigated with transcranial Doppler ultrasonography. Their baseline blood velocities (V) in the middle, anterior and posterior cerebral artery (MCA, ACA and PCA) and in the extracranial internal carotid artery (ICA) were measured and the pulsatility index (PI) calculated for each vessel. Thereafter the vasomotor reserve in both MCAs was tested. Typical patterns of V, PI and vasomotor reactivity are presented. Arterial collaterals were recognized by their relatively increased velocities. We demonstrated a close association of the baseline variables V and PI and the total vasomotor reactivity (hypocapnic plus no, hypercapnic response) by calculating an index of Uhem related to the cerebrovascular tone. The Uhem index is expressed by: Uhem index = VMCA.PIMCA/VPCA.PIPCA The relationship between Uhem index and the total vasomotor reactivity seemed to correspond to a hyperbolic curve. The hyperbolic tangent of Uhem index and total vasomotor reactivity correlated highly significantly, r = 0.8203, p < 0.0001, n = 49, the best fit for the regression line was Y = -0.005 + Uhem index 51.3. On the 99% significance level an Uhem index > or = 0.94 indicated normal total cerebral vasomotor reactivity in contrast to an impaired reactivity when < or = 0.81. Findings in 20 patients investigated post hoc supported the validity of our concept. PMID- 8686529 TI - Increase of interleukin-6 plasma levels after elective craniotomy: influence of interleukin-10 and catecholamines. AB - Accidental and operative trauma are able to induce a systemic reaction of the organism characterized by fever, leukocytosis, catabolism, and an activation of the coagulation system. Interleukin-6 (IL-6) has been found to be an important mediator of this acute-phase response. In this study the influence of elective craniotomy on IL-6 plasma levels was evaluated. Blood samples were obtained from 20 patients undergoing elective craniotomy for vascular or tumorous diseases of the brain. IL-6 increased significantly (p < 0.05) from the pre-operative (0(0 5.4) pg/ml) to the intraoperative (180 min after beginning of surgery) time-point (10.6 (0-18.5) pg/ml). The maximum was reached on the first postoperative morning (13.9(4.3-45.0) pg/ml). Interleukin-10 (IL-10) is an anti-inflammatory cytokine which suppresses IL-6 synthesis in vitro in various cell lines. IL-10 plasma concentrations showed no alterations throughout the study period. Epinephrine plasma concentrations increased significantly from pre-operative values (15 (0 74) pg/ml) to the postoperative time-point (57(9-459) pg/ml). A 4.5-fold increase (p < 0.05) of norepinephrine plasma concentrations was found when comparing the data obtained 60 min after beginning of surgery with the data of the first postoperative morning. In monocytes, which are a major source of plasma IL-6, an elevation of intracellular cAMP stimulates the IL-6 synthesis. The postoperative maximum of IL-6 in plasma could be due to a release of catecholamines. In conclusion this study demonstrated an elevation of IL-6 plasma concentrations during and after elective craniotomy. Increased plasma catecholamine concentrations as well as a damage in the blood-brain barrier due to the surgical trauma with a spill-over of IL-6 from brain tissue into plasma could have contributed to this result. PMID- 8686530 TI - Acetazolamide produced blood flow velocity changes measured by laser Doppler in gerbils with reduced CBF. AB - The effect of acetazolamide on the cerebral blood flow was studied in gerbils with unilateral carotid ligation. According to the effect of ligation the animals were divided into three groups: first group-the reduction more than 70%, second CBF reduction 30-70% and the third group-CBF reduction less than 30%. The effect of acetazolamide administration was closely related to the effect of carotid ligation. More reduction of CBF was produced by carotid ligation, less increase of CBF after acetazolamide injection was noticed. The acetazolamide vascular reserve test was found a sensitive and useful method for detecting even modest reduction of vascular reserve in animals with slight - less than 30% CBF decrease following carotid ligation. PMID- 8686531 TI - Endothelial-cell injury of the basilar artery caused by ethanol infusion in dogs. AB - This study in mongrel dogs was designed to observe the effects of ethanol on both endothelial cells of the basilar artery and brain function. By use of sterile surgical technique, a super-selective catheter was placed in the proximal portion of the basilar artery in the dogs. Five dogs received 3 ml of 25% ethanol and 5 dogs received 3 ml of 50% of ethanol through the catheter over 2 minutes. The remaining 5 dogs received 3 ml of saline as a control. Auditory brain stem response (ABR) was monitored for 2 hours after ethanol infusion, and then perfusion-fixation was performed from the heart with 4% paraformaldehyde. The basilar artery was observed with scanning electron microscopy after routine procedures. The endothelial cells were intact in the control group. The 50% group showed a higher level of injury to the endothelium as well as a higher degree of platelet adhesion and fibrin clot formation compared with the 25% group. The extensive endothelial-cell damage subsequently caused thrombus formation. The ABR disappeared immediately after ethanol infusion in both ethanol groups, and recovered gradually in the 25% group, but did not re-appear during the time course of 2 hours in the 50% group. The ethanol less than 25% in concentration near the endothelium is considered to be safe as a transcatheter embolic agent with the attention to the central toxicity. PMID- 8686532 TI - Changes in lCBF, morphology and related parameters by fluid percussion injury. AB - We investigated the pathophysiological and morphological responses of anaesthetized rats to fluid percussion brain injury generated by an original midline fluid percussion injury device. Following different grades of trauma, lCBF was measured continuously in the right parietal cortex through a burr hole using laser Doppler flowmeter, and physiological parameters were monitored. Pathological changes also were evaluated microscopically. During the first 2 hours following trauma, we found four patterns of cerebral circulatory responses. Little measurable pathophysiological response occurred after percussion pulses of less than 1.33 atmospheres (atm). In animals subjected to pulses of greater than 4.30 atm, lCBF increased synchronously with blood pressure, and then both parameters decreased continuously until death. In animals subjected to pulses of 1.53 to 2.33 atm, trauma produced a transient increase in lCBF with no synchronous rise in blood pressure. In animals subjected to pulses of 2.70 to 3.87 atm, lCBF increased synchronously with blood pressure immediately following the injury, but had decreased markedly by 60 seconds and remained below the pre injury baseline. Blood pressure recovered to baseline within 4 minutes of the injury. The transient increase in lCBF occurred within 5 seconds following percussion pulses of greater than 1.53 atm and appeared to be independent of the rise in systemic blood pressure. Apnoea occurred in animals subjected to pulses of greater than 1.53 atm, and the duration of apnoea and mortality rate correlated with the magnitude of the applied injury. A power decrease in the electroencephalogram post-injury and a delay in its recovery, both depended on the magnitude of the injury with few regional differences in the beta-2 band power. The distribution and extent of blood-brain barrier disruption and small haemorrhages also correlated with the magnitude of the injury. The number of neurons decreased significantly in both hippocampi by 2 weeks following moderate trauma. The four patterns of lCBF changes demonstrated in the present study, as well as the other responses to injury, may be useful for studying graded models of various diffuse brain injuries. PMID- 8686533 TI - Neurosurgery and biology of meningiomas. Proceedings of a symposium. Salzburg, February 4-6, 1994. PMID- 8686535 TI - Evolution of different therapeutic strategies in the treatment of cranial dural arteriovenous fistulas--report of 30 cases. AB - 30 cases of cranial dural arteriovenous fistuals, treated between 1983 and 1992, are reported. Twelve presented with an aggressive clinical course including intracranial haemorrhage, progredient neurological deficit, medically intractable seizures, and cerebellar symptoms. The other 18 patients had a more benign clinical presentation with audible bruit, exophthalmus, chemosis, and cranial nerve dysfunction. One of the latter had symptoms of pseudotumour cerebri due to sinus occlusion with contralateral sinus stenosis. The most common location was at the transverse sinus, followed by the cavemous sinus, the tentorial ring, and the orbita. Four vessel angiography verified the diagnosis and demonstrated all fistulas, mainly supplied by branches of the external carotid artery. 16 of 18 benign lesions were treated by endovascular therapy alone. Two recent patients received adjuvant stereotactic radiosurgery. Among these 18 patients 2 remained untreated, one because of spontaneous fistula thrombosis prior to therapy and one because of poor medical condition. 12 of 16 treated benign dural fistulas were partially occluded. In 6 of them spontaneous fistula thrombosis occurred during the following months. Total endovascular obliteration was achieved in the remaining 4 patients. 7 of 12 aggressive fistulas were embolized only, one of them having additional radiosurgery. Two of them were totally obliterated and five partially. Surgery was performed in the remaining 5 aggressive fistulas. Complete microsurgical excision was achieved in 2 and partial in further two, who presented initially with a life-threatening intracerebral clot. In one early case ligation of the external carotid artery was done, which is now obsolete. Over all 20 of 28 treated patients became asymptomatic or improved clinically. 3 of the remaining 8 patients were unchanged, two deteriorated despite therapy, and 3 worsened after therapy. All of the latter complications occurred early in our series due to thromboembolic events during the procedure. One surgical patient suffered from a new facial nerve palsy postoperatively. Follow up time in all treated patients was between 1 and 139 months with a mean of 48,3 months. PMID- 8686534 TI - Complications after multidisciplinary treatment of cerebral arteriovenous malformations. AB - PATIENTS AND TECHNIQUES: A series of 67 patients treated for cerebral AVMs with a multidisciplinary approach is reported, with special attention for the complications due to treatment. The malformations were classified after the Spetzler Grading Scale, with 67% low-grade and 33% high-grade AVMs. Three modes of treatment were used: surgical resection, endovascular embolization, and radiosurgery (linear accelerator technique). The actual treatment was: resection alone (25% of cases), embolization plus resection (24%), embolization alone (21%), and radiosurgery (30%), either alone or after embolization or surgery. The following eradication rates were obtained: overall 80%, after resection (with or without embolization) 91%, after embolization alone 13%, after radiosurgery 87%. CLINICAL OUTCOME: The outcome was evaluated in terms of deterioration due to treatment. A deterioration after treatment occurred in 19 patients (28%), and was a minor deterioration (19%), a neurological deficit (4%), or death (4%). As far as the mode of treatment is concerned, surgical resection was responsible for deterioration (minor) in 17% of all cases operated upon. Radiosurgery was followed by a minor deterioration in 10% of irradiated cases. Embolization gave a complication in 25% of all embolized cases (minor or neurological deficit, or death). The mechanism of the complications was: resection or manipulation of an eloquent area during surgery, radionecrosis after radiosurgery, ischaemia and haemorrhage (50% each) following embolization. In most cases of haemorrhage due to embolization, occlusion of the main venous drainage could be demonstrated. DISCUSSION: The haemodynamic disturbances to AVMs and to their treatment are reviewed in the literature. The main haemodynamic mechanisms admitted at the beginning of a complication after treatment of cerebral AVMs are the normal perfusion pressure breakthrough syndrome, the disturbances of the venous drainage (venous overload or occlusive hyperaemia), and the retrograde thrombosis of the feeding arteries. CONCLUSIONS: According the authors' experience, the emphasis of treatment for cerebral AVMs has now shifted from surgical resection to endovascular embolization. One of the explanations is that endovascular techniques are now employed in the most difficult cases (high grade AVMs). As severe complications of endovascular embolization may also occur for low-grade malformations, the question arises whether surgery or radiosurgery should not be used first for this low-grade group even if embolization is feasible. PMID- 8686536 TI - Transpedicular reduction and stabilization for postlaminectomy lumbar instability. AB - This study retrospectively reviewed the outcomes of 17 patients with postlaminectomy lumbar instability treated by transpedicular reduction and stabilization. The criteria of instability were defined strictly by both the clinical symptom of "instability catch" and the radiological findings that fulfilled Nachemson's criteria. Low back pain and/or sciatica that interfered largely with the patients' work or quality of life were the indications for this treatment. All the operations were performed by one surgeon with the same spinal instrumentation system-"AO internal fixator". The follow-up period was between 16 and 36 months (mean 24 months). Face to face questionnaire revealed that this treatment modality is encouraging. Fourteen patients (82%) had complete or nearly complete relief from all the pre-operative symptoms. Two (12%) had partial relief of the symptoms that required a subsequent discectomy or wider laminectomy. Only one case (6%) with osteoporosis remained unchanged after the operation. On the follow-up radiographs, sixteen patients (94%) showed good alignment and solid arthrodesis of the treated motion segment. These radiological findings correlated quite well with the absence of the clinical symptom of "instability catch". A common, but acceptable, complication found in this series was a variable degree of low back stiffness secondary to the instrumentation. Fracture of the screw was found in one patient and pull out of the screw was found in another patient. However, they did not elicit detectable symptoms. Osteoporosis, concomitant disc herniation and persistent spinal stenosis at/or adjacent to the operated level were the three main factors that may contribute to unsatisfactory results secondary to this treatment. These problems remain to be resolved in the future. PMID- 8686537 TI - Direct anterior fixation of odontoid fractures with a hollow spreading screw system. AB - Direct fixation of odontoid fractures has the advantage of preserving rotation in the atlanto-axial motion segment. Early mobilisation of patients and minor intra operative trauma increase the value of this technique. The original screw method of Nakanishi, Magerl, and Bohler, was improved by Knoringer who designed a double threaded screw for direct fixation of dens axis fractures. He stated that double screwing is absolutely necessary in order to prevent rotation of fragments against each other. The purpose of the present study was to describe a new single screw for direct fixation of odontoid fractures, which is easy to place into the limited space of the dens axis and which offers enough rotational stability and sufficient compression of fracture fragments. The so-called hollow spreading screw system (HSS) consists of an outer hollow screw, a spreading insert, a toothed washer, an hexagonal nut, and a protective nut. Thirty-five patients with traumatic and arthritic odontoid fractures were treated using direct internal fixation with the HSS system. In 30 cases, there was a type-II-fracture, in 3 a shallow type-III-fracture, and in 2 a type-II-fracture with pseudarthrosis formation. Pre-operative neurological deficits were seen in 16 cases. No additional neurological deficits were caused by the surgical procedure. The bony fusion rate of fresh fractures in the presented series was 100%. With the HSS system, ca. 12% postoperative complications, such as slight reduction of head rotation or neck pain, were found. These results are virtually equal to the results of the double-screw technique. Since a relatively simple technical procedure is required for placement of the screw, the HSS system can be recommended in all cases of odontoid fractures suitable for direct anterior fixation. PMID- 8686538 TI - The interface between ionomer cement and bone in the porcine cervical spine. AB - The interface between bone and ionomer cement has been studied in twelve young adult pigs 1-6 months after anterior cervical discectomy, removal of adjacent end plates and grafting of the bone defect with ionomer cement. Methods used to study the interface were fluorescence microscopy, scanning electron microscopy, electron microprobe analysis and radiological investigation. The interface in all animals consisted of collagenous tissue. The amount of collagenous fibres was related to the amount of residual movement within the motion segment: animals undergoing anterior plating after reconstruction of the bone defect presented with more or less compactly organized collagenous tissue. Sequential fluorochromic marking of osteoid formation revealed a vital bone bed around the interface but no signs of direct bone apposition to the ionomer cement plug. No signs of toxicity or graft rejection were noted. Ionomer bone cement contrary to experimental and clinical experience induces the formation of a connective tissue layer of different density in the porcine cervical spine. PMID- 8686539 TI - Effect of CO2 laser on spinal epidural fibrosis. AB - In this study the effect of CO2 laser on spinal epidural fibrosis was examined in 24 guinea pigs which were divided into two groups. The first group was the control group, the second one the CO2 laser group. All animals had laminectomies at 3 levels. Re-exploration was performed three months after the laminectomy. In the second group the same procedure was performed but at the end of the re exploration, CO2 laser irradiation of the epidural fibrotic tissue was done. The wounds in both groups were closed again. Four months later all animals were sacrificed. For verification and quantification of scar formation (postoperative fibrosis) light microscopic examinations and determination of hydroxyproline were done, using Bergman's spectrophotometric method. The differences which were observed between the two groups were statistically significant (U : 134, P < 0.05). This study demonstrates the reducing effect of CO2 laser irradiation on epidural scar formation. The findings encourage its use as an alternative method of prevention of epidural fibrosis after spinal surgery. PMID- 8686540 TI - Biomechanical evaluation of subcortical versus bicortical screw purchase in anterior cervical plating. AB - The purpose of this in vitro study is to compare the stabilities provided by anterior cervical H-plating with screws purchased either subcortically or bicortically on porcine cervical spines. Nine porcine cervical spines (C3-C4) were challenged by 12 Nm in extension followed by 6 Nm in flexion in 6 consecutive steps, i.e., (1) when disc was intact, (2) after discectomy. Subsequently, a tricortical bone graft was inserted to simulate interbody fusion. Each specimen was tested again (3) when plated with 16 mm screws to purchase subcortically and (4) after cyclic loading (f = 0.5 Hz, n = 1000), (5) when plated with 30 mm screws to purchase bicortically and (6) after cyclic loading. Neutral zone and range of motion were parameters normalized for comparison. The results showed comparable stability in constructs plated with screws purchased either subcortically or bicortically before cyclic loading. Cyclic loading deteriorated construct-bone relation in both groups, yet bicortically purchased screws rendered additional stability in anterior cervical plating. PMID- 8686541 TI - Lesions of the corpus callosum in hydrocephalic patients with ventricular drainage--a CT-study. AB - Patients with ventricular drainage may develop lesions of the corpus callosum. In order to study frequency, pathogenesis and clinical relevance of callosal lesions, 301 routine CT investigations of 79 patients with ventricular drainage were reviewed. Hypodense lesions in the anterior part of the corpus callosum were observed in 7 patients with longstanding hydrocephalus of variable origin, in 2 cases the corpus callosum was slightly swollen. All 7 patients showed signs of forced ventricular drainage. The callosal alterations were clinically inapparent and potentially reversible. Knowledge of these lesions is important to avoid misinterpretation. PMID- 8686542 TI - Management of subarachnoid fluid collection in infants based on a long-term follow-up study. AB - We report the natural history and management of subarachnoid fluid collections in infants and their management based on a longterm follow-up study in 20 cases. These subarachnoid fluid collections were resolved spontaneously in 17 of 20 patients and only 3 by surgical intervention at the age of 2. In our 20 patients the natural history of subarachnoid fluid collection in infants was benign unless the patients sustained head trauma. Surgical treatment was performed in the cases where a subarachnoid fluid collection developed into a subdural haematoma. Head trauma may precipitate subdural haematoma in patients with subarachnoid fluid collection. All patients except one who underwent the placement of subdural peritoneal shunt, attained normal psychomotor development in time. During the follow-up period of 3 to 10 years after resolution of the fluid collection, no patient has had a recurrence once it resolved. PMID- 8686543 TI - One hundred and twenty-seven cases of acute subdural haematoma operated on. Correlation between CT scan findings and outcome. AB - Traumatic acute subdural haematoma is one of the most lethal of all head injuries: the mortality rate is reported to be between 50 and 90%. We reviewed the clinical records of 1688 head injured patients admitted to the Department of Neurosurgery at C.T.O. hospital between 1982 and 1992. In 127 cases (7,5%) CTscan on admission showed acute subdural haematoma requiring surgery because the midline shift was greater than 5 mm. The overall mortality rate was 57% and 23% had functional recovery. The following variables were assessed with regard to morbidity and mortality: mechanism of injury, age, neurological presentation, time delay from injury to intervention, CTscan finding on admission. GCS and CTscan findings were found to be the most important prognostic variable. Timing of operative intervention for clot removal with regard to outcome was not statistically significant. But no conclusions regarding the importance of early haematoma evacuation can be drawn from such an oversimplifying statement, because it does not take into account factors like rapidity of haematoma development and related brain decompensation as well as additional direct brain lesions. The results of this study suggest that the extent of primary brain injury underlying the subdural haematoma is the most important factor affecting outcome. PMID- 8686545 TI - Computer assisted brain surgery for small lesions in the central sensorimotor region. AB - The capacity of a new optical navigation device is demonstrated by six microsurgical procedures for small subcortical lesions within the central sensorimotor strip. This small series is aimed at less invasive resection in this functionally critical region, independently of primary diagnosis and outcome. Guided by high resolution CT imaging data five brain tumours and one cavernous angioma was selectively located and most sparingly removed without additional sensorimotor deficit. In two cases improvement of a pre-operative paresis was observed immediately after surgery. Thanks to light-weight freehand pointing instruments and a ranging accuracy of +/- 1 mm, damage to functionally important brain areas and vessels was avoided by using uncommonly oblique, e.g., transsulcal ways of access which would hardly have been possible even with guidance by conventional stereotaxy. The demanding systematic cortical stimulation of the precentral gyrus applied in three cases was only sensitive in infiltrating tumours-e.g., low grade astrocytomas-where for want of adjuvant therapy it was essential to proceed to the extreme limits of resection. In general, precise anatomical localisation by computer aided surgery (CAS) is sufficient in small central lesions which guarantees minimally invasive surgery. The potential of this new, soon commercially available optical navigation system in (neuro) surgery, quality control and teaching is discussed. PMID- 8686544 TI - Temperature regulation as possible prognostic indicator in patients with acute intracranial lesions. AB - 24 patients, 16 after severe head injury and 8 after spontaneous intracranial haematoma, were investigated by external cold load in order to determine their thermoregulatory capabilities. Tympanic temperature, several skin temperatures and oxygen consumption were measured. The patients where examined for SSEP and AEP. The cold induced thermoregulatory threshold temperature was determined by calculating the mean body temperature and by determining mean body temperature at which oxygen consumption increased due to the external cold load. In all patients core temperature and mean body temperature were significantly elevated by 1 degree C compared to controls. There was no difference of the course of the various body temperatures during cold load in the patient groups. In the trauma group 8 patients were able to increase oxygen use (VO2) during cold exposure, the other 8 patients showed no physiological thermoregulatory reaction. The heatproduction threshold temperature was increased by 1 degree C in the patient groups compared to controls. There was no significant correlation of AEP and SSEP findings to a preserved or disturbed thermoregulatory reaction. In the trauma patients, who were able to respond to a cold load, the outcome was significantly better (GOS = 3-5), than in those patients, who did not show a physiological increase of VO2 due to the cold load (GOS = 1-2). In conclusion, measurement of body temperatures alone is not sufficient to determine termoregulatory capacities. An examination using thermophysiological methods however provides more information about the function and structure damaged after severe head injury. An intact thermoregulatory systems seems to be correlated with a better prognosis after head injury. PMID- 8686546 TI - Long-term follow-up of the residual intracanalicular tumours after subtotal removal of acoustic neurinomas. AB - We examined growth potential of residual intracanalicular tumours left from subtotal removal of large acoustic neurinomas. Eleven patients were followed-up by magnetic resonance (MR) imaging. The interval between surgery and MR study ranged from 12 to 29 years (median, 16 years). MR images of two patients showed no evidence of tumour remnant, and in six a small tumour was localized in the internal auditory canal. The other three showed an intracanalicular tumour protruding slightly towards the intracranial portion. This result suggests that the intracanalicular residual tumours have less risk of regrowth after subtotal removal of acoustic neurinomas. It is advisable to choose intracapsular, subtotal removal without opening the internal auditory canal in the treatment of acoustic neurinoma, if it is large in size and there is a high risk of nerve injury. PMID- 8686547 TI - Volumetric reconstruction and stereotactic computer assisted resection in intracerebral lesions. AB - Since 1990 112 patients have undergone stereotactic resection of intra-axial tumoural lesions with volumetric reconstruction, using the Kelly-Goerss system. Stereotactic integration of CT, angiographic and particularly MRI information, together with three-dimensional information of the lesion, provide an innovative evaluation of the most appropriate surgical approach, even for each single patient. The main limitation of this surgical method is in cases where the infiltrating part of the tumour is pre-eminent, while it can allow "macroscopically complete resection" of well circumscribed lesions, almost independently of their location and volume. Some technical aspects of stereotactic resection of brain tumours are discussed in the light of our experience. PMID- 8686548 TI - Intravenous administration of high doses of carboplatin in multimodal treatment of high grade gliomas: a phase II study. AB - The object of this study is to evaluate the efficacy of a high dose of carboplatin in 20 patients operated on for high grade glioma (Group A) compared with a matched control (Group B) treated with BCNU administered after radiotherapy. The toxicity profile has been evaluated during the therapy. The survival of patients entering this study was measured in terms of months: the mean survival time was 10.45 months and the median 11.0 months in the group treated with carboplatin (8 patients are still alive); the 18-month survival rate was 10%. The mean survival time of the control group was 9.85 months and the median 10.5 months; no patients are still alive and the 18-month survival rate was 0%. On the basis of our phase II clinical study, we could conclude that i.v. administration of high-doses of carboplatin in high grade gliomas is generally well tolerated and the results are better than those of a matched control treated with 1-2 courses of BCNU (low-dose). The adjuvant treatment and the role of carboplatin in the therapy of high grade gliomas is discussed. PMID- 8686549 TI - Callosotomy for severe epilepsies with generalized seizures: outcome and prognostic factors. AB - The purpose of the present study was to verify the effect of callosotomy on generalized seizures, to check the effect on other seizure types and to search for possible prognostic factors. Twenty patients with a minimum follow-up of one year (mean 3.5 years) were available for our analysis. In six of them the callosotomy was performed in two stages (total: 26 surgical procedures). Age ranged from 14 to 40 years (mean 23 years). Different aetiologies were known in 15 patients. Duration of epilepsy ranged from 6 to 23 years (mean 15 years). The frequency of seizures ranged between 19 and 750 per month. The most significant effect of surgery was the complete suppression of the generalized seizures associated with falling in 9/19 and their reduction of more than 80% in 7/19 patients (total "good results": 16/19). The generalized tonic-clonic seizures were less affected. The surgical effect on the partial seizures was very variable, the partial simple seizures being the most affected. A positive statistical association with the outcome of the generalized seizures with fall was found for a presurgical seizure frequency below 90 per month, a prevalent bilateral EEG epileptic activity and, to a less extent, the absence of cerebral structural lesions. The role of age, aetiology, duration of the disease, single or more seizure types, mental impairment and extent of callosotomy remains uncertain. Disconnection syndrome does not appear if the splenium is spared. The present findings confirm that the main indication for callosotomy is the occurrence of generalized seizures with fall. Surgery can be initially limited to the anterior 2/3 of the corpus callosum; further posterior section of the corpus, excluding the splenium, should be regarded as a second step, when necessary. PMID- 8686550 TI - Diagnosis and staging of carpal tunnel syndrome: comparison of magnetic resonance imaging and intra-operative findings. AB - PURPOSE: In order to determine the reliability of magnetic resonance imaging (MRI) in the diagnosis and staging of carpal tunnel syndrome (CTS), the most common entrapment neuropathy, the following prospective study has been performed. METHODS: We compared clinical and electrophysiological studies in 58 cases of CTS with MRI investigations and confirmed the reliability by exact correspondence with intra-operative findings. RESULTS: Typical MRI characteristics of the median nerve in CTS have been established. There is a significant difference in flattening (p < 0.05), swelling (p < 0.01) and signal intensity (p < 0.05) of the median nerve between early and advanced CTS. Comparison of MRI and intra operative findings revealed that median nerve compression was diagnosed correctly in 91% of cases. Additional lesions in the carpal tunnel, which are a primary cause of nerve compression, were established by MRI in 25 cases and confirmed by surgery. CONCLUSION: MRI is a reliable diagnostic tool for assessing as well as staging of CTS. Morphological changes following chronic nerve compression can be visualized. It is particularly useful in cases of suspected lesions within the carpal tunnel as a cause of CTS. The information provided may support the choice of adequate treatment modality. PMID- 8686552 TI - [Colchicinoids--their toxicity and biological activity]. AB - The cytotoxicity of 32 colchicinoids in isolated rat hepatocytes was studied. Their effect was examined by biochemical parameters-lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, lipid peroxidation and by changes in reduced glutathione level. Only compounds with methylsulfonyl group at C-10 were significantly hepatotoxic. PMID- 8686551 TI - Amino-acid release from human cerebral cortex during simulated ischaemia in vitro. AB - The aim of the present study was to investigate the release of amino-acids in human cerebral cortex during membrane depolarization and simulated ischaemia (energy deprivation). Superfluous tissue from temporal Iobe resections for epilepsy was cut into 500 microns thick slices and incubated in vitro. Membrane depolarization with 50 mM K+ caused a release of glutamate, aspartate, GABA and glycine, but not glutamine or leucine. The release of glutamate and GABA was Ca(++)-dependent. Slices were exposed to simulated ischaemia (energy deprivation; ED) by combined glucose/oxygen deprivation. This caused a Ca(++)-independent release of glutamate, aspartate, GABA, glycine, and taurine which started after 8 min, peaked at the end or shortly after the 27 min period of ED, and returned to control levels within 11 min following termination of ED. Preloaded D [3H]aspartate was released both during K(+)-stimulation and ED. Release of D [3H]aspartate during ED was delayed compared to glutamate supporting an initial phase of synaptic glutamate release. Uptake of L-[3H]glutamate was increased during the period of glutamate release, suggesting passive diffusion across the cell membrane or enhanced transport efficacy in cellular elements with functioning uptake mechanisms. PMID- 8686553 TI - Serum lipoprotein fatty acid patterns in various types of familiar combined hyperlipidemia. AB - The relative content of various fatty acids in serum lipoproteins was determined in patients with type IIa (38), IIb (49) and IV (77) of hyperlipoproteinemia and compared with 52 controls. Significant changes were found in hyperlipoproteinemia associated with hypertriglyceridemia (type IV) but not in "pure" hypercholesterolemia (type IIa). In all lipoprotein fractions (VLDL, LDL, HDL) in type IV of hyperlipoproteinemia the increased oleic and linolenic acid proportions were found, while proportions of linoleic, arachidonic and docosahexaenoic acids were decreased. The saturated fatty acids (myristic, palmitic and stearic) were found increased in LDL. Linear regression analysis has shown positive correlation between the content of arachidonic and docosahexaenoic acids in HDL and LDL and the serum levels of total HDL-cholesterol, HDL2 cholesterol, HDL3-cholesterol and ApoA1, while a negative correlation between these fatty acids and serum triglycerides level appeared. These findings can be explained partly by increased content of triglycerides and free fatty acids in lipoproteins. Possible differences concerning mechanisms of accelaration of atherogenesis in various types of hyperlipidemia are discussed. PMID- 8686554 TI - Quantitative histochemical study of differentiation of bile canaliculi and liver sinusoids in the liver of human embryos. AB - The study was performed on the liver tissue of 15 human embryos and foetuses aged 7 to 19 weeks. The combined reaction to dipeptidylpeptidase IV (DPP IV) and alkaline phosphatase (AlP) was performed on cryostat sections. A test grid according to Weibel was used for the evaluation of the DPP IV and AlP-positive areas. During the whole period studied the presence of AlP positive areas prevailed over that of DPP IV positive ones, while the number of areas without activity remained unchanged. The AlP-positive areas vary between 15-29%, the extent of DPP IV positive areas is in the range of 11-18%. PMID- 8686555 TI - Proliferating cell nuclear antigen in tissues and organs of human embryos. AB - The expression of proliferating cell nuclear antigen (PCNA) was demonstrated in some organs in the course of the early intrauterine development. The high expression of PCNA was found in the primitive embryonic myocardium, lungs, primitive gut, liver, pancreas, in the area of "neogene zone" of metanephros (primitive kidney), in the narrow surface zone of the primitive adrenal cortex and in the surface coeloma epithelium, in medullary strips and in the mesenchyme surrounding gonads. PMID- 8686556 TI - Resistance to antibiotics in gram-negative rods from clinical material of hospital and community origin. AB - The authors examined the resistance to 13 antibiotics and chemotherapeutic agents by the diluting micromethod and the routine disk method in the group of 5375 gram negative strains of 7 genera which prevailed in clinical material of an hospital (FN Olomouc) and in material of community (OHS Olomouc) provenance during the years 1992 and 1993. In the majority of cases, the resistance was more frequent in the strains isolated from the hospital material. The most remarkable differences were found in A cinetobacter sp. (9-76%), Enterobacter sp. (10-60%) and Citrobacter sp. (18-58%). In other examined species, the differences varied in the ranges 3-40% in E.coli, 2-33% in Klebsiella sp., 0-28% in P. vulgaris, 2 28% in P.mirabilis, 0-16% in M.morganii, and 0-13% in P. aeruginosa. PMID- 8686557 TI - Hereditary influence on Crohn's disease. AB - In this paper the problem of Crohn's disease incidence among the nearest relatives is discussed. Within a short period of time a daughter, a son and their mother had to undergo an operation successively. PMID- 8686558 TI - Toothpaste Fluocaril bi-fluore 250 in the therapy of cervical dentin hypersensitivity, plaque score influencing. AB - The presented study verifies the desensibilization effect and the plaque score influence of a therapeutical toothpaste Fluocaril bi-fluore 250 applied in a chosen group of patients with sensitive exposed tooth necks. In the course of six week application of the toothpaste Fluocaril bi-fluore 250, a decrease of the sensitivity of the exposed dentin, tested by cold and tactile stimuli and an improvement of the oral hygiene estimated with the help of plaque score were observed in the studied group. After withdrawal of the treatment, the estimated criteria returned to the initial values recorded at the beginning of the experiment. PMID- 8686559 TI - Mortality from major civilised diseases in adult and pediatric populations in the CSFR CR and SR in the period from 1950-1985. AB - This paper assesses the mortality dynamics of the populations of the CSFR, CR and SR from 1950 to 1985 using medical demography techniques and secondary analyses of primary demographic data. Major diseases focussed on include malignant neoplasms and circulatory diseases in adult and pediatric populations. Attention is drawn to risk population groups and predictions are made using a number of statistical methods. The model POPUL is then used to simulate population development given the elimination of causes of mortality. This approach can be used to monitor the mortality dynamics at the level of the population and the model method can be further supplemented with single tests, selective surveys and epidemiological methods. The outcome of this research is a proposed research institute and graduate programme to furnish a body of expertise in the CSFR to pay long term attention to and research on the health status and mortality in this region. PMID- 8686560 TI - Benzo[c]phenanthridine alkaloids sanguinarine and chelerythrine: biological activities and dental care applications. AB - This article reviews chemical, pharmacological, and toxicological research relating to two principal benzo[c]phenanthridine alkaloids, namely sanguinarine and chelerythrine, in the period 1980-1994. The medical applications of these alkaloids in relation to their biological activities are discussed. PMID- 8686561 TI - [Organic personality disorder as a form of presentation of Huntington's disease]. AB - The psychiatric manifestations of certain neurological diseases frequently are unfamiliar to psychiatrists, which often makes it difficult to select the appropriate therapeutic approach. The clinical case presented exemplifies a case of Huntington disease (HD) which debut with insidious psychiatric symptoms. The most frequent psychiatric presentations in HD are affective and psychotic; however, our case would be better defined as organic personality disorder. This diagnosis in the context of HD is uncommon in the literature. PMID- 8686562 TI - [Proposal for improving the integration of drug dependencies in psychiatric nosology]. AB - The classic model of the substance induced psychotic disorder is applicable to the substance dependence. The drugs of abuse produces an organic disorder over basal forebrain systems, which are the biological substrate of desire and impulse control. As a result emerge the specific substance dependence psychopathology. PMID- 8686563 TI - [Clinical aspects of anorexia nervosa in males]. AB - A clinical epidemiological study is carried out on 14 men diagnosed of Anorexia Nervosa According to DSM-III-R and CIE-10. They all were hospitalised and the follow-up after being discharged 1 1/2-2 years. The demographical and social characteristics were analysed; weight loss, main symptoms and stressful factors related with the start of illness. The psychiatric pathologies first degree relatives and personal antecedents. The age of onset was similar to women as well as symptomatology, except more frequent alcohol abuse in males (28.4%), more hyperactivity (71.4% of men), less frequent kleptomania. The personality profile was obsessive-compulsive in half patients, and precipitant stressful factors was found in 71.42% of cases. Affective disorders and alcoholism between first degree relatives were similar to general population. We think that Anorexia Nervosa in males is very similar to females. PMID- 8686564 TI - [Stress during post-graduate medical training]. AB - We report the stress observed during the residency training. The more frequent causes are related to professional ability. The stress induced common anxiety symptoms, with minor repercussion in the daily activities. Despite the relationship between stress and psychopathology, the individual component play an important role: i.e. females are more stressed, but without more symptoms, and they cope with stress more effectively. Some personality features were also associated to the stress and psychopathology. Changes in the use of coping behaviors during the full residence period were not observed, and the use of efficacious behaviors were associated with less symptoms. The use of these coping behaviors were related to work, self-consolation, distraction and support seeking. PMID- 8686565 TI - [Completed suicide in Spain, 1906-1991. Geographical distribution of mortality]. AB - Suicidal behaviour in Spain, from the National Institute of Statistics (INE) data, is analysed. Provincial standardized figures of the first national study on Suicide (INE-1906) and those ones in 1991 (Spanish last Census), are compared. We discuss the consequences from the preventive approach. PMID- 8686566 TI - [The use of "daily life activities profile" for determining incapacity]. AB - The "Life Skill Profile" (LSP) is a test that measures psychophysical function. Fifty-five subjects arraigned in Court to have their psycho-physical ability legally assessed were included in a prospective study in which the clinical evaluation was correlated with the total LSP rating conducted by another evaluator. Age, gender, original accommodation type, diagnosis or type of evaluator were variables not significantly related to the clinical outcome. The results indicated that, using various cut-off scores, different levels of sensitivity and specificity of the LSP test are obtained which can be converted to predictive values in the legal assessment of disability. The LSP test is an efficient measure to be used in conjunction with the clinical evaluation. PMID- 8686567 TI - [Depression and obsessive-compulsive disorder cor-morbidity]. PMID- 8686569 TI - C-fos expression in spinal cord and brainstem following noxious stimulation and electroacupuncture plus noxious stimulation. AB - The present study was to trace the neuronal pathway in the spinal cord and brainstem following noxious stimulation and acupuncture plus noxious stimulation by using immunohistochemical technique to detect the expression of c-fos like protein. The results showed that in both the noxious stimulation group and acupuncture of Zusanli(St.36) and Lanwei(Extra 33) points plus noxious stimulation group a lot of Fos-like immunoreactive (FLI) cell nuclei appeared in the following structures: dorsal horn of lumbar and sacral spinal cord (Laminae I, II, V and X), n. reticularis lateralis, n. reticularis paragigantocellularis lateralis, area A1, n. tractus solitarii, n. raphe magnus, locus coeruleus, n. raphe dorsalis and the periaqueductal grey. In the control group no obvious c-fos expression was shown in the structures mentioned above. It was also shown that in the lumbar and sacral spinal cord the number of FLI nuclei in the acupuncture plus noxious stimulation group was more than that in the noxious stimulation group, but in locus coeruleus and the ventral part of the periaqueductal grey the number of FLI nuclei in the acupuncture plus noxious stimulation group was less than that of the noxious stimulation group. The results imply that acupuncture and noxious stimulation may activate the intrinsic pain modulating system through the spinal dorsal horn, then suppress the c-fos expression induced by noxious stimulation in the locus coeruleus and ventral part of the periaqueductal grey. PMID- 8686568 TI - [Cognitive profile of children with neurological disorders: II. Myelomeningocele]. AB - The Myelomeningocele is a neurological dysfunction, as a consequence of some injury in the SNC. Since, this brain disease has an inevitable influence maturity and psychological development in children who suffer it, it is considered as essential as know the place and extension of the injury, finding out the knowledge competence of child who suffers Myelomeningocele. This would be the main objective of this research, specifically we study that the knowledge development of 25 children with Myelomeningocele (14 boys, 11 girls) aged 5-14 years. 18 suffers Myelomeningocele with Hydrocephalus and 7 are affected with Myelomeningocele without Hydrocephalus. This research wants to improve the knowledge of the cognitive development of these children, to achieve, from a psychological evaluation with psychometric instrument specialized (Wechsler Intelligence Scale for Children-Wisc) a tailed inventory about the development levels reached for these children. Therefore, intending to define the areas of potency and dysfunction in children that we know are affected with a SN pathology. PMID- 8686570 TI - The in vitro effect of bioenergy on the conformational states of human DNA in aqueous solutions. AB - Conformational changes in aqueous solutions of human DNA were used as a new bioassay for bioenergy. Two subjects were tested for their ability to direct their intention to either wind or unwinding DNA presented to them in a quartz cuvette. Conformational changes of the DNA solutions were assessed by measuring the absorption spectra before and after treatment with bioenergy. The results confirm previous experiments indicating that focused human intentionality can produce significant changes in DNA conformation. The results extend previous studies by demonstrating the dynamic changes in DNA conformation over time are complex and dependent on the type of bioenergy generated. Different subjects produced different types of conformational change as indicated by shifts in the absorption spectra at either 260 nm or 310 nm. In some cases, bioenergy produced a decrease absorption at 260nm (reflecting DNA winding) and an increase absorption at 310nm. This is an anomalous response of DNA to bioenergy indicating the conformational changes observed are not due to simple winding and unwinding of the DNA helix PMID- 8686571 TI - Automating data collection, analysis & documentation for medical research. AB - The personal computer (PC) has evolved into a powerful, cost-effective computing platform capable of performing many tasks associated with the management of scientific, clinical, or other information. These activities include: Control of an instrument by the PC; Data acquisition from an experiment or subject; Analysis of the data that the computer has collected; Presentation of the analyzed data in a form that makes it useful; Long term storage of data. Until recently, these tasks required the user to be familiar with a high level programming language (HLL) in order to fulfill these assignments. Arcane text based programs whose logic is often difficult to follow is gradually being replaced by visual programming using a terminology based on icons where ideas familiar to scientists and medical practitioners rely on graphic symbols rather than textual language to describe programming actions. PMID- 8686572 TI - Transverse myelopathy after acupuncture therapy: a case report. AB - Acute transverse myelopathy (ATM) due to acupuncture therapy is a rare neurologic condition. Diagnostic criteria for ATM consisted of acute onset of symmetrical motor, sensory dysfunction and may be associated with sphincter dysfunction with respect to the level of the spinal cord injury. In this report, the mechanism of occurrence of meylopathy and progressive symptoms which appeared after acupuncture therapy is discussed. PMID- 8686574 TI - 2nd International Symposium on the Bi-Digital O-Ring Test. Tokyo, Japan, July 8 9, 1995. Abstracts. PMID- 8686573 TI - Role of mercury (Hg) in resistant infections & effective treatment of Chlamydia trachomatis and Herpes family viral infections (and potential treatment for cancer) by removing localized Hg deposits with Chinese parsley and delivering effective antibiotics using various drug uptake enhancement methods. AB - The authors found that antibiotics used to treat various infections often were ineffective in the presence of abnormal localized deposits of heavy metals like Hg and Pb, which were often observed to co-exist with Chlamydia trachomatis, Herpes Simplex Types I & II, Cytomegalovirus(CMV), and other micro-organisms. Our earlier research revealed that despite rigorous treatment with antibiotics together with various drug uptake enhancement techniques, subjects who had been treated for Chlamydia trachomatis infections, seemingly successfully with disappearance of their symptoms, were often experiencing recurrences within several months after completion of their treatment despite taking precautions against reinfection. Careful examination of the entire body of these symptom-free patients with the Bi-Digital O-Ring Test revealed that the Chlamydia trachomatis had retreated to 3 approximately 5 hiding places with localized increase in uric acid levels: 1) sublingual caruncle, 2) a small round area in the right and/or left axillae, 3) the genitals (Corona Glandis area of the Glans Penis at the Fossa Navicularis of the urethra in the male, and near the orifice of the urethra in the female), 4) Insulin-like Growth Factor positive horizontal lines, particularly above and below the knees, 5) the maxillary, ethmoid and frontal sinuses and the horizontal lines at the base of the nostrils (particularly small areas where Insulin-like Growth Factors exist). We found that all these areas contain Insulin-like Growth Factors I & II which are reduced in the presence of infection. Even when drug uptake of antibiotics was selectively increased in these 3 approximately 5 areas by various drug uptake enhancement methods developed by the 1st author, still the infection persisted. In the spring of 1995, use of Chinese parsley for successful elimination of Hg deposits existing in various organs of the first author as the result of the decay of radioactive Thallium 201 injected for cardiac SPECT, was accidentally discovered after eating Vietnamese soup, which happened to contain Chinese parsley, also called cilantro. We also found Chinese parsley accelerates the excretion of Hg, Pb, and A1 from the body though the urine. Our subjects were given a course of antibiotics (Doxycycline for Chlamydia trachomatis infection) or anti-viral agents (EPA with DHA for Herpes Family Viruses) together with Chinese parsley. Since these vegetable/herbs were eaten, the amount of effective substance absorbed varied and some people did not like the taste of these relatively large amounts of either cooked or raw parsley or its juice, but together with effective antibiotics delivered by drug uptake enhancement methods to the infected areas, the substances worked synergistically, rapidly reducing the generalized symptoms and infection. The micro-organisms retreated to the 3 approximately 5 areas listed above where, with continued treatment, they were significantly reduced, but not completely eliminated. Because of these problems, a pharmaceutical company was asked to produce a Chinese parsley table containing a controlled amount in a highly absorbable form. When 11 subjects were treated with Doxycycline for Chlamydia trachomatis infection, or anti-viral agents (EPA with DHA) for Herpes Family Viruses, drug uptake enhancement methods to selectively increase delivery of the drugs to the affected areas, and Chinese parsley tablets to remove the heavy metal deposits, the last traces of the infections and clinical symptoms disappeared completely. Therefore we hypothesized that the infectious micro organisms mentioned above, somehow utilize the Hg or Pb to protect themselves from what would otherwise be effective antibiotics, and/or that heavy metal deposits in some way make antibiotics ineffective. Since the micro-organisms retreat to areas in which Insulin-like Growth Factors I & II normally exist, they may be utilizing them for their own growth and multiplication. These phenomena ma PMID- 8686575 TI - [Immunological effect of recombinant interferon-gamma on tumor infiltrating lymphocytes of renal cell carcinoma--relationship with clinical stage]. AB - We studied the relationship between clinical stage and tumor infiltrating lymphocytes (TIL) in 26 cases of renal cell carcinoma. In 10 patients, interferon gamma (IFN-gamma) was administered preoperatively (administration group); 5 patients had low stage (Robson < or = I), and the remaining 5 patients had high stage (Robson > or = II) tumors. The other 16 patients underwent nephrectomy alone without preoperative IFN administration (control group); 11 patients had low stage, and the remaining 5 patients had high stage tumors. Immunohistochemical studies of tumor infiltrating lymphocytes in renal cell carcinoma showed a significantly high incidence of CD3, CD8, CD11b and ICAM-1 in the administration group, while CD4, LFA-1 and Ber-MAC3 were increased without significance (p < 0.05). Concerning clinical stage (Robson), a significant increase in CD3, CD8, CD11b and ICAM-1 was observed in the patients with high stage tumors in the administration group compared to those in the control group (p < 0.05). This suggested that TIL could be changed by preoperative administration of IFN-gamma. PMID- 8686576 TI - [Treatment outcome of 288 cases of renal cell carcinoma]. AB - The clinical outcome was analyzed on 288 patients with renal cell carcinoma who were admitted to the Niigata Cancer Center Hospital during the 33 years from 1961 to 1993; 254 patients had had nephrectomy and 244 of them had undergone curable operations. The survival rate was calculated by the Kaplan-Meier method. The 3-, 5- and 10-year survival rates by all causes of death in all 288 patients were 64.8, 55.9 and 36.4%, respectively. According to the stage based on the general rules for clinical and pathological studies on renal cell carcinoma (The 2nd Edition), the 5-year survival rate was 89.5, 78.7, 51.1 and 13.7% for stages I (n = 31), II (n = 128), III (n = 38) and IV (n = 83), respectively. The 5-year survival rate for the patients (n = 88) from 1961 to 1985 was 40.9%, while the rate for the patients (n = 200) from 1986 to 1993 was 64.3%. This improvement of survival rate for the patients after 1986 was brought by the increase of the stage I or II cases and by the improvement of the survival in the stage III cases after 1986. The 5-year disease-specific survival rate for the patients over 50 years old was 55.5%, while the rate for the patients under 50 years old was 83.6%. Female, low pT, low grade and small tumor size were proven to be favourable prognostic factors in renal cell carcinoma. PMID- 8686578 TI - [Retroperitoneal laparoscopic pelvic lymphadenectomy for patients with prostate cancer]. AB - Between February 1994 and February 1995, we performed retroperitoneal laparoscopic pelvic lymphadenectomy on 7 patients with prostate cancer between 63 and 76 years old, consisting of 6 patients with clinical stage B2, and 1 patient with stage C. Retroperitoneal laparoscopic procedures were performed under general anesthesia. First, the prevesical space was separated by a balloon dissector to create the working space. Then, three trocars were inserted into the retroperitoneal space at the lower abdominal midline. Except for the first patient, only two surgeons were needed to dissect the obturator lymph nodes, under 5 mmHg CO2 insufflation. The mean operating time was 133 minutes for bilateral lymphadenectomy. The mean number of removed lymph nodes was 4.8 on the left side and 4.2 on the right side. The estimated blood loss ranged from 10 to 66 ml. As none of the patients showed node involvement on the microscopic examination of the frozen section, they immediately underwent total prostatectomy. Additionally removed lymph nodes were 0.8 on the left side and 1.5 on the right side. As for intraoperative complications, endotidal CO2 was elevated in the first patient, but the other patients had no complications. Retroperitoneal laparoscopic pelvic lymphadenectomy is a safe and useful procedure, and may facilitate a lymphadenectomy better than a peritoneal procedure. PMID- 8686577 TI - [Clinical study of primary carcinoma in situ of the bladder]. AB - In our department 14 patients with primary carcinoma in situ of the bladder were treated. Thirteen patients were male and 1 patient was female. Most of the patients complained of irritative vesical symptoms such as painful urination and/or pollakisuria. Cystoscopic examination revealed no overt tumor but some abnormal findings like localized or diffuse hyperemia or fine granular changes were noted. In 4 patients, total cystectomy was performed primarily and 10 other patients were treated at first with intravesical chemotherapy or intravesical BCG. Five of those 10 patients (50%) developed invasive cancer and total cystectomy was performed secondarily in them. Invasive cancer occurred in the bladder wall in 2 patients, in the prostate in 2 patients and in both bladder and prostate in 1 patient. Five-year and 10-year survival rates of 14 patients in this study were 66.7% and 44.4%, respectively. PMID- 8686579 TI - [Microsatellite instability in renal cell carcinoma and bladder tumors]. AB - We investigated the reduction in the accuracy of DNA replication and repair (i.e. genetic instability) in urinary tract malignancy using microsatellite regions. The subjects were 17 patients with renal cell carcinoma and 14 with bladder tumors. After polymerase chain reaction (PCR) was performed with FITC-labeled primers, CA repeats were analyzed. The primers used were D2S123, D3S1067, and TP53. Tissue positive for all 3 primers was considered to show a replication error (RER). Genetic instability was found in 5 out of 17 patients with renal cell carcinoma (29%) and 3 out of 14 patients with bladder tumors (21%). Among the bladder tumor patients, 2 were positive for only TP53 and 1 was considered to have RER. Among the patients with renal cell carcinoma, one was positive only for D3S1067 and the other 4 were considered to have RER. PMID- 8686580 TI - [The estrogen-induced changes of estrogen receptor in seminal vesicle of immature castrated rat]. AB - We have already reported that estrogen treatment given to immature castrated rats caused proliferative changes in both collagen and smooth muscle in the seminal vesicles of immature rats detected by light microscopy. Herein, we studied the estrogen-induced changes in estrogen receptor (ER) in the seminal vesicles of immature castrated rats by means of enzyme immunoassay, an immunohistochemical method and RT-PCR, to clarify the mechanism of estrogen induced proliferation of collagen and smooth muscle. Immature rats (3 weeks old) were castrated and left untreated for 3 weeks and then injected subcutaneously with estradiol-17 beta (E2 17 beta, 5 micrograms/day) for 7 days before they were killed. The nuclear ER content per gland, mg tissue and mg protein in the seminal vesicles of castrated rats increased markedly compared with those of non-treated rats. Castration also enhanced ERmRNA expression. The immunohistochemical analysis demonstrated the obvious tissue distribution by which the nuclear ER positive cells were densely distributed in the periglandular stroma. The nuclear ER contents per gland, mg tissue and mg protein in the seminal vesicles of estrogen-treated castrated rats were greater than those in castrated rats. Estrogen treatment further enhanced ERmRNA expression in the castrated rats. The immunohistochemical studies demonstrated that the nuclear ER positive cells appeared among the glandular epithelial cells, basal cells and the peripheral stromal cells, in addition to the periglandular stromal cells. These findings suggest that ER is related to the estrogen induced proliferation of collagen and smooth muscle in the seminal vesicles of immature castrated rats. PMID- 8686581 TI - [Renal cell carcinoma with solitary asynchronous adrenal metastasis]. AB - We report 3 cases of renal cell carcinoma (RCC) with solitary asynchronous adrenal metastasis. Case 1; A 43-year-old female was diagnosed with ipsilateral adrenal metastasis 10 years after nephrectomy of RCC (T2, N0, M0). She is alive with no evidence of disease five years after adrenalectomy. Case 2; A 53-year-old female had contralateral adrenal metastasis 10 years after nephrectomy (T3, N0, M0). She died with distant metastasis fourteen months post-operatively. Case 3; A 56-year-old man was diagnosed with contralateral adrenal metastasis 3 years after nephrectomy (T3, N0, M0). He is alive with no evidence of disease twenty months postoperatively. Two of our three cases are alive and tumor-free. However, adrenal metastasis was found in case 1 and case 2, even though more than ten years had passed after nephrectomy. Therefore we should observe the patients periodically after radical nephrectomy for a long time. PMID- 8686582 TI - [Three cases of lung metastases of renal cell carcinoma treated with a combination of interferon-alpha, 5-fluorouracil and leucovorin]. AB - Three patients with lung metastases of renal cell carcinoma (RCC) were treated with a combination of interferon-alpha, leucovorin and 5-fluorouracil. All patients were male between 60 and 66 years and had been treated by nephrectomy prior to the combination therapy. Interferon-alpha was administered at the dose of 9 x 10(6) IU intramuscularly 3 times/week, leucovorin at 30 mg/m2 per day intravenously (day 1 to 5) and 5-fluorouracil at 500 mg/m2 daily by continuous infusion intravenously (day 1 to 5) followed by weekly bolus therapy. One patient achieved complete response for 17 months and the other two achieved stable disease for 6 and 16 months. Side effects related to this therapy were diarrhea, stomatitis, alopecia, leucocytopenia and thrombocytopenia. Grade 3 stomatitis occurred after the continuous administration of 5-fluorouracil in one patient; he recovered by discontinuation of 5-fluorouracil. Combination therapy with interferon-alpha, leucovolin and 5-fluorouracil might be effective for the treatment of lung metastases of RCC. PMID- 8686583 TI - [Spontaneous renal rupture due to xanthogranulomatous pyelonephritis; a case report]. AB - A 47-year-old female was admitted with colicky pain in the left flank. Ultrasonography and abdominal CT revealed left perirenal hematoma. Abdominal CT revealed a multilocular cystic lesion in the upper pole of the left kidney. Renal angiography revealed left renal cell carcinoma. Left nephrectomy was performed under a tentative diagnosis of left renal cell carcinoma. However, pathological diagnosis was xanthogranulomatous pyelonephritis. Xanthogranulomatous pyelonephritis is an atypical form of chronic renal parenchymal infection that can be classified as diffuse type or focal type. Preoperative diagnosis of focal xanthogranulomatous pyelonephritis is difficult because of clinical and radiological similarities to renal cell carcinoma. Our case is presented with a brief review of the literature. PMID- 8686584 TI - [Treatment and prognosis of renal cell carcinoma extending into the inferior vena cava]. AB - Out of 173 patients with renal cell carcinoma diagnosed at our department between January 1984 and December 1994, 9 (5.2%) had an inferior vena caval tumor thrombus. They consisted of 6 men and 3 women between 43 and 74 years old with a mean age of 59.8 years. The tumors were on the right and left sides in 5 and 4 patients, respectively. According to the Novick's classification, 2, 1, 4 and 2 patients had level 1 (perirenal), level 2 (infrahepatic), level 3 (intrahepatic) and level 4 (suprahepatic) tumors, respectively. Five patients without distant metastases underwent nephrectomy and removal of the vena caval tumor thrombus. Although renal tumors and vena caval tumor thrombi were completely resected in all of the 5, 4 died of disease within 3 years. Only 1 patient without tumor invasion into the inferior vena caval wall survived over 5 years without disease. Since surgical treatment is the sole radical method for renal cell carcinoma, surgery is recommended for the patients even with a vena caval tumor thrombus unless there are metastases. PMID- 8686585 TI - [A case of hydronephrosis with high level of serum Span-1 antigen and CA19-9]. AB - A sixty-year-old woman visited our hospital with a complaint of left flank pain. Laboratory data showed a high level of serum CA19-9. Computerized tomography and ultrasonography revealed left hydronephrosis and hydroureter. No tumors were found in the liver, pancreas, gallbladder, gastrointestinal tract or genitourinary tract. The serum SPan-1 antigen level was elevated to 250 U/ml, and the serum CA19-9 level was also elevated to 580 U/ml. Since urological malignancy was not excluded from these findings, left nephroureterectomy was performed. Pathological findings revealed chronic inflammation, and malignant cells were not found in the resected specimens. Although high levels of SPan-1 antigen and CA19 9 have been reported in benign diseases, both are usually less than 100 U/ml. In this case, serum SPan-1 antigen and CA19-9 levels were extremely high (more than 1,000 U/ml). Since the serum SPan-1 antigen and CA19-9 levels were gradually reduced to normal levels within 4 months after the operation, a possible explanation for the high levels of the two tumor markers is hydronephrosis in the left kidney. We report this interesting hydronephrosis associated with high levels of serum SPan-1 antigen and CA19-9. PMID- 8686586 TI - [Two successful deliveries within four years after cadaveric kidney transplantation: a case report]. AB - A woman successfully delivered two children after cadaveric kidney transplantation. She received a kidney graft at the age of 18 years because of end-stage renal failure due to chronic glomerulonephritis. Eighteen months after surgery, she became pregnant. As she was receiving immunosuppressive therapy with cyclosporin, azathioprine, mizoribine and prednisolone, we discontinued mizoribine. The child was delivered by a caesarean section in week 30 of gestation. Both the increase of liver enzymes and the decrease of creatinine clearance were slight and transient. She successfully delivered another child just a few days before the 4th anniversary of her kidney transplantation. Including this patient, we have experienced 11 deliveries by women bearing kidney grafts. Intensive joint management with the obstetric service is necessary to achieve successful delivery without losing the graft. PMID- 8686587 TI - [A case of hemolytic uremic syndrome after cadaveric renal transplantation]. AB - We report a cadaveric renal transplant recipient suffering from hemolytic uremic syndrome (HUS). A 46-year-old woman received a cadaveric renal transplantation on February 16, 1994. From the 20th postoperative day, anemia, thrombocytopenia and deterioration of graft function occurred. Graft biopsy on the 20th postoperative day indicated HUS by microthrombotic arterioglomerulopathy. Plasma exchange and 15-deoxyspergualin improved her graft function. From these clinicopathological findings, we conclude that she had HUS caused by acute humoral rejection. PMID- 8686588 TI - [Asynchronous metastases solely to the bilateral adrenal glands from bladder cancer: a case report]. AB - We report a case of transitional cell carcinoma of the bladder metastasizing to bilateral adrenal glands without other metastasis. A 47-year-old male underwent total cystectomy due to bladder cancer (TCC, G2, pT2) in 1992. One year later, CT scan showed a large tumor in the right adrenal gland. Right adrenalectomy revealed metastatic transitional cell carcinoma. He underwent 3 courses of M-VAC postoperatively. However, one year after the second operation, left adrenal tumor was detected by CT. Because there was no apparent metastasis other than the adrenal gland, left adrenalectomy was performed and the tumor was transitional cell carcinoma of grade 3. He was discharged from the hospital after 2 courses of CISCA chemotherapy, and has been doing well without evidence of recurrence for two years, being supported by the adrenocortical steroids. PMID- 8686589 TI - [Primary squamous cell carcinoma of the prostate: a case report]. AB - The patient was a 77-year-old man who visited our clinic with a chief complaint of dysuria. Digital rectal examination suggested prostatic carcinoma, but prostatic tumor marker levels were within normal limits. Transrectal needle biopsy was performed and histology was squamous cell carcinoma. Radical prostatectomy and pelvic lymph node dissection were performed with the diagnosis of T3N0M0 primary squamous cell carcinoma of the prostate. The 127 gm. tumor was moderately differentiated pT3N2M0 squamous cell carcinoma. Metastasis to the bilateral internal iliac arterial lymph nodes was confirmed histologically. Therefore, four courses of chemotherapy were performed using methotrexate, cisplatin, and pepleomycin. However, local recurrence was observed 11 months postoperatively and multiple pulmonary metastasis was developed at 13 months. The patient died of the disease 14 months after the operation. In Japan, seven cases of primary squamous cell carcinoma of the prostate have been reported, but none of these patients were treated by radical prostatectomy when the diagnosis was established by preoperative biopsy. In this case, changes in the squamous cell carcinoma antigen level in the blood corresponded to the effect of postoperative chemotherapy. PMID- 8686591 TI - The demand side of the job market for diagnostic radiologists and radiation oncologists: hiring by physician groups in 1995. AB - OBJECTIVE: The American College of Radiology sought to assess the hiring activities of radiology groups in 1995, the 1995 employment market for diagnostic radiologists and radiation oncologists, and changes in the employment market since 1991. MATERIALS AND METHODS: We mailed surveys about recruitment and hiring to a stratified random sample of 600 radiology groups in the United States; 85% responded. The responses were weighted to show what they would have been if all of the approximately 3150 radiology groups in the United States had answered the survey. The findings were compared with similar surveys conducted in 1994 and 1991. RESULTS: In 1995, 31% (+/- 1% [SE]) of radiology groups actively recruited diagnostic radiologists or radiation oncologists, seeking to fill 1423 (+/- 119) openings. These figures represent a progressive decline from the 50% of groups recruiting and 2255 positions offered in 1991. In 1995, radiology groups filled 85% of available positions, compared with 76% in 1994 and 71% in 1991. In 1995, positions available because of expansion of radiology groups numbered 613 (+/- 73), considerably fewer than the estimated 720-position increase that takes place each year in the number of posttraining diagnostic radiologist and radiation oncologists in practice. In 1995, general diagnostic radiology accounted for approximately 48% of the full time-equivalent radiologists sought; radiation oncology, 11%; and the diagnostic subspecialties, 41%. We found few statistically significant differences among specialty and subspecialty fields in the percentage of available positions filled. Private, nonacademic groups offered 77% of their positions on a partnership track basis. Groups strongly affected by managed care recruited fewer radiologists and offered fewer expansion positions than similar groups that were less affected by managed care. However, managed care did not influence whether positions were offered on a partnership basis. CONCLUSION: Available positions continued to decline, and the shortfall of expansion positions relative to the annual growth in the workforce may generate serious employment problems. Managed care is having a negative effect on employment opportunities for radiologists. Gaining employment remains about equally difficult, regardless of field. The approximately 200 positions that remained unfilled at the end of the 1995 hiring season did not result from a mismatch between radiologists' skills and the qualifications that radiology groups were seeking. PMID- 8686590 TI - Radiologists and obstetric sonography. PMID- 8686592 TI - MR angiography, the Health Care Financing Administration, and Laetrile. PMID- 8686593 TI - The Academy of Radiology Research. PMID- 8686594 TI - Chromosome 22: a model with implications for diagnostic imaging. PMID- 8686595 TI - MR imaging of sports injuries in the adult elbow: a tailored approach. AB - With an understanding of the normal anatomy of the elbow and a pertinent clinical history, MR imaging of the elbow need not be a source of fear and confusion for the MR radiologist. Because positioning and scan planning are not as straightforward as they are with other joints such as the knee or shoulder, these processes can be time-consuming. The position in which the patient is optimally scanned is inherently uncomfortable. In a busy MR center with rigorous time constraints, these factors and patient fatigue can limit the time available to acquire images. Thus, a tailored approach to designing a scanning protocol for the elbow is warranted. The preceding discussion attempts to address a streamlined approach to MR imaging of the more common pathologic processes occurring around the elbow. The sequences we have described may require some modification on different imaging systems to take into account variations in field strength and to account for disparity in hardware and software parameters of different vendors. In combination with the information provided in the clinical history, the guidelines we provide should serve as a general template upon which the practicing radiologist can base his or her approach to MR imaging of the elbow. PMID- 8686596 TI - A case of sternoclavicular dislocation with scapulothoracic dissociation. PMID- 8686597 TI - MR imaging of the rotator cuff mechanism: comparison of spin-echo and turbo spin echo sequences. AB - OBJECTIVE: Although well documented in other MR imaging applications, the value of turbo spin-echo sequences in evaluating the shoulder has not been addressed. This study was designed to directly compare matched spin-echo and turbo spin-echo sequences in the MR imaging evaluation of the rotator cuff. MATERIALS AND METHODS: Using otherwise matched double-echo sequences of equal time duration, we performed 123 paired spin-echo (TR/TE, 200/25,75; one excitation) and turbo spin echo (3500-5000/22,90; two excitations) sequences in the paracoronal and/or parasagittal plane of the shoulders of 76 patients referred to our institution for possible rotator cuff tear. The sequences were retrospectively analyzed for cuff signal and morphology, fluid conspicuity, coracoacromial arch morphology, and bone marrow signal abnormalities. Surgical and nonsurgical clinical results were correlated when available. RESULTS: We found 100% diagnostic correlation between spin-echo and turbo spin-echo sequences for rotator cuff integrity. Surgical data were available for 26 patients, and clinical follow-up for another 37. For complete rotator cuff tear in the surgical subpopulation, sensitivity was 89%, specificity was 94%, and diagnostic accuracy was 24 of 26 (92%). We found no diagnostically significant difference between the two imaging sequences for fluid conspicuity, coracoacromial morphology, or marrow signal. Signal-to-noise ratios were superior in the turbo spin-echo sequences. CONCLUSION: Turbo spin-echo sequences are an accurate and efficient tool in the MR imaging evaluation of the rotator cuff. Potential benefits include time saving, increased spatial resolution, and improved signal-to-noise ratio. PMID- 8686598 TI - Patellar height on sagittal MR imaging of the knee. AB - OBJECTIVE: The aim of this study was to determine if the radiographic assessment of patella alta using the patellar tendon:patella ratio can be applied to sagittal MR images of the knee. MATERIALS AND METHODS: Sagittal T1-weighted MR images of 46 knees were reviewed with corresponding radiographs. After lengths of the patella and patellar tendon were measured on the lateral radiographs and on the sagittal mid patellar images, the tendon:patella ratios were calculated. RESULTS: We found the mean tendon:patella ratio on radiographs to be 1.0 +/- 0.2 (SD) and on MR imaging, 1.1 +/- 0.1. These two values were not significantly different (p = .01) and had good-to-excellent correlation (r = .7). We found no statistical difference between the sexes on either radiographs or MR imaging, nor did we find statistical differences on MR imaging between the tendon:patella ratios of straight and wavy patellar tendons. CONCLUSION: As on radiographs, patellar height can be reliably assessed on sagittal MR imaging using the patellar tendon:patella ratio. On sagittal MR imaging, patella alta is suggested at values greater than 1.3 (1.1 + 2 SD). PMID- 8686599 TI - A simple restraint system for floating radiography tables. PMID- 8686600 TI - Oncogenic osteomalacia: lesion detection by MR skeletal survey. PMID- 8686601 TI - Bowstring injury of the flexor tendon pulley system: MR imaging. AB - OBJECTIVE. The flexor tendon pulley system is often ruptured when a flexed finger is forcibly extended. In the acute phase, soft-tissue swelling and pain often make clinical evaluation difficult. These pulleys are not constantly visualized on MR imaging. Rupture of the pulley system can be inferred by observing bow stringing of the underlying flexor tendons when MR imaging is obtained with the finger in flexion. Our objective is to describe the flexor tendon pulley system and present our MR technique. PMID- 8686602 TI - Rupture of the anterior tibial tendon: diagnosis by MR imaging. PMID- 8686603 TI - Water fraction of lumbar vertebral bone marrow estimated from chemical shift misregistration on MR imaging: normal variations with age and sex. AB - OBJECTIVE: Our objective was to use the chemical-shift misregistration effect of MR imaging to measure the variation in the water fraction in vertebral bone marrow with respect to patient age and sex. SUBJECTS AND METHODS: We examined prospectively 211 subjects (5-84 years old; 108 male and 103 female subjects) who had no history of hematologic disorders. We obtained midsagittal proton density weighted spin-echo images (2500/22 [TR/TE]) with a narrow sampling bandwidth (6250 Hz). Misregistered signals from lipid protons of 6-10 mm (upward shift in the readout direction) were obtained with the chemical-shift effect. By measuring the mean signal intensities of the water voxels and the water-plus-lipid voxels, we calculated a region of interest in each vertebral body for L1 to L3. The water fraction of bone marrow was then calculated as 100 x (signal intensity of water voxels/signal intensity of water-plus-lipid voxels). Individual water fractions were calculated from the average values for the water fractions of the L1-L3 bodies. RESULTS: In the male subjects, the water fraction showed a rapid decrease in the older patients in the 5- to 34-year-old group. (Mean water fractions for male patients who were 5-14, 15-24, and 25-34 years old were 75.2%, 69.0%, and 53.7%, respectively.) For male patients more than 25 years old, the water fraction remained almost constant (approximately 50%). In female subjects who were 5-44 years old, the water fraction exceeded 69% and remained almost constant. However, the water fraction rapidly decreased in women more than 45 years old. (Mean water fractions for female patients who were 35-44, 45-54, and 55-64 years old were 70.9%, 61.1%, and 49.7%, respectively.) A comparison between male subjects and female subjects showed that the water fraction for women who were 25-54 years old exceeded the water fraction for men in the same age group (25-34 years old, p < .0001; 35-44 years old, p < .001; 45-54 years old, p < .05). CONCLUSION: MR imaging showed that male and female subjects convert hematopoietic marrow to fatty marrow in the lumbar vertebral bodies in significantly different ways. The data obtained for the normal water fraction of bone marrow may prove useful for evaluating diseases that affect marrow. PMID- 8686604 TI - Symptomatic vertebral hemangiomas: MR findings. PMID- 8686605 TI - CT of the craniovertebral junction. PMID- 8686606 TI - The New Hampshire Mammography Network: the development and design of a population based registry. AB - OBJECTIVE: Some authors have proposed a national mammography registry to improve and monitor breast diagnostic practices. However, issues such as confidentiality, accuracy, and direct and indirect costs are practical barriers to implementing such a registry. This paper describes the development and design of a population based mammography registry in New Hampshire. The project's objectives are to assess the accuracy of mammography by comparing interpretive results with pathology and tumor-registry reports and to improve mammographic performance by reporting findings to facilities, radiologists, and pathologists statewide. MATERIALS AND METHODS: We recruited radiologists and pathologists through professional associations and facilities through site visits. Data used to develop and design the registry were collected during site visits, using structured face-to-face interview methods. Only one site refused to provide site specific information. RESULTS: Facilities in New Hampshire estimated the annual mammographic volume to be approximately 148,000. We have noted a great deal of variability in mammography practices. Their principal methods for determining screening versus diagnostic mammograms were by patient self-reports (44% of practices), referring physicians' reports (38%), and radiologists' reports (18%). Although 71% of practices have computers, only 16% have radiology information systems or hospital information systems that offer computerized patient-tracking capabilities. More than 90% of New Hampshire radiologists exclusively use freehand dictation for reporting, and although almost 50% codify reports, only 11% use the American College of Radiology lexicon. These data and concerns expressed by radiologists, pathologists, technologists, and administrators helped shape the New Hampshire registry. CONCLUSION: Heterogeneity of radiologic practices poses major challenges for implementing a population-based mammography registry. Issues such as confidentiality, the difficulty of assessing diagnostic acumen, and the time involved in providing data to a registry must be adequately addressed. For the registry to succeed in such diverse settings, researchers, radiologists, pathologists, technologists, and administrative staff must collaborate and cooperate. PMID- 8686607 TI - Mammography outcomes analysis: potential panacea or Pandora's box? AB - As a consequence of the demand for and perceived value of mammography outcomes analysis, collection of community-based mammography data by the NHMN and others has begun and is supported by the radiologists involved. Radiologists are increasing their use of standardized coding of report data necessary for clear communication and data collection but remain justifiably concerned about the confidentiality of these data. If stronger protection of these data is forthcoming, more radiologists will be encouraged to perform practice audits. The pooling of community-based data as exemplified by NHMN will create statistics that measure the actual practice of mammography and estimate its impact on breast cancer. For individual radiologists, the audit process will improve their mammography skills through direct feedback of results and provide important information about their patterns of interpretation. Although this approach will create community standards, comparisons with such standards may be more applicable among various communities than among individual radiologists because of the statistical variation created by the relatively small numbers of cancers found by individual radiologists, the differences in populations served by these radiologists, and the variability in reproducing the audit by individuals or groups. Pooled community data, however, will still be useful to community radiologists as general standards toward which to strive. We believe that medical audits offer important potential public health benefits for breast cancer control. Insofar as confidentiality issues cannot be effectively addressed by individual radiologists, institutions in a position to be advocates should immediately explore how legal underpinnings can be put in place to protect the audit process from disclosure. With such protection, the audit process may fulfill its potential for the radiologist's pivotal role in breast cancer control; without it, the process may prove to be a Pandora's box for the community radiologist. PMID- 8686608 TI - Physicians' opinions on the delivery of mammographic screening services: immediate interpretation versus double reading. AB - OBJECTIVE: Mammographic services are delivered in many ways. Emphasis has been placed on providing women with immediate reports of their screening mammograms. We believe that double reading of mammograms is more important than an immediate report. We sought to determine physicians' attitudes toward this issue and if education affects their opinions. MATERIALS AND METHODS: Questionnaires were mailed to 1000 physicians in Massachusetts who were randomly selected from 16,000 members of the state medical society. The questionnaire had four sections, of which two were pertinent to this subject. The first section collected general information on the physician's practice and experience. The second section described two common delivery systems for mammographic screening services and asked physicians to choose the delivery system that would most benefit their patients. RESULTS: Of the 1000 physicians, 294 returned the questionnaire, giving a response rate of 29%. Of these, 16 physicians returned blank surveys, leaving 278 for analysis. Two hundred forty-nine (90%) valued off-site, delayed interpretation of mammographic screening for their patients over on-site reading by a single radiologist if an off-site, delayed reading made double reading possible. CONCLUSION: An off-site, double-reading delivery system for mammographic screening services is preferred by many physicians for their patients once they are educated as to the benefits of double reading. PMID- 8686609 TI - The Floating Hospital of St. John's Guild. PMID- 8686610 TI - Mammographically guided fine-needle aspiration cytology of the breast: reducing the rate of insufficient specimens. AB - OBJECTIVE: The purpose of our study was to reduce the rate of insufficient specimens from fine-needle aspiration cytology (FNAC) of impalpable mammographically detected breast lesions. SUBJECTS AND METHODS: Our previous rate of insufficient specimens for FNAC was 27%. We implemented the following strategies to reduce this rate and improve accuracy: retraining of radiologists in FNAC procedures, more vigorous sampling, on-site evaluation of specimens by cytopathologist or cytotechnologist, exclusive use of stereotaxic guidance, stereotaxic equipment calibration program, and verification of initial needle placement. RESULTS: Of 77 patients with impalpable abnormalities who underwent FNAC with the new protocol, six (8%) had insufficient specimens for cytologic diagnosis: Four were incorrectly judged to contain sufficient material at the time of FNAC, one refused to complete the FNAC, and one had a vasovagal reaction. Of the six cases with insufficient specimens, four were benign at biopsy, one was malignant, and one was determined to be benign on the basis of mammographic stability. CONCLUSION: Modification of techniques and implementation of a quality assurance program can significantly improve the insufficient specimen rate for FNAC. Correlation of mammographic and cytologic findings also improves the management of these cases. PMID- 8686611 TI - Autologous breast reconstruction with endoscopic latissimus dorsi musculosubcutaneous flaps in patients choosing breast-conserving therapy: mammographic appearance. AB - OBJECTIVE: The objective of this study was to define and evaluate mammographic changes in patients treated with breast-conserving therapy and a new reconstructive technique that uses autologous tissue from a latissimus dorsi musculosubcutaneous flap. MATERIALS AND METHODS: Of 20 patients who underwent either immediate or delayed endoscopic latissimus dorsi muscle flap reconstruction after lumpectomy, 13 also had postsurgery mammograms available for review. Radiographic findings assessed included skin thickening, density or radiolucency at the reconstruction site, density around the flap, fat necrosis, calcifications, and the presence of surgical clips. RESULTS: Mammograms for three patients (23%) revealed thickening that we believed was attributable to radiation therapy. No patient had increased density in the flap itself; all flaps were relatively radiolucent centrally (13/13; 100%). Mammograms revealed density around the rim of the flap in four patients (31%). This density was most likely secondary to latissimus dorsi muscle fibers and did not limit radiographic evaluation. One patient had calcifications, probably secondary to fat necrosis. No oil cysts were seen. In the majority of patients (11/13; 85%), surgical clips were visible. CONCLUSION: Endoscopic latissimus dorsi muscle flap reconstruction, previously used only for mastectomy patients, is now being used for improved esthetic outcome in selected patients who desire breast conservation. Our results indicate that the mammographic findings are predictable. The most common findings are relative radiolucency centrally, with or without density from muscle fibers around the edges of the area of tissue transfer. The transplanted musculosubcutaneous flap does not interfere with mammographic evaluation. PMID- 8686612 TI - Proper placement of a metallic marker on an area of concern in the breast. PMID- 8686613 TI - Reduction in size of a breast mass due to concurrent chemotherapy: pitfalls in mammographic follow-up. PMID- 8686614 TI - Marked regression of a nonpalpable breast cancer after cessation of hormone replacement therapy. PMID- 8686615 TI - MR imaging evaluation of hemidiaphragms in acute blunt trauma: experience with 16 patients. AB - OBJECTIVE: The aim of this retrospective study was to evaluate the usefulness of MR imaging in excluding or confirming the diagnosis of diaphragmatic injury after blunt trauma. MATERIALS AND METHODS: MR imaging studies were performed in 16 patients with blunt trauma and with indeterminate radiographs of the chest suspicious for but not diagnostic of diaphragmatic injury. T1-weighted images were obtained in all patients, and fast gradient-echo pulse sequence images were obtained in 11 patients. The results of all imaging studies performed before the MR imaging studies and those performed during out-patient follow-up, including chest radiography and thoracoabdominal CT scanning, were reviewed for evidence of diaphragmatic injury. Medical records were reviewed to ascertain the indications for the MR imaging studies as well as the surgical findings and the duration of outpatient follow-up. RESULTS: MR imaging studies confirmed diaphragmatic injury in seven patients (44%) and revealed an intact diaphragm in nine (66%). In seven patients MR imaging studies were able to correctly reveal the site of the diaphragmatic tear and the abdominal viscera that herniated into the thoracic cavity. None of the nine patients with intact diaphragms on MR imaging studies had delayed presentation of a diaphragmatic rupture on outpatient follow-up. CONCLUSIONS: MR imaging studies can be reliably used to diagnose or exclude injury in blunt trauma patients. PMID- 8686616 TI - Effects of dose reduction on digital chest imaging using a selenium detector: a study of detecting simulated diffuse interstitial pulmonary disease. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of dose reduction on the diagnostic performance of a new digital chest imaging system in which amorphous selenium is used as the X-ray detector. Diagnostic performance was assessed for the detection of simulated diffuse interstitial pulmonary disease (DIPD). MATERIALS AND METHODS: DIPD was simulated by superimposing plastic sheets that contained small radiopaque objects (birdseed) on an anthropomorphic chest phantom. We varied the number of sheets from zero to four to simulate the degree of abnormality. We made 80 images with a standard X-ray dose, 80 images with 55% of the standard dose, and 80 images with 35% of the standard dose. Six observers were asked to indicate the presence of DIPD using a five-level scale of confidence. Two hundred forty chest images were then analyzed using receiver operating characteristic (ROC) curves. RESULTS: The area under the ROC curve was 87.2 for all readers with standard-dose imaging (95% confidence interval [CI], 83.7-90.7), 91.7 with 55% of the standard dose (95% CI, 88.8-94.6), and 90.0 with the 35% dose (95% CI, 87.1-92.9). The area under the ROC curve for subtle DIPD (one superimposed sheet) was 75.3 for all readers with standard-dose imaging (95% CI, 67.1-83.5), 79.7 with 55% of the standard dose (95% CI, 71.9-87.5), and 70.3 with the 35% dose (95% CI, 61.7-78.9). For each dose, we observed a gradual improvement of the ROC curves with each additional sheet superimposed on the chest phantom (p < .001). CONCLUSION: We found no significant difference in diagnostic performance among images made with standard X-ray dose, those made with a 55% dose, and those made with a 35% dose (95% CI). PMID- 8686617 TI - Digital X-ray systems based on amorphous selenium. PMID- 8686618 TI - High-resolution CT of the lung: pitfalls in the diagnosis of infiltrative lung disease. PMID- 8686619 TI - Three-dimensional helical CT of the tracheobronchial tree: evaluation of imaging protocols and assessment of suspected stenoses with bronchoscopic correlation. AB - OBJECTIVE: To assess the accuracy of three-dimensional (3D) helical CT of normal airways, we evaluated different imaging protocols in test objects and patients. The clinical value of 3D helical CT was composed with bronchoscopy in patients with suspected stenoses, especially before and after endobronchial procedures. SUBJECTS AND METHODS: Solid test objects--one of central airways and one of peripheral airways--were scanned and assessed for volume defects and stairstep artifacts. Fifty helical studies were performed in 36 patients. We evaluated these images for visualization of segmental bronchi; frequency of artifacts; and presence, localization, and degree of stenoses. Bronchoscopic correlation was available for 40 CT examinations. Follow-up 3D helical CT after endobronchial procedures was performed in nine patients. RESULTS: In test objects, thin sections reduced volume artifacts. Overlapping sections mainly diminished stairstep artifacts. In vivo, overlapping sections were superior to contiguous sections for good visualization of the origin (96% versus 89%, p < .01) and of the course (75% versus 54%, p < .001) of segmental bronchi. Three-dimensional helical CT allowed us to assess accurately 36 of 36 central stenoses that were seen on bronchoscopy; however, on 3D helical CT, we missed two of three segmental stenoses. At bronchoscopy, 18 stenoses could not be passed, whereas 3D helical CT provided details for possible endobronchial procedures: length of stenosis, patency (12/18), and spatial orientation of distal bronchi. Follow-up 3D helical CT documented the efficacy of endobronchial treatment. CONCLUSION: Three dimensional helical CT based on thin overlapping sections accurately visualized the normal airways down to the origin of the segmental bronchi and central stenoses. When it complements bronchoscopy, 3D helical CT allows visualization beyond stenoses, supports planning of endobronchial procedures, and may even substitute for bronchoscopy after endobronchial procedures. PMID- 8686620 TI - Primary mediastinal large-B-cell lymphoma: radiologic findings at presentation. AB - OBJECTIVE: Primary mediastinal large-B-cell lymphoma was recently reclassified as a distinct clinical entity. We wished to review the imaging findings for this disease and to compare the findings with those for other disorders with a similar appearance. MATERIALS AND METHODS: We retrospectively reviewed plain films, gallium scintigrams, MR images, and CT scans for 43 patients with primary mediastinal large-B-cell lymphoma. RESULTS: All but one lesion arose in the anterior mediastinum. Areas of fluid attenuation within the masses were evident on CT scans in 50% of cases. Pleural effusions were seen by chest radiography in 33% of patients. Pericardial effusions were present in 32% of patients who underwent CT scans. Of the 21 patients who underwent gallium scintigraphy, all were reported to have positive findings. Also, MR imaging showed evidence of superior vena cava syndrome in one patient. CONCLUSION: Primary mediastinal large B-cell lymphoma typically is seen as a bulky anterior mediastinal mass that often contains areas of necrosis. PMID- 8686621 TI - History of cardiac radiology. PMID- 8686622 TI - Measurement of coronary artery calcium with dual-slice helical CT compared with coronary angiography: evaluation of CT scoring methods, interobserver variations, and reproducibility. AB - OBJECTIVE: This study was performed to evaluate new scoring methods for quantitating coronary artery calcifications with helical CT and to compare the results with those of quantitative coronary angiography in patients with suspected coronary artery disease. SUBJECTS AND METHODS: Unenhanced dual-slice helical CT and coronary angiography were performed within 24 hr of each other in 101 patients with symptoms of coronary artery disease. Coronary artery calcifications with a density above 90 H were identified on each slice and, with the same regions of interest, quantitative scoring was performed at thresholds of 90 H (new) 130 H (old). Two mathematical algorithms (one new and one old) were evaluated for both thresholds (yielding four scoring systems). By CT imaging, we defined disease as a score of greater than zero. By angiography, we defined disease as a 50% or greater reduction in the luminal diameter of any major vessel. Interobserver variations in calcification scoring were evaluated. Seventeen of our patients. also underwent a second, consecutive CT scan to determine reproducibility. RESULTS: With the new threshold and the new algorithm, the sensitivity, specificity, and accuracy of helical CT in predicting disease were 88%, 52%, and 76%, respectively. We found a moderate positive association between the total CT calcification score and the number of stenotic coronary arteries at angiography (Pearson's correlation coefficient, .43; p = .05 [analysis of variance]). The accuracy and the area under the receiver operating characteristic curve were higher with the new threshold and the new algorithm. Interobserver agreement in calcification scoring was high (intraclass correlation coefficient, .99 [n = 85]), as was reproducibility (intraclass correlation coefficient, .94 [n = 17]). Reproducibility was higher when scoring was based on the new threshold and the new algorithm. CONCLUSION: The quantity of coronary artery calcifications as measured by helical CT correlated positively with obstructive coronary artery disease as measured by angiography. Interobserver agreement and reproducibility were excellent. A new scoring method showed promise. PMID- 8686623 TI - Cardiac-gated MR angiography of the entire lower extremity: a prospective comparison with conventional angiography. AB - OBJECTIVE: The purpose of this study was to prospectively evaluate cardiac-gated two-dimensional (2D) time-of-flight MR angiography in patients with peripheral arterial occlusive disease (PAOD). SUBJECTS AND METHODS: Twenty-three patients with PAOD were studied using cardiac-gated 2D time-of-flight MR angiography in the body coil from each patients' aortic bifurcation to the pedal arches. Blinded comparison with conventional angiograms was used to determine sensitivity, specificity, and positive and negative predictive values of this MR angiography technique. Kappa statistics were used to compare treatment plans of these patients studied with MR angiography and with conventional angiography. RESULTS: In the aortoiliac region, MR angiography had a correlation coefficient of .89 for all degrees of narrowing. For hemodynamically significant lesions, MR angiography had an 89% sensitivity, 98% specificity, 84% positive predictive value, and 99% negative predictive value. In the femoral region, MR angiography had a correlation coefficient of .91 for all degrees of narrowing. For hemodynamically significant lesions, MR angiography had an 89% sensitivity, 98% specificity, 93% positive predictive value, and 97% negative predictive value. In the popliteal region, MR angiography had a correlation coefficient of .93 for all degrees of narrowing. For hemodynamically significant lesions, MR angiography had an 89% sensitivity, 98% specificity, 94% positive predictive value, and 95% negative predictive value. In the tibioperoneal and foot regions, MR angiography had a correlation coefficient of 88% for all degrees of narrowing. For hemodynamically significant lesions, MR angiography had an 86% sensitivity, 93% specificity, 89% positive predictive value, and 91% negative predictive value. When the treatment planning data were classified into one of four outcomes (no intervention, surgery, percutaneous angioplasty, or further diagnostic study), MR angiography and conventional angiography had excellent agreement, with a Cohen's kappa value of .78. CONCLUSION: Cardiac-gated 2D time-of-flight MR angiography that uses the body coil provides a useful examination for PAOD with reasonable resolution. This imaging technique is potentially more time-efficient than techniques using extremity coils. PMID- 8686624 TI - Venous sac embolization of pulmonary arteriovenous malformations in two patients. PMID- 8686625 TI - Nonbiliary laparoscopic gastrointestinal surgery: role of CT in diagnosis and management of complication. AB - OBJECTIVE: Laparoscopic techniques are evolving for a wide range of surgical procedures outside the biliary tree. We describe the CT findings of important complications detected after nonbiliary laparoscopic gastrointestinal surgery and the role of CT in their management. MATERIALS AND METHODS: Over a 3-year period, 209 patients had nonbiliary gastrointestinal laparoscopic procedures (partial or total colectomy, splenectomy, Nissen fundoplication, lymph-node dissection, herniorrhaphy, appendectomy, and exploratory laparoscopy). Thirty-seven abdominopelvic CT studies were performed on 18 (9%) of these patients for complications after surgery. In all cases CT findings were reviewed and correlated with follow-up surgical, clinical, or interventional radiologic findings. RESULTS: Fourteen major complications were detected on CT in 12 of 18 (67%) patients who had undergone partial or total colectomy (6/25, 24%), splenectomy (4/41, 10%), appendectomy (1/15, 7%), or lymph-node dissection (1/43, 2%). These complications included seven abscesses (three of the splenic bed, two of the pelvis, one of the liver, and one of the abdominal wall). The remaining complications were four hematomas (two in the abdominal wall caused by trocar site bleeding, one intraperitoneal, and one retroperitoneal), one case of colon perforation, one case of pancreatitis, and one case of splenic infarction. Percutaneous abscess drainage was performed successfully in seven patients, using CT guidance in six. Six patients had negative CT studies. CONCLUSION: Major complications may occur after complex nonbiliary laparoscopic procedures and are probably related to lack of experience with new surgical techniques. In this study, such complications occurred most often after laparoscopic colectomy and splenectomy. CT valuable in their diagnosis and in the management of abscess collections. PMID- 8686626 TI - Enterocele revealed by simultaneous evacuation proctography and peritoneography: does "defecation block" exist? AB - OBJECTIVE: Pelvic floor weakness may allow prolapse of the bowel into the rectogenital space, forming an enterocele. Enteroceles are believed to obstruct defecation by rectal compression and are therefore considered an abnormal finding on evacuation proctography. With a technique combine evacuation proctography and peritoneography, we prospectively studied constipated patients to reveal the pelvic peritoneal recesses during evacuation and to determine if enterocele actually impairs rectal emptying. SUBJECTS AND METHODS: Fifty constipated patients were studied prospectively, Using 20 ml of water-soluble contrast medium, we performed peritoneography, then evacuation protography with 120 ml of intrarectal paste. Lateral evacuation and posteroanterior stress views were analyzed by computerized video capture. Anatomic features and functional measurements of rectal emptying were noted. Posteroanterior views were compared with views in 31 subjects undergoing peritoneography for investigation of groin pain. RESULTS: Technical failure in three patients left 47 for analysis. A deep rectogenital pouch was seen in 36 patients (77%). Of these, 12 (58%) contained viscera that formed an enterocele, but the remaining 15 patients (42%) showed no visceral filling. Most pouches were apparent only during straining (31 cases, 86%). Peritoneal descent was greater than in controls (p < .0001), of whom only three had small rectogenital pouches. Patients with enterocele were compared with those who had a rectogenital pouch but no visceral filling and those who had no pouch. Standard anatomic measurements by evacuation proctography were not significantly different, but patients with enterocele evacuated more rapidly (p = .008) and completely (p = .021) than did the other two groups. CONCLUSION: Combined evacuation proctography and peritoneography is a new technique to diagnose pelvic hernias that occur during evacuation. This technique has shown that a deep rectogenital pouch is common in constipated patients and that just over half such pouches fill with viscera. However, because an enterocele does not impair rectal evacuation, this proctographic finding should be interpreted with caution. PMID- 8686627 TI - Transpyloric spread of gastric tumors: comparison of adenocarcinoma and lymphoma. AB - OBJECTIVE: Our objective was to determine the relative frequency of transpyloric tumor spread in gastric antral carcinoma and lymphoma. MATERIALS AND METHODS: We reviewed the medical records of 127 cases of pathologically proven gastric malignant tumors, including 102 carcinomas and 25 lymphomas, over a 10-year period. The antrum had carcinoma in 64 cases and lymphoma in 15. We reviewed upper gastrointestinal barium studies and correlated the findings of transpyloric tumor extension with the results of surgery, pathology, and endoscopy. RESULTS: Tumor extension into the duodenal bulb occurred in 16 (25%) of 64 patients with carcinoma and in six (40%) of 15 patients with lymphoma of the gastric antrum. Transpyloric spread of antral carcinoma as revealed by barium study was much more common in our series than has been stated in the literature. CONCLUSION: Duodenal invasion of an antral carcinoma is not rare. Because of the higher incidence of carcinoma, transpyloric spread of gastric tumor as revealed by barium studied should not by itself suggest the diagnosis of lymphoma. PMID- 8686628 TI - Pseudomyxoma peritonei. PMID- 8686629 TI - CT of leiomyomatosis peritonealis disseminata mimicking peritoneal carcinomatosis. PMID- 8686630 TI - Hepatocellular carcinoma: iodized-oil CT TNM classification. AB - OBJECTIVE: We conducted a prospective study to determine the efficacy of iodized oil enhancement in CT for preoperative assessment of the T factor of the TNM classification in patients with hepatocellular carcinoma (HCC). SUBJECTS AND METHODS: Iodized-oil CT was performed as a part of preoperative staging in 28 patients with HCC. We determined the radiologic T factor. Pathologic correlation was obtained after orthotopic liver transplantation (n = 25) or autopsy (n = 3), and the histologic T factor was determined. RESULTS: The sensitivity of iodized oil CT accurately distinguishing between stage-T4 tumors and tumors in stages T1 T3 was 88% (7/8) with a positive predictive value of 100% (7/7). CONCLUSION: Iodized-oil CT is useful for preoperatively assessing the T factor of the TNM classification in HCC, and it improves the accuracy of radiologic staging. Iodized-oil CT can help to better patients with HCC for orthotopic liver transplantation. PMID- 8686632 TI - Recurrent pyogenic cholangiohepatitis. PMID- 8686631 TI - Percutaneous transpulmonary CT-guided liver biopsy: a safe and technically easy approach for lesions located near the diaphragm. PMID- 8686633 TI - Inflammatory pseudotumor of the liver: CT and sonographic findings. PMID- 8686634 TI - MR angiography of renal artery stenosis: value of the combination of three dimensional time-of-flight and three-dimensional phase-contrast MR angiography sequences. AB - OBJECTIVE: It has been reported and also has been our preliminary experience that many false ostial stenoses are attributable to a loss of signal intensity at the origin of the renal arteries when three-dimensional (3D) phase-contrast MR angiography is used. Our objective was to add a 3D time-of-flight MR angiography sequence to the 3D phase-contrast MR angiography sequence to better analyze the origin of the main renal arteries. We assessed the value of the combination of these two MR angiography sequences for the depiction of renal artery stenosis. SUBJECTS AND METHODS: Forty-six patients suspected of having renal artery stenosis on the basis of clinical history, physical examination, and laboratory data were prospectively enrolled. Intraarterial digital subtraction angiography findings were available for all patients. Using intraarterial digital subtraction angiography, we considered stenosis to be significant when the vessel was narrowed more than 50%. During MR angiography, half of the data were reconstructed by interpolation to avoid long acquisition times. Total acquisition times were less than 15 min. MR angiography findings were interpreted independently by two radiologists who were unaware of the findings of intraarterial digital subtraction angiography. With 3D phase-contrast MR angiography, any cutoff in signal intensity or any narrowing of the vessel diameter of more than 50% from the renal ostium to the renal hilum was considered to represent significant stenosis. With 3D time-of-flight MR angiography, our image analysis was focused on the origin of the arteries. Any cutoff in signal intensity in the first centimeter of the renal artery was considered to represent significant stenosis. RESULTS: Intraarterial digital subtraction angiography showed 105 renal arteries, including 15 supernumerary renal arteries. Eleven stenoses were localized to the main hilar renal arteries. Using time-of-flight MR angiography, we found that polar supernumerary renal arteries of small caliber and intrarenal branches of renal arteries were not adequately displayed. Using phase-contrast MR angiography to evaluate only whether the main hilar renal arteries were stenotic, we calculated the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy to be 100%, 65%, 28%, 100%, and 69%, respectively. Using a combination of the two imaging sequences, we found that the specificity, positive predictive value, and accuracy were increased to 90%, 58%, and 92%, respectively. CONCLUSION: For detecting stenoses of the main renal arteries but not for visualizing small accessory renal arteries or distal branches, our results support the use of a combination of the two MR angiography sequences. For now, this combination of sequences should be viewed primarily as a technique for screening patients. PMID- 8686635 TI - Helical CT angiography compared with arteriography in the detection of renal artery stenosis. AB - OBJECTIVE: The aim of the study was to improve the accuracy and detection rate for renal vascular lesions on helical CT angiography with an improved acquisition protocol and postprocessing. SUBJECTS AND METHODS: Fifty hypertensive patients (man age, 53 years old) referred because of clinical suspicion on renal artery stenosis were prospectively studied with digital renal arteriography and helical CT angiography. A 20-sec helical scan (collimation, 3 mm; pitch, 1) was obtained after injection of contrast medium. Interpretation was base on transverse sections, shaded-surface-display and maximum-intensity-projection reconstructions, and two-dimensional multiplanar reconstruction cuts obtained from shaded-surface-display reconstructions. RESULTS: Arteriography visualized 131 renal arteries (including 32 accessory arteries). Sixteen had significant (greater than 50% in diameter) stenosis. On helical CT angiography, 14 of these 16 stenoses were detected; two were missed (false-negatives), and two additional stenoses (false-positives) were reported. Sensitivity and specificity were 88% and 98%, respectively. Considering only main renal arteries, the sensitivity and the specificity of helical CT angiography were 100% and 98%, respectively. Helical CT angiography detected Conn's syndrome, which was responsible for hypertension, in two other patients. CONCLUSION: The accuracy and detection rate for renal artery stenosis on helical CT angiography compared with arteriography is improved with the described protocol. PMID- 8686636 TI - Sonography of the normal extratesticular space. PMID- 8686637 TI - Sonography of the abnormal extratesticular space. PMID- 8686638 TI - Sclerosing peritonitis associated with luteinized thecomas. PMID- 8686639 TI - Large cervical adenomyoma occurring in a first-trimester gravid uterus: radiologic-pathology correlation. PMID- 8686640 TI - Diagnosis of Hirschsprung's disease. AB - OBJECTIVE: Our aims were to determine the validity of using low-osmolality water soluble contrast enemas (WSCE) in neonates and infants with suspected Hirschsprung's disease (HD) and to devise a scoring system that uses a checklist of radiologic signs to determine the probability of HD. MATERIALS AND METHODS: The records of all patients referred by pediatric surgeons from 1988 through 1992 for the radiologic investigation of possible HD were retrospectively reviewed. Thirty-eight patients who were from 2 days to 9 months old were studied; 20 of them were neonates (less than 1 month old). Of all the patients, 24 underwent WSCE and the other 14 underwent barium enema. For all patients, HD had been diagnosed by rectal biopsy or excluded by biopsy, clinical follow-up, or both. Radiographs were read by a gastrointestinal radiologist who used a checklist of diagnostic criteria reported in the literature. The sensitivity had specificity of the findings were compared with those in the literature. RESULTS: Of the 18 patients with HD, 12 were neonates. All reported radiologic diagnostic criteria were seen; the frequency, sensitivity, and specificity of the findings were reported. Twenty percent (n = 2) of HD patients in the WSCE group (n = 10) had negative findings. Two of the 12 neonates developed colonic perforation, one during the enema and the other within 24 hr of the procedure. CONCLUSION: WSCE has a sensitivity and specificity equivalent to those of the barium enema for the detection of HD. For the two patients with perforation, the use of WSCE was of considerable benefit, avoiding the problems associated with barium spillage into the peritoneal cavity. A scoring system for diagnostic enemas is feasible. PMID- 8686641 TI - Tardus-parvus Doppler signals in the renal arteries: a sign of pediatric thoracoabdominal aortic coarctations. PMID- 8686642 TI - Rhabdomyosarcoma of the dome of the urinary bladder: a difficult imaging diagnosis. PMID- 8686643 TI - Pediatric moyamoya syndrome: follow-up study with MR angiography. PMID- 8686644 TI - Needle biopsy of microcalcifications. PMID- 8686645 TI - Re: Cost-effectiveness of MR imaging in evaluating polymyositis. PMID- 8686646 TI - Image-guided percutaneous biopsies of musculoskeletal lesions. PMID- 8686647 TI - Enteroclysis. PMID- 8686648 TI - Helical CT of abdominal aortic aneurysm. PMID- 8686649 TI - Spare the laser or spoil the lecture. PMID- 8686650 TI - CT findings of primary osteosarcoma of the bladder. PMID- 8686651 TI - Spontaneous disappearance of a ruptured anterior communicating artery aneurysm. PMID- 8686652 TI - Non-Hodgkin's lymphoma of the breast causing multiple vague densities on mammography. PMID- 8686653 TI - Giant fusiform oncotic aneurysm: MR and angiographic findings. PMID- 8686654 TI - Mucinous carcinoma of the breast: potential false-negative MR imaging interpretation. PMID- 8686655 TI - Adult T-cell leukemia with multiple pulmonary nodules due to leukemic cell infiltration. PMID- 8686656 TI - Prevalence estimate of elevated pediatric blood leads: two Air Force bases. AB - After the occurrence of several cases of lead poisoning at Offutt and Randolph Air Force Bases, a cross-sectional study on all children of age 12 or younger was initiated to identify those children with possibly undue lead exposure. A total of 1102 and 784 children at these two bases, respectively, were tested for blood lead values. The aim of this study was to estimate the prevalence of elevated blood lead levels of young children living in on- or off-base housing at the two air force bases. To account for analytical errors and the within-person variability in blood lead measurements, a bivariate lognormal model was employed to estimate the true blood lead values of those children whose initial measurements were 10 micrograms/dL or greater. As a result of accounting for the analytical errors and within-person variance in blood lead measurements, many cases of elevated blood lead levels turned out to be false positives. It was also shown that the relative risk for young children at the two bases having elevated blood leads was the same regardless of where they lived and how old they were. By pooling together the cases, a point estimate for the prevalence of elevated blood leads among young children was 4.2 per 1000 children, with a 95% confidence interval of 1.8 to 8.4 children per 1000 children. PMID- 8686657 TI - The relationships between urinary elimination, airborne concentration, and radioactive hand contamination for workers exposed to uranium. AB - The purposes of this study were to estimate the proportional contribution of uranium dust exposure to urinary excretion of the metal, and to examine the influence of hand contamination on the elimination of uranium from the urine of workers who performed different jobs. The study was based on records taken from a gaseous diffusion plant in 1956. Regression techniques were used to investigate the relationship between uranium concentration in urine and exposure variables, including the concentration of uranium dust and the incidence of hand contamination. The proportional contribution of airborne to urinary uranium was estimated by the slope of this relationship. It is concluded that the workers eliminated uranium at relatively constant rates per unit air concentration (0.67 to 1.27 micrograms/L per micrograms/m3). In addition to airborne uranium, hand contamination significantly contributed to the elimination among maintenance crew, but not among production workers. Furthermore, the production index was shown to be a useful surrogate for airborne and urinary uranium. PMID- 8686658 TI - Errors in derivations of the Coburn-Forster-Kane equation for predicting carboxyhemoglobin. AB - An error identified in a 1993 textbook of military medicine led to an investigation of derivations of the Coburn-Forster-Kane equation (CFKE) for predicting carboxyhemoglobin (COHb) levels. Reviews of the scientific literature, military documents, and personal interviews revealed that errors were made in earlier derivations of the CFKE. One flawed derivation was used by the U.S. Army until 1985, and another is still used by the National Institute for Occupational Safety and Health (NIOSH). The original and later CFKE derivations are reviewed and errors in the equations are identified. The effect of the errors is discussed. PMID- 8686659 TI - Quantitation of free-living amoebae and bacterial populations in eyewash stations relative to flushing frequency. AB - This study investigated the concentration of amoebic and bacterial populations in eyewash station water relative to various flushing regimens. Amoebae concentrations averaged approximately 200 amoebae/100 mL in 13 of 15 stations positive for amoebae and consisted of Hartmannella and Acanthamoeba. Bacterial concentrations ranged from 10(0) to more than 10(5) colony forming units per mL. Amoebic concentrations differed notably between stations located in Buildings X and Y (p < 0.0001). Further study indicated that removal of diffusing screens did not substantially change (p > 0.05) the concentration of amoeba. Amoebic and bacterial concentrations temporarily decreased with the various flushing regimens tested. Lower amoebic concentrations were not sustained by a weekly 3-minute or a monthly 1-minute flushing regimen. However, weekly 3-minute flushes appeared to be more effective in maintaining lowered bacterial concentrations (p < 0.0001). PMID- 8686660 TI - Air quality in an animal facility: particulates, ammonia, and volatile organic compounds. AB - Concentrations of ammonia, volatile organic compounds, particles, and mouse allergen were measured in an animal facility. Ammonia concentrations averaged less than 1 ppm, below any health-based standards. The concentrations of volatile organic compounds were in the 5-15 micrograms/m3 range. Among the volatile organic compounds found, only the terpenes a-pinene and a-terpinol (which may be derived from the pine shavings used as bedding) were consistently present in concentrations greater than outdoor air. The primary air contaminant present at concentrations high enough to be of known physiological significance was the mouse allergen, Mus ml. To determine which activities in an animal room generated the highest concentrations of airborne Mus ml, a monitor that counted particles continuously was used. The particle counts were correlated with allergen levels in the worker's breathing zone (r50.83,p,0.05). Thus, a particle counter can be used effectively in an animal facility to identify specific activities that generate high levels of both particles and allergen. Such activities included changing mice from soiled to clean cages, cleaning floors, and changing foam inserts in pressurized individually ventilated cages. To reduce exposure to allergen during cage changing, which is the major activity for an animal caretaker, a capture-type ventilated changing table was designed and tested. Use of such a table reduced exposure to allergen in the worker's breathing zone from 4.961.1 to 2.160.3 ng Mus ml/m3, a level comparable to background levels. PMID- 8686661 TI - A screening method for occupational reproductive health risk. AB - Most currently recognized occupational exposure limits do not consider reproductive toxicological end points consistently when establishing recommended exposure limits. In many cases the information is not available, but perhaps as often, existing data is not employed. Further, many manufacturer's material safety data sheets omit reproductive hazard information. A method for identifying potential reproductive toxins and screening levels for associated health risks useful for hazard communication and exposure control is presented. To date, the Registry of Toxic Effects of Chemical Substances lists between 5000 and 6000 chemicals, drugs, and natural substances that show a positive outcome in at least 1 reproductive effects study. This reproductive health risk assessment began with these substances. Using elements of the Environmental Protection Agency's health risk assessment process, the list was reduced to 213 chemicals during the hazard identification step. Occupational reproductive guidelines (ORGs) were developed in the dose-response evaluation step. At the time of this writing, 85% of the chemicals identified in the hazard identification step have had a screening level dose-response assessment completed. Of these, 13% are greater than or equal to a threshold limit value (TLV). The remaining 87% do not have a TLV or ORGs below the TLV. The reproductive toxins list, along with the corresponding dose-response derived ORGs that have been completed, appears at the end of the text. PMID- 8686663 TI - Consultants listing--July 1996. PMID- 8686662 TI - Humidity and isocyanate readings. PMID- 8686664 TI - ELPAT program report: background and current status (April 1996). Environmental Lead Proficiency Analytical Testing. PMID- 8686665 TI - Treatment mechanics in Class III open bite malocclusion with Tip Edge technique. AB - Nonextraction treatment with nonorthognathic intervention for treatment of a skeletal Class III open bite malocclusion was performed. Light traction with effective uprighting of the lower dentition with Tip Edge brackets (TP Orthodontics, La Porte, Ind.) and anteriorly placed Class III elastics was the modus operandi. Class III elastics can prevent elongation of the upper molars and yet can cause the upper dentition to move forward. Ni-Ti wire with a reverse curve of Spee helped both the uprighting and depression of the mandibular molars. The present case was treated with the Kim philosophy but employing Tip Edge brackets. This combination was found to be very easy to manipulate and achieved good results in a very short period of time. PMID- 8686666 TI - American Board of Orthodontics--past, present, and future. PMID- 8686667 TI - Orthodontia. PMID- 8686668 TI - The ABC's of computer embezzlement. PMID- 8686669 TI - Who sets the standards? PMID- 8686670 TI - Comment on two-phase treatment. PMID- 8686671 TI - Comment on soft tissue profile. PMID- 8686672 TI - Comment on concentration and etch time for phosphoric acid. PMID- 8686673 TI - Magnitude of orthodontic forces and rate of bodily tooth movement. An experimental study. AB - The relationship between the magnitude of a constant continuous orthodontic force and rate of bodily tooth movement was studied. In 25 young adult male beagle dogs, lower third premolars were extracted and bone markers were implanted in the mandible. Sixteen weeks later, an orthodontic appliance was placed, and elastics exerting 50, 100, or 200 gm were attached to the lower second premolar to produce bodily distalization. In each dog, different forces were used on the left and the right sides. As a control group, orthodontic appliances were placed without elastic on eight sides. Tooth movement was measured directly with a digital caliper twice a week during 16 weeks. Resulting curves could be divided in four phases. Large individual differences were found in the rate of tooth movement. Tooth movements on the left and right sides of each dog, however, were highly correlated. No significant differences in the duration of each phase nor in the mean rate of tooth movement during each phase were found between the three force groups. Maximum rate of tooth movement was about 2.5 mm per month in all force groups. There were no significant differences in the mesial movement of the anchorage unit between the force groups. It is concluded that under the circumstances of this study magnitude of force is not decisive in determining the rate of bodily tooth movement, but individual characteristics are. PMID- 8686674 TI - Frequency of Bolton tooth-size discrepancies among orthodontic patients. AB - The purpose of this study was to determine the percentage of orthodontic patients who present with an interarch tooth-size discrepancy likely to affect treatment planning or results. The Bolton tooth-size discrepancies of 157 patients accepted for treatment in an orthodontic residency program were evaluated for the frequency and the magnitude of deviation from Bolton's mean. Discrepancies outside of 2 SD were considered as potentially significant with regard to treatment planning and treatment results. Although the mean of the sample was nearly identical to that of Bolton's, the range and standard deviation varied considerably with a large percentage of the orthodontic patients having discrepancies outside of Bolton's 2 SD. With such a high frequency of significant discrepancies it would seem prudent to routinely perform a tooth-size analysis and incorporate the findings into orthodontic treatment planning. PMID- 8686675 TI - The effect of the tongue retaining device on awake genioglossus muscle activity in patients with obstructive sleep apnea. AB - Knowledge of how dental appliances alter upper airway muscle activity when they are used for the treatment of snoring and/or obstructive sleep apnea (OSA) is very limited. The purpose of this study was to define the effect of a tongue retaining device (TRD) on awake genioglossus (GG) muscle activity in 10 adult subjects with OSA and in 6 age and body mass index (BMI) matched symptom-free control subjects. The TRD is a custom-made appliance designed to allow the tongue to remain in a forward position between the anterior teeth by holding the tongue in an anterior bulb with negative pressure, during sleep. This pulls the tongue forward to enlarge the volume of the upper airway and to reduce upper airway resistance. In this study, two customized TRDs were used for each subject. The TRD-A did not have an anterior bulb but incorporated lingual surface electrodes to record the GG electromyographic (EMG) activity. The TRD-B contained an anterior bulb and two similar electrodes. The GG EMG activity was also recorded while patients used the TRD-B but were instructed to keep their tongue at rest outside the anterior bulb; this condition is hereafter referred to as TRD-X. The GG EMG activity and nasal airflow were simultaneously recorded while subjects used these customized TRDs during spontaneous awake breathing in both the upright and supine position. The following results were obtained and were consistent whether subjects were in the upright or the supine position. The GG EMG activity was greater with the TRD-B than with the TRD-A in control subjects (p < 0.05), whereas the GG EMG activity was less with the TRD-B than with the TRD-A in subjects with OSA (p < 0.01). Furthermore, there was no significant difference between the GG EMG activity of the TRD-A and the TRD-X in control subjects, whereas there was less activity with the TRD-X than with the TRD-A in subjects with OSA (p < 0.05). On the basis of these findings, it was concluded that the TRD has different effects on the awake GG muscle activity in control subjects and patients with OSA. The resultant change in the anatomic configuration of the upper airway caused by the TRD may be important in the treatment of OSA because such a change may alleviate the impaired upper airway function. PMID- 8686676 TI - Orthodontic and orthopedic effects of Activator, Activator-HG combination, and Bass appliances: a comparative study. AB - The orthodontic and orthopedic effects of the Activator, Activator-Headgear Combination (ACHG) and the Bass appliance systems were compared by analyzing the cephalometric records of 64 subjects, who were treated for skeletal Class II malocclusion, with both conventional and Pancherz's methods. Differences between observations on the different occasions (starting and ending values) were tested with Wilcoxon's matched pairs rank test. Kruskal-Wallis nonparametric analysis of variance was carried out in different situations among all three groups. If a level of significance less than 0.05 was observed, Scheffe's method of multiple comparisons was used to determine differences among groups. The results of this study showed that greater improvement in sagittal skeletal relationship (ANB angle) was obtained in both Bass and ACHG groups than in the Activator group. The differences between the groups were most pronounced for dental variables. The Bass appliance was found to be more effective in the control of the unwanted side effects (proclination of lower incisors, retroclination of upper incisors). Unfavorable labial tipping of the lower incisors was also prevented with the ACHG appliance. PMID- 8686677 TI - Associations between changes in selected facial dimensions and the outcome of orthodontic treatment. AB - The purpose of this study was to determine, in children with Class II, Division I malocclusion who were treated with functional appliances, the strength of the associations between the changes over 18 months in selected facial dimensions and the success of orthodontic treatment as determined by the weighted Peer Assessment Rating (PAR). Forty-two children, between 10 and 13 years of age (mean age 11.6 years), were randomly assigned to either an untreated group (control) or a group treated with either a Frankel function regulator or Harvold activator (treatment). The outcome of treatment was assessed on study models and the craniofacial changes were measured on lateral cephalometric radiographs. Correlation coefficients were then calculated between the differences in the cephalometric variables over 18 months and the differences in the PAR scores. In the treatment group, the effects of normal growth were held constant by partial correlation. The partial used was the change in both stature and weight. Significant positive partial correlations were found between the increases in total anterior face height, posterior face height, S-Pg, and treatment success. Significant negative partial correlations were found between downward movement of the maxilla and mandibular body and lower anterior face height and treatment success. It is postulated that these associations occurred mainly in response to the bite opening by the appliances. Treatment success was also significantly associated with maxillary restriction, an increase in the SNB angle and a reduction in the ANB angle. Changes in B point due to proclination of the mandibular incisors were considered to be responsible for the two latter significant associations. Although mandibular length increased significantly in the treatment group, as compared with the control group, it was not significantly associated with treatment success. PMID- 8686678 TI - The effects of the FR-3 appliance on the transversal dimension. AB - The purpose of this study was to examine the effects of the FR-3 appliance on the transversal dimension. The treatment group consisted of 20 patients with Class III malocclusion, who were treated with the FR-3 appliance. The control group consisted of 19 patients with Class III malocclusion. Posteroanterior radiographs and study models were taken at the beginning and at the end of the study in both groups. The results suggested that although FR-3 appliance therapy does not increase the width of the nasal cavity and does not stimulate the growth of the maxillary apical base, it does cause an increase in the intermolar and interpremolar distances in the maxilla both in the dental and the alveolar areas. PMID- 8686679 TI - Effects of fixed anterior biteplane therapy--a radiographic study. AB - Orthodontic treatment of eight overbite cases with a maxillary fixed lingual arch appliance with anterior biteplane involved a reduction in overbite of 4 to 7 mm between the upper and the lower front teeth and a first molar separation of 2 to 4 mm. After a treatment period of 3.5 to 5 months, occlusal contact between the upper and the lower molars was established. The appliance was then removed, and permanent overbite reduction was secured with an edgewise appliance. With the subtraction technique, 15 temporomandibular joints were radiographically investigated in the retruded position for change of condylar position on the glenoid fossa before and directly after insertion of the appliance, as well as after achieved molar contact. All condyles changed position directly after the bite opening, indicating that pure rotation did not occur. The direction of movement varied not only between subjects but also between the two condyles of each subject. With one exception, none or very small further positional changes occurred during treatment. No imaged signs of hard structure remodeling were observed. It may be concluded that other factors than change of condylar position must be responsible for the therapeutic effect of the bite-opening appliance that has been demonstrated in an earlier study. PMID- 8686680 TI - Comparison of malocclusion in preschool black and white children. AB - Previous research confirms ethnic and gender differences among children with malocclusions. A limited amount of information is available on preschool children. With an increasing interest in the early recognition of malocclusion and a corresponding emphasis on preventive procedures, more information on preschool children may prove to be useful. This study compared ethnic and gender differences for Angle's classification, anterior crossbite, and posterior crossbite. The sample consisted of 238 children, 3 to 5 years of age; 99 of the children were black and 139 were white. The acquired data were tested with chi(2). The results indicate significant racial differences in occlusal patterns and little or no gender difference. PMID- 8686681 TI - Signs and symptoms of temporomandibular disorder (TMD) and craniofacial form. AB - Signs and symptoms attributed to temporomandibular disorder (TMD) were registered in 170 persons at an average age of 12.5 years. One hundred and ten were reexamined at an average age of 26.4 years. Craniofacial form was defined on standardized lateral cephalograms, taken at the time points mentioned, by 22 linear and 8 angular measurements. The symptoms, clicking and pain, never appeared to be associated with craniofacial form. The signs, clicking and crepitation, in children did not appear to be associated with craniofacial form either. However, adults with signs were characterized by horizontal facial deficiencies. Adults with clicking joints had a saggitally shorter maxilla and mandibular diagonal, whereas adults with crepitating joints had, in addition, a shorter anterior and posterior cranial base and pharynx. This sagittal "shortness" could already be demonstrated for many of the reported dimensions at the corresponding cephalograms taken about the age of 12.5 years, and did not appear to have changed much over time. It is concluded that the reported TMD signs in adults were associated with a sagittal shorter midface. Part of the typical structure associated with signs antedated the actual detection of these signs by 14 years. This implies that not all TMD signs in adults can be regarded as the exclusive result of some etiologic factor operating after the teenage period. This finding of an association cannot be interpreted as a causal relationship. PMID- 8686682 TI - Progressive mandibular retrusion--idiopathic condylar resorption. Part I. PMID- 8686683 TI - An American Board of Orthodontics case report: the orthodontic-surgical correction of a Class II malocclusion with anterior open bite. AB - This is the case report of a 39-year-old woman who presented with a skeletal Class II malocclusion, anterior open bite, and chronic temporomandibular disorder. Small maxillary lateral incisors and moderate mandibular anterior crowding led to the treatment plan, which involved extraction of a mandibular incisor. A combined orthodontic-surgical treatment plan resulted in greatly improved occlusal function and in a reduction of the patient's temporomandibular disorder symptoms. PMID- 8686684 TI - Rigid-body kinematics and single-tooth displacements. PMID- 8686685 TI - Graduate student research--a valuable resource? PMID- 8686686 TI - Air abrasion of failed bonded metal brackets: a study of shear bond strength and surface characteristics as determined by scanning electron microscopy. AB - Failed bonded orthodontic brackets generally require their replacement with a new bracket. The introduction of air abrasion (microetching) technology to orthodontics may allow for immediate use of these failed brackets. This study compared the in vitro shear bond strengths of previously failed bonded metal brackets (experimental group) subjected to air abrasion with new untreated brackets (control group). All bonding used a light-cured orthodontic bonding system. In addition, representative samples from each group were examined by scanning electron microscopy. The results of this study found no significant differences in shear bond strengths between the two groups. Scanning electron microscopy examination of the air abraded brackets revealed a roughened mesh surface with residual bonded material in the bracket base. This simple technique should allow for the immediate reuse of previously failed bonded metal brackets. PMID- 8686687 TI - Vive la difference! PMID- 8686688 TI - Society for Epidemiologic Research 29th annual meeting. Boston, Massachusetts, June 12-15, 1996. Abstracts. PMID- 8686689 TI - Nontraditional epidemiologic approaches in the analysis of gene-environment interaction: case-control studies with no controls! AB - Although case-control studies are suitable for assessing gene-environment interactions, choosing appropriate control subjects is a valid concern in these studies. The authors review three nontraditional study designs that do not include a control group: 1) the case-only study, 2) the case-parental control study, and 3) the affected relative-pair method. In case-only studies, one can examine the association between an exposure and a genotype among case subjects only. Odds ratios are interpreted as a synergy index on a multiplicative scale, with independence assumed between the exposure and the genotype. In case-parental control studies, one can compare the genotypic distribution of case subjects with the expected distribution based on parental genotypes when there is no association between genotype and disease; the effect of a genotype can be stratified according to case subjects' exposure status. In affected relative-pair studies, the distribution of alleles identical by descent between pairs of affected relatives is compared with the expected distribution based on the absence of genetic linkage between the locus and the disease; the analysis can be stratified according to exposure status. Some or all of these methods have certain limitations, including linkage disequilibrium, confounding, assumptions of Mendelian transmission, an inability to measure exposure effects directly, and the use of a multiplicative scale to test for interaction. Nevertheless, they provide important tools to assess gene-environment interaction in disease etiology. PMID- 8686690 TI - Validation of a method to estimate age-specific human immunodeficiency virus (HIV) incidence rates in developing countries using population-based seroprevalence data. AB - The authors have conducted an analysis to validate a computer model that uses age specific human immunodeficiency virus (HIV) prevalence data to estimate age specific HIV incidence rates. Data for the analysis are from a cohort study of volunteer male workers in Bujumbura, the capital city of Burundi. Testing for HIV prevalence was conducted at baseline, and HIV-negative subjects were retested annually from 1990 to 1993 to determine rates of seroconversion. Input parameters required for the model include age-specific HIV prevalence and estimates of age specific mortality rates for HIV-negative and HIV-positive subjects. Incidence rate estimates from the model were 2.0, 2.7, 1.0, 1.5, and 1.8 per 100 person years for age groups 20-24, 25-29, 30-34, 35-39, and 40-44 years, respectively. Corresponding observed incidence rates for the same age groups were 1.6, 1.8, 2.2, 2.3, and 1.5 per 100 person-years, respectively. Most observed incidence rates fell within the 95% confidence limits of the model estimates. Expected numbers of cases within age intervals did not differ significantly from observed number of cases. The authors conclude that the model proved to be successful in approximating observed incidence rates and that it is a useful tool, particularly in countries where prevalence data are available and where HIV prevalence has stabilized, which is when the underlying assumptions in the model are best met. The model provides crucial information about incidence rates that might not be evident from prevalence data alone. PMID- 8686691 TI - Serum insulin and incident coronary heart disease in middle-aged British men. AB - Earlier studies have not resolved the question of whether elevated circulating insulin levels are independently related to the development of coronary heart disease. Previous studies have not used a specific insulin assay and in all but a minority of studies that have addressed this issue it has not been possible to adjust for possible confounding due to high density lipoprotein (HDL) cholesterol. The authors examined the relation between serum insulin concentration and major coronary disease events (fatal and non-fatal myocardial infarction) in the British Regional Heart Study. The data are based on 5,550 men (aged 40-59 years) in 18 towns whose baseline, non-fasting serum samples were analyzed for insulin using a specific enzyme-linked immunoadsorbent assay (ELISA) method. Known diabetics were excluded. At 11.5 years of follow-up, 521 major coronary disease events had occurred, 261 fatal and 260 non-fatal. A nonlinear relation between serum insulin and coronary disease events was observed with an almost twofold increased relative risk in the 10th decile of the serum insulin distribution (> or = 33.8 mU/liter) relative to the 1st to the 9th deciles combined (age-adjusted relative risk (RR) = 1.9, 95% confidence interval (CI) 1.6 2.4). There was some attenuation of this association on cumulative adjustment for a wide range of biologic and life-style coronary disease risk factors, including HDL cholesterol, though it remained significant in the fully adjusted proportional hazards model (RR = 1.6, 95% CI 1.1-2.3). Similar associations between insulin and coronary disease events were seen in men with and without evidence of coronary disease at screening and in men with baseline serum glucose below the 80th percentile. These data are consistent with the hypothesis that a high level of serum insulin (hyperinsulinemia) is atherogenic, with a threshold effect. However, the markedly nonlinear form of the association and the attenuation in multivariate analysis strongly suggest that elevated insulin levels may only be a marker for common etiologic factors in the development of both coronary disease and non-insulin-dependent diabetes mellitus. PMID- 8686692 TI - Increase in fasting insulin and glucose over seven years with increasing weight and inactivity of young adults. The CARDIA Study. Coronary Artery Risk Development in Young Adults. AB - To characterize 7-year changes in fasting serum insulin and glucose concentrations, the authors analyzed population-based data on 3,095 nondiabetic black and white men and women who were initially aged 18-30 years in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Measurements were made of fasting insulin (by an assay with little cross-reactivity to proinsulin) and fasting glucose on frozen samples from baseline and Year 7 examinations. Over the 7-year period, mean fasting insulin increased 10-25%, mean fasting glucose increased 7-10%, and mean body mass increased 7-12% across the four race-, sex groups. The strongest predictor of both insulin increase and glucose increase was an increase in body mass over the 7 years. Adjusted for age and examination time period in race-, sex-specific repeated measures analyses, fasting insulin increased longitudinally by approximately 5 microU/mL per 5 kg/m2 increase in body mass index (p < 0.05). Adjusted for age and time period, fasting insulin increased over the 7 years by approximately 2.5 microU/mL per 0.08 unit increase in waist/hip ratio (p < 0.05), although this association was much stronger cross sectionally. In a similar model, each 100 unit decrease in physical activity longitudinally predicted a 0.1-0.2 microU/mL increase in fasting insulin (p < 0.05 in black men only); this association was stronger and statistically significant in all race-, sex-groups cross-sectionally. Fasting insulin was not associated with energy intake either cross-sectionally or longitudinally, but age and time-adjusted associations of insulin change with change in several nutrients (e.g., energy from fat) were statistically significant in whites. The authors conclude that marked increased in weight in young adulthood adversely alters glucose and insulin metabolism, and that, if not reversed, this may lead to harmful health consequences in later life. PMID- 8686693 TI - Adverse effect of pregnancy on high density lipoprotein (HDL) cholesterol in young adult women. The CARDIA Study. Coronary Artery Risk Development in Young Adults. AB - The authors analyzed data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study in order to examine associations between parity and lipoproteins. Of 2,787 women recruited in 1985-1986, 2,534 (91%) returned in 1987 1988 and 2,393 (86%) returned in 1990-1991 for repeat evaluations. Two-year change (1987-1988 to 1985-1986) in high density lipoprotein (HDL) cholesterol was significantly different among the parity groups. HDL cholesterol decreased in women who had their first pregnancy of at least 28 weeks duration during follow up (mean +/- standard error, -3.5 +/- 1.2 mg/dl), and this change was significantly different from the increase in women parous at baseline who had no further pregnancies (2.5 +/- 0.3 mg/dl) and in nullipara (2.4 +/- 0.3 mg/dl). There was a nonsignificant trend for a greater decrease in HDL2 cholesterol fraction in the primipara compared with the other groups. The HDL cholesterol decrease remained significant after controlling for race, age, education, oral contraceptive use, and changes in body mass index, waist-hip ratio, physical activity, smoking status, and alcohol intake. Change in HDL cholesterol was also significantly different among the parity groups in analyses of pregnancies that occurred during the subsequent 3 years of follow-up. There were no differences for change in LDL cholesterol or triglycerides. Potential mechanisms for a detrimental effect of pregnancy on HDL cholesterol include hormonal, body composition, or life-style/behavioral changes. PMID- 8686694 TI - Risk factors for osteoporotic fractures in elderly men. AB - Osteoporosis is recognized as an important cause of morbidity and mortality in aging women, but there have been few epidemiologic studies in men. Potential risk factors for osteoporotic fractures were assessed in 220 elderly men aged 60 years or above in the city of Dubbo (Australia). During the follow-up period of 1989 1994, the overall incidence of fractures (determined from x-ray reports) was 220 fractures per 10,000 person-years. Higher risk of fracture was associated with lower femoral neck bone mineral density (BMD), quadriceps weakness, higher body sway, falls in the preceding 12 months, a history of fractures in the previous 5 years, lower body weight, and shorter current height. Use of thiazide diuretics, higher physical activity, and moderate alcohol intake were protective against fracture. In multivariate analysis (Cox's proportional hazards model), femoral neck BMD (odd ratio (OR) = 1.47, 95% confidence interval (CI) 1.25-1.73 per 0.12 g/cm2), quadriceps strength (OR = 1.43, 95% CI 1.18-1.73 per 10 kg), and body sway (OR = 1.25, 95% CI 1.07-1.45 per 5.15 cm2) were independent risk factors. Preventive measures for bone loss and maintaining a physically active, healthy life-style and modification of risk factors for falls in the elderly could yield beneficial effects in the reduction of the incidence of osteoporotic fracture and hence improve the survival among men. PMID- 8686695 TI - Effect of community health education on physical activity knowledge, attitudes, and behavior. The Stanford Five-City Project. AB - The authors studied the effectiveness of community-wide health education on physical activity knowledge, attitudes, self-efficacy, and behavior. Random samples of residents aged 18-74 years who lived in four central California cities (baseline, n = 1,056 men and 1,183 women) were evaluated in 1979-1980 and approximately every 2 years thereafter to obtain four independent samples. Moreover, every subject in the initial independent samples was asked to return for follow-up every 2 years thereafter; subjects who completed all four examinations constituted the cohort sample (n = 408 men and 499 women). Two medium-sized cities received health education and two similarly sized cities served as controls. Results indicated little consistent evidence of a treatment effect on physical activity knowledge, attitudes, or self-efficacy in either men or women. Among physical activity measures, there was an indication of a positive treatment effect for men in the independent samples for estimated daily energy expenditure and percent participation in vigorous activities (p < 0.01), and for women in the independent (p = 0.014) and cohort (p < 0.01) samples for engagement in the number of moderate activities. These results underscore the need for development of more effective interventions to change physical activity than is provided by a broad-based, community-wide health education program and for more sensitive and reliable measures of knowledge, attitudes, and behavior with regard to physical activity. PMID- 8686696 TI - Dietary antioxidants and cognitive function in a population-based sample of older persons. The Rotterdam Study. AB - Antioxidants have been implicated in processes related to atherosclerosis, aging, and selective neuronal damage, all of which may ultimately affect cognitive function. In a sample of older persons, the authors examined the cross-sectional relation between cognitive function and dietary intake of beta-carotene and vitamins C and E. The data were derived from 5,182 community participants aged 55 95 years in the population-based Rotterdam Study in the period 1990 to 1993. Dietary intake was estimated from a semi-quantitative food frequency questionnaire and categorized into five levels of intake. Cognitive function was measured with the 30-point Mini-Mental State Examination (MMSE) and characterized as unimpaired (> 25 points) or impaired (< or = 25 points). Logistic regression analysis was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for cognitive impairment. After adjustment for age, education, sex, smoking, total caloric intake, and intake of other antioxidants, a lower intake of beta carotene was associated with impaired cognitive function (< 0.9 mg vs. > or = 2.1 mg intake, OR = 1.9, 95% CI 1.2-3.1; p for trend < 0.04). There was no association between cognitive function and intake of vitamins C and E. These cross-sectional observations are compatible with the view that beta-carotene-rich foods may protect against cognitive impairment in older people. The finding could also reflect unmeasured confounding, measurement error, or a change in food habits that resulted from rather than preceded the onset of cognitive impairment. PMID- 8686697 TI - Oral contraceptives and invasive adenocarcinomas and adenosquamous carcinomas of the uterine cervix. The World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives. AB - Data from a hospital-based case-control study collected between 1979 and 1988 in 10 participating hospitals in eight countries were analyzed to determine whether use of combined oral contraceptives alters the risks of invasive adenocarcinomas and adenosquamous carcinomas of the uterine cervix. Information on prior use of oral contraceptives, suspected risk factors for cervical cancer, and history of cytologic screening was ascertained from interviews with 271 women with adenocarcinomas, 106 with adenosquamous carcinomas, and a large pool of hospitalized controls, from which 2,887 were matched to the cases included in this report. History of smoking and anogenital warts and blood specimens for measurement of herpes simplex and cytomegalovirus antibodies were obtained from subsets of these women, as was a sexual history from a subset of their husbands. The epidemiologic features and associations with oral contraceptives were similar for adenocarcinoma and adenosquamous carcinoma. For both types combined, risk increased with duration of oral contraceptive use, was highest in recent and current users, and declined with time since cessation of use. These trends in risk were strongest for cancers that occurred in women under age 35 years, and the association with risk was somewhat stronger for high compared with low progestin potency products. The strength of the observed relation with oral contraceptives was about the same as has been observed for invasive squamous cell cervical carcinomas. Women who have used oral contraceptives should be considered at increased risk of adenomatous cervical carcinomas. PMID- 8686698 TI - Helicobacter pylori infection in the Colombian Andes: a population-based study of transmission pathways. AB - In 1992, the authors studied Helicobacter pylori infection and exposures relevant to person-to-person, waterborne, foodborne, and zoonotic transmission in a census sample of 684 2-9-year-old children in Aldana, Narino, a rural community in the Colombian Andes. H. pylori prevalence, as determined by the 13C-urea breath test, was 69%, and prevalence increased from 53% in 2 year-olds to 87% in 9 year-olds. Beginning at 3 years of age, a higher percentage of males compared with females were infected. Odds ratios were estimated by multivariate logistic regression to control for mutual confounding by transmission-pathway proxy variables and socioeconomic indicators. Among transmission-pathway proxies, the strongest predictor of H. pylori status was the number of persons who lived in the home, with the number of children apparently being of greater importance than the number of adults. Swimming in rivers, streams, or pools increased the odds of infection, as did using streams as a drinking water source. Children who frequently consumed raw vegetables were more likely to have the infection, and children who had contact with sheep also had increased prevalence odds. Because the results did not implicate a single mode of transmission, the possibility of multiple pathways is indicated. PMID- 8686699 TI - Population-based recurrence risk of sudden infant death syndrome compared with other infant and fetal deaths. AB - To investigate the recurrence of sudden infant death syndrome (SIDS) among siblings, the authors analyzed data for all 352,475 mothers whose first and second single births were reported to the Medical Birth Registry of Norway during 1967-1988. Recurrence of stillbirths from the 16th week of gestation onward and infant deaths other than SIDS were also studied. Relative risk of recurrence for SIDS was 5.8 (95% confidence interval (CI) 2.1-13.2); for asphyxia- and immaturity-related infant deaths, 12.5 (9.2-17.4); for congenital malformations, 7.2 (4.7-11.0); and for other causes of infant death, 8.0 (2.0-22.1). Deaths due to infections did not recur. Similar categories of infant deaths had higher overall relative risk, 9.1, compared with 1.6 for dissimilar categories. Previous early stillbirth (16-27 weeks) had a high recurrence (relative risk (RR) = 21.8, 95% CI 17.5-26.9), while late stillbirth (> or = 28 weeks) had lower recurrence (RR = 4.6, 95% CI 3.7-5.8). Previous SIDS was associated with an increased risk of all other types of loss. In contrast, previous late stillbirth and previous asphyxia- and immaturity-related infant deaths were associated with a reduced risk of subsequent SIDS (RR = 0.31, 95% CI 0.08-0.84, and RR = 0.23, 95% CI 0.01 1.13, respectively). In conclusion, as with other infant and fetal deaths, SIDS deaths showed strong sibship aggregation consistent with a genetic susceptibility in subsets of SIDS that may interact with environmental factors. The authors also suggest common pregnancy-specific risk factors for late stillbirths, asphyxia- and immaturity-related infant deaths, and SIDS. PMID- 8686700 TI - Modeling prevention strategies for gonorrhea and Chlamydia using stochastic network simulations. AB - A simulation model was used to study the spread of two sexually transmitted diseases (STDs), namely gonorrhea and genital infection with Chlamydia trachomatis. The model is based on a stochastic pair formation and separation process, which describes the underlying structure of the sexual contact pattern. It is implemented as a Monte Carlo simulation model. Spread of the STDs was modeled in an age-structured heterosexual population with a highly sexually active core group. Contact tracing strategies, screening of various subgroups, and the effect of condom use were compared. The authors conclude that contact tracing is very effective as a prevention strategy, that screening should be targeted to the highly active core group, that age is not sufficient as a determinant for high sexual activity to make screening of certain age groups useful, and, finally, that consistent condom use by a fraction of the population can contribute substantially to the prevention of STDs. All strategies proved more effective for gonorrhea than for Chlamydia prevention, which may explain the relatively high prevalence of Chlamydia found in many heterosexual populations. PMID- 8686701 TI - How should subspecialists be trained for clinical careers? PMID- 8686702 TI - End-stage renal disease and systemic lupus erythematosus. AB - OBJECTIVE: To provide an overview of the course of systemic lupus erythematosus (SLE) following the onset of end-stage lupus nephropathy, regarding clinical and serological manifestations, survival on dialysis, and renal transplant outcomes. METHODS: A review of the pertinent literature, identified by a comprehensive Grateful Med search, was performed. RESULTS: There is a tendency for decreased clinical and serological lupus activity following the onset of end-stage renal disease. The pathophysiology of this quiescence remains unclear. Survival of lupus patients on dialysis is no different from that of non-SLE dialysis patients, and is better than that of several other rheumatic diseases. Following renal transplantation, there is no difference in patient or graft survival in lupus versus nonlupus patients. Like their nonlupus counterparts, SLE transplant patients do better with living relative grafts and/or regimens containing cyclosporin A. Transplantation is not recommended within 3 months of the initiation of dialysis to allow possible recovery from the acute renal failure. Transplantation during an acute exacerbation of SLE is controversial, and may increase the risk of poor outcomes. Recurrence of lupus in transplanted allografts, often with the same histopathology as in the native kidney, occurs at a rate (2.7% to 3.8%) comparable to that for all allograft transplant failures (2% to 4%). CONCLUSIONS: End-stage lupus nephropathy patients require less medication owing to decreased disease activity. They are good candidates for dialysis and renal transplantation, with survival and recurrence rates no different from those of other patients with end-stage renal disease. PMID- 8686703 TI - Fifth disease after immunoglobulin administration in an AIDS patient with parvovirus-induced red cell aplasia. PMID- 8686704 TI - Metformin-associated lactic acidosis. PMID- 8686705 TI - Depression and hypercalcemia. PMID- 8686706 TI - Elevated serum ferritin levels: associated diseases and clinical significance. PMID- 8686707 TI - Elevated serum ferritin levels: associated diseases and clinical significance. PMID- 8686708 TI - Elevated serum ferritin levels: associated diseases and clinical significance. PMID- 8686709 TI - Elevated serum ferritin levels: associated diseases and clinical significance. PMID- 8686710 TI - The occurrence of diabetic ketoacidosis in non-insulin-dependent diabetes and newly diagnosed diabetic adults. AB - PURPOSE: To examine the occurrence of diabetic ketoacidosis (DKA) in adults without a prior history of type I diabetes. PATIENTS AND METHODS: A retrospective review was conducted of medical records of adults presenting with DKA between 1987 and 1993. The medical record was reviewed to classify patients as type I, type II, or newly diagnosed diabetics and to determine the status of diabetic treatment following the episode of DKA in those patients without prior history of type I diabetes. RESULTS: Two hundred twenty-six patients were included in the study; 106 (47%) were classified as type I and 58 (26%) as type II from data available in the medical record, and 62 (27%) had DKA as the initial manifestation of the disease. Nineteen percent of the patients in whom diabetes was a new diagnosis and 52% of the patients who had a prior history of NIDDM were > or = 40 years old. Of patients with follow-up of at least 12 months, about 24% of the newly diagnosed and 8% of those with a history of NIDDM were not taking insulin. CONCLUSION: DKA occurs in patients with type II diabetes. Older patients may present with clinically apparent type I diabetes. Some adults who present with DKA do not remain insulin dependent. PMID- 8686711 TI - Diabetes in urban African Americans. III. Management of type II diabetes in a municipal hospital setting. AB - OBJECTIVE: Management of type II diabetes is difficult, particularly in urban populations with limited resources and access to care. To evaluate the effectiveness of structured care delivered by non-physician providers, patients were studied prospectively for 6 months in a municipal hospital diabetes clinic. DESIGN AND METHODS: The population was approximately 90% African American and had median known diabetes duration of approximately 1 year, 54% had incomes below the Federal Poverty Guideline. Primary management was provided by nurse-practitioners and dietitians, and primary outcome measures were hemoglobin A1c (HbA1c), fasting plasma glucose, and changes in body weight. RESULTS: Responses were analyzed in 325 new patients returning for visits at 2, 4, 6, and 12 months; metabolic profiles at presentation were similar to those of subjects who missed intervening visits. Lean patients largely continued on pharmacologic therapy and improved HbA1c from 9.4% to 7.4% at 2 months (P < 0.001), remained stable through 6 months, then rose to 7.9% at 1 year. Obese patients (71%) received dietary instruction. Weaning of pharmacologic therapy was attempted for the first 2 months, resulting in a decline of HbA1c from 9.6% to 8.0% (P < 0.001), with 70% treated with diet alone. In the obese, HbA1c continued to decrease through 6 months (7.7%). Thereafter, providers saw patients at their own discretion and intensified therapy as needed. Although by 1 year, HbA1c had risen to only 8.2%, some patients required reinstitution of pharmacologic therapy; 59% were on diet alone. While 52% lost 4 lb or more (mean 9.3) by 2 months, little additional weight was lost. Interestingly, glycemic control was improved both in those who lost > or = 8.5 lb in the first 2 months (HbA1c 9.6% to 8.1% at 12 months), and in those who gained weight (HbA1c 10.2% to 8.2%). In the obese patients using pharmacologic agents at presentation, 35% were able to discontinue oral agents or insulin by 1 year, with good glycemic control (HbA1c < 8%). For patients who were initially on diet alone, a fasting plasma glucose > 177 mg/dL predicted the need for pharmacologic therapy with 97% certainty. CONCLUSIONS: In urban African American patients, nonpharmacologic management of type II diabetes substantially improves metabolic control; decreases in HbA1c are comparable in those who do and do not lose weight. Therapy managed by nonphysician providers can be an effective cornerstone of diabetes care in this socioeconomically disadvantaged population. PMID- 8686712 TI - Adverse events from drug therapy for human immunodeficiency virus disease. AB - PURPOSE: Drug therapies for patients with human immunodeficiency virus (HIV) infection are associated with adverse events that can potentially limit their effectiveness. We sought to quantify the incidence of these events in clinical practice and determine whether there were demographic and clinical differences in adverse event rates for these drugs. PATIENT AND METHODS: We calculated specific and overall adverse event rates from use of zidovudine, didanosine, zalcitabine, cotrimoxazole, and dapsone in an observational urban cohort of 1,450 HIV-infected patients with a CD4+ count of 500 cells/mm3 or less. We compared adverse event rates by gender, race, age, injecting drug use, and CD4+ count. RESULTS: Overall adverse event rates in order of incidence were dapsone, 16.2 per 100 person-years (PY); didanosine, 24.1 per 100 PY; zidovudine, 26.3 per 100 PY; cotrimoxazole, 26.3 per 100 PY; and zalcitabine, 37.0 per 100 PY. Rates increased significantly with decline in CD4+ count from > 200 to < 100 cells/mm3 for all drugs but dapsone. In addition, women were more likely than men to have an adverse event for didanosine (relative risk [RR] = 2.7, P = 0.03) and from cotrimoxazole (RR 1.5; P = 0.05). Whites were at greater risk than blacks for adverse events from cotrimoxazole (RR = 1.6, P = 0.03). Only 22 of 357 total events (6%) required hospitalization, and there were no deaths. CONCLUSIONS: Adverse events from antiretroviral drugs and Pneumocystis carinii pneumonia prophylaxis that interrupt therapy are relatively common, although serious events requiring hospitalization are rare. Adverse event rates increase progressively with decline in CD4+ count. The gender and race of the patient modify the risk of adverse events for some drugs. PMID- 8686713 TI - Prednisone improves renal function and proteinuria in human immunodeficiency virus-associated nephropathy. AB - PURPOSE: To determine if prednisone ameliorates the course of human immunodeficiency virus-associated nephropathy (HIV-AN). PATIENTS AND METHODS: Twenty consecutive HIV-infected adults with biopsy-proven HIV-AN (n = 17) or clinical characteristics of HIV-AN (n = 3) with serum creatinine concentrations > 177 mumol/L (2 mg/dL) or proteinuria > 2.0 g/d or both were prospectively evaluated and treated with prednisone at a dose of 60 mg/d for 2 to 11 weeks, followed by a tapering course of prednisone over a 2- to 26-week period. Serum creatinine concentration, 24-hour protein excretion, serum albumin, and steroid related adverse effects were assessed before and after treatment. RESULTS: Nineteen patients had serum creatinine concentrations > 117 mumol/L (2 mg/dL). Two of them progressed to end stage renal disease (ESRD) in 4 to 5 weeks. In 17 patients serum creatinine levels decreased from 717 +/- 103 mumol/L (8.1 +/- mg/dL) (mean +/- SE) to 262 +/- 31 mumol/L (3.0 +/- 0.4 mg/dL) (P < 0.001). Five patients relapsed after prednisone was discontinued and were retreated. In these 5 the serum creatinine declined from 728 +/- 107 mumol/L (8.2 +/- 1.2 mg/dL) to 344 +/- 47 mumol/L (3.9 +/- 0.5 mg/dL) (P < 0.01) in response to the second course of prednisone. Twelve of 13 tested patients showed a reduction in 24-hour urinary protein excretion with an average decrement from 9.1 +/- 1.8 g/d to 3.2 +/- 0.6 g/d (P < 0.005). Serum albumin increased from 24.4 +/- 3.6 g/L to 29.3 +/ 2.6 g/L (P = NS) in the 11 patients with paired 24-hour urine collections for whom pre- and post-treatment determinations were available. In one non-azotemic patient with nephrotic syndrome, protein excretion declined from 15.2 to 2.2 g/day and the serum albumin increased from 4.0 g/L to 31.0 g/L. The 20 patients have been followed for a median of 44 weeks (range 8 to 107). Eight ultimately required maintenance dialysis. Eleven died from complications of HIV disease 14 to 107 weeks after institution of prednisone; none was receiving prednisone at the time of death. Seven are alive and free from ESRD a median of 25 weeks (range 8 to 81) from the initiation of prednisone therapy. Six patients developed a total of seven serious infections while receiving prednisone, including Mycobacterium avium-complex infection in 2 and CMV retinitis in 3. CONCLUSION: Prednisone improves serum creatinine and proteinuria in a substantial proportion of adults with HIV-AN. Corticosteroid-related side effects are not prohibitive. A prospective, randomized controlled trial is required to confirm these preliminary results. PMID- 8686714 TI - Is the administration of dopamine associated with adverse or favorable outcomes in acute renal failure? Auriculin Anaritide Acute Renal Failure Study Group. AB - PURPOSE: To explore the relationship between the administration of low-dose dopamine and outcomes in acute renal failure. PATIENTS: Two hundred and fifty-six patients with acute renal failure randomized to the placebo arm of a multicenter intervention trial were examined. Independent correlates of low-dose (arbitrarily defined as < 3 micrograms/kg/min) and high-dose (arbitrarily defined as > or = 3 micrograms/kg/min) dopamine administration were identified. The relative risks of death, and the combined outcome of death or dialysis, were estimated using proportional hazards regression with and without adjustment for potential confounding and bias. RESULTS: There were 93 (36%) deaths documented; an additional 52 (20%) patients who survived required dialysis during the 60-day study period. The relative risk (RR) of death associated with the administration of low-dose dopamine was 1.11 (95% confidence interval [95% Cl] 0.66 to 1.89). The RR of death was modestly but not significantly reduced, after adjustment for the probability of treatment assignment and for relevant covariates (RR 0.82, 95% Cl 0.42 to 1.60). The RR of death or dialysis associated with the administration of low-dose dopamine was 1.10 (95% Cl 0.71 to 1.71). The RR of death or dialysis was attenuated by adjustment, but not significantly (RR 0.95, 95% Cl 0.58 to 1.58). CONCLUSION: There is insufficient evidence that the administration of low dose dopamine improves survival or obviates the need for dialysis in persons with acute renal failure. The routine use of low-dose dopamine should be discouraged until a prospective, randomized, placebo-controlled trial establishes its safety and efficacy. PMID- 8686715 TI - Hereditary iron overload and African Americans. PMID- 8686716 TI - Fibromyalgia syndrome: overnight falls in arterial oxygen saturation. AB - PURPOSE: Sleep alterations and muscular changes suggesting hypoxia have been reported in fibromyalgia syndrome (FS) pathophysiology. We tested the hypothesis that patients with FS show falls in the oxygen saturation of hemoglobin in arterial blood (SaO2%) during sleep. PATIENTS AND METHODS: Overnight SaO2% was measured by digital pulse oximetry in 28 randomly selected women who met 1990 American College of Rheumatology criteria for the diagnosis of FS and 15 similar controls. Considering the results of pulse oximetry and in order to evaluate the possible presence of a sleep apnea syndrome (SAS) as the reason for the nocturnal desaturations, the Epworth Sleepiness Scale (ESS) was mailed to the patients and controls. Patients and controls who had a score higher than 10 on the ESS underwent a polysomnographic study. RESULTS: Patients with FS showed lower overnight minimum SaO2% (86.8 +/- 1.3 versus 90.7 +/- 0.9 in controls, P < 0.05), greater number of desaturations (8.3 +/- 1.8 versus 2.7 +/- 0.8 in controls, P < 0.05) and more desaturations/hour (1.3 +/- versus 0.4 +/- 0.1 in controls, P < 0.05), more night minutes in SaO2% < 92% (56.3 +/- 12.9 versus 9.1 +/- 3.8 in controls, P < 0.01) and more minutes in SaO2% < 90% (14.7 +/- 3.7 versus 2.4 +/- 1.0 in controls, P < 0.05). There were no differences between patients with FS and controls in ESS scores. Five patients (19.2%) in the FS group and 2 (15.4%) in the control group had ESS scores higher than 10. One patient had 1 control subject showed on apnea-plus-hypopnea index higher than 5 (13 and 9, respectively) in polysomnographic study. CONCLUSIONS: Patients with FS showed small overnight falls in SaO2% and spent more time during the night in SaO2% below 92% and 90% than did the control group. These alterations that, as a whole, are not due to the presence of an associated SAS could be important in FS musculoskeletal pathophysiology. PMID- 8686717 TI - The unassisted respiratory rate-tidal volume ratio accurately predicts weaning outcome. AB - PURPOSE: To assess the accuracies of four commonly used parameters in predicting weaning outcome and whether breathing pattern changes during weaning. PATIENTS AND METHODS: We prospectively examined the predictive accuracies of four weaning parameters in mechanically ventilated patients in the medical and cardiac intensive care units of a 270-bed community teaching hospital. The spontaneous respiratory rate:tidal volume ratio (RVRi), negative inspiratory force (NIF), and spontaneous minute volume (VE) at the onset of weaning, and the RVR at 30 to 60 minutes of weaning (RVR30) were measured. Weaning decisions were made by patients' primary physicians independent of this study. Threshold values for computations of predictive values were as follows: RVR 100 < or = breaths per minute/L, NIF < or = -20 cm H2O, VE < or = 10 Lpm. Receiver operator curves were generated for each parameter. RESULTS: One hundred medical/cardiac intensive care unit patients were studied. Their mean age was 64.6 +/- 15.8 years, mean APACHE II score of 15.8 +/- 6.7 and mean duration of mechanical ventilation before the study of 4.9 +/- 8.1 days. RVRi sensitivity was 89%, specificity was 41%, positive predictive value was 72%, negative predictive value was 68%, and accuracy was 71%. The RVR30 sensitivity was 98%, specificity was 59%, positive predictive value was 83%, negative predictive value was 94%, and accuracy was 85%. Accuracies for the NIF and VE were 66% and 62%, respectively. The area under the receiver operator curve of the RVR30 (0.92 +/- 0.03) was higher than the RVRi (0.74 +/- 0.05), NIF (0.68 +/- 0.06) and VE (0.54 +/- 0.06) (p < 0.05). CONCLUSIONS: The RVR is more accurate than other commonly utilized clinical tools in predicting the outcome of weaning from mechanical ventilation. The RVR measured at 30 minutes is superior to the RVR in the first minute of weaning. The predictive accuracy and unique simplicity of the RVR justify its use in the care of mechanically ventilated patients. PMID- 8686718 TI - Oral antibiotic treatment of right-sided staphylococcal endocarditis in injection drug users: prospective randomized comparison with parenteral therapy. AB - PURPOSE: To compare the efficacy and safety of inpatient oral antibiotic treatment (oral) versus standard parenteral antibiotic treatment (intravenous) for right-sided staphylococcal endocarditis in injection drug users. PATIENTS AND METHODS: In a prospective, randomized, non-blinded trial, febrile injection drug users were assigned to begin oral or intravenous (IV) treatment on admission, before blood culture results were available. Oral therapy consisted of ciprofloxacin and rifampin. Parenteral therapy was oxacillin or vancomycin, plus gentamicin for the first 5 days. Antibiotic dosing was adjusted for renal dysfunction. Administration of other antibacterial drugs was not permitted during the treatment or follow-up periods. Bacteremic subjects having right-sided staphylococcal endocarditis received 28 days of inpatient therapy with the assigned antibiotics. Test-of-cure blood cultures were obtained during inpatient observation 6 and 7 days after the completion of antibiotic therapy, and again at outpatient follow-up 1 month later. Criteria for treatment failure and for drug toxicity were prospectively defined. RESULTS: Of 573 injection drug users who were hospitalized because of a febrile illness and suspected right-sided staphylococcal endocarditis, 93 subjects (16.2%) had two or more sets of blood cultures positive for staphylococci; 85 of these bacteremic subjects (14.8%) satisfied diagnostic criteria for at least possible right-sided staphylococcal endocarditis (no other source of bacteremia was apparent) and entered the trial. Forty-four (oral, 19; IV, 25) of these 85 subjects completed inpatient treatment and evaluation including test-of-cure blood cultures. There were four treatment failures (oral, 1 [5.2%]; IV, 3 [12.0%]; not significant, Fisher's exact test). Drug toxicity was significantly more common in the parenterally treated group (oral, 3%; IV, 62%; P < 0.0001), consisting largely of oxacillin-associated increases in liver enzymes. CONCLUSIONS: For selected patients with right-sided staphylococcal endocarditis, oral ciprofloxacin plus rifampin is effective and is associated with less drug toxicity than is intravenous therapy. PMID- 8686719 TI - Prospective and serial study of primary amyloidosis with serum amyloid P component scintigraphy: from diagnosis to prognosis. AB - OBJECTIVE: The purpose of this study was to assess the value of the serum amyloid P (SAP) component scintigraphy in patients with primary amyloidosis (AL). MATERIAL AND METHODS: Pure human SAP labeled with iodine-123 (123I-SAP) was given intravenously to 24 patients with biopsy-proven systemic amyloidosis (15 without multiple myeloma = group 1, and 9 with multiple myeloma = group 2) and to 6 patients with multiple myeloma without any clinical or biological signs of amyloidosis (group 3). Whole-body images as well as regional views and tissue retention levels were obtained after 24 hours. Our study was approved by the institutional review committee and all individuals gave informed consent and were prospectively studied (median 13 months, range 1 to 47 from the date of the scintigraphy to May 1995). RESULTS: Organ localization of 123I-SAP, indicating the presence of substantial visceral amyloid deposits, was observed in all patients in group 1 and 2. The organ uptake of 123I-SAP included the spleen (1 patient was splenectomized) in 20 of 23 cases (87%), the liver in 15 of 24 (60%), and the kidneys in 6 of 24 (25%). Myocardial 123I-SAP was never seen although 13 out of the 24 patients had clinical or echographic data for amyloidosis. Twenty four hour tissue retention was significantly elevated in all patients (group 1 and group 2): 55.66% +/- 19.16% in group 1 and 34.37% +/- 24.92% in group 2, as compared with normal levels < 24%. The sensitivity of the technique was 79% when only organ uptake was considered but reached 100% when tissue retention was also considered. The 24-hour tissue retention might be correlated with the severity of the amyloidosis: mean survival in patients with tissue retention greater than 50% was 11.3 months versus 24.5 months in patients with levels less or equal to 50%. Five of the 6 patients with multiple myeloma without evidence of amyloidosis had abnormal 123I-SAP imaging and 24-hour tissue retention levels. In 2 of them, amyloidosis was secondly detected. In the 9 patients who had two scintigraphies, variations in 24-hour tissue retention values were in accordance with the clinical evaluation. CONCLUSIONS: Spleen and liver distribution of amyloidosis is mostly revealed by 123I-SAP scintigraphy in patients with AL amyloidosis. The uptake of 123I-SAP appeared in proportion to the quantity of amyloidosis present in different tissues, and the relative quantity of amyloid deposits in the myocardium, carpal tunnel, digestive tract, and kidneys was often small and seldom visualized by 123I-SAP scintigraphy. In contrast 24-hour tissue retention levels were abnormal in all cases of known AL amyloidosis. This may be a positive argument for the diagnosis of amyloidosis when histopathological tests are normal. Tissue retention levels appear important as they may be correlated with survival. PMID- 8686720 TI - The incidental adrenal mass. PMID- 8686721 TI - Primary iron overload in African Americans. AB - PURPOSE: To report African Americans with primary iron overload diagnosed during life and to study iron stores in African Americans undergoing autopsy. PATIENTS AND METHODS: We summarized information for 4 African-American patients diagnosed during life with iron overload not explainable by alcohol, blood transfusions, or ineffective erythropoiesis. We reviewed liver specimens and hospital records of 326 unselected adult African Americans who were autopsied, assessing Prussian blue-stained sections for hepatocellular iron and measuring iron quantitatively in specimens that stained positively. We calculated the hepatic iron index (the hepatic iron concentration in mumol/g dry weight divided by the age in years). In autopsy subjects we corrected the index to account for iron administered by blood transfusion (the adjusted hepatic iron index). The hepatic iron index is useful for distinguishing primary iron overload from the moderate siderosis that may accompany alcoholic liver disease. The normal index is < or = 1.0. An index > or = 1.7 cannot be explained by alcohol effects and an index > or = 1.9 indicates the magnitude of iron-loading found in Caucasian homozygous HLA-linked hemochromatosis. RESULTS: The 4 living patients, all males and 27 to 50 years of age, had elevated body iron burdens and one or more of the following: hepatomegaly, cirrhosis, cardiomyopathy, diabetes mellitus, and impotence. Hepatic iron indices were 2.3, 11.5, and 20.2 in the 3 whose liver iron concentrations were measured. Among the autopsy subjects, 4 (1.2%), 2 men and 2 women aged 50 to 63 years, had adjusted hepatic iron indices > or = 1.9 (range 1.9 to 5.6). CONCLUSIONS: Primary iron overload occurs in African Americans. Further studies are needed to define prevalence, pathophysiology and clinical consequences. Clinicians should look for this condition. PMID- 8686722 TI - Strategic business planning for internal medicine. AB - The internal medicine generalist is at market risk with expansion of managed care. The cottage industry of Academic Departments of internal medicine should apply more business tools to the internal medicine business problem. A strength, weakness, opportunity, threat (SWOT) analysis demonstrates high vulnerability to the internal medicine generalist initiative. Recommitment to the professional values of internal medicine and enhanced focus on the master clinician as the competitive core competency of internal medicine will be necessary to retain image and market share. PMID- 8686723 TI - Detection of human cytomegalovirus DNA from allogeneic bone marrow transplant recipients with interstitial pneumonitis. AB - Interstitial pneumonitis (IP) due to human cytomegalovirus (HCMV) infection can kill patients who receive allogeneic bone marrow transplants (BMT). However, making a definitive diagnosis of HCMV-associated IP is difficult, except in pathologically defined cases. The authors tried to detect HCMV DNA amplified by the polymerase chain reaction with nonradioactive Southern blot analysis from paraffin-embedded lung tissue. Human cytomegalovirus DNA was detected in all of ten BMT recipients with IP and all of three non-BMT recipients with histologically diagnosed HCMV IP. Clinical diagnoses indicated that three of ten allogeneic BMT recipients had HCMV IP, and they showed amplified HCMV DNA despite the lack of histologic viral inclusions. However, HCMV DNA was not detected in 11 immunosuppressed patients with non-HCMV pneumonitis who were included as controls. These observations indicate that the polymerase chain reaction and Southern blot analysis used with lung tissue is more sensitive than histologic examination, and that these tests may be applicable to transbronchial lung biopsy specimens for the early specific diagnosis of HCMV IP. Further analysis of allogeneic BMT recipients showed that four patients who died of HCMV IP fewer than 90 days after BMT had higher quantities of HCMV DNA, whereas six patients who died of HCMV IP more than 90 days after BMT showed lower quantities of HCMV DNA. THis result suggests that HCMV IP in the late phase after MBT might not be attributable to active virus replication alone but rather to the immune response involved in the graft-versus-host reaction. PMID- 8686724 TI - Pneumonitis-associated hyperprocalcitoninemia. AB - Elevated serum levels of the prohormone of calcitonin (CT), procalcitonin (ProCT), have been documented in illnesses such as inhalational burn injury, in several sepsis syndromes, and in endotoxemia. In this study, we measured and characterized the circulating precursor forms of CT during the course of infectious pneumonitis. The initial (mean +/- SEM) serum total multiform CT level in 12 patients with acute infectious pneumonia was 1,019 +/- 430 pg/mL. In comparison, the mean level of total CT for 19 age-matched control patients without lung disease was 32 +/- 6 pg/mL (P < 0.001). The mean serum total CT level on initial examination was greater in the 6 patients with bacterial isolates, at 1,793 +/- 752 pg/mL, than in those with nonbacterial infectious pneumonia, at 242 +/- 109 pg/mL (P = 0.018). After admission to the hospital, patients' serum total CT progressively declined concomitantly with the clinical resolution of the pneumonia; at discharge, mean serum level was 121 +/- 34 pg/mL. On discharge, the patients who had persistent radiographic abnormalities had significantly higher levels than did those who had complete resolution. Both the mean serum calcium and phosphate were significantly lower at the initial time of study than at discharge (P < 0.002 and P < 0.0004, respectively). Gel filtration chromatography of sera obtained during the acute pneumonitis phase revealed increased levels of precursor forms of CT, including ProCT; these levels diminished with clinical resolution. In an additional three patients, the serum total CT increased very rapidly after aspiration (within 6 to 12 hours); the peak levels were several times greater than the upper limits of normal. In these patients, the principal serum CT components were ProCT and other precursor forms. These results show that both infectious and aspiration pneumonitis are associated with a rapid increase in circulating ProCT and other precursor forms of CT. PMID- 8686725 TI - Clinical pharmacology forum: motility agents and the gastrointestinal tract. PMID- 8686726 TI - Case reports: trimethoprim-sulfamethoxazole-induced meningitis in patients with HIV infection. AB - Meningitis is a frequent complication of the human immunodeficiency infection. Possible causes include bacterial, fungal, mycobacterial, syphilitic, and vital pathogens (including the human immunodeficiency virus). Drugs must also be considered in the differential diagnosis. Two patients with probable trimethoprim sulfamethoxazole-induced meningitis are described in the setting of human immunodeficiency virus infection. PMID- 8686727 TI - Case report: retinopathy and neuropathy associated with complete apolipoprotein A I deficiency. AB - Genetic deficiencies of plasma high-density lipoprotein cholesterol are associated variably with diseases of the eyes and nervous system. We ascertained a proband with undetectable plasma HDL-cholesterol due to homozygosity for a DNA mutation, APOA1 Q[-2]X, which encodes premature termination of translation of apolipoprotein in HDL. This person had a unique retinopathy, ataxia, and electrophysiologic abnormalities suggesting multifocal central nervous system deficits. Other gene carriers in this family had similar neurologic features, but only the proband had the retinopathy. The presence of retinopathy and neuropathy in affected family members was highly variable. This heterogeneity might results from time-dependent interactions with other genetic or environmental factors. PMID- 8686728 TI - Case report: pancreatic cancer presenting with paraneoplastic gastroparesis. AB - Delayed gastric emptying has been observed in some patients with histologically proved pancreatic cancer without evidence of obstruction. The case of a 73-year old women who had signs and symptoms of delayed gastric emptying is described. Workup included a gastric emptying study that showed 95% retention of the radiolabeled test meal after 2 hours (normal result, <70%). Abdominal computed tomography showed findings consistent with a pancreatic mass. Indirect immunofluorescence study of the patient's serum showed staining of Purkinje cell nuclei and prompted further evaluation for malignant masses. No other cause for the patient's gastroparesis was found, including obstruction. This case illustrates how gastroparesis with no other apparent cause, particularly in elderly patients, may represent a paraneoplastic syndrome. Pancreatic cancer should be included in the list of occult carcinomas that can manifest in this manner. PMID- 8686729 TI - Case report: reactive hemophagocytic syndrome associated with disseminated strongyloidiasis. AB - The reactive hemophagocytic syndrome is a condition characterized by systemic proliferation of benign hemophagocytic histiocytes, fever, cytopenia, abnormal liver function, and frequently coagulopathy and hepatosplenomegaly. Its occurrence has been documented in association with viral, bacterial, fungal and parasitic infections; a wide spectrum of malignant neoplasms; some miscellaneous disorders; and phenytoin. Disseminated strongyloidiasis is reported in a patients with systemic lupus erythematosus treated with corticosteroids in whom a reactive hemophagocytic syndrome developed and who finally died. This reactive hemophagocytic syndrome is reported for the first time in strongyloidiasis and may not have been recognized in former patients. PMID- 8686730 TI - Case report: acute cellulitis and lymphadenitis caused by mucoid Streptococcus pyogenes. AB - Most patients with acute cellulitis due to Streptococcus pyogenes have a striking onset of high fever and systemic toxicity. Even if hospitalization is deemed necessary for initial treatment, most patients respond promptly to appropriate antibiotic therapy and can be managed as outpatients for most of the treatment regimen. Described is a 48-year-old, previously healthy woman with acute cellulitis and lymphadenitis who did not initially respond to treatment despite proved in vitro activity against the patient's S. pyogenes isolate. The strain grew as a mucoid colony phenotype on blood agar plates. The mucoid characteristic of the strain may have accounted for the patient's lack of response to initial therapy, and previously published clinical and laboratory data support this impression. PMID- 8686731 TI - Case report: reversible gastroparesis in patients with hypopituitary disease. AB - A 72-year-old woman with chronic fatigue, malaise, weight loss, nausea, and vomiting was treated unsuccessfully for gastroparesis for more than 2 years. Clinical and biochemical features of hypopituitary disease and symptoms of a nonsecreting pituitary tumor had been overlooked and became apparent only after the differential diagnosis of hyponatremia was considered. Transsphenoidal resection of the pituitary tumor and appropriate 1-thyroxine and hydrocortisone replacement returned her gastric emptying time to normal and relieved her symptoms. Primary and secondary deficits of l-thyroxine and cortisol should be considered when making a possible diagnosis of gastroparesis. PMID- 8686732 TI - Urokinase-type plasminogen activator expression in human prostate carcinomas. AB - The prostate gland is the most common site of cancer in men in the United States. The biologic behavior of an individual tumor, however, varies widely, with some cancers taking a relatively indolent course and other progressing rapidly to disseminated disease. Prognostic factors that might help predict a tumor's aggressiveness and invasiveness are limited. The expression of urokinase plasminogen activator was evaluated in 36 human prostate cancer specimens. Using an immunohistochemical method with monoclonal antibody #394, 70.6% (12 of 17) of cancer specimens with extracapsular extension showed increased expression of urokinase plasminogen activator, compared with 26.6% (4 of 15) of specimens without capsular invasion. Increased expression was localized to the glandular cytoplasm, with tumor stroma yielding predominantly negative results. These findings provide additional evidence of the role of urokinase in determining the biologic behavior and metastatic potential of prostate cancer. PMID- 8686733 TI - Molecular framework for angiogenesis: a complex web of interactions between extravasated plasma proteins and endothelial cell proteins induced by angiogenic cytokines. PMID- 8686735 TI - Cell fusion to study nuclear-cytoplasmic interactions in endothelial cell apoptosis. AB - Studies examining the regulation of nuclear rearrangements during apoptosis have led to conflicting results. Cytoplasmic control of nuclear events has been strongly suggested by cell-free experimental systems. In contrast, strict cytoplasmic control cannot account for the results of fibroblast-thymocyte fusion experiments in which dexamethasone induction of polykaryons led only to thymocyte nuclear apoptosis. Unresolved by these fusion studies was whether fibroblast nuclei were indifferent to heterologous cytoplasmic signals. Our objective was to resolve this discrepancy using cell fusion in a homologous system. Our strategy was to fuse endothelial cells with high levels of susceptibility to the induction of apoptosis (log phase cells arrested in G1 for 48 hours by isoleucine deprivation) with those manifesting low levels of susceptibility (serum-deprived, G0). Resultant fused and unfused cells were induced to undergo apoptosis by incubation with tumor necrosis factor-alpha and cycloheximide. Depending on the parental cell of origin, between 14 and 30% of dikaryons contained one apoptotic and one intact nucleus, indicating that strict cytoplasmic control was not occurring. In accord with this, the total frequency of nuclear apoptosis was unchanged after fusion. However, the distribution of apoptotic nuclei revealed a pronounced cytoplasmic influence, with a two- to fivefold increase in coordinate nuclear behavior. This pattern of nuclear apoptosis was consistent with a model of control in which both the state of nuclear susceptibility to apoptosis and expression of cytoplasmic pro-apoptotic regulators determined whether nuclear apoptosis would eventuate. PMID- 8686734 TI - Tissue factor expression during human and mouse development. AB - In the adult organism the cellular distribution of tissue factor (TF) expression corresponds to biological boundary layers forming a hemostatic barrier ready to activate blood coagulation after tissue injury. Whether TF expression might also play a role in development is unknown. To determine the significance of TF in ontogenesis, we examined the pattern of TF expression in mouse development and compared it with the distribution of TF in human post-implantation embryos and fetuses of corresponding gestational age. At early embryonic periods of murine (6.5 and 7.5 pc) and human (stage 5) development, there was strong expression of TF in both ectodermal and entodermal cells. In situ hybridization and immunohistochemistry demonstrated that TF mRNA and protein were expressed widely in epithelial areas with high levels of morphogenic activity during organogenesis. Staining for TF was seen during ontogenetic development in tissues such as epidermis, myocardium, bronchial epithelium, and hepatocytes, which express TF in the adult organism. Surprisingly, during renal development and in adults, expression of TF differed between humans and mice. In humans, maturing stage glomeruli were stained for TF whereas in mice, TF was absent from glomeruli but was present in the epithelia of tubular segments. In neuroepithelial cells, there was a substantial expression of TF. Moreover, there was robust TF expression in tissues such as skeletal muscle and pancreas, which do not express it in the adult. In contrast, expression of the physiological ligand for TF, factor VII, was not detectable during early stages of human embryogenesis using immunohistochemistry. The temporal and spatial pattern of TF expression during murine and human development supports the contention that TF serves as an important morphogenic factor during embryogenesis. PMID- 8686736 TI - Human carcinomas variably express the complement inhibitory proteins CD46 (membrane cofactor protein), CD55 (decay-accelerating factor), and CD59 (protectin). AB - Normal human tissues express membrane-associated complement inhibitory proteins that protect these tissues from damage by autologous complement. To determine whether neoplasms also express these proteins, we examined the distribution of the complement inhibitors decay-accelerating factor (DAF), CD59 (protectin), and membrane cofactor protein in frozen samples of human breast, colon, kidney, and lung carcinomas and in adjacent non-neoplastic tissues, using immunohistochemistry. All samples were also studied for deposition of C3 fragments and activated C5b-9. Differences between normal tissues and the corresponding neoplasms were often observed, with loss or gain of expression of one or more inhibitors. Ductal carcinomas of the breast showed the most variation in phenotype; some tumors expressed only one inhibitor while others expressed different combinations of two or three inhibitors. Colon carcinomas, by contrast, stained intensely for all inhibitors. Renal cell carcinomas had weak to moderate expression of one to three inhibitors, generally DAF and CD59, whereas non-small cell carcinomas of the lung usually expressed CD59 and membrane cofactor protein with variable DAF immunoreactivity. The two small cell carcinomas of the lung showed little or no staining for any inhibitor. Activated C5b-9 deposition was seen adjacent to tumor nests in a minority of carcinomas and showed no correlation with complement inhibitor expression. C3 fragment deposition was minimal. Our results demonstrate that most carcinomas, with the exception of small cell carcinomas of the lung, do express one or more complement inhibitors at a level likely to inhibit complement-mediated cellular damage. Unexpectedly, large quantities of DAF and CD59 were often observed in tumor stroma, with only limited deposition in normal connective tissue. This suggests that carcinomas may supplement the activity of membrane-associated complement inhibitors by release of soluble forms of DAF and CD59 into the surrounding extracellular matrix. PMID- 8686737 TI - The MDM2 oncoprotein is overexpressed in rhabdomyosarcoma cell lines and stabilizes wild-type p53 protein. AB - MDM2 gene overexpression has been implicated in the pathogenesis of human neoplasia via inhibition of the p53 tumor-suppressor function. To investigate the potential involvement of the MDM2 oncogene in the pathogenesis of childhood rhabdomyosarcoma (RMS) we studied MDM2 abnormalities in six RMS cell lines in correlation with the p53 status. Three showed overexpression of MDM2 mRNA and protein, one with concomitant MDM2 gene amplification. All three lacked p53 mutation and expressed low levels of p53 mRNA but exhibited elevated p53 proteins. Double immunostaining revealed that the overexpressed MDM2 and p53 proteins were co-localized to the same cell nuclei. Furthermore, the two proteins were physically associated, as shown by co-immunoprecipitation and Western blot analysis. The half-life of the p53 protein was prolonged in the MDM2-expressing RMS cells. The extended half-life wildtype p53 protein and its complex formation with the elevated MDM2 suggest that the underlying mechanism for p53 protein accumulation in these cell lines is p53 stabilization by an overabundant MDM2 protein. The overexpressed MDM2 protein had a short half-life. The three remaining RMS cell lines exhibited low MDM2 mRNA and protein levels and carried p53 mutations. This study suggest that MDM2 overexpression represents an alternative mechanism for p53 inactivation in a subset of childhood RMS without p53 mutations. The results further indicate that the elevated MDM2 protein is responsible for wildtype p53 protein accumulation via stabilization. PMID- 8686738 TI - High frequency of aberrant p16(INK4A) expression in human breast cancer. AB - The product of the CDKN2/MTS1 gene, p16(INK4A) (16), inhibits phosphorylation of the retinoblastoma protein, pRB, and thus acts as a negative cell cycle regulator. It is inactivated in a wide range of human malignancies, including breast cancer. Using an immunohistochemical approach, we studied the expression of both p16 and pRB in 104 archival breast tumors, including 63 ductal, 33 lobular, and 8 mixed carcinomas. All specimens except one were evaluable for pRB expression, but only 87 were interpretable for p16 expression, reflecting the lower abundance and greater lability of this protein. Only six tumors showed abnormal RB expression. However, 43 carcinomas (49%) were completely (35) or focally (8) negative for p16. Abnormal p16 expression did not significantly correlate with several histopathological parameters. These findings provide evidence that aberrant p16(INK4A) expression is one of the most common abnormalities in human breast cancer. PMID- 8686739 TI - Incidence of chromosome numerical changes in multiple myeloma: fluorescence in situ hybridization analysis using 15 chromosome-specific probes. AB - The presence of complex karotypes with frequent numerical and structural abnormalities has been reported in 20 to 50% of multiple myeloma (MM) patients. This variability is mainly due to the difficulty of conventional cytogenetics to obtain tumor metaphases representative of all possible neoplastic clones in MM. To gain insight into the real incidence of numerical chromosome changes in MM we have studied by fluorescence in situ hybridization technique 15 different human chromosomes, 1, 3, 6, 7, 8, 9, 10, 11, 12, 13, 15, 17, 18, X, and Y, in a series of 52 MM patients. In all cases, the DNA index assessed by a propidium iodide/CD38 double-staining technique with flow cytometry was simultaneously investigated for correlation, with fluorescence in situ hybridization results. Additional aims of this study were 1) to analyze whether the abnormalities detected were common to all plasma cells or were present in only a subpopulation of tumor cells, 2) to explore changes caused by disease progression, and 3) to establish possible associations among the altered chromosomes. Although the overall incidence of numerical abnormalities was 67%, this frequency increased to 80% in the 41 cases in which 7 or more chromosomes were analyzed. Trisomies were significantly more common than monosomies (84% versus 16%). Chromosomes 9 and 15 were the most frequently altered (52% and 48% of cases, respectively), with all of their abnormalities corresponding to trisomies. The most frequent losses involved chromosomes 13 (26%) and X in females (32%). Other common numerical changes corresponded to chromosomes 1 (39%), 11 (37%), 6 (32%), 3 (31%), 18 (29%), 7 (28%), and 17 (22%). By contrast, chromosomes 8(13%), 10(8%), and 12(3%) were rarely altered. DNA aneuploidy by flow cytometry was detected in 67% of patients, and a high degree of correlation was observed between the DNA index obtained by flow cytometry and the chromosome index derived from fluorescence in situ hybridization studies, calculated according to two mathematical formulas (coefficient of correlation of 0.82 and 0.91 when at least 7 or 12 chromosomes were considered, respectively). The frequency of numeric chromosome aberrations was higher in those patients with progressive disease and, interestingly, trisomy of chromosome 8 was exclusively detected in this latter group of patients. Our study shows that, with the exception of chromosome 8, a possible marker of clonal evolution, the numeric chromosome changes are present in nearly all malignant plasma cells (r > 0.84). Finally, frequent associations between chromosomal aberrations were observed (ie, chromosomes 6, 7, 9, and 17; 7 and 15; and 11 and 17). By excluding them, it was found that two triple combinations of chromosome specific probes, chromosomes 1 and 9 together with either chromosome 13 or 15, could be a useful marker for detection of residual disease, as it permits the identification of most MM patients displaying numerical changes. PMID- 8686740 TI - Induction of lymphocyte proliferation and severe gastrointestinal disease in macaques by a nef gene variant SIVmac239. AB - The molecularly cloned virus known as SIVmac239/YEnef causes extensive lymphocyte activation in unstimulated peripheral mononuclear cell cultures and induces an acute disease syndrome in macaque monkeys. Here we describe the histopathological and immunophenotypic changes and viral localization in peripheral lymph nodes, spleen, and gastrointestinal tract (including the gut-associated lymphoid tissue (GALT) in rhesus monkeys inoculated with SIVmac239/YEnet beginning at day 3 postinoculation (pi). The findings are compared with those of rhesus monkeys inoculated with the same dose of parental SIVmac239. Histopathological examination of peripheral lymphoid tissue and GALT demonstrated marked hyperplasia of T-cell-dependent regions and involution of germinal centers as early as day 7 pi. The most striking lesions were multifocal areas of lymphohistiocytic gastroenteritis and colitis. Cellular infiltrates peaked between day 7 and 14 pi and were composed primarily of CD3+ T lymphocytes and HAM 56+ monocyte/macrophages. Many of these inflammatory cells were also strongly immunoreactive for teh nuclear proliferation antigen Ki-67. Despite the presence of severe gastrointestinal pathology by day 7 pi, no significant difference in the numbers of virus-positive cells in the gastrointestinal tract was observed between these animals and SIVmac239-infected animals examined at the same time point. However, the distribution of virus in the gastrointestinal tract was markedly different, with virus localized to lymphoid nodules of GALT in SIVmac239 infected animals and restricted to areas of lymphohistiocytic gastroenteritis and colitis in animals infected with SIVmac239/YEnef. Our data indicate that the acute disease syndrome induced by SIVmac239/YEnef is not simply related to increased viral replication in the gastrointestinal tract but is likely due to inappropriate virus-induced T lymphocyte activation and proliferation in GALT and subsequent mucosal destruction. PMID- 8686741 TI - Immunodetection of apoptosis-regulating proteins in lymphomas from patients with and without human immunodeficiency virus infection. AB - The expression of the apoptosis-regulating genes Bcl-2, Bcl-x, Bax, Mcl-1, and p53 analyzed in 4 cases of human immunodeficiency virus (HIV)-associated Hodgkin's disease, in 36 cases of HIV-related non-Hodgkin's lymphomas (NHLs), and in 109 cases of non-HIV-related NHLs by using immunohistochemistry. HIV associated Hodgkin's disease samples were positive for all markers. For the HIV related NHL samples, 36, 66, 88, 100, and 94% of the cases were Bcl-2, Bcl-x, Bax, Mcl-1, and p53 were found to be expressed in 69, 65, 82, 83, and 42%, respectively. No significant differences were observed in Bax and Mcl-1 staining between HIV-unrelated NHLs of B cell and T cell types. In contrast, Bcl-2 was positive in 66/79 (83%) and 10/30 (33%) of B cell and T cell HIV-unrelated NHLs, respectively (P2 < 0.001). Peculiar patterns were observed for hairy cell leukemia (Bax+, Bcl-2+, Mcl-1-) and for anaplastic large cell lymphoma (Bax+, Mcl 1+, Bcl-2-) in HIV-unrelated NHLs. Of interest, all cases with a positive expression of Bax were also found to express either Mcl-1 and/or Bcl-2, suggesting that Mcl-1 and Bcl-2 may counteract the pro-apoptosis function of Bax in vivo by protein-protein interaction within the tumor cell, as demonstrated previously in vitro. These results suggest that apoptosis regulation may have a role in the pathogenesis of some HIV-related and HIV-unrelated NHLs. PMID- 8686742 TI - In situ analysis of B7-2 costimulatory, major histocompatibility complex class II, and adhesion molecule expression in schistosomal egg granulomas. AB - Immunopathological damage in schistosomiasis consist of egg granuloma formation, which is a hypersensitivity reaction mediated by antigen-specific CD4+ T helper (Th) lymphocytes. Th cells are dependent on accessory cell-bound co-stimulatory signals for activation. The B7 molecules provide critical costimulation, as in their absence T cells are rendered unresponsive. We investigated the kinetics of B7-2 molecule expression in schistosomal egg granulomas by immunocytochemical analysis in situ. We also monitored major histocompatibility complex (MHC) class II, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) expression, as well as the presence of macrophages, T cells, and B cells. B7-2 expression was elevated in cells of the large granulomas of the acute (6-1/2 week) infection, and sharply declined thereafter. MHC class II expression was similarly elevated in the acute granulomas, but in contrast to B7 2, remained relatively constant throughout 12 1/2 weeks of infection. Moreover, ICAM-1 and VCAM-1 were expressed in acute and chronic granulomas. However, whereas ICAM-1 was constitutively expressed in normal liver, VCAM-1 was dramatically induced in the livers upon onset of disease. The findings suggest that the acute granulomas are rich in accessory cells with overall phenotypic configurations that support Th-cell activation, although at subsequent times, granulomas contain increasing numbers of B7-poor accessory cells capable of inducing Th-cell unresponsiveness. Thus, cellular interactions in early granulomas may be able to amplify egg-induced immunopathology, whereas interactions taking place in succeeding granulomas appear to precipitate its down regulation. PMID- 8686743 TI - Tumor necrosis factor-alpha inhibits collagen alpha1(I) gene expression and wound healing in a murine model of cachexia. AB - The mechanisms responsible for impaired wound healing in patients with cachexia associated infection, inflammation, and cancer are unknown. As tumor necrosis factor (TNF)-alpha is elevated in these diseases, and TNF-alpha inhibits collagen alpha1(I) gene expression in cultured fibroblasts, we analyzed whether chronically elevated serum TNF-alpha affects collagen metabolism in vivo by inoculating nude mice with Chinese hamster ovary cells secreting TNF-alpha (TNF alpha mice) or control Chinese hamster ovary cells (control mice). Before the onset of weight loss, TNF-alpha mice had a selective decrease in collagen synthesis and collagen alpha1(I) mRNA in the skin. In addition, TNF-alpha mice displayed impaired healing of incisional and excisional skin wounds, compared with control animals, before the onset of cachexia. The expression of transforming growth factor-beta1, a potent fibrogenic factor, was inhibited by TNF-alpha in the skin. In studies with transgenic mice expressing the human growth hormone under the direction of 5' regulatory regions of the human collagen alpha1(I) gene, TNF-alpha treatment inhibited the expression of the collagen alpha1(I) human growth hormone transgene containing -2.3 kb of the 5' region, whereas transgene expression directed by -0.44 kb of the 5' region was not affected. These experiments suggest that TNF-alpha may play an important role in the impaired wound healing of chronic diseases that are characterized by a high production of this cytokine and provide insights for potential therapeutic approaches. PMID- 8686744 TI - Up-regulated expression of transforming growth factor-alpha in the bronchiolar alveolar duct regions of asbestos-exposed rats. AB - It has become apparent that the numerous growth factors and cytokines are produced during the development of fibroproliferative lung disease. Investigators must sort out which combinations of these factors are playing mechanistic roles in the disease process. Here we demonstrate that transforming growth factor (TGF) alpha, a potent epithelial and mesenchymal cell mitogen, is upregulated specifically at the sites of asbestos fiber deposition in the lungs of rats exposed for 5 hours. Unexposed animals and those exposed to high concentrations of iron spheres exhibited no increase in TGF-alpha expression at any time during the experiment. Inhaled asbestos fibers deposit initially at the bronchiolar alveolar duct regions and alveolar macrophages accumulate at these sites within hours. Non-isotopic in situ hybridization and immunohistochemistry were used to show that the mRNA that codes for TGF-alpha along with the peptide were clearly up-regulated at the bronchiolar-alveolar duct regions by 24 hours after the single asbestos exposure. The numbers of labeled cells demonstrated that expression of the mRNA and protein remained significantly above background for at least 2 weeks after exposure along with increased cell proliferation assessed by staining for proliferating cell nuclear antigen. This, to our knowledge, is the first demonstration of TGF-alpha expression at sites of lung injury in developing fibroproliferative disease. This finding supports the hypothesis that the growth factor is involved in the dramatic epithelial and mesenchymal proliferation we documented previously, although additional experiments will be essential to establish the precise role of TGF-alpha. PMID- 8686745 TI - Evidence of neuronal oxidative damage in Alzheimer's disease. AB - Oxidative stress has been proposed as a pathogenetic mechanism in Alzheimer's disease. One mechanism of oxidative damage is the nitration of tyrosine residues in proteins, mediated by peroxynitrite breakdown. Peroxynitrite, a reaction product of nitric oxide and superoxide radicals, has been implicated in N-methyl D-aspartate receptor-mediated excitotoxic damage. Reported evidence of oxidative stress in Alzheimer's disease includes increased iron, alterations in protective enzymes, and markers of oxidative damage to proteins and lipids. In this report, we demonstrate the presence of nitrotyrosine in neurofibrillary tangles of Alzheimer's disease. Nitrotyrosine was not detected in controls lacking neurofibrillary tangles. Immunolabeling was demonstrated to be specific nitrotyrosine in a series of control experiments. These observations link oxidative stress with a key pathological lesion of Alzheimer's disease, the neurofibrillary tangle, and demonstrate a pathogenetic mechanism in common with the other major neurodegenerative diseases of aging, Parkinson's disease and amyotrophic lateral sclerosis. These findings further implicate nitric oxide expression and excitotoxicity in the pathogenesis of cell death in Alzheimer's disease. PMID- 8686746 TI - High levels of circulating beta-amyloid peptide do not cause cerebral beta amyloidosis in transgenic mice. AB - We have established transgenic mice that constitutively overproduce the signal sequence and the 99-amino-acid carboxyl-terminal region of the human beta-amyloid precursor protein. The transgenic mice strongly expressed the transgene in multiple tissues under the control of a cytomegalovirus enhancer/chick beta-actin promoter. There were exceptionally high levels of beta-amyloid peptides in the plasma (approximately 17 times or more compared with the human plasma level). Although some transgenic mice from one founder line developed amyloidosis in the intestine, no neuropathology was found in transgenic mice up to age 29 months. Given the absence of cerebral beta-amyloidosis despite extremely high levels of circulating beta-amyloid peptides in the transgenic mice, the results suggest that local cerebral metabolism of beta-amyloid precursor protein may play a predominant role in cerebral beta-amyloidosis in transgenic mice. Such transgenic mice may be useful for the investigation of the etiology of the disease and for the establishment of therapeutic strategies. PMID- 8686747 TI - Chromosome 3 allelic losses and microsatellite alterations in transitional cell carcinoma of the urinary bladder. AB - A deletion analysis of chromosome 3 was conducted in 72 cases of transitional cell carcinoma of the urinary bladder using seven microsatellites spanning the 3p arm and two additional microsatellites in 3q. Results showed that 19 of 72 (26.4%) cases had deletions in one or more 3p regions. Two regions of frequent deletion were identified: 3p12-14 and 3p21-23. Less frequent deletions at 3p24.2 25 were also observed. Deletions at 3p were weakly correlated with tumor grade, but strongly with pathological stage. Among 70 cases with histological grade available, 4 of 29 (13.8%) grade 1 and 2 tumors, and 15 of 41 (36.6%) grade 3 tumors showed allelic losses in one or more of the 3p regions studied (P = 0.055). Among 69 cases with pathological stage available, none of 27 superficial carcinomas (pTa, pTis, and pT1) showed 3p deletions, whereas 18 of 42 (42.9%) muscle invasive lesions (pT2, pT3, and pT4) displayed allelic losses at 3p (P < 0.001). In addition, 12 cases showed microsatellite instability, but there was no correlation between abnormalities and tumor grade or stage. No correlation was found between deletions at 3p21-23 and microsatellite instability. In conclusion, deletions at three discrete regions of 3p were identified in bladder carcinoma, suggesting the involvement of candidate tumor suppressor genes residing in these regions. Moreover, detection of allelic losses in these regions was associated with higher tumor grade and more advanced stage, suggesting their potential involvement in bladder tumor progression. PMID- 8686748 TI - Intratumor heterogeneity of K-ras2 mutations in colorectal adenocarcinomas: association with degree of DNA aneuploidy. AB - Detailed information about intratumor K-ras2 mutations in colorectal adenocarcinomas and a possible association with DNA content heterogeneity is still lacking. DNA diploid and aneuploid subclones, detected among multiple histologically selected primary sectors (57 superficial and 40 deep) and 9 lymph node metastases, were flow cytometrically sorted and separately submitted to codons 12-13 K-ras2 mutation spectrum analysis. DNA aneuploidy was absent among 20 near and 20 distant mucosa sites and present in 7/9 lymph node metastases and in 17/19 primary tumors (90%). Primary intratumor DNA multiclonality was approximately 50%. Degree of DNA aneuploidy (DNA Index) distribution was nonrandom and showed peaks at approximate mean DNA Index values 1.2, 1.5, and 1.8. K-ras2 mutations were detected in 0/20 mucosa cases, in 2/9 lymph node metastases, and in 9/19 adenocarcinomas (47%). No more than one mutation type per tumor was detected. Intratumor distribution of K-ras2 mutations was homogeneous in 6 and heterogeneous in 3 cases. Homogeneous distribution was associated with DNA near-diploid aneuploidy. K-ras2 mutations were strongly associated with DNA Index in the near-diploid region (83%) and almost absent (5%) among DNA near triploid subclones (P = 0.0001). K-ras2 mutation intratumor heterogeneity indicates that sampling of the tumor may be a critical step and suggests that K ras2 activation may be a late event in a subgroup of tumors. Our data also suggest the existence of an early process of the colorectal carcinogenesis that favors both K-ras2 mutations and DNA near-diploid aneuploidy. Onset of DNA near triploid subclones appears, instead, to be independent from K-ras2 activation. PMID- 8686749 TI - Retinoic acid induces cells cultured from oral squamous cell carcinomas to become anti-angiogenic. AB - Retinoids have shown great promise as chemopreventive against the development of squamous cell carcinomas of the upper aerodigestive tract. However, the exact mechanism by which they block new tumors from arising is unknown. Here, we report that 13-cis- and all-trans-retinoic acid, used at clinically achievable doses of 10(-6) mol/L or less, can directly and specifically affect cell lines cultured from oral squamous cell carcinomas, inducing them to switch from an angiogenic to an anti-angiogenic phenotype. Although retinoic-acid-treated and untreated tumor cells make the same amount of interleukin-8, the major inducer of neovascularization produced by such tumor lines, they vary in production of inhibitory activity. Only the retinoic-acid-treated cells produce a potent angio inhibitory activity that is able to block in vitro migration of endothelial cells toward tumor cell conditioned media and to halt neovascularization induced by such media in the rat cornea. Anti-angiogenic activity is induced in the tumor cells by low doses of retinoids in the absence of toxicity with a kinetics that suggest that it could be contributing to the effectiveness of the retinoids as chemopreventive agents. PMID- 8686750 TI - Autocrine secretion of osteopontin by vascular smooth muscle cells regulates their adhesion to collagen gels. AB - Osteopontin (OPN) is a secreted protein postulated to facilitate vascular smooth muscle cell (VSMC) adhesion and migration. Rat aortic VSMC lines were isolated after infection with recombinant retroviruses harboring OPN sense and antisense constructs. All lines grew normally in monolayer culture. On three-dimensional collagen gels, normal VSMCs and lines containing sense constructs (n=15) or empty vector (n=10) attached to gel and invaded the matrix. Four of five antisense clones did not adhere or invade. Antisense clones had lower OPN levels after stimulation with angiotensin II than sense clones or clones containing the empty vector (antisense, 257+/-102 ng/ml; sense, 473+/-104; vector, 434+/-66). Non adhering antisense clones had lower mean OPN levels after angiotensin II stimulation (161+/-47 ng/ml) than sense or antisense lines with normal adhesion (486+/-63 ng/ml). The ability to adhere correlated with OPN levels >250 ng/ml. Adhesion and invasion were fully restored with addition of 100 to 200 ng/ml of exogenous OPN and were inhibited in normal VSMCs by incubation with 1 microgram/ml anti-OPN antibody. The autocrine secretion of OPN appears to play an important role in VSMC adhesion, spreading, and invasion. PMID- 8686751 TI - Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. AB - Matrix metalloproteinase (MMP) family members have been associated with advanced stage cancer and contribute to tumor progression, invasion, and metastasis as determined by inhibitor studies. In situ hybridization was performed to analyze the expression and localization of all known MMPs in a series of human breast cancer biopsy specimens. Most MMPs were localized to tumor stroma, and all MMPs had very distinct expression patterns. Matrilysin was expressed by morphologically normal epithelial ducts within tumors and in tissue from reduction mammoplasties, and by epithelial-derived tumor cells. Many family members, including stromelysin-3, gelatinase A, MT-MMP, interstitial collagenase, and stromelysin-1 were localized to fibroblasts of tumor stroma of invasive cancers but in quite distinct, and generally widespread, patterns. Gelatinase B, collagenase-3, and metalloelastase expression were more focal; gelatinase B was primarily localized to endothelial cells, collagenase-3 to isolated tumor cells, and metalloelastase to cytokeratin-negative, macrophage-like cells. The MMP inhibitor, TIMP-1, was expressed in both stromal and tumor components in most tumors, and neither stromelysin-2 nor neutrophil collagenase were detected in any of the tumors. These results indicate that there is very tight and complex regulation in the expression of MMP family members in breast cancer that generally represents a host response to the tumor and emphasize the need to further evaluate differential functions for MMP family members in breast tumor progression. PMID- 8686752 TI - Morphological relationships of von Willebrand factor, type VI collagen, and fibrillin in human vascular subendothelium. AB - von Willebrand factor (vWF) plays an important role in the process of platelet adhesion after endothelial injury by serving as a bridge between constituents of the vascular subendothelium and platelet membrane receptors. We previously presented evidence that type VI collagen microfibrils serve as a binding site for vWF in human vascular subendothelium. However, others have proposed that vWF is not associated with type VI collagen but rather with the thicker elastin associated microfibrils, which contain several proteins including fibrillin. We therefore investigated the relationships among vWF, type VI collagen, and fibrillin in human vascular subendothelium by immunoelectron microscopy using single- and double-labeling immunogold localization techniques. In addition, we observed the three-dimensional ultrastructure of vWF-microfibril complexes by stereo paired micrographs and stereo viewer. We found that vWF co-localizes only with the type VI collagen microfibrils in subendothelium but not with fibrillin microfibrils or striated collagen. The vWF is present in subendothelium in the form of electron-dense aggregates having diameters varying between 65 and 80 nm that are closely associated with, and enmesh, the type VI collagen microfibrils and have structural similarities to intracellular Weibel-Palade bodies. The occasional co-localization of type VI collagen and fibrillin adjacent to internal elastic lamina was observed. These results are consistent with the hypothesis that type VI collagen, but not fibrillin-containing microfibrils, serves as a physiologically relevant binding site for vWF in the vascular subendothelium, where the type VI collagen-vWF complex may play an important role modulating the hemostatic response to vascular injury. PMID- 8686753 TI - Epidermal growth factor receptor expression in oligodendroglial tumors. AB - A series of 13 oligodendrogliomas (WHO grade II) and 20 anaplastic oligodendrogliomas (WHO grade III) was studied for gene amplification and expression of the epidermal growth factor receptor gene (EGFR). EGFR gene amplification was found in only one case of anaplastic oligodendroglioma, which additionally showed a deletion/rearrangement at the 5' end of the gene. Northern blot analysis, however, revealed increases of EGFR mRNA expression relative to non-neoplastic control brain in 6 of 13 oligodendrogliomas and 10 of 18 anaplastic oligodendrogliomas. All cases with increased mRNA expression showed strong immunoreactivity for EGFR protein. Our findings thus indicate that increased expression of EGFR mRNA and protein is common in low-grade and high grade oligodendroglial tumors and in the vast majority of cases is not caused by gene amplification. PMID- 8686756 TI - Perinuclear distribution of plectin characterizes visceral epithelial cells of rat glomeruli. AB - Plectin is an intermediate-filament-associated protein identified over a wide range of tissue and cell types. The distribution of this protein in glomerular visceral epithelial cells (VECs) during the differentiation and growth of rat kidneys was studied in comparison with that of vimentin. By immunofluorescence microscopy, preferential localization of these two cytomatrix elements was different, although both were observed in the cell body and primary processes of VECs. Strong staining of plectin was always found in the perinuclear region of the VEC body in kidneys of young and adult rat, but vimentin stained distinctly only in the primary processes of young rats yet in both cell bodies and primary processes of the adults. This perinuclear staining was unique to VECs, that is, was absent from other cells. In the neonatal kidney, plectin staining during differentiation of VECs changed from weak and diffuse throughout the cytoplasm in the S-shaped body to prominently perinuclear in the maturing stage. However, after the differentiation of VECs, the staining intensity of plectin did not change further. In contrast, that of vimentin increased conspicuously in parallel with the growth of VECs rather than at differentiation. After a long period of culture and during aminonucleoside nephrosis, situations when VECs lose differentiated phenotypes, most of the cells had no perinuclear plectin. These findings indicate that the perinuclear distribution of plectin may play an important role in the differentiation of VECs. PMID- 8686754 TI - Stimulation of endothelial cell migration by vascular permeability factor/vascular endothelial growth factor through cooperative mechanisms involving the alphavbeta3 integrin, osteopontin, and thrombin. AB - We have identified several mechanisms by which the angiogenic cytokine vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) likely regulates endothelial cells (EC) migration. VPF/VEGF induced dermal microvascular EC expression of mRNAs encoding the alphav and beta3 integrin subunits resulting in increased levels of the alphavbeta3 heterodimer at the cell surface, and VPF/VEGF also induced mRNA encoding osteopontin (OPN), an alphavbeta3 ligand. OPN promoted EC migration in vitro; and VPF/VEGF induction of alphavbeta3 was accompanied by increased EC migration toward OPN. Because thrombin cleavage of OPN results in substantial enhancement of OPN's adhesive properties, and because VPF/VEGF promotes increased microvascular permeability leading to activation of the extrinsic coagulation pathway, we also investigated whether VPF/VEGF facilitates thrombin cleavage of OPN in vivo. Consistent with this hypothesis, co injection of VPF/VEGF together with OPN resulted in rapid cleavage of OPN by endogenous thrombin. Furthermore, in comparison with native OPN, thrombin-cleaved OPN stimulated a greater rate of EC migration in vitro, which was additive to the increased migration associated with induction of alpha v beta 3. Thus, these data demonstrate cooperative mechanisms for VPF/VEGF regulation of EC migration involving the alphavbeta3 integrin, the alphavbeta3 ligand OPN, and thrombin cleavage of OPN. These findings also illustrate an operational link between VPF/VEGF induction of EC gene expression and VPF/VEGF enhancement of microvascular permeability, suggesting that these distinct biological activities may act accordingly to stimulate EC migration during angiogenesis. PMID- 8686755 TI - Secretion of monocyte chemotactic activity by cultured rat aortic smooth muscle cells in response to PDGF is due predominantly to the induction of JE/MCP-1. AB - Inflammation is a critical feature of atherosclerosis and is characterized in part by the migration of circulating monocytes to the atherosclerotic plaque. These monocytes, together with macrophages, are a source of cytokines, growth factors, proteases, and procoagulants, which contribute to the progression of the atherosclerosis lesion. This study employed a modified Boyden chamber to examine the secretion of monocyte chemotactic activity by cultured rat aortic vascular smooth muscle cells in response to growth factors and cytokines. The induction of monocyte chemotactic activity showed a surprising specificity for platelet derived growth factor-BB. This activity was blocked by actinomycin D and cycloheximide and thus required de novo transcription and protein synthesis. The ability to stimulate monocyte migration appeared to be solely due to the secretion of the monocyte chemoattractant protein JE/MCP-1 and was completely blocked by antisense oligonucleotides and antibodies to JE/MCP-1. The induction of chemotactic activity was also blocked by dexamethasone, an inhibitor of JE mRNA accumulation. This study suggests that the secretion of monocyte chemotactic activity by vascular smooth muscle cells is a highly regulatable and specific event and underscores the importance of JE/MCP-1 in the inflammatory response of the vessel wall. PMID- 8686757 TI - Development of a novel rat mutant with spontaneous limbic-like seizures. AB - A new epileptic rat mutant with spontaneous seizures was developed by successive mating and selection from an inherited cataract rat. The procedures for developing the mutant and the symptomatology, electroencephalographic correlates, and neuropathology of the mutant are reported. It is possible that this rat stain will provide a useful animal model for human temporal lobe epilepsy. The seizures of the rat usually begin with face and head myoclonus, followed by rearing, and generalized clonic and tonic convulsions, all of which are symptomatologically the same as limbic seizures. Electrographic recording during generalized convulsive seizures demonstrated that sustained spike discharges emerged at the hippocampus and then propagated to the neocortex. Seizures occurred spontaneously without any artificial stimuli. Furthermore, external stimuli such as auditory, flashing light, or vestibular stimulations could not elicit epileptic attacks. Almost all of the male animals had generalized convulsions, mostly from 5 months after birth, and the frequency of the seizures increased with aging. Generalized convulsions developed in approximately 20% of the female rats. Microdysgenesis, such as abnormal neuronal clustering, neuronal disarrangement, or interruption of pyramidal neurons in the hippocampal formation, was found in the young rats that had not yet had generalized seizures. This microdysgenesis, which is though to be genetically programmed, was very interesting from the aspect of the relationship between structural abnormalities and epileptogenesis in this mutant. In addition to microdysgenesis, there was sprouting of mossy fibers into the inner molecular layer of the dentate gyrus in those adult rats that had repeated generalized convulsions. An increase of glial-fibrillary-acidic-protein-positive astrocytes with thickened and numerous processes, ie, astrogliosis, was also found in the cerebral cortex, amygdala region, and hippocampus of these adult animals. Judging from the characteristics of the symptomatology, electroencephalographic correlates, and neuropathology, this epileptic mutant can be expected to be a useful animal model for studying human temporal lobe epilepsy. PMID- 8686758 TI - Novel predictive assay for contact allergens using human skin explant cultures. AB - Contact allergens sensitize the immune system by the binding to and subsequent activation of Langerhans cells (LCs), the antigen-presenting cells of the skin. At present, new chemicals are usually tested for their contact allergenicity in animal models. To develop an animal-replacing predictive in vivo assay for the identification of potential contact allergens, we compared the effects of epicutaneous application of six known contact allergens, five known irritants and two dermatologically inactive chemicals on LCs in skin biopsy cultures from seven healthy donors. Immunohistochemical analysis of cryostat sections of all the biopsies treated with contact allergens showed 1) a large reduction in the number of LCs in epidermis, as evaluated by a decrease in human leukocyte antigens (HLA) DR-expressing cells, and CD1a-expressing cells and 2) accumulation of the remaining LCs at the epidermal-dermal junction. In contrast, the irritants, inactive chemicals, and solvents did not induce these changes. Morphometrical analysis indicated that the contact allergen-induced reduction in the number of HLA-DR+ and CD1a+ LCs per millimeter of epidermis was significant and was dependent on the concentration of the contact allergens. Flow cytometric analysis of isolated epidermal cells confirmed the immunohistochemical findings. In combination, these results suggest that the culture of ex vivo human skin explants provides a promising model to predict potential allergenicity of newly produced chemical compounds and can therefore replace current animal models. PMID- 8686759 TI - There is no contradiction between increased clinical risk with higher serum ferritin levels and protection by ferritin in vitro. PMID- 8686760 TI - Integrin alphavbeta3 is expressed in selected microvessels after focal cerebral ischemia. AB - The endothelial and smooth muscle integrin alphaVbeta3, a receptor for vitronectin and fibrinogen, participates in angiogenesis associated with wound healing and tumorigenicity. The microvascular expression of alphavbeta3 and fibrin during experimental middle cerebral artery occlusion and reperfusion in a nonhuman primate model was examined by computer-assisted video imaging microscopy. No microvascular expression of alphavbeta3 was seen in the control subjects (n = 3) or the non-ischemic basal ganglia of subjects undergoing 2-hour MCA:O (middle cerebral artery occlusion) or 3-hour occlusion with 1-hour (n = 3), 4-hour (n = 3), and 24-hour (n = 3) reperfusion. In the ischemic territory, alphavbeta3 appeared initially at 2 hours of middle cerebral artery occlusion. Up regulation of alphavbeta3 was confined to the media of 30.0- to 50.0-micron diameter arterioles in the ischemic core and correlated significantly with fibrin deposition in those vessels (P < 0.0005). Integrin alphavbeta3 and its ligand fibrinogen appear in a subpopulation of microvessels after focal cerebral ischemia. PMID- 8686761 TI - Aromatase in human common epithelial ovarian neoplasms. AB - The expression of aromatase was evaluated in 44 ovarian carcinomas, 7 carcinomas of low malignant potential (LMP), and 14 benign adenomas. Aromatase immunoreactivity was observed in stromal cells in 35 of 44 (79.5%) ovarian carcinomas and 3 of 7 carcinomas of LMP. However, no immunoreactivity was pronounced at sites of frank invasion in ovarian carcinoma. To characterize aromatase in ovarian carcinoma, aromatase activity, mRNA expression, and alternative uses of exon 1 were determined. Quantitation of aromatase activity with the tritiated water method demonstrated 41.62 +/- 9.15 pmol/hour/mg protein in 11 ovarian carcinomas. The mean concentration of aromatase mRNA for 14 ovarian carcinomas was 3 +/- 4 amol/ng RNA, which significantly correlated with aromatase immunoreactivity. The alternative use of multiple copies of exon 1 was examined by reverse transcriptase polymerase chain reaction in 11 carcinomas. The transcript, mainly using exons 1c and 1d, was detected in 4 and 5 cases of carcinoma, respectively. Patterns of utilization of exon 1, however, did not significantly correlate with aromatase overexpression. These results suggest that aromatase is expressed in stromal cells of ovarian carcinoma but not in benign ovarian neoplasms. Increased aromatase expression in stromal cells of human ovarian carcinoma is, therefore, considered to play an important role in the biological behavior of these tumors by producing estrogens in situ as in other female sex-steroid-dependent neoplasms. PMID- 8686762 TI - Kaposi's sarcoma-associated herpesvirus in non-AIDS related lymphomas occurring in body cavities. AB - DNA sequences belonging to the recently discovered Kaposi's sarcoma-associated herpesvirus (KSHV), now provisionally designated human herpesvirus 8, have been previously identified in an uncommonly occurring subset of AIDS-related lymphomas, referred to as body-cavity-based lymphomas (BCBLs), which present as lymphomatous effusions. Pyothorax-associated lymphomas (PALS) are non-Hodgkin's lymphomas that arise in the pleural cavity after long-standing pleural inflammation resulting from therapeutic artificial pneumothorax or from tuberculosis pleuritis. Although PALs present as solid tumor masses, they are otherwise similar to BCBLs in that they also are B cell lymphomas, usually exhibit immunoblastic morphology, and contain Epstein-Barr virus. We investigated whether KSHV sequences are present in 2 BCBLs in patients without AIDS and 12 in Japanese and 2 French PALs. The 2 BCBLs were positive for KSHV sequences, whereaas all 14 PALs were KSHV negative. This finding strongly suggests that BCBLs and PALs are distinct clinicopathological entities and further strengthens the association between the presence of KSHV and an effusion phenotype. Based on these findings, we propose replacing the term body-cavity-based lymphoma with the term primary effusion lymphoma, which describes these non-Hodgkin's lymphomas more accurately and avoids confusion with other lymphomas that may occur in the body cavities, such as the PALs. PMID- 8686763 TI - Quantitation and physiological characterization of angiogenic vessels in mice: effect of basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor, and host microenvironment. AB - A prerequisite for the development of novel angiogenic and anti-angiogenic agents is the availability of routine in vivo assays that permit 1) repeated, long-term quantitation of angiogenesis and 2) physiological characterization of angiogenic vessels. We report here the development of such an assay in mice. Using this assay, we tested the hypothesis that the physiological properties of angiogenic vessels governed by the microenvironment and vessel origin rather than the initial angiogenic stimulus. Gels containing basic fibroblast growth factor (bFGF) or vascular endothelial growth (VEGF) were implanted in transparent windows in the dorsal skin or cranium of mice. Vessels could be continuously and non-invasively monitored and easily quantified for more than 5 weeks after gel implantation. Newly formed vessels were first visible on day 4 in the cranial window and day 10 in the dorsal skinfold chamber, respectively. The number of vessels was dependent on the dose of bFGF and VEGF. At 3000 ng/ml, bFGF- and VEGF induced blood vessels had similar diameters, red blood cell velocities, and microvascular permeability to albumin. However, red blood cell velocities and microvascular permeability to albumin were higher in the cranial window than in the dorsal skinfold chamber. Leukocyte-endothelial interaction was nearly zero in both sites. Thus, newly grown microvessels resembled vessels of granulation and neoplastic tissue in many aspects. Their physiological properties were mainly determined by the microenvironment, whereas the initial angiogenic response was stimulated by growth factors. PMID- 8686764 TI - Localized adhesion of monocytes to human atherosclerotic plaques demonstrated in vitro: implications for atherogenesis. AB - Blood-derived macrophages in the arterial intima are a characteristic feature of active atherosclerotic plaques. Adherent monocytes on the luminal surface and increased adhesion molecules on the endothelium have suggested that specific molecular mechanisms are involved in monocyte/macrophage traffic into the arterial wall. Adhesion of human monocytes and related cell lines was therefore studied in vitro to histological sections of human plaques. At 37 degrees C, these cells bound selectively to the plaques. Binding to the endothelium occurred and was also present extensively in the diseased intima. Inhibition studies showed that the endothelial and general intimal binding had largely similar molecular properties. Strong inhibition was produced by antibodies to the monocyte-specific adhesion molecule CD14, to beta2 integrins, and to ICAM-1. Likewise, a peptide containing the Arg-Gly-Asp sequence was strongly inhibitory, suggesting that binding of leukocyte integrins to arterial extracellular matrix was synergistic with cell-cell interactions. A P-selectin antibody was exceptional in giving selective inhibition of endothelial adhesion, which correlates with the specific endothelial localization of this adhesion molecule. These results show that monocytes adhere to atherosclerotic plaques through the focal activation of multiple arterial wall adhesion molecules, confirming the adhesion hypothesis. A positive feedback theory for the pathogenesis of atherosclerosis can be suggested, based on the ability of macrophages in the wall to activate the endothelium, induce adhesion molecules, and facilitate additional monocyte entry. The adhesion assay provides a means for the identification of adhesion inhibitors with therapeutic potential. PMID- 8686765 TI - Role of neutrophils in the pathogenesis of experimental vasculitis. AB - In the Brown-Norway rat, mercuric chloride (HgCl2) induces an autoimmune syndrome characterized by high IgE levels. There is widespread necrotizing leukocytoclastic vasculitis involving lung, skin, mucous membranes, pancreas, liver, and gut, with tissue injury being most marked in the cecum. As in systemic vasculitis in man, there are neutrophils at the site of tissue injury and the animals develop anti-neutrophil cytoplasmic antibodies, which in the Brown-Norway rat are directed against myeloperoxidase. To determine whether neutrophils are involved in the pathogenesis of the vasculitis, we have used a monoclonal antibody that was reported to deplete neutrophils in other rat strains. Rats treated with HgCl2 received antibody by intravenous injection at various time points. Serial blood samples were taken for neutrophil counts and to assay for anti-myeloperoxidase and IgE antibodies. The guts of animals killed after antibody therapy were scored for vasculitic changes and neutrophils infiltrate. RP3 (but not the control antibody MAC6) was shown to bind to Brown-Norway rat neutrophils and to block glycogen-induced influx of neutrophils into the peritoneum. When given at peak disease, RP3 caused a dose-dependent reduction in tissue injury with a marked reduction in circulating blood neutrophil numbers and in tissue neutrophil infiltrate. RP3 treatment did not affect the rise in titer of IgE and anti-myeloperoxidase antibodies. The data presented demonstrate that in this model neutrophils are necessary for the induction of vasculitis and that the degree of vasculitis correlates with neutrophil number. To our knowledge, this study is the first to provide direct evidence for a role for neutrophils in vasculitis. We suggest that antibodies directed against neutrophils, especially if they deplete neutrophils, may be useful in the therapy of vasculitis in man. PMID- 8686766 TI - Paneth cells express high levels of CD95 ligand transcripts: a unique property among gastrointestinal epithelia. AB - CD95 (APO-1/Fas), a cell surface receptor and member of the tumor necrosis factor receptor superfamily, induces apoptosis upon oligomerization. CD95 is broadly expressed in normal tissues. The CD95 ligand (CD95L) is a member of the tumor necrosis factor family of cytokines and exists in a membrane-bound and in a soluble form. In vitro, CD95L is expressed and released by activated T lymphocytes. The range of cell types capable of expressing CD95L in vivo is unknown so far. Using a specific probe for human CD95L and sensitive in situ hybridization, we examined CD95L mRNA expression along the gastrointestinal tract. The scarce lymphohistiocytic infiltrate within the lamina propria contained small subsets of medium-sized labeled cells, some of which bad short cytoplasmic protrusions and others of which were lymphoid in morphology. Autochthonous cells of the gastrointestinal tract did not contain any detectable transcripts except for Paneth cells that expressed CD95L mRNA at high levels. In ulcerative colitis, CD95L mRNA-positive inflammatory cells were increased in number, and metaplastic Paneth cells were the only epithelial cells expressing CD95L. Paneth cells are CD95 negative. Therefore, these cells may not commit CD95 mediated autocrine suicide. By secreting soluble CD95L, however, the Paneth cells might contribute to mucosal integrity. PMID- 8686768 TI - American Society of Tropical Medicine and Hygiene directory of international opportunities. 1996. PMID- 8686767 TI - Accelerated atheromatous lesions in mouse hearts transplanted to apolipoprotein-E deficient recipients. AB - Arteriopathy, sometimes termed accelerated atherosclerosis, often impairs transplants. We employed apolipoprotein-E-deficient, hypercholesterolemic mice to determine how the hyperlipidemic environment affected transplanted hearts. Strain 129 hearts transplanted to C57BL/6 normal or C57BL/6 apolipoprotein-E-deficient recipients were evaluated by immunochemical and histological techniques. Analyses were possible both of differences in the coronary lesions that developed in a normolipidemic as compared with a hyperlipidemic environment and of the coronary atherosclerotic process in transplanted hearts compared with native hearts in the same hyperlipidemic environment. Aortas and coronary arteries of transplanted aortas in both recipient groups developed florid intimal thickening by 4 to 10 weeks, with marked lipid deposition, foamy macrophages, and infiltration of smooth muscle alpha-actin-positive cells in apolipoprotein-E-deficient mice. Lipid was layered against the internal elastic lamina as in human transplants. VCAM-1 was increased in various sites in both groups. Allotransplants to apolipoprotein-E-deficient recipients had more severe aortic and coronary lesions with characteristic T cell infiltration than native hearts. In this sense, transplants suffered from accelerated atherosclerosis. The character of coronary vascular changes in transplanted hearts was distinctly affected by their lipid environment, but their severity, in terms of luminal encroachment, was not markedly different. PMID- 8686769 TI - Reduction of risk of watery diarrhea with point-of-use water filters during a massive outbreak of waterborne Cryptosporidium infection in Milwaukee, Wisconsin, 1993. AB - The occurrence of a massive waterborne outbreak of Cryptosporidium infection in Milwaukee, Wisconsin provided an opportunity to evaluate the effectiveness of point-of-use home water filters in preventing diarrheal illness associated with Cryptosporidium infection. Of 155 filter owners who responded to a televised request to contact the City of Milwaukee Health Department, 99 (64%) completed a self-administered questionnaire regarding their sources of drinking water, the characteristics of their home water filters, and diarrheal illness during the outbreak. Diarrhea among respondents was independently associated with residence in southern or central Milwaukee (the area served by the implicated South water treatment plant), having a home water filter with a pore diameter of greater than 1 micron, and drinking unfiltered tap water in a public building in southern Milwaukee. Among residents of southern and central Milwaukee, two (18%) of 11 persons who drank only submicron-filtered water at home and who did not drink unfiltered South plant water at work had watery diarrhea, compared with 50% (n = 2), 63% (n = 35), and 80% (n = 15) who reported drinking South plant water that was unfiltered or passed through a filter with a pore diameter > 1 micron at work only, home only, or both home and work, respectively (P = 0.02). The data indicate that use of submicron point-of-use water filters may reduce risk of waterborne cryptosporidiosis. PMID- 8686770 TI - High seroprevalence of hepatitis A, B, C, and E viruses in residents in an Egyptian village in The Nile Delta: a pilot study. AB - Hepatitis C virus (HCV) infection is hyperendemic in Egypt, with seroprevalence rates of 10-20% among volunteer blood donors, and even higher rates reported among segments of the general population. We attempted to confirm the high seroprevalence of HCV and to compare it with the age-specific seroprevalence rates for hepatitis A, hepatitis B, and hepatitis E among 155 nonrandomly selected residents of a semiurban village in the Nile River delta. Of the two orally transmitted viruses (HAV and HEV), all 1-3-year-old children had been infected by HAV and the seroprevalence rate of 100% persisted until age 67. In contrast, HEV infections were not detected until children were 4-9-years old, and the 57% seroprevalence rate in this age group did not increase appreciably in older age groups. Of the two parenterally transmitted viruses, HBV was first detected in 1-3-year-olds, whereas HCV was first detected later, in 10-19-year olds. The seroprevalence rates of both viruses increased progressively with age, peaking in the 40-67-year-old group at 66% for HBV and at 51% for HCV. The number of persons who had only one infection, or no infection at all, was too small to allow meaningful statistical analysis of serologically pure groups infected only by HBV, HCV, or HEV. The results of this pilot study revealed extraordinarily high seroprevalence rates of HBV, HCV, and HEV in this village, and distinctive age-specific seroprevalence rates suggesting different patterns of transmission. PMID- 8686771 TI - A waterborne outbreak of hepatitis E virus transmission in southwestern Vietnam. AB - A hepatitis outbreak affecting primarily adults occurred in southwestern Vietnam, along the Hau river bordering Cambodia, in June and July 1994. One month after the outbreak, sera and epidemiologic information were collected from 150 subjects: 50 patient cases, 50 matched, healthy community controls, and 50 geographic controls living 50 km upriver. The prevalence of immunoglobulin G (IgG) to hepatitis E virus (HEV) was significantly (P < 0.001) higher (76%) among cases than among the matched (38%) and geographic (38%) control populations. Immunoglobulin M to HEV was detected by enzyme-linked immunosorbent assay and Western blot in 16% of sera collected from patients one month after the outbreak. Hepatitis E virus RNA was detected with the polymerase chain reaction in 6% of sera from patients; RNA was not detected in either control group. These results indicate that HEV was the etiologic agent responsible for the outbreak. Children were under-represented among clinical cases. River water served as the principal source for drinking and bathing among most (96%) of the case and control study populations. Boiling of drinking water was negatively associated (P < 0.05) with IgG anti-HEV seropositivity. Unusually heavy rainfall likely contributed to conditions that favored the outbreak. This is the first recognized outbreak of epidemic HEV transmission in Indo-China. PMID- 8686772 TI - Geographic distribution and serologic and genomic characterization of Morro Bay virus, a newly recognized bunyavirus. AB - More than 75,000 immature mosquitoes in three genera were collected from coastal California, reared to the adult stage, and tested for virus by plaque assay in Vero cell cultures. Twenty-six strains of Morro Bay (MB) virus, a newly recognized member of the California (CAL) serogroup, were isolated from Aedes squamiger, a pestiferous salt marsh mosquito species restricted to intertidal salt marshes in coastal California and Baja California. The geographic distribution of the isolates was 10 from San Luis Obispo County, one each from Santa Barbara and Orange Counties, and 14 from San Diego County. No virus isolations were made from 23,157 Ae. squamiger collected north of San Luis Obispo County (midpoint in the geographic range of this species in California). Thus, MB virus infection in Ae. squamiger appears to be restricted to the southern range of this species in California. Serum dilution neutralization tests indicated that MB virus represents a novel subtype of the California encephalitis (CE) serotype within the CAL serogroup. Comparative analyses of genomic sequence data from four geographically distinct MB virus isolates indicated that the isolates are genetically similar to each other and distinct from other CE serotype bunyaviruses. Phylogenetic analysis of nucleocapsid protein gene sequence data indicated that MB virus represents a distinct lineage within the CE serotype and thus supports the serologic classification of MB virus as a distinct CAL serogroup virus. PMID- 8686773 TI - Prevalence of antibodies to arenaviruses in rodents from the southern and western United States: evidence for an arenavirus associated with the genus Neotoma. AB - The objectives of this study were to extend our knowledge of the geographic distribution and rodent host range of arenaviruses in North America. Sera from wild rodents collected from the southern and western United States were tested for antibody against Tamiami, Pichinde, Junin, and lymphocytic choriomeningitis viruses, using an indirect fluorescent antibody test. Antibody to at least one arenavirus was found in 220 (3.1%) of 7,106 rodents tested. The antibody-positive animals included Mus musculus from Florida and Texas; Neotoma albigula from Arizona, Colorado, and New Mexico; N. fuscipes and N. lepida from California: N. mexicana from Arizona, New Mexico, and Utah; N. stephensi from Arizona and New Mexico; and Oryzomys palustris and Sigmodon hispidus from Florida. Sigmodon hispidus seropositive for Tamiami virus were found only in Florida (156 [27.0%] of 578 tested), although 463 hispid cotton rats from outside that state were examined. High-titered antibodies to Tamiami virus were present in sera from S. hispidus, (geometric mean antibody titer [GMAT] of 1:792), whereas sera from Neotoma spp. reacted at high titer to both Tamiami (GMAT = 1:905) and Pichinde (GMAT = 1:433) viruses. The results suggest that arenaviruses are widely distributed in the southern United States and that one or more indigenous arenaviruses are associated with Neotoma spp. in North America. PMID- 8686774 TI - Transmission dynamics of Wuchereria bancrofti in East Sepik Province, Papua New Guinea. AB - Bancroftian filariasis is endemic in many areas of Papua New Guinea. This study describes the entomologic indices of transmission near Dreikikir in East Sepik Province, Papua New Guinea. A total of 1,735 culicine mosquitoes, including Culex and Mansonia species, were dissected, but none were infected with filarial larvae. In contrast, Anopheles punctulatus and An. koliensis were found to be potential vectors: 7.3% of Anopheles were infected and the mean number of first- to third-stage larvae per infected mosquito was 2.7. Transmission indices varied significantly in five villages located within a 50-km radius of each other. Annual biting rates ranged from 4,789 to 48,020 bites/person/year; annual infective biting rates from 15 to 836/person/year; and annual transmission potential from 31 to 2,340 third-stage larvae/person/year. Monthly transmission potential and monthly infective biting rate varied significantly in each village, with the highest indices of transmission observed in villages nearest sites where puddles formed in river beds during the dry season. These data indicate that there is small area variation in the intensity and temporal pattern of filariasis transmission and that culicine mosquitoes are not important vectors of W. bancrofti in this area. PMID- 8686775 TI - Effects of high-dose oral vitamin A on diarrheal episodes among children with persistent diarrhea in a northeast Brazilian community. AB - The mean +/- SEM duration of diarrheal episodes decreased from 7.1 +/- 2.2 days to 4.3 +/- 0.9 days (P < 0.05) while the incidence of diarrheal episodes remained steady (2.2 +/- 0.3 versus 2.4 +/- 0.5 episodes; P = not significant) between two three-month periods before and after the oral administration of a single large age-adjusted dose of vitamin A among children at historical risk for persistent diarrhea in an impoverished Brazilian community. PMID- 8686777 TI - The epidemiology of acute adenolymphangitis due to lymphatic filariasis in northern Ghana. AB - A study to investigate the socioeconomic impact of lymphatic filariasis was conducted in a rural community in northern Ghana. The incidence, severity, and duration of acute adenolymphangitis (ADL), as identified by local terminologies and confirmed using World Health Organization diagnostic criteria, were investigated. Local terminologies were found to be highly specific and sensitive for diagnosing ADL (sensitivity = 0.978, specificity = 0.980). The incidence of ADL was 95.9 per 1,000 per annum among adults more than 10 years of age, being much higher in females than in males. Among those with elephantiasis and other chronic filarial symptoms, there was no clear relationship between the stage of chronic lymphedema and the incidence of ADL. The incidence of ADL was found to be closely related to the rainfall pattern. The design of the study, its findings, and the public health implications of the findings are discussed in this paper. PMID- 8686776 TI - Ultrasonography in a Senegalese community recently exposed to Schistosoma mansoni infection. AB - Inhabitants of Ndombo (n = 614), a village in an area recently infected with Schistosoma mansoni in Northern Senegal, were examined clinically, parasitologically, and ultrasonographically to investigate the presence and degree of S. mansoni-related hepatosplenic morbidity after a few years of exposure to schistosomal infection of regional canals. Despite previous praziquantel treatment of 56% of the inhabitants prior to our investigation, the prevalence of S. mansoni infection in 1993 was 90%, and 42% of the villagers excreted more than 1,000 eggs per gram of stool. Previously untreated individuals were found to have significantly higher egg counts than treated ones. Despite the high intensities of infection, ultrasonographically detected severe periportal thickening of the liver was infrequent. Grading according to body length dependent normal values of cross-section diameter of peripheral portal vein branches of a European control group correlated with intensities of infection. Of the total group of patients, 30% (n = 182) had more severe thickening of portal vein branch diameters above the 97th percentile and 70% of these had a splenomegaly. The highest egg counts and the most frequent development of periportal thickening were found in 11-20 year-old individuals. Periportal thickening was less frequent in praziquantel-treated adolescents than in untreated ones. This suggests that early antischistosomal medication may be useful to limit schistosomiasis-induced hepatic morbidity especially in children, even though reinfection seems inevitable. PMID- 8686778 TI - Short report: a case of fibrosing mediastinitis caused by Wuchereria bancrofti. AB - Wuchereria bancrofti is a mosquito-borne filarial nematode that commonly invades lymphatic vessels. Common clinical manifestations include elephantiasis, orchitis, epididymitis, and chyluria. This report concerns an Egyptian man who developed superior vena cava syndrome secondary to a mediastinal mass that was found to contain a filarial nematode consistent with W. bancrofti. This is the first case, to our knowledge, of this parasite causing fibrosing mediastinitis. PMID- 8686779 TI - Human onchocerciasis in Nigeria: isotypic responses and antigen recognition in individuals with defined cutaneous pathology. AB - Antigen (Ag)-specific isotype responses to Onchocerca volvulus Ag (OvAg) were assessed by enzyme-linked immunosorbent assay and immunoblot in 123 residents of a mesoendemic area in northern Nigeria and 16 Nigerians from a nonendemic area. Individuals from an endemic area were divided into six groups on the basis of cutaneous onchocercal pathology: acute papular onchodermatitis (APOD), chronic papular onchodermatitis (CPOD), lichenified onchodermatitis (LOD), atrophy (ATR), depigmentation (DPM) and normal skin, high microfilarial load (NSHMF). Immunoglobulin (Ig)G1-4 levels were all significantly associated with residence in an endemic area after controlling for age and sex (all P values = 0.0001). Both IgG1 and IgG3 were significantly associated with onchocercal clinical category after controlling for age, sex, and microfilarial load (P = 0.0031 and 0.0035, respectively). The IgG1 and IgG3 responses were both highest in LOD and lowest in NSHMF and ATR, respectively. A significant inverse association was found between IgG1 levels and microfilarial load after controlling for age, sex, and clinical category (P = 0.0061). On immunoblotting, 20 (44.4%) of 45 individual onchocerciasis sera contained IgG4 antibodies against a band of 29-31 kD, which was not recognized by pooled sera from individuals with other filarial infections. There was heterogeneity of antigen recognition within each of the onchocercal clinical groups, which together with the small numbers examined by immunoblotting, limits interpretation. Nevertheless, some differences in patterns of antigen recognition were found between the onchocercal groups. The LOD group demonstrated prominent immunoreactivity in IgG1 and IgG3 while a general paucity of low molecular weight reactivity was seen with NSHMF in IgG1-3 subclasses, but there was no specific banding pattern that differentiated NSHMF from those with pathology. Comparison of microfilariae-positive (mf+) and mf- individuals with onchocercal skin disease revealed significantly higher levels of all IgG subclasses and higher overall scores on semiquantitative assessment of immunoblots for IgG1, IgG2, and IgG4 for mf+ individuals. Differing isotypic responses may play a role in the pathogenesis of the clinical spectrum of cutaneous onchocerciasis. PMID- 8686780 TI - Evidence for an age-dependent pyrogenic threshold of Plasmodium falciparum parasitemia in highly endemic populations. AB - The high prevalence of asymptomatic malaria infections and the nonspecific signs and symptoms of the disease make the individual diagnosis of clinical malaria uncertain in highly endemic areas. Longitudinal data obtained during a four-month period from a daily survey of 200 permanent inhabitants (one month-83 years old) living in a holoendemic area were analyzed in a random-effects logistic regression model to investigate the relationship between the level of Plasmodium falciparum parasitemia and risk of fever. It was not possible to build a model that described/summarized correctly this relationship by a continuous function. Findings provide evidence for an age-dependent threshold effect of parasitemia on the occurrence of fever. The level of this threshold varied by 2.45 trophozoites per leukocyte, maximum at one year of age, to 0.5 trophozoites per leukocyte, minimum at 60 years of age. When the parasite density of a person crossed the threshold level corresponding to his or her age, the individual's risk of fever was multiplied by 44 (95% confidence interval = 13.6-144.8). The existence of this threshold effect allows parasite density to be used to distinguish malaria attacks from other causes of fever within an individual and should facilitate the accurate evaluation of the incidence of clinical malaria in highly endemic areas. PMID- 8686781 TI - Effects of Plasmodium vinckei hemozoin on the production of oxygen radicals and nitrogen oxides in murine macrophages. AB - When murine peritoneal macrophages were loaded in vitro with Plasmodium vinckei hemozoin and stimulated with opsonized zymosan for 90 min or with lipopolysaccharide and/or murine interferon-gamma for 24 hr, significant decreases in the production of oxygen radicals and nitrogen oxides, respectively, could be detected by comparison with macrophages without hemozoin. Moreover, nonradioactive in situ hybridization and immunohistologic analysis in liver sections of P. vinckei-infected mice with more than 60% parasitemia showed that liver cells were still expressing considerable levels of inducible nitric oxide synthase in the late phase of murine malaria, but most of the liver macrophages presenting accumulation of malaria pigment were negative in this analysis. These results further indicate that malaria pigment accumulation may be responsible for toxicity and impairment of macrophage functions during murine malaria. PMID- 8686782 TI - Anterior horn cell degeneration in polymyositis associated with human T lymphotropic virus Type-1 in patients from Barbados. AB - Anterior horn cell degeneration has only occasionally been noted in patients with tropical spastic paraparesis associated with human T lymphotropic virus type-1 (HTLV-1) infection. We report on three adult patients with HTLV-1-associated polymyositis who had clinical evidence of anterior horn cell degeneration. One patient had moderate proximal weakness and muscle wasting in all four limbs, while two had mild upper limb weakness with more profound proximal weakness and wasting in the lower limbs. In all three patients, electromyographic findings were compatible with motor unit loss and muscle biopsies showed mononuclear inflammatory cell infiltration; muscle biopsies in two patients showed features of denervation. Immunoglobulin G (IgG) antibodies to HTLV-1 were detected by enzyme-linked immunosorbent assay (ELISA) and confirmed by Western immunoblot in serum and cerebrospinal fluid in all three patients. In two, cell cultures were established from peripheral blood lymphocytes and HTLV-1 antigen was identified by immunofluorescence and the ELISA antigen-capture technique using an anti-p19 HTLV-1 mouse monoclonal antibody. The three cases illustrate the variety of neuromuscular disease, other than spastic paraparesis, that may occur in HTLV-1 infection. In some cases of HTLV-1-associated polymyositis, anterior horn cell degeneration may make a significant contribution to the muscle atrophy observed. PMID- 8686783 TI - Short report: simultaneous detection by polymerase chain reaction of mosquito species and Plasmodium falciparum infection in Anopheles gambiae sensu lato. AB - Total RNA purified from Anopheles gambiae mosquitoes can be used for detection of both 1) infection by Plasmodium falciparum using a reverse transcriptase polymerase chain reaction (RT-PCR) assay specific for P. falciparum ribosomal RNA (rRNA) of sporogonic stage parasites, and 2) mosquito species using a PCR assay that distinguishes members of the Anopheles gambiae complex. PMID- 8686784 TI - Different genetic characteristics of Plasmodium falciparum isolates collected during successive clinical malaria episodes in Senegalese children. AB - A narrow epidemiologic survey was conducted during a four-month period of intense malaria transmission in Dielmo, a holoendemic Senegalese village. Longitudinal clinical and parasitologic follow-up indicate that clinical malaria episodes always occurred after an abrupt increase in parasite densities. Polymerase chain reaction analysis of Plasmodium falciparum parasites was carried out in blood samples collected longitudinally from 10 children who had experienced several clinical episodes during this period. Our data show that the genetic diversity of the parasites circulating in this village is very large. The successive clinical episodes experienced by each child were caused by genetically distinct parasite populations that were recently inoculated and multiplied in an apparently unrestricted manner. Importantly, the genetic characteristics of the parasite populations detected during phases of asymptomatic carriage differed from those causing a clinical episode, suggesting that the various factors that control of parasite growth in these children are strain-specific. PMID- 8686785 TI - Experimental infection and transmission of Leishmania major by laboratory-reared Phlebotomus bergeroti parrot. AB - The ability of colony-reared Phlebotomus bergeroti Parrot to successfully acquire and transmit Leishmania major (strain IPAP/EG 89/SI-177) was demonstrated in the laboratory. Female P. bergeroti were fed naturally on infected mice and artificially on infected blood suspension using a chick-skin membrane apparatus. Groups of sand flies, either infected on mice or by membrane feeding, were dissected and examined using light microscopy at 2-6, 8, 10, and 11 days postfeeding. Heavy promastigote infection of the thoracic and abdominal midgut was observed in 10% (2 of 20) of the naturally infected flies. Promastigote maturation was observed in 87% (81 of 93) of the artificially infected sand flies, with promastigotes observed in the cibarium and mouthparts at five days postinfection, and infective metacyclic stage promastigotes observed at eight days postinfection. Ten days postinfection, 31% (10 of 32) of the remaining artificially infected sand flies refed on an uninfected BALB/c mouse. Twenty eight days following exposure to the infective sand flies, leishmanial lesions were observed on the pads of the mouse's front feet. The development of lesions on mouse foot pads clearly suggests the potential of P. bergeroti to serve as a vector for L. major. PMID- 8686786 TI - Genotypic identification of Rickettsia tsutsugamushi by restriction fragment length polymorphism analysis of DNA amplified by the polymerase chain reaction. AB - We combined the nested polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) for genotypic identification of Rickettsia tsutsugamushi. Four primers were selected from the DNA sequence of the gene encoding a 56-kD serotype-specific antigen of the Karp strain. Nested PCR produced rickettsia specific products of approximately 0.6 kb in the amplification of DNA prepared from three reference strains (Gilliam, Karp, and Kato) and two prototype strains (Irie and Hirano) prevalent in the Miyazaki Prefecture of Japan. When the nested PCR products obtained from these five strains were digested with Hha I, profiles specific to each strain were generated. Fourteen of 17 DNA samples of peripheral blood mononuclear cells from patients with scrub typhus tested positive in the nested-PCR, providing a rickettsia-specific band. The serotype of infected rickettsia of 10 patients were diagnosed as Irie and those of four patients were diagnosed as Hirano by indirect immunofluorescence methods. The fragment profiles of the PCR products of these 14 patients after digestion with Hha I corresponded closely with those serotypes. However, the PCR products from two of four samples, which were similar to Hirano strain by a serologic method and by the pattern of digestion with Hha I, produced different RFLP profiles upon further digestion with Hinf I and Alu I. These results may suggest that genetic variation exists within serotypes. Genotypic identification of R. tsutsugamushi by means of PCR RFLP using three restriction enzymes is apparently useful. PMID- 8686787 TI - Gametocytocidal activity of alpha/beta arteether by the oral route of administration. AB - Arteether (alpha/beta) (a mixture of alpha and beta enantioners) has been reported to possess gametocytocidal activity against Plasmodium cynomolgi B when the drug is given by the intramuscular route, but it would be preferable to use oral route therapy for gametocyte carriers. This is a report of a study of the gametocytocidal action of arteether administered by the oral route. The results indicate high levels of activity at 10 mg/kg in a single dose or in two divided doses when given orally. PMID- 8686788 TI - Cross-reactive epitope among proteins in Plasmodium falciparum Maurer's clefts and primate leukocytes and platelets. AB - Erythrocytes infected with malaria parasites often contain membranous vesicles that are presumed to facilitate macromolecule traffic between the parasite and erythrocyte membranes. One such vesicle network, called Maurer's clefts, is expressed in Plasmodium falciparum-infected erythrocytes and contains a 50-kD polypeptide. Using a monoclonal antibody reactive with this polypeptide, we show that hepatic stages of P. falciparum express an epitope common to this blood stage antigen. In addition, this epitope is cross-reactive with antigens expressed by primate leukocytes and platelets. Such epitopes may induce autoantibodies commonly seen in patients with malaria. PMID- 8686789 TI - Protection of young rats from acute Trypanosoma cruzi infection by interferon gamma given to their mothers during pregnancy. AB - We investigated whether administration of interferon-gamma (IFN-gamma) to pregnant rats, infected or not with Trypanosoma cruzi, was likely to protect their offspring from trypanosomal infection. Upon mating with syngeneic sires, four groups of 70-day-old female 1 rats were subjected to one of the following procedures: treatment with recombinant rat (Rr)IFN-gamma 50,000 IU/rat five times/week for three weeks; infection with 1 x 10(6) trypomastigotes of T. cruzi at 7, 14, and 21 days after mating plus IFN-gamma treatment as given to the former group; the same protocol but IFN-gamma injections being replaced by injection with physiologic saline. Offspring were nursed by their mothers until weaning and then infected with a similar dose of T. cruzi. Pregnant rats showed no exacerbated infection but a self-resolving mild disease, regardless of whether or not they had received IFN-gamma. Maternal infection with T. cruzi and/or IFN gamma treatment did not affect gestational outcome. Offspring born to both groups of IFN-gamma-treated mothers were almost fully protected from acute infection, and showed higher levels of anti-T. cruzi IgG antibodies when compared with young born to their respective IFN-gamma-untreated mothers. Measurements of IFN-gamma serum activities indicated that ameliorated acute disease in offspring whose mothers were given IFN-gamma during gestation, was not associated with increased levels of endogenously produced IFN-gamma. PMID- 8686790 TI - Immunomodulatory properties of maxadilan, the vasodilator peptide from sand fly salivary gland extracts. AB - Sand flies are the arthropod vector of leishmaniasis and salivary gland extracts from these flies exacerbate leishmaniasis in vivo. The mechanism of exacerbation appears to be due to immunomodulatory effects of the saliva on host immune function but the active component is unknown. The following studies reveal that maxadilan, the vasodilatory peptide present in sand fly salivary gland extracts, has immunomodulatory properties. To examine the effect of maxadilan on T cell proliferation, the peptide was added to murine spleen cells stimulated with either concanavalin A or plate-bound anti-T cell receptor antibody. Inhibition of proliferation was noted in a dose-dependent manner for both sets of experiments (P < 0.05). To examine the effect of maxadilan on alloantigen presentation, the peptide was added to mixed lymphocyte and mixed epidermal cell lymphocyte reactions. Inhibition of proliferation was found in these culture systems. Maxadilan also inhibited the delayed-type hypersensitivity reaction in mice (P < 0.05). These observations suggest a role for maxadilan in the pathogenesis of leishmaniasis since the peptide may inhibit the immune response at the site of parasite inoculation, allowing the infection to proceed. PMID- 8686791 TI - Immunoglobulin G subclass antibodies against excretory/secretory antigens of Ancylostoma caninum in human enteric infections. AB - Most patients with proven or suspected enteric infection with the common hookworm of dogs, Ancylostoma caninum, produce immunoglobulin G (IgG) and IgE antibodies to an immunodominant excretory/secretory antigen (Ac68) of the parasite. These antibodies were detected in both enzyme-linked immunosorbent assay (ELISA) and Western blots; the Western blot to detect IgG antibodies to Ac68 was the most specific and sensitive. The subclasses of IgG of the antibody response to the parasite were analyzed using Western blots with anti-IgG subclass-specific monoclonal antibodies as marker systems in an attempt to further improve the specificity of the assay. Eight patients with confirmed enteric infections with A. caninum (positive controls) were tested; six had antibodies in all IgG subclasses against Ac68. Twenty sera from patients with suspected enteric infection with A. caninum (manifested as eosinophilic enteritis or unexplained abdominal pain with peripheral eosinophilia) were tested; 16 had total IgG antibodies to Ac68, while IgG1, IgG2, IgG3, and IgG4 responses were found in 11, 10, 9, and 12 of these sera, respectively. Small numbers of sera from groups of patients infected with other helminths and from healthy blood donors had various combinations of IgG, IgG1, IgG2, and IgG3 antibodies to Ac68, but none of these sera had IgG4 antibodies to Ac68. Sera from all nine patients with human hookworm infection had IgG, IgG1, IgG2, and IgG3 antibodies to Ac68 and eight of the nine were also positive for IgG4 antibodies. These results indicate the Western blot to detect IgG4 antibodies to Ac68 is the most reliable immunodiagnostic test yet described for enteric infection with A. caninum, although this test does not discriminate between infections with human and canine hookworms. PMID- 8686792 TI - Nyhus' half century of surgery. PMID- 8686793 TI - Festschrift for Lloyd M. Nyhus, MD. PMID- 8686794 TI - Incidence and prophylaxis of deep vein thrombosis in a high risk trauma population. AB - BACKGROUND: Pelvic fractures, lower extremity injuries, acute head or spinal injury, and extended bedrest place trauma patients at an increased risk for deep vein thrombosis (DVT) and pulmonary embolism (PE). We reviewed patients with traumatic brain injuries (TBI), spinal cord injuries (SCI), and lower extremity fractures (LEF) to examine our DVT and PE incidence and evaluate the success of our DVT and PE prophylaxis. METHODS: From January 1, 1994 to March 1, 1995, the records of trauma patients with TBI, SCI, and LEF who were admitted to the trauma service and transferred to an inpatient rehabilitation facility were reviewed. RESULTS: Twenty-two patients had a TBI, 16 patients with SCI, and 12 patients with LEF. Forty-nine of the 50 patients received DVT prophylaxis, with 7 inferior vena cava (IVC) filters placed. The DVT incidence was 6% and the PE incidence was 2%. CONCLUSION: The 6% incidence of DVT was lower than expected due to diligent DVT prophylaxis and appropriate screening of symptomatic patients for clinically significant DVT. The 2% incidence of PE was also lower than expected, most likely due to our lower DVT incidence and the use of IVC filters. The lower DVT and PE incidence verifies our success at DVT and PE prophylaxis. PMID- 8686795 TI - Operative ultrasound in general surgery. AB - BACKGROUND: Since the introduction of real-time B-mode ultrasound during surgery almost 20 years ago, the use of operative ultrasound (OUS) has gradually expanded to a variety of surgical fields. METHODS: A review of the history, technology, and specific applications of OUS in general surgery is presented with our clinical results of over 2300 operations. RESULTS: The benefits provided by OUS are the acquisition of new information not otherwise available, complement to or replacement for operative radiography, confirmation of satisfactory completion of an operation, and guidance of surgical procedures. OUS possesses many advantages as an intraoperative tool, including safety, speed, unique imaging information, wide applicability, high accuracy and procedure guidance capability. CONCLUSION: OUS is gaining wider acceptance in hepatobiliary, pancreatic, endocrine, and vascular surgery. Newer OUS modalities-color Doppler imaging and laparoscopic ultrasound-potentially may widen the applications of OUS in general surgery. PMID- 8686796 TI - Hospital admission following ambulatory surgery. AB - BACKGROUND: Ambulatory surgery continues to grow in quantity and complexity of procedures. Effective measures of "quality" are not readily apparent. "Unplanned admission rate" may well reflect the quality of care in this area. Identifying factors related to this event could be helpful in quality assessment and improvement. METHODS: A review of all unplanned admissions for a 3-year period in a University-affiliated teaching hospital. RESULTS: An overall rate of 0.85% (129/15,132) was observed. Rate varies by specialty and no one procedure was at higher risk. Pain control, cardiopulmonary, and bleeding problems as well as larger than anticipated procedures accounted for 73% of the admissions. CONCLUSIONS: Unplanned admission following ambulatory surgery is relatively rare but could reflect overall quality in terms of the system, physician, and patient. Comparisons between institutions and within institution requires defining key demographic elements whose identification for now remains a challenge. PMID- 8686797 TI - Delayed gastric emptying after gastric surgery. AB - BACKGROUND: The reported incidence of delayed gastric emptying (DGE) after gastric surgery is 5% to 25% and usually is based on operations for peptic ulcer disease. Ongoing improvements in perioperative care, nutritional support, and new prokinetic drugs may have had a beneficial effect on the frequency and course of postoperative DGE. METHODS: We therefore studied our recent experience with DGE in 416 patients who had gastric surgery for ulcer disease (283), cancer (92), or trauma and other indications (41) between January 1985 and December 1993. DGE was defined as inability to eat a regular diet by postoperative day 10. RESULTS: DGE occurred in 99 of 416 patients (24%). In 75 of these 99 patients, a postoperative contributing factor for DGE was identified. These factors were sepsis (32), anastomotic edema and leaks (23), obstruction (4), pancreatitis (3), multiple system organ failure (5), and miscellaneous conditions (8). In 24 patients there was no obvious cause for DGE; these patients recovered with nutritional support and time. Re-operation specifically for gastric stasis was not performed. Among the 99 patients with DGE, 67% were eating by day 21, 92% by 6 weeks, and 100% by 10 weeks. Significant risk factors for DGE were diabetes (55%), malnutrition (44%), and operations for malignancy (38%). The Whipple procedure had the highest incidence of DGE (70%), highly selective vagotomy the lowest (0%), while truncal vagotomy had no significant effect. The response to metoclopramide was 20% and unpredictable. CONCLUSION: DGE continues to affect a considerable number of our patients (24%) after gastric surgery and is particularly common in patients with diabetes, malnutrition, and gastric or pancreatic cancer. However, gastric motility does return in 3 to 6 weeks in most patients and the need for re operation for gastric stasis is rare. PMID- 8686799 TI - Reconstruction of complex chest wall defects. AB - BACKGROUND: Reconstruction of complex chest wall defects represents a major challenge and requires close cooperation between the cardiothoracic and reconstructive surgeon to achieve an optimal outcome and reduce the incidence of complications. The principles of chest wall reconstruction include control of infection, local wound care, wide debridement of all necrotic and devitalized tissues, obliteration of all residual cavities and spaces with well-vascularized tissues, reestablishment, when necessary, of the continuity and skeletal stability of the chest wall, and immediate or early definitive coverage of all defects with well-vascularized tissues. METHODS: This paper is based on our experience with 113 patients who underwent chest wall reconstruction for a variety of defects resulting from infection, trauma, tumor extirpation, and radionecrosis. All patients were treated with a variety of muscle flaps and/or omentum which provided obliteration of dead space and coverage. Seven patients with large anterolateral defects required additional skeletal stability with synthetic patches or mesh. RESULTS: 88.6% of patients healed without significant problems. 8.8% had major complications requiring reoperation and prolonged hospitalization while 4.4% had minor complications. CONCLUSIONS: Based on long term experience, we believe that currently the use of well-vascularized tissue is the method of choice for reconstruction of complex chest wall defects. This provides stable coverage, reduces hospital stay, and thus lowers overall care cost for these patients. PMID- 8686798 TI - Anatomical hepatectomy for resection or transplantation. AB - BACKGROUND: Anatomical resection has become the basis for the treatment of hepatic tumors recognizing the portal-based intrahepatic architecture of the liver. In transplantation, these principles have been applied to the creation of partial liver grafts used to treat pediatric recipients with grafts from adult donors. In this study we reviewed the results of application of these techniques in 60 patients undergoing major hepatectomy and in 47 liver transplants in children. METHODS: Records of patients undergoing resection and children undergoing transplantation were reviewed. A descriptive study was performed characterizing the methods and results achieved using anatomic hepatectomy. Outcomes analyzed included surgical morbidity and survival. RESULTS: Sixty consecutive patients underwent major hepatectomy without operative mortality (60 days). Complications occurred in 26% of patients, requiring reoperation in 2 cases (3%); median hospital stay was 8.5 days. Of 47 liver transplants in children, 57% utilized partial grafts, and living donors were used in 15 cases. Actual patient survival is 91% 1-36 months after surgery. No patient deaths were due to technical graft failure. CONCLUSIONS: Major hepatic surgery can be accomplished with low mortality applying portal-based anatomy. Surgical precision is made possible by vascular isolation for hepatectomy and operative ultrasonography. These principles are essential for successful use of partial liver grafts in children. PMID- 8686800 TI - Modern treatment modalities for neonatal and pediatric respiratory failure. AB - BACKGROUND: Respiratory failure secondary to a variety of causes remains a significant cause of morbidity and mortality in the pediatric population. Newer therapies are appearing frequently in an attempt to decrease the number of deaths from this disease state. We briefly review the current literature on some of the newer modalities including: high-frequency ventilation, surfactant, liquid ventilation, and nitric oxide. We then present our experience from the past 11 years in the most invasive, yet successful, therapy for acute respiratory failure extracorporeal membrane oxygenation (ECMO). METHODS: Retrospective review of all patients treated with ECMO from September 1983 to December 1994 was undertaken. Data were collected from bedside ECMO flow sheets and the standardized data entry forms submitted to the Extracorporeal Life Support Organization. All statistical analyses were performed using a standard statistical software program. RESULTS: During the study period, 194 neonates and 47 pediatric patients were treated with ECMO. The survival rate in the neonatal population is 82% and in the pediatric population it is 40%. The neonatal patients required an average of 153 hours of support while the pediatric patients required 220 hours (P = 0.008). CONCLUSIONS: While the newer treatment modalities discussed may have an important role in treating neonatal and pediatric respiratory failure in the near future, ECMO remains a cornerstone of the modern treatment modalities. Although somewhat invasive, ECMO is effective therapy with increasing survival rates each year. PMID- 8686801 TI - Motility of Oddi's sphincter: recent developments and clinical applications. AB - BACKGROUND: In recent years, applications of electromyographic, cineradiographic, scintilographic, and endoscopic manometric techniques have improved our knowledge of normal and abnormal motility of Oddi's sphincter. This sphincter coordinates the time and rate of secretion of about 3 liters of bile and pancreatic juice into the duodenum daily. METHODS: Oddi's sphincter may be evaluated by endoscopic manometry, ultrasound, dynamic hepatobiliary scintigraphy, and laboratory tests. Endoscopic manometry is the best method for evaluating the function Oddi's sphincter. RESULTS: The basal pressure of Oddi's sphincter is usually 5 to 15 mm Hg greater than the bile and pancreatic duct pressures. Phasic contractions of 50 to 150 mm Hg in amplitude and 3 to 8 contractions per minute in frequency are superimposed on the basal pressure. A small percentage of patients with gastrointestinal symptoms after cholecystectomy has sphincter of Oddi dysfunction, which may have structural abnormality (papillary stenosis) or functional abnormality (Oddi's sphincter dyskinesia). CONCLUSIONS: Elevated basal pressure ( > 40 mm Hg) is the most important manometric finding of Oddi's sphincter dysfunction. Endoscopic sphincterotomy is the treatment of choice for patients with Oddi's sphincter dysfunction and elevated basal sphincter pressure. PMID- 8686802 TI - Reassessment of groin anatomy during the evolution of preperitoneal hernia repair. AB - BACKGROUND: Need to define accurately groin anatomy as visualized by the preperitoneal approach. METHODS: Dissections of the right groin in 135 fresh male cadavers carried out during autopsy examination. Documentation by photographs and notes. RESULTS: Classic descriptions of groin anatomy confirmed for the most part. Errors concerning the lacunar ligament and conjoined tendon identified. Accurate descriptions, applicable to groin hernia repair, provided of the iliopubic tract, transversus abdominis arch and aponeurosis, femoral canal, and related structures. CONCLUSIONS: Improved communication and understanding by and among surgeons regarding groin anatomy is needed. PMID- 8686803 TI - Safety of 65 degrees C intravenous fluid for the treatment of hypothermia. AB - BACKGROUND: To demonstrate the safety and efficacy of 65 degrees C (149 degrees F) centrally administered intravenous fluid (CIVF) compared to conventional 40 degrees C (104 degrees F) CIVF in the treatment of hypothermia. METHOD: Ten beagles (9-13 kg) were prospectively randomized to receive 65 degrees C or 40 degrees C CIVF. They were anesthetized and data were collected at baseline, during hypothermia, and after 1 and 2 hours of rewarming. The plasma free/total hemoglobin (PFHb/THb) was measured to detect hemolysis. Each subject was cooled to 30 degrees C (86 degrees F) and then received either 65 degrees C or 40 degrees C CIVF through a specialized catheter in the superior vena cava for 2 hours in addition to conventional rewarming techniques. All subjects survived 7 days, after which they were sacrificed and a complete autopsy was performed. RESULTS: The rewarming rate was 3.7 degrees C/hr in the 65 degrees C CIVF group and 1.75 degrees C/hr in the 40 degrees C CIVF group. Core temperatures were significantly different after 1 hour (33.4 degrees +/- 0.77 degrees versus 31.7 degrees +/- 0.57 degrees, P < 0.01) and 2 hours (37 degrees +/- 1.03 degrees versus 33.4 degrees +/- 0.89 degrees, P < 0.001). PFHb/THb was not different. Two intimal injuries occurred in each group but these were remote from the infusion site. Blinded examination by two pathologists could not differentiate the etiology of these injuries from mechanical trauma. CONCLUSION: CIVF at 65 degrees C is a safe and effective means of treating hypothermia. PMID- 8686804 TI - The impact of quadruple immunosuppression with OKT3 on kidney transplantation in black recipients. AB - BACKGROUND: Black recipients of kidney transplants have been shown to have lower graft survival than other racial groups. There is ongoing controversy about the optimal immunosuppressive protocol for blacks after kidney transplantation. PATIENTS AND METHODS: Five hundred-eighty-two recipients of kidney transplants performed between 1985 and 1994 were divided into three groups: (1) nonblacks who received cyclosporine and prednisone (N = 292); (2) blacks who received "quadruple" cyclosporine based immunosuppression with OKT3 induction (N = 98); and (3) blacks who received cyclosporine and prednisone only (N = 192). Patient and graft survival and incidence of acute rejection episodes were compared among the groups. RESULTS: Blacks had lower graft survival when compared with nonblacks. However, in the subgroup of black recipients who received quadruple immunosuppression, graft survival at 1 year was higher and the incidence of acute rejection episodes was significantly decreased compared with blacks without induction. Graft survival and the incidence of acute rejection in blacks on quadruple therapy was comparable with nonblacks. CONCLUSIONS: Our data support the principle that quadruple immunosuppression should be used routinely for black recipients of kidney transplants. PMID- 8686805 TI - Neuroendocrine insights from the laboratory to the clinic. AB - BACKGROUND: The interaction between adrenergic nerves and enterochromaffin (EC) cells was studied in health and disease using animal models and patients with the midgut carcinoid syndrome. METHODS: The methods included morphological techniques (fluorescence microscopy/cytofluorimetry, electronmicroscopy), experimental models (in vivo/in vitro nerve stimulation, pharmacological analyses, axonal transport, tumor transplantation, tumor cell cultures) and clinical tests (pentagastrin provocation, octreotide scintigraphy). RESULTS: From vagal nerve stimulation studies it was clear that activation of adrenergic fibers could release serotonin (5-HT) from EC cells, which led to the mapping of a vagal adrenergic pathway. Ultrastructurally a direct innervation of EC cells was demonstrated. It was confirmed in vitro that adrenoceptors controlled the release of 5-HT; it was maintained in neoplasia as studied in the tumor models. The tumor cells shared several functional and morphological characteristics with adrenergic neurons and exerted trophic actions on neurons grown in co-culture. CONCLUSIONS: Pentagastrin provocation of 5-HT release in carcinoid patients may be mediated via release of catecholamines from the adrenals in turn activating adrenoceptors on tumor cells. Pretreatment with a somatostatin analog can reduce these reactions and thus minimize the risk for carcinoid crisis during surgery. PMID- 8686806 TI - Surgical infections: prevention and treatment--1965 to 1995. AB - During the 30 year period from 1965-1995, significant advances have been made in the prevention, diagnosis, and management of surgical infections. To a great degree these advances have been provided by surgeons who developed a primary interest in this area. The Surgical Infection Society (SIS) was established in 1980 for surgeons and other physicians and scientists in order to better coordinate efforts in education and research concerning the infected surgical patient. The most significant of these advances were initially the accurate microbiologic definition of the human endogenous microflora in health and disease. Improvements in the techniques utilized to isolate and identity anaerobic microorganisms were of paramount importance. These lead to improvements in the choice of antibiotic agents for prophylaxis and treatment which resulted in improved clinical results. Most recently, emphasis has been placed on the perioperative identification of the high-risk patient who is more likely to develop infection in the postoperative period. By separating high-risk from low risk patients in each operative procedure, rather than assuming their risk based on the traditional classification of surgical procedure, a more rationale plan of prospective alterations of treatment can be offered. PMID- 8686807 TI - A review of carcinoma of the stomach at a tertiary care referral hospital. AB - BACKGROUND: Carcinoma of the stomach continues to cause a significant mortality in the United States. We reviewed the characteristics, treatment modalities, and survival of a group of patients with this cancer at a tertiary care referral hospital. MATERIALS AND METHODS: A retrospective computer based review of all patients with a diagnosis of carcinoma of the stomach in the Ohio State University (OSU) tumor registry was made. One hundred ninety-two analytical cases were found and the data was entered into a computerized database and analyzed. RESULTS: The overall median survival in this series of patients is 10 months with a median survival of 16 months (n.s.) in patients who underwent curative surgery (50% of the patients). There was an increased number of cardia lesion (37%) predominately in male patients (P < 0.05). A significantly greater number of female patients presented with linitis plastica and male patients with adenocarcinoma, although there was no difference in the operability, types of operations, and survival between the genders. Patients with signet ring cell cancer were significantly younger than the other two histological types reviewed but this did not alter outcome. CONCLUSION: Carcinoma of the stomach, despite newer image modalities, continues to present at advanced stages at time of diagnosis with an overall dismal prognosis. The increased incidence of cardia lesions noted require innovative therapies if any progress is to be made. PMID- 8686808 TI - Physiological and cellular mechanisms of myocardial protection. AB - BACKGROUND: Despite 40 years of clinically successful open heart surgery, cardiac surgeons continue to seek the ideal myoprotective strategy to minimize perioperative myocardial damage and maximize clinical outcome. Although crude measures, such as length of hospital stay or operative mortality rate, may provide useful administrative data, the ultimate outcome measure of significance to the patient is the lack of operatively induced myocellular injury. METHODS: An ideal biological marker would thus quantitate the number of viable and functioning myocytes remaining postoperatively. The purpose of the present review was to develop the theoretical framework for modern approaches to intraoperative myocardial protection when considering the fundamental principles of physiological and cellular ischemic mechanisms. RESULTS AND CONCLUSIONS: It is hoped that this review provides insight into the implementation of these fundamental concepts developed at the University of Illinois and applied in our present experiences in advanced myocardial muscle mechanics and molecular biology. PMID- 8686809 TI - The effect of dietary selenium deficiency on acute colorectal mucosal nucleotoxicity induced by several carcinogens in the rodent. AB - BACKGROUND: Selenium (SE) has been inversely associated with colon cancer risk. Two potential mechanisms of this effect were examined in a rodent short-term carcinogenesis assay: whether dietary SE deficiency altered the initiation aspect of carcinogenesis in the colon, and whether SE altered carcinogen metabolism. SETTING: Animal laboratory. SUBJECTS: 52 Sprague-Dawley rats, divided into a SE diet deficient group (0.002 parts per million; ppm) and a SE sufficient (0.2 ppm) group. ENDPOINTS: Weight, serum SE concentration, and karryorhectic index (KI), which is a measure of acute carcinogen induced nuclear toxicity in the colonic mucosa. METHODS: After three weeks of acclimation to the diets, eight animals from each dietary group were injected with one of the following: dimethylhydrazine (DMH), a colon specific carcinogen, its metabolite, methylazoxymethanol (MAM), or 0.9% sodium chloride. Twenty-four hours after injection the colons were removed, blood drawn, and the stained colons assayed for nuclear aberrations. RESULTS: No weight differences were generated by the dietary variations. Low-dietary SE resulted in serum SE declining markedly in the study period to 6 ng/ml versus 33 ng/ml in the SE sufficient group. Diet alone, and variations in weight gain, did not alter the KI. Both carcinogens greatly increased the KI in both the left and right colon. A SE-deficient diet was associated with a higher KI in both carcinogen groups in the right colon, with statistical significance for both the left and right colon in the MAM injection group. CONCLUSIONS: Dietary SE deficiency is associated with increased KI of the colon in MAM treated rats. SE, therefore, has a protective effect in the initiation phase of carcinogenesis. PMID- 8686810 TI - Surgery and human immunodeficiency virus-1 infection. AB - BACKGROUND: HIV and AIDS continues to be a significant health problem with many patients requiring the attention of a general surgeon. METHOD: A retrospective case note review over a two-year period was undertaken. RESULTS: 237 patients underwent invasive procedures. The majority 100 patients (145 procedures) were for venous access. Anorectal problems in 69 patients presents a particular problem in this group and major surgery in 26 patients (30 procedures) has a definite role in selected patients. CONCLUSION: The surgical management of patients with AIDS is discussed with reference to safety. Recognition of specific disease patterns in this group is important and best managed by a dedicated team. PMID- 8686811 TI - A 50-year perspective upon selective gastric vagotomy. AB - BACKGROUND: The occurrence of postvagotomy complications was initially considered an unavoidable but acceptable consequence of duodenal ulcer surgery. Following the description of "selective" vagotomy procedures, however, it became apparent that effective ulcer surgery might be accomplished without unpleasant sequellae. METHODS: In 1957 the experimental basis for "highly" selective vagotomy (HSV), which preserved antral innervation, was reported. HSV was performed in several European centers between 1960 and 1968, and was widely accepted there. Surgeons in the United States, in contrast, were largely reluctant to use HSV, an operation which had an excessive ulcer recurrence rate compared to vagotomy antrectomy. More recently, HSV is recognized as a successful operation, due to more complete division of preganglionic gastric vagal nerves ("extended" HSV) and the liberal use of pyloric reconstruction in patients with juxtapyloric ulcers. RESULTS: HSV is performed with minimal morbidity, with an incidence of recurrent ulcer which is less than 5%. Complications such as dumping, diarrhea, and gastric atony are quite rare. CONCLUSIONS: HSV is an ideal procedure for most patients with duodenal ulcer. Because most operations for ulcer are performed for urgent or life-threatening problems, the most common operation performed in the United States today is truncal vagotomy combined with pyloroplasty or gastric resection. Earlier operation for chronic ulcer has many potential advantages. PMID- 8686812 TI - Technetium 99m sestamibi scan is the useful procedure to locate parathyroid adenomas before surgery. PMID- 8686813 TI - Needle localization biopsy. PMID- 8686814 TI - Smoking and anaesthesia revisited. PMID- 8686815 TI - An economic evaluation of propofol/fentanyl compared with midazolam/fentanyl on recovery in the ICU following cardiac surgery. AB - A comparison was made of the drug costs and nursing dependency of patients undergoing elective cardiac surgery and routine postoperative recovery for two anaesthetic techniques using either propofol with low dose fentanyl or midazolam with high dose fentanyl. Estimates of resource use were based on a randomised clinical trial undertaken at the Northern General Hospital, Sheffield. Times from entry to the intensive care unit until extubation and discharge were recorded for 70 patients and were transformed to nursing shifts. Nursing dependency was calculated on the basis of one nurse per ventilated patient and 0.5 nurse from the start of the shift after extubation. Nursing costs were allocated on the basis of the patient's status at the beginning of each shift in line with the hospital's staffing policy. All drugs used from the morning of the operation until discharge were recorded. Costs of nursing and drugs were calculated. The total cost of patients in the propofol group was 13.3% less than midazolam patients (p = 0.043, for geometric means Cl 0.4% to 27.8%). The clinical study was not designed for economic endpoints; however, it demonstrated achievable savings in propofol-treated patients. PMID- 8686816 TI - Propofol infusion anaesthesia and the immune response in elderly patients undergoing ophthalmic surgery. AB - In our earlier studies, propofol infusion anaesthesia increased the percentage of T helper cells in middle-aged surgical patients undergoing minor or major surgery. In the present study we compared the effects of total intravenous propofol anaesthesia and combined isoflurane anaesthesia on the immune response to ophthalmic surgery in elderly patients. Twenty patients (median age 75 years, ASA 2-3) were randomly allocated to receive total intravenous propofol anaesthesia (median total dose of propofol 710 mg) or combined isoflurane anaesthesia (median end-expiratory concentration of isoflurane 0.45 vol %). The following were measured pre-operatively, at the end of operation and on the first postoperative morning: leucocyte and differential counts: percentages of lymphocyte subpopulations (CD3, CD4, CD8, CD20, CD16) and monocytes (CD14); phytohaemagglutinin-, concanavalin A- and pokeweed mitogen-induced and unstimulated lymphocyte proliferative responses: polyclonal immunoglobulin synthesis as well as serum cortisol concentrations. The immune response to ophthalmic surgery was basically similar in both anaesthetic groups. The percentage of T helper cells in the blood circulation increased in the propofol group (p < 0.05) but not in the isoflurane group. The difference in the time response profile for T helper cell percentages between the groups was also statistically significant (p < 0.01). PMID- 8686817 TI - The effect of passive smoking on the incidence of airway complications in children undergoing general anaesthesia. AB - The aim of this study was to assess whether passive smoking affected the frequency of airway complications in children undergoing general anaesthesia. One hundred and twenty-five children undergoing general anaesthesia for elective daycase surgery were monitored for adverse respiratory events and desaturation during induction, intra-operatively and in the recovery room. Oxygen saturation was monitored throughout and a venous sample was taken for estimation of carboxyhaemoglobin levels. Parents were asked to fill in a questionnaire detailing their smoking habits. Sixty-three of the children were passive smokers with a potential daily exposure varying from 5-130 cigarettes. There was no difference in the frequency of respiratory events between passive smokers and those not exposed to cigarette smoke at induction or intra-operatively. However, in the recovery room, desaturation was significantly more common in passive smokers (p < 0.02). This was related to the cumulative number of cigarettes smoked by individuals to whom the child was exposed (p < 0.05). Neither carboxyhaemoglobin levels nor domiciliary address were predictive of desaturation. This study suggests that passive smoking contributes to postoperative arterial oxygen desaturation following general anaesthesia in children. PMID- 8686818 TI - Patient satisfaction with general anaesthesia. Too difficult to measure? AB - A questionnaire to evaluate patient satisfaction following general anaesthesia was designed with the aid of focus groups. A subsequent audit identified aspects of care which could be improved on the basis of responses to the satisfaction questionnaire. It is possible to design a discriminating satisfaction questionnaire for general anaesthesia. PMID- 8686819 TI - A comparison of retrospective versus contemporaneous nausea scores with patient controlled analgesia. AB - In the search for an effective method of reducing the incidence of postoperative nausea, a standardised system of patient assessment is required. We examined 76 patients who had undergone elective total abdominal hysterectomy and were receiving patient-controlled analgesia with morphine. Nausea scores were obtained using an 11-point rating score. Repeated contemporaneous assessments were compared with a single retrospective score made 5 days after surgery. Retrospective nausea scores were higher than those recorded contemporaneously. Maximum contemporaneous score showed greater agreement with the retrospective score than did the median, mean, or minimum contemporaneous score. Collectively, these results suggest that patients tend to remember their episodes of nausea vividly, even if these episodes were punctuated by relatively nausea-free periods. The variability between the two sets of results suggests that contemporaneous and retrospective nausea scores should not be used interchangeably. PMID- 8686820 TI - Comparison of bladder, oesophageal and pulmonary artery temperatures in major abdominal surgery. AB - In this study we compared urinary bladder and oesophageal temperatures with the core temperature obtained from a pulmonary artery catheter in patients undergoing orthotopic liver transplantation. The bladder temperature was a closer approximation to pulmonary artery temperature in this group of patients than the oesophageal temperature and has much to recommend it in terms of convenience, safety and postoperative patient comfort. PMID- 8686821 TI - Assessment of neuromuscular block at the thumb and great toe using accelography in infants. AB - We assessed neuromuscular block at the thumb and great toe using accelography after the administration of vecuronium in infants. Train-of-four stimuli were simultaneously applied to the ulnar and tibial nerves using cutaneous electrodes. Anaesthesia was maintained with nitrous oxide (66%) in oxygen and sevoflurane (1%). Vecuronium 0.1 mg.kg-1 was used for paralysis and reversed with intravenous neostigmine 0.04 mg.kg-1 with atropine 0.02 mg.kg-1 when the train-of-four ratio on the right great toe returned to 25%. The mean (SD) times from initial administration of vecuronium to completion of maximal block on the thumb and great toe were 78 (21.1) s and 75 (14.3) s, respectively (p > 0.05). The times from maximal block to 25% recovery of twitch height at the thumb and great toe were 46 (9.1) min and 45 (9.0) min, respectively. The reversal time from 25% to 75% of the train-of-four ratio after the administration of neostigmine was 136 (49.1) s. We conclude that neuromuscular monitoring of the great toe in infants may be a suitable alternative when the thumb is inaccessible. PMID- 8686822 TI - Pre-operative anxiety. Effect of early or late position on the operating list. AB - The influence of the relative position on the operating list on pre-operative anxiety was studied in 60 adult female ASA 1 patients undergoing major surgery. Thirty patients were placed first on the operating list (group 1) and 30 were given a time 4-5 h later (group 2). Each patient was visited on the evening prior to surgery and again on the morning of surgery. Anxiety was measured at each visit by objective criteria and part 1 of the State-Trait Anxiety Inventory questionnaire. The pulse rate, systolic blood pressure and the State-Trait Anxiety Inventory questionnaire scores were higher on the second visit than on the first (p < 0.001) in all patients. This increase was greater in group 2 than in group 1 (p < 0.05). The evening anxiety scores were not correlated with those on the morning visit and could not predict them. PMID- 8686823 TI - Pathological changes associated with short-term nasal intubation. AB - In order to define the incidence and anatomical site of nasal damage following nasotracheal intubation, we investigated 100 consecutive patients undergoing dental extractions under general anaesthesia. Patients were questioned pre operatively about the physiological function of their noses and examined by anterior rhinoscopy for anatomical abnormalities. Examinations were repeated postoperatively, looking specifically for haemorrhage, mucosal tears and septal and turbinate disruption. Minor bruising was common (54%) and most frequently involved mucosa overlying the inferior turbinate and adjacent septum. In two cases bruising involved the middle turbinate. There was no relationship between the number of attempts at intubation and subsequent damage. Pre-operative otolaryngological assessment failed to identify those patients who subsequently proved difficult or impossible to intubate nasally and incorrectly predicted difficulty in 11 patients who had pre-existing deviation of the nasal septum. In conclusion, short-term nasotracheal intubation was not associated with significant nasal morbidity, and pre-operative anatomical assessment failed to identify those in whom nasal intubation proved difficult or impossible. PMID- 8686824 TI - The effect of prophylactic clonidine on postoperative shivering. A large prospective double-blind study. AB - The primary goal of this study was to assess the influence of clonidine administered after induction on postoperative shivering after elective peripheral surgery. The effect of clonidine on intra-operative haemodynamics (blood pressure and heart rate) during the first 30 min after induction and on the postoperative sedation of the patient was also investigated. Two hundred and eighty male ASA 1 and 2 patients, undergoing elective peripheral surgery were randomly administered either placebo or clonidine 2 micrograms.kg-1 intravenously over 10 min after induction of anaesthesia. Clonidine was found to reduce the total incidence (p = 0.024), the severity (p = 0.005) and the duration (p = 0.01) of postoperative shivering. Clonidine did not increase postoperative sedation or diminish overall consciousness. We conclude that administration of clonidine 2 micrograms.kg-1 intravenously after induction of anaesthesia is safe and reduces postoperative shivering in this group of patients. PMID- 8686825 TI - Postoperative cognitive impairment in the elderly. Choice of patient-controlled analgesia opioid. AB - This study evaluated the safety and cognitive impact of patient-controlled analgesia with fentanyl compared to patient-controlled analgesia with morphine among elderly postoperative patients. In addition, two screening tests for cognitive impairment, the Mini Mental Status Exam and the Short Portable Mental Status Questionnaire, were compared. Ninety-six elderly patients were randomly allocated to receive patient-controlled analgesia with either fentanyl or morphine following hip or knee arthroplasty. Patients were evaluated postoperatively for clinical confusion, cognitive function test results, adequacy of analgesia, drug use and complications. Fentanyl produced less depression in postoperative cognitive function compared to morphine. The incidence of clinical confusion was not statistically different between groups (4.3% for fentanyl versus 14.3% for morphine). Fentanyl patients used more opioid based on a dose ratio of 100:1 suggesting that this dose ratio is inadequate. The incidence of urinary retention was lower in the fentanyl group. A poor agreement between the two tests of cognitive impairment mandates caution when peri-operative cognitive function is compared using different tests. PMID- 8686826 TI - Doxacurium pharmacodynamics in children during volatile and opioid-based anaesthesia. AB - The interaction between doxacurium and halothane, isoflurane or alfentanil has not been studied in children. Using the cumulative dose-response technique and electromyography, we determined ED50 and ED90 of doxacurium during halothane (n = 9), isoflurane (n = 12) or alfentanil (n = 9) based anaesthesia in children aged 2-10 years. Both isoflurane and halothane potentiated the effects of doxacurium compared to alfentanil. The ED50 for doxacurium/halothane was 23.9 micrograms.kg 1 compared to 32.7 micrograms.kg-1 for doxacurium/alfentanil. The ED90 for doxacurium/isoflurane was 32.7 micrograms.kg-1 compared to 48.2 micrograms.kg-1 doxacurium/alfentanil (p < 0.05). There were no significant time course differences between the groups. When equipotent doses of doxacurium were used to provide muscle relaxation the duration of the neuromuscular block was similar in children who received aflentanil, halothane or isoflurane supplementation of N2O/O2 anaesthesia. PMID- 8686827 TI - Cricoid pressure: are two hands better than one? AB - One hundred and twenty patients were studied to compare the view of the larynx at laryngoscopy with one- or two-handed cricoid pressure applied. A blinded crossover technique was employed. When the grade of laryngeal view achieved with either type of cricoid pressure was compared using a 4-point scale there was no significant difference. However, when the views were compared with greater discrimination the laryngeal view achieved with one-handed cricoid pressure was significantly better than that seen with two-handed cricoid pressure. There was no significant difference between the groups in the need for a gum elastic bougie to facilitate intubation. A two-handed technique has been advocated to improve intubation conditions when cricoid pressure is required. It has several disadvantages, its efficacy has not been proven and this study suggests it does not improve the view at laryngoscopy. Two-handed cricoid pressure should no longer be advocated unless an advantage over one-handed cricoid pressure can be shown. PMID- 8686828 TI - A study of the incorrect use of ventilator disconnection alarms. AB - Pressure-sensitive ventilator disconnection alarms may fail to function correctly when used with discharging compliance ventilators such as the Manley Blease. The increase in gas flow on disconnection generates raised pressure owing to the resistance provided by components of the breathing system. Thirty-four anaesthetists, who were unaware of the nature of the survey, were observed to see if previous recommendations for the correct adjustment of the ventilator alarm were being followed. It was found that 77% of alarms were incorrectly adjusted and would not have alarmed in the event of a true disconnection occurring. PMID- 8686829 TI - Respiratory pattern and rebreathing in the Mapleson A, C and D breathing systems with spontaneous ventilation. A theory. AB - A theoretical analysis is presented of the Mapleson A, C and D breathing systems when used in spontaneous respiration. The influence of the respiratory pattern is explained diagrammatically. Simple equations are derived, predicting the fresh gas flow required to prevent rebreathing with different respiratory patterns. Further equations allow the degree of rebreathing caused by inadequate fresh gas flow to be quantified. These are used to examine the effects of different respiratory patterns on the efficiency of the three systems. It is demonstrated that the single most important determinant of efficiency is the duration of the expiratory pause. The nature of the inspiratory and expiratory waveforms is less important and the I:E ratio far less important. The analysis suggests that the Mapleson A system will always be the most efficient of the three systems. The Mapleson C system will be efficient if inspiration is long and the expiratory pause is minimal. The Mapleson D system will be efficient if the expiratory pause is sufficiently long. PMID- 8686830 TI - Misplacement of multihole epidural catheters--a report of two cases. AB - The misplacement of a multihole (three lateral holes) epidural catheter such that it lies partly in the subdural space is demonstrated in two patients by means of epidurographic studies. PMID- 8686831 TI - Tracheal intubation through the laryngeal mask using a gum elastic bougie in the presence of cricoid pressure and manual in line stabilisation of the neck. AB - Forty adult patients had a gum elastic bougie passed blindly through a laryngeal mask on two occasions, after standard insertion, and after the application of cricoid pressure with manual in line stabilisation of the neck. After standard insertion the bougie entered the trachea on 11/40 occasions. With manual in line stabilisation of the neck and cricoid pressure applied, the bougie entered the trachea on 9/40 occasions. These results were not statistically significant. Blind passage of a gum elastic bougie through a laryngeal mask does not provide a reliable route into the trachea in either of the circumstances studied. PMID- 8686832 TI - Leg and back pain after spinal anaesthesia involving hyperbaric 5% lignocaine. AB - Fifty-four patients, aged 27-90 years, who were given lignocaine 5% in 6.8% glucose solution for spinal anaesthesia were studied. Thirteen of these patients experienced pain in the legs and/or back after recovery from anaesthesia. The patients affected were younger (p < 0.05) and the site of the dural puncture was higher (p < 0.01) than those individuals without pain. Five of the 13 patients (38%) with pain and seven of the 41 patients (17%) without pain admitted to a high alcohol intake, which might be a contributing factor. Leg and/or back pain is associated with the intrathecal use of hyperbaric 5% lignocaine. PMID- 8686834 TI - Acid-base management during cardiopulmonary bypass. Current trends in the United Kingdom. AB - Controversy exists over which method of acid-base management should be used during hypothermic cardiopulmonary bypass: the alpha-stat method or the pH-stat method. We surveyed 40 centres in the United Kingdom to assess current practice; whether practice has changed recently; and if so, why. Ten years ago, 31 centres (77.5%) used pH-stat and seven (17.5%) used alpha-stat. Currently nine centres (22.5%) are using pH-stat, 25 (62.5%) are using alpha-stat and four (10%) are using both. One centre (2.5%) has always used a modified pH-stat technique, and one continues to use alpha-stat in children and pH-stat in adults. Twenty-one of the 22 centres which have changed their practice did so because of increasing reports incriminating pH-stat in postoperative morbidity, particularly cerebral dysfunction. Our results show a marked trend towards using alpha-stat methods rather than the more traditional pH-stat approach. PMID- 8686833 TI - Modification of pain on injection of propofol. A comparison of pethidine and lignocaine. AB - One hundred and fifty ASA 1 and 2 patients were randomly allocated to receive pethidine 25 mg (1 ml), lignocaine 10 mg (1 ml) or 0.9% saline (1 ml) on a double blind basis, as pretreatment to reduce pain on injection of propofol. Both active treatments were significantly better than placebo at preventing pain (p < 0.01). Lignocaine was most effective in preventing pain in men (p < 0.05) whilst pethidine was more effective in women (p < 0.05). PMID- 8686835 TI - Wearing of masks for obstetric regional anaesthesia. A postal survey. AB - A postal survey of 801 members of the Obstetric Anaesthetists Association was carried out in the United Kingdom and Ireland to investigate the use of surgical facemasks whilst performing spinal and epidural blocks. Two hundred and twenty three out of 539 respondents (41.3%) routinely wore masks for both spinals and epidurals; 22 (4.1%) wore masks only for epidurals; 21 (3.9%) wore masks only for spinals and 273 (50.6%) did not wear masks for either spinals or epidurals. Fifty out of 240 (21%) of those who routinely wore masks did not believe that wearing a mask reduced the risk of infection. Only 83 out of 259 (32%) mask wearers changed their masks between cases. PMID- 8686836 TI - Patient consent and rectal drug administration. PMID- 8686837 TI - Patient consent and rectal administration. PMID- 8686838 TI - Patient consent and rectal drug administration. PMID- 8686839 TI - Anaesthetic management of placenta praevia. PMID- 8686840 TI - Controlled drugs--do current handling practices disguise substance abuse? PMID- 8686841 TI - The effects of nerve agent pre-treatment with pyridostigmine on the duration of action of suxamethonium. PMID- 8686842 TI - Hazards of scavenging devices. PMID- 8686843 TI - Prophylactic nitroglycerine and incidence of myocardial ischemia in high risk patients following major surgery. PMID- 8686844 TI - Blocked Yankauer sucker. PMID- 8686845 TI - Bilateral ilioinguinal nerve blocks for analgesia after total abdominal hysterectomy. PMID- 8686846 TI - A leaky circuit. PMID- 8686847 TI - Anterior spinal artery syndrome. PMID- 8686848 TI - Tunnelling in the opposite direction. PMID- 8686849 TI - Use of laryngeal mask airway in cervical manipulation. PMID- 8686851 TI - Laryngeal mask airway in adeno-tonsillectomy in children. PMID- 8686850 TI - Infiltration anaesthesia in the management of Caesarean section in a patient with peripartum cardiomyopathy. PMID- 8686852 TI - Efficacy of patient controlled analgesia may have a diurnal rhythm! PMID- 8686853 TI - Local anaesthesia and venous cannulation. PMID- 8686854 TI - Environmental analysis. PMID- 8686855 TI - Forensic science. PMID- 8686856 TI - Pharmaceuticals and related drugs. PMID- 8686857 TI - Cardiovascular (biochemical assessment of reperfusion). PMID- 8686858 TI - Renal function (microalbuminuria). PMID- 8686859 TI - Endocrine (standardization of glycohemoglobin measurement). PMID- 8686860 TI - Cancer (prostate-specific antigen). PMID- 8686861 TI - Trace metals (lead and cadmium exposure screening). PMID- 8686862 TI - Free radicals (nitric oxide). PMID- 8686863 TI - Solid-organ transplantation. PMID- 8686864 TI - Diseases of metabolism (porphyrias). PMID- 8686865 TI - Nutritional assessment (protein nutriture). PMID- 8686866 TI - Clinical informatics. PMID- 8686867 TI - Molecular biology techniques. PMID- 8686868 TI - Immunoassays. PMID- 8686869 TI - Capillary electrophoresis. PMID- 8686870 TI - Chemiluminescence and bioluminescence. PMID- 8686871 TI - Nuclear magnetic resonance spectroscopy. AB - The range of problems in clinical chemistry that can be addressed by MRS is wide. The number of applications reported in the literature is growing steadily, particularly since the study of the composition of physiological fluids and tissues, and the changes thereof in disease, are well suited to study by MRS. Moreover, the major technical limitations that have impeded its progress into the clinical laboratory in the past have been addressed. Recent hardware and software developments have further improved and simplified MRS analysis. Thus, it would be surprising if MRS of physiological fluids and tissues does not become an essential technique for clinical chemists and pathologists. In practice, three main obstacles remain to be overcome: a greater availability of instruments, a larger data base of spectral changes correlated with pathological conditions, and an enhanced supply of MR-trained individuals in the clinical environment. PMID- 8686872 TI - Clinical instrumentation (immunoassay analyzers). PMID- 8686873 TI - Enantiomeric separation of drugs by mucopolysaccharide-mediated electrokinetic chromatography. AB - Chondroitin sulfate C (sodium salt) and heparin (sodium salt), which are both mucopolysaccharides and natural components, have been employed as chiral selectors in electrokinetic chromatography (EKC) for the separation of enantiomers of drugs. These additives are charged, linear, sulfated polysaccharides having large mass. Ionic and hydrophobic interactions are probably the bases for the separation. Among tested drugs that are electrically neutral or basic, trimetoquinol, diltiazem, and their related compounds were successfully enantioseparated by EKC with mucopolysaccharides, especially with chondroitin sulfate C. The choices of pH and the concentration of mucopolysaccharides were found to be important for improvement of enantioselectivity. The acidic buffer solutions were effective for enantioseparation of the solutes in the chondroitin sulfate C system, although no migration of the basic drugs was observed in the heparin system. The results were compared with the enantiomeric separation by EKC with dextran sulfate (sodium salt). The method using chondroitin sulfate C was successfully applied to the optical purity testing of the drug substances. PMID- 8686874 TI - High-performance anion-exchange chromatography of oligonucleotides and oligodeoxynucleotides on quaternized polyethylenimine-coated zirconia. AB - The use of porous, quaternized polyethylenimine-coated zirconia particles for the separation of nucleosides, nucleotides, oligonucleotides, and oligodeoxynucleotides is described. Separations of these biomolecules on quaternized PEI-zirconia are presented. Quaternized PEI-zirconia and a quaternary amine functionalized silica are compared chromatographically. Quaternized PEI zirconia was able to separate oligonucleotides and oligodeoxynucleotides differing in length by a single nucleotide unit. It could also separate RNAs of the same length but differing by only one deoxynucleotide. In contrast, the silica-based phase was unstable at elevated temperatures (75 degrees C), and all retention toward anions was lost quite rapidly. PMID- 8686876 TI - Electron transfer from electrodes to myoglobin: facilitated in surfactant films and blocked by adsorbed biomacromolecules. AB - In previous work, greatly enhanced rates of electron transfer were found for myoglobin (Mb) in ordered films of surfactants on pyrolytic graphite (PG) electrodes. Direct electron transfer is now reported for Mb in films of didodecyldimethylammonium bromide (DDAB) on platinum, tin-doped indium oxide, and gold electrodes. Rates of electron transfer in these films were similar on all electrodes. In the absence of surfactant, electron transfer was observed on bare electrodes only when Mb was purified by chromatography, and only on hydrophilic tin-doped In2O3 or PG. Treatment of tin-doped In2O3 or PG electrodes with unpurified protein solutions blocked electron transfer to Mb in the purified solutions. Reflectance-absorbance infrared and X-ray photoelectron spectroscopy revealed proteinaceous adsorbates on electrodes exposed to unpurified solutions of Mb. This adsorbate blocks electron transfer to Mb and to ferricyanide in solution. Results suggest that electron transfer in the Mb-DDAB films may be facilitated partly by strong adsorption of surfactants on electrodes. Surfactant adsorbed at electrode-film interfaces appears to inhibit adsorption of macromolecules from Mb solutions which could otherwise block electron transfer between Mb and electrodes. PMID- 8686875 TI - Protein binding chiral discrimination of HPLC stationary phases made with whole, fragmented, and third domain turkey ovomucoid. AB - Individual protein domains and two domains in combination were prepared by enzymatic and chemical cleavage of turkey ovomucoid followed by isolation and purification by size-exclusion and ion-exchange chromatography. Silica bonded phase HPLC columns were made from either whole or isolated domains of turkey ovomucoid. The protein columns were tested for chiral recognition by their abilities to resolve enantiomers among a wide range of racemates. The columns made from whole turkey ovomucoid displayed chiral activity toward many racemates, where as a combination of the first and second domain resolved only a selected number of aromatic weak bases. The first and second domains independently gave no appreciable chiral activity. The turkey ovomucoid third domain exhibited enantioselective protein binding for fused-ring aromatic weak acids. Glycosylation of the third domain did not affect chiral recognition. Titration of the third domain with model compounds in conjunction with NMR measurements enabled the identification of the amino acids responsible for binding. Molecular modeling of the ligand-protein complexation provided insights into the ability of a protein surface to discriminate enantiomers on the basis of multiple intermolecular interactions. PMID- 8686877 TI - Dynamics of acrylodan-labeled bovine and human serum albumin entrapped in a sol gel-derived biogel. AB - We investigate acrylodan-labeled bovine and human serum albumin (BSA-Ac and HSA Ac) entrapped within a tetramethylorthosilane-derived biogel composite. The effects of biogel aging and drying were studied by following the acrylodan steady state and time-resolved emission, the decay of anisotropy, and the dipolar relaxation kinetics as a function of ambient storage time. The results indicate that there is a substantial amount of nanosecond and subnanosecond dipolar relaxation within the local environment surrounding cysteine-34 in both proteins, even when they are fully encapsulated in a dry biogel. Time-resolved anisotropy experiments show that the acrylodan residue and the protein are able to undergo nanosecond motion within the biogel. The semiangle through which the acrylodan can process is the same for a freshly formed biogel and the native protein in buffer. However, once the biogel begins to dry, the semiangle increases (approximately 20 degrees and 10 degrees for BSA-Ac and HSA-Ac, respectively). This suggests that the "pocket" hosting the acrylodan reporter group opens as the biogel dries. PMID- 8686878 TI - High-precision D/H measurement from hydrogen gas and water by continuous-flow isotope ratio mass spectrometry. AB - Two instrumental approaches are described for continuous-flow high-precision determinations of D/H ratios from hydrogen gas or via on-line reduction of water. In the first system, Ar is used as a carrier gas, with a Ni reduction furnace and a water trap to remove minor levels of unreduced water that are a potential source of memory effects. Precisions of SD < 10/1000 (delta DSMOW) over a 600/1000 range from -55 to +532/1000 are obtained for liquid water (0.4 microL). Linearity is excellent over 4 orders of magnitude of D concentration in tap water (r2 > 0.9999), although precision degrades at enrichments delta DSMOW > 5000/1000. In the second system, a heated Pd metal foil functions as a filter to admit purified hydrogen into the mass spectrometer. Hydrogen gas injections are made into flowing Ar and are directed to the Pd filter (approximately 330 degrees C) which passes hydrogen isotopes only while diverting the carrier flow to waste. Precisions of these measurements are SD < 6/1000 over the D enrichment range -213 to 340/1000, with excellent linearity (r2 > 0.9999) and accuracy (< 2/1000). Similar precision is obtained using the on-line reduction apparatus and a water trap prior to the Pd filter with injections of 0.4 microL of liquid water, with acceptable linearity (r2 > 0.999) over 3 orders of magnitude of D concentration. Neither system shows any sign of memory effects when water is analyzed. The data indicate that either one of these systems is a useful means for continuous-flow IRMS of D/H isotope ratio determinations. PMID- 8686879 TI - Ion/molecule reactions for improved effective mass resolution in electrospray mass spectrometry. AB - Tandem mass spectrometry is shown to improve the effective mass resolution in electrospray mass spectrometry. The technique involves selecting a population of ions within a narrow range of mass-to-charge values and allowing the ions to undergo proton transfer reactions. The shifts in mass-to-charge ratios associated with product ions formed by proton transfer allow for mass and charge assignment. The success of the technique relies on the relative enrichment of ions of a particular charge state that occurs in the mass-to-charge selection step. This approach can be used to extend the polymer mass range amenable to measurement, analyze mixtures that might otherwise be too complex for reliable mass measurements, and improve mass measurement precision when a mixture of cations is present within a given charge state. The technique is illustrated with a quadrupole ion trap using multiply-charged ions of cytochrome c, transfer ribonucleic acid from E. coli, strain W, and a synthetic deoxyribonucleic acid 30 mer. PMID- 8686880 TI - Characterization of cytochrome c variants with high-resolution FTICR mass spectrometry: correlation of fragmentation and structure. AB - The dissociation of cytochrome c ions (15+ charge state) generated by electrospray ionization has been studied by Fourier transform ion cyclotron resonance mass spectrometry (FTICR) using a sustained off-resonance irradiation/collision-induced dissociation (SORI-CID) technique. Over 95% of the fragment ions can be accurately assigned (to better than 10 ppm), yielding information on the primary sequences of the various proteins. Up to four stages of mass spectrometry (MS4) have been achieved without the need for quadrupole excitation/collisional cooling of the product ions. The subtle structural differences among the cytochrome c variants (from bovine, tuna, rabbit, and horse) are clearly reflected in their fragmentation patterns: replacing 3 out of 104 residues of the cytochrome c is shown to dramatically change the dissociation pattern. Of particular importance are a variety of results indicating that the dissociation of the cytochrome c's is influenced by higher-order structure and charge location, in addition to the primary structure (i.e., sequence). No fragmentation is observed in the region between residues 10-20 and little dissociation between residues 70-90. This is most likely due to the interactions of the heme group with the polypeptide chain, and such a heme "footprinting" pattern is analogous to the protein conformation in solution. These studies demonstrate that electrospray ionization-FTICR using SORI-CID can be a useful tool to probe not only the small differences in the primary sequences of proteins but also suggest the potential for probing their higher-order structures and yielding information not readily available from H/D exchange or circular dichoism studies. PMID- 8686881 TI - Using capillary electrophoresis to follow the acetylation of the amino groups of insulin and to estimate their basicities. AB - Capillary electrophoresis (CE) is an analytical method that is useful for investigating processes that modify the charge of proteins. This paper explores the ability of CE to rationalize charges and electrophoretic mobilities of a simple protein--insulin and its acylated derivatives--as a function of pH. Insulin is a peptide hormone (MW = 5700) that has two alpha-amino groups (G alpha and F alpha) and one epsilon-amino group (K epsilon). Treatment of insulin with acetic anhydride affords seven derivatives that differ in the sites of acetylation of the three amino groups. Analysis of the pH dependence of the electrophoretic mobilities of these derivatives gives pKa values for the two N terminal ammonium groups: pKa (G alpha) = 8.4; pKa (F alpha) = 7.1. Values of the total charge of insulin estimated from electrophoretic mobility differ from those estimated from values of pKa for its ionizable groups by less than 0.5 unit for both bovine and human insulins over the range of pH from 5.5 to 9.5. Analysis of the concentration dependence of the electrophoretic mobility of insulin yields a lower limit for the association constant for dimerization of insulin of KD > or = 6 x 10(3) M-1 (25 mM tris and 192 mM Gly, pH 8.4). Studies of electrophoretic mobility as a function of pH and extent of acetylation of amino groups rationalize the charge of insulin in detail. The sensitivity of CE to charge permits the quantitative study of electrostatic properties of proteins in solution. Insulin is a useful small-protein model with which to investigate phenomena in electrophoresis. PMID- 8686882 TI - On-line NMR detection of amino acids and peptides in microbore LC. AB - The combination of liquid chromatography (LC) and nuclear magnetic resonance (NMR) offers the potential of unparalleled chemical information from analytes separated from complex mixtures. However, the application of LC-NMR has been hindered by poor detection sensitivity. We develop a theoretical model for predicting signal-to-noise ratio (SNR) performance while scaling NMR detection cells for flowing experiments. The model includes the effects of separation parameters, coil geometry, and NMR acquisition parameters on SNR performance. Although the detector cell should be as large as possible to ensure adequate efficiency for a given separation, reducing the detector cell volume does not significantly degrade SNR. For example, our model predicts a 2-fold reduction in SNR for a 400-fold reduction in cell volume. The results of static NMR measurements of amino acids and peptides in a 50-nL-volume cell (approximately 1 microgram of each) demonstrate the performance of such a small-volume NMR microcell. Using this 50-nL detector cell with microbore LC, two-dimensional LC NMR chromatograms are shown for amino acid and peptide separations. PMID- 8686883 TI - Thrombogenic properties of untreated and poly(ethylene oxide)-modified polymeric matrices useful for preparing intraarterial ion-selective electrodes. AB - In vitro platelet adhesion studies are used to compare the thrombogenic properties of various polymer matrices useful for preparing implantable ion selective membrane electrodes. Conventional plasticized poly(vinyl chloride) and alternate polyurethane materials (Tecoflex, Pellethane) doped with proton- (tridodecylamine) and potassium-selective (valinomycin) ionophores are shown to be potentially thrombogenic. Incorporation of high molecular weight block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., Pluronic F108 and Tetronic 1508) within ion-selective membranes reduces platelet adhesion. A more marked decrease in platelet adhesion is, however, observed when the Tecoflex based membranes are coated with a thin photo-cross-linked layer of poly(ethylene oxide). Such surface-modified membranes are shown to retain potentiometric ion response properties (i.e., selectivity, response times, response slopes, etc.) essentially equivalent to untreated membranes. PMID- 8686884 TI - Oxygen sensors based on luminescence quenching: interactions of pyrene with the polymer supports. AB - Oxygen quenching of pyrene has been studied in a diverse series of polymers. Most measurements were made using homo- or copolymers containing a poly(dimethylsiloxane) region. Systematic variations in the polymer properties have been made in order to delineate the structural features important for satisfactory use as supports for oxygen sensors. In particular, quenching behavior was examined as a function of the type and amount of copolymer cross linkers; these were added to produce domains of different polarity and rigidity that would segregate the sensor molecule. A domain model (Xu, W.; et al. Anal. Chem. 1994, 66, 4133-4141) was used to explain the variations in oxygen-quenching properties as a function of additives and cross-linkers. The relative affinity of the different domains for the pyrene and the efficacy of the domains for oxygen quenching controls the overall behavior of the sensing response. PMID- 8686885 TI - Mining genomes: correlating tandem mass spectra of modified and unmodified peptides to sequences in nucleotide databases. AB - The correlation of uninterpreted tandem mass spectra of modified and unmodified peptides, produced under low-energy (10-50 eV) collision conditions, with nucleotide sequences is demonstrated. In this method nucleotide databases are translated in six reading frames, and the resulting amino acid sequences are searched "on the fly" to identify and fit linear sequences to the fragmentation patterns observed in the tandem mass spectra of peptides. A cross-correlation function is then used to provide a measurement of similarity between the mass-to charge ratios for the fragment ions predicted by amino acid sequences translated from the nucleotide database and the fragment ions observed in the tandem mass spectrum. In general, a difference greater than 0.1 between the normalized cross correlation functions for the first- and second-ranked search results indicates a successful match between sequence and spectrum. Measurements of the deviation from maximum similarity employing the spectral reconstruction method are made. The search method employing nucleotide databases is also demonstrated on the spectra of phosphorylated peptides. Specific sites of modification are identified even though no specific information relevant to sites of modification is contained in the character-based sequence information of nucleotide databases. PMID- 8686886 TI - Capillary electrophoretic enzyme immunoassay for digoxin in human serum. AB - The combined use of capillary electrophoretic (CE) separation and homogeneous enzyme immunoassay for analyzing drugs in hemolyzed, lipemic, or icteric serum samples was investigated. An FDA-approved EMIT assay kit for digoxin in human serum was used. After the enzyme immunoassay, the enzymatic reaction product (NADH) and remaining substrate (NAD+), together with internal standard (p nitrophenol, NP), were electrokinetically injected into a polyacrylamide-coated electrophoresis capillary and separated under applied potential. Detection was made by monitoring the UV adsorption at wavelength of 260 nm. The digoxin level in human serum was determined by comparing the peak area ratio of NADH and NP to the ratios established by the known digoxin standards. In this study, the factors that influence the CE separation were also investigated. Under the optimum conditions, NADH, NAD+, and NP were separated at electric field strength of 438 V/cm in the coated capillary (100 microns x 57 cm) with 200 mM Tris-borate buffer (pH 7.9) containing 0.2% hydroxypropyl methylcellulose. CE analyses of serum samples spiked with NADH standards at concentrations of 100 and 400 microM resulted in detection variabilities of less than 2% and analytical recoveries of 98-102%. Both an internal calibration plot for NADH and a dose-response curve for digoxin in serum were constructed. Calibrator serum, patients' sera with hemolyzed, lipemic, and icteric interference factors, and other pigmented blood components (e.g., serum albumin, bilirubin, hemoglobin, uric acid, coproporphyrin, melanin, protoporphyrin IX, and uroprophyrin) demonstrated no interference in this method. The authors believed that this method is useful for analyzing digoxin in hemolyzed, lipemic, and icteric blood samples that are known to create problems in conventional EMIT assays and may be applicable to other EMIT-based assays for monitoring drugs in complex biological matrices. PMID- 8686887 TI - Dynamics of DNA during pulsed field electrophoresis in entangled and dilute polymer solutions. AB - Using fluorescence video microscopy, DNA electrophoretic behavior under field inversion conditions has been investigated in hydroxyethyl cellulose (HEC) solutions both above and below its entanglement limit. DNA conformational fluctuation periods are found to be strongly influenced by the frequency of the applied electric field. DNA maximum extension is found to be dependent on both the frequency and the strength of the applied field. It is proposed that both above and below the HEC entanglement limit, field inversion serves to keep the average DNA conformation in a size-dependent regime intermediate between full extension and random coil. In this time-averaged geometry, efficient long-chain DNA electrophoretic separation is enabled. PMID- 8686888 TI - Separation of nanoliter samples of biological amines by a comprehensive two dimensional microcolumn liquid chromatography system. AB - A two-dimensional liquid chromatography system based on the combination of a charge separation mechanism, provided by anion exchange chromatography, with a hydrophobic separation mechanism, provided by reversed phase chromatography, is presented. A 90 cm long anion exchange microcolumn is coupled to a 3 cm long reversed phase microcolumn. Both microcolumns are interfaced by two electronically controlled valves. Effluent from the anion exchange microcolumn is collected in a sample loop and then concentrated onto the head of the reversed phase microcolumn. Analyte peaks consisting of tagged amines elute from the second column and are detected by laser-induced fluorescence. The entire operation is controlled by a personal computer. The resolving power of this system is demonstrated with a two-dimensional chromatogram of the peptides obtained from a tryptic digest of porcine thyroglobulin. The sensitivity of the system is demonstrated with a two-dimensional chromatogram of the contents of a single bovine chromaffin cell. PMID- 8686889 TI - Fourier transform spectroscopic imaging using an infrared focal-plane array detector. AB - A powerful new mid-infrared spectroscopic chemical imaging technique combining step-scan Fourier transform Michelson interferometry with indium antimonide focal plane array (FPA) image detection is described. The coupling of an infrared focal plane array detector to an interferometer provides an instrumental multiplex/multichannel advantage. Specifically, the multiple detector elements enable spectra at all pixels to be collected simultaneously, while the interferometer portion of the system allows all the spectral frequencies to be measured concurrently. With this method of mid-infrared spectroscopic imaging, the fidelity of the generated spectral images is limited only by the number of pixels on the FPA detector, and only several seconds of starting time is required for spectral image acquisition. This novel, high-definition technique represents the future of infrared chemical imaging analysis, a new discipline within the chemical and material sciences, which combines the capability of spectroscopy for molecular analysis with the power of visualization. In particular, chemical imaging is broadly applicable for noninvasive, molecular characterization of heterogeneous materials, since all solid-state materials exhibit chemical nonuniformity that exists either by design or by development during the course of material preparation or fabrication. Imaging, employing Raman and infrared spectroscopy, allows the precise characterization of the chemical composition, domain structure, and chemical architecture of a variety of substances. This information is often crucial to a wide range of activities, extending from the fabrication of new materials to a basic understanding of biological samples. In this study, step-scan imaging principles, instrument design details, and infrared chemical imaging results are presented. Since the prospect of performing high resolution and high-definition mid-infrared chemical imaging very rapidly has been achieved with the step-scan approach, the implications for the chemical analysis of materials are many and varied. PMID- 8686890 TI - Monitoring an oxidative stress mechanism at a single human fibroblast. AB - Easily oxidizable substances inside human diploid fibroblast cell strains were monitored amperometrically with a platinized carbon-fiber microelectrode. The experiment involved positioning a microelectrode over a single biological cell, forcing the electrode tip into the cell via micromanipulator control, and measuring the transient current corresponding to the complete electrolysis of electroactive species released by the cell. A second series of experiments involved puncturing a hole into the cell with a micropipet and measuring the transient current corresponding to the complete electrolysis of electroactive species emitted by the cell with an electrode positioned above the cell. The selectivity of both amperometric measurements was demonstrated through the use of known hydrogen peroxide scavengers (added catalase or intracellular peroxidase + added o-dianisidine) to the media bathing the cells. The abolition of the amperometric signal under these conditions suggested that hydrogen peroxide was the primary substance detected. The magnitude and the time course of the transient current measured implied that the hydrogen peroxide detected was not only that initially present in the cell before its membrane was pierced but represented mostly an oxidative stress response of the cell to its injury. PMID- 8686891 TI - Native fluorescence detection and spectral differentiation of peptides containing tryptophan and tyrosine in capillary electrophoresis. AB - A native fluorescence detection system for capillary electrophoresis is described that achieves low attomole detection limits and simultaneous acquisition of complete fluorescence emission spectra. The system is designed for detection of peptides through the intrinsic fluorescence of tryptophan and tyrosine residues. The detection system employs a frequency doubled krypton laser operating at 284 nm for excitation, a sheath flow cell, a reflective f/1.2 microscope objective, an imaging spectrograph, and a CCD detector. The detection capabilities are characterized with tryptophan and tyrosine, which have limits of detection (3 sigma) of 2 x 10(-10) and, 2 x 10(-8) M, respectively. Acquisition of the fluorescence emission spectrum provides the ability to distinguish three classes of peptides: those that contain tryptophan, those that contain tyrosine, and those that contain both tryptophan and tyrosine. PMID- 8686892 TI - Ultrasensitive near-IR fluorescence detection for capillary gel electrophoresis and DNA sequencing applications. AB - Electropherograms of oligonucleotides labeled with near-IR fluorescent dyes, separated by capillary gel electrophoresis and detected using an ultrasensitive near-IR fluorescence detection system, are presented. A universal M13 sequencing primer was labeled on the 5' end with a near-IR dye containing an isothiocyanate functional group. Comparison of the on-column detection limits in capillary gel electrophoresis for the near-IR dye-labeled sequencing primer to those obtained for a visible fluorescein-labeled primer indicated improved sensitivity for the near-IR case. The detection limit was found to be 3.4 x 10(-20) mol (SNR = 3) for the near-IR dye-labeled primer, while the on-column detection limit for the fluorescein analog was 1.5 x 10(-18) mol (SNR = 3). The sequence of nucleotide bases in an M13mp18 template was determined using a single lane, single dye technique. The molar concentrations of the ddNTPs used during chain extension reactions were varied to achieve a ratio of 4:2:1:0 (A:C:G:T), which allowed the identification of each terminal base via fluorescence intensity measurements. Sequencing ladders were prepared from the M13mp18 template using standard Sanger dideoxy chain-terminating techniques, the modified T7 DNA polymerase, and the near-IR dye-labeled M13 universal primer. The data indicated reliable sequence determination by the 4:2:1:0 (A:C:G:T) peak height identification method up to 250 bases from the annealing site. Comparison of the known sequence of the M13mp18 plasmid to that obtained using this protocol yielded a base-calling accuracy of 84% for the 4:2:1:0 ratio. PMID- 8686893 TI - Rapid comprehensive two-dimensional separations of peptides via RPLC-optically gated capillary zone electrophoresis. AB - Coupled-column two dimensional (2D) separation systems offer potentially high peak capacity and are amenable to automation. Reversed phase liquid chromatography (RPLC) and capillary zone electrophoresis (CZE) are complementary techniques well suited for use in a 2D system. Optically gated CZE is a means of performing rapid CZE analyses. In a 2D system, these rapid CZE analyses enable more frequent sampling of the RPLC separation and thus more freedom in control of the RPLC analysis conditions. Complete 2D separations can be done in the time usually required to do the RPLC analysis alone. With the present system, a complete 2D analysis can be done in under 10 min. Because the peak capacity of a 2D method is inherently high, some of the available peak capacity can be exchanged for speed of analysis. Acceleration of the RPLC elution gradient will decrease analysis time, but RPLC resolution will suffer. However, because it is a 2D system, some of the resolution lost in the RPLC can be regained in the second dimension CZE analysis. Here, the RPLC gradient was done over only 2 min, but CZE analyses done every 2.5 s restore some of the resolution lost in the rapid RPLC gradient. PMID- 8686894 TI - Comprehensive three-dimensional separation of peptides using size exclusion chromatography/reversed phase liquid chromatography/optically gated capillary zone electrophoresis. AB - Multidimensional separation methods are attractive because of their potentially high peak capacities. Coupled-column systems in particular offer the advantages of on-line detection and automation. With the development of rapid two dimensional (2D) analysis, it becomes possible to consider three-dimensional (3D) separation systems. In such a 3D system, effluent from a slow first dimension is repetitively sampled into a rapid 2D system. In the resultant data, each sample component has been subjected to three separative displacements, and the overall peak capacity is the product of that of each of the three dimensions. This paper demonstrates a comprehensive coupled-column 3D analysis of peptides. Size exclusion chromatography (SEC) is used as the first dimension to separate sample components by molecular weight, over an analysis time of several hours. The SEC effluent is repetitively sampled on-line into a rapid 2D reversed phase liquid chromatography/capillary zone electrophoresis (CZE) system with an analysis time of 7 min. Detection of sample zones is done only after the final CZE separation, by laser-induced fluorescence detection. Analysis data from this system consist of a series of 2D "slices" of the SEC effluent, which when stacked together give the 3D separation "volume". PMID- 8686895 TI - Resolution of cis and trans isomers of peptides containing proline using capillary zone electrophoresis. AB - Capillary zone electrophoresis (CZE) is known for its high separation efficiency. Optically gated CZE is a form of CZE that allows rapid analyses while high separation efficiency is maintained. Analysis of peptides containing proline with CZE and optically gated CZE gives two peaks for dipeptides and multiple peaks for oligopeptides containing more than one proline. The multiple peaks are believed to be due to the cis and trans forms possible in peptide bonds containing proline. Isomerization between the cis and trans forms takes place at room temperature with a lifetime of seconds to minutes. Resolution of these peaks in CZE is found to be a function of separation efficiency and time of analysis. Rapid analyses with relatively lower separation efficiency give resolution equal to or better than that of longer analyses with much higher efficiency. This confirms the relationship between the multiple peaks and isomerization between the cis and trans forms. To extract kinetic information from the experimental data, a digital simulation is used to model the separation obtained experimentally. The equilibrium constant and rate constants that give the best fit of the simulated data to the experimental data are considered estimates of the actual values for the given experimental conditions. PMID- 8686896 TI - Analysis of organophosphate pesticides by a trochoidal electron monochromator mass spectrometer system. AB - An electron monochromator mass spectrometer was used to study the resonant electron energies versus negative ion masses of the organophosphate insecticides dicapthion, EPN, ethion, fenitrothion, leptophos, leptophosoxon, paraoxon, and parathion. Each compound yielded a unique two-dimensional electron energy/mass spectrum. The most abundant ions are produced with electrons of energies between 0.03 and 1 eV, but ions result also from capture of electrons with energies ranging to 8.5 eV. Both resonance electron capture ions and dissociative electron capture ions are produced with electrons of energies ranging from 0.03 to 8.5 eV, and ions may have as many as three observable resonance states from which they are formed. Substituted thiophenoxide ions are postulated to arise by rearrangement of the parent thiophosphate ions through a spiro intermediate. Most fragment ions can be rationalized as arising through simple homolytic cleavage of the parent radical anions. PMID- 8686897 TI - Use of a nitrocellulose film substrate in matrix-assisted laser desorption/ionization mass spectrometry for DNA mapping and screening. AB - A nitrocellulose film is used as a substrate in matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) studies of DNA. PCR products and DNA fragment digests obtained from biochemical procedures can be analyzed with the use of a nitrocellulose substrate in MALDI MS whereas no signal is observed with the use of a stainless steel substrate. In this method, on-probe purification allows for effective elimination of the interfering effects of salts, buffers, and other contaminants that are usually present in DNA samples, which serve as important limiting factors in the DNA molecular ion yield in the MALDI process. The use of the nitrocellulose film substrate also appears to improve the shot-to-shot and sample-to-sample reproducibility of the ion yield due to the more homogeneous coverage of matrix/analyte over the sample surface. With the use of the nitrocellulose substrate, DNA fragments of up to 622 base pairs in complex mixtures provide mass spectra with minimal sample purification. Although only species corresponding to single-stranded DNA were detected, a mass calibration scheme was established allowing an accuracy of within one base pair for fragments of < 250 bp under the experimental conditions. Despite the low mass resolution of the spectra obtained, the method has been successfully used for rapid DNA screening for sample disease genes and PCR products. PMID- 8686898 TI - LC/MS/MS of carbohydrates with postcolumn addition of metal chlorides using a triaxial electrospray probe. AB - A new technique for on-line postcolumn addition (PCA) formation and tandem electrospray mass spectrometry of carbohydrate-metal complexes is presented. A metal chloride solution is added to a carbohydrate sample directly within the ion source of the mass spectrometer. Using a triaxial electrospray probe, this technique can be applied to form carbohydrate-metal complexes on-line, without the need of previously mixing the carbohydrate and metal chloride. Two basic tasks may be accomplished: structural analysis and sensitivity enhancement. The performance of this approach is demonstrated through PCA of LiCl, NaCl, KCl, RbCl, CsCl, and CoCl2, introduced via the triaxial probe after chromatographic separation of two four-component carbohydrate mixtures. Each metal-carbohydrate complex is subsequently analyzed by on-line MS and MS/MS. This technique is used to enhance sensitivity and also, in the case of cobalt coordination, to assist in carbohydrate structural elucidation. On-line LC/MS with PCA of LiCl was achieved with as little as 1.7 pmol of oligosaccharide (average consumed amount, 1.7 pmol with 1 microL of a 10 pmol/microL carbohydrate test mixture injection). PMID- 8686899 TI - Direct analysis of enzymatic reactions of oligosaccharides in human serum using matrix-assisted laser desorption ionization mass spectrometry. AB - Matrix-assisted laser desorption ionization mass spectrometry has been developed for direct mass analysis of enzymatic reaction products of oligosaccharides in human blood serum without the use of extraction or chromatographic separation. Molecular labeling of the substrate is used to achieve both the detection sensitivity and selectivity required in rapid analysis of reaction products in serum. It is found that tetramethylrhodamine (TMR)-labeled oligosaccharides provide 100-fold sensitivity enhancement over the corresponding underivatized oligosaccharides. In order to selectively retain the TMR-labeled molecules on the sample probe while washing away contaminants in a serum sample, a sample/matrix preparation method is developed. This technique provides detection sensitivity of labeled oligosaccharides in the range of hundreds of femtomoles per microliter. The mass measurement accuracy is better than 0.01% when a linear time-of-flight mass spectrometer is used. The application of the technique is illustrated for the subpicomole detection and quantitation of the conversion of the disaccharide alpha Fuc(1-->2)beta Gal-TMR to the blood group B active trisaccharide alpha Fuc(1-->2)[alpha Gal(1-->3)]beta Gal-TMR, catalyzed by the blood group B galactosyltransferase present in human serum. PMID- 8686900 TI - Capillary electrophoresis/frontal analysis for microanalysis of enantioselective protein binding of a basic drug. AB - A new HPCE method was developed for the enantioselective determination of the unbound concentration of a basic drug under plasma protein binding equilibrium. The racemic basic drug verapamil (VER) and human serum albumin mixed solution was used as a model sample solution. The sample solution was introduced into a fused silica capillary hydrodynamically or electrokinetically. During the electrophoresis following hydrodynamic injection, the unbound drug zone migrated apart from the sample zone and was separated into two zonal peaks with a plateau due to enantiomers by a chiral selector (trimethyl-beta-cyclodextrin) dissolved in the acidic running buffer solution (pH 2.5). By the electrokinetic introduction of the same sample solution from the anodic end, only the unbound drug entered the capillary and was separated into the enantiomers, which also gave the zonal peaks with plateau. The unbound concentration of each enantiomer was determined from the plateau peak height. The results obtained by the different methods for sample introduction agreed well with those determined by conventional ultrafiltration-chiral HPLC, which was employed as a reference method. The unbound concentration of (S)-VER was 1.7 times higher than that of the antipode. The sample size used in the present method was approximately 200 nL, which is about one-thousandth of that in the reference method. The electrokinetic introduction gave a better peak shape than the hydrodynamic introduction. PMID- 8686901 TI - Determination of the binding of ligands containing the N-2,4-dinitrophenyl group to bivalent monoclonal rat anti-DNP antibody using affinity capillary electrophoresis. AB - Affinity capillary electrophoresis has been used to determine the two dissociation constants of the complex between anti-DNP rat monoclonal IgG2b antibody and charged ligands that contained a N-dinitrophenyl group. Singly and multiply charged ligands were used to establish the influence of the charge on the mobility of the complex between Ig and its ligand(s). Zwitterionic buffer additives lessened adsorption of protein to the walls of the capillary. A form of analysis of the binding data is derived that is more useful than Scatchard analysis for certain multivalent systems where cooperativity of binding is in question, but where it is also possible to make plausible assumptions about electrophoretic mobilities of protein and protein-ligand complexes. The uncertainties and assumptions of this analysis are contrasted with those of Scatchard analysis. For this antibody and these monovalent ligands, the dissociation of the ligands from the antibody occurred noncooperatively. The charge on IgG2b at pH 8.3 is estimated to be -8.0 +/- 0.2; this value is obtained by analysis of the electrophoretic mobilities of complexes IgG2bL2, where the ligands L are structurally similar but have different charges (the charges on the ligands were also determined by CE). PMID- 8686902 TI - Predicting drug-membrane interactions by HPLC: structural requirements of chromatographic surfaces. AB - Drug-membrane interactions have recently been studied by immobilized artificial membrane (IAM) chromatography (Pidgeon, C.; et al. J. Med. Chem. 1995, 38, 590 595. Ong, S.; et al. Anal. Chem. 1995, 67, 755-762), and the molecular recognition properties of IAM surfaces toward drug binding/partitioning appear to be remarkably close to the molecular recognition properties of fluid membranes. The structural requirements of chromatography surfaces to emulate biological partitioning are unknown. To begin to elucidate the surface structural requirements needed to predict drug partitioning into membranes, three bonded phases were prepared. The chromatography bonded phases were prepared by immobilizing (i) a single-chain analog containing the phosphocholine (PC) headgroup (IAM.PC.DD), (ii) a long-chain alcohol containing polar OH groups protruding from the surface (12-OH-silica), and (iii) a long-chain fatty acid containing OCH3 groups protruding from the surface (12-MO-silica). The 12-OH silica surface can be considered as an immobilized "octanol" phase with OH groups protruding from the surface and is therefore a solid phase model of octanol/water partitioning systems. As expected, improved capability of predicting solute membrane interactions as found for the chromatographic surface containing the PC polar head-group because the PC headgroup is also found in natural cell membranes. For instance, the IAM.PC.DD column predicted drug partitioning into dimyristoylphosphatidylcholine liposomes (r = 0.864) better than 12-OH-silica (r = 0.812), and 12-MO-silica (r = 0.817). IAM. PC.DD columns also predicted intestinal drug absorption (r = 0.788) better than 12-OH-silica (r = 0.590) and 12-MO-silica (r = 0.681); reversed phase octadecylsilica (ODS) columns could not predict intestinal absorption (r = 0.10). Collectively, these results suggest that chromatographic surfaces containing interfacial polar groups, i.e., PC, OH, and OCH3, model drug-membrane interactions, but surfaces lacking interfacial polar functional groups (e.g., ODS surface) are poor models. Most interestingly, drug partitioning into octanol/water systems does not correlate with drug binding to the immobilized octanol phase. However, drug partitioning into immobilized octanol correlates with drug partitioning into liposomes (r = 0.812). PMID- 8686903 TI - Imaging of immobilized antibody layers with scanning electrochemical microscopy. AB - Visualization of immobilized antibodies can be achieved with scanning electrochemical microscopy (SECM) by saturation of the antigen binding sites with an alkaline phosphatase-antigen conjugate, which catalyzes hydrolysis of the redox-inactive 4-aminophenyl phosphate to the redox-active 4-aminophenol (PAP). PAP was detected in the collection mode at an amperometric SECM tip. The tip current reflects the density of active binding sites in the immobilized antibody layer. The application of this approach for immunosensing research has been demonstrated with the optimization of a covalent immobilization procedure of antibodies on glass. The special advantages and present limitations of the procedures are discussed. PMID- 8686904 TI - Electrocatalytic surface for the oxidation of NADH and other anionic molecules of biological significance. AB - A simple electrochemical treatment of a carbon fiber electrode surface has been found to dramatically improve the voltammetry of NADH and several other anionic molecules under steady-state and fast scan (100 V/s) conditions. The electrocatalytic surface is generated through the electrochemical oxidation of NADH on a carbon fiber electrode that exhibits product adsorption. The oxidative product is reacted with ascorbic acid at elevated temperatures to create a surface which has very little overpotential for the oxidation of dopamine and many metabolites such as NADH, DOPAC, uric acid, and ascorbate. The electrochemical properties of the modified surface were examined voltammetrically at both slow and fast scan rates. The surface shown in this paper shifts the oxidation overpotentials different magnitudes for each analyte tested, thus allowing discrimination between analytes of interest and their major interferences. Another benefit of this new electrocatalytic wave is that it decreases the limit of detection for NADH by approximately 1 order of magnitude. Therefore, this new carbon surface not only gives better discrimination between two analytes but also gives better detection limits for certain analytes of interest. PMID- 8686905 TI - Detection of bioactive oligopeptides after microbore HPLC with electrochemical detection of their Cu(II) complexes: effect of operating parameters on sensitivity and selectivity. AB - We used a microbore reversed phase column for acetonitrile/0.1% aqueous TFA gradient elution separation of peptides with the detection of their copper complexes by electrochemical detection. The copper complexes are formed in a short (1 or 1.5 min) postcolumn reactor following mixing of the eluent with the postcolumn reaction phase. Detection can be at an upstream anode or a downstream cathode of a dual-electrode electrochemical detector. The following parameters have been investigated for their effect on the sensitivity and the selectivity of the procedure: postcolumn pH, buffer type, temperature, reaction time, and anode potential. Of the 23 bioactive peptides used, there are several that fall into classes according to their chemical and electrochemical behavior with copper(II): those with a blocked terminal amine, those with aspartate in the third position, those that have an electroactive amino acid, and those that have a cyclic structure formed by the amide backbone through a Cys-Cys disulfide bridge. Depending on these attributes, the operating parameters have an influence on the sensitivity of the determination. Among the more well-defined results are the following. Uncomplicated peptides with a free amine terminus react rapidly in the postcolumn reactor and give signals in the range predicted by theory. There is evidence that longer peptides, and those with a blocked amine terminus, have a sensitivity limited by kinetic factors. The oxidations of tyrosine and tryptophan in peptides are dramatically influenced by buffer type at pH 9.8. At pH 8.0, there is no signal from several peptides in phosphate buffer, while in borate there is a signal. PMID- 8686906 TI - Patterning and regeneration of surfaces with antibodies. AB - We describe the application of a new technique for the site-specific immobilization of six different proteins within an area of 200 microns x 50 microns. The procedure involves coating the surface with deglycosylated avidin, which binds a photoactive biotin analogue, so providing a light-addressable surface onto which proteins can be immobilized. This is the first time that consecutive patterning of a number of different proteins has been described, and we demonstrate this with the fabrication of an immunospot for the qualitative visualization of the binding of multiple antigens. We also show that such a structured surface can be readily regenerated and subsequently repatterned. PMID- 8686907 TI - Measuring colloidal and macromolecular properties by FFF. PMID- 8686908 TI - Forensic PCR. Primed, amplified, and ready for court. PMID- 8686909 TI - Protein identification by capillary zone electrophoresis/microelectrospray ionization-tandem mass spectrometry at the subfemtomole level. AB - A method for the identification of proteins by their amino acid sequence at the low-femtomole to subfemtomole sensitivity level is described. It is based on an integrated system consisting of a capillary zone electrophoresis (CZE) instrument coupled to an electrospray ionization triple- quadrupole tandem mass spectrometer (ESI-MS/MS) via a microspray interface. The method consists of proteolytic fragmentation of a protein, peptide separation by CZE, analysis of separated peptides by ESI-MS/MS, and identification of the protein by correlation of the collision-induced dissociation (CID) patterns of selected peptides with the CID patterns predicted from all the isobaric peptides in a sequence database. Using standard peptides applied to a 20-microns-i.d. capillary, we demonstrate an ESI MS limit of detection of less than 300 amol and CID spectra suitable for searching sequence databases obtained with 600 amol of sample applied to the capillary. Successful protein identification by the method was demonstrated by applying 50 and 38 fmol of a tryptic digest of the proteins beta-lactoglobulin and bovine serum albumin, respectively, to the system. PMID- 8686910 TI - Raman chemical imaging: histopathology of inclusions in human breast tissue. AB - High-definition Raman chemical imaging microscopy is applied to the histopathological characterization of biopsied human breast tissue containing foreign polymer inclusions. The polymer material is found in a patient with a history of silicone implant breast reconstructive surgery. Silicone implants are, on occasion, anchored to the soft tissues of the chest with polyester patches. In the case studied here, the polyester anchors were incorporated into the patient's fibrous tissue surrounding the implant. High-definition Raman chemical imaging provides molecular-specific image contrast in the complex breast tissue matrix without the use of stains or dyes. This is the first example in which Raman spectroscopic imaging microscopy has been applied to pathology. A goal of this and future studies is to complement traditional histopathologic diagnoses of disease states utilizing vibrational spectroscopic imaging techniques. PMID- 8686911 TI - Concentration of extracellular L-glutamate released from cultured nerve cells measured with a small-volume online sensor. AB - An online sensor with a low detection limit for L-glutamate was developed in order to monitor the change in the extracellular L-glutamate concentration as a result of stimulated release from cultured nerve cells. The sensor consisted of a microdialysis (MD) probe fixed at the manipulator, a small-volume L-glutamate oxidase enzymatic reactor (0.75 mm i.d. and 2.5 cm long), and an electrochemical detector in a thin-layer radial flow cell with an active volume of 70-340 nL. Glassy carbon bulk or carbon film ring-disk electrodes were used as detectors by modifying them with Os poly(vinylpyridine) mediator containing horseradish peroxidase. The overall efficiency of L-glutamate detection with the sensor is 94% under optimum conditions, due to an efficient enzymatic reaction in the reactor and a high conversion efficiency in the radial flow cell. As a result, we achieved a sensitivity of 24.3 nA/muM and a detection limit of 7.2 nM (S/N = 3). The effect of interferents such as L-ascorbic acid can be minimized effectively by applying a low potential to the electrode for hydrogen peroxide detection (O mV) and via the ring-disk electrode geometry by using the disk for preoxidation. In the in vitro experiment, an MD probe for sampling was connected to a manipulator that controls distance between the probe and the stimulated cells. The cells were stimulated by KCl in a glass capillary or electrically with microarray film electrodes fabricated on a substrate. By using the sensor, we can monitor L-glutamate concentration changes at the submicromolar level caused by KCl stimulation of a single nerve cell and micromolar L-glutamate concentration increases caused by electrical stimulation of a brain slice. An increase in L glutamate concentration can also be measured by positioning the probe near the cell that is connected synaptically to the stimulated cell. PMID- 8686912 TI - Bioluminescent assay for heroin and its metabolites. AB - Illicit heroin is trafficked as a solid particulate drug, while heroin abuse is monitored by testing urine samples for its principal metabolites, morphine and morphine-3-glucuronide. Two novel bacterial enzymes were used in the development of a linked-enzyme assay for heroin and its metabolites: heroin esterase, which converts heroin to morphine, and morphine dehydrogenase, which oxidizes morphine to morphinone with the concomitant reduction of NADP+. A bioluminescent assay involving heroin esterase, morphine dehydrogenase, and the bacterial luciferase from Vibrio harveyi was developed and shown to be sensitive to 89 ng/mL heroin and 2.0 ng/mL morphine. Excellent correlation with the results from 83 authentic samples submitted for urine drug screening at a hospital laboratory was obtained. The bioluminescent assay exhibited greater specificity and speed than current immunological screening methods. A novel format of the bioluminescent assay involving immobilized enzymes was sensitive to 101 ng (250 pmol) of heroin and responded well to particulate heroin. This form of the test was sensitive enough to respond to one or two typical particles of illicit heroin. PMID- 8686913 TI - Continuous-flow isotope ratio mass spectrometry using the chemical reaction interface with either gas or liquid chromatographic introduction. AB - A novel method of sample introduction into an isotope ratio mass spectrometer (IRMS) is described. The technique uses the chemical reaction interface (CRI) to convert samples coming from a gas chromatograph (GC) or high-performance liquid chromatograph (HPLC) into CO2 using a microwave-induced helium plasma. Optimization parameters for both GC/CRI/IRMS and HPLC/CRI/IRMS are described. In both modes of operation, it was possible to obtain 13CO2/12CO2 ratios with standard deviations less than 1%. Investigation of HPLC/CRI/IRMS performance at low and high concentrations (0.5-10 micrograms) resulted in no significant deviations of the isotope ratios. The ability to differentiate samples of different biological origins was illustrated using chlorophyll a from spinach and algae, where a large difference was observed but good precision was maintained (SD < 0.60%). PMID- 8686914 TI - Detection and confirmation of beta-agonists in bovine retina using LC/APCI-MS. AB - Beta-adrenergic receptor agonists are growth-promoting drugs with the potential for illegal use in livestock, and human toxicity has resulted from consumption of contaminated meat. On-line liquid chromatography with atmospheric pressure chemical ionization mass spectrometry (LC/APCI-MS) was used for sensitive detection of several beta-agonists in retina, a tissue reported to concentrate and retain such residues for extended periods. Multiresidue extraction, separation, detection, and confirmation procedures were developed for retinal tissue and applied to eyes from cattle treated with clenbuterol (69-201 ppb) and to control eyes spiked with salbutamol (100 ppb) and terbutaline (25-100 ppb). Rapid switching of the potential difference between sampling cone and skimmer in the transport region of the API source was used to optimize acquisition of the protonated molecules and characteristic fragment ions obtained by collision induced dissociation reactions. The respective selected ions were simultaneously acquired using a single quadrupole mass spectrometer. The accurate and precise agreement observed for diagnostic ion intensity ratios between beta-agonists in retinal samples and authentic standards suggests that LC/APCI-MS can be used for confirmation of analyte structure at trace levels and does not require the use of a triple-stage quadrupole mass analyzer. PMID- 8686915 TI - Interlaboratory comparison of autoradiographic DNA profiling measurements. 3. Repeatability and reproducibility of restriction fragment length polymorphism band sizing, particularly bands of molecular size > 10K base pairs. AB - The observed interlaboratory standard deviation (SD) associated with the restriction fragment length polymorphism (RFLP) measurement of DNA fragment size is a predictable function of the observed mean band size (MBS). For DNA fragments of size 1,000 base pairs (bp) to the largest resolved component of commonly used "sizing ladder" calibration materials (about 20,000 bp), the variation in the sizing data from the Technical Working Group on DNA Analysis Methods (TWGDAM) sponsored "Large Fragment Study" is well-described by SD = 7.5 (1 + MBS/19 500)7.1. This sizing variability arises from a 0.1-0.4% SD in the relative positions of sample and calibration bands among electrophoretic gels. Statistically significant sizing differences do exist for bands above 10,000 bp among laboratories that use different calibration materials. The Large Fragment Study was efficiently accomplished through the use of a designed set of DNA samples, requiring but one gel in each of 20 participating laboratories. PMID- 8686916 TI - Antibody-mimicking polymers as chiral stationary phases in HPLC. AB - Antibody-mimicking synthetic polymers, selective for various optically active amino acid derivatives and peptides, were prepared by noncovalent molecular imprinting. A novel approach, in which the branched, trifunctional cross-linkers pentaerythritol triacrylate and 2,2-bis(hydroxymethyl)butanol trimethacrylate were copolymerized with methacrylic acid, is described. The polymers were subsequently applied as chiral stationary phases in high-performance liquid chromatography. They were superior to previously reported noncovalent molecularly imprinted polymers used for chiral separations in that they showed considerably higher load capacity, increased selectivity, and better resolving capability. PMID- 8686917 TI - Isotopic differences in human growth hormone preparations. AB - The 13C/12C isotope ratios have been measured for human pituitary growth hormone and three commercial growth hormone products in an attempt to differentiate endogenous versus exogenous origin. This might be a strategy to detect doping, as has recently been recognized for testosterone. While all preparations are statistically different from each other, we find that only Humatrope from Lilly has a carbon isotope ratio that is markedly different from those of human growth hormone or Genentech's Nutropin and Protropin. The low renal clearance of growth hormone reduces the applicability of this concept. PMID- 8686919 TI - Enhanced resolution in the fingerprinting of short-chain oligonucleotides using the dodecasodium salt of phytic acid in capillary electrophoresis. AB - The inclusion of the dodecasodium salt of phytic acid in separation buffers has been found to improve considerably the separation of a number of synthetic short chain oligonucleotides. A combination of the simplicity and the improved resolving power of this methodology allows the facile analysis of mixtures of such compounds. The presence of a large concentration of sodium ions reduces electroosmotic mobility due to more efficient shielding of negative charges on the inner surface of the capillary wall. This, in turn, leads to a more gradual fall in potential between this surface and the center of the capillary. PMID- 8686918 TI - Comment on "Influence of the chain length and surface density on the conformation and mobility of n-alkyl ligands chemically immobilized onto a silica surface". PMID- 8686920 TI - Probing brain chemistry. PMID- 8686921 TI - X-ray Spectrometry. PMID- 8686922 TI - Mass spectrometry. PMID- 8686923 TI - Hybridization assays using an expressible DNA fragment encoding firefly luciferase as a label. AB - We report the use of a new label, an expressible enzyme-coding DNA fragment, for nucleic acid hybridization assays. The DNA label contains a firefly luciferase coding sequence downstream from a T7 RNA polymerase promoter. The target DNA (200 bp) is denatured and hybridized simultaneously with two oligonucleotide probes. One of the probes is immobilized in microtiter wells, via the digoxigenin/anti digoxigenin interaction, and the other probe is biotinylated. After completion of the hybridization, the hybrids are reacted with a streptavidin-luciferase DNA complex. Subsequently, the solid-phase bound DNA is expressed by coupled transcription/ translation. The synthesized luciferase catalyzes the luminescent reaction of luciferin with O2 and ATP. The luminescence is linearly related to the amount of target DNA in the range of 5-5000 amol. The CVs obtained for 20 and 100 amol of target are 6.5% and 10.8%, respectively (n = 4). PMID- 8686924 TI - In vitro interaction of zeolite fibers with individual cells (macrophages NR8383): measurement of intracellular oxidative burst. AB - Inhalation of fibrous minerals such as asbestos and erionite can cause various lung diseases, including cancer. The mechanism by which these fibers induce disease is an area of active research. Interaction of fibers with lung macrophages leads to release of many substances. Among these, reactive oxygen metabolites (which include hydrogen peroxide, superoxide, and possibly hydroxyl radicals) are proposed to cause cellular damage. In this paper, we report a method for observing intracellular hydrogen peroxide release as rat lung-derived macrophages (NR-8383) phagocytize erionite fibers. This is possible by observing the fluorescence of 2',7'-dichlorofluorescein-the intracellular, oxidized form of 5 (and 6)-carboxy-2', 7'-dichlorodihydrofluorescin formed in the presence of newly released hydrogen peroxide. We are able to image the fluorescence within a single cell, thereby allowing us to get information on the spatial distribution of the metabolites. PMID- 8686925 TI - Laser desorption/ionization time-of-flight mass spectrometry of nitrated polycyclic aromatic hydrocarbons. AB - Mass spectra of four nitrated polycyclic aromatic hydrocarbons (nitro-PAHs), 9 nitroanthracene, 1-nitropyrene, 2-nitro-9-fluorenone, and 2-nitrofluorene, have been investigated using single-step laser desorption/ionization time-of-flight mass spectrometry. Pulsed UV radiation at 266 or 213 nm was used for desorption and ionization of solid samples deposited on an aluminum probe. The positive molecular ion which was observed for each nitro-PAH was of greater relative intensity when 213 nm radiation was used. A strong [M - NO]+ peak was observed in all spectra, and an intense NO+ signal accompanied the [M - NO]+ signal when 213 nm was used but was only weakly present when 266 nm was used. Comparison of the various spectra suggests that nitro-PAHs undergo an excited state nitro-nitrite rearrangement, followed by loss of NO. Multiphoton ionization of the NO fragment appears to be the principal route of formation of NO+ during laser desorption/ionization when 213 nm radiation is used. The presence of the carbonyl group in 2-nitro-9-fluorenone leads to unique and prominent fragments involving losses of CO from the carbonyl bridge. PMID- 8686926 TI - Collision-induced dissociation of branched oligosaccharide ions with analysis and calculation of relative dissociation thresholds. AB - Collision-induced dissociation (CID) is used in an external source Fourier transform mass spectrometer (FTMS) equipped with matrix-assisted laser desorption/ionization (MALDI) to study a number of complex, branched oligosaccharides. The relative dissociation thresholds for various oligosaccharide fragmentation pathways have been calculated in terms of kinetic and center-of-mass frame energy. For two isomers of difucosyllacto-N-hexaose, the loss of the fucose sugar is always the lowest energy fragment observed and occurs at the same energy for both isomers when the oligosaccharide is coordinated to a sodium ion. When the oligosaccharide is complexed to cesium, the threshold for the removal of the fucose moiety increases, indicating that the cesium is involved in a coordination complex that stabilizes the sugar. MS/ MS/MS is performed on a sugar, mannose core, which does not readily fragment during MALDI. In all the sugars examined, CID produces additional structural information relative to MALDI/FTMS. PMID- 8686927 TI - Mass spectrometric determination of isotopic exchange rates of amide hydrogens located on the surfaces of proteins. AB - The rates at which peptide amide hydrogens in folded proteins undergo isotopic exchange are reduced by factors of 10(0)-10(-8) relative to exchange rates at the same peptide linkages in unfolded proteins. To measure the isotopic exchange rates of the most rapidly exchanging peptide amide hydrogens in proteins, a flow quench deuterium exchange-in step has been added to the protein fragmentation/mass spectrometry method (Zhang, Z.; Smith, D. L. Protein Sci. 1993, 2, 522-531). Isotopic exchange rates in eight short segments spanning the entire backbone of cytochrome c have been determined for exchange-in times of 0.2 120 s. These results show that the isotopic exchange rates of 10 of the peptide amide hydrogens in cytochrome c are similar to those expected for unfolded cyt c, while the exchange rates for 33 other non-hydrogen-bonded amide hydrogens are much less than expected for unfolded cyt c. Since the isotopic exchange rates of the most rapidly exchanging amide hydrogens in folded proteins are a direct measure of their access to the aqueous solvent, the ability to determine these isotopic exchange rates points to the possibility of using quenched-flow amide hydrogen exchange and mass spectrometry as a tool for identifying protein surfaces involved with binding. PMID- 8686928 TI - Racemization of amino acids in solid-phase peptide synthesis investigated by capillary electrophoresis. AB - The rate of racemization during solid-phase peptide synthesis was studied using capillary electrophoresis and 18-crown-6 tetracarboxylic acid as chiral selector. For this purpose, the tripeptide D-Tyr-L-Lys-L-Trp as a model compound was synthesized by solid-phase peptide synthesis. A separation method based on capillary electrophoresis was developed which allowed all eight optical isomers of the tripeptide to be separated in a single run. The separation method was validated and was found to be well suited for purity analysis, with a limit of detection of 0.05% of the major compound. The method was revealed to be highly sensitive even to small variations in the buffer pH. Capillary electrophoresis was also employed to prove the enantiomeric purity of the Fmoc-protected amino acids used for peptide synthesis. A separation method based on micellar electrokinetic chromatography and gamma-cyclodextrin was developed for this purpose. The formation of optical isomers during peptide synthesis was investigated in the final product without hydrolyzing the tripeptide. This strategy allowed the rate of racemization to be determined by activation of amino acids in coupling cycles and cleavage of the peptides from the resin and from side-chain protecting groups. The formation of stereoisomers could be verified and was 0.4% or less per synthesis cycle. The experimental data agreed well with theoretical considerations, showing that racemization takes place mainly at the carboxy-activated amino acid during coupling. PMID- 8686929 TI - Experimental and theoretical study of the adsorption behavior and mass transfer kinetics of propranolol enantiomers on cellulase protein as the selector. AB - The thermodynamics and mass transfer kinetics of the retention of the R and S enantiomers of propranolol were investigated on a system comprising an acetic acid buffer solution as the mobile phase and the protein cellobiohydrolase I immobilized on silica as the stationary phase. The bi-Langmuir isotherm model fitted best to each set of single-component isotherm data. The monolayer capacity of the nonchiral type of adsorption sites was 22.9 mM. For the chiral type of sites, it was 0.24 mM for the R enantiomer and 0.64 mM for the S enantiomer. Peak tailing was observed, even at very low concentrations allowing operation of the low-capacity chiral sites under linear conditions. This tailing can be explained on the basis of heterogeneous mass transfer kinetics. At higher concentrations, which are often used in analytical applications, the isotherms on the chiral sites no longer have a linear behavior, and peak tailing is consequently more pronounced. Under those conditions, peak tailing originates from the combined effect of heterogeneous thermodynamics and heterogeneous mass transfer kinetics. These complex phenomena are explained and modeled using the transport-dispersive model with a solid film linear driving force model modified to account for heterogeneous mass transfer kinetics. The rate coefficient of the mass transfer kinetics was found to be concentration dependent. PMID- 8686930 TI - Effects of temperature and humidity on the performance of polymer-coated surface acoustic wave vapor sensor arrays. AB - The influences of temperature and atmospheric humidity on the performance of an array of eight polymer-coated 158-MHz surface acoustic wave vapor sensors were investigated. Sensitivities to the seven organic vapors examined all exhibited negative Arrhenius temperature dependencies, with responses increasing by factors of 1.5-4.4 on going from 38 to 18 degrees C. The magnitudes of the temperature effects, while generally similar, differed sufficiently among certain sensor vapor combinations to cause marked changes in vapor response patterns. In addition, it was found that operating identically coated sensors at different temperatures could provide a means for discriminating certain vapors. The changes in sensor responses with temperature agreed reasonably well with those expected assuming ideal vapor sorption behavior and indicated that changes in the moduli of the sensor coatings were not important mediating factors. Responses to relative humidity (RH) from 0 to 85% RH were important even for the nonpolar sensor coatings. Significant changes in the sensitivities to the organic vapors were observed as a function of atmospheric humidity for several sensor-vapor combinations, which, in turn, affected the patterns of responses obtained from the sensor array. Results indicate that small changes in temperature or humidity have a larger effect on baseline stabilities than on the responses to the vapors. Monte Carlo simulations of sensor responses show that the ability to discriminate vapors in binary and ternary mixtures using a four-sensor array remains high regardless of the operating temperature and ambient humidity, provided that temperature-or humidity-induced changes in the response patterns are taken into account. PMID- 8686931 TI - Electrochemiluminescence-based detection of beta-lactam antibiotics and beta lactamases. AB - Bacterial resistance to clinically administered beta-lactam antibiotics is usually caused by beta-lactamases, enzymes that hydrolytically inactivate the antibiotics. This paper describes the use of electrogenerated chemiluminescence (ECL) to detect beta-lactam antibiotics and their hydrolysis by beta-lactamases. All 10 tested antibiotics were detected on the basis of their ability to participate in an ECL reaction with ruthenium(II) tris(bipyridine). In every case, antibiotic-promoted ECL changed when the antibiotic was hydrolyzed by beta lactamases or NaOH. Standard curves of antibiotic concentration versus ECL intensity showed that antibiotics could be quantitated to low micromolar concentrations. Substrate profiles were generated for four beta-lactamases using six structurally diverse beta-lactam antibiotics. ECL-based antibiotic detection was accomplished in untreated whole milk, and beta-lactamases were detected in crude bacterial broth culture. Because several structurally diverse antibiotics were detectable by ECL, this method may become valuable for the detection of many or all beta-lactam antibiotics and their inactivation by beta-lactamases. PMID- 8686932 TI - Design and evaluation of an automated solid-phase extraction method development system for use with biological fluids. AB - An automated solid-phase extraction method development system, utilizing a Zymate XP robot and a custom-designed solid-phase extraction manifold, has been developed and validated. This system spikes blank liquid matrix, such as plasma, with solutions containing drug, internal standard, and up to three metabolites. Samples are then buffered or diluted with an appropriate reagent. After these samples and corresponding blanks have been prepared, solid-phase cartridges containing selected sorbents are automatically conditioned. Samples are robotically vortexed and transferred to the conditioned cartridges, and analytes are extracted. Validation of this robotic system demonstrated acceptable precision and accuracy for three types of liquid transfer, including metering pump ( < 6% RSD and RE for > or = 2.0 mL dispensation), syringe-based laboratory station ( < or = 2.9% RSD and 0.5% RE for volumes between 0.25 and 1.00 mL), and syringe hands ( < 3.5% RSD and RE for volumes between 0.10 and 1.00 mL). For two example compounds, the system provided data which effectively distinguished good solid-phase sorbents from marginal ones through precision, recovery, and chromatographic selectivity. Solid-phase extraction of these compounds from human plasma gave precision (2-10% RSD) and extraction efficiency (96 +/- 6%) comparable to results obtained from manual extractions (92 +/- 11%). PMID- 8686933 TI - [The antioxidant therapy of cholestatic liver depression in diabetics]. AB - Lipid peroxidation of cell membranes and liquid media of the organism were studied in 54 diabetics with the cholestatic syndrome, and fundamentals of antioxidant therapy of this cohort of patients discussed. The predominant efficacy of bio-oxidants has been revealed. The mechanism of their action is realized primarily at the stages of initiation and ramification of the chain of free radical oxidation. The authors searched for a sufficiently effective combination of antioxidants for the treatment of medium-severe and grave hepatodepression in patients with sub- and decompensated diabetes mellitus, as well as for the optimal method of antioxidant therapy. PMID- 8686934 TI - [The course and prognosis of septic shock in patients with hemoblastoses and aplastic anemia in a state of agranulocytosis]. AB - The course and prognosis of septic shock developing during agranulocytosis were retrospectively studied in 59 hematological patients (52 ones with hemoblastosis and 7 with aplastic anemia). Out of 59 patients with septic shock hospitalized at department for anesthesiology and reanimation, in 5 shock was arrested and they were transferred to other departments of the hospital. All patients with failure of more than three organ systems, with SAPS score of 21 at admission, and a history of splenectomy died in the anesthesiology and reanimation department. The diagnosis of the underlying disease, resistance to chemotherapy administered, disease stage, persistent agranulocytosis, and artificial ventilation of the lungs which had to be resorted to did not influence the prognosis of septic shock. Even after effective antishock therapy all patients with aplastic anemia died, as did the patients with resistance to chemotherapy administered for the underlying disease and those without signs of granulocytopoiesis recovery. Hence, the prognosis is unfavorable for patients with septic shock in a state of agranulocytosis, if their SAPS score on admission is higher than 21, if they develop polyorgan failure with involvement of more than three organ systems, have a history of splenectomy, their hemoblastosis is resistant to chemotherapy, and there are no prospects for granulocytopoiesis recovery. PMID- 8686935 TI - [The epidural administration of pentamine as a method for stimulating the functions of the small intestine in the early postoperative period]. AB - A technique of prolonged sympathetic ganglion blockage with an epidurally applied ganglioblocker pentamine has been suggested. With the help of manometry, using an open catheter and electromyography methods, the effect of the above technique on the recovery of the damaged small intestinal functions in the early postoperative period has been studied in comparison with prolonged epidural blockade with trimecaine in patients after gastric surgery. The effect of epidurally administered drugs on central hemodynamics has been studied. The technique suggested is effective for the recovery of the damaged small intestinal functions and has a number of advantages over conventional prolonged epidural blockade: less pronounced effect on central hemodynamics, the absence of blocking effect on afferent pulsation. All these makes it a technique of choice in patients with severe homeostasis disturbances and low central hemodynamic indexes. PMID- 8686936 TI - [Lipid peroxidation and blood plasma chemiluminescence during artificial circulation]. AB - Removal of the clamp from the aorta is the most hazardous stage from the viewpoint of free-radical injury, for at this moment the myocardium, weak from ischemia, is exposed to blood containing oxygen in excess and toxic products of lipid peroxidation. This was demonstrated by chemiluminescence (CL) and malonic dialdehyde (MDA) measurements. Accumulation of intracellular antioxidants in the blood may have a protective adaptive significance aimed at suppression of the toxic effects of oxygen radicals. CL results are in good correlation with MDA measurements, this making CL fit for rapid assessment of the adequacy of artificial circulation and the possibility of reperfusion injury to the myocardium. PMID- 8686937 TI - [The diagnosis and correction of hemostatic system disorders during surgical coagulopathic hemorrhages in cancer patients]. AB - The hemostasis system was examined before surgery, during the principal stages of the operative intervention, and in the early postoperative period in 280 patients with various malignant tumors. The volume of intraoperative blood loss varied from 280 to 14,000 ml. The studies revealed that the main factor causing the most profound disorders in the hemostasis system which lead to the development of grave coagulopathic hemorrhages is blood loss due to surgical trauma. Coagulopathic bleedings most frequently develop in case of at least a 3000 ml blood loss and course as different variants and stages of the syndrome of disseminated intravascular coagulation (DIC) or hemodilution coagulopathy. Massive blood loss was found to involve primarily damage of the platelet component of the hemostasis system, thrombocytopenia being paralleled by a drastic reduction of the aggregability of these cells, this, in turn, increasing bleeding from small vessels. Laboratory signs of acute DIC diagnosed during surgery anticipate its clinical manifestation. Working classification of operative bleedings and rapid methods for their diagnosis have been developed. PMID- 8686938 TI - [The effect of blood loss on hemostatic regulation by the lungs in puerperae with gestoses complicated by acute kidney failure]. PMID- 8686939 TI - [The possible mechanisms of a fibrinolytic disorder in patients with severe craniocerebral trauma]. AB - Fibrinolysis components were studied in 32 patients with slight and 38 ones with grave craniocerebral injuries on days 1, 3, 5, and 7 after the injury. No expressed disorders of blood fibrinolytic activity were revealed in patients with slight injuries. Grave craniocerebral injuries were associated with disorders of the plasmin system. Depression of the external and internal mechanisms of fibrinolysis were the most manifest starting from day 3 and caused by a number of factors characteristic of the developing disseminated intravascular blood coagulation syndrome and, possibly, by impaired regulation of the plasmin system by the central nervous system. PMID- 8686940 TI - [The characteristics of the effect of different shapes of the gas flow rate curves during artificial pulmonary ventilation]. AB - Five curves reflecting the rate of gas flow into the lungs during artificial ventilation of the lungs (AVL) are compared. The estimations demonstrate that the optimal distribution of gas in the lungs is attained at the peak of the rate at the beginning and during the first third of inhalation phase. At a constant flow rate the increase of the volume is constant, at maximal flow rate at the beginning and during the first third of inhalation the highest increase of the volume is observed during the first third of inhalation, at sinusoidal and increasing flow it is observed during the second third of inhalation. The maximal peak pressure in the airways was observed with the flow increasing, but the mean pressure associated with the curve of this shape was the lowest. The mean pressure is the highest at decreasing flow and at maximal flow during the first third of inhalation. PMID- 8686941 TI - [Anesthesia using clofelin in different types of arterial hypertension in middle aged and elderly patients]. AB - Clonidine in a dose of 2.5 to 3 mg/kg was used as a component of anesthesia in 150 patients aged 60 to 85. Essential hypertension of the second-third stages was diagnosed in 57% patients (group 1), systolic sclerotic arterial hypertension (SSAH) in 43% (group 2). Anesthesia was characterized by stable hemodynamics; however, analysis within the groups showed an increase of systolic and diastolic arterial pressure in 40% patients in group 2. There were no clinical signs of inadequacy of anesthesia. Remembering about the reduction of the reserve potential of the cardiovascular system in this cohort of patients, neurovegetative inhibition was supplemented by peripheral a-adrenoblocker droperidol, starting from the test dose of 1.25 and increasing it to 5 mg over the course of anesthesia; this led to stabilization of the peripheral and improvement of the central hemodynamics. Differences in the changes of central hemodynamics may be explained by specific features of circulation in patients with essential hypertension and SSAH, as well as by a higher tone of the sympathetic component of the CNS in SSAH patients. PMID- 8686942 TI - [Pressure-regulated pulmonary ventilation with an inverse ratio of the duration of the inhalation and exhalation phases]. AB - Clinical and physiological effects of pressure-regulated ventilation of the lungs using the inverse rate of inhalation to exhalation (PCV-IR) were studied in two groups of patients. No appreciable advantages of this mode of pulmonary ventilation in comparison with common ("volumic") method were observed in group 1 patients (following open-heart surgery) with moderately expressed respiratory disorders (PaO2/FIO2 = 340c13 and index of lung comprometation 0.7c0.04). At the same time, the level of the peak inhalation pressure in the airways at PCV-IR was reliably lower than during common artificial ventilation of the lungs (AVL). In patients with grave respiratory disturbances (PaO2/FIO2 = 93c10 and index of lung comprometation 6.88c0.56) application of this scheme brought about an improvement of pulmonary biomechanics and gas exchange, but the hemodynamics was virtually the same. It is noteworthy that the process of PCV-IR adaptation required a thorough preliminary "adjustment" of the ventilation parameters and took rather a long time in the majority of patients. Positive effects of PCV-IR may be due to several mechanisms: a slowing down (ramp-like) flow, limitation of the upper pressure during inhalation, prolongation of exhalation in comparison with inhalation, and a regulated level of internal positive end expiratory pressure. PCV-IR is recommended as a variant of respiratory support in the treatment of patients with severe involvement of the lungs, when the potentialities of common AVL are exhausted. PMID- 8686943 TI - [The monitoring of brain metabolism as the basis for the control of its adequate protection during circulatory arrest under deep hypothermia]. AB - Monitoring of brain metabolism is used to assess the adequacy of brain cooling during operations performed under conditions of deep hypothermal perfusion and temporary arrest of circulation. Such monitoring consists in continuous recording of hemoglobin saturation of the blood flowing from the brain by fiberoptic oximetry and testing of blood samples collected from the upper internal jugular bulb. A patient is described, who had been operated with good results under conditions of deep hypothermal perfusion and 30-min arrest of circulation. PMID- 8686944 TI - [The central hemodynamic changes and reaction of the sympathoadrenal system with the use of an original Russian analgesic fenaridin as the analgetic component of general anesthesia during aortocoronary bypass operations in patients with chronic ischemic heart disease]. AB - The effect of fenaridine on the central hemodynamics and sympathoadrenal system was studied in 12 chronic coronary patients subjected to aortocoronary shunting and administered this drug as an analgetic component of general anesthesia. A reduction of heart rate, systolic arterial pressure, pressure in the pulmonary artery, total pulmonary resistance, more expressed decrease of cardiac index and stroke index, and an increase of total peripheral vascular resistance were observed. Analysis of the results permitted us to propose vasodilating effect of the drug, leading to a moderate reduction of cardiac index, and followed by a compensatory increase of vascular resistance, as the basic mechanism of these changes. These shifts cannot be induced by improper anesthesia, which was confirmed by the results of examining the sympathoadrenal system. PMID- 8686945 TI - [The preventive role of large doses of aprotinin in decreasing the degree of metabolic disorders during aortocoronary bypass operations]. AB - A total of 100 patients were subjected to multiple aortocoronary shunting using autovein and/or internal thoracic artery under conditions of artificial circulation. In a double blind test, all the patients were administered either aprotinin (group 1, n = 50) or placebo (group 2, n = 50). The groups were matched for duration of surgery, number of shunts, duration of artificial circulation and aorta clamping, age, and body weight. Our results indicate that intraoperative prolonged infusion of high (6.0 million KIU) aprotinin doses reduced the incidence and severity of disorders of pulmonary oxygenation function; improved, despite an increase of diuresis, the function of the kidneys, and reduced the severity of circulatory hypoxia caused by both artificial circulation and acute circulatory disorders in the intra- and early postoperative period. PMID- 8686946 TI - [An assessment of the efficacy of Lomir in treating hypertension in patients in the early period after aortocoronary bypass operations]. AB - The authors assessed the efficacy and safety of intravenous lomir used to treat arterial hypertension in 10 coronary patients early after aortocoronary shunting. The following parameters were monitored: systolic, diastolic, and mean arterial pressure, ECG, pressure in the pulmonary artery, blood gases, and minute volume obtained by thermodilution. Intravenous lomir was found to be a highly effective hypotensive agent in patients in the early periods after aortocoronary shunting, well tolerated by the patients, the infusions being easy to monitor and involving virtually no side effects. Lomir improved the coronary bloodstream, virtually did not influence the heart rate, atrioventricular conduction, and pumping function of the heart. PMID- 8686947 TI - [The pathogenesis of hypoventilation in the operated lung]. AB - The content of immunocompetent cells, activity of lipid peroxidation processes, function of the surfactant system, and levels of prostacyclin and thromboxane were studied in 9 patients with resected lungs in the perioperative period separately for the intact and operated on lung. The function of immunocompetent cells deteriorated in both lungs after surgery. The levels of albumin and thromboxane were increased in the bronchoalveolar washings from the lung operated on reliably more than in those from intact lung, and the surface active characteristics deteriorated. Eight patients developed hypoventilation of the operated on lung in the postoperative period. PMID- 8686949 TI - [Experience with using the laryngeal mask during anesthesia in pediatric traumatology]. PMID- 8686948 TI - [A new sorbent for hemosorption]. AB - SIAL, a new granulated white adsorbent, has been obtained. It is characterized by highly porous surface with hydrophilic-hydrophobic properties due to combined effects of the mineral matrix (aluminum oxide) and the coating (organosiloxane fluid) permitted for medical use. The detoxication properties of the adsorbent have been demonstrated in experimental hemosorption. It was shown to exert a moderate effect on the contact phase of blood clotting and on platelet aggregation characteristics. PMID- 8686950 TI - [The combined efferent therapy of a blood-transfusion conflict in a puerpera]. AB - Plasmapheresis, ultrafiltration of blood, and hemodialysis were effectively used in the treatment of a 20-year-old woman after cesarean section who was transfused 300 ml of wrong group blood. The resultant hemotransfusion conflict was characterized by shock, disseminated intravascular coagulation, hemolysis, acute pulmonary edema and renal failure. Plasmapheresis helped abolish the hemolysis. Pulmonary edema was eliminated by ultrafiltration of 2 liters of blood. Six sessions of hemodialysis administered within 10 days arrested renal insufficiency. The treatment administered may be considered as the method of choice in such patients. PMID- 8686951 TI - [A case of the successful treatment of a patient with severe craniocerebral trauma combined with hemophilia]. AB - The described case with a severe craniocerebral injury in a patient with hemophilia A demonstrated that the initial hypocoagulation does not preclude the development of intravascular blood coagulation. Therefore, in patients with severe brain injury, a more rapid reduction of antihemophilic globulin A is possible, in comparison with that occurring during planned surgery, and, hence, higher doses of cryoprecipitate and longer duration of its infusion are needed. Moreover, this case demonstrated that even in patients with a slight form of hemophilia A the treatment with cryoprecipitate should be continued till the levels of thrombinemia markers are reduced and the concentration of antihemophilic globulin A in the blood stabilized at a level of at least 10%; the dose of infused cryoprecipitate should be reduced gradually. PMID- 8686952 TI - [Patient-controlled analgesia as a method for postoperative anesthesia]. PMID- 8686953 TI - [The narcotic properties of xenon and the prospects for its use in anesthesiology]. PMID- 8686954 TI - [The pathogenesis and treatment of the adult respiratory distress syndrome in patients with multiple organ failure]. PMID- 8686955 TI - [The pathogenetic and treatment problems of multiple organ failure in patients with severe combined trauma and massive blood loss in the early postresuscitation period]. AB - Analysis of the results of treatment of 583 patients with grave and terminal stages of shock resultant from severe combined injuries and blood loss, hospitalized in resuscitation wards, showed visceral involvement and development of pyoinflammatory complications in the early postresuscitation period (days 5-10 of treatment) in 43.6% cases. Prolonged mixed type hypoxia and persistence of impaired tissue perfusion, shown by rheovasography, play an important role in the mechanisms of development of complications. Early onset (6-8, 10-12 h after the beginning of treatment) and long standing of disseminated intravascular coagulation (DIC) contributes to the pathogenesis of polyorgan failure. A protocol of pathogenetically validated measures for the prevention and treatment of DIC is presented as one of approaches to the prevention and treatment of polyorgan failure. PMID- 8686956 TI - The influence of angiographic endpoints on the outcome of lipid intervention studies. A proposal for standardization. REGRESS study group. AB - The aims of this study were to evaluate the influence of different coronary angiographic endpoints on the outcome of lipid intervention studies and to formulate a proposal for angiographic endpoint standardization. In recent angiographic intervention studies a confusing diversity in angiographic endpoints has been used to determine the outcome. In addition, differences in study populations (eg, bypass patients included or not) could influence results. This makes comparisons between studies cumbersome and raises the question to what extent the results of various studies may be subject to the selection of angiographic endpoints. The investigators compared three frequently used endpoints (mean segment diameter, minimum obstruction diameter, and % stenosis) in a group of 505 patients who had just finished a trial designed to assess the effect of cholesterol lowering by pravastatin. To exclude a potential bias this analysis was carried out at the time that the study was still blinded. They found poor intercorrelation coefficients for mean segment diameter calculated in different ways, ranging from 0.55 to 0.95, dependent on inclusion or exclusion of segments influenced by coronary angioplasty or bypass grafting and on whether or not a value of 0 was assumed for occluded segments and segments distal to occlusions. The correlation between mean segment diameter and minimum obstruction diameter was 0.79; between minimum obstruction diamete and % stenosis, 0.85; and between mean segment diameter and % stenosis, only 0.64. Different endpoints sometimes correlate poorly. This may lead to differences in results of angiographic intervention trials. The authors propose standardization by (1) using both mean sement diameter and minimum obstruction diameter as endpoints and (2) excluding from the primary analysis segments influenced by mechanical interventions. PMID- 8686957 TI - Angiotensin-converting enzyme gene polymorphism in essential hypertensive patients in Japanese population. AB - Association between angiotensin-converting enzyme (ACE) gene polymorphism and essential hypertension in a Japanese population with the same socioeconomic background was investigated. Insertion-deletion (I/D) polymorphism of the ACE gene located on intron 16 was detected by polymerase chain reaction. Association between ACE gene polymorphism and family history of essential hypertension as well as the development of vascular damage in eye fundi were also investigated. Variation at ACE loci did not contribute to essential hypertension and the vascular damages in eye fundi. These results suggest that the ACE gene was not directly responsible for essential hypertension in this particular Japanese population with the same socioeconomic background. PMID- 8686958 TI - Arachidonic acid metabolites in acute myocardial infarction. AB - Abnormalities of arachidonic acid metabolism are implicated in spasm and thrombosis in coronary arteries. Therefore, arachidonic acid metabolites were examined in patients with acute myocardial infarction (AMI). Plasma levels of thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (6KPGF1 alpha), leukotriene B4 (LTB4), and slow reacting substance of anaphylaxis (SRS-A) composed of leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4), were measured in 19 AMI patients. Plasma levels of TXB2, LTB4, and SRS-A in systemic artery blood were significantly elevated during the acute stage (within twenty four hours after the onset of chest pain) of AMI (TXB2, 0.36 ng/mL; LTB4, 0.75 ng/mL; and SRS-A [LTC4+LTD4+LTE4], 0.96 ng/mL compared with those of normal controls (TXB2, 0.18 ng/mL; LTB4, 0.44 ng/mL; and SRS-A (LTC4+LTD4+LTE4], 0.31 ng/mL). These values decreased to near-normal control levels by one month after the AMI attack. The findings in this study suggest that abnormalities of arachidonic acid metabolism accompany, and may play a role in the pathogenesis of, AMI. PMID- 8686959 TI - White-coat normotension and blood pressure variability. AB - The objective of this study was to assess blood pressure variability in patients with clinical normotension and ambulatory hypertension (the so-called white-coat normotension). In 58 white-coat normotensives (mean age 64.2 +/- 14.9 years; male/female ratio = 1.5:1) the authors evaluated blood pressure variability using the twenty-four-hour coefficient of variability. Fifty-eight essential hypertensives with the same age and sex distribution were recruited as a control group. The coefficient of variability in white-coat normotension was greater than in the control group (14.8/16.1 +/- 4.2/3.8% vs 13.5/15.1 +/- 3.3/3.1%), but this difference was not statistically significant. These findings suggest that white coat normotension is the result of a specific relaxing response to medical visits and not the expression of an elevated blood pressure variability. It is probably due to the reverse of the alerting response, which causes white-coat hypertension. PMID- 8686960 TI - Common carotid artery wall properties in Takayasu's arteritis. AB - The vessel wall properties of the common carotid artery have been noninvasively and quantitatively assessed with an ultrasonic instrument. Stiffness parameter beta, which represents the mechanical properties of the vessel, was calculated from the relationship between blood pressure and the diameter of the artery. There are no reports that quantitatively assess wall properties in Takayasu's arteritis. The authors compared, in vivo, the vessel wall properties of the common carotid artery in 14 patients with Takayasu's arteritis versus those in 60 normal subjects (controls). They measured changes in the inner diameter of the artery between systole and diastole with an ultrasonic, phase-locked, echo tracking system. Beta was significantly higher in Takayasu's arteritis than in normal subjects (better than a 99% confidence interval). The findings for each decade were as follows: 3rd decade (20s): 35.7 +/- 28.9 vs 5.01-6.46, P=0.0001; 4th decade (30s): 19.5 +/- 9.71 vs 6.09-7.80, P=0.02; 5th decade (40s): 26.2 +/- 11.3 vs 7.26-9.28, P = 0.0001; 6th decade (50s): 19.1 +/- 4.27 vs 8.66-11.25, P = 0.0001. Takayasu's arteritis significantly impaired the mechanical performance of the common carotid artery. Thus, beta shows promise as a useful diagnostic indicator of Takayasu's arteritis. PMID- 8686961 TI - Duplex sonography of venous atheromatosis found in the venous part of hemodialysis fistula. AB - Manifestation of atherosclerosis is one of the alterations in venous bypass grafts. Its progression and morphology usually cannot be described by sonography. The venous part of a hemodialysis fistula can be compared to a venous bypass graft. The authors investigated the venous part of hemodialysis fistula in 16 patients. They found atherosclerosis in 7 patients. The morphologic findings were similar to arterial atherosclerosis. Looking at the venous part of hemodialysis fistulas may be an adequate model to investigate the initiation and progression of atherosclerotic lesions in venous bypass grafts. PMID- 8686962 TI - Nitrate-induced headache in patients with stable angina pectoris: beneficial effect of starting on a low dosage. 5-ISMN headache study group. AB - BACKGROUND: Nitrates, although important for the management of angina pectoris, cause significant headache in many patients. METHODS: In a randomized, double blind, crossover study, 89 patients with stable angina pectoris were studied to compare two different dosage strategies of isosorbide-5-mononitrate (5-ISMN). Patients were randomized to either 60 mg 5-ISMN once daily (od) for two weeks or to 30 mg 5-ISMN od for one week followed by 60 mg 5-ISMN od for one week. Then, there was a two-week placebo washout, after which the alternative treatment was given. The authors assessed the occurrence of angina pectoris and headache by diary cards while taking into account the number of isosorbide dinitrate sublingual puffs and paracetamole tablets required. Data were assessed for carryover and time effects. RESULTS: The two dosage regimens were equally efficient for the relief of angina pectoris without development of tolerance. Thirty percent of the patients never experienced headache from the given dosages. In the remainder of them there was a highly significant time effect: the overall numbers of headache attacks in the first period of active treatment versus the second were 2,380 vs 1,400 (P < 0.003). Yet significantly fewer patients had headache on low dosage than on high dosage (45 vs 57, P < 0.02). CONCLUSIONS: (1) Starting on a low dosage was associated with a reduced frequency and severity of headache and did not notably influence the beneficial effect on angina pectoris. (2) One in 3 patients never experienced headache from the given dosages. (3) The overall number of headache attacks in the first period of active treatment was significantly higher than in the second period irrespective of the dosages given. PMID- 8686963 TI - Impairment of the postural venoarteriolar response in young type 1 diabetic patients. A study by laser doppler flowmetry. AB - The skin blood flow and venoarteriolar response (VAR) in the feet of the young type 1 diabetic patients were studied with laser Doppler flowmetery. The findings were correlated with diabetic microangiopathy in 24 young patients without neuropathy--14 with diabetic microangiopathy, 10 without--and 10 healthy controls. In type 1 diabetic patients and skin blood flow, after lowering of the leg, was significantly higher in the microangiopathic patients than in the healthy controls, 5.3 +/- 1.4 vs 3 +/- 1.5, (P < 0.01). The VAR index was significantly lower in both groups of diabetics as compared with controls. In conclusions laser Doppler flowmetry is an easy and reliable noninvasive technique to evaluate skin blood flow abnormalities in the the feet of young type 1 diabetic patients, including those without neuropathy. The VAR has been found abnormal in the feet of young diabetic patients with and without microangiopathy, regardless of the presence of peripheral neuropathy. PMID- 8686965 TI - Reverse jugular flow in a case of thrombosis of the brachiocephalic vein with an artificial arteriovenous fistula. AB - Thrombosis of the thoracic inlet veins following placement of a central venous catheter is a well-known complication, and several findings have been reported by color Doppler sonography. However, reverse jugular flow resulting from this complication is rarely mentioned and should be differentiated from another complication of iatrogenic arteriovenous fistula between neck vessels. The authors here describe a uremic patient with an artificial arteriovenous fistula in the forearm complicated with thrombosis of the ipsilateral brachiocephalic vein. Factors permitting the differential diagnosis by coloer Doppler sonography and clinical conditions are proposed. PMID- 8686964 TI - Morphologic and histologic characterization of cardiac myxomas by magnetic resonance imaging. AB - The purpose of this study was to assess the role of ECG-gated spin-echo (SE) magnetic resonance (MR) images, cine MR images, and gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA)-enhanced MR images for the morphologic and histologic diagnosis of atrial myxomas. Four patients with left atrial myxoma were imaged with a 1.5-T MR imager. The T1-weighted images and the cine MR images were obtained before injection of Gd-DTPA. After the injection of Gd-DTPA, the T1-weighted images were obtained again. Gd-DTPA-enhanced images of the myxomas were histologically compared with the extracted specimens. The tumors were represented more clearly on the cine MR images as low-intensity areas than on the SE images as high-intensity areas. On post-Gd-DTPA images, the 2 tumors were homogeneously enhanced and the other 2 were inhomogeneously enhanced. The locus of enhancement on post-Gd-DTPA images fitted with histologic myxoma or inflammation, and the unenhanced region reflected the necrosis or cystic changes in the specimens, respectively. The morphologic diagnosis of cardiac myxomas by MRI first should be done with SE images, and when the images are unclear, the cine MR images must be supplemented to depict the tumor clearly. Moreover, Gd DTPA-enhanced MRI could elucidate histologic characteristics in myxomas. PMID- 8686966 TI - Cardiac catheterization and selective coronary angiography with tortuous aorta and anomalous coronary artery. AB - The authors report a case of selective coronary angiography by use of a modified technique in a patient with tortuous iliac artery, distorted thoracic descending aorta, and anomalous left coronary artery. This approach to such anatomy can decrease the fluoroscopy time and reduce the likelihood of complications. PMID- 8686967 TI - Acute exacerbation of masked hyperthyroidism after iodine restriction followed by thyrotoxic atrial fibrillation and cerebral embolism. A case report. AB - The authors present a seventy-two-year-old woman complaining of diffuse and firm goiter. At the first visit, she looked almost euthyroid with regular pulse rate of 78 per minute. After iodine restriction, however, she became severely thyrotoxic and developed cerebral embolism associated with atrial fibrillation due to Graves' hyperthyroidism. In conclusion, sudden withdrawal of dietary iodine might lead to exacerbation of Graves' hyperthyroidism resulting in serious cardiovascular or cerebrovascular complications, especially in elderly patients. PMID- 8686968 TI - Paroxysmal atrial tachycardia recorded by Holter monitoring during an episode of fear. A case report. AB - A twenty-four-year-old, white, athletic woman, free of heart disease, experienced an episode of fear when she was assaulted in the street without physical injury while under-going twenty-four-hour Holter monitoring. She developed an important sympathetic response in which, besides the symptoms characterized by palpitations, chest pain, dyspnea, asthenia, dizziness, nausea, and profuse cold sweating, she had an episode of paroxysmal atrial tachycardia. The causes and mechanism of this not well-documented event in humans are discussed. PMID- 8686970 TI - Coumarin-induced skin necrosis following heparin-induced thrombocytopenia and thrombosis. A case report. AB - A severe thrombotic thrombocytopenic status, induced by heparin in a sixty-nine year-old woman undergoing total hip joint arthroplasty, was treated by switching the anticoagulant therapy to coumarin, which induced skin necrosis. There appeared to be a possible causal relation between the severe immune reaction to heparin and the condition that predisposed to skin necrosis in the presence of coumarin. In patients who express a strong immune response to heparin, a different anticoagulant approach other than use of coumarin congeners appears to be justified. PMID- 8686969 TI - Pulmonary valvular stenosis associated with Takayasu's Disease. Favorable response to corticosteroids. A case report. AB - The authors describe the first reported case of type IV Takayasu's arteritis with pulmonary valve stenosis. After thirty months under corticosteroid therapy the disappearance of the pulmonary valve stenosis signs was observed in the patient. In the same patient coarctation of the aorta, aortic insufficiency, stenosis of both pulmonary arteries, and left coronary artery stenosis were observed. This case illustrates the extensive cardiovascular involvement that can occur in Takayasu's arteritis and suggests that pulmonary valvular stenosis could be secondary to the same inflammatory process. PMID- 8686971 TI - Coronary artery discrete aneurysms, ectasia, and occlusive disease ane extensive arteriomegaly. Correlation, constellation, or coincidence? A case report. AB - The case of a sixty-five-year-old man with discrete coronary aneurysms, associated with coronary artery ectasia, stenoses, and total occlusion of the left anterior descending artery, that resulted in an acute anterior myocardial infarction, is presented. Aortography and digital subtraction angiography revealed marked aortic and iliac elongation, tortuosity, and aneurysmal dilatation as well as dilatated femoral and popliteal arteries with aneurysmal dilatation in places. It is considered that the case reflects the broad spectrum of atherosclerosis manifestations. PMID- 8686972 TI - Prolonged luminal narrowing of internal mammary artery graft after percutaneous transluminal angioplasty. AB - The authors describe a case with an internal mammary artery (IMA) graft that demonstrated prolonged, but reversible, luminal narrowing persisting > twenty four hours following percutaneous transluminal angioplasty. Luminal narrowing disappeared spontaneously, however, at the time of follow-up angiography one week after the angioplasty. Since haziness at the dilation site had been shown on preprocedural angiogram, suggestive of intraluminal thrombus, this phenomenon may be attributed to either prolonged vasospasm or distal embolization of the IMA graft. PMID- 8686973 TI - Lamivudine plus zidovudine compared with zalcitabine plus zidovudine in patients with HIV infection. A randomized, double-blind, placebo-controlled trial. North American HIV Working Party. AB - OBJECTIVE: To compare the safety and activity of lamivudine plus zidovudine with the safety and activity of zalcitabine plus zidovudine in patients with moderately advanced human immunodeficiency virus (HIV) infection who had received zidovudine. DESIGN: A multicenter, randomized, double-blind, three-arm, 24-week study with a blinded extension through at least 52 weeks. SETTING: 21 sites in the United States, Canada, and Puerto Rico. PATIENTS: 254 patients who had received zidovudine (median duration of previous therapy, 20 months) and had absolute CD4+ cell counts of 100 to 300 cells/mm3. INTERVENTIONS: Patients were randomly assigned to receive one of three regimens: 150 mg of lamivudine twice daily plus 200 mg of zidovudine three times daily (low-dose lamivudine group); 300 mg of lamivudine twice daily plus 200 mg of zidovudine three times daily (high-dose lamivudine group); or 0.75 mg of zalcitabine plus 200 mg of zidovudine three times daily (zalcitabine group). MEASUREMENTS: Immunologic activity was assessed primarily by changes in absolute CD4+ cell counts; virologic activity was assessed by changes in plasma HIV RNA levels as measured by reverse transcriptase polymerase chain reaction. Safety of the treatment regimens was assessed through the reporting of adverse events. RESULTS: 78% of patients completed 24 weeks of study treatment, and 63% of patients completed 52 weeks of study treatment. Changes in absolute CD4+ cell counts were significantly better for the low-dose and the high-dose lamivudine groups than for the zalcitabine group (median changes at 52 weeks were +42.5 cells/mm3 in the low-dose lamivudine group, +23.33 cells/mm3 in the high-dose lamivudine group, and -29.58 cells/mm3 in the zalcitabine group). Suppression of plasma HIV RNA levels was similar for all groups (median changes at 52 weeks were -0.48 log10 copies/mL in the low-dose lamivudine group, -0.51 log10 copies/mL in the high-dose lamivudine group, and 0.39 log10 copies/mL in the zalcitabine group). No significant differences in safety were seen among the three regimens, although the low-dose lamivudine regimen appeared to be better tolerated than the others. CONCLUSIONS: In patients with HIV infection who had previously received zidovudine, 150 mg of lamivudine plus zidovudine resulted in greater immunologic evidence of benefit than did 0.75 mg of zalcitabine plus zidovudine and was better tolerated than 300 mg of lamivudine plus zidovudine. PMID- 8686974 TI - Black women receive less mammography even with similar use of primary care. AB - BACKGROUND: Black women with breast cancer have a decreased 5-year survival rate in comparison with white women, possibly because of less frequent use of mammography. Having a regular provider or source of health care is the most important determinant of mammography use. OBJECTIVE: To examine whether the difference in mammography use between elderly black women and elderly white women is related to the number of visits made to a primary care physician. DESIGN: Retrospective review of 1990 Health Care Financing Administration billing files (Medicare part B) from 10 states. SETTING: Outpatient mammography services in 10 states. PARTICIPANTS: Black women and white women, 65 years of age and older, residing in one of the 10 states. MEASUREMENTS: Any mammogram. Predictors included race, number of visits to a primary care physician (0, 1, 2, or 3 or more), median income of ZIP code of residence (a surrogate measure of income), and state. RESULTS: The following are findings from Georgia; similar results were found in each state studied. The mean age of the 335,680 women was 75 years; 20% were black. Sixty-eight percent of the black women and 69% of the white women made at least one visit to a primary care physician. Overall, 14% of the women had had mammography; black women had mammography less often than white women (9% compared with 15%). At each primary care visit level (1, 2, or 3 or more visits), black women had mammography less often than white women (1 visit, 7% compared with 15%; 2 visits, 12% compared with 21%; and 3 or more visits, 12% compared with 20%). Even among women who had made at least one visit to a primary care physician, a deficit for blacks occurred in each income quintile (lowest quintile, 13% compared with 20%; low, 10% compared with 18%; middle, 12% compared with 18%; high, 10% compared with 19%; and highest, 12% compared with 22%) and in each state (in Georgia, for example, the percentages were 14% compared with 21%). An age-, income-, and state-adjusted logistic model predicting mammography use for 2.9 million white women in all 10 states shows the powerful effect of primary care use on mammography (odds ratios for 1, 2, and 3 or more visits were, respectively, 2.73 [95% CI, 2.70 to 2.77]; 3.98 [CI, 3.93 to 4.03]; and 4.62 [CI, 4.58 to 4.67]). The same model fit to 250 000 black women shows a lesser effect (analogous odds ratios were 1.77 [CI, 1.67 to 1.87]; 2.49 [CI, 2.36 to 2.63]; and 3.15 [CI, 3.04 to 3.25]). CONCLUSION: Among older women, mammography is used less often for blacks than for whites. More frequent use of mammography is associated with more visits to a primary care physician in both groups, but the deficit for black women persists at each income level and in each state, even after primary care use is considered. Primary care visits are less likely to "boost" mammography use for black women than for white women. PMID- 8686975 TI - Quinolone-based antibacterial chemoprophylaxis in neutropenic patients: effect of augmented gram-positive activity on infectious morbidity. National Cancer Institute of Canada Clinical Trials Group. AB - OBJECTIVE: To determine whether augmented quinolone-based antibacterial prophylaxis in neutropenic patients with cancer reduces infections caused by gram positive cocci and preserves the protective effect against aerobic gram-negative bacilli. DESIGN: Open, randomized, controlled, multicenter clinical trial. SETTING: Centers participating in the National Cancer Institute of Canada Clinical Trials Group. PATIENTS: 111 eligible and evaluable patients hospitalized for severe neutropenia (neutrophil count < 0.5 x 10(9)/L lasting at least 14 days) who were receiving cytotoxic therapy for acute leukemia or bone marrow autografting. INTERVENTION: One of three oral antibacterial prophylactic regimens (norfloxacin, 400 mg every 12 hours; ofloxacin, 400 mg every 12 hours; or ofloxacin, 400 mg, plus rifampin, 300 mg every 12 hours) beginning with cytotoxic therapy. MEASUREMENTS: Incidence and cause of suspected or proven infection. RESULTS: Microbiologically documented overall infection rates for norfloxacin, ofloxacin, and ofloxacin plus rifampin were 47%, 24%, and 9%, respectively (P < 0.001). Corresponding rates were 24%, 13%, and 3%, respectively for staphylococcal bacteremia (P = 0.03) and, 21%, 3%, and 3%, respectively for streptococcal bacteremia (P < 0.01). The pattern of bacteremia suggested that rifampin played a role in suppressing staphylococcal infection. Both ofloxacin alone and ofloxacin plus rifampin had a clinically significant antistreptococcal effect. Aerobic gram-negative rods were cleared from rectal surveillance cultures in all patients after a median of 5.5 days and caused infection in only one patient (0.9%). The reductions in the number of microbiologically documented infections among ofloxacin recipients and ofloxacin plus rifampin recipients were offset by concomitant increases in the number of unexplained fevers (24% of norfloxacin recipients, 53% of ofloxacin recipients, and 49% of ofloxacin plus rifampin recipients; P = 0.02). No statistically significant difference was found among the treatment arms with respect to the overall incidence of febrile neutropenic episodes as defined for this trial (79% for the norfloxacin group, 82% for the ofloxacin group, and 77% for the ofloxacin plus rifampin group). CONCLUSIONS: Quinolone-based antibacterial chemoprophylaxis protected patients from aerobic gram-negative bacillary infections. Augmentation of the gram positive activity reduced the incidence of gram-positive infections but did not influence the overall incidence of febrile neutropenic episodes. PMID- 8686977 TI - Serodiagnosis and monitoring of Aspergillus infections after lung transplantation. AB - OBJECTIVE: To determine whether quantification of specific antifungal antibody responses in serum can provide supplemental information for the diagnosis of Aspergillus fumigatus infections and the monitoring of antifungal treatment in patients after lung transplantation. DESIGN: Retrospective study. SETTING: Center for lung transplantation, University Hospital Groningen, the Netherlands. PATIENTS: 4 patients with proven A. fumigatus infections after lung transplantation and fatal outcome. MEASUREMENTS: The IgG antibody response specific for A. fumigatus antigens was measured by enzyme-linked immunosorbent assay and was compared with radiographic features, cytologic findings, microbiological cultures, and clinical diagnosis. RESULTS: Increasing IgG antibody responses specific for A. fumigatus antigens closely paralleled cytologic or microbiological identification of A. fumigatus from bronchoalveolar lavage fluid and decrease of lung function. Increasing specific IgG antibody responses were found to precede radiographic identification of lung cavitation by 1 to 2 weeks, precede the diagnosis of aspergillosis by 2 to 20 weeks, and detect fungal reinfection. In most cases, successful antifungal treatment decreased specific IgG antibody response. A decrease in specific IgG antibody response correlated with the inability to culture or identify A. fumigatus in bronchoalveolar lavage fluid and with radiographic and clinical improvement. CONCLUSIONS: Specific IgG antibody responses in serum correlate with radiographic, cytologic, and microbiological findings and with the clinical diagnosis of A. fumigatus infections in patients who have had lung transplantation. Increased IgG antibody responses in serum may provide important information that is helpful in the diagnosis and early treatment of pulmonary fungal infections and in monitoring antifungal treatment. PMID- 8686976 TI - The association between mortality rates and decreased concentrations of interleukin-10 and interleukin-1 receptor antagonist in the lung fluids of patients with the adult respiratory distress syndrome. AB - OBJECTIVES: To determine the relation between 1) intra-alveolar concentrations of the proinflammatory cytokines (tumor necrosis factor, interleukin-1 beta, and interleukin-8) and the anti-inflammatory cytokines (interleukin-10 and interleukin-1 receptor antagonist) in patients with early adult respiratory distress syndrome (ARDS) and 2) subsequent patient mortality rates. DESIGN: Prospective cohort study. SETTING: University medical center. PATIENTS: 28 consecutive patients in whom ARDS was prospectively identified during hospitalization and 9 ventilated controls. MEASUREMENTS: Concentrations of proinflammatory cytokines and anti-inflammatory cytokines in bronchoalveolar lavage fluid. RESULTS: The concentrations of proinflammatory and anti inflammatory cytokines within the alveolar air spaces were significantly elevated in patients with ARDS compared with controls (P = 0.01 for tumor necrosis factor [median, 90 pg/mL (range, 0 to 2500 pg/mL) for patients with ARDS; median, 0 pg/mL (range, 0 to 118 pg/mL) for controls]; P = 0.001 for interleukin-1 beta [median, 179 pg/mL (range, 0 to 2200 pg/mL) for patients with ARDS; median, 0 pg/mL (range, 0 to 80 pg/mL) for controls]; P = 0.0001 for interleukin-8 [median, 628 pg/mL (range, 0 to 4700 pg/mL) for patients with ARDS; median, 0 pg/mL (range, 0 to 278 pg/mL) for controls]; P = 0.0005 for interleukin-10 [median, 100 pg/mL (range, 0 to 1600 pg/mL) for patients with ARDS; median, 0 pg/mL (range, 0 to 50 pg/mL) for controls], and P = 0.002 for interleukin-1 receptor antagonist [median, 820 pg/mL (range, 0 to 18,900 pg/mL) for patients with ARDS; median, 50 pg/mL (range, 0 to 240 pg/mL) for controls]). A highly significant correlation was found between low concentrations of anti-inflammatory cytokines and subsequent patient mortality rates (P = 0.003 for interleukin-10 [median, 120 pg/mL (range, 30 to 1600 pg/mL) for survivors; median, 40 pg/mL (range, 0 to 110 pg/mL) for nonsurvivors]; P = 0.008 for interleukin-1 receptor antagonist [median, 1600 pg/mL (range, 80 to 18,900 pg/mL) for survivors; median, 90 pg/mL (range, 0 to 3400 pg/mL) for nonsurvivors. No significant correlation was found between the concentrations of the proinflammatory cytokines and mortality rates. CONCLUSION: Low concentrations of the anti-inflammatory cytokines interleukin-10 and interleukin-1 receptor antagonist in bronchoalveolar lavage fluid obtained from patients with early ARDS are closely associated with poor prognosis. These findings support the hypothesis that failure to mount a localized intrapulmonary anti-inflammatory response early in the pathogenesis of ARDS contributes to more severe organ injury and worse prognosis. Our findings suggest that augmenting anti-inflammatory cytokine defenses would be a beneficial therapeutic approach to patients with ARDS and other inflammatory diseases. PMID- 8686978 TI - Effects of sodium intake on albumin excretion in patients with diabetic nephropathy treated with long-acting calcium antagonists. AB - OBJECTIVE: To determine whether sodium intake alters albumin excretion in patients with nephropathy from non-insulin-dependent diabetes mellitus who were treated with two different long-acting calcium antagonists. DESIGN: Prospective, crossover, open-label trial. SETTING: Rush-Presbyterian-St. Luke's Medical Center. PATIENTS: 9 men and 6 women (mean age +/- SD, 56 +/- 8 years) with non insulin-dependent diabetes mellitus, hypertension, renal insufficiency, and macroalbuminuria. INTERVENTION: Diltiazem (mean dose, 392 +/- 27 mg/d) or nifedipine (mean dose, 83 +/- 9 mg/d) was used to decrease blood pressure to less than 140/90 mm Hg. All patients also received furosemide concomitantly for blood pressure control. RESULTS: Blood pressure reduction with once-daily diltiazem decreased urine albumin excretion (2967 +/- 784 mg/d at baseline compared with 1294 +/- 679 mg/d after diltiazem therapy; P < 0.05) at 4 weeks while patients received a diet consisting of 50 mEq of sodium per day. Albumin excretion did not decrease when sodium intake was increased to 250 mEq/d, and blood pressure was reduced to levels similar to those seen with the low-sodium diet. Similar blood pressure reduction with once-daily nifedipine did not significantly alter albumin excretion regardless of sodium intake. CONCLUSION: Sodium intake affects the albumin-decreasing effects of certain calcium antagonists. Recent studies suggest that antihypertensive medications that reduce albumin excretion and arterial pressure correlate with reduced renal mortality compared with medications that do not have albumin-decreasing effects. Thus, a low-sodium diet should be prescribed to maximize the albumin-decreasing effects of certain calcium antagonists. PMID- 8686979 TI - Prostate cancer: emerging concepts. Part II. AB - OBJECTIVE: To review important topics related to prostate cancer that have arisen since this subject was last covered in Annals in 1993. The review consists of two parts. Part II describes neoadjuvant hormonal therapy, new local treatment options (including three-dimensional conformal radiation therapy, brachytherapy, and cryosurgery), antiandrogen therapy management of erectile dysfunction, funding and legislation for research, and areas for future research, especially in genetics investigations. STUDY SELECTION: Randomized studies identified through a MEDLINE search (1992 to 1996); large, single-institutional conferences and consortiums; and studies presented at regional, national, and international symposia. DATA SYNTHESIS: Qualitative and quantitative data are reported. Part II describes results of completed randomized trials that used neoadjuvant hormonal therapy. Studies have shown that nearly 50% more patients with cT2 disease will have pathologically confined (pT2) prostate cancer as a result of preoperative neoadjuvant hormonal therapy. Time to development of progressive disease and disease-free survival are improved in patients receiving neoadjuvant hormonal therapy before radiation therapy, but the long-term overall effects on survival of neoadjuvant therapy before surgery or radiation are unknown. Other methods for treating localized prostate cancer (three-dimensional conformal radiation therapy, brachytherapy, and cryotherapy) are gaining popularity, despite the lack of long-term efficacy results. Advances in the understanding of the optimal use of antiandrogens and managing treatment-induced erectile dysfunction continue to benefit patients with prostate cancer. CONCLUSIONS: Prostate cancer is being detected with increasing frequency, and many patients are receiving such treatments as radical prostatectomy and radiation therapy. Although refinements in prostate-specific antigen (PSA)-based testing have contributed substantially to the increased rate of detection of prostate cancer, the incidence of disease was increasing dramatically even before PSA detection was possible. Despite earlier detection, the optimal therapy for the early form of the disease is still enigmatic. Further studies and longer follow-up of patients who participated in completed studies are needed to better define the outcomes and importance of prostate cancer therapies. More research is needed to help elucidate the reasons for the increased incidence of the disease; such efforts should help define strategies to ultimately prevent prostate cancer. PMID- 8686980 TI - Update in women's health. PMID- 8686981 TI - Non-insulin-dependent diabetes mellitus in minorities in the United States. AB - PURPOSE: To review the available information on prevalence, complications, and mortality of non-insulin-dependent diabetes mellitus and primary and secondary prevention activities in black persons, Hispanic persons, Native Americans, and Asians and Pacific Islanders in the United States. DATA SOURCE: MEDLINE search from 1976 to 1994 through the PlusNet search system. STUDY SELECTION: Use of the key words non-insulin-dependent diabetes mellitus, the names of each specific minority group, socioeconomic status, acculturation, genetics, diet, complications, mortality, treatment, and intervention (lifestyle or medication) produced 290 unduplicated articles. Additional articles cited in the original articles were also included. DATA EXTRACTION: Risk factors, incidence, prevalence, complications, and mortality of non-insulin-dependent diabetes mellitus. DATA SYNTHESIS: All minorities, except natives of Alaska, have a prevalence of non-insulin-dependent diabetes mellitus that is two to six times greater than that of white persons. Most studies show an increased prevalence of nephropathy that can be as much as six times higher than that of white persons. Retinopathy has variably higher rates in black persons, Hispanic persons, and Native Americans. Amputations are done more frequently among black persons than among white persons (9.0 per 1000 compared with 6.3 per 1000), and Pima Indians have 3.7 times more amputations than do white persons. Diabetes-related mortality is higher for minorities than for white persons, and the rate is increasing. The relative importance of genetic heritage, diet, exercise, socioeconomic status, culture, language, and access to health care in the prevalence, incidence, and mortality of diabetes is not clear. Studies of interventions in minority populations are in progress. CONCLUSION: Diabetes should be treated as a public health problem for minority populations. PMID- 8686982 TI - Heterologous antisera and antivenins are essential biologicals: perspectives on a worldwide crisis. AB - Active immunization against infectious disease is important. However, much of our world faces poverty, social injustice, and warfare, all of which cause universal immunization to remain a distant dream. Agents that provide passive immunity thus remain essential biologicals. The most important of these are human or equine antisera against rabies, tetanus, diphtheria, and snake antivenins. Homologous products are either unavailable or unaffordable in places where they are needed the most. Less expensive heterologous (equine) antisera can be purified and are safe to use, but these antisera are also in short supply. Monoclonal antibodies have been developed but are even less likely to be affordable in poor countries. Several traditional sources of equine antisera are becoming depleted as a result of economic disincentives; a poor reputation based on the high adverse reaction rates of the old, unpurified products; and the activities of animal rights activists who object to the use of horses as blood donors. Purified, pepsin digested equine antisera are preferred; but developing countries sometimes are forced to make crude products that are less safe or have no specific therapy available at all. PMID- 8686983 TI - A compelling research agenda. PMID- 8686984 TI - Can physicians diagnose strengths and weaknesses in health plans? PMID- 8686985 TI - Insurance reform in a voluntary system: implications for the sick, the well, and universal health care. American College of Physicians. AB - In the absence of universal coverage, carefully designed insurance reforms can make health insurance in the individual and small-group markets more affordable for those who need it most--the sick--and more secure for all subscribers. In this position paper, the American College of Physicians calls for specific strong reforms at both the state and federal levels. Substantial reform of the insurance marketplace is a necessary step toward achieving universal coverage. It should reflect the view that providing quality health care is in the best interests of the community and that health care financing should be a community responsibility. PMID- 8686986 TI - The examination. PMID- 8686987 TI - Bone mineral density in non-insulin-dependent diabetes. PMID- 8686988 TI - Asklepios. PMID- 8686989 TI - Asklepios. PMID- 8686990 TI - Asklepios. PMID- 8686991 TI - Asklepios. PMID- 8686992 TI - [TNM staging system of lung carcinoma: historical notes, limitations and controversies]. AB - The TNM System as originally proposed by Denoix in 1946, provides a consistent, reproducible description of the anatomic extent of disease in cancer patients at a specific time in the life history of the cancer. C.F. Mountain first adapted this classification to lung cancer in 1973 on behalf of AJCC. In 1986 he presented the "New Intl. Staging System for Lung Cancers" mainly based on a 13 yr experience of the previous one, which was accepted world-wide through a round of international consensus meetings held in 1985. Clinical Staging is the best estimate of disease extent made prior to the institution of any therapy; Surgical pathological Staging is the classification of disease extent as determined from pathological examination of resected specimens. Accordingly, once the diagnosis is made, it is necessary to stage accurately the tumour determining the size and location of the tumour (T status), the presence or absence of lymphnode involvement (N status), and whether the tumour is metastatic to distant sites (M status). Moreover the uniform staging criteria for lung cancer will assure for each patient the better selection of treatment, the evaluation of operability, the need for adjuvant therapy, as well as the estimation of prognosis. Equally important is the resultant ability to compare the outcome of treatment protocols from different centres. More recently C.F. Mountain has added to the Staging System a new standard logic or "convention" for classifying infrequently observed presentations of lung cancer with which the standard rules of Staging System itself don't fit. These conventions are based on empiric expectation for treatment selection and survival that are similar to those for the Staging definitions, which are based on actuarialsurvival data. Many different types of tumour such as multiple masses, synchronous multiple primitives, discontinuous tumour foci in visceral or parietal pleura as well neoplastic involvement of various mediastinal structures, could be now staged with a major benefit for their treatment protocols. In conclusion the Staging System represents today a standard clinical methodology which basically helps in a better clinical approach to lung cancer even if it cannot fully cover and consider all the innumerable manifestations of the tumor. Therefore, if it is true that in the near future the new molecular predictors of prognosis are expected to measure more deeply the extent of disease, for the present time the International Staging System still continues to act as the best common method for measuring prognosis. PMID- 8686993 TI - [Cervical-mediastinal emphysema of abdominal origin]. AB - Cervical mediastinic emphysema usually does not demand emergency procedures: nevertheless its ethiology must be promptly assessed though his achievement may prove less than easy owing the vague clinical presentation and to the limits imposed by regional topography. Among the possible etiologic factors one should take into account the rare abdominal source too. Indeed the cervical region is connected to the retroperitoneal space through a virtual "visceral space" via the thoracic cavity and some diaphragmatic break-throughs variable in size. The communication allows, in some pathologic conditions, the unopposed circulation of air and fluids. Our interest in the topic is due to the occurrence of a cervical mediastinic emphysema in a patient suffering from a colonic perforation. PMID- 8686994 TI - [Incidental discovery of adrenal neoplasms: our experience]. AB - Incidental radiologic diagnosis of clinically silent adrenal masses is reported with increasing rates. Between 1981 and 1994 we observed 30 patients with "incidentaloma": for each of them a careful hormonal and instrumental evaluation was obtained. 24 patients were surgically treated. No significant biochemical alterations were observed; ETG, TC and RMN had a sensitivity of 86%, 93% and 83%, respectively. At seleno-cholesterol scintigraphy 5 incidentalomas (all adenomas) had a concordant pattern and 5 (none of these adenoma) had a discordant pattern. MIBG scintigraphy showed an uptaking ganglioneuroma. The observed histotypes were: 10 adenomas, 3 cysts, 1 hematoma, 1 myelolipoma, 1 angiomyolipoma, 1 ganglioneuroma, 1 ganglioneurofibroma, 1 paraganglioma, 1 aspecific granulomatous necrosis, 4 cortical carcinoma and 3 metastatic lesions. We did not observe any postoperative acute adrenal failure. The main problem raised by incidentalomas is to define their nature; hence the need of a careful hormonometabolic, morpho functional and instrumental evaluation. The available diagnostic procedures, even when combined, cannot always define if an incidentaloma is a benign or a malignant lesion: in the current clinical practice, the size of the mass is still the most important criterion to define a therapeutic approach. Surgical excision is mandatory in presence of an hormonal production, even subclinic, and/or a large size of the mass (over 5 cm). If the tumor size is less than 5 cm, an aggressive strategy may be chosen in selected low-risk patients, because of the low morbidity of adrenalectomy. In our experience, the transperitoneal subcostal approach has been adopted routinely with good results. PMID- 8686995 TI - [Current trends in the treatment of voluminous eventrations]. AB - The authors speak about their experience on the giant incisional hernias. The surgical treatment of these lesions in not always easy, especially when exist some conditions such as the loss of parietal substance and the loss of residence right. In these cases the use of prosthetic meshes and the Goni Moreno's pneumoperitoneum are very helpful. The Authors point out how important is, for a successful treatment, as well as a correct surgical procedure and opportune pre and post operative management. PMID- 8686996 TI - [Perforation in Crohn's ileitis and its consequences in the natural history of disease. 2. Consequences of perforation in the peritoneal cavity: diffuse septic peritonitis, abscesses, external and internal fistulas]. AB - Perforation of Crohn's ileitis occurring in the peritoneal cavity is always free perforation, but it causes usually a localized peritonitis, i.e. an abscess, and only in rare cases a diffuse septic peritonitis for the reasons expounded in the Part 1. Diffuse septic peritonitis has the common features of all perforative peritonitis; its surgical treatment must be ileocolic resection, simple suture of perforation being a serious mistake. Abscesses develop: as regards the ileum, about 30-45 cm from the ileo-caecal valve; as regards the abdominal cavity, in the right iliac fossa or in the pelvis, at a site where the ileum, weighed down by its chronic inflammation, rests. These abscesses have a wall like that of all abscesses, with no specific crohnian features. On operation, if technical considerations so require, part of the abscess wall may be left in place with no fear of recurrences or fistulas. Nowadays, most abscesses of the right iliac fossa are opened surgically; an enterocutaneous fistula follows. Most abscesses of the pelvis still open spontaneously into a hollow organ (sigma-rectum, urinary bladder), and rarely into the vagina or onto the perineum after penetrating through the levator any muscle and causing suppuration of the ischiorectal fossa. PMID- 8686997 TI - [Emergency surgical treatment in cancer of the colon]. AB - The diagnostic delay which accompanies the colon-rectum neoplastic desease makes that complications are often the first signal. This work means to prove, according to our experience, that the incidence of these complications is high and that only in a few patients undergoing emergency treatment is possible a one stage procedure with radical purpose. In our survey, since Genuary 1975 to December 1993, 473 patients (255 males and 218 females) affected of colon-rectum cancer were treated: among these 54 (11.5%) underwent emergency surgery. The neoplasm was located: in the rectosigmoid junction in 25 cases (46.3%) in the caecum or in the right colon in 10 cases (18.6%), in the left colon and in the hepatic flexure in 6 cases (11.1%), in splenic flexure in 4 cases (7.4%), and in the trasversum colon in 3 cases (5.5%). According to Astler & Coller classification 22 patients (40.8%) were C2, 17 (31.5%) were D, 11 (20.4%) were B2, 3 (5.5%) were A, and only 1 patient (1.8%) was C1. 16 patients (29.7%) underwent a one-stage procedure, 8 (14.9%) had a first stage with a colostomy added together with resective procedure, and 3 (5.5%) patients had a Hartmann procedure. In 27 (50%) patients was possible only a palliative procedure. Finally, 10 patients (18.5%) had post-operative complications such as anastomotic fistula, wound's leakage or subphrenic abscess, and 11 patients (20.4%) died for cardiac insufficiency, ARDS, renal failure or cerebral stroke. PMID- 8686998 TI - [Efficacy of the popliteal to distal bypass in salvage of the ischemic diabetic foot]. AB - Foot revascularization by popliteal-to-distal by-pass is a well documented procedure for limb salvage in diabetic patients. The authors report their experience with a consecutive series of 5 ischemic feet [transcutaneous oxygen (PtO2): 6 +/- 5.6 mmHg] due to extensive tibial artery occlusive disease beginning at the popliteal artery trifurcation. Limb salvage was achieved by popliteal-to-anterior tibial bypass (1 case) and popliteal-to-dorsalis pedis artery by-pass with autogenous inverted saphenous vein. No operative death was observed. At follow-up (range 3-34 months) one patient died at 3 months after surgery because of an intestinal bleeding. All 4 remaining by-passes are well functioning [PtcO2 46 +/- 11.2 mmHg) and all patients have resumed their normal walking distance. This preliminary experience, and a review of the literature, confirm the validity of the popliteal-to-distal by-pass and the need for more aggressive vascular surgical attitude to treat the ischemic diabetic foot. PMID- 8686999 TI - [The distal pedicle fasciocutaneous flaps of the leg. Analysis of 21 cases of lower limb reconstruction]. AB - The fascio-cutaneous flaps with distal pedicle, with the new discoveries on fascial and septal circulation of the lower limbs, are a valid reconstructing method for the loss of substance localized on the third inferior of the leg and in the heel's region. In 21 patients, 18 men and 3 women, fascio-cutaneous flaps were employed for the traumatic loss of substance, just in two cases consequentially to removal of maligns lesions, all of them were omolaterals except in three cases in which cross-leg were used. The results are satisfying if we remember that just in two cases we had partial necrosis and in other two cases we had to reinstate the flap which had survived just in his deep position. The advantages of using this technique are supported by his good results and simple execution, realising anyhow that complicated or contaminated trumas need more complex plastic reconstruction. PMID- 8687000 TI - [Laparoscopic surgery of the spleen]. PMID- 8687001 TI - [Morgagni-Larrey hernia. A case report]. AB - The authors report a case of Morgagni-Larrey hernia. It is anuncommon diaphragmatic hernia, often asymtomatic and occasionally found. The authors point out the disease's clinical, diagnostic and therapeutic aspects. The hernia's repair can be done both abdominal and thoracic via. The operation is always advisable as well as in asymptomatic pazients. PMID- 8687002 TI - [Gardner syndrome: diagnostic, clinical and genetic questions in the light of 2 case reports]. AB - The authors on the base of two cases of Gardner's syndrome recently observed, proceed to a wide review of literature on this subject so as to stress the peculiar aspects of this syndrome, so complex and uncommon. The greatest emphasis is given to the role of genetics as regarding to diagnosis and screening programs, as well as to the more recent acquisitions about diagnosis, therapy and follow up of risk lesions, such as colorectal and duodenal adenomas, as well as of intrabdominal desmoid tumours, which, although not histologically malignant, may often influence prognosis negatively, because of their remarkable local invasiveness and tendency to recurrence. PMID- 8687003 TI - [Infection of aorto-bifemoral vascular prosthesis complicated by multiple visceral fistulas. A case report]. AB - The authors present the case of a late aorto-bifemoral graft infection: the pecularity of the case lies on the contemporary existence of multiple visceral phistulas beetween perigraft collection, the duodenum, the large bowel and the bladder. The phatogenetic mechanism of the clinical event is discussed. PMID- 8687004 TI - [Primary suppurated splenic cysts. A case report]. AB - The authors describe a case of an epidermoidal cyst of the spleen, which they were able to observe in an emergency case, due to suppuration of the cyst. Primary cysts of the spleen represent a rare dysontegenetic pathological condition which is, for this reason, often underestimated. The general clinical summary is related here, with particular reference to supporative complications, which cause problema of differential diagnosis with patients suffering from abscess of the spleen. The diagnosis can be made as a result of standard X-ray procedures and computed tomography and above all, following a simple scan. The treatment recommended in this case is an open splenectomy, in order to check the allarming clinical symptoms of the patient, which can deteriorate. The use of laparoscopical techniques or trans-cutaneous draining is reserved for salected cases. PMID- 8687005 TI - [Rare peritoneal tumors in the aged. Apropos of a case of Castleman's syndrome]. AB - An unusual case is reported of the rare Castleman's disease localized in the retroperitoneal area in an elderly asymptomatic patient. A similar benign lymphoadenopathy of unknown etiology is generally found in the mediastinum and interests just one lymph-node that results abnormally hyperplastic. Histologically, most cases are of the hyaline-vascular type and much more rarely of the plasmacell variant. After a careful review of the literature the anatomical, pathological and clinical characteristics, the main etiopathogenetics hypotheses and diagnostic criteria are explained. The particular size of the neoformation is emphasized and also the impossibility to reach a correct preoperatory diagnosis owing to a suspect kidney parenchyma infiltration observed by RM. Also the intraoperatory report seemed to confirm the diagnostic hypothesis of a malign neoplasm infiltrating the lower pole of the kidney and which necessitated the total ablation of the retroperitoneal mass and left kidney. We concluded that the case which we have observed (the 32nd in world literature dealing with the retroperitoneal space) is not really comparable to those previously described by other authors. In fact the histopathological picture presents a series of ialino-vascular and plasmacell aspects which make any hypothesis of etiopathogenetic uncertain. PMID- 8687006 TI - [Giant mesenteric fibromatosis: a case report]. AB - The fibromatoses represent a broad group of fibroblastic proliferations characterized by infiltrative growth and a tendency toward recurrence but, unlike malignant fibrous tumors, they do not metastasize. Mesenteric fibromatosis arising from the mesentery of the small bowel is rare. It may be sporadic or may occur in association with polyposis coli and other soft tissue tumors as a component of Gardner's syndrome. We report a case of mesenteric fibromatosis in a 52-year-old man with no evidence of Gardner's syndrome. The neoplasm occupied the whole abdominal cavity, weighing 12 kg, with the greatest diameter being 50 cm. Histological findings (i.e moderate degree of cellularity, lack of nuclear pleomorphism and mitotic figures) allowed to rule out malignancy. Surgical removal is actually the only effective treatment for mesenteric fibromatosis. Excision must be as wide as possible in order to prevent local recurrence. Until now, no satisfactory results have been obtained with external radiotherapy. More recently, anti-inflammatory drugs have been used in the management of this tumor. PMID- 8687007 TI - [Laparoscopic surgery in varicocele: description of the technique and preliminary data]. AB - The aim of this work is to remark the scientific worth of the laparoscopic approach in patients with varicocele. PATIENTS AND METHODS: From March 1993 to December of the same year 15 patients suffering from varicocele have been treated with a laparoscopic procedure. The technique is widely described in the next pages. RESULTS: Twelve patients have completed the 3 months follow-up whereas five among them have reached the 6 months control. The results are really interesting specially under a functional point of view. DISCUSSION: The noninvasive advantages provided by laparoscopy are always important, but is the worth of the results we have obtained under a functional point of view and the success in inducing pregnancy in some patients that lead us to remark the utility of this procedure comparing it, with the therapeutic proposals nowadays performed. They are: traditional surgery according to Ivanissevich or Palomo procedures percutaneous transvenous embolization under radiological guide varicocele vein ligation under local anesthesia. CONCLUSIONS: Laparoscopic varicocelectomy represents according to us and some other authors a proposal with a better response if compared to traditional surgery, specially under a functional aspect. Under a costs-benefits evaluation it may be considered more convenient than the radiological approach. PMID- 8687008 TI - [Video-laparoscopic cholecystectomy. Results of 281 treated cases]. AB - From March 1992 to September 1994, 281 patients were submitted to laparoscopic cholecystectomy for cholelithiasis. 27 patients were admitted with diagnosis of acute cholecystitis and in 17 patients common duct stones were discovered and managed by ERCP before laparoscopic procedure. Surgical procedure was the standard one described by Cox. The mean duration of the operation was 60 minutes and was significantly related to the surgeon's experience; the incedence of conversion to open procedure was 5.7%. There was no postoperative mortality; the total morbility rate was 2.8%, with 3 major complications, and 5 minor complications. PMID- 8687010 TI - Critical evaluation of the free radical theory of aging. A proposal for the oxidative stress hypothesis. PMID- 8687009 TI - [In vitro growth of skin fibroblasts of patients with atypical ductal hyperplasia of the breast: effects of 17 beta-estradiol]. AB - In this work we investigated the growth of skin fibroblasts, in vitro cultured, drawn from women suffering Atypical Ductal Hyperplasia (I.D.A.) and from healthy women (controls). Whether in basic conditions or after administration of 17, beta estradiol, in single of repeated dose, cellular growth was valued. The results obtained show that skin fibroblasts drawn from women suffering I.D.A. treated with 100 microliters/ml of estradiol (effective dose), have an increase of the growth. Moreover the increase of the growth seems to be bequest to "effective dose" but not to the number of administrations. PMID- 8687011 TI - Accumulation of deletions and point mutations in mitochondrial genome in degenerative diseases. AB - Accumulation of various mutations in the mitochondrial genome is proposed as an important contributor to aging and degenerative diseases. Extensive fragmentation of mtDNA was detected in association with increased 8-hydroxydeoxyguanosine content in the heart mitochondrial DNA (mtDNA) from a patient with premature aging and mitochondrial cardiomyopathy, who carried a mutation within the mitochondrial tRNA(Asp) gene. This result suggests that damage to mtDNA by hydroxyl radical and accumulation of deleted mtDNA can be accelerated by a specific mitochondrial genotype. Similarly, extensive fragmentation of mtDNA was also detected in cultured cells exposed to a high oxygen concentration atmosphere, implying that mtDNA is vulnerable to reactive oxygen species. To clarify the role of point mutations accumulated in mtDNA, we examined the sequence heterogeneity of mtDNA in the skeletal muscle of a MELAS patient who carried a mutation within the mitochondrial tRNA(leu)(UUR) gene. The analysis revealed that the frequency of mutant clones in the MELAS muscle was significantly higher than those in an age-matched control muscle and a control placenta. Some of these nucleotide substitutions were missense and nonsense mutations, which potentially have deleterious effects on the mitochondrial function. The frequency of nucleotide substitutions in the striatum of three patients with Parkinson's disease was also significantly higher than that in control tissues. We also observed increased protein modification by 4-hydroxy-2 nonenal, a lipid peroxidation by-product, in Parkinson's disease. These results suggests that a vicious cycle contributes to the progression of degenerative process. In this cycle, first a primary mitochondrial mutation(s) induces a mitochondrial respiratory defect, which increases the leakage of reactive oxygen species (ROS) from the respiratory chain. Then the ROS would trigger accumulation of secondary mtDNA mutations in postmitotic cells, leading to further aggravation of mitochondrial respiratory defects and increased production of ROS and lipid peroxides from mitochondria, and thus resulting in degeneration of cellular components. PMID- 8687012 TI - Increased sensitivity to oxidative stress and the loss of muscarinic receptor responsiveness in senescence. AB - Although there are numerous findings which suggest that the pathogenesis of age related neurodegenerative disorders (e.g., AD and PD) may involve oxidative stress (OS), relationships between functional age-related neuronal deficits, especially those with behavioral correlates, and OS have been difficult to establish. We have attempted to establish such relationships by determining the role of OS in the loss of muscarinic receptor (mAChR) sensitivity in aging. These decrements are expressed as age-related reductions in oxotremorine enhancement of K(+)-evoked dopamine release (K(+)-ERDA) from superfused striatal slices. Using this model we have found that: a) The reductions can be restored with in vivo administration of the free-radical trapping agent, N-tert-butyl-alpha phenylnitrone (PBN); b) Striatal slices from old animals showed increased sensitivity (e.g., reduced DA release or oxo-enhancement of K(+)-ERDA) to the in vitro application of sodium nitroprusside, a potent NO generator or to H2O2 which treatment of striatal slices from young animals with these agents or exposure of young animals to low doses of whole-body 56Fe irradiation decreased mAChR sensitivity and signal transduction (ST). Protection from the NO- or H2O2-induced deficits could be prevented with Trolox, PBN or cholesterol pretreatment. Evidence derived from PC-12 cells suggests that OS may directly affect ST by decreasing Ca2+ flux and increasing the length of the recovery period (i.e., return to baseline Ca2+ levels) after KCI (30 mM) depolarization. PMID- 8687013 TI - Leupeptin causes an accumulation of lipofuscin-like substances and other signs of aging in kidneys of young rats: further evidence for the protease inhibitor model of aging. AB - The "protease inhibitor model of aging" has been proposed on the basis of observations that young rat brains, livers, and retinas exposed to a protease inhibitor, leupeptin, accumulate lipofuscin-like substances (LLS) that are similar to age pigment, and also display a variety of other manifestations of aging. In order to validate this hypothesis in more general terms, the present study reports attempts to induce age-like changes in kidney cells of young rats. Male F-344 rats (4-5 weeks of age) were continuously infused intraperitoneally (i.p.) with various doses of leupeptin (1-50 mg/100 g/day) for 2 weeks. Control animals received saline solution and normal aged rats (27-30 months-old) received no treatment. Animals were sacrificed and subjected to histological examination. In kidneys of leupeptin-, but not saline-treated rats, generally round-shaped PAS positive particles were clearly observed, which were predominantly distributed in proximal convoluted tubules, and which resembled particles in normal aged kidneys. With increasing drug doses, particles tended to become bigger and more numerous. The dominant accumulation of LLS in cells of the proximal convoluted tubules had a fine morphologic configuration that resembled age pigments in old rats. Also, there was a concomitant thickening of the basement membrane that was present in leupeptin-treated and aged kidneys, but not in controls. The results, therefore, support the protease inhibitor model of aging and provide an experimental tool for probing the cellular mechanisms of aging. PMID- 8687014 TI - Reactive oxygen species as causal agents in the neurotoxicity of the Alzheimer's disease-associated amyloid beta peptide. PMID- 8687015 TI - Apoptosis and oxidative stress in the aging brain. AB - DNA is a primary site of damage during oxidative stress in the brain. DNA fragmentation occurs within minutes of induction of oxidative stress. This DNA fragmentation probably results from the attack of free radicals on DNA and from the activation of endonucleases. Oxidative stress was induced by intracerebroventricular injection of t-butylhydroperoxide. This results in a very rapid flux of t-butylhydroperoxide, which is cleared from the brain within minutes. This flux of t-butylhydroperoxide results in the formation of hydroxyl radical in the brain and probably in the nuclei of brain cells. Necrosis results from extensive DNA fragmentation caused by massive oxidative stress. Cresyl violet stained brain sections demonstrated necrosis in many brain regions. In addition, previous electron microscopy studies showed degradation of cellular nuclei caused by tBuOOH toxicity. Low doses of t-butylhydroperoxide can induce apoptosis, which is a delayed form of cell death. Apoptosis was found in brains stained to visualize apoptotic DNA fragments. Experiments performed in mice aged 2, 8 or 24 months will be discussed. We have also found that apoptosis and DNA fragmentation can be prevented by pretreating mice with the vitamin micotinamide. Nicotinamide is a precursor for NAD. DNA repair requires high levels of NAD in the nucleus for the activity of poly(ADP-ribose) polymerase. Oxidative stress in the brain produces both necrosis and apoptosis, probably as the result of DNA fragmentation. Senescence is associated with an increase in the production of DNA fragments during brain oxidative stress, which probably leads to more necrosis and apoptosis than in younger mice. PMID- 8687016 TI - A hypothesis on the pathogenesis of Alzheimer's disease. PMID- 8687017 TI - Molecular physiology, biochemistry, and pharmacology of Alzheimer's amyloid precursor protein (APP). AB - The function of APP is not yet known in detail but growing evidence exists that APP may mediate cell interactions with the cell surface or soluble glycoproteins and defense mechanisms in the CNS involving the immune system. We describe here the finding that almost all CD4+ lymphocytes and the majority of CD8+ lymphocytes were positive for A beta and the antibodies against A beta or APP did not inhibit the [3H]-thymidine uptake of mitogen-treated lymphocytes significantly. There were no differences in the A beta immunoreactivity on the cell surface of lymphocytes between Alzheimer's disease (AD) and control samples. Excessive amyloidogenic pathway of APP processing may be the final common pathway involved in the pathogenesis of AD. Thus, the identification of proteases or factors leading to aberrant proteolysis which process APP to yield a variety of potentially amyloidogenic fragments would promise pharmacological targets to develop anti-AD drugs. In attempts to define the proteases or factors which alter the balance between nonamyloidogenic and amyloidogenic processing pathways, our study indicates that thrombin or acetylcholinesterase(AChE)-associated protease may be involved in the amyloidogenic processing pathway of APP in vivo to generate amyloidogenic intermediates linked to amyloid deposition. Highly specific and dose-dependent direct modulation of APP processing by biologically available metal ions including Ca2+, Zn2+, Fe2+/Fe3+ and Al3+ suggest the disrupted metal homeostasis as factors leading to overaccumulation of APP and subsequent aberrant proteolysis utilizing excessive amyloidogenic processing pathway. There is mounting evidence that at least some of the neurotoxicity associated with AD is due to fragments from APP. Most research has focused on the toxic effect and the ion channel activity of A beta in causation of the disease. The possible role of other cleaved products of APP is less clear. We investigated the channel-forming ability of various products of APP when applied to Xenopus oocytes and their neurotoxicity in vitro. CT105 peptide was found to be exceedingly potent at 500 nM concentration in forming nonselective ion channels during application from either outside or inside the oocyte and more toxic than either of the A beta fragments, A beta 25-35, or A beta 1-40. Taken together, these results suggest the possible involvement of CT peptide in inducing the neurotoxicity characteristic of AD through the direct damage on the cell membrane. Therefore, we hypothesize that amyloidogenic CT may make nonselective ion channels or pores in the membrane and may cause neuronal death in the early stage of AD and then further metabolized to more stable and less toxic A beta which may be finally deposited in the brain where it could inflict further toxicity to neurons. Here we report successful inhibition of APP gene expression by antisense oligodeoxynucleotides at the mRNA or the protein level in in vitro and cell culture systems. PMID- 8687018 TI - Fractionation of amyloid beta-protein (A beta) in Alzheimer's disease and Down's syndrome brains. Presence of membrane-bound A beta. AB - To investigate the early stage of beta-amyloidogenesis in Alzheimer's disease (AD), we performed sucrose density gradient fractionation of amyloid beta-protein (A beta) deposited in cerebral cortices from AD and Down's syndrome patients and normal aged individuals. Each fraction was subjected to Western blotting with monoclonal antibodies BA27 and BC05, which specifically recognize A beta 40 and A beta 42, respectively. The samples from brains with a large number of diffuse plaques showed strong BC05 immunoreactivity at the 1.0/1.2 M (F1) and 1.2/1.5 M (F2) interfaces. In contrast, in brains with advanced AD pathology, most of the BC05 immunoreactivity was recovered at the 1.5/2.0 M (F3) interface. In all cases, the level of BA27 immunoreactivity was negligible. Although F1A beta was determined to be A beta 1-42, it was only weakly reactive with BAN50 (monoclonal antibody raised against A beta 1-16). Delipidation of F1A beta restored full BAN50 immunoreactivity, indicating that F1A beta is bound to membrane. The present results suggest that diffuse plaques are associated with this membrane bound A beta and thus that this novel A beta species is an initially deposited one. PMID- 8687019 TI - Lewy bodies: purification from diffuse Lewy body disease brains. PMID- 8687020 TI - Parkinson's disease and free radicals. Mechanism of neurodegeneration and neuroprotection. PMID- 8687021 TI - Oxidative stress and Parkinson's disease. AB - The underlying mechanism of cell death in substantia nigra of Parkinson's disease patients remains unknown. Biochemical changes occurring in substantia nigra in Parkinson's disease (increased iron levels, inhibition of complex I activity and decreased reduced glutathione levels; GSH) suggest that oxidative stress and free radical species may be involved. In particular, a decrease in GSH levels may be an early component of the process, since this also occurs in incidental Lewy body disease (presymptomatic Parkinson's disease). GSH is lost only from the substantia nigra in Parkinson's disease and this does not occur in other neurodegenerative disorders of the basal ganglia. GSH loss appears to be global throughout the substantia nigra and not localized to either the glia or neuronal elements. The activity of enzymes involved in the glutathione cycle are normal with the exception of gamma-glutamyltranspeptidase, the activity of which is increased. This could result in increased removal and degradation of glutathione from cells. Depletion of GSH in rat using L-buthionine-[S, R]-sulfoxamine (BSO) potentiates 6-hydroxydopamine (6-OHDA) toxicity but does not in itself produce degeneration of the nigrostriatal pathway. Oxidative stress may be a potentially important factor in the degeneration of the substantia nigra in Parkinson's disease and warrants further investigation into its role in this process. PMID- 8687022 TI - Role of free radicals in and around vascular endothelial cells in the mechanism of aging. PMID- 8687023 TI - The role of nitric oxide in the cardiovascular system. AB - Nitric oxide (NO) exerts various pathophysiological effects on the cardiovascular system; inhibition of platelet aggregation or leukocyte adhesion on endothelium and vasorelaxation including lethal hypotension in endotoxic shock. In spite of these significant roles of NO, its direct action on individual cardiovascular cells remains unclarified. Therefore, we have investigated the function of NO on cells which constitute vascular wall and heart, and have found this new evidence. 1) ATP increased intracellular ([Ca2+]i) in vascular endothelial cells (ECs) and decreased [Ca2+]i of adjacently cocultured vascular smooth muscle cells (VSMCs), as detected by 2-D fura-2 image analysis. 2) The [Ca2+]i reduction in cocultured VSMCs with ECs by ATP was attenuated by pretreatment of several types of NO inhibitor, whereas the NO inhibitor potentiated the [Ca2+]i elevation in ECs, suggesting that NO affects VSMCs in a paracrine manner while ECs in an autocrine fashion. 3) Physiological concentration of lysophosphatidylcholine, which is an atherogenic constituent of oxidized LDL, but not native phosphatidylcholine, acted on ECs and VSMCs like a NO inhibitor, indicating that this material attenuates NO effect and disturbs vessel relaxation in the short term. 4) Highly efficient transfection of the ecNOS gene in rat heart showed a toxic effect on individual cardiomyocytes in vivo. In conclusion, NO may exert both beneficial and harmful effects on the cardiovascular system. PMID- 8687024 TI - Simultaneous increase of mitochondrial DNA deletions and lipid peroxidation in human aging. AB - Human mtDNA is a naked circular double-stranded DNA, which is continually exposed to the matrix that contains high levels of ROS and free radicals. High oxidative stress and a lack of proofreading during mtDNA replication and efficient DNA repair mechanisms in the mitochondria have rendered mtDNA extremely vulnerable to oxidative damage. More than one dozen large-scale deletions in mtDNA have been identified in various tissues of old humans. The 4,977-bp and 7,436-bp deletions are the most prevalent and abundant ones. The onset age of various mtDNA deletions varies greatly with tissues of each individual and type of deletion. In this and previous studies, we have demonstrated with PCR techniques that the frequency of occurrence and the proportion of the 4,977-bp and 7,436-bp deleted mtDNAs are significantly increased with the age of the human. The mtDNA deletions are not detectable in any tissues from young healthy subjects or blood cells from normal individuals of any age, which indicates that the deletions are generated and accumulated only in postmitotic cells upon aging. Moreover, we found that these mtDNA deletions occur more frequently and abundantly in tissues with high energy demand (e.g., muscle) as compared to those with low energy demand. On the other hand, we found that the amount of lipid peroxides measured as malondialdehyde and the activity of manganese-superoxide dismutase in the mitochondria exhibit an age-dependent increase in various human tissues. The lipid peroxide level in muscle was significantly higher than that in the other tissues. Moreover, we found a positive correlation between the proportion of the 4,977-bp deleted mtDNA and lipid peroxide content in the mitochondria of human tissues during aging. Muscle the tissue of high energy demand, was found to be more vulnerable to oxidative damage that lead to most abundant mtDNA deletions and lipid peroxidation among all the tissues examined. Taking these results together, we suggest that the enhanced generation of reactive oxygen species and lipid peroxides in the mitochondria during the aging process occur simultaneously with large-scale deletions and the other types of mutations in mtDNA, which are early molecular events and major contributory factors of human aging. PMID- 8687025 TI - Modification of high- and low-density lipoproteins by cigarette smoke oxidants. PMID- 8687026 TI - Age-dependent impairment of mitochondrial function in rat heart tissue. Effect of pharmacological agents. PMID- 8687027 TI - Effects of aging on prejunctional control of neurotransmission in the rat. AB - In this study, we have looked in detail at the effects of aging on neurotransmission in isolated atria and intact heart in anesthetized rats, examining adult and aged animals. There was a diminished ability of the norepinephrine reuptake blocker cocaine to increase stimulation-evoked release of norepinephrine in aged rats and in terms of increasing the norepinephrine-evoked tachycardia in anesthetized rats, suggesting that the function of the reuptake process is diminished by aging. The ability of the alpha 2 adrenergic receptor agonist xylazine to inhibit release of norepinephrine neurotransmitter was also diminished in aged rats both in isolated tissues and in vivo in anesthetized animals. In further studies, the ability of the beta-adrenergic receptor agonists isoproterenol (beta 1 and beta 2 agonist) and procaterol (selective beta 2 agonist) to increase stimulation-evoked release of norepinephrine was examined. Both agonists produced a concentration-dependent facilitation of norepinephrine release in rats atria. Although isoproterenol and procaterol increased release in tissues from young and old animals, the magnitude of the increase was significantly reduced in tissues from old rats, so that beta-adrenergic receptor mediated facilitation was diminished. In summary, aging is associated with a decline in prejunctional modulation of neurotransmission, in terms of diminished norepinephrine reuptake, diminished prejunctional alpha 2 adrenergic receptor mediated inhibition and diminished prejunctional beta 2 adrenergic receptor mediated facilitation. TABLE 2 summarizes the possible effects of aging on noradrenergic neurotransmission. Overall, neurotransmission at rest may be little changed by aging, given that postjunctional responsiveness may fall, but scope for modulation may be diminished. PMID- 8687028 TI - Impaired plasticity of neurons in aging. Biochemical, biophysical, and behavioral studies. AB - Age-related correlation of impaired plasticity of neurons (biochemical and biophysical aspects) and behavioral alterations were investigated in young (3.5 months) and extremely aged (approximately 40 months) female Wistar rats. Age dependent significant differences in second messenger (cAMP and Ins (1,4,5)P3) concentration and signal transduction via muscarinic and dopaminergic receptors were found. The results point to the specifically impaired coupling between dopamine D1 receptor and GS protein, which underlies normal brain aging. However, cholinergic neurotransmission may be modulated at another level in extremely aged rats. Thus, it appears that the site of affection in coupling of receptor and G protein and/or G protein-dependent signal transduction in aging cannot be generalized. This indicates that alterations in the coupling of signal transduction depend on diverse neurotransmitter receptors with advanced age. The age-dependent alterations in the cAMP and PI signal pathways could be due to changes in the physical properties of the membranes. To support this hypothesis, age-dependent changes in the physical state and the biochemical composition of synaptosomal membranes from the cortex, cerebellum, and striatum were examined by measuring the steady-state fluorescence amisotropy of the membrane probes 1,6 diphenyl-1,3,5-hexatriene (DPH), trimethylammonium-DPH (TMA-DPH), and trimethylammoniumpropyl-DPH (TMAP-DPH). Significant differences in the physical properties of the synaptosomal membranes existed between young and very aged rats, expressed by a higher anisotropy in the 40-month-old rat brain tissue. The changes in the physical properties of the membranes were in line with the determined age-dependent alterations in the chemical composition, e.g., the increase in cholesterol content of the aged membranes. PMID- 8687029 TI - Cellular and molecular mechanisms of cardiovascular aging. Molecular pharmacological implications. PMID- 8687030 TI - Receptor-effector coupling dysfunctions in Alzheimer's disease. AB - There is now good evidence that in the AD brain, a number of neurotransmitter effector systems are defective. Such abnormalities include defective G, protein and protein kinase C function as well as a drastically reduced level of receptors for the second messenger Ins(1,4,5) P3. Such changes are probably not restricted to the late stages of the disease, and are found in regions of the brain that show little histopathological abnormality, such as the cerebellum. Whether these changes precede or are secondary to primary histopathological changes such as beta-amyloid deposition is not as yet clear. What is clear, however, is that such signal transduction abnormalities are likely to negate therapeutic benefits in clinical strategies based upon the tenet of neurotransmitter replacement. PMID- 8687031 TI - Free intracellular calcium in aging and Alzheimer's disease. AB - Brain cells of aged mice exhibit distinct alterations of [Ca2+]i regulation resulting in lower levels of [Ca2+]i after stimulation. These alterations are probably more related to disturbances of mechanisms regulating transmembraneous Ca2+ fluxes than to mechanisms of intracellular Ca2+ release and storage. Comparable although not identical disturbances of [Ca2+]i regulation are present in mouse, rat, and human lymphocytes. Accordingly, one is tempted to speculate that in the human brain similar alterations of [Ca2+]i regulation might be present in aging as found in the aged mouse and rat brain. Since the downregulation of [Ca2+]i levels in aged brain cells seems to be accompanied by an enhanced intracellular sensitivity for changes of [Ca2+]i, both divergent alterations might compensate each other under normal conditions. However, it seems quite conceivable that the ability of the Ca2+ signal transduction pathway to adopt to periods of over-or understimulation (e.g., hypoxia, stress) might be disturbed in the aging brain. One of those conditions of additional alterations of [Ca2+]i regulation might be AD. Although we did not see AD-specific changes of [Ca2+]i regulation per se, the effect of beta A4 on cellular [Ca2+]i regulation was significantly and specifically disturbed in AD. It is not unlikely that a small, but long lasting (years or even decades) alterations of cellular [Ca2+]i regulation by beta A4, which is a product of normal brain metabolism, might finally contribute to the severe neuronal damage seen during the disease. PMID- 8687032 TI - Aging and disease: extending functional life span. PMID- 8687033 TI - Protection against impairment of memory and immunoreactivity in senescence accelerated mice by acidic fibroblast growth factor. AB - Subcutaneous injection of aFGF once a week into senescence-accelerated mice (SAM)P8 was begun at 3 weeks after birth and continued for 10 months. Saline was injected as a control. Learning and memory and cellular immunological functions in the aFGF group were enhanced significantly, while those of the saline group deteriorated. 1. The number of cholinergic neurons was decreased by less than 20% and choline acetyltransferase activity in individual neurons in the medical septum which send monosynaptic terminals to the hippocampus was significantly decreased in the saline group, but not so much in the aFGF group. 2. The respective densities of muscarinic and NMDA receptors and the aFGF receptor, i.e., FGFR-1 on the hippocampal neurons were also significantly higher in the aFGF group than in the saline group. 3. The long-term potentiation in the hippocampal slice preparations after a brief tetanic stimulation at the Schaffer collateral/commissural afferents was significantly facilitated in the aFGF group, but not in the saline group. 4. These data indicate the normalization caused by aFGF of the medial septohippocampal circuit, which is necessary for learning and memory. 5. The delayed type hypersensitivity reactions (DTH) in the footpad caused by challenge with trinitrophenyl or sheep red blood cells as measured at the end of the 2nd and 7th months, indicated the T cell immune response. Both types of DTHs were reduced in the 7th month as compared with the 2nd month in the saline group, but the aFGF group was protected against this reduction in accordance with age. 6. These results show that aFGF provides protection against impairment of not only learning and memory but also DTH immunoreactivity in SAMP8. They also indicate a close relationship between learning and memory and T cell immune function. PMID- 8687034 TI - Cognitive enhancement. New strategies for stimulating cholinergic, glutamatergic, and nitric oxide systems. AB - The development of treatments for AD is being pursued along many diverse lines. While the ACh hypothesis has generated abundant development efforts, little clinical progress has been achieved to date. Recent efforts aimed at developing more potent, more specific, and safer ChE inhibitors appear to offer greater potential for therapeutic success than achieved to date. Treatments aimed at the NMDA Glu system lag much further behind in their development. Progress in this area must be tempered by the potential for glutamate excitotoxicity mediated through this neurotransmitter system. Development of indirect agonists operating at the glycine and polyamine modulatory sites on the NMDA receptor might offer the safest alternative to applying more direct agonists. While a great degree of interest had been generated by the reports of NO involvement in signal transduction through the NMDA system, this area of research has been complicated by conflicting reports regarding NO involvement in learning and LTP. Moreover, the interaction of drugs acting on NOS with the vascular effects mediated by eNOS has also complicated development of drugs that act specifically on the neural actions of NO. This area will continue to receive extensive research attention; but similar to the development of Glu agonists, attention must be given to the potential neurotoxic effects of overstimulating this system. Perhaps targeting other presynaptic mechanisms that effect glutamate release might be a safer strategy to pursue. Considerable progress has been made over the last two decades in identifying the genetic and neural mechanisms involved in AD. Progress in developing treatments will remain highly correlated with this effort, and with basic research geared to comprehending how memories are formed and why neurons degenerate and regenerate. PMID- 8687035 TI - Melatonin in the context of the free radical theory of aging. PMID- 8687036 TI - Suppression of hydroxyl radical formation and protection of nigral neurons by l deprenyl (selegiline). AB - The present study clearly demonstrated that l-deprenyl confers a substantial protective effect against MPP+ in the substantia nigra zona compacta in vivo. 32.39. The protection provided by l-deprenyl may not depend on its inhibition of type B monoamine oxidase. A unique antioxidant property of l-deprenyl by suppression of cycotoxic. OH formation and associated oxidative damage induced by MPP+ in the A9 melanized nigral neurons may contribute to the protection against MPP+ toxicity in the nigrostriatal system. The likelihood that l-deprenyl may confer neuroprotection against MPP+ toxicity through antioxidant effect is further strongly supported by our recent data that U-78517F (2 methlaminochromans) a potent inhibitor of ironcatalyzed lipid peroxidation, and DMSO an effective. OH scavenger also protect nigral neurons against MPP(+) induced severe oxidative injury in the substantia nigra. This putative antioxidant effect of deprenyl may explore another mechanism which may in part contribute to its overt neuroprotection against several toxins, including 6-OHDA, DSP-4, and MPTP, and the possible clinical effects on slowing the neuronal degeneration in early Parkinson's disease, Alzheimer's disorder and even senescent changes. PMID- 8687037 TI - Upregulation of antioxidant enzyme activities by deprenyl. Implications for life span extension. AB - In order to elucidate the exact role of antioxidant enzyme activities such as superoxide dismutase (SOD) in the aging process of animals, we compared various enzyme activities in different brain regions and in the liver of young (6-8 mo) and old (28-30 mo) Fischer-344 (F-344) rats. While Mn-SOD activities were elevated 3-5-fold in specific brain regions such as hippocampus, striatum and substantia nigra in brains of old male rats compared with the young, in females both forms of SOD (Cu, Zn- and Mn-) enzyme activities remained essentially unchanged with aging. Continued subcutaneous infusion of deprenyl for 3 weeks caused a 2-3-fold increase in activities of both Cu Zn- and Mn-SOD and a 50-60% increase in CAT activities in striatum and substantia nigra but not in hippocampus, cerebellum or the liver. Further, long-term treatment of old male rats with deprenyl caused a significant increase in the remaining life expectancy from 24 months of age by 34%. In conclusion, activities of antioxidant enzymes in these regions examined do not show any uniform age-associated change, suggesting that changes in these enzyme activities do not have any specific role in the life span of rodents in general terms. In contrast, the results of our deprenyl study suggests the possibility that the protection of catecholaminergic neurons by an upregulation of SOD and CAT activities plays a significant role in the life span of animals. PMID- 8687038 TI - Senescence-accelerated mouse. Neurochemical studies on aging. AB - Senescence-accelerated mouse (SAMP8) is known as a murine model of accelerated aging and memory dysfunction. The binding activity of [3H] 1-(2-chlorophenyl)-N methyl-N-(1-methylpropyl)-3-isoquinolinecarboxam ide (PK-11195) as a neurochemical marker of gliosis markedly increased with aging in the cerebral cortex and hippocampus of SAMP8. Immunoreactivity for glial fibrillary acidic protein (GFAP) was also enhanced. A beta-amyloid precursor protein (APP)-like immunoreactivity and 27-kDa-carboxyl terminal fragments of APP increased in SAMP8 brain. In addition, anti-APP antibody stained reactive astrocytes surrounding spongy degeneration in brain stern of SAMP8. These results suggest that astrocytosis and production of APP-derived fragments occur markedly in SAMP8 brains. PMID- 8687039 TI - Catecholestrogen as a natural antioxidant. PMID- 8687040 TI - Growth hormone (GH) retardation of muscle damage due to immobilization in old rats. Possible intervention with a new long-acting recombinant GH. AB - Four weeks immobilization of the right leg of aged rats (26 months old) caused a marked 31% and 27% reduction of muscle mass of the plantaris and soleus muscles, respectively. In animals treated with 0.6 mg/kg body weight of growth hormone (GH), the reduction of weight of the above muscles was only 14.7 and 16.1%, respectively. Biochemical studies of the level of acid phosphatase as a marker of muscle catabolism showed a significant increase of this enzyme in the immobilized muscles. GH treatment had a positive effect in curtailing the increase due to immobilization. Studies on muscle protein oxidation used as another measure of damage in immobilized animals, showed a 400% increase in protein carbonyls in plantaris muscles. GH administration reduced this value significantly. One major issue hampering the clinical use of human GH (hGH) is its short half-life in vivo (14 min). In a previous work it was possible to enhance the in vivo longevity of other hormones such as follicle-stimulating hormone (FSH) and human chorionic gonadotropin (hCG) by fusing carboxyl-terminal peptide (CTP) of the hCG gene to the above hormones. The CTP has four serine-linked oligosaccharides, which have been shown to be important in maintaining the longer half-lives of these hormones. With the above rationale of using the CTP as a general target to increase the potency of bioactive hormones, we have now fused the CTP with hGH. This has provided us with a new successfully constructed recombinant hGH, which is currently being tested for its biological potency and for possible use in aging animals. PMID- 8687041 TI - Mitochondrial aging and lipoperoxidative products. PMID- 8687042 TI - On the possible role of nootropica in geriatric prevention and therapy. PMID- 8687043 TI - The ATPase module and the process of cellular immortalization. AB - The phenotype of normal aging is proposed to result from a progressive decrease in the functional capacity of the mitochondrion as the main supplier of the universal currency of bioenergy, ATP. It is suggested that this aging-related mitochondrial dysfunction specifically concerns the ATPase module of the ATP synthase enzyme complex. Evidence in support of this proposal is reviewed. PMID- 8687044 TI - Alteration of mitochondrial F0F1 ATP synthase during aging. Possible involvement of oxygen free radicals. PMID- 8687045 TI - Involvement of mitochondrial gene abnormalities in the pathogenesis of diabetes mellitus. AB - An A to G mutation at nucleotide position 3243 of the mitochondrial genome has been shown to be associated with insulin-dependent diabetes mellitus (IDDM) and with noninsulin-dependent diabetes mellitus (NIDDM) with deafness. We investigated the prevalence of this mutation in Japanese patients with IDDM, NIDDM, and impaired glucose tolerance (IGT) and in nondiabetic control individuals and identified it in three of 300 patients with NIDDM or IGT (1.0%). None of these individuals had significant sensorineural hearing loss. None of the 94 IDDM or the 115 nondiabetic control subjects was positive for this mutation. Oral glucose tolerance test revealed that a 57-year-old male with this mutation was rather hyperinsulinemic in the fasting state. The insulin secretion in this patient decreased with age; he did not complain of any hearing disorder, although audiometry revealed a slight elevation of hearing threshold at high frequencies. In conclusion, we found that a mitochondrial gene mutation at np 3243 was present in about 1% of NIDDM patients including IGT, and the subtype of diabetes mellitus with this mutation may have a similar clinical profile to that found in patients with NIDDM commonly seen in outpatient clinics. Screening of 116 patients with type 1 diabetes mellitus and 149 patients with autoimmune thyroid diseases revealed that this mutation rarely exists in patients with autoimmune diseases. PMID- 8687046 TI - Tandem duplications and large-scale deletions of mitochondrial DNA are early molecular events of human aging process. AB - Large-scale deletions and tandem duplications of mtDNA, which were originally identified in the patients with KSS or CPEO, have recently been found, although with lower abundance, in various tissues of aged individuals. By use of PCR techniques with back-to-back primers, we demonstrated for the first time that small tandem duplications occur in the D-loop of mtDNA in an age-dependent manner in human tissues. A total of 10 types of such tandem duplications were identified and confirmed by primer-shift PCR and DNA sequencing. Based on the sequence characteristics of the junction sites, we classified these small tandem duplications into 3 groups. Most of the tandem duplications were found to occur at hot spots containing poly C runs, and the number of C residues exhibited wide variations in type I, II, V, VI, VII, and VIII duplications. These observations suggest that these tandem duplications may be generated through similar recombination mechanisms. Among them, type I, II, III, IV and IX duplications were found to occur more frequently and abundantly in aging human tissues. They were not detectable in muscle, testis or skin tissues of young subjects or blood cells from subjects of any age. On the other hand, we also analyzed the samples for the aging-associated 4,977-bp and 7,436-bp mtDNA deletions. The results showed that these two deletions and some of the small tandem duplications could occur alone or in different combinations in human tissues in the aging process. From our data, no clear association between tandem duplications and large-scale deletions of mtDNA could be established. However, one common and important observation is that the incidence and abundance of some of the tandem duplications as well as the large-scale deletions were increased in an age dependent manner. On the basis of these findings and data reported from this and other laboratories, we propose that tandem duplications and large-scale deletions of mtDNA are early molecular events of the human aging process. PMID- 8687047 TI - [Pemphigus: from clinical observation to molecular biology]. PMID- 8687048 TI - [Acquired myelodysplastic syndromes after treatment of melanoma with fotemustine and dacarbazine]. AB - INTRODUCTION: Secondary myelodysplasia after antimitotic therapy is a rare complication usually observed with alkylating agents. The condition usually progresses to acute leukaemia with very poor short term prognosis. CASE REPORT: We report the cases of 2 women who developed myelodysplasia 2 and 9 months after treatment associating dacarbazine and fotemustine for visceral metastases of a malignant melanoma. DISCUSSION: The frequency of these rare complications is probably underestimated because of the rapid unfavourable outcome of metastatic malignant melanoma. We were unable to determine whether dacarbazine, fotemustine or their combination was incriminated in this complication. Risk could be reduced by carefully determining the cumulative doses of these antimitotics. PMID- 8687049 TI - [Anti-beta 2 glycoprotein 1 antibodies in idiopathic livedo reticularis]. AB - INTRODUCTION: Idiopathic livedo reticularis can be a sign of systemic disease since certain complications are frequently associated: cerebral thrombotic events in Sneddon's syndrome, necrotic ulcerations of the lower limbs. Antiphospholipid antibodies have been found in 0 to 85 p. 100 of patients with Sneddon's syndrome and anti-beta 2-glycoprotein 1 antibodies in 65 p. 100 of a series of 20 cases with Sneddon's syndrome. The aim of our study was to determine the prevalence of anti-beta 2-glycoprotein 1 antibodies in idiopathic livedo reticularis. PATIENTS AND METHODS: Twelve patients in a series of 17 with idiopathic livedo reticularis seen between 1981 and 1992 were studied progressively. All underwent a clinical examination and simple laboratory tests with search for anticardiolipin antibodies, lupus type circulating anticoagulant and anti-beta 2-glycoprotein 1 antibodies. RESULTS: Eight of our 12 patients (60 p. 100) were positive for anti beta 2-glycoprotein 1 antibodies, 3 of whom also had episodes of thrombosis similar to those described in antiphospholipid syndrome. Only one of the 8 patients also had anticardiolipin antibodies and no chronic manifestation of thrombosis. DISCUSSION: beta 2-glycoprotein 1 is a cofactor which increases anticardiolipin antibody adhesion to cardiolipin in ELISA. Anti-beta 2 glycoprotein 1 antibodies are associated with thrombosis and antiphospholipid antibodies with lupus. Our results would suggest that the prevalence of anti-beta 2-glycoprotein 1 antibodies is high in idiopathic livedo, but, due to the small number of patients, do not allow confirmation that anti-beta 2-glycoprotein 1 antibodies are associated with thrombosis. Anti-beta 2-glycoprotein 1 antibody assay would be justified in routine evaluation of patients with livedo and at follow-up examinations. PMID- 8687050 TI - [Intra-epidermal pustulosis in a child. Demonstration of a target antigen similar to foliaceus pemphigus antigen]. AB - INTRODUCTION: Intraepidermal IgA pustulosis is a vesiculopustular dermatosis defined by pemphigus type intercellular deposit exclusively of IgA. It is a member of the pemphigus group and may be related to neurtrophilic dermatoses. CASE REPORT: A child had vesiculopustular lesions of the limbs since the age of 11 years. Biopsy showed the subcorneal intraepidermal nature of the pustules and exclusive IgA deposit throughout the epiderma. Indirect immunofluorescence and protein immunoelectrophoreses were negative. Immunotransfer to beef tongue extract evidenced a 150-160 kDa band corresponding to IgA and IgG desmoglein. Treatment with general corticosteroids followed by pristinamycin was successful. DISCUSSION: This is the first case report showing evidence of antiepidermal antibodies directed against the superficial pemphigus antigen. PMID- 8687051 TI - [Primary cutaneous nocardia asteroides nocardiosis in an immunocompromised patient]. AB - INTRODUCTION: Nocardiasis is caused by a germ belonging to the Actinomycetales order. Skin disease usually occurs as a secondary localization of a pulmonary infection in an immunocompromised patient. Purely cutaneous lesions usually occur in immunocompetent subjects. CASE REPORT: We observed primary cutaneous nocardiasis due to N. asteroides with a cold abscess in a patient with a pemphigoid given immunodepression treatment. DISCUSSION: Primary cutaneous nocardiasis can occur by direct contamination of a skin wound. In our patient with a pemphigoid given immunodepression treatment, the erosion of a pemphigoid bulla and general corticosteroid treatment favoured the localized infection. Cure could not be obtained until after 7 months treatment. This long course can be explained by the need to continue high-dose general corticosteroids to control the pemphigoid. PMID- 8687052 TI - [Juvenile xanthogranuloma: a congenital giant form]. AB - INTRODUCTION: Juvenile giant xanthogranuloma (JGX) is usually a benign skin disease which regresses spontaneously in the new-born or infant. Characteristic firm yellow-orange papulonodules lead to diagnosis. The nodules vary in size from a few millimetres to 1 to 2 centimetres. We observed an exceptional case presenting as a congenital giant form. CASE REPORT: A new-born girl had a bright red lesion of the right inguinal region measuring 4 x 2.5 cm. Inguinal node enlargement was found homolaterally. Histological examination of a biopsy specimen gave the diagnosis of JGX. There was no extension. The lesion and node involvement regressed spontaneously leaving a xanthomization of the skin. DISCUSSION: Clinical forms of JGX are rarely described. The large size of these lesions does not apparently affect the clinical course nor associated visceral involvement which remains exceptional. This type of lesion increases in size more rapidly and raises the problem of differential diagnosis requiring biopsy to eliminate other neonatal tumours with a less favourable prognosis. Spontaneous regression of JGX is the rule allowing simple regular surveillance. PMID- 8687053 TI - [Sclerosing lipogranuloma in a male]. AB - INTRODUCTION: Major trauma was the only aetiologic factor found in a male patient presenting sclerosing lipogranuloma. This condition is well-known in women but is rarely described in men. CASE REPORT: A 31-year-old non-obese man with no sign of gynaecomasty presented with well-delimited plaques of pigmented and sclerosous tissue located at the pubis and both breasts as well as hard nodules of the scrotum and the penis. The lesion developed progressively after a major trauma involving the anterior aspect of the thorax and the public area. An inflammatory border persisted eight years after the initial trauma. Histological examination of a biopsy specimen showed evidence of adipocyte necrosis with lipophagia and lipogranuloma. No foreign body was found. DISCUSSION: The diagnosis of post trauma cytosteatonecrosis was retained on the basis of the clinical history and the clinical, histological and radiographic evidence. This condition is a well identified clinical entity which is sometimes confounded with false panniculitis resulting from self-injection of oily products. The endogenous origin of the fatty acids found within the cytosteatonecrosis tissue has recently been proven. Usual localizations are the breast in women and genital organs in men. Favouring factors in women include obesity, age, anticoagulants, frequency and intensity of trauma. The exceptional localization in our patient was strongly related to the earlier trauma. PMID- 8687054 TI - [Mycosis fungoides in the child. Three cases]. AB - INTRODUCTION: Cutaneous lymphoma is unusual in children but according to data in the literature, approximated 5 p. 100 of the cases observed would begin in childhood. CASE REPORT: We retrospectively studied 3 cases of mycosis fungoides where the first manifestations occurred before 10 years of age. In one of the patients, the diagnosis was not definitively confirmed until adulthood. DISCUSSION: Diagnosis in these forms which begin in childhood is usually achieved after a long delay. Clinically, these lymphomas form a homogeneous group. In approximately 15 p. 100, guttate parapsoriasis occurs before mycosis fungoides. Biopsy is indicated if the lesions change in aspect or become atypical. The most frequent presentation in children or young adults is vitiligoid hypo-pigmented macules. Histologically, childhood forms do not differ from the adult forms and also respond to local treatment as in adults. Prospective studies conducted conjointly by paediatricians and dermatologists would be needed to describe the natural history of these cutaneous lymphomas in light of progression to aggressive lymphoma of Hodgkin's disease described in certain cases. PMID- 8687055 TI - [Cryptococcal whitlow in a HIV positive patient]. AB - INTRODUCTION: Cutaneous cryptococcosis is a systemic fungal disease; it is commonly observed in immunocompromised patients. OBSERVATION: We report the case of a cryptococcal whitlow in an HIV positive patient. The mycologic culture of the cutaneous lesion was positive for Cryptococcus neoformans serotype D. The detection of the blood antigen was positive but there was no pulmonary nor central nervous system involvement. The lesions cured with fluconazole (400 mg/day during 2 months and 200 mg/day after). DISCUSSION: This unusual clinical presentation of cutaneous cryptococcosis has never been reported in an HIV positive patient. As the dermatologic manifestations of cryptococcosis are polymorphous mycologic examination of skin lesions is very important. PMID- 8687056 TI - [Lichen planus and thymoma. A case]. AB - INTRODUCTION: Lichen planus is a chronic inflammatory disease of the skin, rarely associated with a thymoma. CASE REPORT: A 72-year-old woman with erosive buccal lichen, hypertrophic lichen planus of the lower limbs, severe myasthenia and acquired hypogammaglobulinaemia associated with thymoma. CD8 lymphocyte count was increased. In the months following surgical ablation of the thymoma, the clinical examination and laboratory findings progressively returned to normal. Two years later, the patient was in good health. DISCUSSION: To our knowledge, this is the first report of favourable outcome after surgical treatment despite the aggressive symptomatology. The particular outcome allow confirmation that the thymoma plays a causal role in this syndrome and emphasizes the effects a thymoma can have on the immune system. PMID- 8687057 TI - [Juvenile palmar dermatitis acquired at swimming pools]. AB - INTRODUCTION: We describe a new childhood mechanical dermatosis of the hands due to swimming pools. OBSERVATIONS: We report two cases of a dermatosis of the hands occurring in children characterized by symetric erythematous plaques on the convexities of the palmar zone of the hands and fingers. It is due to repeated rubbing of the palms on rough pool wall. It disappears spontaneously when stopping this activity. DISCUSSION: We propose the French appellation of "dermatite palmaire juvenile des piscines" to design this entity which has already been described in the English dermatologic literature under the name of "pool palms". Its characteristic aspect should allow a rapid diagnosis. PMID- 8687058 TI - [Hirsutism. Two familial cases of 21-hydroxylase deficiency]. AB - INTRODUCTION: One to six percent of women with hirsutism have 21-hydroxylase deficiency. Beyond these classical congenital forms, the most frequent cases present non-specific signs of hyperandrogenism. The diagnosis of the deficiency is based on 17-hydroxy-progesteron (17-OHP) assay before and after ACTH stimulation. CASE REPORT: We observed 2 sisters with a non-classical deficiency in 21-hydroxylase. Their phenotypes were very different: the elder sister had severe hirsutism and clitoromegaly and was overweight; the younger sister had more moderate hirsutism with no other signs of hyperandrogenism. Hormone patterns were also different. Both baseline and stimulated plasma 17-OHP were higher in the elder sister (47 ng/ml to 126 ng/ml and 5.2 ng/ml to 42.8 ng/ml respectively). The genotype was however identical. Both were homozygous for CYP21A duplication and short C4B and had a Val281Leu mutation on exon 7 of the CYP21B gene. DISCUSSION: This phenotypic variability in subjects with the same genotype could be explained by increased sensitivity to androgens or, more likely, to the presence of currently undetectable mutations. Genetic counselling is often requested due to the high frequency of non-classical forms and the large number of heterozygous subjects with the 21-hydroxylase trait. It is thus important to screen for 21-hydroxylase deficiency in women with hirsutism. In addition, molecular assessment of CYP21B gene should be proposed for all subjects with a non-classical form as well as family members (at least the father and mother). PMID- 8687059 TI - [Lichen planus and vaccination against hepatitis B]. AB - INTRODUCTION: The association of lichen planus with liver diseases is now well established. Lichen planus following hepatitis B vaccination are much more unusual. We report here the fifth case of this kind. CASE REPORT: A 16 years old girl developed a purely cutaneous lichen planus one week after the first injection of hepatitis B vaccine Gen Hevac B (Institut Pasteur), which appeared again 3 days after the second injection. The histologic features shown lichenoid pattern with intense keratinocytes necrosis more in favor of lichenoid drug eruption than lichen planus. DISCUSSION: According to our knowledge, only four similar cases have been previously reported. Comparison between the different vaccines used shows that only the HBs antigen and its epitope S could be involved in the lichen planus eruption. Our case is specific due to the early appearance of the eruption after the first injection and by its histologic features. CONCLUSION: New cases of lichen planus following hepatitis B vaccination should help to explain the causal relationship between lichen planus eruption and hepatitis B vaccination. PMID- 8687060 TI - [Hypopigmented mycosis fungoides]. AB - INTRODUCTION: Isolated areas of hypopigmented skin can be a manifestation of mycosis fungoides. This is a rare clinical form with a particular clinical course and histology which has been described only in black subjects. CASE REPORT: Over a 10-year period, a 28-year-old woman from Mali developed non-infiltrated hypopigmented and discretely squamous macules involving the entire body. The diagnosis of mycosis fungoides was made on pathology evidence of epidermotropic lymphocyte infiltration with a few small nests. PUVA led to rapid regression of the lesions. DISCUSSION: Hypopigmented mycosis fungoides has been described in young black subjects (mean age 19 years). The diagnosis is usually made late because benign skin affection is usually the first diagnosis (pityriasis alba, pityriasis versicolor). The pathogenesis of these hypopigmented lesions is not known. PUVA appears to be effective in most cases. PMID- 8687061 TI - [Desmoplastic and neurotropic subungueal melanoma]. AB - INTRODUCTION: Desmoplastic and neurotropic melanoma is rare and involvement of the subungual skin is an exceptional finding. OBSERVATION: We report the second case of desmoplastic and neurotropic subungual melanoma in the literature occurring in a 71-year-old woman. DISCUSSION: In our patient, the histological diagnosis of desmoplastic melanoma was particularly difficult because of the exceptional involvement of the subungual skin. Microscopic neurotropism and immunohistochemical studies were the clues in diagnosing desmoplastic melanoma. PMID- 8687062 TI - [Cutaneous larva migrans, autochthonous in France. Apropos of a case]. AB - INTRODUCTION: Cutaneous larva migrans is rarely contracted in temperate countries. CASE REPORT: When his house became flooded, he had to stand for a long period of time with mud up to the thigh. Some days later, he developed multiple erythematous, serpiginous pruritic tracts moving 1-2 cm per day over preexisting lesions of the right leg. Local and systemic treatment with thiabendazole led to rapid and definitive cure. DISCUSSION: Cutaneous larva migrans results from the migration of hookworm larvae in the dead-end human host. It is mainly an imported disease and native cases in Europe as reported here are rare. This case demonstrates that the conditions leading to the development of cutaneous larva migrans are rarely found simultaneously in temperate zones. PMID- 8687063 TI - [A case for diagnosis: pellagra]. PMID- 8687064 TI - [A case for diagnosis: acute hemorrhagic edema in an infant]. PMID- 8687065 TI - [Heliodermatitis or photo-induced skin aging]. PMID- 8687066 TI - [Phototherapy of atopic dermatitis]. PMID- 8687067 TI - [Is there any indication for general cortisosteroid therapy in urticaria?]. PMID- 8687068 TI - Training in surgical outpatients. AB - The consultants in this department, where the trainees are predominantly SHOs, organise their outpatient clinics such that one consultant sees mainly new patients (A), another mainly follow-up patients (C) and the third a mixture (B). A prospective audit was conducted to assess the impact of these different arrangements on training. Details of the training received were recorded at 32 consecutive clinics. A training episode (TE) occurred if the trainee and consultant jointly reviewed, or directly discussed, the patient in the clinic. A total of 550 patients attended and trainees were involved with 254 (46 per cent). A TE occurred in only 88 (16 per cent). The 235 (43 per cent) new patients produced 66 (28 per cent) TE and the 315 follow-up patients 22 (7 per cent) TE. Seventeen of 46 (37 per cent) procedures were a TE. The TE for the individual consultants were (new and follow-up): A 0, 8 (7 per cent); B 19 (22 per cent), 7 (8 per cent); C 47 (57 per cent), 7 (6 per cent). Outpatient training was greatly influenced by clinic organisation. Follow-up patients, who often have complex problems, rarely generate a TE. Training in surgical outpatients has not received the same attention as operative training and this deficiency needs to be addressed. PMID- 8687069 TI - Curricular training and the new deal. AB - There is concern that the shortened period of training to be introduced for the new Specialist Registrar Grade is incompatible with the limitation of hours of work required by the New Deal. Surgeons in training may require more experience than other specialties but the Calman proposals introduce the concept of a structured curricular training which will mean a radical change in the way that surgical training is delivered. The changes will be uncomfortable and may need to be modified in the light of experience but the end-result will be worthwhile and should be achievable within the new time constraints. PMID- 8687070 TI - The computerised surgical logbook: why bother? AB - Many people find computers intimidating. Even those happy to use a word processor will often steer clear of database programs since they are often regarded as only useful to people who have special expertise with computers. In fact, this is no more true for databases than it is for word processors. Anyone who can handle the latter can easily reap the many benefits of putting their surgical logbook onto a database program. The author explains what a database is, why he believes it is a good idea to use one to computerise surgical logbooks and how to go about doing it. PMID- 8687071 TI - Paediatric surgical manpower in the 1990s. AB - An accurate audit of consultant manpower in paediatric surgery in the UK was performed based on two surveys carried out in 1992 and 1994. There were 70 paediatric surgeons in 1992 and 84.5 in 1994 (a 21 per cent increase). The ratio of paediatric surgeon per population was approximately 1 in 800,000 for the UK although marked regional differences were noted. The expressed aim of the British Association of Paediatric Surgeons is to achieve a ratio of 1 per 500,000 population which implies a further increase to about 110 consultant posts in the UK. It will be necessary to plan for a commensurate increase in the number of training posts in this specialty. PMID- 8687072 TI - A survey of post-operative care after day case surgery. AB - A prospective survey of patients undergoing day surgery was performed with the main aim of identifying the need for post-operative follow-up after minor or intermediate surgery. The degree of patient satisfaction and the increased workload that this group of patients caused general practitioners was also analysed. Patients underwent either varicose vein surgery, inguinal hernia repair or vasectomy and were asked to return a prepaid reply questionnaire two weeks after surgery. Ninety-eight patients were recruited into the survey, 89 (90.8 per cent) correctly completed forms were returned. Of these patients 58 (69 per cent) believed that they would not benefit from an outpatient appointment, 19 (21.3 per cent) made one or more visits to their general practitioner but had no continuing problem at two weeks postoperation. Six (6.7 per cent) continued to have a problem and thought they would benefit from a surgical outpatient appointment. Of the five patients given routine follow-up appointments before discharge four expected no benefit from an outpatient appointment and only one wished to be seen. This survey suggests that patients should be given the option of an outpatient appointment after minor or intermediate surgery via a postal questionnaire. Unnecessary appointments would thereby be reduced. PMID- 8687074 TI - Vascular surgery at the crossroads. PMID- 8687073 TI - Preiskel Elective Prize. The role of sugar in wound healing. A comparative trial of the healing of infected wounds using traditional gauze/antiseptic packing, and granulated sugar, undertaken during an elective period at Kagando Hospital, Uganda. PMID- 8687075 TI - Thrombogenesis. AB - Thrombosis occurs when there is a breakdown in the balance between thrombogenic factors and protective mechanisms. The thrombogenic factors may be exogenous (e.g. trauma, surgery), endogenous (e.g. cancer, vascular diseases) or both (e.g. atherosclerosis, complicated pregnancy). Defects in the protective mechanisms may be congenital (e.g. factor V R506Q-mutation, deficiency of protein C, protein S or antithrombin) or acquired (e.g. lupus anticoagulans, deficiency of antithrombin in nephrosis). In recent years, research in thromboembolic diseases has been overwhelmed with new observations, rendering it worthwhile to put efforts into the evaluation of thrombotic mechanisms in individuals suffering from or predisposed to thromboembolic diseases. Such efforts will pave the way for more effective prophylaxis in thrombosis-prone patients, more specific treatment of thrombotic diseases, and the mastering of recurrent thrombosis. PMID- 8687076 TI - Clinical distinction of acute and acute on chronic leg ischaemia. AB - The importance of the distinction between acute embolic ischaemia and acute on chronic ischaemia caused by a thrombus superimposed on an arteriosclerotic stenoses has been emphasized during the recent years, as the differentiation should affect the choice of surgical treatment. A retrospective attempt was made to differentiate between acute ischaemia (AI = embolism) and acute on chronic ischaemia (AOCI = thrombosis) of the leg by categorizing the patients according to the clinical characteristics they presented. The material consisted of 194 ischaemic lower limbs of 189 patients who underwent a balloon-catheter thromboembolectomy because of sudden arterial occlusion. The retrospective diagnosis of AI was made in 94 (48%) and AOCI in 69 (36%) cases. The preoperative assessment could not be done in 43 (22%) patients by surgeon working at the emergency room. The retrospective distinction was impossible in 31 (16%) patients. The preoperative diagnosis was in better agreement with the retrospective category when AI, as opposed to AOCI, was the aetiology of occlusion (70% vs 46%). The results of the present study emphasize the difficulties of clinical assessment. These findings suggest a routine angiography as an evaluative tool in the planning of optimal management especially as most of the patients today can be treated simultaneously by thrombolysis. PMID- 8687077 TI - Thrombolysis in extremital arteries--indications and methods. PMID- 8687078 TI - The results of arterial thrombolysis. PMID- 8687079 TI - Selection of treatment in acute ischaemia. PMID- 8687080 TI - Percutaneous transluminal angioplasty in critical limb ischaemia. AB - To determine the utility of percutaneous transluminal angioplasty (PTA) in the treatment of chronic critical lower-limb ischaemia, a prospective study of 103 consecutive patients (117 limbs) was performed. A total of 209 lesions were treated in the iliac (n = 4), femoropopliteal (n = 121), and intrapopliteal (n = 84) arteries. The follow-up time was 1-36 months (mean 12 months). The technical success rate was 92% for stenosis and 80% for occlusion. The cumulative limb salvage rate was 56% at one year, 49% at two years and 49% at three years. The following factors correlated favourably with limb salvage in Cox multiple regression analyses: a small number of diseased lower-limb vessels (one to five vs six to eight) and treated lesions per limb (one to two vs three to five), peripheral runoff after PTA (at least one patent calf vessel vs none) and an occlusion as the successfully treated lesion (instead of stenosis). PMID- 8687081 TI - Local intra-arterial thrombolysis in limb-threatening ischaemia. AB - The purpose of this study was to determine the angiographic and clinical success rate and the immediate limb salvage and mortality rate after intra-arterial thrombolysis in limb-threatening ischaemia. A retrospective study of 66 patients treated with intra-arterial thrombolysis for 71 episodes of limb-threatening ischaemia was carried out. Immediate angiographic recanalisation rate, pre- and post-treatment ankle-brachial index (ABI) and clinical stage were established. Major amputations and deaths were recorded. The immediate primary angiographic recanalisation was complete in 25 cases and partial in 20 cases. Combined complete plus partial recanalisation rate was thus 63.4% (45/71). The overall mean ABI after treatment was significantly higher than before treatment (0.35 versus 0.68), excluding patients undergoing amputation. Clinical improvement was achieved in 59.2% of cases for one month after treatment. The amputation rate was 18.3% during the first month and 29.6% during the median follow-up of 16 weeks. The mortality rates were 6.1% and 33.3% respectively. Despite a high mortality the complications of thrombolysis were few emphasizing the relative safety of this method in treating limb threatening ischaemia. Furthermore, thrombolysis may identify the underlying pathology, which can be corrected by additional surgery or interventional procedure. PMID- 8687082 TI - Thrombolytic treatment of acute on chronic leg ischaemia. AB - The efficacy of thrombolysis was retrospectively studied in patients with acute on chronic ischaemia in the lower extremity. A total number of 68 thrombolytic treatments were given to 65 patients, 58 (85%) because of native arterial occlusions and 10 (15%) because of occluded grafts. Tissue plasminogen activator was the lytic agent used in all patients. In native arteries, thrombolysis alone was successful in 15 (52%) out of 29 legs, whereas 22 (85%) out of 26 thrombolyses followed by angioplasty or surgery were effective. Thrombolysis alone was successful in two and failed in five out of 10 occluded grafts. Patency was achieved by combination with surgery in the other three cases. Twelve-month patency was 34% after thrombolysis alone and 69% (P < 0.05) when combined with surgery or angioplasty. The 30-day mortality rate was 9%. Thrombolysis can be used alone in acute on chronic ischaemia in the lower extremities. The immediate and the long-term results are clearly improved when thrombolysis is combined with angioplasty or reconstructive surgery to treat the underlying cause. PMID- 8687083 TI - Acute leg ischaemia--a case for the junior surgeon? AB - OBJECTIVE: To evaluate the change in the type of acute leg ischaemia and the outcome of its treatment in relation to the experience of the surgeon responsible for the treatment. DESIGN: A 12-year (1980-1991) retrospective study based on hospital records and population vital statistics. SETTING: A defined population of 165,000 served by one central hospital (CH) and two district hospitals (DH). SUBJECTS: 282 interventions performed for acute leg ischaemia. MAIN OUTCOME MEASURES: Type of leg ischaemia, reintervention, amputation and survival rates in relation to the type of ischaemia, treatment and surgical expertise. RESULTS: Thrombotic acute ischaemia increased by 91% and graft occlusions by 130% while embolisation numbers remained unchanged during the period. With junior, general and vascular surgeons operating on acute ischaemia, the respective 30-day amputation rates were 25%, 18% and 9%. Postoperative mortality was 29%, 33% and 8% respectively. The reconstruction rate for the vascular surgeon was 67% with 33% thrombectomies, while the figures for junior surgeons were 2% and 98% and for senior surgeons 6% and 94%. CONCLUSION: Mortality and amputation rates in acute ischaemia are high. By judicious use of different treatment modalities, as judged by vascular surgical experience, better limb salvage rates may be achieved especially in patients with acute on chronic ischaemia. PMID- 8687084 TI - Day surgery--the future. AB - Day surgery is a cost effective, quality approach to treatment which has expanded rapidly in recent years. Changes in attitude and the introduction of new technology will ensure its future growth as long as the purchasers of health care do not focus only on its cost savings aspect but equally concentrate on its quality benefits. PMID- 8687085 TI - Laparoscopic Nissen fundoplication. Initial experience. AB - Fifty-two patients underwent laparoscopic Nissen fundoplication. Oesophagogastroscopy, ambulatory 24-hour pH-recording and oesophageal manometry were evaluated both preoperatively and at follow-up. Forty-seven operations were completed laparoscopically, five were converted to laparotomy. There was no mortality, but minor postoperative complications occurred in four patients. The mean hospital stay after a laparoscopic operation was three days and sick leave 14 days. After three months, 94% of the patients were free of reflux symptoms, oesophagogastroscopy showed normal findings in 95% of the patients and oesophageal 24-hour pH-values were normal in 95% of the patients. Dysphagia (28%) and gas bloating (17%) were the most frequent postoperative complaints. A total of 94% of the subjects were satisfied with the result. Our initial experience of laparoscopic Nissen fundoplication shows that the operation is safe and efficient in the treatment of gastro-oesophageal reflux disease. PMID- 8687086 TI - Effectiveness of autologous blood transfusion in patients undergoing radical hysterectomy. AB - Autologous blood transfusion (ABT) is a safe and useful procedure in patients undergoing elective surgery, but it has not been recommended for radical hysterectomy with pelvic lymphadenectomy. We retrospectively evaluated the results of an ABT programme in 146 consecutive women undergoing radical hysterectomy and pelvic lymphadenectomy for cervical carcinoma at our institution. Forty women underwent autologous blood transfusion after predeposit; 23 underwent preoperative normovolemic haemodilution; 38 were eligible but could not receive autologous blood transfusion for logistic reasons; 45 were excluded for medical reasons. 126 units of blood were collected, of which 100 (80%) were reinfused. The donation procedure was well-tolerated and no transfusion reaction was observed. Homologous blood transfusion was needed in 13% of patients receiving predeposit or haemodilution (8/63), in 42% of patients that were eligible but not receiving autologous blood transfusion (16/(38), and in 71% of non-eligible patients (32/45). The total number of units of homologous blood required for transfusion was lower in patients undergoing predeposit or haemodilution (14) than in those included in the observation arm (43). Autologous blood transfusion is a safe practice which greatly reduces the need for homologous blood transfusion, and radical hysterectomy with pelvic lymphadenectomy represents an adequate indication for this procedure, as the majority of deposited blood is actually reinfused. PMID- 8687087 TI - Four-year survival after hip fractures--an analysis in two Finnish health care regions. AB - We studied the survival of 390 patients with fresh hip fractures sustained in 1989 by a population of about 441 thousand in two health care regions in Finland during four years. The most significant explanatory factors of mortality were place of injury, place after primary treatment and age. The excess mortality of men compared with the reference population at one year was 21% and in women 16%. After this, the excess mortality rates increased slowly in both sexes and were 37% for men and 24% for women at four years. In those who had sustained the fracture in a traffic accident the mortality at four years was slightly lower than that in the reference population, and in those who had sustained the fracture in other accident outdoors there was a 10% excess mortality. Patients who had sustained the injury at home had at four years a 25% and those who had sustained the injury in institutions a 46% excess mortality. The excess mortality at four years was lowest in those who were discharged home (14%) and highest in those who were discharged to other institutions (27%). PMID- 8687088 TI - The value of osteosynthesis in the treatment of bimalleolar fractures. AB - A total of 69 patients with displaced bimalleolar fractures were treated by open reduction and internal fixation, 35 using AO/ASIF implants and 34 using biodegradable self-reinforced polyglycolide or polylactide devices. A third group consisted on 35 patients who were treated non-operatively. The result of treatment was evaluated after a minimum follow-up time of twelve months. A would infection complicated the course in four patients treated with AO/ASIF implants. A transient local fluid accumulation was seen in two patients with biodegradable implants. Four patients under non-operative treatment suffered redisplacement of the fracture. In conclusion, biodegradable internal fracture fixation devices proved to be a valuable new method for the treatment of displaced ankle fractures. PMID- 8687089 TI - One dose cefuroxime prophylaxis in hip fracture surgery. AB - One 3 g intravenous dose of cefuroxime during the induction of anaesthesia was administered randomly in a series of 162 consecutive hip fractures. The overall infection rate was 8.0%, and 2.4% for deep infections. The number of infections was seven in the prophylaxis group and six in the control group. The percentage of deep infections was 3.9 and 1.4, correspondingly. Antibiotic prophylaxis given did not seem to have an effect on the infection rate. PMID- 8687090 TI - Combined treatment with thymosin-alpha1 and low-dose interferon-alpha after ifosfamide in non-small cell lung cancer: a phase-II controlled trial. AB - 22 patients with advanced non-small-cell lung cancer were randomized to receive chemotherapy (ifosfamide) or chemotherapy followed by thymosin alpha1 + low-dose IFNalpha. Chemo-immunotherapy induced an enhanced response rate compared with chemotherapy alone (33% and 10% respectively). Although these differences were not significant, the difference in time to progression was (p=0.0059). CD4+, CD8+ and NK cell counts were significantly depressed after two cycles of chemotherapy, while no difference in cell count were seen in chemo-immunotherapy treated patients. Hematologic toxicity was reduced by the immunotherapy, with no grade 3/4 toxicity seen compared to 50% in patients treated with chemotherapy alone. PMID- 8687092 TI - Comparative prognostic value of Cathepsin D and urokinase plasminogen activator, detected by immunohistochemistry, in primary breast carcinoma. AB - The lysosomal protease Cathepsin D and the serine protease urokinase plasminogen activator (uPA) are suspected to indicate poor prognosis in primary breast carcinoma. We tested Cathepsin D and uPA immunohistochemically in 281 surgical specimens of primary ductal infiltrating breast carcinomas. Staining was evaluated, taking intracytoplasmic immunoreactions into account, in tumour cells and tumour infiltrating macrophages. Positivity was established in 48.4% and 58.0% of tissue samples for cathepsin D and uPA respectively (co-expression: 67.6%). In patients with cathepsin D- or uPA-positive tumours, relapses were more frequent and disease-free survival was shorter irrespective of nodal status, receptor status or menopausal status, (median observation time 74 months). However, this trend was statistically significant only for cathepsin D. With stepwise cox regression analysis, borderline significance (p = 0.07) was calculated for cathepsin D only in node-negative patients. The combination of cathepsin D with uPA measurements did not enhance its prognostic value. Immunohistochemical detection of Cathepsin D could potentially be used to identify patients with poor prognosis in the group of node negative breast cancer patients. PMID- 8687091 TI - Prognostic significance of routine clinical and laboratory data in advanced head and neck cancers. AB - Predictive factors for toxicity and response to chemotherapy in patients with advanced head and neck cancer are seldom reported. Therefore, from a short series of patients with a histologically proven cancer, who were treated by a neo adjuvant protocol with cisplatin and fluorouracil, routine clinical and laboratory data were investigated. ALT (alanine aminotransferase) and Hb (hemoglobin) appeared to be predictive for efficacy. By multivariate analysis (principal component analysis), these laboratory data were involved in two independent axes: one which was considered as "inflammatory" and the other as "hepatic". Initial obesity indices were associated with the former. The predictive variables for toxicity (i.e. age, serum creatinine level, weight loss and plasma cisplatin) were probably biased in this series. Nevertheless cisplatin concentration regularly increased in each cycle. Hence it was dependent on the rank of the course. According to this preliminary study, it would be of interest to conduct future investigations on acquired protein-energy malnutrition, as well as on selected soluble mediators of cellular and humoral immune response. PMID- 8687093 TI - Allogeneic bone marrow transplantation: acute and late complications. AB - Allogeneic bone marrow transplantation (BMT) following high-dose marrow-ablative chemoradiotherapy, has been established as the treatment of choice for various hematologic, neoplastic, and congenital disorders. This procedure is performed to restore lymphohematopoiesis in patients with bone marrow failure states, to replace a diseased marrow by a healthy donor marrow, and as "rescue" to reconstitute lymphohematopoiesis following marrow-ablative chemoradiotherapy to eradicate a malignancy. Only 30 percent of patients requiring marrow transplantation have an HLA-compatible sibling and very few patients have an identical twin donor (syngeneic graft). Over the past few years, marrows from unrelated HLA-compatible donors have been used with increasing frequency and promising outcome in certain hematologic malignancies. Infectious complications, graft-versus-host disease, veno-occlusive disease of the liver, leukemic relapse, and graft failure, remain major obstacles adversely affecting the outcome of patients undergoing allogeneic BMT. Despite these complications, allogeneic BMT remains a highly successful therapeutic procedure associated with a 20% to 90% long-term disease-free survival in a variety of patients. PMID- 8687095 TI - Red blood cell glutathione levels in lung cancer patients treated by radiation and continuously infused carboplatin. AB - Intrinsic resistance in non-small cell lung cancer (NSCLC) curtails the efficacy of chemotherapy and radiotherapy. Glutathione (GSH) may be one of the factors responsible for this phenomenon as it counteracts the cytotoxic effects of platinum containing drugs and radiation. GSH levels were studied in red blood cells of seven smoking patients with NSCLC treated with continuously infused carboplatin and concomitant radiotherapy for 6 weeks. The levels of red blood cell GSH remained unchanged during prolonged combined treatment and were similar to those in non-smoking volunteers. In vitro, in a cell-free system, it was demonstrated that GSH-platinum complex formation occurred with both cisplatin and carboplatin in a time-dependent manner and that this formation decreased total GSH as measured with Tietze's method. This implies that increased consumption of GSH by platinum and free radicals produced by carboplatin and radiation, respectively, seems to induce GSH in red blood cells resulting in an unchanged total GSH level. Although GSH in red blood cells may be relevant as a detoxification pool for platinum, it had no impact on response rates in these patients with NSCLC. PMID- 8687094 TI - Node-negative breast cancers with p53(-)/HER2-neu(-) status may identify women with very good prognosis. AB - BACKGROUND: The contribution of p53 and HER-2/neu to the management of node negative breast cancer (NNBC) could be improved by combining their results. MATERIAL AND METHODS: We studied paraffin-embedded primary tumors for p53 (BP-53 12-1) (n=57) and HER2/neu (pAB1) (n=63) from NNBC patients. The results were grouped in a negative (p53(-)/neu(-)) versus a positive group (one or both overexpressed). The association between both groups (negative and positive) and clinicopathologic parameters, S-phase fraction and DNA ploidy, and patients' outcome, was analyzed. RESULTS: In 28% of the tumors p53 was overexpressed, and HER2/neu in 11%. Sixty-five percent (37 out of 57) were p53(-)/neu(-), and 35% overexpressed one (31.5%) or both (3.5%) oncoproteins. Significant correlations were found between p53(-)/neu(-) tumors and age greater than 50 (p=0.003), S phase fraction lower than 7 (p=0.03), and positive estrogen receptor contents (p=0.049). Actuarial 5-year disease-free and overall survival for p53(-)/neu(-) tumors were 88% and 97%, respectively, versus 50% and 66%, for tumors overexpressing one or both oncoproteins (p=0.004). PMID- 8687096 TI - Increase of genital human papillomavirus infection among men and women in Croatia. AB - The presence of genital human papillomavirus (HPV) among men and women in Croatia was investigated from 1990 to 1993. DNA obtained from 338 cervical and 79 male urethral scrapes was analysed by slot-blot hybridization with digoxigenin labeled HPV type 6, 11, 16 and 18 DNA probes. The prevalence of HPV infection was higher in the male population (26.6%) than in the female population (19.8%). Low risk HPV (HPV 6, 11), high risk HPV (HPV 16, 18) and indeterminate HPV were found in 5.3%, 6.9% and 8.8% cases, respectively. Over the years, the increase (from 4.9% to 37.6%) of HPV infection was almost equal in male and female population suggesting an epidemic feature of this sexually transmitted disease. PMID- 8687097 TI - Expression of the retinoblastoma gene product in renal tumors. AB - BACKGROUND: Alterations in the retinoblastoma (Rb) gene and its protein product have been detected in numerous solid tumor malignancies. Loss of Rb function is believed to contribute to neoplastic transformation or to the development of metastases. To define the role of Rb in renal cancer, we analyzed renal tumor specimens for molecular alterations in the Rb gene and for lack of Rb protein expression, and correlated the results to clinicopathological characteristics. MATERIALS AND METHODS: Thirteen renal cancer cell lines, 62 primary renal tumors, and 5 metastatic renal cancers were studied by Southern blot analysis for defects in the Rb gene, and by immunohistochemistry for Rb protein expression. Results were correlated with histopathological parameters and patient survival. RESULTS: Structural alterations in the Rb gene were not detects in any of the renal cancer cell line or primary renal tumors studied. A rearranged Rb gene was observed in 1/5 metastatic tumor specimens. Western blot analyses revealed a truncated Rb protein in one of 13 renal cancer cell lines; immunohistochemical analysis revealed Rb protein in all papillary and oncocytic tumors, and in 39/44 non papillary tumors. Rb expression patterns did not correlate with pathological stage, histological grade or the development of metastatic disease. CONCLUSION: Molecular alterations of the Rb gene are infrequent (<2%) in renal cancers, and Rb protein is present in the majority of primary (92%) and metastatic (100%) renal tumors. Loss of Rb expression does not appear to significantly contribute to malignant transformation or progression of renal cancers. PMID- 8687098 TI - Human prostate carcinoma cell lines secrete GM-CSF and express GM-CSF-receptor on their cell surface. AB - Using specific ELISA kits, we investigated the secretion of cytokines in five human prostate carcinoma cell lines: ALVA 31, DU145, LNCaP, ND1 and PC3. Three of the five cell lines investigated secreted granulocyte-macrophage colony stimulating factor (GM-CSF); GM-CSF was not identified in ALVA31 or LNCaP. In addition, we have shown that conditioned media of DU145, ND1 and PC3 stimulated proliferation of the GM-CSF-dependent cell line MO7e indicating that these cells secrete biologically active GM-CSF. By flow cytometric analysis we determined that all five cell lines expressed the alpha-subunit of the GM-CSF receptor on the cell surface but only ALVA31 expressed both the alpha- and beta-subunits of the GM-CSF receptor. Varying concentrations of GM-CSF did not stimulate the proliferation rate of any of the prostate carcinoma cell lines. Thus, there does not appear to be autocrine loop of GM-CSF-induced proliferation. However, the expression of E-cadherin and endoglin (CD105) was modulated under GM-CSF treatment in ALVA31. In addition, GM-CSF decreased the level of soluble CD44 in ND1. These results suggest that the GM-CSF receptor alpha-subunit may play a role in metabolic activity of prostate cancer. PMID- 8687100 TI - Induction of cell death by Doxorubicin in multicellular spheroids as studied by confocal laser scanning microscopy. AB - In the present study the effects of the anticancer drug Doxorubicin (Dox) on necrosis development and cell lethality of multicellular DU-145 spheroids (MCS) were examined. Multicellular spheroids consist of a peripheral rim of proliferating cells, a inner shell of nonproliferating, quiescent cells and a central core of dead cells. After the application of Dox for different time periods dead cell areas and single dead cells in MCS of different size classes were identified using a set of lethal fluorescence dyes, and a confocal laser scanning microscope (CLSM). The distribution of Dox within MCS was examined by determining Dox fluorescence in single cells and cell areas. Outgrowth experiments were performed to show the effects of Dox on cancer cell migration and cell proliferation. The application of low (400 nM) concentrations of Dox over a time period of 2hours resulted in distinct Dox fluorescence staining of the most peripheral cell layers of the MCS. After long term incubation (48hours) cell lethality was most prominent in large spheroids (diameter between 350 and 800 micron) which possess a dead cell core and single dead cells at the periphery. These MCS showed an approximately 120 microm +/- 30 microm increased dead cell core as compared to control MCS. The cytotoxic effect of Dox was lower in MCS of a diameter between 150-350 microm and nearly no cytotoxic effects were found in spheroids smaller than 150 microm in diameter. Dox fluorescence persisted in dead cells for at least three days. During this time the cytotoxic agent leaked slowly from dead cells and penetrated into the layers of quiescent cells and proliferating cells mediating a prolonged cytotoxicity. In conclusion, the most efficient cytotoxic effect on MCS larger than 150 microm in diameter, can be achieved using a Dox concentration of 400 nM, and applying the drug for long incubation periods to allow its accumulation and storage in the dead cell core and in the single dead cells within vital cell layers. Dox is gradually delivered from these storage sites and kills proliferating and quiescent cells when no Dox is present in the external medium. PMID- 8687099 TI - Immunohistochemical determination of glutathione S-transferases in gastric carcinomas and in adjacent normal gastric epithelium. AB - Glutathione S-transferases (GSTs) are a family of isoenzymes that play an important role in protecting cells against cytotoxic and carcinogenic agents. The distribution and levels of GST Alpha and Pi in normal and malignant gastric tissue of 34 patients with gastric cancer were examined immunohistochemically. Expression of GST Alpha and Pi was observed in 47 and 100 percent of the tumors, respectively. In normal mucosa both enzyme classes were present in 100 percent of the specimens. Mucous cells showed staining for GST Alpha and Pi in 88 and 97 percent, parietal cells in 93 and 67 percent, and chief cells in 82 and 30 percent, respectively. No correlation was observed between the amount or pattern of GST Alpha or Pi in carcinomas and the clinical and pathological characteristics of the patients. So it can be concluded that both GST Alpha and Pi cannot be considered as prognostic factors for gastric cancer. PMID- 8687101 TI - beta 1-Integrin expression and function in human bladder cancer cells: modulation by TNF alpha. AB - Cytofluorimetric and biochemical analysis in two different grade human bladder cancer cell lines showed that G3 EJ cells exhibited higher levels of alpha5beta1 and alpha6beta1 heterodimers, and the G2 RT112 cell line higher levels of alpha2beta1. Alpha6/beta4 receptor was detected only in RT112 cells. Adhesion assays with extracellular matrix proteins indicated that both cells bound to fibronectin, laminin and collagen 1, the adhesive properties being related to the integrin profile. Inhibition tests revealed that alpha5beta1 mediated adhesion to fibronectin, alpha3beta1 and alpha6beta1 to laminin, and that alpha2beta1 was the main mediator of adhesion to collagen I in both cell lines. In EJ but not in RT112 cells, tumor necrosis factor-alpha induced the upregulation of alpha2, which mediated increased adhesion to collagen I. The different effects of TNFalpha on the two cell lines were not attributable to differences in tumor necrosis factor responsiveness, as both cells expressed comparable levels of tumor necrosis factor receptor-1 and the tumor necrosis factor-inducible intercellular adhesion molecule-1. PMID- 8687102 TI - The NF-kappaB transcription factor in oncogenesis. AB - The NF-kappaB transcription factor complex is a pleiotropic activator that participates in the induction of a wide variety of cellular and viral genes. The active complex is composed of two subunits designated NFKB1 and RelA (formerly called p50 and p65, respectively). Binding sites for NF-kappaB are present in the promoter region of many cell adhesion molecules, cytokines and growth factors. Antisense inhibition of the individual subunits of NF-kappaB exerted differential effects on cell adhesion. Antisense phosphorothioate oligomers to relA but not NFKB1 caused a rapid inhibition of cell adhesion in diverse cell types. Antisense relA oligomers exerted antigrowth effects on diverse transformed cells in vitro and caused a pronounced inhibition of tumorigenicity in nude mice tumor models. Stable transfectants of a fibrosarcoma cell line expressing dexamethasone inducible antisense RNA to relA also showed inhibition of in vitro growth and in vivo tumor development. In response to inducible expression of antisense RNA, a pronounced tumor regression was seen in nude mice. Use of a "decoy" approach to inhibit RelA function directly also caused inhibition of tumor cell growth in vitro and in vivo. Our results indicate that key regulatory molecules such as transcription factors can be selectively targeted for therapeutic intervention in cancer. PMID- 8687103 TI - Antineoplastic activities of alpha-, beta-, and gamma-alkylaminopropiophenone derivatives in mice and in murine and human tissue culture cells. AB - A number of alpha-, beta-, and gamma-alkylaminopropiophenone derivatives were found to be potent antineoplastic agents in CF(I) mice by inhibiting the growth of Ehrlich ascites carcinoma at 8 mg/kg/day and in vitro cytotoxic agents against murine and human cancer cell growth. Two analogs, beta-dimethylaminopropiophenone (1) and beta-pyrrolidinopropiophenone (3), were further tested for their in vitro effects on the metabolism of Tmolt3 cells. beta-Dimethylaminopropiophenone demonstrated potent reduction of DNA synthesis, RNA synthesis, and the pool levels of the dNTPs. Enzyme activities, such as DNA polymerase a, ribonucleotide reductase, PRPP amidotransferase, and most significantly, dihydrofolate reductase, were reduced by the agents from 25 to 100 microM after 60 min. PMID- 8687104 TI - Relationship between resonance energy per pi-electron and carcinogenicity in arenes. AB - The resonance energy per pi-electron of various arenes was calculated using Aihara's TRE theory. There seemed to be a correlation between the resonance energy volume per pi-electron of the cation species (lacking a carbon atom) with the highest approximate superdelocalizability (Sr'(E)) from the parent skeleton and carcinogenicity, i.e. the induction of cancer by arenes (three-ring, four ring, five-ring, six-ring and seven-ring) seems to be dependent on the resonance energy per pi-electron in they contain). PMID- 8687105 TI - Biological activities of phthalocyanines. XVII histopathologic evidence for different mechanisms of EMT-6 tumor necrosis induced by photodynamic therapy with disulfonated aluminum phthalocyanine or photofrin. AB - The necrosis of EMT-6 mammary murine tumors induced by photodynamic therapy (PDT) with Photofrin (PII) or disulfonated aluminum phthalocyanine (AlPcS2) was studied. Attention was given to the spontaneous evolution of angiogenesis and necrosis of such tumors in order to determine the most appropriate moment for treatment. On day 6 after tumor cell inoculation, mice were injected with photosensitizer followed by exposure to red light 24 h later, at which time optimal dye concentrations were reached in the tumor. Animals were sacrificed 3 h or 24 h after illumination and tissues were prepared for histology. Prominent cytopathic alterations were already observed at 3 h and there was massive necrosis at 24 h. In the case of PII vascular damage, congestion and hemorrhage were already present at 3 h and these changes account for the subsequent tumor necrosis through hemorrhagic infarction. With AlPcS2 these early vascular alterations were much less evident and only focal at 24 h, suggesting that AlPcS2 PDT mediated tumor necrosis involves to a large extent direct tumor cell damage. PMID- 8687106 TI - Differentially spliced exon 5 of the Wilms' tumor gene WT1 modifies gene function. AB - The Wilms' tumor gene WT1 encodes a zinc-finger transcription factor that functions as a tumor suppressor gene and repress transcription of a number of growth factors and proto-oncogenes. In the developing kidney, WT1 expression peaks at the onset of the mesenchyme-to-epithelium transition and is required for epithelial differentiation. WT1 mRNA undergoes alternative splicing at two sites, resulting in four mRNA species and proteins expressed in constant ratios. The first alternative splice results in the presence or absence of exon 5, which is 51 nucleotides long and encodes 17 amino acids between the amino-terminal, proline-rich transcriptional repression domain and the carboxy-terminal DNA binding zinc-fingers. We used cell-proliferation assays to determine the effect of exon 5 on WT1 function. Isoforms of WT1 without exon S repressed cell growth. WT1 isoforms with exon 5 slowed cell growth to a lesser extent but resulted in altered cellular morphology. These results provide evidence that WT1 splice isoforms differentially regulate cell proliferation and initiate the mesenchyme to-epithelium transition during metanephric development. PMID- 8687107 TI - A clinical nude mouse metastatic model for highly malignant human pancreatic cancer. AB - Pancreatic cancer is a highly aggressive and treatment-refractory cancer. A clinically-relevant animal model is necessary to develop therapy for metastatic pancreatic cancer. In this study we evaluated the efficacy of mitomycin C (MMC) and 5-FU against the human pancreatic adenocarcinoma cell line PAN-12 in an orthotopic human metastatic pancreatic cancer nude mice model. The model is constructed by surgical orthotopic implantation (SOI) of histologically intact tumor tissue in the tail portion of the pancreas near the spleen. PAN-12 grew very aggressively in the control group of nude mice with extensive local invasion and distant metastasis to various organs with a propensity for the lung but to other organs as well, including the liver, kidney and regional and distant lymph nodes. In a striking effect none of the mice in the MMC-treated group developed tumor. Although mice in the 5-FU treated group survived statistically significantly longer than those in the untreated control, the overall incidence of metastasis in these mice was equivalent to those in the control. However no liver or kidney metastases were found in the 5-FU treated animals perhaps accounting in part for their longer survival. This "clinical" nude mouse model of highly metastatic pancreatic cancer can now be used to discover new effective agents for this disease. PMID- 8687108 TI - Clinical course of human epithelial-type malignant pleural mesothelioma replicated in an orthotopic-transplant nude mouse model. AB - Malignant pleural mesothelioma is an aggressive tumor that is essentially unresponsive to standard medical and surgical therapies. Little is actually known about its biologic response to therapeutic interventions, in part because of a lack of a "patient-like" animal tumor model. Most experimental models thus far have been derived from inhalation or inoculation of asbestos fibers into animal subjects or by subcutaneous transplantation of human mesothelial cell lines into nude mice. These models are not representative of clinical malignant pleural mesothelioma. In this report, an animal model of human pleural malignant mesothelioma obtained by orthotopic transplantation of intact pleural tumor tissue into athymic nude mice is described. Pleural tumor obtained by thoracolscopy from a patient with epithelial-type malignant pleural mesothelioma was implanted as intact tissue by surgical orthotopic implantation (SOI) into the right pleural cavity of nude mice. Animals were sacrificed when moribund or 6 months after implantation. Tumor growth and regional spread in the mice evaluated at post-mortem examination mimicked the clinical pattern of progression of human disease. Histologic findings and the immunohistochemical profile were similar to those demonstrated on examination of thoracoscopic parietal pleural biopsy specimens and post-mortem examination of the original patient's tumor. This "patient-like" nude mouse model of epithelial-type malignant pleural mesothelioma, phenotypically similar to the original human tumor, should facilitate future investigation of tumorigenesis and metastatic potential of this neoplasm. The model should serve as a basis for assessing the impact of experimental and existing therapy on malignant mesothelioma. PMID- 8687109 TI - Abnormalities and the implication of retinoblastoma locus and its protein product in head and neck cancers. AB - Abnormalities in the Retinoblastoma tumor suppressor gene (Rb) have been observed in a large number of human cancers. Loss of heterozygosity (LOH) is a common mode of allelic inactivation of Rb and other tumor suppressor genes. We investigated DNA from 45 primary human head and neck cancers to determine LOH at the Rb locus using a polymerase chain reaction-based restriction fragment length polymorphism assay. Of informative cases, we found LOH in 4 of 28 (14%) head and neck cancers. Of immunohistochemical staining of Rb protein, we found that in one of ten LOH negative cases the nuclei of fibroblasts were stained with anti-Rb antibody but there was no nuclear staining tumor cells. These results suggest that inactivation of Rb protein is involved in the carcinogenesis of head and neck cancer at all levels of the process of protein expression: DNA, mRNA and protein. PMID- 8687110 TI - Study of irradiation effects on cytokine secretion from retrovirally-transduced tumor cells: a model for tumor vaccination. AB - We have examined the effects of irradiation on the cytokine secretion from genetically modified human esophageal and gastric carcinomas. Both cell lines were transduced retrovirally to secrete interleukin-2, interleukin-6 and granulocyte-macrophage colony-stimulating factor, respectively. The metabolism of all the transduced cells was partially inhibited by 6 Gy, and greatly inhibited by 20 Gy irradiation. Cytokine productions, however, was not affected by 6 Gy in many cases, and continued to be detected even after 60 Gy irradiation. The analysis of the dose and time of irradiation in each cytokine producer is useful for the designing of tumor vaccine using cytokine gene transfer. PMID- 8687111 TI - Selective induction of mucosal immune responses to 2-acetylaminofluorene. AB - Mucosal vaccination with chemical carcinogens coupled to enterotoxins such as cholera toxin (CT) can elicit carcinogen-specific immunoglobulin secretion into the intestinal lumen. The present study examines the ability of several related bacterial enterotoxins and their subunits to act as adjuvants or carrier proteins in stimulating an intestinal secretory IgA (S-IgA) response to 2 acetylaminofluorene (AAF). Using Thiry-Vella loops in rabbits, CT, cholera toxin B subunit (CTB) and the recombinant B subunit of the heat labile enterotoxin from E. coli (rLTB) were all found to be effective carrier proteins and adjuvants for eliciting S-IgA anti-AAF. However, marked differences in the ratio of mucosal S IgA to serum IgG production were observed. CT elicited the highest luminal S-IgA anti-AAF titers as well as the highest ratio of intestinal S-IgA/serum IgG when used as an adjuvant. Conversely, rLTB elicited a high serum IgG anti-AAF titer but only a modest intestinal S-IgA response. Dialysis studies using monoclonal IgA versus IgG anti-AAF on opposing sides of a semipermeable membrane demonstrated the potential importance of the intestinal S-IgA/serum IgG ratio. A high "intestinal" IgA/"serum" IgG ratio abolished carcinogen transfer to the "serum" side of the membrane, while a low ratio enhanced transfer. Thus, to generate an active mucosal immune response capable of blocking carcinogen absorption, the carrier protein or adjuvant should be selected to optimize the intestinal S-IgA/serum IgG ratio. PMID- 8687112 TI - Human cancer detection and immunotherapy with conjugated and non-conjugated monoclonal antibodies. AB - Classical therapeutic modalities such as surgery, radiation and chemotherapy not only fail to cure the majority of neoplastic disease, but their employment also leads to severe and debilitating side effects. The severe cancer related morbidity is often associated with the use of radiation and chemotherapy, making them less than ideal forms of therapy. Entirely new approaches to cancer therapy that are tumor cell directed, and specifically lethal to malignant cells and less toxic to normal tissues are being observed and developed, adhering to the old prayer "Destroy the diseased tissues, preserve the normal." Following the initial advances of Ehrlich, immunotherapy as a fourth modality of cancer therapy has already been developed and proven to be quite effective. Unfortunately, the cancer cell population is not a static entity, but rather a continually changing one. Considerable variations have been determined between individual malignant cells. Our strong belief is that it is necessary for present-day clinical oncologists to become aware of the existence of immunotherapy and learn how to employ it in order to improve the efficacy and decrease the side effects of modern cancer therapy. The development of hybridoma technology and the advances in monoclonal antibody (MoAB) production have revitalized the concept concerning the existence of cancer cell-targeted, specific "magic bullets". In addition, a variety of different agents (e.g. toxins, radionuclides, chemotherapeutic drugs) have been conjugated to mouse and human MoABs for selective delivery to cancer cells. Preclinical observations in athymic, nude mice using xenografted human cancers and mouse, anti-human MoABs were more than impressive and have lead to several clinical trials. Strategies for the employment of MoABs for cancer immunotherapy include: a) Immune reaction directed destruction of cancer cells; b) Interference with the growth and differentiation of malignant cells; c) Antigen epitope directed transport of anti-cancer agents to malignant cells; d) Anti-idiotype vaccines. Phase I studies have established the safety of employing immunoconjugates in humans, but the therapeutic results were less impressive. The clinical use of mouse MoABs in humans is limited due to the development of an anti-globulin immune response to the non-human immunoglobulins by the human host. Genetically engineered chimeric human-mouse MoABs have been developed by replacing the mouse Fc region with the human constant region. Moreover, the framework regions of variable domains of rodent immunoglobulins were also experimentally replaced by their human equivalents. These antibodies can also be designed to have specificities and effector functions determined by researchers, which may not appear in nature. The astonishing immunophenotypic (IP) heterogeneity of cancer cells, the different cytotoxic activity associated with the moiety linked to given MoABs, and mostly the impressive genetic modulation capabilities of cancer cells still remain as yet unsolved difficulties in the present immunotherapy of human cancer. Antibodies with two binding ends (bispecific antibodies) provide a great improvement in targeting cancer cells. The existing inadequacies of MoABs in immunotherapy may also be improved by increasing their efficiency with chemical coupling to various agents such as bacterial or plant toxins, radionuclides or cytotoxic drugs. In writing this review article, one of our main goals is to encourage further clinical research with the use of genetically engineered rodent MoABs and various immunoconjugates in the treatment of human cancer, as well as the combination of such immunotherapy with the three conventional modalities of therapy. Finally, we propose that MoAB-based immuno-therapy be accepted as a conventional form of therapy and employed not only in terminal cancer patients, but also, for instance, during and following surgical resection. PMID- 8687114 TI - Therapeutic potency of transduction with herpes simplex virus thymidine kinase gene against multidrug resistant mouse leukemia cells. AB - In order to examine the therapeutic potency of ganciclovir (GCV) against multidrug resistant tumour cells by transduction with the herpes simplex virus thymidine kinase (HSV-TK) gene, vincristine (VCR)-resistant mouse leukemia P388 cells (P388/VCR) were transduced retrovirally with the HSV-TK gene. In vitro, P388/VCR cells expressing HSV-TK (P388/VCR/TK) were approximately 200-fold more sensitive to GCV than P388/VCR cells. Age-matched CDF1 mice were intraperitoneally inoculated with P388/VCR or P388/VCR/TK cells and were treated with either GCV or VCR. The results showed that VCR had little therapeutic effect against P388/VCR/TK-bearing mice, whereas GCV significantly increased the life span of the mice. These results imply the potential value of HSV-TK gene transduction followed by GCV treatment in killing multidrug-resistant tumor cells. PMID- 8687113 TI - Involvement of intracellular glutathione in induction of apoptosis by cisplatin in a human pharyngeal carcinoma cell line. AB - We investigated the effect of intracellular glutathione (GSH) levels on apoptosis in KB cells induced by cisplatin (CDDP). The mode of cell death, apoptosis or necrosis, was evaluated by biochemical and morphological criteria. The treatment of KB cells with D,L-buthionine-(S,R)-sulfoximine (BSO, a gamma-glutamyl cysteine synthetase inhibitor) decreased GSH level to 1/7th of that of control cells, and augmented cell death induced by CDDP via a necrotic rather than apoptotic process (the ratio of necrosis to apoptosis; n/a>14). In contrast, treatment with 2 oxothiazolidine-4-carboxylic acid (OTZ, a precursor of cysteine) increased GSH levels 1.7 fold compared with that of untreated cells, inhibited cell death induced by CDDP and switched the mode of cell death from necrosis to apoptosis (n/a<0.8, similar to untreated cells). These results suggest that the GSH level affects the cytotoxicity of CDDP and plays an important role in switching the mode of cell death induced by CDDP. PMID- 8687115 TI - Preclinical toxicology and tissue gallium distribution of a novel antitumour gallium compound: tris (8-quinolinolato) gallium (III). AB - Tris (8-chinolinolato) gallium (III) compound (KP46), a new organo-metallic gallium (Ga) complex, has been synthesized for potential use in anticancer therapy. Although this agent has a better bioavailability after oral administration than Ga chloride, it also shows a greater toxicity. The purpose of the present study was to assess the acute and subacute toxicity of KP46, and to determine tissue Ga distribution in healthy Swiss mice. Ga assays were performed by inductively coupled plasma atomic emission spectrometry. In the first experiment, the drug was given by gavage at single doses ranging from 464 to 4640 mg/kg. The LD50 values were 2870 mg/kg (410 mg Ga3+/kg) and 2370 mg/kg (339 mg Ga3+/kg) for males and females, respectively. In the second experiment, KP46 was administered by gavage at 0, 62.5, 125, 250, 500 and 750 mg/kg/day for two weeks (8 animals/dose/sex). The dose of 62.5 mg/kg/day was well tolerated, without deaths, decreased weight gain, or renal, hepatic and hematological toxicities. Higher doses decrease the probability of survival. A significant decrease in the number of white blood cells was noted at doses of 125 mg/kg/day (p<0.05), while hemoglobin, hepatic and renal functions were not affected. At 62.5 mg/kg/day, the Ga concentrations were 7.02 +/- 3.14 microg/g in bone, 3.55 +/- 2.10 microg/g in the liver, 1.81 +/- 0.24 microg/g in the kidneys, 1.77 +/- 1.45 microg/g in the spleen. In lungs, brain, testes and ovaries, the Ga concentrations were under the limit of detection (0.030 ng/g). According to these results, the therapeutic potential of KP46, orally administered, should be evaluated with the dose of 62.5 mg/kg/day. The great affinity of Ga for bone could justify the consideration of KP46 for malignant bone tumours. PMID- 8687117 TI - Establishment of a daunorubicin-resistant cell line which shows multi-drug resistance by multifactorial mechanisms. AB - We established a daunorubicin (DNR)-resistant cell line derived from human leukemia cell line K562, (K562/D1-9), which also shows multidrug resistance (MDR). K562 cells were cultured with serially increasing concentrations up to 1.0 microM of DNR and then cloned by the limiting dilution method. K562/D1-9 cells were found to be 28 times more resistant to DNR than their its parent cells. Intracellular accumulation of DNR in K562/D1-9 was less than in the wild type, and P-glycoprotein (PGP) was overexpressed. Both DNR resistance and its intracellular accumulation were partially reversed by addition of verapamil to K562/D1-9 cells, but not to K562 cells. Topoisomerase II (Topo II) activity was decreased in K562/D1-9 cells. In contrast to other drugs, such as doxorubicin and vincristine, verapamil could not reverse drug resistance to VP-16 in the K562/D1 9 cell line, suggesting the importance of Topo II as the target of MDR. Protein kinase C (PKC) level was higher in K562/D1-9 than in K562. These findings suggested that the mechanism of MDR in this cell line might be multifactorial, including PGP, topo II and PKC. The K562/D1-9 cell line may be a good model for studying drug resistance in leukemia chemotherapy. PMID- 8687116 TI - Xeroderma pigmentosum and molecular cloning of DNA repair genes. AB - Human cells from patients suffering with xeroderma pigmentosum (XP) characterized by extreme sensitivity to UV light and a high incidence of skin tumors fall into seven complementation groups, XPA to XPG, and are lacking a functional helicase, endonuclease, or lesion-recognizing protein involved in the initial steps during nucleotide excision repair (NER); a number of proteins involved in DNA repair are termed XPA to XPG depending on which one is defective in a particular complementation group of XP and include: (i) proteins involved in the recognition of (6-4) photoproducts (XPE) and of a broad range of lesions such as pyrimidine dimers (XPA); (ii) proteins that are DNA helicases and integral parts of the general transcription factor TFIIH functioning in both transcription and repair (XPB, XPD); (iii) endonucleases that perform the two incisions, the XPG incising six nucleotides (nt) to the 3' side from a photodimer and the ERCC1-XPF protein complex incising 22 nt to the 5' side of the lesion; and (iv) single-strand DNA binding proteins (XPC). The ERCC6 helicase is largely responsible for coupling transcription to repair whereas XPC seems to be responsible for the repair of the inactive parts of the genome as well as for the repair of the nontranscribed strand in active genes. p53 recognizes insertion/deletion mismatches as well as free ends of DNA produced by ionizing radiation to arrest the cell cycle. Most of the human DNA repair proteins have their counterparts in both budding and fission yeasts and some of them also in E. coli evoking an evolutionary conservation of DNA repair pathways. Accumulation of mutations within repair genes in single cells followed by their escape from the immune surveillance and in clonal expansion may greatly contribute to the appearance and development of human cancers. PMID- 8687118 TI - Synthesis and cytotoxic activity of peptides containing basic amino acids residues. AB - We synthesized eight peptides containing from three to twenty residues of arginine, lysine and histidine, using an automated synthetiser and Fmoc strategy. All peptides were purified by preparative reverse-phase HPLC and characterized by electrospay mass spectometry. Cytotoxic activity was assessed on HeLa cells. One peptide inhibited the colony-forming ability of tumor cells. PMID- 8687119 TI - Interferon-alpha inhibits the DNA synthesis induced by PDGF and EGF in cultured meningioma cells. AB - The growth of meningioma in vivo may be mediated by a growth factor. We evaluated inhibitory effect of IFN-alpha on DNA synthesis promoted by PDGF and EGF on meningioma cell cultures. Eight cases of meningioma were tested for the expression of PDGF receptor. The effects of PDGF AA, PDGF BB, EGF and TGF-beta1 on five meningioma cell cultures were investigated by measuring 3H-thymidine incorporation during 24 hours of incubation with the growth factors under serum free culture conditions. The incorporation of 3H-thymidine was elevated in all of the five tested tumor cell cultures after the addition of PDGF BB and EGF. Maximal stimulation was observed on three cultures with EGF and two cultures with PDGF BB. Under the same culture conditions, simultaneous incubation with IFN alpha inhibited the 3H-thymidine incorporation promoted by PDGF and EGF. Our results indicate the inhibitory effect of IFN-alpha both on DNA synthesis promoted by PDGF and EGF, and on the meningioma cell proliferation. The present study also demonstrates the inhibitory effect of TGF-beta 1 in meningioma cell culture. PMID- 8687120 TI - Influence of cell membrane potential, and selectivity of the Na+/H+ exchanger and Cl-/HCO3- exchanger on the intracellular accumulation of adriamycin. AB - Intracellular accumulation of adriamycin (ADR) has been reported to be influenced by cell membrane potential. We first evaluated intracellular accumulation of ADR and 3,3'-(di-n-hexyl)-2,2'-oxacarbocyanine iodide (NK-2280), an indicator of cell membrane potential, and found a good correlation between ADR and NK-2280 intracellular accumulation in several cell lines. This suggests that ADR accumulation may be influenced by cell membrane potential or the mechanisms of NK 2280 accumulation may be similar to those of ADR accumulation. Next, we observed the influence of the NA+/H+ exchanger and Cl-/HCO3- exchanger on the intracellular accumulation of ADR and NK-2280, and found that ADR accumulation decreased with increasing concentrations of 3,5-diamino-6-chloro-N (diaminomethylene)pyrazinecarboxamide (amiloride), an inhibitor of the Na+/H+ exchanger, and 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid (DIDS), an inhibitor of the Cl-/HCO3- exchanger, however, NK-2280 accumulation was increased by amiloride, and decreased by DIDS. The increased accumulation of NK-2280 induced by amiloride may be due to the increased cell membrane potential caused by the inhibition of H+ ion efflux and NA+ ion influx due to the inhibition of the Na+/H+ exchanger. The decreased accumulation of NK-2280 may be also due to the decreased cell membrane potential caused by the inhibition of Cl- ion efflux due to the inhibition of the Cl-/HCO3- exchanger by DIDS. However, the decreased rate caused by DIDS was greater than the increased rate caused by amiloride. Therefore, it is suggested that the decreased accumulation of NK-2280 by DIDS may be influenced by other factors apart from cell membrane potential. These results suggest that the Cl-/HCO3- exchanger may be related to both ADR accumulation, and NK-2280 accumulation, and that the Na+/H+ exchanger may be related to ADR accumulation, but not NK-2280. This suggests that the Cl-/HCO3- exchanger is of low selectivity. PMID- 8687121 TI - Advantage of in vivo chemosensitivity assay to detect vincristine-resistance in a human epidermoid carcinoma xenograft. AB - We examined both in vitro and in vivo chemosensitivity of the human epidermoid carcinoma xenograft xeKB3-1-R which shows overexpression of the multidrug resistance gene (MDR1). XeKB3-1-R was sensitive to vincristine (VCR, 6%) and doxorubicin (DOX, 9%) in the adhesive tumor cell culture system in vitro. However, this xenograft showed decreased sensitivity to VCR (65%) and DOX (42%) in an in vivo chemosensitivity assay. The in vivo resistance of xeKB3-1-R to both VCR and DOX was reversed by coadministration of cyclosporin A (VCR 22%, DOX 11%). The xenograft xeKB3-1-R expressed significantly higher levels of MDR1 than xeKB3 1. The results confirmed that multidrug resistance in xeKB3-1-R was related to enhanced MDR1 expression in vivo. The observed discrepancies between in vitro and in vivo chemosensitivities suggest that the in vivo sensitivity assay more accurately reflects drug resistance as a result of low-level MDR1 overexpression in solid tumors. PMID- 8687122 TI - Induction of Ley antigen by 5-aza-2'-deoxycytidine in association with differentiation and apoptosis in human pancreatic cancer cells. AB - We investigated the effect of 5-aza-2'-deoxycytidine (ADC) (a specific inhibitor of DNA methylation) on differentiation, Lewisy (Ley) antigen expression, and DNA fragmentation (a biochemical marker of apoptosis) in human pancreatic cancer MIA PaCa-2 cells. ADC markedly inhibited the growth of MIA PaCa-2 cells. Flow cytometric analysis showed that ADC suppressed the cell population in the G1 phase, but enhanced it in the G2/M phase. On the other hand, several markers of cell differentiation including morphological and biochemical alterations were distinctly induced in cells treated with ADC. Morphologically, the cells were enlarged and thinner than the untreated control cells, and intracellular alkaline phosphatase (ALP) activity was markedly increased. Additionally, biochemical markers of apoptosis including DNA fragmentation and Ley antigen expression were induced in association with the appearance of morphological and biochemical markers of differentiation (ALP). These results suggest that the hypomethylation of DNA is involved in the molecular mechanism of growth inhibition, induction of apoptosis, and differentiation in human pancreatic cancer MIA PaCa-2 cells. PMID- 8687123 TI - Tumor oxygenation: a matter of supply and demand. AB - Development of new approaches to ameliorate tumor hypoxia may require understanding of the relative importance of supply vs. demand. On the demand side, abnormalities in energy metabolism are known to be related to defects in regulation of respiratory enzymes, combined with high demand for energy caused by cell proliferation. On the supply side deficiencies in efficiency of nutrient supply, such as low vascular density and uneven vascular distribution appear to play important roles. In theoretical simulations based on actual in vivo data, however, modulation of oxygen consumption is much more efficient in affecting oxygen transport than modification of delivery. PMID- 8687124 TI - Deoxycholic acid as an endogenous risk factor for hepatocarcinogenesis and effects of gomisin A, a lignan component of Schizandra fruits. AB - Although hepatocarcinogensis has been reported to be promoted by exogenous administration of bile acids, the relation of endogenous bile acids to hepatocarcinogenesis is not completely understood. This study investigates the relationship between serum concentration of bile acids, the appearance of preneoplastic change, glutathione S-transferase placental form (GST-P)-positive foci in the liver of male Donryu rats which had been fed 0.06% 3'-methyl-4 dimethylamino-azobenzene (3'-MeDAB), and the effects of gomisin A, previously reported to inhibit the tumor promotion process. During the feeding of 3'-MeDAB for 5 weeks, the concentrations of serum bile acids were found to have increased significantly to several times the levels found at the start of the experiment. The increase of serum bile acids, especially deoxycholic acid (DCA), and the appearance of preneoplastic lesions, the number and area of GST-P-positive foci in the liver, were significantly inhibited by simultaneous oral administration of gomisin A (30 mg/kg). When DCA (100 mg/kg) was orally administered after an initiation by 3'-MeDAB, serum bile acids and preneoplastic changes were significantly increased, these increases were inhibited by combined feeding of 0.03% gomisin A in the diet. There were good correlations between the serum concentration of DCA and the number of GST-P-positive foci in the liver in both experimental protocols. These results confirm that DCA is an endogenous risk factor for hepatocarcinogenesis and suggest that anti-promoter effect of gomisin A is based on improving metabolism of bile acids, including DCA. PMID- 8687125 TI - Chemopreventive activities of C-glucuronide/glycoside analogs of retinoid-O glucuronides against breast cancer development and growth. AB - The O-glucuronide analog of N-(4-hydroxyphenyl)retinamide (4-HPROG) has shown a greater chemopreventive activity than the parent N-(4-hydroxyphenyl)retinamide (4 HPR). However, this compound is relatively unstable. In order to improve stability and efficacy, we have prepared a number of stable C-linked analogs of 4 HPROG (C-phenyl and C-benzyl glucuronosyl, glucosyl, and xylosyl analogs). These analogs are stable toward acid hydrolysis and the glucuronosyl analogs resist the actions of beta-glucuronidase. The analogs were prescreened for their antiproliferative potential in vitro using cultured human MCF-7 breast cancer cells. Selected analogs were then evaluated for their ability to inhibit the development and growth of tumors in the 7,12-dimethylbenzanthracene-induced rat mammary tumor model. Although the stable C-linked analogs bound poorly to the nuclear retinoic acid receptors, many showed more potency than the less stable 4 HPROG in inhibiting tumor incidence and multiplicity in vivo. The glucuronide/glucoside analogs are more potent than the xylosides, and the C benzyl more effective than the C-phenyl analogs. The higher potency of at least two C-linked analogs (retinamidobenzyl glucuronide and retinamidobenzyl glucose) suggests that these analogs may have a chemopreventive advantage over the parent retinamide and its natural O-glucuronide. PMID- 8687126 TI - C-erbB-2: expression in patients with breast carcinoma in comparison to patients with benign breast diseases. AB - C-erbB-2 (Her-2 or c-neu) expression was studied by immunohistochemistry on FNA specimens of 20 breast ductal carcinomas, 20 fibroadenomas and 20 atypical fibrocystic lesions of the breast. Twelve cases of breast carcinomas, six fibroadenomas and five atypical fibrocystic lesions were found to display c-erbB 2 staining. A significant difference was found among c-erbB-2 index of breast carcinomas (mean 70,25), fibroadenomas (mean 43,83) and atypical fibrocystic disease (mean 37,4). We also found variations in c-erbB-2 expression, among individual cases of breast carcinomas, concerning the number and the intensity of carcinoma cells. It would be interesting to correlate these variations in c-erbB 2 expression with the prognosis of breast carcinomas. PMID- 8687127 TI - Possible involvement of calpain in the growth of estrogen receptor positive breast cancer cells. AB - Calpain (Ca2(+)-activated neutral protease, EC 3.4.22.17) has been reported to hydrolyze the estrogen receptor (ER). However, there has been no report available regarding the role of calpain in the growth of breast cancer cells. To investigate the role of calpain in the growth of various breast cancer cell lines, we employed a synthetic peptide, calpeptin, which is a cell permeable specific inhibitor of calpain. Calpeptin inhibited the cell growth of ER positive breast cancer cells, such as MCF-7, T-47D, and ZR-75-1 in a dose dependent manner in the presence of E2. However, the growth of ER negative breast cancer cells, MDA-MB-231, was not inhibited by calpeptin. It is suggested that calpain plays an important role in the growth of ER positive breast cancer cells. PMID- 8687128 TI - A novel PNET cell line with melanotic differentiation. AB - The primitive neuroectodermal tumor (PNET) cell line, ONS-99, was established from a human melanotic neuroectodermal tumor of infancy (MNTI). ONS-99 cells were polygonal adherent cells and transplantable to BALB/c-nu/nu mouse. ONS-99 cells were positive for NSE, HMB-45 (melanoma-associated antigen) and N-myc, but lacked the antigenic features of terminally differentiated neurons or glias. ONS-99 cells had many intermediate filaments in the cytoplasm and tight intercellular junctions with scant cytoplasmic structures by electron microscopy. To date, ONS 99 is the only example of an established PNET cell line with melanotic differentiation. PMID- 8687129 TI - Nasopharyngeal carcinoma: Epstein-Barr Virus significance. AB - Thirty-one cases of NPC were investigated by in situ hybridization, PCR analysis and serology to assess the presence of EBV and to interrelate these findings. Statistical analysis showed a significant correlation between the probability of detecting EBV and NPC. There was no significant association between in situ hybridization, PCR and serology. Tumor size correlated with EBNA, but no correlation between smoking and NPC was found. PMID- 8687130 TI - Action of interferon alpha and beta on four human melanoma cell lines in vitro. AB - Four human melanoma cell lines with different copy numbers of chromosomes 9 and 21q, as studied by the G-band technique, fluorescent in situ hybridisation (FISH) and Polymerase chain reaction (PCR), were tested for their sensitivity to Interferon-alpha (IFN-alpha) and Interferon-beta (IFN-beta) in relation to dosage of interferon genes (#9) and interferon receptor genes (#21p). The two most sensitive cell lines were those containing the highest numbers of #9 per cell, while the number of #21q copies (receptor genes) seemed to have no influence on the interferon sensitivity. PMID- 8687131 TI - Heat turn-over during hyperthermic peritoneal perfusion. An experimental study. AB - In order to study heat turnover, 3 experimental models of chemotherapeutic hyperthermic intraperitoneal perfusion (CHIP) were tested, using 15 rabbits divided into 3 separate groups of 5 animals each. A normal saline perfusate, containing a standard concentration of 10 mg of methotrexate per liter, was recycled through the peritoneal cavity, transmitting, in every group, 6,000 calories of heat. In model I, heat transmission was achieved by a high temperature gradient, in model II by the increased thermocapacity of a great priming volume of perfusate, using a peritoneal expander, and in model III by a high flow rate. The rectal and oesophageal temperatures were recorded and the indications converted to calories. The bowel showed a statistically higher heat uptake in model III, whereas thermodilution was more important in model I and especially in model II. The results indicated that the ideal model of CHIP must combine efficiency and safety. The temperature gradient must be ample, but within safe limits, only for cost-efficiency reasons. The priming volume ought to be abundant enough to achieve homogeneity and constancy of heating, but not excessive, in order to avoid abdominal distension and bodily thermo-dilution. Under these conditions, the target level of heating, always calculated in calories, must be administered by appropriate adjustment of the perfusion flow rate. PMID- 8687132 TI - Dexamethasone induces partial resistance to cisplatinum in C6 glioma cells. AB - Malignant glioma patients are sometimes treated with cisplatinum (CDDP) and dexamethasone (DEX). The question, was addressed as to whether DEX induces cellular resistance to CDDP using the C6 glioma cell line in MTT-tests. 50% of the cells were killed by 2 x 10(-5) M, 5 x 10(-6) M, and 7 x 10(-7) M CDDP after 2, 24, and 72 hours of incubation, respectively. 10-6M DEX treatment protected C6 cells from CDDP 5 x 10(-5) M 72 hours, resulting in twice as many surviving cells, [p<0.01(t-test)]. This protection was also observed in human TE671 rhabdomyosarcoma and T98G human glioma cells but not in A172 human glioma cells. It was mediated by glucocorticoid receptors and increased glutathione. DEX reduced the sensitivity of C6 cells also to carboplatinum, doxorubicin, actinomycin D, cytosine-arabinoside and methotrexate but not to 4 hydroxyifosfamide, vincristine, radiation, 6-mercaptopurine or thioguanine. These data suggest a more restricted use of DEX during chemotherapy of brain tumour patients. PMID- 8687133 TI - Studies on genotoxicity of orally administered crocidolite asbestos in rats: implications for ingested asbestos induced carcinogenesis. AB - The early genotoxic action of oral exposure to UICC crocidolite asbestos fibres was studied in different short-term tests. Fischer-344 rats were gavaged with 50 mg/b.w.kg untreated asbestos fibres and fibres which had been allowed to adsorb benzo(a)pyrene molecules from extremely low concentration (0.25-2.5 microg/ml) aqueous solutions. This system can be considered a model for the drinking of potable water contaminated by asbestos fibres together with biologically active organic micro-pollutants. The Ames Salmonella mutagenicity assay was performed on concentrated urine and serum samples of treated animals. The formation of micronuclei and sister chromatid exchanges was also studied in the bone marrow of the exposed rats. The micronucleus analysis indicated marginal genotoxic activity only upon treatment with crocidolite prepared from the solution of 1 microg/ml. A dose-dependent increase was, however, demonstrated in the sister chromatid exchange frequency upon treatment with benzo(a)pyrene coated fibres. These experiments suggest the acute cogenotoxic activity of such fibres in orally exposed animals. PMID- 8687134 TI - The effects of omega-3 and omega-6 fatty acids on in vitro prostate cancer growth. AB - Dietary intake of essential fatty acids (EFA) may play a role in prostate cancer cell proliferation. Epidemiological studies have demonstrated that men whose dietary intake is high in omega-3 fatty acid (FA) composition have a lower incidence of clinical prostate cancer, suggesting that external factors such as diet may play an important role in development and growth of prostate cancer. Furthermore, in prostate cancer cell lines, omega-6 and omega-3 FAs have demonstrated promotional and inhibitory effects respectively. To investigate the effects of dietary fats on nontumorigenic prostate cell growth we conducted in vitro studies with human metastatic PC-3, LNCaP and TSU prostate cell lines, the rat metastatic Mat-Ly-Lu cell line and rat non-metastatic epithelial cell lines EPYP1, EPYP2 and EPYP3. Cell lines were treated with linoleic acid (LA), an omega 6 FA (n-6), as well as linolenic (LLA) and eicosapentaenoic (EPA) acids, which are both omega-3 FAs (n-3). All cell lines were treated with 10% and 0.5% serum supplemented media plus fatty acid for comparison. Our results demonstrate that linoleic acid(n-6) has promotional effects at doses of 1-100ng/ml in all cell lines with the exception of EPYPl. Experiments with linolenic acid (n-3) demonstrated consistent growth promotion in all cell lines examined with the exception of the EPYP2 cell line in which there was no significant effect. EPA had no effect in culture media supplemented with 10% serum, while in media containing 0.5% serum this FA demonstrated significant promotion in all human lines. Previous studies have indicated that EPA should inhibit human prostate cancer growth in vitro, however our results demonstrated promotion at low concentrations (lng/ml). At higher concentrations, EPA did inhibit prostate cell growth. These data indicate low levels of dietary fat, regardless of composition, may play a role in prostate cancer proliferation and could be an avenue for therapeutic intervention. PMID- 8687135 TI - Cytosolic calcium mobilization concomitant with cell retraction induced by sulphate in oral KB carcinoma cells. AB - Inorganic sulphate is known to induce cell retraction, a process which is important in the cancer metastatic cascade. Using laser scanning confocal microscopy, we showed that sulphate mobilizes intracellular Ca2+ from cytosolic stores in human KB oral cavity epidermoid carcinoma cells as shown by a three fold rise in Ca2+ sensitive Fluo-3 dye fluorescence. As Ca2+ stores are known to be located in the endoplasmic reticulum (ER), we demonstrated the rich network of ER channels in the KB cells by microinjecting live cells with an ER membrane specific dye (DiI). Within 16 minutes after incubation with sulphate, KB cells had retracted and were easily detachable. The reduction in cell profile area as quantified by image analysis with the confocal microscope was statistically significant (p < 10(-6), ANOVA test). This suggests an alternative novel pathway of cell rounding and retraction involving Ca2+ release, induced via inorganic sulphate. PMID- 8687136 TI - Major histocompatibility complex (MHC)-I and MHC-II expression in Hodgkin's disease in relation to the presence of Epstein-Barr Virus (EBV). AB - We have investigated the immunohistochemical expression of beta2-microglobulin and HLA-DR proteins in Hodgkin's disease (HD) in relation to the expression of the EBV-encoded EBER1-2 mRNAs and the LMP-1 protein. beta2-microglobulin is expressed in association with MHC-I molecules on most nucleated cells and HLA-DR belongs to the MHC-II molecules which are expressed mostly on antigen-presenting cells. Formalin-fixed paraffin embedded tissue from 39 cases of lymphonodal HD were stained by immunohistochemistry for beta2-microglobulin, HLA-DR and LMP-1 proteins and by RNA in situ hybridization for EBER1-2 mRNAs. beta2-microglobulin positive staining was found in Reed-Sternberg and Hodgkin cells (HRS cells) in 18/39 cases of HD. HLA-DR positive staining was found in HRS cells in all cases of HD. EBER1-2 transcripts and LMP-1 protein were detected in HRS cells in 16/39 cases of HD. No correlation as found between the presence of EBER 1-2 transcripts or the LMP-1 protein and the detection of beta2-microglobulin and HLA-DR proteins in HD. Thus, EBV does not seem to use downregulation of MHC-I to avoid the T-cell cytotoxic immune response in HD. In addition, EBV does not seem to be the only factor responsible for the HLA-DR expression in HRS cells of HD, although it could participate in the induction of the expression of HLA-DR molecule in the EBV positive cases of HD. PMID- 8687137 TI - Effect of breast cyst fluid on oestrone sulphatase activity in MCF-7 breast cancer cells. AB - Breast cyst fluid is a rich source of growth factors and sex hormones but the pathophysiology of cystic breast disease is largely unknown. In this study the net effects of breast cyst fluid on growth of, and oestrone sulphatase activity (oestrone sulphate --> oestrone) in the hormone-dependent MCF-7 and hormone independent MDA-MB-231 breast cancer cell lines were assessed. Using a final breast cyst fluid dilution of 16.7% (v/v) MCF-7 cell growth was significantly inhibited by 7 of 21 samples (16% - 54%) while MDA-MB-231 cell growth was significantly inhibited by 17 of 20 samples (15% - 45%). Oestrone sulphatase activity was significantly inhibited in the MCF-7 cell line by 19 of 21 samples (22% - 81%) while significant stimulation of oestrone sulphatase activity was observed in MDA-MB-231 cells in 11 of 20 samples (17% - 149%). The presence of endogenous substances in breast cyst fluid which inhibit oestrone sulphatase activity in the MCF-7 cell line is exciting because of the therapeutic potential of oestrone sulphatase inhibition in hormone-dependent breast cancers. PMID- 8687138 TI - The influence of antiestrogens on pS2 and cathepsin D mRNA induction in MCF-7 breast cancer cells. AB - Tamoxifen, although widely used in the treatment of estrogen-dependent tumors, is a partial estrogen agonist producing undesirable effects in breast cancer patients. ICI 182,780 a steroidal antiestrogen displays pure antagonist activity which is due to its ability to prevent dimerization of the estrogen receptor (ER). Our previous studies have shown that 1,1-dichloro-cis-2,3-diaryl cyclopropane (Analog II), a diarylcyclopropyl compound is devoid of estrogenic activity, has a weak binding affinity for the estrogen receptor in the mouse uterine tissue and inhibits the growth of breast cancer cells in culture. These findings suggest that Analog II may not inhibit tumor cell growth at the cellular level by an ER-mediated mechanism of action. Since these three antiestrogens appear to have different mechanisms of antiestrogenic activity, the purpose of this study was to compare the influence of the three antiestrogens on estradiol induced expression of pS2 and cathepsin D (cath-D). These genes are known to be primarily under the influence of estrogen in ER positive MCF-7 human breast cancer cells. The results of this study demonstrate different mechanisms of regulation of the cath-D and pS2 genes by antiestrogens in MCF-7 cells. This study indicates that ICI 182,780 is a pure antagonist at the levels of gene regulation and cell proliferation. The relative order of inhibitory action was found to be ICI 182,780 > tamoxifen > Analog II. PMID- 8687139 TI - Mechanisms of resistance to 6-aminonicotinamide. AB - Several cell lines resistant to 6-aminonicotinamide (6-AN) have been isolated, some selected with 6-AN and others with tiazofurin. These cell lines have been characterized with respect to several parameters including cross-resistance to tiazofurin, ability to metabolize 6-AN or tiazofurin to the respective analog metabolites of NAD, accumulation of 6-phosphogluconate in the presence of drug, and levels of NAD pyrophosphorylase (EC 2.7.7.1). Cell lines selected with 6-AN (ANR) are not cross-resistant to tiazofurin and have retained the ability to synthesize the NAD analogs, 6-aminonicotinamide adenine dinucleotide (6-ANAD), the phosphorylated derivative (6-ANADP) and thiazole-4-carboxamide adenine dinucleotide (TAD) when treated with 6-AN or tiazofurin respectively. The cell lines selected with tiazofurin are all cross-resistant to 6-AN; the most resistant of the lines are unable to form the NAD analog metabolites in detectable amounts and appear deficient in NAD pyrophosphorylase (EC 2.7.7.1) activity, the enzyme that is presumably responsible for their formation. The parent CHO line accumulates 6-phosphogluconate in the presence of 6-AN indicating inhibition of 6-phosphogluconate dehydrogenase. Of the resistant cell lines only two of them accumulate this intermediate. PMID- 8687140 TI - Competitive reverse transcriptase-PCR: an improved method for determination of c erbB-2 gene expression. AB - The aim of our study was to establish a simple method for routine analysis of c erbB-2 gene expression in tumour samples. We constructed a plasmid for the in vitro synthesis of competitor RNA to be used as an internal exogenous control during the RT-PCR detection of c-erbB-2 expression. The competitor RNA harbors a 19-base deletion and 63-base insertion compared to wild-type c-erbB-2 mRNA and generates a PCR product which is easily distinguished from the wild-type PCR product by agarose gel electrophoresis. The sensitivity and reliability of our RT PCR-system was determined. To address this, we measured c-erbB-2 expression in cultured cells, of which c-erbB-2 expression data were available from Northern blot analysis. In conclusion, our experimental strategy correlated well with the results obtained by Northern blot hybridization, however, it overcomes time consuming and expensive procedures used in classical gene expression analysis. PMID- 8687141 TI - Effect of oestrone on the natural killer (NK) cell activity, antioxidant status and tumour growth in athymic mice xenografted with human tumours. AB - Natural killer (NK) cells have been described as being very sensitive to oxidative stress. Thus it has been previously shown that chronic administration of oestrone in drinking water of athymic mice xenografted with a wide variety of human tumours, increases their growth and development. In this study an investigation was made to see whether oestrone supplementation could influence the NK cell activity by changes in the antioxidant defences which result in an oxidative stress and influence the proliferation of tumours. Supplementary oestrone was administered in drinking water of athymic mice xenografted with two different human tumours which lack oestrogen receptors: a bladder carcinoma and a small-cell lung carcinoma. The growth of the urothelial carcinoma was poorly affected by oestrone, but oestrone significantly (p<0.01) increased the proliferation of the small-cell lung carcinoma. The average uterus weight was increased by 62% in oestrone treated mice with no modifications in plasma zinc and selenium status, nor in erythrocyte copper zinc superoxide dismutase level. Nevertheless a slight decrease in erythrocyte glutathione peroxidase activity was noted. Trace elements and antioxidant enzymes in liver homogenates remained unchanged. Oestrone treatment also had no effect on plasma and liver lipid peroxides. The immune response was evaluated by measuring NK activity of splenocytes against 51Cr labelled YAC-I target cells. A 35.5% decrease in the NK activity (p<0.001) was observed after oestrone treatment and may be responsible for graft tolerance. However, the results of these experiments seem to exclude the role of oxidative stress in the modulation of NK activity. PMID- 8687142 TI - Cytokine regulation of ezrin expression in the human colon cancer cell line HT29. AB - Ezrin is a membrane-cytoskeleton linker protein and belongs to the TERM family. It has been implicated in the membrane ruffling, motility, and metastatic process of tumour cells. This study examined the effects of a range of cytokines on the expression of ezrin in the human colon cancer cell line, HT29. Levels of ezrin were determined by Northern and Western blotting and indirect immunofluorescence. We report that IL-2, IL-8, IL-10 and IGF-I had an inhibitory effect on the expression, whereas EGF and IL-11 enhanced cellular ezrin levels. Immunofluorescence confirmed that these changes were seen both in cytosol and generalised membrane. It is concluded that ezrin expression in tumour cells can be regulated by cytokines and this bears importance in the understanding of its role in tumour biology. PMID- 8687143 TI - An open-label phase I/II dose escalation study of the treatment of pancreatic cancer using lithium gammalinolenate. AB - There are currently no satisfactory treatments for inoperable pancreatic cancer. Median survivals for untreated patients are of the order of 100 days and, with one exception, no chemotherapy or radiotherapy regime has been found to produce a worthwhile extension of life with reasonably tolerable side effects. Gamma linolenic acid (GLA) has been found to kill about 40 different human cancer cell lines in vitro without harming normal cells. The lithium salt of GLA (LiGLA) can be administered intravenously and a dose escalation study of a 10 day infusion followed by oral therapy in patients with inoperable pancreatic cancer was carried out in 48 patients in two centres. Peripheral venous infusion caused thrombophlebitis but this could be avoided by infusing via a central vein with appropriate heparinisation. Too rapid infusion caused haemolysis which could be avoided by slow dose escalation in the first few days and maintenance of plasma lithium below 0.8 mmol/l. Doses ranged from 7 to 77g/patient cumulatively delivered over 2-12 days. Other than the above described events there were no important side effects and patients felt well during the infusions. A Kaplan Meier analysis showed that survival was not significantly influenced by which centre the patients were treated in, the sex of the patients or the presence or absence of histological confirmation. The presence or absence of liver metastases, the patients' Karnofsky scores and the-dose of LiGLA had significant effects on survival from treatment. A Cox proportional hazards model revealed similar results: in both centres, in both sexes, and in patients with and without liver metastases according to the model the highest doses of LiGLA were associated with longer survival times as compared with the lowest doses. LiGLA deserves investigation in a randomised prospective study. PMID- 8687144 TI - TPS and CA 15.3 serum values as a guide for treating and monitoring breast cancer patients. AB - BACKGROUND: Tissue Polypeptide-specific Antigen (TPS) and CA 15.3 are two of the most widely studied tumor markers in the serum of breast cancer patients. TPS is a tumor associated proliferative marker which belongs to the cytoskeleton. CA 15.3 is a high molecular weight glycoprotein of clinical relevance in the monitoring of treatment and the detection of recurrence in breast cancer patients. PATIENTS AND METHODS: Serum values of TPS and CA 15.3 were measured in a prospective series of patients with primary breast cancer (n=267) and benign breast disease (n=46). The cut-off levels (95% specificity) determined for each test were 80 U/I for TPS and 30 k/U/l for CA 15.3. RESULTS: The diagnostic sensitivity was 0.31 for TPS and 0.32 for CA 15.3 for the detection of breast cancer. Serum TPS levels in breast cancer patients showed a relatively low positivity rate (33%), which was comparable with that of CA 15.3. Higher concentrations of TPS were found in cases with locally more advanced disease as well as in G3 tumors. By contrast, CA 15.3 basal levels were solely related to tumor size and nodal involvement. TPS and CA 15.3 levels were not related to estrogen and progesterone receptor status, peritumoral vessel invasion, multifocality and the in situ component of the tumor. After primary treatment, 20 patients developed distant metastases. In metastatic breast cancer patients TPS was more frequently and more markedly elevated than CA 15.3. In progressive disease, elevated values of TPS and CA 15.3 were found in 85% and 50%, respectively. The mean lead time was 10 months for TPS and 14 months for CA 15.3. Increasing values of TPS were independent of the site of metastasis, whereas elevated levels of CA 15.3 were mainly related to visceral metastasis. Local recurrences were usually associated with low levels of TPS and CA 15.3. By contrast, elevated values of TPS in locally recurred cases indicated rapidly progressive disease. CONCLUSIONS: Our study indicates that TPS and CA 15.3 are not helpful in distinguishing patients with breast cancer from patients with benign breast lesions. Nevertheless, at the time of diagnosis increased serum levels of the markers may facilitate the selection of high risk patients for whom additional treatment and careful follow up studies should be undertaken. Furthermore, TPS seems to be a reliable tumor marker for the early diagnosis of metastatic breast carcinoma independent of the site of metastasis, while increasing values of CA 15.3 are mainly related to visceral involvement. PMID- 8687145 TI - Intraoperative radioimmunolocalization of an anti-CEA MAb F(Ab')2 (FO23C5) in CEA serum-negative colorectal cancer patients. AB - Serum positivity to an antigen recognized by the monoclonal antibody (MAb) which will be administered is frequently being used as a predictive criterion for positive MAb tumor localization. In the present study, which is based on our previous data that clearly showed no correlation between quantitative levels of CEA in sera and in carcinoma tissues, we selected a population of 12 primary colorectal carcinoma patients which were serum CEA-negative. The main purpose was to assess the potential diagnostic use of Radioimmunoguided Surgery (RIGS) with an anti-CEA FO23C5 F(Ab')2 MAb and its clinical value in this series of patients. In all RIGS patients, the MAb localized to histologically confirmed tumor; this included 96% of primary tumor tissues, 29% of lymph nodes and one occult liver metastasis. Thus, serum CEA positivity should not be a criterion for the use of anti-CEA MAbs for the diagnosis of colon cancer, since the serum CEA level is not indicative of CEA expression in tumors. PMID- 8687146 TI - Retinoblastoma (Rb) protein expression and resistance in squamous cell lung carcinomas. AB - The purpose of this study was to prove the value of Rb protein expression as a prognostic factor for patients with squamous cell lung carcinoma. The expression of Rb in 75 carcinomas was analyzed immunohistochemically and the resistance to doxorubicin was investigated in vitro. Rb-negative carcinomas were more frequently resistant than Rb-positive carcinomas (p<0.05). A trend for a correlation between the expression of Rb and the expression of glutathione S transferase-pi was detectable (p=0.08). Patients with Rb-positive carcinomas had a trend for better prognosis, but this result was not statistically significant. PMID- 8687147 TI - Limited clinical significance of the serum tumour marker Ca 72-4 in colorectal cancer. AB - BACKGROUND: We explored the potential value of CA 72-4 in the staging and prognostic prediction of colorectal cancer, as compared to six previously investigated serum tumour markers - CEA, CA 19-9, CA 50, CA 242, TPA, and TPS. MATERIALS AND METHODS: CA 72-4 was analysed using an immunoradiometric assay in serum samples obtained, prior to surgery, from 196 consecutive patients resected between Jan. 1987 and Nov. 1992. RESULTS: CA 72-4 levels increased with progressive tumour stages; a high level correlated with poor prognosis. However, the information obtained from CA 72-4 did not improve the ease of staging, as compared with other tumour markers. Various combinations of CA 72-4 with the other tumour markers did not add any substantial information to the staging process either. The value of the CA 72-4 in prognostic prediction, as shown in the univariate analysis, was limited in the multivariate tumour marker analyses. CONCLUSIONS: CA 72-4 does not improve the staging and prognostic prediction of colorectal cancer, when compared with other serum tumour markers used. PMID- 8687148 TI - Endometrial carcinoma: the prognostic impact of papillary serous carcinoma (UPSC) in relation to nuclear grade, DNA ploidy and p53 expression. AB - In a histopathological review of 266 women with stage I-IV endometrial carcinoma, the prognostic significance of uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CCC) of the endometrium was compared with that of ordinary adenocarcinoma and adenoacanthoma. UPSC and CCC were diagnosed in 31/266 (12%) and 6/266 (2%) of the patients respectively. The median follow-up time was 79 months (range 3 to 133 months). 49% of the patients with UPSC or CCC died of their cancer compared with 31% in the adenocarcinoma + adenoacanthoma group (RH=2.25; p=0.0022). Strong expression of the mutated p53 gene product was significantly more common in the UPSC + CCC group than in the reference group (64% vs. 19%), (p<0.0001). In a Cox multivariate analysis including histopathological and clinical variables, UPSC and CCC were still significant predictors of survival (p<0.05). When nuclear grade was added to the analysis, UPSC + CCC as well as the degree of differentiation lost most of their prognostic impact. In a final multivariate analysis, DNA ploidy was found to be the strongest predictor of outcome besides age and clinical stage. PMID- 8687149 TI - Notable relationship between the level of tumor marker TPS in serum and survival in breast cancer. AB - Tissue Polypeptide Specific antigen (TPS) in serum was measured once during the follow-up of 200 breast cancer patients and compared with survival. Within 12 months, patients with normal TPS (< 80 U/L) exhibited a 3% death rate (3/96), which was undistinguishable from the mortality of normal females of corresponding age. Patients with moderate TPS (80-400 U/L) suffered 19% death (14/72), and patients with high TPS (> 400 U/L) 72% death (23/32). The relative risk (RR) of death within 6 months was 1 with normal TPS, 8 with moderate TPS, and 48 with high TPS. RR for 12 months was 1, 6, and 23, respectively. Serum TPS at admission had a significant predictive value with regard to survival up to 12 months. PMID- 8687150 TI - Adjuvant treatment for breast cancer in the elderly. AB - Eighty one patients with breast cancer stages I, II and III (T3a) were given adjuvant treatment with tamoxifen (Nolvadex), chemotherapy, or both. Most patients had estrogen and progesterone receptors measurement. Twenty one (63.6%) patients of the tamoxifen group were node positive, all 25 (100%) of the chemotherapy plus tamoxifen group and 13 (56.5%) of the chemotherapy alone group. Tamoxifen was administered for at least 3 years. Disease free survival and overall survival were substantially similar after treatment with tamoxifen or chemotherapy plus tamoxifen. Side effects were more numerous and severe in patients given chemotherapy. In receptor positive elderly breast cancer patients tamoxifen represents an excellent adjuvant therapy independently of disease stage. Chemotherapy should be reserved for subjects at high risk of recurrence in controlled clinical trials. PMID- 8687151 TI - Treatment of advanced pancreatic cancer with mistletoe: results of a pilot trial. AB - Pancreatic cancer is a devastating disease with poor prognosis. It is characterized by its unresponsiveness to chemo- and/or radiotherapy. Therefore, many patients demand alternative drug therapy such as mistletoe treatment. However, there are no controlled data available analyzing the effect of mistletoe treatment in pancreatic cancer. In the present phase I/II study we evaluated the effect of mistletoe (Eurixor) treatment in 16 patients (7 women, 9 men) with histologically verified ductal pancreatic carcinoma. At the time when the patients were enrolled nine patients had lymph node metastases (stage III), and in 7 patients distant metastases (stage IV) were present. Mistletoe was administered twice a week by subcutaneous injection in a dosage of 1 ng per kg body weight. Monthly follow-ups included clinical status, multidimensional evaluation of quality of life, contrast enhanced computed axial tomography scan (CT scan) or ultrasonography, and determination of the tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). Apart from one anaphylactic reaction, which necessitated suspension of treatment for a few days, no severe side effects were observed. No partial or complete remission was seen. Eight patients (50%) showed a CT-verified status of "no change" according to World Health Organization criteria for at least 8 weeks. Median survival time in all patients was 5.6 months (range 1.5 to 26.5 months). Analysis of multidimensional evaluation of quality of life showed a stable course of disease in 7 patients. All except two patients claimed that mistletoe had a positive effect on their quality of life, with an obvious decline only during the last weeks of life. These results indicate that mistletoe is not able to significantly influence tumor growth in advanced pancreatic carcinomas. However, mistletoe treatment can stabilize quality of life, and therefore may help patients to maintain adequate life quality in their few remaining months. PMID- 8687152 TI - Palliative chemotherapy in metastatic colorectal carcinoma: comparison of two chemotherapeutic regimens. AB - BACKGROUND: We retrospectively compared two different palliative chemotherapy regimens for advanced colorectal carcinoma with respect to efficacy and toxicity. PATIENTS AND METHODS: Between April 1986 and September 1994, 84 patients started treatment with 5-fluorouracil (5-FU)-based combination chemotherapy [MFL (Sequential MTX and 5-FU, N=39) or FLV (Sequential 5-FU and FA, N=45)] in our clinic. Treatment was initially administered every two weeks. RESULTS: In the MFL and FLV group, 37 and 41 patients, respectively, were evaluable. The objective response rates were 16% in the MFL group and 26% in the FLV group. Median survival was 10 months in both groups, and the median time to progression was not significantly different. With regard to subjective response, 39% of patients in both groups obtained partial or complete relief of tumor related symptoms. A significantly larger part of the patients in the MFL group (54%) complained about adverse effects when compared to the FLV group (27%). CONCLUSIONS: With regard to efficacy the chemotherapeutic regimens were equivalent, however the MFL regimen appeared more toxic when compared to FLV. PMID- 8687153 TI - The significance of p53 autoantibodies in the serum of patients with breast cancer. AB - Serum p53 autoantibodies were studied in 82 patients with Stage 1 or 2 breast cancer using an ELISA assay. Tissue expression of p53 in these patients was also examined. High levels of serum p53 autoantibodies were detected in 48% (39/82) patients, while 23% (19/82) were tissue positive. Patients with high serum p53 autoantibodies levels were not significantly different to those with low levels with respect to, tissue p53, tumour grade, size, stage or oestrogen receptor status. Tissue immunoreactivity for p53 was significantly associated with tumour grade and negative oestrogen receptor status. Patients in both groups were followed for a median of over five years but the presence of p53 autoantibodies in serum was not prognostic with respect to disease free interval or survival. In this study detection of p53 autoantibodies in serum does not correlate with any of the usual tumour related prognostic factors, nor does it correlate with clinical outcome. PMID- 8687154 TI - Efficacy of the association of 13-cis-retinoic acid (13cRA) and alpha-interferon 2a (alpha-IFN 2a) in moderate-severe cervical intraepithelial neoplasia (CIN II III): a pilot study. AB - Recent in vitro studies have suggested a possible therapeutic synergism between alpha-IFN 2a and 13cRA in certain neoplasias, while encouraging in vivo findings strongly support the enhanced effectiveness of the two agents when used in combination. The specific aim of our study was to evaluate the efficacy and the toxicity of the association of 13cRA and alpha-IFN 2a in patients with CIN II and CIN III who refused surgical treatment. Twenty-one patients (aged between 25 and 58 years), of which 14 were CIN II and 7 CIN III, entered the study. 13cRA (orally at 0.5-1 mg/Kg/day) and alpha-IFN 2a (intramuscular at 3x10(6) I.U./day for the first 15 days, then 3 times/week for the following four weeks) were administered simultaneously for eight consecutive weeks. 13/21 (62%) histologically verified objective responses (6 complete and 7 partial) were achieved. We also obtained 8 stable diseases. Compliance was generally good and no delays in therapy due to toxicity were recorded (except for two patients presenting WHO degree III cutaneous and mucosal toxicity which regressed one week after suspending treatment). Human Papilloma Virus (HPV) was initially detected in 16/21 (76%) patients, while HPV negativization after treatment was observed in 3/16 (19%). Although preliminary and requiring long-term assessment, the encouraging results of this study confirm the need for further investigation on the role of systemic medical therapy in the treatment of CINs. PMID- 8687155 TI - Palliative chemoembolization of hepatocellular carcinoma with mitoxantrone, Lipiodol, and Gelfoam. A phase II study. AB - Transcatheter chemoembolization, in conjunction with various drugs, has been widely used for palliative treatment of hepatocellular carcinoma. A phase II study was carried out on mitoxantrone chemoembolization. High risk cirrhotic patients were excluded from this study. Fourteen mg/m2 mitoxantrone and up to 20 ml Lipiodol were injected, followed by Gelfoam embolization as indicated. Thirty seven patients (33 with cirrhosis) were treated. Sixty-nine cycles were delivered, with mean (+/-SD) Lipiodol and emulsified mitoxantrone doses of 11.3+/ 3.8 ml and 11.8+/-5.2 mg, respectively. Thirteen, 16, and 8 patients received one, two, and three cycles, respectively, with time intervals of 123+/-60 days. Thirty patients received Gelfoam embolization at the first cycle, 9 at the second and 4 at the third. No treatment-related deaths occurred. Complications were mild and transient, including nausea/vomiting in most cases, fever over 38 degrees C 67%, pain 74%, ascites 8%, jaundice 3%, bleeding 3%, pancreatitis 3%, myelosuppression 44%, diarrhea 5%. Treatment response rate was 49% (including 16% minor responses) with 16% early progressions. With a median follow-up of 12 months, the 12-month response duration and survival rates were 56% and 79% respectively. Transcatheter chemoembolization with mitoxantrone appears to be a promising method for the palliation of advanced hepatocellular carcinoma, and deserves to be evaluated in well controlled randomized studies. PMID- 8687156 TI - Histochemically demonstrable protein tyrosine phosphatase in human breast and colorectal cancer: large decrease in its activity in colorectal cancer suggests a tumor suppressor role in colorectal mucosal cells. AB - Many oncogene products and growth factor receptors are protein tyrosine kinases, and exert their cellular effects by the phosphorylation of tyrosyl residues of effector proteins. The balance and dynamic renewal of phosphotyrosine proteins are also regulated by protein tyrosine phosphatases (PTPs), whose inhibition under experimental conditions causes cellular proliferation and transformation, with a concomitant increase in phosphotyrosine protein content. Inverse effects are obtained by increasing PTP activity. On the basis of these effects, PTPs might also function as tumor suppressors in human tissues. This possibility was further investigated here by demonstrating PTP and phosphotyrosine protein content with histochemical techniques. In normal human breast tissue PTP activity was low and in the majority of breast cancers the activity was increased and exhibited great variation between different cases. When the relationship of phosphotyrosine protein content with PTP was evaluated, no inverse dependence was detected, suggesting that in human breast tissue and cancer PTP may not show tumor suppressor activity. In normal colorectal mucosae PTP activity was high, while in all colorectal cancers it was very low, constituting only 14% of the activity present in normal mucosal cells. The great drop in PTP activity together with reported alterations in a gene encoding a PTP and in a chromosome containing a PTP gene in colorectal cancer strongly suggest that PTP may function as a tumor suppressor in human colorectal mucosae. The decrease in PTP activity may be one factor stimulating or causing neoplastic proliferation in multistep colorectal carcinogenesis. PMID- 8687157 TI - Influence of delayed diagnosis on established prognostic factors in endometrial cancer. AB - To evaluate the influence of delayed diagnosis on prognostic factors in endometrial cancer, we conducted a retrospective chart analysis based on the data of 116 postmenopausal patients with FIGO stage I-IV endometrial carcinoma. The interval from the first episode of post-menopausal vaginal bleeding to definitive, histological diagnosis (bleeding interval) was compared with tumor stage and various histomorphologic features in endometrial cancer. The mean bleeding interval was 12.7 +/- 17.8 weeks in 74 patients with FIGO stage IA, IB endometrial carcinoma and 35.2 +/- 69.3 weeks in 42 patients with stage IC-IV disease (t-test, p: 0.011). FIGO stage IA, IB disease was diagnosed in 23/26 (88%) patients with a bleeding interval <4 weeks, and in 22/34 (64%) and 29/56 (51%) patients with bleeding intervals of 4-8 weeks and >8 weeks, respectively (Chi-square 10.358, p=0.006). The correlation with histologic grade, lymph-node status, vessel invasion and histologic subtypes did not reach statistical significance. Our data confirm the clinical impression that postmenopausal vaginal bleeding is an early symptom in patients with endometrial cancer, and that advanced disease in the majority of cases might come from delayed diagnosis in women with poor compliance. PMID- 8687158 TI - Immunohistological p53 staining is of limited value in the staging and prognostic prediction of colorectal cancer. AB - PURPOSE: To compare immunohistochemical staining using different anti-p53 antibodies, and to evaluate the possible clinical implications of the overexpression of p53 in a series of patients resected for colorectal cancer with a long follow-up. METHODS: Tumor biopsy samples were collected from 294 surgical colorectal cancer specimens, obtained from two series of patients with a median follow-up of 4.5 years. The samples stained with four commercially available anti p53 antibodies, (mouse monoclonal antibodies 421, 1801, and DO-7; and rabbit polyclonal antibody CM1), were evaluated and compared with cryosections from a subset of 20 biopsies from tumors in various stages and grades, obtained from patients with different outcomes. RESULTS: DO-7 gave a homogeneous nuclear staining, which, when further investigated, turned out to be identical in the formalin-fixed paraffin-embedded and in the frozen specimens. Therefore, DO-7 was found to be suitable for the further analysis of archival or frozen sections from the sample. p53 overexpression was shown in 162 (55%) cases, with a significantly higher proportion having DNA aneuploidy (p<0.01) in left-sided colonic and rectal tumors (p<0.01). p53 staining was not associated with tumor stage, tumor grade, or survival. CONCLUSIONS: A significantly higher proportion of p53 overexpressing tumors are DNA aneuploid, indicating that mutations in the TP53 gene constitute a sign of genetic instability, which might be of importance in malignant transformation. However, we could not find any indication that TP53 mutations, as reflected in the overexpression of p53, constitute a prerequisite for tumor progression in colorectal cancer. PMID- 8687159 TI - Solitary phalanx plasmacytoma relapse with disseminated extramedullary plasmacytomas and myeloma after short duration of remission. AB - Solitary bone plasmacytomas account for 5-7% of multiple myeloma cases and are assumed to have a fairly good prognosis, with a long duration of relapse-free survival after primary local treatment. Isolated phalanx plasmacytoma is a very rare entity, because involvement of extremities is seen in less than 1% of all solitary bone plasmacytomas, where they are usually localized centripedally, often in the axial skeleton. A 68 year old patient with a lytic lesion involving 5th phalanx was diagnosed as having a biopsy-proven solitary plasmacytoma, with a negative work-up for coexisting plasma cell dyscrasia. Three and a half months after completion of radiotherapy of the involved phalanx, the patient was readmitted with hypercalcemia, renal insufficiency and subsequently diagnosed as having atypical plasma cell infiltration of marrow, and plasmacytomas involving the right vocal cord and the premaxillary region, as well as pathological ulna fracture. Plasmacytoma of the phalanx, with extreme short duration of remission and an aggressive type of clinical relapse, is in sharp contrast with the natural stable course of a solitary plasmacytoma where the use of systemic treatment is subject to intense debate. PMID- 8687160 TI - Prognostic significance of high expression of proliferating cell nuclear antigen in patients with intestinal metaplasia. AB - Although some types of intestinal metaplasia are considered to be potentially pre malignant lesions leading to gastric carcinoma, their high frequency and variability limit their usefulness as early markers of malignant progression. The present study was carried out to search for parameters which could be used in conjunction with histological diagnosis to identify groups of patients with a high risk for developing gastric neoplasia. The expression of proliferating cell nuclear antigen (PCNA), as revealed by immunohistochemical staining of anti-PCNA monoclonal antibody (PC10) in 82 endoscopic biopsy specimens, was compared with the histological classification of intestinal metaplasia, the biochemical composition of gastric mucins and the expression of blood group Lewis antigens. Statistically significant (p 0.001) correlation between the PCNA labelling index (the percentage of positive cells in more than 700 tumor cells per sample) and the histological type of intestinal metaplasia, the presence of sulphomucins, and the presence of anomalous Lewis a antigen was found. We conclude that a high PCNA labelling index in the gastric mucosa, with a histological diagnosis of incomplete intestinal metaplasia, could constitute a good prognostic marker of the severity of the histologic lesion. These parameters, together with others such as the presence of sulphomucins and of cells expressing anomalous Lewis a antigen, may be used to define patients with a high risk of developing a gastric neoplasia. PMID- 8687161 TI - Human papillomavirus DNA in oral squamous cell carcinomas from an African population sample. AB - BACKGROUND: The incidence of oral squamous cell carcinoma (OSCC) is on the increase in developing countries. MATERIALS AND METHODS: Formalin fixed paraffin embedded blocks of OSCCs from a Black South African population sample of peri urban and rural origin were selected as follows: Group 1 - 57 OSCCs with a mean age of 59 years; Group 2 - 43 OSCCs all cases younger than 40 years; Group 3 - 46 OSCCs with blocks containing only tumour tissue without any normal epithelium and Group 4, a control group of 38 non-neoplastic epithelial lesions. Type specific primers were used in a standard PCR to amplify a segment of the E6 region of HPV 6, 11, 16 and 18. RESULTS: HPV 11 and 16 DNA were found in one sample each from groups 1 and 2 respectively. CONCLUSION: HPV is not an etiologic factor in the development of OSCC in the population studied. PMID- 8687162 TI - Topographical immunohistochemical expression of bcl-2 protein in human liver lesions. AB - Immunolocalization of the bcl-2 protein was investigated in 60 hepatocellular carcinomas, 10 cholangiocarcinomas. 15 metastatic adenocarcinomas as well as in 37 non-neoplastic liver lesions. The three-step immunoperoxidase method was performed in archival, routinely processed material. bcl-2 protein was not identified either in neoplastic, dysplastic or normal hepatocytes, whereas it was observed in bile ductules and small bile duct epithelia, but not in the epithelium lining large bile ducts. All cases of cholangiocarcinoma and 60% of metastatic adenocarcinomas were bcl-2 positive. bcl-2 appears to be an additional marker in distinguishing hepatocellular carcinoma from cholangiocarcinoma or metastatic adenocarcinoma. Also, bcl-2 does not seem to be involved in human liver hepatocyte survival. PMID- 8687163 TI - Treatment of superficial bladder cancer with intravesical perfusion of rIL-2: a follow-up study. AB - We have recently reported the results of a phase I study on the intravesical perfusion of recombinant interleukin-2 in patients with superficial bladder cancer. The treatment feasible with mild toxic effects, especially compared with the treatment using TUR and instillations of Bacillus Calmette-Guerin. The follow up of these phase I study patients was continued for another twelve months. During this period, cytoscopy and cytological examination of cells washed from bladder were performed every four months. The results showed that three out of 9 patients relapsed, over a period ranging from 6 to 20 months after treatment. All these data clearly confirm that the intravesical perfusion of rIL-2 is feasible, safe and should be an effective and nontoxic treatment of patients with superficial bladder cancer. PMID- 8687164 TI - Serum CA 242 and CEA detect different patients with recurrent colorectal cancer. AB - The aim of this study was to investigate the clinical value of CA 242 and CEA in the follow-up of patients with colorectal cancer. Serial serum samples were available for analysis in 67 patients with subsequent recurrence, of which 36 patients had been treated for colonic and 31 patients for rectal cancer. Liver metastases were found in 32 patients, local recurrences in 18 patients, lung metastases in 11 patients and other distant metastases in 6 patients. The same serum samples were used in quantitating the serum levels of both CA 242 and CEA. At the time of clinical recurrence an elevated CA 242 level was found in 41 patients and an elevated CEA level in 49 patients. Thirty-six patients (54%) showed an elevation of both CA 242 and CEA, five patients (7%) had increased CA 242 alone and 13 patients (19%) increased CEA alone. Altogether, 54 patients (81%) showed an elevation of either or both markers at the time of clinical recurrence. Initially CA 242 alone began to rise in 14 patients (21%) and CEA alone in 16 patients (24%). The lead time was calculated from 28 patients that had four or more serum samples available during follow-up. CA 242 increased in median 5,7 months and CEA in median 3,4 months before clinical recurrence (p=0.34). CA 242 was more sensitive for lung metastases (64%) than CEA (45%), whereas CEA was superior to CA 242 in liver metastases (88% versus 72%, respectively) and in local recurrences (56% versus 39%, respectively). Both CA 242 and CEA seem to be useful in early diagnosis of a recurrence in the follow-up of patients with colorectal cancer. PMID- 8687165 TI - C-erbB-2 oncoprotein expression in operable non-small cell lung cancer. AB - Although c-erbB-2 oncoprotein immunohistochemical expression has been thoroughly studied in a variety of human tumors, its prognostic significance remains unclear. Moreover, differences in assessment criteria further complicate the evaluation of c-erbB-2 as a prognostic marker. In the present study we examined the expression of c-erbB-2 protein in 107 patients suffering from operable (T 1,2 N0, 1 staged) non-small cell lung cancer (30 adenocarcinomas and 69 squamous cell carcinomas) treated with surgery alone. A 3-7 year of follow up (median 45 months) was available for all patients. Paraffin embedded sections were stained with the NCL-CB11 monoclonal antibody using the immunoperoxidase technique. Analysis was based on cytoplasmic reactivity as membrane staining was impossible to assess against this background. Strong positive cytoplasmic staining was identified in 20/107 (19%) of cases, weak in 30/107 (20%) and negative in 57/107 (53%). Results were correlated with patient variables (age,sex) and tumor parameters (T,N-stage, grade, histology, Ki67 proliferation index, p53 and EGFR expression). C-erbB-2 expression was not related to any of these factors. Although c-erbB-2 defined a worse prognosis, univariate analysis of survival did not confirm any statistically significant difference between the c-erbB-2 staining groups (p=0.5). T,N-stage were the only statistically significant prognostic variables. Any contribution of c-erbB-2 to the development of tumour aggressive behaviour in non-small cell lung cancer requires assessment in the specific subgroups of patients. PMID- 8687166 TI - Diagnostic delay causes more psychological distress in female than in male cancer patients. AB - From July 1990 to July 1991, 263 consecutive cancer patients admitted to our oncological unit for the first time were invited to participate in a questionnaire based study. 252 patients responded and were included in the final analysis. The aim of the survey was to examine the delays involved in diagnosis and treatment of cancer and the possible psychological distress associated to the different periods of delay. A shorter patient delay was found among patients under the age of 30 years (P < 0.005). Patients with higher education had a significantly shorter delay from the time of contact with the GP to admittance to the local hospital (P <0.005). The diagnostic delay was reported to be significantly more distressing for females compared to males (P <0.05). The reported psychological distress, however, correlated positively to the actual length of total delay (P<0.005) for both sexes. All patients reported that the delay between local hospital referral and admittance to the oncological unit to be the most distressing delay period to cope with. PMID- 8687167 TI - [CEP/LTS-X: a simple clinical classification of urinary calculi]. AB - The introduction of new treatment techniques for urinary stones requires a classification of our concepts concerning the application of these various modalities. In order to individualize the treatment of stones as precisely as possible, the authors propose a clinical and therapeutic classification based on the characteristics of the stone, the state of the urinary tract, the state of the parenchyma and renal function, the site of the stone, its dimensions and consistency and the number of stones. On the basis of these criteria, renal stones can be classified into 4 types, ureteric stones can be classified into 3 types and bladder and urethral stones can be classified into 2 types. The stones observed in each category are described together with the most appropriate treatment. PMID- 8687168 TI - [The nucleus of ossification in kidney calculus]. AB - The presence of bone tissue in renal stones has been described for a long time. Two cases of heterotopic ossification are reported in this study. Stone analysis was performed by stereoscopic microscopy, infrared spectrophotometry and fine slice petrographic section and polarized light microscopy. This last technique revealed the existence of osteocytic filling defects inside the stones, an unquestionable sign of mineralized bone tissue. PMID- 8687169 TI - [A metabolic study of urolithiasis. Specificity, sensitivity, efficacy and reproducibility]. AB - A preliminary diagnosis of the disease responsible for the stones is essential to allow appropriate medical treatment of renal stones. In this paper, the authors describe their diagnostic and treatment protocol based on computer-assisted urinary metabolic analysis. 413 subjects, divided into four groups, were prospectively evaluated to calculate their specificity, sensitivity, reproducibility and efficacy and to demonstrate the usefulness of this protocol. PMID- 8687170 TI - [Advancements in the genetics of cystinuria]. AB - Cystinuria is an amino acid disease due to a defect of intestinal and renal tubular transport of cystine and various basic amino acids (lysine, arginine and ornithine). The disease is transmitted horizontally according to an autosomal recessive pattern. The overall prevalence is one per 7,000 live births. It is the commonest hereditary disease affecting amino acid transport (MIM 220100). This disease is characterized by excessive urinary excretion of cystine and basic amino acids. From a clinical point of view, almost 50% of homozygotes will develop cystine renal stones with urinary tract infection, renal colic, partial or total obstruction of the urinary tract and possibly loss of renal function. PMID- 8687171 TI - [Calculi of papillary origin. An undisputed reality]. AB - In 1936, Randall formulated a hypothesis concerning stone formation related to the renal papillae. Randall's hypothesis, discussed for many years, was confirmed by Cifuentes in 1983. The authors studied 830 cases of papillary stones, eliminated spontaneously, 16 of which had a typical Randall plaque with mineralized collecting tubules (1.9%). This study was conducted by scanning electronic microscopy (SEM) using an EDX system. The papillary origin of several renal stones can be confirmed in this way. The origin of these stones would remain unknown without the use of these modern techniques. PMID- 8687172 TI - [Extracorporeal shockwave lithotripsy. A brief review of the types of equipment currently in use]. AB - Presentation of the main lithotriptors used in 1996: Dornier HM3 and 4, Edap Technomed Sonolith, Storz Modulith, Siemens Lithostar, Wolf. Comparison of the efficacy coefficients of these apparatuses. PMID- 8687174 TI - [The double J catheter in the shock wave treatment of kidney calculi]. AB - Review of the literature concerning the use of Double J stents prior to extracorporeal shock were lithotripsy. The advantages and disadvantages of stenting are described together with the marked benefit derived from the pretreatment use of the stent. The authors also try to determine which stones are suitable for preliminary stenting, by noting the degree of stone mass. PMID- 8687173 TI - [Biochemical evaluation of renal lesions produced by electrohydraulic shock waves]. AB - The authors present a biochemical study of the renal lesions produced during extracorporeal electrohydraulic shock wave lithotripsy (ESWL). The sequential variation (before and after ESWL) of various biochemical parameters of the blood and 24-hour urine was analysed in 50 patients. A significant increase of urinary N-Acetyl-Glucosaminidase (NAG), urinary NAG/urinary creatinine quotient, proteinuria, serum creatinine and potassium was detected during the 24 hours following ESWL. A significant fall in creatinine clearance, urinary osmolarity and uric acid clearance was also detected. A positive correlation was observed between these alterations, the number of shocks and the kilovoltage used. On the 7th and 15th days, no significant difference was observed compared to the baseline values before ESWL. This can be explained by the fact that the lesions caused by shock waves are already in the repair phase. PMID- 8687175 TI - [Surgery of kidney calculus. Current practice]. PMID- 8687176 TI - [Open surgery of calculus of the kidney pelvis. Results and complications in the era of extracorporeal lithotripsy]. AB - From 1989 to 1993, 11,535 extracorporeal shock wave lithotripsy (ESWL) sessions were performed in 6,066 patients in our centre. In contrast, simple or extended pyelolithotomy was the treatment of choice in a small group of patients. The object of this paper is to review the results and complications of this type of operation. A total of 57 pyelolithotomies was performed, including 33 extended pyelolithotomies, in 55 patients (26 men and 29 women). The mean age of the series was 50 years (range: 5-77). The operated kidney was the left kidney in 34 cases and the right kidney in 23 cases. The mean interval between the diagnosis and the operation was 31 months. 64% of the patients had history of stone disease (33 ipsilateral and 2 bilateral). Thirteen patients had already been treated by ESWL (10 patients), percutaneous nephrolithotomy (PNL) (2 cases) and one case had previously undergone pyelolithotomy. A urinary tract infection was observed in 26 patients (47%). The incision consisted of lumbotomy in 40 patients (71%), or a subcostal incision in 12 cases. The mean operating time was 161 minutes (range: 90-245) and the mean intraoperative bleeding was 500 ml. Thirteen patients were transfused (23%). The renal artery had to be clamped in 9 cases (for an average of 19 minutes). After a mean follow-up of 20 month, 50.8% of patients were stone free. 49% of patients presented residual caliceal fragments on the immediate postoperative X-ray. One patient had to be treated by percutaneous nephrolithotomy and ESWL. 12 cases (41% of patients with residual fragments) required subsequent treatment by ESWL and the remaining patients with residual fragments were asymptomatic and did not receive any further treatment. The immediate postoperative complication rate was 17% and 10% of patients developed late postoperative complications. Simple or extended pyelolithotomy remains an effective treatment for stones of the renal pelvis, either on its own or associated with ESWL. However, the possibility of serious complications demands meticulous patient selection. PMID- 8687177 TI - [Urinary calculi in a geriatric setting]. AB - The authors report a retrospective series of 174 patients with urolithiasis. They were all age between 65 and 88 years. This group represents one tenth of all patients treated for urinary stones in the Urology department of Sfax over the last decade. Neither the clinical symptoms nor radiological findings observed in this group differed from those other patients hospitalized for urolithiasis; on the other hand associated diseases related to aging appear to be well represented which alters the management, prognosis and outcome in this type of patients. PMID- 8687178 TI - Deficient expression in multiple sclerosis of the inhibitory transcription factor Sp3 in mononuclear blood cells. AB - To evaluate differential gene expression in multiple sclerosis (MS) patients and control subjects, we used differential display to screen for messenger RNAs that are differentially expressed in peripheral blood mononuclear cells from monozygotic twins who are discordant for MS. We identified a 232-bp complementary DNA fragment, present only in material from the normal twin, that exhibited 100% identity with the inhibitory transcription factor Sp3. Oligonucleotide primers corresponding to Sp3 messenger RNA sequences amplified complementary DNA of appropriate size from 83% of control subjects but from only 21% of MS patients (p < 0.001). These results suggest that Sp3 gene transcription is suppressed in peripheral blood mononuclear cells from most MS patients and that other genes whose expression is normally suppressed by Sp3 in immune cells may consequently be overexpressed. PMID- 8687179 TI - Motor neuron disease: a paraneoplastic process associated with anti-hu antibody and small-cell lung carcinoma. AB - Although isolated lower motor neuron disease has been reported as a paraneoplastic complication, it has not been previously described, in association with anti-Hu antibody. We report a 51-year-old man in whom weakness heralded the presence of a small-cell cancer of the lung. His neurological disorder was characterized by an unremitting progression of limb, neck, and chest wall weakness and wasting that commenced and remained predominant in the upper limbs. Electrophysiological studies demonstrated widespread denervation and examination of a muscle biopsy specimen showed evidence of acute and chronic denervation. High titers of anti-Hu antibody were detected in the serum and cerebrospinal fluid. Neither objective measures of strength nor titers of anti-Hu antibody responded to corticosteroids, cyclophosphamide, intravenous immunoglobulins, or plasmapheresis. Death from the complications of motor neuron disease ensued 23 months after the onset of weakness. Autopsy revealed tumor in the lung and on pleural and peritoneal surfaces. There was a loss of anterior horn cells in the spinal cord. Despite the absence of symptomatic cerebellar disease, a decrease in the number of Purkinje cells was also detected. PMID- 8687180 TI - Multiple mutations in the GALC gene in a patient with adult-onset Krabbe disease. AB - A 53-year-old man was diagnosed 8 years earlier with globoid cell leukodystrophy (GLD, Krabbe disease) by his severe deficiency of galactocerebrosidase (GALC) activity. He was found to have eight nucleotide changes on the two copies of his GALC gene, including two in the leader sequence, four considered polymorphisms, and two unique mutations. PMID- 8687181 TI - A dopaminergic neurotoxin, (R)-N-methylsalsolinol, increases in Parkinsonian cerebrospinal fluid. AB - The concentration of (R)-N-methylsalsolinol, which is a dopamine-derived neurotoxin selective to dopamine neurons and induces parkinsonism in rats, was found to be increased significantly in the cerebrospinal fluid of untreated patients with Parkinson's disease. The enantio-specific occurrence of (R)-N methylsalsolinol in cerebrospinal fluid suggests its enzymatic synthesis in the human brain. The individual differences in the activities of the enzymes determining the metabolism of (R)-N-methylsalsolinol in the brain might be involved in the pathogenesis of Parkinson's disease. PMID- 8687182 TI - Careers in academic neurology, 1996. PMID- 8687183 TI - Is hereditary inclusion body myopathy a "familial prion disease" ? PMID- 8687184 TI - Urinary myelin basic protein-like material as a correlate of the progression of multiple sclerosis. PMID- 8687185 TI - Aphasia in acute stroke: incidence, determinants, and recovery. PMID- 8687186 TI - Acute multiple sclerosis (Marburg type) is associated with developmentally immature myelin basic protein. AB - We have studied a case of acute, fulminating multiple sclerosis (MS) (Marburg type) at the pathological and biochemical levels. Postmortem examination of the brain revealed extensive areas of gross rarefaction in the hemispheric white matter. Histologically, well-demarcated areas of demyelination with a large influx of macrophages and a subtle perivascular infiltration of lymphocytes were seen with relative preservation of the axis cylinders. Myelin basic protein (MBP) was isolated and purified [correction of purifed] from noninvolved white matter. It was slightly larger in molecular weight than MBP from normal brain or from chronic MS brain. The increase in mass was accounted for, in part, by the deimination of 18 of 19 arginyl residues to citrulline, making the patient's MBP much less cationic than MBP from normal white matter. When expressed as the ratio of least cationic form of MBP to the most cationic (C-8/C-1), the normal ratio was 0.82, chronic MS 2.5, and the patient in this study 6.7. Because the ratio of 6.7 was similar to 7.5 found for a 15-month-old infant, MBP was considered to be of the immature form. The data are consistent with a genetic factor influencing the charge microheterogeneity of MBP. The resulting less cationic MBP cannot carry out its normal function of compacting multilayers. PMID- 8687187 TI - Deficiency of respiratory chain complex I is a common cause of Leigh disease. AB - We reviewed the clinical features and etiologies of Leigh disease in 66 patients from 60 pedigrees. Biochemical or molecular defects were identified in 50% of all pedigrees, and in 74% of the 19 pedigrees with pathologically proved Leigh disease. Isolated deficiency of respiratory chain complex I was found in 7 patients, though the complex was only assayed in 25 patients, making this the second most common biochemical abnormality after complex IV deficiency. Mutations at residue 8993 of mitochondrial DNA were found in only 2 patients. No correlation was found between the clinical features and etiologies. No defects were identified in the 8 patients with normal lactate concentrations in the cerebrospinal fluid. PMID- 8687188 TI - A possible role for altered myelin basic protein in multiple sclerosis. PMID- 8687189 TI - Language cortex representation: effects of developmental versus acquired pathology. AB - Relatively little is known about language cortex representation in patients with developmental pathology and epilepsy. We report the results of mapping language by electrical stimulation of chronically implanted subdural electrodes in 34 patients (mean age, 12.2 years) evaluated for epilepsy surgery, 28 of whom had magnetic resonance imaging or histological evidence of developmental tumors or cortical dysplasia. Language cortex was identified in the temporal or frontal lobe of 19 patients (left hemisphere in 17, right hemisphere in 2), and overlapped or bordered the epileptogenic region in 12. Language cortex was not found in the frontal or temporal lobe of 15 patients (left hemisphere in 4, right hemisphere in 11) and was presumed to be contralateral to grid placement. Three patients with left-hemisphere perinatal or postnatal cerebral insults before the age of 5 years had no language in the left hemisphere, while 3 patients with insults between the ages of 6 and 16 years had preserved left-hemisphere language. Developmental lesions and early-onset seizures do not displace language cortex from prenatally determined sites, whereas lesions acquired before the age of 5 years may cause language to relocate to the opposite hemisphere, but only when language cortex is destroyed. PMID- 8687190 TI - Cortical myoclonus in Angelman syndrome. AB - Angelman syndrome (AS) results from lack of genetic contribution from maternal chromosome 15q11-13. This region encompasses three GABAA receptor subunit genes (beta3, alpha5, and gamma3). The characteristic phenotype of AS is severe mental retardation, ataxic gait, tremulousness, and jerky movements. We studied the movement disorder in 11 AS patients, aged 3 to 28 years. Two patients had paternal uniparental disomy for chromosome 15, 8 had a >3 Mb deletion, and 1 had a microdeletion involving loci D15S10, D15S113, and GABRB3. All patients exhibited quasicontinuous rhythmic myoclonus mainly involving hands and face, accompanied by rhythmic 5- to 10-Hz electroencephalographic (EEG) activity. Electromyographic bursts lasted 35 +/- 13 msec and had a frequency of 11 +/- 2.4 Hz. Burst-locked EEG averaging in 5 patients, generated a premyoclonus transient preceding the burst by 19 +/- 5 msec. A cortical spread pattern of myoclonic cortical activity was observed. Seven patients also demonstrated myoclonic seizures. No giant somatosensory evoked potentials or C-reflex were observed. The silent period following motor evoked potentials was shortened by 70%, indicating motor cortex hyperexcitability. Treatment with piracetam in 5 patients significantly improved myoclonus. We conclude that spontaneous, rhythmic, fast bursting cortical myoclonus is a prominent feature of AS. PMID- 8687191 TI - Striatal D1 and D2 dopamine receptor loss in asymptomatic mutation carriers of Huntington's disease. AB - We have investigated striatal dopamine D1 and D2 receptor binding in asymptomatic subjects from Huntington's disease (HD) families using positron emission tomography. Nineteen adult subjects at risk of developing HD were scanned with 11C-SCH 23390 and 11C-raclopride to calculate the D1 and D2 receptor binding potential, respectively. Eight of the 19 were shown to have the HD mutation; of these, 4 subjects had significant reductions in striatal dopamine receptor binding. Abnormalities were more common in older subjects and were not correlated with the size of the HD mutation. There was a strong coefficient of correlation between individual levels of striatal D1 and D2 binding in subjects with the mutation. Of 6 other cases with a 50% risk of carrying the HD gene, 1 showed subclinical loss of caudate and putamen D2 binding. Our study suggests that both striatal D1 and D2 dopamine receptors are lost in parallel from both caudate and putamen in presymptomatic HD and that dopamine receptor binding provides a sensitive means of detecting subclinical striatal dysfunction. PMID- 8687192 TI - Genetic heterogeneity in Leigh syndrome. PMID- 8687194 TI - Recovery of sympathetic skin responses after digit-to-digit replantation and toe to-digit transplantation in humans. AB - Sympathetic skin response was utilized to study recovery of sudomotor function in 8 patients who had digit-to-digit replantation and 9 patients who had toe-to digit transplantation. Sympathetic skin responses evoked by median nerve stimulation or magnetic stimulation of the neck were recorded from the tip of the replanted digits or transplanted toes. The contralateral normal fingers served as controls. The mean intervals between surgery and study were 33 and 37 months, respectively, for digit replantation and toe transplantation. In normal subjects, the sympathetic skin responses recorded from the fingertip were abolished by local anesthesia or cooling of the finger, while those recorded from the palm were not affected. Ischemia of the finger only transiently affected the digit sympathetic skin responses. These data indicate that the digit responses were locally generated and mediated by unmyelinated fibers. After digit replantation, the palm and digit sympathetic skin responses were not different between replanted and normal sides. After toe transplantation, palm sympathetic skin responses were normal, but digit ones had prolonged latency and reduced amplitude. The present findings suggest that recovery of sympathetic sudomotor activity can be nearly complete in digit replantation but less satisfactory in toe transplantation. PMID- 8687193 TI - Apolipoprotein E and cognitive change in an elderly population. AB - The apolipoprotein E (apoE) epsilon 4 allele is overrepresented, and the apoE epsilon 2 allele underrepresented, in Alzheimer's disease. To assess the risk of cognitive impairment in individuals with these genotypes in the general population, we studied a population-based sample of 1,899 individuals 65 years and older as a follow-up to the Iowa 65+ Rural Health Study. Multiple regression and logistic regression analyses demonstrated significant effects of apoE epsilon 4 and apoE epsilon 2 in predicting performance on a delayed recall task over a 4- to 7-year period. The magnitude of this effect was, however, fairly modest, with odds ratios for developing impairment of approximately 1.37 (95% confidence interval: 1.007, 1.850; p = 0.045) for apoE epsilon 4 and 0.53 (95% confidence interval: 0.368, 0.777; p = 0.001) for apoE epsilon 2. These effects were more pronounced in women than men. Importantly, 85% of elderly apoE E4/4 individuals (average age, 81) scored in the unimpaired range on a screening mental status test. Thus, many individuals reach old age without cognitive impair- ment despite inheritance of one or two apoE epsilon 4 alleles. This suggests that apoE genotyping will have limited utility as a diagnostic or prognostic indicator of cognitive decline in individuals. PMID- 8687195 TI - X-linked nonprogressive congenital cerebellar hypoplasia: clinical description and mapping to chromosome Xq. AB - We examined a large family in which an X-linked recessive congenital ataxia manifested in 7 males from three generations. The affected boys first exhibited a marked delay of early developmental motor milestones. A neurological syndrome became evident by 5 to 7 years of age and included cerebellar ataxia, dysarthria, and external ophthalmoplegia; there were no symptoms of mental retardation, spastic paraparesis, or sensory loss. Neuroimaging studies revealed hypoplasia of cerebellar hemispheres and vermis. The disease showed no progression beyond early childhood. The unique heredity and clinical features clearly distinguish this new entity from a variety of previously described familial ataxias. Pairwise linkage analysis and haplotype reconstruction allowed us to map the gene responsible for this disorder to a 38-cM interval on chromosome Xp11.21-q24 flanked by the loci DXS991 and DXS1001. Upon multipoint linkage analysis, the disease gene was determined to be located most likely in the proximal part of chromosome Xq, with the maximal lod score of 4.66 at the locus DXS1059 (Xq23). This is the first example of the genetic mapping of a pure congenital cerebellar hypoplasia syndrome. PMID- 8687196 TI - Cerebrovascular complications of Fabry's disease. AB - Fabry's disease (FD) is a rare, sex-linked disorder resulting from alpha galactosidase deficiency. Cerebrovascular complications have been reported in the literature but have not been systematically analyzed. We report 2 patients and review 51 previously reported cases (descriptive meta-analysis) to clarify the clinical, radiologic, and pathologic features. The average age at onset of cerebrovascular symptoms was 33.8 years for hemizygous individuals (n = 43) and 40.3 years of heterozygotes (n = 10). The most frequent symptoms and signs were as follows (in descending order of frequency): hemiparesis, vertigo/dizziness, diplopia, dysarthria, nystagmus, nausea/vomiting, head pain, hemiataxia, and ataxia of gait, in the hemizygote group; and memory loss, dizziness, ataxia, hemiparesis, loss of consciousness and hemisensory symptoms, in the heterozygote group. The vertebrobasilar circulation was symptomatic in 67% of the hemizygotes and 60% of the heterozygotes. Intracerebral hemorrhage was found in 4 patients (3 hemizygotes and 1 heterozygote). Elongated, ectatic, tortuous vertebral and basilar arteries were the most common angiographic and pathologic features. For the hemizygotes, the recurrence rate for cerebrovascular disease was 76% and the death rate was 55%; 86% of the heterozygotes had recurrent cerebrovascular event(s) and 40% died. The cerebrovascular manifestations of FD, in both hemizygotes and heterozygotes, are predominantly due to dilative arteriopathy of the vertebrobasilar circulation, frequently recur, and portend a poor prognosis. PMID- 8687197 TI - Human T-lymphotropic virus type I-associated myelopathy and tax gene expression in CD4+ T lymphocytes. AB - Infection by human T-lymphotropic virus type I (HTLV-I) is associated with adult T-cell leukemia and a slowly progressive disease of the central nervous system (CNS), HTLV-I-associated myelopathy/tropical spastic paraparesis, characterized pathologically by inflammation and white matter degeneration in the spinal cord. One of the explanations for the tissue destruction is that HTLV-I infects cells in the CNS, or HTLV-I-infected CD4+ T lymphocytes enter the CNS, and this drives local expansion of virus-specific CD8+ cytotoxic T lymphocytes, which along with cytokines cause the pathological changes. Because both in the circulation and in the cerebrospinal fluid, CD8+ cytotoxic T lymphocytes are primarily reactive to the product of the HTLV-I tax gene, we sought evidence of expression of this gene within cells in the inflammatory lesions. After using double-label in situ hybridization techniques, we now report definitive localization of HTLV-I tax gene expression in CD4+ T lymphocytes in areas of inflammation and white matter destruction. These findings lend support to a hypothetical scheme of neuropathogenesis in which HTLV-I tax gene expression provokes and sustains an immunopathological process that progressively destroys myelin and axons in the spinal cord. PMID- 8687198 TI - Hemifacial seizures and cerebellar ganglioglioma: an epilepsy syndrome of infancy with seizures of cerebellar origin. AB - We investigated a 6-month-old infant with daily episodes of left hemifacial contraction, head and eye deviation to the right, nystagmoid jerks to the right, autonomic dysfunction, and retained consciousness. The episodes began on day 1 of life and were unresponsive to antiepileptic medication. Interictal and ictal scalp electroencephalographic (EEG) recordings were unremarkable. Magnetic resonance imaging revealed a mass in the left cerebellar hemisphere and peduncle. Ictal single-photon emission computed tomography revealed focal hyperperfusion in the region of the cerebellar mass. Ictal EEG recordings with implanted cerebellar electrodes demonstrated focal seizure discharges in the region of the mass. Resection of the mass resulted in remission of seizures and histopathology revealed ganglioglioma. Six previously reported infants with similar semiology (described as "hemifacial spasm"), imaging findings, and histopathology are reviewed. We believe the previously reported infants and our patient constitute a rare but important clinicopathological syndrome of infancy characterized by epileptic seizures of cerebellar origin. PMID- 8687199 TI - Effect of lazabemide on the progression of disability in early Parkinson's disease. The Parkinson Study Group. AB - Lazabemide (Ro 19-6327) is a relatively short-acting, reversible, and selective type B monoamine oxidase inhibitor that is not metabolized to amphetamines or other active compounds. We previously found lazabemide to be safe and well tolerated at dosages of up to 400 mg/day during a 6-week study of 201 patients with early untreated Parkinson's disease (PD). We now assess whether or not lazabemide influences the progression of disability in untreated PD. Patients (N = 321) were assigned by randomization to one of five treatment groups (placebo, 25 mg, 50 mg, 100 mg, or 200 mg/day) and followed systematically for up to 1 year. The risk of reaching the primary end point (the onset of disability sufficient to require levodopa therapy) was reduced by 51% for the patients who received lazabemide compared with placebo-treated subjects. This effect was consistent among all dosages. The frequency of adverse experiences did not differ among the treatment groups. At dosages ranging from 25 to 200 mg/day, lazabemide was well tolerated and delayed the need for levodopa in early, otherwise untreated PD. The magnitude and pattern of benefits were similar to those observed after 1 year of deprenyl (selegiline) treatment in the DATATOP clinical trial. PMID- 8687200 TI - Cystic fibrosis in Saudi Arabia: common and rare presentations. AB - The clinical presentations of 12 children with cystic fibrosis seen in King Khalid University Hospital are presented. Ten were of Saudi origin and the other two were African. The mean age of onset of symptoms was 2.3 months, and the mean age at diagnosis was 14.3 months (range 3-48 months). Seven children were boys and five were girls. All children presented with growth failure, recurrent chest infection and chronic diarrhoea. The parents of 83% of our cases were first degree relatives. Pseudo-Bartter syndrome was seen in eight children. Sixty-seven per cent of our cases were colonized with Pseudomonas aeruginosa by the time of diagnosis, despite their young age (mean 7 months). Peripheral neuropathy secondary to vitamin E deficiency, meconium ileus, nasal polyps and gall-stones were present, each in one case. On follow-up, one child died and the other 11 are still alive. We concluded that cystic fibrosis is not rare in Saudi Arabia and that increased awareness of the disease is needed to avoid delay in diagnosis. Efforts should be made to prevent early colonization by Pseudomonas aeruginosa. PMID- 8687201 TI - An ELISA assay for the rapid diagnosis of acute bacterial meningitis. AB - A recently introduced ELISA test (EIA-Test) was used for the detection of the common organisms that cause acute bacterial meningitis (ABM). The test--which detects antigens of Haemophilus influenzae type b, Neisseria meningitidis (serogroups A, B, C) and Streptococcus pneumoniae (25 selected types)--is performed in less than 1 hour and read by the naked eye. Cerebrospinal fluid (CSF) specimens of 125 Sudanese children (1 month-14 years) admitted with a provisional diagnosis of meningitis/meningoencephalitis were prospectively examined with the EIA-Test, direct microscopy (DM) using Gram stain and culture. Of the 56 positive CSF specimens, the EIA-Test had the highest yield (100%), followed by culture (33.9%) and DM (30.4%). Nineteen (33.9%) of the positive samples came from children who had been treated with antibiotics prior to admission, and all were positive in the EIA-Test. EIA-Test was also the only positive test in 31 (55.4%) cases. From the present study, and similar to previous observations, the EIA-Test seems to have valuable potential for the rapid diagnosis of ABM and is of particular help in patients who have been pre treated with antibiotics. PMID- 8687202 TI - Immunoglobulin (Ig) and IgG subclasses in Asian children with bronchial asthma. AB - Selective immunoglobulin deficiencies have been shown to be associated with atopic disease. In this study, serum immunoglobulin (Ig) G, A, M, E and IgG subclasses of 92 Asian asthmatic children were studied and compared with those of age-matched controls. The children, aged between 0.7 and 17.4 years (mean age 7.5 years), were recruited from the National University Hospital, Singapore. The serum Ig levels were measured by enzyme-linked immunosorbent assay, except for IgE which was measured by the fluorescent allergosorbent test. As expected, serum total IgE levels were markedly higher in the asthmatic children than in the controls (geometric mean = 513 units/ml and 164 units/ml, respectively; p < 0.0001). Serum IgM levels were also slightly higher in the asthmatic patients than in the controls (geometric mean = 1.74 and 1.51 milligrams, respectively; p < 0.04). Mean serum IgG and A and IgG subclasses (1-4) levels in the asthmatics did not differ significantly from those in the controls. However, four asthmatic children were found to have selective IgA deficiency (serum IgA < 0.08 milligrams). None of the patients was found to be IgG subclass-deficient. PMID- 8687203 TI - Chronic relapsing pancreatitis from a scorpion sting in Trinidad. AB - Chronic relapsing pancreatitis is a rare cause of abdominal pain in children and exceptionally rarely is related to a scorpion sting. We describe a 13-year-old girl who, following envenoming by a scorpion, developed recurrent attacks of sharp, intermittent pain in the umbilical region associated with fever, nausea, anorexia and vomiting, and changes in her psychological behaviour. Thorough clinical evaluation, including CT scanning, disclosed unabated pancreatitis. A modified Puestow procedure was performed with very good results. Physicians should be aware that in chronic relapsing pancreatitis, particularly in children, a scorpion sting should be considered an aetiological possibility. PMID- 8687204 TI - Serum zinc and copper levels in sickle cell anaemia and beta-thalassaemia in North Jordan. AB - Serum zinc and copper levels were determined in 28 beta-thalassaemia and 15 sickle cell anaemia (SCA) patients of 3-10 years of age using atomic absorption spectrophotometry. The results were compared with 25 age-matched controls. Copper levels were significantly increased in beta-thalassaemia and sickle cell anaemia. Zinc levels were significantly increased in beta-thalassaemia but significantly decreased in SCA. The data suggest the occurrence of impaired kidney function and disturbance in the metabolism of zinc and copper in these patients. PMID- 8687205 TI - Pharmacokinetics of amikacin in children with kwashiorkor. AB - The pharmacokinetics of intravenous amikacin, administered as a mean (SD) bolus dose of 5.5 (1.2) mg/kg to children between the ages of 1 and 4 years with kwashiorkor, was studied. Although there was a tendency for the average volume of distribution to increase to the upper limit of normal, plasma elimination half life, first order elimination-phase rate constant and clearance remained close to the reference values for adults. Despite marginal elevation of the average t1/2 beta-value, reflecting a general trend, renal impairment in respect of amikacin clearance could not be demonstrated. It was concluded that the changes in pharmacokinetic parameters found in kwashiorkor are not large enough to amend the current therapeutic regimens for amikacin in this condition. PMID- 8687206 TI - Sacrococcygeal teratoma in Zaria, Nigeria: report of 47 cases. AB - This is a retrospective review of 47 children, 38 girls and 9 boys, with sacrococcygeal teratoma, aged between 1 day and 5 years (mean 30 weeks), and seen in Zaria over 19 years. There were 40 type I, four type II, two type III and one type IV. Only nine children presented during the 1st week of life, ten at 4 weeks and 28 (60%) after the 3rd month of life. All were operated upon soon after admission to hospital. Four of the tumours in children over 1 year of age were malignant. PMID- 8687207 TI - Nutritional rickets in Calabar, Nigeria. AB - The features of 20 cases of nutritional rickets who presented at the University of Calabar Teaching Hospital, Calabar in south-eastern Nigeria over a 9-year period (January 1985-December 1993) are presented. The aim is to compare them with those in the only other reports from Nigeria between 18 and 42 years ago from Ibadan in the west of the country. The ages at presentation ranged between 6 months and 5 years with no sex preponderance. Most of the children were well nourished with the major features being delay in walking, swollen wrists and ankles and genu varum. The majority of cases in the present study occurred among children of elite and middle class parents who deprived their children of sunshine by keeping them indoors most of the day while they were at work. Reasons for the comparatively low prevalence of rickets in Calabar are social and cultural factors which enhance the exposure of children to sunlight. In addition, the relative availability of seafood and vegetables in this coastal city enhances rickets prevention. PMID- 8687208 TI - Role of body surface cultures in prediction of sepsis in a neonatal intensive care unit. AB - An analysis of surface cultures of 35 preterm infants of less than 33 weeks gestational age hospitalized in a neonatal intensive care unit was made. The babies had received neither antiseptic nor antibiotic therapy prior to collection of specimens. Surface cultures were collected on the 4th or 5th day of life from 16 skin or mucosal sites. At the onset of a febrile episode within 14 days of collection of surface swabs, a blood culture was done on 31 infants (four did not develop fever) and the results were compared with the surface cultures. Sepsis was diagnosed by positive blood culture in twenty neonates (57.1%). With this frequency of sepsis, the optimum sensitivity, specificity and positive predictive values of surface cultures were 60%, 27% and 60%, respectively. These values did not improve substantially for any anatomic site cultured or for any pathogen recovered. We conclude that surface cultures are of limited value in predicting the aetiology of sepsis in neonates. PMID- 8687209 TI - Cereal-based oral rehydration solutions in Sudanese children with diarrhoea: a comparative clinical trial of rice-based and sorghum-based oral rehydration solutions. AB - A randomized controlled study was carried out at the Children's Emergency Hospital, Khartoum to evaluate the acceptability, safety and efficacy of (rice or sorghum) cereal-based oral rehydration solutions (ORS) relative to that of the standard WHO ORS formulation in children with acute diarrhoea. Ninety-six children whose ages ranged from 6 to 40 months were enrolled in the study. Thirty two of them were allocated to the rice-based ORS group, 34 to the sorghum-based ORS group and 30 to the control group. Cereal-based ORS solutions were found to shorten the duration of diarrhoea and to reduce both the stool volume and the frequency of diarrhoea and vomiting as well as the mean total ORS intake. These effects were more marked with the sorghum-based ORS than with the rice-based ORS. By the end of day 3, 50% of patients in the rice ORS group and 67.6% in the sorghum ORS group had recovered compared with 40% from the standard ORS group. PMID- 8687210 TI - Progressive familial intrahepatic cholestasis (Byler's disease) in Arab children. AB - The clinical, biochemical and histological characteristics in six Arab children with progressive familial intrahepatic cholestasis (PFIC) (Byler's disease) are described. The autosomal recessive mode of inheritance is established. Jaundice and pruritus were early symptoms, with onset in the 1st 3 months in all patients. Other features included growth failure, developmental delay, ataxia, areflexia, gall-stones and epistaxis. Gamma-glutamyl-transpeptidase and cholesterol were normal, but total bile acid levels were uniformly elevated in all patients. Histology showed features of hepato-canalicular cholestasis, lack of bile duct proliferation and fibrosis or cirrhosis in all patients. Five patients who were followed up were alive at a mean age of 75.8 months. PMID- 8687211 TI - The computed axial tomography of the brain in protein energy malnutrition. AB - Forty consecutive new cases of protein energy malnutrition were evaluated clinically and biochemically; in addition, the brain morphology was assessed by computed tomography within 24 hours of admission. Cerebral shrinkage was shown in six of 14 (42.9%) cases of marasmus, ten of 14 (71.4%) cases of kwashiorkor, and 11 of 12 (91.7%) cases of marasmic-kwashiorkor. Ventricular dilatation was demonstrated in 57.1% of marasmus cases, 71.4% of kwashiorkor cases and 91.7% of patients suffering from marasmic-kwashiorkor. However, none of the subjects studied showed any changes in the brain stem or cerebellum. Only ten returned 2 months after nutritional rehabilitation for repeat tomograms. None of these repeat tomograms showed any residual morphological changes. The study demonstrated that the brain is affected in all types of malnutrition, albeit in different proportions, but these changes are completely reversible. PMID- 8687212 TI - Dengue-associated adult respiratory distress syndrome. AB - In dengue shock syndrome, an acute increase in capillary permeability results in leakage of plasma into the interstitial space. Pleural effusion is commonly seen in dengue shock syndrome. We report three cases of dengue-associated adult respiratory distress syndrome (ARDS) in children, in all of whom dengue haemorrhagic fever, presenting with grade 3 or grade 4 dengue shock syndrome with disseminated intravascular coagulopathy, was confirmed. The criteria for the diagnosis of ARDS were based on the expanded definition of ARDS by Murray et al. Treatment consisted of fluid resuscitation, correction of coagulopathy and mechanical ventilation. All three children had multi-organ impairment, but it was more severe in the two who died. The one survivor was well at discharge. PMID- 8687213 TI - Churg Strauss syndrome in childhood. AB - We describe a 7-year-old boy with Churg Strauss syndrome who presented with a 3 month history of cough, wheeze, fever, weight loss, abdominal pain, skin lesions, proteinuria and pulmonary infiltrates with eosinophilia. He showed a good response to corticosteroid treatment and is currently doing well. The case illustrates the difficulty and importance of reaching a diagnosis in a rare condition for which there is an effective treatment, and serves to remind paediatricians of its existence. PMID- 8687214 TI - [Evaluation of prognostic factors in gynecological cancer examined by molecular biological study]. AB - The usefulness of prognostic factors in gynecological cancer was evaluated using the oncogenes, tumor suppressor genes and DNA viruses detected with the molecular biological technique. In uterine cervical cancer, HPV types 16 and 18 are considered to have a high oncogenic risk, and are commonly associated with high grade CIN and invasive cancer under persistent HPV infection. C-myc overexpression in advanced stage and p53 mutation in HPV negative case are associated with poor survival. In endometrial cancer, oncogene activation and expression are less frequent than in cervical and ovarian cancer. K-ras point mutation (codon 12) tumors are more aggressive and c-erbB-2 overexpression are associated with metastasis and poor survival. In ovarian cancer, there are numerous abnormalities of oncogenes and tumor suppressor genes. Especially, EGF-R and PDGF-R alpha expression are associated with decreased survival. p53 mutation also decreases survival and response to chemotherapy. Recently. MSH2 (Lynch II syndrome) and BRCA1 gene are known to relate with familial ovarian cancer. PMID- 8687215 TI - [LY188011 phase I study. Research Group of Gemcitabine (LY188011)]. AB - LY188011 (Gemcitabine hydrochloride) is a new derivative of deoxycytidine. Phase I study was carried out by a cooperative study group. LY188011 was administered weekly for 3 consecutive weeks starting with an initial dose of 60 mg/m2 (1n) and then increasing the dosage to 1,000 mg/m2 (16.7n). Dose limiting factor was found to be myelosuppression (decreases of WBC, neutrophils and platelet), and MTD was considered to be 1,000 mg/m2. The nadir of WBC and platelet were observed after about 1-3 weeks. It took 1-2 weeks for their recovery. Other adverse reactions included fever, fatigue, anorexia, nausea/vomiting, anemia and transient elevations of GOT and GPT. However, those adverse reactions were mild. T1/2 rho of plasma concentration was about 19 min and the C5min was dependent on the dose. Anti-cancer effects were observed in one gastric cancer and two colon cancer patients. It is recommended that the dosing schedule for an early phase II study is 800 mg/m2 weekly for 3 weeks with 1 week of rest as one cycle, in multiple cycles. PMID- 8687216 TI - [Survival and changes of clinical laboratory data in phase II study with 5' DFUR]. AB - With patients registered in a Phase II study of 5'-DFUR, we analyzed the results of survival and laboratory findings. The 50% survival days in patients with gastric cancer included: 371 days in all evaluable patients; 912 days in patients of CR+PR; 484 days in MR+NC; and 158 days in PD. On the other hand, those in patients with colorectal cancer were: 467 days in all evaluable patients; 1,308 days (66.7% survival) in CR+PR; 586 days in MR+NC; and 276 days in PD. The figures in patients with breast cancer were: 1,761 days (58.5% survival) in all evaluable patients; 1,761 days (82.1% survival) in CR+PR; 878 days in MR+NC; and 546 days in PD. These 50% survivals were markedly longer than for other anti cancer drugs given singly or in combination, although response rates with other drugs were higher than with 5'-DFUR. Laboratory findings in patients with gastric and colorectal cancers given 5'-DFUR disclosed many cases with improved levels of blood cells and liver function. There was a correlation between improved laboratory findings and survival. Furthermore, in animal experiments 5'-DFUR improves cancer cachexia. This is thought to be related to the improved survival and laboratory findings. We concluded that the prolonged survival observed in our study was related to reduction in cancer cachexia and improved laboratory findings. PMID- 8687217 TI - [Mitomycin C-DNA adduct detection in rat organs and human liver]. AB - Mitomycin C-DNA adduct formation was detected in rat organs and also in human tissues by 32P-postlabeling assay. The adduct levels were 1-4 adduct/ 10(8) nucleotides in the human liver after 20 mg of mitomycin C by intra-artery administration and which level was higher comparing with the levels in the rat liver after 10 times more dosages of mitomycin C administration by intra-venous injection. The levels in the human liver were maintained at least 56 days after administration. Organ-specific differences of adduct levels were observed in rat experiments: the adduct levels of liver, lung and kidney were stable but rapidly decreased in stomach and colon. These results, which were obtained from the experiments using the normal parts of each organs may indicate that the drug effectivity for adduct formation was sufficient with smaller dose in the stomach and colon, but disappeared quickly, mean while, the drug effectivity was undergoing in relatively high levels for longer periods in the liver lung and kidney. The analysis of human liver samples may suggest that the selective intra artery injection induced stronger drug effectivity for adduct formation in human organs. PMID- 8687218 TI - [In vitro direct antiproliferative activity and in vivo antitumor activity of bropirimine against bladder cancer]. AB - Bropirimine is an antitumor agent currently used in clinical trials on bladder cancer. It is known to induce IFN, to activate NK cells and to inhibit the growth of tumor cells. In this study, we examined the in vitro and in vivo efficacy of bropirimine on human and murine bladder cancer. Bropirimine showed in vitro antiproliferative activity on the human bladder cancer cell lines, T 24 and KoTCC 1. This activity was not: affected by the neutralizing antibodies against IFN alpha, TNF-alpha or IL-1 beta, indicating it is the direct activity of bropirimine without involvement of cytokine production by tumor cells. Bropirimine was active at the concentrations comparable to those in serum or urine attained in clinical trials, which suggests that this direct antiproliferative activity is one of the important antitumor mechanisms of bropirimine. In in vivo experiments, bropirimine reduced the growth of transplanted murine MBT-2 and human KoTCC-1 bladder cancers by oral administration every 4 days starting on day 1, but did not show efficacy when the drug treatment was started on day 8. The antitumor activity of bropirimine was dependent on the timing for drug treatment initiation. PMID- 8687219 TI - [Expression of CD44 variant 6 and its metastatic potential in squamous cell carcinoma of the oral cavity]. AB - Using antihuman CD44 variant 6 monoclonal antibody (2F10), immunohistochemical screenings were performed for 38 oral squamous cell carcinoma cases and 10 oral mucosa in healthy cases as normal counterpart. Normal epithelium in the oral surface was stained intensely by the antibody. The reactivity was particularly strong in the spinous layers of stratified squamous epithelium. Cells in the basal layers exhibited moderate staining. In contrast, expression of CD44v6 tended to be downregulated in 38 oral squamous cell carcinoma materials. Interestingly, more faint or no staining by the anti-CD44v6 monoclonal antibody was found in the primary squamous cell carcinomas involving regional lymphnode metastasis. Downregulation of CD44v6 isoform was suggested to occur during regional lymphnode metastasis on oral squamous, cell carcinomas. PMID- 8687220 TI - [A clinical study of recurrent breast cancer]. AB - In a recent 14-year period from December 1978 to December 1993, 180 patients with breast cancer were treated at the hospital, and out of these 180 patients, 38 patients (21.1%) who had a recurrent breast cancer were clinically evaluated. The first recurrence occurred in the local skin in 13 patients, regional lymph node in 1, bone in 13, lung in 4, liver in 4 and in other areas in 3. Histologically, the incidence of scirrhous carcinoma recurrence was higher than that of papillotubular carcinomas. There was no recurrence in mucinous carcinomas. The frequency of recurrence became higher in accordance with TNM classification, namely, 6.7% in Stage I, 23.7% in Stage II, 37.5% in Stage IIIa, and 47.1% in Stage IIIb cancers. An increasing tendency in the recurrence rate was also noted with an increase of tumor diameter or lymph node metastasis. Otherwise, there was no difference in cumulative survival after recurrence between TNM classification. There were no correlations between the estrogen receptor and incidence of recurrence or 5-year survival rate. The disease free interval (DFI) was less than 2 years in about 60% of the recurrent cases. DFI of bone metastasis was longer than for the other sites of recurrence. The survival rate increased according to prolongation of DFI. After through evaluation of these results, one should pay close attention to follow-up after mastectomy. PMID- 8687221 TI - [Low-dose combination cytarabine and etoposide for myeloid crisis transformed from unclassified chronic myeloproliferative disorder]. AB - A 65-year-old man visited our department for further leukocytosis examination. Hematological examinations disclosed elevation of the leukocyte count with left deviation. The neutrophilic alkaline phosphatase score was reduced. Bone marrow was hypercellular and consisted almost entirely of granulocytic cells in all stages of maturation. However, cytogenetic analysis revealed no Philadelphia chromosome, and genotypic analysis disclosed no bcr rearrangement. He was ultimately diagnosed as having unclassified chronic myeloproliferative disorder. He had been followed without chemotherapy, and he developed blastic crises (CD10+, CD13+, CD24+). Chemotherapy was effective, and then he was followed with carboquone. However, myeloid crisis (CD13+, CD33+) developed again. Standard chemotherapies had no effect, he developed pneumonia, and he was in poor general condition. Therefore, low-dose combination with cytarabine and etoposide was performed. The result was that the blasts disappeared, his general condition improved and infection was reduced. Major side effects were absent; however, the blasts proliferated again after the treatment was discontinued. In conclusion, this combination may be useful treatment for myeloid blastic crises even if the patient is in poor condition. But the modification of the administration schedule requires some consideration. PMID- 8687222 TI - [A combination chemotherapy with CDDP and 5-FU effective for pulmonary metastases in a case of parotid gland carcinoma]. AB - The patient was a 40-year-old female (154 cm, 45 kg). Several months after receiving radiotherapy, surgery and chemotherapy (Epi-ADR, CDDP, PEP) for an undifferentiated carcinoma of the left parotid gland, she had multiple pulmonary metastases without local recurrence. Following 2 cycles of combination chemotherapy with CDDP (30 mg/1 hr, days 1 approximately 5) and 5-FU (1,000 mg/24 hrs, days 2 approximately 6), most pulmonary nodules disappeared. For the remaining pulmonary nodules, one cycle of combination chemotherapy with 5-FU (850 mg/24 hrs, days 1 approximately 5), leucovorin (9 mg x 3/day, days 1 approximately 5) and CDDP (110 mg/2 hrs, day 7) was added, but further improvement was not obtained on chest CT. Side effects were tolerable in both regimens. It was suggested that the combination chemotherapy with CDDP and 5-FU might be useful for the treatment of advanced parotid gland carcinomas. PMID- 8687223 TI - [A case report of concomitant UFT-E and CDDP against lung epidermoid carcinoma]. AB - A 52-year-old male with the chief complaint of hemo-sputum was diagnosed after detailed examination as epidermoid carcinoma in the right upper lobe bronchus through the bifurcation. Thoracotomy revealed infiltration of carcinoma into the right main pulmonary artery and the superior vena cava, which could not be excised. Subsequent postoperative radiotherapy (69 Gy) showed NC. Then concomitant administration of UFT-E and a low dose of CDDP was started on an outpatient basis. After the third course of treatment (six weeks per course), a significant reduction was noted in the size of the carcinoma. Bronchoscopy revealed CR with the elimination of carcinoma to mere traces. Besides the myelosuppression seen at the end of the second course of treatment, which resulted in a two-week hospitalization for blood transfusion, no adverse effect prevented the patient from continuing the outpatient treatment courses and from returning to work. We consider that the treatment was very successful not only for its effectiveness in reducing the carcinoma but also for the high QOL achieved. PMID- 8687224 TI - [A case of recurrent breast carcinoma with metastatic foci in the lung and pleura treated successfully with biochemical modulation of 5-fluorouracil by low-dose cisplatin]. AB - A 65-year-old female received nipple preserved total glandectomy for breast carcinoma. A 250 mg dose of epirubicin was administered as an adjuvant. After a three-year disease-free interval, breast carcinoma recurred in the lung and pleura. We then used biochemical modulation of 5-fluorouracil by low-dose cisplatin. One course of biochemical modulation resulted in eighty-three percent tumor regression and complete disappearance of the pleural effusion for over six months. PMID- 8687225 TI - [A successful treatment using SMANCS-TAE for hepatocellular carcinoma with tumor thrombus in the portal trunk]. AB - A 62-year-old man was admitted to our hospital for treatment of HCC with a thrombus growing from the right branch to the trunk of the portal vein. His hepatic functional reserve was fairly good. Serum levels of AFP and PIVKA-II were elevated to 1,780 ng/ml and 27 AU-ml, respectively. The hepatic arteriogram showed a hypervascular tumor approximately 4 cm in diameter in the right anterior segment and many ill-defined small tumor stains around the main tumor. Portal phase of superior mesenteric arteriogram revealed filling defect in the portal trunk, and no visualization of the right branch of portal vein. SMANCS-Lipiodol was infused via right hepatic artery, and Spongel was infused via right anterior branch of hepatic artery. Three months after the first therapy, the tumor markers normalized. A computed tomography scan showed that the main tumor and the tumor thrombus were markedly decreased in size, whereas the hepatic angiogram revealed tumor stains around the main tumor. SMANCS-Lipiodol was again infused via proper hepatic artery. He has remained well for 16 months after the first treatment. The combination of the arterial infusion of SMANCS-Lipiodol with the selective TAE was very effective for this case, probably because his hepatic functional reserve was fairly good and the left branch of portal vein was patent. It was suggested that SMANCS-Lipiodol with the selective TAE could be one therapy to be considered for a patient like this case. PMID- 8687226 TI - [A case of effective chemotherapy by combination of 5'-DFUR and MMC for recurrent colon cancer with multiple liver metastasis]. AB - A 63-year-old male had multiple liver metastasis about 7 months after right hemicolectomy. Combination chemotherapy of 5'-DFUR and MMC was started about 2 months after the diagnosis of recurrence. The abdominal US showed a remarkable decrease in size and number of liver metastatic foci 4 weeks after the beginning of this therapy. As this response was continued for 18 weeks by abdominal CT, this was considered to be a case of partial response (PR). We consider that the combination chemotherapy of 5'-DFUR and MMC is available for patient having recurrent colon cancer with multiple liver metastasis. PMID- 8687227 TI - [Clinical implication of p53 analysis on DNA-damaging therapies of human gastric and rectal cancers]. PMID- 8687228 TI - [Therapeutic effect of adenovirus-mediated transfer of the wild-type p53 gene with cisplatin]. PMID- 8687229 TI - [Study on the combined preoperative treatment with CDDP and HCFU for gastric cancer]. PMID- 8687230 TI - [Prognostic factors of bone and soft tissue sarcoma]. AB - The prognosis of bone and soft tissue sarcoma is influenced by factors such as pulmonary metastasis, local curability and sensitivity to chemotherapy. In cases with pulmonary lesion, the prognosis has not been favorable, but recently long term survivors are increasing in number by effective chemotherapy, and the removal of primary and metastatic lesions. As in cases without metastatic lesions, the prognosis of high-grade sarcoma were influenced by local curability and sensitivity to chemotherapy. On the other hand, the prognosis in low grade sarcoma is mainly decided by local curability. To assure local curability the following should be considered. 1) safety surgical margin, 2) preoperative radiation therapy if the safety margin is not predicted, and 3) risk factors in local curability, which are lymph node metastasis, skip metastasis and tumor thrombus. If these risk factors are detected before operation, a more radical procedure should be planned. Moreover, cutaneous angiosarcoma and epithelioid sarcoma, which are occasionally associated with these risk factors, should be operated by ablative procedure even if the risk factors are not detected. 4) In cases with pathological fracture or inadequately operated, surgical intervention to prevent transplantation should be undertaken as soon as possible. Effective chemotherapy could improve the prognosis of high grade sarcoma. Thus, chemotherapy should be used for osteosarcoma, Ewings sarcoma, round cell sarcoma etc. However, non-effective chemotherapy might make the prognosis worse. Therefore, alternative administration of effective chemotherapeutic agents proved by clinical evaluation would be more reasonable than remaining with a certain protocol. PMID- 8687231 TI - [The potential of interleukin-12 for use in cancer therapy]. AB - Interleukin-12 (IL-12) is a cytokine that exerts immunoregulatory effects on T cells and natural killer cells, playing a unique role in promoting type 1 T helper cell responses and, thereby, cell-mediated immunity. IL-12 has been shown to exert striking therapeutic effects at nontoxic doses in mouse tumor models and in mouse models of a variety of infectious diseases and airway inflammation. In mouse tumor models, the therapeutic effects of IL-12 have been shown to result from its immunoenhancing activity, requiring T cells and IFN-gamma. Administration of IL-12 can result in antiangiogenic effects that may also contribute to its antitumor activity in some models. Enhanced antitumor effects may be achieved by administering IL-12 in combination with certain other cytokines or with radiotherapy or chemotherapy. The striking therapeutic effects of IL-12 in these preclinical models have led to the initiation of clinical trials to examine the potential therapeutic activity of IL-12 in human cancer patients and in patients with human immunodeficiency virus infection or with chronic hepatitis B or C virus infections. PMID- 8687232 TI - [Prognostic factors for esophageal cancer--from the viewpoint of molecular biology]. AB - The prognostic factors for esophageal cancer from the viewpoint of molecular biology are reviewed. Among several oncogenes and suppressor genes erbB, int2/hst1/Cyclin D1 and MDM2 gene amplifications are significant prognostic factors for esophageal cancer. The value of p53 mutation, and expression of matrix metalloproteinase (MMPs) in the prediction of patients' survival are controversial, so further research is needed. High expression of tumor proliferation-related factors (Ki67, PCNA, and AgNOR), abnormalities of adhesion molecule (E-Cadherin, alpha-Catenin), activation of autocrine mechanism of growth factor (EGFR-TGF alpha, EGF), and DNA ploidy pattern, which is thought to be the result of an accumulation of genomic abnormalities are also prognostic factors for esophageal cancer. PMID- 8687233 TI - [Prognostic factors of colon cancer from a molecular biology standpoint]. AB - It has been reported that several genes may be good indicators for determining biological behavior, including the prognosis, of colorectal cancers. We have summarized these reported genes, such as tumor suppressor gene, oncogenes, metastasis suppressor gene, adhesion molecules, growth factors, proteinases, and others, including microsatellite instability. Some of the genes such as p53, DCC, c-met, or matrix metalloproteinase are considered to be reliable for determining biological aggressiveness. We introduced several interesting genes which we are focusing using cDNA subtraction library analysis. We hope that these genes are well combined for best analysis of the biological behavior of colorectal cancers and use for practical clinical analysis. In addition, we hope that novel important genes indicative for prognosis will be found. PMID- 8687234 TI - [Genetic abnormalities in lung cancer and their prognostic implications]. AB - Recent advances in molecular biology have revealed various genetic lesions in lung cancer. Mutations of the K-ras gene, amplification or overexpression of myc family genes, erbB2 gene, or bcl2 gene are frequent genetic changes of oncogenes in lung cancer. Inactivation of tumor suppressor genes such as Rb gene, p53 gene, or p16 gene are also seen rather frequently. Furthermore, loss of heterozygosity at certain chromosomal arms such as 3p, 5q, 18q and 22q suggesting inactivation of yet unidentified tumor suppressor genes, also occurs in a significant proportion of lung cancers. Most of these genetic lesions have been reported to be associated with a poor prognostic outcome of the patients. However, great controversy exists as to whether a certain genetic lesion is really a prognostic marker. For example, although about 20 studies have been published, the prognostic implications of the p53 gene for patients with lung cancer still remain unclear. Little is known about the mechanism through which a certain genetic change affects the patient's prognosis. To ultimately improve the prognosis of patients with this deadly disease, definitive studies on which subsequent clinical trials can rely are much awaited. PMID- 8687235 TI - [Molecular prognostic markers for urogenital cancers]. AB - Analysis of the molecular background underlying the development and progression of human cancer is very important for understanding the disease as well as to obtain new molecular markers indicating the prognosis. Several important genes such as oncogenes and tumor suppressor genes might be altered in stepwise fashion in human carcinogenesis. Here, molecular changes of these genes found in major urogenital cancers were described from the viewpoint of new molecular prognostic markers. PMID- 8687236 TI - Hypothyroidism and spontaneous abortions among Hanford, Washington, downwinders. AB - Spontaneous abortions occurred more than twice as frequently in hypothyroid women, compared with nonhypothyroid women. Both groups of women had lived in the same environment during the same period of time. The high incidence of hypothyroidism in a cohort of several hundred women who lived downwind of the Hanford, Washington, nuclear installation was likely associated with environmental contamination from deliberate releases of radioactive iodine from the facility. PMID- 8687237 TI - Is occupationally induced exposure to radiation a risk factor of thyroid nodule formation? AB - The prevalence of thyroid nodules was studied with ultrasonography in a group of male hospital workers (n = 44) who had been exposed occupationally to x-rays. This group was compared with a group of nonexposed workers (n = 88) who were age- and sex-matched with the exposed workers. Thyroid nodules were detected in 18 (41%) of the exposed workers, compared with 11 (13%) of the nonexposed controls. Both groups were subdivided with respect to age (i.e., 30-39 y, 40-49 y, 50-59 y), and there was a higher and significant relative risk for thyroid nodule formation in the exposed group. We also divided the groups into subgroups according to levels of exposure (i.e., nonexposed, exposed for < 20 y, and exposed for > 20 y), and a significant result was obtained with the linear-trend chi-square test. The preliminary results of our study suggest that occupationally induced exposure to radiation may be a risk factor for thyroid nodule formation. PMID- 8687238 TI - Epidemiological study of the systemic ophthalmological effects of carbon disulfide. AB - A total of 123 male viscose rayon workers who were exposed to carbon disulfide, and an additional 67 workers who were not exposed to any toxic agent in the working environment, underwent a thorough ophthalmological examination. The relationship between exposure and ophthalmological results was analyzed with univariate and multivariate methods. The most striking findings were strong associations between exposure and the 100-HUE color vision score and excess of microaneurysms in the exposed group. The current threshold limit value appeared to protect against these effects. PMID- 8687239 TI - Organochlorine compounds: Risk of non-Hodgkin's lymphoma and breast cancer? AB - Organochlorines (i.e., synthetic chlorinated hydrocarbon compounds) are widespread, environmental contaminants that are present throughout the United States. Strong epidemiological evidence has linked occupational exposure to a high incidence of non-Hodgkin's lymphoma. Recently, it has been postulated that exposure to organochlorines increases the risk of developing breast cancer. Human data on this issue remain insufficient, but recent results are very consistent. Observations in human populations of the immunotoxic and hormone-mimicking properties of some organochlorines add biological plausibility to the epidemiologic findings. Limitations in our ability to measure organochlorine exposure still preclude a quantitative risk assessment, relative to these cancer endpoints. Public health action with respect to restriction of ongoing production and use of organochlorines, however, appears warranted for purposes of prevention. PMID- 8687240 TI - Mortality among workers exposed to carbon disulfide. AB - Mortality experience was investigated at a plant in Ontario that produced viscose rayon, with carbon disulfide as a main raw material. Work-history records for 279 deceased workers at the plant (plant A) were obtained and compared with those for 511 deceased workers at a pulp and paper plant in the same city (plant B). In a proportional mortality analysis, using as a reference the general population of Ontario, at both plants there were fewer deaths from ischemic heart disease than expected (the proportional mortality ratios [PMRs] were 83 at plant A and 95 at plant B) but more deaths than expected from cerebrovascular disease (PMRs were 115 at plant A and 149 at plant B). In a subgroup of plant A workers who had been employed in high-carbon-disulfide exposure areas, deaths from ischemic heart disease were less than expected (PMR = 82), particularly among those who worked in these areas for more than 5 y. Most deaths occurred among those aged 65 y or more. Mortality from strokes, however, was greater than expected (PMR = 207, p < .05); the excess was confined to workers who died at age 65 y or older (PMR = 229, p = .01). Proportional mortality from strokes was also increased in the pulp workers among those who died at age 65 y or older (PMR = 153). In a case-control analysis, the risk of ischemic heart disease at plant A was slightly less than at plant B (odds ratio (OR] = 0.92, 95% confidence interval [CI] = 0.60-1.42), with no association between risk and years worked in high-carbon-disulfide areas (OR/y = 0.99, 95% CI = 0.94-1.03). Among those who died at age 65 y or older, the risk of stroke in the high-exposure subgroup was (a) increased significantly, compared with other plant A workers (OR = 4.92, 95% CI = 1.66-14.65); and (b) increased slightly, compared with plant B workers (OR = 1.37, 95% CI = 0.83-2.26). These results suggested an unusually low risk of strokes among other plant A workers. The risk of stroke was associated with years in high-carbon-disulfide areas (OR/y = 1.03, 95% CI = 0.96-1.1 0). The observed increase in proportional mortality from strokes may represent a chance finding, but a causal role for exposure cannot be excluded. PMID- 8687241 TI - Symptoms and health status in individuals with multiple chemical sensitivities syndrome from four reported sensitizing exposures and a general population comparison group. AB - Self-reported information about health and mental health status and history on (a) three diverse samples of individuals who reported multiple chemical sensitivities syndrome (n = 60) and (b) one sample of the general population (n = 60) was collected by telephone interview. Subjects from the general population were selected randomly from the telephone directory and were matched for age, gender, and socioeconomic status with index subjects. Data on an additional 10 subjects with multiple chemical sensitivities syndrome were also available for comparison on many of the variables of interest. The four diverse groups of patients with multiple chemical sensitivities syndrome had very similar general and specific indices of illness and sensitivity to chemicals. Members of the general population reported mild sensitivity to chemicals, and even those with more sensitivity differed from the multiple chemical sensitivities syndrome groups with respect to number and types of symptoms reported, duration and frequency of response, and associated features. Multiple chemical sensitivities syndrome was associated consistently with only one psychiatric variable, elevated negative affect scores, which were correlated significantly with the presence of illness. Patients with multiple chemical sensitivities syndrome from the diverse samples had very similar characteristic features, despite whether they had or had not received treatment by clinical ecologists. PMID- 8687242 TI - Hair lead levels related to children's classroom attention-deficit behavior. AB - The goal of this study was to evaluate the relationship between hair lead levels of children and their attention-deficit behaviors in the classroom. Scalp hair specimens were obtained from 277 first-grade pupils, teachers completed the abbreviated Boston Teacher's Rating Scale for rating classroom attention-deficit behavior, and parents completed a short questionnaire. The children's hair lead concentrations ranged from less than 1 to 11.3 ppm (microg/g). The striking dose response relationship between levels of lead and negative teacher ratings remained significant after controlling for age, ethnicity, gender, and socioeconomic status. An even stronger relationship existed between physician diagnosed attention-deficit hyperactivity disorder and hair lead in the same children. There was no apparent 'safe' threshold for lead. Scalp hair should be considered a useful clinical and epidemiologic approach for the measurement of chronic low-level lead exposure in children. PMID- 8687243 TI - Brief reversible bronchospasm resulting from bichromate exposure. AB - A 50-y-old male worker developed an asthmatic reaction after exposure to bichromate in a metal-plating plant. Evaluation included skin tests, bronchial provocation tests, and specific radioallergosorbent tests with metal salts. A 49 y-old worker who suffered from hard metal asthma was the control. These workers were not atopic, and they exhibited similar bronchial hyperresponsiveness in methacholine-PC20 (74 mg/ml versus 81 mg/ml, respectively) and IgE titers (129 IU/ml versus 130 IU/ml). Positive intradermal and patch tests to bichromate were found in the subject. A bronchial provocation test with inhalation of .01 % bichromate produced an immediate decrease in forced vital capacity in 1 s, followed by a rapid recovery within 5 min absent any treatment. There was no reaction to cobalt (1% cobalt chloride) or to nickel (2% nickel sulfate) salts. In the control, a positive bronchial provocation occurred (absent chromium) with cobalt and nickel. Administration of a subcutaneous preparation of 1 mg atropine sulfate or of 1 puff of disodium cromoglycate or beta-stimulant reduced bronchial responsiveness to methacholine-PC20, and no asthmatic reaction occurred following inhalation of 1% bichromate. No blocking of asthmatic reaction occurred after pretreatment with beclomethasone dipropionate inhalation. Administration of propranolol, however, potentiated the acute bronchoconstriction induced by bichromate. The 50-y-old worker had evidence of IgE antibody to chromium conjugated human serum albumin and to chromium-conjugated exchange resin. His serum selectively bound 51Cr, but antibodies specific to cobalt and nickel were absent. These results, if viewed collectively, suggest that bichromate exposure causes brief reversible bronchospasm via alteration of autonomic balance and increased vagal activation. PMID- 8687244 TI - Pneumoconiosis and pulmonary function defects in silica-exposed fire brick workers. AB - This study was conducted to investigate the health effects of exposure to silica dust in firebrick manufacturing plants. A cross-sectional study was designed, and the health effects in 526 exposed workers were compared with 164 nonexposed control workers. The medical examination included chest x-rays, pulmonary function tests, and a respiratory symptom questionnaire. Radiological evidence of pneumoconiosis was evident in 6.9% of the exposed firebrick workers, and the prevalence of pneumoconiosis increased with duration of employment. No differences in forced vital capacity were noted between the exposed and control groups; however, in both smokers and nonsmokers of the exposed group, forced expiratory flow in 1 s/forced vital capacity, mean maximal expiratory flow, forced expiratory flow at 50% vital capacity, and forced expiratory flow at 75% vital capacity were significantly lower than in the control group. Pulmonary function decreased as the duration of employment increased. The exposed group experienced significantly more wheezing, compared with the control group. There was evidence of a dose-response relationship between prevalence of pneumoconiosis/pulmonary function defects and estimated dust exposure levels. Pneumoconiosis and pulmonary function defects occurred frequently in workers who participated in the crushing and burning operations, both of which cause exposure to high levels of silica dust. We concluded that exposure to silica dust in workers at firebrick factories leads to radiological changes, pneumoconiosis, and pulmonary function damage. PMID- 8687245 TI - Total and inorganic mercury in breast milk in relation to fish consumption and amalgam in lactating women. AB - Total mercury concentrations (mean +/- standard deviation) in breast milk, blood, and hair samples collected 6 wk after delivery from 30 women who lived in the north of Sweden were 0.6 +/- 0.4 ng/g (3.0 +/- 2.0 nmol/kg), 2.3 +/- 1.0 ng/g (11.5 +/- 5.0 nmol/kg), and 0.28 +/- 0.16 microg/g (1.40 +/- 0.80 micromol/kg), respectively. In milk, an average of 51% of total mercury was in the form of inorganic mercury, whereas in blood an average of only 26% was present in the inorganic form. Total and inorganic mercury levels in blood (r = .55, p = .003; and r = .46, p = .01 6; respectively) and milk (r = .47, p = .01; and r = .45, p = .018; respectively) were correlated with the number of amalgam fillings. The concentrations of total mercury and organic mercury (calculated by subtraction of inorganic mercury from total mercury) in blood (r = .59, p = .0006, and r = .56, p = .001; respectively) and total mercury in hair (r = .52, p = .006) were correlated with the estimated recent exposure to methylmercury via intake of fish. There was no significant between the milk levels of mercury in any chemical form and the estimated methylmercury intake. A significant correlation was found between levels of total mercury in blood and in milk (r = .66, p = .0001), with milk levels being an average of 27% of the blood levels. There was an association between inorganic mercury in blood and milk (r = .96, p < .0001); the average level of inorganic mercury in milk was 55% of the level of inorganic mercury in blood. No significant correlations were found between the levels of any form of mercury in milk and the levels of organic mercury in blood. The results indicated that there was an efficient transfer of inorganic mercury from blood to milk and that, in this population, mercury from amalgam fillings was the main source of mercury in milk. Exposure of the infant to mercury from breast milk was calculated to range up to 0.3 microg/kg x d, of which approximately one-half was inorganic mercury. This exposure, however, corresponds to approximately one-half the tolerable daily intake for adults recommended by the World Health Organization. We concluded that efforts should be made to decrease mercury burden in fertile women. PMID- 8687246 TI - Analysis of risk factors in a cluster of childhood acute lymphoblastic leukemia. AB - A case-control investigation of childhood acute lymphoblastic leukemia was conducted in the town of Carbonia (Sardinia, Italy). Parents of 9 cases diagnosed between 1980 and 1989 and 36 controls were interviewed at their respective residences. None of the risk factors analyzed was associated significantly with childhood acute lymphoblastic leukemia. The following were associated with an increased risk for childhood acute lymphoblastic leukemia: parents born outside of Carbonia, family history of cancer, alcohol consumption by fathers that exceeded 60 g/d, exposure of fathers to solvents at their workplaces, maternal smoking, use of antinausea medications during pregnancy, and presence of a well in the backyard. Chance and recall bias likely played a role in generating positive associations. The increases in childhood leukemia risk associated with the presence of a well and with use of antinausea medications during pregnancy are consistent with previous reports and require further investigation. PMID- 8687247 TI - Knowledge about indoor radon in the United States: 1990 National Health Interview Survey. AB - The Year 2000 objectives for environmental health include radon testing in 40% of residences overall and in 50% of residences that house a smoker, former smoker, or a child. Baseline data about radon and radon testing were determined by questions included in the 1990 Health Promotion and Disease Prevention supplement for the National Health Interview Survey. Minorities and individuals with low income or minimal education were significantly less likely to have heard of indoor radon than were whites and those with more education or income. In this survey, only 3%-5% of residences had been tested for radon. A substantial increase above the rate of testing noted for 1990 will be needed to achieve the Year 2000 objectives for indoor radon. PMID- 8687248 TI - Object relations and nursing care of persons experiencing psychosis. AB - Object-relations theory explains human behavior in terms of a person's inner experiences of others, which are called objects. Internalization of relationships, projective identification, and containment are concepts within object-relations theory that help to explain the confusing and frustrating behavior of acutely psychotic patients. These concepts also provide a framework for understanding the reactions of nurse clinicians to psychotic behaviors. This article explains the basic principles of object-relations theory, illustrates the concepts through a case study, and proposes nursing interventions from an object relations perspective. PMID- 8687249 TI - Internal and external environment of individuals with schizophrenia during alcohol and drug use. AB - Explanations for the high prevalence of alcohol and drug abuse in schizophrenia purport that substance use is related to social-affiliative needs or to symptom regulation. Neither explanation was adequate in describing substance-use episodes in the present longitudinal study. The study involved repeated interviews of 10 individuals with schizophrenia about their internal and external environment during substance use. Qualitative analyses of interview responses showed variability in multiple versus single episodes in a day and categories labeled Activities Prior to Use and Social Context of Use. Individual subject's responses each had a unique pattern that characterized their substance-use episodes. PMID- 8687250 TI - Patients' internal world experience of interacting with psychiatric nurses. AB - Research was conducted to explore the patient's perception of interaction with psychiatric nurses. In-depth interviews were conducted with 13 psychiatric patients. The interviews were conducted in two phases. In phase 1 of each interview, the focus was exploratory and phenomenological, where a single central question was posed concerning the nature of a psychiatric patient's experience of interaction with psychiatric nurses. In phase 2 of each interview, the focus was to probe for further patient experience, based on the data elicited in phase one. The results of the research show significant findings within the psychological dimension of psychiatric patients' internal environment with specific reference to: their perception of the interaction (including stereotyping, custodialism, rule enforcement, lack of intimacy, friendliness, and lack of empathy and caring); defense mechanisms, identified during the interaction as denial and avoidance; and anxiety as emotion. These results emphasize the importance of a facilitative psychiatric nurse-patient interaction to assist the patient in the promotion, maintenance, and restoration of mental health. PMID- 8687251 TI - Pattern integrations in young depressed women: Part I. AB - The enduring patterns of interpersonal relations between young depressed women and their significant others create a theater for early interventions. As noted by Hildegard Peplau, interpersonal relations include patterns that are organized around appraisals from significant others, ultimately forming the internal sense of self-regard that is deeply disrupted in depression. Pattern integrations, or the "fit" of the woman and her significant others become maintained as a way of avoiding anxiety and negative appraisals. Complementary, mutual, alternating, and antagonistic patterns have been identified by Peplau, and the relationship to anxiety, the maintenance of self-worth, and the therapeutic use of these patterns by the nurse are explored. PMID- 8687252 TI - Pattern integrations in young depressed women: Part II. AB - Using Hildegard Peplau's theoretical model and focusing on the concept of pattern integrations, clinical data from a pilot intervention program for depressed women were analyzed. The program consisted of a collaborative relationship between primary-care providers and two Psychiatric-Mental Health Clinical Nurse Specialists in which women experiencing symptoms of depression were identified and referred to the research program. Data derived from clinical intervention done over a 4-month period with 6 women (42 hours of clinical tapes) was used for analysis. Clusters of behaviors constituting pattern integrations were analyzed for the reciprocal interactions of the nurses and the clients. Four pattern integrations common to the women in the sample were identified. Clinical examples and a framework for intervention using the patterns integrations is presented. PMID- 8687253 TI - Understanding and helping depressed women. AB - A grounded theory study was conducted to examine the process of recovery for women who have been depressed. The purpose of this study was to enhance our understanding of the recovery process of women with depression by exploring the women's experience directly. The study found that the basic social psychological process of women's recovery from depression could be summarized as (re)defining the self. (Re)Defining the self differs significantly from the common conceptualisations of depression recovery, which focus on signs and symptoms without consideration of the woman or the social context in which her life is situated. (Re)Defining the self is a model that considers the woman as a holistic organism existing within a complex network of social interactions. Because (re)defining the self provides a new perspective for understanding women's experience with depression, there are significant implications for the way we provide nursing care. This paper discusses those implications. PMID- 8687254 TI - Patients' perceptions of psychiatric home care. AB - A qualitative study was designed to explore patients' perceptions of psychiatric home care. Nine patients receiving psychiatric home care from a private home-care agency were interviewed using a tool developed by the researcher. Demographic data was collected from the patients' charts. Descriptive statistics were used to analyze characteristics of the patients. Content analysis was conducted on interview transcripts. The aspects of psychiatric home care that patients described as most valuable include companionship, counseling, assistance with housework, and monitoring of vital signs. Patients described positive effects of psychiatric home care on their compliance with psychotropic medication regimens and on their relationships with family members. All patients in this sample received psychiatric services in addition to psychiatric home care. Psychiatric home care appeared to be a major factor in maintaining patients in the community. Nursing implications, limitations of the study, and recommendations for further research are presented. PMID- 8687255 TI - Psychiatric nurses' attitudes toward sexuality, sexual assault/rape, and incest. AB - This descriptive, exploratory study examined psychiatric nurses' attitudes towards sexuality, sexual assault/rape, and incest, and explored the relationships between these attitudes and the personal characteristics of the nurse. Contrary to previous research on nurses in nonpsychiatric settings, the nurses in this Canadian study had favorable attitudes towards sexuality and did not subscribe to attitudes of victim blaming in sexual assault/rape and incest. The strongest predictor of attitudes was age of the nurse (p < .02); cultural/ethnic background may also be associated with attitudes (p < .02). The results indicate a need to develop more precise measures of attitude for psychiatric nurses. PMID- 8687256 TI - The Lyme disease controversy. Social and financial costs of misdiagnosis and mismanagement. AB - Since it was first described, Lyme disease has emerged as a major public health concern, complicated by an emerging body of beliefs often at odds with scientifically established facts. Disagreement between the belief systems has led to confusion and anxiety, resulting in an alternative, but unproved, approach to management. When Lyme disease is incorrectly diagnosed, the debility related to the true, underlying problems remains unaddressed. The financial cost of the overdiagnosis and overtreatment of Lyme disease includes expenses related to testing and therapy and those of side effects and toxic effects of these treatments. Harder to estimate are the emotional costs to society of incorrectly burdening patients with the diagnosis of a chronic, incurable illness, with attendant assumption of a sick role and a disabled self-image. Better education is a major component of the solution to the problems of misdiagnosis and mistreatment of Lyme disease. PMID- 8687257 TI - Was Osler Verdeutsched? AB - William Osler, considered one of the preeminent American physicians at the turn of the century, studied in North America and in Europe. His later influence in molding the teaching and the specialty of internal medicine is still felt. One may ask to what extent his ideas were generated or influenced by his extensive German experiences? Most certainly his exposure to pathology in Germany was profound and lasting. While there can be no doubt that Osler was a Germanophile throughout his career, one has to conclude that his academic influences were more English and not exclusively German. He was cosmopolitan and used and promulgated good ideas wherever he found them. PMID- 8687258 TI - Prehospital administration of aspirin in patients with unstable angina and acute myocardial infarction. AB - Both experimental and clinical studies suggest that the prehospital administration of aspirin may be beneficial in patients with unstable angina and acute myocardial infarction. Experimental studies indicate that within 1 hour of aspirin administration, serum levels peak and significant inhibition of platelet aggregation occurs. Clinical studies demonstrate that early treatment with aspirin reduces mortality and reinfarction rates in patients with unstable angina and acute myocardial infarction. However, these same studies also indicate that prolonged delays often occur before in-hospital therapy with aspirin is initiated. Since the potential benefits are great and the risks and costs are low, physicians should encourage the prehospital administration of aspirin in patients with symptoms suggestive of unstable angina or acute myocardial infarction. PMID- 8687259 TI - Long-and short-acting beta 2-adrenergic agonists. Effects on airway function in patients with asthma. AB - Inhaled beta-adrenergic agonist bronchodilators are integral components of effective asthma treatment. However, the risk of asthma morbidity and mortality associated with the regular use of certain inhaled beta-agonists was first noted in the United Kingdom during the 1960s and in New Zealand during the 1970s. There are also concerns that long-term use of both long-acting and short-acting inhaled beta-agonists may cause a loss of asthma control in some patients. These experiences have caused some investigators to question the safety of inhaled beta agonists in patients with asthma. This review attempts to address these issues, which are of concern to both physicians and patients alike, and aims to increase the clinician's understanding and awareness of the problems and treatment options. PMID- 8687260 TI - Mortality following fractures in older women. The study of osteoporotic fractures. AB - BACKGROUND: Most investigators have hypothesized that the increase in mortality following osteoporotic fractures reflects poor underlying health status in addition to the acute effects of the fracture. METHODS: We observed 9704 ambulatory women aged 65 years or older enrolled in the Study of Osteoporotic Fractures. We obtained reports of fractures and deaths every 4 months and reviewed death certificates and hospital discharge summaries. Multivariable proportional hazards models were used to determine the association between fractures and age-adjusted mortality. RESULTS: During a mean follow-up of 5.9 years, 1737 women had nonspine fractures, with a postfracture mortality rate of 3 per 100 woman-years, compared with 1.8 per 100 woman-years in those who did not have fractures (P < .001). After adjusting for other factors associated with mortality, women (n = 361) with fractures of the hip or pelvis had a 2.4-fold (95% confidence interval, 1.7-3.3) increase in mortality. However, only 9 (14%) of the 64 deaths that occurred after hip or pelvic fractures were caused or hastened by the fracture. By contrast, 11 (17%) of these deaths seemed to have been a result of chronic conditions that has contributed to the hip or pelvic fracture, and 44 (69%) of the deaths were not clearly related to the fracture. CONCLUSIONS: Mortality is increased following several types of fractures in older women. Most of the increase following hip and pelvic fractures is due to underlying conditions and probably would not be affected by reductions in the incidence of these fractures. PMID- 8687261 TI - Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis. A prospective observational cohort study. AB - BACKGROUND: Gastrointestinal tract (GI) complications associated with nonsteroidal anti-inflammatory drug (NSAID) use are the most common serious adverse drug reactions in the United States. Nonsteroidal anti-inflammatory drugs cause both minor GI side effects such as abdominal pain and vomiting and serious GI events such as ulcers and bleeding. This study evaluates the event rates for all NSAID-induced GI complications in patients with rheumatoid arthritis, describes the time course of these events, and evaluates the role of prophylactic therapy with antacids and H2 receptor antagonists. METHODS: We studied 1921 patients with rheumatoid arthritis from 8 ARAMIS (Arthritis, Rheumatism, and Aging Medical Information System) centers. Patients were selected for the study if they were treated with NSAIDs and had at least 2.5 years of observation available. Information on GI complications attributed to NSAIDs was obtained from validated patient self-reports collected every 6 months and supplemented by review of hospital records for all hospitalizations. RESULTS: Approximately 15% of the 1921 patients reported an NSAID-induced GI side effect during the 2.5 year observation period. Forty-two patients had a serious GI complication requiring hospitalization; 34 of these 42 patients did not have a preceding GI side effect. Patients who were taking antacids and H2 receptor antagonists did not have a significantly lower risk for serious GI complications than did those not taking such medications. Asymptomatic patients taking these medications had a significantly higher risk for GI complications compared with those who did not take these medications (standardized odds ratio, 2.14;95% confidence interval, 1.06-4.32). CONCLUSIONS: A large majority of patients with serious GI complications do not have preceding mild side effects. Prophylactic treatment with antacids and H2 receptor antagonists is of questionable value and may increase the risk for subsequent serious GI complications. PMID- 8687262 TI - Side effects associated with influenza vaccination in healthy working adults. A randomized, placebo-controlled trial. AB - BACKGROUND: Concern about side effects is a barrier to influenza vaccination. This randomized, double-blind, placebo-controlled trial assessed side effects following vaccination among healthy working adults. METHODS: Healthy working adults were recruited during October and November 1994 and were randomized to receive influenza vaccine or placebo injections. Local and systemic symptoms during the week following the injection were evaluated through structured telephone interviews. RESULTS: Of 849 subjects enrolled in the study, 425 received a placebo and 424 received influenza vaccine. Baseline characteristics were similar between the groups, and 99% of subjects completed interviews to assess side effects after the study injection. No differences were seen between the 2 groups for the systemic symptoms of fever, myalgias, fatigue, malaise, or headaches. Overall, 35.2% of placebo and 34.1% of vaccine recipients reported at least 1 of these systemic symptoms (P = .78, chi 2). Vaccine recipients reported a higher rate of arm soreness at the injection site than did placebo recipients (63.8% vs 24.1%, P < .001). Local reactions were mild in both groups and infrequently resulted in decreased use of the arm. After logistic regression, female sex (odds ratio [OR], 1.5;95% confidence interval [CI], 1.1-2.1), age younger than 40 years (OR, 1.6;95% CI, 1.2-2.2), and coincidental upper respiratory tract illness (OR, 4.6; 95% CI, 3.2-6.6) were independently associated with higher rates of systemic symptoms. In the multivariate model, vaccine again was not associated with systemic symptoms (OR, 0.9; 95% CI, 0.7 1.2). CONCLUSIONS: Influenza vaccination of healthy working adults is not associated with higher rates of systemic symptoms when compared with placebo injection. These findings should be useful to physicians and other health care providers as they counsel patients to take advantage of an important opportunity for disease prevention and health protection. PMID- 8687263 TI - Computer reminders to implement preventive care guidelines for hospitalized patients. AB - BACKGROUND: Hospitalizations are an opportunity to provide preventive care. OBJECTIVE: To determine if computer reminders, which we have shown to be effective in our ambulatory care setting, increasing the provision of inpatient preventive care. METHODS: Randomized, controlled trial on the general medicine inpatient service of an urban, university-affiliated public hospital. Study subjects were 78 house staff rotating on the 6 general medicine services. The intervention was reminders to physicians printed on daily rounds reports about preventive care for which their patients were eligible, and suggested orders for preventive care provided through the physicians' workstations. The preventive care guidelines were derived from the US Preventive Care Task Force recommendations. Compliance with preventive care guidelines and house staff attitudes toward providing preventive care to hospitalized patients were the main outcome measures. RESULTS: No significant differences were seen between intervention and control physicians in compliance with preventive care guidelines in the aggregate or when individual preventive care actions individual preventive care actions were analyzed. This was true even though most physicians endorsed providing most kinds of preventive care for hospitalized patients. CONCLUSIONS: Despite past success in increasing preventive care in the outpatient setting, we were unable, using a moderately intensive intervention, to increase the provision of preventive care during hospitalizations. The physicians providing care during the hospitalization were not the patients' primary care physicians, which proved to be an important barrier. More intensive interventions, or more direct linkages between inpatient and outpatient care providers, may be required to overcome this resistance. PMID- 8687264 TI - Factors associated with change in resuscitation preference of seriously ill patients. The SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments. AB - BACKGROUND: During serious illness, patient preferences regarding life-sustaining treatments play an important role in medical decisions. However, little is known about life-sustaining preference stability in this population or about factors associated with preference change. METHODS: We evaluated 2-month cardiopulmonary resuscitation (CPR) preference stability in a cohort of 1590 seriously ill hospitalized patients at 5 acute care teaching hospitals. Using multiple logistic regression, we measured the association of patient demographic and health-related factors (quality of life, function, depression, prognosis, and diagnostic group) with change in CPR preference between interviews. RESULTS: Of 1590 patients analyzed, 73% of patients preferred CPR at baseline interview and 70% chose CPR at follow-up. Preference stability was 80% overall-85% in patients initially preferring CPR and 69% in those initially choosing do not resuscitate (DNR). For patients initially preferring CPR, older age, non-African American race, and greater depression at baseline were independently associated with a change to preferring DNR at follow-up. For patients initially preferring DNR, younger age, male gender, less depression at baseline, improvement in depression between interviews, and an initial admission diagnosis of acute respiratory failure or multiorgan system failure were associated with a change to preferring CPR at follow-up. For patients initially preferring DNR, patients with substantial improvements in depression score between interviews were more than 5 times as likely to change preference to CPR than were patients with substantial worsening in depression score. CONCLUSIONS: More than two thirds of seriously ill patients prefer CPR for cardiac arrest and 80% had stable preferences over 2 months. Factors associated with preference change suggest that depression may lead patients to refuse life-sustaining care. Providers should evaluate mood state when eliciting patients' preferences for life-sustaining treatments. PMID- 8687265 TI - Preferences for home vs hospital care among low-risk patients with community acquired pneumonia. AB - OBJECTIVE: To measure preferences for initial outpatient vs hospital care among low-risk patients who were being actively treated for community-acquired pneumonia (CAP). METHODS: Study patients included 159 patients with CAP, 57 (36%) initially hospitalized, who were identified as being at low risk for early mortality using a validated prediction model. Subjects were enrolled from university and community health care facilities located in Boston, Mass, Halifax, Nova Scotia, and Pittsburgh, Pa, participating in the Pneumonia Patient Outcome Research Team prospective cohort study of CAP. Three utility assessment techniques (category scaling, standard gamble, and willingness to pay) were used to measure the strength of patient preferences for the site of care for low-risk CAP. At the time of initial therapy or during the early recuperative period, patient preferences were assessed across a spectrum of potential clinical outcomes using 7 standardized pneumonia clinical vignettes. RESULTS: Responses to the 7 pneumonia scenarios indicated that most patients consistently preferred outpatient-based therapy. This pattern was observed regardless of whether patients had actually been treated initially at home or in a hospital. Patients (74%) who stated that they generally preferred home care for low-risk CAP were willing to pay a mean of 24% of 1 month's household income to be assured of this preference. Preference for home care, as measured by the category scaling and the willingness to pay, persisted after adjustment for sociodemographic and baseline health status covariates. Sixty nine percent of interviewed patients said that their physician alone determined whether they would be treated in the hospital or at home. Only 11% recalled being asked if they had a preference for either site of care. CONCLUSIONS: Most patients, even those treated initially in a hospital, who were at low risk for mortality from CAP prefer outpatient treatment. However, most physicians appear not to involve patients in the site-of-care decision. More explicit discussion of patient preferences for the location of care would likely yield more highly valued care by patients as well as less costly treatment for CAP. PMID- 8687266 TI - Resolution of a soft-tissue sarcoma in a patient with rheumatoid arthritis after discontinuation of azathioprine therapy. AB - An 85-year-old woman with rheumatoid arthritis that was treated with azathioprine presented with a posterior thoracic soft-tissue mass. A computed tomographic scan demonstrated a large mass in the chest wall that extended into the pleural space and several pulmonary nodules that were consistent with metastatic disease. A fine-needle biopsy was performed, and a morphologic diagnosis of sarcoma was made. As the patient was relatively asymptomatic and the lesion was inaccessible to a surgical procedure, no therapy was recommended. Therapy with azathioprine was discontinued. One year later, the mass had resolved. To our knowledge, this is the first reported case of a soft-tissue sarcoma complicating azathioprine treatment of rheumatoid arthritis. PMID- 8687267 TI - Isolated mediastinal tuberculous lymphadenitis. PMID- 8687268 TI - Understanding patient values requires communication, not empathy. PMID- 8687269 TI - Diastolic blood pressure can be reliably recorded by palpation. PMID- 8687270 TI - Cost-effectiveness of pulmonary embolism diagnosis. PMID- 8687271 TI - Influenza immunization is a safe procedure in patients undergoing long-term anticoagulation. PMID- 8687272 TI - [Unusual findings in death by hanging--reconstruction of capacity for action]. AB - A case of delayed death after suicidal hanging is presented. At first the examination of the scene did not provide any evidence of strangulation. The macroscopic and microscopic findings of the massive neck injury including cricotracheal disruption are described and discussed. In spite of this severe trauma, the capability to act was undoubtedly preserved. Death was due to hypoxia from bilateral pneumothorax caused by the massive neck injury. PMID- 8687273 TI - [Intentional homicides in the Genf canton (1971-1990)]. AB - In the 20-year period from 1971 to 1990, 114 homicide victims have been autopsied by the Universitary Institute of Forensic Medicine in Geneva. The mean annual homicide rate was 1.5/100,000 population. The sex ratio was about 1.7 males for 1 female. The authors found 1.9 Swiss citizens for 1 foreigner. The victim's mean age was 38 years. The largest number of victims were found in the age group 20-39 years (42%). 58% of victims knew their offenders (familiars, friends and acquaintances), 11% did not know their offenders (strangers) while the relationship victim-offender remained unknown in 31% of the homicide cases of which only 16% have not been elucidated. Methods equally used were firearms and stabbing (71% of casts). Alcohol was present in the blood of 25% of the victims at rates varying between 0.7 and 3.61%. Homicides were more likely to occur in the evening and at night, during weekends and during the months of May, June, July, October and November. 50% of homicides took place at the victim's home, 8% at the offender's home and 42% outside lodgings. PMID- 8687274 TI - [Blank firearms--an underestimated weapon class. Dangerousness, mechanical effect and legal classification]. AB - The dangers posed to individuals by blank-cartridge guns are frequently underestimated by German courts. A description is given to the effects, specific dangers and typical consequences of injuries caused by the use of these weapons, inclusion of blank guns in the catalogue of terms applying to weapons law and penal law as well as individual questions of penal decisions regarding their use against man. The paper comes to the conclusion that it is hardly possible to doubt any more the not insignificant probability and objective foreseeability of severe or even fatal injuries when blank guns are used against people. PMID- 8687275 TI - [Drowning by aspiration of oral saline administration]. AB - A fatal case of salt water ingestion of a 35-year old drug addict is presented. Resuscitation by emergency doctor after first-aid was not successful. Autopsy revealed the classical signs of drowning. In the sphenoid sinus sodium-chloride could be detected. The diagnosis and differential diagnosis of drowning is discussed. PMID- 8687276 TI - [Accidental CO poisoning by operating a charcoal grill]. AB - In the hut of a garden plot a male body of at first unknown identity was found. Although a natural death was assumed, autopsy was ordered by the court because of the unclear identity. On autopsy bright red post-mortem lividity was found; an assay of the blood showed 55% CO-Hb. A second inspection of the place, where the body was found, revealed that a garden grill, which had originally stood near the entrance of the hut, had been carried out into the garden. To reconstruct the case, measurements of the carbon monoxide concentration in the air of the room were carried through after starting the charcoal grill. The results showed that within 60 min. the carbon monoxide content rose to 0.21% by volume and thus clearly exceeded the limit of 0.1% by volume considered as lethal. PMID- 8687277 TI - [Lodged bullet or bullet penetration? Re-entry of a projectile and pseudo-shot]. AB - In an extended suicide an 11-year-old boy was killed by two shots into the back. In spite of corresponding entry and exit points one of the projectiles was found inside the body. By laying open the respective bullet track, examination of the deformations of the bullet, on which a total of three ricochet points were identified, and a second visit to the scene both the order in which the shots were fired and the reason why one of the projectiles was lodged inside the body, although there was an exit point, could be clarified: On firing the second shot the victim had been lying on the wooden threshold of a door, from which the projectile ricochetted. The terms "reentry" and "pseudo exit point" are discussed. The retention of the bullet in the depth of an alleged exit wound emphasizes the importance of post-mortal X-ray examinations. PMID- 8687278 TI - [Impression traces from firearms on cadaver skin]. AB - Guns may occasionally leave traces on human skin, for example by compression/impression of the tissue (esp. in the area of livores), by contact transfer of dirt, oil, and rust, or by forming the pattern of blood-smears. The case of a 31-year-old drug-addict is presented in detail: The man committed suicide by shooting himself (entrance hole under the chin). When the dead body was found there was no weapon at the scene. By careful securing of evidence and analyzing the pattern of metallisations (identified as rust from the old pistol) it was reconstructed that the suicident held the pistol (identified as Russian Tokarew TT33-7.62 mm) in his hand for many hours postmortem until it was removed by an unknown thief. PMID- 8687279 TI - Asymmetric synthesis and enantiospecificity of binding of 2-(1,2,3,4-tetrahydro-1 isoquinolyl)-ethanol derivatives to mu and kappa receptors. AB - A number of 2-(1,2,3,4-tetrahydro-1-isoquinolyl)-ethanol derivatives 7a-e have been synthesized in diastereomerically and enantiomerically pure form and have been evaluated for their binding affinity at mu and kappa opioid receptors. The amido ketones 5a-c and ent-5a-c, which were accessible by employing 3b and ent-3b for Asymmetric Electrophilic Amidoalkylation reactions, served as starting compounds. Upon reduction of 5a-c and ent-5a-c the amido alcohols l-6a-c, u-6a-c, ent-l-6a-c and ent-u-6a-c were obtained. Hydrolysis of these compounds yielded the secondary amino alcohols l-7a-c, u-7a-c, ent-l-7a-c and ent-u-7a-c and upon reductive methylation of l-7b-c, u-7b-c, ent-l-7b-c and ent-u-7b-c with CH2O and NaCNBH3 the tertiary amino alcohols l-7d-e, u-7d-e, ent-l-7d-e and ent-u-7d-e were obtained. The binding affinities of the final compounds l-7a-e, u-7a-e, ent l-7a-e and ent-u-7a-e at both the mu and the kappa receptor were strongly dependent on their stereochemistry. In each case isomers exhibited higher affinity at the mu than at the kappa receptor. For the secondary amino alcohols 7a-c the affinity at the mu receptor followed the stereochemical order l-7 > ent l-7 > ent-u-7 > u-7 whereas for the tertiary amino alcohols the order l-7 > u-7 > ent-l-7 > ent-u-7 was found. The stereoisomers l-7d and l-7e of the tertiary amino alcohols were found to be the most active compounds the latter exhibiting a Ki value of 7.17 which is close to that of Morphine (Ki = 1.64). In an in vivo model, the Writhing Test, both compounds l-7d and l-7e displayed high analgetic activity. PMID- 8687280 TI - Synthesis and smooth muscle calcium channel antagonist effects of dialkyl 1,4 dihydro-2,6-dimethyl-4-aryl-3,5-pyridinedicarboxylates containing a nitrooxy or nitrophenyl moiety in the 3-alkyl ester substituent. AB - A group of racemic 3-[2-nitrooxyethyl (1,3-dinitrooxy-2-propyl or 4 nitrophenylethyl)] 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-[2- trifluoromethylphenyl (2-nitrophenyl or 3-nitrophenyl)]-3,5 pyridinedicarboxylates 13-15 were prepared using the Hantzsch reaction that involved the condensation of 2-nitrooxyethyl 9a, 1,3-dinitrooxy-2-propyl 9b or 4 nitrophenylethyl 9c acetoacetate with isopropyl 3-aminocrotonate 11 and 2 trifluoromethyl 12a, 2-nitro 12b or 3-nitro 12c benzaldehyde. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. Compounds 13-15 exhibited superior, or equipotent, calcium channel antagonist activity (10(-8) to 10(-10) M range) relative to the reference drug nifedipine (IC50 = 1.43 x 10(-8) M). The R1 C-3 ester substituent was a determinant of calcium channel antagonist activity where the potency order was CH2CH2ONO2 > CH2CH2-C6H4-4-NO2 > or = CH(CH2ONO2)2. In contrast, the C-4 R2-aryl substituent (2-CF3-C6H4-, 2-O2N-C6H4- or 3-O2N-C6H4-) was not a major determinant of activity. Compounds 13a-15a, which possess a 3-(2 nitrooxyethyl) ester substituent exhibit superior calcium channel antagonist smooth muscle relaxant activity (IC50 = 10(-10) M range) relative to nifedipine, could serve as potential probes to investigate the in vivo release of nitric oxide (NO) which induces vascular muscle relaxation. PMID- 8687282 TI - The anti-inflammatory activity of N-substituted indazolones in mice. AB - N-Substituted indazolones were shown to be potent anti-inflammatory and analgesic agents in mice at 8 mg/kg. In addition, the agents were able to protect against death caused by endotoxins similar to those found in chronic infections. In part, the ability of these agents to suppress the inflammatory process is due to their blockage of cytokine release, e.g.TNF alpha and IL-1, as well as their inhibition of high affinity binding to receptors on target cells of inflammation. Suppressing these receptors can be linked to the inhibition by the agents of lysosomal hydrolytic enzymes, prostaglandin cyclooxygenase and 5'-lipoxygenase activities. Free radical generation involved in inflammation was also stabilized in the presence of most of these agents. PMID- 8687281 TI - (2E,4E)-N-(4-(1H-indol-3-yl)piperidin-1-yl)alkyl-5-(substituted phenyl)-2,4 pentadienamides as antiallergic agents with antihistaminic and anti slow-reacting substance (SRS) activities. AB - As an extension of our study aiming to discover a novel compound with dual activities against histamine and slow-reacting substance (SRS), we synthesized two types of indolylpiperidine derivatives, 3 and 4-20. Testing for in vivo antianaphylactic activity and for in vitro anti-SRS activity revealed that (2E,4E)-5-(3,5-dimethoxy-4-hydroxyphenyl)-N-(2-(4-(1H-indol-3-yl)+ ++piperidin-1- yl)ethyl)-2,4-pentadienamide (11) exhibited potent dual activities with ED50 = 0.89 mg/kg and IC50 = 1.43 microM, respectively. However, the plasma concentration of unchanged 11 was very low when administered orally in guinea pigs. This result can be explained by fast formation of a glucuronic acid conjugate. PMID- 8687283 TI - [Drug allergy--especially on the induction of the oral tolerance and its specificity]. PMID- 8687284 TI - [Pollen information of airborne Japanese cedar pollen using a simulation method]. AB - We have developed a simulation method of airborne Cryptomeria japonica pollen distribution on a map displayed visually on a TV screen. Each patient can be available the information where the place he or she lives. The pollen season in 1995, we served the information about airborne pollen distribution on a map and C. japonica flowering areas on a map to a local resident through TV broadcasting. To verify the simulation method, comparison was made between the result from actual pollen counting and from simulation. It was clarified that both results were comparatively agreed on daily basis. Problem about compatibility among personal computers were solved to rewrite the program of displaying the image using Visual Basic for MS-Windows and create image files. The files can be read continuously by animation software. We think the information can be offered to local resident, local clinicians and patients waiting at the clinics by use of computer networks. PMID- 8687285 TI - [Seven years study on the incidence of Japanese cedar pollinosis among university students and its transition while in college]. AB - The author has investigated the incidence of Japanese cedar pollinosis among university students, for the purpose of making a study of the relation between sensitizing to pollen antigen and manifestation of symptoms. In this report are summarized the results of seven years investigation since 1988. The percentage of specific antibody carriers in freshmen was 27.4% in 1988, and has kept the level of 32.0-38.1% from 1989 to 1993. And the incidence of pollinosis sufferers in freshmen was 12.0% in 1988, and has kept the level of 15.5-17.4% from 1989 to 1993. However in 1994 they reduced to lower levels of 29.3% and 14.7%, and this was considered to be connected with the decrease of pollen counts owing to the abnormal weather conditions of preceding year. In addition to this the author has also investigated the transition of the percentage of specific antibody carriers and the incidence of pollinosis sufferers while in college. Among the students who were matriculated before the year of 1990, the incidence of these kinds when fourth grade increased clearly (antibody carriers 38.6-43.0%, pollinosis sufferers 23.1-24.9%). However in whom matriculated in 1991, they reduced to lower levels in 1994 related to the decrease of pollen counts (antibody carriers 25.2%, pollinosis sufferers 13.6%). From above-mentioned results of investigation, it is concluded that the revelation of pollinosis symptoms has connection directly with the degree of exposure to the pollen antigen. PMID- 8687286 TI - [Endothelin-1 levels in sputum and plasma of asthmatic patient after allergen provocation]. AB - Recently, endothelin-1 (ET-1) has a potent of contractive effect to bronchial smooth muscle, and it suggests that ET-1 contributes to pathophysiology of bronchial asthma. To study the role of endothelin-1 (ET-1) in allergic asthma, we measured ET concentration in plasma and in sputum of nine allergic subjects following allergen provocation by using sandwich-enzyme immunoassay (EIA). ET-1 concentration in plasma were higher during IAR (2.31 +/- 0.24 pg/ml) (0.05 < p < 0.1) and LAR (2.55 +/- 0.27 pg/ml) (0.05 < p < 0.1) than prechallenge value (1.99 +/- 0.23 pg/ml) but there was no significant difference. On the other hand ET-1 concentration in sputum were significantly higher during IAR (14.75 +/- 2.77 pg/ml) (p < 0.05) and LAR (18.51 +/- 4.57 pg/ml) (p < 0.05) than prechallenge values (4.29 +/- 2.55 pg/ml). Thus these results suggest that ET-1 play a role of allergic bronchoconstraction (IAR and LAR) after allergen challenge. PMID- 8687287 TI - [Effect of KW-4679, an antiallergic drug, on antigen-induced airway microvascular leakage in rats passively sensitized with mouse monoclonal IgE antibody]. AB - We studied the effect of KW-4679, an antiallergic drug, on inhaled antigen induced airway microvascular leakage in rats passively sensitized with mouse monoclonal IgE antibody. Inhaled antigen increased extravasation of Evans blue dye content in tracheal and main bronchus tissues. KW-4679 (0.3-10 mg/kg, p.o.) reduced antigen-induced microvascular leakage in trachea with an ED40 value of 4.9 mg/kg. KW-4679 also reduced antigen-induced microvascular leakage in main bronchus with an ED40 value of 0.47 mg/kg. The inhibitory effect of KW-4679 was more potent than those of ketotifen and terfenadine. These results suggest that KW-4679 clearly reduces airway microvascular leakage mediated by antigen-antibody reaction. PMID- 8687288 TI - [Results of patch tests with mite components in atopic dermatitis patients]. AB - House dust mite lipids were investigated in atopic dermatitis (AD) patients. The analysis showed that eicosapentaenoic acid (EPA) was present at 0.88% in total lipid of Dermatophagoides farinae (Df). In the patch tests with crushed 3 live Dfs, the difference of positive rates between AD patients and controls was statistically significant. In the patch test with secretions from opisthonotal glands of mites, 2% citral contained in both D. pteronyssinus (Dp)s and Dfs showed higher rate of positivity with AD patients than controls without statistically significance. In the patch test with the fatty acids of house dust mites, EPA showed higher rate of positivity with AD patients than controls. There was a statistical significance with 100% (as is) EPA. Histopathological findings by hematoxylin and eosin staining with the skin lesions of AD patients and the positive reactions of patch test with crushed 3 live mites and EPA revealed spongiosis in the epidermis and infiltration of mononuclear cells in the upper dermis. The positive subsets of the mononuclear cells were mostly CD4, HLA-DR and ICAM 1, while CD8 positive cells were rare. Based on these findings, not only mite protein but also mite lipids including secretions from mites should be investigated as mite contact allergens in AD. PMID- 8687289 TI - [Plasma interleukin-10 levels in Kawasaki disease]. AB - Time course of interleukin-10 (IL-10) in plasma of patients with Kawasaki disease was measured. The results are as follow: (1) IL-10 concentration in plasma of patients in acute phase of Kawasaki disease (median 37.8 pg/ml) was high, compared with that in convalescent phase (5.77 pg/ml) or that of control children (10.2 pg/ml). (2) From the examination of IL-10 concentration in plasma collected by following its time course, it was revealed that most of cases with this disease showed transiently high figure in the acute phase, then the figure diminished promptly afterwards. PMID- 8687290 TI - [Seven cases of oral allergy syndrome]. PMID- 8687292 TI - The next generation extracorporeal method for the management of atherosclerosis. PMID- 8687291 TI - [Guidelines for standardization of allergens and cedar pollen allergen extract in Japan]. PMID- 8687293 TI - The effects of endotoxin-contaminated dialysate and polysulfone or cellulosic membranes on the release of TNF alpha during simulated dialysis. AB - Simulated dialysis of whole blood was used to determine whether membrane factors (biocompatibility), endotoxin (ET) membrane diffusion, or transmembrane monocyte ET interactions would stimulate tumor necrosis factor (TNF alpha) release. Whole blood containing EDTA and aprotinin was recirculated in the blood compartment of hollow fiber dialyzers containing either regenerated cellulose or polysulfone membranes. ET-free and ET-spiked dialysate were recirculated consecutively in the dialysate compartment for 30 min each. Blood and dialysate samples were collected at to and after each 30 min of simulated dialysis for determination of TNF alpha and ET concentrations. TNF alpha was not detected in any blood samples collected after simulated dialysis with regenerated cellulose (RC) membranes and ET-free or ET-spiked dialysate. However, blood ET concentrations, as determined by the Limulus amebocyte lysate (LAL) assay, increased in RC dialyzers after each 30 min of simulated dialysis even with ET-free dialysate. Since TNF alpha was not detected in these blood samples, the material detected by the LAL assay probably was not ET but an LAL-reactive material. After simulated dialysis with polysulfone dialyzers and ET-free dialysate, TNF alpha and ET were not detected in blood samples. ET also was not detected in blood samples after dialysis with ET-spiked dialysate. However, TNF alpha was detected in 7 of 13 (54%) of the blood samples following the 500 ng/ml of ET dialysate spike. TNF alpha release during simulated dialysis with polysulfone membranes and ET-contaminated dialysate may be due to transmembrane stimulation of circulating mononuclear cells and not diffusion of ET across the membrane. PMID- 8687294 TI - A high selectivity cascade filtration technique for LDL-cholesterol and Lp(a) removal. AB - This work proposes an improvement of the cascade filtration technique in the treatment of familial hypercholesterolemia. A model of the whole process permitted the definition of the parameters that could influence the selectivity of the fractionation: the pore size, the sieving coefficients of both fractionation and plasmapheresis membrane, and the final retentate flow rate. In vivo studies have shown that the dead-end mode for the secondary filter was not always practical because of severe membrane plugging except when a pulsatile pump was included in the extracorporeal circuit. This pump generated hydrodynamic instabilities which decreased membrane fouling and retarded the build up of the polarization concentration layer. Optimization of these specific operating conditions permitted increase in the selectivity index from 1.15 to 2.24. The performances of cascade filtration were then comparable to those of adsorption on dextran sulfate columns. PMID- 8687295 TI - In vitro and in vivo evaluation of a small caliber vascular prosthesis fixed with a polyepoxy compound. AB - A small caliber vascular prosthesis obtained from an ovine internal thoracic artery (3.8-4.5 mm ID) fixed with a polyepoxy compound and treated with heparin has been evaluated. Cytocompatibility was evaluated in vitro using human endothelial cells (HEC). HEC were obtained from human saphenous vein and cultivated in culture medium supplemented with 25% human serum. Graft segments were rinsed using a standard protocol proposed by the manufacturer. Tissue reaction was tested on a rabbit model of subcutaneous implantation. The patency rate and healing patterns were evaluated comparatively with polytetrafluorethylene (PTFE) 4 mm ID prosthesis in a canine model of carotid interposition. Cytocompatibility assay showed that there was low adhesion on vascular grafts (20 +/- 2% of endothelial cells seeded) and no growth of HEC on the graft surface. The graft patency rate was 55% in both groups, and actuarial freedom from occlusion was not different at 3 months (37.7 +/- 15% in Denacol fixed grafts versus 38.1 +/- 14% in PTFE). Histological studies on the biological grafts shows a frequent neointimal hyperplasia at the anastomosis (5/12), a lack of endothelial cells lining the graft surface, a good preservation of the media, and a moderate inflammatory response in the adventicia. The Denacol-fixed graft has presented excellent surgical properties and preservation of the histological structure. Nevertheless, the patency rate was not improved when compared with the PTFE control graft. PMID- 8687296 TI - A potential soft tissue filling material: chloramphenicol loaded poly(D,L lactide) sponges. AB - Poly(D,L-lactide) (PDLLA) homopolymers were produced by the ring opening polymerization of a D,L-lactide dimer by using stannous chloride as the catalyst. Chloramphenicol loaded PDLLA sponges were pre- pared by a solvent evaporation procedure by using the PDLLA homopolymers with three different molecular weights (i.e., 11,000, 20,000 and 35,000 daltons). Chloramphenicol loading was changed by using three different solvents (i.e., acetone, ethyl acetate, and acetonitrile) and by changing the initial polymer concentration and its molecular weight and the initial concentration of the drug. Higher degradation rates of the chloramphenicol loaded PDLLA sponges in alkaline pH 9.0 and at 37 degrees C were observed. Chloramphenicol release rates were also high at these conditions. It was concluded that chloramphenicol release was both degradation and diffusion controlled. PMID- 8687297 TI - A new model for evaluation of biocompatibility: combined determination of neoepitopes in blood and on artificial surfaces demonstrates reduced complement activation by immobilization of heparin. AB - An in vitro technique was developed for assessment of the biocompatibility of materials for use in clinical applications. Artificial materials were exposed to blood, and the resulting complement activation was quantified both in the plasma and on the material surface by enzyme immunoassays based on monoclonal antibodies specific for neoepitopes exposed in complement activation products. Several materials were evaluated, and the effect of surface modifications, including end point immobilized heparin, was studied. The results revealed widely varying complement activation properties of the different materials and confirmed that heparin markedly improves biocompatibility. The present method is superior to analysis limited to either the fluid phase or solid phase since certain materials adsorb activation products (exemplified by Tecoflex) whereas others do not although activation was evident from fluid-phase assay (silicone). Furthermore, direct determination of activation-specific neoepitopes on the surface represents an improvement compared with previously described methods for detection of adsorbed components. PMID- 8687298 TI - Monitoring of TPMT in heart transplant recipients under immunosuppressive therapy with azathioprine. AB - Azathioprine (AZA) is routinely used in double and triple immunosuppressive therapy after cardiac transplantation. In some cases it causes severe myelosuppression. The interindividual differences in AZA toxicity is probably due to differences in the drug metabolism. Thiopurine methyltransferase (TPMT) is thought to be the most important enzyme in the catabolism of AZA. A deficiency in this enzyme will presumably increase the availability of 6-mercaptopurine for the anabolic pathway thereby leading to increased cytotoxicity. A 65-year-old male underwent heart transplantation at our institution with an uncomplicated course. Immunosuppression consisted of cyclosporine, prednisolone, and AZA. Several weeks after the administration of AZA, the patient developed severe leukopenia. TPMT activity was then measured in this patient and found to be below the detection limit. Subsequently the patient died from multiorgan failure due to septicaemia. As a result of this experience, we started to screen all patients for TPMT deficiency. In 58 healthy controls, the mean activity was found to be 11.8 nmol/h/ml of red blood cells (RBC) while in 13 patients on our waiting list, the mean activity was found to be 11.97 nmol/h/ml of RBC. In 15 patients after heart transplantation and azathioprine treatment, the mean activity was found to be 17.2 nmol/h/ml of RBC. We suggest screening for TPMT activity in transplant patients with leukopenia under AZA therapy. If TPMT deficiency is present, the AZA dosage should be adjusted or alternative immunosuppressive regimens should be considered. PMID- 8687299 TI - Evaluation of tilting disc valves after fatigue life testing: preliminary results within a comparison program. AB - A fatigue life test, by accelerating the beat rate, simulates several years of virtual life of a prosthetic heart valve in a short period of time. The correlation between the in vivo life of a valve and in vitro testing expectations is as yet not well established, but reproducible test conditions yield precious information about wear and failure. The paper reports a qualitative analysis of mechanical valve wear as part of a comparison program designed to investigate the significance of fatigue testing with the ultimate aim of defining standard guidelines for these type of tests. Two tilting disc valves (29 mm) were subjected to 16 years of fatigue life simulated by means of a Rowan Ash fatigue tester (accelerated rate of 1,200 bpm). Fatigue-induced effects on valve disc and ring surfaces were observed under a monitor microscope to identify wear sites and patterns. A high speed cinematographic system was used to investigate the mechanisms responsible for the wear (wear modes). Valve closure was inspected at a 6,000 frame/s rate. Because of disc rotation during the tilting movement, the points of contact between disc and ring are distributed all around the disc edge but focally on the ring. On both sides of the disc, the surfaces present ring like concentric grooves. After 16 years of fatigue life the valves showed neither severe wear nor alteration of their fluidodynamic behavior in the pulsatile flow test. PMID- 8687300 TI - Hemolysis and heat generation in six different types of centrifugal blood pumps. AB - What the most causative factor affecting hemolysis is still controversial. To resolve this problem, we investigated the relationship between hemolysis and heat generation in six types of centrifugal blood pumps (Bio-Pump, Delphin, Capiox, Nikkiso, Isoflow, and Toyobo). The analyzed parameters were index of hemolysis in fresh goat blood, pumping performance, and heat generation in a thermally isolated mock circuit. These parameters were analyzed at a flow rate of 5 L/min by changing the pressure head (100 mm Hg and 500 mm Hg). At 500 mm Hg of pressure head, the Bio-Pump needed the highest rotation number and showed the highest hemolytic rate and heat generation. The index of hemolysis is well correlated to heat generation (r2 = 0.721). Heat may originate from the motor by conduction, hydraulic energy loss, and mechanical friction between the shaft and seal. We strongly suspect that hemolysis was caused by a factor such as mechanical friction which generates heat locally. PMID- 8687301 TI - Pulsed Doppler sonography for the guidance of vein puncture: a prospective study. AB - Blind deep venous puncture is an invasive procedure with risks of serious complications compromising the availability of veins for future punctures or endangering the patient's life. We designed a new hand-held pulsed Doppler probe for coaxial guidance of the puncture needle and a dedicated pulsed Doppler device displaying the depth of the measurement volume. We used this technique prospectively in two independent centers (the nephrology department and the intensive care unit) involving senior as well as junior staff members. Either the non-Doppler or the Doppler method were randomly selected for subclavian vein catheterization in 100 patients and for internal jugular vein catheterization in 30 patients. The success rate on the first attempt was 86.2% for the non-Doppler method versus 96.8% for the Doppler method (p = 0.03). The failure rate of the non-Doppler method used by junior staff members was 9.2%, reduced to 1.5% (p = 0.05) by secondary use of the Doppler method and/or help from a senior staff member (rescue procedure). Pulsed Doppler guidance reduced significantly the failure rate of venous punctures especially when used by seniors or by juniors after a training period. PMID- 8687302 TI - Different apheresis methods in the treatment of hypercholesterolemia in primary biliary cirrhosis: a case report. AB - The two different modes of low-density lipoprotein (LDL) apheresis, cascade filtration (CF) and dextran-sulfate cellulose (DSC) adsorption, were compared for efficiency of cholesterol removal in a patient with severe hypercholesterolemia due to primary biliary cirrhosis (PBC). Decrement in the total cholesterol level by the DSC method was less than that by the CF method. Apolipoprotein B was decreased to almost null by both modules whereas the decrease in albumin was much greater in the second filter of the CF method than in the DSC column. Lipoprotein X which constituted the major portion of serum cholesterol in PBC became negative by passing plasma through the second filter. The CF method was preferred to the DSC method for removal of lipoprotein X, but albumin substitution was mandatory to prevent the decrease of serum albumin in the CF method. PMID- 8687303 TI - Reconstruction of liver tissue in vitro: geometry of characteristic flat bed, hollow fiber, and spouted bed bioreactors with reference to the in vivo liver. AB - Bioreactors currently being developed for hybrid artificial livers vary greatly with respect to their microenvironment. The specific architecture modifies the relationship parenchymal and nonparenchymal cells have with the exchange surfaces of the bioreactor. Most designs are either based on hollow fiber, spouted bed, or flat bed devices. This diversity is contrasted by the uniform and unique organization of the in vivo liver. The liver cells are arranged as plates and both sinusoidal surfaces of the hepatocytes are enclosed within the matrix of the space of Disse. In this study we intended to define the in vivo liver tissue characteristics in a manner useful for an organotypical approach to hepatic tissue engineering. Transmission electron microscopy of an in vivo liver was utilized to describe these ratios. The ratios defined in this study are based on the constant hepatocellular expression of two sinusoidal surfaces. A relationship is established between the expression of the sinusoidal surfaces and their use as attachment and exchange surfaces inside a bioreactor. The presence of biliary surfaces and nonparenchymal cell surfaces is compared. The functional relevance of an in vivo like extracellular matrix geometry for oxidative biotransformation of primary hepatocytes in vitro was studied using the two model drugs cyclosporin and rapamycin. The generation of the hydroxylated cyclosporin metabolites AM 9 and AM 1 and four rapamycin metabolites was analyzed by high performance liquid chromatography (HPLC). It is shown that the cell-specific biotransformation rates at 1 week in culture in matrix overlayed hepatocytes was 5-10 times that of hepatocytes without matrix overlay. Bilaminar membrane (BLM) bioreactors were used to reconstruct extracellular matrix geometry, three-dimensional cell plates, and sinusoidal analogs in between cell plates. PMID- 8687304 TI - Right ventricular failure in patients requiring left ventricular assistance. AB - Right ventricular failure may complicate isolated left ventricular assistance. In a series of 8 patients undergoing left ventricular assistance in postcardiotomy cardiogenic shock, right ventricular failure developed in 5, directly contributing to death in all cases despite initially satisfactory support. Difficulty in grafting a dominant right coronary artery was a common factor in all cases. Early consideration should be given to biventricular support under these circumstances. PMID- 8687305 TI - A proposal for a theory and detection method of cavitation potential of mitral bileaflet heart valve. AB - We believe that cavitation damage to mitral bileaflet heart valve (MBHV) is caused by microcracks of hydrophobic pyrolite carbon. Our proposal is to detect cavitation potential of MBHV with an acoustic technique under various conditions of transvalvular pressures, ventricular dp/dt, leakage flow, and gas concentration in fluid, This modality, different from recent research in theory and technique, will lead to a standardized noninvasive and sufficiently sensitive technique for the detection of MBHV, to reject those valves believed to cause cavitation damage, and to develop cavitation-resistant MBHV. PMID- 8687306 TI - Clinical incident monitoring. PMID- 8687307 TI - A strategic plan for general practice. PMID- 8687308 TI - An approach to examination of the foot. AB - Foot problems are common presentations in general practice. A detailed examination, although it is very often overlooked, can usually provide a clue to the correct diagnosis. Musculoskeletal examination of the foot follows the time honoured methods of a careful inspection first, followed by moving the joints, then assessing muscle strength, followed by palpating the parts. PMID- 8687309 TI - Metatarsalgia. AB - Metatarsalgia, or pain in the metatarsal region of the foot, is a common orthopaedic problem, but is generally less well understood than pain in the toes, ankle or heel. The cause of metatarsal pain is often less apparent than in other regions of the foot, and in many cases plain X-rays are of no help. Morton's neuroma, a common cause of severe metatarsalgia, can usually only be diagnosed from the history and clinical examination. The key to diagnosis in the metatarsal region is to have a clear knowledge of the most likely conditions. PMID- 8687310 TI - Feet and systemic disease. AB - Diabetes mellitus and rheumatoid arthritis often affect the foot. Indeed in either of these, the foot is commonly the initial site of symptoms. Early diagnosis appropriate treatment can prevent or at least slow the progression of the disease in the foot. Extra depth shoes and moulded inserts are the keystone of non operative treatment. Surgery is indicated when the deformity is severe. Surgery does have good results in rheumatoid arthritis but in diabetes mellitus it is usually reserved as a salvage procedure. PMID- 8687311 TI - A review of subcalcaneal heel pain and plantar fasciitis. AB - Pain beneath the heel is a common and sometimes very debilitating condition. Although usually described as ?plantar fasciitis' it can be caused by several different conditions. Adequate treatment is aided by determining which cause or causes of subcalcaneal pain is present in a particular patient. This article discusses the approach to the diagnosis and management of pain underneath the calcaneus. PMID- 8687312 TI - Painful feet in childhood. AB - Painful feet are rare in childhood. However, the family physician should be aware of some well recognised causes of pain that occur in the immature foot. Routine clinical assessment and the Tables in this article should direct the physician to the appropriate diagnosis. PMID- 8687313 TI - The foot and footwear. AB - Footwear is the single most significant influence on the foot, but it is the area of least clinical understanding and input. There is confusion in terminology and emphasis, both with, and between professions so that there appears little consistency. This limits the possibility of significant improvements in this field. Some key footwear principles are described as a basis for developing a greater understanding of the interaction between the foot and footwear. PMID- 8687314 TI - Clinical management of fungal infections. AB - Fungal infections require clinical and microbiological diagnosis for optimal therapy. Superficial mycoses often respond to topical agents but newer, less toxic drugs are available for systemic treatment when required. For invasive mycoses, amphotericin B remains the gold standard, with triozoles as the preferred oral agents. PMID- 8687315 TI - Anterior knee pain. PMID- 8687316 TI - Acute traumatic wounds. PMID- 8687317 TI - Childhood immunisation. PMID- 8687318 TI - Infectious diseases case study. Boy with rash and fever. PMID- 8687320 TI - Empowerment and junior doctors. Intern program at the Austin and repatriation medical centre. AB - Involving junior members of the profession in evaluating and developing their training programs engenders a sense of involvement and empowerment. This is a review of an intern program at the Repatriation Campus of the Austin and Repatriation Medical Centre, Melbourne. PMID- 8687319 TI - The dilemma of the unexpected result. AB - Office, laboratory and radiological investigations are valuable tools that facilitate diagnosis, screening and monitoring processes in clinical practice. However, limitations in the sensitivity, specificity and applicability of a given test to a particular clinical scenario must always be remembered before ordering it. This article examines four case histories that illustrate some issues related to the ordering of tests and the difficulties that investigation results can produce. PMID- 8687321 TI - The index theory and the magic of medicine. PMID- 8687322 TI - Influenza vaccination use. PMID- 8687323 TI - Scalp dermatitis, ectodermal dysplasia and cleft lip and palate: rapp-hodgkin or AEC syndrome. AB - A female infant with ectodermal dysplasia, bilateral cleft lip and palate and a recalcitrant scalp dermatitis is presented. She had features of both Rapp-Hodgkin syndrome and AEC syndrome. It has recently been suggested in the literature that these two syndrome are the same condition and this case report supports this viewpoint. PMID- 8687324 TI - Prurigo papules with blisters. AB - A 73 year old woman developed prurigo papules which were complicated by blisters. Skin biopsy and immunofluorescence revealed bullous pemphigoid. The diagnosis of pemphigoid nodularis was made. PMID- 8687325 TI - Juvenile dermatomyositis. AB - Juvenile dermatomyositis (JDMS) is a chronic inflammatory condition characterized by muscle weakness and a distinctive rash caused by underlying vasculopathy. Long term complications include subcutaneous and muscular calcification, contractures and in some cases the gradual development of a second connective tissue disease. Early aggressive treatment with systemic immunosuppressants and other agents such as intravenous immunoglobulin (IVIG) reduces mortality and morbidity. PMID- 8687326 TI - Garlic dermatitis. AB - Allergic contact dermatitis to garlic usually has a typical clinical presentation but this is often masked if it presents concurrently with another form of hand dermatitis. Patch testing with 1% diallyl disulfide in petrolatum is recommended when garlic allergy is suspected. PMID- 8687327 TI - Combination carbon dioxide laser vermilionectomy and wedge excision of the lip. AB - Dermatologic surgeons are very familiar with the use of the carbon dioxide (CO2) laser for treating actinic cheilitis. When squamous cell carcinoma is proven or suspected in the affected lip, then combined CO2 laser vermilionectomy and wedge excision as a one stage procedure has significant advantages for the patient. PMID- 8687328 TI - Linear and whorled naevoid hypermelanosis. PMID- 8687329 TI - Photochemical smog and PUVA cabinets. PMID- 8687330 TI - Pregnancy, abortion and the dangers of prescribing vitamin A analogs in Australia. PMID- 8687331 TI - Office radiotherapy in dermatology: a contemporary perspective. AB - Ionizing radiation was recognized very early after its discovery as a useful weapon against both neoplasia and inflammation. Following an initial period of enthusiastic use, recognition of its drawbacks and the development of safe and effective alternative treatments for many applications have resulted in a marked reduction in the use of radiotherapy in most dermatological offices. Nonetheless, this modality remains an important component of our modern therapeutic armamentarium. It is a treatment of choice in some situations, and a useful alternative in many more. A thorough understanding of the principles and practice of safe radiotherapy remains vital to the full practice of dermatology in 1996. The present review summarizes the current practice of radiotherapy and offers some guidelines for safe and effective use of this important tool. Detailed discussions of radiobiology, deep radiotherapy (DXRT) and electron beam (EB) therapy are beyond the scope of this clinical review. PMID- 8687333 TI - Photodynamic therapy for psoriasis? AB - Photodynamic therapy (PDT), the activation of a photosensitive compound by high intensity red light, is useful for Bowens' disease, thin basal carcinomata and as an adjunctive therapy for various internal malignancies. Its use in the treatment of psoriasis has been attempted only quite recently and some modest success achieved. These clinical experiences are reviewed and the rationale for using PDT for psoriasis is discussed. PMID- 8687332 TI - The descriptive epidemiology of warts in the community. AB - Warts are common skin infections caused by human papillomavirus (HPV) and affect most people sometime in their life. A number of epidemiological studies on the prevalence of warts have been completed in schools, various occupational groups, general practices and hospitals. All studies have relied on a subjective measure for the diagnosis of warts. Cross-sectional studies completed in schools have shown the prevalence in children to vary from 2 to 20%. Occupational handlers of meat, poultry and fish have a higher prevalence than other workers. Children and young adults are the groups most affected. Future studies are needed to investigate the true frequency of warts in the community and the likelihood of an individual developing these lesions during his/her lifetime. PMID- 8687334 TI - Pemphigoid gestationis occurring in a patient with HELLP syndrome. AB - A case of pemphigoid gestationis occurring in a 40 year old female who developed HELLP syndrome during her fourth pregnancy is reported. Seven days after emergency Caesarean section for pre-eclampsia, she developed a pruritic blistering eruption which clinically resembled pemphigoid gestationis. The diagnosis was supported by skin histology and immunofluorescence. She responded rapidly to oral corticosteroids, with no evidence of recurrence after 12 weeks of follow up. In the current case report, the previously unreported simultaneous occurrence of two uncommon conditions is described. PMID- 8687335 TI - Minocycline is a useful adjuvant therapy for pemphigus. AB - Pemphigus is an autoimmune blistering disease with high mortality if untreated. The cases of 10 patients who had minocycline 100 mg daily added as adjuvant therapy are reported. Prior to the use of minocycline, all patients had active disease, nine were on prednisolone (10-40 mg) and five were on azathioprine (100 200 mg). The response was assessed on clinical improvement and reduction of immunosuppressive (IS) drugs. It was graded into four categories: major, minor, equivocal and no significant response. A major response was seen in four patients, minor in two, equivocal in one and no improvement in three patients. The prednisolone dose in the six responders was reduced to 0-6 mg (0 mg in three patients), with an average decrease of 21 mg. The average time to respond was 8 months. Of the six responders, three were on azathioprine, which was ceased in two patients and reduced by two-thirds in the other patient. No patient ceased minocycline because of side effects. In conclusion, minocycline 100 mg daily is a simple, safe and well tolerated treatment that should be tried in patients with pemphigus to reduce disease activity and/or the dose of potent IS agents. PMID- 8687336 TI - Rapid repigmentation after depigmentation therapy: vitiligo treated with monobenzyl ether of hydroquinone. AB - Repigmentation occurred within a few weeks of discontinuing successful depigmentation therapy with monobenzyl ether of hydroquinone, in a patient with extensive vitiligo. Patients undertaking depigmentation therapy should be warned that this may occur. The mechanism is unknown. PMID- 8687337 TI - Sweet's syndrome associated with Behcet's disease. AB - A case of acute febrile neutrophilic dermatosis (Sweet's syndrome) associated with Behcet's disease occurring in a 48 year old woman is reported. She fulfilled the diagnostic criteria for both Sweet's syndrome and Behcet's disease. There have been several reports of this association. Herpes simplex virus was isolated from a genital ulcer in our patient. The possible role of herpes simplex virus in this interesting association of Behcet's disease and Sweet's syndrome is discussed and a review of the literature is made. PMID- 8687338 TI - Mantle irradiation for Hodgkin's disease during pregnancy: safe and practical? PMID- 8687339 TI - An ultrasonographic study of Peyronie's disease. AB - A study was undertaken to determine the usefulness of ultrasonography as an investigative tool, and its role in deciding the management of Peyronie's disease. Fifteen patients with Peyronie's disease were studied by ultrasonography. The plaque could be demonstrated in all patients. The dimensions of the plaque varied from less than 1 cm to more than 7 cm in length and 2-4mm in thickness. The disease was active in 26% of the patients, as indicated by the presence of hypoechoic areas around a central region of hyperechoism. Ultrasonogram was more accurate than clinical assessment in delineating the extent of lesions. In one-third of the patients, sonography demonstrated the plaques to be more extensive than had been detected by clinical examination. Calcification and activity of disease (which are clearly defined by ultrasonogram) are determining factors in the management of Peyronie's disease. This information allows the surgeon to select the modality of treatment, the timing of surgery and extent of excision. Thus, ultrasonography plays a vital role in the preliminary investigation and management of Peyronie's disease. PMID- 8687340 TI - Abdominal wall haematoma in anti-coagulated patients: the role of imaging in diagnosis. AB - Abdominal wall haematomas are uncommon, difficult to diagnose clinically and often associated with systemic anti-coagulation. Seven cases together with the imaging results are presented and the characteristic features and potential pitfalls are discussed. Ultrasound is the first line investigation but the results can be misleading and computed tomography (CT) is often required to confirm the diagnosis. PMID- 8687341 TI - Computed tomography in miliary tuberculosis: comparison with plain films, bronchoalveolar lavage, pulmonary functions and gas exchange. AB - Computed tomography (CT) of the chest, pulmonary function tests, bronchoalveolar lavage (BAL) and arterial blood gas analysis were performed in 26 patients with non-HIV miliary tuberculosis (MTB). CT was repeated after treatment in 11 patients. Nodular lesions were characteristically seen on CT. CT showed discrete and fine nodules in five patients in whom the lesions appeared to be larger than miliary on chest X-rays. Coalescing nodular lesions were noted on chest X-rays (n = 7) and CT (n = 18). Consolidation (n = 6), cavitation (n = 4), fibrosis (n = 9) and air trapping (n = 14) were detected on CT only. During follow up, air trapping increased (n = 14) and in some patients it appeared for the first time (n = 2). Lymph node enlargement and calcification were seen on both chest X-rays (n = 9 and n = 3, respectively) and CT (n = 12 and n = 7, respectively). Pleural involvement was also seen in chest X-rays (n = 4) and CT (n = 5). Total lung capacity was higher in patients with a chest X-ray score > 10. Similarly a higher total cell count in BAL fluid was observed in patients with a CT score > 10. It is concluded from this study that CT is superior to chest X-rays in detecting nodular lesions, lymphadenopathy and air trapping in patients with MTB. PMID- 8687342 TI - Atlanto-axial rotatory fixation: improved demonstration using spiral CT. AB - Atlanto-axial rotatory fixation (AARF) is an uncommon condition which is often missed at presentation because of its rarity and the relative subtlety of plain film X-ray findings, but early detection and appropriate management are vital for a cure. We describe three cases in which the use of spiral computed tomography scanning with 3D and sagittal reconstructions greatly aided diagnosis and management. The 3D images gave a more graphic picture of the overall alignment of the upper cervical spine and the skull base, while the sagittal reconstructions demonstrated the presence or absence of compensatory atlanto-occipital subluxation. The literature is briefly reviewed. PMID- 8687343 TI - Intraventricular neurocytoma. AB - Intraventricular neurocytoma is a rare cerebral tumour which is usually associated with a good prognosis. It has imaging features which help differentiate it from other cerebral tumours. We report three cases including the first to originate from the pineal gland. The report emphasizes the radiological appearance and reviews the literature. PMID- 8687344 TI - Hook wire localization of inferior lesions in the breast. AB - Inferior lesions in the breast can be difficult to localize pre-operatively using the hook wire technique as the equipment does not readily allow an approach from below. Distorting the breast by rolling it against the cassette holder displaces an inferior lesion into a lateral position. The lesion can then be easily localized by the shortest needle path. PMID- 8687345 TI - The whirl sign: a non-specific finding of mesenteric rotation. AB - The whirl sign has been described as a computed tomography (CT) finding of volvulus of the gut. Six cases are presented with a range of clinical diagnoses (a volvulus, adhesive obstruction with volvulus and previous left hemicolectomy, adhesions alone, transverse colectomy, and right hemicolectomy). All demonstrated a whirl sign. A further case simulating a whirl sign is also presented. We propose that the whirl sign, although a finding highly suggestive of volvulus, can occur in any situation that produces rotation or twisting of bowel and its mesenteric attachment. PMID- 8687346 TI - Acute morbidity of radiation therapy for prostate carcinoma. AB - The acute morbidity of high dose radiation therapy for carcinoma of the prostate in a group of 169 patients treated between February 1993 and April 1994 was examined. Morbidity was determined at the start of therapy, then weekly during therapy and at 1, 2, 3, 6 and 12 months after therapy. Morbidity was examined from the view of the treating doctor and the patients. Morbidity was found to peak at the end of the treatment. From the radiation oncologist's perspective, 80 85% of patients experienced significant bladder and bowel morbidity. The level of acute morbidity was acceptable and there was only one patient that was admitted to hospital for symptomatic control of his acute reaction. Recovery was practically complete after 3 months for both bladder and bowel morbidity. Fifty per cent of patients experienced dysuria, 75% perianal discomfort and 87% frequency at the end of the treatment. Most of the individual factors recovered following radiation but urinary frequency and perianal discomfort were the most persistent problems. PMID- 8687347 TI - Radiotherapy for Hodgkin's disease in pregnancy. AB - Hodgkin's disease diagnosed during pregnancy poses a dilemma as there are risks of abortion and fetal malformation with the use of radiotherapy and chemotherapy. A patient with Hodgkin's disease during pregnancy treated with radiotherapy is presented. PMID- 8687348 TI - Guidelines for radiation oncology registrar training. Royal North Shore Hospital. AB - Radiation oncology registrar training varies between centres, reflecting to some extent the varied training experiences of specialists. The attempts of one department to formalize the philosophy, aims and structure of its training are described and illustrated. PMID- 8687349 TI - Low dose rate teletherapy: updated tumour response. AB - This report presents an update of tumour response experience in patients with locally advanced head and neck cancer treated on the low dose rate teletherapy project at the Mater Misericordiae Hospital, Newcastle. Long-term progression free survival figures are disappointing in all dose rate/total dose groupings and offer little encouragement that an improvement in therapeutic ratio can be achieved for head and neck cancer patients using teletherapy apparatus adjusted to treat at low and intermediate dose rates. PMID- 8687350 TI - Mesenteric plexiform neurofibroma: computed tomography appearance. AB - Gastrointestinal involvement in von Recklinghausen's disease is usually in the form of neurofibromas and leiomyomas. Very rarely, plexiform neurofibromas may be seen involving the bowel wall and myenteric plexus with secondary minor involvement of the mesentery. This report describes the computed tomography morphology of a plexiform neurofibroma extensively involving the mesentery with minor involvement of the bowel wall. PMID- 8687351 TI - Wildervanck syndrome. AB - We report a case of the Wildervanck (cervico-oculo-acoustic) syndrome exhibiting Klippel-Feil anomaly, congenital sensorineural deafness and bilateral sixth nerve palsy. Associated anomalies included short stature, microcephaly, mental retardation, and cleft palate. PMID- 8687352 TI - Ultrasound appearance of pseudomembranous colitis. AB - A case illustrating that ultrasound can be useful in the diagnosis of pseudomembranous colitis is reported. Diagnosis of pseudomembranous colitis is usually made from microbiological or histopathological investigations. The ultrasound appearance of grossly thickened bowel wall with luminal narrowing is non-specific, but in the correct clinical context should suggest the diagnosis of pseudomembranous colitis. PMID- 8687353 TI - Liposarcoma of the hypopharynx. AB - A case of the unusual condition of liposarcoma of the hypopharynx extending submucosally down the oesophagus in a 64 year old male is reviewed. The clinical, radiological and pathological features are presented and the role of various radiological modalities is discussed. PMID- 8687354 TI - Computed tomographic and ultrasonographic findings of pseudomyxoma peritonei. AB - Pseudomyxoma peritonei is an unusual clinical entity in which the peritoneal cavity is filled with a gelatinous material that is mucinous in nature. We present ultrasonographic and computed tomography findings in a patient with pseudomyxoma peritonei secondary to ovarain mucinous cystadenocarcinoma. PMID- 8687355 TI - Peliosis hepatis associated with oral contraceptive use. AB - A 35 year old woman with right upper quadrant abdominal pain was found to have peliosis hepatis. This was attributed to oral contraceptive use and 6 month follow up after cessation of oral contraceptives showed these lesions to have reduced in extent. PMID- 8687356 TI - Extraskeletal Ewing's sarcoma presenting with pulmonary embolism. AB - Small round cell tumours with the morphologic characteristics of Ewing's sarcoma arise rarely in soft tissues of the extremities, retroperitoneum, chest and orbit. Patients usually present with symptoms arising from the swelling at the primary site. We report on a patient with a retroperitoneal extraskeletal Ewing's sarcoma who presented with massive tumour embolism to the pulmonary vasculature. To our knowledge, this is the first report of extraskeletal Ewing's sarcoma presenting with pulmonary tumour embolism. PMID- 8687357 TI - Intrathoracic extramedullary haemopoiesis. AB - Intrathoracic extramedullary haemopoiesis is a rare condition accompanying chronic haematologic diseases. A 25 year old male beta-thalassaemia intermedia patient with bilateral posterior mediastinal masses is reported. Computed tomography and magnetic resonance imaging provide detailed information for evaluation of thalassaemia and similar haemolytic diseases. In geographic areas where thalassaemia is prevalent, to avoid unnecessary surgical interventions, extramedullary haemopoiesis should be considered in differential diagnosis of patients who have chronic anaemia with asymptomatic intrathoracic tumours. PMID- 8687358 TI - Central neurocytoma occurring in the thalamus: CT and MRI findings. AB - A case of central neurocytoma occurring in the thalamus, confirmed by electron microscopy and immunohistochemistry, is reported. Computed tomography demonstrated a hypodense mass with an irregular margin arising from the right thalamus, extending into the lateral ventricle and crossing the midline. It contained areas of calcification and showed slight enhancement after contrast injection. On magnetic resonance imaging (MRI) scan, the tumour was hypointense to the brain in T1-weighted images and was heterogeneously hyperintense to the brain in T2-weighted images. PMID- 8687359 TI - Construction of an ultrasound biopsy phantom. AB - The technique for construction of an agar-based ultrasound biopsy phantom is described. Features include tissue equivalent reflectivity, long life and non shadowing targets. The phantom is useful for learning the necessary co-ordination between needle and probe for ultrasound needle guidance. This skill should initially be practised in vitro, on a device such as this. PMID- 8687360 TI - Feeling woozy after MR imaging. PMID- 8687361 TI - Stability of catastrophic cognitions in panic disorder. AB - This study examined the degree to which panic disorder patients recognized the irrationality of their fearful cognitions during the midst of panic and at other times, when not panicking. Also, the degree to which panic-cognitions changed over time was examined. Approximately 40% retained at least moderately strong conviction in their panic-cognitions when not panicking. Females and non medicated patients held stronger convictions. Fearful cognitions about physical dangers were more likely to decrease over time than fearful cognitions about mental or social dangers. PMID- 8687362 TI - Prediction of outcome in the treatment of specific phobia. A cross validation study. AB - The purpose of this study was to investigate possible predictors of treatment outcome in specific phobia at 1 week after treatment, and at I year follow-up. The subjects (n = 138) came from four studies (two on spider phobia, one on blood phobia and one on injection phobia), and all had been diagnosed with simple phobia according to DSM-III-R. The dependent variable was clinically significant improvement in three different factors; avoidance behavior in a behavior test, self-rated anxiety during the test, assessor rating of phobic severity or fainting behavior. Fourteen variables covering self-report, demographic and physiological variables, and data from the behavior test were used as prognostic variables. Multiple regression analyses were used in a cross validation procedure. The results showed that diastolic blood pressure at pretest was a predictor at post-treatment for one sample and credibility was found as a predictor for the other sample both at post-treatment and at 1 year follow-up. Analyses were made for the diagnoses and the treatments but the results were inconclusive. Despite the large sample size and the cross validation procedure no stable predictors were found for short- and long-term outcome. The few significant predictors should be considered as chance findings. PMID- 8687363 TI - Change in danger cognitions in agoraphobia and social phobia during treatment. AB - Cognitive theories of anxiety emphasise the differences in anxious concerns and symptomatology across the anxiety disorders. The nature and extent of danger appraisal in social phobics and agoraphobics was examined and compared with that of a non-phobic group of adult stutterers. All groups were measured before, during and after treatment. Results showed that the form of danger appraisal was related to the fears exhibited, reductions in the particular appraisals of danger were associated with reductions in specific fears, and specific patterns of danger appraisal emerged. Agoraphobics' concerns with physical and loss of control danger normalized during treatment. Despite considerable and significant improvement, social phobics continued to have social evaluation danger scores significantly higher than the control group at the end of treatment. While cognitive behavioural therapy does change relevant fear cognitions, it appears that the intransigence of social phobic concerns about negative evaluations may require extra time and/or therapy. PMID- 8687364 TI - Homework compliance, perceptions of control, and outcome of cognitive-behavioral treatment of social phobia. AB - This study examined the relationship of compliance with homework assignments and posttreatment anxiety in patients who received cognitive-behavioral group therapy (CBGT) for social phobia. Greater homework compliance measured in the first and latter periods of CBGT was associated with lower levels of social interactional anxiety after treatment. Surprisingly, homework compliance during the middle sessions of CBGT was positively related to posttreatment fears of scrutiny and criticism. Perceptions of control in social phobia and their potential effect on homework compliance and the homework compliance/treatment outcome relationship were also examined using the Levenson (Journal of Consulting and Clinical Psychology, 41, 397-404, 1973) Locus of Control Scale. Social phobics were less likely to believe in their own control over events than a comparison sample of community subjects but attributed greater control over events to other powerful persons. Among patients, higher Internality and lower Powerful Others subscale scores were associated with higher levels of pretreatment anxiety. However, neither subscale was significantly related to measures of homework compliance. Furthermore, when included in multiple regression analyses, neither subscale or its interaction with homework compliance added to the prediction of posttreatment anxiety. Limitations of this study and future research to improve assessment of homework compliance and perceptions of control among social phobic patients are discussed. PMID- 8687365 TI - Correcting faulty appraisals of obsessional thoughts. AB - Cognitive techniques are becoming more widely established in the treatment of obsessive-compulsive disorder (OCD). This paper extends previous work by van Oppen and Arntz (1994, Behaviour Research and Therapy, 33, 79-87) on overestimation of threat and excessive responsibility by discussing other types of appraisals that may be involved in OCD, particularly when overt compulsions are absent. Examples are given of types of intervention that may be useful to correct faulty appraisals concerning the overestimation of the importance of thoughts such as thought-action fusion, excessive responsibility, perfectionistic concerns such as the need for absolute certainty, and expectations about anxiety and its consequences. PMID- 8687366 TI - Treatment of generalized social phobia: results at long-term follow-up. AB - This study investigated the long-term follow-up effectiveness of (cognitive-) behavioural group and individual treatments for generalized social phobia. Patients were reassessed 18 months after they had finished one of the following treatment packages: (1) exposure in vivo; (2) cognitive therapy followed by exposure in vivo; or (3) a cognitive-behavioural treatment in which both strategies were integrated from the start. Half of the patients were individually treated, the other half in a group. Self-report assessments were held before and after treatment and at 3-month and 18-month follow-ups. Repeated measures MANOVAs on the patients who completed the long-term follow-up (n = 50) demonstrated significant time effects, indicating lasting improvement compared with the pretest. Between the posttest and the 18-month follow-up no significant changes were observed. ANCOVAs either with the pretest or the posttest as covariate showed a significant interaction at 18-month follow-up between treatment package and treatment modality on three of the four compound outcome variables. The group treatment with exposure in vivo alone had been the most effective in the longer term, the integrated group treatment the least effective, while the individual treatments had given improvements in-between. Results are qualified in view of numbers of dropouts, additional treatments in the respective treatment conditions, and clinical relevance. PMID- 8687367 TI - Cognition-behaviour links in the persistence of panic. AB - The cognitive theory of panic disorder proposes that panic attacks occur as a result of an enduring tendency to misinterpret bodily sensations as a sign of imminent catastrophe such as a heart attack. The persistence of such catastrophic cognitions is in part due to the tendency of patients to avoid and/or escape situations where panic occurs. It is proposed that within-situation safety seeking behaviours also have the effect of maintaining catastrophic cognitions in the face of repeated panics during which the feared catastrophe does not occur. The association between catastrophic cognitions and within-situation safety behaviours matched the pattern predicted from the cognitive theory in 147 panic disorder patients. The implications of these findings for the way in which therapy is conducted are discussed. PMID- 8687368 TI - A model of pain and anxiety associated with acute stressors: distress in dental procedures. AB - Many acute stressful experiences are not inherently very harmful, yet are associated with great pain and anxiety. The characteristics and experiences that the person brings to the situation are more important than any objective characteristics of the experience itself in determining how aversive the experience will be. Dental procedures are excellent examples of this type of stressor. Drawing primarily on the literature related to dental procedures, the present article discusses the nature of pain and anxiety in the face of an acute stressor, and presents the dispositional and situational factors that contribute to the perception of an acute stressor as aversive. A model is presented illustrating how the various factors interact. It is argued that, in addition to being descriptive, the model is also prescriptive of measures that may be taken to ameliorate the distress of persons subjected to acute stressors like dental procedures. PMID- 8687369 TI - Virtual reality exposure therapy in the treatment of fear of flying: a case report. AB - The efficacy of virtual reality (VR) exposure therapy was examined for the fear of flying. Virtual reality exposure involved six sessions of graded exposure to flying in a virtual airplane. The specific contribution of anxiety management techniques (AMT) and the VR exposure was examined in a single case design. The subject was a 42-year-old female with a debilitating fear and avoidance of flying. All self-report measures of the fear and avoidance of flying decreased following AMT and decreased still further following VR exposure. A planned post treatment flight was completed with anxiety measures indicating comfortable flight. The implications of this new medium for exposure therapy are discussed. PMID- 8687370 TI - Evaluative decision latencies mediated by induced affective states. AB - Recent priming studies (e.g. Hermans, De Houwer & Eelen, 1994, Cognition and Emotion, 8, 515-533) have demonstrated that response latencies to target stimuli are mediated by the affective relation between prime and target. The time needed to evaluate or pronounce targets is facilitated if preceded by similarly valenced primes, but is inhibited for trials on which prime and target have an opposite affective valence. These data suggest that information stored in memory is associatively linked with similarly evaluated information, through association with some general representation of goodness or badness. To investigate whether affective priming is merely one type of conventional semantic priming, or whether it is mediated by affective responses, the affective context provided by the primes was replaced in this study by the induction of an emotional state using a Musical Mood Induction procedure (Depression/Elation). Subjects had to evaluate target pictures as quickly as possible. The data revealed a significant Mood Change (More Depressed/Less Depressed/No Change) x Target Valence (Positive/Negative) interaction, indicating that emotional states can mediate evaluate response latencies to affectively valenced target stimuli. The results are interpreted in the context of a biphasic emotion theory, and are related to previous research on mood congruency effects on perceptual responses. PMID- 8687371 TI - Statistical power: concepts, procedures, and applications. AB - This paper discusses the concept of statistical power and its application to psychological research. Power, the probability that a significance test will produce a significant result when the null hypothesis is false, often is neglected with potentially serious consequences. The concept of power should be considered as part of planning and interpreting research. This article provides explication of the concept of power and suggestions for researchers to increase the power of their investigations. PMID- 8687372 TI - Individual differences in thought suppression. The White Bear Suppression Inventory: factor structure, reliability, validity and correlates. AB - The White Bear Suppression Inventory [WBSI; Wegner, D.M. & Zanakos, S. (1994), Journal of Personality, 62, 615-640] is a self-report questionnaire measuring people's general tendency to suppress unwanted negative thoughts. The current article describes two studies investigating the reliability, factor structure, validity, and correlates of the WBSI. Study 1 (n = 172) showed that the WBSI is a reliable instrument in terms of internal consistency and test-retest stability. Factor analyses of the WBSI revealed a 1-factor solution. Furthermore, the WBSI was found to correlate positively with measures of emotional vulnerability and psychopathological symptoms. In Study 2 (n = 40), the relationship between WBSI and levels of intrusive thinking was examined in more detail, using a thought suppression task. In general, results of this thought suppression experiment provided evidence for the validity of the WBSI. That is, subjects with high WBSI scores exhibited higher frequencies of unwanted intrusive thoughts than subjects with low WBSI scores. PMID- 8687374 TI - Discovery that the assembly of the dipyrromethane cofactor of porphobilinogen deaminase holoenzyme proceeds initially by the reaction of preuroporphyrinogen with the apoenzyme. AB - The assembly process of the dipyrromethane cofactor of Escherichia coli porphobilinogen deaminase holoenzyme is initiated by the reaction of the porphobilinogen deaminase apoenzyme with preuroporphyrinogen. The resulting enzyme-bound tetrapyrrole (bilane) is equivalent to the holoenzyme intermediate complex ES2 and yields the dipyrromethane cofactor by reactions of the normal catalytic cycle. These observations indicate that preuroporphyrinogen, rather than porphobilinogen, is the preferred precursor for the dipyrromethane cofactor and explain the existence of the D84A and D84N deaminase mutants as catalytically inactive ES2 complexes. PMID- 8687373 TI - Genomic mechanisms involved in the pleiotropic actions of 1,25-dihydroxyvitamin D3. AB - The biologically active metabolite of vitamin D (cholecalciferol), i.e. 1,25 dihydroxyvitamin D3 [1,25(OH)2D3], is a secosteroid hormone whose mode of action involves stereospecific interaction with an intracellular receptor protein (vitamin D receptor; VDR). 1,25(OH)2D3 is known to be a principal regulator of calcium homeostasis, and it has numerous other physiological functions including inhibition of proliferation of cancer cells, effects on hormone secretion and suppression of T-cell proliferation and cytokine production. Although the exact mechanisms involved in mediating many of the different effects of 1,25(OH)2D3 are not completely defined, genomic actions involving the VDR are clearly of major importance. Similar to other steroid receptors, the VDR is phosphorylated; however, the exact functional role of the phosphorylation of the VDR remains to be determined. The VDR has been reported to be regulated by 1,25(OH)2D3 and also by activation of protein kinases A and C, suggesting co-operativity between signal transduction pathways and 1,25(OH)2D3 action. The VDR binds to vitamin D responsive elements (VDREs) in the 5' flanking region of target genes. It has been suggested that VDR homodimerization can occur upon binding to certain VDREs but that the VDR/retinoid X receptor (RXR) heterodimer is the functional transactivating species. Other factors reported to be involved in VDR-mediated transcription include chicken ovalbumin upstream promoter (COUP) transcription factor, which is involved in active silencing of transcription, and transcription factor IIB, which has been suggested to play a major role following VDR/RXR heterodimerization. Newly identified vitamin D-dependent target genes include those for Ca2+/Mg(2+)-ATPase in the intestine and p21 in the myelomonocytic U937 cell line. Elucidation of the mechanisms involved in the multiple actions of 1,25(OH)2D3 will be an active area of future research. PMID- 8687375 TI - Non-oxidative modification of native low-density lipoprotein by oxidized low density lipoprotein. AB - The oxidative modification of low-density lipoprotein (LDL) has been implicated in the pathogenesis of atherosclerosis, although little is known as yet about the precise mechanism of oxidation in vivo. The studies presented here demonstrate that, in the absence of cells or transition metals, oxidized LDL can modify native LDL through co-incubation in vitro such as to increase its net negative charge, in a concentration-dependent manner. The interaction is not inhibited by peroxyl radical scavengers or metal chelators, precluding the possibility that the modification of native LDL by oxidized LDL is through an oxidative process. Studies with radioiodinated oxidized LDL showed no transfer of radioactivity to the native LDL, demonstrating that fragmentation of protein and the transfer of some of the fragments does not account for the modified charge on the native LDL particle. The adjacency of native to oxidized LDL in the arterial wall may be a potential mechanism by which the altered recognition properties of the apolipoprotein B-100 may arise rapidly without oxidation or extensive modification of the native LDL lipid itself. PMID- 8687376 TI - Functional activation of the egr-1 (early growth response-1) gene by hydrogen peroxide. AB - The redox-based regulation of gene expression is one of the fundamental mechanisms of cellular functions, and hydrogen peroxide seems to act as an intracellular second messenger of signal transduction of cytokines. Hydrogen peroxide at non-toxic doses induced the accumulation of mRNA for the early growth response-1 (egr-1) gene in mouse osteoblastic cells. The Egr-1 protein is a transcription factor that binds the GCGGGGGCG sequence and contains a zinc-finger structure that is essential for DNA binding. Egr-1 protein is sensitive to oxidative stress and loses specific DNA-binding activity when exposed to high levels of oxidative stress. Incubating cells with hydrogen peroxide at about 50 microM, however, increased the accumulation of Egr-1 protein, and the Egr-1 product seemed to be functional, judging by its binding activity to the GCGGGGGCG sequence and its ability to activate the chloramphenicol acetyltransferase reporter gene under the control of the human thymidine kinase enhancer containing the Egr-1 binding sequence. It was reported that the activity of Egr-1 protein as a transcription factor was negatively regulated by active oxygens. However, with appropriate concentrations of active oxygen, its capacity to bind a specific DNA sequence and to enhance the transcriptional activity of target genes is thought to be elevated. PMID- 8687377 TI - Evidence that biliverdin-IX beta reductase and flavin reductase are identical. AB - A search of the database shows that human biliverdin-IX beta reductase and flavin reductase are identical. We have isolated flavin reductase from bovine erythrocytes and show that the activity co-elutes with biliverdin-IX beta reductase. Preparations of the enzyme that are electrophoretically homogeneous exhibit both flavin reductase and biliverdin-IX beta reductase activities; however, they are not capable of catalysing the reduction of biliverdin-IX alpha. Although there is little obvious sequence identity between biliverdin-IX alpha reductase (BVR-A) and biliverdin-IX beta reductase (BVR-B), they do show weak immunological cross-reactivity. Both enzymes bind to 2',5'-ADP-Sepharose. PMID- 8687378 TI - 2-Carboxyarabinitol 1-phosphate (CA1P) formation through a phosphate exchange reaction catalysed by the CA1P phosphatase from French bean (Phaseolus vulgaris L.). AB - Transfer of the phosphate group of 2-carboxy-D-arabinitol 1-phosphate (CA1P) to 14C-labelled 2-carboxy-D-arabinitol (CA) was catalysed by extracts from leaves of Phaseolus vulgaris. This phosphotransferase activity co-purified with CA1P phosphatase, described previously. This activity was increased, up to 16-fold, by addition of bicarbonate ions at pH 9-10, suggesting rate enhancement by enzyme carbamylation. A V(max) of 1.5 mumol/min per mg of protein and a K(m) (for CA) of 1.8 mM were estimated for the exchange reaction, with the purified phosphatase. 2 Carboxy-D-arabinitol 1,5-bisphosphate and 2-carboxy-D-ribitol 1,5-bisphosphate, but not D-ribulose 1,5-bisphosphate, could replace CA1P as phosphate donor to [14C]CA. PMID- 8687379 TI - Modulation of the higher-order folding of chromatin by deletion of histone H3 and H4 terminal domains. AB - The 'tails' of histones H3 and H4 were removed by light in situ trypsin digestion of the nuclei. The alterations in the higher-order folding of chromatin resulting from this treatment were monitored by ethidium bromide titration. We found that DNA-intercalation of ethidium bromide under these conditions exhibited a complex concentration effect that was dependent on the extent of chromatin folding. This most likely reflects the structural transitions of chromatin during its folding as a result of the changes in the nucleosome linker twist [Woodcock, Grigoryev, Horowitz and Whitaker (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 9021-9025]. These results strongly suggest that the H3 and H4 terminal domains play a very important role in chromatin folding. We discuss the molecular basis of this phenomenon and propose a novel generalized model for the higher-order folding of chromatin. PMID- 8687380 TI - Subpopulations of proteasomes in rat liver nuclei, microsomes and cytosol. AB - Mammalian proteasomes are composed of 14-17 different types of subunits, some of which, including major-histocompatibility-complex-encoded subunits LMP2 and LMP7, are non-essential and present in variable amounts. We have investigated the distribution of total proteasomes and some individual subunits in rat liver by quantitative immunoblot analysis of purified subcellular fractions (nuclei, mitochondria, microsomes and cytosol). Proteasomes were mainly found in the cytosol but were also present in the purified nuclear and microsomal fractions. In the nuclei, proteasomes were soluble or loosely attached to the chromatin, since they could be easily extracted by treatment with nucleases or high concentrations of salt. In the microsomes, proteasomes were on the outside of the membranes. Further subfractionation of the microsomes showed that the proteasomes in this fraction were associated with the smooth endoplasmic reticulum and with the cis-Golgi but were practically absent from the rough endoplasmic reticulum. Using monospecific antibodies for some proteasomal subunits (C8, C9, LMP2 and Z), the composition of proteasomes in nuclei, microsomes and cytosol was investigated. Although there appear not to be differences in proteasome composition in the alpha subunits (C8 and C9) in the different locations, the relative amounts of some beta subunits varied. Subunit Z was enriched in nuclear proteasomes but low in microsome-associated proteasomes, whereas LMP2, which was relatively low in nuclei, showed a small enrichment in the microsomes. These differences in subunit composition of proteasomes probably reflect differences in the function of proteasomes in distinct cell compartments. PMID- 8687381 TI - Rapid burst kinetics in the hydrolysis of 4-nitrophenyl acetate by penicillin G acylase from Kluyvera citrophila. Effects of mutation F360V on rate constants for acylation and de-acylation. AB - The kinetics of release of 4-nitrophenol were followed by stopped-flow spectrophotometry with two 4-nitrophenyl ester substrates of penicillin G acylase from Kluyvera citrophila. With the ester of acetic acid, but not of propionic acid, there was a pre-steady-state exponential phase, the kinetics of which were inhibited by phenylacetic acid (a product of hydrolysis of specific substrates) to the extent predicted from Ki values. This was interpreted as deriving from rapid formation (73 mM-1.s-1) and slow hydrolysis (0.76 s-1) of an acetyl derivative of the side chain of the catalytic-centre residue Ser-290. With the mutant F360V, which differs from the wild-type enzyme in its ability to hydrolyse adipyl-L-leucine and has a kcat for 4-nitrophenyl acetate one-twentieth that of the wild-type enzyme, the corresponding values for the rates of formation and hydrolysis of the acetyl-enzyme were 11.1 mM-1.s-1 and 0.051 s-1 respectively. The ratio of these rate constants was three times that for the wild-type enzyme, suggesting that the mutant is less impaired in the rate of formation of an acetyl enzyme than in its subsequent hydrolysis. PMID- 8687382 TI - Multiple-sited interaction of caldesmon with Ca(2+)-calmodulin. AB - The binding of Ca(2+)- and Ba(2+)-calmodulin to caldesmon and its functional consequence was investigated with three different calmodulin mutants. Two calmodulin mutants have pairs of cysteine residues substituted and oxidized to a disulphide bond in either the N- or C-terminal lobe (C41/75 and C85/112). The third mutant has phenylalanine-92 replaced by alanine (F92A). Binding measurements in the presence of Ca2+ by separation on native gels and by carbodiimide-induced cross-linking showed a lower affinity for caldesmon in all the mutants. When Ca2+ was replaced by Ba2+ the affinity of calmodulin for caldesmon was further reduced. The ability of Ca(2+)-calmodulin to release caldesmon's inhibition of the actin-tropomyosin-activated myosin ATPase was virtually abolished by mutation of phenylalanine-92 to alanine or by replacing Ba2+ for Ca2+ in native calmodulin. Both cysteine mutants retained their functional ability, but the increased concentration needed for 50% release of caldesmon inhibition reflected their decreased affinity. Ca2+ -calmodulin produced a broadening in the signals of the NMR spectrum of the 10 kDa Ca(2+) calmodulin-binding C-terminal fragment of caldesmon arising from tryptophans -749 and -779 and caused an enhancement of maximum tryptophan fluorescence of 49% and a 16 nm blue shift of the maximum. Ca(2+)-calmodulin F92A produced a change in wavelength of 4 nm but no change in maximum, whereas Ca(2+)-calmodulin C41/75 binding produced a decrease in fluorescence with no shift of the maximum. We conclude that functional binding of Ca(2+)-calmodulin to caldesmon requires multiple interaction sites on both molecules. However, some structural modification in calmodulin does not abolish the caldesmon-related functionality. This suggests that various EF hand proteins can substitute for the calmodulin molecule. PMID- 8687383 TI - Regulation of the salvage pathway of deoxynucleotides synthesis in apoptosis induced by growth factor deprivation. AB - Here we describe changes in dNTP metabolism that precede DNA fragmentation in a model of apoptosis driven by deprivation of the cytokine interleukin 3 (IL-3). In haemopoietic BAF3 cells, IL-3 withdrawal leads to a rapid decrease in the size of dATP, dTTP and dGTP pools without affecting dCTP levels. This imbalance in dNTP pools precedes DNA fragmentation and is accompanied by down-regulation of enzymes controlling the de novo and salvage pathways of dNTP synthesis, ribonucleotide reductase and thymidine kinase (TK) respectively. Readdition of IL-3 results in a rapid, protein synthesis-independent restoration of normal dNTP pools, enhanced TK activity and increased precursor incorporation through the salvage pathway. Up regulation of TK activity after IL-3 readdition is prevented by the protein kinase C (PKC) inhibitor staurosporin, but not by tyrosine kinase inhibitors. Furthermore activation of PKC by phorbol esters mimics the stimulatory effect of IL-3 on TK activity, suggesting that PKC might be involved in regulating this effect. These results indicate that regulation by IL-3 of the salvage pathway of dNTP synthesis plays a role in the maintenance of cellular dNTP pool balance and suggests that alterations in dNTP metabolism after IL-3 deprivation could be a relevant event in the commitment of haemopoietic cells to apoptosis. PMID- 8687384 TI - The glycosylation of Bowes melanoma tissue plasminogen activator: lectin mapping, reaction with anti-L2/HNK-1 antibodies and the presence of sulphated/glucuronic acid containing glycans. AB - The glycosylation of tissue plasminogen activator (t-PA) obtained from the Bowes melanoma cell line was re-examined using methods of serial lectin affinity chromatography coupled with Bio-Gel P-4 gel filtration chromatography and exoglycosidase sequencing. This study clarified an earlier discrepancy in the literature and confirmed that the major complex N-linked glycans on Bowes t-PA that carry sialic acid as their sole charged group are bi-antennary, core fucosylated, with terminal N-acetylgalactosamine residues. We also report the characterization of a series of related and previously unidentified sialylated glycans. Further we show that Bowes t-PA expresses glucuronic acid/sulphate containing N-linked glycans and is recognized by anti-carbohydrate L2/HNK-1 monoclonal antibodies. The presence on Bowes t-PA of glycans associated primarily with the nervous system is consistent with its expression in a cell line of neuroectodermal origin. PMID- 8687385 TI - Two conformationally vicinal thiols at the active site of Leishmania donovani adenosine kinase. AB - Inactivation of adenosine kinase (Adk) from Leishmania donovani correlates with the modification of two conformationally vicinal cysteine residues. In contrast, Adk from hamster liver, despite being sensitive to monothiol-blocking reagents, was insensitive to dithiol modifiers. Inactivation kinetics and substrate protection studies along with double-modification experiments successively with N ethylmaleimide in the presence of Ado and sodium m-arsenite-2,3 dimercaptopropanol or diazenedicarboxylic acid bis-N,N'-dimethylamide supported assignment of the two thiols at the Ado-binding site. Cystine bridge formation impaired the ability of the modified enzyme to bind to the substrate. Tryptophan fluorescence of the enzyme was quenched after modification by dithiol-blocking reagents with concomitant loss of activity. However, treatment of the enzyme with methylmethanethiosulphonate (MMTS) led to complete inactivation without a marked change in protein fluorescence. Ado protected both fluorescence and catalytic activity against inactivation by both MMTS and dithiol-blocking reagents. Stern Volmer quenching analysis of the native and Ado-complexed enzyme suggested that, of the four tryptophan residues, at least one is located at or near the active site. Furthermore quenching constants of native, Ado-complexed and dithiol modified enzyme in the presence of either acrylamide or KI indicated spatial proximity of tryptophan and two cysteine residues within the hydrophobic domain of the Ado-binding site. Taken together the results suggest important function(s) for the cysteine residue(s). A schematic model is proposed to explain the inactivation of the enzyme by both monothiol- and dithiol-blocking reagents. PMID- 8687386 TI - Both rapamycin-sensitive and -insensitive pathways are involved in the phosphorylation of the initiation factor-4E-binding protein (4E-BP1) in response to insulin in rat epididymal fat-cells. AB - There is mounting evidence that in fat and other insulin-sensitive cells activation of protein synthesis may involve the dissociation of a protein (4E BP1) from eukaryotic initiation factor (eIF)-4E thus allowing formation of the eIF-4F complex. This study compares the effects of insulin and epidermal growth factor (EGF) on the phosphorylation of 4E-BP1 in fat-cells (followed by gel-shift assays and incorporation of 32P) and on its association with eIF-4E. Several lines of evidence suggest that mitogenactivated protein kinase (MAP kinase) is not involved in these effects of insulin. Insulin causes much more extensive phosphorylation and dissociation of 4E-BP1 from eIF-4E than EGF, although EGF activates MAP kinase to a much greater extent than insulin. Moreover, MAP kinase does not phosphorylate 4E-BP1 when it is complexed with eIF-4E. In contrast, insulin activates the 40S ribosomal protein S6 kinase (p70S6K) 18-fold compared with a 2-fold activation by EGF, and the time course of this activation is similar to the phosphorylation and dissociation of 4E-BP1. Rapamycin, a specific inhibitor of the activation of this latter kinase, inhibits dissociation of 4E BP1 from eIF-4E in cells incubated with insulin but reveals a phosphorylated from of 4E-BP1 which remains bound to eIF-4E. It is concluded that in rat epididymal fat-cells, the effects of insulin on 4E-BP1 involves multiple phosphorylation events. One phosphorylation event is rapamycin-insensitive, occurs only on bound 4E-BP1 and does not initiate dissociation. The second event does result in dissociation and is blocked by rapamycin, suggesting that the p70S6K signalling pathway is involved: p70S6K itself is probably not involved directly as this kinase does not phosphorylate 4E-BP1 in vitro. PMID- 8687387 TI - Binding of a protein to an AU-rich domain of tumour necrosis factor alpha mRNA as a 35 kDa complex and its regulation in primary rat astrocytes. AB - Newcastle disease virus (NDV) induces tumour necrosis factor alpha (TNF alpha) gene transcription and increases the mRNA stability. NDV stabilizes TNF alpha mRNA by preventing poly(A) shortening in a protein kinase C-dependent manner. TNF alpha 3'-untranslated region (UTR) contains an AU-rich domain (ARD) with seven AUUUA pentamers, a motif implicated in poly(A) removal and mRNA degradation. In this report, protein binding to TNF alpha ARD and the effects of NDV and kinases on ARD-binding activity were investigated in primary rat astrocytes. Both nuclear and cytoplasmic extracts contained proteins binding to centrally located 27 nt AUUUAUUAUUUAUUUAUUAUUUAUUUA, within TNF alpha ARD. Portions of ARD with a single AUUUA did not show ARD-binding activity. The ARD-protein complexes migrated as two bands on electrophoretic mobility-shift assay. The slower moving complexes appeared either as a broader band or doublets. The UV cross-linked ARD-protein complexes, however, migrated as a single 35 kDa band on SDS/PAGE. In cytoplasmic extracts treated with alkaline phosphatase there was a decrease in the faster moving complex and an increase in the slower moving complex, whereas NDV infection produced the reverse effect. In addition, the faster moving complex was decreased when cytoplasmic extracts from NDV-infected cells were treated with protein phosphatase 1 or 2A. Neither NDV infection nor phosphatase treatment affected the mobility pattern of nuclear extracts. The data indicate that a protein of molecular mass less than 35 kDa binds to a segment of TNF alpha ARD containing primarily UUAUUUAUU motifs, and the ARD-binding activity in cytoplasmic compartment is post-transcriptionally modified. PMID- 8687388 TI - Triplex DNA in the nucleus: direct binding of triplex-specific antibodies and their effect on transcription, replication and cell growth. AB - Jel 318 and Jel 466 are triplex-specific monoclonal antibodies which previously have been shown to bind to cell nuclei and chromosomes by immunofluorescence. Their interaction was further characterized by two methods. First, isolated intact nuclei were encapsulated in agarose. Both antibodies showed significant binding to the nuclei which could be inhibited by adding competing triplex DNA but not by adding Escherichia coli DNA to which the antibodies do not bind. Both triplex-specific antibodies inhibited replication and transcription in the nuclei by about 20%. Secondly, the antibodies were introduced into synchronized myeloma cells by osmotic shock of pynocytic vesicles. Cell-cycle studies showed that the myeloma cells had an S phase of about 10 h and a doubling time of about 20 h. The cells were synchronized with thymidine and both cell growth and cell death were monitored. Introduction of the triplex-specific antibodies caused a marked decrease in cell growth without a significant increase in cell death. The effectiveness of the antibodies was improved by the addition of chloroquine diphosphate which inhibits degradation in the lysosomes. As a control, introduction of an antibody specific for a bacterial protein had little effect. In synchronized cells, inhibition of proliferation reached a maximum at 7 to 13 h after the release from the thymidine block. Thus, cells are most sensitive to the triplex-binding antibodies at the end of S phase and during G2. This result is consistent with the view that triplexes are involved in chromosome condensation/decondensation. PMID- 8687389 TI - The lung enriched transcription factor TTF-1 and the ubiquitously expressed proteins Sp1 and Sp3 interact with elements located in the minimal promoter of the rat Clara cell secretory protein gene. AB - The mechanisms that direct expression of the Clara cell secretory protein (CCSP) gene to the bronchiolar epithelial cells of the lung remain to be elucidated. Previous studies have identified a number of proteins which bind to a functionally important region (Region 1) located -132 to -76 bp from the transcription start site in the rat CCSP gene. Subsequently we have shown that while Region 1 is an important positive regulator of CCSP gene expression, sequences 3' of this region (-75 to +38) are sufficient to confer tissue-specific expression of a reporter gene. In the present study we have used transient transfections with a deletion series of CCSP-CAT reporter plasmids (where CAT is chloramphenicol acetyltransferase) and gel mobility shift assays with a series of overlapping oligonucleotides covering the whole minimal promoter region to study protein-DNA interactions within this region. These studies have identified a conserved functional binding site for the lung and thyroid enriched homeodomain transcription factor TTF-1, located between positions -51 and -42 from the transcription start site. CCSP-CAT chimaeric reporters containing this region are specifically activated by TTF-1 in co-transfection assays, and nuclear extracts from cells which express TTF-1 bind to this region, as does in vitro translated rat TTF-1. Three additional conserved regions were identified, and in further gel mobility shift studies with an oligonucleotide spanning the conserved region immediately 5' to the TTF-1 site we identified a binding site for the ubiquitously expressed zinc-finger-containing proteins Sp1 and Sp3. These studies suggest that cell-type-restricted and ubiquitous nuclear proteins may play a combined role in the regulation of the CCSP gene within the bronchiolar epithelium by interacting with the minimal promoter region. PMID- 8687391 TI - Regulation of a high-affinity diamine transport system in Trypanosoma cruzi epimastigotes. AB - Trypanosoma cruzi epimastigotes take up exogenous [3H]putrescine and [3H]cadaverine by a rapid, high-affinity, transport system that exhibits saturable kinetics (putrescine K(m) 2.0 microM, V(max) 3.3 nmol/min per 10(8) cells; cadaverine K(m) 13.4 microM, V(max) 3.9 nmol/min per 10(8) cells). Putrescine transport is temperature dependent and requires the presence of a membrane potential and thiol groups for activity. Its activity is altered in response to extracellular putrescine levels and as the cells proceed through the growth cycle. This transporter shows high specificity for the diamines putrescine and cadaverine, but low specificity for the polyamines spermidine and spermine. The existence of rapid diamine/polyamine transport systems whose activity can be adjusted in response to the growth conditions is of particular importance, as they seem unable to synthesize their own putrescine [Hunter, Le Quesne and Fairlamb (1994) Eur. J. Biochem. 226, 1019-1027]. PMID- 8687390 TI - Co-operative interactions of oligonucleosomal DNA with the H1e histone variant and its poly(ADP-ribosyl)ated isoform. AB - H1 histone somatic variants from L929 mouse fibroblasts were purified by reverse phase HPLC. We analysed the ability of each H1 histone variant to allow the H1-H1 interactions that are essential for the formation of the higher levels of chromatin structure, and we investigated the role played by the poly(ADP ribosyl)ation process. Cross-linking analysis showed that H1e is the only somatic variant which, when bound to DNA, is able to produce H1-H1 polymers; the size of polymers was decreased when H1e was enriched in its poly(ADP-ribosyl)ated isoform. Measurement of the methyl-accepting ability in native nuclei compared with nuclei in which poly(ADP-ribosyl)ation was induced showed that the poly(ADP ribosyl)ated H1 histone had not been removed from linker regions, in spite of its different interaction with DNA. PMID- 8687392 TI - Degradation of aggrecan precursors within a specialized subcompartment of the chicken chondrocyte endoplasmic reticulum. AB - Chicken chondrocytes in culture synthesize aggrecan proteoglycan as a 370 kDa precursor that is glycosylated and secreted into the medium with a half-life of 30 min. In metabolic studies the 370 kDa precursor was shown to render a degradation intermediate of 190 kDa, which appeared with no measurable lag phase; it was dependent on temperature ( > 20 degrees C) and inhibited by certain serine and serine/cysteine protease inhibitors such as leupeptin and PMSF. By contrast, degradation was unaffected by treatment of the cells with brefeldin A or with lysosomotropic agents. Aggrecan precursors were detected by immunofluorescence analysis within a subcompartment of the endoplasmic reticulum (ER), previously characterized as a smooth-membrane-bound subregion [Vertel, Velasco, LaFrance, Walters and Kaczman-Daniel (1989) J. Cell Biol. 109, 1827-1836]. Analysis of the subcellular fractions derived from chondrocytes indicated that the degradation intermediate was concentrated in the ER subcompartment. Degradation was dependent on the Ca2+ concentration and the redox state in the ER. Treatment of the cells with agents or conditions that alter the degradation rate of aggrecan precursors, such as protease inhibitors, decreased temperature or dithiothreitol, also modified the retention of these molecules in the ER subcompartment, as seen by immunofluorescence. These results indicate that a fraction of the 370 kDa aggrecan precursor is targeted to a smooth ER subcompartment where it undergoes degradation. PMID- 8687394 TI - Modulation of flavocytochrome b2 intraprotein electron transfer via an interdomain hinge region. AB - The two domains of flavocytochrome b2 are connected by a typical hinge peptide. To probe the role of the hinge in modulating the efficiency of intraprotein electron transfer between these two domains, a number of mutant enzymes with truncated hinge regions were previously constructed and characterized [Sharp, Chapman and Reid (1996) Biochemistry 35, 891-899]. In the present study two mutant enzymes with elongated hinge regions have been constructed (HI3 and HI6) to further our understanding of the controlling influence of hinge length and primary structure on intraprotein electron transfer. Modification of the hinge had little effect on the lactate dehydrogenase activity of the enzyme, as was evident from steady-state experiments using ferricyanide as electron acceptor and from pre-steady-state experiments monitoring flavin reduction. However, the hinge insertions lowered the enzyme's effectiveness as a cytochrome c reductase. This effect results from a defect at the first interdomain electron-transfer step (FMNH2 --> haem electron transfer), where the rate constants for haem reduction in HI3 and HI6 were 50- and 100-fold lower than the corresponding value for the wild-type enzyme. Preservation of structural integrity within the hinge region is apparently essential for efficient intraprotein electron transfer. PMID- 8687393 TI - Trout red blood cell arrestin (TRCarr), a novel member of the arrestin family: cloning, immunoprecipitation and expression of recombinant TRCarr. AB - Arrestins are cytosolic proteins involved in the desensitization of G-protein coupled receptors. We report the cloning of trout red blood cell arrestin which shows 76, 82 and 52% identity with bovine beta-arrestin1, beta-arrestin2 and retinal arrestin respectively. Antibodies were generated against the C-terminus of trout red blood cell arrestin. These antibodies detected arrestin in erythrocyte cytosol and were able to precipitate the native protein. The Na+/H+ antiporter of trout red blood cell is activated by beta-adrenergic stimulation and is then desensitized whereas the transmembrane signalling pathway is not. To investigate the subcellular distribution of arrestin on beta-adrenergic activation and desensitization of the antiporter, precipitation experiments were carried out on trout erythrocytes. A desensitization-dependent shift in cytosolic arrestin to the membranes could not be detected using the immunoprecipitation technique but we cannot exclude the possibility that a small number of cytosolic arrestins might be involved in the regulation of membrane proteins in trout erythrocyte. Recombinant trout arrestin was produced in a protease-deficient Escherichia coli strain and its functionality was tested in a reconstituted rhodopsin assay. The recombinant protein provides a suitable tool for investigating the target for arrestin in trout red blood cell, which still remains to be identified. PMID- 8687395 TI - Molecular cloning and expression of a unique rabbit osteoclastic phosphotyrosyl phosphatase. AB - Tyrosyl phosphorylation plays an important regulatory role in osteoclast formation and activity. Phosphotyrosyl phosphatases (PTPs), in addition to tyrosyl kinases, are key determinants of intracellular tyrosyl phosphorylation levels. To identify the PTP that might play an important regulatory role in osteoclasts, we sought to clone an osteoclast-specific PTP. A putative full length clone encoding a unique PTP (referred to as PTP-oc) was isolated from a 10 day-old rabbit osteoclastic cDNA library and sequenced. A single open reading frame predicts a protein with 405 amino acid residues containing a putative extracellular domain, a single transmembrane region, and an intracellular portion. PTP-oc is structurally unique in that, unlike most known transmembrane PTPs, it has a short extracellular region (eight residues), lacks a signal peptide proximal to the N-terminus, and contains only a single 'PTP catalytic domain'. The PTP catalytic domain shows 45-50% sequence identity with the catalytic domain of human HPTP beta and with the first catalytic domain of LCA. The PTP-oc gene exists as a single copy in the rabbit genome. The corresponding mRNA (3.8 kb) is expressed in osteoclasts but not in other bone-derived cells (e.g. osteoblasts and stromal cells). The 3.8 kb PTP-oc mRNA transcript was also expressed in the rabbit brain, kidney and spleen. However, the brain and kidney, but not osteoclasts or spleen, also expressed a larger transcript (6.5 kb). The PTP catalytic domain of PTP-oc was expressed as a GST-cPTP-oc fusion protein. In vitro phosphatase assays indicated that the purified fusion protein exhibited phosphatase activities at neutral pH values toward p-nitrophenyl phosphate, phosphotyrosyl Raytide, and phosphotyrosyl histone, whereas it had no appreciable activity toward phosphoseryl casein. In summary, we have: (a) cloned and sequenced the putative full-length cDNA of a unique PTP (PTP-oc) from rabbit osteoclasts; (b) shown that the mature 3.8 kb PTP-oc mRNA was expressed primarily in osteoclasts and the spleen; and (c) shown that the PTP-oc fusion protein exhibited a phosphotyrosine-specific phosphatase activity. In conclusion, PTP-oc represents a structurally unique subfamily of transmembrane PTPs. PMID- 8687396 TI - Dimerization of truncated melittin analogues results in cytolytic peptides. AB - A synthetic peptide with the sequence of the first 20 residues of melittin and terminating with an additional cysteine amide was found to have cytolytic activity similar to that of melittin. It was apparent from MS data that the cysteine-terminating peptides had formed disulphide dimers. A peptide in which the thiol was blocked by iodoacetate showed no activity, whereas the same peptide blocked by acetamidomethyl showed activity marginally less haemolytic than that of melittin. Cytolytic activity of melittin analogues comprising the full 26 residues could be obtained with wide sequence permutations providing that a general amphipathic helical structure was preserved. In contrast, the activity of the dimers was dependent not only on retention of an amphipathic helix but also on certain individual residues and a free positive charge. A free N-terminus was essential for haemolytic activity. In addition, a lysine or arginine residue at position 7 and a proline at position 14 were found to be necessary for activity, although it was apparent that additional residues are important for retention of the full lytic potential. PMID- 8687397 TI - Characterization of the inhibitory effects of bile acids on very-low-density lipoprotein secretion by rat hepatocytes in primary culture. AB - In this study the effects of bile acids and other organic anions on the secretion of very-low-density lipoproteins (VLDLs) were evaluated in rat hepatocytes in primary culture. Incubation of cells with portal blood concentrations (10-200 microM) of bile acids resulted in dose-dependent suppression of secretion of VLDL associated [3H]triglyceride (TG) formed from [3H]glycerol, and also of TG mass. The degree of the inhibition was highly correlated with intracellular bile acid concentration. Prolonged incubation with 100 microM extracellular taurocholic acid (TC) decreased the secretion of [3H]TG and TG mass to 35% and 50% of the controls respectively. Cellular content of mass and of [3H]TG during prolonged incubation with TC were about 20% and 60% higher than the controls respectively. The inhibitory effect remained for at least 24 h in the presence of TC without altering VLDL-lipid and VLDL-apolipoprotein compositions or the size distribution of the particles. Secretion of apoB-100 and of apoB-48 was inhibited to a similar extent. Cells largely lost their capacity to accumulate bile acids intracellularly after 48 h in culture. In these cells TC was unable to exert its suppressive effects. Taurine and glycine conjugates of all common bile acids were capable of suppressing [3H]TG secretion. Trihydroxylated (cholic acid) and various dihydroxylated (deoxycholic, chenodeoxycholic and ursodeoxycholic acids) bile acids had similar capacities in this respect, suggesting that their common sterol-3 alpha-OH structure is required for the suppressive effect. Neither non bile acid organic anions, e.g. bilirubin ditaurate and dibromosulphthalein, nor dianionic bile acid metabolites, e.g. sulphated taurolithocholic acid and lithocholate-3-O-glucuronide, showed any effect on [3H]TG secretion. These results indicate that bile acids might play a physiological role in regulating VLDL production by the liver, especially in the postprandial state when their enterohepatic circulation is stimulated. PMID- 8687398 TI - Cyclic GMP regulates activation of phosphoinositidase C by bradykinin in sensory neurons. AB - Prior exposure of cultured neonatal rat dorsal root ganglion (DRG) neurons to bradykinin resulted in marked attenuation of bradykinin-induced activation of phosphoinositidase C (PIC). The (logconcentration)-response curve for bradykinin induced [3H]inositol trisphosphate ([3H]IP3) formation was shifted to the right and the maximum response was reduced. Bradykinin increases cyclic GMP (cGMP) in DRG neurons [Burgess, Mullaney, McNeill, Coote, Minhas and Wood (1989) J. Neurochem. 53, 1212-1218] and treatment of the neurons with dibutyryl cGMP (dbcGMP) had a similar, inhibitory, effect on bradykinin-induced [3H]IP3 formation. NG-Nitro-L-arginine (LNNA) blocked bradykinin-induced formation of cGMP. It prevented the functional uncoupling induced by pretreatment with bradykinin, but not the inhibitory effect of dbcGMP on [3H]IP3 formation. The ability of LNNA to prevent desensitization was reversed by excess L-arginine, indicating that its actions were mediated through inhibition of nitric oxide synthase. In addition to functional desensitization, exposure to bradykinin reduced the number of cell-surface receptors detected with [3H]bradykinin, without affecting its KD value for the remaining sites. In contrast to bradykinin, pretreatment with dbcGMP had no effect on either the KD or B(max) for [3H]bradykinin binding. This implies that the inhibitory effect of dbcGMP was down-stream from the binding of bradykinin to its receptor and upstream of IP3 formation. The lack of effect of dbcGMP on [3H]bradykinin binding suggests that the decrease in receptor number induced by bradykinin was mediated by a different mechanism and was not a key factor in the rapid phase of desensitization in these cells. PMID- 8687399 TI - Demonstration of a glycoprotein derived from the 24p3 gene in mouse uterine luminal fluid. AB - A glycoprotein in mouse uterine luminal fluid was purified to homogeneity via a series of purification steps involving Sephadex G-100 chromatography, Sephadex G 50 chromatography and HPLC on a reverse-phase C18 column, in that order. Automated Edman degradation was unable to determine the N-terminal residue of the glycoprotein and the partial sequences determined from its trypsin digests were found to be identical with the protein sequence deduced from 24p3 cDNA. The core protein and the total amount of carbohydrate together gave a molecular mass of 25.8 kDa. Results from the characterization of the glycopeptide bond indicated the presence of N-linked carbohydrate but no O-linked carbohydrate in the protein, which has two potential sites for N-linked carbohydrate at Asn81 and Asn85, as deduced from analysis of the primary structure. The core protein was shown to have a molecular mass equal to that of the putative protein deduced from cDNA, suggesting that this protein may contain no signal peptide. Results of Northern-blot analysis for various tissues of adult mice revealed that the 24p3 gene was expressed in lung, spleen, uterus, vagina and epididymis. PMID- 8687401 TI - Molecular cloning, expression and regulatory activity of G alpha 11- and beta gamma-subunit-stimulated phospholipase C-beta from avian erythrocytes. AB - A turkey erythrocyte phospholipase C (PLC) has been instrumental in delineating the role of G-proteins in receptor-regulated inositol lipid signalling. This isoenzyme is uniquely regulated both by alpha-subunits of the Gq family and by G protein beta gamma-subunits. A 4819 bp cDNA encoding this PLC has been cloned from a turkey erythrocyte cDNA library. The open reading frame of this cDNA encodes a 1211-amino-acid protein (calculated molecular mass 139050 Da) that contains amino acid sequences of 16 peptides sequenced from the turkey erythrocyte PLC. The predicted sequence of the turkey PLC shows considerable similarity with the sequences of previously cloned members of the PLC-beta family, with the highest identity (71%) shared with PLC-beta 2 and lesser identities observed with PLC-beta 1 (49%), PLC-beta 3 (46%) and PLC-beta 4 (37%). The largest differences in sequence between the turkey PLC-beta and other PLC beta isoenzymes occur in the C-terminal domain and in the region between the X- and Y-domains. The turkey isoenzyme and PLC-beta 2, which differ in their regulation by G-protein alpha-subunits, are only 44% similar across the approx. 400 amino acid residues of the C-terminal domain that has been implicated in alpha q activation of these proteins. Recombinant turkey PLC-beta was purified to homogeneity following expression from a recombinant baculovirus in Sf9 insect cells. The immunoreactivity and mobility on SDS/PAGE of the recombinant enzyme were the same as observed with native turkey erythrocyte PLC-beta. Moreover, the catalytic activities of the recombinant enzyme were indistinguishable from those of native turkey erythrocyte PLC-beta in assays carried out in the presence of cholate and Ca2+, or in assays of activity after reconstitution with G alpha 11 or G-protein beta gamma-subunits. The turkey PLC-beta was more sensitive to activation by G alpha 11 than was PLC-beta 2, and was more sensitive to activation by beta gamma-subunits than either PLC-beta 2 or PLC-beta 1. PMID- 8687400 TI - Regulation of proliferation of LLC-MK2 cells by nucleosides and nucleotides: the role of ecto-enzymes. AB - 1. Using the incorporation of [methyl-3H]thymidine as a proliferation marker, the effects of various nucleosides and nucleotides on endothelial LLC-MK2 cells were studied. We found that ATP, ADP, AMP and adenosine in concentrations of 10 microM or higher stimulate the proliferation of these cells. 2. Inhibition of ecto ATPase (EC 3.6.1.15), 5'-nucleotidase (EC 3.1.3.5) or alkaline phosphatase (EC 3.1.3.1) significantly diminished the stimulatory effect of ATP, indicating that the effect is primarily caused by adenosine and not by adenine nucleotides. Also, the effect depends only on extracellular nucleosides, since inhibition of nucleoside uptake by dipyridamole has no influence on proliferation. 3. Other purine nucleotides and nucleosides (ITP, GTP, inosine and guanosine) also stimulate cell proliferation, while pyrimidine nucleotides and nucleosides (CTP, UTP, cytidine and uridine) inhibit proliferation. Furthermore, the simultaneous presence of adenosine and any of the other purine nucleosides is not entirely additive in its effect on cell proliferation. At the same time any pyrimidine nucleoside, when added together with adenosine, has the same inhibitory effect as the pyrimidine nucleoside alone. 4. Apparently these proliferative effects are neither caused by any pharmacologically known P1-purinoceptor, nor are they mediated by cyclic AMP, cyclic GMP, or D-myo-inositol 1,4,5-trisphosphate as second messenger, nor by extracellular Ca2+. 5. Therefore, we conclude that various purine and pyrimidine nucleosides can influence the proliferation of LLC MK2 cells by acting on putative purinergic and pyrimidinergic receptors not previously described. PMID- 8687402 TI - Autoprocessing: an essential step for the activation of HIV-1 protease. AB - Human immunodeficiency virus type 1 (HIV-1) expresses its structural and functional proteins within Gag-Pol precursor polyproteins. Specific proteolytic processing of the precursors by the viral protease is critical for the maturation and infectivity of viral particles. To observe the influence of autoprocessing on the activation of recombinant HIV-1 protease, we constructed different HIV-1 protease forms, with or without the Phe-Pro bond directly upstream of the protease domain, and expressed them in Escherichia coli systems. We found that the presence of a short upstream sequence of the protease domain, which could generate the original N-terminus of the protease by autoproteolysis of the Phe Pro bond, resulted in processing of active protease, whereas for a wild-type protease extended only with the initiator methionine, the proteolytic activity was not recovered. Our results suggested that autoprocessing of the direct upstream sequence of the protease domain is an essential step for the activation of recombinant HIV-1 protease in the E. coli expression system. Expression of HIV 1 protease as fusion proteins revealed that the existence of a fusion portion increased the accumulation of expressed protease by affecting its homotypic dimer formation. PMID- 8687403 TI - Long-term effect of cyclic AMP on N-glycosylation is caused by an increase in the activity of the cis-prenyltransferase. AB - Previously we have shown that long-term pretreatment of JEG-3 choriocarcinoma cells with 8-bromo-cAMP increases the capacity for N-glycosylation that was caused by an 8-10-fold enlargement of the dolichol pyrophosphoryl oligosaccharide (Dol-PP-oligosaccharide) pool [Konrad and Merz (1994) J. Biol. Chem. 269, 8659 8666]. The factors involved in the effect of cAMP on synthesis of Dol-PP oligosaccharide are investigated here. The GlcNAc transfer to dolichol phosphate (Dol-P) was found to be unaffected by pretreatment with 8-bromo-cAMP. By measuring the uptake of [3H]mevalonate, a 20-fold increase in the incorporation of the label into Dol-P was observed in the cells treated with 8-bromo-cAMP. Under the same conditions, the synthesis of dolichol was enhanced 60-fold. However, the incorporation of the radioactivity into cholesterol was not increased in the JEG-3 cells pretreated with 8-bromo-cAMP, which suggests a specific stimulation of the dolichol/Dol-P pathway by cAMP. The cis prenyltransferase activity was found to be increased 10-fold in cells pretreated with 8-bromo-cAMP. Dolichol kinase activity was unaffected by stimulation with 8 bromo-cAMP. The present study suggests that the larger glycosylation capacity in JEG-3 cells treated with 8-bromo-cAMP is caused by an increase in the microsomal cis-prenyltransferase activity. PMID- 8687404 TI - Phospholipase C in mouse oocytes: characterization of beta and gamma isoforms and their possible involvement in sperm-induced Ca2+ spiking. AB - This study involved an investigation of the role of phospholipase C (PLC) in generating repetitive Ca2+ spikes at fertilization. Using a PCR-based strategy we have demonstrated that mouse oocytes have mRNA coding for PLC beta 1, PLC beta 3 and PLC gamma isoenzymes. Furthermore, immunodetection of PLC gamma 1 using monoclonal antibodies reveals that PLC gamma 1 protein is present in mature mouse oocytes, ruling out the possibility that mRNA was being transcribed but not expressed. We were unsuccessful at detecting the presence of PLC beta protein, but the presence of this isoform can be inferred from functional studies. The PLC inhibitor, U73122, exerted an inhibitory effect on oocytes activated by spermatozoa or acetylcholine at concentrations of 10 and 30 microM respectively, while its inactive analogue had no effect. The soluble tyrosine kinase inhibitors, genistein (100 microM), herbimycin (10 microM) and geldanamycin (0.6 microM) which could affect signalling through PLC gamma hindered but never completely inhibited Ca2+ spiking in response to fertilization. We conclude that the activation of PLC to generate InsP3 may play a critical role in fertilization. PMID- 8687405 TI - Evidence for specific annexin I-binding proteins on human monocytes. AB - Recombinant human annexin I and a monoclonal antibody specific for this protein (mAb 1B) were used to investigate surface binding of this member of the annexin family of proteins to peripheral blood monocytes. Flow cytometric analysis demonstrated trypsin-sensitive, saturable binding of annexin I to human peripheral blood monocytes but not to admixed lymphocytes. A monoclonal antibody that blocks the anti-phospholipase activity of annexin I also blocked its binding to monocytes. These findings suggest the presence of specific binding sites on monocytes. Furthermore, surface iodination, immunoprecipitation and SDS/PAGE analysis were used to identify two annexin I-binding proteins on the surface of monocytes with molecular masses of 15 kDa and 18 kDa respectively. The identification and characterization of these annexin I-binding molecules should help us to better understand the specific interactions of annexin I with monocytes that lead to down-regulation of pro-inflammatory cell functions. PMID- 8687406 TI - ERp60 does not substitute for protein disulphide isomerase as the beta-subunit of prolyl 4-hydroxylase. AB - Prolyl 4-hydroxylase (EC 1.14.11.2) catalyses the formation of 4-hydroxyproline in collagens. The vertebrate enzymes are alpha 2 beta 2 tetramers while the Caenorhabditis elegans enzyme is an alpha beta dimer. The beta-subunit is identical to protein disulphide isomerase (PDI), a multifunctional endoplasmic reticulum luminal polypeptide. ERp60 is a PDI isoform that was initially misidentified as a phosphatidylinositol-specific phospholipase C. We report here on the cloning and expression of the human and Drosophila ERp60 polypeptides. The overall amino acid sequence identity and similarity between the processed human ERp60 and PDI polypeptides are 29% and 56% respectively, and those between the Drosophila ERp60 and human PDI polypeptides 29% and 55%. The two ERp60 polypeptides were found to be similar to human PDI within almost all their domains, the only exception being the extreme C-terminal region. Nevertheless, when the human or Drosophila ERp60 was expressed in insect cells together with an alpha-subunit of human prolyl 4-hydroxylase, no tetramer was formed and no prolyl 4-hydroxylase activity was generated in the cells. Additional experiments with hybrid polypeptides in which the C-terminal regions had been exchanged between the human ERp60 and PDI polypeptides demonstrated that the differences in the C terminal region are not the only reason for the lack of prolyl 4-hydroxylase tetramer formation by ERp60. PMID- 8687407 TI - Biogenesis of thermogenic mitochondria in brown adipose tissue of Djungarian hamsters during cold adaptation. AB - After cold exposure, cytochrome c oxidase (COX) activity increased about 2.5-fold within 2 weeks in the brown adipose tissue (BAT) of Djungarian hamsters. The mRNAs for COX subunits I and III and the 12 S rRNA, encoded on mitochondrial DNA (mtDNA), as well as mRNAs for COX subunits IV, Va and mitochondrial transcription factor A, encoded in the nucleus, were unchanged when expressed per unit of total tissue RNA. However, since total tissue RNA doubled per BAT depot, while total DNA remained unchanged, the actual levels of these transcripts were increased within BAT cells. In contrast, the abundance of mRNA for uncoupling protein was increased 10-fold, indicating specific activation of this gene. In addition, the maximal rate of protein synthesis analysed in a faithful in organello system was increased 2.5-fold in mitochondria isolated from BAT after 7 days of cold exposure. We conclude from these data that the biogenesis of thermogenic mitochondria in BAT following cold adaptation is achieved by increasing the overall capacity for synthesis of mitochondrial proteins in both compartments, by increasing their mRNAs as well as the ribosomes needed for their translation. In addition, the translational rate for COX subunits as well as all other proteins encoded on mtDNA is increased. Thus the pool of subunits encoded on mtDNA required for assembly of respiratory chain complexes is provided. By comparison with other models of increased mitochondrial biogenesis, we propose that thyroid hormone (generated within BAT cells by 5'-deiodinase, and induced upon sympathetic stimulation), which is a well known regulator of the biogenesis of mitochondria in many tissues, is also the major effector of these adaptive changes in BAT. PMID- 8687408 TI - Thermostable chaperonin from Clostridium thermocellum. AB - Homologues of the chaperonins Cpn60 and Cpn10 have been purified from the Gram positive cellulolytic thermophile Clostridium thermocellum. The Cpn60 protein was purified by ATP-affinity chromatography and the Cpn10 protein was purified by gel filtration, ion-exchange and hydrophobic interaction chromatographies. The identities of the proteins were confirmed by N-terminal sequence analysis and antigenic cross-reactivity. The Cpn60 homologue is a weak, thermostable ATPase (t1/2 at 70 decrees C more than 90 min) with optimum activity (Kcat 0.07 S-1) between 60 degrees C and 70 degrees C. The ATPase activity of the authentic Cpn60 was inhibited by Escherichia coli GroES. The catalytic properties of a recombinant C. thermocellum Cpn60 purified from a GST-Cpn60 fusion protein expressed in E. coli [Ciruela (1995) Ph.D. Thesis, University of Kent] were identical with those of the authentic C. thermocellum Cpn60. Gel-filtration studies show that at room temperature the Cpn60 migrates mainly as a heptamer. Electron microscopy confirms the presence of complexes showing 7-fold rotational symmetry and also reveals a small number of particles that seem to be tetradecamers with a similar structure to E. coli GroEL complexes. PMID- 8687409 TI - Bip/GRP78 but not calnexin associates with a precursor of glycosylphosphatidylinositol-anchored protein. AB - When fused in-frame with a C-terminal propeptide of placental alkaline phosphatase (PLAP), rat alpha 2u-globulin (alpha GL), a nonglycosylated secretory protein, was expressed on the cell surface as a glycosylphosphatidylinositol (GPI)-linked chimaeric protein (alpha GL-PLAP). In contrast with the wild-type alpha GL-PLAP, a mutant, in which Asp at the cleavage/attachment site of GPI was replaced by Trp, failed to become a GPI-linked mature form and was retained as a precursor form within the cell [Oda, Cheng, Saku, Takami, Sohda, Misumi, Ikehara and Millan (1994) Biochem. J. 301, 577-583]. To elucidate the molecular interactions involved in the retention of the proform within the cell, we examined the association of the proform with molecular chaperones in the endoplasmic reticulum (ER). Antibody against the ER retrieval motif KDEL coimmunoprecipitated a 25 kDa proform, but not a 22 kDa GPI-linked mature form. Pulse-chase experiments showed that the wild-type alpha GL-PLAP with a cleavable propeptide was converted into the mature form, whereas the mutant alpha GL-PLAP with an uncleavable propeptide remained associated with ER-resident proteins with a KDEL motif and underwent rapid degradation in a pre-Golgi compartment. Chemical cross-linking studies showed that, of the several ER-resident proteins immunoreactive with the anti-KDEL antibody, a 78 kDa protein was the only protein associated with the proform. Furthermore this 78 kDa protein was dissociated from the precursor molecule on incubation with ATP, allowing us tentatively to assign it as Bip/GRP78. Anticalnexin antibody, however, failed to coprecipitate any form of the chimaeric protein. Immunoelectron microscopy showed that the proform with the uncleavable propeptide was localized in the ER, but not detected in the Golgi apparatus or plasma membranes. Taken together, these results suggest that Bip/GRP78 is associated with pro alpha GL-PLAP and retains it within the ER until pro alpha GL-PLAP is either modified by GPI or degraded, thereby participating in the quality control of this GPI-linked chimaeric protein. PMID- 8687411 TI - Interaction of Ash/Grb-2 via its SH3 domains with neuron-specific p150 and p65. AB - We found that 180 kDa, 150 kDa (p150), 110 kDa, 100 kDa and 65 kDa (p65) proteins comprise the major Ash/Grb-2-binding proteins in bovine brain. Among these proteins, 180 kDa and 100 kDa proteins have already been identified as Sos and dynamin respectively. Here, p150 and p65 were affinity-purified with glutathione S-transferase-Ash fusion protein and their partial amino acid sequences were determined. Analysis showed p150 and p65 to be new proteins. These two proteins bind to both the N-terminal SH3 domain and the C-terminal SH3 domain of Ash. It was found that p150 and p65 are expressed predominantly in brain, although Ash is widely distributed in all tissues examined by Western blots. Immunohistochemical staining of rat brain showed p150 and p65 to be localized in a variety of neurons in the cerebellum and hippocampus, with p65 being especially concentrated in the nerve terminal. When the Ash-binding-motif peptide of the epidermal growth factor receptor was used to detect complexes formed with Ash in vivo, 180 kDa, 150 kDa, 110 kDa, 100 kDa and 65 kDa proteins were also bound; this shows that these proteins form complexes with Ash in brain. In addition, p150 and p65 co immunoprecipitated with Ash. All these results suggest that Ash may function as a regulator of synaptic vesicle transport through dynamin, p150 and p65. PMID- 8687410 TI - Cloning, sequencing and expression of rat liver pyruvate carboxylase. AB - Overlapping clones encoding rat liver pyruvate carboxylase (PC) have been isolated by screening a liver cDNA library and by performing rapid amplification of cDNA ends polymerase chain reaction on total liver RNA. The sequence of rat PC cDNA contains an open reading frame of 3537 nucleotides encoding a polypeptide of 1178 amino acids with a calculated M(r) of 129848. This is flanked by a 5' untranslated region of 66 bp and a 3' untranslated region of 421 bp including the poly(A) tail. The inferred protein sequence is 96.6% identical with mouse and 96.3% identical with human PCs, 68.4% identical with mosquito PC and 53.5% identical with yeast PC isoenzymes PC1 and PC2. On the basis of partial proteolysis and sequence homology with PC from other organisms (yeast, mosquito, mouse and human) and with other biotin enzymes, three functional domains, namely the biotin carboxylation domain, the transcarboxylation domain and the biotinyl domain, have been identified. Comparison with the known structure of the biotin carboxylase subunit of Escherichia coli acetyl-CoA carboxylase [Waldrop, Rayment and Holden (1994) Biochemistry 33, 10249-10256] highlights the functional importance of 11 highly conserved residues. Northern analysis revealed that PC mRNA is highly expressed in rat liver, kidney, adipose tissue and brain, moderately expressed in heart, adrenal gland and lactating mammary gland, and expressed at a low level in spleen and skeletal muscle. PMID- 8687412 TI - Influence of amino acid residue 374 of cytochrome P-450 2D6 (CYP2D6) on the regio and enantio-selective metabolism of metoprolol. AB - Cytochrome P-450 2D6 (CYP2D6) is an important human drug-metabolizing enzyme responsible for the oxidation of more than 30 widely used therapeutic agents. The enzymes encoded by the published genomic [Kimura, Umeno, Skoda, Meyer and Gonzalez (1989) Am. J. Hum. Genet. 45, 889-904] and cDNA [Gonzalez, Skoda, Kimura, Umeno, Zanger, Nebert, Gelboin, Hardwick and Meyer (1988) Nature 331, 442 446] sequences of CYP2D6, and presumed to represent wild-type sequences, differ at residue 374 and encode valine (CYP2D6-Val) and methionine (CYP2D6-Met) respectively. The influence of this amino acid difference on cytochrome P-450 expression, ligand binding, catalysis and stereoselective oxidation of metoprolol was investigated by the heterologous expression of the corresponding cDNAs in the yeast Saccharomyces cerevisiae. The level of expression of apo- and holo-protein was similar with each form of CYP2D6 cDNA, and the binding affinities of a series of ligands to CYP2D6-Val and CYP2D6-Met were identical. The enantioselective O demethylation and alpha-hydroxylation of metoprolol were also similar with each form of CYP2D6, O-demethylation being R-(+)- enantioselective (CYP2D6-Val: R/S, 1.6; CYP2D6-Met: R/S, 1.4), whereas alpha-hydroxylation showed a preference for S (-)-metoprolol (CYP2D6-Val: R/S, 0.7; CYP2D6-Met: R/S, 0.8). However, although the favoured regiomer overall was O-demethylmetoprolol (ODM), the regioselectivity for O-demethylation of each metoprolol enantiomer was significantly greater for CYP2D6-Val [R-(+)-: ODM/alpha-hydroxymetoprolol (alpha OH), 5.9; S-(-)-: ODM/alpha OH, 2.5) than that observed for CYP2D6-Met [R-(+)-: ODM/alpha OH, 2.2; S-(-)-: ODM/alpha OH, 1.4]. The stereoselective properties of CYP2D6-Val were consistent with those observed for CYP2D6 in human liver microsomes. The difference in the stereoselective properties of CYP2D6-Val and CYP2D6-Met were rationalized with respect to a homology model of the active site of CYP2D6 based on an alignment with the crystal structure of the bacterial cytochrome P-450BM-3' CYP102. PMID- 8687413 TI - Tau protein is phosphorylated by cyclic AMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II within its microtubule-binding domains at Ser-262 and Ser-356. AB - Phosphorylation of tau protein at Ser-262 has been shown to diminish its ability to bind to taxol-stabilized microtubules. The paired helical filaments (PHFs) found in Alzheimer's disease brain are composed of PHF-tau, which is hyperphosphorylated at multiple sites including Ser-262. However, protein kinase(s) able to phosphorylate this site are still under investigation. In this study, the ability of cyclic AMP-dependent protein kinase (cAMP-PK) and calcium/calmodulin-dependent protein kinase II (CaMKII) to phosphorylate tau at Ser-262, as well as Ser-356, is demonstrated by use of a monoclonal antibody (12E8) which has been shown to recognize tau when these sites are phosphorylated. Cleavage of cAMP-PK-phosphorylated tau at cysteine residues by 2-nitro-5 thiocyanobenzoic acid, which cuts the protein into essentially two fragments and separates Ser-262 from Ser-356, revealed that cAMP-PK phosphorylates both Ser-262 and Ser-356. In addition, phosphorylation with cAMP-PK or CaMKII of recombinant tau in which Ser-262, Ser-356 or both had been mutated to alanines, clearly demonstrated that cAMP-PK and CaMKII were able to phosphorylate both sites. Mitogen-activated protein kinase or protein kinase C did not phosphorylate tau at Ser-262 and/or Ser-356. Finally, evidence is presented that phosphorylation of both these sites occurs in cultured nerve cells under certain conditions, indicating their potential physiological relevance. PMID- 8687414 TI - Stimulation in vitro of vitamin B12-dependent methionine synthase by polyamines. AB - Vitamin B12-dependent methionine synthase is an important enzyme for sulphur amino acid, folate polyamine metabolism, S-adenosylmethionine metabolism and also in the methylation pathway of DNA, RNA, proteins and lipids. Consequently, studies aiming at exploring the control and regulation of methionine synthase are of particular interest. Here we report the modulation of enzyme activity in vitro by polyamines. Although putrescine, cadaverine, spermine and spermidine all stimulated enzyme activity, the last two were the most potent, causing increases in enzyme activity up to 400%. The EC50 for spermine was determined as 8 microM and for spermidine 40 microM. The physiological concentration for spermine has been reported to be 15-19 microM. Spermine was found to increase both the Km and the V(max) with respect to methyltetrahydrofolate for the enzyme. These data support the hypothesis that spermine and spermidine are feedback regulators of methionine synthase both in vivo and in vitro and are consistent with the polyamines' regulating cell signalling pathways. PMID- 8687415 TI - Arachidonic acid and lipoxygenase products stimulate protein kinase C beta mRNA levels in pituitary alpha T3-1 cell line: role in gonadotropin-releasing hormone action. AB - The cross-talk of arachidonic acid (AA) and its lipoxygenase products with protein kinase C beta (PKC beta) mRNA levels during the action of gonadotropin releasing hormone (GnRH) was investigated in the pituitary alpha T3-1 cell line. The addition of AA or its 5-lipoxygenase products 5-hydroxyeicosatetraenoic acid (5-HETE) or leukotriene C4 (LTC4) for 30 or 60 min stimulated PCK beta, but not PKC alpha mRNA levels (3-5-fold); PCK gamma is not expressed by the cells. Other HETEs or leukotrienes tested showed no significant effect. The range of effective concentration for LTC4 and 5-HETE (around 10(-10) M) is the range found in GnRH stimulated pituitary cells. Although PKC beta mRNA levels were preferentially elevated by LTC4 and 5-HETE at early time points, PKC alpha mRNA levels were elevated at 6-12 h of incubation when PKC beta mRNA levels returned to basal levels. The addition of the phospholipase A2 inhibitor 4-bromophenacyl bromide or the selective 5-lipoxygenase inhibitor L-656,224 abolished [D-Trp6]GnRH (GnRH-A) elevation of PKC beta mRNA levels, whereas PKC alpha mRNA levels were not increased by this neurohormone. The cyclo-oxygenase inhibitor indomethacin elevated basal PKC beta mRNA levels and potentiated the GnRH-A response. Cross talk exists between AA and some of its lipoxygenase products and PKC beta gene expression during cell signalling. AA, 5-HETE and LTC4 participate in the rapid stimulation of PKC beta mRNA levels by GnRH. PMID- 8687416 TI - Apolipoprotein J and Alzheimer's amyloid beta solubility. AB - Apolipoprotein J (apoJ) has been found associated with soluble amyloid beta (sA beta) in plasma and cerebrospinal fluid in normal individuals and co-deposited with fibrillar A beta in Alzheimer's cerebrovascular and parenchymal lesions. Although studies in vitro and in vivo indicate that apoJ is a major carrier protein for sA beta, its role in the fibrillogenesis process is not known. We report herein that apoJ in its native high-density lipoprotein lipidic environment is fully active to interact with A beta peptides. Furthermore, apoJ prevents aggregation and polymerization of synthetic A beta in vitro. The interaction was stable for at least 14 days at 37 degrees C in physiologic buffers, and the peptide retrieved after complex dissociation at low pH retained its inherent aggregation properties. In addition, the binding to apoJ protects synthetic A beta from proteolytic degradation; both A beta 1-42 and A beta 1-40 were more resistant to proteolysis by trypsin and chymotrypsin when complexed to apoJ. The data suggest that the interaction may preclude sA beta aggregation in biological fluids and point to a protecting role of apoJ for complexed A beta species. PMID- 8687417 TI - An H(+)-ATPase regulates cytoplasmic pH in Pneumocystis carinii trophozoites. AB - Pneumocystis carinii is an opportunistic fungus which causes interstitial pneumonia in patients with acquired immunodeficiency syndrome (AIDS). Cytoplasmic pH (pHi) regulation in short-term-cultured P. carinii trophozoites was studied using the fluorescent dye 2',7'-bis-(2-carboxyethyl)-5-(-6)-carboxyfluorescein. With an extracellular pH of 7.4, the mean baseline pHi of P. carinii trophozoites was 7.40 +/- 0.10 (n = 8). This steady-state pHi was not significantly affected in the absence of extracellular Na+ or K+. Moreover, steady-state pHi was maintained in the nominal absence of HCO3- and was not affected by the Cl-/HCO(3 )-exchanger inhibitor 4, 4'-di-isothiocyanato-dihydrostilbene-2, 2'-disulphonic acid (100 microM), or the Na+/H(+)-exchanger inhibitor N-ethyl-N isopropylamiloride (100 microM). In contrast, the general inhibitors of ATPases, N-ethylmaleimide (1 mM), and dicyclohexylcarbodi-imide (100 microM), and the inhibitor of yeast H(+)-ATPase, diethylstilbestrol (12.5-100 microM), decreased pHi, while the K+/H(+)-ATPase inhibitor omeprazole (50-400 microM), and the vacuolar-type H(+)-ATPase inhibitor bafilomycin A1 (1-5 microM) only produced a dose-dependent acidification of the cells when used at high concentrations. In addition, steady-state pHi depended on the availability of cellular ATP, since it was decreased by the ATP synthase inhibitors oligomycin (1 microgram/ml) and sodium azide (1 mM), and by the uncoupler of oxidative phosphorylation carbonyl cyanide p-trifluorophenylhydrazone (1 microM), agents that were able to deplete significantly the intracellular ATP levels. Taken together, these results are consistent with an important role of an H(+)-ATPase similar to those found in other fungi in the regulation of pHi homoeostasis in P. carinii trophozoites. PMID- 8687418 TI - Enzymic and molecular characterization of NADP-dependent glyceraldehyde-3 phosphate dehydrogenase from Synechococcus PCC 7942: resistance of the enzyme to hydrogen peroxide. AB - NADP-dependent glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been purified to electrophoretic homogeneity from Synechococcus PCC 7942 cells. The native enzyme had a molecular mass of 160 kDa and consisted of four subunits with a molecular mass of 41 kDa. The activity was 6-fold higher with NADPH than with NADH; the apparent Km values for NADPH and NADH were 62 +/- 4.5 and 420 +/- 10.5 microM respectively. The gene encoding NADP-dependent GAPDH was cloned from the chromosomal DNA of Synechococcus 7942. A 1140 bp open reading frame, encoding an enzyme of 380 amino acid residues (approx.molecular mass of 41.3 kDa) was observed. The deduced amino acid sequence of the gene had a greater sequence similarity to the NADP-dependent and chloroplastic form than to the NAD-dependent and cytosolic form. The Synechococcus 7942 enzyme lacked one of the cysteines involved in the light-dependent regulation of the chloroplast enzymes of higher plants. The recombinant enzyme expressed in Escherichia coli as well as the native enzyme purified from Synechococcus 7942 cells were resistant to 1 mM H2O2. PMID- 8687419 TI - Differential distribution of ferulic acid to the major plasma constituents in relation to its potential as an antioxidant. AB - The hydroxycinnamates, intermediates in the phenylpropanoid synthetic pathway, are effective in enhancing the resistance of low-density lipoprotein (LDL) to oxidation in the order caffeic acid > ferulic acid > p-coumaric acid. It is unclear whether the mode of action of ferulic acid as an antioxidant is based on its activities in the aqueous or the lipophilic phase. Partitioning of 14C labelled ferulic acid into plasma and its components, LDL and the albumin-rich fractions, has been studied under conditions of maximum aqueous solubility. The majority of ferulic acid associates with the albumin-rich fraction of the plasma, although a proportion is also found to partition between the LDL and aqueous phases; however, ferulic acid does not associate with the lipid portion of the LDL particle, suggesting that it exerts its antioxidant properties from the aqueous phase. This is of particular interest since the results demonstrate that ferulic acid is a more effective antioxidant against LDL oxidation than the hydrophilic antioxidant ascorbic acid. PMID- 8687420 TI - Updating the sequence-based classification of glycosyl hydrolases. PMID- 8687421 TI - Molecular cloning of human mitochondrial glycerophosphate dehydrogenase gene: genomic structure, chromosomal localization, and existence of a pseudogene. AB - cDNA of mitochondrial glycerophosphate dehydrogenase (mGPDH), a defect of which is a possible cause of non-insulin dependent diabetes mellitus, was cloned from a human insulinoma cDNA library. The deduced amino acid sequence showed 91% and 92% homology with those of rat and mouse mGPDH, respectively. The mGPDH gene was mapped to chromosome 2q23 by FISH analysis. Genomic clones for mGPDH were then isolated using mouse mGPDH cDNA and PCR products of human mGPDH cDNA as probes. Genomic structure was studied by sequencing the exon-intron boundaries and by PCR amplification of intronic regions using genomic clones as templates. The human mGPDH gene was shown to be composed of 15 coding exons, containing a (CA)n repeat region inside the gene, which was not polymorphic in the Japanese population. Genomic cloning also identified a pseudogene located on chromosome 19q13.4. These results provide information useful for analyzing the mGPDH gene in patients with non-insulin dependent diabetes mellitus. PMID- 8687422 TI - Identification of a novel variant hepatocyte growth factor secreted by spleen derived stromal cells. AB - Stromal cells can interact with parenchymal cells by secreting various cytokines to affect the growth, differentiation or movement of the latter. Here we report the identification and characterization of a novel variant hepatocyte growth factor (HGF) from the conditioned medium of stromal cells derived from mouse spleen. Compared to human HGF, it has much lower heparin-binding activity and lacks the beta-chain. Its molecular weight, 70 kDa, is very close to that of the alpha-chain of HGF. Human HGF homologue was not found in the conditioned medium. The conditioned medium of stromal cells, like recombinant HGF, could inhibit the growth of rat hepatoma cells. The inhibitory activity was presumably attributed to this novel HGF because the inhibitory activity, as the existence of this novel HGF, was confined to the identical fractions after heparin-column chromatography. Furthermore, this activity could be specifically abrogated by neutralizing anti HGF antibodies. PMID- 8687423 TI - Inhibition of basophil histamine release by a haptenic peptide mixture prepared by chymotryptic hydrolysis of wheat flour. AB - For application to the treatment of wheat-sensitive allergy, we developed a practical method for producing a haptenic peptide mixture, and evaluated its haptenic properties. Wheat flour was hydrolyzed with chymotrypsin to obtain a hydrolysate, and the diffusible fraction from the hydrolysate was subjected to gel-filtration. The resulting oligopeptide fraction could bind to wheat-specific IgE antibodies in the serum of patients allergic to wheat. Since this peptide mixture did not induce histamine release from basophils in these patients, it was concluded that the peptide mixture was composed of monovalent haptens. Histamine release from antigenstimulated basophils was almost completely inhibited when the basophils were preincubated with the haptenic peptide mixture. These results suggest that this haptenic peptide mixture can regulate the allergenic reaction in an epitope-specific manner. PMID- 8687424 TI - Mutant mtDNA at 1555 A to G in 12S rRNA gene and hypersusceptibility of mitochondrial translation to streptomycin can be co-transferred to rho 0 HeLa cells. AB - Human skin fibroblast line 95-119, which had been isolated from the mother of a Japanese patient with aminoglycoside-induced deafness and a 1555 A to G mutation at 12S rRNA gene in mitochondrial DNA (mtDNA), was used to investigate the relationship between the 1555 mtDNA mutation and its pathogenicity. By the intercellular transfer of mtDNA with or without the 1555 mutation to mtDNA-less (rho 0) HeLa cells, we isolated cybrid clones and found that the mitochondrial translation in a cybrid clone repopulated with the homoplasmic 1555 mutation showed the highest susceptibility to streptomycin. These observations suggest that the genotype of the mutant mtDNA and the phenotype of hypersusceptibility to streptomycin observed in 95-119 fibroblasts were co-transferred simultaneously to rho 0 HeLa cells, supporting the idea that the homoplasmic 1555 mtDNA mutation is involved in the pathogenesis leading to aminoglycoside-induced hearing loss. PMID- 8687425 TI - Inhibition of cADPR-Hydrolase by ADP-ribose potentiates cADPR synthesis from beta NAD+. AB - Cyclic adenosine 5'-diphosphate ribose (cADPR) is a potent Ca2+ releasing agent in a number of tissues. A particular bifunctional NAD+ glycohydrolase is responsible for both the cyclase and hydrolase activity necessary for its synthesis from beta-NAD and degradation to ADPR. We now report that ADPR, the end product of this enzyme, releases Ca2+ at high concentrations (above 100 microM), and at lower concentrations (10-100 microM) inhibits the hydrolysis of cADPR and potentiates the production of cADPR from NAD+. This evidence suggests that ADPR may be an important modulator of the NAD+ glycohydrolase responsible for the production of cADPR. PMID- 8687426 TI - Purification and characterization of the tricarboxylate carrier from eel liver mitochondria. AB - The tricarboxylate carrier from eel (Anguilla anguilla) liver mitochondria was solubilized with Triton X-100 and purified by sequential chromatography on hydroxyapatite and Matrex Gel Blue B. On SDS-polyacrylamide gel electrophoresis, the purified fraction showed a single polypeptide band with an apparent molecular mass of 30.4 kDa. When reconstituted into liposomes, the tricarboxylate transport protein catalyzed a very active 1,2,3-benzenetricarboxylate-sensitive citrate/citrate exchange. It was purified 641-fold with a recovery of 13.3% and a protein yield of 0.02% with respect to the mitochondrial extract. The properties of the reconstituted carrier, i.e., requirement for a counteranion, substrate specificity and inhibitor sensitivity, were similar to those of the tricarboxylate carrier purified from rat liver mitochondria. These studies provide the first information on the mitochondrial tricarboxylate transport protein of a fish. PMID- 8687427 TI - Purification and characterization of recombinant human 5'-methylthioadenosine phosphorylase: definite identification of coding cDNA. AB - 5'-Methylthioadenosine phosphorylase gene maps on the 9p21 chromosome, strictly linked to the important tumor suppressor gene p16INK4A. Chromosomal deletions encompassing both the phosphorylase and p16INK4A genes cause the complete absence of the enzymatic activity in a large number of tumors, thus resulting in well defined metabolic differences between malignant and normal cells. Recently, the cloning of the phosphorylase gene has been reported on the basis of indirect evidence. In order to demonstrate definitely the identification of 5' methylthioadenosine phosphorylase gene, we have cloned the putative enzyme coding sequence in a prokaryotic expression vector and expressed the protein in bacteria. The recombinant phosphorylase has been purified to homogeneity and its physicochemical, immunological and kinetic features have been characterized. The results obtained allowed the conclusive demonstration of 5'-methylthioadenosine phosphorylase gene cloning and the use of recombinant protein for further characterization. PMID- 8687428 TI - Relative ratios of mRNA molecules encoded by genes with homologous sequences using fluorescence-based single-strand conformation polymorphism analysis. AB - The combination of reverse transcribed (RT)-PCR and fluorescence-based single strand conformation polymorphism (SSCP) analysis is proposed for the quantitative determination of the ratio of mRNA molecules with homologous sequences. We applied this procedure to lactate dehydrogenase (LDH) subunits A and B. We designed fluorescence labeled common PCR primers in the sequences highly homologous between LDH-A and LDH-B cDNAs and performed RT-PCR-SSCP analysis. When PCR efficiency was almost the same between the different target sequences, analysis of mixtures of known amounts of LDH-A and LDH-B revealed linear and precise proportions of LDH-A mRNA. Template concentrations and PCR cycles did not affect the determination of proportions of LDH-A to total LDH. The present procedure could be easily applied to investigation of expression levels of genes encoding mRNAs with homologous sequences. PMID- 8687429 TI - HIV-1 tat induces the expression of a new hematopoietic cell-specific transcription factor and downregulates MIP-1 alpha gene expression in activated T cells. AB - MIP-1 alpha is a secreted chemokine which can inhibit hematopoietic stem cells and modulate inflammatory responses. It is also an inhibitor of HIV replication in CD8+ T-cells. The expression of MIP-1 alpha is induced during cellular activation of CD4+ T-cells and monocytes. It is also expressed in transformed B cells. We have previously identified a new transcription factor family (the MNP family) whose expression is crucial for the induction of MIP-1 alpha transcription during cellular activation and in transformed B cells. Monocytes and transformed B-cells normally express MNP-1 strongly and MNP-2 weakly, while T cells strongly express only MNP-2. Recently, we reported that HIV-1 tat downregulates MIP-1 alpha expression in Jurkat T-cells. In this report we show induction of MNP-1 in Jurkat T-cells expressing HIV-1 tat. Expression of neither HTLV-1 tax in Jurkat T-cells nor EBV in B-cells had any effect on MNP-1 or MNP-2 expression, showing that the effect is specific for HIV-1 tat. We propose that HIV-1 tat may inhibit MIP-1 alpha expression by inducing MNP-1 expression in T cells, probably by either competing with MNP-2 for binding to the MIP-1 alpha promoter or by sequestering it into inactive forms. PMID- 8687430 TI - Sterol 14-demethylase P450 activity expressed in rat gonads: contribution to the formation of mammalian meiosis-activating sterol. AB - Sterol 14-demethylase P450 (P45014DM)-dependent formation of 4,4-dimethylcholesta 8,14,24-trienol, that has been reported for a mammalian meiosis-activating sterol, in rat ovaries was confirmed. Transient elevation of ovarian P45014DM activity, that might be related to the female sexual cycle of rat, was observed. The P45014DM activity of immature ovaries was induced by pregnant mare's serum gonadotropin. These facts suggest the contribution of ovarian P45014DM to the gonadotropin-dependent formation of the meiosis-activating sterol, and provide a clue to understanding the mechanism how gonadotropins initiate the resumption of meiosis of mammalian oocytes. It was also found that rat testicular P45014DM participated in the production of 4,4-dimethylcholesta-8,24-dienol that was reported for another meiosis-activated sterol isolated from bull testes. PMID- 8687431 TI - Proadrenomedullin N-terminal 20 peptide is rapidly cleaved by neutral endopeptidase. AB - Proadrenomedullin N-terminal 20 peptide (PAMP) is a novel hypotensive peptide which is processed from an adrenomedullin precursor. PAMP is rapidly cleaved by human neutral endopeptidase (NEP), a protease which plays a key role in the degradation of human atrial natriuretic peptide (ANP). A double reciprocal plot indicated that Km of NEP as a substrate of PAMP was 6.1 microM and V(max) was 3.1 mmol/min/mg of NEP. EDTA, phosphoramidon and thiorphan inhibit the proteolysis of PAMP by NEP. NEP cleaves at least 6 peptide bonds in human PAMP; Arg2-Leu3, Glu8 Phe9, Lys12-Trp13, Lys15-Trp16, Trp16-Ala17 and Ala17-Leu18. The present data suggest that NEP may be involved in the circulation control by degrading PAMP as well as ANP. PMID- 8687432 TI - Spermidine regulation of protein synthesis at the level of initiation complex formation of Met-tRNAi, mRNA and ribosomes. AB - Spermidine regulation of protein synthesis (stimulation at low concentrations and inhibition at high concentrations) was studied using a mRNA with a GC-rich 5' untranslated region. It was found that the initiation complex formation of mRNA, Met-tRNAi, and 40 S ribosomal subunits was regulated by spermidine. The inhibition of initiation complex formation at high spermidine concentrations was greater with 80 S ribosomes than with 40S ribosomal subunits. This was partially explained by the spermidine inhibition of initiation factor-dependent RNA helicase activity. PMID- 8687433 TI - Potential sites for processing of the human invariant chain by cathepsins D and E. AB - Seven peptides of 15-30 amino acid residues were synthesized that covered almost the entire sequence of the lumenal domain of the human invariant chain (Ii), and their hydrolysis by cathepsins D and E was investigated. Two sites were identified that were very susceptible to such cleavage. One site, the Leu174 Phe175 bond, was cleaved by both cathepsins, and the other site, the Met99-Gln100 bond, was specifically cleaved by cathepsin E. These two sites could be the sites at which native Ii is cleaved by aspartic proteinases. The cleavage of the Met99 Gln100 bond by cathepsin E might be important in the inactivation of Ii and its functional derivatives. PMID- 8687434 TI - Phosphorylation of purified estradiol-liganded estrogen receptor by casein kinase II increases estrogen response element binding but does not alter ligand stability. AB - The estrogen receptor is a ligand-activated transcription factor that binds to specific DNA sequences, estrogen response elements. Recent studies have characterized the location of tyrosine and serine residues in the estrogen receptor that are phosphorylated either by purified protein kinases in vitro or in response to ligand and DNA binding in vivo. Here we examined how phosphorylation of purified bovine uterine estrogen receptor in vitro by casein kinase II impacts estrogen receptor-estrogen response element binding and 17 beta estradiol ligand binding stability. Our results show that phosphorylation doubles estrogen receptor-estrogen response element binding, but does not affect estradiol binding stability. These finding suggest that phosphorylation by casein kinase II on serine residues within the A/B domain results in intramolecular interactions affecting the DNA binding domain but not the ligand binding domain of the estrogen receptor. PMID- 8687435 TI - Mutation analysis of the transforming growth factor beta type II receptor in sporadic human cancers of the pancreas, liver, and breast. AB - The transforming growth factor beta (TGF beta) binds the type II TGF beta growth factor receptor (TGF beta RII) to inhibit growth of most epithelial tissues. Most human colon cancers with microsatellite instability have frameshift mutations in two microsatellites within the TGF beta RII coding region; such mutations truncate the receptor to produce resistance to TGF beta. To investigate this pathway in other tissues, we surveyed sporadic human cancers of the pancreas, liver and breast to determine the frequency of microsatellite mutations in the TGF beta RII. We amplified genomic DNA segments containing two microsatellites plus 72% of domain XI of the serine-threonine kinase region. SSCP analysis showed no evidence of mutation in 32 sporadic cancers (12 pancreas, 10 liver, and 10 breast). We conclude that microsatellite mutations in TGF beta RII are uncommon in sporadic tumors of the pancreas, liver and breast. PMID- 8687436 TI - A neutralizing epitope of the superantigen SEA has agonist activity on T cells. AB - We have previously shown that sequence 121-149 of the staphylococcal enterotoxin superantigen SEA plays an important role in superantigen function. A synthetic peptide of this region, SEA(121-149), blocks SEA binding to class II MHC molecules and induces interleukin-1 and tumor necrosis factor production in monocytes. In this study, we further emphasize the structural and functional significance of this region of SEA by showing that the SEA(121-149) peptide induces T cell proliferation in a manner similar to that of SEA. SEA(121-149) reacted with antibodies produced to SEA, and the SEA(121-149) specific antibodies neutralized SEA mitogenic activity. A tetrameric form of SEA(121-149) showed increased binding to antibodies and enhanced T cell activation, consistent with the greater avidity associated with increased valency. These data suggest that the internal domain of SEA corresponding to residues 121-149 plays an important role in superantigen activity. PMID- 8687437 TI - PrP27-30 is a normal soluble prion protein fragment released by human platelets. AB - Prion diseases are neurodegenerative disorders characterized by the accumulation of abnormal isoforms of prion protein (PrPSc) in the central nervous system. PrPSc isoforms differ from their normal homologue (PrPC), in that they possess increased beta-sheet conformation, are partially protease resistant and may be associated with amyloid deposition. Amyloid proteins are thought to derive from soluble precursors or fragments thereof, present in biological fluids, which in the disease state undergo conformational change leading to aggregation and deposition in target tissues. We report here that platelets carry PrP mRNA and release PrPC, a sialoglycoprotein bound to the cell surface by a glycosylphosphatidylinositol (GPI) anchor. Soluble PrPC, and a N-terminal truncated PrPC isoform starting at position 90 are secreted by resting and agonist-stimulated platelets and are detectable after partial deglycosylation of releasates. N-terminal sequence analysis of the soluble 27-30 kDa isoform, GQGGGTHSQ(W)NKP, revealed homology to scrapie PrP27-30, the protease resistant core derived from PrPSc. These findings indicate that in addition to PrPC, platelets process a soluble PrP27-30 isoform. Whether this isoform can be converted in scrapie PrP27-30 remains to be determined. PMID- 8687438 TI - Singlet oxygen (1 delta g) generation from coproporphyrin in Propionibacterium acnes on irradiation. AB - Although singlet oxygen has been postulated to be a highly reactive and toxic intermediate, there has been no evidence of considerable generation of singlet oxygen in vivo level except for special cases. In this work, we firstly measured the near-infrared emission spectra corresponding to the O2(1 delta g) --> O2(3 epsilon g-) transition of singlet oxygen of cutaneous Propionibacterium acnes (P. acnes) porphyrin under laser excitation. A comparison of the singlet oxygen production of coproporphyrin, which is produced predominantly from P. acnes, with that of other photosensitizers revealed coproporphyrin to be a highly efficient singlet oxygen generator under ultraviolet light A irradiation on the skin. These results suggest that singlet oxygen can be generated on the skin surface from P. acnes porphyrin under ultraviolet irradiation and induce serious damage to the skin. PMID- 8687439 TI - Alpha endosulfine is a novel molecule, structurally related to a family of phosphoproteins. AB - We have observed that alpha endosulfine, the 13KDa form of the endogenous ligand for sulfonylurea receptor recently isolated from porcine brain, displays strong similarities with a phosphoprotein of similar size previously isolated from bovine brain and called ARPP-19. To determine whether the two proteins are different entities, we developed an RT-PCR strategy for analyzing the main portion of bovine alpha endosulfine. We show that alpha endosulfine and ARPP-19 are different entities from the same family of proteins, coded by distinct genes. PMID- 8687440 TI - MEKA/phosducin attenuates hydrophobicity of transducin beta gamma subunits without binding to farnesyl moiety. AB - Hydrophobic modifications of transducin (T) gamma, such as farnesyl-and carboxyl methylation, are essential for the association of T beta gamma with the photoreceptor disc membrane, and MEKA/phosducin is known to inhibit the association. In this study, we examined the effect of MEKA on the hydrophobicity of T beta gamma. MEKA could bind to T beta gamma without farnesyl/carboxyl-methyl moieties as well as native T beta gamma. In the Triton X-114 phase separation assay, T beta gamma-MEKA complex was recovered in the aqueous phase, whereas T beta gamma was recover in the detergent phase. N-terminal portion of MEKA which includes T beta gamma-binding domain was not sufficient to reduce the hydrophobicity of T beta gamma or to dissociate T beta gamma from the membrane. The data suggest that MEKA attenuates the hydrophobicity of T beta gamma to result in the dissociation of T beta gamma from the membrane without directly binding to farnesyl/carboxyl-methyl moieties. PMID- 8687441 TI - Biochemical characterization of Alzheimer's soluble amyloid beta protein in human cerebrospinal fluid: association with high density lipoproteins. AB - The soluble form of Alzheimer's amyloid beta protein (sA beta) is associated with high density lipoproteins (HDL) in normal human plasma (BBRC, 1994, 205, 1164 1171). Since sA beta is also present in cerebrospinal fluid (CSF) and the lipoprotein pattern of CSF is different from that of plasma, it was of interest to ascertain whether the interaction of sA beta with HDL also occurs in CSF. Normal human CSF lipoproteins were obtained by sequential flotation ultracentrifugation and analyzed for the presence of sA beta via immunoblot, size exclusion chromatography, immunoelectron microscopy, N-terminal sequence and mass spectrometry analyses. Soluble A beta was associated with CSF-HDL particles of 16.8 +/- 3.2 nm in diameter and approximately 200 kDa of relative molecular mass. A approximately 4.3 kDa component purified by HPLC was immunoreactive with anti-A beta antibodies and exhibited an N-terminal sequence identical to the A beta peptide with a mass of 4325.1 Da, indicating that the main sA beta specie associated with CSF-HDL is A beta 1-40. PMID- 8687442 TI - Genistein directly inhibits L-type calcium currents but potentiates cAMP dependent chloride currents in cardiomyocytes. AB - We have examined the possible modulatory effects of genistein, a specific tyrosine kinase inhibitor, on cardiac L-type calcium currents and cAMP-dependent chloride currents in guinea pig ventricular myocytes. With one-suction electrode voltage-clamp technique, genistein dose-dependently and reversibly inhibited L type calcium currents in cardiomyocytes (Km = 17.5 microM). Neither threshold potential nor the peak potential of current-voltage relationship was affected. Interestingly, daidzein (an inactive analogue of genistein) also depressed L-type calcium currents. When L-type calcium currents were directly activated by Bay K 8644, genistein was able to exert an inhibitory action. In contrast, genistein potentiated cardiac cAMP-dependent chloride currents activated by either isoproterenol or 3-isobutyl-1-methylxanthine. These results suggest that genistein may directly inhibit L-type calcium currents but may potentiate cAMP dependent chloride currents in the heart. PMID- 8687443 TI - The interaction of rabbit reticulocyte guanine nucleotide exchange factor eIF-2B with chain initiation factor 2: studies with N-ethylmaleimide and trypsin. AB - Treatment of eIF-2B and eIF-2 with NEM abolishes nucleotide exchange and GTP binding activities of the proteins. Incubation of eIF-2B with [14C]NEM results in strong labeling of the 82- and 55-kDa subunits and with less labeling of the other subunits. Preincubation of eIF-2B with eIF-2 interferes with [14C]NEM labeling of the 82- and 55-kDa subunits. All three (alpha, beta, and gamma) subunits of eIF-2 are labeled strongly by [14C]NEM. Limited digestion of eIF-2B with trypsin inhibits nucleotide exchange activity but does not interfere with GTP binding. Under these conditions, the 65-kDa subunit is degraded completely while the other subunits remain intact. Treatment of eIF-2 with trypsin results in the generation of eIF-2 lacking the beta-subunit (eIF-2 alpha gamma). eIF 2(alpha gamma) binds [3H]GDP equally well as intact elf-2. In the presence of elf 2B, the exchange of [3H]GDP for GTP from elf-2. [3H]GDP prepared with eIF-2(alpha gamma) is diminished considerably. [3H]GTP binding to eIF-2(alpha gamma) is also four- to five-fold less than to intact eIF-2. In addition, the association of eIF 2B with intact eIF-2, but not with eIF-2(alpha gamma), reduces by two-fold the rate and extent of removal of 32P by alkaline phosphatase from CK-2 phosphorylated 82-kDa subunit. PMID- 8687444 TI - Inhibitors of farnesyl and geranylgeranyl methyltransferases prevent beta 2 integrin-induced actin polymerization without affecting beta 2 integrin-induced Ca2+ signaling in neutrophils. AB - The role of prenylated proteins such as low molecular weight G-proteins (LMW G proteins) in beta 2 integrin-dependent neutrophil signal transduction was investigated using two methyltransferase inhibitors, N-Acetyl-S-farnesyl-L cysteine (AFC) and N-acetyl-s-geranylgeranyl-L-cysteine (AGGC), and an inactive control, N-acetyl-S-geranyl-L-cysteine (AGC). The drugs did not affect beta 2 integrin-induced protein tyrosine phosphorylations or cytosolic calcium transients. However, AGGC inhibited beta 2 integrin-induced actin polymerization (IC50 of approximately 45nM), as did AFC(IC50 of approximately 5.5 microM), but not AGC. Thus, prenylated proteins, such as LMW G-proteins, are responsible for beta 2 integrin regulation of actin filament reorganization downstream of tyrosine kinase(s) activation, and represent a beta 2 integrin signaling mechanism distinct from the pathway which regulates cytosolic calcium transients. PMID- 8687445 TI - Signal transduction in isolated islets from the ob/ob mouse: enhanced sensitivity of protein kinase C to stimulation. AB - The insulin secretory responses of islets isolated from ob/ob mice or their lean litter mates to glucose or the phorbol ester tetradecanoyl phorbol acetate were determined. Glucose-induced phospholipase C activation was also monitored. Even though lean mouse islets contained more insulin than ob/ob mouse islets, the first and second phases of 15mM glucose-induced secretion were significantly greater from ob/ob mouse islets. The kinetics of this amplified response were similar to those seen from lean islets as was the ability of 15mM glucose to activate phospholipase C. A striking dichotomy in responsiveness to the protein kinase C activator tetradecanoyl phorbol acetate was observed between lean and ob/ob mouse islets: while islets from lean animals were unresponsive to tetradecanoyl phorbol acetate (500nM), a rising and sustained insulin secretory response was evoked from ob/ob mouse islets. The combination of 7.5mM glucose plus tetradecanoyl phorbol acetate resulted in dramatic and sustained insulin secretory responses from ob/ob mouse islets, responses that could be duplicated by stimulation with the combination of 3mM glucose, 500nM tetradecanoyl phorbol acetate and 30mM potassium. Significantly smaller responses to these agonist combinations were observed from lean mouse islets. These findings demonstrate that the sensitivity of ob/ob mouse islet protein kinase C to stimulation is markedly enhanced when compared to islets from lean mice and that the activation of protein kinase C or processes distal to and dependent on the enzyme may account, at least in part, for the amplified insulin secretory responses of these islets. PMID- 8687446 TI - Point mutations in the first and third intracellular loops of the glucagon-like peptide-1 receptor alter intracellular signaling. AB - The glucagon-like peptide-1 receptor (GLP-1R) is a member of the glucagon family of seven transmembrane spanning receptors. To investigate how different portions of the GLP-1R may be important in cAMP and intracellular calcium signaling, single amino acid substitutions in the receptor were made by site directed mutagenesis. Receptor binding, cAMP, and intracellular calcium measurements were made in transfected COS-7 cells. The change of amino acid H180R (His to Arg) in the first intracellular loop caused a decrease in the affinity of binding of GLP 1 from 7 nM in the wild type receptor to 150nM and resulted in a 50% decrease in GLP-1 stimulated cAMP production. In response to 10 nM GLP-1, the receptor's ability to stimulate intracellular calcium was altered from a prolonged to a transient response of the same magnitude. Mutation in the 3rd intracellular loop at position R348G (Arg to Gly) decreased receptor affinity from 7 to 83 nM and nearly abolished cAMP production at all concentrations of GLP-1 tested. The GLP-1 stimulated rise in free intracellular calcium was also diminished and this was reversed when cells were treated with forskolin. These results also indicate that GLP-1R signaling via intracellular calcium is dependent on the receptor's ability to also generate cAMP. PMID- 8687447 TI - An early increase in cGMP follows fertilization of sea urchin eggs. AB - It has been proposed that both inositol trisphosphate and ryanodine receptors contribute to the Ca signal generated at fertilization of the sea urchin egg. Pharmacological studies indicate that cyclic adenosine diphosphate-ribose (cADPr) is the endogenous modulator of Ca release by the ryanodine-like receptor in eggs and that cADPR cyclase, the enzyme responsible for cADPR synthesis, can be stimulated by 3',5'-cyclic guanosine monophosphate (cGMP). Also, recent results show that the gaseous transmitter nitric oxide (NO) releases calcium in eggs via a mechanism linked to cGMP and cADPR production. Results reported here show that fertilization induces a rapid and transient increase in the intracellular concentration of cGMP. This increase occurs during the latent period, before the major increase in cytoplasmic free calcium (Cai), consistent with the hypothesis that cGMP production may play a key role in the Ca signal seen at fertilization. PMID- 8687449 TI - Macrophage cytotoxicity against murine meth A sarcoma involves nitric oxide mediated apoptosis. AB - We have studied the cytotoxic effect of stimulated macrophages on Meth A tumor cells in vitro. When stimulated with interferon-gamma and soluble beta-1,3-D glucan, macrophages exerted cytotoxicity towards syngeneic Meth A tumor cells. This cytotoxicity was associated with a high level of nitric oxide production. Both cell death and nitric oxide production were significantly inhibited by the addition of aminoguanidine, a specific inhibitor of inducible nitric oxide synthase (iNOS), to the culture medium. The cytotoxic effect was accompanied by internucleosomal cleavage of DNA as shown by electrophoresis and DNA fragmentation assay. PMID- 8687448 TI - Mammalian mature osteoclasts as estrogen target cells. AB - The decrease in estrogen levels that follows the onset of menopause causes rapid bone loss, resulting in osteoporosis. However, the mechanism by which this occurs remains unclear, especially concerning the regulation of osteoclasts, i.e. the bone-resorbing cells. Using a pit assay involving isolated mature osteoclasts from rabbit long bones, we found that estrogen inhibited the bone-resorbing activity in a dose- and time-dependent manner. Furthermore, we clarified by Northern analysis that estrogen down-regulated the mRNA levels of cathepsin K/OC 2 and that putative estrogen receptor (ER) mRNA was expressed in these osteoclasts. Moreover, other sizes of mRNAs that hybridized with ER cDNA probe were found in these cells. Our results suggest that osteoclasts may be indeed target cells for estrogen and that estrogen might regulate a part of bone metabolism through osteoclasts. PMID- 8687450 TI - Transgenic expression of L-gulono-gamma-lactone oxidase in medaka (Oryzias latipes), a teleost fish that lacks this enzyme necessary for L-ascorbic acid biosynthesis. AB - Transfer of the gene for L-gulono-gamma-lactone oxidase, the missing enzyme in L ascorbic acid biosynthesis in scurvy-prone animals, into medaka (Oryzias latipes) was successfully done. The expression plasmid pSVL-GLO, carrying rat liver L gulono-gamma-lactone oxidase cDNA, was microinjected into the cytoplasm of fertilized eggs during the one-cell stage. Four male F0 fish having the transgene in their germ cells came to maturity, and F1 progeny derived from one of the F0 fish possessed L-gulono-gamma-lactone oxidase activity, indicating that the transgene was functionally expressed in the fish. Genomic Southern blot analysis demonstrated that the transgene existed in both chromosome-integrated and extrachromosomal forms. PMID- 8687451 TI - Identification of a novel inhibitor (NSC 665564) of dihydroorotate dehydrogenase with a potency equivalent to brequinar. AB - A novel inhibitor of dihydroorotate dehydrogenase (DHO-DH) has been discovered using data from the National Cancer Institute's in vitro drug screen. Upon analysis of cytotoxicity results from the sixty tumor cell lines used in this screen, the COMPARE program predicted that NSC 665564 was likely to have the same mechanism of inhibition as brequinar, a known potent inhibitor of DHO-DH. We validated this prediction experimentally using MOLT-4 lymphoblast and found the IC50 of brequinar (0.5 microM) and NSC 665564 (0.3 microM) were comparable and that this induced cytotoxicity was reversed by either uridine or cytidine. The enzyme target of NSC 665564 was shown to be identical to that of brequinar when incubation with each drug followed by a 1 h pulse with [14C] sodium bicarbonate resulted in cellular accumulation of [14C]N-carbamyl-L-aspartic acid and [14C]L dihydroorotic acid, with concurrent marked depletion of CTP and UTP. The Ki's for NSC 665564 and brequinar were 0.14 and 0.24 microM, respectively, when partially purified MOLT-4 mitochondria (the site of DHO-DH) were used. These results show that mechanistic predictions obtained using correlations from the COMPARE algorithm are independent of structure since the structure of NSC 665564 is dissimilar to that of other established DHO-DH inhibitors. PMID- 8687452 TI - Circulating leptin levels are modulated by fasting, cold exposure and insulin administration in lean but not Zucker (fa/fa) rats as measured by ELISA. AB - The development of a sensitive enzyme-linked immunosorbent assay (ELISA) is described for the quantitation of plasma leptin levels in both mice and rats. Approximately 1.5 ng leptin/ml plasma was detected in lean mice but significantly (p < 0.01) less was found in the plasma of ob/ob mice. In lean Zucker rats leptin circulated at approximately 4ng/ml plasma whereas levels were elevated more than 6-fold in fa/fa rats. Circulating leptin levels declined (p < 0.05) in lean rats which were fasted or exposed to 4 degrees C for 24h, but subsequently recovered to normal within 12h of refeeding or warming, respectively. Administration of insulin increased leptin levels in lean rats within 4h (p < 0.01). However, leptin levels were unchanged in fa/fa rats exposed to the same physiological stimuli. PMID- 8687453 TI - AP-2 gene expression and modulation by retinoic acid during keratinocyte differentiation. AB - The transcription factor AP-2 has been suggested to participate in keratinocyte gene regulation, but its precise role in the processes of keratinocyte proliferation and differentiation is largely unknown. We here report on an increase of AP-2 transcripts in proliferating HaCaT keratinocytes preceding the expression and upregulation of the differentiation-related genes keratin 4 (K4) and Ah-receptor (AhR), but a decrease of AP-2 transcript levels during the process of keratinocyte differentiation. Continuous treatment of the keratinocyte cell cultures with retinoic acid (RA) resulted in a premature downregulation of AP-2 mRNA levels, and the transcripts of K4 and AhR remained at basal levels. Furthermore, addition of RA to already differentiated cells failed to exert any effect on K4- and AhR-mRNA levels. The data suggest a role for AP-2 as an intermediate factor in the pathway of RA action in keratinocyte differentiation, explaining both the downregulation of K4 and AhR transcript levels in proliferative keratinocytes and the loss of RA effects in already differentiated cells. It appears thus that AP-2 plays a pivotal role at the onset of differentiation in still proliferating keratinocytes. PMID- 8687454 TI - Long time-scale probing of the protein globular core using hydrogen-exchange and room temperature phosphorescence. AB - Preliminary room temperature phosphorescence measurements of the highly buried Trp109 in E. coli alkaline phosphatase have been used to report on the kinetics of protein hydrogen-deuterium exchange. Upon dilution in D2O the phosphorescence lifetime increases (at 20 degrees C) in a biphasic manner with an immediate change (< 30 seconds) followed by a slow change occurring on an extremely long timescale (days). The immediate D2O-induced lifetime increase is similar to that observed upon dilution into glycerol, a known protein hydrating agent. On the other hand, the slow D2O-induced first order growth in Trp109 lifetime is due to exchange at highly protected protein groups. As the phosphorescence lifetime of Trp109 is dependent on local rigidity, this increase in lifetime reflects changes in alkaline phosphatase structure. This first use of room temperature phosphorescence to monitor proton exchange shows promise as a sensitive and selective probe of protein core dynamics. PMID- 8687455 TI - Immunochemical identification of the glycine receptor/Cl-channel in porcine sperm. AB - Cl- flux is essential for the mammalian sperm acrosome reaction (AR), a required fertilization event involving fusion of sperm head membranes. Our previous inhibitor studies suggested the involvement of a glycine receptor/Cl- channel (GlyR) in the zona pellucida-initiated mammalian sperm AR. Here, using a monoclonal antibody specific for the alpha (48-kDa) and beta (58-kDa) subunits of the rat spinal cord GlyR (mAb GlyR4a), we provide the first direct evidence for GlyR in mammalian sperm. Immunofluorescence studies with mAb GlyR4a detected immunoreactivity on the porcine sperm periacrosomal plasma membrane, a site supporting GlyR involvement in the AR. In Western immunoblotting studies, mAb GlyR4a bound specifically to porcine sperm proteins of 49.2 +/- 2.2 kDa and 58.0 +/- 2.7 kDa. This is the first direct demonstration of both alpha and beta subunits of GlyR in a nonnervous system cell. PMID- 8687456 TI - Identification of a mouse eosinophil receptor for the CC chemokine eotaxin. AB - The CC chemokine eotaxin is a selective chemoattractant for eosinophils in vitro and induces eosinophil migration in vivo. Here we show that the mouse orphan receptor previously named macrophage inflammatory protein-1 alpha receptor-like 2 is a functional eotaxin receptor. For consistency with other nomenclature, we have renamed the receptor mouse CC chemokine receptor 3. Human and mouse eotaxin, but not other chemokines, induced transient increases in [Ca2+]i in human embryonic kidney 293 cells expressing the receptor. RNA for the receptor was abundant in primary eosinophils, but at low levels in neutrophils and macrophages. These properties make this receptor the best known candidate to mediate mouse eosinophil responses to eotaxin. PMID- 8687457 TI - The Fanconi anemia complementation group C gene (FAC) suppresses transformation of mutant fibroblasts by the SV40 virus. AB - Fanconi anemia (FA) is a heterogeneous genetic syndrome manifested by bone marrow failure and consisting of at least five complementation groups (A, B, C, D, E). Mutations in a gene termed FAC are responsible for the C complementation group, but the function of the FAC protein remains obscure. FA patients are also highly cancer-prone; the molecular basis for this susceptibility is unclear but has led to the hypothesis that the wild-type FA gene may act as a tumor suppressor. In vitro, mutant FA primary fibroblasts are 3- to 50-fold more sensitive than normal fibroblasts to transformation in culture by the SV40 virus. We confirmed this marked susceptibility to transformation of a FAC-mutant primary fibroblast cell line, GM449. We then introduced a copy of the wild-type FAC cDNA into GM449 cells using a recombinant adeno-associated virus (rAAV) vector. We found that GM449 cells transduced with a copy of the normal FAC cDNA by a FAC-rAAV vector were at least 10-fold less prone to form transformed foci. Diminished transformation potential of transduced cells was a specific effect of the FAC cDNA since GM449 cells transduced with a rAAV vector not containing FAC retained marked susceptibility to SV40 transformation. PMID- 8687458 TI - Retinoic acid promotes neural and represses mesodermal gene expression in mouse embryonic stem cells in culture. AB - Mouse embryonic stem cells treated with retinoic acid are induced to differentiate into neuron-like cells (Bain et al. (1995) Dev. Biol. 168, 342 357). Here we have examined the expression of a set of neural- and mesoderm specific genes during this in vitro differentiation process. mRNAs encoding the neural genes Wnt-1, MASH1, the light and medium isoforms of neurofilaments, and the neurotransmitter-synthesizing enzyme glutamic acid decarboxylase are all strongly upregulated by retinoic acid treatment; expression of these genes occurs in a temporal pattern resembling that in the developing brain. In contrast, retinoic acid blocks the expression of the mesodermal genes Brachyury, cardiac actin, and zeta-globin. Thus, retinoic acid exerts both pro-neuronal and anti mesodermal activities on mouse embryonic stem cells in culture. PMID- 8687459 TI - Identification of novel alternatively spliced pyruvate carboxylase mRNAs with divergent 5'-untranslated regions which are expressed in a tissue-specific manner. AB - We have identified and characterized multiple mRNA transcripts of rat and human pyruvate carboxylases [EC 6.4.1.1] using rapid amplification of cDNA 5' ends polymerase chain reaction (RACE-PCR). Five alternative forms of rat pyruvate carboxylase cDNAs have been identified in liver, kidney, brain, and adipose tissue and these are expressed in a tissue-specific manner. Two alternative forms of human pyruvate carboxylase cDNA have also been identified in liver. These pyruvate carboxylase cDNAs have a common coding region but differ in their 5' untranslated regions (5'UTRs), suggesting that they are generated by alternative splicing of the primary transcript. Southern blot analysis of restriction enzyme digested rat genomic DNA revealed that pyruvate carboxylase is encoded by a single copy gene. PMID- 8687460 TI - Molecular interaction between TLE1 and the carboxyl-terminal domain of HES-1 containing the WRPW motif. AB - Groucho is a protein implicated in Notch signaling and involved in segmentation and neural development in Drosophila. Groucho forms transcription complexes with the basic helix-loop-helix proteins encoded by the hairy/Enhancer of split ("hairy-like") gene family. These interactions are mediated by the carboxyl terminal WRPW motif of Hairy-like proteins. We are interested in determining whether Groucho and its mammalian homologues, the TLE proteins, perform conserved functions. We show that TLE1 interacts with HES-1, a murine homologue of Drosophila Hairy-like proteins, both in the yeast two-hybrid assay and in an interaction assay based on glutathione S-transferase fusion proteins. These results show that Groucho/TLE proteins and Hairy-like/HES proteins are involved in similar interactions in Drosophila and mammals and further suggest that these proteins perform conserved cellular functions. PMID- 8687461 TI - Isoform-specific intracellular vesicle formation by recombinant annexin XI-A in Sf9 cells. AB - Annexins are a group of structurally related proteins that bind phospholipids in a Ca2(+)-dependent manner and have the ability to self-aggregate and to promote vesicle aggregation and membrane fusion. Two isoforms of annexin XI, termed XI-A and XI-B, were previously identified by screening a bovine chondrocyte cDNA library. But little is known about differences in their biological function. In the present study, we therefore examined the results of expression of the two proteins in Spodoptera frugiperda (Sf9) insect cells, and in mammalian COS-7 cells. Annexin XI isoforms were expressed in Sf9 cells using a baculovirus expression system. Recombinant annexin XI-A but not XI-B caused formation of spherical "annexin XI-associated vesicles, " in the cytoplasm of Sf9 cells. Furthermore, indirect immnocytofluorescence studies showed similar phenomenon, that of local aggregation, with transfected annexin XI-A in COS-7 cells, whereas annexin XI-B remained diffusely distributed throughout the cytoplasm. Since annexin XI isoforms differ in amino acid sequence only in the alternative splicing region of the N-terminal domain, these findings suggest that this domain has distinct biological significance in terms of aggregation and vesicle formation. PMID- 8687462 TI - Is actin polymerization relevant to neurosecretion? A study on neuroblastoma cells. AB - We have investigated the relevance of actin rearrangement to neurotransmitter release, in neuroblastoma cell line SH-SY5Y stimulated with carbachol (1 mM). Carbachol reversibly polymerizes actin and releases norepinephrine in undifferentiated SH-SY5Y cells as well as in tetradecanoylphorbol 13-acetate (16 nM) and retinoic acid (5 microM) differentiated SH-SY5Y cells. Microscopic analysis of F-actin distribution indicates polymerization of cortical actin. Prior treatment with iota toxin E from Clostridium perfringens inhibits both carbachol-induced actin polymerization and norepinephrine release, slightly affecting the basal actin network. These data suggest that actin polymerization is associated with norepinephrine release. PMID- 8687463 TI - Human short-chain L-3-hydroxyacyl-CoA dehydrogenase: cloning and characterization of the coding sequence. AB - The cDNA encompassing the complete coding sequence of human liver short-chain L-3 hydroxyacyl-CoA dehydrogenase (SCHAD) was isolated and characterized. Screening of a cDNA library combined with rapid amplification of 5' cDNA ends resulted in a SCHAD cDNA sequence of 1877 bp. It encodes a protein of 314 amino acids with a calculated molecular weight of 34.3 kDA containing a mitochondrial import signal peptide of 12 amino acids and 302 amino acids of mature SCHAD protein. The deduced amino acid sequence of the mature protein shows a 92 percent identity with SCHAD from pig heart. Northern blot analysis reveals SCHAD mRNA to be expressed in liver, kidney, pancreas, heart and skeletal muscle. The human SCHAD gene was mapped by fluorescence in situ hybridization to chromosome 4q22-26. PMID- 8687464 TI - Hexose recognition by insulin-secreting BRIN-BD11 cells. AB - Clonal BRIN-BD11 cells were produced by electrofusion of NEDH rat islet B-cells with immortal RINm5F cells. Western blotting analysis revealed that unlike RINm5F, novel BRIN-BD11 cells expressed high levels of the glucose transport protein GLUT-2, coupled with a rapid and sustained uptake of D-glucose, significantly greater than RINm5F after only 5 min (p < 0.05). Whereas BRIN-BD11 cells expressed a high glucokinase:hexokinase ratio with 1.4-2.0 fold and 1.4-1.7 fold stepwise stimulation of insulin secretion with 4.2-16.7 mM D-glucose and D mannose respectively, RINm5F had a lower glucokinase:hexokinase ratio (p < 0.001) and were notably unresponsive to D-glucose and D-mannose. Unlike RINm5F cells, BRIN-BD11 were unresponsive to other hexoses, with RINm5F only responding to D galactose (p < 0.05). BRIN-BD11 cells should be useful for studies of nutrient induced insulin secretion. PMID- 8687465 TI - Difference in the mechanism of interaction of Raf-1 and B-Raf with H-Ras. AB - Ras is known to possess multiple cellular targets including Raf-1. Here, we measured both direct binding of various H-Ras mutants to two representative mammalian Ras targets, Raf-1 and B-Raf, and the activity of the mutants to stimulate Raf-1 and B-Raf, and analysed the difference in their Ras-interaction mechanisms. B-Raf was shown to share almost the same H-Ras binding-specificity with Raf-1 by examining binding of the H-Ras mutants to Raf-1 and B-Raf in the yeast two-hybrid and in vitro binding assays. Mutants, Y32F, A59E, and V45E bound to Raf-1 in Sf9 cells coexpressing them, but failed to activate Raf-1. On the other hand, Y32F activated B-Raf in a cell-free system which consisted of rat brain cytosol and recombinant MEK. These results suggest that there is a subtle structural difference in requirements for the interaction of Ras with Raf-1 and B Raf. PMID- 8687466 TI - Effect of platelet-activating factor on cell differentiation of Trypanosoma cruzi. AB - The effects of platelet-activating factor (PAF), at (10)-6M and (10)-9M, on cell growth and cell differentiation of Trypanosoma cruzi were investigated. Cell differentiation was evaluated by both light and electron microscopy. At the concentrations used, PAF slightly interfered with the protozoan growth. However, parasites growth in the presence of PAF were significantly more differentiated than those grown in the absence of PAF, beginning on the fourth day of culture. A specific PAF receptor antagonist (WEB 2086) totally abrogated PAF effect on cell differentiation. These findings indicate that PAF triggers the process of cell differentiation in T. cruzi and suggest that these parasites have receptors for PAF. PMID- 8687467 TI - Phosphorylation by MAPKAP kinase 2 activates Mg(2+)-ATPase activity of myosin II. AB - Mitogen-activated protein kinase activated protein (MAPKAP) kinase-2 was found to phosphorylate the regulatory light chain of myosin II (MRLC) in vitro in the absence of Ca2+/calmodulin. The tryptic peptides recovered from the MRLC phosphorylated by MAPKAP kinase-2 were identical to the phosphopeptides recovered from myosin light chain kinase (MLCK)-phosphorylated MRLC. Phosphoamino acid analysis revealed that MRLC was phosphorylated by these kinases at the serine residue. This phosphorylation by MAPKAP kinase-2 activated the actin-activated Mg(2+)-ATPase activity of myosin II. These findings indicated that MAPKAP kinase 2 may be a kinase that regulates the actin-activated Mg(2+)-ATPase activity of myosin II. PMID- 8687469 TI - Molecular cloning of the rat inducible nitric oxide synthase gene promoter. AB - The inducible nitric oxide synthase (iNOS) is not constitutively expressed but is induced in many types of mammalian cells by cytokines and bacterial endotoxins. Previously, we have reported the most interesting feature of rat iNOS gene that is up-regulated by cyclic AMP at transcriptional level as demonstrated by nuclear run-on assay. We now have isolated and sequenced the rat iNOS gene promoter and determined the transcription start site. Moreover, we have constructed a rat iNOS promoter-chloramphenicol acetyltransferase (CAT) fusion gene and analyzed its inducibility by interleukin 1 beta and cyclic AMP in transiently transfected Swiss 3T3 fibroblasts. PMID- 8687468 TI - HTF: A b-ZIP transcription factor that is closely related to the human XBP/TREB5 and is activated by hepatocellular carcinoma in rats. AB - We screened for rat hepatocellular carcinoma (HCC)-related genes by a novel cDNA subtraction method and obtained one gene. This gene was transcribed as 2.0- and 2.5-kb mRNAs, and its transcription was specifically enhanced in HCC. These cDNAs had the same open reading frame, but the 2.5 kb transcript had an extra 495 bases of 5'-UTR at the 5'-terminus. The deduced aa sequence revealed a basic-leucine zipper (b-ZIP) and proline/glutamine-rich structures, both of which are characteristic motifs for transcription factors. We designated the translation product of this gene HTF (Hepatocarcinogenesis-related Transcription Factor). Electrophoretic mobility shift assay demonstrated the DNA-binding ability of the recombinant HTF. It is most interesting that HTF had a considerable homology with human XBP/TREB5, which has been reported to be a binding factor for the X-box of the MHC class II gene and for the 21-bp enhancer of the HTLV-1 LTR. Genomic Southern analysis suggested that the 2.0- and 2.5-kb mRNAs are transcribed by a dual promoter of a single gene. Our results may suggest that HTF is a b-ZIP-type transcription factor involved in rat hepatocellular carcinoma. PMID- 8687470 TI - Lectin affinity electrophoretic demonstration of tissue specificity and malignant alteration of human alpha-fetoprotein isoforms produced in transgenic mice. AB - Transgenic mouse which produces human alpha-fetoprotein (AFP) ubiquitously was used to study carbohydrate structures of AFP produced by various tissues as well as that in the serum. A series of tissues from the transgenic mouse were cultured in vitro and the AFP produced was analyzed by affinity electrophoreses with 4 kinds of lectins. Variable electrophoretic profiles of them suggested that the fine structures of the carbohydrate of human AFPs expressed in the mouse tissues were different. The characterization of human AFP produced by mouse hepatoma which developed in offspring between the AFP transgenic mouse and hepatoma developing transgenic mouse indicated that the hepatoma AFP was distinct from the liver AFP and that the malignancy-specific phenotypic alteration was common to human and mouse. PMID- 8687471 TI - Human B creatine kinase gene expression in C2C12 cells is regulated by protein interactions involving the first exon. AB - While the activation of muscle specific genes is well characterized, the mechanism mediating the regulation during muscle development of embryonic genes is poorly understood. To begin to investigate this area, the transcriptional regulation of the human brain creatine kinase (BCK) gene was characterized during in vitro myogenesis of C2C12 muscle cells. Initial analyses identified the first exon as important for high level expression in general and for the decrease in expression in response to C2C12 differentiation. In vivo competition confirmed the functional importance of the first exon. Electrophoretic mobility shift assays using portions of the exon showed that two separate proteins bound to sequences +1 to +27 and +25 to +57, respectively. The +1 to +27 interacting factor is present in skeletal but not cardiac muscle and thus may function as a skeletal muscle determining factor. The +25 to +57 interacting factor functions as a positive effector in myoblasts. This region also imparts the differentiation dependent decrease in expression via either modification of the myoblast factor or due to the presence of an additional factor. Site directed mutagenesis show that base pair +26 is critical for appropriate down regulation of BCK. PMID- 8687472 TI - Anaerobic O-demethylations of methoxynaphthols, methoxyfuran, and fluoroanisols by Sporomusa ovata. AB - In vitro experiments with 3,4-dimethoxybenzoate-induced Sporomusa enzymes a broad O-methyl ether cleavage capacity. The O-demethylase activity hydrolized the methyl-oxygen linkages of methoxynaphtholes of the heterocycles 2-methoxyfuran or 2-methoxythiophene as well as of several dimethoxy and monomethoxy aryls under anaerobic conditions. Also, fluoro and chloro substituents of anisoles enhanced the O-demethylation rate, indicating that an electron delocalized aromatic structure supported the methyl ether activation mechanism. Monomethoxy aromatics with additional chargeable groups, however, were less effectively transformed by the O-demethylase activity. No transformations into hydroxylated products occurred with 4-(trifluoromethoxy)benzyl alcohol, 4 (trifluoromethoxy)fluorobenzene, 2,5-dimethoxytetrahydrofuran, or alkyl-O-methyl ethers. The inert ethers did not affect the 3,4-dimethoxybenzoate metabolism. Ether activation or the following methyl transfer to the methyl acceptor tetrahydrofolate involved a prominent 31 kDa peptide from the cytoplasmic cell fraction, because this particular peptide was lacking in cells grown with methanol, betaine or fructose. PMID- 8687473 TI - Potential role of environmental genotoxic agents in diabetes mellitus and neurodegenerative diseases. AB - Epidemiological data suggest that environmental genotoxins are risk factors for some forms of diabetes mellitus and neurodegenerative diseases. The present commentary focuses on mechanisms involved in genotoxin-induced pancreatic beta cell and neuronal damage. These two cell types seem to share a similar vulnerability to different forms of DNA damage, and the long-term consequences of repeated genotoxic insults to post-mitotic neurons or slowly proliferating beta cells remain to be clarified. One intriguing possibility is that genotoxins could act as "slow" toxins in these cells, triggering a cascade of cellular events, which culminates in progressive cell dysfunction and loss. Indeed, exposure to mutagenic nitroso agents such as streptozotocin and cycasin induces long-lasting damage to both beta -cells and neurons. These data on cycasin, a toxin obtained from the cycad plant (Cycas spp.), are of special interest, since this agent may be implicated in both amyotrophic lateral sclerosis/Parkinson dementia complex and diabetes mellitus in the western Pacific area. Future studies are required to sort out the interactions between different genotoxic agents, viral infections, and cellular repair mechanisms on cellular survival and function. Moreover, further epidemiological studies are needed to clarify the role of N-nitrosoureas in diabetes mellitus and neurodegenerative diseases in populations with different genetic backgrounds. Answers to these questions may provide useful information on the pathogenesis of these devastating diseases, and open the possibility for their primary prevention. PMID- 8687474 TI - Nitric oxide (NO), the only nitrogen monoxide redox form capable of activating soluble guanylyl cyclase. AB - In the present study, we determined that of the redox forms of nitrogen monoxide, NO-, NO and NO+, only NO significantly activates soluble guanylyl cyclase (GTP pyrophosphate-lyase cyclizing, EC 4.6.1.2). Neither of the NO-donors tested, Angeli's salt (Na2N2O3) or Piloty's acid (C6H5SO2NHOH), caused a change in the guanylyl cyclase activity relative to the basal activity level. Interference by other reaction products was eliminated as a possible explanation for the lack of activation. To the extent that NO+ could be stabilized in aqueous solution, by dissolution of the nitrosonium salt NOPF6 in dry organic solvent prior to addition to the enzyme in buffer, NO+ had no effect on the activity of soluble guanylyl cyclase. The counter-ion, PF6-, had a minimal effect on the enzyme activity and, therefore was, not responsible for the lack of activation by NO+. These observations suggest that NO- is the natural activator of soluble guanylyl cyclase and is reasonably identical with endothelium-derived relaxing factor, the physiological regulator of soluble guanylyl cyclase activity. PMID- 8687475 TI - 5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside, a uridine phosphorylase inhibitor, and 2',3',5'-tri-O-acetyluridine, a prodrug of uridine, as modulators of plasma uridine concentration. Implications for chemotherapy. AB - 5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside (BBBA), the most potent inhibitor known of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism, and 2',3',5'-tri-O-acetyluridine (TAU), a prodrug of uridine, were used to investigate the possibility of improving the bioavailability of oral uridine in mice. Oral BBBA administered at 30, 60, 120, and 240 mg/kg increased the concentration of plasma uridine (2.6 +/- 0.7 microM) by 3.2-, 4.6-, 5.4-, and 7.2-fold, respectively. After administration of 120 and 240 mg/kg BBBA, plasma uridine concentration remained 3- and 6-fold, respectively, higher than the plasma concentration at zero time (C0) for over 8 hr. On the other hand, BBBA did not change the concentration of plasma uracil. TAU was far more superior than uridine in improving the bioavailability of plasma uridine. The relative bioavailability of plasma uridine released from oral TAU (53%) was 7-fold higher than that (7.7%) obtained by oral uridine. Oral TAU at 460, 1000, and 2000 mg/kg achieved area under the curve (AUC) values of plasma uridine of 82, 288, and 754 mumol.hr/L, respectively. Coadministration of BBBA with uridine or TAU further improved the bioavailability of plasma uridine resulting from the administration of either alone and reduced the Cmax and AUC of plasma uracil. Coadministration of BBBA at 30, 60, and 120 mg/kg improved the relative bioavailability of uridine released from 2000 mg/kg TAU (53%) by 1.7-, 2.7-, and 3.9-fold, respectively, while coadministration of the same doses of BBBA with an equimolar dose of uridine (1320 mg/kg) increased the relative bioavailability of oral uridine (7.7%) by 4.1-, 5.3-, and 7.8-fold, respectively. Moreover, the AUC and Cmax of plasma uridine after BBBA (120 mg/kg) coadministration with TAU were 3.5- and 11.5-fold, respectively, higher than those obtained from coadministration of BBBA with an equimolar dose of uridine. The exceptional effectiveness of the BBBA plus TAU combination in elevating and sustaining high plasma uridine concentration can be useful in the management of medical disorders that are remedied by administration of uridine as well as to rescue or protect from host-toxicities of various chemotherapeutic pyrimidine analogues. PMID- 8687476 TI - Effects of propofol and thiopentone on potassium- and carbachol-evoked [3H]noradrenaline release and increased [Ca2+]i from SH-SY5Y human neuroblastoma cells. AB - We have examined the effects of two intravenous anaesthetic induction agents, propofol and thiopentone, on K+ and carbachol evoked [3H]noradrenaline release from a human neuroblastoma cell line, SH-SY5Y. In this model, we have previously demonstrated that K+ evoked [3H]noradrenaline release was dependent on Ca2+ entry and carbachol evoked release was extracellular Ca(2+)- independent. Propofol inhibited K+ (100 mM)-evoked (IC50 of 42 +/- 11 microM), but not carbachol (1 mM) evoked, [3H]noradrenaline release. Thiopentone inhibited both K+- and carbachol evoked release with IC50 values of 116 +/- 15 microM and 169 +/- 39 microM, respectively. These inhibitory effects were not due to changes in the release dynamics, as assessed using perfused cells. Furthermore, thiopentone inhibition of carbachol-evoked release was not due to muscarinic receptor antagonism. Both propofol and thiopentone caused noncompetitive inhibition of K+-stimulated Ca2+ influx, with IC50 values of 127 +/- 7 microM and 121 +/- 10 microM, respectively. These effects were not due to interaction with GABAA receptors, but suggest that both compounds block voltage-sensitive Ca2+ channels. Thiopentone, but not propofol, inhibited carbachol-stimulated increased intracellular Ca2+ concentrations in the presence and absence of extracellular Ca2+. However, thiopentone had no effect on carbachol-stimulated inositol (1,4,5)-triphosphate formation, suggesting that thiopentone may directly inhibit Ca2+ release from intracellular stores. PMID- 8687477 TI - Enzymology of mitomycin C metabolic activation in tumour tissue. Characterization of a novel mitochondrial reductase. AB - In this study, the enzymology of mitomycin C (MMC) bioactivation in two murine colon adenocarcinomas, MAC 16 and MAC 26, was examined. Subcellular quinone reductase assessment via cytochrome c reduction confirmed a number of active enzymes. MAC 16 exhibited 22-fold greater levels of cytosolic DT-diaphorase than MAC 26, while microsomal NADPH:cytochrome P-450 reductase levels were similar in both tumour types. Metabolism of MMC by subcellular fractions isolated from both MAC 16 and MAC 26 was quantitated by monitoring the formation of the principle metabolite 2,7-diaminomitosene (2,7-DM) via high-performance liquid chromatography (HPLC). In MAC 16 only, activity displaying the properties of cytosolic DT-diaphorase and microsomal NADPH:cytochrome P-450 reductase was detected and confirmed, using the enzyme inhibitors dicoumarol and cytochrome P 450 reductase antiserum, respectively. The highest level of MMC metabolism was associated with the mitochondrial fraction from both tumours and was the sole enzyme activity detected in MAC 26. The greatest mitochondrial drug metabolism was achieved in the presence of NADPH as cofactor and hypoxia (MAC 16-specific activity, 3.67 +/- 0.58 nmol/30 min/mg; MAC 26 specific-activity, 3.87 +/- 0.71 nmol/30 min/mg) and was unaffected by the addition of the inhibitors dicoumarol and cytochrome P-450 reductase antiserum. NADH-dependent mitochondrial activity was only observed in MAC 16 at approximately 4-fold less than that seen with NADPH. MAC 26 homogenate incubations displayed enhanced metabolism under hypoxia, presumably due to the presence of the identified mitochondrial enzyme. MAC 16 homogenates showed no increase in metabolism under hypoxia, suggesting that other enzyme(s) may be predominant. These data indicate the presence of a novel mitochondrial one-electron reductase capable of metabolising MMC in MAC 16 and MAC 26. PMID- 8687478 TI - In vitro characterization of a novel series of platelet-derived growth factor receptor tyrosine kinase inhibitors. AB - In this report, we describe the discovery and characterization of a novel biarylhydrazone series of platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitors typified by the prototype WIN 41662 (3-phenyl-N1-[1-(4 pytidyl)pyrimidine]hydrazone). WIN 41662 inhibited PDGF-stimulated autophosphorylation of PDGF receptors from human vascular smooth muscle cells (hVSMC) with an IC50 value of 60 nM. The inhibitor appeared to be competitive with respect to substrate (Mn(2+)-ATP), having a calculated Ki of 15 +/- 5 nM. WIN 41662 was approximately 500-fold more potent in inhibiting the PDGF receptor tyrosine kinase than the p56lck tyrosine kinase. It was inactive against other serine/threonine and tyrosine kinases tested. WIN 41662 produced concentration dependent inhibition of PDGF-stimulated receptor autophosphorylation in intact hVSMC with an IC50 < 100 nM. Intracellular Ca2+ mobilization and cell proliferation were events that occurred in hVSMC subsequent to PDGF receptor activation. WIN 41662 inhibited PDGF-stimulated Ca2+ mobilization and cell proliferation ([3H]TdR incorporation) with IC50 values of 430 nM and 2.3 microM, respectively. These effects appeared to be specifically related to PDGF receptor tyrosine kinase inhibition since WIN 41662 was not cytotoxic (in vitro) and since WIN 72039, a close structural analog that does not inhibit PDGF receptor tyrosine kinase, also did not inhibit PDGF-stimulated receptor autophosphorylation, Ca2+ mobilization, or hVSMC proliferation. Thus, WIN 41662 is representative of a novel class of selective PDGF receptor tyrosine kinase inhibitors that inhibit PDGF-regulated secondary events in intact cells. PMID- 8687479 TI - Characterization of the catecholamine extraneuronal uptake2 carrier in human glioma cell lines SK-MG-1 and SKI-1 in relation to (2-chloroethyl)-3 sarcosinamide-1-nitrosourea (SarCNU) selective cytotoxicity. AB - Transport of (2-chloroethyl)-3-sarcosinamide-1-nitrosourea (SarCNU) and (-) norepinephrine was investigated in SarCNU-sensitive SK-MG-1 and -resistant SKI-1 human glioma cell lines. [3H]SarCNU influx was inhibited by SarCNU, sarcosinamide, and (+/-)-epinephrine in SK-MG-1 cells with competitive inhibition observed by (+/-)-epinephrine (Ki = 140 +/- 12 microM) and (+/-)-norepinephrine (Ki = 255 +/- 41 microM). No effect on influx was detected in SKI-1 cells. [3H]( )-Norepinephrine influx was linear to 15 sec in both cell lines and temperature dependent only in SK-MG-1 cells. Influx of [3H](-)-norepinephrine was found to be saturable in SK-MG-1 (K(m) = 148 +/- 28 microM, Vmax = 1.23 +/- 0.18 pmol/microL intracellular water/sec) but not in SKI-1 cells. In SK-MG-1 cells, [3H](-) norepinephrine influx was found to be inhibited competitively by (-)-epinephrine (Ki = 111 +/- 7 microM) and SarCNU (Ki = 1.48 +/- 0.22 mM). Ouabain and KCl were able to inhibit the [3H](-)-norepinephrine influx in SK-MG-1 cells, consistent with influx being driven by membrane potential. Several catecholamine uptake2 inhibitors were able to reduce significantly the influx of [3H](-)-norepinephrine and [3H]SarCNU with no inhibition by a catecholamine uptake1 inhibitor. These findings suggest that increased sensitivity of SK-MG-1 to SarCNU is secondary to enhanced accumulation of SarCNU mediated via the catecholamine extraneuronal uptake2 transporter, which is not detectable in SKI-1 cells. The introduction of SarCNU into clinical trials will confirm if increased uptake via the catecholamine extraneuronal uptake2 transporter will result in increased antitumor activity. PMID- 8687480 TI - Cytotoxicity and DNA damage associated with pyrazoloacridine in MCF-7 breast cancer cells. AB - We examined the effects of pyrazoloacridine (PZA), an investigational anticancer agent in clinical trials, on cytotoxicity, DNA synthesis, and DNA damage in MCF-7 human breast carcinoma cells. With PZA concentrations ranging from 0.5 to 50 microM for durations of 3-72 hr, cytotoxicity increased in proportion to the total PZA exposure (concentration x time). Inhibition of DNA and RNA syntheses increased with increasing PZA concentration x time (microM.hr). A 24-hr exposure to 1 and 10 microM PZA reduced DNA synthesis to 62 and 5% of control, respectively, decreased the proportion of cells in S phase with accumulation of cells in G2 + M phase, and inhibited cell growth at 72 hr by 68 and 100%. Newly synthesized DNA was more susceptible to damage during PZA exposure, with subsequent induction of parental DNA damage. Significant damage to newly synthesized DNA as monitored by alkaline elution was evident after a 3-hr exposure to > or = 5 microM PZA. Longer PZA exposures (> or = 10 microM for 16 hr) were required to elicit damage to parental DNA. Induction of single-strand breaks in parental DNA correlated closely with induction of double-strand breaks and detachment of cells from the monolayer. PZA-mediated DNA fragmentation was not accompanied by the generation of oligonucleosomal laddering in MCF-7 cells, but induction of very high molecular weight DNA fragmentation (0.5 to 1 Mb) was detected by pulsed-field gel electrophoresis. In vitro binding of PZA to linear duplex DNA (1 kb DNA ladder) and closed, circular plasmid DNA was demonstrated by a shift in migration during agarose electrophoresis. PZA interfered with topoisomerase I- and II-mediated relaxation of plasmid DNA in a cell-free system, but the cytotoxic effects of PZA did not appear to involve a direct interaction with topoisomerase I or II (stabilization of the topoisomerase I- or II-DNA cleavable complex). PZA-mediated cytotoxicity correlated strongly with inhibition of DNA and RNA syntheses, and damage to both nascent and parental DNA. Neither the cytotoxicity of PZA nor induction of double-stranded DNA fragmentation was prevented by aphidicolin, indicating that PZA-mediated lethality occurred in the absence of DNA replication. Since free radical formation was not detected, induction of nascent and parental DNA damage appeared to be a consequence of the avid binding of PZA to DNA, presumably by interfering with the access of replication, repair, and transcription enzyme complexes. PMID- 8687481 TI - Arylacetamide deacetylase activity towards monoacetyldapsone. Species comparison, factors that influence activity, and comparison with 2-acetylaminofluorene and p nitrophenyl acetate hydrolysis. AB - The deacetylation of monoacetyldapsone (MADDS) was examined in liver microsomes and cytosol from male Sprague-Dawley rats, Golden Syrian hamsters, and Swiss Albino mice. All three rodent species demonstrated greater MADDS deacetylation activity in liver microsomes than in liver cytosol. Further investigations were conducted in hamsters. The velocity of MADDS deacetylation in major organs in the hamster was greatest in the intestine, followed by the liver and kidney. The effect of pretreatment with common inducers on liver microsomal deacetylation activity was also examined in the hamster. Phenobarbital, 100 mg/kg/day x 3 days, did not alter activity, while dexamethasone at the same dose reduced 2 acetylaminofluorene (2-AFF), MADDS, and p-nitrophenyl acetate (NPA) hydrolysis by at least 50%. Due to a previous report that KI activated the deacetylation of an arylacetamide in vitro (Khanna et al., J Pharmacol Exp Ther 262: 1225-1231, 1992), the effects of the halides KF, KCl, KBr and KI on MADDS hydrolysis in vitro were tested. Of the halides studied, only KF altered MADDS hydrolysis, resulting in an almost complete inhibition of deacetylase activity at 50 mM (with the initial concentration of MADDS at 0.6 mM) with an IC50 = 0.16 mM. Cornish Bowden and Dixon plots indicated that the inhibition exerted by KF was non competitive. The rank order of inhibitor potencies was constructed using phenylmethylsulfonyl fluoride (PMSF), bis(p-nitrophenyl)phosphate (BNPP), physostigmine, and KF with 2-AFF, MADDS, and NPA as substrates. Different rank order potencies were obtained for each of the substrates tested. The substrates 2 AFF, MADDS, and NPA did not act as competitive inhibitors on the hydrolysis rates of each other. Liver microsomal arylacetamide deacetylase activity was greater in male hamsters than in females with either MADDS or 2-AAF as substrates; however, hydrolysis of NPA was similar in both male and female hamsters. These data support the hypothesis that the enzyme which catalyzes the hydrolysis of MADDS differs from that catalyzing either 2-AAF or NPA hydrolysis. PMID- 8687482 TI - Bioactivation of mitomycin antibiotics by aerobic and hypoxic Chinese hamster ovary cells overexpressing DT-diaphorase. AB - DT-Diaphorase catalyzes a two-electron reduction of mitomycin C (MC) and porfiromycin (POR) to reactive species. Many cell lines that overexpress DT diaphorase and are sensitive to the mitomycins are protected from the aerobic cytotoxicity of these drugs by the DT-diaphorase inhibitor dicumarol. The cytoprotective properties of this relatively non-specific inhibitor, however, vanish under hypoxic conditions. To ascertain the role of DT-diaphorase in mitomycin bioactivation and cytotoxicity in living cells, a rat liver DT diaphorase cDNA was transfected into Chinese hamster ovary cells. MC was equitoxic to the parental cells under oxygenated and hypoxic conditions. In contrast, POR was less toxic than MC to these cells under aerobic conditions, but significantly more toxic than MC under hypoxia. Two DT-diaphorase-transfected clones displayed increases in DT-diaphorase activity of 126- and 133-fold over parental cells. The activities of other oxidoreductases implicated in mitomycin bioreduction were unchanged. MC was more toxic to both DT-diaphorase-transfected lines than to parental cells; the toxicity of MC to the transfected lines was similar in air and hypoxia. POR was also more toxic to the DT-diaphorase-elevated clones than to parental cells under oxygenated conditions. Under hypoxia, however, the toxicity of POR to the transfected clones was unchanged from that of parental cells. The findings implicate DT-diaphorase in mitomycin bioactivation in living cells, but suggest that this enzyme does not contribute to the differential toxicity of MC or POR in air and hypoxia. PMID- 8687483 TI - Glucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolites. pH stability and synthesis by human and dog liver. AB - Glucuronide conjugates of arylamines are thought to be important in the carcinogenic process. This study investigated the pH stability and synthesis of glucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolites by human and dog liver. Both dog and human liver slices incubated with 0.06 mM [3H]-4 aminobiphenyl produced the N-glucuronide of 4-aminobiphenyl as the major product. After 2 hr of incubation, the N-glucuronide of 4-aminobiphenyl represented 52 and 27% of the total radioactivity recovered by HPLC in dog and human, respectively. When 4-aminobiphenyl, N-hydroxy-4-aminobiphenyl, or N-hydroxy-N-acetyl-4 aminobiphenyl was added to human microsomes containing [14C]UDP-glucuronic acid, a new product peak was detected by HPLC. At 0.5 mM, the rate of glucuronidation was N-hydroxy-N-acetyl-4-aminobiphenyl > N-hydroxy-4-aminobiphenyl > 4 aminobiphenyl. The rate of formation of the N-glucuronide of 4-aminobiphenyl was similar to that observed with benzidine and N-acetylbenzidine. The glucuronides of 4-aminobiphenyl and N-hydroxy-4-aminobiphenyl were both acid labile with T1/2 values of 10.5 and 32 min, respectively, at pH 5.5. The glucuronide of N-hydroxy N-acetyl-4-aminobiphenyl was not acid labile with T1/2 values at pH 5.5 and 7.4 of 55 and 68 min, respectively. The glucuronide of 4-aminobiphenyl was the most acid labile conjugate examined. Thus, the glucuronide of 4-aminobiphenyl is a major product of dog and human liver slice metabolism and likely to play an important role in the carcinogenic process. PMID- 8687484 TI - Effects of modifications in the pentose moiety and conformational changes on the binding of nucleoside ligands to uridine phosphorylase from Toxoplasma gondii. AB - One hundred and fifty analogues of uridine, with various modifications to the uracil and pentose moieties, have been tested and compared with uridine with respect to their potency to bind to uridine phosphorylase (UrdPase, EC 2.4.2.3) from Toxoplasma gondii. The effects of the alpha- and beta-anomers, the L- and D enantiomers, as well as restricted syn and anti rotamers, on binding were examined. Pseudo-, lyxo-, 2,3'-anhydro-2'-deoxy-, 6,5'-cyclo-, 6,3'-methano-, O5',6-methano- and carbocyclic uridines did not bind to the enzyme. Ribosides bound better than the corresponding xylosides, which were better than the deoxyribosides. The binding of deoxyribosides was in the following manner: 2',3' dideoxynucleosides > 2',5'-dideoxynucleosides > 2'-deoxyribosides > 3'- and 5' deoxyribosides. alpha-2'-Deoxyribosides bound to the enzyme, albeit less tightly than the corresponding beta-anomers. The acyclo- and 2,2'-anhydrouridines bound strongly, with the 2,2'-anhydro-derivatives being the better ligands. 2,5' Anhydrouridine bound to UrdPase less effectively than 2,2'-anhydrouridine and acyclouridine. Arabinosyluracil was at best a very poor ligand, but bound better if a benzyl group was present at the 5-position of the pyrimidine ring. This binding was enhanced further by adding a 5-benzyloxybenzyl group. A similar enhancement of the binding by increased hydrophobicity at the 5-position of the pyrimidine ring was observed with ribosides, alpha- and beta-anomers of the 2' deoxyribosides, acyclonucleosides, and 2,2'-anhydronucleosides. Among all the compounds tested, 5-(benzyloxybenzyl)-2,2'-anhydrouridine was identified as the best ligand of T. gondii UrdPase with an apparent Ki value of 60 +/- 3 nM. It is concluded that the presence of an N-glycosyl bond is a prerequisite for a nucleoside ligand to bind to T. gondii UrdPase. On the other hand, the presence of a 2'-, 3'-, or 5'-hydroxyl group, or an N-glycosyl bond in the beta configuration, enhanced but was not essential for binding. Furthermore, the potency of the binding of 2,2'-anhydrouridines (fixed high syn isomers) in contrast to the weaker binding of the 6,1'-anhydro- or 2,5'-anhydrouridines (fixed syn isomers), and the complete lack of binding of the 6,5'-cyclo, O5',6 methano- and 6,3'-methanouridines (fixed anti isomers) to T. gondii UrdPase indicate that the binding of ligands to this enzyme is in the syn/high syn conformation around the N-glycosyl bond. The results also indicate that the parasite but not the mammalian host UrdPase can participate in hydrogen bonding with N3 of the pyrimidine ring of nucleoside ligands. T. gondii UrdPase also has a larger hydrophobic pocket adjacent to the C5 of the pyrimidine moiety than the host enzyme, and can accommodate modifications in the pentose moiety which cannot be tolerated by the host enzyme. Most prominent among these modifications is the absence and/or lack of the ribo orientation of the 3'-hydroxyl group, which is a requirement for a ligand to bind to mammalian UrdPase. These differences between the parasite and host, enzymes can be useful in designing specific inhibitors or "subversive" substrates for T. gondii UrdPase. PMID- 8687485 TI - Mediation of iron uptake and release in erythroid cells by photodegradation products of nifedipine. AB - The effects of five Ca2+ channel antagonists on iron uptake by erythroid cells were investigated using rabbit reticulocytes and erythrocytes, and transferrin bound iron and non-transferrin-bound iron (Fe(II)). All of the antagonists except nifedipine inhibited iron uptake, but only at relatively high concentrations (10 100 microM). Nifedipine markedly stimulated the uptake of Fe(II) but not transferrin-bound iron, but only after it had been photodegraded to its nitrosophenylpyridine derivative. This compound was found to mediate Fe(II) exchange between the cytosol and extracellular medium in both directions with both reticulocytes and erythrocytes, but not by the known iron transport processes. The effect could be reversed by washing the cells with ice-cold NaCl solution. It appeared to be relatively specific for Fe(II) since photodegraded nifedipine had little effect on the uptake of Fe(III) or Mn2+. It is suggested that the nitrosopyridine derivative of nifedipine can act as an Fe(II) ionophore and may be of use as an adjuvant in chelator therapy with desferrioxamine in conditions of iron overload. PMID- 8687486 TI - Effects of aminoguanidine on rat pancreatic islets in culture and on the pancreatic islet blood flow of anaesthetized rats. AB - Aminoguanidine (AG; < or =0.5 mM) is a potent inhibitor of the inducible form of nitric oxide synthase (iNOS) and, at higher concentrations, is also able to prevent advanced glycosylation of proteins. Due to these properties, AG might be an interesting therapeutic compound for prevention of the development of diabetes and for prevention of diabetes complications. In the present study, we examined the effect of AG (0.1, 0.5, 1.0, 5.0, or 10 mM) on prolonged in vitro culture of isolated rat pancreatic islets. Furthermore, the acute effect of AG on pancreatic and islet blood flow in anaesthetized rats was studied with a microsphere technique. Culture for 6 days of pancreatic islets at either 11.1 mM or 28 mM glucose, in the presence of 0.1-1.0 mM AG, was not toxic to the islet cells or impaired insulin secretion. However, when islets were cultured for 8 days with the addition of 5 mM AG at 11.1 mM or 28 mM glucose, a 50% inhibition of glucose stimulated insulin release was observed. Rats injected intravenously with AG (1, 10, or 50 mg/kg body weight) had a decreased pancreatic blood flow 30 min later. Glucose injection (1 g/kg body weight) increased the islet blood flow, and this effect was not attenuated by AG. The present data suggest that AG, when used in concentrations that inhibit iNOS, can affect pancreatic blood flow, but appears not to be directly harmful to beta-cell function. PMID- 8687487 TI - Inhibition of lipid peroxidation in low-density lipoprotein by the flavonoid myrigalone B and ascorbic acid. AB - Lipid peroxidation in human LDL (0.05 mg protein/mL) incubated with Cu(2+)-ions (5 microM) in vitro was dose-dependently inhibited by the flavonoid myrigalone B (MyB) and by ascorbic acid. MyB at 6 microM increased the oxidation lag time by 135 +/- 24 min (approximately 5-fold compared to controls) and reduced the maximum oxidation rate by 46 +/- 5%. Ascorbic acid, at 9 microM, increased the lag time by 179 +/- 29 min (6-fold compared to controls) but did not affect the maximum oxidation rate. The increase in lag time induced by MyB was enhanced in the presence of ascorbic acid. Their effects were additive, except when both were present at the highest concentration tested, when a significant potentiation, giving an increase in lag time of approximately 2 hr more than the sum of separate effects, occurred. Concentration-time curves for MyB in the absence and presence of ascorbic acid showed that the vitamin protected MyB against deterioration during incubation, and indicated that the net consumption of MyB in the oxidation process was reduced. No differences were observed when ordinary ascorbic acid and Ester-C, a commercial vitamin C product, were compared. In conclusion, MyB and ascorbic acid seem to interact in a way that further improves the antioxidant status of the LDL particle relative to each substance separately. PMID- 8687488 TI - Alterations of nitric oxide synthase and xanthine oxidase activities of human keratinocytes by ultraviolet B radiation. Potential role for peroxynitrite in skin inflammation. AB - In the present study, we demonstrated that NO synthase (cNOS) and xanthine oxidase (XO) of human keratinocytes can be activated to release NO, superoxide (O2-) and peroxynitrite (ONOO-) following exposure to ultraviolet B (UVB) radiation. We defined that this photo induced response may be involved in the pathogenesis of sunburn erythema and inflammation. Treatment of human keratinocytes with UVB (290-320 nm) radiation (up to 200 mJ/cm2) resulted in a dose-dependent increase in NO and ONOO- release that was inhibited by N monomethyl-L-arginine (L-NMMA). NO and ONOO- release from keratinocytes was accompanied by an increase in intracellular cGMP levels. Treatment of human keratinocyte cytosol with various doses of UVB (up to 100 mJ/cm2) resulted in an increase in XO activity that was inhibited by oxypurinol. UVB radiation (up to 100 mJ/cm2) of keratinocytes resulted in a 15-fold increase in S-nitrosothiol formation, which directly increased purified soluble guanylate cyclase (sGC) activity by a mechanism characteristic of release of NO from a carrier molecule. In reconstitution experiments, when UVB-irradiated (20 mJ/cm2) purified cNOS isolated from keratinocyte cytosol was combined with UVB-irradiated (20 mJ/cm2) purified XO, a 4-fold increase in ONOO- production, as compared to nonirradiated enzymes, was observed. ONOO- synthesized by NO and O2- following UVB radiation of cNOS and XO was inhibited by oxypurinol (100 microM). UVB radiation of keratinocyte cytosol resulted in an increase in oxygen free radical production, consistent with the increased production of ONOO- by UVB-irradiated keratinocyte cytosol. In in vivo experiments, when experimental animals were subjected to UVB radiation, a protection factor (PF) of 6.5 +/- 1.8 was calculated when an emulsified cream formulation containing nitro-L-arginine (L-NA) (2%) and L-NMMA (2%) was applied to their skin. The present study indicates that UVB radiation acts as a potent stimulator of cNOS and XO activities in human keratinocytes. NO and ONOO- may exert cytotoxic effects in keratinocytes themselves, as well as in their neighboring endothelial and smooth muscle cells. This may be a major part of the integrated response leading to erythema production and the inflammation process. PMID- 8687489 TI - Rapid regulation of a cyclic AMP-specific phosphodiesterase (PDE IV) by forskolin and isoproterenol in LRM55 astroglial cells. AB - Elevation of intracellular cyclic AMP (cAMP) levels by incubation of intact LRM55 astroglial cells with 0.1 mM forskolin or 0.1 microM isoproterenol (IPR) caused a rapid increase in soluble cAMP phospho-diesterase (PDE) activity. Activation did not require de novo protein synthesis and reached a maximum of > or = 100% increase over basal PDE activity after 15 min of treatment. The increase in activity was recovered in a single peak (peak 3) following DEAE chromatography; the other two peaks separated by this procedure showed no change. Peak 3 had all the characteristics of PDE IV: it was sensitive to rolipram, was insensitive to CI-930 and cyclic GMP (cGMP), had a high affinity for cAMP (K(m) approximately equal to 4 microM), and had a very low affinity for cGMP (K(m) > 100 microM). Forskolin treatment resulted in an increase of the Vmax of peak 3 without affecting its K(m). In vitro treatment of peak 3 with the catalytic subunit of protein kinase A increased activity, whereas treatment with alkaline phosphatase decreased activity. The rapid activation of this specific PDE in response to forskolin and IPR represents a novel regulation of PDE IV by a mechanism that seems to involve its phosphorylation by a cAMP-dependent protein kinase. PMID- 8687490 TI - Desensitization of neurotensin-induced phosphoinositide hydrolysis in transfected CHO cells. AB - The regulation of neurotensin-induced phosphoinositide turnover was studied in transfected CHO cells expressing the rat neurotensin receptor. Stimulation of these cells with neurotensin resulted in an important, but transient, increase in inositol phosphate cell content. Preincubation of the cells with neurotensin dramatically decreased their response to further stimulation. This diminution, which was time-dependent and not related to the availability of phospholipase C substrate, is though to reflect a progressive homologous desensitization of the recombinant neurotensin receptor. PMID- 8687491 TI - Isatin: a link between natriuretic peptides and monoamines? AB - Isatin is an endogenous indole with a distinctive distribution in brain and tissues. In the brain, the highest levels have been found in the hippocampus (0.1 microgram/g), and an immunocytochemical stain has shown specific localization within particular cells. In vitro, its most potent known actions are as an inhibitor of monoamine oxidase B (IC50 approximately 3 microM), and of atrial natriuretic peptide (ANP) receptor binding and ANP-induced guanylate cyclase (both with an IC50 approximately 0.4 microM). In vivo, isatin administration (10 200 mg/kg) causes an increase of monoamine neurotransmitter levels in the brain. Isatin is anxiogenic in animal models at doses of 10-20 mg/kg and sedative at higher doses. Its anxiogenic effects are unlikely to be due to inhibition of monoamine oxidase, but may possibly stem from interaction with the ANP system. Isatin may mediate a link between monoamines and the natriuretic peptide system, and its analogues may provide new pharmacological tools. PMID- 8687492 TI - Selective inhibition of the effects of phorbol ester on doxorubicin resistance and P-glycoprotein by the protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2 methylpiperazine (H7) in multidrug-resistant MCF-7/Dox human breast carcinoma cells. AB - The possible regulation of the multidrug-resistant (MDR) phenotype and P glycoprotein by protein kinase C (PKC) was investigated in the doxorubicin (Dox) resistant MCF-7 cell line (MCF-7/Dox). In a clonogenic assay, cells exposed to 100 nM phorbol 12-myristate 13-acetate (PMA) for 1 hr were about 3-fold more resistant to Dox than were cells exposed to Dox alone. The PKC inhibitor 1-(5 isoquinolinesulfonyl)-2-methylpiperazine (H7, 30 microM) completely blocked the PMA-induced effect, but did not reverse the MDR phenotype. Complete down regulation of PKC from MCF-7/Dox cells by 24-hr preincubation with PMA did not alter the degree of Dox resistance. Intracellular accumulation of [14C]Dox decreased from a baseline of 28 pmol/10(6) cells to 15 pmol/10(6) cells in the presence of 100 nM PMA. The reduced Dox accumulation in the presence of PMA was not blocked by pretreatment of cells with H7. Following a 24-hr pretreatment with PMA, the cells accumulated almost equal amounts of [14C]Dox in the absence or presence of PMA. Cells from PMA-treated colonies showed significantly higher levels of expression of P-glycoprotein when compared with those from control colonies. H7 did not affect the basal level of P-glycoprotein in cells from control colonies or PMA-induced overexpression of P-glycoprotein in cells from PMA-treated colonies. Upon stimulation with PMA (100 nM), PKC alpha and beta translocated to the cell membrane and nucleus and PKC delta and epsilon to the perinuclear membrane and the nucleus, respectively. H7 (30 microM) completely inhibited PMA-induced translocations of PKC delta and epsilon, whereas it only partially blocked the translocations of PKC alpha and beta. These results suggest that PMA appears to alter Dox resistance and intracellular Dox accumulation in a PKC-dependent manner and to induce increased expression of P-glycoprotein in MCF 7/Dox cells. Differential effects of H7 on the PMA-induced changes suggest that different isoforms of PKC may be involved in cell growth and drug accumulation processes as well as P-glycoprotein expression. PMID- 8687493 TI - Differential distribution of free and bound glutathione and cyst(e)ine in human blood. AB - The redox status of free and bound glutathione (GSH) and cyst(e)ine (Cys) is altered by oxidative stress, drugs, and disease. Most studies measure only their free forms and not the bound forms, which may have a crucial protective role. For this reason, we determined free and bound, reduced and oxidized GSH and Cys in whole blood, red cells, and plasma of human blood from healthy adults. Distinct compartments of GSH and Cys were found. In whole blood, > 99% GSH was in red cells, of which 16% was bound. GSH values were the same for red cells in whole blood or in cells isolated from the same samples. Only 0.5% of GSH was in plasma, all of which was bound. In contrast, 97% of Cys was in plasma and only 3% in red cells. This was a remarkable separation of these closely related metabolites in the same tissue. In plasma, 60% of Cys was bound. Also, strong correlations were shown of bound vs free Cys and also vs free plus bound Cys. The bound Cys was more constant and suggested that it is a metabolic reserve. Our findings demonstrate the occurrence of significant bound forms of GSH and Cys and have implications for future studies in disease and toxicology. PMID- 8687494 TI - Studies on the N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanin e (A 4166)receptor in HIT T-15 cells. Displacement of [3H]glibenclamide. AB - A-4166 is a new type of oral hypoglycemic agent that does not contain a sulfonylurea moiety. To clarify the mechanism of insulin secretion by A-4166, a specific receptor for A-4166 was investigated in a hamster pancreatic beta cell line (HIT T-15), using [3H]A-4166 or [3H]glibenclamide as a ligand. The saturation binding of [3H]A-4166 to HIT cell membranes was not observed up to 10 microM. In the displacement study, unlabeled A-4166 inhibited [3H]A-4166 binding to HIT cell membranes, but glibenclamide did not. On the other hand, A-4166 inhibited [3H]glibenclamide binding to the sulfonylurea receptor (Ki = 248 nM). A 4166 inhibited 86Rb efflux from HIT cells (IC50 = 350 nM). The EC50 for insulin secretion by A-4166 was 20 microM in HIT cells when they were incubated for 30 min in Krebs-Ringer bicarbonate buffer containing 16 mM HEPES supplemented with 5 mg/mL BSA in the absence of glucose. These data demonstrate the possibility of the presence of two kinds of binding sites for A-4166: one of them is the sulfonylurea receptor, and the other might be a binding site specific for A-4166. PMID- 8687495 TI - Characterization of the 78 kDa mast cell protein phosphorylated by the antiallergic drug cromolyn and homology to moesin. AB - Mast cells (MC) can be stimulated to secrete by cross-linking immunoglobulin E bound to specific surface receptors, as well as in response to polycationic molecules such as substance P and compound 48/80. The antiallergic drug disodium cromoglycate (cromolyn) inhibited MC secretion and rapidly incorporated phosphate into a 78 kDa protein, speculated to be its mode of action. This protein was purified by single and two-dimensional gel electrophoresis, and was shown to be phosphorylated primarily on serine residues by protein kinase C. Partial amino acid sequencing of two generated fragments was identical to that of portions of mouse moesin, a member of the band 4.1 superfamily of proteins, with no definitive function known to date. Polyclonal antibodies raised against the rat basophil leukemia cell moesin cDNA expressed in Escherichia coli immunoprecipitated the 78 kDa phosphoprotein quantitatively, and immunocytochemistry localized it to the plasma membrane. Reversible phosphorylation of this 78 kDa phosphoprotein could affect its possible cytoskeletal binding through which it may regulate stimulus-secretion coupling in MC. PMID- 8687496 TI - Influence of both salvage and DNA damage response pathways on resistance to chemotherapeutic antimetabolites. AB - The resistance of 3 human embryo fibroblast cell lines to the antimetabolites methotrexate (MTX), N-phosphonacetyl-L-aspartate (PALA) and 5-fluorouracil (5-FU) has been studied. The cell lines were of common genetic origin, all originating from the normal KMS parental cell line, which was irradiated with 60Co to produce the immortalised derivative KMST which, in turn, was transfected with an activated N-ras oncogene to produce the tumourigenic KN-NM cell line. Previous work from this group, using dialysed versus nondialysed serum, has provided evidence for the involvement of salvage pathways of purine and pyrimidine biosynthesis in the increased resistance to antimetabolites of those cell lines (KMST and KN-NM) tending towards increased tumourigenicity. The present study has extended this work by using the nucleoside and nucleobase transport inhibitor dipyridamole, to further assess the contribution of the salvage pathways to the increased cellular resistance to the three antimetabolites. The salvage pathways were found to contribute to the resistance of cell lines to PALA and MTX, but had no effect on the resistance to 5-FU. The addition of excess uridine in the case of PALA, and hypoxanthine plus thymidine in the case of MTX, could be used to "rescue" cells from the effects of dipyridamole-induced salvage pathway inhibition. The data will be discussed in relation to 1. the effect of limited substrate availability, 2. the induction of DNA damage and DNA damage-response pathways, and 3. DNA-damage protection by the salvage pathways of purine and pyrimidine biosynthesis. PMID- 8687497 TI - Lovastatin reduces expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells. AB - The thrombospondin and collagen receptor CD36 was recently found to function, also, as a dominating scavenger receptor for oxidized low-density lipoproteins (oxLDL). Thus, CD36 might be a key factor in monocyte adhesion and foam cell formation. We, therefore, studied CD36 expression in monocytic cells under conditions of cholesterol depletion and overload. Human monocytic U937 cells were cultured under control conditions and in the presence of lovastatin, native, and oxLDL. The expression of lipoprotein receptors was measured by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and fluorescence activated cell sorting (FACS). In sharp contrast to the feedback-controlled ApoB100 specific receptor for native low-density lipoprotein (LDL-R), CD36 expression was significantly reduced by lovastatin in a dose-dependent manner, both at the RNA and protein level, resulting in decreased cellular oxLDL binding. The addition of mevalonate completely reversed lovastatin effects, whereas excess LDL was only partially effective. Similarly to native LDL, oxLDL reduced LDL-R transcription, but did not affect CD36 transcription. CD36 protein surface expression fell, however, due to internalization of CD36 loaded with oxLDL. In summary, monocytic expression of CD36, in contrast to the native LDL-R, is reduced by cholesterol synthesis inhibition and not by feedback inhibition from substrate overexposure. CD36 suppression is a new pharmacological action of lovastatin that may contribute to its clinical benefit by attenuating monocyte adhesion and foam cell formation, key steps in atherosclerosis. PMID- 8687498 TI - Effects of diadenosine triphosphate and diadenosine tetraphosphate on rat liver cells. Differences and similarities with ADP and ATP. AB - Liver cells possess multiple types of purinoceptors that mediate the effects of extracellular nucleotides. Like ADP and ATP, the dinucleotides diadenosine triphosphate (Ap3A) and diadenosine tetraphosphate (Ap4A) fully activated glycogen phosphorylase, with ED50 values of 0.31 microM and 1.3 microM, respectively. At variance with ATP, neither the dinucleotides nor ADP significantly increased the levels of IP3.Ap4A (and also ADP) moderately increased IP3 (+/- 72%) whereas Ap3A was completely ineffective. Like ATP, Ap3A, Ap4A, and ADP inhibited the cAMP increase after glucagon. Phorbol-12-myristate-13 acetate (PMA) pretreatment of the hepatocytes clearly inhibited the glycogenolytic potency of Ap3A and ADP, but had only a minor effect on the potency of Ap4A or ATP. It is concluded that, depending upon the effect studied (glycogenolytic effect with or without PMA, increasing IP3 potency, or inhibition of cAMP increase), different analogies between the agonists studied emerged, indicating the complexity of the interaction of ATP and its analogues with liver purinoceptors and/or of the transduction mechanism(s) initiated by the different nucleotides. PMID- 8687499 TI - A noncovalent binding-translocation mechanism for site-specific CC-1065-DNA recognition. AB - The molecular strategy by which small organic compounds recognise specific DNA sequences is of primary importance for rational drug design. CC-1065 is a potent alkylating agent that binds covalently to N3 of adenine and lies in the minor groove of double-stranded DNA. Its reaction with DNA occurs in a site-specific manner, with a preference for A. T-rich nucleotide sequences. In the present study, we developed a drug translocation assay to investigate the mechanism underlying this sequence selectivity. After exposure of plasmid DNA to saturating amounts of CC-1065, we observed that nearly 70% of plasmid-bound CC-1065 molecules formed stable, but noncovalent, complexes with DNA. These noncovalently bound drug molecules resisted purification by ethanol precipitation, dialysis, and sucrose gradient centrifugation, but retained the ability to translocate to DNA fragments containing a single high-affinity site for alkylation. This combination of non-covalent binding interactions and drug translocation provides a mechanism by which CC-1065 may locate specific alkylation sites in DNA. PMID- 8687500 TI - Characterization of novel anthracycline prodrugs activated by human beta glucuronidase for use in antibody-directed enzyme prodrug therapy. AB - Antibody-directed enzyme prodrug therapy (ADEPT) aims at the specific activation of a prodrug by an enzyme-immunoconjugate localized in tumor tissue. The use of an enzyme of human origin is preferable in ADEPT because it might not be immunogenic when administered to patients. In the case of human beta glucuronidase, prodrugs should be designed that are rapidly and completely activated at a neutral pH. Four new daunorubicin glucuronides were synthesized by coupling a glucuronide group to daunorubicin via an aliphatic (GA1 and GB1) or an aromatic (GA3, GB6) carbamate spacer, to be released by electron shift (A-type) or by ring closure (B-type). These prodrugs were characterized in vitro for their usefulness in ADEPT and were compared with the previously described prodrugs epirubicin-glucuronide and doxorubicin-nitrophenyl-glucuronide. The four new prodrugs were stable in serum, hydrophilic when compared to the lipophilic daunorubicin, and at least 20-fold less toxic than the parent compound. The hydrolysis rate at clinically relevant enzyme and prodrug concentrations (1 microgram/mL human beta-glucuronidase, 100 microM prodrug) at pH 6.8 were similar for GA3 (T1/2 160 min) and higher for GB6 (T1/2 40 min) when compared to that of doxorubicin-nitrophenyl-glucuronide (T1/2 170 min). Epirubicin-glucuronide, GA1, and GB1 showed a low hydrolysis rate (T1/2 > 400 min). GA1 and GA3, but not GB1 or GB6, were activated to the parent compound. Complete activation was confirmed in OVCAR-3 cells pretreated with a specific antibody-human beta-glucuronidase conjugate, where GA3 had similar antiproliferative effects to those of daunorubicin. PMID- 8687501 TI - Astroglia-released factor with negative allosteric modulatory properties at the GABA A receptor. AB - We have previously shown, using whole-cell patch-clamp techniques, that astrocytes release a negative allosteric modulator of the gamma-aminobutyric acid type A receptor (GABAA receptor) with beta-carboline-like properties, thus, likely to act at the benzodiazepine site. Here, using patch-clamp and binding techniques, we confirm that the low-molecular-weight fraction of astroglia conditioned medium (ACM lmf) contains a factor(s) that negatively modulates GABAA receptor function. This factor, like beta-carbolines, enhances the specific binding of [35S]t-butyl bicyclophosphorothionate (TBPS) to adult rat cortical membranes in the presence of GABA. However, it fails to interact with various ligands of the benzodiazepine (BZD) site of the GABAA receptor ([3H]flunitrazepam, [3H]Ro 15-1788 and [3H]Ro 15-4513). The question of the actual binding site of the astroglia-derived factor on the GABAA receptor, thus, remains open and can be addressed only after the purification of the active molecule(s) of ACM Imf has been completed, and a labeled form of the endogenous ligand becomes available. Taken together, however, the data suggest that type 1 astrocytes are able to modulate the effects of the main inhibitory neurotransmission in the central nervous system. PMID- 8687502 TI - Cell protein cross-linking by erbstatin and related compounds. AB - The protein-tyrosine kinase inhibitor and stable erbstatin analogue methyl 2,5 dihydroxycinnamate (4) cross-links cell proteins by a non-physiological chemical mechanism (Stanwell et al., Cancer Res 55: 4950-4956, 1995). To determine the structural requirements for this effect, erbstatin (1) and fifteen related compounds, including caffeic acid phenylethyl ester (9) were synthesized and examined for their ability to induce cross-linking of cellular protein at concentrations ranging from low micromolar up to 1000 microM. Tests were conducted in NIH3T3 fibroblasts as well as mouse keratinocytes. Potent cross linking of cellular protein was observed for a number of analogues, including erbstatin, at concentrations as low as 10-50 microM. The inactivity of methoxy and fluoro as compared with their corresponding dihydroxylated counterparts indicated that free aromatic hydroxyls were essential for cross-linking. Additionally, compounds containing phenyl rings with 1,4-dihydroxy substituents were more potent than those having 1,2-dihydroxylated patterns. As with the prototype compound 4, cross-linking was induced at both 37 degrees and 4 degrees, suggesting a chemical rather than physiological mechanism. Consistent with the data, a mechanism of action is proposed which involves initial oxidation to reactive quinone intermediates that subsequently cross-link protein nucleophiles via multiple 1,4-Michael-type additions. Similar alkylation of protein by protein tyrosine kinase inhibitors, such as herbimycin A, has been invoked. While the latter benzoquinoid ansamycin antibiotics contain performed quinone moieties, results of the present study suggest that other hydroxylated kinase inhibitors can potentially participate in similar phenomena. A large number of potential therapeutics, including HIV integrase inhibitors, possess polyhydroxylated nuclei. The non-specific nature of the protein cross-linking reaction demonstrated for these erbstatin analogues, and the fact that cross-linking can occur at micromolar concentrations, may limit the therapeutic usefulness of such compounds to specific applications. PMID- 8687503 TI - Differential induction of apoptosis in oncogene-transformed NIH 3T3 cells by methylmethanesulfonate. AB - Cellular oncogenes have been shown to play crucial roles in the cell death process induced by cytotoxic agents. In this study, we have demonstrated that v-H ras transformed NIH 3T3 cells but not other transformants (v-raf, v-src, v-erbB 2, v-fes and v-mos) exhibited a survival advantage to treatment by a DNA-damaging agent, methylmethanesulfonate (MMS). Subsequently, the biochemical and morphologic criteria of MMS-treated cells were examined. It was found that MMS induced v-H-ras transformants to go through necrosis, but it induced other transformed cells to undergo apoptosis. The levels of glutathione (GSH) within each transformant as well as in NIH 3T3 cells, were determined. The results showed that GSH levels within ras transformants were 2- to 7-fold higher than the levels in other transformants and normal NIH 3T3 cells. By using the GSH synthesis inhibitor buthionine sulfoximine, GSH levels were artificially reduced. This depletion, however, made ras transformed cells more sensitive to MMS killing, but the mode of cell death was still necrosis. Western blot analysis demonstrated that the anti-apoptotic protein Bcl-2 was constitutively expressed in ras transformed cells but not in NIH 3T3 or other transformed cells. The level of Bcl-2 was correlated with the resistant phenotype of ras transformants during MMS treatment. These observations suggest that GSH and Bcl-2 levels may cooperatively confer the resistant phenotype of ras transformants in response to MMS. In addition, the mode of cell death may possibly be determined at least in part by Bcl-2 protein. PMID- 8687504 TI - Enhancing effects of vasoconstrictors on bile flow and bile acid excretion in the isolated perfused rat liver. AB - The effects of vasoconstrictors on bile flow and bile acid excretion were examined in single-pass isolated perfused rat livers. Administration of norepinephrine (NE), 4 nmol/min, plus continuous infusion of taurocholate (TC) (1.0 mumol/min) rapidly increased bile flow in 1 min, and from min 5 until the end of NE administration (late period) bile flow remained above the basal level (111.7 +/- 2.2%), as did bile acid output (114.6 +/- 1.8%). Without TC infusion, administration of NE produced no increase in the late period. Administration of NE plus taurochenodeoxycholate (1.0 mumol/min) increased bile flow and bile acid output in the late period to 121.9 +/- 7.0 and 137.1 +/- 6.8%, respectively. With NE plus taurodehydrocholate, the respective values were only 105.4 +/- 1.6 and 104.1 +/- 4.0%. When horseradish peroxidase (HRP) (25 mg) was infused over 1 min with continuous NE, the late peak (20-25 min) of HRP elimination into bile significantly exceeded that of untreated controls (P < 0.01). These observations suggest that vasoconstrictors enhance biliary excretion of more hydrophobic bile acids, in part by stimulating vesicular transport. PMID- 8687505 TI - Cytochrome P-450 expression in sudden infant death syndrome. AB - In the human liver, the major rise of the cytochrome P-450 isoform content occurs during the first months following birth (e.g., the high vulnerability period to sudden infant death syndrome (SIDS), a syndrome frequently associated with viral infection and drug hypersensitivity. We examined the expression of individual P 450 isoforms in liver samples collected postmortem from SIDS infants and compared values with those of control adults and children of the same age suffering from various pathologies. Hepatic microsomes were prepared and examined for their content in total P-450, the level of individual isoforms (CYP1A2, CYP2E1, CYP4A, CYP3A, and CYP2C) determined with specific antibodies and for their enzymatic activities. Total RNA was extracted and probed with several CYP cDNAs and oligomers. The overall hepatic P-450 content was not modified in SIDS infants. Among cytochrome P-450 isoforms, only CYP2C was markedly increased. This rise resulted from an accumulation of RNA encoding CYP2C and was associated with a stimulation of diazepam demethylation. The precocious expression of CYP2C in SIDS could result in a higher production of epoxyeicosatrienoic acids in the neonate, believed to act as relaxant of pulmonary smooth muscles. Its consequence might be the induction of fatal apnea in SIDS. PMID- 8687506 TI - Calcitriol and lexicalcitol (KH1060) inhibit the growth of human breast adenocarcinoma cells by enhancing transforming growth factor-beta production. AB - The mechanisms involved in the antiproliferative action of calcitriol (1 alpha, 25(OH)2D3) were investigated using human breast carcinoma epithelial cells (the MCF-7 cell line). Calcitriol and KH1060, a synthetic analog, inhibited cell growth in a time-and dose-dependent way. The substances similarly stimulated total TGF-beta secretion after 24 hours, and Northern blot analyses showed that mRNA levels for TGF-beta 1 were increased, as well. When MCF-7 cells were co incubated with calcitriol and a neutralizing anti TGF-beta 1, beta 2, beta 3 antibody, growth inhibition was completely abrogated. With KH1060, the antibody could only partly block growth inhibition. This study shows that TGF-beta is involved in the growth response to calcitriol and KH1060 in MCF-7 cells. PMID- 8687507 TI - [An effective method of purifying recombinant human tumor necrosis factor alpha]. AB - An efficient and productive isolation method for human recombinant tumor necrosis factor alpha from Escherichia coli cells was developed. The method includes a membrane filtration step, two steps of ion-exchange chromatography, and gel filtration on a Sephadex G-25 column. The target product was obtained with approximately 50% total yield and greater than 95% purity according to PAGE and HPLC. PMID- 8687509 TI - [High performance liquid chromatography of fluorescent insulin derivatives]. AB - The reversed-phase HPLC of porcine insulin modified by fluorescent labeling with dansyl chloride, fluorescein isothiocyanate, and an N-hydroxysuccinimide ester of 3-carboxyl derivative of Nile Red was studied. Mono-, di-, and tri-Dns-insulins (substituted at residues Gly1 of the A-chain and Phe1 and Lys29 of the B-chain), as well as isomeric 5'- and 6'-fluorescein thiocarbamoyl-Phe1 insulin derivatives were separated on the analytical and semipreparative scale. The results were interpreted in terms of conservation of the globular structure in the modified proteins and their surface-mediated interaction with the reversed-phase sorbent. Observed retention times correlated with the total hydrophobicity of the surface region containing the incorporated label (in the case of monosubstituted derivatives) or with the total hydrophobicity of chromatographic contact regions located between labels (in the case of di- and trisubstituted derivatives). PMID- 8687508 TI - [An artificial gene, biosynthesis and properties of the recombinant Fc fragment of human immunoglobulin G1]. AB - Chemicoenzymatic synthesis and cloning of a gene encoding the Fc domain of human immunoglobulin G1 were carried out. The artificial gene was expressed in Escherichia coli cells in plasmid vectors under control of a late T7 promoter. The recombinant protein isolated from the bacterial cells is capable of forming dimers and binding protein A from Staphylococcus aureus. PMID- 8687511 TI - [Determination of free d-biotin--comparison of instrumental and non-instrumental methods of analysis]. AB - Simple methods for determining free d-biotin were developed based on the latex agglutination reaction inhibition and competitive ELISA. Biotin-binding protein Str used as a biospecific marker was immobilized on the surface of colored polyacrolein latex particles or a nitrocellulose membrane. The sensitivity of both methods of the free d-biotin assay, which take 1.5 h, is 1.0-3.0 ng/ml. PMID- 8687510 TI - [Immunomodulating properties of synthetic fragments of human interleukin-2]. AB - For the study of the antigenic structure and function of human interleukin 2, the peptides corresponding to its 60-72 sequence were synthesized by conventional methods of peptide chemistry in solution. To enhance the stability of the synthetic peptides towards the proteolysis and to remove their terminal charges, we acetylated their NH2 groups and esterified with methanol their carboxyls. Some of these peptides were converted from being cytotoxic to possessing strong growth stimulating activity for the preliminary activated macrophages both in vitro and in vivo. The biologically active peptides were also shown to enhance regeneration reparation processes in liver and skin. PMID- 8687512 TI - [Leptin--a peptide hormone from adipocytes. Sensation of the 23rd FEBS Meeting]. AB - Studies of the obese gene are reviewed. Recessive mutations in the ob gene in homozygous state cause excessive weight and diabetes in mice. Cloning and expression of cDNA of the human and mouse ob genes revealed that the ob gene is only expressed in white adipose tissue. cDNA encodes the ob protein that consists of 167 amino acid residues, the homology between the mouse and human ob proteins being 84%. The peptide leptin, secreted into blood, consists of 145 amino acid residues and results from the cleavage of a signal peptide off the ob protein. Leptin was obtained by genetic engineering methods. Its injection into ob/ob mice decreases body weight and eliminates diabetes symptoms. Leptin also decreased body weight of healthy mice by activating the utilization of endogenous lipids in energy metabolism. Leptin was found in human and mouse blood and mouse adipose tissue but not in blood or adipose tissue of ob/ob mice. Based on the results obtained, it was postulated that leptin, a product of the ob gene, is a hormone that is secreted into blood in varying quantities by adipocytes and controls the adipose tissue weight by stimulating lipid metabolism in the organism. PMID- 8687513 TI - 1996 Regional meetings of the American College of Rheumatology. Abstracts. PMID- 8687515 TI - Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. AB - BACKGROUND: Insulin resistance and increased ovarian cytochrome P450c17 alpha activity are both features of the polycystic ovary syndrome. P450c17 alpha, which is involved in androgen biosynthesis, has both 17 alpha-hydroxylase and 17,20 lyase activities. Increased activity of this enzyme results in exaggerated conversion of progesterone to 17 alpha-hydroxyprogesterone in response to stimulation by gonadotrophin. We hypothesized that hyperinsulinemia stimulates ovarian P450c17 alpha activity. METHODS: We measured fasting serum steroid concentrations and the response of serum 17 alpha-hydroxyprogesterone to leuprolide, a gonadotrophin-releasing hormone agonist, and performed oral glucose tolerance tests before and after oral administration of either metformin (500 mg three times daily) or placebo for four to eight weeks in 24 obese women with the polycystic ovary syndrome. RESULTS: In the 11 women given metformin, the mean (+/ SE) area under the serum insulin curve after oral glucose administration decreased from 9303 +/- 1603 to 4982 +/- 911 microU per milliliter per minute (56 +/- 10 to 30 +/- 6 nmol per liter per minute) (P = 0.004). This decrease was associated with a reduction in the basal serum 17 alpha-hydroxyprogesterone concentration from 135 +/- 21 to 66 +/- 7 ng per deciliter (4.1 +/- 0.6 to 2.0 +/ 0.2 nmol per liter) (P = 0.01) and a reduction in the leuprolide-stimulated peak serum 17 alpha-hydroxyprogesterone concentration from 455 +/- 54 to 281 +/- 52 ng per deciliter (13.7 +/- 1.6 to 8.5 +/- 1.6 nmol per liter) (P = 0.01). The serum 17 alpha-hydroxyprogesterone values increased slightly in the placebo group. In the metformin group, the basal serum luteinizing hormone concentration decreased from 8.5 +/- 2.2 to 2.8 +/- 0.5 mlU per milliliter (P = 0.01), the serum free testosterone concentration decreased from 0.34 +/- 0.07 to 0.19 +/- 0.05 ng per deciliter (12 +/- 3 to 7 +/- 2 pmol per liter) (P = 0.009), and the serum sex hormone-binding globulin concentration increased from 0.8 +/- 0.2 to 2.3 +/- 0.6 microgram per deciliter (29 +/- 7 to 80 +/- 21 nmol per liter) (P < 0.001). None of these values changed significantly in the placebo group. CONCLUSIONS: In obese women with the polycystic ovary syndrome, decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates hyperandrogenism. PMID- 8687516 TI - Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherectomy. AB - BACKGROUND: Restenosis occurs commonly after coronary angioplasty and atherectomy, but the causes of restenosis are poorly understood. Recently, it has been found that cytomegalovirus (CMV) DNA is present in restenotic lesions from atherectomy specimens. This and other evidence suggest that CMV may have a role in the process of restenosis. METHODS: We prospectively studied 75 consecutive patients undergoing directional coronary atherectomy for symptomatic coronary artery disease. Before atherectomy was performed, we measured blood levels of anti-CMV IgG antibodies to determine whether previous exposure to CMV increased the risk of restenosis, as determined by coronary angiography performed six months after atherectomy. RESULTS: After atherectomy, the mean (+/- SD) minimal luminal diameter of the target vessel was greater in the 49 patients who were seropositive for CMV than in the 26 patients who were seronegative (3.18 +/- 0.51 mm vs. 2.89 +/- 0.45 mm, P=0.01). After six months, however, the seropositive patients had a greater reduction in the luminal diameter (1.24 +/- 0.83 mm vs. 0.68 +/- 0.69 mm, P = 0.003), resulting in a significantly higher rate o restenosis in the seropositive patients (43 percent vs. 8 percent, P = 0.002). In a multivariable logistic-regression model, CMV seropositivity and the CMV titer were independently predictive of restenosis (odds ratios, 12.9 and 8.1, respectively). There was no evidence of acute infection, since the titer of anti CMV IgG antibodies did not increase over time and tests for anti-CMV IgM antibodies were negative in all patients. CONCLUSIONS: Prior infection with CMV is strong independent risk factor for restenosis after coronary atherectomy. If confirmed, these findings may help identify patients at risk for restenosis. PMID- 8687517 TI - Hepatitis C virus-associated fulminant hepatic failure. PMID- 8687518 TI - Hemolytic-uremic syndrome in a six-year-old girl after a urinary tract infection with Shiga-toxin-producing Escherichia coli O103:H2. PMID- 8687522 TI - Insulin and the polycystic ovary syndrome. PMID- 8687523 TI - Pharmacotherapy for obesity -- do the benefits outweigh the risks? PMID- 8687524 TI - Escherichia coli and the hemolytic-uremic syndrome. PMID- 8687525 TI - The legalization of physician-assisted suicide. PMID- 8687526 TI - The promised end--constitutional aspects of physician-assisted suicide. PMID- 8687972 TI - Fibrodysplasia ossificans progressiva: searching for the skeleton key. PMID- 8687973 TI - Secular trends in osteoporotic pelvic fractures in Finland: number and incidence of fractures in 1970-1991 and prediction for the future. AB - To improve the knowledge of the current trends in the number and incidence of osteoporosis-related pelvic fractures, patients who were admitted to Finnish hospitals in 1970, 1975, 1980, 1985, 1988, and 1991 for primary treatment of first osteoporotic pelvic fracture were selected from the National Hospital Discharge Register. The overall incidence (per 100,000 inhabitants) of osteoporosis-related pelvic fractures (high energy traumas were excluded) in a population aged 60 years or more was 20 in 1970 and 63 in 1991. The increase was most pronounced in the older age groups (patients aged 80 years or more) and was observed in both sexes. The proportion of these osteoporotic pelvic fractures of all pelvic fractures increased from 18% in 1970 to 52% in 1991. Similarly, the proportion of patients over 60 years of age increased from 28% in 1970 to 62% in 1991. In 1991, 78% of the patients with an osteoporotic pelvic fracture were women. Across the study period, the age-adjusted total incidence of osteoporotic pelvic fractures also increased in both women and men 60 years of age and over. The proportional increase was more pronounced in men. We conclude that the number of osteoporotic pelvic fractures in Finland is increasing more rapidly than can be accounted for by the demographic changes only and that effective preventive measures are urgently needed to control the increasing number of these age related fractures. PMID- 8687974 TI - Sex and age patterns of quantitative ultrasound densitometry of the calcaneus in normal Japanese subjects. AB - : The speed of sound (SOS), broadband ultrasound attenuation (BUA), and the stiffness index (stiffness), which was derived from SOS and BUA, were measured on the calcaneus using the Achilles ultrasound densitometer (Lunar) in normal Japanese woman (n = 473) and men (n = 218). Sex differences and age-related changes in these variables were investigated. In addition, the bone mineral density (BMD) of the lumbar vertebrae measured by dual X-ray absorptiometry (QDR 2000, Hologic) was compared with SOS, BUA, and stiffness. There were some decreases of ultrasound variables in both young adult men and women. BMD values were similar in young adults of both sexes. BMD was relatively stable in women from 20 to 49 years, then decreased at about 1.5%/year. Ultrasound variables were higher in males than females at all ages, and they decreased from age 20 onward in both sexes with an annual loss of about 0.6%. Age-related changes in SOS, BUA, and stiffness were different from those in BMD in normal Japanese subjects. The correlations between BMD and SOS and BUA and stiffness were higher in women (r = 0.51-0.64) than in men (r = 0. 43-0.49). PMID- 8687975 TI - Exercise and reproductive factors as predictors of bone density among osteoporotic women in Mexico City. AB - We examined the association between physical activity and reproductive factors with bone density among 313 Mexican women, aged 26-83 years. Bone mineral density (BMD) was measured with a HOLOGIC QRD 1000 w, DXA densitometer at the lumbar spine and femoral region. We explored the relation between BMD and parity, age, body mass index (BMI), type of menopause, and level of exercise. Multiple regression models examining determinants of bone density at the lumbar and femoral regions showed that increasing age and lack of exercise were statistically significant predictors of bone demineralization. The number of pregnancies also had a deletereous effect on bone density, especially for lumbar spine, as well as BMI <20 kg/m2. Our results suggest that physical activity, parity, and BMI are important determinants of bone density in this population. PMID- 8687976 TI - Variable efficacy of bone remodeling biochemical markers in the management of patients with Paget's disease of bone treated with tiludronate. AB - The aim of this work was to evaluate the response of different biochemical bone markers to tiludronate administration in Paget's disease of bone. Ten patients (five men and five women), 56-77 years old (67 +/- 6.5), were treated for 3 months with tiludronate tablets (400 mg/day). Bone formation markers: alkaline phosphatase (AP), bone alkaline phosphatase (bAP), osteocalcin (BGP), and procollagen I carboxyterminal propeptide (PICP) in serum; and bone resorption markers: serum cross-linked carboxyterminal telopeptides of type I collagen (ICTP), urinary hydroxyproline/creatinine (Hyp/Cr), pyridinoline/Cr (Pyr/Cr), and alpha-1 collagen chain products degradation (CrossLaps) were assessed. Samples were taken before and at monthly intervals for 3 months after treatment began. The results of the present work show that serum AP and bAP are sensitive and reliable biochemical markers of bone formation in the follow-up of tiludronate in this disease. Serum PICP shows less sensitivity than serum AP, and serum BGP is not indicated as biochemical marker in these types of studies. Urinary hydroxyproline seems to be the most reliable biochemical marker of bone resorption. More studies should be performed with urinary Pyr and CrossLaps determinations. Serum ICTP is not adequate for the follow-up of tiludronate treatment in Paget's disease of bone. PMID- 8687977 TI - Human calcitonin has the same inhibitory effect on osteoclastic bone resorption by human giant cell tumor cells as salmon calcitonin. AB - Human calcitonin (hCT) has been reported to have a less hypocalcemizing effect on rats and to have a lower binding affinity for the receptor of mouse osteoclasts than salmon CT(sCT). In this study we comparatively examined the effect of hCT and sCT on osteoclastic bone-resorbing activity of unfractionated cells obtained from human giant cell tumor of bone and from rabbit and mouse long bones. We found that hCT had the same inhibitory effect as sCT on the bone-resorbing activity of human and rabbit osteoclastic cells, but a different one on that of mouse cells. These results indicate that the activity of drugs should be assayed using human cells if possible. PMID- 8687978 TI - Effect of diacylglycerols on osteoclastic bone resorption. AB - We studied the effect of various synthetic diacylglycerols (DAGs) on bone resorption by rat and chick osteoclasts. 1-stearoyl-2-arachidonoyl-sn-glycerol (DAG IV), at a concentration of 100 microM, caused a significant reduction in resorption pit number in both species at 6 and 24 hours without any toxic effect. Over a 6-hour incubation period, a significant inhibition was seen at 10 and 100 microM in both species. 1,2-dioctanoyl-sn-glycerol (DAG I) and 1,2-dihexanoyl-sn glycerol (DAG III) caused a marked inhibition of resorption by rat osteoclasts at 6 hours, but there was recovery of bone-resorptive ability over a 24-hour incubation period. DAGs with the -rac conformation failed to have any effect on bone resorption. In time-lapse video studies, osteoclast motility was not influenced by any of the DAGs at any of the concentrations used. Our results indicate that DAGs with the -sn conformation inhibit bone resorption, and DAGs with the -rac conformation do not. The finding that DAGs, the physiological activators of protein kinase C (PKC), inhibit bone resorption provides further evidence for an important role of the PKC pathway in the regulation of osteoclast activity. PMID- 8687980 TI - Reduction in dynamic indices of cancellous bone formation in rat tail vertebrae after caudal neurectomy. AB - We have previously noted that a relatively large load (150 N) is required to induce a strain on the cortex of rat vertebrae similar to that induced on weight bearing bones by normal mechanical usage. It seems unlikely that the musculature of the tail normally imposes loads of this magnitude, and this suggests that the quantity of bone in caudal vertebrae is maintained at a higher level than would be expected for the mechanical environment to which it is exposed. This high bone mass could represent a genetically determined minimum, or could be maintained through increased sensitivity to mechanical stimuli. To distinguish between these two possibilities, we denervated the tails of 13-week-old rats by neurectomy at L6, and assessed the response of the caudal vertebrae to mechanical disuse. We found that caudal neurectomy caused a reduction in the cancellous bone formation rate in the eighth caudal vertebrae to 12% of that seen in sham-operated animals. The cancellous bone formation rate in the thoracic vertebrae of neurectomized rats, which are not mechanically disused by caudal neurectomy, was not significantly reduced. This suggests that the cancellous bone formation rate in vertebrae is maintained by substantially less intense mechanical environments than those prevailing in weight-bearing bones, raising the possibility that bones may differ in their sensitivity to mechanical strain. PMID- 8687979 TI - Vitamin D metabolites regulate matrix vesicle metalloproteinase content in a cell maturation-dependent manner. AB - Matrix vesicles are extracellular organelles produced by cells that mineralize their matrix. They contain enzymes that are associated with calcification and are regulated by vitamin D metabolites in a cell maturation-dependent manner. Matrix vesicles also contain metalloproteinases that degrade proteoglycans, macromolecules known to inhibit calcification in vitro, as well as plasminogen activator, a proteinase postulated to play a role in activation of latent TGF beta. In the present study, we examined whether matrix vesicle metalloproteinase and plasminogen activator are regulated by 1, 25(OH)2D3 and 24,25(OH)2D3. Matrix vesicles and plasma membranes were isolated from fourth passage cultures of resting zone chondrocytes that had been incubated with 10(-10)-10(-7) M24, 25(OH)2D3 or growth zone chondrocytes incubated with 10(-11)-10(-8) M 1,25(OH)2D3, and their alkaline phosphatase, active and total neutral metalloproteinase, and plasminogen activator activities determined. 24,25(OH)2D3 increased alkaline phosphatase by 35-60%, decreased active and total metalloproteinase by 75%, and increased plasminogen activator by fivefold in matrix vesicles from resting zone chondrocyte cultures. No effect of vitamin D treatment was observed in plasma membranes isolated from these cultures. In contrast, 1,25(OH)2D3 increased alkaline phosphatase by 35-60%, but increased active and total metalloproteinase three- to fivefold and decreased plasminogen activator by as much as 75% in matrix vesicles isolated from growth zone chondrocyte cultures. Vitamin D treatment had no effect on plasma membrane alkaline phosphatase or metalloproteinase, but decreased plasminogen activator activity. The results demonstrate that neutral metalloproteinase and plasminogen activator activity in matrix vesicles are regulated by vitamin D metabolites in a cell maturation-specific manner. In addition, they support the hypothesis that 1,25(OH)2D3 regulation of matrix vesicle function facilitates calcification by increasing alkaline phosphatase and phospholipase A2 specific activities as well as metalloproteinases which degrade proteoglycans. PMID- 8687982 TI - Retinoic acid stimulates pyrophosphate elaboration by cartilage and chondrocytes. AB - Abnormal metabolism of extracellular inorganic pyrophosphate (PPi) by articular cartilage contributes to calcium pyrophosphate dihydrate (CPPD) crystal formation and the resultant arthritis known as CPPD deposition disease. The factors causing excess PPi elaboration in affected cartilage remain poorly defined. Retinoic acid (RA), a naturally occurring vitamin A metabolite, promotes cartilage degeneration and mineralization, two correlates of CPPD crystal deposition. RA was examined as a potential modifier of cartilage PPi elaboration. All-trans RA (200-1000 nM) increased PPi levels in culture medium of normal porcine cartilage and chondrocytes 2-3-fold over control values at 96 hours of incubation (P < 0.01). IGF1 and anti-EGF antibody diminished the effects of RA on PPi elaboration. RA modestly increased activity of the PPi-generating ectoenzyme NTPPPH in culture medium (P < 0.01). As some RA effects are mediated through increased activity of TGFbeta, a known PPi stimulant, we examined the effect of anti-TGFbeta antibody on RA-induced PPi elaboration. PPi levels in medium were reduced from 30 +/- 7 microM in cartilage cultures with 500 nM RA to 14 +/- 4 microM PPi in cartilage cultures with RA and anti-TGFbeta. Anti-TGFbeta antibody, however, had no significant effect on RA-induced PPi elaboration in chondrocyte cultures. Thus, RA, along with TGFbeta and ascorbate, can now be included in the list of known PPi stimulants. All three of these factors promote mineralization in growth plate cartilage. These data support a central role for TGFbeta in CPPD disease, and provide further evidence linking processes of normal and pathologic calcification in cartilage. PMID- 8687981 TI - Increased bone resorption precedes increased bone formation in the ovariectomized rat. AB - This study describes an increase in biochemical and histomorphometric markers of bone resorption prior to increased bone formation and trabecular bone loss in the ovariectomized rat. Six-month-old, female Sprague Dawley rats were either sham operated or ovariectomized (Ovx) and killed at 0, 6, 9, 15, 18, 21, and 42 days postoperation when femora were collected and trabecular bone volume (BV/TV) was determined from von Kossa silver-stained sections using the Quantimet 520 image analysis system in the distal region. A number of these sections were also examined unstained for fluorochrome labels, and stained for acid phosphatase to detect osteoclast-like cells (ACP surface). At 18 days postoperation, lumbar vertebrae were examined. Blood and urine specimens were analyzed for bone-related biochemical variables. ACP surface was significantly greater in Ovx rats compared with sham at 6 days postoperation (mean ACP surface (%TS) +/- SEM: sham 36.4 +/- 1.9; Ovx 40.3 +/- 1.2, P < 0.05) as was urinary hydroxyproline excretion. Serum osteocalcin and alkaline phosphatase activity were not elevated in Ovx rats compared with Sham until 9 days postoperation. Mineral apposition rate (MAR) was increased at 12 days after ovariectomy (mean MAR (microm/day) +/- SEM: sham 0.85 +/- 0.06; Ovx 1.23 +/- 0.06, P < 0.05). Trabecular bone volume (BV/TV) at a specific site in the metaphyseal-diaphyseal core area was significantly lower at 15 days postoperation (mean (%) +/- SEM: Sham 7.40 +/- 1.23, Ovx 4.25 0 0.65, P < 0.05). There was no difference in lumbar vertebral BV/TV between the two groups at 18 days postoperation, however, ACP surface was elevated in the Ovx rats (P < 0.05). A systemic increase in bone resorption at 6 days postovariectomy precedes increased formation whereas the length of time required for the dissolution of trabeculae postoperation is determined locally. PMID- 8687984 TI - Subacute toxicity of the water-soluble fractions of Kuwait crude oil and partially combusted crude oil on Menidia beryllina and Palaemonetes pugio. AB - As a consequence of the 1991 Gulf War, a substantial amount of crude oil (CO) and partially combusted crude oil (PCO) were emitted into the environment. Therefore, the study objective was to evaluate the toxicity of the water soluble fraction (WSF) of CO and PCO on a fish, Menidia beryllina, and an invertebrate, Palaemonetes pugio, in 16-d flow-through tests. Specific growth rate (SGR) was studied as a function of total petroleum hydrocarbon (TPHC) concentration in water. Reductions in SGR were observed in fish exposed to PCO and CO WSFs, with TPHC water concentration being 10-fold higher in CO exposures (67-145 microg/L) than in PCO exposures (4-12 microg/L). Significant negative correlations were observed between TPHC concentration and fish SGR in both CO (r2=0.730) and PCO (r2=0.867) exposures, with the slope being significantly lower for PCO exposures (-0.169) than CO exposures (-0.009). Differences between CO and PCO toxicity were not as clear in shrimp exposures due to slow growth rates and variability in TPHC concentrations. Qualitative PAH analysis indicated that naphthalene was present in the CO WSF whereas chrysene and benzo(a)pyrene were present in the PCO WSF. Heavy metal analysis of concentrated stock solutions indicated that the PCO WSF had substantially higher concentrations of some metals (Sr=2,521 microg/L, B=556 microg/L, and Ba=130 microg/L) than the CO WSF in which concentrations were less than 55 microg/L. Fish and shrimp tissue analysis did not reveal any uptake of parent PAH compounds from the water, which may be attributed to the formation of PAH metabolites. PMID- 8687985 TI - Metal accumulation in a biological indicator (Ulva rigida) from the lagoon of Venice (Italy). AB - Ulva rigida (C. Agardht) was collected from the Palude della Rosa (lagoon of Venice), a particular area characterized by a salinity gradient, from December 1991 to June 1993. Metal contents (Al, Mn, Fe, Cu, Zn, Cr, Co, Ni, Cd, and Pb) were determined by atomic absorption spectrophotometry and statistically analysed for differences between months and sampling sites. The mean seasonal variability is very significant (p < 0.001) for all studied metals. Seasonal trends are comparable for groups of metals according to possible functional similarities. A significant positive correlation was calculated for the pairs Fe-Al and Fe-Pb. Mechanisms regulating metal uptake are discussed, particularly the role of Fe and its linear relationship with Al. Metal concentrations in relation to salinity also were studied. Larger amounts of Fe, Zn, and Cd accumulated in correspondence of lower salinity, may be owing to both higher metal activity and burden of bioavailable metals in freshwater flowing into the Palude. Calculation of concentration factor (CF) indicates that U. rigida specifically accumulates Fe. CF linearly correlates with dissolved metal concentrations, suggesting that U. rigida is a good bioindicator of metal bioavailability, although seasonal active accumulation occurs in some cases (Mn). Metal concentrations determined in this macroalga support the conclusion that the studied area is rich in bioavailable Fe and poor in toxic metals. In any case, a great affinity for Al in U. rigida may be proposed. PMID- 8687986 TI - Accumulation pattern of butyltin compounds in dolphin, tuna, and shark collected from Italian coastal waters. AB - Tributyltin (TBT) and its breakdown products, mono-(MBT) and dibutyltin (DBT) were determined in bottlenose dolphin (Tursiops truncatus), bluefin tuna (Thunnus thynnus thynnus) and blue shark (Prionace glauca) collected from the Italian coast of the Mediterranean Sea in 1992-1993. Concentrations of total butyltin (BTs) in the liver of dolphin (1,200-2,200 ng/g wet wt) were an order of magnitude higher than in the blubber (48-320 ng/g wet wt). TBT was the predominant butyltin species in the blubber while DBT accounted for an higher proportion in the liver of dolphins. Butyltin concentrations in bluefin tuna were lower than those in dolphins, with TBT highest in the muscle and DBT in the liver. Concentrations of BTs in blue sharks were lower than those in dolphin and tuna, with kidney having the highest concentrations. TBT was the predominant form of butyltin derivatives in all the tissues of shark. Accumulation of butyltin compounds in liver/kidney seems to be associated with the presence of proteins such as glutathione. PMID- 8687988 TI - Fate and effects of soluble or sediment-bound arsenic in oysters (Crassostrea gigas Thun.). AB - Contaminated sediments are a possible source of stress to the benthic biota. In order to examine this way of transfer concurrently with direct exposure, oysters were exposed to As dissolved in natural seawater or loaded to particles. The sediment used as a vector of transfer was a mud from a coastal area devoted to oyster culture, the finest particles of which have been selected. It was submitted to experimental contamination then to in vitro desorption tests, in which enzymes and pH changes were used to mimic the digestive processes in Molluscs. Although different enzymes or pH induced the desorption of 3 to 24% of sediment-bound arsenic, the accumulation of this element in the soft tissues of oysters remained low after exposure to contaminated particles. The uptake of soluble arsenic was also limited although checking the level of arsenic in seawater every day revealed no significant decrease of the contaminant in the experimental medium. However, cytological effects were noted in oysters exposed to sediment-bound arsenic and moreover to soluble arsenic. They consisted of structural alterations of mitochondria and nuclei, suggesting a disturbance of both the cellular respiratory metabolism and nucleotid incorporation. PMID- 8687989 TI - Bioaccumulation and metabolic effects of cadmium on marine fouling dressinid bivalve, Mytilopsis sallei (Recluz). AB - Cadmium (Cd) toxicity and the effect of Cd exposure on oxygen consumption, accumulation and body biochemical composition of a marine dressinid bivalve Mytilopsis sallei were investigated. The 96 h LC50 of Cd for M. sallei was 0.71 mg/L and the safe concentration was 7.1 microg/L. Exposure of M. sallei to Cd resulted in significant decrease in oxygen consumption with increasing metal concentration. Cd accumulation in M. sallei was sensitive to both concentration and duration of exposure to Cd. In both experiments, the concentration of metal was 3-30-fold higher than the normal level. The effect of exposure time and concentration of Cd on body biochemical composition was also studied in M. sallei. Both carbohydrates and proteins were utilized in concentration as well as time-dependent exposure of Cd to M. sallei. The ratios of glycogen/protein and glycogen/lipid were decreasing with increasing exposure concentration of Cd. In time-dependent experiments, these ratios were observed to be decreasing up to the 4th day, but later (10 and 20 days) there was a recovery with values almost reaching the normal level for glycogen/protein ratio. The caloric concentration levels were determined in M. sallei on exposure to Cd but there was not much change either in time- or concentration-dependent exposure of Cd. The results of the present investigation indicate that these bivalves prefer to depend on carbohydrates and proteins rather than on lipids for their utilization on exposure to either sublethal or lethal stress of Cd. The decrease in oxygen consumption together with the utilization of glycogen and carbohydrates during Cd exposure suggest that these bivalves might shift to anaerobic metabolism in order to encounter the heavy metal stress in the environment. PMID- 8687987 TI - Wood preservative leachates from docks in an estuarine environment. AB - Environmental concentrations and biological effects of certain metals and organic compounds found in wood preservatives were examined. The study focused on leachates from private residential docks in South Carolina tidal creeks. Copper, chromium, arsenic, and polynuclear aromatic hydrocarbons (PAHs) were measured in composite samples of surficial sediments and naturally occurring oyster populations (Crassostrea virginica) from creeks with high densities of docks, and from nearby reference creeks with no docks. In some cases, metal concentrations in sediments and oysters were higher immediately adjacent to dock pilings than they were elsewhere in the same creek. Sediments from most sites had concentrations of metals and total PAHs which were below levels reported to cause biological effects, however. Solid-phase Microtox(R) bioassays using whole sediments and rotifer bioassays using sediment pore water showed no significant differences in acute toxicity between creeks with and without docks. Oysters growing directly on dock pilings had significantly higher concentrations of copper than oysters growing at least 10 m away; however, there was no significant difference in the physiological condition of these oysters. Four-day field bioassays measuring percent survival of mummichogs (Fundulus heteroclitus), mud snails (Ilyanassa obsoleta), juvenile red drum (Sciaenops ocellatus), and juvenile white shrimp (Penaeus setiferus) showed no significant differences between sites near to and distant from newly constructed docks. Hatchery-reared oysters showed no significant differences between dock and reference sites in percent survival, growth, or bioaccumulation of metals after six weeks of exposure. The results suggest that, in estuarine environments with a moderate tidal range (1.5-2.0 m), wood preservative leachates from dock pilings have no acutely toxic effects on four common estuarine species, nor do they affect the short-term survival or growth of juvenile oysters. PMID- 8687990 TI - Tissue-level biomarkers and biological effect of mercury on sentinel slugs, Arion ater. AB - The present investigation was to determine the extent to which mercury (Hg) provokes measurable effects on the structure of the digestive gland of slugs as well as to relate the extent of these effects to the cell and tissue distribution of Hg. For this purpose, slugs (Arion ater) received various dietary concentrations of Hg (from 0 to 1,000 microg Hg/g food) as chloride for 30 days and were histologically examined every third day. Autometallography was used to demonstrate Hg as black silver deposits (BSD) in paraffin sections. The lysosomes and residual bodies of digestive cells resulted to be the major accumulation sites. In addition, Hg was also evidenced in lipofuscine granules of vacuoles in excretory cells but, however, it was rarely observed within calcium cells. Generally, the extent of BSD increased with dietary Hg concentration and exposure time but, however, it became significant lowered after exposure to 1,000 microg Hg/g food for 30 when the digestive epithelium appeared almost devoid of digestive cells. On the other hand, significant changes were recorded in the quantitative structure of digestive tubules. Mean Epithelial Thickness (MET), Mean Luminal Radius (MLR) and Mean Diverticular Radius (MDR) were recorded as measures of the sublethal biological effect of Hg. MET, MLR/MET and MET/MDR were affected by Hg concentration (C), exposure time (T) and CxT interaction, changes in MET, MLR, MLR/MET and MET/MDR being explained by regression models after logarithmic transformation of the data. In order to explain the nature of the changes in the quantitative structure of the digestive tubules this investigation was complemented with qualitative histological observations. According to them, the excretory activity in digestive cells was initially enhanced. Afterwards, the relative numbers of digestive cells declined until the extreme cases of exposure to 1, 000 microg Hg/g for 27 to 30 days in which the digestive epithelium was mostly comprised of calcium and excretory cells. Concomitantly, some changes took place in blood vessels where Leydig cells became disrupted and the connective tissue layers thickened. Finally, it is suggested to use slugs in soil quality assessment as sentinel organisms ("Slug Watch") in which biomarkers of exposure to metallic pollutants and of biological effect are recorded. PMID- 8687991 TI - Effects of platinum (Pt4+) on Lumbriculus variegatus Muller (Annelida, Oligochaetae): acute toxicity and bioaccumulation. AB - The acute toxicity and bioaccumulation (rates, kinetic) of tetravalent platinum in Lumbriculus variegatus under different physicochemical conditions (temperature and total water hardness) were investigated. Increased Pt4+ concentration (from 0.05 to 50 mg/L), exposure (up to 30 days), temperature (from 4 to 20 degrees C) and decreasing water hardness (from 300 to 0 mg/L CaCO3) increased Pt toxicity. The metal accumulated at a constant rate that was concentration, temperature and time dependent. The median lethal concentration (96h LC50) varied greatly from 0.397 mg/L in distilled water to 30 mg/L in the hard water from Champagne. Thus, L. var. can tolerate high levels of Pt. As a result, L. var. can be used in the laboratory to analyze mechanisms of adaptation to the induced stress and in the field as an indicator of Pt pollution. PMID- 8687992 TI - The pattern of organochlorines in mussels Mytilus edulis L. from the south west Baltic Sea. AB - The concentration of organochlorines (PCB, DDT and its metabolites, HCH isomers and HCB) were determined in mussel, Mytilus edulis, from the south west Baltic Sea. The harbor Kiel Innenforde showed the highest contamination with PCB (487 microg/kg dry weight), the Gelting bathing beach area the lowest contamination (38 microg/kg). The highest contamination with DDT was measured in Lubeck bay, which may be explained by the long term application of DDT in the former German Democratic Republic. Penta- and hexa-chlorinated PCB were selectively accumulated in Mytilus edulis whereas highly lipophilic PCB with more than seven chlorine atoms were found in negligible concentrations. The accumulation of these compounds in mussels is determined by equilibrium partitioning with ambient water. PMID- 8687993 TI - Life-table evaluation of sediment-associated chlorpyrifos chronic toxicity to the benthic copepod, Amphiascus tenuiremis. AB - A partial life-cycle experiment was conducted to assess chronic effects of sediment-associated chlorpyrifos, an organophosphate pesticide, on a marine, benthic copepod population. The static-renewal experiment was initiated with 4 treatments including control, 13 replicates per treatment with one female (bearing first clutch of eggs) per replicate. No males were added because one fertilization is sufficient for several clutches. Once weekly, all replicate chamber contents (10-ml culture tubes with 1.5 ml of sediment and 5 ml of seawater) were sieved and enumerated to determine survival and fecundity. Surviving adult females were placed back into chambers with newly spiked sediments. This process was repeated for 7 weeks until all initial females were dead or reproduction had ceased for at least two weeks. Survival and fecundity data were then used to determine population dynamic parameters such as r (intrinsic rate of natural increase) for each treatment. Results revealed a chronic toxicity response with significant population effects (p<0.05) in all pesticide treatments versus the control; concentrations that represent 7-32% of the 96-hr LC50. The control treatment had an r value 26-52% higher than the pesticide treatments. This translated into a control population rate increase of up to twice that of pesticide treatments. In addition, significant reductions in weekly and total fecundity were found in all chlorpyrifos treatments. Based on these results, usage of population parameters with benthic copepods allows for an integrative measurement of population effects from chronic exposure to sediment associated contaminants. PMID- 8687994 TI - Effects of organic solvents and solvent-atrazine interactions on two algae, Chlorella vulgaris and Selenastrum capricornutum. AB - When assessing pesticides toxicity on test organisms, the use of organic solvents is frequently required to formulate solutions of pesticides having low or moderate water solubility. These solvents may influence the results of toxicity tests. This study examined the effects of ethanol and dimethyl sulfoxide (DMSO) on two species of algae, Chlorella vulgaris and Selenastrum capricornutum. The interactives effects of these organic solvents with various concentrations of atrazine were tested to analyse how these solvents can affect the toxicity of atrazine. Toxicity was measured as the change in chlorophyll (a) content (estimated via fluorescence) in cultures of the test organism that were incubated over a 96-h period at standard conditions of temperature and light. In the absence of atrazine, ethanol was toxic to both algae, yielding significant inhibition of chlorophyll (a) content at concentrations as low as 0.05%. Morever, S. capricornutum was less sensitive to ethanol than was C. vulgaris. DMSO did not show any toxic effects on either chlorophycea. At concentrations up to 0.5%, DMSO interacted additively with atrazine for both chlorophycea. An additive response was also observed with ethanol towards S. capricornutum. For C. vulgaris, ethanol interacted antagonistically at most of atrazine concentrations and gave few additive and synergistic interactions. An additive response of an atrazine solvent mixture indicate the inherent toxicity of the atrazine. Since DMSO generally gave additive responses for both algae, it can be considered as an adequate organic solvent to use in bioassays. PMID- 8687995 TI - Behavioral and physiological effects of acute sublethal exposure to dimethoate on wood mice, Apodemus sylvaticus. AB - The effects on behavior and cholinesterase (ChE) of an OP pesticide, dimethoate, were examined in wood mice under laboratory conditions. Mice were administered 0, 5, 15, or 50 mg/kg intraperitoneal dimethoate and their behavior was recorded in an open field for one hour. In a second experiment, using only the 0 and the 50 mg/kg dose, mice were subjected to 10-min open field tests repeated at various time intervals during a 24-h period. Shortly after administration of dimethoate, there was a general, dose-dependent, behavioral depression that was characterized by increased inactivity and decreased grooming, rearing, and sniffing. The introduction of a novel object in the open field failed to elicit any reaction in mice treated with the two highest doses of dimethoate. The behavioral impairment completely disappeared 6 h after treatment. A stereotyped compulsive grooming was also observed in the first 30 min after administration of the two highest doses. Exposure to dimethoate caused a dose-dependent decrease in ChE activity in the brain and in serum. Behavioral impairment was associated with maximum levels of ChE inhibition of 65-75% (brain) and 75-85% (serum). Recovery of ChE activity lagged behind that of behavioral impairment and started 3-6 h after dimethoate administration. The possible implications for free-living wood mice which inhabit cereal fields and may be exposed to OPs are discussed. PMID- 8687996 TI - Effects of fertilizer on insecticides adsorption and biodegradation in crop soils. AB - Recent organic fertilizer treatments (cow manure, pig slurry, composts, or green manure) simultaneously increase insecticide adsorption onto soil and the insecticide soil persistence, indicating a mechanism of slow release of insecticide into soil by the organic matter. This occurred in sugar beet crops with aldicarb, thiofanox and imidacloprid; also, in leek, cauliflower and brussels sprouts crops with chlorpyrifos and chlorfenvinphos. In contrast, organic fertilizer treatments applied once or repeatedly in the past, have no significant influence on adsorption or persistence of insecticides; the same is observed for the old soil organic matter, when its soil concentrations change in limited ranges PMID- 8687997 TI - Comparative inhibition of enzymes of human erythrocytes and plasma in vitro by agricultural chemicals. AB - Farm workers generally are exposed to a combination of synthetic agricultural chemicals and natural products while working in the fields. These biologically active compounds control infestation of tobacco by insects, and plant growth. We have investigated, in vitro, the effects of acephate (AP), cadmium (Cd), methamidophos (MAP), maleic hydrazide (MH), and nicotine (NI) on the activities of the erythrocyte enzymes delta-aminolevulinic acid dehydratase (ALAD), superoxide dismutase (SOD), and plasma cholinesterase (CHE). ALAD, SOD, and plasma CHE were assayed, using aminolevulinic acid, pyrogallol, or butyryl thiocholine as substrates, respectively. Different concentrations of the above chemicals were used to obtain minimum and maximum inhibition of the enzymes, and for the development of inhibition dose response curves. These curves were used to determine the concentration of each chemical required to inhibit 50% of enzyme activity (I50). The I50 concentrations of various chemicals for each enzyme were determined in mM for ALAD: AP=95.5, Cd=1.4x10(-3), MH=2.8, MAP=7.1, NI=60.8; for SOD: AP=1.2, Cd=0.8x10(-7), MH=0.04, MAP=0.42, NI=0.81; for CHE: AP=5.6, Cd=18. 8x10(-5), MAP=18.4x10(-4); CHE was not inhibited by MH and NI. Our data indicate that AP inhibited both SOD and CHE to a maximum of 91 and 87%, while MH inhibited both SOD and ALAD to a maximum 78 and 90%. However, SOD was the enzyme that was most sensitive to all the agricultural-chemicals tested in this study. The inhibition of these enzymes will enable the development of a sensitive biomarker and the assessment of long term health risks in farm workers. PMID- 8687998 TI - Lead exposure in Laysan albatross adults and chicks in Hawaii: prevalence, risk factors, and biochemical effects. AB - Prevalence of lead exposure and elevated tissue lead was determined in Laysan albatross (Diomedea immutabilis) in Hawaii. The relationship between lead exposure and proximity to buildings, between elevated blood lead and droopwing status, and elevated liver lead and presence of lead-containing paint chips in the proventriculus in albatross chicks was also examined. Finally, the effects of lead on the enzyme delta-aminolevulinic acid dehydratase (ALAD) was determined. There was a significant association between lead exposure or elevated tissue lead and proximity to buildings in albatross chicks and presence of lead paint chips in the proventriculus and elevated liver lead in carcasses. Although there was a significant association between elevated blood lead and droopwing chicks, there were notable exceptions. Prevalence of elevated tissue lead in albatross chicks was highest on Sand Island Midway and much less so on Kauai and virtually nonexistent in other areas. Prevalence of lead exposure decreased as numbers of buildings to which chicks were exposed on a given island decreased. Laysan albatross adults had minimal to no lead exposure. There was a significant negative correlation between blood lead concentration and ALAD activity in chicks. Based on ALAD activity, 0.03-0.05 microg/ml was the no effect range for blood lead in albatross chicks. PMID- 8687999 TI - Toxicity and oxidative stress of different forms of organic selenium and dietary protein in mallard ducklings. AB - Concentrations of over 100 ppm (mg/kg) selenium (Se) have been found in aquatic plants and insects associated with irrigation drainwater and toxicity to fish and wildlife. Composition of diet for wild ducklings can vary in selenium contaminated environments. Earlier studies have compared toxicities and oxidative stress of Se as selenite to those of seleno-DL-methionine (DL) in mallards (Anas platyrhynchos). This study compares DL, seleno-L-methionine (L), selenized yeast (Y) and selenized wheat (W). Day-old mallard ducklings received an untreated diet (controls) containing 75% wheat (22% protein) or the same diet containing 15 or 30 ppm Se in the above forms except for 30 ppm Se as W. After 2 weeks, blood and liver samples were collected for biochemical assays and Se analysis. All forms of selenium caused significant increases in plasma and hepatic glutathione peroxidase activities. Se as L at 30 ppm in the diet was the most toxic form, resulting in high mortality (64%) and impaired growth (>50%) in survivors and the greatest increase in ratio of oxidized to reduced hepatic glutathione (GSH). Se as both L and DL decreased the concentrations of hepatic GSH and total thiols. Se as Y accumulated the least in liver (approximately 50% of other forms) and had less effect on GSH and total thiols. In a second experiment, in which the basal diet was a commercial duck feed (22% protein), survival was not affected by 30 ppm Se as DL, L, or Y and oxidative effects on GSH metabolism were less pronounced than with the wheat diet. PMID- 8688000 TI - Effects of polyhalogenated aromatic hydrocarbons and related contaminants on common tern reproduction: integration of biological, biochemical, and chemical data. AB - In eight Dutch or Belgian common tern (Sterna hirundo) colonies, breeding biology and food choice were determined, and 15 second eggs were collected from three-egg clutches for artificial incubation, biochemical analysis and analysis of yolk-sac polyhalogenated hydrocarbon (PHAH) levels. Results from these analyses were combined with biological data from the eggs remaining in each clutch. In some breeding colonies severe flooding, rainy and cold weather, and extreme predation caused extensive losses of eggs and chicks. A relationship was found between yolksac mono-ortho polychlorinated biphenyl (mo-PCB) levels and main food species (fish or insects) of the adult terns before egg-laying. Colony average breeding data differed only slightly, and were difficult to relate to PHAH-levels. When the colonies were grouped after yolksac PHAH-patterns and main food species, significant differences in average egg laying date, incubation period, egg volume and chick weight could be related to differences in yolksac PHAH and retinoid levels, and hepatic ethoxyresorufin-O-deethylase (EROD) activity. The data from all colonies also were combined into one data-set and correlated with the biochemical parameters and PHAH levels. In summary higher yolksac PHAH levels or hepatic EROD-activity correlated with and later egg laying, prolonged incubation period and smaller eggs and chicks. Lower yolksac retinoid- and plasma thyroid hormone levels, and a higher ratio of plasma retinol over yolksac retinoids correlated with later egg laying, prolonged incubation periods and smaller chicks and eggs. The dynamic environment of the terns had more obvious detrimental effects on breeding success than PHAHs. However, the more subtle effects observed for PHAHs could still be of importance during specific stress circumstances. To monitor site-specific reproduction effects, tree-nesting birds feeding on relatively big and non-migrating fishes would be most suitable. The use of specific biomarkers for exposure and effect is recommended to establish a causal relationship between a certain class of pollutants and an adverse biological effect. PMID- 8688001 TI - Phase I and II enzymes and antioxidant responses in different tissues of brown bullheads from relatively polluted and non-polluted systems. AB - Brown bullheads (Ameiurus nebulosus) were collected from the St. Lawrence River and compared in their detoxication capacities to bullheads from a relatively non polluted aquatic system, Lac La Peche. The content of polychlorinated biphenyls (PCBs) in white muscle was significantly higher (22-fold) in bullheads from the St. Lawrence River compared with those from Lac La Peche. Activities of liver ethoxyresorufin O-deethylase (EROD), a common Phase I enzyme, were 2.8-fold higher in St. Lawrence River bullheads than in fish from La Peche. Conjugation activity by hepatic glutathione S-transferase (GST) was 3-fold higher in the St. Lawrence River fish, and significantly higher activities were also detected in kidney and white muscle in these fish as compared with the Lac La Peche group. UDP-Glucuronosyltransferase (UDPGT) activities in liver and kidney did not differ between the two groups. Activities of cytosolic superoxide dismutase (SOD) were significantly higher, while lower activities of catalase (CAT) in kidney and glutathione peroxidase (GPX) in red and white muscles were noted in the St. Lawrence River bullheads. Concentrations of total glutathione (TGSH) in the different tissues revealed significantly lower levels in liver, kidney and white muscle of bullheads from the St. Lawrence River. The changes in Phases I and II enzymes and TGSH levels in the various tissues relate to higher PCB concentrations of muscle tissue and suggest activation of detoxication capacities, but weakened antioxidant status in the bullheads from the polluted area. The results implicate the involvement of white muscle along with liver and kidney in the whole fish detoxication process. PMID- 8688002 TI - Effects of air pollution on hematological parameters in passerine birds. AB - The effects of atmospheric air pollution on some hematological, and bioquimic parameters, of passerine birds were analyzed. The studies were undertaken in the area of Cercs (polluted area in Spain), where there is a coal-fired power plant that emanates SO2, NOx, and particles, and the area of St. Jaume de Frontanya (nonpolluted area) located 40 km from the area of Cercs with similar climatology, relief, and altitude, but without air pollution. The results showed that there was a significant decrease in the erythrocyte count, and an increase in erythrocyte size in specimens from the polluted area. An increase in pre albumines and a decrease in beta-globulines in Emberiza cia was observed, while an increase in transaminases (GOT and GPT), and a decrease in weight in Turdus merula from the polluted zone was observed. PMID- 8688003 TI - Effects of air pollution on hematological and plasma parameters in Apodemus sylvaticus and Mus musculus. AB - The effects of atmospheric air pollution on some hematological and plasma parameters, activity, and food and water consumption in Apodemus sylvaticus (wood mouse) and Mus musculus (mouse) were studied. The studies were undertaken in the area of Cercs (polluted area in Spain), where there is a coal-fired power plant that emanates SO2, NOx, and particles, and the area of St. Jaume de Frontanya (nonpolluted area), located 40 km from the area of Cercs, with similar climatology, relief, and altitude, but without air pollution. Apodemus sylvaticus were captured in the field and Mus musculus were placed in cages in both studied areas. The results showed that there is a significant decrease in hematocrit, and a significant increase in leucocyte number, mean corpuscular hemoglobin concentration, osmolality, and gamma-globulin in Mus musculus, and a decrease in albumin (%) and albumin/globulin index in Apodemus sylvaticus. A negative correlation between hematocrit values and pollution was found. In mice placed in cages in the polluted area a slight but significant decrease in water and food consumption, and slower activity, was observed. The results suggest that pollution could induce a decrease in water and food consumption, which may be due to an observed reduction in activity. PMID- 8688004 TI - Characterization of Bacterial Communities from Activated Sludge: Culture Dependent Numerical Identification Versus In Situ Identification Using Group- and Genus-Specific rRNA-Targeted Oligonucleotide Probes AB - The structures of bacterial communities were studied in activated sludge samples obtained from the aerobic and anaerobic zones of a wastewater treatment plant showing enhanced phosphorous removal. Samples were analyzed by in situ hybridization with oligonucleotide probes complementary to selected regions of the 16S and 23S ribosomal RNA (rRNA) characteristic for defined phylogenetic entities (genera and larger groups). The microbial community structures revealed by molecular techniques were compared with the compositions of culturable bacterial communities, obtained from the characterization of 255 isolates from tryptone-soy (TS) agar and R2A agar. These isolates were characterized by 89 physiological tests and their cellular fatty acid patterns, and identified. Culture-dependent techniques indicated the following distribution: different Aeromonas spp. (2.7-8.3% on R2A agar; 45.0-63.7% on TS agar), Acinetobacter spp. (5.4-9.0% on R2A agar; 5.0-9.1% on TS agar), Pseudomonas spp. (up to 10% on R2A agar) and Shewanella putrefaciens (up to 3.0% on R2A agar), all members of the gamma subclass of Proteobacteria, were isolated most frequently. The relatively rare isolates of the beta subclass were identified as Acidovorax spp., Alcaligenes spp., and Comamonas spp.. The Gram-positive bacteria (high DNA G+C) were assigned mainly to Arthrobacter spp., Microbacterium spp., and Mycobacterium phlei. In order to assess the in situ abundance of the most frequently isolated genus, Aeromonas, two rRNA-targeted oligonucleotide probes were developed. The two gamma proteobacterial genera Aeromonas and Acinetobacter constituted less than 5% of all bacteria. In situ, Proteobacteria belonging to the beta subclass and high G+C Gram-positive bacteria were dominant. From filamentous bacteria, Sphaerotilus spp. and Leptothrix spp. could be detected occasionally. In addition, one sample contained a high proportion of the morphologically distinct filaments of Microthrix parvicella. PMID- 8688005 TI - Use of Cluster and Discriminant Analyses to Compare Rhizosphere Bacterial Communities Following Biological Perturbation AB - We present an approach to comparing the diversity and composition of bacterial communities from different habitats and for identifying which members of a community are most affected by an introduced bacterium. We use this method to explore both previously published and new data from field and growth chamber experiments in which we isolated heterotrophic bacteria from samples of root-free soil, roots of nontreated soybean seedlings, and from the roots of soybean seedlings grown from Bacillus cereus UW85n1-treated seeds. We characterize bacterial isolates for 40 physiological attributes, and grouped the isolates hierarchically using two-stage density-linkage cluster analysis. Multivariate analysis of variance and discriminant analysis of the relative frequencies of the clusters in the soil and rhizosphere habitats were then used to determine whether there were differences among the bacterial communities from the various habitats, and which of the clusters were most useful in discriminating among the communities. We used rarefied estimates of richness as a measure of community diversity in the various habitats. Introduction of UW85n1 affected the composition and/or diversity of rhizosphere communities in three of four experiments. PMID- 8688007 TI - Effects of Toluene on Microbially-Mediated Processes Involved in the Soil Nitrogen Cycle AB - The effects of toluene on indigenous microbial populations involved in the soil nitrogen cycle were examined. Ammonia oxidation potential (AOP) and nitrite oxidation potential (NOP) were both reduced after incubation with high toluene concentrations for 45 days, with the former activity showing greater sensitivity. KCl-extractable ammonium (NH4+ext) levels increased dramatically in soil exposed to high toluene levels, and arginine ammonification was not significantly affected. Alfalfa-amended soil incubated in the presence of 200 &mgr;g toluene ml 1 showed progressive accumulation of NH4+ext over 37 days, indicating that mineralization of plant-associated nitrogen was not hindered by toluene. AOP in treated soil was much less than in control soil on days 7 and 37, but the MPN of ammonia oxidizers in control and exposed soil were not significantly different. Soil incubated with 100 &mgr;g toluene ml-1for 28 days, vented and allowed to incubate for an additional 7 to 30 days, exhibited only slight increases in AOP and NOP, while NH4+ext returned to control levels within a week. Soil exposed to 200 &mgr;g toluene ml-1 and treated in the same manner showed no increases in either AOP or NOP, and NH4+extremained elevated for the duration of the experiment, indicating more long-term effects on soil nitrogen cycling had occurred. Ammonia oxidizer levels in control soil and soil incubated with 100 &mgr;g toluene ml-1 were not appreciably different, whereas levels of ammonia oxidizers were very low in soil exposed to 200 &mgr;g toluene ml-1 and increased only slightly by 30 days post vent. Experiments to determine how toluene affects the AOP of soil indicated a competitive inhibition mechanism, with an effective concentration causing 50% reduction in activity (EC50) of 11 &mgr;M toluene, and a competitive inhibition constant (Ki) of 0.1± 0.05 &mgr;M toluene. These results indicate the potential for toluene to adversely impact nitrogen cycling in the terrestrial ecosystem by affecting indigenous soil nitrifiers, which are sensitive to lower levels of toluene than has been previously reported. PMID- 8688008 TI - Bacterioplankton Production Determined by DNA Synthesis, Protein Synthesis, and Frequency of Dividing Cells in Tuamotu Atoll Lagoons and Surrounding Ocean AB - This study compares three independent methods used for estimating bacterioplankton production in waters from the lagoon (mesotrophic) and the surrounding ocean (oligotrophic) of two atolls from the Tuamotu archipelago (French Polynesia).Thymidine and leucine incorporation were calibrated in dilution cultures and gave consistent results when the first was calibrated against cell multiplication and the second against protein synthesis. This study demonstrates that determining conversion factors strongly depends on the selected calculation method (modified derivative, integrative, and cumulative). These different estimates are reconciled when the very low proportion of active cells is accounted for.Frequency of dividing-divided cells (FDDC) calibrated using the same dilution cultures led to unrealistically high estimates of bacterial production. However, highly significant correlations between FDDC and either thymidine- or leucine-specific incorporation per cell were found in lagoon waters in situ. These correlations became more positive when oceanic data were added. This suggests that the FDDC method is also potentially valid to determine bacterioplankton growth rates after cross calibration with thymidine or leucine methods. If recommended precautions are observed, the three methods tested in the present study would give reliable production estimates. PMID- 8688006 TI - Surface Properties and Motility of Rhizobium and Azospirillum in Relation to Plant Root Attachment AB - Plant growth promotion by rhizobacteria is a widely spread phenomenon. However only a few rhizobacteria have been studied thoroughly. Rhizobium is the best studied rhizobacterium. It forms a symbiosis with a restricted host range. Azospirillum is another plant-growth-promoting rhizobacterium which forms rhizocoenoses with a wide range of plants. In both bacteria, the interaction with the plant involves the attraction toward the host plant and the attachment to the surface of the root. Both bacteria are attracted to plant roots, but differ in specificity. Attachment to plant roots occurs in two steps for both bacteria: a quick, reversible adsorption, and a slow, irreversible anchoring to the plant root surface. However, for the two systems under study, the bacterial surface molecules involved in plant root attachment are not necessarily the same. PMID- 8688054 TI - Colossal Magnetoresistance Without Mn3+/Mn4+ Double Exchange in the Stoichiometric Pyrochlore Tl2Mn2O7 AB - Structural analysis from powder neutron and single-crystal x-ray diffraction data for a sample of the Tl2Mn2O7 pyrochlore, which exhibits colossal magnetoresistance (CMR), shows no deviations from ideal stoichiometry. This analysis gives an Mn-O distance of 1.90 angstroms, which is significantly shorter than the Mn-O distances (1.94 to 2.00 angstroms) observed in phases based on LaMnO3 perovskites that exhibit CMR. Both results in Tl2Mn2O7 indicate oxidation states very close to Tl23+Mn24+O7. Thus, Tl2Mn2O7 has neither mixed valence for a double-exchange magnetic interaction nor a Jahn-Teller cation such as Mn3+, both of which were thought to have an important function in CMR materials. An alternate mechanism for CMR in Tl2Mn2O7 based on magnetic ordering driven by superexchange and strong spin-fluctuation scattering above the Curie temperature is proposed here. PMID- 8688055 TI - Direct, Nondestructive Observation of a Bose Condensate AB - The spatial observation of a Bose condensate is reported. Dispersive light scattering was used to observe the separation between the condensed and normal components of the Bose gas inside a magnetic trap. This technique is nondestructive, and about a hundred images of the same condensate can be taken. The width of the angular distribution of scattered light increased suddenly at the phase transition. PMID- 8688009 TI - Ecology of Legionella: From Data to Knowledge with a Little Wisdom AB - The respiratory diseases produced by the Legionella genus of bacteria are collectively called Legionellosis. Presently more than 34 species of Legionella have been identified, 20 of which have been isolated from both environmental and clinical sources. The diseases produced by Legionella include the pneumonic form, Legionnaires' disease, and the flu-like form, Pontiac fever. Because the vast majority of Legionellosis is caused by the L. pneumophila species, this bacterium is the thrust of the discussion.Legionella is a global bacterium. The relationship of the bacterium to its environment has told us many things about infectious diseases. Not until Legionellosis and the discovery of its etiologic agent, Legionella, has such a successful modern-day marriage been consummated between the agent and its environment. Nearly two decades have passed since the term Legionellosis found its way into the vocabulary of the scientific journals, the popular press, and courtroom proceedings. Too often the scientific development, engineering implementation, and societal acceptance are disconnected. The focus of scientific research sometimes does not reflect engineering or societal needs and thus contributes little to the solution of immediate and important problems. At other times, scientific knowledge that could contribute to solutions is overlooked because of poor communication between the problem holders, the scientific community, regulatory agencies, the problem makers, and the public. The scope of this paper provides insights on the ecological niche of Legionella, describes the organism's ecological relationships in the natural world, and provides wisdom for effective control of the bacterium for the industrial and user communities. PMID- 8688056 TI - Homogeneous Linewidths in the Optical Spectrum of a Single Gallium Arsenide Quantum Dot AB - The homogeneous linewidths in the photoluminescence excitation spectrum of a single, naturally formed gallium arsenide (GaAs) quantum dot have been measured with high spatial and spectral resolution. The energies and linewidths of the homogeneous spectrum provide a new perspective on the dephasing dynamics of the exciton in a quantum-confined, solid-state system. The origins of the linewidths are discussed in terms of the dynamics of the exciton in zero dimensions, in particular, in terms of lifetime broadening through the emission or absorption of phonons and photons. PMID- 8688057 TI - Two Calorimetrically Distinct States of Liquid Water Below 150 Kelvin AB - Vapor-deposited amorphous solid and hyperquenched glassy water were found to irreversibly transform, on compression at 77 kelvin, to a high-density amorphous solid. On heating at atmospheric pressure, this solid became viscous water (water B), with a reversible glass-liquid transition onset at 129 +/- 2 kelvin. A different form of viscous water (water A) was formed by heating the uncompressed vapor-deposited amorphous solid and hyperquenched liquid water. On thermal cycling up to 148 kelvin, water B remained kinetically and thermodynamically distinct from water A. The occurrence of these two states, which do not interconvert, helps explain both the configurational relaxation of water and stress-induced amorphization. PMID- 8688058 TI - Helium Isotopic Evidence for a Lower Mantle Component in Depleted Archean Komatiite AB - Archean magnesium-rich komatiites require hot and presumably deep mantle sources, but their trace-element composition and radiogenic isotope composition are similar to those of modern mid-ocean ridge basalts, which originate in the upper mantle. The isotopic composition of helium extracted by sequential crushing of fresh olivines separated from two Archean and one mid-Proterozoic komatiites varies over three orders of magnitude, between a radiogenic end-member rich in helium-4 and a component rich in helium-3. Such helium-3 enrichment suggests the presence of a lower mantle component in Archean komatiites. PMID- 8688059 TI - Transition Element-Like Chemistry for Potassium Under Pressure AB - At high pressure the alkali metals potassium, rubidium, and cesium transform to metals that have a d1 electron configuration, becoming transition metal-like. As a result, compounds were shown to form between potassium and the transition metal nickel. These results demonstrate that the chemical behavior of the alkali metals under pressure is very different from that under ambient conditions, where alkali metals and transition metals do not react because of large differences in size and electronic structure. They also have significant implications for the hypothesis that potassium is incorporated into Earth's core. PMID- 8688060 TI - Detrital Zircon Link Between Headwaters and Terminus of the Upper Triassic Chinle Dockum Paleoriver System AB - New detrital-zircon geochronologic data reveal that a through-going paleoriver connected Texas with Nevada in Late Triassic time. Sandstone from the Upper Triassic Santa Rosa Sandstone (Dockum Group) from northwestern Texas contains a detrital zircon suite nearly identical to that found in western Nevada in the Upper Triassic Osobb Formation (Auld Lang Syne Group, correlative with the Chinle Formation). The Santa Rosa Sandstone was derived in large part from the eroded Cambrian core of the Amarillo-Wichita uplift, as evidenced by abundant zircons with ages of 515 to 525 million years. Other zircon grains in the sandstone are Permian, Devonian, Proterozoic, and Archean in age and, with the exception of the Archean grain, are also matched by the population in the Nevada strata. PMID- 8688061 TI - Late Proterozoic and Paleozoic Tides, Retreat of the Moon, and Rotation of the Earth AB - The tidal rhythmites in the Proterozoic Big Cottonwood Formation (Utah, United States), the Neoproterozoic Elatina Formation of the Flinders Range (southern Australia), and the Lower Pennsylvanian Pottsville Formation (Alabama, United States) and Mansfield Formation (Indiana, United States) indicate that the rate of retreat of the lunar orbit is dxi/dt approximately k2 sin(2delta) (where xi is the Earth-moon radius vector, k2 is the tidal Love number, and delta is the tidal lag angle) and that this rate has been approximately constant since the late Precambrian. When the contribution to tidal friction from the sun is taken into account, these data imply that the length of the terrestrial day 900 million years ago was approximately18 hours. PMID- 8688062 TI - Organic Electroluminescent Devices AB - Electroluminescence from organic materials has the potential to enable low-cost, full-color flat-panel displays, as well as other emissive products. Some materials have now demonstrated adequate efficiencies (1 to 15 lumens/watt) and lifetimes (>5000 hours) for practical use; however, the factors that govern lifetime remain poorly understood. This article provides a brief review of device principles and applications requirements and focuses on the understanding of reliability issues. PMID- 8688063 TI - New Routes in the Preparation of Mechanically Hard Films AB - Superhard nitride superlattice coatings with nanometer-scale multilayers have hardnesses exceeding 50 gigapascals, making these films highly resistant to abrasion. The nitride superlattice films can be deposited economically by reactive sputtering in production-size equipment on a variety of substrates. A model for the superlattice strength enhancement has been developed that accurately predicts which materials can be used together to produce the enhanced hardness. Advancements in sputtering technology-specifically, pulsed dc power and reactive-gas partial-pressure control-make it possible to reactively deposit nonconducting oxide films at high deposition rates. This technology is being used along with the superlattice strength model in the development of oxide superlattice films. PMID- 8688064 TI - Biomimetic Pathways for Assembling Inorganic Thin Films AB - Living organisms construct various forms of laminated nanocomposites through directed nucleation and growth of inorganics at self-assembled organic templates at temperatures below 100°C and in aqueous solutions. Recent research has focused on the use of functionalized organic surfaces to form continuous thin films of single-phase ceramics. Continuous thin films of mesostructured silicates have also been formed on hydrophobic and hydrophilic surfaces through a two-step mechanism. First, under acidic conditions, surfactant micellar structures are self-assembled at the solid/liquid interface, and second, inorganic precursors condense to form an inorganic-organic nanocomposite. Epitaxial coordination of adsorbed surfactant tubules is observed on mica and graphite substrates, whereas a random arrangement is observed on amorphous silica. The ability to process ceramic-organic nanocomposite films by these methods provides new technological opportunities. PMID- 8688065 TI - Synthesis of Novel Thin-Film Materials by Pulsed Laser Deposition AB - Pulsed laser deposition (PLD) is a conceptually and experimentally simple yet highly versatile tool for thin-film and multilayer research. Its advantages for the film growth of oxides and other chemically complex materials include stoichiometric transfer, growth from an energetic beam, reactive deposition, and inherent simplicity for the growth of multilayered structures. With the use of PLD, artificially layered materials and metastable phases have been created and their properties varied by control of the layer thicknesses. In situ monitoring techniques have provided information about the role of energetic species in the formation of ultrahard phases and in the doping of semiconductors. Cluster assembled nanocrystalline and composite films offer opportunities to control and produce new combinations of properties with PLD. PMID- 8688066 TI - Chemical Solution Routes to Single-Crystal Thin Films AB - Epitaxial thin films of inorganic single crystals can be grown on single-crystal substrates with a variety of different solution chemistries. This review emphasizes chemical solution deposition, in which a solution is used to deposit a layer of precursor molecules that decompose to low-density, polycrystalline films during heating. Ways to control film cracking during deposition and heat treatment and why many precursors synthesize metastable crystalline structures are discussed, and the different mechanisms that convert the polycrystalline film into a single crystal are reviewed. Hydrothermal epitaxy, in which single crystal thin films are directly synthesized on templating substrates in an aqueous solution at temperatures <150°C, is also discussed. PMID- 8688067 TI - Device Applications of Side-Chain Ferroelectric Liquid Crystalline Polymer Films AB - Side-chain ferroelectric liquid crystalline polymers are currently used in a number of applications, including displays and electrical sensors. Comparisons with existing technologies and materials indicate that relative to ceramics, such polymers have lower figures of merit but offer greater durability in sensor applications. PMID- 8688068 TI - Structure in Thin and Ultrathin Spin-Cast Polymer Films AB - The molecular organization in ultrathin polymer films (thicknesses less than 1000 angstroms) and thin polymer films (thicknesses between 1000 and 10,000 angstroms) may differ substantially from that of bulk polymers, which can lead to important differences in resulting thermophysical properties. Such constrained geometry films have been fabricated from amorphous poly(3-methyl-4-hydroxy styrene) (PMHS) and semicrystalline poly(di-n-hexyl silane) (PD6S) by means of spin-casting. The residual solvent content is substantially greater in ultrathin PMHS films, which suggests a higher glass transition temperature that results from a stronger hydrogen-bonded network as compared with that in thicker films. Crystallization of PD6S is substantially hindered in ultrathin films, in which a critical thickness of 150 angstroms is needed for crystalline morphology to exist and in which the rate of crystallization is initially slow but increases rapidly as the film approaches 500 angstroms in thickness. PMID- 8688070 TI - Local Control of Microdomain Orientation in Diblock Copolymer Thin Films with Electric Fields AB - Local control of the domain orientation in diblock copolymer thin films can be obtained by the application of electric fields on micrometer-length scales. Thin films of an asymmetric polystyrene-polymethylmethacrylate diblock copolymer, with cylindrical polymethylmethacrylate microdomains, were spin-coated onto substrates previously patterned with planar electrodes. The substrates, 100-nanometer-thick silicon nitride membranes, allow direct observation of the electrodes and the copolymer domain structure by transmission electron microscopy. The cylinders aligned parallel to the electric field lines for fields exceeding 30 kilovolts per centimeter, after annealing at 250°C in an inert atmosphere for 24 hours. This technique could find application in nanostructure fabrication. PMID- 8688069 TI - Search for past life on Mars: possible relic biogenic activity in martian meteorite ALH84001. AB - Fresh fracture surfaces of the martian meteorite ALH84001 contain abundant polycyclic aromatic hydrocarbons (PAHs). These fresh fracture surfaces also display carbonate globules. Contamination studies suggest that the PAHs are indigenous to the meteorite. High-resolution scanning and transmission electron microscopy study of surface textures and internal structures of selected carbonate globules show that the globules contain fine-grained, secondary phases of single-domain magnetite and Fe-sulfides. The carbonate globules are similar in texture and size to some terrestrial bacterially induced carbonate precipitates. Although inorganic formation is possible, formation of the globules by biogenic processes could explain many of the observed features, including the PAHs. The PAHs, the carbonate globules, and their associated secondary mineral phases and textures could thus be fossil remains of a past martian biota. PMID- 8688071 TI - Biomembrane templates for nanoscale conduits and networks. AB - Long nanotubes of fluid-lipid bilayers can be used to create templates for photochemical polymerization into solid-phase conduits and networks. Each nanotube is pulled from a micropipette-held feeder vesicle by mechanical retraction of the vesicle after molecular bonding to a rigid substrate. The caliber of the tube is controlled precisely in a range from 20 to 200 nanometers merely by setting the suction pressure in the micropipette. Branched conduits can be formed by coalescing separate nanotubes drawn serially from the feeder vesicle surface. Single nanotubes and nanotube junctions can be linked together between bonding sites on a surface to create a functionalized network. After assembly, the templates can be stabilized by photoinitiated radical cross-linking of macromonomers contained in the aqueous solution confined by the lipid bilayer boundary. PMID- 8688073 TI - Short-Period Comets: Primordial Bodies or Collisional Fragments? AB - Modeling results show that collisions among Edgeworth-Kuiper Belt Objects (EKOs), a vast swarm of small bodies orbiting beyond Neptune, have been a major process affecting this population and its progeny, the short-period comets. Most EKOs larger than about 100 kilometers in diameter survive over the age of the solar system, but at smaller sizes collisional breakup is frequent, producing a cascade of fragments having a power law size-frequency distribution. Collisions are also a plausible mechanism for injecting EKOs 1 to 10 kilometers in diameter into dynamical resonances, where they can be transported into the inner solar system to become short-period comets. The fragmental nature of these comets may explain their physical properties, such as shape, color, and strength. PMID- 8688072 TI - Metallization and electrical conductivity of hydrogen in Jupiter. AB - Electrical conductivities of molecular hydrogen in Jupiter were calculated by scaling electrical conductivities measured at shock pressures in the range of 10 to 180 gigapascals (0.1 to 1.8 megabars) and temperatures to 4000 kelvin, representative of conditions inside Jupiter. Jupiter's magnetic field is caused by convective dynamo motion of electrically conducting fluid hydrogen. The data imply that Jupiter should become metallic at 140 gigapascals in the fluid, and the electrical conductivity in the jovian molecular envelope at pressures up to metallization is about an order of magnitude larger than expected previously. The large magnetic field is produced in the molecular envelope closer to the surface than previously thought. PMID- 8688074 TI - Penetrative Convection and Zonal Flow on Jupiter AB - Measurements by the Galileo probe support the possibility that the zonal winds in Jupiter's atmosphere originate from convection that takes place in the deep hydrogen-helium interior. However, according to models based on recent opacity data and the probe's temperature measurements, there may be radiative and nonconvective layers in the outer part of the jovian interior, raising the question of how deep convection could extend to the surface. A theoretical model is presented to demonstrate that, because of predominant rotational effects and spherical geometry, thermal convection in the deep jovian interior can penetrate into any outer nonconvective layer. These penetrative convection rolls interact nonlinearly and efficiently in the model to generate and sustain a mean zonal wind with a larger amplitude than that of the nonaxisymmetric penetrative convective motions, a characteristic of the wind field observed at the cloud level on Jupiter. PMID- 8688075 TI - An Archean Geomagnetic Reversal in the Kaap Valley Pluton, South Africa AB - The Kaap Valley pluton in South Africa is a tonalite intrusion associated with the Archean Barberton Greenstone Belt. Antipodal paleomagnetic directions determined from the central and marginal parts of the pluton record a geomagnetic reversal that occurred as the pluton cooled. The age of the reversal is constrained by an 40Ar/39Ar plateau age from hornblende at 3214 +/- 4 million years, making it the oldest known reversal. The data presented here suggest that Earth has had a reversing, perhaps dipolar, magnetic field since at least 3.2 billion years ago. PMID- 8688076 TI - Spectral Properties of Near-Earth Asteroids: Evidence for Sources of Ordinary Chondrite Meteorites AB - Although ordinary chondrite (OC) meteorites dominate observed falls, the identification of near-Earth and main-belt asteroid sources has remained elusive. Telescopic measurements of 35 near-Earth asteroids ( approximately3 kilometers in diameter) revealed six that have visible wavelength spectra similar to laboratory spectra of OC meteorites. Near-Earth asteroids were found to have spectral properties that span the range between the previously separated domains of OC meteorites and the most common (S class) asteroids, suggesting a link. This range of spectral properties could arise through a diversity of mineralogies and regolith particle sizes, as well as through a time-dependent surface weathering process. PMID- 8688077 TI - Arabidopsis AUX1 gene: a permease-like regulator of root gravitropism. AB - The plant hormone auxin regulates various developmental processes including root formation, vascular development, and gravitropism. Mutations within the AUX1 gene confer an auxin-resistant root growth phenotype and abolish root gravitropic curvature. Polypeptide sequence similarity to amino acid permeases suggests that AUX1 mediates the transport of an amino acid-like signaling molecule. Indole-3 acetic acid, the major form of auxin in higher plants, is structurally similar to tryptophan and is a likely substrate for the AUX1 gene product. The cloned AUX1 gene can restore the auxin-responsiveness of transgenic aux1 roots. Spatially, AUX1 is expressed in root apical tissues that regulate root gravitropic curvature. PMID- 8688078 TI - Exclusion of Int-6 from PML nuclear bodies by binding to the HTLV-I Tax oncoprotein. AB - The Tax transactivator of the human T cell leukemia virus type I (HTLV-I) exhibits oncogenic properties. A screen for proteins interacting with Tax yielded a complementary DNA (cDNA) encoding the human Int-6 protein. In mice, the Int-6 gene can be converted into a putative dominant negative oncogene after retroviral insertion. Here, Int-6 was localized in the cell nucleus to give a speckled staining pattern superposed to that of the promyelocytic leukemia (PML) protein. The binding of Tax to Int-6 caused its redistribution from the nuclear domains to the cytoplasm. Thus, Int-6 is a component of the PML nuclear bodies and Tax disrupts its normal cellular localization by binding to it. PMID- 8688079 TI - Activation of the budding yeast spindle assembly checkpoint without mitotic spindle disruption. AB - The spindle assembly checkpoint keeps cells with defective spindles from initiating chromosome segregation. The protein kinase Mps1 phosphorylates the yeast protein Mad1p when this checkpoint is activated, and the overexpression of Mps1p induces modification of Mad1p and arrests wild-type yeast cells in mitosis with morphologically normal spindles. Spindle assembly checkpoint mutants overexpressing Mps1p pass through mitosis without delay and can produce viable progeny, which demonstrates that the arrest of wild-type cells results from inappropriate activation of the checkpoint in cells whose spindle is fully functional. Ectopic activation of cell-cycle checkpoints might be used to exploit the differences in checkpoint status between normal and tumor cells and thus improve the selectivity of chemotherapy. PMID- 8688080 TI - Regulation of cardiac Na+,Ca2+ exchange and KATP potassium channels by PIP2. AB - Cardiac Na+,Ca2+ exchange is activated by a mechanism that requires hydrolysis of adenosine triphosphate (ATP) but is not mediated by protein kinases. In giant cardiac membrane patches, ATP acted to generate phosphatidylinositol-4,5 bisphosphate (PIP2) from phosphatidylinositol (PI). The action of ATP was abolished by a PI-specific phospholipase C (PLC) and recovered after addition of exogenous PI; it was reversed by a PIP2-specific PLC; and it was mimicked by exogenous PIP2. High concentrations of free Ca2+ (5 to 20 microM) accelerated reversal of the ATP effect, and PLC activity in myocyte membranes was activated with a similar Ca2+ dependence. Aluminum reversed the ATP effect by binding with high affinity to PIP2. ATP-inhibited potassium channels (KATP) were also sensitive to PIP2, whereas Na+,K+ pumps and Na+ channels were not. Thus, PIP2 may be an important regulator of both ion transporters and channels. PMID- 8688082 TI - Control of MHC restriction by TCR Valpha CDR1 and CDR2. AB - Individual T cell receptor (TCR) Valpha elements are expressed preferentially in CD4 or CD8 peripheral T cell subsets. The closely related Valpha3.1 and Valpha3.2 elements show reciprocal selection into CD4 and CD8 subsets, respectively. Transgenic mice expressing site-directed mutants of a Valpha3.1 gene were used to show that individual residues in either the complementarity-determining region 1 (CDR1) or CDR2 were sufficient to change selection from the CD4 subset to the CD8 subset. Thus, the germline-encoded Valpha elements are a major influence on major histocompatibility class complex (MHC) restriction, most likely by a preferential interaction with one or the other class of MHC molecule. PMID- 8688081 TI - Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor regulated CREB kinase. AB - A signaling pathway has been elucidated whereby growth factors activate the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB), a critical regulator of immediate early gene transcription. Growth factor-stimulated CREB phosphorylation at serine-133 is mediated by the RAS-mitogen-activated protein kinase (MAPK) pathway. MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90(RSK) family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression. PMID- 8688083 TI - Protection against atherogenesis in mice mediated by human apolipoprotein A-IV. AB - Apolipoproteins are protein constituents of plasma lipid transport particles. Human apolipoprotein A-IV (apoA-IV) was expressed in the liver of C57BL/6 mice and mice deficient in apoE, both of which are prone to atherosclerosis, to investigate whether apoA-IV protects against this disease. In transgenic C57BL/6 mice on an atherogenic diet, the serum concentration of high density lipoprotein (HDL) cholesterol increased by 35 percent, whereas the concentration of endogenous apoA-I decreased by 29 percent, relative to those in transgenic mice on a normal diet. Expression of human apoA-IV in apoE-deficient mice on a normal diet resulted in an even more severe atherogenic lipoprotein profile, without affecting the concentration of HDL cholesterol, than that in nontransgenic apoE deficient mice. However, transgenic mice of both backgrounds showed a substantial reduction in the size of atherosclerotic lesions. Thus, apoA-IV appears to protect against atherosclerosis by a mechanism that does not involve an increase in HDL cholesterol concentration. PMID- 8688084 TI - Cure of short- and long-term experimental Chagas' disease using D0870. AB - Chagas' disease, a protozoan infection by the kinetoplastid Trypanosoma cruzi, constitutes a major public health problem in Latin America. With the use of mouse models of both short- and long-term forms of the disease, the efficacy of D0870, a bis-triazole derivative, was tested. D0870 was able to prevent death and induced parasitological cure in 70 to 90 percent of animals, in both the short- and long-term disease. In contrast, currently used drugs such as nifurtimox or ketoconazole prolonged survival but did not induce significant curing effects. D0870 may be useful in the treatment of human long-term Chagas' disease, a condition that is currently incurable. PMID- 8688085 TI - Auditory neurophysiologic responses and discrimination deficits in children with learning problems. AB - Children with learning problems often cannot discriminate rapid acoustic changes that occur in speech. In this study of normal children and children with learning problems, impaired behavioral discrimination of a rapid speech change (/dalpha/versus/galpha/) was correlated with diminished magnitude of an electrophysiologic measure that is not dependent on attention or a voluntary response. The ability of children with learning problems to discriminate another rapid speech change (/balpha/versus/walpha/) also was reflected in the neurophysiology. These results indicate that some children's discrimination deficits originate in the auditory pathway before conscious perception and have implications for differential diagnosis and targeted therapeutic strategies for children with learning disabilities and attention disorders. PMID- 8688088 TI - Universal Quantum Simulators AB - Feynman's 1982 conjecture, that quantum computers can be programmed to simulate any local quantum system, is shown to be correct. PMID- 8688086 TI - A receptor in pituitary and hypothalamus that functions in growth hormone release. AB - Small synthetic molecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to stimulate and amplify pulsatile growth hormone (GH) release. A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs. On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone. PMID- 8688089 TI - A crosslinked cofactor in lysyl oxidase: redox function for amino acid side chains. AB - A previously unknown redox cofactor has been identified in the active site of lysyl oxidase from the bovine aorta. Edman sequencing, mass spectrometry, ultraviolet-visible spectra, and resonance Raman studies showed that this cofactor is a quinone. Its structure is derived from the crosslinking of the epsilon-amino group of a peptidyl lysine with the modified side chain of a tyrosyl residue, and it has been designated lysine tyrosylquinone. This quinone appears to be the only example of a mammalian cofactor formed from the crosslinking of two amino acid side chains. This discovery expands the range of known quino-cofactor structures and has implications for the mechanism of their biogenesis. PMID- 8688090 TI - Evidence for supersonic turbulence in the upper atmosphere of Jupiter. AB - Spectra of the hydrogen Lyman alpha (Ly-alpha) emission line profiles of the jovian dayglow, obtained by the Goddard High Resolution Spectrograph on the Hubble Space Telescope, appear complex and variable on time scales of a few minutes. Dramatic changes occur in the Ly-alpha bulge region at low latitudes, where the line profiles exhibit structures that correspond to supersonic velocities of the order of several to tens of kilometers per second. This behavior, unexpected in a planetary atmosphere, is evidence for the particularly stormy jovian upper atmosphere, not unlike a star's atmosphere. PMID- 8688087 TI - Complete genome sequence of the methanogenic archaeon, Methanococcus jannaschii. AB - The complete 1.66-megabase pair genome sequence of an autotrophic archaeon, Methanococcus jannaschii, and its 58- and 16-kilobase pair extrachromosomal elements have been determined by whole-genome random sequencing. A total of 1738 predicted protein-coding genes were identified; however, only a minority of these (38 percent) could be assigned a putative cellular role with high confidence. Although the majority of genes related to energy production, cell division, and metabolism in M. jannaschii are most similar to those found in Bacteria, most of the genes involved in transcription, translation, and replication in M. jannaschii are more similar to those found in Eukaryotes. PMID- 8688091 TI - Rapid Variations in Atmospheric Methane Concentration During the Past 110,000 Years AB - A methane record from the GISP2 ice core reveals that millennial-scale variations in atmospheric methane concentration characterized much of the past 110,00 years. As previously observed in a shorter record from central Greenland, abrupt concentration shifts of about 50 to 300 parts per billion by volume were coeval with most of the interstadial warming events (better known as Dansgaard-Oeschger events) recorded in the GISP2 ice core throughout the last glacial period. The magnitude of the rapid concentration shifts varied on a longer time scale in a manner consistent with variations in Northern Hemisphere summer insolation, which suggests that insolation may have modulated the effects of interstadial climate change on the terrestrial biosphere. PMID- 8688092 TI - Late Pleistocene Desiccation of Lake Victoria and Rapid Evolution of Cichlid Fishes AB - Lake Victoria is the largest lake in Africa and harbors more than 300 endemic species of haplochromine cichlid fish. Seismic reflection profiles and piston cores show that the lake not only was at a low stand but dried up completely during the Late Pleistocene, before 12,400 carbon-14 years before the present. These results imply that the rate of speciation of cichlid fish in this tropical lake has been extremely rapid. PMID- 8688093 TI - Simultaneous Measurement of Local Gain and Electron Density in X-ray Lasers AB - X-ray lasers (XRLs) have experimental average gains that are significantly less than calculated values and a persistently low level of spatial coherence. An XRL has been used both as an injected signal to a short XRL amplifier and as an interferometer beam to measure two-dimensional local gain and density profiles of the XRL plasma with a resolution near 1 micrometer. The measured local gain is in agreement with atomic models but is unexpectedly spatially inhomogeneous. This inhomogeneity is responsible for the low level of spatial coherence observed and helps explain the disparity between observed and simulated gains. PMID- 8688094 TI - BTK as a mediator of radiation-induced apoptosis in DT-40 lymphoma B cells. AB - Bruton's tyrosine kinase (BTK) is a member of the SRC-related TEC family of protein tyrosine kinases (PTKs). DT-40 lymphoma B cells, rendered BTK-deficient through targeted disruption of the btk gene by homologous recombination knockout, did not undergo radiation-induced apoptosis, but cells with disrupted lyn or syk genes did. Introduction of the wild-type, or a SRC homology 2 domain or a plecstrin homology domain mutant (but not a kinase domain mutant), human btk gene into BTK-deficient cells restored the apoptotic response to radiation. Thus, BTK is the PTK responsible for triggering radiation-induced apoptosis of lymphoma B cells, and its kinase domain is indispensable for the apoptotic response. PMID- 8688095 TI - Corticofugal modulation of time-domain processing of biosonar information in bats. AB - The Jamaican mustached bat has delay-tuned neurons in the inferior colliculus, medial geniculate body, and auditory cortex. The responses of these neurons to an echo are facilitated by a biosonar pulse emitted by the bat when the echo returns with a particular delay from a target located at a particular distance. Electrical stimulation of cortical delay-tuned neurons increases the delay-tuned responses of collicular neurons tuned to the same echo delay as the cortical neurons and decreases those of collicular neurons tuned to different echo delays. Cortical neurons improve information processing in the inferior colliculus by way of the corticocollicular projection. PMID- 8688096 TI - The representation of brightness in primary visual cortex. AB - Although neurons in primary visual cortex are sensitive to the spatial distribution and intensity of light, their responses have not been thought to correlate with the perception of brightness. Indeed, primary visual cortex is often described as an initial processing stage that sends information to higher cortical areas where perception of brightness, color, and form occurs. However, a significant percentage of neurons in primary visual cortex were shown to respond in a manner correlated with perceived brightness, rather than responding strictly to the light level in the receptive fields of the cells. This finding suggests that even at the first stage of visual cortical processing, spatial integration of information yields perceptual qualities that are only indirectly related to the pattern of illumination of the retina. PMID- 8688097 TI - Pilus assembly by Agrobacterium T-DNA transfer genes. AB - Agrobacterium tumefaciens can genetically transform eukaryotic cells. In many bacteria, pili are required for interbacterial DNA transfer. The formation of pili by Agrobacterium required induction of tumor-inducing (Ti) plasmid-encoded virulence genes and growth at low temperature. A genetic analysis demonstrated that virA, virG, virB1 through virB11, and virD4 are the only Ti plasmid genes necessary for pilus assembly. The loss and gain of pili in various mutants correlated with the loss and gain of transferred DNA (T-DNA) transfer functions, which is consistent with the view that Agrobacterium pili are required for transfer of DNA to plant cells in a process similar to that of conjugation. PMID- 8688098 TI - Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. AB - It is proposed here that the delayed cytotoxicity of thioguanine involves the postreplicative DNA mismatch repair system. After incorporation into DNA, the thioguanine is chemically methylated by S-adenosylmethionine to form S6 methylthioguanine. During DNA replication, the S6-methylthioguanine directs incorporation of either thymine or cytosine into the growing DNA strand, and the resultant S6-methylthioguanine-thymine pairs are recognized by the postreplicative mismatch repair system. Azathioprine, an immunosuppressant used in organ transplantation, is partly converted to thioguanine. Because the carcinogenicity of N-nitrosamines depends on formation of O6-alkylguanine in DNA, the formation of the analog S6-methylthioguanine during azathioprine treatment may partly explain the high incidence of cancer after transplantation. PMID- 8688099 TI - Selective activation of calcium permeability by aspartate in Purkinje cells. AB - Glutamate and aspartate are endogenous excitatory amino acid neurotransmitters widely distributed in the mammalian central nervous system. Aspartate was shown to induce a large membrane current sensitive to N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists in Purkinje cells from mice lacking functional NMDA receptors (NR1(-/-)). This response was accompanied by high permeability to calcium. In contrast, no current was induced by aspartate in hippocampal neurons and cerebellar granule cells from NR1(-/-) mice. Several other glutamate receptor agonists failed to evoke this response. Thus, in Purkinje cells, aspartate activates a distinct response capable of contributing to synaptic plasticity through calcium permeability. PMID- 8688100 TI - Fetal polycystic kidney disease associated with glutaric aciduria type II: an inborn error of energy metabolism. AB - The findings of hyperechoic and enlarged fetal kidneys on routine antenatal ultrasonography is a non-specific finding that alerts the physician to a differential diagnosis of various genetic and non-genetic disorders, including fetal polycystic disease and Beckwith-Wiedeman syndrome. Detection of fetal or neonatal polycystic kidneys should alert the physician to the possibility of an associated lethal autosomal recessive inborn error of fatty acid metabolism known as multiple acyl-CoA-dehydrogenase defect (MADD). We report a case of fetal nephromegaly associated with rare inborn error of MADD. This case highlights the need for appropriate laboratory investigation of hyperechoic, enlarged fetal kidneys, and neonatal polycystic disease. The association of MADD with postnatally diagnosed polycystic disease of the kidney has been reported. The antenatal detection of nephromegaly followed by the subsequent postnatal diagnosis of MADD has not been previously reported. MADD should be considered in the differential diagnosis of this antenatal finding. Appropriate diagnostic procedures should be conducted, either pre- or postnatally, in order that appropriate genetic counseling may be provided for this autosomal recessively inherited disorder. PMID- 8688101 TI - The clinical outcome of preterm premature rupture of membranes in twin versus singleton pregnancies. AB - The purpose of this study was to determine the clinical outcome of preterm premature rupture of the membranes (PPROM) in twin versus singleton pregnancies at less than or equal to 36 weeks' gestation. A retrospective cohort study was conducted in 116 twin pregnancies with PPROM at less than or equal to 36 weeks' gestational age and 116 matched singleton pregnancies. The two groups were analyzed for differences in maternal demographics and perinatal and neonatal outcome. Perinatal and neonatal outcomes were similar in the two groups. The median latency period, however, was significantly decreased in the twin group (11.4 hours, Inter Quartile Range: 6.3-26.4) versus the singleton group (19.5 hours, Inter Quartile Range: 10.2-49.3, p < 0.05). The latency period in each group was notably longer when PPROM occurred at less than 30 weeks' gestation, but was still shorter in the twin pregnancies (27.6 hours, Inter Quartile Range: 20-307 versus 75.1 hours, Inter Quartile Range: 15-189, p < 0.05). Twin pregnancies with PPROM at less than or equal to 36 weeks' gestational age have a decreased latency period when compared to matched singletons. The perinatal and neonatal outcomes, however, are similar. PMID- 8688102 TI - Fetal middle cerebral artery blood flow velocities in pregnancies complicated by intrauterine growth restriction and extreme abnormality in umbilical artery Doppler velocity. AB - If they are not delivered in a timely fashion, pregnancies complicated by severe intrauterine growth restriction (IUGR) can lead to fetal loss. Conventional fetal well-being tests, including ultrasound measurement of fetal growth rate, biophysical profile, nonstress test, and contraction stress test are used to manage these pregnancies. Some fetuses delivered based on abnormal fetal well being tests show long-term sequelae. A better understanding of the malfunction of the placenta and its effect on the fetus is desperately required for better management of these cases. We are reporting our experience of 6 such pregnancies followed by fetal middle cerebral artery (MCA) blood flow velocity measurements. There was significant decrease in MCA flow velocities in all of these fetuses compared to normal population (p < 0.05). Reverting to normal values occurred prior to the appearance of abnormal conventional tests, on average 4 days earlier. In other words, normalization of MCA flow velocities was a harbinger of fetal jeopardy. Although our observation includes a small number of patients, there is a potential for use of MCA blood flow velocity measurement to aid us in understanding and managing fetuses with IUGR. This needs to be evaluated in a larger study. PMID- 8688104 TI - Recurrence risk of low birthweight deliveries among women with a prior very low birthweight delivery. AB - To estimate the risk of repeat low birthweight deliveries among women whose first child was very low birthweight (less than 1500 g), a retrospective cohort of women who had their first and second children in Washington state between 1984 and 1991 was studied. After adjustment for potential confounding factors, a woman whose first infant was very low birthweight experienced an 11.5-fold increased risk of delivering a low birthweight (less than 2500 g) second infant (relative risk 11.5, 95% confidence interval 5.4 to 24.4). Women with a very low birthweight first infant also had a significantly increased risk of repeat very low birthweight infant (p < 0.0001). Women with a previous very low birthweight delivery are at increased risk of repeat low and very low birthweight infants. This high-risk group may benefit from education regarding recurrence risk and modification of factors associated with low birthweight, as well as good prenatal care. PMID- 8688103 TI - Treatment of preterm labor with the oxytocin antagonist atosiban. AB - The purpose of this study was to describe the course of preterm labor in patients receiving a standard intravenous infusion of the oxytocin antagonist atosiban. An open-labeled, non-randomized study was conducted at 4 sites. Successful tocolysis was defined as delay of delivery larger than 48 hours from starting atosiban and no need for an alternate tocolytic. Atosiban was administered by continuous intravenous infusion at a rate of 300 micrograms per minute until uterine contractions were absent for 6 hours, or up to a maximum infusion time of 12 hours. Sixty-two patients of between 20 and 36 weeks' gestation were enrolled over 6 months. One had rupture of membranes and was excluded. Successful tocolysis was noted in 43 of 61 (70.5%). Four delivered spontaneously within 48 hours and 14 (23.0%) required an alternate tocolytic agent. The chance of successful tocolysis was related to the degree of cervical dilation at the start of therapy. Cessation of uterine contractions was noted in 38 patients (62.3%). A decrease in uterine contraction frequency of 50% or more was noted in 50 of 61 patients (82.0%). Four patients reported side effects (nausea, vomiting, headache, dysguesia, chest pain), but in no case did side effects require discontinuation of the medication. Intravenous administration of atosiban is associated with a delay in delivery comparable to that seen with other tocolytics. If this effect is confirmed in planned placebo-controlled trials, its favorable side effect profile may give it a place in the armamentarium. PMID- 8688105 TI - Intraoperative embolization for pelvic hemorrhage following termination of pregnancy. AB - We describe a 37-year-old patient with placenta previa, placenta accreta and a history of four previous cesarean sections who experienced massive hemorrhage after mid-trimester abortion by dilation and evacuation. PMID- 8688106 TI - Mathematical modeling of fetal foot growth: use of the Rossavik growth model. AB - Growth of the fetal foot has been monitored by foot length (FL), from 12 to 41 weeks menstrual age in 173 normal Japanese fetuses. Growth curve for this parameter has been determined using a Rossavik growth model [p = c(t)k+s(t)]. R2 value of 98.0% was obtained for FL. Variability analysis indicated some progressive increase in variability with fetal age for this parameter. Variability data were used with the growth curve model to determine standard curve for this parameter. This standard curve provides a superior means for evaluating the normal fetal foot growth in the fetus and for assessing menstrual age in utero. PMID- 8688107 TI - Prenatal color and pulsed Doppler sonographic documentation of intrathoracic umbilical vein and ductus venosus, confirming extensive hepatic herniation in left congenital diaphragmatic hernia. AB - Prenatal sonographic diagnosis of an unusual case of a large left congenital diaphragmatic hernia is presented. The fetal stomach was located within the right thorax, posterior to the dextropositioned heart. Color and pulsed Doppler ultrasonography documented intrathoracic umbilical vein and ductus venosus vessels and respective waveforms, confirming extensive herniation of the left hepatic lobe. PMID- 8688108 TI - Cocaine is associated with intrauterine fetal death in women with suspected preterm labor. AB - The objectives of this study were to determine the rate of recent cocaine use in a metropolitan population of predominantly Hispanic and African-American women with suspected preterm labor and to evaluate the impact of recent cocaine use on intrapartum complications in this population. Urine toxicology screens were prospectively obtained on 102 women with suspected preterm labor. The urine screen did not influence management decisions. Gestational age at delivery, birthweight, and intrapartum complications were compared using Student's t-test, chi-square analysis, or Fisher's exact test. The rate of positive urine drug screens for cocaine was 12.7%. Women with positive toxicology were older (27.8 +/ 5.7 versus 22.1 +/- 4.8 years, p = 0.002) and of higher parity (2 [1 to 7] versus 1 [0 to 7], p = 0.0). Women with positive toxicology were more likely to be black (92.3%) than Hispanic (7.7% [p = 0.0004]). They had more advanced cervical dilation at presentation (3 cm [0 to 6] versus 1 cm [0 to 8], p = 0.008), were more likely to be admitted (85% versus 32%, p < 0.0001), but less likely to receive tocolysis due to advanced dilation or pregnancy complication (36% versus 79%, p = 0.0002). There was no difference in gestational age or birthweight at delivery. There was a significantly higher intrauterine fetal death rate in the cocaine positive group (18.2% versus 0%, p = 0.02). These data suggest that recent cocaine use among women with suspected preterm labor is common in only some segments of an urban population and significantly impacts pregnancy outcome. PMID- 8688109 TI - Cecal perforation associated with sodium polystyrene sulfonate-sorbitol enemas in a 650 gram infant with hyperkalemia. AB - We report a 650 g, 24 week hyperkalemic newborn who developed both cecal impaction and perforation after treatment with sodium polystyrene sulfonate enemas. Flat plate abdominal radiographs revealed impacted resin as a radiodense material outlining the bowel. Pathological examination showed sodium polystyrene sulfonate crystals contained in the cecal abscess. Review of the literature in both adults and children leads us to conclude that the use of this sodium potassium exchange resin for the treatment of hyperkalemia in this gestational age group is probably not helpful for decreasing serum potassium and may be detrimental to the infant. PMID- 8688110 TI - Conflicts between physicians and patients in non-elective cesarean delivery: incidence and the adequacy of informed consent. AB - A study was undertaken in 372 consecutive patients undergoing non-elective cesarean delivery to explore the incidence and nature of conflicts between physician and patient surrounding the decision to undergo non-elective cesarean delivery; to examine the adequacy of informed consent at the time of non-elective cesarean delivery; and to describe the importance of a preventive ethics approach to non-elective cesarean delivery. During a 6-month interval, all patients who underwent non-elective cesarean delivery and their physicians were asked to take part in a survey in the early postpartum period concerning their response to recommendations for cesarean delivery. The survey included demographics as well as questions pertaining to informed consent and the presence and nature of patient-physician conflict. Of the 326 patients who were interviewed, 319 (98%) agreed to the recommendation for non-elective cesarean delivery and 7 patients (2%) initially disagreed. Reasons for disagreeing included: feared surgery (4 of 7), needed husband's approval (1 of 7), and questioned the medical necessity of surgery (2 of 7). In all 7 cases of initial disagreement, cesarean delivery was eventually performed with the patient's consent. The mean age of patients who initially disagreed was younger (24.7 +/- 6) than that of those who agreed (31.0 +/- 4 [p < 0.05]). Conflicts were present in 7 of 113 clinic patients and 0 of 213 private patients (p < 0.05). Of those surveyed, 26 (8.7%) indicated that they did not have adequate input in the decision for non-elective cesarean delivery. Patients with inadequate input expressed significantly more concerns with regard to the effect of surgery on their own health (p < 0.05) as well as its effect on the baby (p < 0.05). Our findings suggest that even though the incidence of physician-patient conflict about non-elective cesarean delivery was quite low, a significant number of patients (1 in 12) may have reservations concerning the informed consent process at the time of non-elective cesarean delivery. Patients with reservations are more likely to have greater concerns with regard to maternal and fetal risks, suggesting that a more detailed risk disclosure prior to the procedure is warranted for all pregnant patients. Perhaps by incorporating the preventive strategies discussed, the adequacy of informed consent and therefore the patient's autonomy could be enhanced, thus diminishing patient reservations and preventing physician-patient conflict in the intrapartum period. PMID- 8688111 TI - Sonographic diagnosis of traumatic and later recurrent uterine rupture. AB - We report a case of traumatic transverse fundal uterine rupture with fetal death, followed by recurrent rupture during the subsequent (twin) pregnancy. Rupture was sonographically diagnosed within minutes of arrival at hospital following a motor vehicle accident in the first pregnancy and defined operative intervention, which was lifesaving for the mother. Rupture was again diagnosed sonographically in the second pregnancy based on extrusion of the bag of waters through the uterine incision without fetal distress. Emergency cesarean section was performed with good outcomes for both babies. Causes and clinical/sonographic diagnosis of uterine rupture are reviewed and obstetric management discussed. A high level of suspicion, early diagnosis, and expeditious management are keys to favorable outcome. PMID- 8688112 TI - Myocardial infarction and coronary artery dissection during pregnancy associated with type IV Ehlers-Danlos syndrome. AB - Ehlers-Danlos syndrome (EDS) is a rare, genetically transmitted connective tissue disorder which occurs with an incidence of 1 in 5000. Nine subtypes of EDS have been identified, with type IV being associated with sudden death due to rupture of the bowel, uterus, or major blood vessels. We describe a case of a patient with type IV EDS who presented at 30 weeks' gestation with preterm labor which was treated with subcutaneous terbutaline followed by oral maintenance therapy. Approximately 72 hours later she suffered a myocardial infarction, which led to coronary artery dissection and death. This is the first case of type IV EDS in pregnancy that resulted in maternal death due to coronary artery dissection. We suggest that betamimetic tocolytics should be avoided in patients with EDS and preterm labor. PMID- 8688114 TI - Delayed delivery of a triplet pregnancy without surgical intervention: a case report. AB - Multiple gestations have a significantly increased incidence of preterm labor and preterm rupture of membranes. This leads to an increase in neonatal morbidity and mortality due to prematurity. In this case, a 30-year-old woman achieved a triplet pregnancy by ovulation induction and intrauterine inseminations. Preterm premature rupture of membranes occurred at 21 6/7 weeks' gestation. At 24 weeks' gestation, preterm labor ensued and a vaginal delivery of the presenting triplet followed. Magnesium sulfate tocolysis was started after delivery. The patient was placed on bed rest, magnesium sulfate tocolysis, and weekly steroid injections. The second and third triplet delivered vaginally after a 46-day delay due to preterm labor. This is the first reported case of delayed delivery of the two remaining fetuses of a triplet pregnancy, after spontaneous preterm delivery of the presenting triplet, without surgical intervention. Although the first fetus expired 48 hours after delivery secondary to complications of prematurity, the other fetuses were subjected to tocolysis, bed rest, and steroids. This case illustrates that conservative management of a triplet pregnancy after preterm delivery of the presenting triplet may have a good outcome. PMID- 8688113 TI - The effects of fetal blood sampling and placental puncture on umbilical artery and fetal arterial vessels blood flow velocity waveforms. AB - This study was performed to investigate whether fetal blood sampling and/or transplacental puncture are associated with changes of blood flow velocity waveforms in umbilical artery and fetal circulation. The pulsatility index (PI) was measured from umbilical artery, thoracic descending aorta, renal artery, and middle cerebral artery immediately before and after fetal blood sampling (n = 28) or third trimester amniocentesis (n = 32). No significant changes in PI values were evidenced after amniocentesis performed either transamniotically (n = 21) or transplacentally (n = 11). Fetal blood sampling induced a significant decrease of PI values in all the vessels investigated. However, in presence of a transplacental procedure (n = 15) the amplitude of the decrease of PI in umbilical artery was significantly higher than after a transamniotic procedure (n = 13), while no differences were evidenced in the other vessels tested. These findings indicate that umbilical cord puncture at the time of fetal blood sampling is associated with a decrease in PI in umbilical artery and several peripheral arterial vessels. The isolated placental puncture does not induce Doppler-detectable hemodynamic effects, while in conjunction with cord needling, it increases the amplitude of the effects in umbilical artery. PMID- 8688115 TI - The influence of loading time and lubricant on the friction of articular cartilage. AB - Friction of cartilage on metal, metal on cartilage and cartilage on cartilage contact configurations, within a mixed lubrication regime, was measured using synovial fluid, Ringer's solution or with no lubricant present. The main test variable was the period of stationary loading which ranged from 5 s to 45 min, prior to sliding and consequently measuring friction. The coefficient of friction rose gradually with increasing stationary loading time, up to a value of approximately 0.3 at 45 min for all the contact configurations. Following the re application of load, after short periods of load removal, friction was also found to drop sharply. The flow of liquid in the biphasic cartilage and load carriage by the fluid phase was highlighted as being an important factor in reducing friction within the mixed or boundary lubrication regime. Movement of the contact zone over the cartilage counterface ensured very low friction as the slider moved over fully hydrated cartilage. For the cartilage--cartilage contacts synovial fluid significantly reduced friction compared to Ringer's solution. This was attributed to an effective boundary lubrication action, which was not as effective for the cartilage--metal contacts. PMID- 8688116 TI - Time-dependent behaviour of a force-sensitive resistor plantar pressure measurement insole. AB - Thin pressure-measuring insoles have enabled new clinical studies of in-shoe distribution of plantar pressure. One of these new devices, based on force sensitive resistor (FSR) technology, exhibits time-varying behaviour due to the mechanical properties of the sensor materials. This has been variously attributed to initial bedding in, wear or time-dependency behaviour. Cyclic and sustained loading were used in laboratory conditions to investigate this phenomenon. The results show that the sensitivity of the sensor varies rapidly over the first minute of loading. There is also a slower long-term effect which reduces over time. From this information, procedures for optimal calibration and use are suggested. PMID- 8688117 TI - The effect of ultrasonically determined anisotropy on longitudinal fracture of cortical bone. AB - This study examines the effects of density and microstructural anisotropy on longitudinal crack propagation in compact bone. Bovine cortical bone samples were demineralized by acid, producing specimens with a wide range of bone density. Ultrasound velocity was measured in the radial and longitudinal directions of each specimen using a pulse transmission technique. A proposed microstructural anisotropy parameter based on these ultrasound velocities was introduced and evaluated. The critical stress intensity factors K(IC) of these specimens were determined by mechanical fracture toughness tests. A linear regression study demonstrated that assessment of fracture toughness was precisely achieved by the combined effect of density and microstructural anisotropy of compact bone (r2 = 0.951, p < 0.0001). PMID- 8688118 TI - A comparison of finite element codes for the solution of biphasic poroelastic problems. AB - The extent to which three finite element codes can solve problems in biphasic poroelasticity is examined. Both linear and non-linear (that is where the permeability of the material is a function of deformation) formulations are studied using the standard confined compression problem as an example. The results are compared, where possible, to the results of Spilker, Suh and Mow who first presented a solution to this problem for cartilage. The agreement is excellent for the linear case. For the non-linear case, the solutions do differ slightly; however, the difference would not appear to be significant. PMID- 8688119 TI - Fibre recruitment and shape changes of knee ligaments during motion: as revealed by a computer graphics-based model. AB - A computer graphics-based model of the knee ligaments in the sagittal plane was developed for the simulation and visualization of the shape changes and fibre recruitment process of the ligaments during motion under unloaded and loaded conditions. The cruciate and collateral ligaments were modelled as ordered arrays of fibres which link attachment areas on the tibia and femur. Fibres slacken and tighten as the ligament attachment areas on the bones rotate and translate relative to each other. A four-bar linkage, composed of the femur, tibia and selected isometric fibres of the two cruciates, was used to determine the motion of the femur relative to the tibia during passive (unloaded) movement. Fibres were assumed to slacken in a Euler buckling mode when the distances between their attachments are less than chosen reference lengths. The ligament shape changes and buckling patterns are demonstrated with computer graphics. When the tibia is translated anteriorly or posteriorly relative to the femur by muscle forces and external loads, some ligament fibres tighten and are recruited progressively to transmit increasing shear forces. The shape changes and fibre recruitment patterns predicted by the model compare well qualitatively with experimental results reported in the literature. The computer graphics approach provides insight into the micro behaviour of the knee ligaments. It may help to explain ligament injury mechanisms and provide useful information to guide the design of ligament replacements. PMID- 8688120 TI - Stress distributions inside intervertebral discs: the validity of experimental "stress profilometry'. AB - This paper evaluates a technique for measuring the distribution of compressive stress within cadaveric intervertebral discs. A strain-gauged pressure transducer, side-mounted near the tip of a 1.3 mm diameter needle, was inserted into cubes of disc tissue and into intact discs. Regardless of the position and orientation of the transducer within the tissue or disc, its output was found to be proportional to the compressive force applied to the specimen. The distribution of compressive stress was measured by pulling the instrumented needle through the specimen and the resulting stress profiles were reproducible to within 20 per cent. Profiles obtained at different applied loads showed a similar distribution of stress within the disc, suggesting that the compressive stress at any location and direction increased in proportion to the applied load. Since transducer output was also proportional to applied load, it was reasoned that it must be proportional to compressive stress within the disc. The average vertical compressive stresses acting on various regions within a disc were calculated from the stress profiles and multiplied by the cross-sectional area of each region: the resulting force was then compared with the known applied force in order to assess the calibration coefficient of the transducer. Agreement between the two forces was good, indicating that the calibration coefficient established in a saline bath was applicable to disc tissues also. However, artifactual stress peaks could be generated if the transducer was pulled across a bony asperity. It is concluded that the transducer measures the mean compressive stress acting upon it within disc tissues. Errors associated with the technique are small compared to differences in stress distributions which occur naturally, for example when intervertebral discs are loaded to simulate different postures in a living person. PMID- 8688121 TI - Determination of lubricating film thickness for permeable hydrogel and non permeable polyurethane layers bonded to a rigid substrate with particular reference to cushion form hip joint replacements. AB - The lubricating film thickness in a model of compliant layered bearings, using both permeable hydrogels and non-permeable polyurethane elastomers for total hip joint replacements, has been measured using optical interferometry, under both entraining and squeeze-film motion. The film thickness in the lubricated contact was measured for both water and a 40 per cent glycerol solution in water as a function of entraining velocity and squeeze-film time. The measured lubricating film thickness for the permeable hydrogel was compared to that of the non permeable polyurethane elastomer and little difference was found when the lubricating film thickness was sufficiently large (greater than 150 nm). Comparison of the experimental results and the theoretical predictions based upon elastohydrodynamic lubrication analysis showed good agreement in the entraining experiments where the film thickness was greater than 150 nm. In the squeeze-film experiments the experimental measurements were greater than the theoretical predictions for all squeeze times due to the formation of a central pocket of fluid which was not predicted by the simple theory used. This also occurred for the hydrogels for films greater than 150 nm. For longer squeeze times the film thickness for the hydrogel fell below the theoretical prediction. This was considered to be due to the permeability of the hydrogel reducing the film thickness when the film thickness was less than 150 nm. The permeability of the hydrogel was not modelled in the theoretical lubrication analysis used in this study. PMID- 8688122 TI - Proximal interphalangeal joint dimensions for the design of a surface replacement prosthesis. AB - The bones from 83 proximal interphalangeal joints (PIPJs) were dissected in order to determine the shape and size of the articular surfaces. The bones were modelled in acrylic dental bone cement and the original bones and replicas were then sectioned and shadowgraphed. Dimensions were taken from these shadowgraphs to be used in the design of a surface replacement prosthesis for the PIPJ. It was found that the bi-condylar heads of the proximal and middle phalanges were circular in the sagittal plane as was the base of the middle phalanx. However, the radius of curvature of the middle phalangeal base was greater than that of the proximal phalangeal head indicating that the PIPJ is not a conforming joint. The alignment of the radial and ulnar condyles of the proximal phalangeal bones was investigated and it was found that the index and middle finger bones tended to have a more prominent ulnar condyle while the ring and little finger bones tended to have a more prominent radial condyle. This was due to a slight difference in diameters of the two condyles. The proximal phalangeal bone lengths L ranged from 29-52 mm, maximum head widths W from 8.5-15.5 mm and maximum diameters D of the best-fit circles to the sagittal profile of the bone head from 6-11 mm. The middle phalangeal bone lengths ranged from 16-35 mm, maximum head widths from 8.5-12 mm and maximum diameters from 5-7.5 mm. The relationships and ratios between these dimensions for the proximal and middle phalanges have been calculated. PMID- 8688123 TI - [High resolution computerized tomography of middle ear abnormalities]. AB - BACKGROUND: The aim of this study was to analyze malformed petrous bones with computed tomography and to develop a radiologic score which can help to judge the indication for operative reconstructions. METHODS: One hundred forty-two petrous bones in 71 patients with unilateral or bilateral microtia, atresia of the external auditory canal, and malformations of the middle ear were evaluated with high-resolution CT. RESULTS: In 97% of patients with severe auricular dysplasia, there was dysplasia of the middle ear ossicles; in 70% the stapes was malformed. In 32% the oval window was occluded, and in 7% the round window. In 75%, the canal of the facial nerve was displaced, and 16% also showed abnormalities of the labyrinth. A close correlation between the malformation of the auricle and of the middle ear was not found. CONCLUSIONS: High-resolution CT is necessary for the evaluation of malformed middle ears. Based on the abnormalities described, we propose a radiologic score for the assessment of malformed petrous bones. This consists of the following criteria: external auditory meatus, pneumatization of the mastoid and of the tympanic space, size of the tympanic space, facial nerve, vessels, malleus and incus, stapes, oval and round window. The graded points of each structure are added up to the score, which might range between 0 and 28. This score can help to judge the indication for reconstruction of the middle ear. In bilateral malformation we suggest a middle ear reconstruction of the better hearing ear if the score is greater than or equal to 15, and in unilateral malformation if it is at least 20. In patients with lower scores, we only suggest hearing aids. PMID- 8688124 TI - [Evaluation of deprivation manifestations of the auditory system in patients with unilateral middle ear deafness before and after surgical therapy]. AB - BACKGROUND: This paper will discuss whether long term conductive hearing loss leads to late onset auditory deprivation as described in the literature in patients suffering from bilateral sensorineural hearing loss and fitted with monaural hearing aids. METHOD: The patients were examined using the Freiburg speech test in the undistorted and distorted forms (according to Dieroff 1985), and the pure tone threshold was ascertained for each patient. Thirty-six preoperative und postoperative results after tympanoplasty and stapes surgery were evaluated. Follow-up was performed six weeks and six months postoperatively. Twenty-one test persons with normal hearing were investigated. RESULTS: Comparison showed that the quotient obtained from undistorted and distorted tests is significantly higher in the affected patients. We even observed a highly significant improvement of this quotient, the speech recognition score (according to Bonninghaus/Roser), and the pure tone threshold after surgery. Seventy-eight percent of our patients showed an improved quotient, and 73% attained a normal value. But in only 29% of all cases did we see a symmetrical quotient in both ears in this period of time. In the statistical evaluation, we were unable to demonstrate a correlation between the patient's age at that moment, the age at the beginning of hearing loss, and this echo quotient. There is also no correlation between the absolute and relative change of the echo quotient and the duration of hearing loss. CONCLUSION: It was evident that the distorted Freiburg speech test is a good method to demonstrate the deprivation of the auditory system. We observed the improvement of the distorted Freiburger speech test at postoperative intervals of six weeks and six months. Hearing training should be applied after surgery in an effort to improve the hearing results. PMID- 8688125 TI - [Computer-assisted surgery of the paranasal sinuses with an opto-electronic stereotaxic system]. AB - BACKGROUND: A basic problem common to all systems for computer-assisted surgery (CAS) is the exact registration and referencing, that is, the transfer of preoperative image data to the intraoperative pathology. A system for computer assisted ENT surgery should provide high precision as well as noninvasive registration and referencing. We present a system designed for such use in paranasal sinus surgery that is based on optical digitizing with several custom made self-localizing surgical instruments. METHODS AND RESULTS: The system tracks the correct alignment of the head during CT data acquisition and continuously throughout surgery. A transformation matrix and a plane equation of the CT scan are used to match points of the object space to the image space detecting fiducial markers on the CT scans by an automatic algorithm. For position measurements a special reference frame and surgical instruments were developed and equipped with infrared light-emitting diodes that could be detected in real time. Measurements for repositioning of the reference system in a model and during real operations demonstrated a mean error ranging from 0.69 to 1.01 mm and from 0.76 to 1.67 mm respectively. Clinical experience with the application of the system for 15 patients who underwent surgery for different paranasal sinus pathologies is reported. CONCLUSIONS: Results suggest that the non-invasive reference system and the locatable surgical tools may be effective, accurate and useful for computer-assisted identification of intranasal structures. Such systems may contribute to further improvement of minimal invasive intranasal sinus surgery. PMID- 8688126 TI - [Effects of postoperative care on wound healing after endonasal paranasal sinus surgery]. AB - BACKGROUND: There is no standard for postoperative care after paranasal sinus surgery. METHODS: In a prospective study we evaluated the influence of modifications of postoperative care on wound healing after paranasal sinus surgery. We used a new method of documenting the natural dynamics of wound healing after endonasal paranasal sinus surgery that combines morphing and time lapse video. Computer-assisted morphing means transformation of one shape into another by means of two-dimensional interpolation. The computer reconstructs the changes between the single frames taken by videoendoscopy at each examination by morphing. Editing all single frames from videoendoscopy and from morphing together resulted in a 60-second video showing wound healing over a period of six months. We documented wound healing 23 operations. Twelve patients with chronic polypoid sinusitis of similar extent were documented in a similar manner. Minimal postoperative care consisted of packing the operative cavity with rubber fingers for three days and irrigation with Ems brine. The effect of long-term packing and topical application of budesonide were studied. Analysis consisted of evaluating the time-lapse videos and final flexible endoscopy of the sinuses. RESULTS: Wound healing after complete endonasal sinus surgery varies greatly. In the first 7-12 days blood crusts covered the whole wound. Granulation was visible for 2-4 weeks. The increasingly edematous swelling reached its maximum in the 3rd-5th week and decreased in 7th-12th week. A macroscopically normal mucosa was observed from the 12th-18th weeks. Subepithelial changes occurred for longer than 6 months. CONCLUSIONS: The following measures are recommended for decreasing postoperative granulations, edema and swelling: minimizing the surgical trauma, long-term packing with a occlusive, nonadherent material (rubber finger packing), topical steroids (Budesonide). Stenosis of paranasal sinuses due to excessive scarring could not be prevented (especially in the frontal sinus). PMID- 8688127 TI - [Endolaryngeal surgical procedures in glottis expansion in bilateral recurrent nerve paralysis]. AB - OBJECTIVE: Subtotal cordectomy and posterior cordectomy have repeatedly been recommended as surgical interventions restoring the airway, for the treatment of bilateral vocal cord paralysis. The objective of this study was to assess the effectiveness of transoral laser cordectomy and posterior cordectomy as compared to laser arytenoidectomy and to compare the respiratory and phonatory results of these minimally invasive procedures. MATERIAL AND METHODS: Forty patients with bilateral vocal cord paralysis were included in a prospective study and operated upon to improve their laryngeal airways. Twenty-two patients had cordectomy, 13 had arytenoidectomy, and 5 had posterior cordectomy. Lung function tests and voice analysis were obtained preoperatively and postoperatively. Subclinical aspiration was determined by endoscopic evaluation of the larynx during deglutition. The results were compared to determine the relative effectiveness of the three surgical methods. RESULTS: Flow volume spirograms documented equally improved flow rates in both groups. Final voice evaluation revealed maximum phonation time. Peak sound pressure levels and frequency range were reduced in all 28 patients, but phonatory results varied considerably in each group. Subclinical aspiration was noticed in 5 out of 10 patients after arytenoidectomy, but in none of 18 patients after cordectomy. Four previously tracheotomised patients were decannulated within 2 weeks after surgery, while the other 24 patients had no perioperative tracheotomies. CONCLUSION: Transoral laser cordectomy and arytenoidectomy are equally effective and reliable in the management of the restricted airway. Cordectomy and posterior cordectomy offer the advantage of uncompromised deglutition after surgery. Although no clinically relevant aspiration occurred in any of the patients, cordectomy should be considered as the method of choice in patients for whom subclinical aspiration could be potentially harmful due to coexisting pulmonary or cardiac disease. Phonatory outcome is not predictable with both surgical procedures. Subtotal cordectomy and posterior cordectomy are easier and faster to perform, and subclinical aspiration is not encountered with these procedures. PMID- 8688128 TI - [Analysis of cervical lymph node metastasis of oropharyngeal carcinoma in relation to extent of the primary tumor]. AB - PURPOSE: To assess the incidence and patterns of cervical lymph node involvement according to the location and the relation of the primary tumour to the parapharyngeal fasciae, compartments and tissues arising from different branchial arches. PATIENTS AND METHODS: The findings of clinical and CT examinations of 143 patients with histological evidence of oropharyngeal carcinoma were evaluated retrospectively. Local tumour spread, relation of the primary to the parapharyngeal fasciae, compartments and to the borders of tissues arising from different branchial arches were analysed and related to cervical lymph node involvement. RESULTS: Lymph drainage of the oropharynx and neighbouring neck regions is determined by the embryological development of the branchial arches and somites. Oropharyngeal carcinomas are tumours arising from tissues of the 2nd and 3rd branchial arches. The lymph of these tissues is collected by the vessels of the jugular neck node chains. If tumour invades tissues arising from the 1st branchial arch (structures of the oral cavity and floor of the mouth) tumour spreads into the ipsilateral lymphatic vessels arising from the 1st branchial arch and the submaxillary lymph nodes. If tumor invades tissues arising from occipital and cervical somites (posterior wall of the nasopharynx, retropharyngeal compartment and recessus submuscularis) metastases in the retropharyngeal and spinal-accessorial lymph nodes may appear. Regarding the tumour invasion of the subdistricts of the oropharynx totally different tumours were found. Tumour invasion of neighbouring structures was documented for the nasopharynx in 15%, for oral cavity and the floor of the mouth in 34%, the larynx in 24% and the hypopharynx in 22% of the cases. From these different patterns of local tumour spread different patterns of lymph node involvement resulted. Nodal involvement was found in 71%. In all these cases metastases in the ipsilateral upper jugular lymph nodes were present. The frequency of metastases in the jugular lymph node chains decreased in cranio-caudad direction (upper jugular group 100%, middle 18%, lower jugular group 5%). The frequency of bilateral jugular lymph node involvement (25%) increased in the some measure as the tumour approached the midline or crossed it. CONCLUSIONS: Knowledge of regular patterns of spread of oropharyngeal carcinoma is important for treatment procedures, especially for 3-dimensional radiotherapy. PMID- 8688129 TI - [Reconstruction of speech and chewing function after extensive tumor resection in the area of the jaw and face]. AB - BACKGROUND: Following extensive resections of head and neck tumors, re establishing speech and masticatory function are of crucial importance for the patient. METHODS: In 23 patients with vascularised jejunal grafts for reconstruction of the intraoral mucosa, tongue and floor of mouth, a speech intelligibility test was performed, tongue and floor of mouth mobility was investigated using a 3.5 MHz ultrasound scanner. In another 18 patients with vascularised bone grafts for reconstruction of the mandible, masticatory function was analysed using a T-scan system and a miniature pressure transducer. RESULTS: Speech results with jejunal grafts in the lateral floor of mouth/tongue region may attain 91.4%, in anterior floor of mouth reconstructions 63.4%. Patients with implant-bone dentures and vascularised bone grafts prefer the non-reconstructed side for chewing. Masticatory force is significantly diminished compared to a control group. DISCUSSION: Lack of neurosensitive feedback mechanisms may be responsible for diminished chewing pressure and also for inferior speech results despite good floor-of-mouth/tongue mobility. CONCLUSIONS: Despite complex microvascular tissue reconstructions, severe functional impairments remain and necessitate further investigations on improvement of postoperative speech, swallowing and chewing function. PMID- 8688130 TI - [Transoral CO2 laser resection of extensive nasal and oropharyngeal teratoma]. AB - BACKGROUND: Teratomas are quite rare congenital tumours, especially originating from the skull base in the region of the nasopharynx (1:40,000). PATIENTS: We report on a premature 36-week old girl with an extensive nasopharyngeal and oral teratoma. METHOD: With CO2 laser and micro-endoscopic techniques the tumour was successfully resected directly via the transoral route without needing external incisions. RESULTS AND CONCLUSIONS: These techniques, and particularly the use of CO2 laser, allow gentle resection of nasopharyngeal teratomas with only moderate bleeding. General pathological aspects, clinical symptoms and update management or teratomas in the head and neck area are discussed, based on this case. CO2 laser in conjunction with microscope and videoendoscope seems to offer an advantage compared to resection with conventional instruments alone. PMID- 8688131 TI - [Ultrasound diagnosis of orbital floor fractures: an alternative to computerized tomography?]. AB - BACKGROUND: Plain radiography of the paranasal sinuses (Water's view) may fail to demonstrate typical signs of orbital floor fractures. To resolve questionable cases, computed tomography (CT) is performed. B-mode ultra-sonography (US) is investigated concerning its reliability and as a possible alternative to CT. The replacement of standard radiological techniques in primary evaluation will be discussed. METHODS: A skull was used to assess the visualization of the bony floor in the ultrasound-technique. Fifteen patients with suspected fractures of the orbital floor were investigated with plain radiographs, ultrasound of both orbits in closed-eyelid technique, and CT scans. The findings were compared. RESULTS: Thirteen patients were found to have apparent fractures in CT scans. These fractures were also diagnosed on ultrasound. In three patients, ultrasonographic localization was imprecise. These fractures were located behind the lower orbital rim or far posteriorly. Plain radiographs showed positive fracture signs only in five patients. Localization was not possible. The application of the ultrasound probe was well tolerated. CONCLUSIONS: B-mode ultrasonography is a valuable and inexpensive technique to visualize orbital floor fractures. It should be employed in primary evaluation patients with suspected isolated orbital floor fractures prior to taking plain radiographs of the paranasal sinuses. Computed tomography should be used in suspected complex fractures and questionable orbital fractures. PMID- 8688132 TI - [Chronic myeloid leukemia--a rare cause of labyrinth apoplexy]. AB - BACKGROUND: Cochleovestibular lesions in patients with acute myeloid leukemia or the blastic phase of chronic myeloid leukemia are usually due to leukemic infiltration, infection or hemorrhage. In contrast, the most likely cause of cochleovestibular lesions in the chronic phase of the chronic myeloid leukemia seems to be disturbed microvascular perfusion and vascular occlusion. CASE REPORT: A 45-year old patient with a chronic myeloid leukemia presented with the sudden onset of profound deafness in his right ear combined with a total loss of vestibular function on the same side. The hemoglobin count was 10.5 g/dl; the white blood cell count 448 x 10(9)/I; the platelet count 71 x 10(9)/I. All of the plasmatic coagulation factors were in the normal range. The patient was treated with cytostatic drugs and responded well (rapid cytoreduction), but the deafness persisted. DISCUSSION: Cochleovestibular lesions in the chronic phase of the chronic myeloid leukemia are very rare. The most likely cause in the case described above seems to be increased blood viscosity due to the high white cell count and alterations in the leukocyte rheology (leukostasis syndrome). CONCLUSION: In patients with leukemia and acute cochleovestibular lesions in contrast to other patients with sudden deafness and/or sudden loss of peripheral vestibular function, a combination of chemotherapy and leukopheresis capable of rapid cytoreduction is necessary, whereas a conventional hemorrheologic therapy seems to be insufficient. PMID- 8688133 TI - [Neurinoma of the neck area]. AB - BACKGROUND: Neurinomas of the cranial nerves and the sympathetic trunk are rare benign tumors, and as such are rarely considered in differential diagnostics. Neither clinical criteria nor diagnostic imaging studies are usually conclusive. PATIENTS: We present a case report in which the problems of diagnosis, differential diagnosis, and surgical therapy are discussed. RESULTS: Preoperative diagnosis include clinical examination, B-mode sonography, CT, and MRI. A biopsy does not usually help verify the diagnosis. A Glomus tumor has to be excluded preoperatively. The therapy of choice is complete surgical removal of the tumor, with a good postoperative cure rate. The nerve of origin can be preserved in many cases. However, there are some cases in which temporary or permanent damage of the nerve cannot be avoided. Especially where parts of the vagus nerve require resection, autologous nerve grafts are indicated. CONCLUSIONS: A neurinoma should be considered in cases of an uncertain neck tumor. Problems for the surgeon may result from failure to inform patients about possible nerve lesions before therapy. PMID- 8688134 TI - [Prevention of adhesions in the middle ear]. AB - In certain cases of tympanoplasty implantation of silicone sheets is recommended to prevent postoperative adhesion. However, many surgeons feel that silicone would not be the best material in these cases. Here we recommend using PDS sheets instead of silicone. PMID- 8688135 TI - [Brachiocervical syndrome. First case report over 3,000 years ago]. PMID- 8688136 TI - [Treatment error in rhinoseptoplasty and foreshortening of the soft tissues of the palate with considerable nasal obstruction due to osseochondrous nose abnormality and deviated septum]. PMID- 8688137 TI - Synthesis and chemistry of the ionophore antibiotic tetronasin. PMID- 8688138 TI - Synthesis and preliminary pharmacological investigation of N-lupinyl-2 methoxybenzamides. AB - A set of eleven N-lupinyl-2-methoxybenzamides, variously substituted on the benzene ring, together with two related compounds, were prepared and subjected to a large pharmacological screening, though not all compounds were tested in each assay. Compounds 1-10 displaced [125I]-iodosulpride from D2 receptors only at very high concentration (IC50 > 5 microM). At micromolar concentrations, compounds 1, 12, and 13 inhibited the binding of [3H]-pirenzepine and of [3H]-di o-tolylguanidine respectively on M1 and sigma receptors; in the last case comp. 13 was more active (IC50 = 0.3 microM) than the epimeric 1. Compounds 1-10 at 10 25 mg/kg p.o. protected mice against electroshock induced seizures; 1-sulpiride was inactive in this test. Compound 1 exhibited in three tests antiarrhythmic activity superior to that of quinidine and lidocaine. The same antagonized, in vitro, guinea pig ileum contractile response induced by several agents, and enhanced the intestinal transit rate in mice (charcoal bolus test). The last activity (shown in lower degree also by comp. 5) could be related to agonism with 5HT4 receptors, as could be expected for orthopramides with conformationally restricted side chains. This possibility is presently under investigation. PMID- 8688139 TI - Synthesis and alpha,beta-adrenergic blocking potency of 2,3-dihydro-1,4 benzodioxin derivatives. (I). AB - The synthesis of a new series of alpha- and beta-adrenergic blocking agents 14 is described. The affinity and selectivity of these compounds for alpha, beta 1 and beta 2-adrenoceptors were studied in comparison with those of WB-4101 and propranolol. The derivatives 14cx and 14dx are more potent beta 1-blockers than propranolol. PMID- 8688141 TI - Synthesis and antibacterial activity of C-4 thio- and dithiocarbamate monobactam derivatives. AB - New series of monobactam antibiotics, bearing thio-and dithiocarbamate derivatives as C-4 side chain, were synthesized. Some compounds were found to have good antibacterial activity against Gram-negative bacteria. PMID- 8688140 TI - Synthesis and alpha,beta-adrenergic blocking potency of 2,3-dihydro-1,4 benzodioxin derivatives. (II). AB - The four stereoisomers of compound 1 were synthesized from 2,3-dihydro-1, 4 benzodioxin and evaluated as alpha- and beta-adrenergic antagonists. Enantiomer 1 b [2R, 2'S] (Figure 1) is the best beta 1-blocking agent. Furthermore all compounds showed a alpha-blocking activity. PMID- 8688142 TI - Modification of the potent peptide FK888 with unusual aminoacids: effects on activity on neurokinin receptors. AB - We report on the synthesis and the pharmacological properties of a new series of tachykinin antagonists based on the peptide N2-[(4R)-4-hydroxy-1-[(1-methyl-1H indol-3-yl) carbonyl]-L-prolyl]-N-methyl-N-(phe-nylmethyl)-3-(2-naphthyl)-L-al aninamide (FK888) modified on the (2-naphthyl)-L-alanine and the [(1-methyl-1H indol-3-yl)carbonyl] moieties. The compounds were tested on guinea pig ileum for NK-1, rat colon for NK-2 and rat portal vein for NK-3 receptors. The two most potent peptides of this series, 1b and 2b, were selective for the NK-2 receptor (pA2 = 7.5 and 7.3, respectively). PMID- 8688144 TI - Synthesis and antiinflammatory activity of 2,3-dihydro-1,4-benzodioxin methyl carboxylic acids. AB - Synthesis and antiinflammatory properties of new carboxylic acids containing the 2,3-dihydro-1,4-benzodioxin subunit are described. The 2-(2,3-dihydro-1, 4 benzodioxin-6-yl)acetic acid was of comparable potency to Ibuprofen, in carrageenan induced rat paw edema assay. PMID- 8688143 TI - Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. X--Synthesis and inhibition of benzodiazepine receptor binding of new 1,4-thiazine and 1,5 thiazepine polycondensed heterocycles with steroidal structure. AB - Some naphtho[1,2,-b]-s-triazolo[4,3-d]-1,4-thiazine and 1,5-thiazepine and s triazolo[4', 3'-4,5]-1,4-thiazino[3,2-c]quinoline derivatives have been synthesized and tested for their ability to displace [3H]RO 15-1788 binding from bovine brain membranes. Several compounds showed moderate binding affinity for the benzodiazepine receptor. PMID- 8688145 TI - Biological effects of hesperidin, a Citrus flavonoid. (Note III): antihypertensive and diuretic activity in rat. AB - Hesperidin, the most important flavanone of Citrus sp., obtained from the solid residue of orange peel, showed antihypertensive and diuretic effects on normotensive rats and on spontaneously hypertensive rats (SHR). PMID- 8688146 TI - Downexpression of aldehyde dehydrogenase 1 in murine lung tumors. AB - We analyzed the expression of the cytosolic aldehyde dehydrogenase 1 (Aldh1) gene in mouse lung tumors by northern blotting and immunocytochemical analysis. Aldh1 was abundantly expressed in normal lung tissue, with a predominant cellular localization on bronchiolar cells. However, expression of Aldh1 was strongly reduced (more than tenfold) in lung tumors. As aldehyde dehydrogenases metabolize some antitumor alkylating drugs to inactive compounds, the low expression of Aldh1 in lung tumors may account for the drug sensitivity of these tumors to chemotherapeutic agents. PMID- 8688148 TI - Stimulation of ras GTPase activity by an anti-ras monoclonal antibody. AB - Wild-type ras has GTPase activity, and this activity is accelerated substantially by GTPase-activating proteins (GAPs). Oncogenic ras species have an abnormally low intrinsic GTPase activity, and this activity is insensitive to GAPs. We confirmed that the anti-ras monoclonal antibody Y13-238 inhibited GAP activity in vitro, but we also noted that this antibody had GAP activity of its own. We studied the GAP activity of Y13-238 in circumstances in which ras GTPase activity was influenced by the GTPase-inhibitory antibody Y13-259 or by substitutions in ras. The GTPase-inhibitory antibody Y13-259 blocked the GAP associated with Y13 238. A ras species with a substitution in the effector loop that blocked conventional GAP activity was sensitive to stimulation by Y13-238. Both Y13-238 and Y13-259 stimulated the autophosphorylation of Ala59Thr ras. We interpreted these data in terms of a model in which the extrinsic factors influence the ras GTPase reaction by affecting the balance between "committed" and "uncommitted" states. We suggest that there is a mechanism distinct from that exploited by conventional GAPs for stimulating ras GTPase activity. PMID- 8688147 TI - Specific N-ras mutation in bone marrow within 48 H of 7,12 dimethylbenz[a]anthracene treatment in Huggins-Sugiyama rat leukemogenesis. AB - 7,12-Dimethylbenz[a]anthracene (DMBA)-induced leukemias in Long-Evans rats consistently have an A --> T transversion at the second base of codon 61 in the N ras gene. This mutation is also detected in the preleukemic stage. To determine when this specific N-ras mutation occurs in the early stages of leukemogenesis, we designed the mutant allele-specific amplification method, which was sensitive enough to detect one mutant cell among 10(6) normal cells. In the study reported here, N-ras mutation was found in bone-marrow cells 2 d after a single DMBA injection and thereafter throughout the preleukemic stage. These results show that DMBA induces a specific N-ras mutation soon after one DMBA injection and that this mutation is probably the first event in DMBA leukemogenesis. PMID- 8688149 TI - Dissociation of ras oncogene-induced gene expression and anchorage-independent growth in a series of somatic cell mutants. AB - The mechanism or mechanisms by which ras oncogenes induce morphological transformation and anchorage-independent growth are poorly understood but are thought to involve stable alterations in gene expression. We previously described a genetically dominant, mutant rat fibroblast cell line (ER-1-2) that is resistant to ras-induced anchorage-independent growth. We now describe a cell line derived from ER-1-2 cells, termed ER-1-2T, that has apparently sustained a second, dominant mutation that conferred on these cells the ability to form colonies in soft agar. Analysis of these and control cell lines demonstrated that deregulation of many of the genes commonly associated with the transformed phenotype could be dissociated from anchorage-independent growth. After infection with a ras-expressing retrovirus, both control and ER-1-2 cell lines constitutively expressed elevated levels of the c-jun, junB, fosB, c-myc, collagenase, ornithine decarboxylase, osteopontin, stromelysin, cathepsin L, and insulin-like growth factor 1 genes. These data indicate that signaling events downstream of ras were largely intact in ER-1-2 cells and that the defect in these cells lies either on a pathway separate from those that control stable, ras mediated expression of these genes or at a point in the cell-division cycle distinct from those that control expression of the genes. In contrast, only c jun, junB, c-myc, and ornithine decarboxylase were expressed at a significantly elevated level in ER-1-2T cells. Thus, deregulated expression of the genes analyzed was not sufficient for anchorage-independent growth. Furthermore, deregulation of most of them was also not necessary. PMID- 8688150 TI - Estrogen-induced cell transformation and DNA adduct formation in cultured Syrian hamster embryo cells. AB - To study the possible involvement of DNA damage in cell transformation induced by estrogens, we examined whether DNA adduct formation is elicited in cultured Syrian hamster embryo (SHE) cells treated with estrogens and their derivatives by means of the 32P-postlabeling assay. Morphological transformation of the cells was induced by treatment with diethylstilbestrol (DES) at 1-10 micrograms/mL for 24 h but not by treatment with its derivatives trans, trans-dienestrol (alpha DIES) or cis, cis-dienestrol (beta-DIES) at 1-10 micrograms/mL for 24 h. Similarly, DNA adduct formation was elicited by exposure of SHE cells to DES at 1 10 micrograms/mL for 24 h but not by either alpha-DIES or beta-DIES. Treatment of SHE cells with DES at 1-10 micrograms/mL for 2 h in the presence of exogenous metabolic activation with rat liver post-mitochondrial supernatant enhanced morphological transformation in a dose-dependent manner. Our previous studies have demonstrated that exposure of SHE cells to DES under the same conditions with exogenous metabolic activation induces somatic mutations at the Na+/K+ ATPase locus. Therefore, we examined whether with exogenous metabolic activation DES induced DNA adduct formation in SHE cells. DNA adducts were not detected when SHE cells were treated with DES at 1-10 micrograms/mL for 2 h in the presence of exogenous metabolic activation. Treatment with 17 beta-estradiol (E2), 2 hydroxyestradiol (2-OH E2), or 4-hydroxyestradiol (4-OH E2) at 1 microgram/mL for 24 h induced DNA adduct formation in the cells, in parallel with the induction of cell transformation. The rank order of DNA adduct formation was 4-OH E2 > 2-OH E2 > E2. The results indicate that estrogens induce DNA adduct formation in cultured SHE cells, but the induction may not be the only mechanism relevant to the initiation of cell transformation. PMID- 8688151 TI - Gap-junction disassembly and connexin 43 dephosphorylation induced by 18 beta glycyrrhetinic acid. AB - Gap-junction channels connect the interiors of adjacent cells and can be arranged into aggregates or plaques consisting of hundreds to thousands of channel particles. The mechanism of channel aggregation into plaques and whether plaques can disaggregate are not known. Many carcinogenic and tumor-promoting chemicals have been identified that inhibit cell-cell gap-junctional coupling. Here, we provide morphological evidence that 18 beta-glycyrrhetinic acid (18 beta-GA), a saponin isolated from licorice root that is an inhibitor of gap-junctional communication, caused the disassembly of gap-junction plaques in WB-F344 rat liver epithelial cells. This effect was dose (5-40 microM) and time dependent (1 4 h treatment). Gap-junction channels in WB-F344 cells are comprised of connexin 43 (Cx43), and the protein is phosphorylated to a species known as Cx43-P2 coincident with the assembly of channels into plaques. Consistent with this, the disassembly of plaques induced by 18 beta-GA was correlated with decreases in Cx43-P2 levels and increases in nonphosphorylated Cx43. Biochemical evidence indicated that these changes in the P2 and NP forms of Cx43 represented 18 beta GA-induced dephosphorylation of Cx43-P2 and not its degradation or the inhibition of Cx43-NP phosphorylation. Okadaic acid and calyculin A, which are inhibitors of type 1 and type 2A protein phosphatases, prevented the dephosphorylation of Cx43, suggesting that one or both of these phosphatases were involved in Cx43 dephosphorylation. These data indicate that 18 beta-GA causes type 1 or type 2A protein phosphatase-mediated Cx43 dephosphorylation coincident with the disassembly of gap-junction plaques. PMID- 8688152 TI - Expression of oxidative phosphorylation genes in renal tumors and tumoral cell lines. AB - To investigate the regulation of genes encoding the proteins involved in energy metabolism in cancer cells, we studied the expression of several mitochondrial and nuclear genes involved in ATP production. Northern blot analysis was performed on renal tumors of different types: a clear cell carcinoma, an oncocytoma, and urothelial tumors at two different stages. The steady-state transcript patterns were compared with those observed in cell lines derived from renal tumors and in transformed cell lines. Striking differences were revealed among the three types of tumors, their respective controls, and the cultured renal cells. The levels of all mitochondrial transcripts were lower in tumor biopsies and tumoral cell lines than in the normal cell types. Moreover, a higher transcript level of nuclear genes involved in oxidative phosphorylation was observed in the oncocytomas and in the more malignant urothelial tumor. Different transcript patterns were observed in each of the tumoral and transformed cell lines, explaining the difference in metabolism between the different tumors and the tumoral or transformed cell lines. In particular, a high transcript level for the adenine nucleotide translocator isoform 2(ANT2) gene, which is usually not expressed in differentiated cells, was observed in oncocytoma and malignant urothelial renal tumor. This phenomenon was also observed in renal carcinoma cell lines and transformed cells. These data provide the first argument for the involvement of the ANT2 protein in glycolytic ATP uptake in cancer cell mitochondria and suggest a possible ANT2 antisense strategy for cancer therapy. PMID- 8688153 TI - Low pH adaptation and the acid tolerance response of Salmonella typhimurium. AB - Salmonella typhimurium periodically confronts acid environments during its life. These situations arise in chemically compromised ponds, soil, degradative cellular organelles, host digestive systems, and may even result from byproducts of their own metabolism. The levels of acid that are encountered range from mild to extreme. As a neutralophile, S. typhimurium prefers to grown in pH environments above pH 5.5. They can survive down to pH 4 for extended periods of time. However, the limits of endurance can be stretched if the organisms are first adapted to a moderate acid pH before exposing them to acidity below pH 4.0. This adaptation, called the acid-tolerance response (ATR), includes several log phase and stationary phase systems. Some of these systems are dependent on an alternate sigma factor for RNA polymerase called sigma s, whereas other systems are sigma s-independent. A key to the ATR is the synthesis of a series of acid shock inducible proteins (ASPs), 51 for log phase ATR and 15 for stationary phase ATR. Some of these ASPs require sigma s for their synthesis; others require the participation of the ferric uptake regulator protein Fur. Effective acid tolerance involves RecA-independent DNA repair systems, iron, and facets of fatty acid metabolism. Aspects of medium composition and carbon metabolism are also known to influence the nature of acid tolerance in this organism. In addition to aiding survival in the natural non-host environment, aspects of acid tolerance are also tied to virulence, as evidenced by the involvement of the mouse virulence locus mviA and the fact that acid-sensitive strains of S. typhimurium exhibit reduced virulence. This review summarizes these aspects of acid adaptation and includes a discussion of acid-regulated gene expression. PMID- 8688154 TI - Strategies to accelerate the applicability of gene amplification protocols for pathogen detection in meat and meat products. AB - Traditionally, microbiological testing of meat products has involved isolating microorganisms and performing specific biochemical, and in some cases serological, tests to confirm the presence or absence of suspected food-borne pathogens. Given the public attention meat products have received as sources of food-borne disease, there has been considerable interest in the application of rapid detection techniques that require hours rather than days for completion. Theoretically, rapid detection methods could reduce the time from the initial sampling to confirmation so that conclusive results would be available by the time to process the meat product. Both direct gene probe hybridization as well as gene amplification methods show promise as rapid detection techniques. At present, direct gene probe hybridization are being commercially utilized to confirm the presence of a suspected pathogen. A number of gene amplification protocols for detecting food-borne bacterial pathogens have been published. However, many of these studies have utilized spiked samples rather than naturally contaminated samples and many of them have involved extended template extraction/purification methodologies. There is still only a very limited amount of information on the efficacies of the various protocols in detecting bacterial pathogens, especially toxigenic Escherichia coli, Salmonella spp., Campylobacter spp., and Listeria spp., in naturally contaminated food samples. In order to develop gene amplification protocols that have relevance to the meat industry, there must be a concerted effort to utilize naturally contaminated samples in the development and evaluation of protocols, as well as to initiate multilaboratory round robin evaluations of select protocols. Availability of multilaboratory tested methodologies would provide a means to design pathogen detection strategies at the quality control level rather than an end product confirmatory response to an already documented outbreak. PMID- 8688155 TI - Current status of the plasmodiophorids. AB - Plasmodiophorids are a monophyletic group with uncertain systematic affinities. Features of the group include cruciform nuclear division; obligate, intracellular parasitism; biflagellated, heterocont zoospores; and environmentally resistant resting spores. Economically significant members of the group include Plasmodiophora brassicae, the causative agent of clubroot of cabbage; Spongospora subterranea, the causative agent of powdery scab of potato; and two members of the genus Polymyxa, vectors for several plant pathogenic viruses. PMID- 8688156 TI - Formation and analysis of tobacco-specific N-nitrosamines. AB - Chemical-analytical studies during the past 4 years led to several new observations on the formation of tobacco-specific N-nitrosamines (TSNA) and their occurrence in smokeless tobacco, mainstream smoke (MS), and sidestream smoke (SS) of American and foreign cigarettes. When snuff was extracted by means of supercritical fluid extraction with carbon dioxide containing 10% methanol, analysis of this material confirmed that the extraction with organic solvents had been partially incomplete. Epidemiological studies in the northern Sudan showed a high risk for oral cancer for users of toombak, a home-made oral snuff. Toombak contains 100-fold higher levels of TSNA than commercial snuff in the U.S. and Sweden. The TSNA content in the saliva of toombak dippers is at least ten times higher than that reported in the saliva of dippers of commercial snuff. Biomarker studies have shown corresponding high levels of hemoglobin adducts with metabolites of NNN and NNK as well as for urinary metabolites of NNK. These data supported the epidemiological findings. The analyses of MS of U.S. and foreign cigarettes smoked under FTC conditions revealed comparable data for the smoke of nonfilter cigarettes and filter cigarettes except in the case of low- and ultralow-yield cigarettes, which showed reduced TSNA yields. The MS of cigarettes made from Burley or dark tobacco is exceptionally high in TSNA, primarily because of the high nitrate content of those tobacco types. Taking puffs of larger volume and drawing puffs more frequently, practices observed among most smokers of cigarettes with low nicotine yield, results in high TSNA values in the MS. The formation of the lung carcinogen NNK is favored during the smoldering of cigarettes, between puffs, when SS is generated. Consequently, in most samples from indoor air polluted with environmental tobacco smoke (ETS), the highest concentration of an individual TSNA is that of NNK. When nonsmokers had remained for up to 2 h in a test laboratory with high ETS pollution, they excreted measurable amounts of NNK metabolites in the urine, indicative of the uptake of TSNA. PMID- 8688157 TI - Synthesis of tobacco-specific N-nitrosamines and their metabolites and results of related bioassays. AB - Tobacco-specific N-nitrosamines (TSNA) are the most abundant, strong carcinogens in tobacco smoke. Seven TSNA have been identified in tobacco products: N' nitrosonornicotine (NNN), N'-nitrosoanabasine (NAB), N'-nitrosoanatabine (NAT), 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanol (NNAL), 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol (iso NNAL), and 4-(methylnitrosamino)-4-3-pyridyl)butyric acid (iso-NNAC). The syntheses of these compounds are reviewed. The syntheses of 14C- and 3H-labeled NNK as well as metabolites of NNK and NNN are also discussed. Comparative assays for lung tumorigenesis in female A/J mice were carried out for six of the TSNA and for two related compounds, N-nitrosodimethylamine (NDMA) and N nitrosopyrrolidine (NPYR). They yielded the following ranking of potency: NDMA > NNK > NNAL > NPYR > NNN > NAB. Iso-NNAL and iso-NNAC were inactive. These results are also compared with previous assays of TSNA carcinogenicity in rats and hamsters. PMID- 8688159 TI - Recent studies on mechanisms of bioactivation and detoxification of 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific lung carcinogen. AB - This article reviews recent advances in the biochemistry and molecular biology of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific pulmonary carcinogen believed to be involved in the induction of lung cancer in smokers. Several aspects of NNK bioactivation are addressed, including identification of its metabolites in laboratory animals and humans, cytochrome P450 enzyme involvement in its metabolic activation, DNA and protein adduct formation, biological significance of the major DNA adducts formed, and mutations in oncogenes from tumors induced by NNK. Collectively, the presently available data provide a reasonably clear picture of NNK bioactivation in rodents, although there are still important gaps in our mechanistic understanding of NNK-induced tumorigenesis. The studies in rodents and primates have facilitated development of methods to assess NNK bioactivation in humans, which will be applicable to studies of lung cancer susceptibility and prevention. PMID- 8688158 TI - Endogenous formation of nitrosamines and oxidative DNA-damaging agents in tobacco users. AB - One-third of all cancers worldwide can be attributed to various tobacco habits. Both in tobacco smoke and smokeless tobacco, carcinogenic N-nitroso compounds (NOC) are implicated as DNA-damaging agents in cancers of the aerodigestive tract and the pancreas. The exposure from nitrosamines in certain types of tobacco use such as "toombak" in Sudan could be as high as a few milligrams per day. Using the N-nitrosoproline test, it has been shown that smoking contributes to endogenous nitrosation and likely increases NOC formation in vivo. Smokeless tobacco, most widely used in the form of chewing of betel quid (BQ) with tobacco, was shown to particularly enhance endogenous nitrosation in the oral cavity, a site where chewing habits are causally associated with cancer. Poor oral hygiene was found to contribute to the formation of nitrosamines in the oral cavity. The evidence so far accumulated demonstrates that tobacco habits increase endogenous NOC formation, thus adding to the burden of exposure by preformed carcinogenic NOC in tobacco products. In snuff dippers, the unexpected higher level of HPB released from hemoglobin, an exposure marker for carcinogenic tobacco-specific nitrosamines, has been attributed to the endogenous formation of these carcinogens. Recent studies have demonstrated that besides carcinogenic tobacco specific nitrosamines, reactive oxygen species derived from BQ ingredients could also play a role in the etiology of oral cancer in chewers. Although the use of chemopreventive agents may block nitrosation reactions in vivo in tobacco users, cessation of tobacco habits is the only safe way for an efficient reduction of cancer risk, in view of the high exposure to other (preformed) tobacco-related carcinogens. PMID- 8688160 TI - Epidemiology of cancer by tobacco products and the significance of TSNA. AB - Globally, oral cancer is one of the ten common cancers. In some parts of the world, including the Indian subcontinent, oral cancer is a major cancer problem. Tobacco use is the most important risk factor for oral cancer. The most common form of tobacco use, cigarette smoking, demonstrates a very high relative risk- in a recent cohort study (CPS II), even higher than lung cancer. In areas where tobacco is used in a smokeless form, oral cancer incidence is generally high. In the West, especially in the U.S. and Scandinavia, smokeless tobacco use consists of oral use of snuff. In Central, South, and Southeast Asia smokeless tobacco use encompasses nass, naswar, khaini, mawa, mishri, gudakhu, and betel quid. In India tobacco is smoked in many ways; the most common is bidi, others being chutta, including reverse smoking, hooka, and clay pipe. A voluminous body of research data implicating most of these forms of tobacco use emanates from the Indian subcontinent. These studies encompass case and case-series reports, and case control, cohort, and intervention studies. Collectively, the evidence fulfills the epidemiological criteria of causality: strength, consistency, temporality, and coherence. The biological plausibility is provided by the identification of several carcinogens in tobacco, the most abundant and strongest being tobacco specific N-nitrosamines such as N-nitrosonornicotine (NNN) and 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These are formed by N nitrosation of nicotine, the major alkaloid responsible for addiction to tobacco. The etiological relationship between tobacco use and oral cancer has provided us with a comprehensive model for understanding carcinogenesis. PMID- 8688161 TI - The biological significance of tobacco-specific N-nitrosamines: smoking and adenocarcinoma of the lung. AB - In the U.S., there has been a steeper rise of the incidence of lung adenocarcinoma than of squamous cell carcinoma of the lung among cigarette smokers. Since 1950, the percentage of all cigarettes sold that had filter tips increased from 0.56 to 92% in 1980 and to 97% in 1990. The tobacco of the filter cigarettes is richer in nitrate than that of the nonfilter cigarettes manufactured in past decades. Because the smoker of cigarettes with lower nicotine yield tends to smoke more intensely and to inhale the smoke more deeply than the smoker of plain cigarettes, the peripheral lung is exposed to higher amounts of nitrogen oxides, nitrosated compounds, and lung-specific smoke carcinogens. It is our working hypothesis that more intense smoking, deeper inhalation of the smoke, and higher smoke delivery of the organ-specific lung carcinogen NNK to the peripheral lung are major contributors to the increased risk of cigarette smokers for lung adenocarcinoma. Bioassay data and biochemical studies in support of this concept are discussed. PMID- 8688162 TI - Comparative carcinogenicity, metabolism, mutagenicity, and DNA binding of 7H dibenzo[c,g]carbazole and dibenz[a,j]acridine. AB - Complex mixtures that are produced from the combustion of organic materials have been associated with increased cancer mortality. These mixtures contain homocyclic and heterocyclic polycyclic aromatic hydrocarbons (PAHs), many of which are known carcinogens. In particular, N-heterocyclic aromatic compounds (NHA) are present in these mixtures. Studies to determine the metabolic activation of these compounds have been undertaken. The purpose of this review is to compare and contrast the metabolic activation and biological effects of two NHA, 7H-dibenzo[c,g]carbazole (DBC) and dibenz[a,j]acridine (DBA), in order to better assess the contribution of NHA to the carcinogenic potency of complex mixtures and to develop biomarkers of the carcinogenic process. DBC has both local and systemic effects in the mouse; it is a potent skin and liver carcinogen following topical application and a lung carcinogen following i.p. application. On the other hand, DBA is a moderate mouse skin carcinogen following topical application and a lung carcinogen following subcutaneous injection. The biological differences for DBC and DBA are reflected in target organ-specific proximate and mutagenic metabolites and DNA adduct patterns. PMID- 8688163 TI - Electrochemical biosensors for medicine and ecology. AB - Research results obtained in the last 3 years in the area of electrochemical amperometric biosensors are presented. Selective electrochemical biosensors are proposed on the basis of investigations of electrode materials, electrolyte content, selective properties of polymer materials and mediators influence. Biosensor parameters for determination of glucose, phenol and biological oxygen demand are described. PMID- 8688164 TI - Potentiometric biosensors for cholinesterase inhibitor analysis based on mediatorless bioelectrocatalysis. AB - A potentiometric method for cholinesterase inhibitor analysis based on mediatorless bioelectrocatalysis has been developed. The method includes coimmobilization of three enzymes, butyrylcholinesterase, choline oxidase and peroxidase, on composite carbon electrodes. Catalytic hydrolysis of butyrylcholine and subsequent catalytic oxidation of choline result in the formation of hydrogen peroxide leads to a shift in the electrode potential. The detection limit for trichlorfon analysis is 2 x 10(-13) M. Electrodes remain stable for at least 4 weeks when stored at 277 K. PMID- 8688165 TI - Chemiluminescent immunoenzyme biosensor with a thin-layer flow-through cell. Application for study of a real-time bimolecular antigen-antibody interaction. AB - A simple flow enzyme system for real-time continuous monitoring of interaction of biological molecules has been developed. It relies upon a thin-layer flow-through cell placed directly into the measuring compartment of the luminometer. One ligand (antibody) is immobilized on the inner surfaces of the flow cuvette, and a second ligand (antigen) labeled with a peroxidase molecule moves through the flow cell. The quantity of the complex on the surface of the cell may be monitored by measurement intensity of chemiluminescence in the reaction of peroxidase label with substrates (p-iodophenol, luminol and hydrogen peroxide). In such a way one can detect in a real-time regime the kinetics of association (or dissociation) of the complex labeled ligand-receptor on the surface of the cuvette. Due to the small thickness of the flow cell the diffusion limitations of interaction for two kinds of biomolecules (soluble and immobilized) are negligible, so the resulting intensity of chemiluminescent signal reflects the kinetics of interaction between soluble and immobilized components. The system may be successfully used for molecular recognition studies, analyzing the kinetics of bimolecular interaction and for concentration determination. PMID- 8688166 TI - A new approach for creating double-stranded DNA biosensors. AB - The principle of 'sandwich'-type biosensors based on liquid-crystalline dispersions formed from [DNA-polycation] complexes is outlined. These biosensors will find application in the determination of a range of compounds and physical factors that affect the ability of a given polycationic molecule to maintain intermolecular crosslinks between neighbouring DNA molecules. In the case of liquid-crystalline dispersions formed from [DNA-protamine] complexes, the lowest concentration of hydrolytic enzyme (trypsin) detectable was approximately 10-(14) M. PMID- 8688167 TI - Multilayer films containing immobilized nucleic acids. Their structure and possibilities in biosensor applications. AB - Langmuir-Blodgett (LB) and film technologies based on electrostatic attraction self-assembly (SA) are shown to be useful for immobilization of nucleic acids (DNA, polynucleotides) onto solid supports in sensor devices. The nucleic acids were immobilized in complexes with cationic surfactants (for LB) and polycations (for SA). Infrared spectral studies showed that DNA unfolds in multilayer LB films with octadecylamine and conserves its double helical structure in the LB films with dioctadecyldimethylammonium and in the SA films with polyallylamine, polyethylenimine and poly-L-lysine. Atomic groups and the types of interactions determining the complex formation of these films have been identified. The hydration of LB and SA films was studied to find out binding sites of water molecules and to evaluate the flexibility of nucleic acid compounds in the multilayer films. The possibilities of biosensor applications of these LB and SA films were monitored on binding of specific reagents for DNA by DNA-containing films and mononucleotides by a complementary single-stranded polynucleotide immobilized on a positively charged solid support. PMID- 8688168 TI - Acetogenins from Annonaceae, inhibitors of mitochondrial complex I. AB - One-hundred and twenty-eight different linear, epoxy, mono-tetrahydrofuran, bis tetrahydrofuran or tri-tetrahydrofuran acetogenins have been isolated from the Annonaceae. These new secondary metabolites are potent cytotoxic inhibitors of the mitochondrial NADH:ubiquinone oxidoreductase (complex I of the respiratory chain). PMID- 8688169 TI - Carbohydrate moieties of three radish peroxidases. AB - The carbohydrate moieties of two anionic peroxidases, termed A1 and A2, and one cationic peroxidase, named C3, from Korean radish (Raphanus sativus) were studied. For profiling of N-glycans, each peroxidase was treated with peptidyl N glycosidase F and hydrazine. These peroxidases were more susceptible to hydrazine than to peptidyl N-glycosidase F. When these three peroxidases were subjected to trifluoroacetic acid treatment, mannose, fucose and N-acetylglucosamine were released. Two major N-glycans of peroxidase C3 were isolated and treated with several glycohydrolases. Analysis of digested products of the two major N-glycans on polyacrylamide gel suggested that core-fucosylated trimannosylchitobiose may contain a different linkage from the typical alpha-1,6 of native N-linked oligosaccharide. PMID- 8688170 TI - An acidic amino acid-specific protease from germinating soybeans. AB - The degradation of the beta-conglycinin protein reserves in soybean seeds during germination and early growth begins with the proteolysis of its alpha and alpha' subunits by an enzyme called Protease C1. In the pathway, a number of proteolytic intermediates are produced and subsequently degraded. Determination of the N terminal sequences of these intermediates provides insight regarding the requirements of the cleavage sites. The N-terminal sequence of three such proteolytic intermediates has been determined. The sequence has been located in the published sequences of the beta-conglycinin subunits. Comparing these cleavage sites, plus those of two others previously delineated, shows that the P1' and P4' positions always bear either a Glu or an Asp residue while the P1 position always bears either a Glu or a Gln residue. In addition, other sites from P3 to P7' are also rich in either Glu or Asp, and the whole region is predicted to be in a alpha-helix. Consistent with the observation, synthetic poly L-Glu inhibits the Protease C1-catalysed degradation of the alpha and alpha' subunits of beta-conglycinin. Poly-L-Glu (av. M(r) = 1000) at 12.5 mM was more effective at inhibiting the reaction than poly-L-Glu (av. M(r) = 600) or poly-L Glu (av. M(r) = 14,300) at the same concentration. Comparing large synthetic polypeptides at 12.5mM, inhibition by poly-L-Asp (av. M(r) = 15,000) is as effective as poly-L-Glu (av. M(r) = 14,300), while poly-L-Ser (av. M(r) = 15,000) had no effect at all. Poly-D-Glu (av. M(r) = 15,000) is a better inhibitor than poly-L-Glu of the same size. A serine protease of similar molecular weight as Protease C1 and also capable of catalysing the proteolysis of the alpha and alpha' subunits of beta-conglycinin to generate proteolytic intermediates of the same size has been found in mung bean. PMID- 8688171 TI - Effect of cucurbitacins on mRNA coding for laccase in Botrytis cinerea. AB - The effect of cucurbitacin and of Ecballium extract on the formation of mRNA coding for laccase was examined in cultures of Botrytis cinerea grown with inducers of laccase formation, in the presence or absence of the inhibitory compounds. RNA was isolated from the cultures and probed with specific DNA probes for laccase. As an internal control, the RNA was probed for Botrytis beta-tubulin mRNA. From an analysis of the results it is clear that cucurbitacin I and Ecballium extract specifically repress the amount of mRNA coding for laccase. This could account for the previously observed repression of laccase formation by cucurbitacins. PMID- 8688172 TI - Phaeophytins from a cell suspension culture of the liverwort Plagiochila ovalifolia. AB - A suspension culture of the liverwort Plagiochila ovalifolia was established from callus tissue induced by culturing spores. From the cultured cells, four phaeophytins were isolated as major components and their structures determined by spectroscopic methods. The phaeophytin derivatives showed antibacterial activity. A major sesquiterpenoid, ovalifoliene, found in the mother plant, was detected in the cultures by GC-mass spectrometry. PMID- 8688173 TI - A cyclic heptapeptide from Vaccaria segetalis. AB - A new cyclic heptapeptide, segetalin E, cyclo(-Gly-Tyr-Val-Pro-Leu-Trp-Pro-), has been isolated from the seeds of Vaccaria segetalis and the structure elucidated by extensive two-dimensional NMR methods and chemical degradation. PMID- 8688175 TI - Diacylglycerylgalactosides from Arisaema amurense. AB - Previously undescribed 1,2-O-diacyl-3-O-beta-D-galactopyranosyl glycerols and 1,2 O-diacyl-3-O-[alpha-D-galactopyranosyl-(1"-->6')-O-beta-D- galactopyranosyl] glycerols were isolated as single components from Arisaema amurense. The cytotoxicities of these compounds against P388 and DLD-1 are described. PMID- 8688174 TI - Nonprotein amino acids from seeds of Cycas circinalis and Phaseolus vulgaris. AB - Our chemical studies on Cycas circinalis seeds from Guam has provided two new nonprotein amino acids, N-(3'-one-5'-methyl)-hexylalanine and leucine betaine. N methylisoleucine, previously reported as a component of naturally occurring peptides, has been isolated as a free amino acid from the seeds of Phaseolus vulgaris (pinto bean), together with S-methylcysteine, pipecolic acid and a dipeptide, gamma-glutamyl-leucine. PMID- 8688176 TI - The glycosidic precursor of (Z)-5-ethylidene-2(5H)-furanone in Halocarpus biformis juvenile foliage. AB - A new glycosidic lactone, (5R,6R)-5-(1-hydroxyethyl)-2(5H)-furanone beta-D glucopyranoside, has been identified as the principal precursor of (Z)-5 ethylidene-2(5H)-furanone in juvenile foliage of the New Zealand tree Halocarpus biformis. Three related lactone glycosides were isolated in smaller amounts, together with the known phenolic glycosides pyroside, arbutin and picein. The principal lactone glycoside underwent facile elimination of glucose, in neutral or basic conditions, to yield (Z)-5-ethylidene-2(5H)-furanone and its E-isomer. This lactone glycoside was also detected in foliage of H. bidwillii and H. kirkii. PMID- 8688177 TI - Aleppicatines A and B from Euphorbia aleppica. AB - Two new pentacyclic diterpene polyesters, aleppicatine A and B, have been isolated from the acetone extract of the whole plant of Euphorbia aleppica, in addition to five known cycloartane-type triterpenes (24-methylenecycloartanol, cyclolaudenol cycloart-25-en-3 beta-ol-24-one, cycloart-22-en-3 beta,25-diol and cycloart-25-en-3 beta,24-diol), scopoletin, kaempferol and 4-hydroxybenzoic acid and its methyl ether. The structures of the new compounds and their hydrolysis products have been extensively characterized by high-field NMR spectroscopic methods, including 2D NMR techniques. PMID- 8688178 TI - An unusual cycloartane triterpenoid from Cimicifuga foetida. AB - A new cycloartane triterpenoid glycoside has been isolated from the rhizomes of Cimicifuge foetida L. The spectroscopic characteristics of the new compound are different from previously described cycloartane triterpenoids because of the loss of the 24-isopropyl group as well as the presence of a 11 beta-OH group. Based on spectroscopic evidence, including a series of 2D-NMR analyses, the structure of the new triterpene is assigned as 24-des-isopropyl-7-ene-23-one-9,19; 16,24 dicycloart-3 beta,11 beta,16 alpha,24 alpha-tetraol 3-O-beta-D-xylopryanoside, named here as neocimiside. The structure of the aglycone of neocimiside was confirmed by X-ray analysis. PMID- 8688179 TI - Bufadienolides from Urginea maritima from Egypt. AB - Forty-one bufadienolides were isolated from the bulbs of Urginea maritima agg. from Egypt; 26 of them are new natural compounds. Structure elucidation was performed by comparison with authentic substances or by means of 1H, 13C NMR and FAB mass spectroscopy. Sixteen of the glycosides derive from nine structurally new aglycones: 16 beta-hydroxy-scillarenin, 16 beta-O-acetyl- scillarenin, 12 beta-hydroxy-5 alpha-4,5-dihydro-scillirosidin, 16 beta- hydroxy-5 alpha-4,5 dihydro-scillirosidin, 16 beta-O-acetyl-5 alpha-4,5- dihydro-scillirosidin, 12 beta-hydroxy-scillirubrosidin, 16 beta-O-acetyl- scillirubrosidin, 9-hydroxy scilliphaeosidine and 12 beta-hydroxy-desacetyl- scillirosidine. PMID- 8688180 TI - A pyradine-derivative from the mushroom Albatrellus confluens. AB - A novel pyradine-derivative was isolated from the mushroom Albatrellus confluens. This compound promoted melanin synthesis by B16 melanoma cells. PMID- 8688181 TI - Aliphatic and aromatic glycosides from the cell cultures of Lycopersicon esculentum. AB - The beta-D-glucoside, gentiobioside and 6-O-alpha-L-arabinosyl-beta-D-glucoside of benzyl alcohol, androsin and a new simple aliphatic glycoside, isopentylgentiobioside, have been found in the cell cultures of Lycopersicon esculentum. Their structures were elucidated from chemical and spectroscopic evidence. PMID- 8688182 TI - Novel anthocyanins produced in petals of genetically transformed lisianthus. AB - The structures of the pigments in the deep purple flowers of a lisianthus line, transformed with a UDP-glucose:flavonoid-3-O-glucosyltransferase cDNA from Antirrhinum majus, have been studied using paper chromatography, HPLC and 1H and 13C NMR spectroscopy involving the use of 1H-1H COSY and TOCSY techniques. The transgenic line is shown to have produced the new anthocyanins delphinidin-3-O beta-D-(6-O-alpha-L -rhamnopyranosylglucopyranoside)-5-O-beta-D-[6-E (and Z)-p coumaroylglucopyranoside] and delphinidin -3-O-beta-D-glucopyranoside-5-O-beta-D (6-O-E-p -coumaroylglucopyranoside) in addition to those found in the untransformed control plants. PMID- 8688183 TI - Betacyanins from plants and cell cultures of Phytolacca americana. AB - Betacyanins from cell cultures of Phytolacca americana were characterized and compared with those of the stems and ripening fruits of the plant. Whereas in fruits prebetanin (betanin 6'-O-sulphate) and its isoform predominate, in the stem and cell cultures feruloylated derivatives occur as the major components. These were rigorously identified by various spectroscopic techniques (DAD-HPLC, NMR, LC-MS and electrospray MS-MS) and carbohydrate analyses as betanidin 5-O [(5"-O-E-feruloyl)-2'-O-beta-D-apiofuranosyl] -beta-D-glucopyranoside, a new betacyanin of higher plants, and betanidin 5-O-(6'-O-E-feruloyl)-beta-D glucopyranoside (lampranthin II), together with their isoforms. PMID- 8688184 TI - Steroidal saponins from Hosta longipes and their inhibitory activity on tumour promoter-induced phospholipid metabolism of HeLa cells. AB - Three new spirostanol saponins and two new furostanol saponins were isolated from the underground parts of Hosta longipes. Their structures were determined to be (25R)-5 alpha-spirostane-2 alpha, 3 beta-diol (gitogenin) 3-O-{O-alpha-L rhamnopyranosyl-(1-->2)-beta-D-galactopyranoside}, gitogenin 3-O-{O-alpha-L rhamnopyranosyl-(1-->2) -O-[beta-D-glucopyranosyl-(1-->4)]-beta-D galactopyranoside-, (25R)-5 alpha-spirostan-3 beta-ol (tigogenin) 3-O-{O-alpha-L rhamnopyranosyl-(1-->2) -O-[beta-D-glucopyranosyl-(1-->4)]-beta-D galactopyranoside-, 26-O-beta-D-glucopyranosyl-22-O-methyl-(25R)-5 alpha furostane-2 alpha,3 beta, 22 xi,26-tetrol 3-O-{O-alpha-L-rhamnopyranosyl -(1-->2) beta-D-galactopyranoside} and 26-O-beta -D-glucopyranosyl-22-O-methyl-(25R)-5 alpha-furostane-2 alpha,3 beta,22 xi,26-tetrol 3-O-{O-alpha-L -rhamnopyranosyl-(1 ->2)-O-[beta-D-glucopyranosyl -(1-->4)]-beta-D-galactopyranoside}, respectively. The isolated saponins and their derivatives were examined for inhibitory activity on 12-O-tetradecanoylphorbor-13-acetate-stimulated 32P-incorporation into phospholipids of HeLa cells as the primary screening test to find new antitumour promoter compounds. PMID- 8688185 TI - Matesaponin 5, a highly polar saponin from Ilex paraguariensis. AB - The structure of matesaponin 5, a novel saponin isolated from the leaves of the Ilex paraguariensis, was established as ursolic acid-3-0-{beta-D-glucopyranosyl (1->3)-[alpha-L-rhamnopyranosyl-(1->2)]-alpha-L- arabino pyranosyl}-(28->1)-beta D-glucopyranosyl-(1->4)-beta-D-glucopyranosyl-(1 ->6)-beta-D-glucopyranosyl] ester. PMID- 8688186 TI - Araliasaponins XII-XVIII, triterpene saponins from the roots of Aralia chinensis. AB - Seven new oleanane-type saponins, named araliasaponins XII-XVIII, were isolated from the roots of Aralia chinensis, together with 14 known triterpene saponins. On the basis of the chemical and spectroscopic evidence, the structures of these new saponins were elucidated as follows: 3-O-beta-D-glucopyranosyl(1-->3)-[beta-D -glucopyranosyl(1-->2)]-alpha-L-arabinopyranosyl oleanolic acid 28-O-beta-D glucopyranosyl ester, 3-O-beta-D-glucopyranosyl(1-->3)-[beta-D-xylopyranosyl (1- >2)]-alpha-L-arabinopyranosyl oleanolic acid 28-O-alpha-L-rhamnopyranosyl(1-->4) beta-D-glucopyranosyl (1-->6)-beta-D-glucopyranosyl ester, 3-O-beta-D glucopyranosyl(1-->3)-[beta-D-galactopyranosyl(1-->2)] -beta-D-glucopyranosyl oleanolic acid 28-O-beta-D-glucopyranosyl ester, 3-O-beta-D-glucopyranosyl(1-->3) [beta-D -xylopyranosyl(1-->2)]-beta-D-glucopyranosyl oleanolic acid 28-O-beta-D glucopyranosyl (1-->6)-beta-D-glucopyranosyl ester, 3-O-beta-D -glucopyranosyl(1- >3)-[beta-D-galactopyranosyl (1-->2)]-beta-D-galactopyranosyl oleanolic acid 28-O beta-D-glucopyranosyl ester, 3-O-alpha-L -arabinofuranosyl(1-->4)-[beta-D glucopyranosyl (1-->2)]-beta-D-glucuronopyranosyl oleanolic acid dimethyl ester and 3-O-alpha-L-arabinofuranosyl (1-->4)-[beta-D-glucopyranosyl(1-->2)]-beta-D glucuronopyranosyl oleanolic acid 28-O-beta-D -glucopyranosyl(1-->6)-beta-D glucopyranosyl methyl ester, respectively. PMID- 8688187 TI - Saponins from Mussaenda pubescens. AB - Two new triterpenoid saponins, named mussaendosides G and K, were isolated from aerial parts of Mussaenda pubescens by normal and reverse phase chromatography. On the basis of chemical and spectroscopic methods, their structures have been elucidated as heinsiagenin A 3-O-{alpha-L-rhamnopyranosyl(1-->2)-[beta-D glucopyranosyl (1-->6)]-beta-D-glucopyranosyl(1-->2)}-alpha-L -rhamnopyranosyl(1- >4)-O-beta-D-glucopyranoside and 3 beta,19 alpha-dihydroxyl-olean-12-en-24, 28 dioic acid-24,28-di-O-beta-D-glucopyranoside, respectively. PMID- 8688188 TI - Pregnane glycosides from Caralluma retrospiciens. AB - Two pregnane ester glycosides were isolated and identified from the alcohol extract of the aerial parts of Caralluma retrospiciens. Their structures were established as 12 beta-benzoyloxy-20-isovaleroyloxy-8 beta,14 beta dihydroxypregnane-3-O -[beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl -(1- >4)-beta-D-(3-O-methyl-6-deoxy)-galactopyranoside] (caretroside A) and the bioside 12 beta-benzoyloxy-8 beta,14 beta-dihydroxypregn-20-one-3-O-[beta -D oleandropyranosyl-(1-->4)-beta-D-cymaropyranoside]. They were characterized through physical and chemical methods in addition to standard spectroscopic techniques especially 2D NMR (COSY, HMQC and HMBC). This is the first report of the isolation of these compounds from a natural source. PMID- 8688189 TI - Anthraquinones from the polar fractions of Galium sinaicum. AB - The new anthraquinones, 6,7-dimethoxy xanthopurpurin, 6-hydroxy-7-methoxy rubiadin, 5-hydroxy-6-hydroxymethyl anthragallol 1, 3-dimethyl ether, 7-carboxy anthragallol 1,3-dimethyl ether, anthragallol 1-methyl ether 3-O-beta-D glucopyranoside, anthragallol 1-methyl ether 3-O-rutinoside, anthragallol 3-O rutinoside and alizarin 1-methyl ether 2-O-primeveroside were isolated from the CH2Cl2 and n-BuOH extracts of Galium sinaicum roots and their structures were established by various spectroscopic techniques. In addition, two known anthraquinones were also isolated and fully characterized. PMID- 8688190 TI - Nevadensin glycosides from Lysionotus pauciflorus. AB - Two new flavone glucosides, nevadensin 5-O-beta-D-glucoside and nevadensin 5-O beta-D-glucosyl(1-->6)beta-D-glucoside, have been isolated from the aerial parts of Lysionotus pauciflorus. The structures have been determined by means of UV, mass spectral and one- and two-dimensional 1H and 13C NMR techniques. PMID- 8688191 TI - Iridoid glycosides from Thunbergia grandiflora. AB - The novel iridoid glycosides, isounedoside and grandifloric acid, were isolated from Thunbergia grandiflora. Grandifloric acid contains C-10 as a carboxylic acid group, the presence of which was predicted by recent iridoid biosynthesis studies carried out within T. alata. Isounedoside contains a rare 6,7-epoxide functional group. A revision in some of the NMR spectral assignments for the known iridoid glycoside alatoside was also made. PMID- 8688192 TI - Gallotannins and flavonoids from Haematoxylon campechianum. AB - Two new compounds, 2,6-bis-O-digalloyl-3-O-galloylglucose and 2-O-trigalloyl 1,3,4,6-tetrakis-O-galloylglucose, along with four known gallotannins, were isolated and identified from the leaves of Haematoxylon campechianum. In addition, four known flavonoid and three simple phenolic compounds were also detected. PMID- 8688193 TI - Inhibition of polyphenol oxidase by copper-metallothionein from Aspergillus niger. AB - Metallothionein from Aspergillus niger was found to be an inhibitor, in a model system, for the enzymic activity of a commercially purified mushroom tyrosinase. The inhibitory effect of metallothionein was higher on catechin oxidation compared with that on chlorogenic acid. The degree of inhibition of enzymic colour formation by metallothionein, using catechin as substrate, was lower than that of oxygen uptake; however, a reverse pattern was observed with chlorogenic acid as substrate. The demetallization of metallothionein did not increase its inhibitory effect on polyphenol oxidase whereas pre-incubation of the enzyme and metallothionein increased this inhibitory effect. PMID- 8688194 TI - Acetaminophen-induced toxicity to human epidermoid cell line A431 and hepatoblastoma cell line Hep G2, in vitro, is diminished by silymarin. AB - The skin and liver may be targets for cytotoxicity induced by oxidative drug metabolites. We used human epidermoid A431 cells and human hepatoblastoma Hep G2 cells as the experimental model. The aim of the study was to investigate and evaluate the effect of silymarin on acetaminophen (APAP)-induced toxicity under controlled conditions. Silymarin is known to be a potent antioxidant that diminishes toxicity induced by a variety of other hepatotoxins (e.g. Amanita phaloides, algae's toxins, carbon tetrachloride). Glutathione (GSH) depletion was enhanced by adding to the medium buthionine sulfoximine [L-buthionine-(S,R) sulfoximine, BSO]. Cells were incubated with high-concentration 5-20 mM APAP or alpha-(minimum essential medium for 2-24 h to evaluate the drug's ability to reduce cytoviability. Viability was then quantitated by metabolism of the tetrazolium dyes (MTT) and neutral red (NR). Cytoviability was 100% for controls. For Hep G2 treated for 24 h with 20 mM, APAP viability was 56.0% by MTT and 62.5% by NR. BSO-treated cells showed an enhanced cytotoxicity, determined by both assays. Administration of 0.5 mM silymarin reduced cytotoxicity significantly. In A431 cells, treatment with 20 mM APAP reduced viability by 57% (MTT) and 69% (NR) versus control (100%). BSO further decreased viability. Since incubation with silymarin showed significant protection against APAP toxicity, it can be considered a cytoprotective agent in this in vitro model of drug toxicity. GSH concentrations in both cell lines decrease significantly after exposure to 20 mM APAP, or 0.5 mM versus control (p < 0.05), and increased (p < 0.001) if incubated with APAP and silymarin. The protective effect could be through mitochondrial membrane stabilization and/or an increase in available GSH. PMID- 8688195 TI - Role of retinoic acid receptor gamma in the Rhino mouse and rabbit irritation models of retinoid activity. AB - The three retinoic acid receptors (RAR alpha, RAR beta and RAR gamma) are known to modulate the transcription of target genes through interaction of the individual receptors with their naturally occurring ligand, retinoic acid (RA). Since RA has multiple effects in vivo, considerable effort has recently been devoted to finding selective compounds to elucidate the functions of individual receptors and to relate these functions to specific in vivo effects. The racemic synthetic retinoid 6-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)hydroxy methyl]-2- naphthalene carboxylic acid has recently been identified as an RAR gamma-selective agonist. A synthetic method involving lipase-mediated transformation has been developed to prepare the individual enantiomers. Discrimination between the two enantiomers is seen in both transcriptional activity and binding to recombinant receptors with the (S)-enantiomer being the more active. Differences between the two compounds are also seen in the Rhino mouse utriculi reduction assay and the rabbit irritation model. In both animal models, the (S)-enantiomer consistently gave a greater response. Taken together, these results suggest that the activity and irritation seen with RA and related compounds is receptor mediated. Further, the strong selectivity of the compounds reported here for RAR gamma suggests that this receptor plays an important role in these in vivo biological activities. The discrimination between these enantiomers may be useful in the design of novel retinoids with uniquely defined biological properties. PMID- 8688196 TI - Cellular and topical in vivo inflammatory murine models in the evaluation of inhibitors of phospholipase A2. AB - Several novel inhibitors of human synovial fluid phospholipase A2 (HSF-PLA2) were evaluated in cellular models of inflammatory mediator release (murine macrophage and human neutrophil) and topical in vivo inflammatory skin models in mice to ascertain the scope of effects which might be observed for PLA2 inhibitors. Potent inhibition of HSF-PLA2 in vitro can be observed with compounds such as scalaradial and ellagic acid, which both have IC50 values of 0.02 microM (using autoclaved [3H]-arachidonic-acid (AA)-labelled Escherichia coli membranes as substrate). Luffariellolide, a manoalide analog, and aristolochic acid are less potent (IC50 = 5 and 46 microM, respectively) in this assay. An interesting observation is that ellagic acid in cellular assays does not inhibit macrophage eicosanoid production and only 30% inhibition of PAF biosynthesis can be obtained at 50 microM in the human neutrophil. Possibly due to its irreversible mechanism of action, scalaradial retained its potent activity in both the macrophage (IC50 for PGE2 production = 0.05 microM) and neutrophil assays (IC50 for PAF biosynthesis = 1 microM). Aristolochic acid is active in these cellular assays (macrophage IC50 = 2.5 microM and neutrophil IC50 = 100 microM), but is consistently less active than either scalaradial or luffariellolide. The relative potencies of these compounds were determined in several murine in vivo inflammatory models such as oxazolone contact hypersensitivity, AA-induced ear edema and phorbol ester (PMA)-induced ear edema. In the mouse model of oxazolone contact hypersensitivity, these PLA2 inhibitors have little effect (< or = 30% inhibition at 400 micrograms/ear) with scalaradial and luffariellolide being less effective than either aristolochic or ellagic acid. PMA-induced ear edema was effectively inhibited by scalaradial, luffariellolide and aristolochic acid (ED50 = 70, 50 and 50 micrograms/ear, respectively) whereas ellagic acid was less effective (ED50 = 230 micrograms/ear). In AA-induced ear edema, these PLA2 inhibitors had minimal effects, as would be expected for compounds which inhibit PLA2. These results, especially those of ellagic acid, suggest that caution should be taken in the extrapolation of potency against a purified human extracellular type PLA2 to the scope of activities these compounds might have in the cellular and in vivo models. The consistency of scalaradial and luffariellolide may be inherent to their irreversible mechanism of action, which is a factor to be accounted for in the extrapolation of enzyme data to cellular and in vivo models. PMID- 8688197 TI - Evidence that diazoxide promotes calcium influx in mouse keratinocyte cultures by membrane hyperpolarization. AB - We have used fura-2/AM to investigate the effect of diazoxide on the cytosolic calcium concentration (Cai) in primary mouse keratinocyte cultures. Treatment of keratinocytes with 100 microM diazoxide induced a transient peak in Cai, followed by a sustained elevation. Depletion of medium calcium by addition of EGTA abolished the diazoxide-induced Cai response, indicating that the agent promoted calcium influx without release of calcium from intracellular stores. The diazoxide-induced rise in Cai was inhibited both by addition of 60 mM KCl to the assay buffer and by preincubation with glibenclamide, a specific K+ channel blocker. In addition, studies with the membrane potential-sensitive fluorescent probe bis-oxonol demonstrated that diazoxide hyperpolarized keratinocyte membranes. These findings suggest that keratinocytes possess K+ channels, and that the previously reported proliferation effects of K+ channel openers such as diazoxide on keratinocytes may result from hyperpolarization-induced elevation of Cai. PMID- 8688198 TI - Optimization of topical erythromycin formulations by ion pairing. AB - Erythromycin (ERY) is used in the topical treatment of acne vulgaris. In order to decrease the amount of microorganisms markedly, the antibiotic must penetrate into the sebaceous follicles. Firstly, the aim of this study was to improve the lipophilicity of ERY by ion pairing. Secondly, a formulation with optimized penetration of the ion pair was developed. Thirdly, the optimized formulation was compared with formulations containing ethanol and with the commercial product Zineryt. The determination of lipophilicity was based on partition coefficients (PC) and on the penetration of ERY into a modified multilayer membrane system (MMS). It was shown that the penetration of ERY into a lipophilic acceptor system was three times higher when ion pairing between ERY and octadecansulfonate was used in comparison with the penetration of the ERY base alone. The dosage of the antibiotic used can be markedly reduced by optimizing a vehicle for the ion pair. PMID- 8688199 TI - Croconazole: an inhibitor of eicosanoid synthesis in A23187-stimulated human polymorphonuclear leukocytes and human whole blood. AB - The aim of this investigation was to ascertain possible inhibitory effects of the antimycotic agent croconazole on eicosanoid biosynthesis. Human polymorphonuclear leukocytes (PMN) and whole blood of healthy donors were pretreated with croconazole in different concentrations (0.8-100 microM) for 5 min followed by the addition of Ca ionophore A23187 (10 microM) and subsequent incubation for 10 min (PMN) and 30 min (whole blood), respectively. Thereupon the eicosanoids were determined by reversed-phase high-performance liquid chromatography. Croconazole exhibited dose-dependent inhibitory activity on the 5-lipoxygenase (5-LOX) of neutrophils. The mean half maximum inhibition concentration (IC50) of croconazole for synthesis of leukotriene B4 (LTB4) and 5-hydroxyeicosatetraenoic acid (5 HETE) was determined as 7.8 +/- 1.7 and 7.6 +/- 0.3 microM, respectively. The mean IC50 value for LTB4 estimated in whole blood was distinctly higher (27.0 +/- 3.1 microM) compared with that determined in PMN. Additionally, an inhibitory effect (IC50 9.8 +/- 2.0 microM) on the production of the cyclooxygenase (COX) product 12-hydroxyheptadecatrienoic acid (HHT) was demonstrated, whereas the production and/or releasing of 12-hydroxyeicosatetraenoic acid (12-HETE) was not attenuated by the azole. Our results in the cell-free 5-LOX system favor a direct inhibitory action of croconazole on 5-LOX, with a relatively high portion (45 77%) of reversibility. In spite of distinctly lower inhibitory potency compared with reference inhibitors such as nordihydroguaiaretic acid and indomethacin, croconazole is an effective inhibitor of arachidonic acid metabolism. Our results suggest that croconazole may be of some benefit in anti-inflammatory therapy. PMID- 8688200 TI - [Optic nerve diseases in children]. AB - The optic nerve is a part of the white matter in the central nervous system and can easily be observed with a funduscope. Neuro-ophthalmologic studies of the optic nerve is useful in monitoring disorders in the central nervous system. In this paper we presented four cases of optic nerve diseases and discussed them from the standpoint of neuro-ophthalmology. Case 1, a 9-year-old girl, had left retrobulbar optic neuritis and right papillitis which occurred one year after the onset of left optic neuritis. She was treated with a three day course of methylprednisolone (500 mg). Her left optic disc became atrophic, but her right optic disc became normal. Her visual acuity recovered to 1.0 in each eye. Relative afferent pupillary defect was seen in her left eye. Steroid therapy for optic neuritis and pupillary light reaction were discussed. Case 2 was a 7-year old girl with teratoma in the chiasmal region, and case 3 was a 10-year-old boy with craniopharyngioma. Visual field changes caused by tumors in the chiasmal region were discussed. Case 4 was a 7-year-old boy with right optic atrophy and left papilledema, an example of Foster Kennedy syndrome. The effects of papilledema on visual function was discussed. PMID- 8688201 TI - [Quality of life of children with chronic neurological diseases: introductory remarks]. AB - Recent advances in medical technology, such as an assisted ventilation, have made a big impact on pediatrics. With such a progress, many children with intractable diseases have survived intact. On the other hand, chronically ill children with handicaps have also been increasing. Some of them have been artificially supported by a respirator to maintain life in a hospital or at home. Under these social conditions, we should establish a system for total care of these children, to promote their quality of lives, in collaboration with medicine, health & welfare, and education. PMID- 8688202 TI - [Quality of life of patients with chronic neurological diseases living in institutions]. AB - The hospitals or residential institutions for patients with chronic neurological diseases have to provide the function of medical treatment and well living support. The living space should be made at home and familiar. It means 1. providing a small group life, 2. giving warm atmosphere, 3. providing living functions. Medical and living functions are necessary both in housing (hard phase) and in care given by staff (soft phase). For the QOL of children who are treated for their chronic disease in institutions, the next three conditions are important. 1. comfortable physical conditions, 2. human relations, 3. hope. PMID- 8688203 TI - [Home mechanical ventilation for children in Japan]. AB - Children who require prolonged respiratory support often have to spend their whole lives in the hospital. It is important, however, to have time with their families in their own homes. Home mechanical ventilation can make it possible. In Japan, at present, there are probably more than 100 cases in which home mechanical ventilation is being used for children. We have had experience with twelve cases of home mechanical ventilation. By using a transport respirator for these children, there have been excursions 96 times and home stays 123 times. Three of these children could be released for home stay completely. Before taking the patients out of hospital, the patients received training in nursing procedures and in skillful use of the ventilator and equipment. Home mechanical ventilation was, thereby, managed successfully by the family members. Our experience revealed that home mechanical ventilation accelerated social and emotional development of these children, especially patients with neuro-muscular diseases. However, there are also many difficulties such as limitations in regard to social services and support systems, financial and educational problems, etc. Problems related to finances and support systems are the major concerns for the families. It is important to find a way out of these difficulties from the perspective of more human medicine and of quality of life. These problems should be resolved through the government support and social services. In the near future, home mechanical ventilation for children will be probably an important part of pediatrics in Japan. PMID- 8688204 TI - [Transition of patients with chronic neurological diseases from hospital to home]. AB - The following steps are essential in promoting a successful transition. (1) General condition of the patient must be stable. (2) Both parents must give consent to home care. (3) One parent at least must be thoroughly trained in all aspects of care. (4) Medical supplies must be kept in the home, and home modification to provide easy access and movement should be done as much as possible. (5) A medical support system must be established; home visiting nurses must be provided; medical doctors in the neighborhood and the local ambulance dispatch center must be notified of the patient's condition in case of an emergency. PMID- 8688205 TI - [Quality of life for family members: health promotion for severely handicapped persons staying at home and for family members--systemic approach in Yokohama]. AB - A sociomedical study for parents was designed to answer many questions concerning the actual situation of severely handicapped persons staying at home and of their family members. After the onset of the illness, their life was greatly changed and distressful. Under this situation, the family associations sharing same problem gleamed in their daily life. About 70% of parents were satisfied with the situation that their handicapped children were at home. They were generally getting better in health. However, many requests were presented to doctors and to medical institutions including hospitals and administrations. The number of the special hospital, school and respite space must be increased as soon as possible. It was also pointed out that more combined efforts are necessary supported by the medical, educational and welfare staff, with a rapid advance of age and progress of disease. Especially we, neuro-pediatricians, must be key-persons, and have a duty to improve the quality of their life and their families. An example of systemic approach to severely handicapped persons in Yokohama was presented, which was rather successful but incomplete. PMID- 8688206 TI - [Medical care at schools for children with physical handicaps]. AB - As the number of heavily and diversely disabled children has been increasing in schools for physically handicapped children the so-called medical care has been taken up as the most important issue. Following the trend of normalization in social background, we defend children rights for education at the same time. We have to take up medical care at schools as a new educational issue to secure the quality of life for children with handicaps, however heavily and diversely disabled they may be. We have to realize the above urgently, since it is the matter of life and death for children. We have to cope with the problems of consolidation of faculties at schools, substantial in service training for teachers, cooperative work between medical facilities and schools, and other postponed measures. PMID- 8688207 TI - [QOL and nursing care of a ventilator-assisted child at home]. AB - QOL is the important issue for chronically ill children. We visited a girl, 8 years old and 24 hours dependent on a ventilator. We talked to her, and observed her daily life, mainly on the following points: (1) what she is doing; and (2) how often, and what kind of care she needs at school and at home. Then we discussed the problems, QOL and nursing care. She enjoyed her school life with her many friends, and received respiratory care, sanitary care, and other care for 11 hours and 19 minutes in average per day. 93.1% of the care was taken by her parents and volunteer care givers, so that they wanted to have nurses care for her. Many kinds of nursing care service were necessary as soon as possible. PMID- 8688208 TI - [Support system for families with sick children who need medical care at home]. AB - I reported an experience of my family which had a child with a severe chronic neurological disease (subacute sclerosing panencephalitis, SSPE) and activities of private groups to support children with intractable diseases and their families in Japan. Home care system for these handicapped children is very important and meaningful to increase "quality of life" of them and their families. However, their families have to have a lot of physical, psychological and economical stress to perform it. We cannot say that the present supporting system in medical and welfare fields in Japan is sufficient yet. Japan Welfare of Children and Families Association is a foundation to support children with intractable diseases and their families. This Association has done telephone counselling for their families, symposium for the care of them, summer camp for these children and publishing newsletters. However, it is very difficult to gather volunteers and donations as compared with those in other countries. The reason is not only the differences of culture or religion, but also the tax system. In Japan, a donation to a private non-profit group is not tax-free unlike the United States or other countries. We have to do many things to support these children and their families. PMID- 8688209 TI - [Policy for children with chronic neurological diseases]. AB - QOL for children with chronic neurological diseases (CND) depends mainly on the supporting system of children's development and respite measurements of their families. For supporting children's development with CND and for alleviating the burden on the family members, various staffs are needed such as pediatricians, nurses, psychologists, OT, PT, home helpers, etc. Especially children with CND are living at home needs in-home services supplied by these supporting staffs. An in-home care service center is desirable to be established in their living area. According to the maternal and child health law and child welfare law, several measures have been adopted, but these services are not available for children with CND and their family, without registration as handicapped children. All these children should be treated because they have the same problems as physically or mentally handicapped children. The capability of the medical and social service supply has been influenced by recent decrease of the birth rate and improvement of the level in the maternal and child health. The number of facilities, such as pediatric clinics or nursing homes for physically handicapped children, is decreasing because of poor profit. These trends will be continued if appropriate measurements are not introduced. The final estimation of need and supply must be made at the local community level. PMID- 8688210 TI - [Prognosis of severe head injury in childhood: from the viewpoint of brain plasticity]. AB - We investigated prognosis of 12 children with severe head injury, whose Glasgow Coma Scale (GCS) was less than 8 during the acute period. We divided the cases into two groups according to the age of incidence: less than 4 years (6 cases) and more than 4 years (6 cases). We examined the acute conditions (cause, type of the lesion, GCS, period of consciousness loss) and the present status (disability, intelligence quotient: IQ, functional independence measure: FIM). We used IQ and FIM scores for the indices to assess prognosis, and compared those two groups. IQ and FIM scores were better in the group whose onset was under 4 years. This difference was thought to be related to the greater plasticity and to the rehabilitation effect in younger brain. PMID- 8688211 TI - [Therapeutic effect of "Ueda" method for a case of spastic paraplegia as a sequela of transverse myelitis]. AB - This paper showed the therapeutic effect of the "Ueda" method (UM) for one case with spastic paraplegia as a sequela of transverse myelitis. The effects of UM was dramatic. Two weeks after the beginning of UM, spastic gait improved moderately and inner rotation of lower extremities on supine posture changed to external rotation. Transitionally the fast stretch ROM by the procedure of straight leg raising improved to the level of the normal range four months after the beginning of UM. Although UM was originally designed for cerebral palsy, it was effective for spasticity due to transverse myelitis. Spasticity showed reversible changes depending on UM. Therapists will be able to reduce and control spasticity by means of UM. This result suggests that spasticity treated by UM does not depend on the maturity of central nervous system (CNS) or recovery of the CNS lesion, but is caused by the lesions of the spinal loop. PMID- 8688212 TI - [A familial case of Gorlin syndrome]. AB - An 11-year-old girl was admitted to Chiba University Hospital because of the infection of jaw cysts. She had many pits on her palms and soles, basal cell nevus, and typical facial features to Gorlin syndrome (nevoid basal cell carcinoma syndrome). Her 14-year-old sister and 44-year-old father also had similar clinical symptoms, thus they were diagnosed as having a familial Gorlin syndrome. Recently, the father had a complication of maxillary cancer. Colony formation tests after X-ray and ultraviolet irradiation in skin fibroblasts derived from these sisters revealed no remarkable hypersensitivity to these agents. It is important to make an early diagnosis and a proper management in Gorlin syndrome, which has cancer predisposition. PMID- 8688213 TI - [A study on VEP, SSEP in spastic diplegia with visual impairment]. PMID- 8688214 TI - [The clinical implications of Toxoplasma gondii specific DNA detected by quantitative competitive polymerase chain reaction in treated patient with congenital toxoplasmosis]. PMID- 8688215 TI - [Cancers of the base of the tongue and hypopharynx: results of a multicenter randomized trial of chemotherapy prior to locoregional treatment]. AB - The authors report the results of a multicentric randomised trial assessing the effects on survival of neoadjuvant chemotherapy with cisplatin (100 mg/m2, D1) and fluorouracil (1 g/m2, D2-4) delivered before regional treatment in patients with squamous cell carcinoma of hypopharynx and base of tongue. 133 patients were enrolled in the study, and 121 were included in the analysis, 64 in group A (regional treatment alone) and 27 in group B (chemotherapy followed by regional treatment). Despite a high objective response rate to chemotherapy (primary tumour: 85%, 24% complete; nodes: 63%), overall survival was not significantly higher in group B than in group A. PMID- 8688216 TI - [Concomitant radiochemotherapy in locally advanced ORL cancers: a prospective study of 68 cases]. AB - From January 1988 to July 1992, 68 patients presenting with a locally advanced and unresectable carcinoma of the head and neck region were given 3 to 5 courses of chemotherapy (5-FU 1 g/m2, day 1 to 3, cisplatin 4 mg/m2, day 1 and 2, 15 mg/m2 day 8) combined with simultaneous radiotherapy. Patients were enrolled in two protocols. In the initial one a 70 Gy total dose was delivered in 105 days, and in the latter the same dose was given in only 63 days. Toxicity was moderate and acceptable. In the 62 evaluable patients, a complete response was observed in 62%, and partial response in 24%. The complete response rate was higher (80%) in the population enrolled in the second protocol. Overall the median survival is 18 months. At 2 and 3 years, the overall survival is 48% and 30% respectively. These results suggest an influence of overall treatment duration on complete response rate and survival. PMID- 8688217 TI - [Induction polychemotherapy before radiotherapy in carcinoma of the cavum. The experience of the Ibn Rochd-Casablanca Oncology Centre]. AB - This study is an analysis of the induction chemotherapy contribution in non metastatic nasopharyngeal carcinoma. Three chemotherapy cycles ("modified BEC" or not BEC, BEC: bleomycin-epirubicin-cisplatinum,) were delivered before irradiation in 90 patients. The rate of objective response was 57%. The chemotherapy response was better in patients no more than 35 year age, presenting with UCNT and not T4 or N3. Meanwhile, the chemotherapy protocol did not influence the response. The irradiation allowed the sterilization of 51 tumours and 49 of which were in satisfying response after chemotherapy. The sterilization by radiotherapy was influenced by the same factors as chemotherapy. The evolution showed 7 locoregional recurrences, 7 metastatic recurrences, and 2 patients presented with locoregional and metastatic recurrences. According to the Kaplan and Meier method, survival at 36 months was 61%. It was influenced by the same factors as chemotherapy and radiotherapy responses. The determining factor was indeed the chemotherapy response. PMID- 8688218 TI - [Perioperative chemotherapy of squamous cell carcinoma of the hypopharynx]. AB - The aim of this prospective study was to decrease the rate of locoregional recurrence (LRR) and distant metastasis (DM) with a multi-modality approach in hypopharyngeal squamous cell carcinoma (HSCC). Patients presenting with squamous cell carcinoma of the pyriform sinus, epilarynx or postcricoid area with indication of pharyngolaryngectomy, without previous treatment, distant metastasis, multiple primaries or general contraindications for surgery and chemotherapy were included in the study. Patients received three consecutive cycles of chemotherapy (CDDP cisplatinium 100 mg/m2 D1, 5-FU 1 g/m2 D1 to D5) before surgery, then two postoperative courses of the same chemotherapy at day 10 and 31 after surgery. Postoperative radiotherapy was initiated at day 50. Between 1986 and 1989, of 198 patients with HSCC, 60 were included in this study. Tumour response of the induction chemotherapy was: no response (NR): 22; partial response (PR): 25; complete response (CR): 11; non evaluable: 2. Forty-seven patients underwent surgery. Only two patients had no viable tumour in the surgical specimen and two others only keratin debris. Of 39 patients in which protocol treatment was respected, 4 LRR, 4 LRR + DM, 8 DM, three second head and neck primaries, and one acute myeloblastic leukemia were observed. Results were compared with those of historical series, with the same mean delay of follow up. The rate of survival at 2 and 5 years was 78% and 42% in the present series, while it was 77% and 33% in the control group, respectively (NS). PMID- 8688219 TI - [Total glossectomy with laryngectomy]. AB - Because local control of locally advanced cancer of base of tongue and larynx managed with combined chemotherapy and radiotherapy is poor, we proposed total glossectomy with total laryngectomy. Twenty-one patients underwent this operation over a period of 8 years. It was a salvage surgery for 15 patients, and an up front surgery for the 6 others. Postoperative complications occurred in ten patients, and three patients died in the postoperative period. Mean total duration of hospitalisation was 40 days. Oral feeding could be achieved in 14 patients (mean delay: 46 days), but satisfactory oesophageal voice has never been obtained. We can conclude from the analysis of this series that total glossectomy with total laryngectomy is a heavy surgery, which leads to frequent complications, severe functional sequellae, and poor survival. However, control of pain can be obtained, that justifying this heavy procedure. We recommend that patients and relatives should be fully informed about the consequences of surgery before final decision. PMID- 8688220 TI - [Value of the association of partial surgery and postoperative radiotherapy in the management of tumors of the hypopharynx. A study of 141 T1-T2 cases of hypopharyngeal cancer treated by partial surgery, radical surgery or radiotherapy alone]. AB - A retrospective study of 142 T1-T2 hypopharyngeal cancers treated from 1977 to 1988 was carried out. Forty-seven patients were treated by local conservative surgery, curage and postoperative radiotherapy of the remaining pharyngolarynx and cervical node areas (group 1), 48 by radical surgery and postoperative radiotherapy (group 2) and 47 by radiotherapy alone (group 3). There were more T1 tumors in group 1 (64%), than in group 2 (33%), and group 3 (40%). Sixty two percent of the patients of group 1 had clinical nodes, 56% of group 2 and 49% of group 3. There were 70% N+ and 30% N+ with extracapsular invasion (N+ RC+) in group 1, 81% N+ and 35% N+ RC+ in group 2. A histologically non-satisfactory resection was observed in 21% of patients of group 1 and 6% in group 2. Patients more than seventy years old comprised 11% in group 1, 15% in group 2 and 26% in group 3. Indications for radiotherapy alone was for 75% an impossibility for surgery (surgical contraindications or refusal by the patients). Overall survival was 34% at 5 years and 18% at 10 years. Five-year survival for groups 1, 2 and 3 were 48%, 33.5% and 22%. Deaths by cancer evolution was as frequent in group 2 as in group 3 (43%) but deaths by metastatic evolutions were twice as frequent in group 2 and deaths by local regional evolution twice as frequent in group 1 (2%). Treatment of group 1 was recommended because of the good survival at 5 years, 48%, and the good voice conservation, 100% (despite non-satisfactory resections and N+ RC+). At present, some of these conservative surgeries would be replaced by radiotherapy alone in case of complete response after initial chemotherapy, which would be an advantage for cases with an indication for radical surgery, but not necessarily so for cases with an indication for partial surgery, taking into account the good results that we have achieved with an association of partial surgery and radiotherapy. PMID- 8688222 TI - [Intraoperative radiotherapy of ORL cancers. Review of the literature]. AB - An optimal treatment of head and neck carcinoma is to be targeted at obtaining a good local control of the disease. Intraoperative radiotherapy is one of the means of increasing the irradiation dose in the tumoral volume. It appears particularly suitable for initial treatment of locally advanced head and neck lesions and treatment of recurrence of non irradiated tumors. PMID- 8688221 TI - [Radiotherapy of 100 cancers of the cavum]. AB - A retrospective study of 100 nasopharyngeal cancers treated between 1977 and 1991 was carried out. There were 22% T1, 18% T2, 15% T3 and 45% T4 with 31% N0, 20% N1, 36% N2 and 13% N3. Large adenopathies N2c + N3 were twice as frequent in the T1 group than in the T2, T3 and T4 groups. There were 59% UCNT (undifferentiated carcinoma of nasopharyngeal) and 41% epidermoid carcinomas. External beam therapy has been classical with 5 fractions of 1.8 Gy per week and a total dose of 75 Gy to the tumor and palpable nodes. A chemotherapy was carried out before locoregional treatment in 53%. Overall survival was 42% at 5 years and 39% at 10 years with a plateau from 4 years (45%). The major prognostic factor was T4 which gives 21% only at 5 years. The N has nearly no prognostic influence. UCNT have better survival (50% at 5 year) than epidermoid carcinomas (36%). There were more deaths by metastatic evolution with UCNT (46.5% against 17%) and much more deaths by locoregional evolution with epidermoid carcinomas (29% against 12%). Relapses were in the first 3 years in 90%. For 22 isolated local relapses 11 were treated with curative intent (5 brachytherapies and 6 new external beam radiotherapies): 6 were without cancer evolution in the observation times. PMID- 8688223 TI - [Carcinoma of the oropharynx extended to the base of the tongue: radiosurgical treatment with intraoperative radiotherapy]. AB - Treatment by surgery and postoperative radiotherapy is classical for patients with locally advanced oropharyngeal carcinoma. The poor prognosis of these tumors is associated with the frequency of locoregional relapses, and the survival of the patients treated is more limited according to the initial degree of tumoral involvement of the base of the tongue, which is a critical zone: at this level, the surgical resection must not be too large for a good preservation of the function of the tongue; high doses of radiotherapy are also required here for a fair local tumor control. Intraoperative Radiotherapy (IORT) may be available for delivery of high boosting doses of radiotherapy locally in this target volume. Between March 1988 and March 1992, 39 patients were treated for T3-T4 locally advanced oropharyngeal carcinoma, with 1/4 to 1/2 of the base of the tongue involved; 30 patients were treated for a first localization. Surgery was done by transmaxillary buccopharyngectomy (followed by vascularized myocutaneous flap) for 31 patients with lateral tumors; for 8 patients with median tumor (valleculae), either a conservative susglottic laryngectomy (5 patients) or a total laryngectomy was indicated. Patients treated for the first time underwent also a bilateral node dissection. IORT delivered 20 Gy in the target volume of the resected base of the tongue (prescribed at 90% isodose depth) by the mean of an electron beam of 6 to 13 MeV, with a collimator of 4 or 5 cm of inner diameter. Postoperative radiotherapy was indicated for all patients treated with a first localization. After a minimal follow-up of 6 months, the global survival of 28 patients treated for their first localization was 49% at more than 3 years; 64% of patients treated were locally free of disease. In the same delay, and according to the quality of the surgical resection, the survival of patients treated was 67% and 58%, respectively, if non pathological level of resection was beyond 2 mm, or unless 2 mm from the tumor limit. No complication directly related to IORT was noted. These therapeutic results demonstrate the validity of IORT as a part of a radiosurgical treatment indicated for patients with locally advanced oropharyngeal carcinomas. A longer follow-up of patients treated with a first oropharyngeal tumor is warranted for confirmation of the gain on survival observed. PMID- 8688224 TI - [Results of postoperative cervical node irradiation in carcinoma of the pharyngo larynx. A study of the cooperative group of radiotherapists]. AB - From 1981 to 1985, 428 patients presenting with an epidermoid carcinoma of the hypopharynx and/or larynx were treated with a curative intent by surgical resection and postoperative irradiation. Two-thirds of the tumours were T3 and 60% of patients presented with a clinical node involvement. The rates of local failure were 8%, 18% and 13%, respectively, for cancers of the larynx, of the piriform sinus and of the posterior wall; the rates of regional failure were 8%, 23% and 13%, respectively. There is no head and neck site with either a high or low risk of recurrence after resection, but the capsular rupture remains a factor of poor prognosis. The survival rate at 5 years of the whole series is 38%, for laryngeal localisation it reaches 62%. The risk of metastases is related to the node involvement and the interval between surgery and irradiation. PMID- 8688225 TI - [Retrospective study of 136 cases of epidermoid carcinoma of the base of the tongue treated at the Alexis Vautrin Centre 1978-1992]. AB - Out of 332 epidermoid carcinomas of the base of the tongue treated in Centre Alexis Vautrin from 1978 to 1992, 136 received. a treatment with a curative intent. The median age was 58 years, the median follow-up was 57 months. We numbered 55 T1-T2 and 81 N0 or N1. From the therapeutic point of view, the patients were classified into three groups: in group 1 (45 cases), they were treated by external irradiation only (median dose: 71 Gy); in group 2 (72 cases), they were treated by external irradiation and brachytherapy (the mean dose delivered by external irradiation was 50 Gy, and by brachytherapy, the mean dose was 30 Gy with a mean dose rate of 55 cGy/h); in group 3 (19 cases), they were treated by a radiosurgical association, the surgical resection was always mutilating and completed by an external irradiation (55 Gy), 8 patients received an associated barrier brachytherapy. Thirty-nine patients presented a local failure, 50 a locoregional evolution. The rate of local control at 5 years was 19% for group 1, 39% for group 2 and 32% for group 3. The calculation of the equivalent biologic dose in group 1 allows to separate this population into two subgroups whose survival rates are significantly different (at 3 years: 26% and 6%, P = 0.02) and shows the influence of fractionation and treatment time. The actuarial survival at 3 years is 19% for group 1, 55% for group 2 and 45% for group 3, the survival without evolution is 33% for group 1, 66% for group 2 and 72% for group 3. For the whole series, we numbered 18 complications of grade equal or superior to 2 (healing in more than 3 months, or sequelae or death) out of which four bone complication and 14 tissular complications that occurred in a mean delay of 9 months. Because of technical modifications, there have been no grade complications for implantations performed from 1989. The prognosis remains poor for cancers of the base of the tongue. The rates of survival are still low when they are treated by external irradiation only. There seems to exist a slight advantage in favour of the radio-brachytherapy association compared to the radiosurgical association with a lower rate of sequelae and mutilations. PMID- 8688227 TI - Tuberculosis throughout history. PMID- 8688226 TI - [Comparison of concomitant radiotherapy and chemotherapy with radiotherapy alone in advanced cancers of the head and neck: results of a randomized trial]. AB - From April 1987 to October 1992, 67 patients with inoperable squamous cell carcinoma of the head and neck region were included in a randomized trial. All patients had induction chemotherapy with cisplatin (100 mg/m2, D1) and fluorouracil (1 g/m2, from D1 to D5) every three weeks for a total of three cycles. Patients were randomized to concurrent external radiation therapy (70 Gy/39 fractions/8 weeks) and chemotherapy with cisplatin (50 mg/m2 in short infusion, D1, D15, D29, D43) and fluorouracil (5 mg/kg, intra-muscular, every Monday, Wednesday and Friday) (experimental group) versus radiotherapy alone with the same modalities (control group). The followup for living patients was 14 to 60 months with a median of 42 months. Analysis of preliminary results has shown that: 1) early and late side effects are similar in both groups; 2) after completion of treatment, the percentage of patients in complete remission was 71% (20/28) in the experimental group and 43% (12/28) in the control group; this difference was statistically significant among non responders to induction chemotherapy (1/15 versus 13/20, P = 0.001), but non significant among responders (11/13 versus 7/8) and 3) there were no differences between both randomized groups in term of 3-year overall survival and of 3-year loco-regional control. Results are discussed taking into account a review of literature. PMID- 8688228 TI - Imaging of tuberculosis--experience from 503 patients. I. Tuberculosis of the chest. AB - PURPOSE: To give an overview of 503 patients with tuberculosis (TB) and to describe the radiologic findings of chest TB. MATERIAL AND METHODS: A total of 503 patients with proven TB were reviewed; 266 had chest involvement. RESULTS: Lung lesions were demonstrated in 214 patients. Infiltrates in the basal parts of the lungs or pleural effusion were often primarily mistaken for viral or bacterial infections. Consolidations within the lungs and pleural thickening were sometimes indistinguishable from malignancy. Positive culture of the sputum without lung lesions was encountered in 12 cases. Enlarged mediastinal lymph nodes were demonstrated in 67 cases, 35 without lesions in the lungs. The lymphadenopathy could be extensive, and both clinically and radiologically indistinguishable from lymphoma. CONCLUSION: Due to the present increase in incidence of TB and the fact that TB can mimic many other conditions, it is important that both clinicians and radiologists have TB high on the list for differential diagnoses. PMID- 8688229 TI - Imaging of tuberculosis. II. Abdominal manifestations in 112 patients. AB - PURPOSE: To describe the radiological findings of tuberculosis (TB) of the abdomen as reflected at our hospital. MATERIAL AND METHODS: The radiological files of 503 patients (referred to our institution mainly because of a clinical suspicion of malignancy, and found to have culture- or biopsy-proven TB) were reviewed in order to analyze the spectrum of the TB manifestations in this group of patients. RESULTS: Abdominal manifestations were found in 112 patients, in 1/3 abdominal disease was the only evidence of TB. More than half of the patients also had chest TB. The most common abdominal TB manifestations were peritonitis and lymph node enlargement, each occurring in about 1/3 of the patients. Also 1/3 had genitourinary TB manifestations. About 1/5 had TB of the liver, spleen or pancreas or in the gastrointestinal tract, respectively. Multiple organ involvement was common. CONCLUSION: The need to consider TB in the differential diagnosis in patients with obscure abdominal symptoms, especially with multiple organ involvement, is stressed. PMID- 8688230 TI - Imaging of tuberculosis. III. Tuberculosis as a mimicker of brain tumour. AB - PURPOSE: To show that intracranial tuberculosis (TB) often masquerades as brain tumour. MATERIAL AND METHODS: Forty-six patients with intracranial TB, who after CT at the local hospital were referred for surgery or radiotherapy of brain tumour, are presented. Sometimes the correct diagnosis was first established during surgery for brain tumour. RESULTS: The differentiation between TB and gliomas, meningiomas, metastases, or lymphomas may be impossible from the clinical history and CT findings. Angiography, done in 25 of our cases, often helped by not showing the expected tumour vasculature. MR, performed in 9 patients, helped by demonstrating a layered capsule on T2-weighted images in 4 of the lesions (hypointense rim outside hyperintense rim); the centres of the lesions were of decreased, usually very mixed T2 signal intensity. CONCLUSION: Even in patients with findings typical of brain tumour, TB remains an important differential diagnosis. PMID- 8688231 TI - Imaging of tuberculosis. IV. Spinal manifestations in 63 patients. AB - PURPOSE: To describe the radiologic findings in patients with spinal tuberculosis (TB). MATERIAL AND METHODS: Out of a total of 503 patients with TB, 63 (13%) had involvement of the spine. RESULTS: In 40 patients, the spine was the only location; 20 patients had concomitant chest TB. Conventional radiographs gave a good overview, CT visualized the disko-vertebral lesions and the paravertebral abscesses, while MR imaging was useful to determine the spread of disease to the soft tissues and the spinal canal. The typical findings were destroyed vertebrae with associated paraspinal soft-tissue mass, with or without abscess formation, sometimes also involving the epidural space together with adjoining disk lesion and focal gibbus formation. Involvement of a single vertebra was a relatively common finding. Large psoas abscesses could occur without any signs of bone involvement. The TB process could sometimes be indistinguishable from malignant processes, and in 3 patients, with multiple lesions in the spine, it mimicked metastatic disease. CONCLUSION: It is stressed that TB should always be considered in the differential diagnosis when radiologic findings suggest spinal infections or primary or secondary spinal tumors. PMID- 8688232 TI - Imaging of tuberculosis. V. Peripheral osteoarticular and soft-tissue tuberculosis. AB - PURPOSE: To assess frequency, location, and appearance of peripheral osteoarticular and soft-tissue tuberculosis (TB). MATERIAL AND METHODS: Twenty five of 503 patients with TB had peripheral osteoarticular TB and 5 had soft tissue TB. Chest radiography, CT, and MR imaging were applied. RESULTS: The location of the osteoarticular lesion was articular/epiphyseal in 14 patients, articular/metaphyseal in 3, and metaphyseal without joint involvement in 3. Involvement of flat bone was found in 4 patients (5 lesions). The morphologic appearance was similar to that of a lytic tumour in 9 patients (10 lesions) and that of a destructive joint lesion in 16 patients. The soft-tissue TB in all 5 patients presented as an abscess. Twelve patients had a total of 20 additional sites of involvement: chest in 9, abdomen in 4, spine in 4, the neck in 3, and the central nervous system in one patient. CONCLUSION: On the basis of radiologic appearance, it can be difficult to differentiate peripheral osteoarticular and soft-tissue TB from other degenerative, inflammatory, or neoplastic disorders, and the importance of a high awareness is stressed in order to reach an early diagnosis. PMID- 8688233 TI - US and CT findings in the diagnosis of tuberculous peritonitis. AB - PURPOSE: To evaluate the ultrasonographic and CT findings of tuberculous peritonitis. MATERIAL AND METHODS: Ultrasonographic and CT findings of 11 patients with the ascitic type of tuberculous peritonitis were reviewed. RESULTS: All patients had ascites, and ultrasonography (US) demonstrated fine complete and incomplete mobile septations in 10 patients. In 5 of them, the ascites had a lattice-like appearance. Diffuse regular peritoneal thickening was detected in all patients by CT and in 10 patients by US. CT demonstrated infiltration of the greater omentum in 9 patients, whereas US showed omental thickening in only 5 patients. CONCLUSION: Peritoneal and omental thickening detected by CT and ascites with fine, mobile septations shown by US strongly suggest the ascitic type of tuberculous peritonitis. The 2 imaging modalities should be used together for accurate diagnosis of tuberculous peritonitis. PMID- 8688234 TI - Lymph nodes in the hepato-duodenal ligament. A comparison between ultrasound and low-field MR imaging. AB - PURPOSE: We investigated whether a low-field MR unit (0.2 T) could demonstrate and determine the size of the lymph nodes in the hepato-duodenal ligament that were previously found on ultrasound. MATERIAL AND METHODS: Eighteen patients were examined with ultrasound, MR and liver biopsy on consecutive days. RESULTS: Two thirds of the enlarged nodes detected by ultrasound were also detected with the low-field MR technique. However, the size of the nodes was slightly larger on ultrasound. CONCLUSION: Compared to low-field MR, ultrasound appears to be superior in the evaluation of lymph nodes in the liver hilus. PMID- 8688235 TI - Transurethral microwave thermotherapy. A comparison between clinical outcome and morphologic effects assessed by urethrography. AB - PURPOSE: To detect possible morphologic changes in the urethra in an attempt to clarify the effects of thermotherapy (TUMT). MATERIAL AND METHODS: Eighteen patients with symptomatic disturbance in micturition and a prostatic volume of 14 133 cm3 underwent voiding cystourethrogram and retrograde urethrogram before and 6 and 12 months after treatment. TUMT treatment was carried out with a Prostatron unit. RESULTS: No correlation was found between subjective improvement in symptoms and morphologic changes of the urethra. There were more responders among patients who received a high microwave effect. CONCLUSION: We conclude that there is no evidence to support the view that TUMT leads to significant necrosis in the prostrate with loss of tissue and retraction. Our results support the view that TUMT causes denervation of the prostate. PMID- 8688236 TI - Cervicocranial artery dissection. Detection by Doppler ultrasound and MR angiography. AB - PURPOSE: To evaluate pulsed Doppler ultrasound and MR angiography (MRA) in the diagnosis of cervicocranial dissection. MATERIAL AND METHODS: Fourteen patients with cervicocranial artery dissection were examined over a 3-year period. Twelve patients had dissection of the extracranial part of the internal carotid artery, and 2 had vertebral artery dissection. All patients were examined with pulsed Doppler ultrasound. In addition, all patients had conventional angiography (n = 9) and/or MR imaging including MRA (n = 9). RESULTS: Doppler ultrasound disclosed unspecific abnormalities in 11 of 14 dissected vessels; 3 patients had false negative Doppler findings. MRA showed vessel abnormalities in 9 of 9 patients; 2 vessels were occluded, and 7 vessels had changes typical of dissection (double lumen and/or string sign). Twelve patients had follow-up examinations with pulsed Doppler ultrasound (n = 12), conventional angiography (n = 3), and MRA/MR (n = 11). Follow-up Doppler showed complete or partial normalization in 6 of 9 patients, all confirmed by either angiography or MRA. CONCLUSION: Our findings suggest that Doppler ultrasound may be used in follow-up of pathologic Doppler findings in known dissections, and that MRA may replace angiography in the confirmative diagnosis of cervicocranial dissection. PMID- 8688237 TI - Simplified percutaneous gastrostomy. AB - PURPOSE: The aim of this study was to develop a simple radiological method for the creation of percutaneous gastrostomy. MATERIAL AND METHODS: Percutaneous gastrostomy was created in 15 patients. After a blunt dissection of the abdominal wall under local anesthesia, puncture of the stomach was performed. A 6-mm peel off introducer sheath was used to place the permanent catheter. Immediate use of the catheter was allowed. RESULTS: The procedure was successful in all cases and no procedural complications were seen. CONCLUSION: The method is simple, cost saving, and may be recommended as an alternative to other methods. PMID- 8688238 TI - Percutaneous superselective coil-embolization of intrarenal arteriovenous fistulas. Case reports. AB - PURPOSE: To evaluate the role of percutaneous transcatheter coil-occlusion in the management of uncontrollable postoperative hematuria due to iatrogenic arteriovenous (AV) fistulas. MATERIAL AND METHODS: In 2 patients, AV fistulas were occluded with percutaneous catheter-guided superselective coil embolization. RESULTS: In both cases, occlusion of the AV fistulas was successful. Only small parts (less than 10%) of the parenchyma had to be sacrificed. No hypertension occurred. CONCLUSION: Percutaneous coil embolization is a useful alternative to surgery in cases of postoperative AV fistulas. Hematuria can be effectively controlled without resulting hypertension. PMID- 8688239 TI - Percutaneous transluminal treatment of an iliac pseudoaneurysm with endoprosthesis implantation. A case report. AB - PURPOSE: Evaluation of a covered stent in the treatment of an iliac pseudoaneurysm. MATERIAL AND METHODS: During PTCA, a 61-year-old man with angina pectoris was shown to have an asymptomatic pseudoaneurysm, 5 x 4 x 4 cm, of the left common iliac artery (CIA). The patient was not a candidate for surgery. The pseudoaneurysm was treated by insertion of a covered stent (8 mm/6 cm). RESULTS: By 30 s after stent placement, the pseudoaneurysm was angiographically excluded. Twelve and 17 months after stent implantation, the patient had no symptoms from the lower extremities and the left CIA was open with normal flow in the stent. CONCLUSION: Our case illustrates the ability of a covered stent to exclude a pseudoaneurysm. Percutaneous intravascular stent placement in the management of iliac pseudoaneurysms might be the treatment of choice in patients with increased risk of major anesthesia and surgery. PMID- 8688240 TI - Reproducibility of Doppler ultrasound measurements. AB - PURPOSES: The reproducibility of Doppler ultrasound measurements was studied in a group of radiologists with different experience of such measurements. MATERIAL AND METHODS: The 12 participating radiologists measured peak systolic velocity (PSV), resistance index (RI), and pulsatility index (PI) from 3 arteries and PSV alone in one artery of a healthy person under standardized circumstances. Each participant repeated the measurements 10 times. RESULTS: Significant (p < 0.005) interobserver variation was seen in all of the variables, with an up to 14-fold difference in the PSV values measured and most variation resulting from differences between observers. The reproducibility of RI was better, most variation being within observers. Experience improved the reproducibility of the Doppler US measurements. Significant difference (p < 0.05) in Doppler US measurements was seen between the 3 experience groups. The difference was marked between the highly experienced and the medium experienced group when the variances of the measured values of PSV, RI, and PI from all 4 arteries were combined. CONCLUSION: The reproducibility of Doppler ultrasound measurements is poor. The value of the method is questionable. PMID- 8688241 TI - MR imaging in the presence of small circular metallic implants. Assessment of thermal injuries. AB - PURPOSE: The thermal effects of MR imaging in the presence of circular nonferro magnetic metallic implants were studied in 6 rabbits. MATERIAL AND METHODS: A sternotomy was performed and fixed with stainless steel wires, and small titanium rings (diameter 3 mm) were placed on the surface of the ascending aorta and subcutaneous tissue of the thigh. Four of the rabbits were exposed to an imaging procedure with a 1.5 T scanner applying a T1-weighted spin-echo sequence and a gradient echo sequence. Two of the animals served as unexposed controls. Thirty six hours after the exposure, tissues adjacent to the implants were examined histologically and compared with corresponding samples of the control animals. RESULTS: In the area of the titanium rings, histologic analysis revealed slight inflammatory changes apparently caused by the operation. No evidence of thermal injury was found, suggesting that the presence of the rings does not contraindicate MR examinations. Necrosis was noted in all of the sternal specimens. This was probably post-operative, but it impaired the assessment of thermal injury in this area. PMID- 8688242 TI - Spatial resolution requirements in digital radiography of scaphoid fractures. An ROC analysis. AB - PURPOSE: To investigate the spatial resolution requirements in digital radiography of scaphoid fractures. MATERIAL AND METHODS: Included in the study were 60 scaphoid radiographs with and 60 without fractures of the scaphoid bone. The film-screen images were digitized using pixel sizes of 115, 170, and 340 microns along with 170 microns with a 10:1 wavelet compression. The digital images were displayed on a 1280 x 1024 x 8 bits monitor, and 5 observers evaluated the images in 5 randomized sessions. The results for each pixel size were then compared to the film-screen images by ROC analysis. RESULTS: The mean area under the ROC curves was larger for the film-screen images than for the digital images at all resolutions. However, this difference was not significant when the areas under the ROC curves for the film-screen images were compared to the digital images of 115, 170, and 170 microns with 10:1 compression. There was a significant difference for the 340-microns pixel size in favour of the film screen images. The mean ROC curves for the digital images were very similar for the 115 and 170 microns pixel sizes, although slightly better for 115 microns. At 170 microns, the compression seemed to have a relatively small negative effect on the diagnostic performance; the deterioration was greater when the pixel size was increased to 340 microns. There was no obvious correlation between diagnostic performance and the experience of the observers in using work-stations. CONCLUSIONS: The pixel size of 170 microns is adequate for the detection of subtle fractures, even after wavelet compression by a ratio of 10:1. PMID- 8688243 TI - Conventional radiography and bone scintigraphy in the prognostic evaluation of Legg-Calve-Perthes disease. AB - PURPOSE: The role of conventional radiography and bone scintigraphy in predicting the outcome of Legg-Calve-Perthes disease was investigated. MATERIAL AND METHODS: The 75 children reviewed (86 hips) were followed up to the primary healing of the disease. The findings at conventional radiography (obtained at presentation, at the time of maximum capital head involvement, and at the end of the healing process of the disease) were compared to early bone scintigraphy features. RESULTS AND CONCLUSIONS: Bone scintigraphy provided more accurate information concerning the extent of the necrotic process than initial radiographs. Moreover it could determine revascularization and consequently the stage of the disease. The methods was, however, unable to predict the outcome of the disease in some cases, particularly if it was performed late after the onset of symptoms. Conventional radiography provided important information about other parameters such as "head-at-risk" signs which facilitated treatment selection. Of these signs not only lateral subluxation but also metaphyseal changes strongly predispose to severe deformity of the hip joint. PMID- 8688244 TI - MR evaluation of mediopatellar plica. AB - PURPOSE: Evaluation of the usefulness of MR imaging for diagnosing mediopatellar plica (MP) of the knee joint. MATERIAL AND METHODS: We prospectively examined MR images of 40 knee joints in 30 patients with symptoms. The pulse sequences were SE T1-weighted images (600/26 ms), T2-weighted images (1800/70), and FLASH images (320/15/flip angle 90 degrees). When a low-intensity band was found above the medial condyle of the femur on T1-weighted and T2-weighted MR images, we defined it as MP. We compared these MR findings with arthroscopic findings, including the SAKAKIBARA classification of MP. RESULTS: In 29 of the 40 knee joints in which MP was arthroscopically found, 27 were correctly diagnosed as having MP on MR. In the remaining 11 without MP, 9 were correctly diagnosed by MR. CONCLUSION: MR images are useful not only for detecting MP but also for evaluating its extension. Our results suggest that MR imaging is useful as a screening method for detecting MP before arthroscopy. PMID- 8688245 TI - Painful ankle region in rheumatoid arthritis. Analysis of soft-tissue changes with ultrasonography and MR imaging. AB - PURPOSE: To establish the diagnostic usefulness of ultrasonography (US) and MR imaging in patients with rheumatoid arthritis (RA) suffering from prolonged pain in the ankle region, where plain radiography did not demonstrate any changes. MATERIAL AND METHODS: Seventeen patients were studied with 0.1 T MR imaging and with high-frequency US. Talocrural and subtalar joints (including talonavicular joints), and medial, lateral, and extensor tendons and their synovial sheaths were examined by MR and US. RESULTS: Abnormal findings were found by MR imaging and US in altogether 76% of the patients, by MR alone in 53%, and by US alone in 59%. In 41% of the patients, lesions were demonstrated only by one method. Talocrural and subtalar joints were the most often affected sites (41% each), followed by the peroneus tendon (23%). In the joints, the abnormal findings were interpreted as synovitis; in the tendon areas, mostly as tenosynovitis. MR and US were highly significantly concordant (p < 0.0001), but correlation with clinical features was poor. CONCLUSION: In patients with pain in the ankle region, US and MR imaging can contribute to the diagnosis and localization of the abnormality when the plain radiography is normal. Easily available and inexpensive US can be recommended as the first imaging method after plain radiography. Some divergence seems to exist between US and MR, and in complicated cases both methods are recommended. PMID- 8688246 TI - Brain penetration of intrathecal iomeprol in dogs. AB - PURPOSE: Iomeprol, a new nonionic iodinated compound for intravascular use, is being evaluated as a myelographic contrast agent because of its low neurotoxicity. This study aimed to assess the degree of brain penetration of iomeprol after intrathecal administration. MATERIAL AND METHODS: Brain penetration in dogs was investigated by CT and compared with that of iopamidol, iohexol, and ioversol, currently used as myelographic contrast media (CM). Nervous tissue density was determined in different brain structures by recording Hounsfield values. RESULTS: The experiments revealed that CM diffused from the cisternae into the parenchyma, reaching a maximum at 5-24 h after injection. The density of the examined brain regions was still higher than the preinjection levels 24 h later. No differences in brain penetration were observed among the CM investigated. CONCLUSION: The study has shown that iomeprol penetrates into the brain to the same extent as the most widely used myelographic CM. PMID- 8688247 TI - Iohexol clearance for renal function measurement in gynaecologic cancer patients. AB - PURPOSE: To determine a valid and practical routine for glomerular filtration rate measurement in gynaecologic cancer patients. MATERIAL AND METHODS: The established method, endogenous creatinine clearance, was compared to 51Cr-EDTA clearance and contrast medium clearance in 68 women with various gynaecologic carcinomas. Contrast medium clearance was determined in association with conventional urography (iohexal 300 mg I/ml, 40 ml) for evaluation of urinary tract involvement by the tumour. Automated X-ray fluorescence analysis equipment was used for the plasma analysis of iohexol and clearance calculations. Endogenous creatinine clearance and 51Cr-EDTA clearance were determined according to standard routine procedures. Simultaneous determinations of contrast medium clearance and 51Cr-EDTA clearance (n = 33), contrast medium clearance and endogenous creatinine clearance (n = 50), as well as 51Cr-EDTA clearance and endogenous creatinine clearance (n = 30) were compared. RESULTS AND CONCLUSION: The mean differences were -2.8 (SD 6.6), -1.8 (SD 22.3), and 2.7 (SD 18.3) ml/min/1.73 m2, respectively. It is concluded that contrast medium clearance is as adequate as 51Cr-EDTA clearance for glomerular filtration rate measurement. We suggest that contrast medium clearance should replace endogenous creatinine clearance, especially in patients referred for urography. PMID- 8688248 TI - Effects of isosmolar contrast media on the renal cortical blood flow in mice. AB - PURPOSE: In vivo fluorescence microscopy was used in experimental studies of renal cortical microcirculation in mice. The effects of i.v. infusion of a nonionic monomeric contrast medium (iohexol), a nonionic dimeric contrast medium (iodixanol), and mannitol of corresponding osmolalities were studied. RESULTS: All infusions produced marked effects on the distribution and velocity of renal cortical blood flow. Renal cortical blood flow was inhomogeneous as regards the different capillaries. There was an initial rapid rise in the blood flow in some capillaries after all infusions, while decreased flow was seen in other capillaries. The initial increase in renal cortical blood flow (RCBF) was significantly (p < 0.05) more pronounced after infusion of iohexol than after infusion of mannitol 0.69 mol/l. In all other respects, the effects of contrast media on RCBF were the same as the effects of mannitol solutions with a corresponding osmolality. The effects of each contrast medium were the same as those of mannitol of corresponding osmolality. In the capillaries showing increased blood flow, the peak value was encountered slightly later after the infusion of iodixanol than after the infusion of iohexol. This was considered to be related to differences in viscosity rather than osmolality. CONCLUSION: The difference in osmolality between iodixanol and iohexol is of no significance with regard to their effects on RCBF. PMID- 8688249 TI - Effects of mannitol and iohexol infusions on the renal cortical blood flow in dehydrated mice. AB - In vivo fluorescence microscopy was used in experimental studies of renal cortical microcirculation in mice. The effects of intravenous infusions of equimolar concentrations of mannitol and iohexol were studied in normal lean mice and obese/hyperglycemic mice after dehydration overnight. All infusions produced marked effects in distribution and velocity of renal cortical blood flow. Initially increased blood flow was seen in a number of capillaries after infusion of both mannitol and iohexol, and renal cortical blood flow was inhomogeneous for different capillaries. A significantly (p < 0.05) larger number of capillaries with decreased blood flow, within the first minutes after start of infusion, was observed after infusion of iohexol to normal mice when the animals had been dehydrated overnight. Our results indicate that the minor adverse effects on renal cortical blood flow caused by the infusion of contrast medium are potentiated by dehydration. PMID- 8688252 TI - Lithofibrin. A new remarkably stable substance found in renal stones. AB - Besides inorganic constituents, renal stones contain organic matter known as stone matrix. We have examined such matrix obtained from stones that had been crushed by extracorporeal shock-wave lithotripsy, in order to determine its chemical properties. Morphologically, the matrix was composed of fibers of different colors, most of them exhibiting autofluorescence. Proteins or any other well-known biochemical material were not present. It was remarkably stable against chemical degradation, and could not be dissolved in hot concentrated acids or bases or any common organic solvent. Elementary analysis revealed carbon (60.8%), oxygen (26.9%), nitrogen (7.6%), hydrogen (5.3%) and sulfur (0.77%) to be present. Furthermore, X-ray emission spectroscopy revealed the presence of titanium and chromium. Solid-phase 13C NMR spectroscopy revealed the presence of aromatic and aliphatic carbon as well as carbon bound to O and/or N. The material was paramagnetic. All findings indicated the matrix to be composed of a new class of organic compound, probably a polyaromatic heterocyclic organic material. We welcome suggestions on further methods that can ultimately elucidate the nature of lithofibrins. PMID- 8688251 TI - Ether, carbonate and urethane deoxynucleoside derivatives as prodrugs. AB - 3'-Deoxythymidine and its 3'-azido derivative, 2',3'-dideoxycytidine, 2',3' dideoxyinosine and 2',3'-dideoxyadenosine have been acylated to form carbonates and urethanes in chemoselective reactions. The nucleosides have been N- and/or O alkylated by alpha-chloroethyl or chloromethyl alkyl carbonates to form alpha alkyloxycarbonyloxyethyl or alkyloxycarbonyloxymethyl derivatives. The products are lipophilic in order to facilitate transport through biological membranes and are designed to be cleaved by esterases with liberation of the bioactive nucleoside. Initial esterase cleavage of the alkylated derivatives produces hemiacetals or -aminals which subsequently dissociate to the active nucleoside. PMID- 8688250 TI - Rathke's cleft cyst. Two cases with uncommon MR signals. AB - Two patients with Rathke's cleft cyst with uncommon MR signals, hyperintensity on T1-weighted, and hypointensity on T2-weighted 3-D fast field echo (FFE) imaging are reported. We suggest that this is due to high content of cholesterol or mucopolysaccharide, possibly combined with cell debris from the cyst wall. PMID- 8688253 TI - Perioperative inadvertent hypothermia: what do we need to prevent? PMID- 8688254 TI - Gastric tonometry to monitor tissue oxygenation: more than a gut feeling? PMID- 8688256 TI - Patient-controlled extradural analgesia with bupivacaine, fentanyl, or a mixture of both, after Caesarean section. AB - In this randomized, double-blind study of 60 patients, we have assessed the analgesic efficacy of extradural bupivacaine and extradural fentanyl, either alone or in combination, after Caesarean section. Patients received 0.1% bupivacaine (group B), fentanyl 4 micrograms ml-1 (group F) or 0.05% bupivacaine combined with fentanyl 2 micrograms ml-1 (group BF) by patient-controlled extradural analgesia (PCEA). Adding fentanyl to bupivacaine reduced the dose of bupivacaine by up to 68%, improved analgesia at rest and decreased PCEA use. Motor and sensory block were decreased, but there was more pruritus. Overall patient satisfaction was increased. Adding bupivacaine to fentanyl reduced the dose of fentanyl by up to 57% without altering pain scores or PCEA use. Sensory block increased but pruritus did not decrease. Bupivacaine 0.05% produced clinically significant leg weakness in three patients. Overall patient satisfaction was not altered. There was a significant additive analgesic effect between 0.05% bupivacaine and fentanyl but no clinical benefit was demonstrated from using the combination compared with fentanyl alone for this group of postoperative patients. PMID- 8688255 TI - Continuous extradural infusion of ropivacaine for prevention of postoperative pain after major orthopaedic surgery. AB - We studied 151 patients undergoing total hip or knee arthroplasty, or cruciate ligament reconstruction in a multicentre study in Australia and New Zealand. Patients were openly allocated randomly to one of five treatment groups or to a control group. General anaesthesia was induced after introduction of extradural block with 0.5% ropivacaine. After surgery, patients received an extradural infusion of 0.2% ropivacaine at 6, 8, 10, 12 or 14 ml h-1 or received no postoperative extradural infusion (control group). All patients had access to i.v. PCA morphine for supplementary analgesia. Morphine consumption was lower in all treatment groups compared with the control group, decreasing with increasing ropivacaine infusion rate. Median VAS scores were lower in all ropivacaine infusion groups compared with the control group for the first 10 h of the study; however by the end of the study, VAS scores were similar in all groups. The higher ropivacaine infusion rates caused a slower convergence of spread of the initial sensory block and a higher degree of motor block. The overall incidence of side effects was similar, with the exception of a higher incidence of urinary retention and hypotension in the groups receiving the higher rates of ropivacaine. The quality of treatment scores were similar for all treatment groups (Br. J. Anaesth. 1996; 76: 606-610). PMID- 8688257 TI - Maternal and uteroplacental haemodynamic state in pre-eclamptic patients during spinal anaesthesia for Caesarean section. AB - We have studied the effects of crystalloid (Ringer's acetate 1 litre) preloading and subsequent spinal anaesthesia in 12 pre-eclamptic parturient patients undergoing elective Caesarean section. Maternal placental uterine artery circulation was measured using a pulsed colour Doppler technique with simultaneous measurement of maternal haemodynamic state. Despite preloading, mean maternal systolic arterial pressure (SAP) decreased significantly and marked maternal hypotension (SAP < 80% of baseline value) was recorded in two patients after induction of spinal anaesthesia. Mean central venous pressure increased significantly after preload, but decreased to baseline shortly after induction of spinal anaesthesia. Mean pulsatility index (PI) in the uterine artery did not change during preload or spinal block. In one patient, uterine artery PI increased significantly when SAP decreased to 71% of the baseline value, 14 min after induction of spinal anaesthesia. These results suggest that preload with crystalloid solution does not prevent maternal hypotension in pre-eclamptic patients, and that changes in uterine artery velocity waveforms were minor when SAP was 80% or more of baseline during spinal anaesthesia. These changes did not appear to have any major effect on the clinical condition of the neonate, as assessed by Apgar score and umbilical artery pH values. PMID- 8688258 TI - Effect of antagonism of mivacurium on recovery of extraocular muscle function. AB - We have measured extraocular muscle function in 41 patients who received neuromuscular block with mivacurium 0.2 mg kg-1 during anaesthesia with propofol, ketorolac, fentanyl and isoflurane in nitrous oxide and oxygen, which was antagonized at the end of surgery with neostigmine 0.05 mg kg-1 and glycopyrronium 0.01 mg kg-1 in 21 of these patients. Extraocular muscle function was measured before and after surgery in each group with the Maddox Wing apparatus and compared with a control group (n = 20) who breathed spontaneously the same gaseous anaesthetic mixture via a reinforced laryngeal mask airway. In patients where the action of mivacurium was antagonized, extraocular muscle function was improved significantly 20 min after antagonism (P < 0.001) compared with those who received no antagonism. At 60 min after antagonism, there were no differences between the groups. There were no differences between patients who received no neuromuscular blockers and those who received blocker and antagonist. PMID- 8688259 TI - Pharmacokinetics and pharmacodynamics of cisatracurium in patients with end-stage liver disease undergoing liver transplantation. AB - We determined the pharmacokinetics and pharmacodynamics of cisatracurium, one of the 10 isomers of atracurium, in 14 patients with end-stage liver disease undergoing liver transplantation and in 11 control patients with normal hepatic and renal function undergoing elective surgery. Blood samples were collected for 8 h after i.v. bolus administration of cisatracurium 0.1 mg kg-1 (2 x ED95). Plasma concentrations of cisatracurium and its metabolites were determined using an HPLC method with fluorescence detection. Pharmacokinetic variables were determined using non-compartmental methods. Neuromuscular block was assessed by measuring the electromyographic evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve using a Puritan-Bennett Datex (Helsinki, Finland) monitor. Pharmacodynamic modelling was completed using semi parametric effect-compartment analysis. Volume of distribution at steady state was 195 (SD 38) ml kg-1 in liver transplant patients and 161 (23) ml kg-1 in control patients (P < 0.05), plasma clearance was 6.6 (1.1) ml kg-1 min-1 in liver transplant patients and 5.7 (0.8) ml kg-1 min-1 in control patients (P < 0.05), but elimination half-lives were similar: 24.4 (2.9) min in liver transplant patients vs 23.5 (3.5) min in control patients (ns). The time to maximum block was 2.4 (0.8) min in liver transplant patients compared with 3.3 (1.0) min in control patients (P < 0.05), but the clinical effective duration of action (time to 25% recovery) was similar: 53.5 (11.9) min in liver transplant patients compared with 46.9 (6.9) min in control patients (ns). The recovery index (25-75% recovery) was also similar in both groups: 15.4 (4.2) min in liver transplant patients and 12.8 (1.9) min in control patients (ns). After cisatracurium, peak laudanosine concentrations were 16 (5) and 21 (5) ng ml-1 in liver transplant and control patients, respectively. In summary, minor differences in the pharmacokinetics and pharmacodynamics of cisatracurium in liver transplant and control patients were not associated with any clinically significant differences in recovery profiles after a single dose of cisatracurium. PMID- 8688260 TI - Soluble E-cadherin concentrations in patients with systemic inflammatory response syndrome and multiorgan dysfunction syndrome. AB - We have assessed the role of the cell-cell adhesion molecule, E-cadherin, in the pathogenesis of multiorgan failure in 24 intensive care patients with sepsis and varying degrees of organ dysfunction, compared with 21 healthy subjects. Plasma soluble E-cadherin (sE-cadherin) was measured by enzyme immunoassay. The median concentration of sE-cadherin in normal subjects was 3.21 micrograms ml-1 compared with 6.00 micrograms ml-1 in patients with sepsis and organ dysfunction (P = 0.0019). There was no statistically significant difference in concentrations of sE-cadherin in survivors compared with non-survivors. Concentrations of sE cadherin tended to increase with the severity of organ failure. We conclude that sE-cadherin is increased in inflammation and injury, and may be related to the degree of multiorgan failure after sepsis. PMID- 8688261 TI - Preoperative inhibition of angiotensin-converting enzyme improves systemic and renal haemodynamic changes during aortic abdominal surgery. AB - We studied 22 patients undergoing aortic surgery, allocated randomly to receive, before induction of anaesthesia, a single i.v. dose of enalapril 50 micrograms kg 1 or saline. During infrarenal aortic cross-clamping, we observed similar reductions in oxygen uptake in the two groups, despite greater systemic oxygen delivery in enalapril-treated patients; angiotensin-converting enzyme inhibition prevented the reduction in cardiac output and attenuated the decrease in glomerular filtration. Changes in glomerular filtration secondary to aortic clamping were related positively to changes in renal plasma flow (r = 0.83 (saline group) and r = 0.65 (enalapril group)). Creatinine clearance on the first day after operation was significantly higher in the enalapril compared with the saline group. We conclude that enalapril pretreatment is effective in improving systemic oxygen delivery, renal plasma flow and glomerular filtration during aortic abdominal surgery. PMID- 8688262 TI - Laparoscopic cholecystectomy: haemodynamic and neuroendocrine responses after pneumoperitoneum and changes in position. AB - We have assessed the potential for myocardial ischaemia during laparoscopic cholecystectomy in 16 otherwise healthy patients. Continuous ambulatory ECG monitoring was commenced 12 h before operation and continued for 24 h after operation. The neuroendocrine stress response was assessed by measuring plasma concentrations of adrenaline and noradrenaline, human growth hormone, cortisol, renin and aldosterone, and prolactin, at specified times during surgery. Acute ST segment changes in the ECG occurred in only two patients. These episodes were independent of creation of pneumoperitoneum and changes in position. Acute intraoperative increases in MAP were noted during insufflation of carbon dioxide and reverse Trendelenburg positioning (P < 0.05). A four-fold increase in plasma concentrations of renin and aldosterone was noted after pneumoperitoneum and reverse Trendelenburg positioning (P > 0.05). There was a linear correlation between changes in plasma renin and aldosterone concentrations and MAP (r = 0.97 and r = 0.85, respectively). Prolactin concentrations increased four-fold after induction of anaesthesia. Cortisol, HGH, adrenaline and noradrenaline concentrations increased after deflation of the pneumoperitoneum. The time profile-concentration changes of increased MAP and renin-aldosterone suggests a cause-effect relationship. Increased intra-abdominal pressure and reverse Trendelenburg positioning may reduce cardiac output and renal blood flow. The early increase in prolactin concentration was probably secondary to the effect of the opioid fentanyl. PMID- 8688263 TI - Comparison of the effects of urapidil and sodium nitroprusside on haemodynamic state, myocardial metabolism and function in patients during coronary artery surgery. AB - We have compared, in an open randomized study, the effects of sodium nitroprusside (SNP) and urapidil on haemodynamic state and myocardial function and metabolism in two groups of patients undergoing elective coronary artery surgery. Sixty patients were allocated randomly to one of two groups: group SNP (n = 29) received SNP at an initial rate of 1-2 micrograms kg-1 min-1; group URA (n = 31) received one or more bolus injections of urapidil 25 mg and an i.v. infusion at an initial rate of 11-21 micrograms kg-1 min-1. Baseline measurements were obtained 10 min after introduction of an echotransducer into the oesophagus. Subsequently, vasodilator therapy was started in both groups. Infusion rates were adjusted to maintain systolic arterial pressure at 80-120% of baseline values (or mean arterial pressure < 100 mm Hg). Additional measurements were obtained 10 min after the start of vasodilator therapy and after sternotomy when the pericardium was opened. At each measuring time a complete haemodynamic profile, coronary sinus blood flow (CSBF) curves, transoesophageal echocardiographic images, and arterial and coronary venous blood samples were obtained. Arterial pressure was controlled adequately in both groups. After sternotomy, heart rate and cardiac index increased in both groups. At that time, there was a significant increase in myocardial oxygen consumption and CSBF in group URA (P < 0.05). However, the ratio between myocardial oxygen demand and oxygen supply remained unchanged and there was no difference in the number of ischaemic episodes between the groups. PMID- 8688264 TI - Kinetics of methaemoglobin and serum nitrogen oxide production during inhalation of nitric oxide in volunteers. AB - Inhaled nitric oxide is used increasingly to treat pulmonary hypertension and ventilation/perfusion mismatching in seriously ill patients, but little is known of the pharmacokinetics of its two principal metabolites, methaemoglobin and nitrogen oxides (nitrates and nitrites). We have studied the changes in these metabolites in six healthy volunteers during and after 3 h inhalation of 100 volumes per million of nitric oxide. Mean nitric oxide uptake was 0.49 (SD 0.08) ml min-1 at standard temperature and pressure, corresponding to 74% of the inhaled dose. During inhalation, methaemoglobin increased monoexponentially with a time constant of 45.6 (11.1) min by 1.77 (0.47)% of total haemoglobin. Serum nitrogen oxides increased from 36.7 (7.6) to 124 (17) mumol litre-1, with a time constant of 172 (91.4) min and a volume of distribution of 331 (104) ml kg-1. The volume of distribution for methaemoglobin calculated from nitric oxide uptake and the increase in methaemoglobin, was, on average, 14.3% less than predicted blood volume, suggesting that most of the absorbed nitric oxide initially forms methaemoglobin. Serum nitrogen oxides declined initially after inhalation ceased but then increased to a second peak between 45 and 180 min later. The cause of the second peak was not determined. PMID- 8688265 TI - Heart rate variability in patients recovering from general anaesthesia. AB - We studied heart rate variability (HRV) using spectral analysis techniques in 58 adult patients recovering from general anaesthesia. The aim was to discover how HRV was affected by a variety of common preoperative, intraoperative and postoperative factors. ECG, respiration, level of consciousness, nausea, pain and arterial pressure were recorded during the first hour of recovery from general anaesthesia. HRV was found to decrease with increased weight, age, complexity of operation, use of reversal agents for neuromuscular block and preoperative beta block. These effects were not mediated by changes in respiration. HRV was unaffected by administration of morphine. The level of nausea or pain had no effect on HRV except that pain decreased the relative ratio of high frequency to low frequency power within the power spectrum. In the group of patients that did not receive reversal agents, there was an abrupt increase in HRV when patients became responsive to verbal command. PMID- 8688266 TI - Comparison of sedation with midazolam and ketamine: effects on airway muscle activity. AB - Male patients, aged 27-74 yr, without hypertension or overt cardiovascular disease were premedicated with temazepam 20 mg orally and allocated randomly to receive sedation with either midazolam (12 patients) in a dose sufficient to provide light sedation (retained response to loud voice) or ketamine 1 mg kg-1 (11 patients). Median midazolam dose was 0.08 (interquartile range 0.02) mg kg-1. The activity of the muscles of the tongue, anterior neck and scalene group was measured with surface electrodes and compared with the awake state. Muscle activity decreased significantly after midazolam in each group of muscles, to median values of 42%, 28% and 33%, respectively, of awake values. Airway obstruction occurred in 10 of 12 patients and during obstruction muscle activity increased significantly to 69%, 73% and 52% of awake values, but in all cases this was insufficient to overcome the obstruction. After ketamine, activity did not change significantly and there were no episodes of airway obstruction. Phasic muscle activity was noted after sedation in 11 subjects but there was no difference in the incidence between the two groups (midazolam, six patients; ketamine, five patients). PMID- 8688267 TI - Accumulation of foreign gases during closed-system anaesthesia. AB - In a previous study, accumulation of methane was found at the end of closed system ventilation. As on-line analysis of gas concentrations is now available, we examined the progressive increase in concentrations of methane, carbon monoxide and acetone during modern, closed-system conditions, and their influence on infrared halothane analysis, in 26 non-pregnant, gynaecological patients. A computer-controlled closed-system anaesthesia apparatus (PhysioFlex) was used for ventilation during total i.v. anaesthesia (excluding nitrous oxide or potent inhalation anaesthetics) for gynaecological laparoscopy. Methane, carbon monoxide and acetone concentrations were analysed every 15 min in a photoacoustic infrared monitor and halothane concentrations by built-in infrared spectrometry. Mean methane concentrations increased progressively after 105 min to 941 (SD 1094) ppm, but concentrations of carbon monoxide and acetone did not increase significantly. In 18 patients, the infrared measurement falsely indicated 0.79 (0.52)% "halothane" after 60 min, but no reading appeared in the other eight patients. We conclude that methane accumulated progressively under strict closed system conditions in higher concentrations than reported previously. In two thirds of patients it induced false "halothane" readings. PMID- 8688268 TI - A new tracheal tube for difficult intubation. AB - We have compared a new Portex tracheal tube with the Oxford tube in performing simulated grade 3 difficult intubations. The Portex tube was modified so that the bevel faced backwards, as in the Oxford tube. A gum elastic introducer was used with both tubes. The time taken and number of attempts needed were recorded, with changes in arterial pressure, heart rate and incidence of sore throat. Both tubes were successful in avoiding the problem of obstruction at the cords, which occurs when a standard Magill tube is used with an introducer. Thus the new tube has the merits of the Oxford tube without the disadvantages of rubber. It is suitable for both easy and difficult intubations with advantages in safety, cost and convenience. An unexpected but important finding was a clear learning effect, despite both investigators being familiar with the technique at the outset. Over the course of the study, intubation time decreased progressively (P < 0.001). This provides new evidence of the need for trainees to practise the art of intubation when the cords are not visible. Our estimate of the learning "half life" was 15 intubations; we conclude that 30 simulated grade 3 intubations would be a reasonable objective for trainees before handling high-risk cases. PMID- 8688269 TI - Failed intubation revisited: 17-yr experience in a teaching maternity unit. AB - We have reviewed 5802 Caesarean sections performed during general anaesthesia. Our use of general anaesthesia had decreased from 83% in 1981 to 23% in 1994. Despite this, the incidence of failed intubation has increased from 1 in 1984 to 1 in 250 in 1994. The problems associated with general anaesthesia in the obstetric population are increasing. Asians and African/Afrocaribbeans were represented disproportionately because of the increased use of general anaesthesia in these patients. Exposure of trainees to obstetric general anaesthetics has decreased by one-third. PMID- 8688270 TI - Haemodynamic responses to incision and sternotomy in relation to the auditory evoked potential and spontaneous EEG. AB - We investigated the effect of incision and sternotomy on the auditory evoked potential (AEP) and EEG, to try to predict a haemodynamic response to incision or sternotomy using the AEP and EEG in 41 patients undergoing cardiac surgery during propofol and alfentanil anaesthesia. The AEP and EEG were recorded before incision, between incision and sternotomy, and after sternotomy. Peak latencies and amplitudes of AEP peaks V, Na, Pa, Nb, Pb and Nc were determined. From the EEG the median, spectral edge and peak power frequencies, and percentages of delta, theta, alpha and beta power were calculated. Each patient was classified as responsive, equivocally responsive or unresponsive to incision or sternotomy based on increase in arterial pressure and heart rate on incision and sternotomy. Before incision, Nb and Pb latency and propofol concentration were higher for unresponsive patients but heart rate and median frequency before incision were lower. After sternotomy, Pa and Nb amplitude, peak power frequency and percentage alpha power were higher, and percentage theta power lower for responsive patients. Pa latency was higher after sternotomy for unresponsive patients. Using a combination of heart rate, arterial pressures and features derived from the AEP (all recorded before incision), the occurrence of a response to incision could be predicted in individual patients with a sensitivity of 85%, positive predictive accuracy of 63% and total accuracy of 72%. We conclude that AEP are more sensitive to pain stimuli than spectral features of the spontaneous EEG. In addition, the AEP may help in predicting inadequate anaesthesia. PMID- 8688271 TI - Double-blind, randomized trial of cessation of smoking after audiotape suggestion during anaesthesia. AB - We studied the use of intraoperative tape suggestion to improve the rate of cessation of smoking in 363 smokers who wanted to stop smoking. They were allocated randomly to hear a taped message encouraging them to stop smoking or to a blank tape, played during general anaesthesia. Overall 56 patients (15.4%, 95% confidence interval (CI) 11.7-19.1%) had claimed to have stopped smoking at 2 months and 29 patients (8.0%, 95% CI 5.9-10.1%) were confirmed to have stopped smoking at 6 months. There was no significant difference between the groups at either 2 or 6 months (risk ratios 1.06 and 1.09, respectively, P = 0.78). A preoperative:postoperative ratio of a visual analogue scale measuring the patient's motivation to stop smoking was not significantly different (control group 1.13 vs message group 1.10, P = 0.55). This study does not support the hypothesis that intraoperative tape suggestion can change smoking behaviour. PMID- 8688272 TI - Recall during intermittent propofol anaesthesia. AB - We discontinued temporarily an infusion of propofol for surgical reasons in 20 patients undergoing incontinence surgery. The patients, who had not received neuromuscular blockers, were allowed to regain consciousness to a level enabling them to cough on command, open their eyes, and identify and verbally confirm a randomly assigned digit shown on paper. Thereafter, 5-14 min after discontinuation of the propofol infusion, anaesthesia was reinstituted. Memory of the request to cough, a standard conversation and the digit shown was tested 1 h after anaesthesia and on the following day. Only 35% of patients were able to recall one or more of the stimuli presented during wakefulness or were even able to recall having been "awake", and there were very few differences in memory on the day after surgery compared with 1 h after anaesthesia. In comparison with corresponding stimuli given before anaesthesia, memory of material learned during wakefulness was significantly impaired (P < 0.0001). Thus patients temporarily capable of cognitive action during propofol anaesthesia may have no subsequent explicit recall of intraoperative events. PMID- 8688273 TI - Volatile anaesthetics antagonize nitrous oxide and morphine-induced analgesia in the rat. AB - We reported previously that nitrous oxide induces pre-emptive analgesia that is partially antagonized by naloxone and totally antagonized by halothane. The aims of this study were to determine if halothane and isoflurane are similar in this respect and to examine if volatile anaesthetics antagonize the analgesic effect of exogenous opioids. We found that 75% nitrous oxide prolonged tail-flick latency by 37% and this analgesia was dose-dependently inhibited by halothane and, less effectively, by isoflurane. In contrast, morphine 1.25 mg kg-1 i.v. also prolonged tail-flick latency by 35% but, unlike nitrous oxide-induced analgesia, this effect was attenuated only by high doses of halothane and was unaffected by isoflurane. Neither halothane nor isoflurane alone altered the tail flick response. We conclude that both halothane and isoflurane dose-dependently antagonized nitrous oxide analgesia but antagonized morphine-induced analgesia to a lesser extent. PMID- 8688274 TI - Effect of low-dose dopamine on intestinal villus microcirculation during normotensive endotoxaemia in rats. AB - Hypoperfusion of the gut mucosa is thought to be a factor in the development of gut barrier failure during sepsis and septic shock. Dopamine stimulates DA-1 receptors which mediate regional vasodilatation in the gut. Therefore, we have investigated the effect of low-dose dopamine (3 micrograms kg-1 min-1) on the intestinal villus microcirculation during endotoxaemia in a rat model of normotensive endotoxaemia, using in vivo videomicroscopy. Blood flow in and the diameters of central villus arterioles were measured before, immediately after and 60 min after a 1-h continuous infusion of endotoxin 1.5 mg/kg body weight. After baseline measurements were obtained, rats received either an infusion of 0.9% saline (group A; n = 7) or a volume-equivalent infusion of dopamine 3 micrograms kg-1 min-1 (group B; n = 7) throughout the study. Control animals (group C; n = 7) received no endotoxin or dopamine. In group A, villus blood flow (mean baseline 8.4 (SEM 0.9) nl min-1) decreased by 29.7 (8.9)% to 5.9 (0.9) nl min-1 immediately after endotoxin challenge and by a total of 43.1 (7.3)% to 4.7 (0.7) nl min-1 after another 60 min. Simultaneously, villus arteriolar diameters decreased from 7.8 (0.2) to 6.9 (0.3) microns and to 6.5 (0.3) microns, respectively. In group B, villus blood flow (baseline 8.7 (0.4) nl min-1) was unchanged immediately after the 1-h infusion of endotoxin (8.3 (0.4) nl min-1). However, another 60 min later blood flow decreased by 28.8 (8.0)% to 6.1 (0.7) nl min-1. In contrast with group A, the diameters of the central villus arterioles were unchanged despite administration of endotoxin (7.9 (0.2) microns; 8.1 (0.4) microns; 8.2 (0.5) microns). In group C, there were no changes in villus blood flow or arteriolar diameters throughout the study. Our results indicated that low dose dopamine did not prevent, but delayed and attenuated, the decrease in intestinal villus blood during normotensive endotoxaemia. PMID- 8688275 TI - Early effects of total hepatectomy on haemodynamic state and organ uptake of catecholamines in the pig. AB - In a previous study, we showed that plasma concentrations of catecholamines were increased during the anhepatic phase in pigs. In this study, we investigated if a constant depth of anaesthesia would prevent these changes and, if not, if the changes were caused by impaired extraction of catecholamines. We measured arterial and venous pressures, heart rate and cardiac output in 10 anaesthetized pigs. Hepatic arterial and portal venous flows were measured. Blood for measurement of catecholamines was sampled from carotid and pulmonary arteries and portal, hepatic and renal veins. After a 2-h observation period, the liver was removed and the circulation reconstituted. Measurements were made and samples obtained for another 2 h. Catecholamine concentrations increased 2-10-fold after hepatectomy. Before hepatectomy, noradrenaline was extracted by the lung (mean extraction ratio 23 (SEM 8)%) and the liver (30 (11)%); after hepatectomy, there was extraction by the kidney (24 (12)%) but extraction by the lung (29 (8)%) was unchanged. Before hepatectomy, adrenaline was extracted predominantly by the kidney (73 (5)%) and the liver (70 (6)%), with minimal extraction by the lung; after hepatectomy, extraction by the lung increased (25 (4)%) and decreased slightly in the kidney (56 (6)%). While mean arterial pressure did not change, heart rate increased by approximately 50% and cardiac index declined (ns) within 2 h after hepatectomy. There was a sharp increase in pulmonary vascular resistance after removal of the liver and changes correlated with increases in arterial plasma concentrations of catecholamines. PMID- 8688276 TI - Sevoflurane, enflurane and isoflurane have no persistent postanaesthetic effects on the central nervous system in cats. AB - Several reports have appeared on postanaesthetic convulsive disorders in humans after enflurane and isoflurane anaesthesia. However, it is controversial if enflurane induces epileptiform electroencephalogram (EEG), abnormal behaviour, or both, lasting for several days after anaesthesia in laboratory animals. We chronically implanted electrodes for EEG recording in the cortex, medial amygdala and dorsal hippocampus, and for reticular multi-unit activity (R-MUA) in the midbrain reticular formation in five cats. Two weeks later they were anaesthetized with 5.0% sevoflurane, 3.5% enflurane or 4.8% isoflurane for 3-4 h. EEG recordings, R-MUA and behaviour were observed for 1-3 h, during both wakefulness and sleep, every day for 5-7 days after anaesthesia. None of the cats showed abnormal behaviour, or EEG or R-MUA abnormalities after any of the anaesthetics, not only during wakefulness but during slow-wave and paradoxical phases of sleep. These results suggest that if seizures occur after anaesthesia, volatile anaesthesia itself may not be the cause. PMID- 8688277 TI - Prehospital monitoring of trauma patients: experience of a helicopter emergency medical service. PMID- 8688278 TI - Hydroxyethylstarch compared with modified gelatin as volume preload before spinal anaesthesia for Caesarean section. AB - We studied 90 patients undergoing elective Caesarean section under spinal anaesthesia who received lactated Ringer's solution 1000 ml with up to 1000 ml of modified gelatin, lactated Ringer's solution 1000 ml with up to 1000 ml of 6% hydroxyethylstarch or only up to 1000 ml of 6% hydroxyethylstarch. Lumbar puncture was performed as soon as 500 ml of the colloid were infused. The incidence of hypotension, number of patients requiring a vasopressor and doses of ephedrine required to restore arterial pressure were significantly lower in favour of those receiving the crystalloid-hydroxyethylstarch combination. In both groups receiving the 2000 ml preload, packed cell volume (PCV) values decreased by more than 20%, which may be of concern in patients already presenting with mild anaemia. In patients who received the colloid without the crystalloid, PCV values decreased by 14% but the risk of severe hypotension was comparable with the crystalloid-gelatin combination. PMID- 8688279 TI - Hypotension during subarachnoid anaesthesia: haemodynamic effects of colloid and metaraminol. AB - We have studied 45 patients, aged 60-95 yr, receiving subarachnoid block for neck of femur fractures. Patient received either colloid (polygeline, Haemaccel) 8 ml kg-1 (n = 15), metaraminol 5 micrograms kg-1 and 1.7 micrograms kg-1 min-1 (n = 15) or a combination of both treatments to maintain systolic arterial pressure (SAP) between 75 and 100% of baseline. If necessary, additional colloid 2 x 4 ml kg-1 or metaraminol 3 x 2.5 micrograms kg-1 was given. Arterial pressure was measured by automated oscillotonometry, central venous pressure (CVP) by a manometer and cardiac index (CI), stoke index (SI) and heart rate (HR) by transthoracic electrical bioimpedance. Systemic vascular resistance index (SVRI) was derived. Colloid was less effective than metaraminol (P < 0.05). In the colloid group, SAP and SVRI decreased and CVP, CI and SI increased (P < 0.001). In the metaraminol group, initial decreases in SAP, SVRI and CVP were restored after 10-15 min and HR decreased after 12 min (P < 0.001). In the combined group, initial decreases in SAP and SVRI were restored after 4 and 16 min, and CVP, CI, SI and HR increased (P < 0.001). Metaraminol was more effective than colloid because it increased SVRI, whereas colloid increased CVP without significantly increasing CI. PMID- 8688280 TI - Interference of volatile anaesthetics with infrared analysis of carbon dioxide and nitrous oxide tested in the Drager Cicero EM using sevoflurane. AB - In theory, setting an infrared multi-gas analyser to measure a volatile anaesthetic different from that in the sampled gas mixture may cause interference with carbon dioxide and nitrous oxide readings. The theory was investigated during evaluation of the Drager Cicero EM anaesthetic workstation for the Medical Devices Agency. Interference occurred as predicted, and was most pronounced when the vapour analyser of the Cicero EM was deliberately and erroneously set to measure isoflurane, but with sevoflurane present in the gas mixture. With 6% sevoflurane in the gas mixture, the carbon dioxide reading decreased from 5% to 3.6%, and the nitrous oxide reading increased from 0% to 8% although, as the apparent isoflurane reading was 9%, the Cicero EM would alert the operator to the problem. However, operators are encouraged to ensure that, when using gas analysers such as that incorporated into the Cicero EM, the analyser is set to measure the correct volatile anaesthetic (the Cicero EM does this automatically when a Vapor vaporizer is attached) and the breathing system does not contain any other volatile anaesthetic agents. PMID- 8688281 TI - Use of recombinant human erythropoietin to facilitate liver transplantation in a Jehovah's Witness. AB - A 46-yr-old woman with rapidly progressing primary biliary cirrhosis presented for liver transplantation. The use of preoperative recombinant human erythropoietin enabled this to be achieved without prohibited blood products. Perioperative management of this patient and general principles of management of Jehovah's Witnesses undergoing major surgery are discussed. PMID- 8688282 TI - Validation of the Edslab dual lumen oximetry catheter for continuous monitoring of jugular bulb oxygen saturation after severe head injury. AB - Continuous jugular bulb venous oximetry has been validated previously for periods of up to 12 h after calibration. We assessed a new Edslab venous oximetry catheter in 15 patients with brain injury in the intensive care unit. After insertion into the jugular bulb, the catheter was calibrated using a laboratory co-oximeter. Subsequent comparisons were made at varying intervals (range 20 min to 100 h); 78 paired samples were obtained during periods of stable recordings. Estimation of haemoglobin saturation by the methods correlated well (r2 = 0.97, P < 0.0001). Mean difference (d) was small (0.28% (SD 2.35%)) and limits of agreement (d +/- (SD x 1.96)) were acceptable (-4.88% to 4.32%). There was no appreciable drift and there was negligible bias. This catheter did not suffer from problems of light intensity described with other systems, and it provided acceptable accuracy for clinical use for periods of up to and exceeding 24 h after calibration. PMID- 8688283 TI - Ventilatory response to carbon dioxide. PMID- 8688284 TI - Improving preoxygenation. PMID- 8688285 TI - Serotonin in pre-eclampsia. PMID- 8688286 TI - Cost of volatile agents. PMID- 8688287 TI - Effect of transdermal hyoscine on nausea and vomiting. PMID- 8688288 TI - Gastric tonometry. PMID- 8688289 TI - The usefulness of method patents for surgical procedures. PMID- 8688290 TI - Histologic observation of continuity of transmural microvessels between the perigraft vessels and flow surface microostia in a porous vascular prosthesis. AB - To ascertain the histologic relationship between flow surface microostia and perigraft vessels in the healing of a porous vascular prosthesis, a series of careful histologic examinations were carried out on a preclotted, knitted Dacron graft, 8 mm in diameter and 7 cm long, after implantation in the canine infrarenal abdominal aorta for 3 months. Four adjacent longitudinal tissue blocks were taken from the middle for evaluation by means of light microscopy, scanning electron microscopy, transmission electron microscopy, and immunocytochemical staining, and the remainder of the specimen was stained with silver nitrate to allow visualization of microostia and cell borders on the flow surface. Following identification of two microostia adjacent to the area where samples had been taken for general healing evaluation, a 3 x 8 mm full-thickness block containing the microostia was embedded in glycol methacrylate and stained with hematoxylin and eosin. Of 240 serial sections cut from this block, 80 were prepared and examined. Silver staining revealed 42 microostia on the flow surface. Light, scanning, and transmission electron microscopy with endothelial factor VIII/von Willebrand factor stain confirmed a single layer of endothelial cells on the flow surface, and beneath was a well-organized neointima containing fusiform cells confirmed as smooth muscle by alpha-actin stain. Light microscopy of the serial sections revealed transmural microvessels, lined with endothelium, extending continuously between the flow surface ostia and the perigraft vessels in this porous vascular prosthesis. PMID- 8688291 TI - Protective effect of a platelet-activating factor antagonist (WEB-2086) in postischemic renal failure. AB - The purpose of this study was to evaluate the renoprotective effect of a specific platelet-activating factor antagonist (WEB-2086) in an experimental model of normothermic renal ischemia. Twenty New Zealand white rabbits were studied for 2 days before and 24 hours after a 60-minute period of renal ischemia induced by bilateral clamping of the renal arteries. The animals were divided into two groups: a control group (group A; n = 10) and a treated group (group B; n = 10). In group A the urinary flow rate decreased significantly (from 0.098 +/- 0.008 ml/min to 0.029 +/- 0.005 ml/min) (p < 0.001) and there was a significant reduction in creatinine clearance (from 11.4 +/- 1.2 ml/min to 3.4 +/- 1.1 ml/min) (p < 0.001). In group B no significant changes were observed, although the urinary flow rate increased even in the postischemic period (from 0.09 +/- 0.008 ml/min to 0.11 +/- 0.02 ml/min). Microcirculatory cortical flow showed a postischemic reduction in both groups, although it was most significant in the control group (group A = 43.7%, group B = 71.5%; p < 0.001). Histologic study showed mild damage with patchy tubular necrosis in both groups, although this injury was less severe in the treated group. The results suggest that the preoperative administration of WEB-2086 produces a potent diuretic effect with significant attenuation of postischemic acute renal failure. PMID- 8688292 TI - Outcome analysis of carotid endarterectomy in Connecticut: the impact of volume and specialty. AB - The purpose of this study was to define the relationship between the surgeon's operative experience and specialty and the postoperative morbidity and mortality of carotid endarterectomy. All patients undergoing carotid endarterectomy (code ICD-9CM 38.12) in Connecticut between October 1985 and September 1991 were retrospectively identified. A total of 3997 carotid endarterectomies were performed by 226 surgeons in four specialties: general, cardiac, vascular, and neurosurgery. Individual surgeon volume ranged from fewer than one per year to 27.5 per year (mean 2.9 carotid endarterectomies per year). Outcome was measured as a combined stroke and/or death percentage. The average combined stroke and/or death rate for the entire group was 4.9%. The combined stroke and/or death percentage was influenced significantly by the surgeon's annual volume. Surgeons who performed one or fewer carotid endarterectomies (43% of total surgeons) were 2.5 times more likely (p < 0.002) to have a poor postoperative outcome than those who performed 10 or more per year (9.3% of total surgeons). Overall there was a statistically significant correlation between a surgeon's annual volume and outcome, particularly for general surgeons. PMID- 8688293 TI - Color duplex-guided compression therapy for postcatheterization pseudoaneurysms in a community hospital. AB - Diagnostic or therapeutic arterial catheterization may be complicated by postcatheterization pseudoaneurysm. Pseudoaneurysms have generally been treated surgically, but more recently, encouraging results with duplex-guided compression therapy (DGCT) of pseudoaneurysms have been reported from university hospitals. We reviewed our experience with DGCT to assess the applicability of DGCT in a community hospital setting. Sixty-two patients presented with 63 symptomatic postcatheterization pseudoaneurysms between January 1, 1990, and December 31, 1993. Prior to October 28, 1991, all pseudoaneurysms were treated surgically. Subsequently we initiated DGCT as primary treatment for pseudoaneurysms, reserving surgery for DGCT failures and unstable patients. DGCT patients were indistinguishable from primary surgery patients, and the number of pseudoaneurysms treated did not appear to increase during the study period. DGCT was initially successful in 27 (75%) of 36 patients. Three pseudoaneurysms recurred, yielding cumulative success in 24 (67%) of 36 patients. Three of 12 DGCT failures were due to patient intolerance. DGCT was unsuccessful in three of four intra-aortic balloon pump (IABP)-associated pseudoaneurysms. There was some variation in pseudoaneurysm volume between the successful and failed groups, and a trend toward failure with larger pseudoaneurysm was not significant (13 vs. 6 cm3, p > or = 0.25). DGCT failure appears more likely in post-IABP pseudoaneurysms and possibly with larger pseudoaneurysms. Anticoagulation, type of procedure (exclusive of IABP), obesity, and other patient characteristics examined did not appear to predict success or failure of DGCT. Treatment was reserved for symptomatic patients throughout the period of study and there was no evidence that patients were more likely to be treated for pseudoaneurysms after DGCT was initiated. We conclude that DGCT is usually successful and is appropriate primary treatment for all symptomatic postcatheterization pseudoaneurysms in stable patients. PMID- 8688294 TI - Vascular operations in nonagenarians. AB - This is a retrospective study describing our experience with vascular surgical procedures performed in patients 90 years of age or older. Thirty-four procedures, including major and minor vascular reconstruction and amputation, were performed in 20 patients. The 30-day mortality rate was 6% for planned surgical procedures. The 24-month survival rate was 82% for elective major revascularizations and limb salvage was 80% in these patients. We believe that vascular reconstruction can be carried out with acceptable morbidity and mortality when the operations are planned and the patients have been chosen carefully. PMID- 8688295 TI - Endothelial cell modulation of smooth muscle cell morphology and organizational growth pattern. AB - Intimal hyperplasia is characterized by smooth muscle cell (SMC) dedifferentiation from a contractile to a synthetic phenotype prior to migration and proliferation. Regulatory mechanisms controlling SMC phenotype are not well known. This study examined the effect of endothelial cells (ECs) on SMC morphology in coculture. Subcultured bovine ECs and SMCs were plated on opposite sides of a 13 microns thick, semipermeable membrane (0.45 micron pores, Cyclopore) to allow potential humoral and cellular cross-membrane communication. SMCs were studied (5 wells/group) in coculture opposite confluent ECs (EC/SMC) and alone (SMC controls). After 4 days of culture in Dulbecco's modified Eagle medium/2.5% calf serum, SMCs were harvested. The ratio of protein/DNA was measured as an index of SMC hypertrophy (synthetic SMC phenotype). SMCs were examined with light and scanning electron microscopy to evaluate cell surface area, cellular morphology, and macroscopic growth characteristics. Flow cytometry was used to determine the cellular RNA/DNA ratio. SMC control cultures had a significantly greater protein-to-DNA content than SMCs cocultured with ECs (175 +/- 9 vs. 115 +/- 7 micrograms protein/micrograms DNA; p < 0.001). SMC control cultures also had 6.5 times greater cell surface area (5.8 +/- 0.3 x 10(3) microns2) than cocultured SMCs (0.9 +/- 0.1; p < 0.001). In SMC control cultures, SMC hypertrophy and rapid "hill and valley" formation were observed. In contrast, SMCs from the EC/SMC group exhibited a more spindle-shaped, contractile-appearing phenotype with more uniform, evenly distributed cells and no hill and valley formation. SMC control cultures also had a higher RNA/DNA ratio. Thus the presence of confluent ECs substantially altered the morphology and growth characteristic normally observed for SMCs in vitro. This coculture system provides a model to further study EC-SMC interaction, which could have important in vivo consequences. PMID- 8688296 TI - Primary aortoenteric fistula: report of eight new cases and review of the literature. AB - Primary aortoenteric fistula, a direct communication between the aorta and the intestinal tract, is a rare cause of gastrointestinal hemorrhage. Eight patients who were all treated at one hospital are described, followed by a review of all surgically treated patients reported within the past 10 years. The usual cause is erosion of an atherosclerotic aneurysm into the adherent duodenum, but a wide variety of other causes and localizations have been described. The clinical presentation is usually one of intermittent gastrointestinal hemorrhage resulting in lethal exsanguination within a matter of hours or days. Pain, a pulsatile abdominal mass, or fever may not be present. Endoscopy, arteriography, ultrasound, and CT scan can be useful in the evaluation of these patients, but physical examination and a high index of suspicion remain key to diagnosis. Primary aortoenteric fistula is more often discovered unexpectedly during exploratory laparotomy and is not usually considered as a presumptive preoperative diagnosis. Although contamination is unavoidable, most patients are treated with an in situ vascular graft and primary closure of the intestinal defect with good results. PMID- 8688297 TI - Vena cava filter disruption and central migration due to accidental guidewire manipulation: a case report. AB - Vena cava filters are now widely used as a safe and effective means of reducing the risk of pulmonary embolus in patients hospitalized with acute stroke or trauma. We report a case of traumatic disruption of vena cava filter resulting from guidewire manipulation with migration of the main structure to the heart after successful initial placement of the filter. PMID- 8688298 TI - Posterior exposure of the popliteal artery in reoperative vascular surgery. AB - Reoperative vascular surgical procedures play an important role in the successful salvage of ischemic limbs. Such secondary procedures frequently involve difficult situation where the surgical incisions and the vascular anatomy have been compromised by infection of prior surgery. In such instances an alternative surgical approach may provide a significant advantage and aid in successful revascularization. Use of the posterior approach in reoperative vascular surgery is unusual. The application of this exposure may facilitate selected secondary surgical procedures. We review the use of the posterior approach to the popliteal vessels in three patients who required reoperative vascular reconstruction. These cases illustrate the judicious application of this technique and the resultant benefit of this unusual surgical approach. PMID- 8688299 TI - Internal iliac artery aneurysm following aortic reconstruction. AB - Fewer than 100 internal iliac artery aneurysms have been reported in the English literature. Of these the incidence of true aneurysms occurring after aortic reconstruction is exceedingly low. A 73-year old man presented with 7 cm asymptomatic left internal iliac artery aneurysm 12 years after repair of an abdominal aortic aneurysm with a bifurcation graft. We report our experience with this patient along with a review of the literature and recommendations for aneurysm surveillance. PMID- 8688300 TI - Injury of a medial sacral vessel during lumbar laminectomy. AB - Vascular injury sustained during neurosurgical procedures is surprisingly rare, especially considering the anatomic proximity of major blood vessels to the vertebral column. Mortality rates are high if the injury is not recognized and definitive management is delayed. Case reports include massive hemorrhage, arteriovenous fistulas, and development of false aneurysms. Diagnostic CT scan and arteriography are useful if the patient's condition permits; however, rapid intervention is crucial to the patient's survival. After reviewing the current surgical literature, we present a case of medial sacral artery injury occurring during laminectomy. PMID- 8688301 TI - Angioscopy in vascular surgery: the state of the art. AB - Although angioscopy is considered by many vascular surgeons to be a valuable clinical tool, others view it as expensive and unnecessary. To better define the appropriate role for angioscopy in vascular surgery, a critical review of the recent literature was undertaken. Angioscopy allows more complete valvulotomies with fewer endothelial injuries when preparing autogenous veins to be used as arterial conduits, and results in more complete thromboembolectomy of native arteries and grafts. Angioscopy can replace completion arteriography in infrainguinal arterial reconstructions with an equivalent clinical outcome. Angioscopy may be useful in the assessment of carotid endarterectomy, femoral vein valve repair, and pulmonary embolectomy. It has been useful in various research applications. The rate of complications is less than 1%. Angioscopy is of benefit in preparing veins to be used as arterial conduits and in performing thromboembolectomy. In some circumstances it can replace intraoperative arteriography. Other applications await further validation. The risks of angioscopy are acceptably low. PMID- 8688302 TI - Cervical carotid to petrous carotid bypass for lesions of the upper cervical carotid artery. PMID- 8688303 TI - Lymphedema. PMID- 8688304 TI - Jean Kunlin (1904-1991). PMID- 8688305 TI - Above-knee femoropopliteal bypass grafting using endothelial cell seeded PTFE grafts: five-year clinical experience. AB - Early clinical trials using endothelial cells seeded vascular grafts failed to confirm the successful results observed in animals. Differences in seeding methods could at least partially account for this failure. The purpose of the present study was to ascertain the feasibility and intraoperative efficacy of a two-stage technique that allowed high-density seeding as in animals. The first stage of the technique consists of harvesting an autologous vein specimen under local anesthesia followed by enzymatic isolation and in vitro culture of endothelial cells. The second stage is vascular repair. During the procedure the prosthesis is precoated with autologous whole blood or plasma for 30 minutes and seeded at high density with endothelial cells incubated for 45 minutes. Between May 1988 and June 1993, 32 patients were enrolled in this study. In 11 of them, however, the technique could not be completed for various reasons including preoperative infarction in one case, failure to achieve isolation and/or cell cultures in nine cases, and contamination of cell culture in one case. Twenty-one patients (18 men and 3 women) whose mean age was 62 years (range 38 to 78) underwent above-knee femoropopliteal bypass using an endothelial cell seeded polytetrafluoroethylene graft (7 mm). The indication for surgery was intermittent claudication in 20 patients and rest pain in one. The mean size of the vein specimen was 10.5 +/- 3.5 cm2. The mean duration of in vitro cell culture was 23.5 +/- 8.5 days. The mean density of seeding was 2.9 +/- 0.8 x 105 cells/cm2 prosthesis. No major complications were encountered during the immediate postoperative period (30 days). During follow-up two patients with patent bypasses died of intercurrent causes at 2 and 36 months, respectively, one patient had an abscess in the femoral triangle that required removal of the prosthesis (75 days), and three patients presented with bypass failure (2 occlusions and 1 thromboembolic complication) at 3, 10, and 53 months, respectively. Mean follow-up in the 20 patients surviving at 3 months was 42 +/- 15 months. Cumulative primary patency (Kaplan-Meier analysis) was 95% (+/- 10) at 3 months, 89% (+/- 13) at 10 and 48 months, and 67% (+/- 39) at 53 and 76 months. The two-stage seeding technique described herein was feasible in 69% of patients not requiring emergency reconstruction and did not increase perioperative morbidity and mortality. Bypass patency in patients who underwent above-knee femoropopliteal bypass for intermittent claudication was promising. PMID- 8688306 TI - Outcome of infrainguinal endovascular revascularization procedures for limb threatening ischemia. AB - This report describes the results of 96 infrainguinal endovascular revascularization procedures performed in 86 patients with limb-threatening ischemia over a 3-year period. There were 41 women and 45 men (mean age 72.9 +/- 11.9 years) including 47 patients (51.1%) with diabetes and 13 (15.1%) with renal insufficiency. All patients had severe ischemia characterized by rest pain (18.8%), ulceration (12.5%), or gangrene (68.8%). Twelve procedures were carried out in association with conventional surgical reconstruction and in eight patients with mixed ulcers a venous procedure was performed during the same session. A total of 143 arterial lesions were treated including 61 occlusions (mean length 5.9 +/- 3.5 cm) and 82 stenoses (mean length 4.6 +/- 3 cm). The following techniques were used: transluminal angioplasty in 99 cases, laser in five cases, Rotablator in 24 cases, and aspiration thrombectomy in 15 cases. Nine patients (10.5%) died in the hospital. Initial failure was observed in 32 patients, of whom 18 underwent subsequent surgical revascularization and 14 required amputation of the extremity within 2 months. Analysis of variance was used to assess the following 12 risk factors for initial failure of endovascular revascularization: sex, age, diabetes, renal insufficiency, associated surgery, treatment of multiple lesions, artery treated, type of lesion, length of lesion, quality of runoff, use of an atherotome, and stent placement. Results showed a significant correlation between initial failure and both quality of runoff (12.9% in patients with two or more patent leg arteries vs. 36.5% in patients with one or fewer patent leg arteries; p < 0.05) and type of lesion (14.5% for stenosis vs. 45.9% for occlusion). Mean follow-up was 9.98 +/- 9.9 months and 4.7% of patients were lost. Restenosis was observed during follow-up of 16 of the 74 initially successful procedures. ANOVA was used to assess the same 12 risk factors for restenosis. Results showed a significant correlation between restenosis and both sex (10.8% in women vs. 32.4% in men; p < 0.05) and age (8% for patients > 80 years of age vs. 28.6% for patients < 80 years; p < 0.05). Primary patency, secondary patency and limb salvage rates calculated according to the actuarial method were 65%, 75%, and 84%, respectively, at 6 months and 47%, 67%, and 81%, respectively, at 1 year. Limb salvage rates for the endoluminal techniques used in this study were satisfactory, especially in elderly patients with either segmental lesions or contraindications for distal bypass. PMID- 8688307 TI - Arterial emboli of the lower limbs: analysis of risk factors for mortality and amputation. Association Universitaire de Recherche en Chirurgie. AB - To evaluate risk factors for mortality and amputation after arterial embolism of the lower limbs, we reviewed the records of 397 patients (201 men [mean age 69 +/ 14 years] and 196 women [mean age 79 +/- 12 years]) who were enrolled in a prospective study. The degree of ischemia was rated as follows: grade I in 26% of patients, grade II in 46%, and grade III in 27%. Among patients with complete obstruction, the emboli were located above the inguinal ligament in 213 limbs (46%), in the superficial or popliteal artery in 196 (43%), and at the infrapopliteal level in four (3%). The emboli were bilateral in 59 cases (15%). In 11% of patients the emboli also involved either an upper limb or a visceral or cerebral artery. The origin of the embolus was the heart in 55% of patients, an artery in 12%, and was unknown in the remaining cases. Two hundred two patients (50%) had arterial fibrillation, 33 (8%) had cardiac conduction abnormalities, 186 (47%) had ischemic heart disease, 55 (14%) had valvular heart disease, and 43 (11%) had cardiac insufficiency. The in-hospital mortality rate was 15% (n = 60) and major amputations or severe ischemic sequelae were observed in 23% (n = 91). Logistic regression analysis revealed four independent preoperative factors associated with a significantly higher risk of death: associated visceral emboli with a relative risk (RR) of 6.7 (p < 0.001), invalidism with an RR of 4.3 (p < 0.001), cardiac insufficiency with an RR of 2.4 (p = 0.001), and creatinemia > 180 ml/L with an RR of 2.1 (p = 0.01). The variables associated with an increased risk of amputation were invalidism (p = 0.001), severity of ischemia (p = 0.001), infrapopliteal location of the embolus (p = 0.001), delay of more than 12 hours before treatment of severe ischemia was initiated (p = 0.01), failure to restore arterial patency (p = 0.001), and postoperative cardiac complications (p = 0.01). PMID- 8688308 TI - Anastomosis over a stent for heavily calcified arteries. AB - In this report we describe the use of an indwelling stent for end-to-end anastomosis of an arterial prosthesis. Designed as an alternative to conventional suturing in patients with heavily calcified arteries harvested from human cadavers. After the prosthesis is introduced into the artery, an angioplasty balloon catheter is inflated to expand the Palmaz stent and press the prosthesis against the calcified wall of the popliteal artery. From January 1993 to February 1994 we used this technique for end-to-end anastomosis of a polytetrafluoroethylene graft on the popliteal artery in six patients with extensive circumferential calcification of the popliteal artery. In all patients surgery was indicated to avoid amputation and no other method was suitable (no available vein graft, poor runoff). Stent anastomosis was successful in all six patients with no postoperative complications. Intraoperative controls using arteriography and angioscopy and postoperative Doppler ultrasound studies were normal in all patients. During follow-up, graft occlusion occurred in two patients at 10 and 14 months, respectively. Three patients died after control studies at 2, 6, and 8 months had shown the grafts to be patent. No false aneurysms were detected by clinical examination or ultrasound imaging. Although our data do not allow assessment of long-term outcome, this study demonstrates the feasibility of stent anastomosis in patients with extensive, circumferential calcification of the popliteal artery. PMID- 8688309 TI - Low-molecular-weight heparin vs. unfractionated heparin in femorodistal reconstructive surgery: a multicenter open randomized study. Enoxart Study Group. AB - Several clinical trials have been conducted to study the role of low-molecular weight heparin (LMWH) in the prevention and treatment of venous thrombosis. In contrast, there have been few studies investigating LMWH in the prophylaxis in arterial thrombosis. After informed consent and institutional approval were obtained, 201 consecutive patients scheduled for femorodistal reconstructive surgery under general anesthesia were enrolled in an open randomized multicenter (n = 14) study (from November 1990 to November 1992). Immediately before arterial cross-clamping, patients were given an intravenous bolus of either enoxaparin (ENX), 75 anti-Xa IU/kg (n = 100), or unfractionated heparin (UFH), 50 IU kg (n = 101). Meanwhile the saphenous vein or a prosthetic graft was flushed with ENX (25,000 anti-Xa IU) or UFH (25,000 IU) in 250 ml of saline solution. Subsequent treatment consisted of subcutaneous administration of ENX, 75 anti-Xa IU/kg, or UFH, 150 IU kg, beginning 8 hours after the intravenous injection and then every 12 hours thereafter for 10 days. The primary end point was graft patency on day 10 +/- 2 after surgery as assessed clinically and/or by arteriography on day 10 +/- 2 and/or during reintervention or autopsy. Analysis of patients on an intention-to-treat basis (patients who received at least on injection of ENX or UFH and who had at least one end-point evaluation) showed that graft thrombosis occurred in 30 of 199 cases: eight (8%) in the ENX group and 22 (22%) in the UFH group (p = 0.009). Among the 131 patients who were evaluated by arteriography before day 12, twelve (9.1%) had graft thrombosis: four (6%) in the ENX group and eight (12.5%) in the UFH group (NS). There were no significant differences between the two groups in terms of safety--that is, there were 12 major hemorrhages in each group, and during the follow-up period five patients in the ENX group died compared to nine in the UFH group (NS). These results indicate that ENX is as safe as but more effective than UFH when used for the prevention of early graft thrombosis in patients undergoing femorodistal reconstructive surgery. PMID- 8688310 TI - Transluminal recanalization of occluded iliac arteries: a surgical experience. AB - The purpose of this study was to evaluate the feasibility of transluminal techniques in an unselected group of patients and to assess long-term outcome in successful procedures. All patients in whom iliac artery recanalization was attempted were included in this study. Patients with an occluded prosthesis or recent embolism were excluded. A total of 37 patients were studied. Assessment of the success or failure of the procedure was based on the results of control arteriography. Recanalization was deemed successful in 31 patients. This study demonstrates that transluminal recanalization of occluded iliac arteries by a surgeon is indeed feasible. Primary patency was 66% at 24 months. The potential risk, however, is long-term restenosis. Thus follow-up examination every 6 months is recommended including pressure index measurements after exercise and color Doppler ultrasonography of the recanalized zone. PMID- 8688311 TI - Isolated atherosclerotic aneurysms of the iliac arteries. AB - Atherosclerotic aneurysms limited to the iliac arteries are rare and entail a high risk of rupture. To evaluate the efficacy of prophylactic surgery, we retrospectively studied 15 patients (13 men and two women; mean age 69 years) treated for isolated iliac aneurysms in the Department of Cardiovascular Surgery at the University Hospital of Liege over a period of 18 years. They had a total of 25 aneurysms (20 common iliac and five internal iliac). Six patients were treated electively and nine on an emergency basis for rupture. Five of the emergency patients (33%) died in the early postoperative period (< 30 days); in each case the aneurysm had ruptured and an emergency operation was performed (55.5% mortality in the ruptured iliac aneurysm group). On the other hand, all patients treated electively survived. Our study is comparable to other recent series in the literature, which also reported a high incidence of rupture and death in emergency operations. Prophylactic elective surgery is recommended for iliac aneurysms. PMID- 8688312 TI - Value of angioscopy for intraoperative assessment of carotid endarterectomy. AB - From March 1992 to November 1993 we used angioscopy and arteriography for intraoperative assessment of 103 carotid endarterectomies in 96 patients. The indication for surgery was asymptomatic stenosis in 55 cases and neurologic and/or ocular symptoms in 48. Intraoperative angioscopy and arteriography were performed to allow comparison of findings. Intraoperative angioscopic images were normal in 67 cases and abnormal in 36. The defect was an intimal flap in 26 cases, detachment of the distal plaque in seven cases, and an intimal wedge in five cases. In two cases both detachment and a wedge were observed. The defect was not considered severe enough to warrant revision in 31 cases and was corrected in five cases by either vein bypass (n = 1) or revision of the endarterectomy (n = 4). In the latter four cases repeat angioscopy showed normal findings. Arteriographic and angioscopic findings were compared in 102 cases. In the 71 cases in which angioscopic findings were normal, arteriography revealed a major abnormality in three cases: kinking in one and stenosis > 40% in two. Kinking was treated by attachment of the common carotid artery and stenosis by venous bypass. In the 31 cases in which angioscopy revealed defects not considered to warrant revision, arteriography revealed stenosis > 40% in three cases treated by either prosthetic bypass (n = 2) or revision of the endarterectomy (n = 1). The false negative rate for angioscopy was 5.9% and concordance between the two methods was 94.1%. The combined mortality-morbidity rate was 1.9% (one stroke and one death). Postoperative evaluation of anatomic findings by arteriography or Doppler ultrasonography revealed asymptomatic internal carotid occlusion in one and internal carotid stenosis < 30% in four cases. Angioscopy is a simple, low-cost method in intraoperative control that can be used either as an adjunct to arteriography or as an alternative if arteriography cannot be performed. PMID- 8688313 TI - Cryopreserved arterial allografts for limb salvage in the absence of suitable saphenous vein: two-year results in 20 cases. AB - From January 1992 to November 1992, 20 cryopreserved arterial allografts were used as below-knee bypasses for repeated limb salvage in 18 patients lacking saphenous vein grafts. Arteries were obtained during multiorgan harvesting. A scheduled program of cryopreservation with 15% dimethylsulfoxide was used. Mean storage period was 37 days. All cases were matched for blood group compatibility. Patency was checked at 10 and 90 days and twice a year thereafter. Conventional arteriography was routinely performed 3 months postoperatively. Average follow-up was 26.8 months for the 18 patients and 20.8 months for the 20 bypass grafts. No patients were lost to follow-up. Aneurysmal dilation developed in one graft, which was replaced by another homograft. During follow-up 10 grafts occluded: five once, four twice, and one four times. These 10 grafts underwent a total of 16 reinterventions. Thrombectomy with angioplasty was performed 15 times and graft replacement once because of proximal and distal arterial deterioration. Primary actuarial patency was 68% at 1 year and 42% at 2 years. Secondary actuarial patency was 89% at 1 year and 72% at 2 years. Preliminary results of cryopreserved arterial allografts for repeated limb salvage in the absence of available saphenous veins are encouraging. Further studies are needed to determine the long-term deterioration rate of cryopreserved arterial allografts. PMID- 8688314 TI - Silent brain infarct after carotid artery surgery: incidence and prevention. AB - To determine the prevalence and mechanisms of postoperative silent brain infarct, brain CT was routinely performed before and after carotid endarterectomy during the same period of hospitalization. Between June 1991 and May 1993, 69 patients who underwent 74 carotid endarterectomies (five two-staged bilateral procedures) were enrolled in the study. Ipsilateral brain infarct was observed on the preoperative CT scans in 25 cases. Of these 25 infarcts, three occurred in 20 patients (15%), without symptoms, 13 in 41 patients (32%) with transient ischemic attacks (TIAs), and 9 in 13 patients (70%) with cerebrovascular accident. After surgery, two patients (2.7% of procedures) had monoparesia of an upper limb with no corresponding abnormality seen on CT scans, and two (2.7%) had TIAs, associated with CT evidence of a new lesion in one patient. Five silent brain infarcts (6.8%) were detected, including four in the hemisphere contralateral to the restored carotid artery. These study results indicate there is no correlation between the occurrence of postoperative silent brain infarct and the presence of ulcerated stenosis of the carotid artery documented by Doppler ultrasound examination. Silent infarct was not observed in any of the 24 patients (32%) in whom a shunt had been used during the procedure. After a review of the literature, we propose wider use of intraoperative shunts to prevent postoperative silent brain infarct. PMID- 8688315 TI - Improvement of postischemic kidney function by reperfusion with a specifically developed solution (BT01). AB - Reperfusion is a critical phase of organ preservation. The purpose of this study was to develop a solution specifically for postischemic kidney reperfusion. Unilateral left normothermic kidney ischemia was induced for 60 minutes in two groups of micropigs. In group 1 (control pigs, n = 6) the kidney was reperfused immediately with pure blood at systemic pressure by unclamping the renal artery. In group 2 (test animals, n = 6) the kidney was initially reperfused with an intracellular flush solution enriched with solution BT01 composed of cytoprotectors (natriuretic factor, PGI2), free radical chelating agents (allopurinol, mannitol), and substrates for the mitochondrial respiratory chain (aspartate, glutamate). This solution was mixed immediately before use with blood in a ration of 1:4 parts and injected into the left renal artery with a perfuser at a constant pressure of 60 mm Hg. After 20 minutes, the kidney was reperfused with systemic blood for 100 minutes. Glomerular filtration rate (GFR) was determined by measuring inulin clearance. Kidney blood flow was measured throughout the experiment. After 120 minutes of reperfusion, the kidneys were removed for histologic examination. In the control pigs (group 1) 50% of the animals were anuric. The ratio between GFR measured in the left kidney at the end of perfusion and at equilibrium in the remaining animals was 0.16 +/- 0.01. In test animals (group 2) all animals recovered diuresis. The ratio between GFR measured in the left kidney at the end of perfusion and equilibrium was 0.51 +/- 0.12 (p < 0.001, group 2 vs. group 1). In group 2 postperfusion kidney blood flow was higher than in group 1 (63.0 ml/min vs. 27.4 ml/min; p < 0.05) because of a decrease in renal vascular resistance. Light microscopic examination of kidneys form animals in group 1 revealed tubular necrosis that extended to the parenchyma, with exposure of tubular interstitium. In group 2 only degenerative lesions with edema of tubular cells and disappearance of brush borders were observed. Our findings indicate that flushing the kidneys with BT01 solution mixed with blood improves postischemic kidney function by reducing reperfusion damage. PMID- 8688316 TI - The LGM Vena-Tech caval filter: results of a multicenter study. AB - Caval filters have proved essential to the progress being made in the prevention of recurrent pulmonary embolism. A prospective multicenter study was conducted to evaluate the efficacy and possible complications relating to the LGM Vena-Tech percutaneous caval filter, which has been used in Europe since 1989. A total of 222 patients who had undergone LGM Vena-Tech filter placement between September 1989 and December 1991 were included in this study. Two hundred twenty caval filters were positioned via the percutaneous route: 154 of them via the jugular or subclavian vein and 66 via the femoral vein. Two filters could not be implanted. The in-hospital mortality rate was 1.7% (four patients), which included one patient who died of intraoperative recurrent pulmonary embolism. Mean follow-up was 15 months. Forty-one patients died during follow-up (actuarial survival 65.4% +/- 6% at 30 months). There were five cases of recurrent pulmonary embolism (cumulative freedom from pulmonary embolism 93.2% +/- 3.8% at 30 months). Ten patients had thrombosis of the inferior vena cava (actuarial caval patency 94% +/- 3.6% at 30 months). Eight filters (3.6%) migrated over distances that were less than the height of one vertebra. Shifting did not lead to any cases of thrombosis or recurrent pulmonary embolism. Ten filters tilted between 15 and 25 degrees in relation to the inferior vena cava axis. Recurrent pulmonary embolism never occurred concurrently with filter tilting. The LGM Vena-Tech caval filter ensures satisfactory prevention of pulmonary embolism with a low rate of complications. However, because its long-term fate is not known, its use should be restricted to cases in which heparin treatment has failed or is contraindicated. PMID- 8688317 TI - Clinical and pathological associations with p53 tumour-suppressor gene mutations and expression of p21WAF1/Cip1 in colorectal carcinoma. AB - Inactivation of the p53 tumour-suppressor gene is common in a wide variety of human neoplasms. In the majority of cases, single point mutations in the protein encoding sequence of p53 lead to positive immunohistochemistry (IHC) for the p53 protein, and are accompanied by loss of the wild-type allele. Recently, the WAF1/Cip1 gene was identified as one of the genes induced by wild-type p53, and increased expression of p21WAF1/Cip1 has been found to reflect the status of the p53 tumour-suppressor pathway. We investigated the inactivation of p53 in a relatively small, but well-characterised, group of 46 colorectal carcinomas that were previously studied for allelic alterations, ras oncogene mutations and DNA aneuploidy. Alterations in p53 were identified by IHC, loss of 17p and DNA sequence analysis of exons 5-8, whereas p21WAF1/Cip1 protein expression was determined by IHC. p53 mutations were identified in 19 of the 46 tumours (41%), whereas positive IHC for p53 was found in 21 of the 46 tumours (46%). Positive IHC for p21WAF1/Cip1 was detected in 16 of 42 cases (38%). We found no relationship between p21WAF1/Cip1 staining and p53 protein expression or p53 mutational status. Inactivating mutations in the p53 gene correlated with LOH at 17p but not with LOH at 5q or 18q, Dukes' stage, tumour grade or DNA ploidy. There was a higher survival rate independent of Dukes' stage in the group with no alterations in p53 compared with those with evidence of dysfunction of p53, but the difference was not statistically significant. We conclude that inactivation of p53 and altered expression of p21WAF1/Cip1 are common in colorectal carcinoma but do not correlate with each other or with the clinical or pathological parameters investigated. PMID- 8688318 TI - Drug resistance against gemcitabine and topotecan mediated by constitutive hsp70 overexpression in vitro: implication of quercetin as sensitiser in chemotherapy. AB - Heat shock proteins have been reported to confer resistance to certain antineoplastic drugs. We investigated the impact of hsp70 overexpression on the efficacy of two new anti-cancer drugs, topotecan and gemcitabine. We used the fibrosarcoma WEHI-S cells stably transfected to overexpress the hsp70 cDNA from the constitutive SV40 promoter and appropriate control cells. After topotecan and gemcitabine treatment hsp70-overexpressing cells showed a marked elevation in cell survival, suggesting that hsp70 overexpression was sufficient to confer resistance to the drugs. In addition, hsp70-overexpressing cells were capable of starting cell proliferation after treatment with drug dosages that were lethal to control cells. Our results demonstrate that hsp70 overexpression represents a possible cause of drug resistance. In order to transfer these data to tumour cells constitutively expressing stress hsp70 due to the constitutive activity of the original hsp70 promoter we sought to supress the heat shock response pathway by the natural flavonoid quercetin, known to inactivate the heat shock transcription factor (HSF). Using a suitable cell line, we demonstrated the sensitising activity of quercetin. We found that antineoplastic drug concentrations exerting cytotoxic activity were markedly lower when cells were pretreated with quercetin. Concomitantly, hsp70 expression was strongly down regulated under quercetin treatment. Our data indicate that quercetin may be useful as a sensitiser in chemotherapeutically treated patients suffering from hsp70-overexpressing tumours. PMID- 8688319 TI - A serum-mediated mechanism for concomitant resistance shared by immunogenic and non-immunogenic murine tumours. AB - Resistance of tumour-bearing mice to a second tumour challenge, that is concomitant resistance, was evaluated in euthymic and nude mice using nine tumours with widely different degrees of immunogenicity. Two temporally separate peaks of concomitant resistance were detected during tumour development. The first one was exhibited only by small immunogenic tumours; it was tumour specific and mediated by classical immunological T-cell-dependent mechanisms. The second peak was shared by both immunogenic and non-immunogenic large tumours; it was non specific, thymus independent and correlated with the activity of a serum factor (neither antibody nor complement) that inhibited the in vitro proliferation of tumour cells. This factor was eluted from a Sephadex G-15 column at fractions corresponding to a molecular weight of approximately 1000 Da and it was recovered from a high-performance liquid chromatography column in one peak presenting maximum absorption at 215 and 266 nm. The data presented in this paper suggest for the first time, to our knowledge, that in spite of the differences between immunogenic and non-immunogenic tumours, a common serum-mediated mechanism seems to underlie the concomitant resistance induced by both types of tumours at late stages of tumour development. PMID- 8688320 TI - Daunorubicin and doxorubicin but not BCNU have deleterious effects on organotypic multicellular spheroids of gliomas. AB - In the present study organotypic multicellular spheroids (OMS) were used to study the effects of chemotherapeutic agents on malignant gliomas. Compared with the frequently used cell line models, OMS have several advantages with respect to the preservation of the cellular heterogeneity and the structure of the original tumour. OMS prepared from seven glioma specimens were treated with 1,3-bis(2 chloroethyl)-1-nitrosourea (BCNU), daunorubicin or doxorubicin. After exposure to these drugs, the histology and cell proliferation of the OMS were analysed by immunohistochemistry and image analysis. Furthermore, the expression of P glycoprotein (P-gp) and multidrug resistance-related protein (MRP), which both can contribute to resistance to daunorubicin and doxorubicin, were immunohistochemically investigated. We found that OMS from gliomas are sensitive for daunorubicin and doxorubicin but not for BCNU in terms of tissue destruction and decrease in cell proliferation. In addition, all gliomas were P-gp and MRP negative, which is in accordance with the sensitivity for daunorubicin and doxorubicin. Considering the potential use of several new alternative drug delivery methods, such as intratumoural implantation of drug-impregnated polymers or liposomal encapsulation of cytostatic drugs, daunorubicin and doxorubicin might be effective in the treatment of malignant gliomas. PMID- 8688321 TI - Metastatic potential of human melanoma cells in nude mice--characterisation of phenotype, cytokine secretion and tumour-associated antigens. AB - Incidence and mortality of human malignant melanoma has risen rapidly over recent decades. Although the notorious resistance to treatment is characteristic for metastatic malignant melanoma, only a few experimental models have been established to study the metastatic cascade or to test new alternative treatment modalities. Thus, new human models are wanted. Here, we describe the metastatic behaviour of seven human melanoma cell lines derived from two primary cutaneous melanomas (WM 98-1, WM 1341) and five metastases established from liver (UKRV-Mel 4), skin (M7, M13), pleural effusion (UKRV-Mel-2) and lymph node (MV3). All cell lines were analysed for their capacity to grow in nude mice after s.c. and i.v. administration. M13 cells developed liver metastases spontaneously after s.c. injection, and subsequent passages of M13 and M7 melanoma cells caused liver metastases after i.v. injection, whereas MV3 and WM98-1 gave rise to lung metastases, using the same inoculation route. In contrast, WM 1341, UKRV-Mel-2 and UKRV-Mel-4 grew only very slowly in nude mice after s.c. injection and did not cause any metastases after i.v. or s.c. administration. The pattern of metastases or growth kinetics did not correlate with the interleukin 8 or tumour necrosis factor secretion of cell lines. Adhesion molecules and growth factor receptor expression on the cell lines differed widely, as determined by flow cytometry, with the low metastatic cell lines (UKRV-Mel-2, UKRV-Mel-4 and WM 1341) demonstrating a marked reduction in VLA-1 and VLA-5 expression compared with the metastatic lines (M7, M13, MV3 and WM 98-1). Expression of pigment related proteins such as tyrosinase, TRP-1, TRP-2, Melan-A/MART-1, gp100, MAGE1 or MAGE-3 was not associated with growth and metastatic characteristics of the melanoma cell lines analysed. In conclusion, the established human melanoma cell lines exhibited diverse growth behaviour in nude mice in congruence with some early established prognostic markers such as VLA-1 and VLA-5. The xenografts provide good models for further study of metastatic processes as well as for evaluation of alternative treatment modalities including new pharmaceutical drugs and gene therapeutic targeting using tissue-specific gene regulatory elements for gene targeting. PMID- 8688322 TI - A new human breast cancer cell line, KPL-3C, secretes parathyroid hormone-related protein and produces tumours associated with microcalcifications in nude mice. AB - Parathyroid hormone-related protein (PTHrP) is the main cause of humoral hypercalcaemia of malignancy (HHM). We recently established a new human breast cancer cell line, designated KPL-3C, from the malignant effusion of a breast cancer patient with HHM. Morphological, cytogenetic and immunohistochemical analyses indicated that the cell line is derived from human breast cancer. The KPL-3C cells stably secrete immunoreactive PTHrP measured by a two-site immunoradiometric assay, possess both oestrogen and progesterone receptors and are tumorigenic in female nude mice. The addition of phorbol-12-myristate-13 acetate to the medium significantly increased PTHrP secretion from the cells. In contrast, hydrocortisone, medroxyprogesterone acetate and 22-oxacalcitriol decreased PTHrP secretion in a dose-dependent manner. Unexpectedly, a number of microcalcifications were observed in the transplanted tumours. Radiographical examination indicated that the microcalcifications in the tumours are very similar to those commonly observed in human breast cancer. These findings suggest that this KPL-3C cell line may be useful for studying the regulatory mechanisms of PTHrP secretion and the mechanisms that lead to the deposition of microcalcifications in breast cancer. PMID- 8688323 TI - p21WAF1 immunohistochemical expression in breast carcinoma: correlations with clinicopathological data, oestrogen receptor status, MIB1 expression, p53 gene and protein alterations and relapse-free survival. AB - p21 protein (p21) inhibitor of cyclin-dependent kinases is a critical downstream effector in the p53-specific pathway of growth control. p21 can also be induced by p53-independent pathways in relation to terminal differentiation. We investigated p21 immunoreactivity in normal breast and in 91 breast carcinomas [three in situ ductal carcinomas (DCIS) with microinfiltration and 88 infiltrating carcinomas, 17 of which with an associated DCIS; 57 node negative and 34 node positive] with long-term follow-up (median = 58 months). Seven additional breast carcinomas with known p53 gene mutations were investigated. In normal breast p21 expression was seen in the nuclei of rare luminal cells of acinar structures, and in occasional myoepithelial cells. Poorly differentiated DCIS showed high p21 expression, whereas well-differentiated DCIS tumours showed few p21-reactive cells. p21 was seen in 82 (90%) infiltrating tumours; staining was heterogeneous; the percentage of reactive nuclei ranged from 1% to 35%. High p21 expression (more than 10% of reactive cells) was seen in 24 (26%) cases, and was associated with high tumour grade (P = 0.032); no associations were seen with tumour size, metastases, oestrogen receptor status, MIB1 expression and p53 expression. p21 expression in cases with p53 gene mutations was low in six cases and high in one. High p21 expression was associated with short relapse-free survival (P = 0.003). PMID- 8688324 TI - Prognostic significance of p53 overexpression and mutation in colorectal adenocarcinomas. AB - The p53 tumour-suppressor gene is found altered in the majority of colorectal cancers. Lesions include allelic loss, mutation of the gene and overexpression of the p53 protein. All of these lesions have been analysed for prognostic significance, and whereas both mutation and allelic loss have been shown to be reasonably useful markers of prognosis, the utility of overexpression of the p53 protein is more ambiguous. Given that many authors use p53 overexpression as a marker for point mutation this issue is of some importance. We have therefore examined 100 colorectal carcinomas for mutation of the p53 gene, as well as overexpression of the p53 protein. Results show that whereas mutation of the p53 gene is associated with p53 overexpression, the degree of association depends, at least in part, upon the particular antibody used. Moreover, although mutation of the p53 gene does provide prognostic information, overexpression of the p53 protein, as detected with two antibodies, does not. These results suggest that immunohistochemistry is not a suitable alternative to direct detection of mutation in assessing prognosis in colorectal cancer patients. PMID- 8688325 TI - Activity- and schedule-dependent interactions of paclitaxel, etoposide and hydroperoxy-ifosfamide in cisplatin-sensitive and -refractory human ovarian carcinoma cell lines. AB - Paclitaxel has demonstrated broad clinical activity in a variety of malignancies both alone and in combination with other chemotherapeutic agents. The in vitro cytotoxicity of a 2 h exposure to paclitaxel, hydroperoxy-ifosfamide and etoposide alone, in combination and in sequence, was evaluated against established cisplatin-sensitive and cisplatin-refractory human ovarian carcinoma cell lines using isobologram analysis. The combinations of either paclitaxel hydroperoxy-ifosfamide or paclitaxel-etoposide were found to be additive or synergistic when the drugs were given simultaneously or when paclitaxel was given 24 h before hydroperoxy-ifosfamide or etoposide respectively. However, when etoposide or hydroperoxy-ifosfamide were given before paclitaxel, antagonistic interactions were observed. With regard to etoposide this antagonism was evident for up to 24 h. In agreement with our data with the schedule-dependent interactions of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell lines, these data demonstrate that the interactions of paclitaxel, etoposide and hydroperoxy-ifosfamide are also highly schedule dependent and applications of etoposide or ifosfamide before paclitaxel may result in pronounced antagonism. These findings could have implications for the design of further clinical protocols. PMID- 8688326 TI - C-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators. AB - A series of 346 patients with primary operable breast cancer and a series of 145 patients with advanced breast cancer were investigated for c-erbB-3 protein expression using the monoclonal antibody RTJ1. Formalin-fixed, paraffin-embedded tumour samples were stained using a standard immunochemical method and staining was assessed on a four-point scale. The study aimed to observe the expression of the c-erbB-3 protein and investigate any relationship between expression and established prognostic indicators and prognosis. In both the primary and advanced series breast tumour tissue was found to stain heterogeneously for c-erbB-3. The staining was observed to be predominantly cytoplasmic and the majority of tumours exhibited moderate positivity. However, 15% and 35% of cases in the primary operable and advanced series respectively displayed strong positive staining. No significant difference was found between the staining in the primary and advanced series. In the primary operable breast cancers, no significant associations were demonstrated with overall survival, disease-free interval, regional recurrence, the presence of distant metastases, age, menopausal status, oestrogen receptor status, histological grade, lymph node stage, vascular invasion and c-erbB-2 protein expression. However, a significant association was seen between the degree of c-erbB-3 immunoreactivity and both tumour size (P < 0.01) and tumour type prognostic group (P = 0.05). No overall association with local recurrence was seen when the four groups of c-erbB-3 expression were analysed (P = 0.12), but when those tumours showing no or weak staining were compared with those showing moderate and strong immunoreactivity it was seen that the latter were significantly more likely to develop local recurrence (P = 0.03). In the series of patients with advanced disease, no significant associations were demonstrated with survival, UICC criteria, age, menopausal status, oestrogen receptor status, histological grade, c-erbB-2 status or the presence of vascular invasion. In conclusion this study found variable expression of c-erbB-3 protein in human breast carcinoma and an association with some recognised prognostic factors in those patients with primary operable breast carcinoma. It seems, however, unlikely that c-erbB-3 protein expression will emerge as a powerful enough prognostic factor to be of value in clinical practice. PMID- 8688327 TI - Progressive growth of human papillomavirus type 16-transformed keratinocytes is associated with an increased release of soluble tumour necrosis factor (TNF) receptor. AB - Analysis of conditioned media generated by weakly and highly tumorigenic SKv-1 keratinocyte lines harbouring integrated human papillomavirus type 16 (HPV16) DNA sequences revealed a factor inhibiting TNF-alpha and TNF-beta cytotoxic activity. This inhibitory activity was specifically blocked by htr-9 monoclonal antibody (MAb) recognising 55/60 kDa type I TNF receptor suggesting that it is related to a soluble form of this particular receptor (sTNF-RI). The presence of sTNF-RI was confirmed by Western blot analysis of SKv-1 cell-conditioned medium showing a band of 31.5 kDa as well as by the specific enzyme-linked immunobiological assay (ELIBA). Release of sTNF-RI was a result of shedding because Northern blot analysis showed that SKv-1 cells expressed a full-length TNF-RI mRNA, and radioimmunoprecipitation of TNF-RI from [32S]cysteine-labelled cell extracts demonstrated the presence of normal 55 kDa molecule. Evaluation by ELIBA showed that highly tumorigenic SKv-12 cells released significantly more sTNF-RI than their weakly tumorigenic SKv-11 parental cells. Furthermore, human recombinant as well as SKv cell-derived sTNF-RI stimulated proliferation of weakly tumorigenic SKv-11 cells. This suggests that a progressive growth of some neoplastic cells may be, at least partially, a result of an increased spontaneous release of sTNF RI that enables the cells to escape from local TNF-alpha-mediated growth inhibition. PMID- 8688328 TI - Abnormal expression of integrin alpha 6 beta 4 in cervical intraepithelial neoplasia. AB - We have used subunit-specific monoclonal antibodies (MAbs) and immunohistochemistry to examine the distribution of integrin alpha 6 beta 4 in normal ectocervical epithelium and various grades of cervical intraepithelial neoplasia (CIN). Antibodies were first characterised by immunoprecipitation from two surface-labelled tumour cell lines. Monoclonal antibody G71 was found to precipitate integrin beta 4 from BeWo but not T47D cells, while other anti-beta 4 antibodies precipitated beta 4 from both cell lines. Both G71 and an antiserum to the C-terminal peptide of beta 4 precipitated free beta 4 from surface-iodinated BeWo cells. Neither antibody recognised truncated beta 4 chains observed at approximately 160 kDa. These data suggest that different isoforms of beta 4 are expressed in different tumour cell lines, and that there may be a pool of beta 4 at the cell surface that is not complexed to alpha 6. In normal cervix, both the alpha 6 and beta 4 subunits occur at the basal surface of the basal cell layer. In CIN, the distribution is markedly altered, with strong expression of alpha 6 and beta 4 in the upper cell layers of the ectocervical epithelium. All 40 cases of CIN that were studied exhibited this alteration. Furthermore, the extent of extrabasal staining appeared to correspond with the grade of CIN. The form of integrin beta 4 recognised by antibody G71 also appears in the upper cell layers in CIN, but it shows a more restricted distribution than the normal isoform. PMID- 8688329 TI - Differential allele loss on chromosome 9q22.3 in human non-melanoma skin cancer. AB - Familial predisposition to basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin are apparent in the autosomal dominant syndromes naevoid basal cell carcinoma syndrome (NBCCS) and multiple self-healing squamous epitheliomata (MSSE) respectively. The gene responsible for NBCCS has been proposed to be a tumour-suppressor gene and is mapped to the same 2 Mb interval on 9q22.3 as the MSSE gene ESS1. In an attempt to further map the NBCCS gene, we have examined loss of heterozygosity (LOH) in 16 sporadic BCCs and two familial BCCs using microsatellite markers located within the candidate gene region. The overall frequency of LOH observed was 67% in the BCCs and partial or interstitial deletions were found in eight tumours, with the highest LOH frequency at markers D9S280, D9S287 and D9S180. To determine if the same genomic region also shows frequent LOH in tumours with a squamous phenotype, we have examined 11 SCCs, four actinic keratoses and 13 cases of Bowen's disease for LOH at 9q22.3. An overall LOH frequency of 50% was observed at D9S180, and occurred in all types of squamous tumours. In contrast, a much lower LOH frequency of only 6% was found at the D9S287 locus. Our observation of different patterns of LOH at 9q22.3 in sporadic BCCs and SCCs implies that more than one tumour-suppressor gene might be located in this genomic region. PMID- 8688330 TI - Chromosome rearrangements in synovial chondromatous lesions. AB - Short-term cultures from one synovial chondroma and three cases of synovial chondromatosis, a lesion for which no previous karyotypic information exists, were cytogenetically analysed. Whereas the chondroma displayed the relatively simple karyotype 46,XY,add(12)(q13),der(17)t(12;17)(q13;q21), more complex changes were found in the three cases of chondromatosis: case 1, 47,XY,der(1)inv(1)(p13q25)del (1)(q25q32), t(1;12)(q25;q13), + 5,der(12)add(12)(p11)t(1;12)(p22;q13); case 2, 47,XY,add(10)(q26), + 20/46 idem, 6/46,XY,t(2;4)(q33;q21), add(21)(p11); and case 3, 44,XY,add(1)(p36), del(1)(p13p22),add(6)(p25), del(7) (q22q32),del(10)(q21),add(11)(q13),-17,-18. The cytogenetic findings strongly suggest that synovial chondro-matosis is a clonal proliferation. Apart from a near-diploid chromosome number, the only recurrent cytogenetic features among the four cases were loss of band 10q26 and rearrangements of 1p13 and 12q13, found in two cases each. While chromosome bands 1p13 and 10q26 have not been reported to be involved in other types of benign chondromatous lesions, the 12q13-15 segment is recurrently rearranged in a variety of chondromatous tumours, e.g. pulmonary chondroid hamartomas. The present finding of translocations affecting band 12q13 in two of the cases emphasises that, irrespective of the anatomical localisation of the tumours, rearrangements of genes in 12q13-15 are important in the development of a large subset of benign and malignant cartilage-forming tumours. PMID- 8688331 TI - Rarity of microsatellite alterations in acute myeloid leukaemia. AB - We have analysed samples from 20 patients with acute myeloid leukaemia for microsatellite alterations by comparing constitutional DNA and DNA from leukaemic samples. Twelve microsatellites were amplified by PCR and investigated for novel bands, indicative of microsatellite instability, or for loss of heterozygosity. Out of 215 paired amplifications, no additional bands were observed at any locus in any of the samples analysed and loss of heterozygosity was found only as four loci from three patients. These results suggest that microsatellite alterations are very uncommon in acute myeloid leukaemia. PMID- 8688332 TI - Enhancement of anti-tumour immunity in syngeneic mice after MHC class II gene transfection. AB - The relationship between tumorigenicity and expression of MHC class II molecules in a class II-negative murine leukaemia cell line (LBC) was studied. Analysis of structural DNA sequences encoding MHC class II proteins was performed by Southern blot with DNA isolated from both the original LB tumour and LBC cell line, digested with EcoRI, BamHI and HindIII and hybridised with specific probes for I A alpha d and I-A beta d chains. Similar patterns were obtained for LB, LBC and normal BALB/c lymphocytes. In vitro treatment with IFN-gamma (20 - 1000 IU ml-1) failed to induce the expression of MHC class II antigens in LBC cell line. LBC cells were tri-transfected by a liposome-mediated protocol with I-A alpha d, I-A beta d genes and pSV2neo. Cells were selected for growth in medium containing Geneticin (G418). Surviving transfectants were cloned and three I-A+ clones were obtained after 20 days (LBCT cells). Syngeneic mice inoculated with 1.0 x 10(3) LBCT (I-A+) cells failed to develop a tumour, whereas the DT50 of mice injected with 1.0 x 10(6) LBCT cells was three times the value for mice injected with LBC cells (I-A-). Furthermore, specific CTL response against tumour cells was significantly enhanced upon priming with irradiated LBC-transfected cells (27 +/- 2%) compared with irradiated LBC cells (15 +/- 1.5%) in a 4 h 51Cr-release assay. It is suggested that neoexpression of MHC class II molecules enhances anti-tumour response by transforming tumour cells into professional antigen-presenting cells (APCs), which may be used to improve tumour-specific immunity in the autologous host. PMID- 8688333 TI - P53 tumour-suppressor gene mutations are mainly localised on exon 7 in human primary and metastatic prostate cancer. AB - Mutations in the p53 tumour-suppressor gene are among the most common genetic alterations in human cancers. In the present study we analysed the mutations in the p53 tumor-suppressor gene in 25 primary and 20 metastatic human prostate cancer specimens. DNA extracted from the paraffin-embedded sections was amplified by hot-start polymerase chain reaction, and p53 gene mutations in the conserved mid-region (exons 4-9) were examined using single-strand conformation polymorphism (SSCP) analysis and immunohistochemistry. In the present study, we used a novel hot-start PCR-SSCP technique using DNA Taq polymerase antibody, which eliminates primer-dimers and non-specific products. Because of this new technique, the results of PCR-SSCP showed very high resolution. Polymerase chain reaction products were sequenced directly for point mutations for the p53 gene. Mutations were found in 2 out of 25 primary prostate cancers (8%) and 4 out of 20 metastatic cancers (20%). Mutations were observed exclusively in exon 7 and not in exons 4, 5, 6, 8 or 9. Nuclear accumulation of p53 protein, determined by immunohistochemistry, correlated with the degree of metastasis in prostatic cancer. PMID- 8688334 TI - A constitutional de novo mutation in exon 8 of the p53 gene in a patient with multiple primary malignancies. AB - We report a constitutional point mutation of codon 278 in exon 8 of the TP53 gene that has not yet been described as a germ-line mutation. A 52-year-old female developed multiple primary malignancies (liposarcoma, breast cancer, malignant histiocytoma, occult adenocarcinoma). The mutation found in her tumour and peripheral blood lymphocyte DNA is a cytosine to thymine transition at the second position of codon 278 resulting in an amino acid exchange from proline to leucine in the DNA-binding domain. Evaluation of the patient's family revealed that both of her sons were affected by the same mutation. Although the patient's mother had died already, we were able to demonstrate by polymorphic microsatellite analysis that the defective allele originated from the maternal side. As four brothers and one sister had inherited the same allele, which however was wild type, we were able to show that the mutation must have occurred in the germ cells of the patient's mother and that it may therefore be called de novo. This explains the lack of a high cancer incidence in the family history. All tumours tested showed positive immunohistochemical staining for p53. Loss of heterozygosity was found in five of seven tumours, one showing chromosome 17 monosomy. PMID- 8688335 TI - Transforming growth factor beta 1 (TGF-beta 1) produced in tumour tissue after chemotherapy acts as a lymphokine-activated killer attractant. AB - Using an under agarose migration (UAM) assay, we studied lymphokine-activated killer (LAK)-attractant activity in cultured conditioned medium of tumour tissues after chemotherapy as a possible mechanism of enhanced LAK cell accumulation into tumour tissues after chemotherapy. BMT-11 is a fibrosarcoma developed in C57BL/6 mice. The conditioned medium of BMT-11 tumour tissues obtained from mice treated with various anti-cancer drugs had chemotactic activity for LAK cells (LAK attractant activity). mRNA expression of interleukin (IL)-1 alpha, IL-6, IL-8, interferon (IFN)-gamma, and tumour necrosis factor (TNF)-alpha was observed in untreated tumour tissues, which were not enhanced by cyclophosphamide treatment. mRNA expression of TGF-beta 1 was not detected in untreated tumour tissues by reverse transcription-polymerase chain reaction (RT-PCR), but was detected in tumour tissues treated with cyclophosphamide. Recombinant human TGF-beta 1 showed LAK-attractant activity at a concentration of 0.1 ng ml-1 and 1 ng ml-1, whereas fresh splenocytes were not attracted by TGF-beta 1. Anti-TGF-beta 1 antibody inhibited LAK-attractant activity in the conditioned medium of tumour tissues treated with cyclophosphamide to approximately 35% that of control at 100 micrograms ml-1. These findings indicate that TGF-beta 1 produced in the tumour tissues of mice treated with anti-cancer drugs could be a LAK attractant. By a 4 h 51Cr release assay of natural killer cell-resistant BMT-11 tumour cells, we observed that TGF-beta 1 at a concentration from 0.01 ng ml-1 to 10 ng ml-1 did not inhibit LAK activity in an effector phase. Taken together, we suggest that TGF-beta 1 produced in tumour tissues after chemotherapy participates in gathering transferred LAK cells and contributes to the therapeutic effects of transferred LAK cells. PMID- 8688336 TI - Cancer incidence in the first-degree relatives of ovarian cancer patients. AB - Cancer incidence was studied among 3072 first-degree relatives of 559 unselected ovarian cancer patients. Among cohort members there were 306 cancer cases. The overall cancer incidence was not increased: the standardised incidence ratio (SIR) in males was 0.9 (95% confidence interval 0.8-1.1) and in females 1.0 (0.8 1.1). The female relatives had a significantly increased risk for ovarian cancer (SIR 2.8, 1.8-4.2). The excess was attributable to sisters only (SIR 3.7, 2.3 5.7). The relative risk for ovarian cancer among sisters decreased both by increasing age of the sister and by increasing age at diagnosis of the index patient: the SIRs were 7.3 (1.5-21.4), 4.5 (1.6-9.8) and 3.1 (1.7-5.4) for sisters of index patients diagnosed in age < 45, 45-54 and 55-75 years respectively. The age dependency of the risk supports the role of genetic factors in familial ovarian cancer. Although the risk of ovarian cancer among sisters from families with breast cancer (SIR 9.2, 3.7-19.0) was significantly higher than among sisters from families with no breast cancer patients (SIR 2.9, 1.6 4.8, rate ratio 3.1, P < 0.05), the excess was not solely attributable to coaggregation of breast and ovarian cancer. Among the 27 families with two or more ovarian cancers, only sisters were affected in 24 families, which might implicate recessive inheritance or shared environmental factors influencing ovarian cancer risk in sisters. PMID- 8688337 TI - Improved survival in cervical cancer cases in a rural Indian population. AB - In the first Rural Cancer Registry in India, 194 cervical cancer cases were registered during 1988-91. The 3 year survival was significantly higher in cases registered in 1990-91 (40.0%), than in those registered in the earlier years (26.6%). This improvement was due to the cancer education activities undertaken by the Registry. PMID- 8688338 TI - Epidemiological characteristics of myelodysplastic syndrome in a well-defined French population. AB - Data on myelodysplastic syndromes (MDS) are seldom collected by cancer registries and unbiased findings from population-based studies remain rare. We report detailed information on MDS in a well-defined French population in the period 1980-1990. The crude incidence rate was 3.2 per 100000 per year and no significant change in incidence was noted in the study period. The sex ratio was 1.9 and the male predominance was present in all age groups. We observed a rise in incidence after 60 years of age but no significant change in incidence of MDS as a whole was observed over the period studied. Refractory anaemia with excess of blasts (RAEB) was the most frequent subtype. Overall 5 year transformation rate of MDS was 31% (+/- 4%) but it was 100% in RAEB in transformation. The observed 5 year survival rate was 23% +/- 3% and the corresponding corrected rate was 33%. The prognosis of RAEB in transformation was worse than the prognosis of other subtypes (P < 0.01). Discrepancies with epidemiological data from other European countries are discussed. PMID- 8688339 TI - Fertility, reproductive outcomes, and health of offspring, of patients treated for Hodgkin's disease: an investigation including chromosome examinations. AB - Reproductive outcomes and health of offspring were investigated in 340 patients with Hodgkin's disease first treated at Mount Vernon Hospital, Middlesex, England, at ages under 40 (females) or 45 (males) during 1970-91. Information on offspring was obtained from case-notes and postal questionnaires to the patients. Eleven men and 16 women who had conceived any children after treatment were then interviewed. There was no excess of stillbirths, low birthweight or cogenital malformations, and no cancers have occurred in the 49 offspring after treatment. There was a significant excess of twins, compared with national expectations, in offspring of female patients (RR = 8.52, P = 0.025). Aggregation of series from the literature also showed an excess of twins. Chromosomes from cultures of peripheral lymphocytes from 45 children born to 25 patients (11 men and 14 women) after treatment were examined for numerical abnormalities and for structural abnormalities at the 550 or greater band level of resolution. All were normal except in one child with Down's syndrome (47, XY, +21), for whom we found the origin of the trisomy was from the parent without Hodgkin's disease. The chromosome constitution was also abnormal in one miscarriage (69, XXY; originating from the parent without Hodgkin's disease) and one termination (45, X; for with the parental origin could not be determined) after treatment. The study adds to previous questionnaire data and for the first time provides data also from chromosome analysis, that offspring of patients treated in adulthood for Hodgkin's disease are not at greatly raised risk of genotoxic or other adverse outcomes as a consequence of their parent's treatment. The numbers of offspring assessed in the literature remains small, however, and surveillance of larger numbers of subjects is needed to enable reliable treatment-specific analyses. PMID- 8688340 TI - Randomised comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer. The Scottish Cancer Trials Breast Group. AB - In 1985 a second randomisation was initiated for women in the treatment arm of the Scottish Tamoxifen Trial either to stop tamoxifen at 5 years or to continue indefinitely. A preliminary analysis of outcome in 342 patients at a median follow-up of 6 years suggests that a worthwhile gain in disease control from continuing adjuvant tamoxifen beyond 5 years is unlikely. [Hazard ratio for events (relapse or death without relapse) is 1.27, 95% CI = 0.87 - 1.85.] There is a suggestion that therapy for longer than 5 years may increase the risk of endometrial carcinoma (P = 0.064). PMID- 8688341 TI - Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti oestrogen ICI 182780 in women with advanced breast cancer. AB - We have assessed the pharmacokinetics, pharmacological and anti-tumour effects of the specific steroidal anti-oestrogen ICI 182780 in 19 patients with advanced breast cancer resistant to tamoxifen. The agent was administered as a monthly depot intramuscular injection. Peak levels of ICI 182780 occurred a median of 8-9 days after dosing and then declined but were above the projected therapeutic threshold at day 28. Cmax during the first month was 10.5 ng/ml-1 and during the sixth month was 12.6 ng ml-1. The AUCs were 140.5 and 206.8 ng day ml-1 on the first and sixth month of dosing respectively, suggesting some drug accumulation. Luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels rose after withdrawal of tamoxifen and then plateaued, suggesting no effect of ICI 182780 on the pituitary-hypothalamic axis. There were no significant changes in serum levels of prolactin, sex hormone-binding globulin (SHBG) or lipids. Side-effects were infrequent. Hot-flushes and sweats were not induced and there was no apparent effect of treatment upon the endometrium or vagina. Thirteen (69%) patients responded (seven had partial responses and six showed "no change' responses) to ICI 182780, after progression on tamoxifen, for a median duration of 25 months. Thus ICI 182780, given by monthly depot injection, and at the drug levels described, is an active second-line anti-oestrogen without apparent negative effects on the liver, brain or genital tract and warrants further evaluation in patients with advanced breast cancer. PMID- 8688342 TI - Inhaled sodium cromoglycate to treat cough in advanced lung cancer patients. AB - C-fibres probably represent the common final pathway in both ACE inhibitors and neoplastic cough. A recent report demonstrated that inhaled sodium cromoglycate is an effective treatment for ACE inhibitors' cough; this effect might be due to the suppression of afferent unmyelinated C-fibres. We tested the hypothesis that inhaled sodium cromoglycate might also be effective in lung cancer patients who presented with irritative neoplastic cough. Twenty non-small-cell lung cancer (NSCLC) patients complaining of cough resistant to conventional treatment were randomised to receive, in a double-blind trial, either inhaled sodium cromoglycate or placebo. Patients recorded cough severity daily, before and during treatment, on a 0 to 4 scale. The efficacy of treatment was tested with the Mann-Whitney U-test for non-parametric measures, comparing the intergroup differences in the measures of summary of symptom scores calculated in each patient before and after treatment. We report that inhaled sodium cromoglycate can reduce cough, also in NSCLC patients and that such reduction, observed in all patients treated, is statistically significant (P < 0.001). Inhaled sodium cromoglycate appears to be a cost-effective and safe treatment for lung cancer related cough. PMID- 8688343 TI - The reduction of radiation mucositis by selective decontamination antibiotic pastilles: a placebo-controlled double-blind trial. AB - The aim of this study was to see if antibiotic pastilles could reduce radiation mucositis, pain, dysphagia and weight loss in patients undergoing radical radiotherapy for head and neck cancer. A total of 275 patients with T1-T4 tumours entered the study; 136 were allocated to suck four times daily a pastille containing amphotericin, polymyxin and tobramycin. The remaining 139 patients received an identical placebo. In all, 54 patients were unevaluable (24 active, 30 placebo). Bacteriological monitoring was carried out before and twice weekly during treatment. Both arms of the study were well balanced for T and N stage, age, sex and radiation dose (60 Gy). There was a slight imbalance in the site of disease which had no substantive effect on the results. The primary study end point was the percentage of patients who developed intermediate or thick pseudomembranes. No statistically significant difference was found in this end point, with 36% of patients in the active arm developing this type of membrane compared with 48% in the placebo arm (P = 0.118). The estimated odds ratio (placebo/active) of developing an intermediate or thick pseudomembrane was 1.59 (95% CI 0.89-2.82). However a more sensitive test comparing the worst recorded mucositis grade between the two arms was statistically significant (P = 0.009). This indicated that the active pastilles had a beneficial effect, but the magnitude was probably smaller than the trial was designed to detect. There was a reduction in mucositis distribution (P = 0.002), mucositis area (P = 0.028), dysphagia (P = 0.006) and weight loss (P = 0.009) in the active arm. There was a clear tendency for patients with positive cultures for aerobic Gram-negative bacteria (AGNB) (P = 0.003) and yeasts (P = 0.026) during treatment to have more severe mucositis. The active pastilles reduced the percentage of patients with yeast cultures (P = 0.003) but had less effect on AGNB. The benefit derived from the pastilles should materially increase patient tolerance to radical radiotherapy for head and neck cancer. PMID- 8688344 TI - A randomised comparison of a third-generation regimen (PACEBOM) with a standard regimen (CHOP) in patients with histologically aggressive non-Hodgkin's lymphoma: a British National Lymphoma Investigation report. AB - A combination of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) has been a standard therapy for histologically aggressive non-Hodgkin's lymphomas for over 20 years, but several newer regimens, referred to as second or third generation, have been reported to give improved results in single-centre studies. Positive evidence from randomised trials has been lacking, and the British National Lymphoma Investigation therefore commenced a randomised comparison of CHOP vs a third-generation regimen, PACEBOM, in November 1987. A total of 459 eligible patients were entered into the trial: 226 in the CHOP arm and 233 in the PACEBOM arm. Overall, there was no significant difference in outcome between the two arms of the trial. In patients with stage IV disease there was an apparent improvement in survival for those treated with PACEBOM, but considerable caution must be exercised with such subgroup analysis. PMID- 8688345 TI - Pharmacokinetic profile and clinical efficacy of a once-daily ondansetron suppository in cyclophosphamide-induced emesis: a double blind comparative study with ondansetron tablets. AB - We investigated the pharmacokinetic profile and the efficacy of ondansetron (day 1) given as 16 mg suppository once a day, as compared with ondansetron 8 mg tablets twice daily, in patients receiving moderately emetogenic chemotherapy. The study was primarily aimed at investigating the pharmacokinetics and was part of a large multinational, randomised, double-blind, double-dummy efficacy trial. Pharmacokinetic data were obtained in a total of 20 patients, 11 of whom had received a suppository containing ondansetron, and nine patients had received the oral formulation. The median area under the plasma concentration curve (AUC) obtained with the oral formulation was 226 ng ml-1h-1 (range 91-750), and the median maximum plasma level (Cmax) was 50.5 ng ml-1 (range 24.7-199.6) after a dose of 8 mg. For the ondansetron suppository the median AUC was 140 ng ml-1h-1 range (77-405) and the median Cmax was 17.1 ng ml-1 (range 13-48.3) after a dose of 16 mg. The systemic exposure after correction for the dose difference after the suppository was on average 70% lower than after the tablet. The median time to reach the maximum level (Tmax) was 60 min (range 28-120) with the oral formulation and 209 min (range 90-420) with the suppository. For both the tablet and suppository, there was no apparent relationship between either Cmax or AUC, and efficacy. Although the patient numbers were too small for a formal exposure response relationship to be derived, the slightly poorer pharmacokinetic performance of the suppository did not appear to be associated with a lessening of control of emesis following chemotherapy. The study demonstrates that the pharmacokinetic analysis of a once-daily 16 mg ondansetron suppository results in appropriate plasma concentrations and AUC, and that this rectal formulation is effective in the protection against nausea and vomiting associated with cyclophosphamide chemotherapy. This formulation will provide a useful alternative to the currently available oral formulation. PMID- 8688346 TI - Occult filum terminale. PMID- 8688347 TI - Occult filum terminale syndrome. AB - Thirty-two pediatric patients presenting with symptoms of urinary dysfunction, stool incontinence and/or severe back and/or leg pain are described. In patients with urological dysfunction, urodynamic testing was consistent with a neurogenic etiology. Imaging studies demonstrated the tip of the conus medullaris to lie above the L2 vertebral body, and the filum terminale to be of normal diameter ( < 2 mm) in all patients. A diagnosis of an occult filum terminale syndrome was made based on clinical presentation in the absence of associated imaging abnormalities and section of the filum terminale was performed. Postoperatively, the majority of patients (97%) experienced significant ( > 50%) relief of their symptoms. The management of these patients is discussed. PMID- 8688348 TI - Mechanisms of mutant genes in spina bifida: a review of implications from animal models. AB - Spina bifida (spinal neural tube defects) has been shown to be caused by an abnormality in closure of the neural tube. Basic scientific research has rapidly progressed in experimental embryology and molecular genetics to give new insights into the pathogenesis of defective neural tube closure. The chick and the mouse have proved to be the best animal models for study because of similarities to human neurulation. The embryonic mechanisms for spina bifida appear to be under the control of mutant early regulating genes and modifying genes. Faulty early gene function in chicks and mice has been reported to result in abnormalities of neuronal and nonneuronal tissues important for neural tube closure. Research efforts are being aimed at understanding the inductive interactions and downstream target sites for early regulating genes. Elucidation of the genetic roadmap for the control of neurulation will give further insights into the causes of spina bifida. PMID- 8688349 TI - Morphological analysis of progressive hydrocephalus and shunt-dependent arrested hydrocephalus. An experimental study. AB - This experimental study was performed to determine if surgically treated feline hydrocephalus could produce any morphological and physiological changes in the periventricular tissue. The result was analyzed with clinical outcome, comparing two differently prepared models in which the biomechanical characteristics of the container property of the brain were altered. Craniectomies were performed in adult mongrel cats and the dura mater was left untouched in group A, while the dura was incised in crucial fashion in group B. Thirty-four animals underwent ventriculopleural shunt surgery 6-8 weeks after kaolin induction into the cisterna magna. In 19 animals, no shunt was implanted; they served as sham controls. These and 10 normal animals were subjected to transmission electron microscopic study or measurement of white matter water content. The regions studied were divided into three sections according to their depth from the ventricular surface (W1, W2 and W3). Considering the efficacy of shunting, the increased water content observed in preshunt animals decreased and was almost identical to normal controls after effective diversion surgery. On the other hand, the animals with ineffective shunt failed to normalize the water content and the figures were similar to the time-matched sham animals. These trends were preserved in groups A and B, but water content was much higher in group B. On histological observation, the chronological profile of subependymal extracellular space (W1, W2) in chronic condition did not correspond to the chronological changes in water content, while both changes observed after successful shunt were apparently linked. Subependymal glial proliferation was increased in volume as a function of time in all animals observed, but this was much more marked in group A than group B. Furthermore, gliosis was more evident in shunted animals than in the other group and was more prominent in cats with effective shunts than in those with ineffective shunts. These histological changes and clinical outcome were not closely related in this study. These results indicated that: (1) The shunting procedure itself could promote subependymal gliosis and this progresses unexpectedly even if CSF pressure is low enough after effective shunting. (2) This histological change is not necessarily a sufficient explanation for clinical improvement after successful shunting. (3) A biomechanical characteristic of the differently treated container property of the brain exerts an influence on the histological change and change in CSF dynamics in periependymal tissue mostly at an early stage of hydrocephalus rather than at a later stage. Therefore early treatment should be considered while avoiding an overindication for shunting. PMID- 8688350 TI - Epidemiology of cerebrospinal fluid shunting. AB - The epidemiology of cerebrospinal fluid (CSF) shunting in the United States is not well known; however, with recent national surveys, the prevalence, incidence, and cost of these procedures can be estimated. The prevalence of CSF shunts in the United States appears to be greater than 125,000, though this is likely an underestimate of the true value. There are approximately 69,000 discharges each year with the diagnosis of hydrocephalus. These visits produce nearly 36,000 shunt-related procedures, 33,000 of which involve the placement of a shunt. CSF shunting procedures account for almost US$ 100 million of national health care expenditures each year. Unfortunately, nearly half of these dollars are spent on revision. The rates and costs of CSF shunting underscore the need for continued improvement in both materials and techniques. PMID- 8688351 TI - Primary craniovertebral anomalies and the hindbrain herniation syndrome (Chiari I): data base analysis. AB - This prospective study analyzes 100 patients with Chiari malformation and primary craniovertebral junction (CVJ) anomalies (3-66 years). Neurodiagnostic investigations employed tomography, gas myelography, CT and CT myelography, and MRI. Factors considered were reducibility, mode of encroachment, cerebrospinal fluid (CSF) dynamics and syringohydromyelia. Sixty-six patients with irreducible pathology underwent ventral or ventrolateral decompression and dorsal stabilization. Dorsal occipitocervical fixation was performed in reducible lesions that also required dorsal decompression (n = 34). Proatlas remnants were identified in 8 and atlas assimilation in 92 patients. Paramesial invagination was present in 20, syringohydromyelia in 46, and vertebral segmentation defects in 66 others. Completely reducible abnormalities were identified in 16 of 20 patients aged 2-14 years, and partially reducible abnormalities in 4 of 16 patients aged 14-20 years, 8 of 48 patients aged 20-40 years and 6 of 16 patients aged 40-60 years. The critical sagittal canal diameter at the foramen magnum was 19 mm. Twenty-two patients had previous posterior decompression and 27 had previous syrinx to subarachnoid shunt with delayed deterioration. Improvement occurred in all after ventral or ventrolateral decompression with resolution of the syringohydromyelia and normalization of CSF flow. We conclude that: (1) hindbrain herniation syndrome is frequently seen with fourth occipital sclerotome abnormalities; (2) Chiari malformation with craniovertebral abnormalities become symptomatic with a canal diameter of < 19 mm; (3) abnormal ventral bony pathology is reducible in children wit atlas assimilation and later becomes irreducible invagination, therefore early operation with fusion is recommended; (4) ventral decompression relieves brain stem, cerebellar symptoms and syringohydromyelia; (5) CSF studies with cine MRI shows reversal of craniospinal CSF dissociation after ventral CVJ decompression and; (6) craniovertebral anomalies associated with Chiari malformations must be addressed early and appropriately. PMID- 8688352 TI - Abnormal venous system in occipital meningoencephalocele: MR angiography. AB - In the literature, the combination of an abnormal cerebral venous system at conventional cerebral angiography with meningoencephalocele has been described. To our knowledge an abnormal venous system in patients with a meningoencephalocele disclosed by magnetic resonance angiography (MRA) has never been reported. A case is presented and the value of MRA, especially in the pediatric population, is stressed. PMID- 8688353 TI - Meningiomatosis cranii in childhood: a case report. AB - Tumors of the meninges in infancy and childhood are unusual; childhood meningiomatosis is thought to be more common in neurocutaneous diseases. The case presented here is one of multiple recurrent and de novo benign meningeal tumors in a child who has no other signs or symptoms of a neurocutaneous syndrome. PMID- 8688354 TI - Spontaneous involution of an intra-axial brain stem lesion: a case report. AB - This report describes the spontaneous involution of an intrinsic brain stem lesion whose clinical and MRI characteristics strongly suggest a tumor etiology. Nonoperative experiences with central nervous system tumors have shown that they may sometimes exhibit prolonged periods of dormancy. There are several reports of 'disappearing' CT lesions which have all been inflammatory, infective, or immunological. No histologically proven tumor has been shown to spontaneously involute, nor have 'disappearing' lesions been described for MRI. PMID- 8688355 TI - Complementary therapies. PMID- 8688356 TI - Oral complications of cancer therapies: prevention and management. AB - There is no doubt that, when the oncology team includes a dentist, the risks of development of serious complications such as osteoradionecrosis are significantly reduced for the cancer patient [15,157,158]. Ideally, all patients should be rendered dentally fit before the commencement of cancer therapy. Those receiving radiotherapy should then be seen weekly by the dentist during the course of radiotherapy and approximately every 1-2 weeks during the intensive phases of treatment, if receiving chemotherapy or surgery. All patients should be carefully followed up after cancer therapy in order to minimize orofacial complications and be in a position to intervene at an early stage, when therapy is likely to be easier and more rapidly effective. PMID- 8688357 TI - Normal tissue radiosensitivity--how important is it? AB - The success of radiotherapy in eradicating tumours depends on the total radiation dose, but what limits this dose is the tolerance of the normal tissues within the treatment volume. Selection of the appropriate dose for all patients is based on a balance between minimising the incidence of severe normal tissue complications and maximizing the probability of local control. In patients treated to the same radical dose, a wide range of reactions is seen; in many clinical situations, radical doses are limited by the minority of patients whose normal tissues are particularly sensitive. Clinical studies of radiotherapy reactions have demonstrated that a large part of the spectrum of normal tissue reactions, perhaps as much as 80%, is due to differences in individual normal tissue sensitivity. This suggests that it might be possible to measure this sensitivity and to change treatment accordingly. The main objective of normal tissue sensitivity testing is to permit dose escalation without increased normal tissue complication rates in patients with more resistant normal tissues. Calculations suggest that the most "resistant' 40% of patients could be dose escalated by 17% 18%, which is likely to be associated with significant gains in local control, perhaps by as much as 34%-36%; this should translate into an increase in overall survival. It should also be possible to identify those relatively few patients who suffer serious normal tissue morbidity with conventional doses. Thus, if successful, predictive testing of normal tissue response should improve the therapeutic ratio of radiotherapy. PMID- 8688358 TI - Informed consent in oncology: do we need it? PMID- 8688359 TI - Split course radical radiotherapy for bladder cancer in the elderly: nonsense or commonsense? A report of 76 patients. AB - The role of split course radical radiotherapy in bladder cancer is controversial. We have pursued such a policy in elderly patients in view of the unpredictable toxicity of radical radiotherapy in this group. Between 1987 and 1992, 76 patients were treated in this way, with 2 weeks' treatment followed by a 3-week gap. Patients were then reassessed and, if considered fit enough, a further 2 weeks of treatment was given. Fifty-three patients (mean age 78.4 years) completed treatment and 23 (mean age 78 years) received phase 1 alone. Thirty seven of 53 patients completing treatment has a follow-up cystoscopy at 6 months. Twenty-five percent of all patients, 36% of those completing treatment, and 51% of those undergoing cystoscopy, achieved a complete response. The reasons for not completing treatment and not being followed up cystoscopically are examined. We feel that this policy has a role in selected patients whose fitness to tolerate a conventional radical course of radiotherapy is in doubt. PMID- 8688360 TI - An audit of the management of malignant hypercalcaemia. AB - A protocol was designed to help junior doctors to manage patients with malignant hypercalcaemia (MH). Seventy-five patients received 30 mg, 60 mg or 90 mg doses of pamidronate, depending on their initial serum calcium level. Fifty-four (72%) patients achieved normocalcaemia (NC) within 5 days after a single infusion of pamidronate. A further ten (13%) patients reached NC after a second dose, and 11 (15%) remained hypercalcaemic until death. NC was maintained for a median duration of 24 days. Patients received, on average, 30 mg less pamidronate than that given in the manufacturer's dosing schedule. The protocol was considered effective, economical and practical in the routine management of MH. PMID- 8688361 TI - Economic evaluation of new treatments: haematopoietic growth factors. AB - The clinical benefits of new healthcare interventions usually receive considerable attention, but their impact on the economic aspects of care provision are not so well considered. Among the issues that different audiences will want to see addressed are: how clinical benefits translate into resource use savings in practice; the extent to which clinical trial outcomes can be said to be representative or normal practice and the value of the economic impact to purchasers and providers. In this review we consider these elements using the haematopoietic growth factors as an example. PMID- 8688362 TI - Effects on pulmonary function of two regimens of chemotherapy for AIDS related Kaposi's sarcoma. AB - We retrospectively analysed serial pulmonary function tests in 14 HIV infected patients receiving either bleomycin and vincristine or liposomal doxorubicin therapy (Doxil) for AIDS related Kaposi's sarcoma. There was a significant reduction in the carbon monoxide transfer coefficient in bleomycin treated patients compared with patients treated with Doxil. No other significant changes in pulmonary function, including the carbon monoxide diffusing capacity, were observed. These preliminary findings suggest that HIV infected patients with Kaposi's sarcoma, who are receiving bleomycin, may be at risk of accelerated pulmonary dysfunction. A larger prospective study should be performed to enable further investigation. PMID- 8688363 TI - The use of PET-18FDG imaging in the clinical evaluation of head and neck lymphoma. AB - Four patients with non-Hodgkin's lymphoma in the head and neck region were studied with positron emission tomography (PET), using the radioactive tracer 2 [F-18]-fluoro-2-deoxy-D-glucose (18FDG). This technique, which exploits the high metabolic rate of glucose in tumour tissue, enabled the extent of disease to be visualized. The localization of the tumour was improved by combining the data from the PET scan with those from CT scans or MRI. This technique (of PET-18FDG), using visual and semiquantitative analysis in the form of standardized uptake values, allowed the differentiation between reactive hyperplasia and nodal involvement with lymphoma. We believe that PET using the tracer 18FDG may play an important role in the evaluation of patients with head and neck lymphoma. PMID- 8688364 TI - Nasopharyngeal carcinoma with metastatic disease to mediastinal and hilar lymph nodes: an indication for more aggressive treatment. AB - Nasopharyngeal carcinoma (NPC) is a highly chemo- and radiosensitive tumour, distinctive from other head and neck squamous cell carcinomas. Distant metastatic rates correlate directly with T and N stages. The prognosis of metastatic NPC is grave and long term survivors are anecdotal. We encountered an 18-year-old man with locoregionally advanced NPC, who was initially treated with neoadjuvant chemotherapy and radiotherapy, but subsequently relapsed 6 months later in the superior mediastinal and right hilar nodal regions. Further chemotherapy and consolidation radiotherapy resulted in complete remission. He is currently alive and free of disease 5 years and 6 months after the completion of salvage treatment. We recommend aggressive treatment of NPC with isolated intrathoracic nodal relapse and imaging of the mediastinum for non-metastatic Ho's Stage N3 NPC patients. PMID- 8688365 TI - Primary choriocarcinoma of the urinary bladder: a case report. AB - We present a 37-year-old patient with primary choriocarcinoma arising in the urinary bladder, who received 5 months of intensive chemotherapy with a very good response. He died of a pulmonary embolus before his treatment could be completed. A post-mortem examination revealed extensive necrotic nodules in the lungs and brain. There was only one small focus of viable tumour in the brain. There was no residual tumour in the bladder, and no testicular tumours or scars fulfilling the criteria for a true extragonadal teratoma. It is likely that the origin of the bladder choriocarcinomas is from metaplasia/de-differentiation of a transitional cell carcinoma to the level of trophoblast. Lesser degrees of differentiation producing functional changes in the carcinoma cells with secretion of beta hCG without structural changes are much more common. PMID- 8688366 TI - Controversies in the management of metastatic spinal cord compression. PMID- 8688367 TI - Neurological assessment of high grade astrocytomas following high dose radiotherapy as sole treatment. PMID- 8688368 TI - Positron emission tomography: a new investigational area for cancer research. PMID- 8688369 TI - Differentiation between patients with schizophrenia and borderline disorders in the Percept-genetic Object-Relation Test, PORT. AB - Schizophrenics (12 males), borderline patients (12 males), and self-selected normal controls (11 males, 17 females) were compared using PORT (Percept-genetic Object-Relation Test), a projective test, diagnosis being on the basis of DSM-III and Kernberg's six descriptive borderline criteria. The aim of the study was to compare the three groups in order to distinguish the two clinical groups from the control group, but also to distinguish the borderlines from the schizophrenic patients with specified diagnosis. The two patient groups differed from the controls on 15 different PORT signs/patterns. In addition, the borderline patients and the three schizophrenics of unspecified diagnosis showed signs in PORT of dissolution anxiety, splitting, whole configuration (fusion) and sexualization as defence, which the schizophrenics with specified diagnosis did not, although catatonic/hebephrenic, simplex, and paranoid schizophrenics could be distinguished in the test. Characteristic of the schizophrenics was also diffusion of domains of object relationships. In a blind prediction study with PORT involving five male and five female patients with severe psychiatric disorders (diagnosed by DSM-III-R), borderline patients could also be distinguished satisfactorily from schizophrenics. PMID- 8688370 TI - Subject matter and poetic devices in psychotics' poetry. AB - It has long been supposed that there is a connection between the mental processes of psychosis and those of creativity. The present study aimed to investigate this idea by means of a comparison between the poetic output of psychotics and that of normals, taking as its starting-point the notion that if there are observable differences between these two groups in terms of subject matter and linguistic features, this would suggest that creativity and psychosis are not to be identified with each other. Eighty poems by contemporary, non-professional poets (40 by psychotics and 40 by normals) were analysed on 11 different dimensions. The two samples of poems were highly similar on most of the dimensions investigated. The main differences found were in the incidence of self-analysis as a theme, reference to proper names and specific locations, and in the proportion of metaphors which fell into the category 'psychological/physical'. The two latter differences appeared to be largely a product of the first. It was concluded that although 'normal' and 'psychotic' poetic activities are not identical, they are closely related. This may be either because general poetic creativity does have psychotic features, or because the poetic function of language was relatively spared in at least this sample of psychotics. PMID- 8688371 TI - Life-events and the course of chronic fatigue syndrome. AB - Life-events have been implicated in the onset and course of various illnesses. The present study examined their role in chronic fatigue syndrome, in the context of the ongoing illness. Using the PERI list, events experienced during the past year were elicited in interviews with 130 patients. The analyses were restricted to those events implying moderate or major life change, and separate analyses were carried out for positive and negative events. Positive events were found to be associated with lower scores for fatigue, impairment, anxiety and depression, as assessed at the time of the life-events interview, and these relationships were also significant when prior scores at the beginning of the year were statistically controlled. Negative life-events were associated with higher anxiety, but were unrelated to the other measures. It was concluded that positive life-events and experiences may contribute to the process of recovery in chronic fatigue syndrome, though their occurrence may also be facilitated by a preceding lifting of symptoms. PMID- 8688372 TI - Life-events and psychiatric symptoms in a general psychiatry clinic: the role of intrusion and avoidance. AB - Recent literature has been concerned with the relationship between life-events and psychological symptoms, and more particularly studies of communities subsequent to disasters have suggested the presence of intrusive cognitions to be a mediating variable. In this investigation new patients presenting to a general community psychiatric clinic over a four-month period completed a brief life event scale, the Impact of Event Scale (IES) and the 28-item General Health Questionnaire (GHQ). Appropriate statistical methods were employed to model the intervening role of IES scores between numbers of life-events and subsequent psychiatric symptomatology. Data was collected on 48 subjects, for whom it was shown that IES score accounted for the reporting of psychiatric symptoms following adversity. It appeared to be the dimension of cognitive intrusion that mediated this effect, with cognitive avoidance occupying a subsidiary, reactive role. There was also evidence of specific relationships between intrusion and anxiety and somatic subscales of the GHQ, and between avoidance and depression. Despite small numbers and simple measures, the findings supported the post disaster studies, and raises further questions about the emotional processing of adversity. PMID- 8688373 TI - An outbreak of copycat fire raising. AB - A dangerous outbreak of fire setting occurred on two wards of a Bristol Psychiatric Hospital, in which six patients set eight fires over a five-week period. One was the Intensive Care Unit, the other an admission ward serving the inner city of Bristol. Five of the six patients had moved between the two wards. The sequence of fires is in part explained by 'copycat' behaviour. The fires were set at a time when the hospital was particularly vulnerable because of major service changes. We emphasize the institutional and situational variables that led to disturbed behaviour in a vulnerable group of individuals, with inadequate controls over tension and anxiety. PMID- 8688374 TI - Case report: psychological response of a woman with schizo-affective disorder on discovering she had ovarian cancer. AB - Studies have shown that medical illness in those with psychiatric illness often exacerbates symptoms (Hall et al., 1981). This paper reports the case of a 53 year-old Chinese American woman with schizo-affective disorder who surprisingly had a remission in psychiatric symptoms on discovering she had ovarian cancer. PMID- 8688375 TI - The elusive factor structure of the Inventory of Interpersonal Problems. AB - This paper reports data on the psychometric properties of the Inventory of Interpersonal Problems (IIP; Horowitz, Rosenberg, Baer, Ureno & Villasenor, 1988) obtained from a UK inner city sample of 286 out-patient clients presenting for cognitive analytic therapy or treatment in a sexual dysfunction clinic. The results are compared with those of Barkham, Hardy & Startup (1994): only moderate replication of their eight components in the raw data, and four bipolar components from analysis of ipsatized data were found. Split halves of the data were analysed and compared in order to explore the possible influences of clinical and demographic variables on the component structure. PMID- 8688376 TI - Breast implants: facts, controversy, and speculations for future research. AB - The breast implant crisis has been widely publicized. Beyond its immediate problems for the patients, the crisis has also discredited the use of silicone rubber as one of the most widely used biomaterials. Silicone elastomer or gel, the primary material in mammary prostheses, may be exposed to the body's tissues via envelope rupture, gel bleed, or elastomer fragmentation. Local responses to silicone include granulomatous inflammation, capsular contraction, and infection, all in varying degrees depending on ill-defined factors, which may include patient condition, peri- and postoperative complications, and hereditary predisposition, as well as material properties such as surface texture. The theory that silicone breast implants cause immunological disorders has not been proven. However, further study is necessary because some patients report autoimmune-like disorders (human adjuvant disease) following implant placement. Like autoimmune disease, human adjuvant disease is characterized by abnormalities of the immune response, autoantibody formation, and chronic inflammation. Silicone has been shown to play the role of an adjuvant, providing constant nonspecific stimulation of the immune system. Some researchers have hypothesized the role of silicone in specific immune reactions, including immunoglobulin formation and T-cell activation. This report examines the role of silicone as an agent of disease, focusing on material surface-tissue interactions. PMID- 8688377 TI - Sutureless cholecystojejunostomy in pigs using an absorbable intraluminal stent and fibrin glue. AB - The absence of foreign bodies in sutureless anastomoses provides faster healing. The first sutureless cholecystojejunostomies were reported by Murphy in 1892. The common bile duct was tied and 11 cholecystojejunostomies plus 12 jejunojejunostomies were performed in 12 Landrace pigs employing sliding absorbable intraluminal nontoxic stents (SAINTs) and fibrin glue. One cholecystojejunostomy was not performed owing to a gallbladder morphologic anomaly. Three animals died of problems unrelated to the SAINT-glue anastomoses. Of the 18 anastomoses in the 9 remaining animals, all were patent at the verification times of 14, 30, 120, and 480 days. Morphologically,there was greater edema and reduced height of the glandular epithelium in the 30-day CJs when compared to the jejunojejunal anastomoses. Results indicate that the sutureless SAINT-fibrin glue procedure is quite versatile and may be utilized for cholecystoenteric anastomoses. PMID- 8688378 TI - Skeletal muscle used as experimental cardiac assist: Russian experience. AB - This manuscript presents experimental data in the area of biomechanical cardiac support obtained at the Bakulev Institute for Cardiovascular Surgery in Moscow, Russia. After creation of the left ventricular aneurysm and subsequent cardiomyoplasty, active functioning of the muscle-heart complex was observed. In the late postoperative stages (3-6 months) hemodynamic parameters did not reach original preoperative values, but were satisfactory to support decreasing heart function: Cardiac index was decreased by 9.8%, the pumping coefficient of the left heart (KLH) by 24.7%, and left ventricular stroke work index (LVSWI) fell by 25%. Acute aneurysm of the left ventricle is a good model to study the effectiveness of cardiomyoplasty. Determination of parameters for stimulation of the muscle autograft showed that from the point of view of hemodynamic parameters of the muscle-heart complex, the optimal initial training schedule is a burst of seven pulses, each from 0.07 to 0.6 ms in duration, with a frequency of 30-50 Hz an amplitude of 6 V, and a burst following frequency of 15-30 per minute. PMID- 8688379 TI - Esophago-sphincter inhibitory reflex: role in the deglutition mechanism and esophageal achalasia. AB - The effect of esophageal distension on the lower esophageal sphincter (LES) in 14 normal volunteers and 6 esophageal achalasia (EA) patients was studied. A balloon tipped catheter was introduced into the LES and a second one into the esophagus. The pressure response of LES to balloon distension of the esophagus and pharyngoesophageal sphincter (PES) was recorded. In normal subjects, esophageal distension caused significant decrease of LES pressure; this reflex action was reproducible and was called "esophagosphincter inhibitory reflex" (ESIR). PES distension caused insignificant LES pressure changes (p > .05). Distension of the anesthetized esophagus or PES did not evoke LES pressure response. The ESIR was nonfatigable. In EA patients, the resting LES pressure was significantly higher than normal (p < .01). Upon esophageal distension, the LES pressure increased, while no response occurred with PES distension. There was paradox ESIR in EA with a resulting esophago-sphincter dyssynergia. To conclude, the ESIR seems to be of significance in esophageal motility disorders and may be incorporated as investigative tool in such conditions. PMID- 8688380 TI - Thoracoabdominal wall repair with glutaraldehyde-preserved bovine pericardium. AB - Glutaraldehyde-preserved bovine pericardium (GPBP) is evaluated as a bioprosthesis for the reconstruction of surgical defects in the thoracoabdominal wall. The mechanical properties of bovine pericardium preserved at different concentrations of glutaraldehyde were studied. Samples preserved in 0.5% glutaraldehyde showed a significantly higher tensile strength (11.7 +/- 0.8 N/mm2) than samples preserved in 2.5, 5, or 10% (similar to pericardium preserved in normal saline). The percentage of elongation was significantly lower than samples preserved in 1, 2.5, and 5% glutaraldehyde. GPBP at 0.5% was used to repair experimentally induced defects of the abdominal wall (n = 9), chest wall (n = 6), diaphragm (n = 6), and sternum (n = 7). All animals presented adequate tolerance to the material used and no case of infection or rejection of the material was seen in any of the animals. Finally, 0.5% GPBP was used clinically in a series of 40 patients: postincisional abdominal hernia (n = 30), inguinal hernia (n = 8), diaphragmatic hernia (n = 1), and congenital pelvic defect with prolapse of abdominal organs (n = 1). Surgical use showed that GPBP was a very manageable material and long-term results were good in 37 patients with a mean follow up of 18 months (range 5-35 months). Six patients presented seroma formation (all abdominal hernia patients), three of which eventually developed infection and had the GPBP patch removed at 3, 5, and 7 months postoperatively. The rest of the patients presented good scar formation with adequate resistance at the area of implantation. GPBP is a biological material with sufficient resistance to be used surgically in the repair of thoracoabdominal defects. Ideal concentration of glutaraldehyde to be used in the preparation-preservation of the material is 0.5% since higher concentration negatively affect its tensile rupture strength and elongation. PMID- 8688381 TI - Multicentre trials in obstetrics and gynaecology. Smaller explanatory trials are required. PMID- 8688382 TI - Where next for prophylaxis against pre-eclampsia? PMID- 8688383 TI - Choice and instrumental delivery. PMID- 8688384 TI - Preterm breech babies and randomised trials of rare conditions. PMID- 8688385 TI - Potential pathogenic roles of aberrant lipoprotein and fatty acid metabolism in pre-eclampsia. PMID- 8688386 TI - Interstitial cystitis--still an enigma after 80 years. PMID- 8688387 TI - Prediction of pre-eclampsia by abnormal uterine Doppler ultrasound and modification by aspirin. AB - OBJECTIVE: To assess the effect of low dose aspirin on severe pre-eclampsia when given to women identified as high risk by abnormal uterine artery Doppler ultrasound. DESIGN: Women with abnormal uterine artery flow velocity waveforms were recruited to the CLASP trial at 24 weeks. Abnormal uterine artery waveforms, with a high resistance index or an early diastolic notch, were identified at the 18-22 week anomaly scan and confirmed at 24 weeks. Of those women with persistently abnormal waveforms, 63 agreed to enter the CLASP trial. Three women were lost to follow up and five did not comply. Thus, 60 were randomised: 29 to placebo and 31 to low dose aspirin (60 mg daily) and analysis by intention to treat is reported. RESULTS: There were nine cases (29%) of pre-eclampsia in the aspirin group and twelve (41%) in the placebo group (odds ratio (OR) 0-58, confidence interval (CI) 0.2-1.69, P = 0.32). Severe pre-eclampsia developed in four women in the aspirin group and eleven women in the placebo group (OR 0.24, CI 0.07-0.88, P = 0.03) and intrauterine growth retardation occurred in eight cases in the aspirin group and twelve in the placebo group (OR 0.49, CI 0.17 1.47). The mean birthweight and gestation at delivery were 2.69 kg and 38.5 weeks in the aspirin group and 2.38 kg and 37.4 weeks in the placebo group, neither of which were statistically significant using the unpaired t test; P = 0.09 and P = 0.23, respectively. CONCLUSION: In high risk pregnancy low dose aspirin commenced at 24 weeks may reduce the incidence of severe pre-eclampsia. PMID- 8688388 TI - The effects of the antihormones RU486 and tamoxifen on fetoplacental development and placental bed vascularisation in the rat: a model for intrauterine fetal growth retardation. AB - OBJECTIVE: To examine the effect of administration of the antihormones RU486 and tamoxifen in early pregnancy during the period of maximal decidual development in the rat upon fetoplacental and placental bed development. DESIGN: Case-control study in an experimental animal model. SETTING: Academic department of obstetrics and gynaecology in a UK medical school. ANIMALS: Small laboratory animal-the rat exhibiting haemochorial placentation. INTERVENTION: Administration of antiprogesterone or antioestrogen (RU486 and tamoxifen respectively) during early pregnancy. MAIN OUTCOME MEASURES: Weight of the whole pregnancy implant, fetus, mesometrial decidua and placenta; incidence of intrauterine fetal death: and histological changes in the placental bed. RESULTS: RU486 produced resorption of all implants when administered above a threshold dose, below which it had no effect upon subsequent fetoplacental development. Tamoxifen treatment on days 9 to 11 resulted in significant reduction of decidual weight (35.1% on day 12 of pregnancy, P < 0.001). This was associated with a higher rate of implants or fetuses weighing below the 10th centile (59.6% and 5.7% on day 12, P < 0.001; 42.9% and 7% on day 16, P < 0.001; 25.4% and 7.6% on day 20, P < 0.001 in treated and control animals, respectively). This was also associated with a higher rate of intrauterine fetal death (30.7% on day 16 compared with 4.5% in controls, P < 0.001; 47.8% on day 20 compared to 0.83% in controls, P < 0.001). Histologically, the placental bed of treated animals failed to develop a dilated uteroplacental artery although trophoblast cells migrated endovascularly to a level equivalent to untreated animals. CONCLUSIONS: RU486 had an all or none dose-dependent effect on fetoplacental development, resulting in either abortion or normal development of pregnancy. Tamoxifen produced significant impairment of decidual development, which was associated with altered blood vessel transformation in the placental bed, impaired fetoplacental development and higher incidence of growth retarded fetuses and fetal death. PMID- 8688389 TI - Is intrapartum vibratory acoustic stimulation a valid alternative to fetal scalp pH determination? AB - OBJECTIVES: To determine the association between fetal heart rate accelerations, whether spontaneous or induced by vibratory acoustic stimulation, and subsequent scalp pH values in presence of a suspicious intrapartum fetal heart rate tracing, and thereby assess the ability of accelerations to predict a concurrent normal fetal scalp blood pH. DESIGN: Prospective observational study of 253 labours involving 421 pH samples. SETTING: Tertiary care university hospital of Genoeva. INTERVENTION: Vibratory acoustic stimulation through the maternal abdominal wall for five seconds prior to fetal blood sampling. MAIN OUTCOME MEASURES: Spontaneous fetal heart rate reactivity (accelerations) in the 10 min preceding vibratory acoustic stimulation, vibratory acoustic-induced reactivity prior to fetal blood sampling, and scalp pH value. RESULTS: The positive predictive value of a reactive fetal heart rate response after vibratory acoustic stimulation was 78% (95% CI 73-84%) and 97% (95% CI 94-99%) for scalp pH values of > 7.25 and > or = 7.20, respectively. Similar observations occurred with spontaneous reactivity. Of concern, 7 out of 31 (23%) occasions where the scalp blood pH was less than 7.20 appeared to be associated with a normal fetal heart rate response to vibratory acoustic stimulation. CONCLUSION: Fetal heart rate acceleration induced by vibratory acoustic stimulation was significantly associated with a normal scalp blood pH higher than 7.25. However, vibratory acoustic stimulation offers no advantage over observation of spontaneous fetal heart rate tracings and cannot safely replace fetal blood sampling during labour. PMID- 8688390 TI - Fetal fibronectin in cervicovaginal secretions as a predictor of preterm birth. AB - OBJECTIVE: To determine whether fetal fibronectin detected in cervicovaginal secretions of patients with symptoms suggestive of preterm labour is a predictor for preterm birth. DESIGN: A blind prospective observational study. SETTING: A teaching hospital. PARTICIPANTS: One hundred and forty-one women presenting to the delivery suite between 24 and 37 weeks of gestation (112 were between 24 and 34 weeks of gestation) with symptoms suggestive of preterm labour, with intact membranes and cervical dilation of < 2 cm. INTERVENTION: Specimens of cervicovaginal secretions were collected from the ectocervix and posterior fornix. Fetal fibronectin levels were measured by an ELISA and samples were considered positive if the level of fetal fibronectin present was > or = 0.05 microgram/ml. MAIN OUTCOME MEASURES: Gestation at birth and sampling-birth interval. RESULTS: The preterm birth (before 37 weeks of gestation) rate in the population studied was 19.1%. Fetal fibronectin predicted preterm birth with sensitivity of 63%, specificity of 95.6%, positive predictive value of 77.3%, and negative predictive value of 91.6%. Analysis of the data from women at less than 34 weeks of gestation showed similar results. A negative test accurately excluded (97.9%) the chance of subsequent birth during the three weeks interval following sampling. CONCLUSIONS: The presence of fetal fibronectin in the cervicovaginal secretions of women admitted with symptoms suggestive of preterm labour indicates a significant risk for subsequent preterm birth. The absence of fetal fibronectin in this group is a very strong indication that subsequent preterm birth is unlikely to occur. Fetal fibronectin test, if combined with clinical findings, has a potentially important role in clinical management of women with symptoms suggestive of preterm labour. PMID- 8688392 TI - Common iliac artery flow velocity waveforms in fetuses with a single umbilical artery: a longitudinal study. AB - OBJECTIVES: In fetuses with a single umbilical artery the entire blood flow to the placenta is transported through the common and internal iliac arteries from the side of the single artery, whereas the pelvic vessels from the side of the missing artery do not participate in the fetoplacental circulation. The aim of this study was to investigate the effect of gestational age on pelvic arterial blood flow in fetuses with single umbilical artery. DESIGN: In 15 fetuses with a single umbilical artery (SUA), common iliac artery flow velocity waveforms were studied longitudinally using high resolution colour Doppler ultrasonography at three gestational ages: 18 to 20 weeks, 28 to 30 weeks, and 35 to 37 weeks. The pulsatility index was measured in each common iliac artery and mixed model analysis of variance was used to examine the effect of gestational age and side. RESULTS: There was a highly significant difference in pulsatility index between common iliac arteries at all gestational ages, the values always being higher on the side that did not participate in the fetoplacental circulation (P < 0.001). For increasing gestation, the pulsatility index fell significantly in the SUA side but remained high in the non-SUA side (P < 0.001). CONCLUSIONS: This study shows that the asymmetry in the pelvic arterial blood flow in fetuses with SUA increases as pregnancy progresses, consistent with decreasing vascular resistance in the placenta and increasing resistance in the lower extremities. PMID- 8688391 TI - Insulin-like growth factor-binding protein 1 and insulin-like growth factor binding protein 3 in pre-eclampsia. AB - OBJECTIVE: To investigate circulating levels of insulin-like growth factor binding protein 1 (IGFBP-1) and IGFBP-3 in the mother and the fetus in pregnancies complicated by pre-eclampsia, and the relationship between serum levels of IGFBPs and fetal birthweight. DESIGN: A prospective study over an 18 month period. SETTING: A tertiary care academic medical centre. PARTICIPANTS: Sixty-six pregnant women with pre-eclampsia (35 cases of mild/moderate pre eclampsia and 31 cases of severe pre-eclampsia) and 78 nonpre-eclamptic pregnant women of matched gestational weeks and maternal ages. MAIN OUTCOME MEASURES: Serum concentrations of IGFBP-1 and IGFBP-3 at the time of delivery. RESULTS: In pre-eclampsia associated with intrauterine growth retardation (IUGR), maternal and cord serum IGFBP-1 levels at the time of delivery were elevated. By contrast, circulating IGFBP-3 levels in both the mother and the fetus were lower in pre eclampsia with IUGR than in nonpre-eclamptic pregnancy. However, there was no difference in serum IGFBP-1 and IGFBP-3 levels between pre-eclampsia without IUGR and nonpre-eclamptic pregnancy in both the mother and the fetus. CONCLUSIONS: In pre-eclampsia, elevated concentrations of circulating IGFBP-1 and decreased serum IGFBP-3 levels were observed in both the mother and the fetus. However, these changes may simply reflect low birthweight in pre-eclampsia. PMID- 8688394 TI - Differentiation of growth retarded from normally grown fetuses and prediction of intrauterine growth retardation using Doppler ultrasound. AB - OBJECTIVE: To assess the hypothesis that infants exhibiting catch-up growth as an indicator of intrauterine growth retardation (IUGR) have a higher incidence of predelivery abnormal Doppler results. SETTING. Obstetric unit, St James's University Hospital, Leeds. PARTICIPANTS: One hundred and ninety-six women with singleton pregnancies at high risk of IUGR, delivered between October 1992 and August 1993. MAIN OUTCOME MEASURES: Postnatal catch-up growth during the first seven months. RESULTS: Forty-six of the 196 infants demonstrated catch-up growth and were therefore classified as growth retarded; 85% of this group had had abnormal Doppler results prior to delivery, compared with 14% of the normally grown group. However, there is considerable overlap in birthweight ratio distribution between the two groups. CONCLUSION: This study confirms the existence of a population of IUGR infants of average birthweight ratio. Doppler appears to distinguish IUGR (as defined by catch-up growth) from normal growth more successfully in infants with an average birthweight ratio than in infants with a low birthweight ratio and is a better predictor of IUGR than SGA. PMID- 8688393 TI - Bacterial 16S rDNA polymerase chain reaction in the detection of intra-amniotic infection. AB - OBJECTIVE: Bacterial polymerase chain reaction (PCR) was used to detect early subclinical intraamhiotic infection. We used universal primers which amplify a DNA fragment of 16S ribosomal DNA (rDNA) from all known bacteria and sequenced the positive samples to identify the bacterial species. DESIGN: Transabdominally obtained amniotic fluid samples from 20 pregnant women with prelabour rupture of the fetal membranes (PROM), showing no signs of clinical infection, and 16 control samples were analysed with universal bacterial PCR. In addition, routine bacterial culture and amniotic fluid glucose were studied. RESULTS: Out of 20 PROM patients, five were positive in the PCR. PCR detected Ureaplasma urealyticum in two cases, Haemophilus influenzae in one case, Streptococcus oralis in one case and Fusobacterium sp. in one case. Only two of these were positive in a routine bacterial culture. Both were multibacterial infections, which caused discrepancies between the PCR and culture results. Two patients developed infectious complications: both were identified with the PCR assay. Amniotic fluid glucose was lower in PCR positive patients compared with PCR negative patients. CONCLUSION: Bacterial 16S rDNA PCR, in properly controlled conditions, promises to be a fast and reliable test for early intra-amniotic infection especially concerning Ureaplasma urealyticum. PMID- 8688395 TI - Prenatal genetic services for Down's syndrome: access and provision in 1990-1991. Steering Committee of the National Confidential Enquiry into Counselling for Genetic Disorders. AB - OBJECTIVE: To examine access to and provision of prenatal genetic services relating to Down's syndrome. DESIGN: Retrospective review of obstetric casenotes. SAMPLE: Pregnancies involving Down's syndrome in England and Wales in 1990-1991 in women aged 38 or over. Information was obtained in 430 cases from a questionnaire completed by the obstetric team who were asked to provide details based only on documentation in the antenatal casenotes. The outcome of pregnancy was a termination in 268 (62%) cases, a liveborn child with Down's syndrome in 144 (34%), a stillbirth in 9 (2%), a miscarriage in 8(2%) and in one case was not known. RESULTS: Overall, prenatal diagnosis was not offered in 7% pregnancies (95% CI: 4.4-9.2%) with late booking given as the main reason. Of women offered prenatal diagnosis, 76% accepted (95% CI: 72.3-80.6%). Counselling was documented before prenatal diagnosis in 89% of cases (95% CI: 86.0-92.3%) and after the procedure, to discuss the results, in 73% (95% CI: 67.5-77.7%). In 10% of pregnancies terminated for Down's syndrome, fetal products were not sent to the laboratory. There was no report of a normal fetus having been terminated as a consequences of incorrect prenatal diagnosis. However, in 10% (95% CI: 5.9 to 14.0%) of cases examined in the laboratory the diagnosis of Down's syndrome could not be confirmed. Details of prenatal diagnosis were not provided in five cases where a child with Down's syndrome was born. Of the remaining 139 livebirths, prenatal diagnosis was not offered in 27 (19%) cases, offered and declined in 92 (66%) and accepted in 20 (14%). In two cases a normal fetal karyotype was reported following prenatal diagnosis. CONCLUSIONS: The study has demonstrated that in 1990-1991: 1. There were certain shortcomings in the documentation of antenatal care; 2. Late booking was the main factor precluding the offer of prenatal diagnosis to women aged 38 or over, and 3. The rate of confirmation of Down's syndrome in terminated fetuses was incomplete. PMID- 8688396 TI - A multicentre randomised controlled trial comparing elective and selective caesarean section for the delivery of the preterm breech infant. AB - OBJECTIVE: To determine the optimum mode of delivery for women in preterm breech labour at a gestational age of 26 to 32 weeks. DESIGN: A multicentre randomised controlled trial. SETTING: Twenty-six hospitals in England, UK. PARTICIPANTS: Women with a singleton breech fetus in spontaneous preterm labour between 26 and 32 completed weeks of gestation, with no clear indication for a caesarean section or vaginal breech delivery. INTERVENTION: Random allocation to either "intention to delivery vaginally' or "intention to deliver by caesarean section'. MAIN OUTCOME MEASURES: Perinatal mortality, neonatal morbidity, maternal morbidity and gestation at delivery. RESULTS: The trial was closed after 17 months because of low recruitment, by which time substantial numbers of women had been in the eligible gestation period. Thirteen women from six hospitals were recruited. One infant, randomised to and delivered vaginally, was stillborn. Three fetal presentations were cephalic at delivery despite a diagnosis of breech presentation at trial entry. No formal statistical analysis was performed due to the small numbers. CONCLUSIONS: No conclusions about the optimum mode of delivery for women in preterm labour with a fetus presenting by the breech can be drawn from this trial. The low accrual rate was due to clinicians' reluctance to randomise eligible women, reflecting the circumstances and nature of the trial. PMID- 8688397 TI - Nonclosure of the visceral and parietal peritoneum at caesarean section: a randomised controlled trial. AB - OBJECTIVE: To assess the short term morbidity of nonclosure of the peritoneum at caesarean section. DESIGN: Women undergoing a lower segment caesarean section were randomly allocated to either closure or nonclosure of the visceral and parietal peritoneum. SETTING: Tertiary Care University Hospital of Geneva. MAIN OUTCOME MEASURES: Length of post-operative hospital stay. Other outcomes include maternal pain as assessed by both a visual analogue scale and the amount of post operative analgesics administered, post-operative ileus, and febrile morbidity. Operative time was recorded. RESULTS: We allocated 137 women to the nonclosure group and 143 to the closure group. Population characteristics were similar between groups. The mean length of hospital stay was 6.5 (SD 1.9) days for the nonclosure group and 6.8 (SD 2.2) days for the closure group (P = 0.21). No differences were found in the level of post-operative pain, the number of analgesic doses given, nor in the proportion with febrile morbidity. Post operative ileus resolved later in the closure group (P = 0.006). The mean operative time was shorter by 6 min (P = 0.006) in the nonclosure group. CONCLUSIONS: Short term post-operative morbidity and maternal pain are not increased by a shorter and more simple surgical procedure in which the peritoneum is left unsutured. PMID- 8688398 TI - Randomised comparison between a loading and incremental dose model for ritodrine administration in preterm labour. AB - OBJECTIVE: To compare a new loading dose regimen for intravenous ritodrine administration in preterm labour with the conventional dose regimen. DESIGN: Multicentre randomised trial using numbered opaque sealed envelopes. SETTING: Five teaching hospitals in the Netherlands. PARTICIPANTS: Women (n = 203) in preterm labour at less than 34 weeks of gestation. INTERVENTIONS: Women received either a loading dose ritodrine infusion followed, as soon as tocolysis was reached, by a decrease in infusion rate or the conventional schedule of increasing doses until uterine quiescence was achieved. RESULTS: Frequency of successful tocolysis (71%) and duration of treatment (55 h) were similar in both groups, but the loading dose schedule was better tolerated with fewer adverse events. Also the number of dose adjustments was smaller than in the incremental dose group (P < 0.001). Overall, the differences between the two regimens were unexpectedly small. CONCLUSIONS: Despite the small differences, the loading model is easier to apply, requires fewer dose adjustments, is better tolerated with less side effects, and reduces the likelihood of clinical error. PMID- 8688399 TI - Double-blind evaluation of ritodrine sustained release for oral maintenance of tocolysis after active preterm labour. AB - OBJECTIVE: To evaluate the effect of ritodrine sustained release capsules for maintaining uterine quiescence after successful treatment of active preterm labour. DESIGN: Multicentre placebo-controlled trial. SETTING: Five teaching hospitals in the Netherlands. PARTICIPANTS: Women (n = 95) at less than 35 weeks of gestation in whom active preterm labour had been stopped with intravenous ritodrine. INTERVENTIONS: Women received either two 40 mg ritodrine sustained release capsules (n = 50) or identical placebo capsules (n = 45) three times a day for seven days. RESULTS: The proportion of women who received another course of active treatment was significantly smaller with the sustained release than with placebo (1 of 50 versus 11 of 45: P = 0.003) as was the number delivering because of preterm labour during treatment (0 of 50 versus 4 of 45: P = 0.04). There were no other significant differences between the two groups. CONCLUSIONS: Maintenance treatment with ritodrine sustained release capsules after arrest of preterm labour reduces the risk of recurrences of preterm labour that necessitate treatment or precipitate delivery. PMID- 8688400 TI - A comparison of 600 and 200 mg mifepristone prior to second trimester abortion with the prostaglandin misoprostol. AB - OBJECTIVE: To compare the use of 600 and 200 mg mifepristone prior to second trimester termination of pregnancy with the prostaglandin misoprostol. DESIGN: A randomised study. SETTING: A Scottish teaching hospital. PARTICIPANTS: Seventy women undergoing legal induced abortion between 13 and 20 weeks of gestation. INTERVENTION: Administration of either 600 or 200 mg mifepristone 36 to 48 hours prior to prostaglandin. MAIN OUTCOME MEASURE: Induction-abortion interval. RESULTS: The geometric mean induction abortion interval was 6.9 (95% CI 5.8-8.4) h and 6.9 (95% CI 5.8-8.2) h in the 600 and 200 mg groups, respectively (no significant difference). The median dose of misoprostol was 1600 micrograms (three doses) in each group. Analgesic requirements and prostaglandin-related side effects were similar between groups. Overall, 11.4% of women required surgical evacuation of the uterus as a result of retained placenta. CONCLUSIONS: The dose of mifepristone used in second trimester abortion can be reduced from 600 to 200 mg. PMID- 8688401 TI - Is there any value in the long term follow up of women treated for endometrial cancer? AB - OBJECTIVE: To evaluate the clinical benefit of routine follow up of women after treatment for endometrial adenocarcinoma. DESIGN: Retrospective case analysis. PARTICIPANTS: All cases diagnosed and treated for endometrial adenocarcinoma in Tayside, Scotland during 1982 to 1984 inclusive. METHODS: Case-note and cancer registration document review. RESULTS: Of 102 patients, 97 had complete follow up for 10 years or until death. Recurrent disease was diagnosed in 17 women, only six of whom were asymptomatic at the time of diagnosis. There was no difference in survival between cases with symptomatic and asymptomatic recurrences. No recurrences were diagnosed more than six years after initial diagnosis. CONCLUSIONS: The diagnosis of asymptomatic recurrent endometrial carcinoma was not associated with improved long term survival. This small study showed no evidence of improved survival from the current practice of routine clinical review following treatment for endometrial adenocarcinoma. The effect of follow up on patient anxiety remains to be assessed. PMID- 8688402 TI - A more objective fetal heart rate baseline estimation. PMID- 8688403 TI - Changes in bone density and biochemical markers of bone turnover in pregnancy associated osteoporosis. PMID- 8688404 TI - ECPPA: randomised trial of low dose aspirin for the prevention of maternal and fetal complications in high risk pregnant women. PMID- 8688405 TI - Evaluation of the home pad test in the investigation of female urinary incontinence. PMID- 8688406 TI - Antenatal serology testing in pregnancy. PMID- 8688407 TI - Maternal smoking and fetal carboxyhaemoglobin and blood gas levels. PMID- 8688408 TI - Oscilometric blood pressure measurements in severe pre-eclampsia: validation of SpaceLabs 90207. PMID- 8688409 TI - A comparative study of the cosmetic appeal of abdominal incisions used for hysterectomy. PMID- 8688410 TI - The management of recurrent genital herpes infection in pregnancy: a postal survey of obstetric practice. PMID- 8688411 TI - The modern preventive treatment of recurrent miscarriage. PMID- 8688412 TI - The modern preventive treatment of recurrent miscarriage. PMID- 8688413 TI - Echogenic foci in the fetal heart: a marker of chromosomal abnormalities. PMID- 8688414 TI - Proteodermatan and proteokeratan sulfate (decorin, lumican/fibromodulin) proteins are horseshoe shaped. Implications for their interactions with collagen. AB - The small proteoglycans proteodermatan and proteokeratan sulfates organize collagen fibrils in extracellular matrix [Scott, J. E. (1992) FASEB J. 6, 2639 2645], thus helping to maintain tissue shape. Their interaction with fibrils is probably via the protein. They have been examined by rotary shadowing-electron microscopy, which showed that these leucine-rich-repeat proteins are horseshoe shaped. Morphometry and comparison with polypeptide sequences suggest ways in which decorin could interact with tissue collagen fibrils. It is proposed that decorin is a bidentate ligand attached to two parallel neighboring collagen molecules in the fibril, helping to stabilize fibrils and orient fibrillogenesis. PMID- 8688415 TI - Large heat capacity change in a protein-monovalent cation interaction. AB - Current views about protein-ligand interactions state that electrostatic forces drive the binding of charged species and that burial of hydrophobic and polar surfaces controls the heat capacity change associated with the reaction. For the interaction of a protein with a monovalent cation the electrostatic components are expected to be significant due to the ionic nature of the ligand, whereas the heat capacity change is expected to be small due to the size of the surface area involved in the recognition event. The physiologically important interaction of Na+ with thrombin was studied over the temperature range from 5 to 45 degrees C and the ionic strength range from 50 to 800 mM. These measurements reveal an unanticipated result that bears quite generally on studies of molecular recognition and protein folding. Binding of Na+ to thrombin is characterized by a modest dependence on ionic strength but a large and negative heat capacity change of -1.1 +/- 0.1 kcal mol-1 K-1. The small electrostatic coupling can be explained in terms of a minimal perturbation of the ionic atmosphere of the protein upon Na+ binding. The large heat capacity change, however, is difficult to reconcile with current views on the origin of this effect from surface area changes or large folding transitions coupled to binding. It is proposed that this change is linked to burial of a large cluster of water molecules in the Na+ binding pocket upon Na+ binding. Due to their reduced mobility and highly ordered structure, water molecules sequestered in the interior of a protein must have a lower heat capacity compared to those on the surface of a protein or in the bulk solvent. Hence, a binding or folding event where water molecules are buried may result in significant heat capacity changes independent of changes in exposed hydrophobic surface or coupled conformational transitions. PMID- 8688416 TI - Structural influence of cation binding to recombinant human brain S100b: evidence for calcium-induced exposure of a hydrophobic surface. AB - The dimeric calcium-binding protein S100b is proposed to undergo a calcium induced structural change allowing it to interact, via a hydrophobic surface, with other proteins. Previously it has been suggested that calcium binding to S100b leads to the exposure of at least one phenylalanine residue (Mani et al., 1982, 1983). This effect appears to be "reversed" at higher ionic strength, leading to a possible reburying of phenylalanine residues (Mani et al., 1982, 1983). To study these effects, we monitored calcium binding to recombinant human S100b by NMR spectroscopy under different salt (KCI) conditions. 15N-Labeled glycine residues in S100b showed calcium-induced chemical shift changes similar to those reported for the related monomeric protein calbindin D9k, suggesting similar conformational changes are occurring in the calcium-binding loops of these two proteins. Calcium binding to S100b also resulted in a shifting and broadening of several 1H resonances from the Ca-S100b form only including those from the side chains of residues F14, F70, and F73 but not those of residue Y17. This broadening was enhanced with increased ionic strength (KCI). However, small additions ( < 15% v/v) of the hydrophobic solvent trifluoroethanol relieved this phenomenon, leading to narrower line widths. These observations are consistent with the calcium-induced exposure of at least one of these hydrophobic residues, resulting in self-association of the S100b dimer. Trifluoroethanol serves to dissociate these complexes back to the dimeric calcium species. We propose that this cluster of hydrophobic residues which include F14, F73, and F88 may be important for interactions with a target protein. PMID- 8688417 TI - Structural and conformational analysis of glycan moieties in situ on isotopically 13C, 15N-enriched recombinant human chorionic gonadotropin. AB - The conformational properties in solution of the glycans on the alpha subunit of recombinant human chorionic gonadotropin are described, using high-resolution multinuclear NMR studies on uniformly 13C, 15N-enriched recombinant glycoprotein expressed in CHO cells. The glycan important for full biological activity of hCG, namely, that at Asn 52, appears to extend into solution both in the isolated alpha subunit and in complex with the beta subunit. The disposition of this glycan with respect to the protein backbone suggests that glycosylation maintains full biological activity of hCG either by interacting with a lectin-like region of the hCG receptor or by reducing the affinity of the hormone for the hCG receptor and preventing its down-regulation. PMID- 8688418 TI - Three-dimensional solution structure of mu-conotoxin GIIIB, a specific blocker of skeletal muscle sodium channels. AB - The three-dimensional solution structure of mu-conotoxin GIIIB, a 22-residue polypeptide from the venom of the piscivorous cone snail Conus geographus, has been determined using 2D 1H NMR spectroscopy. GIIIB binds with high affinity and selectivity to skeletal muscle sodium channels and is a valuable tool for characterizing both the structure and function of these channels. Structural restraints consisting of 289 interproton distances inferred from NOEs and 9 backbone and 5 side chain dihedral angle restraints from spin-spin coupling constants were used as input for simulated annealing calculations and energy minimization in the program X-PLOR. In addition to the 1H NMR derived information, the 13C resonances of GIIIB were assigned at natural abundance, and hydroxyproline C beta and C gamma chemical shifts were used to distinguish between the cis and trans peptide bond conformations. The final set of 20 structures had mean pairwise rms differences over the whole molecule of 1.22 A for the backbone atoms and 2.48 A for all heavy atoms. For the well-defined region encompassing residues 3-21, the corresponding values were 0.74 and 2.54 A, respectively. GIIIB adopts a compact structure consisting of a distorted 310 helix, a small beta-hairpin, a cis-hydroxyproline, and several turns. The molecule is stabilized by three disulfide bonds, two of which connect the helix and the beta-sheet, forming a structural core with similarities to the CS alpha beta motif [Cornet, B., Bonmatin, J.-M., Hetru, C., Hoffmann, J. A., Ptak, M., & Vovelle, F. (1995) Structure 3, 435-448]. This motif is common to several families of small proteins including scorpion toxins and insect defensins. Other structural features of GIIIB include the presence of eight arginine and lysine side chains that project into the solvent in a radial orientation relative to the core of the molecule. These cationic side chains form potential sites of interaction with anionic sites on sodium channels. The global fold is similar to that reported for mu-conotoxin GIIIA, and the structure of GIIIB determined in this study provides the basis for further understanding of the structure-activity relationships of the mu-conotoxins and for their binding to skeletal muscle sodium channels. PMID- 8688419 TI - Solution structure of an engineered insulin monomer at neutral pH. AB - Insulin circulates in the bloodstream and binds to its specific cell-surface receptor as a 5808 Da monomeric species. However, studies of the monomer structure and dynamics in solution are severely limited by insulin self association into dimers and higher oligomers. In the present work we use site directed mutagenesis of the dimer- and hexamer-forming surfaces to yield the first insulin species amenable for structure determination at neutral pH by nuclear magnetic resonance (NMR) spectroscopy. The preferred insulin mutant, i.e., (B1, B10, B16, B27) Glu, des-B30 insulin retains 47% biological potency and remains monomeric at millimolar concentrations in aqueous solution at pH 6.5-7.5 as judged by NMR and near-UV circular dichroism (CD) spectroscopy. From a series of 2D 1H-NMR spectra collected at pH 6.5 and 34 degrees C, the majority of the resonances are assigned to specific residues in the sequence, and nuclear Overhauser enhancement (NOE) cross-peaks are identified. NOE-derived distance restraints in conjunction with torsion restraints based on measured coupling constants, 3JHNH alpha, are used for structure calculations using the hybrid method of distance geometry and simulated annealing. The calculated structures show that the major part of the insulin mutant is structurally well defined with an average root mean square (rms) deviation between the 25 calculated structures and the mean coordinates of 0.66 A for backbone atoms (A2-A19 and B4-B26) and 1.31 A for all backbone atoms. The A-chain consists of two antiparallel helices, A2-A7 and A12-A19, connected by a loop. The B-chain contains a loop region (B1 B8), an alpha-helix (B9-B19), and a type I turn (B20-B23) and terminates as an extended strand (B24-B29). The B1-B4 and B27-B29 regions are disordered in solution. The structure is generally similar to crystal structures and resembles a crystalline T-state more than an R-state in the sense that the B-chain helix is confined to residues B9-B19. PMID- 8688420 TI - Chiral phosphorothioates as probes of protein interactions with individual DNA phosphoryl oxygens: essential interactions of EcoRI endonuclease with the phosphate at pGAATTC. AB - The contact between EcoRI endonuclease and the "primary clamp" phosphate of its recognition site pGAATTC is absolutely required for recognition of the canonical and all variant DNA sites. We have probed this contact using oligonucleotides containing single stereospecific (Rp)- or (Sp)- phosphorothioates (Ps). At the GAApTTC position, where the endonuclease interacts with only one phosphoryl oxygen at the central DNA kink, Rp-Ps inhibits and Sp-Ps stimulates binding and cleavage [Lesser et al. (1992) J. Biol. Chem. 267, 24810-24818]: in contrast, at the pGAATTC position both diastereomers inhibit binding. For single-strand substitution, the penalty in binding free energy (delta delta G0bind) is slightly greater for Sp-Ps (+ 0.9 kcal/mol) than for Rp-Ps (+ 0.7 kcal/mol). Binding penalties are approximately additive for double-strand substitution (Rp,Rp-Ps or Sp,Sp-Ps). Neither Ps diastereomer in one DNA strand affects the first-order rate constants for cleavage in the unmodified DNA strand, and only Sp-Ps inhibits the cleavage rate constant (3-fold) in the modified DNA strand. Thus, the second order cleavage rate (including binding and catalysis) is inhibited 14-fold by Sp Ps and 45-fold by Sp,Sp-Ps. In the canonical complex, the phosphate at pGAATTC is completely surrounded by protein and each nonbridging phosphoryl oxygen receives two hydrogen bonds from the endonuclease, such that in either orientation the increased bond length of P-S- inhibits binding. However, the pro-Sp oxygen interacts with residues that are connected (by proximity or inter-side-chain hydrogen bonding) to side chains with essential roles in catalysis, so cleavage is preferentially inhibited when these side chains are slightly displaced by the Sp-Ps diastereomer. PMID- 8688421 TI - A rapid screen of active site mutants in glycinamide ribonucleotide transformylase. AB - Specific and saturation site-directed mutageneses have been used to alter each polar residue within 6 A of the catalytic center of glycinamide ribonucleotide transformylase (EC 2.1.2.2). These mutants were rapidly screened for catalytic activity using functional complementation of auxotrophic cells. This screen allows a rapid qualitative estimate of enzyme activity for each of these mutants. These results have shown that none of the polar residues close to the catalytic center of the enzyme are irreplaceable, although several are important for full catalytic activity, namely, Asn106, His108, Ser135, and Asp144. A mechanism is proposed in which a fixed water molecule mediates the required proton transfers between substrate and cofactor, while the formyl group is transferred from 10 formyltetrahydrofolate by direct nucleophilic attack by the amine of glycinamide ribonucleotide. The active site polar residues may act to alter the pKa values of the attacking and leaving amino groups within a putative tetrahedral intermediate in order to facilitate the transfer of the formyl group. PMID- 8688422 TI - Enhanced peptide nucleic acid binding to supercoiled DNA: possible implications for DNA "breathing" dynamics. AB - The influence of DNA topology on peptide nucleic acid (PNA) binding was studied. Formation of sequence-specific PNA2/dsDNA (double-stranded DNA) complexes was monitored by a potassium permanganate probing/primer extension assay. At low ionic strengths, the binding of PNA was 2-3 times more efficient with supercoiled than with linear DNA. In the presence of 140 mM KCI, the PNA binding rate was reduced but, notably, highly dependent on template topology. Negative supercoiling (mean superhelix density, sigma approximately -0.051) increased the rate of binding by 2 orders of magnitude compared to that of relaxed DNA. The pseudo-first-order rate constant [k psi (sigma)] obeys an exponential function, k psi (sigma) = k psi (lin)e-sigma delta, where delta is a constant of 105 and k psi lin is the rate of PNA binding to linear DNA (sigma = 0). The activation energy [Ea(sigma)] was determined as approximately 93 and approximately 48 kJ mol 1 for PNA binding to linear and supercoiled DNA, respectively. The results are discussed in relation to the possible future use of PNA as an antigene agent and in the framework of DNA "breathing" dynamics. PMID- 8688423 TI - Solution structure of bovine angiogenin by 1H nuclear magnetic resonance spectroscopy. AB - The three-dimensional structure of bovine angiogenin has been determined using two- and three-dimensional proton NMR spectroscopy. The solution structure is very close to that recently determined by X-ray diffraction analysis. This structure appears well defined, even if five loops and one helix exhibit greater flexibility. Analysis of the active site geometry confirms the position of the Glu-118 residue which obstructs the pyrimidine binding site. There is no experimental evidence of an unobstructed conformation of angiogenin in solution. In addition, it appears that the Glu-118 and Ser-119 residues and the cell receptor binding loop may play an important role in the differences of C-terminal fragment organization and ribonucleolytic activity observed between angiogenins and ribonuclease A. PMID- 8688424 TI - Antithrombin-heparin affinity reduced by fucosylation of carbohydrate at asparagine 155. AB - The two human plasma antithrombin isoforms, alpha and beta, differ in glycosylation at asparagine 135. Only the alpha form carries carbohydrate at this position and has lower affinity for heparin than the beta form. We previously found additional heterogeneity in a recombinant N135Q antithrombin variant, evidenced by two isoforms with a 2-fold difference in heparin affinity [Turko, I. V., Fan, B., & Gettins, P. G. W. (1993) FEBS Lett. 335, 9-12]. To test whether this heterogeneity of heparin affinity results from specific glycosylation differences, we have determined the carbohydrate composition at the three remaining glycosylation sites, asparagine residues 96, 155, and 192, in each of the two N135Q isoforms, by a combination of peptide fragmentation and electrospray mass spectrometry. Patterns of glycosylation at residues 96 and 192 were similar for each isoform and showed the presence of mono-, bi-, and triantennary complex carbohydrate, as well as fucosylation of all types of chains. At position 155, however, there was a marked difference between the isoforms, with the form with lower heparin affinity being 97% fucosylated at this position, whereas the form with higher affinity for heparin was not fucosylated. Other differences in carbohydrate type showed no strong correlation between the two isoforms. We conclude that formation of the two heparin-affinity isoforms of N135Q antithrombin results from the specific difference in fucosylation at residue 155, which may result in different structural properties of the carbohydrate. Consistent with these findings was the elimination of heparin affinity heterogeneity in a double N135Q-N155Q variant antithrombin. It is possible that fucosylation of antithrombin may occur in vivo as a means of modifying the physiological properties of the antithrombin through alteration of the amount of antithrombin bound to surface heparin-like species. PMID- 8688425 TI - A binding site expressed on the surface of activated human platelets is shared by factor X and prothrombin. AB - We have demonstrated the presence of a saturable, reversible, and Ca(2+) dependent binding site for 125I-labeled factor X ([125I]factor X) on human platelets (16000 +/- 2000 sites per platelet, Kd = 320 +/- 40 nM, n = 12) activated with either thrombin or the thrombin receptor agonist peptide, SFLLRN amide, but not with ADP. Bound [125I]factor X could be completely removed by the addition of a Ca2+ chelator or an excess of unlabeled factor X. Antibodies that inhibit binding of factor X to the MAC-1 integrin receptor of monocytes and those directed against human factor V, failed to disrupt [125I]factor X binding to platelets. Prothrombin, but neither factor VII, factor IX, protein C, nor protein S, was an effective competitor of [125I]factor X binding with a K1 approximately Kd. [125I]Prothrombin also binds to activated (but not unactivated) platelets in a saturable, reversible, and Ca(2+)-dependent manner (20500 +/- 1500 sites, Kd = 470 +/- 110 nM, n = 3). Annexin V potently inhibited the binding of both [125I]factor X and [125I]prothrombin (IC50 approximately 3 nM). Factor X, prothrombin, and prothrombin fragment 1 (residues 1-155) were equipotent inhibitors of [125I]prothrombin and [125I]factor X binding, whereas Gla-domain less factor X was unable to compete with [125I]factor X for platelet binding sites. Thus, it is the Gla-domains of factor X and prothrombin that appear to contain the regions necessary for platelet binding. The results of studies utilizing artificial phospholipid surfaces have led to the hypothesis that the substrates (FX and prothrombin) for the intrinsic pathway FXase and prothrombinase complexes are bound to the phospholipid surface. The factor X/prothrombin binding site we have described on the surface of activated platelets permits the utilization of surface-bound substrates by these complexes when they are assembled on a physiologic surface. PMID- 8688426 TI - Factor X bound to the surface of activated human platelets is preferentially activated by platelet-bound factor IXa. AB - Factor X is a zymogen in the blood coagulation system which is activated by the serine protease, factor IXa, in a reaction that is promoted by the presence of stimulated platelets. We have shown previously that platelets possess a binding site for factor IXa, the occupancy of which is correlated with the rate of factor X activation (Ahmad et al., 1989b,c). Similarly, we have described a different binding site on the surface of activated platelets to which the substrate for this reaction, factor X, can bind (see the accompanying paper). This "zymogen binding site" is of moderate affinity and is relatively nonspecific; apparently shared to some degree by factor X and other vitamin K-dependent proteins, most notably prothrombin. We have found that prothrombin fragment 1 not only is able to displace factor X from this platelet binding site but also possesses the ability to inhibit the platelet-dependent activation of factor X. We have developed two mathematical models for the activation of factor X by platelet bound factor IXa. The first model assumes that factor X is activated in a manner that is totally unrelated to the presumptive zymogen binding site, whereas the second model requires factor X to first bind to this site before it may interact with platelet-bound factor IXa and become activated. Within the context of each of these models, we have evaluated three mechanisms by which prothrombin fragment 1 may inhibit factor X activation. The data presented herein are most consistent with the precept that platelet-bound factor X is activated by platelet-bound factor IXa (kcat approximately 0.0011 s-1) in an explicitly two-dimensional reaction (Km.2D approximately 230 molecules per platelet). Prothrombin fragment 1 is believed to disrupt this reaction by competing with factor X for the zymogen binding site (Ki approximately 470 nM) and, to a lesser degree, by displacing factor IXa from its binding site (Ki approximately 7 microM). These findings suggest that platelet-bound zymogen factor X represents a kinetically important pool of substrate that is preferentially activated on the surface of activated platelets. PMID- 8688427 TI - Characterization of the specificities of human blood group H gene-specified alpha 1,2-L-fucosyltransferase toward sulfated/sialylated/fucosylated acceptors: evidence for an inverse relationship between alpha 1,2-L-fucosylation of Gal and alpha 1,6-L-fucosylation of asparagine-linked GlcNAc. AB - The assembly of complex structures bearing the H determinant was examined by characterizing the specificities of a cloned blood group H gene-specified alpha 1,2-L-fucosyltransferase (FT) toward a variety of sulfated, sialylated, or fucosylated Gal beta 1,3/4GlcNAc beta- or Gal beta 1,3GalNAc alpha-based acceptor structures. (a) As compared to the basic type 2, Gal beta 1,4GlcNAc beta-(K(m) = 1.67 mM), the basic type 1 was 137% active (K(m) = 0.83 mM). (b) On C-6 sulfation of Gal, type 1 became 142.1% active and type 2 became 223.0% active (K(m) = 0.45 mM). (c) On C-6 sulfation of GlcNAc, type 2 showed 33.7% activity. (d) On C-3 or C-4 fucosylation of GlcNAc, both types 1 and 2 lost activity. (e) Type 1 showed 70.8% and 5.8% activity, respectively, on C-6 and C-4 O-methylation of GlcNAc. (f) Type 1 retained 18.8% activity on alpha 2,6-sialylation of GlcNAc. (g) Terminal type 1 or 2 of extended chain had lower activity. (h) With Gal in place of GlcNAc in type 1, the activity became 43.2%. (i) Compounds with terminal alpha 1,3-linked Gal were inactive. (j) Gal beta 1,3GalNAc alpha- (the T-hapten) was approximately 0.4-fold as active as Gal beta 1,4GlcNAc beta-. (k) C-6 sulfation of Gal on the T-hapten did not affect the acceptor activity. (l) C-6 sulfation of GalNAc decreased the activity to 70%, whereas on C-6 sulfation of both Gal and GalNAc the T-hapten lost the acceptor ability. (m) C-6 sialylation of GalNAc also led to inactivity. (n) beta 1,6 branching from GalNAc of the T-hapten by a GlcNAc residue or by units such as Gal beta 1, 4GlcNAc-, Gal beta 1,4(Fuc alpha 1,3)GlcNAc-, or 3-sulfoGal beta 1,4GlcNAc- resulted in 111.9%, 282.8%, 48.3%, and 75.3% activities, respectively. (o) The enhancement of enzyme affinity by a sulfo group on C-6 of Gal was demonstrated by an increase (approximately 5-fold) in the K(m) for Gal beta 1,4GlcNAc beta 1,6(Gal beta 1,3)GalNAc alpha-O-Bn in presence of 6-sulfoGal beta 1,- 4GlcNAc beta-O-Me (3.0 mM). (p) Among the two sites in Gal beta 1, 4GlcNAc beta 1,6(Gal beta 1,3) GalNAc alpha-O-Bn, the enzyme had a higher affinity ( > 3-fold) for the Gal linked to GlcNAc. (q) With respect to Gal beta 1,- 3GlcNAc beta-O-Bn (3.0 mM), fetuin triantennary asialo glycopeptide (2.4 mM), bovine IgG diantennary glycopeptide (2.8 mM), asialo Cowper's gland mucin (0.06 mM), and the acrylamide copolymers (0.125 mM each) containing Gal beta 1,3GlcNAc beta-, Gal beta 1,3(6-sulfo)GlcNAc beta-, Gal beta 1,3GalNAc alpha-, Gal beta 1,3Gal beta-, or Gal alpha 1,3Gal beta- units were 153.6%, 43.0%, 6.2%, 52.5%, 94.9%, 14.7%, 23.6%, and 15.6% active, respectively. (r) Fucosylation by alpha 1,2-L-FT of the galactosyl residue which occurs on the antennary structure of the bovine IgG glycopeptide was adversely affected by the presence of an alpha 1,6-L fucosyl residue located on the distant glucosaminyl residue that is directly attached to the asparagine of the protein backbone. This became evident from the 4-fold activity of alpha 1,2-L-FT toward bovine IgG glycopeptide after approximately 5% removal of alpha 1,6-linked Fuo. PMID- 8688428 TI - Specificity analysis of three clonal and five non-clonal alpha 1,3-L fucosyltransferases with sulfated, sialylated, or fucosylated synthetic carbohydrates as acceptors in relation to the assembly of 3'-sialyl-6'-sulfo Lewis x (the L-selectin ligand) and related complex structures. AB - Unique specificities of the cloned alpha 1,3-L-fucosyltransferases (FTs), FT III (Lewis type), FT IV (myeloid type), and FT V (plasma type), and the alpha 1,3-FTs of Colo 205 (colon carcinoma), HL 60 (myeloid), B142 (lymphoid), EKVX (lung carcinoma), and calf mesenteric lymph nodes (CMLN) were discerned with sulfated, sialylated, and/or fucosylated Gal beta 1,3/4GlcNAc beta-based acceptor moieties. (a) FT V was 1.0-, 20.8-, and 4.6-fold active in forming Lewis x, Lewis y, and 3' alpha-galactosyl Lewis x, respectively. (b) FT III and FT V formed approximately 4-fold 3'-sulfo Lewis x, as compared to 3'-sialyl Lewis x. (c) FT IV showed great efficiency in forming 3'-sulfo Lewis x (249%) and Lewis x (345%) in mucin-type branched chains. (d) FT III, FT IV, and FT V formed 19%, 62%, and 47% 6-sulfo Lewis x as compared to Lewis x. (e) 6'-Sulfo Lewis x and 3'-sialyl-6'-sulfo Lewis x (GLYCAM ligand) were not synthesized from their immediate precursors by FT III, FT IV, or FT V. (f) FT III, FT IV, and FT V were 311%, 9%, and 188% active, respectively, with 2'-fucosyl lactose but were not active with 2'- fucosyl-6' sulfo lactose. (g) FT III and FT V were 7.0- and 0.5-fold active in forming Lewis a as compared to Lewis x, whereas, FT IV was inactive. (h) FT III was -2.0-fold more active in forming 3'-alpha-galactosyl Lewis a than Lewis b. (i) FT III synthesized 6-sialyl Lewis a (40% efficiency as compared to Lewis a) from 6 sialyl type 1. (j) FT III did not act on 6'-sulfo or 6'-sialyl type 1 but was 106% and 22% active with 3'-sulfo and 6-sulfo type 1, respectively. (k) The Colo 205 FT activities with type 1 compounds almost paralleled that of FT III except for the low activity (9%) with Gal beta 1,3(NeuAc alpha 2, 6)GlcNAc beta-O-Bn, but with type 2 considerable differences between Colo 205 FT and FT III were noticed. (l) The alpha 1,3-FTs of CMLN, HL60, B142, and EKVX were 1.2-1.7 times active with Fuc alpha 1,2Gal beta 1,4GlcNAc beta- O-pNP and Gal alpha 1,3Gal beta 1,4 GlcNAc beta-O-Bn with respect to Gal beta 1,4GlcNAc beta-O-Al. (m) Both CMLN and HL60 FTs were 2-fold active with 3-sulfoGal beta 1,4GlcNAc in a mucin-type branch structure such as 3-sulfoGal beta 1,4GlcNAc beta 1,6(Gal beta 1,3)GalNAc alpha-O-Bn. (n) The 3'-sulfoLacNAc/acrylamide copolymer, either as an acceptor or as a competitive inhibitor, had the potential to distinguish myeloid type alpha 1,3-FT from the plasma type. PMID- 8688429 TI - Active site of 5-aminolevulinate synthase resides at the subunit interface. Evidence from in vivo heterodimer formation. AB - 5-Aminolevulinate synthase (EC 2.3.1.37) is the first enzyme in the heme biosynthetic pathway of animals, fungi and some bacteria. It functions as a homodimer and requires pyridoxal 5'-phosphate as an essential cofactor. In mouse erythroid 5-aminolevulinate synthase, lysine 313 has been identified as the residue involved in the Schiff base linkage with pyridoxal 5'-phosphate [Ferreira, G. C., et al. (1993) Protein Sci. 2, 1959-1965], while arginine 149, a conserved residue among all known 5-aminolevulinate synthase sequences, is essential for function [Gong & Ferreira (1995) Biochemistry 34, 1678-1685]. To determine whether each subunit contains an independent active site (i.e., intrasubunit arrangement) or whether the active site resides at the subunit interface (i.e., intersubunit arrangement), in vivo complementation studies were used to generate heterodimers from site-directed, catalytically inactive mouse 5 aminolevulinate synthase mutants. When R149A and K313A mutants were co-expressed in a hem A- Escherichia coli strain, which can only grow in the presence of 5 aminolevulinate or when it is transformed with an active 5-aminolevulinate synthase expression plasmid, the hem A- E. coli strain acquired heme prototrophy. The purified K313A/R149A heterodimer mixture exhibited K(m) values for the substrates similar to those of the wild-type enzyme and approximately 26% of the wild-type enzyme activity which is in agreement with the expected 25% value for the K313A/R149A coexpression system. In addition, DNA sequencing of four Saccharomyces cerevisiae 5-aminolevulinate synthase mutants, which lack ALAS activity but exhibit enzymatic complementation, revealed that mutant G101 with mutations N157Y and N162S can complement mutant G220 with mutation T452R, and mutant G205 with mutation C145R can complement mutant Ole3 with mutation G344C. Taken together, these results provide conclusive evidence that the 5 aminolevulinate synthase active site is located at the subunit interface and contains catalytically essential residues from the two subunits. PMID- 8688430 TI - Essential cysteines in 3-deoxy-D-manno-octulosonic acid 8-phosphate synthase from Escherichia coli: analysis by chemical modification and site-directed mutagenesis. AB - The enzyme 3-deoxy-D-manno-octulosonic acid 8-phosphate synthase (EC 4.1. 2.16) (KDO 8-P synthase) that catalyzes the condensation of D-arabinose 5-phosphate (A 5-P) with phosphoenolpyruvate (PEP) to give 3-deoxy-D-manno-octulosonic acid 8 phosphate (KDO 8-P) and inorganic phosphate (Pi) was inactivated by the thiol modifying reagents 5,5-dithiobis (2-nitrobenzoate) (DTNB) and methyl methanethiosulfonate (MMTS). Reaction of cloned native KDO 8-P synthase with DTNB correlated with modification of two of the four cysteine sulfhydryls per monomer of enzyme and total loss of enzymatic activity which could be partially restored by treatment with dithiothreitol (DTT). Cyanolysis of the DTNB-inactivated enzyme with KCN led to the elimination of 2 equiv of 5-thio-2-nitrobenzoate and partial recovery of activity. The presence of either substrate(s) or product(s) provided no protection against inactivation nor affected the number of cysteines modified, indicating that the cysteines modified are most likely not at the active site of KDO 8-P synthase. Titration of denatured enzyme with DTNB resulted in the modification of all four cysteines. After treatment of native enzyme with MMTS, no cysteines could be titrated with DTNB and no enzymatic activity could be detected. Treatment of the MMTS-inactivated KDO 8-P synthase with DTT resulted in restoration of enzymatic activity and the presence of two DTNB-titratable cysteine residues. Based on these observations and a report that KDO 8-P synthase is inactivated in a time-dependent manner with 3-bromopyruvate and that the substrate PEP protects against this inactivation, all four cysteines (38, 166, 206, and 249) were individually mutated to alanines via a modified PCR methodology. The C206A and C249A mutants were both enzymatically active with K(m) and Vmax values approximately identical to those of wild-type KDO 8-P synthase, and both native mutants reacted with DTNB to modify only one of the three remaining cysteine sulfhydryls per monomer of enzyme. Titration of denatured C206A and C249A mutants resulted in the modification of three cysteines. The C38A and C166A mutants were both for the most part enzymatically inactive. Titration of native C38A and C166A with DTNB resulted in modification of two cysteines while titration of the denatured mutant protein resulted in modification of the three remaining cysteines. Circular dichroism measurements of wild-type KDO 8-P synthase and the four C --> A mutants indicate modest but significant changes in the structure of the mutants. These results indicate that C206 and C249 in native KDO 8-P synthase are readily accessible to the modification reagent DTNB and therefore inactivation may result from structural changes in the DTNB-modified KDO 8-P synthase or blockage of access of substrates to the active site. The C38 and C166 in native KDO 8-P synthase are inaccessible to the modification reagent DTNB, indicating that they are located in the interior of KDO 8-P synthase, and loss of activity in the C38A and C166A mutants suggests their essentiality in the KDO 8-P synthase reaction. PMID- 8688431 TI - Evidence for a tryptophan tryptophylquinone aminosemiquinone intermediate in the physiologic reaction between methylamine dehydrogenase and amicyanin. AB - The tryptophan tryptophylquinone (TTQ) cofactor of methylamine dehydrogenase (MADH) is covalently modified by nitrogen during its two-electron reduction by methylamine to form an aminoquinol (N-quinol). It is possible, in vitro, to generate unmodified O-quinol and O-semiquinone forms of MADH with dithionite, as well as an N-semiquinone form which contains a substrate-derived nitrogen. Rapid scanning stopped-flow spectroscopy and global kinetic analysis are used to demonstrate that N-semiquinone is a true physiologic reaction intermediate which accumulates during the two sequential one-electron oxidations of N-quinol MADH by amicyanin. In contrast, no detectable O-semiquinone accumulates during the two sequential one-electron oxidations of the O-quinol form of MADH by amicyanin. This is because the reaction of N-semiquinone with amicyanin is much slower (70 s 1 at 25 degrees C) than the reaction of O-semiquinone ( > 1000 s-1). These rate constants obtained from global analysis of the overall reaction are the same as those obtained when each semiquinone form was made in vitro and then mixed with oxidized amicyanin. The presence of 200 mM NH4Cl during the reaction of O-quinol MADH with amicyanin does not cause any detectable accumulation of a semiquinone species. Thus, the accumulation of the intermediate in the reactions of the N quinol is not due to the influence of noncovalently bound ammonia at the active site of the O-semiquinone. These data indicate that the intermediate which accumulates during the complete oxidation of substrate-reduced N-quinol MADH is not the O-semiquinone, but the more slowly reacting N-semiquinone, and that the N semiquinone is a physiologically relevant reaction intermediate. These results also provide good evidence in favor of an aminotransferase mechanism, as opposed to an imine elimination mechanism, for the reaction of MADH with substrate methylamine. PMID- 8688432 TI - The conformation of the isoprenyl chain relative to the semiquinone head in the primary electron acceptor (QA) of higher plant PSII (plastosemiquinone) differs from that in bacterial reaction centers (ubisemiquinone or menasemiquinone) by ca. 90 degrees. AB - The conformation and partial electron spin density distribution of the reduced primary electron acceptor (QA-), a plastosemiquinone-9 (PQ-9-) anion radical, in photosystem II protein complexes from spinach as well as free PQ-9- in solution have been determined by EPR and 1H ENDOR spectroscopies. The data show that the conformation of the isoprenyl chain at C beta relative to the aromatic ring differs by 90 degrees for QA- in higher plant PSII versus both types of bacterial reaction centers, Rhodobacter sphaeroides and Rhodopseudomonas viridis [containing ubiquinone (UQ) or menaquinone (MQ) at QA site, respectively]. This conformational distinction between the QA- species in PSII vs bacterial RCs follows precisely the conformational preferences of the isolated semiquinone anion radicals free in solution; type II semiquinones like PQ-9- have the isoprenyl C beta C gamma bond coplanar with the aromatic ring, while type I semiquinones like UQ- and MQ- place the C beta C gamma bond perpendicular to the ring. This conformational difference originates from nonbonded repulsions between the isoprenyl chain and the C6 methyl group present in type I semiquinones, forcing the perpendicular conformation, but absent in type II semiquinones having the smaller H atom at C6. Thus, the QA binding site in both higher plant PSII and bacterial reaction centers accommodates the lower energy conformation of their native semiquinones observed in solution. The energy difference between ground (C beta C gamma bond perpendicular to the ring) and excited (C beta C gamma bond coplanar with the ring) conformations of UQ- and vitamin K1- radicals is estimated to be sufficiently large (ca. 6 kcal/mol) to produce greater than a 10 fold difference in populations of these conformations at room temperature. For PQ 9-, a similar number is estimated. We propose that the strong confornational preferences of type I and type II semiquinones has lead to the evolution of different reaction center protein structures surrounding the isoprenyl/quinone head junction of QA to accommodate the favored low energy conformers. This predicted difference in protein structures could explain the low effectiveness (high selectivities) observed in quinone replacement experiments for type II vs type I quinones seen in higher plant PSII and bacterial reaction centers, respectively. PMID- 8688433 TI - UV-B-induced inhibition of photosystem II electron transport studied by EPR and chlorophyll fluorescence. Impairment of donor and acceptor side components. AB - Inhibition of photosystem II electron transport by UV-B radiation has been studied in isolated spinach photosystem II membrane particles using low temperature EPR spectroscopy and chlorophyll fluorescence measurements. UV-B irradiation results in the rapid inhibition of oxygen evolution and the decline of variable chlorophyll fluorescence. These effects are accompanied by the loss of the multiline EPR signal arising from the S2 state of the water-oxidizing complex and the induction of Signal IIfast originating from stabilized Try-Z+. The EPR signals from the QA-Fe2+ acceptor complex, Tyr-D+, and the oxidized non heme iron (Fe3+) are also decreased during the course of UV-B irradiation, but at a significantly slower rate than oxygen evolution and the multiline signal. The decrease of the Fe3+ signal at high g values (g = 8.06, g = 5.6) is accompanied by the induction of another EPR signal at g = 4.26 that arises most likely from the same Fe3+ ion in a modified ligand environment. UV-B irradiation also affects cytochrome b-559. The g = 2.94 EPR signal that arises from the dark- oxidized form is enhanced, whereas the light inducible g = 3.04 signal that arises from the photo-oxidizable population of cytochrome b-559 is diminished. UV-B irradiation also induces the degradation of the D1 reaction center protein. The rate of the D1 protein loss is slower than the inhibition of oxygen evolution and of the multiline signal but follows closely the loss of Signal IIslow, the QA Fe2+ and the Fe3+ EPR signals, as well as the release of protein-bound manganese. It is concluded from the results that UV-B radiation affects photosystem II redox components at both the donor and acceptor side. The primary damage occurs at the water-oxidizing complex. Modification and/or inactivation of tyrosine-D, cytochrome b-559, and the QAFe2+ acceptor complex are subsequent events that coincide more closely with the UV-B-induced damage to the protein structure of the photosystem II reaction center. PMID- 8688434 TI - The mitochondrial oxoglutarate carrier: sulfhydryl reagents bind to cysteine-184, and this interaction is enhanced by substrate binding. AB - The interaction of sulfhydryl reagents with the oxoglutarate carrier (OGC) of bovine heart mitochondria was investigated in proteoliposomes reconstituted from purified carrier and lipids. Incubation of the proteoliposomes with maleimides or mercurials led to inhibition of the oxoglutarate carrier protein. The inhibition of oxoglutarate transport by mercurials was removed by dithioerythritol (DTE), whereas inhibition by maleimides was not. Preincubation of the proteoliposomes with mercurials protected the carrier protein against inactivation by the fluorescent sulfhydryl reagent N-(1-pyrenyl)maleimide (PM) and decreased the fluorescence associated with the carrier, indicating that mercurials bind to the same cysteine which is modified by PM. The presence of the substrates oxoglutarate and malate increased the binding of PM to the reconstituted carrier as well as the degree of inhibition of the reconstituted transport activity caused by PM, other maleimides, and mercurials. This result is consistent with the assumption that substrate binding causes a change in the tertiary structure of the carrier protein. The primary sequence of the oxoglutarate carrier contains three cysteines (Cys-184, Cys-221, and Cys-224). We provide evidence that PM labels only Cys-184, whereas Cys-221 and Cys-224 are linked by a disulfide bridge. PMID- 8688435 TI - Structural flexibility of chiral macroaggregates of light-harvesting chlorophyll a/b pigment-protein complexes. Light-induced reversible structural changes associated with energy dissipation. AB - In this paper, we show that stacked lamellar aggregates of the purified chlorophyll a/b light-harvesting antenna complexes (LHCII) and granal thylakoid membranes are capable of undergoing light-induced reversible changes in the chiral macroorganization of the chromophores as well as in the photophysical pathways. In granal thylakoids, the light-induced reversible structural changes, detected by circular dichroism (CD) measurements, are accompanied by reversible changes in the fluorescence yield that indicate an increased dissipation of the excitation energy. These changes become gradually more significant in excess light compared to nonsaturating light intensities, and can be eliminated by suspending the membranes in hypotonic, low-salt medium in which the chiral macroaggregates are absent. In lamellar aggregates of LHCII, the light-induced reversible changes of the main, nonexcitonic CD bands are also accompanied by reversible changes in the fluorescence yield. In small aggregates and trimers, no light-induced delta CD occurs, and the fluorescence changes are largely irreversible. It is proposed that the structural changes are induced by thermal effects due to the excess light energy absorbed by the pigments. Our data strongly suggest that the structure and function of the antenna system of chloroplasts can be regulated by the absorption of excess light energy with a mechanism independent of the operation of the photochemical apparatus. PMID- 8688436 TI - Characterization of manganese(II) binding site mutants of manganese peroxidase. AB - A series of site-directed mutants, E35Q, E39Q, and E35Q-D179N, in the gene encoding manganese peroxidase isozyme 1 (mnp1) from Phanerochaete chrysosporium, was created by overlap extension, using the polymerase chain reaction. The mutant genes were expressed in P. chrysosporium during primary metabolic growth under the control of the glyceraldehyde-3-phosphate dehydrogenase promoter. The mutant manganese peroxidases (MnPs) were purified and characterized. The molecular masses of the mutant proteins, as well as UV-vis spectral features of their oxidized states, were very similar to those of the wild-type enzyme. Resonance Raman spectral results indicated that the heme environment of the mutant MnP proteins also was similar to that of the wild-type protein. Steady-state kinetic analyses of the E35Q and E39Q mutant MnPs yielded K(m) values for the substrate MnII that were approximately 50-fold greater than the corresponding K(m) value for the wild-type enzyme. Likewise, the kcat values for MnII oxidation were approximately 300-fold lower than that for wild-type MnP. With the E35Q-D179N double mutant, the K(m) value for MnII was approximately 120-fold greater, and the kcat value was approximately 1000-fold less than that for the wild-type MnP1. Transient-state kinetic analysis of the reduction of MnP compound II by MnII allowed the determination of the equilibrium dissociation constants (KD) and first- order rate constants for the mutant proteins. The KD values were approximately 100-fold higher for the single mutants and approximately 200-fold higher for the double mutant, as compared with the wild-type enzyme. The first order rate constants for the single and double mutants were approximately 200 fold and approximately 4000-fold less, respectively, than that of the wild-type enzyme. In contrast, the K(m) values for H2O2 and the rates of compound I formation were similar for the mutant and wild-type MnPs. The second-order rate constants for p-cresol and ferrocyanide reduction of the mutant compounds II also were similar to those of the wild-type enzyme. PMID- 8688437 TI - Cysteine ligand swapping on a deletable loop of the [2Fe-2S] ferredoxin from Clostridium pasteurianum. AB - The [2Fe-2S] ferredoxin from Clostridium pasteurianum is unique among ferredoxins, both by its sequence and by the distribution of its cysteine residues (in positions 11, 14, 24, 56, and 60). In previous investigations, a combination of site-directed mutagenesis and of spectroscopic techniques showed that cysteines 11, 56, and 60 are ligands of the [2Fe-2S] cluster in the wild type protein and that cysteine 14 is not, but the status of cysteine 24 remained unclear. New mutated forms of this ferredoxin have been obtained and characterized. The data show that cysteine 24 is a ligand of the cluster in the wild type protein. When cysteine 24 is mutated into alanine, it is replaced as a cluster ligand by cysteine 14. The fourth ligand of the cluster can also be a cysteine residue newly introduced in position 16 when both cysteines 14 and 24 are replaced by alanine. These results suggest that the region encompassing cysteines 14 and 24 is a solvent-exposed flexible loop, in agreement with structure predictions. A number of nondeleterious deletions of variable length (3 14 residues) have been performed in the region of residues 17-32. The deletions were found to modify only marginally the spectroscopic properties of the [2Fe-2S] cluster but resulted in variations of its redox potential over a range of nearly 100 mV. This is the first instance of ligand swapping in a [2Fe-2S] protein, and the first time in any ferredoxin that a large loop has been excised from the structure without preventing the assembly of the iron-sulfur chromophore. Some of the molecular variants described here also highlight the similarities between the C. pasteurianum [2Fe-2S] ferredoxin and the 25 kDa subunit of the proton translocating NADH: ubiquinone oxidoreductase of Paracoccus denitrificans. PMID- 8688438 TI - Proceedings of the 9th European Bioenergetics Conference. Louvain-la-Neuve, Belgium, August 17-22, 1996. PMID- 8688439 TI - Channelling of dioxygen into the respiratory enzyme. PMID- 8688440 TI - Mitochondrial damage as a source of diseases and aging: a strategy of how to fight these. AB - Some aspects of a defense against an oxidative stress are reviewed. All these aspects are focused on the necessity to defend mtDNA against damage. Protecting mechanisms involve the regulation of mitochondrial transport of nucleic acids, and the development of antioxygen defense as preventive measures. In the first case an exclusive role is supposed to play the mitochondrial benzodiazepine receptor and components, regulating the activity of its participants (mitochondrial porin and adenine nucleotide translocator). The possible transport of nucleic acids through Ca(2+)-dependent permeability transition pore, representing one of the functional states of mitochondrial benzodiazepine receptor, is put forth. Such mechanisms can also cover the genomic nuclear mitochondrial exchange. The second aspect reviews the possible complex of measures to lower the harmful effect of oxygen. Among these measures are mild uncoupling, the opening of a permeability transition pore and cellular apoptosis as was recently suggested by Skulachev. Problems such as cellular aging and mitochondrial diseases, are discussed in light of the relevance to the problem of oxidative stress. PMID- 8688441 TI - F1F0-ATP synthase: development of direct optical probes of the catalytic mechanism. AB - Using strategically-placed tryptophan (Trp) residues as optical probes to monitor nucleotide binding and hydrolysis, we demonstrate that all three catalytic nucleotide binding sites in F1-ATPase must be filled to obtain physiological (Vmax) MgATP hydrolysis rates. At Vmax hydrolysis rates, the predominant enzyme species has one of the three catalytic sites filled with unhydrolyzed substrate MgATP, the other two sites are filled with product MgADP. A specifically-inserted Trp probe was also developed to characterize nucleotide binding to the noncatalytic sites, and a model to explain the specificity of these sites is shown. These sites appear to play no role in ATP hydrolysis. PMID- 8688442 TI - Structure-function relationships in the Ca(2+)-ATPase of sarcoplasmic reticulum: facts, speculations and questions for the future. AB - Structural data on the Ca(2+)-ATPase of sarcoplasmic reticulum are integrated with kinetic data on Ca2+ transport. The emphasis is upon ATPase-ATPase interactions, the requirement for phospholipids, and the mechanism of Ca2+ translocation. The possible role of cytoplasmic [Ca2+] in the regulation of the synthesis of Ca(2+)-ATPase is discussed. PMID- 8688443 TI - Site-directed mutagenesis studies of energy coupling in the sarcoplasmic reticulum Ca(2+)-ATPase. AB - Site-directed mutagenesis studies identifying residues important to energy transduction in the sarcoplasmic reticulum Ca(2+)-ATPase are reviewed. Mutations blocking the crucial E1P to E2P transition are located in the small and the large cytoplasmic domains, in the stalk segment S4 linking transmembrane segment M4 with the catalytic site, as well as in transmembrane segments M4 and M8. Mutations that block the dephosphorylation of the E2P phosphoenzyme intermediate are located in transmembrane segments M4, M5, and M6, i.e., in the same domain as the Ca(2+)-binding sites. Removal of the sidechain of Tyr763 located at the boundary between transmembrane segment M5 and the corresponding stalk segment S5 linking M5 with the catalytic site leads to uncoupling of ATP hydrolysis from Ca2+ uptake. Uncoupling may be due to efflux through the Ca(2+)-ATPase of Ca2+ that has been transported, and may thus be caused by a defective gating process in the late part of the catalytic cycle. A nearby located residue Lys758 is also involved in energy coupling, since its substitution with Ile activates dephosphorylation at high pH and slows the E2 to E1 transition. PMID- 8688444 TI - Cation transport in mitochondria--the potassium cycle. AB - The existence in mitochondria of separate, highly regulated pathways for K+ influx and efflux strongly implies that mitochondrial volume is subject to regulation in vivo. Volume, in turn has been shown to regulate activity of the electron transport chain. Thus, the mitochondrial K+ cycle appears to play a key signalling role in regulating cellular bioenergetics, including the metabolic fate of fatty acids. Consistent with this role, the channel is inhibited by long chain acyl-CoA esters and activated by GTP, and these ligands interact with sites that face the cytosol. The work to be summarized shows that KATP channels from mitochondria and plasma membranes are regulated by the same biochemical and pharmacological ligands. We hypothesize that the mitochondrial KATP channel, like its counterparts in the plasma membrane, is heteromultimeric, consisting of a regulatory sulfonylurea receptor (mitoSUR) and an inward-rectifying K+ channel (mitoKIR). PMID- 8688445 TI - Mitochondrial metabolite transporters. PMID- 8688446 TI - The yeast ADP/ATP carrier. Mutagenesis and second-site revertants. AB - Results of mutagenesis and selection of spontaneous second-site revertants of the yeast ADP/ATP carrier AAC2 is described. Currently, 50 mutants have been made in AAC2 at 35 locations. Yeast carrying mutations at K38, K48, R96, D149, R152, R204, D249, R252, R253, R254 and R294 are all unable to grow on glycerol. Seven of these mutants have yielded second-site revertants when plated on rich yeast media containing glycerol and ethanol. The R96 mutants and the R254 and R253 mutants produce similar changes in the AAC2 molecule because the same sites are affected by their revertant mutations. This system of mutations and revertants is now poised to yield insights into the dynamics of ADP and ATP transport, and mitochondrial carrier structure in general. PMID- 8688447 TI - Respiratory chains of archaea and extremophiles. AB - Extremophilic organisms are adapted to harsh environmental conditions like high temperature, extremely acidic or alkaline pH, high salt, or a combination of those. With a few exceptions extremophilic bacteria are colonizing only moderately hot biotopes, whereas hyperthermophiles are found specifically among archaea (formerly 'archaebacteria') which can thrive at temperatures close to or even above the boiling point of water. It has been a challenging question whether the special properties of their proteins and membranes have been acquired by adaptation, or whether they might reflect early evolutionary states as suggested by their phylogenetic position at the lowest branches of the universal tree of life. PMID- 8688448 TI - Energetic problems of extremely alkaliphilic aerobes. AB - Over a decade of work on extremely alkaliphilic Bacillus species has clarified the extraordinary capacity that these bacteria have for regulating their cytoplasmic pH during growth at pH values well over 10. However, a variety of interesting energetic problems related to their Na(+)-dependent pH homeostatic mechanism are yet to be solved. They include: (1) the clarification of how cell surface layers play a role in a category of alkaliphiles for which this is the case; (2) identification of the putative, electrogenic Na+/H+ antiporter(s) that, in at least some alkaliphiles, may completely account for a cytoplasmic pH that is over 2 pH units lower than the external pH; (3) the determination of whether specific modules or accessory proteins are essential for the efficacy of such antiporters; (4) the mechanistic basis for the increase in the transmembrane electrical potential at the high external pH values at which the potential consuming antiporter(s) must be most active; and (5) an explanation for the Na(+) specificity of pH homeostasis in the extremely alkaliphilic bacilli as opposed to the almost equivalent efficacy of K+ for pH homeostasis in at least some non alkaliphilic aerobes. The current status of such studies and future strategies will be outlined for this central area of alkaliphile energetics. Also considered, will be strategies to elucidate the basis for robust H(+)-coupled oxidative phosphorylation by alkaliphiles at pH values over 10. The maintenance of a cytoplasmic pH over 2 units below the high external pH results in a low bulk electrochemical proton gradient (delta p). To bypass this low delta p, Na(+) coupling is used for solute uptake even by alkaliphiles that are mesophiles from environments that are not especially Na(+)-rich. This indicates that these bacteria indeed experience a low delta p, to which such coupling is an adaptation. Possible reasons and mechanisms for using a H(+)-coupled rather than a Na(+)-coupled ATP synthase under such circumstances will be discussed. PMID- 8688449 TI - Energy conservation by bifurcated electron-transfer in the cytochrome-bc1 complex. AB - The overall electron- and proton-pathways within the cytochrome-bc1 complex are described by a widely accepted mechanism known as the protonmotive Q-cycle. Within this reaction scheme, the unique bifurcation of electron flow into a high potential and a low potential pathway occurring at the ubihydroquinone-oxidation center is the energy conserving reaction. It is this reaction, which results in vectorial proton translocation, as it allows the 'recycling' of every second electron across the membrane onto the ubiquinone-reduction center. However, the Q cycle reaction scheme does not address the detailed chemistry of this central step. Based on a structural model of the ubihydroquinone-oxidation pocket and the assumption that the reaction involves two ubiquinone molecules in a stacked configuration, here I propose a detailed chemical model for the reactions occurring during steady-state catalysis. In this proton-gated charge-transfer mechanism the reaction is controlled by the deprotonation of the substrate ubihydroquinone and not, as proposed earlier, by the formation of a highly unstable semiquinone species. PMID- 8688450 TI - Crystallization and preliminary structure of beef heart mitochondrial cytochrome bc1 complex. AB - The method reported for isolation of ubiquinol-cytochrome-c reductase complex from submitochondrial particles was modified to yield a preparation for crystallization. The cytochrome bc1 complex was first crystallized in large thin plate form and diffracts X-rays to 7 A resolution in the presence of mother liquor. This crystalline complex was enzymatically active and contains ten protein subunits. It had 33 mol phospholipid and 0.6 mol ubiquinone per mol protein. With slightly modified crystallization conditions, different crystal forms were obtained. Crystals grown in the presence of 20% glycerol diffracted X rays up to 2.9 A resolution using a synchrotron source. Four heavy atom derivatives have been obtained. The 3-D structure of the cytochrome bc1 complex was solved to 3.4 A resolution. Crystalline cytochrome bc1 complex is a dimer: most of the masses of core proteins I and II protrudes from the matrix side of the membrane, whereas the cytochrome b protein is located mainly within the membrane. There are 13 transmembrane helices in each monomer. Most of the mass of cytochrome c1 and iron-sulfur protein including their redox centers are located on the cytoplasmic side of the membrane. The distances between these redox centers have been determined, and several electron transfer inhibitor binding sites in the complex have been located. PMID- 8688451 TI - The permeability transition pore. Control points of a cyclosporin A-sensitive mitochondrial channel involved in cell death. AB - The permeability transition pore (MTP) is a high conductance channel of the mitochondrial inner membrane inhibited by cyclosporin A. While the physiological role of the MTP has not been clarified yet, it is becoming clear that this channel plays an important role in the pathways leading to cell death. The recent demonstrations that the MTP is controlled by the membrane potential, that a variety of physiological and pathological effectors can modulate the threshold voltage at which pore opening occurs, and that surface potential may contribute to pore modulation provide a useful framework to describe the mechanistic aspects of pore function in isolated mitochondria. Here we (i) briefly review the key features of pore regulation, and report our recent progress on the role of oxidants and mitochondrial cyclophilin; and (ii) elaborate on how MTP regulation by cellular pathophysiological effectors (such as cytosolic [Ca2+] transients, oxidative stress, and changes in the concentration of polyamines, nitric oxide, and metabolites of both the sphingomyelin and phospholipase A2 pathways) might take place in vivo. Further definition of the MTP checkpoints should help in the design of specific modulators, and offers great promise for the development of new conceptual and pharmacological tools aimed at therapeutic intervention in pathological conditions where pore opening is a critical event. PMID- 8688452 TI - Functional implications of the structure of the 'Rieske' iron-sulfur protein of bovine heart mitochondrial cytochrome bc1 complex. AB - Recently, we have determined the structure of the catalytic domain of the 'Rieske' iron-sulfur protein of bovine heart mitochondrial bc1 complex at 1.5 A resolution (Iwata, S., Saynovits, M., Link, T.A. and Michel, H. (1996) Structure, 4, 567-579). This is the first structure of a bis-histidine coordinated [2Fe-2S] cluster. The spectroscopic, electrochemical, and functional implications of the structure will be discussed. PMID- 8688453 TI - A compilation of mutations located in the cytochrome b subunit of the bacterial and mitochondrial bc1 complex. AB - In anticipation of the structure of the bc1 complex which is now imminent, we present here a preliminary compilation of all available cytochrome b mutants that have been isolated or constructed to date both in prokaryotic and eukaryotic species. We have briefly summarized their salient properties with respect to the structure and function of cytochrome b and to the Qo and Qi sites of the bc1 complex. In conjunction with the high resolution structure of the bc1 complex, this database is expected to serve as a useful reference point for the available data and help to focus and stimulate future experimental work in this field. PMID- 8688454 TI - ATP hydrolysis by membrane-bound Escherichia coli F0F1 causes rotation of the gamma subunit relative to the beta subunits. AB - We recently demonstrated that the gamma subunit in soluble F1-ATPase from Escherichia coli rotates relative to surrounding beta subunits during catalytic turnover (Duncan et al. (1995) Proc. Natl. Acad. Sci. USA 92, 10964-10968). Here, we extend our studies to the more physiologically relevant membrane-bound F0F1 complex. It is shown that beta D380C-F1, containing a beta-gamma intersubunit disulfide bond, can bind to F1-depleted membranes and can restore coupled membrane activities upon reduction of the disulfide. Using a dissociation/reconstitution approach with crosslinked beta D380C-F1, beta subunits containing an N-terminal Flag epitope (beta flag) were incorporated into the two non-crosslinked beta positions and the hybrid F1 was reconstituted with membrane-bound F0. Following reduction and ATP hydrolysis, reoxidation resulted in a significant amount of crosslinking of beta flag to the gamma subunit. This demonstrates that gamma rotates within F1 during catalytic turnover by membrane bound F0-F1. Furthermore, the rotation of gamma is functionally coupled to F0, since preincubation with DCCD to modify F0 blocked rotation. PMID- 8688455 TI - Sequence and neuronal expression of mouse endothelin-1 cDNA. AB - We have isolated and sequenced a cDNA that encodes mouse endothelin-1 (ET-1). The putative protein contains 202 amino acids corresponds to the prepro-form of ET-1. Twenty-one amino acids sequence of the putative mature ET-1 was identical with that of rat, porcine, bovine, and human. In situ hybridization histochemistry indicate that ET-1 mRNA was expressed in several hypothalamic nuclei including the suprachiasmatic nucleus (SCN) in rodent brain. PMID- 8688456 TI - RNA editing in the cox3 mRNA of Magnolia is more extensive than in other dicot or monocot plants. AB - The Magnoliaceae are discussed as one of the key species at the root of the flowering plants. To obtain molecular information for one of these phylogenetically interesting plant species, we determined genomic and cDNA sequences of the mitochondrial cox3 gene in Magnolia grandiflora. Twenty-two RNA editing events are identified to alter cytidines in the mRNA to uridines, all but one of which change the encoded amino acid identity. RNA editing in the cox3 coding region is thus more frequent in Magnolia than in other dicot or monocot plants investigated and almost as predominant as in some gymnosperms. The cox3 RNA editing frequency in Magnolia thus occupies an intermediate position between angiosperms and gymnosperms consistent with the phylogenetic position of the Magnoliales. PMID- 8688457 TI - A duplicated sequence in sugarbeet mitochondrial transcripts is differentially edited: analysis of orfB and its derivative orf324 mRNAs. AB - RNA editing of the duplicated sequences was investigated in the transcripts of orfB and orf324 genes from sugarbeet mitochondria. The orf324 shares the first 59 bp of the reading frame and 321 bp upstream sequence with orfB. Two cytidine-to uridine editing sites were found in orfB, but the corresponding cytidine residues remained unchanged in the transcripts of orf324. In the vicinity of the non edited cytidine residues within the shared sequence element of orf324 were identified three point mutations that may abolish orf324 editing. Our results also suggest that selection of editing sites depends on primary sequence. PMID- 8688458 TI - Cloning and sequencing of cDNAs encoding the human sperm protein, Sp17. AB - In the present study we have cloned and sequenced two testis-specific cDNAs (1.3 kb and 1.6 kb) encoding a human sperm protein, designated HSp17. Each cDNA gave rise to identical protein sequences and differed only in the 5' untranslated region. The predicted amino-acid sequence revealed a protein of 17.5 kDa which exhibited a high degree of homology with both rabbit and mouse Sp17. Analysis of native and recombinant Sp17 by SDS-PAGE has shown the apparent molecular weight of the protein to be 24.5 kDa. PMID- 8688459 TI - Cloning and sequence analysis of the murine Gli3 cDNA. AB - The zinc finger gene Gli3 plays a role in limb and brain development. To facilitate the molecular analysis of different mouse mutations of this gene, the murine cDNA was isolated and sequenced. This 5113 bp cDNA encodes a putative protein of 1596 amino acids. Comparison of the murine and human GLI3 cDNA revealed an overall homology of 85% between the deduced amino acid sequences. More importantly, several regions of the protein, including the zinc fingers, are more highly conserved ( > 95%), suggesting that these represent functional domains in the Gli3 protein. PMID- 8688461 TI - Isolation and sequence of the Drosophila virilis 60 A gene, a transforming growth factor-beta superfamily member related to vertebrate bone morphogenetic proteins. AB - The complete protein-coding region of the Drosophila virilis 60 A gene, a member of the transforming growth factor-beta superfamily, was isolated and sequenced. The mature domain of the protein-coding region is 99% identical to the Drosophila melanogaster 60 A gene and 73% identical to human bone morphogenetic protein 5. In the pro-domain, a number of large blocks of amino acids are also highly conserved, indicating an important functional role for this portion of the protein as well. In the putative 5' and 3' untranslated regions, several short sequence motifs are conserved between D. virilis and D. melanogaster. PMID- 8688460 TI - Characterization of two genes, p11 and p5, on the Borrelia burgdorferi 49-kilo base linear plasmid. AB - A putative operon encoding two Borrelia burgdorferi N40 genes, p11 and p5 was cloned and localized to the 49 kilobase linear plasmid. p11 encodes an 11 kDa protein and p5 encodes a 5 kDa protein. The first 88 nucleotides of p11 have 81% identity with orf5 on a circular plasmid from Borrelia afzelii strain Ip21, suggesting that homologues of these genes may be present in different regions of the B. burgdorferi genome. PMID- 8688462 TI - Cloning and identification of exon-intron organization of the rat ATP-citrate lyase gene. AB - The rat ATP-citrate lyase gene was cloned and the complete exon-intron organization of the gene has been identified. The ATP-citrate lyase gene, spanning about 55 kb, is divided into 29 exons that range in size from 30 to 986 base pairs. The sequences bordering the splice site junctions universally follow the GT/AG rule. Reverse transcription-polymerase chain reaction showed two forms of ACL mRNA; the one containing complete exons and the other lacking exon 14 were found in the brain, kidney, mammary gland, lung and liver. Also, the restriction fragment length polymorphisms were observed at intron 10 and intron 11 regions. PMID- 8688464 TI - Sequence and expression pattern of an evolutionarily conserved transcript identified by gene trapping. AB - We have isolated and analysed embryonic stem (ES) cell clones after electroporation with a gene trap vector. Clones were screened for changes in their lacZ reporter gene activity upon in vitro differentiation. The cDNA of one of the trapped transcripts, T10-2A2, was isolated and analysed in detail. Although not expressed constitutively in differentiating ES cells, the transcript was present in most organs of adult mice and widely expressed in midgestation mouse embryos. Zoo blot analysis indicated a conservation of this novel gene in yeast, rat and human. PMID- 8688463 TI - Identification and characterization of two promoters of rat kallikrein-binding protein gene. AB - Rat kallikrein-binding protein (RKBP) is a serine proteinase inhibitor (serpin) which binds to and inhibits tissue kallikrein activity [1,2]. In this study, we have sequenced and identified two promoter regions of the RKBP gene (RKBP). One promoter is located in the 5' flanking region (P1) of the gene and the other is located in the first intron (P2). Both promoters contain a consensus TATA and CAAT box. These RKBP promoters were fused with a chloramphenicol acetyltransferase (CAT) reporter gene and their promoter activities were determined by measuring CAT levels using a specific ELISA. The P1 promoter exhibited high promoter activities in Hep3B hepatoma cells but not in La fibroblastoma cells, indicating its tissue-specificity. By deletion analysis, we have identified a negative regulatory element of the P1 promoter between -739 and -472, and defined a minimal sequence between -183 and -2 for maintaining the intact promoter activity. The P2 promoter showed a strong activity only when linked to an SV40 enhancer. Activity of the P1 promoter can be induced by growth hormone in Hep3B cells. Gel retardation assay has identified 5 DNA fragments which were bound by nuclear proteins from rat liver. Two DNA fragments are in the 5' flanking region, one contains a putative glucocorticoid and growth hormone response element and the other one contains a CAAT box and two putative AP-1 binding sites. The remaining three are in the first intron and contain a putative thyroid hormone response element, a putative GATA site and three consensus CAAT boxes, respectively. Nuclear proteins from the kidney showed that spontaneously hypertensive rats (SHR) have a distinct trans-acting factor which binds with the DNA fragment containing the glucocorticoid and growth hormone response elements, as compared with normotensive rats. This result indicates that different trans acting factors in the kidney of SHR may contribute to the decreased RKBP expression in these hypertensive rats. PMID- 8688465 TI - Universality of mitochondrial RNA editing in cytochrome-c oxidase subunit I (coxI) among the land plants. AB - Plant mitochondrial pre-mRNAs often undergo C-to-U conversions, a phenomenon termed RNA editing. The molecular source of specificity and phylogenetic depth of the editing machinery remain to be determined. We amplified coxI gene fragments via the polymerase chain reaction from a diversity of taxa within the land plants, and sequenced each. Alignment and comparison of 25 homologous coxI gene sequences with those from plant species having known RNA editing sites which restore amino acid sequence consensus was used to infer sites of C-to-U conversions. Our results, derived using the comparative approach, imply that the plant mitochondrial editing machinery extends throughout vascular plant phylogeny, and also that this phenomenon is present in every major branch of the (non-vascular) Bryophyta: liverworts (Hepaticae), hornworts (Anthocerotae), and mosses (Musci). These results have important consequences for our thoughts on the evolutionary history of the plant RNA editing process, as they imply that editing is older than was previously believed. PMID- 8688466 TI - Cloning and characterization of cDNAs encoding the epsilon-subunit of eukaryotic initiation factor-2B from rabbit and human. AB - A rabbit reticulocyte lysate cDNA library was screened with a polyclonal antiserum directed against eukaryotic initiation factor eIF-2B (eIF-2B). A 2508 base pair cDNA (pA1) was isolated and determined to encode the epsilon-subunit of eIF-2B based on the immunoreactivity of the fusion protein expressed from the cDNA in Escherichia coli and the presence of two peptide sequences obtained from two V8 fragments of purified nonrecombinant eIF-2B epsilon in the deduced amino acid sequence of the cDNA. The open reading frame of the cDNA began with the third nucleotide of the cDNA with the first AUG codon at nucleotide 522. Mutational analysis of pA1 indicated that the cDNA did not code for full-length eIF-2B epsilon. Seven missing codons of the reading-frame and the 71 nucleotide 5' non-coding region of the eIF-2B epsilon mRNA were obtained by 5' RACE. A human eIF-2B epsilon cDNA fragment, which corresponded to a similar 2.3 kb fragment generated by digestion of the rabbit pA1 cDNA with EcoRI, was isolated from a human histiocytic lymphoma (U-937) cell cDNA library constructed in lambda gt10. The nucleotide and amino acid sequences were highly conserved between the rabbit and human cDNAs, showing approx. 90% sequence identity within the open reading frame. Northern and Western blot analyses of reticulocyte lysate and other rabbit tissue extracts indicated that the eIF-2B epsilon polypeptide has a similar apparent molecular weight in all tissues examined, and is coded for by a single approximately 2.8 kilobase mRNA species which is ubiquitously expressed. PMID- 8688467 TI - Cloning and characterization of complementary and genomic DNAs encoding the epsilon-subunit of rat translation initiation factor-2B. AB - Eukaryotic initiation factor-2B (eIF-2B) is a guanine nucleotide-exchange protein involved in the recycling of eIF-2 during peptide-chain initiation. Regulation of eIF-2B activity occurs under a wide range of conditions by diverse mechanisms. To better understand the regulation of eIF-2B activity as well as the coordinate expression of its five subunits, we have begun to clone and characterize the cDNAs and genes encoding these proteins. In the present study, complementary and genomic DNAs encoding the epsilon-subunit of rat eIF-2B were cloned and characterized. The cDNA is 2517 bp in length, including a 30 nt poly(A) tail, and recognizes both 2.7 and 3.5 kb mRNA species on Northern blots of rat RNA. The cDNA contains a 2151 bp open reading frame encoding 716 amino acids producing a protein with a predicted molecular mass of 80 kDa. The derived amino acid sequence contains regions identical to three peptides obtained from bovine liver eIF-2B epsilon and is 31% identical to Gcd6, the putative yeast eIF-2B epsilon. Examination of the derived amino acid sequence of rat eIF-2B epsilon reveals phosphorylation site motifs for several protein kinases which have been implicated in regulation of guanine nucleotide exchange activity. The mRNA for eIF-2B epsilon is expressed to a similar extent in most rat tissues examined with the exception of testis, where its expression is approx, three-fold greater. We have also isolated and sequenced the coding and 5'-flanking region of the rat eIF 2B epsilon gene. The 16 exons encoding rat eIF-2B epsilon are contained within 9.5 kb of genomic DNA. Examination of the promoter region of the gene reveals a consensus binding site for the alpha-Pal transcription factor as well as possible cytokine-response elements and binding sites for testis-specific transcription factors. PMID- 8688468 TI - Studies on electrotransfer of DNA into Escherichia coli: effect of molecular form of DNA. AB - Effects of several molecular forms of DNA were examined on voltage-pulse-mediated transfection or transformation. Among circular DNAs, the single-stranded microvirid DNA was less infective than the double-stranded replicative form, whereas transfectivity of the relaxed or nicked molecule was nearly equal to or slightly lower than that of the supercoiled DNA. The linearized double-stranded DNA derived from phage or plasmid electrotransfects Escherichia coli, albeit at a reduced efficiency. Alkaline denaturation of the linearized DNA resulted in complete loss of the infectivity. Relationship between terminal structure of the linearized DNA and efficiency of the transfection was investigated. Host recombination function did not significantly affect the infectivity of the linearized DNA. PMID- 8688469 TI - Structural relationships among members of the mammalian sulfotransferase gene family. AB - Sulfotransferases constitute a superfamily of related enzymes that play critical roles in the regulation of steroid hormone action, neurotransmitter function, detoxification, and carcinogenesis. Understanding the functional relationships among these enzymes has so far been difficult due to their overlapping substrate specificities. To help clarify these relationships, we conducted a thorough and comprehensive molecular phylogenetic analysis of 25 different mammalian sulfotransferase cDNA and gene (St) sequences using maximum parsimony and distance matrix methods. This analysis suggested five distinct gene families: an alcohol/androgen/hydroxysteroid/dehydroepiandrosterone (Std) family, an aryl/minoxidil/phenol (Stp) family, an estrone/estrogen (Ste) family, a thyroid hormone family (St1b1), and a family (St1c1) defined so far only on the basis of its specificity for the carcinogen N-hydroxy-2-acetylaminofluorene. New insights obtained through this study include (1) a bootstrap analysis supporting the reliability of family subgroupings, (2) identification of an insertion that appears to be characteristic of the St1b1 and Stlc1 families, (3) identification of sequences likely to represent paralogs of multigene families, and (4) identification of species likely to contain, or not contain, orthologous multigene families and thus their specialized functions. PMID- 8688470 TI - Structure and functional expression of a complementary DNA for porcine parathyroid hormone/parathyroid hormone-related peptide receptor. AB - A complementary DNA (cDNA) encoding the receptor for porcine parathyroid hormone/parathyroid hormone-related peptide (PTH/PTHrP) was isolated from a porcine kidney cDNA library. The porcine PTH/PTHrP receptor is a 585 amino acid protein containing seven putative membrane-spanning domains. The porcine PTH/PTHrP receptor has amino acid identity of 95.6%, 80.4%, and 88.7% with human, opossum, and rat PTH/PTHrP receptors, respectively and 53.4% identity to the recently cloned human PTH2 receptor. The receptor cDNA was subsequently cloned into a mammalian cell expression vector (pRC/CMV) which contains a human cytomegalovirus promoter. A human kidney cell line (293), stably transfected with this vector, expressed the receptor at a high level and, when challenged with human PTH(1-34), increased cytoplasmic cAMP and inositol triphosphate production. Radioligand binding studies revealed that the receptor bound both human PTH(1 34), and PTHrP(1-36). Scatchard analyses of three clones showed that the cells harbor a single class of high affinity receptor (Kd = 1-4 nM for human PTH(1-34)) but had varying receptor numbers (10(5)-10(6) receptors/cell). In contrast to PTH(1-34), the [Arg2]PTH(1-34) analog bound to the porcine PTH/PTHrP receptor with low affinity and was a weak agonist for cAMP stimulation with the cloned receptor. These response characteristics differentiate the porcine receptor from the previously cloned rat and opossum PTH/PTHrP receptors. PMID- 8688471 TI - [Pulmonary manifestations in Sjogren's syndrome]. PMID- 8688472 TI - [Effects of Sjogren's syndrome on pulmonary function impairment in patients with rheumatoid arthritis]. AB - The influence of Sjogren syndrome (SS) on pulmonary function impairment in rheumatoid arthritis (RA) patients has been few studied. The aim of this study was to analyse the pulmonary function impairment in RA patients, and to establish differences between patients associated or not to SS. Pulmonary function of 57 patients, non smokers and without another pulmonary disease, diagnosed of RA were studied. Fourteen (24.6%) were associated to SS, and 43 (75.4%) to RA without SS. Age and time of evolution of disease were similar. Eight patients with associated SS (57.2%), and in 20 (46.5%) without SS showed pulmonary function disorder. Airflow obstruction and DLCO diminution were the most common types of impairment, respectively. The comparison between the types of impairment and the mean values of FEVI, FVC, FEVI/FVC %, FEF 25-75 and DLCO were not statistical different. This results suggest a poor influence on pulmonary function impairment in RA patients with SS. PMID- 8688473 TI - [Epidemic Kaposi's sarcoma. Apropos of 14 cases]. AB - The epidemic Kaposi's sarcoma is the most common AIDS associated cancer. The lesions are located in any part of the organism. The skin affection is the most frequent. The risk group with a highest incidence is the "male homosexuals". Though the diagnosis of Kaposi's sarcoma doesn't determine "per se" the prognosis "quad vitam", there exist some analytic parameters at the time of the diagnosis that are useful for the prognosis of the HIV infection. We present 14 Kaposi's sarcoma and HIV infected cases analyzing some parameters and evaluating their prognosis and surviving hope. PMID- 8688474 TI - [Disparity between cytohistopathological results of diagnostic specimens and the resected tumor piece in bronchopulmonary carcinoma]. AB - In 88 patients diagnosed and intervened of lung carcinoma, we evaluate the security of the Diagnostic method--cytology: sputum, brushed bronchial, bronchial aspiration, puncture pulmonary aspiration and histology of the bronchial biopsy- when we correlate them with the histology of the dried up tumour. From the 88 patient, in 11 (12.5%) there was a disparity between some specimen and the piece tumour. If we analyze the specimen: the bronchial biopsy, was different in 3 cases, (4.8%); the brushed and the bronchial biopsy, aspiration in 2, (2.7% and 2.3% respectively); the puncture pulmonary aspiration in 6, (26%) and the cytology of sputum in 2 cases, (2.4%). In 8 patients (9%), the outputs of some specimen were not conclusive, if we remove these we find that: the bronchial biopsy was not conclusive in 2 cases, (3.2%), the brushed bronchial in 5, (6.8%); the bronchial aspiration in 9 (10.2%) and the cytology of sputum in 2 cases, (2.4%). With this data we could infer that sometimes the positive outputs of the specimen have no correlation with the histology of the tumour dried up. This disparity has not been observed in the oat-cells. Therefore when we send the specimens to the pathologist, it would always be advisable for him to inform us if there are any different cells belonging to the principal group of the tumor. PMID- 8688475 TI - [Risk factors associated with etiopathogenesis of non-melanoma skin cancer in Valencia]. AB - A series of personal, occupational and sociocultural characteristics have been described in patients with non-melanoma skin cancer (NMSC). A case-control retrospective study was undertaken to determine these characteristics in patients with NMSC treated in the La Fe University Hospital (Valencia, Spain) between October 1992 and June 1993. NMSC is seen in elderly individuals, the risk being greater among males than in females. A light complexion clearly increased risk, as did a tendency to sunburn easily. Open-air occupational activities were in turn related to an increased risk of developing NMSC. A significant rise in risk was also observed as age-adjusted occupational exposure to sunlight increased. PMID- 8688476 TI - [Cardiac osteogenic sarcoma with chondroblastic differentiation]. AB - Cardiac tumors are a rare disease. We show here one patient with a heart osteogenic sarcoma with chondroblastic differentiation. The clinical status was initiated with a cadre of cardiac tamponade. Transesophageal echocardiography and thoracic scanner were used to diagnose the cardiac tumor. The definitive diagnosis was confirmed with biopsy. At the present moment, there are very few cases reported in the references on osteogenic sarcoma with chondroblastic differentiation. The methods of diagnosis, the treatment and the histopathology are discussed. PMID- 8688477 TI - [Relapsing polychondritis with atypical presentation]. AB - Relapsing polychondritis is an episodic systemic disorder, characterized by recurrent inflammation that affects cartilaginous structures, the cardiovascular system, eyes and ears. Although the etiology is unknown, experimental evidence strongly suggest that immunologically mediated mechanisms are implicated. Auricular, articular and nasal manifestations are the most frequent disturbances. In about 30% of cases, relapsing polychondritis is associated with other connective tissue diseases and vasculitis. Actually, the diagnosis is based on the criteria proposed by McAdam, and modified by Damiani. We present a case, whose first manifestations of relapsing polychondritis were an intermittent fever and transient arthralgias. Eight months later, auricular chondritis appeared, and gave us the key to diagnosis. PMID- 8688478 TI - [Bacteremia caused by Capnocytophaga sp: presentation of 2 cases, one with endocarditis. Review of the literature]. AB - Capnocytophaga sp. is a gram-negative bacilli, scarcely documented as the cause of bacteremias. Two cases of bacteremia caused by Capnocytophaga sp, one of them with endocarditis, are reported here. A review of previous published cases is also presented. One of the patients was immunocompromised, because of chemotherapy, the other, suffered from a rheumatic-cardiopathy which was complicated with endocarditis. Both patients developed an alteration of the oral mucosa. Antibiotic therapy proved to be effective with two patients. PMID- 8688479 TI - [Chronic eosinophilic pneumonia and difficult to control asthma]. AB - We report a case of typical chronic eosinophilic pneumonia (CEP), in a female of 27 years-old suffering bronchial asthma light. Although the initial answer to the treatment with steroids was satisfactory, the patient develop difficult to control asthma (DCA). DCA is a clinical situation which requires careful investigation of several potential factors which can be solved. We suggest a protocol of treatment for patients affected with DCA. PMID- 8688480 TI - [Thyroglossal duct cyst with anomalous localization]. AB - The cyst of thyroglossal duct (CTD) are the more frequent congenital mass of the neck, so you must consider them in the differential diagnosis of the neck's tumours. We present one case of CTD with certain clinical peculiarities. PMID- 8688481 TI - [Considerations on the treatment of incipient diabetic nephropathy (lst of 2 parts)]. AB - Diabetic nephropathy is the third cause of renal failure after pyelonephritis and glomerulonephritis. Lately, many efforts have been made for the early identification (on the silent stage) of patients with a high risk of developing this disease. On these initial stages, therapeutic attitude has changed very much, emphasizing nowadays the importance of glucose levels control, avoiding maintained conditions of hyperglycemia and maintaining blood pressure within the limits, by using the therapeutic store available, basically calcium antagonists and angiotensin-converting enzyme inhibitors. PMID- 8688482 TI - [Cocaine-induced neurological complications]. AB - Cocaine intake growth is a well-known fact, and that involves the appearance of unknown or forgotten complications. We have wanted to make a checking of neurologic complications due to the intake of this drug, make a special point of the physiopathological mechanisms and stopping at those related to treatment. We also want to contribute with our experience with regard to these processes. PMID- 8688483 TI - [Danazol and cholestatic hepatitis]. PMID- 8688484 TI - [Brucella spondylitis with epidural abscess healed by drug treatment. Apropos of a case diagnosed by nuclear magnetic resonance (NMR)]. PMID- 8688485 TI - [Primary splenic non-Hodgkin's lymphoma]. PMID- 8688486 TI - [Pulmonary nocardiosis in an immunocompromised patient: the significance of the epidemiologic factor]. PMID- 8688487 TI - [Chronic meningococcemia: a rare cause of migratory arthritis]. PMID- 8688488 TI - [Arterial hypertension secondary to Conn's syndrome]. PMID- 8688489 TI - The transcription factor AP-1 binds to the human interleukin 1 alpha promoter. AB - Despite numerous reports on IL-1 and the obvious importance of IL-1 in the cytokine network, very little is known regarding the molecular details of IL-1 regulation. While information is now emerging for IL-1 beta, mechanisms in IL-1 alpha gene regulation remain largely unknown. Examination of the 5'-flanking region of the human interleukin-1 alpha promoter (IL-1 alpha) and its first intron revealed several potential binding sites for known transcription factors. We thus studied this region by using an electrophoretic mobility shift assay (EMSA). EMSA studies showed that the region -12 to -6 of the human IL-1 alpha promoter contains an LPS-inducible AP-1-binding site composed of Jun and Fos proteins. On the other hand, no NF-kappa B binding within the IL-1 alpha promoter and its first intron was shown. PMID- 8688490 TI - Maintenance and expansion of erythropoiesis in human long-term bone marrow cultures in presence of erythropoietin plus stem cell factor and interleukin-3 or interleukin-11. AB - Recently there has been great interest in the ex vivo expansion and/or purging of human bone marrow cells prior to transplantation in order to obtain a long lasting restoration of normal hematopoiesis and freedom from relapse. Long-term human bone marrow cultures (LTHBMC) represent the best available approximation of in vivo hematopoiesis. In the traditional LTHBMC, erythropoiesis is short lived (about 2 weeks). The longevity and productivity of erythropoiesis in LTHBMC may be limited by the insufficient production of certain cytokines such as Erythropoietin (Epo), SCF, IL-3 and/or IL-11 by the stromal and hematopoietic cells ex vivo and/or suboptimal addition of these cytokines. Therefore, we have investigated the optimal presence of erythropoietin plus SCF, IL-3, and/or IL-11 as requirements for the maintenance and expansion of erythropoiesis in LTHBMC in an effort to overcome the defective erythropoiesis of the traditional LTHBMC. In LTHBMC containing Epo alone and its combinations with SCF, IL-3, and/or IL-11, the nonadherent cells consisted mainly of erythroblast and normoblast cells which became the majority in the third and fourth weeks whereas granulocytes and macrophages declined steadily from the second week. A significant increase in the number of erythroblast and normoblast cells was produced throughout the whole period of LTHBMC containing Epo + IL-11 or Epo + SCF + IL-11 or Epo + SCF + IL-3 + IL-11. In the presence of Epo alone, BFU-E decreased steadily throughout LTHBMC. However, the erythroid clonogenic cells were successfully maintained in cultures containing Epo + SCF IL-3 or Epo + SCF + IL-11 or Epo + SCF + IL-3 + IL 11 for the 4 weeks and even significantly expanded by 4.5-5.7, 8.1-10 and 5-7 fold more than in the presence of Epo alone in the second, third and fourth weeks, respectively, p < 0.01. Our optimum cultures, including Epo + SCF + IL-3 or Epo + SCF + IL-11, maintained the production of nonadherent erythroid clonogenic cells for 4 weeks in culture, representing a significant improvement over the traditional LTHBMC that exhibits a progressive decline in erythropoiesis during the first 2 weeks. We conclude that Epo alone could not maintain erythroid clonogenic cell production and the supplementation with either of the two combinations: Epo + SCF + IL-3 or Epo + SCF + IL-11 is sufficient for maintaining erythropoiesis in LTHBMC. The present LTHBMC system should have applications to the analysis and manipulation of human erythropoiesis. PMID- 8688492 TI - 6th International TNF Congress. Rhodes, Hellas, Greece, 8-12 May 1996. Abstracts. PMID- 8688491 TI - Transforming growth factor beta 1 alters rat peritoneal macrophage mediator production and improves survival during endotoxic shock. AB - Transforming Growth Factor beta 1 (TGF-beta 1) is a potent anti-inflammatory cytokine involved in wound healing. Because of its anti-inflammatory actions, the effects of TGF-beta 1 were studied in vitro on rat macrophage inflammatory mediator production and in vivo on Salmonella enteritidis endotoxin (LPS) induced lethality. TGF-beta 1's effect on stimulated rat peritoneal macrophage (MO) production of prostacyclin and nitric oxide were assessed via measurement of their stable metabolites, 6-keto-PGF-1 alpha and nitrite, respectively. TGF-beta 1 (10 ng/ml) pretreatment (3 hours) resulted in significant reductions (p < 0.05) of LPS (50 micrograms/ml) stimulated, lipid A (1 and 10 micrograms/ml) stimulated, arachidonic acid (16 microM) stimulated, and Ca++ ionophore (10 microM) stimulated MO 6-keto-PGF 1 alpha production. These data suggest that TGF beta 1 inhibits LPS stimulated MO 6-keto-PGF-1 alpha production by acting at, or distally to, phospholipase A2, possibly at the level of cyclooxygenase in the arachidonic acid cascade. In a similar study, TGF-beta 1 pretreatment led to a significant (p < 0.05) reduction of LPS stimulated MO nitrite production. In subsequent studies, the effects of TGF-beta 1 were studied in vivo on rats challenged with lethal doses of LPS. Rats pretreated with TGF-beta 1 (250 ng/rat i.v.) exhibited a significant increase (p < 0.01, n = 15 rats/group) in mean survival time compared to control rats. The increased survival time of TGF-beta 1 pretreated rats with LPS shock may be due, in part, to altered production of MO mediators. PMID- 8688493 TI - Tumor necrosis factors: developments during the last decade. PMID- 8688494 TI - Induction of Goodpasture antibodies to noncollagenous domain (NC1) of type IV collagen in mice by idiotypic manipulation. AB - The characteristic pathogenic autoantibodies in Goodpasture's syndrome (GPS) are directed to the noncollagenous domain (NC1) of basement membrane type IV collagen. To examine whether immunization with anti-NC1 antibodies could lead to GPS-like pathology, naive BALB/c mice were immunized intradermally with a mouse IgG anti-NC1 monoclonal antibody or IgG serum fraction derived from patients with GPS. Mice immunized with normal mouse or human IgG and nonimmunized mice served as controls. Anti-NC1 antibodies of IgG isotype were detected in the sera of mice injected with anti-NC1 antibodies, but not in the sera of control mice. The presence of circulating anti-NC1 antibodies coincided in some of the mice erythrocyturia or proteinuria and pathological changes in the kidneys. No pathologic alterations were seen in the control mice. The results show that specific idiotypic manipulation can induce anti-NC1 antibodies and pathological changes resembling human GPS. PMID- 8688495 TI - A genetically engineered fusion protein M4/TNF with increased bifunctional activity refolded in the presence of protein disulfide isomerase. AB - Recombinant DNA techniques were used to clone, to construct and to express a fusion protein M4/TNF in Escherichia coli. The fusion protein includes the chimeric F(ab')2 fragment (M4) recognizing the human tumor-associated TAG72 antigen and the tumor necrosis factor alpha (TNF) moiety. The M4/TNF purified from inclusion bodies of the bacteria homogenates was further solubilized in a denaturing buffer containing 6 mol l-1 guanidine and refolded in a refolding buffer. Our results showed that the M4/TNF refolded in a buffer containing 6 mmol l-1 oxidized glutathione (GSSG), 0.2 mmol l-1 dithioerythione (DTE) and 0.5 mumol l-1 protein disulfide isomerase (PDI) displayed a 4-fold higher anti-TAG72 immunoreactivity and a 5-fold higher TNF activity than that refolded in the same refolding buffer but without PDI. Our data thus indicates that the protein disulfide isomerase not only facilitates the correct formation of disulfide-bonds of the antibody molecule, but also the correct refolding of the TNF moiety in vitro. PMID- 8688496 TI - Immunocytochemical detection of lung cancer cells with monoclonal antibodies to 14-3-3 proteins. AB - Murine monoclonal antibodies were raised against 14-3-3 proteins, the antigen of human monoclonal antibody AE6F4 which had been shown potentially useful for the immunochemical diagnosis of lung cancer via sputum cytology. Enzyme-linked immunosorbent assays of the murine anti-14-3-3 monoclonal antibodies with isolated bovine brain 14-3-3 isoforms showed that the antibodies were classified into four different profiles of isoform reactivity. The comparison of 14-3-3 isoform and lung cancer tissue on the reactivity with murine monoclonal antibodies indicated that beta isoform can be responsible for cancer recognition, whereas human monoclonal antibody AE6F4 showed preferential binding to zeta isoform. No murine monoclonal antibody of the same isoform specificity as human monoclonal antibody AE6F4 was obtained. Since murine monoclonal antibodies with different isoform specificities could immunostain lung cancer cells in sputum successfully, the combination use of murine monoclonal anti-14-3-3 antibodies with human monoclonal antibody AE6F4 is potentially useful for facilitating the sputum cytodiagnosis of lung cancer. PMID- 8688497 TI - A human monoclonal antibody to carbohydrate moiety of carcinoembryonic antigen. AB - Hybridoma BSRF-S-97, secreting a human monoclonal antibody of IgG1 subclass reactive to the carcinoembryonic antigen, was generated by fusing the regional lymph node lymphocytes from a cervical cancer patient with RF-S1 human-mouse heteromyeloma fusion line. This monoclonal antibody was found specifically reactive to carinoembryonic antigen-producing cell lines, including those of cervical cancer (SKG-II), mucinous type ovarian cancer (RMUG-L), stomach cancer (MKN-45), and lung cancer (PC-10). The monoclonal antibody reactivity with pepsin and periodate-treated carcinoembryonic antigen demonstrated that this monoclonal antibody recognizes the carbohydrate moiety of carcinoembryonic antigen specifically. Possibilities of the monoclonal antibody reaction with mucin and blood-group antigens were excluded by the comparative studies with a placental mucin-containing protein which reacted with carcinoembryonic antigen-specific rabbit polyclonal antibody. The monoclonal antibody conjugated with Pseudomonas exotoxin showed potent regression effects on the growth of the MKN-45 cell line in both the dish culture and xenografted nude mice, indicating potential usefulness of this human monoclonal antibody as a promising tumor targeting vehicle. PMID- 8688498 TI - Macrophage subpopulations in the thymic hyperplasia of patients with myasthenia gravis. AB - Macrophages were studied in sections of the thymus from patients with Myasthenia Gravis, using a panel of monoclonal antibodies against the monocyte/macrophage lineage. In normal areas, CD14 and CD35 were preferentially expressed in the medulla while RM3/1 and 25F9 markers stained essentially cortical macrophages. CD11c-labelled cells were densely located throughout the thymus. The antibody 27E10 recognized clusters of cells located around or in the perivascular areas, that could be migrating monocytes. In the germinal centers, cells were stained with CD14, CD35, CD11c and 25F9 but not with RM3/1 and 27E10 markers. The numbers of CD14- and CD35-positive cells were significantly increased in Myasthenia Gravis thymic hyperplasia compared to control thymus (p < 0.025 and p < 0.01, respectively). This increase was clearly due to the higher number of positive cells in the germinal centers and in the areas surrounding the lymphoid follicles. The potential role of these cells in accessory cell function and antigen presentation could be relevant in terms of intrathymic sensitization and autoantibody production that have been demonstrated in thymic hyperplasia from Myasthenia Gravis patients. PMID- 8688499 TI - A genetically engineered single-gene-encoded anti-TAG72 chimeric antibody secreted from myeloma cells. AB - SP2/0Ag14 murine myeloma cells transfected with the expression vector mpSV2neo-EP FV-CH2-3-PA containing the single gene FV-CH2-3 secreted a single-gene-encoded chimeric antibody molecule FV/M4. This single-chain protein consisted of the heavy- and light-chain variable (VH and VL) domains covalently joined through a flexible linker peptide, while the carboxyl end of VL domain was connected to the amino terminus of hinge region of the ccM4 heavy-chain. Our data showed that the FV/M4 retained both its immunoreactivity for tumor-associated TAG72 antigen and its cytolytic activity to tumor cells as did the parental ccM4 antibody. Therefore, this single-gene-construct approach circumvents inefficiencies inherent in delivering two genes into a mammalian cell for assembly of a functional chimeric antibody and provides an alternative for construction of chimeric antibodies. It is particularly attractive for ex vivo transfection of cells from patients for certain gene-therapy modalities not only for cancer but also for a range of diseases in which immunotherapeutic approaches are used. PMID- 8688500 TI - [Triphasic spiral CT in the diagnosis of liver diseases: comparison with CT arteriography and CT arterio-portography]. AB - PURPOSE: Assessment of the diagnostic efficacy of triphasic spiral-CT scanning (TPS-CT) for liver disease evaluation. CT arteriography (CTA) and CT arterio portography (CTAP) were used as reference, methods which together have the highest sensitivity for detecting tumours and the perfusion conditions of the liver. MATERIAL AND METHODS: 50 TPS-CT and CTA/CTPA were performed in 49 patients. After an initial examination without enhancement the first scan was initiated 15-25s after the peripheral bolus injection of contrast medium, the second after an interscan delay of 20-25s. By this means the liver was imaged in different phases of perfusion. In the course of the CTA/CTPA-exam the imaging was carried out after selective, intraarterial application of contrast agent. RESULTS: The differentiation of the perfusion phases succeeded in 90% of the patients. When compared with standard CT, which images only the portal venous phase, the new technique, which additionally shows the arterial perfusion, accomplished an increase in sensitivity for hypervascular lesions (51% vs. 60%). Yet in comparison with CTA/CTPA fewer lesions could be detected (87 vs. 138). Furthermore, by documenting the contrast agent kinetics, characterisation of the lesion was also facilitated. CONCLUSION: DPS-CT is a valuable additional tool for imaging the liver, even if the information yield is less when compared to CTA/CTPA. PMID- 8688501 TI - [Infiltration patterns of plasmacytomas in magnetic resonance tomography]. AB - PURPOSE: To define the different infiltration patterns in the spine in multiple myeloma, in correlation with histological and clinical findings. Quantitative signal evaluation with contrast media (Gd-DTPA). To compare the results in MRI with X-ray films. MATERIAL AND METHODS: 61 patients with proven multiple myeloma and 50 controls were examined (1.0 Tesla, T1-w SE, opposed phase GE images). RESULTS: Five infiltration patterns with different clinical stages were detected: normal bone marrow (11%) in cases of low interstitial marrow infiltration (biopsy), pure diffuse infiltration (25%), focal involvement (33%), combined diffuse/focal infiltration (23%) and a "salt-and pepper" pattern (8%). In diffuse plasmacytoma the 40% signal intensity increase was modification of diffuse infiltration. MRI proved to be more sensitive than radiography. CONCLUSION: MRI is able to show the type and the extension of bone marrow infiltration in multiple myeloma. Diffuse involvement can be objective with gadopentetate dimeglumine. PMID- 8688502 TI - [Flow contrast behavior in fast MR angiography with an ECG-triggered, slice selective inversion recovery turbo-FLASH technique]. AB - PURPOSE: To optimise and evaluate fast "inflow"-based contrast-prepared gradient echo magnetic resonance angiography (MRA) of blood vessels with pulsatile flow. MATERIAL AND METHOD: We used a standard 2-D Turbo-FLASH sequence with an acquisition time of 0.9 s and a slice-selective hyperbolic secant inversion (SSIR) pulse for contrast preparation. Trigger delay and inversion time were systematically varied. RESULTS: Abdominal blood vessels of volunteers showed high signal intensity compared to stationary tissue without pulsatile artifacts. However, depending on cardiac cycle and inversion time, venous vessels in particular exhibited a periodic signal drop by maximum 70% of the peak value. Using optimised parameters SSIR turbo-FLASH images of patients could be obtained with high flow contrast between normal and pathological structures. CONCLUSION: With ECG triggering SSIR Turbo-FLASH MRA enables fast imaging of pulsatile vessels with optimised flow contrast. PMID- 8688503 TI - [MR-mammography assessment of tumor response after neoadjuvant radiochemotherapy of locally advanced breast carcinoma]. AB - PURPOSE: We investigated the role of magnetic resonance mammography in monitoring tumour response of locally advanced breast cancer (LABC) after neoadjuvant radiochemotherapy. MATERIAL AND METHODS: 17 patients with LABS had a magnetic resonance mammography and ultrasonography before and after neoadjuvant radiochemotherapy. RESULTS: After neoadjuvant radiochemotherapy 14 patients showed in MR-mammography less pronounced and prolonged enhancement without washout. After treatment three patients had signal intensity-time curves still characteristic for tumour. Ultrasonography was true negative in two patients, true positive in 12 and false positive in three patients. CONCLUSION: Magnetic resonance mammography is suitable for monitoring tumour response after radiochemotherapy of LABC. However, a negative MRI does not exclude a residual tumour. Ultrasonography is of limited value in monitoring therapy of LABC. PMID- 8688504 TI - [Standardization and acceleration of quantitative analysis of dynamic MR mammographies via parametric images and automatized ROI definition]. AB - PURPOSE: To evaluate quantitative analysis of dynamic breast MRI studies using a dedicated PC based diagnosis system (DS) providing parametric images and automatic ROI definition as compared to the standard subtraction image, manual ROI based procedure. METHODS: We compared the diagnostic usefulness of parametric versus subtraction images in terms of visualisation of enhancement inhomogeneities and enhancement velocities. Quantitative analysis of enhancing lesions of 15 breast MRI studies was performed using both the DS and the system's console software (SC). We assessed the time needed for complete quantitative analysis and number of lesions evaluated. This was followed by assessment of within-reader and between-reader variability or within-case reproducibility of results of quantitative analysis. RESULTS: Parametric images are superior to subtraction images in visualizing enhancement inhomogeneities or ring enhancement in breast cancers. Mean time needed for analysis at DS and SC was 4 (3-5) min. and 23 (8-39) min., respectively. During this time period, significantly more lesions were evaluated per case using the DS as compared to the SC (2-14 vs. 1 6). Mean within-reader variability of enhancement velocities of the same lesions was 0% and 25% (DS and SC); between-reader variability of enhancement values obtained in the same lesions was 11% (DS) versus 41% (SC). CONCLUSION: The DS significantly cuts down the time needed for quantitative analysis. It significantly improves reproducibility of quantitative enhancement values due to standardization of ROI analysis. PMID- 8688505 TI - [Hallux rigidus operated on by Keller and Brandes method: radiological parameters of success and prognosis]. AB - PURPOSE: The aim of this study was to evaluate the pre- and postoperative radiographic findings of hallux rigidus treated with Keller and Brandes arthroplasty to determine the radiographic outcome and to identify a prognostic marker. METHODS: 83 patients with a total of 121 cases of hallux rigidus operated using Keller and Brandes arthroplasty were followed up (mean 9.7 y). A comparison of the pre- and postoperative radiographs, the clinical and subjective findings was predicated on a five point scale: 1. percentage of proximal phalanx resected ( < 33%, 33-50%, > 50%), 2. joint space, 3. ratio of the length of the first and second metatarsals, 4. first intermetatarsal angle, and 5. hallux valgus angle. RESULTS: In the patient group which had 33-50% of the proximal phalanx excised (n = 67. 55%) the highest patient satisfaction was observed (96%). If resection of the proximal phalanx exceeded 50% (n = 13. 11%), non physiologic dorsiflexion of the toe occurred and patients were dissatisfied (62%). Excision of less than 33% of the hallux (n = 41. 34%) was associated with a recurrent hallux rigidus. No other evaluated radiological parameter proved to be of significance. CONCLUSION: The most important radiological parameter in the evaluation of the outcome of Keller and Brandes arthroplasty as a surgical treatment method for hallux rigidus was the percentage of the proximal phalanx which had ben excised. PMID- 8688506 TI - [Therapeutic efficiency of of pulsed spray lysis in peripheral arterial occlusions]. AB - PURPOSE: To determine the clinical efficacy of pulse-spray thrombolysis. MATERIAL AND METHODS: In a prospective trial 28 patients with acute arterial (n = 14) and bypass (n = 14) occlusions of the lower extremities were treated with pulse spray thrombolysis. 23/28 legs were at risk. RESULTS: Technical and clinical success were 89% and 68% respectively. Time interval until restitution of antegrade flow was less than two hours, the median duration of the complete intervention was 17 hours. Two patients (7.1%) needed transfusions for inguinal haematomas. After six months 50% of occluded segments remained patent, secondary patency is comparable at 53%. Bypasses show significantly lower patency (p = 0.04) and higher amputation (p = 0.009) rates than native arteries. Bad run-off (< or = 1 artery patent) is a significant predictor for clinical failure and early amputation. CONCLUSIONS: The distinct advantage of pulse-spray thrombolysis is fast restoration of antegrade flow and thereby effective treatment of acute ischaemia. The complication rate is low without associated mortality. PMID- 8688507 TI - [Stent implantation as a palliative therapeutic measure in stenosing tumors of central airways]. AB - PURPOSE: Stent implantation was used to treat patient with malignant tracheobronchial obstructions to determine the effectiveness in producing symptomatic palliation. METHODS: 18 patients (15 men and three women; median age 57 years) with malignant tracheobronchial stenosis were treated by application of metal stents (15 Palmaz-, 10 Gianturco-, 4 Wallstents). The indication for stent implantation was given in 13 patients by clinically significant dyspnea, besides in 5 patients by therapy resistant postobstructive pneumonia. RESULTS: In 17 patients correct positioning of the stents was achieved and the symptoms completely disappeared until tumor related death. Median survival was 137 days (min. 10 days to max. 322 days). In one patient symptoms recurred three months after stent implantation. CONCLUSION: The application of metal stents in patient with malignant tracheobronchial obstruction appears to be a useful palliation procedure. The treatment was well tolerated and very effective. PMID- 8688508 TI - [Interventional therapy of nonocclusive mesenteric ischemia with captopril: an experimental animal study]. AB - PURPOSE: To clarify whether in nonocclusive mesenterial disease the extent of damage to the intestinal wall can be limited by local intraarterial application of Captopril. METHOD: Producing shock by means of pericardial tamponade in 18 piglets. Examination of three groups: Intraarterial application of Captopril at the beginning of the shock phase (n = 6) or administration one hour after the beginning of the shock phase (n = 6), as well as a control group (n = 6). Analysis of clinical pathology (laboratory chemistry) and haemodynamic parameters over a test period of 4 hours and histological preparation of resected segments of the small intestine. RESULTS: The initiation of therapy at the beginning of the shock improved the blood supply of the intestinal wall (measured by means of laser sonography in relative flow units RFU) from 226 RFU to 303 RFU; the rise in lactate from 2.7 to 3.6 mmol/l was significantly less (p = 0.05) than for the control group (from 3.1 to 11.5 mmol/l). The frequency and severity of the histological changes that are typical for ischaemia were less pronounced. If therapy was started only after a one-hour shock phase, this effect was no longer noticeable (rise in lactate from 5 to 9.5 mmol/l, intestinal wall blood flow from 168 to 170 RFU). CONCLUSION: Intraarterial administration of Captopril can reduce the extent of damage in nonocclusive mesenterial ischaemia (nonocclusive disease) if therapy is initiated early enough. PMID- 8688509 TI - [Technical modification of the rheolytic thrombectomy]. AB - A 48-year-old male patient with acute occlusion (5 cm) of a leg artery was treated with the rheolytic thrombectomy (RT). As recommended the catheter is applied via a single coaxial running guide wire, which is removed later. If an additional wire has been placed in the occluded vessel segment, the occlusion can be passed repeatedly. A 30 degrees bent catheter tip improves the removal of wall adherent thrombotic material. The occluded segment was successfully recanalized with the RTC, 270 ml of heparinised saline had been injected. The blood examinations showed mild haemolysis. PMID- 8688510 TI - [Percutaneous embolization of a prosthetic leak after implantation of an endoluminal bifurcation prosthesis]. PMID- 8688511 TI - [Multifocal periostitis in SAPHO syndrome]. PMID- 8688512 TI - [Infantile fibrosarcoma of the cheek]. PMID- 8688513 TI - [Simulation of breast carcinoma by diabetic mastopathy]. PMID- 8688514 TI - [Intravasal pedunculated sarcoma metastasis of the proximal vena cava inferior]. PMID- 8688515 TI - [Iliac-ureteral fistula, a rare complication of ureteral splinting]. PMID- 8688516 TI - [Unusual extracardiac extension of atrial myxoma]. PMID- 8688517 TI - [Effect of substance P on behavioral indicators in "open field" and "forced swimming" tests in rats of different behavioral types]. PMID- 8688518 TI - [Effect of delta sleep-inducing peptide on the status of the calcium transport system of the sarcoplasmic reticulum and activity of antioxidant defense enzymes in the myocardium]. PMID- 8688519 TI - [Effect of adapting to periodic hypoxia on kinetic parameters of respiratory chain enzymes in the rat brain]. PMID- 8688520 TI - [Effect of a Rhodiolae rosea extract on the level of inducible HSP-70 in the myocardium under stress]. PMID- 8688521 TI - [Effect of etimizol on development of a neuropathic pain syndrome]. PMID- 8688522 TI - [Alkaline phosphatase isoforms in murine organs after bilateral adrenalectomy]. PMID- 8688523 TI - [Inhalation effect of low doses of ethanol during pregnancy on development of rat offspring]. PMID- 8688524 TI - [Additional groups of nonapeptidergic neurosecretory cells in secretory cells of the hypothalamus and adjacent brain areas in dehydrated rats]. PMID- 8688525 TI - [Accumulation of ATP in rat and human hepatocyte cell membranes exposed to certain growth factors and phosphatidylcholine]. PMID- 8688526 TI - [Is Na,K-ATPase the target of oxidative stress?]. PMID- 8688527 TI - [Hemispheric features of serotonin involvement in processing information of significant and little importance in rats]. PMID- 8688528 TI - [Level of tocopherol and lipid peroxidation products in tissues of rats with an inherited ability to hyperproduce reactive free radicals]. PMID- 8688529 TI - [Effect of thymoptin on behavior of experimental animals]. PMID- 8688530 TI - [Mechanism of action of befol on calcium metabolism in cardiomyocytes using the fluorescent probe fura-2]. PMID- 8688531 TI - [Dependence of the anti-aggression properties of buspirone on time of day]. PMID- 8688532 TI - [Identification of specific binding sites for nerve growth factor on human blood platelets and bovine brain membranes]. PMID- 8688533 TI - [Formation of T-lymphocytes which inactivate allogeneic stem cells, during interaction of macrophages with thymocytes]. PMID- 8688534 TI - [Number of lymphocyte subpopulations in the spleen and level of hematopoietic tissue proliferation in mice undergoing surgery]. PMID- 8688536 TI - [Immunocytochemical localization of alpha-subunits of G-proteins in macrophages and Escherichia coli during their interaction]. PMID- 8688535 TI - [Comparative study of the effect of recombinant tumor necrosis factor and synthetic peptides, corresponding to its fragments, on phagocytosis,mediated by Fc- and MF-receptors]. PMID- 8688537 TI - [Ultrasonic concentration of tissue culture cells]. PMID- 8688538 TI - [Latent specific antibodies are found in the serum of patients with acquired immunodeficiency syndrome]. PMID- 8688539 TI - [Effect of nimodipine on the intracellular calcium level and platelet aggregation in ischemic stroke patients]. PMID- 8688540 TI - [Plasticity and stability of synapse architectonics of the cerebral cortex]. PMID- 8688541 TI - [Mechanism of pulmonary hypertension in rats with high altitude hypoxia]. PMID- 8688542 TI - [Formation of adhesions and change in activity of tissue plasminogen activator in the parietal peritoneum of the anterior stomach wall in rats depending on the method of restoring it]. PMID- 8688543 TI - [Pathomorphological study of intraorgan arteries in patients with aortic coarctation]. PMID- 8688544 TI - [Features of secretory activity of enterochromaffin cells of the duodenal mucosa in the red-cheeked squirrel under various physiological conditions]. PMID- 8688546 TI - [Nerve growth factor activity in the rat regenerating liver tissue]. PMID- 8688545 TI - [Reactions of the murine ovary to blockade of opioid receptors in early postnatal ontogenesis]. PMID- 8688547 TI - [Interconnection between changes in the status of mitochondria and intercellular connections of hepatocytes during internal administration of silicon-containing water]. PMID- 8688548 TI - [Effect of hemodilution and hemoconcentration on postischemic changes in microvessels of the rabbit ear]. PMID- 8688549 TI - [Selection of anxious mice by three-stage testing in a elevated cross maze]. PMID- 8688550 TI - [Cell death and effectiveness of the erythropoietic system]. PMID- 8688551 TI - [Effect of localization of erythroid cell death on the kinetics of erythropoiesis]. PMID- 8688552 TI - Characterization of novel complexes on the cell surface between integrins and proteins with 4 transmembrane domains (TM4 proteins). AB - Here we identified several new integrin/TM4 protein complexes on the cell surface. By immunoprecipitation using nonstringent conditions, and by reciprocal immunoprecipitation, we found that alpha 3 beta 1 and alpha 6 beta 1 integrins but not alpha 2 beta 1, alpha 5 beta 1, or alpha 6 beta 4 integrins associated with CD9 and CD81 in alpha 3 beta 1/CD81, alpha 3 beta 1/CD9, alpha 6 beta 1/CD81, and alpha 6 beta 1/CD9 complexes. Also, cross-linking experiments established that alpha 3 beta 1/CD81, alpha 3 beta 1/CD9, and alpha 3 beta 1/CD63 associations occur on the surface of intact cells and suggested that a critical interaction site is located within extracellular domains. Cross-linking in conjunction with reimmunoprecipitation indicated that larger multi-component alpha 3 beta 1/TM4/TM4 complexes (alpha 3 beta 1/CD9/CD63, alpha 3 beta 1/CD81/CD63, and alpha 3 beta 1/CD9/CD81) also could be detected on the cell surface. Immunofluorescent staining showed redistribution of alpha 3 beta 1/TM4 complexes toward the periphery of cells plated on various extracellular matrix substrates and also showed that these complexes were localized in cell footprints. Staining of human tissues yielded additional results consistent with co-localization of alpha 3 beta 1 and CD9, CD63, and CD81 proteins. In conclusion we suggest that the prevalence of integrin/TM4 complexes in diverse cellular environments is indicative of their general physiological importance. PMID- 8688553 TI - Novel alterations in CDK1/cyclin B1 kinase complex formation occur during the acquisition of a polyploid DNA content. AB - The pathways that regulate the S-phase events associated with the control of DNA replication are poorly understood. The bone marrow megakaryocytes are unique in that they leave the diploid (2C) state to differentiate, synthesizing 4 to 64 times the normal DNA content within a single nucleus, a process known as endomitosis. Human erythroleukemia (HEL) cells model this process, becoming polyploid during phorbol diester-induced megakaryocyte differentiation. The mitotic arrest occurring in these polyploid cells involves novel alterations in the cdk1/cyclin B1 complex: a marked reduction in cdk1 protein levels, and an elevated and sustained expression of cyclin B1. Endomitotic cells thus lack cdk1/cyclin B1-associated H1-histone kinase activity. Constitutive over expression of cdk1 in endomitotic cells failed to re-initiate normal mitotic events even though cdk1 was present in a 10-fold excess. This was due to an inability of cyclin-B1 to physically associate with cdk1. Nonetheless, endomitotic cyclin B1 possesses immunoprecipitable H1-histone kinase activity, and specifically translocates to the nucleus. We conclude that mitosis is abrogated during endomitosis due to the absence of cdk1 and the failure to form M phase promoting factor, resulting in a disassociation of mitosis from the completion of S-phase. Further studies on cyclin and its interacting proteins should be informative in understanding endomitosis and cell cycle control. PMID- 8688554 TI - Signals from the spindle midzone are required for the stimulation of cytokinesis in cultured epithelial cells. AB - The interaction between the mitotic spindle and the cellular cortex is thought to play a critical role in stimulating cell cleavage. However, little is understood about the nature of such interactions, particularly in tissue culture cells. We have investigated the role of the spindle midzone in signaling cytokinesis by creating a barrier in cultured epithelial cells with a blunted needle, to block signals that may emanate from this region. When the barrier was created during metaphase or early anaphase, cleavage took place only on the sides of the cortex facing the mitotic spindle. Microtubules on the cleaving side showed organization typical of that in normal dividing cells. On the noncleaving side, most microtubules passed from one side of the equator into the other without any apparent organization, and actin filaments failed to organize in the equatorial region. When the barrier was created after the first minute of anaphase, cells showed successful cytokinesis, with normal organization of microtubules and actin filaments on both sides of the barrier. Our study suggests that transient signals from the midzone of early anaphase spindles are required for equatorial contraction in cultured cells and that such signaling may involve the organization of microtubules near the equator. PMID- 8688555 TI - Connexin 35: a gap-junctional protein expressed preferentially in the skate retina. AB - We have used low stringency hybridization to clone a novel connexin from a skate retinal cDNA library. A rat connexin 32 clone was used to isolate a single partial clone that was subsequently used to isolate seven more overlapping clones of the same cDNA. Two clones containing the entire open reading frame have a consensus sequence of 1456 bp and predict a protein of 302 amino acids length and molecular mass of 35,044 daltons, referred to as connexin 35 or Cx35. Southern blot analysis suggests that the cloned sequence lies in a single gene with one intron. Polymerase chain reaction amplification from genomic DNA and partial sequencing of this intron showed that it was approximately 950 bp in length, and located within the coding region 71 bp after the translation start site. Hydropathy analysis of the predicted protein and alignments with previously cloned connexins indicate that Cx35 has a long cytoplasmic loop and a relatively short carboxyl terminal tail. Multiple sequence alignments show that Cx35 has similarities to both alpha and beta groups of connexins and suggests that its origins may be near the divergence point for the two groups. Consensus sequences consistent with sites for phosphorylation by protein kinase C and by cAMP - or cGMP -dependent protein kinase were identified. Two transcripts were detected in Northern blot analysis: a 1.95-kb primary transcript and a 4.6-kb minor transcript. In RNA samples from 10 tissues, transcripts were detected only in the retina. PMID- 8688556 TI - SCD5, a suppressor of clathrin deficiency, encodes a novel protein with a late secretory function in yeast. AB - Clathrin and its associated proteins constitute a major class of coat proteins involved in vesicle budding during membrane transport. An interesting characteristic of the yeast clathrin heavy chain gene (CHC1) is that in some strains a CHC1 deletion is lethal, while in others it is not. Recently, our laboratory developed a screen that identified five multicopy suppressors that can rescue lethal strains of clathrin heavy chain-deficient yeast (Chc - scd1-i) to viability. One of these suppressors, SCD5, encodes a novel protein of 872 amino acids containing two regions of repeated motifs of unknown function. Deletion of SCD5 has shown that it is essential for cell growth at 30 degrees C. scd5-delta strains carrying low copy plasmids encoding C-terminal truncations of Scd5p are temperature sensitive for growth at 37 degrees C. At the nonpermissive temperature, cells expressing a 338-amino acid deletion (Scd5P-delta 338) accumulate an internal pool of fully glycosylated invertase and mature alpha factor, while processing and sorting of the vacuolar hydrolase carboxypeptidase Y is normal. The truncation mutant also accumulates 80- to 100-nm vesicles similar to many late sec mutants. Moreover, at 34 degrees C, overexpression of Scd5p suppresses the temperature sensitivity of a sec2 mutant, which is blocked at a post-Golgi step of the secretory pathway. Biochemical analyses indicate that approximately 50% of Scd5p sediments with a 100,000 x g membrane fraction and is associated as a peripheral membrane protein. Overall, these results indicate that Scd5p is involved in vesicular transport at a late stage of the secretory pathway. Furthermore, this suggests that the lethality of clathrin-deficient yeast can be rescued by modulation of vesicular transport at this late secretory step. PMID- 8688557 TI - Identification of a cyclase-associated protein (CAP) homologue in Dictyostelium discoideum and characterization of its interaction with actin. AB - In search for novel actin binding proteins in Dictyostelium discoideum we have isolated a cDNA clone coding for a protein of approximately 50 kDa that is highly homologous to the class of adenylyl cyclase-associated proteins (CAP). In Saccharomyces cerevisiae the amino-terminal part of CAP is involved in the regulation of the adenylyl cyclase whereas the loss of the carboxyl-terminal domain results in morphological and nutritional defects. To study the interaction of Dictyostelium CAP with actin, the complete protein and its amino-terminal and carboxyl-terminal domains were expressed in Escherichia coli and used in actin binding assays. CAP sequestered actin in a Ca2+ independent way. This activity was localized to the carboxyl-terminal domain. CAP and its carboxyl-terminal domain led to a fluorescence enhancement of pyrene-labeled G-actin up to 50% indicating a direct interaction, whereas the amino-terminal domain did not enhance. In polymerization as well as in viscometric assays the ability of the carboxyl-terminal domain to sequester actin and to prevent F-actin formation was approximately two times higher than that of intact CAP. The sequestering activity of full length CAP could be inhibited by phosphatidylinositol 4,5-bisphosphate (PIP2), whereas the activity of the carboxyl-terminal domain alone was not influenced, suggesting that the amino-terminal half of the protein is required for the PIP2 modulation of the CAP function. In profilin-minus cells the CAP concentration is increased by approximately 73%, indicating that CAP may compensate some profilin functions in vivo. In migrating D. discoideum cells CAP was enriched at anterior and posterior plasma membrane regions. Only a weak staining of the cytoplasm was observed. In chemotactically stimulated cells the protein was very prominent in leading fronts. The data suggest an involvement of D. discoideum CAP in microfilament reorganization near the plasma membrane in a PIP2-regulated manner. PMID- 8688558 TI - M-phase-specific phosphorylation and structural rearrangement of the cytoplasmic cross-linking protein plectin involve p34cdc2 kinase. AB - Plectin, a widespread and abundant cytoskeletal cross-linking protein, serves as a target for protein kinases throughout the cell cycle, without any significant variation in overall phosphorylation level. One of the various phosphorylation sites of the molecule was found to be phosphorylated preferentially during mitosis. By in vivo phosphorylation of ectopically expressed plectin domains in stably transfected Chinese hamster ovary cells, this site was mapped to the C terminal repeat 6 domain of the polypeptide. The same site has been identified as an in vitro target for p34cdc2 kinase. Mitosis-specific phosphorylation of plectin was accompanied by a rearrangement of plectin structures, changing from a filamentous, largely vimentin-associated state in interphase to a diffuse vimentin-independent distribution in mitosis as visualized by immunofluorescence microscopy. Subcellular fractionation studies showed that in interphase cells up to 80% of cellular plectin was found associated with an insoluble cell fraction mostly consisting of intermediate filaments, while during mitosis the majority of plectin (> 75%) became soluble. Furthermore, phosphorylation of purified plectin by p34cdc2 kinase decreased plectin's ability to interact with preassembled vimentin filaments in vitro. Together, our data suggest that a mitosis-specific phosphorylation involving p34cdc2 kinase regulates plectin's cross-linking activities and association with intermediate filaments during the cell cycle. PMID- 8688559 TI - Kinesin-related proteins in the mammalian testes: candidate motors for meiosis and morphogenesis. AB - The kinesin superfamily of molecular motors comprises proteins that participate in a wide variety of motile events within the cell. Members of this family share a highly homologous head domain responsible for force generation attached to a divergent tail domain thought to couple the motor domain to its target cargo. Many kinesin-related proteins (KRPs) participate in spindle morphogenesis and chromosome movement in cell division. Genetic analysis of mitotic KRPs in yeast and Drosophila, as well as biochemical experiments in other species, have suggested models for the function of KRPs in cell division, including both mitosis and meiosis. Although many mitotic KRPs have been identified, the relationship between mitotic motors and meiotic function is not clearly understood. We have used sequence similarity between mitotic KRPs to identify candidates for meiotic and/or mitotic motors in a vertebrate. We have identified a group of kinesin-related proteins from rat testes (termed here testes KRP1 through KRP6) that includes new members of the bimC and KIF2 subfamilies as well as proteins that may define new kinesin subfamilies. Five of the six testes KRPs identified are expressed primarily in testes. Three of these are expressed in a region of the seminiferous epithelia (SE) rich in meiotically active cells. Further characterization of one of these KRPs, KRP2, showed it to be a promising candidate for a motor in meiosis: it is localized to a meiotically active region of the SE and is homologous to motor proteins associated with the mitotic apparatus. Testes-specific genes provide the necessary probes to investigate whether the motor proteins that function in mammalian meiosis overlap with those of mitosis and whether motor proteins exist with functions unique to meiosis. Our search for meiotic motors in a vertebrate testes has successfully identified proteins with properties consistent with those of meiotic motors in addition to uncovering proteins that may function in other unique motile events of the SE. PMID- 8688560 TI - Biochemical and functional analysis of the YME1 gene product, an ATP and zinc dependent mitochondrial protease from S. cerevisiae. AB - Inactivation of YME1 in yeast causes several distinct phenotypes: an increased rate of DNA escape from mitochondria, temperature-sensitive growth on nonfermentable carbon sources, extremely slow growth when mitochondrial DNA is completely absent from the cell, and altered morphology of the mitochondrial compartment. The protein encoded by YME1, Yme1p, contains two highly conserved sequence elements, one implicated in the binding and hydrolysis of ATP, and the second characteristic of active site residues found in neutral, zinc-dependent proteases. Both the putative ATPase and zinc-dependent protease elements are necessary for the function of Yme1p as genes having mutations in critical residues of either of these motifs are unable to suppress any of the phenotypes exhibited by yme1 deletion strains. Yme1p co-fractionates with proteins associated with the mitochondrial inner membrane, is tightly associated with this membrane, and is oriented with the bulk of the protein facing the matrix. Unassembled subunit II of cytochrome oxidase is stabilized in yme1 yeast strains. The data support a model in which Yme1p is an ATP and zinc-dependent protease associated with the matrix side of the inner mitochondrial membrane. Subunit II of cytochrome oxidase, when not assembled into a higher order complex, is a likely substrate of Yme1p. PMID- 8688561 TI - Drosophila MCM protein complexes. AB - MCM genes encode a family of evolutionarily conserved proteins required for DNA replication. In Saccharomyces cerevisiae, where they were first identified, MCM genes interact genetically with each other. Allele specificity in these interactions suggests that MCM proteins physically associate with one another and that this association is essential for function. We describe here an analysis of physical interactions among three Drosophila MCM proteins. Using specific antibodies we detect Drosophila MCMs almost exclusively in 600-kDa protein complexes. Co-immunoprecipitation data demonstrate the existence of at least two distinct types of 600-kDa complexes, one that contains DmCDC46 and one that appears to contain both DmMCM2 and Dpa (a CDC54 homologue). These complexes are stable throughout embryonic division cycles, are resistant to treatments with salt and detergent, and are present during development in tissues undergoing mitotic DNA replication as well as endoreplication. When extracts are prepared under low salt conditions all three MCM proteins co-immunoprecipitate. Consequently, we suggest that the 600-kDa complexes interact in a higher order complex. PMID- 8688562 TI - Identification and developmental regulation of a neuron-specific subunit of cytoplasmic dynein. AB - Cytoplasmic dynein is the microtubule minus-end-directed motor for the retrograde axonal transport of membranous organelles. Because of its similarity to the intermediate chains of flagellar dynein, the 74-kDa intermediate chain (IC74) subunit of dynein is thought to be involved in binding dynein to its membranous organelle cargo. Previously, we identified six isoforms of the IC74 cytoplasmic dynein subunit in the brain. We further demonstrated that cultured glia and neurons expressed different dynein IC74 isoforms and phospho-isoforms. Two isoforms were observed when dynein from glia was analyzed. When dynein from cultured neurons was analyzed, six IC74 isoforms were observed, although the relative amounts of the dynein isoforms from cultured neurons differed from those found in dynein from brain. To better understand the role of the neuronal IC74 isoforms and identify neuron-specific IC74 dynein subunits, the expression of the IC74 protein isoforms and mRNAs of various tissues were compared. As a result of this comparison, the identity of each of the isoform spots observed on two dimensional gels was correlated with the products of each of the IC74 mRNAs. We also found that between the fifteenth day of gestation (E15) and the fifth day after birth (P5), the relative expression of the IC74 protein isoforms changes, demonstrating that the expression of IC74 isoforms is developmentally regulated in brain. During this time period, there is relatively little change in the abundance of the various IC74 mRNAs. The E15 to P5 time period is one of rapid process extension and initial pattern formation in the rat brain. This result indicates that the changes in neuronal IC74 isoforms coincide with neuronal differentiation, in particular the extension of processes. This suggests a role for the neuronal IC74 isoforms in the establishment or regulation of retrograde axonal transport. PMID- 8688563 TI - Lumped-density population models of pioneer-climax type and stability analysis of Hopf bifurcations. AB - The effects of population density on the survival and growth of an individual species are modeled by assuming that the species per capita growth rate (i.e., fitness) is a function of a weighted total density. A species is called a pioneer population if it thrives at low density but its fitness decreases monotonically with increasing density. A species is called a climax population if its fitness increases up to a maximum value and then decreases as a function of its total density. Hopf bifurcations for deterministic models of the interaction of pioneer and climax populations are discussed. Stability properties for the Hopf invariant curves in the discrete models are compared to the stability properties of the Hopf periodic orbits in the corresponding continuous models. Examples illustrate that stability may be more common in the discrete models. PMID- 8688564 TI - Competitive exclusion between axons dependent on a single trophic substance: a mathematical analysis. AB - A mathematical model is presented of competition between axons for a trophic substance, such as is believed to occur particularly during development. The model is biologically realistic. The growth-stimulating activity of the trophic molecules is assumed to result from their binding to high-affinity receptors on neurons and their axons, but the model also incorporates uptake by nonneuronal cells possessing only lower affinity receptors. Plausible and fairly general assumptions are made concerning the kinetics of binding and internalization and the effects on axonal growth. The model takes into account the possibility that trophic factor production may be regulated by the afferent axons or autoregulated. The variables specified are the "axonal vigor" of each axon, representing the ability of each axon to take up trophic molecules, and the concentration of trophic molecules in the extracellular space of the axonal target region. Of the several parameters introduced, the most important turns out to be the "zero vigor-growth parameter," which is defined as the concentration of trophic molecules that gives zero growth of the vigor of a given axon. By means of a Lyapunov function, it is shown that the system will approach asymptotically to a stable equilibrium characterized by the survival of only the axon whose zero growth parameter is lowest. Or, if several axons share the same lowest zero growth parameter, these will all survive. The model may be particularly relevant to the elimination of polyneuronal innervation from developing muscle fibers and from autonomic ganglion cells. PMID- 8688565 TI - A biologically based model for the analysis of premalignant foci of arbitrary shape. AB - In many animal carcinogenesis experiments, quantitative data on putative premalignant foci are now routinely collected. Moolgavkar et al. [Carcinogenesis 11:1271 (1990)] considered the analysis of such data from a rat hepatocarcinogenesis experiment within the framework of a two-stage model for carcinogenesis using the assumption that the premalignant clones were spherical. This assumption seems questionable in many organs, including the liver. In this paper, it is relaxed and arbitrary shapes are allowed for the clones. The proposed method is illustrated by reanalysis of the data considered in the earlier paper. The new analysis yields parameter estimates that are more plausible biologically than those of the original analysis. PMID- 8688566 TI - On the theory of partially inbreeding finite populations. IV. The effective population size for polyploids reproducing by partial selfing. AB - Consider a population of size N in which there is reproduction by selfing with probability beta and by random mating with probability 1-beta. In each cell of any individual, homologous chromosomes appear 2n times, with n among them having been contributed by each parent. Wright [Proc. Natl. Acad. Sci. 24:372 (1938)] showed that if beta = 0, there is no double reduction in gamete formation, and a Poisson offspring distribution, the probability of nonidentity by descent of two random copies of a gene in an individual of generation t + 1 is approximately 1 1/2nN times as large as it is in generation t if N is large. This result will be generalized to populations with any beta > or = 0 and any offspring distribution. If n = 2 or 3, a result will be obtained that also holds for any probability of double reduction. PMID- 8688567 TI - Queueing models of potentially lethal damage repair in irradiated cells. AB - Some of the ideas arising in queueing theory are applied to describe the repair mechanisms responsible for recovery of cells from potentially lethal radiation damage. Two alternative versions are presented of a queueing model of damage repair after a single dose of irradiation. The first version represents a linear misrepair model, and the second invokes the idea of spontaneous lesion fixation. They are pieced together in the third model, allowing for both mechanisms. The consistency of the proposed models with published experimental data is tested. PMID- 8688568 TI - [Public health services between "new public health" and "new public management"]. AB - Today, a substantial reorientation of the Public Health services in the Federal Republic of Germany is broadly seen necessary. Patterns of functional and organisational restructuring of Public Health services on the regional and the communal level are closely linked with concepts of prevention and health promotion. Hence, a number of agencies have already adopted new tasks and functions like comprehensive and transorganizational planning, coordination and evaluation as well as the establishment of new reporting systems. Presently, the transformation process from the bureaucratic mode of administering matters of health to a new Public Health orientation receives new impacts from the international "New Public Management" movement. Comparatively late, with the beginning of the 1990s, a growing number of German municipalities has introduced new concepts of administration. Local government administrations, of which the Public Health services are a part, follow the model of modern service organizations producing services in a more efficient, professionalized and consumer-oriented way. Specific elements of economising modernisation programmes like re-distribution of tasks, de-centralisation, extension of managerial capacities, setting of stimulating working conditions that provide employees with greater independence of action as well as career opportunities, are at the same time prerequisites for innovative strategies of health protection and coordination policies of Public Health services. PMID- 8688569 TI - [A documentation procedure for community social psychiatry services--a pilot project in Bielefeld and Minden]. AB - The status of health reporting (on community levels) has improved considerably during recent years. It is being increasingly used as an instrument for planning, controlling and evaluating political processes. In addition to individual studies the statistics within the departments of the health authorities are an important factor for meaningful health reporting on a local level. The IDIS (from Jan. 1st, 1995 LOGD) and the social psychiatric services on the Minden-Lubbecke district and the city of Bielefeld have developed a programme for automation-aided management of the statistics for social psychiatric services on a local level. Details on the personal situation and illnesses of the clients as well as on the activities of the services staff are recorded and analysed. Based on the WHO programme EPI-info 6.01 the documentation programme SPD-STAT was developed. This programme is menudriven and, in addition to the functions for the statistical data input and retrieval of fixed table sets, also offers the possibility of processing data with the full functionality of the ANALYSIS-module of EPI-Info. Thus interactive ad-hoc evaluations for current questions are made possible. Using SPD-STAT in as many local regions in NRW as possible may be a big step forward for health reporting on local levels as well as for health reporting on a state level. PMID- 8688570 TI - [Epidemiology of psychotropic drug utilization in homes for the aged]. AB - Cross-sectional studies conducted in 1988 and 1992 using identical assessment methods also determined the prevalence of psychotropic drug consumption by the residents of homes for the elderly in the city of Mannheim. Another purpose of the studies was to find out the extent of a possible interrelation between treatment with psychotropics on the one hand and sociodemographic sociodemographic characteristics and behaviour problems of the residents on the other. In addition, in all consecutive new admissions to the homes not only the prevalence of consumption of psychotropics was investigated, but also the question to what extent the use of psychotropic drugs increases the mortality rate. In a total of 12 Mannheim old-age homes each in 1988 (n = 542) and 1992 (n = 497) all the residents older than 65 years of age were investigated. Between 1986 and 1988 all consecutive admissions (n = 239) to Mannheim old-age homes were interviewed and the mortality risk determined in a subsequent investigation in 1992. Taking a period of four weeks as reference period, 42.1% of the residents were treated during that period with psychotropics in 1988, of which 13.3% received neuroleptics, 11.7% hypnotics, 8.9% antidepressants and 13.0% tranquilizers. There were considerable variations between the individual homes in respect of the intake of psychotropics (minimum 18.2%, maximum 58.3%). In 1992 the prevalence of the use of psychotropics rose to 47.6%, the increase being mainly due to neuroleptics (23.8%) and, to a lesser extent, to antidepressants (12.9%). Compared with 1988 there was a slight decrease in the consumption of tranquilizers (10.9%) and hypnotics (10.7%). In 1988 there was no statistically significant connection between intake of psychotropics and gender, age, frequency of visits by relatives/friends, duration of residence and behaviour problems (aggression, suspiciousness, wandering, depression, dementia) of the residents. This result was also confirmed for 1992, albeit with two exceptions: a significantly higher consumption of psychotropic drugs by home residents characterised by the "behaviour problems wandering" and "depression". Examination of the consecutively newly admitted inmates revealed that psychotropic drug consumption was already relatively high (38.0%) at the time of admission. The mortality risk, determined after having checked on possibly confounding variables, was not significantly enhanced in residents who had already been treated with psychotropics at the time of admission (odds ratio: 0.52; Cl: 0.25 1.08). Compared with elderly persons in private households the consumption of psychotropics is markedly higher in old-age homes. However, the intake is not due to institutionalisation, but had already been high at the time of admission. Prospective studies of the course with relatively short follow-up intervals would be necessary for a differentiated examination of the determinants and effects of high psychotropics consumption and to establish a sound foundation for an appropriate prescription of psychotropics for home residents. PMID- 8688571 TI - [Methadone substitution in public health management--results of a random day study sample]. AB - Subject of this paper is methadone-maintenance given by the office-based physicians in Germany within the framework of the statutory health insurance (SHI). Results of a survey of the associations of SHI-accredited physicians are presented, comprising the number of substituted patients, the distribution of indications and the number of physicians engaged in this field. The increasing trend in the number of substituted patients continues, although less steeply. Strongholds of methadone maintenance are still the cities of Hamburg, Berlin, and Bremen, where the highest rates of substituted patients were found in relation to the resident population. The method of data-gathering used trends to overestimate the number of substituted patients. Comparing the determined numbers with different data sources, the actual number of addicts who are substituted in the longer term at the cost of the SHI is estimated to be 10 000 patients. PMID- 8688572 TI - [Requirements and provision of services for severely handicapped patients according to SGBV regulations 1991-1993]. AB - Benefits for non-institutionalised severely disabled persons by the German statutory health insurance system were introduced in 1989 and extended in 1991. They were provided depending upon a standardised medical examination. We analysed 4185 examinations carried out in the city and the region of Augsburg in Southern Germany during 1991-1993 with regard to social and medical conditions of applicants. A total of 2706 persons examined (64.7%) were considered to meet the criteria of permanent dependence on nursing. The majority of applicants were more than 75 years of age (56.9%) even though all age groups were represented. The leading cause for dependence on nursing were diseases of the circulatory system (29.4%), followed by diseases of the nervous system (20.5%) and musculoskeletal disorders (14.6%). The main burden of nursing care was borne by the relatives; professional institutions played only a minor role. The degree of dependence with regard to basic activities of daily living, especially "turning in bed", "dressing" and "using toilet" showed the strongest association with the overall assessment of nursing dependence. With the introduction of a new nursing care insurance system in Germany ("Pflegeversicherung") in January 1995, benefits for disabled persons have been extended further. To improve prevention of nursing care dependence and to ensure the best possible care of patients in need of such care, further investigations are required which should focus on risk factors for both nursing-care dependence and long-term nursing home and hospital admission of disabled persons. PMID- 8688573 TI - [The roentgen patient record--a useful document for quality assurance or failed attempt? A study of distribution and utilization of the roentgen patient record among patients and institutions in Bremen]. AB - Use and effectiveness of X-ray cards were investigated in a sample of 640 clients who had come for X-ray screening to the Public Health office in Bremen between April 1993 and September 1994 (n = 640). Only 8% of 541 possible clients with former X-ray examinations had their card completely filled in. A survey among 53 institutions which are expected to distribute or fill in X-ray cards revealed that only 5 distributed and only another 5 filled actively filled in the cards. PMID- 8688574 TI - [Conversion of results of expert evaluation in disputed work disability(section 275 paragraph 1a SGB V regulation)]. AB - A statutory insurance for persons who are unable to care for themselves and require nursing attention, has been introduced in Germany. Employers must contribute to the insurance funds, and employees are likewise compelled to pay their share. To compensate employers to some extent for these expenses they can now take recourse to expertising by the Medical Services of the statutory insurance bodies if they have any doubts about an employee's inability to work. The results of such expertising have been assessed statistically and their translation into reality has been examined. Recommendations on how to improve the expertising procedure are given in this article. Laymen's wrong ideas regarding signs for possibly unjustified claims for inability to work are corrected. PMID- 8688575 TI - [Epidemiology of HIV in Germany (status: 30 June 1995)--transmission among heterosexuals and value of HIV screening programs]. AB - As compared to the earlier publication [1], the current publication further refines the figures published for the first time 1988-90 by the author [2,3] and adds additional sources. Sample sizes for and feasibility of anonymous unlinked testing (AUT) are discussed in greater detail. PMID- 8688576 TI - [Solvent emissions in a school building after using a construction moisture protection substance]. AB - A wall of a school building was treated with a moisture repellent containing a silicone resin and white spirit. In the temporal connection with this a child experienced an exacerbation of its bronchial asthma. Some weeks after the second application the users of the rooms complained about unpleasant odor and discomfort. As shown by analysis the white spirit containing aliphatic and aromatic hydrocarbons diffused through the 50 cm thick stone wall into the classrooms. Due to the considerable concentration of the pollutant a part of the building could not be used any longer. In Germany no guideline values exist for white spirit or any mixtures of hydrocarbons in indoor air for non-occupational workplaces. For the reopening of the rooms a target value of 300 micrograms VOC/m3 was set. The incident shows that building materials can cause health problems and discomfort even if instructions of application are followed. PMID- 8688577 TI - [What is the attitude of parents to dental preventive examinations in schools and kindergarten? Results of a parent survey]. AB - The aim of this study is to explore the opinion of parents on dental screening in schools and kindergartens. A sample of 490 parents attending a school medical inspection was asked to fill in a self-administered questionnaire. The parents could express their level of agreement with five statements concerning dental screening and the recall system existing in Baden-Wurttemberg. The answers were conceived according to the Likert scale. The results of this study show that a large majority of the interviewees had a positive attitude towards screening and a less positive attitude towards the recall system. Compared to the Germans, the immigrants had a more positive attitude towards screening and a less positive attitude towards the recall system. Compared to the parents with lower education level, the parents with a higher educational level were more in favour of the recall system and less in favour of dental screening. The high acceptance of school dental inspections among parents should encourage the responsible authorities to expand dental screening, which is laid down in social legislation, to a greater number of schools and kindergartens. PMID- 8688578 TI - [Public health fairs on "environment and human health"--participants, topics, attitudes]. AB - 19 meetings dealing with environment and human health, including 7 public hearings related to the planning of an incineration plant and 5 training courses for asthmatic patients, were analysed with regard to participation, persons participating in the discussions, topics covered by the remarks and also emotional involvement and standard of information. There was a total of 835 participants; 1471 "units of statements" were assessed. In the open meetings 18 33% of the participants took part in the discussion, in the closed training sessions the number was 66%. About one-third of the remarks ("units") dealt with the pollution of water, soil and air; a health risk was mentioned in about 20%. The frequency distribution of topics mentioned at the various kinds of meeting is presented. It was surprising that annoyance and anxiety were rarely expressed. The standard of information was classified rather high at the hearings concerned with the incineration of waste, and rather low at the training sessions. PMID- 8688579 TI - [Evaluation of the educational curriculum in psychosocial fields and general medicine in human medicine subjects--results of a total Germany pilot study in the 1995 summer semester]. AB - With the discussion of the quality of medical education in Germany the importance of evaluating the curriculum has grown. A working group of representatives of the German scientific societies for general medicine and the so-called "psychosocial" disciplines in medical education had adapted a questionnaire from Harvard Medical School and tested this version for the first time in summer 1995. 56 teachers and 1250 students took part in this pilot study. The instrument proved to be sufficiently valid to evaluate the quality of different types of teaching lessons. The disciplines (Medical Sociology, Medical Psychology, Social Medicine, General Medicine, Psychotherapy/Psychosomatics) were valued equally with concern to their relevance for medical education. They got significantly better values for quality of teaching and teaching engagement of the professors. It is recommended to notice these results in the actual debate on the reform of the medical curriculum and to include other disciplines in further evaluative investigations. PMID- 8688580 TI - Reduced allele dropout in single-cell analysis for preimplantation genetic diagnosis of cystic fibrosis. AB - BACKGROUND: For couples at risk of transmitting a known single-gene defect, preimplantation genetic diagnosis (PGD) allows the identification and transfer of only unaffected embryos following in vitro fertilisation (IVF), single-cell biopsy at about the eight-cell stage, and genetic analysis by PCR. This technique therefore avoids the risk of terminating an affected pregnancy diagnosed later in gestation. METHODS AND RESULTS: Using nested PCR, the delta F508 mutation causing cystic fibrosis can be detected in single cells and we previously reported successful PGD in a couple in whom both partners carry the delta F508 mutation. To date we have treated 12 couples in a total of 18 cycles. This resulted in five singleton births confirmed to be homozygous normal. Single blastomeres from disaggregated embryos which had not been transferred were analysed to confirm the original diagnosis and assess reliability in clinical practice. Amplification efficiency and accuracy were high, with blastomeres from embryos diagnosed as homozygous normal or affected. In a proportion of blastomeres from presumed carrier embryos, one of the parental alleles failed to amplify, apparently at random (allele dropout, ADO). A possible explanation is the relative inaccessibility of one of the target allele early in the PCR. To test this we have used single lymphocytes from delta F508 carriers and investigated the effects of various denaturation temperatures in the early cycles of amplification. CONCLUSIONS: Increasing the denaturation temperature reduced the rate of ADO without affecting amplification efficiency. PMID- 8688581 TI - Polymerase chain reaction amplification specificity: incidence of allele dropout using different DNA preparation methods for heterozygous single cells. AB - PURPOSE: The purpose was to evaluate methods of DNA preparation in a single cell to determine the ability to amplify and correctly diagnose a targeted gene. METHODS: One- or two-cell lymphoblasts (n = 100/group), heterozygous for the normal and 4-base pair insertion on exon 11 of the beta-hexosaminidase A gene, were collected and prepared under the following conditions: (1) freeze-thaw liquid nitrogen, then boiling (LN2); (2) potassium hydroxide/dithiothreitol, heated to 65 degrees C, followed by acid neutralization (KOH); (3) boiling only (Bl); and (4) water only (H2O). Cells were analyzed by polymerase chain reaction using nested primers. RESULTS: The total number of cells amplifying [in brackets] and the cells with amplification for both alleles (heterozygous), the normal allele, or the mutant allele were as follows, respectively: LN2 [38], 11, 16, 11; KOH [97], 91, 5, 1; Bl [41], 17, 13, 11; and H2O [85], 41, 16, 28. With two cells per reaction tube the results were as follows: LN2 [85], 53, 14, 18; and KOH [97], 96, 1, 0. CONCLUSIONS: KOH lysis was significantly greater than with all other methods (P < 0.006) and should be used for single cells. This study also demonstrates the importance of using heterozygous cells to determine the ability to amplify both alleles as a method of quality control for single-cell analysis. PMID- 8688582 TI - Allelic dropout caused by allele-specific amplification failure in single-cell PCR of the cystic fibrosis delta F508 deletion. PMID- 8688583 TI - Allele dropout in sequential PCR and FISH analysis of single cells (cell recycling). AB - PURPOSE: Our purpose was to investigate the feasability of using sequential PCR and FISH analysis of single cells for preimplantation diagnosis. METHODS: Protocols for sequential PCR and FISH analysis of a single fibroblast (cell recycling) were optimized for six loci and the rates of allele specific dropout (ADO) were determined. RESULTS: Conditions that allow reliable genotyping of single cells in lysis buffer were not optimal for amplifying fibroblasts fixed to coverslips. After optimizing conditions, we observed a success rate of 85% for both analyses in sequential PCR-FISH experiments in single cells for the four loci studied. The individual success rates for each technique revealed a slightly higher rate for FISH (91-95%) than for PCR (85-87%) for single cells on coverslips. The presence of two hybridization signals in FISH experiments demonstrated that the failure to amplify both alleles from heterozygous cells on coverslips was due to true ADO, and not the loss of chromosomal material. The ADO rate observed on coverslips varied between 10 and 14%, which is significantly higher than that observed in solution, even after meticulous optimization. CONCLUSIONS: Sequential PCR and FISH analysis of single cells remains an attractive possibility. However, until the problem of the increased rate of ADO is resolved, cell recycling should be applied to clinical preimplantation genetic analysis. PMID- 8688584 TI - Identifying the sex of human preimplantation embryos in X-linked disease: amplification efficiency of a Y-specific alphoid repeat from single blastomeres with two lysis protocols. AB - INTRODUCTION: Preimplantation diagnosis involves detecting genetic defects in one or two blastomeres biopsied from cleavage stage embryos following a vitro fertilization (IVF). For X-linked recessive disease, identification of the sex of embryos allows transfer of only unaffected females. To examine how critical the preparation of the single blastomere is for amplification of a Y chromosome specific repeat sequence using the polymerase chain reaction (PCR), the incidence of amplification failure has been examined following two lysis protocols. MATERIALS AND METHODS: Amplification of a Y alphoid repeat sequence from single blastomeres disaggregated from cleavage stage embryos was examined after either (1) lysis in distilled water and freeze-thawing twice or (2) a two-step lysis protocol involving an initial treatment in potassium hydroxide and dithiothreitol. Some of the embryos had been previously sexed by cleavage-stage biopsy and fluorescent in situ hybridization with X- and Y-specific probes. RESULTS: Amplification failure occurred in 6 of 50 (12%) and 4 of 60 (7%) single blastomeres from male embryos following lysis in distilled water or using the two step protocol, respectively. Conversely, amplification from contaminating DNA occurred in 5 of 63 (8%) single blastomeres from female embryos and 6 of 94 (6%) of control medium-blanks. CONCLUSIONS: The incidence of amplification failure was improved but not eliminated using the two-step lysis protocol. At least two cells, therefore, would be necessary for accurate identification of males by amplification of Y-specific repeat sequences alone. Nevertheless, this protocol for preparing cleavage-stage blastomeres is likely to give more consistent amplification of any unique or repeat sequences. PMID- 8688586 TI - Detection of chromosomal abnormalities in human preimplantation embryos using FISH. AB - PURPOSE: Multicolour FISH has been used for the preimplantation diagnosis of sex for X-linked disorders and to examine the chromosome constitution of early human embryos. MATERIALS AND METHODS: Single blastomeres and whole embryos were spread using HCI and Tween 20. Multicolour FISH was performed using directly-labelled human DNA probes for chromosomes X, Y, and 1 in a two hour FISH procedure. RESULTS: Four groups of chromosome arrangements have been found in human preimplantation embryos (i) normal, all nuclei uniformly diploid, (ii) diploid mosaics, majority of the nuclei diploid, with a small number of nuclei aneuploid (iii) chromosomally abnormal, all nuclei uniformly chromosomally abnormal, e.g. XO, XXY, XXX and (iv) chaotic, all nuclei showing different chromosome complements. CONCLUSIONS: For the preimplantation diagnosis of sex, an XX nucleus has always been representative of a female embryo. However, for the diagnosis of dominant disorders or chromosome abnormalities, two cells should be analysed to reduce the chance of misdiagnosis which may arise from chromosomal mosaicism. Implantation and further embryo development may be possible from mosaic or chromosomally abnormal embryos, but those showing chaotic chromosome arrangements would be unlikely to implant. PMID- 8688585 TI - Clinical application of FISH for sex determination of embryos in preimplantation diagnosis of X-linked diseases. PMID- 8688587 TI - Cytogenetics of uncleaved oocytes and arrested zygotes in IVF programs. AB - PURPOSE: Cytogenetic studies of arrested oocytes and zygotes were used to understand in vitro fertilization (IVF) failures. METHODS: We investigated the cytogenetics (Giemsa banding and FISH) of 710 uncleaved oocytes and 94 arrested zygotes from 208 patients undergoing IVF procedures. RESULTS AND CONCLUSIONS: Of uncleaved oocytes without a polar body, 39% were judged cytogenetically abnormal (17% unbalanced predivision and 21.5% diploid). Of 575 oocytes with a polar body, 124 (21.5%) showed numerical or structural chromosome aberrations. In arrested zygotes, approximately equal cases were found with separate condensed haploid complements (no syngamy), nuclear asynchrony and pulverized DNA, and apparently cytogenetically normal zygotes arrested at mitosis. These data on chromosome abnormalities were also analyzed with respect to two ovarian stimulation protocols and to maternal age. Both ovarian stimulation protocols and to maternal age. Both ovarian stimulation protocols showed the same levels of chromosome abnormalities. Overall chromosome abnormalities and premature chromosome condensation were also unchanged with maternal age. These data illustrate the significance of chromosome aberrations in IVF failures. PMID- 8688589 TI - Polar body diagnosis of common aneuploidies by FISH. AB - PURPOSE: The purpose of this work was to investigate the reliability and accuracy of polar body analysis for preimplantation diagnosis of common aneuploidies in IVF patients of advanced maternal age. DESIGN: We have previously introduced polar body analysis as an approach for nondestractive evaluation of the genotype of human oocytes. The method has recently been applied in a clinical trial involving 45 infertile patients, demonstrating the feasibility of preconception diagnosis of common aneuploidies by fluorescent in situ hybridization (FISH). The present paper describes the experience of polar body diagnosis in 135 IVF patients (161 cycles) of advanced maternal age. RESULTS: FISH results of the first and/or second polar bodies were available in 648 (72.4%) of 895 biopsied oocytes subjected to FISH analysis. Of 648 oocytes with FISH results, 208 demonstrated chromosomal abnormalities. Of 440 oocytes predicted to be free from monosomy or trisomy of chromosomes X, 18, and/or 13/21, 314 were normally fertilized, cleaved, and transferred in 122 treatment cycles, resulting in 6 healthy deliveries and 12 ongoing pregnancies following confirmation of the polar body diagnosis by CVS or amniocentesis. CONCLUSIONS: The method may be useful for detection of oocytes with common chromosomal trisomies in IVF patients of advanced maternal age. PMID- 8688588 TI - Reduction in signal overlap results in increased FISH efficiency: implications for preimplantation genetic diagnosis. AB - BACKGROUND: In the absence of mosaicism, one of the problems of preimplantation genetic diagnosis with FISH is the occurrence of false-negative hybridization results. It has been hypothesized that missing signals are produced by spatial overlap of signals. METHODS AND RESULTS: To investigate the relation among cell density, signal overlap, and hybridization signal detection, 371 blastomeres and 4556 lymphocytes were fixed in different cellular concentrations and analyzed by FISH using probes for chromosomes X, Y, and 18, and their nuclear diameters and FISH results scored. The results showed that the lower the diameter of fixed nuclei, the higher the number of signal overlaps and missing signals. The minimum number of missing signals was obtained when lymphocyte and blastomere nuclei had 40 or more microns in diameter after fixation and FISH. Since blastomeres were fixed individually, results with blastomeres were invariably better than with lymphocytes. PMID- 8688590 TI - Single-cell analysis of unstable genes. AB - PURPOSE: We have developed sensitive diagnostic procedures for studies on the normal and mutant alleles of the triplet repeat genes associated with myotonic dystrophy and fragile X in single human somatic cells, gametes and embryos. METHODS: Polymerase chain reaction (PCR) assays for the normal alleles of the myotonic dystrophy and fragile X loci have been refined to the sensitivity of the single cell. In addition, we have developed a simple PCR-based technique, termed ?Repeat Primer PCR', which can detect the full fragile X expansion in small samples of buccal cells. CONCLUSIONS: The assay for the triplet repeat sequence in the myotonic dystrophy locus could not be used to study stability since we observed additional PCR products derived from in vitro expansion of the triplet repeat sequence during the PCR reaction itself. The implications of in vitro expansion and allele drop-out for studies on the timing of the expansion in development and preimplantation diagnosis of triplet repeat diseases are discussed. The development of a new PCR procedure to identify the expanded alleles of the fragile X locus could prove invaluable for monitoring the timing of repeat expansion in early embryonic development. Triplet repeat polymorphisms provide a means of identifying the maternally and paternally-derived alleles of the myotonic dystrophy gene. Using single cell reverse transcriptase PCR analysis, we have monitored the onset of the myotonic dystrophy gene transcription in early preimplantation embryos. Transcripts from the paternally inherited allele of the myotonic dystrophy gene are already detectable in the 1 cell stage human embryo. PMID- 8688591 TI - Assessing congenital anomalies after preimplantation genetic diagnosis. AB - BACKGROUND: Preimplantation genetic diagnosis is an exciting advance in prenatal diagnosis. However, the safety of embryo biopsy must be determined with respect to both pregnancy rate and cogenital anomalies. ANALYSIS: Too few pregnancies have been reported to allow meaningful inferences to be drawn, for which reason data on pregnancy losses and anomalies after conventional IVF were first reviewed. Loss rates are approximately 25%, and anomaly rates are not increased over that observed in the general population. Unfortunately, considerable methodological problems exist in published surveys: lack of proper controls, failure to take into account potential confounding variables, anomaly surveillance that is inconsistent with respect to the vigor with which anomalies are sought, inclusion or exclusion of minor anomalies, inclusion or exclusion of anomalies evident only on ultrasound, and even inclusion or exclusion of anomalies present in terminated pregnancies. We recommend prospective surveillance for major anomalies, defined as those causing death, major handicap or requiring surgery. Prospective surveillance ideally dictates collection of intake information at the time pregnancy is diagnosed, surveillance during pregnancy to exclude teratogenic influences, and systematic neonatal anomaly surveillance. PMID- 8688592 TI - Expression of homebox-containing genes in human preimplantation development and in embryos with chromosomal aneuploidies. AB - PURPOSE: The purpose of the study was to investigate homeobox gene expression in human oocytes and preembryos and in postimplantation embryos with impaired embryonic development determined by chromosomal abnormalities. METHODS: Reverse transcriptase-polymerase chain reaction (RT-PCR) with intron spanning primer sets for Homeobox gene sequences was used. RESULTS: The homeobox genes HoxA4, HoxA7, HoxB4, and HoxB5 were present in human oocytes and cleaving normal and triploid embryos. The expression pattern was different between chromosomally abnormal and normal first-trimester embryos. Of four homeobox transcripts (HoxA7, HoxB4+ ++, HoxB5, and HoxC6) that are expressed in diploid embryos, only HoxA7, HoxB4 and HoxC6 were present in a trisomy 7 embryo, and only HoxB4 and HoxB 5 in triploid embryos and an embryo with trisomy 9. Cloning experiments revealed differences in the number of homeobox clones obtained from trisomy 7 and control embryos. CONCLUSIONS: The transcripts of homeobox genes, HoxA4, HoxA7, HoxB4, and HoxB5, were present in oocytes and cleaving embryos. The pattern of expression of homeobox genes in cultured fibroblasts derived from spontaneously aborted embryos with aneuploidies was different from that in control diploid cells. PMID- 8688594 TI - Selected papers from the 5th annual meeting of the International Working Group on Preimplantation Genetics. Hamburg, Germany, June 28, 1995. PMID- 8688593 TI - Homeobox genes and male reproductive development. AB - PURPOSE: Homeobox genes encode transcription factors that dictate developmental events in philogenetically diverse organisms. In comparison to what is known about their role in embryogenesis, we know very little concerning homeobox gene function in neonates or adults. In this communication, we review studies that address the possible role of homeobox genes in male reproductive development, a system active in neonate and adult animals. METHODS: Studies have shown that many homeobox genes are expressed in germ cells of the testis, while less is known about the identity of homeobox genes expressed in somatic cells of the testis or epididymis. Hox homeobox genes display a pattern of expression in testis that is dependent on their paralogous and orthologous position within the Hox gene chromosome clusters. Other homeobox genes are expressed in the male reproductive system, including many POU and Prd/Pax homeobox gene family members. More recently, it has been shown that the orphan homeobox gene, Pem, originally isolated by subtraction hybridization on the basis of its differential expression in tumor cell lines, is selectively expressed in reproductive tissue. Alternatively spliced Pem transcripts accumulate in testis and epididymis that differ from those expressed in tumors and placenta. Pem transcripts accumulate postnatally in the epididymis in a developmentally regulated manner. CONCLUSIONS: The highly regulated pattern of expression exhibited by many homeobox genes in the male reproductive system suggests that homeobox transcription factors may dictate developmental events in this system. However, future studies are needed to determine the specific functional roles homeobox genes in male reproductive development and spermatogenesis. PMID- 8688595 TI - Preimplantation genetic diagnosis. PMID- 8688596 TI - Preimplantation diagnosis of inherited disease by embryo biopsy: an update of the world figures. AB - PURPOSE: Cleavage stage embryo biopsy and preimplantation diagnosis was first reported five years ago. The annual collation of the world figures for centres offering this procedure is important to continually assess the efficiency and success of the biopsy, diagnosis and pregnancies obtained. MATERIALS AND METHODS: Data was collected from 14 centres worldwide. The largest series of diagnosis has been performed for those patients carrying X-linked disease where the embryos have been sexed either by PCR or FISH. PCR has also been used for the specific diagnosis of a number of single gene defects, mainly for cystic fibrosis but also for the diagnosis of Lesch Nyhan syndrome, Fragile X, Duchenne muscular dystrophy, Tay Sachs, haemophilia and RhD blood typing. RESULTS: For PCR sexing, a total of 62 cycles have been performed with 14 pregnancies, 8 deliveries and 11 babies born. For FISH sexing, 70 cycles have resulted in 15 pregnancies, 8 deliveries and 11 babies born. For the specific diagnosis of single genes defects, a total of 65 cycles resulted in 21 pregnancies, 12 deliveries and 12 babies born. Overall, 197 cycles were performed, with 171 embryo transfers (86%), 50 pregnancies (25% per cycle, 29% per transfer), 28 deliveries and 34 babies born. CONCLUSIONS: New methods are being developed to increase the scope of preimplantation diagnoses that can be offered. From next year, the biochemical and miscarriage rates will also be recorded. PMID- 8688598 TI - Histology of nasal polyps in various conditions. AB - At the Salata ENT Department in Zagreb, 28 patients with nasal polyps were examined in the 1992-1993 period. Results of histologic analysis of these nasal polyps are presented. In 10 cases, nasal polyps were histologically examined at three horizontal levels, and the rest by vertical section. The method of hemalaun eoisin and histochemical methods (PAS, Alcian, Mallory, Giemsa and orcein) were used to analyze the following parameters: epithelium, stroma, basement membrane, cell infiltrate and glands. Patients were grouped according to the presence or absence of allergy, relapse of polyps and age group ( < 40 and > 40 years of age). The lateral nasal wall mucosa served as control. Histologic picture of the polyps showed some differences related to allergy and other groups of polyposis. In conclusion, histologic study of polyps should not be taken as the only indicator of the etiology of polyposis but, supplemented with other examinations, as an evidence supporting the diagnosis. PMID- 8688597 TI - Fluorescent PCR: a new technique for PGD of sex and single-gene defects. AB - BACKGROUND: For single-cell diagnosis, particularly preimplantation genetic diagnosis to be successful four main criteria must be achieved: sensitivity, reliability, accuracy, and identification/elimination of contamination. METHODS AND RESULTS: Fluorescent PCR achieves all four necessary criteria and, in addition, currently allows genes on up to nine chromosomes to be simultaneously investigated. Fluorescent PCR has high sensitivity (approximately 1000 x conventional analysis systems), high reliability (97%), and high accuracy (97%) rates for both sex and CF diagnosis in single somatic cells. The low detection threshold allows allelic dropout (one of the main causes of misdiagnosis) to be easily distinguished from PCR phenomena such as preferential amplification. High reliability (90%) and accuracy (97-100%) have been achieved in sex and CF diagnosis in human blastomeres. Fluorescent PCR can also be used to DNA fingerprint (STR profiling) single cells to identify the source/origin of the cell and determine if contamination has occurred. CONCLUSIONS: Fluorescent PCR is therefore a suitable method for PGD. PMID- 8688599 TI - An unsuspected cause of excessive ultrafiltration during maintenance hemodialysis. AB - Undetected excessive ultrafiltration occurred in a patient on maintenance hemodialysis using a Gambro AK-10 monitor and Ergo 120 A-G blood lines. In spite of alarms present on the hemodialysis monitor, the dialysis staff were not alerted of the failure. The patient had nausea, vomiting, abdominal cramps and hypotension. The monitor was withdrawn from service and subjected to careful technical checks, but no failure could be detected. Thorough investigation of the hemodialysis 'set-up' at the time of the incident revealed a partial obstruction (kinking) to have occurred in the extracorporeal blood circuit where the flexible tubing joined the venous chamber. This had created a very high positive pressure within the dialyzer compartment and excessive ultrafiltration, which the blood circuit pressure monitoring transducer was unable to detect. To prevent kinking of the blood lines, dialysis staff and patients should be instructed to ensure that blood lines lie in smooth curves. PMID- 8688600 TI - Are chlorine-free compounds a solution for health problems caused by ozone depleting substances? AB - In January 1996, the Government of Croatia and United Nations Environment Programme (UNEP) signed an agreement on the phasing out of ozone-depleting substances in Croatia, making the problem of identifying adequate substitutes a high priority. In this paper, the main ecologic characteristics of chlorine containing fully halogenated chlorofluorocarbons (CFCs) and partially halogenated chlorofluorocarbons (HCFCs) compared with chlorine-free hydrofluorocarbons (HFCs) are presented. The data showed HCFCs to be ecologically more acceptable than CFCs, particularly regarding the ozone-depleting potential (ODP), and have therefore been proposed as substitutes for CFCs. However, although having lower ODP, long-term they could still harm the stratospheric ozone layer, and are therefore hardly acceptable. HFCs are promising substitutes which, having no chlorine, have no ODP. Six were toxicologically evaluated; three of them were found flammable. Toxicological characteristics of three nonflammable compounds (HFC 125, HFC 134a and HFC 227ea) are presented. Their toxicity, not yet completely evaluated, appears to be low. PMID- 8688601 TI - Effect of chronic hemodialysis on thyroid function tests in patients with end stage renal disease. AB - In patients with end-stage renal disease (ESRD), serum concentrations of thyroid hormones are often found to be disturbed. The aim of the study was to evaluate the effect of chronic hemodialysis (CHD) on the regulation of decreased levels of thyroid hormones and thyroxine-binding globulin (TBG) in serum of patients with ESRD. This effect was analyzed during two phases of CHD in patients with ESRD. The first period of CHD (FCHD) lasted 14.6 months and the second period (SCHD) was prolonged by additional 16.7 months. The concentrations of thyroid hormones (T4, FT4, T3, FT3, rT3), thyrotropin (TSH) and TBG were determined in serum samples obtained before the patients started hemodialysis (BHD) and at the end of FCHD and SCHD. From the first group of 48 patients with ESRD who had previously been tested BHD, 28 patients received FCHD and only 10 of them continued to receive additional SCHD. The levels of all thyroid hormones were found to be decreased, especially some hormones such as FT3 (87% BHD), T3 (93% FCHD) and FT4/FT3 (90% SCHD). The concentration of TSH did not change significantly during CHD and about 10% of decreased and 10% of increased values were recorded. Only TBG level from decreased values (37% BHD) returned to the normal range at the end of SCHD. Results of rT3 could not be interpreted with certainty, because two different commercial kits were used during the study. Although CHD lasted for 31.3 months, it did not have any positive effect on the regulation of disturbed thyroid hormones to the normal levels. PMID- 8688602 TI - Articular chondrocytes interact with basement membrane Matrigel through laminin active binding sites. AB - Laminin-like molecules are detected during the differentiation of embryonic mesenchyme into cartilage and in cartilage during amphibian limb regeneration and fracture repair. Since primary articular chondrocytes in culture recognize and respond to laminin from basement membrane, the author studied the effect of laminin-derived peptides, which are thought to be responsible for biological activities of laminin. The biologically active peptides from both the laminin B1 and A chains containing YIGSR, RGD and IKVAV sequences all promoted chondrocyte attachment, and blocked laminin mediated cell attachment, with the IKVAV containing peptide being the most effective. Laminin promoted cell migration with a maximum activity at 20 micrograms/ml. YIGSR at 100 micrograms/ml was the most active peptide exhibiting about 48% of the chemotactic activity of laminin, whereas the IKVAV-and RGD-containing peptides were much less active. When added in solution to the primary chondrocytes grown on Matrigel, YIGSR-containing peptides prevented cell alignment, whereas in the presence of peptides containing IKVAV sequence the cells spread rapidly and proliferated for 24 h. RGD-containing peptides had no effect on cell behavior on Matrigel. PMID- 8688603 TI - Heart rate and heart rate variability in acute coronary heart disease. AB - The parameters of cardiac autonomic function, heart period length and heart period length variability were investigated in 70 patients, 50 males and 20 females, mean age 54.8 +/- 9.6 years, admitted to coronary care unit. There were 15 unstable angina patients, 21 anterior wall infarction patients, 20 posterior wall infarction patients, and 14 non-Q-wave infarction patients, who survived to discharge. Heart period length and heart period length variability for each patient were manually measured on the basis of 30 consecutive sinus normal-to normal RR intervals in ECG every 20 minutes during the initial 24 hours of their stay at the coronary care unit and in the third week after admission. For each interval analyzed, the mean duration of RR interval was computed. RR interval variations were expressed as coefficient of variation (CV). On admission, heart rate was significantly slower (848 +/- 173 ms vs. 837 +/- 163 ms) and CV significantly lower (4.8 +/- 4.2 vs. 5.0 +/- 3.4%) than on discharge (p < 0.01). The significant difference in the mean RR interval between anterior wall infarction patients (802 +/- 186 ms) and inferior wall infarction patients (879 +/- 181 ms) recorded on admission disappeared on discharge from hospital (806 +/- 144 vs. 783 +/- 100 ms). CV was lower in acute myocardial infarction patients (4.7 +/- 3.6; 4.1 +/- 3.2) than in unstable angina patients (5.3 +/- 5.6) on admission (p < 0.05). Heart rate variability was greater in anterior wall infarction patients and unstable angina patients (CV = 5.3 +/- 3.1; 5.2 +/- 3.6%) than in posterior wall infarction patients and non-Q-wave infarction patients (CV = 4.7 +/- 3.5; 4.8 +/- 3.6%). The findings showed that different degrees of cardiac sympathovagal activity may occur in acute coronary heart disease patients during the first 24 hours of their stay at coronary care unit and on discharge from hospital. PMID- 8688604 TI - Role of the parasympathetic autonomic nervous system in digitalis intoxication: electrocardiographic and histological study. AB - The role of the parasympathetic autonomic nervous system (ANS) in digoxin intoxication was investigated in atropine pretreated conscious rabbits. Both the electrocardiographic registration and the histologic analysis indicated possible prevention of lethal arrhythmias by atropine pretreatment. The hearts of animals pretreated with atropine appeared less damaged, since they presented only a light cytoplasmic vacuolization. It was evident that the administration of digoxin without atropine pretreatment provoked dramatic signs of digitalis intoxication followed by animal death. Myocardia of these rabbits were highly damaged. On the other hand, our experimental data indicated that the abolishment of the vagal tone by atropine blockade caused only signs (i.e. inversion of the T wave) due to myocardial ischemia, to which the light cytoplasmic vacuolation could be correlated. Myocardial ischemia could be caused by constriction of coronary blood vessels, which could be consequential to both the prevalent activity of the orthosympathetic ANS, following parasympathetic blockade, and direct digoxin effects on vascular fibrecells, which both produce vasoconstriction. Therefore, it is reasonable to assume that the parasympathetic ANS plays a major role in digitalis intoxication in rabbits. PMID- 8688605 TI - Functional effects of typical lung resections for primary bronchogenic carcinoma. AB - In 60 patients with primary bronchogenic carcinoma undergoing surgery, pulmonary function studies were performed before, and then 10 days and 3 to 6 months after typical lung resection. Preoperative profiles showed a slight restrictive pattern without air trapping and slightly disturbed gas exchange. The restrictive pattern was not related to clinical, X-ray and endoscopy findings. The alveoloarterial oxygen gradient was smaller in the patients requiring lobectomy than in pneumonectomy patients. After surgery, the volume loss was related to the amount resected, being greater after right pneumonectomy than after left pneumonectomy, smaller after bilobectomy and the least after lobectomy. The obstructive pattern remained unchanged. Diffusion of carbon monoxide decreased significantly less than the volumes after pneumonectomy, but proportionally after lobectomy and bilobectomy. Those with increased alveoloarterial oxygen gradient or increased physiologic dead space showed a significant improvement of their gas exchange after surgery. PMID- 8688606 TI - Triple procedure 'a chaud'. AB - Although it is widely accepted that acute uveitis is the main contraindication for intrabulbar procedures, conditions in the presented group of 24 patients (mean age 63 years, ranging from 35 to 74) required immediate surgery. The corneal pathologies included: perforated corneal ulcer in 12, imminent corneal perforation in ten and corneal melting syndrome in two patients. Partial perforative keratoplasty was accompanied by various combinations of surgical procedures, depending on the preoperative status. In cases of aphakia (N = 5) and anterior chamber pseudophakia (N = 5) secondary PCIOL implantation with sulcus fixation was performed, combined with ACIOL explanation in the latter group. The largest group included patients with complicated cataract (N = 14), where classic triple procedure was performed in ten patients. In three patients, the surgery had to be completed with sulcus fixation of the PCIOL, due to posterior capsule rupture. Associated glaucoma in one patient required trabeculectomy along with triple procedure. Postoperative complications that could not be treated with conservative measures for subsequent corneal decompensation, required rekeratoplasty in three (12.5%) patients. Visual acuity amelioration, ranging from 0.2-0.8, was achieved in seven (29.2%) and nine (37.5%) patients after 3 and 6 months, respectively. PMID- 8688607 TI - Airway responses in healthy and asthmatic subjects following exposure to low ambient air temperature. AB - Ventilatory capacity following exposure to low ambient air temperature (-5 degrees C) was measured in 46 male and 37 female medical students. In healthy subjects there was an increase in all test parameters during a four-hour exposure as compared to preexposure values. However, six students with bronchial asthma showed a decrease in ventilatory capacity tests following exposure to low temperature. The changes in healthy subjects as well as in asthmatics were most pronounced for the maximal flow rates at 50% and the last 25% of the vital capacity (FEF50, FEF25). The mean increase in FEF25 for healthy subjects was recorded up to a +15.1% and +6.4% increase in nonsmokers and smokers, respectively. In asthmatics, the largest decrease of FEF25 was -21.5%. Authors' data indicated that environmental exposure to low ambient air temperature caused an increase of ventilatory function tests in healthy subjects and a decrease in asthmatics, particularly in flow rates at lower lung volumes. PMID- 8688608 TI - Shaking infants: a case for public education? PMID- 8688609 TI - Is team midwifery good for midwives? PMID- 8688610 TI - Babies past and present: a social history of infancy. PMID- 8688611 TI - Attitudes to contraception among Asian women in Britain. AB - To understand the attitudes of a woman from the Indian subcontinent towards contraception, it is necessary to be aware of her religious and cultural background. A strict sexual morality is practised by Muslim, Hindu and Sikh women, for whom pre-marital and extra-marital sexual relationships are forbidden. Girls are brought up to be shy and modest, and submitting to a vaginal examination is regarded with abhorrence except as a matter of life and death. Large families, and particularly sons, are regarded as blessings from the Almighty. The condom and IUD are considered the least offensive methods, although among more enlightened women the pill is gaining ground. PMID- 8688612 TI - Person to person: Rosie Barnes. Interview by Sue Clarke. PMID- 8688613 TI - Present-day principles in weaning babies. AB - For parents, the principles of weaning are to be flexible, offer variety, keep calm and show tolerance. Weaning is usually begun between three and six months old. Premature introduction of solids is inadvisable, as is delaying beyond six months. A wide range of home-prepared and/or manufactured baby foods broadens the experience of taste and smell at a receptive age. Foods during weaning should be given without added salt or added sugar. A low-fat diet is not appropriate for babies. Skimmed or semi-skimmed milk are not suitable. Fibre need not be excluded but should be given only in small amounts. Current Department of Health guidelines are that breast or complete formula milk should preferably be continued throughout the first year of life. Follow-on milk or whole cow's milk may be given from six months onwards Follow-on milk is preferable to cow's milk because it is a more reliable source of iron and vitamin D. The need for fluid increases with the intake of solids. Watch the sugar content in fruit juices and give well diluted. Children's vitamin drops should be given from six months up to two years, and preferably up to five years. PMID- 8688615 TI - Nursing standards in general practice: do they exist? PMID- 8688614 TI - Remedies for common family ailments: 3. Hay fever and allergic rhinitis. AB - Hay fever is an allergic reaction to pollen, and is seasonal (Spring to Autumn). Allergic rhinitis is a similar allergic reaction to substances such as house-dust mite, fungal spores or animal hairs, and tends to occur throughout the year. Both are common in the population, affecting one in five to one in ten. Apart from avoiding the offending substance as much as possible, treatment consists of prevention or of relieving the symptoms. Drugs include antihistamines sodium cromoglycate and corticosteroids. Homoeopathic remedies are also worth considering. Many antihistamines are available over the counter, and a steroid preparation (Beconase) and sodium cromoglycate are about to be changed from prescription-only to being sold in pharmacies. Some antihistamines cause drowsiness. A doctor should be consulted in the case of children or pregnant women, and of patients with heart and other conditions, or who are already taking other medications. PMID- 8688616 TI - Encouraging children's development through play. AB - Play is a major part of a young child's education. Children deprived of play experiences can develop learning and other problems from which they may take years to recover. Parents should be encouraged to buy toys which are right for their child's stages of development. "Educational toys" can be useful in stimulating particular aspects of development, eg hand-eye co-ordination, manual dexterity, association of cause and effect. A good variety of toys is important. Children become more quickly bored than adults because their attention span is shorter. A good principle is to buy toys that are challenging without being too difficult, However, children also need time to relax with older, more familiar toys and easily completed activities. PMID- 8688617 TI - Making it all run smoothly. PMID- 8688618 TI - Genetics and biochemistry of antibiotic production. PMID- 8688619 TI - Genetic and environmental control of antibiotic production. PMID- 8688620 TI - Autoregulators. PMID- 8688621 TI - Peptide and peptide-derived antibiotics. PMID- 8688622 TI - Peptides. AB - If we include beta-lactam antibiotics on the grounds that they have the same biosynthetic origin, peptides remain commercially the most important group of pharmaceuticals. However, our increasing knowledge of the genetic and enzymic background to biosynthesis, and of the regulation of metabolite production, will eventually bring a more unified approach to bioactive compounds. Mixing of structural types will become important, and we will be able to use our knowledge of biosynthetic genes and their regulatory networks. We will also benefit from an appreciation of the modular organization of catalytic functions, substrate transfer mechanisms and signalling between interacting enzymes. Since all of this is, in fact, the basis for enzymic synthesis of complex natural products in vivo, the exploitation of living cells requires mastery of a formidable network of cellular controls and compartments. For the present we are able to see fascinating connections emerging between genes in a variety of reaction sequences, not only in biosynthetic but also in degradative pathways. Peptide synthetases show surprising similarities to acylcoenzyme A synthetases, which are key enzymes in forming polyketides as well as in generating the CoA-derivatives that serve as substrates in degradative pathways. 4'-Phosphopantetheine, the functional half of CoA, plays a key role as the intrinsic transfer cofactor in various multienzyme systems. The comparatively small catalogue of reactions modifying natural products, notably epimerization, methylation, hydroxylation, decarboxylation (of peptides) and reduction/dehydration (of polyketides) can be found within or amongst biosynthetic proteins, generally as modules and organized in a specified order. The biochemist is coming close to the synthetic chemist's recipes, and may soon be recruiting proteins to carry them out. PMID- 8688623 TI - Peptidolactones. PMID- 8688624 TI - Bialaphos. PMID- 8688625 TI - Thiopeptides. PMID- 8688626 TI - Beta-lactams. PMID- 8688627 TI - Glycopeptides. PMID- 8688628 TI - Lantibiotics. PMID- 8688629 TI - Microcins. PMID- 8688630 TI - Anthracyclines. PMID- 8688631 TI - Tetracyclines. PMID- 8688632 TI - Macrolides. PMID- 8688633 TI - Avermectins. PMID- 8688634 TI - Polyethers. PMID- 8688635 TI - Rifamycin SV and related ansamycins. PMID- 8688636 TI - Chloramphenicol. PMID- 8688637 TI - Streptomycin and related aminoglycosides. PMID- 8688638 TI - Aminoglycosides and aminocyclitols (other than streptomycin). PMID- 8688639 TI - Agrocins. PMID- 8688640 TI - Isoprenoid antibiotics. PMID- 8688641 TI - Genetics of antibiotic production in Streptomyces coelicolor A3(2), a model streptomycete. PMID- 8688642 TI - Global physiological controls. PMID- 8688643 TI - Mast cells in laser and surgical wounds. AB - Precooling of tissues was investigated as a possible means of reducing thermal damage during CO2 laser surgery of the oral mucosa. The changes in mast cells in scalpel, and in non-cooled and precooled (tissue temperature lowered to approximately 10 degrees C) CO2 laser wounds were studied. Standard wounds five mm in length were created with the CO2 laser or scalpel on the dorsum of the tongues of 32 Sprague-Dawley rats under general anesthesia with fentanyl/fluanisone and midazolam. Animals were killed with excess anesthetic immediately or six hours after surgery, their tongues were removed, trimmed, fixed in neutral formalin and processed to paraffin wax. Acid (pH 1.4) toluidine blue stained sections were used to count normal and degranulated mast cells in five fields (0.1 mm2) located at defined positions immediately adjacent to the wound site. At both 0 and 6 hours normal mast cell numbers were significantly different between treatment groups (P<0.045; ANOVA) with mean numbers highest in scalpel wounds and lowest in uncooled laser wounds. Similarly, at 0 time, there were significant differences in degranulated mast cells between treatment groups (P=0.004; ANOVA) but highest numbers were detected in uncooled laser wounds and lowest in scalpel wounds. There were no significant differences in degranulated mast cell counts at six hours although there was a similar distribution in numbers between groups. Total numbers of mast cells (normal + degranulated) did not differ between treatment groups. These results demonstrated that i) laser wounds are associated with greater levels of mast cell degranulation than scalpel wounds and ii) precooling of tissues prior to laser treatment decreases the level of mast cell degranulation. It is concluded that tissue damage in CO2 laser surgery may be reduced by precooling of tissue. PMID- 8688644 TI - Evaluation of the implant-connection interface using scanning electron microscopy. AB - The objective of the present study was to evaluate the implant-connection interface using scanning electron microscopy for implants commercially available in Brazil, correlating these findings with the possible effects of a badly fitted interface on the clinical failure of the implant. PMID- 8688645 TI - In vitro study of cervical enamel projection in human molars. AB - The authors studied the cervical enamel projection (CEP) in 1903 extracted permanent molars. The incidence of CEP was greater on the buccal and lingual surfaces than on the mesial and distal surfaces and occurred more frequently in maxillary molars than in mandibular molars. PMID- 8688646 TI - Susceptibility of Actinobacillus actinomycetemcomitans strains to norfloxacin. AB - The minimal inhibitory concentration of norfloxacin to Actinobacillus actinomycetemcomitans strains isolated from patients with localized juvenile periodontitis was determined by using an agar dilution method. All the tested strains, including the three reference strains, were susceptible at concentrations lower than the breakpoint used, with 90% of the strains susceptible to 0.125 micrograms/ml. PMID- 8688647 TI - Effect of topical fluoride application on the surface roughness of composites. AB - The influence of fluoride solutions on the surface roughness of polished and nonpolished composites with Sof-Lex discs was verified. Concise and Herculite XR samples were exposed to the action of 1.23% acidulated phosphate fluoride rinse, 1.23% acidulated phosphate fluoride gel, and 0.2% neutral phosphate fluoride rinse for 4 min each. The average roughness values obtained by perfilometer showed that all fluoride solutions produced surface alterations in the samples. In the unpolished samples, more roughness was produced in Concise etched by 1.23% acidulated phosphate fluoride rinse. In the polished samples, the 1.23% acidulated phosphate fluoride gel produced greater alterations in Herculite XR, and the neutral rinse in Concise samples. PMID- 8688648 TI - A clinical evaluation of 2% buffered glutaraldehyde in pulpotomies of human deciduous teeth: a 24-month study. AB - The purpose of this study is to evaluate the clinical results obtained with the use of glutaraldehyde in pulpotomies performed on deciduous teeth, in a recall of 24 months. Our results showed a success greater than 90%, similar to other clinical studies. PMID- 8688649 TI - Contamination of dental radiographic solutions. AB - Thirteen groups of periapical radiographic films were evaluated to determine and compare within and between groups the effects of contamination of the fixer solution with developing solution during radiographic processing. An aluminum penetrometer was used as the radiographic object to produce different optical densities. The images were compared using radiographic density and contrast as parameters. There were significant differences between the control groups and the groups processed with a contaminated fixer solution. No statistically significant differences were observed in the intragroup comparisons. PMID- 8688651 TI - CPITN: time and cost estimates for periodontal prevention and treatment procedures. AB - The aim of this study was to estimate the necessary time and cost for periodontal prevention and treatment in a working population from sugar and alcohol refineries in Araraquara, SP, Brazil. A stratified sample of 528 employees aged 18-64 from administrative, industrial and agricultural staffs was examined by one examiner, previously trained, according to the community periodontal index of treatment needs (CPITN). The time required for procedures and the cost was extrapolated to the total worker population. The results showed that the estimated time required for periodontal prevention/treatment was 4527 hours. Of this time, 1783 hours were required for oral hygiene instruction, 2531 for scaling, 151 for surgery and 62 for maintenance. The cost would be US $17,655 for hiring a dentist for 8 hours/day to provide oral hygiene instruction, scaling, surgery and maintenance. However, the cost would be US $9,028 for hiring a dentist for 4 hours/day to provide surgery and maintenance and a dental hygienist for 8 hours/day to provide scaling and oral hygiene instruction. Taking into account epidemiologic, technical and economic aspects, the decision relating to manpower should be this second option. PMID- 8688650 TI - Dentinal diffusion of hydroxyl ions of various calcium hydroxide pastes. AB - The aim of this study was to analyze in vitro the dentinal diffusion of hydroxyl ions of calcium hydroxide pastes, prepared with different acid-base vehicles, in an inert nitrogen atmosphere. Sixty maxillary incisors with mature apexes were selected and after access and root canal preparation each root was filled with calcium hydroxide pastes prepared with different vehicles: saline solution, anesthetic and polyethylene glycol 400. The roots were then sectioned 2 mm from the apical vertex and the teeth mounted in the center of a round platform, filled with saline solution up to 2 mm from the root tip. The platforms remained inert in an atmosphere of nitrogen, completely sealed, in the absence of light and with a constant temperature of 36.5 degrees C. Diffusion analysis of the hydroxyl ions was carried out by a colorimetric method on days 7, 15, 30, 45 and 60. Calcium hydroxide pastes prepared with saline solution and anesthetic showed a pH change of 5-7 to 7-8 after 30 days, remaining at this level at 60 days. In the polyethylene glycol 400 group, the same alteration occurred at 45 days, and continued at 60 days. PMID- 8688652 TI - Squamous odontogenic tumor-like proliferation in residual cyst: case report. AB - A case of squamous odontogenic tumor-like proliferation (SOT-LP) in residual cyst is described. Based on clinico-pathological data, the relationship to the squamous odontogenic tumor (SOT) was analyzed. The possibility of SOT-LP representing an early manifestation of the squamous odontogenic tumor was discussed. PMID- 8688653 TI - Three-dimensional CT scan of hemimandibular hyperplasia: case report. AB - Three-dimensional images of craniofacial structures are reconstructed from conventional CT scans with the use of special computer software. These reconstructed images do not exhibit magnification nor superimposition of CT scans of structures. Quantitative measurements of three-dimensional craniofacial structures can be very precise. This technique has broad applications in the field of special patient care and is demonstrated in a case report of hemimandibular hyperplasia. PMID- 8688655 TI - Tensile bone strength of Panavia Ex to a Ni-Cr alloy using different surface treatments. AB - Panavia Ex resin has been claimed to require only air abrasion of the alloy with 50 micrometers aluminum oxide particles to reach acceptable bond strength values. This study discusses the consequences of changes in the type of air abrasion and surface oxidation of the alloy. Thirty pairs of discs of a Ni-Cr alloy were treated by three methods: 1) air abrasion with 50 micrometers aluminum oxide (control); 2) air abrasion with glass beads; 3) air abrasion with a mixture of aluminum oxide and glass beads (ratio 1:1). The Tukey test showed statistical differences only for air abrasion with glass beads. PMID- 8688654 TI - Hydroxylapatite and tricalcium phosphate implants in the dental alveolus of rats. A histometric study. AB - The objective of the present study was to analyze histomorphometrically the biological behavior of microgranular hydroxylapatite (HA 40), and tricalcium phosphate (TCP) implanted in the dental alveolus of rats. All three materials retarded alveolar repair when compared to controls, since less bone was formed during all periods of study. Nevertheless, MIC and TCP showed higher compatibility than HA 40. PMID- 8688656 TI - Bone morphology of the temporomandibular joint and its relation to dental occlusion. AB - The mandibular and temporal osseous components were analyzed in a sample of 30 dry skulls and their morphology was correlated with occlusal characteristics. In skulls with condyles of a more rounded shape, the depth of the fossa was greater. Furthermore, there was a significant correlation between greater depth of the fossa and skulls with normal overbite. However, no correlation was observed between depth of the fossa, tooth attrition and Spee curve. PMID- 8688657 TI - Iontophoresis: an alternative in the treatment of dental caries? AB - This study deals with some aspects of caries decay etiology and treatment using iontophoresis, when there is no cavity, and discusses remineralization of decayed teeth. PMID- 8688658 TI - Oral manifestations of diabetes mellitus in controlled and uncontrolled patients. AB - The authors studied the oral manifestations of a sample of 70 diabetic patients, divided into controlled and uncontrolled patients. Medical history and stomatological data were analyzed and diabetic controlled patients were matched to uncontrolled patients. The main symptoms observed were hyposalivation, taste alterations and burning mouth, with the main sign being parotid enlargement. The lesions observed were candidosis of the erythematous type and proliferative lesions both associated to the use of total prosthesis. No pathognomic lesions or alterations could be observed in relation to the disease. The frequency of carriers of Candida albicans and also the lesions observed could be compared to normal patients also using total dentures. PMID- 8688659 TI - Interruption of breast feeding caused by the presence of neonatal teeth. AB - The authors report the case of a 6-month old girl treated at the Pediatric Dentistry Clinic at the School of Dentistry of the Federal University of Rio de Janeiro. The patient's breast feeding was interrupted prematurely due to the presence of neonatal teeth. The authors have included a brief review of previous reports of this pathology. PMID- 8688660 TI - Radicular grooves in maxillary lateral incisor: case report. AB - The authors present a case report of a radicular groove in a maxillary lateral incisor in a 58-year old male patient. Endodontic and periodontal treatment was not carried out and therefore, avulsion of the tooth was indicated. The radicular grooves were very deep with pulp chamber communication. PMID- 8688661 TI - Osseous regeneration in the presence of fibrin adhesive material (Tissucol) and epsilon-aminocaproic acid (EACA). AB - The effects of Tissucol and Tissucol/EACA on bone healing were evaluated histologically. Experimental defects were made in both tibias of 25 rats. Test materials were placed in defects in right tibias and left tibias served as control. Five animals in each group were killed at 1, 3, 7, 14 and 21 days after surgery. Results showed that: a) Tissucol did not interfere with connective and osseous tissue formation; b) Tissucol allowed new bone formation; c) Tissue residues in Tissucol groups in sections of 21-day specimens did not impair healing; d) Tissucol/EACA was usually completely resorbed and healing was complete 21 days after surgery in the Tissucol/EACA group. PMID- 8688662 TI - Mechanism of action of calcium and hydroxyl ions of calcium hydroxide on tissue and bacteria. AB - The biological and bacteriological action of calcium hydroxide confer to its current success as an intracanal dressing. For this reason the mechanism of action of calcium and hydroxyl ions on tissue and bacteria deserves further study. The objective of the present paper is to analyze and discuss the mechanism of action of calcium and hydroxyl ions on anaerobic bacteria, starting from the isolated study of the influence of pH on these bacteria , as well as the mechanism of action of calcium hydroxide on tissue. PMID- 8688664 TI - Creation of the gingival immunologic defense index (GIDI) to evaluate the immunological potential of the gingiva and the possible risk for periodontal disease. AB - The objective of the present study was to create an index for the adequate evaluation of gingival immunological defense with respect to IgA levels. The gingival immunological defense index (GIDI), which is based on the simple count of the inflamed gingival surfaces of a child plus the measurement of salivary IgA content, provides clinicians with important information about the immunological defense potential of each subject. PMID- 8688663 TI - Effect of acyclovir on rat fetus palate mucosa. AB - Five pregnant rats were treated during organogenesis with sc injections of acyclovir (50 mg/kg body weight) on days 9, 10 and 11 of pregnancy. The fetuses (N=62) were evaluated on day 20 of gestation and presented decreased body weight as well as delayed differentiation of fetal rat palate epithelium, with increased nuclear volume, decreased cytoplasmic and cellular volumes, decreased epithelial and keratin thicknesses, and increased cellular numerical density. PMID- 8688665 TI - The immunopathology of psoriasis. AB - Psoriasis affects approximately 2% of the population in Western countries. Although clinically rather monomorphic, the disease presents with a number of phenotypically distinct and heterogeneous subgroups showing differences in their pathogenetic pathways. Patients with type I (early onset) psoriasis demonstrate inflammatory lesions with epidermal hyperproliferation and the presence of activated T cells as well as intraepidermal polymorphs as principal features. In contrast to pustular types of psoriasis, these patients show genetic susceptibility and strong association with MHC class I and class-I haplotypes. There is evidence for a T-cell-mediated pathomechanism leading to a large spectrum of regulatory mediators including cytokines and growth factors as well as lipid mediators which are abnormally expressed. Pathogenetically psoriasis shows features in common with chronic relapsing T-cell-mediated diseases including Crohn's disease, rheumatoid arthritis and others. PMID- 8688666 TI - Pathophysiology of allergic rhinitis. AB - Allergy rhinitis results from an IgE-mediated allergy associated with nasal inflammation of variable intensity. The mechanisms of allergic rhinitis have been clarified using nasal challenge with allergen or proinflammatory mediators and measuring cells and mediators released during the early- and late-phase allergic reaction. However, the priming effect of the nasal mucosa is of importance since a single challenge does not perfectly mimic the ongoing allergic reactions induced by repeated allergen exposure. In seasonal and chronic allergic rhinitis, the same cells and mediators are of importance but nonspecific nasal hyperreactivity develops. The regulation of the inflammation of allergic rhinitis is dependent on adhesion molecules and cytokines. PMID- 8688667 TI - Razi's report about seasonal allergic rhinitis (hay fever) from the 10th century AD. AB - Seasonal allergic rhinitis (hay fever) is considered a disease of the postindustrial revolution era. Clinical reports of patients are readily available from the 19th century starting with John Bostock's description of his own summer symptoms. Also patients with "rose catarrh' are described in the 16th and 17th century. Although asthma is well described by Maimonides, clear descriptions of diagnosis, prevention and treatment of hay fever are rare in the first millennium. This report by Razi (prior to 925 AD) is perhaps the earliest such report yet. It is contained in a compendium written by Ibn Sharabeyun ben Ibrahim in the 13th or 14th century AD. The volume also contains work by Avicenna (Abo Ali-Sina; a friend of Razi) and other contemporary writers. Some of the treatments suggested in this early report may not be so acceptable to modern sufferers. PMID- 8688668 TI - Effect of interleukin-10 on anti-CD40- and interleukin-4-induced immunoglobulin E production by human lymphocytes. AB - We studied the effect of IL-10 on the in vitro synthesis of IgE and IgG by human peripheral blood mononuclear cells (PBMC) following stimulation with anti-CD40 monoclonal antibody and IL-4. Anti-CD40- and IL-4-stimulated PBMC showed an increase in IL-10 synthesis together with increases in IgE and IgG production. Addition of anti-IL-10 antibody to this system suppressed IgE as well as IgG production without affecting the proliferation of PBMC. Addition of IL-10 enhanced IgE and IgG production if PBMC were activated with anti-CD40 and IL-4. PBMC costimulated with anti-CD40, IL-4 and IL-10 showed a remarkable increase in IL-6 production, but had no effect on IFN-gamma production. Addition of IL-10 to purified human tonsillar B cells stimulated with anti-CD40 and IL-4 enhanced B cell proliferation and IgG production, but not IgE production. These results suggest that IL-10 accelerates IgE production by anti-CD40- and IL-4-stimulated PBMC by enhancing IL-6 production through activation of T lymphocytes. PMID- 8688669 TI - Intraepithelial gamma/delta-positive T lymphocytes and intestinal villous atrophy. AB - We have evaluated the expression of different molecular forms of T cell antigen receptor (TcR) in duodenal biopsies of pediatric patients with different forms of villous atrophy: celiac disease, autoimmune enteropathy, intractable diarrhea of unknown origin, and severe cow milk intolerance. A panel of monoclonal antibodies recognizing alpha/beta and gamma/delta TcR (and gamma/delta TcR subsets) was used for immunostaining. The results showed an increase of T cells with gamma/delta type TcR in celiac patients and also in patients with other forms of villous atrophy with respect to normal controls. Amongst the gamma/delta TcR-positive cells, the subset expressing the molecular product of V delta 1 region was the most represented. The gamma/delta TcR-positive T cells were mainly located within the epithelium: few of them were observed in the lamina propria. On the basis of these results, we hypothesize that the increased homing of gamma/delta TcR positive T lymphocytes in gut epithelium observed in celiac disease is, at least in part, related to villous atrophy per se. PMID- 8688670 TI - Regulation of CD95 (APO-1) expression and the induction of apoptosis in human T cells: changes in old age. AB - CD95 (APO-1) is a member of the TNF/nerve growth factor receptor superfamily, which is expressed on the surface of different types of cells. Cross-linking of CD95 leads to the induction of apoptosis. This may be of importance in many physiological systems, but seems to play a special role for the maintenance of immunological homeostasis. In view of the known decline of immune function in old age it seemed of interest to study the expression and inducibility of CD95 in peripheral blood T lymphocytes from young and old healthy subjects selected according to the guidelines laid down in the Senieur protocol of the European Community's Concerted Action Programme on Aging. Resting T cells did not express CD95. T cell activation by anti-CD3 monoclonal antibody (OKT3) did, however, lead to a rapid increase in the number of CD95 expressing cells. This increase was slower and less pronounced in old healthy subjects than in young ones. The activation-induced increase in CD95 expression was followed by a decrease, which was observed in both age groups, but was less pronounced in old subjects. Under long-term culture conditions T cell lines derived from both young and old individuals progressively lost the capacity to decrease the expression of CD95 at the end of their activation cycle and an increasing susceptibility to activation driven programmed cell death was noted. The latter change was more pronounced in T cell lines derived from aged donors. The results suggest that a lowered sensitivity in the regulation of CD95 as well as an increased susceptibility to apoptosis-inducing mechanisms during clonal expansion are features of T cell senescence. PMID- 8688671 TI - Eosinophilia in Hodgkin's disease: a role for interleukin 5. AB - In order to clarify the mechanisms of the eosinophilia frequently observed in patients with Hodgkin's disease (HD), 18 patients and 16 age- and sex-matched controls were studied. Increased eosinophil numbers in peripheral blood and serum IgE, as well as decreased cell-mediated immunity were present in HD patients compared with control individuals. Advanced disease was accompanied by lower eosinophil levels, increased IgE, and lower CD4+ T cell counts in peripheral blood. Eosinophilia correlated with CD4+ T cell counts, suggesting that eosinophil production could be under CD4+ T cell control. GM-CSF production in vitro by Phytohemagglutinin-stimulated mononuclear cells was significantly lower in HD patients with eosinophilia. On the other hand, an eosinophil-survival enhancing activity was found in sera and culture supernatants from controls and HD patients; this activity was stronger for HD patients and was higher for those with eosinophilia. Furthermore, this activity was completely abolished by preincubation with monoclonal antibodies to IL-5, but not with normal mouse serum. Our results suggest that defects of cell-mediated immunity present in patients with HD are accompanied by a predominant type 2 cytokine profile. IL-5 is involved in the increased eosinophil production observed in these patients. PMID- 8688672 TI - Immunophenotypic analysis of HL-60 cells during basophilic differentiation. AB - Differentiation along specific myeloid lineages may be accompanied by characteristic cell surface marker changes. We have examined leukemic HL-60 cell changes under conditions which induce basophilic differentiation. An increased surface expression of CD35, CD11b, and decreased expression of CD15 was found by flow cytometry during the 5-day induction period. Further investigation revealed two cell populations after 5 days in vitro: (i) a CD35-positive population (61% of cells present) containing a significant number of CD15-negative cells, and (ii) a CD15-positive/CD35-negative population. The CD35-positive subset appears to account for the majority of the basophilic cells induced under these conditions, as measured by histamine content and metachromatic staining. In addition, this subset contains a small number of early monocytic cells (CD14 and CD23 positive). The expression of CD11b is variably found on the CD15-positive/ CD35-negative subset of induced cells. These results suggest that CD35 and CD15 surface immunophenotyping can be used to map steps involved in myeloid development. A role for CD35 and CD15 in early basophil differentiation is proposed. PMID- 8688673 TI - Basophil histamine release and leukotriene production in response to anti-IgE and anti-IgE receptor antibodies. Comparison of normal subjects and patients with urticaria, atopic dermatitis or bronchial asthma. AB - The IgE receptor-dependent in vitro mediator release in basophils is characterized by a large interindividual variability both in normal and atopic subjects. The mechanism and the clinical impact of this finding, however, is largely unclear. The aim of the present study was to examine the role of surface bound IgE and of response-modifying cytokines such as interleukin 3 (IL-3) as possible factors determining basophil releasability in atopic patients and normal controls. Cells from 30 individuals (6 with urticaria, 7 with asthma, 7 with atopic dermatitis, and 30 healthy controls) were isolated and stimulated for mediator release by IL-3 and different triggering antibodies directed against IgE or IgE receptor. Our data suggest that serum IgE levels and basophil receptor occupancy with IgE are not involved in the mechanism of basophil releasability. Furthermore, IL-3-induced similar effects on mediator release in almost all individuals, rather excluding the possibility that releasability is regulated by cytokine priming of basophils. Interestingly, we found that patients with atopic disease have a reduced capacity of releasing mediators upon activation, the mechanism of which is unclear. In conclusion, our findings support the hypothesis that basophil releasability is dependent on cell-imminent mechanisms in basophils, which may be altered in selected atopic patients. PMID- 8688674 TI - Inhibition of histamine synthesis by glycyrrhetinic acid in mast cells cocultured with Swiss 3T3 fibroblasts. AB - The effect of glycyrrhetinic acid (18-O-beta-glycyrrhetinic acid, GA) on histamine metabolism was investigated in cultured mast cells (CMCs) cocultured with Swiss 3T3 fibroblasts. GA strongly inhibited histamine synthesis in the cocultured CMCs. Since 50 microM GA inhibited about 80% of histidine decarboxylase (HDC) activity, the inhibitory activity of GA for histamine synthesis was considered to be derived from the inhibition of HDC activity. The number of berberine-sulfate-positive cells also decreased in the presence of GA, which indicated that maturation of CMCs was inhibited by GA. Furthermore, we examined the effect of GA on the mRNA expression of novel protein kinase C delta (nPKC delta), a major isoform of CMCs, by northern blot analysis. The expression of nPKC delta mRNA in the presence of GA was significantly lower than in the absence of GA. These results suggest the possibility that the inhibition of histamine synthesis by GA is regulated by nPKC delta. PMID- 8688675 TI - Inhibition of leukotriene synthesis by honokiol in rat basophilic leukemia cells. AB - The effects of honokiol, a diphenyl compound extracted from a Chinese herbal medicine, on leukotriene (LT) synthesis were evaluated in rat basophilic leukemia (RBL) cells. The production of LTC4 and LTB4 stimulated by the Ca2+ ionophore A23187 was measured in RBL-1 cells by high-performance liquid chromatography. Honokiol inhibited the production of LTC4 and LTB4 stimulated by A23187 in RBL-1 cells. Honokiol did not inhibit either phospholipase A2 activity, measured by the release of 3H-arachidonic acid (AA), or LTC4 synthase and LTA4 hydrolase activities, measured with LTA4-free acid as substrate. The synthesis of LTC4 and LTB4 from AA in RBL-1 cell lysates in the presence of Ca2+ was inhibited by honokiol. These results indicate that honokiol blocks LT synthesis by inhibiting 5-lipoxygenase activity. Honokiol also inhibited immunoglobulin E-mediated production of these LTs in RBL-2H3 cells, which was measured by a specific radioimmunoassay (RIA). These results suggest that honokiol may exhibit antiallergic actions by inhibiting LT synthesis in immediate-type hyperreactivity. PMID- 8688676 TI - High-level expression of tree pollen isoallergens in Escherichia coli. AB - cDNAs coding for the major allergen of alder (Alnus glutinosa) pollen Aln g 1, for nine isoforms of Bet v 1, the major birch (Betula verrucosa) pollen allergen, and for four isoforms of Cor a 1, the major allergen of hazel (Corylus avellana) pollen, were inserted into the plasmid pMW175 or pMW 172 and expressed in Escherichia coli as recombinant non-fusion proteins. These constructs produced between 20 and 160 mg protein/l. The recombinant tree pollen isoallergens were tested in immunoblots for their antibody binding properties. For this purpose, we used two monoclonal antibodies (BIP 1 and BIP 4) raised against natural Bet v 1, a polyclonal rabbit anti-recombinant Bet v 1a, as well as serum IgE from allergic patients. Our results show that this expression system is suitable for the production of milligram amounts of tree pollen isoallergens which can be used for the characterization of allergenic epitopes recognized by T and B cells. PMID- 8688677 TI - Purification and characterization of an allergenic monomeric hemoglobin from a chironomid distributed worldwide, Polypedium nubifer. AB - The Pol n component MV, a potent experimental allergen for mice, was purified to homogeneity from extracts of a chironomid distributed worldwide, Polypedium nubifer (PN). The Pol n I component MV was shown to have cross-reactivity to hemoglobins (Hb) derived from all species of chironomids tested. Determination of the amino acid sequence of the first 37 N-terminal residues revealed that it had 30-59% homology to Hb of an European chironomid, Chironomus thummi thummi, which had been known as an important allergen for humans. By Western blot analysis, we showed that sera from asthmatic patients, which had positively reacted to the extract of the adult PN midge, bound to the purified Pol n I component MV. Furthermore, using rabbit polyclonal antibodies raised against synthetic polypeptides corresponding to the N-terminal residues, it was demonstrated that the N-terminal amino acid sequence between position 15 and 35 contained antigenic epitope(s) for human IgE. The results indicate that the Pol n I component MV is an allergen for human beings as well as for mice, and useful as a diagnostic tool for chironomid allergy. PMID- 8688679 TI - More than just a pretty face. Workings of the CFP Editorial Advisory Board. PMID- 8688678 TI - Levels of soluble ICAM-1 are slightly elevated in the serum of patients with atopic dermatitis. PMID- 8688680 TI - Normal people with special needs. PMID- 8688681 TI - Getting more mileage out of your resident project. PMID- 8688682 TI - Comparing survey results. PMID- 8688683 TI - Women's health: getting the message across. PMID- 8688684 TI - Time to apply pressure. PMID- 8688685 TI - Setting the record straight. PMID- 8688686 TI - Carbon monoxide poisoning in pregnancy. PMID- 8688687 TI - Dermacase. Mucocele. PMID- 8688688 TI - Radiology rounds. Chondrocalcinosis. Pseudogut. Calcium pyrophosphate dihydrate. PMID- 8688689 TI - Dilemmas in care of the elderly. PMID- 8688691 TI - Lesbian health care needs. AB - OBJECTIVE: To define the special health care needs of Canadian lesbians. DESIGN: A questionnaire containing 61 yes-or-no and multiple-choice questions sought information on six areas: demographics; health care use; habits, diet, and exercise; preventive care; mental health; and physical health. SETTING: The organizational meeting of a lesbian softball league in Toronto. PARTICIPANTS: Of 360 women eligible for the meeting, 205 attended and 195 completed the survey. Questionnaires used for analysis were those of the 186 women who answered yes to the question, "Are you a lesbian?" MAIN OUTCOME MEASURES: How lesbian health care needs differ from those of women in general. Results of the survey were compared with results of the 1991 Canadian General Health Survey and the 1986 Health Promotion Survey (for comparable sex and age groups). RESULTS: The lesbians were young, white, and middle class. They visited the same health care professionals as other Canadian women but for different reasons. They smoked, drank alcohol, used caffeine, and exercised somewhat more than other women, but they were not very knowledgeable about healthy diets. The lesbians got Pap smears less often than other Canadian women, even if they were at high risk. They examined their breasts less frequently, but got their blood pressure checked with comparable frequency. Lesbians had a high incidence of mental health problems and often had nontraditional support systems. Lesbians were less prone to gynecologic complaints, especially infectious diseases, but had about the same incidence of common chronic illnesses. CONCLUSIONS: Although lesbians are not afflicted uniquely by any illness, they do have special health care needs. Canadian family physicians should be aware that lesbians are part of family practice and that, like other identifiable group, they have common health concerns that differ from those of the general population. PMID- 8688690 TI - Non-insulin-dependent diabetes mellitus among First Nations children. New entity among First Nations people of north western Ontario. AB - OBJECTIVE: To describe the emergence of a new clinical form of non-insulin dependent diabetes mellitus (NIDDM) among First Nations children. DESIGN: Case series developed through retrospective review of a computerized diabetes registry and of records from a hospital and clinic. SETTING: Sioux Lookout Zone Hospital, a secondary care referral hospital for 28 remote First Nations communities in northwestern Ontario, affiliated with the University of Toronto's Sioux Lookout Program. PARTICIPANTS: Eighteen First Nations youths younger than 16 years identified via the Sioux Lookout Diabetes Program registry and via hospital discharge records from 1978 to 1994. Three of the 18 subjects were excluded because data essential to the study were missing from their records. MAIN OUTCOME MEASURES: Prevalence of NIDDM in this population, clinical presentation at diagnosis, and associated risk factors (including family history, obesity, and clinical management). RESULTS: Age-adjusted prevalence was 2.5/1000 in this population, the highest yet reported for NIDDM in this age group. Ratio of female to male subjects was 6:1. Typical patients were asymptomatic, obese adolescents who were not prone to ketosis and whose families had a strong history of NIDDM. CONCLUSIONS: Non-insulin-dependent diabetes mellitus can occur during childhood, particularly among First Nations people. PMID- 8688692 TI - [Profile of biostatistics utilization in three medical reviews. Implications for medical education]. AB - OBJECTIVE: To identify the most commonly used biostatistical concepts and tests in three journals read by family physicians. DESIGN: Descriptive study of the biostatistical content of 12 issues of the Canadian Medical Association Journal (CMAJ), Canadian Family Physician (CFP), and the New England Journal of Medicine (NEJM). MAIN OUTCOME MEASURES: Frequency of citations of concepts and tests, and Spearman's correlation coefficients comparing the biostatistical profiles of the three journals. RESULTS: Biostatistical content of NEJM was diverse (on average, 39 concepts and 21 tests per issue). In CFP, we found 10 concepts and four tests per issue. In CMAJ, there were, on average, nine concepts and five tests per issue. CONCLUSIONS: The journals' profiles (order of importance of concepts and tests) were fairly similar. PMID- 8688693 TI - Cancer in remission. Challenge in collaboration for family physicians and oncologists. AB - OBJECTIVE: To explore oncologists' perspectives on the process of cancer patient follow up and to identify what oncologists need from family physicians during the remission stage of cancer disease. DESIGN: Qualitative study with in-depth interviews. SETTING: Regional cancer centre serving a catchment area of 1.4 million people. PARTICIPANTS: A purposive sample of 10 oncologists. One was unable to participate because of sabbatical leave. The nine who participated represented both radiation and medical oncology. Oncologists who had practised at the cancer centre for less than 2 years were excluded from the study. MAIN OUTCOME MEASURES: Existing barriers to communication and collaboration between oncologists and family physicians in cancer patient follow up. RESULTS: Oncologists described roles for themselves in reassuring patients, detecting recurrence, monitoring toxicity of treatment, and gathering data for clinical trials. Collaboration with family physicians in the remission phase was identified as desirable but inhibited by variable and unpredictable interest, poor communication with family physicians, and patients' own preferences for follow up. Oncologists perceived the cancer system structure as a "black box" within which multidisciplinary teams worked well but seldom included family physicians. Oncologists expressed a need to see healthy patients and to have more understanding and support from family physicians, preferably through sharing follow-up care. Developing dialogue and a more collaborative approach were suggested. CONCLUSIONS: Family physicians should maintain a role in remission follow-up. However, a more collaborative approach with oncologists is warranted. Communication barriers, patient preferences, and misperceptions between groups must be addressed before roles are redefined. PMID- 8688696 TI - Alcohol withdrawal at home. Pilot project for frail elderly people. AB - The need for safe, accessible, client-centred, alcohol withdrawal services for seniors was recognized by health service workers in Victoria. A partnership of health and support service organizations developed and implemented a pilot project for treating alcohol withdrawal in the home. The project provided service that integrated well with a substance-abuse treatment program for seniors. PMID- 8688695 TI - Dysphagia in the elderly. AB - OBJECTIVE: To review the problem of dysphagia in the elderly so that primary care physicians are better able to recognize and manage it. QUALITY OF EVIDENCE: Dysphagia, a prevalent problem in the elderly, causes significant morbidity and even mortality. Age-related deterioration of the oropharyngeal phase of swallowing is well documented. Diagnosis and treatment of dysphagia in the elderly is based mainly on clinical experience with large groups of patients. Few controlled clinical trials have been conducted. MAIN FINDINGS: Oropharyngeal dysphagia in the elderly is often due to irreversible neuromuscular disease. These patients benefit from swallowing therapy performed by speech pathologists. Esophageal causes of dysphagia are similar in the elderly and young patients, and the approach to treatment is also similar, although noninvasive forms of therapy play a larger role for elderly patients. CONCLUSIONS: Dysphagia is a common problem that lowers quality of life for the elderly. Primary care physicians must be aware of causes of dysphagia for which specific treatments are available, as well as of the role of nonspecific treatments offered by ancillary health professionals. PMID- 8688694 TI - Managing early presentation of rheumatoid arthritis. Systematic overview. AB - OBJECTIVE: To describe evidence-based management of patients presenting to family physicians with typical signs and symptoms of recent onset of rheumatoid arthritis (RA). STUDY SELECTION: Articles for critical review were included if relevant to primary care management of early RA (less than 1 year duration). Sources included MEDLINE from 1966 to December 1995, the reference library of the Arthritis Community Research and Evaluation Unit, and conference abstracts. FINDINGS: Evidence from randomized, controlled trials supports the short-term benefit of nonsteroidal anti-inflammatory drugs, disease-modifying agents for rheumatic diseases, intravenous pulse corticosteroid therapy, intra-articular therapy, aerobic exercise, patient education, psychologic intervention, home physiotherapy, home occupational therapy, and rehabilitation programs. Some evidence favours acetaminophen for analgesia, low-dose oral corticosteroids for symptom control, and referral to a rheumatologist. Evidence for rest, ice, and heat for symptom control is conflicting and based on low-quality studies. CONCLUSION: Family physicians play an important role in establishing early and accurate diagnosis of RA, coordinating therapy, and providing ongoing support, education, and monitoring to patients and their families. PMID- 8688697 TI - Drug management of Parkinson's disease. AB - Levodopa remains the cornerstone for managing Parkinson's disease. Physician's preference usually determines the dopamine agonist chosen for the early phases of treatment. The concept of neuro-protection, however, remains unproven. A better understanding of the cause of the disease and treatment-related complications could make managing Parkinson's disease more rewarding. PMID- 8688698 TI - Certification examination of the College of Family Physicians of Canada. Part 1: History and implications for the present and future. PMID- 8688699 TI - Latex allergy: a new threat to patients and health professionals. AB - Because latex products are essential in preventing the transmission of blood borne diseases, reports of severe, immediate allergic reactions to latex exposure have become a major public health concern. In recent years, immunoglobulin E (IgE)-mediated reactions to latex have been reported with increasing frequency and have been associated with anaphylaxis and death. The most severe reactions have been reported in the health care setting. Three groups appear to be at highest risk: children with spina bifida or with a history of multiple surgeries, workers with industrial exposure to latex and health care workers. This review presents the scope of this problem in the various risk groups, the different techniques available for diagnosis and the consensus on principles of management. Because latex is a component of many commonly used medical devices, including surgical and examination gloves, it behooves us to identify latex-sensitive patients and be prepared to treat allergic reactions promptly. PMID- 8688700 TI - Invasive Streptococcus pneumoniae infection associated with rapidly fatal outcome in Taiwan. AB - We observed 42 cases of invasive Streptococcus pneumoniae infections from 1991 through 1993 in southern Taiwan. The antimicrobial susceptibilities and distribution of serotypes of the 42 isolates from these invasive infections were determined. Serotypes 14, 3, 6, 23, 15 and 4 were most commonly identified. Serotypes 14 and 6 most frequently caused infections in pediatric patients, while serotypes 3, 14 and 23 were commonly encountered in adults. Overall, 85.7% of the isolates were included in the serotypes represented in the 23-valent pneumococcal vaccine. Three isolates were intermediately resistant to penicillin and none were fully resistant. Resistance rates were: erythromycin, 61.9%; clindamycin, 47.6%; chloramphenicol, 19%; and tetracycline, 73.8%. Resistance to three or more classes of antibiotics was found in 33.3% of the isolates, in which the majority were serotypes 14 and 6 and nontypeable isolates. Bacteremic pneumonia and primary bacteremia accounted for 64.3% of the infections. Mortality was 42.6%. Factors associated with higher mortality included age of > 16 years, the presence of underlying diseases, development of one or more septic complications, bacteremic pneumonia and the presence of serotype 3 isolates. Rapidly fatal outcome (the illness developed less than 48 hours prior to admission and the death occurred within 48 hours of hospitalization) occurred in 12 (66.7%) of the 18 patients who died. All these patients received adequate antibiotic treatment and aggressive intensive care, indicating the fulminant nature of this infection. Mucoid serotype 3 isolates caused rapidly fatal outcomes. Given the severity of these infections despite adequate antibiotic therapy and the vulnerability of patients with altered immune responses, there is a dire need for introduction of new therapeutic options and preventive measures to prevent mortality due to invasive S. pneumoniae infections. PMID- 8688702 TI - Computed tomography, endoscopic ultrasonography and intraoperative assessment in TN staging of gastric carcinoma. AB - In a prospective study from November 1989 to December 1993, the accuracy of computed tomography (CT), endoscopic ultrasonography (EUS) and intraoperative surgical assessment were compared for the evaluation of the depth of invasion (T category) and involvement of lymph nodes (N category) in patients with gastric carcinoma. Sixty-nine consecutive patients who received preoperative CT and EUS underwent subsequent surgery. CT and EUS results were compared with histopathologic staging of tumor invasion depth and regional lymph node metastasis (pT and pN categories). T categories were staged correctly in 42% of the cases by CT, 71% by EUS and 55% by intraoperative surgical assessment. CT correctly staged 49% of N1 and N2 lymph nodes compared with 65% for EUS and 45% for intraoperative surgical assessment. CT was more accurate for advanced cancer but had a tendency to understage the T and N categories. EUS was more accurate for serosal cancer and displayed a tendency to overstage T categories and understage N categories. Intraoperative surgical assessment overstaged early T stages, understaged the T4 stage and had a tendency to overstage N categories. CT and intraoperative surgical assessment of T and N categories were of limited value in the staging of gastric carcinoma compared to EUS. EUS is a valuable form of assessment to evaluate gastric cancer staging before surgery. PMID- 8688701 TI - Breast-conserving surgery and radiotherapy for early breast cancer. AB - Breast conservation is not a commonly prescribed treatment option for breast cancer in Taiwan. We report 42 patients with 43 early-stage breast cancers who were treated with breast-conserving surgery and radiotherapy at the Koo Foundation Sun Yat-Sen Cancer Center from April 1990 to December 1994. Included in this study were 33 patients with stage I cancers and 10 with stage II. Breast conserving surgery consisted of wide local excision and ipsilateral axillary lymph node dissection. Radiotherapy was given 2 to 6 weeks after surgery, with a dose of 46 to 50 Gy, 2 Gy per fraction per day, to the whole breast, and an additional 14 to 18 Gy to the original tumor site. Irradiation to the regional lymph nodes was not performed in patients with negative axillary lymph nodes. Sixteen out of 43 (37%) patients were treated with adjuvant chemotherapy. The local control rate 3 years after treatment was 97% and relapse-free survival was 91%. The cosmetic outcome in 41 treated breasts that were rendered relapse-free by conserving treatment were evaluated and graded by the physicians as excellent, good, fair or poor using a standardized scale. Forty breasts (98%) were scored as excellent or good for their cosmetic results. Breast-conserving surgery and radio therapy offer Taiwanese women with early breast cancer excellent local control and a highly satisfactory cosmetic outcome. PMID- 8688703 TI - Prenatal diagnosis of osteogenesis imperfecta congenita by ultrasonography. AB - As well as being a rare connective tissue disorder, osteogenesis imperfecta congenita (OIC) is also the most severe form of osteogenesis imperfecta (OI). We report a case that was diagnosed by sonography in a fetus at 22 weeks of gestation. The diagnosis was confirmed by postnatal radiography and autopsy. The prenatal sonographic findings were: short bowed femurs with fractures and thin skull with unusual clarity of intracranial structures. The postnatal radiography showed crumbled long bones and beaded ribs compatible with multiple fractures, similar to the prenatal sonographic findings. The major findings on autopsy were deformed skull and ribs and asymmetric deformity of the four extremities. The microscopic findings of the skeleton, including skull, vertebrae, ribs and long bones, revealed normal cartilagenous development but abnormal bone formation. The pathologic features of the skeleton were compatible with osteogenesis imperfecta type II, ie, OIC. Fractures and bone deformities are the cardinal symptoms of OIC which make intrauterine diagnosis possible. It should be differentiated from other types of OI (I, III and IV), as their prognoses are different. As OIC is lethal, the option of pregnancy termination should be offered at the time it is diagnosed. In the present report, termination by extraovular induction was performed immediately after OIC was noted on sonography. PMID- 8688704 TI - Hemolytic disease of the newborn caused by anti-M antibody. AB - An unusual case of hemolytic disease of the newborn caused by anti-M antibody is presented. Hyperbilirubinemia was noted in a full-term baby boy at 4 days of age. A total of 160 mL of M-positive packed red blood cells from the baby's father were transfused during the next 9 days and the hemolytic process became aggravated. The baby was referred to our hospital at 14 days of age. Maternal anti-M was detected and the baby was transfused with 50 mL of M-negative packed red blood cells. The baby's condition stabilized and he was discharged uneventfully at 18 days of age. PMID- 8688705 TI - Congenital anomalies following maternal varicella infection during early pregnancy. AB - We report a typical case of congenital varicella syndrome following a maternal varicella infection during the 10th week of pregnancy. The presenting symptoms in the small gestational age baby were: cicatricial skin lesion, Horner's syndrome,dysphagia with resulting aspiration pneumonia and delayed developmental milestones. Serologic studies revealed persistence of varicella zoster virus IgG for at least 10 months. Although congenital varicella syndrome is rare, it should be kept in mind when counseling families where maternal varicella infection has occurred during the first 20 weeks of gestation. A maternal history of varicella infection, typical manifestations and serologic proof are crucial in the diagnosis of congenital varicella syndrome. PMID- 8688706 TI - Functional MRI of the activated human visual cortex. AB - We explored the possibility of performing functional magnetic resonance imaging of visual evoked response in the primary visual cortex with a clinical MRI imager of 1.5 tesla. Gradient echo pulse sequence was chosen to acquire the functional image and binocular flash visual stimulation by light-proof goggles containing light emitting diodes was used as the source of cerebral activation. Data processing was performed utilizing direct subtraction for averaged images, correlation coefficient, statistical parametric mapping and matched filter. Of those methods, correlation coefficient and statistic parametric mapping proved to be the methods of choice in our study. PMID- 8688707 TI - High-resolution computed tomography in pulmonary lymphangio(leio)myomatosis and pulmonary tuberous sclerosis. AB - We report two cases where high-resolution computed tomography (HRCT) assisted in the diagnosis of a patient with lymphangioleiomyomatosis and a patient with pulmonary tuberous sclerosis. HRCT was used in both cases where the chest radiographs and conventional computed tomographic scans appeared relatively normal but the conditions were strongly suspected. PMID- 8688708 TI - Eosinophilic gastroenteritis with esophageal involvement. AB - Eosinophilic gastroenteritis is an unusual disease entity characterized by eosinophilic infiltration of the gut with gastrointestinal disturbance. The disease commonly involves the stomach and small bowel. Esophageal involvement is rarely reported. We present a patient with simultaneous achalasia, pyloric stenosis, and ascites. Macroscopically, the esophagus, stomach and small intestine were involved. Microscopically, the mucosa was involved to the serosa. The patient has remained well under low dose prednisolone treatment for 7 years since his condition was diagnosed. PMID- 8688710 TI - Infections in febrile granulocytopenic patients: clinical features and pathogens. AB - From 1990 to 1994, we prospectively evaluated patients with cancer or aplastic anemia who had granulocyte counts of less than 500/mm3 and fever, in order to study infections in febrile granulocytopenic patients in Taiwan. A total of 100 episodes in 95 patients were evaluated. Aerobic Gram-negative bacilli were responsible for 72.5% of the 80 organisms identified in the infections. Escherichia coli was the most common isolate, accounting for 46.5% of Gram negative bacilli. Pseudomonas aeruginosa and Klebsiella spp caused 24.1% and 18.9% of these infections, respectively. Aerobic Gram-positive cocci were responsible for 12.5% of the 80 organisms identified in the infections. Fungal infections were responsible for 8.8% of isolates. Septicemia, predominantly due to Gram-negative bacilli, accounted for 39 episodes. Infection sites included the respiratory tract, urinary tract, skin and soft tissue, oral cavity, intestines, anus and ear canal. Identification of the pathogens and their clinical features is important in the immediate treatment of such infections. PMID- 8688709 TI - Alimentary tract duplications. AB - A total of 17 patients with alimentary tract duplications underwent surgery at National Taiwan University Hospital from 1978 to 1994. Fifteen patients (88%) had gastrointestinal duplication and two (12%) had esophageal duplication. Common presenting symptoms of gastrointestinal duplication were melena and abdominal pain. The ileum was the most common site of duplication. Multiple duplications were seen in three patients. All duplications were cystic, except for one single appendiceal duplication. Ectopic gastric mucosa was detected in nine of the 16 nongastric duplications. One patient with ileal duplication had ectopic pancreatic tissue. Twelve patients received resection of the duplication with a segment of bowel and primary anastomosis, three patients underwent simple excision and two patients had partial resection of the duplication and stripping of the residual mucosa. Two patients had other associated congenital anomalies: one had ventricular septal defect and the other, imperforate anus and malrotation of intestine. There was no operative mortality or morbidity in this series. PMID- 8688711 TI - Quality of medical care for noninsulin-dependent diabetic patients in a community teaching hospital in Taiwan. AB - To evaluate the quality of diabetes management provided by a community teaching hospital in Taipei County, the medical records of 208 noninsulin-dependent diabetes mellitus (NIDDM) patients who attended the Department of Internal Medicine, Taiwan Provincial Taipei Hospital, from July to December 1994, were selected at random and reviewed. First visit examination results were compared to the practice guidelines established by the Diabetes Association, Taiwan ROC. The frequency of biochemical tests within the last 3 years was traced for 142 NIDDM patients who had been treated regularly in the hospital. Physicians knowledge and attitudes towards diabetes management were assessed by a questionnaire. The results revealed that the practice guidelines were not followed closely by the physicians. Urinalysis, glycosylated hemoglobin A1c and high-density lipoprotein cholesterol were the items most frequently neglected. Chest x-rays, electrocardiograms, hemograms and serum electrolytes were seldom arranged for patients without specific symptoms. Although not recommended in the guidelines, most of the physicians arranged liver function tests for their patients. Factors such as physicians knowledge and attitudes, medical insurance, high patient loads and educational levels of patients influenced medical behavior in this study. The results of the study showed that the quality of medical care for diabetes mellitus patients in this community hospital should be improved. PMID- 8688712 TI - Food-borne disease outbreaks in Taiwan, 1994. AB - In 1994, 102 outbreaks of food-borne disease involving 4,726 cases were reported to the Taiwan Department of Health. This is the highest number of outbreaks and cases in recent years in Taiwan. Of these outbreaks, 72.5% (74/102) were caused by bacterial pathogens, with Vibrio parahaemolyticus responsible for 56.7% (42/74), Staphylococcus aureus 20.3% (15/74), Bacillus cereus 14.9% (11/74) and Salmonella spp other than S. typhi and S. paratyphi 8.1% (6/74). V. parahaemolyticus has been a leading cause of problems in Taiwan for many years. Contamination of seafood with this organism has been reported frequently, particularly in the warmer months. In 1994, small outbreaks (fewer than 5 cases) and large outbreaks (more than 50 cases) represented 31.4% (32/102) and 12.7% (13/102), respectively, of the total. The median outbreak size was 10 cases. A high proportion (54%, 7/13) of the large outbreaks was associated with commercial lunch-boxes supplied to elementary and junior high schools. Health education to improve food sanitation and supervision of food sanitation practices need to be strengthened. PMID- 8688713 TI - Anabolic steroid abuse by body builders and male subfertility. PMID- 8688714 TI - What an old age psychiatrist does. PMID- 8688715 TI - Launching the Nigerian edition of the BMJ: implications for Nigeria's health care. PMID- 8688716 TI - Measurement error proportional to the mean. PMID- 8688717 TI - Misconduct in research. Medical Research Council is setting up rigorous procedures. PMID- 8688718 TI - Misconduct in research. Misconduct is not reported in biomedical journals in France. PMID- 8688719 TI - Misconduct in research. Profession must police itself. PMID- 8688720 TI - Double reading of screening mammograms will have resource implications. PMID- 8688721 TI - Endothelium dependent arterial dilatation in non-insulin dependent diabetes. Author's finding is not new. PMID- 8688722 TI - Low blood pressure is unlikely to be complication of dementia process. PMID- 8688723 TI - Providing intensive care. Authors misinterpreted results of study that they cited. PMID- 8688724 TI - Providing intensive care. Criticisms of situation in Birmingham are unsubstantiated. PMID- 8688725 TI - GPs' views of consultants' non-urgent referral of patients to other consultants. Time is wasted if GPs make the second referral. PMID- 8688726 TI - GPs' views of consultants' non-urgent referral of patients to other consultants. GPs' participation in decisions about non-urgent tertiary referral is appropriate. PMID- 8688727 TI - Urological emergencies in general practice. Herpes simplex not mentioned as cause of acute urinary retention. PMID- 8688728 TI - Urological emergencies in general practice. Simple test diagnoses or excludes epididymo-orchitis. PMID- 8688729 TI - Urological emergencies in general practice. Symptoms and diagnoses should have been distinguished. PMID- 8688730 TI - Centres that work with cochlear implants listen to views of deaf community. PMID- 8688731 TI - Minerva's comment was not evidence based. PMID- 8688732 TI - Reservations about conservative surgery for early breast cancer are unjustified. PMID- 8688733 TI - Evidence used to formulate guidelines on managing asthma did not include costs. PMID- 8688734 TI - Evidence based general practice. Drug treatment in general practice in Japan is evidence based. PMID- 8688735 TI - Evidence based general practice. Findings of study should prompt debate. PMID- 8688736 TI - Evidence based general practice. Studies using more sophisticated methods are needed. PMID- 8688737 TI - Over the counter drugs. Both doctors and pharmacists should prescribe better. PMID- 8688738 TI - Over the counter drugs. Working party will see whether antimicrobials should be available. PMID- 8688739 TI - Over the counter drugs. GPs' rate of recommending over the counter drugs varies. PMID- 8688740 TI - Over the counter drugs. GPs lack awareness of non-steroidal anti-inflammatory drugs available over the counter. PMID- 8688742 TI - Errors by locums. Each locum should carry a logbook. PMID- 8688743 TI - Adulterants of herbal products can cause poisoning. PMID- 8688741 TI - Over the counter drugs. Telematics will be useful in providing information. PMID- 8688744 TI - Errors by locums. Histopathology departments already audit diagnostic errors. PMID- 8688745 TI - Unicef should do more in Sri Lanka. PMID- 8688746 TI - Oral contraceptives and breast cancer. PMID- 8688747 TI - Guidelines for managing raised blood pressure. PMID- 8688748 TI - Extreme poverty: an obligation ignored. PMID- 8688749 TI - Joint responsibility: the need for a national arthroplasty register. PMID- 8688750 TI - Vaccines, malaria, and a host of resistance. PMID- 8688751 TI - Labour's draft election manifesto. PMID- 8688752 TI - Human papilloma-virus classified as carcinogenic. PMID- 8688753 TI - Epidemic of acute renal failure in Haiti. PMID- 8688754 TI - Cyclospora outbreak in US. PMID- 8688756 TI - Revisiting the Medicare crisis. PMID- 8688755 TI - AIDS message not getting through to young gay men. PMID- 8688757 TI - Randomised placebo controlled trial of effect on mood of lowering cholesterol concentration. Oxford Cholesterol Study Group. AB - OBJECTIVE: To evaluate the effects on mood of a substantial and prolonged reduction in total cholesterol concentration. DESIGN: Randomised placebo controlled comparison of patients who had been allocated to receive simvastatin 20 mg or 40 mg daily versus those allocated matching placebo in a ratio of 2:1. Follow up at an average of 152 weeks after randomisation. SUBJECTS: Men and women aged between 40 and 75 years at entry with blood total cholesterol of 3.5 mmol/l or greater, who were considered to be at higher than average risk of coronary heart disease based on medical history. MAIN OUTCOME MEASURES: The shortened profile of mood states questionnaire, reported use of psychotropic medication, and symptoms possibly related to mood. RESULTS: Simvastatin reduced total cholesterol by 1.9 mmol/l (26.7%) at the time of follow up. Among all 621 patients randomised to simvastatin (414 patients) or placebo (207 patients) there were no significant differences in the use of psychotropic medication or in reports of symptoms possibly related to mood. Of these patients, 491 (334 simvastatin, 157 placebo) completed the mood questionnaire, and there were no significant differences between the treatment groups in total or subscale scores, even when patients with low baseline cholesterol concentrations or elderly subjects were considered separately. CONCLUSION: These results do not support the hypothesis that treatment to lower cholesterol concentration causes mood disturbance. PMID- 8688758 TI - Cardiovascular risk factors in British children from towns with widely differing adult cardiovascular mortality. AB - OBJECTIVE: To examine whether cardiovascular risk factors differ in children from towns in England and Wales with widely differing adult cardiovascular death rates. DESIGN: School based survey conducted during 1994 in 10 towns, five with exceptionally high adult cardiovascular mortality (standardised mortality ratio 131-143) and five with exceptionally low adult cardiovascular mortality (64-75). Towns were surveyed in high-low pairs. SUBJECTS: 3415 white children aged 8-11 years with physical measurements (response rate 75%), including 1287 with blood samples (response rate 64%), of whom 515 had blood samples taken 30 minutes after a glucose load. RESULTS: Children in towns with high cardiovascular mortality were on average shorter than those in towns with low mortality (mean difference 1.2 cm; 95% confidence interval 0.3 to 2.1 cm; P = 0.02) and had a higher ponderal index (0.34 kg/m3; 0.16 to 0.52 kg/m3; P = 0.006). Mean systolic pressure was higher in high mortality towns, particularly after adjustment for height (2.0 mm Hg; 0.8 to 3.2 mm Hg; P = 0.009). Mean waist:hip ratio, total cholesterol concentration, and 30 minute post-load glucose measurements were similar in high and low mortality towns. The differences in height and blood pressure between high and low mortality towns were unaffected by standardisation for birth weight. CONCLUSIONS: The differences in height, ponderal index, and blood pressure between towns with high and low cardiovascular mortality, if persistent, may have important future public health implications. Their independence of birth weight suggests that the childhood environment rather than the intrauterine environment is involved in their development. PMID- 8688760 TI - Effect of smoking cessation on plasma ascorbic acid concentration. PMID- 8688759 TI - Dietary fat and risk of coronary heart disease in men: cohort follow up study in the United States. AB - OBJECTIVE: To examine the association between fat intake and the incidence of coronary heart disease in men of middle age and older. DESIGN: Cohort questionnaire study of men followed up for six years from 1986. SETTING: The health professionals follow up study in the United States. SUBJECTS: 43 757 health professionals aged 40 to 75 years free of diagnosed cardiovascular disease or diabetes in 1986. MAIN OUTCOME MEASURE: Incidence of acute myocardial infarction or coronary death. RESULTS: During follow up 734 coronary events were documented, including 505 non-fatal myocardial infarctions and 229 deaths. After age and several coronary risk factors were controlled for significant positive associations were observed between intake of saturated fat and risk of coronary disease. For men in the top versus the lowest fifth of saturated fat intake (median = 14.8% v 5.7% of energy) the multivariate relative risk for myocardial infarction was 1.22 (95% confidence interval 0.96 to 1.56) and for fatal coronary heart disease was 2.21 (1.38 to 3.54). After adjustment for intake of fibre the risks were 0.96 (0.73 to 1.27) and 1.72 (1.01 to 2.90), respectively. Positive associations between intake of cholesterol and risk of coronary heart disease were similarly attenuated after adjustment for fibre intake. Intake of linolenic acid was inversely associated with risk of myocardial infarction; this association became significant only after adjustment for non-dietary risk factors and was strengthened after adjustment for total fat intake (relative risk 0.41 for a 1% increase in energy, P for trend < 0.01). CONCLUSIONS: These data do not support the strong association between intake of saturated fat and risk of coronary heart disease suggested by international comparisons. They are compatible, however, with the hypotheses that saturated fat and cholesterol intakes affect the risk of coronary heart disease as predicted by their effects on blood cholesterol concentration. They also support a specific preventive effect of linolenic acid intake. PMID- 8688761 TI - Hepatotoxicity associated with herbal tablets. PMID- 8688762 TI - Rapidly reversible increase in insulin requirement with interferon. PMID- 8688763 TI - What constitutes controlled hypertension? Patient based comparison of hypertension guidelines. AB - OBJECTIVES: To investigate and quantify the extent to which variations in guidelines influence assessment of control of hypertension. DESIGN: Cross sectional study. Selected patients had hypertension assessed as controlled or uncontrolled with guidelines from New Zealand, Canada, the United States, Britain, and the World Health Organisation. SETTING: 18 general practices in Oxfordshire. SUBJECTS: 876 patients with diagnosed hypertension and taking antihypertensive drugs. MAIN OUTCOME MEASURES: Proportion of patients with controlled hypertension according to each set of guidelines. RESULTS: The proportion of patients with controlled hypertension varied from 17.5% to 84.6% with the different guidelines after adjustment for the sampling method. All five sets of guidelines agreed on the classification for 31% (277) of the patients. The New Zealand guidelines calculate an absolute risk of a cardiovascular event. When this was taken as the standard half of the patients with uncontrolled hypertension by the United States criteria would be treated unnecessarily and 31% of those classified as having controlled hypertension by the Canadian guidelines would be denied beneficial treatment. CONCLUSIONS: Hypertension guidelines are inconsistent in their recommendations and need to make clear the absolute benefits and risks of treatment. PMID- 8688765 TI - Managed care and disease management in the NHS. PMID- 8688764 TI - Tobacco control. PMID- 8688766 TI - Physical activity and health. PMID- 8688767 TI - A primary care market? PMID- 8688768 TI - Vitamins in early pregnancy. PMID- 8688769 TI - Postmenopausal cystitis. PMID- 8688770 TI - HIV pre-test discussion. PMID- 8688771 TI - Complementary medicine is booming worldwide. PMID- 8688772 TI - Back up drug found for severe malaria. PMID- 8688773 TI - Sex related differences in short and long-term prognosis after acute myocardial infarction: 10 year follow up of 3073 patients in database of first Danish Verapamil Infarction Trial. AB - OBJECTIVE: To re-examine the prevailing hypothesis that women fare worse than men after acute myocardial infarction. DESIGN: 10 year follow up of all patients with confirmed acute myocardial infarction registered in the database of the Danish verapamil infarction trial in 1979-81. SETTING: 16 coronary care units, covering a fifth of the total Danish population. PATIENTS: 3073 consecutive patients with acute myocardial infarction, 738 (24%) women and 2335 (76%) men. MAIN OUTCOME MEASURES: Early mortality (before day 15). For patients alive on day 15: mortality, cause of death, admission with recurrent infarction, and mortality after reinfarction. RESULTS: Early mortality increased significantly with age (P < 0.0001) but was not significantly related to sex, with a 15 day mortality of 17% in women and 16% in men. Adjustment for age and sex simultaneously revealed a significant interaction (P = 0.02) between these variables, with a greater increase with age in early mortality for men than for women (early mortality was equal for the two sexes at age 64 years). Ten year mortality in patients alive on day 15 was 58.8%. The overall age adjusted hazard ratio (95% confidence interval) for women versus men was 0.90 (0.80 to 1.01); 0.90 (0.78 to 1.04) for 10 year reinfarction (48.8%); and 0.98 (0.82 to 1.16) for 10 year mortality after reinfarction (82.3%). No difference in cause of death was found between the sexes. With a follow up of up to 10 years for patients alive on day 15 mortality, rate of reinfarction, and mortality after reinfarction increased with increasing age (P < 0.0001). CONCLUSION: Sex by itself is not a risk factor after acute myocardial infarction. PMID- 8688774 TI - Efficacy of a small single dose of oral dexamethasone for outpatient croup: a double blind placebo controlled clinical trial. AB - OBJECTIVE: To assess the efficacy of a single dose of oral dexamethasone 0.15 mg/kg in children with mild croup not admitted to hospital. DESIGN: Double blind, randomised, placebo controlled clinical trial. SETTING: The emergency department of a tertiary paediatric hospital. SUBJECTS: 100 children aged 4-122 months presenting with mild croup. INTERVENTION: A single oral dose of dexamethasone 0.15 mg/kg or placebo. MAIN OUTCOME MEASURE: Return to medical care with ongoing croup. RESULTS: Baseline characteristics of the two treatment groups were similar. Eight children (all from the placebo group) returned to medical care with ongoing croup, one being admitted. There was no reported difference in duration of croup symptoms, duration of viral symptoms, or rate of return to medical care for other reasons. CONCLUSION: Oral dexamethasone in a dose of 0.15 mg/kg is effective in reducing return to medical care with ongoing croup in children with mild croup. PMID- 8688775 TI - Chronic memory impairment after cardiac arrest outside hospital. AB - OBJECTIVES: To evaluate the nature, prevalence, and severity of chronic memory deficit in patients resuscitated after cardiac arrest outside hospital and to determine whether such deficits are related to duration of cardiac arrest. DESIGN: Case-control study. SUBJECTS: 35 survivors of cardiac arrest outside hospital and 35 controls matched for age and sex who had had acute myocardial infarction without cardiac arrest. MAIN OUTCOME MEASURES: Subjects assessed at least two months after index event for affective state (hospital anxiety and depression scale), premorbid intelligence (national adult reading test), short term recall (digit recall test), and episodic long term memory (Rivermead behavioural memory test). RESULTS: Cases and controls showed no difference in short term recall. Cases scored lower on Rivermead test than controls (mean (SD) score out of 24 points: 17.4 (5.4) v 21.8 (2.0), P < 0.001), particularly in subtests relating to verbal and spatial memory. Moderate or severe impairment was found in 37% of cases and in no controls. Severity of impairment of memory correlated significantly with measures of duration of cardiac arrest. This deficit was not significantly associated with subjects' age, interval from index event to assessment, occupation, measures of comorbidity, social deprivation, anxiety or depression scores, or estimated premorbid intelligence. CONCLUSIONS: Clinically important impairment of memory was common after cardiac arrest outside hospital. Improvement in response times of emergency services could reduce the severity of such deficits. With an increasing numbers of people expected to survive cardiac arrest outside hospital, rehabilitation of those with memory deficit merits specific attention. PMID- 8688776 TI - Blood pressure and risk of stroke in patients with cerebrovascular disease. The United Kingdom Transient Ischaemic Attack Collaborative Group. PMID- 8688777 TI - Influence of ethnic group on asthma treatment in children in 1990-1: national cross sectional study. AB - OBJECTIVE: To examine the extent to which the prescription of drugs for asthma adhered to recommended guidelines in 1990-1 and to assess the influence of ethnic group on prescription. DESIGN: Cross sectional. SETTING: Primary schools in England and Scotland in 1990-1. SUBJECTS: Children aged mainly 5-11 years. The representative samples included 10628 children. The inner city sample included 7049 children, 4866 (69%) from ethnic minority groups. For the prevalence estimation 14490 children were included in the analysis (82% of the eligible children). For the treatment analysis a subgroup of 5494 children with respiratory symptoms was selected. MAIN OUTCOME MEASURES: Prevalence of respiratory symptoms and drugs commonly prescribed for asthma, method of administration, inappropriate treatment, and odds ratios to assess the effect of ethnic group on rate of prescription and method of administration. RESULTS: Children with respiratory symptoms in the inner city sample were less likely to be diagnosed as having asthma. Of children with reported asthma attacks, those in inner city areas had a higher risk of not having been prescribed any drug for asthma (odds ratio 1.87 (95% confidence interval 1.26 to 2.77). Overall, 773 (75%) of these children had received a beta 2 agonist, 259 (25%) had received steroids, 148 (14%) had received sodium cromoglycate, and 194 (19%) had received no drug treatment in the previous year. When prescribed, beta 2 agonists were inhaled in 534 (69%) of cases, and this percentage was even lower in ethnic minority groups. Children of Afro-Caribbean and Indian subcontinent origin who had asthma were less likely to receive beta 2 agonists, and those from the Indian subcontinent were less likely to receive anti-inflammatory drugs. Antibiotics were less prescribed and antitussives more prescribed in children from ethnic minority groups than in white children. CONCLUSION: In 1990-1 the risk of underdiagnosis and undertreatment of asthma was higher in children from ethnic minority groups. The implementation of indicators and targets to monitor inequalities in the treatment of asthma in ethnic groups could improve equity and effectiveness in the NHS. PMID- 8688778 TI - Home ventilation of a child with motor and sensory neuropathy. PMID- 8688779 TI - Some legal aspects of mental capacity. AB - This article discusses some practical matters which arise when competence to make decisions is in question. Consent, testamentary capacity, powers of attorney, the Court of Protection, "living wills," and research on people with dementia are briefly considered. PMID- 8688780 TI - The rise of counselling and the return of alienism. AB - Current services for those with mental disorders show two trends. Psychiatric services are becoming concentrated on the care of those with "severe mental illness," largely (but unjustifiably) synonymous with chronic psychosis. The retreat of psychiatry from the care of those with non-psychotic mental disorders has helped the growth of counselling services for these patients. However, there is no evidence that non-directive counselling is effective for such disorders, in contrast to the evidence for the effectiveness of other treatments that are usually delivered by psychologists or community psychiatric nurses. By retreating from the concerns of general practice and general medicine, psychiatry is returning to the days of alienism: in Victorian terms, the care of "the mad." Possible consequences include increasing expectations of psychiatric services that cannot be met, a loss of skills within psychiatry, and increased demoralisation in the mental health services. PMID- 8688781 TI - ABC of work related disorders. Hazards of work. PMID- 8688782 TI - Bed occupancy in psychiatric units in greater London is 113%. PMID- 8688783 TI - Effect of antihypertensive treatment on cognitive function of older patients. Effect is not proved. PMID- 8688784 TI - Reduced schedule of antenatal visits. Differences in psychosocial outcomes between groups were not large. PMID- 8688785 TI - Reduced schedule of antenatal visits. Study ignored influence of parity on women's needs. PMID- 8688786 TI - Reduced schedule of antenatal visits. Effect of fewer visits on postnatal depression is important. PMID- 8688787 TI - Reduced schedule of antenatal visits. Attention should be paid to what women want. PMID- 8688788 TI - Reduced schedule of antenatal visits. Postnatal care also requires evaluation. PMID- 8688789 TI - Recent advances in ophthalmology are not solely technological. PMID- 8688790 TI - Evidence based medicine. Rich sources of evidence are ignored. PMID- 8688791 TI - Evidence based medicine. Scientific method and raw data should be considered. PMID- 8688792 TI - Evidence based medicine. Authors' redefinition is better but not perfect. PMID- 8688793 TI - Evidence based medicine. Needs to be within framework of decision making based on decision analysis. PMID- 8688794 TI - Evidence based medicine. Cost effectiveness and equity are ignored. PMID- 8688795 TI - Bovine spongiform encephalopathy. Disease is due to pressure on farming industry. PMID- 8688796 TI - Bovine spongiform encephalopathy. Media coverage had shortlived effect on beef consumption by pregnant women. PMID- 8688797 TI - Bovine spongiform encephalopathy. Doctors are less likely than patients to have stopped eating beef. PMID- 8688798 TI - Rehabilitation after brain injury. Author's experience is not unique... PMID- 8688799 TI - Rehabilitation after brain injury...or new. PMID- 8688800 TI - Laboratory tests for Helicobacter pylori should be more widely available. PMID- 8688801 TI - Drop out rate in medical schools seems reasonable. PMID- 8688802 TI - Epidemiology of aortic aneurysm and peripheral vascular disease may show ethnic differences. PMID- 8688803 TI - Temperature-dependent sex determination: the interplay of steroid hormones and temperature. AB - Sex determination is the product of coordinated gene expression. Mutational analyses have yielded great progress in our understanding of mammalian sex determination, and insight into the evolution of this sex chromosome system would be valuable. Mammals arose from turtle-like reptiles, and in many turtles the incubation temperature of the egg determines the sex of the offspring, a process known as temperature-dependent sex determination. There is mounting evidence that sex steroid hormones are the physiological equivalent of incubation temperature and serve as the proximate trigger for male and female sex determination. Temperature appears to accomplish this end by acting on genes coding for steroidogenic enzymes and sex steroid hormone receptors. The ability to manipulate sex determination in turtles both by temperature and by sex steroid hormones extends our understanding of the evolution as well as the physiology and molecular biology of sex determination. PMID- 8688804 TI - A triplex DNA structure of the polypyrimidine: polypurine stretch in the 5' flanking region of the sea urchin arylsulfatase gene. AB - Previously we reported that a long (522 bp) polypyrimidine: polypurine stretch in the 5' flanking region of the arylsulfatase gene of the sea urchin, Hemicentrotus pulcherrimus, took an unusual, perhaps triplex, DNA structure, when subjected to an acidic pH (pH 5) (Yamamoto et al., 1994). In the present study we have isolated a polypyrimidine: polypurine containing fragment from the arylsulfatase gene and surveyed the sensitivities of the polypyrimidine: polypurine stretch to base modification by diethylpyrocarbonate and osmium tetroxide under various levels of negative supercoiling. Based on the sensitivity of highly negatively supercoiled DNA to these base-modifying reagents, we conclude that, when highly negatively supercoiled, the polypyrimidine: polypurine stretch can take a triplex DNA structure even at a neutral pH and under physiological ionic strength in the presence of Mg2+. PMID- 8688805 TI - Cloning of mRNA sequences for two antibacterial peptides in a hemipteran insect, Riptortus clavatus. AB - Escherichia coli injection rapidly induced bactericidal activity in the hemolymph of a hemipteran insect, Riptortus clavatus. This activity reached its maximum at 9 hr after injection and thereafter declined slowly. Two types of cDNA clones involved in this response were isolated by differential screening. The predominant type encoded for an open reading frame of 678 amino acids, which consisted of fourteen tandem repeats. Each repeat was rich in charged residues and had a proline-rich region which had striking sequence similarities to proline rich antibacterial peptides from other insect species, indicating these clones encode a multipeptide precursor of antibacterial peptides. The other type encoded for a glycine-rich peptide similar to a known antibacterial peptide as well. Northern blot analyses revealed rapid induction of mRNAs corresponding to these clones after the injection. To our knowledge, this is the first report on the mRNA sequences of antibacterial peptides of hemimetabolous insects, and the second report on the occurrence of multipeptide precursor structure in insect antibacterial peptides. PMID- 8688806 TI - Molecular cloning of a partial cDNA clone encoding the C terminal region of chicken breast muscle connectin. AB - The cDNA sequence encoding the C terminal region of chicken skeletal muscle connectin was described. Its predicted amino acid sequence had 1,021 amino acids comprising six motif Ils (Immunoglobulin C2 domain) and five interdomains. The sequence showed 70-75% homology with that of human cardiac connectin, but 168 amino acids including one motif II were missing in chicken skeletal muscle connectin. The C terminal sequence of chicken skeletal muscle connectin reported by the previous work (Maruyama et al., 1994) was erroneous due to the accidental ligation of the cDNA clone encoding a N terminal region of connectin with a partial porin cDNA clone. PMID- 8688807 TI - Nucleotide sequence of a cDNA coding for cyclophilin of the sea urchin Hemicentrotus pulcherrimus. AB - We present the nucleotide sequence of a cDNA coding for cyclophilin homologue of the sea urchin Hemicentrotus pulcherrimus. The 1,755-nucleotide sequence contains a 492-bp open reading frame corresponding to a translation product of 164 amino acids. Comparison of the deduced amino acid sequence with the previous data shows a high degree of conservation (approximately 80% homology). Southern blot analysis of genomic DNA suggests the presence of a multigene for sea urchin cyclophilin. Northern blot analysis indicates a mRNA size of approximately 3 kb and that message is accumulated at blastula stage. PMID- 8688808 TI - Effects of follicle-stimulating hormone administration on oestradiol-induced cystic ovaries in guinea pigs. AB - A consistent defect in follicle-stimulating hormone (FSH) secretion is seen in humans with Polycystic Ovarian Syndrome (PCOS); therefore, we evaluated whether Metrodin (a highly purified urinary FSH) administration concurrent with cyst induction or following cyst induction inhibits estrogen-induced cyst development and augments ovarian follicular growth in an established guinea pig model. All animals in these studies received subcutaneous implants containing oestradiol-17 beta (E2)-filled Silastic capsules for a 48-hour period. Guinea pigs in study #1 were administered four 0.25 mL injections of FSH or placebo at twelve-hour intervals simultaneously with the E2 treatment; guinea pigs assigned to study #2 were administered four 0.25 mL injections of FSH or placebo at twelve-hour intervals following the induction of the cystic condition by E2. Exogenous FSH appears to negate cyst formation when superimposed upon the cyst-inducing agent (E2). Further, treatment with FSH augmented the number of mid-sized follicles in both paradigms. This study is the first to establish evidence of an anti-cystic effect of FSH in an animal model. PMID- 8688809 TI - Effect of estrogen on ontogenic expression of progesterone and estrogen receptors in rat uterus. AB - The ontogenic expression of progesterone and estrogen receptors (PR and ER) and effect of estrogen on these receptors were investigated immunohistochemically in rat uterus from the day of birth ( = 0 day) to 30 days of age. Uterine epithelial and stromal cells showed a negative PR immunoreaction at 0 day. The PR in the epithelial cell nuclei appeared by 5 days, while the stromal cells showed a negative PR reaction until 12 days. The staining of the stromal cells appeared from 12 to 15 days. In both the epithelial and stromal cells, the initiation of the PR appearance was not affected by ovariectomy performed at 0 day or 5 days prior to the appearance of PR in the epithelial and stromal cells. Estrogen injections from 0 day failed to initiate the appearance of PR in the epithelial cells, regardless of doses of estradiol-17 beta (0.1, 1 and 10 micrograms daily), but induced PR in the stromal cells. The staining of ER appeared at 5 days in the epithelial cells and at 1 day in the stromal cells, respectively. ER appeared after 2-3 daily injections of estrogen from 0 day depending upon the doses. These results suggest that steroid hormones secreted from neonatal ovary do not play any important role in ontogenic expression of PR during the postnatal uterine maturation. PMID- 8688810 TI - Hypertrophy of oxytocinergic magnocellular neurons in the hypothalamic supraoptic nucleus from gestation to lactation. AB - In the present experiments, we examined the changes in cell size (profile area) of oxytocinergic magnocellular neurons during reproductive states and dehydration with quantitative immunohistochemistry. During lactation, hypertrophy was observed in oxytocinergic magnocellular neurons but not in vasopressinergic ones in the supraoptic nucleus. In virgin rats, chronic dehydration increased the cell size in both oxytocinergic and vasopressinergic neurons. After normal weaning time, the cell size decreased, returning to virgin level within 20 days. However, if the mothers were deprived of their litters immediately after parturition, the cell size rapidly returned to virgin level within 5 days. Furthermore, the increase in the cell size of the mothers was not affected by the size of their nursing litters. PMID- 8688811 TI - Genetic relationship among three subspecies of Oncorhynchus masou determined by mitochondrial DNA sequence analysis. AB - It is generally accepted that there are 3 subspecies of Oncorhynchus masou in Japan, namely, Masu salmon (Oncorhynchus masou masou (Brevoort)), Amago salmon (O. masou ishikawae Jordan & McGregor), and Biwa salmon (O. masou rhodurus Jordan & McGregor or O. masou subsp. Kimura). Since the genetic relationship of these three taxa is not well known, there has been considerable confusion over their nomenclature. We have clarified the genetic relationship among these three taxa by partially sequencing their mitochondrial DNA. Sequences of 948 base pairs from the 3' region of the ATPase subunit 6 gene to the 5' region of the cytochrome oxidase subunit 3 gene were obtained for 20 individuals including wild Biwa salmon, wild and farmed Amago and Masu salmon. Furthermore, 2,162 base pairs from the 3' region of ATPase subunit 6 gene to the 5' region of NADH dehydrogenase subunit 4L gene were determined in 4 individuals. In total, there were 26 sites of base substitutions. The haplotypes of Masu salmon and Amago salmon were similar. On the other hand, 17 of the 26 sites had substitutions characteristic of Biwa salmon. A matrix of genetic distances and maximum parsimony analysis among the haplotypes indicated that Biwa salmon is genetically more distant from Masu and Amago salmon, than Masu salmon is from Amago salmon. This means that Biwa salmon diverged from the common ancestor of the Oncorhynchus masou complex before the divergence between Masu salmon and Amago salmon. PMID- 8688812 TI - Off-depolarization and off-hyperpolarization after termination of quinine-HCl stimulation in frog taste cells. AB - Off-responses in frog taste cells evoked by a Ringer rinse following 1 mM quinine HCI (Q-HCl) stimulation were investigated with an intracellular recording technique. Three types of off-responses were found; a transient off depolarization, a rebound-type off-depolarization and a transient off hyperpolarization. The time to peak and duration of off-responses were in the order of rebound type-off-depolarization > transient off-depolarization > transient off-hyperpolarization. The reversal potential for the rebound-type off depolarization existed in more positive level than the resting potential. The reversal potential for the transient off-depolarization was around 0 mV, and that for the transient off-hyperpolarization was -58 mV. These three off-responses in frog taste cells may be initiated by an increase in permeability of the apical receptive membrane to Na+, K+ and CI-. A kind of principal ion is dependent on off-response types. PMID- 8688813 TI - A substance secreted from Tetrahymena and mammalian sera act as mitogens on Paramecium tetraurelia. AB - We previously isolated and purified Paramecium growth factor (ParGF) from a cell free fluid of an early stationary mass culture of Paramecium tetraurelia (Tanabe et al., 1990). The mitogenic activity of the purified ParGF and of the crude sample (ca. a 100-fold concentrate obtained by ultrafiltration of cell-free fluid) has been assessed based on restoration of the fission rate of the jumyo mutant of P. tetraurelia in daily reisolation cultures. With this assay system, we found that crude samples of Tetrahymena pyriformis and T. thermophila showed mitogenic activity. This suggests that Tetrahymena cells secrete a mitogenic factor(s) like ParGF. To some extent, fetal bovine serum (FBS) and calf serum (CS) also acted as mitogens on the jumyo mutant. Of nine mammalian growth factors assayed for their mitogenic effects on the jumyo mutant, epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) were slightly and occasionally effective. These results support the idea of actual use of similar kind of growth factors to control cell divisions from protozoa to mammals. PMID- 8688814 TI - Effect of tryptophan metabolites on fluorescent granules in the Malpighian tubules of eye color mutants of Drosophila melanogaster. AB - Fluorescent granules that are stained with Nile blue sulfate are present in larval Malpighian tubules in the wild type strain of Drosophila melanogaster, Oregon-R. These granules emit a weak blue fluorescence and most of them are about 2 microns or more in diameter. The ommochrome precursor 3-hydroxy-kynurenine (3 HK) is actively transferred into the tubules of Oregon-R. Changes in the fluorescent granules in the Malpighian tubules on administration of ommochrome precursors were investigated in eye color mutants of Drosophila. The fluorescent granules in the tubules of the nonautonomous mutants v;bw and cn bw emit a strong blue fluorescence and most of them are about 1 micron or less in diameter. When v;bw and cn bw larvae were cultured on medium supplemented with kynurenine or 3 HK, respectively, the fluorescence intensity of their granules decreased, and their size increased. These additions resulted in almost equal accumulation of 3 HK to that in Oregon-R. On the other hand, no 3-HK accumulated in the tubules of larvae of the autonomous mutants bw;st, ltd bw and w, which lack the fluorescent granules. These findings indicate that the fluorescent granules are an important intracellular site for uptake or storage of ommochrome precursors in larval Malpighian tubules of Drosophila. PMID- 8688815 TI - Work-site variation in managerial drinking. AB - To assess cross-work-site variation in the general drinking behaviors (on and off the job) of employees, we conducted a cross-sectional survey of managers (n = 7255) at 114 places of work located throughout the continental United States. The work-site mean for the total number of drinks consumed on a typical drinking day ranged from 1.4 to 3.17, a two-fold differential. Regression analysis showed an independent work-site effect, controlling for respondents demographics and type of work. This finding suggests that modifiable work-site characteristics could influence what employees drink on and off the job. PMID- 8688816 TI - Psychopathology and alcohol consumption among treatment-seeking alcoholics: a prospective study. AB - The association between psychopathology and alcohol consumption was studied in a nation-wide representative sample of inpatient alcoholics (n = 245) who were examined at intake and 15 months later. As regards baseline observations men and women with antisocial personality disorder or cognitive impairment had consumed more alcohol in the month prior to admission than those not so affected. In contrast, men with panic disorder drank less compared with those not so affected. The prognosis for men consuming more than the median amount of alcohol was worse than that of women. However, after controlling for psychiatric distress and alcohol consumption at baseline, the prognosis of women was worse. Women but not men who had stopped drinking had a higher degree of psychiatric distress at follow-up compared with those still drinking at a low level. Regarding the prognostic significance of psychiatric disorders at baseline, among men panic disorder predicted continued drinking. Psychiatric distress and alcohol consumption at baseline interacted in the prediction of alcohol consumption at follow-up. The study highlights the importance of a thorough assessment of psychopathology and course of drinking when evaluating the outcome of alcoholism treatment. PMID- 8688817 TI - Expectancies relate to symptoms of alcohol dependence in young adults. AB - A significant relationship between the Alcohol Dependence Scale (ADS, Skinner & Allen, 1982) and positive expectancies for alcohol use (AEQ, Brown et al., 1987) is reported that has implications for educational programmes designed to promote sensible drinking. Expectancies predicted current drinking and dependence scores among a sample of young adults that contained 14.6% of subjects scoring above the cut-off point on the ADS. AEQ scores were found to predict ADS scores over and above current drinking and the AEQ subscales successfully differentiated between heavy drinking and dependent drinking. Canonical correlations revealed that for males higher scores on Increased social assertiveness, Sexual enhancement and Arousal and power were related to higher symptoms of loss of control over drinking. The picture was more complex for females in that three canonical variates were found. First, personal expectancies elevated across all the subscales of the AEQ were related to Loss of control. Secondly, females with high scores on Global positive changes and Sexual enhancement showed more symptoms of obsessive drinking and finally, females with higher Arousal and power expectancies but lower Sexual enhancement also had higher scores on the Perceptual withdrawal subscale from the ADS. PMID- 8688818 TI - Combining methods to identify new measures of women's drinking problems. Part II: The survey stage. AB - This is the second of a two-part report on a study aimed at investigating novel indicators of drinking problems among women drinkers. The study was motivated by the suspicion that most measures of drinking problems grew out of studies of male populations with the likelihood that such measures would be less relevant for female drinkers. The first part of this report describes the background for the study and the steps that were taken to generate a short list of "novel" indicators which were then incorporated into an instrument for a general population survey. Using several measures of alcohol consumption as criteria for evaluating the indicators, this paper reports on which indicators may uncover dimensions of alcohol problems not already subsumed by a standard population screen, the CAGE. In particular, results suggest that indicators of "high capacity for alcohol", "seeking out a 'wet' environment", and "planning opportunities to drink" are promising for both women and men, with more qualified support for less "frequent illness" (for women) and "excessive behavior" (for men). These results must be viewed within the context of an exploratory study and indicate avenues for further research. PMID- 8688819 TI - High sugar intake in a group of women on methadone maintenance in south western Sydney, Australia. AB - Nutritional assessment comprising dietary and anthropometric measurements was conducted in a group of 86 women attending a methadone maintenance clinic in South Western Sydney, Australia. Dietary data were obtained by two 24-hour recall interviews using a standardized interview format. Nutrient intake was analysed using the NUTTAB data base of Australian foods (1992). Mean age of the sample was 29.8 (range 18-46) years and mean body mass index was 22.7 (range 16.2-43.4) kg/m2. The diet of the study group was characterized by a low energy intake of 6.48 MF (95% CI 6.02-6.94), a high sugars intake of 122 g (95% CI 112-132), a high percentage of total energy (31%, 95% CI 29-32) derived from sugars, and a low dietary fibre intake of 10.7 g (95% CI 9.7-12.3). This eating pattern may contribute to the high prevalence of a dental caries and chronic constipation observed in the group. The results pattern also support anecdotal evidence of a craving for sweetness described by addicts. Despite the low energy intake, body mass indices of the group were no different from the normal population. It is possible that 2 days' intake was insufficient to accurately measure accustomed diet in this group of women. Alternatively, the low intake may be a consequence of their largely sedentary life-styles. PMID- 8688820 TI - A comment on science and the alcohol beverage industry. PMID- 8688821 TI - Is there a role for contact tracing in preventing HIV transmission among injecting drug users? PMID- 8688822 TI - Addictive drugs as reinforcers: multiple partial actions on memory systems. AB - This review applies some new experimental findings and theoretical ideas about how reinforcers act on the neural mechanisms of learning and memory to the problem of how addictive drugs affect behaviour. A basic assumption of this analysis is that all changes in behaviour, including those involved in drug addiction and the initiation of drug self-administration, require the storage of new information in the nervous system. Animal studies suggest that such information is processed in several (this review deals with three) more or less independent learning and memory systems in the mammalian brain. Reinforcers can interact with these systems in three ways: they activate neural substrates of observable approach or escape responses, they produce unobservable internal states that can be perceived as rewarding or aversive, and they modulate or enhance the information stored in each of the memory systems. It is suggested that each addictive drug maintains its own self-administration by mimicking some subset of these actions. Evidence supporting the notion of multiple memory systems and data on the actions of several drugs (amphetamine, cocaine, nicotine, alcohol and morphine) on these systems are briefly reviewed. The utility of the concept of "reward" for understanding the effects of drugs on behaviour is discussed. Evidence demonstrating actions of drugs on multiple neural substrates of reinforcement suggests that no single factor is likely to explain either addictive behaviour in general or self-administration in particular. Some of the findings on the development and maintenance of self-administration by animals of the five exemplar drugs are discussed in the context of these ideas. PMID- 8688824 TI - Incidence of death and hospitalization from assault occurring in and around licensed premises: a comparative analysis. AB - The aim of the research was to: determine the incidence of serious assault in and around licensed premises in New Zealand, and to compare the circumstances of assault with those that occurred in other locations. For the period 1978-87, inclusive, 49 assault fatalities occurred in or around licensed premises representing 9.4% of all homicides and 12.9% where a place was specified. The comparable figures for assaults resulting in hospitalization in 1988 were: 251, 10.2% and 18.4%, respectively. Further analyses suggests that our estimate of the incidence rate is likely to be an underestimate due to changes over time in the large number of assault cases which have no specific place of occurrence identified. In comparison with homes homicides in licensed premises were more likely to involve: males; Maori, unarmed fights and brawls; unknown assailants; alcohol; occur during the evening and toward the end of the week; and result in head injury. For non-fatal events similar differences were found. In comparison with homes non-fatal assaults were more likely to involve: males; young adults, Maori, the unemployed, unarmed fights and brawls, and head injury. There have been a number of significant policy changes in New Zealand since 1988 which may have resulted in a change to the situation reported here. PMID- 8688823 TI - The geography of availability and driving after drinking. AB - This paper reports on an analysis of geographically based data from four communities conducted to evaluate relationships between measures of the physical availability of alcohol and rates of driving after drinking. From a review of the literature, it was expected that rates of driving after drinking would be directly related to the availability of alcohol at on-premise establishments. Based on theoretical arguments regarding the life activities which underlie drinking and driving it was expected that the effects of availability upon these outcomes would extend significantly beyond the local areas of outlets. Taking into account the geographic variations in environmental characteristics (road network density, traffic flow, population density), and socioeconomic (age, gender, race, marital status, income, employment) and drinking characteristics (rates of abstention, frequency and quantity of use) of resident populations, a spatial analysis of drinking driving and alcohol-related crashes was conducted. The results of the analysis showed that physical availability was unrelated to self-reports of driving after drinking and driving while intoxicated and significantly related to rates of single vehicle night-time crashes. In the latter case, physical availability affected both local and adjacent area rates of crashing. PMID- 8688825 TI - Sex under the influence of alcohol among Norwegian adolescents. AB - The purpose of this paper is to study alcohol consumption among Norwegian adolescents at their most recent experience of sexual intercourse. The material comprises a stratified sample of 920 adolescents aged 16-20 years in a Norwegian county (52.3% of the girls and 41.4% of the boys had coital experience). Data were collected by means of questionnaires; 21.0% of the adolescents reported sex under influence of alcohol. A logistic regression analysis showed that the best predictors of sex under influence of alcohol were intercourse location, sexual enjoyment and sexual intercourse motivated by "Don't know, it just turned out that way". Adolescents who had their most recent experience of intercourse away from home, who had problems enjoying sex and/or who said it just turned out that way, were more likely than others to have had sex under influence of alcohol. A multivariate logistic regression analysis showed that among adolescents who reported that the intercourse took place away from their homes, the odds ratio (OR) for sex under influence of alcohol increased by 8.7. Those who had consumed alcohol before sex, more often than non-drinkers, tended to enter into sexual intercourse motivated by factors external to their own person. This tendency was more pronounced among boys than girls. PMID- 8688826 TI - Cyclin B (p56cdc13) localization in the yeast Schizosaccharomyces pombe: an ultrastructural and immunocytochemical study. AB - The eucaryote cell cycle is driven by a set of cyclin dependent kinases (CDKs) associated to cyclins, which confer not only the activity but also the substrate specificity and the proper localization of the kinase activity. In the fission yeast Schizosaccharomyces pombe, only one cyclin, the product of the cdc13 gene (p56cdc13), is required to be associated with p34cdc2, to control the complete cell cycle. Earlier studies have localized this complex mainly in the nucleus and its periphery. Using new improved electron microscopy (EM) technologies, based on high pressure freezing fixation, we refined previous studies, evidencing cytoplasmic localization of p56cdc13, in addition to the nuclear localization previously observed. Further immunofluorescence studies, performed on aldehydically fixed cells, confirmed our EM results, emphasizing the major cytoplasmic localization of p56cdc13 in interphase cells and the relocalization towards the nucleus in mitotic cells, suggesting that the S pombe cyclin B localization is cell cycle-regulated. PMID- 8688827 TI - Increased expression of the molecular chaperone BiP/GRP78 during the differentiation of a primitive eukaryote. AB - Giardia lamblia, a major cause of intestinal disease worldwide, is a parasitic protozoan that represents the earliest branch of the eukaryotic lineage. Trophozoites, which possess two nuclei but lack mitochondria, peroxisomes and a typical Golgi apparatus, colonize the small intestine of the vertebrate host where they may differentiate into infective cysts. Encystation is a regulated process characterized by the biosynthesis, secretion and formation of a protective extracellular cyst wall. In previous studies, we demonstrated the biogenesis of the Golgi apparatus during encystation and identified two leucine rich proteins (CWPs), which localize within encystation-specific secretory granules before their incorporation into the cyst wall. Here, we used immunological, biochemical and molecular biological approaches to analyze the expression of BiP/GRP78, an endoplasmic reticulum (ER)-resident chaperone, during the Giardia life cycle. A monoclonal antibody specific for Giardia BiP permitted the visualization of the ER of this protozoan and showed that BiP expression increased simultaneously with the increased expression of CWPs during encystation. However, in contrast to the 140-fold increase in levels of CWP transcripts, the steady-state level of BiP mRNA did not increase during encystation. Furthermore, potent inducers of BiP expression in higher eukaryotic cells, including agents that perturb the ER environment, did not affect BiP expression in Giardia. These results, when considered together with the profound changes that occur in the secretory pathway during Giardia encystation, indicate an important role for this molecular chaperone during the differentiation of this primitive eukaryote. PMID- 8688828 TI - Calcium-dependent peripheral localization of 4.1-like proteins and fodrin in cultured human keratinocytes. AB - Recently, several proteins immunologically related to erythrocyte membrane skeletal proteins, such as protein 4.1 and fodrin (non-erythroid spectrin), have been found in keratinocytes. In the present study, in order to investigate the roles of these proteins in cell-cell contact, we analyzed the distribution of non erythroid protein 4.1, beta-fodrin and actin in cultured human keratinocytes at low (0.15 mM) and standard (1.85 mM) Ca2+ concentrations. Immunofluorescence microscopy revealed that immunoreactive forms of protein 4.1, beta-fodrin and actin filaments were present in the cytoplasm of cells cultured in low Ca2+ medium, while in cells in the standard Ca2+ medium, these proteins were localized at the cell boundary and partially in the cytoplasm. When cells in the low-Ca2+ medium were treated with 100 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) for 1 h, these proteins were also present at the cell boundary. Increasing extracellular Ca2+ concentration from low to standard in the medium induces cell cell contact among the cultured human keratinocytes, accompanied by the translocation of protein 4.1 and beta-fodrin from the cytoplasm to the membrane. On the basis of the present study, movement of membrane skeletal proteins from the cytosol to the membrane suggests that either these proteins or the membrane skeletal lattice plays an important role in the regulation of cell-cell intergigitations in response to changes in the Ca2+ concentrations in culture medium, and that phosphorylation of these skeletal proteins might be involved in the regulation of the membrane skeletal proteins of keratinocytes in response to Ca2+. PMID- 8688829 TI - Smooth muscle-type myosin heavy chain isoforms in bovine smooth muscle and non muscle tissues. AB - The distribution of smooth muscle (SM)-type myosin heavy chain isoforms in several bovine muscular and non-muscular (NM) tissues was evaluated by immunofluorescence tests using monoclonal antibodies SM-E7, reactive with 204 (SM1) and 200 (SM2) kDa isoforms, and SM-F11, specific for SM2 isoform. SM-E7 reacted equally with vascular, respiratory and intestinal SM tissues, whereas SM F11 stained heterogeneously SM cells in the various muscular systems examined and in some peculiar tissues was unreactive (perisinusoidal cells of hepatic lobule, pulmonary interstitial cells and intestinal muscularis mucosae) or uniquely reactive (nerve cells). On the whole, our findings indicate that SM1 and SM2 isoforms are unequally distributed at the cellular level in various SM and NM tissues and support previous results obtained with tissue extracts and electrophoretic procedures. PMID- 8688830 TI - Inhibition of trichocyst exocytosis and calcium influx in Paramecium by amiloride and divalent cations. AB - Regulated exocytosis of defensive secretory organelles, the trichocysts, as well as a transient Ca(2+)-influx can be induced in Paramecium by aminoethyldextran (Kerboeuf and Cohen, J Cell Biol (1990) 111, 2527). Knoll et al (Febs Lett (1992) 304, 265) reported that veratridine was also a secretagogue for Paramecium. Here we show that, like aminoethyldextran, veratridine induces a transient Ca(2+) influx. Both aminoethyldextran- and veratridine-induced exocytosis and associated Ca(2+)-influx were: i) blocked in the ndl2 thermosensitive mutant at the non permissive temperature; and ii) inhibited by amiloride and four divalent cations, Ba2+, Mg2+, Sr2+ and Co2+. This suggests that, although of different chemical nature, aminoethyldextran and veratridine act through the same physiological pathway. In addition, the inhibitory doses are comparable to the ones found to inhibit a hyperpolarization-sensitive Ca(2+)-current described in Paramecium (Preston et al (1992) J Gen Physiol 100, 233). The possibility that the activation of this Ca(2+)-current by the secretagogue represents an early step in the regulation of trichocyst exocytosis is discussed. PMID- 8688831 TI - High resolution localization of cruzipain and Ssp4 in Trypanosoma cruzi by replica staining label fracture. AB - The replica staining label fracture technique was used to analyse the distribution of cruzipain and Ssp4 in Trypanosoma cruzi. Intense labeling for the two proteins was seen on the E fracture face of amastigote forms. Gold particles did not co-localize with the intramembranous particles. Labeling was abolished by previous treatment of the parasites with phospholipase C from Trypanosoma brucei, which removes glycosylphosphatidyl inositol (GPI) anchored proteins. These observations suggest that cruzipain and Ssp4 are attached to the parasite surface via a GPI anchor. PMID- 8688832 TI - The pericardial glands of the zebra mussel: ultrastructure and implication in lead detoxication process. AB - Ultrastructural and microanalytical investigations of the pericardial gland of the freshwater mussel, Dreissena polymorpha have been performed to investigate the possible functional role of this organ in the detoxication process of lead. The cell-type of this organ exhibits the feature characteristics of podocytes, ie the typical pedicel-basal lamina complex and the well developed lysosomal vacuolar system. X-ray microanalysis demonstrated that large electron-dense granules referred to as lysosomes are the main target organelles in these cells to accumulate and sequestrate lead where the metal was associated with phosphorus and sulphur. Consequently, the pericardial gland plays an important role in the detoxication process and allows the organism to tolerate high lead concentration without suffering severe cell injury. PMID- 8688834 TI - Glycosaminoglycan metabolism in otosclerotic bone cells. AB - Normal and otosclerotic bone cells were cultured in vitro in serum-free medium to evaluate single glycosaminoglycan (GAG) class synthesis and secretion. Moreover, the degradative process was studied by inhibiting the lysosomal functions through the addition of ammonium chloride to the cultures, an ammine known to inhibit lysosomal degradation by neutralizing organelle activity. Otosclerotic bone cells accumulated a lower amount of GAG both in the cellular and extracellular pool compared to normal ones. The decrease was markedly higher for secreted GAG. Moreover a different pattern of single GAG class distribution was observed in the two cell types considered. In the medium of otosclerotic cells a percentage increase of hyaluronic acid (HA) and dermatan sulphate (DS) and a percentage decrease of heparan sulfate (HS) and chondroitin sulfate (CS) were observed compared to normal bone cells. Ammonium chloride had a lower effect on pathologic than on normal cells, indicating a decrease in the degradative process in otosclerotic bone cells. These results were also confirmed by the experiments on GAG uptake and degradation and by the dosage of enzymatic activity of two exoglycosidases. Since extracellular GAG composition influences bone deposition and mineralization, these data support the hypothesis that otosclerosis is the result of an error in the connective tissue matrix structure. PMID- 8688833 TI - Effects of different vertebrate growth factors on primary cultures of hemocytes from the gastropod mollusc, Haliotis tuberculata. AB - A useful experimental system from primary cultures of hemocytes from Haliotis tuberculata has been established. Six days after initiation of the culture, the viability of hemocytes remained constant as measured by the MTT assay. In addition, hemocytes showed physiological responses as judged by protein and DNA syntheses in response to treatment with vertebrate growth factors. Porcine insulin and human epidermal growth factor (EGF) stimulated [3H]-leucine and [3H] thymidine incorporation in hemocytes in a dose-dependent manner. No additive effect of insulin and EGF is observed either for [3H]-leucine or for [3H] thymidine incorporation. The response of primary cultures of abalone hemocytes to vertebrate growth factors confirms their growth potential in vitro and provides a suitable model for further studies on regulation of the control of cellular processes such as cell growth, differentiation and migration in invertebrate cells. PMID- 8688835 TI - A model of growing vascular structures. AB - Increasing attention is being paid to the configuration and development of vascular structures and their possible correlations with physiological events. The study of angiogenesis in normal and pathological states as well as in embryo and adult has provided new insights into the mechanism of vessel growth and organization of the vasculature. Various mathematical branching models have been developed. These constructions are mainly geometrical and only involve a branching phenomenon. We propose the use of a deterministic non-linear model based on physiological laws and hydrodynamics. Growth, branching and anastomosis, the three actual main events occurring in vascular growth, are included in this model. Space growth, including cells and vessels, is defined by a decreasing transformation. Space density and the length of new sprouts are controlled by a set of parameters. The conditions on these parameters are well established, which allows the production of realistic patterns. PMID- 8688836 TI - A mathematical model of periodically pulsed chemotherapy: tumor recurrence and metastasis in a competitive environment. AB - A competition model describing tumor-normal cell interaction with the added effects of periodically pulsed chemotherapy is discussed. The model describes parameter conditions needed to prevent relapse following attempts to remove the tumor or tumor metastasis. The effects of resistant tumor subpopulations are also investigated and recurrence prevention strategies are explored. PMID- 8688837 TI - Coding of stimulus intensity in an olfactory receptor neuron: role of neuron spatial extent and passive dendritic backpropagation of action potentials. AB - The olfactory receptor neuron provides a good opportunity to analyze a biophysical model of a single neuron because its dendritic structure is simple and even close to a cylinder in the case of the moth sex-pheromone receptor cell. We have considered this cylindrical case and studied two main problems. First, we were concerned with the effect of the neuron's length on the receptor potential for a constant stimulus-induced conductance change. An analytical solution for the receptor potential was determined by using input resistances. It was shown that the longer the neuron, the greater its ability to code over a wide range of values of the intensity of the stimulus. Second, we studied numerically the passive backpropagation of action potentials into the dendrite and its influence on firing frequency. While propagating along the dendrite, the action potential decreases in amplitude and its shape becomes rounded. The firing frequency in the model with backpropagation was found to be greater than that obtained analytically in the absence of backpropagation. However, for any given conductance change, when normalized with respect to their maxima, both firing frequencies were found to be very similar over a wide range of parameter values. Therefore, the actual firing rate (with backpropagation) may be approximated by the analytical solution without backpropagation if the actual firing rate for a large conductance change is known. PMID- 8688838 TI - Melanin granule model for laser-induced thermal damage in the retina. AB - An analytical model for thermal damage of retinal tissue due to absorption of laser energy by finite-sized melanin granules is developed. Since melanin is the primary absorber of visible and near-IR light in the skin and in the retina, bulk heating of tissue can be determined by superposition of individual melanin granule effects. Granules are modeled as absorbing spheres surrounded by an infinite medium of water. Analytical solutions to the heat equation result in computations that are quick and accurate. Moreover, the model does not rely on symmetric beam profiles, and so arbitrary images can be studied. The important contribution of this model is to provide a more accurate biological description of sub-millisecond pulse exposures than previous retinal models, while achieving agreement for longer pulses. This model can also be naturally extended into the sub-microsecond domain by including vaporization as a damage mechanism. It therefore represents the beginning of a model which can be applied across the entire pulse duration domain. PMID- 8688839 TI - Making sense of the combined effect of interleukin-2 and interleukin-4 on lymphocytes using a mathematical model. AB - The cytokines are the information superhighway of the immune system. They are an important component of the integrated behavior of the system. In order to be able to have a good understanding of the immune system, we must be able to model the effect of cytokines and their combined effect. This work is a step in that direction. We study the combined effect of two cytokines: interleukin-2 (IL-2) and interleukin-4 (IL-4) on some cells of the immune system. Interleukin-2 and interleukin-4 are important growth and differentiation factors for B and T cells. Interleukin-4 antagonizes the effect of interleukin-2 on B cells and some T cells while it synergizes with interleukin-2 on other T cells. We build a mathematical model of the interaction of both cytokines on T and B cells as a building block toward a model of the Th1/Th2 cross-regulation. The response of a given cell to the combination of interleukin-2 and interleukin-4 is shown to involve competing dynamical effects which can lead to either antagonistic or synergistic combined effect. PMID- 8688840 TI - [The need of emergency services for the hand]. AB - Microsurgical techniques have been able to realize anastomoses of small vessels and nerves, with a high rate of success when performed by teams involved in that field. This has changed the concept of surgery of the hand. Reconstruction aims now at a functional result. Organisation of emergencies in hand surgery requires facilitations: hand surgeons, equipment and a team on a 24-hour basis, able to operate any kind of hand trauma. Since 1979, Liege is affiliated to the European Federation. Advantages of the immediate repair are significant repair are significant: reduction of the permanent disability rate, and in many instances, return to work at the same position. In conclusion, early treatment of the injuries of the hand is very effective, but need to be performed by specialists in the field of hand surgery. PMID- 8688841 TI - [Problems in the adjustment of evaluation and repair of bodily injuries in tomorrow's Europe]. AB - The evaluation of traumatic body damage raises difficult problems when considered in the frame of European Community in view of the major differences currently existing between modes of compensation of such damages in the different countries of the Union. While the economic loss resulting from a given damage should no doubt continue to be fully compensated, obvious financial constraints at the level of insurances will probably make it necessary to consider lump compensation for the non-economic losses which involve the physical and/or psychical integrity of the person. It is proposed to use the term 'personal incapacity' to describe the latter losses whose numerical evaluation now requires the elaboration of new modes of rating (in french, 'bareme'). A number of principles are proposed for the actual design and elaboration of this instrument, namely by taking into account the detailed estimation of each of relevant human functions in daily living, thus outside any professional context. Such the new approach proposed should eventually provide an essential instrument for the calculation of these lump compensations, no matter in which country the accident took place nor which are the countries of citizenship of victim, defendant, and insurance companies involved. PMID- 8688842 TI - [Simple glycine derivatives from lipid transporter systems of glycine. Carrier test of a small-size neutral acid amine to the central nervous system]. AB - Glycine, an important amino acid, does not cross the blood-brain barrier. Some simple derivatives have been designed to improve the unfavourable physico chemical parameters: N-benzyloxycarbonylglycine and its methyl ester exhibit anticonvulsant activities superior to the parent amino acid. The incorporation of N-benzyloxycarbonylglycine in a pseudo-triglyceride pattern led to more active substances. PMID- 8688843 TI - [Academic eulogy of Professor Charles Mertens de Wilmars, titulary member]. PMID- 8688844 TI - The complex structure and function of G-proteins in cellular communication. PMID- 8688845 TI - [Contribution and limitations of experimental models to the understanding of certain abnormalities of the face and ear]. AB - The analysis of 4 craniofacial teratological models in the mouse (13-cis-retinoic acid and methyl triazene administration, irradiation, 'far' strain) permits to study the similarities, but also the differences between these models and malformative syndromes in the human. Retinoic acid administration provides a phenocopy of mandibulofacial dysostosis, and irradiation gives rise to a centrofacial dysplasia evoking several holoprosencephalia and Crouzon syndrome. However, triazene administration does not reproduce the hemicraniofacial microsomia. PMID- 8688846 TI - Transport of glutathione S-conjugates in the yeasts Saccharomyces cerevisiae. AB - Transport of 2,4-dinitrophenyl-S-glutathione (DNP-SG) and a fluorescent glutathione S-conjugate, bimane-S-glutathione (B-SG) was studied in the baker's yeasts (S. cerevisiae). Both conjugates were exported from the cells; the transport was inhibited by fluoride and vanadate like in mammalian cells. B-SG was also found to be accumulated in the vacuoles. The transport rate of DNP-SG outside the cell was higher in a vacuolar-deficient strain. A significant ATP dependent uptake of (3H)-DNP-SG by vacuoles was found. These results indicate that S. cerevisiae transport glutathione S-conjugates both outside the cells and into the vacuoles. PMID- 8688847 TI - Implication of involvement of rat chromosome #2 in spontaneous transformation of the rat-2 cell line. AB - Using an in vitro model for cell transformation, the relationship between specific chromosomal aberration and phenotypic changes was studied at different passages of Rat-2 cell line. A marker chromosome resulting from a translocation [t(2;7)] was found to be associated with focus formation in soft agar. Conversely, the loss of this marker chromosome was found to be associated with phenotypic reversion. These results suggest an association of this marker chromosome with phenotypic transformation for the Rat-cell line. PMID- 8688848 TI - Synergistic regulatory effects of TNF alpha, IL-1 alpha and IFN alpha on the growth and differentiation of Daudi lymphoma cells. AB - The regulatory effects of the combined treatment of tumour necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha) and interferon alpha (IFN alpha) on the growth and differentiation of Daudi lymphoma cells were investigated. By means of anti-BrdU monoclonal antibodies and [3H-thymidine] incorporation a reduced proliferation rate was shown both through a combination of TNF alpha with either IL-1 alpha or IFN alpha and, above all, through simultaneous treatment with the three cytokines. In parallel, the degree of differentiation was evaluated via morphological criteria and detection of Fc receptors (FcR) and appeared higher after treatment with the three cytokines. Our results provide evidence of the increased sensitivity of this cell line to this combined treatment supporting the existence of a synergistic interaction in inducing the antiproliferative and differentiative effects. PMID- 8688849 TI - Imprinting effects of three amino acids (alanine, lysine and glycine) and their oligopeptides in Tetrahymena pyriformis. Data from the hormone and hormone receptor evolution. AB - Hormonal imprinting takes place at the first encounter of the hormone and receptor, and results in a changed binding capacity and reaction of the cell and its progeny generations. The imprinting effect of three amino acids and their oligopeptides is studied using fluorescent-labelled peptides. Glycine and lysine could provoke positive imprinting (increased binding in the progeny generations) for their own peptides, but alanine could not. Mostly positive imprinting was provoked by glycine and lysine peptides for their own peptides of different chain length. The optimal chain length provoking self-imprinting was four for glycine, two for lysine and three for alanine. Except in this case, alanine was neutral or provoked mostly negative imprinting. After reaching the optimal chain length, there is a decline in binding. Evolutionary conclusions are discussed. PMID- 8688851 TI - Human sperm beta-glucuronidase is poorly extractable by Triton X-100. AB - A part of sperm glycosidase activities was detected as detergent-insoluble after sequential extractions with Triton X-100. Sixty per cent of total beta glucuronidase activity was found in the detergent-insoluble fraction. This portion of beta-glucuronidase was resistant to extractions in the presence of 1 M KCl, chaotropic agents, colchicine or cytochalasine B, being only partially solubilized by 3 M KCl or DNAse I treatment. Results demonstrate that beta glucuronidase is tightly associated to the Triton X-100 resistant fraction. PMID- 8688850 TI - Studies on nitric oxide free radicals generated from polymorphonuclear leukocytes (PMN) stimulated by phorbol myristate acetate (PMA). AB - The interaction of NO and O2- free radicals generated from PMA (phorbol myristate acetate)-stimulated PMN (polymorphonuclear leukocytes) was studied by a nitroxide spin trap, DMPO (5,5-dimethyl-1-pyrroline-1-oxide). It was found that addition of L-arginine to the system would significantly decrease the trapped O2- by DMPO and addition of NG-monomethyl-arginine (NGMA) would significantly increase the trapped O2- by DMPO. It was proved that the formation of ONOO- by the reaction of NO and O2- was the main reason for the decrease of trapped O2- in the experiment with xanthine/xanthine oxidase and irradiation of riboflavin systems. The yield of NO during this process was calculated. The generation dynamic of NO was studied by a luminol-dependent chemiluminescence technique and it was found that after stimulation of PMN by PMA, there would be an immediate, significant chemiluminescence, which came mainly from the active oxygen free radicals generated by PMN. If L-arginine was added to this system, the chemiluminescence would increase about 100-fold, but NGMA inhibited the increase of the chemiluminescence. Ten minutes after addition of L-arginine, this increase did not change, the chemiluminescence peak decreased gradually, but the half life increased. The ESR and chemiluminescence properties of NO and ONOO- synthesized were also studied in model systems. PMID- 8688852 TI - Enhancement of 5-fluorouracil cytotoxicity by cisplatin in brain tumour cell lines. AB - Cisplatin reportedly plays an important role as a chemical modulator in enhancing the chemotherapeutic effects of 5-fluorouracil on tumour cells. The aim of the present study was to test the synergistic cytotoxicity of cisplatin and 5 fluorouracil in 5-fluorouracil-resistant (C6) and -sensitive (9L) rat brain tumour cell lines. Survival fractions, determined using colony-formation assays, were compared following 5-fluorouracil treatment, with and without cisplatin. The presence of cisplatin (1-10 microM) enhanced cytotoxicity by more than three times compared with 5-fluorouracil alone in 5-fluorouracil-resistant C6 cells, whereas no enhancement effects were noted in 9L cells. These results suggest that a cisplatin-fluorouracil-based regimen may be promising in the treatment of 5 fluorouracil-resistant brain tumours. PMID- 8688853 TI - alpha-Ketoglutarate uptake in human fibroblasts. AB - Glutamine requirements are increased during injury, in particular to sustain the needs of rapidly growing cells. This includes fibroblasts involved in wound healing. alpha-Ketoglutarate (alpha-KG) has been proved to be a potent precursor of glutamine. However, little is known about the process of its cell uptake. Since this first step could be crucial in alpha-KG metabolism, we have characterized alpha-ketoglutarate uptake in fibroblasts. Total uptake of alpha ketoglutarate was linear up to 1 mmol and temperature independent. Rate of uptake was independent of the presence of Na+ in the medium. Competition studies with another ketoacid demonstrated the nonspecificity of alpha-ketoglutarate uptake. In addition, 4-hydroxy-alpha-cyanocinnamate, a known inhibitor of anion transport, was ineffective on alpha-ketoglutarate uptake. Taken as a whole, these data provide evidence that alpha-ketoglutarate uptake in fibroblast occurs by an unmediated diffusion process. This suggests that alpha-ketoglutarate uptake is not the controlling step in fibroblasts, i.e. only the availability of extracellular alpha-ketoglutarate. This could be an advantage since during injury, cell membrane depolarization and dissipation of Na+ gradient may limit cellular glutamine uptake. PMID- 8688854 TI - Partial characterization of a putative 110 kDa myosin from the green alga Chara corallina by in vitro binding of fluorescent F-actin. AB - Using the binding of heterologous, rhodamine phalloidin-labelled F-actin in vitro, two F-actin binding proteins were identified in protein extracts from the green alga Chara corallina after fractionation by anion exchange chromatography. The first protein, a putative myosin, released laterally bound F-actin at ATP concentrations as low as 1 microM; equivalent concentrations of ADP were not effective. Binding of F-actin was inhibited by the sulfhydryl-alkylating agent N ethylmaleimide (NEM). Binding of F-actin was also abolished by a monoclonal anti myosin (J14) previously used for immunodetection and immunolocalization in internodal cells (Grolig et al., 1988, Eur J Cell Biol 47: 22-31). Immunoblotting with J14 detected a 110 kDa polypeptide only in those protein fractions that had revealed ATP-sensitive binding of F-actin. The putative myosin bound with mediocre affinity to immobilized calmodulin and free Ca(2+)-concentration made no difference to this binding affinity. In contrast to the putative myosin, the second, less abundant protein revealed ATP-insensitive and end-wise binding to the microfilament and was not recognized by the anti-myosin antibody. PMID- 8688855 TI - Slow induction of gelatinase B mRNA by acidic culture conditions in mouse metastatic melanoma cells. AB - Gelatinase B has been thought to be a key enzyme for degradation of extracellular matrix in tumour invasion and metastasis. In this study, we examined the effect of acidic culture medium (pH 5.9) on the expression of gelatinase B mRNA in mouse metastatic melanoma cell line (B16-F10). Using reverse transcription-polymerase chain reaction (RT-PCR) analysis, we found that gelatinase B was induced by the acidic culture medium at 24 h, and then gradually diminished to 72 h. By gelatin zymographic analysis, gelatinase B was first detected at 24 h, continued to increase and then reached a plateau at around 48 h. These results suggest that the induction of gelatinase B secretion by acidic culture medium occurs as a result of the gene expression. PMID- 8688857 TI - The conformation of clathrin light-chains on triskelions probed by antibody inhibition. AB - The conformation of clathrin light-chains along the proximal arm of the clathrin triskelion was studied by using rabbit anti-(light-chain peptides) to inhibit the binding of a mouse monoclonal antibody against an epitope in the amino-terminal region. Prior incubation of triskelions with rabbit antisera raised against the extreme carboxyl-terminal of the light-chains partially inhibited binding. The inhibition was largely removed when tested on light-chains that had been freed from triskelions. This suggests that when the light-chains bind the heavy-chain, they adopt a conformation in which the amino and carboxyl-terminal domains are not fully extended, but fold such that these two domains face each other. PMID- 8688856 TI - Brefeldin A distorts discoid and polarized morphological organizations of epithelial cells in culture. AB - Brefeldin A (BFA), an agent disorganizing organelle traffic, was used to find out the role of this traffic in the maintenance of shape and cytoskeletal organization of cultured epithelial MDCK cells. Cell shape was assessed using dispersion and elongation indices (Dunn and Brown, 1986, J Cell Sci 83: 313-340). BFA reversibly transformed discoid MDCK cells with circular actin pattern into moderately polarized cells with straight actin bundles. In other experiments the same MDCK cells were first transformed into highly polarized fibroblast-like cells by incubation with 'scatter factor' (HGF/SF) and then treated with BFA. In these conditions BFA significantly decreased the degree of polarization. It is suggested that both highly polarized and discoid morphological organizations are controlled by organelle traffic. PMID- 8688858 TI - The effects of post-weaning environment, biological dam, and nursing dam on feeding neophobia, open field activity, and learning. AB - Using rats in a cross-fostering design we examined the effects of pre- and post weaning rearing environments on feeding neophobia, open field activity, runway training, and visual discrimination learning. Fostering had no effect on the offspring behaviors. The animals reared, post-weaning, in an enriched environment consumed more food in a novel situation, were less active in the open field, and learned the first of two discrimination tasks faster than did the animals reared in the standard condition. Inter-correlations among these measures were nonsignificant, suggesting that the effect of environment on learning cannot be reduced to temperamental factors. The deficit in learning resulting from rearing in standard environment does not, however, appear to be irreversible; animals reared in the standard condition reached performance levels on the second discrimination task characteristic of those reared in the enriched environment. PMID- 8688859 TI - Detection of Taenia saginata antigens in faeces by ELISA. AB - Stool samples were examined by capture ELISA for the presence of T. saginata antigens. The specimens were from 303 patients infected with T. saginata, 43 samples from individuals suffering from bacterial, fungal, protozoan and nematode infections and 36 ones deriving from uninfected persons. The samples were diluted 1:10 (w:v) in PBS + 0.35% Tween 20, centrifuged twice at 5000 g for 20 min at room temperature and resulting supernatant at 12,000 g for 30 min at 0 degree C. The capturing and detecting polyclonal antibodies were prepared in rabbits immunizing them with T. saginata surface antigens. The stool samples freshly obtained, stored at 4 degrees C not longer than 72 h, or kept at at -20 to -30 degrees C even for 24 months showed reliable results in ELISA. The samples kept for a long time at 4 degrees C, dried and covered with moult were negative in the test. All samples taken from patients infected with other than T. saginata parasites or uninfeced were negative. PMID- 8688860 TI - A comparison of two methods for assessing drug sensitivity in Giardia duodenalis. AB - This study compared two published methods for assessing the in-vitro drug sensitivity of Giardia duodenalis: the 3H-thymidine incorporation assay (BOREHAM et al. 1984) which radiometrically measures nucleic acid synthesis; and inhibition of adherence (MELONI et al. 1990). Giardia trophozoites were exposed to a range of concentrations of metronidazole or albendazole for 24 hours and their viability measured by both assays in order to determine the degree of correlation between the two methods of measuring viability. Due to the different modes of action of metronidazole and albendazole on Giardia, measuring the inhibition of adherence appears to be a more accurate indicator of trophozoite viability than measuring 3H-thymidine incorporation. PMID- 8688861 TI - Investigations on a Swiss area highly endemic for Echinococcus multilocularis. AB - Anecdotal information suggested that a focus of hyperendemicity may be present in a small area of the Canton of Fribourg in Switzerland. Therefore, the prevalence of E. multilocularis was assessed both in the fox and the rodent population over a two-season-period. A high prevalence ranging between 47% and 56% was consistently determined in the fox population. An Arvicola terrestris population was infected at 39% in the first season of investigation and at 11% in the following season. A subsequent seroepidemiological survey in the population of inhabitants surrounding the area provided no indication of seroconversion and thus no indication of infection for humans. However, a longer-term survey will be needed to assess more precisely the risk of disease occurrence among these inhabitants. PMID- 8688862 TI - Enhanced efficacy of a liposomal pentamidine preparation in Pneumocystis carinii in an ex vivo/in vitro culture model without feederlayer cells. AB - The effects of pentamidine isethionate, phosphatidylcholine-liposomes (PPC-lip) and combinations of both on the survival of Pneumocystis carinii trophozoites in a culture system without feederlayer cells were quantified. Pentamidine or PPC lip alone reduced significantly the number of cells, with a clear dose dependence. Combinations of both drugs showed overadditive effects on cell counts reduction. Additional EM-investigations showed a rapid destruction of cell structures especially with the pentamidine/phospholipids-combinations. Our results could justify clinical tests with these combinations in AIDS patients in order to reduce the pentamidine dose, reduce local side effects with inhaled pentamidine while at least maintaining efficacy. PMID- 8688863 TI - Immunochemical characterization of Ancylostoma caninum antigens. AB - Adult worms of Ancylostoma caninum were dissected and manually separated into cephalic glands, cervical glands, intestine, esophagus and cuticula. These fractions as well as third stage larvae were fractionated with Triton X-114 into water soluble (hydrophilic), Triton soluble (hydrophobic) and unsoluble proteins. These fractions were characterized by immunoblotting with serum from rabbits immunized either with a pool of cervical, cephalic glands and intestine, or the esophagus fraction as well as with sera from percutaneously infected dogs and rabbits. Immunodominant antigens were found that reacted with dog or rabbit post infection sera and could be suited as antigens in serodiagnostic tests. Hidden antigens were found in the several fractions. Those from esophagus and intestine could be vaccine candidates that will be tested in immunization trials. PMID- 8688864 TI - Histology of the skin and determination of blood and serum parameters during the recovery phase of sarcoptic manage in cattle after avermectin (Ivomec) treatment. AB - Calves experimentally infested with Sarcoptes bovis were treated 14 weeks post infectionem with an avermectin pour-on preparation (Ivomec). On day 0 before and 14, 28 and 56 days after treatment mite count, scabies lesion score, histological sections of the skin, blood- (number of erythrocytes, PCV, Haemoglobin, MCV, MCH, MCHC, number of leukocytes, differential blood picture) and serum parameter (GOT/AST, GGT, GLDH, glucose, calcium, magnesium, phosphate, sodium, potassium and chloride) and Sarcoptes specific immunoglobulin G and immunoglobulin M were determined. 14 days after treatment no mites could be found in skin scrapings and the mange lesions were in recovery stage. 28 days after treatment the skin mostly was macroscopically unchanged. On all examination days in skin biopsies hyperkeratosis, mostly accompanied by epidermal hyperplasia and perivascular infiltration with eosinophil granulocytes and mononuclear cells was observed. The dominance of eosinophil granulocytes in the tissue decreased after treatment, while mononuclear cells increased and dominated in most cases on day 28 over eosinophil granulocytes. The differential blood count in most cases showed elevated lymphocytes on all examination days, increase of neutrophil granulocytes and decrease of eosinophil granulocytes between day 0 and 14. Monocytes on day 28 showed a marked decrease, thereafter on day 56 a marked elevation. Slightly increased serum enzyme activities were seen with GLDH and GOT on day 0 before treatment and with GLDH on day 56 after treatment. The specific antibody titer against Sarcoptes antigen showed decreasing immunoglobulin G titre and increasing immunoglobulin M titre during the investigation. PMID- 8688865 TI - Lung eosinophilia in response to intravenously injected Trichinella spiralis. AB - Mice were injected intravenously with killed muscle-stage larvae of the parasitic nematode Trichinella spiralis. This induced eosinophilic lung inflammation, the degree of eosinophilia was detected and measured by broncho-alveolar lavage. Subsequent in vivo restimulation by Trichinella antigens produced an enhanced lung response, showing that exposure to killed larvae generated an effective immunological memory. The kinetics and characteristics of the eosinophil response suggested that it was locally rather than systemically controlled. This conclusion is based on the fact that, in contrast to the situation seen after oral infection with T. spiralis, there was little change in bone marrow eosinophilopoiesis, blood eosinophil numbers or in serum interleukin-5 levels. PMID- 8688866 TI - Factors conditioning detection of Taenia saginata antigens in faeces. AB - The conditions which optimize detection of T. saginata antigens in faeces were subject of examination. The most appropriate appeared diluent of PBS + 0.3% Tween 20. The highest effectiveness was achieved using capturing and detecting antibodies to surface antigens in comparison with somatic and metabolic ones. Two step centrifugation and final dilution of samples 1:10 (w:v) were recommended. The stability of freezed faecal supernatants after the first centrifugation was limited to 2 months. The sensitivity of capture ELISA established in our examinations allow to signalize 1 ng/ml antigen in high absorbance values. The antigens recognized by the test had MW bigger than 100,000. PMID- 8688867 TI - Technology. Mile-high medicine. PMID- 8688868 TI - Policy. The infectious disease fight goes global. PMID- 8688869 TI - Physicians ... California has taken a step to eliminate credentialing application hassles for its doctors. PMID- 8688870 TI - Physicians. To each his own. PMID- 8688871 TI - Information systems ... survey of 50 group practices. PMID- 8688872 TI - Continuum of care. Building healthier communities. PMID- 8688873 TI - Reengineering ... New York City Health and Hospitals Corp. (HHC) PMID- 8688874 TI - Managed care. Agreeing to disagree. PMID- 8688875 TI - Medicare malaise. PMID- 8688876 TI - If it works for the military, why not Medicare? PMID- 8688877 TI - There is nothing like an aim. PMID- 8688878 TI - Quick study. Interview by Kevin Lumsdon. PMID- 8688880 TI - Walk on by. As Medicaid managed care changes the need for--and nature of- emergency departments, will the poor and needy be left behind? PMID- 8688879 TI - Talk shows ... the CEOs of seven large health systems take you on a verbal journey. AB - In this exclusive panel discussion with H&HN, the CEOs of seven large, integrated health systems take a verbal journey, trekking across country and into inner cities to explore issues ranging from community health to the future of leadership. It's a fictitious journey about the real issues that lie ahead. PMID- 8688881 TI - Look at it this way. AB - Ask some of the brightest executives, policymakers, entrepreneurs and analysts to predict the future of health care. We did. The answers may surprise you. They may amuse you. They may rekindle a fear of the unknown. But this is certain: From now on, today's thinking about tomorrow will never be the same. PMID- 8688882 TI - Prenatal ethanol diminishes reactivity of presumed dopamine D3 receptors in rats. AB - Ethanol abuse in pregnancy is known to produce serious damage to the developing central nervous system of mammalian species. As with several other classes of nerves, the ontogenetic influence of ethanol on dopamine (DA) nerves is long lived. To test whether reactivity of DA receptors might be altered by prenatal ethanol administration, rats were given 10% (v/v) ethanol in their drinking water, starting 10 days before mating and continuing to the end of pregnancy. Male offspring were tested at 3 months for behavioral effects known to be induced by DA agonists acting at specific subtypes of DA receptors. The oral activity dose-effect curve for SKF 38393, a DA D1 agonist, was not altered from control. However, quinpirole-induced yawning behavior, reputedly a DA D3-associated event, was markedly impaired in the male rats that had been exposed in utero to ethanol. These findings indicate that prenatal ethanol exposure may predominately produce diminished reactivity of the DA D3, but not DA D1 subtype of DA receptor. PMID- 8688883 TI - The effect of prolonged lithium administration on the cAMP level in the rat striatum. AB - In the present paper the effect of lithium on the level of cAMP in the rat striatum was studied. Incubation of the striatal slices in the presence of LiCl (1 mM) resulted in the significant decrease in the cAMP level stimulated by dopamine (via dopaminergic receptor), guanylyl-5-imidodiphosphate (GppNHp, via G protein) and forskolin (a direct activator of adenylate cyclase), without any effect on the basal level of cAMP. On the other hand, the effect of prolonged administration of LiCl (5 mEq/kg po) on the cAMP level in the striatal tissue was much more complicated and strongly depended not only on the stimulating factor used ex vivo (i.e. dopamine, GppNHp or forskolin) but also on the period of lithium administration (i.e. 1, 3, 7 or 21 days) and on the time after each of the above mentioned doses (i.e. 3 or 24 h). From the obtained results it can be concluded that initial inhibitory effect of LiCl on the cAMP level can be overcome upon the prolonged administration of the drug, by the adaptive changes which take place apparently at the level of catalytic unit of adenylate cyclase. PMID- 8688884 TI - The effect of mu and kappa opioid receptor agonists on cAMP level in hippocampus of kainic acid-treated rats. AB - The effect of opioid receptor activation in vitro on the cAMP level was studied in the slices of hippocampus obtained from kainic acid (KA)-treated rats. In the tissue obtained from control rats both U50,488H (kappa opioid receptor agonist) and morphine (mu opioid receptor agonist) produced an increase in the cAMP level, reversed by nor-binaltorphimine (nor-BNI) and naloxone, respectively. When the level of cAMP was stimulated by forskolin (5 microM), the effects of U50,488H and morphine differentiated. Namely, the activation of kappa opioid receptor led to the decrease in this stimulation, but activation of mu opioid receptor was without any effect. The basal level of cAMP in the hippocampal tissue obtained from rats treated with KA, 24 h after the single dose (12 mg/kg ip), was significantly increased, as compared to the control value. Activation of kappa opioid receptors by U50,488H, ex vivo, in such tissue produced a marked decrease in the level of cAMP, while morphine was without any effect. Our results indicate, that in the excited hippocampal tissue, i.e. following KA administration, activation of kappa opioid receptors lowers also the increased level of cAMP. Since the modulation of the intracellular cAMP level may be an important mechanism in regulation of the excitatory transmission in the hippocampus, the above result might point to an additional mechanism, by which U50,488H participates in the lowering the susceptibility of the limbic system to the excitatory effects of KA. PMID- 8688885 TI - The pharmacokinetics of promazine and its metabolites after acute and chronic administration to rats--a comparison with the pharmacokinetics of imipramine. AB - This study was aimed to investigate the pharmacokinetics of promazine (a phenothiazine analogue of imipramine) after its single and repeated administration. Male Wistar rats received promazine as a single injection (10 mg/kg ip) or they were treated chronically with the neuroleptic, once a day for two weeks. Plasma and brain concentration of promazine, desmethylpromazine and promazine sulphoxide were determined using the HPLC method devised by us. The results of the present study were compared with our earlier data obtained in analogous experiments with imipramine. The obtained data showed that the pharmacokinetics of promazine and imipramine was similar, though certain differences could be noticed. Both those drugs were unevenly distributed throughout the body, occurring in low concentrations in the blood plasma and reaching considerably higher concentrations in the brain. However, the uptake of promazine by the brain was more efficient than that of imipramine. The brain/plasma AUC ratio after a single dose amounted to 28.72 for promazine and 12.78 for imipramine. Their demethylated metabolites behaved in a similar way, where as the level of promazine sulphoxide in the brain was three times lower than that in the plasma. Chronic treatment with promazine or imipramine increased concentrations of the parent compounds and their demethylated metabolites, and prolonged their half-life in the plasma and brain. The plasma level of promazine sulphoxide did not change, and its brain level was decreased by chronic treatment with promazine. The half-life of promazine sulphoxide was prolonged in the plasma but shortened in the brain after repeated administration of promazine. The observed considerable amounts of desmethylpromazine and promazine sulphoxide, formed in vivo, suggest that the two compounds are major metabolites of promazine, and that the metabolic pattern of promazine in the rat and man is similar. PMID- 8688886 TI - The effect of amitriptyline on the cell-mediated immunity of stressed rats. AB - The effects of single and repeatedly administered amitriptyline (10 mg/kg ip) on the ability of the splenocytes of the restraint-stressed (for 2.5 h) Sprague Dawley rats to induce the Graft versus Host (GvH) reaction in vivo and to respond to the concanavalin A (Con A) stimulation in vitro were studied. In acute experiments single immobilization, amitriptyline administration, or single amitriptyline treatment of the previously stressed rats did not change the reactivity of splenocytes to both mitogen and alloantigens. On the other hand, in the "chronic" experiment, when rats were stressed 2.5 h daily for five days with or without concurrent amitriptyline treatment, a statistically significant decrease in the reactivity of splenocytes to Con A and increase in the reactivity to alloantigens were visible only in the stressed, but not in stressed, amitriptyline treated animals. PMID- 8688887 TI - The influence of selected antiarrhythmic drugs on the hemodynamic parameters in rabbits during anesthesia. Part I. Propofol anesthesia. AB - Cardiac arrhythmia can be a serious complication during general anesthesia. On the other hand, there is a need for general anesthesia of patients suffering from cardiac arrhythmias and using antiarrhythmic drugs. The aim of the present experiments was to establish the way in which procainamide, N-acetyl procainamide, verapamil and propranolol influence hemodynamic parameters of rabbits during propofol anesthesia. The experiments were performed on rabbits. Heart rate was counted from ECG. Blood pressure was measured directly in the carotid artery. Cardiac output, stroke volume, and total peripheral resistance were estimated using the method of human Cr51 albumin dilution. Hepatic blood flow was estimated after single injection of 99mTc/Sn Hepida. Renal blood flow was estimated after a single injection of 125J-hippurate. Propofol decreases renal and hepatic blood flows, decreases blood pressure and peripheral vascular resistance. Propranolol given alone or in combination with propofol decreases hepatic blood flow. The administration of antiarrhythmic drugs during propofol anesthesia decreases renal blood flow. Propofol decreases blood pressure in rabbits as a result of decreased peripheral vascular resistance. It also decreased RBF and HBF. Disadvantages of interactions of propofol and antiarrhythmic drugs concern mainly with RBF and HBF. Propranolol (given alone or in combination with propofol) strongly decreases HBF. NAPA given during P anesthesia exerts a weaker effect on HBF. The administration of antiarrhythmic drugs during propofol anesthesia decreases RBF. The strongest disadvantageous action is exerted by propranolol, the slightest one--by verapamil. PMID- 8688888 TI - The influence of selected antiarrhythmic drugs on the hemodynamic parameters in rabbits during anesthesia. Part II. Thiopental anesthesia. AB - The aim of the study was to investigate the combined influence of thiopental and antiarrhythmic drugs: procainamide, N-acetylprocainamide, verapamil or propranolol on hemodynamic parameters in rabbits: arterial blood pressure, heart rate, cardiac output, stroke volume, peripheral vascular resistance, renal and hepatic blood flows. Propranolol used during thiopental anesthesia deepened the decrease of hepatic and renal blood flow resulting from the action of the anesthetic drug. Verapamil in a dose that did not change hepatic blood flow caused significant decrease of that parameter during thiopental anesthesia. Other hemodynamic changes observed after administration of antiarrhythmic drugs during thiopental anesthesia are essentially similar to those resulting from the action of antiarrhythmic drugs alone. The administration of procainamide or N acetylprocainamide during thiopental anaesthesia in rabbits had no significant influence on hemodynamic changes evoked by thiopental alone. Verapamil injected to rabbits together with thiopental caused a significant decrease of blood flow in the liver, which was not observed after thiopental alone or verapamil alone. Propranolol injection together with thiopental caused a decrease of blood pressure, heart rate, cardiac output but an increase of vascular peripheral resistance, which was similar to the action of propranolol alone. Propranolol administered during thiopental anesthesia caused a significant decrease of the renal and hepatic blood flow, more marked than after the injection of that beta blocker alone. PMID- 8688890 TI - The influence of new 9-(omega-[4-(2-pyrimidinyl)-1-piperazinyl]alkyl) pyrimidino[2,1-f]purines on the central nervous system. AB - Synthesis and the results of preliminary pharmacological evaluation of four new 9 substituted pyrimidino[2,1-f]purines, containing pyrimidinyl-piperazine substituent are described. Some of these substances induced hypothermia, antagonism of amphetamine action and neurotoxic effects. All compounds had weaker activity on the central nervous system than previously studied compounds containing phenyl-piperazine substituent. PMID- 8688889 TI - The effect of coronary angioplasty on superoxide anion generation and lipid peroxidation. Propriety of pharmacological intervention. AB - In patients with unstable angina pectoris, subjected (n = 20) or not subjected (n = 12) to percutaneous transluminal coronary angioplasty (PTCA), baseline superoxide anion (O.2-) generation by neutrophils in the coronary sinus blood was significantly higher than that found in the basilic vein blood of control healthy subjects (n = 12). During reperfusion following effective PTCA, neutrophil counts in the coronary sinus blood tended to decrease, an effect accompanied by a significant decrease in the neutrophil O.2- generation and enhancement of blood plasma lipid peroxidation as reflected by increased malonyldialdehyde concentrations. PMID- 8688891 TI - Immunomodulating activity of Echinacea gloriosa L., Echinacea angustifolia DC. and Rudbeckia speciosa Wenderoth ethanol-water extracts. AB - The effect of the ethanol-water extracts of Echinacea gloriosa L., Echinacea angustifolia DC. and Rudbeckia speciosa Wenderoth on immunological system of inbred mice was investigated. The extract of the root of Rudbeckia speciosa had the highest immunostimulatory activity. PMID- 8688892 TI - The role of calcium channel entry blocker in experimental ischemia-reperfusion induced intestinal injury. AB - The effect of verapamil on mesenteric ischemia reperfusion trauma was evaluated. Ischemia was performed with clamping a mesenterica superior for a period of 15 min. In 55 rats in histopathologically investigated group, the abdomen was opened 4 h after from ischemia and intestinal biopsies were performed. 55 rats were classified into 5 groups. In the first group 13 rats were chosen as control, in the second group 11 rats were chosen as SHAM control. Only midline incision was made for these animals without superior mesenteric artery clamping; in the third group (n = 10) intravenous verapamil (0.3 mg/kg) was given 15 min before ischemia; in the group 4 (n = 10) 10 min after ischemia; in the group 5 (n = 11) 10 min after reperfusion. There was statistically significant difference between group 2 and group 1 in injury severity (p < 0.05). Similarly, the injury severity of group 3 was statistically significant as compared to group 1 (p < 0.05). There was no significant change in severity of injury in group 4 and group 5 as compared to group 1 (p > 0.05). We concluded that verapamil was protective when administered during the ischemic period but did not exert this action if administered after established ischemia. PMID- 8688893 TI - Failure of excitatory amino acids receptor agonists NMDA and quiscalate to affect the cell proliferation. AB - The effects of NMDA and quiscalate on proliferation of primary cell cultures of human glioma, rat estrogen induced pituitary tumor and mouse spleen lymphocytes were investigated in vitro. The tritiated thymidine incorporation into DNA was used as an index of cell proliferation. Neither NMDA nor quiscalate affected the tritiated thymidine incorporation in the cell cultures herein studied. This finding contradicts the idea of the involvement of EAA receptors in the control of cell proliferation although does not exclude it. PMID- 8688894 TI - Conditioned place preference after prolonged pre-exposure to ethanol. AB - Conditioned place preference (CPP) paradigm has been used to test ethanol (EtOH) rewarding properties after repeated (20 days) injections of EtOH. Rats injected with 0.5 g/kg ip of EtOH during pre-exposure period and CPP procedure showed significant place preference to the compartment paired with the drug. Animals receiving higher dose of EtOH (1.0 g/kg) showed no CPP but rather relative aversion to the paired compartment (relatively to saline-treated group). Our result suggests a development of sensitization to EtOH rewarding effect after prolonged administration of low dose of EtOH. PMID- 8688895 TI - Antagonism of behavioral effects of electroconvulsive shock but not those of desipramine by the selective 5-HT-3 receptor antagonist, ondansetron. AB - The influence of ondansetron (ON) on desipramine (DMI) and electroconvulsive shock (ECS) effects in the open field (OFT) and forced swim test (FST) were studied in Wistar male rats. ON failed to influence the action of DMI but abolished stimulatory effect of ECS in the OFT and, in the lower dose (0.01 mg/kg) reduced ECS action in the FST. This result suggests that 5-HT-3 receptors are involved in behavioral effects of ECS but not DMI. PMID- 8688896 TI - Scavenging of reactive oxygen species as the mechanism of drug action. AB - Reactive oxygen species (ROS) are generated when oxygen is supplied in excess and/or its reduction is insufficient. The best explored ROS are superoxide anions, hydroxyl radicals and hydrogen peroxide. The first two are free radicals. ROS are harmful for the living cells and are implicated in a variety of pathological processes and diseases. Drugs used in the treatment of these states are either stimulators of endogenous defense mechanisms against ROS or inhibitors of ROS formation. Six groups of anti-ROS substances have been described in this paper. 1) Antioxidant substances used in substitutive therapy such as enzymes (e.g. superoxide dismutase), substances containing thiol groups and vitamins (A, E, P, C). 2) Chelating agents (e.g. desferoxamine), which lower the level of prooxidative transition metal ions. 3) Inhibitors of superoxide ions generation by stimulated cells or xanthine oxidase. Such mechanism of action was described for xanthine oxidase inhibitor-allopurinol. 4) Superoxide scavengers. Many known drugs were investigated for this activity, but the best documentation was presented for flavonoids. 5) Substances which eliminate hydrogen peroxide, mainly glutathione and its precursors. 6) Scavengers of hydroxyl radicals. Studies of the above activity were conducted mainly using an unspecific method--estimation of malondialdehyde generated during the action of hydroxyl radicals on lipids or on desoxyribose. Inhibition of malondialdehyde formation was described for many drugs of plant and synthetic origin. PMID- 8688897 TI - Lack of a strong influence of neuroleptic decanoates on dopaminergic and GABAergic functions. AB - Data concerning the incidence of extrapyramidal symptoms and the development of the supersensitivity to dopamine after administration of depot neuroleptics are controversial. The aim of the study was to examine the influence of depot neuroleptics on the sensitivity of dopamine receptors and GABA nigral receptors. Haloperidol decanoate (30 or 60 mg/kg im) and fluphenazine decanoate (12.5 or 25 mg/kg im) were injected twice at a 15 day interval. These treatments induced weak but very long-lasting catalepsy (60-105 days depending on the neuroleptic and its dose). The only significant enhancement of the apomorphine (0.25 mg/kg sc) stereotypy was observed 135 days after the lower dose of haloperidol and 230 days after the lower dose of fluphenazine. Haloperidol decanoate (30 mg/kg) did not influence the number of contralateral rotations induced by muscimol (10 or 25 ng/0.5 microliter) injected into the substantia nigra pars reticulata 35, 55 and 135 days after the first injection. Present results indicate that the dopaminergic supersensitivity after administration of depot neuroleptics is weak and appears very late, and that haloperidol decanoate does not induce nigral supersensitivity to GABA. It is suggested that the depot neuroleptics might induce less extrapyramidal symptoms in the clinic than the daily neuroleptic treatment. PMID- 8688898 TI - [Fertility]. PMID- 8688899 TI - [Should patients be informed of potential but not confirmed risks of cancer linked to menopausal hormone replacement treatment?]. PMID- 8688900 TI - [Vitamin supplementation for pregnant women]. PMID- 8688901 TI - [Individual screening of breast cancer: the gynecologists's point of view]. PMID- 8688903 TI - [Antalgic treatment in pelvic pain]. AB - We study indications, advantages, disadvantages and dosage of different antalgic for pelvic pain. Peripheral antalgics are listed in 3 groups in accordance with their properties: purely antalgic, antalgic-antipyretic, antalgic-antipyretic and anti-inflammatory. -Central drugs are listed in accordance with their narcotic properties or not, and the power of their pharmacological action. PMID- 8688902 TI - [Prognostic value of uterine arteries Doppler blood flow during in vitro fertilization]. PMID- 8688904 TI - [Prevention of sexually transmitted diseases. The norwegian experience]. AB - A significant decrease in the incidence of most STDs has been reported in Norway during the last decade, especially the last 5 years. Today, syphilis, hepatitis B and gonorrhoea are almost non-existent with incidence rates (IR) of 1.1, 0.9 and 4.4 per 100,000 respectively. The frequency of genital herpes, however, has remained unchanged (IR = 45), while chlamydial infection has shown a decrease of 13% during the last year (IR women = 240). The Chlamydia epidemic became evident in the early 1980-ies and since then has represented the major threat to the reproductive condition in young women resulting in PID, tubal occlusions and ectopic pregnancies. In Norway a preoperative screening program in connection with the performance of abortions was introduced 8-9 years ago. Since then a gradual decrease in the frequency of chlamydial positivity has been notified. At our hospital a reduction of 75% (from 11.7% to 3.1%) in the prevalence of C. trachomatis has been observed in women seeking abortion. The decrease is evident is all age groups, but predominantly in those below 25 years. At the same time the frequency of PID has decreased by 80%, while so far only a slight reduction in the frequency of ectopic pregnancies has been observed. Public and professional awareness, together with an increased prescription of anti chlamydial drugs to women with genital infections may have contributed to this decrease. Partner tracing is not satisfactory, being performed in only one out of 5 cases. A new act for the prevention of communicable diseases will be introduced next year. This act will make partner notification mandatory and STD treatment free of charge. In Norway, 350,000 chlamydial tests (8 per 100 inhabitants) are performed per year, 39% in women < 25 years. Even today the age-specific prevalence of these women are so high that Chlamydia screening is cost-effective. PMID- 8688905 TI - [Physiological review of the mammary gland development during pregnancy]. AB - The mammary gland underwent during pregnancy morphological, histological and physiological modifications that ensure the lactation in the post-partum. On the morpho-histological side, the epithelial growth and the milk synthesis during pregnancy allow secondary the lactation. The physiological modifications, beside the endocrines factors such as prolactin, estrogens, progesterone or growth hormone, lead to an auto-paracrines interactions involving the growth factors and the molecules synthetized by the extracellular matrix. PMID- 8688906 TI - [Vaginismus]. AB - This paper defines vaginismus in depth, discusses therapeutic options with emphasis on the psycho-therapeutic approach in combination with behavioural therapy. Of 26 couples completing such treatment, 22 (85%) on completion were able to achieve full penetrative intercourse without discomfort and reported greater fulfillment in their sexual relationship. Although not all wanted to conceive, seven have since reported a pregnancy. PMID- 8688907 TI - [Human embryo cryopreservation: current state in France (1985-1993). French Federation of IVF Biologists]. AB - The French Federation of IVF Biologists (BLEFCO) reports the first survey on the fate of 102,812 human embryos frozen in France during a nine-year period (1985 1993). Ninety-four per cent of surviving embryos were transferred to the parental couple, 6% were thawed to conclude their storage while embryo donation remained exceptional (0.2%). Fifty-five per cent of all thawed embryos survived the freeze thaw procedure. However, only 3.5% of the transferred embryos achieved full-term development (as compared to 9% for unfrozen embryos). Thus, embryo freezing efficiency remains low but high14 variable among different centers. Therefore, cryopreservation has led to the birth of more than 1,200 babies and for several group, has contributed up to 22% of IVF deliveries. The variability observed in the results can be largely related to the adequacy of programmable freezers. Indeed, 68% of frozen embryos survived after thawing in case of manual seeding (15% pregnancy per transfer) versus 42% in case of automatic seeding (9% pregnancy per transfer p < 0.001). Freezing has no adverse effect on the rate of anomalies at birth (1.8%). PMID- 8688908 TI - [Recurrent vaginal candidiasis. Reflections of a psychosomatic gynecologist]. AB - Chronic vaginal candidiasis is a frequent reason for consulting a doctor and its treatment is not simple. Emotional and psychological pain due to the duration make it not only a medical problem. Psychological and organic factors are combined. The use of the body shows the archaism of the psychological function of the patient. It's by studying the past of these women that we can really understand the interaction between the psychological and organic functioning. The somatic symptoms express a pain. The result for these women is a breakdown in their personal balance, either in their present or in the past, particularly in the development of their femininity. Psychodynamic theories can help us to take these patients in charge by giving them a psychosomatic dimension to chronic candidiasis. PMID- 8688909 TI - [Validation of a questionnaire for the evaluation of the quality of life in menopause]. AB - A 15 item-questionnaire designed and weighted by experts has been validated in terms of acceptability, validity, reproducibility and responsiveness. This French original tool allows a precise clinical evaluation of quality of life in menopausal women and of its changes with hormonal therapy. PMID- 8688910 TI - Comparison of the pharmacological characteristics of 2-[125I]iodomelatonin binding sites in the lung, spleen, brain and kidney of chicken. AB - We have compared the pharmacological characteristics of 2-[125I]iodomelatonin binding to crude membrane preparations of the lung, spleen, brain and kidney of chicken. Saturation studies indicated significant differences (p < 0.05) in the equilibrium dissociation constant (Kd) and maximum number of binding site (Bmax) values among the four tissues studied. The descending order of affinities was lung = spleen > brain > kidney. Competition curves of 2-[125I]iodomelatonin binding to crude membrane preparations of all four chicken tissues by melatonin were studied simultaneously to reduce individual, physiological, age and interassay variations. Similar competition experiments were also performed on 2 phenylmelatonin, 2-iodomelatonin, 6-chloromelatonin, 6-hydroxymelatonin and N acetylserotonin (NAS). Concentrations of indoles which inhibited 50% of specific 2-[125I]iodomelatonin binding (IC50) were calculated. The IC50 of 2 [125I]iodomelatonin inhibition curves by the indole compounds in different tissues showed the following descending orders of affinity: (1) melatonin: lung = spleen > brain > kidney, (2) 2-phenylmelatonin: lung = spleen = brain = kidney, (3) 2-iodomelatonin: lung = spleen = kidney > brain, (4) 6-chloromelatonin: lung = spleen = kidney > brain, (5) 6-hydroxymelatonin: kidney > lung = spleen = brain, and (6) NAS: kidney > lung = spleen > brain. The non-hydrolizable GTP analog, guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S), exhibited differential effects on the saturable binding of the four tissues. GTP gamma S increased the Kd of 2-[125I]iodomelatonin binding by 2- to 3-fold in the lung and spleen, 0.5 fold in the brain and 1-fold in the kidney. Based on our findings, we would like to suggest that the 2-[125I]iodomelatonin binding sites in these four tissues may belong to three different high affinity (picomolar) subtypes of melatonin receptor. We name them cML1A represented by the lung and spleen, cML1B by the brain and cML1C by the kidney. PMID- 8688911 TI - Time course of the melatonin-induced increase in glutathione peroxidase activity in chick tissues. AB - The hormone synthesized by the pineal gland, melatonin, has been shown to be a direct free radical scavenger both in vivo and in vitro. Thus, it potently protects cells from the damage induced by oxidative agents. In this study, we demonstrate that melatonin increases glutathione peroxidase activity in several tissues from chicks. This stimulation is time dependent and maximal increases are seen 90 min after melatonin injection (500 micrograms/kg intraperitoneally), although enzymatic activity is still elevated 135 min after its administration. No significant increases were detected 45 min after the injection. Glutathione peroxidase is generally considered to be an important antioxidative enzyme because it metabolizes hydrogen peroxide and other hydroperoxides. Thus, melatonin not only is a direct scavenger of toxic radicals but in an avian species, as in mammals, it stimulates the antioxidative enzyme glutathione peroxidase. The ability of melatonin to increase glutathione peroxidase activity is consistent with its general role as an antioxidant. PMID- 8688914 TI - Bat brings rabies to Britain. PMID- 8688912 TI - Different regulation of the formation of intra- and extracellular oxygen radicals in macrophages. AB - The formation and accumulation of reactive oxygen species within liver macrophages and their release into the medium were determined by lucigenin enhanced chemiluminescence, the reduction of cytochrome c, the formation of formazan from nitroblue tetrazolium and the fluorescence of 5- (and 6)-carboxy 2',7'-dichlorodihydrofluorescein. Zymosan, phorbol ester and fluoride induced the formation and accumulation of oxygen radicals intra- and extracellularly, ionomycin and lipopolysaccharide led to an intracellular accumulation of oxygen radicals, while after arachidonic acid and tumor necrosis factor-alpha, no reactive oxygen species were formed. While zymosan and phorbol ester predominantly induced the formation and release of superoxide, hydroperoxide was the main form released by fluoride. These results indicate that agents of different biological potencies induce reactive oxygen species within and/or outside liver macrophages and that different techniques must be used to detect different oxygen species within and outside cells. PMID- 8688913 TI - Hemodynamic effects of centrally administered adrenomedullin (13-52) in anesthetized rats. AB - This study was conducted to investigate the effect of intracerebroventricular administration of adrenomedullin (13-52) [ADM(13-52)], a novel hypotensive peptide, on the hemodynamic parameters of anesthetized rats. ADM(13-52) was administered centrally in a dose of 0.4-3.2 nmol/kg. It provoked marked, prolonged and dose-dependent increases in mean arterial blood pressure, heart rate, stroke volume, cardiac index, left ventricular pressure, left ventricular dp/dtmax and dp/dtmin, but reduction in total peripheral resistance index. In addition, intracerebroventricular administration of ADM(13-52; 1.6 nmol/kg) provoked a marked increase in renal sympathetic nerve activity. Intracerebroventricular administration of artificial cerebrospinal fluid had no effect on the hemodynamic parameters and renal sympathetic nerve activity. The results indicate that ADM(13-52) exerts a central action on the cardiovascular system. The mechanisms of hemodynamic changes induced by central ADM(13-52) were preliminarily analyzed in this study. ADM might play a role in the central control of the cardiovascular system, although the confirmed mechanisms and the physiological implications are undetermined. PMID- 8688915 TI - Legionella and the European Council for Package Travel. PMID- 8688916 TI - AIDS and HIV-1 infection in the United Kingdom: monthly report. PMID- 8688917 TI - The effect of detachment of cultured epithelial sheets on cellular ultrastructure and organisation. AB - In this morphological study the (ultra)structural changes that lead to contraction of detached cultured epithelium were investigated. Keratinocytes, isolated from human skin and oral mucosa, were grown to form stratified cell sheets. The multilayers were examined with light and electron microscopy before, during and after detachment from the culture vessel. Attached epithelium had a stretched morphology with flattened cells and nuclei. Evidence is provided that after enzymatical detachment with dispase (1) basal cells became columnar by contraction of actin bundles in the basal cortex, which was accompanied by blebbing of the basal cell membrane; (2) in all cell layers cytokeratin bundles contracted resulting in displacement of desmosomes and a spherical shape of the cells and nuclei. By slow dispase-detachment at 4 degrees C or by quick mechanical detachment, shrinkage of the sheet was partly suppressed but contraction of cytokeratin and related events occurred indicating that these were the result of the spontaneous reassembly of the intermediate filament system. The results suggested that the shape and ultrastructure of all cells in an epithelial multilayer are dependent on the interaction of the basal cells with the underlying extracellular matrix. PMID- 8688918 TI - Epidermal growth factor receptor expression on human breast luminal and basal cells in vitro. AB - The expression of EGF receptors has been studied on luminal and basal cells of human breast in vitro. Primary cultures of normal adult human breast epithelium were prepared as single cell suspensions containing a mixture of luminal and basal cells. The cells were simultaneously immunolabelled with antibodies recognising EMA (luminal epithelial cells), CALLA/CD10 (basal cells) and the epidermal growth factor receptor (EGFR). Flow cytometric analysis of these triple labelled cells detected low levels of EGFR on both cell types, with proportionally more EGFR on basal cells compared with luminal cells. Separated populations of basal and luminal cells were prepared from single cell suspensions by flow sorting or by immunomagnetic methods and cultured with and without EGF. Increased proliferation was detected in both cell types in the presence of EGF. To determine the localisation of the EGF receptor, purified cell populations were immunolabelled with anti-EGFR antibody and an FITC-labelled second antibody for fluorescence light microscopy and colloidal gold-labelled antibody for scanning electron microscopy (SEM). Low levels of EGFR were detected by indirect immunofluorescence on both cell types with higher levels on basal cells compared with luminal cells. The detailed subcellular distribution of the receptor was examined by SEM, with gold-labelling of EGFR detected using a field emission scanning electron microscope with a YAG crystal backscattered electron detector. Both luminal and basal cells expressed EGFR over the upper surface of individual cells when these were growing in isolation, but when cells formed part of a confluent island, levels of EGFR on the upper surface of cells were obviously reduced. Observations made by SEM on cells at the edges of such confluent islands showed that cultured basal cells expressed much higher levels of EGFR on their basal, as compared with their upper surfaces. PMID- 8688919 TI - Immunofluorescence and immunoblot studies on the reactivity of pemphigus vulgaris and pemphigus foliaceus sera with desmoglein 3 and desmoglein 1. AB - We have investigated expression of pemphigus vulgaris (PV) antigen, desmoglein 3 (Dsg3), and pemphigus foliaceus (PF) antigen, desmoglein 1 (Dsg1), in various tissues. Immunofluorescence studies suggested that Dsg1 and Dsg3 are preferentially expressed in the upper and lower epidermis, respectively. With immunoblotting of human epidermal extracts, all PV sera reacted with Dsg3 but not with Dsg1. By contrast, only half of PF sera reacted with Dsg1 but none reacted with Dsg3. These results confirm the distinct antibody specificity between PV and PF sera. They also suggest that PV sera contain antibodies against linear epitopes present even on the denatured antigen, while some PF sera contain antibodies only against conformational epitopes present on the native antigen. With immunoblotting of bovine desmosome preparations, certain PV sera and an anti Dsg monoclonal antibody reacted with both Dsg1 and Dsg3. Affinity-purification of these PV antibodies suggested that the simultaneous reactivity with Dsg1 and Dsg3 was produced by two different subsets of antibodies and not by cross-reactivity of single antibodies. This study indicates that pemphigus serum is a useful probe with which we learn various aspects of keratinocyte biology. PMID- 8688920 TI - A hemidesmosomal transmembrane collagenous molecule, the 180-kDa bullous pemphigoid antigen (BPA II), is phosphorylated with 12-O-tetradecanoylphorbol-13 acetate in a human squamous cell carcinoma cell line (DJM-1). AB - We have previously shown that the 180-kD bullous pemphigoid antigen (BPAII), which is a transmembrane collagenous protein of hemidesmosomes, is distributed at adhesion sites on glass coverslips on the basal membrane forming a concentric ring, or arch pattern, in a human squamous cell carcinoma cell line (DJM-1), when studied by immunofluorescence microscopy using monoclonal antibodies to BPA II. This concentric ring/arch pattern of "footsteps" of BPA II has been shown to be collapsed in association with a transient activation of protein kinase C by treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA). In the present study, therefore, the effects of TPA on the phosphorylation of BPA II was examined. DJM 1 cells, which were metabolically labelled with [32Pi], were lysed and the extracts were subjected to immunoprecipitation with anti-BPAII and anti-230 kDa bullous pemphigoid antigen (BPAI) monoclonal antibodies. The results showed that only BPA II, but not BPA I, was phosphorylated at serine residues before TPA treatment. After TPA treatment phosphorylation was prominently increased so as to generate a 190 kDa-phosphorylated peptide. This 190-kDa peptide was reacted with anti-BPA II monoclonal antibodies by immunoblotting, and it was not detected when cells were pretreated with a specific protein kinase C inhibitor (H7) before TPA treatment, suggesting that the 190 kDa peptide is phosphorylated BPAII with TPA. Prolonged treatment with TPA abolished both of 180- and 190-kDa BPA II from Triton X-100-soluble fractions. These findings suggest that the BPA II, but not BPA I, is a substrate of protein kinase C, and the generation of 190-kDa phosphorylated BPA II has a key role in the TPA-induced collapse of the assembly of BPA II on the basal plasma membrane, probably, at hemidesmosomes. PMID- 8688921 TI - The isolation and culture of adult mouse colonic epithelium. AB - A technique is described for the reproducible primary culture of colonic epithelium from adult mice. A collagenase-dispase digestion technique (adapted form Evans et al. 1992) is used to release the epithelium, followed by differential sedimentation to produce a high purity crypt preparation with maintained structural integrity and minimal mesenchymal contamination. The crypt units attach to collagen coated plastic within 24 h and the epithelial cells quickly begin to migrate outwards producing a monolayer surrounding the attached crypts. Electron microscopy revealed that the migrating epithelial cells possessed both desmosomes and microvilli. Proliferation in the colony supports the outward migration of cells until the migratory cells of adjacent colonies connect and a confluent monolayer begins to form. Proliferation is routinely maintained for 10 days (although cultures have now been maintained without subculturing for 35 days) and is demonstrated by increased cell numbers in spite of continuous cell loss into the culture media. Culture growth is enhanced by increasing concentrations of fetal calf and mouse serum and EGF but does not appear to respond significantly to added transferrin. Growth is also stimulated by a murine small intestinal extract thought to contain a potentially novel growth factor or cocktail of factors. This culture model has considerable potential for studies on growth factor control of this carcinoma susceptible tissue and its differentiated function as well as studies into the mechanisms of carinogenesis. PMID- 8688922 TI - Stimulation of HT29-D4 cell growth by excretory/secretory products of the parasite nematode Trichostrongylus colubriformis. AB - The presence of the nematode parasite Trichostrongylus colubriformis in the small intestine is associated with an increase in epithelial renewal. To assess the possible role of excretory/secretory products from the worm on cell proliferation, adult Trichostrongylus colubriformis were incubated in vitro in Dulbecco's Modified Eagle's Medium for 24 h and the conditioned medium was added to the culture medium of the transformed epithelial cell line HT29-D4. A stimulation of the HT29-D4 cell growth was ascertained at concentrations of 0.25 1.0 micrograms protein/ml using counts of cell numbers, the MTT method and incorporation of tritiated thymidine. An increased incorporation of tritiated thymidine was also observed with the excretory/secretory products from T. colubriformis fourth stage larvae at 1.0 microgram/ml. Dialysis of the medium conditioned by the worms indicated that the molecular weight of the factor is greater than 8000 Daltons in size. Heat treatment, acid hydrolysis and precipitation by trichloracetic acid of the conditioned medium resulted in the disappearance of the proliferative effect while treatment with trypsin partially depleted the stimulative activity. These results suggest that T. colubriformis produce some protein factor which could increase the epithelial regeneration in the host small intestine. PMID- 8688924 TI - Use of experimental and quasi-experimental methods for data-based decisions in QI. AB - BACKGROUND: Decisions made by quality improvement (QI) teams, as reported in the literature, are usually based on nonexperimental methods for data collection. Pretest-posttest designs, in particular; are common in reports of QI teams' evaluations of changes or interventions. Yet in such designs the results are inherently confounded; it is impossible to rule out alternative explanations for any differences found. USING EXPERIMENTAL METHODS TO MAKE QI DECISIONS: As suggested by one study, QI teams can design and implement experimental interventions in relevant organizational processes. In an attempt to reduce the no-show rate for first appointments at a Residents Clinic at the Medical University of South Carolina (Charleston), the Youth Outpatient Improvement Team designed an experiment to test two possible modifications to the admission process. Those seeking services were randomly assigned to one of three groups (the control group or one of the experimental groups). Not only did results not support the team's hypothesis that one of the experimental procedures would produce a lower no-show rate, subjects in the experimental groups were less likely to enter treatment. Given these data, the decision was made to maintain current admission procedures. CONCLUSIONS: Since the quality of a decision is dependent on the quality of the data on which it is based, QI teams should consider experimental methods when planning data collection to evaluate their recommended interventions. When such methods are not feasible, quasi-experimental strategies can be used to strengthen the quality of nonexperimental data. PMID- 8688923 TI - The California Hospital Outcomes Project: using administrative data to compare hospital performance. AB - BACKGROUND: The California Hospital Outcomes Project was created by an act of the state legislature in 1991. The California Office of Statewide Health Planning and Development (OSHPD) publishes annual reports on risk-adjusted hospital outcomes for medical, surgical, and obstetric patients. These outcomes indicators were chosen: in-hospital mortality within 30 days (acute myocardial infarction [AMI]), reported post-operative complications (diskectomy, delivery), post-operative length of stay (diskectomy), and readmission within 6 weeks (delivery). Project reports are based on discharge abstracts submitted by hospitals and edited by OSHPD. For each outcome, two risk adjustment models were used to estimate expected and risk-adjusted hospital outcome rates, along with p values representing the likelihood that the observed number of adverse outcomes occurred by chance. RESULTS: The first hospital outcomes report was distributed to hospitals in June 1993 and released to the public in December 1993. The total number of hospitals labeled as "better than expected" was 14 for AMI, 5 for cervical diskectomy, and 25 for lumbar diskectomy. The second hospital outcomes report was distributed to hospitals in June 1995. RESPONSE AND CONCLUSIONS: Letters submitted for 168 hospitals in response to the 1993 report demonstrated that hospitals had studied and used project results to evaluate their coding practices and quality of care. Media coverage of the 1993 report was balanced but sometimes critical of OSHPD's failure to identify "worse" hospitals. In response to providers' concerns, OSHPD has undertaken a validation study to explore whether differences in coding, unmeasured risk factors, or processes of care explain the reported differences in risk-adjusted outcome rates. PMID- 8688925 TI - An inpatient diabetes QI program. AB - OBJECTIVE: The goal of this study was to establish a continuous quality improvement (CQI) program for diabetes which would identify patterns in the problems of care encountered by hospitalized patients with diabetes and improve the in-hospital process of diabetes care delivery. RESEARCH DESIGN AND METHODS: The laboratory information system in an acute and tertiary care 1,000-bed urban teaching hospital provided us on a daily basis with a list of patients on the medical service having blood glucose (BG) levels < 40mg/dl or > 450mg/dl and positive serum acetones. We performed concurrent implicit chart review when BG levels were hypoglycemic (< 40mg/dl) or hyperglycemic (> 450mg/dl on two occasions) or when diabetic ketoacidosis (DKA) was present (acetones were > 1+) using preset indicators for documentation and appropriate medical management. Data were expressed as the ratio of number of cases in compliance with the indicator over total number of cases identified. A test for trend in proportions was used to assess compliance with the indicators over time. RESULTS: Documentation of nursing unit-based capillary blood glucose (CBGM) and insulin infusion monitoring improved significantly over time (p < 0.001 for both). The medical management of hypoglycemia, hyperglycemia and DKA improved (p = 0.1) over the three-year period. Identification of recurrent multidisciplinary process problems in the management of DKA, intravenous insulin infusion constitution and delivery, CBGM determination in the setting of anemia, and recognition of clinical settings conducive to the development of hypo- and hyperglycemia were identified and addressed with standardization in documentation, an insulin infusion protocol, administrative rules, and staff education. CONCLUSIONS: Efforts to standardize specific clinical and documentation processes had a positive impact on the care of hospitalized patients with diabetes and resulted in an institutional effort to improve inpatient diabetes care with a CQI team. PMID- 8688926 TI - Collaborative QI in community-based long term care. AB - BACKGROUND: In a statewide demonstration project funded by The Robert Wood Johnson Foundation, the state of Indiana, vendors, clients and Indiana University researchers began working together in 1992 to use quality improvement (QI) techniques to improve the delivery of community-based long term care services. QI STRATEGIES: These collaborators, working with state Area Agencies on Aging (AAAs) case managers, are implementing two strategies--Normative Treatment Planning (NTP), which standardizes the clinical assessment of client needs and the prescription of services by case managers, and the Client Feedback System (CFS), a systematic method for obtaining feedback from long term care clients on the quality of in-home services. CURRENT STATUS: This community-based long term care project has been implemented in AAAs throughout the state of Indiana. In January 1995 the state's 16 AAAs were randomly assigned to four experimental or control groups to assess the project's effectiveness. In the interim, clients are surveyed by telephone every six months to evaluate their satisfaction with services and clinical needs. LESSONS LEARNED: The experience suggests several lessons: (1) build on existing and successful activities; (2) involve a wide range of participants, not just innovators; (3) obtain buy-in from trade and professional associations that represent program participants; (4) turn national attention given to the program into an asset; (5) conduct separate data collection to evaluate an intervention's success; (6) visit the field often; (7) pay as much attention to program implementation as to development; and (8) provide ongoing, informal educational opportunities for the field. SUMMARY AND CONCLUSIONS: This project has resulted in significant movement toward a shared quality improvement vocabulary, information system, and a shared vision of high quality home care. PMID- 8688927 TI - Notes on the changing face of health professions education. PMID- 8688928 TI - [The venous bed of the central nervous system in disorders of the cerebral venous circulation]. AB - The morphology and distribution of the vascular changes in the brain and spinal cord, degrees and stages of the intracranial venous congestion course and morphology and dynamics of the venous haemorrhages were studied by means of clinico-sectional observations. Interrelations between vascular changes and anatomic structure were demonstrated so as the topography of the CNS venous bed. PMID- 8688929 TI - [The neurobiological aspects of the regulation of reparative histogenesis]. AB - In mature male rabbits and outbred male rats (body weight 180-280 g) the implantation of the different tissues (adenohypophysis, ventricular myocardium, pharyngeal and bronchial epithelium) with hypothalamic nonapeptidergic nuclei in vivo and in vitro was performed by means of light microscopy, histochemistry, immunocytochemistry, histoautoradiographic (3H Thymidine) and electron microscopy methodics. It is demonstrated that hypothalamic nonapeptides (oxytocin and vasopressin) and monoamines are the interlevel regulatory factors of the proliferation, growth and cytodifferentiation of the different genesis tissues. Their role in realization by tissues of histo- and organotypic potentiality adaptive properties and adequate intercellular correlations in appropriate histotypes is indicated. PMID- 8688931 TI - [The nerve cells of the hemispheric cerebral cortex in an extracranial arterial shunt]. AB - Condition of nerve cells of the cerebral hemisphere cortex was studied in 105 dogs with induced one-side caroticojugular anastomosis in terms from one day to one year. Acute swelling and hydropical reversible changes were found in nerve cells in early stages of the caroticojugular anastomosis existence. Irreversible changes-desquamation and progressing atrophia of nerve cells, leading to appearance of the cell devastation foci in cerebral hemisphere cortex in late stages developed after one month. PMID- 8688930 TI - [The experimental morphological bases for using a microsurgical technic and demineralized bone in the restorative surgery of hollow organs and blood vessels]. AB - By means of experimental material from 339 animals it was shown that microsurgical technique provides primary recovery of the wounds of the hollow organs, their anastomoses and blood vessels: demineralized bone is found to be a suitable material easily adapting in implantation. The use of microsurgical methods and technique and demineralized osseus matrix for nonosseous plastics is a perspective direction in improvement of the results of reconstructive and restorative operations on hollow organ and blood vessels. PMID- 8688932 TI - [The morphology and topography of the vascular changes in the spinal cord in experimental systemic venous stasis]. AB - The data on morphology, topography, dynamic and individual variability of vascular changes in the spinal cord were obtained by means of hystological methods in the experimental morphological study performed in 50 dogs. PMID- 8688933 TI - [The microcirculatory bed of the brain and bulbar conjunctiva in disorders of the venous circulation]. AB - Microcirculatory bed of the brain was studied in patients with cardiac and cardiopulmonary insufficiency. The findings on the biomicroscopic and histological changes in the vessels of the conjunctiva in experimental animals in the systemic venous stagnation were presented. PMID- 8688934 TI - [The structural reorganization of the wall of the inferior mesenteric vein and of its vascular-neural components in fetuses and children]. AB - Structural changes of the inferior mesenteric vein wall and it vascular-nervous apparatus were studied in 93 inferior mesenteric veins of human foetuses and children, aged to 3 years using the complex of histological and neuromorphological methods. While changing the structure of the wall became more complicated in myocyte and fibres number. PMID- 8688935 TI - [The adaptation of the microcirculatory bed of the major veins to the intermittent action of high-altitude hypoxia]. AB - The present research was aimed at studying the structural trace of the adaptation of the large venous vessels microcirculatory bed to the interrupted action of high hypoxia. To obtain the adaptation 94 Wistar line rats were kept every day for 6 hours in the altitude chamber on the modelled height of 5000 meters for 45 days (control group made 20 animals). Intramural vascular bed was revealed by non injective methods. The data obtained showed that morphological changes in the anterior and posterior venae cavae microcirculatory bed responding to hypoxia were of compensatory-adaptive nature and displayed in the increase of arteriolo venulary anastomoses number, growth of all the links capacity and reserve capillaries opening. PMID- 8688937 TI - [Changes in the myocardium of adult rats when cultured in diffusion chambers in vivo]. AB - Morpho-functional changes of left ventricle myocardium were studied in 30 adult male rats by the method of subcutaneous implantation of diffusion chambers. The transplants were examined in 1, 3, 6, 8 and 10 days after the beginning of cultivation. The method of light microscopy at the 1-2 microm sections was used after histological processing of specimens for the identification of muscle and non-muscle cells and studying of their particular changes. In the muscular fibres there were cardiomyocytes of the destructive, survived and reconstructed forms. It was shown that smooth muscle cells and periocytes are separated from blood microvessels and migrated into the interstitial space. Multinuclear drawing rods formated from activational endotheliocytes were detected between the muscular fibers. Furthermore the cells containing large amount of lipid granules ?lypophags? and the two types of macrophage-like cells were demonstrated. The area of growth including fibroblast-like and spindle-shaped cells were observed around the margins of transplants on the late stages of implantation. PMID- 8688936 TI - [The structure of the wall of the normal rat coronary arteries and after chemical sympathectomy]. AB - Methods of transmissive electron microscopy were used for studying the structure of the rat coronary vessels wall in normal state and in chemical quanethidine desympathization. Changes in endothelial cells, in smooth myocytes and in some elements of connective tissue of the magistral heart artery were found in desympathized animals. Appearance of great number of contacts between endothelial cells and smooth myocytes as a response to sympathethic denervation was noted. PMID- 8688938 TI - [A structural analysis of the myocardium in 2-month-old rats cultivated in vitro from the viewpoint of tissue homeostasis]. AB - Ventricular myocardium of 6 mature male Wistar line rats (100-129 g of body weight) cultured in vitro was exposed to the effect of vasopressin, oxitocin, dophamin and norepinephrine. The cell structures were observed by means of light microscopy. Nonapeptides and monoamines were found to cause cardiomyocyte hypertrophy and hyperplasia Vasopressin and oxytocin stimulate the endotheliocyte and myocyte proliferation and interstitial fibrillogenesis. Adequate trophic conditions were created to maintain energetic and anabolic metabolism of the surviving, hypertrophic and reorganizing cardiomyocytes. PMID- 8688939 TI - [The morphofunctional characteristics of the epithelium of the salivary glands and the neuroendocrine regulation of its histogenesis]. AB - Stageness in the protein glands development is influenced by the nervous system mediators. Adrenergic mediation was established not to be developed by the period of provisory differentiation and appears to grow weaker by senile age. Acetylcholine stimulates growth and proliferation in the form of layers and bands. Adrenalin exerts its influence on organotypical level, which manifestates in reservation of the specific differentiation and protein type functioning of the gland. Hypothalamic neurohormones (oxytocin, vasopressin) influence the maintainance of the secretory epithelium viability. PMID- 8688940 TI - [The histogenetic characteristics of the epithelial tissues of the mucosa of the pharyngeal and oral surfaces of the soft palate in ontogeny and under experimental conditions]. AB - Processes of the development and growth of the soft palate mucosas in ontogenesis and also proliferation, growth and differentiation of epithelial structures were studied in the experiment. The epithelium of the soft palate nasal surface was established to be more labile and to be characterized with polymorphism forming single-layer and pseudostratified structures. Under these conditions the oral surface epithelium keeps stratified structures firmly. On the basis of discovered differences of the epithelium biological qualities a suggestion is made on the different genetic origin of epithelial tissues of mucosas of the soft palate oral and pharyngeal surfaces. PMID- 8688941 TI - [The morphofunctional characteristics of the interstitial endocrinocytes (Leydig cells) of the testes in vertebrates under conditions of seasonal change in reproductive activity]. AB - By means of light and electron microscopy the structural organization of Leydig cells was studied in Rana ridibunda, Lacerta agilis, Columba livia in the periods of reproductive activity and reproductive break. The dynamics of structural changes of some parameters of the testicles (interstitial tissue square, endocrinocytes number, state of the cytoplasm, structural components and the volume of nuclei) was shown in the process of the reproductive activity seasonal changes. Nuclear volume and the degree of the agranular endoplasmic reticulum development were found to correlate. Clear dependence between the Leydig cells functional activity and reproductive activity in lizards and pigeons was demonstrated. This dependence is slightly expressed in frog. PMID- 8688942 TI - [The structural-functional changes in the epithelium of the respiratory area of the nose and intrapulmonary bronchi in human ontogeny]. AB - The epithelia of nasal respiratory area and intrapulmonary bronchi were studied in human ontogenesis by means of light and electron microscopy. The results indicate the stageness of morphofunctional organization of epithelia of the organs studied. The succession of the respiratory tract epithelium cytodifferentiation, dynamics of correlation between the epithelial layer cell elements in ontogenesis and peculiarities of ultrastructural organization of the nasal mucosa epithelial cell were established. PMID- 8688943 TI - [The macro- and microscopic topography of the left coronary artery and the great cardiac vein]. AB - Macromicroscopic topography of the left coronary artery, anterior interventricular branch, circumflex branch and vena cordis magna were studied on the heart preparations of 26 corpses of the people aged 19-52. Macromicroscopic preparation and studying the histotopography reveal individual differences in topographic interrelations of the left coronary artery branches and vena cordis magna in sulcus interventricularis and sulcus coronarius, peculiarities of the cardiac coronary vessels relationship with epicardium, subepicardial fat, myocardium and nerve bundles of the anterior cardiac plexus. PMID- 8688944 TI - [An x-ray and anatomical comparison of the surface cerebral veins in connection with surgery of the parasagittal area of the brain]. AB - Cerebral surface veins (CSV) of Parasagittal brain area (PSBA) were studied in 31 angiogrammes of 26 persons' living brains and in 50 cerebral hemispheres of 25 corpses. The comparison of findings showed adequate addition of roentgenoanatomical data concerning the quantity and the distribution of CSV in PSBA, and the character of intervenous anastomosis; it also revealed the brain areas free from CSV and possibility of additional mobilization of dura mater encephali in the surgery of PSBA. PMID- 8688945 TI - [Ontogenetic patterns in the morphology of human venous vessels]. AB - The results of the investigation in the complex study of veins morphology during the pre- and postnatal periods of human ontogenesis were summarized in the Department of Human Anatomy, Orenburg Medical Academy. The subject of our study were the central and organs veins from the system of upper and lower vena cava. The complex of modern morphological methods was used in our investigation. This allowed us to reveal the quantitative changes of macroanatomical parameters (cross section length and square) of veins, and of structural changes of the wall and its vascular-nervous components in ontogenesis. PMID- 8688946 TI - [The macro- and microscopic topography of the extrahepatic bile ducts]. AB - Macromicroscopic topography of extrahepatic biliary ducts was studied on the serial histotopogrammes from the level of gallbladder up to major duodenal papilla. The peculiarities of macroscopic topography and their possible application in microsurgical operations on the extrahepatic biliary ducts were shown. PMID- 8688947 TI - [The histotopography of the fallopian tubes in relation to an anatomical basis for microsurgical interventions]. AB - Histotopographical study of the uterine tube different regions was performed on 50 specimens taken from 25 corpses of reproductive age women who died from the extragenital pathology. The data on peculiarities of the tube different regions structure, its layer expression and interrelations between the surrounding vessels and serous coat were obtained. Anatomic base of the use of microsurgical technique in operative interventions on the uterine tubes was established. PMID- 8688948 TI - [The modern aspects of the microsurgical anatomy of the pancreas]. PMID- 8688949 TI - [New possibilities for F. M. Lazarenko's experimental histological method in the study of tissue biology]. PMID- 8688950 TI - [Technical support for morphometric and stereological research in microsurgical anatomy]. PMID- 8688951 TI - [Means for shaping professional interest during the study of human anatomy]. PMID- 8688952 TI - [Experience with early specialization in the teaching of operative surgery and topographic anatomy]. PMID- 8688953 TI - [Materials on the morphology departments of the Orenburg Medical Academy]. PMID- 8688954 TI - Testing models of female reproductive migratory behaviour and population structure in the Caribbean hawksbill turtle, Eretmochelys imbricata, with mtDNA sequences. AB - Information on the reproductive behaviour and population structure of female hawksbill turtles, Eretmochelys imbricata, is necessary to define conservation priorities for this highly endangered species. Two hypotheses to explain female nest site choice, natal homing and social facilitation, were tested by analyzing mtDNA control region sequences of 103 individuals from seven nesting colonies in the Caribbean and western Atlantic. Under the social facilitation model, newly mature females follow older females to a nesting location, and subsequently use this site for future nesting. This model generates an expectation that female lineages will be homogenized among regional nesting colonies. Contrary to expectations of the social facilitation model, mtDNA lineages were highly structured among western Atlantic nesting colonies. These analyses identified at least 6 female breeding stocks in the Caribbean and western Atlantic and support a natal homing model for recruitment of breeding females. Reproductive populations are effectively isolated over ecological time scales, and recovery plans for this species should include protection at the level of individual nesting colonies. PMID- 8688955 TI - Migration and evolution of lesser long-nosed bats Leptonycteris curasoae, inferred from mitochondrial DNA. AB - We used sequence variation within 297 bp of control region mitochondrial DNA (mtDNA) amplified from 53 lesser long-nosed bats, Leptonycteris curasoae (Phyllostomidae: Glossophaginae) captured at 13 locations in south-western United States and Mexico and one site in Venezuela to infer population structure and possible migration routes of this endangered nectar- and fruit-eating species. Phylogenetic analysis using maximum parsimony and UPGMA confirmed species and subspecies distinctions within Leptonycteris and revealed two clades exhibiting 3% sequence divergence within the Mexican subspecies, L. c. yerbabuenae. Even though many roots contained L. c. yerbabuenae from both clades, weak population structure was detected both by a correlation between genetic differentiation, F(st), and geographical distance and by a cladistic estimate of the number of migration events required to align bat sequences with geographical location on maximum parsimony, as compared to random, trees. Three results suggest that L. c. yerbabuenae are more likely to migrate between sites along the Pacific coast of Mexico or along the foothills of the Sierra Madre Occidental than between these regions. (1) Seventeen of 20 bats which shared an identical sequence were captured up to 1800 km apart but within the same putative migration corridor. (2) Residuals from a regression of F(st) on distance were greater between than within these regions. (3) Fewer migration events were required to align bats with these two groups than expected from random assignment. We recommend analysing independent genetic data and monitoring bat visitation to roost sites during migration to confirm these postulated movements. PMID- 8688956 TI - Widespread geographical distribution of mitochondrial haplotypes in rock-dwelling cichlid fishes from Lake Tanganyika. AB - The spectacularly diverse cichlid fish species flocks of the East African Rift Lakes have elicited much debate on the potential evolutionary mechanisms responsible for the origin of these adaptive radiations. An historical perspective on population structure may offer insights into the processes driving population differentiation and possibly speciation. Here, we examine mitochondrial DNA (mtDNA) sequence variation in two endemic species of rock dwelling cichlids, Simochromis babaulti and S. diagramma, from Lake Tanganyika. Phylogeographic analyses were used to infer what factors might have been important in the genetic structuring of Simochromis populations. Patterns of mtDNA differentiation in Simochromis were compared to those of other rock dwelling cichlids to distinguish between competing hypotheses concerning the processes underlying their evolution. In striking contrast to previous findings, populations of Simochromis, even those separated by up to 300 km, were found to share mitochondrial DNA haplotypes. There is no correspondence between mtDNA genealogies and the geographical distribution of populations. Only S. babaulti, but not S. diagramma was found to have a significant association between genetic and geographic distance. These phylogeographic patterns suggest that the evolutionary effects of abiotic and biotic factors shaping population genetic structure may differ substantially even among closely related species of rock dwelling cichlids. Physical events and barriers to gene flow that are believed to have had a major impact on the geographical distribution and intralacustrine speciation of Tropheus do not seem to have equally strongly affected its close relative Simochromis. These findings emphasize that no single mechanism can be responsible for the formation of population structure, speciation, and the adaptive radiation of all cichlid fishes. PMID- 8688957 TI - A wide-range survey of cross-species microsatellite amplification in birds. AB - The possibility to perform cross-species microsatellite amplification in birds was surveyed by analysing sets of primers developed from the swallow and the pied flycatcher genomes on a panel of 48 different bird species. In total, 162 cases (species/marker combinations) of heterologous amplification were recorded. Ten amplification products were sequenced and all were found to be true homologues of the original loci. There was a significant and negative relationship between microsatellite performance and evolutionary distance between the original species and the tested species. As a rough indicator of expected cross-species microsatellite performance we estimate that 50% of markers will reveal polymorphism in a species with a DNA-DNA hybridization delta T(m)H value of 5 separating it from the original species. This corresponds to a divergence time of = 11 million years before present for passerine birds. The established relationship between performance and evolutionary distance agrees very well with data obtained from some mammalian species. The proportion of polymorphic loci among those markers that amplified decreased with increasing genetic distance, suggesting that few long repeats are preserved during evolution. One of the swallow markers, HrU2, amplified a specific product in all species analyzed and will thus allow access of nuclear sequence data over a broad range of species. The only predictor of cross-species performance was the amount of non-specific amplification seen in the original species. An analysis of 10 species from within the family Hirundinidae with the swallow primers consistently revealed extensive polymorphism with average probabilities of identical genotypes ranging from 6 x 10(-4) to 6 x 10(-7). There were distinct allele frequency differences between the Hirundinidae species and we envisage that microsatellite cross-species amplification will be a useful tool in phylogeny construction and in species identification. PMID- 8688959 TI - Use of microsatellite loci to classify individuals by relatedness. AB - This study investigates the use of microsatellite loci for estimating relatedness between individuals in wild, outbred, vertebrate populations. We measured allele frequencies at 20 unlinked, dinucleotide-repeat microsatellite loci in a population of wild mice (Mus musculus), and used these observed frequencies to generate the expected distributions of pairwise relatedness among full sib, half sib, and unrelated pairs of individuals, as would be estimated from the microsatellite data. In this population one should be able to discriminate between unrelated and full-sib dyads with at least 97% accuracy, and to discriminate half-sib pairs from unrelated pairs or from full-sib pairs with better than 80% accuracy. If one uses the criterion that parent-offspring pairs must share at least one allele per locus, then only 15% of full-sib pairs, 2% of half-sib pairs, and 0% of unrelated pairs in this population would qualify as potential parent-offspring pairs. We verified that the simulation results (which assume a random mating population in Hardy-Weinberg and linkage equilibrium) accurately predict results one would obtain from this population in real life by scoring laboratory-bred full- and half-sib families whose parents were wild caught mice from the study population. We also investigated the effects of using different numbers of loci, or loci of different average heterozygosities (He), on misclassification frequencies. Both variables have strong effects on misclassification rate. For example, it requires almost twice as many loci of He = 0.62 to achieve the same accuracy as a given number of loci He = 0.75. Finally, we tested the ability of UPGMA clustering to identify family groups in our population. Clustering of allele matching scores among the offspring of four sets of independent maternal half sibships (four females, each mated to two different males) perfectly recovered the true family relationships. PMID- 8688958 TI - Cytonuclear genetic structure of a hybrid zone in lizards of the Sceloporus grammicus complex (Sauria, Phrynosomatidae). AB - Lizards of the Sceloporus grammicus complex are comprised of multiple chromosome races that form several zones of parapatric hybridization in central Mexico. We scored diagnostic mitochondrial DNA (mtDNA) haplotypes and autosomal chromosome markers in a sample of 342 lizards from one well-defined zone between 2n = 34 and 2n = 46 races. A two-part analysis was performed on this data set in an attempt to infer the predominant evolutionary forces shaping the cytonuclear structure of this zone. The complications posed by its spatial structure were addressed by analysing a hierarchical series of smaller subsamples chosen to approximate single mating units. Two critical conclusions were drawn from this first-stage analysis. First and foremost, the three chromosomes have largely concordant cytonuclear disequilibrium patterns within each subsample with adequate numbers of individuals for detecting nonrandom cytonuclear associations. This suggests that the cytonuclear structure of this zone is predominantly a result of deterministic genome-wide forces rather than genetic drift of deterministic forces specific to individual chromosomes or loci. Second, the fit of a series of migration models to the data shows that the cytonuclear structure of the subsamples is well accounted for by continued gene flow from the two parental races alone, with random mating with respect to cytonuclear genotype and no other evolutionary forces. These results motivate several further empirical and theoretical investigations to refine our understanding of the relative roles of migration and other potentially important forces such as natural selection and genetic drift, in this and other hybrid zones. PMID- 8688960 TI - Diversity and distribution of subterranean bacteria in groundwater at Oklo in Gabon, Africa, as determined by 16S rRNA gene sequencing. AB - This paper describes how ground water was sampled, DNA extracted, amplified and cloned and how information available in the ribosomal 16S rRNA gene was used for mapping diversity and distribution of subterranean bacteria in groundwater at the Bangombe site in the Oklo region. The results showed that this site was inhabited by a diversified population of bacteria. Each borehole was dominated by species that did not dominate in any of the other boreholes; a result that probably reflects documented differences in the geochemical environment. Two of the sequences obtained were identified at genus level to represent Acinetobacter and Zoogloea, but most of the 44 sequences found were only distantly related to species in the DNA database. The deepest borehole, BAX01 (105 m), had the highest number of bacteria and also total organic carbon (TOC). This borehole harboured only Proteobacteria beta group sequences while sequences related to Proteobacteria beta, gamma and delta groups and Gram-positive bacteria were found in the other four boreholes. Two of the boreholes, BAX02 (34 m) and BAX04 (10 m) had many 16S rRNA gene sequences in common and also had similar counts of bacteria, content of TOC, pH and equal conductivity, suggesting a hydraulic connection between them. PMID- 8688962 TI - Ecological interaction between sympatric Mytilus species on the west coast of Canada investigated using PCR markers. AB - M. californianus is the dominant marine mussel species on exposed rocky shores, while M. trossulus is usually the dominant mussel species in more sheltered waters on the west coast of North America. Since these species are physical indistinguishable when small (< 10.0 mm), we developed two polymerase chain reaction (PCR) -based markers to discriminate between them. Using these markers, we identified mussels taken from an exposed coast (n = 114), a sheltered harbour (n = 80), and an upper-intertidal pool (n = 42) on the west coast of Vancouver Island, British Columbia, Canada. M. californianus were found only on the open coast. Small M. trossulus (< 20.0 mm) were common to all three sample sites, but were extremely rare at larger sizes (> 20.0 mm) on the open coast. Our results indicate that M. californianus are excluded from sheltered waters via early life factors, while M. trossulus are excluded from the open coast due to mortality later in life. PMID- 8688961 TI - RAPD identification of microsatellites in Daphnia. AB - Simple sequence repeats (SSRs, or microsatellites) have been constantly gaining importance as single-locus DNA markers in population genetics and behavioural ecology. We tested a PCR-based strategy for finding microsatellite loci in anonymous genomes, which avoids genomic library construction and screening, and the need for larger amounts of DNA. In the first step, parts of a genome are randomly amplified with arbitrary 10mer primers using RAPD fingerprinting. Labelled SSR-oligonucleotides serve as probes to detect complementary sequences in RAPD products by means of Southern analyses. Subsequently, positive RAPD fragments of suitable size are cloned and sequenced. Using GA and GT probes, we applied this approach to waterfleas (Daphnia) and revealed 37 hybridization signals in 20 RAPD profiles. Thirteen positive RAPD fragments from three Daphnia species and two hybrid 'species' were cloned and sequenced. In all cases simple sequence repeats were detected. We characterized seven perfect repeat loci, which were found to be polymorphic within and between species. PMID- 8688964 TI - A simple new method for estimating null allele frequency from heterozygote deficiency. PMID- 8688963 TI - Last male sperm precedence in a damselfly demonstrated by RAPD profiling. AB - We used the random amplified polymorphic DNA technique to determine last male sperm precedence (P2) in the damselfly Calopteryx splendens xanthostoma (Charpentier). We amplified DNA from mothers, putative fathers and from the embryos of individual offspring, and subsequently calculated band-matching coefficients between known first-order relatives (offspring within a clutch) and non-relatives (mothers and fathers) to estimate last-male paternity. The data indicate that, as in other Calopterygidae, P2 is high (0.98) in the bout of oviposition immediately following copulation, despite the fact that the males of this species do not completely remove the sperm of previous males (Siva-Jothy & Hooper 1995). PMID- 8688965 TI - Marine mammal faeces as a source of DNA. PMID- 8688966 TI - Trinucleotide microsatellite loci in a swarm-founding neotropical wasp, Parachartergus colobopterus and their usefulness in other social wasps. PMID- 8688967 TI - Heterogeneity of expression of immunohistochemical tumour markers in testicular carcinoma in situ: pathogenetic relevance. AB - Testicular carcinoma in situ (CIS) is the precursor of germ cell tumours in adults, except for spermatocytic seminoma. The mechanism of the progression from premalignant CIS to invasive and overt tumours is largely unknown. There are currently two main hypotheses: one is that CIS can progress directly to either seminoma or nonseminoma; according to the other, seminoma is the intermediate stage between CIS and nonseminoma. CIS cells express several tumour antigens, such as placental-like alkaline phosphatase (PLAP), TRA-1-60, or the c-kit proto oncogene protein product (Kit), which are present to varying degrees in the invasive germ cell tumours. In this study, CIS cells adjacent to either pure or combined tumours were examined by double immunohistochemical staining for simultaneous expression of TRA-1-60 (typical for embryonal carcinoma) and either Kit (expressed by seminomas) or PLAP (found mainly in seminomas, but also in some cases of nonseminoma). Marked differences in the expression of these antigens were found among CIS cells, especially those adjacent to mixed tumours. We conclude that CIS is a phenotypically heterogeneous lesion, and that the CIS cells, despite identical morphology and close spatial localization, may be in different stages of progression. The results lend support to the hypothesis that CIS can progress directly to both seminomatous and nonseminomatous tumours. PMID- 8688968 TI - Expression of CD44 splice variants in human skin and epidermal tumours. AB - Splice variants of the adhesion molecule CD44 (CD44v) are important in the lymphatic spread of rat carcinoma cells. In several human tumours expression of CD44v correlates with tumour progression. However, little is known about the physiological functions of distinct variant exons. Here we report on the immunohistological evaluation of CD44 expression in normal human skin and epidermal tumours which do not metastasise, or do so vary rarely. Frozen tissues were stained with a panel of monoclonal antibodies, recognizing epitopes of the CD44 standard isoform, as well as of variant exons v5, v6, v7, v7-v8 and v10. Stratum basale and spinosum as well as the root shaft of hairs reacted strongly with the whole panel of anti-CD44 antibodies. Stratum corneum, acinar cells of sebaceous and eccrine sweat glands stained with anti-CD44v5, anti-CD44v6 and anti CD44v7, but not with anti-CD44v10, the latter recognizing the "epithelial isoform" (CD44v8-v10) of CD44. Ductal cells of glands and apocrine glands did not express CD44v. Compared with its expression in normal human skin, CD44v expression was reduced in basal cell carcinoma and squamous cell carcinoma of the skin. This was particularly true of CD44v10. The expression of CD44v in normal skin and dermal appendages indicates that not all combinations of variant exons are involved in tumour progression. Since the epithelial isoform is particularly downregulated in basal cell carcinoma and squamous cell carcinoma of the skin, it is unlikely that exons v8-v10 play a role in tumour progression. Rather, they may be of functional importance in maintenance of the epidermal structure. PMID- 8688970 TI - Immunohistochemistry of cyclin D3 in pulmonary carcinomas. AB - Cyclin D3, a cell cycle regulator, is encoded in the 6q21 chromosome region. Abnormalities of this gene and its protein product have not been found in normal tissues or in malignancies from human subjects. The expression of cyclin D3 was studied immunohistochemically in archival formalin-fixed, paraffin-embedded specimens from normal organs obtained from three autopsy cases and 237 human primary pulmonary carcinomas. In normal organs, nuclear positivity for cyclin D3 was observed in reactive type-2 pneumocytes, islets of Langerhans, lymphocytes from lymph nodes, superficial cells of transitional epithelium, epithelium of oesophagus, stomach, small intestine and gallbladder, endothelium, smooth muscles, and brain. Proliferating cells such as lymphocytes in the germinal centres and non-proliferating cells such as neurons both demonstrated cyclin D3 immunoreactivity. Cyclin D3 showed obvious nuclear immunoreactivity in 168 pulmonary carcinomas (71%). The proportion of tumour cells that were cyclin D3 positive ranged from 1% to 73% (median, 16%). There was no relationship between cyclin D3 immunoreactivity and histological typing, tumour differentiation, or pathological TNM staging. In pulmonary carcinomas, distinct expression of the cyclin D3 protein is unlikely to be implicated in tumorigenesis, because of its expression in only a small fraction of cancer cells. It may relate to cancer progression. The distribution of cyclin D3 reactivity in the normal tissues suggests that cyclin D3 affects other processes than cell cycle regulation in a lineage-specific manner. PMID- 8688969 TI - Detection of human papillomavirus in cervical intra-epithelial neoplasia, using in situ hybridization and various polymerase chain reaction techniques. AB - One hundred and forty-eight randomly chosen neutral-buffered formaldehyde-fixed cervical biopsies in which cervical intra-epithelial neoplasia (CIN) I-III had been diagnosed were tested for HPV (human papilloma virus) DNA by in situ hybridization (ISH) and polymerase chain reaction (PCR). For ISH, we utilized a biotinylated panprobe and type-specific, genomic probe sets. For PCR, we used the general primers GP5/GP6 and their recently described, elongated version GP5+/GP6+, and included the modification of hot-start PCR. Amplified DNA was detected by gel electrophoresis and slot blot hybridization. The positivity rate of ISH was 59% for all biopsies and 69%, 62% and 46% for CIN I, II and III, respectively. The sensitivity of GP5/GP6 was 74% with cold-start PCR and 78% with hot-start PCR. When GP5+/GP6+ was used, the sensitivity increased to 89% with cold-start PCR and to 95% with hot-start PCR. Based on the most sensitive PCR technique, HPV detection was 93%, 95% and 96% in CIN I, II and III, respectively. The number of HPV types decreased with the severity of the lesion, and HPV 16 was the predominant type. Multiple HPVs were rare and almost all HPV-positive cases could be typed. ISH and slot blot hybridization correlated well regarding HPV typing specificity. Our results confirm that distinct HPV types are present in a high proportion of cases of CIN. The sensitivity of ISH is lower than that of PCR. Furthermore, the modified general primers GP5+/GP6+ give a higher yield than GP5/GP6, while hot-start PCR increases sensitivity even further. PMID- 8688971 TI - Ultrastructure of multinucleated giant cell apoptosis in foreign-body granuloma. AB - To elucidate the role of apoptosis in the disappearance of multinucleated giant cells from the granulation tissue in cases of foreign-body granuloma, we induced a foreign-body reaction by implanting a collagen sponge into the dorsum of the rat and observed apoptotic changes within the multinucleated giant cells using electron microscopy. Two types of multinucleated giant cells were identified presenting apoptotic characteristics morphologically. One was characterized by apoptosis of only one nucleus, followed by cytoplasmic changes, rupture of the plasma membrane and necrosis evoking an inflammatory reaction. The other showed typical apoptotic changes in the majority or in all of the nuclei, followed by phagocytosis of the apoptotic syncytia. The results of the present study suggest that apoptosis occurring within only one nucleus might be triggered by overexpression of the p53 protein, because DNA abnormalities are confined to this single nucleus. In contrast apoptosis occurring simultaneously in the majority or all of the nuclei is most probably due to cell death caused by senescence. PMID- 8688972 TI - Loss of GLUT2 glucose transporter expression in pancreatic beta cells from diabetic Chinese hamsters. AB - The diabetic Chinese hamster is a well-established animal model for NIDDM with a defective glucose-induced insulin secretory response. In the pancreas of nondiabetic hamsters, the GLUT2 glucose transporter was localized in the plasma membrane of insulin-positive beta cells. At variance with the rat, immunoreactivity was also detected in the cytoplasm. Other islet cell types were not GLUT2 positive. GLUT2 immunoreactivity was already significantly reduced in beta cells from mildly diabetic animals in spite of a normal insulin immunoreactivity. In severely diabetic animals the majority of the beta cells had lost GLUT2 immunostaining. This observation was confirmed in a Western blot analysis of the GLUT2 protein in isolated pancreatic islets. Only beta cells that were densely immunostained for insulin were still GLUT2 positive. However, around 40% of the beta cells devoid of GLUT2 immunoreactivity were still insulin immunoreactive. Thus, the loss of GLUT2 immunoreactivity, which is an important component of the glucose recognition apparatus of the pancreatic beta cell, is an early indicator of beta cell dysfunction before the development of degenerative lesions or the loss of insulin immunoreactivity. GLUT2 loss may be important in the deterioration of glucose-induced insulin secretion in the diabetic Chinese hamster. PMID- 8688973 TI - Early detection of metastasis by alterations in the cellular immune system in the murine liver and blood. AB - We investigated the reaction of the cellular immune system of liver and blood in the C57BL/6 mouse to a metastasizing Lewis lung carcinoma. The cellular immune system of the liver consists of mature and immature macrophages, B-cells, T-cells including their subpopulations, and natural killer cells, and their percentage frequencies differ significantly from those in the corresponding mononuclear blood cell (MBC) compartment. This suggests that the hepatic immune cells represent a system with autonomous function showing a typical homing of its members. Imminent metastasis to the liver is signalled by impressive alterations in the percentage frequencies of nonparenchymal liver cells (NPLC). There are a dramatic loss of mature macrophages, an increase in immature macrophages, a reduction of T-helper cells leading to a low CD4/CD8 ratio, and an increase in natural killer cells. In the blood, the corresponding precursor cells show comparable changes with a delay of at least 2 days. Early metastasis is accompanied by a significant increase in mononuclear NPLC producing tumour necrosis factor alpha. The alterations in percentage frequencies of the NPLC during tumour metastasis differ markedly from the changes in these cells in the liver during endotoxinaemia. PMID- 8688974 TI - Papillary adenoma of type II pneumocytes might have malignant potential. AB - Papillary adenoma of type II pneumocytes is a rare tumour. It is considered to be a benign neoplasm and is derived from immature cells in the bronchioloalveolar epithelium, however, its biological nature has not been elucidated. We report a case of an adenomatous tumour; a papillary adenoma of type II pneumocytes, which we regard as possessing malignant potential. Light microscopically, as well circumscribed, papillary tumour of predominantly cuboidal cells resembling type II pneumocytes was found, but Clara type and ciliated cells were also present. Immunohistochemically, the tumour cells reacted positively with antibodies to surfactant apoproteins (A, B), carcinoembryonic antigen, cytochrome P-450 1A1-2 and 2B1-2. Ultrastructurally, many osmiophilic lamellar bodies and electron-dense granules were demonstrated. Semi-serial sections revealed signs of transbronchial dissemination and vascular invasion. Morphometry using 12-dimensional cluster analysis disclosed features of the tumour cells which resembled those of pneumocyte type II adenocarcinoma. These findings suggest that the present case has some malignant characteristics and originates from immature bronchiolar or alveolar cells, with a potential to develop into both type II pneumocyte and Clara cell type adenocarcinomas. PMID- 8688975 TI - Changes in sacral transcutaneous oxygen tension in the evaluation of different mattresses in the prevention of pressure ulcers. AB - Transcutaneous oxygen tension (TCPO2) is a recognized techniques for evaluating support surfaces as a pressure ulcer prevention method. Transcutaneous oxygen tension was measured over the sacral area of 20 volunteers positioned on five different mattresses, including a standard mattress. No specific change was noted on resting values (M = 68.2 mm Hg, SD = 9.4) before each of the five protocols were begun. Mean values were 17.9 mm Hg (SD = 27.9) for a nonspecific hospital mattress, 30.15 mm Hg (SD = 29.5) for the first foam mattress, 30.25 mm Hg (SD = 28.5) for the second foam mattress, 50.5 mm Hg (SD = 23.1) for the air mattress, and 50.95 mm Hg (SD = 21.6) for the water-filled mattress. Results showed statistical differences between the standard mattress and the four mattresses tested and between the foam mattresses and the two other mattresses. There was an inverse correlation between skinfold thickness and a decreased TCPO2 in contact area. Skinfold thickness could be an indicator of pressure ulcer risk. Further studies are needed to confirm the interest of this parameter. PMID- 8688976 TI - Skin care in the frail, elderly, dependent, incontinent patient. AB - Despite a plethora of recommendations, protocols and dictums in the nursing literature, no research studies have defined the basic elements of preventive skin care for incontinent patients, and the prevalence of skin problems associated with incontinence is unknown. Yet the importance of skin care for incontinent elderly or immobilized patients has long been acknowledged. This literature review sought to determine current practices and principles for skin care of frail, elderly, dependent, incontinent patients. Protocols vary widely. And although there is mounting evidence that incontinence, particularly fecal incontinence, is a primary risk factor for pressure ulcer development, most preventive efforts focus on pressure relief, repositioning, and nutrition, rather than incontinence care. More clinical trials are needed in this area. The design and analysis of these trials should take into account the frequency and manner in which skin is cleansed, products used for skin care, risks and benefits of absorbent products and devices, the presence of infection, and patients' concomitant medical conditions and degree of immobility. PMID- 8688977 TI - The effect of intermittent noise exposure on wound healing. AB - This study used an animal model to investigate whether exposure to intermittent noise affects wound healing. Forty male and female rats were anesthetized and received a 2.5 x 2.5-cm excisional wound on the back. For 19.5 days, 20 of the rats were exposed to periods of broad-band white noise ranging from 2 to 16 KHz. Data analysis revealed that the treatment group's wounds healed more slowly than the control group's (F = 12.64, p < or = .01). The rats' food intake and weights were also measured, and the treatment group's average weight was lower than the control group's (F = 18.94, p < or = .01), although food intake did not differ significantly for the two groups. The rats' gender had no apparent effect on the study results. Because this study used healthy animal subjects, more research is needed to determine if noise delays wound healing in hospitalized patients. PMID- 8688978 TI - The need for collaboration in wound care. PMID- 8688980 TI - When is no treatment the right treatment? PMID- 8688979 TI - Peer-identified expert nurses' approaches to risk assessment for pressure ulcers. AB - A small group of peer-identified expert nurses was studied using qualitative methods to identify how they assessed patients' risk for pressure ulcers. The factors used by these expert nurses were compared to those used in formal pressure ulcer risk assessment instruments. The analysis revealed that the expert nurses weighed risk factors used in the formal scales preferentially. There was a close association in their reports between experiences with wound healing and pressure ulcer prevention. They used subjective sensory modalities such as appearance and odor. Setting and specialty-specific factors figured prominently in their evaluations and they included psychosocial as well as physiological factors in their assessments. PMID- 8688981 TI - Cimetidine does not alter sparfloxacin pharmacokinetics. AB - The interaction between cimetidine and sparfloxacin was studied in 10 healthy volunteers who received a single oral dose of 400 mg sparfloxacin on the third day of an 8 day cimetidine (400 mg t.i.d.) or placebo randomly assigned treatment. No statistically significant differences were observed in the pharmacokinetic parameters (Cmax-AUC-T1/2-urinary excretion and metabolic ratio) of sparfloxacin following the 2 treatment. Cimetidine does not affect absorption, metabolism or urinary excretion of sparfloxacin; consequently, patients exposed to this drug combination are not at risk. PMID- 8688983 TI - Fatal course of toxic epidermal necrolysis under treatment with lamotrigine. AB - We report on the first fatal course of toxic epidermal necrolysis (Lyell's disease) occurring under treatment with lamotrigine, following the development of a skin rash caused by carbamazepine. PMID- 8688982 TI - Study of the bioequivalence of two controlled-release formulations of morphine. AB - The management and treatment of chronic pain in cancer patients is a clear priority for practitioners regularly confronted by the situation. This investigation was carried out to evaluate the bioavailability of a recent sustained-release (SR) formulation of morphine sulphate (30 mg), Skenan, consisted of capsules, relative to a recognized product, Moscontin which is a matrix tablet SR form. The bioavailability was carried out on 12 healthy male volunteers who received a single dose (30 mg) of the test (T) and the recognized (R) products in a randomized balanced 2-way crossover design. After dosing, serial blood samples were collected for a period of 24 hours. Morphine and its main metabolites (i.e. glucuronides M6G and M3G) were assayed by high-performance liquid chromatography using a ion-pair formation. Data were analyzed by a noncompartmental method and were compared by ANOVA method and, each subject taken as his own control, by the Wilcoxon T test. Mean bioavailability of the T formulation was greater than that of R. The parametric confidence intervals (90%) of the mean values of the pharmacokinetics characteristics for T:R ratio were in each case without the bioequivalence acceptable ranges of 0.8-1.25 and 0.70-1.43 respectively for AUCs (i.e. AUCo-->24h and AUCo-->infinity) and Cmax, while confidence intervals symmetric of Westlake (CIW90%) was invariably greater than 20%, i.e. 62.8, 71.1 and 39.3% respectively. Further, the test formulation was not found bioequivalent to the reference formulation by Schuirmann's 2 one-sided t-test. These results justify the conclusion of the non-bioequivalence of the two forms at the unit dose of 30 mg. This information must be considered above all as a dosage adjustment tool enabling use of the two forms by application of a correction factor of the order of 15% when prescribing Skenan in comparison with Moscontin. Assessment is needed of the possible clinical consequences of this finding. PMID- 8688984 TI - Relating spontaneous adverse experience reports to scores on a questionnaire querying tolerability. AB - In this study, we examined the relation between spontaneously reported adverse experiences and responses given on the comparison of ophthalmic medications for tolerability (COMTOL) checklist questionnaire which queries the frequency and bother of specific side-effects known to be associated with topical ophthalmic agents used to treat ocular hypertension or open-angle glaucoma, and the impact that the side-effects have on health-related quality of life. The study was a 4 week, randomized, open-label, two-period cross-over clinical trial comparing dorzolamide and pilocarpine in 92 patients who were also receiving timolol for the treatment of ocular hypertension or open-angle glaucoma. Patients completed the COMTOL questionnaire at baseline and at the end of each period and spontaneous reports of adverse experiences (AEs) were collected throughout the study by the investigator. Since there were only 3 spontaneously reported AEs related to drug treatment while patients received dorzolamide and since COMTOL scores indicated a low level of side-effects, the analyses were limited to pilocarpine treatment periods. We discovered that during the pilocarpine treatment periods, a large percentage (94%) of the 47 patients, who failed to spontaneously report any adverse experiences, indicated on the COMTOL that they had experienced side-effects. These discrepancies between the methods of spontaneous reports and a checklist questionnaire are similar to those previously reported in the literature for other drugs. Unlike previous literature, we went beyond identifying discrepancies with the two reporting methods and we looked for possible explanations for why the discrepancies existed. We discovered that patients who spontaneously reported AEs expressed more bother from these specific side-effects on the questionnaire than patients who did not spontaneously report AEs. As well, patients who spontaneously reported AEs and discontinued drug as a result of the AEs expressed on the COMTOL the greatest bother from side-effects. This trend of increasing negative impact (as patients reported AEs and discontinued) was also observed with COMTOL global question scores on the impact of side-effects on health-related quality of life, the impact of activity limitations on quality of life, satisfaction with medication and compliance with medication. Therefore, spontaneous reporting of side-effects appears to be detecting the most clinically meaningful side-effects. PMID- 8688985 TI - New and simple method for estimating metildigoxin dosing regimens by multiple trough screen analysis. AB - The pharmacokinetics of digitalis glycosides were studied using routine therapeutic drug monitoring data to evaluate the role of patient characteristics for estimating metildigoxin dosing regimens. The 232 serum glycoside concentration data at steady-state after repetitive oral administration in 144 hospitalized patients was analyzed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. Pharmacokinetic analysis of digitalis glycosides was described using a simple steady-state pharmacokinetic model. The effect of a variety of developmental and demographic factors on glycoside clearance was investigated. NONMEM estimates indicated that this digitalis glycoside clearance was influenced by the demographic variables of age, total body weight, serum creatinine, gender, daily dose and the coadministration of spironolactone. An elderly patient was expected to have a lower rate of clearance than a young patient of equal body weight and serum creatinine. The interindividual variability in glycoside clearance was modelled with proportional error with an estimated coefficient of variation of 19.7% and the residual variability was 21.8% The dosing method based on glycoside clearance value obtained by NONMEM analysis allowed the prediction of the minimum steady state glycoside concentration as a function of metildigoxin maintenance dose with acceptable error for therapeutic drug monitoring. PMID- 8688987 TI - Bioequivalence and pharmacokinetics of chlorpheneramine in healthy human volunteers. AB - This study was carried out to evaluate the bioavailability of a new regular release tablet formulation of chlorphenamine (CPA) (Histop) relative to a reference formula (Piriton) using 13 human healthy volunteers. Each one received the two formulations as two 4 mg tablets in a two-way double-blind, crossover study. The concentration of CPA was measured with a sensitive high performance liquid chromatography (HPLC). The geometric mean for the area under the curve up to the last concentration (AUC0-t), to infinity (AUC0-oo) and the maximum concentration (Cp max) were 316.5, 315 + 439.8, 431.2 (ngh/ml) and 22, 20.5 (ug/ml) for the test (T) and reference (R) formulations, respectively. The parametric 90% confidence intervals of T/R ratio of the above parameters were within the bioequivalence acceptable range of 80-125%. The mean time to the maximum concentration Tmax (h) were 2.5 and 2.08 for the two formulations respectively and the parametric 90% confidence intervals of the Tmax difference (T-R) were in the range of -0.26-1.14 h, with point estimate of 0.44 h. The two formulations were found to be bioequivalent by the Schuirmann two one-sided t test. Based on the pharmacokinetic results obtained frequent (ie, Q 4-6 h) CPA daily dosing may not be required particularly for the adults because of its long elimination half-life. PMID- 8688986 TI - Evaluation of efficacy and safety of erdosteine in patients affected by chronic bronchitis during an infective exacerbation phase and receiving amoxycillin as basic treatment (ECOBES, European Chronic Obstructive Bronchitis Erdosteine Study). AB - An international multicentric study was conducted with the aim of demonstrating that erdosteine improves the efficacy of amoxycillin in the treatment of infective exacerbation of chronic bronchitis mainly on the clinical symptomatology (primary objective), on spirometric tests and body temperature, without negatively influencing the tolerance (secondary objectives). The study was conducted as a prospective evaluation, with 2 comparative groups treated with erdosteine (300 mg x 2/day) or placebo in association with amoxycillin (1500 mg/day) for a maximum of 10 days. The design of the trial was double-blind and parallel group with 2 subgroups. The treatments have been assigned randomly to a population of chronic bronchitic patients in exacerbation phase of n = 237 subjects. The study was conducted according to the principles of the Declaration of Helsinki and its amendments (Hong Kong, September 1989). The primary end-point used to determine effectiveness in this study was the global clinical assessment (GCA) which was choosen as a general indication of activity with objective/subjective evaluation of the clinical picture. Secondary endpoints of efficacy are sputum parameters, functional signs of chronic obstructive bronchitis, spirometric tests and overall judgement of efficacy. Safety was evaluated with adverse drug reactions reporting, arterial blood pressure, heart rate and laboratory tests monitoring. The obtained values have been analyzed with two-way and factorial ANOVA, Least Squares Catmod-SAS, Wilcoxon and Chi-square tests. The number of patients included in the effectiveness analysis is of n = 226 subjects, due to the fact that 11 patients were lost due to different reasons. In term of results as far as the primary objective of the study was concerned, erdosteine resulted more active than placebo. The analysis evidenced a very significant difference for treatment, time and interaction time x treatment. No difference on the contrary was observed for center and the interaction center x treatment. Sputum volume, body temperature and spirometric parameters were not significantly influenced by both treatments. Viscosity, appearance as well as functional signs evidenced a modification over time in favour of erdosteine. As safety is concerned the majority of adverse events, both in the erdosteine and in the placebo group, were related to the gastrointestinal area. For erdosteine, of 9/17 side-effects, 3 were epigastralgias, 3 nauseas, 1 diarrhoea, 1 taste loss, 1 hemorrhoids. For placebo of 13/17 related events 3 were epigastralgias, 4 nauseas, 4 diarrhoeas, 1 pyrosis, 1 dry mouth. In terms of severity they have been all defined as mild or moderate degree. Also from a qualitative perspective it is clear that there are no relevant differences between the 2 treatments under evaluation, concerning safety. In conclusion of particular interest is the datum arising from the efficacy/safety evaluation, which indicates that the clinical picture is modified earlier and at deeper degree by the synergistic activity of erdosteine and of the antibiotic without the risk of an augmentation of side effects incidence. PMID- 8688988 TI - Disposition kinetics of dibekacin in patients with renal failure and in patients undergoing hemodialysis. AB - Dibekacin pharmacokinetics was studied in 3 healthy volunteers, 5 patients with renal failure presenting Clcr, between 4.0 and 67 ml min-1 per 1.73 m2 of body surface and 5 anephric patients given as a 30 minute intravenous infusion. The antibiotic was assayed in plasma and urine by means of a high performance liquid chromatography (HPLC) method. A two compartment kinetic model was used to describe the bi-phasic decline of plasma concentration and to calculate the different pharmacokinetic parameters. Slow disposition and elimination rate constants beta and k10 respectively, and total body clearance were markedly diminished in anephric patients (p << 0.001): t1/2 beta = 2.12 h, k10 = 0.642 h-1 and Cl = 0.882 ml/min per kg, in normal subjects and t1/2 beta = 4.73 h, k10 = 0.278 h-1 and Cl = 0.693 ml/min per kg in anephric patients. The apparent volumes of distribution increased while the creatinine clearance of the patients decreased. Thus Vd(area) of volunteers with normal renal function was statistically significantly lower than that of anephric patients (p < 0.001), from a value of 0.162 to 0.281 l/kg respectively. A good correlation (r = 0.982) between patient's slow disposition constant beta and creatine clearance was found. Urinary recovery at 24 h was 85.6% of the dose given to normal volunteers. This value decreased while impairment increased. The mean extraction coefficient, during hemodialysis was about 0.35. PMID- 8688989 TI - Is atropine alone sufficient in acute severe organophosphorus poisoning?: experience of a North West Indian Hospital. AB - Between January 1990 and December 1992, 18 patients with severe organophosphate poisoning (OPP) were admitted to our respiratory intensive care unit (RICU). Suicidal ingestion was the commonest cause of poisoning (15/18). The treatment comprised of atropine in bolus doses. 2-PAM in conventional dose and mechanical ventilation (MV) with positive end expiratory pressure (PEEP) wherever indicated. The mean dose of atropine on day 1 was 178.9 mg (range 60-480 mg) and then gradually reduced. The mean duration of treatment with atropine was 9.6 days (range 1-24 days). We felt that aggressive atropinization and MV with PEEP is adequate and the role of 2-PAM given in 3 gm dose in 12 h is not clear. There is a need for controlled study to assess the efficacy of atropine and MV alone vs. atropine, 2-PAM in suggested doses and MV in severe OPP patients. PMID- 8688990 TI - Pharmacokinetics and pharmacodynamics of cloprednol. AB - The pharmacokinetics and pharmacodynamics of cloprednol after oral administration in doses of 2.5 to 15 mg to healthy volunteers were determined. The half-life of cloprednol ranged from 1.8 h to 2.7 h, the oral clearance (CL/F) was determined to be 15-22 l/h. Since cloprednol shows nonlinear plasma protein binding, the plasma concentrations were converted to their free, unbound concentrations for the PK/PD-analysis. Due to this nonlinearity, the half-life of free, unbound cloprednol was shorter than that of the total drug. For the assessment of pharmacodynamics, differential white blood cell counts were obtained over 24 hours. An integrated pharmacokinetic-pharmacodynamic (PK/PD) approach using a modified Emax-model was applied to link unbound corticosteroid concentrations to the effect on lymphocytes and granulocytes. The E50 value for unbound cloprednol ranged from 3.6 to 4.7 ng/ml and 1.2 to 4.6 ng/ml for granulocytes and lymphocytes, respectively. The PK/PD model allowed a good prediction of the observed effects and was consistent with reported values for glucocorticoid receptor binding affinities for cloprednol. PMID- 8688991 TI - beta-blockade, atrial natriuretic peptide and exercise. AB - Changes in the release of atrial natriuretic peptide (ANP) and vasopressin (VP) may contribute to the final outcome of beta-adrenoceptor blocking therapy. Therefore, we administered 2 hours before a bicycle exercise test (a 30-minute exercise with 100 W work load) in a randomized, double-blind, placebo-controlled crossover study orally 50 mg atenolol, 80 mg propranolol or 10 mg pindolol to 15 healthy volunteers. Hormone release and sympathoadrenal activation were estimated by measuring plasma ANP-, VP-, adrenaline and noradrenaline concentrations. beta blockade and -antagonism were estimated by measuring the reduction of exercise induced tachycardia and the extent to which the drugs occupied rabbit lung beta 1 and rat reticulocyte beta 2-adrenoceptors in the circulating plasma. We noticed clear differences in the animal beta 1- and beta 2-receptor occupancy between these agents. The agents and placebo during the exercise augmented plasma ANP level similarly, on average by 34-72%. Pindolol administration enhanced the decline of plasma ANP level after exercise (ANCOVA rep meas, pindolol vs placebo, p < 0.05). Although pindolol increased the mean plasma VP level by 25% (ANCOVA rep meas for the increase, pindolol vs placebo, p < 0.05), drug effects on plasma VP-level were generally negligible. In conclusion, in healthy volunteers beta 1- and beta 2-antagonism by pindolol, atenolol and propranolol do not markedly potentiate plasma ANP- and VP-responses to physical exercise. The responses are, however, slightly influenced presumably by the beta-agonist activity of pindolol. PMID- 8688992 TI - Disposition of remoxipride in Chinese schizophrenic patients. AB - The disposition of remoxipride was evaluated in 13 male chronic schizophrenic patients. A single 150 mg dose of remoxipride was administered and blood sampling performed over the following 48 hours. The mean (SD) oral clearance and half-life of remoxipride were 74.46 (25.9) ml/min and 5.46 (0.87) hours, respectively. The mean (SD) AUC for remoxipride was 25,320 (9,820) ng.h/ml. A wide interpatient variability was observed. Compared to Caucasian studies there were no significant differences in the disposition of remoxipride. PMID- 8688993 TI - Intrasubject variability in bioequivalence studies illustrated by the example of ibuprofen. AB - Based upon the results of a bioequivalence study in 18 male and female healthy volunteers receiving each ibuprofen 400 mg at a time interval of 3 days the issue of the intrasubject variation is discussed. It was shown that there was bioequivalence as to the parameters Cmax, AUC0-tlast und AUC0-infinity in the volunteers who repeatedly received the same preparation. The same is true for the secondary target parameters tmax und t1/2. In the present study the intrasubject variability was determined to be 10%. Since ibuprofen does not belong to the drugs with problematic bioavailability it can be expected that in case of repeated application at an interval limited in time equal results are achieved with considerable intra-and intersubject variations. PMID- 8688994 TI - Bioequivalence study of alpha-dihydroergocryptine: utility of metabolite evaluation. AB - Metabolite assessment is an open question in bioequivalence studies. In situations of low absorption, high first-pass metabolism, and intrasubject variability, metabolites may reflect absorption more adequately than the parent drug, and their determination may help decision-making in bioequivalence issues. Treating alpha-dihydroergocryptine (DHECT) as a model, we used both unchanged DHECT and a pool of DHECT metabolites to evaluate the bioequivalence of 2 oral DHECT formulations (reference-R and test-T) in 12 subjects. DHECT and its metabolites were immunoassayed. There was no difference between the 2 formulations in terms of the AUC0-infinity (area under the curve) values determined from unchanged DHECT or DHECT with metabolites profiles: 572 +/- 490 pg/ml.h (R) and 442 +/- 276 pg/ml.h (T) for unchanged DHECT, and 7,141 +/- 2,936 pg/ml.h (R) and 6,941 +/- 1,462 pg/ml.h (R) for DHECT with metabolites. Confidence intervals were within the ranges 0.8-1.25 (AUC0-infinity) and 0.7-1.43 (Cmax) for DHECT with metabolites but not for unchanged DHECT. This study describes a particular case where only measurements on the basis of the metabolites can justify the assumption of bioequivalence. PMID- 8688995 TI - Oxidative phenotype polymorphism (P450 2D6) and metabolism of toluene. AB - Oxidative phenotype P-450 2D6 was examined using sparteine test in 3 groups of persons to determine if there is a coincidence in the defect of the oxidative biotransformation of sparteine and impaired oxidation of toluene, which could explain interindividual differences in the amounts of hippuric acid in the urine in exposed persons. The following groups of persons were examined: 30 rotogravure printers exposed to toluene vapors at concentrations of 8-307 ppm; 20 workers, 2 months after the cessation of the long-term exposure to toluene at concentrations of 104-1,170 ppm; 48 healthy volunteers with no exposure to toluene. Among the 98 persons 5 poor metabolizers (PMs) of sparteine were found, none in the group of printers exposed to toluene. In the experimental exposure chamber 5 PMs and 6 extensive metabolizers (EMs) were exposed to toluene concentration of 245 ppm for 5 hours. Hippuric acid and o-cresol in the urine, and toluene both in blood and in alveolar air were measured. However, no significant differences were found in either of these parameters between the PM and EM groups. Thus, the sparteine test does not appear to be applicable in the identification of persons with higher risk arising from toluene exposure. PMID- 8688996 TI - Utilization of antidiabetic drugs in Hong Kong: relation to the common occurrence of antidiabetic drug-induced hypoglycemia amongst acute medical admissions and the relative prevalence of NIDDM. AB - Antidiabetic drug-induced hypoglycemia as a cause of acute medical admissions is more common in Hong Kong (1.7%) than in other countries (0.1-0.5%). To determine if this higher incidence may be related to the frequent use of some sulphonylureas, we have studied the overall prescribing patterns in the public sector in 1994 by reviewing the utilization of antidiabetic drugs in the general out-patient/general practice clinics (GOPD) and Hospital Authority public hospitals and affiliated specialist clinics (HA). The vast majority of patients (90.5%) receiving antidiabetic treatment were taking sulphonylureas and/or metformin, confirming that diabetes mellitus in Hong Kong is predominantly of the noninsulin-dependent type. The GOPD and the HA each accounted for approximately half of the sulphonylureas (55% vs 45%) and metformin (43% vs 57%) prescribed. Glibenclamide (84.9% vs 79.1%, 83.7% overall) and gliclazide (12.8% vs 16.6%, 14.5% overall) were the 2 most frequently used sulphonylureas. Only 9.5% of patients on antidiabetic drugs were receiving insulin and 92% of this was prescribed by the HA. For comparison, Singapore has a similar prevalence of diabetes mellitus but a much lower incidence of antidiabetic drug-induced hypoglycemia amongst acute medical admissions (0.5%). Tolbutamide was the most frequently used there sulphonylurea (66.6-72.2%) with glibenclamide only contributing 20.8-28.6%. Thus, the predominant use of glibenclamide in Hong Kong may contribute to the high incidence of antidiabetic drug-induced hypoglycemia amongst acute medical admissions. PMID- 8688998 TI - [Leukocytospermia]. PMID- 8688997 TI - Pharmacokinetics of losigamone, a new antiepileptic drug, in healthy male volunteers. AB - Losigamone (AO-33), a new potential antiepileptic drug, was tested in 52 healthy male volunteers in 4 placebo-controlled phase I studies. In study 1 single doses of 100, 200, 300, 500, 700, and 1,000 mg losigamone were given as a fast releasing capsule to 12 subjects. The pharmacokinetics of losigamone measured after administration of 100, 300, and 700 mg was linear. Clearance and t1/2 were about 350 ml/min and 4 h, respectively, the Cmax values of 0.7, 1.7, and 4.4 micrograms/ml were reached after 2.5 h. In study 2,500 mg losigamone were given as a fast release capsule for 6 days (t.i.d.) to 12 subjects. There was a small but statistically significant decrease for the AUC but no change in t1/2, Cmax or tmax comparing single dose kinetics on day 1 and 8. There appeared to be no change in caffeine clearance on days 1 and 9. Study 2 was repeated in 20 volunteers with a film-coated tablet. Pharmacokinetic parameters appeared to be unaffected by this change in galenical formulation. In study 4 daily doses of 400, 1,200, and 1,800 mg losigamone were given 28 days to 24 subjects. The kinetics of caffeine and antipyrine were compared on days 1 and 29. With the exception of t1/2 for antipyrine in the 400 mg group there was no statistically significant change in pharmacokinetic parameters. Generally, losigamone was well tolerated and no serious adverse side-effects occurred. In some subjects a reversible increase in transaminases was observed. PMID- 8688999 TI - [Ultrasonic diagnosis during embryonic and early fetal development]. PMID- 8689000 TI - [Histogenesis of ovarian tumors]. PMID- 8689001 TI - [Comparison of the incidence of selected congenital defects in the Czech Republic 1988-1993 with the ICBDMS and EUROCAT international registries]. PMID- 8689002 TI - [Famous cases of conjoined twins and their development]. PMID- 8689004 TI - [The effect of the duration of administration of epidural analgesia on delivery]. AB - The authors compared the length of labour periods, number of surgical deliveries, the use of oxytocin, analgetics, spasmolytics and intensity of pain in two groups of primiparae, who were in labor under continuous epidural analgesia (CEA). In the first group CEA was started when the cervix was dilated not more than 3 cm, in the second one when the cervix was dilated more than 3 cm. The length of labour, oxytocin consumption and frequency of vaginal surgery did not differ in the two groups. In the first group there was great consumption of analgetics and spasmolytics, more motor blocks of the lower extremities and a higher rate of Caesarean sections on account of dystocia. In some of the women of the first group the intensity of pain at the end of the first stage of labour and during the second stage was higher than before the onset of CEA. CONCLUSION: It seems to be better to start CEA when the cervix is dilated more than 3 cm. PMID- 8689003 TI - [Screening for Down's syndrome--results of a 3-year study]. AB - In a group of 5382 examined pregnant women the authors demonstrate the results of systematic prenatal screening of Down's syndrome. From the results it is apparent that it is essential to supplement each examination of alpha-fetoprotein by assessment of total HCG which is considered a parameter of greater impact for prediction of chromosomal aberrations. Since the beginning of 1993 all examinations were evaluated, using the commercial software ALPHA; its advantage is in particular that it expresses the overall risk due to age and two parameters assessed by laboratory tests and the reduction of the magnitude of the risk group to the acceptable level of 6.6%. PMID- 8689005 TI - [A combination of normal physiologic management of delivery and epidural analgesia]. AB - From the anaesthesiological aspect the authors recommend the method of loss of resistance during verification of the epidural space as a safer method (lower percentage of perforations of the spinal dura mater). At the mentioned concentrations and dosage the authors did not observe any motor disorders of the lower extremities. The assembled experience with a combination of physiological delivery with emphasis on the second stage of labour and epidural analgesia justify not only the statement that this combination is possible but that it is favourable for mother and foetus. The combination reduces considerably the disadvantages of both types of management of labour, it used isolated. It puts, however, much greater demands on the staff and the costs are higher. These disadvantages should, however, not influence humanitarian trends in obstetrics. PMID- 8689006 TI - [Adrenal cortex hormones in the mother and fetus in premature labor]. AB - In a group of 126 pregnant women with imminent premature delivery between the 20th and 37th week of gestation where after weekly intervals the serum cortisol and corticosterone levels from the cubital vein was assessed, it was revealed that in the group of women who aborted or had a premature delivery, as well as in women who had the delivery in term the corticoid values vary greatly: cortisol between 370 and 500 nmol/1 and corticosterone 70 to 240 nmol/1. In both groups there is a marked difference in final values. The latter have in women with premature deliveries a rising trend and in the group where pregnancy proceeded successfully to term a declining trend. Glucocorticoid blood levels from the umbilical arteries in the group of women who had an abortion or premature delivery, as compared with women who delivered their baby in term, no significant differences were recorded. However, the glucocorticoid blood levels from the umbilical veins were significantly higher in women who had premature deliveries or abortions, as compared with women who gave birth to their babies in term. The glucocorticoid levels in amniotic fluid collected during delivery did not manifest significant differences between the two groups of pregnant women. PMID- 8689007 TI - [Evaluation of sperm morphology using the "strict" method]. AB - The asset of evaluation of the morphology of sperm cells for prediction of their fertilizing power is generally accepted. Advances in the sphere of extracorporeal fertilization and the onset of micromanipulation techniques (intracytoplasmic injection of a single sperm cell - IC-SI) called for a stricter evaluation which is the prerequisite for a high standard indication and selection of different methods of extracorporeal fertilization. We obtained the consent of Prof. Gruger and Prof. Menkveld from the Tygerberg University (South African Republic) who elaborated this evaluation, to publish their criteria in our journal. PMID- 8689008 TI - [The Stamey urethrovesicopexis operation--4 years' experience]. PMID- 8689009 TI - [Therapy of ovarian carcinoma in pregnancy]. PMID- 8689010 TI - [Surgical treatment of sleep apnea-hypopnea syndrome]. PMID- 8689011 TI - [What is brought by asthma management consensus meetings?]. PMID- 8689012 TI - [Study of the expression of proliferating cell nuclear antigen and p185 in non small cell lung carcinoma]. AB - We assessed immunohistochemical expression of p185 and the proliferating cell nuclear antigen (PCNA) in 68 patients undergoing surgery for non-small cell lung cancer. Adenocarcinoma of the lung was the histological type whose expression of p185 at levels exceeding 10% was greater to a statistically significant degree. Epidermoid carcinoma, on the other hand, was associated with the highest PCNA indices. Although these 2 markers had no prognostic value in the survival study, it must be pointed out that the longest survivors were patients with p185 expression less than 10% in neoplastic cells. PMID- 8689013 TI - [Lung diseases due to opportunistic environmental Mycobacteria in patients uninfected with human immunodeficiency virus. Risk factors, clinical and diagnostic aspects and course]. AB - Diseases caused by opportunistic ambient mycobacteria (OAM) are common in HIV positive patients, although they also occur in immunocompetent individuals. The objective of the present study was to describe the risk factors, clinical signs, course and microbiological spectrum of OAM that cause pulmonary diseases in non HIV-infected individuals in our community. We reviewed 29 consecutive patients with OAM-caused pulmonary disease between 1989-1994 (26 men and 3 women, mean age 58 +/- 14 years). Infections were by Mycobacterium kansasii, 19 (66%) cases; M. avium complex, 7 (24%) cases; M. chelonei, 2 (7%) cases, and M. flavescens, one (3%) case. Risk factors most often associated to infection were smoking and a history of pulmonary disease (chronic obstructive pulmonary disease or residual tuberculosis). Clinical signs were non specific, although toxic syndrome and unproductive cough predominated. Chest films were indistinguishable from those for infection by M. tuberculosis, with cavitated alveolar fibrosis being the main pattern. In vitro drug sensitivity tests showed that all strains were resistant to isoniazid, and that M. avium complex and M. chelonei strains were resistant to rifampicin, streptomycin and, to a lesser degree, to ethambutol. With prolonged medical treatment lasting from 12 to 24 months with first line drugs, outcome was good for the 17 patients for whom full follow-up information was available. Therapy failed to eradicate the bacteria in only 2 patients. PMID- 8689014 TI - [Accuracy and validity of the lactic threshold compared to other noninvasive methods of measuring the anaerobic threshold in patients with metabolic myopathies]. AB - Poor correlation among the various methods for measuring anaerobic threshold (AT) has been reported, and some authors have even reported interobserver variability within a single method. It is unknown whether such variability exists in patients with metabolic myopathies (MM). OBJECTIVE: To determine intra- and interobserver variability in the measurement of AT in patients with MM and analyze the differences for each method used. We enrolled 16 patients with differing forms of MM for exercise testing. AT was determined by 4 methods: lactic threshold (LT), semi-log LT, respiratory equivalent and V-slope. AT was assessed by 2 observers, who analyzed plots in random order on 2 different occasions, locating the AT in each plot. The respiratory equivalent method gave the best intraobserver correlation (r' = 0.95; p < 0.05) and was superior to the LT method (r' = 0.68; p < 0.05). Interobserver correlation was equally acceptable for all except the V slope method (r' = 0.36; p > 0.05). The most important finding after comparison of the methods was the significant difference in VO2 (ml/min) in AT between the LT method and the non invasive methods (LT = 1,006; respiratory equivalent 1,312; p < 0.05; LT = 1,095; V-slope = 1,251; p < 0.05). CONCLUSION: Intra- and interobserver variability is slight in patients with MM; the best method in this respect is that of the V-slope. AT appears later with non invasive methods and for that reason, invasive measurement (LT) is preferable. PMID- 8689015 TI - [Endoscopic evaluation of endobronchial tuberculosis in children]. AB - The aim of this study was to determine the role of fiberoptic bronchoscopy (FB) in pulmonary tuberculosis in children. We assessed bronchoscopic findings of 36 procedures performed in 30 children who presented the following abnormalities on chest films: lobular or segmentary atelectasis (17), paratracheal or parahilar adenopathies (14), parenchymatous consolidation (9) and localized hyperinflation (5). Premedication for FB included intravenous atropine and diazepam plus ketamine for sedation, as well as lidocaine 2 and 5% in aerosol form for topical anesthesia. FB results showed that involvement was endobronchial in 29 patients. In the 18 patients with X-rays suggestive of endobronchial tuberculosis (EBT), the diagnosis was confirmed by FB. Significantly, EBT was found by FB in 11 (36.6%) patients with no clinical or radiological signs of such involvement. EBT was in the early stages in 3 (10%) patients and was advanced in 8 (26.6%). M. tuberculosis was isolated in 9 (30%) of the 30 patients. Culture was of bronchoalveolar lavage in three, of gastric lavage in four and of endobronchial biopsy in two. We conclude that FB is a safe, important tool for the confirmation of EBT in the management of pulmonary tuberculosis in children. It serves as a guide for the start of steroid treatment, especially in children with no radiological suggestion of EBT. PMID- 8689016 TI - [Atypical pneumonias]. PMID- 8689017 TI - [Pneumology in Spain]. PMID- 8689018 TI - [Paroxysmal melanoptysis secondary to the cavitation of pulmonary pneumoconiosis conglomerate]. AB - Progressive massive fibrosis (PMF) secondary to pneumoconiosis involves the formation of fibrotic masses that eventually cause death from multiple complications. We present a rare but potentially serious complication in a patient with coal pneumoconiosis with PMF, in whom the appearance of paroxysmal melanoptysis was attributed to the cavitation of one of the pneumoconiotic masses. We emphasize the need for differential diagnosis to exclude other more common causes, as well as the use of bronchoscopy for diagnosis and confirmation. Strict control is needed to prevent possible respiratory failure when melanoptysis is massive. PMID- 8689019 TI - [Congenital tracheoesophageal fistula in a 15-year-old male]. AB - We report a case of a 15-years-old boy with presumably congenital tracheoesophageal (H type) fistula. He has a history of recurrent bronchitis, bronchopneumonia and cough after liquid swallowing. Soon after an episode of blood stained sputum, a tracheal orifice in the pars membranacea that opened into the esophagus was found by fiberoptic bronchoscopy study. Chest and abdominal X rays showed esophageal air and abdominal distention, respectively. The esophagram showed the passage of contrast agent to the tracheobronchial tree and no additional concurrent lesions. Cervical and thoracic magnetic resonance images revealed the location, morphology and anatomical relation to the neighbouring structures of the tracheoesophageal fistula, which was repaired surgically by left lateral cervicotomy and direct section and suture. The posterior wall of the trachea was reinforced with a muscle flap, with good results. PMID- 8689020 TI - [Isolated laryngeal candidiasis. Description of 2 cases and review of the literature]. AB - Infection of the larynx by Candida is rare and usually accompanies lung or disseminated candidiasis. The incidence of isolated laryngeal candidiasis (ILC) is low, although it may be underestimated. We describe 2 patients with ILC confirmed during autopsy: a 45-years-old male with pulmonary fibrosis and a 4 years-old girl with acute myeloblastic leukemia. Hoarseness and dysphagia are the most common symptoms of ILC. The most effective diagnostic technique is laryngoscopy with specimen culture and/or histopathology. Specimens usually show whitish plaques on the larynx. Most ILC patients have some associated disease and/or predisposing factors, with frequent antibiotic treatment prior to the advent of candidiasis. Intravenous amphotericin B provides the most effective therapy, although other antimycotics are also useful. Early diagnosis and initiation of therapy curtail the disease and can prevent systemic dissemination. PMID- 8689021 TI - [Multiple nodules as presentation of giant cell carcinoma of the lung]. PMID- 8689022 TI - [Pneumonia, recurrent respiratory infections and congenital tracheobronchomegaly]. PMID- 8689023 TI - [Patient compliance to the prescription of domiciliary oxygen therapy by transtracheal catheter]. PMID- 8689024 TI - [Spontaneous bilateral pneumothorax]. PMID- 8689025 TI - [Bronchoesophageal fistula and broncholithiasis]. PMID- 8689026 TI - Second annual meeting of the American Society for Neural Transplantation. PMID- 8689027 TI - Embryonic stem cells differentiated in vitro as a novel source of cells for transplantation. AB - The controlled differentiation of mouse embryonic stem (ES) cells into near homogeneous populations of both neurons and skeletal muscle cells that can survive and function in vivo after transplantation is reported. We show that treatment of pluripotent ES cells with retinoic acid (RA) and dimethylsulfoxide (DMSO) induce differentiation of these cells into highly enriched populations of gamma-aminobutyric acid (GABA) expressing neurons and skeletal myoblasts, respectively. For neuronal differentiation, RA alone is sufficient to induce ES cells to differentiate into neuronal cells that show properties of postmitotic neurons both in vitro and in vivo. In vivo function of RA-induced neuronal cells was demonstrated by transplantation into the quinolinic acid lesioned striatum of rats (a rat model for Huntington's disease), where cells integrated and survived for up to 6 wk. The response of embryonic stem cells to DMSO to form muscle was less dramatic than that observed for RA. DMSO-induced ES cells formed mixed populations of muscle cells composed of cardiac, smooth, and skeletal muscle instead of homogeneous populations of a single muscle cell type. To determine whether the response of ES cells to DMSO induction could be further controlled, ES cells were stably transfected with a gene coding for the muscle-specific regulatory factor, MyoD. When induced with DMSO, ES cells constitutively expressing high levels of MyoD differentiated exclusively into skeletal myoblasts (no cardiac or smooth muscle cells) that fused to form myotubes capable of spontaneous contraction. Thus, the specific muscle cell type formed was controlled by the expression of MyoD. These results provided evidence that the specific cell type formed (whether it be muscle, neuronal, or other cell types) can be controlled in vitro. Further, these results demonstrated that ES cells can provide a source of multiple differentiated cell types that can be used for transplantation. PMID- 8689029 TI - Migration patterns of neonatal subventricular zone progenitor cells transplanted into the neonatal striatum. AB - Our previous studies have shown that the progeny of the neuronal progenitor cells localized in a discrete region of the anterior part of the neonatal subventricular zone, referred to as the SVZa, migrate tangentially along a stereotypical and extended pathway to the olfactory bulb, and then turn radially into one of the overlying cellular layers. In this study we have examined whether the SVZa cells retain their ability to migrate and disperse when heterotopically transplanted into the striatum. SVZa cells from P0-P2 rat pups were microdissected, dissociated, labeled with the lipophilic, fluorescent dye PKH26 or the cell proliferation marker BrdU, and then transplanted into the neonatal (P0-P2) striatum. Examination of the striatum a few days after transplantation revealed aggregates of heavily labeled BrdU-positive, SVZa cells in the striatum, often situated near blood vessels. Two to four weeks after transplantation, however, the labeled SVZa cells had disseminated from their site of implantation and showed three patterns of distribution. In none of the cases was the implantation site detectable in the striatum, signifying that the cells had become incorporated in the host brain. Of the 12 brains analyzed for cell distribution, transplanted SVZa cells were confined to the striatum in 4 cases. The cells were present as individual cells or in small groups of usually two to four cells. When PKH26 was used, we found that many of the transplanted cells extended processes into the striatum. In 3 out of the 12 animals, the labeled SVZa cells were distributed along the dorsal and lateral aspects of the striatal boundary. In the remaining five animals, labeled SVZa cells appeared in both locations: within the striatum as well as along the striatal boundary. The dispersion of the transplanted cells within the striatum and the presence of the transplanted SVZa cells all along the striatal boundary, a region corresponding to the lateral cortical stream of migration of the developing forebrain, demonstrates that the isochronically transplanted SVZa cells retained their capacity to migrate. PMID- 8689028 TI - Expression of tyrosine hydroxylase in an immortalized human fetal astrocyte cell line; in vitro characterization and engraftment into the rodent striatum. AB - The use of primary human fetal tissue in the treatment of neurodegenerative disorders, while promising, faces several difficult technical and ethical issues. An alternative approach that would obviate these problems would be to use immortalized cell lines of human fetal central nervous system origin. An immortalized human fetal astrocyte cell line (SVG) has been established (45) and herein we describe the in vitro and in vivo characteristics of this cell line which suggest that it may be a useful vehicle for neural transplantation. The SVG cell line is vimentin, GFAP, Thy 1.1 and MHC class I positive, and negative for neurofilament and neuron specific enolase, consistent with its glial origin. To determine whether the cell line could be used as a drug delivery system, a cDNA expression vector for tyrosine hydroxylase was constructed (phTH/Neo) and stably expressed in the SVG cells for over 18 months as demonstrated by immunohistochemistry and Western blotting of the stable transfectants. HPLC analysis of the supernatant from these cells, termed SVG-TH, consistently found 4 6 pmol/ml/min of l-dopa produced with the addition of BH4 to the media. Furthermore, in cocultivation experiments with hNT neurons, PC-12 cells and primary rat fetal mesencephalic tissue, both the SVG and SVG-TH cells demonstrated neurotrophic potential, suggesting that they constituitively express factors with neuroregenerative potential. To determine the viability of these cells in vivo, SVG-TH cells were grafted into the striatum of Sprague-Dawley rats and followed over time. A panel of antibodies was used to unequivocally differentiate the engrafted cells from the host parenchyma, including antibodies to: SV40 large T antigen (expressed in the SVG-TH cells), human and rat MHC class 1, vimentin, GFAP, and tyrosine hydroxylase. While the graft was easily identified with the first week, over the course of a four week period of time the engrafted cells decreased in number. Concomittantly, rat CD4 and CD8 expression in the vicinity of the graft increased, consistent with xenograft rejection. When the SVG-TH cells were grafted to the lesioned striatum of a 6-hydroxydopamine lesioned rats, rotational behavior of the rat decreased as much as 80% initially, then slowly returned to baseline over the next four weeks, parallelling graft rejection. Thus, the SVG-TH cells can induce a functional recovery in an animal model of Parkinson's disease, however as a xenograft, the SVG cells are recognized by the immune system. PMID- 8689030 TI - Morphological differentiation of astroglial progenitor cells from EGF-responsive neurospheres in response to fetal calf serum, basic fibroblast growth factor, and retinol. AB - Procurement of multipotential neuroglial stem cells is possible with the addition of epidermal growth factor (EGF). Stem cells will differentiate into neurons and glia upon the removal of EGF from the culture medium. We have previously characterized the neuronal differentiation of stem cells derived from long-term cultured nonpassage neurospheres. In the current study, we (1) characterize the morphological differentiation of the astroglial progenitor cell from 3-mo-old neurospheres, (2) examine whether the astroglial progenitor cells from neurospheres of different brain areas exhibit different differentiation responses to the same exogenous signals, and (3) test the effects of basic fibroblast growth factor (bFGF) and retinol on differentiation. Cerebral cortex, striatum, and mesencephalon cells were obtained from Embryonic Day 14 (E-14) rat fetuses and were dissociated for the procurement of neurospheres in chemically defined medium supplemented with EGF. After 3 mo in culture, the neurospheres, derived from each of the three brain areas, were subcultured into three groups on chamber slides: (1) basal medium, (2) the basal medium plus 20 ng/mL bFGF, and (3) the basal medium plus 10 muM retinol. Phenotypic expression of astroglial cells was examined after 14 days subculture. Our findings indicate that the 3-mo-old cultured nonpassage neurospheres contained numerous multipotential stem cells that stained positive with nestin, and that environmental factors played an important role in influencing the differentiation of astroglial progenitor cells. As detected by glial fibrillary acid protein (GFAP), astroglial progenitor cells turned into protoplasmic astrocytes in the FCS-containing basal medium, fibrous astrocytes in the presence of bFGF, and spindle-shaped astrocytes in the presence of retinol. There were no noticeable differences in differentiation among astroglial progenitor cells of the various brain region-derived neurospheres in any of the three medium conditions. Peculiar varicosity-and growth cone-like structures on the long slender GFAP-positive processes suggest that neuroblasts and glioblast may share common morphologies, features, or common progenitor cells during initial differentiation in vitro. PMID- 8689031 TI - Grafts of fibroblasts genetically modified to secrete NGF, BDNF, NT-3, or basic FGF elicit differential responses in the adult spinal cord. AB - Neuronal and axonal responses to neurotrophic factors in the developing spinal cord have been relatively well characterized, but little is known about adult spinal responses to neurotrophic factors. We genetically modified primary rat fibroblasts to produce either nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or basic fibroblast growth factor (bFGF), then grafted these neurotrophic factor-secreting cells into the central gray matter of the spinal cord in adult rats. Spinal cord lesions were not made prior to grafting. From 2 wk to 6 mo later, sensory neurites of dorsal root origin extensively penetrated NGF-, NT-3-, and bFGF-producing grafts, whereas BDNF-secreting grafts elicited no growth responses. Putative noradrenergic neurites also penetrated NGF-secreting cell grafts. Local motor and corticospinal motor axons did not penetrate any of the neurotrophic factor secreting grafts. These results indicate that unlesioned or minimally lesioned adult spinal cord sensory and putative noradrenergic populations retain significant neurotrophic factor responsiveness, whereas motor neurites are comparatively resistant even to those neurotrophic factors to which they exhibit survival dependence during development. Grafts of genetically modified cells can be a useful tool for characterizing neurotrophic factor responsiveness in the adult spinal cord and designing strategies to promote axonal regeneration after injury. PMID- 8689032 TI - Effects of intraventricular encapsulated hNGF-secreting fibroblasts in aged rats. AB - Exogenous NGF administered into the central nervous system (CNS) has been reported to improve cognitive function in aged rats. However, concerns have been expressed about the risks involved with supplying NGF to the CNS. In this study, baby hamster kidney cells (BHK) genetically modified to secrete human NGF (hNGF) were encapsulated in semipermeable membranes and implanted intraventricularly. ChAT/LNGFR-positive basal forebrain neurons were shown to atrophy and degenerate with age, especially in cognitively impaired rats. The encapsulated BHK-NGF cells produced less than 10% of doses previously reported to be effective, but this was sufficient to increase the size of ChAT/LNGFR-positive basal forebrain neurons in the aged and learning-impaired rats to the size of the neurons in young healthy rats. The hNGF from these encapsulated cells also improved performance in a repeated-acquisition version of the Morris water maze spatial learning task in learning-impaired 20.6- and 26.7-mo-old rats. Furthermore, there was no evidence that these doses of hNGF impaired Morris water maze performance in the youngest 3.3-5.4 mo rats, and analyses of mortality rates, body weights, somatosensory thresholds, potential hyperalgesia, and activity levels, suggested that these levels of exogenous hNGF are not toxic or harmful to aged rats. These results suggest that CNS-implanted semipermeable membranes, containing genetically modified xenogeneic cells continuously producing these levels of hNGF, attenuate age-related cognitive deficits in nonimmunosuppressed aged rats, and that both the surgical implantation procedure and long-term exposure to low doses of hNGF appear safe in aged rats. PMID- 8689033 TI - Cell-mediated delivery of brain-derived neurotrophic factor enhances dopamine levels in an MPP+ rat model of substantia nigra degeneration. AB - Brain-derived neurotrophic factor (BDNF) promotes the survival of fetal mesencephalic dopaminergic cells and protects dopaminergic neurons against the toxicity of MPP+ in vitro. Supranigral implantation of fibroblasts genetically engineered to secrete BDNF attenuates the loss of substantia nigra pars compacta (SNc) dopaminergic neurons associated with striatal infusion of MPP+ in the adult rat. Using this MPP+ rat model of nigral degeneration, we evaluated the neurochemical effects of supranigral, cell-mediated delivery of BDNF on substantia nigra (SN) dopamine (DA) content and turnover. Genetically engineered BDNF-secreting fibroblasts (approximately 12 ng BDNF/24 h) were implanted dorsal to the SN 7 days prior to striatal MPP+ administration. The present results demonstrate that BDNF-secreting fibroblasts, as compared to control fibroblasts, enhance SN DA levels ipsilateral as well as contralateral to the graft without altering DA turnover. This augmentation of DA levels suggests that local neurotrophic factor delivery by genetically engineered cells may provide a therapeutic strategy for preventing neuronal death or enhancing neuronal function in neurodegenerative diseases characterized by dopaminergic neuronal dysfunction, such as Parkinson's disease. PMID- 8689034 TI - Cytoskeletal protein immunoexpression in fetal neural grafts: distribution of phosphorylated and nonphosphorylated neurofilament protein and microtubule associated protein 2 (MAP-2). AB - The present study examined the immunocytochemical expression of important cytoskeletal proteins within the neurons of an extended series of neocortical grafts and smaller group of ventral mesencephalic (nigral) grafts. Using antibodies that were directed at all three neurofilament (NF) epitopes, NF-L, NF M, and NF-H, we attempted to determine whether these neurons would have an altered cytoskeletal profile following the stress of transplantation, because previous studies have shown such changes following ischemia or direct brain injury. We studied phosphorylated NF protein, which is found predominantly in axons, nonphosphorylated NF protein, which is found predominantly in the somata dendritic compartment, and MAP-2, a specific microtubule marker that is localized exclusively in the somato-dendritic compartment. The results show that in all neocortical grafts examined, both phosphorylated and nonphosphorylated NF immunoexpression was significantly downregulated and appeared only in relatively few axons and somatic profiles, respectively, even though there were numerous Nissl-stained neuronal profiles in the grafts. There was no particular pattern to the immunopositive profiles. At later times occasional neuronal profiles were positive for phosphorylated NF protein, suggesting a reaction to cellular injury. In contrast to neocortical grafts, the cytoskeletal profiles of MAP-2 and phosphorylated NF protein in nigral grafts appeared very similar to age-matched control although the nonphosphorylated NF protein expression did appear somewhat lessened at 1-2 mo postoperative. Because cytoskeletal proteins play important roles in neuronal size, shape, and structural stability, they may subserve key cellular issues in neural grafting. These results show a significant loss of cytoskeletal protein expression in neocortical grafts that does not occur in nigral grafts. These results suggest that fetal neurons from different brain regions (i.e., graft source) may respond differently to the grafting procedure insofar as their cytoskeletal makeup is concerned. In addition, a potential lack of appropriate growth substrates or synaptic contacts may also produce cytoskeletal alterations. As such, the cytoskeletal protein profiles in central nervous system (CNS) grafts may be useful markers for functional performance, perhaps reflecting a degree of cellular injury. PMID- 8689035 TI - Immunomodulation with intrathymic grafts or anti-lymphocyte serum promotes long term intraspinal allograft survival. AB - In this study, we sought to test whether introduction of fetal cells into the adult rat thymus would promote immunotolerance to subsequent donor-type allografts in the injured spinal cord. To first evaluate intrathymic survival of fetal central nervous system (CNS) tissue, fragments of E14 Sprague-Dawley (SD) fetal spinal cord (FSCSD) were injected into the thymuses of either adult, outbred SD, or Wistar rats. Histological examination revealed well-differentiated grafts in both the SD (10 out of 13) and Wistar (7 out of 13) recipients. We next examined whether prior intrathymic exposure to FSC graft-derived alloantigens leads to enhanced survival of subsequent allografts into the injured, adult spinal cord. Wistar rats thus first received FSCSD tissue as intrathymic grafts coupled with single-dose, anti-lymphocyte serum (ALS) ablation of the circulating host T-cell population. Ten days later, FCSSD was transplanted into an aspiration lesion of each intrathymic graft recipient's spinal cord. After 60 days, 87% of two-stage graft recipients (n = 15) exhibited viable intraspinal (IS) grafts compared to 38% (3 out of 8) observed in the controls (i.e., not receiving intrathymic grafts). Another group of Wistar rats that had received ALS (only) at the time of the IS FSCSD transplant (n = 8) also had 75% graft survival rates after 60 days. These initial findings show that the intrathymic microenvironment can be a compatible ectopic site for fetal SC graft development and survival. Also, the enhanced survival of intraspinal grafts in animals with previous intrathymic implants or ALS administered at the time of grafting suggests the potential for inducing immunoprotection of some fetal neural allografts in adult recipients. PMID- 8689036 TI - Bovine chromaffin cells for CNS transplantation do not elicit xenogeneic T cell proliferative responses in vitro. AB - Adrenal chromaffin cells have been utilized for several neural grafting applications, but limitations in allogeneic donor availability and dangers inherent in autografting limit the widespread use of this approach clinically. While xenogeneic donors offer promise as a source for cell transplantation in the central nervous system (CNS), immunologic responses to cellular components of the adrenal medulla have not been well characterized. To further study the host T cell xenogeneic response to chromaffin and passenger cells of the adrenal medulla, an in vitro lymphocyte proliferation assay was used. Lymphocyte proliferation was determined by mixing rat lymphocytes with potential stimulator cell subpopulations of the bovine adrenal medulla: isolated chromaffin cells, isolated endothelial cells, or passenger nonchromaffin cells, which include a mixture of fibroblasts, smooth muscle cells, and endothelial cells. As a positive control, bovine aortic endothelial cells were also used. 3[H]-thymidine incorporation, corresponding to lymphocyte proliferation, was measured. Results indicated that isolated bovine chromaffin cells produce only a mild, statistically insignificant stimulation of rat lymphocytes. In contrast, there was a significant response to passenger nonchromaffin cells of the adrenal medulla, especially endothelial cells. The inclusion of low levels of cyclosporin A in the cultures completely eliminated the mild proliferative response to isolated bovine chromaffin cells, while near toxic levels were necessary to abrogate the response to endothelial cells. Immunocytochemical analysis revealed that routine chromaffin cell isolation procedures result in the inclusion of a small percentage of endothelial cells, which may be responsible for the slight lymphocyte stimulation. The results of this study indicate that isolated chromaffin cells possess low immunogenicity, and suggest that passenger cells in the adrenal medulla, particularly endothelial cells, may be primarily responsible for progressive rejection in CNS grafts. Thus, removal of passenger nonchromaffin cells from xenogeneic donor tissues prior to transplantation may produce a more tolerated graft in rodent models of neural transplantation. PMID- 8689037 TI - Amelioration of the behavioral phenotype in genetically ataxic mice through bilateral intracerebellar grafting of fetal Purkinje cells. AB - We have previously applied neural grafting to "Purkinje cell degeneration" mutant mice (gene symbol pcd, mouse chromosome 13), a model of recessively inherited cerebello-olivary atrophy, to create appropriate interactions between wild-type and mutant cells in elucidating gene effects on the involved neuron populations and to address issues of the structural integration of donor Purkinje cells into the disrupted cerebellar loop. Behaviorally, pcd homozygotes manifest ataxic signs beginning at 3-4 wk of age. The functional effects of cerebellar transplants on motor performance have long remained an open question. The aim of the present study was to determine the recovery of motor responses in pcd mutants in a battery of behavioral tasks after bilateral transplantation of cerebellar cell suspensions (prepared from wild-type mice) into the parenchyma of the deep cerebellar nuclei of the hosts, according to a protocol that emphasizes the reconstruction of the missing inhibitory cortico-nuclear projection. With this approach, the denervated deep nuclei of the host receive a new Purkinje axonal innervation; further, most transplanted Purkinje cells end up occupying cortical localities anyway and display a correct dendritic tree orientation toward the pia. Motor coordination and fatigue resistance were assessed in a rotarod treadmill apparatus, a behavioral paradigm useful in studying various brain abiotrophies and treatments, including developmental perturbations of the cerebellar cytoarchitecture. Locomotor activity was quantified by the number of squares mice crossed as they moved about in an open-field matrix. Grafted pcd mice performed significantly better than sham-operated mutants in both of these tasks. Moreover, graft-recipient mice were able to sustain their abdomen above the floor on their limbs during movement, contrasting to the typical lowered, widened stance of sham-operated pcd mutants. These findings clearly demonstrate that bilateral transplants of fetal Purkinje cells have functional effects on motor performance in the pcd model of hereditary cerebellar ataxia. PMID- 8689038 TI - The effect of fetal neocortical transplants on lesion-induced cerebral cortex plasticity. AB - Sensorimotor cortical lesions in newborn rats lead to the formation of abnormal projections from the opposite intact sensorimotor cortex. In the present study the influence of fetal neocortical transplants on this lesion-induced plasticity was examined. Newborn rats received unilateral frontal neocortical lesions. One experimental group received grafts of fetal neocortical tissue (E14-E16) into the lesion cavities. Another group served as lesion-only animals, while a third group was left unlesioned and without grafts as normal controls. At 3 mo of age, the animals received injections of the anterograde tracer biotinylated dextran amine (BDA) into the sensorimotor cortex contralateral to the lesion/transplantation area. After sacrifice 2 wk later, the brains were processed histochemically for detection of BDA-labeled cells and fibers. As a measure of the lesion-induced axonal sprouting response, corticothalamic and corticopontine fibers crossing the midline were counted. Significantly fewer cortical efferent fibers crossed the thalamic midline in the transplanted rats compared to the lesion-only controls. In contrast, the presence of transplants did not reduce the corticopontine sprouting response. These results therefore indicate that fetal neocortical grafts have a modulatory, yet variable effect on the lesion-induced axonal sprouting of contralateral sensorimotor cortical neurons. PMID- 8689039 TI - Intracerebroventricularly transplanted embryonic neuronal tissue from inflammatory-resistant F344/N rats decreases acoustic startle responses in inflammatory-susceptible LEW/N rats. AB - Recently, we have shown that intracerebral transplantation of fetal F344/N hypothalamic tissue into LEW/N rats converts the LEW/N inflammatory-susceptible phenotype into an inflammatory-resistant phenotype in LEW/N hosts. Because LEW/N rats also exhibit relatively high acoustic startle responses (ASRs) compared to F344/N rats, in the present study we examined the effects on ASR of transplantation of F344/N hypothalamic tissue into the third ventricle of LEW/N rats. Dissected neuronal tissue from F344/N rats (Day E15-16) was implanted into the third ventricle of LEW/N rats. After 4 wk of postoperative survival, the animals' responses to acoustic startle stimuli were tested. Compared to naive and sham-operated animals, LEW/N rats transplanted with hypothalamic tissue exhibited significant decreases in ASR amplitudes. A similar decrease in ASR amplitude was observed in the group of LEW/N rats transplanted with embryonic striatal tissue. Our results indicate that the third ventricular neuronal grafts may modulate behavioral responses in the LEW/N rats. Although the mechanism of this effect is unknown, these studies suggest that intracerebral neuronal transplantation is a viable method with which to explore mechanisms of behavioral, neuroendocrine, and inflammatory response associations. PMID- 8689040 TI - Effects of tectal grafts on sound detection deficits induced by inferior colliculus lesions in hooded rats. AB - The midbrain inferior colliculus (IC), a major integrating center for auditory processing, provides a model for structural, functional, and behavioral recovery. The present study examined the role of IC in spatial sound detection, and the effects of neural transplantation in sparing of behavioral performance. Hooded rats were presented noise bursts at ambient noise levels and 15 dB above this level randomly at one of eight locations in the horizontal plane, and rats were required to suppress licking upon detecting signal presentations. Following training, rats received bilateral IC lesions, bilateral lesions followed in 1 wk by bilateral tectal grafts (embryonic Day 18), or were sham operated. During repeated testing 15 to 30 days and 40 to 45 days following surgical procedures, rats with lesions showed impaired detection task performance when compared to grafted or sham animals. Detection ratios were statistically higher for grafted rats than for rats with lesions at repeated testing times. Performance of grafted animals was not statistically separable from the sham control group; however, grafted rats never achieved preoperative detection rates nor rates as high as sham rats. Postmortem implantation of diI crystals unilaterally into grafts demonstrated fiber labeling in the ipsilateral IC and lateral lemniscus, and retrograde labeling of neurons in the remaining host IC and dorsal nucleus of lateral lemniscus. Combined with results of previous studies, the results of this study suggest that sparing of detection performance for sounds occurring at random spatial locations may be attributable to partial integration of host-graft pathways. PMID- 8689041 TI - Development of an intact blood-brain barrier in brain tissue transplants is dependent on the site of transplantation. AB - Transplantation of fetal septal forebrain tissue was performed to the anterior chamber of the eye, or intracranially to the rostral hippocampal formation in rats, to evaluate the impact of transplantation site on the development of an intact blood-brain barrier (BBB). The tissue was studied at 1,2,3, and 4 wk following transplantation by means of intravenous injection of Trypan blue, which is a vital stain not normally penetrating the BBB, as well as with an antibody specifically directed against the rat BBB, SM171. In the intraocular septal transplants, there was a significant leakage of Trypan blue 1 wk postgrafting, associated with a few laminin-immunoreactive blood vessels that did not contain any SM17I-immunoreactivity. However, at 2 wk postgrafting, the intraocular grafts exhibited an extensive plexus of thin-walled blood vessels expressing SMI71 immunoreactivity and no Trypan blue leakage. Thus, it appeared that a BBB had developed to some degree by 2 wk postgrafting in oculo. In the intracranial grafts, on the other hand, Trypan blue leakage could be seen as long as 3 wk postgrafting, and a dense plexus of blood vessels with SMI71 immunoreactivity was first seen at 4 wk postgrafting. Thus, the development of Trypan blue impermeability was delayed with 1 to 2 wk in the intracranial versus the intraocular grafts. Control experiments using psychological stress in adult rats as a means to transiently disrupt the BBB revealed that an increase in Trypan blue leakage correlated well with the disappearance of SMI71 immunoreactivity. Taken together, these studies demonstrate that the site of transplantation can influence the development of an intact BBB in neural tissue grafts. PMID- 8689043 TI - Clinical study of fetal mesencephalic intracerebral transplants for the treatment of Parkinson's disease. AB - This study reports our findings from 22 patients (ages ranging from 42 to 73 yr; mean = 55.2) with recalcitrant idiopathic Parkinson's disease (PD) who received implants of fetal ventral mesencephalic tissue using an MRI-guided stereotactic procedure and who have been followed for at least 6 mo postoperatively, employing the guidelines established by the Core Assessment Program for Intracerebral Transplantations. Evaluations were videotaped and were performed both on and off levodopa medications. To date, we have seven patients with 24 mo, three with 18 mo, three with 12 mo, and nine with 6 mo post-surgical assessments. Comparing surgical outcomes to levels prior to fetal transplants we found: 1) mean levodopa levels were reduced 46% at 6 mo, 12% at 12 mo, 20% at 18 mo, and 54% at 24 mo; 2) Unified Parkinson's Disease Rating Scale (UPDRS) scores with patients on levodopa were improved by an average of 38% (6 mo), 50.2% (12 mo), 69.3% (18 mo), and 73.9% (24 mo), while off medication scores showed reductions ranging from 24.7% at 6 mo to 55.1% at 24 mo. Other measures, including Hoehn-Yahr staging, Activities of Daily Living, and dyskinesia rating scales, were also significantly improved following fetal transplants. Timed motor tasks (finger dexterity, supination-pronation, foot tapping, and Stand-Walk-Sit) performance also demonstrated highly significant improvements. Patient's self-rating scores indicated that the patients typically perceived substantial improvements in their condition. However, substantial variability in the improvements following surgery still persists and range from nominal improvements in performance to significant changes that can be classified as altering the overall lifestyle of the patients. To date, 4 of the 22 subjects were considered by the physicians to be nonresponders; that is, there were no clinically relevant improvements in these patients' conditions. PMID- 8689042 TI - Restoration of dopamine transporter density in the striatum of fetal ventral mesencephalon-grafted, but not sham-grafted, MPTP-treated parkinsonian monkeys. AB - Transplantation of fetal dopamine neurons to the adult striatum potentially offers a means to reverse the striatal dopamine deficiency that characterizes Parkinson's disease. Many investigations in rodents have supported the hope that neural grafting may be a useful treatment for parkinsonism. However, clinical studies have generally produced more modest improvements in motor abnormalities than observed in lower species. It is possible that the number of fetal dopamine neurons that survive transplantation is insufficient to restore dopaminergic innervation of the large human striatum to a level where striking recovery is obtained. In fact, there has been no quantitative study of graft outgrowth to indicate what portion of the dopamine-depleted striatum might be reinnervated with present techniques. Furthermore, it has been speculated that regeneration of the host dopamine system in response to the implantation surgery may play an important role in the beneficial effects of neural grafting in primates. The present study used nine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated parkinsonian monkeys to investigate these issues. Sham implantation procedures produced no increase in either dopamine transporter density (measured by quantitative autoradiography) or tissue dopamine concentration (measured by HPLC) in the striatum of MPTP-treated monkeys. In sham-grafted and nonimplanted MPTP-treated monkeys, the striatal dopamine concentration was reduced by 99%, based on analysis of 16 sampled sites in the caudate nucleus and putamen of each monkey. No behavioral recovery was seen in the sham-grafted and nonimplanted MPTP treated groups. In contrast, transplantation of fetal dopamine neurons to the caudate nucleus or putamen of MPTP-treated monkeys resulted in a significant elevation of dopamine transporter density and dopamine levels in the grafted striatal nucleus. Each grafted MPTP-treated monkey received ventral mesencephalon dopamine neurons from one donor harvested during putative neurogenesis. Donor ventral mesencephalon was divided equally and implanted into six sites either in the caudate nucleus or putamen. One graft site in each monkey was examined by dopamine transporter autoradiography. In sections in which graft fibers were present, a mean of one-third of the volume of the grafted nucleus was occupied by an elevated density of dopamine transporters. This increase in dopamine transporter density was defined to be at least 5-10% of the control density. However, full behavioral recovery was not observed in the grafted MPTP-treated group. These data provide no support for the hypothesis that regeneration of the host dopamine system occurs in response to a sham implantation procedure in severely parkinsonian monkeys. The current study illustrates the power of the applied techniques for delineating the relationship between the level of host dopamine depletion, the extent of graft-induced dopaminergic restoration, and behavioral recovery. PMID- 8689044 TI - Neural transplantation for Huntington's disease: experimental rationale and recommendations for clinical trials. AB - Huntington's disease (HD) is a neurodegenerative disorder affecting motor function, personality, and cognition. This paper reviews the experimental data that demonstrate the potential for transplantation of fetal striatum and trophic factor secreting cells to serve as innovative treatment strategies for HD. Transplantation strategies have been effective in replacing lost neurons or preventing the degeneration of neurons destined to die in both rodent and nonhuman primate models of HD. In this regard, a logical series of investigations has proven that grafts of fetal striatum survive, reinnervate the host, and restore function impaired following excitotoxic lesions of the striatum. Furthermore, transplants of cells genetically modified to secrete trophic factors such as nerve growth factor protect striatal neurons from degeneration due to excitotoxicity or mitochondrial dysfunction. Given the disabling and progressive nature of HD, coupled with the absence of any meaningful medical therapy, it is reasonable to consider clinical trials of neural transplantation for this disease. Fetal striatal implants will most likely be the first transplant strategy attempted for HD. This paper describes the variable parameters we believe to be critical for consideration for the design of clinical trials using fetal striatal implants for the treatment of HD. PMID- 8689045 TI - [Characterization of Pseudomonas aeruginosa strains isolated at therapeutic institutions of Moscow]. AB - Investigation of 108 P. aeruginosa strains isolated from various clinical material revealed that 54.63% of them belonged to serogroups 2, 5, 16, 18, 20 and 12.96% to serotype 4. Five strains were polyagglutinated. Monocultures of P. aeruginosa were isolated from 55% of patients, in the majority of cases (31 out of 36) these strains were isolated from the urine. Bacterial associations were more frequently detected in discharge from wounds (11 out of 21), in the material obtained by bronchoscopy (9 out of 15), and in the throat (5 out of 6). Assessment of antibioticograms of the isolated P. aeruginosa strains permitted us characterize polymixin, forte ceftazidime, and biseptol as effective agents. PMID- 8689046 TI - [Methodological aspects of the determination of total blood proteins]. PMID- 8689048 TI - [Age-specific features of the cyclic nucleotide system in children]. AB - The content of cyclic nucleotides (cAMP and cGMP) in the plasma and peripheral blood leukocytes, levels of their daily urinary excretion, and the activities of adenylate cyclase and cAMP-dependent phosphodiesterase responsible for the synthesis and degradation of cAMP in the leukocytes were studied in 114 healthy children aged 0 to 15 years. The levels of cyclic nucleotides in the blood plasma and leukocytes were found to gradually increase with age, as well as urinary excretion of cAMP. Both cAMP synthesis and degradation were found intensified with age. The detected age-specific features of cyclic nucleotides are important criteria for the assessment of the development of children and their health status. The findings may be used as reference values in assessment of the status of cyclic nucleotides in children with various diseases. PMID- 8689047 TI - [Fluorometric determination of amide protein groups]. AB - A new fluorometric method for detection of amide protein groups is proposed. The method has a number of advantages over the routine phenol hypochlorite method, this permitting its wider application in clinical and laboratory practice. The suggested method may be used for direct detection of ammonium in biological samples. PMID- 8689049 TI - [Lipid contents in blood of healthy subjects and patients with peptic ulcer during regular motor activity of the gastrointestinal tract]. AB - The concentrations of total cholesterol, beta-lipoproteins, and triglycerides were measured three times in 20 to 65 min in venous blood of 45 men (8 normal and 37 patients with peptic ulcer). Lipid concentration in the blood was shown to vary within a wide range in just few minutes, particularly so in normal subjects. In some cases the maximal values surpassed the minimal ones twofold and even more. The chi 2 test helped detect a correlation between the content of cholesterol and triglycerides in the blood and the phase of regular motor activity of the gastrointestinal tract, which was registered by tensotransmitters located in the stomach and small intestine. Soon after the beginning of a new cycle of this motor activity cholesterol concentration in the blood increased and triglyceride level reduced. The phase of the motor activity of the gastrointestinal tract should be taken into consideration when measuring the concentrations of lipids in human blood serum. PMID- 8689050 TI - [Determination of free and conjugated catecholamines, 3,4-dihydroxyphenylalanine, 3,4-dihydroxyphenylacetic acid in the urine and blood plasma by high pressure liquid chromatography]. AB - A method for simultaneous measurement of free and conjugated forms of adrenalin, noradrenaline, dopamine, 3,4-dihydroxyphenylalanine, and 3,4 dihydroxyphenylacetic acid in the blood plasma and urine by high-pressure liquid chromatography with electrochemical detector has been developed. The levels of the said substances in 36 normal volunteers and 20 patients with mental disorders are presented. Simultaneous measurements of excretion of free catecholamines and their conjugates permitted a more complete characterization of catecholamine metabolism, which is important for understanding the mechanisms of disorders in catecholamine system in various diseases. PMID- 8689051 TI - [Use of a mathematical model to establish normal serum parameters characterizing the function of the fetoplacental complex]. AB - Based on the author, data on the content of alpha-fetoprotein, trophoblastic beta 1-glycoprotein, and nonconjugated estriol in the blood serum of 278 somatically healthy women in various periods of normal gestation, the author proposes an approach to the definition of normal range of values. Using mathematical simulation methods, the values of normal concentrations of the fetoplacental complex products were calculated for every week of gestation, this permitting a different representation of laboratory findings and a dynamic follow-up of the course of gestation. PMID- 8689053 TI - [Methodological approaches to the study of the pulmonary surfactant system]. PMID- 8689052 TI - [Bacteremia: clinico-bacteriological aspects (literature review)]. PMID- 8689054 TI - [Micronucleus analysis as a rapid method of evaluation of the cytogenetic status of blood cells in patients with lung cancer]. PMID- 8689055 TI - [Eosinophilic reactions in patients with bronchial asthma and possibilities of their neutralization during health resort treatment]. AB - Patients with the eosinophilic variant of bronchial asthma were found to be characterized by a high level of fibrinolytic activity in bronchial secretion and a low level of IgA in it, as was detected in the course of health resort treatment. The said changes were as a rule not corrected by routine spa therapy. Addition of sodium hydrocarbonate and heparin aerosols to the therapeutic complex was conducive to neutralization of cationic proteins and of the major eosinophilic protein in the bronchial lumen. These measures led to normalization of IgA level in the sputum and to reduction of the fibrinolytic activity of the sputum. PMID- 8689056 TI - [Analysis of cell image]. PMID- 8689057 TI - [Topographic rapid pH-metry. Possibilities and prospects of use in the functional diagnosis of stomach diseases]. AB - More than 700 patients were examined by rapid intragastric pH-metry with the use of original pH-microtubes and K -2 device. Numerous advantages of the method were observed: the tube is easy to introduce into the stomach, the procedure is short, there are no contraindications against it, it involves no complications, pH values can be recorded along the entire stomach (30 cm) with just 1 cm intervals (topographic pH-metry). Diagnostic potentialities of the method are limited because there are no standard pH values for each specific site of the stomach under conditions of basal and stimulated secretion. To specify the standard values. 30 normal subjects and 40 patients with various gastric diseases were examined. Prevailing pH values at all sites of the stomach in health and disease both in basal and pentagastrin-stimulated secretion were established. To make the results more objective, the authors distinguish such parameters as the intermediate and maximal acidity zones, and carry out variation statistical analysis of pH-grams with plotting the variation statistical curves. Reliable differences in all the examined parameters in normal subjects and patients with initial gastric hypo- and hyperacidity were detected. Pentagastrin test is recommended for all patients with initial hypoacidity during express pH-metry. The proposed methods of statistical processing of express pH-grams and the established standard values appreciably extend the diagnostic potentialities of rapid pH-metry of the stomach. PMID- 8689058 TI - [A comparative assessment of diagnostic value of the study of leukocytes and lymphocytes by microscopy and laser flow cytometry in patients with HIV infection]. AB - A total of 135 subjects, 54 of them HIV infected and 81 donors (controls) were examined by microscopy and laser flow cytometry. A certain reduction of the total leukocyte count and of absolute lymphocyte count in the peripheral blood and a comparatively higher percent content of these cells were observed in HIV infected subjects examined for the first time. Laser flow cytometry proved to be a more informative method both for the assessment of the total count of leukocytes (p < 0.05) and for a complex assessment of cell counts (total leukocyte count, absolute and relative counts of lymphocytes) in the peripheral blood (p < 0.01) of patients with HIV infection. PMID- 8689060 TI - [Immunocytochemical method of assessment of the proliferative status of lymphoid cells in lymphoproliferative diseases]. AB - Search for the new approaches to the diagnosis of lymphoproliferative diseases and transition to the classification scheme "Working Classification of Non Hodgkin's Lymphomas for Clinical Use" involved assessment of the proliferative status of pathological lymphoid cells by immunocytochemical method with the use of DAKO-PC (Ki-67) monoclonal antibodies. The course and specific features of immunocytochemical reaction with the use of peroxidase-antiperoxidase immune complexes and complexes of alkaline phosphatase and monoclonal antibodies to it on various types of preparations are described in detail, this appreciably extending the potentialities of the use of this method. The studies were carried out with lymphoid cells of different organs of the immune system and peripheral blood of 44 patients with lymphoproliferative diseases and of 5 donors. The results permit considering the developed and tried immunocytochemical method for assessment of the proliferative status of pathological cell populations informative as regards the use of the "Working Classification of Non-Hodgkin's Lymphomas". PMID- 8689059 TI - [Optimized recording of results of the lymphocytotoxicity test using a luminescent attachment to Biolam-P-I microscope]. AB - The fluorescent attachment appreciably simplifies the procedure of recording the results of the lymphocytotoxic test, is compact, economic, and easily inserted in the Biolam-P-I inverted microscope. Use of fluorescent stains helps selectively stain viable and intoxicated cells, thus simplifying their estimation. The said modification may be used in HLA typing and assessment of the principal lymphocyte subpopulations in the peripheral blood. PMID- 8689062 TI - [Modified microcolorimeter MKMF-1 for recording of erythrocyte aggregation]. PMID- 8689061 TI - [Criteria in selection of the investigation method (literature review)]. PMID- 8689063 TI - [An additional test in the identification of Enterobacteriaceae and some representatives of the genus Vibrio]. AB - An additional test: aerobic redox fermentation in semiliquid Hiss' medium with mannitol is recommended for the indication of Enterobacteriaceae, Vibrio, etc. The majority of mannite-fermenting enterobacteria change the color of the indicator in a thin upper layer of a column of semiliquid Hiss' medium in comparison with the bulk of medium after 20-24 h growth in it. Such changes of the indicator are never observed with Shigella, Salmonella, Vibrio bacteria of the studied strains, Yersinia, some cocci, etc., which may be considered as an additional differential diagnostic test at early stages of investigation with due consideration for other known signs. The aerobic redox test does not require additional quantities of nutrient media, reagents, or glassware. PMID- 8689064 TI - [Vibrios pathogenic to humans and laboratory diagnosis of diseases caused by them]. AB - Present-day taxonomic status of vibrios pathogenic for humans is discussed, as are the phenotypical characteristics of some species, factors of virulence, and clinical manifestations of diseases caused by these agents. A scheme of isolation and identification of vibrios pathogenic for humans is offered. PMID- 8689065 TI - [The 70th anniversary of the Saint Petersburg Research Institute of Industrial Hygiene and Occupational Diseases]. AB - The article reviews research activities of the Institute for 70 years. The main research spheres represent occupational hygiene, industrial toxicology, sanitary and industrial chemistry, occupational diseases. The Institute is reported to have scientific priority and merits in improving the work conditions and treating the workers engaged into nonferrous metallurgy, in production of polymer materials, in radio and electronic industry. PMID- 8689066 TI - [Hygienic assessment of the working conditions for repairmen in the production of pure nickel and copper metals at nickel mills]. AB - Mechanic workers in electrolysis shops of copper and nickel production appear to work in conditions characterized by some occupational hazards, mostly by air pollution with aerosol of nickel sulfate. The study covered influence of work conditions and complexity on the workers' health state, that is demonstrated by higher morbidity and present occupational diseases. PMID- 8689067 TI - [The effect of the working conditions on the health status of female assemblers and their children]. AB - The study covered work conditions and health state of female assemblers and their children. The authors represent the results and evaluate gonadotoxic and embryotoxic effects of lead-tin solder in experiments on animals. PMID- 8689068 TI - [Experimental research on the biological action of the pulse-modulated microwave radiation created by shipboard radar stations]. AB - The article represents experimental data on influence of impulse modulated microwave irradiation with discontinuous effects varying in intensity and exposure. Becavior, peripheral blood, biochemical and morphologic parameters were assessed in the laboratory animals exposed. The response appeared to correlate with individual and typologic features of the examinees. PMID- 8689069 TI - [Quantitative characteristics of the causes of functional overstrain of the hands]. AB - Functional studies of hands strain covered 2351 women who performed multiple manual maneuvers with absent, mild and moderate efforts. Considered reasons of the functional strain were: number of the maneuvers per shift, applied efforts, work intensity, length of service, previous work hardiness, hand efforts beyond the worktime, specific traits of workers (age, health state). Functional strain of hands was assessed by means of an Articular Pain Index which is general evaluation of severity, intensity and frequency of pain in hand joints. The authors suggest norms for allowable and hazardous quantity of hand maneuvers in accordance with their structure. PMID- 8689070 TI - [Evaluation of oxygen-dependent processes in in-vitro experiments for the purpose of the hygienic regulation of chemical substances]. AB - The article suggests evaluation of tissue respiration in a pilot experiment, so as to promptly forecast toxicity, jeopardy and reveal metabolic activity and selective effects of industrial poisons. PMID- 8689071 TI - [The effect of increased voice and psychophysiological loads on the health status of interpreter guides]. AB - Clinical, functional and psychologic evaluation of interpreters revealed new data about influence of intensive vocal work and psychoemotional stress on occurrence of vocal apparatus disorders, cardiovascular diseases and central nervous system disturbances. The results are essential for early diagnosis and prophylaxis of vocal disorders and central nervous system disturbances. PMID- 8689072 TI - [The combined action of intermittent vibration and physical loads (exemplified by the grinder-buffers of turbine vanes)]. AB - The article presents hygienic evaluation of interrupted vibration in grinding of turbine vanes by stationary machines with consideration of static and dynamic load. Criteria estimating the operation are set, clinical features of the occupational diseases are determined. PMID- 8689073 TI - [Evaluation of the quality and efficiency of the activities of state epidemiological health surveillance centers]. AB - The article covers data on methodic approaches to evaluation and control of sanitary and epidemiologic supervision activities, systemizes terminology of the problem. PMID- 8689074 TI - [Setting standards for laser radiation]. AB - The article presents principles of a universal theory of hygienic regulation, proves a principle of regulation warranty. Maximal allowable level of laser irradiation (wavelength 0.63 and 10.6 mic) was subjected to feedback test, i.e. health state of the examinees was evaluated after the norm setting. The test proved that the Maximal Allowable Level for laser irradiation needs adjustment. PMID- 8689075 TI - [Early diagnosis and effective prevention of occupational allergies caused by hexavalent chromium]. AB - Clinical and allergologic evaluation covered a large group of workers engaged into alumina production and exposed to chromate. Those workers were also subjected to long-standing follow-up. The studies helped to find correlation of chromium concentration in air with occurrence of the occupational allergies and latent sensibilization of respiratory tract to chromium. Immune modulator Levamisol was proved to act as a desensibilizer in prophylaxis of the occupational allergies in individuals with the latent sensibilization. PMID- 8689076 TI - [Phytotherapy of the sensitization state caused by metal allergens]. AB - Experimental study revealed noticeable desensibilization caused by the use of medicinal herbs collections in laboratory animals sensibilized by chromium and nickel. That desensibilization effect of herbal medications is believed to result from activation and normalization of processes removing the agents from the body. Revealed experimentally and supported by clinical trials, therapeutic efficiency of the medicinal herbs collections makes them applicable for treatment and prophylaxis of allergies associated with metals. PMID- 8689077 TI - [N. A. Vigdorchik, founder of the Leningrad Research Institute for the Study of Occupational Diseases]. PMID- 8689078 TI - [An anamnestic method for studying the cause-effect connections between the status of public health and manufacturing, ecological and social factors]. AB - The authors elaborated a medical and ecologic questionnaire for specific history. The questionnaire was applied to express-evaluation of public health state and environmental factors in the certain settlement. The health state was proved to be influenced significantly by occupational conditions, hardiness and intensity of work, psychologic climate. The most hazardous environmental factors are: unsatisfactory quality of drinkable water, air pollution and traffic noise. The lifestyle of the population examined is strongly associated with bad habits (smoking, short sleep, alcohol abuse). PMID- 8689079 TI - [The air-circulation system in buildings with precision and sterile-environment technologies]. AB - The article covers recommendations on calculations for ventilation and air conditioning to maintain fixed air settings in buildings with precise and sterile technologies. PMID- 8689081 TI - [The basic research results and outlook of the Institute on the Problems of Child and Adolescent Hygiene]. AB - The article covers main spheres of research on the topic "Children's and Adolescents' Hygiene" from the foundation of the laboratory till now, destinations for further research are set. PMID- 8689080 TI - [Collagenosis-like syndromes as the possible manifestations of poisoning by the components of a compound]. PMID- 8689082 TI - [Industrial hygiene problems in the manufacture of polymetal materials]. AB - The article deals with results of hygienic and toxicologic research in production of some polymetallic compositions: electric vacuum glass, glass enamel, crystallic cement, eutectic solder and permanent magnets. PMID- 8689083 TI - Lactic acid production from molasses by Sporolactobacillus cellulosolvens. AB - Sporolactobacillus cellulosolvens (NCIMB 12173) isolated from an anaerobic digester and characterised biochemically is being reported for homofermentative lactic acid production from molasses in a batch culture. The effect of various process parameters on lactic acid production were optimized. A maximum lactic acid (24.2 g/l) and yield coefficient (0.79) was achieved using 3% (v/v) inoculum of 36 h old culture in molasses medium containing sugars (5%; w/v) supplemented with peptone (2.5 g/l) and (NH4)2SO4 (7.5 g/l), pH 6.5 at 40 degrees C after 72 h of fermentation. PMID- 8689084 TI - Antibodies to spotted fever group rickettsiae and Coxiella burnetii among domestic animals in southern Croatia. AB - The sera of dogs, goats, sheep and cattle (total 153) from the Kastelas' bay area (middle part of the eastern coast of the Adriatic Sea) were tested for antibodies against Rickettsia conorii and Coxiella burnetii by a complement fixation test. The overall percentages of positive sera among the tested animals were 23.9% for R. conorii and 16.4% for C. burnetii. The results show that animals in this area are clearly being exposed to spotted fever group rickettsiae as well as to C. burnetii. For comparison, six sheep sera from the flock, living in known Q fever focus in hinterland area and linked with outbreak of Q fever among owners were tested. Antibodies to C. burnetii but not for R. conorii were present in all six sera. PMID- 8689085 TI - Kinetic characterization of thyroid peroxidase enzyme and its inhibition by autoantibodies. AB - A guaiacol method was developed to measure thyroid peroxidase (TPO) activity and the inhibitory effect of anti-TPO antibodies using purified porcine TPO. The TPO preparation was characterized kinetically and identified by western-blotting technique. The K(M) for guaiacol determined in vitro was 5.6 x 10(-4) M. Investigating the effect of IgG's from 23 hypothyroid patients on TPO activity inhibition was detected in 15 cases with the guaiacol method. It was found that anti-TPO antibodies exerted a competitive inhibition TPO activity with respect to the substrate guaiacol. The inhibition is carried by IgGF(ab')2 fragment. We wanted to gain a method which is interpreted immunologically and can be well employed in the clinical practice. PMID- 8689086 TI - Seroepidemiologic study of anti-HAV IgG in health-care workers. AB - The seroprevalence of Hepatitis A virus IgG antibody (Anti-HAV IgG) was assessed in 410 health-care workers, included 97 physicians, 174 nurses, 57 auxiliary staff, 23 cleaning staff, and 59 from various professions. The overall seroprevalence rate was 50.2% with a mean age of 38.2 years, physicians 41.9%, nurses 48.6%, auxiliary staff 47.4% cleaning staff 87.0%, various professions 57.6%. A low seroprevalence was found in young employees, while a high seroprevalence increasing with age was demonstrated in older employees. The low seroprevalence rate may be returned to improvements of the socioeconomic conditions in Hungary. PMID- 8689087 TI - Comparison of selected species of Bipolaris, Drechslera and Exserohilum by random amplification of polymorphic DNA. AB - Forty-six strains representing 15 species of Drechslera, five of Bipolaris and four of Exserohilum, as well as two formae of Drechslera teres were compared by RAPD analysis. Drechslera formed a large, heterologous group, while species of Bipolaris and Exserohilum were more closely related. Strong pair-wise affinities were observed between D. graminea and D. teres, D. tritici-repentis and D. bromi, D. siccans and D. biseptata, D. fugax and D. poae, B. sorghicola and B. zeicola, as well as between E. rostratum and E. turcicum. PMID- 8689088 TI - Oxygen and carbon dioxide requirements of Helicobacter pylori. AB - The oxygen and carbon dioxide requirements of 25 clinical isolates of Helicobacter pylori were studied in relation to pyruvate metabolism. A maximal number of 16 strains grew without added carbon dioxide under an atmosphere containing 6% oxygen and 0.04% ambient atmospheric carbon dioxide contrary to a generally accepted idea. Enzymes acting on pyruvate as a parameter of the ATP regeneration system were only pyruvate:ferredoxin oxidoreductase (EC 1.2.7.1) and pyruvate formate-lyase (EC 2.3.1.54). The microaerophilism may be partly due to the conversion of pyruvate to acetyl-CoA by the two anaerobic enzymes, although the organism requires oxygen. PMID- 8689089 TI - Microbial counts and characteristics of Streptoverticillium strains isolated from soils in the Jordan valley. AB - A microbial survey of total bacterial count, agrobacteria, streptomycetes, and fungi was carried out in six locations in the Jordan Valley. The highest microbial counts for the four populations were in spring, the lowest mostly in autumn. No significant differences at p < 0.05 were observed either in the counts between the six locations, or in the seasonal counts of agrobacteria and streptomycetes between the six locations as well as within each location. The total bacterial counts (at p < 0.01) and fungi (at p < 0.05) differed significantly in the six locations. Microbial counts and the studied environmental conditions showed no significant regression. Of 552 streptomycetes strains isolated from soils collected from these locations, 58 belonged to the genus Streptoverticillium. They were distributed in five colour series grey (41%), red (31%), green (17%), blue (7%) and white (3%). Forty-eight strains had biverticillium spore bearing hyphae while only 10 had monoverticillium. While 28 strains produced distinctive reverse side pigment, only 8 and 6 strains produced soluble pigment and melanin pigment, respectively. Most strains utilized arabinose followed by fructose, mannitol, rhamnose, xylose, sucrose, inositol, and raffinose. Sixty-nine per cent of the strains exhibited activity in vitro test against Pseudomonas aeruginosa, and 45, 41, 28, and 7% against Staphylococcus aureus, Bacillus cereus, Agrobacterium tumefaciens and Escherichia coli, respectively. PMID- 8689090 TI - Antibiotic resistance of Acinetobacter calcoaceticus strains isolated from patients treated in intensive care units. AB - The distribution according to specimens and susceptibility to antimicrobial agents of 481 Acinetobacter calcoaceticus strains isolated from patients treated in intensive care units were studied. They occurred most frequently in tracheal specimens and pus. Using disk diffusion test the strains proved to be multiple resistant to ampicillin (86.3%), azlocillin (86.7%), mezlocillin (84.0%), cefamandole (99.7%), cefoxitin (94.1%), cefuroxime (90.6%), cefoperazone (84.9%), cefotaxime (82.0%), ceftriaxone (81.0%), tobramycin (71.2%), gentamicin (86.2%), chloramphenicol (90.5%) and tetracycline (89.8%). Based on the lowest incidence of resistant strains imipenem (0%), netilmicin (2.6%), amikacin (4.9%), ampicillin+sulbactam (8.9%), amoxicillin+clavulanic acid (29.4%), pefloxacin (26.2%), ciprofloxacin (30.1%), ofloxacin (34.3%), cotrimoxazole (41.6%), carbenicillin (41.2%) or ceftazidime (55.4%) may be the drug of choice in nosocomial A. calcoaceticus infections. PMID- 8689091 TI - Is seminal fluid a suitable specimen for detecting chlamydial infection in men? AB - As genital chlamydia infection is considered the most prevalent sexually transmitted bacterial disease worldwide, its correct diagnosis has a great clinical and epidemiological importance. Urethra is the recommended site for collecting specimen for detection of Chlamydia trachomatis in men, but urethral swabbing is very inconvenient for the patients. Testing of seminal fluid has two advantages: taking the sample is more convenient for the patient, and the ejaculate would provide more information on the possible infection of the upper genital tract. Three non-culture methods-enzyme immunoassay (EIA), DNA hybridization, and polymerase chain reaction (PCR)-were used for evaluation of suitability of seminal fluid as a sample for detection of Chlamydia in 4 patient groups comprising 259 symptomatic and asymptomatic, urology and andrology patients. The seminal fluids were tested parallel with the urethral samples. In one group of patients with typical prostatic complaints expressed prostatic secretion was examined parallel with urethral swab. C. trachomatis positivity rates were much higher in symptomatic (49.1%) than in asymptomatic patients (12.3%) in all kinds of sample. Seminal fluid was somewhat more frequently positive (7.9%) than urethral sample (6.2%). Simultaneous positivity was relatively rare (3.3%), it occurred most frequently in samples of patients with possible accessory gland infection tested by EIA. In a group of 17 patients with typical prostatic complaints the expressed prostatic secretion alone was positive in 7 cases, whereas only other two of the parallel urethral samples proved positive by PCR, simultaneous positivity occurred in one case. These findings suggest that testing of the ejaculate and/or the prostatic secretion parallel with the urethral sample would improve the sensitivity of detection of chlamydial infections. PMID- 8689092 TI - Interaction between Bordetella pertussis vaccine and chlorpromazine in mouse experiments. AB - In acute toxicity experiments the mortality of mice pretreated with Bordetella pertussis vaccine increased on the first day following chlorpromazine (CPZ) treatment, compared to control animals treated with CPZ alone. Initially, the increased drug sensitivity observed after combined treatment was attributed to summation of the toxic effects. However, the cumulation of mortality did not cease on the following days, furthermore, an increase of bacterial translocation was observed on days 6 and 7, i.e. when the lymphocytosis, splenic hypertrophy and shrinkage of thymus-changes consequent to the vaccination-were at their maximum levels. On the basis of all these and on literary data it is supposed that the early cumulation of deaths after combined treatment may be in connection with an interaction between the two agents and that the side-effects following vaccination of humans may be induced by undesirable pharmacological interactions. PMID- 8689093 TI - A higher production of platelet activating factor in ex vivo heterologously secondary dengue-2 virus infections. AB - Patients with a dengue-1 virus (DV-1) infection followed by another DV-2 infection were reported to have a higher incidence of dengue haemorrhagic fever (DHF). Mononuclear leukocytes (MNLs) are principal cells for DV replication so that we challenge MNLs obtained from non-immune and previously DV-1-infected donors with DV-2 to mimic primary and heterologously secondary DV-2 infections. Production of platelet activating factor (PAF), thromboxane B2 (TxB2), and prostaglandin D2 (PGD2) by MNLs in the DV-2 infections was measured by radioimmunoassay. We found that MNLs, no matter primary or heterologously secondary exposure to DV-2, could release significant amount of PAF, TxB2, and PGD2. PAF but not TxB2 or PGD2 levels released by MNLs were significantly higher in those obtained from previously DV-1-infected donors (75.8 +/- 28.5 vs 21.2 +/- 13.4 pg/ml; p < 0.05). These results suggest that PAF, which is known to enhance inflammatory reactions and to augment platelet aggregation, may in part participate in the pathogenesis of DHF. PMID- 8689094 TI - Radiodetoxified endotoxin-induced tolerance. Effect on endotoxin lethality and macrophage arachidonic acid metabolism. AB - Endotoxin (LPS) tolerance produces changes in macrophage mediator production which is thought to be responsible for the acquired LPS resistance. Detoxification of LPS by gamma irradiation has been reported to diminish certain noxious properties while retaining its tolerance inducing actions. We compared the efficacy of LPS and radiodetoxified (RD)-LPS from Escherichia coli O101 on stimulating rat peritoneal macrophage arachidonic acid (AA) metabolism, measured by thromboxane (TXB2). Changes in macrophage production of these mediators were also assessed after tolerance induction. LPS tolerance was induced by i.p. injection of LPS, RD-LPS or vehicle on day 1 (100 micrograms/kg, i.p.) and day 2 (500 micrograms/kg, i.p.). On day 5 or 4 weeks after pretreatment, peritoneal macrophages were harvested for in vitro studies, or rats were tested for lethality resistance. Macrophages were incubated +/- LPS (0.1 ng to 50 micrograms/ml), lipid A (1 or 10 micrograms/ml) or Ca+2 ionophore A23187 (10 microM) for determination of TXB2 production. Minimum effective concentrations of LPS and RD-LPS for stimulation (P < 0.05) of TXB2 were 100 ng/ml and 1 microgram/ml, respectively. Maximal stimulation of TXB2 occurred at 10 micrograms/ml of LPS or RD-LPS. Macrophages from LPS or RD-LPS tolerized rats were refractory to stimulated TXB2 with LPS or RD-LPS (0.1 ng to 50 micrograms/ml). The suppressed in vitro macrophage TXB2 production was apparent 4 weeks after rats were tolerized with LPS or RD-LPS. In subsequent mortality studies, LPS challenge of control or tolerance rats at day 5 in vivo with Salmonella enteritidis LPS (15 mg/kg, i.v.) produced a 90% mortality in control rats (N = 22), versus 13% mortality in the LPS pretreated group (N = 23) and a 20% in the RD-LPS pretreated group (N = 10) (P < 0.05 vs control). However, this lethality resistance was not apparent at 4 weeks after LPS or RD-LPS pretreatment. Both LPS and RD-LPS appear to be equipotent in inducing macrophage alterations, and in lethality resistance during LPS tolerance induction. However, these observations suggest that during LPS tolerance suppression of LPS stimulated AA in peritoneal macrophage metabolism persists longer than acquired lethality resistance. PMID- 8689095 TI - Serologically verified hantavirus infections in Hungary. AB - Between 1987 and 1993 the etiological diagnosis of haemorrhagic fever with renal syndrome (HFRS) of 55 patients was confirmed using hantavirus-specific serology. The geographical distribution of cases indicated that at least two different territories of Hungary are endemic for hantaviruses. These possible natural foci are different from, but overlapping with the region endemic for tick-borne encephalitis virus. Patients sera were shown to react differently with reagents prepared from different hantaviruses, indicating that different types are present simultaneously in both natural foci. PMID- 8689096 TI - Role of nitrogen fixing bacteria on the phyllosphere of wheat seedlings. AB - Two diazotrophic bacteria Azotobacter chroococcum (REN2) and Corynebacterium sp. (Pot N2) isolated from rice and potato phyllosphere, respectively, were tested on wheat seedlings in vitro, for their efficiencies to increase dry weight and total nitrogen content of the plant, to establish their utility as potential biofertilizers. An average increase in dry weight nearly by 35-50% and total nitrogen content by 56-52% was obtained which was near to that available by nitrogenous chemical treatment. A comparatively better result was obtained by REN2 than Pot N2. PMID- 8689097 TI - Making sense of symptoms: self-categorization and the meaning of illness and injury. AB - A central theme in both medical sociology and health psychology is how people make sense of their symptoms. Both literatures, despite their stress on different aspects of the health evaluation process, see illness in terms of matching present symptoms to an underlying understanding of illness. In this paper we argue that such accounts have difficulty in explaining the impact of contextual factors on how symptoms are evaluated. We therefore propose a model based on self categorization theory (Turner, Hogg, Oakes, Reicher & Wetherell, 1987). It is proposed that symptoms are evaluated, not against pre-existing illness representations, but by reference to their impact on situationally salient identities. In support of this and experiment is described which involves students who are training to be physical education (PE) teachers. They are defined either in terms of a 'PE student' identity or in terms of a 'gender' identity and asked to evaluate a number of scenarios which describe different illnesses and injuries. Overall, the results provide clear evidence that the significance ascribed to scenarios depends on which identity is salient and hence indicate the viability of a self-categorization theory approach to symptom evaluation. PMID- 8689098 TI - Mental health and adequacy of social support: a four-wave panel study. AB - LISREL analyses with manifest variables were used to examine the causal relationship between mental health and adequacy of social integration and of attachment, measured at four consecutive waves each four months apart, in a representative sample of 225 adult residents in Canberra. Mental health was assessed with the 30-item General Health Questionnaire. The analyses suggest that while there is no temporal relationship between adequacy of attachment and mental health, adequacy of social integration is influenced by earlier mental health. The temporal relationship between adequacy of attachment and adequacy of social integration appears to be reciprocal. PMID- 8689099 TI - Seeking influence through characterizing self-categories: an analysis of anti abortionist rhetoric. AB - This paper presents an analysis of an anti-abortionist's speech to a medical audience. It is shown that central to the speech is the way in which the speaker defines the context of the abortion debate and hence the categories of people involved. In particular, the speaker construes himself as a member of a common in group with his audience, construes the entire audience as part of an anti abortion category and claims that abortion is in contradiction with the defining features of the audience's medical identity on a series of levels. This analysis is used to make two suggestions. Firstly, following self-categorization theory, that the ways in which self-categories are defined may be central to the process of mass social influence. Secondly, however, self-categories may not be specified by intra-psychic processes but rather are discursively constructed and argued over. The implications of such a position for future research on self categorization and category salience are discussed. PMID- 8689100 TI - Perceived antecedents of emotional reactions in inter-ethnic relations. AB - It is argued that the aspects of intergroup relations that potentially can arouse emotions in the perceiver are likely to become central and motivationally relevant elements of group stereotypes. Asking participants to report on the perceived antecedents of their emotional reactions to in-group and out-group members should therefore be an especially useful method to reveal the content of stereotypes. Native Dutch participants reported both the frequencies with which different emotions were felt in different intergroup relations and the perceived causes of these emotions. Analysis of self-reported antecedents of emotional reactions revealed that (a) despite a general in-group favourability bias, both the in-group and the two out-groups employed arouse different kinds of negative and positive emotions; and (b) differences in emotional reactions to the two out groups are related to salient differences in perceived antecedents between these groups. Theoretical and practical implications of the present emphasis on the cognitive foundation of emotion in intergroup relations are discussed. PMID- 8689102 TI - Phase II trials in Ta, T1 bladder cancer. The marker tumour concept. PMID- 8689101 TI - Peptide growth factors in the prostate as mediators of stromal epithelial interaction. AB - Peptide growth factors play a role in the maintenance of normal prostatic growth and differentiation (Fig. 2). It seems likely that the androgen sensitivity of human prostate is mediated by the production of peptide growth factors from stromal cells which act as the direct intermediate of androgen action on epithelial cells. TGF-beta 1 inhibition of epithelial cells is opposed by the stimulatory action of EGF, IGF and FGFs to maintain an equilibrium of epithelial cell numbers. The indirect mitogenic action of androgens appear to act by down regulation of TGF-beta 1 and possibly EGF receptors. There is also interaction with the effects of IGF-II, produced by prostatic stromal cells and acting on epithelial cells to increase proliferation. The growth of normal prostatic fibroblasts is under the control of bFGF and TGF-beta 1. However, although our understanding of the actions of these growth factors in the normal prostate has improved over the last decade, their role in the development and maintenance of prostate cancer is less clearly defined. TGF-beta 1, classically considered to be inhibitory for epithelial cells, may be up-regulated in prostatic tumours, stimulating growth. Alternatively, autocrine production of such growth factors by tumour cells may lead to loss of inhibitory effects from exogenous TGF-beta 1, a mechanism also witnessed with TGF-alpha and bFGF. The role of EGF in the development of prostate cancer is confusing because results from the use of different cell types and experimental conditions is contradictory. It may be that a switch in the production of the predominant EGFr ligand from EGF to TGF-alpha is an important feature in the development and maintenance of the malignant phenotype. The presence of TGF-alpha autocrine loops has been shown clearly in some tumour cell lines. This switch in the production of a particular ligand may also be a feature of IGFs in prostate cancer. IGF-II may be replaced by IGF-I during malignant progression, both of which are able to act via the type 1 receptor. This change in IGF expression appears to be accompanied by altered expression of the IGF-BP2, with less detectable within prostatic tissues but elevated serum levels [58]. Basic FGF is normally produced by prostatic fibroblasts but is also produced by some prostatic cancer cell lines [64]. However, as with all growth factors, the expression of the bFGF protein and its receptor is dependent on the cell line examined. The autocrine and paracrine control of normal and abnormal prostatic growth by growth factors is important in determining their role in the development and maintenance of prostate cancer. Better understanding of such mechanisms is essential for the development of novel therapeutic strategies in the control and treatment of prostate cancer. PMID- 8689103 TI - A phase II study of interferon-alpha, interleukin-2 and 5-fluorouracil in advanced renal carcinoma: clinical data and laboratory evidence of protease activation. AB - OBJECTIVE: To confirm the activity and evaluate the toxicity of the combination of subcutaneous interferon-alpha (IFN-alpha) and interleukin-2 (IL-2) with intravenous 5-fluorouracil (5-FU) in patients with advanced and recurrent renal carcinoma and of performance status 0-2. Additionally, to examine protease, complement and neutrophil activation as potential mediators of IL-2 toxicity. PATIENTS AND METHODS: Fifty-five patients were treated in an 8-week cycle with IFN-alpha (6 MU/m2 on day 1 in weeks 1 and 4 and thrice weekly in weeks 2-3, and 9 MU/m2 thrice weekly in weeks 5-8) IL-2 (20 MU/m2 on days 3-5 in weeks 1 and 4 and 5 MU/m2 thrice weekly in weeks 2-3) and 5-FU (750 mg/m2 on day 1 of weeks 5 8). Patients responding to the first cycle were eligible to continue with further cycles. Toxicity and effects on quality of life were assessed using World Health Organization criteria and the Rotterdam Symptom Checklist and Hospital Anxiety and Depression Scale. Serum levels of C3a, prekallikrein and elastase-alpha 1 proteinase inhibitor (elastase-alpha 1-antitrypsin) were assayed in a subset of patients before, during and after the administration of high-dose IL-2 in week 1. RESULTS: There were partial remissions in nine patients, with responses in 24% (95% CI 10-38%) of evaluable patients and 16% of all patients. Amongst 25 evaluable patients who had undergone nephrectomy, the response rate was 32% (95% CI 14-50%), whereas there was only one response amongst 22 patients who had not undergone nephrectomy. The median survival for patients with stable disease or partial remission exceeded 22 months. Outcome and survival were related to performance status, number of sites of metastases and nephrectomy. This group of patients was of relatively poor performance status and 18 patients (36%) failed to complete one 8-week treatment cycle. Cardiovascular and renal toxicities were less than those seen with intravenous IL-2 schedules but 44% of patients experienced at least one grade III toxicity and only 14% reported less than two grade II toxicities. Plasma levels of elastase-alpha 1 proteinase inhibitor exceeded the normal range in three of seven patients tested before treatment and increased in all seven patients after treatment with IL-2. The same three patients had raised levels of C3a before treatment and in all patients examined, C3a increased after treatment with IL-2. In contrast, plasma prekallikrein concentrations were below normal before treatment and decreased further afterwards. CONCLUSIONS: This study confirms the activity of this regimen in patients of good performance status, with limited sites of disease and in those who are fit for nephrectomy, but also showed that treatment was associated with considerable toxicity. The administration of IL-2 is associated with protease activation which may be a suitable target for pharmacological intervention in attempts to ameliorate toxicity. PMID- 8689105 TI - The value of exfoliative urine cytology in combination with flexible cystoscopy in the diagnosis of recurrent transitional cell carcinoma of the urinary bladder. AB - OBJECTIVE: To study the value of exfoliative urine cytology in predicting recurrent tumour in patients undergoing surveillance for transitional cell carcinoma (TCC) and to assess the suitability of these patients for flexible cystoscopy. PATIENTS AND METHODS: Specimens of early-morning and freshly voided urine were submitted 2 weeks before surveillance cystoscopy by 111 consecutive patients with known TCC. All patients then underwent cystoscopy under general anaesthesia. The urine specimens were analysed by two pathologists with no knowledge of the patients' history. Cytological findings were correlated with the findings of cystoscopy. RESULTS: Urine cytology predicted 82% of all recurrent tumours found subsequently at cystoscopy; 60% of patients with non-neoplastic pathology had normal cystoscopy. Only 51% of patients with positive urine cytology were shown to have recurrent TCC, but 87% of patients with negative cytology had no recurrent tumours. CONCLUSION: Urine cytology is a good adjunct to assessing the suitability of flexible cystoscopy in the follow-up of patients with transitional cell tumours. PMID- 8689104 TI - Quantitative assessment of vascular surface density in renal cell carcinomas. AB - OBJECTIVE: To evaluate the extent of vascularization by assessing vascular surface density in renal cell carcinomas (RCCs) of different nuclear grades, and in normal renal cortex and medulla. MATERIALS AND METHODS: Specimens of 79 RCCs of different nuclear grades (16 of G1, 42 of G2 and 21 of G3) were immunostained with the lectin Ulex europaeus agglutinin-I (UEA I). The vascular surface density of tumour tissue was assessed stereologically using a test grid at x400 magnification and compared to the values obtained in normal renal tissue. RESULTS: G3 tumours had a lower vascular surface density than had G1 and G2 RCCs and normal renal tissue of the cortex and medulla (P < 0.001, respectively). G1 tumours had a significantly higher vessel density than had normal medullary parenchyma and G2 carcinomas (P < 0.001). Vessel density was not significantly different among G1 tumours and cortical parenchyma in controls and among normal medullary tissue and G2 tumours. Statistical analysis showed that the vascular surface density was independent of tumour stage and size and the age and sex of the patients. CONCLUSION: The degree of vascularization in RCCs decreased with their grade of differentiation, suggesting that the extent of neovascularization in tumour tissue reflects the relationship between tumour cell proliferation and vascular growth. The values of vascular surface density in normal renal tissue of the cortex and medulla partially overlapped with those obtained in tumour tissue. PMID- 8689106 TI - Overexpression of p53 protein and its significance for recurrent progressive bladder tumours. AB - OBJECTIVE: To determine the prognostic value of the overexpression of p53 protein as determined by immunohistochemistry in recurrent progressive transitional cell carcinomas of the bladder. PATIENTS AND METHODS: A total of 222 tumours from 86 patients with recurrent disease, 20 from patients with no evidence of recurrence after resection of initial tumour and 11 normal bladder (controls) were investigated. Using a microwave technique to expose antigens, formalin-fixed sections were immunohistochemically stained for p53 using a polyclonal antiserum. Two independent observers scored the sections for evidence of overexpression of p53. RESULTS: Of 86 patients with recurrent disease, 51 demonstrated overexpression of p53 protein, as did six of 20 patients with non-recurrent disease. Overexpression was not linked to recurrence (P = 0.5) but was related to worsening histological stage (P < 0.01) and increasing grade (P < 0.01). Regression analysis showed that overexpression of p53 for the primary tumour was not of predictive prognostic value for death from bladder cancer, time to progression or time to recurrence. Tumour grade was the only variable of prognostic value in all the statistical models. Patients with overexpression of p53 showed no reduction in overall survival. CONCLUSION: These findings suggest that overexpression of p53, as determined immunohistochemically, appears to have no predictive prognostic value over stage and grade in bladder tumours. PMID- 8689107 TI - Early clinical experience with 5-aminolevulinic acid for the photodynamic therapy of superficial bladder cancer. AB - OBJECTIVE: To report clinical experience with intravesical instillations of 5 aminolevulinic acid (ALA) for the photodynamic therapy of superficial bladder cancer and to assess any side-effects of the treatment. PATIENTS AND METHODS: Ten patients (six men and four women, mean age 62.3 years, range 42-73) with refractory superficial bladder cancer were treated with photodynamic therapy using 5 g of ALA dissolved in 30 mL sodium bicarbonate instilled intravesically. After a mean retention of 5.1 h, the bladder interior was illuminated transurethrally at radiation integrals of 15, 30 or 60 J/cm2. At integrals of 15 or 30 J/cm2 red light (635 nm) was used and at 60 J/cm2, green light (514 nm, 40 J/cm2) was combined with a subsequent application of red light (635 nm, 20 J/cm2). RESULTS: After 10-12 weeks, four patients had a complete remission, two a partial remission, there was no change in three and one had progressive disease. Of those patients responding, the bladder was preserved in five after a mean follow-up of 15 months (range 6-27). There were no photodermatoses or bladder shrinkage in any patient. CONCLUSIONS: Photodynamic therapy with intravesically applied ALA is effective in destroying superficial urothelial carcinomas of the bladder. There were no serious side-effects which could preclude further clinical testing. PMID- 8689108 TI - Polymorphism and smoking in bladder carcinogenesis. AB - OBJECTIVE: To study the relationship between smoking, a cytochrome P-450 gene polymorphism and the development of bladder cancer. PATIENTS AND METHODS: The study comprised 126 patients with a diagnosis of bladder cancer from whom a full history was obtained. Genomic DNA was extracted from blood sampled from each patient and genotyping of the CYP2D6 locus, the gene responsible for debrisoquine hydroxylase activity, was performed using a polymerase chain-reaction technique. RESULTS: Of the 126 patients, 78% had a history of smoking. There was a relationship between the number of cigarettes smoked and the grade of the presenting bladder tumour; heavy smokers developed high-grade disease. There was a trend for those heterozygous at the CYP2D6 locus and with a history of smoking to develop more aggressive disease, but this trend did not reach statistical significance. CONCLUSION: The link between smoking and bladder cancer was confirmed. Furthermore, the grade of the presenting tumour was related to the 'cigarette-years'. The CYP2D6 genotype may influence the type of bladder cancer that develops in smokers. PMID- 8689109 TI - Bacillus Calmette-Guerin perfusion therapy for carcinoma in situ of the upper urinary tract. AB - OBJECTIVE: To analyse the clinical and therapeutic consequences of bacillus Calmette-Guerin (BCG) perfusion therapy for carcinoma in situ (CIS) of the upper urinary tract. PATIENTS AND METHODS: Eight pyelo-ureteric systems in five patients with cytologically confirmed CIS of the upper urinary tract were treated using perfusion of BCG through a percutaneous nephrostomy tube in five and a retrograde ureteric catheter in three. Follow-up cystoscopy, retrograde pyelography and selective urinary cytology were obtained 4 weeks after the last treatment and every 3 months thereafter. RESULTS: In three patients (five pyelo ureteric systems) the cytology remained negative for 10-46 months after the treatment was completed. The remaining two patients (three pyelo-ureteric systems) had persistently positive cytology. Of two patients who received BCG therapy through a ureteric catheter, one developed a ureteric stricture and the other developed renal tuberculosis. CONCLUSIONS: Although long-term adaptation to a nephrostomy tube disturbs the quality of life of the patient, percutaneous perfusion therapy through a nephrostomy tube seems to be safer than retrograde perfusion through a ureteric catheter. PMID- 8689110 TI - High-dose pelvic irradiation followed by ileal neobladder urinary diversion: complications and long-term results. AB - OBJECTIVE: To determine the risk of post-operative complications in patients receiving high-dose pelvic irradiation before radical cystectomy and urinary diversion. PATIENTS AND METHODS: Of 300 patients who underwent orthotopic bladder replacement at our institution from 1986 to 1994, 11 patients (mean age 63 years, range 53-74) did so after receiving high-dose pelvic irradiation. The indication for cystectomy and urinary reconstruction was bladder cancer in seven men, prostate cancer in two men and a contracted bladder due to combined external pelvic irradiation and afterloading radiotherapy in two women. RESULTS: The post operative course, including the duration of hospital stay, peri-operative complications and early functional results, did not differ from a control group of non-irradiated patients, and no patients died. The mean follow-up was 22 months (range 10-37) and revealed satisfactory results in seven of 11 patients. A neovesicoperitoneal fistula developed in one woman 10 months after surgery and was repaired by laparotomy. A neovesicovaginal fistula led to supravesical urinary diversion in the second woman. CONCLUSIONS: High-dose pelvic irradiation should not be a primary contra-indication for orthotopic urinary diversion using segments of small intestine. For patients who undergo combined external and afterloading radiotherapy, the indication for orthotopic bladder replacement should be considered critically. PMID- 8689111 TI - Stones in enterocystoplasties. AB - OBJECTIVES: To assess the aetiology of stones which occur in enterocystoplasties and continent diversions, generally attributed to the presence of foreign material, e.g. staples, or to recurrent urinary infection, in patients with augmented or substituted bladders. PATIENTS AND METHODS: The study comprised 467 patients who had undergone reconstruction of the lower urinary tract and had been followed up for at least 3 years using videourodynamics and ultrasonography. RESULTS: Stones were found in 42 patients (9%); 50% were found incidentally and the remaining patients presented with symptomatic infections (27%) or deterioration in urinary continence (23%). Stones occurred in 6% of patients with augmentation, in 7% of those with substitution cystoplasty and in 22% of patients with continent diversions. Most patients with stones (88%) used clean intermittent self-catheterization (CISC). Stones were 5-10 times commoner in patients using CISC than in patients voiding spontaneously. CONCLUSION: Urinary stasis was a more important cause of stone formation than was bacteriuria in patients with cystoplasty. The presence of mucus and bacteriuria are presumed to be contributory. To reduce the risk of stone formation, orthotopic cystoplasty and spontaneous voiding are to be preferred to continent diversion and CISC. Periodic bladder washouts may be an alternative solution. PMID- 8689112 TI - Bladder replacement by detubularized ileal loop: 10 years of experience using a personal technique. AB - OBJECTIVE: To evaluate the results obtained with a technique of bladder replacement using a detubularized ileal tract, developed by the authors. PATIENTS AND METHODS: Since 1983, 34 patients have undergone an orthotopic bladder replacement using 35-40 cm of ileum, detubularized and shaped into an 'S' to create a neobladder with a capacity of 100-120 mL. The ureters were anastomosed directly to a 10 cm long intact afferent loop which serves as an anti-reflux mechanism, while a 2 cm long efferent, spatulated loop was used for urethral anastomosis. The mean (SD) follow-up was 32 (33) months. RESULTS: All the patients were continent during the day, with socially convenient intervals between voids; 3 years after the operation, 10 of 12 patients were continent during the night, with intervals of 2-4 h between voids. The mean post-void residual urine volume was 41 mL and no patient required self-catheterization. There were no derangements of the metabolic status of patients. CONCLUSION: This technique was applied knowing that a detubularized intestinal loop has the remarkable ability to increase in capacity over time. Therefore, to maintain the reservoir in good condition over a long period it is important to construct it with an intra-operative capacity of < 120 mL, thus reducing the length of intestine required. This may explain the satisfactory metabolic status of these patients. Moreover, the triplication of the mesentery helps to maintain the sphericity of the neobladder and provides support for the neobladder in the lower pelvis, where it retains the same position as a normal bladder. PMID- 8689114 TI - A self-expanding, self-retaining temporary urethral stent (Urocoil(TM)) in the treatment of recurrent urethral strictures: preliminary results. AB - OBJECTIVE: To determine the efficacy of a self-expanding self-retaining temporary urethral stent (Urocoil) in patients with recurrent urethral strictures at different levels in the urethra. PATIENTS AND METHODS: Urocoil stents were placed in 18 patients (mean age 42 years, range 28-60) with recurrent urethral strictures. The stents were left for a mean of 8 months (range 6-14) and patients followed for a mean of 9 months (range 6-18) after removal of the stent, being assessed by urine culture, urethrography, flexible cystoscopy and urinary flow rate. RESULTS: The stents were easy to insert and remove under local anaesthesia. All patients except one had a satisfactory outcome. Complications included stent migration (3), encrustation (2), hyperplasia of the mucosa (2) and the one failure, where the stent was extruded by a long fibrous stricture. CONCLUSION: The use of the temporary stent is an encouraging development in the treatment of this complicated problem but a longer follow-up is necessary to exclude the possibility of late recurrence. PMID- 8689113 TI - Endoscopic rollerball electrovaporization of the prostate--the sandwich technique: evaluation of the initial efficacy and morbidity in the treatment of benign prostatic obstruction. AB - OBJECTIVES: To evaluate the safety, initial efficacy and morbidity of a new treatment for benign prostatic hyperplasia (BPH), endoscopic rollerball electrovaporization (EREV) of the prostate. PATIENTS AND METHODS: Endoscopic rollerball electrovaporization with or without a modified transurethral prostatectomy (TURP) was performed in 51 patients (mean age 69 years). Before treatment, patients were evaluated by measuring maximum flow rate, post-void residual volume (PVR) and a symptom score. After undergoing EREV and modified TURP the operative and hospital records were reviewed and the duration of the procedure, hospital stay and the incidence of complications and/or morbidity were recorded. The urodynamic variables were re-evaluated after 3-8 months. RESULTS: Five patients were operated on for retention: of the remaining patients, the pre operative mean symptom score was 18 (maximum 30), the mean maximum flow rate was 11.5 mL/s, the mean PVR was 159 mL and the mean duration of the procedure was 28 min. Of the 51 patients, 30 were discharged catheter-free on the first day after surgery. No patient required transfusion for associated blood loss, none had evidence of symptomatic bacteraemia and the transurethral resection syndrome did not occur. One patient who had a bladder carcinoma resected at the same operation was readmitted 2 weeks later with haematuria and clots. Three patients presented as emergencies within 8 weeks because of retention; one was admitted and required further EREV. On re-evaluation, the symptom scores decreased by a mean of 11 points, the maximum flow rate increased by a mean of 6.2 mL/s and the mean PVR decreased by 102 mL. CONCLUSIONS: EREV of the prostate is a safe, effective and economic alternative to a standard TURP. PMID- 8689115 TI - The significance of terminal dribbling in men with lower urinary tract symptoms. AB - OBJECTIVE: To determine the relationship between the symptom of terminal dribbling, objective evidence of terminal dribbling on recordings of uroflow, benign prostatic enlargement (BPE) and bladder outlet obstruction (BOO) in men with lower urinary tract symptoms (LUTS). PATIENTS AND METHODS: The prevalence of the symptom of terminal dribbling was determined from a symptom questionnaire completed by 165 men presenting with LUTS. Objective evidence of terminal dribbling during voiding was assessed from uroflow recordings and prostate volume was measured by transrectal ultrasonography. Combined pressure-flow studies were performed to determine the presence or absence of BOO. RESULTS: There was relatively poor agreement between the symptom of terminal dribbling and objective evidence of its presence; 48% of the patients who reported terminal dribbling most or all of the time showed no objective evidence of terminal dribbling on uroflowmetry. The symptom of terminal dribbling was not significantly related to the presence of BOO (P = 0.74) and the group-specific urethral resistance factor (URA) did not differ significantly (P = 0.79) between those men who complained of terminal dribbling and those who did not (median URA 33 and 31 cmH2O, respectively). However, objective evidence of terminal dribbling on uroflow traces was significantly related to BOO (P < 0.001) and those patients with objective evidence of terminal dribbling had higher values of URA (median 39 compared with 28 cmH2O). Objective terminal dribbling had a specificity of 92% and positive predictive value of 88% for the presence of BOO. Neither the symptom of terminal dribbling nor objective evidence of its presence were significantly related to prostatic enlargement. CONCLUSION: While the symptom of terminal dribbling is probably not related to BOO or prostatic enlargement, objective evidence of terminal dribbling on flow curve recording is specific for BOO and as such, its presence could potentially be of value in the assessment of men with LUTS. PMID- 8689116 TI - Treatment of female stress urinary incontinence with a new anatomically shaped vaginal device (Conveen Continence Guard). AB - OBJECTIVE: To evaluate the clinical efficacy of a new vaginal device for the treatment of female stress urinary incontinence. PATIENTS AND METHODS: This multicentre study comprised 90 women with stress incontinence (mean age 47.5 years, range 31-65). The diagnosis of stress urinary incontinence was based on the result of a quantitative provocation test. The device was used daily for 4 weeks. Urinary leakage with and without the device was assessed using a 24 h pad test at home. The patient's subjective opinion concerning their urinary leakage and the efficacy and function of the device were assessed using a questionnaire. RESULTS: Eighty-five women completed the study and successfully performed the pad test on both occasions. The mean (SEM) urinary leakage at the end of the study period whilst using the device was 13.9 (3.2) mL, which was less than the 41.6 (7.6) mL mean leakage measured before treatment (P < 0.001). Of the 85 women, 39 (46%) were completely dry during the pad test with the device in situ, 29% had a smaller leakage, 17% had the same leakage and 8% had a greater leakage. Accordingly, the overall objective improvement was 75%; 72% of the women considered the product to function satisfactorily and 60% expressed a wish to continue with the treatment. The vaginal device caused some local discomfort in 62% of the patients, but 72% of these women wished to continue with the device despite the reported discomfort. CONCLUSION: The new vaginal device reduced urinary leakage in stress incontinent women and 46% became continent. Even women with severe leakage had some improvement when using the device. PMID- 8689117 TI - A comparison of various methods to burst Foley catheter balloons and the risk of free-fragment formation. AB - OBJECTIVE: To compare the efficiencies of bursting balloons and the risks of forming free fragments after rupture using needles, the stylet of a ureteric catheter, instillation with ether or overinflation. MATERIALS AND METHODS: Two hundred 18 F 'silkolatex' Foley balloon catheters were divided into four groups of 50. Each balloon was inflated with 30 mL of distilled water, the catheters immersed in urine collected from healthy volunteers and maintained at 37 degrees C for 48 h. Attempts were made to burst the balloons with a needle (group 1), by overinflation (group 2), by ether instillation (group 3) and using the stylet of 7 F ureteric catheter through the inflation channel (group 4). RESULTS: The ratio of the burst to deflated balloons and the formation of free fragments were 100% and 0% in the group 1, 94% and 83% in the group 2, 100% and 100% in group 3 and 16% and 0% in the group 4, respectively. CONCLUSION: Bursting the catheter balloons using a needle seems to be the most appropriate method, being efficient and having little risk of forming free fragments. PMID- 8689118 TI - Histochemical detection of intranuclear DNA fragmentation and its relation to the expression of bcl-2 oncoprotein in human prostatic cancer. AB - OBJECTIVE: To assess the incidence of intranuclear DNA fragmentation and the expression of the bcl-2 oncoprotein in prostatic carcinoma, both of which are related to programmed cell death. PATIENTS, MATERIALS AND METHODS: Specimens of tumour obtained from 17 patients with newly diagnosed prostatic carcinoma and 16 with hormone-treated prostatic carcinoma undergoing total prostatectomy were evaluated. DNA fragmentation was detected using the terminal-labelling method (d uridine triphosphate conjugated with digoxigenin) and the expression of bcl-2 was detected immunohistochemically. RESULTS: There was a high incidence of intranuclear DNA fragmentation in 14 of 17 untreated tumours and 15 of 16 hormone treated tumours. There were no differences between the positive cases in hormone treated tumours and untreated tumours. There was significantly greater expression of bcl-2 in tumours treated with non-steroidal anti-androgen drugs (eight of nine were positive) than in those untreated (seven of 17) or treated with other drugs (one of seven) (P < 0.05). There was a consistent and marked dissociation between DNA fragmentation and bcl-2 positivity; most of the cells positive for bcl-2 showed no DNA fragmentation. CONCLUSION: The results indicated that cells positive for bcl-2 might potentially be hormone resistant and that the administration of non-steroidal anti-androgen drugs might have a role in the induction of hormone-resistant cells. PMID- 8689119 TI - A single positive prostate biopsy in six does not predict a low-volume prostate tumour. AB - OBJECTIVE: To evaluate whether a single positive prostate biopsy in six systematic transrectal ultrasonography (TRUS)-guided biopsies is predictive of a small tumour volume in a subsequent radical prostatectomy (RP) specimen. PATIENTS AND METHODS: Of 158 patients submitted to RP for T1-T2 prostate cancer, 15.2% had one positive biopsy. The rate of positive margins (M+) and extra-capsular involvement (C+) were assessed on the RP specimen in those with one positive biopsy (group I) and in those diagnosed by more than one positive biopsy (group II). The percentage of those with postoperative biological progression (P+), having a prostate-specific antigen (PSA) level > 0.1 ng/mL, was evaluated in both groups. The Gleason scores in biopsies and specimens were also compared. Fifteen patients diagnosed by a single positive biopsy were management conservatively. RESULTS: The percentage of patients who were categorized C+, M+ and P+ was 29.2, 16.7 and 26% in group I and 70, 46.5 and 49.5%, respectively, in group II. All patients with < 10% of the biopsy core length invaded by cancer had intracapsular (P2) disease, whereas if all the core length was invaded by tumour, all patients had extracapsular (P3) disease. The Gleason scores for biopsy cores and whole specimens were identical in 38.7% of the cases; the Gleason score was underestimated on biopsy in 48.4% of cases. In the group treated conservatively, nine of 15 patients were in biological progression, with a mean follow-up of 22 months. CONCLUSION: A single positive needle-biopsy in six systematic TRUS-guided prostate biopsies is not predictive of low-volume prostate cancer on an individual basis and does not guarantee a favourable outcome after RP. PMID- 8689120 TI - Penile Mondors' disease: an underestimated pathology. AB - OBJECTIVE: To report the aetiological, diagnostic and therapeutic aspects of penile Mondor's disease treated with non-steroidal anti-inflammatory drugs (NSAIDs) or surgery. PATIENTS AND METHODS: During the last 3 years, 10 patients (mean age 35 years, range 20-57) were treated for superficial penile vein thrombophlebitis. The main aetiological factors were prolonged and excessive sexual intercourse, operations for inguinal hernia and deep vein thrombosis. All patients had noticed sudden and almost painless cord-like induration on the penile dorsal surface. Doppler ultrasonography was useful in both diagnosis and follow-up. Eight patients were treated with NSAIDs and platelet drugs. RESULTS: The mean interval to resolution of symptoms was 3 weeks. Two patients who did not respond to drug therapy underwent surgery (dorsal vein resection). CONCLUSION: Medical therapy and, when indicated, vein resection are successful and effective in treating penile Mondor's disease. PMID- 8689121 TI - Peyronie curvature treated by plication of the penile fasciae. AB - OBJECTIVE: To evaluate the results of plication of the penile fascia in patients with penile curvature secondary to Peyronie's disease. PATIENTS AND METHODS: Twenty-eight men with Peyronie curvature underwent plication of the penile fascia. Before operation, the deviation of the penis was so severe (median 60 degrees) in 24 men that they were unable to perform sexual intercourse. Follow-up was based on hospital records, one postal questionnaire sent to all patients and a clinical evaluation of the men in the out-patient clinic. RESULTS: After an uncomplicated operation and a median follow-up of 34 months, 20 of the 28 men were able to perform sexual intercourse and 23 were satisfied with the result of the operation. The most frequent reasons for dissatisfaction with the outcome of the operation were insufficient straightening, pain from sutures and uncharacteristic pain related to the penis and/or scrotum. CONCLUSION: The technique is simple to perform and the method gives functional and cosmetic results equal to those of more invasive procedures. The provision of adequate information to patients before the operation is important to ensure their satisfaction with the outcome. PMID- 8689122 TI - Ketanserin plus prostaglandin E1 (PGE-1) as intracavernosal therapy for patients with erectile dysfunction unresponsive to PGE-1 alone. AB - OBJECTIVE: To evaluate the treatment of patients with erectile dysfunction and who were unresponsive to intracavernosal injections of prostaglandin E-1 (PGE-1) alone with a combination of PGE-1 and ketanserin, a peripheral vasodilator antagonizing 5-hydroxytryptamine receptors and with mild alpha-blocking effects. PATIENTS AND METHODS: The study comprised 98 men with erectile dysfunction all of whom received an intracavernosal injection of 5-40 micrograms of PGE-1. The 45 patients unresponsive to the maximum dose of 40 micrograms were selected for further treatment using a combined dose of 40 micrograms PGE-1 and 2-7 mg of ketanserin. Their erectile response was assessed both subjectively, by interviewing the patient and their partner, and objectively using the 'Rigiscan' monitor. RESULTS: The combined therapy was effective in producing an erection sufficient for sexual intercourse in 34 (76%) of the patients. The combined dose was tolerated well and there were no adverse effects. CONCLUSIONS: The results of this preliminary study suggest that the combination of PGE-1 and ketanserin may be a therapeutic alternative to the implantation of a prosthesis in patients unresponsive to PGE-1. PMID- 8689124 TI - Management of female urethral diverticula by transurethral incision. PMID- 8689123 TI - Salvage procedures for failed Benchekroun hydraulic valves: experience in four patients. AB - OBJECTIVE: To describe the complications encountered with the Benchekroun hydraulic valve and the salvage procedures used to convert it into a successful continent diversion. PATIENTS AND METHODS: Seven patients with spina-bifida (two males and five females) presenting with neurogenic incontinence were treated originally with a combined urethral lengthening (Pippi-Salle procedure), detubularized ileocystoplasty and Benchekroun hydraulic valve. Four of these patients presented with immediate (three) or subsequent (one) complications related to the devagination or the overdistension of the hydraulic valve, and stomal problems. Two techniques were used to create a catheterizable conduit with the intestinal material of the Benchekroun hydraulic valve; one used the inner tube of the valve and the other one used the appendix. These techniques are described and illustrated. RESULTS: All four patients made a satisfactory recovery and had no difficulty in catheterizing their bladder through the revised continent diversion. However, the follow-up of these patients was short (1-8 months) and a long-term assessment is required to evaluate these salvage procedures. CONCLUSIONS: The Mitrofanoff procedure remains our first choice to create a continent diversion in children with neuropathic bladders. However, when the appendix is not available or unusable, alternative procedures such as the Benchekroun hydraulic valve might be used to create a continent catheterizable conduit. Nevertheless, complications or failure of the Benchekroun valve and its variants (e.g. Guzman's technique) are common and salvage procedures are often necessary to recreate an efficient continent conduit. PMID- 8689125 TI - The ileal neobladder: simple detubularization technique using automatic surgical staplers and absorbable staples. PMID- 8689126 TI - Urodynamic evaluation of an infant with complete bladder and colonic duplication, sacral dysgenesis, and an imperforate anus. PMID- 8689127 TI - Compartment syndrome: a very rare but potentially lethal complication of prolonged pelvic surgery. PMID- 8689128 TI - Risk of compartment syndrome and aortic thrombosis following prolonged surgery in the Lloyd-Davies position. PMID- 8689129 TI - Ruptured kidney--an unusual presentation of renal malakoplakia. PMID- 8689130 TI - Penile metastasis from renal cell carcinoma. PMID- 8689131 TI - Absent vas deferens and ipsilateral multicystic dysplastic kidney in a child. PMID- 8689132 TI - CA19-9-negative pancreatic cancer mimicking renal cancer. PMID- 8689133 TI - Extramammary Paget's disease requiring scrotectomy and scrotal reconstruction. PMID- 8689134 TI - Congenital vesicovaginal fistula. PMID- 8689135 TI - Penile ectopic testis. PMID- 8689136 TI - Doppler ultrasound in the management of acute testicular pain. PMID- 8689137 TI - Urinary tract obstruction and nephrostomy drainage in pelvic malignant disease. PMID- 8689138 TI - Transurethral microwave thermotherapy. PMID- 8689139 TI - Clinical outcome and quality of life following enterocystoplasty for idiopathic detrusor instability and neurogenic bladder dysfunction. PMID- 8689140 TI - Interconnectivity in endoscopy: the DICOM endoscopy supplement. PMID- 8689141 TI - Nonulcer dyspepsia. AB - There is considerable confusion in the literature about the entity of nonulcer dyspepsia and its epidemiology, mechanisms, and management. In this review, we discuss the mechanisms and develop a strategy for diagnosis and management of nonulcer dyspepsia in the era of cost-containment. This analysis was based on a computerized literature search on epidemiology, pathophysiology, and management of nonulcer dyspepsia. Inconsistencies in the inclusion criteria of several studies result in disparities in the data from epidemiological and physiology based studies. We propose that the inclusion criteria need to be unrestricted by the symptom of "pain," and that epidemiological features must be refined further because recent data used pain/discomfort as the dominant feature for identifying "dyspepsia." The interplay between three factors (impaired motor and sensory functions, psychosocial factors, and Helicobacter pylori infection) deserves further study. Advances in this field will follow rigorous reappraisal of the epidemiology using an unrestricted definition of the symptom complex and development of strategies in clinical practice that focus on either the cost effective investigation of the mechanism and its treatment or an effective sequence of therapeutic trials. An algorithm proposed for patient evaluation needs to be tested, with emphasis on outcome (i.e., symptom control, cost efficacy, and societal costs). PMID- 8689142 TI - Current management of gastroesophageal reflux disease. AB - Gastroesophageal reflux disease (GERD) is a chronic condition that is very common, and may result in considerable morbidity as well as mortality (from complications). I present data on the therapy of patients with GERD and offer a practical approach to their management. The goals of management of GERD are relief of symptoms, healing of esophagitis, prevention of complications, and maintenance of remission. Simple lifestyle changes may control GERD in up to 20% of patients. Promotility therapy addresses the pathophysiology of this disorder, but the best results are only 50 to 60% control using cisapride, whereas the older agents (metoclopramide and bethanechol) are limited by side effects. Acid suppression using histamine receptor antagonists controls GERD in 50 to 60% of patients, whereas proton pump inhibitors offer the most effective control (80 100%). A surgical approach (especially using newer laparoscopic techniques) will provide effective therapy of GERD in a high percentage of patients, but further careful comparisons are needed to define the long-term efficacy and cost issues associated with both surgical and chronic medical therapy of GERD. Despite this lack of long-term data, we know that GERD is a chronic, often lifelong illness, and maintenance therapy should be offered to most patients. This therapy may include aggressive medical therapy (up to and including chronic proton pump inhibitor therapy) or antireflux surgery in selected patients. PMID- 8689143 TI - Image management: the viewpoint of the clinician. PMID- 8689144 TI - Pancreatic pseudocyst. AB - Pseudocyst formation is a well-known complication of pancreatitis. Pseudocysts of the pancreas are localized collections of fluid occurring within the pancreatic mass or the peripancreatic spaces often following acute pancreatitis or in a patient with chronic pancreatitis without any previous history of an acute episode. The pathogenesis depends on the etiology: in acute pancreatitis, enzyme rich fluid and products of autodegradation accumulate; in chronic pancreatitis, the cyst results from an obstructed duct. The natural history of the diseases has become clearer with the advent of ultrasound and computed tomographic scanning. The incidence of pseudocysts is noted to be higher as a result of better diagnostic techniques. Pseudocysts must be suspected in patients who have persistent abdominal pain or consistently elevated levels of pancreatic enzymes. Nearly one third of pancreatic pseudocysts resolve spontaneously. Some, however, require intervention. Surgery was the only option available for many years. Recently, newer methods, such as percutaneous drainage and endoscopic cystenterostomy, have been used. Percutaneous drainage is inexpensive, has a low complication rate, and is done under local anesthesia. The recurrence rate is high with a one-time needle aspiration; this rate can be reduced to less than 10% by using an indwelling catheter. On the basis of a review of literature and our own experience, we believe that percutaneous continuous catheter drainage should be the first choice in the management of pseudocysts that require intervention. Experience with the endoscopic technique is increasing, and it may prove to be a viable alternative in skilled hands in the future. PMID- 8689145 TI - Sphincter of Oddi. AB - It has been more than 100 years since Rugero Oddi described the sphincter that bears his name. In that time, investigators have determined its precise anatomy and they have demonstrated its independence from the duodenal muscle wall. Modern manometric techniques have defined the motor activity of the sphincter and motility abnormalities in patients presenting with either recurrent biliary-type pain or idiopathic recurrent pancreatitis. The term Sphincter of Oddi dysfunction is used to describe motility disorders of the sphincter. Clinical studies have shown that in patients with manometrically determined stenosis, division of the sphincter is associated with cure of the symptoms in more than 70%. For patients with biliary-type pain, division of the bile duct sphincter is all that is required, whereas in patients with idiopathic recurrent pancreatitis, division of the septum between the bile duct and the pancreatic duct is mandatory. PMID- 8689146 TI - Primary gastrointestinal lymphomas. AB - Recent evidence suggests that a significant proportion of primary gastrointestinal lymphomas are driven by exogenous agents/antigens. In the stomach, Helicobacter pylori appears to be responsible for most cases of low grade lymphomas (MALToma), whereas an infectious etiology is suspected in immunoproliferative small intestine disease (IPSID). Similarly, enteropathy associated T-cell lymphomas appear to result from a disordered response to gluten, although this profile remains controversial. Accordingly, although traditional antineoplastic treatments, such as surgery and radiation, are still important for the treatment of primary GI lymphomas, antibiotics may be the first line of therapy for low-grade gastric MALToma, and they are often used alone or in combination with chemotherapy for IPSID. In patients with celiac sprue, a gluten-free diet appears to markedly reduce the risk for lymphoma. An important caveat for the treatment of gastric lymphomas is that only low-grade gastric MALTomas have consistently responded to antibiotics. Treatment of high-grade gastric lymphoma is evolving. Although surgery was once considered central to diagnosis, staging, and treatment of gastric lymphoma, most patients can now have a diagnosis established by endoscopic biopsy and are candidates for chemotherapy and adjuvant radiation. The risks of fatal hemorrhage and perforation have probably been vastly overestimated and appear to be equal or less than the mortality associated with surgery. In addition, the long-term effects of gastric resection on quality of life have been almost completely ignored. Systemic lymphomas involve the GI tract far more often than is clinically apparent. In most cases, treatment should not be affected. PMID- 8689147 TI - Variety and evolution of American endoscopic image management and recording systems. AB - The rapid evolution of computing technology has and will continue to alter the practice of gastroenterology and gastrointestinal endoscopy. Development of communication standards for text, images, and security systems will be necessary for medicine to take advantage of high-speed computing and communications. Professional societies can have an important role in guiding the development process. PMID- 8689148 TI - Liver disease in preeclampsia. PMID- 8689149 TI - Gallstone pancreatitis: an update. AB - Gallstone pancreatitis is one of the more prevalent causes of pancreatitis. It accounts for more than two thirds of the cases of acute pancreatitis worldwide and 25 to 45% of the cases in the United States. Furthermore, it is one of the most important treatable causes of pancreatitis. These two important features of the disease make its recognition and proper management critical. Key to recognition and proper management of gallstone pancreatitis is understanding that this disease can exist in three different forms. It can exist as impacted gallstone pancreatitis, as nonimpacted gallstone pancreatitis, or as sludge related pancreatitis. Each of these forms of the disease will have some unique features relating to their pathogenesis, diagnosis, and treatment. This update focuses on "take-home" features that will allow (1) clinical differentiation between the three forms of the disease and (2) understanding the unique features that relate to their pathogenesis, diagnosis, and management. PMID- 8689150 TI - The changing pattern of surgery. PMID- 8689151 TI - Renal transplantation from non-heart-beating donors. PMID- 8689152 TI - Local recurrence after breast-conserving surgery for breast cancer. AB - Local recurrence following breast-conserving surgery for breast cancer is a significant failure of local treatment. This article reviews the mechanisms, risk factors and overall significance of such local recurrence. The presence of disease at excision margins, an extensive intraduct component, lymphatic vessel invasion, tumour grade and tumour size are currently the best predictors of risk for local recurrence. Early local recurrence is due to residual disease and is associated with both decreased distant disease-free survival and overall survival; it appears to reflect aggressive biological characteristics of the primary tumour. The importance of adequate local treatment for breast cancer is discussed. PMID- 8689153 TI - Prognostic significance and surgical management of lymph node metastasis in gastric cancer. AB - Regional lymph node metastasis is a critical prognostic factor in gastric cancer, and extended lymph node dissection and routine microscopic examination of all resected nodes could potentially provide accurate information regarding lymph node status. On the other hand, the therapeutic value of extended lymph node dissection is controversial. While retrospective and prospective nonrandomized comparative studies have shown that extended lymph node dissection significantly improves the survival rate, two prospective randomized trials have failed to demonstrate the efficacy of extended dissection, although the number of patients in these studies was limited. There is a further, ongoing, trial involving a larger series of patients; the final results of this study should help to determine whether extended lymph node dissection is of therapeutic or merely prognostic value in gastric cancer. PMID- 8689154 TI - Renal ischaemia--reperfusion injury. AB - Ischaemia-reperfusion injury is a complex interrelated sequence of events that classically involves the vascular endothelium and activated leucocytes. During the ischaemic phase the endothelium is primed both to produce free radicals and to secrete chemoattractants. The resultant neutrophil sequestration serves to amplify the injury, but damage is not confined to the postischaemic area and more generalized effects typically follow. The situation in the kidney is complex for, while ischaemia primes the tissue for reperfusion damage, it also causes early and irreversible tubular injury. Furthermore, it appears that relatively less importance should be attached to the involvement of neutrophils than at other sites, and relatively more to a local postischaemic imbalance in the levels of nitric oxide and endothelin. Despite a greater understanding of the pathogenesis of ischaemia-reperfusion injury, effective treatment remains elusive and research is hampered by apparent species and organ-specific differences. PMID- 8689156 TI - Completion pancreatectomy for surgical complications after pancreaticoduodenectomy. AB - Significant complications continue to occur in a minority of patients undergoing pancreaticoduodenectomy; these frequently have fatal consequences. Analysis of 458 patients undergoing the Whipple procedure in this institution from 1972 to 1994 revealed that 16 patients with malignant periampullary tumours (ampullary, eight; pancreatic, seven; bile duct, one), and one patient with chronic pancreatitis subsequently required completion pancreatectomy. Postoperative difficulties after pancreaticoduodenectomy and indications for re-exploration were multifactorial: leakage (n = 8), pancreatitis (n = 7), bleeding (n = 1), and a delayed report of cancer at the margin of the pancreatic transection (n = 1). Completion pancreatectomy was often difficult (mean operating time 2.7 h, mean estimated blood loss 1897 ml). There was considerable significant postoperative morbidity (41 per cent) and mortality (24 per cent) after completion pancreatectomy. Patients who survived completion pancreatectomy lived a mean of nearly 4 years (range 4 months to 9.7 years, median 2.6 years). Tumour recurrence led to death in ten of 13 patients. Three patients remain alive and free of recurrence each more than 8 years after resection. Re-exploration and subsequent completion pancreatectomy after pancreaticoduodenectomy is rarely necessary, but if clinical manifestations occur secondary to failure of the pancreaticojejunostomy, early surgical intervention may maximize survival. PMID- 8689155 TI - Value of routine intraoperative cholangiography in detecting aberrant bile ducts and bile duct injuries during laparoscopic cholecystectomy. AB - A prospective study was performed to determine the frequency and type of bile duct abnormalities, and to determine whether routine use of intraoperative cholangiography during laparoscopic cholecystectomy might aid in the prevention of bile duct injuries. Overall, anatomical aberrations of the bile ducts were found in 98 (19 per cent) of 513 cholangiograms. The most common anomalies were at the hepatic confluence and constituted different types of right hepatic subsegmental ducts draining separately into the biliary tree (n = 43, 8.4 per cent), either close to the cystic duct or directly into the cystic duct. Three bile duct injuries (0.5 per cent) occurred during the study period. These results show that routine intraoperative cholangiography is feasible and provides valuable information about the anatomy of the biliary tract, thereby improving the safety of laparoscopic cholecystectomy. If an injury to the biliary tract occurs early during operation, the cholangiogram allows the surgeon to detect the injury, to make a prompt repair and thereby reduce the morbidity associated with a delayed diagnosis. Routine use of intraoperative cholangiography is strongly recommended. PMID- 8689157 TI - Percutaneous removal of a 'bullet' from the liver. PMID- 8689158 TI - Endoscopic drainage aborts endotoxaemia in acute cholangitis. AB - Forty patients with acute calculous cholangitis had successful endoscopic drainage. Bile from nasobiliary drains and venous blood was collected at 0, 12, 24, 36 and 48 h after endoscopy. Endotoxin levels were measured by the chromogenic Limulus Amoebocyte Lysate assay. There was a significant reduction in both bile and serum endotoxin levels after endoscopic drainage (P < 0.001). Endotoxaemia occurred when bile endotoxin reached 10(3) EU/ml and rose exponentially beyond this threshold. Significant association was demonstrated between both bile and serum endotoxins to the clinical features of cholangitis (P < 0.05). No correlation was evident between serum endotoxin and the parameters of white cell count, serum bilirubin and alkaline phosphatase (r = 0.53, 0.00 and 0.00 respectively). Endoscopic drainage is effective in lowering bile and serum endotoxin levels and clinical signs and symptoms reliably predict endotoxaemia. PMID- 8689159 TI - Management of hepatic duct injury during hemihepatic vascular occlusion. PMID- 8689160 TI - Choledochal cysts--differences in children and adults. AB - Choledochal cysts in children and adults may behave differently. To identify these differences the records of 49 patients (22 children and 27 adults) who underwent surgery for choledochal cysts over a period of 7 years were analysed retrospectively. In two adult patients who had undergone a previous cholecystectomy an acquired malformation could not be excluded. Cholangitis was more common in adults. Choledochal cysts in children were predominantly Type I cystic lesions, whereas Type IV cysts were more common in adult patients. Anomalies of the pancreatic duct and associated hepatobiliary problems were seen exclusively in adults and the latter can make excision of the cyst more difficult and complicated. To prevent the development of complications choledochal cysts should be excised as soon as they are detected. PMID- 8689161 TI - Bradykinin antagonists HOE-140 and CP-0597 diminish microcirculatory injury after ischaemia-reperfusion of the pancreas in rats. AB - Ischaemia-reperfusion of the pancreas was performed in 35 anaesthetized Sprague Dawley rats. The effects of two bradykinin antagonists, HOE-140 (13 micrograms kg 1 intravenous bolus injection, n = 7) and CP-0597 (18 micrograms kg-1 h-1 intravenous infusion, n = 7) on pancreatic microvascular perfusion and leucocyte endothelium interaction were quantitatively analysed by intravital fluorescence microscopy. Three further groups underwent sham operation (n = 7), ischaemia of 2 h without treatment (n = 7), and ischaemia of 2 h with infusion of phosphate buffer (n = 7). Functional capillary density was significantly greater in animals treated with HOE-140 or CP-0597 than in sham-treated animals, and was decreased to only 60 per cent. Adherence of leucocytes to the endothelium of postcapillary venules was significantly reduced when compared with ischaemia without antagonist. These results demonstrate a positive effect of the two bradykinin antagonists HOE-140 and CP-0597 on microvascular perfusion failure after ischaemia-reperfusion of the pancreas. PMID- 8689162 TI - Anabolic and cardiovascular effects of recombinant human growth hormone in surgical patients with sepsis. AB - The clinical and metabolic effects of 7 days of recombinant human growth hormone (rhGH) and total parenteral nutrition (TPN) in surgical patients with sepsis were determined in a randomized controlled trial. In patients with a mean(s.e.m.) pretreatment rate of net protein catabolism (NPC) of 1.5 g per kg per day or less rhGH treatment decreased NPC from 0.93(0.14) to -0.20(0.24) g per kg per day (n = 5; P < 0.0005) and rendered these patients anabolic. TPN alone decreased NPC from 1.12(0.11) to 0.61(0.11) g per kg per day (n = 5; P < 0.001). In patients with an initial NPC of more than 1.5 g per kg per day rhGH treatment decreased NPC from 2.72(0.12) to 1.08(0.24) g per kg per day (n = 5; P < 0.001) while TPN alone decreased it from 2.41(0.32) to 1.28(0.28) g per kg per day (n = 5; P < 0.005). Use of rhGH was not associated with any adverse effects or improvement in clinical course but did decrease the mean systolic and diastolic pressures during the study period. Thus rhGH is a useful anabolic agent and may have a role in the haemodynamic management of the catabolic patient with sepsis. PMID- 8689163 TI - Long-term results of giant prosthetic reinforcement of the visceral sac for complex recurrent inguinal hernia. AB - The results of recurrent inguinal hernia repair in a prospective cohort study were evaluated. From May 1986 to December 1990 75 patients with 150 hernias (24 primary, 126 recurrent) were operated using a technique based on Stoppa's preperitoneal mesh repair (giant prosthetic reinforcement of the visceral sac; GPRVS). All patients were at high risk for recurrence: they all had bilateral hernias, mostly bilateral recurrent and often repeatedly recurrent. All patients had a physical examination 1 week, 6 weeks and 1 year after operation. Sixty patients (94 per cent of surviving patients) had a physical examination after a mean follow-up of 5.7 (range 4-9) years. There were no major complications. There was one deep infection that healed without removing the mesh. One of the 75 patients (1 per cent) had a recurrence 2 months after the operation, due to a technical failure. Because of the excellent results, the ease of the procedure and the low complication rate, GPRVS is the authors' operation of choice for any recurrent inguinal hernia. PMID- 8689164 TI - Transanal endoscopic microsurgery--initial experience from three centres in the United Kingdom. AB - Over a 28-month period, 100 transanal endoscopic microsurgical excisions of rectal tumours were carried out in three centres. The histological diagnosis was benign adenoma in 77 and invasive adenocarcinoma in 23. Complete excision of the tumour with histological confirmation was achieved in 70 (91 per cent) of the adenomas and in all but one of the carcinomas. Of the carcinomas, 18 were recognized before operation and the remaining five were diagnosed on postoperative histology. Of the patients with carcinoma, one had immediate further surgery, nine had radiotherapy and 13 had no extra treatment. To date, four patients have had a recurrence of villous adenoma, and two of the patients treated for invasive carcinoma have had local recurrence. These initial results of transanal endoscopic microsurgery in the UK compare well with those of earlier reports, indicating that the technique has a useful place in the management of sessile adenomas of the mid and upper third of the rectum, and of some carefully selected carcinomas. PMID- 8689165 TI - Prospective study of the proctographic and functional consequences of transanal endoscopic microsurgery. AB - A prospective study of clinical, manometric and proctographic results in 36 patients presenting for transanal endoscopic microsurgery was performed. Anorectal manometry showed no difference in maximal squeeze pressure before and 12 months after operation, but resting pressures were lower after surgery (mean(s.e.m.) preoperative 86.1(27.6) mmHg versus postoperative 67.2(23.2) mmHg, P < 0.05). The rectoanal inhibitory reflex was lost in a significant group of patients (reflex present in 34 of 36 patients before operation and in 27 of 36 12 months after operation, P < 0.05). Proctography, manometry and questionnaire showed preserved function of most modalities 12 months after operation such that if objective function was impaired clinical function was adequate. PMID- 8689166 TI - Mesorectal excision for rectal cancer. AB - A series of 103 consecutive rectal cancers was prospectively documented. Laparotomy was performed in 78 patients of whom five did not undergo resection. Resection was considered curative unless there were liver metastases or biopsy proven residual disease. Nine patients had a palliative resection. Thus 64 patients underwent a curative resection, 52 (81 per cent) of whom had an anterior resection of which 26 (46 per cent) were performed by trainees. There were three deaths after operation. Eight (14 per cent) patients developed a clinical anastomotic leak. Thirty patients were available for a minimum follow-up of 24 (mean 33, range 24-49) months. Four (13 per cent) patients developed distant recurrence. There were no isolated pelvic or anastomotic recurrences. One patient with distal recurrence may have had pelvic disease. The cumulative recurrence free survival rate at 24 months was 84 per cent. These results support the suggestion that mesorectal excision may reduce local recurrence. PMID- 8689167 TI - 'Residual' appendicitis following incomplete laparoscopic appendicectomy. PMID- 8689168 TI - Incidence of third-degree perineal tears in labour and outcome after primary repair. AB - The incidence and outcome of third-degree tears following 16,583 vaginal deliveries were prospectively assessed over a 5.5-year period. Ninety-three deliveries (0.56 per cent) were complicated by a third-degree tear and the patients underwent primary repair. Eighty-one patients were reviewed 3 months postpartum at a colorectal clinic. Third-degree tears were significantly more common in primigravidae and mothers with higher birth-weight babies. They were significantly associated with the use of forceps and were not prevented by episiotomy. Of the 81 patients reviewed, 30 had an abnormal anorectal examination. Six patients (7 per cent) were incontinent of faeces. A further ten (12 per cent) were incontinent of flatus only. The overall incidence of faecal incontinence was 0.04 per cent. An important group of women with significant subclinical sphincter injury was identified. Obstetric trauma causes significant anorectal dysfunction and patients with third-degree tears require assessment by a colorectal specialist. PMID- 8689169 TI - Balloon tamponade for control of massive presacral haemorrhage. PMID- 8689170 TI - The retrocaecal appendix appears to be less prone to infection. PMID- 8689171 TI - Overexpression of p53 in duodenal tumours in patients with familial adenomatous polyposis. AB - Duodenal polyps and tumours of different histology from patients with familial adenomatous polyposis (FAP) were examined for p53 overexpression to determine the genetic events in duodenal tumorigenesis. Samples from endoscopic biopsy specimens of 152 duodenal adenomatous polyps (taken from 79 patients) and from 13 surgically resected adenomatous polyps or cancers (taken from nine patients) were studied by routine histological examination and immunohistochemistry. p53 was overexpressed in: 0 per cent of normal mucosa samples (none of 29), 25 per cent of tubular adenomas (28 of 111), 72 per cent of tubulovillous and villous adenomas (13 of 18) and 100 per cent of duodenal cancers (seven of seven); and in 28 per cent of mildly dysplastic polyps (32 of 113), 56 per cent of moderately or severely dysplastic polyps (nine of 16) and 100 per cent of cancers (seven of seven). Overexpression of p53 increased with passage down the adenoma-carcinoma pathway and might therefore be a valuable additional marker of risk for duodenal malignancy in patients with FAP. PMID- 8689172 TI - Sisters with familial adenomatous polyposis affected with thyroid carcinoma, desmoid tumour and duodenal polyposis. PMID- 8689173 TI - Vitamin D3 analogue (EB 1089) inhibits in vitro cellular proliferation of human colon cancer cells. PMID- 8689174 TI - Non-invasive assessment of arterial disease: a comparison of Quickscan with intra arterial digital subtraction angiography. AB - The ability of Quickscan to identify haemodynamically significant lesions in the arteries of the lower limb was studied. Quickscan was prospectively compared with intra-arterial digital subtraction angiography (IADSA) of the iliac, femoral and popliteal arteries. In 155 patients, 631 arterial segments were evaluated. A Quickscan frequency ratio of 1:3 or greater had a sensitivity of 93 per cent and a specificity of 85 per cent in detecting a stenosis of more than 50 per cent diameter reduction (67 per cent area reduction) in the iliac artery, as shown on IADSA. The sensitivity and specificity in the femoral artery were 85 and 96 per cent respectively, and in the popliteal artery 82 and 98 per cent respectively. In the detection of occlusion, Quickscan had a sensitivity and specificity of 84 and 98 per cent respectively in the iliac artery, 94 and 97 per cent respectively in the femoral artery, and 94 and 85 per cent respectively in the popliteal artery. Quickscan is an inexpensive, quick and non-invasive method of screening for peripheral vascular disease in the lower limb. PMID- 8689175 TI - Mid-aortic syndrome presenting in childhood. AB - Mid-aortic syndrome (MAS) is an uncommon condition characterized by segmental narrowing of the proximal abdominal aorta and ostial stenosis of its major branches. It is usually diagnosed in young adults, but may present in childhood as a challenging problem. Over the past 20 years 13 patients with MAS have presented to this institution. All had hypertension, four had associated neurofibromatosis, three persistent eosinophilia and three had Williams syndrome. In all cases arteriography showed a smooth segmental narrowing of the abdominal aorta with concomitant stenosis at the origins of the renal arteries. Six children were successfully treated with antihypertensive medication alone. Percutaneous transluminal angioplasty was attempted in two cases with poor result. Surgery was indicated in seven children with refractory hypertension and progressive renal impairment. Techniques used to revascularize the kidneys included thoracoabdominal to infrarenal aortic bypass with renal artery reimplantation, splenorenal bypass, gastroduodenal to renal bypass, aortorenal bypass and autotransplantation. PMID- 8689176 TI - Amputation rates as a measure of vascular surgical results. AB - Reconstructive surgery for critical leg ischaemia (CLI) increased in both hospital- and population-based patient samples over 12 years. In the referral centre amputation numbers were unchanged over this period, although amputation carried out for patients with CLI decreased from 58 to 35 per cent. In the population sample amputation numbers decreased by 25 per cent and amputations of patients with CLI decreased from 79 to 43 per cent. Patient characteristics and amputation patterns were different in the two settings. Amputation rates as a measure of the efficacy of an arterial reconstruction policy should be used only on a population basis. The analysis is skewed by selection bias in referral centres. PMID- 8689177 TI - Intra-arterial lignocaine in embolectomy. PMID- 8689179 TI - Relation between aetiology and treatment of leg ulcers. PMID- 8689178 TI - Magnetic resonance imaging in the management of diabetic foot infection. AB - A prospective study was carried out of 22 patients admitted with 25 diabetic foot infections. All had cellulitis, 12 had discharging ulcers and eight had digital gangrene. In one case magnetic resonance imaging (MRI) was unhelpful owing to patient movement. Thirteen scans suggested deep-seated infection, including abscess (ten), osteomyelitis (seven) and ankle effusion (one). Overall, imaging provided a specificity of 77 per cent, a positive predictive value of 77 per cent, a sensitivity of 91 per cent and a negative predictive value of 91 per cent. MRI is valuable in determining the presence and extent of infection, which allows appropriate planning of surgical intervention. PMID- 8689180 TI - Role of neutrophil-endothelial adhesion in skeletal muscle reperfusion injury. AB - During postischaemic revascularization neutrophil-endothelial adhesion in the skeletal muscle microcirculation, promoted by the neutrophil adhesion molecule Mac-1, may impair muscle blood flow and release oxygen free radicals and proteolytic enzymes which causes further tissue injury. This study has assessed the effect of an anti-Mac-1 monoclonal antibody on the severity of skeletal muscle injury in a rat model of 6-h hindlimb ischaemia and 4-h reperfusion. In control animals a sustained impairment of muscle perfusion was associated with neutrophil sequestration, muscle infarction and muscle oedema (P < 0.001 versus normal rats). In contrast, intravenous administration of anti-Mac-1 monoclonal antibody before revascularization prevented neutrophil recruitment, reduced muscle necrosis and improved postischaemic muscle perfusion at 120 and 240 min (not significantly different from normal), thus confirming that neutrophils are important cellular mediators of skeletal muscle reperfusion injury. Monoclonal antibodies targeting neutrophil adhesion molecules may, therefore, have a role in the prevention of this complication of limb revascularization. PMID- 8689181 TI - The prevalence of chronic lower-limb ulceration has been underestimated: results of a validated population questionnaire. AB - A validated population questionnaire was used to survey 12,000 randomly selected inhabitants, aged 50-89 years, in two defined regions of Sweden. The sample included 7 per cent of the total population in the age interval. Overall response rate was 91 per cent. Open ulcers were reported by 306 subjects and 143 (47 per cent) agreed to be examined. The false-positive response rate was high (43 per cent). The observed point prevalence of open leg ulcers was 0.63 (95 per cent confidence interval 0.54-0.72) per cent of the total population. The overall prevalence of leg ulcer history (open plus healed) in the population was estimated to be around 2 per cent and the ratio of open: previous ulcers was 1:2. This study shows a point prevalence more than double that expected, indicating a high rate of self treatment. Assessments of leg ulcer prevalence through the health care system, without knowledge of the rate of self care, measure only the workload of health care professionals. The problem of leg ulcers has generally been underestimated. PMID- 8689182 TI - Time-dependent histamine release from stored human blood products. AB - Perioperative transfusion of whole blood has been shown to amplify trauma-induced immunosuppression, which could be attenuated by perioperative administration of histamine2 receptor antagonists. Supernatants from different blood products were, therefore, analysed for histamine content during storage. Whole blood (six units), plasma-reduced whole blood (six units), and plasma- and buffy coat reduced (saline-adenine-glucose-mannitol) (SAGM) blood (six units) from unpaid healthy donors were stored in the blood bank for 35 days at 4 degrees C. Plasma histamine and total cell-bound histamine content at donation, and histamine concentration in samples drawn from the units on days 0, 2, 5, 9, 14, 21, 28 and 35 were analysed with an enzyme-linked immunosorbent assay. Median plasma histamine concentration was 4.8 (range 1.9-14.3) nmol/l (n = 18). Median total cell-bound histamine content was 417.0 (range 176.0-910.0) nmol/l in whole blood and 475.0 (range 360.0-1560.0) nmol/l in plasma-reduced whole blood, while it was undetectable in SAGM blood. Spontaneous histamine release increased in a time dependent manner from a median of 6.7 (range 2.2-17.4) nmol/l at the time of storage to 175.0 (range 33.0-485.0) nmol/l at day 35 in whole blood, from 18.8 (range 8.2-38.5) to 328.5 (range 224.0-1137.0) nmol/l in plasma-reduced whole blood, and from 0.5 (range 0.5-1.5) to 2.2 (range 1.4-6.9) nmol/l in SAGM blood. These results show spontaneous histamine release during storage of human blood products which contain full amount of leucocytes, and this may play a significant role in detrimental effects of blood transfusion. PMID- 8689183 TI - Adrenal ganglioneuroma. PMID- 8689184 TI - Assessment of the acceptability of conservative management of fibroadenoma of the breast. AB - A prospective study was performed in 202 patients with 219 fibroadenomas, diagnosed by a combination of clinical examination, ultrasonography and fine needle aspiration cytology. Patients were given the choice of excision or conservative management with regular monitoring by ultrasonography. Sixteen patients with 18 fibroadenomas opted for excision and all 18 lesions were histologically confirmed as fibroadenomas. A further 152 patients with 163 fibroadenomas were observed for a minimum period of 2 years; 13 fibroadenomas increased significantly in size (all 13 were excised and confirmed histologically as fibroadenomas), 19 decreased significantly in size, 42 resolved and the remaining 89 showed no change in size. Conservative management of fibroadenomas in patients under the age of 40 is safe and acceptable to the majority of women. PMID- 8689185 TI - Postoperative evaluation of pylorus-preserving gastrectomy for early gastric cancer. AB - Physical results after pylorus-preserving gastrectomy (PPG) with preservation of the vagus nerve were evaluated. The status of 15 patients with early gastric cancer after PPG was compared with that of 14 patients after distal gastrectomy (DG). The postoperative/preoperative body-weight ratio of the PPG group (0.99) was significantly greater than that of the DG group (0.92). Patients who had PPG had fewer postoperative abdominal symptoms than those who underwent DG. The gastric emptying pattern of patients who had a pylorus-preserving procedure was slower than that of those who had conventional gastrectomy, and more similar to the preoperative pattern. Contraction of the gallbladder after PPG was better than after DG. Gastroscopy revealed that the mucosa of the stomach remnant after PPG was less abnormal than after DG. In conclusion, PPG is a more physiological operation than conventional DG and should be applied in carefully selected cases of early gastric cancer. PMID- 8689186 TI - Conversion operation for alkaline reflux after total gastrectomy and Schloffer reconstruction. PMID- 8689187 TI - Intraoperative fine-needle aspiration cytology of abdominal lesions--a safe alternative to surgical biopsy. PMID- 8689188 TI - Conservative treatment versus antireflux surgery in Barrett's oesophagus: long term results of a prospective study. AB - The results obtained for the treatment of 59 patients diagnosed with Barrett's oesophagus, randomized to receive medical treatment (n = 27) or antireflux surgery (n = 32) were assessed prospectively. Median follow-up for the patients undergoing medical treatment was 4 (range 1-11) years and for patients undergoing surgical treatment 5 (range 1-11) years. Satisfactory symptomatic control (excellent to good results) was achieved in 24 patients after medical therapy and in 29 after antireflux surgery. The proportion of patients with persistent inflammatory lesions (54 per cent) and persistent or recurrent stenosis (47 per cent) was significantly higher after conservative treatment than after surgery (5 and 15 per cent, respectively). A decrease in the length of the segment of columnar mucosa was observed in eight of the patients who underwent antireflux surgery, and in only two of those given medical therapy. Conversely, an upward progression of the columnar lining was more frequent in the latter group (11 versus three). Mild dysplasia was observed in five patients, all from the group undergoing medical treatment. Severe dysplasia was detected in two patients, one undergoing medical treatment and the other following surgical therapy, in whom an antireflux procedure had failed previously. Both patients underwent oesophageal resection, with confirmation of a carcinoma in situ. The patients in whom antireflux surgery proved effective showed no dysplastic change or progression to adenocarcinoma. These results, despite the small number of patients and methodological limitations, question the systematic conservative approach in the initial management of patients with Barrett's oesophagus. PMID- 8689189 TI - Healing process of sutureless choledochojejunostomy in an experimental model. PMID- 8689190 TI - Randomized trial of laparoscopic cholecystectomy and mini- cholecystectomy. PMID- 8689191 TI - Randomized trial of laparoscopic cholecystectomy and mini-cholecystectomy. PMID- 8689192 TI - Postocclusive hyperaemic duplex scan: a new method of aortoiliac assessment. PMID- 8689193 TI - Two-layer closure of typhoid ileal perforations: a prospective study of 46 cases. PMID- 8689195 TI - Trauma and bacterial translocation. PMID- 8689194 TI - Trauma and bacterial translocation. PMID- 8689196 TI - Management of soft tissue sarcoma. PMID- 8689197 TI - Thrombolysis for acute deep vein thrombosis. PMID- 8689198 TI - Ultrasonographic carotid plaque morphology in predicting stroke risk. AB - A number of new studies have provided evidence which suggests that carotid plaque surface characteristics and internal structure, as seen on ultrasonography, contribute to the development of cerebrovascular endpoints. This review is a critical presentation of the evidence that has emerged so far supporting the hypothesis that the ultrasonographic morphology of the carotid plaque may be an independent variable in predicting the risk of stroke. It is concluded that ultrasonographic plaque morphology should be used together with other local risk factors in prospective natural history studies which aim to identify a subgroup of patients at high risk of stroke. PMID- 8689199 TI - Adhesion molecules as determinants of disease: from molecular biology to surgical research. AB - Cellular adhesion is mediated by distinct cell surface receptors (adhesion molecules) and plays a pivotal role in the biological processes of morphogenesis, cell migration and cell-cell communication. During the past decade many adhesion molecules have been identified and structurally analysed. This has allowed an understanding of their role in the pathophysiology of disease, including inflammation and sepsis, ischaemia and reperfusion, transplant rejection, atherosclerosis and thrombosis, angiogenesis and wound healing, as well as carcinogenesis and tumour metastasis. Understanding of the molecular mechanisms of cellular communication is not only vital for advances in surgical pathophysiology, it also has the potential to widen the spectrum of diagnosis and therapy of disease. Analysis of expression of individual surface molecules may help in the diagnosis of transplant rejection and allow a prognostic determination of tumour progression and metastasis formation. Moreover, manipulation of adhesion molecule function by monoclonal antibodies, antisense oligonucleotides or single gene products may open the door for novel therapeutic regimens to prevent transplant rejection and ischaemia-, sepsis- and shock induced tissue injury. PMID- 8689200 TI - Spontaneous rupture of hepatocellular carcinoma. AB - Spontaneous rupture of hepatocellular carcinoma (HCC) is a life-threatening condition; the mechanism is not clear but it is suggested that rupture is usually preceded by rapid expansion of the tumour secondary to bleeding from within its substance. Diagnosis may be made by abdominal paracentesis, ultrasonography, computed tomography or angiography; the positive rates of diagnosis are 86, 66, 100 and 20 per cent respectively. Prognosis is poor. Based on treatment results reported in the literature, the mean survival time for patients who underwent hepatectomy, transcatheter arterial embolization (TAE) and conservative therapy were 247, 98 and 13 days respectively. Judging from the reported results the first choice for emergency treatment of haemostasis is TAE. If laparotomy is undertaken, hepatic artery ligation, preferably of the branch supplying the liver lobe bearing the tumour, should be considered, together with haemostasis of the rupture site by various means (suture plication, packing, argon beam coagulation, use of microwave or absolute ethanol). Emergency hepatectomy should be reserved for patients with an easily resectable lesion who are in a stable cardiovascular condition. Conservative therapy may be used for selected patients in extremely poor condition. The rational treatment for the majority of patients with ruptured HCC is TAE, followed by hepatectomy if the lesion is resectable. PMID- 8689201 TI - Nutritional pharmacology and malignant disease: a therapeutic modality in patients with cancer. AB - It is now established that certain nutrients have a significant effect on cellular metabolism and growth, tissue repair and regeneration, and modulation of host defences. So far, however, potential clinical benefits have been difficult to demonstrate. Nevertheless, the use of nutrients in combinations seems to have promise and may be associated with a reduction in infectious complications and length of hospital stay. Nutritional pharmacology in the future may be able to improve tumour response to chemotherapy and may minimize the metabolic effect of cachexia. PMID- 8689202 TI - Assessment of splanchnic tissue oxygenation by gastric tonometry in patients undergoing laparoscopic and open cholecystectomy. AB - This experimental study compared the effects of laparoscopic (n = 31) and open (n = 32) cholecystectomy on gastric intramucosal pH (pHi). For this purpose, pHi was measured tonometrically before induction of anaesthesia, at 30-min intervals during surgery, and 1, 2 and 4 h after operation in otherwise healthy patients undergoing elective cholecystectomy. Additionally, perioperative arterial pH (pHa), arterial carbon dioxide tension (PaCO2), intramucosal carbon dioxide tension, arterial bicarbonate concentration, end-tidal carbon dioxide pressure (PECO2), levels of serum lactate, lactate dehydrogenase (LDH) and gamma-glutamyl transferase (GGT), haematocrit and arterial blood pressure were recorded. In the two groups no significantly different changes occurred in pHi, pHa, serum lactate concentration or haematocrit at any of the observation times. PECO2 and PaCO2 were significantly raised during the laparoscopic procedure, whereas levels of LDH and GGT and arterial blood pressure rose during and after open cholecystectomy. In spite of the increased intra-abdominal pressure and the peritoneal carbon dioxide absorption related to the creation of a pneumoperitoneum, no decrease in pHi was detectable during laparoscopic cholecystectomy. PMID- 8689203 TI - Survival after resection for ductal adenocarcinoma of the pancreas. AB - A retrospective study was performed of 113 patients who underwent surgical resection of carcinoma of the pancreas from 1970 to 1992. The postoperative mortality rate was 15 per cent (5 per cent in the last 11 years). The actuarial 5 year survival rate was 12 per cent. Survival was significantly influenced by age (P = 0.03), vascular resection (P = 0.02), radicality of operation (P = 0.01), number of transfused blood units (P = 0.01), tumour differentiation (P = 0.002), lymph node status (P = 0.001), perineural invasion (P = 0.01), tumour size (P = 0.008), preoperative diabetes (P = 0.001) and stage (P = 0.0001). Multivariate analysis showed that stage, diabetes, age and grade were independent predictors of long-term survival. The type of pancreatic resection (Whipple, subtotal, total or distal pancreatectomy) did not influence prognosis. The 5-year survival rate was 14 per cent in the period 1970-1981 and 11 per cent in the period 1982-1992, with no statistical difference. These results suggest that patient characteristics and tumour findings rather than operative procedures affect long term survival after resection for pancreatic carcinoma. PMID- 8689204 TI - Spontaneous splenic rupture: a rare complication of acute pancreatitis. PMID- 8689205 TI - Immune function early in acute pancreatitis. AB - Circulating lymphocyte numbers and activation together with granulocyte function were measured in 20 patients in the early stages of an attack of acute pancreatitis and in 20 healthy controls. Circulating lymphocytes, T lymphocytes, and CD4 and CD8 T lymphocyte subsets were decreased in both mild pancreatitis (67 80 per cent of controls) and severe pancreatitis (22-40 per cent of controls). CD4:CD8 ratios were unchanged and median (interquartile range) interleukin 2 receptor expression was increased from less than 1 per cent in controls to 14(6) per cent in severe pancreatitis, suggesting lymphocyte activation. Median granulocyte chemiluminescence was increased to 293 per cent of controls in severe pancreatitis and random motility was reduced to 77 per cent of controls, indicating increased metabolic activity. Complement-mediated antibody-independent opsonization and chemotaxis toward endotoxin were normal. Immune function is not reduced early in acute pancreatitis. Granulocyte hyperactivity may be important in the development of multiple organ failure. PMID- 8689206 TI - Donor arterial variations in liver transplantation: management and outcome of 527 consecutive grafts. AB - The impact of donor arterial variations and their management was investigated retrospectively in 527 consecutive allografts. Anomalous arteries were found in 161 grafts (30.6 per cent). There was no significant difference in the overall incidence of arterial complications between grafts with normal (3.6 per cent) and abnormal (5.6 per cent) anatomy. However, there was a higher incidence of arterial complications in transplants requiring multiple arterial anastomoses (P = 0.02), or anastomosis of donor vessels to recipient aorta with (P = 0.0003) or without (P = 0.04) an interposition graft for arterial reconstruction. The incidence of biliary complications was similar in grafts with a normal (18.8 per cent) or anomalous (18.0 per cent) arterial supply. Anomalies of hepatic arterial anatomy occur in one-third of all livers and do not compromise graft outcome unless multiple anastomoses or direct anastomosis to the recipient aorta are required for arterial reconstruction. PMID- 8689207 TI - Antegrade colonic enemas. AB - Thirteen children aged 6-14 (mean 8) years in whom an antegrade colonic enema procedure was performed were reviewed retrospectively. All presented with refractory constipation or faecal soiling over a 3-year period. Nine of the children had previously undergone pull-through procedures for Hirschsprung's disease or high anorectal malformations. Two were suffering from spina bifida and two from idiopathic functional constipation. The operation was performed through a right iliac fossa incision. A catheterizable conduit was created. The appendix was brought out to the wound edge and made continent by intussuscepting the appendix base into the caecum. When the appendix was absent or unusable, a caecal tube was formed. Five patients suffered minor morbidity, six required a further operative procedure and two eventually required a sigmoid colostomy. However, the eventual outcome of a continent stoma was attained in 11 of the 13 children, all of whom would have been considered for sigmoid colostomy before introduction of the antegrade colonic enema procedure. PMID- 8689208 TI - Acute right iliac fossa pain in acquired immunodeficiency: a comparison between patients with and without acquired immune deficiency syndrome. AB - A retrospective review was performed of the clinical features present in 17 patients who were human immunodeficiency virus (HIV) positive requiring a diagnostic or therapeutic procedure for suspected appendicitis. Patients who were acquired immune deficiency syndrome (AIDS) free (n = 11) and those with AIDS (n = 6) were compared. Ten of the 11 patients who were AIDS-free had appendicitis. The morbidity rate was 9 per cent, similar to that expected in seronegative patients, but the appendix perforation rate was 50 per cent. Only two of the six patients with AIDS had appendicitis. Three suffered from an HIV-related disease process. Computed tomography (CT) was performed in four of the six patients with AIDS, and was considered of diagnostic help in three. In patients with AIDS, the morbidity rate rose to 50 per cent. Surgical decision-making with regard to HIV-positive patients who were AIDS-free with suspected appendicitis should be similar to that for seronegative patients. For patients with AIDS, alternative diagnostic strategies, including preoperative CT, or possibly laparoscopy, should be considered. PMID- 8689209 TI - Two cases of solitary metastases from carcinoma of the lung presenting as primary colonic tumours. PMID- 8689210 TI - Role of segmental colonic transit time studies to select patients with slow transit constipation for partial left-sided or subtotal colectomy. AB - This prospective study investigated the value of segmental colonic transit time studies in the surgical treatment of slow transit constipation. Overall, 346 patients with chronic constipation were analysed; slow transit constipation was diagnosed in 86 (25 per cent). Based on the results of segmental colonic transit time studies, 18 patients underwent partial left-sided colectomy and 24 subtotal colectomy. Recurrent constipation was seen in three of 18 patients and seven of 24 respectively. Severe abdominal discomfort was noted in six of 18 and 15 of 24 respectively. Disabling diarrhoea and faecal incontinence developed in two of 14 and five of 20 patients with an anastomosis respectively. Although these results indicate that segmental colonic transit time studies are useful in selecting patients with slow transit constipation for partial left-sided or subtotal colectomy, both procedures should be performed with prudence. PMID- 8689211 TI - Response to regional chemotherapy in patients with variant hepatic arterial anatomy. AB - Regional chemotherapy for colorectal liver metastases is conventionally delivered by a catheter inserted into the gastroduodenal artery. However, up to 40 per cent of patients have 'unconventional' hepatic arterial anatomy. The response rate to regional chemotherapy was examined in 28 patients with normal and in 17 with variant hepatic arterial anatomy. There was no significant difference in response rates between the two groups. PMID- 8689212 TI - Aortic prosthetic infection: 50 patients treated by radical or local surgery. AB - Fifty patients with aortic prosthetic infection were managed in a period of 10 years from 1983 to 1993. Twenty-five patients had recurrent sepsis after local surgery (group 1) and 22 of these eventually required radical surgery. Twenty five patients had radical graft excision as the first procedure (group 2). Group 1 contained an excess of patients with local groin symptoms (11 in group 1 versus five in group 2, P = 0.03) and in this group fewer radiological techniques were used to document the extent of graft infection. The perioperative mortality rate was similar in both groups (seven in group 1 versus five in group 2). The number of amputations was also similar (five in group 1 versus four in group 2). The triad of occlusive disease, aortobifemoral bypass and groin symptoms was associated with eight of nine amputations. While the authors would consider using local techniques if the anastomosis was intact, the graft remained patent and infection appeared to be confined to the groin, this combination is uncommon and radical graft excision remains the preferred treatment. PMID- 8689213 TI - Inhibition of neutrophil respiratory burst and cytokine priming by gamma linolenic acid. AB - The effect of n-6 fatty acids, particularly gamma-linolenic acid (GLA), on the oxidase response and neutrophil priming by tumour necrosis factor alpha and interleukin 8 was studied in both normal volunteers and patients with obstructive jaundice. GLA inhibited the neutrophil respiratory burst at concentrations higher than 50 mummol/l, but abolished cytokine priming at concentrations as low as 1 mummol/l. Inhibition was not the result of either cytotoxicity to the neutrophils or alteration in cytosolic free calcium homoeostasis. It is concluded that GLA is a potential inhibitor of neutrophil priming by cytokines and of the oxidative response. PMID- 8689214 TI - Transient rise in intact parathyroid hormone concentration after surgery for primary hyperparathyroidism. AB - Two-site immunometric assays for determination of the level of intact parathyroid hormone (PTH) in serum have enabled detailed clinical studies of PTH secretion. Fifty-one patients with primary hyperparathyroidism were studied before surgery and 2 years after operation. PTH levels dropped to low values after operation. A rebound increase in PTH concentration occurred from 10 days to 3 months after surgery. Abnormally raised postoperative PTH concentrations were noted in 31 per cent of the patients, who had lower serum concentrations of ionized calcium (Ca2+) than the rest (P < 0.003). Before operation these patients had a more pronounced hyperparathyroidism than the others. At 2 years after surgery there was still a positive correlation between PTH concentrations before and after surgery (P < 0.001). The rebound increase in the level of PTH was a general phenomenon probably caused by low Ca2+ concentrations at the time of remineralization of bone. This phenomenon was transient. The positive correlation between preoperative and postoperative PTH concentrations shows that effects of hyperparathyroidism can remain for a long time after surgical cure. PMID- 8689215 TI - Use of a laparoscopic trocar for percutaneous introduction of drains into intra abdominal abscesses. PMID- 8689216 TI - Prognostic value of positive cytology findings from abdominal washings in patients with gastric cancer. AB - The poor prognosis of patients with gastric cancer with free abdominal tumour cells on cytological examination has been described in Japan. In a randomized trial in the Netherlands comparing D1 and D2 lymphadenectomy for gastric cancer, patients were subjected to cytological examination of abdominal washings on an optional basis; findings were of no consequence for scheduled treatment. Cytology results in 535 patients were obtained, in 457 (85.4 per cent) after curative resection and in 78 (14.6 per cent) after palliative operation. There was a clear association of positive cytology results with serosal invasion (12 per cent positive cytology) and lymph node infiltration (7.5 per cent positive cytology). Survival of those with positive cytology results was significantly lower than that of those with negative findings, irrespective of the procedure employed (curative or palliative). Cytological examination of abdominal washings increases the accuracy of staging and improves the selection of patients suitable for curative or palliative resection. PMID- 8689217 TI - No obvious advantages for thoracoscopic two-stage oesophagectomy. AB - Thoracoscopically assisted Ivor-Lewis oesophagectomy potentially combines the pulmonary advantages of transhiatal oesophageal dissection, with the visibility and control permitted by thoracotomy. This study reviewed 17 patients who underwent this procedure with an intrathoracic anastomosis. Five patients required conversion to thoracotomy, four because of technical difficulties with the anastomosis. After operation 13 patients had radiological evidence of atelectasis, six developed a left pleural effusion and five had clinically significant pneumonia. Three patients developed an anastomotic leak, two of whom died giving an in-hospital mortality rate of 12 per cent. Median postoperative hospital stay was 12 days. Four patients developed benign anastomotic strictures requiring dilatation. The 1- and 2-year survival rates were 73 per cent (11 of 15 patients) and 63 per cent (five of eight) respectively. The use of minimal access techniques in this context does not appear to reduce the postoperative incidence of either pulmonary or anastomotic complications. PMID- 8689218 TI - Cystic duct laceration by metallic clips: a cautionary note. PMID- 8689219 TI - Randomized trial of laparoscopic cholecystectomy and mini-cholecystectomy. PMID- 8689220 TI - Long-term follow-up of a prospective randomized study of endoscopic versus surgical treatment of bile duct calculi in patients with gallbladder in situ. PMID- 8689221 TI - Mesenteric ischaemia: a multidisciplinary approach. PMID- 8689222 TI - Presentation of endometriosis to general surgeons: a 10 year experience. PMID- 8689223 TI - Factitious disorders and the surgeon. PMID- 8689224 TI - Intermittent vascular exclusion of the liver (without vena cava clamping) during major hepatectomy. PMID- 8689225 TI - Wandering spleen: a rare emergency condition. PMID- 8689226 TI - Laparoscopic hernia repair without the use of staples or knotting manoeuvres. PMID- 8689227 TI - Preoperative total parenteral nutrition is not associated with mucosal atrophy or bacterial translocation in humans. PMID- 8689228 TI - Self-expanding metal stents for the palliation of dysphagia due to inoperable oesophageal carcinoma. PMID- 8689229 TI - New drugs--reports of new drugs recently approved by the FDA. Valacyclovir. PMID- 8689230 TI - Novel designed enediynes: molecular design, chemical synthesis, mode of cycloaromatization and guanine-specific DNA cleavage. AB - The molecular design and chemical synthesis of novel enediyne molecules related to the neocarzinostatin chromophore (1), and their chemical and DNA cleaving properties are described. The 10-membered enediyne triols 16-18 were effectively synthesized from xylitol (10) in a short step, and found to be quite stable when handled at room temperature. The representative and acylated enediyne 16 was cycloaromatized by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in cyclohexa-1,4 diene-benzene to give the benzenoid product 21 through a radical pathway. On the other hand, the enediyne 16 was cycloaromatized by diethylamine in dimethyl sulfoxide-Tris-HCl, pH 8.5 buffer to afford another benzenoid product 22 as a diethylamine adduct through a polar pathway. Furthermore, the enediynes 16-18 were found to exhibit guanine-specific DNA cleavage under weakly basic conditions with no additive. PMID- 8689231 TI - MS-271, a novel inhibitor of calmodulin-activated myosin light chain kinase from Streptomyces sp.--I. Isolation, structural determination and biological properties of MS-271. AB - A novel cyclic peptide, MS-271, was isolated from the culture broth of an actinomycete, Streptomyces sp. M-271 as an inhibitor of smooth muscle myosin light chain kinase (MLCK). MS-271 inhibited the MLCK from chicken gizzard with an IC50 value of 8 microM. MS-271 did not inhibit cyclic AMP-dependent protein kinase, protein kinase C or calcium/calmodulin-dependent cyclic nucleotide phosphodiesterase at concentrations up to 400 microM. The primary structure of MS 271 was identical to that of siamycin I, an anti-HIV peptide isolated from a microbial source. PMID- 8689232 TI - MS-271, a novel inhibitor of calmodulin-activated myosin light chain kinase from Streptomyces sp.--II. Solution structure of MS-271: characteristic features of the "lasso' structure. AB - MS-271 is a potent inhibitor of smooth muscle myosin light chain kinase (MLCK), obtained from Streptomyces sp. In the previous paper, we reported on the isolation, structural determination and biological properties of MS-271.(1) In this paper, we report on the three-dimensional structure of MS-271 determined by 1H NMR in deuterated dimethyl sulphoxide. MS-271 consists of 21 amino acid residues with a novel internal linkage between the beta-carboxyl group of Asp9 and the alpha-amino group of Cysl, and two disulfide bonds, Cys1-Cys13 and Cys7 Cys19. The internal linkage between the side chain of Asp9 and the alpha-amino group of the N-terminal residue is the same as that of the endothelin B receptor selective antagonist, RES-701-1, that we previously reported. The structural calculations involved the combined use of distance geometry and simulated annealing calculations. The results indicated that MS-271 undergoes extraordinary folding, i.e. the "tail' (Phe10-dTrp21) passes through the "ring' region (Cys1 Asp9) ("lasso' structure). This folding of MS-271 turned out to be the same as the "lasso' structure of RES-701-1. The features of this "lasso' structure are discussed on the basis of comparison between the structures of MS-271 and RES-701 1. PMID- 8689233 TI - Overexpression, one-step purification and characterization of UDP-glucose dehydrogenase and UDP-N-acetylglucosamine pyrophosphorylase. AB - Two enzymes of the Leloir pathway, UDP-GlcNAc pyrophosphorylase and UDP-Glc dehydrogenase, which are involved in the synthesis of activated sugar nucleotides have been cloned, overexpressed in Escherichia coli, and purified to homogeneity in only one step by chelation-affinity chromatography. The gene KfaC of E. coli K5 was thus demonstrated to encode UDP-Glc DH. Some properties of the cloned enzymes, such as stability, pH dependence, and substrate kinetics, were studied in order to facilitate the use of these enzymes in carbohydrate synthesis, especially in the synthesis of hyaluronic acid. PMID- 8689234 TI - The absolute configuration of adjacent bis-THF acetogenins and asiminocin, a novel highly potent asimicin isomer from Asimina triloba. AB - A novel acetogenin, asiminocin (1), was isolated by activity-directed fractionation from the stem bark of the paw paw tree, Asimina triloba. By spectral and chemical methods, 1 was identified as (30S)-hydroxy-4-deoxyasimicin. The absolute configuration of 1, along with those of previously reported acetogenins asimin, asiminacin, bullatin, (30S)-bullanin, and (30R) bullanin, was determined by Mosher ester methodology. Compound 1 was highly inhibitory to three human solid tumor cell lines with over a billion times the potency of adriamycin. PMID- 8689235 TI - New drugs--reports of new drugs recently approved by the FDA. Alendronate. PMID- 8689236 TI - The design of dipeptide helical mimetics: the synthesis, tachykinin receptor affinity and conformational analysis of 1,1,6-trisubstituted indanes. AB - The design and synthesis of conformationally constrained, nonpeptide templates (1,1,6-trisubstituted indanes) which allow the incorporation of two adjacent amino acid side chains, plus a third binding group in an orientation similar to that found in alpha-helices are reported. Six racemic and two homochiral Phe-Phe and Trp-Phe mimetics were synthesised and evaluated in tachykinin receptor binding assays as molecular probes for the binding conformation of the endogenous peptides. Several were found to bind with micromolar affinity to the NK1 and/or NK3 receptor. The conformation of one of the homochiral indanes, (1R)-N-((S)-1 hydroxymethylbenzyl)-1,6-dibenzylindan-1-carbo xamide, was analysed by X-ray crystallography and was found to be in an alpha-helix conformation. PMID- 8689237 TI - Synthesis and in vitro antibacterial activity of spermidine-based mixed catechol- and hydroxamate-containing siderophore--vancomycin conjugates. AB - The first antibiotic conjugates of vancomycin (1) and siderophore analogues containing spermidine-based catechol ligands (conjugate 11) as well as mixed catechol and hydroxamate ligands (conjugate 13) are described. The design of the conjugates was based on the earlier observation that conjugation of siderophore components to beta-lactam antibiotics induced active iron transport-mediated drug delivery. The novel conjugates (11 and 13) were synthesized by selective acylation of the primary amino group of 1. Preliminary biological studies indicated that siderophore modified vancomycins lost some activity (4- to 16 fold) against Gram-positive bacteria relative to vancomycin itself, and were generally similar to vancomycin in activity against Gram-negative bacteria under iron-sufficient conditions. However, under iron-depleted conditions which mimic human serum, conjugate 11 displayed enhanced antibacterial activity against an antibiotic hypersensitive strain of Pseudomonas aeruginosa. PMID- 8689238 TI - Inhibition of aldose reductase by maesanin and related p-benzoquinone derivatives and effects on other enzymes. AB - A naturally occurring p-benzoquinone derivative, maesanin, inhibited porcine lens aldose reductase. Systematic investigation of related p-benzoquinone derivatives revealed that 2,5-dihydroxy-p-benzoquinone was a potent inhibitor of aldose reductase and aldehyde reductase but had no effect on NADH oxidase. Kinetic analysis showed this p-benzoquinone exhibited uncompetitive inhibition against DL glyceraldehyde and noncompetitive inhibition against NADPH. PMID- 8689239 TI - Peptide nucleic acids (PNA): synthesis, properties and potential applications. PMID- 8689240 TI - Vinyl fluoride as a mimic of the "intermediate' enol form in the 5 alpha reductase transformation: synthesis and in vitro activity of (N-1',1' dimethylethyl)-3-haloandrost-3,5-diene-17 beta-carboxamides. AB - (N-1',1'-Dimethylethyl)-3-haloandrost-3,5-diene-17 beta-carboxamides (9-11) and the methyl ester 8 were prepared from 3-chloro/bromoandrost-3,5-diene-17 beta carboxylic chloride/bromide (6/7), which were obtained from pregnenolone. In comparison with finasteride and 4-MA, compounds 8-11 showed very weak inhibitory activity ( < or = 10% inhibition) on human type I 5 alpha-reductase (transfected 293 cells) at 100 and 1000 nM concentrations. Against the type II enzyme, chloro compounds 8 and 9, and bromo 10 had no effect at 100 nM concentration, however, they were weak inhibitors of the type II (6.0% < inhibition < 30%) at a higher concentration. The best activity (IC50 = 480 nM) was observed with the 3-vinyl fluoride analogue 11. PMID- 8689241 TI - Using SAR and QSAR analysis to model the activity and structure of the quinolone DNA complex. AB - A set of 78 quinolone derivatives were used in a structure-activity study to identify structural features correlating with antibacterial activity. Distinct combinations of functional properties were identified for Gram-negative and Gram positive bacteria. 3-D Quantitative structure-activity relationship (QSAR) studies identified specific hydrophobic, topologic and electronic properties of the molecules for both in vitro and in vivo activities. From these results, a three-dimensional model of a DNA-quinolone complex was built using molecular modeling techniques. It was based on the intercalation of quinolone into the double helix of DNA. We conclude that the intercalation model is consistent with most available data on the structure of the quinolone complex. This predicted structure is stabilized by the binding of magnesium ion with the sp2 oxygens present in quinolone, a phosphate and a purine base of the DNA. Substituents R1 and R7 are predicted to make hydrophobic interactions in the major and minor groove of DNA, respectively. R7 could also form hydrogen bonds with amino groups of guanines and the aspartic acid residue at position 87 in DNA gyrase subunit A. PMID- 8689242 TI - N-cubylmethyl substituted morphinoids as novel narcotic antagonists. AB - N-Cubylmethylnormorphine (1) and N-cubylmethylnoroxymorphone (2) have been synthesized and found to be more potent ligands at the mu and kappa opioid receptors than morphine and oxymorphone respectively. In the guinea-pig ileum preparation, compounds 1 and 2 were characterized as opioid mu antagonists (Ke = 68 and 16 nM, respectively). Compound 2 also showed effective kappa-antagonism (Ke = 22 nM). The narcotic antagonism activity of 1 has been confirmed by in vivo assays. PMID- 8689244 TI - Synthesis and activity of 1-N-iminosugar inhibitors, siastatin B analogues for alpha-N-acetylgalactosaminidase and beta-N-acetylglucosaminidase. AB - N-Acetylgalactosamine-based 1-N-iminosugars, new types of glycosidase inhibitor have been synthesized by modeling on siastatin B, isolated from a Streptomyces culture. The analogues of siastatin B were proved to be potent inhibitors for alpha-N-acetylgalactosaminidase and/or beta-N-acetylglucosaminidase. PMID- 8689243 TI - Synthesis of Hexahydrocyclopentimidazol-2-(1H)-one derivatives displaying selective DP-receptor agonist properties. AB - The rationale for investigating conformationally restricted analogues of BW245C as DP-receptor ligands and the syntheses of three such racemic bicyclic imidazolidinone analogues are described. Compounds 7 (BW587C), 8 (BW480C85), and 9 (BW572C85) were found to be potent inhibitors of human platelet aggregation and selective DP-receptor agonists in washed platelet and jugular vein isolated tissue assays. PMID- 8689246 TI - From relief to development: the long-term effects of 'temporary' accommodation on refugees and displaced persons in the Republic of Croatia. AB - The increasing scale of international intervention in conflict is generating new pressures on the humanitarian community. Increased expenditure on emergency relief, static levels of overseas development aid and subsequent lack of funds for development are dictating that agencies design relief projects that positively effect developmental reconstruction. This paper examines the provision of shelter for refugees and displaced persons in the Republic of Croatia and identifies ways in which it has encouraged and discouraged sustainable reconstruction. It argues that to promote lasting reconstruction, programmes must focus on saving livelihoods as well as lives, thus minimising the long-term psychological and physical impacts of aid on refugees, displaced persons and host communities. PMID- 8689245 TI - Design, synthesis and in vitro evaluation of pyridinium ion based cyclase inhibitors and antifungal agents. AB - The design, synthesis and in vitro biological evaluation of pyridinium ion based inhibitors of oxidosqualene cyclase enzymes are reported. N-Alkyl- and N prenylpyridinium ions have been found to be potent and specific inhibitors of Candida albicans oxidosqualene-lanosterol cyclase and to exhibit antifungal activity. The ability of pyridinium ions to inhibit the C. albicans cyclase increases with increasing structural resemblance to a putative monocyclized species formed during the course of the cyclization process. The N-(4E,8E)-5,9,13 trimethyl-4,8,12-tetradecatrien-1- ylpyridinium cation 1 inhibits the C. albicans enzyme at concentrations more than 100-fold lower than does the directly analogous piperidinium derivative 4. PMID- 8689248 TI - Improving the efficiency and cost-effectiveness of food aid grain delivery. AB - Grain food aid averages 13 million tons per year. Donors have a duty to deliver food aid grain in an adequate and acceptable condition at least cost. This paper reviews commodity procurement, packaging, inspection, shipping and storage with regard to overall quality assurance and cost-effectiveness. Experience at ports of loading and discharge and in food aid delivery programmes indicates that sufficient attention is rarely paid to quality assurance and loss minimisation. Grain procurement specifications that are normally appropriate for safe handling and storage in temperate climates, particularly moisture content, are commonly inappropriate for tropical climates. The technology for safe delivery of food aid grain is well established but not always implemented. Procurement of food aid grain in developing countries has increased recently, creating a need to improve operational and management aspects of tendering and quality assurance procedures. Such purchases entail potential cost savings but are associated with lengthening delivery lead times for non-urgent consignments. Although woven polypropylene sacks are cheaper to buy than jute ones, the losses associated with handling and storage problems indicate that jute sacks are preferable for food aid delivery. PMID- 8689249 TI - Defensive development? Re-examining the role of the military in complex political emergencies. PMID- 8689247 TI - The World Trade Center bombing: injury prevention strategies for high-rise building fires. AB - The WTC disaster provided an opportunity to look for ways to prevent morbidity among occupants of high-rise buildings during fires. This paper first describes the overall morbidity resulting from the explosion and fire, and second, presents the results of a case-control study carried out to identify risk factors for smoke-related morbidity. The main ones include: increased age, presence of a pre existing cardio-pulmonary condition, entrapment in a lift and prolonged evacuation time. Study results point to the importance of the following safety systems during high-rise building fires: smoke-control systems with separate emergency power sources; lift-cars, lift-car position-monitoring systems, and lift-car communication systems with separate emergency power sources; two-way emergency communication systems on all floors and in stairwells; stairwells with emergency lighting and designed for the rapid egress of crowds; evacuation systems/equipment to assist in the evacuation of vulnerable people (elderly, infirm). Also important are evacuation plans that include regularly scheduled safety training and evacuation drills. PMID- 8689250 TI - Researching under fire: issues for consideration when collecting data and information in war circumstances, with specific reference to relief and reconstruction projects. AB - The post-Cold War era has witnessed an increased number of conflicts and higher levels of international intervention by the humanitarian community and the military. Those who undertake to research the actions of relief and development agencies acting in these wars must act within new parameters that require a flexible, innovative and reflective approach. Not much is known about data collection in war. The most relevant publications come from the field of development studies. This paper is a beginning in a much-needed discourse on researching under fire; it is offered not as a definitive work, but as a starting point for discussion. PMID- 8689251 TI - Improving the nutrition of refugees and displaced people in Africa: workshop in Machakos, Kenya, 5-7 December 1994. PMID- 8689252 TI - The IDNDR seminar on preventing 'natural' disasters--the role of risk control and insurance, Royal Society, London, 6 October 1995. PMID- 8689254 TI - Special education for students with disabilities. A selected bibliography. PMID- 8689253 TI - Structural vs non-structural flood-alleviation measures in the Yangtze Delta: a pilot survey of floodplain residents' preferences. AB - This study was initiated to test if structural flood-alleviation measures were more popular than non-structural measures among the floodplain residents of the Yangtze Delta, because of the long tradition of "living with embankments and other flood control structures'. The results of a pilot questionnaire survey among 239 respondents from four sample villages of two typical floodplains of the delta indicated that, contrary to expectations, the non-structural measure of flood insurance attracted more favourable responses (97 per cent) than any one of the structural measures, although the latter were also frequently selected by the respondents (64-92 per cent). A number of multivariate logit regressions between each of the preferred flood-alleviation measures and the respondents' flood adaptations identified some of the determinants of these preferences. For a more complete explanation of the causes of popularity of various flood-alleviation measures, further research should incorporate a behavioural model with trade-offs for alternative measures. PMID- 8689255 TI - Transition from high school to work or college: how special education students fare. AB - Results are reported from the National Longitudinal Transition Study of Special Education Students. Dropout rates were high: 30% of students with disabilities dropped out of high school, and another 8% dropped out before entering high school. The average dropout with disabilities was 18 years old at the time of leaving but had earned less than half the credits needed to graduate. Employment successes were strongly related to taking a concentration (four courses) in vocational education. Youths with learning disabilities or speech impairments were most likely to approach the rate of employment found in the general population. Postsecondary education was low: 37% of high school graduates with disabilities had attended a postsecondary school, compared with 78% of high school graduates generally. Students with hearing or visual impairments were most likely to attend college. Students with disabilities were significantly more likely to be poor than were youths in the general population, and poverty tended to exacerbate the impact of having a disability. Impoverished students with disabilities were less likely than wealthier students with disabilities to be enrolled in those postsecondary education and training programs that could enable them to break out of poverty. When employed, the poorer students with disabilities earned significantly less per year than did those from wealthier families. Placement in regular education (rather than special education) was associated both with better and worse postschool outcomes. Students with sensory or motor disabilities appeared to benefit from regular education placement. However, for many students, more time in regular education was associated with a higher likelihood of course failure, which was a strong predictor of dropping out of school. PMID- 8689256 TI - Financing special education. AB - The best available data indicate that approximately 12% of K-12 public education budgets are allocated to special education and that the cost per student is about 2.3 times the cost of regular education. About 8% of special education funds come from the federal government, 56% from state governments, and the remainder from local school districts. However, the division of fiscal responsibility between state and local sources varies considerably from state to state. Fiscal pressures on special education have increased markedly in recent years as a result of increasing overall school populations, increasing proportions of students found eligible for special education services, and increasing fiscal pressures on schools. At least six states have recently adopted, and the federal Department of Education has recently recommended, special education funding based on census counts of total school populations rather than on the number of students identified for special education services. Proponents of census-based funding foresee greater efficiency of services, while opponents fear a loss of services targeted to individualized needs. An additional proposal is that census-based funding be modified to increase funding to jurisdictions with higher rates of poverty. Criteria for evaluating state special education funding formulas are proposed. PMID- 8689257 TI - Children in special education. PMID- 8689258 TI - The effects of Medicaid expansions on insurance coverage of children. PMID- 8689259 TI - The legislative and litigation history of special education. AB - Between the mid 1960s and 1975, state legislatures, the federal courts, and the U.S. Congress spelled out strong educational rights for children with disabilities. Forty-five state legislatures passed laws mandating, encouraging, and/or funding special education programs. Federal courts, interpreting the equal protection and due process guarantees of the Fourteenth Amendment to the U.S. Constitution, ruled that schools could not discriminate on the basis of disability and that parents had due process rights related to their children's schooling. Congress, in legislation now retitled the Individuals with Disabilities Education Act (IDEA), laid out detailed procedural protections regarding eligibility for special educational services, parental rights, individualized education programs (IEPs), the requirement that children be served in the least restrictive environment, and the need to provide related (noneducational) services. Decisions on instructional matters such as curricula and the elements of the IEP remain the province of local and state authorities. Advocates for students with disabilities have continually sought separate (categorical) funding for special education services. Current movements toward block grants rather than categorical programs and toward greater inclusion of special education students in general education classrooms raise concerns in some quarters about whether students with disabilities will continue to have full access to the special services they need. While the cost of special services may be an unexpressed criterion in many decisions made by school districts, nowhere does the IDEA explicitly allow cost to be considered. Where a service is necessary for an individual child, cost considerations would not allow a school district to escape its obligations to the child. However, in instances where more than one appropriate configuration of services is available to meet a child's needs, the school district may be allowed to consider the cost of different alternatives. PMID- 8689260 TI - Special education for students with disabilities: analysis and recommendations. AB - Twenty years ago, the educational rights of students with disabilities were dramatically and firmly established in law and practice. Prior to that time, many students were refused enrollment or special educational services. As recently as 1973, at least one million students were denied enrollment in public schools solely on the basis of their disabilities, and at least two million others were not receiving an education appropriate to their needs. Although every state has provided some form of special education throughout this century, these services were largely at the discretion of local school districts. Only since a federal court case in 1972 and the passage of federal legislation in 1975 have all states been mandated to provide a free, appropriate public education to all students with disabilities. Today, as Parrish and Chambers point out in this journal issue, special education for students with disabilities is the largest categorical program in public schools, costing an estimated $32 billion. Since the passage of Public Law 94-142 in 1975 (later retitled the Individuals with Disabilities Education Act, or the IDEA), the number of elementary and secondary students receiving special education has increased from 3.7 million to 4.6 million, increasing also from 8% to 11% of all students in public schools. According to Parrish and Chambers, the population of students eligible for special education is expected to continue to rise. The IDEA governs the educational rights of individuals from birth to age 21, though only students in elementary and secondary school are addressed in this journal issue. The IDEA allowed access to the public schools for many students who had previously been denied enrollment. The IDEA has also been given partial credit for decreasing the rate of institutionalization of individuals with disabilities. Before the IDEA, many parents had the sole responsibility of meeting all the needs of their severely disabled children 24 hours per day; once schools began to provide extensive services to students with severe disabilities, more families were able to avoid institutionalization. Under the IDEA, states and local districts were given a mandate to provide specialized educational programs to students with special needs, and students and parents were given a mechanism for enforcement of their rights. In a 1989 survey, 94% of parents of students with disabilities agreed that services for these students had improved since the implementation of the IDEA. Yet special education today is widely criticized as expensive, ineffective, inadequately coordinated with regular education, and/or culturally biased. The National Association of State Boards of Education has recommended radical reduction in the size of special education. Special education also has its champions, who argue that many students perform better academically and have better self-esteem when provided with special services, often in a separate setting. This analysis addresses five questions concerning special education under the IDEA: (1) Why are so many students considered disabled? (2) What are the educational needs of students with disabilities? (3) How should appropriate, individualized services be funded? (4) Are the IDEA's procedural protections necessary? (5) Can regular education meet the needs of more students? PMID- 8689261 TI - Identification and assessment of students with disabilities. AB - Students with disabilities or suspected disabilities are evaluated by schools to determine whether they are eligible for special education services and, if eligible, to determine what services will be provided. In many states, the results of this evaluation also affect how much funding assistance the school will receive to meet the students' special needs. Special education classification is not uniform across states or regions. Students with identical characteristics can be diagnosed as disabled in one state but not in another and may be reclassified when they move across state or school district lines. Most disabilities with a clear medical basis are recognized by the child's physician or parents soon after birth or during the preschool years. In contrast, the majority of students with disabilities are initially referred for evaluation by their classroom teacher (or parents) because of severe and chronic achievement or behavioral problems. There is evidence that the prevalence of some disabilities varies by age, the high-incidence disabilities such as learning disabilities and speech-language disabilities occur primarily at the mild level, the mild disabilities exist on broad continua in which there are no clear demarcations between those who have and those who do not have the disability, and even "mild" disabilities may constitute formidable barriers to academic progress and significantly limit career opportunities. Problems with the current classification system include stigma to the child, low reliability, poor correlation between categorization and treatment, obsolete assumptions still in use in treatment, and disproportionate representation of minority students. Both African-American and Hispanic students are disproportionately represented in special education but in opposite directions. The disproportionately high number of African Americans in special education reflects the fact that more African American students than white students are diagnosed with mild mental retardation. Though poverty, cultural bias, and inherent differences have been suggested as reasons for this disproportionate representation, there are no compelling data that fully explain the phenomenon. In most states, classification of a student as disabled leads to increased funding from the state to the school district. This article suggests a revised funding system that weights four factors (number of deficits, degree of discrepancy, complexity of intervention, and intensity of intervention) in a regression equation that would yield a total amount of dollars available to support the special education of a particular student. PMID- 8689262 TI - Learning disabilities. AB - Approximately 5% of all public school students are identified as having a learning disability (LD). LD is not a single disorder, but includes disabilities in any of seven areas related to reading, language, and mathematics. These separate types of learning disabilities frequently co-occur with one another and with social skill deficits and emotional or behavioral disorders. Most of the available information concerning learning disabilities relates to reading disabilities, and the majority of children with learning disabilities have their primary deficits in basic reading skills. An important part of the definition of LD is its exclusions: learning disabilities cannot be attributed primarily to mental retardation, emotional disturbance, cultural difference, or disadvantage. Thus, the concept of LD focuses on the notion of a discrepancy between a child's academic achievement and his or her apparent capacity to learn. Recent research indicates, however, that disability in basic reading skills is primarily caused by deficits in phonological awareness, which is independent of any achievement capacity discrepancy. Deficits in phonological awareness can be identified in late kindergarten and first grade using inexpensive, straightforward testing protocol. Interventions have varying effectiveness, depending largely on the severity of the individual child's disability. The prevalence of learning disability identification has increased dramatically in the past 20 years. The "real" prevalence of LD is subject to much dispute because of the lack of an agreed-upon definition of LD with objective identification criteria. Some researchers have argued that the currently recognized 5% prevalence rate is inflated; others argue that LD is still underidentified. In fact, it appears that there are both sound and unsound reasons for the increase in identification rates. Sound reasons for the increase include better research, a broader definition of disability in reading, focusing on phonological awareness, and greater identification of girls with learning disabilities. Unsound reasons for the increase include broad and vague definitions of learning disability, financial incentives to identify students for special education, and inadequate preparation of teachers by colleges of education, leading to overreferral of students with any type of special need. There is no clear demarcation between students with normal reading abilities and those with mild reading disability. The majority of children with reading disabilities have relatively mild reading disabilities, with a smaller number having extreme reading disabilities. The longer children with disability in basic reading skills, at any level of severity, go without identification and intervention, the more difficult the task of remediation and the lower the rate of success. Children with extreme deficits in basic reading skills are much more difficult to remediate than children with mild or moderate deficits. It is unclear whether children in the most severe range can achieve age- and grade-approximate reading skills, even with normal intelligence and with intense, informed intervention provided over a protracted period of time. Children with severe learning disabilities are likely to manifest an increased number of and increased severity of social and behavioral deficits. When children with disabilities in reading also manifest attention deficit disorder, their reading deficits are typically exacerbated, more severe, and more resistant to intervention. While severe reading disorders are clearly a major concern, even mild deficits in reading skills are likely to portend significant difficulties in academic learning. These deficits, too, are worthy of early identification and intervention. Even children with relatively subtle linguistic and reading deficits require the expertise of a teacher who is well trained and informed about the relationships between language development and reading development. PMID- 8689263 TI - Effectiveness of special education: is placement the critical factor? AB - Research indicates that various program models, implemented both in special education and general education, can have moderately positive academic and social impacts for students with disabilities. However, no intervention has been designed that eliminates the impact of having a disability. With few exceptions, students with disabilities have not achieved commensurately with their nondisabled peers; even students with learning disabilities as a group have not been able to achieve at the level of low-achieving nondisabled students. In general, the most effective interventions for students with disabilities, whether in special education or general education settings, have employed intensive and reasonably individualized instruction, combined with careful, frequent monitoring of student progress. There is no compelling evidence that placement rather than instruction is the critical factor in student academic or social success. Further, studies have indicated that typical practice in general education is substantially different from practice in the model programs that showed greatest success for students with disabilities. The interventions that were effective in improving academic outcomes for students with disabilities required a considerable investment of resources, including time and effort, as well as extensive support for teachers. The research does not support full-time inclusion for all students with disabilities. On the contrary, it appears that there is a clear need for special education. At the same time, given adequate resources, schools should be able to assist more students to be more successful in general education settings. PMID- 8689264 TI - Calcium homeostasis. PMID- 8689265 TI - Neuroprotective properties of calcium-channel blockers. AB - Increases in intraneuronal Ca2+ concentration, which accompany cerebral ischemia and traumatic brain injury, initiate a cascade of biochemical events that can eventually result in cell lysis and death. Calcium-channel blockers, in certain experimental models of focal and global ischemia, attenuate the increase in intracellular Ca2+ concentration and thereby ameliorate neurologic damage. Clinical efficacy varies among disease states. After nontraumatic subarachnoid hemorrhage, nimodipine has become a standard of care. Calcium-channel blockers improve outcome, whether given before or after onset of vasospasm. Although the precise mechanism of their beneficial effect remains unclear (vasodilation vs. attenuation of increases in intracellular Ca2+ concentrations), numerous studies have demonstrated decreased neurologic morbidity. Although there also is suggestive evidence of benefit in human stroke, these results have not been sufficiently impressive to result in the widespread use of these drugs as neuroprotectants. In clinical trials after cardiac arrest, calcium-channel blockers have been ineffective. In clinical traumatic brain injury, data suggest moderate efficacy in younger patients and those with post-traumatic subarachnoid hemorrhage, although overall outcome is not changed. The future role of calcium channel blockers as neuroprotectants appears bright. Newer classes of compounds, with greater specificity and fewer side effects, may provide greater clinical benefit. PMID- 8689266 TI - The use of calcium-channel blockers in pregnancy. AB - Over the past 10 yrs, calcium-channel blockers have been used in obstetrics and gynecology for the treatment of patients with both gestational hypertension and preterm labor. Several randomized trials have been performed which demonstrated that calcium-channel blockers are at least as efficacious as other, better-known antihypertensive agents. Despite animal studies which have shown unfavorable outcomes with the use of some of these agents, the use of calcium-channel blockers in pregnancy has been increasing. As we gain further information on the correlation between calcium homeostasis and several additional disease states, the role of calcium-channel blockers will become further elucidated. PMID- 8689267 TI - Calcium antagonists and the kidney. AB - Calcium antagonists have evolved as an important class of cardiovascular therapeutic agents. Usefulness in treating hypertension, angina pectoris, and cardiac arrhythmias has been established. Investigations show that calcium antagonists have a role in altering renal functions. They are natriuretic and may benefit salt-sensitive hypertensives. They have been shown to block vasoconstriction of the afferent arteriole in the presence of constrictors such as endothelin, thromboxane, norepinephrine, and angiotensin II. These vasoconstrictors may be mediators of nephrotoxins such as radiocontrast agents, and cyclosporine A. Actions of calcium antagonists which are being investigated for potential benefit in ameliorating chronic renal disease include: preventing glomerular hypertrophy, blocking angiotensin II-mediated macromolecule entry into mesangial cells and cytokine release, free-radical scavenger activity, and decreasing calcium deposition within the kidney. Slowing the progression of renal disease with the calcium antagonists has been demonstrated in both short- and long-term trials. Further studies are currently underway. PMID- 8689268 TI - The role of calcium-channel antagonists in solid organ transplantation. AB - Calcium-channel antagonists play a role not only in the management of cardiovascular disease, but they may also play a role in solid organ transplantation. Part of the success of solid organ transplantation over the last several years has been the development of potent immunosuppressive agents such as cyclosporine A and tacrolimus. The calcium-channel antagonists have been shown to decrease cyclosporine A-induced nephrotoxicity by blocking the vasoconstrictive effects of endothelin and thromboxane A2 on the afferent arteriole induced by this agent. The role of calcium antagonists in avoiding tacrolimus-induced nephrotoxicity has not been studied to date. Calcium antagonists have been shown to have an immune-modulating effect as well, via inhibition of calcium-mediated lymphocyte proliferation. This immune-modulating effect has resulted in a decreased incidence of acute rejection in those patients receiving concomitant cyclosporine and calcium antagonists. A third role for calcium antagonists in organ transplantation has been as an additive to organ preservation solutions to avoid calcium-mediated ischemic damage. Despite several successful investigations demonstrating a role for calcium antagonists in solid organ transplantation, widespread acceptance of such a role awaits larger randomized clinical trials. PMID- 8689269 TI - Calcium regulation and nonprotective properties of calcium in surgical ischemia. AB - Calcium is one of the most important electrolytes in the body. Calcium regulation involves the intricate interaction between intracellular and extracellular levels with the free form of calcium determining function. The parathyroid gland is the principal regulator of ionized calcium in the serum. The kidney and gastrointestinal tract calcium receptors respond to the incorporation of calcium into the cytosol for muscle contraction, cell-cell communication, coagulation, and hormonal and neurotransmitter release functions. The regulation of calcium and the role of calcium antagonists are discussed as they relate primarily to the gastrointestinal tract and liver functions. The use of calcium-channel blockers has augmented myocardial function and has met with some success in decreasing hemorrhagic mucosal ischemia after shock. However, clinical studies evaluating the role of these agents in ischemia have yet to be initiated. PMID- 8689270 TI - The mechanisms of calcium-mediated cell injury and cell death [correcgted]. AB - It has been known for some time that all pathophysiologic changes in shock and trauma have their basis at the cellular and molecular levels. These changes have been and continue to be studied in vivo in human patients and animal models and in vitro using a number of human and animal cell cultures. Cell injury and cell death have been studied in our laboratories for many years with reversible and irreversible cell responses having been characterized by functional, morphological, and biochemical methodologies. Recently, new technologies such as molecular biological experimentation for gene expression studies and digital imaging fluorescence microscopy to measure and localize ions, specifically the concentration of intracellular ionized calcium ([Ca2+i]), have been undertaken. Data from these studies have led us to propose a working hypothesis for a number of principle subcellular events that occur following a lethal injury. Dysregulation of [Ca2+i] is central to this hypothesis, since the effects of such dysregulation appear to affect many phenomena either positively or negatively. These phenomena are briefly discussed here. Much additional experimentation needs to be performed which should lead to further understanding of these events and to improved therapy, including modifiers of Ca(2+)-mediated events, new regulators of gene expression, and even gene therapy itself. PMID- 8689271 TI - Acute hypertension and calcium-channel blockers. AB - Acute arteriolar vasoconstriction is considered to be the common physiologic pathway for hypertensive crises. Calcium plays a critical role in this process as a required element in the generation of vascular smooth muscle contraction. Within the vascular smooth muscle cell, calcium homeostasis is maintained through a complex set of mechanisms that control cellular calcium influx and efflux as well as intracellular calcium storage. Extracellular calcium enters the intracellular free space of the vascular smooth muscle cell through four portals: a passive slow leak, voltage-gated channels, hormone-mediated receptor-operated channels, and stretch-activated channels. The myofilaments actin and myosin contract upon the increase in cytosolic calcium. Calcium-channel blockers are commonly used as vasodilators for the treatment of hypertensive crises. There are three families of commercially available calcium-channel blockers: 1,4 dihydropyridines, phenylalkylamines, and benzothiazepines. These drugs block extracellular calcium entry through the L-type voltage-gated channel. Systemic vasodilation is produced as the cytosolic calcium level is lowered and myosin actin contraction cannot be maintained. The precise mechanism of blockade and the tissue site selectivity varies among the three drug families. The 1,4 dihydropyridines are selective for the arteriolar beds, while the phenylalkylamines and benzothiazepines are selective for the atrioventricular node. Of the calcium-channel blockers, the dihydropyridines nifedipine and nicardipine are recommended as first-line agents for hypertensive emergencies and urgencies because of their peripheral arteriolar bed selectivity and their pharmacologic and kinetic profiles. PMID- 8689272 TI - Calcium homeostasis in smooth muscle cells. AB - Calcium triggers muscle contraction and is a second messenger of hormones and growth factors that regulate metabolism, gene expression, and secretion in smooth muscle cells (SMC). SMC contain dozens of proteins that bind Ca2+ either to buffer changes in ionized calcium or to elicit a cellular response such contraction or secretion. Although there practically an infinite supply of Ca2+ in extracellular medium, SMC respond to a variety of stimuli by mobilizing Ca2+ accumulated in the sarcoplasmic reticulum (SR), where most cellular Ca2+ resides. The SR of smooth muscle resembles the endoplasmic reticulum of nonmuscle cells and accumulates Ca2+ via the sarcoendoplasmic reticulum Ca2+ adenosine triphosphatase (ATPase). Stimuli, such as angiotensin II, produce inositol 1,4,5, trisphosphate (IP3), which regulates a Ca2+ channel of the SR. IP3 binding opens the channel and produces a "spike" in the cytoplasmic concentration of free Ca2+ ([Ca2+]i). The spike is largely due to the release of stored Ca2+ because hormonal stimulation produces similar spikes in the presence and absence of extracellular Ca2+. Ca2+ ejection from the cell, rather than reaccumulation by the SR, is responsible for rapidly decreasing [Ca2+]i from the peak level produced by the stimulus. Release of SR Ca2+ and activation of plasma membrane Ca2+ efflux mechanisms markedly decrease total cell Ca2+. Two independent Ca2+ transporters in the plasma membrane, the Na(+)-Ca2+ exchanger and the Ca2+ ATPase, actively eject Ca2+ from SMC. The Na(+)-Ca2+ exchanger is largely responsible for the acute phase of Ca2+ ejection, whereas the plasma membrane Ca2+ ATPase contributes to the sustained increase in Ca2+ efflux from stimulated SMC. Following Ca2+ release from the SR and ejection from the cell, Ca2+ enters via channels, which sustain a modest increase in [Ca2+]i and a gradual refilling of the SR. Mitochondria have an important role in intracellular Ca2+ signaling. Mitochondrial metabolism is highly responsive to transient increases in [Ca2+]i, although mitochondria are not a Ca2+ repository. Ca2+ uptake by mitochondria is driven by the highly favorable electrochemical potential difference across the inner membrane. Mitochondria actively expel Ca2+ via a H(+)-Ca2+ or Na(+)-Ca2+ exchanger. Ca2+ uptake and ejection by mitochondria contributes to temporal and spatial oscillations in [Ca2+]i. accelerated Ca2+ cycling between the Sr, cytoplasm, mitochondria, and the environment is a hallmark of cell stimulation. PMID- 8689273 TI - Carnosine: a novel peptide regulator of intracellular calcium and contractility in cardiac muscle. AB - Myocardial contractile failure is a common cause of morbidity and mortality in patients with ischemic heart disease and inflammatory disorders such as sepsis. Recent research indicates that contractile failure is associated with dysregulation of cytoplasmic calcium levels in the myocyte. However, the specific biochemical alterations responsible for calcium dysregulation remain unclear. In a search for mechanisms which might explain the altered calcium regulation in cardiac cells during ischemia and sepsis, we discovered new roles for an intracellular peptide which regulates intracellular calcium and contractility in myocardial cells. The intracellular peptide carnosine improves contraction in the isolated rat heart and increases free intracellular calcium levels. It stimulates calcium release from the ryanodine calcium-release channel, inhibits calcium uptake by the sarcoplasmic reticulum calcium pump, and sensitizes the contractile proteins to calcium. We believe that this peptide represents a new intracellular messenger system for the regulation/modulation of intracellular calcium. Changes in levels of carnosine may play a role in the altered contractility seen during critical illness. PMID- 8689274 TI - Measurement of calcium transport in heart using modern approaches. AB - Cellular Ca balance and the dynamic Ca fluxes which occur during each cardiac cycle are complicated by numerous and interdependent different Ca transport systems and binding sites in cardiac myocytes. Since alterations in cellular Ca regulation can be crucial determinants of cardiac dysfunction (both mechanical and arrhythmogenic), it is important to have a fairly clear and somewhat quantitative fundamental understanding of how these systems interact in the intact ventricular myocyte. Several different methods are described for the measurement of Ca fluxes in cardiac myocytes: Ca electrodes, voltage/patch clamp, and fluorescent indicators. With these tools, the roles of Ca entry via Ca current and Na/Ca exchange and sarcoplasmic reticulum (SR) Ca release are discussed in terms of the activation of contraction. The relative roles of Ca removal during relaxation via the SR Ca-adenosine triphosphatase (ATPase), Na/Ca exchange, sarcolemmal Ca-ATPase, and mitochondrial uniporter are also evaluated quantitatively (with the first two being dominant). There are also significant species-dependent differences in the Ca fluxes (where the SR Ca-ATPase is stronger in rat than rabbit and the converse is true for the Na/Ca exchange). There are even differences in the direction of net Ca transport across the cell membrane during the cardiac cycle. In the steady state, it is also clear that the amount of Ca which enters the cell during each cycle must equal the amount extruded from the cell in order to maintain a steady state and prevent progressive Ca overload or loss. In this context, it appears that the amount of Ca which enters the cell via Ca current during the action potential is extruded via Na/Ca exchange during contraction and relaxation. PMID- 8689275 TI - Antiarrhythmic and anti-ischemic properties of calcium-channel antagonists. AB - The calcium-channel blockers are an ever-enlarging, heterogeneous group of drugs with widely variable effects on myocardium, sinoatrial and atrioventricular nodal function and conduction, peripheral blood vessels, and coronary circulation. Since the development and characterization of calcium-channel antagonists in the 1960s, these agents have become increasingly important in the treatment of many cardiovascular diseases. Nine calcium-channel blockers-nifedipine, nicardipine, amlodipine, felodipine, isradipine, nimodipine, diltiazem, verapamil, and bepridil-are all approved for use in the United States. Each major category has its own unique physiologic features. These drugs are extremely useful in the management of cardiac arrhythmias (particularly supraventricular arrhythmias) and/or ischemia. As future generations of calcium-channel blockers are developed with greater vasoselectivity, less negative inotropic effects, and reduced tendency to activate the renin-angiotensin system, their indications for use will continue to grow. PMID- 8689276 TI - Calcium: a regulator of the inflammatory response in endotoxemia and sepsis. AB - Calcium functions as a critical intracellular second messenger and regulates many cellular processes such as muscle contractility, glycogen and protein turnover, hormone secretion, and vascular smooth muscle tone which are markedly abnormal during sepsis/endotoxemia. There also is increasing recognition of the role of calcium in the production of a variety of cytokines such as tumor necrosis factor alpha and interleukin-1 beta, which are important mediators of sepsis. Our hypothesis is that disturbances in cellular calcium regulation are responsible for or contribute to many of the metabolic manifestations of sepsis/endotoxemia and may be the driving force behind the development of multiorgan failure. In this article, we focus on a) new insights into calcium's regulation of the inflammatory cascade, b) the controversy concerning whether free cytosolic calcium concentration ([Ca2+]i) is increased in the disorder, and c) the potential therapeutic uses of calcium antagonists. An important message is that there are fundamental differences in the pathophysiology of the endotoxin model versus the cecal ligation and perforation (CLP) model of sepsis. Although calcium antagonists improve survival in the endotoxin model, they increase mortality in the CLP model of sepsis. Possible reasons for the differences in the effect of the drugs in the two different models and insight into the mechanisms of cell injury in endotoxin versus sepsis are presented. PMID- 8689277 TI - Alterations in calcium signaling and cellular responses in septic injury. AB - The immune and endocrine mediators that are released during sepsis (e.g., tumor necrosis factor [TNF] alpha, interleukin [IL]-1, IL-6, transforming growth factor [TGF] beta, prostaglandin [PG] E2, catecholamines, vasopressin, glucagon, insulin, and glucocorticoids) can produce inappropriate detrimental cellular responses contributing to exacerbation of septic injury. Examples of such sepsis related inappropriate responses are: exaggerated hepatic acute-phase protein (APP) expression and release skeletal muscle insulin resistance, and suppressed T lymphocyte proliferation. The studies discussed in this article present evidence that the generation of the sepsis-related hepatic, skeletal muscle, and T lymphocyte responses emanate from alterations in intracellular Ca2+ (Ca2+i) homeostasis. In hepatocytes, there is indication of a sepsis-mediated increase in Ca2+ influx from the extracellular milieu leading to a sustained increase in the apparent resting cell Ca2+i concentration ([Ca2+]i) and its depressed elevation on stimulation with Ca2+-mobilizing hormones such as catecholamines and vasopressin. These Ca(2+)- related changes can affect not only the signaling pathways in which Ca2+i itself serves as a signaling component, but also the signaling systems turned on by other sepsis-induced agonists which may not be dependent on Ca2+ signaling. TGF-beta, IL-1, TNF alpha, and IL-6 activate a primarily protein kinase C (PKC)-dependent intracellular signal system for the elicitation of a normal hepatic APP response (APPR). The increased apparent basal [Ca2+]i in sepsis can hypersensitize PKC activation and thus lead to an exaggerated APPR. In the skeletal muscle, an evident increase in Ca2+ membrane flux during sepsis pointed to an increase in the basal [Ca2+]i resulting from a plausible cytokine-mediated overactivation of the voltage-sensitive Ca2+ channels. The increased basal [Ca2+]i can negatively modulate the insulin mediated stimulation of GLUT4-dependent glucose transport despite the possibility that Ca2+i might not participate as a component in the insulin-receptor-regulated signaling pathway. Increased [Ca2+]i in skeletal myocytes can either directly promote the phosphorylation of GLUT4 or prevent its dephosphorylation, both of which effectively block insulin stimulation of glucose uptake, thereby contributing to insulin resistance. In T lymphocytes, septic injury appears to induce an attenuation in the mitogen and, thus, presumably a T-cell antigen receptor (TCR)-mediated elevation in [Ca2+]i without affecting the basal [Ca2+]i. This decrease in TCR-related Ca2+i mobilization evidently contributes to the suppression of T lymphocyte proliferation during sepsis, probably via an in vivo action of prostaglandin (PG) E2 on the T cells during sepsis. The blockade of PGE2 production after indomethacin administration to septic animals prevents alterations in both T-cell Ca2+i mobilization and proliferation. PGE2 probably acts through its second messenger, cyclic adenosine 3'5'-monophosphate, which can antagonize Ca2+i signaling in T cells. PMID- 8689278 TI - Regulation of endothelial permeability by second messengers. AB - The mechanisms by which mediators such as oxidants released by neutrophil (PMN) activation increase endothelial permeability are poorly understood. The focus of this article is to identify some of these mechanisms. Studies using endothelial cell monolayers in culture have shown that PMN activation increases endothelial permeability both in the presence and absence of PMN-endothelial monolayer contact. Hydrogen peroxide (H2O2), an oxidant released by PMN activation, plays an important role in PMN-induced increases in endothelial permeability. The results of these studies suggest that, as with other mediators of inflammation (e.g., histamine, thrombin) the mechanism of H2O2-induced increase in endothelial permeability involves activation of endothelial protein kinase C (PKC) and increase in endothelial cytosolic Ca2+. PMID- 8689279 TI - Calcium blockage in pulmonary hypertension and hypoxic vasoconstriction. AB - Both extracellular and intracellular calcium (Ca2+) play important roles in hypoxic pulmonary vasoconstriction (HPV) and the vasoconstrictor responses to endogenous pulmonary vasoconstrictor substances, as evidenced by the effect of calcium-channel blockers on these vasoconstrictor responses and the measurement of changes in Ca2+ flux or intracellular Ca2+ concentrations in isolated cells. The more vasoselective the calcium-channel blocker, the greater its effect on pulmonary vasoconstriction. However, these drugs are not selective for the pulmonary vascular bed and are not as potent as pulmonary vasodilators when compared with other vasodilator drugs, including prostaglandin E1, isoproterenol, prostacyclin, or nitroglycerin. Moreover, the primary effect of vasoselective calcium-channel blockers on pulmonary vascular resistance is secondary to the effects of these agents on systemic vascular resistance and cardiac output. Although there is improvement in oxygen delivery, exercise tolerance, and survival in patients with primary pulmonary hypertension who respond to calcium channel blockers, the response of individual patients to these drugs is difficult to predict because the extent of reversible versus irreversible changes in the pulmonary vasculature is not known. The use of these drugs in patients with chronic hypoxia-induced pulmonary vasoconstriction may be associated with a worsening of ventilation-perfusion mismatching secondary to inhibition of HPV. PMID- 8689280 TI - Peripheral pyogenic arthritis. A study of one hundred seventy-nine cases. AB - A retrospective medical record-based study of cases of peripheral pyogenic arthritis diagnosed in a rheumatology department between 1966 and 1993 was conducted. Of the 197 cases, 179 were evaluable. Pyogenic arthritis accounted for 0.68% of admissions and 30.3% of bone and joint infections during the study period. Incidence rose gradually from 2.2 new cases per year between 1966 and 1970 up to 6 to 10 new cases per year since 1991. In 88% of cases a single joint was involved, with the most commonly affected sites being the knee (32.5%), hip (22.2%), shoulder (12%) and sacroiliac joint (11.4%). Of the 22 patients with polyarticular arthritis, 19 had involvement of two joints. A portal of entry was identified in 53% of cases. Of the 13% of iatrogenic cases, half occurred after a local corticosteroid injection. The pathogen was identified in 65% of cases. Staphylococcus aureus was the most common organism (56%) followed by streptococci (9.5%) and E. coli (7%). Only three patients had gonococcal arthritis. Mean duration of therapy was four months. Although complications were exceedingly rare, three patients died and three others developed septic shock. Our data suggest that the presentation of pyogenic arthritis has remained essentially unchanged. In particular, we found no increase in iatrogenic forms, in contrast to recent experience with vertebral osteomyelitis. PMID- 8689281 TI - Fate of human IgG from lupus erythematosus antinuclear antibody positive sera passively transfered to mice. AB - An animal model to study the fate of antinuclear antibodies (ANA) in vivo is reported. Newborn Balb/c mice were passively transferred by injection with sera from patients with autoimmune disease. The following antinuclear antibodies were found in the liver, spleen, kidneys and skin shortly after the injection: anti dsDNA, nRNP, Ro/SSA and La/SSB. Clearance of all these antibodies occurred within 48 hours. The cytoskeleton, Fc immunoglobulin domain and Fc immunoglobulin-cell surface interaction may play a major role in the entry of antinuclear antibodies into cells, which may occur via endocytosis. Our animal model may be useful for studying the kinetics of binding of antinuclear antibodies to nuclear components and the effects of such binding in vivo. PMID- 8689282 TI - Bacterial endocarditis revealed by infectious discitis. AB - A study of 30 patients admitted for infectious discitis identified four cases with concomitant bacterial endocarditis. All four patients were male and had concomitant streptococcal septicemia. Two patients had known aortic valve disease. The vertebral infection was located to the thoracic or lumbar spine. Ultrasonography disclosed aortic lesions in all four patients and mitral lesions in two. Management consisted of intravenous antimicrobial therapy for four weeks followed by a three-month course of oral antimicrobial therapy. The outcome of the discitis was favorable within the usual period of time. However, the endocardial lesions continued to progress, and three patients rapidly required valve replacement. Analysis of available data in the 30 patients with discitis showed that half the patients with streptococcal discitis also had bacterial endocarditis and that the latter condition developed in all the patients with streptococcal discitis and a history of valve disease. A number of risk factors were identified. An echocardiogram should be done routinely in patients with infectious discitis and risk factors for bacterial endocarditis. PMID- 8689283 TI - Risk factors for gastrointestinal complications of nonsteroidal antiinflammatory drugs. PMID- 8689284 TI - Prevention of gastrointestinal damage induced by nonsalicylate nonsteroidal antiinflammatory drugs. PMID- 8689285 TI - Biochemical effects of calcium and vitamin D supplementation in elderly, institutionalized, vitamin D-deficient patients. AB - Forty-five subjects (41 women and 4 men) in long-stay and medium-stay facilities, aged 74 to 95 years (mean 86.4 years), with 25-hydroxy-vitamin D levels less than 12 ng/ml, were treated for six consecutive months with two tablets per day of a preparation containing vitamin D3 (800 IU/day) and calcium carbonate (1 g elemental calcium/day). Serum levels of 25-hydroxy-vitamin D were very low at baseline (5.6 +/- 0.4 ng/ml) and rose significantly under treatment, to normal values, 33.2 +/- 1.2 and 40.9 +/- 2.1 ng/ml after three and six months, respectively (p < 0.001 for both comparisons). Serum calcium increased significantly, by 4.5% (p < 0.001) during the first three months, and remained at a plateau thereafter. Corrected serum calcium rose by 8.9% (p < 0.001) during the trial. No patient developed hypercalcemia. Serum parathyroid hormone levels, which were elevated at baseline (71.6 +/- 5.8 pg/ml; normal, 12 to 54 pg/ml), decreased gradually and significantly throughout the treatment period, by 43.0% and 67.1% after three and six months, respectively (p < 0.001 for both comparisons). Serum alkaline phosphatase activity fell concomitantly, by 9.9% after three months (p < 0.01) and 36.5% after six months (p < 0.001). In conclusion, the preparation used in our study is effective in correcting both the vitamin D deficiency that is prevalent in elderly institutionalized patients and the resultant increase in bone turnover. PMID- 8689286 TI - Membranoproliferative glomerulonephritis, p-antineutrophil cytoplasmic antibodies, and rheumatoid arthritis. Report of a case. AB - Many rheumatoid arthritis patients have renal dysfunction induced either by the drugs used to treat their joint disease or by the chronic inflammation. A case of rheumatoid arthritis with p-antineutrophil cytoplasmic antibodies and mesangial glomerulonephritis that progressed to type I membranoproliferative glomerulonephritis is reported. The glomerular abnormalities were diagnosed by two renal biopsies done at a one-year interval. Reasons for the first and second renal biopsies were renal dysfunction with hematuria and impure nephrotic syndrome, respectively. Unusual features in this case include the succession of two histologic forms of glomerular disease in a patient with rheumatoid arthritis, the correlation between p-antineutrophil cytoplasmic antibody titers and activity of the renal disease. In addition, type I membranoproliferative glomerulonephritis is exceedingly rare in rheumatoid arthritis patients. PMID- 8689287 TI - Facial edema and giant cell arteritis. AB - Many atypical manifestations that can be inaugural in giant cell arteritis are well known. Three cases with facial edema as the first manifestation are described. Similar cases reported to date are reviewed. PMID- 8689289 TI - Acquired lumbar kyphosis as the first manifestation of a motor neurone disease. PMID- 8689288 TI - Two osteoarcheological cases of ankylosing spondylitis, possibly in genetically related individuals. PMID- 8689290 TI - Two cases of multiple autoimmune disorders in patients with selective IgA deficiency. PMID- 8689291 TI - Parathyroid hormone-related protein. An analog of parathyroid hormone involved in regulation of growth, development, and gestation. PMID- 8689292 TI - Cytokines and osteoporosis. AB - Bone remodeling is a complex process that involves cells from various lineages, the calcified extracellular bone matrix and a multitude of regulation factors that act at both the tissular and cellular levels. Resorption and formation of bone are regulated at various levels during the series of events that lead from stem cell proliferation to differentiation of mature cells. These events are controlled by calciotropic hormones, whose indirect cellular effects are mediated by the production of local factors. A host of cytokines and growth factors influence the proliferation and differentiation of bone cells, and their activities are modulated by a large number of hormones. Resorption by osteoclasts is regulated at various stages of the differentiation process by cytokines produced by osteoblasts or stromal cells. Experimental studies in mice suggest that these local factors play a role in postoophorectomy bone loss, although their exact mechanisms of action are not known. Evidence that these factors are involved in postmenopausal bone loss is beginning to accumulate, opening up a vast field of investigation. PMID- 8689293 TI - Features associated with juvenile onset of spondylarthropathies in north Africa. AB - To determine whether juvenile onset of spondylarthropathy is associated with specific features, a prospective, cross-sectional study comparing juvenile-onset and adult-onset spondylarthropathies was conducted in the Maghreb in 523 patients meeting Amor's criteria or the ESSG's criteria for spondylarthropathy. Demographic data and clinical findings at the time of inclusion and during the first two years of the disease were compared in the 437 patients with onset at 16 years of age or older and in the 86 patients with onset before 16 years of age using a Student's t test or a chi-square test. The risk of hip involvement during the course of the disease was estimated using Kaplan-Meier curves and compared in the two groups using a Cox model. Early in the disease, patients in the juvenile onset group were more likely to have peripheral arthritis (52% vs 39%, p = 0.021) and enthesopathies (55% vs 40%, p = 0.002) and less likely to have axial manifestations (41% vs 62%, p = 0.0001), as compared with the adult-onset group. These differences persisted after a follow-up of 9.2 years. Juvenile-onset disease was associated with a greater likelihood of hip involvement (54 +/- 6% vs 34 +/- 3% after ten years, p = 0.012). The male bias was more marked in the juvenile onset group (85%) than in the adult-onset group (72%) (p = 0.016). These data confirm that demographic characteristics, clinical manifestations, and disease severity differ between juvenile-onset and adult-onset spondylarthropathies. PMID- 8689294 TI - Comparison of the efficacy of nonsurgical synovectomy (synoviorthesis) and joint lavage in knee osteoarthritis with effusions. AB - OBJECTIVE: Radioactive or chemical synovectomy (synoviorthesis) is widely used as local therapy for inflammatory joint disease in France. The objective of this retrospective study was to compare the efficacy of osmic acid or radiation synovectomy with that of joint lavage for the treatment of knee osteoarthritis with effusions. PATIENTS AND METHODS: All study patients met American College of Rheumatology criteria for knee osteoarthritis, which was symptomatic despite conservative therapy including local corticosteroid injections. Fifty-four patients were treated by synoviorthesis (osmic acid, n = 16; yttrium 90, n = 76) and 45 by joint lavage (total 67 lavages). RESULTS: Thirty two per cent of the patients in the synoviorthesis group had a good or excellent outcome after six months. Results were better with yttrium 90 than with osmic acid. Improvements were most marked in patients with chondrocalcinosis. Efficacy was negatively correlated with the femorotibial lesions but not with the patellofemoral lesions. Patients with knee alignment disorders had poorer outcomes. In the joint lavage group, 30% of the knees showed improvements after three months and results were significantly better after three and six months when the lavage was followed by an injection of triamcinolone hexacetonide. No side effects were recorded. CONCLUSION: Our data suggest that chemical or radiation synovectomy or joint lavage followed by injection of a delayed-action steroid may be useful for the treatment of knee osteoarthritis with chronic or recurrent effusions. PMID- 8689295 TI - [Indications and contraindications for liver transplantation]. AB - Liver transplantation (LT) is a therapeutic method in many, otherwise infaust diseases of the liver. During the recent decade the experimental therapeutic procedure has become a routine therapeutical method. The stage of clinical experiment was ultimated by the Washington Conference held on the consensus in LT indications (1983). Large centries (USA, England, Germany) yield 80-100 liver transplantations per year. The recent years have recorded a change in some principal opinions on LT. It is possible to state that liver transplantation is being abstained from cases with more extensive primary neoplamatic affliction of the liver. Conservative therapy in primary biliary cirrhosis of the liver by means of ursodeoxycholic acid has shifted the LT indication into the later stages of the disease. The opinions on the meaning of LT in alcoholic cirrhosis remain still unsettled. LT remains unambiquously indicated in life-endangering fulminant and subfulminant liver failures. Among the viral diseases, attention is paid to liver cirrhosis caused by infection by the hepatitis C virus. Cirrhosis due to hepatitis B has a better prognosis, owing to the complex antiviral therapy. Liver transplantation represents, beside the main indications, the therapy of first selection, e.g. also in Wilson's disease, alpha-1-antitrypsin deficiency, alveolar echinococcosis etc. (Tab. 1, Fig. 2, Ref. 54.) PMID- 8689296 TI - [Chemoprevention of cancer]. AB - Chemoprevention, as one of the newest components of the fight against cancer, deals with various chemical compounds which can prevent the occurrence of malignant tumours. New experimental results achieved during the recent decades in the field of understanding of the process of carcinogenesis, have enabled a more rational approach to the prevention of normal cell malignization. It has been shown, that a number of investigated compounds are able to interact selectively with the particular phase (initiation, promotion, progression) of the multistep process of carcinogenesis. Activity of chemopreventive compounds can be evaluated by systematic analysis of various biomarkers in patients who are in high risk. The biomarkers include genetic markers (mutations, gene amplification), cellular markers (rate of proliferation), histologic markers (leukoplakia, metaplasia), or biochemical markers (blood level of various enzymes, or tumour antigens). The number of extensive clinical trials has recently increased and some positive results have been reported in the testing of various compounds preventing the appearance of some malignant tumours (breast, colon, prostate, etc.). The search for new, effective chemopreventive compounds might provide a valuable new tool aimed at the decrease in both cancer morbidity and mortality. (Ref. 37.) PMID- 8689297 TI - [Epidemiologic and microbiologic aspects of mycobacteriosis in Slovakia. M. avium complex]. AB - BACKGROUND: Mycobacteria belonging to M. Avium Complex (MAC) are strains very similar in structure and biochemistry but very different from the point of serology. OBJECTIVES: They are divided into 28 serotypes. The objective of the research is to describe the epidemiological situation in mycobacterioses caused by Mycobacterium Avium Complex in Slovakia and to compare it with the situation in the developed countries. METHODS: The study is methodologically based on the surveillance of tuberculosis and applied to the problem of mycobacterioses. RESULTS: During the period of 19 years we have registered in Slovakia 43 new cases caused by Mycobacterium Avium Complex. The number of new cases per year ranged from 0 to 4 cases. The majority of cases were males in permanent residence in Slovakia. 74.4% of them were from central and eastern Slovakia. CONCLUSIONS: Over the past 19 years the stabilized trend of incidence of mycobacterioses caused by Mycobacterium Complex has not changed. (Ref. 22.) PMID- 8689298 TI - [Crohn's disease and symptoms of appendicitis]. AB - Retrospective analysis of 47 patients surgically treated at the IInd Surgical Clinic LFUK due to Crohn's disease and its complications indicates that in 16.3% of patients the diagnosis of Crohn's disease was stated in coincidence with laparotomy which had been indicated due to the suspicion of appendicitis. The reasons of this situation, as well as the recommendation of surgical tactics are analysed. (Tab. 3, Ref. 11.) PMID- 8689299 TI - [Familial occurrence of tumors and developmental anomalies of the testis]. AB - BACKGROUND: Family occurrence ranks belong the factors followed in etiology and pathogenesis of germ-cell tumours of the testis. Its association with abnormal testicular development, respectively with other risk factors is relatively frequent. OBJECTIVES: The aim of this study was to indicate this coherence by means of case histories of author's patients and to propose further procedures. METHODS AND RESULTS: There were 535 patients treated for testicular cancer in the period of 1982-1994. Family occurrence was observed in 6 cases (1.12%), most frequently incombination with maldescensus testis. Individual families were analysed in detail, including HLA typization. Bilaterality of testicular cancer was observed in two brothers who were HLA identical. Other two brothers had the history of bilateral maldescensus testis, one of whom was subdued to bilateral orchiectomy in childhood, the other at the age of 16, a tumour in one testicle following orchidopexy performed in childhood. The history of maldesensus testis was observed in four members of another family, two of whom developed tumours. CONCLUSIONS AND MEANING FOR PRACTICE: Authors recommend supplementation of the initial examination of each patient with suspective testicular cancer with detailed family history aim at the occurrence of urogenital anomalies and tumours. General knowledge of the first-degree relatives about the possibility of family occurrence of tumours, and instructions for testicular self-examination are considered as the most suitable method from the stand point of secondary prevention. (Ref. 21.) PMID- 8689300 TI - Iatrogenic injuries of large vessels. AB - At the beginning of the article the authors emphasized that the frequency of iatrogenic injuries of great vessels is very high now. They draw attention to the damage caused in coincidence with invasive diagnostic or therapeutic methods. The iatrogenic injuries are brought about during extensive operations due to advanced tumors, during transplantations and extensive reconstructive or corrective operations. But even some simple and common operations are not protected from these complications. The authors present their series of 10 patients with iatrogenic injuries treated during the years 1989-1991. The submitted case reports indicate interesting aspects of these accidents. The conclusions show the importance and danger of these accidents, and also the possibility of incorrigible results being caused by incorrect steps. (Tab. 1, Ref. 14.) PMID- 8689301 TI - [Radiotherapy of chiasmal gliomas in children]. AB - Chiasmal gliomas are rare tumors occurring predominantly in children. Their treatment consists of surgery, radiotherapy and chemotherapy. Surgical removal can usually be only partial, and radiotherapy frequently follows. There are supporters of radiotherapy, as well as opponents. The author has been engaged in problems of optimal treatment of this entity for more than 10 years. He offers a review of knowledge provided by literature concerning radiotherapy of this disease in children. In the past he was enthusiastic for radiotherapy. Nevertheless after passing the Postgraduate course in paediatric neurosurgery in Bonn (1989), where J.F. Hirsch demonstrated very pessimistic progressive long term harmful sequellae of irradiation of the developing child's brain, the author has re-evaluated his attitude to this therapy. The short history and basic physical principles of radiotherapy are reviewed. Some new trends of this therapy are also mentioned (hyperbaric oxygenation, radiosensitizing agents, hyperthermia etc.). Great attention is paid to the deleterious adverse effects of radiotherapy and to the possible technical parameters enabling to avoid them (optional daily fractions, optimal total dose, limiting age in infants etc.). Harmful effects of radiotherapy are reviewed in detail. The most frequent are chronic sequellae: brain atrophy, radiation-induced brain necrosis, progressive intellectual deterioration, growth retardation, panhypopituitarism, galactorea, learning disabilities, moya-moya syndrome, radiation-induced secondary brain tumors (especially gliomas). Risks of radiotherapy combined with chemotherapy are also emphasized. Nevertheless radiotherapy has remained an important therapeutical measure in the treatment of chiasmal gliomas in children with progressive disease in cases when surgery and chemotherapy have failed. PMID- 8689302 TI - [Diagnosis of renal tumors with percutaneous biopsy]. AB - The authors describe four, out of 506 cases of renal biopsies in which this diagnostic procedure enabled to reveal a tumour. Two cases of tumours which were intentionally subdued to renal biopsy justified an angiomyolipoma and a focus (metastasis) of tubulopapillomatous carcinoma) in the kidney. In one case the renal biopsy revealed renal infiltration thus enabling to state the diagnosis of chronic lymphatic leukaemia subsequently, and in the last case where the diagnosis of chronic lymphatic leukaemia had been stated in advance, the renal biopsy was performed due to suspective glomerulonephritis. In these cases the unexpected results of renal biopsy were of great diagnostic value. Such intentional use of biopsy is rare. (Fig. 3, Ref. 6.) PMID- 8689303 TI - [Endoanal transrectal ultrasonography in the diagnosis and care of patients with rectal carcinoma]. AB - Endoanal sonography in rectal tumor is diagnostically significant. This method helps to specify the prognosis of patients with malignant rectal tumor. Endoanal sonography examination before the operation corresponds with postoperative histopathological findings (endoanal sensitivity uT--91.6%). The method is most important during the follow-up of patients after surgery and in ascertainment of local recurrence (endoanal sensitivity recidivation uT--86%). The authors present their experience with 402 patients. The advantages of endoanal transrectal sonography are possibilities of determination of staging the tumors which can not be reached physically, information of the way of spreading and penetration depth of the tumor, information about their growth, simplicity and easy repetition of the process and economical convenience. (Tab. 2, Fig. 2, Ref. 14.) PMID- 8689304 TI - [Heart transplantation--one possibility in the treatment of advanced congestive heart failure]. AB - The authors present epidemiological data about congestive heart failure, its most common etiology and prognosis. They justify the performance of heart transplantation (HTx) in the treatment of congestive heart failure. They analyze the present state of HTx in the world and describe also the history of HTx in Slovakia. They present the review of contraindications and indications for the inclusion of recipients into the HTx programme and describe the further fates of these patients. They regard the HTx as an integral component of the therapeutical approach to the precisely defined group of patients with otherwise refractory congestive heart failure. (Tab. 4, Fig. 6, Ref. 38.) PMID- 8689305 TI - [The effect of age and risk factors on postoperative complications and mortality in patients with surgery for colorectal carcinoma]. AB - The authors analyzed the risk factors and their impact on perioperative complications and mortality in aged patients electively operated due to colorectal cancer at the II. Surgical Clinic LFUK in Bratislava during the period from January 1, 1986 to October 31, 1994. The patients were divided into three groups according to WHO criteria, those younger than 65, from 65 to 75, and older than 75 years of age. The results are in correlation with the data published in literature. According to the accomplished results the age per se does not represent contraindication to surgical intervention. However, the lethality in the aged patients with two or more risk factors significantly increases. In regard to the latter the authors recommend a strictly individual consideration as to whether these patients would benefit more from palliative therapy procedures as to life prolongation and its quality improvement. (Tab. 5, Ref. 25.) PMID- 8689306 TI - [Hylacombun in inflammatory bowel diseases]. AB - Treatment of non-specific bowel inflammation (NBI) particularly of Crohn's disease (MD) and ulcerative colitis is very complicated, especially because of the fact, that in spite of atrial successful findings, the etiology of both main diseases of this group remain unknown. Nevertheless, manifestations, particularly in MC vary, often unexpectedly and surprisingly. Different medical teams elaborate therapeutic schedules, but none of them has been accepted world-wide. As it is still possible to state that NBI is untreatable by drug therapy, even the surgical removal of the affected part of the bowel does not protect against the relapse, it may indicate that no therapeutical approaches are sufficient at present. Using drug therapy, the biochemical chain of numerous inflammatory mediators is being tried to be disrupted. Despite the advances achieved, there are still many difficulties related to drug therapy. It is necessary to take into account the fact that the lack of knowledge in causative therapy and failure, poor response to initial therapy lead to the use of more new drugs. Therefore a careful consideration of every used or recommended drug is necessary. The principle of using Hylacombun (Merckle) in therapy was not applied due to the presumption of influencing the disease fundamentally, but due to an effort to reduce some symptoms of the disease, which deteriorate the life quality of patients. Data given by patients in questionnaires as well as biochemical and haematological parameters were evaluated statistically. Besides the commonly used Student t-test, we used Box and Whisker plots, linear trend analysis and the method of 9 aggregation numbers to follow both dynamics of the disease and drug effect. Laboratory, as well as the questionnaire data were equilibrated and graphically illustrated by the spline method. We found out that Hylacombun was effective in all patients. Subjective improvement was shown after 10 days of therapy, stabile improvement after 2 months. (Tab. 3, Fig. 7, Ref. 9.). PMID- 8689307 TI - [Treatment of choledocholithiasis in the era of laparoscopic cholecystectomy]. AB - Laparoscopic cholecystectomy (L-CHE) is currently considered to be the optimal standard in the therapy of cholecystolithiasis. However, it is choledocholithiasis which is problematic, especially the timing of the solution in relation to L-CHE. In general, the opinion predominates that in preoperatively verified choledocholithiasis the ERCP with EPS and extraction of choleliths should be performed 24-28 hours prior to the elective L-CHE. Surgical removal of choleliths from the main biliary ducts indicated only in a small group of patients. The authors of the study reflect upon the current trends of the choledocholithiasis therapy in the era of laparoscopic cholecystectomy. They present their own set of patients and recommend the procedure of the choledocholithiasis therapy concommitted with cholecystolithiasis with the subjective of the full use of endoscopic methods in the therapy of this disease. (Ref. 14.). PMID- 8689308 TI - [The role of Prof. Frantisek Subik in the development of pathology in Slovakia]. PMID- 8689309 TI - [Activation of the neuroendocrine system during changes in homeostasis during stress conditions]. AB - Neuroendocrine response to stress stimuli is aimed to maintain body homeostasis. The activation of the neuroendocrine system is accomplished mainly by two ways: by feedback regulation based on the recognition of altered metabolic homeostasis by appropriate receptors sending the signal into the CNS, and by forward regulation involving a direct stimulation of the neuroendocrine system by a central command coming from an activated brain regulatory center. With regard to mechanisms of neuroendocrine activation, the signal specificity and site of its origin are of particular importance. The significance of the signal in neuroendocrine responses has been evaluated in three different stress conditions: hypoglycemia, surgical trauma and dynamic physical exercise. The stimulus inducing neuroendocrine response during hypoglycemia is the glucopenia. The signal for the activation of the neuroendocrine response is generated in glucosensitive cells which are not located in a single brain structure (hypothetical glucostat). The signal for growth hormone, vasopressin and oxytocin release is produced in brain structures protected by the blood-brain barrier, that for ACTH release in regions both protected and unprotected by the barrier, while the signal for prolactin release is generated in tissues lacking the blood brain barrier. The neuroendocrine response during surgical trauma is activated by a signal formed in the damaged tissue reaching the CNS by neural pathways. Moreover, cytokins may participate on endocrine stimulation in those surgical interventions in which a large amount of bacterial endotoxins is released. During a complicated surgery, e.g. during a bypass other signals and modifying factors, such as hypothermia, dilution of blood, hypoperfusion of organs, rewarming of the body and hormone degradation in the oxygenator are important. On the On the other hand, during a short-term dynamic exercise, a forward regulation by a central signal from the activated CNS motor center comes into play with the consequent release of catecholamines, growth hormone, etc. In the control of some other hormones (beta-endorphin, partly ACTH) and especially during a long term exercise, neural signals from working muscles (feedback) are also involved. During a static exercise mainly catecholamines triggered by signals from working muscle cells are activated. The understanding of the signal and mechanisms of neuroendocrine activation during stress is indispensable for selective modulation of physiological and pathological responses. PMID- 8689310 TI - [New approaches in the evaluation of sympathoadrenal system activity during periods of rest and stress]. AB - The sympathoadrenal system (SAS) activity in mammals has usually been evaluated by measuring plasma and urinary catecholamine (CA) levels. The aim of this work was to explain theoretically and to demonstrate practically in own experiments new methods for evaluation of SAS activity. Nowadays methods are available which estimate not only plasma levels of CA but also CA release, spillover, reuptake, degradation, and also in vivo CA synthesis by determination of plasma dihydroxyphenylalanine (DOPA) levels. In our experiments simultaneous measurements of plasma CA, their precursor DOPA, the deaminated metabolites dihydroxyphenylglycol (DHPG) and dihydroxy phenylacetic acid (DOPAC), and the O methylated metabolites normetanephrine (NMN), methoxyhydroxyphenylglycol (MHPG) and homovanillic acid (HVA) were performed in humans and rats during basal and stress conditions. Plasma CA levels are determined by the rate of CA spillover into the bloodstream and by plasma CA clearance. Immobilization stress(IMO) markedly increased plasma noradrenaline (NA) levels but NA spillover was less elevated because the NA clearance was reduced in IMO rats. Dissociation between changes of plasma NA and DHPG levels can indicate changes in neuronal reuptake of NA. We found such a dissociation in humans during bicycle ergometry suggesting a reduced NA reuptake. DOPA circulates in plasma at higher levels than NA. During stress, increased sympathoadrenal outflow stimulates DOPA synthesis and release into the circulation supporting the view that changes in plasma DOPA levels reflect in vivo changes in CA synthesis. Thus, the presented data demonstrate the importance of simultaneous measurement of plasma CA levels, CA synthesis, release, reuptake, and degradation for evaluation of SAS activity in basal and stress conditions of the organism. (Fig. 10, Ref. 56.). PMID- 8689311 TI - [Effect of infusion of hyperosmolar mannitol on left ventricular function in essential hypertension]. AB - The left ventricular function of the heart was examined by means of the method of equilibrium-radionuclide ventriculography in 40 patients with essential hypertension (EH)--20 patients in stage I (H1), 20 patients in stage II (H2) according to WHO criteria--and in 18 normotensives (N). The examination was performed at rest and immediately after stress by intravenous infusion of hyperosmolar mannitol. At rest, the parameters of global systolic and diastolic functions of the left ventricle in normotensives do not differ significantly from the values in both groups of hypertensives. The global ejection fraction (GEF), peak ejection rate (PER) and peak filling rate (PFR) were in H2 significantly lower than in H1. Sectorial ejection fraction (SEF) in the apicoseptal area is in H2 significantly lower than H1 and N. After infusion of hyperosmolar mannitol the GEF and PFR increased in N and H1 only. When comparing all groups after infusion of mannitol the PFR in H2 is significantly lower also in comparison with N with the tendency (significant limit) to lower values of GEF and PER. PER and PFR were significantly lower and the end-diastolic volume (EDV) was significantly higher in H2 in comparison with H1. SEF was significantly lower in H2 in comparison with N in 3 out ot 9 sectors and in comparison with H1 in 8 out of 9 sectors. The infusion of hyperosmolar mannitol reveals subclinical disturbances of the diastolic and partially also of the systolic function of the left ventricle in stage II of EH which is very useful for diagnosis and treatment. (Tab. 4, Fig. 3, Ref. 22.). PMID- 8689312 TI - [Comprehensive prevention of postoperative thrombosis]. AB - Thromboembolic disease with its high mortality and morbidity is currently one of the most serious postoperative complications. Its occurrence in high-risk patients in surgical wards is 25-50%. Since 1979, the authors have examined 160 risk patients in whom no prevention had been performed. In this group of patients they detected the occurrence of profound venous thrombosis by means of the accumulation fibrinogen test, targeted phlebography under skiascopic control. At the same time the clinical symptomatology was followed in detail. Since the thrombosis is a multifactorial process, the effective preventive measure must affect and normalize as many disturbed homeostatic processes as possible. Into the group of 176 high-risk patients, the authors introduced a complex prevention into surgical routine residing in classical low-dose heparinization by 5000 u.s.c. with the first dose administered 1 hours prior to surgery, preoperational haemodilution with the administration of minimally 500 ml of Dextran and in preoperation administration of antiaggregants (Acylpyrin). by means of this tactic, the greatest antithrombotic effect is brought about preoperatively and in the first postoperative hours while the patient is protected minimally 5 to 7 postoperative days. Both preoperative and postoperative procedures are monitored by means of a complex haemocoagulation examination of the basic 10 haemocoagulation factors. The occurrence of thrombosis in patients without prevention with minimally 5 thrombogenetic risk factors during the control by means of the accumulation fibrinogen test was 32.4% and during the control by means of targeted phlebography is 24%. The differences are not statistically significant. In the group of patients with prevention the occurrence is 5.6%. In this group the screening is represented by the accumulation fibrinogen test and its positivity is verified by its localization by means of selective phlebography. The occurrence of deep vein thrombosis in the group with prevention and in the control groups statistically highly significant p > 0.0005. Haemocoagulation examination is aimed at the determination of the normalization impact of prevention on the state of hypercoagulation ability associated with the depression of spontaneous fibrinolysis in patients without prevention. The thrombi detected in patients with prevention are localized in short segments of crural veins. Clinically more significant bleeding in the group of patients with prevention occurred only in 2 patients, i.e. in 1%. Complex multifactorial prevention is not only simple and safe for patients, but also highly effective in the group of patients with high risk of postoperative thrombosis. The clinical diagnosis is unreliable and misleading with low sensitivity and specificity. (Tab. 2, Fig. 2, Ref. 28.). PMID- 8689313 TI - [The time factor in cauda equina syndrome]. AB - Cauda equina syndrome is a rare but potentially catastrophic complication of lumbar disc disease. In spite of properly performed surgical decompression, the outcome is mostly unsatisfactory. One of the important factors influencing the recovery of motor function of the lower extremities, sensation, bladder and rectum control, sexual function, as well as working ability is thought to be the duration of cauda equina compression. The evaluation of data obtained in a group of 58 persons (21 women and 37 men) operated upon for discogenic cauda equina syndrome in the period of time from January 1, 1982 to December 31, 1991 did not confirm this opinion. (Tab. 7, Ref. 23.). PMID- 8689314 TI - [Changes in the epidemiology of human leptospirosis in the Slovak Republic]. AB - BACKGROUND: The epidemiologic patterns of infectious diseases are liable to change in the course of time. References to such changes in leptospirosis are very rare and of low systematic value. OBJECTIVES: The study is aimed at the detection of changes in the epidemiology of leptospirosis within the 20 years in Slovakia. METHODS: Basic epidemiologic characteristics of leptoospirosis were compared within two chronological periods. 598 registered cases were analyzed during the first period (1970-1976), and 200 cases of leptospirosis were analysed during the second period (1986-1991). MAIN RESULTS: The second period yielded a decrease in total incidence to approximately 50% (yearly average was 0.9/10(5) of the population). At the same time the cyclic character of morbidity has almost entirely disappeared. The incidence of leptospirosis has significantly decreased in the group of population between 40 and 59 years of age, thus causing a particular shift in morbidity towards the younger population. Cases of leptospirosis caused by L. tarassovi and L. canicola ceased to occur, however one case of infection caused by L. hardjo has been registered in the Slovak population. A significant decrease in the incidence of diseases caused by the Sejroe group serovars was detected, especially in housewives, retired people, industrial and agricultural workers. In contrast to the latter, the proportion of leptospirosis cases caused by L. icterohaemorrhagiae/copenhageni increased particularly in pupils and students, as well as those caused by L. pomona in slaughter-house workers. Consequently, the most dominating disease is represented by field fever (L. gripotyphosa), the second highest incidence is ascribed to Weil disease (L. icterohaemorrhagiae/copenhageni), while the incidence of infections caused by the group of Sejroe serovars dropped from the first to the fourth place. The possible reasons of these changes are presented. No changes in the incidence of leptospirosis according to sex and seasonal occurrence were registered. CONCLUSION: The results of this study are in accordance with the current knowledge of the development of epidemiologic signs of infectious diseases, including leptospirosis. The results provide a pattern of the current situation in the field of leptospirosis epidemiology in the territory of Slovakia and emphasize the importance of systematic surveillance enabling the assessment of appropriate measures suppressing these infections. (Fig. 7, Ref. 7.). PMID- 8689315 TI - [Triple combination antimicrobial therapy of Helicobacter pylori and basal levels of serum gastrin]. AB - BACKGROUND: The etiopathogenic relationship of Helicobacter pylori (HP) infection to chronic active antrumgastritis and peptic ulcer disease has been confirmed by a number of studies. The key role in the development of peptic lesions belongs to hypergastrinemia. This is supposed to be related to ammonium synthesis in the antral area influenced (promoted by HP and resulting in interruption) weakening of the negative feedback mechanism maintaining intraluminal acidity. OBJECTIVES: In our present study we focus our attention to the effectiveness of triple antimicrobial therapy in HP positive patients with chronic active antrumgastritis residing in the lowering of the level of serum gastrin. METHODS: There was a group of 15 patients in our current study with HP positivity as well as chronic active antrumgastritis documented by endoscopy, histology, microbiology and serology respectively. Endoscopical and histological findings were classified according to "The Sydney System". The whole group was evaluated on an ambulatory basis, those with active ulcer, endocrinopathy and biliary tract disorders were excluded. The basal level of serum gastrin was evaluated by RIA-test-gastrin before and after successful antimicrobial therapy. RESULTS: In our group of 15 patients with HP infection in coexistence with chronic active antrumgastritis we have found a significant decrease in the basal level of serum gastrin (p = 0,01) after successful therapy. CONCLUSION: The decrease in the basal level of serum gastrin after eradication of HP confirms the importance of HP infection in the pathogenesis of peptic lesions in stomach and duodenum. We consider the antimicrobial therapy in chronic active antrumgastritis in HP positive patients to be a fully indicated therapeutic approach. (Tab. 1, Fig. 1, Ref. 10.). PMID- 8689317 TI - [Intracoronary pressure and its significance in the clinical evaluation of patients with ischemic heart disease]. AB - Assessment of coronary artery disease is a highly relevant problem in current cardiology. Although, coronary angiography still remains the ultimate diagnostic test to prove the presence of coronary narrowings, it is increasingly becoming obvious that a refine understanding of the atherosclerosclerotic lesions and its consequences on perfusion of the underlying myocardium requires much more than just the silhouette of the arterial lumen provided by contrast angiography. This knowledge together with the current therapeutic invasive approaches has led to the introduction of new invasive methods to demonstrate the haemodynamic significance of a given lesion. In this brief review we describe the importance, feasibility and usefulness of transstenotic pressure gradient measurements. Furthermore, we provide the description of myocardial fractional flow reserve as a new functional index for the assessment of the coronary stenosis severity and its effects on maximal myocardial perfusion. This index, by interpreting the transstenotic pressure gradient in combination with mean aortic and central venous pressure offers a complex and easy assessment of coronary haemodynamics. On the basis of our recent experience we discuss the applications of the presented concept in daily clinical practice. (Tab. 3, Fig. 4, Ref. 25.). PMID- 8689316 TI - [Antioxidative enzyme activity in the blood of healthy persons]. AB - BACKGROUND: Under physiological conditions the dynamic balance between the reactive oxygen production and detoxication is maintained. OBJECTIVES: The study was aimed at the detection of the activity of antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) in erythrocytes and the level of malondialdehyde (MDA) in the serum of healthy subjects, their relation to age, body weight, sex, smoking, and the possible correlation between individual parameters. METHODS: The authors have examined 128 healthy volunteers (57 men and 71 women) from 20 to 72 years of age. The results were statistically evaluated by means of the ANOVA programme. RESULTS: The group of healthy people had a large dispersion of interindividual activities of antioxidant enzymes and MDA levels. Age and weight were reversely correlated to the CAT activity in erythrocytes. The CAT activity was significantly higher in women than in men, and the GPx activity was lower in smokers than in non-smokers. The rest of investigated parameters were not significantly influenced by sex of examined people and smoking. Mutual correlation between individual enzymes were highly significant. CONCLUSIONS: A large dispersion of activities of the investigated enzymes and MDA levels in healthy individuals do not allow to make a standard use of these parameters in clinical practice. (Tab. 5, Fig. 2, Ref. 20.). PMID- 8689318 TI - [Aneurysms of the extracranial supraaortic vessels--8 years' experience]. AB - BACKGROUND: There has been an obvious evidence of a rising incidence of the supraaortic arteries aneurysms during the last 10-15 years. It is probably the consequence of both improved diagnostics and surgical technique. MAIN PURPOSE AND STARTING POINTS (OBJECTIVES). Because of a relatively high incidence of this group of aneurysms the authors of this paper analyzed their own patients population. METHODS: From 1st Jan. 1987 to 31st Dec. 1994 10 patients were admitted 10 patients with altogether 11 supraaortic trunk aneurysms. Last year 5 patients with 5 aneurysms (45 percent) were admitted. The mean age of all patients was 57.5 (20-88) years. The mean age in the group of carotid artery aneurysms was 75.2 (71-88) years, and 31 (20-43) years in the group of subclavian artery aneurysms, respectively. Both carotid and subclavian arteries aneurysms were managed by the same technique--aneurysm resection and graft interposition. There were two exceptions. One of them was a young woman with a small asymptomatic subclavian artery aneurysm in connection with the thoracic outlet syndrome. The aneurysm has been left in its place and followed up. The second exception was a young man with a posttraumatic false aneurysm of the intrathoracic part of the right subclavian artery. He died without surgery because of massive haemorrhage due to the a false aneurysm rupture. MAIN RESULTS: The hospital mortality of the group of operated patient was zero. There has been one head nerve injury in this group and 100 percent immediate patency, as well. All patients have been followed up. There have been found an asymptomatic internal carotid artery occlusion, the rest of reconstructions has been functioning. CONCLUSIONS: The aneurysms of the extracranial supraaortic arteries are rare vascular lesions. They have, however, a high incidence of unfavorable sequelae, most of them of neurologic nature. The authors emphasize the importance of proper diagnosis and early surgical intervention in selected cases put into the hands of an experienced vascular surgeon. (Tab. 2, Fig. 1, Ref. 17.). PMID- 8689319 TI - [Characteristics of multiresistant gram-negative bacteria and their occurrence at the Medical School Hospital in Olomouc]. AB - Currently, a persistent growth of bacterial resistance to antibiotics takes place. Multiresistant bacterial strains thus represent a serious danger for therapy in practice. The aim of the study was to characterize the multiresistant Gram-negative bacteria and to judge their antibiograms by using the minimum inhibition concentrations (MIC). At the same time the study evaluates the relations to the most frequent diagnoses and epidemiologic data concerning the occurrence of these strains in different clinical cases treated at individual departments of the Faculty Hospital in Olomouc. Out of the total of 4.988 strains of Gram-negative rods, the number of isolated multiresistant strains reached 316 (6.3%). Individual bacterial species were isolated in the following order: Pseudomonas aeruginosa (28.8%), Enterobacter cloacae (23.4%) and Acinetobacter Baumannii complex (Acb complex) (18.7%). The most frequent occurrence of investigated bacteria was registered at the departments in the following order: urology (45.9%), internal medicine (18%), paediatrics (13.6%), and surgery (11.1%). The most frequent diagnoses based on positive cultivation of these bacteria were the infections of the urogenital tract (53.8%), postoperative infections (16.8%), and the infections of the upper respiratory ducts (7.3%). 64.2% of strains were cultivated from urine, 16.1% from pus, and 6.9% from swabs taken from the upper respiratory ducts. (Tab. 8, Ref. 18.). PMID- 8689320 TI - [Epidemiologic and microbiologic aspects of mycobacteriosis in Slovakia]. AB - Mycobacterioses are diseases caused by mycobacteria other than those that induce the classical tuberculosis: M. tbc (previously to as "human" type) and M. bovis (previously to as "bovine" type of mycobacteria). The purpose of this paper is to confront the limited knowledge about the epidemiology of this disease abroad with the information obtained in Slovakia. The methodology of this paper is based upon the surveillance of tuberculosis as applied on mycobacterioses. Pulmonary mycobacteriosis caused by M. kansasii was diagnosed in 51 subjects in Slovakia within the period 1979-1993: 47 men and 4 women. The average age of men was 47 and of women 55 years. The highest incidence of the disease was observed in Central Slovakia (25 subjects), followed by Eastern Slovakia (18 subjects) and Western Slovakia (8 subjects). Geographic distribution coincides with the profession of Slovak miners who work either in the Slovak mining area or in Ostrava-Karvina mining complex. Miners accounted for 20 out of 51 patients. Apart from preventive measures applied in tuberculosis caused by M. tbc, it is vitally important to pay great attention to the prevention and treatment of pneumoconioses and chronic obstructive bronchitis. Both miners and heavy smokers should avoid working in an environment where M. kansasii is present. Examinations within the focus of the disease should be targeted at the working environment (Ref. 13.). PMID- 8689321 TI - [Atypical infection caused by Microsporum gypseum mimicking circumscribed scleroderma]. AB - The authors describe a case of a 31 year old woman who suffered from sclerodermia circumscripta on her right leg. The diagnosis was histopathologically verified. Capillaroscopy and respiratory obstruction were positive. A new lesion appeared on the right arm thus imitating morphea. However, by means of mycological examinations Microsporum gypseum infection was recognized. (Fig. 3, Ref. 13.). PMID- 8689322 TI - [Changes in thermoregulation and age. Hypothermia and hyperthermia]. AB - The author presents a review of changes in thermoregulation in various ages. The changes at infant and older ages are compared in contrast to thermoregulation in healthy adults. Hypothermia occurs in all age groups, especially in the aged. Then it is determined by both low temperature of environment and impairment in production and expenditure of heat despite the normal environment temperature. A special form of hypothermia is represented by intraoperative hypothermia in the course of surgical performance under general anaesthesia. Hyperthermia occurs most frequently as heatstroke in consequence of high environmental temperature. The author presents etiopathogenesis and pathomechanisms, possible treatment and prevention in thermoregulation disturbances. (Tab. 6, Ref. 79.). PMID- 8689323 TI - [Immunopathogenic mechanisms in autoimmune processes: autoantigens]. AB - The primary function of the immune system is the recognition of the organism's own structures (self) which are to be tolerated, and alien structures (non-self) which are to be eliminated. In some cases, however, the immune mechanisms react against their own structures thus resulting in autoimmune processes which lead to autoimmune diseases. The paper analyzes the problem of autoantigens (sequestered, modified, cross-reacting), superantigens and the problem of cryptic determinants in the development of autoimmune processes, namely on the basis of the loss of the central or peripheral tolerance. (Tab. 4, Fig. 5, Ref. 38.) PMID- 8689324 TI - [Levels of erythrocyte glutathione and ceruloplasmin and transferrin in the serum and their role in antioxidant protection]. AB - All organisms are protected from harmful reactive oxygen which is produced also under physiological conditions by a complex antioxidative system. Our work was aimed at the ascertainment of the level of reduced and oxidated glutathione in erythrocytes of healthy people, the concentrations of ceruloplasmin (GSH) and transferrin (GSSG) in the serum, as well as the investigation of the relationship to antioxidative enzymes ---Cu, Zn-superoxide dismutase (SOD), catalase (CAT) and Se-glutathione-peroxidase (GPx) in erythrocytes. We discovered a mutual direct linear correlation between the levels of GSH, GSSG, CPL and TRF, indirect linear relation between the concentrations of TRF, GSH, GSSG and activities of SOD and GPx, between the concentrations of CPL and GPx activities, and a direct linear relation between concentrations of GSH and TRF with CAT activity. The results indicate to a mutual dependence of investigated nonenzymatic antioxidative factors and antioxidative enzymes. (Tab2, Fig. 4, Ref.13.). PMID- 8689325 TI - [Surgery in patients with organ transplants]. AB - Patients after successful transplantation with immunosuppressive therapy form a "new circle of surgical patients" who can develop various surgical diseases, or injuries which bring about an inevitable urgent or planned surgical treatment. The authors present the results in three patients with transplanted organs (1993 1995) who were subdued to various surgical treatments. The first patient underwent a classical cholecystectomy, choledochotomy, and extraction of concrement from the choledochus after orthotopic transplantation of the heart. The second patient underwent transplantation of the kidneys precedingly to bilateral subtotal resection of both lobes of the thyroid gland due to marked bilateral nodal goitre intervening deeply retrosternally with a severe pressure syndrome on trachea and oesophagus. The immediate and long-term results were excellent. Orthotopic transplantation of the heart in the third patient preceded to intercostal drainage of the thorax and evacuation of pus due to an extensive empyema of the thorax and septic state, and later thoracotomy and decortication with extirpation of the substantial part of the empyema sack was performed with an excellent immediate and long-term effect. The authors present the principles which must be inevitably fulfilled in coincidence with successive surgical treatment in patients with transplanted organs in a permanent immunocomplex regime. (Fig 2, Ref. 11.) PMID- 8689326 TI - Vascular complications in reconstructive and replantation surgery. AB - Authors deal with the causes of complications in reconstructive and replantation surgery of the hand. The most common complications are of vascular origin. Early revision, removal of all devitalized tissue and autoplastics of arteries and veins combined with ATB treatment contribute to their successful management. (Fig. 7, Ref. 6.) PMID- 8689327 TI - [Imaging of the transplanted liver]. AB - The study brings about the newest information on possibilities of imaging the liver, its vessels, biliary ducts and further organs in coincidence with liver transplantation. (Fig. 7, Ref. 39.) PMID- 8689328 TI - [Treatment of fractures of the lower cervical spine (C3-C7)]. AB - Spinal surgery dealing with reparation of injury consequences by stabilisation implantates is a relatively new surgical branch. The experience and results at individual departments in Slovakia in this field differ significantly as to their qualitative degree. The Trauma Surgery Department IVZ in Bratislava and the National Rehabilitation Center in Kovacova cooperate since 1989 in a mutual spinal programme. 177 out of 189 patients survived after undergoing a surgical treatment due to the injury of the lower cervical spine performed from 1988 to 1994. 68 patients (Frankel A, B, C) were included into the spinal programme. The authors present the therapeutical results evaluated according to morphologic, neurologic, functional and subjective criteria. The most frequently used stabilizing method is the so-called method of Caspar and the technique of Morscher, the latter being less frequently applied. Both methods are fully secure, causing minimal blood loss, perfectly stable as to the angle and axis. Both techniques enable a sufficient approach to the decompression of the spinal cord. Since they do not demand any additional external rigid fixation, they are excellently tolerated by patients and only minimally restrict movement. (Tab. 2, Fig. 4, Ref. 8.) PMID- 8689329 TI - [Laparoscopic cholecystectomy versus classical cholecystectomy]. AB - The authors evaluated the results after classical (CCHE) and laparoscopic cholecystectomies (LCHE) in the period from March 16 1994 to June 30 1995. In this period they operated on 408 patients, out of which 208 were operated by the laparoscopic technique. There were no differences in postoperative morbidity. The mortality after laparoscopic surgery was 0% and the classical cholecystectomy reached the morbidity of 1.4%. Complicated patients were usually operated in the classical way. The time of hospitalisation after LCHE was 5.2 days and after CCHE 8.3 days. The results of LCHE were as follows: morbidity 10.5%, conversions 2.4%, reoperations 1.4%, and no leakage of the bile duct. We saved 40% of costs using LCHE. All these facts show that LCHE is advantageous, secure and well tolerated by patients. The patients prefer comfort after the operation, good cosmetic effect and a short hospital isation. CCHE did not lose its position, especially in complicated cases. (Tab. 5, Ref. 21.) PMID- 8689330 TI - [Clinical diagnosis, special characteristics and therapy of Buerger's disease]. AB - Some authors still doubt that the Buerger's disease is an independent disease entity and differs principally from obliterating atherosclerosis. This is why the author draws attention to many specific characteristics of this disease and differences which distinguish it from atherosclerosis of peripheral arteries. After some introductory notes the author presents that the prevalence of thrombangiitis in Europe ranges from 0.5 to 2% out of all ischemic diseases of limbs, while in Japan it reaches 20-30%. Previously the ratio of affliction of men and women was 100:1; presently some authors present the ratio being 10:1. The upper limbs are usually afflicted by this disease much more often than by obliterating atherosclerosis, and frequently already at the beginning of the disease. The main and only proved risk factor is smoking. However a predisposition is necessary (the predisposition is more frequent in the yellow race). The Buerger's disease is an autoimmune disease responding to the antigen antibody complex. Laboratory results are positive in coincidence with inflammatory markers, especially in recurrent cases. Histology appoints to inflammatory vascular lesions, sometimes accompanied by a positive finding of IgG deposits, IgM, and immunocomplexes. Clinically, particularly peripheral vessels are afflicted, the disease is initiated usually before 40 years of age and is of a typical arteriographic pattern. It is also characteristic for its migrating phlebitis. The clinical picture has some specific features. The disease can be localized also in the coronary, cerebral and visceral arteries. Besides the general procedures in ischemic diseases of the limbs, the therapy must necessarily, respect also some particulars, as e.g. antiinflammatory therapy (antibiotics, antirheumatics, corticoids) and some specific surgical procedures. (Ref. 75.) PMID- 8689331 TI - [Crohn's disease in the adult population in Slovakia]. AB - The requirement of preparing a fundamental epidemiological study concerning the incidence of Crohn's disease in Slovakia became very important after the splitting of Czecho-Slovakia. The authors in cooperation with the regional gastroenterologists present the study concerning the incidence of this inflammatory bowel disease in the Slovak Republic up to 30th April 1994. The multidimensional Kruskal-Wallis test for analyzing statistical differences in incidence of Crohn's disease according to age, sex, and regions was used. Cluster analysis was used for investigation of the regional differences. This study has shown that there is 6.75 cases of Crohn's disease per 100 000 inhabitants in Slovakia. There are no differences in incidence rate of Crohn's disease between the regions. There are differences between the districts: some of districts have both, absolutely and relatively high number of cases, and in another districts, young people are more involved in the analysed disease. The highest age specific incidence rate of Crohn's disease was between 30-49 years. (Tab. 1, Fig. 7, Ref. 14.) PMID- 8689332 TI - [Results of long-term follow-up of surgical treatment of pulmonary metastases of testicular germ cell tumors]. AB - The authors analyse 34 cases of surgeries performed due to residual pulmonary metastases with germinative testicular tumours. Good results in the length of survival are ascribed to thoracotomy, or sternotomy with the resection of metastatic foci, i.e. the only method which reliably ascertains the biological nature of residual pulmonary lesion after chemotherapy. (Tab. 1, Fig. 2, Ref. 17.) PMID- 8689333 TI - [EuroTransMed--physician training via satellite]. PMID- 8689334 TI - Evaluation of the minimally prolonged APTT: Passovoy factor or lupus anticoagulant? PMID- 8689335 TI - Intrathecal leucovorin after intrathecal methotrexate. PMID- 8689336 TI - Pediatric phase I drug tolerance: a review and comparison of recent adult and pediatric phase I trials. AB - PURPOSE: We evaluated the ratio of pediatric to adult maximum tolerated doses (MTDs) from 70 Phase I studies conducted between 1975 and 1995. The aim of this study was to determine whether previously observed differences in drug tolerance between adult and pediatric Phase I patients have persisted over the 20-year period of this analysis. PATIENTS AND METHODS: Phase I trials of pediatric and adult patients with solid tumors as the predominant diagnosis and sharing similar dosing regimens were evaluated. For consistent comparison between Phase I studies, the MTD was defined as the drug dose one level below that yielding dose limiting toxicity in >30% of patients. The ratio of pediatric to adult MTDs was calculated and plotted chronologically by year of pediatric study closure. Statistical evaluation of MTD ratios included regression and correlation analysis. The extent of therapy before Phase I study entry was also examined. RESULTS: Ninety-three Phase I studies were reviewed. Twenty-one drugs (70 studies) met our criteria for paired review of MTDs and analysis of the variation of ratio with time. The pediatric to adult MTD ratios ranged from 0.4 to 2.8, with a median of 1.2. Regression analysis of the ratio of MTD versus date of pediatric study closure supports a linear relationship of decreasing ratio with time (p<0.01). Analysis of the regression line predicts MTD ratios of 2.02 and 0.76 for 1974 and 1995, respectively. Of patients included in this analysis, 37.1% and 68.6% of adult and pediatric patients, respectively, were considered to have been heavily pretreated before study entry. A significant (p<0.001) downward trend with time was observed in the proportion of adult patients entering Phase I studies who had received both radiation and chemotherapy. CONCLUSIONS: The results of this review continue to show an equal or greater drug tolerance in the pediatric population when compared with adult patients for most drugs studied during Phase I trials. However, there appears to be significant trend of decreasing differences in drug tolerance between pediatric and adult Phase I patients with time, as defined by the descent of the MTD ratio toward values <1.0. Mechanisms to explain greater drug tolerance in children and the observation of decreasing maximum tolerated dose ratios with time are discussed. Limited data suggest that changes in degree of therapy before Phase I study entry may be influencing the MTD ratio. PMID- 8689337 TI - Outpatient therapy with ceftriaxone and oral cefixime for selected febrile children with sickle cell disease. AB - PURPOSE: Children with sickle cell disease are at increased risk for bacterial sepsis and, when febrile, are usually hospitalized for intravenous antibiotic therapy pending results of blood cultures. In this study, we prospectively identified a group of febrile patients with sickle cell disease who were at low risk for sepsis and treated them with outpatient therapy. PATIENTS AND METHODS: Children identified as low risk for sepsis were treated with an initial dose of intravenous ceftriaxone, followed by outpatient therapy with oral cefixime, and were monitored for 14 days after the initial visit. Compliance was assessed by phone calls to parents and by analysis of urine samples. RESULTS: In 107 eligible febrile episodes (80 patients) over a 21-month period, no patient developed sepsis. One child developed bacteremia 3 days after completing the course of cefixime, and one had splenic sequestration on the fourth study day. Both patients did well. Side effects of cefixime were modest, and overall compliance was excellent (approximately 95%), although urine samples were returned by only 56% of parents. CONCLUSION: We conclude that outpatient therapy is safe and effective in febrile patients with sickle cell disease who meet the criteria for a low risk of sepsis. PMID- 8689338 TI - Testing for Passovoy defect in children with prolonged activated partial thromboplastin time (APTT) AB - PURPOSE: To investigate the value of testing for Passovoy defect using the commercially available Passovoy trait plasma (PTP) in children with prolonged activated partial thromboplastin time (APTT). PATIENTS AND METHODS: We studied 13 children with prolonged APTT that corrected in a 1:1 mix with normal human plasma but not with PTP. In most children, a thorough laboratory investigation of the intrinsic pathway factors and von Willebrand factor was performed. RESULTS: Five patients had bleeding manifestations and eight were asymptomatic. Measurement of von Willebrand factor and intrinsic pathway factors revealed abnormal values in eight patients (low von Willebrand activity in six patients, low factor XII in one patient, and the presence of lupus anticoagulant in one patient). CONCLUSION: Our data suggest inability to diagnose Passovoy defect based on a mixing study. This study also raises the question of whether Passovoy defect exists as a distinct coagulation disorder. PMID- 8689339 TI - Bone marrow aspirates and biopsies in children with human immunodeficiency virus infection. AB - PURPOSE: Hematopoietic abnormalities are common in patients infected with the human immunodeficiency virus (HIV). We evaluated the role of diagnostic bone marrow aspirations and biopsies in HIV-infected children. METHODS: Seventy-eight bone marrow biopsies and aspirates performed during the last 8 years at the Pediatric Branch of the National Cancer Institute from 60 children with symptomatic HIV infection were reviewed retrospectively. The results were correlated with clinical stage, use of antiretroviral therapy or hematopoietic growth factors, and hematopoietic parameters. RESULTS: Most patients (84%) showed a normal or hypercellular marrow, associated with diffuse lymphocytosis (50%) or therapy with hematopoietic growth factors (33%). Dyspoietic features were very common in all three cell lineages. Twenty-seven (44%) of the patients had decreased iron stores in the bone marrow that correlated with iron deficiency as documented by serum tests in more than one-third of our study population. Bone marrow cultures were not more helpful than peripheral cultures in establishing the diagnosis of an opportunistic infection. CONCLUSION: Although bone marrow abnormalities are very common in HIV-infected children, they are rarely specific. The role of diagnostic bone marrow aspirates and biopsies appears to be limited, and this invasive procedure should be reserved for specific situations (e.g., to rule out a malignancy). PMID- 8689340 TI - Growth and final height after treatment for childhood Hodgkin disease. AB - PURPOSE: To evaluate in children the impact of contemporary treatment for Hodgkin disease on the pattern of growth and final height. PATIENTS AND METHODS: We studied 80 patients (54 males) aged <14 years at diagnosis, with newly diagnosed, pathologically confirmed Hodgkin disease, treated at a single institution. Forty six patients received chemotherapy (CT) + radiotherapy (RT), 23 patients received RT alone, and 11 patients received CT alone. Heights were obtained at diagnosis, at the end of treatment, 1, 2, and 3 years after the end of treatment and at attainment of final height. Heights were converted to age- and sex-adjusted SD scores (SDS). RESULTS: There was a significant change in height SDS at the end of treatment compared to height SDS at diagnosis for all three groups (CT + RT: 0.33, p<0.001; RT: +0.09, p=0.027; CT: -0.24, p=0.012). Over the 3 years following treatment, the rate of change of height SDS was not statistically different between the three treatment groups. Final height SDS was decreased for patients receiving RT + CT (-0.41 SDS, p=0.02; n=31). The change in final height SDS for patients receiving RT or CT only was -0.36 (n=14) and +0.42 (n=4), respectively. Loss of final height SDS correlated with younger age at diagnosis (p=0.005). Patients receiving higher RT doses tended to fare worse (p=0.08). CONCLUSIONS: Pediatric patients treated for Hodgkin disease with the combination of RT and CT suffer a small but significant decrease in their final height SDS. Younger patients and those treated with higher RT doses appear to experience the greatest loss of height potential. PMID- 8689341 TI - Flow cytometry of neonatal platelet RNA. AB - PURPOSE: Serious disorders of hemostasis occur more often in the small, stressed preterm infant, partly due to immaturity of the newborn hemostatic mechanism. Information regarding the maturational development of platelets in infants has been limited by the large amounts of blood historically needed for platelet studies. The objective of this study was to determine differences between platelets in adults and infants by flow cytometric analysis of "reticulated" platelets. PATIENTS AND METHODS: Eighteen normal adults, 42 healthy term infants, and 27 preterm infants were studied. The infants were subdivided by mode of delivery: vaginal or Caesarean section. Platelet-rich plasma from adult whole blood and infant cord blood samples was divided into aliquots containing 5 X 10(6) platelets, fixed with 1% paraformaldehyde, and stained with thiazole orange for RNA content. The percentage of RNA positive "reticulated" platelets in each aliquot was then determined by flow cytometry. RESULTS: Group comparisons using ANOVA statistical analysis showed a significant difference (p<0.05) for platelet RNA content between adults and term infants, the adults having a higher percentage of reticulated platelets. Although the difference was smaller, adults also had a higher percentage of reticulated platelets than preterm infants. There was no significant difference in reticulated platelet values between infants within one gestational age group compared by type of delivery. CONCLUSION: There are demonstratable differences in adult and infant platelet RNA content that may reflect developmental differences in megakaryocytic/platelet kinetics. PMID- 8689342 TI - Sweet syndrome in a child with aplastic anemia receiving recombinant granulocyte colony-stimulating factor. AB - PURPOSE: To elucidate the pathogenesis of Sweet syndrome, one patient with aplastic anemia was evaluated. PATIENT AND METHODS: A 15-year-old girl presented with intermittent fever and progressive pallor for 3 months after non-A, non-B, non-C hepatitis. Aplastic anemia was diagnosed and therapy was begun with recombinant granulocyte colony-stimulating factor (G-CSF), methylprednisolone pulse therapy, antilymphocyte globulin and cyclosporin A. There was only an increase in the neutrophil counts. We continued G-CSF therapy of 300 micrograms/m2 on alternate days for 7 months. At this time the white blood cell count was 10,000/microliters and the patient developed high-grade fever and a painful, erythematous, tender plaque (3 X 3 cm) on the left thigh. We diagnosed the lesion as a skin infection and stopped G-CSF therapy and started antibiotics. Cultures were negative. The lesion slowly resolved, G-CSF was restarted after 2 months, and 1 month later disseminated lesions occurred. Antibiotic therapy was not effective. RESULTS: Biopsy of the lesion demonstrated infiltration of the dermis by sheets of neutrophils. We stopped G-CSF and began corticosteroid therapy. The skin lesions resolved rapidly. CONCLUSION: We postulated that Sweet syndrome was induced by G-CSF treatment. PMID- 8689343 TI - Myelodysplastic syndrome with t(5;12)(q31;p12-p13) and eosinophilia: a pediatric case with review of literature. AB - PURPOSE: Myelodysplastic syndrome with chromosomal translocation t(5;12)(q31 33;p12-13) and eosinophilia is a new entity recently described. Nine cases have been described in adults. We report the first pediatric case with a long follow up (7 years). PATIENTS AND METHODS: An 8-year-old girl presented with hyperleukocytosis, eosinophilia, and no clinical symptoms. Bone marrow investigations revealed myeloid hyperplasia and clonal chromosomal translocation t(5;12)(q31;p12-13). No treatment was prescribed, but 4 years later the white blood cell count reached 144 X 10(9)/L with immature myeloid cells and splenic enlargement. Hydroxyurea chemotherapy led to a hematopoietic remission. The patient is now 16 years old and well, >7 years after the initial diagnosis. RESULTS: The association: myelodysplastic syndrome, eosinophilia and translocation t(5;12)(q31-33;p12-13), seems to be a specific hematologic disorder. Study of cases previously reported in the literature shows the most important characteristics of this disease. However, there are still a number of questions about the disease itself (especially its treatment) and the significance of the chromosomal abnormalities. CONCLUSION: This case seems to be the first report of the disease in a child and has had the longest follow-up. Other data should be collected to improve our knowledge of this hematopoietic disorder. PMID- 8689344 TI - Intraabdominal desmoplastic small round cell tumor presenting as a gastric mural mass with hepatic metastases. AB - PURPOSE: An atypical case of childhood intraabdominal desmoplastic small round cell tumor (DSRCT) is presented. PATIENT AND METHODS: An 11-year-old boy presented with progressive nausea and vomiting, abdominal pain, hepatomegaly, and an epigastric mass. Computed tomographic scanning as well as findings at gastroscopy and laparotomy revealed a large gastric mural tumor accompanied by multiple large intrahepatic masses. Histopathologic examination of biopsy samples revealed evidence of a polyphenotypic neoplasm diagnostic of DSRCT. RESULTS: Unlike most reported cases of DSRCT, no evidence of peritoneal involvement or ascites was detected. Despite an excellent initial response to multiagent chemotherapy, the patient eventually died of progressive tumor. CONCLUSIONS: Though the radiographic and surgical findings in DSRCT usually suggest a mesenteric, peritoneal, or retroperitoneal site of tumor origin, this case demonstrates that intraabdominal DSRCT can present with a primary visceral lesion without evidence of peritoneal or mesenteric involvement or ascites. Combination chemotherapy using vincristine, doxorubicin, cyclophosphamide, cisplatin, and 5 fluorouracil may be of some benefit to patients with this rare tumor. PMID- 8689345 TI - Desmoplastic small cell tumor: a report of three cases and a review of the literature. AB - PURPOSE: Desmoplastic round cell tumor (DSCT) is a highly malignant abdominal tumor first described in 1991, with subsequent cases predominantly noted in pathologic case reports. The authors evaluated response to alternating, intensive chemotherapy in three patients with DSCT, and reviewed the clinical experience with this newly described tumor as reported in the literature. PATIENTS AND METHODS: Three adolescent boys with DSCT were treated intravenously with vincristine 2 mg/m2, doxorubicin 75 mg/m2, cyclophosphamide 1.8 g/m2, alternating with 5-day cycles of etoposide 100 mg/m2/day, ifosfamide 1.8 g/m2/day for a total of 11-15 courses. RESULTS: Each patient showed initial tumor regression during chemotherapy, but developed progressive disease within 8-18 months. One patient subsequently showed a transient response to doxorubicin 45 mg/m2 plus 5 fluorouracil 500-600 mg/m2. All three patients died of disease within 20 months of diagnosis. A comprehensive literature review of clinical data on 101 reported cases of DSCT is presented. The median age was 21 years (range 6-38 years) with 78 male patients and 23 female patients. Ninety-nine cases involved tumor mass in the abdominal-pelvic cavity in proximity to the mesentery. Metastatic seeding to the omentum was most common, followed by spread of disease to liver, distant lymph nodes, lung, and occasionally to scrotum or to ovary. Tumor response to chemotherapy was noted in approximately 50% of 40 patients who received combinations of doxorubicin, cisplatin, cyclophosphamide, etoposide, and/or 5 fluorouracil. Four of 13 patients who received additional radiotherapy were alive at 24-48 months. Median survival was 17 months (range: 3-72 months), with only two patients reported disease free beyond 2 years at 40 and 48 months. CONCLUSION: DSCT should be included in the differential diagnosis of small round cell tumors in children and young adults. Tumor regression has been noted during multiagent chemotherapy, but prolonged survival is rare with current therapies. PMID- 8689346 TI - Myelodysplasia associated with Turner syndrome. AB - PURPOSE: This study reports the association of myelodysplasia with Turner syndrome. PATIENT AND METHODS: An 11-year-old girl with Turner syndrome was found to have mild macrocytic anemia that persisted during 2 years. RESULTS: Examination of the bone marrow revealed dyserythropoietic features with multinucleation consistent with refractory anemia. Levels of hemoglobin F were also markedly elevated (57%). She also had transient neutropenia and thrombocytopenia, as well as abnormal platelet function studies. The hematopoietic abnormalities were mild and may have been missed were she not followed for her hypertension and aortic coarctation. CONCLUSIONS: Myelodysplastic syndromes in children are frequently associated with chromosomal abnormalities, but an association with Turner syndrome has not been previously described. This could be due to the fact that mild hematopoietic abnormalities in these patients may not be investigated. PMID- 8689347 TI - Intrathecal leucovorin after intrathecal methotrexate overdose. AB - PURPOSE: Intrathecal methotrexate is a standard and important therapy in acute leukemia. Unfortunately, overdose is a well reported complication of this therapy. We report a fatal event secondary to intrathecal leucovorin. PATIENTS, METHODS, AND RESULTS: An 11-year-old boy with a 6-month history of treatment of acute lymphocytic leukemia received an "overdose" of 20 mg of intrathecal methotrexate. He was treated with intrathecal leucovorin and subsequently experienced severe neurotoxicity and died. This was attributed to the use of intrathecal leucovorin, the first such case reported in the medical literature. CONCLUSION: A review of the literature indicates that a careful definition of overdose needs to be applied in cases of intrathecal methotrexate: those <100 mg need less intervention, >500 mg will not respond to any intervention, and the middle group, 100-500 mg, can be treated with a variety of approaches, which are outlined. The standard treatment includes the use of ventriculolumbar washout, CSF exchange, or intravenous pharmacotherapy with leucovorin. Recently, the use of carboxypeptidase has been under investigation. All clinicians who administer intrathecal medications should be aware of these complications and the appropriate treatments of them (including rescue). Leucovorin should not be given intrathecally. PMID- 8689348 TI - Rhabdomyosarcoma presenting as acute leukemia. AB - PURPOSE: We describe a case of a very unusual presentation of rhabdomyosarcoma. PATIENT AND METHODS: An 18-year-old woman presented with symptoms and signs compatible with acute leukemia. The bone marrow picture showed diffuse involvement sustained by undifferentiated blasts that turned out to be of striated muscle origin by immunochemistry. While it is well known that rhabdomyosarcoma may metastasize to the bone marrow, extensive marrow involvement with leukemic spread as a unique clinical manifestation is extremely rare. CONCLUSION: Our observation further confirms the need to consider rhabdomyosarcoma among the possible differential diagnoses in patients who present with a leukemic picture and atypical blasts lacking all hematopoietic markers. PMID- 8689349 TI - Epidural hematoma of a cauda equina in a child with hemophilia A. AB - PURPOSE: The presenting signs, treatment, and outcome of an epidural hematoma of the cauda equina in a child with severe hemophilia are reported for the first time. PATIENTS AND METHODS: A 20-month-old boy with severe hemophilia A (factor VIII <0.01 U/ml) presented with a 12-day history of refusal to stand and constipation of 5-7 days duration. He had normal deep tendon reflexes with normal sensation and withdrawal to pinprick of his lower extremities bilaterally. He stood on his right leg, but had inversion of his left foot and refused to bear weight on his left leg. MRI revealed an epidural hematoma of the cauda equina and a distended bladder. Factor VIII replacement therapy and lumbosacral laminectomy with evacuation of the hematoma resulted in recovery of a normal gait, but bladder dysfunction persisted for 11 months. Clean intermittent catheterization (CIC) was required until bladder function returned. RESULTS: Complete neurologic recovery occurred 11 months after presentation CONCLUSION: This case demonstrates the following points: (a) an epidural hematoma of the cauda equina in a child with severe hemophilia can present with neurologic findings that are as subtle as those seen in normal children; (b) CIC can be performed safely over an extended period without factor VIII replacement; and (c) complete recovery is possible, despite prolonged bladder dysfunction and a 12-day interval between the onset of symptoms and treatment. PMID- 8689350 TI - Childhood acute lymphoblastic leukemia relapse in the uterine cervix. AB - PURPOSE: Extramedullary relapse outside the testes and CNS is rare in children with acute lymphoblastic leukemia (ALL). We describe a case of a recurrence of ALL in the uterine cervix during hematopoietic remission. RESULTS: Primary recurrence in the uterine cervix was diagnosed by cytology with immunochemistry 43 months after initial diagnosis. She was successfully treated with systemic chemotherapy, without hysterectomy or irradiation. She remains in second complete remission 54 months after relapse. CONCLUSIONS: Immunocytochemistry using monoclonal antibodies against cell surface antigens made the cytologic diagnosis of leukemic relapse in the uterine cervix possible. Systemic chemotherapy is the first treatment of choice for ALL recurrence in the genital tract in a patient without poor prognostic factors in order to spare gonadal function and reproductive potential. PMID- 8689351 TI - Successful treatment of a primary cardiac leiomyosarcoma with ifosfamide and etoposide. AB - PURPOSE: Primary cardiac leiomyosarcoma is a rare malignant tumor in childhood. Patients with unresectable or partially resected cardiac leiomyosarcoma typically have a poor prognosis. The role of chemotherapy in the treatment of these patients has not been well defined. PATIENT AND METHODS: A 6-week-old infant with an incompletely resected cardiac leiomyosarcoma was treated postoperatively with ifosfamide and etoposide. RESULTS: The patient is disease-free and without apparent late effects 5 years following the completion of therapy. CONCLUSION: The combination of ifosfamide and etoposide warrants further evaluation in patients with leiomyosarcoma. PMID- 8689352 TI - Langerhans cell histiocytosis and hypercalcemia: clinical response to indomethacin. AB - PURPOSE: Hypercalcemia is a known complication of childhood malignancies but has never been reported to be associated with Langerhans cell histiocytosis (LCH) in a pediatric patient. PATIENTS AND METHODS: We describe an infant with multisystem LCH who developed hypercalcemia on two occasions. After being placed on indomethacin, the hypercalcemia did not recur despite disease progression. CONCLUSION: Hypercalcemia may complicate LCH. If it is demonstrated, indomethacin should be considered as a treatment. PMID- 8689353 TI - Metastatic osteosarcoma of the kidney presenting as renal hemorrhage. AB - PURPOSE: Renal osteosarcoma may arise as a metastasis from a primary bone osteosarcoma or as a primary renal tumor. Metastatic renal osteosarcoma has been found at autopsy in approximately 10% of patients who die of this disease. PATIENT AND METHODS: A case report of a young Chinese patient presenting with acute onset of renal infarction and hemorrhage from a renal metastasis of osteosarcoma is presented, as well as a review of the literature. RESULTS: Some patients with solitary renal metastatic osteosarcoma may have long-term disease free survival after nephrectomy. Early diagnosis and thus increased awareness of this condition is important. PMID- 8689354 TI - Pyomyositis during induction chemotherapy for acute lymphocytic leukemia. AB - PURPOSE: Pyomyositis is a rare disease in temperate climate regions and frequently has a subacute presentation. Because of this, the entity is often misdiagnosed. PATIENTS AND METHODS: Two boys with acute lymphocytic leukemia (ALL) who presented with muscle pain, shortly after receiving induction chemotherapy, were evaluated. RESULTS: Presenting physical examination and laboratory findings were unremarkable except for extremity pain and tenderness. These symptoms were initially attributed to a neurotoxic side effect of vincristine. As the children's symptoms progressed, muscle abscess formation was finally delineated by gallium and computed tomography scans, and the diagnosis of pyomyositis was made. In both cases, the invading organism was Staphylococcus aureus. Both children responded well to incision and drainage of the abscesses and antibiotic therapy. CONCLUSION: Four cases of pyomyositis occurring in ALL patients shortly after induction chemotherapy have now been described. We feel that when children from this population present with muscle pain, pyomyositis should be part of the differential diagnosis. With early medical and surgical intervention, morbidity and mortality can be avoided. PMID- 8689355 TI - Renal venous thrombosis complicating acute myeloid leukemia with hyperleukocytosis. AB - PURPOSE: Leukemic hyperleukocytosis may cause organ- or life-threatening complications. Patients at highest risk appear to be those with acute myeloid leukemia (AML). Blast cell aggregation and thrombus formation in the microvasculature most commonly involves the central nervous system and the pulmonary circulation. We describe a child with AML and renal venous thrombosis (RVT), a previously unreported complication of hyperleukocytosis. PATIENTS AND METHODS: A 17-month-old boy had a white blood cell count of 103 X 10(9) cells/L and RVT (hematuria, arterial systolic hypertension, unilateral nephromegaly, poor renal venous blood flow) at diagnosis of acute myelomonocytic leukemia (AML, FAB M4). CONCLUSION: This case emphasizes the danger of hyperleukocytosis in AML and demonstrates that there may be other organ system dysfunction in addition to the well-described central nervous system and pulmonary complications. Renal venous thrombosis should be considered in the patient with leukemic hyperleukocytosis, hematuria, arterial hypertension, and appropriate radiographic findings. Aggressive cytoreductive measures should be pursued in such cases. PMID- 8689356 TI - TCD in sickle cell disease. PMID- 8689357 TI - Oral care with vancomycin paste for alpha-hemolytic streptococcal sepsis. PMID- 8689358 TI - Oral care with vancomycin paste for alpha-hemolytic streptococcal sepsis. PMID- 8689359 TI - The experiment that cannot be done. PMID- 8689360 TI - Economic grand rounds. Leased psychiatric beds. PMID- 8689361 TI - Datapoints. Psychiatrists' interests by year of medical school graduation. PMID- 8689362 TI - Law & psychiatry. Who is responsible when a patient's insurance runs out? PMID- 8689363 TI - Personal accounts. Can institution-induced anger prolong hospitalization for patients who repress anger? PMID- 8689364 TI - Managed care. Getting managed care organizations to cover extended psychotherapy for patients with personality disorders. PMID- 8689365 TI - Clinical computing. Computer-administered symptom rating scales. PMID- 8689366 TI - Emerging issues in international mental health services research. AB - In developed nations, interest in mental health services research is increasing, which parallels an increased appreciation of the social and financial costs of mental illness and a growing need to identify cost-effective patterns of care. This paper examines common challenges in mental health services research, such as adjudicating between competing mental health priorities, designing research to better understand key elements in successful interventions, defining treatment outcomes more broadly to reflect consumer and family preference and quality of life, and linking services to improve community care. Using the assertive community treatment model as an example, the paper focuses on some of the differences between services research and controlled clinical investigations and the difficulties of looking inside the "black box" of effective interventions. PMID- 8689367 TI - Use of mental health services by households in the United States. AB - OBJECTIVE: The study examined differences in the use of mental health services by persons living in different types of households. METHODS: Data were obtained from the Epidemiologic Catchment Area (ECA) survey, a multistage probability sampling procedure of households in five U.S cities conducted in 1981-1984. Data from 12,417 persons living in four of the five ECA sites (Baltimore, St. Louis, Durham, North Carolina, and Los Angeles) were classified according to household categories used by the U.S. Bureau of the Census. Logistic regression analysis was used to examine the relationship of mental health service use to household type, relationship of survey respondent to head of household, household income and size, number of children in the household, ECA site, presence of mental disorders, and sociodemographic factors. RESULTS: Use of mental health services varied by type of household but not by individual within the same household. Persons in female-headed families and persons living alone had the highest use of mental health services, even after other variables were controlled. CONCLUSIONS: The findings highlight the need for outreach efforts to determine needs and preferences for health, mental health, and social services by persons in various households, especially persons in female-headed families and persons living alone. PMID- 8689368 TI - Housing preferences and perceptions of health and functioning among homeless mentally ill persons. AB - OBJECTIVE: Most homeless persons who have received services for serious mental illness want to live on their own, but mental health professionals usually recommend group housing. This study examined the relationship between the types of residential arrangements preferred by homeless mentally ill persons and their demographic and clinical characteristics and perceptions of their health and functional status. METHODS: The study sample consisted of 118 homeless mentally ill persons living in publicly funded shelters in Boston who were enrolled in a research demonstration project that would provide them with housing. Before random assignment to housing, study participants were interviewed about their interest in moving, in staff support, and in living with others. Their clinical status and functional strengths and impairments were assessed using a variety of objective and subjective measures. RESULTS: Study participants reported a marked preference for independent living but expressed substantial interest in staff support. The desire for independent living was associated with a perceived ability to manage independent living, but was also associated with current substance abuse. Most indicators of clinical status and functional ability were not associated with housing preferences. CONCLUSIONS: Self-perceived functional ability may not be an influence on housing preferences, except when that ability is perceived as making independent living more difficult. Symptoms of mental illness did not appear to interfere with study participants' rational decision making about where to live. However, the study finding that substance abusers expressed a desire for independent living suggests the need for caution in adhering to homeless mentally ill persons' housing preferences, given the problems posed by substance abuse for their ability to maintain stable community housing. PMID- 8689369 TI - New developments in employee assistance programs. AB - Employee assistance programs have developed from alcoholism assessment and referral centers to specialized behavioral health programs. Comprehensive employee assistance programs are defined by six major components: identification of problems based on job performance, consultation with supervisors, constructive confrontation, evaluation and referral, liaison with treatment providers, and substance abuse expertise. Other services have been added as enhancements to the basic model and include managed behavioral health activities and professional assistance committees, which provide services for impaired professionals and executives. Recent developments in the field are illustrated through examples from the experience of the employee assistance program at the University of Maryland Medical System in Baltimore. PMID- 8689370 TI - Neighborhood locations of Section 8 housing certificate users with and without mental illness. AB - OBJECTIVE: The study examined whether participants with mental illness in the federal Section 8 housing subsidy program settle in neighborhoods different from those of Section 8 participants without mental illness. The nature of these differences and the reasons they occur were also examined. METHODS: Data sources included the Section 8 survey for Baltimore and Cincinnati of the national evaluation of the Robert Wood Johnson Foundation Program on Chronic Mental Illness, police records, and 1990 census tract files, supplemented with the addresses of all Section 8 users and mental health services in both cities. Analyses consisted of calculations of dissimilarity indexes, comparisons of means, and multiple regressions. RESULTS: Dissimilarity index scores were .54 for Baltimore and .48 for Cincinnati, indicating that roughly half of all Section 8 users with mental illness would have to move to eliminate neighborhood disparities between them and Section 8 users without mental illness. Section 8 users with mental illness settled in somewhat better neighborhoods than those without mental illness. This finding was largely attributable to the sizable disparities in the racial composition of the two groups of Section 8 users: a greater proportion of users with mental illness were white. CONCLUSIONS: The neighborhood quality of Section 8 users with mental illness was found to be at least as high as that for users without mental illness. It is not clear whether the Section 8 program of the Program on Chronic Mental Illness disproportionately served whites, although the racial composition of the Section 8 program in both cities is disproportionately black. PMID- 8689371 TI - Deaths among former psychiatric inpatients in an outreach case management program. AB - OBJECTIVE: The mortality rate of discharged psychiatric inpatients has long been known to be higher than that of persons in the general population. This study assessed the effectiveness of outreach case management in reducing the mortality rate of recently discharged psychiatric inpatients in New York City. METHODS: A sample of 292 patients discharged from an inpatient psychiatry service at an urban general hospital were randomly assigned either to an intervention group (N = 147), which received intensive outreach case management for periods ranging from 15 to 52 months after discharge, or to a control group (N = 145), which received standard aftercare services. Both groups were offered and received regular aftercare and other services during the study period. Both groups were followed for comparable periods of time to determine their rate of mortality. RESULTS: The overall mortality rate for the total group of 292 patients was 7.2 percent, 2.25 times higher than among persons in the general population matched for age, sex, and race. The mortality rates for the intervention group and the control group were 7.5 percent and 6.9 percent, respectively, not a significant difference. CONCLUSIONS: Discharged psychiatric inpatients who received outreach case management did not have a lower mortality rate than similar patients who did not receive this intervention. PMID- 8689372 TI - Factors associated with homicide recidivism in a 13-year sample of homicide offenders in Finland. AB - OBJECTIVE: Data on persons known to have committed homicide during a 13-year period were studied to determine factors associated with increased risk of repeating homicide. METHODS: Between 1981 and 1993, a total of 1,649 homicides were committed in Finland. In 1,089 cases (66 percent), the offenders received an exhaustive forensic psychiatric examination. Data from reports of these examinations were analyzed to determine whether mental disorder and other factors were associated with homicide recidivism. RESULTS: Thirty-six homicide recidivists were identified. Twenty-four were alcoholics, 23 had a personality disorder, in most cases combined with alcoholism, four had schizophrenia, and two had major depression. Homicidal behavior was ten times more likely in men who had committed a previous homicide than in the general male population. Alcoholism increased the odds ratio of additional homicidal behavior in male homicide offenders about 13 times, and schizophrenia increased the odds ratio more than 25 times. During their first year after release from prison, male homicide offenders were about 250 times more likely to commit homicide than members of the general male population. CONCLUSIONS: The data suggest that mentally abnormal offenders are overrepresented among homicide recidivists in Finland. The risk of repeat homicide appears to be very high during the first year after release from prison. PMID- 8689373 TI - Elements of a successful short-stay inpatient psychiatric service. AB - In 1989 Johns Hopkins Hospital modified the Meyer 3 short-stay psychiatric service, which has allowed the hospital to comply with state requirements to control inpatient costs and has increased revenues. Strategies and organizational changes that were implemented to reduce length of stay include use of a screening tool by the admitting physician to ensure appropriate referrals to the service, modification of morning and afternoon rounds and strengthening of linkages with the psychiatric emergency department and outpatient services to enhance communication, replacement of inexperienced first-year residents in the emergency department with senior residents on 24-hour call who are closely supervised by short-stay service staff, and enhanced training for service nurses. Patients who are functionally disabled and who need assistance in activities of daily living have longer stays. Patients with substance use disorders are now referred to an ultra-short-stay unit. PMID- 8689374 TI - Comparison of clinicians' housing recommendations and preferences of homeless mentally ill persons. AB - Housing recommendations made by two clinicians for 86 homeless mentally ill consumers were compared with the consumers' own housing preferences. Clinicians recommended independent living much less often than did the consumers. The two groups varied less on specific housing features such as eagerness for consumers to leave the shelter and consumers' need for part-time staff help. Only one of the clinicians took into account some aspects of social background and health status in formulating housing recommendations. The authors conclude that housing providers should encourage clinicians to work together with consumers to identify appropriate placements. PMID- 8689376 TI - The value of consultation-liaison interventions to the general hospital. AB - Changes in health care funding have greatly enhanced the value of consultation liaison services to their parent hospitals. This paper reviews representative studies showing that consultation-liaison interventions improve patient care, enhance patients' satisfaction with treatment, and reduce polypharmacy, adverse drug reactions, and subsequent hospitalizations. Reductions in costs of hospitalization realized by consultation-liaison interventions are also described, including average reductions in hospital stays of one to one and a half days, upgrades in diagnosis-related group (DRG) codes, and timely patient transfers to inpatient medical-psychiatric units or inpatient psychiatric facilities. These data suggest that consultation-liaison services will become increasingly important over the next few years. PMID- 8689375 TI - Preliminary evaluation of cognitive adaptation training to compensate for cognitive deficits in schizophrenia. AB - Cognitive adaptation training is a treatment approach designed to alter the physical environment of patients with schizophrenia to compensate for cognitive deficits and improve adaptive function. A wide range of environmental manipulations such as labels, signs, schedules, and rearrangement of objects are employed. In a preliminary study at a state hospital, outcomes for cognitive adaptation training were compared with outcomes for standard psychosocial treatment for two groups of patients with schizophrenia, matched on levels of functional impairment and symptoms. Both groups showed improvement in symptoms and adaptive function, but patients receiving the specialized training showed greater improvement in adaptive function than did the standard-treatment group. PMID- 8689377 TI - Self-reported effects of alcohol use on symptoms of schizophrenia. AB - Forty-two acute inpatients with schizophrenia, 23 of whom had a past or current alcohol use disorder, were given a structured interview that focused on reasons for alcohol use and changes in perceived effects of alcohol on psychiatric symptoms from the first episode of illness to the current episode. Drinking for sociability or celebration decreased over time, while drinking to relieve depression or problems increased. Subjects who experienced hallucinations, paranoia, or both significantly more often reported an increase in these symptoms after drinking. Subjects with an alcohol-related diagnosis were significantly more likely than those without such a diagnosis to cite relief of depression and problems or worries as a reason for alcohol use. PMID- 8689378 TI - Symptoms of stress disorder and depression among trauma counselors after an airline disaster. AB - Psychological symptoms of 21 therapists who provided counseling to individuals affected by the crash of a commercial airliner were compared with those of 20 therapists from the same mental health center who did not participate in the disaster relief efforts. A symptoms checklist instrument was completed by both groups at four, eight, and 12 weeks after the crash. At four and eight weeks, the trauma counselors experienced significantly more symptoms of posttraumatic stress disorder and depression than the therapists in the control group. At 12 weeks the only significantly increased symptom among the trauma counselors was avoidance behavior. PMID- 8689379 TI - Comorbidity of DSM-III-R axis I and II disorders among female inpatients with eating disorders. AB - Structured diagnostic interviews were used to determine DSM-III-R axis I and II diagnoses among 136 female psychiatric inpatients. To distinguish comorbidity of eating disorders with axis I and II disorders from simple diagnostic overlap, the frequency and distribution of diagnoses among the 31 patients with an eating disorder and the 105 without an eating disorder were compared. Social phobia, substance use disorders, borderline personality disorder, and avoidant personality disorder were diagnosed in a significantly larger proportion of the group with eating disorders. Future studies should focus on interpreting the meaning of the co-occurrence of these disorders in patients with eating disorders. PMID- 8689380 TI - Predicting dangerousness. PMID- 8689381 TI - Novel antipsychotics and neuroleptic malignant syndrome. PMID- 8689382 TI - VA services for women. PMID- 8689383 TI - Civil commitment and managed care. PMID- 8689384 TI - Advocacy group contends proposed changes in Medicaid would imperil community services. PMID- 8689385 TI - CMHS launches national campaign to increase awareness of children's mental health problems. PMID- 8689386 TI - Washington psychiatrists protest calls to close historic D.C. hospital, citing lack of other settings. PMID- 8689387 TI - Effects of three inhibitors of nitric oxide synthase on host resistance to bacterial infection. AB - OBJECTIVE: To examine the effects of three nitric oxide synthase inhibitors on survival in a murine sepsis model. DESIGN: Prospective randomized experimental trials. SETTING: Laboratory. SUBJECTS: Female Balb/c mice. INTERVENTIONS: Escherichia coli (10(8) colony-forming-units/body) were injected into the peritoneal cavities of Balb/c mice. NG-nitro-L-arginine-methyl-ester, NG monomethyl-L-arginine, or N-iminoethyl-L-ornithine was given at various concentrations, intraperitoneally, one hour before bacterial challenge. MEASUREMENTS: One hundred and fifteen animals were observed for survival. RESULTS: These inhibitors provided the mice no protection from the bacterial challenge. Notably, pretreatment with NG-nitro-L-arginine-methyl-ester (100 mg/kg i.p.) actually reduced survival time after E. coli challenge. CONCLUSIONS: Inhibition of nitric oxide production improved neither the survival time nor rate in this murine sepsis model. PMID- 8689388 TI - Mitoxantrone induces nonimmunological histamine release from rat mast cells. AB - The antineoplastic drug mitoxantrone (MTX) elicits a fast noncytotoxic and nonimmunological histamine release from peritoneal and pleural rat mast cells. The non specific phosphodiesterase inhibitor isobuthyl-methylxantine (1 mM) decreases the potency of MTX. Theophylline (10 mM) decreases both the potency and the efficacy of MTX-induced histamine secretion. The protein kinase C (PKC) activator, tetradecanoyl-phorbol-13-acetate (50 ng/mL), enhances the effect of MTX, whereas the non specific PKC inhibitor trifluoperazine (10 microM) exerts no effect. Histamine release was also unaffected by substances acting on G-proteins, namely pertussis toxin (200 ng/mL), cholera toxin (300 mg/mL) and benzalkonium chloride (10 micrograms/ mL). The inhibition of protein phosphatases 1 and 2A by okadaic acid (1 microM) does not modify the response. The results indicate that mitoxantrone elicits the exocytosis in mast cells by a mechanism similar to the parent compound adriamycine, but different to the polyamine compound 48/80. PMID- 8689389 TI - Histamine forming capacity (HFC) and its modulation by H3 receptor ligands in a model of bronchial hyper-responsiveness. AB - The histamine forming capacity (HFC) of acutely challenged airways from sensitised guinea pigs was investigated. After exposure to nebulised bovine serum albumin (BSA) or normal saline, animals were sacrificed, the pulmonary HFC determined and concurrent in vitro histamine log concentration response curves were constructed for parenchymal strips and tracheal muscle, the latter was field stimulated to record neurogenic responses. Exposure to BSA increased the HFC above controls for 24 hours (p < 0.001) and log concentration response curves for the parenchymal strips were shifted slightly to the left with an increased maximum response. This change appeared 3 hours after exposure and remained elevated at 24 hours. Similar changes did not occur with the trachea. Pre treatment with thioperamide augmented (p < 0.02) HFC and this increase was inhibited by alpha-methylhistamine (p < 0.05). A possible relationship may exist between increased responsiveness of lower airways to exogenous histamine and a raised endogenous formation, regulated by the H3 receptor. PMID- 8689390 TI - Lack of a role for bradykinin in allergen-induced airway microvascular leakage and bronchoconstriction in the guinea pig. AB - We have investigated the role of bradykinin in allergen-induced airway microvascular leakage and bronchoconstriction in sensitized guinea pigs. We used a selective bradykinin B2 receptor antagonist, HOE140, which has been shown to prevent the airway effects induced by bradykinin. Lung resistance (RL) was measured for 6 min after challenge with allergen. Extravasation of Evans blue dye into airway tissues was used as an index of the airway microvascular leakage. Aerosolized ovalbumin (5 mg/ml, 30 breaths) induced a significant increase in RL and leakage of dye in the trachea, main bronchi and intrapulmonary airways in the ovalbumin-sensitized guinea pigs. HOE140 given by inhalation (200 microM, 60 breaths) had no effect on the airway microvascular leakage and bronchoconstriction induced by the allergen. I.v. HOE140 (200 nmol/kg) did not significantly inhibit these airway responses. We conclude that bradykinin mediated mechanism may not play a significant role in airway microvascular leakage or bronchoconstriction induced by allergen. PMID- 8689392 TI - The distribution of carnosine and related dipeptides in rat and human tissues. AB - Carnosine and anserine are present in high concentrations in most skeletal muscles. In addition, carnosine and homocarnosine have been detected in brain and cardiac muscle. Other tissues have been found to be devoid of these histidine containing dipeptides. However, Flancbaum et al. reported that carnosine was present in every rodent and human tissue analyzed. These authors postulated that carnosine serves as a non-mast cell reservoir for histidine which becomes available for histamine synthesis during periods of physiological stress. We have analyzed many rat and human tissues using an immunohistochemical procedure. Carnosine and related dipeptides were detected in skeletal muscle, cardiac muscle and brain, but not in kidney, liver, lung or several other organs. These negative results seem valid since the immunoassay gave positive staining in the tissues generally known to contain carnosine. PMID- 8689391 TI - Reconstitution of chemokine-induced actin polymerization in undifferentiated human leukemia cells (HL-60) by heterologous expression of interleukin-8 receptors. AB - The chemokines interleukin-8 (IL-8) and GRO alpha bind in neutrophils to the interleukin-8 receptor alpha and beta (IL-8R alpha and beta) triggering reorganization of the actin cytoskeleton and activation of phospholipase C (PLC). Reconstitution of chemokine-induced activation of PLC indicated coupling of IL-8R alpha and beta to pertussis toxin-insensitive G alpha 16-proteins as well as to pertussis toxin-sensitive G alpha i2- or G alpha i3-proteins. To identify the signal transduction mechanisms of chemokine-induced actin response, undifferentiated human leukemia cells (HL-60 cells) constitutively expressing G alpha 16-, G alpha i2- and G alpha i3-proteins were chosen for reconstitution studies. Expression of recombinant receptors after transfection of the cells with the cDNA of IL-8R alpha and beta was confirmed by binding studies with radiolabeled ligands. IL-8R alpha bound IL-8 with high affinity (Kd approximately 1 nM) and GRO alpha with low affinity (Kd approximately 1 microM), whereas IL-8R beta bound both IL-8 and GRO alpha with high affinity (Kd approximately 1nM). Flow cytometric actin measurements indicated that high affinity ligand-receptor interactions in both receptor transfectants displayed inducible responses. Pretreatment of transfectants with pertussis toxin caused ADP-ribosylation of G proteins and blocked chemokine-induced polymerization, indicating involvement of G alpha i2- or G alpha i3-proteins, but not G alpha 16-proteins in this response. PMID- 8689393 TI - TNF-alpha participates in an IgE-mediated cutaneous reaction in mast cell deficient, WBB6F1-W/Wv mice. AB - The participation of tumor necrosis factor-alpha (TNF-alpha) in a IgE-mediated cutaneous reaction in WBB6F1-W/Wv (W/Wv), mast cell deficient, mice and the effect of prednisolone on this cutaneous reaction were investigated. Mice were passively sensitized by an intravenous injection of monoclonal anti-dinitrophenol (DNP) IgE, and their ears challenged epicutaneously with dinitrofluorobenzene 24 h later. The cutaneous reaction estimated by ear thickness reached a peak 48-72 h after the antigen challenge. A monoclonal anti-tumor necrosis factor (TNF)-alpha antibody inhibited the IgE-mediated cutaneous reaction. An increase of TNF-alpha mRNA was demonstrated 4 h after the application of antigen by the reverse transcriptase-polymerase chain reaction. The injection of recombinant murine TNF alpha induced a cutaneous reaction which peaked at 24 h in nonsensitized mice. Prednisolone at doses of 3 to 10 mg/kg clearly inhibited the IgE-mediated cutaneous reaction, however, it did not affect the expression of TNF-alpha-mRNA. Prednisolone at doses of 1 to 10 mg/kg clearly inhibited the TNF-alpha-induced cutaneous reaction. These results suggest that TNF-alpha plays a role in the IgE mediated cutaneous reaction in W/Wv mice and that prednisolone inhibits the cutaneous reaction at least in part by inhibiting the action of TNF-alpha. PMID- 8689394 TI - Changes in histamine and serotonin secretion from rat peritoneal mast cells caused by antidepressants. AB - Psychotropic agents modify the release of histamine and serotonin from rat peritoneal mast cells induced by compound 48/80. Some antidepressants, such as clomipramine and fluoxetine (10(-8) - 10(-5) mol/l), increase the percentage of released serotonin in the incubation medium but have no effect on histamine release. In contrast, amitriptyline (10(-4) mol/l) inhibits the secretion of histamine and permits that of serotonin. The varying effects of antidepressants on the secretion of histamine and serotonin could be explained either by a differential mechanism of secretion of both amines from mast cells or by a selective effect of drugs on the reuptake of serotonin into mast cells after stimulation by compound 48/80. These hypotheses were further investigated in our present study on rat peritoneal mast cells. Our findings suggest that antidepressants influence the secretion and the reuptake process of amines used. Their effects depend on the concentration of the drug. At lower concentrations, antidepressants (amitriptyline, doxepine and clomipramine) produce no effect on the secretion of the amines whereas at higher concentrations ( > 10(-5) mol/l), they inhibit the release. Additionally, mast cells are capable of removing released serotonin from the incubation medium. Serotonin uptake is an active process which increases with the time of incubation with exogenous serotonin and depends on the presence of extracellular Ca2+ and on the temperature of the medium. Preincubation of mast cells with antidepressants inhibits the reuptake of serotonin into mast cells and thus increases the concentration of serotonin in the incubation medium. Since the reuptake of serotonin is a relatively slow process, the elevation of serotonin in the medium is evident only after longer times of incubation. PMID- 8689395 TI - Activity of histamine metabolizing and catabolizing enzymes during reperfusion of isolated, globally ischemic rat hearts. AB - Myocardial ischemia-reperfusion injury increases both tissue levels and release of histamine. To study the possible effects of ischemia-reperfusion on histamine metabolism tissue activities of histidine decarboxylase (HDC), histamine N-methyl transferase (HNMT) and diamine oxidase (DAO) were investigated in isolated rat hearts subjected to either 20 min global ischemia and 40 min reperfusion (n = 10) or control perfusion (n = 8). Histamine in the coronary effluent increased from 21 +/- 4 nmol/min (mean +/- SEM) before ischemia to 55 +/- 5 and 50 +/- 7 nmol/min after 4 and 10 min reperfusion (p < 0.004 and p < 0.004). Tissue HDC activity did not change during observation in any group. HNMT activity was unchanged in controls, but increased from 0.37 +/- 0.04 to 0.84 +/- 0.18 and 0.96 +/- 0.22 pmol methylhistamine/mg protein hour after 4 and 10 min reperfusion (p < 0.008 and p < 0.01). DAO decreased similarly in controls and ischemic-reperfused hearts during observation. In conclusion, the previously observed increase of tissue histamine during reperfusion cannot be explained by increased histamine synthesis or decreased histamine catabolism. PMID- 8689397 TI - Michael S. Brown, MD and Joseph L. Goldstein, MD. 1985 Nobel laureates in medicine. AB - When Michael S. Brown, MD and Joseph L. Goldstein, MD first met as interns at the Massachusetts General Hospital in 1966, they could hardly have imagined that their careers would continue to be intertwined some 30 years later. It was shortly following their arrival as clinical associates at the National Institutes of Health in 1968 that the pair developed an interest in abnormalities of cholesterol metabolism. Bolstered by epidemiologic data that showed elevated cholesterol levels in many patients with myocardial infarction, Brown and Goldstein, who relocated to the University of Texas Southwestern Medical Center in 1972, began a search for receptors important in cholesterol homeostasis. These studies, performed in their early stages while juggling clinical duties at Parkland Hospital, culminated in a series of scientific achievements which merited among other honors the Hazen Award in 1982, the Lasker Award in 1985, and the Nobel Prize in Medicine in 1985. Today, as Regental Professors of the University of Texas, Brown and Goldstein head a laboratory group which continues to test the cutting edge of medical research. Although impressed with the pace of technological advances in biology, the declining role of clinically oriented physicians in biomedical research troubles the pair. Interviewed in their library in Dallas, Brown and Goldstein spoke about the complicated balance of science, medicine, and education necessary to produce another generation of successful investigators. PMID- 8689396 TI - Effects of metamizol on nociceptive responses to stimulation of the ureter and on ureter motility in anaesthetised rats. AB - In this study, we have examined the effects of metamizol (dipyrone), a non-opioid analgesic which is effective in relieving renal colic pain, on nociceptive responses evoked by stimulation of the ureter, on pyeloureteral motility and on intraureter pressure after ureter obstruction in anaesthetised rats. Metamizol (5 50 mg/kg i.v.) dose-dependently inhibited reflex pressor responses evoked by distensions of the ureter to pressures of 30, 55 and 75 mmHg for 30 s (ID50 = 8 +/- 1 mg/kg). Metamizol also dose-dependently reduced intraureter pressure during total ureter occlusion (25 mg/kg produced a reduction of 25% in 10 min). However, metamizol at doses up to 50 mg/kg had no effect on pyleoureteric motility (contraction amplitude, rate or intraureter pressure) under normal pressure conditions. We conclude that metamizol has a direct antinociceptive action on pain of ureteric origin, and spasmolytic effects after ureter obstruction (but not under normal conditions) which may also contribute to pain relief. PMID- 8689398 TI - Amebiasis and the Entamoeba histolytica Gal/GalNAc lectin: from lab bench to bedside. PMID- 8689399 TI - A proposed sequence of reactions leading to collagen biosynthesis, fibrosis, and hypertension in alcoholics. PMID- 8689400 TI - Distribution of messenger RNAs for aldehyde dehydrogenase 1, aldehyde dehydrogenase 2, and aldehyde dehydrogenase 5 in human tissues. AB - BACKGROUND: The distribution of aldehyde dehydrogenases in human tissues is incompletely understood, in part because of technical limitations of gel electrophoretic and other enzyme assay methods used previously and because of the instability of the enzymes. Since these enzymes participate in detoxification of endogenous and exogenous compounds, including ethanol, their tissue distribution may be relevant to the toxicology of a number of substances and to the medical consequences of alcoholism. METHODS: The abundance of mRNA for aldehyde dehydrogenase 1 (ALDH1), aldehyde dehydrogenase 2 (ALDH2), and aldehyde dehydrogenase 5 (ALDH5) was determined by Northern blotting using poly A+ RNA from 16 adult human tissues and 5 fetal tissues. RESULTS: The highest levels of ALDH1 mRNA were found in liver, kidney, muscle, and pancreas. ALDH2 and ALDH5 were expressed in a larger number of tissues than ALDH1, with highest levels in liver, kidney, muscle, and heart. Fetal heart, brain, liver, lung, and kidney expressed ALDH2 and ALDH5, while ALDH1 was present mainly in fetal liver, kidney, and lung. CONCLUSIONS: The results are in general agreement with the distribution of enzymes studied in a limited number of tissues in the past, with the exception that the ALDH1 activity reported to exist in heart and brain may, in fact, be ALDH5. The only mRNA detected in placenta was that for ALDH5. This study extends the knowledge of the expression of these enzymes to several tissues not previously studied and establishes the tissue distribution of the new enzyme ALDH5. PMID- 8689401 TI - Hyaluronan is exocytosed from serous, but not mucous cells, of human nasal and tracheobronchial submucosal glands. AB - BACKGROUND: Hyaluronan is a large, nonsulfated glycosaminoglycan that is a major component of many extracellular matrices. Secretion of hyaluronan has been associated with inflammation in the lungs and other tissues. The purpose of the present study was to determine the distribution of hyaluronan in human respiratory tissues and to determine if hyaluronan was present in human nasal secretions. METHOD: Hyaluronan was localized in histological sections of human nasal and tracheobronchial mucosa using a biotinlabeled affinity-purified hyaluronan binding probe derived from cartilage proteoglycan (b-PG) (Green et al. Exp Cell Res 1988; 178:224-32). Subjects had saline nasal provocation to collect baseline nasal secretions, then ate chili peppers to provoke parasympathetic cholinergic nasal glandular secretion (gustatory provocation). Total protein and hyaluronan concentrations were measured in the lavage fluids. RESULTS: Staining for hyaluronan was intense in basement membranes of epithelium, glands and vessels, and perivascular adventitia. Many epithelial cells contained hyaluronan, but the staining intensity was less than that on the basolateral aspects of these cells. Submucosal gland serous cells contained variable amounts of hyaluronan. Hyaluronan was not present in goblet cells, submucosal gland mucous cells, or sub basement membrane collagen deposits. The gustatory, parasympathetic stimulus induced a 4-fold increase in hyaluronan secretion (P < 0.01) and a 3.5-fold increase in total protein release (P < 0.0010). Hyaluronan accounted for 75% to 80% of the polymeric uronic acids in human nasal secretions. CONCLUSION: Hyaluronan was present human respiratory epithelial cells and submucosal gland serous cells and was exocytosed in response to parasympathetic stimulation. This distribution suggests roles in packaging cationic proteins in serous cells, cellular adhesion to basement membranes, and activation of macrophages in airway lumens. PMID- 8689402 TI - Thermotolerance attenuates heat-induced increases in [Ca2+]i and HSP-72 synthesis but not heat-induced intracellular acidification in human A-431 cells. AB - BACKGROUND: Thermotolerance affects cell viability, retards translation of heat shock proteins, and protects RNA slicing mechanisms. We reported previously that heat shocking nonthermotolerant cells causes an intracellular acidification and an increase in cytosolic free Ca2+ ([Ca2+]i) in addition to an induction of heat shock protein 72kDa (HSP-72) production. This study characterized heat-induced changes in cytosolic Ca2+, H+, and HSP-72 synthesis in thermotolerant A-431 cells. METHODS: We studied heat-induced changes in pH(i), [Ca2+]i, and HSP-72 using thermotolerant A-431 cell monolayers. pH(i) and [Ca2+]i were determined using fluorescence probes, and HSP-72 was measured by SDS-PAGE. The mRNA encoding HSP-72 was measured by Northern blots probed with a [32P]-labeled 2.3 kb fragment of an HSP-70 cDNA insert. RESULTS: Heat shocking thermotolerant cells induced the same degree of intracellular acidification as that induced in nonthermotolerant cells, but the heat-induced increase in [Ca2+]i was less in thermotolerant cells. This diminished response was characterized by an increase in Km for external Ca2+ and was blocked by pretreatment with cycloheximide, indicating a newly synthesized protein is involved. Similar to what was seen in nonthermotolerant cells, the heat-induced increase in [Ca2+]i in thermotolerant cells depended on external Na+ concentration and was blocked by dichlorobenzamil, though thermotolerant cells were more sensitive to the inhibitor (IC50 = 0.21 mumol/L for nonthermotolerant, 0.025 mumol/Lm for thermotolerant). Thermotolerant cells contained high resting levels of HSP-72. Heat shocking these cells attenuated the HSF translocation from cytosol to nucleus and did not induce a further synthesis of HSP-72 mRNA and protein. CONCLUSIONS: The results suggest that thermotolerance desensitizes the machinery required for Ca2+ entry. Low [Ca2+]i levels probably result in diminished HSP-72 mRNA production and less HSP-72 synthesis. PMID- 8689403 TI - The acute effects of TNF-alpha on the isolated perfused rat liver. AB - BACKGROUND: TNF-alpha mediates the hepatic response to sepsis by mechanisms which are not well understood. TNF-alpha is known to stimulate the hepatocellular uptake of specific amino acids in vivo; however, little is known about the direct effects of TNF-alpha on hepatic amino acid or glutathione homeostasis, which is a potential factor in the acute hepatic response to sepsis. METHODS: Using the isolated perfused rat liver, we characterized the effects of TNF-alpha on the secretion of amino acids and glutathione into bile and perfusate. Livers taken from adult male Sprague-Dawley rats were perfused with TNF-alpha at a dose of 1 or 2 micrograms. Bile and perfusate were collected for the quantitation of amino acid and glutathione concentrations. RESULTS: Administration of 2 micrograms TNF alpha resulted in significant increases in biliary and perfusate concentrations of branched chain, gluconeogenic, and total amino acids. TNF-alpha was also associated with dose-related increases in oxygen uptake, and greater biliary concentrations of glutathione. CONCLUSION: TNF-alpha has direct effects upon hepatic amino acid metabolism, which represent some of the early events involved in the mechanism of response to sepsis. PMID- 8689405 TI - Gerald S. Levey, MD. AB - While academic medical centers all over the country currently face challenging times, no area has been harder hit by managed care than California. The ruthless cost-cutting and competition for health care contracts dealt a severe blow to both public and private hospitals. While many physicians in that market are looking to relocate elsewhere, Gerald Levey recently returned from a top level position at Merck & Co. to helm the school of medicine at the University of California, Los Angeles. Prior to Merck, Levey was chairman of medicine at the University of Pittsburgh, president of the Association of Professors of Medicine, and a member of the Board of Governors of the American Board of Internal Medicine. Now, as other Los Angeles hospitals are on the brink of closure, Levey has the formidable task of directing the UCLA Medical Center into the future. Interviewed in his office in sunny southern California, Levey reflected on UCLA's strategy in a highly competitive market and the cloudy horizon facing academic centers in the United States. PMID- 8689404 TI - Effects of Carbicarb and sodium bicarbonate on hypoxic lactic acidosis in newborn pigs. AB - BACKGROUND: Use of sodium bicarbonate (NaHCO3) may result in intracellular acidosis due to the generation of CO2. Carbicarb, has been reported to be superior to sodium bicarbonate (NaHCO3) because of lesser generation of CO2. The present study was designed to investigate whether Carbicarb or NaHCO3 is superior to normal saline in the treatment of hypoxic lactic acidosis. METHODS: Hypoxia was induced by ventilation with 8% O(2) in 30 piglets with fixed ventilation. When the pH fell to < 7.2, hypoxia was reversed by placing the animals in 21% O2 (experiment 1) or 100% O(2) (experiment 2) and either saline, Carbicarb or NaHCO3 were given. Data were collected for 120 minutes after therapy. RESULTS: In both experiment 1 (severe acidosis, pH < or = 7.1) and 2 (moderate acidosis, pH < or = 7.2) use of Carbicarb and NaHCO3 increased the arterial carbon dioxide tension (pCO2) significantly (p < 0.05). With moderate acidosis: 1) use of alkalinizing agents compared to saline resulted in an initial improvement in arterial pH at 1 minute, but thereafter, the differences were not statistically significant; and 2) there were no differences in hemodynamic variables and plasma lactic acid concentration between the three groups. CONCLUSIONS: The data demonstrate that 1) both Carbicarb and NaHCO3 significantly increase arterial pCO2; and 2) use of either alkalinizing agent in moderate acidosis does not alter the course of acidosis. PMID- 8689406 TI - Role of kinases in HTLV-I transformation. PMID- 8689407 TI - Cellular adhesion molecules in rheumatoid arthritis: regulation by cytokines and possible clinical importance. PMID- 8689408 TI - Is clinical subspecialty training necessary to become a physician-scientist? PMID- 8689409 TI - Viability of transgenic mice expressing a platelet derived growth factor (PDGF) antagonist in plasma. AB - BACKGROUND: Many studies have implicated PDGF in the development of diseases such as atherosclerosis. Previously, we showed in tissue culture that the soluble extracellular domain of the PDGF beta-receptor is capable of binding BB-PDGF with high affinity; therefore antagonizing the ability of BB-PDGF to stimulate cell growth. METHODS: This work describes the efforts of expressing the soluble extracellular domain of the PDGF beta-receptor in transgenic mice. Driven by the albumin promoter, which is activated relatively late during embryonic development, the secreted form of the PDGF receptor protein was detected in plasma of the homozygous mice at a high concentration (approximately 60 micrograms/microL or approximately 545 nm). RESULTS: Plasma from these transgenic mice was capable of blocking PDGF-induced receptor autophosphorylation in tissue culture. The mice appeared to be healthy, demonstrating that full PDGF beta receptor function is not required for viability. CONCLUSION: By expressing a high level of a soluble form of the extracellular domain of the PDGF receptor in transgenic mice, we have established a novel animal model that will allow us to gain insight into the role of the PDGF receptor in vascular diseases and other diseases involving PDGF stimulated cell proliferation. PMID- 8689410 TI - Increases in HSF1 translocation and synthesis in human epidermoid A-431 cells: role of protein kinase C and [Ca2+]i. AB - BACKGROUND: It is known that heat shock increases both heat shock protein 70 kd (HSP-70) mRNA synthesis, and intracellular cytosolic free calcium concentration ([Ca2+]i). The latter enhances the heat inducible form of HSP-70 production by increasing the complex formation between heat shock transcriptional factor (HSF) and heat shock elements (HSE). In this study, we investigated the effect of agonists (PMA; ionomycin) and antagonists (BAPTA; staurosporine) of protein kinase C (PKC), and calcium channel on translocation and synthesis of HSF1, and activation of HSP-70 gene in human epidermoid A-431 cells. METHODS: Cells were incubated with poly 12-myristate 13-acetate (PMA) or ionomycin at different concentrations for various periods of time. Messenger RNAs of HSF and HSP-70 were measured with RT-PCR. The HSP-70 protein was determined with Western blots, and HSF protein was measured by gel mobility retardation assay. RESULTS: Significant increases in HSF binding to [32P]labeled HSE were found at 30 minutes in nuclear extract and at 4 hours in both nuclear and cytosol extracts. The PMA- and ionomycin-induced increases in HSF were in a concentration-dependent manner with a maximal increase at 10(-6) mol/L of each drug. Meanwhile, the mRNAs encoded for HSF1 and HSP-70, but not HSF2, were significantly increased and reached the maximum at 1 hour after the treatment. The PMA increased [Ca2+]i by 92% because of Ca2+ influx. The increases in mRNA of HSF1 and HSP-70 induced by treatment with 1 mumol/L PMA were completely blocked by preincubating cells with either 2 mumol/L staurosporine in the presence of extracellular Ca2+ or 100 mumol/L BAPTA am in absence of extracellular Ca2+. Like PMA, the increases induced by ionomycin were also inhibited by 100 mumol/L BAPTA-am in absence of extracellular Ca2+. Furthermore, Western blots show that 1 mumol/L PMA or ionomycin induced maximal increase in HSP-70 after 7 hours of continuous incubation with either agent. When cells were simultaneously treated with 1 mumol/L PMA and ionomycin together for 1 hour, the increase in HSP-70 and HSF1 mRNAs reached a greater level than the level stimulated by either drug alone. CONCLUSIONS: These results indicate that both PMA and ionomycin stimulate HSF1, but not HSF2, translocation and synthesis leading to the HSP-70 expression and that their effects are Ca(2+)-dependent. PMID- 8689411 TI - A variant of beta fibrinogen is a genetic risk factor for coronary artery disease and myocardial infarction. AB - BACKGROUND: Coronary artery disease is a complex trait caused by a number of genetic and environmental factors. Genes involved in hemostasis and coagulation are excellent candidate genes for CAD and its thrombotic complications, i.e., myocardial infarction (MI) and unstable angina. METHODS: We determined the frequency of beta-fibrinogen genotypes in a homogenous patient population with CAD undergoing coronary angioplasty and in a comparable group in the general population. DNA was extracted from the blood and genotypes were determined by polymerase chain reaction, restriction mapping with Hha-1 and gel electrophoresis. Cases and controls were also genotyped for a G17382T polymorphism in the (beta-Myosin heavy chain) (beta-MyHC) gene, which is not a candidate gene for CAD. RESULTS: The distribution of beta-MyHC G/T genotypes and the frequency of alleles were similar in cases and controls. However, the beta fibrinogen G/G genotype was present in 71% of patients with CAD as compared to 54% in the general population (p = 0.00001, OR: 2.1, 95% CI: 1.7-2.8). Seventy one percent of patients with MI and 72% of patients with unstable angina had G/G genotype (p = 0.003, OR: 2.0, 95% CI: 1.3-3.3, and p = 0.005, OR: 2.1, 95% CI: 1.3-3.7, respectively). Sixty-nine percent of male and 82% of female patients with CAD had the G/G genotype as compared to 56% and 53% in in general population, respectively (p = 0.0381, and 0.0003, respectively). Multivariate regression analysis showed that the allele G was an independent predictor of case control status or risk of MI in a codominant manner (F = 86.8 p < 0.0001). CONCLUSIONS: beta-fibrinogen G/G genotype is a genetic risk factor for predisposition to CAD and its thrombotic complications. PMID- 8689412 TI - Cardiac reflex effects of intracoronary bradykinin in humans. AB - BACKGROUND: Endogenous production of bradykinin (BK) has been postulated to cause hemodynamic changes and cardiac pain during myocardial ischemia, presumably because of the stimulation of cardiac afferent fibers. METHODS: To test the hypothesis that BK results in cardiac reflex responses and can cause the sensation of angina, 10 patients with and without coronary atherosclerosis had BK injected into their right (RCA) and left (LCA) coronary arteries in graded concentrations up to 10(-5) m. Patients were monitored for hemodynamic changes and the presence and quality of pain. RESULTS: Intracoronary BK 10(-5) m caused a significant reduction in blood pressure in most patients with either injection into the RCA or LCA (RCA: 151 +/- 10/90 +/- 5 mm Hg to 119 +/- 11/70 +/- 6 mm Hg, LCA: 161 +/- 11/88 +/- 6 mm Hg to 118 +/- 10/65 +/- 6 mm Hg) that began 12 to 14 seconds after injection. Injection into the LCA also resulted in a significant increase in heart rate (69 +/- 4 to 81 +/- 7 beats/minute), while injection into the RCA did not. Pain occurred after changes in blood pressure in all but one patient, which was present in 5 of 9 patients with RCA injection and 8 of 9 patients with LCA injection, and was often associated with flushing and nausea. Pain caused by BK was not similar to previous clinical ischemic pain in the patients with coronary atherosclerosis. CONCLUSIONS: The absence of a chronotropic response associated with arterial hypotension following injection of BK into the RCA is consistent with activation of cardiac vagal afferents in the left ventricle. The latency and quality of pain in these patients following injection of BK suggests that, while BK is nociceptive, it likely is not the cause of angina in patients with myocardial ischemia. PMID- 8689414 TI - European Spine Society--the AcroMed Prize for Spinal Research 1995. Unexpected load and asymmetric posture as etiologic factors in low back pain. AB - Unexpected loads, which often occur in the working environment, can lead to high forces in the spine and, thus, may be a cause of low back injury. This paper discusses the effect of "sudden load" on the erector spine reaction and amplitude. Muscle responses were mediated by several factors, including fatigue, posture, expectation and rehabilitation, in chronic low back pain patients. The subjects were fatigued by holding a 20% maximum voluntary contraction for 1 min. A functional restoration program was tested for its efficacy in reducing reaction time and EMG amplitude in chronic low back pain patients. Reaction time was longer and EMG amplitude lower in patients than in their matched controls. EMG reaction time and magnitude decreased in patients after a 2-week rehabilitation program, including specific training of coordination and posture control. The results of the modelling showed higher spinal compressive load and lower shear forces when the load was expected than when the load was unexpected. The effect of sudden loads can be exacerbated if a worker is not standing on a flat surface or is fatigued. Chronic low back pain patients have less ability to protect themselves from sudden loads, but they can be trained to improve their response by means of an appropriate rehabilitation program. PMID- 8689413 TI - Clinical efficacy of imaging modalities in the diagnosis of low-back pain disorders. AB - This review provides methodological background and some guidelines for the evaluation of imaging modalities for the lumbar spine and reviews the current literature on the basis of different levels of efficacy which consider standards beyond technical quality or diagnostic accuracy. From a MEDLINE search, 672 articles (1985-1995) were retrieved which focused on the development or application of imaging modalities for lumbar spinal disorders. The papers were categorized according to different efficacy levels at which the imaging modalities were assessed. This review has demonstrated that the vast majority of reports evaluate imaging studies for the lumbar spine only at the technical efficacy level. A minor proportion of the articles focus on the evaluation at the level of diagnostic accuracy. Articles which assess imaging studies on a higher level of efficacy (e.g., diagnostic and therapeutic impact, patient outcome and cost-benefit analysis) are sparse. This review has outlined frequent methodological flaws in patient selection and design of imaging studies for the lumbar spine. The spine specialist should therefore become very critical in the interpretation of those studies and pay attention to patient selection and spectrum, choice of the reference standard, sample size, various forms of biases, and the reasoning behind clinical recommendations in order to improve his patient care. PMID- 8689416 TI - Local control after surgical treatment of spinal metastatic disease. AB - Surgery was carried out on 118 patients with spinal metastatic diseases; 80 operations were palliative and 38 were curative. All patients who survived 1 year or more and all those who had local recurrence before dying (total n = 58) were included in this study. The aim of the study was to identify the factors that determine the success of local control in order to develop a new technique that could prevent local recurrence. From among the different factors that may influence the oncological result, a retrospective study concentrated particularly on the following items: sex of the patient, location and extension of the tumor on the spine, tumor involvement on the vertebra itself, and quality of tumor excision. These factors seem to have no or little influence on local control. However, sensitivity of the primary cancer to adjuvant treatments (e.g., chemotherapy, radiation therapy, hormonotherapy) and correct timing of the radiation therapy, which must be performed after, rather than before, surgery, seem to improve local control significantly. The authors therefore suggest two options for treatment. When the primary cancer is sensitive to adjuvant treatments, 'palliative' surgery with posterior fixation and nerve decompression seems sufficient to attain good function and adequate oncological results. On the other hand, when the primary cancer is resistant to adjuvant treatment or when the lesion recurs after radiation therapy, more aggressive surgery must be carried out. Complete excision of the tumor after embolization, with may be even associated local chemotherapy, is required. However, even when this is carried out, local control is difficult to achieve. PMID- 8689415 TI - Outcome after limited posterior surgery for thoracic and lumbar spine metastases. AB - The efficacy of 'limited posterior surgery' for metastases in the thoracic and lumbar spine was studied prospectively in 51 patients (32 men and 19 women, mean age 64 years). The most common primary tumors were prostate, breast, and renal carcinoma, 37 patients had metastases in the thoracic spine and 14 in the lumbar spine. Indications for surgery were severe pain or neurologic deficit. Of the 46 patients with neurologic symptoms, 25 were unable to walk. Surgery was confined to direct or indirect decompression and stabilization with a pedicle screw fixator over few segments as possible. Pain, as well as a variety of functional performance parameters and residential status were registered preoperatively and after surgery at 3, 6, 9, and 12 months, and at 6-monthly intervals thereafter. Pain was rated by the patient on a Visual Analog Scale, and functional performance was assessed with the Eastern Co-operative Oncology Group (ECOG) Performance Status Scale. We had no perioperative neurologic deterioration or death. Nineteen of the 25 nonambulatory patients regained their walking ability. Postoperative pain relief was significant and lasting over time. Nearly half of the patients attained improvement in functional performance. The median survival was 8 months. Older age and intact postoperative walking ability were positive factors for survival. PMID- 8689417 TI - Spinal fractures in patients with ankylosing spondylitis. AB - Thirty-one consecutive patients with ankylosing spondylitis and spinal fractures were reviewed. There were 6 women and 25 men with a mean age of 60 +/- 11 years; 19 had cervical and 12 had thoracolumbar injuries. Of the patients with cervical fracture, two had an additional cervical fracture and one had an additional thoracic fracture. Three trauma mechanisms were identified: high-energy trauma in 13 patients, low-energy trauma in 13 and insufficiency fracture in 5. One-third of the patients suffered immediate neurological impairment, a further one-third developed neurological impairment before coming for treatment and only one-third remained intact. Two patients with thoracolumbar fractures had deteriorated neurologically due to displacements during surgery at other hospitals. All patients were treated operatively except the two patients with two-level cervical fractures, who were managed in halo vests. In the cervical spine both anterior and posterior approaches were employed. In the thoracolumbar spine the majority of the patients were initially treated using a posterior approach only. Complications were common. Of the 27 patients with neurological compromise, 10 had remained unchanged; 12 had improved one Frankel grade; 4 had improved by two Frankel grades; 1 had improved by four Frankel grades. We conclude that even minor trauma can cause fracture in an ankylosed spine. A high proportion of patients with spinal fractures and ankylosing spondylitis have neurological damage. The risk of late neurological deterioration is substantial. As the condition is very rare and the treatment is demanding and associated with a very high risk of complications, the treatment of these patients should be centralised in special spinal trauma units. A combined approach that stabilises the spine from both sides is probably beneficial. PMID- 8689418 TI - Simultaneous anterior and posterior approaches for correction of late deformity due to thoracolumbar fractures. AB - Thirty-one patients with an average age of 27 years were included in this study to analyze the short-term results of simultaneous anterior and posterior approaches in the treatment of late complications of thoracolumbar fractures. The complications treated were pseudoarthrosis and malunion resulting in neurologic compromise and pain. There were 20 burst fractures, 2 fracture/dislocations, and 9 compression fractures in this group. Average preoperative Sagittal Index was 35 degrees, which improved to an average of 4 degrees after surgical treatment. The average Motor Index Score improved from 90 to 98 after surgery. Average follow-up was 16 months. Average estimated blood loss was 2000 ml and average operation time was 5 h. It was concluded that the late problems associated with thoracolumbar fractures can be addressed quite adequately with simultaneous anterior and posterior approaches. The simultaneous anterior and posterior approach is associated with decreases in operating time, blood loss, and hospital stay. Technical advantages of the simultaneous technique include elimination of acute instability between the stages, protection against dislodgment of the graft, and application of the posterior instrumentation under complete visualization of the anterior graft. PMID- 8689419 TI - Fractures of the odontoid process in small children: biomechanical analysis and report of three cases. AB - Odontoid "fractures" in young children typically involve the cartilaginous plate (synchondrosis) that separates the odontoid process from the body of the axis; 58 cases have been described in the literature. We report two cases in which 2-year old children were involved as backseat passengers in head-on motor vehicle accidents, both were restrained by four-point child's seat harnesses. A biomechanical investigation was carried out using simulation in a real car crash test with a child dummy. This revealed that head-on collisions with a speed absorption of at least 40 km/h are the typical mechanism of injury in children under the age of 3 years involved in motor vehicle accidents. Shearing force is all that is necessary to explain the dens fracture. Both children were immediately symptomatic, and the diagnosis was obvious on radiographs. Neither child had neurological deficit, which correlates well with the literature, where neurological injuries were found only in conjunction with head injuries. After closed reduction, both cases were initially treated conservatively with halo and plaster vest for 12 weeks. In one case, in which the anterior dislocation was less than the diameter of the odontoid shaft, eventless healing occurred. In our second case, despite an anatomic reduction, the odontoid fracture failed to unite. After a temporary posterior fixation of C1/C2 we reamed the synchondrosis from anterior and performed autogenous bone grafting. The posterior fixation wire was removed after 5 months. In contrast to the literature, we do not recommend a permanent posterior fusion of C1/C2. Our two young patients were both followed-up for more than 3 years. Clinical and radiological examination at final follow-up was normal with no signs of atypical growth of the odontoid. In cases of major dislocation with greater instability we recommend primary open reduction and osteosynthesis with appropriate implants. This was done in a third case: a 1 1/2 year-old boy who fell down the stairs and sustained a head injury and an unstable lesion of the odontoid with subtotal paraplegia. The odontoid was fixed with two screws. PMID- 8689420 TI - Pull-out strength of pedicle hooks with fixation screws: influence of screw length and angulation. AB - The pull-out force of thoracic spinal pedicle hooks secured by long fixation screws engaging the posterior portion of the vertebral endplate was measured. The performance of these hooks was compared with that of hooks using a shorter screw and different screw orientation such that the vertebral endplates were not perforated. The longer and differently angulated screws, engaging the endplate, significantly enhanced the fixation potential of the hooks. PMID- 8689421 TI - Central retinal artery occlusion after spinal surgery. AB - Central retinal artery occlusion can be caused by excessive extrinsic pressure on the eyeball during surgery. It is a rare and severe complication after elective spinal surgery. The authors report a case of central retinal artery occlusion in an adult after posterior lumbar spinal fusion in which a rectangular headrest was used. PMID- 8689422 TI - Isotretinoin and recombinant interferon alfa-2a therapy of metastatic malignant melanoma. AB - Twenty-five patients with metastatic malignant melanoma were treated with isotretinoin (13-cis-retinoic acid) orally at 1 mg/kg daily and recombinant interferon alfa-2a (INF-alpha) subcutaneously at 3 million units daily for 16-48 weeks. Therapy was well tolerated; fatigue and hyperlipidemia were the most frequent dose-limiting toxicity and necessitated dose reductions in 14 patients. Two patients achieved a complete response, and 3 responded partially for a total response rate of 20% (95% confidence interval: 4-36%). Responses occurred primarily in patients with limited tumor burden and disease confined to the skin and lymph nodes. Significant elevations in peripheral blood 2'-5'-oligoadenylate synthetase activity and natural killer activity were observed with therapy. The magnitude of these changes, however, was not predictive of response. Biopsy specimens of two responding lesions showed extensive necrosis of tumor. One specimen showed large aggregates of melanophages in association with tumor. The combination of isotretinoin and IFN-alpha is an active, easily administered regimen with acceptable toxicity for metastatic malignant melanoma. PMID- 8689423 TI - Interleukin-3 plus low-dose cytosine arabinoside for advanced myelodysplasia: a pilot study. EORTC Leukemia Group. AB - In an attempt to reestablish normal hematopoiesis in symptomatic myelodysplasia (MDS) and to show the tolerability of a combination treatment of low-dose cytosine arabinoside (LD AraC) and interleukin-3 (IL-3), we treated 31 patients (pts., median age 65 years) who had more than 10% blasts in the bone marrow (BM) and hematopoietic failure with LD AraC (2 x 10 mg/m2 sc, day 1-14) plus IL-3 (once daily sc, day 8-21) at different dose steps (1.0, 2.5, 5.0, and 10.0 micrograms/kilogram body weight). The numbers of each 21-day cycle varied between 1 (3 pts.), 2 (6 pts.), 3 (8 pts.), 4 (1 pt.), 5 (5 pts.), and 6 (8 pts.), in total 116 cycles on an outpatient basis. Subjective tolerability was good in 20 cases (65%). Toxicities were fever (29 pts.), flu-like symptoms (17 pts.), infections (15 pts.), hepatic toxicity (10 pts.), and skin reactions (8 pts.). Overall response was seen in 13 cases (42%) and 5 complete responses (CR), while 10 pts. had stable disease (SD), 5 progressed (2 to acute leukemia), 2 were considered toxic deaths, and 1 died due to the disease. Median survival is 18 months, progression-free survival is 12.5 months (18.0 months in responding pts.), with an actuarial follow-up of 31 months. The data from this phase I/II study show that a combination of LD-AraC and IL-3 is well tolerated and that stable responses can be achieved in MDS by means of an easy outpatient therapy. PMID- 8689424 TI - Alterations in platelet function in patients receiving interleukin-6 as cytokine therapy. AB - Platelet function in 12 cancer patients was studied sequentially over 97 hr of interleukin-6 (IL-6) daily bolus or continuous infusion (C.I.) therapy. During this period, enhanced ex vivo agonist-induced platelet maximum aggregation (MA) was paralleled by an increase in plasma levels of TXB2 and PF4 as measured by RIA and ELISA, respectively. Platelet-rich plasma (PRP) specimens from bolus IL-6 treated patients demonstrated an increased incorporation of actin-binding protein and myosin in the cytoskeletal core (triton insoluble residue) as shown by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) in comparison to control specimens. Similarly, the integrin glycoprotein IIIa (GPIIIa) was also observed to be retained into the cytoskeleton by immunoblot. A significant decrease in hypotonic shock response (HSR) was observed over 87 hr of treatment in IL-6 C.I. patients, whereas in IL-6 bolus patients, a significant increase in HSR occurred immediately after the bolus, which was followed by a significant decrease in HSR after 23 hr. These results suggest that IL-6 alters platelet function in vivo. PMID- 8689425 TI - Delay in the diagnosis of glioblastoma multiforme: is age a factor? AB - Discrimination in the delivery of health care, based on the age of the patient, is attracting increased attention. We investigated this problem by studying possible age-related delay in diagnosis in patients treated for glioblastoma multiforme (GBM). A total of 213 charts of patients with GBM seen from 1972 to 1992 were evaluated for type and duration of symptom, with 204 charts having sufficient data to be analyzed. The mean and median duration of symptoms for the entire group was 48.9 and 28 days, respectively. No age-related difference in duration of symptoms was noted. In light of the increasing incidence of GBM in patients above 60 years of age, further investigation of other possible areas of age discrimination in patients with GBM is warranted. PMID- 8689426 TI - Clinical pharmacokinetics of amonafide (NSC 308847) in 62 patients. AB - Amonafide (A) demonstrates dose-related increases in area under the curve (AUC) and Cmax values. Total body clearance for A (ranging from 44.2 to 53.8 L/hr/m2) is relatively constant within the dosing range of this study. The dose-related increase of AUC was also observed for the two identified metabolites, acetylamonafide (AA) and noramonafide (NA). A and NA plasma data could be described by a four-compartmental model (two compartments for A, one compartment each for NA and AA). The fitting for NA was poor owing to its low plasma concentration. The terminal half-lives for A, NA, and AA were in the range of 3-6 hr. No cumulative accumulation of parent compound or metabolites was detected after daily administration, The concentrations of A, NA, and AA 24 hr after dosing were either below or very close to the quantitative limits of the assay. Polymorphic disposition of A was confirmed by a frequency distribution of AUC value versus dose plot. PMID- 8689427 TI - Role of vitamin D3 on the activity patterns of hepatic drug metabolizing enzymes in transplantable murine lymphoma. AB - Vitamin D3 (D3) has been found to exert varied pharmacological actions including restriction of cell growth of a number of malignant cell lines in vitro and inhibition of the promotion of chemical carcinogenesis in mouse skin. In an attempt to confirm the efficacy of D3 as an antineoplastic agent, the present investigation aims at characterizing the importance of D3 in modulating hepatic drug metabolizing enzymes, namely, cytosolic glutathione S-transferase (GSHT), microsomal UDP glucuronyl transferase (UDPGT), and cytochrome P-450, which have been reported by us in recent literature as significant neoplastic markers in mice bearing Dalton's lymphoma (DL). Results show that D3 causes a 150% elevation of GSHT activity and the maintenance of normal, near-control UDPGT activity and cytochrome P-450 content, up to almost 30 days following tumor transplantation, along with bringing about a twofold increase in survival of the host mice. In conclusion, we confirm the definite and significant antitumorigenic role of D3 and its involvement with the discussed hepatic tumor markers in monitoring the processes that lead to cell survival. PMID- 8689428 TI - Response of small cell carcinoma of pancreas to a small cell lung cancer regimen: a case report. AB - Small cell carcinoma of the pancreas is a very rare malignancy with 18 cases reported in the literature, of which only 3 were treated with chemotherapy. A 52 year-old man was diagnosed with small cell carcinoma originating in the head of the pancreas and invading the duodenum. He was treated with a similar approach as for localized small cell lung cancer, with six cycles of combination chemotherapy and local radiotherapy, and went into complete remission. After 3 months, he developed liver metastases along with an enlarged left supraclavicular lymph node. He was treated with two cycles of CVA, but developed lung metastases and was treated with ifosfamide/mesna. However, his overall condition deteriorated and hospice care was instituted until the patient's demise. The patient survived 14 months following diagnosis, significantly longer than the 15 reported patients with small cell pancreatic carcinomas not treated with chemotherapy. Combination chemotherapy and radiation therapy as it is utilized for small cell lung cancer appear to be beneficial for small cell carcinoma of the pancreas. PMID- 8689430 TI - The potential applications of gene transfer in the treatment of patients with cancer: a concise review. PMID- 8689429 TI - Hypertensive reactions associated with paclitaxel. PMID- 8689431 TI - The case against the routine use of radiation therapy in advanced-stage Hodgkin's disease. PMID- 8689432 TI - The case for adjuvant radiation therapy in advanced Hodgkin's disease. PMID- 8689433 TI - A century of breast cancer surgery. AB - Presented are three consecutive breast cancer series totaling 1912 women, treated by three generations of surgeons. All operations were done in one institution over the last 100 years. Most of the early patients underwent radical mastectomy. The 673 patients in the last series were treated by an assortment of different modalities, reflecting the changing therapeutic concepts of the past 25 years. This report is primarily an historical account showing the improvement in operating conditions and survival figures. Of greater scientific significance is the collection of 50 patients with late-appearing metastases (more than 10 years postoperatively) as well as a group of long-surviving patients with advanced stage II disease. PMID- 8689434 TI - Autologous bone marrow and peripheral blood stem cell transplantation in multiple myeloma. PMID- 8689435 TI - Pilot survey of opinions on data falsification in clinical trials. PMID- 8689436 TI - Alternative cancer medicine: a ten-year update. PMID- 8689437 TI - Glad and terrified: on the ethics of BRACA1 and 2 testing. PMID- 8689438 TI - Breast cancer surgery: a century of change. PMID- 8689439 TI - Urban ozone plumes and population distribution by income and race: a case study of New York and Philadelphia. AB - Who lives in the downwind areas of urban ozone plumes? Location theory suggests that the poor should disaproportionately populate the downwind area, while the rich are most likely to live outside urban ozone plumes. Dynamically, we would expect that the downwind area would become poorer over time because the rich would "vote with their feet" under the serious impacts of urban ozone plumes. However, the importance of urban ozone pollution could be discounted due to the public's risk perception. According to risk and air quality perception literature, one would expect that the public would likely perceive ozone air pollution as a relatively low risk, compared with other environmental risks and social concerns. Therefore, actual population distribution might not follow what location theory suggests. Who actually does live in the downwind areas of urban ozone plumes? The results from a case study of New York and Philadelphia show that the ozone downwind areas are currently populated by a considerably larger proportion of upper income households and whites than the source areas. Furthermore, the population dynamics data do not provide any evidence for the "vote with their feet" hypothesis. While these findings deviate from the hypotheses prescribed by location theory, they are consistent with what we could expect from theories of risk perception. PMID- 8689440 TI - The politics of U.S. health care reform. PMID- 8689441 TI - Market ideology in health care and the Catholic church. PMID- 8689442 TI - Practice-building seminars in chiropractic: a Petit Bourgeois response to biomedical domination. AB - As biomedicine evolved into the preserve of upper-class and upper-middle-class physicians, working-class and lower-middle-class individuals turned to chiropractic as a vehicle of upward social mobility. Practice-building seminars constitute a largely overlooked strategy by which many chiropractors have sought to address their marginal status within the U.S. medical system. Using archival and research data, this article discusses the role of these seminars in assisting chiropractors to convince their patients of the efficacy of their treatment modalities, increase their incomes, and bolster their confidence as heterodox medical practitioners. PMID- 8689443 TI - The Catholic church and U.S. health care reform. AB - The Catholic Church is the largest (and arguably the best organized) single denomination in the United States, and it has extensive holdings in the health care field. It therefore has a material stake in the current debate over health care reform, as well as a moral interest in a question touching on the ethics of resource distribution. The position of the church on health care is analyzed as a case study of how organized religion interacts with and attempts to influence social policy in a pluralistic society. PMID- 8689444 TI - Mandinka mothers and nurslings: power and reproduction. AB - In a traditional Mandinka village of the Casamance Region of Senegal, indigenous understanding of the interdependencies of women and their children include not only patterns of nursing but the prospects for continued fertility as an outcome of the mother/nursling relationship. Based on two years of participant observation and focused observations of 40 nursing mothers and their children from birth to over 12 months of age, this study examines breastfeeding as a relationship that is part of the process of dali lo, or socialization to the "Mandinka way." Patterns of nursing are elaborated by women's recognition of the power of fetuses and young children to control fertility, a power that affirms the concomitant role of nursing mothers as being agents of culture who nurture and wean cultural novices. The methodological implications of the female ethnographer as a social location for traditional fertility work and the ethnographers' child as resistant cultural novice are also discussed. PMID- 8689445 TI - The purity of water at hospital and at home as a problem of intercultural understanding. AB - Women in a provincial town in southern Nepal were instructed by medical doctors and compounders to boil water, and to keep it boiling for 15 minutes before mixing it with infant formula or oral rehydration salts. Most women ignored the advice. Those who seemed to follow it merely brought the water to boil. This report describes how and why women boil water and assesses the health implications of their practices. The failure of women to adopt "proper" procedures procedures provides a point of entry into an analysis of the role of intercultural dialogue in exposing one's presuppositions about health and empowering one to change them. PMID- 8689446 TI - HIV and the social world of female commercial sex workers. AB - This research, based on repeated interviews with 12 female commercial sex workers (SWs) in Perth, Australia, attempts to explain why SWs in that city are not a source of transmitting HIV to clients during sexual intercourse. Perth SWs report that they routinely use condoms during work-sex. But it was also found that they are at risk of being infected with HIV through sexual intercourse with boyfriends and husbands because use of condoms during sexual intercourse with these men is reportedly rare. This pattern of selective condom use is part of the larger social world within which SWs use, with varying degrees of success, six strategies to demarcate work-sex from nonwork-sex. Within this social world SWs also construct six rationales to help them cope with the threat of HIV infection during nonwork-sex. Further research into this social world may help to lessen the threat of HIV infection to these women. PMID- 8689447 TI - Sex, drugs, and the spread of HIV/AIDS in Belle Glade, Florida. AB - Belle Glade, Florida, an agricultural community in the heart of the state's vegetable and sugar cane production areas, has the highest cumulative per capita incidence of AIDS in the United States. A risk reduction intervention program was introduced to lessen unsafe AIDS-related behaviors and to generate data on the epidemiology of HIV infection. Initial attention focused on individuals who were believed to be at the core of the transmission pattern, injection drug users and their sexual partners. We found, however, that injection drug use was much less widespread than anticipated. Results suggested that the primary mode of HIV transmission is heterosexual intercourse-mediated by drug taking (particularly crack smoking) and a flourishing sex industry-a finding that is corroborated by the increased and disproportionate rate of heterosexual AIDS in Belle Glade. The prevalence and types of risk behaviors engaged in would not have been completely explained without the use of ethnographic methods including observation of, and lengthy interviews with, the populations at risk. PMID- 8689448 TI - Antineoplastic agents. AB - Advances in the field of oncology have led to the development of many antineoplastic agents for the treatment of cancer. Combination with other agents and modalities, along with dose intensification, has resulted in more toxicities, often requiring careful management and monitoring in the critical care setting. Critical care nurses must meet this challenge by expanding their knowledge of antineoplastic therapy in order to skillfully care for these patients. The six major categories of antineoplastics, mechanism of action, indications for use, common route of administration, and major side effects are discussed. PMID- 8689449 TI - The challenge of handling chemotherapy in the intensive care unit. AB - Newer, more intensive cancer treatments and even some standard treatments in critically ill cancer patients mandate provision of care in the intensive care unit (ICU). Traditionally, the ICU nurse has not had specialized training in the preparation or administration of chemotherapeutic agents. This article discusses educational needs and specific information related to safe handling of chemotherapy administration. PMID- 8689450 TI - Oncology emergencies. AB - Oncology patients have numerous complications that are life threatening and may require an admission into the intensive care unit (ICU). Most ICU nurses have a limited understanding of how to assess and treat this type of patient population. Three of the most common oncologic emergencies that can be seen in an ICU are malignant pleural effusion, cardiac tamponade, and superior vena cava syndrome. Each of these disease entities will be defined to introduce the ICU nurse to oncologic emergencies. PMID- 8689451 TI - Hematologic emergencies in the intensive care unit. AB - Hematologic emergencies in the oncology population may require an admission to the intensive care unit (ICU). Syndrome of inappropriate antidiuretic hormone, hypercalcemia, tumor lysis syndrome, and disseminated intravascular coagulation are diseases defined in this article. These are common conditions in oncology patients that are reduced or prevented with close monitoring and accurate assessments. The purpose of this article is to introduce intensive care nurses to these disease entities so they will have a better understanding of the care involved with an oncology patient in the ICU unit. PMID- 8689452 TI - Ethical considerations in treating oncology patients in the intensive care unit. AB - The care of oncology patients within an intensive care unit (ICU) setting poses an added dimension of ethical concerns faced by practitioners. This article reviews/highlights some of the issues confronting ICU staff when caring for an oncology patient. The issues addressed include: access/admission of the oncology patient to the ICU, advance directives, and the withdrawal of life-sustaining treatments. PMID- 8689453 TI - An introduction to music therapy: helping the oncology patient in the ICU. AB - Oncology and critical care patients have unique and complex problems. With the explosion of technology and advances in medicine, many intensive care units are seeing an increase in oncology patients. Intensive care units are stressful and frightening; music therapy is a noninvasive holistic approach to bridging the gap between oncology patients and intensive care units. PMID- 8689454 TI - A new collaborative practice: critical care and hematology/oncology--altering the misconceptions. AB - For the two decades of development, intensive care units and hematology/oncology units have been separate entities, very territorial over their patient populations and precise in their expertise. The interactions between these units were minimal, and, therefore, many misconceptions have developed through the years. Some of these views have truth, and others are challengeable. A competitive rivalry has often developed between these two areas of expertise. However, with new technologies and therapies being investigated, these two units are interfacing to benefit patient care. Misconceptions can lead to fragmented care of the patient; poor communication between staff, units, patients and family members; and an increased stress level. The intent of this article is to define some of the most common misconceptions between these two disciplines and increase an understanding of each discipline's contribution to the well-being of the patient. PMID- 8689455 TI - A holistic perspective on comfort care as an advance directive. AB - Critical care nurses are frequently involved with patients and families who must choose among the various advance directives. Although "comfort care" is a familiar option, there is a lack of clarity about specific components of comfort as well as the nurse's role as a member of the interdisciplinary team. This lack of clarity can result in disruption of the patient or family decision-making process surrounding impending death. This article defines comfort care as a holistic and positive choice for patients and families among advance directive options. A two-dimensional grid is applied to assist with discussion and decision making regarding the dying process. Methods for applying the framework and developing a care plan are presented in case study format. Practicing these methods will enable critical care nurses and other team members to empower patients and families to work through the dying process with optimal comfort. PMID- 8689456 TI - Care of the elective intracoronary stent patient. AB - Recently, the Palmaz-Schatz coronary stent was approved by the FDA as an alternative to coronary angioplasty in the treatment of de novo native coronary stenosis. Developed by Dr. Julio Palmaz and Dr. Richard Schatz, the Palmaz-Schatz intracoronary stent design was implanted in 1987 at Brooke Army Medical Center. During the past 7 years, The University of Texas Health Science Center-San Antonio (clinical sites include University Hospital, Brooke Army Medical Center, and Audie Murphy Veterans Administration Hospital) has used this intracoronary stent to treat more than 300 patients. Nursing care for this patient population is both distinct and challenging. Successful patient outcomes require a knowledgeable staff and a team approach. This article will emphasize the nursing care and patient education required both before and after the stent procedure, as well as considerations for long-term follow-up. PMID- 8689457 TI - The role of viscosupplementation with hylan G-F 20 (Synvisc) in the treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone. AB - To determine the safety and efficacy of viscosupplementation with hylan G-F 20, a cross-linked hyaluronan preparation, used either alone or in combination with continuous non-steroidal anti-inflammatory drug (NSAID) therapy, a randomized, controlled, multicenter clinical trial, assessed by a blinded assessor, was conducted in 102 patients with osteoarthritis (OA) of the knee. All patients were on continuous NSAID therapy for at least 30 days prior to entering the study. Patients were randomized into three parallel groups: (1) NSAID continuation plus three control arthrocenteses at weekly intervals; (2) NSAID discontinuation but with three weekly intra-articular injections of hylan G-F 20; and (3) NSAID continuation plus three injections, one every week, intra-articular injections of hylan G-F 20. Outcome measures of pain and joint function were evaluated by both the patients and an evaluator at baseline and weeks 1, 2, 3, 7 and 12, with a follow-up telephone evaluation at 26 weeks. At 12 weeks all groups showed statistically significant improvements from baseline, but did not differ from each other. A statistical test for the equivalence, the q-statistic, demonstrated that viscosupplementation with hylan G-F 20 was at least as good or better than continuous NSAID therapy for all outcome measurements except activity restriction. At 26 weeks both groups receiving hylan G-F 20 were significantly better than the group receiving NSAIDs alone. A transient local reaction was observed in three patients after hylan G-F 20 injection; only one patient withdrew from the study as a result and all recovered without any sequela. Hylan G-F 20 is a safe and effective treatment for OA of the knee and can be used either as a replacement for or an adjunct to NSAID therapy. PMID- 8689458 TI - Phenotypic modulation of newly synthesized proteoglycans in human cartilage and chondrocytes. AB - The proteoglycans synthesized by human osteoarthritic femoral head cartilage and nonarthritic articular cartilage age-matched to the osteoarthritic cartilage specimens was studied in explant cultures and in chondrocytes generated by explant outgrowth from the cartilages. Twenty-four hours after explanation, both nonarthritic articular cartilage and osteoarthritic cartilage synthesized principally one large proteoglycan core protein that migrated on 3-5% acrylamide gels with an apparent molecular mass (M(r)) of approximately 520 kDa after enzymatic digestion with chondroitinase ABC and keratanase. The proteoglycan was found in both the explant itself and in the medium compartment of the culture as well. This proteoglycan contained chondroitin-6-sulfate, keratan sulfate and the hyaluronan binding region as evidenced by immunoblotting with murine anti proteoglycan monoclonal antibodies indicating that the proteoglycan was aggrecan. To a much lesser extent two additional proteoglycan core proteins were also found in the explant but were not seen in the culture medium compartment. These proteoglycans possessed apparent M(r)'s of approximately 480 kDa and approximately 390 kDa on 3-5% acrylamide gels after chondroitinase ABC and keratanase digestion. The medium compartment contained principally the approximately 520 kDa proteoglycan core protein. In osteoarthritic cartilage explants, the pattern of newly synthesized proteoglycans recovered from the tissue as assessed on 3-16% polyacrylamide gradient gels remained relatively the same from day 1 after explantation up to 36 days of culture. By contrast, the proteoglycans recovered from the culture medium contained chondroitin sulfate and keratan sulfate after 1, 7, and 21 days in culture but by 36 days appeared to contain only chondroitin sulfate. Chondrocytes generated from osteoarthritic cartilage and age-matched nonarthritic articular cartilage synthesized different patterns of large (greater than 200 kDa) proteoglycan. Whereas chondrocytes derived from osteoarthritic cartilage continued to synthesize principally the approximately 520 kDa proteoglycan core protein, the chondrocytes derived from nonarthritic cartilage synthesized in addition to this proteoglycan, abundant amounts of the other two proteoglycan core proteins as well. PMID- 8689459 TI - The interactions of 'non-aggregating' proteoglycans. AB - The small proteoglycans decorin, biglycan and fibromodulin were prepared as a mixture from bovine nasal cartilage. The proteoglycans in this mixture were shown to interact with hyaluronate immobilized on Sepharose beads under isotonic conditions. The interaction could be disrupted by increasing the ionic strength of the solvent by enhancing the concentration of NaCl. To further characterize the proteoglycans of this mixture, they were visualized with the glycerol spraying/rotary shadowing technique for electron microscopy. They were shown to have a globular core protein and one or more glycosaminoglycan chains. The molecules, moreover, were organized as multimeric complexes, and their association one with another appeared to be mediated by either core protein or glycosaminoglycan chain interactions. Complexes were shown by rotary shadowing microscopy to associate with hyaluronate in solution. The combined results necessarily as discrete monomers but rather as multimeric complexes. The observations made in this study also suggest that a similar interaction could occur in vivo, where the interaction between small proteoglycans and hyaluronate may have a functional significance in the maintenance of cartilage homeostasis. PMID- 8689460 TI - Standardization of nutrient media for isolated human articular chondrocytes in gelified agarose suspension culture. AB - Human articular cartilage cells were cultured in 1.5% agarose in Dulbecco's modified Eagle's medium (DMEM) with 10% fetal calf serum or in serum-free DMEM with 0.15% bovine serum albumin. 35S-aggrecan synthesis in serum-free DMEM was between 20% and 30% of the value observed in DMEM supplemented with 10% fetal calf serum. The extent to which different growth or differentiation factors were able to restore 35S incorporation in aggrecan in serum-free DMEM was determined: human serum transferrin had no effect on aggrecan synthesis levels; bovine pancreas insulin, insulin-like growth factor (IGF)-1 and IGF-2 restored 35S aggrecan synthesis to 35-50% of the control levels. The effects were dose dependent, to level off at 100 ng/mL for the three factors. No cumulative or synergistic activities were observed when these factors were combined. Transforming growth factor (TGF)-beta, at concentrations ranging from 10-50 ng/mL stimulated aggrecan synthesis to approximately 50% of the control values in the chondrocytes obtained from two out of four donors, while the cells of the other two maintained within the range of the control levels. In th presence of insulin (100 ng/mL) 10 ng/mL of TGF-beta stimulated aggrecan synthesis to more than 90% of the control level in the chondrocytes of all donors. PMID- 8689461 TI - Osteoarthritis of the knee after injury to the anterior cruciate ligament or meniscus: the influence of time and age. AB - The degree of cartilage changes by arthroscopic and radiologic examination was evaluated in a retrospective, cross-sectional study of 1012 patients with knee complaints at different times after knee injury. Patients were classified by age, sex, trauma date and type of injury. The condition of the cartilage was graded on a 1-10 scale based on findings at arthroscopy and on weight-bearing radiographs. Patients with injury to the anterior cruciate ligament (isolated or combined with injury to meniscus or collateral ligaments) showed the first radiologic signs (joint space narrowing) of osteoarthritis (OA) at an average age of about 40 years, while patients with isolated meniscus injury had the same stage of disease at an average age of about 50 years. Both study groups displayed the first radiologic signs of OA on average about 10 years after the injury and showed increasingly serious arthroscopic and radiologic signs of joint damage with increased time between injury and examination. For patients who sustained an isolated meniscus injury between the ages of 17 and 30, the average time until development of radiologic signs of OA was about 15 years, while for those who had the same injury over the age of 30, the corresponding time interval was only about 5 years. We conclude from this that knee OA becomes increasingly severe with increased time between joint injury and examination. OA changes appear sooner in older patients with knee injury than in the young. PMID- 8689462 TI - Intra-articular hyaluronic acid compared to intra-articular triamcinolone hexacetonide in inflammatory knee osteoarthritis. AB - The aim of this study was to determine the comparative efficacy and safety of intra-articular (i/a) triamcinolone. hexacetonide (TH) and i/a hyaluronic acid (HA) in inflammatory knee osteoarthritis. A randomized double-blind comparative trail was carried out in a rheumatology outpatient department. There were 63 patients (24 male, 39 female, mean age 70.5 years) with bilateral symptomatic knee osteoarthritis with effusion. Each was given five HA injections at weekly intervals; or 20 mg TH followed by four placebo (saline) injections. Patients were examined weekly during the treatment period and then at monthly intervals for a further 6 months. Assessment included recording of: visual analog scores (VAS) for pain; duration of stiffness; range of movement; joint effusion; local heat; synovial thickening; joint-line and periarticular tenderness. The principal outcome measure was pain on a self-selected activity assessed by Vas. The two groups were comparable at entry and no significant differences between the groups developed at any time during the treatment period. However, there was a high drop out rate and intention to treat analysis failed to demonstrate statistically significant differences between the groups. In patients remaining in the study, significantly less pain was experienced by the HA group during the 6 month follow up period. Other parameters showed a similar trend in favor of experienced by the HA group during the 6 month follow-up period. Other parameters showed a similar trend in favor of HA. We could not, however, demonstrate significant differences between the placebo and active treatments. HA may therefore be a useful additional therapy for symptomatic knee osteoarthritis and may have a long duration of action. PMID- 8689463 TI - Cyclic loading is harmful to articular cartilage from which proteoglycans have been partially depleted by retinoic acid. AB - We studied whether cyclic loading is harmful to degraded cartilage. Sets of four cartilage-bearing sesamoid bones were dissected from 5-year old cows. One bone from each set was cultured for 17 h in control medium to serve as an ex vivo control. The three others were cultured for 1 week in control medium to which 0, 10 or 300 ng/mL retinoic acid (RAc), which depletes the cartilage matrix of proteoglycans, had been added. Two were then cultured for another week in control medium. During the last week, one of the two was subjected to a cyclic load (1 MPa, 0.2 Hz). Following treatment with RAc, glycosaminoglycan content and synthesis were significantly decreased, as confirmed by safranin O staining and autoradiography. They were further diminished by loading during the second week of culture. Increased amounts of 3-B-3(-)epitope were found in cartilage that had been treated with 300 ng/mL RAc and then loaded. While loading cartilage matrix that was only slightly degraded proved to be damaging, loading severely degraded cartilage matrix apparently induced osteoarthritic-like changes. PMID- 8689464 TI - [Physical complaints in old age: standardization of the Giessen Complaint Questionnaire GBB-24 in over 60-year-old patients]. AB - Psychosomatic and functional body complaints in the elderly became more significant in psychosomatic research and therapy during recent years. On the other hand, there is a lack of epidemiological studies on this topic. The present paper presents results of a study with a community sample of 764 elderly older than 60 years. Body complaints were self-rated by the Giessener Beschwerdebogen (The Giessen Subjective Complaints List) GBB (Brahler and Scheer, 1995). This study presents age-specific and sex-specific norms for the GBB. Compared to representative samples of younger people (< 30 years of age, 30-60 years of age) we found a significantly higher amount of body complaints in the elderly (exhaustion, stomach trouble, rheumatic pains, heart trouble, and the sum score of body complaints). Within the age group over 60 years, there is an increasing amount of body complaints with higher age. The amount of body complaints is higher for women than for men. Besides analyzing age-specific and sex-specific body complaints, the correlation with personality characteristics and with life satisfaction and the influence of health-related beliefs were analyzed. There were greater body complaints in elderly with depressive mood and with low internal control beliefs regarding health. The elderly that consider the psychological influence on health significant experience a greater amount of body complaints than the other. PMID- 8689465 TI - [Aging and performance in various tasks of prospective memory]. AB - Studies on the prospective memory performance of adults suggest that in everyday tasks like sending postcards at appointed times there is no age deficit for older subjects compared to younger adults. In contrast, laboratory prospective memory tasks often find age deficits. In a study with young and old adults we tested the hypothesis of older people being better in prospective memory performance in a number of different prospective memory tasks. We also related the performances in everyday and laboratory prospective memory tasks. In addition, we compared performances with respect to the amount of cognitive resources demanded by the different prospective memory tasks. Our results suggest that age deficits in prospective memory tasks are more likely the more laboratory-like a task is, that there is no simple relationship between performances in everyday and laboratory tasks, and that older adults are particularly handicapped when a prospective memory task makes high monitoring demands. PMID- 8689466 TI - [Longitudinal analysis of change in sports performance of women between ages 30 and 75: a comparison between peak and leisure sports participation]. AB - The paper considers motor development in women aged 30 to 75 years. The present research examines performance changes in several track and field disciplines comparing senior master athletes and competitors on a mass sport level. The change itself and its acceleration is expressed by the linear and the coefficients of quadratic polynomials fitted to the original and the z transformed data. Correlation-, regression- and cluster analysis as well as Manova were conducted with the coefficients and the original data from 585 and 224 repeated measurement series. Significant differences were found for the original data and the change parameters: 1) Between the two groups considered longitudinally and cross-sectionally, 2) within both groups concerning several disciplines and age groups considered longitudinally and cross-sectionally. Further research will be conducted with additional methods to support the present findings. The most important issue will be to investigate the interaction between the observed pattern and external variables concerning training effort, lifestyle, state of health, life events and personality traits gathered from the group at the mass sport level. PMID- 8689467 TI - [Quality of life of over 60-year-old patients with breast and uterine carcinoma, 5 years after primary operation]. AB - In the 5-year follow-up period, we studied the quality of life of 145 patients who were at least 60 years old at the time of primary operation. Of the patients, 70 women had breast cancer and 75 endometrium cancer. We used the questionnaire "short form health survey: medical outcomes study". The areas which were analyzed were stress due to therapy, body image/femininity and social contacts. The Karnofsky-Index was determined by the physician. In both groups, most stress was felt due to the operation and at the first knowledge of the diagnosis. In the area of emotional stress 1/3 of the patients of both groups declared continuous stress due to feelings of fear, helplessness and passivity. In the area of body image/femininity half the patients with breast cancer and 2/3 with endometrial cancer felt stress. In the area of social contact 2/3 of the patients felt uncertainty in contact with others and this led to social retreat in 1/3 of the women. The Karnofsky-Index of all patients was between 50-100%. Our study supports the view that older patients with cancer should also be offered psychosocial counseling. PMID- 8689468 TI - [Perception of stress by caregiving relatives of dementia patients]. AB - The increasing interest in research on burden and health risks of family caregivers was furthered by the increasing prevalence rate of dementias in the elderly and by the fact that 80-90% of the demented are cared for by near family members. The present paper presents some results of a study investigating stress related symptoms of family caregivers. From a clinical perspective these results point to needed interventions for supporting the caregivers. Specific burden components, depression, and body complaints were assessed in n = 70 family caregivers of dementia patients. A substantial degree of social isolation, depressive disorders, and physical complaints could be found. The level of burden experienced was not directly related to severity of dementia and to impairment of the demented or to structural conditions of the care (degree and length of care). Differences were observed between spouse caregivers and other relatives; spouses suffer more psychosomatic complaints and depression. PMID- 8689469 TI - [Guidelines for integrated management of demented patients in nursing homes for the elderly]. AB - Currently, 30% and above of residents of geriatric care centers are suffering from dementia, most of them in an advanced stage of disease. In 1987, the "Landschaftsverband Rheinland" introduced the so-called "Zuschlagsverfahren" (i.e., additional nursing fees) to promote an integrative care concept for demented people in these institutions. This procedure includes expert rating of the residents, "screening" of the quality of care and teaching of the institutional staff in the field of gerontopsychiatry. The introduced guidelines for integrated care of demented residents of geriatric care centers emerged from practical work in and for such institutions. The guidelines emphasize the inmate oriented care and housing concept, focusing on the individual biography and on qualified personnel management. An organizational structure is needed that supports the revised care and housing concept. PMID- 8689470 TI - [Current status: nursing care insurance shortly before the introduction of the second stage--attempt at sociopolitical interim evaluation]. PMID- 8689471 TI - [Aspects of physical capacity and quality of life in old age]. PMID- 8689473 TI - Measurement of astigmatism arising from the internal ocular surfaces. AB - A method is described for measuring internal ocular surface (posterior cornea, anterior and posterior crystalline lens) astigmatism. This involves the use of videokeratography, A-scan ultrasonography, and autorefractometry along with multi meridional phakometric measurements of Purkinje images I(anterior corneal surface) II(posterior corneal surface) and IV(posterior lens surface). Data was collected from both eyes of 66 subjects. Right and left eyes exhibited similar mean levels of astigmatism from the posterior corneal surface (R + 0.21 DC axis 82 degrees; L + 0.22 DC axis 80 degrees), anterior lens surface (R + 0.52 DC axis 8 degrees; L + 0.49 DC axis 165 degrees) and posterior lens surface (R + 1.48 DC axis 99 degrees; L + 1.16 DC axis 90 degrees). It was generally found that astigmatism arising from the anterior corneal and lens surfaces in conjunction with intraocular distance effectivity are almost completely compensated for by the posterior corneal and lens surface. Repeatability was assessed on 20 subjects. Although the methods is prone to accumulated experimental errors, these are random in nature so that the difference between repeat group averaged data never exceeded +/- 0.27 DC cylindrical component and +/- 6 degrees cylinder axis. PMID- 8689472 TI - [Wellbeing, health and autonomy in old age: the Basal IDA Study (Interdisciplinary Aging Study)]. AB - Current research on successful aging reflects a multicriteria approach, although a consensus on the interrelationship between different factors has not yet been achieved. The longitudinal-sequential study presented here aims at identifying psychological, biological and sociobiographical predictors of well-being, health and autonomy in old age and their interdependency. The concern of this study is thus a multidisciplinary approach including psychology, psychiatry, geriatrics and sports sciences. The ongoing study is described and first findings are reported. Four hundred and forty-two people, aged 65 to 94, were tested twice (1993 and 1995). Since this project is a pursuit of a medical longitudinal study (Basler-Studie), bio-medical parameters from former status measurements (1960, 1965, 1971, 1985, 1990) are available and taken into account for comparison with the newly collected data from 1993 and 1995. The tests included both a medical examination and cognitive and personality measurements. The medical test battery included: clinical and anthropometrical data, bio-chemical data as well as the medical history, health behaviour, complaints and subjective health. The psychological assessment included psychological well-being, health-related control beliefs, causal attribution, religiosity, etc. For memory assessment a computerized test was used which allows to test 1) perceptual error-scanning, 2) naming speed, and memory resources in terms of 3) capacity, 4) explicit and 5) implicit components. It therefore integrates direct (free recall, recognition) and indirect memory tests (perceptual identification: clarification), that were used previously in different experimental and quasi-experimental studies to investigate memory performance over the life-span. Furthermore, the following three experimental interventions are performed: memory and reattribution training, physical training and psychoanalytical group therapy. First descriptive results are presented concerning age-correlated changes in biological and medical parameters, health behavior, cognitive performances and psychological well-being and functional autonomy. The results show the strongest age effects in the cognitive variables (with the exception of priming). Beside age effects in speed variables and episodic memory we also find an age-correlated decline in semantic memory. Psychological well-being however, is not affected by age. PMID- 8689474 TI - Distribution of alpha 6 and beta 4 integrins following epithelial abrasion in the rabbit cornea. AB - Integrin complex alpha 6 beta 4 is a component of the hemidesmosome. In the unwounded cornea both the integrin subunits face the laminin-containing basement membrane, but the alpha 6 subunit is also located between the basal cells. While the migrating epithelium is known to be without hemidesmosomes, we investigated the distribution of alpha 6 beta 4 during epithelial healing. Epithelial abrasion 7.5 mm in diameter was mechanically created. The rabbits were killed 1-24 h or 2, 3, or 7 days later. Monoclonal antibodies against alpha 6, beta 4, and laminin A were used to detect their distributions by immunohistochemistry. Positive immunostaining for laminin A on the surface of the unepithelialized stroma indicated that basement membrane was intact after the epithelial abrasion. Three hours after corneal wounding, alpha 6, was detectable around the entire cell up to the leading edge of the migrating epithelium. In the peripheral wound, alpha 6, was also prominently present around the basal and suprabasal cells with only the superficial cell layers being negative. The beta 4 subunit showed a dissimilar distribution; it was not detectable subjacent to the leading edge. After 1 h the immunoreaction for the beta 4 subunit had faded 15 - 20 microns peripheral to the wound margin. Thereafter the subepithelial band was segmentally reassembled, starting from the periphery and progressing toward the central area of the wound. One week after epithelial wounding, immunolabeling for both integrin subunits was indistinguishable from that of the control cornea. Our results indicate that in addition to the beta 4 in the rabbit cornea, the alpha 6 subunit is also complex with another beta subunit during the epithelial healing phase. The results also suggest that basal cells 15 - 20 microns peripheral to the wound margin disassemble their HDs prior to the migration process. PMID- 8689475 TI - Isolation and in vitro propagation of human choroidal fibroblasts. Morphology and characterization of the cultures. AB - Subretinal ingrowth of choroidal fibroblasts is of importance in several clinical settings such as age-related macular degeneration or after traumas such as laser treatment and infection. In the present investigation we describe a method for isolation and propagation of human choroidal fibroblasts in vitro. Outgrowth from the outseeded choroid was studied by means of phase contrast microscopy, scanning electron microscopy and by immunohistochemical methods. The secondary cultures were found to contain almost only fibroblasts (more than 95% of the cells), some contaminating retinal pigment cells were also found. Choroidal fibroblasts contribute to the fibrovascular subretinal scarring process, and our cell culturing system seems to be a suitable tool for studying factors regulating the behavior of these cells in vitro. PMID- 8689476 TI - Dominant optic atrophy mapped to chromosome 3q region. II. Clinical and epidemiological aspects. AB - Sixty-two patients from three large Danish families with autosomal dominant optic atrophy were clinically examined, and retrospective follow-up was made on 30 patients. We found great inter-and intrafamiliar variation in visual acuity and visual decline. One hundred and seventy-five chromosomal markers were analyzed in 118 family members. Linkage was demonstrated between the disease gene (OPA1) and the microsatellite markers D3S1314, D3S1262, D3S1265 and D3S1601, with the highest Lod score to D3S1601 Z=11.75. All markers are located on chromosome 3q in the telomeric area, the most probable location for the OPA1 gene being D3S1601 OPA1-D3S1265. Using data from the Danish Family Register of Hereditary Eye Diseases, the minimum prevalence rate was estimated to 1:12.301, making DOA the most common hereditary optic atrophy. PMID- 8689477 TI - The effect of TGF-beta 1 and TGF-beta 2 on the proliferation of human Tenon's capsule fibroblasts in tissue culture. AB - This study examines the effect of transforming growth factor beta 1 and 2 (TGF beta 1 and TGF-beta 2) on the proliferation of human Tenon's capsule fibroblasts in tissue culture. Both TGF-beta 1 and TGF-beta 2 were shown to stimulate proliferation at 1000 and 100 pg/ml concentrations. We discuss the significance of these findings with respect to wound healing following trabeculectomy, and postulate why some eyes are more at risk of failure than others. PMID- 8689478 TI - Vascular occlusion in diabetic retinopathy. A qualitative and quantitative histopathological study. AB - The retinal vessels from seven diabetic patients and from six age-matched normal controls were studied qualitatively and quantitatively using various histological staining techniques. In diabetic patients the walls of retinal arterioles and capillaries showed significantly more staining than normals for periodic acid Schiff (neutral glycoproteins), Sirius red (connective tissue), and for Alcian blue at pH 2.6, pH 5.8 and at pH 5.8 combined with MgCl22 in concentrations less than 0.9 M (acid mucopolysaccharides). In the retina from diabetic patients there was no difference between the number of capillaries staining with these dyes in areas of vascular occlusion, and in adjacent control areas. Furthermore, in areas of vascular occlusion, the material accumulated centrally to occlude the lumen of ghost vessels did not stain with any of the dyes used. A homogenous material, accumulated in the outer retina in areas of vascular occlusion in the retina from diabetic patients, only stained with Alcian blue at pH 5.8 combined with MgCl2 in concentrations less than 0.4 M, suggesting a different molecular composition from the Alcian blue material accumulated in the retinal vascular walls. The findings are in accordance with the knowledge that basement membranes of retinal vessels are thickened in diabetes mellitus. However, the findings also indicate that basement membrane thickening cannot fully account for vascular occlusion in diabetic retinopathy. PMID- 8689479 TI - Effects of hyper- and hypo- thyroidism on oxidative stress of the eye in experimental acute anterior uveitis. AB - Glutathione peroxidase activities and malondialdehyde levels were measured in the homogenated anterior segment of rat eyes with endotoxin induced acute anterior uveitis in euthyroid, hyperthyroid and hypothyroid rats. Malondialdehyde concentrations were found to be significantly increased (p < 0.0005) and glutathione peroxidase activities significantly decreased (p < 0.01) in the hyperthyroid group when compared with controls. Malondialdehyde concentrations of the hypothyroid rat eyes were higher than the control group (p < 0.05), but glutathione peroxidase activities of the same group showed no difference with controls (p > 0.05). These results suggest that excess or deficiency of the thyroid hormones cause alterations in the malondialdehyde levels and glutathione peroxidase activities of the rat eyes in endotoxin induced uveitis, and hyperthyroidism may increase the oxidative stress in endotoxin induced acute anterior uveitis. PMID- 8689480 TI - Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). AB - The blepharophimosis-ptosis-epicanthus inversus syndrome is characterized by shortening of the horizontal orbital fissure (blepharophimosis), congenital ptosis and epicanthus inversus. The condition may occur either as an autosomal dominant trait (blepharophimosis-ptosis-epicanthus inversus syndrome types 1 and 2), or sporadically. Blepharophimosis-ptosis-epicanthus inversus syndrome type 1 is associated with female infertility. Mental subnormality may occur, especially in the sporadic cases. Chromosome analysis from a few patients suggests that the genetic defect causing the syndrome is localized to chromosome 3q22. PMID- 8689481 TI - Frequency of congenital hypertrophy of the retinal pigment epithelium in familial adenomatous polyposis. AB - Congenital hypertrophy of the retinal pigment epithelium is a recognized clinical marker in familial adenomatous polyposis as an expression of the altered gene in this autosomal dominant disease. Ocular lesions could be discovered years before the development of intestinal polyposis. We studied 29 diagnosed patients, 38 relatives (first degree) of familial adenomatous polyposis kindreds and 26 controls (general population). Number, size and bilaterality of pigmented lesions were analysed in order to separate members affected and non affected by intestinal polyposis in familial adenomatous polyposis kindreds. Three of 26 families (23%) had patients with polyposis and normal fundus. Bilaterality and more than 4 lesions improved specificity or sensibility of the fundus examination. However, the best efficacy of the test was obtained with large lesions (sensibility 0.82 and specificity 0.97). PMID- 8689482 TI - Pattern dystrophies of the retinal pigment epithelium. AB - Pattern dystrophies of the retinal pigment epithelium are infrequent fundus abnormalities arranged in various patterns of dots, lines and branches. The basic lesion appears to be yellow deposits of abnormal lipofuscin accumulated within degenerated retinal pigment epithelium cells. Examinations were carried out on two families who had developed different patterned alterations in the retinal pigment epithelium. The proband of family 1 had diffuse changes associated with equatorial folds. One sister had a macular alteration. A daughter was normal; a son had bilateral atrophy of the temporal retinal pigment epithelium. The proband of family 2 had bilateral, symmetrical retinal pigment epithelium lesions that simulated fundus flavimaculatus. His first daughter had a central lesion in her right eye. The second daughter, a peripapillary crescent of hyperpigmentation in her right eye, and circumpapillary chorioretinal atrophy associated with foveolar abnormalities in the left. This report provides further evidence that variable types of pattern dystrophy can occur within a single family pedigree and support the current opinion that all forms of pattern dystrophies are variants of a single pathogenic mechanism. PMID- 8689483 TI - Practices styles and preference of Danish cataract surgeons--1995 survey. AB - A survey of the practice styles and preferences of the 348 members of the Danish Ophthalmological Society with address in Denmark was performed in January 1995, 51.4 percent (179) of the questionnaires were returned. The low percentage of returned answers is mainly due to non-response from ophthalmologists not performing cataract surgery. The data from the questionnaire were compared to similar reports from Sweden and the US. PMID- 8689484 TI - Assessment of cataract surgery in rural India. Visual acuity outcome. AB - A socio-epidemiological assessment of what happens to the visual outcome after camp-based intracapsular cataract extraction was conducted in 6 villages and periurban areas in North India. 120 patients (143 eyes) were included in the study. The mean age at cataract extraction was 64.39 (range 33-83 years). 44.7% of the operated eyes obtained a good vision ( > or = 6/18) while 39.9% had low vision (6/24-3/60). The duration since the cataract extraction was seen to influence visual outcome. 70% of the respondents were satisfied with the surgical outcome. 76% of those with unilateral aphakia and 8.3% of those with bilateral aphakia were regularly using spectacles. 58.3% were satisfied with the spectacles. Dissatisfaction was generally due to lack of visual improvement. The major benefits accruing to the patients were improved personal activity, increased mobility and recognition of family members. It is our opinion that camp based intracapsular cataract extraction with aphakic correction is still an important alternative in rural India. PMID- 8689485 TI - Increased incidence of cataract extractions in women above 70 years of age. A population based study. AB - During 1987 and 1988 all patients undergoing a cataract extraction at the eye Clinic of Sahlgrenska University Hospital were registered to determine the yearly incidence of cataract extractions according to sex and age. We found that after the age of 70 years the incidence of cataract extractions was higher for females than males. This difference was most pronounced for operations of the first eye. In this case the relative risk to undergo a cataract extraction for a woman compared to a man was 1.71 with 95% confidence interval 1.51-1.94, which showed a significantly increased risk. The preoperative VA of the best eye at the time of the first operation did not differ significantly between older men and women, indicating that women had no tendency to come earlier to operation. Our results show that after the age of 70 years the operation incidence of women is significantly higher than for men. This probably reflects a generally increased prevalence of various stages of cataract among females above 70 years in a Nordic population. PMID- 8689486 TI - Changes of visual function and visual ability in daily life following cataract surgery. AB - We conducted a prospective study of 56 patients aged 70 to 79 years undergoing cataract surgery, in order to determine the impact of surgery on subjective and objective measurements of visual ability. In 46 cases we could obtain all necessary data. Binocular visual acuity, near vision and contrast sensitivity improved due to surgery. Self-assessed ability to perform visually related tasks was examined in form of a questionnaire. The results show that there was no simple relationship between objective measurements and perceived visual ability. An impairment in preoperative visual acuity cannot be related to a specific loss of visual ability. In order to increase the quality of cataract surgery more subtly, subjective aspects of vision must be taken into consideration when operation is decided upon and in the evaluation of the results. PMID- 8689487 TI - Cataract extraction in Behcet's disease. AB - Cataract is one of the most common complications of ocular inflammation due to Behcet's disease. A retrospective clinical trial was performed to review the management and discuss the outcome of cataract extraction in patients with Behcet's disease in order to find the best method of treatment. Fifty-five eyes of 40 patients were included into the study group. The surgical methods used were intracapsular cataract extraction (ICCE), extracapsular cataract extraction (ECCE), extracapsular cataract extraction+intraocular lens (ECCE+IOL), and extracapsular cataract extraction+trabeculectomy (ECCE+T). The postoperative visual prognosis was not satisfactory with any of the surgical methods because of the severe posterior segment complications of ocular Behcet's disease, particularly optic atrophy. PMID- 8689488 TI - Alport's syndrome with bilateral macular hole. AB - In this study 8 patients with Alport's syndrome are presented. The ocular manifestations of these patients were retinal flecks, macular depigmentation, microspherophakia and anterior lenticonus. One patient revealed bilateral macular hole which was an unusual feature. Four patients had renal biopsies with the characteristic electron microscopic changes of the disease. According to these findings our conclusion is that Alport's syndrome is a disorder of selected basement membranes. PMID- 8689489 TI - Electroretinographic alterations in the Laurence-Moon-Bardet-Biedl phenotype. AB - Maximal 0.5-Hz and cone 30-Hz ERG responses were recorded from 19 patients showing a Laurence-Moon-Bardet-Biedl (LMDD) phenotype. Off-line averaging of 80 to 100 iterations was routinely performed. When needed, our previously described low-noise techniques and off-line fast Fourier transform procedures were used. The maximal ERG response was non-detectable in 52.6% of cases. About half of the recordable signals were below 5% of the lower normal amplitudes. Cone 30-Hz ERGs were measurable in 64.7% of cases. Of these, 63% of tracings were below 5% of the lower normal range. In most cases no dystrophic pattern was definable, due to severe reduction of both signals. Statistical analyses showed no correlation between ERG amplitudes and residual visual field areas. Clinical and electroretinographic observations suggest that retinopathy in most LMBB patients is a widespread form of degeneration, initially affecting rods but rapidly involving cones as well. However, there are also cases with a clear-cut cone-rod pattern, with fairly well preserved maximal ERG responses. The lack of correlation between maximal ERG responses and visual field residual areas, different from non-syndromic retinitis pigmentosa (RP) patients, could be related either to a low reliability of visual field testing in LMBB patients or to mechanisms accounting for the ongoing retinal degeneration in LMBB syndrome that are different from those of pure RP. Variable findings are in line with the documented genetic heterogeneity of the syndrome. PMID- 8689490 TI - Three HLA-A29 positive patients with uveitis. AB - We evaluated the ocular symptomatology in 3 HLA-A29 positive patients with uveitis. In two patients we saw bilateral flecked fundus lesions known as birdshot retinochoroidopathy. One patient with an idiopathic vasculitis had no depigmented fundus flecks. The differences and similarities in these 3 patients are described. PMID- 8689491 TI - Vitrectomy in diabetic patients with a blind fellow eye. AB - Results of pars plana vitrectomy for complications of proliferative diabetic retinopathy were analysed in 32 consecutive patients with a blind fellow eye due to diabetic eye disease. The mean follow-up period was 22.3 months. Only 16% of all eyes examined had received full scatter photocoagulation prior to referral for vitrectomy. Out of 9 eyes with vitreous haemorrhage, 8 improved to a visual acuity of > or = 0.2 postoperatively. Amid 23 eyes which were vitrectomized for advanced traction retinal detachment, only 4 eyes improved to a postoperative visual acuity of > or = 0.02. In this group 12 eyes deteriorated after vitrectomy, 3 eyes progressing to no light perception. The postoperative visual outcome after vitrectomy for traction retinal detachment in this group of diabetics with a blind fellow eye (mean postoperative visual acuity 0.03 +/- 0.05) was significantly worse (p < 0.000) compared to a group of 196 patients with a seeing fellow eye who were vitrectomized for traction retinal detachment at our clinic (mean postoperative visual acuity 0.09 +/- 0.11). Therefore we conclude that traction retinal detachment in this subgroup of patients is a particularly severe presentation of diabetic retinopathy with a guarded functional prognosis after vitrectomy. Our results demonstrate the importance of timely full scatter photocoagulation and early vitrectomy in eyes with progressive fibrovascular proliferation not responding to panretinal photocoagulation. We conclude that especially diabetic patients with a blind fellow eye must be followed closely and assigned to vitrectomy at an earlier stage of their disease in order to improve functional prognosis. PMID- 8689492 TI - Simple iris coloboma in a Greek family. AB - We report the presence of simple iris coloboma in 4 out of 5 female members comprising four generations of a Greek family. A varied degree of simple iris coloboma (i.e. not associated with a choroidal coloboma) was present in one eye of the maternal grandmother, mother, daughter and one out of 2 granddaughters of this family. The iris colobomata were associated with congenital lens opacities in 2 out of 4 of the females, macular degenerative changes in 2 cases and ocular hypertension in one case. The pathogenesis, heredity and associations of simple iris colobomata is discussed. PMID- 8689493 TI - Acute zonal occult outer retinopathy. AB - Retinal photoreceptor dysfunction is an uncommon and often unrecognized cause of acute visual loss. Acute zonal occult outer retinopathy (AZOOR) has been reported to cause cone and rod dysfunction. Patients with AZOOR may present with normal visual acuity, normal fluorescein angiography, and a normal fundus examination despite severe loss of visual field. A healthy young white female presented with acute, unilateral loss of visual field and an afferent pupillary defect, but normal visual acuity, color vision, fundus examination, and fluorescein angiogram. A pattern visual evoked potential was normal, but an electroretinogram showed a unilateral peripheral photoreceptor dysfunction consistent with the diagnosis of AZOOR. Ophthalmologists should be aware of the diagnosis of AZOOR and should consider an ERG in the evaluation of any patient with unexplained visual field loss even in the presence of normal visual acuity, color vision, fluorescein angiography, or retinal examination. PMID- 8689495 TI - Conjunctival damage induced by long-term topical anti-glaucoma therapy. PMID- 8689494 TI - Myotonic dystrophy (MyD) is an autosomal dominant multisystem disorder. PMID- 8689496 TI - Children's dental health under the capitation scheme. AB - A study was undertaken of the dental health of 7870 eight-year-old children resident in the City of Birmingham, using the standard British Association of Community Dentistry epidemiological procedures. There were variations in the dental health of children from different ethnic backgrounds. Asian children had the poorest dental health and Afro-Caribbean children, the best. There were also variations in the dental health of children from different ACORN Categories. Children from the highest ACORN Category 'Thriving' had better dental health than those from the lowest, 'Striving' Category. Positive consent was obtained from every parent or guardian to link the findings with the Dental Practice Board's records as to whether each child was registered under the NHS capitation scheme for the provision of primary dental care to children. The dental state of those who were registered in the capitation scheme, (54.5 per cent), was compared with those who were not, (45.5 per cent). The highest proportion of children registered with a dentist were Caucasian and from a high social class i.e. ACORN Category 'Thriving'. In order to ensure that differences were due to their capitation status and not to other differences within the groups, analyses were undertaken according to the ethnic background and ACORN Category of the children. Overall, there were only very small differences between the caries state of the registered and non registered children. However 32 per cent of those children registered in the scheme still had active decay which was not restricted to the primary dentition. The greatest reduction in the average number of decayed teeth together with the greatest increase in the average number of fillings in registered children when compared to their non registered colleagues was observed in the lowest ACORN Category. Unfortunately this group had the lowest proportion of children who were registered in the capitation scheme and 40 per cent of them, both registered and non registered, still had active decay. Overall, oral hygiene was good, and there was little difference between registered and non-registered children in the ACORN Category 'Thriving'. However, in the ACORN Category 'Striving', there was a higher proportion of children with good oral hygiene amongst those who were registered than amongst those who were not. Provision of preventive treatment was low in all registered and non registered groups, but lowest in those groups of children with the poorest dental health. It would appear that, for a proportion of children registered in the capitation scheme, the practitioners were failing to achieve the requirement of "securing and maintaining their oral health". PMID- 8689497 TI - An assessment of capitation in the new General Dental Service contract. AB - A 2-year study has been completed to examine the dental health and patterns of treatment of samples of children registered under capitation in three areas of England. The opportunity was taken to compare some of these results with those reported in the same areas in 1989 when the dentists were remunerated under fee for-service. In addition, the validity of the dental health information supplied by general dental practitioners on the FP17C form was assessed. The dental health of 14-15-year-old patients registered for more than a year was compared with that of similar patients in the same areas in 1989. There was a large reduction in the caries experience (mean DMFT) in these patients in all areas between 1989 and 1994 mainly due to a significant fall in the mean numbers of teeth filled. The mean number of teeth extracted for caries remained low in all areas. There was a small increase in the mean number of decayed, untreated teeth in all areas. There was a large increase in the proportion of patients with one or more fissure sealants present. The dental health of 7-8-year-old patients registered for more than a year was examined but, as this age group were not examined in 1989, no comparative data were available. Regularly attending child patients had, on average, one untreated decayed deciduous tooth, but few had more than two. Caries experience in first permanent molars was low in all areas. Data were collected from a sample of general dental practitioners in three areas on the treatment provided over a 12-month period for random samples of patients in two age groups: 6-12 and 13-15 years. There was an increase in two of the three areas in the provision of oral hygiene instruction and dietary advice. The level of fissure sealant use was maintained or increased. There was a reduction in the numbers of both deciduous and permanent teeth filled. Fewer children had teeth extracted. The proportions of patients having bitewing radiography reduced. The mean number of both visits and check-up examinations reduced. There validation of the dental health information on the FP17C was carried out by comparing the data collected for 7-8 and 14-15 year old patients during the dental health examinations with that submitted by general dental practitioners on FP17C forms to the Dental Practice Board for the same children. For the permanent dentition, agreement was good for missing and filled teeth but poor for decayed, untreated teeth. For deciduous teeth, levels of agreement were generally poor except for filled teeth where it was fair. PMID- 8689498 TI - [Cancer epidemiology of radiation workers]. AB - Ionizing radiation-induced cancer risk has been estimated mainly from the Radiation Effects Research Foundation study of atomic bomb survivors who were exposed to a high instant radiation dose. With the development of nuclear industries, the cancer risk has recently been estimated directly from epidemiological studies of radiation workers who were exposed to low-level protracted doses, though the results still remain controversial due to the lack of statistical power. The present article is to review, summarize and comment on epidemiological papers on radiation workers in various job types published up to 1994. PMID- 8689499 TI - [Studies on the evaluation of exposure to industrial chemicals]. AB - Among the biological exposure indices of lead, lead in plasma was the most direct indicator of current exposure. Lead mobilized into plasma as well as in urine could be used as an indicator of the internal dose of lead. The ratio of non treated to restored activity of delta-aminolevulinic acid dehydratase (ALA-D) was a more specific index than ALA-D activity itself at low levels of lead exposure, excluding the familial or genetic variation in the activity. The methods using HPLC for determining heme intermediate improved the evaluation of the lead effect: delta-aminolevulinic acid in plasma, blood, and urine (ALA-P, ALA-B, and ALA-U), coproporphyrin in urine, and zinc protoporphyrin in blood (ZP). ROC (Receiver operating characteristic) curve analyses indicated that the diagnostic values for lead exposure decreased in the order ALA-D ratio > ALA-D activity = ALA-P > ALA-U = ZP. Pyrimidine 5'-nucleotidase activity or pyrimidine nucleotide concentrations in blood was also useful for the monitoring or diagnosis of lead intoxication. Using the HPLC method with inclusion compounds in the mobile phase, hippuric acid, methylhippuric acids, mandelic acid and phenylglyoxylic acid could be simultaneously determined in the urine of workers exposed to a mixture of toluene, xylenes, and ethylbenzene. The correction of the urinary metabolite concentration for specific gravity or creatinine allowed the more specific evaluation of the solvent exposure. In the biological monitoring of chlorinated hydrocarbons such as trichloroethylene, prolonged excretion of the metabolites resulted in a bias between metabolite concentrations and TWA levels of the solvent in a day. The background levels of 2,5-hexanedione (HD) were affected by acid hydrolysis conditions, age, sex and lipid metabolism. Substances hydrolyzed to HD in urine from non-exposed subjects were different from HD detected in the workers exposed to n-hexane. Urinary concentrations of N-acetyl-S-(N methylcarbamoyl) cysteine (AMCC) served as an index of the average exposure to N, N-dimethylformamide during several preceding work days and may indicate the internal dose, while N-methylformamide may be an index of daily exposure. A simple and rapid method for the determination of urinary alkoxyacetic acids was recently developed for the biological monitoring of workers exposed to glycolethers and their acetates. Urinary butoxy acetic acid (free plus conjugated ones) could be simply determined by gaschromatography after acid hydrolysis of urine. The urinary acetone or methanol concentration determined by the head space technique was also useful for the biological monitoring of workers exposed to isopropanol and/or acetone, or methanol, respectively. Evaluation of exposure to the solvents described above could be carried out by comparing the urinary metabolite concentrations with reference values and the biological exposure index values which were defined as the urinary metabolite concentration corresponding to the threshold value for each solvent. PMID- 8689500 TI - [Study on correlation between chest X-P course findings and change in antinuclear antibody in asbestos plant employees]. AB - In order to investigate the correlation between a course of chest radiograms and changes in antinuclear antibody (ANA), 140 asbestos workers who had a chest radiogram and measurement of ANA in 1987 and had been working in the same plant were given the same examination again in 1992. In the group who showed a change in ANA to positive, the progression of pulmonary asbestosis was significantly higher than in the group who remained negative. Progression in pleural lesions was not significantly correlated. PMID- 8689501 TI - [Skin disorders of students engaged part-time in painting]. PMID- 8689502 TI - Prostate screening--the Singapore experience. AB - BACKGROUND: The prevalence of benign prostatic hyperplasia (BPH) is believed to be highly significant in most communities. In our country, many elderly men are unaware that something can be done for their troublesome urinary symptoms. The main objective of our prostate health screening was to educate our elderly male population that this is an abnormality, for which treatment is readily available. At the same time, we attempted to determine the prevalence of BPH, to detect possible prostate cancer, and to derive normal prostate specific antigen (PSA) and uroflow values for our population. METHODS: Over an eight-day period in April 1994, 799 men above the age of 50 years volunteered to participate in a free prostate screening exercise held at our hospital. The parameters assessed were PSA level, American Urological Association (AUA) symptom score, uroflowmetry, and digital rectal examination (DRE) of the prostate. RESULTS: Elevated PSA levels of more than 4 micrograms/L were detected in 105 men (13.1%). Of these, 23 men (2.9%) had PSA values above 10 micrograms/L. Abnormal AUA symptom scores of more than eight (moderate and severe categories) were noted in 540 men (67.6%). Clinically enlarged prostate glands of more than 20 g on DRE were noted in 80 men (10.0%), and abnormal DRE findings were detected in 48 men (6.01%). Impaired maximal uroflow rates of less than 10 mL/s were recorded in 224 men (39%), while another 167 men (29.1%) had maximal uroflow values in the equivocal zone (between 10 to 15 mL/s). The reference PSA levels at the 5th percentile, 10th percentile, median, mean, 90th percentile and 95th percentile were 0.38, 0.47, 1.05, 1.57, 3.27 and 4.25 micrograms/L, respectively. The age-specific PSA values were 3.51, 3.78 and 6.02 micrograms/L in the 50 to 59, 60 to 69, and 70 to 79 years age groups, respectively, and the reference mean maximal uroflow rates was 14.8 mL/s. CONCLUSIONS: Although controversial, our experience with prostate screening was generally positive. As far as our population is concerned, the free prostate screening exercise generated publicity, and succeeded in enhancing public awareness for better prostate health. PMID- 8689503 TI - A non-randomized comparative study of visual laser ablation and transurethral resection of the prostate in benign prostatic hyperplasia. AB - BACKGROUND: Transurethral resection of the prostate (TURP) has been the preferred surgical treatment for benign prostatic hyperplasia (BPH) for the past 50 years. Alternative methods for treating BPH such as visual laser ablation (VLAP) have been established during the past decade. In order to assess the safety and efficacy of VLAP, this alternative method was performed using a Urolase fiber and neodymium: yttrium-aluminum-garnet laser, and compared to results obtained in patients treated with TURP for BPH. METHODS: In this non-randomized comparative study, 100 BPH patients were equally split between treatment with VLAP or TURP, and their cases compared. The efficacy was assessed using an International Prostate Symptom Score, urinary flow rates, post-void residual urinary volume and an estimated prostate volume. RESULTS: There was a clinically significant improvement in all parameters in both groups. In the VLAP and TURP groups, 92.0% and 81.6%, 90.2% and 86.2 and 93.1% and 100.0% were categorized as effectively treated cases at 3, 6 and 12 months post-operatively, respectively. No severe side effect was seen in VLAP group. The total and post-operative lengths of hospitalization in the VLAP group were shorter, but the duration of post operative bladder irrigation was longer in these patients. CONCLUSIONS: Although TURP remains the standard surgical treatment for BPH, VLAP is associated with less morbidity and the clinical outcome is similar compared to patients treated with TURP. VLAP in conjunction with TURP may result in less risk of postoperative urinary retention and vesical irritability. PMID- 8689504 TI - bl-2 [corrected] Expression on prostate cancer and its relationship to cell cycle and prognosis. AB - BACKGROUND: bcl-2 protein is an oncoprotein encoded by a protooncogene bcl-2 which is thought to be a key gene for the regulation of cell life and death. bcl 2 protein has been reported to be expressed in a subset of prostate cancers, and its biological role in this disease has not yet been elucidated. This present study focused on the cell cycle analysis of bcl-2 immunoreactivity in prostate tumor samples and correlated findings with the prognosis of the patients. METHODS: Archival tissues from 37 prostate cancers were submitted for immunohistochemistry and DNA analysis via flow cytometry. All tissues were obtained before the patients received any treatment. Immunohistochemistry was performed using streptavidin biotin procedures, and DNA flow cytometry was done by a combination of two methods. RESULTS: Fourteen of 37 prostate cancers (38%) exhibited bcl-2 immunoreactivity. bcl-2 positive prostate cancers significantly correlated with DNA aneuploidy and higher proliferation indices, but not with histological differentiation. Clinically, there was a poorer prognosis for patients with bcl-2 positive prostate cancer. CONCLUSIONS: Our data indicates that bcl-2 protein expression in prostate cancer is associated with cell proliferation and may serve as a predictive factor for the prognosis of prostate cancer. PMID- 8689505 TI - Serum prostate specific antigen and prostate specific antigen density in patients receiving radical prostatectomy. AB - OBJECTIVE: To study the significance of prostate specific antigen (PSA) and prostate specific antigen density (PSAD) for predicting the risk of occult metastatic disease and extra-prostatic invasion of prostate cancer in patients receiving radical prostatectomy. PATIENTS AND METHODS: The cases of 41 consecutive patients who underwent radical prostatectomy were reviewed. Relations of PSA and PSAD using Markit M PATM assay for grade, preoperative clinical stage, postoperative pathological stage, capsular penetration, seminal vesicle invasion, resection margins and lymph node metastasis are discussed. RESULTS: Although serum PSA was correlated with PSAD and PSA was correlated with preoperative prostate volume, PSAD was not influenced by prostate volume. PSA correlated only with the grade, while PSAD was correlated with grade, preoperative clinical stage, postoperative pathological stage, capsular penetration, seminal vesicle invasion, resection margins and lymph node metastasis. In addition, sixty-two percent (8/13) of margin positive patients showed a PSAD value of more than 0.4, while 93% (26/28) of margin negative patients showed less than 0.4. Sixty-seven percent (6/9) of lymph node positive patients showed a PSAD of more than 0.4, while 91% (29/32) of lymph node negative patients showed less than 0.4. CONCLUSION: We concluded that PSAD was useful for predicting extra-prostatic involvement of prostatic cancer. PMID- 8689506 TI - Injection of glutaraldehyde cross-linked collagen for urinary incontinence: two year efficacy by self-assessment. AB - BACKGROUND: Glutaraldehyde cross-linked (GAX) collagen has recently become available as injection material for treatment of urinary incontinence and should be evaluated for its long-term efficacy. METHODS: The subjects included 78 females with genuine stress incontinence (GSI) and 19 male or female patients with intrinsic sphincter deficiency (ISD: urinary incontinence due to urethral sphincter damage). GAX collagen was injected transperineally or transurethrally through an injection needle under direct endoscopic observation. The efficacy was evaluated by the patients' overall assessment at two years post-treatment. RESULTS: Under local or regional anesthesia, GAX collagen was injected 1.9 times on average (total injection volume: 23.5 mL) in GSI patients and 2.2 times (40.1 mL) in ISD patients. Improvement at two years post-treatment by patients' assessment was observed in 71.7% of GSI patients and 53.3% in ISD patients. Side effects were urinary retention and difficulty in voiding after 48 of the total of 188 injections (25.5%), a large amount of residual urine in four (2.1%) and miscellaneous in 19 (10.1%), for a short period after injection and were not serious. CONCLUSION: Our study indicates that GAX collagen injection is an effective, safe and easy non-medical treatment for urinary incontinent patients. PMID- 8689507 TI - In vitro parathyroid hormone release in patients with secondary hyperparathyroidism. AB - BACKGROUND: The purpose of this study was to determine the precise endocrine characteristics of parathyroid function in secondary hyperparathyroidism (sHPT). METHODS: We examined the effects of extracellular ionized calcium (Ca2+) varying from 0.5 to 2.0 mM on parathyroid hormone (PTH) release in parathyroid cell suspensions using a mid-regional PTH assay. Cells were obtained from 26 patients with sHPT who were divided into two groups according to the type of hyperplasia they exhibited, either nodular (n = 16) or diffuse (n = 10). For comparison, we also analyzed data from nine patients with primary hyperparathyroidism (pHPT; adenomas). RESULTS: Significant in vitro suppression of PTH release by Ca2+ was observed in the majority of subjects, regardless of the histologic abnormality. The pHPT group exhibited no significant relationship between clinical and in vitro data. In contrast, in the sHPT group (taken as a whole), suppression of PTH release by Ca2+ exhibited a plateau at a total serum calcium concentration of 2.5 mmol/L, and a parathyroid gland weight of 2 g. CONCLUSIONS: These findings suggest that there is a curvilinear relationship in sHPT, but not pHPT, between the in vitro calcium sensitivity of parathyroid cells and total serum calcium, as well as gland weight. The in vitro calcium sensitivity in sHPT remains constant when the total serum calcium concentration exceeds 2.5 mmol/L, or when the gland weight exceeds 2 g. PMID- 8689508 TI - Cumulative renal damage in dogs by repeated treatment with extracorporeal shock waves. AB - BACKGROUND: Extracorporeal shock wave lithotripsy (ESWL) has become a routine method for the treatment of renal and ureteral calculi. Occasionally, multisequential ESWL treatments and high energy shock waves are required to treat large calculi. The purpose of the study was to compare renal histopathologic damage caused by varying the application of shock waves. METHODS: Six groups of dogs were defined by the frequency of shocks, application time and numbers of sessions. Bilateral nephrectomies were performed immediately, 3, 7 and 60 days after the application of shock waves. Histopathologic features of the kidneys were assessed by both light and electron microscopy. RESULTS: Irreversible damage was observed in all exposed kidneys. After a single session of low application frequency, damage by shock waves occurred with progressive deterioration of the nephron. At any frequency rate, the damage was caused by tissue hypoxia due to rupturing of the interstitial capillaries. As the application frequency increased, capillary rupture became more severe, and consequently, morphological damage tended to be more intense. Repeated sessions at any application frequency made the damage more intense, suggesting that an accumulation of damage had occurred. CONCLUSIONS: Minimal doses of shock waves cause renal damage and repeated ESWL sessions may result in an accumulation of damage. Considering that the damage is dose-dependent, divided ESWL treatments at a low frequency rate are advisable in a clinical setting. PMID- 8689509 TI - Pharmacokinetics and antitumor effects of an interleukin-2 immunocomplexing agent in murine renal cell carcinoma. AB - BACKGROUND: Conventional therapy for renal cell carcinoma (RCC) using systemic administration of interleukin-2 (IL-2) has shown limited anti-tumor action. The purpose of this study was to investigate the anti-tumor effects of a newly developed immune complex of IL-2 (IC) against RCC. METHODS: IC was prepared by mixing IL-2 and an anti-IL-2 monoclonal antibody at a molar ratio of 2:1. The pharmacokinetics and anti-tumor effects of IC were then studied in a murine RCC line, Renca. RESULTS: Serum IL-2 levels were sustained longer in mice given IC than in mice given IL-2 alone after either subcutaneous or intratumoral injections. After an intratumoral injection of IC, the IL-2 concentration in the tumor nodules remained higher compared with mice given IL-2 alone. The anti-tumor effect was most pronounced in mice treated with intratumoral injections of IC. CONCLUSIONS: Results obtained here indicate that an immune complex of IL-2 provides a useful tool for the treatment of RCC by altering the pharmacokinetics of IL-2 in vivo. PMID- 8689511 TI - Bilateral renal cell carcinoma in a patient with tuberous sclerosis. AB - A case of pure bilateral renal cell carcinoma (RCC) in a 21-year-old female diagnosed as having tuberous sclerosis is reported. She underwent a left nephrectomy because of her loss of appetite, possibly caused by the tumor compressing her intestines. The preoperative CT scan showed the presence of adipose tissue in bilateral renal tumors, which is highly suggestive of angiomyolipoma (AML). Histological examination, however, revealed no area or component of the tumor with features characteristic of AML. PMID- 8689510 TI - Effect of cyclosporin A on isolated rabbit bladder and urethral smooth muscle. AB - BACKGROUND: The effects of Cyclosporin A (CsA) on vascular smooth muscle inducing hypertension have been established. However, there is no information available concerning the effects of CsA on urinary smooth muscle. Therefore, the effects of CsA were investigated on the bladder and urethral smooth muscle in rabbits. METHODS: CsA (10 mg/kg/day, intravenously) was given to rabbits for 14 days. Rabbit bladder and urethral smooth muscles were then isolated and evaluated using a muscle bath technique. RESULTS: 10(-10)-5 x 10(-6)M CsA alone had no direct effect on bladder or urethral smooth muscles. The Emax (maximum contractile response) and ED50 values for acetylcholine-induced contractions and the Emax (maximum relaxation response) for isoproterenol-induced relaxation in bladder smooth muscles were not significantly different between CsA-treated and control groups. The ED50 for isoproterenol-induced relaxation was significantly lower in the CsA group (P < 0.05). The Emax for phenylephrine- and clonidine-induced contractions in urethral smooth muscle was significantly higher in the CsA treated group (P < 0.05). The ratio of the maximum response of the urethral smooth muscle to phenylephrine and clonidine in Ca+2-free solution to the normal solution in the CsA group (13.42% and 4.40%, respectively) was significantly higher than the maximal response ratios in the control group (6.34% and 3.00%, respectively; P < 0.05). CONCLUSIONS: CsA treatment augments the relaxation response of the bladder to isoproterenol and the contractile response of the urethra to phenylephrine and clonidine. In addition, CsA increases the filling of intracellular stores of releasable Ca+2, and also increases the permeability of Ca+2 in rabbit urethral smooth muscle. Thus, it is suggested that CsA may cause a urinary disturbance in patients treated with CsA via increased urethral resistance. PMID- 8689512 TI - Bladder cancer producing granulocyte colony-stimulating factor: a case report. AB - A rare case of bladder cancer producing granulocyte colony-stimulating factor (G CSF) is reported. A 63-year-old man with a progressive, grade 3 transitional cell bladder carcinoma, showed marked leukocytosis (maximum 181,800/mm3) and an elevated serum G-CSF to 131.7 pg/mL. After radical cystectomy and neoadjuvant chemotherapy, the tumor recurred locally. Immunohistochemical examination with monoclonal antibody specific for G-CSF revealed positive staining in the local recurrent tumor. To our knowledge, there have been only seven cases reported of bladder cancer producing G-CSF. PMID- 8689513 TI - A case of prostate carcinoma metastasizing to renal cell carcinoma. AB - Metastasis of one cancer to another cancer is extremely rare. The most frequent metastasizing tumor is a lung carcinoma, and the most common recipient tumor is a renal cell carcinoma. We report herein a case of prostate carcinoma metastasizing to a renal cell carcinoma, which has previously been reported only four times. PMID- 8689514 TI - Phyllodes type of atypical prostatic hyperplasia. AB - This report documents an uncommon prostatic hyperplasia which developed within a thick capsule between the bladder and rectum grossly showing a phyllodes type of growth. It was simply excised, but recurred locally two years later. A total prostatectomy was performed, and microscopic examination of the tissue revealed no malignant transformation. PMID- 8689515 TI - Fournier's disease: adjunctive hyperbaric oxygen therapy to classic therapy. AB - Fournier's disease is a very rare and highly fatal necrotizing fasciitis of genital and perineal tissues. Conventional treatment of Fournier's disease includes surgical debridement and antibiotic therapy. We describe a case of Fournier's disease where we added hyperbaric oxygen therapy to the conventional treatment regimen. PMID- 8689516 TI - A case of primary localized amyloidosis of the penile urethra. AB - Primary localized amyloidosis of the penile urethra is rare. We report a case in which the urethra was obstructed by amyloid tissue without evidence of systemic amyloidosis. After urethral dilatation, the patient reported a markedly improved urinary stream with minimal dysuria. PMID- 8689517 TI - Laparoscopy in urology: present status, controversies, and future directions. PMID- 8689518 TI - Local toxicity patterns associated with intravesical bacillus Calmette-Guerin: a Southwest Oncology Group Study. AB - BACKGROUND: While the efficacy of bacillus Calmette-Guerin (BCG) immunotherapy has been demonstrated, the relative benefit, given a seemingly high incidence and severity of toxicities, remains an issue. Adequate understanding and management of toxicities can maximize the safety of the treatment and enable the administration of required doses of BCG intravesical therapy. METHODS: All week to-week symptoms recorded for the 143 immunotherapy-naive participants assigned to the BCG arm of SWOG-8216, BCG vs. Doxorubicin in Superficial Bladder Cancer were analyzed in order to document the pattern of toxicities in the first six week induction course of intravesical BCG treatments. The statistical analysis consisted of fitting logistic regression models to these data for the probability of irritative bladder symptoms (IBS). RESULTS: In the optimal model, the probability of IBS depends only on whether there was IBS associated with the previous treatment, and not on which treatment. The estimated probability of having IBS when there were no IBS associated with the previous instillation is 0.136, whereas the estimated probability of having IBS when there was IBS associated with the previous instillation is 0.689. CONCLUSIONS: Irritative bladder symptoms are unlikely in the week after the first intravesical BCG treatment. Once a patient experiences IBS, he or she is more likely to have IBS with the next and subsequent treatments. Clinicians can use the findings of this analysis when informing their patients about the treatment course and when making decisions about continuing treatments. PMID- 8689519 TI - Effects of growth hormone injection to embryos on growth and myosin heavy chain isoforms in growing turkeys (Meleagris gallopavo). AB - Effects of embryonic imprinting with growth hormone (GH) on growth and myosin heavy chain (MyHC) isoforms in pectoralis muscle were determined by injecting turkey embryos with ovine growth hormone (oGH) at a dose of 10 micrograms three times a day. Injections were made on days 20 and 26 (Treatment 1), days 14 and 20 (Treatment 2) or days 14 and 26 (Treatment 3) of incubation. In Treatment 1 poults, plasma GH concentrations were elevated at 3 days posthatch and in Treatment 3 poults, plasma GH concentrations were elevated at 15 days posthatch, as compared to control poults. At 4 weeks of age, in males, body weights, shank length and weights of pectoralis, gastrocnemius and sartorius muscles were increased in Treatment 3, and in females, body weights, shank length and weights of gastrocnemius muscle of female turkeys were increased in Treatment 1. The growth rate of female turkeys from 4 weeks through 16 weeks was increased by Treatment 1. Treatment 1 resulted in a delay in the transition from the embryonic MyHC isoform to the neonatal MyHC isoform and to the adult MyHC isoform. Treatment 3 induced an earlier appearance of the adult MyHC isoform. No effects on body and muscle growth and MyHC isoforms were observed by Treatment 2. PMID- 8689520 TI - Reproductive period affects water intake in heat-stressed dehydrated goats. AB - Water intake following dehydration was studied in pregnant (N = 5), lactating (N = 4) and nonpregnant, nonlactating (N = 5) Swedish domestic goats (Capra hircus) to investigate if reproductive period affected drinking. Plasma cortisol concentration and the hematocrit value were measured to evaluate stress. The goats were water deprived from 9.00 h until 15.05 h the next day. They were fed at 7.00 and 15.20 h. On the second day, ambient temperature was increased from 20 degrees C to 38-39.5 degrees C for 5.15 h to accelerate water losses. Water temperature during rehydration was 35 +/- 1 degree C. Plasma Na concentration and osmolality increased most in dehydrated and heat-stressed pregnant and lactating goats. Pregnant goats lost 2.2 kg of their body weight. They drank 3.5 l immediately, followed by 2.5 l during afternoon eating. Lactating goats lost 4.9 kg and drank 6.3 l at once, and 3.9 l during feeding. Nonpregnant, nonlactating goats lost 1.7 kg and drank 2.6 l followed by 0.6 l. The large water consumption in pregnant and lactating goats caused hyponatremia and hemodilution, but they continued to drink during the night (0.5 +/- 0.2 l and 0.8 +/- 0.5 l, respectively). Renal free water clearance increased in all periods, with a long lasting water diuresis during pregnancy. Plasma cortisol concentrations and the hematocrit values rose in connection with water intake. These results imply that the thirst center became less sensitive to inhibitory signals from the oropharyngeal tract and the diluted blood plasma during pregnancy and lactation. Catching sight of water was the most exciting procedure during these experiments. PMID- 8689521 TI - Renal compensation for cecal loss in Gambel's quail (Callipepla gambelii). AB - Some studies have implicated the avian digestive cecae as important sites of water and solute reclamation working in concert with the lower intestine and the kidneys as part of an integrated osmoregulatory system. In Gambel's quail (Callipepla gambelii), we studied compensatory adjustments in renal function on days 6-7 and 16-17 following ligation of cecae. Plasma osmolality (Posm) varied significantly between groups with sham-operated birds (Cs), with an average (Posm) of 348 mOsm/kg H2O and quail with ligated cecae (Cx) having a (Posm) of 355 mOsm/kg H2O. We detected no change in the rate of glomerular filtration (GFR) between experimental and control groups either shortly after cecectomy or after 16-17 d following surgery. Regression analysis of GFR and urine flow rate (V) showed that Cx birds had a significantly lower V at a given GFR than did controls, evidence that Cx quail absorbed more fluid in their renal tubules. Increased fluid reabsorption was apparently driven by an enhanced reabsorption of sodium. Indeed, sodium excretion was lower in Cx quail as compared to sham operated birds. On days 6-7, Cx quail drank more water than Cs birds, but by days 16-17 drinking rates were similar. At the end of the experiments, Cx quail showed a proliferation of microvilli along the apical membrane of the rectum, an adjustment consistent with the idea that the rectum alters its absorption capacity to adjust for the loss of cecal function. PMID- 8689522 TI - The effects of ambient pH on nitrogen excretion in early life stages of the American toad (Bufo americanus). AB - Acidification of breeding ponds has been identified as a potential threat to the survival and health of North American amphibian populations. The effects of acid exposure on ion and acid-balance are well known, but there is little information on how environmental water pH influences nitrogen balance in amphibians. The aim of this study was to determine the effects of moderately acidic water (pH 6.0) on nitrogen excretion in early life stages of the toad, Bufo americanus. Acid exposure (pH 6.0, 54 h) resulted in a 20-80% increase in ammonia-N excretion rates in embryos and early, middle and late tadpoles stages, whereas there was no significant effect on urea-N excretion. Tissue ammonia concentrations were significantly higher (+33%) in the embryos and 35-65% lower in the three groups of tadpoles exposed to water of pH 6.0 compared to control animals (pH 8.5). In embryos, ammonia excretion accounted for greater than 90% of total nitrogen excretion (ammonia-N + urea-N), but by the late tadpole stage this value had decreased to approximately 65%. These findings indicate that exposure of embryonic and larval B. americanus to moderately acidic water disrupts nitrogen balance by increasing nitrogen loss as ammonia, with no compensatory decrease in urea excretion. PMID- 8689523 TI - The influence of the invasion of Trichinella sp. on immunologic reactions in mice: 1. analysis of the reaction of skin allograft rejection. PMID- 8689524 TI - Changes in liver and fat depots of west African dwarf goats (Capra aegagus hircus) after an infection with T. vivax. AB - Nine West African dwarf goats (Capra aegagus hircus) were each infected experimentally with 3 x 10(7) Trypanosoma vivax parasites. The changes in the plasma concentration of nonesterified fatty acids (NEFA) were monitored during the infection and the level of hepatic triacylglycerols and glycogen was measured postmortem. During the infection they had higher plasma NEFA concentrations than nine uninfected control goats and at postmortem their total liver triacylglycerol and glycogen contents were found to be increased. These observations suggest that the mobilization of the goats' defense mechanisms against the T. vivax infection induced a more intensive fat mobilization resulting in changes in fat metabolism of the liver. PMID- 8689525 TI - Hemoglobin affinity and structure in high-altitude and sea-level carnivores from Peru. AB - We compared hemoglobin affinity (P50) and structure of high altitude (HA) carnivores with populations of the same species or genus living at sea level (SL). P50 was measured in cats, pumas and foxes. It differed in animals occupying both niches. SL: cat 29.3 torr, puma 36.3 torr, fox 26.2 torr; HA: cat 22.5 torr, puma 31.1 torr, fox 18.5 torr. Heme and globins were fractionated by HPLC. Puma and fox hemoglobins also showed structural differences. P50 is lower in genotypically HA-adapted species studied and can differentiate SL and HA populations of the same species. PMID- 8689526 TI - Inhibitory action of 5-hydroxytryptamine on propulsive activity of the guinea-pig isolated colon. AB - The effects of 5-hydroxytryptamine (5-HT) and its receptor subtype agonists on spontaneous propulsive activities of the segment, and on changes in tension of the muscle strips were examined in the guinea-pig isolated distal colon. 5-HT, 5 carboxamidotryptamine (5-CT), alpha-methyl-5-HT and t-methoxytryptamine (5-MeOH), applied to the serosal side of the segment, inhibited spontaneous propulsive activities, but 2-methyl-5-HT did not. On the indomethacin-treated segment, 5-HT and its receptor subtype agonists all stimulated propulsive activity. 5-HT, 5-CT, alpha-methyl-5-HT and 5-MeOH relaxed circular muscle strips, which were inhibited in the presence of tetrodotoxin. However, these agonists showed contractile effects on the indomethacin-treated circular muscle strips. These results suggest that 5-HT may inhibit spontaneous propulsive activities of the colonic segment via release of endogenous PGs (e.g., E and I types) in the circular muscle cells mediated by an inhibitory neurotransmitter, which release was stimulated by 5-HT1 like 5-HT2 and 5-HT4 receptors on the myenteric neurones in the circular muscle layer. PMID- 8689527 TI - Plasma thyroid hormone and growth hormone patterns in precocial Japanese quail and altricial European starlings during postnatal development. AB - Plasma concentrations of thyroid hormones (TH) and growth hormone (GH) during postnatal development in the precocial Japanese quail (Coturnix japonica), and the altricial European starling (Sturnus vulgaris) were measured. Developmental changes in plasma TH found in the starling, differ considerably from those detected in quail. In quail rather high triiodothyronine (T3) values were measured during the first few days after hatching. Subsequently a steady decrease of plasma T3, to adult levels, was observed. Thyroxine (T4) concentrations did not change significantly during the period studied. In starlings, on day 1, plasma T3 was low and T4 was at or below the assay detection limit. An increase in concentrations of both hormones occurred between day 1 and day 5 after hatching. A gradual increase of T4 occurred afterwards, while plasma T3 levels remained nearly constant during this growing period. Plasma GH concentrations showed a similar pattern in both species. There was an increase during first days after hatching and GH concentrations peaked at day 7 in quail and day 5 in starlings. A subsequent decrease was observed in both species. Although the GH profiles in species studied were comparable, there were noticeable differences in their growth rates. Thus different developmental strategies have been reflected in different developmental patterns of TH in precocial Japanese quail and altricial European starling whereas developmental changes of GH levels were similar in both species. PMID- 8689528 TI - Effects of endophyte-infected tall fescue, environmental temperature and prazosin injection on the rat. AB - Effects of an alpha 1 antagonist, prazosin, injection on the rat (Rattus rattus) exposed to warm vs normal environments and fed endophyte-infected (E+) or -free (E-) tall fescue seed were studied. Rats were injected IP daily with placebo or prazosin (1 mg/kg BW). Daily skin and rectal temperatures and food intake measurements were recorded. Selected brain tissues were dissected to determine treatment effects on monoamine receptor density. Rats fed E+ and injected with placebo had reduced (P < 0.01) food intake compared with all other treatments. By day 5 of injection, an endophyte x temperature interaction for increased (P < 0.03) skin and rectal temperatures was measured when rats were fed E+ and housed at 32 degrees C. Also by day 5, injection of rats consuming E+ with prazosin reduced (P < 0.01) skin and rectal temperatures 0.4 degree C compared with those consuming E+ and injected with placebo. Monoamine receptor (alpha 1, alpha 2, and D2) densities were similar (P > 0.10) among treatments. Prazosin injection reduced E+ induced body temperature increases chronically and increased food intake acutely to E- levels. Monoamine receptor densities were unchanged; therefore, E+ effects via monoamine receptors may be due to acute modulation of receptor-associated activity. PMID- 8689529 TI - Glutathione inhibition of silver-enhanced sodium transport across toad skin. AB - Silver stimulated short-circuit current and transepithelial potential difference. Glutathione inhibited the silver-induced short-circuit current. There was a dose response inhibition of silver-induced short-circuit current by glutathione. The silver-induced short-circuit current is carried by a net active sodium transfer from the outside to the inside bathing solution. PMID- 8689530 TI - Comparative biochemical effects of low doses of mercury II chloride in the F344 rat and the multimammate mouse (Mastomys natalensis). AB - The biochemical effects and comparative nephroxicity of mercury II chloride (HgCl2) dosed at 0.75 mg/kg i.p. was investigated in the Fisher 344 rat (F344) and Mastomys natalensis using high resolution 1H nuclear magnetic resonance (NMR) spectroscopy of urine, histopathology and clinical chemical techniques. The effects of HgCl2 treatment were followed for up to 4 days post-dosing (p.d.). In F344 rats there was extensive proximal tubular damage and renal cortical necrosis together with elevated levels of urinary gamma-glutamyl transpeptidase (gamma GT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). The 1H NMR spectra of urine obtained from Hg-treated F344 rats also showed increased levels of glucose, alanine, lactate, valine and hippurate (0-48h p.d.) with decreased levels of citrate, succinate and 2-oxoglutarate (24-48h p.d.). Mastomys were found to be highly resistant to HgCl2 toxicity at 0.75 mg/kg and the histological appearance of the renal cortex of treated animals was virtually identical to controls. There were no elevations in urinary ALP, gamma GT and LDH activities in HgCl2-treated Mastomys and there were no biochemical abnormalities in low MW components of Mastomys urine following HgCl2-treatment, as shown by 1H NMR spectroscopy. Urinary gamma GT activity was found to be much higher in F344 rats than Mastomys. Since gamma GT activity is involved in the tubular reabsorption of Hg2+, the lower levels of gamma GT in Mastomys might partially account for the lower toxicity of Hg2+ in this species. PMID- 8689531 TI - Temporal expression of retinoic acid receptors in hamster fetus during organogenesis and alteration by retinoic acid treatment. AB - Retinoic acid receptors alpha, beta and gamma (RAR alpha, beta, gamma) mRNAs from whole 8- to 15-day-old hamster fetuses were characterized and quantitated by Northern blots and solution hybridization using riboprobes from cloned hamster RAR cDNAs, derived from 12-day fetal hamster library. Two RAR alpha transcripts of approximately 3.1 and approximately 3.5 kb, one transcript of RAR beta approximately 2.8 kb and one transcript of RAR gamma approximately 3.1 kb were observed. The relative abundance levels of these transcripts were RAR gamma > beta > alpha. RAR beta and gamma levels peaked at day 11, increasing approximately 4-fold (beta) and approximately 2.5-fold (gamma) above their initial values at day 8. RAR alpha did not change appreciably and peaked on day 14 at 1.7 x of its lowest level at day 9. Regulation patterns of the three RARs diverged between days 8 and 9 and 13 and 14 postcoitum (p.c.) and coordinately increased between days 9 and 13 and decreased between days 14 and 15 p.c. In 12 day-old conceptuses exposed to all-trans-retinoic acid, RAR alpha did not increase significantly, but RAR beta increased 12-fold at 4 hr and RAR gamma 2 fold at 1 hr after the maternal treatments. PMID- 8689532 TI - Daily changes in thyroid activity in the frog Rana perezi: variation with season. AB - Plasma triiodothyronine (T3) and thyroxine (T4) levels, as well as thyroid free (f) and bound (b) thyroid hormones (TH) content, were determined by radioimmunoassay (RIA) in adult Rana perezi frogs during a 24 h cycle in winter, spring, summer, and autumn. Significant daily changes in plasma T3 levels were present in all the seasons except for winter, being the lowest values observed during the scotophase. In contrast, plasma T4 only showed significant changes in spring, following a similar pattern to the one described for T3. Thyroid fT3 content did present day/night significant changes only in spring showing high contents at early scotophase. Mean fT4 content was higher at the beginning of light phase than during the rest of daily photocycle in spring and autumn, but significant differences appeared only in autumn. Regarding the thyroid bound content of TH, bT3, and bT4 presented significant daily changes in spring and autumn. However, different profiles were observed in these two seasons. High bound contents were found at early photo- and scotophase with lower values at late dark phase in spring, whereas higher contents were detected at this time in autumn. The present results indicate the existence of seasonally changing daily fluctuations in thyroid activity in Rana perezi and it seems that an interaction between photoperiod and temperature plays a role in the regulation of these daily changes. PMID- 8689533 TI - Bacterial pericarditis after heart transplantation: successful management of two cases with catheter drainage and antibiotics. AB - OBJECTIVE: To describe the diagnosis and management of bacterial pericarditis after heart transplantation. PATIENTS AND METHODS: Two patients with Staphylococcus aureus pericarditis after heart transplantation were successfully treated conservatively with closed catheter drainage and antibiotics. RESULTS: The patients were alive three and six years, respectively, following surgery. At follow-up, right heart catheterization demonstrated normal hemodynamics in one patient and a pattern of constrictive pericarditis in the other patient which was man-aged with furosemide. CONCLUSIONS: Conservative management of bacterial pericarditis by closed catheter drainage and antibiotics can be considered in selected patients after heart transplantation. PMID- 8689534 TI - Modified Blalock-Taussig shunts: to heparinize or not to heparinize? AB - OBJECTIVE: To demonstrate shunt function of modified Blalock-Taussig Shunts (MBTSs) when no heparin is administered postoperatively. PATIENTS AND INTERVENTIONS: Twenty-four MBTSs were performed on 23 children with various congenital heart problems needing palliation before the primary repair could be completed. A single low dose of heparin was given intraoperatively and no heparin was given postoperatively. Patients were evaluated for shunt patency, bleeding problems and the incidence of significant seromas at the graft site. MAIN RESULTS: There was one perioperative death and no incidence of early shunt failure. Two children died from causes unrelated to shunt function. There were no postoperative bleeding difficulties (no reoperations), and no seromas surrounding the grafts. Late follow-up (mean 18 +/- 1 months) revealed no shunt failure. CONCLUSIONS: Avoidance of heparin after an MBTS procedure is a safe practice and may reduce bleeding problems and the incidence of significant seromas surrounding the graft. Postoperative shunt thrombosis is more likely related to intraoperative technical difficulty or extremely small pulmonary artery size. PMID- 8689535 TI - Myocardial uptake and washout kinetics of T1-201 with the VEX (vasodilator plus exercise) test: contribution of stress mode components and coronary stenosis severity. AB - OBJECTIVE: To assess the vasodilator plus exercise (VEX) test as an adjunct to myocardial perfusion imaging with respect to the accuracy of kinetics of thallium 201 (Tl-201) and other indicators of ischemia. SETTING: A nuclear medicine laboratory in which patients referred for myocardial scintigraphy are triaged to undergo the stress component with symptom-limited bicycle exercise, dipyridamole or VEX as appropriate. DESIGN: Cases having correlating scintigraphy and angiography (n = 425) were selected retrospectively. Immediate poststress and redistribution images were quantified using a circumferential profile analysis with interpolative background subtraction. For each of nine sectors on the left anterior oblique image, multivariate analyses were performed, comparing the relative uptake and net washout of Tl-201 to the exercise workload attained, use of dipyridamole, time to redistribution, gender, and the angiographic presence and severity of stenoses at five key sites. Washout values standardized according to gender, exercise level and time to redistribution, were compared with relative uptake profiles and ST depression using receiver operating curves. RESULTS: For each sector, a significant contribution to Tl-201 washout was made by the exercise level (P < 0.001) and by at least one site of stenosis (P < 0.0001), but not by use of dipyridamole (P > 0.5); female gender was associated with increased washout (P < 0.01) except for the three lateral sectors. For each stress modality, standardized washout performed better than ST depression but not as well as relative uptake profiles in detecting coronary artery disease. CONCLUSIONS: For combined pharmacological-exercise stress, quantitative uptake profiles may assist in confirming subjective scan interpretation; washout profiles, even when standardized for gender and stress level, are suboptimal for confirming defect reversibility. PMID- 8689536 TI - Alteration of peripheral blood lymphocyte subsets in essential hypertension. AB - OBJECTIVE: To assess lymphocytic subpopulation by labelled monoclonal antibody technique in a small group of patients with untreated essential hypertension (EH) and to detect any alteration with control of blood pressure. DESIGN: Prospective study with phenotypic estimation of lymphocytes at presentation and a minimum of two weeks after the control of blood pressure. SETTING: Referral, tertiary care hospital. PATIENTS: Group 1, normotensive controls (n = 10); group 2, mild to moderate essential hypertension (n = 10); group 3, severe (accelerated/malignant) hypertension (n = 10). All the secondary causes of hypertension were ruled out by a thorough history, physical examination and appropriate radiological and biochemical investigations. TESTS: Venous blood samples, taken at entry and a minimum of two weeks after control of blood pressure, were analyzed by alkaline phosphatase antialkaline phosphatase (APAAP) antibody technique for CD4, CD3, CD8 and CD22. Peripheral lymphocytes were separated and cocultured with phytohemagglutinin (PHA) for 72 h and assayed for CD25 by the APAAP technique. MAIN RESULTS: In untreated patients with EH (groups 2 and 3), there was a significant down regulation of CD3, and CD4 lymphocytes whereas the proportion of mature CD22 cells increased. In group 3 there was a significant down regulation of CD25 with PHA stimulation. A negative correlation was observed between CD25 and diastolic pressure upon pooling the results of groups 2 and 3. No significant alteration in these parameters was observed following control of blood pressure with drugs for up to two weeks. CONCLUSION: In this small group of patients with untreated EH, a significant alteration in the lymphocytic repertoire was observed. Whether this will be found in large groups of hypertensives remains to be seen. PMID- 8689537 TI - Smoking, plasma antioxidants and essential fatty acids before and after nutratherapy. AB - OBJECTIVE: To study the effect of smoking on plasma antioxidants with and without antioxidant vitamin nutratherapy. DESIGN: Chronic smokers (n = 10, 16 +/- 4 cigarettes a day) and nonsmokers (n = 17) of both sexes were recruited from patients with arthritis-like symptoms. After baseline studies of plasma antioxidant vitamins Q (ubiquinone) and E (alpha-tocopherol) and essential fatty acids (EFA, vitamin F), three months' nutratherapy with vitamins Q (90 mg) and E (350 mg) was administered and plasma reanalyzed. RESULTS: No sex differences were seen in smoking habits or plasma nutrients. Smokers had normal Q (0.71 +/- 0.07 mg/L) but depressed E (9.4 +/- 0.6 mg/L, P < 0.01). EFA were the same in both groups. Nutratherapy increased Q by about 90% in both groups and E by 47% in smokers and 101% in nonsmokers (P < 0.01). In nonsmokers, nutratherapy protected omega-3 fatty acids (vitamin F1)-plasma docosahexaenoic acid increased by 39%. The vitamin F index (omega-6:omega-3, ratio) remained unchanged in the smokers but decreased in the nonsmokers and became related to the individual plasma vitamin Q but not to vitamin E. CONCLUSIONS: There was no difference between smokers and nonsmokers before nutratherapy. Nonsmokers may have suffered from passive smoking. After nutratherapy the quantitatively most important antioxidant, ie, vitamin E, increased more in nonsmokers than in smokers. This resulted in less vitamin F1 peroxidation. Nutratherapy cannot overcome disadvantages associated with smoking. Nonsmokers might achieve an antioxidant protection with nutratherapy, which could mean a possible reduced risk of developing cardiovascular disease. PMID- 8689538 TI - Sex differences in the features of coronary artery disease of patients undergoing coronary angiography. AB - OBJECTIVE: To examine sex differences in the features of coronary artery disease (CAD) of patients who have undergone coronary angiography. DESIGN: Retrospective study which reviewed clinical and angiographic results from eligible patients who underwent coronary angiography under one cardiologist during a consecutive period. SETTING: Tertiary referral women's health centre. PATIENTS: 515 patients (167 women, 348 men) who underwent coronary angiography for suspected CAD, excluding those with previously known primary valvular disease, valvular replacement, congenital heart disease, nonischemic cardiomyopathy, history of cocaine-induced myocardial ischemia or infarction, and those who had previously undergone coronary angiography, coronary artery bypass graft or percutaneous transluminal coronary angioplasty. MAIN RESULTS: Overall, females and males presented at similar ages and with similar prevalences of smoking, diabetes, hypertension, and family histories of premature CAD, albeit women were less likely than men to have a prior history of myocardial infarction. The observed age difference between females and males with coronary disease was less than expected (3.3 +/- 2.3 years, 95% confidence limits). At angiography, women were three times more likely than men to have normal coronary arteries. Yet, in patients found to have coronary disease, there was no sex difference in either the severity or the distribution of the disease. Women were twice as likely as men to have normal left ventricular function on catheterization. However, when all cases of normal angiograms were excluded, multivariate logistic regression analysis showed that, after controlling for other important confounding factors, females were as likely as males to have significant CAD and left ventricular dysfunction on angiography. CONCLUSIONS: Women can develop serious ischemic heart disease that is similar to that in men and at a relatively younger age than previously described. The vulnerability to ischemic heart disease in nonelderly women needs to be emphasized. PMID- 8689539 TI - Coronary 'Y' stenting: a technique for angioplasty of bifurcation stenoses. AB - This report describes a case of successful percutaneous coronary transluminal angioplasty (PTCA) of a coronary artery bifurcating lesion using multiple intracoronary stents in an inverted 'Y' configuration. Balloon angioplasty of bifurcation coronary stenoses has a lower procedural success rate, higher restenosis rate and potential for side branch occlusion compared with nonbifurcation lesions. Numerous techniques, including two ('kissing') angioplasty balloons, have been used to overcome these problems. The authors believe that the technique described in this report, inserting stents into both branches simultaneously followed by a third proximal stent in a 'Y' configuration, allows successful dilatation of the bifurcation lesion while preserving flow into both branches and should be considered for similar complex anatomical subsets. PMID- 8689540 TI - Torsade de pointes, acquired complete heart block and inappropriately long QT in childhood. AB - After spontaneously acquiring complete heart block, two children presented with torsade de pointes as a result of inappropriate prolongation of the QT interval. Although both remain well following pacemaker insertion, their cases illustrate the importance of QT interval assessment in patients with atrioventricular block, and demonstrate that syncopal episodes, and possibly sudden death, in children with acquired heart block can be due to bradycardia-induced ventricular tachyarrhythmias, rather than extreme bradycardia per se. PMID- 8689541 TI - Reversible cardiogenic shock in an angry woman--case report and review of the literature. AB - A previously healthy woman presented with ischemic cardiac pain and ST elevation suggestive of acute myocardial infarction following a 45 min argument. Despite receiving tissue plasminogen activator, she developed cardiogenic shock and objective evidence of recurrent ischemia, with only a small creatine kinase rise. Angiography revealed the unexpected findings of normal coronary anatomy and akinesis of the distal two-thirds of the left ventricle. Apart from an iliac vein thrombosis, the remainder of her course was characterized by dramatic recovery of cardiac function. The differential diagnosis of myocardial infarction with angiographically normal coronary arteries is discussed, with emphasis on aspects relevant to this case. The presence of high titre anticentromere antibodies, anticardiolipin antibodies, protein S deficiency and supportive physical findings, suggested the diagnosis of concurrent antiphospholipid antibody syndrome (with secondary acquired protein S deficiency) and CREST syndrome. The pathogenesis likely involved an interaction between stress, vasospasm, and thrombosis. PMID- 8689542 TI - CAD and south Asians. PMID- 8689543 TI - [Implantation of intraocular lenses in myopia]. AB - The objective of the investigation was to evaluate implantation of an intraocular lens in patients with cataract and myopia. Posterior chamber intraocular lenses (IOL)+15 D and lens with a length of the axis of 25.00 mm and more were implanted after ECCE or phacoemulsification in the year 1994 in 81 eyes of 71 patients with mean age of 69 years (range 45 - 81 years). The mean length of the axis was 27.05 mm +/- 1.49 mm, the mean value of the IOL was +11.2 +/- 2.83 diopters. Vision of 6/12 and better with supplementary correction was achieved in 62.7% of the eyes during the last check-up examination. The mean refraction value after surgery was -2.11 +/- 1.63 diopters with a range from +2.0 to -6.0 diopters. Surgery of cataract in myopia gravis with implantation of a posterior chamber intraocular lens is fully justified and makes it possible to achieve excellent functional results. PMID- 8689544 TI - [Treatment of herpes simplex keratouveitis with systemic and local administration of acyclovir]. AB - Sixteen patients with relapsing or chronic HSV keratouveitis were treated during a new attack by acyclovir 15 mg/kg/day by the i.v. route for 5 days with local combination of acyclovir 3% ung. and steroids. In all 16 patients improvement of signs of keratouveitis occurred on the fourth day of therapy, in 10 patients with improvement of visual acuity. In 5 patients perforating keratoplasty was performed on account of turbidity of the cornea. The authors observed four relapses of the disease in the course of 12 months after termination of treatment. PMID- 8689546 TI - [A supporting ring for the lens capsule]. PMID- 8689545 TI - [Mechanical principles of continuous curvilinear capsulorhexis]. PMID- 8689547 TI - [Excimer laser photorefractive keratectomy in myopia]. AB - The authors present an account on excimer laser photorefractive keratectomy on 254 myopic eyes with a minimal follow-up period of 6 months. The mean preoperative refraction -6.31 +/- 4.02 D was reduced to -0.92 +/- 1.3 D. A difference between the planned and achieved correction of less than 0.5 was recorded in 33.5% eyes, less than 1.0 D in 59.4% eyes and less than 1.5 D 77.6% eyes. As to complications the following were recorded: astigmatism more than 0.5 D (7.9%), problems with epithelialization (5.5%), steroid induced increased intraocular pressure (3.9%), corneal turbidity higher than 2 (1.2%). Based on the results the authors revealed that excimer laser photorefractive keratectomy is safe and effective refraction surgery for low and medium myopia with the possibility to predict the resulting postoperative refraction. PMID- 8689548 TI - [LASIK = laser in situ keratomileusis. Initial experience]. AB - Electron microscopic picture of human and rabbit corneas treated by LASer In situ Keratomileusis (LASIK) are presented. Clinical part of this paper deals with first 11 eyes operated by LASIK in the Czech Republic (10 eyes with myopia and myopia with astigmatism and 1 eye with hyperopia with astigmatism). Follow up 2 months. Refraction and BCVA changes are demonstrated on scales. Refraction in the myopic group decreased from -16,3 (+/- 7,05) D sf.eq.preop. to -1,7 (+/- 2,45) D postop. Complications preop.: 3x undercorrection, 1x overcorrection, 3x residual astigmatism and 5x detritus at the interface. One case of early reoperation because of undercorrection is demonstrated. Short term results show that LASIK seems to be a very good methods of surgical correction of higher and high myopia and myopia with astigmatism with good predictability. It is possible to perform successful early reoperation with good centration of ablation zone and good functional outcome. LASIK eliminates postop. pain. There were no corneal hazes even with low term application of steroids in this group of 11 eyes. Promising results were achieved in hyperopia treated by LASIK. PMID- 8689549 TI - [Extraction of a clear lens-cataract as refractive surgery in severe myopia]. AB - Fukals operation (extraction of a transparent lens in severe myopia) was of a long time considered risky in particular because of possible retinal complications. Based on ten years experience (1985 - 1994) the authors provide evidence that modern microsurgical methods, in particular phacoemulsification make it possible to perform this operation at a qualitatively higher level, much more safety and with a lower rate of complications. In a group of 284 operated eyes with myopia (15.96 diopters) were 4.57% transparent lenses, 37.68% with mild partial turbidity and 57.75% with dense or complete turbidity. Corrected vision 5/5 - 5/10 was achieved in 44.37%. Peroperative prolapse of the vitreous body occurred in 5.28%. The most frequent late complication was secondary cataract (26.76%). During the mean follow-up period of 37.57 months there was no case of cystoid oedema of the macula or detachment of the retina. Extraction of a transparent lens or incipient cataract in severe myopia is becoming an alternative method of other refractive operations. PMID- 8689550 TI - [Fluorescein angiography of angioid streaks]. AB - Author observed two patients affected by Pseudoxanthoma elasticum with different extent of alternation on the eye background. The separate states of progression of this eye disease are observed by fluorescein angiography. Beside the finding of angioid streaks fluorescein angiography more precisely demonstrates extent of Bruch membrane abnormalities and alteration of pigmentary epithelium of the retina. This way fluorescein angiography significantly contributes to clarification of other accompanying pathology of this eye disease. PMID- 8689551 TI - [Correction of aphakia with transcleral fixation of the lens in the ciliary sulcus]. AB - The posterior chamber intraocular lens particularly for ciliary sulcus fixation is a very good solution of correction of aphakia in cases when any part of capsule is missing. With proper surgical technique the obtained results are very good and the number of complications reported can be minimized. The authors demonstrate it in a group of 38 eyes with ciliary sulcus fixation. A very low occurrence of complications and good visual acuity including long follow-up confirm, that this method can be successfully used in the case od correction of aphakic patients. PMID- 8689552 TI - [Cataract surgery in patients with endogenous uveitis]. AB - The authors present an account of surgery of complicated cataract in 20 patients with anterior and intermediate uveitis. During a one-year follow-up period they evaluate the difference of postoperative development and visual acuity in extracapsular extraction without or with implantation of an intraocular lens. In 10 patients (5x m. Fuchs, 3x anterior uveitis, 2x intermediate uveitis) they performed only ECCE. In 10 patients with the same diagnosis an intraocular lens was implemented. The authors did not find marked differences between the ECCE operation and ECCE operation with an intraocular lens in patients with uveitis. The visual acuity improved in all 20 patients, a marked inflammatory reaction in the anterior chamber was observed in both groups only during the first days after surgery. The two groups did not differ markedly as regards late complications. From the investigation ensues that implantation of an intraocular lens is well tolerated in patients with anterior and intermediate uveitis assuming a minimum 12-week remission of the disease. PMID- 8689553 TI - Receptor-mediated protein sorting to the vacuole in yeast: roles for a protein kinase, a lipid kinase and GTP-binding proteins. AB - In this review we summarize the structural and functional characteristics of the VPS (vacuolar protein sorting) gene products that have provided insight into the regulatory interactions and molecular mechanisms underlying protein sorting pathways in eukaryotic cells. Genetic selections in yeast have resulted in the identification of more than 40 genes required for the vesicle-mediated sorting of proteins to the lysosome-like vacuole. Molecular characterization of these VPS gene products has revealed a number of biochemical activities involved in this process. Analogous to the mannose-6-phosphate receptors in mammalian cells, the VPS10 gene encodes a transmembrane sorting receptor for the yeast vacuolar hydrolase carboxypeptidase Y. The VPS15 and VPS34 genes encode components of a novel signal transduction complex essential for the delivery of soluble vacuolar hydrolases. VPS15 and VPS34 encode a serine/ threonine protein kinase and a phosphatidylinositol 3-kinase, respectively, that interact at the cytoplasmic face of an intracellular membrane compartment, most likely corresponding to the late Golgi. Other VPS gene products have homologues that are involved in membrane trafficking pathways: The VPSI and VPS21 genes encode GTPases of the dynamin and rab families, respectively, and the products of the VPS33, VPS45, and PEP12/VPS6 genes are homologues of proteins involved in regulated synaptic vesicle exocytosis. The VPS gene products constitute components of a molecular apparatus responsible for the recognition, packaging, and vesicular transport of proteins to the vacuole in yeast. PMID- 8689554 TI - Keratins and the skin. AB - Keratins are the major structural proteins of the vertebrate epidermis and its appendages, constituting up to 85% of a fully differentiated keratinocyte. Together with actin microfilaments and microtubules, keratin filaments make up the cytoskeletons of vertebrate epithelial cells. Traced as far back in the evolutionary kingdom as mollusks, keratins belong to the superfamily of intermediate filament (IF) proteins that form alpha-helical coiled-coil dimers which associate laterally and end-to-end to form 10-nm diameter filaments. The evolutionary transition between organisms bearing an exoskeleton and those with an endoskeleton seemed to cause considerable change in keratin. Keratins expanded from a single gene to a multigene family. Of the approximately 60 IF genes in the human genome, half encode keratins, and at least 18 of these are expressed in skin. Vertebrate keratins are subdivided into two sequence types (I and II) that are typically coexpressed as specific pairs with complex expression patterns. The filament-forming capacity of a pair is dependent upon its intrinsic ability to self-assemble into coiled-coil heterodimers, a feature not required of the invertebrate keratins (Weber et al 1988). Approximately 20,000 heterodimers of type I and type II keratins assemble into an IF. Mutations that perturb keratin filament assembly in vitro can cause blistering human skin disorders in vivo. From studies of these diseases, an important function of keratins has been unraveled. These filaments impart mechanical strength to a keratinocyte, without which the cell becomes fragile and prone to rupturing upon physical stress. In this review, studies on the pattern of expression, structure, and function of skin keratins are summarized, and new insights into the functions of these proteins and their involvement in human disease are postulated. PMID- 8689555 TI - Protein import into the nucleus: an integrated view. AB - The directed movement of macromolecules into and out of the nucleus is a fundamental process in eukaryotes and occurs through the nuclear pore complex (NPC). A diverse array of molecules are transported across the nuclear envelope including proteins, mRNAs, tRNAs, snRNP complexes, ribosomal subunits, and in specialized cases, DNA. The structural and functional differences between these molecules point to the mechanistic complexity of NPCs and other components of the nuclear transport apparatus. This machinery must not only recognize within transported molecules specific targeting signals that differ between proteins, RNA, and RNA/protein complexes, it must translocate these molecules across the nuclear envelope. Additional levels of complexity are necessary because molecules such as proteins may continually undergo bidirectional transport across the envelope. Beyond these basic functions, the nuclear transport apparatus is regulated at the level of individual substrates and at more global levels such as coupling to cell cycle regression. PMID- 8689556 TI - Drosophila gastrulation: from pattern formation to morphogenesis. AB - The major morphogenetic movements during Drosophila gastrulation--germ band extension and the invagination of the mesoderm and endoderm--are driven by cell intercalation and cell shape changes, respectively. The regions of the early embryo in which these movements occur and which give rise to the germ layers are demarcated by a small number of zygotically expressed genes. These genes code for transcription factors that regulate cell behavior by controlling expression of target genes whose products modulate the cytoskeleton and other subcellular compartments. PMID- 8689557 TI - The cell biology of infection by intracellular bacterial pathogens. AB - Listeria monocytogenes and Shigella flexneri are unrelated bacterial pathogens that have independently evolved similar strategies of survival within an infected host animal. Bacteria coming into contact with the surface of an epithelial cell induce cytoskeletal rearrangements resulting in phagocytosis. They then secrete enzymes that degrade the phagosomal membrane, releasing the bacteria into the host cytoplasm. Intracytoplasmic bacteria move rapidly, in association with a "comet tail" made up of host cell actin filaments. When moving bacteria reach the cell margin, they push out long protrusions with the bacteria at the tips that are then taken up by neighboring cells, allowing the infection to spread from cell to cell. This review summarizes what is currently known about the interactions between the bacteria and the host at each stage of the infection and discusses what mammalian cell biologists can learn by studying bacterial pathogens. PMID- 8689558 TI - Biological atomic force microscopy: from microns to nanometers and beyond. AB - In recent years, atomic force microscopy (AFM) has become the most rapidly developing imaging method. We summarize its recent applications in structural biology, with emphasis on high-resolution imaging, and illustrate these applications with images of cell membranes, DNA, and soluble and membrane proteins. With present technology, and at room temperature, nanometer resolution of DNA and soluble proteins is achievable, although the resolution attained on cell surfaces is more limited (10-50 nm). We suggest that high-resolution imaging of cell surfaces and very high (sub-nanometer) resolution molecular imaging requires an approach that increases specimen rigidity. Operation at cryogenic temperatures, the most promising approach, is discussed, and a cryo-AFM designed for operating at ambient pressure and liquid nitrogen temperature is described. The results include high-resolution images and evidence of increased molecular rigidity at low temperatures. PMID- 8689559 TI - How MHC class II molecules acquire peptide cargo: biosynthesis and trafficking through the endocytic pathway. AB - The antigen-specific receptors of T lymphocytes rely on products of the major histocompatibility complex (MHC) to recognize and engage antigen. MHC molecules display antigen on the cell surface in the form of small peptides, generated intracellularly by fragmentation of the intact protein antigen. They acquire these peptides at distinct intracellular locations: In the endoplasmic reticulum (ER), class I molecules bind peptides derived from cytosolic proteins, whereas class II molecules acquire their peptide cargo in an endocytic compartment. Sequestration of class II molecules from the constitutive secretory pathway is mediated by their interaction with an additional polypeptide, the invariant chain (Ii). The Ii contains sorting signals in its cytoplasmic tail that target class II molecules to the endocytic pathway where they encounter peptides generated from protein antigens that have also accessed this route. PMID- 8689560 TI - TCR gamma delta cells: a specialized T-cell subset in the immune system. AB - Specificity, memory, and self/nonself discrimination are the essential principles that underlie the acquired immune response. From birth through one's life, the immune system is continually responding to new environmental challenges (e.g. bacteria and viruses) and developing a specific, long-lasting immunity to those challenges. The first exposure to a pathogen results in the recruitment of multiple cell types, including macrophages, dendritic cells, and assorted leukocytes, that initiate an antigen nonspecific inflammatory response designed to attract T cells and B cells to the inflammatory sites including the draining lymph nodes. The foreign antigens are concentrated within the professional antigen-presenting cells (APCs) that process and present small antigenic peptides to CD4+ and CD8+ T cells in association with class II and class I major histocompatibility complex (MHC) molecules, respectively. The activated CD4+ T cell receptor (TCR) alpha beta cells respond vigorously to the pathogen in an antigen-specific manner, liberating a barrage of cytokines that induce B cells to differentiate to antibody-secreting plasma cells and likewise cause CD8+ cells to differentiate into cytolytic effectors. The T cells and B cells expand in an evolving, highly specific manner to control the initial infection while developing long-term acquired immunity such that any further infection by that pathogen is virtually impossible. Thus TCR alpha beta T cells are the central lymphocyte in the immune system, providing specific pathogen recognition and long term memory all within the context of distinguishing foreign from self antigens. Yet, during a primary immune response, there is a lag time of approximately 3 to 4 days before antigen-specific responses are evident, and TCR alpha beta responses do not peak until approximately day 7. Therefore, it is essential that other strategies are employed by the immune system in order to mount an aggressive early immune response. PMID- 8689561 TI - The biology of hematopoietic stem cells. AB - Hematopoietic stem cells (HSC) are the only cells in the blood-forming tissues that can give rise to all blood cell types and that can self-renew to produce more HSC. In mouse and human, HSC represent up to 0.05% of cells in the bone marrow. HSC are almost entirely responsible for the radioprotective and short- and long-term reconstituting effects observed after bone marrow transplantation. The subsets of HSC that give rise to short-term vs long-term multilineage reconstitution can be separated by phenotype, demonstrating that the fates of HSC are intrinsically determined. Here we review the ontogeny and biology of HSC, their expression of fate-determining genes, and the clinical importance of HSC for transplantation and gene therapy. PMID- 8689562 TI - Transcription factors responsive to cAMP. AB - In eukaryotes, transcriptional regulation upon stimulation of the adenylate cyclase signaling pathway is mediated by a family of cAMP-responsive nuclear factors. This family consists of a large number of members that may act as activators or repressors. These factors contain the basic domain/leucine zipper motifs and bind as dimers to cAMP-response elements (CRE). The function of CRE binding proteins is modulated by phosphorylation by several kinases. The ICER (inducible cAMP early repressor) protein is the only inducible member of this family. The induction of this powerful repressor is likely to be important for the transient nature of cAMP-induced gene expression. CRE-binding proteins have been found to play an important role in the physiology of the pituitary gland, in regulating spermatogenesis, in the response to circadian rhythms, and in the molecular basis of memory. PMID- 8689563 TI - The molecular architecture of focal adhesions. AB - This article outlines the present knowledge of the architecture, molecular composition, and dynamics of focal contacts of adhesive animal cells. These structures, developed at the plasma membrane at sites where cells touch their substratum, are essential for cellular attachment in tissue formation during embryogenesis and wound healing. In tissue culture, they are particularly prominent and thus amenable to detailed investigation. Focal contacts consist of a cytoplasmic face, comprising cytoskeletal elements, a transmembrane connecting region, and a extracellular face composed of proteins of the extracellular matrix. The molecular anatomy of the numerous proteins involved, the basis for classifying them as structural or regulatory components, and their in vitro interactions are described. Based on this information, current models on the dynamics of their assembly and of possible regulatory mechanisms involving a variety of signal transduction pathways are discussed. PMID- 8689565 TI - Heat shock transcription factors: structure and regulation. AB - Organisms respond to elevated temperatures and to chemical and physiological stresses by an increase in the synthesis of heat shock proteins. The regulation of heat shock gene expression in eukaryotes is mediated by the conserved heat shock transcription factor (HSF). HSF is present in a latent state under normal conditions; it is activated upon heat stress by induction of trimerization and high-affinity binding to DNA and by exposure of domains for transcriptional activity. Analysis of HSF cDNA clones from many species has defined structural and regulatory regions responsible for the inducible activities. The heat stress signal is thought to be transduced to HSF by changes in the physical environment, in the activity of HSF-modifying enzymes, or by changes in the intracellular level of heat shock proteins. PMID- 8689564 TI - Nitric oxide: a neural messenger. AB - Nitric oxide (NO) is a messenger molecule that is now a well established neurotransmitter in the central and peripheral nervous systems. NO was initially characterized as the "endothelium-derived relaxation factor" and subsequently found to mediate the elevation in cGMP following glutamatergic stimulation in the nervous system. Pharmacological and immunohistochemical data suggest numerous roles for NO throughout the body. NO knockout mice have demonstrated that NO is essential in behavioral and autonomic function. NO also appears to have neurotoxic and neuroprotective effects and may have a role in the pathogenesis of stroke and other neurodegenerative disorders. PMID- 8689566 TI - Structure and function of kinetochores in budding yeast. AB - Kinetochores are DNA-protein structures that attach and move chromosomes along the microtubules of the mitotic spindle. This review focuses on centromeres and kinetochores from the budding yeast Saccharomyces cerevisiae. Because of their relative simplicity, budding yeast centromeres are particularly well suited to detailed molecular analysis. The review begins with a description of chromosome movement and microtubule attachment in living yeast cells. We then describe how centromeric DNA was cloned and analyzed and how this analysis has led to the isolation of centromere-binding proteins by both biochemical and genetic means. Modes of microtubule attachment in vitro are discussed with an attempt to relate in vitro studies to the events that occur in vivo. Finally, we conclude with a speculative model for the organization of the budding yeast centromere a consideration of possible future developments. PMID- 8689567 TI - Control of actin assembly at filament ends. AB - Actin filament polymerization involves exchange of subunits of filament ends, which can be controlled in vitro and in vivo by other proteins that bind actin filaments and inhibit subunit addition or loss at the ends. Proteins that bind to the barbed end, including capping protein, the gelsolin super-family, tensin, and profilin are discussed, as are proteins that bind to the pointed end, including tropomodulin and spectrin/band 4.1. Some proteins that bind along the sides of filaments and influence assembly at ends are also discussed. Functional roles in vivo are emphasized. PMID- 8689568 TI - Silencing and heritable domains of gene expression. AB - Silencing is a process that assembles particular regions of eukaryotic chromosomes into transcriptionally inactive chromatin structures. Silencing involves specialized regulatory sites known as silencers and a combination of general DNA-binding proteins and proteins dedicated to silencing. In the yeast Saccharomyces cerevisiae, these proteins include transcription factors and the origin recognition complex (ORC). Silencing has three recognizably separate phases: establishment, maintenance, and inheritance. At least some silencers are origins of replication, and the establishment of the silenced state requires an S phase-specific event. Once established, the silenced state is heritable, even in the absence of proteins required for its establishment. The silencing of mating type genes bears many similarities to telomere position effects, and the two processes require many of the same proteins. PMID- 8689569 TI - Integrins: emerging paradigms of signal transduction. AB - Integrins receive signals from other receptors that lead to activation of ligand binding (inside-out signaling) and matrix assembly. Upon binding ligands, they also activate intracellular signaling pathways. These signals converse with pathways that are initiated by soluble ligands to regulate cell functions. In this way, cell adhesion is coordinated with other events to orchestrate complex cellular behavior. PMID- 8689571 TI - Unconventional myosins. AB - Myosins are molecular motors that upon interaction with actin filaments convert energy from ATP hydrolysis into mechanical force. Evidence has emerged for the existence of a large, widely expressed and evolutionarily ancient superfamily of myosin genes. In addition to the well-catheterized conventional, filament forming, two-headed myosin-II of muscle and nonmuscle cells, at least ten additional classes of myosins have been identified. In vertebrates, at least seven of the eleven classes are expressed, and many myosins can be expressed in a single cell type. This review summarizes known structural and functional features of these novel unconventional myosins. PMID- 8689570 TI - Carbohydrate-protein interactions in vascular biology. AB - Carbohydrate-protein interactions participate in a wide variety of biological and pathological events. In recent years, particular attention has been paid to the carbohydrate-protein interactions that occur in vascular biology. Sialylated oligosaccharides are ligands of a structurally diverse group of proteins that include the selectins and members of the immunoglobulin superfamily. Various glycosaminoglycans can be recognized by an overlapping set of proteins that include two of the selectins and CD44. Emerging knowledge of carbohydrate-protein interactions in human pathophysiology are discussed. PMID- 8689572 TI - COPs regulating membrane traffic. AB - Cytosolic coat proteins (COPs) regulate membrane traffic in eukaryotic cells. Three classes of coat protein complexes have so far been identified: clathrin and its adaptor proteins, coatomer (COPI), and COPII. Coatomer (composed of seven different subunits) and ADP-ribosylation factor (ARF), which form the COPI coat, are required for budding of coated vesicles from membranes. COPI has been implicated in several steps of transport from the intermediate compartment to the cis-Golgi network, through cisternae of the Golgi stack, and is essential for retrieval to the endoplasmic reticulum (ER) of membrane proteins containing the carboxy-terminal dilysine ER-retention motif. A family of structurally and functionally related COPs may regulate all membrane traffic steps in eukaryotic cells. PMID- 8689573 TI - Vasculogenesis. AB - Induction by fibroblast growth factors of mesoderm during gastrulation leads to blood-forming tissue, including angioblasts and hemopoietic cells, that together constitute the blood islands of the yolk sac. The differentiation of angioblasts from mesoderm and the formation of primitive blood vessels from angioblasts at or near the site of their origin are the two distinct steps during the onset of vascularization that are defined as vasculogenesis. Vascular endothelial growth factor and its high-affinity receptor tyrosine kinase flk-1 represent a paracrine signaling system crucial for the differentiation of endothelial cells and the development of the vascular system. Specified cell adhesion molecules such as VE cadherin and PECAM-1 (CD-31), and transcription factors such as ets-1, as well as mechanical forces and vascular regression and remodeling are involved in the subsequent events of endothelial cell differentiation, apoptosis, and angiogenesis. PMID- 8689574 TI - The nucleolus. AB - The nucleolus is the site within the eukaryotic nucleus of transcription of rDNA, of processing of the rDNA transcripts, and of the formation of pre-ribosomal particles. We review current ideas for the molecular organization of these processes. The earliest transcriptional events take place near the junction of the fibrillar centers and the dense fibrillar component; nascent transcripts occupy the dense fibrillar component, and the later stages of pre-ribosome formation take place in the granular component. We review current knowledge of non-ribosomal nucleolar proteins. Nucleoli contain a group of proteins that bind RNA and are likely to act as chaperones to facilitate the molecular structural events in the folding and interaction of the many components of ribosomes. Some of these nucleolar proteins are also engaged in a shuttling cycle between the nucleus and the cytoplasm and may serve to transport other proteins. PMID- 8689575 TI - Studies on development of hairless descendants of Mexican hairless dogs and their usefulness in dermatological science. PMID- 8689576 TI - Changes in nasal cavity volume and target area of exposure to nasal drops with age in rats. AB - The changes in the nasal cavity volume of rats with age and the area exposed to nasal drops administered into the nasal cavity were investigated. Results indicated that the nasal cavity volume lineally increased as rats grew older. In 7-week-old rats, the exposed area in the case of an administration volume of 25 microliters, based on practice, was naso-, maxillo-, and ethmoid turbinate and this volume was enough to expose the whole area of the nasal cavity including the ethmoid turbinate. On the other hand, in 27-week-old rats, administration volumes of 10 and 25 microliters were not enough to expose the ethmoid turbinate. This indicated that the exposed area tended to become narrower in 27-week-old rats than in 7-week-old rats, but the exposed area in the case of an administration volume of 50 microliters was naso-, maxillo-, and ethmoid turbinate in 27-week old rats. In this case, the volume was enough to spread to the ethmoid turbinate. Differences in the exposed area might be caused by differences in the volume of the nasal cavity. It was also indicated that the main exposed area was the inferior meatus in the 30 min immediately after administration. At all administration volumes, however, notice should be taken of the outflow of nasal drops into the oral cavity through the nasopalatine. PMID- 8689577 TI - A possible mechanism of increase in serum alkaline phosphatase activity in rats given granulocyte colony-stimulating factor. AB - Recombinant human granulocyte colony-stimulating factor (G-CSF) at a dose of 1 to 300 micrograms/kg/day was administered intravenously to rats daily for 13 weeks. Serum alkaline phosphatase (ALP) activity increased dose-dependently with leukocytosis. Most of the increased leukocytes were segmented neutrophils, and neutrophil alkaline phosphatase (NAP) scores were elevated markedly. Serum ALP activity correlated very well with the segmented neutrophil counts, and the coefficient of correlation was more than 0.97 in both sexes. Pathological examinations revealed splenomegaly and a marked increase in neutrophils in the red pulp of the spleen. In the spleen, phagocytosis of neutrophils by macrophages was observed. These data indicate that the increased ALP was of neutrophil origin. Serum ALP activity may be increased by the direct release of ALP from the high number of neutrophils into the blood, or by the leakage of ALP into the blood mainly from the spleen where many neutrophils are pooled and destroyed by the macrophage system. PMID- 8689579 TI - Hematological and serum biochemical values in pregnant and postpartum females of the squirrel monkey (Saimiri sciureus). AB - The hematological and serum biochemical values of a total of 18 pregnant female squirrel monkeys were determined during the pre- and postpartum period. Pregnancy was determined by abdominal palpation in adult females cohabiting with robust males. The mean body weight of the pregnant females gradually increased toward parturition and dramatically decreased at parturition due to delivery of the infant monkey. The red blood cell count, hematocrit and hemoglobin levels diminished toward parturition and then increased to their normal levels by week 6 after delivery. The Wintrobe constant, MCHC, did not fluctuate, but MCH and MCV values increased in late pregnancy and the early nursing periods. The mean white blood cell count varied between 65.8 and 87.3 (x 10(2)/mm3) during the experimental periods. The mean serum total cholesterol concentration and glutamic oxaloacetic transaminase activity were lower in the pregnant group during the mid and late gestation stage than in nonpregnant and nursing females. The mean serum total protein and albumin values were lower in pregnant females than in the controls. Alkaline phosphatase activity increased in late pregnancy and the nursing periods. Since the pregnant females examined gave birth to healthy newborn monkeys and nursed them normally, the hematological and serum biochemical measurements should represent the physiological values for squirrel monkeys during pregnancy and the postpartum period. PMID- 8689578 TI - Rederivation of mice by means of in vitro fertilization and embryo transfer. AB - In vitro fertilization and embryo transfer were performed for rederivation of four strains of mice harbouring mouse hepatitis virus (MHV) and/or Pasteurella pneumotropica (P. pneumotropica). Superovulated oocytes were fertilized by preincubated cauda epididymis sperm in vitro. Fertilized eggs at 2-cell stage were transferred into the oviducts of specific pathogen free (SPF) recipients. Microbial examination of sperm and/or oocyte donors verified the presence of P. pneumotropica and/or of antibodies to MHV in all strains, but neither in the recipients nor in the offspring antibodies to MHV could they be detected. The results indicate that an in vitro fertilization-embryo transfer (IVF-ET) system is an effective and simple alternative to cesarean operation in infected mice. PMID- 8689580 TI - Establishment and characterization of transplantable tumor derived from a spontaneous malignant fibrous histiocytoma in the mouse. AB - A tumor developed spontaneously in the subcutaneous tissue of the hind leg of a 7 month-old female ddY mouse. Light and electron microscopical examinations revealed that the original tumor was composed of an admixture of fibroblast-like and histiocyte-like cells arranged predominantly in a storiform or cartwheel pattern. The tumor cells gave positive reactions for acid phosphatase, N-acetyl beta-glucosaminidase, non-specific esterase, beta-glucuronidase, alpha-1 antitrypsin and fibronectin. The original tumor was diagnosed as a malignant fibrous histiocytoma (MFH). The tumor was serially transplanted into syngeneic mice up to the 92nd generation. The tumor was also consistently transplanted into allogeneic mice of several inbred strains. The allogeneic mice used in the present study were strains having different H-2 haplotypes. During succeeding passages, transplanted tumors showed aberrant growth properties. The tumor transplanted into mice of inbred strains took well to back transplantation for mice of original strain and allotransplantation for other inbred strains. The pathological features of these transplantable tumors were basically similar to those of the original tumor. As mentioned above, a MFH developed spontaneously in the ddY mouse was consistently transplantable into both syngeneic and allogeneic mice. PMID- 8689582 TI - Effect of chronic high protein intake on magnesium, calcium, and phosphorus balance in growing cats. AB - The effects of high protein feeding on food and water intake, and the retention and urinary excretion of macrominerals (magnesium (Mg), phosphorus (P), and calcium (Ca)) were examined in growing cats. Seven female cats aged 4 months were fed diets containing 55% crude protein (n = 4) or 29% crude protein (n = 3) for 12 months on an ad libitum basis. Mineral balances were determined at 0.5, 2, 6, 10, and 12 months of feeding. The higher protein intake stimulated daily water intake and urine excretion throughout the study, although daily food intake was not affected by dietary protein levels. The urinary Mg concentration was decreased by the high protein intake, resulting from both increased urine volume and reduced excretion of urinary Mg. In contrast, the concentration and daily excretion of urinary P were increased by the high protein intake. The protein induced increase in urinary P would not necessarily imply the increased excretion of PO4(3-), the anion responsible for struvite crystallization, because the dissociation of phosphate depends on urinary pH. Urinary Ca excretion was not affected by the dietary protein levels, but the high protein intake caused less retention of P and Ca as a result of enhanced urinary P excretion and lowered Ca absorption. The possibility of high protein feeding for the prevention of struvite crystallization in growing cats is discussed. PMID- 8689581 TI - Dietary effects of corn oil, oleic acid, perilla oil, and evening [corrected] primrose oil on plasma and hepatic lipid level and atherosclerosis in Japanese quail. AB - To compare the atherogenecity of different fats and oils, a total of forty, 40 day-old male Japanese quails were fed one of the following diets for three months: basal diet (control), a diet-containing 15% corn oil (CO) and 2% cholesterol (CH), a diet-containing 15% oleic acid (OL) and 2% CH, a diet containing 15% perilla oil (PE) and 2% CH, a diet-containing 15% evening [corrected] primrose oil (PR) and 2% CH. A higher plasma cholesterol concentration was found in the birds in the CO and OL groups, whereas the PE and PR groups showed a much lower level of plasma cholesterol than the CO and OL groups. In proportion to the increased plasma cholesterol, both CO and OL groups showed narrowing of the lumen of the ascending aorta and its large branches due to marked lipid-rich intimal thickening. Ultrastructural changes in the ascending aorta and its large branches were correlated with the degree of intimal thickening. The major foam cell types were macrophages and fibroblastic cells. The PE and PR groups showed the fewest lipid-rich intimal thickening lesions in their ascending aorta and its large branches. These findings suggest that the alpha-linolenic acid contained in perilla oil is less atherogenic than oleic and linoleic acid, and gamma-linolenic acid contained in evening [corrected] primrose oil has a tendency to decrease the plasma lipid level. PMID- 8689583 TI - Mapping of the dilute-opisthotonus (dop) gene on chromosome 8 of the rat. AB - The rat dilute-opisthotonus (dop) autosomal recessive gene, causing ataxia and coat color dilution, was mapped on chromosome 8 by PCR-amplified microsatellite markers. To facilitate the linkage analysis, an intersubspecific cross with a Japanese wild rat strain was used. The recombination frequencies were 12.8% between Apoc3 and dop, and 32.1% between dop and Mylc1v. The following order of three genes is proposed; Apoc3-dop-Mylc1v. This mutation appears to be homologous to dilute-lethal (d1) of the mouse in terms of clinical symptoms, coat color effect and chromosomal location of the gene loci. Key words: ataxic mutant rat, dilute-opisthotonus (dop), gene mapping. PMID- 8689584 TI - Involvement of macrophages in the development of encephalomyocarditis (EMC) virus induced diabetes in mice. AB - The role of macrophages in the development of diabetes following infection with encephalomyocarditis (EMC) virus was examined in 3 strains of mice (DBA/2 and BALB/c: susceptible, C57BL/6: resistant). After infection with 100 plaque forming units (PFU)/head of EMC-D (highly diabetogenic variant), the incidence of diabetes at 3 days post infection (DPI) (DBA/2: 7/8, BALB/c: 3/8, C57BL/6: 0/8) was well correlated with the severity of macrophage infiltration with beta cell damage in the pancreatic islets (DBA/2: sever, BALB/c: moderate, C57BL/6: slight). Silica-pretreatment depleted macrophage infiltration in the pancreatic islets and decreased the incidence of diabetes at 7 DPI from 100% to 40% in DBA/2 and from 80% to 0% in BALB/c mice, respectively. These results suggest that macrophages play a critical role in the process of pancreatic beta cell damage in EMC virus infection in mice. PMID- 8689585 TI - Role of CD4+ and CD8+ T cells in mouse hepatitis virus infection in mice. AB - Viral growth and histopathological changes in the liver after intraperitoneal infection with mouse hepatitis virus, strain JHM were compared among normal C57BL/6 mice, those depleted of CD4+ T cells, CD8+ T cells and both T cell subsets. Viral growth in mice depleted of CD4+ T cells increased slightly, but pathological changes resembled those in normal mice. In contrast, the hepatitis was exacerbated in mice depleted of CD8+ T cells and those depleted of both T cell subsets. These results suggest that CD8+ T cells play a key role although both T cell subsets are involved in protection against mouse hepatitis virus infection in mice. PMID- 8689586 TI - Distribution of copper in biopsied canine liver. AB - Biopsied canine liver tissues were investigated histochemically by electron microscopy to demonstrate copper localization. The samples were fixed and stained with the modified sulfide-silver method with a combination of iron and zinc removal. Using this method, the hepatic copper, even at a low concentration of 30 micrograms/g dry weight, was detectable. Copper was found in the hepatocyte lysosomes or in the cytoplasm as electrondense granules. PMID- 8689587 TI - Smooth muscle cell proliferation in the arterial intima after stretch injury: relationship between the severity of stretching and intima hyperplasia in New Zealand white rabbits. AB - We examined histologically whether the severity of arterial stretch injury is related to the degree of subsequent intimal hyperplasia. In six male New Zealand White rabbits, the common carotid artery was hyperextended with a 3F Fogarty balloon catheter. Two weeks later, no proliferative change was evident in the intima in the most hyperextended portion. Paradoxically, however, intimal hyperplasia due to smooth muscle cell proliferation was observed in the moderately extended portions. The intimal hyperplasia appeared to be exacerbated where the arterial stretching was more severe. It is concluded that the severity of arterial stretch injury is closely related to the intimal proliferation of smooth muscle cells. PMID- 8689588 TI - Skeletal malformations caused by the Dh (Dominant hemimelia) gene in mice. AB - Morphological characterization of the skeletal malformations caused by the Dh gene was carried out. Skeletal preparations from newborn mice of Dh/Dh, Dh/+ and +/+ genotypes, and adult Dh/+ mice were examined. The Dh gene induced skeletal deformities at the axial regions from the thorax to the tail. Attachment of the ribs to the sternum was sometimes irregular, and normal segmentation of the sternum was also disrupted. Abnormal fusion of the ventral part of the rib was observed in some cases. Lumbar vertebrae were fewer in number and abnormal in shape. Although it was rare, a curled tail was also observed due to distortion of the caudal vertebrae. PMID- 8689589 TI - High lethality of F1 (Dh/+) male mice from the cross between DDD female and DH (Dh/+) male. AB - The present study demonstrates the incidence of high lethality of F1 (Dh/+) male mice, the offspring of DDD females and inbred DH (Dh/+) males. Among the newborn pups, the numbers of F1 (Dh/+) males are comparable to those of mice having other genotypes (+/+ male, Dh/+ female and +/+ female), but many F1 (Dh/+) males died before weaning. On the other hand, among the F1 mice from the cross between DH (Dh/+) females and DDD males, there are no biased numbers of Dh genotype pups. These results suggest the existence of defects in the interaction between the male derived Dh gene and the genetic traits of the DDD female. PMID- 8689590 TI - The Animal Health Trust of Canada (nee the Canadian Veterinary Research Trust Fund) 1972-1994. PMID- 8689591 TI - Liver disease in young dalmatians. PMID- 8689592 TI - An ethicist's commentary on the case of the veterinarian failing to prescribe prescription drugs and losing practice income. PMID- 8689593 TI - Raccoon rabies in eastern Canada (1963 to 1994): a retrospective report. PMID- 8689594 TI - A case-control study of the congenital hypothyroidism and dysmaturity syndrome of foals. AB - A case-control study was conducted to identify risk factors for the congenital hypothyroidism and dysmaturity syndrome of foals. A questionnaire was used during personal interviews of foal owners and farm managers to collect information on animal signalment, farm environment, and mare management. Information on 39 foals with the congenital hypothyroidism and dysmaturity syndrome were compared with 39 control foals. Foals with the syndrome had a significantly (P < 0.0001) longer gestation (357.6 d) than control foals (338.9 d). Pregnant mares that were fed greenfeed, did not receive any supplemental mineral, left their "home farm" during gestation, or grazed irrigated pasture had 13.1 (P = 0.0068), 5.6 (P = 0.0472), 4.3 (P = 0.0076), and approximately 15.3 (P = 0.0245), respectively, greater odds of producing an affected foal than mares not experiencing these events. Greenfeed often contains high levels of nitrate (NO3-), which is known to impair thyroid gland function. In light of this, forage samples from participating farms were analyzed for nitrate levels. The odds of one or more congenitally hypothyroid and dysmature foals being born on a farm feeding forage with at least a trace of nitrate was 8.0 times greater (P = 0.0873) than the odds of the disease occurring on a farm that fed forage free of nitrate. Further, the odds of a mare producing an affected foal when fed forage containing at least a trace of nitrate were 5.9 times greater (P = 0.0007) than those of a mare fed nitrate free forage. This study suggests that congenital hypothyroidism and dysmaturity syndrome in foals may be the result of diets that contain nitrate or that are low in iodine being fed to pregnant mares. PMID- 8689595 TI - Acute isopropyl alcohol intoxication in a horse. PMID- 8689596 TI - Eosinophilic bronchitis caused by Crenosoma vulpis infection in dogs. PMID- 8689597 TI - Investigation of pregnancy losses in beef cattle herds associated with Neospora sp. infection. PMID- 8689598 TI - Potomac horse fever in southwestern Ontario. PMID- 8689599 TI - Portrait of a Canadian veterinarian: E.A.A. Grange, VS, MSc (1848-1921). PMID- 8689600 TI - Most commonly asked questions about anesthetic equipment. PMID- 8689601 TI - Diagnostic ophthalmology. Idiopathic endophthalmitis with secondary retinal detachment. PMID- 8689602 TI - dup(10q) lacking alpha-satellite DNA in bone marrow cells of a patient with acute myeloid leukemia. AB - A marker chromosome was identified in leukemic cells on an AML patient. The G banding pattern resembled on i(10q), but its centromeric position was not clear; in some cells it had a telocentric shape, in others a metacentric or acentric shape. The origin of the marker chromosome was confirmed by FISH, using chromosome-10-specific painting. To determine the centromeric position, C-banding and alpha-satellite probes were applied in FISH, and none of them gave a positive signal. Despite the absence of the centromeric alpha-satellite sequences and the constricted feature of the centromere, the essential centromeric activity was retained in this chromosome, namely, the separation of sister chromatids in anaphase. PMID- 8689603 TI - Proto-RET is rearranged in the new human papillary thyroid cancer cell line PTC 1113A. AB - The receptor tyrosine kinase proto-RET is believed to contribute to thyroid oncogenesis by activation of its tyrosine kinase either by point mutation or rearrangement. The papillary thyroid cancer cell lines PTC-1113A, L, and R were established from a recurrent thyroid cancer and its metastases. The rearrangement of the proto-ret oncogene in the cell line PTC-1113A is demonstrated by Southern analysis utilizing the probe for rearranged ret that encodes the fusion protein H4/tyrosine kinase. In contrast, rearranged ret alleles were not found in the cell lines that developed from metastases, nor in DNA isolated from the recurrent tumor. The cell line PTC-1113A may represent a population of tumor cells that gained a growth advantage due to rearranged ret. This is the second human thyroid cancer cell line harboring rearranged ret, and may serve to study the function of ret activation in thyroid cancers. PMID- 8689604 TI - Cytogenetic analysis in human bone marrow transplantation. AB - Bone marrow transplantation (BMT) is a therapeutic process used to treat a variety of hematologic diseases. After BMT, the documentation of engrafting with the use of genetic markers is obligatory. C-band polymorphism is an excellent genetic marker because it occurs with high frequency in all populations studied and shows a high stability in vitro and in vivo. We studied a total of 36 patients: 15 with myeloid leukemia and 21 with severe aplastic anemia (SAA), submitted to BMT. The majority of the patients with chronic granulocyte leukemia (CGL; 10/15, 67%) and with SAA (17/21, 81%) showed a frequency of host cells around 15% (CGL) and 8% (SAA) in the first period analyzed (day +30 post-BMT); with a decrease in the others (+90, +180 to CGL and SAA and +365 only to CGL). In our study, the persistence of host cells in these proportions did not imply an unfavorable prognosis. On the contrary, some patients with myeloid leukemia (5/15 33%) and SAA (4/21, 19%) showed high proportions of host cells in one or more periods analyzed. If compared to the first group, these patients had, in general, a poor clinical evolution, with rejections, relapses, and deaths in greater numbers. These results show the important contribution of cytogenetic analysis in the follow-up of patients submitted to BMT. PMID- 8689605 TI - Trisomy 15 in hematological malignancies: six cases and review of the literature. AB - We report six cases of trisomy 15 in patients with hematological malignancy. In four cases trisomy 15 was the sole abnormality and in two cases it was associated with sex chromosome loss. The patient age range was 6-91 years, and three patients were male. Four patients had myelodysplasia (refractory anemia), one patient each had acute myeloid leukemia and acute lymphoblastic leukemia. A literature review identified ten other cases of trisomy 15 as the sole abnormality in hematological malignancies. Trisomy 15 as the sole autosomal abnormality in hematological malignancy is uncommon, but can occur in both myeloid and lymphoid malignancies. It appears to occur most frequently in myelodysplasia. PMID- 8689606 TI - Loss of telomeric sequences in a ring derived from chromosome 8 in refractory anemia with excess of blasts in transformation. AB - Using the fluorescence in situ hybridization technique, we analyzed a ring chromosome that appeared as a karyotype evolution in a patient affected by refractory anemia with excess of blasts in transformation. Metaphases hybridized with a chromosome-8-specific centromeric probe indicated that the ring retained the centromere of chromosome 8. Successively, utilizing a probe specific for all human telomeres, we observed that the ring lost telomeric sequences. This study demonstrated that the formation of a ring chromosome in hematologic disorders can cause loss of genetic material not revealed by banding techniques and therefore providing further proof of the advantages of molecular cytogenetic techniques. PMID- 8689607 TI - A nonbalanced translocation (10;16) demonstrated by FISH analysis in a case of alveolar adenoma of the lung. AB - Short-term cultures from an alveolar adenoma of the lung were cytogenetically examined. Of the 54 metaphases studied, 44 were characterized by an apparently normal karyotype and 10 showed a pseudodiploid karyotype: 46,XX,add(16)(q24). Fluorescence in situ hybridization studies permitted identification of the add(16)(q24) as a der(16)t(10;16)(q23;q24). This is the first report of a chromosomal aberration in an alveolar adenoma of the lung. PMID- 8689608 TI - Genotypic characterization of a primary mucoepidermoid carcinoma of the parotid gland by cytogenetic, fluorescence in situ hybridization, and DNA ploidy analysis. AB - We present a case of mucoepidermoid carcinoma with t(3;12)(q24;p13) and polysomy X by cytogenetic and fluorescence in situ hybridization (FISH) techniques. Flow cytometric DNA analysis of the primary tumor showed DNA aneuploidy and analysis of cultured tumor cells showed DNA diploidy indicating restricted growth of the diploid tumor cells in short-term tissue culture. Interphase cytogenetic analysis of chromosomes 1, 3, 6-12, 16-18, and X in the primary tumor showed polysomy 1, 9, 18, and X, monosomy 8 and 17, and disomy 3, 6, 7, 10-12, and 16. Except for chromosome X, other numerical chromosomal abnormalities were not detected by conventional cytogenetic analysis. Our combined approach allowed for better characterization of the genotypic features of this neoplasm. PMID- 8689609 TI - Tetrasomy 8 in a patient with acute nonlymphocytic leukemia: a metaphase and interphase study with fluorescence in situ hybridization. AB - Tetrasomy 8 constitutes a relatively rare recurring chromosome defect in myeloid disorders. The patient reported here, a 71-year-old man, presented with tetrasomy 8 as the sole chromosome abnormality associated with an acute nonlymphocytic leukemia of the M2 type. He failed to respond to chemotherapy and died one year after diagnosis. Following conventional cytogenetics and fluorescence in situ hybridization (FISH) with a centromeric probe specific for chromosome 8, tetrasomy 8 was detected in 61% of the metaphases analyzed and trisomy 8 in 39%. FISH analysis of interphase nuclei confirmed the existence of tetrasomic (35%) and trisomic cells (56%) and revealed a number of cells with two chromosomes 8 (8%). This normal population may represent lymphocytes or myeloid cells that escaped conventional analysis due to their inability to divide or to the small number of metaphases available. The relatively higher proportion of tetrasomic cells in metaphase compared with interphase may be attributed to a proliferative advantage of tetrasomic cells in vitro or to the longer duration of their cell cycle. The simultaneous presence of trisomic and tetrasomic cells confirms the hypothesis of a clonal relationship between trisomy 8 and tetrasomy 8. Our case brings further evidence to the specificity of tetrasomy 8 to myeloid disorders and to the association of this chromosome abnormality with a relatively poor prognosis. However, new patients must be studied to further delineate this cytogenetic entity. PMID- 8689610 TI - Cytogenetic analysis of dedifferentiated chondrosarcoma. AB - Cytogenetic analysis of a dedifferentiated chondrosarcoma with a fibrosarcomatous component revealed the following chromosomal complement: 47,XX,i(1)(q10), add(6)(q13),+7,+8,t(10;12) (p11.2;q11.2),+14,-15,-17, add(19)(q13,4). Chromosome studies of dedifferentiated chondrosarcoma are sparse. Three of the anomalies in the present study are similar to those previously described in dedifferentiated chondrosarcoma. PMID- 8689611 TI - Complex t(1;15;17) in acute promyelocytic leukemia with duplication of RAR alpha and PML sequences. AB - A 46-year-old white male presented with a two-week history of a flu-like illness and bleeding gums. A diagnosis of acute promyelocytic leukemia was made on bone marrow examination with accompanying DIC. All cytogenetically abnormal cells (28/30 at intake and 30/30 at two weeks post-induction) represented a single clone with apparent deletion of 1(p22) and 3(p25), and with a large, derivative chromosome 17. By conventional G- and C- banded analysis, the monocentric der(17) appeared to be disrupted distal to the typical (17q21) APL breakpoint, chromosome 15 did not demonstrate gross rearrangement, and the source of the additional material on the der(17) was unknown. Fluorescence in situ hybridization (FISH) with t(15;17), RAR alpha, and 17qter probes and with chromosome 1, 15, and 17 paints demonstrated that the der(17) consisted of a complex rearrangement with duplication of both RAR alpha and PML, insertion of chromosome 1 sequences, and double insertion of chromosome 15 sequences. The fusion of RAR alpha and PML consistent with APL appears to have occurred at the distal juxtaposition of these sequences in the derivative chromosome. PMID- 8689612 TI - Cytogenetic investigation of synchronous bilateral renal tumors. AB - Cytogenetic investigations on synchronous bilateral renal tumors are scarce. We report our findings on 13 renal tumors from 5 patients and review the literature. In bilateral as well as in solitary tumors, cytogenetic findings in each tumor correlated with the histological patterns, i.e. combinations of trisomies for papillary renal cell carcinoma, loss of 3p-material for non-papillary renal cell carcinoma, and coincident loss of the Y chromosome and chromosome 1 in oncocytomas. Bilateral multifocal renal cell carcinomas were always of the papillary type and the karyotypes showed more or less the same numerical anomalies, with trisomies in different combinations in tumors within the same kidney as well as in both kidneys. Structural changes, in contrast, were different from tumor to tumor. PMID- 8689613 TI - Loss of an X chromosome in aggressive angiomyxoma of female soft parts: a case report. AB - Cytogenetic analysis of an aggressive angiomyxoma of the vulvar region of a 16 year-old female revealed loss of one X chromosome (45,X,-X) in eight of 20 metaphase cells analyzed. Fluorescence in situ hybridization (FISH) performed on disaggregated cells from paraffin embedded lesional tissue confirmed loss of an X chromosome in 31% of cells. Cytogenetic analysis performed on peripheral blood showed a normal chromosomal complement (46,XX). Thus, loss of one X chromosome appears to be confined to the neoplasm. This anomaly has not been previously described in aggressive angiomyxoma. PMID- 8689614 TI - Renal cell carcinoma in an end-stage kidney of a patient with a functional transplant: cytogenetic and molecular genetic findings. AB - Renal cell carcinomas (RCCs) occur at an increased rate and at a younger age in patients with end-stage renal disease (ESRD) than in the general population. A papillary RCC from a patient with ESRD treated by hemodialysis and then by renal transplantation was karyotyped and showed a 55,XY,+2,+4,+7,+10,+12,+16,+17,+17,+20 mainline. No loss of gene sequences in the short arm of chromosome 3 was identified by chromosomal or molecular genetic analysis. Together with one prior report of a cytogenetic study of a RCC in an end-stage kidney, the findings indicate that papillary RCCs that arise in ESRD patients have genetic changes that are similar to those found in sporadic tumors. The increased frequency of tumors and the younger age of the patients may be due to an increased rate at which abnormal mitoses occur in diseased renal tissues. PMID- 8689615 TI - Relaxation of imprinting in carcinogenesis. AB - The study of genes at the heat of tumorigenesis has helped unveil an elaborate biochemical circuitry that governs the proliferation and differentiation of cells. Genomic imprinting is rapidly being recognized as a fundamental process in tumor biology. Aberrant relaxation of imprinted genes have been detected in a wide variety of cancers, of both embryonal and nonembryonal origin. However, despite a vast array of experimental observation, both the purpose and pathogenic mechanism of relaxation of imprinting remain an enigma. Hypotheses are examined in this regard along with speculation for future research. PMID- 8689616 TI - Gains and losses of DNA sequences in malignant mesothelioma by comparative genomic hybridization. AB - The molecular basis of malignant mesothelioma is poorly known. We examined genetic changes in 11 mesothelioma specimens by comparative genomic hybridization (CGH). Five DNA specimens originated from uncultured tumor tissues and six from cell lines established from the same patients. Findings from the classical karyotypic characterization of both primary tumors and cell lines have been reported previously. In the CGH analyses the most common genetic alterations in the 11 mesothelioma specimens were losses of chromosomal regions in 1p, 8p, 14q, and 22q and gains of 5p, 6p, 8q, 15q, 17q, and 20. The cell lines had on average a much higher total number of genetic changes than the uncultured tumor specimens. Clonal relationship between the cell lines and the uncultured tissue specimens could not usually be demonstrated even though they originated from the same patient. The observed differences may partly be due to high frequency of chromosomal rearrangements, which CGH cannot detect, partly due to contamination of tumor specimens with normal tissue, and partly due to genetic evolution in tumor cell lines. PMID- 8689617 TI - Essential thrombocythemia with BCR/ABL rearrangement. AB - Essential thrombocythemia (ET) was diagnosed clinically in three patients Karyotypic analysis and reverse transcription polymerase chain reaction for the bcr-abl chimeric transcript showed that two were Philadelphia chromosome (Ph) positive, bcr-abl positive, whereas the third was Ph negative, bcr-abl positive. The first patient received an allogeneic bone marrow transplantation but relapsed as localized blastic transformation, thus behaving similarly to chronic myeloid leukemia (CML). However, the other patients showed clinical courses more in keeping with ET. Essential thrombocythemia with BCR rearrangements may resemble CML but there are clinical differences. These may be due to genetic changes in addition to the BCR rearrangement. PMID- 8689618 TI - Clinical and cytogenetic studies of two cases of Klinefelter syndrome with hereditary retinoblastoma and rhabdomyosarcoma. AB - Two children with Klinefelter syndrome (KS), one associated with bilateral hereditary retinoblastoma (RB) and the other with rhabdomyosarcoma (RMS) are reported. Both were boys and chromosomally mosaic for KS. The hereditary retinoblastoma case yielded 46,XY,del(13)(q12q14.2)/47, XXY(c),del(13)(q12q14.2) in PHA-stimulated lymphocytes. The rhabdomyosarcoma case yielded 46,XY/ 47,XXY(c) in peripheral blood cells whereas tumor revealed trisomy 8, trisomy 7, and t(7;13)(q33;q32) in addition to 46,XY/47,XXyc mosaicism. PMID- 8689619 TI - Normal expression of fra(3)(p14.2) in lymphocytes of lung cancer patients. AB - Fragile site (FS) analysis was performed in 10 bronchogenic carcinoma families (non-small cell type) each represented by the patient and one adult offspring. Twenty age- and sex-matched controls were evaluated simultaneously for FS expression. The question whether increased fragility at band 3p14 exists in lung cancer patients or their offspring was examined. The expression level was found to be similar among patients, offspring, and controls. PMID- 8689620 TI - Extra Y chromosome in T-cell acute lymphoblastic leukemia. AB - We describe a 66-year-old man who developed T-cell acute lymphoblastic leukemia (ALL) with a sole clonal chromosomal abnormality of 47,XY,+Y. Leukemic cells were positive for CD2, CD7, terminal deoxynucleotidyl transferase and cytoplasmic CD3. T-cell receptor beta, gamma, and delta genes remained germline configurations. The bone marrow aspirate was 47,XY,+Y in all metaphase cells observed. The patient achieved complete remission by chemotherapy, and the bone marrow cells and the phytohemagglutinin stimulated peripheral blood lymphocytes showed a normal karyotype of 46,XY at that time. This fact suggests that an extra Y chromosome may be a kind of new chromosomal abnormality of T-cell ALL. PMID- 8689622 TI - Correction: cytogenetic findings in a breast stromal sarcoma. Application of fluorescence in situ hybridization to characterize the breakpoint regions in an 11;19 translocation: Cancer Genet Cytogenet 63:47-51, 1992. PMID- 8689621 TI - Ring marker containing 17q and chromosome 22 in a case of dermatofibrosarcoma protuberans. PMID- 8689623 TI - A colorimetric immunoassay for the detection of E-cadherin and carcinoembryonic antigen (CEA) expression on human colon carcinoma cell lines in vitro. AB - An immunohistochemical assay, using 96-well microtiter plates and based on the avidin-biotin peroxidase reaction, was developed for the quantitation of E cadherin and CEA expression on HT-29 and SW620 colon carcinoma cells. The optical density of the generated dye was measured after solubilization with alkaline SDS solution. The staining procedure was evaluated with respect to reproducibility (coefficient of variation and intra-class correlation coefficient). On HT-29 cells the level of agreement for both E-cadherin and CEA were substantial, on SW620 cells almost perfect. The method allows testing compounds for their differentiation inducing capacity in screening programmes on the basis of protein marker expression. PMID- 8689624 TI - p53 mutations in transitional cell carcinomas of the urinary bladder in rats treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine. AB - Involvement of p53 gene alterations has been demonstrated in a variety of human neoplasias including urinary bladder carcinomas. N-Butyl-N-(4 hydroxybutyl)nitrosamine (BBN)-induced urinary bladder carcinogenesis models in rodents have been widely used to study carcinogenic processes in this organ. In the present study, transitional cell carcinomas induced in the urinary bladders of male F344 rats treated with 0.05% BBN for 16 or 32 weeks and then sacrificed at experimental week 32 were analyzed for mutational changes in the p53 and H-ras genes by polymerase chain reaction-single strand conformation polymorphism (PCR SSCP) analysis and subsequent DNA sequencing. The total p53 mutation incidences were 3/10 (30%) and 8/12 (66.7%) in rats treated with BBN for 16 weeks followed by 16 weeks' non-treatment, or in rats treated with BBN for 32 weeks, respectively, while the H-ras mutation incidences were 0/10 (0%), and 1/12 (8.3%), respectively. The present results indicate that mutations in the p53 gene might be involved in the process of urinary bladder carcinogenesis by BBN as part of a multistep pathway. However, considering the decreasing tendency in lesions with p53 mutations after stopping BBN administration, a p53 mutation alone would not appear to be sufficient to give a marked selective advantage to mutant cells. No evidence of H-ras mutation involvement was gained even for the late course of rat urinary bladder carcinogenesis. PMID- 8689625 TI - Modification of mitomycin C-induced clastogenicity by Terminalia catappa L. in vitro and in vivo. AB - The water extract of the leaves of Terminalia catappa L. was tested for inhibition of mitomycin C-induced micronuclei in CHO-K1 cells. The simultaneous and pre-treatment of CHO-K1 cells with T. catappa extract (75 and 150 micrograms/ml) significantly (P < 0.05) suppressed mitomycin C-induced micronuclei. Furthermore, gastric intubation of T. catappa extract (4.8 and 24 mg/animal per day) to male ICR mice for 8 days significantly (P < 0.01) reduced mitomycin C-induced micronuclei in peripheral blood. In addition, T. catappa dose dependently inhibited lipid peroxidation in vitro and TPA-induced hydrogen peroxide formation in human mononuclear leukocytes. The anticlastogenic effects of T. catappa in vitro and in vivo may be attributed to its antioxidative potential. PMID- 8689626 TI - A comparative study on expression of mucin related antigens in preneoplastic and neoplastic rat colorectal mucosa. AB - A polyclonal antibody (PAb35) defined antigen (Ag) was characterized in association with two monoclonal antibody (MAbM1 and MAb660) defined mucin M1 and 660 Ags in colorectal mucosa during 20-methylcholanthrene-induced rat carcinogenesis in the same organ. Immunohistochemistry and ELISA revealed that these three antibodies were reactive with most of the colorectal carcinomas. MAbM1 and MAb660 were reactive with preneoplastic colorectal mucosa in rats with no detectable carcinoma, in contrast to non-reactivity with PAb35. PAb35 reacted with preneoplastic mucosa, present adjacent to the cancerous tissues only. Staining was mainly localized in the cytoplasm of cancer cells, goblet cells and luminal mucous deposits. In control rats, M1 and 660 Ags were present in gastric mucosa, but not in colorectum. PAb35 defined Ag was absent in gastrointestinal mucosa of controls. ELISA revealed 82% reduction in reactivity, when PAb35 was reacted with 2-mercaptoethanol (2ME) treated colorectal mucosal extracts. Ninety percent reduction was seen in the case of MAbM1. However, 50% reduction was demonstrated when MAb660 was reacted with 2ME treated extracts. PMID- 8689627 TI - Inhibition by verapamil of cholecystokinin-enhancement of pancreatic carcinogenesis induced by azaserine in Wistar rats. AB - The effect of a calcium channel blocker, verapamil, on cholecystokinin (CCK) enhancement of pancreatic carcinogenesis induced by azaserine was investigated in Wistar rats. During and after 25 weekly injections of azaserine, each rat received alternate-day injections of CCK-octapeptide (CCK-8) and/or verapamil. Carcinogen-induced pancreatic lesions staining for mu class glutathione S transferase (GST-mu) were examined histochemically at week 62. Prolonged administration of CCK-8 significantly increased the number and area as a percentage of parenchyma of GST-mu-positive lesions. Concomitant administration of verapamil significantly attenuated the enhancing effect of CCK-8. These findings indicate that calcium may play an important role in CCK-enhancement of pancreatic carcinogenesis. PMID- 8689628 TI - Mobilization of glutamine and asparagine in mouse kidney during Ehrlich cell carcinoma development. AB - Glutamine, glutamate, asparagine, and aspartate contents in mouse kidney during Ehrlich ascites carcinoma development were determined. Significant changes in the concentrations of these amino acids were observed only 24 h after tumour inoculation, and they were highest during the exponential phase of tumour growth. These data agree with other previously reported studies and point to a potential of tumour cells to modulate host metabolism for its benefit. Discussed under this hypothesis, the new data reported here seem to indicate that there is an increase in the mobilization of the amino acids studied in mice kidney to provide Ehrlich tumour cells with sources of nitrogen (asparagine and glutamine) which they consume avidly. PMID- 8689629 TI - Augmentation of in vivo growth of Lewis lung carcinoma cells transduced with granulocyte macrophage-colony stimulating factor gene. AB - Cloned high-metastatic Lewis lung carcinoma. A11 cells were retrovirally transduced with either granulocyte macrophage-colony stimulating factor (GM-CSF) or beta-galactosidase gene and examined for their tumorigenicity. GM-CSF engineered A11 cells produced a much higher amount of GM-CSF than the parental and control cells. Unexpectedly, GM-CSF-engineered A11 cells grew more rapidly than the control cells, while in vitro growth rates of these cells were almost the same. The enhanced tumor growth seemed to be unique to GM-CSF among various cytokines, because interleukin 2 (IL-2), interleukin 4 (IL-4) and interleukin 6 (IL-6) producer cells exhibited suppressed tumor growth. PMID- 8689630 TI - Cationic liposomes enhance retrovirus-mediated multinucleated cell formation and retroviral transduction. AB - A retroviral vector carrying herpes simplex virus thymidine kinase (HSV-TK) gene was introduced into psi 2 packaging cells (psi 2tkn) and XC tumor cells (XCtkn). psi 2tkn, XCtkn and XC cells co-cultured with TK-carrying cells were killed by ganciclovir (GCV) treatment. The growth of XC cells transplanted into nude mice was also suppressed by intratumoral injection of psi 2tkn or XCtkn cells and subsequent GCV administration. In addition, the XC cells cultured with either psi 2tkn cells or cell-free retrovirus suspension formed giant multinucleated cells. The multinucleated cell formation was specific to the combination of XC cells and the retrovirus produced by the psi 2tkn cells. Cationic liposomes enhanced the retrovirus-induced multinucleated cell formation and retroviral transduction. The correlation between the two actions of liposomes suggests that liposomes which enhance multinucleated cell formation are potent enhancers of retroviral transduction. PMID- 8689631 TI - Quantification of glioma cell invasion by confocal laser scanning microscopy in an in vitro co-culture system. AB - Malignant invasion in co-cultures of spheroids from the glioma cell line GaMg into brain cell aggregates (BA) was determined by two different techniques: by confocal laser scanning microscopy (CLSM) and by conventional light microscopic observations of semi-thin sections obtained from co-cultures. The remaining BA volumes were detected by CLSM in vital dye-fluorescent-stained co-cultures. The same specimens were fixed and embedded in Epon, and cut for histologic and morphometric analyses. The results show that CLSM can be used for continuous determination of progressive glioma invasion. Compared to the light microscopic observations, the degree of invasion appeared slightly lower when analyzed by CLSM. We conclude that the CLSM provides the possibility for continuous studies on interaction between normal and malignant cells. Therefore it considerably improves existing methods for studying tumor cell invasion in vitro. PMID- 8689632 TI - Altered glutathione metabolism in oxaliplatin resistant ovarian carcinoma cells. AB - Elevation of glutathione (GSH) is commonly observed in cellular resistance to a number of anticancer agents. Most frequently reported change in GSH metabolism that is associated with the elevated GSH levels is increased mRNA expression and activity of gamma-glutamyl cysteine synthetase (gamma GCS), the first enzyme of the GSH biosynthetic pathway. We have isolated sublines of the A2780 ovarian carcinoma cell line (C10 and C25) that are 8- and 12-fold resistant to oxaliplatin by repeatedly exposing the cells to increasing concentrations of the platinum agent. The GSH levels in C10 and C25 cell sublines are 3.1- and 3.8-fold higher than the parent A2780 cell line. The mRNA levels and activities for gamma GCS and that for gamma-glutamyl transpeptidase (gamma GT), the GSH salvage pathway enzyme, were measured in these cells. The mRNA for gamma GT and gamma GCS were measured by RT-PCR, with quantitation of the PCR product by HPLC; mRNA levels are expressed as ratios to beta-actin mRNA, used as an endogenous standard. GSH and gamma GCS activity were measured by HPLC assays and gamma GT activity by a colorimetric assay. The increase in GSH in C10 and C25 was associated with an elevation in gamma GT mRNA (2.5- and 8-fold) and gamma GT activity (2.7- and 2.8-fold). No changes were observed in gamma GCS mRNA levels or activity. The data indicate that alterations in GSH metabolism leading to elevations in cellular GSH in A2780 ovarian carcinoma cells selected for low levels of resistance to oxaliplatin are mediated by gamma GT, the "salvage' pathway, rather than an increase in GSH biosynthesis. PMID- 8689634 TI - Comparative effects of flavonoids on the growth, viability and metabolism of a colonic adenocarcinoma cell line (HT29 cells). AB - The aim of the present study was to compare the effect of five structural classes of flavonoids on the viability and metabolism of a colonic adenocarcinoma cell line (HT29 cells). The most prominent structural features of flavonoids favoring both their cytotoxic activity and their capacity to inhibit lactate release appear to be the desaturation of the 2, 3 bond and the position of attachment of the B ring. Indeed, flavonol and flavone are the most potent and, in both classes, the order of potency can be modulated by hydroxyl or methoxyl substituents. On the other hand, in our model, we did not find any correlation between flavonoid structure and their capacity to modulate cAMP level. This last point is discussed. PMID- 8689633 TI - Inhibition of stilbene estrogen-induced cell proliferation of renal epithelial cells through the modulation of insulin-like growth factor-I receptor expression. AB - In the present study, we have investigated the effects of stilbene estrogen, diethylstilbestrol (DES), on the proliferative activity and expression of insulin like growth factor-I (IGF-I) receptor in Syrian hamster renal epithelial cells. DES exposure to renal epithelial cells caused both dose- and time-dependent increases in proliferative activity. We also tested the effects of antiestrogen ICI 182780 and insulin-like growth factor-I receptor (IGF-IR) antibody on cell proliferation. Cotreatment of cells with ICI 182780 (250 nM) and DES resulted in a 50% decrease in cell growth compared to DES alone. Treatment of cells with an anti-IGF-IR antibody (alpha IR3, 1 microgram/ml) also significantly reversed the growth-stimulatory effects of DES. A nuclear binding assay revealed that an enhanced level (approximately 2-fold) of [125I]IGF-I binding to nuclear protein occurred in DES treated renal epithelial cell nuclei compared to controls. IGF-I receptor gene expression analyzed by Northern blotting revealed that DES treatment increased the level of IGF-IR mRNA by 2-fold compared to controls. We also tested the effect of ICI compound on the induction of IGF-I receptor gene. The cotreatment of ICI 182780 strongly inhibited DES-induced IGF-I receptor gene expression (50-60% inhibition). Stimulation of the proliferative activity of renal epithelial cells by stilbene estrogen, its prevention by IGF-I receptor antibody, and inhibition of DES-induced proliferative activity and the expression of IGF-I receptors by ICI 182780 suggest the possibility that the stimulatory effect of DES on the proliferative activity of renal epithelial cells may be mediated through the up-regulation of IGF-I receptors. PMID- 8689635 TI - A possible medium-term assay for detecting the effects of liver and colon carcinogens in rats. AB - The aim of the present study was to verify whether the tumorigenic effect of a rat liver carcinogen, 2-acetylaminofluorene (AAF), and of a promoter of rat colon carcinogenesis, chenodeoxycholic acid (CDCA), could be detected with a single medium-term assay using as markers gamma-glutamyltranspeptidase (GGT)-positive foci in the liver and aberrant crypt foci (ACF) in colon mucosa. In rats given in the first 2 weeks of treatment both N-nitrosodiethylamine (NDEA), as initiator of liver carcinogenesis, and azoxymethane (AOM), as initiator of colon carcinogenesis, the subsequent 6-week feeding on a diet containing AAF (0.01%) produced a significant marked increase of the number and area of GGT-positive foci which is consistent with the results of long term assays. When rats initiated with both NDEA and AOM were fed for 6 weeks on a diet containing CDCA (0.1%) a significant increase of large ACF as well as of crypt multiplicity was observed, consistently with the promoting effect of CDCA in colon carcinogenesis. The results obtained in this preliminary study suggest that this medium-term assay might be able to screen both liver and colon carcinogens in rats. PMID- 8689636 TI - Partial deletions of the CDKN2 and MTS2 putative tumor suppressor genes in a myxoid chondrosarcoma. AB - Cytogenetic abnormalities of chromosome 9 (9p21) have been reported in a large number of tumors that include malignant melanomas, gliomas, lung cancers and leukemias. These aberrations on 9p have been previously shown to involve the loss of the interferon gene cluster and the gene for methylthioadenosine phosphorylase (MTAP), both of which have been mapped to the 9p21 region. Recently, two putative tumor suppressor gene(s) CDKN2 and MTS2, have been mapped to the 9p21 region, and have been shown to be deleted in a large number of hematopoietic and solid malignancies. In this study we report a cytogenetic and a detailed molecular analysis of a myxoid chondrosarcoma cell line 105KC and its clonal derivatives 105AJ, 105AJ1.1, 105AJ3.1, and 105AJ5.1. Specifically, we have demonstrated chromosome 9p21 related abnormalities by cytogenetic analysis, the associated loss of the interferon gene cluster, and the loss of the immunoreactive MTAP protein and activity. In addition, we have also shown the presence of deletions involving the CDKN2 and the MTS2 putative tumor suppressor genes in these chondrosarcoma cell lines. The above studies were extended to other chondrosarcoma cell lines and primary tumors, where similar deletions of the CDKN2 and MTS2 genes were found to be present (unpublished data). This suggests a potential role for the involvement of the CDKN2 and MTS2 putative tumor suppressor genes in the development of chondrosarcomas. PMID- 8689638 TI - Capsaicin-sensitive sensory-motor neurotransmission in the peripheral control of cardiovascular function. PMID- 8689637 TI - Chromosome 9 related aberrations and deletions of the CDKN2 and MTS2 putative tumor suppressor genes in human chondrosarcomas. AB - Deletions on the short arm of chromosome 9 (9p21 region) have been reported in a number of hematopoietic and solid tumors. These aberrations on 9p have been previously associated with the loss of the interferon gene cluster and the gene for methylthioadenosine phosphorylase (MTAP), localized to the 9p21-22 region. Recently, two putative tumor suppressor gene(s) CDKN2 and MTS2 have been mapped to the 9p21 region, and shown to be deleted in a large number of tumors including leukemias, melanomas, bladder cancers and brain tumors. We have previously reported a similar 9p21 abnormality and deletions of the CDKN2 and MTS2 genes in a myxoid chondrosarcoma cell line and its subclones. In this study we report consistent abnormalities of chromosome 9 in additional chondrosarcomas examined by a detailed cytogenetic and molecular analysis. Seven chondrosarcoma cell lines, one primary chondrosarcoma, and a benign chondroma were examined. Four of the seven tumor cell lines examined showed grossly visible aberrations of chromosome 9. Molecular analysis of these chondrosarcoma cell lines revealed hemizygous deletions of the interferon genes, and the absence of the MTAP gene, protein or activity. In addition, four of the seven chondrosarcoma cell lines also showed deletions of the CDKN2 and/or MTS2 putative tumor suppressor genes, or the absence of the CDKN2 protein product. No such chromosome 9 related aberrations were detected in the benign chondroma. These data suggest that chromosome 9p21 abnormality, and deletions of the CDKN2 and MTS2 tumor suppressor genes may be a significant event in the development of chondrosarcomas. PMID- 8689639 TI - Mahaim, Kent and abnormal atrioventricular conduction. PMID- 8689640 TI - Stretching the evidence in the case of cardiac growth. PMID- 8689641 TI - Function and expression of endothelin receptor subtypes in the kidneys of spontaneously hypertensive rats. AB - OBJECTIVE: The renal endothelin system has been implicated in the development and maintenance of hypertension in spontaneously hypertensive rats (SHR). However, little is known about the function and cellular distribution of endothelin receptor subtypes in the kidneys of SHR. METHODS: We analyzed the expression of endothelin receptor subtypes in the kidneys of 16-week-old SHR using Scatchard analysis, receptor autoradiography, Northern blot analysis and in situ hybridization. Wistar-Kyoto rats (WKY) served as controls. Furthermore, we investigated the effects of the mixed (A/B) endothelin receptor antagonist bosentan and the ETA receptor antagonist BQ 123 on mean arterial blood pressure (MAP), renal blood flow (RBF) and glomerular filtration rate (GFR) in conscious chronically instrumented rats. RESULTS: In SHR, we found by receptor autoradiography an overexpression of the endothelin A receptor (ETA) in the glomeruli (2.2 +/- 0.4-fold; P < 0.05) and smooth muscle cells of intrarenal arteries (1.9 +/- 0.2-fold; P < 0.05) compared to age-matched WKY. In addition, our study revealed a pronounced upregulation of endothelin B receptor (ETB) in the glomeruli of SHR (5.6 +/- 0.8-fold; P < 0.01). Blockade of endothelin receptors in SHR with bosentan (A and B receptor blockade) as well as with BQ 123 (A receptor blockade) led to a significant decrease in MAP (-18.6 +/- 2.1 and -19 +/- 1.3 mmHg, respectively; P < 0.05 in both cases) and a significant increase in RBF (+2.8 +/- 0.5 and +3.1 +/- 0.37 ml/min, respectively; P < 0.05 in both cases). The blockade of both ETA and ETB by bosentan had no further effect on MAP reduction or RBF increase in SHR compared to the ETA blockade by BQ 123. The ETA antagonist BQ 123 had no effect on GFR either in SHR or in WKY, whereas the combined blockade of ETA and ETB by bosentan significantly decreased GFR in SHR by about 50% but not in WKY. CONCLUSIONS: Our data demonstrated a correlation between the overexpression of vascular ETA receptors and the pronounced upregulation of glomerular ETB receptors in the kidneys of SHR and their impact on the regulation of renal blood flow, glomerular filtration rate and blood pressure in these animals. PMID- 8689642 TI - Lack of a pharmacologic interaction between ATP-sensitive potassium channels and adenosine A1 receptors in ischemic rat hearts. AB - OBJECTIVES: An interaction between adenosine A1 receptors and ATP-sensitive potassium channels (KATP) has been hypothesized to mediate preconditioning in several species. Unlike other species tested, KATP blockers and A1 antagonists do not abolish preconditioning in rat hearts. The purpose of this study was to determine if KATP and A1 receptors are pharmacologically linked in rat hearts as they are in other species. METHODS: Isolated rat hearts were given 0.03-1.00 microM R-PIA (adenosine A1 receptor agonist) with or without concomitant 0.3 microM glyburide starting 10 min pre-ischemia. After 25 min global ischemia, the hearts were reperfused for 30 min. Rat hearts were also treated with 1-30 microM cromakalim in the presence of 10 microM DPCPX (adenosine A1 antagonist). RESULTS: R-PIA produced a concentration-dependent bradycardia before ischemia which was blocked by DPCPX. R-PIA increased the time to onset of contracture in a concentration-dependent manner (EC25 = 0.13 microM) and this was unaffected by 0.3 microM glyburide (EC25 = 0.20 microM). This concentration of glyburide completely abolished the protective effects of 10 microM cromakalim. R-PIA also significantly enhanced post-ischemic recovery of function and reduced LDH release, and glyburide did not alter these responses. Cromakalim significantly increased the time to onset of contracture (EC25 = 4.5 microM) and 10 microM DPCPX had no effect on this (EC25 = 5.6 microM). Cromakalim also significantly enhanced post-ischemic recovery of function and reduced LDH release. DPCPX did not alter these cardioprotective effects while glyburide completely abolished the cardioprotective effects of cromakalim. CONCLUSIONS: While both cromakalim and R PIA are cardioprotective in isolated rat hearts, they are not pharmacologically linked, possibly explaining why preconditioning may be different in this species. PMID- 8689643 TI - Cells expressing angiotensin II receptors in fibrous tissue of rat heart. AB - OBJECTIVE: Following left coronary artery ligation, markedly increased angiotensin II (AngII) receptor binding appears at the site of myocardial infarction (MI). This is also true for the fibrosed visceral pericardium in rats following pericardiotomy (with or without MI). Cells expressing AngII receptors at these sites remain unknown. In the present study, we sought to identify cells expressing AngII receptors at these sites of fibrosis in the rat heart during both early and late stages of wound healing. METHODS: MI was created by left coronary artery ligation. Sham operation included thoracotomy, pericardiotomy and placement of silk ligature around the left coronary artery without MI. Hearts were collected at postoperative week 1 and 4. In serial sections: autoradiography (125I[Sar1,Ile8]AngII) was used to determine cells expressing AngII receptors; hematoxylin-eosin and alpha smooth muscle actin were used for identification of cell morphology and phenotype, respectively; and picrosirius red for identification of fibrillar collagen. RESULTS: (1) at week 1, necrotic tissue at the site of MI was surrounded by granulation tissue that included macrophages, alpha smooth muscle actin fibroblast-like cells, or myofibroblasts, fibrillar collagen, and new vessels; (2) at week 4, scar tissue had formed and remaining cells were primarily myofibroblasts; (3) pericardial fibrosis was evident at weeks 1 and 4 and contained myofibroblasts, not macrophages or new vessels; (4) at week 1 and 4 myofibroblasts were the predominant cell expressing high-density AngII receptors at the site of MI, while fibroblasts, macrophages and vessels demonstrated low-density AngII receptor binding; and (5) at weeks 1 and 4, myofibroblasts express high-density AngII receptor binding in pericardial fibrosis. CONCLUSION: In a rat model of tissue repair involving either MI or pericardial fibrosis, increased AngII receptor expression is primarily associated with myofibroblasts. This suggests AngII may play a role in mediating the fibrogenic response provided by this wound healing cell at sites of tissue injury in the rat heart. PMID- 8689644 TI - The evolution of diabetic response to ischemia/reperfusion and preconditioning in isolated working rat hearts. AB - OBJECTIVE: Studies have shown that the diabetic heart exhibits abnormalities in cellular ion transport, which can affect susceptibility to reperfusion-induced ventricular fibrillation (VF), tachycardia (VT) and functional derangements. It has been shown that "preconditioning" renders the heart very resistant to a subsequent prolonged ischemic episode. This phenomenon has been extensively studied in healthy myocardium, but such a study has not been previously done in diseased (hypertrophic or myopathic) hearts. METHODS: We studied the incidence of reperfusion-induced VF, VT, cardiac function, and ion shifts (Na+, K+, Ca2+, and Mg2+) induced by ischemia/reperfusion in isolated hearts from rats with streptozotocin-induced diabetes. Following 2, 4, 6, and 8 weeks of diabetes, hearts were isolated and subjected to 30 min global ischemia followed by reperfusion. RESULTS: In the 2-week diabetic group the total incidence of VF and VT was reduced from their non-diabetic age-matched control value of 100 and 100% to 42 (P < 0.05) and 42% (P < 0.05), respectively. Such a reduction in the incidence of VF and VT was not observed with progressive diabetes (4, 6, and 8 weeks). In the 2-week diabetics, the reduction in the VF and VT was reflected in the improvement of postischemic function, the reduction of ischemia and reperfusion-induced Na+ and Ca2+ gains, and the prevention in K+ and Mg2+ loss. This diabetes-induced initial protection was not seen in the 4- and 6-week diabetics, and a deterioration of postischemic function was observed in the 8 week diabetics. Four cycles of preconditioning, each consisting of 5 min ischemia followed by 10 min reperfusion, failed to reduce the incidence of VF and VT, improve cardiac function, and prevent ion shifts induced by 30 min ischemia followed by 30 min reperfusion in 4- and 8-week diabetics. CONCLUSIONS: In the early phase of diabetes the heart is more resistant to ischemia/reperfusion than the non-diabetic heart. Preconditioning does not afford protection against a prolonged period of ischemia in diabetics, indicating that preconditioning may be a "healthy heart phenomenon". PMID- 8689645 TI - Enhancement of myocardial reactive hyperemia with manganese-superoxide dismutase: role of endothelium-derived nitric oxide. AB - OBJECTIVE: To test the hypothesis that superoxide radicals generated during myocardial ischemia and reperfusion influence reactive hyperemia (RH) by reacting with endothelium-derived nitric oxide (EDNO), we examined the effect of manganese (Mn)-superoxide dismutase (SOD) on RH in anesthetized dogs. METHODS: Twelve dogs were pretreated with 8-phenyltheophylline (8PT) to block adenosine's effect. Five dogs were pretreated with 8PT and NG-nitro-L-arginine methyl ester (L-NAME) to block adenosine's and EDNO's effects. Following occlusion of the left circumflex artery (LCX) for 10 and 60 s, RH was observed before and after Mn-SOD. In another group of 6 dogs pretreated with 8PT, RH following 60-s LCX occlusion was observed before and after Mn-SOD and catalase. For comparison with the effect of Mn-SOD, that of copper, zinc (Cu,Zn)-SOD was also examined in another group of 5 dogs. RESULTS: In the dogs pretreated with 8PT, Mn-SOD significantly increased excess flow and repayment of flow debt during RH after 60-s LCX occlusion but did not affect RH after 10-s LCX occlusion. Mn-SOD-induced augmentation of RH following 60-s LCX occlusion was not affected by catalase, while it was completely abolished by L-NAME. In contrast to Mn-SOD, Cu,Zn-SOD showed no effect on RH following 60-s LCX occlusion in the dogs pretreated with 8PT. CONCLUSIONS: Superoxide radicals generated during ischemia for 60 s and reperfusion attenuates myocardial RH through inactivation of EDNO. Mn-SOD shows more beneficial effects on myocardial RH than Cu,Zn-SOD. PMID- 8689646 TI - Angiotensin II-induced myocardial fibrosis in rats: role of nitric oxide, prostaglandins and bradykinin. AB - OBJECTIVE: Chronic elevations in plasma angiotensin II (AngII) are associated with an efflux of plasma macromolecules into the perivascular and contiguous interstitial space. This is followed by the appearance of macrophages and type I collagen-producing, fibroblast-like cells that precede the accumulation of fibrous tissue at these sites. Whether this perivascular and interstitial fibrosis is a direct effect of AngII on collagen turnover of these cells or an indirect response mediated by nitric oxide, prostaglandins and/or bradykinin released in response to AngII, is uncertain. METHODS: We measured perivascular and interstitial fibrosis (picrosirius-stained tissue) in response to 14-day infusion of AngII (150 ng/kg/min, s.c.) in male Sprague-Dawley rats. Treated animals were compared to untreated controls and to groups receiving AngII together with either an NO-synthase inhibitor [NG-nitro-L-arginine methyl ester (L-NAME) 10 mg/kg/day in drinking water], a cyclo-oxygenase inhibitor (indomethacin, 2 mg/kg/day in drinking water), or a bradykinin B2 receptor antagonist (Hoe140, 115 ng/kg/min, s.c.). RESULTS: When left and right ventricles of treated rats were compared to untreated controls, AngII led to a respective 68 and 48% increase in perivascular collagen volume fraction (PCVF) and a 54 and 22% increase in interstitial collagen volume fraction (ICVF). Co-administration of AngII + L-NAME did not attenuate either PCVF or ICVF while indomethacin significantly attenuated PCVF by 37 and 33% of left and right ventricle, respectively, but did not alter ICVF in either ventricle when compared to AngII treated animals. Co-administration of AngII + Hoe140 completely prevented perivascular and interstitial collagen accumulation with the extent of perivascular fibrosis comparable to untreated controls. CONCLUSION: The perivascular and interstitial fibrosis of the rat right and left ventricles seen in association with the exogenous administration of AngII is mediated by the release of bradykinin and prostaglandins, and therefore is an indirect response to elevated circulating AngII. PMID- 8689647 TI - Contrasting effects of blockade of nitric oxide formation on resistance and conductance coronary vessels in conscious dogs. AB - OBJECTIVES: To determine the differential effects of blockade of nitric oxide (NO) formation by an arginine analogue on basal and stimulated NO release in conductance and resistance coronary vessels. METHODS: In conscious dogs, instrumented for measuring coronary blood flow (CBF) and external epicardial coronary artery diameter (CD), intracoronary (ic) acetylcholine (ACH, 3.0 ng/kg), adenosine (ADENO 100.0 ng/kg) and nitroglycerin (NTG, 10.0 ng/kg) were injected before and after ic N omega-nitro-L-arginine methyl ester (L-NAME, 50.0 micrograms.kg-1 min-1 for 12 min) to block NO synthesis. RESULTS: Before L-NAME, ACH increased CBF by 65.3 +/- 9.0 from 42.4 +/- 2.9 ml/min and CD by 0.199 +/- 0.035 from 3.374 +/- 0.193 mm. L-NAME failed to alter baseline CBF but reduced (P < 0.01) CD to 3.220 +/- 0.199 mm. CBF responses to ACH were smaller (P < 0.01) (32.8 +/- 5.3 ml/min) after L-NAME. In contrast, ACH-induced increases in CD (0.184 +/- 0.053 mm) were not altered. L-NAME did not change CBF responses to NTG but increased CD responses (0.345 +/- 0.062 vs 0.217 +/- 0.043 mm, P < 0.01). ADENO-induced increases in CBF were smaller after L-NAME (46.5 +/- 5.6 vs 79.8 +/ 10.9 ml/min, P < 0.01). Increases in CD created by ADENO, a flow-dependent phenomenon, were nearly abolished after L-NAME (0.043 +/- 0.018 vs 0.195 +/- 0.026 mm, P < 0.01) and partially restored by ic L-arginine. The effects of L NAME on CBF and CD responses to ACH and ADENO continuously delivered into the coronary artery were similar to those of boluses. CONCLUSIONS: L-NAME selectively reduced ACH-induced dilation in resistance coronary vessels but failed to prevent responses of conductance coronary vessels in spite of reducing baseline CD and blocking flow-dependent effects of ADENO. Therefore, blockade of NO formation resulted in disparate effects on receptor-operated dilation of resistance and conductance coronary vessels. PMID- 8689648 TI - The effect of AT1 receptor antagonist on chronic cardiac response to coronary artery ligation in rats. AB - OBJECTIVE: The aim was to study the effect of the AT1 receptor antagonist losartan on hemodynamic and morphometric changes following experimental infarction. METHODS: Experimental infarction was produced in adult male rats by ligating the coronary artery. Treatment with losartan was compared to untreated controls, in rats with experimental infarction and sham-operated animals. RESULTS: Infarcted hearts were characterized by significant decreases in left ventricular developed pressure, as well as positive and negative (dP/dt)max, whereas left ventricular end-diastolic pressure (LVEDP), relaxation constant tau and right ventricular systolic pressure (RVSP) significantly increased. Treatment with losartan decreased the LVEDP, the relaxation constant tau and RVSP in the infarcted hearts. Right ventricular weight significantly increased in rats with infarction; this was attenuated by losartan. Infarct size was not significantly influenced by losartan treatment. Morphometric data revealed decreased capillary supply in infarcted hearts, especially in regions close to infarction; the decrease was less pronounced after losartan treatment. Capillary density in near infarct region decreased from 2826/mm2 to 1471/mm2 in untreated animals but in the treated animals it decreased from 2982/mm2 to only 2037/mm2. Simultaneous significant decrease in myocyte-to-capillary ratio in treated animals compared to untreated rats (0.87 to 0.67) seems to indicate formation of new capillary channels after losartan treatment. LVEDP was dependent on the size of infarction in untreated but not in treated animals. A close correlation between LVEDP and capillary density was found. CONCLUSIONS: Decreased ventricular contractility, prolonged relaxation and decreased coronary capillary density in rat experimental cardiac infarction confirm and amplify previous reports dealing with this experimental model. Moreover, we have found evidence of improved hemodynamics and coronary angiogenesis after losartan treatment. PMID- 8689649 TI - Vascular alpha-2 adrenoceptor function is decreased in rats with congestive heart failure. AB - OBJECTIVE: Vascular alpha-2 adrenoceptor function of rats with congestive heart failure (CHF) was characterized in both in vivo and in vitro experiments. METHODS: CHF was induced in Sprague-Dawley rats by coronary artery ligation. Sham operated rats served as normal controls. Postjunctional alpha-2 adrenergic responsiveness was assessed in vivo using the pithed rat model and in vitro in organ bath. Vascular alpha-2 adrenoceptor density was studied by receptor binding assay. RESULTS: Four to 6 weeks after this surgical procedure, plasma catecholamines were markedly increased in CHF rats. In vivo vascular responses to alpha-2 adrenoceptor agonists BHT933 and clonidine were significantly decreased in CHF rats (P < 0.001). Clonidine elicited dose-dependent responses in endothelium intact mesenteric arteries in both CHF and sham-operated rats. The dose-response curve in CHF was shifted to the right with a pD2 value of 5.5 +/- 0.2 compared with control rats 6.2 +/- 0.2 (P < 0.05). The response to clonidine was selectively blocked by an alpha-2 adrenergic antagonist rauwolscine in both groups. Endothelium denuded arteries showed an enhanced response to clonidine in both CHF and control rats. However, the response to clonidine is still decreased in CHF compared to sham-operated rats (P < 0.05). Alpha-2 adrenoreceptor density, as determined by [3H]yohimbine binding in membrane preparations from mesenteric arteries was decreased in CHF compared to sham-operated rats (Bmax 43 +/- 6 vs. 104 +/- 20 fmol/mg protein, P < 0.05). CONCLUSIONS: Vascular alpha-2 adrenoceptor function is decreased in rats with CHF. PMID- 8689650 TI - Mediators of perivascular inflammation in the left ventricle of renovascular hypertensive rats. AB - OBJECTIVE: Inflammatory cells invade the fibrotic myocardium of spontaneously hypertensive rats at the same sites as where fibroblasts are produced. The role of these inflammatory cells in myocardial fibrogenesis was studied in the present work. METHODS: The production and distribution of proteins that may be implicated in inflammation was examined by immunohistochemistry of sections of left ventricles from 1-month and 4-month renovascular hypertensive and age-matched control rats using antibodies against ICAM-1, LFA-1, TGF beta 1, PDGF-A, T and H kininogens, IgG, IgM, C3, and C5b-9. Infiltrating inflammatory cells were phenotyped by immunohistochemistry. The TGF beta 1 and PDGF-A mRNA levels were checked by RT-PCR. RESULTS: Infiltrating cells were mainly T helper lymphocytes and macrophages, and there were more inflammatory cells in hypertensive rats than in control rats, localized especially around coronary arteries and in microscars. There were more ICAM-1 and LFA-1 in the ventricles of hypertensive than in control rats at 1 month, but the ICAM-1 expressions in hypertensive and control rats were similar at 4 months. TGF beta 1 and PDGF-A mRNA steady states increased in 4-month hypertensive rats, but there was no labeling for TGF beta or PDGF by immunohistochemistry. There was only faint labeling for T and H kininogens, and it was not increased in hypertensive rats. There were deposits of IgM and C5b-9 only in hypertensive rats. CONCLUSION: Thus, inflammatory cells infiltrate the cardiac tissue of renovascular hypertensive rats as in the case of spontaneously hypertensive rats and these cells may use the ICAM-1/LFA-1 system to infiltrate, but neither TGF beta 1 and PDGF-A, nor the kininogen system seem to be associated with cardiac fibrogenesis. Otherwise, the complement system could act as arteriosclerotic and/or leukocyte mobilizing factors. PMID- 8689651 TI - Ultrafiltration after cardiopulmonary bypass in children: effects on hemodynamics, cytokines and complement. AB - OBJECTIVES: The purpose of the study was to evaluate the clinical and hemodynamic effect of intraoperative extracorporeal ultrafiltration (UF) and its potential in reducing the plasma concentration of circulating cytokines and complement activation products following open heart surgery in children. METHODS: Eighteen children with congenital heart disease were prospectively randomized into a control group (n = 9) and a group who underwent UF (n = 9). Serial plasma samples for measurements of circulating cytokines (interleukin 6 (IL-6), tumor necrosis factor alpha (TNF), and its soluble receptor (sTNF receptor)), and complement factors (C3 activation products (C3a and C3bc) and terminal complement complex (TCC)) were obtained before, during and up to 48 h after cardiopulmonary bypass (CPB). A pulmonary artery thermodilution catheter was introduced preoperatively for hemodynamic monitoring. RESULTS: Postoperative hemodynamics were similar in both groups. Plasma levels of IL-6, sTNF receptors, C3a, C3bc and TCC increased significantly perioperatively (P < 0.01) in both groups. TNF was detected transiently in 16 patients perioperatively and in 4 of the 9 ultrafiltrate samples in concentrations similar to the plasma levels. Complement activating products were not detected in the ultrafiltration samples except for small amounts of C3a in two cases. Compared to the control group the plasma levels of C3a, C3bc and TCC were unaffected by the ultrafiltration procedure. The level of IL-6 and sTNF receptors increased significantly after 15 min of UF but there was no significant difference between the two groups postoperatively. CONCLUSIONS: In this study no clinical or hemodynamic effect was registered after UF. TNF and C3a were occasionally detected in the ultrafiltrate but we were unable to demonstrate reduction of these or any of the other markers tested in the group subjected to ultrafiltration. PMID- 8689652 TI - Risk of overestimation of free malondialdehyde in perfused rat hearts due to homogenization artifacts. AB - OBJECTIVES: The aims of the present study were to determine (1) whether free malondialdehyde (MDA) was artifactually formed during homogenization of myocardial tissue and (2) whether free MDA was increased in reperfused rat hearts. METHODS: Groups of isolated buffer-perfused rat hearts were subjected to control perfusion, or 20 min of ischemia, or 20 min of ischemia followed by 5 or 30 min of reperfusion. The hearts were subsequently assayed for free MDA by ion pairing high-performance liquid chromatography following homogenization in the absence or presence of the antioxidant butylated hydroxytoluene (0.01%). RESULTS: Tissue homogenates prepared in the absence of butylated hydroxytoluene contained significantly higher (P < 0.001) free MDA levels than tissue homogenates from the same hearts prepared in the presence of butylated hydroxytoluene. Free MDA levels of tissue homogenates prepared in the presence of butylated hydroxytoluene were below the detection limit (20 pmol/mg protein) in 27 of 30 tissue homogenates, irrespective of the perfusion protocol. Control experiments showed that the presence of butylated hydroxytoluene did not interfere with the detection of free MDA. CONCLUSIONS: These results indicate that free MDA was formed artifactually during tissue homogenization in the absence of butylated hydroxytoluene. Furthermore, free MDA could not be detected in perfused rat hearts after control perfusion, or 20 min of ischemia, or 20 min of ischemia followed by 5 or 30 min of reperfusion. PMID- 8689653 TI - The development of an in vitro flow model of human saphenous vein graft intimal hyperplasia. AB - OBJECTIVE: Although the role of blood flow has been investigated in animal models of intimal hyperplasia, there have been no detailed studies in intact human vein owing to the difficulties in designing a suitable laboratory model. The aim of this study was to develop a flow model of human vein graft intimal hyperplasia. METHODS: Organ cultures of human saphenous vein were exposed to laminar flow by culturing in a closed circulatory system under predetermined conditions of venous and arterial shear stress for 14 days. Following fixation and processing, paraffin sections were immunostained and neointimal thicknesses measured. RESULTS: It was found that arterial flow completely inhibited neointima formation, but venous flow only partly suppressed the response when compared with vein cultured under static conditions. These results are in agreement with previous in vivo studies in a primate graft model, where increased shear stress inhibited intimal proliferation. CONCLUSION: The endothelial cell is believed to be the key mediator of haemodynamic effects which influence smooth muscle cell proliferation, and the flow rig developed in this study offers the potential to study inter-cellular interactions within the intact vessel. Furthermore, this method provides the facility to study the effects of different flow conditions on segments of vein from the same patient. This model has scope for further development and sophistication which may ultimately lead to increasing our understanding of the aetiology of vein graft stenoses, and hence formulation of preventative strategies. PMID- 8689654 TI - CFTR chloride channels in human and simian heart. AB - OBJECTIVES: The cAMP-dependent Cl- conductance in heart is believed to be due to cardiac expression of the cystic fibrosis transmembrane conductance regulator (CFTR). While CFTR expressed in rabbit and guinea-pig heart (CFTRcardiac) is an alternatively spliced isoform of the epithelial gene product, little information is known regarding possible expression of CFTR in primate heart. In this study, we examined molecular expression of CFTR in human and simian atrium and ventricle and functional expression of cAMP-dependent Cl- currents in isolated human atrial and simian ventricular cells. METHODS: The reverse transcription polymerase chain reaction (RT-PCR) was performed on human and simian atrial and ventricular mRNA using primers designed to border regions of the CFTR gene product corresponding to transmembrane segments I-VI (TSI-VI), the first nucleotide binding domain (NBD1), transmembrane segments VII-XII (TSVII-XII), and the large cytoplasmic domain which includes the regulatory (R) domain and NBD1. Functional expression of CFTR Cl- channels in human atrial and simian ventricular myocytes was determined using whole-cell and giant inside-out patch-clamp techniques. RESULTS: Southern blot analysis of these RT-PCR products demonstrated expression of CFTR transcripts in human and simian atrial and ventricular tissue and revealed a novel pattern of expression compared to most animal species studies: both the exon 5 plus (unspliced) and exon 5 minus (spliced) CFTR transcripts are co expressed in human and simian atrium and ventricle. Whole-cell experiments demonstrated a Cl- sensitive time-independent background conductance in both human atrial and simian ventricular myocytes that was activated by forskolin (FSK) and insensitive to 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS). In inside-out patches utilizing the giant patch technique on human atrial myocytes, unitary Cl- sensitive channels resembling CFTR Cl- channels (approximately 14 pS conductance) were activated by the catalytic subunit of protein kinase A (PKA) in 3/12 patches examined. CONCLUSIONS: These results clearly demonstrate the molecular expression of CFTR Cl- channels and provide electrophysiological evidence consistent with functional expression of these channels in human atrial and simian ventricular myocardium. PMID- 8689655 TI - Messenger RNA expression and immunological quantification of phospholamban and SR Ca(2+)-ATPase in failing and nonfailing human hearts. AB - OBJECTIVES: Human heart failure is associated with prolonged relaxation and prolonged Ca2+ transients which indicates an impaired function of the sarcoplasmic reticulum (SR) and may be detrimental for cardiac function. Controversy exists whether the altered SR function is accompanied by changes in the expression of phospholamban (PLB) and cardiac SR-Ca(2+)-ATPase (SERCA2) on mRNA and/or protein levels. METHODS: We determined mRNA and/or protein levels for PLB and SERCA2 in the same left ventricular tissue of patients undergoing heart transplantation due to idiopathic dilated cardiomyopathy (IDC) or ischemic cardiomyopathy (ICM) in comparison to left ventricular tissue from nonfailing human hearts (NF). Total protein extracts were prepared and subjected to SDS gel electrophoresis. PLB and SERCA2 were identified with specific antibodies. Total RNA was isolated and hybridized with 32P-labeled cDNAs for human PLB and rat SERCA2. RESULTS: Hybridization revealed the three expected mRNAs with the PLB probe (3.3 kb, 1.9 kb and 0.6 kb) and a single band with the SERCA2 probe (4.5 kb). Determination of respective proteins by immunoblotting revealed unchanged protein levels for PLB and SERCA2, whereas the mRNA levels for PLB and SERCA2 were reduced by about 30% and 50%, respectively. CONCLUSIONS: These data show the level of SERCA2 and PLB protein and mRNA in the same hearts. The reduced mRNA level of SERCA2 and PLB is in accordance with previous data. However, the unchanged protein levels may indicate that the diminished RNA expression is not accompanied by a corresponding decrease for these proteins in human heart failure. These data also show that the altered SR function in human heart failure cannot be explained by altered protein levels of PLB and SERCA2. Furthermore, it is suggested that extrapolations from cardiac mRNA levels to protein expression may be misleading. PMID- 8689656 TI - A controlled study of the autonomic changes produced by habitual cigarette smoking in healthy subjects. AB - OBJECTIVES: An increased sympathetic drive, in view of its proarrhythmic, proatherosclerotic, and prothrombotic actions, could contribute to the elevated cardiovascular risk of habitual smokers. However, the underlying mechanisms are still debated. In this study we address the hypothesis that spectral analysis of RR interval and systolic arterial pressure short-term variabilities may be used to assess the complex autonomic changes produced by habitual cigarette smoking. METHODS: A cross-sectional design compared heavy (> 20 cigarettes/day) habitual smokers (n = 20; 40 +/- 3 years), with similar age controls. Spectral analysis of RR interval variability provided markers of the sympatho-vagal balance modulating the SA node, by way of the normalised low frequency (LF approximately equal to 0.10 Hz) and high frequency (HF approximately equal to 0.25 Hz) components. The LF component of systolic arterial pressure (SAP) variability assessed the sympathetic vasomotor modulation. The frequency domain index (alpha) measured the baroreflex gain of the SA node. Subjects were studied at rest, and during the sympathetic excitation produced by active standing. RESULTS: In smokers LFRR was, at rest, greater than in controls (70.6 +/- 3.8 vs 46.0 +/- 2.5 normalised units, nu); concurrently HFRR was reduced (22.1 +/- 3.2 vs 42.0 +/- 2.8 nu). Baroreflex gain and RR variance were also smaller in smokers. LFSAP was, instead, similar in the smokers and control groups. The standing induced increase in LFRR was blunted (P < 0.001) in smokers. CONCLUSIONS: Spectral analysis of RR interval and systolic arterial pressure variability indicates that habitual cigarette smoking induces selective alterations in neural control of the SA node. An increase at rest in markers of sympathetic modulation is accompanied by signs of reduced vagal drive and depressed baroreflex gain; while sympathetic vasomotor modulation appears similar in controls and smokers. Data are consistent with the hypothesis that autonomic alterations may contribute to the increased cardiovascular risk present in smokers. PMID- 8689657 TI - Negative dromotropic effects of class I antiarrhythmic drugs in anisotropic ventricular muscle. AB - OBJECTIVE: In a computer simulation study to mimic cardiac action potential, the total open time of the sodium channel at each excitation has been shown by other authors to be longer during propagation parallel (longitudinal, L) to fiber orientation than perpendicular (transverse, T) to that. If this is the case in actual cardiac tissue, the Class I antiarrhythmic drug action on conduction would be affected by their mode of sodium channel block. The present study was designed to test this hypothesis. METHODS: Effects of flecainide (F), quinidine (Q), aprindine (A) and SD3212 (S) on conduction velocity (theta), amplitude of extracellular potentials (phi e), and maximum upstroke velocity (Vmax) of action potentials were examined in isolated rabbit ventricular muscles with microscopic anisotropy. RESULTS: F (0.1-1 microM) or Q (2-10 microM), which blocks the sodium channel mainly during the activated state, caused a concentration- and frequency dependent decrease in theta and phi e. The reduction was more prominent during L than T propagation, giving rise to a decrease in their anisotropic ratio (theta L/theta T). A (1-5 microM) or S (3-10 microM), which blocks the channel during the inactivated state, also decreased theta and phi e. However, the reduction was similar during L and T propagation, and the anisotropic ratio of theta and phi e remained unaffected. The decrease of maximum upstroke velocity (Vmax) of action potential by F or Q was greater during L than T propagation; VmaxL/VmaxT was decreased significantly. In contrast, the Vmax reduction by A(3 microM) or S (10 microM) was similar during L and T propagation. CONCLUSION: Different state dependence of sodium channel block may underlie different negative dromotropic effects of Class I drugs in anisotropic cardiac muscle. PMID- 8689658 TI - Experimental myocarditis in the guinea-pig. AB - In guinea-pigs, myocarditis was induced under experimental conditions by immunizing the animals with rabbit skeletal muscle myosin-beta. The salient histopathological features were foci of perivascular lymphonononuclear aggregates, necrosis, and degeneration of myocardial cells. Antimyosin-beta antibodies in the immune complexes were demonstrated in the sera of the guinea pigs. An immune-complex-mediated tissue-injury is proposed in the pathogenesis of myocarditis. PMID- 8689659 TI - Anti-arrhythmic protection by ischaemic preconditioning in isolated rat hearts is not due to depletion of endogenous catecholamines. AB - OBJECTIVES: The present study addresses whether the mechanism of anti-arrhythmic protection by ischaemic preconditioning involves depletion of myocardial catecholamines. METHODS: In a randomised series of studies isolated rat hearts, perfused with whole blood, underwent episodes of regional ischaemia and reperfusion induced with a snare around the left coronary artery. Control hearts (Group 1, n = 12) were subjected to 40 min aerobic perfusion, 30 min ischaemia and 10 min reperfusion. Preconditioned hearts (Group 2, n = 12) were subjected to 10 min aerobic perfusion, three cycles of ischaemia and reperfusion (5 min each), 30 min ischaemia and 10 min reperfusion. Cardiac rhythm was recorded continuously and arrhythmias quantified during the final periods of ischaemia and reperfusion. At the end of the experiment samples of right ventricular (RV; non-ischaemic) and left ventricular (LV; ischaemic territory) tissue were separated and frozen. In 5 additional groups (n = 6/group) tissue samples were taken after 10 min aerobic perfusion, after 10 min aerobic perfusion followed by 1, 2 or 3 preconditioning cycles and after 40 min of aerobic perfusion. All tissue samples were analysed for catecholamine content. RESULTS: Preconditioning resulted in reductions in the incidence of ischaemia-induced VF from 67% in Group 1 to 8% in Group 2, the incidence of ischaemia-induced VT from 100% to 17% and the number of ischaemia induced VPBs from 246 +/- 25 to 59 +/- 19 (each P < 0.05). The mean content of noradrenaline and adrenaline was consistently higher in RV than LV tissue. Within the LV, however, neither preconditioning nor prolonged ischaemia had any significant effect upon tissue catecholamine content at any time in the experimental protocol. CONCLUSIONS: Depletion of myocardial catecholamines is not involved in the mechanism of anti-arrhythmic protection by ischaemic preconditioning in isolated rat hearts. PMID- 8689660 TI - [Melatonin--the hormone of darkness]. AB - Melatonin is a hormone produced mainly by the pineal gland during the dark phase of the circadian cycle with typical circadian rhythm with maximal secretion at night and depression during the day. The indoleamine has wide regulatory and integrative functions. Perhaps there is no organ and system which can escape the influence of epiphysis, incl. reproductive, cardiovascular gastrointestinal, respiratory as well as renal system and water and mineral metabolism. Melatonin regulates not only neuroendocrine functions but also has immunoenhancing and antitumor effects. That is why there are trials/attempts these properties to be utilized in the treatment of malignancies and AIDS patients. The hormone plays a certain role in temperature regulation in mammals as well as in the onset of puberty and senescence. Attention has been paid to its role as a scavenger of toxic free radicals and it is believed that melatonin is the most effective lipophilic antioxidant. However, the exact mechanism of action of this high active hormone remains to be elucidated. Further studies are also necessary for discovering the next its properties and functions. PMID- 8689661 TI - [Photobiologic effects of porphyrins and their use in therapy of tumors]. AB - Principles and mechanisms of the photobiological effects of porphyrin derivatives on the cell components and their employment for the selective destruction of cancer tissues (photodynamic therapy) are discussed. The present status of the photodynamic therapy for the treatment of various cancers is given. PMID- 8689662 TI - Intensification of the conditioning regimen by the addition of anthracyclines results in a higher incidence of sustained molecular remissions after allogeneic bone marrow transplantation for chronic myeloid leukaemia with marrow depleted of lymphocytes by counterflow centrifugation. AB - BACKGROUND: Relapse remains a significant problem in patients after bone marrow transplantation. The aim of the study was an effort to decrease the incidence of relapses in patients transplanted for chronic myeloid leukaemia (CML) by different conditioning regimens. METHODS AND RESULTS: 28 patients with CML who underwent allogeneic bone marrow transplantation with grafts depleted of 98% of lymphocytes were divided into two groups according to the conditioning regimen used. Patients in group 1 were conditioned without anthracyclines, and patients in group 2 were conditioned with the addition of anthracyclines. Bone marrow samples taken 6 and 12 months after BMT, and annually thereafter, were analyzed by polymerase chain reaction (PCR) for residual disease. Median time of bone marrow sampling and medium number of samples analyzed did not differ significantly between two groups of patients. In group 1, consisting of 11 patients, 40% of samples were negative, and in group 2 with 17 patients, PCR was negative in 79% of samples. It is evident that the addition of anthracyclines favourably influences posttransplantation development. CONCLUSIONS: The addition of anthracyclines to the conditioning regimen in recipients of grafts depleted of 98% of lymphocytes, significantly decreases the incidence of relapses even 4 years after BMT. PMID- 8689663 TI - [Changes in the incidence and clinical manifestations of herpes zoster]. AB - BACKGROUND: Shingles is the manifestation of activated latent disease caused by the varicella-herpes zoster virus. The prerequisite of its activation is a reduction of the immunity of the organism: the incidence (with some reservations) of herpes zoster in the population can be therefore considered an indicator of the general immune state. The objective of the submitted paper was to assess whether and to what extent the frequency of herpes zoster increased (whether the number of patients hospitalized at the Clinic for Infectious Diseases increased in 1974-1994, and if so, by how much). METHODS AND RESULTS: By comparing clinical manifestations of herpes zoster in a group of 348 patients hospitalized in 1992 1994 with results of a similar investigation made in the same department in a group of 308 patients hospitalized in 1979-1983 the following was revealed: the annual numbers of treated patients with herpes zoster doubled during the last 15 years. Almost 70% of the affected patients were then and now above 60 years of age, among the patients women predominated markedly (chi 2 = 69.540), the number of malignancies increased greatly (chi 2 = 4.435), there was also a significant increase of ischaemic heart disease, hypertension (chi 2 = 39.741) etc. As to the ratio of different sites of the shingles, no significant changes were observed, while there was a significant increase of manifestations of dermal generalization (chi 2 = 36.377) and a significant increase of peripheral pareses (chi 2 = 5.615). The author explains the fact that the period of hospitalization was not longer and that there was even a significant decrease in the number of postherpetic neuralgias persisting for more than a month, by the early onset of treatment with acyclovir administered by the i.v. route. CONCLUSIONS: The annual numbers of patients hospitalized on account of herpes zoster doubled during the past 15 years, the number of malignancies increased as well as the number of cardiovascular diseases, and the frequency of skin generalizations and peripheral pareses increased. Treatment with acyclovir had a favourable effect on the period of hospitalization. PMID- 8689664 TI - [Changes in elastase and collagenase serum levels in patients with sclerosing connective tissue diseases treated with uropancreozymin]. AB - BACKGROUND: The objective of this work is to clarify the mechanism of the therapeutic effect of uropancreozymin upon the sclerosal process. METHOD AND RESULTS: The sick suffering from sclerosed connective tissue formation underwent uropancreozymin treatment. Their elastase and collagenase blood serum level was contemporaneously determined. One day after the administration of uropancreozymin the elastase level rose by 144.6%, after the third day by 187.4%, after the seventh day by 150.2%. The collagenase activity was elevated after the first day of treatment to 234.7%, after the third day by 187.4%, after the seventh day by 150.2%. The collagenase activity was elevated after the first day of treatment to 144.6%, after the third day to 132.7%, and after the seventh day to 150.8%. CONCLUSIONS: The therapeutic effect of uropancreozymin is explained as the faculty to wash out the pancreatic enzymes in active form, mainly elastase et collagenase, into the blood circulation. So it differs from pancreozymin which does not elevate the pancreatic enzyme level in blood in these diseases and which contains more hormonal factors. For this reason uropancreozymin is therapeutic and pancreozymin diagnostic. Pancreozymin was later mistakenly characterized as cholecystokinin (4.9) but this error has been already repaired (17). PMID- 8689665 TI - [The effect of electrostimulation with the Rebox apparatus on ischemic renal injury in rats]. AB - BACKGROUND: With developing transplantation programmes the problem of protection against ischaemic renal damage had become important. The results of experimental pharmacological protection of the kidneys are not quite conclusive. The objective of the presented paper was to assess the effect of electrostimulation by means of a Rebox apparatus (generator of direct rectangular impulses at a frequency of 1 to 10 kHz), on the development of ischaemic damage of the renal parenchyma induced experimentally in rats. METHODS AND RESULTS: The experiments were made on Wistar strains rats (n = 15) which were subjected to dextrolateral nephrectomy and the left renal artery was closed by a clamp which was released in the tested and the control group after 30 minutes. In the rebox group electrostimulation with the Rebox apparatus was implemented immediately after release of the clamp. In rats which were in metabolic cages the following parameters were assessed: diuresis, period of survival, endogenous creatinine clearance, plasma creatinine level, urea level and excretion, as well as sodium and potassium urinary excretion. No significant difference in the survival time of the rats was found nor in the plasma levels of creatinine, urea and urinary excretion of potassium and urea between the control and the Rebox group. In the Rebox group, as compared with the control group, a significantly higher diuresis was found 22.8 vs 5.6 (p < 0.001) and natriuresis 0.44 vs 0.11 (p < 0.01). CONCLUSIONS: Electrostimulation by rebox currents in rats increases significantly the diuresis and natriuresis of the solitary kidney exposed to 30-minute ischaemia but has no impact on other parameters. The mechanism of action is not quite clear, apparently the reabsorption of sodium in the proximal tubule is inhibited. PMID- 8689667 TI - [Institutional conflict of interest]. PMID- 8689666 TI - [An unusual case of paternity dispute resolved by examination of HLA antigens of a former wife, daughter and a sister of the deceased man]. AB - The author describes a peculiar case of a paternity suite where the accused died and his parents were also dead. Possible paternity was assessed by examination of HLA antigen of his ex-wife and daughter from his former marriage and in his sisters. PMID- 8689668 TI - Calmodulin-antagonists inhibit vesicular Ca2+ uptake in Dictyostelium. AB - Chemotactic stimulation by cAMP elicits Ca2+ entry across the plasma membrane and uptake into intracellular Ca2+ stores. In order to better understand Ca2+ regulation in Dictyostelium we measured 45Ca2+ uptake in homogenates of aggregation competent cells. Besides the InsP3-sensitive store the acidosomes are responsible for Ca2+ transport. About 50% of the vesicular 45Ca2+ accumulation was inhibited by the calmodulin antagonist W-7 and 14% by the less efficacious analogue W-5. Half maximal inhibition by W-7 occurred at 37 microM concentration. Calmodulin antagonised the activity of W-7, and a monoclonal antibody against Dictyostelium calmodulin inhibited Ca2+ sequestration as did calmodulin antagonists of different classes. 100 microM BHQ-a SERCA-type Ca2+ transport ATPase blocker-inhibited most of the W-7 sensitive compartment and oxalate increased Ca2+ uptake into this compartment indicating that intracellular Ca2+ stores are the target of W-7. Ca2+/calmodulin thus seems to provide for a feedback regulation of Ca2+ sequestration. PMID- 8689669 TI - Ca2+ signalling in rat chromaffin cells: interplay between Ca2+ release from intracellular stores and membrane potential. AB - Cytosolic Ca2+ oscillations are physiologically important in a range of excitable and non-excitable cells. The combined techniques of whole-cell patch clamp and photometric measurement of cytosolic Ca2+ has enabled us to identify the components of Ca2+ spiking in rat chromaffin cells. We show that Ca2+ oscillations continue at a fixed membrane potential and that infusion of the InsP3 receptor antagonist, heparin, substantially blocked the cytosolic Ca2+ spikes. However, even in the presence of heparin we observed spikes of membrane potential depolarization due to the repetitive activation of a transient inward cation current. We conclude that Ca2+ oscillations are dependent on Ca2+ release from heparin sensitive Ca2+ stores and possibly on Ca2+ entry associated with the repetitive activation of a transient cation current. The depolarizing action of the cation current would, in turn, recruit voltage-sensitive Ca2+ channels and further Ca2+ entry would augment the cytosolic Ca2+ spikes. Our results demonstrate that Ca2+ oscillations in rat chromaffin cells are due to a complex interplay of Ca2+ entry and Ca2+ release. PMID- 8689670 TI - Pancreastatin inhibits insulin secretion in RINm5F cells through obstruction of G protein mediated, calcium-directed exocytosis. AB - To elucidate the regulatory pathway through which pancreastatin inhibits insulin secretion, RINm5F insulinoma cells were challenged with physiological and pharmacological probes known to stimulate insulin release through different mechanisms. Utilizing the electrophysiological technique of capacitance measurements as a correlate to exocytosis, pancreastatin was found to significantly diminish maximum capacitance changes evoked by glyceraldehyde, an effect which was attenuated in pertussis toxin-treated cells. In static incubations of this cell line, pancreastatin significantly inhibited insulin secretion stimulated by glyceraldehyde, carbachol and A23187, secretagogues known to directly elevate beta-cell cytosolic Ca2+. This peptide also inhibited insulin secretion stimulated by phorbol myristate acetate (PMA), but only at incubation times < or = 15 min. It was without effect on insulin secretion stimulated by mastoparan and longer incubations (30 min) with PMA, where the secretory mechanisms are not necessarily Ca(2+)-dependent. Additionally, pancreastatin had no effect on carbachol-generated inositol phosphate accumulation but inhibited simultaneously stimulated insulin secretion. All inhibitory effects of pancreastatin were pertussis toxin sensitive. These results suggest that pancreastatin inhibits insulin secretion in RINm5F cells through a G-protein regulated mechanism at a control point involved in the Ca(2+)-directed exocytotic machinery, a feature shared by other physiologic inhibitors of insulin secretion. PMID- 8689671 TI - Agonist-stimulated free calcium in subcellular compartments. Delivery of recombinant aequorin to organelles using a replication deficient adenovirus vector. AB - Changes in the concentration of calcium ions ([Ca2+]) within cellular organelles play a central role in controlling cellular function. We have engineered the Ca2+ sensitive photoprotein aequorin to monitor selectively [Ca2+] within defined subcellular compartments, namely the cytosol, nucleus and endoplasmic reticulum. DNA encoding the engineered aequorins have been inserted into a replication deficient adenovirus (Ad) type 5 E1-vector, under control of the cytomegalovirus (CMV) major immediate early promoter. The Ad vector provides a simple and efficient method to express the photoproteins in a wide variety of mammalian cell types. Efficient targeting of the photoproteins to the appropriate cellular compartment was established immunocytochemically in COS7 cells, where it was expressed in up to 100% of the target population. Levels of expression could be controlled by virus dose and chemical agents which affect the activity of the CMV promoter. In HeLa cells expressing nuclear targeted aequorin or cytosolic aequorin, ATP or histamine induced immediate biphasic elevations of both nuclear and cytosolic [Ca2+]; subsequent challenge with agonist evoked similar responses. In addition to epithelial type adherent cell lines (COS7 and HeLa), aequorin expression was also readily detected in non-adherent cells of myeloid lineage (K562 and HL60) and non-adherent primary cells polymorphonuclear leucocytes (neutrophils). The Ad vectors can, therefore, be used to express targeted aequorin in a range of different cell types and represents a novel method to monitor changes in free [Ca2+] in cellular organelles. PMID- 8689672 TI - [Ca2+]i oscillations induced by bradykinin in rat glioma cells associated with Ca2+ store-dependent Ca2+ influx are controlled by cell volume and by membrane potential. AB - Long-term superfusion with bradykinin causes oscillations of cytosolic Ca2+ activity ([Ca2+]i) in Fura-2 loaded rat glioma cells. The [Ca2+]i rise is associated with synchronous plasma membrane hyperpolarization oscillating with a frequency of 0.8-1.8 per min. The initial large transient [Ca2+]i rise, induced immediately with bradykinin admission results from InsP3-mediated Ca2+ release, whereas the subsequent oscillations depend mainly on Ca2+ influx, as demonstrated: (i) by blockade of [Ca2+]i oscillations by reduction of [Ca2+]ex' or addition of Ca(2+)-channel blockers; and (ii) evidence from Mn2+ quench experiments. Suppression of [Ca2+]i oscillations with high K+ depolarization and with block of Ca(2+)-dependent K+ channels proves that membrane hyperpolarization is required for Ca2+ influx during the oscillation. Ca2+ release from intracellular stores by inhibitors of endoplasmic reticulum Ca(2+)-ATPase attenuates or blocks the [Ca2+]i oscillations. This suggests that bradykinin induced Ca2+ influx is controlled by the filling state of the stores. The [Ca2+]i oscillations are suppressed by hypertonic medium and enhanced by hypotonic medium. Cell swelling enhances Ca2+ influx. We propose the following model for generation of the oscillations in the glial cell line: InsP3-induced Ca2+ release from internal stores periodically evokes Ca2+ influx through Ca(2+)-permeable cation channels. Hyperpolarization of the plasma membrane due to the activation of Ca(2+)-dependent K+ channels enhances the Ca2+ influx. The concomitant K+ efflux could lead to cell shrinkage which suppresses Ca2+ influx. Cell volume and membrane potential probably serve as feedback regulators during the [Ca2+]i oscillations. PMID- 8689674 TI - Mechanisms for Ca signaling in vascular smooth muscle: resolved from 45Ca uptake and efflux experiments. AB - Established cell lines are now widely used in experiments concerning vascular smooth muscle (VSM) function; however, considerable evidence suggests that cultured VSM cells are functionally different from VSM cells in intact blood vessels. In order to test the hypothesis that calcium signaling mechanisms are comparable in these two preparations, we developed a new method for high resolution 45Ca efflux studies in A7r5 cells. Briefly, this method involves plating cells in the lumen of a tubular glass efflux chamber and, after loading the cells with 45Ca, perfusing the chamber with a physiological saline solution and collecting the effluent. Using this method we found that the plasma membrane in cultured cells is not rate limiting for calcium efflux, since the efflux curves from both permeabilized and intact cells are kinetically the same. We also found the plasma membrane is not rate limiting in whole aortic segments by using a depolarizing solution followed by dihydropyridine solution. Thus, we demonstrated that the data obtained from cells or tissues with intact membranes reveal information about the intracellular stores (sarcoplasmic reticulum and mitochondria). Combining efflux data with a detailed kinetic model of cellular Ca transport allows least-squares estimation of the rate constants for release and uptake of Ca2+ by intracellular stores with a high degree of confidence (CV < 25%) as well as the Ca2+ contents and transmembrane fluxes associated with these stores. Quantitative comparison of results obtained from A7r5 cells with those we previously obtained for rabbit aortic segments reveals marked similarities and suggests that A7r5 cells serve as excellent model experiments for VSM cell Ca2+ homeostasis. PMID- 8689673 TI - The lysosomal compartment as intracellular calcium store in MDCK cells: a possible involvement in InsP3-mediated Ca2+ release. AB - To test for a possible role of lysosomes in intracellular Ca2+ homeostasis, the effects of glycyl-L-phenylalanine-beta-naphthylamide (GPN), known to permeabilize these organelles by osmotic swelling, were studied in single MDCK cells. Fluorescence of acridine orange, rhodol green dextran, lysotracker green and FITC dextran indicated that GPN (0.2 mmol/l) elicited a reversible permeabilization of lysosomes. Cytosolic Ca2+ ([Ca2+]i) as determined by Fura-2 fluorescence increased from 60 +/- 11 to 534 +/- 66 nmol/l (n = 41) in the presence of GPN. Whereas only a single intracellular Ca2+ release could be induced by GPN in a Ca(2+)-free perfusate, repetitive release could be evoked in Ca2+ containing solutions suggesting reuptake of Ca2+ into lysosomal stores. GPN-induced Ca2+ release was blunted after pretreatment with thapsigargin (TG), an inhibitor of Ca(2+)-ATPase, or repeated applications of ATP inducing Ca2+ release from inositol trisphosphate (InsP3) sensitive Ca2+ stores. The effect of ATP on Ca2+ release was, however, not abolished by preceding GPN treatment. GPN-induced Ca2+ release from lysosomes was independent of InsP3 formation or Ca(2+)-induced Ca2+ release, since it was unaffected by the phospholipase C inhibitor U-73, 122 or by caffeine and ruthenium red. These results suggest that Ca2+ largely accumulates in lysosomal vesicles. Moreover, these organelles seem to be part or functionally coupled with InsP3-sensitive Ca2+ stores. PMID- 8689675 TI - Endothelium-dependent vasodilators do not cause propagated intercellular Ca2+ waves in vascular endothelial monolayers. AB - Local application of a number of vasoactive agents affects vasomotor tone not only downstream to the point of application but also upstream. The mechanism(s) of upstream propagation is unknown. In endothelial cell monolayers, mechanical stimulation of one cell leads to intercellular propagation of increases in endothelial cell (EC) [Ca2+]i. In this study, we tested whether increases in EC [Ca2+]i induced by the local application of the endothelium-dependent vasodilators ATP, bradykinin and acetylcholine could spread across the monolayer. We demonstrate that unlike the response seen to a mechanical stimulus, there was no significant propagation of increases in EC [Ca2+]i levels in response to localized application of these agents. These findings suggest that upstream vasodilation in response to endothelium-dependent vasodilators is not mediated by propagation of EC [Ca2+]i waves and suggest that other electrical or chemical signals are responsible. PMID- 8689676 TI - Chemokine receptors and HIV-1: an attractive pair? PMID- 8689677 TI - Meiotic transvection in fungi. AB - The Neurospora crassa Asm-1+ (ascospore maturation 1) gene encodes an abundant nucleus-localized protein required for formation of female structures and for ascospore maturation. Deletion mutants of Asm-1+ are "ascus-dominant," i.e., when crossed to wild type, neither Asm-1+ nor Asm-1 delta spores mature. To explain this behavior, we considered three models: an effect of reduced dosage of the gene product, failure of internuclear communication, and failure of transvection (regulation dependent on pairing of alleles). We found that for proper regulation of subsequent sexual sporulation, Asm-1+ must be in proximity, probably paired, to its allelic counterpart in the zygote: i.e., transvection must occur. Disruption of pairing causes failure of ascospore progeny to mature. Transvection in Neurospora, unlike in Drosophila, occurs immediately before meiosis, and can be demonstrated between wild-type alleles. PMID- 8689678 TI - The COP9 complex, a novel multisubunit nuclear regulator involved in light control of a plant developmental switch. AB - Arabidopsis COP9 is a component of a large protein complex that is essential for the light control of a developmental switch and whose conformation or size is modulated by light. The complex is acidic, binds heparin, and is localized within the nucleus. Biochemical purification of the complex to near homogeneity revealed that it contains 12 distinct subunits. One of the other subunits is COP11, mutations in which result in a phenotype identical to cop9 mutants. The COP9 complex may act to regulate the nuclear abundance of COP1, an established repressor of photomorphogenic development. During the biogenesis of the COP9 complex, a certain degree of prior subunit association is a prerequisite for proper nuclear translocation. Since both COP9 and COP11 have closely related human counterparts, the COP9 complex probably represents a conserved developmental regulator in higher eukaryotes. PMID- 8689679 TI - Tomato Prf is a member of the leucine-rich repeat class of plant disease resistance genes and lies embedded within the Pto kinase gene cluster. AB - In tomato, resistance to Pseudomonas syringae pv. tomato (Pst) strains expressing the avirulence gene avrPto requires the presence of at least two host genes, designated Pto and Prf. Here we report that Prf encodes a protein with leucine zipper, nucleotide-binding, and leucine-rich repeat motifs, as are found in a number of resistance gene products from other plants. prf mutant alleles (4) were found to carry alterations within the Prf coding sequence. A genomic fragment containing Prf complemented a prf mutant tomato line both for resistance to Pst strains expressing avrPto and for sensitivity to the insecticide Fenthion. Prf resides in the middle of the Pto gene cluster, 24 kb from the Pto gene and 500 bp from the Fen gene. PMID- 8689680 TI - Chromatin unfolds. PMID- 8689681 TI - Direct evidence of a role for heterochromatin in meiotic chromosome segregation. AB - We have investigated the mechanism that enables achiasmate chromosomes to segregate from each other at meiosis I in D. melanogaster oocytes. Using novel cytological methods, we asked whether nonexchange chromosomes are paired prior to disjunction. Our results show that the heterochromatin of homologous chromosomes remains associated throughout prophase until metaphase I regardless of whether they undergo exchange, suggesting that homologous recognition can lead to segregation even in the absence of chiasmata. However, partner chromosomes lacking homology do not pair prior to disjunction. Furthermore, euchromatic synapsis is not maintained throughout prophase. These observations provide a physical demonstration that homologous and heterologous achiasmate segregations occur by different mechanisms and establish a role for heterochromatin in maintaining the alignment of chromosomes during meiosis. PMID- 8689682 TI - Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. AB - A cell-free system based on cytosols of normally growing cells is established that reproduces aspects of the apoptotic program in vitro. The apoptotic program is initiated by addition of dATP. Fractionation of cytosol yielded a 15 kDa protein that is required for in vitro apoptosis. The absorption spectrum and protein sequence revealed that this protein is cytochrome c. Elimination of cytochrome c from cytosol by immunodepletion, or inclusion of sucrose to stabilize mitochondria during cytosol preparation, diminished the apoptotic activity. Adding back cytochrome c to the cytochrome c-depleted extracts restored their apoptotic activity. Cells undergoing apoptosis in vivo showed increased release of cytochrome c to their cytosol, suggesting that mitochondria may function in apoptosis by releasing cytochrome c. PMID- 8689683 TI - Atm-deficient mice: a paradigm of ataxia telangiectasia. AB - A murine model of ataxia telangiectasia was created by disrupting the Atm locus via gene targeting. Mice homozygous for the disrupted Atm allele displayed growth retardation, neurologic dysfunction, male and female infertility secondary to the absence of mature gametes, defects in T lymphocyte maturation, and extreme sensitivity to gamma-irradiation. The majority of animals developed malignant thymic lymphomas between 2 and 4 months of age. Several chromosomal anomalies were detected in one of these tumors. Fibroblasts from these mice grew slowly and exhibited abnormal radiation-induced G1 checkpoint function. Atm-disrupted mice recapitulate the ataxia telangiectasia phenotype in humans, providing a mammalian model in which to study the pathophysiology of this pleiotropic disorder. PMID- 8689684 TI - Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain. AB - Autocatalytic processing mediated by the carboxyterminal domain of the hedgehog (hh) protein precursor (Hh) generates an amino-terminal product that accounts for all known signaling activity. The role of autoprocessing biogenesis of the hh signal has been unclear, since a truncated unprocessed protein lacking all carboxy-terminal domain sequences retains signaling activity. Here, we present evidence that the autoprocessing reaction proceeds via an internal thioester intermediate and results in a covalent modification that increases the hydrophobic character of the signaling domain and influences its spatial and subcellular distribution. We demonstrate that truncated unprocessed amino terminal protein causes embryonic mispatterning, even when expression is localized to cells that normally express Hh, thus suggesting a role for autoprocessing in spatial regulation of hh signaling. This type of processing also appears to operate in the biogenesis of other novel secreted proteins. PMID- 8689685 TI - Nuk controls pathfinding of commissural axons in the mammalian central nervous system. AB - Eph family receptor tyrosine kinases have been proposed to control axon guidance and fasciculation. To address the biological functions of the Eph family member Nuk, two mutations in the mouse germline have been generated: a protein null allele (Nuk1) and an allele that encodes a Nuk-beta gal fusion receptor lacking the tyrosine kinase and C-terminal domains (Nuk(lacZ)). In Nuk1 homozygous brains, the majority of axons forming the posterior tract of the anterior commissure migrate aberrantly to the floor of the brain, resulting in a failure of cortical neurons to link the two temporal lobes. These results indicate that Nuk, a receptor that binds transmembrane ligands, plays a critical and unique role in the pathfinding of specific axons in the mammalian central nervous system. PMID- 8689686 TI - The T cell leukemia oncoprotein SCL/tal-1 is essential for development of all hematopoietic lineages. AB - The T cell leukemia oncoprotein SCL/tal-1, a basic-helix-loop-helix transcription factor, is required for production of embryonic red blood cells in the mouse yolk sac. To define roles in other lineages, we studied the hematopoietic potential of homozygous mutant SCL/tal-1 -/- embryonic stem cells upon in vitro differentiation and in vivo in chimeric mice. Here we show that in the absence of SCL/tal-1, hematopoiesis, Including the generation of red cells, myeloid cells, megakaryocytes, mast cells, and both T and B lymphoid cells, is undetectable. These findings suggest that SCL/tal-1 functions very early in hematopoietic development, either in specification of ventral mesoderm to a blood cell fate, or in formation or maintenance of immature progenitors. PMID- 8689687 TI - X chromosome inactivation, XIST, and pursuit of the X-inactivation center. PMID- 8689689 TI - Influence of PAX6 gene dosage on development: overexpression causes severe eye abnormalities. AB - Aniridia in man and Small eye in mice are semidominant developmental disorders caused by mutations within the paired box gene PAX6. Whereas heterozygotes suffer from iris hypoplasia, homozygous mice lack eyes and nasal cavities and exhibit brain abnormalities. To investigate the role of gene dosage in more detail, we have generated yeast artificial chromosome transgenic mice carrying the human PAX6 locus. When crossed onto the Small eye background, the transgene rescues the mutant phenotype. Strikingly, mice carrying multiple copies on a wild-type background show specific developmental abnormalities of the eye, but not of other tissues expressing the gene. Thus, at least five different eye phenotypes are associated with changes in PAX6 expression. We provide evidence that not only reduced, but also increased levels of transcriptional regulators can cause developmental defects. PMID- 8689688 TI - LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. AB - To identify genes important for human cognitive development, we studied Williams syndrome (WS), a developmental disorder that includes poor visuospatial constructive cognition. Here we describe two families with a partial WS phenotype; affected members have the specific WS cognitive profile and vascular disease, but lack other WS features. Submicroscopic chromosome 7q11.23 deletions cosegregate with this phenotype in both families. DNA sequence analyses of the region affected by the smallest deletion (83.6 kb) revealed two genes, elastin (ELN) and LIM-kinase1 (LIMK1). The latter encodes a novel protein kinase with LIM domains and is strongly expressed in the brain. Because ELN mutations cause vascular disease but not cognitive abnormalities, these data implicate LIMK1 hemizygosity in imparied visuospatial constructive cognition. PMID- 8689691 TI - Do changes in chromosomes cause aging? PMID- 8689690 TI - A 450 kb transgene displays properties of the mammalian X-inactivation center. AB - X inactivation results in inactivation of one X chromosome to compensate for gene dosage differences between mammalian females and males. It requires the X inactivation center (Xic) and Xist in cis. We report that introducing 450 kb of murine Xic/Xist sequences onto autosomes activates female dosage compensation in male ES cells. Xist is induced upon differentiation and can be expressed from both endogenous and ectopic loci, suggesting that elements for counting and choosing Xs are present in the transgene. Differentiating transgenic ES cells undergo excessive cell death. Postnatally, Xist is expressed only from the transgene. Ectopic Xist RNA structurally associates with the autosome and may inactivate a marker gene in cis. These results argue that the Xic is contained within 450 kb and that these sequences are sufficient for chromosome counting, choosing, and initiation of X inactivation. PMID- 8689692 TI - Chromosomal inheritance of epigenetic states in fission yeast during mitosis and meiosis. AB - Inheritance of the active and inactive states of gene expression by individual cells is crucial for development. In fission yeast, mating-type region consists of three loci called mat1, mat2, and mat3. Transcriptionally silent mat2 and mat3 loci are separated by a 15 kb interval, designated the K-region, and serve as donors of information for transcriptionally active mat1 interconversion. In a strain carrying replacement of 7.5 kb of the K-region with the ura4 gene, we discovered that ura4 silencing and efficiency of mating-type switching were covariegated and were regulated by an epigenetic mechanism. Genetic analyses demonstrated that epigenetic states were remarkably stable not only in mitosis but also in meiosis and were linked to the mating-type region. This study indicates that different epigenetic states are heritable forms of chromatin organization at the mat region. PMID- 8689693 TI - Noncardiogenic pulmonary edema. AB - Pulmonary edema is a consequence of high pressures in the pulmonary microcirculation (predominantly capillaries) or an increase in the permeability of the alveolar-capillary barrier (generally of its endothelial aspect) or a combination of both. It occurs when the rate of transudation from the capillaries exceeds the rate of lymphatic drainage from the interstitium. If the plasma oncotic pressure is low due to hypoproteinemia, transudation of fluid occurs at lower pressures. Permeability pulmonary edema is strongly influenced by fluctuations in pulmonary capillary pressures: an increase in pulmonary capillary pressure can add a large component of hemodynamic pulmonary edema to that originating in leaky vessels. Noncardiogenic forms of pulmonary edema are described. PMID- 8689694 TI - [50 years' of Czechoslovak pharmacology and celebrated pharmacologists]. PMID- 8689695 TI - [Abstracts of reports presented at the 45th Pharmacology Seminar in Brno (26-28 October 1995)]. PMID- 8689696 TI - [Receptors--one component of intercellular communication pathways]. AB - Every event, which occurs in the cell, can be an information capable to propagate. The existence of the structures which are capable of transmission (i.e. RECEPTORS) is necessary for the effective signal propagation. In this review the receptors are divided according their localization in the cell, genetic and structural similarity to cytoplasmatic, organelic and membrane receptors. Structure and function (including basic characteristics of intracellular signalization) of the main representatives of the previously mentioned groups are described. The possible interactions between receptors are mentioned too. PMID- 8689697 TI - Good morning, evening primrose oil. PMID- 8689698 TI - Intestinal worms: our turn to turn. PMID- 8689699 TI - Preventing diabetes mellitus; the epidemiological basis. PMID- 8689700 TI - Anatomy of the origin of the deep femoral artery. AB - OBJECTIVE: To study the variability in the level of origin of the deep femoral artery in relation to the different patterns of origin of the femoral circumflex arteries. DESIGN: 124 femoral triangles obtained from cadavers were dissected. The origins of the circumflex femoral arteries were classified into two groups. In group A medial and lateral circumflex arteries arose from the deep femoral artery. In group B either one or both femoral circumflex arteries arose from the common femoral artery. The distance of origin of the deep femoral artery from the mid point of the inguinal ligament was measured in both groups and compared. SETTING: Department of Anatomy, Faculty of Medicine, Colombo. RESULTS: A statistically significant difference was noted in the two groups regarding the level of origin of the deep femoral artery. CONCLUSION: There is a distal migration of the level of origin of the deep femoral artery when either one or both circumflex femoral arteries arose from the common femoral artery. PMID- 8689701 TI - Injuries due to antipersonnel land mines in Sri Lanka. AB - This series comprises 191 victims injured by antipersonnel land mines in the North-east of Sri Lanka. The pattern of mine injuries is described and the injuries to the lower limb are classified according to the level of injury. Injuries to the lower limb were the commonest and over 73% required a below knee amputation. Recommendations are made for the improved care of these victims. The socio-economic effects of mines experienced by other countries affected by internal conflicts are described. The preventive measures that could be taken to avert such a situation in Sri Lanka are stressed. PMID- 8689702 TI - Pattern and prevalence of oral carcinoma in a surgical unit at Cancer Institute Maharagama, 1985 to 1994. AB - OBJECTIVE: To determine the range and prevalence of oral carcinoma requiring surgery. DESIGN: Retrospective study. SETTING: Surgical unit I at Cancer Institute, Maharagama. PATIENTS: 353 oral cancer patients admitted and operated on during a 10 year period from 1985 to 1994 RESULTS: Lateral wall of the oral cavity (cheek and mandible) accounted for 55.6% of oral cancers. The other sites involved were as follows: tongue 33.4% (73.7% of these involved anterior tongue), maxilla 7.4%, floor of the mouth 2.6%, lip 1.1%. The male to female ratio was 3.7:1. CONCLUSIONS: Lateral wall oral cancers are the commonest requiring surgery and the lip is the most infrequent site. Of the central lesions anterior tongue is the commonest. Compared with previous figures prevalence of maxillary cancer has halved, whereas tongue cancer has increased. More women are now coming to surgery. PMID- 8689703 TI - Family medicine in the undergraduate curriculum. PMID- 8689704 TI - Carcinosarcoma arising in a solitary cylindroma of the hand. PMID- 8689705 TI - Papillary and solid epithelial neoplasm of the pancreas. PMID- 8689707 TI - Prevention of AIDS in Sri Lanka, the debate continues. PMID- 8689706 TI - Chronic volvulus of the stomach with eventration of the diaphragm. PMID- 8689708 TI - Bisalbuminaemia--a biochemical curiosity. PMID- 8689709 TI - Observation period for dogs in rabies. PMID- 8689710 TI - Early audiological findings of NF2 with an acoustic neuroma. PMID- 8689711 TI - A case of Kawasaki disease with coronary artery aneurysm. PMID- 8689712 TI - Experience with sublingual nifedipine in paediatric hypertensive emergencies. PMID- 8689713 TI - Double failed female sterilisation. PMID- 8689714 TI - Burkitt's lymphoma presenting with obstructive jaundice. PMID- 8689716 TI - Compositional analysis of hyaluronan, chondroitin sulfate and dermatan sulfate: HPLC of disaccharides produced from the glycosaminoglycans by solvolysis. AB - An ion-exchange high-performance liquid chromatography procedure was developed for analysis of mixtures of N-acetyldermosine, N-acetylchondrosine and N acetylhyalobiuronic acid produced quantitatively by heating dermatan sulfate, chondroitin sulfate and hyaluronan in dimethyl sulfoxide (DMSO) containing 0.1% (v/v) H20 at 80 degrees C for 48 h. These disaccharides were eluted from a TSK gel SAX column using 0.1 M acetic acid containing KCl, and detected fluorometrically by post column derivatization. The eluate was mixed with 2 cyanoacetamide solution and alkaline solution, and heated at 110 degrees C for 4 min. The resultant compounds were detected fluorometrically (Ex. 335 nm and Em. 390 nm). The usefulness and practicality of the present method were verified by applications to the determination of glycosaminoglycans in tissues. PMID- 8689715 TI - Novel 5-hydroxytryptamine (5-HT3) receptor antagonists. II. Synthesis and structure-activity relationships of 4,5,6,7-tetrahydro-1H-benzimidazole derivatives. AB - A novel series of 4,5,6,7-tetrahydro-1H-benzimidazole derivatives 4,5,6 and 7 was prepared and evaluated for activities as 5-hydroxytryptamine (5-HT3) receptor antagonists which may be useful for the treatment of irritable bowel syndrome (IBS) as well as nausea and vomiting associated with cancer chemotherapy. These compounds were designed by modifying the aromatic-carbonyl part of N-(2 methoxyphenyl)-4,5,6,7-tetrahydro-1H-5-benzimidazolylcarboxamide 3, leaving the imidazole moiety unchanged as the amine part. The indole derivatives 7d, g, h and indolizine derivatives 7k, l were found to be highly potent on the von Bezold Jarisch (B.J.) reflex test with ID50 values of below 0.1 microgram/kg, and the indoline derivative 6c, indole derivatives 7a, d, g, benzofurane derivative 7j and indolizine derivative 7k were observed to be very potent on the colonic contraction with IC50 values of below 0.1 microM. In particular, 7l was the most potent on the B.J. reflex (ID50 = 0.018 microgram/kg), approximately 200 and 50 times more potent than ondansetron 1 and granisetron 2, and 7k was the most potent on the colonic contraction (IC50 = 0.011 microM), approximately 70 and 6 times more potent than 1 and 2, respectively. PMID- 8689717 TI - Cyclic peptides from higher plants. XXVIII. Antitumor activity and hepatic microsomal biotransformation of cyclic pentapeptides, astins, from Aster tataricus. AB - Antitumor activities on Sarcoma 180A of a series of cyclic pentapeptides, astins, isolated from the roots of Aster tataricus, were examined. The activities on various congeners of the dichlorinated proline residues prepared by chemical conversion and a hepatic microsomal biotransformation in rats suggested that 1,2 cis dichlorinated proline residues of astins A, B and C play an important role in the antitumor activity of astins. PMID- 8689718 TI - Studies on quinolone antibacterials. IV. Structure-activity relationships of antibacterial activity and side effects for 5- or 8-substituted and 5,8 disubstituted-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-1, 4-dihydro-4 oxoquinoline-3-carboxylic acids. AB - A series of 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-1,4-dihydro-4- oxoquinoline 3-carboxylic acids bearing various substituents (H, F, C1, Me, OH, OMe, OEt, OCH2F, OCHF2, OCF3, SMe) at the C-8 position was prepared and evaluated for in vitro antibacterial activity against both standard laboratory strains and bacteria resistant to quinolones such as ciprofloxacin (CPFX, 1) and ofloxacin (OFLX, 2) from clinical isolates. The 8-methyl (8a), 8-fluoro (9a), 8-chloro (10a) and 8-methoxy (12a) compounds were 4 times more potent than CPFX (1) against both gram-positive and gram-negative bacteria. But these four compounds caused injury to the chromosomes of mammalian cells at a concentration of 100 micrograms/ml. Next, a series of quinolones having various substituents (H, C1, Me, NH2, NHMe, NMe2) at the C-5 position was prepared and evaluated for antibacterial activity and injurious effect on the chromosome. We found that the 5-amino-8-methyl compound (8d) showed strong antibacterial activity (in vitro antibacterial activity of 8d is 4 times more potent than that of CPFX (1) against both gram-positive and gram-negative bacteria), reduced injury to the chromosome, and reduced quinolone-type toxicity (free from both phototoxicity at a dosage of 30 mg/kg in guinea pigs (i.v.) and convulsion-inducing activity when coadministered with fenbufen at dosage of 100 mg/kg in mice (i.p.)). PMID- 8689719 TI - Characterization of carbohydrate-peptide linkage of acidic heteroglycopeptide with immuno-stimulating activity from mycelium of Phellinus linteus. AB - The carbohydrate-peptide linkage in acidic heteroglycopeptide from Phellinus linteus was characterized. Amino acid analysis showed large amounts of serine and threonine. Beta-Elimination results in the reduction of serine and threonine and a subsequent increase in alanine after reduction. These results indicated the presence of O-type linkage in the polymer. PMID- 8689720 TI - Amino acids and peptides. XXVII. Solid phase synthesis of fibrinogen-related peptides with disulfide bond formed on solid support. AB - Fibrinogen-related peptides, monomeric cyclic peptides through a disulfide bond [cyclo(H-Cys-Arg-Gly-Asp-Phe-Cys-NH2), cyclo(H-Cys-Arg-Gly-Asp-Phe-Cys-Gly-NH2), cyclo(H-Cys-Arg-Gly-Asp-Cys-NH2) and cyclo(H-Cys-Arg-Gly-Asp-Cys-Gly-NH2)], were prepared by the solid phase method with disulfide bond formation on the solid support. The acetamidomethyl group was used for protection of the thiol group of Cys and synthetic peptide-resins were treated with iodine to give the disulfide bond. Monomeric cyclic peptides were obtained as main products. Purified S acetamidomethylated peptides were also oxidized with iodine, but the desired materials could not be isolated by HPLC. The disulfide formation from S acetamidomethylcysteine-containing peptide resin by iodine treatment on the solid support was more effective than that from S-acetamidomethylcysteine-containing peptide. The inhibitory effect of the cyclic peptides on platelet aggregation were much more potent than that of H-Arg-Gly-Asp-NH2. PMID- 8689721 TI - Synthesis and characterization of a carbene-generating biotinylated lactosylceramide analog as a novel chromogenic photoprobe for GM3 synthase. AB - A new biotinylated lactose derivative bearing a nitro-substituted chromogenic diazirine was synthesized. The biotinyl group within the structure enabled the performance of a convenient assay of GM3 synthase based on avidin-biotin technology, and the Km values of this biotinylated photoprobe were determined as 40 and 47 microM using bovine brain and rat liver Golgi as enzyme sources, respectively. Furthermore, the sialylation of lactosylceramide, a natural acceptor substrate for GM3 synthase, was competitively inhibited by this synthetic analog. The reagent could be a useful chromogenic photoprobe for GM3 synthase. PMID- 8689722 TI - Cholestane glycosides from Solanum abutiloides. AB - From the roots of Solanum abutiloides, glycosides of 26-hydroxy- and 26 aminocholestane were obtained and their structures were characterized. Both of them were regarded as key intermediates in the biogenesis of steroidal alkaloids. PMID- 8689723 TI - Inhibitory effects of catechol derivatives on hydrophilic free radical initiator induced hemolysis and their interaction with hemoglobin. AB - The effects of pyrocatechol and its monosubstituents on the hemolysis of bovine erythrocytes induced by the hydrophilic free radical initiator, 2,2'-azobis(2 amidinopropane)dihydrochloride (AAPH), were investigated. Relatively hydrophilic derivatives such as the 4-COO- substituent (protocatechuic acid), which are almost completely ionized at physiological pH, have a more inhibitory effect than the more hydrophobic derivatives such as the 4-C(CH3)3 substituent. In the presence of relatively low concentrations of the latter derivatives, the onset of hemolysis was retarded, but the hemolysis then proceeded more rapidly and the time, at which almost complete hemolysis occurred, was almost the same as that in their absence. Regression analysis on the relationships between the inhibitory effects of the derivatives and their redox potentials and hydrophobic parameters revealed that the inhibitory activity of the catechol derivatives on AAPH-induced hemolysis was controlled by low hydrophobicity as well as electron donor activity. In the presence of relatively hydrophobic catechol derivatives, oxidation of hemoglobin was observed. These findings suggest that interaction of these derivatives with hemoglobin after their penetration erythrocytes reduced the scavenging activity against free radicals. Their interaction with membrane or cytoplasmic components may cause the increased hemolysis rate after the onset of hemolysis at relatively low concentrations. PMID- 8689724 TI - Six trigalactosylceramides from the leech (Hirudo nipponica). AB - Six neutral glycosphingolipids were isolated in the pure state from the leech, Hirudo nipponica (Annelida). In contrast to the zwitterionic monogalactosylceramides carrying a choline phosphate group so far obtained, all compounds are non-zwitterionic glycosphingolipids, trigalactosylceramides. Five compounds possess a Ga1 alpha 1-6Ga1 alpha 1-6Ga1 beta 1-Cer core, and one is unique in having a Ga1 alpha 1-6Ga1 beta 1-Cer structure. Their full structures have been determined on the bases of chemical and spectral evidence. PMID- 8689725 TI - Meisenheimer rearrangement of azetopyridoindoles. VIII. Synthesis and antiviral activities of 12-carbaeudistomin analogs. AB - Eudistomins, isolated from the colonial tunicate Eudistoma olivaceum, have been a synthetic target due to their strong antiviral activity against Herpes simplex virus (HSV-1) and activities against certain types of tumors in vivo. In order to examine the structure-activity relationship of eudistomins, 12-carbaeudistomin analogs were synthesized and their activities against influenza A and B virus, HSV-1, HSV-2 and human cytomegalovirus were investigated. Among them, racemic 6 methoxy-12-carbaeudistomin showed similar activity to (-)-debromoeudistomin K, synthesized as a control compound. PMID- 8689726 TI - meso-DNAs with homopurine sequences: analysis of their interaction with natural DNAs. AB - Two homopurine sequences of meso-DNAs (DNAs having an alternating sequence of 2 deoxy-L-ribose and 2-deoxy-D-ribose in their sugar moieties), d(LADG)5 and d(LGDA)5, were prepared. Both d(LADG)5 and d(LGDA)5 interacted with the corresponding complementary natural DNAs, d(DCDT)5 and d(DTDC)5, respectively. In the interactions, pH-dependent duplex/triplex selectivity was observed, i.e., meso-d(Pu)10 formed a duplex at pH 7.5 and a triplex at pH 5.0 with the complementary D-d(Py)10. The meso-d(Pu)10/D-d(Py)10 complex showed a CD spectrum similar in shape to that of the natural complex, suggesting that meso/natural complexes form right-handed helices. At pH 7.5, ethidium bromide intercalated into both d(LADG)5/d(DCDT)5 and d(LGDA)5/d(DTDC)5 duplexes. A clear difference between d(LADG)5/d(DCDT)5 and d(LGDA)5/d(DTDC)5 was observed at pH 5.0. Addition of ethidium bromide did not affect the formed d(LADG)5/d(DCDT)5 triplex, and ethidium bromide did not intercalate into the triplex. On the other hand, d(LGDA)5 did not form a triplex with d(DTDC)5 in the presence of ethidium bromide even at pH 5.0, but it formed a duplex. Ethidium bromide intercalated into the duplex at pH 5.0. PMID- 8689727 TI - Synthesis and trazodone-like analgesic activity of 4-phenyl-6-aryl-2-[3-(4 arylpiperazin-1-yl)propyl]pyridazin -3-ones. AB - A series of 4,6-diaryl pyridazinones, chemically related to trazodone, ws synthesized and evaluated for analgesic activity. With ED50 values ranging from 8.4 to 46.7 mg kg(-1) i.p. in the phenylbenzoquinone-induced writhing test (PBQ test), most compounds were several times more potent than acetaminophen (ED50 = 231.3 mg kg(-1) i.p.) and noramidopyrine (ED50 = 68.5 mg kg(-1) i.p.). A multiple linear regression analysis demonstrated a correlation between antinociceptive activity and lipophilicity, as well as electronic and steric factors. The most active pyridazinones 2c and 2j exhibited minimal sedative and neurotoxic effects at the dose of 25 mg kg(-1) i.p. They were devoid of activity in the hot plate test and their analgesic activity was not significantly reversed by naloxone in the PBQ test. The antinociceptive response induced by morphine (0.15 mg kg(-1) s.c.) in the PBQ test was greatly potentiated by 2c and 2j administered at the low doses of 1 and 2.5 mg kg(-1) i.p., respectively. On the other hand, their analgesic effects were enhanced synergistically by 5-hydroxytryptophan combined with carbidopa. All these data imply that a significant part of the antinociceptive effect induced by 2c and 2j may involve both opioid and serotonergic pathways. In addition, these two pyridazinones did not exhibit any antidepressant properties in the forced swimming test, nor did they potentiate yohimbine-induced toxicity. PMID- 8689728 TI - 5-Alkoxyimidazoquinolones as potential antibacterial agents. Synthesis and structure-activity relationships. AB - 4-Substituted 6-cyclopropyl-6, 9-dihydro-5-methoxy-9-oxo-1H-imidazo[4,5-f] quinoline-8-carboxylic acids (6) and 8-substituted 1,5,6,11-tetrahydro-5-methyl-1 oxo-imidazo[4,5-g]pyrido[1,2,3-de][1,4] benzoxazine-2-carboxylic acids (7) were prepared as potential antibacterial quinolone derivatives. The appendages at C-4 of -6 and at C-8 of -7 were selected from 1-piperazinyl, 4-methylpiperazinyl, 3 aminomethylpyrrolidinyl, and 3-aminomethylpyrrolidinyl groups. The 5 methoxyimidazoquinolones 6 were superior to the corresponding ofloxacin type analogues 7 in in vitro antibacterial activity. The activity of 6 was equipotent against S. aureus, but 2 to 16 times less potent against E. coli and P. aeruginosa compared to that of the 5-fluoro analogue 3. PMID- 8689729 TI - Novel 5-hydroxytryptamine (5-HT3) receptor antagonists. I. Synthesis and structure-activity relationships of conformationally restricted fused imidazole derivatives. AB - We prepared a novel series of conformationally restricted fused imidazole derivatives 4b, 4c and 4d (possessing 4,5,6,7-tetrahydroimidazo[4,5-c] pyridine and substituted 4,5,6,7-tetrahydro-1H-benzimidazole for 4b, 5,6,7,8 tetrahydroimidazo[1,2-a]pyridine for 4c and 5,6,7,8-tetrahydroimidazo[1,5 a]pyridine for 4d as a basic amine part and (2-methoxyphenyl)aminocarbonyl group as an aromatic-carbonyl part). Their activities were then evaluated as an 5 hydroxytryptamine (5-HT3) receptor antagonist which may be useful for the treatment of irritable bowel syndrome (IBS) as well as for nausea and vomiting associated with cancer chemotherapy. The most potent compound was N-(2 methoxyphenyl)-4,5,6, 7-tetrahydro-1H-benzimidazole-5-carboxamide 14 in this series with an ID50 value of 0.32 microgram/kg on the von Bezold-Jarisch reflex in rats and an IC50 value of 0.43 microM on the isolated colonic contraction in guinea pig, approximately ten and two times more potent than ondansetron 1, respectively. The structure activity relationships (SAR) study suggested that the high potency of 14 may be attributed to the suitable position and direction of the N-C-N centroid in the conformationally restricted imidazole ring against the planar (2-methoxyphenyl)aminocarbonyl part in the binding of 14 to the receptor. PMID- 8689730 TI - Coaggregation between Porphyromonas gingivalis and Treponema denticola. AB - To elucidate an ecological profile of several periodontopathogens, the authors examined the coaggregation between cells of Porphyromonas gingivalis and oral bacterial strains including Treponema denticola in vitro. Coaggregation between cells of plaque bacteria was examined by visual assay and phase-contrast microscope. P. gingivalis cells coaggregated with strains of T. denticola and Treponema socranskii subspecies socranskii, but did not coaggregate with T. socranskii subspecies buccale, T. socranskii subspecies paredis, Treponema vincentii, or Treponema pectinovorum. The extracted hemagglutinin from P. gingivalis was active agglutinating T. denticola cells. Addition of serum and saliva somewhat affected the coaggregation, but no effects of tested sugars or amino acids were found. Heat treatment of T. denticola cells did not reduce the coagregation: heat treatment of P. gingivalis cells eliminated it. Growth inhibitory activity among these bacterial species was examined by the stab culture method. Strains of T. denticola ATCC 35404 and 35405 and T. vincentii inhibited the growth of some P. gingivalis strains, but not others. No strain of Treponema was inhibited by black-pigmented anaerobic rods. The coaggregation observed between P. gingivalis and T. denticola indicates the potential importance of their simultaneous existence in human periodontal pockets and development of the disease. PMID- 8689731 TI - Isolation of dental papilla from young rat lower incisor by three step digestion. AB - In order to establish an in vitro model system, a three step digestion procedure, trypsin + collagenase pretreatment, followed by trypsin or collagenase treatment, and then trypsin posttreatment, was employed for the dissociation of rat lower incisors into dental papilla and enamel organ. Both the pre- and post-treatments promoted destruction of the basement membrane located between the dental papilla and enamel organ, resulting in effective dissociation of the tissues. The isolated dental papilla, including differentiating odontoblasts, was well preserved after this treatment. The results indicated that the three step digestive treatment may be very useful in isolating the dental papilla from the rat-incisor enamel organ accompanied by the basement membrane. The material provides a model system for studying odontoblast differentiation, development, and maturation in vitro. PMID- 8689732 TI - In vitro study of differentiating odontoblasts in isolated rat incisor dental papillae. AB - The dental papillae isolated from rat incisor were examined morphologically and autoradiographically in order to investigate progressive odontoblast differentiation in vitro. Four to eight days after incubation, the preodontoblasts which were labelled with 3H-thymidine became elongated, polarized, odontoblast-like cells with long cytoplasmic processes. They produced an 3H-proline labelled extracellular matrix on the substrate with which the dental papillae were coated. In addition, the odontoblasts located on the initially formed predentin maintained their ordinary shape as elongated cell bodies with long cytoplasmic processes and polarity fo the organelles during the term of culture. The results indicate that the surface of the agar gel substrate may be a critical requirement for odontoblast differentiation, development, and maturation in the absence of both the basement membrane and the enamel epithelium in the culture system used in this study. PMID- 8689733 TI - Histo-pathological study of a glass-ionomer/resin (Geristore) restoration system. AB - The purpose of this experiment was to investigate histo-pathologically the pulpal reaction to a glass-ionomer/resin (Geristore) restoration system in human teeth. Black's class I cavities were prepared in 22 human teeth; these were divided into 2 groups, one with the Geristore after cavity was cleaned with 10% NaOCl solution and 3% H2O2 solution (Group G) and the other with the Geristore after the cavity was applied with Mirage-Bond (Group MG). The treated teeth were observed clinically over 90 days after operation. They were then extracted for histological examination. No unpleasant symptoms were noted. A few pathological changes were observed. No histo-pathological score differences were observed between groups G and MG. The average evaluation score of pathological results in both groups G and MG were excellent. Microorganisms observed in the cavity dentin of the group G was fewer than in group MG. In some cases, microorganisms were observed along the dentin walls. In conclusion, the pulpal injury due to this Geristore restoration system was slight, and the system was considered to be safe for the pulp and clinically useful. PMID- 8689734 TI - Effect of initial therapy on dynamics of immunogloblin G levels to some periodontopathic bacteria in serum and gingival crevicular fluid. AB - Using enzyme-linked immunosorbent assay, the IgG antibody levels to specific gram negative periodontopathic bacteria in serum of 21 adult periodontitis patients and the gingival crevicular fluid (GCF) from 42 sites with destructive lesions and 21 healthy sites were evaluated before and after initial preparation. Porphyromonas gingivalis, Bacteroides forsythus, Prevotella intermedia, Prevotella nigrescens, Campylobacter rectus, Treponema denticola and Actinobacillus actinomycetemcomitans in subgingival plaque samples from the patients were examined by indirect immunofluorescence microscopy. Subgingival plaque, GCF, and serum samples were taken at baseline and three weeks after initial preparation. For 14 patients, changes in clinical parameters due to the initial preparation were correlated with reduction of periodontopathogens and to IgG antibody levels in GCF and serum against them. P. gingivalis, T. denticola and C. rectus were found to be predominant in destructive sites. No significant differences were found in GCF IgG antibody levels between destructive and healthy sites. In destructive sites, the prevalence of P. gingivalis and C. rectus was significantly correlated with elevated IgG antibody against these microorganisms in GCF. The initial preparation resulted in significant reduction of serum IgG antibody levels against all microorganisms tested. No decrease in GCF IgG antibody was observed, but levels to P. gingivalis and C. rectus were significantly increased (p<0.05). The assessment of GCF IgG antibodies to specific periodontopathic bacteria may be of considerable value in reflecting the conditions of periodontitis. PMID- 8689736 TI - The 57 kDa protein is a major antigen in the outer membrane of invasive Porphyromonas gingivalis strains. AB - The antigenicities of the outer membranes from invasive strains of Porphyromonas gingivalis were characterized by double and triple immunostaining of Western blots. It was found that a protein estimated at approximately 57 kDa is a major antigen in the outer membrane of invasive P. gingivalis strains. PMID- 8689737 TI - Evaluation of dimensional stability of elastomeric impression materials during disinfection. AB - Disinfection of impression materials is recommended for preventing cross contamination in dental clinics. However, aspects of the evaluation of elastomeric impression materials only slightly subjected to the effects of disinfectants have not been established. Therefore, the effects of sodium hypochlorite, glutaral, iodine, and ethanol disinfectants on elastomeric impression materials, condensation silicone, polysulfide, addition-type silicone (vinyl silicone), hydrophilic vinyl silicone, and polyether, were evaluated directly in a time-dependent manner by a non-contact displacement meter. Condensation silicone impression materials and polysulfide rubber impression materials greatly shrank over time, but their shrinkage decreased with immersion in disinfectants. Vinyl silicone impression materials and polyether impression materials showed excellent dimensional stability in air. However, hydrophilic vinyl silicone impression materials and polyether impression materials expanded greatly when immersed in disinfectants, especially when immersed in ethanol. Hydrophobic vinyl silicone impression materials showed excellent dimensional stability regardless of the presence or absence of disinfectants. PMID- 8689735 TI - Detection of methicillin-resistant staphylococcus aureus in human saliva and on denture surfaces. AB - The prevalence of Staphylococcus species and methicillin-resistant Staphylococcus aureus (MRSA) in human saliva and on denture surfaces was examined with selective media. A total of 166 saliva samples from dental students and individuals using dentures and 39 swab samples from denture surfaces were subjected in this study. The detected percentage of MRSA from saliva samples was 2.3%. Five out of 39 swab samples of denture surface contained MRSA or methicillin-resistant Staphylococcus epidermidis (MRSE). The isolated MRSA and MRSE were resistant to beta-lactam antibiotics. PMID- 8689738 TI - Estimation of fluoride intake in relation to F, Ca, Mg and P contents in infant foods. AB - The purposes of this present study were to determine F, Ca, Mg and P contents of infant foods available in Thailand and Japan in relationship to ionization of F from dietary sources and also to estimate the daily F intake of infants during the first six months of life. Samples of 31 and 24 foods from Thailand and Japan were analysed. Microdiffusion technique was used to separate F from food samples. The combination of an F electrode with an ion analyzer was used to determine F. Determination of Ca and Mg of ashed samples were carried out by the atomic absorption spectrophotometry and Chen, Toribara and Warner method was used in P analysis. F content found in infant formulas and supplemented foods were generally low, especially in infant foods in Thailand, while Ca, Mg and P contents were high in various food items tested. The estimation of daily F intake showed that foods cannot provide an infant with a daily F intake at the optimal level. The results of this study indicate that some food constituents play significant roles in daily F intake by influencing F absorption. PMID- 8689739 TI - Eliminating effects of an air purifier on infectants during dental procedure. AB - Blood and drill dust from dental plaque microorganisms, teeth, and filling materials can cause environmental pollution in the dental clinic. Currently, as a preventive measure against air pollution from a patient's mouth during dental treatment, dust-collecting aspirators such as an extra-oral vacuum aspirator (EOVA) are coming into general use. We tested the eliminating effects by the EOVA with the plaque solution aerosol and the aerosol from drilling a tooth by examining the distribution of floating aerosol in the air turbine's tank when a plaque solution was sprayed and when a human tooth was drilled with a plaque solution. We concluded that infectious aerosol increases in diameter with the drilling of human teeth to the size of about 0.5-5.0 micrometers, which is microbiologically and hygienically hazardous and also can be inhaled without much difficulty. PMID- 8689740 TI - The structural patterns and mineralization values of prismless enamel, a case of mild enamel hypoplasia. AB - In examining the prismless enamel (PL) distribution from the inner to surface layers of a human incisor with hypoplastic perikymatas with enamel pits, we determined the structural patterns and mineralization values by microradiographic, optical, and scanning electron microscopic observations. The PL containing abnormal prisms ranged from 20 to 250 micrometers in thickness. The alternated layers of the PL and prismatic enamel, in parallel with the Retzius lines, showed a roughly zigzag pattern based on the main orientation of enamel crystals. Such a pattern suggests an alternation of the disappearance and reappearance of Tomes' processes, which may have strong restorative and reactive capacities. In the mineralization values determined by microradiography, the PL was higher in the well-marked lines of Retzius, while the PL under the hypoplastic enamel pit and an area within the thick PL showed hypomineralization. The backscattered electron images indicated that the fine laminate striations and abnormal prismatic rows within the PL were hypomineralized, and the PL in the inner enamel showed a lower mineralization than the adjacent prismatic layer. Thus, the disappearance of Tomes' processes, which form prismless structures, may be unrelated to changing the mineral amount in amelogenesis. PMID- 8689741 TI - Cell surface polysaccharide and protein antigens of an encapsulated Porphyromonas gingivalis 16-1 strain. AB - We have extracted the cell surface polysaccharide antigen (PS) and protein antigen from an encapsulated and virulent strain of Porphyromonas gingivalis 16 1. The PS was separated from lipopolysaccharide (LPS) by Sephacryl S-300 gel chromatography. It was distinguished from LPS by immunodiffusion with homologous rabbit antiserum. The PS reacted specifically with serogroup b antiserum against P. gingivalis 16-1 and Su63 strains, but not with antisera against serogroup a (ATCC 33277) or serogroup c (W83). The outer membrane protein was extracted with the Zwittergent 3-16 and sarcosyl detergents in a Tris-EDTA buffer. SDS-Page analysis revealed that the extracted protein antigen of P. gingivalis 16-1 contained 2 immunodominant proteins with molecular weights of 41 KDa and 27 KDa. PMID- 8689742 TI - A clinical evaluation of guided tissue regeneration in the treatment of class II and class III furcation bony defects. AB - This investigation was designed to compare the clinical efficacy of open flap/expanded polytetrafluoroethylene (e-PTFE) membrane combination therapy to open flap therapy alone in the treatment of class II and class III furcation bony defects. The efficacy was evaluated by statistical analysis of the change in values for probing pocket depth, gingival recession, and relative (probing) attachment level. The statistical analysis indicated that the guided tissue regeneration (GTR)-applied group had better efficacy than the non-applied group in the treatment of furcation bony defects. Moreover, the GTR-applied maxillary group had better efficacy than the GTR-applied mandibular group, and the GTR applied class III group was better than the GTR-applied class II group. These results were diametrically opposed to the results from the non-applied class II group. These results were diametrically opposed to the results from the non applied group. By histological examination, new attachment of newly formed cementum with inserting of oriented collagen fibers was noted. We also found new bone formation and partial bone repair in the former furcation bony defect. PMID- 8689743 TI - Observer performance in the assessment of contract enhanced CT: effects of contrast medium and grey scale window on detection of defects in a simulated peripheral rim border. AB - The image contrast of X-ray CT systems depends on the properties of the imaging system, the number of grey scales used in the digital sampling process, and the addition or otherwise of a contrast medium. The effect of contrast medium is often emphasized in the peripheral rim of pathologic masses. In this study, a special hexagonal test object made of acrylic phosphate and a cylindrical container were employed. When the contrast medium IOPAMIRON 300 was used to fill the space between the test object and its cylindrical container, a contrast enhanced peripheral rim with or without signal of defect was observed. Visual perceptibility was examined from the signals resulting from varying contrast by use of contrast medium and adjusting the grey scale by image processing. Threshold contrast influenced by window width was recorded in each image contrast, different ranges of window width was recorded in each instance using statistical analyses. While window width was inversely proportional to image contrast, different ranges of window width and image contrast provided better visual perceptibility for each concentration of the contrast medium. The range of window width for obtaining the best visual perceptibility was determined for a contrast-enhanced image. PMID- 8689744 TI - Objective and subjective assessments of Kodak Ektaspeed plus new dental X-ray film: a comparison with other conventional X-ray films. AB - A new dental X-ray film called EKTASPEED Plus has been released by the Eastman Kodak Company. Its sensitometric properties, inclusive of modulation transfer function (MTF) and Wiener spectrum (WS) and the visibility of radiographic details, were compared with those of other conventional dental X-ray films, EKTASPEED EP-22 (Eastman Kodak Co.) and Ultra-Speed DF-57 (Eastman Kodak Co.). The base plus fog density of EKTASPEED Plus was between those for EKTASPEED and Ultra-Speed. Relative speed of EKTASPEED Plus was slightly faster than EKTASPEED, and about two times faster than that of Ultra-Speed. The contrast of EKTASPEED plus was close to that of Ultra-Speed. Only minor differences existed between the film types studied when the sharpness and the granularity were compared. The MTF and WS also revealed no substantial differences between the films. Perceptibility testing showed minor differences between the three films, with EKTASPEED Plus consistently revealing more defects at lower exposures irrespective of whether a Burger's phantom or aluminum test block was used. PMID- 8689745 TI - A modified device for long term sampling of parotid saliva in various experimental conditions. AB - A parotid cup has been widely used as an intraoral device for the collection of parotid saliva. However, in long duration sampling, the cup tends to disconnect under circumstances such as mastication, sleep or physical exercise. We have designed a modified device of parotid cup for saliva collection to overcome these unfavorable conditions. The parotid cup was modified by fixing it to the bite plate appliance which was adjusted individually to the occlusal plane in order to avoid disconnection of the cup under varying conditions. Using this device, we could measure salivary flow rate during mastication, sleep or physical exercise. Additional advantages of this device are that it is easy to make with acrylic resin and is inexpensive. The preliminary study using this device showed that flow rates of unstimulated parotid saliva varied from 0.06 +/- 0.04 ml/min. to 0.16 +/- 0.10 ml/min. (mean +/- s.d) from 7 a.m. to 12 p.m. in 7 subjects. In five subjects, the flow rate of parotid saliva during meal (lunch) was much higher than that of resting on a chair, playing table tennis, or sleeping at night for 6-8 hours. This might be considered due to the stimuli of the meal content. Flow rates of saliva were also examined with various stimuli. The results showed that salty pickled plum > sour lemon juice > 10% ascorbic acid > sweet milky candy > 1% ascorbic acid. These data suggest that our modified device is useful for various experiments in salivary research. PMID- 8689746 TI - Purification and characterization of bone morphogenetic protein derived from bovine bone matrix. AB - Bone morphogenetic protein (BMP) was extracted from bovine bone matrix and purified. The 6M guanidine-HCL soluble fraction and the final purified substance were bioassayed by implantation of about 3 mg into the thigh muscles of C3H strain mice. These specimens induced new bone in three weeks when implanted into muscle pouches of the C3H mouse. The final fraction purified by liquid chromatography (fraction III) was shown to be homogeneous by sodium dodecyl sulfate-polyacrylamide slab gel electrophoresis (SDS-PAGE). The molecular weight of the bovine bone matrix-derived BMP was estimated to be about 14-18 kDa in MW. The main components correspond to a MW of 18 kDa and 14 kDa when they are compared with the mobilities of standard proteins. These were invariably present in fractions with osteoinductive activity. PMID- 8689747 TI - Suprahyoid myotomy from an extraoral approach. AB - On several occasions, the suprahyoid muscles have been detached from the lingual surface of the mandible at the same time as sagittal split advancement procedures in treatment of class II malocclusion and/or open bite patients. We usually perform suprahyoid myotomy through a degloving type incision (the Steinhauser technique) when genioplasty is planned. However, sometimes genioplasty is not necessary. In such cases, we perform the myotomy through a small submental skin incision. This method has some advantages: 1. Surgical stress is less and operating time is shorter than the Steinhauser method. 2. The risk of detachment of the major portion of the genioglossus muscles is lower than in the Allison method. We present this procedure of suprahyoid myotomy carried out from an external approach. PMID- 8689748 TI - The effects of delta-opioid receptor agonists on synaptic transmission in hamster submandibular ganglion. AB - The effects of agonists for delta-opioid receptors on synaptic transmission in hamster submandibular ganglion were studied in vitro, using an intracellular recording technique. [Met5]enkephalinamide (17 microM), [D-Ser2?Leu-enkephalin Thr (14 microM) and [D-Pen2, D-Pen5]enkephalin (10 microM), delta selective agonists caused reversible depression of the fast EPSP amplitude in 10 of 30 cells tested. The inhibitory actions of [D-Pen2, D-Pen5]enkephalin were antagonized by ICI 174,864, a delta selective antagonist. Naloxon a non-selective antagonist and ICI 174,864 both also potentiated the fast EPSP amplitude in 5 of 11 cells tested. PMID- 8689749 TI - Case report of lateral crossbite. Part I. Mixed dentition. AB - Lateral crossbite on mixed dentition does not always cause facial asymmetry or functionally abnormal movement of the mandible in children. However, it is often observed that facial asymmetry will worsen during growth in the absence of orthodontic treatment. In adult cases, lateral crossbite is one of the etiological factors of temporomandibular joint disorder. This case report presents two cases of lateral crossbite of mixed dentition. The terms of treatment were shorter than those in cases with permanent dentition. Also, methods of treatment were simpler, and the patients developed favorably. The opposite results were obtained in cases of permanent dentition. PMID- 8689750 TI - Study of a Pd-Ag-Sb system alloy for metal-ceramics. AB - The present study is aimed at developing a palladium silver based alloy containing antimony and other elements for metal-ceramics. Composition 54.2Pd 36.2Ag-4.7Sb-2.9In-1.0Sn-1.0Ga++ + (alloy No. 10) was finally selected as the best for practical applications. Liquidus and solidus temperatures of this alloy were 1,250 degrees C and 1,087 degrees C. Under fired conditions, the Vickers hardness number, tensile strength, and elongation were 270, 647 MPa, and 3.4%, respectively. In the temperature range from 20 degrees C to 600 degrees C, the thermal expansion rate was 0.87%, and the thermal expansion coefficient was 15.0 X 10(-6)/degrees C. The mechanical and manipulation properties of this alloy were satisfactory for clinical applications. PMID- 8689751 TI - An electron microscopic study of the processes of nerve regeneration after lyophilized nerve homografting. AB - The objective of the present study was to investigate the role of the Schwann cell basal lamina in nerve regeneration. To achieve this goal, we observed the process of axonal regeneration within a lyophilized nerve graft, in which only the basal lamina of the Schwann cell persisted. Sciatic nerves were removed from rats and lyophilized to kill the Schwann cells and other components. These grafts were transplanted to rat sciatic nerve defects. The rats were then killed after lapses of time. We observed the processes of axonal regeneration using a transmission electron microscope. Regeneration of axons along the inner surface of the Schwann cell basal lamina was clearly seen. These results suggest that, if tubular basal laminae persist, Schwann cells are not always necessary, and axonal regeneration can be induced in the direction toward the basal lamina. PMID- 8689752 TI - Microvascular free tissue transfer in oral and maxillofacial reconstruction. AB - Forty-two patients with head and neck cancer were submitted to microvascular reconstructive procedures. We divided patients in three groups; a first group of 30 patients, in whom the oral floor (8 patients), the part of tongue (14 patients), the lower gingiva (6 patients) and the oropharynx (2 patients) were reconstructed using various sizes of forearm flaps; a second group of 7 patients who underwent buccal mucosa reconstructions with the forearm flaps; and a third group of 5 patients who received rectus abdominis flaps for total tongue reconstruction. Three illustrative cases, one from each group, are presented in detail. Good results were obtained in 39 patients (94%), with both functional and morphological rehabilitation. There were three flap losses due to thrombosis of the microvascular anastomoses. There was no surgical mortality. The average operating time was about 10 hours in total. We concluded that there is a place for these complex procedures in the treatment of selected cases of head and neck tumors. PMID- 8689753 TI - Stability of occlusion after orthodontic treatment with tooth extraction in adult cases. AB - The purpose of this study was to evaluate stability of occlusion in adult cases at least 4 years after orthodontic treatment and to clarify parameters influencing this stability. The subjects were 25 cases (mean age: 19 y 8 m) who had been treated with Edgewise technique involving first-premolar extraction. During orthodontic treatment, decreases in the maxillary and mandibular incisors' irregularity index (Max.I.I. and Mand.I.I.), posterior movement of the upper and lower incisors, increases in upper incisal height, decreases in lower incisal height, and increases in upper and lower canine width were noted. In the posttreatment period, increases in Max.I.I. and Mand.I.I., anterior movement of incisors, increases in incisal height, and decreases in canine width were observed. The amounts of overjet and overbite decreased during the treatment period and increased during the post-treatment period. Multiple regression analysis was useful to deduce which parameters influenced stability of occlusion after orthodontic treatment. PMID- 8689754 TI - Studies on the development of the articular part of the temporal bone with special reference to the postglenoid process. AB - The development and significance of the postglenoid process on the articular surface of the temporal bone were studied using 217 Indian skulls, which were divided by their level of tooth eruption into 6 developmental stages; preeruption period (Stage I), initial stage (m1 eruption) of the deciduous dentition period (Stage II), middle stage (m2 eruption) of the deciduous dentition period (Stage III), late state (eruption of 20 deciduous teeth) of the deciduous dentition period (Stage IV), mixed dentition period (Stage V), and permanent dentition period (Stage VI). Each skull was mounted on a Kraniophor in such a way that the auriculoorbital (Frankfurt) plane was positioned vertical to the horizontal plane and photographed at a focal distance of 40 cm. Using the Frankfurt plane as a base line, the vertical distances to the lowest point of the postglenoid process (a-A), to the deepest point of the mandibular fossa (b-B), and to the mid-point of the articular tubercle (c-C) were measured. The distances from various points of the mandibular fossa to the articular surface of the temporal bone were measured at the level of the Frankfurt plane. The results may be summarized as follows: The length of the postglenoid process as measured from the Frankfurt plane was 0.58 mm at Stage I and 0.75 mm at Stage II. It increased by 0.6-1.0 mm at each developmental stage. By Stage VI, it had increased to 3.85 mm (six- to seven-fold increase from the initial value). The anteroposterior width of the postglenoid process remained almost unchanged throughout the developmental stages. The growth of the articular structures of the temporal bone from the preeruption to deciduous dentition period increased 73% in the total anteroposterior dimension (5.22 mm) and 44% in the total vertical dimension (3.32 mm). The vertical dimension of the mandibular fossa began to rapidly increase following the eruption of the deciduous first molars. PMID- 8689755 TI - An application of powder metallurgy to dentistry. AB - Generally, the dental casting method is used to fabricate dental prostheses made with metal. The method of fabricating dental prostheses from sintered titanium alloy has certain advantages: the elimination of casting defects, a sintering temperature that is lower than the melting point, and a shorter processing time. By examining (1) the properties of green, sintered compacts of titanium powder, (2) the effects of adding aluminum powder on the properties of green, sintered compacts of Ti-Al compound, and (3) the effects of adding copper powder on the properties of green, sintered compacts of Ti-Al-Cu compound, the authors developed a sintered titanium alloy on a trial basis. Because the properties satisfied the requirements of dental restorations, a powder metallurgical method of making dental restorations from this sintered titanium alloy was devised. Applications of such sintered titanium alloys for the metal coping of metal ceramic crowns and denture base plates were discussed. PMID- 8689756 TI - Dental health indicator based on a questionnaire. AB - Dentistry has lacked an effective indicator of the impact of dental problems on a person's daily life. Subjective factors in dental health need to be included in order to improve current indicators. The purpose of this research was to develop a new type of indicator recorded from a questionnaire which takes account of subjective factors in dental health. The indicator we constructed has the following advantages. 1. Calculation process is simple in practice. 2. The indicator values range from 0 to 100, with values closer to 100 indicating a more favorable condition for the individual. 3. The distribution of indicator values is similar to the normal distribution. 4. The score of each item is reflected on the indicator, suggesting the individual's characteristics in terms of dental health. 5. Although it is principally an indicator for individuals, it can also be applied to groups. This study will also provide a model for the preparation of a dental health indicator. PMID- 8689757 TI - Transfer to a nitrocellulose membrane allows of the bone forming activity of bone morphogenetic protein. AB - When we purify bone morphogenetic protein (BMP), its activity diminishes, and the quantity we are able to extract decreases. It is difficult to evaluate the effects of each of the processes involved in BMP purification because it is unstable. In order to resolve the problem, a modified bioassay method using only slight quantities of BMP which do not decrease its bone-forming activity, is needed. We transferred BMP separated by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) onto nitrocellulose membranes (NC) and cut out the bands. Then we used each band as implanted material. The NC membrane firmly bound the BMP activity fraction and held it in the implantation area of the mouse thigh. No formation of bone-like tissue was detected histologically at 14 days after the implantation, but, by 21 days after implantation, cartilage like tissue had clearly formed and newly formed bone was seen by 28 days. By implanting BMP transferred to individual NC membranes, we could perform a bioassay easily with small amounts of BMP without any reduction in activity. PMID- 8689758 TI - A study on prevention of hospital infection control caused by tooth preparation dust in the dental clinic. Part 1. Preventive measures against environmental pollution in the dental clinic caused by microbial particles. AB - Tooth preparation dust, an indispensable part of dental treatment, contains bacteria and viruses. In order to examine environmental pollution in the dental clinic during tooth preparation, we monitored microorganism spread by counting colony forming units (CFU) with the "Andersen Microbe Sampler." This test was conducted in a "Clean Booth." Mitis-salivarius medium was used to count the oral streptococcus species. The ability of the "Extra-Oral Vacuum Aspirator (EOVA)" to effectively eliminate contamination was also tested, and the EOVA was found to reduce the spread of oral-streptococci, significantly. The EOVA was therefore viewed as an effective method for reducing air pollution in the dental clinic, and should be used when treating patients with certain infectious diseases. PMID- 8689759 TI - Topical retinoids and cutaneous biology. PMID- 8689760 TI - Evaluation of the 2-mm punch biopsy in dermatological diagnosis. AB - This prospective study was undertaken to determine whether the 2-mm punch biopsy technique yields specimens of sufficient size and quality to allow a reliable histological diagnosis to be made. A histopathological comparison was made between tissue obtained from a 2-mm punch biopsy and a standard ellipse biopsy taken from a wide range of dermatoses and benign and malignant skin tumours. In 79 of the 84 cases studied, the same histopathological diagnosis was reached with the 2-mm punch biopsy and the standard ellipse. Use of the 2-mm punch biopsy technique produces specimens which allow an accurate histological diagnosis to be made in a wide range of dermatological conditions. Skin biopsy techniques should ideally be quick and easy to perform, yielding specimens of high quality and adequate size while leaving the smallest possible tissue defect and a good cosmetic result. The aim of this study was to compare the effectiveness of the 2 mm punch biopsy with that of the standard ellipse biopsy technique in providing skin specimens which permit an accurate pathological diagnosis to be made. PMID- 8689761 TI - Likely photosensitizing agents available in the United Kingdom--an update. PMID- 8689762 TI - An histological and ultrastructural study of the 'dirty neck' appearance in atopic eczema. AB - The 'dirty neck' appearance is a characteristic disorder of pigmentation, which has previously been found to affect approximately 2% of adult atopics. This disorder results in a rippled pattern of hyperpigmentation similar to that seen in macular amyloidosis. Biopsy specimens from affected skin of three patients were examined by histological and electron microscopical techniques. In addition to eczematous changes, marked pigmentary incontinence was observed. Amyloid-like material was detected by electron microscopy but not by light microscopy in all three specimens. Some deposition of amyloid occurs in this condition but the pigmentary changes are attributable to melanin incontinence. In 1987, two separate groups, Manabe et al. and Colver et al., described a distinctive type of hyperpigmentation, found particularly on the neck in some patients with chronic atopic eczema. Manabe's group found that 1.7% of 700 patients with atopic eczema showed this clinical characteristic, and that only adolescents and adults were affected. This condition has been called the 'dirty neck' appearance or 'ripple pigmentation of the neck in atopic dermatitis'. The clinical features are a rippled pattern of hyperpigmentation seen particularly on the anterior and lateral aspects of the neck (Fig. 1). We have also observed the same appearance in the inguinal areas. A number of factors could contribute to the development of hyperpigmentation in chronic atopic eczema. It is possible that the 'dirty neck' appearance is a form of post-inflammatory pigmentation due to previous eczema, ultraviolet exposure or even the application of photosensitizing products, and that the rippled appearance is related to the cutaneous anatomy of the neck. The pathogenesis of the 'dirty neck' is obscure, but in common with previous authors, we have noted that the rippled appearance of the hyperpigmentation resembles that seen in macular amyloidosis. In order to determine whether deposition of amyloid contributes to the development of this type of pigmentation in atopic dermatitis, an histological and ultrastructural examination of skin biopsies from three patients with the condition was undertaken. PMID- 8689763 TI - Bullous pemphigoid--a report of 86 cases from Taiwan. AB - We reviewed 86 cases of bullous pemphigoid and the results were compared with those reported in the literature. Seventy-eight per cent of the patients developed generalized blisters and 22% had localized blisters, including three cases of dyshidrosiform pemphigoid and one case of pretibial pemphigoid. Oral mucosal involvement was noticed in 12.8% of the patients. Fifteen per cent of the patients had internal malignancies but the incidence was not significantly different from the control group. Direct immunofluorescence in our series showed a high positive rate of 98.8%. Indirect immunofluorescence was positive in 48.1% of the 54 patients in whom this was carried out. Peripheral blood eosinophilia was observed in 22.1% of the patients. Prednisolone alone or in combination with immunosuppressive agents was the mainstay of treatment. Treatment side-effects was observed in 33% of the patients. Thirty per cent of the patients had a complete remission after a mean follow-up period of 26.9 months. Bullous pemphigoid (BP) is a chronic debilitating autoimmune blistering disease. It is characterized clinically by generalized tense bullae and histologically by subepidermal blisters. Immunofluorescence is crucial in the diagnosis and shows linear deposits of C3 and/or IgG at the basement membrane zone (BMZ). Information regarding this disease in Chinese patients is quite limited. In this study, 86 patients with BP were reviewed. The clinical and histological features, immunofluorescence, modes of therapy and outcome were studied. PMID- 8689764 TI - Clinical manifestations in 100 Japanese bullous pemphigoid cases in relation to autoantigen profiles. AB - The relationship between clinical findings and antigen profiles in 100 bullous pemphigoid (BP) patients has been investigated. The patients were divided into four groups based upon the results of immunoblot analysis, namely patients whose sera detected the 230-kDa BP antigen (BP230) and the 180-kDa BP antigen (BP180), those recognizing either BP230 or BP180 alone, and those recognizing neither antigen. Analysis by the chi-squared test showed predominant occurrence of oral (P < 0.05) and facial lesions (P < 0.005) in patients whose sera detected BP180, and these patients also tended to have more extensive lesions (P < 0.005). Patients that were positive for BP180 alone needed treatment with higher doses of steroids than the patients positive for BP230 alone (P < 0.05). Furthermore, all five recalcitrant cases, which did not respond well to steroid treatment, were shown to possess autoantibodies against BP180 in their sera. Patients with antibodies to BP230 had a tendency to have a high titre of anti-BMZ antibodies (P < 0.005). These results suggest that anti-BP180 antibodies may be more related to the disease severity than anti-BP230 antibodies. Bullous pemphigoid (BP) is an autoimmune blistering disorder characterized clinically by tense blister formation and immunologically by the presence of tissue-bound and circulating antibasement membrane zone (BMZ) autoantibodies. A number of immunoblot analyses have indicated that two major antigenic proteins of epidermal extracts, the 230 kDa BP antigen (BP230 or BPAG1) and the 180-kDa BP antigen (BP180, BPAG2 or type XVII collagen), are detected by sera from patients with BP in various patterns. Some BP sera recognize both antigen proteins, while others detect only BP230 or BP180 or none. Recently, cDNAs for these antigens have been isolated, and the characteristics for these molecules have been investigated in more detail. The exact relationship between these two proteins is still unclear; however, more recent studies showed that BP180 has an extracellular domain and polyclonal rabbit antibodies raised against an extracellular non-collagenous domain of the murine BP180 antigen were pathogenic in a passive transfer model. Several investigators have suggested a relationship between clinical findings and laboratory data in BP. Arbesman et al. compared the extent and duration of the disease with age, serum levels of IgE, IgA and IgG and titre of anti-BMZ antibodies. The results indicated that serum level of IgE and IgA correlated significantly to the extent of the disease and that titre of anti-BMZ antibodies correlated significantly (only in males) to the duration. There has been only one report which has analysed the relationship between pemphigoid antigens and clinical findings or laboratory data; no correlation was found. In a previous study, the reactivities of BP sera by immunoblotting using human epidermal extracts and two recombinant polypeptides produced from a mouse cDNA clone BPM1 were examined. The results of immunoblotting using epidermal extracts revealed that the two major BP antigens, BP230 and BP180, were detected by 74% and 51% of BP sera, respectively. Comparison of the clinical data with BP antigens gave the impression that the cases whose sera reacted only with BP180 were clinically more severe and less respondent to steroid treatment than the cases which detected BP230 alone on immunoblots. In the study reported here we have examined further the relationship between clinical and immunoblot data by applying a statistical analysis to the results previously obtained. PMID- 8689765 TI - Endothelial cell activation in cutaneous vasculitis. AB - Markers of endothelial cell activation were measured in 28 patients presenting with various forms of limited or focal type cutaneous vasculitis. Plasma levels of tissue plasminogen activator antigen (t-PA:Ag), plasminogen activator inhibitor type 1 antigen (PAI-1:Ag) and PAI-1 activity, fibrin plate, von Willebrand factor antigen (vWF:Ag), tissue factor (TF) and soluble thrombomodulin (sTM) were measured. In comparison with the control group (n = 20) there was a significant increase in t-PA:Ag, vWF:Ag and TF (P < 0.05, Mann-Whitney U-test) in the cutaneous vasculitis group. This study confirms that measurable degrees of endothelial activation occur in cutaneous vasculitis. Cutaneous vasculitis includes a diverse group of clinical conditions, which are associated with inflammatory changes in cutaneous blood vessels with local fibrin deposition. The aetiology and pathogenesis of the majority of these entities remain unknown. Causative mediators are thought to include immune complexes, anti-endothelial cell antibodies, cytotoxic lymphocytes and viruses. Histologically, immune complexes and complement are frequently detected on the vessel wall, and serologically anti-endothelial antibodies are often detected in patients with vasculitis and in systemic lupus erythematosus (SLE) which correlate with the severity of cutaneous vasculitis, arthritis and nephritis. Lymphocyte-mediated toxicity to endothelial cells has been reported in a small number of patients with giant cell arteritis and Takayasu's arteritis. The vascular endothelium plays a central part in the control of haemostasis. Under physiological conditions endothelial cells present an anticoagulant surface to blood constituents, partially due to surface expression of heparan sulphate and thrombomodulin (TM). Heparan sulphate binds antithrombin III (ATIII), thereby accelerating inactivation of intrinsic coagulation enzymes. Thrombomodulin is an endothelial cell surface glycoprotein which promotes anticoagulation by forming a complex with thrombin which then activates protein C. Activated protein C together with a cofactor, protein S, inactivates FVa and FVIIIa. von Willebrand factor (vWF) is synthesized by endothelial cells, stored in Weibel-Palade bodies and released into the circulation upon endothelial stimulation. vWF mediates the binding of platelets to the subendothelium and is the carrier molecule for FVIIIC. The endothelium controls fibrinolysis by producing t-PA and its inhibitor PAI-1. Inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor (TNF) activate endothelial cells, causing a shift from an antithrombotic to prothrombotic state, including expression of tissue factor, increased synthesis of PAI-1 and decreased expression of TM. Fibrin deposition and intravascular thrombosis are seen in cutaneous vasculitis syndromes, suggesting local endothelial cell activation. The aim of this pilot study was to assess whether perturbation of the endothelium in cutaneous vasculitis could be detected in the patients' plasma samples. If so, further studies to assess any correlation in levels of these markers with disease activity might prove useful in the future. PMID- 8689767 TI - Absence of human T-lymphotrophic virus type I in patients with systemic lupus erythematosus. AB - The role of the human T-cell lymphotropic/leukaemia virus type I (HTLV-I) in the pathogenesis of autoimmune diseases of unknown cause, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS) or Sjogren's syndrome (SS) has been discussed extensively. We have investigated whether SLE is in any way associated with exogenous HTLV-I. Using enzyme immunoassay (EIA), we found no seroreactivity against HTLV-I antigens in any of 24 SLE patients under investigation. Using a radioimmunoprecipitation assay (RIPA), there was also no expression of retroviral tax-protein demonstrable in 24 individuals with SLE. DNA preparations of peripheral blood cells, as well as isolated CD4- and CD8-positive cells, were examined for HTLV-I sequences (pol-, env-, gag-, LTR- and tax-region) using polymerase chain reaction (PCR). We were unable to demonstrate any specific HTLV I PCR products in SLE specimens. Our data suggest that exogenous HTLV-I is not involved in the pathogenesis of SLE. Systemic lupus erythematosus (SLE) is a multisystem disease of unknown cause characterized by B-cell hyperactivity with hypergammaglobulinaemia and the formation of pathogenic autoantibodies. Patients may also show altered suppressor/helper T-cell ratios. Abnormalities in T-cell function include T-cell lymphopenia, expression of activation antigens and alteration of responses to mitogens and lymphokines. Human retroviruses are known to cause immune aberrations, such as diminished T-cell function and polyclonal B cell stimulation, which are observed in patients with leukaemias, lymphomas and the acquired immunodeficiency syndrome (AIDS). Human T-cell lymphotropic/leukaemia (HTLV-I) is aetiologically linked with adult virus type I T-cell leukaemia (ATL) and tropical spastic paraparesis. A common feature of the HTLV family is an LTR encoded protein (tax protein, p40tax) which triggers viral protein production in the early stages of a retroviral infection. Detection of p40tax may indicate transcriptional activity of a provirus. Several investigators have examined the possible involvement of HTLV-I in SLE and have produced conflicting results, especially so far as seroreactivity against HTLV-I antigens is concerned. The discovery of HTLV-I like particles in murine lupus might also indicate an important role of exogenous viruses in SLE. Olsen and colleagues describe a high seropositivity to anti-HTLV-I- and anti-HTLV-III antibodies and evidence of viral replication in patients with SLE. Lin et al. also demonstrated anti-HTLV-I antibodies in SLE patients. However, other authors failed to detect anti-HTLV-I antibodies, proviral structures or viral transcripts in SLE. We investigated whether or not there are any indications of the presence of the exogenous retrovirus, HTLV-I, in patients with SLE, at immunological and genetic levels. We found neither immunological nor molecular biological evidence for the existence of HTLV-I in SLE patients. There were some weak suggestions of the presence of possibly endogenous retroviral sequences. PMID- 8689766 TI - Effects of H1- and H2-antihistamines on platelet-activating factor and bradykinin induced inflammatory responses in human skin. AB - Previous studies show that oral antihistamines affect the weal and flare response to intradermal injections of the inflammatory mediators platelet-activating factor (PAF) and bradykinin (BK). The aim of this study was to compare the effects of terfenadine (an H1-antagonist) and cimetidine (an H2-antagonist) on weal and flare responses to PAF and BK in healthy non-atopic human volunteers. The effects of doxepin on PAF responses were investigated, as there is evidence that doxepin may have direct anti-PAF effects in addition to its known antihistaminic actions. Terfenadine significantly reduced weal and flare responses to PAF (mean reduction 53 and 73%, respectively) and flare responses to BK (mean reduction 78%) but had no effect on weal responses to BK. Doxepin significantly reduced both weal and flare responses to PAF (mean reduction 43 and 68%, respectively, at higher doses of PAF). Cimetidine had no effect on weal or flare responses to PAF or BK. These findings suggest that the flare response to intradermal BK is mediated via histamine release while the weal response is not. The effects of the various antagonists of PAF-induced responses suggest that its effects too may be mediated via histamine, the similarity of the effects of terfenadine and doxepin on these responses indicating that the effects of doxepin may be due to its known antihistamine activity rather than to any specific PAF antagonistic properties. Platelet-activating factor (PAF) is a phospholipid which is released from a wide range of cell types and also from vascular endothelium. PAF is formed by the conversion of ether-linked phospholipids initially to the biologically inactive lyso-PAF and then by acetylation to PAF. Intradermal injection of PAF in human skin causes vasodilatation and increased vascular permeability, producing a weal and flare response with accompanying pruritus. Bradykinin (BK) is a vasoactive polypeptide formed by the action of enzymes known as kallikreins on inactive precursors called kininogens. Its effects include an increase in blood flow and vascular permeability and stimulation of the release of prostaglandins and histamine. On intradermal injection in human skin it causes a weal and flare response with associated pain rather than pruritus. Previous studies have suggested that the weal and flare response to PAF may be mediated in part by histamine release. Given that BK is known to cause histamine release it appears possible that the responses to both compounds may be modified by conventional antihistamines. Experiments based on this premise have found that antihistamines have a pronounced effect on the flare response to PAF but a less marked effect on weal responses. The weal response to BK was unaffected by systemic antihistamines but studies have produced conflicting results with regard to effects on the flare response. The aim of this study was to compare the effects of terfenadine (an H1-antagonist) and cimetidine (an H2-antagonist) on PAF- and BK-induced weal and flare responses in healthy, non-atopic human volunteers. Based on the treatment of cold urticaria it has been suggested that doxepin, which has known H1- and H2-antagonistic effects, may in addition show specific anti-PAF activity. We compared the effects of doxepin on PAF-induced intradermal responses with those of terfenadine and cimetidine in this study. PMID- 8689768 TI - Multiple keratoses and squamous carcinoma after PUVA treatment of vitiligo. AB - PUVA is known to be carcinogenic when used in the treatment of psoriasis. To date skin cancer has not been demonstrated after PUVA treatment of vitiligo. We report a patient in whom multiple squamous cell carcinomata and keratoses developed in vitiligo areas after a prolonged course of PUVA. PUVA therapy of vitiligo induces repigmentation of affected skin in some patients. An increased frequency of cutaneous neoplasms in depigmented areas is a potential hazard, as in these sites the photoprotective effect of melanin is lacking. PMID- 8689769 TI - Photosensitivity induced by fleroxacin. AB - A case of photosensitivity induced by fleroxacin (FLRX) is reported. A 71-year old man had erythema on sun-exposed areas after 5 months FLRX treatment for prostatitis. The minimal erythema dose to UVA was reduced at the initial examination and became normal 4 weeks after he stopped taking FLRX. Oral photo challenge with FLRX 100 mg was positive, but photopatch testing was negative. Fleroxacin (FLRX), in use since 1992, is a fluoroquinolone antibacterial derived from quinoline. Photosensitivity induced by FLRX is not uncommon, but a photobiological study has not been reported. The mechanism of action of photosensitivity induced by the fluoroquinolones is considered to be phototoxic in origin in that in vitro technique studies are positive. FLRX, a quinoline derivative may be a photosensitizer as well as enoxacin, lomefloxacin and sparfloxacin. PMID- 8689770 TI - Disseminated superficial porokeratosis: what is the association with ultraviolet radiation? AB - A female patient is presented who consistently developed lesions of disseminated superficial porokeratosis (DSP) whilst on holiday abroad. The lesions resolved completely within 4-6 weeks of return to the UK. Induction of the lesions by exposure to artificial sources of UVA and UVB was unsuccessful. Disseminated superficial porokeratosis (DSP) is thought to be a clonal disorder of keratinization and the histological hallmark is the cornoid lamella. The aetiology of DSP is unclear although it has been suggested that local or systemic immune suppression may allow the development of mutant clones of keratinocytes. Chernosky and Freeman first proposed an actinic aetiology for DSP in 1967 but the mechanism of induction is unclear. PMID- 8689771 TI - Annular elastolytic giant cell granuloma--actinic granuloma? AB - A 56-year-old woman with annular elastolytic giant cell granuloma is reported. She had annular, slowly growing lesions on sun-exposed areas and the dorsum of one foot. Biopsies from both areas revealed a mid-dermal inflammatory infiltrate with many giant cells engulfing elastic fibres. The current nosological situation of this process is discussed. Actinic granuloma (AG) is a term coined by O'Brien in 1975 to describe a cutaneous process characterized by multiple annular lesions located on sun-exposed skin areas. The histopathology is defined by the presence of multinucleated giant cells containing elastic fibres at the lesion edge, and the absence of these fibres at the lesion centre. The nosology of this disease and the role of actinic exposure as a triggering factor for it has been much discussed in recent years. We report a new case of AG not limited to photo exposed areas. PMID- 8689772 TI - Enalapril-induced toxic pustuloderma. AB - Enalapril is widely prescribed for hypertension and cardiac failure. Rashes are an uncommon side-effect, occurring in approximately 1.4% of patients, and in approximately 0.4% of patients the rash is sufficient to require discontinuation of enalapril. (Merck Sharp and Dohme, pers. comm.) We report a case of toxic pustuloderma related to enalapril therapy for congestive cardiac failure. To our knowledge enalapril-induced toxic pustuloderma has not been previously reported. PMID- 8689773 TI - Erosive and generalized lichen planus responsive to azathioprine. AB - Systemic corticosteroids are of value in severe lichen planus which interferes with the patient's life or is ulcerative or where there is nail destruction. Azathioprine has been shown to be effective steroid sparing treatment for generalized lichen planus. We report two patients with severe lichen planus who responded to azathioprine alone and suggest it may be an alternative therapy, especially when there are risk factors against corticosteroid use. Lichen planus accounts for approximately 1% of new presentations to a dermatology unit. It can affect all body areas and markedly interfere with a patient's life. Mucous membrane lesions are common (30-70%) but ulcerative lesions in the mouth are uncommon. Lichen planus seems to be immunologically mediated with evidence favouring a lymphocytotoxic process described in the literature. Treatment is mainly symptomatic and can be difficult. Systemic corticosteroids are of value in treating severe cases where the disease is interfering with a patient's life or when ulcerative mucous membrane lesions have occurred or if there is severe nail destruction. Relapse can occur on cessation of steroids. Azathioprine has been shown to be effective steroid sparing therapy for generalized lichen planus. However, the use of azathioprine alone has not been described. We report two cases of generalized, erosive lichen planus that responded well to azathioprine alone. PMID- 8689774 TI - Milia en plaque--a new site and novel treatment. AB - Milia en plaque is an unusual eruption typically occurring in the retroauricular area. Two cases of this disorder occurring in a novel position and treated with oral minocycline are now reported. PMID- 8689775 TI - Mycosis fungoides associated with unusual epidermal hyperplasia. AB - A 58-year-old white woman presented with widespread pruritic brownish plaques and hyperpigmented flexural lesions with a velvety appearance. On histopathological examination, the macules were diagnostic of mycosis fungoides, plaque stage, and the flexural lesions showed epidermal hyperplasia with a seborrhoeic keratosis like appearance. There was intense mucin deposition and marked reduction of elastic fibres in the papillary dermis, as well as a moderately dense dermal lymphoid infiltrate composed of CD4+ T cells with occasional atypia and focal epidermotropism. The clinical and pathological manifestations of cutaneous T-cell lymphomas, including mycosis fungoides (MF), may show considerable variation. Apart from the three classic stages, a number of unusual clinical presentations and a broad spectrum of histopathological findings have been reported in the literature. In this report, a case of MF, plaque stage, with flexural lesions clinically reminiscent of (pseudo)acanthosis nigricans is presented. On histopathological examination, there was epidermal hyperplasia with a seborrhoeic keratosis-like appearance, with intense deposition of mucin and marked reduction of elastic fibres in the papillary dermis, together with a lymphoid infiltrate composed mainly of CD4+ cells with occasional atypia and epidermotropism. Cytokines produced by the lymphocytes in the infiltrate might account for the epithelial and dermal changes that characterize this peculiar variant of MF. PMID- 8689776 TI - Tuberculous lymphadenitis presenting with cutaneous leucocytoclastic vasculitis. AB - Cutaneous leucocytoclastic vasculitis is an inflammatory vascular disorder due to deposition of immune complexes in dermal vessels. A direct or indirect role of infectious agents in the pathogenesis of such vasculitis has been postulated. We describe a patient with cervical lymphadenitis due to Mycobacterium tuberculosis infection who developed cutaneous vasculitis. The vasculitis resolved with standard antituberculous therapy. The association between leucocytoclastic vasculitis and tuberculous infection has only rarely been reported. Tuberculous infection may present in a number of different clinical forms depending in part on variations in the number and virulence of the bacilli, route of infection, presence or absence of an internal tuberculous focus, age and specific immunity of the host. Although the association between infection and vasculitis is well known, Mycobacterium tuberculosis as a causative agent of cutaneous leucocytoclastic vasculitis is uncommon. PMID- 8689777 TI - Ofuji's disease with unusual histological features. AB - A 20-year-old lady presented with a 3-month history of an itchy eruption affecting her face and trunk. Erythematous annular plaques with follicular papules and pustules at the margins were present on her face consistent with Ofuji's disease. A perifollicular and perivascular eosinophil-rich infiltrate was seen histologically, with infiltration of the follicular epithelium by eosinophils and formation of eosinophilic microabscesses. An unusual feature was the presence of follicular mucinosis. Treatment with dapsone resulted in an improvement in the eruption after 2 weeks. Ofuji's eosinophilic pustular folliculitis is becoming increasingly frequently recognized, and may not be as rare as initial reports suggested. In 1965, Ise and Ofuji reported the case of a Japanese woman who had recurrent episodes of follicular pustules affecting her face and back accompanied by a peripheral eosinophilia. Following this, in 1970 Ofuji et al. reported three further cases and proposed the name eosinophilic pustular folliculitis. Although many of the early cases were in Japanese patients, reports of this disease affecting individuals from Europe and the United States have been increasing. PMID- 8689778 TI - Facial granulomatous lymphoedema and syringomyelia. AB - The term orofacial granulomatosis was introduced for orofacial lesions which resemble Crohn's disease clinically and histologically in patients without gastrointestinal disease. The Melkersson-Rosenthal syndrome and its oligosymptomatic form Meischers granulomatous cheilitis are usually felt to be part of the same spectrum of disease. Oedema usually involves tissues of the lower half of the face. We describe a patient with histological changes consistent with those found in orofacial granulomatosis, but with isolated localized oedema of the right periorbital tissues. The patient also had syringomyelia which has not previously been described in association with orofacial granulomatosis. PMID- 8689779 TI - Cutaneous gangrene due to hyperparathyroidism secondary to chronic renal failure (uraemic gangrene syndrome) AB - Cutaneous and subcutaneous gangrene are serious sequelae of secondary or tertiary hyperparathyroidism which may accompany chronic renal failure. Based on analysis of the present typical case and a retrospective survey of similar cases in the literature, we propose the term 'uraemic gangrene syndrome' for this association. These skin lesions in chronic renal failure patients represent the most serious clinical manifestation of calciphylaxis, a condition originally described by Selye. The appearance of early skin lesions should be regarded as an indication for subtotal parathyroidectomy. The association of cutaneous gangrene with vascular calcification was first described by Bryandt and White in 1989, and was termed by these authors as 'gangrenous calcification'. A total of 80 cases of this rare complication of chronic renal disease had been reported up to early 1994. A retrospective review of these reports has strongly suggested a close interrelationship between renal failure, secondary hyperparathyroidism, vascular calcification and cutaneous gangrene. The present report concerns a characteristic case to draw attention to this syndrome which is accompanied by serious, predominantly cutaneous, changes. PMID- 8689780 TI - Acquired tufted angioma frequently develops at sites other than the neck and upper trunk. PMID- 8689781 TI - [Motor initiation difficulty of right upper extremity induced by tactile stimulation after infarction in the left anterior cerebral artery territory]. AB - We report a patient who manifested motor initiation difficulty of the right upper extremity, which was caused by tactile-stimulation on his right palm or back. The patient was a 62-year-old right-handed man, who showed reduction of spontaneous speech, slight paresis in the right lower extremity, and left unilateral ideomotor apraxia. He initially showed grasping reflex in the right hand, which disappeared in a month. MRI revealed infarction in the left medial frontal lobe and anterior-half of the corpus callosum. He complained that he was not able to initiate to move his right hand after his right palm or back touched something. He showed no paresis, no abnormal muscle tonus, no involuntary movement. Detailed examination revealed that it was an initiation disturbance caused by tactile stimulation on his right palm or back. We concluded that this phenomenon, motor initiation difficulty, is one of the disturbances among motor process such as motor initiation, maintainance, and termination. The medial frontal lobe seems to manage the execution of motor process, therefore, lesions in the frontal lobe cause disturbance of motor process. And tactile-stimulation has a close relation to the reaction through the medial frontal lobe, thus, frontal lobe lesion may cause a misinteraction which retrieves a wrong reaction from a certain stimulation. PMID- 8689782 TI - [Serum levels of soluble adhesion molecules in patients with inflammatory myopathies]. AB - Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured by ELISA in patients with 18 inflammatory myopathies as well as 23 healthy controls. Both serum sICAM 1 and sVCAM-1 levels were elevated in patients with active polymyositis. Serum sVCAM-1 levels were elevated in the active stage of dermatomyositis, while sICAM 1 levels were elevated only in patients with dermatomyositis complicated with interstitial pneumonia. In paired serum samples before and after prednisolone therapy, elevated serum sICAM-1 and sVCAM-1 levels decreased in patients responding well to steroid therapy without complications. These findings suggested that soluble adhesion molecules reflect as the clinical activity of inflammatory myopathies. PMID- 8689783 TI - [Dysphagia following lateral medullary infarction]. AB - We studied 10 patients with lateral medullary infarction. Six patients had severe dysphagia from the onset, and needed tube feeding or intravenous hyperalimentation. Three of these 6 patients resolved dysphagia within 3.5 months. Pharyngoesophagography showed aspiration and pooling in the pharynx in other three patients who showed persisting dysphagia for more than 6 months. The cause of dysphagia was not unilateral paralysis of the pharynx and the larynx. Because there were decreased functions of elevation of the larynx, closure of the vocal cord and the pharyngeal movement, the dysphagia of our patients may be due to disturbance of the neurogenic swallowing control. Persistent dysphagia was associated with anterolateral extension of the infarction in the medulla. Two patients with laryngectomy and permanent tracheostomy were able to be discharged to home. We conclude that surgical treatment is a choice in patients with dysphagia which persists for more than 6 months. PMID- 8689784 TI - [Polymyositis after interferon beta treatment of chronic hepatitis type C]. AB - We reported a case of polymyositis manifested after beta-interferon therapy for chronic viral hepatitis type C. In November 1992, a 62-year-old female was diagnosed as having chronic viral hepatitis type C. In January 1993, she was treated with beta-interferon(total 2.52 x 10(8)IU). In March 1993, after the treatment, she noticed weakness and atrophy of her lower extremities. Neurological examination revealed proximal dominant muscle weakness and atrophy of the extremities. Increased levels of serum CK and aldolase were disclosed on admission. By needle EMG, a low voltage with short duration interference pattern was noted. February 7, by muscle biopsy of the right quadriceps, necrotic myofibers, marked variation in fiber diameter, stromal mononuclear cell infiltration, and endomysial fibrosis was detected. The immunological stain of infiltrating cells in the muscle fibers revealed CD4:CD8 ratio as 64:55, whereas in conventional polymyositis CD8 cells dominate CD4 cells. Diagnosis of polymyositis was made and oral prednisolone 60 mg a day was started. Her symptoms and signs improved gradually and she was discharged after 2 months. Many adverse effects due to immunological disturbances caused by interferon treatment have been reported, but polymyositis due to interferon has been very rare. When interferon will be prescribed, manifestation of polymyositis should be considered. PMID- 8689785 TI - [Localized cardiac uptake defect with 123I-MIBG SPECT in a case with pure progressive autonomic failure]. AB - A 60-year-old man with 3 years' history of autonomic nervous system disturbances such as orthostatic hypotension, anhidrosis and atonic bladder is presented. He had an episode of paroxysmal atrial fibrillation as well. He had neither extrapyramidal nor cerebellar signs, and was diagnosed as having pure progressive autonomic failure. His cardiac SPECT with 123I-MIBG showed the loss of uptake at the apex and the inferior wall and the diminished uptake at lateral walls. But 99mTc-tetrofosmin SPECT following an exercise stress showed a normal cardiac uptake. It was suggested that non-cardiac disease-associated postganglionic sympathetic fiber abnormality began from an inferior wall and would extend to a whole heart in this disease. The cardiac 123I-MIBG SPECT is thought to be useful for localizing the denervated area of cardiac sympathetic nervous system. PMID- 8689786 TI - [Therapeutic trials with topical capsaicin cream and iontophoretically applied lidocaine for diabetic painful truncal neuropathy]. AB - We report a 63-year-old man with a history of diabetes mellitus for 23 years. Painful dysesthesia developed in his toes and trunk with weight loss of 2kg in two months, after the therapy for diabetes mellitus. Truncal painful dysesthesia was symmetrically distributed in the bilateral posterior and anterior T8-11 dermatomes, sparing the bilateral lateral tholacic areas. Electromyography showed denervation potentials in bilateral abdominal rectus muscles at the levels of Th8 10. Histopathological study of the biopsied right sural nerve revealed small fiber neuropathy. We suspected the truncal painful dysesthesia of this patient resulted from diabetic small fiber polyneuropathy, which was resistant to ordinary medical treatments such as non-steroidal anti-inflammatory drugs. Capsaicin cream containing 0.075% capsaicin, and lidocaine delivered by iontophoresis were both effective for his painful dysesthesia. PMID- 8689787 TI - [Visual illusion with 90-degree forward rotation on the sagittal plane due to acute paramedian pontine infarction]. AB - We report an unusual and dramatic type of visual illusion, a 90-degree forward rotation of vision on the sagittal plain in 2 cases of acute paramedian pontine infarction. At initial neurological examination, they were both alert and well oriented. The one case had slight right lateral gaze palsy, left motor paresis and hallucinose pedunculaire, and the other case had slight right gaze palsy, right Horner's syndrome, slight left sensory deficit and left limb ataxia. They complained that they felt as if they themselves, the bed, the floor and the ceiling were standing vertically, although actually they were lying on the bed horizontally. The sensation of the 90-degree rotation of vision frequently occurred as soon as they awoke or opened their eyes, and continued for a few minutes. The illusion disappeared within several days after the onset of the pontiue infarction. These visual symptoms may be contributed to imbalance of the integrated processing among the vestibular, visual and somatosensory systems resulting from the brainstem lesion involving the vestibulo-cortical network fibers, or may be considered as dysfunction of the ascending reticular activating system similar to the mechanism of hallucinose pedunculaire. PMID- 8689788 TI - [A case of posttraumatic spinal pseudomeningocele which caused spinal cord compression 20 years after injury]. AB - We reported an extremely rare case of posttraumatic spinal pseudomeningocele which caused spinal cord compression 20 years after getting injury, and demonstrated that sequelae of an injury may occur many years after the original wound. A 39-year-old man, who got left cervical root avulsion due to a traffic accident when he was 17 years old, began to complain of progressive muscle atrophy and weakness of left lower extremity 1 year ago. Myelography demonstrated pseudomeningocele at left C6-C8 level, and MRI and CT myelography revealed that the pseudomeningocele extends through the intervertebral foramen and compresses the spinal cord to the right side in the spinal canal. Bilateral functional compression of spinal cord dorsal and lateral column was also verified with SEP and MEP electrophysiologically. PMID- 8689789 TI - [Medial medullary infarction following neck manipulation]. AB - Reported is a case of a 39-year-old man with medial medullary infarction following chiropractic neck manipulation. Neurologically, he showed right hemiparesis sparing the face, right deep sensory impairment and tongue deviation to the left in five hours after neck manipulation. A cranial MRI revealed an ischemic lesion in the left medial portion of the medulla oblongata. Cerebral angiography demonstrated no apparent organic lesion of the right vertebral artery (VA), but showed hypoplasia of the left VA. We suspect that the left medial medullary infarction occurred because of the reduced VA blood flow following the contralateral VA compression, in addition to the ipsilateral VA hypoplasia. This case is the first one reported in which medial medullary infarction was possibly induced by neck manipulation. PMID- 8689790 TI - [A case of a thoracic extradural arachnoid cyst presenting with slowly progressive muscle weakness in the right upper and lower limbs]. AB - A 49-year-old woman developed slowly progressive muscle weakness of the right upper and lower limbs. Physical examination revealed exaggeration of deep tendon reflexes in bilateral lower extremities and a Th5-Th6 girdle sensation. Weakness in her right upper extremity suggested cervical or intracranial lesion. Neuroradiological studies detected no abnormalities in her cervical cord and cranium. So the symptoms and signs were similar to those of motor neuron disease except for the sensory disturbance. MRI study of thoracic cord demonstrated a thoracic extradural arachnoid cyst. After removal of the cyst, the patient's muscle weakness was prominently relieved. We postulate that the cyst stretched spinal cord and dura mater, which led to affection of her cervical cord. We propose weakness of an upper limb as a pseudo-localizing sign of a thoracic extradural arachnoid cyst. PMID- 8689792 TI - [A case of cervical liquorrhea with headache in and around the area of the great occipital nerve]. AB - We report a 44-year-old man who had sudden-onset severe pain with ardor at the left occipital and nuchal region without trauma in July, 1992. Severe pain disappeared soon after, but dull pain continued intermittently. Four months later, he was referred to our hospital. Neurological examination showed no abnormalities. Cervical CT scan and myelography disclosed liquorrhea. Digital subtraction myelography confirmed cerebrospinal fluid leakage from the level of C1/2 disc. He underwent laminectomy of C1 and C2, and dural plasty on April 6, 1993 with subsequent disappearance of headache. We suppose that this headache was due to rupture of the root sleeve and compression to the root and dorsal root ganglia by outflowed liquor. PMID- 8689791 TI - [Electrophysiological assessment of median sensory nerve function in HMSN type I by intraneural neurography]. AB - Microneurography (MNG) performed in the forearm segment of the median nerve enabled us to assess compound nerve action potentials reflecting the density of large myelinated sensory fibers around the microelectrode. We examined sensory nerve function of the median nerve in seven patients with hereditary motor and sensory neuropathy type I (HMSN-I) with conventional surface-electrode technique and MNG. In six of seven patients sensory nerve action potentials were not elicited with the surface-electrode method. In contrast, compound nerve action potentials (CNAPs) were evoked in all seven patients with MNG. Although the normal waveform of CNAP is characterized by a large triphasic wave with subsequent small multiphasic waves, the triphasic wave was diminished and prolonged small multiphasic waves were prominent in the patients. Maximal nerve conduction velocity and amplitude of the wave were decreased to 69% and 9% of age matched control values, respectively. These changes detected in patients with HMSN-I could be interpreted as a result of large myelinated fiber loss and segmental demyelination of sensory nerves. We showed that sensory fiber dysfunction in HMSN-I could be quantitatively evaluated with MNG, even though the sensory action potential was not elicited with the surface-electrode method. PMID- 8689793 TI - [A case of erythroleukemia found after multiple cerebral hemorrhage]. AB - A 61-year-old man without hypertension was admitted for unconsciousness. Brain CT showed multiple cerebral hemorrhage of the left frontal lobe and right occipital lobe. The hemoglobin was 7.0 g/dl, the platelet count 7,000, the white-cell count 7,600 with erythroblasts, and the fibrinogen 327 mg/dl. No disseminated intravascular coagulation was found. Bone marrow examination demonstrated 69.2% erythroblasts including abnormal types of nucleus, 12.8% myeloblasts, 12.8% neutrophils, 0.8% monocytes, 4% lymphocytes, and 0.4% reticulocytes. Chromosomal examination showed 7 of 20 bone marrow cells were variously abnormal. A diagnosis of erythroleukemia with major karyotype aberrations (MAKA) was made. The patient died 5 days after admission. Histologically, cerebral hemorrhagic lesions showed complete necrosis, but neither invasion of leukemic cells nor amyloid angiopathy. We suspected that the cause of cerebral hemorrhage was severe loss of platelets. This is a rare case of erythroleukemia found after multiple cerebral hemorrhage. As a cause of cerebral hemorrhage in an old man without hypertension, one should consider not only cerebral amyloid angiopathy but also leukemia. PMID- 8689794 TI - [Immunostaining of mitochondrial heat shock proteins (mtHSPs) in skeletal muscle fibers of mitochondrial cytopathy]. AB - Expression of the mtHSPs (HSP60 and mtHSP70) was immunohistochemicall observed in biopsied limb muscles of genetically determined mitochondrial cytopathies (chronic progressive ophthalmoplegia 14, MELAS 4, limb girdle syndrome with the A to-G transition at nt.3243 of tRNALeu(UUR), exertional myoglobinuria with multiple deletions of mtDNA 2, and Leber's hereditary optic neuropathy 2). mtHSP 70 and HSP 60 were strongly localized at ragged-red fibers. In strongly succinate dehydrogenase-reactive vessels of MELAS, mtHSP70 was expressed. GRP78 was expressed in the cytoplasmic body, which is often observed in this disorder. The present data suggest that expression of mtHSPs may reflect increased numbers of mitochondria, an impairment of assembly of mitochondrial proteins encoded by the genomic DNA and abnormal mitochondrial DNA, and/or an impaired mitochondrial function due to recurrent oxygen radical attacks against mitochondria. PMID- 8689795 TI - [Midmotoraxonal reexcitation observed in a patient with hereditary motor and sensory neuropathy (HMSN) type IA]. AB - We report a unique late motor unit potential observed in a patient with hereditary motor and sensory neuropathy (HMSN) type IA. The characteristics of the potential were as follows; (1) constant appearance with more than 20 mA of the stimuli, without disappearance with supramaximal stimuli, (2) constant wave form and amplitude, (3) shorter latency with more proximal stimulation (indirect pathway), (4) remarkable fluctuation of the latency, and (5) disappearance with paired stimuli. The characteristics (1)-(3) correspond to Tomasulo's "peripheral late wave". But our late potential had fluctuation in its latency and was cancelled by paired stimuli, which indicates that this potential originated from the reflection at the midmotoraxonal demyelinating portion. Demyelinating portion is electrically unstable, where the duration of action potential is elongated. Consequently, nerve action potential at that site continues even after the refractory period is over at the adjacent distal portion, which might be the reason that this reflecting potential was evoked. PMID- 8689796 TI - [A case of left atrial myxoma with repeated ischemia of left anterior cerebral artery territory]. AB - A 52-year-old woman was admitted to our hospital because of paralysis of her right lower limb and dysarthria. After admission, she had exacerbations of paralysis of the right lower limb twice. Brain CT scan revealed a low density area in the left anterior cerebral artery territory. MRI disclosed the lesion of the body of the corpus callosum. On the fifth day, trans-esophageal echocardiography detected a mass lesion in the left atrium. There was no recurrence after treatment with heparin. On the 23rd day, the left atrial mass was removed surgically, which was elastic and soft and was confirmed to be myxoma pathologically. It was suggested that the embolic material originated from an adherent thrombus on the surface of the myxoma, since heparin was effective. She showed unique movements of her right hand like diagonistic dyspraxia. The right hand with mild paresis took away an object held in the left hand. The patient was able to move the right hand voluntarily and to imitate with it. She did not show grasping reflex, instinctive grasp reaction and apraxia of the left hand. The lesion of the body of corpus callosum may be responsible for this peculiar neurological symptom. PMID- 8689797 TI - [Estimation of cardiac function by plasma concentration of brain natriuretic peptide in patients with Duchenne muscular dystrophy]. AB - We investigated the usefulness of the plasma concentration of brain natriuretic peptide (BNP) for evaluating cardiac function in patients with Duchenne muscular dystrophy (DMD). The plasma BNP concentration was measured by immunoradiometric assay in 55 patients with DMD and in 34 healthy subjects. Cardiac function was evaluated by the cardiothoracic ratio (CTR) on chest roentgenogram, left ventricular end-diastolic dimension (LVDd) and fractional shortening (FS) on echocardiogram, and the ratio of ejection time to pre-ejection period (ET/PEP) on mechanocardiogram. The function of skeletal muscle was evaluated in terms of the disability of lower limb function, serum creatine kinase (CK) activity and % vital capacity (% VC). The plasma concentration of BNP was increased in patients with DMD (32.7 +/- 14.8 pg/ml, mean +/- SEM) compared with that in normal subjects (4.3 +/- 0.5 pg/ml). Two of the DMD patients had symptoms of heart failure, with markedly increased plasma BNP concentrations. The other DMD patients with increased plasma BNP concentrations showed abnormal cardiac function but no symptoms of heart failure. In addition, in patients with DMD, the plasma BNP concentration showed significant positive correlations with CTR and LVDd (p < 0.01), and negative correlations with ET/PEP and FS (p < 0.01). In severe DMD patients who had advanced disability and decreased CK activity, the plasma BNP concentration tended to be elevated. There was no significant correlation between the plasma BNP concentration and % VC. These findings suggest that the plasma BNP concentration is useful for evaluating cardiac dysfunction, whether manifest or latent, in patients with DMD, in whom accurate evaluation of cardiac function by conventional methods is difficult due to severe muscle atrophy and deformity of the thorax. PMID- 8689798 TI - [Midbrain hemorrhage presenting with trochlear nerve palsy--a case report]. AB - A case of midbrain hemorrhage with isolated trochlear nerve palsy was reported. A 70-year-old female noticed vertical diplopia of insidious onset. Ouclar motility was normal. But her diplopia increased with right head tilt and in the left downward gaze, and disappeared with left head tilt. She had no other neurological symptoms and signs. CT scan revealed high density spot in the left tectum of lower midbrain. This lesion decreased over months but small high density spot existed five months later, which means calcified lesion, probably vascular anomaly. This is the first stroke case of trochlear nerve palsy without other neurological symptoms and signs. The first reason this patient showed isolated trochlear nerve palsy is that hematoma was small. The second is that hematoma developed slowly. PMID- 8689800 TI - The use of ultrasonography in the labor and delivery suite. AB - Ultrasonography has increasingly become essential in the practice of obstetrics and gynecology. Its antenatal use is well described in the literature and is a continuing subject of study. However, the use of ultrasonography in the labor and delivery suite has not been the subject of many articles. The purpose of this chapter is to review the pertinent literature along with the experience of the authors in order to define the role of ultrasonography in the Labor and Delivery Suite. PMID- 8689799 TI - Management issues for the neonatal patient. AB - Immediate management needs of the neonate are defined in terms of the physiology of maternal-fetal gas transport and the oxyradical hypothesis of cellular injury as it pertains to hypoemic-ischemic encephalopathy. Resuscitation, stabilization, and assessment needs are defined as related to outcome and factors of information systems. Psychosocial and legal issues are included as factors in neonatal management. PMID- 8689801 TI - Vaginal birth after cesarean delivery. AB - The rate of vaginal birth after a previous cesarean delivery continues to rise due to both national organization recommendations and trials spanning 10 years of experience demonstrating its effectiveness and general safety. Broadening eligibility criteria and investigation of the clinical and nonclinical factors influencing this rate should place us on the glide path to reduction of the overall cesarean rate by the year 2000. Remaining controversies and management strategy will be discussed. PMID- 8689802 TI - Intrapartum management of breech presentation. AB - Breech presentation is associated with significantly increased risk of perinatal morbidity and mortality. Most of the morbidity and mortality associated with breech delivery results from cord compression, nuchal arm, and difficulty in the delivery of the aftercoming head. Routine cesarean delivery of term breeches may not be an unreasonable option, according to many physicians. In our view, the best results for vaginal delivery are achieved using strict protocols that select term or near-term frank breeches of normal size and with proper demonstration of pelvic dimensions. Serious consideration for cesarean delivery should be given to all others. If cesarean delivery is chosen for the very low-birth-weight infant, it is important to use a vertical uterine incision and appropriate anesthesia techniques to ensure atraumatic delivery and optimize out-come. ECV is safe and effective for reducing the incidence of breech presentation but will have little, if any, impact on the overall cesarean delivery rate. PMID- 8689803 TI - Critical management of the very low birth weight infant and macrosomic fetus. AB - The two extremes of birth weight ( < 1500 g and > 4000 g) require antepartum surveillance and anticipation of complications during labor and delivery. Prognosis for the very low birth weight carries with it inherent neurologic impairment even when cared for under the best of conditions. In contrast, the macrosomic fetus enjoys a generally excellent outcome regardless of management. The current concern is too much intervention to avoid a low probability of complications. PMID- 8689804 TI - Intrapartum management of multiple gestations. AB - The proper intrapartum management of multiple gestations continues to be debated in the obstetric community. Ultrasonography is key in this management, through its initial assessment of the fetuses in the labor and delivery suite, observations of the second twin after the first has delivered, and its role in external cephalic version. The proper route of delivery requires further investigation for each combination of twin presentations and estimated fetal weights. It is recommended that the nonvertex second twin that is greater than 24 weeks' gestational age and fewer than 1700 g estimated fetal weight should have an attempt made at ECV and, if unsuccessful, a cesarean section should be performed. In the nonvertex second twin weighing greater than 1700 g, ECV or assisted breech extraction is appropriate. It is believed that all triplet gestations should be delivered abdominally. The use of intravenous nitroglycerin for uterine relaxation in multiple gestations is still experimental but may prove to be useful in the abdominal delivery of the nonvertex fetus. Further research is required to elucidate the most critical issues associated with the labor and delivery management of multiple gestations. PMID- 8689805 TI - Survey of clinical pharmacology training in the United States and Canada. AB - A survey of 139 medical schools in the United States and Canada was conducted in 1993-1994 to determine where active training programs in clinical pharmacology were located. A secondary survey of clinical pharmacology program directors followed in 1994-1995. Thirty-nine active programs were identified where 113 fellows (84 physicians and 29 nonphysicians) were enrolled. Sixty-eight percent of current physician fellows were trained in internal medicine before they entered their clinical pharmacology program. Forty-four percent of trainees were reported to be U.S. citizens. Fewer than 20 fellows complete training each year. The reported content of training programs was 12% didactic, 72% research, 12% clinical service, and 9% supervised teaching. Funding sources for trainees varied considerably. Nearly 50% of trainees were supported all or in part by funds from the National Institutes of Health (NIH), and approximately 40% relied on international sources of support. No correlation between salary and funding source or fellow degree was found. Nearly two-thirds of recent program graduates obtained employment in an academic setting, whereas 15% entered the pharmaceutical industry. These data indicate that subspecialty training in clinical pharmacology is available at 39 medical schools in the United States and Canada. Current fellowship training is primarily research based and nearly equally supported by NIH and international sources. PMID- 8689806 TI - Buprenorphine and naloxone interactions in opiate-dependent volunteers. AB - OBJECTIVE: Sublingual buprenorphine appears useful in the treatment of opiate dependence. A combination sublingual dose of buprenorphine and naloxone could have less potential for parenteral use by opiate-dependent individuals. To estimate the abuse potential of a combination formulation, we assessed the parenteral effects of a buprenorphine and naloxone combination in untreated heroin addicts. METHODS: Eight healthy, opiate-dependent daily users of heroin were given, under double-blind conditions on four separate occasions, either (1) 2 mg buprenorphine, (2) 2 mg naloxone, (3) 2 mg buprenorphine and 2 mg naloxone combined, or (4) placebo as a single intravenous infusion during a 30-second interval. Opiate agonist and antagonist physiologic and subjective effects were measured. Data were analyzed by analysis of variance. RESULTS: Buprenorphine increased opiate intoxication and relieved withdrawal. The buprenorphine and naloxone combination precipitated opiate withdrawal and was unpleasant and dysphoric in all subjects. Fifty percent of the subjects were unable to distinguish between naloxone alone and the combined medications during the first hour of testing. CONCLUSIONS: The buprenorphine and naloxone combination has a low abuse potential in opiate-dependent daily heroin users. PMID- 8689807 TI - First-pass metabolism of midazolam by the human intestine. AB - The in vivo intestinal metabolism of the CYP3A probe midazolam to its principal metabolite, 1'-hydroxymidazolam, was investigated during surgery in 10 liver transplant recipients. After removal of the diseased liver, five subjects received 2 mg midazolam intraduodenally, and the other five received 1 mg midazolam intravenously. Simultaneous arterial and hepatic portal venous blood samples were collected during the anhepatic phase; collection of arterial samples continued after reperfusion of the donor liver. Midazolam, 1'-hydroxymidazolam, and 1'-hydroxymidazolam glucuronide were measured in plasma. A mass balance approach that considered the net change in midazolam (intravenously) or midazolam and 1'-hydroxymidazolam (intraduodenally) concentrations across the splanchnic vascular bed during the anhepatic phase was used to quantitate the intestinal extraction of midazolam after each route of administration. For the intraduodenal group, the mean fraction of the absorbed midazolam dose that was metabolized on transit through the intestinal mucosa was 0.43 +/- 0.18. For the intravenous group, the mean fraction of midazolam extracted from arterial blood and metabolized during each passage through the splanchnic vascular bed was 0.08 +/- 0.11. Although there was significant intersubject variability, the mean intravenous and intraduodenal extraction fractions were statistically different (p = 0.009). Collectively, these results show that the small intestine contributes significantly to the first-pass oxidative metabolism of midazolam catalyzed by mucosal CYP3A4 and suggest that significant first-pass metabolism may be a general phenomenon for all high-turnover CYP3A4 substrates. PMID- 8689808 TI - Erythromycin-felodipine interaction: magnitude, mechanism, and comparison with grapefruit juice. AB - OBJECTIVE: To investigate a potentially marked effect by erythromycin on felodipine pharmacokinetics, to characterize the mechanism, and to compare the interaction with that between grapefruit juice and felodipine. METHODS: Felodipine, 10 mg extended release, was administered with 250 ml water, 250 mg erythromycin, or 250 ml grapefruit juice in a randomized crossover study of 12 healthy men. Erythromycin base, 250 mg four times a day, was started the day before and continued on that study day. Pharmacokinetic values of felodipine, the primary metabolite dehydrofelodipine, and the major secondary derivative M3 metabolite were studied. RESULTS: Compared with water, erythromycin produced severalfold higher felodipine area under the plasma drug concentration-time profile (AUC), plasma peak drug concentration (Cmax), and apparent elimination half-life (t1/2); however, the effect was variable among individuals. Erythromycin augmented dehydrofelodipine AUC, Cmax, and t1/2 but decreased dehydrofelodipine/felodipine ratios. The AUC of the M3 metabolite and the M3 metabolite/dehydrofelodipine ratios were reduced. These findings support inhibition of both metabolic pathways likely mediated by CYP3A4. Grapefruit juice produced similar mean effects but did not prolong felodipine or dehydrofelodipine t1/2. Individually, felodipine AUC with erythromycin was greater than or similar to that with grapefruit juice. Relative felodipine AUC (erythromycin compared with grapefruit juice) correlated with relative felodipine Cmax but not with relative felodipine t1/2, suggesting felodipine AUC differed between these treatments, mainly from factors affecting presystemic drug elimination. CONCLUSIONS: Erythromycin produced an important pharmacokinetic interaction with felodipine by inhibition of drug metabolism. Although erythromycin and grapefruit juice shared a common mechanism, erythromycin likely reduced felodipine biotransformation at the gut wall and liver, whereas single-dose grapefruit juice had an effect mainly at the gut wall. PMID- 8689809 TI - Flavanone absorption after naringin, hesperidin, and citrus administration. AB - Disposition of citrus flavonoids was evaluated after single oral doses of pure compounds (500 mg naringin and 500 mg hesperidin) and after multiple doses of combined grapefruit juice and orange juice and of once-daily grapefruit. Cumulative urinary recovery indicated low bioavailability ( < 25%) of naringin and hesperidin. The aglycones naringenin and hesperitin were detected in urine and plasma by positive chemical ionization-collisionally activated dissociation tandem mass spectrometry (PCI-CAD MS/MS). After juice administration, PCI-CAD MS/MS detected naringenin, hesperitin, and four related flavanones, tentatively identified as monomethoxy and dimethoxy derivatives. These methoxyflavanones appear to be absorbed from juice. Absorbed citrus flavanones may undergo glucuronidation before urinary excretion. PMID- 8689810 TI - Steady-state serum concentrations of the neuroleptic perphenazine in relation to CYP2D6 genetic polymorphism. AB - Steady-state serum concentration to dose ratios of the neuroleptic agent perphenazine were related to CYP2D6 metabolizer status for 96 psychiatric inpatients: 88 extensive metabolizers and eight poor metabolizers. The median concentration per dose of the poor metabolizer group (0.195 nmol/L per milligram) was about twice the median (0.098 nmol/L per milligram) of the 56 extensive metabolizers without interacting medicine (p < 0.01). The rest of the extensive metabolizers (n = 32), who were comedicated with drugs that compete with perphenazine for metabolism by CYP2D6, had an intermediate median value of 0.140 nmol/L per milligram. The range of concentration/dose values for the total extensive metabolizer group extended from 0.025 to 0.688 nmol/L per milligram, that is, an almost thirtyfold variation. The concentration/dose range of the eight poor metabolizer subjects was 0.096 to 0.750 nmol/L per milligram. Serum levels not corrected for dose overlapped to a large degree among the groups, with a total range from 0.5 to 12 nmol/L. This study points toward a limited information value of CYP2D6 genotyping in the context of therapeutic drug monitoring of perphenazine. PMID- 8689811 TI - Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics. AB - BACKGROUND: Divalproex sodium has been found to be efficacious in the prophylaxis of migraine headaches and the management of the manic phase of bipolar syndrome. Because amitriptyline is also prescribed in these patient populations, data are needed on their potential for interaction. METHODS: The effect of concomitant administration of divalproex sodium on the pharmacokinetics of amitriptyline and its active metabolite, nortriptyline, was investigated in an open-label, sequential, two-period phase I study. Ten healthy male and five healthy female subjects received 50 mg amitriptyline hydrochloride on two occasions: (1) alone (period 1) and (2) 2 hours after receiving the ninth dose of 500 mg divalproex sodium (Depakote) administered once every 12 hours (period 2). RESULTS: Amitriptyline area under the curve was increased 31% from the combined effect of decreased first-pass metabolism and inhibition of systemic metabolism. The elevated nortriptyline plasma levels reflected primarily the increase in amitriptyline concentrations but also appeared to involve modest inhibition of nortriptyline elimination. For the sum of amitriptyline and nortriptyline concentrations, the peak plasma concentration mean was 19% higher with concomitant divalproex dosing. The mean area under the curve for the sum of amitriptyline and nortriptyline concentrations was 42% higher with concomitant divalproex dosing than it was for dosing with amitriptyline alone. CONCLUSION: These results suggested that a lower dose of amitriptyline might be considered when divalproex is administered concomitantly. PMID- 8689812 TI - Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. AB - BACKGROUND: Lovastatin is a cholesterol-lowering drug that can cause myopathy as a rare side effect. Concomitant use of certain drugs (e.g., cyclosporine) increases the risk of skeletal muscle toxicity. Lovastatin is metabolized by CYP3A4. Because itraconazole is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between these drugs. METHODS: In this double-blind, randomized, two-phase crossover study, 12 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a single 40 mg dose of lovastatin. Plasma concentrations of lovastatin, lovastatin acid, itraconazole, hydroxyitraconazole, and creatine kinase were measured up to 24 hours. RESULTS: On average, itraconazole increased the peak concentration (Cmax) of lovastatin and the area under the lovastatin concentration-time curve (AUC) more than twentyfold (p < 0.001). The mean Cmax of the active metabolite, lovastatin acid, was increased 13-fold (range, tenfold to 23-fold; p < 0.001) and the AUC(0-24) twentyfold (p < 0.001). In one subject plasma creatine kinase was increased tenfold within 24 hours of lovastatin administration during the itraconazole phase but not during the placebo phase. No increase in creatine kinase was observed in the other subjects. CONCLUSIONS: Itraconazole greatly increases plasma concentrations of lovastatin and lovastatin acid. Inhibition of CYP3A4-mediated metabolism probably explains the increased toxicity of lovastatin caused not only by itraconazole but also by cyclosporine, erythromycin, and other inhibitors of CYP3A4. Their concomitant use with lovastatin and simvastatin should be avoided, or the dose of 3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitors should be reduced accordingly. PMID- 8689813 TI - N-acetyltransferase 2 polymorphism in patients infected with human immunodeficiency virus. AB - OBJECTIVES: To evaluate the prevalence of slow acetylation of hepatic N acetyltransferase 2 (NAT2) in patients with different stages of human immunodeficiency virus (HIV) infection, to assess the relationship between acetylation capacity and the degree of immunosuppression, and to study the concordance between NAT2 phenotype and genotype. METHODS: This prospective study in a consecutive sample of HIV-infected patients was performed in the outpatient department of a university hospital that provides primary and tertiary care. The NAT2 genotype was assessed by polymerase chain reaction and restriction fragment length polymorphism, the NAT2 phenotype was determined by caffeine test (urinary metabolic ratio of the caffeine metabolites 5-acetylamino-6-formylamino-3 methyluracil and 1-methylxanthine). RESULTS: Fifty patients with Centers for Disease Control HIV infection stages A (10 patients), B (20 patients), and C (20 patients) were included in the study after each gave informed consent. According to genotyping and phenotyping, 32 (64%) patients were slow acetylators, with a concordance of the two methods of 96%. The overall distribution was similar to distributions reported in other white populations. The slow acetylator phenotype was found in seven, 16, and nine patients with stage A, B, and C, respectively. Eight of the 10 patients with previous adverse reactions to sulfonamides had slow acetylator phenotypes. Acetylation capacity was independent of CD4 cell counts. CONCLUSIONS: This study revealed an excellent agreement between genotypes and phenotypes of NAT2 in patients with HIV infection. There was no increase in prevalence of slow acetylation in patients with advanced stages of the disease. This apparent discrepancy to an earlier study may be the result of differences in co-medication of the patients studied and may point to the relevance of drug interactions in the treatment of patients with HIV infection. PMID- 8689814 TI - Thiopurine methyltransferase activity in a Korean population sample of children. AB - Thiopurine methyltransferase (TPMT) is a cytoplasmic enzyme that catalyzes the S methylation of the cytotoxic drugs 6-mercaptopurine and azathioprine. Red blood cell (RBC) TPMT activity is subject to genetic polymorphism, and we have previously demonstrated an interethnic difference in TPMT activity. To investigate whether there was a race-related difference in RBC TPMT activity, TPMT was measured in a Korean population sample of 309 healthy children. Mean TPMT activity in healthy Korean children was 12.4 +/- 2.4 units/ml RBC, which is similar to the earlier reported TPMT activities in white populations. In contrast to the bimodal or trimodal frequency distributions of RBC TPMT activity in most other population samples, the frequency distribution histogram, the probit plot, and the Shapiro-Wilk test supported a normal distribution of TPMT activity in this Korean population sample of healthy children. Mean RBC TPMT activity showed a tendency to decrease with age, but it was not statistically significant. No gender-related difference in RBC TPMT activity was found. PMID- 8689815 TI - Pharmacodynamic modeling of furosemide tolerance after multiple intravenous administration. AB - OBJECTIVE: Physiologic indirect-response models have been proposed to account for the pharmacodynamics of drugs with an indirect mechanism of action, such as furosemide. However, they have not been applied to tolerance development. The aim of this study was to investigate the development of tolerance after multiple intravenous dosing of furosemide in healthy volunteers. METHODS: Three repetitive doses of 30 mg furosemide were given as rapid intravenous infusions at 0, 4, and 8 hours to eight healthy volunteers. Urine samples were collected for a period up to 14 hours after the first dose. Volume and sodium losses were isovolumetrically replaced with an oral rehydration fluid. RESULTS: Tolerance was demonstrated as a significant decrease in diuretic and natriuretic response over time. Total mean diuresis was 35% lower (p < 0.01) and total mean natriuresis was 52% lower (p < 0.0001) after the third dose of furosemide compared with the first dose. However, there were considerable interindividual variations in the rate and extent of tolerance development for both diuresis and natriuresis. Pharmacokinetic pharmacodynamic modeling of tolerance development was performed with use of an indirect-response model with an additional "modifier" compartment. This model gave an accurate description of the diuretic and natriuretic data after multiple dosing of furosemide and enabled the estimation of a lag-time for tolerance and a rate constant for tolerance development. Physiologic counteraction was demonstrated as a significant increase in plasma active renin levels (p < 0.00001) and a decrease in atrial natriuretic peptide levels (p < 0.005) during the day, concomitantly with the development of a negative sodium balance. This may be viewed as physiologic reflections of the modifier in our model. CONCLUSION: Indirect-response models may be successfully applied for tolerance modeling of drugs after multiple dosing. PMID- 8689816 TI - Black Americans have an increased rate of angiotensin converting enzyme inhibitor associated angioedema. AB - OBJECTIVE: To study the association of race and other patient characteristics associated with angiotensin converting enzyme (ACE) inhibitor-associated angioedema. METHODS: This was a retrospective cohort study of participants in the Tennessee Medicaid Program ( >or= 15 years of age) to whom ACE inhibitors had been prescribed from 1986 through 1992. RESULTS: We identified 82 patients with confirmed angioedema during 51,752 person-years of ACE inhibitor use, giving an overall rate of angioedema of 1.6 per 1000 person-years of ACE inhibitor use. After potential confounding factors were controlled for, the adjusted relative risk (RR) of angioedema among black American users of ACE inhibitors was 4.5 (95% confidence interval [CI] 2.9 to 6.8) compared with white subjects. In addition to race, other factors associated with a significantly increased relative risk in the entire population were the first 30 days of ACE inhibitor use (RR, 4.6; 95% CI, 2.5 to 8.5) compared to > 1 year of use, use of either lisinopril (RR, 2.2; 95% CI, 1.2 to 3.9) or enalapril (RR, 2.2; 95% CI, 1.4 to 3.5) compared to captopril, and previous hospitalization for any diagnosis within 30 days (RR, 2.0; 95% CI, 1.1 to 3.6). Neither ACE inhibitor dose nor concurrent diuretic use was associated with the risk of angioedema. CONCLUSIONS: These data suggest that black Americans have a substantially increased risk of ACE inhibitor-associated angioedema compared with white subjects and that this increased risk cannot be attributed to an effect of dose, specific ACE inhibitor, or concurrent medications. PMID- 8689818 TI - The effects of the menstrual cycle, race, and gender on adrenergic receptors and agonists. AB - OBJECTIVE: To examine possible effects of race, sex, and the menstrual cycle on adrenergic receptors (beta 2 and alpha 2) and agonists. METHODS: Sixty-three normotensive black men and women and white men and women were studied twice, approximately 6 weeks apart. Women were studied once during the follicular phase and once during the luteal phase of the menstrual cycle. beta 2-Adrenergic receptors and adenylate cyclase activity were examined on lymphocytes, and alpha 2-adrenergic receptors were examined on platelets. Norepinephrine and epinephrine were determined in plasma. RESULTS: Women showed greater lymphocyte beta 2 receptor sensitivity (isoproterenol-stimulated cyclic adenosine monophosphate; p = 0.009). Women also showed greater postreceptor adenylate cycle activity independent of the beta-receptor (forskolin stimulation; p = 0.006). When these differences were controlled for, the gender-related differences in beta 2 receptor sensitivity were no longer evident. Black women had a reduced beta 2 receptor sensitivity in the luteal phase compared with the follicular phase, whereas white women showed no significant change (p = 0.018). Black subjects had lower lymphocyte beta 2-receptor density (Bmax) values than white subjects (p = 0.047). There were no significant effects on alpha 2-adrenergic receptors. CONCLUSION: The findings suggest that although there is no generalized effect of the menstrual cycle on adrenergic receptors in white women, such an effect may occur in black women. The findings also suggest that previously reported gender related differences in beta 2-receptor sensitivity may be due to gender-related differences in postreceptor activity and not the beta 2-receptor per se. PMID- 8689817 TI - Stereoselective cardiotoxic effects of terodiline. AB - OBJECTIVE: To study the cardiovascular and electrocardiographic (ECG) effects of the R(+)- and S(-)- enantiomers of terodiline. The racemic drug was previously used to treat detrusor instability but was withdrawn after it caused serious ventricular arrhythmias associated with prolongation of the QT interval. METHODS: A double-blind, placebo-controlled, randomized crossover study was performed that involved nine healthy volunteers who were given single oral doses of racemic terodiline hydrochloride (200 mg), R(+)-terodiline hydrochloride (100 mg), S(-) terodiline tartrate (100 mg), or placebo. Plasma concentrations of each enantiomer and cardiovascular and ECG effects, including QT intervals and QT dispersion, were measured over 14 days after each treatment. RESULTS: Both racemic and R(+)-terodiline significantly increased QT interval, corrected QT interval (QTc), and QRS duration (all p < 0.05), without affecting QT dispersion. S(-)-Terodiline tartrate (100 mg) did not affect QTc. Peak effects occurred 8 hours after dosing when increases in QTc from baseline (95% confidence intervals) were -3 (-20, 13) for placebo, 23 (8, 37) for racemic terodiline, 19 (6, 33) for R(+)-terodiline, and 0 (-10, 9) ms1/2 for S(-)-terodiline. Although differences were observed between the pharmacokinetics of the two enantiomers, these were not sufficient to account for the differences in ECG effects, and elimination half lives were similar. Elimination of terodiline enantiomers was not significantly delayed in two genotypic poor metabolizers of debrisoquin (CYP2D6). CONCLUSIONS: QT prolongation associated with racemic terodiline is caused exclusively by the R(+)-enantiomer, which therefore appears to be responsible for the ventricular arrhythmias caused by the drug. PMID- 8689819 TI - Pictorial review: radiology of the masticator space. AB - The suprazygomatic portion of the masticator space (MS) or the temporal fossa is superficial and accessible to clinical assessment. The nasopharyngeal masticator space or infratemporal fossa is deep and can only be adequately evaluated by imaging studies. Infection secondary to odontogenic abscess or malignant otitis extema commonly affects this space. Primary tumours may arise from both soft tissues and bony structures. Malignant invasion of the MS from surrounding structures may take place. The delineation of these lesions is readily achieved by both computed tomography (CT) and magnetic resonance imaging (MRI). However, perineural infiltration and intracranial extension is better seen on MRI. Accurate assessment of disease extent is necessary for drainage procedures, surgical intervention or radiotherapy planning. PMID- 8689820 TI - Long-term effects of treatment of childhood malignancy. PMID- 8689821 TI - Sub-cortical white-grey matter contrast on MRI as a quantitative marker of diffuse HIV-related parenchymal abnormality. AB - White matter change occurs in human immunodeficiency virus (HIV) encephalopathy, which may be difficult to assess subjectively especially in the early stages of disease. This study applies a quantitative approach to the assessment of this finding. Sixty-three HIV seropositive subjects, 47 seronegative blood donors and 17 seronegative homosexual men underwent axial T2 weighted MRI of the brain at 1.5T. Quantitative analysis was performed by obtaining the pixel contrast between parieto-occipital white matter and head of caudate grey matter (Cwg). Highest values of Cwg were found in a subgroup of subjects with AIDS who had diffuse/patchy white matter abnormalities and atrophy on qualitative image assessment. Statistically significant differences were found in Cwg between subjects with high (> or = 200 x 10(6)/I) and low (< 200 x 10(6)/I) CD4 lymphocyte counts (P < 0.05) and between subjects with and without HIV-1 associated cognitive/motor complex (P < 0.05). This technique provides an objective measure of diffuse HIV-related parenchymal abnormality seen on T2 weighted MRI. PMID- 8689822 TI - Computed tomography of the brain in acute carbon monoxide poisoning. AB - Of 107 patients admitted to the South Western Hyperbaric Medical Centre with acute carbon monoxide poisoning for hyperbaric oxygen therapy 19 had cerebral imaging performed: 17 patients had CT, one patient had MRI and CT and one patient MRI alone. The role of brain CT is established in determining the prognosis from acute carbon monoxide poisoning. Brain imaging was indicated because of unconsciousness on admission and failure or delayed improvement in neurological status after initiation of hyperbaric oxygen therapy. Of the 18 patients who underwent brain CT, seven were found to have the characteristic changes of bilateral low attenuation areas within the globus pallidus and six had low attenuation changes within cerebral white matter. In two patients there were both globus pallidus and cerebral white matter changes. Out of the total of the 19 patients who were studied, four patients died, 10 recovered fully and five had variable disabilities ranging from short term memory loss to more severe cognitive impairment and physical disability. The role of CT and the practicalities of hyperbaric oxygen therapy for acute carbon monoxide poisoning are discussed in the light of the experience from a regional dedicated medical diving centre. PMID- 8689823 TI - Mn-DPDP enhanced MR imaging of the liver: analysis of pulse sequence performance. AB - AIM: To compare liver enhancement and lesion-liver contrast on T1-weighted (T1W) gradient recalled echo (GRE), spin-echo (SE) and fat-suppressed SE (FS-SE) pulse sequences at Manganese-DPDP (Mn-DPDP) enhanced magnetic resonance (MR) imaging of the liver. PATIENTS AND METHODS. Twenty-one patients with known liver lesions were administered 5 mumol/kg of Mn-DPDP. TIW GRE (78/2.3/80 degrees), SE and F-SE (300/12) images were obtained before and 15 min after Mn-DPDP. Signal/noise ratio (SNR) and lesion-liver contrast/noise ratio (CNR) were calculated for each pulse sequence. RESULTS: Liver SNR (n = 21) and lesion-liver CNR (n = 10) increased significantly after Mn-DPDP on all three pulse sequences (P < 0.0001). Liver SNR was highest on the FS-SE and GRE pulse sequences (FS-SE = 43.8, GRE = 38.4, SE = 29.2). Lesion-liver CNR was highest on the FS-SE pulse sequence (FS-SE = -29.3, SE = -23.2, GRE = -19.8), which was significantly higher than the GRE pulse sequence (P < 0.05). CONCLUSION: The T1-weighted fat-suppressed SE (FS-SE) pulse sequence provides highest liver enhancement and lesion-liver contrast and is recommended for Mn-DPDP enhanced MR imaging. PMID- 8689824 TI - Advantages of an increased dose of MRI contrast agent for enhancing inflammatory synovium. AB - MRI intravenous contrast enhancement of inflammatory synovium has been studied at two different doses to determine to what extent enhancement is dose dependent. 19 patients with clinically active rheumatoid arthritis involving a knee were scanned twice, one week apart, using 0.1 mmol/kg of gadoteridol (ProHance) on the first occasion and 0.3 mmol/kg on the second. Static pre-and post-contrast images together with dynamic images immediately following injection were obtained on a 1.0T scanner. On subjective assessment, 84% of patients showed improved enhancement. 47% showed more enhancing tissue, a clearer delineation of enhancing tissue or both. Objectively, enhancement was increased significantly at the higher dose, as judged by the percentage increase in mean signal intensity within regions of interest plotted over the suprapatellar pouch (1723% v. 1005% enhancement P < 0.05). In practical terms the better visualization of enhancing tissue achieved with higher doses is likely to reduce margins of error in attempts at quantification from MRI scans, particularly of synovial volume, but emphasizes also the need for care and consistency to be exercised in calculating the exact dose of contrast medium to be administered. PMID- 8689825 TI - Portable chest radiology in intensive care: a comparison of a new dual characteristic film-screen system (Insight) incorporating a flexible grid with a standard film-screen system. AB - Insight (Insight, Kodak, UK) is a new dual image receptor system which utilizes an asymmetric film screen combination. Conventional radiography was compared with the Insight system, in combination with a cassette incorporating a flexible grid, in fifty patients on the intensive care unit. Radiographs were analysed by intensive care junior medical staff, nursing staff and two groups of radiologists. Insight provided better visualization of lung parenchyma, mediastinal detail and position of endotracheal tubes than conventional radiography. Central venous catheters were generally seen better on conventional radiographs than on Insight. Insight system produces a significant improvement in plain chest radiography in the intensive care unit. In the absence of digital radiography it is a suitable technique for routine radiography in the intensive care unit. PMID- 8689826 TI - Is admission chest radiography of any clinical value in acute stroke patients? AB - Chest radiographs are frequently requested on admission of patients with a clinical diagnosis of acute stroke. This study assesses their value in subsequent management of these patients. A retrospective analysis of 435 patients with a clinical diagnosis of acute stroke was made. All admission chest radiographs were reviewed to document both radiographic quality and any radiological abnormality. In those patients with an abnormal radiograph, clinical records were reviewed to assess their impact on clinical management. Eighty-six percent of patients had a chest radiograph performed on admission. 77.5% of these films were deemed to be technically unsatisfactory, the commonest problems being positioning and suboptimal inspiration. Radiological abnormality was demonstrated in 61 patients (16.4% of radiographs obtained). Clinical management was altered in 14 of the 61 patients (3.8% of the total number of patients radiographed). Radiological abnormality was missed by the admitting clinicians in four radiographs (1 hilar mass, 2 cases of consolidation, one of pulmonary oedema). One abnormality not clinically suspected was recorded (multiple metastases). We conclude that admission chest radiographs in patients with an acute stroke are not indicated in the absence of appropriate clinical indications. PMID- 8689827 TI - CT-guided transthoracic needle biopsy: a comparison between automated biopsy gun and fine needle aspiration. AB - AIMS: We retrospectively investigated the diagnostic accuracy and complication rate of transthoracic core biopsy using an automated biopsy gun and compared the findings with those of aspiration needle biopsy. PATIENTS AND METHODS: Seventy three patients underwent 74 core biopsy procedures and 50 patients underwent 52 aspiration biopsy procedures. Of these, a final diagnosis was obtained in 107 lesions with surgery or clinical course. Fifteen patients in which a final diagnosis was not obtained were excluded from the study on diagnostic accuracy. Thus, in the study of diagnostic accuracy, 63 core biopsy procedures for 62 lesions are included. Core biopsy was performed with an 18 G cutting needle using an automated biopsy gun. Aspiration biopsy was performed with a 20 G aspiration needle. RESULTS: Core biopsy yielded sufficient material in 57/63 procedures (90.5%). A correct diagnosis was obtained in 36 procedures (85.7%) for malignant leisons and a specific benign diagnosis was obtained in 11 procedures (52.4%). Aspiration biopsy yielded a correct diagnosis in 26 procedures (81.3%) for malignant leisons and in seven (46.7%) for benign lesions. The overall correct diagnosis were 75.8% and 71.7% with core biopsy and aspiration biopsy, respectively. Core biopsy gave a higher predictive rate than that of aspiration biopsy for both benign and malignant lessons (P < 0.02). Pneumothorax occurred in 18/74 (24.3%) patients with core biopsy and in 18/45 (40.0%) patients with aspiration biopsy. Of these, three with core biopsy and two with aspiration biopsy needed tube drainage. The other complication was haemoptysis, which occurred in six patients following core biopsy and in three after aspiration biopsy. All nine cases subsided spontaneously. There were no fatal complications. CONCLUSIONS: Core biopsy with a biopsy gun increase the diagnostic accuracy with a higher histologic predictive rate and no obvious additional risk of complications. PMID- 8689828 TI - The significance of increased 111indium platelet accumulation at post-angioplasty sites. AB - We assessed prospectively the significance of 111indium labelled platelet accumulation following angioplasty procedures in 12 patients (9 femoral angioplasties (2 laser, 1 atherectomy) and 3 iliac stents). Autologous 111indium labelled platelets were re-injected immediately after angioplasty. Radioactivity was measured over treated and reference sites, by single probe and gamma camera, and expressed as a radioactivity ratio (RR). All patients had duplex ultrasound assessment and occlusions were confirmed by arteriography. RR was always raised after angioplasty. Three patients who had acute occlusions showed markedly raised average RRs (significant at 99% ANOVA). RR was not raised after laser assisted angioplasty, however, our numbers were small. 111Indium platelet radioactivity did not predict subsequent occlusion after angioplasty but effectively detected existing acute post-angioplasty occlusions. PMID- 8689829 TI - Multiple rice body formation in chronic subacromial/subdeltoid bursitis: MR appearances. AB - Multiple rice body formation is an unusual complication of chronic bursitis. Clinically and macroscopically, it can resemble synovial osteochondromatosis. Radiographic and MR appearances, however, may allow an accurate pre-operative diagnosis. The imaging features of two middle-aged women with multiple subacromial/subdeltoid bursa rice bodies are described. PMID- 8689830 TI - Case report: low femoral artery puncture: a cause of diagnostic error. PMID- 8689831 TI - Case report: benign solitary schwannoma of the greater omentum: a rare cause of acute intraperitoneal bleeding--diagnosis by CT. PMID- 8689832 TI - Case report: a migrating biliary wallstent: an unusual complication. PMID- 8689833 TI - Case report: angiosarcoma in a patient with von Recklinghausen's disease. PMID- 8689834 TI - Case report: haemangioma of the breast--appearances on mammography and ultrasound. PMID- 8689835 TI - Kinking of a Simon nitinol vena caval filter during insertion. PMID- 8689836 TI - Wessex regional radiology audit: barium enema in colo-rectal carcinoma. PMID- 8689837 TI - Primary malignant rhabdoid tumour of the brain. PMID- 8689838 TI - True massive thymic hyperplasia. PMID- 8689839 TI - Diabetes on the Old Silk Toad. PMID- 8689840 TI - HLA and glutamic acid decarboxylase in human insulin-dependent diabetes mellitus. AB - Insulin-dependent diabetes mellitus (IDDM) is linked to HLA factors on human chromosome 6 and strongly associated with the presence of autoantibodies against the glutamic acid decarboxylase isoform GAD65. These autoantibodies, GAD65Ab are detected both before and at the time of clinical diagnosis. Molecular sequencing of HLA alleles and PCR-based genotyping have improved our understanding of the linkage between HLA and IDDM. At the same time, the molecular cloning of human islet GAD65 and the development of precise and reproducible GAD65Ab assays with recombinant human GAD65 has given new insights to the problem of to what extent HLA control the development of a GAD65 immune response or to the development of IDDM. Recent data are briefly reviewed. In new onset IDDM patients GAD65Ab were associated with the DQ2/8 or DQ2/X genotype. However, in patients with an older age at onset the association was particularly pronounced with the DQ2/8 genotype. The DQ5/8 genotype was significantly decreased among GAD65Ab positive patients. Certain DQ genotypes, therefore, seem permissive for the formation of GAD65Ab in IDDM. Studies of the general population is needed to determine if the DQ2, 8 or both alleles predispose to GAD65 autoreactivity. This is important since other factors may control the development of IDDM in only a fraction of GAD65 antibody positive individuals detected following a screening of the general population. PMID- 8689841 TI - Restitution of neurophysiological functions, performance, and subjective symptoms after moderate insulin-induced hypoglycaemia in non-diabetic men. AB - The restoration of cognitive function was studied in 10 healthy men aged 26 years (25.5 +/- 1.2 years; mean +/- SD) after insulin-induced hypoglycaemia (arterialized blood glucose 2.5 +/- 0.4 mmol l-1) for 62 +/- 8 min. Another group of six men participated in a single blind sham study for comparison. The hypoglycaemic event caused a significant increase (p = 0.006) in serum adrenaline levels. Ratings of adrenergically mediated symptoms increased during hypoglycaemia (p = 0.006), as did neuroglycopenic symptoms (p = 0.002), although neuroglycopenia ratings increased in both studies. During hypoglycaemia, P300 amplitudes in a relatively demanding visual search task decreased (p = 0.02), whereas easier tasks were unaffected. The amplitudes were restored after 40 min of normoglycaemia. Reaction time deteriorated after restoration of normoglycaemia, suggesting an effect of hypoglycaemia on learning. Thus, hypoglycaemia at a blood glucose level that is common among patients treated with insulin causes clear cognitive dysfunction, although restoration of the cognitive dysfunction to normal was fast. PMID- 8689842 TI - Correcting for ethnicity when defining large for gestational age infants in diabetic pregnancies. AB - The large-for-gestational-age (LGA) infant, defined as > 90th birthweight percentile, is associated with mild disturbances of maternal glucose tolerance. In the UK the same birthweight percentile charts are used for all ethnic groups when assessing LGA infants. The influence of maternal hyperglycaemia on LGA infants of Asian (Indian Subcontinent) mothers in the UK is likely to be under reported, as Asian birthweights tend to be lower than White/Europid birthweights. We assessed the number of LGA infants born consecutively to 21 Asian and 26 White/Europid mothers with gestational diabetes mellitus (GDM), delivered between 37 and 42 weeks gestation, and also in 34 Asian and 121 White/Europid mothers with a positive screening test for GDM but a normal 75 g oral glucose tolerance test (OGTT). Large-for-gestational-age infants were identified using both the standard UK percentile charts of the Medical Research Council and percentile charts constructed from 30,418 Asian and 162,477 White/Europid singleton births, delivered between 37 and 42 weeks gestation to non-diabetic mothers delivered in the North West Thames Region of England. The standard Medical Research Council percentile charts, compared with the ethnically derived charts, identified fewer LGA Asian (7/56 vs 15/56) but more White/Europid infants (33/147 vs 21/147). When correcting for ethnicity more Asian than White/Europid GDM mothers delivered LGA infants (9/21 vs 3/26, chi 2 = 4.76, p < 0.05). The maternal 2 h OGTT plasma glucose was a significant independent contributor to birthweight in the Asian (r2 = 0.319, p < 0.0005) but not the White/Europid infants, in whom gestational age and maternal height were significant independent contributors to birthweight (r2 = 0.158, p < 0.0001). We conclude that ethnic influences are important when defining LGA infants and that mild disturbances of maternal glycaemia have a greater influence on the birthweight of Asian than White/Europid infants. PMID- 8689843 TI - Familial aggregation of type 2 (non-insulin-dependent) diabetes mellitus in south India; absence of excess maternal transmission. AB - The family histories of 976 South Indian Type 2 diabetic patients were recorded in a questionnaire-based survey to establish whether the excess maternal transmission of Type 2 diabetes reported in low prevalence Europid populations was also evident in this medium prevalence population. In 450 families (46.1%), no parental history of diabetes was reported. In 423 families with one parent diabetic, 222 fathers (52.5%) and 201 (47.5%) mothers were diabetic. In the remaining 103 (10.6%) families, both parents were diabetic. In contrast to previous studies, we found no evidence for substantial maternal excess in the transmission of diabetes (325 diabetic fathers vs 304 mothers; p = 0.4; p = 0.07 when compared using life table methods). The age of diagnosis of diabetes in probands was lower than that of their diabetic parents (p < 0.001): furthermore increasing parental history of diabetes was associated with an earlier diagnosis of diabetes in probands (p < 0.001). These results emphasize the extensive familial aggregation of Type 2 diabetes in this population but fail to replicate the evidence for excess maternal transmission evident in lower prevalence Europid populations, suggesting ethnic differences in the extent of this phenomenon. PMID- 8689844 TI - Serum sialic acid and the long-term complications of insulin-dependent diabetes mellitus. AB - Elevated serum sialic acid (SSA) predicts cardiovascular disease in the non diabetic population and is also associated with the presence of microalbuminuria and clinical proteinuria in patients with insulin-dependent diabetes (IDDM). We have studied 121 patients with IDDM of long duration (mean duration 25.2 years) to investigate the relationship of SSA concentrations to the presence of retinopathy, nephropathy, and neuropathy. SSA levels were elevated in patients with retinopathy (0.578 +/- 0.161 gl-1, n = 98) when compared with those without retinopathy (0.468 +/- 0.145 gl-1, n = 23, p = 0.002). Patients with nephropathy (urinary albumin:creatinine ratio of > 3 mg mmol-1 in all of three early morning specimens of urine) also had raised SSA levels (0.625 +/- 0.169 gl-1, n = 30) compared with those without nephropathy (0.533 +/- 0.160 gl-1, n = 91, p = 0.006). There was a significant correlation of SSA with urinary albumin:creatinine ratio (correlation coefficient 0.33, p < 0.001). SSA levels were not related to the presence or absence of neuropathy (0.567 +/- 0.181 gl-1, n = 28, vs 0.533 +/- 0.160 gl-1, n = 93, p = 0.92, respectively). In conclusion, retinopathy and nephropathy but not neuropathy are associated with increased SSA levels in patients with IDDM. The significance of this is not yet clear but it is possible that sialic acid is involved in the pathophysiology of microvascular disease in IDDM. PMID- 8689845 TI - Risk factors for lower extremity arterial disease in non-insulin-dependent diabetic persons. AB - The relationship of lower extremity arterial disease to the different risk factors for atherosclerosis in non-insulin-dependent (Type 2) diabetes mellitus is a matter of continuing investigation. The present study was conducted on a random sample of 193 non-insulin-dependent diabetic patients in order to compare the frequency and severity of some known risk factors for atherosclerosis among such persons with and without indications of lower extremity arterial disease. Conventional risk factors for atherosclerosis (smoking, existence of hypertension, total plasma cholesterol, HDL-cholesterol, and triglycerides) were assessed. In addition body mass index, waist-to-hip ratio, body fat mass, and albumin excretion were determined. Criteria for the presence of lower extremity arterial disease were an ankle brachial pressure index < 0.89 and/or the existence of intermittent claudication. Age, length of diabetes, and waist-to-hip ratio appeared to be factors significantly related to lower extremity arterial disease in most cases. Blood lipids, body mass index, HbA1 (except in males), smoking, and type of antidiabetic treatment were not significantly related to disease. The multivariate analysis confirmed the significant contribution of the duration of diabetes (p = 0.002), and waist-to-hip ratio (p = 0.024) and further showed a significant relation with triglycerides (p = 0.020). Thus, lower extremity arterial disease in non-insulin-dependent diabetes mellitus is significantly related to a long duration of diabetes and to central body fat distribution (but not to body mass index), as well as to triglyceride levels. PMID- 8689846 TI - Relative fasting hypoinsulinaemia and ultrasonically measured early arterial disease in type 2 diabetes. The SENDCAP Study Group, St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention Study. AB - Macrovasular disease is the most important cause of morbidity and mortality in Type 2 (non-insulin-dependent) diabetes. Dyslipidaemia and hyperinsulinaemia have been proposed as aetiological factors. This paper describes the interrelationships between fasting serum insulin, serum lipids, and the extent of ultrasonically measured early arterial disease in Type 2 diabetic subjects screened for entry into a prospective study set up to ascertain whether improving serum lipids can alter the progress of arterial disease in Type 2 diabetes. Measurements were made of the initima media thickness (IMT) in the carotid artery, and an arterial ultrasound score (AUS) based on appearances of both carotid and femoral arteries was calculated for 192 established Type 2 diabetic subjects, males and females, mean age 51 (range 35-66) years, median duration of diabetes 3.5 years, with no known cardiovascular disease. Multiple regression analysis showed that carotid IMT increased with age and was inversely related to serum insulin (variance accounted for, R2, = 8.8%, p = 0.0002). AUS increased with age and was related inversely to serum insulin, or to C-peptide when this was substituted in the model. In addition to age and serum insulin, AUS was positively associated with non-HDL cholesterol and negatively with HDL 3 cholesterol (R2 = 26%, p = 0.0001). Early thickening and damage to the arterial wall in Type 2 diabetes may be related to relative fasting hypoinsulinaemia. PMID- 8689847 TI - Physical work capacity in diabetic children and adolescents with and without cardiovascular autonomic dysfunction. AB - The aim of the present study was to evaluate the influence of autonomic nervous system dysfunction on work capacity in children and adolescents with Type 1 (insulin-dependent) diabetes. Fifteen patients with autonomic dysfunction (abnormal autonomic tests, age: 14.9 +/- 2.3 years), 35 patients without autonomic dysfunction (normal autonomic tests, age: 15.2 +/- 2.5 years), and 25 non-diabetic subjects (age:15.0 +/- 2.3 years) were investigated. Resting heart rate, deep breathing heart rate variation, standing/lying heart rate ratio, decrease in blood pressure during orthostasis, and increase in blood pressure during sustained handgrip were used to assess cardiovascular autonomic dysfunction. Physical work capacity at heart rate of 170 min-1 was determined by bicycle ergometry. Glycated haemoglobin level was higher in patients with than without autonomic dysfunction (12.3 +/- 3.1 vs 9.4 +/- 2.9%, p = 0.04). Patients with autonomic dysfunction had significantly lower physical work capacity at heart rate of 170 min-1 than those with normal autonomic function or non-diabetic subjects (0.81 +/- 0.12 vs 1.49 +/- 0.16 and 1.54 +/- 0.20 W kg-1 p = 0.01). Physical work capacity at heart rate of 170 min-1 was related to glycated haemoglobin level (r = -0.55, p = 0.01), to resting heart rate (r = 0.57, p = 0.01), and to deep breathing heart rate variation (r = 0.51, p = 0.02). In conclusion, impaired work capacity is associated with poor blood glucose control and cardiovascular autonomic dysfunction. Autonomic tests can help to identify those patients who may need special consideration during exercise. PMID- 8689848 TI - Abnormal response to exercise in middle-aged NIDDM patients with and without autonomic neuropathy. AB - The cardiovascular response to exercise in middle-aged non-insulin-dependent diabetes mellitus (NIDDM) patients and the potential role of clinical characteristics and autonomic function were evaluated. One hundred and eight NIDDM patients, aged 40-65 years, were compared with a control group of 112 subjects, matched by age, sex, physical fitness, and presence of hypertension. All subjects performed a maximal exercise test. The diabetic patients completed cardiovascular autonomic neuropathy (CAN) tests: deep breathing, postural hypotension and lying to standing. There were no significant differences in total work capacity, heart rate, and blood pressure, either at rest or at peak exercise between the two groups. Diabetic patients showed significantly lower values of systolic and diastolic blood pressure during exercise, significantly slower recovery of heart rate (at 5th minute the average values were 102.7 +/- 14.1 beats min-1 vs 91.9 +/- 11.1, p < 0.001); and significantly higher proportion of blunted increase of heart rate (9.2% vs 0.9%, p < 0.001) and systolic blood pressure (9.2% vs 0.7%, p < 0.001) during exercise. No correlation between the exercise results and the main clinical characteristic (presence of hypertension, BMI, duration of diabetes, treatment, microalbuminuria, total score of CAN) was observed. These findings suggest that the cardiovascular response to exercise could be impaired also in the absence of signs of CAN. This impairment was higher in patients showing a dysfunction of orthosympathetic activity. PMID- 8689849 TI - A novel method for the assessment of autonomic neuropathy in type 2 diabetic patients: a comparative evaluation of 123I-MIBG myocardial scintigraphy and power spectral analysis of heart rate variability. AB - The correlation between the degree of sympathetic denervation measured through 123I-MIBG Myocardial Scintigraphy and Power Spectral Analysis of consecutive R-R records was investigated in order to evaluate their potential application for the assessment of myocardial autonomic neuropathy in patients with diabetes mellitus. This study comprised 42 patients with Type 2 diabetes. Low frequency (0.02-0.09 Hz) components of the power spectral density were measured as markers of sympathetic activity. The myocardial uptake of 123I-MIBG was measured by using the single photon emission computed tomography (SPECT) and the early and delayed images were recorded. Scoring from 0 to 3 of the 123I-MIBG uptake of various cardiac segments (7) was performed and the total uptake was calculated. The washout rate in the whole myocardium was determined. The values obtained in the group with diabetic autonomic neuropathy (DAN) without orthostatic hypotension (OH) were significantly lower as compared to those of the (DAN (-)) group in the delayed images. The washout rate of the OH (-) group was also significantly higher than the DAN (-) group. There was significant difference between the images and the washout rate of OH (+) and OH (-) groups. There was a significant correlation between Power Spectral Analysis and SPECT (early, delayed images, and washout rate). Of these, the delayed image showed the strongest correlation (r = 0.55, p < 0.01). Further, the QTc interval showed a significant inverse correlation with the delayed image (r = -0.44, p < 0.05). In conclusion, these results suggest that the cardiac 123I-MIBG scintigraphy could be a useful method for the assessment of the myocardial autonomic neuropathy in patients with diabetes mellitus. PMID- 8689850 TI - Patterns of in and out-patient activity for diabetes: a district survey. AB - The objective was to describe, by means of a retrospective study of three years' routine District information (financial years 1991/92 to 1993/94), the in- and out-patient activity for patients with diabetes, and compare this with the non diabetic population. The clinical resource usage by patients with diabetes relative to those without was estimated by (a) their relative probability of admission by specialty, (b) attendance rates at out-patient clinics, (c) primary diagnosis, and (d) operations and procedures. The setting was a District Health Authority with a population of 408 000. All in-patient and out-patient records were reclassified as attributable to a patient with or without diabetes by cross referral to routine records of patients with identified diabetes from separate hospital databases. The main outcome measures were: (a) relative frequency, and crude and age-specific relative probability of admission by specialty, ICD9 primary diagnosis, and OPCS4 primary operation and procedure, and (b) out-patient attendance rates by specialty. Patients with diabetes were responsible for 5.5% of admissions and 6.4% of out-patient attendances. However, because of increased length of stay, patients with diabetes occupy 9.4% of bed days. The relative risk of admission for diabetes related complications was: coronary heart disease 11.8 (95% CI = 11.4-12.3), cerebrovascular disease 11.8 (10.8-12.8), neuropathy and peripheral vascular disease 15.6 (13.6-17.9), eye complications 10.4 (9.3-11.7), and renal disease 14.7 (12.6-17.3). Recognised diabetes related vascular (9.3 11.7), and renal disease 14.7 (12.6-17.3). Recognised diabetes related vascular complications accounted for at least 23% of admissions of patients with diabetes. The relative risk of admission for diagnoses and procedures not known to be related to diabetes were similar for non-diabetic and diabetic patients. The pattern of out-patient activity mirrored that of the relative probability of admission. It is concluded that previous estimates of the proportion of NHS resources used for the treatment of patients with diabetes had been significantly underestimated. Patients with diabetes were found to occupy 1 in 10 non obstetric, non-psychiatric beds. Many of these admissions were for diagnoses and procedures that are known to be related to diabetes. PMID- 8689851 TI - Aggressive limb salvage using tibio-pedal bypass grafting with free tissue transfer in a diabetic patient. AB - A 63-year-old man presented with intermittent claudication, diabetes, and an ischaemic heel ulcer. After control of infection, the os calcis was left exposed. An aggressive combined infra-inguinal revascularization and reconstruction procedure involving free-tissue transfer resulted in rapid wound healing with independent walking by day 26. Recent improvements in surgical techniques mean that this approach should be considered in selected patients. PMID- 8689852 TI - Urine hydroxyproline increase in patients with diabetes mellitus. PMID- 8689854 TI - Expert workshop on impaired glucose tolerance. London, United Kingdom, 29 March 1995. Proceedings. PMID- 8689853 TI - Serum sialic acid concentrations in Asian diabetic patients in the UK. PMID- 8689855 TI - New data on the rate of progression of impaired glucose tolerance to NIDDM and predicting factors. AB - The Hoorn study has investigated the prevalence of impaired glucose tolerance (IGT) and diabetes in a random sample of the population, 50-75 years of age, in the small Dutch town of Hoorn. The percentage of the population identified as having IGT was 10.3%, while 8.4% had diabetes. The prevalence of both diabetes and IGT was higher in older subjects (70-74 years of age) than in younger subjects (50-54 years of age), suggesting that age is a major determinant of the prevalence of IGT and diabetes in a population. A prospective study of the development of non-insulin dependent diabetes mellitus (NIDDM) in the subjects identified as having IGT was then initiated. Preliminary results for the 158 subjects who have been followed for a mean of 2 years indicated that 28.5% (95% confidence interval, 15-42%) have progressed to NIDDM within this period. The progression rate calculated from this value is 13.8%/year (95% confidence interval, 3.5-24%/year). Analysis of possible determinants of conversion has revealed that 2-hour plasma glucose levels greater than 9.4 mmol/litre and increased fasting proinsulin levels are predictive of progression to NIDDM. This suggests that beta cell dysfunction, rather than increased insulin resistance, is responsible for the development of NIDDM. PMID- 8689856 TI - The cardiovascular risk associated with impaired glucose tolerance. AB - Subjects with fasting and/or postprandial plasma glucose levels that are higher than those in normal subjects but less than those in patients with manifest NIDDM are at increased risk of cardiovascular disease (CVD). This association between glucose intolerance and cardiovascular disease was first hypothesized in the 1950s but was not substantiated until the results of several long-term prospective studies became available. The results suggest that there is not a continuously variable association between blood glucose levels and the risk of CVD but that the risk of CVD becomes evident at the upper end of the distribution of glucose tolerance, though different studies yield different threshold levels. With the introduction of the descriptive term Impaired Glucose Tolerance (IGT), studies were undertaken to establish the relations between IGT and CVD. To date most data refer to people of European origin. In several populations CVD has been observed to be more prevalent in subjects with IGT and/or the incidence of CVD is higher in subjects with IGT than in normoglycaemic controls. A causal link between hyperglycaemia and CVD seems unlikely from the published evidence. The most probable explanation of the association is "a common soil', that is, a number of associated metabolic abnormalities which may lead to CVD and IGT/NIDDM or both. PMID- 8689857 TI - Review of previous impaired glucose tolerance intervention studies. AB - Long-term intervention studies have evaluated the effect of diet, exercise and pharmacological regimens on the conversion rate of impaired glucose tolerance (IGT) to non-insulin dependent diabetes mellitus (NIDDM). Two UK studies, the Bedford study (10 years) and the Whitehall study (5 years), found that a diet which restricts carbohydrate intake to less than 120 g/day had no effect on the development of NIDDM in subjects with IGT. In contrast, the Swedish Malmohus study (10 years) found that the conversion rate was reduced from 29% in the control group to 13% in a group told to limit their intake of carbohydrates and lipids and to reduce weight when overweight. A further Swedish study, the Malmo study (6 years and ongoing) is investigating a combination of dietary intervention and a strenuous exercise programme. In this study the conversion rate decreased from 29% in the control group to 11% in the diet plus exercise group. The Bedford and Whitehall studies also investigated intervention with tolbutamide and phenformin, respectively. Neither drug was found to have an effect on the conversion rate in either study. In contrast, positive results for tolbutamide were obtained in the Malmohus study. No subjects in the tolbutamide plus diet group developed NIDDM compared with 29% in the control group. This regimen was also found to have beneficial effects on blood pressure, serum lipids and on cardiovascular morbidity and mortality. PMID- 8689859 TI - Economic implications of IGT intervention: the case of a "phantom alternative'? AB - Diabetes is a major chronic disease (or group of diseases). It is associated with a variety of risk factors which promote its occurrence. It is also associated as a risk factor for structural and function damage (complications) in various body systems, especially the cardiovascular, renal, eye and neurological systems. Undoubtedly, diabetes is a disease of major public health importance, both in terms of its impact on the well-being of the population and its economic burden. It is thus natural to look into interventions aimed at reducing the long-term sequelae of the disease or more specifically looking into primary prevention strategies (i.e., interventions prior to the onset of the disease) and their economic implications. The purpose of this paper is to asses whether it is possible to perform economic evaluation of primary prevention strategy(ies) in subject with IGT or whether such a strategy represents, at present, a 'Phantom Alternative'. Unfortunately, the evidence about the effectiveness of primary prevention type interventions are weak at best. It is not surprising that no one has suggested a comprehensive strategy (i.e., who is doing what, to whom, where and how often) for an intervention for subjects with impaired glucose tolerance (IGT). The absence of good evidence about the effectiveness of different IGT interventions preclude a valid economic analysis. 'What-it' or 'modelling' type studies are likely to result in the typical answer-'it depends'. It is recommended, therefore, that an economic evaluation should be performed in conjunction with a clinical trial to determine the effectiveness of different IGT interventions. PMID- 8689858 TI - The effect of acarbose on insulin sensitivity in subjects with impaired glucose tolerance. AB - Acarbose is an alpha-glucosidase inhibitor which delays the absorption of glucose from the intestine. Taken orally before a meal, acarbose delays absorption of carbohydrates and decreases the postprandial plasma glucose and plasma insulin rise. A pilot study has been carried out to investigate whether acarbose can improve insulin sensitivity in subjects with impaired glucose tolerance (IGT). 18 subjects were randomized to receive either acarbose, 100 mg t.d.s., or placebo for 16 weeks. Acarbose therapy was found to decrease 2-hour plasma glucose and plasma insulin levels and to increase insulin sensitivity. Insulin resistance is an important factor in the development of non-insulin dependent diabetes mellitus (NIDDM).these results suggest that acarbose therapy may be able to prevent or delay the progression of IGT to NIDDM. A multicentre phase III clinical trial is now planned to investigate this possibility. PMID- 8689860 TI - Summary and perspectives on impaired glucose tolerance. AB - There is much evidence to link impaired glucose tolerance (IGT) with the risk of developing non-insulin dependent diabetes mellitus (NIDDM) and of cardiovascular disease. However, it is unclear whether IGT is merely a marker or a risk factor or whether it is causally related to the development of these conditions. It is also unclear whether all individuals with IGT have an equal probability of developing NIDDM or cardiovascular disease. The exact pathogenetic relationship between IGT and these disease has important implications for preventive therapy which might be offered to such people. Patient compliance, physician motivation and supportive health-care funding will be greater if IGT is seen to be a definite stage in the development of a serious disease rather than simply a risk factor with statistically defined predictive power. As yet, there are insufficient data to justify routine therapy of subjects with IGT but further research into this condition and the development of effective preventive therapies could lead to widespread treatment. PMID- 8689861 TI - Impaired glucose tolerance--fact or fiction. AB - The WHO and the National Diabetes Data Group have produced definitions to classify subjects with blood glucose levels following oral ingestion that are higher than normal, but are less than for patients with diabetes. The term impaired glucose tolerance (IGT) has been used to describe this group who have an increased risk of developing non-insulin dependent diabetes mellitus and cardiovascular disease, compared with subjects with normal glucose tolerance. Wide intra-subject variability has been observed when glucose tolerance tests are carried out on separate occasions. This has led some researchers to suggest that IGT merely constitutes a blurred boundary between normality and diabetes but accumulating evidence now supports the hypothesis that IGT is a useful risk factor category. PMID- 8689862 TI - Impaired glucose tolerance--prevalence and conversion to NIDDM. AB - Impaired glucose tolerance (IGT) has been investigated in a large number of populations from different parts of the world and with differing lifestyles. The occurrence of IGT varies widely. IGT prevalence tends to increase with age, but there is no consistent relationship with gender. Prevalence is lower in groups with less obesity and having physically active lifestyles, such as those living in rural areas and having traditional lifestyles, even when subjects with the same genetic background are compared. Risk factors for IGT are similar to those for non-insulin dependent diabetes mellitus (NIDDM). IGT, characterized by hyperglycaemia and insulin resistance, is probably a stage in the pathogenesis of NIDDM. Therapies aimed at improving glucose tolerance and decreasing insulin resistance in subjects with IGT may, therefore, be able to delay or prevent the development of NIDDM. PMID- 8689863 TI - Colorectal cancer and polyps: clinical decisions for screening, early diagnosis, and surveillance of high-risk groups. PMID- 8689864 TI - High-dose chemotherapy for malignancies: a review. PMID- 8689865 TI - Benign to malignant progression in cervical squamous epithelium. PMID- 8689866 TI - Some cytogenetic and molecular aspects of cancer therapy. PMID- 8689867 TI - The treatment of hormone refractory prostate cancer. PMID- 8689868 TI - Management of cancer in the aged. PMID- 8689869 TI - Physical activity: breast and reproductive cancer. PMID- 8689870 TI - Detection of motion during tomographic acquisition by an optical flow algorithm. AB - An automatic procedure to detect and quantify patient motion during the acquisition of the tomographic views in single photon emission computerized tomography (SPECT) is proposed. This method first computes the optical flow vector field which assigns to each pixel of a tomographic view the two dimensional displacement vector that describes its motion between two successive views. The average optical flow in a region of interest is then computed to measure its inter-view global motion. This algorithm is tested on a point source, on a cardiac phantom (with and without induced motion), and on a patient. The proposed method can accurately detect the presence of motion, localize the camera angle at which motion occurred, and measure the distance of motion. The optical flow method can be used to control the quality of the tomographic acquisition and to alert the user to the potential of reconstruction artifacts due to patient motion. It can also be used to correct for the translational motion in the direction of the axis of rotation of the camera. PMID- 8689871 TI - An expert system to diagnose anemia and report results directly on hematology forms. AB - An attempt was made to create an expert system with sufficient accuracy to diagnose classes of anemia and report presumptive diagnoses directly on the hematology form. The system should simulate the processes of human experts who can reliably achieve diagnostic separability by pattern analysis. A hybrid expert system combining rule-based and artificial neural network (ANN) models was constructed to evaluate microcytic anemia in a 3-layered program using hematocrit (HCT), mean corpuscular volume (MCV), and coefficient of variation of cell distribution width (RDWcv) as inputs. These measurements are available as standard output on most hematology analyzers. Three categories of microcytic anemia were considered, iron deficiency (IDA), hemoglobinopathy (HEM), and anemia of chronic disease (ACD). A novel feature of the model is its construction and training using human expert input alone. Model construction is described in detail. The model's performance was evaluated with actual case data. It was successful in correctly classifying 96.5% of 473 documented cases of microcytic anemia and anemia of chronic disease. It thus exhibits sufficient accuracy for it to be considered for use in reporting microcytic anemia diagnoses on hematology forms. PMID- 8689872 TI - ANC schemes for the enhancement of EEG signals in the presence of EOG artifacts. AB - One of the most important applications of adaptive systems is in noise cancellation using adaptive filters. In this paper, we propose adaptive noise cancellation schemes for the enhancement of EEG signals in the presence of EOG artifacts. The effect of two reference inputs is studied on simulated as well as recorded EEG signals and it is found that one reference input is enough to get sufficient minimization of EOG artifacts. This has been verified through correlation analysis also. We use signal to noise ratio and linear prediction spectra, along with time plots, for comparing the performance of the proposed schemes for minimizing EOG artifacts from contaminated EEG signals. Results show that the proposed schemes are very effective (especially the one which employs Newton's method) in minimizing the EOG artifacts from contaminated EEG signals. PMID- 8689873 TI - Improving clinician's coded data entry through the use of an electronic patient record system: 3.5 years experience with a semiautomatic browsing and encoding tool in clinical routine. AB - This report presents data on clinicians' use of a browsing and encoding utility. Traditional and computerized discharge summaries during three phases of coding ICD-9 diagnoses were compared: phase I (no coding), phase II (manual coding), and phase III (computerized semiautomatic coding). Our data indicate that only 50% of all diagnoses in a discharge summary are encoded manually; using a computerized browsing and encoding utility this rate may increase by 64%; when forced to encode diagnoses manually users may "shift" as much as 84% of relevant diagnoses from the appropriate section to other sections, thereby "bypassing" the need to encode. This effect can be partially reversed by up to 41% with the computerized approach. Using a computerized encoding help can ensure completeness of encoding data (from 46 to 100%). We conclude that the use of a computerized browsing and encoding tool by clinicians can increase data quality and the volume of documented data. Mechanisms bypassing the need to code can be reversed. PMID- 8689874 TI - Computer-aided differential diagnosis of small solitary pulmonary nodules. AB - A new digital processing method was developed to improve the specific diagnosis of small (up to 3 cm) solitary pulmonary nodules on lung tomograms. The proposed method gives advanced imaging of diagnostically important details and structures of the nodule. It helps the physician easily identify known diagnostic features and discover some additional ones that are useful for reliable verification of cancer, tuberculoma, and hamartoma. X-Ray morphological comparison confirmed that all details, displayed on the processed tomogram, corresponded to morphological structures on postsurgical histotopograms. The method can give additional information to data from conventional and computed tomography, especially in the case of small radiographically indeterminate pulmonary opacities. PMID- 8689875 TI - Software for attributable risk and confidence interval estimation in case-control studies. AB - The increasing interest in obtaining model-based estimates of attributable risk (AR) and corresponding confidence intervals, in particular when more than one risk factor and/or several confounding factors are jointly considered, led us to develop a program based on the procedure described by Benichou and Gail for case control data. This program is structured as an SAS-macro. It is suited to analysis of the relationship between risk factors and disease in case-control studies with simple random sampling of controls, in terms of relative risks and ARs, by means of unconditional logistic regression analysis. The variance of the AR is obtained by the delta method and is based on three components, namely, (i) the variance-covariance matrix of the vector of the estimated probabilities of belonging to joint levels of the exposure and confounding factors conditional on being a case, (ii) the variance-covariance matrix of the odds ratio parameter estimates from the logistic model, and (iii) the covariances between these probability and parameter estimates. Only a limited number of commands is requested from the user (i.e., the name of the work file and the names of the variables considered). The estimated relative risks for all the factors included in the model, the attributable risk for the exposure factor under consideration, and the corresponding 95% confidence intervals are given as outputs by the macro. Computational problems, if any, may arise for large numbers of covariates because of the resulting large size of vectors and matrices. The macro was tested for reliability and consistency on published data sets of case-control studies. PMID- 8689876 TI - Oral contraceptives and thrombotic diseases: impact of new epidemiological studies. AB - Oral contraceptives (OCs) are, or perhaps more correctly, were, until recently, being taken by approximately 65 million women worldwide, which corresponds to approximately 6% of all women of reproductive age. OCs have been available since the early 1960s, and there is substantial evidence to suggest that no single medication has had such a profound impact on our reproductive and social life than the pill. In the Scandinavian countries, 30-50% of young women have been reported to be using OCs. Its widespread use throughout the world for several decades indicates that women and their doctors have considered that the benefits of OCs outweigh potential side effects. On October 18, 1995, the Committee on Safety of Medicines in the United Kingdom sent a warning to all British doctors and pharmacists about OCs containing desogestrel or gestodene. A similar warning was subsequently distributed by the German and Norwegian health authorities. As these OC types dominate the market in Northern Europe, many gynaecologists, general practitioners, women of reproductive age, different national bodies on drug safety, and people in general have been asking: * What was the background for these actions? * How do we interpret the new studies? * What do we do now concerning prescription of OCs? * What is the moral of this story? PMID- 8689877 TI - The male polyurethane condom: a review of current knowledge. AB - Condoms are one of the oldest form of contraceptive and the best recognized form of protection against sexually transmitted diseases. Their use, however, is limited by both behavioral factors and device-related factors, including complaints about decreased sensitivity and sexual enjoyment. To address these limitations, a male condom made of polyurethane was developed. Polyurethane is a strong impermeable material with good heat transfer characteristics that is less susceptible to deterioration during storage than latex. Because little information is available comparing polyurethane and latex condoms in terms of consumer preferences as well as breakage and slippage, we reviewed four pre marketing studies of polyurethane condoms, one of which included comparison to latex. No significant differences in slippage and breakage rates between latex and polyurethane condoms were reported in the study that included a latex comparator, and other studies of polyurethane condoms alone resulted in rates in the same range as published for latex condoms. Subjectively, consumers expressed significantly greater preference for the polyurethane condom over latex in regard to appearance, lack of smell, likelihood of slippage, comfort, sensitivity, natural look, natural feel, and overall. While additional testing is needed, these preliminary results suggest that the male polyurethane condom reviewed performed at least as well as latex condoms and is preferred by consumers. If preference translates to greater use, the male polyurethane condom may address important barriers that have been linked with inadequate condom use in the past. These results, however, may not be generalizable to other brands of polyurethane condom currently under development. PMID- 8689878 TI - Comparison of spermicides on vulvar, vaginal, and cervical mucosa. AB - The objective of this study was to compare the tolerability of Advantage 24 to two other spermicides containing non-oxynol-9 (N-9). These spermicides were Today Sponge (Sponge) and Conceptrol. In order to examine the incidence of complaints and the clinical observation of vaginal ulceration and irritation of the three spermicides, a randomized, open label, three period cross-over trial was conducted. Thirty-three women, ages 18-45, with a normal vaginal environment based on physical exam, Pap smear, vaginal wet prep, colposcopy, and serum N-9 were randomized into four treatment groups. Each treatment was for seven consecutive days with a 21-day washout. Data obtained were studied by one-way analysis of variance, chi-square, and Kruskal-Wallis test. No vulvar or vaginal abnormality was observed from either spermicide. Subjects had fewer and less severe cervical lesions by colposcopy during treatment with Advantage 24 than with Conceptrol or Sponge (p < 0.01). Comparison of the incidence of abnormal gynecological findings, serum N-9 levels, and the incidence of adverse events before and after treatment with the three study drugs indicate that most subjects had normal examinations pre- and post-treatment. Pap smear and colposcopy changes from normal to abnormal accounted for about 50% of all gynecological findings during the Conceptrol and Sponge treatments, but less than 20% during treatment with Advantage 24. All serum N-9 levels were below the level of detection (< 1.9 microgram/ml). Advantage 24 is better tolerated than Conceptrol or the Sponge. Furthermore, the cervical mucosa appears to be less resilient to spermicides than vulvo-vaginal mucosa. PMID- 8689879 TI - Does additional lubrication reduce condom failure? AB - It has been suggested that using additional spermicide with condoms provides added contraceptive effect and protection from infection, and that water-based lubricants may lower condom breakage rates. This questionnaire-based study investigated the use of additional lubrication with condoms amongst 525 female students presenting for post-coital contraception, and the current and past experience of condom and additional lubrication use amongst 481 controls attending the same health centre. Of those requesting post-coital contraception, 83% claimed condom failure as the cause, with 66% of the control group having also experienced condom failure at some time. Use of additional water-based lubrication was significantly associated with lower condom failure rates (odds ratio 8.88, 95% C.I.: 3.79, 20.8). Gender, regularity of use of condoms and using oil-based lubricants were not associated with higher failure rates. Additional lubricant use was not significantly associated with increased condom slippage. PMID- 8689880 TI - Removal of deeply inserted, nonpalpable levonorgestrel (Norplant) implants. AB - Deeply inserted, nonpalpable contraceptive implants can often be removed easily using 6-8 cm3 of 1% lidocaine and a single 1 cm incision. There is no need for suturing of the incision. The location of nonpalpable implants not retrieved by this procedure can be determined by a plain, soft tissue x-ray (standard AP and lateral and internal oblique; 45-55 kVP) of the area where the implants are inserted. Removal can then be accomplished several weeks later. PMID- 8689881 TI - Clinical and hormonal effects of ethinylestradiol combined with gestodene and desogestrel in young women with acne vulgaris. AB - The effect of gestodene 75 micrograms (GTD) versus desogestrel 150 micrograms (DSG) combined with 30 micrograms of ethinylestradiol (EE) on acne lesions and plasma androstenedione (A), total testosterone (T), sex hormone binding globulin (SHBG) and "free androgen index" (FAI) was evaluated in an open study on 19 patients aged 18-35 years affected with postpubertal or persistent non-severe acne vulgaris. The patients were randomly allocated into two groups receiving EE GTD (n = 8) and EE-DSG (n = 11), 21 tablets per cycle for 9 consecutive cycles. Clinical and hormonal evaluations were made between days 17-21 in the cycle before treatment and between days 17-21 of the cycle 3, 6 and 9 of treatment. During treatment, acne improved in most patients, reaching at cycle 9 a low score (absent or minimal) in 62% of the cases in the GTD group (mean acne score = 1.25) and in 90% of the cases in the DSG group (mean acne score = 0.90). Before treatment, about 75% of the patients showed one or more signs of biochemical hyperandrogenism, including elevated FAI (57%), elevated A (15%), elevated total T (15%) and decreased SHBG (21%), and there was evidence of inverse correlation between SHBG and acne scores (p < 0.05). The echogenic texture of the ovaries was multifollicular in 55% of the cases. By the end of the third cycle of treatment, the hormonal changes observed in both groups included significant decreases, with normalization of individual elevated levels of T, and a 3-fold rise of the initial values of plasma SHBG, which showed a further gradual increase at cycle 9 of EE-DSG administration. At cycle 9, normalization of the echogenic ovarian texture was observed. Acne improvement under treatments with estrogen and progestin (EP) could be significantly correlated with the normalization of biochemical hyperandrogenism. In conclusion, the biochemical and clinical efficacy of EE-GTD and EE-DSG indicate that both these preparations can be a good choice in the therapy of acne vulgaris, with a non-significant better clinical result with EE-DSG. PMID- 8689882 TI - Changes in androgens during treatment with four low-dose contraceptives. AB - The aim of the present study was to compare changes in the endogenous androgen environment in healthy women while on low-dose oral contraceptives (OCs). One hundred healthy women were randomized to receive one of four OCs during six months: 21 tablets of Cilest, Femodeen, Marvelon, or Mercilon. During the luteal phase of the pretreatment cycle, body weight and blood pressure were recorded and the following parameters were measured: sex hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), testosterone (T), free testosterone (FT), 5 alpha-dihydrotestosterone (DHT), androstenedione (A), dehydroepiandrosterone sulphate (DHEA-S) and 17 alpha-hydroxyprogesterone (170HP) while also the free androgen index (FAI) was calculated. Measurements were repeated during the 3rd week of pill intake in the 4th and the 6th pill month. There were no differences on body mass and blood pressure with the use of the four OCs. The mean serum DHEA S decreased significantly in all groups though less in the Mercilon group when compared to Cilest and Marvelon (approximately 20% vs 45%). Mean serum SHBG and CBG increased significantly in all four groups approximately 250% and 100%, respectively. In each group CBG also increased significantly but less in women taking Mercilon (-75%) as compared to the others (-100%). Current low-dose OCs were found to have similar impact on the endogenous androgen metabolism with significant decreases of serum testosterone, DHT, A, and DHEA-S. They may be equally beneficial in women with androgen related syndromes such as acne and hirsutism. PMID- 8689883 TI - Norplant subdermal contraceptive system: experience in Taiwan. AB - From November 1988 to December 1994, a total of 567 female volunteers were enrolled in Norplant implant studies at the National Taiwan University Hospital. After a median follow-up of 29 months, only 3 of the 529 available cases became pregnant (a cumulative rate of 1.2 pregnancies per 100 users over 5 years). Chromosome analysis of 2 of the 3 abortuses revealed 46,XX/46,XX,inv(3) and 46,XX. Menstrual problems were the most common adverse effects and were also the main reason for discontinuation (65%, 108/166). The continuation rate was 90%, 78%, 70%, 61%, and 42% at the end of 1, 2, 3, 4, and 5 years after insertion, respectively. In the 21 patients who wished to become pregnant, fertility recurred soon after removal of the Norplant implants. The data suggested that the Norplant implants system is a highly effective, safe, and long-acting method of reversible contraception. It would be worthwhile to introduce this contraceptive system to Taiwan's family planning program. PMID- 8689884 TI - Effect of prostaglandin F2 alpha and methylxanthines on enzymic release of bull epididymal spermatozoa in vitro. AB - The in vitro effect of PGF2 alpha and methylxanthines (theophylline and caffeine) on enzymatic release of bull epididymal spermatozoa was investigated. Epididymal spermatozoa were diluted with egg yolk citrate-based diluent to a concentration of 50 x 10(6) spermatozoa per ml. Aliquots were supplemented with PGF2 alpha at levels of 0, 300, 600 and 1200 micrograms/ml, theophylline or caffeine was added at levels of 0, 500 and 1000 micrograms/ml and incubated at 37 degrees C for 4 h. Spermatozoal motility was decreased with increasing level of PGF2 alpha and the activities of transaminases in the extracellular medium showed a continuous increase. Addition of theophylline or caffeine at both dose levels significantly increased the sperm motility; the activities of transaminases either were not significantly changed or were significantly decreased during the 4 h incubation. These results suggest that supplementation of bull spermatozoa with high levels of PGF2 alpha suppressed motility and induced sperm membrane damage and permeability. However, supplementation of bull spermatozoa with methylxanthines enhanced sperm motility and was not harmful to the integrity of the sperm membrane. PMID- 8689885 TI - Reproductive function in rats after mifepristone-induced termination of pregnancy. AB - The effect of mifepristone, a potent progesterone receptor antagonist, on the reproductive function during early pregnancy in rats was examined. A single dose of this drug (10 mg/kg) was injected s.c. at 1200 h on day 4 (Group 1), day 7 (Group II) or day 10 (Group III) of pregnancy. Gestation was interrupted and the vaginal cytology showed a typical proestrus condition two days after mifepristone treatment in all groups. When compared with cycling proestrus rats, serum LH concentrations at 1800 h in the mifepristone-induced proestrus were lower in Group I, similar in Group II and higher in Group III, and serum prolactin (PRL) values were lower in Group I, but not different in Groups II and III. Serum progesterone levels were higher in the three experimental groups when compared with cycling proestrus rats, and similar to that of pregnant rats. Rats in Group I showed a significantly lower sexual receptivity and ovulation rate when compared with Groups II and III or cycling proestrus rats. Most of the mifepristone-treated rats that copulated during the night of the induced proestrus did not become pregnant and showed a delayed pseudopregnancy-like condition. These results indicate that mifepristone administered in a single dose to early pregnant rats terminates pregnancy and induces a proestrus condition two days after treatment followed by successful postovulatory contraception. The mifepristone-induced proestrus is characterized by a differential pattern of serum LH, PRL and progesterone concentrations, mating behavior and ovulation rates, depending on the day of pregnancy when mifepristone is administered. PMID- 8689886 TI - Normal calves obtained after direct transfer of vitrified bovine embryos using ethylene glycol, trehalose, and polyvinylpyrrolidone. AB - In the present study, IVF bovine embryos were vitrified using as the cryoprotectants, ethylene glycol plus trehalose plus the polymer, polyvinylpyrrolidone (PVP). In Experiment I, toxicity of the vitrification solution (VS) containing 20% PVP was tested in relation to temperature and exposure time. One hundred percent embryo development was observed with treatment at 5 degrees C for 5 min, whereas only 55.5% embryos were developed when the treatment was carried out at 20 degrees C for 5 min. In Experiment II, embryos were vitrified using one of the three treatments (Treatment A, 40% ethylene glycol (EG); treatment B, 40% EG + 11.3% trehalose; and treatment C, 40% EG + 11.3% trehalose + 20% PVP and rehydrations) was performed directly in mPBS. Highest development (84.1%) and hatching rate (68.2%) were obtained when embryos were vitrified with the vitrification solution used in treatment C. In Experiment III, embryos were vitrified as in Experiment II (treatment C). The development and hatching rates were compared after rehydration in different rehydration solutions. No significant difference was observed among the development and hatching rates when rehydration was carried out in different concentrations of trehalose. Five vitrified-warmed bovine embryos were transferred directly to five recipients and three recipients gave birth to three normal calves. PMID- 8689887 TI - In vitro maturation and transmission electron microscopic observation of horse oocytes after vitrification. AB - The study was designed to examine the suitability of immature horse oocytes for vitrification. Immature oocytes derived from slaughtered horse ovaries were transferred to a vitrification solution (EFS; 40% ethylene glycol, 18% Ficoll, and 0.3 M sucrose in modified phosphate-buffered saline) directly (Groups 1 and 4) or were first exposed to 20% ethylene glycol solution for 10 min (Groups 2 and 5) or 20 min (Groups 3 and 6). Oocytes were handled at 20 degrees C (Groups 1, 2, and 3) or 30 degrees C (Groups 4, 5, and 6). After vitrification and warming, their viability was assessed by maturation culture for 32 h. The percentages of oocytes reaching the metaphase II stage after the in vitro maturation in Groups 2, 3, 5, and 6 (16.0, 16.7, 10.0. and 8.2%, respectively) were higher than those in Groups 1 and 4 (2.2 and 1.9%, respectively). In untreated control oocytes, 55.6% completed meiosis in vitro. Transmission electron microscopy was used to compare the fine structure of vitrified oocytes (treated as Group 2) with those of untreated control oocytes and EFS-exposed, nonvitrified oocytes (n = 10 each). The viability of EFS-exposed oocytes, assessed by in vitro maturation, was 27.7%. Vitrification induced some ultrastructural changes, such as the swelling of mitochondria together with reduced matrix density, the destruction of communication between oocytes and their surrounding cumulus cells, and the presence of vacuoles located in the periphery of the ooplasm. However, these changes were not always observed. Exposure of the oocytes to EFS solution induced similar ultrastructural changes in mitochondria and cell-cell communication but to a lesser extent. However, the exposure to EFS induced vacuoles in the periphery of the ooplasm to the same extent as did the vitrification. Thus, immature horse oocytes can be cryopreserved by vitrification with EFS solution. Reduced viability of EFS-exposed and/or vitrified horse oocytes may relate to morphological changes such as destruction of the intercellular communications between cumulus cells and oocytes. PMID- 8689888 TI - Improvement of motility and fertilization potential of postthaw human sperm using glutamine. AB - The effectiveness of three amino acids, glutamine, proline, and histidine, and one amino acid-related compound, betaine, in preserving human sperm diluted v/v in a basal medium (BM) containing 14% glycerol during the freeze-thaw (FT) process was studied. At 80 mM in BM, only glutamine improved the 5- to 60-min postthaw total and progressive motilities and velocity. The presence of glutamine at 80 mM is not sufficient to achieve lower concentrations of the toxic agent glycerol in FT medium. Glutamine may therefore have a mechanism of protection on human spermatozoa that is independent from that of glycerol. The zona-free hamster egg penetration test showed that the percentage of eggs penetrated was significantly greater when spermatozoa were frozen-thawed with 80 mM glutamine in BM. Consequently, the presence of glutamine at 80 mM in a glycerol-FT medium maintains human sperm motility and fertilizing ability during the FT process. PMID- 8689889 TI - Effects of phosphatidylserine and cholesterol liposomes on the viability, motility, and acrosomal integrity of stallion spermatozoa prior to and after cryopreservation. AB - Computer-assisted motion analyses (CASA) and flow cytometry were used to evaluate stallion spermatozoa prior to and after cryopreservation. Spermatozoa were pretreated with: (1) Hepes-buffered medium (SHB); (2) phosphatidylserine (PS) liposomes; or (3) liposomes composed of both PS and cholesterol (PSCH) prior to dilution in either SHB or skim milk-egg yolk extender (SMEY). After cooling to 5 degrees C in SHB, PS and PSCH pretreatment (23%). Spermatozoal motion parameters were higher for spermatozoa diluted in SMEY than dilution in SHB. In Experiment 2, motion parameters were compared for spermatozoa pretreated with PSCH liposomes and cryopreserved in either SMEY or a high salt-skim milk-egg yolk extender (CO). Spermatozoal motion characteristics were similar for all spermatozoal treatments after cooling at 5 degrees C. After cryopreservation, PSCH liposome-treated samples had higher percentages of motile spermatozoa than untreated samples regardless of freezing extender. Samples frozen in CO medium had higher percentages of motile spermatozoa than samples frozen in SMEY (P < 0.05; 63% in CO + PSCH and 54% in CO vs 55% in SMEY + PSCH and 48% in SMEY, respectively). In Experiment 3, spermatozoa were treated with dilauroylphosphatidylcholine (PC12) to induce the acrosome reaction. The percentages of viable cells and viable acrosome-reacted spermatozoa were higher for fresh spermatozoa than for cryopreserved spermatozoa (P < 0.05), but were not affected by PSCH liposome treatment (P > 0.05). Addition of PSCH liposomes improved recovery of motile spermatozoa after cryopreservation but did not affect the ability of spermatozoa to undergo a PC12-induced acrosome reaction. PMID- 8689890 TI - Cryopreservation of an attenuated vaccine strain of the protozoan parasite Toxoplasma gondii. AB - Toxoplasma gondii is a protozoan parasite that infects birds and mammals, including humans. T. gondii T-263 is an attenuated mutant strain that is being developed as a live vaccine to protect cats from shedding oocysts. A cryopreservation procedure for T. gondii T-263 bradyzoites has been developed to meet the requirement for product stability. A Me2SO-based procedure for the cryopreservation of tachyzoites was used as a basis for process optimization. A modified cell culture plaque assay was used to determine the effects of selected cryobiological parameters on bradyzoite viability. The major parameters evaluated were: (i) cooling rates; (ii) intermediate plunge temperature; and (iii) thawing and dilution rates and temperatures. The optimized cryopreservation protocol comprised incubation in 12.5% Me2SO and 4% BSA for 30 min at room temperature, cooling at 1 degree C min-1 to -40 degrees C, followed by direct transfer into liquid nitrogen. Rapid thawing (approximately 120 degrees C min-1) followed by slow dilution of cryoprotectant over 15 min resulted in the highest survival. The optimized procedure increased survival 10,000-fold over that obtained using an established tachyzoite protocol. This procedure is to be adapted for the large scale cryopreservation of T. gondii T-263 bradyzoites in individual vaccine doses. PMID- 8689891 TI - Effect of hypothermia on skeletal muscle metabolism in perfused rat hindlimb. AB - Temperature-induced metabolic change was studied with isolated rat hindlimb muscle to elucidate how tissue viability is maintained under hypothermia. The hindlimb was perfused with Krebs-bicarbonate buffer containing 4% (w/v) polyvinylpyrrolidone (PVP-40T) in a flowthrough mode at 35-8 degrees C. When the temperature was lowered, the following results were observed: (i) Vascular resistance (defined as perfusion pressure divided by flow rate) increased proportionally with elevation of the viscosity of the perfused medium, suggesting that the capillary bed in the perfused muscle is maintained under a similar condition under these temperatures; (ii) the Arrhenius plot of the O2 uptake rate showed a break at ca. 20 degrees C; (iii) the rates of O2 uptake and lactate release decreased, but the lactate/pyruvate ratio increased even under aerobic conditions; (iv) oxygenation of myoglobin and oxidation of cytochromes increased, suggesting a reduced electron-transfer rate in spite of improved or sufficient oxygenation of the tissue. Based on these results, we concluded that oxidative phosphorylation is more affected by temperature than glycolysis, and thus under hypothermia, the role of glycolysis in energy production increases in rat skeletal muscle, especially below 20 degrees C. PMID- 8689892 TI - Effect of supplementation of University of Wisconsin solution with glycoproteins from psychrophilic strains of yeast on hypothermic liver storage of rats. AB - Extracellular yeast glycoproteins (YG) produced by Rhodosporidium toruloides have been shown to increase the survival rate of different yeast species after storage in liquid nitrogen. The purpose of this study was to investigate the effect of YG on cold-stored rat livers. Water-soluble YG produced either by Phaffia rhodozyma (G3) or by Leucosporidium antarcticum (G4) were added to a modified University of Wisconsin solution (mUW) and used for cold storage (1 degree C) of isolated livers. The functional status of each liver was then assessed under conditions of 90-min normothermic reperfusion. The 46-h cold storage in mUW without G3 and G4 resulted in serious preservation-reperfusion injury of the liver. The addition of G3 to mUW for 46-h preservation of the liver resulted in significantly higher bile flow (4.32 +/- 0.35 vs 2.35 +/- 0.49 microliters/min/10 g at 75-90 min), higher portal blood flow (10.99 +/- 0.2 vs 4.78 +/- 1.07 ml/min/g at 90 min), lower liver weight after reperfusion (102.4 +/- 1.5 vs 116.7 +/- 6.6% of weight before preservation), and lower total tissue water after reperfusion (2.49 +/- 0.05 vs 2.92 +/- 0.13 g water/g dry weight). However, the activity of ALT, AST, and LDH in perfusate was not changed. The beneficial effect of G4 was less pronounced. The 24-h storage in mUW resulted in a significant increase of AST and LDH activity in perfusate; the addition of G3 to mUW for 24-h preservation did not affect these parameters. In conclusion, the addition of 0.05% G3 or G4 to mUW was only partially beneficial in improving rat liver preservation. PMID- 8689893 TI - Cryopreservation of isolated rat islets of Langerhans in the presence of ethylene glycol or dimethyl sulfoxide: evaluation of toxicity and the dynamic pattern of subsequent insulin release in vitro. AB - The toxic effect of ethylene glycol (EG) on the pattern of dynamic insulin release from rat pancreatic islets with or without freezing was investigated in comparison with that of dimethyl sulfoxide (Me2SO). Sixty islets were perifused (1 ml/min) consecutively with D-glucose (1.67 mM for 30 min followed by 16.7 mM for 60 min and 1.67 mM for 60 min) after exposure to 2.0 M EG or Me2SO for 1 h at either 22 or 0 degrees C. During the second period of perifusion, the insulin output from islets exposed to Me2SO or EG at 22 degrees C decreased to 53 and 51% of that from nontreated control islets, respectively. On the other hand, the islets exposed to EG at 0 degrees C exhibited 86% of the control insulin output under the same perifusion conditions, and this appeared to be higher than that of islets exposed to Me2SO (60%) at 0 degrees C. Frozen islets, after exposure to 2.0 M EG or Me2SO for 1 h at 0 degrees C, responded positively to 16.7 mM D glucose, and the typical biphasic pattern of insulin secretion was observed. The insulin output from these islets during the second period of perifusion was not comparable to that from unfrozen control islets. In particular, the mean insulin output of EG-cryopreserved islets during the second period accounted for 99% of that from unfrozen control islets. The present findings suggest the possible use of EG as an alternative cryoprotectant to Me2SO. PMID- 8689894 TI - Mechanisms of cryoinjury and cryoprotection in split-thickness skin. AB - Successful cryopreservation of tissues will ultimately require a more detailed understanding of how the in situ environment modifies cell responses during cooling and warming. Low-temperature responses of porcine split-thickness skin and isolated basal keratinocytes were compared after various cooling protocols and in the presence and absence of cryoprotectants. Recovery was assessed by measuring oxygen consumption kinetics in skin and tetrazolium reduction in isolated cells. Freeze substitution was used to visualize ice nucleation and growth in skin. The results indicated that the time required for diffusion of water in split-thickness skin delayed osmotic responses in the basal keratinocytes and resulted in increased intracellular and intercellular ice formation. Rapid cooling (-200 degrees C/min) in the presence of cryoprotectants resulted in a reduction in the number of cells containing ice and the size of the intercellular ice crystals and an increase in tissue recovery. These observations support other reports which suggest that cell-to-cell and cell-to-substrate interactions are sensitive sites for cryoinjury. A practical recommendation from this study is that high recovery of split-thickness skin may be achieved with protocols using high cooling rates. PMID- 8689895 TI - The spectrum of first-trimester ultrasound findings. AB - A wide spectrum of sonographic findings can be seen in the first trimester of pregnancy. One must have an appreciation of embryology to recognize normal and abnormal early pregnancy development. In this article we emphasize discriminatory criteria for identification of normal structures, as well as ultrasound findings in threatened abortion, failing pregnancy, multiple gestations, ectopic pregnancy, and trophoblastic disease. Sonoembryology, the identification of embryonic anatomy, is discussed, as are examples of early identification of anomalies. PMID- 8689896 TI - Influence of freezing at different temperatures on the transcription activity of buffalo sperm chromatin. AB - The effect of freezing at different temperatures, -20 degrees C, -70 degrees C and -196 degrees C, on the transcription activity of buffalo sperm chromatin was investigated. The kinetic data of incorporation of 3H-UTP in pre-mRNA indicate that temperatures of -70 degrees C and -196 degrees C are the most favourable for preservation, since transcription activity gradually increases with time, reaching maximum values within 30 min. Freezing at -20 degrees C or preservation at 4 degrees C leads to a rapid decrease of transcriptional activity within 10 and 20 min, respectively. It is suggested that the optimal temperature for storage of buffalo spermatozoa is below -20 degrees C as judged by the transcription assay. PMID- 8689897 TI - Reverse transcription in a macromolecular complex of ovine bone marrow: possible involvement in the antigen receptor mediated signal transduction process. AB - A macromolecular fraction was isolated from ovine bone marrow and designated the active fraction (AF). Two distinct enzymatic activities were detected in the AF: (1) a RNA-dependent RNA polymerase, and (2) a reverse transcriptase. RNA polymerase uses an endogenous RNA molecule of the AF as the template while the product of this RNA polymerase reaction forms the template for the reverse transcriptase. Synthetic reactions are initiated exclusively upon the exposure of the in vitro system to one of the external proteins, selected at random, ovalbumin or insulin. Ovalbumin specific (OS) and insulin specific (IS) AF fractions were prepared. OS-AF binds 14C-ovalbumin and the IS-AF binds 14C insulin, but not vice versa. Reverse transcription activity of OS-AF is stimulated only upon its exposure to ovalbumin and not to insulin while the reverse is true for the activity associated with IS-AF. Indirect evidence indicates that the enzymes which synthesize nucleic acids are closely associated with the antigen receptor on the B-lymphocyte plasma membrane, the mlgM, and that the antigen binding to its receptor helps in the activation of these enzymes. PMID- 8689898 TI - Effects of caffeine on mating frequency and pre-copulation and copulation durations in Drosophila prosaltans. AB - Parameters of sexual behaviour were studied in Drosophila prosaltans treated with 2,500 micrograms/ml of caffeine per 1 ml of banana culture medium. The mating frequency and copulation duration were greater in control than in treated flies, while the pre-copulation duration was greater in treated flies than in controls. Statistical analysis showed that for the pre-copulation duration the difference was significant. PMID- 8689899 TI - New categories of missing children: injured, lost, delinquent, and victims of caregiver mix-ups. AB - A national survey of 10,367 households uncovered cases of missing children that did not fall into one of the four federally defined categories of missing children. Qualitative and quantitative procedures disclosed the existence of four additional categories: children missing due to injury in an accident, delinquent and rebellious behavior, getting lost, and miscommunication among adult caregivers. Two of these categories, injured and lost children, should particularly be included in missing children's typologies because of their potential seriousness. Vulnerability to all four kinds of episodes was associated with certain family characteristics, suggesting that they were not simply accidental occurrences. In addition to help in locating their children, these families may need other forms of assistance. PMID- 8689900 TI - Association between H. pylori, duodenal mechanosensory thresholds, and small intestinal motility in chronic unexplained dyspepsia. AB - Alterations of small intestinal sensory thresholds and small intestinal dysmotility are associated with functional dyspepsia. Because gastric and duodenal afferents partly project to the same areas, we postulated that patients with functional dyspepsia and H. pylori infection would be characterized by lower duodenal sensory thresholds. We evaluated 16 patients with functional dyspepsia and 16 age- and sex-matched controls. All patients had undergone an extensive diagnostic work-up to exclude organic lesions. Mechanosensitive function was tested in the third portion of duodenum utilizing a barostat device, and small intestinal motility was assessed before and during duodenal nutrient infusion with a five-channel low-compliance perfusion system. H. pylori status was assessed by a validated serological test. Small intestinal sensory thresholds (first perception and maximal tolerated pressure) were significantly lower in patients (21.1 +/- 2.1 and 30.9 +/- 1.8 mm Hg) compared to controls (33.0 +/- 2.2 and 38.8 +/- 0.9 mm Hg, all P < 0.003). Nine of 16 patients compared with five of 16 controls were H. pylori positive (P = 0.15). Thresholds for H. pylori-negative (28.7 +/- 2.8 and 36.5 +/- 1.1 mm Hg) or -positive subjects (25.0 +/- 3.0 and 32.7 +/- 2.4 mm Hg) were overall not significantly different (P > 0.3). However, in patients with defined high H. pylori titers (>50 units/ml) defined a priori, thresholds for first perception were significantly lower (14.7 +/- 2.9 mm Hg, N = 5) compared to patients with H. pylori titers below this threshold (24.3 +/- 2.9 mm Hg, N = 4) or without H. pylori infection (23.8 +/- 3.4 mm Hg, P < 0.05). During duodenal nutrient infusion, the duodenal motility index increased (P < 0.03). This increase was not significantly different in patients and controls or in H. pylori-negative or -positive subjects. Sensory abnormalities are present in patients with functional dyspepsia. In a small subgroup of patients with high H. pylori titers, sensory abnormalities may be linked to H. pylori infection. PMID- 8689901 TI - Electrogastrography in chronic intestinal pseudoobstruction. AB - This study aimed to characterize the disturbance of gastric electrical control activity in chronic intestinal pseudoobstruction (CIP) and to determine whether surface electrogastrography (EGG) could be used to diagnose the presence and type of CIP. Gastric electrical control activity was recorded for 30 min in each of the fasting and fed states by EGG in 14 adults with CIP proven on clinical, radiological, and histological grounds, and in 14 age- and sex-matched controls. Electrical activity was recorded from four pairs of Ag-AgCl bipolar skin electrodes, the captured signal amplified and digitalized, and running spectral analysis performed. The dominant frequency and power of spectrum were calculated using a sequence of computerized algorithms. Results were correlated with the known pathological diagnoses [visceral myopathy (M), N = 7; visceral neuropathy (N), N = 4; undifferentiated (U), N = 3]. Dysrhythmias were present in 13 of 14 patients. Tachygastria (electrical control activity frequency >5 cycles/minute) and a normal amplitude response to food, was seen in five patients (N = 4, U = 1). Irregular continuous activity without a dominant frequency or bradyarrhythmia, together with a diminished electrical response activity (ERA) to food, were found in six patients (M = 5, U = 1). Mixed abnormalities were seen in two patients (M = 1, U = 1), and normal activity with a clear dominant frequency of 3 cycles/minute was present in only one patient (M = 1). This noninvasive technique is both sensitive and specific in providing evidence of a dysrhythmia in patients with CIP and discriminates between primary pathologies. EGG may prove diagnostically useful in these disorders and may provide insight into the disturbance of electrical control activity. PMID- 8689902 TI - Idiopathic constipation is not associated with increased NCAM expression on intestinal muscle. AB - Our previous study of neural cell adhesion molecule (NCAM) in childhood Hirschsprung's disease demonstrated increased expression on intestinal muscle, especially muscularis mucosae, in aganglionic bowel. The present study was undertaken to test whether this increased NCAM expression is a feature of congenital aganglionosis rather than being a nonspecific feature of constipation. We studied specimens from six patients (20-60 years old; five women and one man) operated on for idiopathic long-standing constipation, using immunocytochemistry for NCAM and protein gene product 9.5 (PGP 9.5). Results showed that in adult constipated bowel the pattern of NCAM expression is similar to that seen in controls. There was no expression of NCAM on muscle in any of the specimens studied. Thus, it seems likely that increased NCAM expression in gastrointestinal smooth muscle in congenital aganglionosis is a result of the abnormal innervation rather than any symptomatic or clinical feature. PMID- 8689904 TI - Bipolar electrode implantation for myoelectrical recordings of rat bowel. AB - This report describes a technique to implant bipolar electrodes into the rat bowel. We implanted a total of 129 pairs of bipolar electrodes into the bowel of rats. 124 pairs of electrodes (96.3%) have continuously functioned allowing repeated myoelectrical readings. Of these, 69 electrodes functioned over 8 weeks. Only 5 electrodes (3.7%) failed. The advantage of our technique includes: (1) high success rate in implantation, (2) long term durability, and (3) less technical difficulty. PMID- 8689903 TI - Nitric oxide mediates mechano- and chemoreceptor-activated intestinal feedback control of gastric emptying. AB - The effect of nitric oxide (NO) synthase inhibition on the gastric emptying of nutrient and nonnutrient meals was investigated in nine dogs. The inhibition of NO synthase delayed the gastric emptying time of both nutrient and nonnutrient meals, but the percentage delay of nutrient meals was significantly greater than that of nonnutrient meals. The inhibition of NO synthase during the emptying of nonnutrient meals enhanced mainly the amplitude of antral, pyloric, and distal duodenal contractions. However, NO synthase inhibition during the emptying of nutrient meals stimulated several spatial and temporal parameters of gastropyloroduodenal contractions. We conclude that NO is one of the neurotransmitters of intestinal feedback that regulates the gastric emptying of both nutrient and nonnutrient meals. The nature and intensity of intestinal feedback by the stimulation of both chemo- and mechanoreceptors by nutrient meals is different from that by the stimulation of mechanoreceptors only by the nonnutrient meals. PMID- 8689905 TI - Efficacy of metronidazole lavage in treatment of intraperitoneal sepsis. A prospective study. AB - In a prospective study, 182 consecutive patients were included for the treatment of intraabdominal sepsis with adjuvant metronidazole lavage that was carried out at the end of the operative procedures. Eighty of them underwent emergency surgery for peritonitis and 102 elective surgery for a variety of lesions. Although fecal peritonitis was found in 23 and malignant tumors in 84 patients, there was not a single instance of intraabdominal abscess in 182 patients, but the incidence of wound infection was 2.66% in the emergency group and 0% in the elective group; mortality was 5% and 3.9%, respectively. Therefore, adjuvant metronidazole lavage provides confidence in the treatment of intraperitoneal abscess, and it enhances a quick recovery. It is safe to use and cost effective. PMID- 8689907 TI - Does Helicobacter pylori-induced gastritis enhance food-stimulated insulin release? AB - The fact that H. pylori gastritis results in an increased secretion of basal and meal-stimulated gastrin, which is also a physiologic amplifier of insulin release directed us to investigate whether H. pylori gastritis may lead to an enhancement of nutrient-stimulated insulin secretion. For this purpose, we have investigated the insulin responses to both oral glucose and a mixed meal in 15 patients with H. pylori gastritis before and one month after the eradication therapy and also in 15 H. pylori-negative control subjects. The areas under the curve (AUC) for serum insulin following both oral glucose and a mixed meal in the patients with H. pylori gastritis before the eradication were significantly (P < 0.05) higher than those in the H. pylori-negative controls. After the eradication of H. pylori, the AUC for serum insulin following oral glucose and mixed meal decreased by 9.4% and 13.1%, respectively (P < 0.001 in both), and serum basal and meal stimulated gastrin levels decreased significantly (P < 0.001). These results suggest that H. pylori gastritis enhances glucose and meal-stimulated insulin release probably by increasing gastrin secretion. PMID- 8689906 TI - Long-term use of nonsteroidal antiinflammatory drugs and other chemopreventors and risk of subsequent colorectal neoplasia. AB - Our objective was to study the relationship between dispensed aspirin, nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), steroidal antiinflammatory drugs (SAIDs), acetaminophen, calcium, psyllium, and multivitamin preparations and the risk for subsequent colorectal adenoma and adenocarcinoma. The design was a case control study. The patient population was from a large municipal teaching hospital in Atlanta, Georgia. In logistic regression models, the risk of colorectal adenoma or adenocarcinoma decreased in the first two years of continuous NSAID use in a linear, time-dependent manner. The risk of colorectal neoplasia after two years of continuous NSAID use was reduced significantly (P < 0.01) as compared to nonusers. Risk reduction appeared greater for adenocarcinoma than adenoma. The use of SAIDs, calcium, multivitamins, and psyllium, as prescribed to our patient population during the mean six-year study period, conferred no measurable risk reduction. These results suggest that in prospective chemoprevention trials, a significant risk reduction can be expected after only two years of aspirin use, in doses similar to those recommended for the prevention of cardiovascular disease, or nonaspirin NSAIDs [correction of nonaspirin. NSAIDs], in doses commonly prescribed for the management of musculoskeletal pain. The results also imply that any short-term reduction in the incidence of colorectal adenoma detected in a phase II trial would underestimate the chemopreventive effect of NSAIDs on the risk of adenocarcinoma. PMID- 8689908 TI - Blood leukocyte differential in Helicobacter pylori infection. AB - Helicobacter pylori causes a chronic infection in gastric mucosa, but its systemic effects are largely unknown. Our aim was to characterize the effect of H. pylori infection and gastric mucosal inflammation on the peripheral blood leukocyte count. An endoscopic series of 96 patients (40 men and 56 women), with a mean age of 62 years (range 49-80) was studied. Endoscopy with eight stepwise biopsies was performed and the occurrence of H. pylori was studied from sections stained with Warthin-Starry. The severity of inflammation in antral and body mucosa was estimated. The peripheral blood leukocyte count and differential count were determined by the automatic flow cytometric method. The total number of blood leukocytes and the numbers of lymphocytes and basophils were significantly increased in H. pylori-positive patients (N = 58), as compared with H. pylori negative ones (N = 38). The total number of blood leukocytes correlated with the numbers of neutrophils, eosinophils, and mononuclear cells in the gastric mucosa. The number of basophils correlated with the number of mucosal neutrophils and mononuclear inflammatory cells. The results show that mucosal inflammation due to H. pylori infection is reflected in the amount of peripheral blood leukocytes. Basophilia suggests involvement of allergic mechanisms in H. pylori gastritis. PMID- 8689909 TI - Endoscopic-pathologic correlates of Candida esophagitis in acquired immunodeficiency syndrome. AB - Although Candida esophagitis is one of the most common opportunistic infections in patients with acquired immunodeficiency syndrome (AIDS), there has been no systematic study of the endoscopic and pathologic manifestations of this disease. During a 53-month period, 141 patients with AIDS and Candida esophagitis were studied. All patients had the severity of esophagitis graded prospectively and esophageal mucosal biopsies performed. Tissue biopsies were evaluated for histologic evidence of ulceration, extent of candidiasis, and presence of viral cytopathic effect. Follow-up was obtained. There appeared to be a uniform endoscopic appearance; with increasing severity, the scattered mucosal plaques coalesced, resulting in circumferential disease and luminal impingement. The pathologic pattern of Candida esophagitis was homogenous. Plaque material was composed primarily of desquamated superficial hyperplastic hyperkeratotic squamous epithelium and inflammatory cells, with infiltration by fungal elements and bacteria consistent with superinfection. Although endoscopic and histopathologic ulcer was commonly seen in these patients (32%), only four patients had ulcer believed secondary to Candida esophagitis alone. In conclusion, in patients with AIDS, Candida esophagitis is a superficial mucosal infection resulting in characteristic endoscopic and histopathologic patterns. PMID- 8689911 TI - Esophageal smooth muscle dysfunction in oculopharyngeal muscular dystrophy. AB - Oculopharyngeal muscular dystrophy (OPMD) is a rare genetic disorder with late onset progressive myopathy affecting mainly head and neck striated muscles. It is more common in certain ethnic communities. Dysphagia was usually attributed to the malfunction of striated pharyngeal muscles. We studied a group of Bukharan immigrants affected by this disorder (N = 13). Esophageal studies, including endoscopy, manometry, and scintigraphic emptying were performed. Very low pharyngeal pressures were measured. Upper esophageal pressures (UEP) were in the normal range in eight patients, and above normal in three patients. Four also had low lower esophageal sphincter pressure. Esophageal body peristaltic activity was grossly impaired in all patients: mainly nonpropulsive, simultaneous, retrograde, and failed activity was recorded. Marked retention of isotopic material was demonstrated in all patients studied, usually in the middle and lower parts of the body, ranging from 17 to 100% retention. The dysphagia in OPMD is due not only to dysfunction of pharyngeal and upper esophageal striated muscle, but also has a significant smooth muscle component. PMID- 8689910 TI - Manometric diagnosis of diffuse esophageal spasm. AB - There are no requirements concerning the amplitude of simultaneous contractions among the present criteria for the manometric diagnosis of diffuse esophageal spasm. The purpose of this investigation was to determine whether the current criteria effectively identify an appropriately homogenous patient population. Sixty consecutive motility tracings that met the criteria for diffuse esophageal spasm were evaluated. A bimodal distribution of the highest simultaneous esophageal contraction for each patient was observed. One group's (N = 29) highest simultaneous esophageal contractile amplitude was < or = 74 mm Hg, the other's (N = 31) highest simultaneous esophageal contractile amplitude was > or = 100 mm Hg. Group 1 had significantly decreased lower esophageal sphincter pressure, lower peristaltic amplitude, more aperistalsis, fewer simultaneous contractions, and fewer complaints of chest pain. These comparisons suggest that consideration be given to the amplitude of simultaneous esophageal contractions in the manometric diagnosis of diffuse esophageal spasm. PMID- 8689912 TI - Optimal evaluation of patients with nonobstructive esophageal dysphagia. Manometry, scintigraphy, or videoesophagography? AB - The aims of this study were to compare diagnostic accuracy, cost, and patient tolerance of videoesophagography and esophageal transit scintigraphy to esophageal manometry in the evaluation of nonobstructive esophageal dysphagia. Eighty-nine consecutive patients underwent videoesophagography, scintigraphy, and manometry. The sensitivities for diagnosing specific esophageal motility disorders, using esophageal manometry as the standard, were 75% and 68% for videoesophagography and scintigraphy, respectively, with positive predictive accuracies of 96% and 95% for achalasia, 100% and 67% for diffuse esophageal spasm, 100% and 75% for scleroderma, 50% and 67% for isolated LES dysfunction, 57% and 48% for nonspecific esophageal motility disorders, and 70% and 68% for normal esophageal motility. The cost for videoesophagography is less than that for either manometry or scintigraphy. Both videoesophagography and scintigraphy were better tolerated than manometry. It is concluded that videoesophagography and scintigraphy accurately diagnose primary esophageal motility disorders, achalasia, scleroderma, and diffuse esophageal spasm, but are less accurate in distinguishing nonspecific esophageal motility disorders from normal. When considering accuracy, cost, and patient acceptance, these findings suggest that videoesophagography is a useful initial diagnostic study for the evaluation of nonobstructive esophageal dysphagia. PMID- 8689914 TI - Time pattern of gastric acidity in Barrett's esophagus. AB - Increased gastroesophageal acid reflux is frequently found in patients with Barrett's esophagus, and it has been hypothesized that gastric acid hypersecretion could be an important factor aggravating the exposure of esophageal mucosa to acid and then contributing to the development of this disorder. The aim of the present study was to assess whether the circadian pattern of gastric acidity differs between refluxer patients with and without Barrett's esophagus and normal subjects. Continuous 24-hr gastric pH monitoring was performed in 119 healthy volunteers, 20 patients with Barrett's esophagus, 37 patients with moderate and 10 patients with severe reflux esophagitis without Barrett's esophagus. In all these diseases the final diagnosis was ascertained by means of endoscopy plus biopsy. There was no difference in the 24-hr and daytime patterns of gastric pH between healthy subjects and patients with Barrett's esophagus, while nocturnal acidity was significantly lower (P < 0.05) in the latter population. Gastric acidity, in contrast, was higher (P < 0.05) in controls than in patients with both moderate and severe reflux esophagitis without Barrett's esophagus during the whole 24-hr period. There was no difference between refluxer patients with and without Barrett's esophagus in any of the three time intervals we analyzed. Because normal subjects had lower gastric pH than patients with Barrett's esophagus during the night and than patients with reflux esophagitis during the whole 24-hr period, gastric hyperacidity is not a relevant factor in the development of both metaplastic columnar epithelium and inflammatory changes in the distal esophagus, and other pathophysiological mechanisms are involved in these histological alterations. PMID- 8689913 TI - Symptom improvement from prokinetic therapy corresponds to improved quality of life in patients with severe dyspepsia. AB - Prokinetic therapy has been shown to improve patients' symptoms associated with gastrointestinal motility disorders and quality of life. This study investigated the correlation between clinical improvement and quality of life after 12 months of treatment with cisapride or domperidone in patients with severe dyspepsia. Psychological and quality-of-life measures were assessed at baseline and after 12 months of therapy using three patient-administered, standardized questionnaires: the Minnesota Multiphasic Personality Inventory, the Millon Behavioral Health Inventory, and the Sickness Impact Profile. Changes in clinical symptoms were correlated with changes in these measures. Twenty-seven patients with symptoms of severe dyspepsia were treated with cisapride or domperidone (60-80 mg/day) for 12 months. Symptoms and quality-of-life measures were improved at the end of therapy. There were significant correlations between improvement in clinical symptoms and improvement in quality of life parameters. Patients with more marked symptom improvement had more significant improvements in quality of life measures. We conclude that prokinetic therapy improved symptoms and quality of life. Standardized questionnaires can be used to quantify response to prokinetic therapy and to individualize treatment regimens for patients with dyspepsia who have specific psychologic or behavioral characteristics. PMID- 8689916 TI - Insulin-like growth factor I in suckling rat gastric contents. AB - The small intestinal mucosa of the neonatal rat expresses primarily lactase activity until just prior to weaning when lactase falls to low levels and a full complement of adult digestive enzymes appears. Insulin-like growth factor 1 (IGF I) is a normal component of maternal milk of humans and experimental animals. Experiments were performed to examine the concentrations of IGF-I in dam milk and the gastric content of suckling pups. Lactase activity in 1-day-old neonates was 0.66 micromol glucose formed/mg protein/hr (unit) and fell progressively until day 25, whereas sucrase activity at day 1 postpartum was 0.07 units and rose progressively to 0.21 units at day 25. The IGF-I content of dam milk was measured at 1, 5, 10, 15, 18, and 20 days postpartum by radioreceptor assay (RRA). Milk contained 1.02 pmol IGF-I/ml milk at one day postpartum, peaked at day 18 with 5.08 pmol IGF-I/ml, and fell to 2.31 pmol/ml at day 20. By day 25, dams were dry. The IGF-I content of the neonate gastric lumen was also measured by RRA. At day 1 the gastric lumen contained 2.63 pmol IGF-I/ml of luminal contents, fell to 1.06 pmol IGF-I/ml at day 5, and then rose again to peak at 3.37 pmol/ml at day 15 just prior to weaning. Two days after weaning, the level of luminal IGF-I had fallen to 1.15 pmol/ml. These data demonstrate the concentration of IGF-I in maternal milk is reflected in the concentration of the peptide in gastric contents of suckling pups and that the concentration in the gastric lumen may be high enough to affect epithelial cell proliferation and differentiation. PMID- 8689915 TI - Gastric acid and pepsin secretion in patients with Barrett's esophagus and appropriate controls. AB - The objective of this study was to determine whether gastric secretion of acid and pepsin is different in the subset of esophagitis patients who also have Barrett's esophagus. Basal and stimulated gastric secretions were studied for 1 hr in the unstimulated state and 1 hr after pentagastrin 6 microg/kg subcutaneous injection. Because Barrett's patients are predominantly male, the 30 patients were matched with patients who had esophagitis, but not Barrett's, for sex (26 men, 4 women) and age as well as for background gastrointestinal disease (duodenal ulcer in 10, no ulcer disease in 17 and Zollinger-Ellison hypersecretors in 3). Patients with Barrett's weighed more than controls (P < 0.05). Acid and pepsin output in the basal and stimulated state were no different in Barrett's and their appropriately matched controls. Overnight fasting residue- volume, pH, acid and pepsin concentrations, and bile content--were also alike. The severity of esophagitis or prevalence of esophageal ulcer or stricture was not different between those with and without Barrett's and in neither was the grade of esophagitis related to acid or pepsin output. It is concluded that Barrett's esophagus patients do not have gastric secretions different from appropriately matched controls with esophagitis alone. When present, esophagitis due to reflux in Barrett's epithelium should be treated on its merits by appropriate reduction of acid exposure. PMID- 8689917 TI - Changes in parietal cell structure and function in HIV disease. AB - The mechanisms underlying acid secretory failure in patients with HIV disease are unknown. We evaluated, in a series of preliminary studies, changes associated with parietal cell structure and function in early and late HIV disease, in an attempt to elucidate possible underlying mechanisms. Gastric acid and intrinsic factor secretion, vitamin B12 absorption, and light and electron microscopic evaluation of gastric mucosa were evaluated in patients with early and late HIV infection (AIDS) and compared to non-HIV-infected controls. Immunolocalization of HIV-related antigens in gastric mucosa was also examined. Fasting gastric juice pH and intrinsic factor (IF) concentration in AIDS and HIV infected subjects were significantly different from controls (P = 0.012 and P = 0.025, respectively for pH, and 0.029 and 0.035 for IF; ANOVA LSD test). By contrast, maximal acid output (MAO) was significantly lower in AIDS, but not HIV-infected subjects (P = 0.043 and P = 0.322, respectively). Similarly, Schilling test phases 1 and 2 results were significantly lower in AIDS, but not HIV-infected subjects. Varying degrees of vacuolar degeneration of parietal cells were seen on light microscopy. On electron microscopy (EM), tubulovesicles were reduced and intracellular canaliculi dilated with striking loss of microvilli. Immunofluorescent staining with antibodies to gp120, gp41, p24, and p17 demonstrated positive punctate signals in the cytoplasm of gastric glands, which includes parietal cells. Immunogold EM with anti-gp120, localized predominantly to the microvilli of intracellular canaliculi in parietal cells. Abnormal secretory function of parietal cells occurs early in HIV disease, affects acid as well as intrinsic factor secretion, and is associated with morphological changes in the acid secretory apparatus. PMID- 8689918 TI - Decreased vasoactive intestinal peptide levels and glutathione depletion in acquired megacolon. AB - We reported decreased vasoactive intestinal peptide levels in acquired megacolon. The origin of altered neuropeptide levels is unknown, but recent work suggested that tissue antioxidants may function as neuroprotectants. Our hypothesis was that altered levels of inhibitory neurotransmitters in human colon are associated with depletion of the tripeptide thiol, glutathione. Normal colon samples (N = 10; from patients 41-80 years old) and acquired megacolon samples (N = 10; from patients 31-98 years old) were obtained at surgery. Vasoactive intestinal peptide levels were decreased in muscularis externa from acquired megacolon (P = 0.01), while there was a modest increase in NADPH diaphorase activity in muscularis externa from megacolon (P = 0.10). Glutathione in acquired megacolon was detectable in muscularis externa from only five specimens (P < 0.05), but was not significantly different (P > 0.05) in the mucosal-submucosal layer. The results supported the presence of vasoactive intestinal peptide and NADPH diaphorase in distinct subpopulations of nerves in human colon. The results also supported the hypothesis that glutathione functions as a neuroprotectant in a subset of patients with acquired megacolon. PMID- 8689919 TI - Crohn's disease and vitamin B12 metabolism. AB - The concentrations of vitamin B12, its analogs, and the haptocorrin and transcobalamin carriers in 21 patients suffering from Crohn's disease and a group of controls (20 adults) were measured. There were no significant differences in the mean values for vitamin B12, total corrinoids (vitamin B12 + analogs), or vitamin B12 or total corrinoids bound to haptocorrin or transcobalamin of the Crohn's and control patients. There was a significant increase in the binding capacity of transcobalamin in the Crohn's patients compared to the controls (P < 0.001), but there was no difference in the binding capacities of haptocorrin. The serum concentrations of the markers of vitamin B12 status, homocysteine and methylmalonic acid, showed an increase (P < 0.01) in homocysteine in the Crohn's disease patients, but no change in methylmalonic acid. As the hyperhomocysteinemia was associated with normal folate concentrations, there may have been a defect in the activation of the enzyme due to altered intracellular vitamin B12 status. PMID- 8689920 TI - Enhanced absorption of macromolecules. A secondary factor in Crohn's disease. AB - We explored the function of the intestine's mucosal barrier to foreign antigen entry in Crohn's disease. Macroscopically and microscopically uninvolved areas of the small intestines of patients with Crohn's disease were examined. We studied 27 endoscopic biopsy samples from 17 patients with Crohn's disease and 14 samples from nine controls. The absorption and degradation of horseradish peroxidase (molecular weight 40,000 Da) were studied in Ussing chambers. The absorption of intact horseradish peroxidase was significantly increased in patients with moderate or severe Crohn's disease: 271 (95% confidence interval 119-616) ng/hr/cm2, but not in those with slight disease activity: 42 (18-98), compared with controls: 45 (32-64); F = 10.90, P = 0.0002. The transport rates of degraded horseradish peroxidase were comparable in the Crohn's disease samples and controls. Our results indicate that enhanced absorption of macromolecules is associated with clinical activation of Crohn's disease, and impairment of the mucosal barrier function is a secondary phenomenon in Crohn's disease. PMID- 8689921 TI - Cosegregation of familial intestinal pseudoobstruction and presence of digital arches in a large multigenerational pedigree. AB - Previous studies have suggested a relationship between the presence of digital arches and the occurrence of early-onset chronic intestinal pseudoobstruction (CIP). We recently had under our care a patient who died of complications from neuropathic familial CIP (FCIP) and who had family members with symptoms and radiographic findings consistent with FCIP. Our aim was to determine if there is a relationship between FCIP and digital arches using members of this patient's family tree. Questionnaires, telephone follow-up, and clinical and radiographic evidence were all utilized to determine whether a diagnosis of CIP could be made for the family members of this deceased FCIP patient. Fingerprints were sought for all study subjects. Eight of the 26 study subjects who were fingerprinted had clinically diagnosed FCIP and four of these eight had radiographic confirmation. All eight were positive for one or more arches (sensitivity = 100%). Only one of the 18 subjects without a diagnosis of FCIP who were fingerprinted had arches (specifically 94%). The likelihood of linkage between the presence of digital arches and FCIP in our study family was significant by genetic linkage analysis criteria. These results show a significant correlation between FCIP and digital arches (P < 0.0001). Whether this relationship is a causal one, ie, the gene responsible for digital arches is also responsible for FCIP, or is the result of linkage between the genes for FCIP and digital arches remains unclear. PMID- 8689922 TI - Analysis of structural and biochemical events occurring in the small intestine after dietary polyamine ingestion in suckling rats. AB - In the present investigation, we analyzed the mechanism involved in spermine induced intestinal maturation in suckling rats. Spermine was given orally to suckling pups and biochemical as well as morphological parameters were studied at different times after the beginning of the treatment. Eight hours after administration, spermine produced cell elimination at the villus tops and a decrease in intestinal DNA and protein content. In parallel, protein and DNA concentration and disaccharidase activity were enhanced in the chyme. These transitory alterations were not induced by growth inhibition, as DNA synthesis was not modified, although a brief decrease in protein synthesis was observed. Spermine was not metabolized in cytotoxic products: rat pretreatment with MDL72527 (an inhibitor of polyamine oxidase) did not avoid the decrease in disaccharidase activity and in DNA and protein content. Three days after treatment, sucrase and maltase activity was higher in rats treated with spermine and MDL72527 than that in animals receiving spermine alone. Lactulose or acetylspermine ingestion induced intestinal maturation. Our data suggest that dietary polyamines exert a direct and specific maturational effect on rat small intestine and that an early decrease in lactase activity plays an important role in this phenomenon. PMID- 8689923 TI - Effect of pluronic L-81 on intestinal lipoprotein secretion in the rat. AB - The hydrophobic nonionic detergent Pluronic L-81 has been shown to lower plasma very-low- and low-density lipoprotein cholesterol, thus preventing diet-induced atherogenesis. The major effect of this agent is a pronounced interference with intestinal lipid metabolism. For studying mesenteric lymph lipoproteins during detergent exposure, a combined micromorphological and biochemical assessment of mucosa and lymph during steady-state lipid absorption was performed. Pluronic L 81 was infused intraduodenally at a constant rate in combination with mixed micellar solutions or saline in mesenteric lymph fistula rats. Pluronic L-81 impairs transepithelial lipid flux during fat absorption, trapping export lipids within the enterocytes and leading to a cytosolic and endoplasmic reticulum lipid accumulation sparing the Golgi region. Pluronic L-81 markedly (P < 0.001) reduces mesenteric triglyceride, phospholipid, and total cholesterol secretion almost exclusively by a reduction of chylomicron formation. Chylomicron and very-low density lipoprotein lipid composition was only insignificantly altered, except for somewhat higher phospholipid/triglyceride ratios. The chylomicron apoprotein pattern was almost unaffected. Thus, chylomicron formation decreased dramatically without major compositional alterations. The reduction of lipid and apoprotein secretion without particle augmentation is not in favour of a selective interference of Pluronic L-81 with intestinal apoprotein B-48 secretion. PMID- 8689924 TI - Intravenous nucleosides and a nucleotide promote healing of small bowel ulcers in experimental enterocolitis. AB - Our aim was to evaluate the possible beneficial effect of intravenous nucleosides and a nucleotide in healing small bowel ulceration in a rat model of enterocolitis. Fourteen Lewis female rats were randomized into total parenteral nutrition (TPN, N = 7) and TPN + nucleosides and a nucleotide (NS/NT, N = 7) groups. After adaptation, two doses of indomethacin (7.5 mg/kg) were administered subcutaneously 24 hr apart to each animal in both groups. Concomitant with the first dose of indomethacin, TPN or TPN + NS/NT were infused for four days. The TPN and TPN + NS/NT were isocaloric and isonitrogenous. At the end of four days, total ulcer length in the entire small bowel was measured. The mucosa surrounding ulcers was studied by optical microscopy. Immunohistochemistry was performed for proliferating cell nuclear antigen (PCNA). Ileal crypt and villus lengths were measured with an eyepiece micrometer, crypt-villus ratios were calculated, and crypt mitotic index and percentage of PCNA-labeled cells determined to assess cellular proliferation. Total ulcer length decreased significantly in the TPN + NS/NT group compared to the TPN group (42 vs 76 mm). In the TPN + NS/NT versus TPN group, the ileal mucosa surrounding ulcers showed significantly greater crypt length (21%) and there was increased crypt-villus ratio (0.53 vs 0.39), crypt mitotic index (1.2 vs 0.9), and PCNA labeling (43% vs 30%). We conclude that in rats with indomethacin-induced enterocolitis, administration of TPN + NS/NT for four days resulted in significant healing of small bowel ulcers, as indicated by decreased ulcer length. This effect of NS/NT appears to relate, in part, to increased cell proliferation, evidenced by increased crypt length, crypt-villus ratio, mitotic index, and PCNA labeling. PMID- 8689925 TI - Evaluation in rats of the dose-response relationship among colonic mucosal growth, colonic fermentation, and dietary fiber. AB - The dose-response relationship among dietary fiber, colonic fermentation, fecal weight, and mucosal growth were evaluated in this study. The morphometric parameter of total mucosal volume was used to assess diet-induced differences in colonic mucosal growth. Dietary fibers with a wide range of fermentability and that have previously been shown to inhibit the development of colonic neoplasia in rats were used. Sprague-Dawley rats were fed Purina Rodent Chow, AIN-76a fiber free diet, or an AIN-76a diet supplemented with three different dietary fibers, (cellulose, guar gum, or wheat bran) at 2, 5, 10, or 15% of the diet. Diets were fed for 28 days. Total colonic mucosal volume was determined using stereologic principles and computerized image analysis; 48-hr fecal weight was measured; and the concentration of short-chain fatty acids (SCFA) in colonic contents was determined at study termination. Each type of fiber induced a dose-dependent increase in total mucosal volume of the colon and fecal weight. Mucosal volume and fecal weight were closely correlated (R2 > 0.95). Total mucosal volume was not correlated with the concentration of total SCFA or butyrate in the colon. These results indicate that diet-induced change in colonic mucosal growth, as measured by total mucosal volume, is positively correlated with fecal weight and not related to alterations in colonic fermentation. Enhanced colonic mucosal growth occurs in rats fed dietary fibers that have previously been shown to inhibit the development of genotoxin-induced colonic neoplasia in rats. PMID- 8689926 TI - Intracellular accumulation of unconjugated bilirubin inhibits phytohemagglutin induced proliferation and interleukin-2 production of human lymphocytes. AB - Decreased immune responses have been documented in hyperbilirubinemic patients. This study investigates the effects of intracellular bilirubin accumulation on lymphoproliferative response to phytohemagglutin A (PHA). Human peripheral blood mononuclear cells (PBMNC) were preincubated with unconjugated bilirubin dissolved in bovine albumin solution at pathological levels seen in clinical hyperbilirubinemia (0-12 mg/dl), washed, and further cultured with PHA. DNA synthesis was measured by [3H]thymidine uptake. Interleukin-2 (IL-2) activity was determined by the CTLL proliferation assay. The amount of intracellular bilirubin and expression of cell surface antigens were analyzed by flow cytometry. In vitro exposure of normal PBMNC to bilirubin resulted in the accumulation of intracellular bilirubin and a decrease in DNA synthesis after PHA stimulation in a time- and dose-dependent manner. Addition of autologous untreated monocytes could not correct the decreased DNA synthesis of bilirubin-treated lymphocytes. IL-2 production by bilirubin-treated PBMNC after PHA stimulation was significantly decreased compared to bilirubin-untreated PBMNC. However, addition of exogenous IL-2 to pretreated PBMNC could not correct the decreased DNA synthesis. Expression of Tac antigen and transferrin receptor on bilirubin treated lymphocytes after PHA stimulation was not significantly different from bilirubin-untreated cells. These results suggest that decreased PHA-induced T lymphocyte proliferation following bilirubin-pretreatment may result from impairment of proliferation at a step beyond transferrin receptor expression. These observations may help explain the increased susceptibility to infection often observed in hyperbilirubinemic patients. PMID- 8689927 TI - Hepatic stimulator substance administration enhances regenerative capacity of hepatocytes in cadmium-pretreated partially hepatectomized rats. AB - The liver is of central importance in the metabolism of essential and toxic metals such as cadmium (Cd). Cd pretreatment suppressed the regenerative capacity of hepatocytes, which normally occurs 24 hr after partial hepatectomy, due to the inhibition of the activity of the enzyme thymidine kinase. The effect of hepatic stimulator substance (HSS) administration (10, 20, and 40 mg protein/kg body weight) on hepatocyte proliferation was investigated in Cd-pretreated partially hepatectomized rats. HSS administration partly restored the suppressed hepatocyte DNA biosynthesis in Cd-pretreated partially hepatectomized rats. The hepatocyte mitotic activity and the percentage of proliferating cell nuclear antigen positive nuclei were in accordance with the liver proliferative status. The administration of HSS did not affect in a statistically significant manner the activity of the enzyme thymidine kinase in Cd-pretreated partially hepatectomized rats. It is suggested that the administration of HSS ameliorates the diminished hepatocyte regenerative response to partial hepatectomy in this model of acute liver injury, due to Cd intoxication. PMID- 8689930 TI - Transjugular intrahepatic portosystemic shunt (TIPS) for Budd-Chiari syndrome. PMID- 8689929 TI - Ursodeoxycholic acid corrects defective natural killer activity by inhibiting prostaglandin E2 production in primary biliary cirrhosis. AB - We evaluated the effect of ursodeoxycholic acid on the defective natural killer activity in primary biliary cirrhosis. Administration of ursodeoxycholic acid (600 mg daily) for one month significantly increased natural killer activity in patients with primary biliary cirrhosis (P < 0.05). Ursodeoxycholic acid also enhanced the in vitro natural killer activity of lymphocytes from healthy volunteers, while other hydrophobic bile acids depressed it. Furthermore, ursodeoxycholic acid reduced the prostaglandin E2 concentration in culture supernatants of lymphocytes from healthy volunteers to a lower level than that in culture incubated with chenodeoxycholic acid (P < 0.05) or control cultures (P < 0.01). Urosdeoxycholic acid normalized the defective natural killer activity in primary biliary cirrhosis by reducing the levels of other hydrophobic bile acids and inhibiting prostaglandin E2 production, suggesting that it may be a useful immunomodulating agent for primary biliary cirrhosis. PMID- 8689928 TI - Anticoagulant pretreatment attenuates production of cytokine-induced neutrophil chemoattractant following ischemia-reperfusion of rat liver. AB - We investigated whether anticoagulation would diminish ischemia-reperfusion injury of the liver. Liver ischemia was induced in rats by occluding the portal vein for 30 min. Anticoagulant was injected intravenously 10 min before occlusion. Serum concentrations of cytokine-induced neutrophil chemoattractant (CINC) in untreated rats increased following reperfusion, reaching a peak at 6 hr, then decreasing gradually to control levels by 24 hr. CINC levels in rats pretreated with heparin (50 units/kg), AT-III (250 units/kg), or DEGR-Xa (10 mg/kg) peaked at 3 hr after reperfusion and declined to baseline within 12 hr; peak CINC values were significantly lower than in untreated control rats. Expression of CINC mRNA in liver tissue paralleled the CINC serum levels. Both myeloperoxidase activity and the number of neutrophils in the liver were decreased in the anticoagulant groups. In addition, significant correlations were observed between the maximum values of AST, ALT, and LDH versus the peak CINC levels following ischemia-reperfusion. These results indicate that the release of CINC after ischemia-reperfusion of the liver is mediated by activation of coagulation within the hepatic microcirculation. PMID- 8689932 TI - An exceptional genealogy for hereditary chronic pancreatitis. AB - Nearly one hundred families affected with hereditary chronic pancreatitis (HCP) have been reported in the literature. However, the fact that the disease involved only a few members of each family limits the informativeness of these reports and accounts for the infrequency and disappointing results of pathogenetic and genetic research. Our study concerned an exceptional HCP genealogy which would seem to provide an ideal model for the detection of a genetic anomaly linked to the expression of the disease. We studied 249 members of a family (214 still alive), covering eight generations born between 1800 and 1993. According to the customary criteria, 63 had definite and 17 probable HCP. Fifty-eight members under 18 years of age were still susceptible to developing the disease. This series confirms the mode of autosomal dominant heredity with variable penetrance. The clinical features and disease course were typical, except that symptoms tended to appear earlier. The series represents the most extensive HCP genealogy compiled and is one of the largest families studied in the field of genetic disease, regardless of etiology. Blood samples were taken from 146 subjects to facilitate pathogenetic and genetic research. PMID- 8689931 TI - Interferon-associated left ventricular dysfunction in a liver transplant recipient. PMID- 8689935 TI - Vertebral osteomyelitis mimicking chronic pancreatitis. AB - Vertebral osteomyelitis rarely mimics pancreatitis. However, the potential consequences of longstanding unrecognized disease, including neurological impairment and bony deformity, should make it an item in the differential diagnosis of chronic pancreatitis. In the evaluation of our patient, four items were of particular importance: awareness of his previously documented S. aureus bacteremia, a markedly elevated ESR, an abnormal chest radiograph, and the positive bone scan. PMID- 8689936 TI - American Diabetes Association: clinical practice recommendations 1996. PMID- 8689933 TI - Effects of cholecystokinin and carbachol on membrane fluidity in pancreatic acini. AB - The effects of pancreatic secretagogues on the membrane fluidity of pancreatic acini were investigated using 1-[4-(trimethylammonium)phenyl]-6-phenyl-1,3,5 hexatriene iodide as a probe. Two kinds of pancreatic secretagogues, one category of which induces acute pancreatitis (cholecystokinin and carbachol) and another which does not induce acute pancreatitis (bombesin, CCK-JMV-180, and secretin), as well as lecithin were used to investigate the effect of changes in membrane fluidity of acini. Our study revealed that the membrane fluidity of the pancreatic acini was unaffected by a physiological dose (10(-11) M) of cholecystokinin. However, stimulation with a supramaximal dose of cholecystokinin (10(-8) M) increased membrane fluidity markedly within 20 min. Membrane fluidity increased dose-dependently with increasing CCK stimulation. A supramaximal dose of cholecystokinin also induced bleb formation and increased LDH release. These phenomena were blocked by simultaneous incubation with CR1505 (Loxiglumide), a potent antagonist of peripheral cholecystokinin receptors. A supramaximal dose of carbachol (10(-3) M) also induced increases in the membrane fluidity. Pancreatic secretagogues that do not induce acute pancreatitis did not induce alterations in membrane fluidity. Lecithin increased both membrane fluidity and LDH release. These observations suggest that this increase in membrane fluidity of the pancreatic acini may be related to membrane alteration and to functional damage of the acini. These observations [correction of observation] can serve as a window to detect the development of acute pancreatitis at an early stage. PMID- 8689934 TI - Salutary and prophylactic effect of pentadecapeptide BPC 157 on acute pancreatitis and concomitant gastroduodenal lesions in rats. AB - The superior effectiveness of a new pentadecapeptide, BPC 157, on gastrointestinal and liver lesions, in conjunction with an antiinflammatory and analgetic activity was recently noted. In the present study, BPC 157 was tested as either a protective or healing agent in bile duct ligation-induced acute pancreatitis in rats. In addition, the positive influence of BPC 157 on concomitantly developed gastric and duodenal lesions was simultaneously investigated. BPC 157 (10 microg, 10 ng/kg body wt, intraperitoneally or intragastrically) was given prophylactically 1 hr before ligation, whereas the therapy was given once daily beginning with the 24 hr following ligation (last application 24 hr before killing). The effect was investigated at daily intervals until the end of the fifth day after ligation. In the pretreatment regimen, a strong pancreas protection was obtained. When applied in the condition of already established severe acute pancreatitis, an obvious salutory effect was consistently noted. Assessing the appearance of the necrosis, edema, neutrophils, and mononuclears, consistently less necrosis, edema, and neutrophils, but more mononuclears, were found in BPC-treated rats. Likewise, in studies of the serum amylase values, relative to control data, a markedly lower rise (BPC pretreatment regimen) as well as a worsening of the already raised values (BPC therapy regimen) was noted. Along with its beneficial effect on pancreatitis, a positive influence of BPC 157 on the gastric and duodenal lesion course in bile duct ligated rats was noted in both the pre- and posttreatment regimen. Taken together, in further studies of acute pancreatitis therapy, BPC could be an interesting and useful agent with an additional positive impact on concomitant gastroduodenal pathology. PMID- 8689937 TI - Reduction and glucuronidation of naftazone by human and rat liver microsomes. AB - Reduction and glucuronidation of the vasoprotectant drug, naftazone, by human and rat liver microsomes and by recombinant UDP-glucuronosyltransferases (UGT) stably expressed in V79 cells were studied. The oxo group was first reduced in the presence of NADPH or NADH, and was subsequently readily glucuronidated on the phenolic moiety leading to a 1 beta-O-glucuronide, as revealed from MS and by proton and 13C-NMR. Glucuronide extracted from the urine of rats treated with the drug presented the same structure. In all enzyme systems tested, NADH was the most efficient electron donor, when compared with NADPH. The reaction was strongly inhibited by quercitrin, a specific inhibitor of carbonyl reductase. Attempts to isolate the reduced intermediate were unsuccessful because of its marked instability. In humans, a large interindividual variation for the formation of glucuronide was observed with microsomes of seven different liver samples (3.98 +/- 3.22 nmol/min.mg). In rat, glucuronidation of reduced naftazone was strongly induced (12-fold) by 3-methylcholanthrene and, to a lesser extent (2.6-fold) by phenobarbital, but was not affected by clofibrate. In addition, liver microsomes from Gunn rats, which present a genetic defect in bilirubin and phenol UGTs could not form glucuronide of reduced naftazone. The drug, after addition of NADH, was a substrate of the human liver recombinant UGT1*6 that presents a strict specificity toward planar phenolic substances, but not that of UGT2B4 and UGT2B1 expressed in V79 fibroblasts. The reducing step by the endogenous V79 cellular reductase was rate-limiting. In conclusion, the powerful inducing effect exerted by 3-methylcholanthrene, the lack of glucuronidation in the Gunn rat and the ability of UGT1*6 encoded by the UGT1 gene to glucuronidate reduced naftazone suggest that, in humans and in the rat, the compound is metabolized by a UGT isoform (UGT1*6 and the rat orthologous form) belonging to family 1, with a restricted specificity toward the drug. PMID- 8689938 TI - Metabolism of the immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug interactions, and interindividual variability. AB - The small intestinal metabolism of tacrolimus, which is used as an immunosuppressant in transplantation medicine, was investigated in this study. Tacrolimus was metabolized in vitro by isolated human, pig, and rat small intestinal microsomes. The metabolites generated were identified by HPLC/MS. Tacrolimus and its metabolites were quantified using HPLC or HPLC/MS. The cytochrome P450 (CYP) enzymes responsible for tacrolimus metabolism in small intestine were identified using specific CYP antibodies and inhibitors. For characterization of the interindividual variability, microsomes were isolated from small intestinal samples of patients who had undergone resection for various reasons. In an in vitro model using pig small intestinal microsomes, 32 drugs were analyzed for their interactions with tacrolimus metabolism. After incubation with human, rat, and pig small intestinal microsomes, the metabolites 13-O demethyl and 13,15-O-demethyl tacrolimus were identified. The metabolism of tacrolimus by human small intestine was inhibited by anti-CYP3A, troleandomycin, and erythromycin, indicating that, as in the liver, CYP3A enzymes are the major enzymes for tacrolimus metabolism in the human small intestine. Metabolism of tacrolimus by small intestinal microsomes isolated from 14 different patients varied between 24 and 110 pmol/13-O-demethyl tacrolimus/min/mg microsomal protein, with a mean +/- SD of 54.2 +/- 29.2 pmol/min/mg. Of 32 drugs tested, 15 were found to inhibit small intestinal tacrolimus metabolism: bromocryptine, corticosterone, cyclosporine, dexamethasone, ergotamine, erythromycin, ethinyl estradiol, josamycin, ketoconazole, nifedipine, omeprazole, progesterone, rapamycin, troleandomycin, and verapamil. All of these drugs inhibited tacrolimus metabolism by human liver microsomes as well. It is concluded that tacrolimus is metabolized by cytochrome CYP3A enzymes in the small intestine. The rate of the CYP3A enzymatic activities varies about 5 times from patient to patient, and drugs that interfere with the in vitro metabolism of tacrolimus in the liver also inhibit its small intestinal metabolism. PMID- 8689939 TI - Microsomal metabolism of the 5-lipoxygenase inhibitors L-746,530 and L-739,010 to reactive intermediates that covalently bind to protein: the role of the 6,8 dioxabicyclo[3.2.1]octanyl moiety. AB - Hepatic microsomes from different species were used to study the oxidative metabolism of L-746,530 and L-739,010, two potent and specific 5-lipoxygenase inhibitors. HPLC analysis of the incubates obtained from the microsomal incubations of L-739,010 and L-746,530 showed only traces of metabolites. However, recovery of the starting material in the supernatant was less than quantitative in all of the species studied (approximately 90% in rat, approximately 70% in the dexamethasone-induced rat, approximately 70-90% in humans, and approximately 60% in the rhesus monkey for both compounds). The recovery of the starting material was found to be time- and NADPH-dependent, suggesting that metabolite(s) were formed and reacting with the microsomal proteins. Evidence that the cytochrome P4503A (CYP3A) contributed to the formation of the reactive metabolite(s) was shown by the low recovery of material that was observed upon incubation with microsomes obtained from dexamethasone treated rats (a CYP3A inducer), compared with microsomes obtained from untreated rats. Also, the recovery of material was improved when troleandomycin, a CYP3A inhibitor, was added to rhesus monkey microsomal incubations (25% more parent compound detected in the supernatant with 100 microM of troleandomycin). Using radiolabeled L-746,530 and gel electrophoresis analysis, it was confirmed that radiolabeled material was covalently bound to the microsomal protein. Incubations of L-739,010 and L-746,530 in the presence of semicarbazide resulted, in both cases, in the formation of two adducts. Using a combination of NMR, liquid secondary-ion MS, and UV techniques, these adducts were identified as isomers of an oxidized metabolite that had been trapped by semicarbazide. The site of oxidation was determined to be on the dioxabicyclo moiety. The importance of this moiety in the formation of reactive metabolite(s) was verified by incubating analogs of the 5-lipoxygenase inhibitors that contained blocking methyl groups at the proposed site of oxidation on the bicyclo moiety. Incubations of these gemdimethyl analogs of L-746,530 and L-739,010 with microsomes from different species resulted in significantly improved recovery of the starting material (approximately 94% in the rat, 85% in the dexamethasone-induced rat, 95% in humans, and 85% in the rhesus monkey for both compounds) and significantly less radioactive binding to the microsomal protein. PMID- 8689940 TI - Relative potency of mexiletine, lidocaine, and tocainide as inhibitors of rat liver CYP1A1 activity. AB - Mexiletine and tocainide are lidocaine congeners that share similar chemical structures. Clinical studies suggest that the in vivo inhibitory effect of mexiletine on the CYP1A family of isoforms is substantially greater than that of tocainide. We investigated the inhibitory property of mexiletine, lidocaine, and tocainide on the in vitro activity of the cytochrome P4501A1 (CYP1A1) isozyme in the rat. Hepatic microsomes were prepared from rat livers induced with 3 methylcholanthrene. The rate of ethoxyresorufin-O-dealkylation (EROD) was used as an index of CYP1A1 activity. Vmax and KM of the reactions were determined from Lineweaver-Burk plots. The Ki values for the inhibitors were derived from Dixon plots. Results showed that mexiletine is a competitive inhibitor, lidocaine is a mixed inhibitor, and tocainide is a noncompetitive inhibitor of EROD. The Ki values for mexiletine and tocainide were 0.30 +/- 0.02 mM and 12.4 +/- 0.7 mM, respectively. Two Ki values for lidocaine were determined. They were 0.65 +/- 0.07 mM and 4.1 +/- 1.3 mM, respectively. The relative inhibitory potency of these agents on rat CYP1A1 activity is mexiletine > lidocaine > tocainide. This difference in potency, which is most likely attributable to the change in the chemical composition in the aliphatic chain among the compounds, suggests that these compounds may be useful probes for studying the mechanism of the interaction with the active site of CYP1A1. PMID- 8689941 TI - Human cytochromes P4501A1 and P4501A2: R-warfarin metabolism as a probe. AB - Two forms of the cytochrome P450 enzyme superfamily, P4501A1 and P4501A2, that are heterogeneously distributed in populations and are induced in response to environmental factors are important because of their capacity to bioactivate procarcinogens. Phenotyping P4501A1 and P4501A2 in individuals will thus provide assessments of those individuals' susceptibility to procarcinogens. The anticoagulant drug warfarin is metabolized by human P4501A1 and P4501A2, and we have characterized this metabolism for the R-warfarin enantiomer as a potential in vivo probe. cDNA-expressed human P4501A1 and P4501A2 are regioselective for R warfarin 6- and 8-hydroxylation with very similar KM values: 1.4 mM (6 hydroxylation), 1.2 mM (8-hydroxylation), 1.6 mM (6-hydroxylation), and 1.4 mM (8 hydroxylation), respectively, indicating possible binding competition for R warfarin between the two forms. However, when comparing 6- and 8-hydroxylation, P4501A1 showed weak regioselectivity for 8-hydroxylation, whereas P4501A2 exhibited strong regioselectivity for 6-hydroxylation, with 6-hydroxylation/8 hydroxylation ratios of 0.6 and 5.0, respectively. These findings were confirmed by using microsomes from 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated HepG2 and MCF-7 cells expressing only P4501A1 (ratios of 0.7), and from human hepatic microsomal preparations containing only P4501A2 (average ratios of 4.0). P4501A2 levels in the liver preparations, as assessed by densitometry of immunoblots, correlated with R-warfarin 6-hydroxylation rates (r2 = 0.83) and caffeine 3 demethylation rates (r2 = 0.67), but not with R-warfarin 8-hydroxylation rates. P450s 2A6, 2B6, 2C9, 2D6, 2E1, and 3A4 did not yield either 6- or 8-hydroxy warfarin from R-warfarin. We conclude that R-warfarin 6-hydroxylation rates are markers for human hepatic P4501A2, whereas ratios of 6-hydroxylation/8 hydroxylation could be used in vitro as a marker for P4501A1. PMID- 8689942 TI - Enzyme- and sex-specific differences in the intralobular localizations and distributions of aryl sulfotransferase IV (tyrosine-ester sulfotransferase) and alcohol (hydroxysteroid) sulfotransferase a in rat liver. AB - Aryl sulfotransferase (AST) IV and alcohol (hydroxysteroid) sulfotransferase a (STa) catalyze the formation of sulfuric acid esters from a diverse array of xenobiotic and endogenous molecules in the liver. Despite the fact that many studies have addressed the metabolic importance and catalytic characteristics of these two sulfotransferases, relatively little is known about their comparative in situ localizations and intralobular distributions in liver. The present investigation utilized specific rabbit antisera prepared against AST IV and STa for immunoperoxidase staining of serial sections from livers of male and female Sprague-Dawley rats and computer-assisted image analysis of immunohistochemical staining intensity by means of microdensitometry. The overall concentration of AST IV was greater in males than in females, although the intralobular distribution of the enzyme was similar in the livers of both male and female rats, wherein centrilobular hepatocytes contained a greater level of AST IV than did midzonal cells, and midzonal hepatocytes had a greater concentration of AST IV than did periportal hepatocytes. In marked contrast, STa was present in livers of female rats at a much greater overall concentration than in livers of male rats. Furthermore, whereas the intralobular distribution of the enzyme was similar in both males and females, STa was present at greater concentrations in periportal hepatocytes than in midzonal hepatocytes and at greater concentrations in midzonal cells than in centrilobular hepatocytes. Significant intrazonal heterogeneity in STa levels within hepatocytes was also observed, particularly in livers of female rats. These results indicate that, whereas the overall hepatic concentrations of these enzymes are clearly sex-dependent, the intralobular distributions of AST IV and STa are characteristic of each particular sulfotransferase. PMID- 8689943 TI - Slow acetylation in mice is caused by a labile and catalytically impaired mutant N-acetyltransferase (NAT2 9). AB - Three N-acetyltransferase genes (NAT*) were detected in inbred parental and congenic mice. Direct sequencing of NAT2* and liver cytosolic N-acetylation activity determinations with NAT2-specific (p-aminobenzoic acid) and NAT2 selective (2-aminofluorene) substrates have established that the acetylator congenic A.B6 and B6.A mice are genotypically and phenotypically identical to the parental B6 ("wild-type"; rapid acetylator) and A (mutant; slow acetylator) mice, respectively, from which they originated. The apparent KM for p-aminobenzoic acid and thermal inactivation rates determined with liver cytosol from the mutant (A and B6.A) mice were 3-fold and one order of magnitude higher than the corresponding values with liver cytosol from the wild-type (B6 and A.B6) strains. Northern blotting and immunoblotting revealed hepatic NAT2 mRNA and protein bands of equal size and intensity, regardless of the NAT2* genotype or phenotype of the animals. Incubation of liver cytosol from mutant A and B6.A mice at 37 degrees C for 6 hr resulted in virtual cessation of p-aminobenzoate N-acetylation activity, whereas the steady-state level of immunoreactive NAT2 remained unchanged. The results indicate that the amino acid change (N99I) in mutant NAT2* from slow acetylator mice does not hinder the synthesis of hepatic NAT2 protein, but, rather, leads to production of a conformationally modified NAT2 molecule that resists degradation by tissue proteases but is labile and catalytically impaired. PMID- 8689944 TI - Synthesis, pharmacokinetics, and biodistribution of 67GA deferoxamineacetyl cysteinylbiotin. AB - The exceptionally high affinity of streptavidin for biotin may be exploited for two-step in vivo approaches for delivering radiolabelled biotin derivatives to lesion-bound streptavidin-conjugated monoclonal antibodies. A radiolabeled biotin derivative was prepared, and its characterization, stability, pharmacokinetics, and biodistribution studies are presented. This derivative contains deferoxamine, a chelating moiety with high affinity for trivalent metals suitable for imaging and therapy. Deferoxamineacetyl-cysteinylbiotin (DACB) was synthesized in three steps: nucleophilic reaction of deferoxamine with N-hydroxysuccinimide iodoacetate, aminolysis of N-hydroxysuccinimide biotin by L-cysteine, followed by coupling of cysteinylbiotin with N-iodoacetyldeferoxamine. DACB was characterized by matrix-assisted laser desorption/ionization MS. Radiolabeling of DACB with 67Ga led to a labeling efficiency of > 95%. Pharmacokinetics of 67Ga DACB exhibited rapid blood clearance, with < 10% circulating at 30 min and < 1% at 6 hr. Plasma samples collected at various time intervals showed > 95% binding with streptavidin, indicating in vivo stability of 67Ga DACB. Urinalysis showed > 80% of the administered dose excreted at 6 hr. Biodistribution data at 6 hr showed < 1% radioactivity remaining per organ. PMID- 8689945 TI - Pharmacokinetics of sodium mercaptoundecahydrododecaborate after intravenous injection in rats. AB - Boron neutron capture therapy (BNCT) is a binary therapy aimed at treating various forms of cancer. Sodium mercaptoundecahydrododecaborate (Na2B12H11SH) or BSH is the compound most widely used for BNCT. The pharmacokinetics of BSH were studied in rats after intravenous bolus injection at two doses of BSH (50 mg/kg and 100 mg/kg). BSH was analyzed by a high performance liquid chromatography (HPLC) method specific to BSH. The elimination of BSH from plasma was slow; the average elimination half life was approximately 15 hr for both doses. Estimates of the steady state volume of distribution and total clearance were 2.11 +/- 0.49 liters/kg and 0.28 +/- 0.03 liters/hr/kg, respectively, for the 50 mg/kg dose and 2.06 +/- 0.38 liters/kg and 0.32 +/- 0.06 liters/hr/kg, respectively, for the 100 mg/kg dose. The differences in the mean values of the parameters for the two doses were not statistically significant; this indicates that BSH exhibits linear pharmacokinetics over the dose range studied. BSH was moderately bound to plasma proteins and the binding was linear over the concentration range studied. Approximately 60% of the drug was recovered unchanged in urine after 24 hr. When we compared our results with the limited data available in the literature on BSH disposition in rats with use of nonspecific analysis methods, it seems that the BSH disposition determined by our HPLC method is not likely to be different from the total boron disposition measured by other methods. PMID- 8689946 TI - Transport and metabolism of delta sleep-inducing peptide in cultured human intestinal epithelial cell monolayers. AB - A cultured human intestinal epithelial (Caco-2) cell monolayer was used to study the transport and metabolism of delta sleep-inducing peptide [DSIP (Trp-Ala-Gly Gly-Asp-Ala-Ser-Gly-Glu)]. DSIP is of interest because it has been reported to be capable of permeating biological barriers (e.g. blood-brain barrier), and this property has been related to its solution conformation. When applied to the apical (AP) side of Caco-2 cell monolayers, DSIP was rapidly metabolized (8.2 +/- 1.1% remaining after a 2-hr incubation), affording Trp as the major metabolite and Trp-Ala as a minor metabolite. When DSIP was added to the basolateral (BL) side of the monolayer, the same metabolites were detected, but the peptide was more stable (70.6 +/- 3.0% remaining after a 2-hr incubation). Inclusion of bestatin, an inhibitor of aminopeptidases, at concentrations up to 0.29 mM with DSIP on the AP side of the Caco-2 cell monolayer increased the stability of the peptide only slightly but dramatically altered the distribution of the metabolites (Trp-Ala became the major metabolite, and Trp became the minor metabolite). Inclusion of other aminopeptidase inhibitors (e.g. amastatin, puromycin) alone, dipeptidylpeptidase IV inhibitors (e.g. diprotin A, Gly-Pro) alone, inhibitors of proteases that require heavy metals for proper activity (e.g. EDTA, 1,10-phenanthroline) alone, or cysteine protease inhibitors (e.g. leupeptin) alone did not lead to significant stabilization of the peptide. However, inclusion of a combination of 0.29 mM bestatin and 1 mM diprotin A with DSIP on the AP side of the monolayers resulted in a substantial increase in the stability of the peptide (83.2 +/- 3.7% remaining after a 2-hr incubation). However, under these conditions, a new metabolite (Trp-Ala-Gly-Gly-Asp-Ala-Ser) was observed with a formation that could be inhibited by inclusion of 1 mM captopril, an inhibitor of peptidyl dipeptidase A. Therefore, the stability of DSIP could be further increased (95.1 +/- 1.6% remaining after a 2-hr incubation) by incubating the peptide with 0.29 mM bestatin, 1 mM diprotin A, and 1 mM captopril. However, even when the major metabolic pathways were inhibited on the AP side of the cell monolayer, no DSIP was detected on the BL side of a Caco-2 cell monolayer. These results suggest that a yet unidentified metabolic pathway is preventing the AP-to-BL flux of DSIP or that DSIP has lower "intrinsic" ability to permeate across cultured intestinal epithelial cells than across cultured brain endothelial cells, a cell culture model of the blood-brain barrier. PMID- 8689947 TI - Enhanced rates of cytochrome P450 metabolic-intermediate complex formation from nonmacrolide amines in rifampicin-treated rabbit liver microsomes. AB - The formation of cytochrome P450 metabolic-intermediate (MI) complexes from amine containing drugs unrelated to macrolide antibiotics was investigated in hepatic microsomes from rifampicin-induced rabbits. Rifampicin treatment doubled the amount of total cytochrome P450 present. As evidenced by increased rates of erythromycin N-demethylation and MI complex formation from troleandomycin without increases in other isozyme selective oxidation reactions, the increase was predominately in the cytochrome P4503A subfamily. Fluoxetine, benzylamphetamine, propoxyphene, and norpropoxyphene formed MI complexes at rates similar to that for troleandomycin. Rates for 1-alpha-acetylmethadol and SKF 525A were 2- to 3 fold higher, and rates for the secondary amine derivatives of these two compounds, nor-1-alpha-acetylmethadol and SKF 8742A, were approximately 5-fold higher than with troleandomycin. For the SKF and acetylmethadol compounds, the rates were much higher in rifampicin-induced microsomes, compared with phenobarbital-induced microsomes. MI complex formation from benzylamphetamine was the reverse. The rate of MI complex formation from benzylamphetamine in phenobarbital-induced microsomes was similar to that from SKF 8742A and nor-1 alpha-acetylmethadol in microsomes from rabbits treated with the highest dose of rifampicin. Cytochrome P450 MI complex formation from all compounds was either low or absent from microsomes of vehicle-treated animals. PMID- 8689949 TI - Oxidation of aldehydes catalyzed by pig liver flavin-containing monooxygenase. AB - Flavin-containing monooxygenase-1 (FMO1) purified to homogeneity from pig liver microsomes catalyzes NADPH- and oxygen-dependent oxidation of salicylaldehyde to pyrocatechol and formate. These products, formed in equimolar amounts, were the only ones detected that suggests that FMO1 catalyzes the oxidation of salicylaldehyde by Baeyer-Villiger chemistry. In addition to salicylaldehyde, 2 hydroxy-1-naphthaldehyde, 5-chlorosalicylaldehyde, 5-nitrosalicylaldehyde, ferrocene carboxaldehyde, 2-pyridine carboxaldehyde, and acetylacetone also stimulated NADPH-dependent oxygen uptake in the presence of FMO1. On the other hand, benzaldehyde, 2-methoxybenzaldehyde, 4-pyridine carboxaldehyde and 3- or 4 hydroxybenzaldehyde, and none of the alkylaldehydes tested had detectable substrate activity. Pig liver FMO1 apparently only catalyzes C-oxidation of reactive aldehydes with a hydrogen ion acceptor function adjacent to the carbonyl. PMID- 8689948 TI - The pharmacokinetics of valproic acid in pregnant sheep after maternal and fetal intravenous bolus administration. AB - The pharmacokinetics and disposition of valproic acid (VPA) have been assessed in pregnant sheep after both maternal and fetal iv bolus administration. The time course of VPA and 16 of its metabolites was followed in maternal and fetal arterial blood, amniotic fluid, and fetal tracheal fluid for 48 hr after administration. Fetal blood gas, acid-base, metabolic, cardiovascular, and fetal breathing activity parameters were also monitored. The disposition of VPA in maternal serum is best described by a biexponential function with a terminal elimination half-life of 2.13 +/- 0.49 hr and volume of distribution of 0.242 +/- 0.036 liter/kg. VPA transfer to fetal serum and other fetal fluids was rapid after drug administration. There was significant fetal exposure to VPA after maternal dosing (mean AUCinfinityFA/AUCinfinityMA = 0.410 +/- 0.118). Similarly, the disposition of VPA in fetal serum after fetal dosing is best described by a biexponential decay with a terminal elimination half-life of 3.37 +/- 1.37 hr. Once again, VPA transfer to other fluids was rapid. However, unlike basic compounds studied previously, VPA did not accumulate extensively in either amniotic or fetal tracheal fluid. The following metabolites were detected after drug administration in these experiments: (E)- and (Z)-2-ene VPA, (E)- and (Z)-3 ene VPA, 4-ene VPA, 3-keto VPA, 4-keto VPA, 3-OH VPA, 4-OH VPA, 5-OH VPA, and 2 PGA. Both maternal and fetal bolus administration of VPA elicited a significant reduction in fetal breathing movements, which may be attributed to the drug's action on gamma-aminobutyric acid dynamics in the central nervous system (CNS). This suggests that the significant fetal exposure to VPA may produce further CNS related effects in utero. PMID- 8689950 TI - Pharmacokinetics of O6-benzylguanine in rats and its metabolism by rat liver microsomes. AB - O6-Benzylguanine is an effective inhibitor of the DNA repair protein, O6 alkylguanine-DNA alkyltransferase, and enhances the effectiveness of 1,3-bis(2 chloroethyl)-1-nitrosourea in cells in culture and animal tumor models. To prepare O6-benzylguanine for clinical trials and to determine the availability and disposition of O6-benzyl-7,8-dihydro-8-oxoguanine (O6-benzyl-8-oxoguanine), its major metabolite, pharmacokinetic parameters of these compounds were investigated in male Sprague-Dawley rats. Noncompartmental pharmacokinetic parameters were determined following intravenous administration of O6 benzylguanine or O6-benzyl-8-oxoguanine in rats. Half-life, clearance, and volume of distribution were respectively, 1.6 hr, 160 ml/hr/kg, and 405 ml/kg for O6 benzylguanine, and 1.2 hr, 312 ml/hr/kg, and 507 ml/kg for O6-benzyl-8 oxoguanine. At least 37% of O6-benzylguanine was converted to O6-benzyl-8 oxoguanine after administration of O6-benzylguanine. Renal excretion accounted for 8 and 62% of the administered O6-benzylguanine and O6-benzyl-8-oxoguanine, respectively. Administration of phenobarbital to rats before O6-benzylguanine resulted in a 17- to 19-fold increase in the amount of oxidized product in the urine. Kinetic constants, KM and Vmax were estimated as 19.6 microM and 0.02 nmol/min/mg protein and 13.4 microM and 0.96 nmol/min/mg protein, for uninduced and induced rat liver microsomes, respectively. The use of inhibitors of cytosolic enzymes, xanthine oxidase, and aldehyde oxidase indicated that aldehyde oxidase is primarily involved in the cytosolic oxidation of O6-benzylguanine. PMID- 8689951 TI - Immunoglobulin G, F(AB')2, and fab fragment uptake kinetics in isolated perfused rat liver and rat hepatic cells. AB - The interaction of 125I-radiolabeled immunoglobulin G (IgG), F(ab')2, and Fab fragments with different modes of production (polyclonal or monoclonal), belonging to different subclasses (IgG1 and IgGT) and derived from different sources (mouse, rat, and horse) with liver, was investigated by using isolated perfused rat liver and isolated rat hepatic parenchymal cells (PCs) and non parenchymal cells (NPCs) in suspension. Lactosaminated-bovine serum albumin (Lac BSA) and formaldehyde-bovine serum albumin were used as markers of specific binding to PCs and NPCs, respectively. Using the isolated perfused rat liver model, data clearly indicated a very weak hepatic extraction ratio (< 0.003) for IgGs and fragments in comparison with Lac-BSA (extraction ratio = 0.398) over the 3 hr of the experiments. No breakdown or higher molecular weight compounds were observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. Biliary excretion of IgGs and fragments ranged from 0.07 to 0.3%, mainly as free iodine-125. In contrast, 7% of Lac-BSA was excreted unchanged in bile, and 10% of free iodine was excreted at 3 hr. In vitro binding studies showed no specific binding of any antibody and fragment proteins at 4 degrees C or 37 degrees C. In contrast, saturable uptake was observed for Lac-BSA with PCs and formaldehyde bovine serum albumin with NPCs. Both models demonstrated that nonspecific antibody/fragment interactions occurred with rat liver. Several hypotheses can be formulated to explain why liver-antibody interactions depend on more complex antibody molecular states (aggregated structure and immune complex) rather than the monomeric structure investigated in the present study. PMID- 8689952 TI - Effect of cimetidine on hepatic cytochrome P450: evidence for formation of a metabolite-intermediate complex. AB - Cimetidine is an inhibitor of hepatic cytochrome P450 (CYP) in vivo and in vitro in both rats and humans. However, the concentrations of cimetidine required to inhibit drug metabolism in hepatic microsomes in vitro are 100-1000-fold higher than those associated with a similar degree of inhibition in vivo. Recently, we provided evidence indicating that cimetidine selectively inhibits CYP2C11 in the rat and that it acts by forming a metabolite-intermediate (MI) complex. To investigate this further, optical-difference spectroscopy was performed with the use of microsomes from uninduced and phenobarbital-induced male rats treated with cimetidine in vivo or, after a preincubation step, in vitro. In microsomes from uninduced rats treated with cimetidine in vivo or in vitro, a spectral peak at 428-430 nm was observed that was not dissociated by the addition of potassium ferricyanide. The spectral peak obtained with cimetidine in vitro was dependent on the presence of NADPH and on the concentration of cimetidine in the reaction mixture, indicating the presence of an MI complex. The magnitude of this complex was reduced in microsomes from phenobarbital induced rats that were administered cimetidine either in vivo or in vitro. The formation of the complex was also inhibited by preincubation of the microsomes with anti-rat CYP2C11 immunoglobulin. These results are consistent with the hypothesis that cimetidine inhibits CYP in vivo in the rat by forming an MI complex, largely with CYP2C11, and that this complex can be generated in vitro by incubating microsomes with cimetidine in the presence of NADPH. PMID- 8689953 TI - Metabolism of bromodichloroacetate in B6C3F1 mice. AB - Trichloroacetate (TCA), dichloroacetate (DCA), and bromodichloroacetate (BDCA) are byproducts of the chlorination of drinking water. TCA acts primarily as a peroxisome proliferator, but DCA produces tumors at doses less than required for peroxisome proliferation. BDCA does not induce peroxisome proliferation even at high doses. This study attempts to determine whether differences in the metabolism of the trihaloacetates (THAs) may contribute to their differing toxicological properties. Studies were performed in male B6C3F1 mice given [14C1,2]TCA, [14C1]BDCA, and [14C1,2]DCA by gavage. The replacement of a Cl by a Br greatly enhances THA metabolism. Much less radiolabel from BDCA is retained in the carcass after 24 hr than from TCA. Radiolabel from BDCA is largely found in the urine, with oxalate being the major metabolite. TCA is largely eliminated unchanged in the urine. There are dose-related changes in the rate of CO2 production from BDCA. The initial rate of CO2 production is reduced from 4.1 +/- 0.3 hr-1 at 5 and 20 mg/kg to 2.7 +/- 0.6 hr-1 at 100 mg/kg, but the net conversion to CO2 in 24 hr is greater at the highest dose. As would be predicted, substitution Br for Cl on TCA greatly increased its metabolism. PMID- 8689954 TI - Biotransformation of amitriptyline by Cunninghamella elegans. AB - A fungal biotransformation system as an in vitro model for mammalian drug metabolism was investigated. Amitriptyline, a widely used antidepressant, was effectively biotransformed within 72 hr by the filamentous fungus, Cunninghamella elegans. Eight major metabolites in HPLC elution order (11-hydroxyamitriptyline N oxide, 11-hydroxynortriptyline, 11-hydroxyamitriptyline, 10-hydroxyamitriptyline, 3-hydroxyamitriptyline, 2-hydroxyamitriptyline, nortriptyline, and amitriptyline N-oxide) were produced at estimated molar ratios of 2:1:10:0.6:0.1:1.2.5:0.5, respectively. These metabolites were isolated by HPLC and identified by UV/MS analyses, as well as NMR spectroscopic analysis for most of these metabolites. In some cases, they were also compared with authentic standards. Glucose, culture age, and substrate concentration significantly affected the extent of amitriptyline metabolism. Kinetic studies indicated that nortriptyline and 11 hydroxyamitriptyline were produced as initial major metabolites. The hydroxylated metabolite was excreted from mycelia, but amitriptyline and its N-demethylated metabolite, nortriptyline, were not. An 18O2 labeling experiment showed that the oxygen atoms in 11-hydroxyamitriptyline and 2-hydroxyamitriptyline were derived from molecular oxygen. The cytochrome P450 inhibitors SKF 525-A (1.5 mM), metyrapone (2.0 mM), and 1-aminobenzotriazole (1.0 mM) inhibited the biotransformations of amitriptyline by 50, 75, and 95%, respectively. A microsomal preparation was shown to catalyze the 11-hydroxylation of amitriptyline, which was inhibited by SKF 525-A and carbon monoxide. The similarities of amitriptyline metabolism in C. elegans and in humans and rats are discussed. PMID- 8689955 TI - Stereoselective metabolism of enflurane by human liver cytochrome P450 2E1. AB - The toxicity of the chiral fluorinated volatile anesthetics halothane, enflurane, and isoflurane is closely related to their metabolism by hepatic cytochrome P450. Although individual anesthetic enantiomers have been shown to exhibit a difference in anesthetic efficacy, metabolism of anesthetic enantiomers has not been reported. Human liver enflurane metabolism to difluoromethoxydifluoroacetic acid (DFMDFA) and inorganic fluoride is catalyzed in vivo and in vitro by cytochrome P450 2E1. The purpose of this investigation was to characterize enflurane racemate and enantiomer metabolism to test the hypothesis that fluorinated ether anesthetic metabolism by cytochrome P450 2E1 exhibits substrate stereoselectivity. Enflurane metabolism by microsomes from three human livers and by microsomes containing cDNA-expressed human P450 2E1 was measured at saturating enflurane concentrations. DFMDFA was quantitated with gas chromatography-mass spectrometry by detection of the ethanolamide derivative. In microsomes from all three livers, (R)-enflurane metabolism was significantly greater than that of (S) enflurane, whereas rates of racemic enflurane metabolism were generally between those seen for the R- and S-enantiomers. The ratio of (R)-enflurane to (S) enflurane metabolism in the three livers studied was 2.1:1, 1.9:1, and 1.4:1. (R) , (S)-, and racemic enflurane were all metabolized by expressed P450 2E1. The ratio of (R)-enflurane to (S)-enflurane metabolism was 1.9:1. The metabolic enantiomeric selectivity of human liver P450 2E1 for (R)-enflurane suggests that enflurane metabolism by P450 2E1 occurs by direct substrate oxidation, rather than indirectly through the generation of a P450-dependent reactive oxygen species, and supports the hypothesis that the P450 2E1 active site is somewhat restrictive and capable of stereochemical discrimination. PMID- 8689956 TI - Selectivity of flavin-containing monooxygenase 5 for the (S)-sulfoxidation of short-chain aralkyl sulfides. PMID- 8689957 TI - Benzyloxyresorufin as a specific substrate for the major phenobarbital-inducible dog liver cytochrome P450 (P4502B11). PMID- 8689958 TI - Epithelial pearl following myringoplasty. PMID- 8689959 TI - Vocal fold nodules and acute vocal fold hemorrhage. PMID- 8689960 TI - Otorhinolaryngological manifestations of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu Disease). PMID- 8689961 TI - Otoplasty. PMID- 8689962 TI - Friedrich Siebenmann (1852-1928). PMID- 8689963 TI - Cross-face facial nerve anastomosis: historical notes. AB - The anastomosis between the two facial nerves for the treatment of facial paralysis, in which the proximal stump of the severed facial nerve is not accessible, was utilized in eleven patients. The palsy was secondary to resection of an acoustic tumor in nine patients, sarcoma of the petrous bone was the cause in one and an automobile accident in the other. The original concept of anastomosing a branch of the normal pes anserinus to the trunk of the paralyzed facial nerve, as first presented by the author at the Second International Symposium on Facial Nerve Surgery held in Japan in September, 1970, has been modified. The technique of anastomosing the cervico-facial division of the normal facial nerve, and directing it to the temporo-facial division of the paralyzed facial nerve via a sural autograft 20-22 cm long, was combined with the utilization of the ipsilateral descendens cervicalis (hypoglossi). This nerve was anastomosed to the cervico-facial division of the paralyzed facial nerve and utilized in four patients. The technique is illustrated in detail. PMID- 8689964 TI - A survey of facial paralysis: etiology and incidence. AB - Facial paralysis has numerous etiologies ranging from the most common, Bell's palsy and trauma, to rare tumors and congenital anomalies. This paper divides the etiologies of facial paralysis into five major classifications: idiopathic, traumatic, infectious, neoplastic and neurologic. The incidence of each of these classifications has been estimated from incidence rate information published in the United States and abroad. Using this information, an estimate of the incidence rate has been determined. This information was previously untabulated, thus making statistical analysis nearly impossible regarding this disorder. PMID- 8689965 TI - Powered instrumentation in dissection of the frontal recess. AB - The use of powered instrumentation in functional endoscopic sinus surgery has become very popular due to its safety and thoroughness. An area which has been more problematic in the use of this technique has been the frontal recess, due to its anatomic location and associated risk of serious complications. We have done a number of powered dissections of the frontal recess as a surgical treatment of refractory frontal sinusitis, and find that it is extremely safe and effective. The ability of the powered devices to preserve normal mucosa allows an adequate surgical approach while significantly decreasing the postoperative risk of frontal recess stenosis and reocclusion. We feel that powered dissection of the frontal recess offers a significant advantage over standard techniques in this anatomic location. PMID- 8689966 TI - Tumor-associated paralysis of the mastoid portion of the facial nerve: report of three unusual cases. AB - Tumors of the mastoid portion of the facial nerve are rare and often are misdiagnosed because they have subtle clinical manifestations. We have described three cases of tumor affecting the mastoid portion of the facial nerve seen in our hospital. In all cases, diagnosis proved problematic. Routine and careful use of imaging techniques and a certain amount of intuition are necessary to reach the correct diagnosis. Facial paralysis diagnosis requires histopathological examination following mastoidectomy. PMID- 8689967 TI - Postoperative bleeding in tonsillectomy patients. AB - A three-year retrospective study was performed on 494 patients to compare the effects of two techniques of tonsillectomy, with respect to rates of postoperative bleeding. One surgeon performed primarily mechanical dissections, while the other primarily performed electrocautery dissections. Intraoperative blood loss was assessed and correlated to the age and gender of the patient and to the size of the tonsil. Postoperative bleeding was seen in 2.8% of patients who underwent electrocautery tonsillectomy and in 7.6% of patients who underwent mechanical tonsillectomies. Patients undergoing electrocautery dissection lost an average of 37 ml of blood intraoperatively, whereas those undergoing mechanical dissection lost 105 ml. Mechanical tonsillectomies exhibited higher intraoperative blood loss than electrocautery tonsillectomies. A higher rate of postoperative bleeding was seen in mechanical tonsillectomies, but this difference was lost when peritonsillar abscesses were removed from the study. PMID- 8689968 TI - Management of malignant schwannomas of the paranasal sinuses and anterior skull base. AB - The evolution of skull base surgery has facilitated the extirpation of previously unresectable tumors. As experience with skull base surgery increases, the feasibility of resection and long-term outcomes is becoming apparent for the more common lesions. Neoplasms such as malignant schwannomas are rare and, therefore, defy single-institution analysis. The treatment and four-year follow-up of a malignant paranasal sinus and anterior skull base schwannoma is described. Analysis of the literature confirms the low incidence of this tumor and supports the efficacy of skull base surgery in its treatment. PMID- 8689969 TI - Diagnosis and over diagnosis of typhoid fever. PMID- 8689970 TI - Salmonella typhi and Salmonella paratyphi antibodies in Kenya. AB - The distribution of Salmonella typhi, S. paratyphi A. and S. paratyphi C. agglutinins among 364 sera from a randomly selected group of healthy individuals in Nairobi and Naivasha (Kenya) were analysed in relation to bacteriologically confirmed cases of typhoid fever at the Kenyatta National Hospital (KNH). Out of these, 30% of the healthy individuals had no detectable Widal titres. Overall agglutinin titres obtained for the healthy population showed that 96% of the individuals had low level reactivity with titres < 1:80 for both H and O antigens of S. typhi, while 4% had titres of 1:160 or above. Agglutinins for S. paratyphi A and C were rarely present in the sera tested. Age and sex were found to have no effect on antibody titre distribution in the two populations but differences in the water source may have affected the percentage of positive tests recorded. In this typhoid endemic region titres upto 1:80 are not uncommon but both H and O titres of 1:160 and above found in conjunction with the clinical picture may be taken to be suggestive of typhoid fever. PMID- 8689971 TI - Torsion of the testis in Africans in Nairobi. AB - Scrotal explorations were performed on 110 patients with clinical suspicion of testicular torsion over an eight-year period from January 1988 to January 1995 at the various government and private hospitals within Nairobi metropolis. Ninety five (86.36%) patients had testicular torsion. 14 (12.73%) patients had epididymo orchitis and one (0.91%) patient had normal testis. The mean age was 20.5 years. Forty six (48.42%) patients were young adults of over 21 years of age. The overall salvage rate was low at 21% with an orchidectomy rate of 79%. All the patients (40%) who presented to the surgeon more than 48 hours from the onset of symptoms lost their testicles. This may be due to the fact that in this study, forty three (45.26%) patients were placed on antibiotics and analgesics without prior scrotal or external genital examination by the first doctor to examine them before eventual referral to the surgeon. Recurrent torsion was reported in four (4.21%) patients who had previous testicular fixation in the locality. PMID- 8689972 TI - Nature of referrals to the psychiatric unit at Muhimbili Medical Centre, Dar es Salaam. AB - During a 24-month period, 205 consecutive new referrals to Muhimbili psychiatric unit were studied. Their socio-demographic characteristics, sources of referral, types of treatment received before referral and the nature of their clinical problems were identified. Their neuropsychiatric disorders were classified according to ICD-10. The ratio of males to females was found to be 1.6:1. The average age was 29.3 years. 23.4% of adult patients were unemployed, two fifths of all patients were single and 70% of all subjects had less than eight years of formal education. Whereas 42.9% of all referrals were from other departments of Muhimbili hospital, the remaining were largely from parastatal dispensaries, district and regional hospitals within Dar es Salaam city. At least a fifth of all patients had consulted traditional healers prior to referral and antimalarials had been given inappropriately to 34 patients with mental problems. Mental disorders consisted of functional psychosis, 36.6% of which three quarters were schizophrenia, neurosis (19.5%), seizures (16.6%), substance abuse (8.8%), organic mental disorders (5.3%), headache (4.9%), sexual dysfunction (2.9%). The rest had conduct disorders and pseudocyesis. Seventeen percent of all cases had concomitant physical disorders. Most patients had delayed to seek medical help. PMID- 8689973 TI - Empyema thoracis in adults in Saudi Arabia. AB - Empyema thoracis in adults is an uncommon disease in the Asir region of Saudi Arabia. In a period of seven years (1988 to 1994), 24 patients were treated for empyema thoracis with a hospital incidence of about 23 patients in 100,000 admissions. The community acquired empyemas are more common and less aggressive in non-Saudi patients (six males and one female) as compared to Saudi patients (11 males and 6 females) whose empyemas are mostly nosocomial with an aggressive course. The peak age in both Saudi and non-Saudi patients is 45 years and 25 years respectively, and the right pleura is more commonly affected than the left pleura in both groups. Risk factors include diabetes mellitus, pulmonary tuberculosis, post-pneumonectomy infections, trauma and pneumonia. The commonest organisms grown are Pseudomonas aeruginosa, Klebsiella species and Staphylococcus aureus, although in almost 40% of the patients the empyemas were sterile. The commonest method of treatment was closed thoracostomy tube drainage. PMID- 8689974 TI - Clinical presentation of ectopic pregnancy in Transkei, South Africa. AB - Due to advances in diagnostic techniques, it has become possible to identify and manage ectopic pregnancies before they cause clinical symptoms in many developed countries. However, the situation appears not to be the same in developing countries. We carried out a cross-sectional study at Umtata General Hospital, which serves an underprivileged black South African population in order to document the incidence, risk factors, clinical presentation and complications of ectopic pregnancy. We found the incidence of ectopic pregnancy was 11 per 1000 reported pregnancies, and the mortality rate was 2.0%. Of 148 consecutive cases of ectopic pregnancy, 62.2% were in shock and two thirds were severely anaemic on arrival. About 71% of the cases had tubal rupture and 25% were chronic leaking ectopics. Only four intact unruptured ectopics were found in spite of the availability of modern diagnostic techniques such as ultrasonography and sensitive pregnancy tests. About 86% of the cases had evidence of previous pelvic infection, thus making pelvic inflammatory disease (PID) the most important risk factor for ectopic pregnancy. We conclude that most ectopic pregnancies in Transkei are associated with previous pelvic infection, and still present as acute emergencies. Preventive measures should aim at controlling sexually transmitted diseases and PID. PMID- 8689976 TI - Prevalence of oral mucosal lesions in a Kenyan population with special reference to oral leukoplakia. AB - The prevalence of oral leukoplakia and related lesions in a Kenyan rural population was determined in a systematic house to house survey of individuals aged 15 years and above. Among the 803 individuals examined, the following prevalence of lesions was observed: leukoedema (26%), melanosis (12.7%), leukoplakia (10.6%), palatal keratosis (6.4%), frictional keratosis (5.5%), pre leukoplakia (4.1%), borderline leukoplakia (2.4%), cheek/lip biting (1.3%), and snuff dippers lesion (0.4%). 48.6% of the subjects had at least one of these lesions. Statistically significant preponderance was demonstrated for oralleukoplakia, palatalkeratosis, leukoedema and frictional keratosis among males and melanosis among females. With regard to clinical classification of oral leukoplakia, the prevalence was 10% for homogeneous and 0.6% for nonhomogeneous lesions. On the basis of aetiological classification; the prevalence was 8.3% for tobacco associated and 2.2% for idiopathic leukoplakia. 22.5% of leukoplakia lesions biopsied had evidence of epithelial dysplasia. In view of the premalignant potential of oral leukoplakia, our findings suggest a need for greater attention towards prevention and control of this lesion in the study community. PMID- 8689975 TI - Complications of induced abortions and their preventions in Ghana. AB - Two hundred and twelve patients were admitted because of complications of induced abortions. 58% of those abortions had been performed outside designated health institutions despite the liberalisation of the abortion law in Ghana about ten years ago. Ghanaian society still seems to perceive abortions as illegal or unethical and hence to be procured clandestinely. The overall mortality rate was 2.4% whilst the case fatality rate for septic abortions was over three times this rate. The surgical intervention rate was high at about 94%. Over 50% of laparotomies were for ectopic pregnancy. Suspicion of ectopic pregnancy must always be borne in mind if undue delay in their management is to be avoided in all cases of complicated induced abortions especially when the patients have risk factors. None of the patients used a modern contraceptive method over the three months preceding the index pregnancy and post-arbortal contraceptive counselling was infrequent. Effective and widespread contraceptive use and continuing education of doctors remain pivotal if the incidence of abortions and their complications are to be reduced. PMID- 8689977 TI - Adenomatoid odontogenic tumours in Ibadan, Nigeria. AB - Only a few reports of adenomatoid odontogenic tumour (AOT) in Africans have been published. Clinical, histological and radiographic features as well as treatment results of thirteen new cases of AOT seen at the University College Hospital, Ibadan were reviewed. This lesion constituted 12.1% of odontogenic tumours. This study shows a male: female ratio of 1.2:1. This contrasts with the reported male: female ratio of 1:3 in the United States, Britain, Sri Lanka and Japan. The higher male incidence may be peculiar to Nigeria. Although the peak incidence was in the second decade of life, four patients were over 20 years of age. The mean age was 23.2 years for all patients. None of the patients presented with recurrence on follow up. PMID- 8689978 TI - Sequestrectomy and local muscle flap implantation for chronic osteomyelitis in children and adolescents. AB - Forty one children and adolescents (mean age 11.9 years) with chronic osteomyelitis that were not previously managed surgically were prospectively studied during a 5-year period in the University of Calabar Teaching Hospital, Calabar, Nigeria. All cases were managed by sequestrectcomy of curretage and local muscle flap implantation into the space so created. Preoperative care in this series included blood transfusion for anaemic patients and augmentin (amoxycillin and clavulanic acid) while definitive antibiotic therapy depended on the antimicrobial sensitivity pattern of Staphylococcus aureus and Pseudomonas species which were the predominant bacterial isolates. Overall, the incidence of wound dehiscence and recurrence of chronic osteomyelitis were low (19.5%), and complete healing of all cases occurred by two years of follow-up. The major complications were joint stiffness, limb shortening and pathological fractures. PMID- 8689979 TI - Cavernous sinus thrombosis: a report of eight consecutive comatose patients. AB - Septic thrombosis of the cavernous sinus is a severe and lethal condition if left untreated. The mortality is particularly high in those patients admitted in a comatose state. Eight patients treated successfully in Bulawayo, Zimbabwe in Mpilo Central Hospital over a period of three years are reported. In the discussion, emphasis is placed on the treatment of raised intracranial pressure in this particular group of patients and early treatment with appropriate antibiotics. Clinicians must be aware of this serious complication of infections around the face and must treat them early and aggressively. PMID- 8689980 TI - Efficacy of halofantrine in the treatment of uncomplicated falciparum malaria. AB - In the last decade, Plasmodium falciparum resistance to a number of commonly used anti-malarials especially chloroquine, has increased considerably. Newer anti malarial drugs are therefore being aggressively evaluated as alternatives. A randomized double-blind controlled trial was therefore undertaken, to compare the efficacy of halofantrine to that of metakelfin, in the treatment of moderately severe infections of Plasmodium falciparum in an endemic malaria area in Kenya. Three hundred and thirty five subjects with laboratory confirmed malaria were recruited and randomized to receive treatment with either halofantrine (171 subjects) or metakelfin (164 subjects). Two thirds (66%) of the study subjects were under the age of five years, and were therefore considered to have minimal immunity. All study subjects were initially admitted to hospital for three days and then followed up as out-patients on days 7, 14, 21, and 28. The level of parasitaemia, the presence of fever and the occurrence of adverse effects were evaluated. Halofantrine was found to be comparable to metakelfin in terms of resolution of fever (mean time 45 and 51 hours respectively). No major adverse side effects were observed. Halofantrine is a viable drug in the treatment of uncomplicated P. falciparum malaria. PMID- 8689981 TI - Quality of intravenous infusion fluids manufactured in Kenya. AB - The incidence and nature of microbial contamination of intravenous fluids prepared by four manufacturing establishments in Kenya was evaluated using the European Pharmacopoeia membrane filtration method for sterility testing. The percentage failures were 28.6% for source D, 18.8% for source A, 12.5% for source B and 10.5% for source C. The major contaminant was aspergillus which was isolated from samples from three sources. Candida and Staphylococcus accounted for the contamination of samples from two sources. Failure rates due to the chemical composition of the products was 66.7% for Source A, 60.0% for D, 41.7% for C and 13.3% for B. The experience of the manufacturing sites appeared to correlate with the quality of the products, with the older manufacturing establishments showing lower percentage failures. PMID- 8689982 TI - Standardization of Leishmania dovovani parasite inoculum dose and route of challenge for use in infectivity studies: is it necessary? PMID- 8689983 TI - Common causes of neonatal bacteraemia in Accra, Ghana. AB - This study is a retrospective review of admissions, discharge records and blood culture results of neonates admitted to the Neonatal Intensive Care Unit of Korle Bu Teaching Hospital in Accra, from the first of January 1991 to the 31st of December 1992. During this two year period there were 443 positive blood cultures. Ninety percent of the blood cultures were from babies born in Korle Bu Teaching Hospital, thus making the incidence of neonatal bacteraemia 22.2 per 1000 live births. The overall mortality rate was 37.2%. Gram negative bacteria accounted for 70.9% and Gram positive bacteria for 29.1% of all neonatal bacteraemia. The most common isolates were Enterobacter species 29.6%; Streptococcus faecalis 14.4%; Staphylococcus aureus 10.8%; Acinetobacter species 9.5%; Klebsiella species 9% and Escherichia coli 8.8%. It is concluded that the incidence of neonatal bacterial sepsis is high in our hospital and is associated with a very high mortality rate. There is thus an urgent need to institute appropriate preventive and therapeutic measures. PMID- 8689984 TI - Comparison of three DOT-ELISA techniques in diagnosing Schistosoma haematobium infection. AB - The DOT-STRIP-ELISA was evaluated in the laboratory as a serodiagnostic tool for Schistosoma haematobium infection in order to assess the potential of introducing the technique under field conditions in the developing world. Out of 100 individuals with parasitologically confirmed Schistosoma haematobium, 87 reacted positively (sensitivity 87%), whereas 45 out of 50 sera from individuals from a non-endemic area reacted negatively (specificity 90%). Results were reproducible. Cross-reactions were observed with sera from individuals infected with Schistosoma mansoni, Echinococcus, Leishmania and Wuchereria. The DOT-STRIP-ELISA offers more advantages with regard to practicability and test-time when compared with the DOT-DISC-ELISA and DOT-MILLIPORE-ELISA. PMID- 8689985 TI - Hepatitis B virus infection among pregnant women in Zambia. AB - The prevalence of hepatitis B virus (HBV) markers was studied in pregnant women attending antenatal clinics in Zambia. A total of 2,098 pregnant women were recruited into the study at three urban health centres in Lusaka, the capital city and four district hospitals in rural areas of different provinces of Zambia. The overall prevalence of HBsAg was 6.5% (137/2,098), and HBeAg was present in 16.1% (22/137) of those positive for HBsAg. Antibody positive rate (HBsAb and/or HBcAb) was 51.3% in randomly selected HBsAg negative samples. HBsAg positive rate varied between 3.3% and 13.6% in each study sites. Prevalence for both HBsAg and antibodies to HBV were significantly higher in rural areas (district hospitals) than in urban areas (urban health centres in Lusaka). These data show that although HBV is endemic in Zambia, the prevalence varies from region to region. PMID- 8689986 TI - Triadic nose drops in the treatment of chronic sinusitis. AB - Thirty patients with chronic sinusitis have been treated with triadic nose drops consisting of ephedrine, dexamethason and lincomycin. Twenty three cases were cured, five cases improved and there was no effect in two cases. This study suggests that triadic nose drops are beneficial in chronic sinusitis. The pathogenesis and treatment of chronic sinusitis is discussed. PMID- 8689988 TI - Distinguishing forms of generalized epilepsy using magnetic brain stimulation. AB - In this study, we have used paired transcranial stimulation of the motor cortex to test the hypothesis that cortical inhibition is decreased in juvenile myoclonic epilepsy (JME). The double shock technique was adopted here because it offers a means for highlighting abnormal inhibitory mechanisms. From previous experiments performed on healthy subjects, it is known that a magnetic conditioning stimulus, of subthreshold intensity, suppresses the MEP in response to a subsequent suprathreshold stimulus delivered after 1-4 msec. JME patients were selected as a potential contrast with other forms of idiopathic generalized epilepsy, because they complain of myoclonic jerks without loss of consciousness, indicating with certainty a dysfunction of the motor cortex. Two patients with sporadic grand mal and one non-epileptic patient were also investigated. Paired stimulation was produced by a Bi-stim (Magstim) stimulator, with a figure-of-8 coil placed over the hand area of the motor cortex, and a set of interstimulus intervals (ISIs) ranging from 1 to 6 msec was analyzed. In JME patients there were two indications of abnormality with respect to normal subjects and to the other epileptic patients: (1) the absence of MEP suppression to paired stimulation; (2) a progressive amplitude increase of MEPs to the test stimulus alone. In the two patients with the other form of epilepsy the pattern of inhibition was broadly preserved, even though there was some difference from the normal profile. The results suggest that the loss of MEP inhibition can be regarded as a marker of JME. PMID- 8689987 TI - Malignant phyllodes tumour: report of two cases. AB - Malignant phyllodes tumours are rare fibroepithelial tumours of the breast. The tumours consist of a benign looking epithelium surrounded by a cellular stroma with malignant features. Two cases of a malignant phyllodes tumour are presented. Both cases showed recurrence before metastasizing. One case was treated by a radical mastectomy and the other needed only a toilet mastectomy. Radiotherapy had no effect in one of the cases. PMID- 8689989 TI - In memoriam M.A.B. Brazier. PMID- 8689990 TI - EEG findings in fetal alcohol syndrome and Down syndrome children. AB - Results from previous studies evaluating the electroencephalograms (EEGs) of infants born to alcoholic mothers suggest that the neonatal EEG may be a sensitive measure of prenatal ethanol exposure. Few studies, however, have examined EEG records of adolescent children with fetal alcohol syndrome (FAS). The present study investigated the resting EEG recordings of 18 matched triads of FAS, Down syndrome, and normal control subjects. Significant reductions in mean power of the alpha frequencies (7.5-12 Hz) were seen for both clinical groups, however, each syndrome appeared to have distinct EEG spectral distributions. Down syndrome children overall had diffuse EEG slowing while the EEG records of the FAS children showed reduced power, particularly in the alpha frequencies in the absence of significant slow activity. In the Down syndrome children, significant decreases in alpha power was seen in posterior cortical regions, whereas FAS children were more affected in the left hemisphere. This study suggests that certain EEG variables may be helpful in characterizing the neurophysiology of FAS. PMID- 8689991 TI - Effect of flumazenil on the electroencephalogram of patients with portosystemic encephalopathy. Results of a double blind, randomised, placebo-controlled multicentre trial. AB - The efficacy of the benzodiazepine antagonist flumazenil has been assessed clinically in a double blind, randomised, placebo-controlled multicentre study in patients with grade I-III portosystemic encephalopathy. In an ancillary study reported here the effect of flumazenil on the electroencephalogram (EEG) was analysed in 32 patients who had EEG grading according to protocol. Following the baseline observation period, patients were randomised to receive (at 1 min interval) 3 sequential bolus injections of flumazenil (0.4, 0.8 and 1 mg) or placebo followed by infusions of flumazenil (1 mg/h) or placebo for 3 h. Patients were monitored for 5 h after infusion. A positive response was defined as 1 point improvement in EEG grade. After independent analysis of the EEG gradings 5 out of 17 (29%) flumazenil treated patients showed an improvement in EEG grading (3 after bolus, 2 during follow-up) compared to 2 out of 15 (13%) placebo treated patients (1 after bolus, 1 during follow-up) (95% confidence interval of difference: -12% to + 50%). Of the 5 EEG responders after flumazenil, 3 also had an improvement in clinical PSE grading (none after bolus, 2 during infusion, 1 during follow-up), compared to neither of the 2 EEG responders after placebo. EEg responders did not differ from non-responders with respect to Child-Pugh score, basal EEG, PSE grade and positivity for benzodiazepines. In conclusion, treatment perspectives for flumazenil in portosystemic encephalopathy appear to be present for only a minority of patients; however, this study yields no support for a major role of benzodiazepine antagonists in the treatment of hepatic encephalopathy. PMID- 8689992 TI - Differentiation of alpha coma from awake alpha by nonlinear dynamics of electroencephalography. AB - The electroencephalogram, as a probe of scalp-recorded electrical activity arising from the human cortex, provides useful information because of its temporal and spatial organization. Recent developments in nonlinear dynamics suggest that an object can be constructed in an n-dimensional space out of a temporal sequence of data such as an EEG signal and that its organization is characterized by the dimensionality of the object (in this case, human brain activity). We have carried out an analysis of a set of alpha coma EEG patterns in comparison to the awake alpha EEG patterns of normal volunteers and patients. Alpha coma recorded from a single channel is visually indistinguishable from normal resting alpha due to its similar frequency spectrum (a broad-band spectrum with 1/f characteristics). Our results show that alpha coma dimensionality, however, differs from that of normal alpha in that it has a greater variability over different temporal segments of EEG. Single channel recordings in 7 patients with alpha coma were differentiable from those of 10 subjects with "normal" EEGs. Through dynamic analysis of the EEG, novel methods of signal extraction from EEG may become evident and applicable to clinical practice. PMID- 8689993 TI - Body temperature and the return of slow wave activity in extended sleep. AB - The time courses of slow wave sleep (SWS) and EEG slow wave activity (SWA) were examined in relation to core body temperature (CBT) during extended sleep periods of 15 h. Ten subjects (4 male, 6 female; aged 18-29 years) slept in the laboratory for 3 consecutive nights (2 of 8 h, and the last of 15 h). Bedtime was as close as possible to subjects' habitual bedtimes, but was always between 23.00 h and 1.00 h, and was the same on all nights. Standard polysomnographic measures as well as rectal temperature were collected continuously each night. Using 3 h blocks, SWS and SWA declined with time asleep, then showed a significant increase in the final 3 h. Using a more specific measure with 15 min means, 8 of the 10 subjects showed SWA returns late in sleep, that were not related to preceding amounts of waking after sleep onset (WASO), rapid eye movement sleep (REMS), or WASO+REMS. The timing and magnitude of the SWA return was significantly associated with the phase of CBT as indexed by delay from sleep onset to CBT minimum. The findings are consistent with a 12 h rhythm of SWS and SWA that is related to the phase of the CBT rhythm, with the minor pole of SWS/SWA occurring independently of WASO and/or REMS. PMID- 8689994 TI - Periodic lateralized epileptiform discharges in multiple sclerosis. AB - We report an unusual cause of periodic lateralized epileptiform discharges (PLEDs) in a young man with a long history of multiple sclerosis. Two exacerbations of multiple sclerosis, 3 years apart, were complicated by complex partial status epilepticus. After each episode, serial electroencephalograms revealed PLEDs (right frontal PLEDs in the first episode and right frontotemporal and bifrontal PLEDs in the second one), which resolved within 2 weeks. With the first episode, magnetic resonance imaging revealed an enhancing white matter lesion in the right frontal area, which improved after 3 weeks. We concluded that in each instance an exacerbation of multiple sclerosis caused the seizures. PMID- 8689995 TI - Asymmetry of rapid eye movements in chronic unilateral neglect does not change with behavioral improvement induced by rehabilitation treatment. AB - A strong reduction of leftward rapid eye movements (REMs) during REM sleep was recently documented in patients with severe and chronic left unilateral neglect. The aim of the present research was to study the stability of the unilateral suppression of REMs before and after a rehabilitative treatment for neglect disorders. Six right-brain-damaged patients were tested for neglect at the beginning and at the end of a 2 month cognitive rehabilitation treatment. REMs were recorded during 1 night of undisturbed sleep before and after the training. Five out of 6 patients improved considerably their ability to attend the previously neglected left hemispace; in all patients REM asymmetry remained unchanged. The lack of relationship between the improvement of the neglect disorder and the persistence of REM asymmetry suggests that the sensorimotor mechanisms activated by rehabilitation are different from those involved in the production of REMs. It is proposed that: (a) the directional vectors of REMs are computed on the basis of the exclusive or predominant endogenous activation of the central attentional mechanisms related to vestibular input; (b) the presence of rightward and leftward saccades and the positive effects of the rehabilitation treatment are functionally linked to attentional oculomotor mechanisms that are not active in REM sleep. PMID- 8689996 TI - Disintegration and reorganization of cortical motor processing in two patients with cerebellar stroke. AB - Cerebello-cerebral interaction plays a fundamental role in movement processing. Extensively studied in monkeys, cerebello-thalamo-cerebral information processing is less clear in humans. Taking advantage of the tight linkage between cerebellum and cerebral motor cortex, the objective of this experiment was to gain information on cerebellar function, dysfunction and recovery by analyzing movement-related cortical potentials (MRCPs). MRCPs were recorded prior to voluntary repetitive finger movements from two cerebellar stroke patients, in the acute phase of cerebellar stroke and after clinical recovery. Ten normal subjects served as controls. The main result was a significant depression of late MRCP components over the contralateral motor cortex when patients performed index finger movements of the affected side in the acute phase, and improvement of depressed components after clinical recovery, 8-10 months later. Topographic maps of late MRCP components showed diffusely enlarged potential fields with ataxic movements in the acute phase, and re-focused fields on follow-up. We conclude that (1) late MRCP components are particularly sensitive to cerebellar input in humans and can reflect different functional states of the cerebellum, (2) disturbance of motor cortex function after cerebellar stroke (diaschisis) can occur as a temporary phenomenon that reverses with good clinical recovery. PMID- 8689997 TI - Development of relative power contribution ratio of the EEG in normal children: a multivariate autoregressive modeling approach. AB - The relative power contribution ratio using a multivariate autoregressive model was applied to determine the spread of delta, theta, alpha and beta activity over the scalp in childhood. EEGs of 264 normal healthy subjects from 3 to 26 years were recorded from Fp1, Fp2, C3, C4, O1 and O2 with linked ears during the resting relaxed state with eyes closed. After selecting the epoch to remove artifacts, the relative power contribution ratio at each frequency band was calculated from the digitized EEG. The most noticeable developmental change was seen in the alpha frequency, where the relative power contribution ratio from its own area decreased significantly with age, and ratios from the other areas increased significantly. The change was larger at the frontal and smaller at the occipital region. Consequently, the occipital alpha wave was stable after 3 years of age. Developmental change at beta frequency was similar to alpha activity, but the number of components with significant change was smaller at delta and theta frequencies. Thus the relative power contribution of the EEG enabled us to observe how relationships among each location of EEG matured. PMID- 8689998 TI - High-frequency cortical responses reflect lexical processing: an MEG study. AB - Meaningful words and matched pseudowords, such as moon vs. noom, are of equal perceptual complexity, but invoke different cognitive processes. To investigate high-frequency cortical responses to these stimuli, biomagnetic signals were recorded simultaneously over both hemispheres of right-handed individuals listening to words and pseudowords. Consistent with earlier EEG studies, evoked spectral responses recorded from the left hemisphere revealed depression of spectral power in the low gamma band (around 30 Hz) after pseudowords but not after words. Similar differences between stimulus categories were present in the beta range. These results indicate that distinct patterns of high-frequency cortical responses correspond to the different cognitive processes invoked by words and pseudowords. It is hypothesized that differential high-frequency cortical responses signal the activation or activation failure of distributed Hebbian cell assemblies representing words and other elements of cognitive processing. PMID- 8689999 TI - The start-stop-start phenomenon in scalp-sphenoidal ictal recordings. AB - The start-stop-start (SSS) phenomenon is an apparent abortive ictal onset separated from the main seizure discharge. It was previously described in seizures recorded with subdural electrodes. We have observed this phenomenon in scalp-sphenoidal ictal recordings as well. We retrospectively reviewed 435 seizures recorded with scalp-sphenoidal electrodes from 61 patients with temporal lobe epilepsy. We found SSS onset in 15 seizures of 8 patients, representing 26% of these patients' seizures. The first "start" usually had a narrow field, typically in the sphenoidal electrode. The mean duration of the first "start" was 11 sec and that of the stop 8 sec. The restart had a different morphology and frequency in 87% and had a wider field in 67% of seizures. The clinical onset followed the first start and preceded the restart in most of the seizures. In 1 patient, 1 seizure with SSS was correctly localized and lateralized, whereas 5 of 7 without SSS were falsely lateralized. The recognition of the SSS phenomenon may improve the accuracy of seizure localization in scalp-sphenoidal recordings. PMID- 8690001 TI - Recent developments in peroxisome biology. AB - Peroxisomes are subcellular organelles that are present in all eukaryotic organisms. These organelles are the focus of much contemporary interest among cellular and medical biologists--an interest which coincides with the realization of their vital role in higher organisms, their unique metabolic and biogenetic characteristics, and their widespread involvement in genetic and degenerative disease. This article reviews some of the major recent developments in peroxisome biology. PMID- 8690000 TI - Structural mechanics of bent DNA. AB - The DNA molecule is a familiar object. It is often depicted in magazines and advertisements as a double helix, with the letters of the genetic code strung along the two spiral backbones and joined together in pairs. In such pictures the molecule is usually shown as straight; yet in the chromosomes of living organisms, DNA is curved and wound up into condensed packages. This article explains what is involved in such bending of DNA in the cell. It uses the ideas of structural mechanics--a tool of engineers--to show how the various components fit together when the molecule is bent. PMID- 8690002 TI - Isoprene synthesis by plants and animals. AB - Isoprene is emitted from both plants and animals at significant rates. There is evidence for a specific enzyme, isoprene synthase, that produces isoprene from dimethyl allyl pyrophosphate, one of the intermediates involved in the synthesis of higher-order isoprenoids such as cholesterol, carotenoids and monoterpenes (for example, pine scent). The role of isoprene in animals is unknown, but there is recent evidence that isoprene helps protect plant membranes involved in photosynthesis from thermal damage. Isoprene emission from plants is a natural process that contributes more hydrocarbon to the atmosphere than all of the anthropogenic hydrocarbons. PMID- 8690003 TI - How the brain goes out of its mind. AB - Dreaming is characterized by formal visual imagery (akin to hallucination), by inconstancy of time, place and person (akin to disorientation), by a scenario like knitting together of disparate elements (akin to confabulation) and by an inability to recall (akin to amnesia). Taken together, these four dream features are similar to the delirium of organic brain disease. By studying the brain during rapid-eye-movement (REM) sleep--the phase of sleep in which most dreaming occurs--we can begin to understand its basis in the altered neurophysiology of REM. PMID- 8690004 TI - Prolactin response to suckling and maintenance of postpartum amenorrhea among intensively breastfeeding Nepali women. AB - The aim of the study was to determine the association between PRL responses to suckling and maintenance of postpartum amenorrhea among breastfeeding mothers. Three blood spot samples (5, 30, and 50 min following a timed nursing bout) were collected from 71 intensively breastfeeding Nepali women for PRL determination. Maternal age, BMI (weight/height2), menstrual status, caste, infant age, nursing bout length, and duration of supplementation were recorded at time of sample collection. Independent and paired t tests, linear regression analyses, and general linear models were used to evaluate differences between cycling (n = 36) and amenorrheic (n = 35) women and associations among variables. Logistic regression analyses were used to relate PRL measures to the odds of maintaining lactational amenorrhea. Amenorrheic breastfeeding mothers had higher (P < .001) PRL levels at all 3 collection times than cycling breastfeeding mothers, and PRL levels declined with time since birth (P < 0.05). The odds (OR) of having ceased lactational amenorrhea was significantly higher (OR = 5.0, 95% Cl = 1.3-19.9) among mothers with lower PRL levels (< or = 10 ng/mL) at 50 min post-sucking, and PRL at 50 min showed a significant dose response relationship with menstrual status. The association between 50 min PRL levels and lactational amenorrhea appears to be independent of time postpartum, maternal age, BMI, nursing bout length, and duration of supplementation. Among intensively nursing women, maintenance of elevated PRL levels across the interbout interval increases the odds of maintaining lactational amenorrhea. PMID- 8690005 TI - Regulation of a uterine 250 kDa protein by estradiol and antiestrogens. AB - A 250 kDa secretory protein was isolated from the uterine luminal fluid (ULF) obtained from estradiol-treated ovariectomized rats. Antiestrogens blocked the production of this protein. The protein components were separated and purified by SDS-PAGE. Polyclonal antibodies were raised against the 250 kDa protein and used to identify the protein by Western blot. 17 beta-estradiol (E2) at a dose of 0.005 mg/kg/d administered s.c. for 3 days to ovariectomized rats stimulated a marked increase in the production of the 250 kDa protein. Anordiol at a low dose of 5 mg/kg/d x 3 p.o. or 0.25 mg/kg/d x 3 s.c. stimulated the production of the 250 kDa protein. Treatment with higher doses (10 mg/kg/d x 3 p.o., or 1.25 mg/kg/d x 3 s.c.) was less effective in inducing production of this protein. Also anordiol partially inhibited the stimulatory action of E2; whereas ICI 182,780, a pure antiestrogen, at a dose of 0.3 mg/kg/d x 3 s.c. completely blocked the stimulatory action of E2. The 250 kDa protein was not detected in the blood obtained from E2-treated ovariectomized rats. The anti-complement C3 and anti alpha 2-macroglobulin antibodies did not react with the ULF 250 kDa protein. The present results show that the production of the ULF 250 kDa protein is regulated by estradiol and is not a component of blood plasma. It is proposed that the estrogen-responsive 250 kDa protein may be involved in maintaining the viability of the fertilized ova and in the implantation of the blastocyst. PMID- 8690006 TI - In rats, atrial natriuretic peptide secretion is regulated differently in the right and left atria. AB - Recent studies have suggested the secretion of Atrial Natriuretic Peptide (ANP) is regulated by receptor mediated activation of protein kinase C, which causes the autocrine release of prostaglandins. Prostaglandins stimulate ANP secretion via the adenylate cyclase second messenger system. This report examined the response of right and left atrial ANP secreting cells to the three endothelin isopeptides and to cyclooxygenase inhibition. Our results show that right atrial ANP secretion is stimulated by endothelin 1 and 2 but not 3. In addition, right atrial ANP secretion is reduced by inhibition of cyclooxygenase. In contrast, left atrial ANP secretion is stimulated by endothelin 2 and 3 but not 1. Inhibition of cyclooxygenase did not affect left atrial ANP secretion. These results show the regulation of ANP secretion is different between the two atrial chambers. Right atrial cells appear to contain the prostaglandin-mediated response to protein-kinase C activation, whereas left atrial cells regulate ANP secretion differently. PMID- 8690007 TI - Cytochrome c oxidase in rat adrenal and liver: effects of anti-androgen treatment and studies in testicular feminized rats. AB - The role of androgen receptors in androgen-induced changes in rat adrenocortical and liver cytochrome c oxidase (COX) has been investigated. The anti-androgen flutamide, blunted the increase in COX activity and COX subunits II/III and IV, that is seen with androgen treatment. Testicular feminized (Tfm) rats had levels of COX activity and COX subunits II/II and IV in adrenal cortex and liver that were intermediate between the high levels found in normal male rats and the lower levels of normal female rats. These data suggest that androgen effects on adrenal and liver COX are mediated through interactions with androgen receptors known to be present in these issues. However, the observed changes in COX activity and COX subunits were not accompanied by altered levels of mRNAs encoding for COX II or COX IV. PMID- 8690009 TI - Predicting endurance limits in arm cranking exercise with a subjectively based method. AB - The purpose of this study was to compare a method for predicting endurance capacity at different workloads based on subjective perception of effort with the technique for determining 'critical power' (CP) proposed by Moritani et al. (1981). Three trained paraplegic subjects performed two protocols during separate sessions. The 'subjective' protocol consisted of graded and continuous tests on an arm crank ergometer, during which cardiorespiratory (heart rate, oxygen consumption, ventilation and respiratory exchange ratio) and subjective (Borg's 10-point scale) parameters were monitored continuously. A statistical regression analysis for power functions was performed to obtain the individual ?iso perception' curves in a power/duration reference system. The other protocol consisted of the determination of the CP of the muscle groups involved in arm cranking exercises according to the protocol proposed by Moritani et al. (1981). Subjects performed three tests in which the power output remained constant (50, 37.5 and 25 W) and led to the onset of muscular fatigue. The results of the two protocols were compared. The validity of the subjective perception of effort as a predictor of individual endurance capacity was confirmed by the relationship between time to exhaustion and work performed during constant-power tests as proposed by Moritani et al. (1981). PMID- 8690008 TI - Melatonin and 2[125I]iodomelatonin binding sites in the human colon. AB - 2[125I]Iodomelatonin binding sites were identified in the mucosa of the human colon from Chinese patients with carcinoma of the rectum or colon using biochemical receptor assay and autoradiography. Melatonin in the colonic mucosa/submucosa and muscle layers were quantitated by radioimmunoassay. The binding of 2[125I]iodomelatonin to the membrane preparations of the human colonic mucosa/submucosa was stable, saturable, reversible and of high affinity. Rosenthal analysis from saturation studies performed at 21 degrees C yielded an equilibrium dissociation constant (Kd) of 61.7 +/- 4.48 pmol/L (n = 3) and maximum number of binding sites (B(max)) of 1.65 +/- 0.51 fmol/mg protein (n = 3). The linearity of the Rosenthal plots and unity of the Hill coefficient suggested that 2[125I]iodomelatonin was bound to a single class of binding sites. The radioligand binding was displaced by 2-iodomelatonin (Ki = 0.02 nmol/L), melatonin (0.65 nmol/L), 6-chloromelatonin (Ki = 5.33 nmol/L), 6-hydroxymelatonin (Ki = 33.8 nmol/L) and N-acetylserotonin (Ki = 122 nmol/L). The characteristic of the binding sites were similar to those reported in the jejunum of duck, chicken, and human but of higher affinity than those in the mouse colon. Autoradiography localizes the binding to the mucosa of the human colon. Radioimmunoassay revealed a melatonin concentration of 467 +/- 99 pg/g wet tissue of human colon (n = 6). Our findings suggest that melatonin may influence the human colonic functions through interaction with its receptors in the mucosa. PMID- 8690010 TI - Adjustments of posture and viewing parameters of the eye to changes in the screen height of the visual display terminal. AB - To understand the motions caused by the interaction among the different body parts, adjustments of both eye position and body posture to screen height settings of 80, 90, 100, 110 and 120 cm were determined in 10 subjects. The subjects engaged in a non-keyboard, interactive computer game requiring constant visual monitoring. Changes in body positions were determined by video image analysis for the posture parameters and by video frame analysis for the eye parameters. Analysis of variance and correlation analysis showed that neck angle, thoracic bending and vertical eye position were significantly affected by changes in the screen height of the VDT. The study of the interrelationship of eye position and body posture suggested that changes in body positions served to complement the eye position in attaining a better view of the visual target. Viewing angle was observed to be decided mainly by inclination of the neck and the eye. Thoracic bending was also noted to contribute in setting the viewing angle, although to a lesser extent. On the other hand, viewing distance and trunk inclination showed significant correlation. PMID- 8690011 TI - Human errors in fatal and serious occupational accidents in Finland. AB - The aim of this study is to examine the effect of human error on industrial accidents. One hundred and seventy-eight fatalities and 99 serious accidents were classified according to Rasmussen's SRK model. Of accidents, 84-94% were due mainly to human error. Most of the errors were skill-based, next came rule-based errors and then knowledge-based errors. The type of error was analyzed by age, work experience and work tasks of the victims. The results showed that the SRK model is suitable for analyzing accidents in industrial work using rather simple technology. PMID- 8690012 TI - Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB). Enzyme nomenclature. Recommendations 1992. Supplement 2: corrections and additions (1994). PMID- 8690013 TI - Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB). Enzyme nomenclature. Recommendations 1992. Supplement 3: corrections and additions (1995). PMID- 8690014 TI - In vivo assembly kinetics of fluorescently labeled Xenopus lamin A mutants. AB - The assembly kinetics of Xenopus wild type lamin A and 7 mutants were analyzed by the microinjection of renatured 5-iodoacetamidofluorescein (5-IAF)-labeled protein into mouse 3T3 cells. This experimental system has the advantage that the masking of the mutant phenotype by the formation of heterooligomeric complexes with newly synthesized lamins of the microinjected cell is negligibly small. The wild type protein and all mutants containing a nuclear localization signal were transported within 10 min into the nucleus. The wild type protein exhibited a strong lamina fluorescence 30 min after microinjection, whereas mutant molecules showed a delayed but complete, a delayed and incomplete, or no lamina assembly at all. The lamin A mutant lacking the carboxy-terminal cysteine of the CxxM-motif exhibited a delayed but complete assembly, whereas previously performed transfection experiments demonstrated no significant interaction of this mutant wih the lamina. According to present knowledge this phenotype in transfected cells can be explained by an overexpression of this mutant. We have identified an additional domain in the carboxy-terminal tail of lamin A that promotes its assembly into the lamina. In vitro this domain is required for the chromatin binding of lamin A. Lamin A molecules lacking the non-helical amino-terminal head domain showed no significant lamina staining, whereas point mutations in conserved regions of the alpha helix resulted in an incomplete assembly. PMID- 8690015 TI - Disruption of vimentin intermediate filaments in transgenic mice by expression of a dominant negative mutant desmin subunit. AB - To investigate putative functions of vimentin intermediate filaments in the context of intact tissues and the developing organism, a construct (pVDV), driven by the vimentin promoter and encoding a truncated desmin subunit, was introduced into the murine germ line. The mutant desmin was assembly-incompetent and capable of disrupting preexisting vimentin filaments in a dominant negative fashion, both in transgenic mouse tissues and in fibroblast cultures derived from these mice. Mutant desmin expression strongly enhanced vimentin turnover. In tissues of some transgenic mouse lines, high level expression of pVDV occurred in 10 to 40% of vimentin-containing cells and, surprisingly, in 1 to 10% of the skeletal and tongue muscle cells. Immunohistochemical staining of muscle tissue showed a diffuse staining pattern instead of the punctated aggregates into which mutant desmin typically accumulates in other cell types. The overexpression of pVDV and the concomitant disruption of the endogenous vimentin filament network and enhanced vimentin turnover in a significant percentage of cells did not cause detectable developmental abnormalities. PMID- 8690017 TI - Cytosolic and nuclear localization of protein phosphatase 2C beta 1 in COS and BHK cells. AB - We have recently elucidated the structure of an isoform of the Mg(2+)-dependent protein phosphatase 2C (PP2C beta 1) from rat liver (Wenk, J., H.-I. Trompeter, K.-G. Pettrich, P. T. W. Cohen, D. G. Campbell, G. Mieskes, FEBS Lett. 297, 135 138 (1992)). In the present study the subcellular distribution of PP2C beta 1 was investigated in COS and BHK cells. We modified the PP2C beta 1 cDNA with a c-myc tag coding sequence at either its 3' or its 5' end end to distinguish the plasmid derived PP2C beta 1 from the endogenous phosphatase and to examine the influence of the modification on the enzymatic activity. Transient transfections of COS or BHK cells with pCMV2 derived vectors containing these constructs showed that the expressed hybrid protein with the lowest activity (N-terminal tagged < untagged < C-terminal tagged PP2C beta 1) was expressed to the highest level and vice versa. These experiments point to a possible toxic effect or a selection disadvantage after overexpression of PP2C beta 1. In immunofluorescence studies with antibodies specific for the PP2C beta isoform, all overexpressed proteins showed the expected cytoplasmic as well as a significant nuclear localization. The nuclei remained stained even after selective perforation of the plasma membrane with digitonin and washing out the cytosolic PP2C beta 1. We conclude that PP2C beta 1 has obligatory and important functions in metabolic as well as in nuclear processes. PMID- 8690016 TI - Immunocytochemical localization of protein kinases Yes and Src in amoeboid microglia in culture: association of Yes kinase with vimentin intermediate filaments. AB - Amoeboid microglia isolated from primary cultures of neonatal rat brain correspond to a transient form of activated microglia, a resident population of macrophage-like cells. In order to understand the molecular aspects of microglial activation, we have studied amoeboid microglia in primary culture for the presence of Yes and Src protein tyrosine kinases, two kinases which have been implicated in signal transduction process during monocyte/macrophage activation. Immunofluorescence with an antibody raised against the peptide from unique N terminal domains of Yes and Src demonstrated that Yes and Src kinases are enriched in perinuclear areas of amoeboid microglia. In addition, the antibody to c-yes peptide had a cytoplasmic distribution which coincided with the distribution of vimentin-containing intermediate filaments. Preadsorption of anti c-yes antibody with an excess of antigenic peptide inhibited anti-c-yes immunofluorescence, while vimentin immunofluorescence remained unchanged. Double immunofluorescence images analyzed with the two-dimensional intensity distribution program (2-D scattered histograms) on Zeiss confocal scanning laser microscope demonstrate the colocalization of c-yes with vimentin. The extent of colocalization was more prominent after exposure of intact cultured microglia to dibutyryl cyclic AMP (dBcAMP), or to phorbol ester TPA (12-O-tetradecanoylphorbol 13-acetate) or to okadaic acid, an inhibitor of protein phosphatases. The findings suggest that vimentin might serve as molecular support for Yes kinase and, since previous studies have shown that vimentin in amoeboid microglia is one of the major protein substrates of serine/threonine protein kinases, this function could be regulated by phosphorylation. PMID- 8690018 TI - Spectrin in the leading lamella of cultured chicken fibroblasts. AB - The leading lamella is a highly dynamic cell compartment of locomoting fibroblasts. Based on its well-characterized internal cytoskeletal architecture, the leading lamella can be divided into three structurally distinct zones. Much less is known about the membrane components of the leading lamella. In this study, we looked at the distribution of spectrin, the major component of the subplasmalemmal membrane skeleton, in the leading lamella and its relation to the subdivision of the lamellar space in cultured fibroblasts. In immunofluorescence microscopy, a general, plasma membrane-associated staining of spectrin was observed especially in the more central regions of detergent-extracted cells. In the leading lamella, spectrin was seen particularly along the lamellar edge and as small protrusions, or nodes, along the lamellar periphery. A weaker staining was observed in the more proximal regions of the lamella. In wet-cleaved cells also, spectrin was observed along the leading edge and in the protrusions of the lamella. In double immunofluorescence microscopy, a close colocalization of spectrin and actin was seen in the lamellar region. In immunoelectron microscopy of whole-mount preparations, spectrin was also found to be in close association with the actin meshwork in the most peripheral zone of the lamella and it was also associated with the actin-containing microspikes. A weaker labeling for spectrin was observed along the filaments in the proximal regions of the lamella. The node-like accumulations of spectrin seen along the lamellar edge were reactive to antibodies raised against talin and paxillin, suggesting that they represent evolving focal adhesions. The results show that spectrin is particularly present along the leading edge of the leading lamella. It is also present in the active protrusion sites of translocating cells, probably representing evolving adhesion sites. The role of spectrin should therefore be considered when studying the mechanisms of events associated with the locomotive behavior of fibroblasts. PMID- 8690019 TI - Segregation of ERGIC53 and the mammalian KDEL receptor upon exit from the 15 degrees C compartment. AB - Protein trafficking along the exocytotic pathway occurs by vesicular transport between successive membranous compartments. Transport from the endoplasmic reticulum (ER) to the Golgi apparatus has been proposed to be bridged by a morphologically defined ER-Golgi intermediate compartment (ERGIC). Using the subcellular dynamics of two markers for the ERGIC, the 53 kDa protein ERGIC53 and the mammalian KDEL receptor (KDEL-R), we have investigated the biochemical and physiological characteristics of ER-Golgi anterograde and retrograde transport. The KDEL-R at steady state is mainly confined to the perinuclear Golgi region while the ERGIC53 has a more elaborate distribution, including the ER. Both proteins can be colocalized to spotty structures distributed throughout the cytoplasm by incubating the cells at 15 degrees C. Upon returning the cells to 37 degrees C, the direction of transport for the two proteins diverged. KDEL-R was seen to emanate into tubular structures which eventually culminated in a focused, perinuclear staining. These dynamic changes are consistent with the anterograde transport process from the ER to the Golgi apparatus. ERGIC53, on the other hand, was distributed into an extended reticular network as well as the nuclear envelope, a staining pattern characteristic of the ER. With time, ERGIC53 was seen to return to the spotty structures again. The ER retrieval of ERGIC53 is consistent with the fact that the protein contains a dilysine motif which may function as an ER retrieval signal. The movement of ERGIC53 into the ER is not affected by microtubule disrupting agents, which inhibit the movement of KDEL-R to the Golgi. Both the processes are, however, sensitive to the alkylating agent N-ethylmaleimide. When reconstituted in vitro using digitonin permeabilized cells, the movement of ERGIC53 into the ER has a requirement for metabolic energy, is partially inhibited by the nonhydrolyzable guanine nucleotide analog GTP gamma S but could not be made to be cytosol dependent. These results documented the convergence of anterograde transport and retrograde transport at the 15 degrees C compartment and implied the existence of a segregation or a sorting process that would result in the segregation of proteins with different targeting signals in the structure. PMID- 8690020 TI - Expression of the cartilage matrix protein gene at different chondrocyte developmental stages. AB - Cartilage matrix protein (CMP), a major noncollagenous component of certain types of hyaline cartilage, is synthesized by chondrocytes in a developmentally regulated manner. In this study, we monitored the accumulation of CMP in the developing chicken limb and sternum by immunostaining. In older embryos, the specific extracellular staining was restricted to the resting/proliferative zone of metaphyseal cartilage and to the immediately adjacent hypertrophic cartilage. A lack of staining was observed in the peripheral layers of articular cartilage. Data were compared with the accumulation of CMP mRNA measured by Northern analysis relative to other cartilage-specific messages in cell cultures representing different stages of chondrocyte differentiation, as well as with the steady state mRNA levels in tissue samples. We found a correlation between the gene expression pattern of the in vitro cultures and the one observed in certain in vivo differentiation stages. The high-density mesenchyme culture was utilized as a model for studying the events at early stage I (stage Ia) of chondrogenesis. This culture was characterized by relatively low steady state mRNA levels for cartilage proteins, including the later activation of the CMP gene as compared to type II collagen or link protein genes, and relatively high steady state mRNA levels for type VI collagen and beta-actin. Chicken embryo chondrocyte cultures obtained from sterna of 14-day-old embryos, however, consisted predominantly of stage Ib chondrocytes, and showed high steady state levels for cartilage proteins, but relatively lower levels for type VI collagen and beta-actin mRNAs. In accordance with the in vivo data, a relatively high steady state level was detected for CMP mRNA in cultures of hypertrophic (stage II) chondrocytes. We also performed transient expression assays in the various culture systems to study the role of the promoter upstream and intronic control regions in the tissue- and developmental stage-specific regulation of the CMP gene. We showed that the enhancer worked in a lineage-specific manner, by further stimulating the minimal promoter activity independent of the developmental stage of chondrocytes, while it did not in other tissues. The promoter upstream control regions, however, seemed to play a role in restricting the promoter activity to a certain chondrocyte developmental stage. PMID- 8690021 TI - Mammalian homologue of the calcium-sensitive phosphoglycoprotein, parafusin. AB - Three specific antipeptide antibodies and oligonucleotide probes synthesized to internal sequences of parafusin have been used to search for mammalian counterpart(s) of this protein. Parafusin is an exocytic-sensitive phosphoglycoprotein from a unicellular eukaryote Paramecium that was recently cloned and sequenced (Subramanian et al., Proc. Natl. Acad. Sci. USA 91, 9832 9836 (1994)). Western and Southern blot analyses, polymerase chain reaction (PCR) and reverse transcriptase coupled PCR (RT-PCR) techniques have been used to examine rat liver and pancreas, human pancreas and a murine pancreatic beta-cell line (beta TC3) arising in transgenic mice. The parafusin-specific antibodies showed cross-reaction with a protein at approximately 63 kDa in 4 tissues, whereas a phosphoglucomutase-specific antibody also detected a second band of similar molecular weight in the beta TC3 cells. The presence of two bands shows that parafusin homologue(s) and phosphoglucomutase are separate entities. beta TC3 cells were shown to incorporate [beta 35]UDPGlc into the parafusin homologue in a Ca(++)-sensitive manner characteristic of parafusin. Southern blot analysis revealed that the parafusin-specific probe hybridized with restriction enzyme digests of rat DNA in distinct patterns different from those observed with a phosphoglucomutase-specific probe. Rat genomic DNA and mRNA from the beta TC3 cells were used as the templates for PCR and RT-PCR using internal parafusin primers. In both cases similarly sized products were obtained which hybridized in Southern analysis with a specific parafusion probe located within the amplified region. These results indicate that a parafusin homologue exists in mammalian cells. PMID- 8690022 TI - E-cadherin expression and in vitro invasion of canine mammary tumor cells. AB - E-cadherin is considered to be an invasion suppressor molecule. We have studied the expression and function of E-cadherin in three cell lines derived from a dog mammary tumor, namely SH15, SH24, and SH27. In monolayer culture the cell lines can be distinguished by their morphotype: epithelioid (SH15), fibroblast-like (SH24) and intermediate type (SH27). SH27 was unable to form colonies in collagen gel in contrast to SH15 and SH24. All three cell lines expressed the E-cadherin antigen, as evident from immunocytochemistry, and alpha-, beta-, and gamma catenins as evident from immunoprecipitation with E-cadherin antibody. Only SH27 showed E-cadherin-dependent aggregation, and little invasion into collagen type 1 gels, in contrast to SH15 and SH24 cells. However, in the precultured embryonic chick heart assay all three cell lines were invasive, demonstrating that invasion depends upon the microenvironment. We assume that in the embryonic chick heart, factors were present or were induced by the SH27 cells, interfering with the function of E-cadherin. PMID- 8690023 TI - T4 accumulation in lysosomes of rat thyroid remnants after subtotal thyroidectomy. AB - In chronically stimulated rat thyroids after subtotal thyroidectomy, lysosomes increased in number and volume. They contained iodocompounds and did not appear in iodine-deficient animals. In this study, we analyzed the subcellular localization and the nature of these intracellular iodocompounds. Classical subcellular fractions were isolated from homogenates of rat thyroids and remnants 14 weeks after sham-operation or subtotal thyroidectomy. Two lysosome subpopulations of increasing density, a light fraction, lysosomes 2 (L2, density 1.065-1.08 g/ml) and a dense fraction, lysosomes 1 (L1, density > 1.08 g/ml) were separated from crude lysosomal particulate fractions (ML) by centrifugation in Percoll gradients. Results obtained with thyroids of normal rats were used as controls. In TSH-stimulated thyroid remnants, total activities of three lysosomal enzymes and iodine concentration were increased by 1.6-fold compared with thyroids of sham-operated rats. Total iodoprotein-derived T3 and T4 concentrations, measured after pronase hydrolysis, were slightly decreased. Thyroglobulin (Tg) concentration in the supernatant was reduced by 50%. Iodine, T3 and T4 contents of Tg were not modified. After differential centrifugation, the iodine excess of remnants sedimented with subcellular particulate fractions. The concentration of iodine in dense lysosomes (L1) was 6 times that in sham L1. Intact Tg did not accumulate in L1. Two thirds of the iodine in L1 was soluble in methanol, double the normal proportion, with twice as much iodine included in hydrophobic peptides eluted after T4 by reverse-phase HPLC. Although iodoprotein derived T4 and T3 concentrations were decreased in the remnant homogenate, they were increased in particles, particularly in L1 where they were increased by 8 and 4-fold, respectively. In contrast, specific activities of lysosomal enzymes in ML and L1 remained unchanged. It is concluded that the chronic TSH stimulation of thyroid remnants in subthyroidectomized rats receiving a normal iodine supply induces the endocytosis of a normal Tg with iodine kept in dense lysosomes. The expansion of the lysosomal compartment resulted from a limitation in iodopeptides degradation as though secondary lysosomes would be overloaded with Tg. The accumulation in L1 of hydrophobic iodopeptides and of more iodoprotein-derived T4 than T3 suggests that exopeptidases involved in the liberation of T4 become rate limiting. PMID- 8690024 TI - Origins of the parasitophorous vacuole membrane of the malaria parasite: surface area of the parasitized red cell. AB - There is conflicting evidence on whether the parasitophorous vacuole membrane, in which the malaria parasite becomes encapsulated when it enters the red cell, represents a part of the host cell membrane or is derived, at least in part, from the parasite. We have measured the surface area of populations of red cells before and after invasion by up to four merozoites of the malaria parasite, Plasmodium falciparum. The dimensions of the merozoite are such that, if it enveloped itself entirely in host cell membrane during entry, the loss of surface area would amount to some 4 square microns 2 or 3% of the total for each parasite internalized. Our measurements show that within the 99% level of confidence any loss of surface area is less than 1 square micron 2 per parasite internalized. Area measurements on red cells that have been allowed to lose known proportions of their membrane by metabolically induced vesiculation reveal, moreover, that diminutions in surface area in the range of interest are readily detectable. Our observations on recently invaded (young ring-stage) parasites appear to exclude any significant change in surface area of the host cell following invasion. This implies that, if indeed there is internalization of host cell membrane lipid on invasion, as the best evidence shows, it is compensated by parasite-derived lipid, and conversely the parasitophorous vacuole membrane probably contains a contribution of parasite-derived material, presumably that seen to be discharged by the apical organelles, the rhoptries, at the time of invasion. PMID- 8690026 TI - Hypertonic stress induces c-fos but not c-jun expression in the human embryonal EUE epithelial cell line. AB - Recent evidence has indicated a role for the two early response genes c-fos and c jun in transcriptional regulation of genes acting in osmoregulation. On this basis we investigated their expression in response to hypertonic stress in the human embryonal EUE epithelial cell line. EUE cells have proven to be a useful tool for studying long-term in vitro adaptation to hypertonic stress. After culturing EUE cells in hypertonic medium a marked c-fos induction was observed, both at the mRNA and the protein level. Northern analysis of fos-mRNA showed a peak expression at 4 h, followed by a progressive decline till complete extinction at 8 h. Immunofluorescence analysis of FOS protein evidenced a similar, although slightly delayed kinetics of expression. Conversely, neither c jun nor c-myc up-regulation could be detected. The treatment of EUE cells with cycloheximide led to superinduction of c-fos expression, (with high levels up to 12 h), and to a c-jun expression that was just detectable. Hypertonic stimulation of the transformed cell lines A549, MCF7 and JR induced both c-fos and c-jun only in JR cells. Hypertonic shock was also effective in inducing c-fos expression in fetal human diploid fibroblasts, although the response was earlier and more transient than in EUE cells. These findings indicate that c-fos is a primary response gene in hypertonic stress-activated cells, although the pattern and kinetics of its induction may differ according to the type of cell. PMID- 8690027 TI - Nod factors produced by Rhizobium leguminosarum biovar viciae induce ethylene related changes in root cortical cells of Vicia sativa ssp. nigra. AB - Vicia sativa ssp. nigra plants develop the "Thick short root" (Tsr) phenotype when both (i) the roots are inoculated with the root nodule inducing bacterium Rhizobium leguminosarum biovar viciae, and (ii) the plants, including the roots, are grown in the light. Tsr roots have a reduced length, are locally twice as thick as normal roots and have an increased number of root hairs. Development of the Tsr phenotype is correlated with the presence of nod (nodulation) genes in the rhizobia. Nod factors (lipochitin oligosaccharides), products of these nod genes, can induce the Tsr phenotype in the absence of rhizobia. The Tsr phenotype can be mimicked by addition of the ethylene-releasing compound ethephon. Using several microscopical techniques, we compared roots showing the Tsr phenotype (Tsr roots) with normal roots and roots grown in the presence of the ethylene inhibitor aminoethoxyvinylglycine (AVG). The thickening of Tsr roots appeared to be caused by a swelling of the cortical cells, which corresponded with (i) a reorientation of the interphase cortical microtubules from a transverse to a longitudinal direction, (ii) general cell wall modifications, (iii) frequent absence of middle lamellae, and (iv) local maceration. The same changes could be induced by ethephon and were inhibited by AVG. This strongly suggests that the Tsr phenotype is caused by excessive ethylene production. The ethylene-related changes mentioned above are also seen during infection thread formation, but only very locally. Apparently, Vicia roots when grown in the light overrespond to Nod factors leading to overproduction of ethylene and to a non-local "ripening" process. These phenomena inhibit nodulation of the main root by preventing formation of pre-infected threads and by reducing formation of root nodule primordia. Local controlled production of ethylene, as induced by Nod factors, may, however, be an essential element of the nodulation process. PMID- 8690029 TI - Effects of muscarinic agents on cultured human trabecular meshwork cells. AB - Intracellular calcium measurements were performed in cultured human trabecular meshwork cells preloaded with the cell permeant dye fura 2-AM. Fluctuations in calcium levels were then monitored with microscope-based ratio fluorometry. Carbachol increased intracellular calcium in a dose-dependent manner; as did oxotremorine-M, aceclidine, and pilocarpine. Carbachol's effect was blocked by the non-selective muscarinic antagonist atropine, as well as by muscarinic receptor subtype-selective antagonists such as pirenzepine (M1-selective), p fHHSiD (M3-selective), and 4-DAMP (M1, M3 subtypes). Rank order of potencies for the antagonists' effects was atropine = 4-DAMP > p-fHHSiD > pirenzepine, a profile suggesting that the M3 receptor subtype is essential in the carbachol effect. Phospholipase C activity was estimated via measurement of total production of inositol phosphates in cultured human trabecular meshwork cells pre exposed to 3H-myoinositol. In these cells, carbachol also stimulated phosphoinositide production in a dose-dependent manner, and an antagonist profile similar to that seen for calcium response was obtained when carbachol was used as the effector. The data indicate that muscarinic effects on cultured human trabecular meshwork calcium mobilization and phospholipase C activity are mediated by an M3-like receptor subtype. Therefore, the muscarinic M3 receptor may play a role in trabecular meshwork cell function(s). PMID- 8690028 TI - Detection of specific messenger RNA by electron microscopic in situ hybridization: implications for nucleocytoplasmic transport. PMID- 8690025 TI - Superoxide anion generation in Drosophila during melanotic encapsulation of parasites. AB - Quinoid precursors of melanin and/or reactive oxygen species (ROS) generated during melanogenesis have been implicated as cytotoxic molecules in the immune responses of insects against their internal metazoan parasites. No study has yet identified the killing components produced in conjunction with melanotic encapsulation responses, or explained how cytotoxic molecules generated in the open circulatory system of an insect can selectively destroy foreign tissues. Strains of Drosophila melanogaster with differing immune capabilities against the wasp parasitoid Leptopilina boulardi were examined for superoxide anion (O2-.) formation during parasitization. Elevated levels of O2-. were produced by immune reactive (R-strain) hosts during melanotic encapsulation of the parasitoid, but not by susceptible (S-strain) hosts in which the parasitoid developed unmolested. Both a superoxide dismutase (SOD)-deficient strain (cSODn108, red/TM3/Sb Ser) and a catalase (CAT)-deficient strain (Catn1) also produced melanotic capsules and elevated levels of O2-. when infected, but these reactions were unsuccessful and the parasitoids survived, indicating that neither the quinoid precursors of melanin nor O2-. per se were cytotoxic. Immune incompetence in SOD-deficient and CAT-deficient hosts is attributed in part to defects in hydrogen peroxide (H2O2) metabolism, and/or the inability of these metalloenzyme-deficient strains to initiate the metal-mediated reductive cleavage of H2O2 required for the production of the cytotoxic hydroxyl radical (.OH). The role proposed for O2-. in Drosophila cellular immunity is one of potentiating the formation of .OH. Melanin, which contains both oxidizing and reducing components, may serve a dual role in producing O2-. and sequestering redox-active metal ions, thereby confining the production of ROS. Host-parasite susceptibility in the Drosophila Leptopilina system may be determined by the ability of the parasitoid to modulate hemocyte activity and prevent both effective melanotic encapsulation and the generation of cytotoxic levels of ROS. PMID- 8690030 TI - Studies on the mechanism of early onset macular degeneration in cynomolgus (Macaca fascicularis) monkeys. I. Abnormal concentrations of two proteins in the retina. AB - Cynomolgus (Macaca fascicularis) monkeys from three families, which showed symptoms of early onset macular degeneration was studied. Two proteins, albumin and glyceraldehyde 3-phosphate dehydrogenase, were found to have markedly altered concentrations in whole retina of the monkeys with early onset macular degeneration, compared with normal controls. SDS-polyacrylamide gel patterns detected a 40-70% increase in the concentration of albumin and about 65% decrease in the concentration of glyceraldehyde 3-phosphate dehydrogenase in these affected retinas. There was however no significant difference in the relative concentrations of albumin in the plasma samples of affected and normal monkeys belonging to the three families studied and to an unrelated family. These initial findings suggest that degradative as well as antioxidant enzymes might be involved in the mechanisms leading to macular degeneration. In addition, the results also correlate with a possible role of these two proteins in H2O2 toxicity and appear to indicate that oxidative stress is significant in the etiology of early onset macular degeneration. PMID- 8690031 TI - Purification and characterization of a new enzyme dipeptidase from human lens. AB - A new enzyme dipeptidase has been purified to homogeneity from human lens tissue adopting isoelectric focusing, preparative electrophoresis and gel filtration HPLC. The purified enzyme hydrolyses a wide variety of dipeptides containing aliphatic as well as aromatic amino acids but does not act on tripeptides and proteins. The identity of this enzyme as a dipeptidase has been confirmed by the use of dipeptides with modified amino or carboxyl groups. The optimum temperature and pH for this enzyme are 25 +/- 2 degrees C and 5.5 respectively and pI is 6.5. The Km for different dipeptides varied from 0.04 mM to 4.2 mM. The molecular weight of the native enzyme as determined by gel permeation HPLC is 52 kDa. Preparative electrophoresis, followed by HPLC gave two active proteins, with molecular weights of 52 kDa and 13 kDa. That with the molecular weight of 52 kDa was found to be the tetramer of the other by SDS-PAGE, and peptide mapping of tryptic digests. Properties of this enzyme have been compared with those reported for other proteinases and peptidases of the lens and dipeptidases of Escherichia coli and mouse tumour cells and they render additional support to the finding that this is a new enzyme. The physiological function of this enzyme is also discussed. PMID- 8690033 TI - Distribution and type of morphological damage in human nuclear age-related cataracts. AB - The distribution and type of fiber cell damage was evaluated in human age-related nuclear cataracts and in aged normal (non-cataractous) lenses. Ten age-related nuclear cataracts (53 to 89 years old) and four normal lenses (59 to 67 years old) were examined by electron microscopy of fixed Vibratome sections. Images from the adult, juvenile, fetal and embryonic nuclear regions were compared. Each cataractous lens contained a central region of increased light scattering which involved the embryonic and fetal regions with progressively less involvement in the juvenile and adult nuclear regions. Some damaged fiber cells were observed in all specimens, although damage was minor and infrequent in the normal lenses. Degeneration of single or groups of fiber cells was noted in all the adult nuclei of the cataractous lenses, becoming less frequent in the juvenile nuclei. The types of damage included localized voids, multilamellar membrane aggregates, globular bodies, enlarged cells and regions of highly convoluted membranes. The fetal and embryonic nuclei of the cataractous lenses exhibited rare and minor morphological defects, and were virtually identical to the equivalent regions of the normal aged lenses. Examination of cell interfaces in opaque regions of cataractous lenses revealed that the oldest fiber cells sustained apparent membrane loss. Extracellular spaces in the embryonic, fetal and juvenile regions of the cataractous lenses often contained dense deposits, presumably cytoplasmic material lost from adjacent fibers. The results indicate that the region of greatest nuclear opacity, located in the lens center, does not contain any significant cellular damage. This suggests that older fiber cells respond differently to pathological and senescent changes than younger cells made after fetal development. The observed loss of membranes and cytoplasmic material from the oldest fiber cells may be a contributory mechanism in the formation of age related human nuclear cataracts. PMID- 8690034 TI - Biomechanical measurements of the porcine lens capsule. AB - Biomechanical measurements were carried out on capsular rings prepared from the anterior lens capsule by means of photoablation technique (excimer laser). The outer diameter of the metal ring used to shape the laser output was 3.2 mm and the width (wall thickness) was 100 microns. Thickness of the lens capsule (depth of the tissue ring) was measured with a microscope coupled to an electronic length gauge as the difference in focus between latex spherules placed on the upper and lower surfaces of the capsular rings. For mechanical measurements the capsular rings were mounted around two pins connected to a motorized micropositioner and a force transducer, respectively, and stretched at a constant rate until rupture. Estimates of the precision of the test method were based on differences between measurements of paired eyes from 15 6-month-old pigs. Thickness of the lens capsules was 59 microns (50-66) (median, range). Repeatability of a single measurement was +/- 2 microns for a probability of 95%. Maximum strain as a percentage of the initial length was 78% [68-89] with a repeatability of +/- 6%. Maximum stiffness (elastic modulus) was 23.0 N mm-2 [10.0-31.5] with a repeatability of +/- 4.3 N mm-2, and maximum stress was 4.4 N mm-2 [2.8-7.7] with a repeatability of ./:1.27 N mm-2. There were no significant differences between paired eyes, but a significant variance component between individuals. The experimental set-up described in this paper seems reliable and useful for biomechanical measurements of the lens capsule, in the physiological as well as the surgical function range. PMID- 8690035 TI - The significance of ascorbate in the aqueous humour protection against UV-A and UV-B. AB - It has previously been suggested that the aqueous humour acts as a UV-filter protecting the structures behind. This hypothesis has here been further evaluated by use of spectrophotometry and spectrofluorimetry. Principally three different aspects of the protecting mechanism have been unveiled: absorption, fluorescence quenching and wavelength transformation. The extremely high ascorbate values obviously play a key role in all of them. Thus, aqueous ascorbate both increased absorption and suppressed fluorescence of radiation below roughly 310 nm wavelength. In addition, as a consequence of ascorbate quenching, fluorescence emission to the UV-A range (320-400 nm) is substantially reduced. PMID- 8690032 TI - Prolonged intraocular pressure reduction following intravitreal barium injection in rabbits. AB - The isolated ciliary epithelium contains barium-inhibitable potassium channels. The present study was aimed at testing the in vivo effects of barium on aqueous humor dynamics in rabbits. BaCl2 was administered to one eye by topical delivery or intravitreal injection. Dynamic measurements included intraocular pressure, outflow facility, episcleral venous pressure and aqueous flow (fluorophotometry). Barium dynamics were studied using 133Ba. Intraocular pressure was not altered after topical administration of BaCl2. 133Ba was not detected in the aqueous after delivery of eyedrops containing the radiochemical. Intraocular pressure decreased following intravitreal injection of BaCl2 (0.15 microgram). The onset of this pressure reduction was 12 to 16 hr, the maximum decrease (-11.3 mmHg) occurred at 2 days, and the effect persisted (-4.2 mmHg) for approximately 12 days after the injection. Outflow facility and episcleral venous pressure were not altered. However, aqueous humor flow 5 to 6 days after the injection was decreased by 42% to 63% as determined by fluorophotometry or calculated tonographic data. The injection was not associated with findings of intraocular inflammation. Radioactivity was detected in the vitreous within the first 3 days after the injection; however, activity was present in the ciliary body, equally distributed between the cell membrane and soluble fractions, seven days after the injection. Intravitreally injected BaCl2 results in a prolonged intraocular pressure decrease relating to reduced aqueous formation. While the mechanism(s) for the BaCl2-induced decrease in pressure are not clear, possibilities include a Ba2+ interaction with ciliary epithelial K+ or N-type Ca2+ channels. PMID- 8690036 TI - Light scattering parameters of rat lenses with calcium-induced cataracts. AB - Light scattering intensities of rat lenses obtained in the I,, and I+ modes were analysed using the random density and orientation fluctuation theory. Rat lenses incubated in calcium rich media had the same density fluctuation parameters as rat lenses incubated in control (low-calcium) media. However, the correlation length of the orientation fluctuations decreased during cataract formation by 100 to 200 nm while the amplitude of the fluctuations increased. The correlation length, or the size of the optically anisotropic domains, is related to the size of the cytoskeleton, especially vimentin. Vimentin has been shown to degrade when calcium activates calpain. This has been observed in SDS-gel electrophoretic experiments in rat lenses in calcium rich media. The amplitude factor of orientation fluctuations, that is, the mean squared deviation from the average refractive index, increased between two- and seven-fold during cataractogenesis. These results indicate that calcium cataract formation at the beginning (first 72 hr incubation) has little to do with aggregation or syneresis but it is largely the result of changes in the intrinsic birefringence of the lens due to vimentin degradation. PMID- 8690037 TI - Spatial and temporal variations in extracellular matrix of periocular and corneal regions during corneal stromal development. AB - The development of the avian corneal stroma occurs in discrete developmental stages. During this sequence of events, the neural crest-derived corneal fibroblast precursor cells are surrounded by distinct extracellular matrices which change both spatially and temporally. To elucidate the role of these matrices, extracellular matrix components in the periocular mesenchyme and cornea were analysed prior to and during migration and differentiation of corneal fibroblasts using antibodies against collagens, proteoglycans and glycoproteins. Previous work has concentrated on the matrix of the corneal stroma rather than the matrix of the periocular mesenchyme. Since the precursors of the corneal fibroblasts are present within the must migrate through the periocular mesenchyme prior to entry into the cornea proper, this environment was fully evaluated. The present study documents the matrix composition of both the cornea and periocular mesenchyme at developmental stages that are prior to and after initiation of corneal invasion by the corneal fibroblast precursors. Variations in matrix molecules comprising both the periocular mesenchyme and cornea were demonstrated. These include changes in the distribution of collagen types I, II, III, IV and VI; the proteoglycans decorin and lumican; as well as the adhesive glycoproteins tenascin, fibronectin and laminin. It is hypothesized that the variations in matrix localization are important in the regulation of cell migration and differentiation during normal corneal development. Any regulation is likely to involve a combination of components found in the extracellular matrices and therefore, a consideration of the matrix rather than isolated components is required. PMID- 8690038 TI - The nucleus of the human lens: demonstration of a highly characteristic protein pattern by two-dimensional electrophoresis and introduction of a new method of lens dissection. AB - A practical method for dissection of human lenses is described. The method utilizes the suture patterns as a guide to identify the developmental stage in which fiber cells were formed. Lenses were separated into cortex and adult, infantile, fetal and embryonic nuclear regions. Analysis of the proteins in each of these regions in adult lenses shows that the lens nucleus has a highly characteristic two-dimensional protein pattern distinct from that of the cortex. Each of the nuclear regions has essentially the same protein pattern. The data suggest that the conversion of cortical fibers to mature nuclear fibers involves well controlled processes. PMID- 8690039 TI - Iris color and macular pigment optical density. AB - The present study was designed to assess the relationship between iris color and macular pigment optical density. Both melanin and carotenoids (responsible for iris color and macular pigment composition, respectively) appear to protect the retina through similar mechanisms and higher concentrations may reduce the incidence of retinal degenerations. To evaluate this relationship, 95 subjects were examined and the following variables were measured: iris color; macular pigment optical density (MP); plasma concentrations of lutein and zeaxanthin and beta-carotene; dietary intake of lutein and zeaxanthin and beta-carotene; and total fat intake. Iris color was determined by self assessment and classified as blue or gray (group I), green or hazel (group II) or brown or black (group III). MP density was measured psychophysically by measuring foveal and parafoveal sensitivities to lights of 460 and 550 nm, using the method of heterochromatic flicker photometry. Plasma carotenoid concentrations were measured using reverse phase high-performance liquid chromatography. Dietary intake was determined by a detailed food-frequency questionnaire. Despite similarities in diet and in blood concentrations of carotenoids, significant differences in macular pigment density (P < 0.02) were found for different colored irises (group I, n = 38, MP = 0.25; group II, n = 26, MP = 0.32; group III, n = 31, MP = 0.38). The covariation of iris color and MP indicates that past epidemiologic studies have not adequately determined the independent effects of either factor. The relationship of MP and iris color may be the result of one or two factors: the evolution of a shared tendency to accumulate melanin and carotenoids due to similar environmental pressures (e.g. light and oxygen); and/or MP might be depleted due to the tendency for eyes with light irises to transmit more light than eyes with dark irises, thus causing increased oxidative stress. PMID- 8690042 TI - Dendritic cells and immune-based therapies. AB - The dendritic cell (DC) lineage of white blood cells specializes in capturing antigens and stimulating T-dependent immunity. Because of their efficacy in inducing T cell responses in vivo without other adjuvants, DCs can be considered "nature's adjuvant." DCs are the least abundant of leukocytes, but methods for generating large numbers of DCs are being developed. Ex vivo, DCs develop from CD34+ progenitors cultured in the presence of a combination of granulocyte macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha). This kind of work is stimulating interest in charging DCs with clinically relevant antigens and inducing active immunity in patients. Targeting antigens to DCs may become feasible also because of the identification of distinct antigen receptors such as DEC-205, a DECalectin with 10 contiguous, C type lectin domains. DEC-205 can mediate adsorptive uptake and presentation via DCs. AIDS is another disease for which DCs should be considered in designing new therapies, since DCs can play a major role in promoting HIV-1 replication. Many HIV-1 isolates induce syncytia between DCs and CD4+ memory T cells. These syncytia in turn are the site for a productive infection with HIV-1, possibly because requisite transcription factors like NF-kappaB and Sp1 are separately provided by DCs and T cells, respectively. Further attention to the DC lineage should provide new avenues for manipulating the immune system in several clinical contexts. PMID- 8690041 TI - Fate of biotinylated basic fibroblast growth factor in the retina following intravitreal injection. AB - Exogenous basic fibroblast growth factor (bFGF) stimulates proliferation of non neuronal retinal cells in vivo. To help understand how this proliferative effect is mediated, we followed the fate of biotinylated bFGF after injection into the vitreous of normal rabbit eyes. The retinal distributions, binding, and processing of biotinylated bFGF (bFGF-biotin) was examined from 2 hr to 7 days after intravitreal injection using laser scanning confocal microscopy, electron microscopy and Western blot analysis. At 2 hr, bFGF-biotin was detected throughout the extracellular space and on retinal basement membranes. At 6 hr, discrete punctate material first appeared within the cytoplasm of Muller cells, astrocytes, endothelial cells, retinal pigment epithelial (RPE) cells, and ganglion cells. Labeling was also present in the invaginations of the photoreceptor synaptic terminals at this time. This general pattern persisted up to 4 days after injection but was greatly attenuated by post-injection day 7. Labeling in the inner retina decreased progressively over the seven days; whereas labeling in the outer retina, primarily within the RPE, increased at 4 days post injection and then gradually decreased to nearly undetectable levels by 7 days. Western analysis of retinal protein homogenates following injection showed that an 18 kDa component representing intact bFGF, can be identified up to 1 week following injection. This component, as well as a 15 and 9 kDa biotinylated fragment, showed a progressive reduction during the one week post-injection period. Cross-linking experiments demonstrated that bFGF-biotin binds to three putative receptors with approximate molecular weights of 54, 62, and 110 kDa. These data are consistent with binding of exogenous bFGF to: (a) low affinity bFGF receptors associated with retinal basement membranes; (b) invaginations at the base of photoreceptor synapses; and (c) putative high affinity bFGF receptors on the plasma membranes of glial cells, endothelial cells, RPE cells and ganglion cells. bFGF-biotin apparently binds to, and is then internalized by, the same non neuronal cell types that are stimulated to proliferate following retinal injuries such as detachment. PMID- 8690040 TI - Porcine S-antigen: cDNA sequence and expression in retina, ciliary epithelium and iris. AB - cDNA clones encoding S-antigen (arrestin) were isolated from the expression library constructed from porcine retina and sequenced. The 1490 base pair fragment contained a 1215 base pair open reading frame. From the nucleotide sequence, an amino acid sequence consisting of 405 residues was deduced and a molecular mass of 45,102 daltons was calculated. In order to determine whether the S-antigen mRNA transcript was expressed in anterior eye tissues, mRNA from ciliary non-pigmented epithelial cells and pigmented epithelial cells and iris was analysed by the reverse transcription polymerase chain reaction (PCR) using primers taken from sequences flanking the coding and non-coding regions of retinal S-antigen. Sequence analysis of the expected 611 base pairs in the 5' region and 672 base pairs in the 3' region of DNA fragments indicated that an identical mRNA for S-antigen was expressed in the anterior tissues examined. To investigate the in situ expression of S-antigen mRNA, 35S-labeled sense and antisense RNA probes were synthesized from the cDNA to label frozen sections of retina, ciliary body and iris and the treated sections were examined by autoradiography. The antisense probe labeled the layer between retinal pigmented epithelium and the outer nuclear layer of the retina, ciliary epithelium, and iris epithelium. From the results of sequencing PCR products and in situ hybridization, we concluded that, in porcine eye, the mRNA for S-antigen is expressed not only in the retina but also in the anterior tissues such as the ciliary epithelium and iris epithelium. PMID- 8690044 TI - Modulation of osteoclast-activating factor activity of multiple myeloma bone marrow cells by different interleukin-1 inhibitors. AB - We have studied the effects of several interleukin-1 (IL-1) inhibitors--IL-1 receptor antagonist (IL-1ra), soluble IL-1 receptor (sIL-1R) types I and II, and neutralizing monoclonal antibody (mAb) specific for IL-1 receptor type I--on the osteoclast-activating factor (OAF) activity of recombinant IL-1beta and of culture supernatants of unfractionated bone marrow mononuclear cells from multiple myeloma (MM) patients. The latter activity sharply correlated with the IL-1 content of culture supernatants (r = 0.949; p < 0.001). IL-1ra and sIL-1R types I and II had a clear-cut modulating effect on the OAF activity of IL-1beta at saturating doses (2-10 ng/mL); their effect was evident at 2 ng/mL and was dose-dependent over a large range of concentrations. Similarly, the three reagents neutralized the OAF activities of all MM cell supernatants in a dose dependent fashion and completely abolished them when tested at the fixed concentration of 5 nM. The bone-resorbing activity of tumor necrosis factor-alpha (TNF-alpha) or lymphotoxin (LT), tested alone or added to MM cell supernatants, was affected not at all by IL-1ra and only minimally by sIL-1R types I and II, suggesting that little or no endogenous IL-1 was produced by the rat cells in the assay under TNF-alpha or LT stimulation. Consistent with these findings, PGE2 production elicited by IL-1beta or IL-1-rich supernatants in the rat long-bone assay was abolished by each reagent. Also, mAbs to the IL-1R p80 (type I) chains could modulate the effects of IL-1--recombinant or plasma cell-derived--in the OAF assay, but their activity was markedly less pronounced when compared with the IL-1 inhibitors, since they could never completely abolish bone resorption. Taken together, these findings demonstrate that inhibition of IL-1 interaction with cognate surface receptors on bone cells effectively counteracts its biologic activity. The findings also strongly indicate that OAF activity in conditioned medium of unfractionated myeloma bone marrow cells is predominantly, if not solely, related to IL-1beta. PMID- 8690043 TI - Inhibition of interleukin-11 by interferon-alpha in human bone marrow stromal cells. AB - Interleukin-11 (IL-11), which has been detected as a stromal cell-derived cytokine, regulates multiple steps of early hematopoiesis. Synthesis of IL-11 is induced by IL-1 and transforming growth factor-beta (TGF-beta) in stromal cells and fibroblasts, but the cytokines that inhibit its production remain to be defined. In the present study, we demonstrate that interferon-alpha (INF-alpha) downregulates IL-1-induced IL-11 in human bone marrow stromal cultures. In Northern blot experiments, expression of IL-11 mRNA was reduced in the presence of INF-alpha; this inhibiton was prevented by the addition of cycloheximide. In eight independent experiments, IL-1-stimulated production of IL-11 was significantly inhibited by INF-alpha (p = 0.0117) as measured in stromal cell supernatants by specific enzyme-linked immunosorbent assay (ELISA). Dose titration experiments revealed a dose-dependent inhibition already beginning at a dose level of 10 U/mL IFN. These results are in keeping with our previous observation defining an inhibitory role of INF-alpha in the production of hematopoietic growth factors produced by the bone marrow microenvironment. PMID- 8690045 TI - Lineage commitment of CD34+ human hematopoietic progenitor cells. AB - Hematopoietic cells occur in a continuum of many different stages of functional differentiation, from totipotential stem cells to terminally differentiated lineage-specific cells. At some point during differentiation, progenitor cells become committed to a particular lineage. Little is known about the surface molecules that distinguish lineage-committed progenitor cells from multipotential progenitor cells; this study was undertaken to address this issue. Exploiting a thymic stromal cell co-culture system, we show that CD34+ bone marrow cells expressing the T lymphocyte-associated CD2 and CD7 molecules, the B lymphocyte associated CD10 and CD19, or the myeloid-associated CD33, contain progenitor cells that can generate T lymphocytes, granulocytes, and monocytes, indicating that the expression of any of these molecules on progenitor cells does not imply lineage commitment. CD34+CD13bright, CD34+CD14+, and CD34+CD15+ cells generated myeloid progeny, and CD34+CD20+ cells failed to differentiate along the T lymphoid and myeloid lineages. Thus expression of CD13, which precedes that of CD14 and CD15 during early hematopoiesis, appears to coincide with commitment to myeloid development. Our findings also indicate that expression of CD20 is restricted to progenitor cells committed to B lymphocyte development. PMID- 8690046 TI - v-src interferes with the in vitro erythropoietic stimulatory ability of spleen stromal cells through repression of vascular cell adhesion molecule-1 and stem cell factor. AB - A mouse spleen stromal cell line, MSS62, can create an in vitro erythropoietic microenvironment in which development of erythropoietin-responsive progentor cells is stimulated by cell-cell contact via stem cell factor (SCF)/c-Kit and vascular cell adhesion molecule-1 (VCAM-1)/very late activation antigen-4 (VLA-4) interactions between stromal and erythroid cells. To find out the effect of src on the erythropoietic microenvironment, MSS62 cells were transfected with v-src oncogene, and its effect on erythropoietic stimulatory activity was measured. Transfectants with high v-Src activity showed reduction in erythropoietic stimulatory activity. A decrease in cell-surface VCAM-1 and SCF mRNA was accompanied by high v-Src activity. These results suggest that v-Src interferes with the erythropoietic stimulatory activity of the stromal cells through repression of VCAM-1 and SCF. PMID- 8690048 TI - Profile of cell cycle in hematopoietic malignancy by DNA/RNA quantitation using 7AAD/PY. AB - Using 7-amino-actinomycin-D/pyronin Y (7AAD/PY), we analyzed the surface phenotypes and cell cycle of 22 hematopoietic cell lines based on their cellular DNA/RNA content. Populations of G1a, G1b, S, and G2M, the DNA index (DI), and the RNA index of S phase (SRI) were calculated by means of DNA/RNA dot plots. Two new parameters were extracted from the cell-cycle profiles: the nucleic acid index of S phase (NI) and the coefficient of variations in the RNA at S phase (SVC). DNA/RNA dot plots of cell lines revealed four characteristic profiles of the cell cycle, defined with the calculated NI and SCV. These were type 0 (small NI, large SCV), type I (small NI, small SCV), type II (large NI, small SCV), and type III (large NI, large SCV). Type O included four stem cell lines: one t(1;19) leukemia, two Ph1+ acute lymphocytic leukemia (ALL), and one biphenotypic crisis of chronic granulocytic leukemia (CGL). Type I included five ALL cell lines: three T-ALL and two common B-ALL. Type II contained 10 myeloid cell lines: five AML and five myeloid crisis of CGL. Type III contained three relatively immature lymphoma cell lines: two Burkitt's lymphoma and one follicular center lymphoma. Calculated NI/SCV (%) were as follows: type 0, 2.27 +/- 0.19/16.7 +/- 3.7; type I, 2.20 +/- 0.30/11.1 +/- 0.7; type II, 3.64 +/- 0.52/11.8 +/- 1.0; and type III, 3.60 +/- 0.53/17.5 +/- 1.9. Cell-cycle analysis of blasts using 7AAD/PY combined with surface phenotyping may yield important information for classifying hematopoietic malignancy within 2 hours of patient admission. PMID- 8690047 TI - Characterization of eosinophils generated in vitro from CD34+ peripheral blood progenitor cells. AB - Methods for isolation and cultivation of CD34+ peripheral blood progenitor cells (PBPCs) have facilitated their use in autologous transplantation and as potential targets for gene therapy. In this work, we present the possibility of using these isolated cells to study lineage-specific hematopoietic differentiation. We have shown that differentiating PBPCs faithfully replicate transcriptional events that occur during maturation of the eosinophil lineage; messenger RNAs encoding the five eosinophil granule proteins were detected by reverse-transcriptase polymerase chain reaction (RT-PCR) after 2-3 days of cytokine-stimulated growth. Only three of the five proteins were detected by immunofluorescence staining after 14 days of cytokine-stimulated growth; the percentage of Charcot-Leyden crystal protein (CLC)-containing cells (16-18%) exceeded that of eosinophil peroxidase (EPO)-containing cells (7-8%), which in turn exceeded that of eosinophil-derived neurotoxin (EDN)-containing cells (2-4%). While the electrophoretic mobilities of both CLC and EPO synthesized by differentiating PBPCs were similar to those of their normal counterparts, immunoreactive EDN was found to be heterogeneous and of higher molecular weight that EDN found in mature eosinophils. It is not clear whether our results, which show progressive, but incomplete, differentiation of PBPCs into eosinophils, reflect a lack of knowledge as to what factors are essential for complete differentiation in vitro or relate to the inherent capacity of PBPCs to differentiate along this lineage. PMID- 8690050 TI - A functional tethered ligand thrombin receptor is present on human hematopoietic progenitor cells. AB - The processing of inflammatory signals occurs through a variety of mechanisms; the recent descriptions of the tethered ligand receptor for thrombin (JA Hoxie et al., J Biol Chem 268:13756, and TK Vu et al., Cell 64:1057) provide a novel route and mechanism for cellular activation after inflammation and thrombosis. Using standard flow-cytometric techniques, it has been shown that the tethered ligand receptor is found on a number of terminally differentiated hematopoietic cells including platelets, lymphocytes, and monocytes. In this paper, we show that the CD34+ subset of hematopoietic stem cells bears the tethered ligand receptor on its surface; in addition, stimulation of this receptor with the agonist peptide SFLLRN results in a dose-dependent increase in intracellular calcium levels. We also show that culturing bone marrow mononuclear cells in the presence of thrombin or the tethered ligand receptor agonist peptide results in a statistically significant increase in colony-forming units-erythroid and granulocyte/macrophage (CFU-E and CFU-GM). Although more work is needed to establish the exact mechanism of this effect, our results suggest that activation of the tethered ligand thrombin receptor may modulate the proliferative responses of CD34+ hematopoietic progenitor cells. PMID- 8690049 TI - Facilitating cells enable engraftment of purified fetal liver stem cells in allogeneic recipients. AB - It has been reported that while stem cells purified from adult bone marrow engraft in syngeneic recipients, they fail to engraft in allogeneic recipients. We have recently shown that the addition of as few as 30,000 facilitating cells (CD8+/CD3+/CD45R+/Thy 1.2+/TCR-), a unique bone marrow-derived population that does not possess stem cell properties, results in the permanent engraftment of stem cells in a major histocompatibility complex (MHC)-disparate allogeneic host. It has been suggested that fetal hematopoietic tissue may be a source of stem cells with enhanced proliferative and self-renewal properties compared with adult bone marrow. We were interested, therefore, in whether fetal stem cells demonstrated a superior capacity to engraft in allogeneic recipients. In this study, we have examined the engraftment properties of mouse fetal liver cells in syngeneic and allogeneic recipients. Transplantation of unmodified fetal liver cells into allogeneic recipients results in stable multilineage chimerism with donor-specific tolerance, indicating that the pluripotent hematopoietic stem cell is present in fetal liver and is capable of engraftment in allogeneic adult recipients. Similarly, 2000 to 3000 sorted fetal liver stem cells (Sca+/c kit+/Lin-) successfully reconstituted lethally irradiated syngeneic adults and adults differing only in minor histocompatibility antigens. Two thousand to 10,000 fetal stem cells failed to rescue lethally irradiated allogeneic recipients, but the addition of 30,000 MHC-matched purified facilitating cells to the fetal stem cell inoculum resulted in sustained engraftment with multilineage production. These results, which parallel our earlier work with stem cells derived from adult bone marrow, indicate that the pluripotent fetal stem cell behaves in a fashion similar to that of adult stem cells with regard to allogeneic transplantation. PMID- 8690051 TI - Anti-CD45 and anti-CD52 (Campath) monoclonal antibodies effectively eliminate systematically disseminated human non-Hodgkin's lymphoma B cells in Scid mice. AB - Severe combined immunodeficient (Scid) mice inoculated with the human (t(14;18) positive B cell lines DoHH2 and BEVA develop lethal systemically disseminated lymphoma (de Kroon et al., Leukemia 8:1385, and Blood 80 [suppl 1]:436). These models were used to study the therapeutic effect of rat-anti-human CD52 (Campath 1G) or CD45 monoclonal antibodies (mAbs) on systemically disseminated tumor cells and on tumor cells present in solid tumor masses. Both mAbs were effective in inhibiting growth of systemically disseminated malignant cells. When treatment with anti-CD52 or anti-CD45 mAbs at a dose of 30 micrograms/mouse/d for 4 days was started 24 hours after intravenous inoculation of human DoHH2 or BEVA cells, a 3-log kill of tumor cells was observed as measured by prolonged survival. After treatment, surviving animals injected with high numbers of BEVA cells showed tumor masses in liver, kidney, and mesenteric lymph nodes. In contrast to nontreated animals, however, only low numbers of malignant cells were found in peripheral blood, and bone marrow was free of tumor cells. Similarly, after mAb treatment of mice inoculated subcutaneously (sc) with DoHH2 cells, no tumor cells could be found in the bone marrow, and few DoHH2 cells could be detected in the peripheral blood, spleen, liver, kidney, or lung. In contrast, tumor cells present in subcutaneous tumors and axillary lymph nodes were relatively unaffected by mAb therapy. The presence of rat immunoglobulin (Ig) could be demonstrated on surviving tumor cells. The presence of murine macrophages in areas in these tumors that were depleted of DoHH2 cells suggested that the mAb mediated antitumor effect observed in the Scid mouse model is mediated by cellular mechanisms. Apparently these mechanisms were not sufficient to eliminate the fast-growing tumor cells present in the protected sites. Our results indicate that treatment with anti-CD52 or anti-CD45 mAbs potentially may be useful as adjuvant immunotherapy for systemically disseminated B cell lymphoma. PMID- 8690052 TI - Culture and characterization of hematopoietic progenitor cells from miniature swine. AB - Miniature swine are being used as a large animal model in which cultured and retrovirus-transduced hematopoietic stem cells (HSC) can be tested in a reproducible manner for their long-term in vivo repopulating ability. As part of these studies, long-term bone marrow culture (LTBMC) and progenitor colony assay systems were developed and used to characterize the in vitro growth potential and in vivo frequency of hematopoietic progenitors in this species. We found that LTBMCs initiated with a single marrow inoculum produced myeloid colony progenitors continuously for at least 7 weeks. The sites of myelopoietic activity in these cultures were uniquely restricted to isolated, morphologically diverse germinal centers rather than more disperse cobblestone patches. We also used the progenitor assay to screen several human and murine recombinant cytokines for cross-reactivity to swine bone marrow cells, including interleukin-3 (IL-3), IL 6, Il-11, granulocyte and granulocyte-macrophage colony-stimulating factors (G CSF and GM-CSF), c-kit ligand (also called mast cell growth factor [MGF]), and erythropoietin (Epo). With the exception of human and murine IL-3, each of the cytokines tested induced swine progenitor colony formation to varying degrees, with some combinations leading to the formation of primitive multilineage and high proliferative potential colonies. Finally, in an attempt to characterize alternative sources of HSC from swine, we compared the progenitor content of adult and juvenile swine bone marrow and fetal liver. The fetal liver samples were found to be highly enriched for both primitive and mature progenitors, while analysis of postnatal marrow samples revealed an approximately two-fold decline in overall progenitor frequency between the ages of 10 and 20 weeks. Taken together, these studies demonstrate the development and use of in vitro culture methods for characterizing hematopoietic elements from miniature swine and suggest a hierarchy of progenitor cell content in various hematopoietic tissues from the large animal model. PMID- 8690053 TI - High-level expression of a novel epitope of CD59 identifies a subset of CD34+ bone marrow cells highly enriched for pluripotent stem cells. AB - To further define the hierarchy of human hematopoietic progenitor cells, we have attempted to identify antibodies to cell-surface molecules expressed on CD34+ progenitor cell subsets. Herein we describe the utility of a new monoclonal antibody, HCC-1, which binds to a novel epitope of CD59 differentially expressed among CD34+ progenitor cells. HCC-1 subdivides the adult marrow CD34+ population into HCC-1high and HCC-1low/- fractions of approximately equal size. Cobblestone area-forming cells (CAFC) in long-term bone marrow culture were enriched 10-30 fold in CD34+HCC-1high cells compared with CD34+HCC1-low/- cells and two-fold compared with CD34+ cells. When injected into fetal human bone fragments implanted in SCID mice, the CD34+HCC-1high population showed potent engrafting activity leading to the production of myeloid, lymphoid, and erythroid elements, as well as the retention of progenitor cell phenotype. These studies demonstrate that the CD34+HCC-1high population contains primitive pluripotent hematopoietic stem cells. No hematopoietic engrafting activity was detected in the CD34+HCC 1low/- population. Consistent with this finding, simultaneous five-color flow cytometric analysis revealed that HCC-1high cells include virtually all CD34+Thy 1+Lin- cells, a cell population previously characterized as highly enriched for primitive pluripotent hematopoietic stem cells. The ability of CD34+ cells divided into subsets by HCC-1 to produce T cells was assessed by transplantation of sorted cells into human fetal thymus implanted into SCID mice. A higher frequency of thymus-engrafting activity was observed in the CD34+HCC-1high than in the CD34+HCC-1low/- population. Consistent with the limited ability to engraft in the SCID-hu thymus model, the CD34+HCC-1low/- population was shown to contain a low frequency of CD34+CD10+ lymphoid progenitor cells. We conclude that the HCC 1 epitope is expressed at high levels on a subset of CD34+ cells that contain virtually all primitive pluripotent hematopoietic stem cells and that the population of CD59 molecules expressed on CD34+ cells is not homogeneous. PMID- 8690054 TI - Autocrine BDNF secretion enhances the survival and serotonergic differentiation of raphe neuronal precursor cells grafted into the adult rat CNS. AB - RN46A cells are a temperature-sensitive neuronal cell line derived from the E13 rat raphe nucleus. RN46A cells grafted into the adult rat hippocampus and cerebral cortex do not survive beyond 2 weeks. Brain-derived neurotrophic factor (BDNF) regulates the in vitro survival and serotonergic phenotype of RN46A cells, and we hypothesized that expression of BDNF in RN46A cells would potentiate their survival and serotonin (5HT) expression in vivo. The gene encoding rat BDNF was transfected into RN46A cells and the clonal 46A-B14 cell line isolated, 46A-B14 cells synthesize and secrete biologically active BDNF in vitro and synthesize 5HT following partial membrane depolarization. Two weeks following 46A-B14 cell transplantation into the adult rat cortex and hippocampus, there is a threefold increase in survival of 46A-B14 cells compared to RN46A cells transfected with the vector alone. The grafted 46A-B14 cells immunohistochemically stain for BDNF and 5HT, while RN46A cells transfected with vector only are negative for both BDNF and 5HT. In addition, 46A-B14 cells attain more morphologically complex phenotypes, indicating enhanced neuronal differentiation. Autocrine secretion of BDNF by RN46A cells thus potentiates survival and can be used to deliver both BDNF and 5HT in vivo. PMID- 8690055 TI - Manganese and copper-zinc superoxide dismutases in the human olfactory mucosa: increased immunoreactivity in Alzheimer's disease. AB - Superoxide dismutases are the cell's major enzymatic defenses against cytotoxic reactive oxygen species and oxidative stress. Reactive oxygen species, which induce the expression of these enzymes, have been implicated in the neurodegeneration associated with Alzheimer's disease (AD), and individuals with AD exhibit early, severe deficits in olfactory ability. We used immunohistochemistry to examine the cellular localization of managanese and copper-zinc superoxide dismutases in the olfactory mucosae of nondemented young/middle-aged and old subjects as well as age-and postmortem-interval matched nondemented elderly individuals and those with AD. Tissues were obtained at autopsy from individuals ranging in age from 19 to 98 years old. Immunoreactivity for both enzymes was localized in olfactory receptor neurons, sustentacular and basal cells in the olfactory epithelium, and in olfactory and extrinsic nerves, Bowman's glands, and vascular endothelium in the lamina propria. Computer assisted quantitative analysis demonstrated that very intense immunoreactivity for both managanese and copper-zinc superoxide dismutases occupied significantly more area, particularly near the surface and in the basal region, of the olfactory epithelium from subjects with AD than from the age-and postmortem interval-matched nondemented elderly subjects. The pronounced increase in superoxide dismutase immunoreactivity in the olfactory epithelium of AD subjects suggests that oxidative stress may be responsible, at least in part, for the olfactory deficits in subjects with AD. PMID- 8690057 TI - Alterations in fibroblast growth factor receptor expression following brain injury. AB - Traumatic injuries to the central nervous system result in astrogliosis and the formation of a dense scar at the site of the wound. Basic fibroblast growth factor (bFGF) has mitogenic and morphogenic effects on astrocytes, and an interaction between bFGF and its receptor is likely to play a role in astrogliosis. We examined trauma-induced changes in the spatial and temporal expression of FGF receptor (FGFR) in adult rats over a 28-day period following a stereotaxic lesion through the cortex and hippocampus. Immunohistochemistry and image analysis were used to evaluate the changes. Antibody characterization studies strongly suggested that staining represented FGFR 1, but did not rule out possible cross-reactivity with FGFR 2 or 3. Double immunohistochemistry for FGFR and glial fibrillary acidic protein demonstrated that mature astrocytes expressed FGFR. Expression was increased on astrocytes adjacent to the wound cavity by Day 2 postlesion. Staining increased further through Day 10 and decreased to control values by Day 28, except for a sustained increase in staining of reactive astrocytes immediately adjacent to the wound cavity. Basic FGF was detected in the nuclei of cells staining for FGFR, suggesting that FGFR-expressing astrocytes also contained bFGF. These data demonstrate a time course for astrocyte expression of FGFR that precedes and parallels the time course for astrocyte hypertrophy. Our observations suggest that endogenous bFGF, acting directly on FGFR-expressing astrocytes, may contribute to astrogliosis. PMID- 8690059 TI - Single unit discrimination among discharges from neighboring myelinated fibers in human peripheral nerves: improved unit identification by interspike interval analysis of nerve responses evoked by tactile stimuli. AB - Clustered rapidly adapting (RA) or slowly adapting type I (SA I) units recorded with concentric needle electrodes from median nerves of healthy human volunteers may exhibit overlapping receptive fields in the skin as also Paccini afferents (PC units) and slowly adapting type II unitary elements (SA II units) with their much larger innervation areas. Fundamental for the discrimination of such pairs of neighboring units in the nerve with overlapping peripheral fields was the refractory period of the studied fibers, which was assumed to be normal, i.e., of the order of 1-2 ms. When a unit belonging to one of the categories mentioned was found, it was activated by different tactile stimuli in the palm or fingers. Simultaneously, interspike interval analysis of the evoked responses was performed. In situations when the minimal interspike intervals were longer than the absolute refractory period of a single fiber the response derived from one single unit. Responses from at least two units were considered to contribute to the recorded sequences when computer analysis showed that the durations of the minimal intervals were shorter. In this way, the reported procedure facilitated the discrimination of both pairs of RA and SAI units and, in particular, pairs of neighboring PC or SA II units with overlapping receptive fields in human palmar skin. PMID- 8690056 TI - Polymer-encapsulated genetically modified cells continue to secrete human nerve growth factor for over one year in rat ventricles: behavioral and anatomical consequences. AB - The long-term delivery of growth factors and other proteins into the CNS at putatively therapeutic yet safe levels continues to be technically constrained. In the present studies, the gene encoding human nerve growth factor (hNGF), introduced into a dihydrofolate reductase-based pNUT expression vector system, was engineered into a clonal baby hamster kidney (BHK) cell line. BHK-hNGF23 and mock-transfected cells were encapsulated in an immunoisolating polymeric device and transplanted into the lateral ventricles of healthy young adult rats for 13.5 months. As measured by ELISA, nanogram quantities of hNGF were released by encapsulated cells both prior to implantation (3.6 +/- 0.8 ng/device/24 h) and upon removal from rat lateral ventricles after 13.5 months in vivo (2.2 +/- 0.4 ng/ device/24 h). In addition, the hNGF released into the tissue culture medium was biologically active. Long-term encapsulated cell survival was confirmed by histologic analysis. The presence of genomic DNAs (hNGF transgene), as determined by PCR analyses, revealed that the transgene copy number from the recovered BHK hNGF23 cells after 13.5 months in vivo was equivalent to preimplant levels. No deleterious effects from hNGF were detectable on body weight, mortality rate, motor/ambulatory function, or cognitive function as assessed with the Morris water maze and delayed matching to position in healthy young adult rats. In addition, there was no evidence that hNGF from these encapsulated cells produced hyperalgesia. Only tests of somatosensory thresholds revealed statistically significant effects related to the hNGF delivered in the present study, and that effect was limited to a decrease in the number of trials to asymptote. Animals receiving BHK-hNGF23 implants exhibited a marked hypertrophy of cholinergic neurons within the striatum (22% increase) and nucleus basalis (7% increase) but not the medial septum ipsilateral to the capsule. Moreover a robust sprouting of cholinergic fibers was observed within the frontal cortex and lateral septum proximal to the implant. These results indicate that encapsulated xenogeneic cells provide a safe and effective method for the long-term delivery of hNGF and potentially other neurotrophic factors within the CNS. PMID- 8690058 TI - Distribution of radioiodinated recombinant human nerve growth factor in primate brain following intracerebroventricular infusion. AB - The distribution of radioiodinated recombinant human nerve growth factor ([125I]rhNGF) was evaluated in adult cynomolgus monkeys following unilateral intracerebroventricular (icv) administration. Animals were cannulated into the right ventricle and recovered for 7 days. Monkeys were infused with 1.2 micrograms of [125I]rhNGF or [125I]rhNGF with a 140-fold excess of rhNGF. Twenty four hours after infusion, animals were anesthetized and transcardially perfused with an aldehyde fixative. Coronal brain sections were processed for quantitative film autoradiography or for choline-acetyltransferase immunohistochemistry and then emulsion dipped. Specific radiolabel was distributed bilaterally and, with equal density, throughout the basal forebrain and was colocalized with choline acetyltransferase-positive neurons. Specific labeling was also present in the superficial ventral cortex. Nonspecific binding was observed surrounding the ventricles and lining blood vessels. These results demonstrate that unilateral icv infusion is an effective approach for delivering NGF to basal forebrain cholinergic neurons in primates and represents a viable drug delivery strategy for the therapeutic use of NGF in Alzheimer's Disease. PMID- 8690060 TI - Effects of adrenal medulla transplantation into the third ventricle on the onset of puberty in female rhesus monkeys. AB - To test the hypothesis that prepubertal exposure of LHRH neurons to a source of catecholamines and neuropeptides accelerates the onset of puberty, we examined the effects of autologous adrenal transplantation into the base of the third ventricle of the brain in juvenile female rhesus monkeys at 11-13 months of age. The adrenal medulla, which contains catecholamines and neuropeptide Y (NPY), was cut into small pieces and mixed with gelfoam in artificial CSF and injected into the third ventricle, adjacent to LHRH neurons and their neuroterminals. Sham control monkeys received artificial CSF with gelfoam alone. Animals were monitored for signs of pubertal development. While menarche was not altered by adrenal transplantation, the timing of first and second ovulations occurred significantly (P < 0.05) earlier in adrenal-transplanted monkeys. Histological examination indicated that the grafts survived in all transplanted monkeys. The presence of catecholamines and NPY in graft tissue was confirmed by tyrosine hydroxylase-positive, dopamine beta-hydroxylase-positive, and NPY-positive cells. Endogenous LHRH fibers were observed innervating the graft tissue. We conclude that: (1) adrenal medulla transplantation into the third ventricle accelerates the age of first ovulation; (2) this is likely due to neuroactive substances (e.g., catecholamines and NPY) from the graft tissue; and (3) grafted adrenal medulla tissue can survive for at least 30-40 months. However, the age of menarche was not accelerated by this grafting, suggesting that an additional mechanism (e.g., removal of tonic inhibition) may be necessary for the onset of puberty. PMID- 8690061 TI - Loss of striatal DA innervation increases striatal trophic activity directed at DA neurons in culture. AB - Male rats received intraventricular infusions of the dopamine (DA) neurotoxin 6 hydroxydopamine (6-OHDA; 0, 75, 150, and 250 micrograms) in order to determine if DA neuron loss was associated with an increase in striatal trophic activity. After 4 weeks, the animals were sacrificed and perfused with normal saline, and the brains were removed, immediately frozen, and processed. Intraventricular infusions of 6-OHDA were associated with a dose-dependent reduction in striatal DA content and tyrosine hydroxylase-immunoreactive (THir) cell counts in the substantia nigra while striatal DA activity ([HVA]/[DA]) was increased. Extracts of the striatum from these animals increased the survival of E15 primary, dissociated rostral mesencphalic cultures growing at low cell density. This growth effect was positively correlated with the dose of 6-OHDA infused. THir cell counts present in high-cell-density mesencephalic cultures following 72 h of extract incubation were similarly correlated to 6-OHDA dose but inversely correlated with striatal DA content and THir cell counts in the substantia nigra. Trophic activity in the cerebellar extracts from these animals was significantly lower than that present in striatal extracts and was not influenced by 6-OHDA lesions. These data suggest that loss of DA innervation in the striatum is associated with an increase in striatal trophic activity directed at DA neurons. A compensatory response to the loss of DA neurons involving increased striatal trophic activity may result in increased DA terminal sprouting of remaining viable DA neurons that, in turn would serve to help reinstate normal DA tone. PMID- 8690062 TI - Insulin-like growth factors reverse or arrest diabetic neuropathy: effects on hyperalgesia and impaired nerve regeneration in rats. AB - Diabetic neuropathy is a debilitating disorder whose causation is poorly understood. A new theory proposes that neuropathy may arise as a consequence of loss of neurotrophic insulin-like growth factor (IGF) activity due to diabetes, superimposed on a slow continual loss due to aging. The prediction that IGF-I and IGF-II gene expression are reduced in diabetic nerves was recently tested and validated. Here we tested the prediction that IGF administration can prevent or reverse diabetic sensory neuropathy. Subcutaneous infusion of IGF-I or IGF-II, but not vehicle, halted (P < 0.01) the progression of hyperalgesia in streptozotocin-diabetic rats. Moreover, impaired sensory nerve regeneration was partially reversed within 2 weeks after treatment of diabetic rats with IGFs (P < 0.01). Impaired regeneration could also be prevented by daily subcutaneous IGF injections. The low replacement doses of IGFs were effective despite unabated hyperglycemia and weight loss. These results show that IGF replacement therapy can reverse or prevent diabetic sensory neuropathy independently of hyperglycemia or weight loss. PMID- 8690063 TI - Differentiation of ionic currents in CNS progenitor cells: dependence upon substrate attachment and epidermal growth factor. AB - Multipotential progenitor cells grown from central nervous system (CNS) tissues in defined media supplemented with epidermal growth factor (EGF), when attached to a suitable substratum, differentiate to express neural and glial histochemical markers and morphologies. To assess the functional characteristics of such cells, expression of voltage-gated Na+ and K+ currents (INa, IK) was studied by whole cell patch clamp methods in progenitors raised from postnatal rat forebrain. Undifferentiated cells were acutely dissociated from proliferative "spheres," and differentiated cells were studied 1-25 days after plating spheres onto polylysine/laminin-treated coverslips. INa and IK were detected together in 58%, INa alone in 11%, and IK alone in 19% of differentiated cells recorded with K(+) containing pipettes. With internal Cs+ (to isolate INa), INa up to 45 pA/pF was observed in some cells within 1 day after plating. I Na ranged up to 150 pA/pF subsequently. Overall, 84% of cells expressed I Na, with an average of 38 pA/pF. INa had fast kinetics, as in neurons, but steadystate inactivation curves were strongly negative, resembling those of glial INa. Inward tail currents sensitive to [K+]out were observed upon repolarization after the 10-ms test pulse with internal Cs+, indicating the expression of K+ channels in 82% of cells. In contrast to the substantial currents observed in differentiating cells, little or no INa or Ik-tail currents were detected in recordings from cells acutely dissociated from spheres. Thus, in the presence of EGF, ionic currents develop early during differentiation induced by attachment to an appropriate substratum. Cells switched from EGF to basic fibroblast growth factor (bFGF) when plated onto coverslips showed greatly reduced proliferation and developed less neuron-like morphologies than cells plated in the presence of EGF. INa was observed in only 53% of bFGF-treated cells, with an average of 9 pA/pF. Thus, in contrast to reports that bFGF promotes neuronal differentiation in some CNS progenitor populations, our EGF-generated postnatal rat CNS progenitors do not develop neuronal characteristics when switched to medium containing bFGF. Thus, differentiated CNS progenitors can express a mix of neuronal and glial molecular, morphological, and electrophysiological properties that can be modified by culture conditions. PMID- 8690065 TI - Two-dimensional crystallization of rabbit C-reactive protein on lipid monolayers. AB - Two-dimensional (2D) crystals of rabbit C-reactive protein (CRP) have been obtained by protein binding on lipid monolayers at the air/water interface. Two different types of crystalline arrays of CRP were obtained, by specific binding and non-specific adsorption to the lipids. Electron crystallographic analysis of the negatively stained specimens showed that the unit cell parameters of the CRP 2D crystals formed by specific binding were a=81 angstroms, b=78 angstroms, gamma=118.35 degrees, and those formed by nonspecific adsorption were a=74 angstroms, b=67 angstroms, gamma=95.5 degrees, both with the layer group p1. Projection maps were obtained at a resolution of 26 angstroms and 22 angstroms respectively. They showed that only the monomers of the CRP were packed in the 2D arrays and the orientations of the monomers on the lipid monolayers were different in the two types of crystals. By comparing the two projection maps, a preliminary shape of the CRP monomer has been derived. A model of the pentameric structure of the oligomeric CRP has been proposed. PMID- 8690064 TI - Nerve growth factor promotes regeneration of sensory axons into adult rat spinal cord. AB - Injured adult mammalian axons are unable to regenerate spontaneously in the central nervous tissue. This study investigated in two adult rat models the effects of nerve growth factor (NGF) on the capacity of central primary sensory axons to regenerate back into the spinal cord. Sensory fibers were conditioned by transection of the peripheral nerve 1 week prior to the experiment and identified by anterograde tracing with cholera toxin B subunit injected in the sciatic nerve. In the first model, a predegenerated autologous peripheral nerve graft was implanted as a bridge for the transected sensory fibers into a resection gap in the dorsal columns at the tenth thoracic (T10) spinal cord segment. Vehicle or vehicle with purified mouse or recombinant human NGF was continuously infused for 2 weeks directly into the dorsal column at T9, 3 mm from the rostral border of the nerve graft. With vehicle infusion many ascending sensory axons had grown across the nerve bridge, but essentially none had grown back into the rostral cord. In sharp contrast, NGF promoted the reentry into the denervated dorsal columns of 51% of the sensory axons that had reached the rostral level of the nerve graft. Twenty-six percent had grown 2 mm into the spinal tissue and 10% had reached the NGF-infusion site at 3 mm from the nerve graft. A few fibers were found circling around, but not beyond, the infusion site, perhaps due to the chemoattractant action of NGF. In a second model, the fourth lumbar (L4) dorsal root was crushed 2 mm from its insertion point into the spinal cord and the dorsal roots L2, L3, L5, and L6 were transected. Vehicle or vehicle with purified mouse NGF was infused for 2 weeks directly into the lumbar spinal cord, 2.5 mm rostral to the transition zone of the crushed L4 root. With vehicle, only 6% of the regenerating fibers at the transition zone had crossed the root-spinal cord barrier, but not farther than 0.5 mm into the spinal tissue. With NGF, 18% of the fibers at the transition zone were found at 0.5 mm, 9% at 1.5 mm, and 5% at 2.5 mm (the infusion site) from the transition zone. The present results demonstrate that NGF can promote the regeneration of adult sensory fibers into the otherwise nonpermissive spinal cord white matter. PMID- 8690066 TI - Divinyl ether synthase from garlic (Allium sativum L.) bulbs: sub-cellular localization and substrate regio-and stereospecificity. AB - Sub-cellular localization and some properties of 13-hydroperoxide-specific divinyl ether synthase from garlic bulbs were studied. Sub-cellular fractions from garlic bulbs were incubated with [1-(14)C](9Z,11E,13S)-13-hydroperoxy-9,11 octadecadienoic acid (13-HPOD). The predominant part of divinyl ether synthase activity from garlic bulbs was found in the microsomal fraction. The enzyme utilizes 13(S)-HPOD as its preferential substrate. Other hydroperoxides, including 9(S)-HPOD, gave much poorer yields of divinyl ethers. Unreacted hydroperoxide after incubation of 13(R,S)-HPOD with enzyme was composed of up to 94% 13(R)-HPOD. Thus, divinyl ether synthase possesses stereoselectivity, utilizing preferentially the (S)-enantiomer. PMID- 8690067 TI - Liposomes with detachable polymer coating: destabilization and fusion of dioleoylphosphatidylethanolamine vesicles triggered by cleavage of surface grafted poly(ethylene glycol). AB - Plasma-stable liposomes (100 nm) were prepared from dioleoylphosphatidylethanolamine (DOPE) and 3-6 mol% of a new disulfide-linked poly(ethylene glycol)-phospholipid conjugate (mPEG-DTP-DSPE). In contrast to similar preparations containing non-cleavable PEG-phospholipid conjugate, thiolytic cleavage of the grafted polymer chains facilitated rapid and complete release of the liposome contents. Furthermore, the detachment of PEG from DOPE liposomes resulted in liposomal fusion. Finally, while formulation of pH sensitive DOPE/cholesterol hemisuccinate liposomes with mPEG-DTP-DSPE abolished the pH sensitivity, cleavage of the PEG chains completely restored this property. These are the first examples of new useful properties of liposomes grafted with cleavable polymer. PMID- 8690068 TI - Increased levels of 4-hydroxynonenal in human monocytes fed with malarial pigment hemozoin. A possible clue for hemozoin toxicity. AB - In human monocytes, lipoperoxides were increased 3-fold at 2 h, 6-fold at 5 h and 7.5-fold at 12 h after hemozoin phagocytosis. 4-Hydroxynonenal (HNE) was also increased, reaching 40 nmol/10(10) cells at 2 h (approximate intracellular concentration [AIE] 8 microM) 230 nmol/10(10) cells at 5 h (AIE 46 microM) and 79 nmol/10(10) cells (AIE 16 microM) at 12 h. A moderate increase in HNE, approx. 20 nmol/10(10) cells (AIE 4 microM) was also observed after phagocytosis of anti-D IgG-opsonized erythrocytes. HNE in unfed controls was approx. 5 nmol/10(10) cells (AIE 1 microM) during the whole incubation period. An increased amount of protein kinase C (PKC)/HNE adduct was demonstrated in hemozoin-fed monocytes. Purified PKC was profoundly inhibited at HNE > 10 microM. The impairment of PKC previously observed in hemozoin-fed monocytes can thus be explained by direct interaction with increased HNE levels. PMID- 8690069 TI - Molecular cloning and functional expression of a novel rat heart P2X purinoceptor. AB - Here we describe a novel purinergic receptor, the P2X5 receptor, cloned from rat heart. The full-length cDNA encodes a protein 455 amino acids long which shares an overall identity of 40-47% with other members of the P2X purinergic receptor family. P2X5 mRNA transcripts are found predominantly in rat heart but are also present in brain, spinal cord and adrenal gland. Functional expression of the recombinant receptor in HEK-293 cells shows a current that resembles mostly the P2X2 phenotype: the ATP-activated current reveals little agonist desensitization, is not activated by alpha,beta-meATP and is completely blocked by suramin and PPADS. PMID- 8690071 TI - Dephosphorylated but not phosphorylated microtubule associated protein MAP1B binds to microfilaments. AB - We have reported that purified native MAP1B interacts with microtubules but not with microfilaments [Pedrotti and Islam, Cell Motil. Cytoskel. (1995) 30, 301 309]. However, MAP1B can be phosphorylated at multiple sites by casein kinase 11 (CKII) and proline-directed protein kinases (PDPK) and immunoblotting studies show that purified native MAP1B is phosphorylated at least at two CKII sites and at one PDPK site [Pedrotti et al., Biochemistry (1996) 35, 3016-3023]. We now show that phosphorylation affects the in vitro binding of MAP1B with microfilaments. Native MAP1B does not bind to microfilaments but after treatment with alkaline phosphatase the dephosphorylated MAP1B binds and cosediments with microfilaments. Dephosphorylation kinetics suggest that the PDPK site, but not CKII sites, may negatively regulate the interaction with F-actin. The ability of dephosphorylated MAP1B to crosslink microfilaments was also examined and showed that MAP1B exhibits only a weak crosslinking of F-actin when compared with MAP2. PMID- 8690070 TI - Effect of ganglioside GM3 on the activity and conformation of reconstituted Ca2+ ATPase. AB - Trace amounts of gangliosides were found in rabbit skeletal muscle sarcoplasmic reticulum and their main part was shown, by high performance thin layer chromatography. to be GM3. Addition of GM3 to the soybean phospholipids used for reconstitution of proteoliposomes markedly increased ATP hydrolysis as well as Ca2+ uptake activity of sarcoplasmic reticulum Ca2+-ATPase incorporated into the proteoliposomes. Conformation changes of Ca2+-ATPase induced by GM3 were also observed by intrinsic fluorescence and circular dichroism measurements. PMID- 8690072 TI - Urinary output of hydroxylysine glycosides and pyridinium cross-links in detecting rat bone collagen turnover rate. AB - Glucosylgalactosylhydroxylysine (GGHYL), galactosylhydroxylysine (GHYL), pyridinoline (PYD) and deoxypyridinoline (DPD) were measured in the urine (6 h serial specimens over 96 and 24 h urine specimens for 4 days) collected from four adult Sprague Dawley rats and in the femoral and tibia] bone as well as in the dorsal skin of the same rats. No significant daily variations were found in the urine excretion of GGHYL, GHYL, PYD and DPD but significant diurnal variations. The GGHYL/GHYL ratio in rat urine (0.46 +/- 0.1) reflected neither the bone collagen ratio (1.9 to 2.4) nor the skin collagen ratio (1.22 +/- 1.07), a finding that may reflect GGHYL conversion into GHYL. The content of both pyridinolines was very low in the skin and high in the bone collagen and the urinary PYD/DPD ratio (1.46 +/- 0.15) reflected essentially the bone collagen ratio (0.8-3.0). These results suggest the usefulness of measuring GGHYL, GHYL, PYD and DPD in 24 h urine specimen and, based on the inter-animal variations, the necessity to consider each animal as its own control when bone turnover needs to be monitored. PMID- 8690074 TI - Oligomerization of VIP21-caveolin in vitro is stabilized by long chain fatty acylation or cholesterol. AB - VIP21-caveolin is one of the components which form the cytoplasmic surface of caveolae. In vivo, this integral membrane protein is found in homo-oligomers with molecular masses of approximately 200, 400 and 600 kDa. These oligomers are also formed by the addition of cytosol to the in vitro synthesized and membrane inserted VIP21-caveolin. Here we show that long chain fatty acyl coenzyme A esters can completely substitute for cytosol in inducing 200 kDa and 400 kDa complexes, whereas 25-hydroxy-cholesterol can produce the 200 kDa oligomer. In order to understand whether acylation of VIP21-caveolin itself is a prerequisite for oligomerization, we studied a mutant protein lacking all three cysteines. When analyzed by velocity sucrose gradient centrifugation in the presence of the non-ionic detergent octylglucoside, both palmitoylated and non-palmitoylated VIP21-caveolin formed oligomers that were indistinguishable. However, only the oligomers of the non-palmitoylated protein are disrupted when analyzed by SDS PAGE without boiling. These data suggest that the protein domains of VIP21 caveolin are the primary determinants of oligomerization, but that palmitoylation of cysteine residues can increase the stability of the oligomers. PMID- 8690073 TI - PCR cloning and expression analysis of a cDNA encoding a pectinacetylesterase from Vigna radiata L. AB - A cDNA clone encoding a pectinacetylesterase (PAE) was isolated from 3-day-old mung bean seedlings using PCR-based techniques. Degenerate oligonucleotide primers were designed according to the N-terminus and internal peptides from the purified PAE. The full-length clone of 1453 bp codes for a signal peptide of 24 amino acids and a mature protein of 375 amino acids. The Mr and the pI of the cDNA-deduced amino acid sequence agree with the values estimated for the purified enzyme. No significant sequence identity between the PAE and any known protein could be found in the databases. Northern analysis revealed developmentally regulated expression of the mRNA in mung been seedlings. PMID- 8690075 TI - T-type Ca2+ channels and alpha1E expression in spermatogenic cells, and their possible relevance to the sperm acrosome reaction. AB - There is pharmacological evidence that Ca2+ channels play an essential role in triggering the mammalian sperm acrosome reaction, an exocytotic process required for sperm to fertilize the egg. Spermatozoa are small terminally differentiated cells that are difficult to study by conventional electrophysiological techniques. To identify the members of the voltage-dependent Ca2+ channel family possibly present in sperm, we have looked for the expression of the alpha 1A, alpha 1B, alpha 1C, alpha 1D and alpha 1E genes in mouse testis and in purified spermatogenic cell populations with RT-PCR. Our results indicate that all 5 genes are expressed in mouse testis, and in contrast only alpha 1E, and to a minor extent alpha 1A, are expressed in spermatogenic cells. In agreement with these findings, only T-type Ca2+ channels sensitive to the dihydropyridine nifedipine were observed in patch-clamp recordings of pachytene spermatocytes. These results suggest that low-threshold Ca2+ channels are the dihydropyridine-sensitive channels involved in the sperm acrosome reaction. PMID- 8690076 TI - Insulin-like growth factor-I (IGF-I) mRNA in the small intestine of suckling and adult rats. AB - The presence and cellular localization of insulin-like growth factor-I (IGF-I) mRNA in the small intestine of suckling and adult rats was studied. A sensitive reverse transcription (RT) competitive-polymerase chain reaction (PCR) revealed IGF-I gene expression in both age groups. Adult tissue contained 3-fold higher levels of IGF-I mRNA in comparison with sucklings. Using an in situ hybridization technique, IGF-I transcripts were localized mainly in enterocytes and goblet cells in the intestinal crypts of adult rats. By using this technique, IGF-I mRNA was not detected in jejunum of 12-day-old rats. PMID- 8690078 TI - Cytotoxic and chemotactic potencies of several aldehydic components of oxidised low density lipoprotein for human monocyte-macrophages. AB - We have investigated the cytotoxic and chemotactic potencies of malondialdehyde (MDA), hexanal, 4-hydroxyhexenal (HHE), 4-hydroxynonenal (HNE) and 4 hydroxyoctenal (HOE), which are aldehydes found in oxidised low density lipoprotein (LDL), for human monocyte-macrophages. They were toxic in the following order: hexanal99% of the preparation's protein content, allowing SC administration. CONCLUSION: There is no doubt that recombinant gonadotropins produced by genetic engineering technology are here to stay and will represent an important treatment modality in various fertility disturbances. PMID- 8690101 TI - The future of infertility services. PMID- 8690102 TI - Projections of impaired fecundity among women in the United States: 1995 to 2020. AB - OBJECTIVE: To determine the number of women aged 15 to 44 years with impaired fecundity every 5 years from 1995 to 2020. DESIGN: Data are used from cycle IV of the National Survey of Family Growth conducted by the National Center for Health Statistics. Population projections prepared by the U.S. Census Bureau are used for the expected population base for 1995 to 2020. Prospective demographic projection analysis is used to estimate the number of women with impaired fecundity. PARTICIPANTS: The National Survey of Family Growth interviewed 8,450 women aged 15 to 44 years as of March 15, 1988. MAIN OUTCOME MEASURE: Number of women with impaired fecundity. RESULTS: The number of women with impaired fecundity may drop from 5.1 million in 1995 to 4.7 million in 2015 and then rise to 4.8 to 5.9 million in 2020. CONCLUSION: The age structure of the population will cause the absolute number of women with impaired fecundity in the United States to increase slowly, if at all, over the next 25 years. PMID- 8690103 TI - Recanalization of obstructed fallopian tube by selective salpingography and transvaginal bougie dilatation: outcome and cost analysis. AB - OBJECTIVE: To investigate effectiveness and cost of transcervical salpingography and recanalization in the management of infertility caused by tubal occlusion. DESIGN: Retrospective analysis of patients investigated with transcervical selective salpingography and, in some instances, treated by transcervical recanalization. SETTING: Four hundred patients with hysterosalpingography diagnosis of obstructed fallopian tubes (clinical environment) are investigated. A repeat hysterosalpingogram after administration of a prostaglandin antagonist demonstrated patency of the tubes in 82 patients and selective transcervical salpingography demonstrated patency in an additional 131 patients. INTERVENTION: Transcervical tubal recanalization. Of the remaining 187 patients, recanalization by transcervical technique was successful in 145 patients. The underlying etiology for tubal obstruction was salpingitis isthmica nodosa in 62, salpingitis and perisalpingitis in 71, endometriosis in 8, failed surgical anastomosis in 43, and undeterminate cause in 3 patients. Pregnancy was attained in 24 patients, there were 10 minor and 1 major complication. OUTCOME MEASURE: Attained and maintained patency of tubes, pregnancy, attendant complications. CONCLUSION: A pregnancy rate of 12.8% was attained after transcervical recanalization of obstructed tubes. An attendant increased rate of pregnancy in patients proven patent after selective salpingography, valuable detailed information about proximal and distal tubes after recanalization of the obstructed proximal tube segment, the low rate of complications, and low cost are factors recommending the use of this technique. Moreover, tubal surgery or IVF treatment are not influenced adversely by prior transcervical tubal recanalization and remain an option for patients who failed to attain pregnancy. PMID- 8690104 TI - Comparison of spironolactone-oral contraceptive versus cyproterone acetate estrogen regimens in the treatment of hirsutism. AB - OBJECTIVE: To compare the efficacy of two antiandrogens, cyproterone acetate (CPA) and spironolactone, in the treatment of hirsutism. DESIGN: Prospective randomized single-blinded study. SETTING: A tertiary hirsutism clinic. PATIENTS: Forty-two premenopausal patients with hirsutism were selected. INTERVENTIONS: Subjects were randomized to receive either 100 mg spironolactone and an oral contraceptive (OC) containing 150 microg desogestrel and 30 microg ethinyl E2 or 50 mg CPA daily on days 1 to 10 of the menstrual cycle, which was administered with 35 microg ethinyl E2 daily on days 1 to 21. MAIN OUTCOME MEASURES: Hirsutism scores were measured according to Ferriman-Gallwey scoring system and side effects were monitored for 9 months of treatment. Blood samples were taken at each visit for assessment of endocrine, biochemical, and hematologic parameters. RESULTS: Hirsutism scores were decreaded significantly in both groups at the end of 9 months. The percent of change in hirsutism scores in CPA and spironolactone group were as follows: 19.23% +/- 14.77% and 24.48% +/- 14.27% at 3 months; 39.01% +/- 19.77% and 37.46% +/- 16.90% at 6 months; and 51.89% +/- 20.87% and 46.39% +/- 16.10% at 9 months, respectively. There was a trend toward a better response with CPA treatment, which did not achieve significance. None of the patients stopped treatment because of side effects. CONCLUSION: The present data suggest that both spironolactone and CPA were similarly effective in treatment of hirsutism. PMID- 8690105 TI - The efficacy of 250 mg/day flutamide in the treatment of patients with hirsutism. AB - OBJECTIVE: To investigate the effects of low dose flutamide (250 mg/d) on hirsutism score and hormone levels in women with hirsutism. DESIGN: Nonrandomized, prospective clinical trial. PATIENTS: Forty-one patients with moderate-severe hirsutism were included in the study. INTERVENTION: Hirsute patients received 250 mg/d flutamide for a period of 6 months. MAIN OUTCOME MEASURES: Hirsutism score, FSH, LH, E2, total T, free T, androstenedione, DHEAS, PRL, 17-hydroxyprogesterone, and sex hormone-binding globulin levels were detected in all the patients before treatment and every 3 months during treatment. RESULTS: Treatment with the antiandrogen flutamide resulted in a particularly rapid and marked decrease in the hirsutism score, which decreased from 17.48 +/- 5.35 to 5.07 +/- 2.89 after 6 months. No significant changes in the levels of hormone and no serious side effects were observed in the study. CONCLUSION: The low-dose flutamide, 250 mg/d, is a cost-effective drug in the treatment of hirsutism. Low-dose flutamide may be used in place of high-dose flutamide, 500 to 750 mg/d. PMID- 8690106 TI - Zoladex (goserelin acetate) and the anemic patient: results of a multicenter fibroid study. AB - OBJECTIVE: To compare the effects of goserelin acetate treatment with or without iron with iron alone. DESIGN: Multinational, multicenter, prospective, randomized, double-blind study. PATIENTS: Premenopausal women with menorrhagia or metrorrhagia and anemia associated with uterine leiomyomata awaiting hysterectomy. INTERVENTION: Patients were randomized to one of three 12-week treatment groups namely goserelin acetate 3.6 mg once monthly plus placebo iron; 3.6 mg goserelin acetate once monthly plus 600 mg/d iron; or sham injection once monthly plus 600 mg/d iron. MAIN OUTCOME MEASURE: Preoperative hemoglobin concentration; preoperative uterine and fibroid volumes and operative blood loss. RESULTS: Considering the entry and preoperative hemoglobin concentrations, there was a difference in least square means of just over 1 g/dL between the goserelin acetate plus iron and iron only groups and 2.6 g/dL between the goserelin acetate plus iron and goserelin acetate only group. These differences were both statistically significant. Uterine and fibroid volumes were decreased in the goserelin acetate-treated patients by between 37% and 40% and 44% and 47%, respectively, compared with 7% decreases for both in the iron only group. The differences in absolute changes were statistically significant for both the goserelin acetate-treated groups versus the iron-treated group. The least square geometric mean operative blood loss was greatest in the iron only group. CONCLUSION: In the patient with uterine leiomyomata and anemia, goserelin acetate in combination with iron therapy has shown significant advantages over the iron alone in restoring hematologic normality, decreasing uterine and fibroid volumes, and reducing operative blood loss. PMID- 8690107 TI - Age-dependent decrease in the growth hormone response to growth hormone-releasing hormone in normally cycling women. AB - OBJECTIVE: To establish possible changes in GH secretion in normally cycling women with increasing age. DESIGN: Controlled clinical study. PATIENTS: Nine younger (18 to 33 years) and nine older (41 to 46 years) healthy women. SETTING: Tests were performed on the 22d day of regular cycles. INTERVENTION: All subjects were tested with GH-releasing hormone (GH-RH) (1 mg/kg body weight), the acetylcholinesterase inhibitor pyridostigmine (120 mg by mouth), the somatostatin inhibitor arginine (30 g infused IV over a 30-minute period) alone, and the combination of GH-RH plus arginine or GH-RH plus pyridostigmine. MAIN OUTCOME MEASURES: Glucose, cortisol, androgens, estrogens, thyroid hormones, and insulin growth-like factor (IGF-I) were measured in basal samples. Serum GH levels were measured in samples taken before and over a 2-hour period after drug administration. RESULTS: All basal hormonal values were similar in younger and older women. Insulin growth like factor-I levels were lower in older women. The GH responses to GH-RH alone, pyridostigmine alone, or the combination were lower in the older than in the younger group and were correlated negatively with age. In contrast, either arginine alone or GH-RH plus arginine produced similar GH responses in the two groups. CONCLUSION: These data indicate that the cholinergic stimulatory regulation of GH release is reduced in the older cycling women. Because acetylcholine inhibits hypothalamic somatostatin release, the reduced cholinergic tone in other subjects may result in an increased somatostatinergic tone. Normalization in older women of the reduced GH response to GH-RH by arginine supports this hypothesis. PMID- 8690108 TI - Insulin-like growth factor (IGF)-I and IGF-II stimulate progesterone production by human luteal cells: role of IGF-I as mediator of growth hormone action. AB - OBJECTIVE: To examine the possible direct effect of insulin-like growth factor (IGF)-I and IGF-II on basal and hCG-stimulated P production by cultured human luteal cells. The possible role of IGF-I as mediator of GH action on luteal steroidogenesis also was investigated. DESIGN: Cultures of human luteal cells from early and midluteal phase. SETTING: All corpora lutea were obtained from the Obstetrics and Gynecology Department of the Universita Cattolica, a public care center. PATIENTS: Eight nonpregnant women between 35 and 47 years of age underwent surgery for various nonendocrine disorders such as leiomyomatosis. INTERVENTIONS: Corpora lutea were obtained at the time of hysterectomy. MAIN OUTCOME MEASURES: Luteal cells were incubated with IGF-I or IGF-II with or without hCG at different concentrations. Growth hormone also was used alone and with an anti-IGF-I-antibody. RESULTS: We found that IGF-I and IGF-II were able to stimulate directly the P production at all used concentrations and that both of them significantly amplified the steroidogenic hCG effect. Finally, IGF-I was shown to mediate the positive GH action on P synthesis. PMID- 8690109 TI - Gonadotropin-releasing hormone agonist-induced hypoestrogenism and blood flows in cerebral arteries. AB - OBJECTIVE: To evaluate the effect of the hypoestrogenism induced by GnRH agonist (GNRH-a) therapy on cerebral vessel blood flow. DESIGN: Open, controlled study. SETTING: Tertiary care units of the University of Milan, Italy. PATIENTS: Young women scheduled to undergo 6 months of therapy with a GnRH-a; a control group was also enrolled. INTERVENTIONS: In both groups, the pulsatility index of both the internal carotid artery (ICA) and middle cerebral artery (MCA) was measured by means of Doppler ultrasound over a period of 6 months. MAIN OUTCOME MEASURE: The ICA and MCA pulsatility index. RESULTS: No variation in the pulsatility index of either artery was found in either group. CONCLUSIONS: A 6-month period of GnRH-a induced hypoestrogenism in young women does not lead to any variation in the blood flow of cerebral vessels. This provides some reassurance as to the safety of these drugs in relation to the role that the reactivity of peripheral arteries may play in determining risk of cardiovascular disease. Furthermore, our results show that blood flow in the cerebral vessels of young subjects is under extraestrogenic control and that this may counterbalance estrogen deprivation through mechanisms that probably are no longer active in the perimenopausal years. PMID- 8690110 TI - Sonographic assessment of endometrial pattern and thickness in patients treated with human menopausal gonadotropins. AB - OBJECTIVE: To analyze sonographically the endometrium in patients undergoing controlled ovarian stimulation with menotropins in order to determine the significance of endometrial pattern and thickness on pregnancy rate. DESIGN: This is a prospective, nonrandomized study comparing pregnancy rates in patients with hyperechoic homogeneous patterns with those in patients with isoechoic or hypoechoic trilaminar patterns. SETTING: Tertiary infertility center. PATIENTS: All patients receiving menotropin therapy at a tertiary infertility center. INTERVENTIONS: All patients received individualized dosing of hMG starting on cycle day 3. Transvaginal sonography was performed 15 hours before hCG administration and the endometrium was assessed. MAIN OUTCOME MEASURE: Occurrence of pregnancy as determined by serially rising beta-hCG titers and sonographic confirmation. RESULTS: During the study period, 175 patients were evaluated. Thirty-four (19%) patients had a homogeneous endometrium, whereas 141 (81%) patients had a trilaminar pattern. There was 1 pregnancy (2.9%) among women with a homogeneous endometrial pattern and 33 pregnancies (23%) among those with a trilaminar pattern. No significant differences were found in mean E2 level, follicle numbers, parity, and diagnosis between the two groups. CONCLUSION: In patients receiving menotropins, a homogeneous pattern is a bad prognostic sign, regardless of endometrial thickness. PMID- 8690111 TI - Aneuploidy 16 in human embryos increases significantly with maternal age. AB - OBJECTIVE: To determine aneuploidy for chromosome 16 by recycling nuclei of cells already analyzed for chromosomes X, Y, 18, 13, and 21 using multiple fluorescence in situ hybridization in preimplantation human embryos in a time frame compatible with clinical IVF and to asssess the incidence of chromosome 16 aneuploidy in embryos related to maternal age. DESIGN: Prospective experimental study. SETTING: In vitro fertilization program in a tertiary center. PATIENTS: One hundred four consenting patients undergoing IVF. MAIN OUTCOME MEASURES: Chromosome 16 ploidy was analyzed in a total of 195 embryos. In 89 embryos, a standard multiple-probe fluorescence in situ hybridization was used for chromosomes X, Y, 18 and 16 (series 1). The remaining 106 embryos (series 2) were reanalyzed with a new procedure for chromosome 16, which involves rehybridization with a digoxigenin labeled alpha satellite probe after the standard analysis for chromosomes X, Y, 18, 13, and 21 was completed. The embryos were assigned to one of three groups according to the women's age; group 1: /= 40 years (n = 23). RESULTS: Successful analysis, including biopsy, fixation, and fluorescence in situ hybridization was achieved in 86% of the blastomeres within approximately 10 hours. A significant relationship was found between the rate of aneuploidy for chromosome 16 and increasing maternal age: group 1: 0%, group 2: 6.3%, and group 3: 11.7%. Monosomy for chromosome 16 was found in 72.7% of the 11 embryos carrying chromosome 16 anomalies, with the remaining three embryos having two trisomies and one tetrasomy. This new protocol was applied clinically to five patients undergoing preimplantation aneuploidy assessment. Aneuploidy for chromosome 16 was found in five embryos from three of those patients. CONCLUSIONS: This study demonstrates that preimplantation genetic diagnosis of the major human aneuploidies is achievable within a time frame compatible with IVF. In addition, this study confirms, for embryos, the existing data from spontaneous abortions suggesting that chromosome 16 aneuploidy increases with maternal age. The high prevalence of embryonic monosomy, which is rarely found in spontaneous abortions, suggests that monosomy 16 could be a factor associated with failure of implantation, as well as pointing to a different mechanism involved in the generation of chromosome 16 aneuploidy. PMID- 8690112 TI - Successful intracytoplasmic sperm injection without performing cytoplasmic aspiration. AB - OBJECTIVE: To compare the effect of cytoplasmic aspiration versus no aspiration before intracytoplasmic sperm injection (ICSI) on the rate of oocyte damage, fertilization rate, and embryo quality. DESIGN: A randomized prospective study on sibling oocytes. SETTING: The Egyptian IVF-ET Center, Cairo, Egypt. PARTICIPANTS: Fifty-eight patients who were infertile due to male factor who underwent 60 ICSI cycles. INTERVENTION: Intracytoplasmic sperm injection was performed on randomly allocated metaphase II oocytes with cytoplasmic aspiration in group I and without cytoplasmic aspiration in group II before sperm injection. MAIN OUTCOME MEASURE: Fertilization rate, oocyte damage rate, and embryo quality. RESULTS: Normal fertilization rate per injected oocyte was 61.4% in group I compared with 62.5% in group II. The damage rate per injected oocyte was 16.8% in group I compared with 4.6% in group II. Grade I embryos were 24.5% in group I compared with 48.5% in group II. CONCLUSION: Cytoplasmic aspiration before sperm injection in ICSI is not essential for oocyte activation. It did not improve the rate of normal fertilization. On the other hand, it increased the damaged oocyte rate and the rate of cytoplasmic fragments. PMID- 8690113 TI - Effect of age on sperm fertility potential: oocyte donation as a model. AB - OBJECTIVE: To determine the effect of age on sperm fecundability using oocyte donation as an in vivo model. SETTING: Oocyte donation and IVF programs at the Instituto Valenciano de Infertilidad. DESIGN: Retrospective study in which four groups of oocyte donation cycles were established according to age of the male providing the semen sample: group 1 (n = 31) < 30 years; group 2 (n = 195) 31 to 40 years; group 3 (n = 98) 41 to 50 years; group 4 (n = 21) > 51 years, the oldest being 64 years. All donated oocytes were obtained from patients < 35 years old. MAIN OUTCOME MEASUREMENTS: Male age, sperm characteristics (volume, concentration, motility, morphology), fertilization, embryo quality, pregnancy, implantation, and abortion rates among recipients. RESULTS: Similar sperm characteristics in fresh as well as after preparation for IVF were observed among males of different ages. Fertilization, embryo quality, pregnancy, and implantation were similar among the established groups. The mean age of the females included in each group significantly increased from group 1 to group 4. CONCLUSIONS: Age (up to 64 years) does not affect sperm characteristics or its ability to fertilize human eggs. Similarly, embryo development in vitro as well as implantation in recipient uteri are not affected by age of the male providing the semen sample. PMID- 8690114 TI - Age does not affect uterine resistance to vascular flow in patients undergoing oocyte donation. AB - OBJECTIVE: To determine whether uterine vasculature is affected by age using oocyte donation as an in vivo model. DESIGN: Prospective longitudinal study in which recipients were grouped according to age. They underwent a successful oocyte donation cycle, and single pregnancies were followed during the first trimester by color Doppler ultrasound in uterine arteries. SETTING: Oocyte donation and IVF program at the Instituto Valenciano de Infertilidad. INTERVENTIONS: Serum E2, P, and hCG levels in single ovum donation pregnancies; pulsatility and resistance indexes in uterine arteries during initial pregnancy. RESULTS: Similar serum levels of E2, P, and hCG in both groups of patients were observed. There was no difference between groups regarding the flow indexes analyzed. CONCLUSIONS: The increased incidence of early pregnancy losses observed in patients > 40 years cannot be attributed to defective response of uterine vasculature to exogenous hormone replacement. Thus, uterine aging does not appear to be a factor influencing the poor reproductive performance of women with advancing age. PMID- 8690115 TI - A novel method of ovarian stimulation for in vitro fertilization: bromocriptine rebound method. AB - OBJECTIVE: To examine whether a new method of ovarian stimulation, bromocriptine rebound method, improves IVF outcomes compared with the conventional long protocol of GnRH agonist and hMG regimen. DESIGN: A prospective clinical trial. SETTING: In vitro fertilization program at a university hospital. PATIENTS: Endocrine-normal ovulatory women less than 40 years of age, with normal male partners and previous failed IVF-ET using long protocol. INTERVENTIONS: Patients were assigned to either bromocriptine-rebound method (group 1) or long protocol (group 2). The bromocriptine-rebound method was the same as the long protocol, except that bromocriptine was administered daily from day 4 of the preceding cycle until 7 days before hMG stimulation. MAIN OUTCOME MEASURES: The number of cleaved and morphologically superior embryos, pregnancy rate per oocyte pick-up, and serum PRL concentrations during administrations of hMG. RESULTS: Significantly more embryos were cleaved and had superior morphology in group 1 than group 2. Clinical and ongoing pregnancy rates per oocyte pick-up were significantly higher in group 1 (42% and 38%, respectively) than group 2 (24% and 21%, respectively). The mean PRL concentration was significantly higher in the group 1 than group 2. A significant correlation between the number of superior embryos and PRL concentrations was observed in group 1, but not in group 2. CONCLUSION: The bromocriptine-rebound method enhanced embryonic development, resulting in an increased pregnancy rate compared with the long protocol. PMID- 8690116 TI - Premature luteinization in in vitro fertilization cycles using gonadotropin releasing hormone agonist (GnRH-a) and recombinant follicle-stimulating hormone (FSH) and GnRH-a and urinary FSH. AB - OBJECTIVE: To determine if premature luteinization can occur in GnRH agonist (GnRH-a) and FSH (recombinant FSH and human urinary FSH) IVF cycles and whether premature luteinization affects IVF and clinical outcome. DESIGN: Retrospective evaluation of 171 IVF-ET cycles. The cycles were divided into two groups according to the P level on the day of hCG: group I (serum P /= 1.1 ng/mL). MAIN OUTCOME MEASURES: Comparison of cycles characteristics and of cumulative exposure of follicular serum E2, FSH, LH, and P as well as of IVF and clinical outcome were made between the study groups. RESULTS: Twenty-three of the 171 cycles (13.4%) demonstrated premature luteinization. The age of the patients, the E2, and LH exposure were similar between the groups. The number of the ampules of gonadotropins (recombinant FSH and urinary FSH) used and the area under FSH and P curve were higher in cycles with premature luteinization. The area under the FSH curve correlated with the area under the P curve. Similar IVF and clinical outcomes were observed in cycles with and without premature luteinization. CONCLUSION: The greater FSH exposure and its correlation with the P exposure suggest that one of the possible factors inducing premature luteinization is the increased FSH-induced LH receptivity in granulosa cells. No adverse effects of premature luteinization on the IVF and clinical outcome were observed. PMID- 8690117 TI - A change in practice: current urologic practice in response to reports concerning vasectomy and prostate cancer. AB - OBJECTIVE: To examine the practice patterns of urologists performing vasectomy in response to studies reporting an increased risk of prostate cancer in vasectomized men. DESIGN: A mailed survey. SETTING: A university medical institution. PARTICIPANTS: One thousand five hundred randomly selected United States urologists under the age of 65 years. MAIN OUTCOME MEASURE: Urologists reported practice patterns of vasectomy in response to studies showing possible link between vasectomy and prostate cancer. RESULTS: A response rate of 51% (759/1,500) was obtained. Although > 90% state that these studies have had little or no effect upon their practice of vasectomy, 27% screen vasectomized men earlier for prostate cancer, and 20% would be reluctant to recommend a vasectomy to a man with a strong family history of prostate cancer. CONCLUSIONS: Over one fourth of urologists who screen for prostate cancer have altered their screening patterns even though they responded that the studies have not affected their practice patterns. PMID- 8690118 TI - A prospective study on the predictive value of normal sperm morphology as evaluated by computer (IVOS). AB - OBJECTIVE: To evaluate the IVOS (Hamilton Thorne Research Version 2.1 Dimension Program, Beverly, MA) system's ability to predict fertilization in vitro in a prospective study. DESIGN: Hospital-based academic ART program. PATIENTS: Eighty patients from the IVF-GIFT program were evaluated. The same semen sample was analyzed on a day-to-day basis by both laboratory (manual method) and the computerized system for percentage normal morphology, concentration/mL, motility, and forward progression. Only patients with two or more metaphase II (MII) oocytes available were allowed into the study and excluded where the male partner had antisperm antibodies or qualified for intracytoplasmic sperm injection (<500,000 motile spermatozoa obtained after glass wool separation). STATISTICAL ANALYSIS: Logistic regression analysis was used to study predictors of fertilization in vitro. RESULTS: Three hundred thirty-eight oocytes were obtained from 80 patients of which 239 fertilized. The logistic regression analysis of the manual method (percentage normal morphology) and IVOS indicated that both were predictors of fertilization. Sperm morphology as evaluated by IVOS in patients with <10 x 10(6) motile spermatozoa/mL retrieved after swim-up was a significant predictor of fertilization as was the number of oocytes obtained. Thus, the more oocytes obtained in the lower morphological groups, the better the chance of fertilization. The fertilization rate in the morphology group of 0% to 4% normal forms was 45.6% (37/81) and in the group >14% normal forms was 85.2% (69/81). CONCLUSIONS: It was shown that in patients where 15 x 10(6) sperm/mL) males. The patient groups had a significantly lower GH response to an arginine GH stimulation test as compared with a control group. RESULTS: Serum insulin-like growth factor I (IGF-I) and serum IGF-binding protein 3 (IGFBP-3) levels increased significantly during GH treatment, as did seminal IGF-I. Serum E2, T, PRL, FSH, LH, and GH-binding protein were unchanged during the study. Sperm motility was increased significantly during GH treatment in both patient groups. There was no difference in sperm count during the treatment. There were three pregnancies in the nine couples from the asthenozoospermic group and no pregnancies in the oligozoospermic group. CONCLUSION: The biologic and clinical results in this study encourage the initiation of double-blind, placebo controlled trials. PMID- 8690121 TI - Effect of growth hormone cotreatment with human chorionic gonadotropin in testicular steroidogenesis and seminal insulin-like growth factor-1 in oligozoospermia. AB - OBJECTIVE: To study the GH synergy with hCG in testicular steroidogenesis and seminal insulin-like growth factor-1 (IGF-1) in oligozoospermia. SETTING: University endocrine unit. PATIENTS: Eight oligospermic, non-GH-deficient men. INTERVENTIONS: Three different protocols spaced 3 months apart were applied in each man: plain hCG protocol: 1,500 IU IM three times every other day; GH + hCG protocol: with the addition of 4 IU SC GH daily 8 days before and throughout the hCG phase; placebo + hCG: substitution of GH by NaCL 0.9%. Blood sampling was performed before and on the 8th day (for 2nd- and 3rd-day protocols) and 24 hours after each hCG administration. Semen was collected three times during each protocol. MAIN OUTCOME MEASURES: Plasma for P, 17-OHP, androstenedione, DHEA, DHEAS, T, and E2 and plasma and seminal IGF-1 three times during each study. RESULTS: Serum IGF-1 levels increased more than threefold after GH administration. Seminal IGF-1 activity was unaffected by GH treatment or hCG administration, showing random fluctuations within each subject without correlation to the respective plasma levels. The incremental response of each steroid under hCG did not differ between the three protocols, apart from increased P levels under GH. CONCLUSIONS: Short-term GH cotreatment with hCG did not affect seminal IGF-1 concentration and had a weak synergist effect on steroidogenesis. PMID- 8690122 TI - Relationship between the zona pellucida (ZP) and ionophore A23187-induced acrosome reaction and the ability of sperm to penetrate the ZP in men with normal sperm-ZP binding. AB - OBJECTIVE: To determine whether the proportions of sperm undergoing the acrosome reaction (AR) on the zona pellucida (ZP) or on exposure to the calcium ionophore A23187 correlate with sperm-ZP penetration in men with normal sperm-ZP binding. DESIGN: Sperm samples from 14 fertile, 50 normozoospermic, and 21 teratozoospermic men with normal sperm-ZP binding were used to study ZP and ionophore-induced AR and sperm-ZP penetration. SETTING: University research unit associated with a clinical infertility and IVF program. MAIN OUTCOME MEASURES: The proportion of sperm undergoing the AR induced by ZP and A23187, the number of sperm bound to and penetrating into the ZP, the proportion of ZP penetrated by sperm, and semen characteristics were analyzed. RESULTS: There were highly significant correlations between the percentage AR of sperm bound to the ZP and both the proportion of ZP penetrated and average number of sperm penetrating per ZP (Spearman r = 0.697 and 0.703). In contrast, A23187-induced AR did not correlate with either ZP-induced AR or sperm-ZP penetration. Although sperm concentration in semen correlated with both ZP-induced AR and sperm-ZP penetration by Spearman test, it was not significant in multivariate regression analyses. CONCLUSION: Ionophore A23187-induced AR does not correlate with either ZP-induced AR or sperm-ZP penetration. The ZP-induced AR is correlated highly with sperm-ZP penetration. Testing ZP-induced AR may be useful for assessing infertile men with normal sperm-ZP binding. In particular, it will identify failure of ZP penetration because of specific defects of the AR on the ZP. PMID- 8690123 TI - Antigenic cross-reactivity of human tracheal mucin with human sperm and trophoblasts correlates with the expression of mucin 8 gene messenger ribonucleic acid in reproductive tract tissues. AB - OBJECTIVE: To test whether autoimmunity to sperm in men with cystic fibrosis (CF) is a result of cross-reactivity between sperm and carbohydrate sequences of the abnormal CF mucins, we investigated the possible epitope sharing between sperm surface antigens and CF mucin antigens using specific monoclonal antibodies (mAbs) directed to purified CF tracheobronchial mucin-1 (HTM-1) and the expression of tracheal mucin 8 gene (MUC8) mRNA in normal male and female reproductive tract tissues by Northern blot analysis. DESIGN: A panel of mAbs directed to HTM-1 subspecies (types I to V) and polyclonal antibodies (pAb) to native and deglycosylated HTM-1 were tested for their ability to agglutinate motile sperm. An indirect immunofluorescence assay was used to detect expression of cross-reactive HTM-1 epitopes on sperm, term placenta (n = 3), and purified trophoblasts (n = 9). Northern blot analysis was used to detect MUC8 messenger RNA (mRNA) in male and female reproductive tract tissues. SETTING: University of Oklahoma Health Sciences Center, a tertiary care referral center. MAIN OUTCOME MEASURES: The demonstration of cross-reactive mucin at the protein and mRNA levels in reproductive tract tissues. RESULTS: Of the five mucin subspecies, type II, IV, and V mucin-specific mAbs (21.3, 33.3, and 54.1) induced head-to-head agglutination of motile sperm; pAb to deglycosylated mucin had no effect. Sperm agglutination mediated by type IV mucin mAb 33.3 was abrogated completely by D mannose. Within the term placental villi, type II mucin, was localized to fetal endothelium, type IV mucin was localized to syncytiotrophoblast, and type V mucin was localized to cytotrophoblasts. Immunologic studies correlated with the results of Northern blot analysis, which revealed strong MUC8 mRNA expression in the human testis, placenta, endometrium, and cervix and weak or undetectable levels in the human epididymis, seminal vesicle, ovary, fallopian tube, and uterus. CONCLUSIONS: Both male and female reproductive tract tissues synthesize tracheal MUC8 mucin. Monoclonal antibodies specific to human tracheal mucin subtypes induced "immune-type" agglutination of motile sperm. Therefore, expression of cross-reactive MUC8 mucin epitopes in reproductive tract tissues may contribute to the development of low affinity, carbohydrate-specific, agglutinating antisperm antibodies in the genital tract. PMID- 8690124 TI - Localization of seminal plasma transforming growth factor-beta1 on human spermatozoa: an immunocytochemical study. AB - OBJECTIVE: To localize immunocytochemically transforming growth factor beta1 (TGF beta1) in human spermatozoa. DESIGN: Incubation of spermatozoa with anti-TGF beta1 antiserum at various pH. SETTING: Human volunteers in an academic research institute. PATIENTS: Young healthy fertile men. INTERVENTIONS: Semen specimens were collected. RESULTS: At neutral pH and at physiological pH of seminal plasma, TGF-beta1 immunostaining was detected predominantly at the postacrosomal region of the head, at the neck, and at the middle piece of the tail. Transforming growth factor-beta1 also was found occasionally at the axial filament complex of the connecting piece and the ring. The acrosomal cap section of the head, the principal piece, or the end piece of the tail were immunocytochemically negative for TGF-beta1. The TGF-beta1 immunostaining pattern at acidic pH was similar to that at neutral pH and at physiological pH of seminal plasma, but a greater intensity of immunostaining was found at acidic pH than that at neutral pH. CONCLUSION: These results suggest that an in vivo activation of seminal plasma latent TGF-beta1 may take place in the acidic environment of vagina, which results in a greater amount of activated TGF-beta1 and, in turn, with an enhanced "coating" of TGF-beta1 to spermatozoa. PMID- 8690125 TI - The use of testicular sperm for intracytoplasmic sperm injection in patients with necrozoospermia. AB - OBJECTIVE: To investigate whether intracytoplasmic sperm injection (ICSI) using testicular spermatozoa from necrozoospermic patients results in acceptable fertilization and transfer rates. DESIGN: Retrospective clinical study. SETTING: Tertiary referral center. PATIENTS: Five patients presenting consistently with 100% dead spermatozoa in their ejaculates. INTERVENTIONS: In seven treatment cycles, an open testicular biopsy was performed to increase the chances for retrieving viable spermatozoa which were used for ICSI. MAIN OUTCOME MEASURES: Sperm recovery, fertilization, and transfer rates. RESULTS: Testicular sperm were recovered in all treatment cycles and fertilization occurred in six of seven cycles. Overall normal fertilization and transfer rates were 67% and 71%, respectively. One live birth was obtained after five ETs. CONCLUSION: We recommend testicular sperm recovery for ICSI in patients who invariably or occasionally present with absolute necrozoospermia. PMID- 8690126 TI - Transfer of embryos from yeast-colonized dishes. AB - OBJECTIVE: To report yeast colonization in IVF dishes, where ET was carried out, and the IVF outcome was not compromised. DESIGN: Retrospective study of patients who underwent IVF cycle during the last 4 years. SETTING: In vitro fertilization program at the Shaare-Zedek hospital in Jerusalem. PATIENTS: Five couples who underwent standard IVF cycles and whose dishes were colonized with yeast. After thorough discussion ET was carried out. RESULTS: Although colonized with yeast, the quality of the embryos was not compromised. One to three of these embryos were transferred. All five women conceived. CONCLUSIONS: In vitro fertilization outcome is not necessarily compromised by yeast colonization. Nevertheless, the possible teratogenic effect of yeast on embryos has not been investigated and research is required to address this concern. PMID- 8690127 TI - Insecticide susceptibility status of some anophelines in district Bikaner, Rajasthan. AB - Insecticide susceptibility tests were conducted on the adults of four anopheline species namely. Anopheles annularis, An. culicifacies, An. stephensi and An. subpictus against the diagnostic doses of six insecticides, viz. DDT (4.0%), dieldrin (0.4%), malathion (5.0%). fenitrothion (1.0%), propoxur (0.1%) and permethrin (0.25%) in District Bikaner (Rajasthan). A time dependent effect has been observed with each insecticide. All the four species were found resistant to DDT and dieldrin and susceptible to fenitrothion and permethrin. An culicifacies and An. subpictus showed susceptibility to malathion, while further verification for the other two species was required. However, with propoxur An. annularis showed resistance, whereas for other three species further studies are required. DDT and dieldrin, the two organochlorines, were found least effective as compared to organophosphates and carbamates. PMID- 8690128 TI - Hut-scale trial of pyraclofos against malaria vectors in Malkangiri District of Orissa. AB - A hut-scale trial of pyraclofos 50% EC applied as an indoor residual spray at 1 gm/sq m was carried out against malaria vectors. Anopheles fluviatilis and An. culicifacies in Kandhaguda village of Malkangiri district, Orissa. Bandhaguda village was kept as control. Pyraclofos was effective in reducing the vector density by 80-96% after 24 h of spray, but the density increased within three weeks. Parity rates were reduced only for three weeks as measured by diurnal indoor resting collection. Contact bioassays on mud wall showed pyraclofos has a residual life of only three weeks. No adverse effect was noticed among villagers or spraymen. Cockroaches were found to be very sensitive to this compound. PMID- 8690129 TI - Malaria survey in Tarajulie tea estate and adjoining hamlets in Sonitpur District, Assam. AB - Malaria survey in Tarajulie tea estate (TE) and its adjoining hamlets revealed that Pf was the predominant parasite species (79%) and morbidity was alarming. Malaria positive cases were recorded in all age groups including infants. However, morbidity was much pronounced in the hamlets than among garden dwellers. Mostly Anopheles minimus were recorded in the day resting collections from human dwellings (indoor) and in overnight man biting catches in the hamlets. From these collections. An. minimus was incriminated and the sporozoite infection rate was found to be 4.23 per cent. An. minimus were not recorded in the garden premises. Thus morbidity in the garden population was attributed to the movement of labourers to and fro between hamlets and the garden premises. The hamlets served as reservoirs for malaria infection. PMID- 8690130 TI - Mosquito breeding in relation to aquatic vegetation and some physico-chemical parameters in rice fields of central Gujarat. AB - Mosquito breeding in relation to aquatic vegetation and certain physico-chemical parameters was studied in rice fields of Kheda district in central Gujarat. A total of 14 anopheline and 15 culicine species were encountered in close association with different types of aquatic vegetation in different proportions. Among anophelines, Anopheles annularis, An. nigerrimus, An. subpictus and An. tessellatus were of general distribution and were found associated with each aquatic vegetation. An. culicifacies showed poor association with most of the aquatic weeds. Maximum number of anophelines were found associated with algae. Culex vishnui sub-group predominated among culicines and showed frequent association with Ceratophyllum, Hydrilla and algae. Physico-chemical parameters also exerted some impact on mosquito larval population. PMID- 8690131 TI - Malaria parasite density in pregnant women of district Jabalpur, Madhya Pradesh. AB - Twenty-two cases (nineteen Plasmodium falciparum and three P. vivax) of severe malaria among 200 pregnant women from District Jabalpur, M.P. were studied for malaria parasite density. Almost all of them were found anaemic. The patients were treated with quinine/chloroquine intravenously but seventeen Pf cases died within 96 h of admission in hospital. Out of twenty-two, thirteen were primigravidae. PMID- 8690132 TI - A note on present trend of chloroquine sensitivity of P. falciparum in Malkangiri District, Orissa. PMID- 8690133 TI - Determination of levels of HCH and DDT in soil, water and whole blood from bioenvironmental and insecticide-sprayed areas of malaria control. AB - Concentrations of HCH and DDT in soil, water and whole blood were determined in two areas under malaria control. These were, (i) bioenvironmental control of malaria at BHEL, and (ii) residual spraying of insecticides in rural and urban area of Bahadrabad PHC of Hardwar district. Mean concentrations of HCH in soil and whole blood samples from BHEL was 2.26 micrograms/kg and 1.20 micrograms/l and from Bahadrabad 61.12 micrograms/kg and 24.3 micrograms/l respectively. Similarly, the mean concentration of DDT in soil and whole blood from BHEL was 3.68 micrograms/kg and 4.71 micrograms/l, while in Bahadrabad 270.51 micrograms/kg and 38.13 micrograms/l respectively. HCH and DDT were never detected in any water samples from BHEL area, while the mean concentration of these compounds in water of Bahadrabad area was 0.18 and 0.07 microgram/l respectively. Residual level of HCH and DDT were 27 and 73.5 times higher in soil and 20.2 and 8.1 times higher in whole blood samples from Bahadrabad as compared to their corresponding values from BHEL respectively. PMID- 8690134 TI - Community and contraceptive choice in rural Thailand: a case study of Nang Rong. AB - This paper blends quantitative with qualitative data in an investigation of community and contraceptive choice in Nang Rong, Thailand. Specifically, it develops an explanation of 1) method dominance within villages, coupled with 2) marked differences between villages in the popularity of particular methods. The quantitative analysis demonstrates the importance of village location and placement of family planning services for patterns of contraceptive choice. The qualitative data provide a complementary perspective, emphasizing the importance of social as well as physical space and giving particular attention to the structure of conversational networks. PMID- 8690135 TI - Racial differences in occupational status and income in South Africa, 1980 and 1991. AB - Using data on employed men from the 1980 and 1991 South African Censuses, we analyze the determinants of occupational status and income. Whites are found to have much higher occupational status, and especially income, than members of other racial groups. Most of the racial differentials in occupational status con be explained by racial differences in the personal assets that determine occupational attainment (especially education), but only a much smaller fraction of the White/non-White income differential can be so explained. Despite a modest reduction between 1980 and 1991 in the role of race in socioeconomic attainment, the overall picture shows more stability than change. PMID- 8690136 TI - The determinants of the duration of contraceptive use in China: a multilevel multinomial discrete-hazards modeling approach. AB - Often in demography, individuals may change state over time for a variety of reasons. Competing-risks hazards models have been developed to model such situations. This paper describes the extension of the discrete-time competing risks hazards model to a multilevel framework that allows for data at different levels of aggregation. The model is illustrated with data from the 1988 Chinese National Survey of Fertility and Contraceptive Prevalence, which collected complete contraceptive histories. Women may stop using a method of contraception for a number of reasons; this paper describes how one can control for correlations between the outcomes of repeated spells of contraceptive use. PMID- 8690137 TI - Comment on "a theory of the value of children". PMID- 8690138 TI - The impact of postpartum redundant use of contraception on contraceptive failure rates. AB - Redundant use of contraception occurs when periods of contraceptive use overlap with periods of reduced fecundity, and will downwardly bias estimates of contraceptive failure rates. This paper investigates this bias using calendar data from the Demographic and Health Surveys. The paper presents unadjusted and adjusted 12-month failure rates for each of nine countries. The impact of redundant use on failure rates is generally modest. It tends to be greater in Indonesia, however, where both the incidence and the duration of overlap are relatively large. PMID- 8690139 TI - Latino, Asian, and black segregation in U.S. metropolitan areas: are multiethnic metros different? AB - This study examines 1990 residential segregation levels and 1980-1990 changes in segregation for Latinos, Asians, and blacks in U.S. metropolitan areas. It also evaluates the effect of emerging multiethnic metropolitan area contexts for these segregation patterns. While black segregation levels are still well above those for Latinos and Asians, there is some trend toward convergence over the decade. More than half of the areas increased their Latino segregation levels over the 1980s, and almost three-fourths increased their Asian segregation levels. In contrast, black segregation levels decreased in 88% of metropolitan areas. Multiethnic metropolitan area context is shown to be important for internal segregation dynamics. Black segregation levels are lower, and were more likely to decline in multiethnic metropolitan areas and when other minority groups grew faster than blacks. Latino segregation was also more likely to decline in such areas, and declines in both Latino and Asian segregation were greater when other minority groups were growing. These findings point up the potential for greater mixed-race and mixed-ethnicity coresidence in the neighborhoods of multiethnic metropolitan areas. PMID- 8690140 TI - Immigration cohorts and residential overcrowding in southern California. AB - To what degree do immigrants reduce their high rates of residential overcrowding with increasing length of residence in the United States? This question is addressed through the application of a "double cohort" method that nests birth cohorts within immigration cohorts. This method enables duration of immigration effects to be separated from aging effects as cohorts pass through life course phases, when family sizes may be growing or shrinking. The analysis finds that cohort trends differ sharply from the cross-sectional pattern observed at a single point in time. Cohorts' growth in income is found to contribute substantially to the decline in overcrowding over time. Cohort trends among Hispanic immigrants, however, diverge from those among others, indicating much less decrease in overcrowding and even increases over certain age spans. PMID- 8690141 TI - The influence of parents' martial dissolutions on children's attitudes toward family formation. AB - We investigate the influence of parents' martial dissolutions on their children's attitudes toward several dimensions of family formation. Hypotheses focus on the role of patients' attitudes as a mechanism linking parents' behavior to their children's attitudes. We test these hypotheses using intergenerational panel data that include measures of children's attitudes taken directly from children. Results demonstrate strong effects of parental divorce, remarriage, and widowhood on children's attitudes toward premarital sex, cohabitation, marriage, childbearing, and divorce. The results also show that parents' own attitudes link their behavior to their children's attitudes, although substantial effects of parental behavior remain after controlling for parents' attitudes. PMID- 8690142 TI - Economic incentives for financial and residential independence. AB - In this paper we examine the impact of the resource of children and of their parents on the children's transition to residential and financial independence. Previous studies of this transition focused primarily on the impact of family structure and parent-child relationships on the decision to leave home, but much less in known about the role of economic factors in the transition to independence. Using data from the Panel Study of Income Dynamics (PSID) for the period 1968-1988, we estimate discrete-hazard models of the probability of achieving residential and financial independence. We find that the child's wage opportunities and the parents' income are important determinants of establishing independence. The effect of parental income changes with the child's age. We also find some evidence that federal tax policy influences the decision to become independent, although the magnitude of this effect is quite small. PMID- 8690143 TI - Estimating seasonality effects on child mortality in Matlab, Bangladesh. AB - This paper estimates the net effect of seasonality on child morality in Matlab. Results suggest that childhood mortality was well above average monthly level in the hot, dry month of April and in November, the first harvest month of the aman crop. It was found to be remarkably low in the postharvest months of February and March, and also in August. During the hungry months of September and October, children were at a considerably increased risk of mortality, particularly from diarrheal diseases, if mothers had no schooling, but this was not the case if mothers had schooling. The protective effect of the Matlab interventions on childhood death from diarrheal diseases was also greater during the hungry months than during other months of the year. PMID- 8690144 TI - Hexosamines and insulin resistance. AB - Glucose is an important regulator of cell growth and metabolism. Thus, it is likely that some of the adverse effects of hyperglycemia are reflections of normal regulation by abnormal concentrations of glucose. How the cell senses glucose, however, is still incompletely understood. Evidence has been presented that the hexosamine biosynthesis pathway serves this function for regulation of aspects of glucose uptake, glycogen synthesis, glycolysis, and synthesis of growth factors. Excess hexosamine flux causes insulin resistance in cultured cells, tissues, and intact animals. Further evidence for the possible role of this pathway in normal glucose homeostasis and disease is that the level of activity of the rate-limiting enzyme in hexosamine synthesis, glutamine:fructose 6-phosphate amidotransferase, is correlated with glucose disposal rates (GDRs) in normal humans and transgenic mice. PMID- 8690145 TI - Low insulin secretion and high fasting insulin and C-peptide levels predict increased visceral adiposity. 5-year follow-up among initially nondiabetic Japanese-American men. AB - Insulin resistance and hyperinsulinemia occur more frequently in subjects with greater visceral adiposity, but it is not known whether these metabolic abnormalities precede or follow visceral fat accumulation. We prospectively studied the development of visceral adiposity in relation to fasting and stimulated insulin and C-peptide levels. We followed 137 nondiabetic, second generation Japanese-American men for changes in visceral adiposity over 5 years. Intra-abdominal fat (IAF) area (square centimeters) was measured at the umbilicus by computed tomography at baseline and after 5 years. Plasma insulin and C peptide levels were measured after an overnight fast and during an oral glucose tolerance test. Beta-cell function was measured by the insulin secretion ratio (30-0 min plasma insulin difference)/(30-0 min plasma glucose difference). After adjustment for baseline IAF in multiple linear regression models, baseline fasting insulin (coefficient = 0.241, P = 0.048) and C-peptide (coefficient = 38.538, P < 0.001) levels were positively correlated, while the baseline insulin secretion ratio was negatively correlated with IAF change (coefficient = -0.099, P = 0.027). With IAF difference coded as a dichotomous variable (> 0 cm2 vs. < or = 0 cm2), the highest versus lowest tertile of baseline fasting insulin (odds ratio [OR] = 3.0, 95% CI 1.0-9.7) and fasting C-peptide (OR = 8.1, 95% CI 2.4 26.8) levels and the lowest versus highest tertile of the insulin secretion ratio (OR = 3.3, 95% CI 1.0-10.0) were associated with higher odds of IAF gain. Greater insulin resistance and reduced insulin secretion precede visceral fat accumulation in nondiabetic Japanese-American men. PMID- 8690146 TI - Identification and characterization of vascular endothelial growth factor receptor (Flt) in bovine retinal pericytes. AB - Vascular endothelial growth factor (VEGF) plays an important role in the hypoxia stimulated neovascularization of ischemic retinal diseases such as proliferative diabetic retinopathy. VEGF exerts its effect through two known high-affinity tyrosine kinase receptors, named kinase insert domain-containing receptor (KDR) and the fms-like tyrosine kinase (Flt). VEGF receptors are located primarily on endothelial cells, although receptors on a few other nonocular cell types also have been described. In the present study, we demonstrate the expression of Flt, but not KDR, in bovine retinal pericytes (BRPCs). Although KDR is expressed predominantly in retinal endothelial cells, Northern blot analysis demonstrated substantial expression of the Flt gene in BRPCs without detection of KDR despite using polyadenylated RNA. Hypoxia increased Flt gene expression in BRPCs (2.7 fold, P < 0.01). 125I-labeled VEGF binding analysis on BRPCs demonstrated two apparent high-affinity receptor subtypes (Kd = 14 and 215 pmol/l), with 2.9 x 10(4) and 1.4 x 10(5) receptors/cell, respectively. 125I-VEGF affinity cross linking demonstrated VEGF-specific binding complexes at 150, 172, 187, and 200 kDa under reducing conditions. Western blot analysis using an anti phosphotyrosine antibody demonstrated VEGF-induced tyrosine phosphorylation of several proteins. VEGF stimulation had little effect on initial BRPCs growth rates but significantly increased BRPCs number after 7 days. These results suggest that two classes of high-affinity VEGF receptors are present on BRPCs, at least one of which is analogous to Flt and is capable of intracellular protein phosphorylation. Thus, VEGF might regulate the function of both retinal endothelial cells and retinal pericytes to induce pathological angiogenesis and vascular remodeling during proliferative diabetic retinopathy and other ischemic retinal diseases. PMID- 8690147 TI - The antioxidant alpha-lipoic acid enhances insulin-stimulated glucose metabolism in insulin-resistant rat skeletal muscle. AB - Insulin resistance of muscle glucose metabolism is a hallmark of NIDDM. The obese Zucker (fa/fa) rat--an animal model of muscle insulin resistance--was used to test whether acute (100 mg/kg body wt for 1 h) and chronic (5-100 mg/kg for 10 days) parenteral treatments with a racemic mixture of the antioxidant alpha lipoic acid (ALA) could improve glucose metabolism in insulin-resistant skeletal muscle. Glucose transport activity (assessed by net 2-deoxyglucose [2-DG] uptake), net glycogen synthesis, and glucose oxidation were determined in the isolated epitrochlearis muscles in the absence or presence of insulin (13.3 nmol/l). Severe insulin resistance of 2-DG uptake, glycogen synthesis, and glucose oxidation was observed in muscle from the vehicle-treated obese rats compared with muscle from vehicle-treated lean (Fa/-) rats. Acute and chronic treatments (30 mg.kg-1.day-1, a maximally effective dose) with ALA significantly (P < 0.05) improved insulin-mediated 2-DG uptake in epitrochlearis muscles from the obese rats by 62 and 64%, respectively. Chronic ALA treatment increased both insulin-stimulated glucose oxidation (33%) and glycogen synthesis (38%) and was associated with a significantly greater (21%) in vivo muscle glycogen concentration. These adaptive responses after chronic ALA administration were also associated with significantly lower (15-17%) plasma levels of insulin and free fatty acids. No significant effects on glucose transporter (GLUT4) protein level or on the activities of hexokinase and citrate synthase were observed. Collectively, these findings indicate that parenteral administration of the antioxidant ALA significantly enhances the capacity of the insulin-stimulatable glucose transport system and of both oxidative and nonoxidative pathways of glucose metabolism in insulin-resistant rat skeletal muscle. PMID- 8690148 TI - Impact of recent antecedent hypoglycemia on hypoglycemic cognitive dysfunction in nondiabetic humans. AB - To test the hypothesis that glycemic thresholds for hypoglycemic cognitive dysfunction, like those for neuroendocrine responses to and symptoms of hypoglycemia, shift to lower plasma glucose concentrations after recent antecedent hypoglycemia, 16 healthy young adult subjects (7 women and 9 men) were studied on two separate occasions in random sequence, once with hyperinsulinemic hypoglycemia (2.6 +/- 0.1 mmol/l, 47 +/- 1 mg/dl) and once with otherwise identical hyperinsulinemic euglycemia (4.8 +/- 0.1 mmol/l, 86 +/- 5 mg/dl) between 1430 and 1630. Neuroendocrine, symptomatic, and cognitive responses to hyperinsulinemic stepped hypoglycemic (4.7, 4.2, 3.6, 3.0, 2.8, 2.5, and 2.2 mmol/l; 85, 75, 65, 55, 50, 45, and 40 mg/dl) clamps were quantitated the following morning on both occasions. Cognitive function tests included measures of information processing (Serial Addition), attention (Stroop Arrow Word), pattern recognition and memory (Delayed Non-Match to Sample), and declarative memory (Paragraph Recall). As expected, plasma glucagon (P = 0.0094), epinephrine (P = 0.0063), and pancreatic polypeptide (P = 0.0046) responses to stepped hypoglycemia were reduced significantly, and symptomatic responses tended to be reduced after afternoon hypoglycemia. Performance on the cognitive function tests deteriorated (P < 0.0001) during stepped hypoglycemic clamps, but there were no significant overall effects of antecedent hypoglycemia on hypoglycemic cognitive dysfunction. Although deterioration was reduced (P < 0.05) from the 2.8 mmol/l (50 mg/dl) to the 2.5 mmol/l (45 mg/dl) steps on the Serial Addition and Delayed Non-Match to Sample tasks after afternoon hypoglycemia, comparable differences were not found on the Stroop Arrow Word or Paragraph Recall tasks. Thus, glycemic thresholds for hypoglycemic cognitive dysfunction, unlike those for neuroendocrine responses to and symptoms of hypoglycemia, do not seem to shift to substantially lower plasma glucose concentrations after recent antecedent hypoglycemia in nondiabetic humans. PMID- 8690149 TI - Advanced glycation end products of the Maillard reaction in aortic pepsin insoluble and pepsin-soluble collagen from diabetic rats. AB - Recent immunohistological studies using antibodies against advanced glycation end products (AGEs) have demonstrated the presence of AGEs in several tissues. By an enzyme-linked immunosorbent assay using the monoclonal anti-AGE antibody, the present study aimed to determine AGEs in pepsin-insoluble collagen (PIC) as well as in pepsin-soluble collagen (PSC) from the aortas of streptozotocin (STZ) induced diabetic rats (at 4, 16, and 28 weeks after STZ injection) and those of age-matched control rats. Addition of EDTA to the immunoassay buffer has led us to successful determination of AGEs in the aortic PIC samples with following results: 1) in diabetic rats, there was a time-related increase in the AGE contents at 28 weeks (n = 9, 226.4 +/- 13.5 ng/mg collagen [mean +/- SE]), compared with that at 4 and 16 weeks (n = 6, 79.6 +/- 9.5 ng/mg collagen, and n = 8, 149.4 +/- 30.9 ng/mg collagen at 4 and 16 weeks, respectively; both P < 0.05, between 4 and 16 weeks and 28 weeks); 2) after 28 weeks of diabetes, the AGE contents in PIC of aortas were significantly higher in diabetic rats than in controls (n = 9, 226.4 +/- 13.5 ng/mg collagen vs. n = 8, 129.6 +/- 14.9 ng/mg collagen, P < 0.01, diabetic vs. control); and 3) the level of the AGE content was strongly correlated with the PIC/total collagen (TC) ratio (n = 45, r = 0.698, P = 0.0001). By treating the samples of PSC with alkaline solution, the AGE content of PSC was also determined. In the PSC fraction, the AGE levels in the diabetic rats tended to increase with time and to be higher than those of control rats at 28 weeks although these changes were not statistically significant (diabetic: n = 4, 19.4 +/- 9.7; n = 6, 22.3 +/- 6.2; n = 6, 39.6 +/- 10.8; control: n = 4, 19.7 +/- 9.8; n = 6, 22.9 +/- 7.3; n = 7, 30.7 +/- 7.2; at 4, 16, and 28 weeks, respectively). Compared with the AGE levels of PSC, those of PIC were about four to seven times and four to five times higher in diabetic and control rats, respectively (PIC versus PSC in diabetic or control rats, all P < 0.001, at 4, 16, and 28 weeks, respectively). These findings provide the first immunochemical evidence that AGE adducts are present in the materials extracted sequentially by pepsin and collagenase and that these adducts in PIC accumulated as a function of the increase in the aortic PIC/TC ratio. PMID- 8690150 TI - Evidence for a circadian rhythm of insulin sensitivity in patients with NIDDM caused by cyclic changes in hepatic glucose production. AB - Diurnal variation in insulin sensitivity in patients with NIDDM has long been suspected but has been difficult to document mainly because of the interdependence of changes in glucose and insulin. Stable serum insulin levels during hyperglycemic clamping in patients with NIDDM in the present study provided the opportunity to examine changes in insulin sensitivity unaffected by changes in blood glucose and insulin concentrations. Six patients with NIDDM (four men and two women, BMI 33.9 +/- 2.5) underwent hyperglycemic (11.1 mmol/l, approximately 200 mg/dl) clamping for 72 h. Measured were serum insulin, free fatty acid (FFA), cortisol, and growth hormone concentrations and rates of insulin secretion, insulin clearance, and glucose infusion rate (GIR) needed to maintain hyperglycemia. In addition, five patients (three men and two women, BMI 32.6 +/- 0.6) underwent hyperglycemic clamping for 24 h with hourly determinations of hepatic glucose production (HGP) and glucose disappearance rates (GRd). GIR, reflecting insulin sensitivity, changed rhythmically with a cycle duration of 22.9 +/- 1.4 h and an amplitude of 47.8 +/- 11.2%. GIR was lowest at 8:31 a.m. (+/- 52 min) and highest at 7:04 p.m. (+/- 58 min). Circadian changes in GIR were completely accounted for by changes in HGP, while GRd remained unchanged. Plasma levels of FFAs and cortisol also exhibited circadian fluctuations, and their blood levels correlated negatively with GIR (r = -0.72 and -0.64, respectively). We concluded that insulin sensitivity in patients with NIDDM changed with circadian (approximately 24 h) rhythmicity (decreasing during the night and increasing during the day). These changes were unrelated to blood levels of glucose and insulin, insulin clearance, exercise, food intake, and sleep. They were caused by circadian changes in HGP, which in turn were closely correlated with circadian changes in blood FFA and cortisol levels. We believe that recognition of these circadian changes has implications for the diagnosis and the treatment of patients with NIDDM. PMID- 8690151 TI - Glucose ingestion causes GLUT4 translocation in human skeletal muscle. AB - In humans, ingestion of carbohydrates causes an increase in blood glucose concentration, pancreatic insulin release, and increased glucose disposal into skeletal muscle. The underlying molecular mechanism for the increase in glucose disposal in human skeletal muscle after carbohydrate ingestion is not known. We determined whether glucose ingestion increases glucose uptake in human skeletal muscle by increasing the number of glucose transporter proteins at the cell surface and/or by increasing the activity of the glucose transporter proteins in the plasma membrane. Under local anesthesia, approximately 1 g of vastus lateralis muscle was obtained from six healthy subjects before and 60 min after ingestion of a 75-g glucose load. Plasma membranes were isolated from the skeletal muscle and used to measure GLUT4 and GLUT1 content and glucose transport in plasma membrane vesicles. Glucose ingestion increased the plasma membrane content of GLUT4 per gram muscle (3,524 +/- 729 vs. 4,473 +/- 952 arbitrary units for basal and 60 min, respectively; P < 0.005). Transporter-mediated glucose transport into plasma membrane vesicles was also significantly increased (130 +/- 11 vs. 224 +/- 38 pmol.mg-1.s-1; P < 0.017), whereas the calculated ratio of glucose transport to GLUT4, an indication of transporter functional activity, was not significantly increased 60 min after glucose ingestion (2.3 +/- 0.4 vs. 3.0 +/- 0.5 pmol.GLUT4 arbitrary units-1.s-1; P < 0.17). These results demonstrate that oral ingestion of glucose increases the rate of glucose transport across the plasma membrane and causes GLUT4 translocation in human skeletal muscle. These findings suggest that under physiological conditions the translocation of GLUT4 is an important mechanism for the stimulation of glucose uptake in human skeletal muscle. PMID- 8690152 TI - Lithium stimulation of rat pancreatic beta-cell replication is mediated through pertussis toxin-sensitive GTP-binding proteins and occurs independently of Ca2+ influx, cAMP, or protein kinase C activation. AB - We recently demonstrated the mitogenic and secretagogic actions of lithium in the insulin-producing pancreatic beta-cell (Sjoholm A, Welsh N, Hellerstrom C: Lithium increases DNA replication, polyamine content and insulin secretion by rat pancreatic beta-cells in vitro. Am J Physiol 262:C391-C395, 1992). In this study, the influence of lithium on beta-cell signal transduction pathways was monitored and their importance for the stimulated cell replication and hormone secretion was elucidated by selective pharmacological probes. To this end, fetal rat pancreatic islets enriched in beta-cells were isolated and cultured for 3 days with or without 10 mmol/l LiCl. This resulted in a marked mitogenic response by the beta-cells, of similar magnitude to that obtained by pharmacological activation of cAMP-dependent protein kinases by forskolin or the Sp-diastereomer of cAMP or protein kinase C stimulation by phorbol ester. However, neither did lithium affect the islet content of cAMP (whereas forskolin did), nor was the mitogenic response to the ion impeded when islets were pretreated with the Rp diastereomer of cAMP, a specific antagonist of cAMP-dependent protein kinases, or by the Ca2+ channel blocker D-600. The protein kinase C inhibitor 1-(5' isoquinolinesulfonyl)-2-methylpiperazine prevented the mitogenicity of phorbol ester, but not that of lithium. Conversely, addition of increasing concentrations of inositol along with lithium also did not affect the mitogenicity of the ion, providing indirect evidence against the involvement of protein kinase C in mediating the growth-promoting effect of lithium in this system. It was found that pretreatment of islets with pertussis toxin, which inactivates GTP-binding proteins by ADP-ribosylation, prevented the mitogenicity and part of the secretagogic action of lithium. It is concluded that although specific activation of the cAMP and protein kinase C signaling systems appears sufficient to trigger a mitogenic response of the beta-cell, lithium seemingly does not work through any of these systems nor via Ca2+ influx in promoting beta-cell mitogenesis. Our results, moreover, suggest that the actions of lithium are conveyed by pertussis toxin-sensitive GTP-binding proteins. PMID- 8690153 TI - Beta-cell destruction may be a late consequence of the autoimmune process in nonobese diabetic mice. AB - The NOD mouse is an animal model of IDDM that shows many of the characteristics of human IDDM. It has been proposed that beta-cell destruction in IDDM progresses over time in a linear manner. Recently, we and others have demonstrated that T helper type 1 (Th1) cells have pathogenic roles in the NOD model and proposed that cytokine balances change as the disease progresses. However, it has not been demonstrated how or when the cytokine balances change or how the beta-cell destruction progresses. We have recently demonstrated that the cytokine profiles of CD45RB(low) CD4+ cells correlate either with their pathogenic or with their protective roles in the NOD mouse. To further analyze this apparent correlation between the shift in cytokine level and IDDM, we examined the anti-CD3-induced cytokine profiles of this subset from NOD mice of various ages compared with that from age-matched I-Ak transgenic NOD and BALB/c mice as controls. A significantly higher ratio of anti-CD3-induced interferon-gamma/interleukin-4 was found in diabetic NOD mice (P < 0.0001) but not in age-matched nondiabetic NOD mice. This cytokine ratio did not change significantly until the onset of diabetes in NOD mice. Based upon these results, we propose that IDDM in the NOD mouse progresses as a predominant inflammatory beta-cell dysfunction without actual beta-cell destruction until late in the disease process. This supports the possibility that late-stage immunotherapy may preserve islet beta-cell mass. PMID- 8690154 TI - Glucose regulates the maximal velocities of glucokinase and glucose utilization in the immature fetal rat pancreatic islet. AB - The cause of the poor secretion of insulin in response to glucose by the beta cell in the fetal rat pancreas is thought to be immaturity of the metabolism of glucose. Glucokinase (GK), a key enzyme in glycolysis, is the glucose sensor that maintains glucose homeostasis in the adult beta-cell; its role in the fetal beta cell has not been determined. The aim of this study was to examine whether GK was functional in phosphorylation of glucose in the fetal islet, and if so, to determine what factors regulated this activity. Similar Km values were found in both fetal and adult islets: 7.4 vs. 7.7 mmol/l. The maximal GK velocity (Vmax) of the fetal islet and the contribution of GK to total glucose phosphorylation were also not significantly different from their adult counterparts. Western blot analysis of protein extracts from fetal and adult islets confirmed the presence of GK at 52 kDa. To determine if glucose had any effect on the Vmax of GK, islets were cultured for 7 days in medium containing low (1.4 or 2.8 mmol/l), normal (5.6 mmol/l), or high (11.2 or 16.8 mmol/l) concentrations of glucose. The maximal GK velocity increased linearly with increasing concentrations of glucose (r = 0.93; P < 0.01). To determine whether it was possible to up- and down regulate Vmax of GK, islets were cultured in either a low (1.4 mmol/l) or high (30 mmol/l) concentration of glucose for 7 days and then switched to the opposite concentration for a further 3 days. The Vmax of GK in the fetal islet was upregulated 3.8-fold when the glucose concentration was raised. Conversely, the Vmax was downregulated 3.6-fold when the glucose concentration was lowered. The same phenomenon was also observed in the adult islet. These data indicate that GK is the glucose sensor for the fetal rat islet, just as it is for the adult islet. Since glucose did not cause insulin secretion from the fetal islet, it was important to examine whether this substrate had any effect on its own metabolism. Glucose utilization was estimated, and its Vmax was found to increase linearly with increasing concentrations of glucose (r = 0.96; P < 0.01). We conclude that the inability of the fetal rat beta-cell to secrete insulin in response to glucose cannot be explained by immaturity of GK or the glycolytic pathway. PMID- 8690155 TI - Evidence for a major role for glucagon in regulation of plasma glucose in conscious, nondiabetic, and alloxan-induced diabetic rabbits. AB - Effects of glucagon immunoneutralization on plasma glucose, insulin, and glucagon were studied 2-4 h after intravenous injection of a high-affinity, monoclonal glucagon antibody into normal as well as moderately and severely alloxan (ALX) induced diabetic rabbits (n = 5-7). A monoclonal trinitrophenyl antibody was used in control studies. Endogenous glucagon was completely neutralized as evidenced by undetectable levels of free glucagon and high plasma glucagon-binding capacities. In postabsorbtive normal rabbits, glucagon neutralization decreased plasma glucose by 2.2 +/- 0.3 mmol/l, and the resulting plasma levels of insulin and glucagon (indirectly measured) were 8 +/- 3 and 640 +/- 129% of baseline, respectively. However, when euglycemia was maintained by means of glucose infusion (steady-state plasma glucose and glucose infusion rate: 6.6 +/- 0.1 mmol/l and 3.0 +/- 0.4 mg.kg-1.min-1), both plasma insulin and glucagon remained unaltered. Thus, the glucose infusion rate accurately reflects glucagon's contribution to postabsorbtive glucose production. In both moderately and severely diabetic rabbits, immunoneutralization of glucagon decreased plasma glucose by approximately 8 mmol/l, leading to euglycemia (7.3 +/- 1.1 mmol/l) and reduced hyperinsulinemia (41 +/- 9% of baseline) in the former and to partial restoration of euglycemia (12.7 +/- 1.8 mmol/l) and unchanged insulin levels in the latter group of diabetic rabbits (P < 0.05 vs. controls in all studies). No significant changes were observed in control studies. In conclusion, glucagon is an important regulator of postabsorbtive glucose production in normal rabbits and plays an important role in the maintenance of hyperglycemia in ALX-induced diabetic rabbits. PMID- 8690156 TI - The insulin-mimetic agent vanadate promotes receptor endocytosis and inhibits intracellular ligand-receptor degradation by a mechanism distinct from the lysosomotropic agents. AB - Vanadate (sodium orthovanadate) is an insulin-mimetic agent and phosphotyrosine phosphatase inhibitor that has been proposed as a potential therapeutic agent for diabetes. We previously reported that vanadate decreased the number of cell surface insulin receptors but inhibited receptor degradation in cultured lymphocytes (IM-9) (1). To determine whether vanadate affected receptors without intrinsic tyrosine kinase activity, its effects on LDL and transferrin receptors and their ligands were examined. Vanadate exposure resulted in a dose- and time dependent decrease in LDL binding to cultured human fibroblasts associated with a decrease in cell surface receptor number while total solubilized cell LDL receptors increased. Vanadate also inhibited the LDL-mediated downregulation of total cellular LDL receptors in the absence and presence of cycloheximide consistent with an inhibition of LDL receptor degradation. In the case of the ligand, vanadate augmented the accumulation of intact 125I-LDL associated with an inhibition of up to 80% of the ability of LDL to decrease cholesterol synthesis. Since these actions were similar to the effects of lysosomotropic agents, we examined the effect of vanadate on intraendosomal pH using the fluorescent probe acridine orange. In contrast with chloroquine and NH4Cl, vanadate did not neutralize the pH of the acidic intracellular compartment. Furthermore, after a transient insulin-like effect, chronic exposure to vanadate diminished 125I diferric transferrin binding to rat adipocytes. In contrast with the inhibitory action of NH4Cl, intracellular 59Fe uptake remained unaffected and was proportional to cell-surface binding capacity in the presence of vanadate. These data demonstrate a chronic effect of vanadate to promote the accumulation of intracellular receptors and to inhibit ligand and receptor degradation. The latter effect is not mediated by pH changes, appears to be localized to a late endosomal/lysosomal compartment, and suggests a possible role for tyrosine dephosphorylation in the regulation of receptor-ligand degradation. PMID- 8690157 TI - Treatment with growth hormone and dexamethasone in mice transgenic for human islet amyloid polypeptide causes islet amyloidosis and beta-cell dysfunction. AB - Islet amyloid derived from islet amyloid polypeptide (IAPP) is a well-recognized feature of type II diabetes. However, the mechanism of islet amyloidogenesis is unknown. In vitro studies suggest that amino acid residues 20-29 in human, but not mouse, IAPP confer amyloidogenicity consistent with the absence of spontaneous islet amyloidosis in mice. Several clinical and in vitro studies suggest that increased synthetic rates of IAPP predispose to IAPP-amyloidosis. In the present study, we sought to test the hypothesis that pharmacological induction of insulin resistance in a mouse transgenic (TG) for human IAPP would induce islet amyloid and beta-cell dysfunction. TG and non-transgenic (N-TG) control mice were treated with both rat growth hormone (12 micrograms/day) and dexamethasone (0.24 mg/day) (dex/GH) or received no treatment for 4 weeks, after which animals were killed to examine islet morphology. Treatment with dex/GH caused hyperglycemia (7.3 +/- 0.4 vs. 5.2 +/- 0.1 mmol/l, TG vs. N-TG, P < 0.001) associated with a decreased plasma insulin concentration (595 +/- 51 vs. 996 +/- 100 pmol/l, TG vs. N-TG, P < 0.05) in TG versus control mice. Islet amyloid was induced in treated TG mice but not in control mice. Islet amyloid was identified in both intra- and extracellular deposits, the former being associated with evidence of beta-cell degeneration. We conclude that dex/GH treatment in mice TG for human IAPP induces IAPP-derived islet amyloid, hyperglycemia, and islet dysfunction. The present model recapitulates the islet morphology and phenotype of type II diabetes. PMID- 8690158 TI - Kinetics of intraperitoneally infused insulin in rats. Functional implications for the bioartificial pancreas. AB - Intraperitoneal transplantation of encapsulated islets can restore normoglycemia in diabetic recipients but not normal glucose tolerance nor normal insulin responses to a physiological stimulus. This study investigates whether the intraperitoneal implantation site as such contributes to the interference with optimal transport kinetics between the islets and the bloodstream. Insulin was infused into the peritoneal cavity of conscious and freely moving rats in doses of 20, 40, and 80 pmol.l-1.min-1 during 15 min, to mimic the gradual release of insulin from an encapsulated, i.e., a nonvascularized, islet graft. With 20 pmol.l-1.min-1, we observed virtually no rise of insulin levels, and it took 30 min until glucose levels had dropped significantly. With 40 and 80 pmol.l-1.min-1 insulin infusions, there was a dose-dependent rise of insulin and decrease of glucose levels. When compared with intraportal infusions with the same insulin dosages, however, they were strongly delayed and reduced as well as prolonged. Similar results were obtained when inulin instead of insulin was intraperitoneally infused, with indicates that the transport of insulin from the peritoneal cavity to the bloodstream is mainly by passive diffusion. With a view on the clinical efficacy of the bioartificial pancreas, our findings indicate that we should focus on finding or creating a transplantation site that, more than the unmodified peritoneal cavity, permits close contact between the bloodstream and the encapsulated islet tissue. PMID- 8690159 TI - Ductal cyst formation in collagen-embedded adult human islet preparations. A means to the reproduction of nesidioblastosis in vitro. AB - Neogenesis of endocrine islets from ductal epithelium termed nesidioblastosis has been described in vivo after various experimental conditions (90% pancreatectomy or pancreas wrapping in the rodent) and in clinical pathologies. In the adult regenerating pancreas, a proliferation and organization of ductal epithelium into tubular structures precedes its differentiation into endocrine cells. Reproduction of nesidioblastosis in vitro may provide a novel approach to human islet propagation in vitro. With this aim, adult human islet preparations were cultured in diverse three-dimensional (3D) gels in the presence of serum. After 3 5 days in rat tail collagen gels, proliferating (bromodeoxyuridine-positive) cystic structures appeared associated with islets and as isolated spheres. Percentage labeling indexes of the cysts were 4.1, 18.7, 15.4, and 13.3% after 3, 5, 7, and 10 days of culture, respectively. Immunohistochemistry confirmed the ductal (carbohydrate antigen 19-9) and epithelial (keratin-1) nature of the cysts. No cysts were formed in agarose gels or Vitrogen 100, whereas the cyst number was increased by the quantity of serum (20% > 10%) and gels rich in extracellular matrix components and growth factors (Matrigel). The latter lead to tubular networks. Single endocrine islet cells were observed in the ductal cysts after 7 (2.8%) to 10 (5.6%) days in rat tail collagen. Our observations paralleled the changes characteristic of the regenerating pancreas in vivo. 3D culture may permit the identification of matrix and media constituents promoting the neogenesis of islets and may be the means to increase the mass of endocrine tissue obtained from adult cadaveric pancreases for transplantation. PMID- 8690160 TI - Insulin sensitivity and body weight changes in young white carriers of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor gene. AB - Recently, a missense mutation replacing tryptophan with arginine at codon 64 of the beta 3-adrenergic receptor gene was shown to be associated with insulin resistance in nondiabetic subjects and to an earlier onset of NIDDM in Pima Indians. We studied whether the codon 64 amino acid polymorphism of the beta 3 adrenergic receptor gene in a cohort of young healthy Danes was associated with high birth weight, accelerated weight gain during childhood and adolescence, present obesity, or impaired insulin sensitivity. The protocol included 380 unrelated white subjects in whom insulin sensitivity and secretion were measured during a combined intravenous glucose and tolbutamide tolerance test. A number of biochemical and anthropometric characteristics were determined for each subject. The subjects were genotyped for the codon 64 polymorphism by applying polymerase chain reaction restriction fragment-length polymorphism screening with the use of endonuclease BstN1. The allelic frequency of the mutated allele was 7% (95% CI: 5 10%), and it was similar in obese and nonobese subjects. The beta 3-adrenergic receptor gene variant was not related to birth weight or weight gain during childhood or adolescence. In its heterozygous form, the gene variant was not associated with an altered insulin sensitivity index (SI) or other features of the insulin resistance syndrome (BMI, blood pressure, fasting serum lipid levels, or fasting serum fibrinolytic variables). Three homozygous carriers of the polymorphism were identified, and each had a significantly higher BMI (27.4 +/- 1.3 vs. 23.5 +/- 3.7 kg/m2 [mean +/- SD]; P = 0.032), lower SI [4.9 +/- 2.9 vs. 15.4 +/- 9.0 10(-5) x (min x pmol/l)-1; P = 0.013], and higher fasting serum C peptide (730 +/- 155 vs. 471 +/- 158 pmol/l; P = 0.016) than the wild-type carriers. The homozygous carriers also had significantly higher levels of fasting serum triglyceride (P = 0.042) and serum LDL cholesterol (P = 0.013). When adjustments were made for age, sex, BMI, and VO2max in a multiple regression analysis, a significantly negative association was found between homozygosity for the codon 64 variant and the SI (P = 0.009). We conclude that in young healthy Danes, the homozygous form but not the heterozygous form of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor may be associated with obesity and, independent of BMI, with a low SI. Since only three homozygous carriers were identified among 380 subjects, the results must be interpreted with caution, and studies of larger population samples are needed. PMID- 8690161 TI - Major histocompatibility complex class I-restricted infiltration and destruction of pancreatic islets by NOD mouse-derived beta-cell cytotoxic CD8+ T-cell clones in vivo. AB - NOD mouse-derived beta-cell-specific cytotoxic T-cell (beta-CTL) clones are diabetogenic in adult NOD mice, but only if co-injected with splenic CD4+ T-cells from diabetic animals. This investigation was initiated to determine whether infiltration of pancreatic islets by beta-CTL is a major histocompatibility complex (MHC) class I-restricted response, and whether beta-CTL has a direct cytopathic effect on beta-cells in vivo. Pancreatic islets from BALB/c (H-2d) or B6 (H-2b) mice were transplanted under the renal capsule of streptozotocin (STZ) induced diabetic (NOD x BALB/c) F1 (H-2Kd, H-2Dd,b) or NOD x B6) F1 (H-2Kd,b, H 2Db) mice, respectively. H-2Kd-restricted beta-CTL clones from NOD mice were transfused into euglycemic mice within 3 days after transplantation. In all of the H-2d islet-grafted (NOD x BALB/c) F1 mice that received the beta-CTL clones, the beta-CTLs homed into the grafts, recruited host Mac-1+ cells and CD4+ and CD8+ T-cells, and caused diabetes within 7 days. In contrast, none of the H-2b islet-grafted (NOD x B6) F1 mice who received the beta-CTL clones and none of the H-2d islet-grafted (NOD x BALB/c) F1 mice who received a non-beta-cell cytotoxic CTL clone (N beta-CTL) developed graft inflammation or diabetes. Depletion of CD4+ T-cells in H-2d islet-grafted (NOD x BALB/c) F1 mice did not prevent beta CTL clone-induced diabetes but reduced its severity. In contrast, when the beta CTL clones were injected > 8 days after transplantation, none of the H-2d islet grafted (NOD x BALB/c) F1 mice became diabetic or developed graft inflammation. We conclude that (1) islet-derived beta-CTLs can destroy beta-cells in vivo; (2) infiltration of grafted islets by beta-CTLs is an MHC class I-restricted response; (3) beta-CTLs can recruit naive CD4+ T-cells to the site, leading to further beta-cell damage; and (4) revascularized islet grafts are, like pancreatic islets of irradiated adult NOD mice, "sequestered" from circulating beta-CTLs. PMID- 8690162 TI - Characterization of a novel glucose-responsive insulin-secreting cell line, BRIN BD11, produced by electrofusion. AB - A novel insulin-secreting cell line (BRIN-BD11) was established after electrofusion of RINm5F cells with New England Deaconess Hospital rat pancreatic islet cells. Wells of cell fusion mixture with insulin output 5-10 times greater than parent RINm5F cells were subcultured with eventual establishment of clones, including BRIN-BD11. Morphological studies established that these cells grow as monolayers with epithelioid characteristics, maintaining stability in tissue culture for > 50 passages. Culture of these cells for 24 h at 5.6-33.3 mmol/l glucose revealed a 1.8- to 2.0-fold increase of insulin output compared with 1.4 mmol/l glucose. Dynamic insulin release was recorded in response to 16.7 mmol/l glucose, resulting in a rapid threefold insulin secretory peak followed by a sustained output slightly above basal. In acute 20-min tests, 4.2-16.7 mmol/l glucose evoked a stepwise two- to three-fold stimulation of insulin release. 3 Isobutyl-1-methylxanthine (1 mmol/l) served to increase basal and glucose stimulated insulin release, shifting the threshold from 4.4 to 1.1 mmol/l glucose. Stimulation of insulin secretion with 16.7 mmol/l glucose was abolished by mannoheptulose or diazoxide (15 or 0.5 mmol/l). In contrast, glyceraldehyde (10 mmol/l) and 25 mmol/l K+ evoked 1.7- to 9.0-fold insulin responses. L-Alanine (10 mmol/l) evoked a twofold secretory response, which was potentiated 1.4-fold by increasing the Ca2+ concentration from 1.28 to 7.68 mmol/l. Forskolin (25 mumol/l) and phorbol 12-myristate 13-acetate (10 nmol/l) both increased insulin secretion in the presence of L-alanine (1.4- and 1.8-fold, respectively). Western blotting confirmed that BRIN-BD11 cells expressed the GLUT2 glucose transporter. This, coupled with a high glucokinase/hexokinase ratio in the cells, confirms an intact glucose sensing mechanism. High-performance liquid chromatography analysis demonstrated that insulin was the major product secreted under stimulatory conditions. Collectively, these data indicate that the BRIN-BD11 cell line represents an important stable glucose-responsive insulin-secreting beta-cell line for future studies. PMID- 8690163 TI - Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr). AB - The rat fatty (fa) mutation produces profound obesity of early onset caused by hyperphagia, defective nonshivering thermogenesis, and preferential deposition of energy into adipose tissue. Genetic mapping studies indicate that fa and diabetes (db) are homologous loci in the rat and mouse genomes, respectively. It has been shown that db alleles carry mutations in the Lepr (leptin receptor) gene. This paper describes a point mutation in the fatty allele of Lepr. A nucleotide substitution at position 880 (A-->C) causes an amino acid substitution at position 269 (Gln-->Pro). The mutation generates a novel Msp I site that cosegregates with fa in 1,028 meioses examined in obese F2 progeny from two crosses (Bnx13M and WKYx13M) and is still segregating in three rat colonies. PCR based mutagenesis was used to introduce the fa mutation into the mouse Lepr cDNA. Transient transfection studies indicate that the mutant Lepr cDNA has greatly reduced binding of leptin (Lep) at the cell surface. These data are strong evidence that the single nucleotide substitution in the fa allele of Lepr (Leprfa) is responsible for the obese phenotype. PMID- 8690164 TI - Increased phosphorylation of focal adhesion kinase in diabetic rat kidney glomeruli. AB - Altered extracellular matrix production by the glomerular mesangium is a feature of diabetes mellitus. Matrix proteins, including fibronectin, via interaction with cell-surface receptors (the integrins) may activate intracellular pathways such as prostaglandin production, shown previously to be stimulated by addition of fibronectin to glomerular cores. However, the signalling pathways involved are unclear. An intracellular tyrosine kinase (focal adhesion kinase), associated with focal adhesions, is known to be phosphorylated after interaction with matrix proteins. We now show for the first time, in glomeruli from diabetic rats, that focal adhesion kinase has increased phosphorylation on tyrosine, when compared with non-diabetic control rats. This phosphorylation was labile and disappeared with extended time of sample preparation or digestion of glomeruli to glomerular cores. Cultured mesangial cells, from non-diabetic rats, plated onto fibronectin also showed increased tyrosine phosphorylation of focal adhesion kinase accompanied by a twofold increase in prostaglandin production. However, it may not be possible to replicate fully the diabetic ?state? in vitro merely by use of raised glucose concentrations, as these conditions (for 3 weeks) resulted in decreased focal adhesion kinase phosphorylation, despite increased fibronectin and prostaglandin levels. A role for increased focal adhesion kinase phosphorylation in kidney glomeruli isolated from diabetic rats, and any linkage to intracellular signalling pathways remains to be determined. PMID- 8690165 TI - Low incidence of autoimmune type I diabetes in BB rats fed a hydrolysed casein based diet associated with early inhibition of non-macrophage-dependent hyperexpression of MHC class I molecules on beta cells. AB - Diabetes-prone BioBreeding (DPBB) rats were fed a diabetogenic, mainly plant based rodent diet, Purina Chow 5001, or a diabetes-retardant, hydrolysed casein based diet. The expression of MHC class I antigens on pancreatic beta cells occurred at around 25 days of age in Purina Chow-fed rats, and progressively increased with the length of time of feeding with the Purina diet. Most of the Purina Chow-fed DPBB rats revealed hyperexpression of MHC class I antigens on their pancreatic beta cells by 50 days of age. Approximately 92% of the hyperexpressed Purina Chow-fed DPBB rats developed severe insulitis and diabetes. In contrast, the majority of hydrolysed casein-fed DPBB rats did not show MHC class I antigen hyperexpression and these rats failed to develop insulitis or diabetes. Purina Chow-fed Wistar-Furth rats and diabetes-resistant BioBreeding (DRBB) rats showed only very weak background staining for MHC class I antigens on their beta cells. When Purina Chow-fed (DPBB rats were treated with silica to inhibit macrophage infiltration into the pancreatic islets, the hyperexpression of MHC class I antigens was seen even more clearly, as beta cells remained intact. MHC class II antigens were not detected on pancreatic beta cells from DPBB, DRBB or Wistar-Furth rats, regardless of their diet. On the basis of these observations, we concluded that hyperexpression of MHC class I antigens on pancreatic beta cells was mainly restricted to Purina Chow-fed DPBB rats and that suppression of non-macrophage-dependent MHC class I antigen hyperexpression on pancreatic beta cells by a hydrolysed caseinbased diet resulted in the prevention of insulitis and diabetes. PMID- 8690166 TI - Alterations in insulin signalling pathway induced by prolonged insulin treatment of 3T3-L1 adipocytes. AB - Insulin-induced glucose transport stimulation, which results from the translocation of glucose transporter 4 (GLUT 4)-containing vesicles, is completely blocked after prolonged insulin treatment of 3T3-L1 adipocytes. Since GLUT 4 expression was reduced by only 30%, we looked at the insulin signaling pathway in this insulin-resistant model. Insulin-induced tyrosine phosphorylation of the major insulin receptor substrate IRS 1 was reduced by 50 +/- 7%, while its expression was decreased by 70 +/- 4%. When cells were treated with worthmannin (a PI3-kinase inhibitor) together with insulin, the expression of IRS 1 diminished to a much lower extent. Associated with the decrease in IRS 1 expression and phosphorylation, the activation by insulin of anti-phosphotyrosine immunoprecipitable PI3-kinase activity and of p44mapk activities was altered. However, the expression of these proteins was normal and p44mapk activity remained responsive to the tumour promoter TPA. Those results indicate that prolonged insulin treatment of 3T3-L1 adipocytes induces an insulin-resistant state with a reduced ability of insulin to stimulate the PI3-kinase and the MAP kinases and a blockade of glucose transporter translocation. PMID- 8690167 TI - Endothelial relaxation is disturbed by oxidative stress in the diabetic rat heart: influence of tocopherol as antioxidant. AB - Increased oxidative stress has been suggested to contribute to disturbances in the regulation of coronary flow and the increased cardiac risk in diabetes mellitus. Using the isolated perfused heart of streptozotocin-diabetic rats our study shows that basal and maximal coronary flow (tested by infusion of sodium nitroprusside) are not altered in diabetes, but that 5-hydroxytryptamine (5-HT) stimulated endothelium-dependent increase in coronary flow becomes progressively impaired. This defect of the endothelium-dependent vasodilatation was prevented by perfusion of the hearts with superoxide dismutase and pretreatment of the diabetic rats with tocopherol-acetate. Morphological studies also revealed that pretreatment with tocopherol-acetate was cardioprotective, and largely prevented severe alterations of myocardial structure typically observed after a diabetes duration of 3 months; deterioration and fragmentation of myofilament bundles were seen less, and the numbers of areas of focal necrosis and of contraction bands were clearly reduced. In contrast to untreated diabetic hearts the autonomic nerve fibers detected by catecholamine fluorescence were running in parallel in hearts of tocopherol-treated diabetic rats, and the amount of catecholamines was not different from that of healthy control rats. Trichrome staining and immunohistochemical staining of collagen I and III showed a dramatic increase in number and the size of deposits of collagen fibers at precapillary locations in the diabetic hearts which were significantly reduced by anti-oxidative treatment. These findings demonstrate that oxidative stress may not only play a major role in the impairment of endothelium-dependent regulation of coronary flow, but also in the development of perivascular fibrosis and severe changes of the autonomic nerves and contractile system in myocardium. PMID- 8690168 TI - Reduction of heparan sulphate-associated anionic sites in the glomerular basement membrane of rats with streptozotocin-induced diabetic nephropathy. AB - Heparan sulphate-associated anionic sites in the glomerular basement membrane were studied in rats 8 months after induction of diabetes by streptozotocin and in age- adn sex-matched control rats, employing the cationic dye cuprolinic blue. Morphometric analysis at the ultrastructural level was performed using a computerized image processor. The heparan sulphate specificity of the cuprolinic blue staining was demonstrated by glycosaminoglycan-degrading enzymes, showing that pretreatment of the sections with heparitinase abolished all staining, whereas chondroitinase ABC had no effect. The majority of anionic sites (74% in diabetic and 81% in control rats) were found within the lamina rara externa of the glomerular basement membrane. A minority of anionic sites were scattered throughout the lamina densa and lamina rara interna, and were significantly smaller than those in the lamina rara externa of the glomerular basement membrane (p<0.001 and p<0.01 for diabetic and control rats, respectively). Diabetic rats progressively developed albuminuria reaching 40.3 (32.2-62.0) mg/24 h after 8 months in contrast to the control animals (0.8 (0.2-0.9) mg/24 h, p<0.002). At the same time, the number of heparan sulphate anionic sites and the total anionic site surface (number of anionic sites x mean anionic site surface) in the lamina rara externa of the glomerular basement membrane was reduced by 19% (p<0.021) and by 26% (p<0.02), respectively. Number and total anionic site surface in the remaining part of the glomerular basement membrane (lamina densa and lamina rara interna) were not significantly changed. We conclude that in streptozotocin diabetic rats with an increased urinary albumin excretion, a reduced heparan sulphate charge barrier/density is found at the lamina rara externa of the glomerular basement membrane. PMID- 8690169 TI - Serum proinsulin levels are disproportionately increased in elderly prediabetic subjects. AB - Insulin resistance and impaired insulin secretion are thought to be the primary defects in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). Disproportionately increased proinsulin relative to insulin levels are suggested to be an early indicator of a failing pancreas. We examined the relationship of fasting specific insulin, proinsulin, and 32, 33 split proinsulin concentrations, and the proinsulin: insulin ration to the risk of developing NIDDM 3.5 years later in 65-74-year-old non-diabetic Finnish subjects participating in a population-based study (n=892) on diabetes and heart disease. Altogether 69 subjects developed NIDDM over a 3.5-year follow-up (cases). The cases were compared to randomly-selected gender-matched control subjects (n=69) and control subjects matched for gender, glucose tolerance status (normal or impaired), and body mass index (n=69). There were no differences in insulin concentrations between cases and random or matched control subjects [median and interquartile range: 123 (77-154), 108 (74-143), 118 (83-145) pmol/l, p=0.271]. Random control subjects had lower proinsulin and 32, 33 split proinsulin concentrations and split proinsulin: insulin ratios compared to cases [5.7 (3.8-9.0) vs 7.3 (4.8 10.0) pmol/l, p=0.005; 7.3 (4.5-13.0 vs 10.4 (7.1-18.0) pmol/l, p=0.002; 0.073 (0.057-0.110) vs 0.097 (0.060- 0.135), p=0.003]. Matched control subjects had lower proinsulin concentrations and proinsulin: insulin ratios compared to cases [5.9 (4.0-7.7) vs 7.3 (4.8-10.0) pmol/l, p=0.019; 0.048 (0.035-0.071) vs 0.064 (0.045-0.100), p=0.008]. When cases were compared to matched control subjects a 1 SD increase in baseline proinsulin: insulin ratio was associated with a 1.37-fold risk (p=0.020) of developing diabetes. Moreover, this association was independent of fasting glucose concentration at baseline. Thus, in elderly prediabetic subjects disproportionately increased proinsulin concentration, an indicator of defective insulin secretion, is associated with conversion to diabetes over a short time period. PMID- 8690170 TI - Prolonged but partial impairment of the hypoglycaemic physiological response following short-term hypoglycaemia in normal subjects. AB - Recent studies have reported reduced endocrine and symptomatic responses to hypoglycaemia 18-24 h after antecedent hypoglycaemia in both non-diabetic subjects and those with insulin-dependent diabetes mellitus. We examined these and peripheral physiological responses in eight non-diabetic subjects aged 23-35 years in the week following antecedent hypoglycaemia. Blood glucose levels were held at plateaus of 5 mmol/l and 2.5 mmol/l for 30 min during hyperinsulinaemic (60 mU x m-2x min-1) morning clamps on days 1, 3 and 8 of two study periods separated by at least 4 weeks. Measurements were made at time 0, 15 and 30 min of each plateau on each day. One the afternoon of Day 1 we also induced either euglycaemia with a blood glucose level of 5 mmol/l (control week) or hypoglycaemia of 2.9 mmol/l (hypo week) for 2 h in random order. The adrenaline response to morning hypoglycaemia (p<0.001 on all days) was attenuated on Day 3 (p<0.05) and Day 8 (p<0.05) compared to Day 1 of hypo week only. Sweating was also attenuated on Day 3 (p<0.05) and Day 8 (p<0.02) of hypo week only. Noradrenaline levels and tremor increased during hypoglycaemia on each study day (p<0.05) but did not differ between days in either week. During hypo week only, the total symptom score response to hypoglycaemia was attenuated on Day 3 (p<0.03) but not Day 8 (p=0.10). Autonomic symptoms were similarly affected. In summary, the physiological responses to hypoglycaemia are affected differentially by antecedent hypoglycaemia with sweating and adrenaline responses remaining impaired for at least adrenaline responses remaining impaired for at least 5 days. PMID- 8690171 TI - Motor pathway function in normoalbuminuric IDDM patients. AB - Central motor pathways were studied in 17 normoalbuminuric insulin-dependent diabetic (IDDM) patients who had been diabetic for more than 20 years, and compared with findings in 17 age-, sex-, and height-matched control subjects. The central motor conduction time was calculated from recordings of the compound muscle action potentials of the abductor pollicis brevis muscle after single transcranial and spinal root magnetic stimulation. The central motor conduction time from motor cortex to cervical spinal roots was 9.8 +/- 1.65 ms in diabetic patients and 10.1 +/- 1.48 ms in control subjects. In diabetic patients with neuropathy the central motor conduction time was 9.5 +/- 1.76 ms vs 10.1 +/- 1.56 ms in patients without neuropathy. The excitability of the motor pathways was studied by paired transcranial magnetic stimulation at interstimulation intervals of 30-1000 ms. In normal control subjects, an early facilitation of the amplitude of the compound muscle action potential at an interstimulation interval of 30 ms was found, while no facilitation was present in diabetic patients. In addition the compound muscle action potential latencies were prolonged at interstimulation intervals of 30-50 ms in diabetic patients. The changes of excitability did not correlate with the presence of peripheral neuropathy, metabolic control or diabetes duration. It is concluded that long-term normoalbuminuric IDDM patients have imparied excitability but normal central conduction time of the motor pathways. PMID- 8690172 TI - Glomerular epithelial foot processes and filtration slits in IDDM patients. AB - Diabetic nephropathy is associated with functional changes in the glomerular filtration barrier but the structural counterpart remains unknown. Width of glomerular epithelial cell foot processes and of filtration slits were determined by morphometric methods in 11 non-diabetic kidney donors and in 28 diabetic patients with albumin excretion rates ranging from normal to proteinuria. Foot process width was estimated from the ratio of tuft surface density to length density of slits. At high magnification independently sampled, perpendicularly cut slits were classified. Foot process width on peripheral basement membrane was increased in microalbuminuric compared to normoalbuminuric diabetic patients (p<0.05) but showed no significant correlation with the level of albumin excretion when patients with increased barrier permeability were considered. Width of filtration slits in normo- and microalbuminuric diabetic patients exceeded that in non-diabetic control subjects (p<0.05). Filtration slits were narrower in patients with overt proteinuria than in patients with microalbuminuria (p<0.05) and correlated with glomerular filtration rate in all of the diabetic patients (r=0.65, p<0.005). The results show that insulin dependent diabetic patients with nephropathy present changes of epithelial cells and filtration slits, demonstrable already in the stage of microalbuminuria. The mechanism of albumin leakage is not achieved by these measures. The dimension of filtration slits may play a contributing role in the level of glomerular filtration rate in diabetic patients. PMID- 8690173 TI - A relationship between impaired fetal growth and reduced muscle glycolysis revealed by 31P magnetic resonance spectroscopy. AB - Thinness at birth is associated with insulin resistance and an increased prevalence of non-insulin-dependent diabetes mellitus in adult life. As muscle is an important site of insulin resistance, and because thin babies have reduced muscle mass, thinness at birth may affect muscle structure and function and impair carbohydrate metabolism. We have therefore used 31P magnetic resonance spectroscopy to investigate the bioenergetics of gastrocnemius and flexor digitorum superficialis muscles in 16 normoglycaemic women who had a low ( < or = 23 kg/m3) and 9 women who had a high (> 23 kg/m3) ponderal index at birth. In the flexor digitorum superficialis study anaerobic metabolism was stressed with a constant heavy workload. Low ponderal index subjects fatigued more rapidly (3.3 vs 5.8 min); as phosphocreatine decreased, the accompanying drop in muscle pH was less than in the high ponderal index group. In the first minute of exercise phosphocreatine fell and adenosine diphosphate rose more rapidly (p=0.04 and 0.03, respectively). Gastrocnemius showed a similar trend late in exercise (this exercise was more oxidative, becoming more anaerobic with increasing workload). These changes were not explained by differences in body composition, muscle mass or blood flow. The findings are consistent with a decreased lactic acid and glycolytic adenosine triphosphate production in the low ponderal index group and suggest the possibility that the mechanisms which control substrate utilisation and metabolism in adult life be programmed during prenatal life. PMID- 8690174 TI - A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM. AB - To assess the role of fasting plasma non-esterified fatty acids (NEFA) in the development of non-insulin-dependent diabetes mellitus (NIDDM), data were analysed from annual examinations of 190 non-diabetic Pima Indians. Glucose tolerance was measured by a 75-g oral glucose tolerance test, insulin action by a euglycaemic hyperinsulinaemic (40 mU x m-2 x min-1) clamp and in vitro lipolysis using isolated abdominal fat cells. After a mean follow-up period of 4.0 +/- 2.4 years (mean +/- SD), 47 subjects developed NIDDM. Risk factors for NIDDM were estimated by proportional-hazards analysis and risk ratios (RR) with 95% confidence intervals (95% CI) calculated at the 90th and 10th percentile of the predictor variables. A large average fat-cell volume was predictive of NIDDM (RR=2.4; 95% CI=1.2-4.8) independent of age, sex, percent body and body fat distribution. A high fasting plasma NEFA concentration was also a risk factor for NIDDM (RR=2.3; 95% CI=1.1-4.7) independent of sex, percent body fat, waist/thigh ratio, insulin-mediated glucose uptake and fasting triglyceride concentration. We conclude that large fat cells and the resulting increased plasma NEFA concentrations are risk factors for the development of NIDDM. PMID- 8690175 TI - Albumin excretion rate levels in non-diabetic offspring of NIDDM patients with and without nephropathy. AB - Familial clustering of diabetic nephropathy points to genetic susceptibility. The observation that in non-diabetic subjects microalbuminuria occurs more frequently in the presence of a parental history of diabetes supports this hypothesis. However, the role of inherited factors in poorly understood in non-insulin dependent diabetes mellitus (NIDDM). This study investigated the albumin excretion rate in non-diabetic offspring of NIDDM patients with increased albumin excretion rate (> 20 micrograms/min) or normal albumin excretion rate (< 20 micrograms/min). We recruited 20 offspring of NIDDM patients with increased albumin excretion rate (A-off) and 20 offspring rate (N-off), matched for age, sex, body mass index, blood pressure and estimated protein intake. All offspring were normotensive, had normal creatinine clearance, normal glucose tolerance and sterile urine collection. Albumin excretion rate was measured on three sterile overnight urine collections and median values were used for calculations. Albumin excretion rate was significantly higher in A-off than in N-off (7.7 +/- 1.2 vs 3.4 +/- 0.6 micrograms/min p<0.01) and significantly related to parents' albumin excretion rate (p<0.01, r=0.53). These results suggest that an increased glomerular permeability is present in non-diabetic offspring of NIDDM patients with increased albumin excretion rate. PMID- 8690176 TI - In Finland insulin gene region encoded susceptibility to IDDM exerts maximum effect when there is low HLA-DR associated risk. DiMe (Childhood Diabetes in Finland) Study Group. AB - An association between insulin-dependent diabetes mellitus (IDDM) and polymorphisms of the insulin gene on chromosome 11p15 (INS) is a consistent finding in Europid populations. While one study suggested that the INS association is restricted to HLA-DR4-positive individuals, studies in other Europid populations have shown the disease-associated INS genotype to confer susceptibility independently of HLA-DR. We have investigated the role of INS in susceptibility to IDDM in Finland, which has the highest incidence of diabetes mellitus in the world, at two polymorphic restriction sites, 5' and 3' to the insulin gene. From the DiMe (Childhood Diabetes in Finland) Study we studied 154 diabetic children without regard to HLA-DR type; 108 DR4 positive/non-DR3 diabetic children; 39 DR3 positive/non-DR4 diabetic children; 30 DR4/DR3 positive diabetic children; 31 non-DR4/non-DR3 diabetic children; 96 matched DiMe control subjects and 86 other healthy, non-diabetic Finnish control subjects. We found an overall association between IDDM and INS in the high-risk Finnish population only with the 5' polymorphism and identified an INS haplotype negatively associated with IDDM in Finland. However, among diabetic subjects with a reduced HLA associated susceptibility (non-DR4/non-DR3) both 3' and 5' INS loci showed an association with IDDM (p values 0.02 and 0.0002, respectively). Thus, in the Finnish population insulin gene-encoded susceptibility to IDDM exerts a maximum effect in those with reduced HLA-associated risk. PMID- 8690179 TI - Lack of association between the Gly40Ser polymorphism in the glucagon receptor gene and NIDDM in Finland. AB - A heterozygous polymorphism changing GGT40 (Gly) to AGT40 (Ser) (Gly40Ser) in the glucagon receptor gene was reported to be associated with non-insulin-dependent diabetes mellitus (NIDDM). A possible involvement of this polymorphism in impaired glucose tolerance was also suggested in a French population. To replicate this finding we screened 311 unrelated NIDDM patients, 101 unrelated individuals with impaired glucose tolerance and 306 control subjects for the presence of the Gly40Ser polymorphism by use of polymerase chain reaction restriction fragment length polymorphism in a Finnish population. None of the NIDDM or impaired glucose tolerant patients had this polymorphism. Instead, four of the control subjects (1.3%) were heterozygous carriers of the polymorphism (NS). The age, body mass index, 2-h blood glucose level, 2-h insulin level, and incremental insulin are of the four subjects with this polymorphism were similar to those of the control subjects homozygous for the wild type. Taken together, the data do not support the suggested involvement of the Gly40Ser polymorphism in impaired glucose tolerance and the hypothesis of an association between NIDDM and the glucagon receptor gene in this population. PMID- 8690178 TI - Glucose intolerance and impairment of insulin secretion in relation to vitamin D deficiency in east London Asians. AB - Vitamin D deficiency reduces insulin secretion and still occurs in East London Asians in whom the prevalence of diabetes mellitus is at least four times that of Caucasians. Vitamin D status was assessed in 44 of 65 non-diabetic subjects 'at risk' of diabetes (spot blood glucose level >6.0 mmol/l <2 h post cibum, or>4.6 mmol/l >2 h post cibum on two separate occasions) and in 15 of 60 age and sex matched 'low-risk' control subjects who attended for oral glucose tolerance test (OGTT) after screening of 877 omnivorous subjects not known to have diabetes. It was found that 95% of at-risk and 80% of low-risk subjects were vitamin D deficient (serum 25-hydroxy-vitamin D <11 ng/ml). Diabetes was present in 16, impaired glucose tolerance in 12 and normoglycaemia in 19 at-risk subjects, imparied glucose tolerance in 2, and normoglycaemia in 13 low-risk subjects. Correlation of 30-min OGTT blood glucose, specific insulin and C-peptide levels with 25-hydroxy-vitamin D concentrations in 44 at-risk subjects were -0.31 (p=0.04), 0.59 (p=0.0001) and 0.44 (p=0.006). In 15 'not-at-risk' subjects 30-min OGTT specific insulin and C-peptide levels correlated with 25-hydroxy-vitamin D, r=0.39 (p=0.04) and 0.16 (p=0.43), respectively. Serum alkaline phosphatase concentration was higher in at-risk than not-at-risk subjects (59.6 vs 46.5 IU/l, p=0.012); corrected calcium concentrations were comparable (2.38 vs 2.39 mmol/l, p=0.7). Following treatment with 100,000 IU vitamin D by i.m. injection, specific insulin, C-peptide [30 min on OGTT] and 25-hydroxy-vitamin D concentrations had risen 8-12 weeks later [mean +/- DS] from 57 +/- 62 to 96.2 +/- 82.4 mU/l [p=0.0017], 1.0 +/- 0.4 to 1.7 +/- 0.8 pmol/ml [p=0.001] and 3.6 +/- 1.8 to 13.5 +/- 7.4 ng/ml [p=0.0001], (but not to low-risk group values of 179 +/- mU/l, 2.7 +/- 1.14 pmol/ml and 8.16 +/- 6.4 ng/ml), respectively. Both total serum alkaline phosphatase and corrected calcium concentrations rose following vitamin D treatment in the at-risk subjects by 11.1 +/- 8.22 (from 44 to 55 IU/l) and 0.15 +/- 0.18, (2.43 to 2.57 mmol/l), respectively (p=0.004). Abnormal glucose tolerance was unchanged by vitamin D treatment. The value of early and sustained repletion with vitamin D in diabetes prophylaxis should be examined in communities where vitamin D depletion is common. PMID- 8690177 TI - Unchanged gene expression of glycogen synthase in muscle from patients with NIDDM following sulphonylurea-induced improvement of glycaemic control. AB - We have previously shown that the mRNA expression of muscle glycogen synthase is decreased in non-insulin-dependent diabetic (NIDDM) patients; the objective of the present protocol was to examine whether the gene expression of muscle glycogen synthase in NIDDM is affected by chronic sulphonylurea treatment. Ten obese patients with NIDDM were studied before and after 8 weeks of treatment with a weight-maintaining diet in combination with the sulphonylurea gliclazide. Gliclazide treatment was associated with significant reductions in HbA1C (p=0.001) and fasting plasma glucose (p=0.005) as well as enhanced beta-cell responses to an oral glucose load. During euglycaemic, hyperinsulinaemic clamp (2 mU x kg-1 x min-1) in combination with indirect calorimetry, a 35% (p=0.005) increase in whole-body insulin-stimulated glucose disposal rate, predominantly due to an increased non-oxidative glucose metabolism (p=0.02) was demonstrated in teh gliclazide-treated patients when compared to pre-treatment values. In biopsies obtained from vastus lateralis muscle during insulin infusion, the half maximal activation of glycogen synthase was achieved at a significantly lower concentration of the allosteric activator glucose 6-phosphate (p=0.01). However, despite significant increases in both insulin-stimulated non-oxidative glucose metabolism and muscle glycogen synthase activation in gliclazide-treated patients no changes were found in levels of glycogen synthase mRNA or immunoreactive protein in muscle. In conclusion, improved blood glucose control in gliclazide treated obese NIDDM patients has no impact on the gene expression of muscle glycogen synthase. PMID- 8690180 TI - The glycogen synthase gene in NIDDM and hypertension. PMID- 8690181 TI - [Anatomo-clinical correlations of cardiopathies diagnosed during fetal life: analysis of 110 cases of cardiopathies]. AB - BACKGROUND: Fetal echocardiography has achieved high sensibility and specificity rates and it has become a reliable tool to detect intra-uterine congenital heart defects. OBJECTIVES: The purpose of the present study was to clarify the potential of anatomo-clinical correlation in fetal echocardiography not only for diagnosing heart defects, but also for understanding and following their morphogenesis and natural history in utero. METHODS: Nine hundred pregnancies, referred by several first-level centers, have been followed up from the sixteenth week to birth, and the newborn baby has been studied, too. In case of either voluntary abortion, or intra-uterine or neonatal death, a post-mortem examination was performed whenever possible. RESULTS: Since 1982, 110 fetal heart defects have been detected: 94 were diagnosed by means of fetal echocardiography (in 21/94 an autopsy was carried out) and 16 were directly observed at the post mortem (spontaneous or voluntary abortions not previously referred). The heart defects most commonly observed were the atrioventricular (14.5%), ventricular (9.0%), and atrial (7.2%) septal defects, the absent left atrioventricular connection (8.1%), and atrial isomerism (6.3%). The congenital heart defects diagnosed in utero vary from those observed in the newborn and infants in terms of distribution (because of difficulties in diagnosis, selection of pregnancies, and differences in manifestation) and morphology (because of the coexistence with other extracardiac malformations, the changes due to altered fetal hemodynamics, and the intrauterine evolution of the morphology of cardiac defects). CONCLUSIONS: Heart defects observed in utero have a peculiar prevalence and a different morphology in respect to their infantile counterparts and can be followed in their morphologic evolution. PMID- 8690182 TI - [Results and prognostic significance of echocardiography-dobutamine + atropine test in recent non-Q wave myocardial infarction]. AB - BACKGROUND: Patients with non-Q wave myocardial infarction (NQ AMI) are usually considered to have an increased risk of recurrent ischemic events and reinfarction. We wished to assess whether dobutamine stress echocardiography with the addition of atropine (DOB-E + ATRO) can detect jeopardized myocardium after a recent NQ AMI and to assess the prognostic significance of this test in a group of patients with a first uncomplicated NQ AMI: METHODS AND RESULTS: Fourty-one consecutive patients (38 men, mean age 52 +/- 9 years, 31 anterior, 68% treated with thrombolysis) underwent low and high-dose DOB-E (from 5 to 40 mcg/kg/min); ATRO was added in 14/41 (34%) patients. A significant deterioration of wall motion in the infarcted region (IR) indicative of residual myocardial ischemia was present in 36/41 patients (88%). Significant electrocardiographic changes and angina developed in 61% and 32% of patients, respectively. Coronary angiography was performed in 30/41 patients (73%) and showed 1-vessel coronary artery disease (CAD) in 70% of cases, multivessel CAD in 23% of cases and no significant CAD in 7% of patients. Three patients were lost at follow-up and 10 other patients were excluded from the analysis because a revascularization procedure was performed during diagnostic angiography. On a mean follow-up period of 9.5 +/- 9 months, the incidence of coronary events (re-infarction, recurrent angina, revascularization procedures) was higher (15/36 vs 1/5, 42% vs 20%) in patients with a DOB-E + ATRO positive test (1 reinfarction, 9 recurrent angina, 5 revascularized) than in those with a negative test (1 recurrent angina). CONCLUSIONS: DOB-E + ATRO early after a first uncomplicated NQ AMI documents the presence of myocardial ischemia in the IR in the great majority of patients. A positive DOB-E + ATRO was found to be associated with a higher incidence of cardiac events at follow-up, but the results of this non prospective study (high sensitivity but low specificity and predictive value for cardiac events at follow up) suggest to utilize with caution this test for risk stratification of patients with recent NQ AMI until prospective and larger studies are performed. PMID- 8690183 TI - [Stratification of the thromboembolic risk in patients with non-rheumatic atrial fibrillation: assessment of left atrial dysfunction]. AB - BACKGROUND: Patients with non rheumatic atrial fibrillation (NRAF) have an increased risk for thromboembolic complications. Recent evidence suggests that left atrial appendage function (contraction, filling dynamics) may provide clues to the thrombogenic potential of this structure. The aim of this study was to identify left atrial spontaneous echocontrast and thrombus between patients with NRAF and their relationship with left atrial appendage function. METHODS: Transthoracic (TTE) and biplane or multiplane transesophageal echocardiography (TEE) were performed in 143 patients with chronic NRAF enrolled in the Trieste Area Study on non rheumatic Atrial Fibrillation (TASAF), an ongoing prospective community study with a follow-up period of 2 years. The maximal and minimal areas of the left atrial appendage were measured during three cardiac cycles and the peak emptying and filling velocities profile were obtained by pulsed wave Doppler at the orifice of the left atrial appendage. The left atrium and appendage were inspected for thrombus and spontaneous echocontrast. RESULTS: Left atrial appendage thrombus was present in 37 patients (26%) and spontaneous echocontrast in 60 patients (42%), 45% of patients with spontaneous echocontrast had thrombus. Univariate analysis identified positive correlation of thrombus with duration of atrial fibrillation (p = 0.05), hypertension (p = 0.01), left atrial area (p = 0.005), mitral annular calcification (p = 0.01), left ventricular dysfunction (p = 0.03) and a non significant correlation with the mitral valve prolapse (p = 0.08) in the TTE. The presence of mitral regurgitation did not demonstrate a protective effect (p = 0.73) against thrombosis. The variables of left atrial appendage function identifying a subgroup of patients with increased risk of thrombus formation were: shortening fraction of the area in the horizontal and vertical sections (p = 0.0001 and p = 0.002 respectively), the peak filling and emptying velocity in horizontal (p = 0.0001 equal for both) and vertical sections (p = 0.0001 equal for both). In summary these patients have a larger left atrial maximal area (p = 0.004) and a lower flow velocity profile (p < 0.00001) and more intense spontaneous echocontrast (p < 0.00001) than the others. Spontaneous echocontrast was correlated with left ventricular dysfunction (p = 0.008), left atrial area (p = 0.02) and there was a non-significant correlation with mitral annular calcification (p = 0.09) and lower left ventricular shortening fraction (p = 0.06). Transesophageal echocardiography variables have identified the subgroup of patients with an increased risk of echocontrast formation. This was positively associated with a low flow velocity profile (p = 0.0001), a left atrial appendage low shortening fraction in horizontal section (p = 0.001) and in vertical section (p = 0.05) and a low peak filling velocity in horizontal section (p = 0.003) and in vertical section (p = 0.004) and a low peak emptying velocity in horizontal section (p = 0.003) and in vertical section (p = 0.001). Prophylactic therapy with anticoagulant or antiplatelet agents has little benefits in our experience. CONCLUSIONS: Spontaneous echocontrast and low flow profile velocity (low peak emptying and filling velocity) and increased area of left atrial appendage were strongly associated with left atrial and/or appendage thrombus in patients with NRAF. The assessment of left atrial appendage function by TEE is an important component of the comprehensive evaluation of potentially increased risk of thrombus formation. PMID- 8690184 TI - [Standardization of the methods of lipid determination according to WHO in the regional project of prevention of cardiovascular diseases in Friuli-Venezia Giulia]. AB - BACKGROUND: The recognition of dyslipidemias as a major modifiable risk factor for atherosclerosis and coronary heart disease underlines the need to obtain precise and accurate assay results of plasma lipids. Today the use of automatic laboratory methods and of internal quality control favours the precision of the results but does not guarantee accuracy. The efficiency of a laboratory can be ensured by a standardization programme, systematically monitoring precision and accuracy by means of independent internal and external quality control, international reference standards (e.g. those of CDC-NHLBI and WHO) and protocols to identify and reduce the errors due to biological variability and pre analytical factors. After the foundation of the Regional Project for Prevention of Cardiovascular Diseases in Friuli-Venezia Giulia, a lipid standardization programme was set-up, covering the 20 chemico-clinical laboratories of the Region. The programme was directed by the International WHO-MONICA-Lipid Reference Centres of Prague-Udine. METHODS: During the years 1993-1994, three sets of lyophilized human serum samples were dispatched to each laboratory for the blind evaluation of total cholesterol, triglycerides and HDL-cholesterol. The samples were obtained by the combination of three serum pools at least at different lipid concentration. The first set included 20 samples to be tested in 5 weeks, the second set included 30 samples to be tested in 8 weeks and the third set included 21 samples to be tested in 9 weeks. The assay results were sent to the Prague-Udine WHO-MONICA Centres where they were computerized and evaluated, particularly considering precision for each set, estimated by the variation coefficient (i.e. standard deviation/mean value of the measurements per cent) and accuracy (the bias was computed as mean of the measurement minus the reference value/reference value per cent). RESULTS: In the three assay series for total cholesterol, almost all the laboratories showed the variation co-efficient (precision) to be less than the WHO-MONICA limit of 3.7% (for a cholesterol level of 250 mg) (Tab. II) and in 8 cases out of 20, less than the CDC limit of 3%; the accuracy bias was less than the WHO-MONICA limit of 5% in 17 laboratories out of 20 and less than the CDC limit of 3% in 11 cases out of 20. For the HDL cholesterol standardization programme the reference values were based upon the phosphotungstate method. However, the pools were also controlled by the other precipitation methods used in the 20 participating laboratories: 11 laboratories worked within the WHO-MONICA limits of precision and accuracy (respectively 6.5% and 7.5%) in at least two of the three sets. Concerning triglycerides, the regional laboratories showed a greater variability and, though most of the variation coefficients were within the WHO-MONICA limit of 5%, half of the accuracy biases were greater than the limit of 10%. The bias of the measurement average of all the laboratories was excellent for total and HDL-cholesterol, not quite good but acceptable for triglycerides. Laboratory performance improved progressively from the first to the last set, on more than one occasion. CONCLUSIONS: The lipid standardization experience carried out in the framework of the Regional Project for Prevention of Cardiovascular Disease demonstrates that it is possible to set up a wide and co-ordinated collaboration with laboratories of an entire region with positive and improving results. For this global quality control system, the resource allocated is limited but widely rewarded by the community benefits in terms of assay reliability and savings at medical care level, basic research and population studies. PMID- 8690185 TI - [Effects on myocardial perfusion of epidural spinal cord stimulation in refractory angina. Description of a case studied with positron emission tomography]. AB - We describe a case of patient with severe angina pectoris unresponsive to medical therapy who was treated with spinal cord stimulation. The patient was studied by dynamic positron emission tomography (PET) (13-N ammonia) and with heart rate variability. Spinal cord stimulation was effective in reducing anginal attacks and PET documented an enhancement of myocardial perfusion when spinal stimulator was activated. Heart rate variability did not change during spinal cord stimulation. PMID- 8690186 TI - [Electrocardiogram in pre-excitation]. PMID- 8690187 TI - [How to use and improve DRG: role of the cardiologist]. PMID- 8690188 TI - [The budget in health structures: business management and diffuse responsibility]. PMID- 8690189 TI - [Health concerns and responsibility of the cardiologist: technical-organizational management]. PMID- 8690190 TI - [Approaches to health: concrete examples of joining efficacy and efficiency in cardiology]. PMID- 8690191 TI - [Heart transplantation in childhood: heredity of Baby Fae]. PMID- 8690192 TI - Study of the interstitial cells of Cajal in infantile hypertrophic pyloric stenosis. AB - BACKGROUND & AIMS: The interstitial cells of Cajal form a network in close association with the smooth muscle of the gut. They are regarded as pacemaker cells and might be involved in motility disorders. Their distribution was studied in a common disorder with a dysfunction of the pyloric sphincter called infantile hypertrophic pyloric stenosis. METHODS: Specimens from 27 infants with pyloric stenosis and 12 controls were processed for immunohistochemistry using a specific antiserum raised against c-kit, a tyrosine kinase receptor expressed by interstitial cells. RESULTS: In the normal pylorus, numerous interstitial cells were labeled throughout the tissue. In pyloric stenosis, c-kit immunoreactivity was absent in the major part of the tissue. Interstitial cells were observed only in the inner part of the musculature, near the submucosal edge, and in the antrum, at the proximal end of the biopsy specimens. CONCLUSIONS: The lack of interstitial cells in the pylorus possibly contributes to the motility disturbance of infantile pyloric stenosis. PMID- 8690193 TI - Colonic fermentation and proximal gastric tone in humans. AB - BACKGROUND & AIMS: Some carbohydrates escape small intestinal absorption, and their presence in the ileum can affect proximal gut motility. Carbohydrates reaching the colon can inhibit gastric and pancreatic secretions. The hypothesis of this study was that colonic fermentation products of carbohydrates (short chain fatty acids [SCFAs]) affect proximal gut motility and especially gastric tone. METHODS: Healthy volunteers were studied after oral administration of 20 g lactulose (n = 6) and intracolonic infusions of 20 g lactose (n = 7) and SCFAs (54 mmol/180 mL and 90 mmol/180 mL, respectively). Gastric tone (electronic barostat) and H2 concentrations in exhaled air were simultaneously monitored, and peripheral intestinal peptide levels were measured by specific radioimmunoassays. RESULTS: After oral lactulose administration (but not after saline), a significant decrease in gastric tone was observed, which rapidly followed the increase in H2 concentrations. Gastric tone also decreased after intracolonic infusions of both lactose and SCFAs; the most marked effect occurred after the highest SCFA dose. No significant changes in the level of plasma oxyntomodulin like immunoreactivity and glucagon-like peptide 1 were found, whereas the level of peptide YY increased significantly over time, but not differently after saline and test solutions. CONCLUSIONS: Colonic fermentation of undigestible carbohydrates can inhibit gastric tone, and SCFAs may be responsible for this colonic brake. The role of intestinal peptides, if any, was not identified. PMID- 8690194 TI - Oropharyngeal accommodation to swallow volume. AB - BACKGROUND & AIMS: The oropharyngeal swallow accommodates a range of bolus volumes with substantial impact on its dynamic radiographic appearance despite being a nearly reflexive sequence. The aim of this study was to analyze the mechanism of volume accommodation. METHODS: Coordination of the glossopalatal junction, velopharyngeal junction, laryngeal vestibule, and upper esophageal sphincter (UES) and intraluminal pharyngeal dimensions were measured from biplane videofluoroscopic swallowing studies in 8 volunteers during 1- and 20-mL swallows. These measurements were applied to three-dimensional reconstructions of the pharyngeal swallow, permitting analysis of their effect on intraluminal volume and propulsive function. RESULTS: Dividing the pharyngeal swallow into periods of reconfiguration, sustained reconfiguration, and offset of reconfiguration, volume accommodation occurred by a 0.2-second prolongation of reconfiguration, preserving the coordination of the onset and offset events. Augmented reconfiguration increased the dimensions of the pharyngeal chamber, caused more rapid bolus expulsion, and increased UES distention. However, maximal transphincteric flow per unit area across the UES was constant, showing its compliance. CONCLUSIONS: Volume accommodation is accomplished by augmenting and prolonging pharyngeal reconfiguration from a respiratory to deglutitive pathway. This modification in the timing of neurally mediated events is amplified by its mechanical consequences, resulting in the different cineradiographic appearance and propulsive attributes of large and small volume swallows. PMID- 8690196 TI - In siblings of celiac children, rectal gluten challenge reveals gluten sensitization not restricted to celiac HLA. AB - BACKGROUND & AIMS: Inflammatory changes in the rectum of patients with celiac disease after local instillation of gluten have been reported. The aim of this study was to examine rectal mucosa after local gluten challenge in children with celiac disease and their siblings. METHODS: Rectal biopsy specimens were obtained before and 6 hours after rectal challenge with a peptictryptic digest of gliadin in 33 children with treated celiac disease, 12 controls, and 19 siblings of children with celiac disease. Epithelium and lamina propria volumes were determined, and CD3+ and gamma delta + lymphocytes were counted. RESULTS: After local instillation of gliadin, a significant increment in the absolute number of intraepithelial lymphocytes was noted in patients with celiac disease but not in controls. Immunohistochemical analysis showed a significant increase in CD3+ and gamma delta + cells, with the gamma delta/CD3 ratio remaining unchanged after challenge. A discriminant analysis allowed correct classification of 100% of patients with celiac disease and controls. The same analysis was used to classify 6 of 13 siblings as having celiac disease. The positivity was not associated with the presence of the heterodimer encoded by the DQA*0501 DQB1*0201 alleles in any of the siblings. CONCLUSIONS: All patients with celiac disease were identified by rectal gluten challenge. Approximately half of the siblings reacted to rectal instillation of gluten. The genetic background of such sensitization to gluten remains to be elucidated. PMID- 8690197 TI - Somatostatin receptor subtype 2 mediates somatostatin inhibition of ion secretion in rat distal colon. AB - BACKGROUND & AIMS: Somatostatin peptides are potent inhibitors of intestinal ion secretion, providing the rationale for their use in treating secretory diarrhea. However, the nature of the receptors that mediate these effects is unclear. The aims of this study were to investigate expression of somatostatin receptor subtypes (SSTRs) 1-5 in rat colonic epithelium and to identify which subtype(s) mediate inhibition of adenosine 3', 5'-cyclic monophosphate (cAMP)-activated secretion using SSTR-selective analogues. METHODS: SSTR expression was determined by reverse-transcription polymerase chain reaction and immunoblotting. Effects of somatostatin analogues on electrogenic ion secretion were studied in isolated colonic mucosa mounted in Ussing chambers. RESULTS: Crypt epithelium expressed messenger RNA for SSTR1 and SSTR2 and low levels of SSTR5. A splice variant of SSTR2 (SSTR2B) was also detected. The SSTR2 selective analogue NC-812 was a potent inhibitor of forskolin-activated secretion and cAMP accumulation. In contrast, peptides selective for SSTR3 (DC-25/12) and SSTR5 (DC-23/99) were weak inhibitors of secretion. NC-812 also inhibited dibutyryl cAMP-activated secretion, indicating a site of action distal to cAMP production. Immunoblot analysis confirmed expression of a 93-kilodalton SSTR2 protein in crypt cell membranes. CONCLUSIONS: SSTR2 receptors expressed by colonocytes mediate somatostatin's antisecretory actions in rat colon. Somatostatin analogues directed to specific SSTRs may provide the basis for more selective antidiarrheal drugs. PMID- 8690195 TI - Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. AB - BACKGROUND & AIMS: Microsatellite instability (replication error [RER]) is a characteristic of tumors in hereditary nonpolyposis colon cancer (HNPCC), but the mechanism of HNPCC carcinogenesis is not yet understood. To clarify the nature of HNPCC tumors, RER and genetic changes were compared between HNPCC and non-HNPCC tumors. METHODS: RER and genetic changes were analyzed in 21 HNPCC, 389 familial adenomatous polyposis, and 206 sporadic tumors using polymerase chain reaction, single-strand conformation polymorphism, sequencing, and Southern hybridization. RESULTS. in HNPCC, 95% tumors at all stages showed RER positivity (altered loci, 4.3 of 5). In familial adenomatous polyposis and sporadic tumors, RER positivity (1.7 of 5) was 3% in adenoma and intramucosal carcinoma, 13%-24% in invasive carcinoma, and 35% in carcinoma metastasized to liver. Fifty percent of RER positive HNPCC tumors had both germline and somatic mutations of hMSH2 or hMLH1 gene, whereas 6% of RER-positive non-HNPCC had somatic mutation. APC, p53, and K ras-2 mutations and loss of heterozygosity of tumor-suppressor genes were significantly less frequent (P = 0.03 to 0.0006) but transforming growth factor beta type II receptor mutation was significantly more frequent (P = 0.000001) in HNPCC than in non-HNPCC. CONCLUSIONS: RER positivity occurs from an early stage of carcinogenesis in HNPCC but in later stages in non-HNPCC. Most HNPCC tumors may develop through different genetic changes from those in the adenoma-carcinoma sequence, although a certain percentage develops through APC mutation. PMID- 8690198 TI - The effects of Lactobacillus strains and oat fiber on methotrexate-induced enterocolitis in rats. AB - BACKGROUND & AIMS: Administration of methotrexate to rats on an elemental diet results in severe enterocolitis and death. Lactobacilli, an integral part of the healthy gastrointestinal microecology, may provide therapeutic benefits to help the recovery from enterocolitis. The purpose of this study was to evaluate the effects of lactobacilli and oatbase on methotrexate-induced enterocolitis in rats. METHODS: Rats received continuous intragastric infusion of elemental diet or with supplementation of oatbase, Lactobacillus reuteri R2LC, and Lactobacillus plantarum DSM 9843, with and without fermentation, from the beginning of the study. Methotrexate (20 mg/kg) was injected intraperitoneally on day 3, and the sampling was performed on day 6. RESULTS: Lactobacilli and oatbase decreased body weight loss and intestinal permeability and increased bowel mucosal mass in enterocolitic rats. Administration of lactobacilli, but not oatbase, decreased the intestinal myeloperoxidase level, reestablished intestinal microecology, and reduced bacterial translocation to extraintestinal sites. Both lactobacilli and oatbase reduced plasma endotoxin levels. The effects of lactobacilli were greater with fermentation than without fermentation or oatbase alone, and L. plantarum was more effective in reducing intestinal pathogens than L. reuteri. CONCLUSIONS: Exogenous administration of lactobacilli, especially L. plantarum with fermentation, is helpful in reducing the severity of enterocolitis in rats. PMID- 8690199 TI - Geranylgeranylacetone induces heat shock proteins in cultured guinea pig gastric mucosal cells and rat gastric mucosa. AB - BACKGROUND & AIMS: An antiulcer drug, geranylgeranylacetone (GGA), rapidly induces resistance of gastric mucosal cells to irritants in vivo and in vitro. The aim of this study was to elucidate the mechanism of this action. METHODS: Heat shock proteins (HSPs) were detected by immunoblotting with antibody against HSP90, HSP70, heat shock cognate protein 70, or HSP60. HSP70 messenger RNA level was measured by Northern hybridization with an HSP70 complementary DNA probe. Activation of the heat shock factor was detected by gel mobility shift assay with the heat shock element oligonucleotide. RESULTS: GGA induced resistance of cultured guinea pig gastric mucosal cells against ethanol-induced exfoliation and damage within 30 minutes, proportionally to the induction of the HSPs. This protection was blocked by cycloheximide but not by indomethacin. GGA caused rapid activation of heat shock factor 1 and expression of HSP70 messenger RNA in the cells. Intragastric administration of GGA to rats induced HSPs in gastric mucosa. The administration of GGA additionally enhanced the heat shock response and reduced ulcer formation in rats subjected to restraint and water-immersion stress. CONCLUSIONS: GGA may induce transcriptional activation of HSP genes, and this novel action may increase gastric mucosal defense at conditions of stress. PMID- 8690200 TI - Effect of omeprazole on the distribution of metronidazole, amoxicillin, and clarithromycin in human gastric juice. AB - BACKGROUND & AIMS: The mechanism by which antimicrobial therapy against Helicobacter pylori is enhanced by acid suppression is unknown. The aim of this study was to investigate the effect of omeprazole on gastric juice, plasma, and saliva concentrations of metronidazole, amoxicillin, and clarithromycin. METHODS: Single doses of antibiotic were administered intravenously to 24 healthy men (each antibiotic to 8 subjects) while taking placebo or omeprazole. Antibiotic concentrations were measured in gastric juice, plasma, and saliva. The pharmacokinetic parameters gastric clearance and gastric transfer fraction were calculated for each antibiotic. RESULTS: In the omeprazole group compared with the placebo group, mean maximum antibiotic gastric juice concentrations (in milligram per liter) of metronidazole decreased from 33.6 to 8.3 (P = 0.0001), whereas those of clarithromycin were unchanged, and those of amoxicillin increased from 0.13 to 0.68 (P = 0.02). Omeprazole increased salivary concentrations of metronidazole (P = 0.02) but had no effect on clarithromycin concentrations (no amoxicillin was detectable in saliva). CONCLUSIONS: Omeprazole decreases the intragastric concentrations of metronidazole by reducing acid secretion and increases intragastric concentrations of amoxicillin partly by reducing gastric juice volume. Novel pharmacokinetic parameters have been described that provide an insight into the mechanisms underlying drug transfer across the blood-stomach barrier. PMID- 8690202 TI - Characteristics of lower esophageal sphincter relaxation induced by pharyngeal stimulation with minute amounts of water. AB - BACKGROUND & AIMS: Injection of minute amounts of water in the pharynx leads to a long-duration lower esophageal sphincter (LES) relaxation that is an important feature of a transient LES relaxation. The aims of this study were to determine if a pharyngeal stimulus-induced LES relaxation is associated with crural diaphragm inhibition, esophageal common cavity, and acid reflux in normal subjects. METHODS: Esophageal and LES pressure, crural diaphragm electromyographs, and pH were recorded in the fasting and postprandial states in normal subjects. The pharynx was stimulated by injection of water at bolus volumes of 0.05 and 0.1 mL and then in 0.1-mL increments. RESULTS: Pharyngeal stimulation induced a long-duration LES relaxation in the absence of swallow and esophageal peristalsis. In the fasting state, none of the LES relaxations induced by pharyngeal stimulation were associated with inhibition of crural diaphragm, esophageal common cavity, and acid reflux. In the postprandial periods, only 8% of the pharyngeal stimuli resulted in crural diaphragm inhibition and esophageal common cavity. Esophageal reflux was found only at the times of simultaneous LES and crural diaphragm relaxation. CONCLUSIONS: Stimulation of the pharynx has different effects on the LES and crural diaphragm. Relaxation of crural diaphragm along with LES relaxation is essential for the occurrence of gastroesophageal reflux in normal subjects. PMID- 8690201 TI - Hyperventilation alters colonic motor and sensory function: effects and mechanisms in humans. AB - BACKGROUND & AIMS. Hyperventilation-induced hypocapnia affects hemodynamic function and enhances colonic motility. The aims of this study were to determine the effects of hypocapnic hyperventilation on colonic motility and sensation in health and to explore the putative neurohumoral mechanisms. METHODS: In experiment 1, colonic tone, sensation, plasma levels of cortisol, beta-endorphin, selected gut neuropeptides, norepinephrine, epinephrine, and splanchnic blood volume were measured during two sequences of hypocapnic hyperventilation. In experiment 2, colonic tone and sensation were assessed during eucapnic hyperventilation and abdominal compression. RESULTS: Hypocapnic hyperventilation, but not eucapnic hyperventilation or abdominal compression, significantly increased colonic tone and sensitivity to balloon distention (P = 0.017) without altering humoral mediators or splanchnic blood volume. Plasma norepinephrine level increased (P = 0.017) and splanchnic blood volume decreased (P = 0.028) during 5 minutes after hyperventilation, consistent with homeostatic responses. CONCLUSIONS: Increased colonic tone and sensation during hypocapnic hyperventilation are not caused by colonic compression. These effects of hyperventilation are not mediated humorally but may result from direct metabolic effects of hypocapnia on colonic muscle or from changes in central autonomic control of colonic smooth muscle. PMID- 8690203 TI - Care of patients with upper gastrointestinal hemorrhage in academic medical centers: a community-based comparison. AB - BACKGROUND & AIMS: A common perception among purchasers is that academic medical centers are inefficient and overutilize technology; however, little empirical information exists. The aim of this study was to compare treatment and outcomes of patients with upper gastrointestinal hemorrhage admitted to major teaching hospitals and other hospitals in a large metropolitan area. METHODS: Data on 3801 consecutive eligible patients admitted to five major teaching hospitals and 25 other hospitals from 1991 to 1993 were obtained by review of medical records. Admission severity of illness was measured using validated multivariable models. RESULTS: Rates of upper endoscopy were somewhat lower among the 1004 patients discharged from fellowship hospitals, compared with the other 2797 patients (82.9% vs. 85.6%; P < 0.05), and the use of other procedures was similar. Although patients admitted to fellowship hospitals tended to have a higher severity of illness, both unadjusted (6.3 +/- 9.0 vs. 7.1 +/- 7.5 days; P < 0.01) and risk-adjusted length of stay were somewhat shorter. Mortality rates were similar between hospitals, and patients admitted to fellowship hospitals were somewhat less likely to be transfused. CONCLUSIONS: In patients with upper gastrointestinal hemorrhage, teaching hospitals do not appear to provide inefficient care or overutilize expensive treatments when compared with community facilities. These findings are noteworthy at a time when viability of academic centers and fellowship training is threatened. PMID- 8690204 TI - The influence of Helicobacter pylori infection on postprandial duodenal acid load and duodenal bulb pH in humans. AB - BACKGROUND & AIMS: Recently, we postulated a new concept of duodenal ulcer pathogenesis suggesting that antral Helicobacter pylori infection blocks inhibitory pathways to the gastrin and parietal cells, resulting in an increased and prolonged postprandial acid secretion. the aim of this study was to examine duodenal acid load and duodenal bulb pH after a meal before and after eradication of H. pylori. METHODS: Using a marker-dilution method and a pH electrode in the duodenal bulb, gastric emptying, acid secretion, gastrin release, duodenal acid load, and duodenal bulb pH were studied during 2 hours after peptone meals of pH 7.0 and 2.0 in 8 H. pylori-negative controls and 8 H. pylori-infected subjects before and 6 months after eradication. RESULTS: The H. pylori-infected subjects had an increased gastric emptying, gastrin release, and acid secretion, higher duodenal acid load, and lower duodenal bulb pH after the meals. These responses were normalized after eradication. CONCLUSIONS: H. pylori-infected subjects have an increased and prolonged postprandial acid secretion, partly caused by an impaired low pH inhibition of acid secretion, gastrin release, and gastric emptying, resulting in an increased duodenal acid load and a prolongation of low pH in the duodenal bulb, as a general prerequisite for the development of duodenal ulcer disease. PMID- 8690205 TI - Choline acetyltransferase immunoreactivity in the human small and large intestine. AB - BACKGROUND & AIMS: Choline acetyltransferase, an enzyme involved in the synthesis of acetylcholine, is a marker of cholinergic neurons. In this study, the distribution of choline acetyltransferase immunoreactivity in human intestine is described. METHODS: Frozen-section and whole-mount preparations of human small and large bowels were made and labeled with antiserum to choline acetyltransferase. Double labeling with antiserum to neuron-specific enolase enabled the proportion of all neurons that were immunoreactive for choline acetyltransferase to be determined. RESULTS: Nerve fibers, immunoreactive for choline acetyltransferase, were frequent in the circular and longitudinal muscle layers and were widespread in the myenteric and submucous plexuses, but none was observed in the mucosa. Myenteric neurons, immunoreactive for choline acetyltransferase, showed various morphologies, the most common being unipolar and having an irregular outline with several short, lamellar processes. Sixty four percent of all myenteric neurons were immunoreactive for choline acetyltransferase. Cholinergic submucous neurons were homogeneous in appearance with oval, smooth cell bodies and filamentous dendrites and accounted for 53% of all submucous neurons. A number of cells resembling enteroendocrine cells in the epithelium of the small and large bowels had intense choline acetyltransferase immunoreactivity. CONCLUSIONS: The majority of neurons in human small and large intestines are cholinergic. PMID- 8690206 TI - Nitric oxide inhibits rat intestinal secretion by Clostridium difficile toxin A but not Vibrio cholerae enterotoxin. AB - BACKGROUND & AIMS: Intestinal inflammation is associated with increased synthesis of nitric oxide, whereas inhibition of NO synthase (NOS) reduces experimental chronic intestinal inflammation. The aim of this study was to test the effects of NO blockers and donors on acute intestinal inflammation induced by Clostridium difficile toxin A in rat ileum. METHODS: Rats received NOS inhibitors or NO donors before measurement of toxin-mediated ileal secretion and permeability changes. Mucosal mast cell and neutrophil activity were measured by release of rat mast cell protease II and myeloperoxidase activity, respectively. RESULTS: NOS inhibitors augmented but an NO donor inhibited toxin A-mediated ileal secretion and permeability when given before but not after toxin administration. Neither an NOS inhibitor nor an NO donor had any effect on cholera toxin-mediated secretion. Mast cell degranulation and neutrophil infiltration occurred after injection of toxin A or an NOS inhibitor, whereas the NO donor blocked both toxin A effects. CONCLUSIONS: NOS inhibitors augmented and an NO donor blocked the intestinal effects of toxin A but not of cholera toxin. NO protects against toxin A by inhibition of intestinal mast cells and neutrophils, which are activated by toxin A, but not by cholera toxin. PMID- 8690207 TI - Helicobacter pylori urease is a potent stimulus of mononuclear phagocyte activation and inflammatory cytokine production. AB - BACKGROUND & AIMS: Helicobacter pylori surface proteins induce the production of proinflammatory mediators by mononuclear phagocytes, but the protein responsible for this stimulation has not been identified. This study determined whether urease, the major component of the soluble proteins extracted from H. pylori grown in culture, activates mononuclear phagocytes and stimulates them to produce proinflammatory cytokines. METHODS: Primary human blood monocytes were incubated with column-purified H. pylori urease and assayed by flow cytometry, Immunoassay, and reverse-transcription polymerase chain reaction for phenotypic, functional, and molecular evidence of activation. RESULTS: H. pylori urease induced monocyte expression of surface interleukin 2 receptors and increased expression of HLA-DR, phenotypic changes consistent with activation. Urease also stimulated dose dependent production of interleukin 1 beta, interleukin 6, interleukin 8, and tumor necrosis factor alpha peptides and messenger RNA. These urease-induced phenotypic and functional changes were inhibited by preincubation of the urease with antisera to H. pylori whole bacteria, purified urease, or the 31-kilodalton subunit of urease. CONCLUSIONS: Among the soluble proteins released by H. pylori, urease is capable of activating monocytes for proinflammatory cytokines production. The local production of cytokines by urease-stimulated mononuclear phagocytes may play a central role in the development of H. pylori gastroduodenal inflammation. PMID- 8690208 TI - Association of gastric adenocarcinoma with the HLA class II gene DQB10301. AB - BACKGROUND & AIMS: The HLA class II gene DQB1*0301 has been linked to several cancers. This study was designed to determine if HLA-DQB1*0301 is present at altered frequency in patients with gastric, colorectal, or pancreatic adenocarcinoma. METHODS: Oligotyping for HLA-DQB1*0301 was performed for 159 Caucasian patients with 160 gastrointestinal adenocarcinomas (52 gastric, 62 colorectal, and 46 pancreatic adenocarcinomas) and compared with 260 Caucasian noncancer controls. Patients with gastric adenocarcinoma underwent extended HLA class II region oligotyping. Immunoglobulin G to Helicobacter pylori was detected by enzyme-linked immunosorbent assay. RESULTS: HLA-DQB1*0301 was more common in patients with gastric adenocarcinoma than controls (54% vs. 27%; bonferroni corrected chi 2 P = 0.003; odds ratio, 3.2). HLA-DQB1*0301 was not associated with colorectal or pancreatic adenocarcinoma. No other HLA-DQB1 allele and no HLA DQA1 or transporter associated with antigen processing 2 (TAP2) allele were present at altered frequency in patients with gastric adenocarcinoma. Serological evidence for H. pylori infection was less frequent in HLA-DQB1*0301-positive patients with gastric adenocarcinoma compared with HLA-DQB1*0301-negative patients (52% vs. 88%; Fisher's Exact Test; P = 0.007). CONCLUSIONS: HLA DQB1*0301 is more common in caucasian patients with gastric adenocarcinoma than noncancer controls. The mechanism linking HLA-DQB1*0301 with gastric adenocarcinoma is not likely through increased susceptibility to H. pylori infection. PMID- 8690209 TI - A receptor decoy inhibits the enterotoxic effects of Clostridium difficile toxin A in rat ileum. AB - BACKGROUND & AIMS: Clostridium difficile toxin A causes secretion and intestinal inflammation in rodents by binding to a specific trisaccharide Gal alpha 1-3Gal beta 1-4 GlcNAc on enterocyte receptors. The purpose of this study was to explore the ability of Synsorb 90 (Synsorb Biotech Inc., Calgary, Alberta, Canada), and inert support carrying this trisaccharide, to bind toxin A in vitro and to inhibit its enterotoxic effects in vivo. METHODS: Binding of [3H]toxin A to Synsorb 90, Synsorb 83 (beta-mannose attached), and Chromosorb P (inert support with no sugar attached) (Synsorb Biotech Inc.) was measured. The inhibitory effects of these compounds on toxin A-mediated fluid secretion, mannitol permeability, and histological damage were measured in ileal loops in vivo. RESULTS: Toxin A showed specific binding to Synsorb 90, bearing the specific trisaccharide that binds toxin A, but not to Synsorb 83 or to Chromosorb P. Pretreatment of rats with Synsorb 90 by gavage (200 mg/kg body wt), but no Synsorb 83 or Chromosorb P at the same doses, dramatically reduced toxin A associated fluid secretion and permeability. CONCLUSIONS: An immobilized toxin A receptor sequesters toxin A in the intestinal lumen and inhibits its effects of ileal mucosa. These results suggest a potential use for this agent in treating patients with C. difficile colitis. PMID- 8690210 TI - Cytomegalovirus DNA level on biopsy specimens during treatment of cytomegalovirus gastrointestinal disease. AB - BACKGROUND & AIMS: There is no clear and point for the response to treatment of gastrointestinal human cytomegalovirus (HCMV) disease. HCMV-DNA quantitation on gastrointestinal biopsy specimens has proven its value for the diagnosis of gastrointestinal HCMV disease in patients with acquired immunodeficiency syndrome (AIDS). The aim was to study HCMV-DNA levels on gastrointestinal biopsy specimens during the treatment of gastrointestinal HCMV disease. METHODS: HCMV-DATA quantitation was performed using two different polymerase chain reaction assays on 90 biopsy specimens obtained before anti-HCMV therapy, during the induction phase, or during maintenance therapy for gastrointestinal HCMV disease in 21 patients with AIDS. RESULTS: HCMV-DNA was detected on all the biopsy specimens ranging from 9 to > or = 80,000 Eq/0.1 microgram DNA. Pretherapeutic mean level was 69,000 +/- 27,000 Eq/0.1 microgram DNA. Induction therapy was followed by a mean decrease of 1.7 +/- 1.3 log10 Eq/0.1 microgram DNA. HCMV-DNA levels decreased during induction therapy to < 1000 Eq/0.1 microgram DNA in 60% of patients but remained > 80,000 Eq/0.1 microgram DNA in 20% of patients. Relapse occurred in all the patients in a mean time of 100 days. HCMV-DNA level at the end of the induction phase seems to influence the time to relapse. CONCLUSIONS: Quantitation of HCMV-DNA on gastrointestinal biopsy specimens seems to be useful for monitoring gastrointestinal HCMV disease in patients with AIDS. PMID- 8690211 TI - Characterization of Prostaglandin G/H Synthase 1 and 2 in rat, dog, monkey, and human gastrointestinal tracts. AB - BACKGROUND & AIMS: In the gastrointestinal tract, prostaglandins are implicated as important mediators of normal physiological processes. Prostaglandin G/H synthase (PGHS) is the first enzyme leading to the formation of prostaglandins. Two forms exist: the constitutive PGHS-1 and the inducible PGHS-2 isoforms. The purpose of this study was to examine the expression of PGHS-1 and -2 in gastrointestinal tissues. METHODS: PGHS-1 and -2 expression and activity were examined in rat, dog, monkey, and human gastrointestinal tracts by immunoblot and biochemical assays. RESULTS: PGHS-1 but not PGHS-2 protein was identified in all gastrointestinal tissues. PGHS-1 protein varied throughout the gastrointestinal tracts; interspecies differences were also noted. Immunohistochemical studies showed PGHS-1 staining of rat endothelial cells in all gastrointestinal regions; PGHS-2-specific staining was noted in a subset of macrophages in 3 of 22 rats examined. Elevated activity was shown in tissues expressing greater concentrations of PGHS-1 protein. Indomethacin, a nonsteroidal anti-inflammatory drug that inhibits both isoforms, inhibited prostaglandin synthesis, whereas NS 398, a selective PGHS-2 inhibitor, showed little or no inhibition of prostaglandin synthesis in gastrointestinal tissues. CONCLUSIONS: These results indicate that prostaglandins produced in normal gastrointestinal tissue and required for normal physiological functioning are derived from the PGHS-1 isoform. PMID- 8690212 TI - Clonal analysis of precancerous lesion of hepatocellular carcinoma. AB - BACKGROUND & AIMS: It remains to be established whether precancerous lesion (dysplastic nodule) of hepatocellular carcinoma (HCC) is a neoplastic or hyperplastic lesion. Clonal analysis of this lesion was conducted to elucidate this important issue on histogenesis. METHODS: The method for clonal analysis was based on restriction fragment length polymorphism of the X chromosome-linked phosphoglycerokinase gene and on random inactivation of the gene by methylation. Clonal somatic mutations were also analyzed by DNA fingerprinting with two multilocus probes (33.6 and 33.15), and loss of heterozygosity was studied using five single-locus probes (MS1[1p33-p35], MS31[7p22-pter], MS43a[12q24.3-qter], MS8[5q35-qter], and g3[7q36-qter]). RESULTS: Clonal analysis by the phosphoglycerokinase gene-based method showed that all of the five dysplastic nodules and seven HCCs were monoclonal in origin. DNA fingerprinting showed clonal somatic mutations in six of 10 dysplastic nodules and in six of nine HCCs. Loss of heterozygosity was found in one dysplastic nodule (7p22-pter) and two HCCs (1p33-p35 and 12q24.3-qter). CONCLUSIONS: These results confirm monoclonality of HCC and show that hepatic precancerous lesion (dysplastic nodule) is not a hyperplastic but a neoplastic lesion, consisting of monoclonal cells with genetic alterations. PMID- 8690213 TI - Interferon gamma plays a critical role in T cell-dependent liver injury in mice initiated by concanavalin A. AB - BACKGROUND & AIMS: T cell-dependent liver injury involving endogenous tumor necrosis factor (TNF) alpha can be induced by either concanavalin A in naive mice or by activating anti-CD3 antibody or staphylococcal enterotoxin B in D galactosamine-sensitized mice. In this study, the role of interferon gamma (IFN gamma) in these T-cell models was addressed. METHODS: Mice were pretreated with a neutralizing anti-mouse IFN-gamma antiserum before injection of T cell-activating agents. Plasma cytokine and transaminase levels were determined. Apoptotic cell death was assessed by hepatic DNA fragmentation. RESULTS: Anti-IFN-gamma antiserum significantly protected mice from concanavalin A-induced liver injury. Circulating IFN-gamma was completely suppressed, and TNF was reduced by 50%. Recombinant TNF-alpha administered to mice treated with concanavalin A and anti IFN-gamma antiserum failed to initiate liver injury. Similar results were obtained with recombinant IFN-gamma in concanavalin A-challenged mice under the condition of TNF neutralization. Neither hepatic DNA fragmentation nor release of transaminases was inhibited by anti-IFN-gamma antiserum when liver injury was induced by staphylococcal enterotoxin B or anti-CD3 antibody in D-galactosamine sensitized mice. CONCLUSIONS: Both TNF as well as IFN-gamma are critical mediators of liver injury in concanavalin A-treated mice, whereas hepatic DNA fragmentation and liver failure in the D-galactosamine models depend only on TNF. PMID- 8690214 TI - Lobular distribution of human liver phenol and bilirubin uridine 5'-diphosphate glucuronosyltransferase messenger RNAs. AB - BACKGROUND & AIMS: Heterogeneity in uridine 5'-diphosphate (UDP) glucuronosyltransferase expression across the human hepatic acinus may be important in the manifestation of certain zone-specific chemical hepatotoxicities. Previous immunohistochemical studies suggested that a phenol transferase induced by polycyclic aromatic hydrocarbons may be differentially expressed in centrilobular hepatocytes of rats. The aim of this study was to assess the distribution of the phenol and bilirubin transferases in human liver at the RNA level. METHODS: In situ RNA hybridization was used with two human liver samples and specific probes for the phenol transferase RNA, HLUG P1, and the bilirubin transferase RNAs, HUG-Br1 and HUG-Br2. RESULTS: The highest density signals were observed for the bilirubin transferase RNAs, both appearing to be evenly expressed in hepatocytes across the liver lobule. Slightly higher density of HUG-Br1 message was observed in some centrilobular hepatocytes surrounding larger central vein structures. HLUG P1 RNA was expressed at low levels (approximately fivefold greater than background signal) and was evenly distributed. CONCLUSIONS: The data suggest that a species difference exists in the distribution of the human and rat phenol transferase. No evidence was found for significant zonation in the pattern of expression of either the phenol or bilirubin transferase genes in human liver. PMID- 8690215 TI - Progressive disruption of acinar cell calcium signaling is an early feature of cerulein-induced pancreatitis in mice. AB - BACKGROUND & AIMS: Disruption of pancreatic exocrine secretion is an important feature of acute pancreatitis. Because cytosolic calcium is a key intracellular messenger controlling pancreatic secretion, this study examined patterns of calcium signaling during the early stages of cerulein-induced pancreatitis. METHODS: Mice were administered hourly intraperitoneal injections of cerulein (50 micrograms/kg), and paired controls were administered saline. Acini were isolated by collagenase from pancreatic tissue harvested after injections 1, 3, 5, and 7 and were loaded with Fura-2. Individual cellular calcium responses to acetylcholine and cholecystokinin were studied using digital imaging. RESULTS: The proportion of cells maintaining a normal oscillatory calcium response to physiological secretagogue stimulation diminished progressively after increasing cerulein injections. Also, the normal polarized spatial pattern of calcium Increase within individual acinar cells was progressively lost. A sustained response to high-dose stimulation was maintained but with diminishing amplitude. The characteristic calcium response to the Ca(2+)-adenosine triphosphatase inhibitor thapsigargin was maintained, implying that calcium reuptake and extrusion were not impaired. CONCLUSIONS: Progressive disruption of physiological patterns of pancreatic acinar cell calcium signaling, notably in the secretory pole of the cell, is an early feature of pancreatitis induced by cerulein hyperstimulation. These changes may be important in contributing to the disruption of exocrine secretion in acute pancreatitis. PMID- 8690217 TI - Successful practice in a managed care environment: managing costs while managing care. PMID- 8690216 TI - A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract. AB - Electrical rhythmicity in gastrointestinal muscles has been studied for a century, but the pacemakers driving this phenomenon have been elusive. Anatomic studies suggest that interstitial cells of Cajal (ICC) may be pacemakers and conductors of electrical activity. ICC may also mediate neurotransmission from enteric neurons. Functional evaluations of ICC include the following. (1) Electrophysiology experiments on dissected muscle strips show that slow waves originate from specific sites. These pacemaker areas are populated by networks of ICC that make gap junctions with smooth muscle cells. Removal of pacemaker regions interferes with slow wave generation and propagation. (2) Chemicals that label ICC histochemically can damage ICC and abolish rhythmicity. (3) isolated ICC are spontaneously active, and several voltage-dependent ion channels, including a low-threshold Ca2+ conductance, are expressed. (4) ICC are innervated by enteric neurons, and they respond to neurotransmitters. ICC may produce nitric oxide and amplify inhibitory neurotransmission. (5) Some classes of ICC fall to develop in animals with mutations in c-kit or stem cell factor, the ligand for c Kit receptors. Without ICC, electrical slow waves are absent. Many questions remain about the function of ICC, but modern technologies should now facilitate rapid progress toward determining the role of these cells in normal physiology and pathological conditions. PMID- 8690218 TI - Loss of DNA mismatch repair: life in the fast lane? PMID- 8690219 TI - Pharmacology of the gastric mucosa: a rational approach to Helicobacter polytherapy. PMID- 8690220 TI - HLA and disease association: the case of gastric cancer. PMID- 8690221 TI - Cirrhosis and hepatocellular neoplasia: more like cousins than like parent and child. PMID- 8690222 TI - Identification of K-ras mutations: from microscope to endoscope. PMID- 8690223 TI - "Kapping" visceral pain in patients with irritable bowel syndrome: does it work? PMID- 8690224 TI - Dual nature of colonic crypts revealed. PMID- 8690225 TI - Training and education in gastroenterology. List of available training programs. PMID- 8690226 TI - Massive ascitic fluid loss after liver transplantation. PMID- 8690227 TI - Barrett's esophagus. PMID- 8690228 TI - Ki-ras mutations in chronic pancreatitis: which relevance? PMID- 8690229 TI - Apoptosis in the intestine. PMID- 8690230 TI - Hepatobiliary function and toxicity in vitro using isolated hepatocyte couplets. AB - 1. Hepatocyte couplets can be routinely prepared from rat liver to produce a suitable in vitro model for polarized primary cells. 2. Centrifugal elutriation provides a means of producing enriched subpopulations of periportal and perivenous couplets from the same liver, thus providing a means of studying the influence of zonal heterogeneity on hepatobiliary function. 3. The maintenance of structural and secretory polarity demonstrated by hepatocyte couplets provides a convenient in vitro system for mechanistic studies of factors both regulatory and adversely affecting hepatobiliary functions. 4. Couplets are also uniquely appropriate for specific studies of regulation at the biliary pole, on the performance of junctions and on the maintenance and rate of transcytotic movement. 5. The possibility also exists that effects of an in vivo pre-exposure to agents causing hepatobiliary dysfunction can be assessed in couplets ex vivo. PMID- 8690231 TI - Non-steroidal anti-inflammatory drug-induced gastric damage in experimental animals: underlying pathological mechanisms. AB - A major impetus to experimental studies examining the pathogenesis of NSAID induced gastric damage is the hope that key mechanisms can be identified that may lead to the design of "safer" NSAIDs or to the development of novel cytoprotectives to co-administer with current NSAIDs. Virtually every hypothesis proposed to explain the pathogenesis of NSAID-induced gastric damage has arisen from studies examining fundic lesions. Our results suggest that not only is the pathogenesis of gastric damage in the fundus and antrum of the rat potentially very different but that it is NSAID-induced damage to the rat gastric antrum (and not the fundus) that more closely resembles that of humans. Thus, hypotheses constructed from experimental studies examining fundic damage may not be predictive of the clinical setting. We would suggest, therefore, that future studies should concentrate on studying the pathogenesis of antral ulceration induced by NSAIDs. In particular, we believe that future research should assess whether NSAIDs do indeed reduce blood flow in the gastric antrum and define the mechanism(s) involved. Identification of these processes should significantly advance our understanding of antral ulceration and may suggest novel approaches in the design of cytoprotective agents. Recent work has established that two distinct forms of the enzyme cyclooxygenase (COX) can catalyse the metabolism of arachidonic acid and initiate prostaglandin synthesis. It is hypothesised (De Witt et al., 1993) that the analgesic/anti-inflammatory effect of current NSAIDs is achieved through inhibition of COX 2, whereas their side effects (such as antral ulceration) result as a consequence of inhibition of gastric COX 1. The recently described selective inhibitor of COX 2, NS398, has been shown to be analgesic and anti-inflammatory without causing gastric ulceration (Futaki et al., 1993; Masferrer et al., 1994). If key mechanisms (such as alterations in blood flow) of NSAID-induced antral damage can be identified, then it would be hypothesised that selective inhibitors of COX 1 would be ulcerogenic and reduce antral blood flow, whereas inhibitors of COX 2 would not share either of these properties. If this hypothesis can be substantiated, then inhibitors of COX 2 may be the next generation of "gastric safe" NSAIDs. PMID- 8690232 TI - Dapsone toxicity: some current perspectives. AB - 1. Dapsone is a potent anti-inflammatory and anti-parasitic compound, which is metabolised by cytochrome P-450 to hydroxylamines, which in turn cause methaemoglobinaemia and haemolysis. However, during the process of methaemoglobin formation, erythrocytes are capable of detoxifying the hydroxylamine to the parent drug, which may either reach the tissues to exert a therapeutic effect or return to the liver and be re-oxidised in a form of systemic cycling. This glutathione-dependent effect, combined with the un-ionised state of the drug at physiological pH, may contribute to its efficacy. 2. Paradoxically, other aspects of the glutathione-dependent cycling of the hydroxylamine metabolite may contribute to the major adverse reaction of the drug, agranulocytosis. Erythrocytes exposed to the metabolite and repeatedly washed may still release the hydroxylamine in sufficient concentration to kill mononuclear leucocytes in vitro. Thus, erythrocytes may be a conduit for the hydroxylamine to reach the bone marrow to covalently bind to granulocyte precursors, which may trigger an immune response in certain individuals and may lead to the potentially fatal eradication of granulocytes from the circulation. 3. Attempts to increase patient tolerance to dapsone have been most successful using a metabolic inhibitor to reduce hepatic oxidation of the drug to the hydroxylamine. Methaemoglobin formation in the presence of cimetidine was maintained at 30% below control levels for almost 3 mo, and patients' reported side effects such as headache and lethargy were significantly reduced. 4. As clinical application of new and safer dapsone analogues is years away, the use of cimetidine provides an immediate route to increasing patient compliance during dapsone therapy, especially in those maintained on dapsone dosages in excess of 200 mg/day. PMID- 8690233 TI - Metabolism of Zidovudine. AB - 1. The anti-HIV drug zidovudine (3'-azido-2',3'-dideoxythymidine; ZDV) has three important pathways of metabolism. ZDV is a prodrug and must be phosphorylated in lymphocytes in order to exert its antiviral action. However, in quantitative terms this is a minor pathway probably accounting for less than 1% of the overall metabolic profile. The predominant pathway of metabolism is glucuronidation to GZDV and the metabolite is renally excreted. A further metabolite, derived by reduction of the azido moiety is 3'-amino-3'-deoxythymidine (AMT). 2. Zidovudine glucuronidation has been characterised in human liver microsomes. A number of drugs (e.g., naproxen, indomethacin and probenecid) have been shown to inhibit the in vitro conjugation of ZDV. Some of these drugs have also been co administered with ZDV in HIV-positive patients. Significant pharmacokinetic interactions have been demonstrated with probenecid, naproxen and fluconazole. 3. 3'-amino-3'-deoxythymidine formation is probably mediated by both cytochrome P450 isozymes and NADPH-cytochrome P450 reductase. Peak plasma concentrations of AMT are approximately 10-15% of ZDV in patients. This is a potentially important metabolite because of its alleged cytotoxicity. 4. Measurement of intracellular ZDV phosphates in patients provides the key to our understanding of both the efficacy and toxicity of ZDV. Important recent work has demonstrated that as patients deteriorate (i.e., CD4 counts decrease below 100 x 10(6)/L), there is a corresponding increase in intracellular ZDV-monophosphate. This could have toxicological implications. PMID- 8690234 TI - Gentamicin nephrotoxicity in humans and animals: some recent research. AB - It would appear from the literature cited in this article, that interest in gentamicin nephrotoxicity is still thriving. Despite extensive studies, the mechanism(s) of the nephrotoxicity is uncertain. Several clinical and experimental strategies have been employed in order to ameliorate or abolish the signs of gentamicin nephrotoxicity. Most of these were unsuccessful, impractical or unsafe. Therefore there is still a need for further studies to elucidate the mechanism(s) of action of the drugs nephrotoxicity, and to discover safe, practical and effective agents to ameliorate the nephrotoxicity in patients at risk. PMID- 8690235 TI - Thromboxane A2 receptor-mediated signal transduction in rabbit aortic smooth muscle cells. AB - 1. 9,11-Epithio-11,12-methenothromboxane A2 (STA2), a stable analogue of thromboxane A2 (TXA2), contracted rabbit aortic smooth muscles (RASM) and accumulated [3H]inositol phosphates in cultured RASM cells. The contraction and phosphoinositide hydrolysis were competitively inhibited by TXA2 receptor antagonists, including ONO NT-126, S-145, SQ29548, KW3635, GR32191B and ONO3708. 2. STA2 inhibited [3H]ONO NT-126 binding in a concentration-dependent manner in membranes derived from cultured aortic smooth muscle cells, but GTP gamma S, a stable GTP analogue, did not affect STA2-induced inhibition of [3H]ONO NT-126 binding. 3. The time course analysis revealed that STA2 rapidly decreased inositol phosphate level and therefter increased. Pertussis toxin did not attenuate but rather increased STA2-induced phosphoinositide hydrolysis. 4. TXA2 receptor stimulation results in at least two signaling pathways in RASM cells: stimulation and inhibition of phosphoinositide hydrolysis. PMID- 8690236 TI - Analysis of the mechanisms underlying the antinociceptive effect of the extracts of plants from the genus Phyllanthus. AB - 1. We examine some of the mechanisms underlying the analgesic effects of the hydroalcoholic extracts (HE) of Phyllanthus urinaria and P. niruri against formalin-induced nociception in mice. In addition, we also investigate the action of both HEs against capsaicin-mediated pain. 2. Both prazosin and yohimbine (0.15 mg/kg, i.p.) induced a marked inhibition of the analgesic effect caused by phenylephrine (10 mg/kg, i.p.) and clonidine (0.1 mg/kg, i.p.), respectively, but had no effect on the antinociceptive action caused by HE of P. urinaria (10 mg/kg, i.p.) or P. niruri (30 mg/kg, i.p.). 3. NG-nitro-L-arginine (L-NOARG, 75 mg/kg, i.p.) caused marked analgesic effect against the second phase of formalin induced pain. Treatment of animals with L-arginine (600 mg/kg) completely antagonized the antinociceptive effect of L-NOARG but had no significant effect against the HE of P. urinaria (10 mg/kg, i.p.) or P. niruri (30 mg/kg. i.p.) analgesic properties. 4. The antinociceptive effects caused by the HEs of P. urinaria (10 mg/kg, i.p.) and P. niruri (30 mg/kg, i.p.) were unaffected by methysergide (5 mg/kg, i.p.), p-chloro-phenylalanine-methyl-ester (100 mg/kg, i.p., once a day for 4 consecutive days) or after previous adrenalectomy of animals. 5. The HE of P. urinaria and P. niruri given either intraperitoneally (1 30 mg/kg) or orally (25-200 mg/kg) caused marked and dose-related inhibition of capsaicin-induced pain with ID50 of 2.1 and 6.1 mg/kg given intraperitoneally and 39 and 35 mg/kg given orally, respectively. PMID- 8690237 TI - Competitive and selective antagonistic action of NPC 17731 on bradykinin-induced relaxant and contractile responses of the guinea pig isolated ileum. AB - 1. The aim of the present study was to evaluate, by means of functional studies, the effect of the newly developed bradykinin (BK) receptor antagonist NPC 17731, D-Arg0, Arg1-Pro2-Hyp3-Gly4-Phe5-Ser6-[DHype (transpropyl)7]-Oic8-Arg9, against BK-mediated biphasic response in the guinea pig ileum "in vitro" (circular and longitudinal layers). 2. In the circular muscle, NPC 17731 (0.1-1000 nM) dose dependently and reversibly antagonized, with similar potency, both the contractile and relaxant responses caused by BK, as well as BK-induced contraction in longitudinal smooth muscle with IC50 of 23, 29 and 37 nM, respectively. 3. NPC 17731 (10-300 nM) also caused a concentration-dependent displacement to the right of BK-induced contraction and relaxant responses in the circular smooth muscle of guinea pig ileum, without changing BK maximal response. Schild plot analyses were linear (correlation close to 1), yielding pKb values of 8.89 +/- 0.19 and 8.73 +/- 0.18, respectively, and slopes not significantly different from unity, providing evidence that NPC 17731 acts as a pure B2 competitive receptor antagonist against both BK responses. 4. Similarly, NPC 17731 (3-100 nM) antagonized, in a graded and competitive manner, BK-induced contraction in longitudinal muscle from guinea pig ileum with a slope not different from unity, yielding a pKb value of 8.62 +/- 0.13. 5. These results indicate that the new B2 BK receptor antagonist NPC 17731 antagonizes, with high affinity and with similar potency through simple competitive and selective mechanisms, BK receptor-mediating contraction or relaxant responses in circular and longitudinal smooth muscles from guinea pig ileum. In addition, these results also suggest that although BK-induced contraction or relaxation responses in guinea pig ileum are coupled to distinct second messengers, NPC 17731 interacts with a homogeneous population of B2 receptors in both guinea pig ileum preparations. PMID- 8690238 TI - Bumetanide and bicarbonate increase short-circuit current in fetal lung epithelium. AB - 1. We studied the effects of bumetanide (a Na+/K+/2Cl- cotransport inhibitor) and HCO3(-) on beta-adrenergic-agonist-stimulated short-circuit current (beta-Isc) in rat fetal distal lung epithelium (FDLE). 2. Bumetanide significantly increased beta-Isc in the absence of amiloride but decreased it in its presence. The amiloride- and bumetanide-insensitive beta-Isc was diminished by a removal of HCO3(-) in the bathing solution. 3. Our results suggest that bumetanide stimulates the amiloride-sensitive beta-Isc in FDLE and that the amiloride insensitive beta-Isc is composed of two different pathways: bumetanide-sensitive and HCO3(-)-dependent Cl- secretion in FDLE. PMID- 8690239 TI - Influence of strip size and location on contractile responses of rat urinary bladder body strips. AB - 1. We investigated the influence of strip length and dorsal or ventral location of rat urinary bladder strips on contractile responsiveness. 2. No differences occurred in the contractile responses of 0.5, 1.0 and 2.0 cm strips to field stimulation, carbachol, ATP, substance P or to KCl when the data were expressed as either absolute tension or as tension per cross-sectional area. However, correction for strip mass resulted in significant decreases in the contractile responses of the 2.0-cm strips compared with the 0.5-cm strips. 3. No differences occurred in length-tension curves for ventral and dorsal bladder strips, even though the strips from the dorsal surface appeared thinner than those from the ventral surface. 4. Strips from the ventral surface exhibited more variability in response to field stimulation and were less sensitive to atropine pre-treatment than were those from the dorsal surface. They were also less sensitive to the contractile effects of carbachol than dorsal strips. Dorsal and ventral strips were equally responsive to ATP, substance P and KCl. 5. Our data indicate that the contractile responsiveness of rat urinary bladder strips is independent of strip length. Although there are some differences between the cholinergic responsiveness of strips from the ventral and dorsal surfaces of the bladder, the differences are so small that for most studies they will probably have no influence on data interpretation. PMID- 8690240 TI - Cholinergic receptor agonists inhibit pirenzepine-induced dysfunction of spontaneous alternation performance in the mouse. AB - 1. The present study was designed to examine the effects of intracerebroventricular injection of several cholinergic drugs on the impairment of spontaneous alternation performance induced by the M1-selective muscarinic receptor antagonist pirenzepine. 2. Pirenzepine (3 and 10 micrograms) significantly reduced spontaneous alteration performance related to working memory without producing any marked increase in total arm entries, which are considered to reflect locomotor activity. 3. Physostigmine (3.47 micrograms), a cholinesterase inhibitor, and McN-A-343 (20 micrograms), and M1-selective muscarinic receptor agonist, significantly improved the pirenzepine (3 micrograms)-induced impairment of spontaneous alternation performance, although oxotremorine (0.68 microgram), a nonselective muscarinic receptor agonist, showed a tendency to reverse the pirenzepine (3 micrograms)-induced impairment. 4. These findings suggest that the blockade of muscarinic M1 but not M2 receptors results in the impairment of spontaneous alternation performance associated with working memory. PMID- 8690242 TI - Screening for antibacterial agents in three species of sea cucumbers from coastal areas of Sabah. AB - 1. Three species of sea cucumbers found in the Sabah coastal areas were screened for the presence of antibacterial activity using three methods of extraction. Tests were conducted in vitro using the agar absorption method. 2. Both the lipid extract and the methanol-solvent extract from Holothuria atra, Holothuria scabra and Bohadshia argus were found to show no antibacterial activity. 3. Phosphate buffered saline (PBS) from H. atra and B. argus, however, inhibited the growth of all gram-positive and gram-negative bacteria. 4. Comparisons were also made between extracts from the outer layer of H. atra and its inner part, and it was found that the extract from the outer layer showed less bacterial growth inhibition property. 5. The bacterial growth inhibition property of the PBS extract from H. atra, however, is dependent on the extract's concentration. Bacterial growth inhibition was apparent after 48 hr incubation. PMID- 8690241 TI - Effects of acute and short-term repeated application of fullerene C60 on agonist induced responses in various tissues of guinea pig and rat. AB - 1. Effects of fullerene C60 in trachea, right atria, ileum and stomach (fundus) of guinea pig and vas deferens and uterus of rat were studied pharmacologically. 2. C60 (4 microM) had no direct effect in all tissues. In guinea pig trachea and heart, relaxation and positive inotropic and chronotropic actions of isoprenaline and in isolated rat vas deferens and uterus the responses on norepinephrine and oxytocin were not affected by the short-term repeated application of C60 30 mg/kg i.p. for 4 wk. 3. The pD2 values (potencies) of acetylcholine in ileum and its longitudinal muscle from guinea pig after the short-term repeated application of C60 were significantly smaller than those obtained without the application. The value of 5-hydroxytryptamine in rat stomach (fundus) also tended to be smaller than obtained without the application. 4. Atropine inhibited competitively the contractions for acetylcholine in the longitudinal muscles prepared from C60 treated and non-treated guinea pigs, and the pA2 values for atropine were not significantly different with each other. 5. These results suggest that C60 has no direct effects or antagonistic properties toward drug receptors, but sub-chronic exposure of C60 decreased responsiveness. This may be due to a change in post receptor processes. PMID- 8690243 TI - Adenosine A1 receptor enhancer, PD 81,723, and cerebral ischemia/reperfusion injury in the gerbil. AB - 1. The adenosine A1 receptor enhancer, PD 81,723, was tested for its neuroprotective activity in a Mongolian gerbil model of forebrain ischemia/reperfusion cerebral ischemia. 2. Gerbils were injected with PD 81,723 (1, 10 and 125 mg/kg i.p.) 20 min before a 5-min episode of forebrain ischemia. The extent of ischemic injury was assessed by monitoring the increases in locomotor activity and from the degree of damage to the CA1 hippocampal pyramidal cell layer after 5 days of recovery. 3. By both criteria, PD 81,723, at all three dose levels, failed to protect against ischemia/reperfusion evoked cerebral injury. PMID- 8690244 TI - Endothelin-1 inhibition of the ATP-sensitive K+ channel in guinea-pig ventricular cardiomyocytes. AB - 1. Effects of endothelin-1 on the ATP-sensitive K+ channel were examined in guinea-pig ventricular cardiomyocytes. 2. The ATP-sensitive K+ channel was activated outwardly with amplitude of about 2.2 pA at 0 mV. The conductance was 31 pS at 5.4 mM external K+ solution. The open probability was inhibited, and was completely blocked at 1 nM of endothelin-1. 3. In contrast, endothelin-3 (1 nM) did not cause any effects on the channels. 4. Endothelin-1 (10 nM) significantly prolonged the action potential duration. These responses were reversible. 5. These results suggest that endothelin-1 may reverse the physiological responses to the stimulation of ATP-sensitive K+ channels, indicating its regulatory mechanisms under the disease conditions. PMID- 8690245 TI - Inhibition of gastric mucosal mucin receptor by H. pylori lipopolysaccharide: effect of ebrotidine. AB - 1. H. pylori infection causes the loss of mucus coat continuity and its patchy appearance. Here, we present evidence that the bacterium, through its cell wall lipopolysaccharide, disrupts the interaction between mucin and its mucosal receptor, and that ebrotidine is capable of counteracting this process. 2. The receptor for mucin, isolated from the solubilized gastric epithelial cell membrane by affinity chromatography on Sepharose-bound wheat germ agglutinin, displayed a molecular weight of 97 kDa and exhibited specific affinity towards mucin-coated surface. 3. The mucin binding to the receptor was susceptible to the inhibitin by H. pylori lipopolysaccharide and reached a maximum of 91%. This effect of the lipopolysaccharide was counteracted by ebrotidine, which caused a dose-dependent relief of the lipopolysaccharide inhibitory effect with maximum restoration in mucin-receptor binding of 51% at 60 microliters/ml ebrotidine. 4. The results show that H. pylori, through its lipopolysaccharide, is capable of disrupting the integrity of mucus perimeter of gastric mucosal defense and that antiulcer agent, ebrotidine, counteracts this untoward effect. PMID- 8690246 TI - Effects of KRN2391, a novel vasodilator acting as a nitrate and a K+ channel opener, on the rabbit lower urinary tract. AB - 1. The relaxant effect of KRN2391, suggested to act both as a nitrate and a K+ channel opener, was investigated in the rabbit lower urinary tract and compared with the effects of the NO-donor SIN-1 and the K+ channel opener levcromakalim. 2. KRN2391 10(-4) M was able to relax precontracted urethral preparations by 87 +/- 4%. Corresponding values for levcromakalim 10(-4) M and SIN-1 10(-4) M were 58 +/- 8% and 103 +/- 2%, respectively. The -logEC50 values for KRN2391, SIN-1 and levcromakalim were 6.0 +/- 0.1, 4.9 +/- 0.2 and 5.8 +/- 0.2. The relaxant effect of KRN2391 on the bladder was small (29 +/- 3%). 3. The levels of cyclic GMP in the urethral preparations were significantly increased after administration of KRN2391 10(-4) M and SIN-1 10(-4) M, but not after levcromakalim 10(-4) M, the levels measured being 9.9 +/- 2.2, 20.9 +/- 5.1, and 5.2 +/- 1.0, compared to the control value, 3.7 +/- 0.5 pmol/mg protein. The levels of cyclic AMP were, however, not changed. 4. The relaxations, caused by KRN2391 in the urethral preparations, were accompanied by a hyperpolarization (14 +/- 4 mV) of the membrane potential. 5. Methylene blue 3 x 10(-5) M and glibenclamide 10(-5) M significantly reduced the relaxant effect of KRN2391 in the urethral smooth muscle. 6. We suggest that in the rabbit lower urinary tract, KRN2391 acts mainly as an NO-donor. PMID- 8690247 TI - Functional and antiischaemic effects of Monoacetyl-vitexinrhamnoside in different in vitro models. AB - 1. Functional and antiischaemic effects of monoacetyl-vitexinrhamnoside (AVR), a flavonoid with phosphodiesterase (PDE)-inhibitory properties contained in Crataegus species (Hawthorn, Rosaceae) were studied in several in-vitro models. 2. In rabbit isolated femoral artery rings, AVR concentration-dependently reduced developed tension. Vasodilation by AVR was reduced after inhibiting EDRF formation by L-NG-nitro arginine. 3. In spontaneously-beating Langendorff-guinea pig hearts, AVR concentration-dependently enhanced heart-rate, contractility, lusitropy and coronary flow. 4. In isolated electrically-driven Langendorff rabbit hearts, acute regional ischemia (MI) was induced by coronary artery occlusion and quantified from epicardial NADH-fluorescence photography. AVR (5 x 10(-5) mol/l) induced a slight numerical increase of left ventricular pressure and coronary flow (p > 0.05). MI was reduced (p < 0.05). 5. Monoacetyl vitexinrhamnoside is an inodilator whose vasodilatory action may be mediated in part by EDRF in addition to PDE-inhibition. Monoacetyl-vitexinrhamnoside does possess marked antiischemic properties even in isolated hearts, suggesting an improvement of myocardial perfusion. PMID- 8690248 TI - Endothelial modulation of vascular tone and 5-hydroxytryptamine-induced responses in human chorionic arteries and veins. AB - 1. In vitro studies were undertaken to evaluate the potential role of endothelium through release of vasodilators compounds on basal tension and on vasoconstrictor response induced by 5-hydroxytryptamine (5-HT) in chorionic arteries and veins rings from normotensive gestants. 2. N omega-nitro-L-arginine (100 microM) and methylene blue (10 microM) increased significantly the basal tension in chorionic arteries but not in veins. However, indomethacin (10 microM) inhibited the basal tension in both kinds of vessels. 3. The sensitivity to 5-HT was significantly lower in placental arteries than in veins. Removal of endothelium increased the sensitivity of placental arteries to 5-HT in 2.2-fold; however, in veins denudation had no significant effect. 4. N omega-nitro-L-arginine potentiated the 5-HT-induced tone in both types of vessels, but the increase of contraction was greater in chorionic arteries than in veins. However, indomethacin decreased the 5-HT-induced contractions in arteries and veins. 5. These results indicate that NO is more important than vasodilators prostanoids in the control of vascular tone and in 5-HT-induced placental contractile response. PMID- 8690249 TI - Modification by muscimol of naloxone-precipitated withdrawal symptoms in morphine dependent mice. AB - 1. In morphine-dependent mice, muscimol, a GABAA agonist when given i.p. 30 min before naloxone, attenuated the naloxone-precipitated withdrawal symptoms of jumping, "wet dog" shakes and burrowing, but not body weight loss. 2. Muscimol produced a hypothermic effect which was further aggravated by naloxone. PMID- 8690250 TI - Regulation of exocytosis by the small GTP-binding protein Rho in rat basophilic leukemia (RBL-2H3) cells. AB - 1. We investigated the effect of Clostridium botulinum C3 ADP-ribosyltransferase upon beta-hexosaminidase release induced by various stimuli from streptolysin-O (0.5-1 U/ml)-permeabilized rat basophilic leukemia (RBL-2H3) cells. 2. The C3 transferase inhibited beta-hexosaminidase release induced by Ca2+ or by guanosine 5'-(3-thiotriphosphate) (GTP gamma S) plus Ca2+. 3. The C3 transferase also inhibited beta-hexosaminidase release induced by stimulating high affinity IgE and m3 muscarinic acetylcholine receptors. 4. The substrate for the C3 transferase was present in cytosol of RBL-2H3 cells, indicating the presence of rho p21. About 60% of the total cellular substrate protein remained within the cells permeabilized by 1 U/ml of streptolysin-O. 5. The protein rho p21 appears to be regulated by several pathways and it may function as an integration point for exocytosis. PMID- 8690251 TI - Dantrolene blocks the tonic contractions to carbachol and histamine with smaller effects on the phasic due to release of intracellular Ca2+ in ileal longitudinal muscle. AB - 1. Dantrolene (10(-5)-10(-4) M) inhibited carbachol- or histamine-induced tonic response according to the decrease in Ca2+ uptake as determined by La method more than the phasic response in ileal muscle. However, dantrolene further reduced the second phasic response to sequential application of carbachol or histamine. 2. After saponin-treatment of the fibres, which leaves the Ca2+ storage sites intact, dantrolene had no effect on the IP3-induced contraction. 3. The results suggest that dantrolene inhibited the carbachol- or histamine-induced tonic response mainly by inhibiting Ca2+ influx through receptor operated Ca2+ channels in ileum with only slight effect on the intracellular Ca2+ release from the storage sites. However, when dantrolene was continuously present, dantrolene might reduce a part of the Ca2+ supply into the Ca2+ storage sites. PMID- 8690252 TI - Multiplicative interaction between intrathecally and intracerebroventricularly administered morphine for antinociception in the mouse: effects of spinally and supraspinally injected 3-isobutyl-1-methylxanthine, cholera toxin, and pertussis toxin. AB - 1. Either intrathecal (i.t.) or intracerebroventricular (i.c.v.) administration of morphine alone at the dose of 0.2 microgram slightly increased inhibition of the tail-flick response. However, combined i.t. and i.c.v. injections of morphine at the same dose increased the inhibition of the tail-flick response in a synergistic manner. 2. Cholera toxin (CTX, 0.05 to 0.5 microgram) pretreated i.t. or i.c.v. for 24 hr or pertussis toxin (PTX, 0.05 to 0.5 microgram) for 6 days dose-dependently attenuated inhibition of the tail-flick response induced by combined i.t. and i.c.v. injection of morphine. 3. 3-Isobutyl-1-methylxanthine (IBMX, 0.001 to 0.1 ng) pretreated i.t. for 10 min dose-dependently attenuated the inhibition of the tail-flick response induced by combined i.t. and i.c.v. injections of morphine. However, IBMX pretreated i.c.v. for 10 min was not effective in attenuating the inhibition of the tail-flick response induced by combined i.t. and i.c.v. injections of morphine. 4. It is concluded that both spinal and supraspinal CTX- and PTX-sensitive G-proteins are involved in the antinociception produced by morphine-induced multiplicative interaction between spinal and supraspinal sites. However, only spinal but not supraspinal cAMP phosphodiesterase is involved in mediating antinociception induced by morphine induced multiplicative interaction. PMID- 8690253 TI - Pentobarbital differentially inhibits N-methyl-D-aspartate and kainate-stimulated [3H]noradrenaline overflow in rat cortical slices. AB - 1. This study examined the ability of pentobarbital to inhibit NMDA and kainate stimulated [3H]noradrenaline ([3H]NA) overflow in rat brain cortical slices. 2. Pentobarbital inhibited NMDA-evoked [3H]NA overflow at 100 microM and greater and inhibited kainate-evoked [3H]NA overflow at 10 microM and greater. 3. The ability of pentobarbital to inhibit concentration-response curves for NMDA and kainate evoked overflow of [3H]NA were also examined. Pentobarbital (300 microM) caused a 20% reduction in NMDA and a 50% reduction in kainate-induced maximal responses. PMID- 8690254 TI - Diazepam decreases the response to the electrical stimulation of the nerve-skin preparation of the toad Caudiverbera caudiverbera. AB - 1. The effect of diazepam was examined in the nerve skin preparation of the toad Caudiverbera caudiverbera. 2. Nerve stimulation was followed immediately by a transient increase in short-circuit current (SCC) and in the potential difference (PD), which consisted of a rapid and then a slow component. 3. Diazepam concentrations from 5.0 x 10(-5)M to 5.1 x 10(-4)M caused a dose-dependent block of both components to a 30% of their control values and also reduced the stimulatory responses to noradrenaline in this preparation. 4. Diazepam antagonized the potassium blocking effect of barium. 5. These results, based on electrophysiological and pharmacological evidence, are consistent with a calcium and sodium blocking effect of diazepam on the nerve skin junction of C. caudiverbera. PMID- 8690255 TI - Vascular smooth muscle reactivity to norepinephrine in ovariectomized rats: relationship to vascular PGE2/PGF2 alpha ratio. AB - 1. We have recently demonstrated that, in normal female rats, vascular reactivity (VR) and vascular prostaglandin-E2 (PGE2) and prostacyclin production are influenced by the ovarian cycle. 2. In this study, we investigated the vascular reactivity (VR) of isolated rat thoracic aorta to norepinephrine (NE 10(-12)-10( 6)M) in ovariectomized rats (OVX-rats), 48 hr and 8 days after surgical removal of the ovaries and in normally cycling rats (NR) at the proestrus stage of the estrous cycle, when the level of circulating estrogen was higher. 3. In addition, we determined the vascular synthesis of PGE2 and protaglandin-F2 alpha (PGF2 alpha) in both groups of OVX-rats, and in NR during the proestrous stage. 4. The results showed that VR to NE 10(-12)-10(-10) M was similar between OVX-rats and normal rats. 5. However, aortic rings obtained from both groups of OVX-rats showed a significant increase of the contraction response induced by NE 10(-9) 10(-6) M. 6. Furthermore, the contractile response to NE 10(-7)-10(-6) M was greater in the aortic rings from OVX-rats 8 days after ovariectomy compared to OVX-rats 48 hr (p < 0.001). 7. Vascular PGE2 and PGF2 alpha synthesis (ng/mg protein/hr) was significantly higher in both groups of OVX-rats than NR. But the vascular PGF2 alpha synthesis increased more than PGE2 in these OVX-rats, thus the ratio PGE2/PGF2 alpha was decreased significantly in both groups of OVX-rats (p < 0.01 and p < 0.001 OVX-rats 48 hr and 8 days after surgery, respectively) compared to NR-ratio. PMID- 8690256 TI - Cholestasis as a liver protective factor in paracetamol acute overdose. AB - 1. The effect of paracetamol overdoses on its disposition was investigated in cholestatic rats. 2. Paracetamol plasma concentration and hepatic accumulation decrease about 70-80% in cholestatic rats. 3. Cholestatic rats intoxicated with paracetamol showed less hepatic damage as concluded from biochemical and histological findings. These data are correlated with liver and plasmatic paracetamol. 4. These results indicate a decrease in paracetamol toxicity related to stagnant bile. PMID- 8690257 TI - Quality dental care: what is it? PMID- 8690258 TI - Ethics and advertising. PMID- 8690259 TI - FDA drug approvals from 1994 to 1995. PMID- 8690260 TI - Myths of single-visit endodontics. AB - There has been much controversy about the safety and efficacy of initiating and completing endodontic therapy in a single visit. The literature concerning single and multiple-visit endodontics is reviewed, and advantages and disadvantages of single-visit endodontics are discussed. Single visit endodontic therapy is shown to be a safe, effect alternative to multi-visit treatment for most vital and nonvital teeth. PMID- 8690261 TI - Effect of rubber-dam retainers on porcelain fused to metal. AB - Metal ruber-dam retainers may damage tooth structure, restorations, and the porcelain surface of crowns. In this study, effects of metal versus plastic retainers on the surface of porcelain fused to metal (PFM) were compared, specifically: defects at point of beak contact, and porcelain fracturing. Evaluation was performed with scanning electron microscopy (SEM); micrographs were examined for porcelain defects. No damage was evident with metal or plastic retainer placement. In conclusion, neither metal nor plastic retainers consistently damaged PFM surfaces. PMID- 8690262 TI - Recognition and treatment of radpdly progressive periodontitis. AB - Rapidly progressive periodontitis (RPP) affects adolescents and young adults. Plaque composition is about 75 percent gram-negative and 25 percent gram-positive microorganisms. In most cases of periodontal disease, the degree of destruction is related to the quantity of local irritants, but in the case of RPP, the amount of microbial deposits varies. Functional defects in the immune response system are believed to play an important role in RPP. Most patients require a combination of nonsurgical, antibiotic, and surgical treatment. The inverse-bevel periodontal-flap procedure is recommended when periodontal pockets extend apically to the mucogingival junction, and when bone defects are present. PMID- 8690263 TI - Endosseous implants for total support and retention of a complete mandibular removable prosthesis. AB - This is a clinical report illustrating and discussing the use of endosseous root form implants, both anterior and posterior to the mental foramen, in support of three separate Hader bars which in turn provide total occlusal support, resistance, and retention for a conventionally fabricated full mandibular overdenture. Principles of design, advantages, and disadvantages are listed. PMID- 8690264 TI - A matrix solution for severly broken-down teeth. AB - A technique is described for preparation of a dead-soft copper band matrix for tooth restorations. Such a matrix is particularly useful in the restoration of teeth with significant variation in occlusogingival height. PMID- 8690265 TI - Managed care seizes the attention of dentistry. AB - Throughout the health care reform debates of 1993 and 1994, the dental profession steadfastly maintained that dentistry was distinct from medicine and that the proposed solutions to the problems in medicine should not be applied to dentistry. The American Dental Association (ADA) supports the position that dental care delivery and financing systems successfully promote access, quality, and cost-containment. Important distinctions exist between the delivery and financing systems of dentistry and medicine. Dentistry is a cottage industry of solo practitioners financed overwhelmingly by private funds. The driving forces behind the growth of managed dental care are the business conditions in dentistry and employers' cost-containment concerns. Dentists should be informed about managed care, which is certain to grow and become an important part of the dental delivery and financing systems but is unlikely to achieve the dominance that it has in medicine. PMID- 8690266 TI - Effect of sterilization on stiffness and dimensional stability of rubber-dam clamps. AB - Simulated clinical conditions were used to test the effect of sterilization on rubber-dam clamp stiffness and dimension. Sixty Hygienic and Ivory W7 clamps were either steam or dry heat sterilized and compared to controls. Stiffness and dimensional change between Ivory clamp groups was significant (p<.0001); the sterilized clamps showed less change than the controls. Hygienic groups showed a significant different between the control and dry heat groups (p<.05); the sterilized clamps showed less change than the controls. The change in stiffness and interjaw width for all Ivory clamps compared to all Hygienic clamps was significant (p<.0001). The Hygienic clamps changes less than the Ivory clamps. The results indicate that steam and dry heat sterilization do not affect retention of rubber-dam clamps. PMID- 8690267 TI - Erythema multiforme. AB - The diagnosis of erythema multiforme was established on the basis of physical examination, biopsy specimen evaluation, and the patient's medication history. Use of a triamcinolone mouthrinse and discontinuation of Triphasil-28 contraceptive led to resolution of the lesions. PMID- 8690268 TI - "Tevilah or not tevilah"--a religious consideration for the dental profession. AB - General dentists are the primary care providers of the dental profession. As a result, they are at the forefront in encountering the range of circumstances for which patients seek dental care. To provide the best care, dentists must sometimes interface with other disciplines. Although dental treatment should be based on scientific principles, it should not be forgotten that a person is attached to every tooth. Here, a case is presented in which a patient's observance of orthodox Jewish law was a factor in her dental treatment. PMID- 8690269 TI - Genetic control of male cuticular hydrocarbons in Drosophila melanogaster. AB - 7-tricosene (7-T) and 7-pentacosene (7-P) are the two main hydrocarbons on the cuticle of male Drosophila melanogaster. These two substances might play a pheromonal role during courtship behaviour. We investigated the genetic basis of the quantitative polymorphism observed in the production of 7-T and 7-P. Strains of different geographic origin, with males producing either predominantly 7-T or predominantly 7-P, were hybridized with strains carrying genetic markers. We found that chromosome II changes the balance between 7-T and 7-P while chromosome III regulates the overall quantity of both 7-monoenes. We have also characterized and roughly mapped sept and smoq, two genetic factors on chromosome II that act additively on the production of both cuticular hydrocarbons. The genetic control of the variation in 7-T and 7-P varies between D. melanogaster strains and between D. melanogaster and its sibling species D. simulans. The possible evolutionary and physiological causes of this variation as well as its functional implication for courtship behaviour are discussed. PMID- 8690270 TI - Lack of correlation between dysgenic traits in the hobo system of hybrid dysgenesis in Drosophila melanogaster. AB - Currently in the hobo system of hybrid dysgenesis, strain classification is based on the presence/absence of the 2.6 kb Xho I restriction fragment. Using this criterion, strains are classified as: (1) H strains when full-size elements are detected by presence of a 2.6 kb Xho I restriction fragment; they can also contain internally deleted elements; (2) DH strains when only deleted elements are detected (Xho I restriction fragment less than 2.6 kb); (3) E strains, devoid of any restriction fragment equal to or less than 2.6 kb in length. In addition, the strains can be classified on their ability to generate gonadal atrophy (GD sterility) when males of a studied strain are crossed with females from an E strain (dysgenic cross). Here we try to define the nature of the dysgenic cross, which leads us to analyse the different components of the dysgenic syndrome and to look for eventual correlations between them. Molecular analysis, GD sterility tests, hobo mobilization with the haw strain and the vg(al) strain, and hereditary transmission of the instability at the vg locus have been assayed in different strains. We show that the occurrence of GD sterility depends on the tested H strains as expected, but also on the E strains used. On the other hand we do not find any correlation between the different dysgenic parameters. Our data reveal that molecular and GD sterility tests are not sufficient to classify strains in the hobo system, and that all the components of the dysgenic syndrome must be taken into account. Our results are discussed with regard to active and full-size elements in relation to the structure of the S region where an amino acid sequence (TPE) presents a repetition polymorphism. PMID- 8690271 TI - Evolution of multiple families of non-LTR retrotransposons in phlebotomine sandflies. AB - In this paper we report on the diversity and distribution of a set of non-LTR retrotransposon (RTP) reverse transcriptase (RT) sequences isolated from phlebotomine sandflies, and their potential for investigating the evolutionary histories of members of this subfamily of flies (Diptera:Psychodidae, Phlebotominae). The phlebotomine RT sequence families derived from one species were as different from each other as they were from RT sequences derived from other species. When each was used to probe Southern blots of sandfly genomic DNA they hybridized only to the species of source and, usually, to others of the same subgenus, but not to DNA from other subgenera-a hybridization pattern consistent with vertical evolution. There was considerable intraspecific variation in hybridization pattern, suggesting the RTs were part of non-LTR RTPs that are (or were recently) subject to flux in genomic position and copy number. Most of the RT families detected in phlebotomines are monophyletic with respect to previously described RTs, and all are monophyletic with RTs of the F/Jockey (Drosophila melanogaster) type of RTP. Orthologous sequences were isolated from the closely related species Phlebotomus perniciosus and P. tobbi (subgenus Larroussius), and different populations of P. perniciosus. The level of sequence divergence among these orthologous RTs, the subgeneric distribution of each RT family, and the intraspecific variation in hybridization pattern of many of them, indicate this class of sequence will provide genetic markers at the sub-generic level. PMID- 8690272 TI - A study of meiotic pairing, nondisjunction and germ cell death in laboratory mice carrying Robertsonian translocations. AB - Frequencies of anaphase I nondisjunction, germ cell death and pairing abnormalities at pachytene were assessed in male mice singly heterozygous and homozygous for the Robertsonian (Rb) translocations: Rb (1.3)1Bnr, Rb(11.13)4Bnr and Rb(10.11)8Bnr. Rb homozygotes showed low frequencies of nondisjunction but substantial germ cell death. This germ cell death could not be attributed to problems at pachytene as Rb homozygotes showed no increase in pairing abnormalities over the (C3H/HeH x 101/H)F1 controls. Instead genic factors are involved. Rb heterozygotes showed substantial frequencies of nondisjunction and even greater germ cell death than found in the homozygotes. Pachytene pairing abnormalities were observed and it appears that these, together with genic factors, cause physiological perturbation of meiocytes, thereby promoting germ cell death, with nondisjunction of the trivalent as a sublethal response. PMID- 8690273 TI - An additional type of male sterility and inherited urinary obstruction in mice with the t-haplotype th7. AB - The t-complex on mouse chromosome 17 results in transmission ratio distortion in males heterozygous for complete haplotypes, and sterility in those homozygous for semi-lethal or doubly heterozygous for complementing lethal haplotypes. This sterility is due to inability of spermatozoa to fertilize. The haplotype th7 is an unusual laboratory-derived haplotype, postulated to carry a small duplication of t chromatin. Males heterozygous for th7 show a new form of sterility, apparently due to failure to form copulation plugs during mating. This is accompanied by a strong propensity to acute urinary obstruction. It is suggested that both the failure to form copulation plugs and the urinary obstruction are due to some abnormality in function of the accessory sex glands, and are the result of incorrect dosage of a gene in the postulated duplication. The symbol Msu for male sterility and urinary obstruction is suggested for the locus concerned. Previously a recessive form of abnormal behaviour had also been attributed to this duplication. PMID- 8690274 TI - Interaction of selection and recombination in the fixation of negative-epistatic genes. AB - We investigated the interaction of recombination and selection on the process of fixation of two linked loci with epistatic interactions in fitness. We consider both the probability of fixation of newly arising mutants (the static model) and the time to fixation under continued mutation (the dynamic model). Our results show that the fixation of a new advantageous combination is facilitated by higher fitness of the advantageous genotype and by weaker selection against the intermediate deleterious genotypes. Fixation occurs more rapidly when the recombination rates are small, except when selection against intermediate genotypes is weak and selection in favour of the double mutant is very strong. In these cases fixation is more rapid when the recombinant rate is large. Mutations of strong effects, deleterious when alone but beneficial when coupled, are fixed more easily than mutations of intermediate effects, at least for large recombination rates. Among the possible pathways the process of fixation might follow, independent substitutions lead to the fixation of the double mutant only when selection is weak. The relative importance of the other pathways depends on the interaction between recombination and selection. The coupled-gamete pathway (i.e. when the population waits until the double mutant appears and then drives it to fixation) is more important as selection intensity increases and the recombination rate is reduced. For all recombination rates, asymmetries in fitness of the intermediate genotypes increase the rate at which fixations occur. Finally, throughout the fixation process, the population will be monomorphic at least at one of the two loci for most of the time, which implies that there would be little opportunity to detect the presence of negative epistasis even if it were important for occasional evolutionary transitions. PMID- 8690275 TI - Waiting for a compensatory mutation: phase zero of the shifting-balance process. AB - In highly integrated genetic systems, changes in any one component may have a deleterious effect on fitness, but coordinated, or compensatory, change in these components could lead to an overall increase in fitness compared with the current state. Wright designed his shifting-balance theory to account for evolutionary change in such systems, since natural selection alone can not lead to the new optimal state. A largely untreated aspect of the shifting-balance theory, that of the limiting impact of waiting for the production of new mutations, is analysed here. It is shown that the average time to double fixation of compensatory mutations is extremely long (of the order of tens or hundreds of thousands of generations), because selection is too effective in large populations, and mutations are too rare in small populations. Further, the probability that a new mutant will arise and undergo fixation quickly is extremely small. Tight linkage can reduce the time to fixation somewhat, but only in models in which the double heterozygote does not have reduced fitness. It is argued that the only reasonable way for compensatory mutations to become fixed in a population is if the new mutants are first allowed to achieve a moderate frequency through the relaxation of selection. Under these conditions, the time required to reach fixation is reasonably low, although the probability of being fixed is still small when the initial allele frequencies are low. It is likely that the waiting time for fixation of new mutants, which is here called phase zero, is the major limiting factor for the success of the shifting-balance process. PMID- 8690276 TI - Microsatellite polymorphisms in a wild population of Drosophila melanogaster. AB - Highly variable DNA polymorphisms called microsatellites are rapidly becoming the marker of choice in population genetic studies. Until now, microsatellites have not been utilized for Drosophila studies. We have identified eight polymorphic microsatellite loci in Drosophila melanogaster and used them to characterize the genetic variation in a wild population from the Tyrrell's winery in Australia. Microsatellites were isolated from a partial genomic DNA library. All microsatellites consist of (AC)n repeats ranging from n = 2 to n = 24. Six loci were assigned to chromosomal location by genetic mapping, with three loci on chromosome II, one locus on chromosome III and two loci on the X chromosome. Up to four microsatellite loci were multiplexed in the same reaction. Microsatellite variation is substantially greater than allozyme variation in the Tyrrell's Drosophila population. 80% of the microsatellite loci examined are polymorphic, compared with 28% of allozymes. The mean number of alleles per polymorphic locus is 5.2 in microsatellites compared with 3.0 in allozymes. The average observed heterozygosity of polymorphic microsatellites is 47% compared with 26% for allozymes. Microsatellite variation in Drosophila melanogaster is similar to that reported for other insects. Higher variability commends microsatellites over allozymes for genetic studies in Drosophila melanogaster. PMID- 8690277 TI - Whither tamoxifen. PMID- 8690278 TI - Risk factors for cervical intraepithelial neoplasia in Taiwan. AB - A population-based case-control study was conducted in Taiwan between July 1991 and June 1994 to evaluate the significance between risk factors for cervical intraepithelial neoplasia (CIN) among Taiwanese women. Personal interviews were compiled with 288 histologically confirmed CIN who were matched by age to 576 randomly selected controls with normal cervical smears. Using logistic regression models to simultaneously evaluate the effects of multiple factors as predictors of CIN, we found that the strongest risk was associate with HPV infection (OR = 5.02). Other significant risks included husband's visiting prostitutes (OR = 2.56), four or more vaginal deliveries (OR = 2.01), two or more induced abortions (OR = 1.96), and multiple sex partners (OR = 1.87). A protective effect was also noted with the use of condoms (OR = 0.38). These data support the hypothesis that CIN is sexually transmitted in Taiwan's population and may have a viral etiology. Furthermore the results indicate the important role of the husband's visiting prostitutes and the nonuse of condoms as contributing factors in the high incidence rate for CIN in a population. PMID- 8690279 TI - Phase II evaluation of altretamine for advanced or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study. AB - A Phase II trial was conducted by the Gynecologic Oncology Group to determine the activity of altretamine in previously treated patients with squamous cell carcinoma of the cervix. Thirty-two women with advanced or recurrent squamous cell carcinoma of the cervix were entered. The starting dose was 260 mg/m2/day for 21 days every 4 weeks. Twenty-six patients were evaluable for response and 29 were evaluable for toxicity. Among the 26 evaluable patients, 21 had received prior radiotherapy and 24 had received prior chemotherapy. A median of two courses were given (range, 1-6). Grade 3 or 4 gastrointestinal toxicity, occurring in 17%, was the most common complication (grade 3, 13.8%; grade 4, 3.4%). Grade 3 anemia was slightly less common occurring in 13.8%. Grade 3 peripheral neurotoxicity occurred in 3.4%. There were no objective responses, demonstrating that this agent is useful in previously treated squamous cell carcinoma of the cervix. PMID- 8690280 TI - Palliative treatment of upper intestinal obstruction by gynecological malignancy: the usefulness of percutaneous endoscopic gastrostomy. AB - The usefulness of percutaneous endoscopic gastrostomy (PEG) for decompression in patients with unresolving intestinal obstruction by gynecological malignancy is examined. Between April 1993 and August 1995, 34 consecutive patients with small bowel obstruction by gynecological cancer, heavily pretreated with surgery and chemotherapy, were admitted to our prospective study. PEG was performed in 32/34 patients (94.1%). Failure in the placing of the tube occurred in 2 patients (5.9%). Twenty-seven patients (84.4%) experienced symptomatic relief after a few days from PEG and tolerated soft and liquid foods. All of these patients were discharged from the hospital and underwent parenteral nutrition at home. The median postoperative hospital stay was 7 days (range 3-45). No major complications due to PEG placement itself occurred in our patients. Only 4 patients (12.5%) had postprocedure nausea and vomiting that was unresponsive to the conventional therapy. The use of Octreotide (0.6 mg/24 hr) obtained relief from symptoms until death. The gastrostomy remained in place for a median of 74 days (range 5-210). Relief from symptoms after PEG placement and total parenteral nutrition permitted continuation of palliative chemotherapy in 8 patients (25%). We suggest percutaneous endoscopic drainage gastrostomy technique as the procedure of choice for long-term drainage of unresolving small bowel obstruction in patient with metastatic abdominal gynecologic malignancy. PMID- 8690281 TI - Expression of A, B, and H blood group antigens in epithelial ovarian cancer: relationship to tumor grade and patient survival. AB - The expression of A, B, and H blood group antigens in epithelial ovarian cancer was evaluated in 137 patients with advanced disease by staining frozen sections with specific monoclonal antibodies using an indirect immunoperoxidase method. Expression of blood group antigens was observed in a proportion of ovarian carcinomas and in some areas of ovarian surface epithelium. Forty-eight percent of the tumors tested from 130 blood group A, B, or 0 individuals showed no expression of the appropriate blood group antigen, 32% had heterogeneous antigen expression, and 20% had strong expression. In the 7 blood group AB patients studied, no expression, heterogeneous expression of both antigens, or absence of one, but not the other antigen, was observed. No tumor showed A, B, or H antigen expression that was not compatible with the patient's blood group type. Histologic Grade 3 tumors showed absence of blood group antigen expression more often than did Grade 2 tumors. The presence or absence of A, B, or H antigen expression did not correlate with survival in this group of patients. This is in contrast to studies in other epithelial tumor types in which the normal epithelium synthesizes blood group antigens and loss of ABH antigen expression is observed in the corresponding tumors. PMID- 8690282 TI - Epithelial ovarian carcinoma metastatic to the central nervous system: a report on two cases with review of literature. AB - Metastasis to the central nervous system (CNS) from ovarian malignancy is rare. We describe two such patients who developed CNS metastasis in the form of multiple deposits in brain parenchyma after an interval of 27 and 16 months from the diagnosis of ovarian carcinoma. Both patients received cranial radiotherapy but survived only 2 weeks and 5 months, respectively. Data on 99 patients collected from the literature (Medline, National Library of Medicine, Bethesda, MD) are reviewed and an attempt is made to suggest therapeutic guidelines depending on the extent of the intracranial and extracranial disease and performance status of the patients. PMID- 8690283 TI - Benign cervical leiomyoma leading to disseminated fatal malignancy. AB - A case study is reported of incomplete excision of a sessile leiomyoma of the posterior cervix followed by rapid tumor growth of the same region in a pregnancy commencing 2 months later. Cesarean section for placenta previa was followed 10 days later by hysterectomy for massive hemorrhage. The tumor was considered, following multiple review, to be a leiomyoma of the cervix with mitosis consistent with recent pregnancy. Widespread peritoneal recurrence occurred within 3 months requiring further laparotomy for excision of widespread tumor and ligation of internal iliac arteries. Death occurred 4 weeks later with widespread peritoneal occurrence. No postmortem was performed. The case emphasizes the rare potential for malignant change in histologically benign leiomyomas with no indications to this potential apart from biological behavior. PMID- 8690284 TI - Neoadjuvant chemotherapy in uterine papillary serous carcinoma. AB - Uterine papillary serous carcinoma (UPSC) is an aggressive variant of endometrial cancer that frequently imitates serous carcinoma of the ovary in its clinical presentation and histologic appearance. Unlike the ovarian lesion, however, it is known to be particularly resistant to chemotherapy. A patient with a putative diagnosis of unresectable Stage IV ovarian cancer was treated with three cycles of neoadjuvant chemotherapy containing paclitaxel and carboplatin. After a remarkable response, interval cytoreductive surgery was performed. A primary endometrial tumor with the pathologic features of UPSC was found. To our knowledge, the use of paclitaxel-containing chemotherapy in UPSC has not been reported. We suggest that this therapy might be useful in the treatment of patients with advanced uterine papillary serous carcinoma, as well as in an adjuvant setting. PMID- 8690285 TI - Late recurrences of vaginal clear cell adenocarcinoma. AB - Recurrent vaginal clear cell adenocarcinoma was diagnosed in two DES-exposed patients 17 and 19 years after initial therapy. These cases demonstrate the need for continued clinical evaluation, since patients with clear cell carcinoma of the vagina seem to be at greater risk for developing late recurrences than patients with squamous cell carcinomas. PMID- 8690286 TI - Lymphatic spread of cervical cancer: an anatomical and pathological study based on 225 radical hysterectomies with systematic pelvic and aortic lymphadenectomy. AB - To assess the patterns of lymphatic spread in cervical carcinoma, radical hysterectomy with systematic lymphadenectomy was performed in 66 patients FIGO stage IB-IIA <4 cm, and 159 patients stage IB-IIA >4 cm to stage IV. The latter patients were treated with neoadjuvant chemotherapy (NACT). Parametria were evaluated by the giant section technique in 109 patients. In 40 of these, the superficial and deep layers of the vesicouterine ligament, the sacrouterine ligament, and the distal part of the cardinal ligament were separately evaluated. The median number of nodes removed was 48 pelvic (range 20-107) and 22 aortic (range 7-64). Positive nodes were found in 14 (21%) stage IB-IIA <4 cm and in 38 (23%) NACT-treated patients, all having pelvic node metastasis. Aortic nodes were involved in 2 (3%) and 5 (3%) patients, respectively. Solitary metastases were found in the superficial obturator (21% of stage IB-IIA <4 cm and 31% of NACT treated positive node patients, respectively), external iliac (7 and 3%, respectively), and common iliac nodes (7 and 3%, respectively). Parametrial nodes were found in 59% of giant sections (8% metastatic). The superficial and deep layers of the vesicouterine ligament, the uterosacral ligament, and the distal part of the lateral parametrium revealed the presence of nodes in 33% (no metastatic nodes), 26% (3% metastatic), 5% (no metastatic nodes), and 70% (5% metastatic) of patients, respectively. Overall, parametrial nodes were positive in 12% of stage IB-IIA <4 cm and 7% of NACT-treated patients. The diameter of node metastasis was <10 mm in more than 80% of positive nodes. In conclusion, parametrial nodes were mainly located in the cardinal and vesicouterine ligaments, both being a potential site of metastasis. The superficial obturator, external iliac, common iliac, paracaval, intercavoaortic, and paraaortic nodes were the groups more frequently involved. These data may be useful for tailoring radical hysterectomy and lymphadenectomy according to the primary tumor and the surgeon's intent. PMID- 8690287 TI - Uterine leiomyosarcoma: analysis of treatment failures and survival. AB - The objective of this retrospective multicenter study was to assess the rates, times, and sites of recurrences of 126 patients with uterine leiomyosarcomas. Surgery was the initial therapy for all patients. Median follow-up of survivors was 50 months (range, 3-168 months). Of the 90 patients with stage I-II disease, 26 received postoperative irradiation and/or chemotherapy. Thirty-five (38.9%) patients developed recurrent disease after a median time of 16 months (range, 2 102 months). Recurrence was pelvic in 5 (14.3%) patients, distant in 23 (65.7%), and pelvic plus distant in 7 (20.0%). The overall recurrence rate was similar in patients who received adjuvant treatment and in those who did not. None of the 15 patients who underwent pelvic irradiation developed local recurrences, but 5 of them failed in distant sites. Of the 16 patients with stage III leiomyosarcomas, 2 died of intercurrent disease within 1 month from surgery and 11 received postoperative irradiation and/or chemotherapy. Thirteen patients developed recurrent tumor after a median time of 8 months (range, 1-21 months). Recurrence was pelvic in 3, distant in 4, and pelvic plus distant in 6 patients. Of the 20 patients with stage IV leiomyosarcomas, after surgery 6 were clinically free of disease (group A) and 14 had clinically evaluable residual disease (group B). With regard to group A, 3 patients received postoperative irradiation and/or chemotherapy. Five patients developed recurrent disease after a median time of 11 months (range, 8-16 months). Recurrence was distant in 3 patients and pelvic plus distant in 2. With regard to group B, 11 patients underwent postoperative chemotherapy. Eleven patients died after a median time of 6 months (range, 1-15 months), and 3 are still alive with clinical evidence of disease after 4, 5, and 8 months, respectively, from surgery. Cox model showed that stage (P = 0.0001), mitotic count (P = 0.0002), and age (P = 0.0048) were independent prognostic variables for disease-free survival. In conclusion, uterine leiomyosarcomas have an aggressive clinical behavior, with a propensity to recur both locally and moreover at distant sites. Tumor stage is the strongest prognostic variable. Only patients with early-stage disease have a chance of surviving, whereas the treatment of patients with advanced or recurrent disease is palliative. PMID- 8690288 TI - Association of allele-specific HLA expression and histopathologic progression of cervical carcinoma. AB - Immunohistochemical studies have shown that loss of HLA expression is observed in cervical carcinomas but not in premalignant CIN lesions, indicating that downregulation of HLA is linked to tumor progression. The present study was performed to investigate whether the degree of HLA expression in cervical cancer correlates with more advanced disease as defined by histopathological features. Frozen tissue sections from 49 patients with squamous carcinoma of the cervix FIGO stage IB to IIB were stained with HLA class I monomorphic, locus- and allele specific monoclonal antibodies. Histological data indicative of local disease, i.e., depth of invasion, tumor size, stage, and systemic spread of the disease, such as tumor-positive lymph nodes, were collected by reviewing the histological slides. Univariate analysis revealed that loss of HLA-A locus and A2-allele expression showed a positive, significant correlation with both presence of tumor positive lymph nodes (P = 0.04 and 0.02, respectively) and the number of lymph nodes involved (both P = 0.04). These results strongly support the idea that, specifically in an immunogenic cancer type such as cervical cancer, tumor cells escape immunosurveillance and gain growth advantage by allele-specific downregulation of the HLA-A2 molecule. In view of the development of immunotherapeutical interventions in cancer, upregulation of HLA class I molecules may prove to be a useful additional tool in the combat against immunogenic tumors. PMID- 8690289 TI - Tamoxifen in platinum-refractory ovarian cancer: a Gynecologic Oncology Group Ancillary Report. AB - There is a critical need to find additional effective therapies in the management of ovarian cancer. A previously reported Gynecologic Oncology Group trial demonstrated that tamoxifen is an active drug when used in the salvage setting in this malignancy. Unfortunately, this original report did not specifically examine the utility of tamoxifen in patients with clinically defined platinum-refractory disease. In this reanalysis of the results of treatment of 102 evaluable patients entered into this multi-institutional trial, an objective response rate of 13% (95% confidence interval, 6.4-22.6%) was observed in patients with cisplatin refractory ovarian cancer. The median response duration in this patient population was 4.4 months (range 1.2-9.2 months). Although the response rate is modest, this well-tolerated hormonal agent is a reasonable therapeutic option in selected patients with ovarian cancer when salvage therapy is to be considered. A possible role for this hormonal agent in other clinical settings in ovarian cancer will need to be defined through the conduct of carefully designed randomized clinical trials. PMID- 8690290 TI - Characterization of the protein synthesis independent TNFalpha lytic mechanism in human ovarian and cervical carcinoma cell lines. AB - The analysis of the lytic mechanism initiated by TNFalpha in three human ovarian cell lines (CAOV-3, SK-OV-3, and OVCAR-3) and in three human cervical cell lines (SIHa, HT-3, and ME-180) in the presence of inhibitors of protein synthesis indicates that this lytic mechanism is similar to the protein synthesis independent lytic mechanism initiated by TNFalpha in L929 cells. In addition to being independent of protein synthesis, the lytic mechanism initiated by TNFalpha in human ovarian and cervical carcinoma cells is also not dependent on the formation of oxygen radicals, as shown by the inability of the oxygen radical scavengers DMSO or glutathione to inhibit lysis. In spite of the fact that oxygen radicals are not involved in lysis, the TNFalpha lytic mechanism initiated in the human ovarian and cervical carcinoma cells is dependent on the activity of lipoxygenase enzymes. This was shown by the ability of the lipoxygenase enzyme inhibitor, NDGA, to block TNFalpha-mediated lysis. Using DNA-specific staining (DAPI and Apoptag) it was shown that when the human ovarian and cervical carcinoma cells are lysed by TNFalpha, death occurs via apoptosis. PMID- 8690291 TI - Expression and mutation of H-ras in uterine cervical cancer. AB - In cervical cancer, abnormalities of ras genes have not been fully investigated. We studied the expression and mutation of H-ras oncogene in cervical cancer to investigate their relationship and usefulness as an independent prognostic indicator. Twenty-seven paraffin-embedded resection specimens of cervical cancer (21 squamous, 3 adeno, 2 adenosquamous, and 1 small cell) were examined by immunohistochemistry using a mAb H-ras p21 and by PCR and allele-specific oligonucleotide hybridization using H-ras codon 12 and 61 amplimers and oligonucleotide probes. A strong immunoreaction was noted in 10 cases (37%) and weak immunoreaction in an additional 6 cases (22%). H-ras codon 12 mutations were detected in 6 of 27 cases (22%) and all of the mutations were guanine to adenine transitions. There was no mutation in codon 61. Cases with codon 12 mutations included all 3 squamous, 2 adeno, and I adenosquamous carcinoma. Only 3 of 16 (19%) cases with positive staining and 3 of 11 (27%) cases with negative staining showed mutations. No correlation was found between ras gene alterations and patient survival time. Our findings indicate that expression and mutation of H ras oncogene occur in cervical cancer but their determination adds no useful prognostic information. PMID- 8690292 TI - Surgically documented responses to paclitaxel and cisplatin in patients with primary peritoneal carcinoma. AB - Intra-abdominal carcinomatosis indistinguishable from ovarian cancer may occur after removal of the ovaries or in association with surface ovarian involvement. Because its histologic pattern and behavior approximate those of ovarian cancer, this entity, known as primary peritoneal carcinoma, has been treated in a similar fashion--cytoreductive surgery followed by systemic chemotherapy. This review was undertaken to assess the efficacy of combination chemotherapy with paclitaxel and cisplatin, the current front-line chemotherapeutic regimen for ovarian cancer, in patients with primary peritoneal carcinoma. Sixteen patients diagnosed between January 1989 and July 1994 with primary peritoneal carcinoma were treated at the Hospital of the University of Pennsylvania. The records of the three patients whose initial chemotherapeutic regimen included paclitaxel and cisplatin were reviewed. An additional case from the Robert Wood Johnson Medical Center, Camden, New Jersey, was included. Pathologic review of all cases was conducted at the time of clinical management and again as part of this study. Reassessment laparotomy was performed in all patients after the completion of chemotherapy. Complete clinical information was available on all patients. All four patients presented with intra-abdominal carcinomatosis, and large volume (> 1 cm) residual disease was present following initial cytoreduction. Following chemotherapy, second-look laparotomy documented one complete pathologic response and three partial (>50% tumor volume reduction), but marked, responses. Combination chemotherapy with paclitaxel and cisplatin produces surgically documented responses in patients with primary peritoneal carcinoma. PMID- 8690293 TI - DNA index reflects the biological behavior of ovarian carcinoma stage I-IIa. AB - The prognostic significance of histologic grade, morphometric analysis, and DNA flow cytometry was evaluated in 64 patients with well-differentiated (group A) and 30 patients with moderately and poorly differentiated (group B) early-stage (FIGO stages Ia, Ib, Ic, and IIa) epithelial ovarian cancer. The extent of the well-defined staging procedure was assessed strictly in every patient. Of 94 patients, 13 had recurrent ovarian cancer (5 from group A and 8 from group B) and 12 of these patients died. A significant difference was found between groups A and B for 5-year disease-free survival (91% versus 75%), the menopausal status, surgical staging procedure, volume percentage epithelium (VPE), morphometric category, DNA ploidy, and DNA index, but not for histologic cell type. For the 94 patients from groups A and B together, a significant difference was observed between diploid and aneuploid tumors with regard to mean mitotic activity index (MAI), mean VPE, and the morphometric categories that combined MAI and VPE characteristics. Prognostic reliability for the occurrence of tumor relapse was highest for DNA index class, followed by tumor grade and DNA ploidy pattern. With multivariate analysis the primary prognostic factor for disease-free survival appeared to be the DNA index. DNA index class was the only parameter that added prognostic information when histologic grade was selected as the primary prognostic factor. If the DNA index was taken as primary prognostic factor, none of the tested parameters including tumor grade added useful information. It was concluded that the DNA index is a primary prognostic factor for disease-free survival in early-stage ovarian cancer patients. Morphometric measurements do not add supplementary prognostic information. PMID- 8690294 TI - Clinical value of CA125, CA19-9, CEA, CA72-4, and TPA in borderline ovarian tumor. AB - Five tumor markers were analyzed clinically in 101 patients with borderline ovarian tumors who were treated by the Tokai Ovarian Tumor Study Group, an association comprising Nagoya University and its affiliated hospital, between January 1986 and December 1994. The positive rate of CA125 was 68.2% in serous tumor and 51.9% in mucinous tumor. The positive rate of CA19-9 was 51.5% in serous tumor and 44.7% in mucinous tumor. The positive rates and mean serum levels of CA125 in serous and mucinous tumor by stage had rising tendencies with an increase in each stage. The mean serum levels of CA19-9 in serous and mucinous tumor by stage had rising tendencies with an increase in each stage. CA125 and CA19-9 were useful for screening of borderline ovarian tumors. The positive rates of CEA and TPA in mucinous tumor were 32.5 and 27.3%, respectively, although none of the patients with serous tumor were positive in CEA and TPA. The positive rates and mean serum levels of CEA in mucinous tumor by stage had rising tendencies with an increase in each stage. The positive rate of CA72-4 was significantly lower than that of CA125 (P < 0.05). PMID- 8690295 TI - A gynecologic oncologist looks at obstetrics and gynecology of today and tomorrow. PMID- 8690296 TI - Groin dissection practices among gynecologic oncologists treating early vulvar cancer. AB - OBJECTIVE: To survey the surgical practice of gynecologic oncologists regarding the extent of groin dissection for early vulvar cancer. METHODS: A 14-item questionnaire was developed and presented to the Annual Meeting of the Felix Rutledge Society. Gynecologic oncologists were asked to describe in descriptive, categorical, and visual terms the groin procedure that they perform as part of management of early vulvar cancers. Three ink-line drawings were created by a medical illustrator for the purpose. Fifty returned surveys were evaluable. RESULTS: The most commonly performed procedures were removal of the lymph nodes above the cribriform fascia and those medial to the femoral vein (40%), removal of lymph nodes above the cribriform fascia (34%), and removal of all nodes above and below the cribriform fascia (22%). Respondents performing the first procedure termed it "superficial inguinal lymphadenectomy" (40%), "inguinal femoral lymphadenectomy" (25%) and a variety of other names (35%). Respondents performing the second two procedures were much more consistent in the figure and name that they matched with their description of the nodes removed. When respondents were asked to match the figures with categorical definitions based on their understanding of the literature, the figure depicting Scarpa's triangle following removal of the superficial inguinal and medial femoral nodes was named superficial inguinal lymphadenectomy by 24% despite the fact that the femoral vein was clearly visible and labeled. CONCLUSIONS: We conclude that (1) among this group of gynecologic oncologists superficial inguinal and medial femoral lymphadenectomy is the most commonly performed procedure for women with early vulvar cancer and that the procedure is frequently called superficial inguinal lymphadenectomy; (2) publications and protocols on this topic must provide complete descriptions of procedures performed, and investigators must assure that individual surgeons are performing the same procedure; and (3) treatment results with superficial inguinal and medial femoral lymphadenectomy are poorly described and a fertile area for further study. PMID- 8690297 TI - Intraoperative liver biopsy with the loop electrosurgical excision procedure in patients with gynecologic malignancies. AB - When patients with gynecologic malignancies undergo exploratory surgery, hepatic lesions suggestive of malignancy are occasionally encountered. In 18 patients undergoing laparotomy for gynecologic cancer, visible liver lesions suggestive of malignancy were biopsied with the loop electrosurgical excision procedure (LEEP). Hemostatic suture placement was required in 3 of these 18 patients, and in 15, hemostasis was achieved with electrocautery only. Three of the 18 biopsies (16.7%) were positive for malignancy. No intraoperative or postoperative complications were attributed to the liver biopsy. One patient required postoperative transfusion of 2 units packed red blood cells. A new technique is described using the LEEP to remove suspicious lesions during exploratory laparotomy in patients with gynecologic malignancies. PMID- 8690298 TI - Establishment and characterization of three new cell lines derived from the ascites of human ovarian carcinomas. AB - Three human cancer cell lines (OC 314, OC 315, and OC 316) were newly established in permanent culture from the ascites of patients with serous adenocarcinoma of the ovary. OC 314 was derived from an untreated tumor presenting with ascites at diagnosis; OC 315 was isolated from a neoplasm progressing after cisplatin containing regimen; and OC 316 was collected from a patient with pleural metastasis at diagnosis, resistant to different chemotherapeutic treatments including Taxol. These cell lines were repetitively subcultured once to twice a week through 75-80 passage generations. Tumor cells grew as monolayers and displayed epithelial-like morphology, consistent with a feature of adenocarcinoma, which was then confirmed by the expressions of cytokeratins and vimentin. The cell lines proved highly tumorigenic when transplanted into nude mice, both subcutaneously and intraperitoneally. In addition, the mice inoculated with subcutaneous OC 316 developed extremely aggressive tumor, also invading the peritoneum, which correlated with the malignant behavior of the original tumor. Drug sensitivity, evaluated by the MTT assay, showed that the three cell lines expressed similar sensitivity to doxorubicin. Responses to cisplatin essentially reported low sensitivity of OC 314 and OC 315 and resistance of OC 316, thus reflecting the original sensitivity at the clinical level. PMID- 8690300 TI - [Techniques for measurement of nitric oxide in biological systems: principles and practice]. AB - Despite being small and simple in structure the nitric oxide free radical (NO.) is now proving to be of vital physiological significance, and it has been shown to play important roles in complex processes such as vasodilatation, inflammation, thrombosis, immunity and neurotransmission. To conduct meaningful research into the role of NO., it is necessary to accurately determine its concentration. Its direct and quantitative measurement, however, has been little discussed inspite of the abundance of studies on this compound. Generally most authors refer to indirect qualitative measurements, such as employment of NO synthase inhibitors, measurement of cGMP or citrulline, and the detection of NO. induced physiological effects such as vascular relaxation. The primary difficulties in the direct measurement of NO stem from its short lifetime and very low concentrations. Notwithstanding these problems, several quantitative methods for measuring NO. have been established. The most commonly used techniques are as follows: 1) UV-visible spectrophotometry of the diazotization product of the nitrite, NO-hemoglobin or methemoglobin, 2) fluorometry of the fluorescent product of the nitrite, 3) detection of chemiluminescence by its reaction with ozone or luminol/H2O2, 4) amperometric microelectrode assay, and 5) electron spin resonance spectrometry. All the aforementioned techniques have certain limitations that should be considered carefully prior to each application. PMID- 8690299 TI - Characterization of gelatinases linked to extracellular matrix invasion in ovarian adenocarcinoma: purification of matrix metalloproteinase 2. AB - Substantial evidence indicates that proteolytic degradation of the extracellular matrix is necessary for invasion and metastasis by cancer cells. Our previous work has demonstrated elevated secretion by cultured ovarian adenocarcinoma cells of two gelatinolytic metalloproteinases, a 72-kDa enzyme resembling matrix metalloproteinase 2 (MMP-2) and a 92-kDa enzyme resembling MMP-9 (Moser et al, Int. J. Cancer 56, 552-559, 1994). To assess the potential in vivo relevance of these enzymes, we have examined ovarian carcinoma ascites using gelatin substrate zymography. MMP species identical to those secreted from several well characterized ovarian adenocarcinoma cell lines were found in the majority of ascites: MMP-2-like gelatinase (23 of 23 cases) and MMP-9-like gelatinase (18 of 23 cases), suggesting a prevalence of these species in the ovarian carcinoma microenvironment and their availability for tumor-associated proteolysis. The contribution of these proteinases to ovarian cancer invasion was further demonstrated by experiments measuring tumor cell-mediated proteolysis of native endothelial cell extracellular matrix (ECM) and tumor cell invasion of reconstituted basement membrane (Matrigel). These data showed that secretion of type IV collagenase activity by a series of independently isolated ovarian adenocarcinoma cell lines correlated well with the ability of these cells to proteolyze the ECM and invade the basement membrane. Furthermore, we have identified and characterized an ovarian carcinoma-associated gelatinase, the 72 kDa MMP found in conditioned media of the DOV 13 cell line, as MMP-2. This enzyme was identical to the previously described MMP-2 from other sources by Western blot, amino terminal sequence, and substrate specificity. Additionally, a large portion of the MMP-2 activity found in DOV 13 conditioned media is active without organomercurial treatment, suggesting that ovarian cancer cells have an endogenous activator of the zymogen. Together, these data suggest that ECM proteolysis mediated by tumor-associated proteinases plays an important role in the invasion and/or metastasis of ovarian carcinoma. PMID- 8690301 TI - [Effect of KSG-504, a new CCK-A-receptor antagonist, on experimental acute pancreatitis in rats and mice]. AB - We investigated the protective and/or therapeutic effects of a new cholecystokinin receptor antagonist, KSG-504, on different types of experimental pancreatitis in the rat and mouse. The intravenous injection of KSG-504 (10, 25, 50 and 100 mg/kg) before caerulein administration to the rat inhibited the increases in plasma amylase, lipase and of pancreatic wet weight in a dose dependent manner. The histological changes due to caerulein-induced acute pancreatitis were also decreased by KSG-504 when KSG-504 (25, 50 and 100 mg/kg) was administered after the induction of acute pancreatitis; the increases in plasma amylase, lipase and pancreatic wet weight were reduced, but the histological changes of the pancreas were not decreased significantly. In the second experiment, acute pancreatitis was induced in rats by injecting 0.3 ml of 6% sodium taurocholate into the pancreatic interstitial tissue. KSG-504 administered immediately and 1.5 hr after sodium-taurocholate injection at 100 mg/kg reduced the increases of pancreatic enzymes in the plasma, pancreatic wet weight and ascites. Moreover, KSG-504 (50 and 100 mg/kg, i.v., x 2) mitigated the histological changes of taurocholate-induced acute pancreatitis. Another type of acute pancreatitis was induced in mice by dl-ethionine (0.5 g/kg, p.o., x 4) and a choline-deficient diet. KSG-504 (10, 30 and 100 mg/kg) was subcutaneously administered five times every 12 hr during the experiment. KSG-504 elongated the survival of mice in a dose-dependent manner. These findings suggest that KSG-504 has potent protective and/or therapeutic effects against acute pancreatitis and that cholecystokinin may be involved in the development of pancreatitis. PMID- 8690302 TI - [Effect of ethanol on expression of nitric oxide synthases in the cerebral culture cells from chick embryo]. AB - The effect of ethanol on nitric oxide synthase (NOS) activity was examined histochemically and biochemically in cultured cerebral cells of chick embryos. The cells were isolated from 13- to 14-day-old chick embryos to which 10% ethanol (ethanol group) or saline (control) had been injected on the 3rd day of embryogenesis. Expression of NADPH diaphorase in cultured cells was stained using nitro blue tetrazolium (NBT). The activity of NOS was observed by the following 2 assays: NADPH diaphorase activity was determined using the substrate NBT with the cofactor NADPH, and NOS activity was determined by measurement as radiochemical activity of the conversion of [3H]L-arginine to [3H]L-citrulline. The number of isolated cells and viability from one cerebrum of chick embryo were 3 approximately 4 x 10(6) and more than 97%, respectively. In the neuronal cells, moderately positive expression of NADPH diaphorase was first detected on about the 3rd day of culture in both the control and ethanol group. The NADPH diaphorase and NOS activities in the isolated cells were higher in the ethanol group than in the control group. The NADPH diaphorase and NOS activities were significantly higher in the ethanol group than in the control group on the 4th and 2nd day of culture, respectively. These findings suggest that NO-released by elevated NADPH diaphorase activity and NOS activity is responsible for the induction of neuronal cell disorders attributed to chronic ethanol damage. PMID- 8690303 TI - [Developmental aspects of electrophysiology in cardiac muscle]. AB - Electrical properties of the cardiac muscles drastically change with development. The changes in the current density of ionic currents of cardiomyocytes are inconsistent among species. In cultured embryonic chick ventricular myocytes, the developmental changes in the fast Na+ channel properties (3- to 17-day-old) are reviewed. The sensitivity to TTX, with a KD as high as 2 nM, remains unchanged. The limiting conductance (GNa) increased by 8-10-fold. The activation kinetics such as the steady-state activation (m infinity) and time constant of activation (tau m) remain unchanged. The voltage-dependence of inactivation kinetics such as the steady state inactivation (h infinity) and time constant (tau h) shift in the hyperpolarizing direction. The window conductance tends to be reduced. On the other hand, the L-type Ca2+ channel is important during the development of rat heart, and also the fe-type current (dihydropyridine-resistant) is important in the fetal stage. In chick embryo cardiomyocytes, the L-type channel exhibits long lasting opening behavior. The behavior is gradually abolished during development, cAMP-dependent protein kinase enhances the Ca2+ channel current on and after the late fetal/embryonic stage. cGMP-dependent protein kinase markedly inhibits the Ca2+ channel current in the fetal/embryonic stage, compared with adult heart. These changes would play an important role for cardiac functions during development. PMID- 8690304 TI - [Nephrotoxicity and drug interaction of vancomycin (2)]. AB - Vancomycin hydrochloride (VCM) has an antibacterial action against Gram positive bacteria, e.g., Methicillin-resistant Staphylococcus aureus (MRSA). In the clinical situation, there are patients with serious infections, being infected with not only MRSA, but also with Gram negative bacteria like Pseudomonas aeruginosa. Because VCM has the adverse reaction of nephrotoxicity, we are apprehensive about using VCM with other antibiotics, which might increase this problem. Therefore, the nephrotoxic effects and pharmacokinetics of VCM were examined in rabbits and compared with those in rabbits administered with VCM and other antibiotics. Responses indicating nephrotoxicity such as increases of serum creatinine concentration and BUN and morphological changes of the kidney were induced by the single injection of VCM at 300 mg/kg, i.v. In contrast, no abnormality of clinical data and morphological alteration were observed in the groups injected with VCM and imipenem (IPM)-cilastatin sodium (CS), flomoxef sodium (FMOX) or fosfomycin sodium (FOM). This was not true for groups injected with VCM and ceftazidime, cefpimizole sodium (CPIZ) or cefoperazone sodium. Clearance of VCM increased obviously in the groups injected with VCM and IPM-CS, FMOX or FOM, but decreased in those given VCM and CPIZ. Since the renal concentrations of VCM in the groups that were administered VCM with IPM-CS, FMOX or FOM were lower than that in the control group, IPM-CS, FMOX and FOM may decrease the nephrotoxicity of VCM by inhibiting its uptake into the kidney. PMID- 8690305 TI - [Montirelin hydrate (NS-3), a TRH analog, improved the disturbance of consciousness caused by head concussion and pentobarbital in mice]. AB - Effects of a novel TRH analog, montirelin hydrate (NS-3), on the coma caused by head concussion and narcosis induced by pentobarbital were compared with those of TRH in mice. Head concussion caused a behavioral comatose state with loss of the righting reflex and spontaneous motor activity. NS-3 shortened the latent periods to the recovery of the righting reflex (0.03-0.1 mg/kg, i.v.) and spontaneous motor activity (0.1 mg/kg, i.v.) following the head concussion. In the case of TRH, higher doses were needed to induce such effects. NS-3 (0.1-0.3 mg/kg, i.v.) reversed the pentobarbital-induced narcosis in a dose-dependent manner. A similar effect was elicited by 30- to 100-fold higher doses of TRH than NS-3. The analeptic effect of NS-3 in the pentobarbital-narcotized mice was antagonized by SCH23390, a dopamine D1 antagonist or by the combined treatment with prazosin and scopolamine, while neither prazosin nor scopolamine alone antagonized the analeptic effect of NS-3. Taken together with the finding that NS-3 did not bind to dopamine, adrenaline or muscarine receptors, it is suggested that NS-3 may restore the disturbance of consciousness by activating the brain dopamine, noradrenaline and acetylcholine neurons without stimulating these receptors directly. PMID- 8690307 TI - [Developmental changes in the pacemaker current and membrane currents of the guinea pig myocardium]. AB - The pacemaker current (I(f)) in embryonic chick ventricular myocytes is present, but decreases during development. beta-Adrenergic agonists stimulate I(f), whereas muscarinic cholinergic agonists inhibit I(f) and reverse beta adrenoceptor stimulation. G-proteins directly and indirectly couple autonomic receptors to I(f) channels in embryonic ventricular cells. The I(f) may contribute partly to the electrogenesis of the pacemaker potential. On the other hand, Ito current, voltage-dependent and 4-AP-sensitive, exists even in young embryonic cardiomyocytes, but not in all cells. The Ito increases during development, resulting in modulation of the action potential configuration. The action potential duration of guinea pig ventricular myocardium decreases during the late fetal period and increases postnatally. Single cell voltage clamp analyses revealed that the decrease and increase in action potential duration are due to developmental increases in the current densities of the calcium current and delayed rectifier potassium current, respectively. The role of the sarcoplasmic reticulum in contraction and relaxation of the guinea pig myocardium increases during fetal development. PMID- 8690306 TI - [The affinities of mosapramine for the dopamine receptor subtypes in human cell lines expressing D2, D3 and D4 receptors]. AB - The affinities of mosapramine hydrochloride, an iminodibenzyl antipsychotic drug, for dopamine receptor subtypes were determined by human dopamine D2, D3 and D4 receptors expressed in several cell lines and compared with those of other neuroleptics. Tritiated spiperone bound to the membrane of transfected cells in a saturable manner, and the Kd values for dopamine D2, D3 and D4 receptors were 0.021, 0.12 and 0.10 nM, respectively. Mosapramine showed the highest affinities for these receptor subtypes among the antipsychotics tested. The ratio of Ki values between D2 and D3 (D2 Ki/D3 Ki ratio) in mosapramine was higher than that of haloperidol, indicating that the effects of mosapramine on D3 receptors were more potent than those of haloperidol. On the other hand, clozapine, risperidone and raclopride had higher affinity to D4, D2 and D3 subtypes, respectively. The affinities of mosapramine for D4 receptors was 8 times higher than that of clozapine, and the affinity for D3 receptors was 40 times higher than that of raclopride. These results suggest that the effect on D3 receptors may underlie at least a portion of mosapramine's atypical clinical profile. PMID- 8690308 TI - [Montirelin hydrate (NS-3), a TRH analog, improved disturbance of consciousness in cats: electroencephalographical studies]. AB - Central effects of montirelin hydrate (NS-3) were electroencephalographically investigated in cats with experimentally induced disturbance of consciousness. All experiments were conducted under the gallamine-immobilized and artificially ventilated acute experimental condition. NS-3 and TRH produced EEG activation in cats with lesions in the midbrain reticular formation in a dose-dependent manner. Similar effects were observed in cats with bilateral lesions of the posterior hypothalamic area. These effects of NS-3 were 30 to 100 times more potent than those of TRH. NS-3 at doses higher than 0.003 mg/kg restored the suppressed EEG dose-dependently in cats with cerebral ischemia produced by clamping the bilateral common carotid arteries and basilar artery. TRH showed no effect at a dose of 10 mg/kg. These results indicate that NS-3 might be an effective drug for treating the disturbance of consciousness. PMID- 8690309 TI - [Effect of (-)-N-[(S)-hexahydro-l-methyl-2, 6-dioxo-4-pyrimidinylcarbonyl]-L histidyl-L-prolinamide (TA-0910), a new TRH analog, on plasma levels of TSH and thyroid hormones in rats]. AB - The stimulatory effect of TA-0910 on the secretions of thyroid-stimulating hormone (TSH) and thyroid hormones was investigated in male and female rats. Single intravenous administration of TA-0910 at 8.3 nmol/body acutely elevated the plasma TSH level, with delayed and moderate increases of T3 and T4 in plasma. Similar increments of plasma TSH and thyroid hormones were observed when TRH was injected at the dose of 0.83 nmol/body. Oral administration of TA-0910 at 2.75 mumol/body was equally potent or slightly more potent to secrete TSH than TRH at 0.275 mumol/body. The elevated TSH by TA-0910 decreased to the control level within 2 hr after intravenous injection or within 6 hr after oral administration; on the other hand, the higher levels of the thyroid hormones were retained for up to 4 and 6 hr after intravenous and oral administration, respectively. These findings indicate that TA-0910 and TRH stimulate the secretion of TSH and thyroid hormones by a similar manner and that the TSH-secreting activity of TA-0910 is lower by an order of magnitude compared with that of TRH. PMID- 8690310 TI - The effect of teas on the in vitro mutagenic potential of heterocyclic aromatic amines. AB - Water extracts of eight brands (five types: 'green', 'black', 'oolong', decaffeinated and instant) of common teas (derived from Camellia sinensis) and infusions of six randomly selected herbal teas were examined for inhibitory or potentiating effects on the mutagenicity of eight heterocyclic aromatic amines (HAA) using the Ames Salmonella typhimurium TA98 and S-9 assay. HAA, produced in foods during regular heat processing of meat, exhibit mutagenic/carcinogenic activities. Tea extracts from C. sinensis displayed very potent antimutagenic effects against most HAA: total or substantial inhibition of mutagenic activity of the eight HAA was obtained with extracts equivalent to 50 mg tea leaves/plate (mgEq) and potent inhibition was frequently achieved even with 10 mgEq/plate. Decaffeinated tea produced the same effect as observed for 'regular' teas. However, lower concentrations of some tea extracts enhanced mutagenic activity of 2-amino-3,4,7,8-tetramethyl-3H-imidazo[4,5-f]quinoxaline (4,7,8-TriMeIQx) and 3 amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). Herbal tea extracts displayed variable effects on the mutagenicity of different HAA. While some extracts had no effect, others exhibited a moderate inhibitory effect on the mutagenicity of IQ type HAA. In contrast to common tea, herbal teas showed substantial potentiating effects on the mutagenicity of several HAA, especially Trp-P-2 and 4,7,8 TriMeIQx. PMID- 8690311 TI - Subchronic toxicity study of domoic acid in the rat. AB - Male and female Sprague-Dawley rats were dosed by gavage for 64 days with 0, 0.1 or 5 mg/kg/day domoic acid. Treated animals showed no clinical abnormalities. Terminal values in haematology and clinical chemistry did not reveal differences between treated and control groups. Findings in histopathology and immunohistochemistry were unremarkable. The 24-hr urinary excretion rate for domoic acid determined at three time points was approximately 1.8% of the dose and remained unchanged during the study. PMID- 8690312 TI - A 90-day feeding study of lupin (Lupinus angustifolius) flour spiked with lupin alkaloids in the rat. AB - Three groups of 20 male and 20 female Sprague-Dawley rats were given diets based on lupin (Lupinus angustifolius) flour (55.4 g/100 g diet) that had been spiked to provide dietary concentrations of 250, 1050 or 5050 mg lupin alkaloids/kg diet. A control group of 20 males and 20 females received 50 mg/kg (derived from the background level of alkaloid in lupin flour). The rats were treated for a minimum of 90-98 days. A dose-related reduction in red blood cell count and haematocrit (HCT) occurred in both sexes after 45 days, and the mean cell volume (MCV) was decreased in all the male treatment groups. The reductions in HCT and MCV persisted in the males until termination of the study when decreased haemoglobin levels were also observed in the top-dose males. The relative liver weights of female rats showed a dose-related increase. Altered foci of liver parenchymal cells were seen in five females receiving dietary levels of 5050 mg/kg, in one female fed 250 mg/kg and in one male from each of the 250 mg/kg and 1050 mg/kg treatment groups. No foci were seen in the control group. Basophilic foci are uncommon in young rats suggesting that the low incidence in this study is compound related. PMID- 8690313 TI - Non-carcinogenicity of 2,2'--(4-aminophenyl)imino-bisethanol sulfate in a long term feeding study in Fischer 344 rats. AB - 2,2'-[(4-aminophenyl)imino]bisethanol sulfate (4APE) was administered at dietary levels of 0 (control), 300, 1000 and 3000 ppm to groups of 50 male and 50 female Fischer 344/DuCrj rats for 104 wk. As slight body weight retardation was observed in the male 3000 ppm group in the preliminary 13-wk feeding study, this dose was selected for the highest exposure level. Mean body weights of both sexes in the 3000 ppm group were lower than those of the controls from wk 2 to termination. However, there were no treatment-related clinical signs or adverse effects on survival rate, food consumption or haematology data. Very slight but statistically significant increases in relative thyroid weights were found in males of the 3000 ppm group, but there was no significant treatment-related increase in the incidence of any non-neoplastic or neoplastic lesions. Thus, under the experimental conditions used, 4APE was not carcinogenic in Fischer 344 rats of either sex. PMID- 8690314 TI - Prenatal exposure of Balb/c mice to ochratoxin A: effects on the immune system in the offspring. AB - Effects of prenatal exposure to the mycotoxin ochratoxin A (OA) on the immune system were evaluated in Balb/c mice. Dams were exposed to OA in their diet at doses of 0.18 (control), 30 or 200 micrograms/kg before and during gestation. At birth, pups were cross-fostered to non-exposed dams. OA exposure of the dams did not influence reproductive outcome, that is, the numbers of litters, litter sizes and body weight of the pups. Flow cytomety analysis of T-lymphocyte subpopulations on days 14 and 28 postpartum revealed a decrease in the percentages of splenic CD4+ and CD8+ cells in offspring from the high-dose group (200 micrograms/kg diet), but no significant alterations in absolute numbers of these cell populations nor in the total numbers of splenocytes were observed. In the thymus, a relative as well as an absolute increase in the CD4+ subpopulation was seen in exposed pups on day 14. On day 28, the absolute numbers of CD4+, CD8+ and CD4+CD8+ (double positive) cells were increased, reflecting an elevated number of thymocytes in the high-dose group. No significant differences were found in the proliferative responses of splenic or thymic lymphocytes to mitogens, or in the production of interleukin-2 in concanavalin A-stimulated cell cultures. Further, the plaque-forming cell response to sheep red blood cells and the humoral antibody response to the viral antigen PR8 were not affected by prenatal exposure to OA. No significant differences in natural killer cell activity were observed. The results indicate that exposure of dams to relatively low levels of dietary OA alters absolute and relative numbers of lymphocyte subpopulations in lymphoid organs, but does not suppress immune functions in the offspring. PMID- 8690315 TI - Effect of dietary arginine on urinary nitrate excretion in germ-free rats. AB - The effect of dietary arginine on the endogenous synthesis of nitrate in germ free rats was investigated. The animals were fed, for up to 18 days, purified diets containing either casein or lactalbumin (proteins differing in arginine content) with or without additional free arginine. Urine was collected from all animals for 4 days, and the animals were then dosed ip with Escherichia coli lipopolysaccharide (LPS) to stimulate nitrate synthesis and urine collected for a further 4 days. The urine samples were analysed for nitrate by ion chromatography. Although the excretion of nitrate was markedly stimulated by LPS treatment, there were no significant effects of protein source or arginine supplementation of the diet. PMID- 8690316 TI - Mutagenicity of white grape juice in the Ames test. AB - The mutagenicity of commercially available white grape juice was evaluated in the Ames mutagenicity test. Grape juice elicited a positive mutagenic, response in Salmonella typhimurium strain TA104 and a weaker response in strains TA97, TA98, TA100 and TA1530. The mutagenic response was evident in the absence of an activation system and inclusion of such a system did not influence mutagenicity. The grape juice-mediated mutagenic response was not due to histidine residues in the juice or likely treatment with sulfite. Moreover, freshly prepared grape juice displayed a similar mutagenic response. Three different brands of commercially available white grape juice were investigated in the Ames test; they all provoked a clear positive mutagenic response, but the degree of mutagenicity differed and could not be attributed to differences in the content of solids. It is concluded that grapes contain direct-acting genotoxic component(s). PMID- 8690317 TI - Oxidation of ascorbic acid by lipoxygenase: effect of selected chemicals. AB - The ability of soybean lipoxygenase to mediate ascorbic acid oxidation was examined. The oxidation of ascorbic acid was dependent on the concentration of linoleic acid, ascorbic acid and the enzyme. The optimal conditions to observe maximal enzyme velocity included the presence of 800 microM linoleic acid, 500 microM ascorbic acid and 25 nM soybean lipoxygenase in 50 mM Tris buffer, pH 8.3. The reaction displayed a K(m) value of 100 microM for ascorbic acid and an average specific activity of about 460 nmol/min/nmol enzyme under the optimal conditions. The effect of ascorbic acid on the lipoxygenase-catalysed co oxidation of xenobiotics was also evaluated. Ascorbic acid markedly decreased the rate of oxidation of test xenobiotics by the lipoxygenase. In contrast, the rate of ascorbic acid co-oxidation was enhanced significantly by the presence of xenobiotics, which are co-oxidized simultaneously by lipoxygenase through the formation of free radicals. Superoxide generation was not observed during lipoxygenase-mediated ascorbic acid co-oxidation. PMID- 8690319 TI - Current research and case work activities of criminalistics in Japan. AB - The current research and case work activities of criminalistics in Japan are described. The selected forensic science disciplines are forensic osteology including specialized technology of skull identification, forensic serology, forensic DNA analysis of poisonous materials, forensic hair and fiber analysis, trace evidence analysis, document analysis, forensic psychology mainly concerned with the so-called lie-detector, forensic image analysis, voice print analysis, fire and explosion analysis, forensic engineering, firearm and toolmark analysis. The current activity of the Training Institute of Forensic Science at the National Research Institute of Police Science is also briefly described with special regard to the education and training course of forensic DNA typing analysis. Instruments for analytical and methodological use are listed according to the availability in evidence sample analyses. PMID- 8690318 TI - Experimental assessment of the sensitizing properties of formaldehyde. AB - Formaldehyde causes upper respiratory tract irritation and has been reported in some investigations to be a cause of occupational allergic asthma. The data are equivocal, however, and it has proved difficult to confirm that exposure to formaldehyde induces respiratory sensitization or provokes the production of specific immunoglobulin E (IgE) antibody. In this study the sensitizing properties of formaldehyde were examined experimentally. This chemical elicited strong positive responses in three independent methods for the prospective identification of contact sensitizing chemicals-the guinea pig maximization test, the occluded patch test of Buehler and the murine local lymph node assay. In contrast, in a novel predictive test method for assessment of respiratory sensitization potential-the mouse IgE test-formaldehyde at the same test concentrations was negative. Furthermore, formaldehyde induced in mice a pattern of cytokine secretion by draining lymph node cells inconsistent with the stimulation of IgE antibody responses or respiratory sensitization. These data indicate that, although formaldehyde is a potent contact allergen, it lacks a significant potential to cause sensitization of the respiratory tract. PMID- 8690321 TI - Forensic immunochemistry. AB - Immunoassay has been established with polyclonal or monoclonal antibody even for a low molecular weight compound which has no antigenicity. In spite of the cross reactivities of an antibody and also the difficulty in identification of the compound, an immunoassay is a useful method of choice for the detection of the compound in biological fluids because of the pretreatment simplicity and ability to treat many samples in a short time. Therefore, immunoassay has been established as a sensitive analytical and screening method for use in forensic sciences. In our laboratory, a radioimmunoassay (RIA) and an enzyme immunoassay (EIA) for phenobarbital, and enzyme-linked immunosorbent assays (ELISA) and latex agglutination inhibition reaction tests (LAIRT) for methamphetamine, benzoylecgonine and morphine have been established. These assays are described in addition to the two commercially available immunoassay kits, enzyme multiplied immunoassay technique (EMIT; Syva Co., USA) and Triage Biosite Piagnostics, Inc, USA. PMID- 8690320 TI - Molecular genetic basis of red cell markers and its forensic application. AB - (1) The polymerase chain reaction (PCR) was used to amplify Rh-related cDNAs from erythroid cells cultured by the selective two-phase liquid culture system for human erythroid progenitors in peripheral blood. Two Rh polypeptide cDNAs have been isolated from the PCR products and tentatively designated RhPI cDNA and RhPII cDNA. Both cDNA clones have an open reading frame composed of 1251 nucleotides. The RhPI cDNA clone shows a single nucleotide substitution with no amino acid substitution compared with the published sequence. The RhPII cDNA clone differs from the above by 41 nucleotide substitutions in the open reading frame, resulting in 31 amino acid substitutions. Besides these cDNA clones, eleven and five truncated isoforms of the RhPI and RhPII cDNAs, have been isolated, respectively. (2) The promoter region of the Duffy gene was cloned by IPCR of 1.1 kb SacI fragment and the 3' flanking sequence was cloned by IPCR of 1.9 kb EcoRI fragment. The IPCR products contained the known Duffy cDNA sequence without introns. By comparing the coding area of the Duffy gene in 28 Duffy positive individuals, we elucidated that one base change that results in an amino acid substitution (GAT(Asp44)-->GGT(Gly)) is in accordance with the Fya/Fyb polymorphism. This fact proves that the Duffy cDNA and its gene encode the Duffy blood group system. (3) Two common alleles in Esterase D (EsD) polymorphism, EsD1 and EsD2 were characterized by the substitution of one amino acid (Gly-Glu) caused by the point mutation of one nucleotide (G-A). The point mutation between cDNAs of EsD1 and EsD2 alleles was detectable as restriction fragment length polymorphism (RFLP) using Ssp1. The RFLP makes it possible to determine the EsD phenotypes using DNA samples from forensic materials without EsD enzymatic activity. (4) The authors report studies on 19 pairs of donors and recipients in bone marrow transplantation. A broad range of genetic markers at 42 gene loci, including one DNA marker 11 red blood cell markers, five human lymphocyte antigen types, 12 serum protein markers, five red cell enzyme markers, and eight salivary markers was evaluated before and after BMT over about 2 months. As a result, 11 out of 42 gene loci of genetic markers in recipients were transformed into the donor type. PMID- 8690322 TI - Investigations on the mechanism of adipocere formation and its relation to other biochemical reactions. AB - In the adipocere, which is one of the postmortem changes, some specific fatty acids possessing higher melting points, together with soap, play an important role in the formation of adipocere. These fatty acids were shown to be mainly 10 hydroxystearic and 10-hydroxypalmitic acids. Moreover, slight amounts of 10 oxostearic and 10-oxopalmitic acids, which have higher melting points than those of hydroxy fatty acids, exist in the adipocere as well. The substantial adipocere is formed and stabilized by these specific fatty acids together with the soap. The hydroxy fatty acid (OHFA) and oxo fatty acid (OXOFA) are biosynthesized by some bacterial enzymes. Various aerobic and anaerobic bacteria are involved in the formation of adipocere. For example, microbial conversion of various unsaturated fatty acids to 10-OHFA by Micrococcus luteus was investigated. It turned out that 10-OHFA was synthesized only from fatty acids possessing cis-9 unsaturation. It was also shown that 10-OHFAs were converted to the corresponding 10-OXOFAs but the 10-OXO compounds were inactive as substrates. Furthermore, it was found that the enzyme preparations from Flavobacterium meningosepticum solubilized by sonication catalyzed not only hydration of oleic acid to produce 10-hydroxystearic acid, but also dehydrogenation of this product in the presence of deuterium. On the other hand, we found out that there was 10-hydroxy-12 octadecenoic acid (10-OHODA) from linoleic acid in some kinds of adipocere. Recently, 10-epoxy-12-octadecenoic acid (leukotoxin, LTx), which is one of the lipid peroxides, was found not only in rice plants but in polymorphonuclear leukocytes. Since LTx was found in leukocytes related to inflammatory response, interest has been focused on its involvement, not only in the basic mechanism of biological defense, but also on the mechanism of shock as a vasoactive substance. A postmortem change itself is only remotely associated with a phenomenon in a living body. However, 10-OHODA found in adipocere seemed to exist also in polymorphonuclear leukocytes, suggesting that this compound might be closely related to a biological reaction. PMID- 8690323 TI - Forensic application of organ-specific antigens. AB - A highly sensitive sandwich enzyme immunoassay for organ-specific antigen is described for use in forensic practice. The sandwich enzyme immunoassays for specific antigens to the liver (LSA), the small intestine (sucrase-isomaltase), and the heart (cardiac troponin I) were developed. High levels of antigen could be detected to exist in forensic materials, and it is clearly possible to differentiate between samples from these stabbed organs and those originating from other stabbed organs. In addition, a sandwich enzyme immunoassay for prostate-specific antigen (gamma-seminoprotein, gamma-sm) was developed for sex discrimination of blood and bloodstains. The ratio of gamma-sm to hemoglobin was significantly higher in male adults than in female adults. PMID- 8690324 TI - Suffocation and related problems. AB - Experiments were carried out on rats, rabbits and dogs to investigate the course of respiration and circulation during various types of suffocation. From the results of dogs, the course of respiration on obstructive asphyxia consists of three stages; the stage of dyspnea, of apnea, and of terminal respiration. The respirations in the stage of dyspnea and the stage of terminal respiration are generally inspiratory. In typical hanging, the course of respiration is characterized by shorter stages of dyspnea and apnea and a longer stage of terminal respiration as compared with that in obstructive asphyxia. In non obstructive asphyxia, the course of respiration has the initial stage before the stage of dyspnea. The results of experiments simulating deficiency of oxygen in the external atmosphere suggested that the lethal oxygen percentage is approximately 2.2%. In drowning, the course of respiration consisted of four stages: initial stage (surprise-respiration and initial apnea), stage of dyspnea, stage of apnea and stage of terminal respiration. The surprise-respiration is suggested to be induced by the contact of water with the mucus membrane of larynx or trachea. The respirations during the stage of dyspnea are essentially inspiratory, and do not always have a convulsive character. In a few dogs, the precipitous fall of blood pressure and flat electroencephalogram appeared immediately after aspiration of water. This seemed to be caused by the reflex vagal inhibition of the heart, which was induced by the contact of water with the mucus membrane of larynx or trachea. It is suggested that the reflex vagal inhibition of the heart is one of the causes of loss of consciousness and drowning during swimming. PMID- 8690325 TI - Molecular biological studies on teeth, and inquests. AB - Reviewed here are three dental approaches to identification work. One is that using racemization of amino acids. Age estimation of a high correlation of 0.99 was achieved from using the whole dentine from the central vertical section. The highest correlation was also seen when soluble peptide from dentine was used, suggesting its usefulness for age estimation. The racemization rate was highest for Asp, followed by Glu and Ala in that order. The other approach reviewed in DNA typing. DNA is extracted from dental pulp for DNA fingerprinting with Y specific probe. DNA typing is especially useful for sex determination, allowing valid determination from teeth extracted up to 21 months before the examination. A 3-cycle repetition of PCR provided an accurate sex determination from a considerably degraded DNA specimen, comparable to one freshly sampled. The other approach discussed is the content and scope of the inquests performed by dentists who participate in the identification work in mass disasters etc. In this context, the antemortem dental information including dental records and radiological records provided by families of the victims, play a major role in speedy identification. PMID- 8690326 TI - Forensic applications of genetic polymorphisms detected in human body fluids (urine, semen and blood). AB - The development of a new genetic marker with forensic usefulness is difficult and costly work, but it is necessary. We discovered several new markers detected in urine, semen and blood. In particular, deoxyribonuclease I-polymorphism is one of the most useful markers for practical purposes, since it has a well-balanced gene frequency, high concentration in body fluids, stability against severe conditions, and easy and accurate detectability. PMID- 8690327 TI - Fundamental studies on alcohol dependence and disposition. AB - This article reviews some recent studies on alcohol preference, dependence, metabolism and pharmacokinetics which were mainly carried out in our department. The inbred strains of mice with genetically different alcohol drinking behavior and alcohol animal model treated with the neurotoxins, 6-hydroxydopamine and 5,7 dihydroxytryptamine, are useful for a behavioral and pharmacological approach to evaluate the contribution of specific neural systems to alcohol, drug dependence mechanism and alcohol drinking behavior. The relations between alcohol preference and some physiological conditions are reviewed. On the drug-alcohol interaction, some drugs containing the chemical group = CHONO2, antimony and methamphetamine are addressed. This article also deals with recent topics in the pharmacokinetics and pharmacodynamics of alcohol. The dose-dependency of the alcohol elimination rate, the first-pass metabolism during alcohol drinking, and the pharmacodynamic model for describing pulse rate reaction to plasma acetaldehyde are discussed. PMID- 8690328 TI - [Secondary cerebral vasculitis in suppurative meningitis. Clinical aspects and findings in color-coded transcranial duplex ultrasound]. AB - Transcranial Doppler ultrasonography carried out in cases of bacterial meningitis has often shown a reversible increase in blood flow velocity in basal cerebral arteries, that is interpreted as caused by segmental vasospasm brought on by vasculitis. We report for the first time on findings of transcranial colour-coded duplex ultrasonography performed on a patient with pneumococcal meningitis who suffered a subcortical infarction in the territory of the right middle cerebral artery. Doppler ultrasonography revealed an increase in blood flow velocity of the right middle basal cerebral artery, while the B-scan revealed thickening of the main trunk on the right. These findings suggest an inflammatory thickening of the blood vessel wall with secondary narrowing of the lumen as a result of secondary vasculitis. PMID- 8690329 TI - [Criteria for using tumor markers. 3: Indications and interpretation]. PMID- 8690330 TI - [Exclusion of wound physicians from health care in Germany 1871/72]. AB - At the beginning of the 1870s, non-academic surgeons were finally banished from officially accepted medical practice in Wurttemberg - the last German Land in which they had still been recognized. As contemporary reports by barber-surgeons make clear, they had agreed to the elimination of their handiwork - in the hope of winning thereby generous "terms of transition" for the remaining practitioners of their trade. The fact is that in this point, too, barber-surgeons - at least for the most part - had but little success, clearly put them on the losing side in political conflict of professional interests. PMID- 8690331 TI - [Good chewing--basis for healthy nutrition. Experiences with tooth and jaw implants. Interview by Elisabeth B. Moosman]. PMID- 8690332 TI - [Dental implants--indications and long-term outcome]. AB - Osteo-integratable dental implant systems were developed 25 years ago. The mean life of such implants is about 20 years when they are properly inserted for the right indications. The most important indication is the edentulous mandible, but also the toothless maxilla, the free-end situation in the case of bridges, and single-tooth replacement. Effective procedures have since been developed for eliminating bone deficits that once excluded the use of implants. PMID- 8690333 TI - [Cerebrovascular metabolism in patients undergoing chronic hemodialysis]. PMID- 8690334 TI - Chronic toxicity of indium arsenide and indium phosphide to the lungs of hamsters. AB - Chronic toxicity of indium arsenide (InAs) and indium phosphide (InP) was studied in male Syrian golden hamsters which received InAs or InP particles containing a total dose of 7.5 mg of arsenic or phosphorus by intratracheal instillations once a week for 15 weeks. As a control, hamsters were treated with the vehicle, phosphate buffer solution. During their total life span, the cumulative body weight gain of hamsters in the InAs group was suppressed significantly compared with that in the control group, but not in the InP group when compared with that in the control group. Concerning the histopathological findings of the lung, the incidence rates of proteinosis-like lesions, alveolar or bronchiolar cell hyperplasia, pneumonia, emphysema and metaplastic ossification observed in the InAs or InP group were significantly higher than those observed in the control group. From these results, it would seem that InAs and InP produced severe damage to the lungs of hamsters. PMID- 8690335 TI - [Analysis of carbapenem resistant plasmid isolated from Serratia marcescens]. AB - Four nontransferable plasmids of about 28-32 kbp were isolated in 120 Serratia marcescens strains isolated from patients with urinary tract infection. All of these plasmids were tranformable in Escherichia coli, and showed a high frequency of mobilization by R9-5 plasmid of incompatibility group F II. The MICs of carbapenems were significantly lower than those of cephalosporins. This trend was more marked when MICs were determined at 10(6)cfu/ml. Based on the substrate profiles and on the effect of inhibitors of the beta-lactamase, the enzyme was classified as a class B beta-lactamase, so called carbapenemase. The carbapenem resistance genes of these 4 plasmids were cloned into vector plasmid pHSG398 using Bam H1 digestion and the size of the DNA was found to be 4.9 kb. PMID- 8690336 TI - Demagoguery and debate over Medicare reform. PMID- 8690337 TI - Fee-for-data: a strategy to open the HMO black box. AB - This paper outlines a simple proposal to maintain utilization data in the face of managed care growth. Health maintenance organizations (HMOs) would be required to submit claims (encounter-level data) and in return would be paid a percentage of what Medicare would pay fee-for-service providers. The capitation payment rate would be lowered to maintain budget-neutrality. This proposal would enable the collection of key data that might not otherwise be captured in a Medicare program dominated by HMOs and other forms of managed care. The data are necessary to drive Medicare policies and to gauge the impact of changes to the program. The program would be well advised to make the small additional investment to make the data system complete. The key issue in implementing such a proposal will be HMOs' ability to generate those data at reasonable cost. PMID- 8690338 TI - Health care purchasing and market changes in California. AB - This paper analyzes the process and outcomes of collective negotiations among large private employers and health maintenance organizations (HMOs) in California. In 1994, prior to collective negotiations, differences in benefit packages, risk mix, and volume of purchasing accounted for only one-third of the variance in premiums among firms and HMOs. The 1995 collective negotiations reduced the variance by 22 percent and the enrollment-weighted mean premium by approximately 9 percent, while enriching the standard benefit package. Savings for the eleven participating firms totaled $36.5 million. Large purchasers are reducing the number of health plans offered to their employees, standardizing the benefit package, using collective negotiations to contain costs, and shifting from vendor to partner relations with HMOs. PMID- 8690339 TI - Inside California's HMO market: a conversation with Leonard D. Schaeffer. Interview by John K. Iglehart. PMID- 8690340 TI - Insurance coverage for experimental technologies. AB - As the number and cost of new technologies grow, it is increasingly important that we develop sound policies for payment for those technologies while their clinical impacts are being defined. Such policies need to balance social interests in promotion of innovation, early access to promising technology, patient safety, control of health care costs, and return on investment. We present a rationale, policy options, and a proposal for insurance coverage of experimental technology. PMID- 8690341 TI - Health system change: the view from Wall Street. PMID- 8690342 TI - No-fault compensation for medical injury: a case study. AB - Changes in malpractice law remain an important goal of health care reform. Many state and federal legislators continue to call for measures that would limit the ability of injured patients to sue. There is also growing interest in alternatives to fault-based litigation. As legislators consider no-fault proposals, they can look to Florida's experience with the Neurological Injury Compensation Association (NICA), which for the past four years has been providing no-fault compensation for injured newborns. NICA provides some insights into the ways in which claims are generated, the nature of risk spreading, and the financial viability of a no-fault model. PMID- 8690343 TI - Medical necessity: do we need it? AB - The term medical necessity has been mainly a placeholder in insurance plans for over thirty years. More recently, the national health care reform debate and litigation over denials of costly experimental treatments have broken the term out into open discussion about what a necessary service is and who should decide if it is covered. This paper summarizes the history of the term and its evolution from an insurance concept controlled by practicing physicians to a rationing tool used by insurance administrators. How did national reform efforts address this terminology, and how should we define medical necessity in a changing delivery system? PMID- 8690344 TI - Great expectations: the limits of state health care reform. PMID- 8690345 TI - Through the looking glass: decision making and chemotherapy. PMID- 8690346 TI - The patient/physician relationship: one doctor's view. PMID- 8690347 TI - Disability and the managed care frenzy: a cautionary note. PMID- 8690348 TI - Who has the best health care system? A second look. AB - A 1994 opinion survey again shows Americans less satisfied with their health care system than Canadians and (West) Germans are with theirs. Americans also report more problems in paying for care and receiving needed services. However, overall satisfaction in Canada and Germany has fallen. Important cultural differences between the countries were identified. Americans have higher expectations for medicine and a stronger preference for spending more nationally on health care. The most dramatic difference is Americans' antipathy to government. Public confidence in heads of U.S. federal health agencies is the lowest of any institution or agency in the three countries. PMID- 8690349 TI - Three decades of Medicare: what the numbers tell us. AB - The Medicare program was first implemented to meet a critical need in American society, and over its thirty-year history it has evolved into an integral part of the U.S. health care system. This DataWatch provides a broad overview of the program, outlining both historical and current trends in coverage, financing, payment mechanisms, beneficiary status, benefits, and spending. PMID- 8690350 TI - Medicare and the Social Security Disability Insurance program. AB - This DataWatch traces changes over time in the age and health characteristics of persons awarded Social Security Disability Insurance (SSDI) benefits. SSDI beneficiaries are increasingly younger and more likely to be incapacitated by health conditions that at any age lengthen spells of disablement. These changes have had a significant impact on SSDI operations; they also have important implications for financing the Medicare program. PMID- 8690351 TI - A shifting picture of health insurance coverage. AB - Data from the Current Population Survey are used in this DataWatch to explore the changing composition of health insurance coverage of the U.S. nonelderly population. The authors analyze coverage trends across various subpopulations for 1988-1993. During this time significant declines in employer-sponsored coverage coincided with equally significant increases in Medicaid coverage. Thus, the increase in the proportion of nonelderly persons without health insurance appears relatively small. However, this analysis reveals that the relative stability of the uninsurance rate for the entire nonelderly population belies more significant changes in insurance coverage--and lack of coverage--among various groups. The authors also discuss the extent to which a growing level of public insurance "crowds out" (or substitutes for) private health insurance. PMID- 8690352 TI - Are small firms greater health risks? AB - To test whether use of health care services is a function of firm size, we analyzed a three-year database (1988-1990) of private insurance claims, representing 28,990 firms and approximately 1.4 million subscribers in western Pennsylvania. In this database both small and large firms had higher medically underwritten costs than mid-size firms had. Furthermore, risk-pooling alternatives that included small companies had a lower cost per subscriber than the risk pools that included large companies, especially companies of more than 500 contract holders. Age, sex, health status, and the types of hospitals used for inpatient care of pooled subscribers, in combination, were found to be the important determinants of costs. With risk adjustment based on these factors to correct for adverse risk selection, community rating can be a feasible approach to increasing the affordability and accessibility of health insurance to the majority of those who lack it. PMID- 8690353 TI - Foundations' impact on policy making: results from a pilot study. PMID- 8690354 TI - Any-willing-provider and freedom-of-choice laws: an economic assessment. PMID- 8690355 TI - Preserving and strengthening Medicare. AB - Any restructuring or reform of Medicare should first and foremost preserve the integrity of the program. Contrary to current rhetoric, Medicare offers mainstream medical care for the most difficult-to-insure Americans, and over the past ten years its record of holding down costs has been better than that of the private insurance sector. For the very long term, when demographic changes place even greater pressures on Medicare, all dimensions of the program need to be considered in the search for a long-range solution, including asking beneficiaries and/or taxpayers to contribute more to the program. Expansion of managed care choices should certainly be part of any restructuring, but careful attention to improving the basic fee-for-service Medicare program--which will continue to serve a majority of beneficiaries for many years to come--also is needed. PMID- 8690356 TI - Creative and innovative change in managed behavioral health care. PMID- 8690357 TI - Bridging the gap between mental illness and health. PMID- 8690358 TI - Budget cuts and mental health. PMID- 8690359 TI - More on medical savings accounts. PMID- 8690360 TI - Exporting Minnesota's health care solution: the reality. PMID- 8690361 TI - Erroneous conclusions from medical screening data. PMID- 8690362 TI - The FEHBP as a model for a new Medicare program. AB - The deficiencies of the Medicare program are rooted in its defined-benefit structure and in its use of price controls. Medicare should be transformed into a defined cash contribution made to beneficiaries' private plans or to the traditional Medicare program. The Federal Employees Health Benefits Program (FEHBP) is essentially such a system and is a good model for Medicare reform. The FEHBP has been highly successful at holding down costs while offering a wide range of benefits and types of plans. Its features for consumer information and plan standards also would be useful in a reformed Medicare program. PMID- 8690363 TI - Who pays for Medicare? PMID- 8690364 TI - What Medicare's architects had in mind. PMID- 8690365 TI - Medicare quality and getting older: a personal essay. PMID- 8690366 TI - The Medicare reform debate: what is the next step? AB - Medicare costs are rising faster than projected revenues. Action to close the emerging deficit is inescapable. We propose converting Medicare from a "service reimbursement" system to a "premium support" system. These changes would resemble many that are now reshaping private employer-based insurance. Our reform would encompass not just the "public" Medicare program but also the "real" Medicare, which includes the supplemental plans to which most Medicare beneficiaries have access. Approved plans would have to offer stipulated services. We review numerous technical issues in moving to a new system that cannot be solved quickly and that preclude quick budget savings. PMID- 8690367 TI - The future of Medicare: one senator's vision. PMID- 8690368 TI - Securing health care quality for Medicare. PMID- 8690369 TI - Competition in the health system: good news and bad news. AB - Competition among health plans, hospitals, and physicians has taken place in fifteen health care markets primarily on the basis of price and secondarily on network breadth and style of care. In most markets, competition resulted in lower (or slowly growing) premium prices. Within a type of plan product, competition was leading to similar prices and networks and was reducing product differentiation among health plans. Competition was not taking place on the basis of measured and reported quality of care, which limited the capacity of employers and enrollees to make informed health plan choices. As a result, there was a substantial gap between competition as envisioned by the architects of the managed competition model and competition as it is evolving today. PMID- 8690370 TI - Context and catalysts for change in health care markets. AB - Understanding the nature of change in health care markets involves recognizing that not all communities are alike, and hence not all health care markets look or act the same. In a study of fifteen communities sponsored by The Robert Wood Johnson Foundation, the characteristics and culture of each community interacted with market conditions to influence the magnitude, direction, and sustainability of health system change. A catalyst attuned to a market's context can ignite change, giving the market focus and direction. Recognizing the importance of context to the process of change enhances our ability to understand the consequences of proposed market activities. PMID- 8690371 TI - Health care spending in 1994: slowest in decades. AB - Falling medical prices and slowing growth in private health insurance premiums diverted the spotlight from large-scale reform of the health care system in 1994. In aggregate, growth in health expenditures dropped to its lowest rate in more than thirty years. Even at this low rate, health spending grew faster than gross domestic product (GDP), but the economy easily absorbed these modest increases. In this picture of moderation, there was one disconcerting note: Medicare spending continued to increase at double-digit rates. Although Medicare's more rapid spending growth seems out of sync with the current modest health spending growth trends in the private sector, closer examination of factors accounting for growth in 1994 suggests that some difference is warranted. PMID- 8690372 TI - Spending more through 'cost control:' our obsessive quest to gut the hospital. PMID- 8690373 TI - The dynamics and limits of corporate growth in health care. AB - This paper analyzes the economic dynamics of five forms of organizational growth in health care: horizontal integration within a single geographic market; horizontal integration across different geographic markets; diversification among multiple products and types of service; diversification among multiple distribution channels; and vertical integration with suppliers. These principles are illustrated through brief case studies of three firms that have grown by way of internal expansion, mergers, acquisitions, and diversification: WellPoint Health Networks, UniHealth America, and Mullikin Medical Enterprises. The paper analyzes the potential limits of organizational growth in health care and explores the implications of integration and diversification for antitrust policy. PMID- 8690374 TI - Effects of market reforms on doctors and their patients. AB - The outcome of the competitive revolution in health care will depend critically on how it affects physicians' behavior and their interaction with patients. From the standpoint of physicians, competition often seems mediated by three influences affecting their day-to-day practice environment: the organizational phenomenon, the customer phenomenon, and the commodification phenomenon. A careful examination of these three phenomena offers reasons to believe that both the supporters and detractors of competition may be partially correct. Competitive markets may work extraordinarily well for some consumers and very poorly for others. The competitive restructuring of our health care system will accentuate the divisions and inequalities that existed in our society before the transition to a market-based health care system. PMID- 8690375 TI - Can managed care plans control health care costs? AB - The health insurance sector has been transformed in the past fifteen years, with managed care replacing indemnity insurance as the norm. This transformation was intended to change the nature of competition in the health care system so that market forces could be used to control costs. Empirical studies have shown that this objective has been met, as areas with high managed care penetration have tended to have much lower rates of increase in their costs. Creating a more efficient health care system will require additional efforts to produce useful measures of quality and to maintain competitive markets. PMID- 8690376 TI - Academic health centers in a changing environment. AB - To evaluate the potential problems facing academic health centers (AHCs) as a result of market-driven health care reforms, we conducted case studies of seven nationally prominent AHCs during 1994. Findings suggest that although AHCs were not yet feeling the predicted impact of competition on their financial health and ability to sustain their academic missions of teaching, research, and care of vulnerable populations, they were adopting a variety of strategies for responding to those perceived threats, especially networking and cost reduction. They were placing considerably less emphasis on restructuring their research and teaching missions to prepare for anticipated fiscal pressure. Our analysis suggests that even the most successful AHCs are likely to be fundamentally altered by the revolutionary changes occurring in health care markets. PMID- 8690377 TI - Tracking consumers' reactions to the changing health care system: early indicators. AB - A survey in fifteen communities and nationwide of consumers' opinions about changes in their local health care system reveals that Americans are surprisingly positive about recent changes in their personal access to and quality of care and consistently negative about changes in the cost of care. Although many consumers think that changes in the system are making things worse, they are optimistic about the trend toward managed care. Subgroup analysis shows that uninsured persons and persons with health problems reported high rates of concern about many of the health system issues we explored, while Medicaid recipients, Hispanics, and African Americans reported positive changes in their access to and quality of care. PMID- 8690378 TI - Re-minding our Ps and Qs: medical cost controls in Canada. AB - During the past few years the landscape of Canadian physician reimbursement policy has undergone dramatic change. Rapidly eroding fiscal environments for provincial (and federal) governments have forced provinces to "get serious" about controlling a significant, previously uncontrolled, budget line: physician expenditures. All provinces now impose medical expenditure caps, with eight of these being hard caps under which any overruns are the responsibility of the profession. In addition, policies in five provinces now include individual income caps. One of the effects of this new environment has been a rush to adopt supply control policies. This paper explores a number of other side effects, such as heightened interest in alternative methods of payment, as well as the emergence of, and difficulties for, joint province/medical association management committees. PMID- 8690379 TI - Shifting paradigms and the role of research. PMID- 8690380 TI - Managing the physician workforce: hands off, the market is working. PMID- 8690381 TI - Powerful hands: making the most of graduate medical education. PMID- 8690383 TI - Self-insured employer health plans: prevalence, profile, provisions, and premiums. AB - Data from three recent surveys indicate that about 40 percent of workers with employment-based health insurance are enrolled in plans that their employers self insure. Despite the considerable differences between federal regulation of these self-insured plans and state regulation of employer plans purchased from an insurance company, we find striking similarities in the populations they serve, the benefits they offer, and their premium costs. Implications for health policy are discussed. PMID- 8690382 TI - All payer, single payer, managed care, no payer: patients' perspectives in three nations. AB - We present data on patients' experiences with access to and cost and quality of health services in the United States, Canada, and Germany. In general, patients report favorably about their care. U.S. respondents report more problems with access to care, even controlling for the severe problems of the uninsured. Differences in managed care versus fee-for-service plans in the United States mirror some of the problems observed in international comparisons--access to specialists and tests and waiting times for and quality of some services. Different cost containment strategies have measurable effects on patients' perspectives, particularly among patients who are sicker. PMID- 8690384 TI - Grants to shape the health care workforce: the Robert Wood Johnson Foundation experience. PMID- 8690385 TI - The public's stake in nonprofit health plan conversions. PMID- 8690386 TI - Federal nursing home regulation. PMID- 8690387 TI - Effects of health system changes on safety-net providers. AB - Growing competition in health care markets and Medicaid managed care, combined with cuts in government funds that subsidize care to the uninsured, are challenging the viability of the safety net. In response to these pressures, "safety-net" providers in fifteen communities are integrating vertically and horizontally, contracting with or forming managed care plans, and seeking to attract paying patients. Such strategies appear to be successful for community based primary care clinics, but other providers--including hospitals that cannot quickly develop primary care capacity, most local health departments, and providers that fail to attract Medicaid patients--are more vulnerable to health system changes. While the safety net may be intact now, access to care among the uninsured is more at risk in communities without state programs or local taxes that subsidize such care. PMID- 8690389 TI - Tracking the transformation of health care. PMID- 8690388 TI - Hospitals in a changing health care system. AB - Health system change is happening locally, and hospitals are at the center of this change. This paper, which presents data from a 1995 study of fifteen diverse communities, sketches the broad economic and organizational forces affecting hospitals in these communities and the hospitals' responses. Within these larger trends, local flavors and differences emerge. These appear to reflect variations in each community's employment base and health care purchasing experience, in the history and political strength of health system stakeholders, and in regional issues of culture or religious affiliation for some hospitals. PMID- 8690390 TI - Impact of purchasing strategies on local health care systems. AB - Efforts to control health care costs increasingly rely on purchasers to seek the best value for their investment. In this examination of purchasing strategies in fifteen communities, most purchasers employed traditional strategies to reduce their direct costs, such as shifting costs to employees and switching from indemnity to managed care plans. Fewer purchasers--mostly large companies, public agencies, and coalitions--were using more resource-intensive strategies such as direct contracting with providers or selecting plans based on quality to improve value or efficiency. Although both sets of strategies might help to reduce costs, they are not yet changing the delivery of health care in local communities. PMID- 8690391 TI - The RWJF Community Snapshots Study: introduction and overview. AB - Teams of researchers visited fifteen communities--selected to reflect a range of health care market development, regions, and population size--to obtain a "snapshot" of health system change. The study found that organizational change is pervasive, even in those communities that do not receive attention in the trade press, but that much of the change has not yet affected consumers. While the forces driving change are similar across the communities, the responses--and the shape of change--differ in important ways. Factors leading to the differences include the size and capabilities of existing health care organizations, the community's experience with managed care, and the political and business cultures of the community. PMID- 8690392 TI - The role of public policy in health care market change. AB - Market forces appear dominant in the transformation of health care systems across the United States. However, in many markets public policy remains an important factor--guiding, facilitating, and in some cases prompting change. This paper reviews how the debate over health care reform acted as a catalyst in local health care financing and delivery systems, and how other public policy tools are affecting the fifteen markets studied in the Community Snapshots project. We then discuss prospects for public policy in the near term and the longer term, using two scenarios to illustrate possible future roles. PMID- 8690393 TI - Health system integration: a means to an end. AB - The creation of integrated firms and contractual networks in health care often is a precondition for other forms of integration that could actually lower costs and improve quality of care. Although different types of integration activities are leading to innovations in the production of services and the care of populations, the continued influence of the "old" indemnity insurance/fee-for-service system creates important obstacles to those integration activities. If creation of integrated firms and contractual networks races ahead of other forms of integration, it could produce uncompetitive markets that reduce pressures to integrate in ways that can cut costs and improve quality of care. Purchasers' actions could play a major role in determining the future of various integration activities. PMID- 8690394 TI - An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. AB - Histological activity reflects the global assessment of basic necroinflammatory lesions and is a criterion of major importance in chronic hepatitis C. The aim of this study was to propose and test the accuracy of a simple algorithm that generates a single activity score based on basic pathological features. A panel of 10 pathologists reviewed 363 chronic hepatitis C liver biopsies and graded the activity of hepatitis according to their own experience (reference activity). Then, a consensual algorithm on the grading of activity was established by the 10 experts in a panel discussion. Finally, stepwise discriminant analysis was performed to define which basic features had been intuitively used in the reference activity (statistical activity). To test the accuracy of the algorithm, concordance between the activity defined by the algorithm and the reference activity was assessed. It was compared with concordance between the activity defined by the statistical model and the reference activity. The algorithm proposed by the panel for the grading of activity included piecemeal necrosis and lobular necrosis. Concordance between reference activity and activity defined by the algorithm was substantial (305 cases, 84%, kappa = .75). Discriminant analysis showed that piecemeal necrosis, lobular necrosis, and portal inflammation were independently used to grade the activity. Concordance between reference activity and activity defined by the statistical model was substantial (300 cases, 83%, kappa = .73), virtually identical to the concordance between reference activity and activity defined by algorithm. This study proposes a simple algorithm for the grading of activity in chronic hepatitis. Its accuracy is as high as that obtained using a statistical approach. PMID- 8690395 TI - Inhibition of viral replication by genetically engineered mutants of the duck hepatitis B virus core protein. AB - The hepatitis B virus (HBV) nucleocapsid consists of 240 viral core proteins that are arranged in a highly symmetrical structure, HBV replication can only take place inside intact nucleocapsids. In the present study, we investigated whether genetically engineered core mutants can inhibit viral replication by interfering with the formation of intact nucleocapsids. Using the duck hepatitis B virus (DHBV) model, a series of core protein mutants was generated. Polymerase chain reaction-amplified fragments from the bacterial lacZ gene expressing up to 282 amino acids were added either to the amino- or carboxy-terminus of the DHBV core protein. In addition, carboxy-terminal extensions were generated by fusing the DHBV core protein with the DHBV small surface protein or various fragments of the viral polymerase. Finally, the green fluorescent protein (GFP) was fused in-frame to the carboxy-terminus of the DHBV core protein. In this chimeric protein, GFP is still functional and can act as a reporter molecule. The various core protein mutants were tested for their potential antiviral activity by cotransfection with a replication-competent DHBV construct into the avian hepatoma cell line LMH. Carboxy-terminal, but not amino-terminal, DHBV core mutants inhibited DHBV replication by up to 90% at an effector-to-target ratio of 1:10, thus displaying a dominant negative phenotype. Antiviral activity was species-specific and caused by posttranslational interference with viral replication. The DHBV core-GFP fusion protein should be an ideal tool to assess the antiviral potential of dominant negative core proteins in vivo. PMID- 8690396 TI - Hepatitis B virus genomes of patients with fulminant hepatitis do not share a specific mutation. AB - The pathogenesis of fulminant hepatitis B virus (HBV) infection is not well understood. The aim of this study was to investigate whether there is an association between specific viral variants and a fulminant disease course. The entire HBV genomes from the serum of eight patients with fulminant HBV infection and one patient with fulminant hepatitis during reinfection after liver transplantation were investigated. After isolation and amplification of viral DNA by polymerase chain reaction (PCR), plus and minus strands were directly sequenced. Sequence data were analyzed by comparative sequence alignments with 35 and 2 complete HBV genome sequences from patients without and with fulminant hepatitis, respectively. Several point mutations were present in all regions of the genomes. Many nucleotide changes had never or rarely been found in the reported HBV isolates from patients without fulminant hepatitis. A distinct mutation present in all genomes was not identified. Clusters of rare and unique mutations were observed in the enhancer II core promoter region. Mutations previously suggested to be associated with fulminant HBV infection were not consistently found. A precore stop codon mutation at nucleotide position 1896 or an A-to-T mutation at nucleotide position 1762 and a G-to-A mutation at nucleotide position 1764 in the core promoter region were present in four and three cases, respectively. Fulminant HBV infection does not appear to be caused by a specific genomic mutation. However, various mutations clustering in the enhancer II core promoter region may contribute to a fulminant disease course. PMID- 8690397 TI - Comparison of the characteristics of hepatocellular carcinoma between hepatitis B and C viral infection: tumor multicentricity in cirrhotic liver with hepatitis C. AB - Clinicopathological and prognostic features in patients who had undergone hepatectomy for hepatocellular carcinoma (HCC) were examined in relation to viral infection. Among 175 patients, cirrhosis was diagnosed histologically in 134, while 41 had noncirrhotic livers. One hundred twenty-four patients were positive for antibody to hepatitis C virus (anti-HCV) (HC group), 32 for hepatitis B virus surface antigen (HBsAg) (HB group), and 19 negative for both anti-HCV and HBsAg (non-B, non-C group). In the HB group, the mean patient age was significantly younger, and liver function in terms of the plasma retention rate of indocyanine green at 15 minutes and the serum total bilirubin level was significantly better than in either the HC or the non-B, non-C group. Seventeen patients had synchronous multicentric HCCs: the HC group showing a significantly higher incidence than the HB group (P < .05). In the HC group, the proportion of cirrhotic liver in patients with multicentric HCCs was significantly larger than in patients with unicentric HCC (P < .05). No significant differences in disease free survival rate after hepatectomy were observed between the three groups. The present retrospective study of surgically treated patients showed that anti-HCV positive HCCs tended to occur in older individuals who showed worse liver function and a higher incidence of cancer multicentricity compared with HBsAg positive HCCs. The prognosis of anti-HCV-positive HCCs, which had the disadvantageous characteristic of multicentricity, did not differ from that of HBsAg-positive HCCs. PMID- 8690398 TI - Current therapy for Crigler-Najjar syndrome type 1: report of a world registry. AB - This study represents a multicenter survey on the management of patients with Crigler-Najjar syndrome (CNS) type 1. The aim of the survey was to find guiding principles for physicians in the care of these patients. Fifty-seven patients were included. At the time of inclusion, 21 patients had received a liver transplant (37%). The average age at transplantation was 9.1 +/- 6.9 years (range, 1-23 years); the age of the patients who had not been transplanted at the time of inclusion was 6.9 +/- 6.0 years (range, 0-23 years). Brain damage had developed in 15 patients (26%). Five patients died, and 10 are alive with some degree of mental or physical handicap. In 2 patients, ages 22 and 23 years, early signs of bilirubin encephalopathy could be reversed, in 1 by prompt medical intervention followed by liver transplantation and in the other by prompt liver transplantation. Seven patients underwent transplantation with some degree of brain damage at the time of the surgery; 1 of these died after retransplantation, 2 improved neurologically, and 4 remained neurologically impaired. The age of 8 patients with and 13 without brain damage at or before transplantation was 14.3 +/- 5.9 and 5.9 +/- 5.4 years (P < .01), respectively. Therapy of CNS type 1 consists of phototherapy (12 h/d), followed by liver transplantation. Phototherapy, although initially very effective, is socially inconvenient and becomes less efficient in the older age group, thus also decreasing compliance. Currently, liver transplantation is the only effective therapy. This survey shows that, in a significant number of patients, liver transplantation is performed after some form of brain damage has already occurred. From this, one must conclude that liver transplantation should be performed at a young age, particularly in situations in which reliable administration of phototherapy cannot be guaranteed. PMID- 8690400 TI - Expression of hepatocyte growth factor, transforming growth factor alpha, and transforming growth factor beta 1 messenger RNA in various human liver diseases and correlation with hepatocyte proliferation. AB - Hepatocyte growth factor (HGF) and transforming growth factor alpha (TGF-alpha) stimulate liver regeneration, whereas transforming growth factor beta 1 (TGF-beta 1) inhibits it in rats. However their significance in human liver diseases, especially in severe acute liver injury, remains unclear. We studied HGF, TGF alpha, and TGF-beta 1 messenger RNA (mRNA) expression in the livers of patients with live diseases using a competitive reverse transcriptase polymerase chain reaction. As little as a twofold difference in mRNA expression could be detected from minute liver biopsy samples. We then examined cell proliferation using proliferating cell nuclear antigen (PCNA) staining. HGF mRNA levels were significantly higher (approximately threefold) in acute hepatitis (AH) than in exacerbation of chronic liver disease (EX) (P < .05). TGF-alpha mRNA levels were significantly greater in AH (approximately twofold) than EX (P < .05), and the levels were significantly higher (approximately threefold) in chronic hepatitis (CH) than in EX (P < .05). The TGF-beta 1 mRNA levels in all the groups were not significantly different. In acute liver injury (AH and EX), there was a significant correlation between HGF mRNA expression and the PCNA labeling index (LI) in the liver (r = .87, P < .005). TGF-alpha mRNA expression also correlated with the PCNA LI (r = .92,P < .0001). There was no significant correlation between the serum HGF and the PCNA LI in the liver. In conclusion, HGF and TGF alpha produced in the liver stimulate hepatocyte proliferation in response to acute liver injury in humans. PMID- 8690399 TI - Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. AB - The prognosis for hepatocellular carcinoma (HCC) depends mainly on the clinicopathological characteristic regarding invasion and metastasis. In addition, another distinguishing feature of HCC is the high incidence of concomitant liver cirrhosis, in which the extracellular matrix proliferates markedly. Therefore, the present study was designed to investigate the molecules responsible for the invasion potential of HCC by focusing on matrix metalloproteinase (MMP) in particular, MMP-2 and MMP-9 and the corresponding tissue inhibitor of metalloproteinase (TIMP-2 and TIMP-1), because these enzymes participate in the degradation of the extracellular matrix including the basement membrane. Tumorous and adjacent nontumorous liver samples were obtained from 23 HCC patients who underwent a partial hepatectomy. In 16 of the 23 HCC samples, transcripts for MMP-9 were detected in the tumorous tissues, and 15 of 16 of these samples showed stronger expression in the tumorous tissues than in the nontumorous tissues. On the other hand, MMP-2 messenger RNA (mRNA) was detected in 18 of the 23 cases. Eight of these 18 cases showed more intense expression in the tumorous tissues than in the nontumorous tissues, whereas the expression levels were lower in the tumorous tissues than in the nontumorous tissues in 7 of 18 samples. With respect to the correlation between the clinicopathological features and mRNAs expression, it was found that the expression of MMP-9 mRNA in HCC with capsular infiltration was significantly higher than in HCC without capsular infiltration. HCC with capsular infiltration also tended to have a higher ratio of MMP-9 mRNA expression to TIMP-1 mRNA expression. In addition, the expression of MMP-2 mRNA in nontumorous cirrhotic tissues was significantly higher than in nontumorous tissues from patients with chronic hepatitis. Immunohistochemical examinations revealed that MMP-9 immunoreactivity was the most intense in the HCC cells, particularly in those cells in the marginal areas of the tumorous tissues. In conclusion, the present study shows that MMP-9 is closely participated in capsular infiltration in HCC. PMID- 8690401 TI - Effects of epinephrine on glucose metabolism in patients with alcoholic cirrhosis. AB - The cirrhotic liver has been shown to be resistant to the actions of various glucoregulatory hormones. The objective of this study was to investigate the effects of epinephrine on hepatic glucose metabolism in cirrhotic patients. Thirteen cirrhotic and eight healthy subjects were studied. Hepatic glucose production and turnover of alanine and glycerol were measured using stable isotope technique before and during 70 and 150 minutes of epinephrine infusion (0.1 microgram/kg/min). beta-Adrenoreceptor binding sites and affinity in mononuclear leukocyte membranes also were determined. Hepatic glucose production and alanine turnover in normals significantly increased during epinephrine infusion, but did not change in cirrhotics. Glycerol turnover increased after 70 minutes of epinephrine infusion in both groups. Epinephrine induced a significant rise of high-affinity beta-adrenoreceptor binding sites in normals, yielding a significant correlation between hepatic glucose production and receptor density (r = .94, P < .0001). In cirrhotic patients, similar changes in the number of high-affinity beta-adrenoreceptors were observed, but no correlation with hepatic glucose production was detected. The cirrhotic liver did not respond normally to the stimulatory effect of epinephrine on hepatic glucose production. Because this blunted response was not related to changes of beta-adrenoreceptors, our findings suggest that epinephrine resistance in cirrhosis was caused by a postreceptor defect. PMID- 8690402 TI - Transplantation of conditionally immortalized hepatocytes to treat hepatic encephalopathy. AB - Transplantation of hepatocytes has been shown to provide metabolic support during liver failure in experimental models. The potential clinical application of hepatocyte transplantation, however, is limited by the need for readily available, well-characterized cells, and a worldwide shortage of donor organs. A clonal hepatocyte cell line that could be grown economically in vitro and would exhibit a differentiated, nontransformed phenotype following transplantation would be an attractive solution to this problem. To test this alternative, primary Lewis rat hepatocytes were conditionally immortalized by retroviral transduction with a thermolabile mutant Simian virus 40 (SV40) large T antigen. The cloned immortalized cells proliferate in culture at 33 degrees C and stop growing at 37 degrees C to 39 degrees C. Transplanted into normal livers, these hepatocytes integrate normally into liver cords. When transplanted into the spleens of portacaval-shunted rats, they protect recipients from hyperammonemia induced hepatic encephalopathy. The cells engrafted in the spleen exhibit normal morphology, secrete bile, and express albumin messenger RNA. The protection from hyperammonemia is reversed by splenectomy. These studies show that hepatocytes can be conditionally immortalized, expanded in culture, and are capable of providing metabolic support in chronic liver insufficiency. Safeguards that could make these cells clinically useful can be accomplished using currently available technology. PMID- 8690403 TI - Differences in the mechanisms of uptake and endocytosis of small and large chylomicron remnants by rat liver. AB - Initial binding and subsequent endocytosis of small and large chylomicron remnants by rat liver were compared. Small and large chylomicrons were obtained from mesenteric lymph of glucose- or fat-fed rats, respectively. The low-density lipoprotein (LDL) receptor was up- and down-regulated as shown by LDL receptor messenger RNA (mRNA). The rate of removal of small chylomicron remnants by isolated perfused rat livers followed closely the activity of the LDL receptor. When mRNA was undetectable, the uptake was as low as that of lymphatic small chylomicrons. In contrast, the uptake of large chylomicron remnants into perfused rat livers was unaffected by changes of the LDL-receptor activity, but significantly reduced after livers were flushed with heparin or heparinase. Large chylomicron remnants were cleared from plasma much faster than small chylomicron remnants, but were more slowly internalized into hepatocytes. Both, small and large chylomicron remnants entered the pathway of receptor-mediated endocytosis as shown by electron microscopy and analysis of isolated endosomes. Yet, large chylomicron remnants were taken up into the compartment of uncoupling of receptors and ligands and multivesicular bodies at a much slower rate. This was independent of the activity of the LDL receptor and the heparin-releasable binding site. From these findings it is concluded that large chylomicron remnants initially bind rapidly to surface components other than the LDL receptor, one of which may be hepatic lipase. Yet, the consecutive internalization is slow. In contrast, small chylomicron remnants are removed at a slower rate from plasma, binding predominantly to the LDL receptor, but are more readily taken up into endosomes. PMID- 8690404 TI - Transforming growth factor beta 1-regulated gene expression of Ito cells. AB - During liver fibrogenesis, Ito cells are regarded as the principal matrix synthesizing cells and transforming growth factor beta 1 (TGF-beta 1) appears to be the main fibrogenic mediator. This study analyzed the effects of TGF-beta 1 on Ito cell activation, proliferation, and on the expression of a set of matrix proteins, antiproteases, and TGF-beta receptors both in "early cultured" and "culture-activated" Ito cells. Rat liver Ito cells at day 2 of primary culture ("early cultured" cells) were mainly smooth muscle alpha actin (SMA)-negative, whereas cells at day 6 were judged as "activated" cells (SMA-positive). Following 24-hour exposure to 1 ng/mL TGF-beta 1, total protein synthesis, cell proliferation, and expression of the "activation" marker SMA were not significantly changed. In addition to previously described stimulatory effects on collagen types I and III, fibronectin, undulin, and proteoglycan-gene expression, TGF-beta also dose-dependently increased synthesis and secretion of tenascin, laminin, entactin, collagen type IV, and alpha 2-macroglobulin, but decreased C1 esterase inhibitor production by Ito cells, as revealed by immunoprecipitation of endogenously labeled proteins and by Northern blot analysis. The stimulatory effect of TGF-beta was evident both in "early cultured" as well as "culture activated" Ito cells. By reverse-transcription polymerase chain reaction (RT-PCR) analysis, TGF-beta type II, III, and TGF-beta/activin type I receptors were present in Ito cells, and their expression pattern was not changed upon TGF-beta exposure. Northern blot analysis demonstrated that type I TGF-beta/activin receptor was induced during in vitro activation and that TGF-beta exposure resulted in a slight increase of type I and III receptor messenger RNAs. In summary, the data illustrate that TGF-beta is an important fibrogenic mediator acting both on "early cultured" as well as "culture-activated" Ito cells, rather than a mitogenic or morphogenic mediator. The differential regulation of TGF beta/activin receptors during in vitro activation and their up-regulation by TGF beta 1 might represent a mechanism by which the receptor complex regulates TGF beta signalling in Ito cells. PMID- 8690405 TI - Intravenous administration of follistatin: delivery to the liver and effect on liver regeneration after partial hepatectomy. AB - When 1 microgram 125I-follistatin was administered into a rat intravenously, radioactivity levels in serum decreased rapidly. Analysis with a biexponential equation showed that the initial half-life and the terminal half-life were 4.0 and 130.8 minutes, respectively. After 2 hours of infusion, approximately 9% of the follistatin infused remained in the liver, which was much more than that in kidney, spleen, pancreas, intestine, or lung. Autoradiography of the liver obtained at 24 hours of infusion revealed that numerous grains were located in parenchymal cells. Radioactivity of 125I-follistatin in the liver remained elevated until 72 hours and declined markedly thereafter. When a booster shot of 125I-follistatin was administered at 72 hours, radioactivity in the liver at 120 hours was markedly increased compared with that in rats that received a single shot of 125I-follistatin. We then examined the effect of intravenous infusion of follistatin on liver regeneration after hepatectomy of 70%. Immediately after the hepatectomy, either 1 microgram follistatin or saline was infused intravenously. In some rats, a booster shot was infused at 72 hours. After 120 hours of hepatectomy of 70%, remnant liver weight, liver regeneration rate, and DNA content were significantly (P < .05) higher in rats that received a booster shot of follistatin at 72 hours than those in control rats. These results indicate that follistatin administered intravenously accumulates in the liver and promotes liver regeneration after partial hepatectomy. PMID- 8690406 TI - Interferon gamma down-regulates cytochrome P450 3A genes in primary cultures of well-differentiated rat hepatocytes. AB - Administration of interferons of both the gamma and alfa/beta classes down regulates hepatic cytochrome P450 (CYP) genes when administered to humans or rats. In male rats, interferons decrease expression of CYP3A2 at a pretranslational level, but because interferons also release other cytokines in vivo, it is unclear whether this is a direct effect on hepatocytes. We therefore examined the effects of rat recombinant interferon gamma (IFN-gamma) on CYP3A2, other 3A genes, and 2C11 in stable primary cultures of male rat hepatocytes. Hepatocytes were cultured on matrigel in Williams' E, and messenger RNAs (mRNAs) for 3A2, 3A1-like CYPs, and 2C11 mRNA were determined by RNase protection assays. CYP3A and 2C11 proteins were immunoquantified, and their catalytic activities were estimated by testosterone hydroxylation pathways. In control cells, 3A2 mRNA decreased initially but then recovered, and stable levels (15% of freshly isolated cells) were attained between days 3 and 7. Phenobarbital increased 3A2 mRNA to 60-120% values of freshly isolated cells, and mRNA for 3A1-like CYPs were increased 20-fold. In both control and phenobarbital-treated hepatocytes, rat recombinant IFN-gamma (33 U/mL) reduced mRNA for 3A2 and 3A1-like CYPs, as well as 3A protein and testosterone 6 beta-hydroxylase activity. Interferon had no effect on CYP2C11 at mRNA or protein levels in untreated cells, although a reduction in 2C11 protein was evident in phenobarbital-treated cultures. It is concluded that interferon directly alters expression of constitutive and inducible CYP3A genes in well-differentiated male rat hepatocytes in culture, but has no effect on constitutive expression of CYP2C11. PMID- 8690407 TI - Interferon gamma protects against hepatic tumor growth in rats by increasing Kupffer cell tumoricidal activity. AB - An increasing number of hepatic resections are being performed as potentially curative surgery for malignant liver neoplasms. Hepatectomy and subsequent liver regeneration produce a local environment that enhances growth of microscopic residual tumor. To determine if pretreatment with murine interferon gamma (IFN gamma) can protect against such enhanced tumor growth, Buffalo rats were randomized to receive a 3-day treatment of IFN-gamma (50,000 U/qD intraperitoneally) or saline. Groups then underwent intrasplenic injection of 10(6) Morris hepatoma cells, followed 1 hour later by sham (control) or partial hepatectomy (PH) of 70%. PH significantly enhanced tumor growth within the liver (control, 8 +/- 3 nodules per liver; PH, 73 +/- 12 nodules per liver; P < .001). This enhancement was attenuated by prior administration of IFN-gamma IFN gamma/PH, 16 +/- 3; P < .001 vs. PH). Growth factor release and liver regeneration were not affected significantly by pretreatment with IFN-gamma. The effect of IFN-gamma on tumor growth is associated with a significant enhancement of Kupffer cell (KC)-mediated tumoricidal activity (percentage of specific lysis, 55 +/- 10% control, 78 +/- 11% IFN-gamma, P < .01) but not lymphocyte-mediated tumoricidal activity. Because microscopic residual disease may be present after hepatectomies for cancer, IFN-gamma may be useful agent in retarding growth of residual tumors. PMID- 8690408 TI - The peptide-based thrombin inhibitor CRC 220 is a new substrate of the basolateral rat liver organic anion-transporting polypeptide. AB - The peptidomimetic thrombin inhibitor CRC 220, 4-methoxy-2,3,6 trimethylphenylsulfonyl-L-aspartyl-D-4-amidinop henylalanyl- piperidide, is taken up into isolated rat hepatocytes through active, carrier-mediated transport. This uptake is inhibited by bile acids. Functional expression in Xenopus laevis oocytes was performed to identify the transport system responsible for the hepatocellular CRC 220 uptake. Injection of poly(A)+RNA in X. laevis oocytes resulted in a two- to three-times higher uptake of CRC 220, compared with uninjected or water-injected control oocytes. Taurocholate (200 mumol/L) inhibited this uptake completely. No uptake of the peptidomimetic thrombin inhibitor was observed, when X. laevis oocytes were injected with complementary RNA (cRNA) encoding either the cloned rat liver Na(+)-dependent taurocholate transporter Ntcp, the renal oligopeptide carrier rhaPT or the intestinal oligopeptide transporter PepT1. However, after injection of cRNA of the cloned rat liver Na(+)-independent organic anion transporting polypeptide oatp, a specific and saturable CRC 220 uptake was observed (Michaelis-Menten constant 29.5 mumol/L). Cis-inhibition with known oatp-substrates, e.g., 20 mumol/L Bromsulphalein (BSP), 2007 mumol/L taurocholate and 2007 mumol/L cholate, occurred in oatp-expressing X. laevis oocytes, whereas substrates of the two peptide carriers as well as dipeptide- and single-amino acid constituents of the thrombin inhibitor itself lacked any significant inhibitory effects. These data show that the modified dipeptide CRC 220 is a highly selective substrate of the organic anion transporting polypeptide oatp in the basolateral plasma membrane of rat hepatocytes. PMID- 8690409 TI - Oxidative metabolism in a rat hepatoma (N13) and isolated rat hepatocytes: a flow cytometric comparative study. AB - Recently, we have developed a new and fast kinetic method for assessing mitochondrial membrane potential by flow cytometry, based on the quantitation of the initial rate of rhodamine 123 (Rh123) uptake by living cells. This test has proved suitable to detect metabolic and toxic effects on mitochondria. To characterize energy metabolism in a rat hepatoma cell line (N13), we applied this method to assess several metabolic pathways that eventually generate mitochondrial membrane potential. Using this approach, we found that N13 hepatoma cells retain an oxidative capacity comparable with that observed in isolated hepatocytes under the same conditions. These results show that this cell line may represent an adequate biological model to perform metabolic and toxicological studies in vitro. PMID- 8690410 TI - Nimodipine, a dihydropyridine-type calcium channel blocker, prevents alcoholic hepatitis caused by chronic intragastric ethanol exposure in the rat. AB - It has been shown recently that inactivation of Kupffer cells prevents free radical formation and early alcohol-induced liver injury, and that hypoxia subsequent to a hypermetabolic state caused by activated Kupffer cells is likely involved in the mechanism. Calcium is essential for the activation of Kupffer cells, which contain L-type voltage-dependent Ca2+ channels. Therefore, the purpose of this study was to determine whether a Ca2+ channel blocker, nimodipine, prevents early alcohol-induced liver injury in vivo and to evaluate its effect on intracellular calcium ([Ca2+]i) in Kupffer cells in vitro. Male Wistar rats were exposed to ethanol (10-12 g/kg/d) continuously for up to 4 weeks via intragastric feeding using an enteral model developed by Tsukamoto and French. In this model, ethanol causes steatosis, necrosis, and inflammation in only a few weeks. In the experimental group, nimodipine (10 mg/kg/d) was added to the diet and was shielded from direct light. Nimodipine had no effect on body weight over a 4-week treatment period, nor were mean ethanol concentrations or their cyclic pattern in urine affected. The mean urine ethanol values were 154 +/ 11 mg/dL in ethanol-fed and 144 +/- 38 mg/dL in ethanol + nimodipine-fed rats. After 4 weeks, serum aspartate transaminase (AST) levels were elevated in ethanol treated rats to 183 +/- 78 U/L. In contrast, values only reached 101 +/- 9 U/L in rats given nimodipine + ethanol-values which were significantly lower. Steatosis and necrosis assessed histologically were also reduced significantly by nimodipine. Nimodipine (10 micrograms/kg) also blocked the swift increase in alcohol metabolism and elevated oxygen consumption in perfused livers from rats treated with alcohol in vivo. Further, in cultured Kupffer cells, nimodipine (1 mumol/L) largely prevented the elevation in [Ca2+]i caused by lipopolysaccharide (LPS) (LPS, 200 +/- 11 nmol/L; LPS + nimodipine, 94 +/- 31 nmol/L; P < .05). These results indicate that nimodipine prevents alcoholic hepatitis, possibly by inhibition of endotoxin-mediated Kupffer cell activation. PMID- 8690411 TI - Functional differences between hepatocytes and biliary epithelial cells in handling polymeric immunoglobulin A2 in humans, rats, and guinea pigs. AB - Immunoglobulin A (IgA) in bile plays an important role in preventing the biliary tract from infection. In the present study, to clarify the functional differences between hepatocytes and biliary epithelial cells (BEC) in handling polymeric IgA2 (pIgA2), the major and important IgA in bile, we have determined in different species the binding characteristics of 125I-labeled pIgA2 to tissue sections of human, rat, and guinea pig livers. We have also examined the binding and transport features of 125I-labeled and gold-labeled pIgA2 in cultured hepatocytes and cultured BEC of rat and guinea pig. Asialofetuin, an asialoglycoprotein, or an antisecretory component antibody was used for determining the binding characteristics of pIgA2 to the cells. Grains of 125I-pIgA2 were morphometrically analyzed. In tissue sections, 125I-pIgA2 was predominantly bound to rat hepatocytes as well as to human and guinea pig BEC. The binding of 125I-pIgA2 to the cells was significantly inhibited by pretreatment with an antisecretory component (SC) antibody (P < .001), but not by preloaded asialofetuin. In cultured cells, labeled pIgA2 was observed binding predominantly to rat hepatocytes and guinea pig BEC as compared with rat BEC and guinea pig hepatocytes (both P < .001), respectively, and gold particles of gold-labeled pIgA2 were localized in the tubulovesicular structures and biliary luminal spaces of those cells. These results suggested that pIgA2 was bound selectively to hepatocytes in the rat liver, and to BEC in the human and guinea pig livers, through the SC but not through an asialoglycoprotein receptor, and was transported transcellularly and secreted into bile. PMID- 8690412 TI - Development of the ornithine cycle in rat liver: zonation of a metabolic pathway. AB - Ammonia-fixation in mammalian livers is, via the ornithine cycle and glutamine synthetase, strictly compartmentalized, occurring in a wide upstream periportal compartment and in the very last downstream pericentral hepatocytes, respectively. This conclusion is based on the well-known distribution patterns of carbamoyl phosphate synthetase I (CPS) and glutamine synthetase in the developing and adult liver. To determine to what extent the expression patterns of the ornithine cycle enzymes are coordinated with that of CPS, we investigated the patterns of expression of the individual messenger RNAs (mRNAs) of the ornithine cycle pathway in developing and adult rat liver. Our results show that, within the liver, all mRNAs of the ornithine cycle pathway are zonated. The patterns of expression of the different mRNAs match almost perfectly, with variations only in the steepness of the gradients of the mRNAs, suggesting that, in the rat, common regulatory factors are involved in the establishment of the zonation pattern. PMID- 8690413 TI - Population of hepatic macrophages and response of perfused liver to platelet activating factor during production of thioacetamide-induced cirrhosis in rats. AB - The response of hepatic macrophages and the effects of platelet-activating factor (PAF) in perfused liver were studied during production of experimental cirrhosis induced by thioacetamide (TAA) in female Sprague-Dawley rats. Within 4 weeks of TAA administration (300 mg/L drinking water), an increase in hepatic macrophage population and enlargement in cell size preceded the alterations characteristic of cirrhosis. During 12 weeks of TAA administration, the changes in hepatic macrophages were maintained and cirrhosis of the micronodular type developed with a marked increase in hydroxyproline content. Although TAA treatment for 4 weeks had no effect on oxygen consumption or hepatic portal pressure in the perfused liver, the increment in hepatic portal pressure and decrement in oxygen consumption induced by PAF in TAA-treated rats were double those in control rats. The amounts of prostaglandin D2 (PGD2) and thromboxane B2 (TxB2) in perfusate induced by PAF were seven- and fivefold greater, respectively, in TAA-treated rats than in control rats. Zymosan mimicked the effects of PAF. These results are consistent with the hypothesis that hepatic macrophages and PAF play important roles in the development of cirrhosis induced by TAA. PMID- 8690414 TI - Inhibition of experimentally induced cirrhosis in rats by hypothyroidism. AB - The coexistence of hyperkinetic circulation, hypermetabolism, and hyperactivity of the sympathetic nervous system is encountered in both cirrhosis and hyperthyroidism. Several drugs, such as propylthiouracil and propranolol, that are beneficial for treating some patients with chronic liver diseases are also prescribed for the treatment of thyrotoxicosis. We investigated the effects of experimentally induced hypo- and hyperthyroidism on the development of cirrhosis induced in rats by thioacetamide (TAA). We specifically examined whether hypothyroidism could prevent and hyperthyroidism could aggravate liver damage. Hypothyroidism induced by methimazole (MMI, 0.04%), propylthiouracil (PTU 0.05%), and by thyroidectomy was confirmed by a significant elevation of thyroid stimulating hormone (TSH) levels. Hyperthyroidism (decreased TSH levels) was induced by eltroxin (ELT:50 micrograms/kg). Thirteen groups of 10 rats each were studied: euthyroid controls (3 groups: water, TAA 1.5 months, and TAA 3 months), hypothyroid (6 groups: MMI, PTU, surgical, MMI-TAA, PTU-TAA, surgical-TAA), and hyperthyroid (4 groups:ELT 1.5 months and 3 months, and ELT-TAA for 1.5 months and 3 months). Hepatic fibrosis (scored from 0 to 3) was significantly reduced (P < .0001) in hypothyroid rats as compared with euthyroid controls, and was aggravated in TAA-treated hyperthyroid rats (P < .0001). Quantitative microscopic analysis of liver biopsy specimens from all groups confirmed the semiquantitative histopathological scores (P < .001). Direct intrasplenic pressure measurement revealed a significant portal pressure elevation in the TAA and the ELT-treated rats (from 4.7 +/- 0.1 in the euthyroid group to 8.1 +/- 2.3 and 10.2 +/- 2.1 and 12.5 +/- 1.6 in the TAA, ELT and ELT-TAA groups, respectively). However, in the hypothyroid-TAA groups, the portal pressure was found to be within the euthyroid normal range (4.6 +/- 1.2 and 5.8 +/- 0.6 in the PTU-TAA and surgical-TAA, respectively). After 12 weeks, the mean spleen weight of rats receiving only TAA was significantly higher than the TAA-treated hypothyroid rats (P < .0001), indicating that the hypothyroid TAA-treated rats were less portal hypertensive. These results suggest that induced hypothyroidism can inhibit, whereas hyperthyroidism can aggravate, the development of cirrhosis in a rat model. PMID- 8690415 TI - Effects of dietary cholesterol on hepatic production of lipids and lipoproteins in isolated hamster liver. AB - The effect of 2-week 2% cholesterol vs. chow feeding on regulation of hepatic lipoprotein, lipids and apoprotein (Apo), and biliary lipids production was evaluated by the isolated perfused hamster liver model. Cholesterol feeding did not change very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) particle size but significantly increased the hepatic production of VLDL-cholesterol fourfold, VLDL-triglyceride two and one half-fold but not phospholipid in VLDL. It also increased LDL-cholesterol fourfold but not triglyceride or phospholipid in LDL, whereas lipids in HDL remained unchanged. Gradient sodium dodecyl sulfate-polyacrylamide gel electrophesis (SDS-PAGE) and Western blot analysis (density of apoprotein/density of albumin/g liver) indicated that cholesterol feeding enhanced Apo B tenfold, Apo A-I fivefold but not Apo E in VLDL. Apo E and Apo B did not change in LDL. Apo E but not Apo A-I increased (threefold) in HDL by cholesterol feeding. Cholesterol feeding decreased bile salt secretion 28% but increased cholesterol secretion 118% in bile, whereas phospholipid and bile volume remained unchanged. Increased Apo A-I in VLDL suggested that Apo A-I is involved in enhanced hepatic export of cholesterol and triglyceride. Different patterns of lipid and Apos in VLDL and LDL after cholesterol feeding also suggested separate VLDL and LDL export mechanisms. Elevated Apo E but not lipids in HDL after cholesterol feeding suggests that hepatic HDL may function as a carrier of newly synthesized hepatic Apo E into the circulation for transfer to other lipoproteins (chylomicron [CM], CMr) to facilitate hepatic cholesterol uptake and clearance. PMID- 8690416 TI - Regulation of the last two enzymatic reactions in cholesterol biosynthesis in rats: effects of BM 15.766, cholesterol, cholic acid, lovastatin, and their combinations. AB - The Smith-Lemli-Opitz syndrome is a common inherited birth disorder caused by markedly reduced 7-dehydrocholesterol delta 7-reductase activity, the final enzyme in the cholesterol biosynthetic pathway. BM 15.766 (4-[2-[1-(4 chlorocinnamyl)piperazin-4-yl]ethyl]-benzoic acid) inhibits 7-dehydrocholesterol delta 7-reductase activity, reduces plasma cholesterol levels, and increases 7 dehydrocholesterol levels to reproduce the biochemical abnormalities of the syndrome in rats. Cholesterol, cholic acid, and lovastatin, alone or in combinations, were fed to rats given BM 15.766, and hepatic activities of the last two enzymes in the cholesterol biosynthetic pathway, lathosterol 5 dehydrogenase and 7-dehydrocholesterol delta 7-reductase, were measured. After feeding BM 15.766, hepatic 7-dehydrocholesterol delta 7-reductase activity decreased by 77% while lathosterol 5-dehydrogenase activity tended to increase, so that the ratio of 5-dehydrogenase to delta 7-reductase activities increased from 0.33 to 2.8. In BM 15.766-fed rats, treatment with cholesterol suppressed both 5-dehydrogenase and delta 7-reductase activities by 76% and 66%, respectively, and decreased the 5-dehydrogenase: delta 7-reductase activities ratio from 2.8 to 2.2. In contrast, treatment with cholic acid and BM 15.766 further inhibited delta 7-reductase activity by 67% without changing significantly the 5-dehydrogenase activity that had increased the ratio to 5.5. Combining BM 15.766 with lovastatin increased 5-dehydrogenase activity fivefold but did not change delta 7-reductase activity, raising the ratio to 14.3. In BM 15.766-treated rats, the first and last two enzymatic reactions in the cholesterol biosynthetic pathway catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, lathosterol 5-dehydrogenase, and 7-dehydrocholesterol delta 7-reductase are down-regulated by cholesterol. Thus, only cholesterol and not cholic acid or lovastatin could reduce elevated plasma 7-dehydrocholesterol levels induced by BM 15.766. PMID- 8690417 TI - Blocking late cholesterol biosynthesis inhibits the growth of transplanted Morris hepatomas (7288CTC) in rats. AB - The conversion of 7-dehydrocholesterol to cholesterol is the last reaction in the cholesterol biosynthesis pathway catalyzed by the microsomal enzyme, 7 dehydrocholesterol-delta 7-reductase. We studied whether malignant tumor growth that depends on cholesterol could be slowed by inhibiting late cholesterol biosynthesis. The inhibitor 7-dehydrocholester-delta 7-reductase, BM 15.766 alone, or in combination with 2% cholesterol was fed to 20 male Buffalo rats for 2 weeks immediately after Morris hepatoma 7288CTC was implanted in both flanks. Tumor weights were compared and sterol composition, hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase activity, and low-density lipoprotein (LDL) receptor binding in the tumor were correlated with those in the liver. In the plasma of rats treated with BM 15.766, cholesterol levels dropped 75% and the precursor, 7-dehydrocholesterol rose substantially. Tumor weights were 43% less (P < .05) than controls (5.9 +/- 1.5 g vs. 10.4 +/- 2.2 g) with sterol concentrations reduced 25%, and the precursor, 7-dehydrocholesterol, increased to represent 71% of the tumor sterols. Feeding cholesterol with BM 15.766 normalized plasma but only partially restored tumor cholesterol concentrations, which still remained 49% below the hepatomas in the control group. With BM 15.766, hepatic cholesterol decreased 76% and was associated with a marked rise of 7 dehydrocholesterol that could be almost entirely prevented by feeding cholesterol. After the tumor was implanted, hepatic HMG-CoA reductase activity increased 56% and was 8.6 times higher than in the tumor. Enzyme activities were enhanced about 50% in the liver and the tumor after BM 15.766 was administered but decreased 38% below control when cholesterol was added to the diet. Hepatic receptor-mediated LDL binding rose 67% after tumor implantation, and declined to control levels with cholesterol feeding. These results suggest that de novo cholesterol synthesis in Morris hepatoma 7288CTC is much lower than the liver and tumor growth depends on circulating plasma cholesterol. Inhibiting the last step in cholesterol biosynthesis profoundly reduced tissue and plasma cholesterol concentrations and accumulated precursors substantially to slow hepatoma growth. Feeding cholesterol restored liver but not hepatoma cholesterol levels. Thus, inhibiting late cholesterol synthesis hinders growth of rapidly enlarging malignant tumors. PMID- 8690418 TI - Characterization of the activin receptor in cultured rat hepatocytes. AB - Activin A is an autocrine inhibitor of initiation of DNA synthesis in rat hepatocytes. The present study was conducted to characterize the cell-surface receptors for activin A in cultured rat hepatocytes by measuring 125I-activin A binding. Scatchard analysis of 125I-activin A binding indicated the existence of two classes of binding sites with apparent Kd values of 3 x 10(-10) mol/L and 3.5 x 10(-9) mol/L. Pretreatment of the cells with heparitinase reduced the number of low-affinity binding sites, whereas pretreatment with excess exogenous follistatin increased the number of low-affinity binding sites. Affinity cross linking of 125I-activin A to hepatocytes revealed distinct protein complexes with molecular weights of approximately 48, 65, and 85 kd, which may represent cross linked cell-bound follistatin, type I and type II activin receptors, respectively. Another band with a molecular weight of 180 kd was also found, which may represent the type III activin receptor. When hepatocytes were cultured with epidermal growth factor (EGF), both high- and low-affinity binding sites increased at 12 hours without altering their affinities. At 60 hours of the incubation with EGF, the high-affinity binding sites decreased while the number of low-affinity binding sites increased slightly. These results indicate that two classes of 125I-activin A binding sites exist in cultured hepatocytes: the high affinity binding site may represent oligomeric complex of the type I and type II receptors, and at least part of the low-affinity binding site may represent cell bound follistatin. The number of activin receptors in hepatocytes is increased after the stimulation with EGF. PMID- 8690419 TI - Cirrhotic cardiomyopathy: getting to the heart of the matter. AB - In cirrhosis, cardiac contractile function has been extensively documented to be abnormal. At baseline, cardiac output is increased, and this is one of the characteristics of hyperdynamic circulation. However, when cirrhotic patients are challenged by pharmacological or physiological stress, ventricular hyporesponsiveness is revealed. Similar patterns have been noted in cirrhotic animal models. This phenomenon has been termed "cirrhotic cardiomyopathy." Although alcohol abuse may contribute to some cases of cirrhotic cardiomyopathy, it has been clearly documented to occur even in the absence of alcohol ingestion. Diminished myocardial beta-adrenergic receptor signal transduction function, possibly caused by a persistent elevation in norepinephrine content, has been shown to play an important role. Alternation in cardiac plasma membrane properties due to impaired lipid metabolism is also crucial. Other possible pathogenic factors are reviewed, including accumulation of cardiodepressant substances caused by hepatocellular insufficiency, and ventricular overload secondary to increased blood volume and hyperdynamic circulation. Because the cardiac reserve function is borderline in patients with cirrhosis, cardiovascular status should be carefully monitored, especially when patients undergo stresses such as liver transplantation or portosystemic shunting procedures. PMID- 8690420 TI - Interferon sensitivity determining sequence of the hepatitis C virus genome. PMID- 8690421 TI - Hepatitis G: a virus in search of a disease. PMID- 8690422 TI - The four-legged hepatocyte: lessons learned about cholesterol metabolism from new technologies. PMID- 8690423 TI - Have you seen the hepatitis C virus? PMID- 8690424 TI - The evolution and status of genetics education in nursing in the United States 1983-1995. AB - Despite rapid advances in genetic diagnosis and gene therapy, only a few nurses are addressing the need for widespread dissemination of genetic information. A critical question is: How long will nurses be able to maintain high-quality care and contend with the conundrums of genopathic medicine? The purpose of this state of-the-science paper is to trace progress in nursing education in genetics and to recommend curriculum change. A recurrent theme-the need for knowledge-is found in nursing studies and national forums in genetics. Genetic knowledge for nurses should be a priority. PMID- 8690425 TI - Problem-focused coping in HIV-infected mothers in relation to self-efficacy, uncertainty, social support, and psychological distress. AB - A preliminary investigation of relationships among perceived self-efficacy, uncertainty, social support, psychological distress, and problem-focused coping was conducted in a convenience sample of 41 HIV-infected mothers. The mothers represented 93% of the clients in a large HIV clinic in 1992 who met the study criteria. Support was found for using Lazarus and Folkman's stress, appraisal, and coping framework to understand the health-related needs of HIV-infected mothers. Maternal coping was related to living with one's children and their HIV status. The feasibility of studying this population of women was demonstrated. Findings suggest the need for exploration of family-focused interventions. PMID- 8690426 TI - Intervention model for substance-using women. AB - Treatment programs for pregnant women using alcohol, tobacco, and other drugs are generally ineffective because of a focus that is male-oriented and because of an emphasis on primarily fetal outcomes. This paper examines women's addiction to alcohol and other drugs from a feminist perspective. Published literature over the past decade on the importance of relationships in the etiology of women's drug-use behavior is reviewed and an intervention model based on home visits and framed in the context of women's relationships is proposed. PMID- 8690427 TI - The lived experience of women military nurses in Vietnam during the Vietnam War. AB - The lived experience of 24 military nurses during the Vietnam war is described in addition to common elements of their lives after returning from Vietnam. In-depth interviews generated data about personal and professional aspects of the lives of women nurses in the war zone. Data analysis incorporated the qualitative methods of Colaizzi, Lincoln and Guba, and Van Manen. Findings revealed that the nurses struggled with moral and ethical dilemmas of wartime nursing, felt out-of-place, and lacked privacy. The nurses described a deep and special bonding, and many found serving in Vietnam to be the most rewarding experience in their careers. The Vietnam War continues to have an effect on the lives of the nurses who served there. They balance their personal and professional growth gleaned from this experience with the physical and emotional stresses experienced during the war and since the war. The findings of this study have implications for further research about nurses in Vietnam and nurses who have served in other wars. PMID- 8690428 TI - Adolescents' views of sexual decision-making. AB - The purpose of this study was to ascertain the reasons adolescents give for abstinence, safer sex, and unprotected sexual intercourse. Participants were 115 high school students living in a midwestern state; average age was 17.5 years. Students completed a two-part questionnaire about (a) their expectations for the outcome of a vignette in which two teenagers had the opportunity for intercourse and (b) their ideas about the reasons, thoughts, and feelings associated with three possible endings to the vignette-abstinence, intercourse with a condom, unprotected intercourse. Content analysis of responses indicated that four interconnected factors are significant contributors to sexual behavior: social norms, fear, gratification or pleasure, and availability of condoms. PMID- 8690429 TI - Reformulation of deviance and labeling theory for nursing. AB - Caring for a "difficult patient" is a concern frequently communicated among nurses and reported in the clinical and research literature. A theoretical perspective explaining the phenomenon of difficult patients is proposed and is based on a reformulation of propositions from labeling theory and the concept of social deviance. Applications to nursing practice focus on patient characteristics judged as deviant by nurses, communication of the deviant label, and exclusionary and inclusionary reactions to perceived patient deviance. PMID- 8690430 TI - Defining nursing interventions. AB - Nurses are giving increasing attention to independent nursing interventions. However, numerous conceptualizations of interventions have evolved and are being used. The purpose of this essay is to examine some of the existing definitions and classification systems for interventions and to provide a rationale for a common universal language for nursing interventions. Definitions and approaches used in five intervention classification systems are examined in relation to inclusion of assessment and evaluation activities, autonomy, level of conceptualization, and inclusiveness of intervention labels. Lack of a common intervention language can deter international collaboration, development of a scientific basis for practice, and reimbursement for nursing services. PMID- 8690431 TI - Discharge planning: comparison of patients and nurses' perceptions of patients following hospital discharge. AB - Planning for hospital discharge is an important component of nursing. Results are presented of a study to determine how well primary nurses predict the functional ability of their patients following discharge and to assess whether patients and nurses agree about their patients' understanding of the post-discharge treatment plan. Comparing nurses' predictions with patients' reports of functional status 2 months following discharge, we found that nurses consistently underestimate the functional ability of their patients. Comparing nurses' perceptions of their patients' understanding of their post-discharge treatment plan with patients' reports about their understanding, significant differences were found between nurses' perceptions and patients' reports. Nurses' perceptions were that patients were much more knowledgeable than their patients reported. These preliminary data suggest that hospital discharge planning is an area for further investigation and intervention. Nurses should explore new paradigms for patient education as lengths of hospital stay decrease and care shifts from acute care to community care. PMID- 8690433 TI - Building community participation in health care: a model and example from South Africa. AB - A conceptual model was developed for a community-based intervention study in a Black township in South Africa. The model shows a useful way to structure the complex role public health nurses play as they meet community health needs using a community's priorities and building toward community involvement in health and self-care. The model was applied over a 2-year period in an under-developed community of 100,00 people where the unemployment rate was over 50%, fewer than 10% of the homes had electricity, and only one-third had access to the sewage removal system. Over half of older adults interviewed were illiterate. The residents, in collaboration with the nurse researcher, gathered data, prioritized needs, and chose projects to produce solutions. The model guided activities for community empowerment through a deliberate transfer of information and expertise from the nurse to members of the community. Conceptual models or paradigms are useful to focus nursing strategies, to guide professional nursing practice, and to support interdisciplinary goals for cooperative efforts. The principles are also applicable in the United States and other developed countries as more effective ways to achieve health goals are sought. PMID- 8690432 TI - Advance directives and opportunities for nurses. AB - Technical, social, and economic factors are an impetus for expressing end-of-life decisions as advance directives (ADs) including a living will and durable power of attorney. Despite opportunities, nurses do not appear to be widely involved in practice and research regarding ADs. To provide perspectives for nursing participation, the literature was reviewed, and a set of outcomes regarding ADs were identified. The historical background and the ethical issues associated with ADs are examined. Appropriate roles for nurses with respect to ADs are suggested. Research and practice opportunities are identified. The databases reviewed were the Cumulative Index to Nursing and Allied Health Literature from 1983 to January 1996, and MEDLINE, from 1985 to January 1996. PMID- 8690434 TI - Health education in Jinja, Uganda. AB - A community-based health care program in Uganda is described. Perceived learning needs of a group of adults with 3-4 years of elementary school education were assessed and prioritized. A decision was made to teach a few subjects in depth as opposed to many superficially after hearing the large amount and type of topics requested. Teaching sessions included practical applications based upon the availability of materials and local practices and beliefs. Basic needs, such as the need for food and water, were continuously addressed. Traditional ways of healing were only encouraged when these did not endanger health. Teaching a group of adults with limited knowledge of anatomy or physiology was a challenge that demanded simplification of complex problems and the use of interventions that were sometimes unusual. PMID- 8690435 TI - Advice for beginning nurse researchers. AB - Heideggerian hermeneutics was used to illuminate the advice of six nurse researchers who were interviewed by the authors. The advice given to us as beginning researchers included identifying a planned program of research with a topic that we "love" and conducting research that is meaningful. Additional advice included keeping an idea log, networking, mentoring, and developing collegial relationships. The words of these researchers are intended for future investigators, yet much wisdom exists for all nurses. PMID- 8690436 TI - Dialectical analysis concerning the rational aspect of the art of nursing. AB - It is often claimed that nursing is both a science and an art. Science, it is argued, involves a rational process in which empirical findings are used to determine what is the case. Art, on the other hand, is associated with creative and intuitive activities. The author steps back from this position and examines the question of whether the art of nursing is properly conceived as involving a rational aspect. The study upon which this paper is based involved the analysis of a discourse contained in the work of 43 nurse scholars, published between 1860 and 1992. A philosophical approach is used to examine two contrary positions regarding the place of the rational aspect in relation to the art of nursing. The analysis attempts to expand the discourse by delineating questions and concerns that, as yet, have not been fully considered. PMID- 8690437 TI - The seventh star: Dorothy Ford Buschmann and the founding of Sigma Theta Tau. AB - Several women from the Indiana University Training School for Nurses founded Sigma Theta Tau in 1922. While the legend identifies six student founders, this historical study examined the contributions of Dorothy Charlotte Ford Buschmann (1895-1953), a key advisor whom some might consider the seventh founding star. Sources include primary data from Sigma Theta Tau archives. The findings suggest that Dorothy Buschmann believed that the foundations of professional nursing were love, honor, and courage and that the enduring value of nursing was its contribution to the social good. While Buschmann did not claim credit as a founder, she played a vital role in designing Sigma Theta Tau's philosophy and constitution, extended membership throughout the Midwest, and served as the first national president from 1927-1934. PMID- 8690439 TI - Conflict, not cooperation, is nursing's tradition. PMID- 8690438 TI - Development of biological studies to support biobehavioral research at the National Institute of Nursing Research. PMID- 8690440 TI - A giant step backward. PMID- 8690441 TI - Nursing as an academic discipline loses something. PMID- 8690442 TI - Reform nursing education for clinical relevance. PMID- 8690443 TI - Encouraging and preserving spirituality. PMID- 8690444 TI - Balance care and technology. PMID- 8690445 TI - Physiologic variables in nursing research: progress, yes ... but more work is needed. PMID- 8690446 TI - Comparison of nurses and alternative healers. AB - Nurses and alternative healers often share a common holistic philosophy of health and healing as well as the use of therapeutic touch. This ethnography compared the concepts of health and healing used by nurses and alternative healers. Seven categories of activities in healing or health domains common to both groups were physical, mental, attitudinal, relational, spiritual, self-caring, and help seeking. Similarities were in the holistic approach. Differences were found in locus of responsibility and spirituality. These differences may be largely explained by various social factors in practice settings. PMID- 8690447 TI - Human constant regions influence the antibody binding characteristics of mouse human chimeric IgG subclasses. AB - Although antibody affinity is primarily determined by immunoglobulin variable region structure human IgG antibodies of the four subclasses specific for the same antigen have been shown to differ in their affinity. To explore the influence of the immunoglobulin constant region on functional antibody affinity, a set of V region identical mouse-human chimeric IgG subclasses specific for TAG72 (tumour-associated glycoprotein) were studied. Biomolecular interaction analysis (BIA) was used to determine the binding kinetics of whole IgG subclasses and F(ab')2 fragments. Despite identical V regions, binding kinetics differed for the four subclasses. The apparent dissociation rate constants of the intact immunoglobulins ranked IgG4 < IgG3 < IgG2 < IgG1. In contrast, analysis of the binding characteriztics of the F(ab')2 fragments derived from IgG1, IgG2 and IgG4 revealed identical binding kinetics. The structure of the constant regions of the humanized IgG subclass antibodies clearly influenced functional antibody affinity, as has been described for the murine IgG subclasses. The exact mechanism for this phenomenon remains obscure but such differences should be taken into account when designing or choosing antibodies for therapeutic use. PMID- 8690448 TI - Chimaeric monoclonal antibodies encoded by the human VH26 gene from naive transgenic mice display a wide range of antigen-binding specificities. AB - To elucidate the molecular basis for the ability of antibodies encoded by the human VH26 heavy-chain variable region gene to react with diverse antigens, we have generated 34 hybridomas secreting chimaeric monoclonal antibodies (human mu heavy chain/mouse light chains) from transgenic mice. The transgenic mice carry an immunoglobulin minilocus containing the human VH26 gene, human DH and JH gene segments, and genes encoding the human C mu region. The minilocus in these animals undergoes functional rearrangement resulting in the production of chimaeric antibodies in which human mu heavy chains utilizing the VH26 gene are paired with mouse kappa or lambda light chains. The hybridomas described in this study were generated from naive animals and were selected solely on the basis of human mu-chain expression. The antibodies described have covalently attached mouse light chains and are multimeric in structure. The binding properties of the antibodies were examined using a panel of both self- and foreign antigens using enzyme-linked immunosorbent assays, agglutination or radio-immunoprecipitation assays and immunofluorescence. Chimaeric immunoglobulins from 21 of the 34 hybridoma clones (61.7%) reacted with one or more antigens, of which 13 (38.2%) reacted with more than two antigens. These studies demonstrate that the VH26 gene, in combination with human DH and JH gene segments, and mouse light-chain genes, is able to encode antibodies with a wide range of ligand-binding specificities. These findings have important implications in the context of the possible origins of autoantibodies encoded by VH26 which may play a role in the pathogenesis of a number of autoimmune conditions. PMID- 8690449 TI - Recognition of CD52 allelic gene products by CAMPATH-1H antibodies. AB - Cloning of the CD52 from a B-lymphocyte tumour cDNA library revealed two closely related sequences differing only at two amino acids C-terminal to the proposed point of glycosylphosphatidylinositol (GPI)-linkage. When transfected into CHO cells only one of these sequences gave high-level expression of the antigen recognized by the prototypic anti-CD52 antibody CAMPATH-1 whereas in JURKAT cells good expression levels were obtained with both sequences. Fusion of the sequence from the second sequence to DNA encoding the extracellular domain of CD4 indicated that this sequence was capable of directing GPI linkage. The possible implications for the function of CD52 and serotherapy with anti-CD52 antibodies are discussed. PMID- 8690450 TI - Pulmonary immune memory: localized production of antibody in the lung after antigen challenge. AB - In comparison to primary immune responses after lung immunization, the level of antigen-specific antibody and the number of cells producing specific antibody are significantly increased after challenging the lungs with antigen. The response of immune memory cells in the lung to an antigen challenge could be responsible for this elevated immune response. However, increased numbers of antibody-producing cells, possibly produced in the lung-associated lymph nodes, are also found in the blood after an antigen challenge. Therefore, it is possible that both the response of immune memory cells in the lung, and the recruitment of antibody producing cells from the blood, contribute to the elevated levels of antibody in the lung after an antigen challenge. This study compared the level of antibody produced in the lung by the response of pulmonary immune memory cells with the level of antibody produced by antibody-forming cells that enter the lung from blood after an antigen challenge. This comparison was made possible by immunizing and challenging two lung lobes of dogs with two antigens. The immune responses to both antigens were then evaluated in both lung lobes after primary immunization and challenge. Data from these evaluations showed that most antibody in the lung after an antigen challenge is produced by a localized anamnestic response of pulmonary immune memory cells. A significantly lower level of antibody entered the lung from the vasculature and/or was produced by antibody-forming cells that entered the lung from blood after an antigen challenge. PMID- 8690451 TI - Histidine-rich glycoprotein binding to T-cell lines and its effect on T-cell substratum adhesion is strongly potentiated by zinc. AB - Histidine-rich glycoprotein (HRG), a plasma protein that binds heparin and divalent cations, has been implicated in immune regulation through its ability to modulate complement function, macrophage Fc receptor expression and phagocytosis, and its ability to inhibit the proliferation of human peripheral blood T cells in vitro. In the present work we used fluorescence flow cytometry to study the binding of human HRG to the human T-cell lines Jurkat and MT4, and to the murine antigen-specific T-cell clone D10, and to study the effect of divalent cations zinc and copper on this binding. Our results show that HRG binds strongly to these cell lines at 4 degrees, and that the binding is markedly potentiated by physiological concentrations of zinc (20 microM), and to a lesser extent by copper (10 microM). In contrast to previous studies, HRG binding was largely inhibited by 50 micrograms/ml heparin, both in the absence and in the presence of zinc, suggesting that HRG interacts primarily through glycosaminoglycans on the T cell surface. Studies using confocal fluorescence microscopy indicated that following incubation of MT4 cells with HRG in the presence of zinc at 4 degrees, the HRG was localized exclusively at the plasma membrane, but was actively internalized after incubation at 37 degrees. Interestingly, HRG interfered with the ability of D10 cells to adhere to tissue culture plastic, as well as to laminin-, collagen- or fibronectin-coated culture dishes. This effect was markedly potentiated by 20 microM zinc, and was partially reversed by heparin. The results suggest that zinc markedly potentiates the binding of HRG to T cells, and that HRG and zinc may play an important role in regulating the adhesion of T cells to other cells and the extracellular matrix. PMID- 8690453 TI - Alloantigen-specific T-cell anergy induced by human keratinocytes is abrogated upon loss of cell-cell contact. AB - The activation of primary human T cells largely depends on the expression of both major histocompatibility complex (MHC) class II and B7 molecules on antigen presenting cells (APC), whereas APC expressing HLA class II but not B7 antigens are expected to induce anergy. According to this concept, interferon-gamma (IFN gamma)-activated keratinocytes (KC) expressing HLA class II but not B7 costimulatory antigens should be able to induce anergy. However, in terms of anergy versus activation contradicting data have been published on the outcome of interaction between T cells and human KC. In addition, it has been shown that human KC can express a B7-like molecule with unknown function, whereas MHC expression may be functionally impaired. To evaluate this item we transfected the human A431 KC cell line with B7-1 coding sequences and up-regulated HLA-DR by treatment with IFN-gamma, yielding A431DR,B7-1 cells. Irradiated A431DR,B7-1 cells were found to be capable of inducing vigorous proliferative primary T-cell responses in resting allogeneic T cells, whereas A431DR cells could induce proliferation only when interleukin-2 (IL-2) was added. These data indicate that KC can present alloantigens, and that lack of costimulatory molecules on KC is the main reason why these cells cannot induce primary T-cell responses. Surprisingly, however, no evidence could be obtained of stable anergy induction by A431DR cells, as T cells contacted with A431DR cells and then transferred to A431DR,B7-1 cells clearly demonstrated alloresponsiveness. T-cell non responsiveness was maintained only when T cells remained in contact with A431DR cells. These data indicate that, despite expression of HLA class II in the absence of B7 costimulatory molecules, human KC cannot induce stable anergy but rather induce short-term anergy in primary resting T cells. PMID- 8690452 TI - CD2-mediated stimulation of the naive CD4+ T-cell subset promotes the development of skin-associated cutaneous lymphocyte antigen-positive memory cells. AB - Directed migration of lymphocytes from blood into lymph nodes and organ associated lymphatic tissue, also referred to as homing, is initiated by T-cell adhesion to specialized high endothelial cells of postcapillary vessels. Here, we demonstrate that selective signal transduction pathways specifically modulate the expression of the cutaneous lymphocyte antigen (CLA), the putative skin-homing receptor, during naive to memory transition of CD4+ T cells in vitro. The results show that the expression of CLA is strongly induced by activation via CD2 [T11.1 + T11.2 monoclonal antibodies (mAb)]. Addition of transforming growth factor-beta 1 (TGF-beta 1), interleukin-6 (IL-6), and, to a lesser extent, IL-2 further enhanced the generation of CLA+ T cells, whereas the induction of this antigen was markedly inhibited by IL-4. Periodic restimulation via CD2 and long-term culture of activated cells in the presence of IL-2 and TGF-beta 1 resulted in stable expression of CLA during a culture period of more than 100 days. In contrast, activation of naive CD4+ T cells via CD3, CD28 or by mitogens induced a rapid naive to memory phenotype transition but a much lower percentage of CLA+ T cells showing only weak expression of the antigen. Furthermore, activation of purified CD4+ memory T cells by CD2 strongly induced expression of activation related antigens CD25 and HLA-DR, but failed to up-regulate CLA expression. Our results show that primary stimulation conditions highly modulate the development of skin-associated T cells and indicate a new functional role for costimulatory adhesion pathways in regulating the expression of molecules associated with T cell homing. PMID- 8690454 TI - Effect of adoptive transfer of CD4, CD8 and B cells on recovery from MHV3-induced immunodeficiencies. AB - A chronic viral infection can occur when the host fails to mount an effective immune response to clear the virus. Mouse hepatitis virus type 3 (MHV3) appears to be an excellent model for the study of the relationship between viral-induced immunodeficiency and chronic disease development. (C57BL/6 x A/J)F1 mice surviving acute hepatitis develop a chronic disease characterized by T- and B cell immunodeficiencies, viral persistence in various organs including the brain, spleen and thymus, and death within 3 months postinfection (p.i.). We have reported that T- or B-cell deficiencies, observed in MHV3 chronically infected (C57BL/6 x A/J)F1 mice, can be partially or totally thwarted by adoptive transfer of CD4+, CD8+ and/or B cells, at 15 days p.i. in mice surviving the acute phase of the disease. Adoptive transfer of syngeneic CD4+ and/or CD8+ allowed a partial restoration of the T-cell deficiencies, as characterized by thymic atrophy, decrease in splenic T cells, and in all thymocyte subpopulations. B-cell immunodeficiency, as defined by a decrease in splenic B cells, as well as in the bone marrow pre-B- and B-cell compartments, and the occurrence of abnormally larger forms of bone marrow pre-B and B cells, were partially thwarted by B-cell treatment only. Splenic B cells and the bone marrow B-cell compartment, respectively, returned partially or totally to normal values, whereas the pre-B cell compartment remained depleted in infected mice treated with B cells. Levels of all immunoglobulin classes returned to normal values in MHV3 chronically infected mice when treated with CD4+ in combination with CD8+ cells. All T- and/or B-cell treatments, however, were sufficient to thwart the process of the chronic disease, and favoured the survival of mice for up to 6 months p.i. PMID- 8690455 TI - Sensitization of T-cell receptor-alpha beta+ T cells recovered from long-term T cell receptor downmodulation. AB - Although the survival of fully allogeneic skin grafts was prominently prolonged by adult thymectomy in anti-T-cell receptor-alpha beta monoclonal antibody (TCR alpha beta mAb)-treated mice compared with that of non-adult thymectomized (ATX) mice, the skin allografts were eventually rejected. In the anti-TCR-alpha beta mAb-treated ATX mice, as shown in the present study, most of TCR-alpha beta+ cells were promptly activated on day 2 and then rapidly disappeared by day 7, but some TCR-alpha beta- Thy-1+ cells remained at that time. These TCR-alpha beta- Thy-1+ cells which have downmodulated their TCR-alpha beta expression may be refractory to depletion events by the mAb treatment. Although these downmodulated T cells re-expressed their TCR-alpha beta on day 50, they could not respond to stimuli via TCR such as TCR cross-linking or alloantigens. However, they recovered the reactivity to donor antigens on day 85. These results indicate that the downmodulated T cells by anti-TCR-alpha beta mAb treatment are long-lived and re-express their TCR-alpha beta at a late stage to be sensitized to donor antigen, which suggests that additional regimens may be required to get permanent, or very long-term, graft acceptance. PMID- 8690456 TI - Differentiation between MHC-restricted and non-MHC-restricted porcine cytolytic T lymphocytes. AB - The immune system of swine is unique in that the expression of CD4 and CD8 antigens defines four subpopulations of resting extrathymic T lymphocytes. Beyond phenotypic differences to other species, porcine T lymphocytes, particularly when derived from infected animals, are known to show high non-specific cytolytic in vitro activity. Here we describe the putative porcine CD6 antigen (workshop CD6; wCD6) which enables a phenotypic separation of T lymphocytes responsible for major histocompatibility complex (MHC)-restricted and non-MHC-restricted cytotoxicity. The putative porcine CD6 analogue, wCD6, a protein with a molecular mass of 110,000, shows high specificity for T lymphocytes and is neither expressed on B lymphocytes nor on cells of the myeloid lineage. In the extrathymic T-lymphocyte compartment wCD6 characterizes two T-lymphocyte fractions: wCD6+ T lymphocytes including both CD4+ T-helper cell subpopulations (CD4+CD8- and CD4+CD8+) and within the CD4-CD8+ fraction cells with high CD8 antigen density. In contrast the CD4-CD8- gamma/delta T-cell receptor (TCR) subset and CD4-CD8+ cells with low CD8 antigen density are included in the wCD6- T-lymphocyte fraction. Functional studies with separated wCD6 fractions revealed that the wCD6- cells can be characterized by spontaneous and non-MHC restricted cytolytic activity, whereas the wCD6+ T lymphocytes are responsible for MHC restricted T-cell functions. Thus, the porcine wCD6 is an important antigen to discriminate between MHC-restricted and non-MHC-restricted cytotoxicity. PMID- 8690457 TI - Expression of Th-2 cytokines interleukin-4 and -5 and of Th-1 cytokine interferon gamma in ovalbumin-exposed sensitized Brown-Norway rats. AB - We determined the expression of Th-2 type cytokines, interleukin-4 (IL-4) and IL 5, and of the Th-1 type cytokine, interferon-gamma (IFN-gamma), in the Brown Norway rat. Rats were intraperitoneally sensitized with ovalbumin and 21 days later were either exposed to ovalbumin or saline aerosol. The value -log PC300 (PC300 = concentration of acetylcholine needed to increase baseline lung resistance by 300%) was 2.49 +/- 0.15 in sensitized, exposed rats, was higher than in sensitized, saline-exposed or naive rats (1.54 +/- 0.27 and 1.63 +/- 0.06 respectively, P < 0.05). There was a significant increase in eosinophils in bronchoalveolar lavage fluid and in airway submucosal airway tissues in the sensitized exposed group. Reverse-transcriptase polymerase chain reaction was performed on total lung RNA using primers for IL-4, IL-5, IFN-gamma and beta actin. IL-4 and IL-5 mRNA levels in control and sensitized saline-exposed rats were not detectable, but increased levels were found in sensitized and ovalbumin exposed rats with levels of 0.25 +/- 0.01 and 0.98 +/- 0.02% of beta-actin mRNA as assessed by densitometric measurements. Expression of IFN-gamma mRNA was significantly reduced in sensitized and ovalbumin-exposed rats. As in asthmatic airways, there is an increased expression of Th-2 cytokines, IL-4 and IL-5, together with a reduction in the Th-1 cytokine, IFN-gamma, thus supporting a role for Th-2 cytokines in allergic eosinophilic inflammation. PMID- 8690458 TI - The contrasting effects of CD8+ T cells on primary, established and Nippostrongylus brasiliensis-induced IgE responses. AB - Recent data have indicated that CD8+ T cells suppress rodent IgE responses. In this study we investigated the effect of CD8+ T cells on primary and established IgE responses in euthymic and athymic nude rats. Euthymic PVG rats were depleted of CD8+ T cells by intraperitoneal injection of a CD8-specific monoclonal antibody (OX8), which resulted in an apparent loss of 92% of splenic and 98% of peripheral blood CD8+ T cells. The CD8+ T-cell depleted animals failed to mount a significant IgE response compared with control animals given an irrelevant monoclonal antibody (OX21). Furthermore, PVG nude rats reconstituted with purified CD4+ thoracic duct lymphocytes (TDL) alone failed to mount a significant IgE response, while animals given unfractionated TDL (containing CD4+ and CD8+ T cells) did. Depletion of CD8+ T cells 7 days prior to immunization and subsequent reconstitution at the time of immunization restored the IgE response. In contrast, removal of CD8+ T cells 1 month after induction of IgE by immunization with ovalbumin (OVA) and ricin prolonged the IgE response. In all cases IgG antibody responses were unaffected by the presence or absence of CD8+ T cells. This study shows that some CD8+ T cells are required for IgE, but not IgG, production to soluble antigen in a primary immune response. However, later in the immune response CD8+ T cells were shown to inhibit IgE production. These effects were apparently restricted to the immune response to soluble antigen, as Hooded Lister rats infected with 9000 larvae of the nematode Nippostrongylus brasiliensis produced high sustained levels of circulating IgE, in excess of 10 micrograms/ml, regardless of whether CD8+ T cells were depleted before or 1 month after infection. PMID- 8690459 TI - Functional difference between Thy-1-positive and Thy-1-negative gamma delta T cells induced by Escherichia coli infection in mice. AB - There is an increase in number of gamma delta T cells in the peritoneal cavity after intraperitoneal (i.p.) inoculation with Escherichia coli. The E. coli induced gamma delta T cells in C3H/He mice contain a large amount of Thy-1 negative population in addition to the Thy-1-positive population. We investigated the difference between the Thy-1-positive and the Thy-1-negative gamma delta T cells. Although it was found that only up to 4% of the gamma delta T cells on day 5 after infection were in cycling phase, and that the gamma delta T cells did not proliferate by immobilized anti-T-cell receptor (TCR) gamma delta monoclonal antibody stimulation, the gamma delta T cells proliferated in the presence of interleukin-2 (IL-2) and IL-7. The Thy-1-negative gamma delta T cells showed higher proliferative response compared with the Thy-1-positive gamma delta T cells. Furthermore, the Thy-1-negative gamma delta T cells showed lower IFN-gamma mRNA expression than the Thy-1-positive gamma delta T cells. On the other hand, both the Thy-1-positive and Thy-1-negative gamma delta T cells predominantly expressed V gamma 1, V gamma 4, V gamma 5, V gamma 6 and V delta 1, and no difference of V region usage was detected between them. These results suggest that functions of Thy-1-positive gamma delta T cells differ from Thy-1-negative gamma delta T cells although Thy-1-positive and Thy-1-negative gamma delta T cells may have similar V region repertoire and, possibly, similar antigen specificity. PMID- 8690460 TI - Activation of an interleukin-4 mRNA-producing population of peripheral blood mononuclear cells after infection with Mycobacterium bovis or vaccination with killed, but not live, BCG. AB - This study examines the expression of mRNA for the Th2 cytokine, interleukin-4 (IL-4). Peripheral blood mononuclear cells from deer infected with Mycobacterium bovis or vaccinated with live or killed M. bovis bacillus Calmette-Guerin (BCG) were cultured with mycobacterial antigens. IL-4 mRNA production was assayed using the polymerase chain reaction. Elevated levels of IL-4 mRNA were detected in response to at least one antigen preparation in all animals infected with M. bovis as compared with none of the non-infected control animals. After a primary immunization, elevated levels of IL-4 mRNA were detected in only a proportion of vaccinated animals and this did not correlate with whether the vaccine was live BCG or killed BCG in oil. After boosting, all the animals vaccinated with killed BCG in oil exhibited elevated IL-4 mRNA production whereas none of the animals vaccinated with live BCG showed elevated levels. The data suggest that IL-4 is turned off during the immune response to live BCG, that boosting of low-dose live BCG vaccine may be required to 'imprint' this signal and that this may be important in the development of protective immunity to tuberculosis. Killed BCG in adjuvant is not protective and as with experimental infection with virulent M. bovis it failed to switch off the IL-4 response. IL-4 may be useful as a diagnostic tool and as an in vitro marker of vaccine efficacy. PMID- 8690461 TI - Immunogenicity of peptides coupled with multiple T-cell epitopes of a surface protein antigen of Streptococcus mutans. AB - A surface protein antigen (PAc) of Streptococcus mutans, in particular the A region of the molecule, has been noted as a possible target of effective dental caries vaccine. We have previously shown that two peptides of 19 amino acids (residues 361-379, NAKATYEAALKQYEADLAA, and residues 301-319, ANAANEADYQAKLTAYQTE), which correspond to parts of the A-region, contain both T- and B-cell epitopes for the induction of cross-reacting antibodies to the PAc. In this study, for development of an appropriate antigen as a peptide vaccine for use in prophylactic dentistry, we analysed in detail the localization of the T- and B-cell epitopes of PAc(361-379) peptide and the T-cell epitope of PAc(301 319) peptide in B10 congenic mice. In four murine major histocompatibility complex (MHC) haplotypes (H-2f,d,a and k), PAc(361-377) peptide showed T- and B cell epitopes forming a cluster. It was found that the antibody which was induced by the immunization with the peptide was strongly cross-reactive with recombinant (r)PAc. Meanwhile, PAc(305-318) peptide, recognised by five strains of mice of different MHC haplotypes (H-2f,d,a,k and s), also bore multiple T-cell epitopes. PAc(361-377) peptide coupled to PAc(305-318) significantly elevated cross reacting antibody levels compared to immunization with PAc(361-377) only in four H-2 haplotypes. Moreover, a peptide with PAc(305-318) coupled to the N-terminal region of PAc(361-377) produced significant cross-reacting antibody against rPAc, even in B10.S mice which had not responded to immunization with PAc(361-379) peptide. Therefore, it was suggested that coupling among the peptides forming a cluster might be effective in increasing immunogenicity. These results may provide us with a useful strategy for the design of peptide-based vaccines for S. mutans in the future. PMID- 8690462 TI - Tumour necrosis factor receptor II (p75) signalling is required for the migration of Langerhans' cells. AB - Langerhans' cells (LC) represent the major antigen-presenting cells within the epidermis. Following exposure of the skin to antigen, LC take up antigen, migrate into draining lymph nodes (DLN) and present processed antigen to T lymphocytes, thereby initiating an immune response. The molecular mechanisms responsible for LC migration remain unclear. Cytokines, in particular tumour necrosis factor alpha (TNF-alpha) have been suggested to influence LC migration. There are two distinct membrane receptors for TNF-alpha, TNF receptor I (TNF-R1, p55) and TNF receptor II (TNF-R2, p75), thought to be responsible for distinct TNF-alpha activities. It is believed that most of TNF biological activities are mediated via TNF-R1. In order to examine the role of TNF-R1 signalling in LC migration, we utilized TNF-R1 gene-targeted mutant mice. Following application of the hapten fluorescein isothiocyanate (FITC), FITC-bearing cells in DLN were examined by flow cytometry. A normal number of FITC+/Ia+ cells (LC) were found in DLN from TNF-R1-deficiency mice, suggesting that TNF-R1-dependent signalling is not crucial for LC migration. To investigate the possibility of signalling through TNF-R2, blocking studies using a neutralizing anti-TNF-alpha antibody were performed. The results revealed that anti-TNF-alpha antibody significantly inhibited LC accumulation in DLN in TNF-R1-deficient mice, thus suggesting that TNF-R2 signalling is involved in LC migration from skin to DLN and that murine LC express TNF-R2. PMID- 8690463 TI - CD27/CD70 interaction directly induces natural killer cell killing activity. AB - The CD27 molecule is expressed on a portion of natural killer (NK) cells as well as T and B cells. To provide the functional capacity of CD27 molecule on NK cells, we here highly purified CD3- CD56+ NK cells by flow cytometry (purity > 98%), and investigated their NK cell activity via CD27/CD70 interaction using a CD70-transfectant by a 4 h 51Cr-release assay. The enhancement of NK activity by purified NK cells in the presence of interleukin-2 (IL-2) or interleukin-12 (IL 12) against CD70/Nalm-6 was not recognized as compared to against mock/Nalm-6. However, after a coculture with the fixed CD70/300-19, the purified NK cells increased the NK cell activity against K562, the value being 10 to 20% higher than coculture with the mock/300-19 in the presence of IL-2 or IL-12. The enhancement of NK activity was blocked by the addition of anti-CD70 monoclonal antibody (mAb). In addition, conjugation of NK cells to the target was increased by coculture with the CD70/300-19 without increased expression of adhesion molecules. In the parallel experiment, there was no increase in the killing capacity of NK cells. These results strongly show that CD27/CD70 interaction directly enhances NK activity in the presence of IL-2 or IL-12 by increasing the effector and target conjugate formation, indicating that CD27/CD70 interaction plays an important role in the cytotoxic function of NK cells. PMID- 8690464 TI - Properties of mouse CD40: differential expression of CD40 epitopes on dendritic cells and epithelial cells. AB - In this study we describe the tissue distribution of mouse CD40 using two monoclonal antibodies (mAb) against different epitopes of the molecule. In lymphoid tissues CD40 was expressed by B lymphocytes. Most B cells in typical B cell compartments were CD40-positive, including germinal centre B cells. Interestingly, the two CD40 epitopes were differentially distributed on subpopulations of dendritic cells and epithelial cells. The 3/23 mAb, but not 3/3, recognized interdigitating dendritic cells (IDC) in lymph nodes, spleen and thymus. Langerhans cells were CD40 negative. In contrast, epithelial cells in the thymus and some other tissues (e.g. skin) were stained with the 3/3 mAb, but not with the 3/23 mAb. The expression of CD40 on dendritic cells and epithelial cells is in agreement with earlier findings in humans. Our data also demonstrate that different epitopes of CD40 are differentially expressed on dendritic cells and epithelial cells. This suggests the existence of different forms of CD40, that are expressed in a cell-type-specific fashion. PMID- 8690465 TI - Analysis of recombinant human tumour necrosis factor-alpha-induced CD4 expression on human eosinophils. AB - We examined the hypothesis that one of the pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha), could induce expression of the adhesion molecule CD4 on human eosinophils. We further examined the effector function of CD4 and the mechanisms regulating CD4 expression. Human eosinophils were cultured with various concentrations of recombinant human TNF-alpha (rhTNF-alpha) with or without various drugs for 24 hr. After culture, eosinophils were stained for CD4 using a monoclonal antibody and then analysed by flow cytometry. Eosinophil derived neurotoxin (EDN) release as eosinophil degranulation was examined by cross-linking of CD4 on eosinophils. The rhTNF-alpha induced CD4 expression on human eosinophils in a dose- and time-dependent fashion; rhTNF-alpha-induced CD4 expression was significantly inhibited by 10(-6) M cycloheximide, 10(-8) M dexamethasone, or 10(-6) M herbimycin A. Recombinant human interferon-gamma inhibited rhTNF-alpha-induced CD4 expression in a dose-dependent manner. However, cross-linking of CD4 on eosinophils did not evoke EDN release, suggesting that newly expressed CD4 molecules on human eosinophils do not play any role in triggering degranulation. Our data indicate that TNF-alpha-induced CD4 expression on human eosinophils is dependent on protein synthesis and may be dependent on tyrosine kinase activity. PMID- 8690466 TI - Stem cell factor-dependent human cord blood derived mast cells express alpha- and beta-tryptase, heparin and chondroitin sulphate. AB - The present study sought to determine the expression of alpha- and beta-tryptase in in vitro differentiated human cord blood derived mast cells. We also analysed the glycosaminoglycan composition and the phenotype of the cells. The major protease in human mast cells is tryptase, and cDNAs for two different human tryptases have been characterized, the so-called alpha- and beta-tryptase. By reverse transcriptase-polymerase chain reaction (RT-PCR) we could show that stem cell factor (SCF)-dependent cord blood derived mast cells express both alpha- and beta-tryptase. Furthermore, the cells were stained with a monoclonal antibody (mAb) against tryptase, and the tryptase was enzymatically active cleaving the substrate Z-Gly-Pro-Arg- methoxy-2- naphthylamide (MNA). The majority of the cord blood derived mast cells could also be stained with mAbs against chymase, cathepsin G and CD68. They also expressed Kit/SCFR (CD117), CD13, CD29 and CD45 on the cell surface. The proteoglycan-derived polysaccharide composition of the cells was estimated to be 25-35% of heparin origin and 65-75% of chondroitin sulphate origin. Hence, the cord blood derived mast cells exhibit a phenotype in common with the so-called MCTC type of human mast cells. PMID- 8690468 TI - Destruction of some polycyclic heterocyclic compounds using oxidation by potassium permanganate. PMID- 8690469 TI - Degradation of some polycyclic heterocyclic compounds using hydrogen peroxide and iron(II) chloride. PMID- 8690467 TI - Transfer of type II collagen-induced arthritis from DBA/1 to severe combined immunodeficiency mice can be prevented by blockade of Mac-1. AB - Collagen-induced arthritis in susceptible mice is widely accepted as an experimental model for human rheumatoid arthritis (RA). We have investigated the role of the Mac-1 integrin beta 2 in the development and maintenance of arthritis by means of in vivo administration of 5C6 monoclonal antibody (mAb) to block this receptor. Injection of a single dose of 5C6 mAb (0.5 mg, intraperitoneally) prior to the expected onset of collagen-induced arthritis in DBA/1 mice diminished the severity of subsequent disease in these animals, as assessed both clinically and histologically (P < 0.01, chi 2). In the DBA/1 to severe combined immunodeficiency (SCID) transfer model of arthritis, the incidence of clinical arthritis was significantly reduced in SCID mice receiving maintained 5C6 treatment commencing the day prior to administration of donor splenocytes. Histological evaluation of joints from animals without clinically evident arthritis confirmed the absence of an inflammatory infiltrate in 22/27 joints examined. In a minority of these joints, however, synovial hyperplasia was apparent. In contrast, delaying antibody administration until 10 days after donor spleen cell transfer failed to protect three of five SCID recipients. These results confirm a functional role for Mac-1 in the generation of collagen-induced arthritis in mice. Since mAb 5C6 is non-cytotoxic, its action must be by blockade of the interactions between Mac-1 and its natural ligand(s). Our findings support the hypothesis that cells expressing Mac-1 play an important role in the induction and maintenance of joint damage in collagen-induced arthritis. PMID- 8690470 TI - Destruction of some polycyclic heterocyclic compounds using concentrated sulfuric acid. PMID- 8690471 TI - Destruction of some polycyclic heterocyclic compounds using oxidation by potassium permanganate in alkaline solution. PMID- 8690472 TI - National health policy--a need for review. PMID- 8690473 TI - The role of secondary sex ratios in the declining sex ratio of India. AB - The sex ratio in India has been gradually declining since the beginning of this century during the intercensus period of 1981-91, this ratio declined from 933 to 929. In the past the difference in sex ratios was wholly attributed to higher mortality amongst the females. However date for the years 1990-92 on secondary sex ratios i.e. sex ratio at birth presented in this paper suggest that the difference in sex ratio can also be attributed to a statistically significant higher number of males being born most probably as a result of selective abortion of female fetuses. PMID- 8690474 TI - Role of distance learning in health manpower training. AB - In order to meet the challenges of training of the health workers at various levels, there is a definite requirement of the involvement of various disciplines. Distance education can meet the need for training of the medical and para-medical personnel by utilising a variety of educational technology. Distance education has tremendous potential in training of the medical and para-medical workers in the health sector. PMID- 8690475 TI - Profile of sterilized women from a rural area of Haryana: a hospital based study. PMID- 8690476 TI - Knowledge & practices of urban and rural high school children regarding minor injuries. AB - High school students of urban (112) and rural area (110) were surveyed in 1990-91 to assess their knowledge and practices for regarding management of minor injuries. A variety of lacal application for wound were described. Burnol, Vaseline, talcum powered GV paint, mercurochrome were told only by urban students while irritating on wound was told only by rural students. Washing of wound with water, use of termeric, ointment, dettol, leaves spirit, sucking were told more by urban students while more of rural students told about use of mustard oil & mobile oil. Need of tetanus toxoid and immediate washing of would was told more by urban students. Need of relevant health education is emphasized. PMID- 8690477 TI - Changes in age incidence of kala-azar in India. AB - The mean age of 80 kala-azar cases was 20. 26 +/- 10.68 years, much higher than previously reported. This higher age incidence is probably related to fall of herd immunity particularly in the young adults resulting from less chance of natural infection during their childhood at such times when kala-azar in India had been largely controlled. PMID- 8690478 TI - AIDS phobia--a case report. PMID- 8690479 TI - Prevalence of VDRL sero-positivity in women in reproductive age group in an urban slum community in Bombay. AB - A cross sectional survey was carried in an Urban Slum Community in Bombay having a population of 60,000. A total of 393 women in reproductive age group were screened for VDRL reactivity. The highest prevalence was in 15 to 29 years of age group. The sero-positivity rate at 1:8 dilution and above was 0.50%. The seropositivity rate can be further brought down by properly planned and implemented STD (Sexually Transmitted Diseases) Control activities at a community level. PMID- 8690480 TI - Rapid Dot enzyme immuno assay for the quantitation of rabies antibodies. AB - A rapid dot enzyme immuno assay (Dot ELISA) for rabies antibody estimation has been standardized in which nitrocellulose sheet has been used as a solid support absorbing a commercial tissue culture rabies vaccine as antigen. The test was compared with a standard plate ELISA test. The results were comparable and the student "t' test for proportion revealed that plate ELISA test is significantly better (P 0.05) when compared to Dot ELISA for the number of sera with titre < 0.5 Iu/ml and in the case of > 0.5 IU/ml Dot ELISA is found to be better over plate ELISA test at the same significance level. PMID- 8690481 TI - Health services epidemiology. PMID- 8690482 TI - Presidential address. The Indian Public Health Association. PMID- 8690483 TI - Dr. B. C. Dasgupta Memorial Oration. Priorities, issues, inter-state variations and challenges. AB - India spends only 1.5% of GDP on health as against the recommended 5% by W.H.O. for equity and universal coverage. States have a high share (89%) of funding their health care activities as against 9% by centre and 2.8% by U. T.'s. Increasing proportion of health expenditure on salaries (60-90%) and a markedly reduced (29%-5%) proportion on non-salary components is reflected in low-level of utilization of health services. Committed involvement by others in selected crucial areas is lacking. Health financing seems to be directed towards the urban sector with maximum outlays to curative care. There are high inter-state variations in health expenditure and health status. Higher share of SDF on public health does not guarantee a better health status. Health services sector urgently & legitimately needs additional resources. There is need to set up technical committee and research cells to sensitise policy makers, academicians and others and to steer and guide research. Health Financing and Management must be considered together to address issues of equity, efficiency and effectiveness in health care services. PMID- 8690484 TI - K. N. Rao Memorial Oration. Primary health care--developing leadership. PMID- 8690485 TI - Dr. A. L. Saha Memorial Oration. Healthy cities vision--an emerging global awareness and Indian perspective. PMID- 8690486 TI - Dr. P. C. Sen Memorial Award--1994. An epidemiological study of risk factors in preschool children of rural areas of Jaunpur District. PMID- 8690487 TI - An assessment of AIDS awareness program--for I.C.D.S. functionaries. AB - An assessment of the "One Day AIDS Awareness Program" for I.C.D.S. functionaries was done. The pre-training knowledge level scores were 55.3%, 39.3% and 60.4% of the total score, in 24-Parganas (S), Burdwan and Calcutta districts respectively. However, the post-training assessment scores were observed to be 91.9%, 84.9% and 94.8% in 24-Parganas (S), Burdwan and Calcutta districts respectively. The percentage increase in mean scores was found to be 66.5%, 115.8% and 57.1% in 24 Parganas (S), Burdwan and Calcutta districts respectively. PMID- 8690488 TI - Awareness on AIDS among health care professionals. PMID- 8690489 TI - AIDS awareness among nursing students. AB - Nursing students are being identified as a potential risk group for the AIDS spread. Awareness regarding AIDS in this group is crucial for AIDS management and prevention. This cross-sectional study was planned and carried out to assess the awareness of nursing students regarding AIDS and to identify the areas of confusion that might serve as an important target of educational intervention. The study consisted of 204 nursing students selected from Nursing school, Govt. Medical College, Nagpur. The overall knowledge regarding etiology, risk factors, transmission, treatment and prevention of AIDS was confusing among the students. The average knowledge score was estimated to be 17.6 of 28. However, more knowledge was found to be correlated with more positive and fearless attitude towards AIDS patients. PMID- 8690490 TI - Lessons from home based care for persons affecting with HIV and AIDS. PMID- 8690492 TI - HIV-2 and HIV-1/2 seropositivity in Bihar. AB - 1802 serum samples from high risk group of persons were tested for sero positivity for HIV-1 and HIV-2 by using immunocomb bioassay procedure. Out of 16 sero-positive serum samples, 5 (31.25%) was positive for HIV-2 only. It is, therefore, suggested that all kits employed for initial serotesting must include both HIV-1 and HIV-2. PMID- 8690491 TI - A cross-sectional seroprevalence survey for HIV-1 and high risk sexual behaviour of seropositives in a prison in India. AB - This study was conducted to know whether prisoners constitute a "high risk group" for HIV transmission in India today. A sero-epidemiological period prevalence survey was conducted in Central Prison, Bangalore, South India covering 1007 undertrials and 107 permanent convicts during January to December 1993. Twenty (1.98%) undertrials and none of the permanent convicts were seropositive for HIV infection. All of them were males and 1.6(80%) of them were in the age group of 20-30 years. Low literacy, poor income, sexual promiscuity and low condom usage were observed among the seropositives. Thus, prisoners constitute a high risk group and routine screening and counselling are recommended. PMID- 8690493 TI - Counselling in HIV/AIDS--an Indian perspective. AB - AN overview of the general principles of counselling for HIV/AIDS are overviewed. Relevance of 'shared confidentiality' in Indian context is recommended. PMID- 8690494 TI - Beyond medical model of STD intervention--lessons from Sonagachi. AB - Sonagachi, a red-light area in Calcutta has experienced a successful STD control program. Social issues behind this success and importance of non biological parameters to evaluate the success of the project are highlighted. PMID- 8690495 TI - HIV and AIDS. PMID- 8690496 TI - Estimation of adult HIV prevalence as of the end of 1994 in India. AB - It is estimated that as of the end of 1994 approximately 1,750,000 adults were infected with HIV in India. This estimate is based upon a review of data provided by the National AIDS Control Organization. The methods to reach such estimate are succinctly reviewed and a series of scenarios presented. PMID- 8690497 TI - A cross-sectional study on factors including HIV testing and counselling determining unsafe injecting practices among injecting drug users of Manipur. AB - In India, a steep increase in the prevalence of HIV (0% to 50% within six months) among the IDUs has been reported in Manipur, a north eastern state in 1990. In spite of large scale intervention program like educational campaign and widespread voluntary HIV testing in this state, the infection has quickly spread to the heterosexual population at large. The determinants of risk taking behaviors like sharing of unclean needle among the IDU population has been explored in this paper. A cross sectional study has been carried out among all of the 488 IDUs who attended any detoxification centers and prison during last two years at Imphal, the capital city of this state. Self reported behaviors based on the pre-scheduled interview were recorded and participation rate was satisfactory. The data was compared to a similar survey carried out by us in 1990. Although there has been decline in risk behavior among the IDUs, a logistic regression analysis reveals that unsafe needle sharing behavior is not influenced by the knowledge on HIV transmission, educational status or history of HIV testing or serostatus of the individual. The limitation of cross sectional nature of the study, bias due to collection of data in prison, self reported behavior, possible differences with street samples of the addict are discussed. PMID- 8690498 TI - Sexually transmitted disease services in Madras: could their role in AIDS prevention be strengthened? AB - A baseline evaluation of the quality of STD case management was conducted in five areas of Madras city in 1992, using HIV prevention indicators recommended by the World Health Organization. Eighty-four interviews and 108 observations of private and public clinic practitioners were conducted. Sixty-one percent of interviewed doctors reported making only specific "clinical" diagnoses and 17% reported making only the WHO recommended syndrome-based diagnoses while 22% reported making both types of diagnosis. The adequacy of treatment was compared against various standards, including the Indian National Guidelines for STD management. Almost half of the health care providers (HCP) reported using a treatment effective against the two main pathogens that may cause male urethritis, while 20% reported using a treatment that was not effective against either. For male ulcers only 12% of HCPs reported using treatment effective against both syphilis and chancroid. Seventy-nine percent of the HCP reported that they advised their patients to use condoms, but in 30% only of observed consultations, condoms were promoted for STD or HIV/AIDS prevention. As information concerning the relative prevalence of pathogens in different areas is unlikely to be available, there is an urgent need for the syndromic approach to STD treatment be adopted by health care providers. PMID- 8690499 TI - Iodine deficiency disorders in India. PMID- 8690500 TI - Iodine deficiency disorders (IDD) and iodised salt in Assam: a few observations. PMID- 8690501 TI - Indicators to monitor progress of National Iodine Deficiency Disorders Control Programme (NIDDCP) and some observations on iodised salt in west Bengal. AB - Iodine Deficiency Disorders (IDD) are widely prevalent in our country and their consequences for human development are well known. The scope of National Goitre Control Programme (NGCP) launched in 1962 was expanded and the programme was renamed as National Iodine Deficiency Disorders Control Programme (NIDDCP) to connote wider implications of iodine deficiency in population. It is necessary to monitor the progress of NIDDCP using quantifiable indicators to ensure achievement of programme objectives. Prevalence of iodine deficiency disorders, status of iodised salt and level of knowledge. Attitude & practice (KAP) of community regarding IDD and iodised salt are a few such indicators. Children in the age group of 8-10 years are considered most appropriate target group to monitor IDD prevalence. The quality of iodised salt assessed at various levels in West Bengal (using field testing kit) indicated 'satisfactory' iodine content (i.e. > or = 15 ppm) at wholesalers (84.3 per cent), retailers (74.3 per cent) and consumers (71.2 per cent) level. It is suggested that the quality of iodised salt should be periodically assessed and intensive educational campaigns on IDD be launched to create increased demand for consumption of iodised salt in the community. PMID- 8690502 TI - National Iodine Deficiency Disorders Control Programme in India. AB - Iodine Deficiency Disorders are one of the biggest worldwide public health problem of today. Their effect is hidden and profound affecting the quality of human life. An attempt has been made to describe the various aspects of the National Iodine Deficiency Disorders control Programme (NIDDCP) being implemented in the country. The paper also focuses about the problems associated in implementing this national programme. PMID- 8690503 TI - Rijiv Gandhi mission for the elimination of IDD in Madhya Pradesh. PMID- 8690504 TI - Informing, educating and communicating with people iodine deficiency disorders elimination drive in Madhya Pradesh. PMID- 8690505 TI - Iodised salt is safe. AB - Iodine deficiency disorders are prevalent in all the States and Union Territories in India. Under the National Iodine Deficiency Disorders control programme, the Government of India has adopted a strategy to iodisation of all edible salt in the country which is a long term and sustainable preventive solution to eliminate iodine deficiency disorders. The benefits to be derived from universal salt iodisation are more to the population. Iodised salt is safe and does not cause any side effect. PMID- 8690506 TI - Process of implementation of National Iodine Deficiency Disorders Control Programme activities in Himachal Pradesh, India. PMID- 8690507 TI - IgG immune response to Helicobacter pylori antigens in patients with gastric cancer as defined by ELISA and immunoblotting. AB - Helicobacter pylori infection is considered to be a risk factor for gastric cancer. A high prevalence of H. pylori infection and high gastric-cancer incidence are characteristic of the Estonian population. To evaluate the relationship between these 2 events, we studied the seroprevalence of H. pylori in gastric cancer patients (n = 182) and in healthy blood donors (n = 306). A relative anti-H. pylori IgG antibody activity, as detected by ELISA and immunoblot patterns, was correlated with age, stage of the disease and tumor morphology. A significantly higher H. pylori seroprevalence was found in patients in the early stages of tumor development compared with both advanced cancer patients and controls. No significant difference in H. pylori seroprevalence between patients with the intestinal and diffuse types of tumor growth was observed. A decline in the recognition of putatively cross-reacting (33-66 kDa) antigens was noted in the cancer group. The response to vacuolating toxin-related 85-kDa and CagA 120-kDa protein antigens was not altered and was observed more often in the younger group of cancer patients. PMID- 8690508 TI - Overexpression of bax sensitizes human breast cancer MCF-7 cells to radiation induced apoptosis. AB - Resistance to apoptosis plays an important role in tumors that are refractory to chemotherapy and ionizing radiation (IR). bax, which forms a heterodimer with bcl 2 and accelerates apoptosis, is not, or only weakly, expressed in most human breast cancer cells, and weak bax expression is considered to be related to the resistance of breast cancer cells to apoptosis. bax expression vector was introduced to human breast cancer MCF-7 cells, which exhibit weak expression of bax, to demonstrate its role of modulating radiation-induced apoptosis. bax overexpression in MCF-7 cells by stable transfection does not affect viability by itself, but each stable transfectant was more sensitive to IR than the parental MCF-7 cells. The degree of enhancement in radiosensitivity was dependent on the expression level of bax. IR upregulated p53 and p21WAF1 about 5- to 10-fold and downregulated bcl-2 and bcl-XL by 80-90% at 6 hr in both parent and bax stably transfected MCF-7 cells to the same degree. FACS analysis and DNA electrophoresis revealed that this sensitization was due to apoptosis. We suggest that exogenous bax expression might be one of the factors determining cellular radiosensitivity in MCF-7 breast cancer cells and may have therapeutic applications for enhancing radiation sensitivity in breast cancer cells. PMID- 8690509 TI - Wild-type p53-induced apoptosis in a Burkitt lymphoma cell line is inhibited by interferon gamma. AB - The tumor suppressor p53 plays a central role in negative growth control, including growth arrest and apoptosis. Interferons (IFNs) are capable of modulating a variety of cellular responses, including apoptosis. In this study, we have evaluated the influence of gamma- and alpha-interferon (IFN) on wild-type (wt) p53-induced apoptosis using a Burkitt lymphoma cell line, BL41, transfected with a temperature-sensitive p53 construct, gamma-IFN, but not alpha-IFN, was found to protect cells from wt p53-induced apoptosis. The gamma-IFN-dependent protection was due neither to down-regulation of p53, nor to the p53-induced genes, p21 (WAF-1) and bax, nor to up-regulation of bcl-2 or bcl-xL. Expression of the proto-oncogene c-myc, implicated in the control of both proliferation and apoptosis, was not affected by gamma-IFN. We conclude that gamma-IFN can suppress p53-induced apoptosis, and that the cytokine microenvironment may be decisive in the cellular response to wt p53 expression. PMID- 8690510 TI - Loss of heterozygosity at locus F13B on chromosome 1q in human medulloblastoma. AB - Medulloblastoma is a primitive neuroectodermal tumor of the cerebellum with poorly understood pathogenesis. Previous studies have reported loss of heterozygosity (LOH) on chromosome arms 17p, 11p and 9q and cytogenetic abnormalities of chromosome 1 in medulloblastoma. We have used the polymerase chain reaction to amplify 10 microsatellites on the short arm and 8 microsatellites on the long arm of chromosome 1 to assess allelic loss in 22 medulloblastomas. Loss of heterozygosity (LOH) on chromosome 1 was found in 9 cases. Eight medulloblastomas (36%) showed an interstitial LOH on chromosome 1q. The common region of overlap was mapped between D1S 1604 and D1S237 and included the locus F13B in the chromosomal region 1q31-q32.1. An additional tumor had LOH in a proximal region of 1p, but did not exhibit LOH on 1q. None of the medulloblastomas exhibited LOH of the telomeric portion of chromosome 1p, which has been associated with several other human malignancies. Our data suggest the presence of a putative tumor suppressor gene located near the locus F13B on chromosome arm 1q that appears to be involved in the pathogenesis of medulloblastoma. PMID- 8690511 TI - Recombinant single-chain and disulfide-stabilized Fv-immunotoxins that cause complete regression of a human colon cancer xenograft in nude mice. AB - Monoclonal antibody (MAb) 55.1 specifically recognizes an antigen on the surface of human colon adenocarcinoma cells. We constructed recombinant immunotoxins composed of the heavy- and light-chain variable regions of MAb 55.1 fused to a recombinant form of Pseudomonas exotoxin (PE). The heavy- and light-chain variable regions are stabilized by 2 means. One is by a flexible peptide linker to form a single-chain antigen binding protein (scFv) and the second by an interchain disulfide bond engineered between structurally conserved framework regions. These are termed disulfide stabilized Fvs (dsFv). The 2 Fv forms are fused to truncated forms of PE lacking the cell binding domain. The recombinant scFv- and dsFv-immunotoxins were expressed in E. coli and purified to near homogeneity. The scFv- and dsFv-immunotoxins were shown to be specifically cytotoxic to human colon adenocarcinoma cell lines. The scFv-immunotoxin containing PE38KDEL was more active than the immunotoxin containing PE38 with the native carboxyl terminus (REDLK). However, the PE38KDEL immunotoxin is about 2 fold more toxic in mice, and therefore it does not appreciably increase the therapeutic window in mice. Intravenous administration of the scFv- and dsFv- recombinant immunotoxins caused complete regression of a human colon carcinoma (Colo205) growing subcutaneously in immunodeficient mice. The dsFv-immunotoxin has better antitumor activity compared with its scFv-immunotoxin counterpart. PMID- 8690512 TI - Expression of a 32 kDa protein in rat mammary tumors induced by anti benzo[c]phenanthrene-3,4-diol-1,2-epoxide. AB - Racemic anti-benzo[c]phenanthrene-3,4-diol-1,2-epoxide (BcPDE) is a powerful rat mammary carcinogen and a metabolite of benzo[c]phenanthrene, a polynuclear aromatic hydrocarbon found in the environment. In elucidating potential molecular mechanisms that may play a role in the development of BcPDE-induced rat mammary tumors, we have identified a 32 kDa protein in 16 of 26 tumors analyzed but in only 1 of the 15 normal mammary tissues that were examined. The 32 kDa protein was identified with antibodies to Ets, which also recognized the 55 kDa Ets-1 protein that was expressed at similar levels in normal mammary tissues. The expression of the 32 kDa protein was also observed in mammary tumor-derived cell lines of both rat and human origin and in human melanoma, but not in normal human keratinocytes or rat fibroblast cell lines. Further characterization via 2D gels revealed that the protein exhibits a PI of 5.5. Southwestern analysis using Ets-1 target sequence revealed binding of the 55 kDa Ets-1 but not of the newly identified 32 kDa protein. Overall, the preferential expression of the 32 kDa protein in mammary tumor tissues may serve as a biomarker to follow the development of this tumor type. PMID- 8690513 TI - Cellular pharmacology of idarubicinol in multidrug-resistant LoVo cell lines. AB - Idarubicin (IDA) is a daunorubicin (DAU) analog that is being used to treat a variety of human malignancies. The major circulating metabolite of IDA is idarubicinol (IDOL). After administration of IDA to patients, the systemic exposure to IDOL is greater than IDA. We investigated the cytotoxic effect of IDOL in the LoVo human colon-carcinoma cell line and its derivative multidrug resistant (MDR) sub-lines. In LoVo-sensitive cells, the extracellular IDOL concentration inhibiting cell growth by 50% (IC50) was about 2-fold higher than IDA IC50 but lower than DAU IC50. After continuous exposure of the LoVo parental cells to 20 nM IDOL, 5 drug-resistant clones were obtained. All these clones exhibited an MDR phenotype, indicating that IDOL is involved in multidrug resistance. The resistance index (RI) to IDOL was investigated in LoVo MDR sub lines obtained by IDOL (LoVo-IDOL-1), IDA (LoVo-IDA-1) and DOX (LoVo-DOX-1) selection. In spite of the drug used for their selection, all the MDR sub-lines exhibited an RI to IDOL lower than DAU and only 2-fold higher than IDA. In LoVo IDOL-1 cells the RI was 5, 11 and 32 for IDA, IDOL and DAU respectively. Differences in the RI were explained by the greater intracellular tolerance exhibited by MDR cells to DAU than to IDOL and IDA. In the LoVo-IDOL-1 sub-line, the intracellular drug concentration inhibiting cell growth by 50% (IC50int) was higher than in the sensitive cells by 11.4-, 4.7- and 2.8-fold for DAU, IDOL, and IDA respectively. Differences in the intracellular tolerance were explained by the different intracellular distribution of DAU compared with IDOL and IDA. While DAU had a higher nuclear location in LoVo-sensitive cells than in resistant cells, IDOL and IDA maintained the same distribution both in sensitive and in resistant cells. In conclusion, contrary to what has been observed for other derivative metabolites of anthracyclines, the metabolism of IDA to IDOL must not be considered an inactivation pathway. IDOL is a potent inhibitor of cell growth and retains good activity in MDR cells. PMID- 8690514 TI - Induction of the death-promoting gene bax-alpha sensitizes cultured breast-cancer cells to drug-induced apoptosis. AB - Resistance to apoptosis plays an important role in malignancies that are refractory to chemotherapy treatment. Recently we have shown that the expression of bax-alpha, a death-promoting member of the bcl-2 family, is down-regulated in breast cancer and have provided evidence that low bax expression might contribute to the pathogenesis of breast cancer. In this study we were able to demonstrate the role of this gene in chemotherapy-induced apoptosis. We transfected bax-alpha into the breast-cancer cell lines R30C and MCF-7 under the control of an inducible tetracycline-dependent expression system. Induction of bax-alpha expression did not affect viability by itself but strongly increased chemosensitivity to epirubicin. We were able to demonstrate that this sensitization is due to apoptosis. These data might explain the recently published observation that reduced expression of bax is associated with poor response rates to chemotherapy in breast cancer. PMID- 8690515 TI - Overexpression of v-abl uniquely cooperates with c-myc dysregulation in induction of plasma cell tumors, bypassing the need for T-lymphocytic help and overcoming T lymphocytic interference. AB - We have investigated the effects of T lymphocytes on induction of mouse plasma cell tumors. We show that ABL-MYC, a plasmacytomagenic retrovirus that constitutively expresses v-abl and c-myc, is able to induce plasmacytomas in 100% of athymic BALB/c mice, with or without intraperitoneal pristane pretreatment. Other induction regimens are ineffective under these conditions, indicating that the combination of v-abl and c-myc oncogenes is uniquely able to transform plasma cells in mice that are deficient in T lymphocytes. Furthermore, in the absence of pristane, ABL-MYC-infected athymic congenics developed plasmacytomas in half the time required for euthymic BALB/c mice, suggesting that T lymphocytes can have a negative effect and can retard, but not totally inhibit, the outgrowth of plasmacytomas. This phenomenon could not be appreciated in other regimens of plasmacytoma induction, because only ABL-MYC is sufficient to induce plasmacytomas in athymic mice or in euthymic mice in the absence of pristane pretreatment. PMID- 8690516 TI - A quantitative assay using basement membrane extracts to study tumor angiogenesis in vivo. AB - We describe a quantitative assay for assessing tumor angiogenesis in vivo using basement membrane extracts (Matrigel). Nude mice were injected s.c. with liquid Matrigel mixed with HT1080 human fibrosarcoma cells. Since Matrigel rapidly forms a solid gel at body temperature, the gel containing tumor cells can be removed immediately and then processed for histological studies. Tumor angiogenesis was monitored quantitatively by measuring both the number and the total area of neovessels present in the gels using an image analyzer, which could be achieved approximately 72 hr later. Furthermore, HT1080 cell-conditioned medium, which may contain various tumor-derived factors, promoted the basement membrane degradation, migration, proliferation and tube formation of endothelial cells in vitro, as did Matrigel, although to a lesser extent. In addition, Northern blot analysis demonstrated that the amount of vascular endothelial growth factor (VEGF) mRNA in HT1080 cells was much higher than that in human fibroblasts or NIH3T3 cells. Our results suggest that angiogenesis observed in our assay may be due to the synergic effects of tumor angiogenic factors such as VEGF, and Matrigel. The advantages of our assay are: 1) it is possible to assess early angiogenesis quantitatively; and 2) this assay may be applicable for screening anti-angiogenic therapeutic agents to be used against human neoplasms. PMID- 8690517 TI - Tissue norepinephrine depletion as a mechanism for calcium chloride inhibition of gastric carcinogenesis in rats after treatment with N-methyl-N'-nitro-N nitrosoguanidine and sodium chloride. AB - The effects of oral calcium chloride (CaCl2) on sodium chloride (NaCl)-enhanced induction of gastric carcinogenesis by the carcinogen N-methyl-N'-nitro-N nitrosoguanidine, and the norepinephrine (NE) concentration in the gastric wall, were investigated in Wistar rats. Animals were given the carcinogen for 25 weeks and then chow pellets containing 10% NaCl with or without 8% or 4% CaCl2. In week 52, the incidence of gastric cancers, the NE concentration in the antral portion of gastric wall and the labelling index of antral epithelial cells were significantly greater in rats fed NaCl alone than in untreated control rats. Concomitant oral treatment with CaCl2 at 8%, but not 4%, significantly reduced the incidence of gastric cancers, the NE concentration in the antral portion of gastric wall and the labelling index of the antral epithelial cells in week 52 compared with those in rats fed NaCl alone. Because NE concentration reflects sympathetic nervous system activity, our findings suggest that the sympathetic nervous system could play a role in NaCl-enhanced gastric carcinogenesis. Our findings also suggest that NE depletion by CaCl2 may be related to its inhibition of NaCl-enhanced carcinogenesis. PMID- 8690518 TI - Abundance and state of phosphorylation of the retinoblastoma gene product in human pituitary tumors. AB - Targeted disruptions of the retinoblastoma (Rb) gene result in a high frequency of pituitary tumors in heterozygous mice. While our group and others have reported that loss of heterozygosity (LOH) at the Rb locus in human pituitary tumors is rare, these studies have not excluded small inactivating Rb-gene abnormalities more frequently found in human tumors and undetectable by LOH-PCR assays. As a more sensitive means of detecting evidence of these lesions, we have performed Western-blot analysis of several human pituitary tumors to identify Rb loss at the protein level as well as truncated forms of the Rb protein frequently associated with Rb-gene mutations. In 24 tumors, Rb protein was detected at levels 1.4- to 3.9-fold those detected in normal postmortem pituitary. There was no evidence of truncated forms of the Rb protein and only the hypophosphorylated (active) form of the protein was detected in normal and in pituitary tumor specimens. To investigate the possibility of loss of function mutations in certain tumors resulting in the expression of stable, mutant, hypophosphorylated Rb protein, we further performed SSCP analysis of exons 20 through 24 corresponding to the pocket domain of the Rb protein. Of 20 pituitary tumors examined, no mobility shifts could be demonstrated in this analysis. Our findings provide further evidence that primary Rb inactivation is not common in human pituitary tumors. Our detection of only the hypophosphorylated form of the Rb protein probably reflects the low proliferative state of these tumors. PMID- 8690519 TI - Association of resistance-related protein expression with poor vascularization and low levels of oxygen in human rectal cancer. AB - Rectal carcinomas of previously untreated patients were analyzed for oxygen status using a computerized polarographic needle electrode histograph. Microvessel density and expression of c-jun, vascular endothelial growth factor (VEGF) and several resistance-related proteins (glutathione S-transferase-pi, GST; thymidylate synthase, TS; metallothioneine, MT) were determined using immunohistochemistry. To examine whether a relationship exists between intratumoral vessel density and tumor oxygenation, microvessel counts were determined in a 400x field using factor-VIII-related antigen and were correlated with the corresponding pO2 values. Linear regression analysis revealed a significant relationship between vessel density and oxygenation status of the tumors. Expression of c-jun, VEGF and resistance-related proteins was correlated with microvessel counts and pO2 values. Significantly lower vessel counts were found in GST- and MT-positive tumors and in tumors with overexpression of c-jun and VEGF than in negative tumors. In addition, significantly lower pO2 values were found in c-jun- and VEGF-positive tumors as well as a tendency for pO2 values to be lower in tumors where MT, GST and TS were expressed. These data show that expression of c-jun, VEGF, and resistance-related proteins is linked with poor vascularization and low oxygenation status in rectal cancer. PMID- 8690520 TI - Site distribution of different types of skin cancer: new aetiological clues. AB - Since the investigation, at an individual level, of lifetime sun exposure remains difficult the site distribution of different types of skin cancer can be an important source of aetiological clues. The present report deals with 1,149 cases of cutaneous malignant melanoma (CMM), 7,685 of basal-cell carcinoma (BCC) and 3,049 of squamous-cell carcinoma (SCC) reported between 1976 and 1992 to the Vaud Cancer Registry, in Switzerland. Site- and type-specific age-standardized (on the world population) incidence rates per 100,000 population and per 100,000 unit surface were computed, together with relative age-standardized incidence rates (i.e., rates per 100,000 surface unit in each anatomical site relative to rates for the body as a whole). The highest rates per unit surface were seen for both genders in the face, thus indicating same role of cumulative sun exposure in all skin-cancer types. Relative to the incidence in the whole body, the excess on the face was, however, more than 20-fold for BCC and SCC, but only 4-fold for CMM. The relative incidence in males was very much higher for SCC than for CMM and BCC in the neck, ears and scalp, a heavily sun-exposed area in men but not in women. Conversely, a substantial lack of SCC was seen in the trunk. In conclusion, site distribution of different skin-cancer types suggests that short-duration UV-light exposure is sufficient to increase CMM risk substantially, but has little influence on SCC risk. With the increase of exposure, however, SCC rises more steeply than BCC. Age-related behaviour (i.e., another indirect indicator of duration of exposure to UV light) is consistent with the anatomical distribution of skin cancer. PMID- 8690521 TI - Status and expression of the p16INK4 gene in human thyroid tumors and thyroid tumor cell lines. AB - The p16INK4 tumor-suppressor gene (also known as CDKN2, CDK41 and MTS1) encodes a negative regulator of the cell cycle. This gene, located in 9p21, is mutated or homozygously deleted in a high percentage of tumor cell lines and specific types of primary tumors. We have examined the status of the p16INK4 gene in 31 thyroid tumors and 7 thyroid cell lines. No DNA abnormalities were found in primary tumors. Conversely, p16INK4 gene structural alterations, deletions and point mutations were found in 4 thyroid cell lines. The expression of the 2 different p16INK4 mRNAs, the p16alpha and p16beta transcripts, was determined by RNA-PCR experiments. All the primary thyroid tumors expressed the beta transcript, while the p16alpha was barely detectable. The thyroid cell lines always expressed the p16beta transcript, while the alpha transcript was absent or, whenever present, coded for a mutated form of the p16INK4 gene product. Taken together, our results suggest that loss of p16INK4 function is not directly involved in the process of thyroid-tumor development, but it probably gives cells in tissue culture a selective growth advantage. PMID- 8690523 TI - Predictors of late mortality in cutaneous malignant melanoma--a population-based study in Sweden. AB - We determined risk factors for late deaths from cutaneous malignant melanoma (CMM) based on clinical characteristics at diagnosis, initial surgical treatment, histopathologic features of the primary tumor and type of eventual recurrences during follow-up. We examined deaths from CMM 8 or more completed years after the initial diagnosis in a case-control study nested in a nationwide cohort comprising all 8,838 patients with CMM diagnosed in Sweden during 1960-1978 with complete follow-up through 1986. There were 285 case patients and 285 control patients, individually matched by sex, age and follow-up time. Conditional logistic regression was used to obtain odds ratios (OR) as estimates of the relative risk. The risk of late mortality increased stepwise, almost 19-fold, with increasing tumor thickness from < or = 0.75 to > or = 7.00 mm. Besides the thickest tumors (> or = 7.00 mm), those of intermediate thickness (1.50-2.49 mm) had the highest risk (OR 8.5). After adjustment for tumor thickness, non-radical primary surgical treatment increased the risk of late mortality almost 3-fold while prophylactic lymph node dissection entailed a significantly reduced risk of late mortality (OR 0.5); the histopathologic features increasing level of invasion and vertical growth phase also remained significantly associated with a poor outcome. In a multivariate model, non-radical primary surgical treatment, prophylactic lymph node dissection, vertical growth phase, level of invasion and lymphocyte reaction were independent predictors of late mortality. PMID- 8690522 TI - HCV infection and liver cancer mortality in a Japanese population with HTLV-I. AB - In a cohort study of human T-lymphotropic virus type I (HTLV-I) infection in Japan, 10 cases of liver cancer death occurred from 1984 through 1993. To analyze the role of hepatitis C virus (HCV), which has been associated with an increasing incidence of hepatocellular carcinoma (HCC) in Japan, a nested case-control study was performed. Five of the 10 liver cancer cases were positive for antibody to HTLV-I (anti-HTLV-I). The possible interaction between HCV and HTLV-I infections in the etiology of HCC was investigated, with each liver cancer case matched to 5 cohort controls by gender, age, serum sample date and anti-HTLV-I status. Using a matched analysis odds ratio (OR) were generated for the relationship between HCV serologic status and death liver cancer. Based on second-generation enzyme immunoassay with confirmation by recombinant immunoblot assay, 8 of 9 cases with adequate serum available (89%) and 9 of 50 (18%) controls were found to be positive for antibody to HCV (anti-HCV). Liver cancer death was highly associated with anti-HCV (matched OR = infinity; p < 0.001). Anti-HTLV-I seroprevalence was some what correlated with HCV infection. However, the high risk of liver cancer death observed for anti-HCV-positive Individuals in this population did not vary with respect to whether or not the subjects were also infected with HTLV-I. PMID- 8690524 TI - Adenomatous transformation of the human anterior pituitary is associated with alterations in integrin expression. AB - Integrins are heterodimeric transmembrane molecules that mediate cell-cell and cell-substratum adhesion. Because alterations in the adhesive properties of tumor cells influence tumor growth and progression, the distribution of different alpha and beta integrin subunits was studied in both the parenchyma and the connective tissue in 6 normal and 25 adenomatous human anterior pituitaries. All normal parenchymal cells expressed the alpha3beta1 and alpha6beta4 integrins. By contrast, in adenomatous parenchymal cells the expression of alpha3beta1 was down regulated and that of alpha6beta4 abrogated. Neoexpression of alphavbeta3 Occurred in the parenchyma of a subset of adenomas. All normal connective tissue cells expressed the alpha1 and beta1 subunits, a third subunit (alpha5) being present in the normal endothelium. By comparison, all adenomatous stromal cells expressed many more integrin subunits (alpha1, alpha3, alpha5, alphav, beta1 and beta3), adenomatous endothelial cells bearing additional subunits (alpha6, beta4 and beta5). Vitronectin, absent from the normal connective tissue, was constantly observed in the adenomatous stroma. To conclude, compared with cells of the normal gland, adenomatous anterior pituitary cells display a decreased expression of integrins whereas the adenomatous stroma expresses a rich repertoire of integrins. These changes are not related to the secretory type, grade or invasiveness of the adenoma. The resulting alterations in the adhesive properties of adenomatous cells could facilitate their dissemination. Enrichment of the integrin repertoire expressed by the adenomatous vasculature is indicative of its dual nature, systemic and tumoral. PMID- 8690525 TI - Granulocyte-macrophage-colony-stimulating factor enhances immune responses to melanoma-associated peptides in vivo. AB - Peptide epitopes derived from differentiation antigens of the melanocyte lineage were recently identified in human melanomas as targets for MHC-restricted cytotoxic T lymphocytes (CTL). The characterization of multiple CTL-defined antigenic determinants has opened possibilities of development of antigen targeted vaccines. In the present study, we determined CTL reactivity against melanoma-associated peptides derived from Melan A/MART-1, tyrosinase, and gp100/Pmel17 in 3 HLA-A2+ melanoma patients. Then, we assessed the immune responses to synthetic melanoma-associated peptides injected intradermally. After 3 cycles of immunization with peptide alone, we used systemic GM-CSF as an adjuvant during the fourth cycle of immunization. Enhanced DTH reactions and CD8+ CTL responses were observed after treatment with systemic GM-CSF. Immunohistochemical characterization of DTH-constituting elements revealed infiltrates of CD4+ and CD8+ T lymphocytes and strong expression of IL-2 and gammaIFN, suggesting the activation of CD4+ ThI and CD8+ CTL by peptides presented by MHC-class-I molecules of dermal APC. Objective tumor regression was documented in all patients. We conclude that systemic GM-CSF enhances immune responses to melanoma-associated peptides and supports CTL-mediated tumor rejection in vivo. PMID- 8690526 TI - Incidence of second primary malignancies after a malignant tumor in childhood: a population-based survey in Piedmont (Italy). AB - We have studied the frequency of second primary malignancies (SPM) among the 2,328 children registered in 1967-1969 at the Childhood Cancer Registry of Piedmont, the largest population-based childhood cancer registry in Southern Europe. Since the population of Piedmont is not served by a conventional cancer registry covering all ages, SPMs were identified through a number of ad hoc surveys within a variety of sources. Eighteen SPM (all histologically diagnosed) were observed after a thorough survey conducted in the ontological departments in Piedmont and after a postal questionnaire addressed to general practitioners. Death certificates were also examined. The crude incidence rate was 116.5 per 100,000 person-years. Risk was higher among children whose first malignancy was diagnosed more recently (SIR = 9.8 for diagnoses in 1983-1989 vs. 4.5 for diagnoses in 1967-1974). The same tendency was confirmed in analyses restricted to children in whom leukemia was diagnosed as the first cancer. Clinical data regarding the treatment of the first malignancy were available for 16 children out of 18: 15 had received chemotherapy and 12 radiotherapy (9 SPM originated in the irradiation field). The interest of measuring the risk of SPM on a population basis (and not only in clinical series) and the advantage of close cooperation between epidemiologists and clinical oncologists are underlined. PMID- 8690527 TI - Cigarette smoking and pancreas cancer: a case control study of the search programme of the IARC. AB - A multi-centre case-control study of pancreas cancer, designed to be population based, to use a random sample of local populations as controls and to use a common protocol and core questionnaire, was conducted as the first study of the SEARCH programme of the International Agency for Research on Cancer. "Ever smokers" were found to be at increased risk for pancreas cancer compared with "never-smokers" consistently in all strata of gender, response status and centre. Risk of pancreas cancer was found to increase with increasing lifetime consumption of cigarettes, the relative risk rising to 2.70 (95% C.I. 1.95 to 3.74) in the highest intake category. The overall trend in risk was highly significant and the association was found consistently in each stratum of gender, response status and centre. Fifteen years had to pass from quitting cigarette smoking until the risk fell to a level compatible with that in never-smokers among the heaviest group of smokers; among the 2 lowest tertiles this happened within 5 years. Further, reported smoking habits more than 15 years before diagnosis appeared to have no influence on pancreas-cancer risk, irrespective of amount smoked. The results are consistent with a causal role for cigarette smoking in the aetiology of pancreas cancer and illustrate that ceasing to smoke cigarettes can lead to reductions in the elevated risk of pancreas cancer produced by this habit. PMID- 8690528 TI - Tetraphenylphosphonium chloride induced MR-visible lipid accumulation in a malignant human breast cell line. AB - The effect of the cationic lipophilic phosphonium salt tetraphenylphosphonium chloride (TPP) on a human malignant breast cell line, DU4475, was monitored with proton nuclear magnetic resonance (1H MRS). TPP caused a dose- and time- dependent increase in resonances arising from MR-visible lipid as measured by the CH2/CH3 ratio in the 1-dimensional 1H MR spectrum. Two-dimensional MRS identified increases in the glycerophosphocholine/lysine cross-peak ratio and corresponding decreases in the phosphocholine/lysine ratio in a dose- dependent fashion in TPP treated cells. Lipid metabolic changes are discussed in the light of other MR experiments, and the data indicate that accumulation of MR-visible lipids may arise from the rearrangement of phospholipids accompanying mitochondrial destruction or from the catabolism of phospholipids associated with early events in the cytotoxic process. PMID- 8690529 TI - alpha(1,3)Fucosyltransferase expression in E-selectin-mediated binding of gastrointestinal tumor cells. AB - E-selectin recognizes the oncofetal antigen sialyl-Lewis X, which is highly expressed in adenocarcinoma. Five alpha(1,3)fucosyltransferases (FT) have been cloned that confer cell-surface expression of sialyl-Lewis X on transfected cells. We show here that 12/18 gastrointestinal-tumor cell lines bind specifically to immobilized E-selectin and that in sialyl-Lewis-X-positive cells binding is inhibited with a monoclonal antibody against sialyl-Lewis X. Using RT PCR, we determined the expression of the alpha(1,3)fucosyltransferases III, IV, V, VI and VII in gastrointestinal tumor cells. Transcripts of FT IV and FT VII are abundantly expressed in all tested cells. Therefore no single fucosyltransferase could be correlated with the expression of sialyl-Lewis X and the ability of the tumor cells to bind to E-selectin. The data suggest that in gastrointestinal-tumor cells sialyl-Lewis X is necessary but not sufficient for E selectin binding. PMID- 8690530 TI - Expression of Epstein-Barr virus latent infection genes and oncogenes in lymphoma cell lines derived from pyothorax-associated lymphoma. AB - Malignant lymphomas frequently develop in the pleural cavity of patients with long-standing pyothorax. The term pyothorax-associated lymphoma (PAL) has been proposed for this type of tumor. Most PALs are diffuse lymphomas of the B-cell type and contain Epstein-Barr virus (EBV) DNA. We have established 2 lymphoma cell lines from biopsy specimens of PAL cases, OPL-1 and OPL-2, and examined their growth characteristics and the expression of EBV latent infection genes and oncogenes. OPL-2 exhibited a more rapid growth and higher saturation density than OPL-1, and only OPL-2 exhibited colony-forming activity in soft agar. OPL-1 and 2 were positive for B-cell differentiation markers and showed clonal surface immunoglobulins. Both line contained a single predominant form of episomal EBV DNA, indicating clonal cellular proliferation of an EBV-infected progenitor cell. OPL-1 and -2 contained type B and A EBV genome, respectively. Expression of EBV nuclear antigen (EBNA)2 mRNA and protein was detected by Northern and Western blot analysis in OPL-1, but not in OPL-2. On the other hand, the expression of latent membrane protein (LMP)1 mRNA in both OPL-1 and -2 was extremely weak and detectable only by reverse transcription-polymerase chain reaction. Protein expression of LMP1 was not observed by Western blot analysis or immunocytochemistry. Both lines expressed c-myc mRNA. Only OPL-1 expressed mRNA of c-fgr, an oncogene whose expression is upregulated by EBNA2. Both OPLs expressed bcl-2 mRNA without detectable expression of LMP1 protein. PMID- 8690531 TI - Increase of metaiodobenzylguanidine uptake and intracellular half-life during differentiation of human neuroblastoma cells. AB - Iodine-labelled metaiodobenzylguanidine (MIBG) is a radiopharmaceutical used for diagnostic imaging and targeted radiotherapy of neuroendocrine tumors. We previously reported that the ability of a neuroblastoma (NB) cell line, LAN-5, to accumulate MIBG was powerfully stimulated by interferon-gamma (IFN-gamma), a well known NB differentiation-promoting agent. To extend the above findings, we have investigated 5 NB cell lines for their ability to accumulate 125I-MIBG in basal conditions or after various combinations of differentiative stimuli. Our results show that association of IFN-gamma and tumor necrosis factor-alpha boosts MIBG uptake in the early times of incubation in LAN-5 and GI-LI-N cells, while both SK N-SH and SK-N-BE(2)c cells are strongly stimulated by co-treatment with IFN-gamma and all-trans retinoic acid. Moreover, although only LAN-5 and GI-LI-N cells are sensitive to IFN-gamma alone, the combination of IFN-gamma and IFN-alpha causes a synergistic increase in MIBG uptake in all the NB cell lines tested. From experiments on MIBG release we conclude that no intracellular storage within specialized structures took place during differentiation. The observed enhancement in MIBG accumulation results from an increased uptake of the drug only. This conclusion was confirmed by analyzing MIBG-transporter gene expression, which was increased in cells subjected differentiative regimens. According to these findings, inducing differentiation of NB cells in vitro appears to improve their MIBG incorporation ability powerfully. PMID- 8690532 TI - A national survey of hypnosis training--its status in psychiatric residency programs: a brief communication. AB - Hypnosis training in psychiatric residency programs has not previously been well documented in the literature. This article examines the extent of such training in residency programs and the attitudes of residency directors to training and the use of hypnosis. A brief survey requesting information on hypnosis training was sent to all psychiatric residency directors in the United States. Sixty-three percent of responding program directors (n = 154) report offering either required or elective coursework in hypnosis. Of programs offering hypnosis training, the mean number of hours was 8, suggesting that many psychiatrists have only limited exposure to hypnosis during residency. The authors conclude that hypnosis training is widely variable within psychiatric residency programs and is dependent on the faculty and training director interests within individual programs. PMID- 8690533 TI - Psychological and hypnotic preparation for anesthesia and surgery: an individual differences perspective. AB - Multiple reviews indicate that psychological preparation for surgery can provide psychological, physiological, and economic benefit to the patient. Research demonstrating that hypnosis adds to this benefit is both limited and encouraging. The content and status of this literature, however, are confusing, with little coherent theoretical basis to account for the contradictions and inconsistencies across multiple studies whose methodologies often limit generalization. A model is presented regarding pertinent individual differences that include patient coping styles, prior medical experiences, and hypnotic ability, as well as differences in types of coping demanded by different surgical procedures. This model (a) helps explain some of the confusion, (b) offers a theoretical focus for patient assessment as well as development and selection of preparation strategies, and (c) clarifies future research goals. PMID- 8690534 TI - Hypnosis for pain and neuromuscular rehabilitation with multiple sclerosis: case summary, literature review, and analysis of outcomes. AB - Videotaped treatment sessions in conjunction with 1-month, 1-year, and 8-year follow-up allow a unique level of analysis in a case study of hypnotic treatment for pain and neuromuscular rehabilitation with multiple sclerosis (MS). Preparatory psychotherapy was necessary to reduce the patient's massive denial before she could actively participate in hypnosis. Subsequent hypnotic imagery and posthypnotic suggestion were accompanied by significantly improved control of pain, sitting balance, and diplopia (double vision), and a return to ambulatory capacity within 2 weeks of beginning treatment with hypnosis. Evidence regarding efficacy of hypnotic strategies included (a) direct temporal correlations between varying levels of pain relief and ambulatory capacity and the use versus nonuse of hypnotic strategies, (b) the absence of pharmacological explanations, and (c) the ongoing presence of other MS-related symptoms that remained unaltered. In conjunction with existing literature on hypnosis and neuromuscular conditions, results of this case study strongly suggest the need for more detailed and more physiologically based studies of the phenomena involved. PMID- 8690535 TI - Trait factors, state effects, and hypnotizability. AB - This study examined the relationship of 15 trait (e.g., absorption, ego permissiveness) and 21 phenomenological variables (assessed by the Phenomenology of Consciousness Inventory) with performance on the Harvard Group Scale of Hypnotic Susceptibility, Form A. Factor analyses suggested three trait factors (absorption-permissiveness, general sensation seeking, and social desirability) and five state factors (dissociated control state, positive affect, negative affect, attention to internal processes, and visual imagery). The factors correlated to hypnotizability were absorption-permissiveness, dissociated control, positive affect, and attention to internal processes. In predicting hypnotizability, the amount of variance accounted for by the trait factors was approximately 9%; an additional 22% was accounted for by state factors. The interactions did not account for any additional variance in predicting hypnotizability. PMID- 8690536 TI - A multivariate approach to the prediction of hypnotic susceptibility. AB - The present study examined the relation between various self-report measures and two measures of hypnotizability within a multivariate framework. A group of 748 participants was tested on the Harvard Group Scale of Hypnotic Susceptibility, Form A (HGSHS:A), the Tellegen Absorption Scale (TAS), as well as the Preference for an Imagic Cognitive Style (PICS) questionnaire. One hundred ninety of these participants also completed the Paranormal Experiences Questionnaire (PEQ). Data were analyzed using hierarchical multiple regression equations, and the results of the analyses indicated that both the TAS and PICS accounted for significant amounts of unique variance in each of two 373-member samples of HGSHS:A scores. A further sub-sample of participants (n = 161) was tested on the Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C) to see if these results would generalize to another measure of hypnotizability. Hierarchical multiple regression analyses revealed that although the PEQ predicted significant amounts of unique SHSS:C variance over and above that predicted by the TAS, the PICS failed to do so. This inconsistency in results may be due in part to the generally low intercorrelation between the different hypnotizability scales and points to the need to develop new predictor variables that are orthogonal to each other. PMID- 8690537 TI - Characterization of the clinical and anatomical pathological changes associated with Hepatozoon mocassini infections in unnatural reptilian hosts. AB - Laboratory-reared Aedes aegypti mosquitoes were employed in the successful transmission of Hepatozoon mocassini from a cotton-mouth moccasin (Agkistrodon piscivorus leucostoma) to 3 lizard species (Sceloporus undulatus, Eumeces obsoletus and Sceloporus poinsetti). Marked to severe lethargy and anorexia developed in the S. undulatus, E. obsoletus and S. poinsetti at 15, 38, and 96 days postinfection (PI), respectively. All 3 lizards developed a leukocytosis and had increased plasma aspartate aminotransferase activity (AST) by 14 days PI. Multifocal random hepatocellular necrosis and intrahepatic aggregates of heterophils centered on mature H. mocassini meronts were demonstrated in all 3 lizards. The pulmonary interstitium was multifocally thickened by aggregates of heterophils centered on meronts. No comparable clinical or anatomical pathological changes were demonstrated in naturally infected snakes. The results of this study suggest that H. mocassini is capable of inducing necrotizing inflammatory by lesions in unnatural reptilian hosts. PMID- 8690538 TI - The Enterobiinae subfam. Nov. (Nematoda, Oxyurida) pinworm parasites of primates and rodents. AB - Recent redescriptions of most members of the Oxyuridae Cobbold, 1864 parasitic in primates revealed that they share following derived characters: sexual dimorphism of lateral alae (single-crested in the males, double-crested in the females); in males a second pair of genital papillae always surrounded by strongly cuticularized rings; in females, uterine tube divided into 2 parts by a cellular wall forming a diaphragm. These characters are interpreted as synapomorphies, providing evidence that these taxa represent a monophyletic group, and we propose to classify them in a new subfamily of the Oxyuridae: the Enterobiinae subfam.nov. The Enterobiinae as recognized herein occurs in both Old World and New World Primates and rodents of the family Sciuridae (tribe Sciurini in the Holarctic region and tribe Xerini in the Ethiopian region). The new subfamily includes the following genera: Enterobius Leach, 1853; Colobenterobius Quentin, Betterton & Krishnasamy, 1979; Rodentoxyuris Quentin & Tenora 1974; Xeroxyuris Hugot, 1995; Lemuricola Chabaud & Petter, 1959; Protenterobius Inglis, 1961; Madoxyuris Chabaud, Brygoo & Petter, 1965; Trypanoxyuris Vevers, 1923; Hapaloxyuris Inglis & Cosgrove, 1965 and Paraoxyuronema Artigas, 1936. The genus Paraoxyuronema is revalidated as a subgenus of Trypanoxyuris due to its specialized buccal structures. This genus groups all pinworm nematodes specific for primates of the family Atelidae, including: P. brachytelesi Artigas, 1937 occurring in Brachyteles arachnoides; P. atelis (Cameron, 1929) occurring in Ateles spp., and P. duplicidens (Buckley, 1931) and P. lagothricis (Buckley, 1931), which are parasites of Lagothrix spp. Inglisoxyuris inglisi Chabaud, Petter & Golvan, 1961, included in the monospecific genus Inglisoxyuris and previously classified as a subgenus of the Lemuricola, does not share the characters of the new subfamily and, until its precise classification can be considered with more information, it is proposed to refer to this species as an Oxyuridae sensu lato. A diagnosis and a key of the genera included in the new subfamily are given. PMID- 8690539 TI - Cholinergic and aminergic nervous systems in developing cercariae and metacercariae of Diplostomum pseudospathaceum Niewiadomska, 1984 (Digenea). AB - Comparative studies on the cholinergic (ChNS) and aminergic (ANS) nervous systems were carried out in developing cercariae and metacercariae of Diplostomum pseudospathaceum. A method for the localization of cholinesterase and nonspecific esterase activities, and the method for the histofluorescence of biogenic amines were used. The first traces of the ChNS were found in the cercarial embryo, and during growth of the cercaria, the brain ganglia and commissure, as well as anterior and posterior nerve trunks joined by commissures, were progressively developed. The fully developed ChNS was observed in the emerged cercaria. Further development in metacercariae leads to an orthogon-like structure. Histofluorescence of catecholamines appeared in the brain ganglia and the proximal part of the ventral trunks only in young cercaria (having furcae, tail stem and body of the same size). The emerged cercaria had an ANS different from the ChNS (in part of the nervous system there was no fluorescence). The differences disappeared during the development of the metacercaria. The evolutionary and functional interpretation of the various developmental rates of the ChNS and ANS were discussed. PMID- 8690540 TI - Toxoplasma gondii: the role of parasite surface and secreted proteins in host cell invasion. AB - The potential role of the 5 surface proteins of Toxoplasma gondii tachyzoites in host cell invasion was investigated using an in vitro neutralization assay. Supporting earlier findings, TG05.54, a monoclonal antibody recognizing the major surface protein SAG 1, was shown to cause a consistent and significant blockade of invasion into bovine kidney cells, indicating a functional role for this protein in host cell invasion. The neutralizing effect was only seen with certain anti-SAG 1 monoclonal antibodies, suggesting the presence of a functional ligand within the molecule. A second surface protein, SAG 2 was also shown to be involved in the invasion process. Anti-SAG 2 antibodies prevented parasite reorientation, leaving zoites immobilized on the host cell membrane and resulting in increased internalization of tachyzoites. Antibodies recognizing other surface, rhoptry, dense granule and microneme molecules had no effect on invasion. PMID- 8690541 TI - Viability of Theileria parva trivalent stabilate after thawing and maintenance at 4 degrees C for up to 15 hours. AB - Two experiments were conducted to determine the effect of prolonged maintenance at 4 degrees C on thawed Theileria parva stabilates. Samples maintained at 4 degrees C for 1, 12, 15 and 18 h were all infective for cattle. Immunized cattle were able to resist potentially lethal challenges 29 days later. These results indicate that the handling of T. parva trivalent stabilates for immunization against East-Coast fever in the field should be much easier than previously envisaged. PMID- 8690542 TI - Patterns in the evenness of gastrointestinal helminth communities. AB - Within a parasite community, the relative abundance of each parasite species, or species evenness, is a key component of the structure of that community. However, little is known about which, if any, ecological factors determine the evenness of the parasite community in a given host. Here, the associations between selected ecological variables and the evenness of gastrointestinal helminth communities were evaluated across species of vertebrate hosts. Using host species as statistically independent observations, evenness correlated negatively with parasite abundance in fish hosts, and positively with community richness in bird hosts. After controlling for host-phylogenetic effects, the correlation between evenness and parasite abundance in fish hosts was still present. In addition, a link between parasite community evenness and host body size became apparent among fish hosts, and evenness correlated positively with richness in mammal hosts. These trends lack solid explanations, and point to new directions in the study of parasite community ecology. PMID- 8690543 TI - Studies on caprine responsiveness to nematodiasis: segregation of male goats into responders and non-responders. AB - Eighty-three 2-4-year-old intact male goats exposed to a combination of artificial and natural challenge were segregated into responders and non responders by ranking of weekly faecal egg counts (FECs). Retrospective analysis of samples over a 15-week-period showed responders had a statistically lower mean FEC than non-responders. Estimates of repeatability between consecutive egg counts were significant in both groups. The 6 top responders and bottom non responders were subsequently given an artificial trickle challenge with Teladorsagia circumcincta and Trichostrongylus vitrinus. Mean faecal egg output was significantly lower in responders than non-responders. Peripheral eosinophil numbers following challenge were significantly greater in responder than non responder goats. Abomasal and intestinal worm burdens were considerably lower in responders, with evidence of retardation of worm development compared to non responders. Both abomasal and jejunal tissue eosinophil numbers were significantly higher in responders, although there was no difference in mucosal mast cell or globule leucocyte numbers. These results suggest that under temperate climatic conditions, it is possible to segregate male goats into responders and non-responders on the basis of simple parasitological criteria. PMID- 8690544 TI - Identification and cDNA cloning of two novel low molecular weight host-protective antigens from Taenia ovis oncospheres. AB - Oncosphere antigens of Taenia ovis were solubilised in sodium dodecyl sulphate and separated by electrophoresis in polyacrylamide gels (SDS-PAGE). Antigen containing gel fractions cut from the region covering 18-12 kDa were shown to be highly immunogenic in sheep challenge experiments. Specific antisera against 2 candidate antigens at 18 and 16 kDa were used to screen a cDNA library prepared from T. ovis oncosphere mRNA. Recombinant proteins selected with antibody to the 16 and 18 kDa native antigens were expressed as GST fusion proteins. Vaccination trials using either of the 2 fusion proteins To16.17-GST and To18-GST, revealed that each was capable of inducing high levels of immunity in sheep against challenge infection with T. ovis eggs. Antibodies induced by vaccination with the recombinant antigens reacted specifically with their respective 18 or 16 kDa native oncosphere antigens. There was no apparent homology between the T. ovis cDNA coding for To18 and To16.17, or with another host-protective antigen, To45W, described previously. These additional host-protective antigens should prove a valuable adjunct to To45W and permit the development of effective vaccination strategies. PMID- 8690545 TI - Secretion of anti-parasite substances and leukotrienes from ovine gastrointestinal tissues and isolated mucosal mast cells. AB - The presence of larval migration inhibitory (LMI) compounds in the gastrointestinal mucus of nematode resistant sheep has been shown previously to be associated with increased numbers of gastrointestinal mucus of nematode resistant sheep has been shown previously to be associated with increased numbers of gastrointestinal mucosal mast cells (MMC) and globule leukocytes (GL). This experiment was designed to determine if LMI compounds were secreted by MMC/GL in response to nematode antigenic challenge and if so, could secretion account for levels observed in mucus. Romney sheep were immunized by repeated cycles of infection with Trichostrongylus colubriformis or Haemonchus contortus larvae and anthelmintic treatment. After slaughter, gastrointestinal tissue was taken for examination of histology and mucus anti-parasite activity. Segments of small intestine were ligatured to form sacs which were incubated with exsheathed nematode larvae or larval excretory/secretory antigens. Tissue slices from small intestine or abomasum were also incubated with nematode larvae or antigens. After homologous challenge, levels of leukotrienes secreted into small intestinal tissue sacs were significantly higher than levels in heterologously challenged sacs or unimmunized sheep intestinal sacs challenged with larvae of any nematode species (279.4 +/- 33.7, 141.0 +/- 27.8 and 39.5 +/- 15.2 ng h-1 respectively). Tissue slices gave a similar pattern of leukotriene secretion. LMI activity was also significantly elevated in intestinal sacs from immunized sheep challenged homologously with nematode larvae or antigen (64 +/- 10 and 68 +/- 14% respectively cf. heterologous challenge 32 +/- 10% and unimmunized sheep sacs 15 +/- 6%). Histological examination of abomasal and small intestinal sections showed that immunized sheep had significantly greater numbers of MMC/GL than unimmunized sheep. MMC/GL isolated and purified from immunized sheep secreted leukotrienes and compounds having LMI activity when cultured with homologous nematode larvae or antigens. Secretion of leukotrienes and molecules having LMI activity from MMC/GL could account for the levels of these substances observed in small intestine mucus. PMID- 8690546 TI - Lice and cospeciation: a response to Barker. AB - "The student who intends working on the Mallophaga should take warning that he will be tried almost beyond endurance by the paradoxes and complexities which beset his subject but he will also find, in the dual and inter-related aspect of insect and bird, an infinite fascination." (Rothschild & Clay, 1952: pp. 156 157). The study of host louse coevolution will benefit greatly from the phylogenetic perspective offered by recent advantages in molecular systematics. However, in order to make best use of phylogenies we need to appreciate the complexities of the possible relations between host and parasite phylogeny. At the same time, the very complexity of louse-host systems has a potentially useful consequence; the presence of multiple lineages of lice on the same hosts allow for replicated tests of coevolutionary hypotheses. For example, if a number of louse clades infest the same host clade but some lice show more cospeciation than others, we might ask whether there are features of louse biology that correlate with this difference in host tracking fidelity. It may further be possible to ascertain the relative importance of these features in ecological time through controlled transfer experiments. By beginning to appreciate "the paradoxes and complexities" of host-louse evolution, lice may offer us not only "infinite fascination" but also a chance to address important questions in coevolution. PMID- 8690547 TI - Lice, cospeciation and parasitism. PMID- 8690548 TI - More "misconceptions" about the measurement of aggregation. PMID- 8690549 TI - Measuring parasite aggregation: defending the index of discrepancy. PMID- 8690550 TI - The tension between cost containment and the underutilization of effective health services. AB - One of the common ingredients in all attempts to slow escalating health care costs is to control the utilization of services that provide little or uncertain benefit. To reform existing delivery systems, the organization, provision, and financing of health care need to be evaluated critically. Successful reform requires that more rational methods be used to determine which services to provide. The preferences of physicians, patients, and payers of care do not appear optimal from a societal perspective in choosing health care services. While reducing the use of interventions of little or unknown benefit should save money, a policy to restrict the use of medical services may lead to an unwanted result: the underutilization of interventions of proven clinical benefit. Through the determination of the value--by rigorous assessment of both costs and benefits of available alternatives--in a context sensitive to the unique cultural, political, and economic characteristics of individual nations, the health of the population should be improved and growth of health expenditures constrained. This is the first step in health care reform. PMID- 8690551 TI - A cost-utility analysis of laser-assisted angioplasty for peripheral arterial occlusions. AB - Despite the perception of many people that lasers represent the cutting edge of high-technology medicine, this form of medical technology has been subject to relatively little rigorous evaluation. This dearth of research relates particularly to economic evaluation, where there have been few attempts to justify the high cost of laser equipment. This paper details an economic evaluation of the use of laser technology as a secondary adjunct to angioplasty to treat peripheral arterial occlusions. Using data from a range of sources, including a published randomized trial, a cost-utility model is developed to estimate the costs and benefits of the laser, relative to standard angioplasty. The best available data indicate a cost-effective role for the laser, but important areas of uncertainty exist, including the laser's secondary recanalization rate, which has been estimated on the basis of limited numbers of patients. This uncertainty suggests that further research is required before widespread diffusion of the laser for use in this clinical context. PMID- 8690552 TI - Assessing health benefit from hospitalization. Agreement between expert panels. AB - Agreement between two expert panels in assessing gain in life expectancy and quality of life from unselected stays in a department of internal medicine was investigated. Weighted kappa statistics of 0.45 for gain in life expectancy and 0.63 for gain in quality of life were found. PMID- 8690553 TI - Assessment of waiting time and priority setting by means of a national register. AB - To increase access to care for cataract patients in Sweden, it was decided, starting in 1992, that all cataract patients listed for surgery and with priority should have their cataract extraction performed within three months. To evaluate the effect of this waiting time guarantee, a National Cataract Register (NCR) was initiated in late 1991. In 1992, 81% of all cataract extractions performed in Sweden were reported to the NCR; in 1993 this figure was 92%. Reasons for this high participation ratio are discussed. In 1993, 74.4% (range between different clinics, 40-99%) of the patients with priority had their operation performed within three months. Great variation in visual acuity and age was found in patients with priority among the different surgical units. PMID- 8690554 TI - A risk assessment and control model for the failing Bjork-Shiley convexo-concave heart valve. AB - For risk assessment and control of the failing Bjork-Shiley convexo-concave heart valve, we present a life cycle-based complex system model and a risk intensity assessment model, allowing consistent analysis of this complex medical problem and identification of all pertinent aspects of product-related risks to patients. PMID- 8690555 TI - Cost-effectiveness of breast cancer screening in Spain. AB - In the last several years, the development of an effective breast cancer screening procedure has increased the possibility of the early detection of this cancer. We investigated the cost-effectiveness of a breast cancer screening program to screen 100,000 women 50-64 years of age in Catalonia (Spain). The cost effectiveness ratio was measured in terms of the cost per cancer detected comparing program costs to the estimated number of cancers detected. We assumed a participation rate, sensitivity, and specificity of 70%, 92%, and 94%, respectively, and that 0.36 breast cancers could be detected per 100 women screened. We estimated a total cost of $2.1 million with $1.4 million for the mammographic stage and $0.7 million for the detection of the true positive mammographic results. The cost per woman screened was $30. We estimated that 252 cases of breast cancer could be detected with the program. The cost-effectiveness ratio obtained in this study was $8,424 per cancer detected. Sensitivity analysis has shown that cost-effectiveness results are sensitive to the variations in the following variables: specificity, cancer detection rate, and screening costs. In planning preventive programs, breast cancer screening should be considered one of the priorities. PMID- 8690556 TI - The measurement of utility in multiphase health states. AB - To examine the validity of the additive quality-adjusted life year model used to evaluate a multiphase health state, data from a pilot study of mammography were used to determine whether the values assigned to a multiphase postmastectomy health state could be estimated from a combination of the independently rated constituent health state values. The results suggest that they cannot. PMID- 8690557 TI - Making choices in hospital resources allocation. The use of an assessment tool to decide which new projects are financed. AB - We designed a scoring system to rank acute care hospital projects and allocate resources between them. The evaluation tool assessed projects on an ordinal scale; the criteria scored were medical interest, feasibility, interest for teaching and research, and compatibility with the hospital's strategy. Clinical and technical projects were ranked separately. In 1994, 25 new projects, representing a total cost of $1.4 million, were reviewed by two independent reviewers. The scores ranged from 30 to 18 over 36. Projects presented by clinical departments scored higher than projects presented by medicotechnical departments. PMID- 8690558 TI - The clinical effectiveness and financial impact of utilizing peripheral blood progenitor cells as rescue therapy following autologous bone marrow transplant. AB - The use of peripheral blood progenitor cell transplant as rescue therapy after high-dose chemotherapy and autologous bone marrow transplant significantly decreases transfusion, laboratory, room, and total charges. An improvement in clinical indicators also points toward decreased patient morbidity. Additional cost reductions may be realized by greater utilization of outpatient care, thereby further reducing room and total charges. PMID- 8690559 TI - Pharmacoeconomic studies. Pitfalls and problems. AB - The literature on economic evaluation of pharmaceuticals is growing rapidly. Although there have been substantial methodologic advances, there remain serious problems and pitfalls. This presentation focuses on three aspects, i.e., use (and abuse) of evaluation studies, methodologic problems, and the quality of published studies. PMID- 8690560 TI - Health status index models for use in resource allocation decisions. A critical review in the light of observed preferences for social choice. AB - In the last two decades a number of health status index models have been developed for assessing the value of health outcomes in terms of quality-adjusted life years. The models can be tested by comparing their implications with direct observations of how societies think resources should be distributed across patient groups. This paper reviews empirical evidence of this kind from various countries and summarizes the evidence in three rules of thumb for selecting values for health states. Nine different models are judged relative to these rules of thumb. Eight of the models underestimate the strength of social preferences for treating the severely ill before the less severely ill. The ninth has a strong bias against states associated with emotional distress. As a consequence, none of the models can be seen as sufficient stand-alone instruments for valuing health outcomes. Instead, the models may be seen as complementary and adjustable parts of a tool kit that should also include the rules of thumb suggested in this paper. PMID- 8690561 TI - The internationalization of health technology assessment. AB - Health technology assessment as a formalized set of activities has a relatively short history. At its current stage of development, it is clear that it has global dimensions and impact. In this paper we review the history of health technology assessment, its development as a form of health services research, and its "institutionalization." We then identify the reasons for its internationalization, review current international initiatives, and propose actions to be taken to improve cooperation among countries. PMID- 8690563 TI - Models for determining cost of care and length of stay in neonatal intensive care units. AB - New models for determining the cost of care and length of stay in the neonatal intensive care unit (NICU) were developed using financial and clinical data from 588 admissions to our NICU. The model for determining costs explained 71% of the variability in total hospital costs. Models such as the ones developed in this study can be used to compare costs in different institutions, determine temporal trends in costs, and examine the financial impact of using new technologies. Such models can also be useful components of a rational prospective pricing system for the NICU. PMID- 8690562 TI - A multinational economic evaluation of rhDNase in the treatment of cystic fibrosis. AB - Economic evaluations of pharmaceuticals are increasingly being conducted in conjunction with randomized phase III clinical trials to meet the demand for pharmacoeconomic data when new products are launched. While the need for such data is often global, the trials in which relevant information may be collected are often conducted in only one or a limited number of countries. A critical issue is how data from pivotal clinical trials in one setting can serve as the basis for pharmacoeconomic evaluations in others. We address this issue and report on four economic evaluations that we undertook in conjunction with a recent U.S. phase III clinical trial of recombinant human deoxyribonuclease (rhDNase), which is used to improve pulmonary function in patients with cystic fibrosis (CF). The objective of these evaluations was to estimate the potential impact of rhDNase therapy in France, Germany, Italy, and the United Kingdom on the direct costs of medical care for the treatment of respiratory tract infections (RTIs) in patients with CF. Analyses of economic impact were undertaken both with and without adjustment for differences in practice patterns between the United States and the countries of interest. Our findings suggest that rhDNase therapy may reduce the cost of RTI-related care by between US$600 and US$1,100 over a 24-week period; the cost of rhDNase is not included in these figures, as a price was unavailable when our analyses were undertaken. Despite methodologic challenges, economic evaluations that meet the information needs of decision makers in diverse countries can nonetheless be undertaken in conjunction with phase III clinical trials. PMID- 8690564 TI - Predicting nursing home length of stay and outcome with a resource-based classification system. AB - The anticipated demographic changes with an increasing number of elderly force us to plan and use health care resources more efficiently. In this study we have used the components of a case-mix measure for nursing homes; the Resource Utilization Groups (RUG-II), to predict length of stay (LOS) and outcome in geriatric institutions. We have shown that the RUG categories and an activities of daily living (ADL) index differ significantly in both respects, but that other variables might be of more clinical value when establishing a prospective payment system, based on LOS in geriatric institutions. PMID- 8690565 TI - A cost-effectiveness analysis of neonatal ECMO using existing evidence. AB - A cost-effectiveness analysis is part of the U.K. ECMO Trial. In preparation for this analysis, existing evidence on the costs and effectiveness of neonatal ECMO was evaluated. ECMO appears to be more costly but may be more or less effective than conventional treatment. No case can be made for introducing ECMO before trial results are available. PMID- 8690566 TI - The role of perspective in defining economic measures for the evaluation of medical technology. AB - Perspectives in an economic analysis of medical technology reflect who makes decisions about the use of or payment for medical resources. Commonly used perspectives include those of providers, insurers, the individual, and society. Perspective is a critical determinant of study design, affecting the time horizon, types of resources considered, and economic cost measures assigned to those resources. Individuals involved in technology assessment for either research or policy-making purposes should be aware of the complexities of defining costs from different perspectives. PMID- 8690567 TI - Technology and staffing in Japanese university hospitals. Government versus private. AB - We examined staffing levels, acquisition of medical technologies, and utilization of those technologies in private and government teaching hospitals in Japan. Adjusting for size and case mix, we found that government hospitals acquire more technology, use that technology less, and employ a more highly skilled staff than do private hospitals. PMID- 8690568 TI - First case report of spontaneous pulmonary hemorrhage following heparin therapy in acute myocardial infarction. AB - Since its discovery in 1916, heparin has been used extensively for treatment of thromboembolic disorders. Bleeding is its most well-known and frequent complication. We are describing the first case report of overt pulmonary hemorrhage in a patient who received heparin after emergent angioplasty for prevention of coronary artery rethrombosis. PMID- 8690569 TI - The pregnant worker: how much is too much? Assessing safe activity levels. AB - Physicians should be able to advise pregnant women about safe amounts of physical activity in the workplace. A computerized literature search was used to review reproductive risks of physical activity, proper clinical evaluation and recommendations of the pregnant worker regarding physical activity, and current State of Hawaii disability legislation pertinent to pregnant workers. This article highlights the importance of making accurate clinical assessments regarding the continuation of work for the healthy pregnant worker and also provides physicians with an approach to assessing physical exposure risks of pregnant workers. PMID- 8690572 TI - Wilhelm Conrad Roentgen: The American Association of Physicists in Medicine 1995 Radiology Centennial Hartman Oration. PMID- 8690571 TI - Pathway to a paradigm: the linear nonthreshold dose-response model in historical context. The American Academy of Health Physics 1995 Radiology Centennial Hartman Oration. AB - This paper traces the evolution of the linear nonthreshold dose-response model and its acceptance as a paradigm in radiation protection practice and risk analysis. Deterministic effects such as skin burns and even deep tissue trauma were associated with excessive exposure to x rays shortly after their discovery, and carcinogenicity was observed as early as 1902. Still, it was not until 1925 that the first protective limits were suggested. For three decades these limits were based on the concept of a tolerance dose which, if not exceeded, would result in no demonstrable harm to the individual and implicitly assumed a threshold dose below which radiation effects would be absent. After World War II, largely because of genetic concerns related to atmospheric weapons testing, radiation protection dose limits were expressed in terms of a risk based maximum permissible dose which clearly implied no threshold. The 1927 discovery by Muller of x-ray induced genetic mutations in fruit flies, linear with dose and with no apparent threshold, was an important underpinning of the standards. The linear nonthreshold dose-response model was originally used to provide an upper limit estimate of the risk, with zero being the lower limit, of low level irradiation since the dose-response curve could not be determined at low dose levels. Evidence to the contrary such as hormesis and the classic studies of the radium dial painters notwithstanding, the linear nonthreshold model gained greater acceptance and in the centennial year of the discovery of x rays stands as a paradigm although serious questions are beginning to be raised regarding its general applicability. The work includes a brief digression describing the work of x-ray protection pioneer William Rollins and concludes with a recommendation for application of a de minimis dose level in radiation protection. PMID- 8690570 TI - Radioactivity: conception to birth. The Health Physics Society 1995 Radiology Centennial Hartman Oration. AB - Rontgen's description of his discovery of x rays was convincing and comprehensive. The response of the scientific community and public was immediate and intense. In contrast, the discovery of radioactivity was a muddled affair that excited little interest. While it would prove far more revolutionary than that of x rays, the discovery of radioactivity began, in the words of Alfred Romer, as something of a dead horse. There it lay, too big to ignore, but what did you do with it? Even the discoverer, Henri Becquerel, left it to decay and went on to pursue other interests. For various reasons, others chose to investigate: Marie and Pierre Curie in France, William Crookes in England, and Ernest Rutherford in Canada. But it was Frederick Soddy, a young chemist with a fascination for alchemy, who, together with Rutherford, revealed the true nature of radioactivity: transmutation. PMID- 8690573 TI - 32P and beta emitting radionuclides in microbiology and cell biology. AB - Microbiology and cell biology researchers make extensive use of beta emitting nuclides. Because of the short half-lives or difficulty of direct measurement some researchers do not view radionuclide use with proper care and respect. Radionuclide use in microbiology and cell biology research is unique. Review of the isotopes and processes may be useful to the health physicist and research alike. PMID- 8690574 TI - Comparison of dose histories for U.S. nuclear power plant workers, based on records held by a major dosimetry service company and on the NRC REIRS database. AB - In order to conduct valid epidemiological studies of nuclear power plant workers, good information on the workers' radiation dose histories is essential. Dose records held by a major dosimetry service company and on the Nuclear Regulatory Commission's Radiation Exposure Information and Recording System have been compared for a sample of 99 workers. About half of the workers in the sample had no records on the Radiation Exposure Information and Recording System, since they had not terminated employment at a Nuclear Regulatory Commission-licensed facility; accordingly, their career doses (as recorded by the service company) were generally higher than those for workers on the Radiation Exposure Information and Recording System. For nearly half of the workers with records on both databases, the total dose recorded for terminated employments at nuclear power plants differed by at least a factor of 5 between the databases. In absolute terms, these differences were of the order of 100 mSv or more. An approach that utilized both the Radiation Exposure Information and Recording System and the dosimetry service company's records might be of value in constructing dose histories for a large epidemiological study. However, the comparisons presented here support the initiatives of the Nuclear Regulatory Commission to request licensees to report voluntarily career doses for current employees. These data are essential if a large and valid epidemiological study of nuclear plant workers is to be conducted in the foreseeable future. PMID- 8690575 TI - Comparison of direct alpha spectrometry and neutron activation analysis of aerosol filters for determination of workplace thorium air concentrations. AB - Direct alpha spectrometry with three different filter types was investigated for the determination of thorium air concentrations at workplaces in the manufacturing process of discharge lamps containing thoriated tungsten electrodes. The method was compared with neutron activation analysis over an activity range of five orders of magnitude. Within the experimental limits of error, both methods were found to be comparable with respect to sensitivity and accuracy. The advantage of direct alpha spectrometry, however, is that it is less laborious than neutron activation analysis and that it supplies information on the degree of radioactive equilibrium of the thorium series, which is important with regard to the estimation of dose. PMID- 8690576 TI - Simplified organ retention functions for physiologically based recycling biokinetic models. AB - Recent ICRP Publications on biokinetic models show a movement from simple schematic models to more complex, physiologically-based models. Such models require considerably greater computing resources to implement than their predecessors, effectively making them inaccessible to many users. Fortunately, retention in most of the compartments of these large recycling models can be adequately approximated by the sum of a few exponential functions compatible with the simple catenary models used almost exclusively in ICRP Publication 30. An eigenvalue method is used to solve the plutonium model of ICRP Publication 67 for intakes by inhalation, ingestion, and injection. The organ retention expressions so obtained are reduced by least squares minimization to functions consisting of the sum of a few exponential terms only. These simplified functions give committed doses accurate to within 5% and activities to within 10%. A similar treatment is used to obtain simplified expressions for daily excretion rates of plutonium. PMID- 8690577 TI - Countermeasures for radiocesium in animal products in Norway after the Chernobyl accident--techniques, effectiveness, and costs. AB - Nine years after the reactor accident in Chernobyl contamination by radiocesium is still a significant problem in sheep and reindeer production in Norway. To reduce the impact of the accident, effective countermeasures had to be developed and implemented. The levels of radiocesium in meat were reduced by a combination of countermeasures such as special feeding, use of cesium binders (bentonite and Prussian blue), and changing of slaughtering time. The countermeasures were labor intensive and expensive. Costs per averted dose per person-Sv were calculated to range from NOK 1,000 to 100,000 (7 NOK = $1 U.S.), with the use of cesium binders being the least expensive and condemnation of meat the most costly. Dietary advice, which did not include any compensation costs, had a cost of NOK 40 per person-Sv. Apart from the rejection of meat in 1986, countermeasures were deemed to be justified on a cost-benefit basis (less than NOK 600,000 per person-Sv). PMID- 8690578 TI - A new beaded carbon molecular sieve sorbent for 222Rn monitoring. AB - A new commercially available beaded carbon molecular sieve sorbent, Carboxen-564 (20/45 mesh), was tested and compared to Calgon-PCB (40/80) activated carbon for its adsorptive and desorptive characteristics under controlled conditions of temperature (25 degrees C) and relative humidity (RH). The amount of water vapor adsorbed by the beaded carbon molecular sieve material was typically a factor of 4 lower than the activated carbon, with a concomitant fourfold increase in the 222Rn adsorption coefficient, K(Rn). The maximum K(Rn) value for a thin layer of Carboxen-564, following a 2-d exposure at 40% RH, was 7.2 Bq kg(-1) per Bq m(-3). The K(Rn) or a 1-cm bed, following a 2-d exposure was 5.5 Bq m(-3), a 25% reduction. Under dynamic sampling conditions, where 0.4 g of the beaded carbon molecular sieve was contained in a 6 cm x 0.4 cm diameter tube, the maximum K(Rn) value was 6.5 Bq m(-3) after 2.5 h of sampling at 29% RH when the input flow rate was 4.2 x 10(-3) m3 h-1. Kinetic studies were also conducted under passive sampling conditions. The data show that the 222Rn buildup time-constant for a thin layer of the beaded carbon molecular sieve material was 1.3 h, whereas that of a 1 cm bed was 13 h. The 222Rn desorption time-constants, from gram amounts of the beaded carbon molecular sieve material into air and into a commercially available toluene based liquid scintillation cocktail, were 2 h and 3 h, respectively. Carboxen's high 222Rn adsorbing capacity, rapid kinetics, hydrophobicity and physical properties makes it an attractive alternative to other commercially available activated carbon used in passive and dynamic sampling devices. PMID- 8690579 TI - Microdosimetric approach to the problem of lung cancer induced by radon progeny. AB - The increased risk of lung cancer arising from chronic exposure to radon progeny in Czech uranium mines was analyzed on the basis of specific energy distributions for basal and secretory cell nuclei. The distributions were calculated from published results of lung microdosimetry. Whereas classical concepts consider that cell nuclei are hit one or more times by alpha particle tracks, the microdosimetry is able to distinguish glancing (non-lethal, possibly carcinogenic) hits from alpha particle traversals near to nucleus center (which probably inactivate the cell). The simple microdosimetric model differentiates both cases by the quantity termed boundary specific energy. The importance of some confounding factors is examined. Particularly the continuous replacement of bronchial epithelium cells by the new ones is worth considering. Still, the lung cancer frequency seems to be related to the number of sensitive cells with glancing hits. This might be a relevant argument to the toxicity of radon progeny. The central idea of the model, the boundary specific energy, was tested on the basis of radiobiological experiments with isolated cell lines. PMID- 8690580 TI - Indoor 222Rn concentrations in Central Asturias. AB - A survey of the 222Rn concentrations in 106 homes in the four main towns of the Central Asturias region was carried out over three years. A total of 1,014 measurements was obtained using passive radon charcoal canisters. The 222Rn concentrations fit a log-normal distribution law, with a geometric mean of 23 Bq m(-3). There is a marked difference between the 222Rn concentration for the ground inhabited floors and first floors. For the other floors, the 222Rn concentrations remain practically constant. The 222Rn concentrations are lower in summer than in winter time. The annual equivalent dose for the general public due to the inhalation of 222Rn is equal to 0.81 mSv (81 mrem). PMID- 8690581 TI - Particle deposition in human and canine tracheobronchial casts: a determinant of radon dose to the critical cells of the respiratory tract. AB - The radiation dose to the sensitive cells of the bronchial epithelium from inhaled short-lived radon progeny depends critically on the efficiency with which the particles are deposited on the airway surfaces. Measurements of deposition for particles 50, 100, 180, and 400 nm in diameter have been carried out along three single pathways in full hollow airway casts of the human and canine tracheobronchial trees. The pathways are a major branch path, a minor branch path, and one which consists of alternating major and minor branches. The casts, prepared from whole lungs obtained at autopsy, extend to airways with diameters less than 1 mm. Monodisperse test aerosols were nebulized from either a 99mTc ferric oxide or 99mTc-NaCl solution and size classified with an electrostatic classifier or formed by condensation of triphenyl phosphate onto 99mTc-salt nuclei. Measured deposition fractions (etaFs) form a family of curves with etaF being highest for the 50 nm particles and lowest for 400 nm. This agrees with expectations for this particle size range where diffusion is the dominant deposition mechanism. The etaF pattern is strongly influenced by the morphometry and resulting airflow distribution. Results of the experiments obtained in the human cast are compared with two predictive deposition models. The model, that is more explicit with respect to flow and geometric parameters, appears to be a marginally better predictor of the data. PMID- 8690582 TI - Complete decay of radionuclides: implications for low-level waste disposal in municipal landfills. AB - The time required for the complete decay of a radioactive source can be quantified by specifying an acceptable probability and using an original derivation. The physical phenomenon of complete decay may be used as the technical basis to change regulations and permit, with public acceptance, the inexpensive disposal of short half-lived radioactive waste into municipal landfills. Current regulations require isolation of trash from the biosphere for 30 years during the post-closure control period for municipal landfills. Thirty years is sufficient time for complete decay of significant quantities of short lived radionuclides, and there is a large decay capacity in the nation's landfills. As the major generators of low-level radioactive waste with relatively short half-lives, the academic, medical, and research communities likely would benefit most from such regulatory relief. Disposal of such waste is prohibited or costly. The waste must be specially packaged, stored, transported, and disposed in designated repositories. Regulatory relief can be initiated by citizens since the Administrative Procedures Act gives citizens the right to petition for regulatory change. PMID- 8690583 TI - Radon and thoron emanation from uranium-glazed tableware. AB - Radon and thoron gas emanation from tableware with ceramic glazes containing elevated uranium levels was determined using alpha-scintillation cells. Though gamma spectroscopy noted significant uranium concentrations in the glazed, no radioactive gas emanation was observed, contradicting a previous report. PMID- 8690584 TI - On designing room shielding for total-body irradiation. AB - When designing shielding for total-body irradiation as an additional modality of treatment in an ordinary radiation therapy room, the extended treatment distance used for these patients greatly increases the workload because of the inverse square factor. In a seeming contradiction to logic, for a facility with an exterior wall in the path of one lateral primary beam, and a restricted area behind the other primary wall, the overall shielding requirements are lower if the TBI patients are treated with the machine oriented toward the occupied interior. PMID- 8690585 TI - Development of a general equation to determine the transfer factor feed-to-meat for radiocesium on the basis of the body mass of domestic animals. AB - Transfer factors from feed to meat (T f), taken from literature for monogastric animals and ruminants have been correlated to their corresponding animal body mass (mb). Taking all data into account, a close relationship between both transfer factor and body mass becomes evident, yielding a regression function of T f = 8.0 x mb(-0.91) (r = -0.97). For monogastric animals (including poultry), the corresponding relationships are T f = 5.8 x mb(-0.70) (r = -0.97), for ruminants T f = 1.9 x mb(-0.72) (r = -0.78). The equations offer the opportunity to estimate the transfer factor for individual animals more precisely taking individual body masses into account. They are of interest for animals, on which no or only poor data concerning radiocesium transfer factors are available. The determination of radiocesium transfer factors are reduced to a simple weighing process. PMID- 8690586 TI - Bases for secondary standards for residual radionuclides in soil and some recommendations for cost-effective operational implementation. AB - The future use of land contaminated with radionuclides depends upon scientifically defensible bases for setting limits for radionuclides in soil. The purpose of this work is to develop such bases for establishing "posting criteria" to protect nonradiological workers at the Nevada Test Site and to provide a rationale for cost-effective measurements to readily determine the boundary conditions. The analysis begins with a mandated limit on total effective dose equivalent (1 mSv y(-1)) via all pathways. The possible pathways of exposure are external gamma exposure, inhalation of resuspended material, and incidental soil ingestion. These pathways are evaluated for each radionuclide of interest on the Nevada Test Site, and the results are used to define for each radionuclide the deposition-density limits for each pathway of exposure. The minimum deposition density limits are noted to occur via the external gamma-exposure pathway for most radionuclides; exceptions are incidental soil ingestion for 90Sr/90Y and inhalation for 238Pu, 239,240Pu, and 241Am. The limiting values of deposition density or average concentration in soil are then determined appropriately by combining all pathways. Procedures are developed for dealing with mixtures of many radionuclides and to apply the principles developed so that even a simple measurement of external gamma-exposure rate may be used to define the boundary conditions in the field, provided that the relative abundance of the radionuclide mixture is known and that the defining level of exposure rate is sufficiently above background. PMID- 8690587 TI - Estimation of radiation doses for atomic-bomb survivors in the Hiroshima University Registry. AB - The present study presents the Hiroshima University Registry of atomic bomb survivors, of which the total number is about 270,000, and application of absorbed doses. From this registry, we picked up 49,102 survivors and applied organ doses based on the dosimetry system 1986 (DS86), which is named the Atomic Bomb Survivor 1993 Dose (ABS93D). The applied dose data are based on the tables listed in the DS86 final report such as the free-in-air kermas, the house shielding factors, and organ dose factors for the active bone marrow and the breast. Calculations for the 13 other organs provided in DS86 are possible. To obtain the organ doses for each survivor, it is necessary to obtain information concerning (1) place exposed, (2) whether they were shielded or not, and (3) age. ABS93D body transmission factors for active bone marrow for neutrons and gamma rays agreed with DS86 to within a few percent. Of the survivors studied, 35,123 of them were used for the relative risk estimation of leukemia mortality, adopting the same method as the Radiation Effects Research Foundation (RERF) for comparison. For the observation period from 1968 to 1989, the analyzed relative risks for leukemia mortality at 1 Gy by shielded kerma and by active bone marrow dose are 2.01 and 2.37, respectively, which are consistent with the RERF results. PMID- 8690588 TI - Assessing the service provided by an institutional radiation safety survey program. AB - Routine radiation safety surveys are a required part of every institutional radiation protection program. Although mandated by regulation, surveys are really performed to help clinicians and researchers establish and maintain radiologically-safe working and learning environments. In some cases, however, the priorities established by a radiation protection program may not coincide with the needs perceived by the institution's workers, leading to possible alienation, dissatisfaction, and non-compliance with policies, procedures, and regulations. To determine if a typical survey program was perceived as providing a good or valued service to workers, a simple questionnaire was created and utilized for a 6-mo period The results obtained from this targeted assessment tool indicate that the radiation safety survey services were perceived as useful by most of the workers. In addition, the actual process of comment solicitation provided a positive feedback mechanism from the service recipients to the radiation safety staff, managers, committee members, and institution administrators. PMID- 8690589 TI - 237Np in hemp-palm leaves of Bontenchiku for fishing gear used by the Fifth Fukuryu-Maru: 40 years after "Bravo". AB - The alpha radioactive components in the Hemp-palm of Bontenchiku were determined with emphasis on the measurement low-level 237Np by alpha-ray spectrometry after chemical separation. Bontenchiku is a kind of fishing gear for long-line fishing used by the Fifth Fukuryu-Maru (Lucky Dragon). This gear was exposed to fallout from the second thermonuclear test explosion (Bravo) at Bikini Atoll in March 1954. The 237Np content in the Bontenchiku sample was determined to be 11.5 +/- 0.8 mBq g(-1), with an activity ratio of 237Np:239,240Pu and an atom ratio of 237Np:239Pu estimated to be (2.2 +/- 0.2) x 10(-3) and 0.42 +/- 0.04, respectively. The data showed the existence of a chain reaction of 238U and its ratio to be 237Np:239Pu, as well as the presence of 237U at the time of fallout from Bravo event in March 1954. PMID- 8690590 TI - Clarification of Moghissi and Straja's "Consistency in radon dosimetry and nomenclature". PMID- 8690591 TI - Radiation risk communication in human subjects research. PMID- 8690592 TI - Comments on determination of waterborne 222Rn concentrations using AC canisters. PMID- 8690593 TI - Risk of radiation at low doses. PMID- 8690594 TI - The fission track detector revisited: application to individual neutron dosimetry. AB - A system based on fission fragment tracks had previously been developed for individual neutron dosimetry. The dosimeter detects both fast neutrons by means of the 232Th(n,f) reaction, and thermal and albedo neutrons by means of the 235U(n,f) reaction. The fission tracks produced in a plastic foil are chemically etched and counted by spark discharges. The response of the dosimeter has recently been re-investigated in 36 different neutron fields: monoenergetic beams, reference fields near isotopic sources, and radiation fields encountered in a variety of situations inside nuclear power plants. The results obtained have been compared to those computed by convolution of the neutron spectra with the energy response functions of the dosimeters. In practical situations, it is essential to know the shape of the neutron spectrum, approximately at least, in order to perform an acceptably accurate dose evaluation. For that purpose, the neutron fields encountered inside nuclear power plants have been grouped into four categories, for which algorithms for dose evaluation have been developed. Concerning the neutron equivalent dose, the error associated with this approach does not exceed a factor of 2, a performance which is comparable to other detection systems used in the field of individual neutron dosimetry. PMID- 8690595 TI - A pure beta line source to assess hot particle effects in vitro. AB - A model system is presented for assessing the biological effects of inhomogeneous irradiation fields resulting from exposure to particulate radioactive matter (hot particles). The resulting harm per unit dose to tissue is qualitatively different from homogeneous irradiation sources because of specific hot particle effects such as wasting of dose to necrotic tissue (overkill) and formation of microlesions leading to growth stimulation in adjacent tissue. In the case of beta-emitters, many of the cells in adjacent tissue receive considerable sublethal doses. To assess the influence of local necrosis and growth stimulation on radiation transformation in vitro, a neutron activated short 90Y wire was attached to the bottom foil of a cell culture dish. The system achieves doses of up to 200 Gy h(-1) directly above the wire, rapidly falling off within a few mm to less than 0.5 Gy h(-1). Acute cell death of murine M3-1 cells was observed in the highest dose regions. Colony-forming ability as a function of distance from the wire was investigated. The surviving fraction decreased over several orders of magnitude between 3 and 10 mm from the wire. This report describes the physical characteristics of the model system and subsequent biological survival data for mammalian cell culture. It is a useful and versatile system for modeling inhomogeneous radiation field effects. PMID- 8690596 TI - Residual radioactivity in the soil of the Semipalatinsk Nuclear Test Site in the former USSR. AB - This paper deals with our efforts to survey residual radioactivity in the soil sampled at the Semipalatinsk Nuclear Test Site and at off-site areas in Kazakhstan. The soil was sampled at the hypocenter where the first Soviet nuclear explosion was carried out on 29 August 1949, and at the bank of the crater called "Bolapan," which was formed by an underground nuclear detonation on 15 January 1965 along the Shagan River. As a comparison, other soil was also sampled in the cities of Kurchatov and Almaty. These data have allowed a preliminary evaluation of the contemporary radioactive contamination of the land in and around the test site. At the first nuclear explosion site and at Bolapan, higher than background levels of 239,240Pu with weapons-grade plutonium were detected together with fission and activation products such as 137Cs, 60Co, 152Eu, and 154Eu. PMID- 8690597 TI - Summary of the BIOMOVS A4 scenario: testing models of the air-pasture-cow milk pathway using Chernobyl fallout data. AB - A unique opportunity to test dose assessment models arose after the Chernobyl reactor accident. During the passage of the contaminated plume, concentrations of 131I and 137Cs in air, pasture, and cow's milk were collected at various sites in the northern hemisphere. Afterwards, contaminated pasture and milk samples were analyzed over time. Under the auspices of the Biospheric Model Validation Study (BIOMOVS), data from 13 sites for 131I and 10 sites for 137Cs were used to test model predictions for the air-pasture-cow milk pathway. Calculations were submitted for 23 models, 10 of which were quasi-steady state. The others were time-dependent. Daily predictions and predictions of time-integrated concentrations of 131I and 137Cs in pasture grass and milk for six months post accident were calculated and compared with observed data. Testing against data from several locations over time for several steps in the air-to-milk pathway resulted in a better understanding of important processes and how they should be modeled. This model testing exercise showed both the strengths and weaknesses of the models and revealed the importance of testing all parts of dose assessment models whenever possible. PMID- 8690598 TI - The adsorption of argon, krypton, and xenon on activated charcoal. AB - Charcoal adsorption beds are commonly used to remove radioactive noble gases from contaminated gas streams. The design of such beds requires the adsorption coefficient for the noble gas. Here an extension of the Dubinin-Radushkevich theory of adsorption is developed to correlate the effects of temperature, pressure, concentration, and carrier gas on the adsorption coefficients of krypton, xenon, and argon on activated carbon. This model is validated with previously published adsorption measurements. It accurately predicts the equilibrium adsorption coefficient at any temperature and pressure if the potential energies of adsorption, the micropore volume, and the van der Waals constants of the gases are known. PMID- 8690599 TI - Radionuclides in fishes and mussels from the Farallon Islands Nuclear Waste Dump Site, California. AB - The Farallon Islands Nuclear Waste Dump Site (FINWDS), approximately 30 miles west of San Francisco, California, received at least 500 TBq encapsulated in more than 47,500 containers from approximately 1945 to 1970. During several seasons in 1986/87 deep-sea bottom feeding fishes (Dover sole = Microstomus pacificus; sablefish = Anoplopoma fimbria; thornyheads = Sebastolobus spp.) and intertidal mussels (Mytilus californianus) were collected from the vicinity of the FINWDS and from comparable depths at a reference site near Point Arena, CA. Tissues were analyzed for several radionuclides (137Cs, 238Pu, 239+240Pu, and 241Am). Radionuclide concentrations for fish mussel tissue ranged from non-detectable to 4,340 mBq kg(-1) wet weight, with the following means for Farallon fishes: 137Cs = 1,110 mBq kg(-1); 238Pu = 390 mBq kg(-1); 239+240Pu = 130 mBq kg(-1); and 241Am = 1,350 mBq kg(-1). There were no statistically significant differences in the radionuclide concentrations observed in samples from the Farallon Islands compared to reference samples from Point Arena, CA. Concentrations of both 238Pu and 241Am in fish tissues (from both sites) were notably higher than those reported in literature from any other sites world-wide, including potentially contaminated sites. Concentrations of 239+24OPu from both sites were typical of low values found at some contaminated sites worldwide. These results show approximately 10 times higher concentrations of 239+240Pu and approximately 40-50 times higher concentrations of 238Pu than those values reported for identical fish species from 1977 collections at the FINWDS. Radionuclide concentrations were converted to a hypothetical per capita annual radionuclide intake for adults, yielding the following values of annual Committed Effective Dose Equivalent (CEDE) from ionizing radiation emitted from these radionuclides: 0.000 mSv y(-1) for 137Cs, 0.009 mSv Y(-1) for 228Pu, and 0.003 mSv y(-1) for 239+240Pu. For 241Am, projected CEDE for Dover sole, sablefish, and thornyheads were higher, averaging 0.03 mSv y(-1). The observed isotopic ratio of 238Pu/239+240Pu was about 4 (which is two orders of magnitude higher than the ratio of 0.03 associated with fallout from weapons tests and accidental releases in the north temperate zone of the earth), indicating a considerably higher environmental mobilization for 238Pu compared to 239+240Pu. Likewise, the observed ratio of 241Am/239+240Pu of about 30 was nearly two orders of magnitude higher than the fallout ratio of 0.43 in the north temperate zone of the earth. The projected ionizing radiation CEDE to people from the ingestion of fish with fallout radionuclides was three times higher for 241Am than from the plutonium isotopes. PMID- 8690600 TI - A study of factors affecting indoor radon properties. AB - The factors affecting indoor radon properties in Hong Kong have been studied, including the radon concentration, the total potential alpha energy concentration of radon progeny, the equilibrium factor, and the fraction of unattached radon progeny. These factors fall into three categories, namely, (1) the building characteristics, including cooling method, age of the buildings, wall coverings and floor coverings; (2) the location of sites, including nearby environments, geological materials of the area, and the elevation of the sites; and (3) the meteorological parameters, including rainfall, relative humidity, pressure, temperature, and wind speeds. For category (1), only the ventilation is found to affect the indoor radon properties. For category (2), only the nearby environments have effects. For category (3), the rainfall and temperature are found to have significant effects. PMID- 8690601 TI - Radon and lung cancer in Finland. AB - A study with 291 cases and 495 controls on indoor radon and lung cancer incidence was conducted in a Finnish population residing in a high-exposure area. Relative risks of 1.8 and 1.5 for the incidence of lung cancer were observed for those exposed to concentrations of 95-185 Bq m(-3) and 186 Bq m(-3), respectively. The increase in risk was not statistically significant. PMID- 8690602 TI - Prussian Blue decorporation of 137Cs in beagles of different ages. AB - A 6-wk study was conducted using immature (4.7 mo), young adult (2.4 y), and aged (13.5 y) male beagles to determine the modifying effect of age on the effectiveness of Prussian Blue decorporation therapy for the removal of injected 137Cs. Whole-body clearance rates for injected 137Cs decreased with increasing age in the dogs. Treatment with Prussian Blue changed the ratio of fecal to urinary 137Cs excretion from 0.8 in untreated dogs to 2.2 in treated animals. The 137Cs concentrations in tissues of untreated and Prussian Blue-treated dogs at the end of the 6-wk study were similar, with the greatest concentrations in the skeletal muscle tissue, spleen, and kidneys. There was a lower concentration of 137Cs in the livers of the treated dogs. The reductions in the average total whole-body doses resulting from Prussian Blue treatment during the course of this study were 51% in the immature, 31% in the young adult, and 38% in the aged dogs. Because of the differences in the intake of Prussian Blue by the dogs in the different groups relative to their body weight, it is unclear as to the relative effectiveness of Prussian Blue in dogs of different ages. PMID- 8690604 TI - A comparison of current regulations and regulatory guide governing quality control of dose calibrators. AB - The U.S. Nuclear Regulatory Commission recently amended its regulation governing the calibration of dose calibrators. The changes include (1) the radioactivity of radiopharmaceutical dosages that contain photon-emitting radionuclides has to be measured by a dose calibrator prior to administration to patients and human research subjects; (2) the lower end of the radioactivity limits for linearity testing has been raised to 1.1 MBq (30 microCi) to be consistent with the Nuclear Regulatory Commission Quality Management Program Requirements; and (3) the requirement for signature of the Radiation Safety Officer on the records for accuracy, linearity, and geometry dependence tests has been removed. Although these are practical amendments, further clarification of the new Nuclear Regulatory Commission regulation is required for the following issues: (1) inconsistency in individual's identification requirement for the record keeping (i.e., initials of the individual who performed the constancy check and identity of the operator for the accuracy, linearity, and geometry dependence tests); (2) whether the use of 99mTc is adequate for linearity testing when other radionuclides are being measured in the dose calibrator; and (3) lack of provision for dose calibrator adjustment when conducting the accuracy test. In addition, Nuclear Regulatory Commission Regulatory Guide 10.8 should be revised to become consistent with the Nuclear Regulatory Commission's regulation in order to assist licensees with full compliance of the requirements or recommendations. PMID- 8690603 TI - The distribution and effects of inhaled 239Pu(NO3)4 deposited in the liver of dogs. AB - The distribution and effects of inhaled 239Pu(NO3)4 deposited in the liver of dogs were studied in five groups of 20 beagles exposed to initial lung depositions ranging from 1.0 to 520 Bq g(-1) lung. Following life-span observations, the liver contained 40 +/- 1% of the final body deposition of plutonium, second only to the skeleton. The liver-to-skeleton ratio of deposited plutonium for total organ was 0.8, or 3.5 when expressed on a per-gram basis. There was no effect of exposure level on liver-to-skeleton ratios. Autoradiographs showed that the dose rate delivered to parenchymal cells was higher than evident from radiochemical analysis of the whole organ. Elevated levels of serum liver enzymes were observed in groups with mean liver concentrations of 1.3 Bq g(-1) and liver doses of 3 Gy or higher. Nodular hyperplasia of liver and bile-duct hyperplasia were observed. Liver tumors, principally of bile-duct epithelium, were late-occurring and were observed at lower exposure levels at which life span was not shortened by lung or bone tumors. PMID- 8690605 TI - The BRMD thyroid-neck phantom: design and construction. AB - The Human Monitoring Laboratory, which acts as the Canadian National Calibration Reference Center for In Vivo monitoring, has constructed a robust neck-thyroid phantom for use in the Canadian Thyroid Intercomparison Program. The phantom is rugged and capable of being distributed through the mail with no expectation of a leak of radioactive materials; it is anthropomorphic; the thyroid inserts simulate 125I and 131I; the phantom can be used to mimic different layers of adipose tissue over the thyroid insert; and it is cost effective. This paper describes the design criteria and the manufacturing process; the performance characteristics have been described in an earlier publication. PMID- 8690606 TI - The distribution of fallout 137Cs in Costa Rica. AB - Baseline levels of 137Cs on different sites throughout the Costa Rican territory are presented in this study from local and undisturbed soils. They are believed to represent the fallout input to the land surface. Seventy samples were collected from September 1991 to December 1993, and analyzed by gamma spectroscopy. The territory was divided in three regions, Caribbean, Pacific, and Central, based on meteorological and geographical conditions to study spatial distribution of cesium. The results show a higher activity in the Caribbean region perhaps due to the wind influence and higher rain precipitation throughout the year. No relevant time variation of the activity levels for each location was found. The highest value of 17.6 Bq kg(-1) of 137Cs is compared with its generalized derived limit, being only 1.97% of the generalized derived limit value. The mean country activity value ranges from 0.4 to 17.8 Bq kg(-1) with an average of 3.7 Bq kg(-1). PMID- 8690607 TI - Alternative methods of obtaining the computed tomography dose index. AB - The most direct way of getting the value of the multiple scan average dose (MSAD) in computed tomography is to employ a pencil chamber for integration of a single scan dose profile. Because the active length of the pencil chamber is fixed, the measurement can represent the value of the MSAD from a different number of contiguous scans depending on the slice thickness. This characteristic makes it difficult to compare the value of MSAD using the pencil chamber to the information required by Federal regulations on the computed tomography dose index (CTDI). The CTDI, which is the MAD at the center of a set of 14 contiguous scans, is the dose descriptor used in the Federal Performance Standard. Two alternative methods were developed to make the CTDI measurements at the center of a CT dosimetry phantom. These alternative methods were compared to the results of thermoluminescent dosimeter (TLD) measurements from more than 20 different CT scanners. One alternative method involved the use of radio-opaque sleeves with the pencil chamber to limit the length of the single scan dose profile incident on the pencil chamber. In addition, the TLD data were also used to obtain a set of conversion factors for converting the results of a measurement with the pencil chamber without a radio-opaque sleeve to a value of the CTDI. The alternative methods of obtaining the CTDI agree on the average to better than 10% for all values of slice thickness on the different CT scanners. PMID- 8690608 TI - Overview of radiation safety in the tin by-product (amang) industry of South East Asia. AB - Processing of by-product heavy minerals (amang) from tin mining involves potential exposure to external and internal sources of radioactivity. The radioactivity arises through the presence of thorium and uranium series radionuclides in the various minerals. Monazite is the most radioactive mineral, containing 3% to 7% thorium by weight, while ilmenite is generally the least radioactive mineral containing typically less than 0.05% thorium. External exposure occurs when workers are in close proximity to accumulations or stockpiles of the radioactive minerals, whereas internal exposure occurs when workers are involved in dusty processes. This paper summarizes the nature of the amang industry in South East Asia and presents the results of preliminary measurements of external radiation and airborne radioactivity in twelve Malaysian and Thai plants. Although constrained by a paucity of exposure data, it is concluded that radiation doses to some amang plant workers may approach or exceed international standards and that appropriate control measures are required as a matter of priority, Radiation doses may approach or exceed 100 mSv in situations where workers are exposed to excessive levels of ambient dust and no protective measures are used. Observations and recommendations are made relating to monitoring and surveillance, instruction and training, and engineering and administrative protection measures. PMID- 8690609 TI - Neutron fields inside containment of a CANDU600-PHWR power plant. AB - Neutron fields in six locations inside containment of a CANDU600-PHWR power plant were characterized using Bonner-sphere spectrometry. Unfolded fluence spectra were used to predict and understand the behavior of a rem meter (a moderator-type dose equivalent survey instrument). The suitability of employing commonly-used sources such as 241Am-Be for calibrating the rem meter was investigated by calculational means. Results of these calculations suggest that employing a calibration field more representative of the power-plant fields would likely provide more accurate dose equivalents. PMID- 8690610 TI - The probability of developing cancer due to a large dose of radiation. PMID- 8690611 TI - Cytogenetical observations in a canalicular adenoma of the minor salivary glands. PMID- 8690612 TI - Karyotype abnormalities in a variant Chinese hamster cell line resistant to methyl methanesulphonate. AB - A variant cell population, isolated from V79-C13 Chinese hamster cells after two consecutive treatments with methyl methanesulphonate (MMS), was found to be highly resistant to killing by this alkylating agent. The resistant cell line was cytogenetically characterized both by the presence of a stable translocation involving metacentric chromosome 2 and acrocentric chromosome 6 and by a supernumerary chromosome originated by the duplication of a small telocentric chromosome. This cell population also showed a transient transformed phenotype, seen as formation of transformed foci containing cells with high chromosomes counts and multiple chromosomal aberrations. As MMS-resistance and karyotype changes are permanent and heritable traits, we suppose that they are related events. PMID- 8690613 TI - Heat-shock resistance in Drosophila populations: analysis of variation in reciprocal cross progeny. AB - Genetic variation for resistance to high temperature stress was studied in populations of D. melanogaster and D. buzzatii from different geographic regions. Drosophila melanogaster individuals were presented with either a direct short exposure to a high temperature or exposure to high temperature after receiving a pretreatment, which increased resistance. Heat-stress resistance varied among populations, with one much more resistant than all others under both treatments. Another possessed low stress resistance when exposed without the heat pretreatment; but with pretreatment, resistance increased relative to the other populations. Evidence from reciprocal crosses suggests that the X chromosome of the more resistant population carries alleles that greatly increase resistance, and that one or more factors on the autosomes also affect resistance. Non additive interaction effects among the three less resistant population, were suggestive that all differ for various elements that contribute to stress resistance, and that some clearly change inducible resistance more than basal levels. In D. buzzatii, the two least resistant populations were genetically very similar. Crosses to the more resistant population gave results suggesting that the low resistance to heat is dominant. A small X-chromosome effect that increased resistance, and a dominant enhancer of male resistance also may have contributed to variation in resistance. PMID- 8690614 TI - Offspring sex-ratio and reproductive performance in heterogametic females of the South American field mouse Akodon azarae. Reproduction in heterogametic Akodon azarae females. AB - We have compared the breeding performance of homogametic (XX) and heterogametic (XY*) females of the South American sigmodontine rodent Akodon azarae under laboratory conditions. XY* females showed an enhanced reproductive performance when compared with normal, XX, females. The XY* females had a longer reproductive lifespan. They started to reproduce early, had more frequent litters, and stopped reproduction later than XX females. Their progeny showed a biased 1:2 male:female sex ratio which may be explained by the early loss of YY* zygotes after fertilization. However, litter size at birth was similar both in XY* and XX females, and no difference in ovulation rate was detected between them. This indicates that an "automatic" rather than an "evolved" reproductive compensation mechanism may be acting in heterogametic females. A separate study has shown that self-synapsis of both the X and Y* chromosomes takes place during meiosis, allowing the oocytes to escape from functional deterioration. It is suggested that self-synapsis and "automatic" reproductive compensation account for the preservation of fertility in heterogametic females in spite of the heteromorphic sex chromosomes and the early embryo loss they experience. However, these mechanisms do not account for the enhancement of reproductive lifespan. The possibility that an intrauterine position phenomenon is acting in A. azarae is discussed. PMID- 8690616 TI - Electron micrograph map of the Drosophila melanogaster polytene chromosome 3R divisions 91 through 100. AB - The banding pattern of the distal half of the polytene salivary gland 3R chromosome of Drosophila melanogaster was studied by means of the thin section electron microscopy. Bands were identified according to the revised light microscopic map of Bridges. Bridges' map contains 332 single bands and 137 double bands within the region 91 through 100. This makes a total of 606 bands when the doublets are counted as two bands each, but 469 bands when the doublets are counted as one band. In the electron micrographs we found a total of 443 bands within this region. 109 Bridges' singlets were easily detected in almost all thin sections, while 144 mainly faint bands could be seen only in some micrographs. 79 Bridges' single bands and one doublet (94D7-8) could not be found. 42 Bridges' doublets were made up of two separate bands each, 87 Bridges' doublets looked single, and three pairs of Bridges' doublets formed dark complexes in the thin sections. The telomere region with the most distal band 100F4-5 was gray. A total of 15 new bands, which are not drawn on Bridges' map, were detected. Most of the new bands were in the divisions 96 and 99. PMID- 8690615 TI - Increased specificity of colloidal silver staining by means of chemical attenuation. AB - A modification of the silver staining procedure of Howell and Black (1980) is reported which makes use of teleostean gelatin as protective colloid and renders a high signal-to-noise ratio. We demonstrate that this ratio can be further increased by subsequent attenuation with a chemical reducer consisting of a mixture of potassium ferricyanide (III) and sodium thiosulphate. It is shown that slight changes of the concentration of the reactive compounds of the chemical reducer make the protocol applicable to human, plant (Aliium cepa, Rhinanthus minor) as well as meiotic insect (Acheta domesticus) chromosome preparations. Due to its broad applicability, the method could find utilization in studies on chromatin and chromosome functions in many species. PMID- 8690617 TI - Physical localization of 5S rRNA genes in the pig by fluorescence in situ hybridization. PMID- 8690618 TI - Home screening test for HIV approved. PMID- 8690619 TI - Didanosine (DDI) alone is now considered the first-line therapy for symptomatic children infected with the human immunodeficiency virus (HIV) PMID- 8690620 TI - Teaching CPR: someone's life depends on it. PMID- 8690622 TI - Use of astemizole in a large group practice. AB - Astemizole was released in 1988. In late 1992, a new warning label was added in response to reports of syncope and death from arrhythmia. Records of patients given new prescriptions for astemizole were reviewed to assess compliance with the warnings in a large multispecialty practice. The indication was appropriate in 89% of cases. Excessive doses were used in 4% of cases. Two percent of prescriptions were given to patients with contraindications. Only two complications were documented. Despite carrying a drug warning, astemizole continues to be used inappropriately and is a medicolegal concern. Education and drug evaluations can be used to enhance compliance and decrease the risk associated with the use of astemizole. PMID- 8690621 TI - Efficacy of combination therapy with insulin and oral hypoglycemic agents in patients with type II diabetes during a 1-year period. AB - In this retrospective study, the authors assess the efficacy of combined insulin and oral hypoglycemic agents (OHAs) in controlling glycemic levels, as well as lipid levels and insulin requirements, in 48 patients with type II diabetes mellitus during a 1-year period. Thirty-two of these patients had secondary failure to an OHA (group 1). Sixteen patients (group 2) were taking high doses of insulin alone. Overall, 64.6% of all the patients responded to the combination therapy and insulin at 6 months. Response was defined as a decrease in hemoglobin A1c of more than 0.5%. At 12 months, 50% of these patients continued to respond to this regimen. No significant differences were seen in the patients' total cholesterol and triglyceride levels between responders and nonresponders in each group. After 1 year of combination OHA and insulin therapy, 50% of the patients showed a 21.4% reduction in their daily insulin dose. PMID- 8690623 TI - ERISA: pillar of pension reform, roadblock to healthcare reform. AB - With Republicans and Democrats agreeing to strategies that move the resources and responsibilities for healthcare reform to the states, the Employee Retirement Income Security Act of 1974 (ERISA) presents even greater barriers than surfaced in federal planning. The single most formidable obstacle to state healthcare reforms, ERISA's preemption clause supersedes all state laws that "relate to" employee benefit plans. The authors trace the history of pension legislation that led to the strong ERISA protections and explain the interpretations of the law which affect healthcare. They explain the history of the Hawaii plan's waiver; the continual refinement of the law through legislation; and the growing body of case law that interprets ERISA's application through the "relate to" requirement, the "savings" clause, and the "deemer" clause. Finally, they point out that the political solutions being acted out in Congress are leading to poor healthcare policy. Overriding or waiving ERISA would not lead to national health policy solutions and could endanger millions of workers' pension and benefit plans. Meanwhile, the only relief for states comes in slow and incremental steps through the court system. PMID- 8690624 TI - Pneumoscrotum: an unusual complication of pulmonary resection. AB - Pneumoscrotum occurred in a 53-year-old man as a complication after pulmonary resection for carcinoma. Recognition of this entity and its conservative management are crucial to a positive outcome and prevention of unnecessary interventions based on the differential diagnosis. A review of the literature is included with this description of an unusual complication. PMID- 8690625 TI - Spontaneous hemoperitoneum. AB - Massive hemoperitoneum seen without an obvious precipitating event is rare. A 21 year-old man was seen with diffuse abdominal pain of 48 hours' duration. He had no fever, nausea, or vomiting, and most laboratory values were normal. Exploration of the abdomen revealed free intraperitoneal blood with clotting but failed to reveal a source. The patient could recall no trauma or other inciting event. The only abnormalities found during laparotomy were multiple adhesions of the omentum to the lateral abdominal wall and localization of most of the clot within the greater omentum. The author cautions that a high index of suspicion followed by laparotomy are the management tools for controlling spontaneous hemoperitoneum. Conservative management produces a high mortality rate. PMID- 8690627 TI - Radiation-induced sarcoma of the breast. AB - A small but growing number of radiation-induced sarcomas after breast-conserving surgery for carcinoma have been reported. Because breast-conserving surgery followed by irradiation is becoming increasingly popular, the potential for the emergence of these sarcomas is growing. Unfortunately, because of postirradiation changes in the affected breast, detection of a new lesion can be difficult, resulting in a delay in diagnosis. This case history describes a 48-year-old woman in whom a malignant fibrous histiocytoma was discovered 5 years after she had had a lumpectomy followed by radiation therapy for infiltrating ductal carcinoma. Although the exact mechanism of radiation-induced carcinogenesis is unclear, one theory is discussed. Also discussed are the histologic composition of the malignant fibrous histiocytoma, its latency period, and the best treatment modality for radiation-induced sarcomas. PMID- 8690626 TI - Sweet's syndrome after splenic irradiation for chronic myelogenous leukemia. AB - Sweet's syndrome is defined as acute febrile neutrophilic dermatosis. Characteristic features are fever; peripheral neutrophilia; and painful cutaneous nodules and plaques on the face, neck, trunk, and limbs. Biopsy specimens of these lesions show a mature neutrophilic infiltrate of the dermis. Vasculitis is absent. Sweet's syndrome is associated with malignancy in approximately 20% of reported cases. The pathogenesis is unknown. The authors describe Sweet's syndrome in a 39-year-old man 5 weeks after splenic irradiation for chronic myelogenous leukemia. Treatment with parenteral corticosteroids resulted in dramatic improvement of the patient's condition. The authors discuss the diagnosis of Sweet's syndrome and the fact that it is thought to be cytokine induced. PMID- 8690628 TI - Acute diplopia and a solitary lung mass: a unique presentation of light-chain myeloma. AB - The patient described, a 51-year-old woman, had diplopia and cephalgia of two weeks' duration. On admission, the radiologic evaluation revealed a mass in the sphenoid sinus, multiple lesions in the calvarium and a solitary lung mass. Biopsy of the lung mass revealed an atypical plasmacytic infiltration. Laboratory findings confirmed the diagnosis of light-chain myeloma presenting with a pulmonary plasmacytoma and cranial nerve involvement. PMID- 8690629 TI - Breast-conserving therapy as a model for creating new knowledge in clinical oncology. PMID- 8690630 TI - Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. International Breast Cancer Study Group. AB - PURPOSE: A controversy exists regarding whether it is safe to delay radiation therapy until the completion of chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. Within the context of two concurrent randomized clinical trials we had the opportunity to evaluate outcomes for patients who received breast irradiation after completing different durations of chemotherapy. METHODS AND MATERIALS: From July 1986 to April 1993 the International Breast Cancer Study Group (IBCSG) Trial VI randomly assigned 1554 pre/perimenopausal node-positive breast cancer patients to receive cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) for either three consecutive courses on months 1-3, or six consecutive courses on months 1-6, both with or without reintroduction CMF. IBCSG Trial VII randomly assigned 1266 postmenopausal node-positive breast cancer patients to receive tamoxifen for 5 years, or tamoxifen for 5 years with three early cycles of CMF, both with or without three courses of delayed CMF. Both trials allowed a choice of mastectomy, or breast-conserving surgery plus radiation therapy, and both were stratified by type of surgery. Radiotherapy was delayed until the initial block of CMF was completed; 4 or 7 months after surgery for pre/perimenopausal patients, and 2 or 4 months after surgery for postmenopausal patients. Over both trials, 718 eligible patients elected to receive breast-conserving surgery plus radiation therapy: 433 on Trial VI, and 285 on Trial VII. Four-year actuarial total failure rates (failure at any site), risks of developing distant metastases (DM at any time during observation), and overall survival (OS) were estimated using the Kaplan-Meier method. To avoid potential bias due to competing causes of failure, only patients who could be followed for at least 4 years (enrolled prior to July 1, 1990) were used to evaluate the patterns of first relapse site. Crude percents of local failure with or without other sites (LF), distant metastases including regional nodal failure (DM/RNF), or other first events (second primaries/death without recurrence) were estimated for each treatment group. For this report, an intent to treat analysis was performed at a median follow-up of 48 months. RESULTS: No differences were found in the 4-year actuarial total failure rates, risk of developing distant metastases, and overall survival among the two radiotherapy groups of each study. The cumulative incidence of types of first failure and the 4-year crude rates showed no treatment differences in the patterns of site of first event. Estimates for the 4-year crude percent of local failures were 8 and 9% for pre/perimenopausal patients who had radiation therapy at 4 or 7 months after surgery, and 3 and 6% for postmenopausal patients who had radiation therapy at 2 months or 4 months after surgery. CONCLUSIONS: For node positive patients receiving breast-conserving surgery followed by radiation therapy, the incidence of breast recurrence in the conserved ipsilateral breast within 4 years was between 8 and 9% for pre/perimenopausal patients and between 3 and 6% for postmenopausal patients. After 48 months of median follow-up, administering radiation therapy after three or six cycles of CMF for pre/perimenopausal women, or after no cycles or three cycles of CMF for postmenopausal women does not influence overall efficacy or local control in this series. PMID- 8690631 TI - The effects of sequence and type of chemotherapy and radiation therapy on cosmesis and complications after breast conservation therapy. AB - PURPOSE: Chemotherapy plays an increasingly important role in the treatment of both node-negative and node-positive breast cancer patients, but the optimal sequencing of chemotherapy and radiation therapy is not well established. The purpose of this study is to evaluate the interaction of sequence and type of chemotherapy and hormonal therapy given with radiation therapy on the cosmetic outcome and the incidence of complications of Stage I and II breast cancer patients treated with breast-conserving therapy. METHODS AND MATERIALS: The records of 1053 Stage I and II breast cancer patients treated with curative intent with breast-conserving surgery, axillary dissection, and radiation therapy between 1977-1991 were reviewed. Median follow-up after treatment was 6.7 years. Two hundred fourteen patients received chemotherapy alone, 141 patients received hormonal therapy alone, 86 patients received both, and 612 patients received no adjuvant therapy. Patients who received chemotherapy +/- hormonal therapy were grouped according to sequence of chemotherapy: (a) concurrent = concurrent chemotherapy with radiation therapy followed by chemotherapy; (b) sequential = radiation followed by chemotherapy or chemotherapy followed by radiation; and (c) sandwich = chemotherapy followed by concurrent chemotherapy and radiation followed by chemotherapy. Compared to node negative patients, node-positive patients more commonly received chemotherapy (77 vs. 9%, p < 0.0001) and/or hormonal therapy (40 vs. 14%, p < 0.0001). Among patients who received chemotherapy, the majority (243 patients) received concurrent chemotherapy and radiation therapy with two cycles of cytoxan and 5-fluorouracil (5-FU) administered during radiation followed by six cycles of chemotherapy with cytoxan, 5-fluorouracil and either methotrexate (CMF) or doxorubicin(CAF). For analysis of cosmesis, patients included were relapse free with 3 years minimum follow-up. RESULTS: The use of chemotherapy had an adverse effect on cosmetic outcome compared to no chemotherapy, which was of borderline significance at 3 years (92% excellent or good cosmetic outcome vs. 96% respectively, p = 0.057); however, cosmesis was not different at 5 years (91 vs. 93% respectively, p = 0.67). Cosmesis was not significantly different between patients treated sequentially and those treated concurrently (3 year: 87 vs. 93% respectively, p = 0.33), nor was it different between patients who received CMF vs. CAF (3 year: 92 vs. 93% respectively, p = 0.89). Hormonal therapy did not influence cosmetic outcome (p = 0.78). The incidence of Grade 4 or 5 arm edema (> or = 2 cm difference in arm circumference) was 2% without chemotherapy vs. 8% with chemotherapy (p = 0.00002). However, the incidence of arm edema was not affected by sequencing or type of chemotherapy (all p > or = 0.52). Patients treated sequentially had a 10% incidence of Grade 4 or 5 arm edema vs. 7% in the patients treated concurrently (p = 0.52). The incidence was 7 vs. 9% in patients treated with CMF vs. CAF (p = 0.73). The incidence of clinical pneumonitis and rib fracture was not influenced by use of chemotherapy, sequence of chemotherapy or use of hormonal therapy (all p > or = 0.06). CONCLUSIONS: Chemotherapy can be given concurrently with radiation therapy in the treatment of Stage I and II breast cancer with breast-conserving therapy without seriously compromising cosmetic outcome or incidence of complications compared to patients receiving other sequences of chemotherapy. Hormonal therapy did not affect cosmesis or complications. The chemotherapeutic regimen of cytoxan and 5-FU concurrent with radiation therapy followed by more chemotherapy is one reasonable option for breast conservation therapy in patients requiring chemotherapy. PMID- 8690632 TI - The impact of tamoxifen on breast recurrence, cosmesis, complications, and survival in estrogen receptor-positive early-stage breast cancer. AB - PURPOSE: To evaluate the impact of tamoxifen on breast recurrence, cosmesis, complications, overall and cause-specific survival in women with Stage I-II breast cancer and estrogen receptor positive tumors undergoing conservative surgery and radiation. METHODS AND MATERIALS: From 1982 to 1991, 491 women with estrogen receptor positive Stage I-II breast cancer underwent excisional biopsy, axillary dissection, and radiation. The median age of patient population was 60 years with 21% < 50 years of age. The median follow-up was 5.3 years (range 0.1 to 12.8). Sixty-nine percent had T1 tumors and 83% had histologically negative axillary nodes. Re-excision was performed in 49% and the final margin of resection was negative in 64%. One hundred fifty-four patients received tamoxifen and 337 patients received no adjuvant therapy. None of the patients received adjuvant chemotherapy. RESULTS: There were no significant differences between the two groups for age, race, clinical tumor size, histology, the use of re-excision, or median total dose to the primary. Patients who received tamoxifen were more often axillary node positive (44% tamoxifen vs. 5% no tamoxifen), and, therefore, a greater percentage received treatment to the breast and regional nodes. The tamoxifen patients less often had unknown margins of resection (9% tamoxifen vs. 22% no tamoxifen). The 5-year actuarial breast recurrence rate was 4% for the tamoxifen patients compared to 7% for patients not receiving tamoxifen (p = 0.21). Tamoxifen resulted in a modest decrease in the 5-year actuarial risk of a breast recurrence in axillary node-negative patients, in those with unknown or close margins of resection, and in those who underwent a single excision. Axillary node-positive patients had a clinically significant decrease in the 5 year actuarial breast recurrence rate (21 vs. 4%; p = 0.08). The 5-year actuarial rate of distant metastasis was not significantly decreased by the addition of adjuvant tamoxifen in all patients or pathologic node-negative patients. Pathologically node-positive patients had a significant decrease in distant metastasis (35 vs. 11%; p = 0.02). There were no significant differences in cause specific survival for patients receiving tamoxifen when compared to observation (95% no tamoxifen vs. 89% tamoxifen; p = 0.24). Similar findings were noted for pathologically node-negative patients. However, axillary node-positive patients receiving tamoxifen had an improvement in 5-year actuarial cause-specific survival (90% tamoxifen vs. 70% no tamoxifen; p = 0.10). Cosmesis (physician assessment) was good to excellent in 85% of the tamoxifen patients compared to 88% of the patients who did not receive tamoxifen. CONCLUSION: The addition of tamoxifen to conservative surgery and radiation in women with Stage I-II breast cancer and estrogen receptor positive tumors resulted in a modest but not statistically significant decrease in the 5-year actuarial risk of a breast recurrence. Tamoxifen significantly decreased the 5-year actuarial risk of distant metastasis in axillary node-positive patients and there was a trend towards improvement in cause-specific survival that was not statistically significant. Tamoxifen did not decrease the 5-year actuarial rate of distant metastasis in axillary node negative, patients and in this group, there was no improvement in cause-specific survival. Tamoxifen did not have an adverse effect on cosmesis or complications. PMID- 8690633 TI - Long-term outcome in patients with four or more positive lymph nodes treated with conservative surgery and radiation therapy. AB - PURPOSE: The purpose of this study was to review management strategies with respect to systemic therapy, radiation therapy treatment techniques, and patient outcome (local regional control, distant metastases, and overall survival) in patients undergoing conservative surgery and radiation therapy (CS + RT) who had four or more lymph nodes involved at the time of original diagnosis. METHODS AND MATERIALS: Of 1040 patients undergoing CS + RT at our institution prior to December 1989, 579 patients underwent axillary lymph node dissection. Of those patients undergoing axillary lymph node dissection, 167 had positive nodes and 51 of these patients had four or more positive lymph nodes involved and serve as the patient population base for this study. All patients received radiation therapy to the intact breast using tangential fields with subsequent electron beam boost to the tumor bed to a total median dose of 64 Gy. The majority of patients received regional nodal irradiation as follows: 40 patients received RT to the supraclavicular region without axilla to a median dose of 46 Gy, 10 patients received radiation to the supraclavicular region and axilla to a median dose of 46 Gy. Thirty of the 51 patients received a separate internal mammary port with a mixed beam of photons and electrons. One patient received radiation to the tangents alone without regional nodal irradiation. Adjuvant systemic therapy was used in 49 of the 51 patients (96%) with 27 patients receiving chemotherapy alone, 14 patients receiving cytotoxic chemotherapy and tamoxifen, and 8 patients receiving tamoxifen alone. RESULTS: As of December 1994, with a minimum evaluable follow-up of 5 years and a median follow-up of 9.29 years, there have been 18 distant relapses, 2 nodal relapses, and 5 breast relapses. Actuarial statistics reveal a 10-year distant metastases-free rate of 65%, 10-year nodal recurrence free rate of 96%, and a 10-year breast recurrence-free rate of 82%. All five patients who sustained a breast relapse were successfully salvaged with mastectomy. Both patients with nodal relapses (one supraclavicular and one axillary/supraclavicular) failed within the irradiated volume. Of the 40 patients treated to the supraclavicular fossa (omitting complete axillary radiation), none failed in the dissected axilla. With a median follow-up of nearly 10 years, 29 of the 51 patients (57%) remain alive without evidence of disease, 15 (29%) have died with disease, 2 (4%) remain alive with disease, and 5 (10%) have died without evidence of disease. Overall actuarial 10-year survival for these 51 patients is 58%. CONCLUSIONS: We conclude that in patients found to have four or more positive lymph nodes at the time of axillary lymph node dissection, conservative surgery followed by radiation therapy to the intact breast with appropriate adjuvant systemic therapy results in a reasonable long-term survival with a high rate of local regional control. Omission of axillary radiation in this subset of patients appears appropriate because there were no axillary failures among the 41 dissected but unirradiated axillae. PMID- 8690634 TI - Local control and functional results after twice-daily radiotherapy for Ewing's sarcoma of the extremities. AB - PURPOSE: Radiotherapy (RT) has been the predominant local treatment for Ewing's sarcoma of bone at the University of Florida. Twice-daily hyperfractionated RT was initiated in 1982 to improve local control and functional outcome. This retrospective review compares the results of once-daily vs. twice-daily RT in patients with primary Ewing's sarcoma of an extremity, with emphasis on functional outcome. METHODS AND MATERIALS: Between June 1971 and January 1990, 37 patients were treated at the University of Florida for nonmetastatic Ewing's sarcoma of bone with a primary lesion in an extremity. Three patients underwent amputation. Of 34 patients treated with RT, 31 had RT alone and 3 had a combination of RT and local excision. Before 1982, 14 patients received once daily RT; since 1982, 17 patients have received twice-daily RT. Doses of once daily RT varied from 47 to 61 Gy at 1.8-2 Gy per fraction. Doses of twice-daily RT varied, depending on the response of the soft-tissue component of the tumor to chemotherapy, and ranged from 50.4 to 60 Gy at 1.2 Gy per fraction. Some patients in the twice-daily RT group also received total body irradiation 1-3 months after local RT as part of a conditioning regimen before marrow-ablative therapy with stem cell rescue. They received either 8 Gy in two once-daily fractions or 12 Gy in six twice-daily fractions. The six patients who received surgery were excluded from local control analysis. Local control rates were calculated using the Kaplan Meier (actuarial) method. Fifteen patients had a formal functional evaluation. RESULTS: In the 31 patients treated with RT alone, the actuarial local control rate at 5 years was 81% for patients treated twice daily and 77% for those treated once daily (p = NS). No posttreatment pathologic fractures occurred in patients treated twice daily, whereas five fractures occurred in those treated once daily (p = 0.01). On functional evaluation, less loss in range of motion (15 degrees vs. 28 degrees of loss, p = 0.02) and a lesser degree of muscle atrophy (8% vs. 21% loss in muscle circumference, p = 0.0004) occurred with twice-daily than with once-daily RT. A trend toward less fibrosis and less local alopecia was seen in patients treated twice daily. Patients treated twice daily received a higher Musculoskeletal Tumor Society functional rating (determined by the Department of Orthopaedics) than those treated once daily (29.4 vs. 26.0, p = 0.15). CONCLUSIONS: Local control rates were similar in the two groups (77% vs. 81%), but functional results were superior in the group treated twice daily. PMID- 8690635 TI - Hip stiffness following mixed conformal neutron and photon radiotherapy: a dose volume relationship. AB - PURPOSE: To determine the relationship between dose, volume, and the incidence of hip stiffness in patients who received conformal neutron irradiation for prostate cancer. METHODS AND MATERIALS: A series of dose-searching studies using neutron irradiation for prostate cancer were performed to determine the optimal dose, fraction size, field size, technique, and proportions of photon and neutron dose. Neutron doses ranged from 9 to 20 Gy and photon doses ranged from 0 to 38 Gy. Data were analyzed by using a hip stiffness grading scale. RESULTS: Hip stiffness was recorded on follow-up examination in 30% of patients (40 out of 132) treated with fast neutrons or mixtures of fast neutron and photon radiation for prostate cancer. Hip stiffness was categorized as none (Grade 0, 92 patients), mild (Grade 1, 24 patients), moderate (Grade 2, 10 patients), or severe (Grade 3, 6 patients). The incidence of hip stiffness differed significantly by dose and volume in the five dose levels studied (p < 0.001). CONCLUSIONS: By using a mixture of conformal neutron and photon irradiation and limiting the total neutron dose to less than 13 Gy, hip stiffness toxicity could be reduced to acceptable levels. PMID- 8690636 TI - The relationship between tumor oxygenation and cell proliferation in human soft tissue sarcomas. AB - PURPOSE: In malignant tumors the oxygenation status and tumor cell proliferation are known to influence local tumor control after radiotherapy. However, the relationship between oxygenation status and tumor cell kinetics in human tumors has not yet been described. Newly developed clinically applicable techniques such as oxygen electrode measurements and assessment of tumor cell proliferation rates have been suggested as promising predictive assays. The purpose of the present study was to characterize tumor oxygenation status in soft tissue sarcomas and to compare this with tumor cell kinetics and clinical parameters. METHODS AND MATERIALS: Pretreatment tumor oxygenation status was measured by polarographic oxygen needle electrodes and evaluated as the median pO2 and the percentage of pO2 values < or = 5 mmHg and < or = 2.5 mmHg in 22 patients with primary soft tissue sarcomas. All tumors were characterized by histology, grade of malignancy, the level of microscopic necrosis, the level of effective hemoglobin, and magnetic resonance imaging estimation of tumor volume. The tumor cell potential doubling time and labeling index were measured by flow cytometric and immunohistochemical analysis of tumor biopsy specimens after in vivo incorporation of iododeoxyuridine. RESULTS: There was a significant correlation between the median pO2 and the tumor cell potential doubling time (p = 0.041), whereas no correlation was found between the level of hypoxia expressed by the percentage of pO2 values < or = 2.5 and < or = 5 mmHg, respectively, and tumor cell potential doubling time. Furthermore, no correlation was found between either of the three tumor oxygenation parameters and labeling index. The material represented large intertumor heterogeneity in oxygenation status, cell kinetics, and tumor volume, and no correlation was found between oxygenation status and either volume, histopathology, grade of malignancy, or effective hemoglobin. CONCLUSION: This report is the first to suggest a correlation between tumor oxygenation and tumor cell doubling time, as the fastest proliferating tumor cells were found in the poorest oxygenated soft tissue sarcomas. More data are needed to clarify if this relation is really a true biological phenomenon. Furthermore, tumor oxygenation status of soft tissue sarcomas was heterogeneous and independent of clinical and histopathological parameters. PMID- 8690637 TI - Ionizing radiation effects on the KG1a primitive hematopoietic cell line. AB - PURPOSE: Better understanding of radiation-induced effects on the hematopoietic system is important in both the context of therapeutic intervention and accidental exposure. However, direct study of these effects on the hematopoietic stem cell pool is hampered by the small number of accessible cells. We, thus, studied radiation-induced effects on the KG1a stem cell line. METHODS AND MATERIALS: We confirmed and extended the immunophenotype of KG1a with monoclonal antibodies, established a radiation survival curve, and quantified mRNAs by Northern blotting 30 min after 1, 2, and 3 Gy of ionizing radiation (IR) and followed for up to 48 h after a 3 Gy dose. Cell cycle status and apoptosis were assessed by fluorescent-activated cell sorter (FACS) analysis, cell morphology, and DNA fragmentation. RESULTS: KG1a was found to be CD34+, CD7+, Thy1 low, CD38 low, lineage negative (neg), C-KITneg and HLA-DRneg, a phenotype consistent with a primitive hematopoietic origin. This immunophenotype was not altered by x-ray irradiation. The D0 value was 1.75 Gy. We showed a time-dependent variation of c jun mRNA expression with an early and transient dose-dependent induction followed by a second increase at 24 and 48 h: a biphasic dose-dependent variation of bcl-2 expression 30 min after irradiation with a reduction of mRNA level at 1 Gy, and a normalization at higher doses and stable levels of mRNA for c-fos, c-myc, G-CSF, GM-CSF, IL-6, TNF-alpha, TGF-beta, and MIP-1 alpha genes. Cell cycle analysis showed the absence of G1/S phase arrest, a point consistent with the absence of detection of P53 mRNA by Northern blot analysis. The dose-dependent G2/M phase arrest was not followed by significant apoptotic cell death. CONCLUSION: Taken together, this data indicates that radiation-induced cell death of KG1a, a cell line that has a relatively high D0 value, does not seem to be the result of the apoptotic pathway but occurs subsequent to a G2/M phase arrest. PMID- 8690639 TI - Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group. AB - PURPOSE: Claims for the value of hyperthermia as an adjunct to radiotherapy in the treatment of cancer have mostly been based on small Phase I or II trials. To test the benefit of this form of treatment, randomized Phase III trials were needed. METHODS AND MATERIALS: Five randomized trials addressing this question were started between 1988 and 1991. In these trials, patients were eligible if they had advanced primary or recurrent breast cancer, and local radiotherapy was indicated in preference to surgery. In addition, heating of the lesions and treatment with a prescribed (re)irradiation schedule had to be feasible and informed consent was obtained. The primary endpoint of all trials was local complete response. Slow recruitment led to a decision to collaborate and combine the trial results in one analysis, and report them simultaneously in one publication. Interim analyses were carried out and the trials were closed to recruitment when a previously agreed statistically significant difference in complete response rate was observed in the two larger trials. RESULTS: We report on pretreatment characteristics, the treatments received, the local response observed, duration of response, time to local failure, distant progression and survival, and treatment toxicity of the 306 patients randomized. The overall CR rate for RT alone was 41% and for the combined treatment arm was 59%, giving, after stratification by trial, an odds ratio of 2.3. Not all trials demonstrated an advantage for the combined treatment, although the 95% confidence intervals of the different trials all contain the pooled odds ratio. The greatest effect was observed in patients with recurrent lesions in previously irradiated areas, where further irradiation was limited to low doses. CONCLUSION: The combined result of the five trials has demonstrated the efficacy of hyperthermia as an adjunct to radiotherapy for treatment of recurrent breast cancer. The implication of these encouraging results is that hyperthermia appears to have an important role in the clinical management of this disease, and there should be no doubt that further studies of the use of hyperthermia are warranted. PMID- 8690638 TI - Conformal radiation treatment of prostate cancer using inversely-planned intensity-modulated photon beams produced with dynamic multileaf collimation. AB - PURPOSE: To implement radiotherapy with intensity-modulated beams, based on the inverse method of treatment design and using a multileaf collimation system operating in the dynamic mode. METHODS AND MATERIALS: An algorithm, based on the inverse technique, has been integrated into the radiotherapy treatment-planning computer system in our Center. This method of computer-assisted treatment design was used to derive intensity-modulated beams to optimize the boost portion of the treatment plan for a patient with a T1c cancer of the prostate. A dose of 72 Gy (in 40 fractions) was given with a six-field plan, and an additional 9 Gy (in five fractions) with six intensity-modulated beams. The intensity-modulated fields were delivered using dynamic multileaf collimation, that is, individual leaves were in motion during radiation delivery, with the treatment machine operating in the clinical mode. Exhaustive quality assurance measurement and monitoring were carried out to ensure safe and accurate implementation. RESULTS: Dose distribution and dose-volume histogram of the "inverse method" boost plan and of the composite (72 Gy primary + 9 Gy boost) plan were judged clinically acceptable. Compared to a manually designed boost plan, the inverse treatment design gave improved conformality and increased dose homogeneity in the planning target volume. Film and ion chamber dosimetry, performed prior to the first treatment, indicated that each of the six intensity-modulated fields was accurately produced. Thermoluminescent dosimeter (TLD) measurements performed on the patient confirmed that the intended dose was delivered in the treatment. In addition, computer-aided treatment-monitoring programs assured that the multileaf collimator (MLC) position file was executed to the specified precision. In terms of the overall radiation treatment process, there will likely be labor savings in the planning and the treatment phases. CONCLUSIONS: We have placed into clinical use an integrated system of conformal radiation treatment that incorporated the inverse method of treatment design and the use of dynamic multileaf collimation to deliver intensity-modulated beams. The system can provide better treatment design, which can be implemented reliably and safely. We are hopeful that improved treatment efficacy will result. PMID- 8690640 TI - Initial results of a phase II trial of high dose radiation therapy, 5 fluorouracil, and cisplatin for patients with anal cancer (E4292): an Eastern Cooperative Oncology Group study. AB - PURPOSE: A prospective clinical trial was performed to assess the response and toxicity associated with the use of high dose radiation therapy, 5-fluorouracil, and cisplatin in patients with anal cancer. METHODS AND MATERIALS: Patients with anal cancer without distant metastasis were eligible for this study. Radiation therapy consisted of 59.4 Gy in 33 fractions; a 2 week break in treatment was taken after 36 Gy had been given. A treatment of 5-fluorouracil, 1,000 mg/m2 per day intravenously, was given for the first 4 days of radiation therapy, and cisplatin, 75 mg/m2 intravenously, was given on day 1 of radiation therapy. A second course of 5-fluorouracil and cisplatin was given after 36 Gy of radiation, when the radiation therapy was resumed. RESULTS: Nineteen patients entered this study and received treatment. Thirteen (68%) had a complete response, 5 (26%) had a partial response, and 1 (5%) had stable disease. The patient with stable disease and one of the patients with a partial response had complete disappearance of tumor more than 8 weeks after completion of radiation therapy. Fifteen patients had toxicity of Grade 3 or higher: the worst toxicity was Grade 3 in eight patients, Grade 4 in six patients, and Grade 5 in one patient. The most common form of toxicity of Grade 3 or higher was hematologic. The one lethal toxicity was due to pseudomembranous colitis, which was a complication of antibiotic therapy for a urinary tract infection. CONCLUSION: Radiation therapy, cisplatin, and 5-fluorouracil resulted in an overall response rate of 95%. Significant toxicity occurred, an indication that this regimen is near the maximal tolerated dose. A Phase III clinical trial is planned in which radiation therapy, cisplatin, and 5-fluorouracil will be used as an experimental arm. PMID- 8690641 TI - Evaluation of HER-2 neu oncoprotein expression as a prognostic indicator of local recurrence in conservatively treated breast cancer: a case-control study. AB - PURPOSE: The purpose of this study is to determine the prognostic significance of overexpression of the HER-2 neu oncoprotein with respect to local relapse following conservative surgery and radiation therapy (CS + RT). METHODS AND MATERIALS: Twenty consecutive patients who sustained a local recurrence as the first and only site of failure following CS + RT comprised the case population base for this study. Only patients who received no adjuvant systemic chemotherapy or tamoxifen were selected for analysis. Following the identification of 20 consecutive local-relapse patients, the patient database was searched for 20 matching control patients who did not sustain a local relapse. Each control patient was matched to the index case with respect to age, menopausal status, follow-up, primary histology, axillary nodal status, and primary tumor size. Both index cases and the matched control group received full course radiation therapy, to a total dose of 64 Gy to the tumor bed. The paraffin-embedded blocks of the original primary tumor of the local-relapse cases and the primary tumor of 20 matched controls were processed for immunohistochemical staining of the HER-2 neu oncoprotein. Each slide was rated on the 3-point scale, 0 representing no stain, 1+ indicating light staining, and 2+ denoted heavy staining (overexpression). RESULTS: Of the 20 index cases, with each of the matched controls, 16 were evaluable for analysis. The 4 cases that were eliminated had inadequate paraffin embedded material in either the case or the match control for adequate staining. By design of the study, the index case group and control group had similar ages (52 years index vs. 51.4 control), follow-up (10.8 years index vs. 10.5 years control), and histologies. For the immunostaining, a value of 2+ was considered to denote high activity and overexpression, and 0 and 1+ were considered negative values. Using these criteria, a total of 9 of the 16 index cases (56%) exhibited overexpression of HER-2 neu oncoprotein, and only 3 of the 16 control cases (18%) demonstrated high immunoreactivity. The difference in immunostaining between the index and control cases was statistically significant by a Pierson chi-square analysis at the p = 0.03 level. CONCLUSIONS: In this matched case-control study, overexpression of the HER-2 neu oncoprotein appears to have prognostic significance with respect to local relapse in the conservatively treated breast. The correlation of overexpression of HER-2 neu by multivariable analysis with other prognostic factors for local recurrence warrants further investigation. The clinical implications of the study are discussed. PMID- 8690642 TI - Local excision and external beam radiotherapy in early rectal cancer. AB - PURPOSE: To assess the local control and survival of local excision and postoperative radiation in patients with early stage rectal cancer. METHODS AND MATERIALS: From 1980 to 1992, 21 patients with clinical stage T1-2NxM0 adenocarcinoma of the middle and lower rectum were treated with transanal excision and postoperative external beam radiotherapy (44.6 Gy). The pathologic T stages were: 9 T1 (43%) and 12 T2 (57%). One patient had unassessable resection margins. The median follow-up was 54 months (range: 18-128 months). RESULTS: The actuarial local recurrence-free survival at 5 years was 85.2%, and the overall survival at 5 years was 80.6%. One patient developed a local recurrence and distant metastases at 22 months, and two patients had local recurrence at 11 and 15 months, respectively; both had abdomino-perineal resection (APR) and one remained free of disease 16 months after APR. The incidence of Grade 3 diarrhea was 5%. Sphincter function was good to excellent in the 18 patients with local control. No patients developed clinical evidence of pelvic lymph node recurrence. CONCLUSION: These results are similar to other published series and suggest that this approach is feasible in selected patients with T1-2NxM0 rectal cancer and results in good long-term control of the disease. PMID- 8690643 TI - A method for producing uniform dose distributions in the junction regions of large hinge angle electron fields. AB - PURPOSE: The planning problems presented by abutting electron fields are well recognized. Junctioning electron fields with a large hinge angle compounds the problems because of the creation of closely situated high dose and low-dose regions. METHODS AND MATERIALS: The technique involving a compensated superficial x-ray (SXR) field to treat the junction region between electron fields was developed and used in a particular clinical case (treatment of a squamous cell carcinoma of the forehead/scalp). The superficial x-ray beam parameters were chosen and the compensator was designed to make the SXR field complementary to the electron fields. RESULTS: Application of a compensated SXR field eliminated low dose zones in the junction region and reduced high dose zones to 110%. In the clinical case discussed, the high-dose areas due to the SXR field would not appear because of increased attenuation of the soft X-rays in bone. CONCLUSION: The technique proposed produces uniform dose distribution up to 3 cm deep and can be considered as an additional tool for dealing with electron field junctioning problems. PMID- 8690644 TI - Dynamic radiotherapy: interactive movement of patient couch for treatment of craniospinal axis. AB - PURPOSE: The various techniques that have been described for treatment of the craniospinal axis show the common challenge of edge matching between adjacent orthogonal and parallel photon beams. Such edge matching is needed because the maximum field length provided by modern treatment machines is generally insufficient to treat adults with less than three matching fields. Using the common techniques, field edge matching becomes difficult, if for medical reasons, the patient cannot be treated in the prone position. METHODS AND MATERIALS: A scanning couch technique is proposed, with the patient lying in supine position. After treating the cerebral and upper neck regions by two lateral opposed half beam fields defined by asymmetric collimators (split beam), the patient is being moved along the spinal axis through an 8.0 cm wide by 15.0 cm long posterior split beam (allowing edge matching with the lateral fields at the neck region) by means of remote controlled couch movement. Stopping and starting of the scanning field resulted in a linear decrease of dose on both sides of the scan. Two ways of resolving this problem were investigated. RESULTS: The administered dose varied less than 8.5% through the craniospinal axis. Flatness of the rectangular scanned field was 0.76%. Apart from dose homogeneity, patient comfort and decreased simulation time are major advantages. CONCLUSIONS: The proposed technique represents a suitable alternative using a common linear accelerator, requiring a remote couch controller as an additional component. PMID- 8690645 TI - Accuracy of field alignment in abdominal radiation therapy. AB - PURPOSE: To assess the accuracy of field alignment in a homogeneous group of patients undergoing radiotherapy of the abdomen (adjuvant treatment of the paraaortic region in Stage I testicular seminoma). To evaluate the predictive value of the first verification on field placement errors during subsequent treatment delivery. METHODS AND MATERIALS: In 45 patients, linear and rotational discrepancies were measured between simulation and first check and between 10 consecutive verification films. RESULTS: For the total group of patients, the distribution of all deviations showed mean values between 2.3 mm and -2.7 mm with standard deviations of 3.9 mm to 4.7 mm for linear discrepancies, and -0.5 degree to 0.3 degree with standard deviations of 1.2 degrees to 2.1 degrees for rotational discrepancies, respectively. For all patients, deviations for the transition from simulator to the treatment machine were similar to deviations during subsequent treatment delivery, with 95% of all absolute deviations < 10.0 mm and 4 degrees, respectively. When performing correlation analysis between deviations at first check and during treatment delivery, a correlation for lateral displacements and a borderline correlation for caudal displacements could be found. There was no correlation for cranial and rotational displacements. CONCLUSIONS: Although a trend of deviations for subsequent treatment delivery may be shown at first check, our analysis indicates that the first verification cannot reliably predict inaccuracies during treatment delivery. Random fluctuations of field displacements of up to 1.0 cm prevail. They must be considered when prescribing the safety margins of the planned target volume and determining cutoff points for corrective actions in abdominal radiation therapy. PMID- 8690646 TI - The use of scattering foil compensators in electron beam therapy. AB - PURPOSE: This study was undertaken to show that scattering foils could be used as electron beam compensators. METHODS AND MATERIALS: Two scattering foils were designed to improve the dose homogeneity when a curved surface is irradiated with electrons. One scattering foil, constructed of mylar, was designed for use with a single 6 MeV electron field. The second scattering foil, constructed of lead, was designed to homogenize the dose along the matchline of two abutting electron fields. Measurements with the second compensator were made at energies of 6, 9, and 12 MeV. The compensators were mounted over the topmost opening of the electron cone. A simple method for modeling the effect of the second compensator using a conventional treatment planning system was also evaluated. RESULTS: When the mylar compensator was placed atop the 25 x 25 cm cone and a Rando phantom irradiated with 6 MeV electrons, the dose at the field edges was increased by about 10%. Use of the lead foil compensator for two abutting fields gave a highly uniform dose along the matchline, without perturbing the isodoses at depth or at the other field edges. Measured hot spots in the Rando phantom for 6 and 9 MeV electrons were 104 and 108%, respectively. The effect of the lead foil compensator was successfully modeled on a conventional treatment planning system by summing beams of different field sizes. CONCLUSIONS: Both compensators were effective in improving the dose homogeneity within the target volume. PMID- 8690647 TI - How radiation oncology emerged as a discipline in Finland. AB - The news about the discovery of Rontgen's new rays spread over Finland quite early, and the first Finnish writing about the rays appeared in February 1896. The first x-ray machine was installed in 1897. Proper training of radiologists began, however, at a comparatively late date. For a long time the position of radiologists remained a subordinate one. Radiology had the nature of a spare time hobby, because in most hospitals surgeons treated x-ray machines as a sideline. Because of this, scientific research work was delayed. The specialty of x-ray diagnosis and therapy was, however, established in 1921, and the Finnish Society of Radiology was founded in 1924. The first radiotherapy department with its own beds was opened in 1936 in Helsinki. In 1950, the first professor of medical radiology was appointed at the University of Helsinki. The Finnish Cancer Society played an important role in developing the radiotherapy net in the country by supplying cobalt devises and auxiliary hospital activities in the 1960s. In the early 1960s roentgen diagnosis and radiotherapy were separated into two distinct disciplines. There are now five medical faculties with chairs in radiation oncology. The country is divided into five regions for cancer care. The managing groups in each region are headed by the professor of radiotherapy and oncology. The radiation oncologists in Finland are involved in diagnosis and staging of cancer and are responsible for radiation therapy, chemotherapy and hormones. They are responsible for follow-up of treated patients, their own wards, and the general care of their patients. PMID- 8690648 TI - An outline of the history of radiation oncology in Poland. PMID- 8690649 TI - The development of radiotherapy in Slovenia. AB - The historical data on the development of radiotherapy in Slovenia are presented from its first use in this county in 1902 until the present. The Institute of Oncology in Ljubljana was established in 1938 with the intention of providing a sound development of radium and roentgen cancer treatment. After World War II, the development of radiotherapy was dynamic, which is evident from the data on new radiation sources in external beam therapy (accelerators, telecobalt units), in brachytherapy (various sealed radioisotopes) as well as in the introduction of therapy with unsealed radioisotopes. In 1947, a Chair of Oncology and Radiotherapy was instituted at the Medical Faculty of the University of Ljubljana (with the seat at the Institute of Oncology). In 1955, radiotherapy and oncology were officially recognized as a separate branches of medicine requiring special obligatory postgraduate residency training. Within the Medical Society of Slovenia, the Section for Radiotherapy was established in 1987. The following year, the Section for Radiotherapy of Slovenia became a member of the European Society for Therapeutic Radiology and Oncology. Considering the size of population of Slovenia (nearly 2 million), it was reasonable that by this time radiotherapy became almost completely concentrated in one central institution, the Institute of Oncology, whose core and cohesive activity were represented in the multidisciplinary cancer treatment approach. PMID- 8690650 TI - A short history of the development of oncology in Israel. PMID- 8690651 TI - Manpower needs for radiation oncology: a preliminary report of the ASTRO Human Resources Committee. American Society for Therapeutic Radiology and Oncology. AB - In summary, the ASTRO Committee on Human Resources believes that there is ample evidence for the existence of an oversupply of radiation oncologists in the United States at the present time. It believes that this oversupply has already affected the specialty in a variety of ways that are difficult to measure, for example, increased competition, conflicts between radiation oncology groups, conflicts between the private sector and academics, and increased costs, and that it is beginning to have a significant effect on the job market. This oversupply came about because of the rapid expansion in medical school enrollment in the 1970s. This led to an increased number of graduates available for enrollment into specialty residencies, one of which was radiation oncology. The actual number of radiation oncology residency positions offered has not changed significantly since 1972. However, only about half of the residency positions were filled in the early years. Since 1986, virtually all radiation oncology training positions in the United States have been filled, and this has led to a significantly greater number of radiation oncologists entering the field than have left the field through death or retirement. Preliminary data suggest that a shift to a managed care system would result in decreased demand for radiation oncology services, and that would increase the manpower problem for our specialty. PMID- 8690652 TI - Training the radiation oncologist for the twenty-first century. PMID- 8690653 TI - Economic analyses in health care: an introduction to the methodology with an emphasis on radiation therapy. AB - Payers are increasingly interested in knowing whether they are receiving value for the dollars they spend on health care. Because economic analysis will be used as a means of evaluating radiation therapy, it is important that radiation oncologists understand the basic methodology employed in such analyses. This review article describes the four basic types of economic analyses: cost minimization, cost effectiveness, cost utility, and cost benefit. Specification of alternative therapies, choice of perspective of the analysis, measurements of costs and benefits, and the role of discounting and sensitivity analyses are discussed. Published economic analyses that pertain directly to treatment with radiation therapy are reviewed. Finally, we close with a brief discussion of the potential areas for future economic outcomes research in radiation oncology. PMID- 8690654 TI - Sequencing: one big tree in the forest on breast cancer management. PMID- 8690655 TI - Intensity-modulated radiation therapy. PMID- 8690656 TI - Economic analyses: new endpoints for clinical trials. PMID- 8690657 TI - On manpower needs and solutions. PMID- 8690658 TI - Too many radiation oncologists? An empirical report. PMID- 8690659 TI - Regarding Lee et al. IJROBP 33(2):375-389; 1995. PMID- 8690660 TI - Prostate cancer--evaluating cancer-free survival: regarding Hahn et al. IJROBP 34(1):41-47; 1996. PMID- 8690661 TI - Regarding Fein et al. IJROBP 34(5):1009-1017; 1996. PMID- 8690662 TI - Glenn Wade Salisbury, 1910-1994: a brief biography. PMID- 8690663 TI - Metabolic changes and nutrient repletion in lambs provided with electrolyte solutions before and after feed and water deprivation. AB - Providing feeder calves and lambs with electrolyte solutions before and(or) after a transport period could potentially reduce tissue shrink and speed repletion of nutrients and weight that are lost during transport. This trial was conducted to determine metabolic changes and nutrient repletion in lambs provided with electrolyte solutions before and after feed and water deprivation. Solutions were 1) deionized water, 2) ES1 (g/10 L: NaCl, 2.0; K carbonate, 2.8; Mg sulfate.7H2O, 2.0; equal mixture of amino acids [Lys, Thr, Phe, His, Trp, Met, Leu, Ile, and Val], .45; and phosphoric acid to pH 7.0), 3) ES2 (twice the concentrations as in ES1), and ES3 (g/10 L: NaCl 2.0; K carbonate, 8.0; Mg sulfate.7H2O, 4.0; amino acid mixture from ES1, .45; and phosphoric acid to pH 7.0). Eight Suffolk x Hampshire crossbred lambs (average BW 35 +/- 2 kg) were used in an 8 x 8 Latin square design with treatments arranged in a 2 x 4 factorial. Main treatments consisted of two deprivation electrolyte solutions (deionized water or ES1) and four realimentation electrolyte solutions (deionized water, ES1, ES2, and ES3). Lambs were limit-fed (600 g/d, as-fed basis) before and after a 3-d feed and water deprivation phase. Lambs provided the ES1 solution during the pre deprivation phase had greater (P < .05) Na, Mg, Zn retention during the pre deprivation phase, had greater (P < .05) Na and Mg losses during the 3-d deprivation phase, and greater (P < .05) cumulative Na, Cu, and Fe retentions than lambs given deionized water during the pre-deprivation phase. Compared to lambs provided water, lambs provided the ES1 solution during the realimentation phase had greater Na retention but similar K, Mg, and water retentions. However, when the concentration of electrolytes in the solution was doubled (i.e., ES2 solution), Na, K, and Mg retentions were increased (P < .05) compared with those of lambs provided deionized water or the ES1 solution. These results suggest that as the length or severity of the stress period increases, the concentration of electrolytes in the electrolyte solution may need to be increased to improve nutrient balance. PMID- 8690664 TI - Heat tolerance in two tropically adapted Bos taurus breeds, Senepol and Romosinuano, compared with Brahman, Angus, and Hereford cattle in Florida. AB - Two trials were conducted with heifers to determine heat tolerance among temperate Bos taurus (Angus, Hereford), Bos indicus (Brahman), tropical Bos taurus (Senepol, Romosinuano), and the reciprocal crosses of Hereford and Senepol. Differences among breeds in temperament score, circulating concentrations of cortisol, and blood packed cell volume were also investigated. Trial 1 used 43 Angus, 28 Brahman, 12 Hereford, 23 Romosinuano, 16 Senepol, 5 Hereford x Senepol (H x S), and 5 Senepol x Hereford (S x H) heifers. Trial 2 used 36 Angus, 31 Brahman, 9 Hereford, 14 Senepol, 19 H x S, and 10 S x H heifers. On the hottest summer date in Trial 1, rectal temperature of Angus was greater (P < .001) than that of Brahman, Senepol, or Romosinuano. Rectal temperature and plasma cortisol were significantly less in Senepol than in Brahman, suggesting that the differences in rectal temperature between these breeds may be due to differences in stress response possibly related to differences in temperament. Reciprocal crosses of Hereford and Senepol had rectal temperatures nearly as low as that of Senepol and displayed substantial heterosis (-9.4%, P < .05) in log10 rectal temperature on the hottest summer date. On both the hottest and coolest dates in Trial 1, Angus heifers had significantly faster respiration rates than Brahman, Romosinuano, or Senepol heifers, and Brahman had significantly slower respiration rates than Romosinuano or Senepol. On the hottest summer date in Trial 2, rectal temperature in Angus heifers was greater (P < .001) than in Brahman or Senepol had rectal temperatures similar to that of Senepol, or heterosis for log10 rectal temperature was similar to that in Trial 1 (-9.8%, P < .05). Considering rank order among breeds, Brahman always had the slowest respiration rate and greatest packed cell volume. Brahman had significantly greater temperament scores and plasma cortisol concentrations than Angus or Senepol, except that plasma cortisol was not different between Brahman and Senepol on the hottest summer date. On this date, rectal temperature did not differ between Brahman and Senepol, which supports the hypothesis that there is a relationship between response to stress and rectal temperature that helps explain differences in rectal temperature between Brahman and Senepol. The results of these trials demonstrate heat tolerance of the Senepol and Romosinuano, two Bos taurus breeds. Furthermore, the results suggest a substantial level of dominance of the Senepol's ability to maintain constant body temperature in a hot environment as measured by rectal temperature in crosses with a non-adapted breed. PMID- 8690665 TI - Effect of phenotypic expression of Brahman breeding on marbling and tenderness traits. AB - Steers with known proportions of Brahman and Hereford breeding (80 quarter bloods, 25% Brahman x 75% Hereford and 79 half-bloods, 50% Brahman x 50% Hereford) were used to determine the effect of phenotype on marbling and beef tenderness characteristics. Three experienced evaluators independently classified each live steer according to estimated proportion of Brahman breeding based on phenotypic evidence of Brahman breed characteristics. The steers were slaughtered, their carcasses were graded, and a carcass. Samples of longissimus muscle were obtained for measurement of 24-h calpastatin activity, sensory panel evaluation, and Warner-Bratzler shear (WBS) force measurements. Paired steaks were aged (6 and 18 d postmortem) and palatability determinations were completed. Estimates of live animal phenotype ranged from 0/16 to 9/16 for quarter-blood Brahman steers and from 1/14 to 13/16 for half-blood Brahman steers. Neither live animal phenotype nor carcass hump height was correlated with marbling score. Live animal phenotype was correlated (P < .01) with taste panel tenderness ratings (rd6 = -.36; rd18 = .36) and shear force values (rd6 = .36; rd18 = .30). Moreover, carcass hump height exhibited low, negative correlations (P < .05) with panel tenderness scores (rd6 = -.16; rd18 = -.28) and low, positive correlations (P < .10) with shear force (rd6 = .13; rd18 = .16). Steaks from steers classified as more than 3/8 Brahman were tougher (P < .05) than steaks from steers classified as 3/8 or less Brahman. Steaks from carcasses with hump height measurements of 7.60 cm or greater had lower panel tenderness ratings and higher WBS values (P < .05) than steaks from carcasses with hump heights less than 6.35 cm. Quarter-blood and half-blood Brahman steers that were similar in phenotype produced steaks that were similar in tenderness. Results of this study suggest that as phenotypic evidence of Brahman breeding increases the tenderness of cooked steaks from Brahman crossbred steers decreases. PMID- 8690666 TI - Influence of flake density on the feeding value of steam-processed corn in diets for lactating cows. AB - Four primiparous Holstein cows (112 d in lactation) with cannulas in the rumen and proximal duodenum were used in a 4 x 4 Latin square design. Dry-rolled (DR) corn (density .52 kg/L) was compared with stream-flaked (SF) corn processed to three flake densities: .39, .32, and .26 kg/L. The basal diet contained (DM basis) 43.4% alfalfa hay, 39.5% corn (DR or SF), 2.2% yellow grease, 9.6% cane molasses, .7% sodium bicarbonate, and 4.6% protein-mineral supplement. Steam flaking increased DM intake (P < .01). There were no treatment effects on ruminal pH (P > .10). Ruminal molar ratios of acetate and propionate were lower (P < .01) for SF than for DR corn and declined (linear component, P < .01) as flake density decreased. Ruminal digestibility of OM was not affected (P > .10) by corn processing. Ruminal starch digestibility increased (linear component, P < .05) as flake density decreased. Ruminal ADF digestibility was decreased by SF (P < .01); this effect was exacerbated by degree of processing (linear component, P < .05). Ruminal N efficiency (duodenal nonammonia N/N intake) was greater (P < .10) for SF than for DR corn because of an improved (P < .10) microbial efficiency. Steam flaking at all densities increased postruminal digestibility of OM (42.4%, P < .01), starch (84.9%, P < .01) N (13.6%, P < .01), and lipid (11.8%, P < .05). Total-tract digestibilities of OM, N, starch, DE and ME were greater (15.2, 11.5, 25.2, 14.9, and 20.0%, respectively, P < .01) for SF (mean of the three densities) than for DR corn. Total-tract digestibility of starch increased (linear component, P < .10) with degree of processing. However, this effect was offset by decreased (linear and quadratic components, P < .05) ADF digestibility. Steam flaking improved the feeding value of corn for lactating cows by improving diet acceptability and digestibility of lipid, starch, and N. Steam flaking increased the estimated NEl of corn by 33%. Optimal flake density probably is between .32 and .39 kg/L. PMID- 8690667 TI - Unconstrained procedures for the estimation of positive definite covariance matrices using restricted maximum likelihood in multibreed populations. AB - Two unconstrained procedures to ensure that intrabreed and interbreed genetic and environmental covariance estimates for multibreed populations are computed within the permissible ranges were developed. These procedures were called Partial Scoring and Cholesky Maximization. The Partial Scoring procedure uses partial steps to keep estimates of covariance matrices positive definite at each expectation-maximization (EM) iteration, and the Cholesky Maximization procedure achieves the same goal by computing the elements of the Cholesky Decomposition of each intrabreed and interbreed genetic and environmental covariance matrix. Groups of small simulated data sets containing either direct genetic effects of two traits (90 bulls, 13,500 calves) or direct and maternal genetic effects for a single trait (135 bulls, 32,400 calves) were used to test the computational feasibility of these two procedures. The overall means (and ranges) of the numbers of expectation-maximization iterations, times to convergence, and accuracy of estimation were 10 (2 to 184), 26.2 min (4.1 to 773.2 min), and 40.1% (12.7 to 81.9%) for the Partial Scoring procedure and 7 (3 to 37), 16.7 min (9.5 to 64.6 min), and 37.8% (3.1 to 67.8%) for the Cholesky Maximization procedure. Although the overall accuracy of both procedures was similar, the Cholesky Maximization procedure should be preferred because it converged faster and its covariance estimates were less affected by the values of the covariance priors than those computed using the Partial Scoring strategy. Application to large unbalanced multibreed data sets will require an iterative version of these procedures. PMID- 8690668 TI - Genetic relationships of lamb weight, maternal ability, and mature ewe weight in Swedish finewool sheep. AB - Genetic parameters were estimated for weights of lambs from birth to 1 d before slaughter and mature ewe weight (EMW) using REML procedures and single- and two trait animal models. The data consisted of weight registrations from 5,001 animals descended from 131 sires, 788 dams, 48 maternal grandsires, and 530 maternal granddams in an experimental flock with Swedish finewool sheep. Direct heritabilities increased with lamb age from .07 for birth weight to .21 for weight before slaughter. Maternal heritabilities declined with age from .30 to .07. Direct-maternal genetic correlations were positive and increased with age from .11 for birth weight to .73 for weight before slaughter. For daily gain during shorter periods, direct heritability increased from .07 for the period from birth until 3 wk of age to .14 for the period from weaning until 1 d before slaughter. The values for maternal heritabilities were .16 and .03, respectively. The direct-maternal genetic correlations ranged from -.11 to .59. The direct heritability for EMW varied between analyses from .29 to .63. A nonsignificant maternal heritability of .22 was noted for EMW. Direct genetic correlations between EMW and various lamb weights varied between .36 to .85. Genetic correlations between direct effects on EMW and maternal effects on lamb weights varied between .39 and .53. Direct and maternal genetic correlations between the lamb weights were positive. The results showed that the maternal influence on lamb weights decreased with age. It was indicated that positive genetic relationships exist between ewe weight and maternal effects on lamb weight. Therefore, selection for larger lamb weights alone will not only increase ewe weights but also improve the maternal ability to the ewe. PMID- 8690669 TI - Lack of maternal influence of lamb consumption of locoweed (Oxytropis sericea). AB - Locoweeds (Oxytropis and Astragalus spp.) are toxic plants found on many rangelands. Preferences for locoweed are learned; livestock often initially reject the plant, but learn to eat locoweed after continued exposure. Maternal influences are important in shaping diet selection in young animals. We studied the influence of ewe consumption of locoweed on lamb selection of the plant. Twenty-four ewes were divided into three treatment groups (n = 8): 1) ewes conditioned to eat locoweed (Oxytropis sericea) and avoid sodgrass (Poa pratensis) (Loco+Sod-); 2) ewes conditioned to avoid locoweed and eat sodgrass (Loco-Sod+); and 3) ewes conditioned to eat sodgrass and not exposed to locoweed (Loco0Sod+). A control group (n = 8) was composed of orphan lambs with no maternal influence (Orphans). All ewes were exposed to locoweed and(or) sodgrass without their lambs for 1 wk. Lambs were exposed to either locoweed or sodgrass with ewes for 5 min/d for 6 d. After weaning, lambs were tested for preferences by offering both locoweed and sodgrass for 3 min/d for 5 d; lambs were then offered only locoweed for 5 min/d for 5 d. Sodgrass was preferred by lambs. Lambs in the Loco+Sod- treatment group tended (P = .06) to take more bites of locoweed than lambs in the Loco0Sod+ group. Also, lambs in the Loco0Sod+ and Loco-Sod+ groups tended (P = .07) to take fewer locoweed bites compared with Orphans. Even though these results tended towards significance, the magnitude of the effect was small. There were no treatment effects when locoweed was offered alone. Although exposure with the mother did not strongly influence lambs to eat (or avoid) locoweed, all lambs ate some locoweed during testing. Short-term maternal influence does not seem to be sufficient to condition a preference for locoweed in lambs. PMID- 8690670 TI - Isolation and characterization of a cDNA clone encoding ovine type I carbonic anhydrase. AB - To identify genes involved in the postnatal development of sheep ruminal epithelium, a lambda gt22a cDNA library was constructed from poly(A)+ RNA isolated from mature sheep ruminal epithelium. A plus/minus screening procedure was used to identify genes expressed in mature but not in neonatal ruminal epithelium. One of the cDNA clones isolated encodes an ovine carbonic anhydrase, based on nucleotide and deduced peptide sequence analysis. The deduced peptide is most closely related to eukaryotic type I carbonic anhydrase, based on comparison with all available carbonic anhydrase sequences. Northern blot hybridization confirmed that the amount of mRNA complementary to the carbonic anhydrase cDNA clone is more than five times higher in ruminal epithelium for mature sheep (12 wk old) than in ruminal epithelium from neonatal lambs (< 12h old). Messenger RNA complementary to this cDNA clone was found only in the epithelium of the ruminant forestomach compartments (i.e., rumen, reticulum, and omasum), but small amounts of hybridizable mRNA were also found in sheep skin. This carbonic anhydrase cDNA clone will allow the study of transcriptional regulation of the carbonic anhydrase gene during ruminal epithelial development. PMID- 8690671 TI - Cytochemical studies of adipose tissue-associated blood vessels in untreated and thyroxine-treated hypophysectomized pig fetuses. AB - Fetal hypophysectomy (hypox) slightly enhances lipid accretion in adipose tissue and markedly increases fat cell size and de novo lipogenesis. Thyroxine (T4) treatment (14 to 20 d) had no influence on fat cell size but markedly increased lipogenesis, lipid accretion, and apparent fat cell number in hypox fetuses. Although vascular development is intimately associated with preadipocyte development in the fetus, little is known concerning the regulation of vascular development per se by T4 and other adipogenic hormones. Therefore, the purpose of the present study was to evaluate the development of qualitative traits of the adipocyte-associated vasculature after fetal hypox with and without T4 treatment. Type IV collagen immunoreactivity of and lectin binding by capillaries in large fat cell clusters was reduced by hypox, and binding of the soybean agglutinin lectin was completely lost. Reactivity for cytosolic markers in capillaries was also reduced by fetal hypox. These blood vessel traits were not influenced by T4 treatment. The qualitative aspects of capillary development in large fat cell clusters were not influenced by hypox or T4 treatment. On a qualitative basis, blood vessels in the skin and in small fat cell clusters were not affected by hypox. Lectin binding by adipocytes was enhanced by hypox regardless of the size of clusters, and T4 augmented this response to hypox. These studies demonstrate that endocrine regulation of the differentiation of the adipocyte-associated vasculature is more complex than the endocrine regulation of adipocyte differentiation per se. PMID- 8690673 TI - Stimulation of circulating insulin-like growth factor I (IGF-I) and insulin-like growth factor binding proteins (IGFBP) due to administration of a combined trenbolone acetate and estradiol implant in feedlot cattle. AB - Objectives of this study were to analyze alterations in circulating IGF-I and insulin-like growth factor binding protein (IGFBP) concentrations due to administration of a combined trenbolone acetate (TBA) and estradiol (E2) implant. This study was part of a larger serial slaughter study in which 64 large-framed (394.1 kg) crossbred steers were randomly assigned to one of four pens. Pens were assigned to one of two treatments: implanted (120 mg of TBA and 24 mg of E2) and nonimplanted. After d 2, 24 steers/treatment remained on the study. These steers were assigned to one of three serial slaughter dates (d 40, 115, and 143). Blood samples were obtained on d 0, 2, 21, 40, 115, and 143 from remaining steers. Serum was harvested and analyzed for IGF-I, IGFBP, and mitogenic activity. Glycyl glycine (GG) extraction of serum was performed to reduce IGFBP interference in the IGF-I RIA. Implantation with TBA+E2 interference in the IGF-I RIA. Implantation with TBA+E2 increased (P < .001) circulating IGF-I concentrations during the period from d 0 to d 40. On d 21 and 40, steers implanted with TBA+E2 had 16 and 22%, respectively, greater (P < .001) circulating IGF-I concentrations than nonimplanted steers. For steers in the study for at least 115 d, TBA+E2 increased (P < .05) IGF-I concentrations 9, 13, and 19% on d 21, 40, and 115, respectively, compared with nonimplanted steers. Implantation with TBA+E2 resulted in greater (P < .05) serum concentration of a 49/39-kDa IGFBP (IGFBP-3) on d 21 and 40 after implantation. Sera from steers implanted with TBA+E2 stimulated proliferation of cultured muscle satellite cells to a greater extent (P < .05) than did sera from nonimplanted steers on d 21, 40, 115, and 143 after implantation. In summary, TBA+E2 increased serum concentrations of both IGF-I and IGFBP-3. Additionally, implantation increased mitogenic activity of sera from implanted as compared to nonimplanted steers. These alterations may be partially responsible for the positive effects of TBA+E2 implants on feedlot performance and rate of protein accretion in steers. PMID- 8690672 TI - Effect of a combined trenbolone acetate and estradiol implant on feedlot performance, carcass characteristics, and carcass composition of feedlot steers. AB - Objectives of this study were to determine the influence of trenbolone acetate (TBA) and estradiol (E2) in a combined implant on feedlot performance, carcass characteristics, and carcass composition in finishing steers. Sixty-four large framed (394.1 kg) crossbred steers were randomly assigned to one of four pens. Subsequently, pens were randomly assigned to one of two treatments, implanted (120 mg of TBA and 24 mg of E2) and nonimplanted. Eight steers/treatment were slaughtered for initial carcass composition. Remaining steers were assigned to one of three serial slaughter dates (d 40, 115, or 143). Implantation increased circulating trenbolone (TBOH) and E2 concentrations throughout the trial. Implantation increased ADG 18% (P < .001) during d 0 to 40, 21% (P < .001) from d 0 to 115, and 16% for the entire 143 d. Implant status had no effect (P > .05) on dry matter intake. Feed efficiency was improved 13% during d 0 to 40 (P < .01) and from d 41 to 115 (P = .07). Longissimus muscle area was larger (P < .05) in implanted steers than in nonimplanted steers on d 115. Carcasses from implanted steers had a smaller (P < .05) percentage of kidney, pelvic, and heart (KPH) fat on d 143 than those from nonimplanted steers. Carcasses from implanted steers possessed more carcass protein (P < .05) on d 40. Implanted steers had an 82% increase (P < .05) in daily carcass protein accretion during the first 40 d. Implantation increased (P < .01) carcass water but did not affect carcass fat accumulation throughout the feeding period. The combined TBA+E2 implant improved feedlot performance and stimulated carcass protein accretion in feedlot steers. PMID- 8690674 TI - The relationship between plasma epinephrine concentration and the activity of the calpain enzyme system in porcine longissimus muscle. AB - The relationship between plasma epinephrine and postmortem activity of the calpain system in porcine longissimus muscle was investigated. Two groups of Large White pigs were continuously infused intravenously with either placebo (control) or epinephrine (treated) at a rate of .15 micrograms.kg-1.min-1 for a period of 1 wk before slaughter. Samples of longissimus muscle were taken at 0, 1, 2, 4, 8, 24, 48, and 192 h (t0 to t192) after slaughter and immediately snap frozen in liquid nitrogen for subsequent analysis of mu-calpain, m-calpain, and calpastatin activity. Epinephrine infusion had no effect on the activities of mu- and m-calpain at t0. Calpastatin activity at t0 was increased (P < .01) in treated pigs by 97%. The ratio of total calpain:calpastatin activity at t0 was reduced (P < .01) in treated pigs. The activity of mu-calpain decreased rapidly after slaughter, irrespective of treatment, dropping to less than 10% of the initial activity within 8 h. The activity of m-calpain also decreased over the first 8 h, although the rate of decrease was less (P < .05) in treated pigs. Consequently, m-calpain activity remained greater in treated pigs compared with controls throughout the period normally associated with tenderization. Postmortem values for calpastatin activity tended to be highly variable, with activities being similar between control and treated pigs within 1 h after slaughter. Over the entire 192 h sampling period, calpastatin activity decreased (P < .001), although the effect was independent of treatment. In general the results imply that variations in plasma epinephrine concentrations, which may naturally occur as part of the stress response, perturb the calpain enzyme system. PMID- 8690675 TI - Histology and composition of muscles from normal and callipyge lambs. AB - The histology and composition of muscles from normal (n = 10) and callipyge (n = 11) wether lambs was compared. Normal Rambouillet ewes were mated with callipyge Dorset rams, and their progeny were visually classified as callipyge or normal based on muscle definition in the loin and hind quarters. The muscles examined included three muscles that hypertrophy in callipyge lambs (semitendinosus, longissimus, and gluteus medius) and one muscle believed not to hypertrophy (supraspinatus). The hypertrophy-responsive muscles from callipyge lambs had a higher (P < .001) percentage of fast-twitch glycolytic (FG) fibers and lower (P < .001; P < .02 for SO in gluteus medius) percentages of slow-twitch oxidative (SO) and fast-twitch oxidative glycolytic (FOG) fibers. The diameters of the FG and FOG fibers were larger (P < .005 and P < .04, respectively) in hypertrophy responsive muscles from callipyge lambs, but the SO fiber diameter was smaller (P < .05). Also, the protein:DNA ratio, an indicator of cell size, was greater (semitendinosus, P < .05); longissimus, P < .002; gluteus medius, P < .008) in the hypertrophy-responsive muscles from callipyge lambs. Thus, hypertrophy in callipyge lambs was, at least in part, due to fiber type changes and muscle cell enlargement. Hypertrophy was strongly associated with changes in the FG fibers, the only fiber type that increased in both proportion and average diameter in callipyge muscles. The protein:RNA ratio and RNA:DNA ratio, which are indicators of translational and transcriptional activity in the muscle cells, were not different between callipyge and normal muscles. This indicated that the accumulation of protein necessary for myofiber enlargement occurred without differences in the translational or transcriptional activity of callipyge muscle. PMID- 8690676 TI - A simple model for predicting the response of chicks to dietary enzyme supplementation. AB - Two experiments with Leghorn chicks and data from five publications were analyzed to determine whether a simple general equation could be used to predict the relationship between the amount of a crude enzyme added to a diet and chick performance. The maximum improvements in weight gain and feed: gain ratio in Leghorn chicks fed rye diets containing different concentrations of enzymes were as high as 61 and 42%, respectively. Regression analyses demonstrated that there was usually a high linear correlation (r2 > 0.9, P < 0.05) between the concentration of the enzyme when transformed into its logarithmic value and weight gain or the feed:gain ratio. The general prediction equation was Y = A + B(logX), where Y is the performance value (i.e., weight gain, grams), A is the intercept (y-axis), B is the slope of the line (change in performance per units of enzyme in the diet), and X is the amount of enzyme in the diet. The slope of the line provides an index of the overall efficacy of the enzyme treatment. The log-linear model shows that for every ninefold increase in amount of enzyme in the diet (i.e., when the amount was increased to 10 times the starting amount), there was only a doubling of improvement in chick performance. High correlations (r2 values) were also obtained when data from the literature were analyzed. The equation was applicable to different classes and ages of poultry fed diets containing rye, wheat, barley, and lupins. These studies demonstrate that there is a linear relationship between the amount of enzyme added to the diet, when expressed as a logarithmic value, and the corresponding performance of chickens. PMID- 8690677 TI - Apparent digestibility of nutrients in diets with different energy density, as estimated by direct and marker methods for pigs with or without ileo-cecal cannulas. AB - The objective of this study were a) to compare the apparent total tract digestibility (TD) between non-cannulated (intact) and cannulated (steered ileo cecal valve technique, SICV) pigs fed diets differing in energy density (Exp. 1) and b) to compare the direct vs marker (Cr2O3) methods for estimation of the TD and apparent ileal digestibility (ID) in SICV-cannulated pigs (Exp. 2). In Exp. 1, 24 intact and 18 SICV-cannulated castrates of approximately 40 kg initial BW were randomly assigned to six treatments in a 2 x 3 x 2 factorial arrangement (two pig types, three carbohydrate sources, and two fat levels). In Exp. 2, the same SICV-cannulated pigs from Exp. 1 were given those treatments in a 2 x 3 x 2 factorial arrangement (two methods of digestibility estimation, three carbohydrates sources, and two fat levels). In both experiments either cornstarch, soybean hulls, or pure cellulose, without or with fat, were incorporated into a barely-soybean meal based diet to alter energy density. Daily diets were isoenergetic (based on NEf), and water supply was .33 L/MJ of NEf. In Exp. 1, the pig type effect on the TD of DM, OM, CP, and the pig type x carbohydrate interactions for the TD of DM, OM, and crude fiber (CF) were significant (P < .05), merely due to a larger difference found for the diet enriched with cellulose. In Exp. 2, the TD and ID evaluated with the marker method were significantly lower (except for the TD of CF) than with the direct method, mainly because Cr recovery was below 100%. Overall, the marker method seems to be superior because the TD means obtained from Cr ratios were closer to the TD obtained from intact pigs. In general, the SICV technique seems to be suitable for long-term digestibility studies to measure the TD and ID in the same pig fed low-or high-fiber diets. PMID- 8690678 TI - Factors regulating the concentrations of 16-androstene steroids in submaxillary salivary glands of pigs. AB - The measurement of 16-androstene steroids in submaxillary salivary glands is a potentially good way to estimate boar taint. The objective of this work was to identify factors regulating the concentrations of these steroids in salivary glands. Large White x Pietrain male pigs were divided into four treatments: T-1, intact untreated (n = 18); T-2, intact treated with porcine somatotropin (pST, n = 18); T-3, intact immunized against LHRH (n = 20); and T-4, castrated untreated (n = 19). The pigs were slaughtered at 105 mg of live weight. The mean concentrations of the compounds measured after slaughter for T-1 were as follows: 16-androstene steroid binding protein (pheromaxein) in salivary glands, 2.08 +/- .19 micrograms/g; 16-androstene steroids in salivary glands, 43.3 +/- 2.9 micrograms/g; androstenone in fat, .67 +/- .07 micrograms/g. In all other treatments, the concentrations were reduced (P = .001); T-2 and T-3 had intermediate and T-4 had the least concentrations of the measured compounds. The reduction of 16-androstenes in salivary glands was less than androstenone in fat, probably due to pheromaxein. The overall correlation between androstenone and 16 androstenes was r = .602 (P < .001) and for T-1 was r = .613 (P < .001). The overall correlation between pheromaxein and 16-androstenes was r = .777 (P < .001) and r = .928 (P < .001) for T-1. Only in T-3 was the estimation of the relationship between androstenone and 16-androstenes improved by measuring pheromaxein. These results indicate that pheromaxein is more closely related to the concentration of 16-androstene steroids in salivary glands than in fat. Synthesis of pheromaxein is dependent on mature, functional testes. We conclude that boar taint can be estimated by measuring the concentrations of 16-androstene steroids in salivary glands. PMID- 8690679 TI - Effects of prenatal androgenization and postnatal steroid treatment on growth hormone, insulin-like growth factor I and II, insulin, thyroxine, and triidothyronine concentrations in beef heifers. AB - A 2 x 3 factorial arrangement of treatments was used to elucidate the mechanism(s) by which prenatal androgenization improves postnatal rate and efficiency of growth and composition of gain in beef heifers. Fifteen control (C) and 15 prenatally androgenized (PA) Angus x Simmental heifers (prenatal treatment, Pretrt) received no (N), estrogen (E), or estrogen and testosterone (ET) implants postnatally (postnatal treatment, Posttrt) to evaluate whether the postpubertal growth response after prenatal androgenization could be induced in prepubertal heifers. Blood was collected from the heifers at 6 +/- 1, 9 +/- 1, and 12 +/- 1 mo of age and analyzed from serum concentrations of growth hormone (GH), IGF-I, IGF-II, insulin, thyroxine (T4), and triiodothyronine (T3). Season of the year had a greater effect on hormone concentrations than either Pretrt or Posttrt, and there were no Pretrt x Posttrt interactions. Prenatal treatment, PA, had no effect on GH; however, Posttrt E and ET increased (P < .001) GH concentrations. Prenatal treatment, PA, increased (P < .05) IGF-I concentrations, and there was a nonsignificant increase (P = .11) in IGF-I concentrations with Posttrt E and ET. Concentrations of IGF-II were unaffected by Pretrt PA; however, they were lower (P < .01) in the Posttrt E and ET groups. Insulin, T4, T3, BW, and ADG were not affected by Pretrt and Posttrt. Concentrations of GH and IGF-I were increased in heifers that received Pretrt PA and(or) Posttrt E and ET in a manner to support improved growth performance; however, BW and ADG were similar. In prepubertal beef heifers, factors in addition to increased GH and IGF-I seem to be necessary for improved growth performance. PMID- 8690680 TI - Localization of a heparin-binding protein to distinct regions of bovine sperm. AB - Heparin-binding proteins (HBP) in bull seminal fluid bind to epididymal sperm membranes at ejaculation. Peptides recognized by a monoclonal antibody (M1) correspond to proteins identified in complexes that have the greatest affinity for heparin and are present on sperm from bulls with higher fertility. Presence of specific HBP on sperm regulates the ability of sperm to bind heparin, and heparin binding to sperm correlates with the fertility potential of a bull. In these studies, the interaction of HBP with sperm from 10 bulls of proven fertility was analyzed by immunofluorescence of M1 to determine the localization of heparin-binding proteins during capacitation, and the fluorescent binding patterns were compared to bull nonreturn rates. Immunofluorescent localization of M1 binding sites revealed the existence of specific membrane domains containing HBP in acrosomal and postacrosomal regions of ejaculated but not in epididymal sperm. Monoclonal antibody recognition of HBP localized on membranes of sperm revealed variable binding patterns of M1 to the acrosomal region in sperm from bulls of known fertility. Regression analysis indicated a negative relationship between sperm displaying exclusively acrosomal fluorescence and bull nonreturn rate. These data indicate that HBP bind to sperm in distinct patterns, one of which differed among bulls of varying fertility, and indicate no apparent relocalization of these sites during cellular changes that occur in preparation for fertilization. PMID- 8690681 TI - In situ particle size reduction as affected by forage species and grinding mesh size. AB - Two ruminally cannulated heifers were used to evaluate effects of three forage species (gamagrass, orchardgrass, and red clover) ground through two mesh sizes (2 and 5 mm) in a 3 x 2 factorial arrangement on particle size reduction in situ. Residues in polyester bags incubated for 3, 6, 12, 24, 36, 48, 60, and 72 h were analyzed for mean particle size. Initially, gamagrass had a 10.2% greater (P < .05) proportion of DM as particles larger than 300 microns that did orchardgrass or red clover, whereas forages ground through a 5-mm mesh (5-mm forage) had a 7.5% greater (P < .05) proportion of DM as 300 microns or larger particles than forages ground through a 2-mm mesh (2-mm forage). Mean particle size decreased with incubation time, resulting in reductions of 44, 42, 53, and 49% of gamagrass, orchardgrass, and 2- and 5-mm forages, respectively, after 60 h. Mean particle size of red clover was reduced 67% after 36 h of incubation. Particle size reduction was initiated earlier (12 vs 36 h) and occurred at a 150% faster (P < .01) rate for red clover than for gamagrass or orchardgrass. Although there was no difference (P > .10) between grinding mesh size at the time at which particle size reduction was initiated (24 h), particle reduction occurred at a 136% faster (P < .05) rate for forages ground through a 5-mm screen than for forages ground through a 2-mm screen. A greater (P < .10) reduction (595 microns by 36 h) in mean particle size occurred in red clover than in gamagrass or orchardgrass (average 376 microns by 60 h) during ruminal incubation. In addition, 5-mm forages exhibited a greater (P < .10) reduction in mean particle size (527 microns) than did 2-mm forages (372 microns) after 60 h of incubation. Substantial particle size reduction occurred in situ due to microbial digestion. The faster particle size reduction found in red clover may contribute to the greater observed intake for legumes. PMID- 8690682 TI - Comparative assessment of bacterial inoculation and propionic acid treatment of aerobic stability and microbial populations of ensiled high-moisture ear corn. AB - High-moisture ear corn (HMEC) was untreated, treated with propionic acid (PA), or inoculated with a mixture of Lactobacillus plantarum and Enterococcus faecium and allowed to ensile in laboratory silos for 0, 7, 21, 42, 138, or 202 d. The silages were evaluated for fermentation quality, microbial populations, and aerobic stability. In all treatments, silage pH declined rapidly within 7 d, but the rate of decline seemed greatest with the inoculum. The lactic acid content of inoculated HMEC was higher (P < .05) than that of control of PA-treated HMEC. Regardless of treatment, the population of lactic acid bacteria (LAB) increased (P < .1) up to 7 to 21 d of fermentation then declined; LAB counts decreased (P < .05) up to 42 d in control and PA-treated silage but continued to decline until 138 d for inoculated silage. Yeast and mold counts tended to decrease up to 42 d of ensiling then decreased (P < .05) as fermentation progressed. Between 138 and 202 d of ensiling, the control silage showed a marked increase (P < .10) in pH and yeast and mold populations, providing evidence of secondary fermentation; PA treatment and bacterial inoculation prevented secondary fermentation. Inoculation tended to reduce estimates of sample temperature for silage stored for 138 d and exposed to air, but not for the corresponding silage stored for 202 d. Treatment with PA prevented the loss (P > .05) of acetic acid and the rise (P > .05) in pH during air exposure of the 138-d silage; both control and PA-treated silage showed an increase (P < .05) in yeast and mold populations, but the increments were 38% and 23%, respectively. Compared with PA, the relative efficacy of inoculation in improving aerobic spoilage of HMEC depended on the period of silo storage and the criterion used to assess aerobic stability. PMID- 8690683 TI - Forage characteristics, steer performance, and water quality from bermudagrass pastures fertilized with two levels of nitrogen from swine lagoon effluent. AB - Four .8-ha pastures of bermudagrass (Cynodon dactylon [L.] Pers.) were fertilized with either 456 or 873 kg/ha of nitrogen (N) from swine lagoon effluent (two replicates per treatment) and grazed by steers over two summers. Within each pasture, steers received forage only, an energy source (corn), a mixture of corn and soybean meal, or a mixture of corn and blood meal via electronic Calan feeders. All supplements were offered at a level of 1.36 kg/d, and the soybean meal and blood meal supplements provided similar among quantities of protein. Weight gains were similar among supplemented steers, but supplemented steers gained faster (P < .05) than controls. Nitrogen fertilization level had no effect on steer gains, steer grazing days per hectare, or in vitro dry matter disappearance, NDF, and ADF of clipped forage samples. Plant protein and nitrate ion concentrations were greater (P < .06) in clipped forage samples receiving the higher N application rate. Nitrate ion concentrations were greater in available forage samples from the pastures with the high N application rate. Mean total N and nitrate N concentrations were similar in water samples obtained from monitoring wells for the two N treatments over the 2 yr and there were no year x N interactions. Chloride concentrations were greater (P < .05) and pH and specific conductance were less in water samples collected from the 873 kg than from the 456 kg/ha N treatment. Long-term studies are needed to examine the possible cumulative effects of applying various levels of swine waste to the same land area. PMID- 8690684 TI - Effects of feed and water deprivation on ruminal characteristics and microbial population of newly weaned and feedlot-adapted calves. AB - Two experiments were conducted to determine the effects of length of feed and water deprivation on ruminal microbes and ruminal characteristics. In Exp. 1, treatments were as follows: 1) weaned, but not trucked (0 h), 2) weaned, trucked, and fasted for 48 h (48 h), and 3) weaned, trucked, and fasted for 72 h (72 h). On d 0 (arrival back at the feedlot after treatment), DMI, ruminal contents (P < .05) decreased as length of feed and water deprivation increased. However, on d 4, there were no longer any differences (P > .10) in DMI or weight of ruminal contents. On d 0, percentage of ruminal DM in the 48- and 72-h treatment groups was lower (P < .01) than in the 0-h treatment group, but there were no differences (P > .10) by d 4. After the steers used in Exp. 1 had been in the feedlot for 28 h, they were reallotted, and the three treatments (except for weaning) were repeated; the 0-h group remained at the feedlot. On d 0, DMI of the 48-h group was lower (P < .05) than that of the 0-h group; DMI of the 72-h group was intermediate. On d 0, the 0-h treatment group had a greater ruminal DM percentage than the 48- and 72-h treatment groups (P < .05); however, due to large within-treatment variation the total weight of ruminal contents did not differ (P > .10) among treatments. There were no decreases (P > .10) in cellulolytic or total bacterial concentration or in the ruminal numbers of cellulolytic or total bacteria due to length of feed and water deprivation on d 0 in either Exp. 1 or 2. In both trials, 48 and 72 h of feed and water deprivation decreased (P < .05) protozoal numbers on d 0 and 4 compared with the 0-h treatment group. PMID- 8690685 TI - Use of sodium dodecyl sulfate polyacrylamide gel electrophoresis to measure degradation of soluble soybean proteins by Prevotella ruminicola GA33 or mixed ruminal microbes in vitro. AB - Degradation of soluble soybean meal proteins by Prevotella ruminicola GA33 and mixed ruminal bacteria was studied using SDS-PAGE. This technique facilitated the quantification of peptides (molecular weight > or = kDa) released during the partial hydrolysis of soybean proteins. In P. ruminicola incubations, conglycinin alpha and alpha' subunits were degraded completely within 4 h, whereas the beta subunit of beta-conglycinin as well as the basic and acidic polypeptide components of glycinin were more resistant to degradation. Several peptides derived from digested soybean proteins appeared during the incubation. The N terminal amino acid sequences of these peptides were similar to amino acid sequences in soybean proteins. The N-terminus of a 23-kDa peptide was identical to the N-terminus of the beta subunit of beta-conglycinin; the N-terminus of a 59 kDa peptide differed from amino acids 101 to 115 of the alpha subunit of beta conglycinin by two of 15 amino acids; the N-terminus of a 64-kDa peptide differed from amino acids 67 to 76 of the alpha' subunit of beta-conglycinin by three of 10 amino acids. The transient accumulation of these peptides when soluble soybean proteins were incubated with mixed ruminal microorganisms suggests a role for P. ruminicola in the early stages of protein digestion in the rumen. Approximately 30% of the soluble soybean protein incubated with mixed ruminal microorganisms was not degraded after 9 h, and SDS-PAGE indicated that the basic subunit of glycinin and several peptides (molecular weights less than 23 kDa) make an appreciable contribution to metabolizable protein when soybean protein is fed to ruminants. PMID- 8690686 TI - Effect of form of nitrogen on growth of ruminal microbes in continuous culture. AB - A study was conducted to determine the effect of various forms of N on the growth of ruminal microbes in a continuous culture system with solids and liquid dilution rates comparable to those of a high-producing dairy cow. Nitrogen forms were isolated soy protein, soy peptides, individual amino acids (AA) blended to profile soy protein, and urea, which were fed alone and in combinations so that the total N provided was 1.6% of the diet DM. The 100% soy protein treatment resulted in reduced digestion of N and nonstructural carbohydrate compared with other N forms, and outflow of bacterial N/24 h was less than when peptides were fed. This suggested that proteolysis rather than peptide uptake was the rate limiting step in N utilization in this study. Non-urea N forms increased ADF digestion, total VFA production and the molar percentages of isobutyrate, isovalerate, and valerate compared to urea, which reflected the contribution of carbon skeletons of AA. When combinations of N forms were used, each form contributed an equal quantity of N, 50% of the total treatment, which was .8% of the diet DM. Combinations of N forms did not enhance, and in most cases reduced, ADF and NDF digestion when compared with individual N forms, and no combinations increased microbial growth over that of the individual forms. These results confirm that N forms other than ammonia are needed not only for maximum microbial growth, and they further demonstrate a need for non-protein N for the fiber digestion. In addition, results of this study suggest a requirement for a minimum level of peptide or AA N, which was met only when individual N forms were fed. PMID- 8690687 TI - Effect of type of practice in a computer-aided design environment in visualizing three-dimensional objects from two-dimensional orthographic projections. AB - The purpose of this study was to determine the effect of practice in manipulating 2- and 3-dimensional (D) wireframe images on a learner's ability to visualize 3-D objects. Practice, either rotational or not, consisted of visualizing 2- and 3-D objects generated by personal computer (PC)-based computer-assisted design software. Results indicated that participants in the rotation treatment group performed significantly better than those in either the nonrotation or control group on measures of spatial ability and 3-D visualization ability. Both treatment groups performed significantly better than the control group on measures of metacognition, effort, and worry. These results support a conclusion that spatial ability can be improved through practice that allows the learner to see the relationship between the 2-D and 3-D features of objects. PMID- 8690688 TI - Effects of impression management and self-deception on the predictive validity of personality constructs. AB - This study tests whether 2 types of response distortion (self-deception and impression management) affect the predictive validity of 2 of the "Big 5" personality dimensions, conscientiousness and emotional stability, in 2 applicant samples of long-haul semitruck drivers (n = 147 and n = 139). As hypothesized, conscientiousness (p = -.26 and -.26) and emotional stability (p = -.23 and -.21) were valid predictors of voluntary turnover in the 2 samples. Also as hypothesized, conscientiousness was a valid predictor of supervisory ratings of performance (p = .41 and .39) in the 2 samples. Although not hypothesized, emotional stability was also significantly related to supervisor ratings of performance (p = .23 and .27). Results from structural equations modeling indicated that applicants did distort their scores on both personality dimensions and the distortion occurred both through self-deception and impression management; however, neither type of distortion attenuated the predictive validities of either personality construct. PMID- 8690689 TI - Psychophysiological detection through the guilty knowledge technique: effects of mental countermeasures. AB - The effects of mental countermeasures on the efficiency of psychophysiological detection with the Guilty Knowledge Technique were examined in a mock-crime experiment with 4 groups of participants: innocent participants who were not involved in the mock crime, guilty controls who committed the mock crime but received no countermeasure instructions, and guilty participants who received countermeasure instructions, and guilty participants who received countermeasure instructions and were allowed to practice the countermeasures. The countermeasure instructions encouraged participants to recall emotional situations from their past and imagine themselves in these situations during presentation of irrelevant questions. Results revealed a significant reduction in electrodermal detection efficiency under the 2 countermeasure conditions with no differences between them. No countermeasures effects were observed with the respiration line length measure. PMID- 8690690 TI - Race, gender, and opportunity: a study of compensation attainment and the establishment of mentoring relationships. AB - In this article, hypotheses concerned with how race, gender, and mentoring experiences account for compensation outcomes among master of business administration (MBA) program graduates are considered. African-American and Hispanic MBAs were less likely than their White counterparts to establish mentoring relationships with White men. Women with MBAs were less likely than men with MBAs to form such relationships. Graduates who had been able to establish mentoring relationships with White men displayed an average annual compensation advantage of $16,840 over those with mentors displaying other demographic profiles. There were no compensation differences between those who had established mentoring relationships with women or minority men and those who had not established a mentoring relationship. PMID- 8690691 TI - The experience of work and turnover intentions: interactive effects of value attainment, job satisfaction, and positive mood. AB - The researchers proposed that the phenomenological experience of work is multifaceted and that simultaneously considering the combined effects of the different aspects of the work experience holds considerable promise for increasing understanding of turnover intentions and other organizationally relevant outcomes. Research in subjective well-being and other areas suggests that there are 3 important aspects of the experience of work: attainment of values, attitudes, and moods. It was hypothesized and found that the relationship between job satisfaction and turnover intentions is jointly moderated by value attainment and positive mood. The nature of this triple interaction was such that the job satisfaction-turnover intention relationship was strongest when workers' jobs did not help them to attain terminal values and positive moods were experienced, and the relationship was weakest when jobs helped workers to attain terminal values and positive moods were experienced. PMID- 8690692 TI - Evaluation and treatment of anxiety symptoms and disorders in alcoholics. AB - Anxiety symptoms are common among alcoholics. Despite evidence suggesting that anxiety symptoms eventually resolve in most alcoholics during persistent abstinence, clinical care often requires rapid evaluation and intervention. This article provides guidelines to differentiate transient from persistent anxiety states, a distinction that has important treatment implications. Psychosocial support and coping skills training to maintain abstinence are recommended for treatment of transient anxiety states. The use of medication should be reserved for persistent anxiety states. Recent placebo-controlled trials of buspirone, a non-benzodiazepine anxiolytic, suggest that this medication may help to retain anxious alcoholics in treatment and to reduce anxiety symptoms and heavy drinking. Guidelines are provided for the appropriate use of buspirone in alcoholics with persistent anxiety symptoms. PMID- 8690693 TI - Augmentation strategies: focus on anxiolytics. AB - Approximately 20% to 40% of patients will fail to respond to the first antidepressant used for their current major depressive episode. Furthermore, it has been suggested that a further 20% to 30% of patients will have only a partial response. There are four main options to consider in the treatment of these patients: optimization, substitution, augmentation, and combination therapy. Several combination antidepressant treatments have been used in treatment refractory depression. Moreover, various augmentation strategies have also proved to be successful. Although the empirical data to support these treatment options are limited, augmentation treatment has several potential advantages over the other clinical options available, particularly substitution. These data are reviewed and clinical applications discussed. Particular attention is paid to the role of anxiolytics as augmentation agents in the treatment of major depression. PMID- 8690694 TI - Generalized anxiety disorder: issues in epidemiology. AB - Despite the considerable attention that has been focused on the anxiety disorders by the medical and research communities over the last decade, relatively little attention has been devoted to the investigation of generalized anxiety disorder (GAD). However, the available population-based studies have provided clinically relevant information about this disorder. The emerging picture is that GAD is a common and chronic disorder, affecting primarily women, and one that leads to significant distress and impairment. Subjects with GAD frequently utilize health care services and require medication treatment. Since a major portion of health care services is consumed by a small fraction of patients, early detection and effective intervention may reduce unnecessary and costly health care. PMID- 8690695 TI - Management of persistent anxiety and novel uses for anxiolytics. PMID- 8690696 TI - Overview of generalized anxiety disorder in the elderly. AB - Both situational anxiety and pathologic anxiety are common in the elderly. Pathologic anxiety, however, may significantly disable a previously functioning older adult. Moderate-to-severe anxiety is important to accurately diagnose and treat in older persons in order to improve daily functioning and because individual symptoms of anxiety can be easily confused with even more severe geropsychiatric disorders such as dementia, delirium, depression, and psychosis. These particular symptoms include impaired concentration and attention, impaired memory, dizziness, disabling fear, severe insomnia, and hypervigilance, among others. This article will review epidemiology, characteristics of anxiety in late life, patterns of medication use, and treatment. PMID- 8690697 TI - Treating the agitated Alzheimer patient. AB - Dementia is a syndrome that consists of cognitive, psychiatric, and behavioral changes. Studies report from 42% to 62% of nursing home residents and at least 50% of outpatients with dementia exhibit behavioral disturbances. Agitation is a frequent behavioral disturbance associated with dementia. The Omnibus Budget Reconciliation Act (OBRA) regulations have made it imperative that physicians review and be familiar with alternative treatment options. We review and present strategies for the evaluation and treatment of agitation in demented patients. PMID- 8690698 TI - Agitation as a possible expression of generalized anxiety disorder in demented elderly patients: toward a treatment approach. AB - Symptoms of generalized anxiety disorder are commonly observed in elderly persons and especially in those suffering from dementia. In the demented elderly, these symptoms are often defined as agitation. Approximately 60% of demented persons will present with symptoms of agitation at some point during the course of their illness. The presence of agitation has devastating consequences for the patient and the caregiver. This paper reviews some of the existing literature with regard to the etiology and treatment of agitation in the demented elderly. Agitated behaviors are generally divided in three categories (verbal agitation physically nonaggressive agitation, and aggressive agitation). It is suggested that each category may have a different etiology and treatment; verbal agitation is often related to underlying medical conditions, physically nonaggressive behavior responds to behavioral treatment, and aggressive agitation is more likely to respond to a combination of behavioral and pharmacologic treatment. PMID- 8690699 TI - Epidemiology and psychopharmacology of anxiety in medical patients. AB - A wide variety of comorbid anxiety disorders have been described in patients with medical disorders, with the most common being adjustment disorder with anxiety, panic disorder, and generalized anxiety disorder. This article briefly reviews representative studies of the prevalence of anxiety disorders in several medical conditions, placing emphasis on cardiovascular, pulmonary, cerebrovascular, and dermatologic disease. Psychotropic medications appropriate for the treatment of anxiety disorders in these medical-psychiatric populations (benzodiazepines, cyclic antidepressants, and buspirone) as well as beta-adrenergic blocking agents and antihistamines are discussed with an emphasis on pharmacokinetic and drug interactions of major clinical importance for the medically ill patient. PMID- 8690700 TI - Compliance issues in primary care. AB - Primary care medical practice is a broadly based medical discipline, emphasizing continuity of care in both sickness and health and effective doctor/patient communication and involving the patient as a partner in the provision of health care services. Against this background, there is troubling evidence that psychosocial (mental health) problems are not being adequately diagnosed and treated by physicians in general, and primary care practitioners in particular. This deficiency is the first step down the road to poor compliance. This author assumes that a goodly portion of the blame can be laid on the doorstep of the medical education establishment with its emphasis on the biomedical, reductionism, and high-tech tertiary care. Physicians exit the educational system with a predisposition to deal with problems from a biomedical perspective. They are unaware that, by the very nature of the doctor/patient relationship, they possess considerable ability to effectively intervene in the psychosocial area. Suggestions are given as to how primary care practitioners can improve on this dimension of their medical practice and deal with psychosocial issues. Available evidence would indicate that effectively dealing with these issues will improve patient compliance and outcomes. PMID- 8690701 TI - Generalized anxiety and mixed anxiety-depression: association with disability and health care utilization. AB - Generalized anxiety and mixed anxiety-depression have received less attention than the major mood and anxiety disorders ith respect to their possible effects in increasing disability and health care utilization. A review of recent studies, however, indicates that these conditions are prevalent in primary care medical settings and are associated with significant social and occupational disability. Generalized anxiety disorder is also one of the most common diagnoses seen in patients presenting with medically unexplained somatic complaints such as chest pain, irritable bowel symptoms, and hyperventilation and in patients prone to overutilize health care services in general. It is poorly recognized by primary care physicians, possibly due to its chronicity, which may limit the ability of symptoms to "stand out" and be easily detected. However, it is disproportionately present in "high utilizer" samples found to be particularly "frustrating" to their physicians and is accompanied by a high rate of personality disorders, suggesting that maladaptive personality traits and styles of interaction in such patients may also contribute to underrecognition of symptoms by primary care physicians. These preliminary associations between generalized anxiety disorder/mixed anxiety-depression and both disability and increased health care utilization need to be confirmed with carefully designed and controlled studies. PMID- 8690702 TI - The long-term management of generalized anxiety disorder: issues and dilemmas. AB - Accumulating evidence suggests that a large proportion of patients diagnosed with generalized anxiety disorder suffer from a chronic or recurrent condition that is associated with a moderate amount of disability and impairment in quality of life. Acute drug therapy is well studied and appears to be highly effective in providing symptom relief, but relapse/recurrence is high. Little research has been reported that identifies predictors of recurrence or studies the clinical parameters of maintenance drug therapy, including benefit-risk assessments or optimal doses or durations of treatment. PMID- 8690703 TI - Pyridoxal enzymes: mechanistic diversity and uniformity. AB - Pyridoxal 5'-phosphate (PLP) acts as the coenzyme in a vast number of reactions in amino acid metabolism. The study of PLP enzymes is one of the most fascinating frontiers in enzymology, and now the mechanism s of several types of PLP enzymes are being discussed at the atomic level based on crystallographic, spectroscopic, and site-directed mutagenesis studies. In this review, I summarize the important findings, including those provided by classical studies, on the reaction mechanisms of several PLP enzymes, with the intention of discussing the chemically and thermodynamically consistent principle of the catalytic action of PLP enzymes common to all the enzymes of this group, and the uniqueness of individual enzymes that endows them substrate and reaction specificity. PMID- 8690704 TI - Crystal structure of the unliganded alkaline protease from Pseudomonas aeruginosa IFO3080 and its conformational changes on ligand binding. AB - The crystal structure of the unliganded alkaline protease from Pseudomonas aeruginosa IFO3080 has been determined at 2.0 A resolution by the X-ray method. The enzyme consists of N-terminal catalytic and C-terminal beta-helix domains. On structural comparison between the present unliganded enzyme and structurally- known liganded enzyme, some structural changes were observed around the active site. In the unliganded enzyme, Y216 serves as the fifth ligand for the active site zinc ion. On ligand binding, Y216 may move to form a hydrogen-bond with the carbonyl oxygen of the P1 residue of a ligand peptide. D191 in the flexible loop, Y190 to D196, over the active site cleft forms hydrogen-bonds with the backbone atoms of the P1 and P2 residues of the ligand to close the entrance to the cleft. The water molecule which is the fourth ligand for the zinc ion is replaced by the carbonyl oxygen of the P1 residue. These structural changes around the active site may reflect the substrate-binding mode during the enzymatic reaction. PMID- 8690705 TI - Production of a paraquat-specific murine single chain Fv fragment. AB - Producing an effective antidote against poisoning by the herbicide paraquat (PQ) has proven to be an elusive goal. One approach that holds some promise is immunotherapy with antibody fragments. In this study we detail the production of a single chain Fv fragment (scFv) specific for paraquat by linking cloned heavy (Vh) and light chain (VL) variable region genes via the peptide spacer (Gly4 Ser)3. These genes were obtained from hybridoma cells secreting a PQ-specific murine monoclonal antibody. The scFv (28 kDa) was expressed at 4% of the total cell protein by the Escherichia coli vector, pPOW, but was associated with the membranes. After solubilization and reduction, the scFv was renatured by rapid dilution. Western blotting confirmed that the refolded scFv had similar structural properties to the parental mAb. The isoelectric point of the scFv (7.0) is equal to the value calculated from the deduced amino acid sequence. Surface plasmon resonance was used to demonstrate specific PQ binding by the refolded scFv(Ka=1.24x10(6)M(-1)) which is similar to that determined for the parent Fab fragment (4.6x10(6)(-1)). PMID- 8690706 TI - Purification and characterization of RNA polymerase holoenzyme (E sigma B) from vegetative-phase mycelia of Streptomyces griseus. AB - RNA polymerase was purified from vegetative-phase mycelia of Streptomyces griseus by a series of ion-exchange chromatographies. By western blot analysis using antiserum against S. coelicolor HrdB, which is a principal sigma factor (sigma(hrdB)), the purified holoenzyme was found to contain sigmaB (=sigma(hrdB)) of S. griseus. Significant amounts of HrdB protein were, however, eluted from the DEAE column at lower concentrations of KCl than that required for for elution of the holoenzyme containing sigmaB, suggesting that sigmaB is dissociated from the core enzyme, or an excess amount of sigmaB exists in S.griseus cells. The holoenzyme containing sigmaB (EsigmaB) transcribed in vitro the dagA promoter of S. coelicolor, and the hardB and hsp70 promoters of S. griseus, suggesting that it is involved in transcription of the essential genes. EsigmaB may be a major form of RNA polymerase holoenzyme in the growing phase of S. griseus. PMID- 8690707 TI - Nucleotide sequence of a principal sigma factor gene (hrdB) of Streptomyces griseus. AB - The hrdB homologue was isolated from a streptomycin-producing Streptomyces griseus 2247 strain, which is independent of A-factor. The nucleotide sequence of the cloned DNA fragment revealed the presence of an open reading frame (ORF) of 1,542bp, which predicted a primary product of 514 amino acids and Mr 56,100. The N-terminal sequence of the purified HrdB protein of S. griseus was identical to the amino acid sequence deduced from the nucleotide sequence. The deduced amino acid sequence contains an "rpoD box" conserved in the principal sigma factors of eubacteria, and shows high similarity to the hrdB products of S. coelicolor A3(2)(89.9%) and S. aureofaciens (88.1%). The cloned gene encodes a principal sigma factor of S. griseus. The promoter region was identified by using a promoter-probe vector and by means of primer extensions experiments. The transcription start point is located 158-bp upstream of the initiation codon. PMID- 8690708 TI - Opposite actions of transforming growth factor-beta 1 on the gene expression of atrial natriuretic peptide biological and clearance receptors in a murine thymic stromal cell line. AB - The regulation of the gene expression of the atrial natriuretic peptide receptor (ANPR) subtypes, ANPR-A, ANPR-B, and ANPR-C, was investigated in a murine thymic stromal cell line, MRL 104.8a. When MRL 104.8a cells were cultured with transforming growth factor (TGF)-beta1, [125I]ANP binding sites increased with increasing dose of TGF-beta1. These binding sites were identified as ANPR-C by a displacement experiment with ANPR-C-specific ligand, C-ANF, and by the affinity cross-linking of the [125I]ANP binding sites with a chemical cross-linker to determine the molecular weight of the ANPR. This augmentation of the ANPR-C expression was elucidated to occur at the transcriptional level by Northern blot experiment, comparison of the relative amounts of mRNA by reverse transcription (RT)-PCR, and in vitro nuclear transcription assay. Conversely, the expression of the ANP biological receptors, ANPR-A and ANPR-B, was shown to be down-regulated by TGF-beta1. These data suggest that TGF-beta1 regulates the gene expression of ANPRs in the thymic stromal cells and that ANP and TGF-beta1 might affect the thymic stromal cell functions. PMID- 8690709 TI - Contribution of peroxidation products to oxidative inactivation of rat liver microsomal glucose-6-phosphatase. AB - Exposure of rat liver microsomes to ascorbic acid/Fe(2+) caused decreases in the membrane-bound glucose-6-phosphate (G-6-Pase) activity and the protein thiols after a short lag period (4 min). Under the same conditions, the production of thiobarbituric acid-reactive substances and fluorescent products was also initiated from 4 min after the start of the treatment, although conjugated diene was formed immediately on incubation of the microsomes with ascorbic acid/Fe(2+). After centrifugation of the treated microsomes, the fluorescent products and the enzyme activity remained in the membrane fraction. The results of kinetic studies of the enzyme activity indicated that ascorbic acid/Fe(2+)-induced inhibition of the enzyme activity is mainly due to an increased Km value for the substrate. A decreased activity of the microsomal G-6-Pase was also observed when the microsomes were incubated with aldehydes such as malondialdehyde, n-heptaldehyde, acetaldehyde, and trans-2-nonenal. However, loss of protein thiols was detected only upon treatment of the microsomes with trans-2-nonenal. Glucose-6-phosphate (G-6-P)effectively prevented ascorbic acid/Fe(2+)- or trans-2-nonenal-induced inhibition of the enzyme activity, but the substrate failed to protect the protein thiols in both systems. The results of fluorescence anisotropy measurements of diphenylhexatriene-labeled microsomes suggested that changes in the lipid dynamics are not directly related to peroxidation- mediated inhibition of the enzyme activity. Based on these results, a possible reason for the inhibition of the microsomal G-6-Pase activity associated with ascorbic acid/Fe(2+) treatment is discussed. PMID- 8690710 TI - Neuropeptide YY1 receptors-mediated increase in intracellular Ca2+ concentration via phospholipase C-dependent pathway in porcine aortic smooth muscle cells. AB - In porcine aortic smooth muscle cells, neuropeptide Y (NPY) stimulates mobilization of CA(2+) from intracellular store sites via Y1 receptors. However, it has been debated whether or not Ca(2+) mobilization by Y1 receptors depends on the generation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] following activation of phospholipase C. To examine this question, we studied the effect of U73122, an inhibitor of phospholipase C-mediated inositol phosphate accumulation on the NPY-induced rise in cytosolic free Ca(2+) concentration ([Ca(2+)]i) in comparison with that on angiotensin II (AII)-induced [Ca(2+)]i increase, which is dependent on Ins(1,4,5)P3 generation. Digital-imaging microscopy study using the Ca(2+)-sensitive dye fura-2 revealed that application of AII induced a rapid but transient [Ca(2+)]i increase in a single cell, arising from intracellular calcium stores. Application of NPY to the same cell induced a [Ca(2+)]i rise with a pattern similar to that induced by AII. AII increased the formation of Ins(1,4,5)P3 by about 3.0 fold, while the NPY-induced [Ca(2+) formation was very small. U73122 completely inhibited not only Ins(1,4,5)P3 synthesis, but also Ca(2+) mobilization induced by either agonist. The effect of U73122 on the NPY induced Ca(2+)i increase was about 10-fold more potent that on the AII-induced one. U73343, an inactive analog of U733343, had no influence on any of the AII- and NPY-mediated effects. Herbimycin A completely inhibited the platelet-derived growth factor-induced [Ca(2+]i increase but had no effect on the NPY-induced [Ca(2+)]i increase, indicating that phospholipase C-gamma is not involved in the NPY effect. These results suggest that NPY-induced Ca2+ mobilization from intracellular stores in porcine smooth muscle cells is secondary to the very small generation of Ins(1,4,5)P3 following stimulation of phospholipase C-beta, which may account for the hypersensitivity of the NPY effect to U73122. PMID- 8690711 TI - Release of a soluble form of growth hormone receptors (growth hormone-binding proteins) from human IM-9 cells by proteolytic cleavage. AB - Soluble forms of growth hormone receptors, growth hormone-binding proteins (GH BPs), with molecular weights of 60 and 55kDa were found to be constitutively released from human IM-9 cells. The release of the GH-BPs was not inhibited by inhibitors of protein synthesis (cycloheximide) and transport (brefeldin A). Down regulation by human growth hormone or trypsin pretreatment of surface growth hormone receptors abolished the GH-BP release, suggesting that cell-surface human growth hormone receptors are involved in the GH-BP release. Several inhibitors of serine-, thiol-, and acid-proteases did not affect the GH-BP release. EDTA efficiently blocked the GH-BP release. This inhibition by EDTA was restored by addition of Mg(2+) and Co(2+). These results suggest that human GH-BPs are constitutively released by proteolytic cleavage of cell-surface growth hormone receptors by a metalloprotease. PMID- 8690712 TI - Fast atom bombardment and electrospray ionization tandem mass spectrometry of sulfated Lewis(x) trisaccharides. AB - Structural characterization of mono-, di-, and trisulfated trisaccharides by fast atom bombardment (FAB) and electrospray ionization (ESI) mass spectrometry is described. Both FAB and ESI collision-induced dissociation tandem mass spectrometry (CID-MS/MS) of sulfated trisaccharides allowed identification of the sulfated sugar and provided information on the saccharide chain sequence. The ESI CID-MS/MS of multiple-charged ions provided even more structural information, and some of the useful daughter ions appeared in the higher mass region than the precursor owing to a lower charge-state. These methodologies can be applied to the structural analyses of glycoconjugates with much larger molecular masses and higher polarity, such as the poly-sulfated analogs. PMID- 8690713 TI - Induction of CD40 in promyelocytic HL60 cells cultured with retinoic acid and/or various cytokines. AB - The antigenic protein CD40 on the surface of B lymphocytes plays an important role in their proliferation, immunoglobulin class switching, and rescue from apoptosis in the germinal center through interaction with T lymphocytes expressing CD40 ligand. The protein is also found on the cell surface of other antigen-presenting cells such as monocytes, dendritic cells, and thymic epithelium cells, but its presence in other myeloid cells has not been reported. We show here that CD40 protein is induced in promyelocytic HL60 cells, when cultured with retinoic acid, a vitamin that converts them to granulocyte-like cells. The cultured cells also expressed CD15, a marker for granulocytes, and cytochrome b(558), an essential component of the superoxide-generating system in phagocytes, on their surface. No detectable amount of mRNA for CD40 was found in naive HL60 cells, whereas a large amount of the message was induced in the cells cultured with the vitamin. Although CD40 expression was enhanced when the cells were further cultured with GM-CSF or IFN-gamma, expression of CD14, a marker for monocytes, was also enhanced. HL60 cells, therefore, express CD40 protein during differentiation not only toward monocytes but also toward granulocytes, at least transiently. PMID- 8690714 TI - Purification and characterization of secretory-type GDP-L-fucose: beta-D galactoside 2-alpha-L-fucosyltransferase from human gastric mucosa. AB - alpha-(1,2)-Fucosyltransferase (GDP-L-fucose:beta-D-galactoside 2-alpha-L fucosyltransferase) from human gastric mucosa was purified to homogeneity by column chromatographies on Ultrogel AcA34, phenyl-Sepharose, hydroxylapatite, SP Sephadex, and GDP-hexanol-amine Sepharose. The molecular weight of the purified enzyme was estimated to be 65,000 by SDS-PAGE. The Km value of this enzyme for a type 1 sugar acceptor was a little smaller than that for a type 2 one, indicating this enzyme is a secretor-type alpha-(1,2)-fucosyltransferase. However, the difference between the Km value for a type 1 precursor and that for a type 2 one was very small, suggesting that this enzyme can use both types of precursors as sugar acceptors approximately equally, unlike the purified alpha-(1,2) fucosyltransferase from human serum as the secretor-type reported previously. The characteristics of the purified enzyme were compared with those of H-type alpha (1,2)-fucosyltransferase from human plasma. The activities of both enzymes were inhibited by salt and N-ethylmaleimide, but they showed a significant difference in their divalent cation requirements. PMID- 8690715 TI - Insect lysozyme from house fly (Musca domestica) larvae: possible digestive function based on sequence and enzymatic properties. AB - Lysozyme was purified from the homogenate of the whole body of house fly (Musca domestica) larvae by standard chromatographic techniques. The purified lysozyme was sequenced and its enzymatic properties were examined. This lysozyme was a chicken-type lysozyme composed of 122 amino acids, showing about 75% identity with fruit fly lysozymes and 38% with human lysozyme. This enzyme was inactive towards Micrococcus luteus and under the physiological conditions of PH 7.0 and ionic strength 0.1, but was as active toward glycol chitin as was hen lysozyme. The pH-dependent profile of lytic activity towards M. luteus showed that house fly lysozyme has an acidic pH optimum and shows no enzymatic activity above Ph 7. These features are analogous with those of ruminant stomach lysozymes which have evolved for the digestive function, suggesting that this lysozyme does not function as a self-defense protein, like hen and human lysozyme, but as a digestive enzyme, probably in the gut of the insect body. Although a similar functional conversion to digestive enzyme was reported in fruit fly, phylogenetic tree analysis indicates that the evolutionary change of lysozyme to a digestive enzyme occurred similarly in fruit fly and house fly, but the events are not related and occurred independently in each strain. This observation is in contrast with the case of ruminant stomach lysozymes, which were recruited before the divergence of each species of ruminants. PMID- 8690716 TI - Determination of the absolute configuration of urothion. AB - In order to determine the absolute configuration of urothion (1), the CD spectra of tri-4-chlorobenzoyl derivatives of 2-amino-6-[(3R)-3,4-dihydroxybutyl]pteridin 4(3H)-one and its (3S) compound were compared with that of the tri-4 chlorobenzoyl derivative obtained from the natural product. R-Configuration was concluded for the secondary hydroxyl group on the side chain of 1, which is the same configuration as that of molybdopterin (2). This supports the view that 1 might be a urinary metabolite of 2. PMID- 8690717 TI - Cloning and expression of dipeptidase from Acinetobacter calcoaceticus ATCC 23055. AB - The gene encoding dipeptidase was cloned from Acinetobacter calcoaceticus ATC 23055. Determination of the nucleotide sequence revealed that the gene had an open reading flame of 1,050 bp coding a protein of 350 amino acids. The deduced amino acid sequence showed 48.8% similarity to human renal dipeptidases and conserved two amino acid residues identified in human and pig renal dipeptidases as essential ones for the catalytic activity. Purified recombinant enzyme expressed in Escherichia coli did not hydrolyze the unsaturated dipeptide, glycyldehydrophenylalanine. On the other hand, it preferentially hydrolyzed dipeptides having a D-amino acid, when compared with those having an L-amino acid at the C-terminal. Furthermore, it could not hydrolyze tripeptides. These results indicate that the dipeptidase produced by A. calcoaceticus ATC 23055 has a unique substrate specificity and preferentially hydrolyzes dipeptides having a D-amino acid at the C-terminal. PMID- 8690718 TI - Construction of a plasmid used for the expression of a sevenfold-mutant barley beta-amylase with increased thermostability in Escherichia coli and properties of the sevenfold-mutant beta-amylase. AB - To increase the thermostability of beta-amylase, seven kinds of single-mutant plasmids were constructed with an expression vector of barley beta-amylase by mutagenesis. The remaining activity versus temperature curves were used to determine the temperatures (T50) at which 50% of the initial activity was lost during a 30-min heating period. These mutations increased the T50 values by amounts ranging from 0.8 to 3.2 degrees C. To express the sevenfold-mutant beta amylase in Escherichia coli, plasmid pB927 was constructed. E. coli harboring plasmid pB927 produced sevenfold-mutant beta- amylase. The T50 value of purified sevenfold-mutant beta-amylase (69.0 degrees C) was higher than that of not only the original recombinant beta-amylase (57.4 degrees C) by 11.6 degrees C but also soybean beta-amylase (63.2 degrees C) by 5.8 degrees C. The intragenic amino acid replacements were found to have simple additive effects on the thermostability of beta-amylase. The sevenfold-mutant beta-amylase was found to be stable at pHs up to 12.5, while the original recombinant beta-amylase was unstable at pHs above 9.5. The data obtained from kinetics studies suggested that the sevenfold-mutant beta-amylase acquired enhanced thermostability, but its function as a beta amylase remained unchanged. PMID- 8690719 TI - cDNA cloning, expression, and chromosomal localization of a human UDP GalNAc:polypeptide, N-acetylgalactosaminyltransferase. AB - Oligonucleotide primers derived from the cDNA encoding a full-length bovine UDP GalNAc:polypeptide, N-acetylgalactosaminyltransferase (GalNAc-transferase) [Homa, F. L., Hollander, T., Lehman, D. J., Thomsen, D. R., and Elhammer, A. P. (1993) J. Biol. Chem. 268, 12609-12616], were used for PCR to isolate sequences encoding a homologous enzyme from human salivary gland cDNA. Comparison of the human and bovine nucleotide sequences reveals 94.8% sequence identity in their coding regions and 87% identity in their 3-untranslated regions. The translation of the human GalNAc-transferase coding region predicts an amino acid sequence which is nearly identical (99.6%) to that of the bovine counterpart; there are five conservative and one non-conservative amino acid substitutions between the two enzymes. Expression of the bovine and human cDNAs in the insect cell line, Sf9, resulted in the synthesis of proteins which appeared identical on SDS-PAGE and which had similar enzymatic properties. Screening of a somatic cell human/rodent hybrid panel with a probe derived from the human GaLNAc-transferase cDNA sequence indicated that the human GalNAc-transferase gene is localized to chromosome 18. PMID- 8690720 TI - Interaction of the Pseudomonas cepacia DSM3959 lipase with its chaperone, LimA. AB - The lipA gene of Pseudomonas cepacia DSM3959 requires a downstream gene, limA, in oder to express lipase activity. The product of the lim gene, LimA, is a molecular chaperone required during the folding of lipase in oder for the lipase to adopt an active conformation. The lipase and LimA proteins have been shown to form a complex precipitable with either an anti-lipase or anti-LimA antibody. LimA has been shown to form a 1:1 complex with with prelipase and lipase isolated from "natural" P. cepacia system. The mature lipase (lacking its signal peptide) has been expressed in the presence and absence of LimA in Escherichia coli. LimA can activate mature lipase during a urea denaturation-renaturation experiment, indicating that the signal peptide is not required for the lipase to be activated by LimA. The effects of various reagents on the renaturation of lipase from 8 M urea have been examined. We propose a mechanism for the function of the LimA chaperone during the production of active extracellular lipase. PMID- 8690721 TI - Modulation of elastin expression by heparin is dependent on the growth condition of vascular smooth muscle cells: up-regulation of elastin expression by heparin in the proliferating cells is mediated by the inhibition of protein kinase C activity. AB - The effect of heparin on elastin expression in the proliferating and quiescent phases of growth of smooth muscle cells was studied. Heparin stimulated elastin synthesis and its mRNA level 2-3 fold in the proliferating cells while it inhibited the cell proliferation. The inhibition of cell proliferation and the stimulation of elastin expression by heparin in the proliferating cells were mimicked by a potent protein kinase C antagonist, H-7, but not by H-89, W-7, and HA1004, suggesting that the effect of heparin is mediated by the inhibition of protein kinase C. In contrast, heparin inhibited elastin synthesis and its mRNA level slightly but exhibited no effect on cell proliferation in the growth arrested cells. This result indicates that heparin reciprocally affects elastin expression depending on the growth state of smooth muscle cells. Heparin thus exerts a complex influence on elastin expression in smooth muscle cells. PMID- 8690722 TI - Properties of glutamate dehydrogenase and its involvement in alanine production in a hyperthermophilic archaeon, Thermococcus profundus. AB - Thermococcus profundus, a hyperthermophilic archaeon, did not exhibit detectable glutamine synthetase activity, although the organism possessed an extraordinarily high level of glutamate dehydrogenase (GDH), the content of which reached over 10% of total soluble proteins. This GDH was purified to homogeneity. The enzyme had a molecular weight of 263,000 and was composed of six homogeneous subunits of molecular weight 43,000. The enzyme was extremely thermostable with a half life of 1 h at 90 degrees C. Circular dichroism (CD) spectra of the enzyme revealed gradual unfolding of alpha-helices upon exposure to increasing temperature. The enzyme reaction was strongly biased toward glutamate formation. T. profundus excreted L-alanine into the medium, and the concentration reached mM. High activity of alanine aminotransferase (AAT) was present in the cells, while no alanine dehydrogenase activity was detected. The alanine formation may be initiated by ammonia uptake by GDH followed by aminotransfer from glutamate to pyruvate by AAT. PMID- 8690723 TI - Inducible expression of erythroid-specific mouse glycophorin gene is regulated by proximal elements and locus control region-like sequence. AB - Cis-acting elements of the gene for mouse glycophorin, an erythroid-specific membrane glycoprotein, were determined by transient and stable transfection assays using murine erythroleukemia (MEL) cells. Cis-acting elements proximal to the transcription start site of the gene can be separated into the basal promoter (-1 to 191 bp) and the distal element (-133 to -92). The basal promoter contained GGTGG and GATA motifs and the distal element contained GATA-1 and NF-E2 motifs. Deletion analysis of the distal GATA site and its neighboring sequence and DNase I footprinting/EMSA (electrophoretic mobility shift assay) analysis indicated that induced nuclear factor binding to GATA-1 and its neighboring sequence may be required for expression during MEL cell differentiation induced by dimethyl sulfoxide treatment. The NF-E2 site was also shown to be essential for the promoter activity. An approximately 400 bp far upstream region (-1325 to -948bp) containing the binding motifs for GGGTGG, GATA-1 and NF-E2 showed no enhancing activity when this region was examined by transient transfection assay, but it did show enhancement of the differentiation-specific promoter activity in the stable transfection assay. The far upstream region of mouse glycophorin gene may have a function similar to that of the locus control region (LCR) of human beta globulin gene cluster. PMID- 8690724 TI - Copy-dependent and position-independent expression of rat aldolase A gene. AB - In order to understand the molecular mechanisms of the temporal and spatial differences of gene expression in higher organisms, rat aldolase A gene carrying two distinct promoters was introduced into fertilized eggs and the resulting transgenic mice were analyzed. The transgene expression is tissue-specific and is developmentally regulated. In addition, the expression is regulated in a copy dependent manner irrespective of where the transgene is integrated, suggesting that a mechanism excluding the effect of the integration site exists within the transgene itself. To explore the conformational change of this gene in the genome, the DNase I hypersensitive sites of the gene were examined. Three sites (DHS-1,2, and 3) were identified upstream and downstream of the gene and these sites were retained in the transgene as well as in the gene observed endogenously. PMID- 8690725 TI - Three ATP1 genes are present on chromosome II in Saccharomyces cerevisiae. AB - Chromosome fragmentation, ATP1 disruption, and Southern blot analyses of total DNAs and prime clones of chromosome II showed that three identical ATP1s are present, directing from the telomere to the centromere on the 35-55 kb far from the left telomere sequence of chromosome II. That is, the coding and 5'-, 3'-non coding regions of ATP1 are repeated 3 times at approximately 7 kb intervals. These three ATP1s are expressed, and one and two ATP1s-disrupted strains, respectively, showed ca.70 and 40% decreases in their ATPase activities and alpha subunit contents, compared to those of the wild type, DC-5 or W303-1A strain, but could grow on glycerol. PMID- 8690726 TI - Structures of charge-transfer complexes of flavoenzyme D-amino acid oxidase: a study by resonance Raman spectroscopy and extended Huckel molecular orbital method. AB - The structure of the ligand in a charge-transfer complex of oxidized D-amino acid oxidase (DAO) formed upon aerobic addition of chloropyruvate and ammonium sulfate was determined by resonance Raman spectroscopy. The ligand in the complex is in the enamine form, 2-amino-3-chloracrylate, not in the imine form, 2-imino-3 chloropropionate. This conclusion is consistent with our hypothesis that the ligands in the charge-transfer complexes of oxidized DAO and reduced DAO are generally in the enamine and imine forms, respectively. The calculation of HOMO and LUMO of some enamine and imine forms by the extended Huckel molecular orbital method indicated that the enamine form is a better electron donor than the imine form and the imine form is a better electron acceptor than the enamine form. These results, as well as the information about the structure of enzyme-bound ligand, support the following ideas. (i) In the charge-transfer complex of reduced DAO, the reduced flavin is an electron donor. (ii) In the charge-transfer complex of reduced DAO, the reduced flavin is an electron donor and the ligand is an electron acceptor. Resonance Raman studies on the charge-transfer complexes of oxidized DAO and those of reduced DAO, and calculated results of HOMO and LUMO for some enamine and imine forms, corroborated the structure of the stacking form between the flavin ring and the ligand in the active site of DAO. PMID- 8690727 TI - Loss of immunostaining of the RBP-J kappa transcription factor upon F9 cell differentiation induced by retinoic acid. AB - RBP-Jkappa is a novel type of transcriptional regulatory protein that does not contain any known DNA-binding motif. We raised anti-RBP-Jkappa monoclonal antibodies (K0043 and T6709) to investigate the roles of RBP-Jkappa in cell differentiation. These antibodies stained nuclei of undifferentiated embryonic stem cells and F9 cells but not those of the other differentiated cell lines tested so far although the RBP-Jkappa protein is expressed at similar levels. Interestingly, differentiated F9 cells lost the immunostaining reaction with the anti-RBP-Jkappa monoclonal antibodies. Biochemical subcellular fractionation study showed that the majority of RBP-Jkappa was localized in nuclei of F9 cells and that there are at least two forms of the RBP-Jkapppa protein in the nuclei of undifferentiated F9 cells, a free form and a chromatin-bound form. Upon induction of F9 cell differentiation, free nuclear RBP-Jkappa disappeared concomitantly with the loss of immunostaining, suggesting that the anti-RBP-Jkapppa antibodies cannot recognize chromatin-bound RBP-Jkappa. Since there is no evidence to indicate covalent modification of RBP-Jkappa, we assume that chromatin-bound RBP Jkappa interacts with a large number of proteins which block the exposure of RBP Jkappa epitopes to the monoclonal antibodies. PMID- 8690728 TI - Modulation of the stress-induced synthesis of stress proteins by a phorbol ester and okadaic acid. AB - The expression of alphaB crystallin, hsp27, and hsp70 in C6 cells increased when they were exposed to arsenite (50 microM for 1 h) or heat (42 degrees C for 30 min), as detected by specific immunoassays, Western blot analysis, and Northern blot analysis. When cells were exposed to arsenite in the presence of 0.1 microM phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, or 0.2 microM okadaic acid, an inhibitor of phosphoserine/phosphothreonine protein phosphatases, expression of alphaB crystallin was markedly enhanced. The induction of hsp27 and hosp70 expression was also stimulated to a considerable extent in the same cells. The stimulatory effect of PMA was further enhanced in the presence of okadaic acid, but it was strongly inhibited in the presence of 0.5 microM staurosporine, an inhibitor of protein kinase C. PMA and okadaic acid also stimulated the response to heat stress of the expression of alphaB crystallin, but they barely stimulated the response to heat stress of hsp27. The extent of stimulation of the arsenite-induced responses by PMA and okadaic acid was greater when the concentration of arsenite (i.e. the magnitude of the stress) was relatively low (25-50 microM). The arsenite-induced release of arachidonic acid from cells was also stimulated in the presence of PMA and/or akadaic acid, and the stimulatory effects of PMA and okadaic acid on the arsenite-induced accumulation of alphaB crystallin and hsp27 were strongly suppressed by quinacrine, an inhibitor of phospholipase A2. These results suggest that the stimulatory effects of PMA and okadaicacid on the stress responses are cuased, in part, by the increased metabolic activity of the arachidonic acid cascade, as a consequence of the activation of phospholipase A. PMID- 8690729 TI - Significance of the highly conserved Gly-4 residue in human cystatin A. AB - The expression system for human recombinant cystatin A has already been established to be a fusion protein with porcine adenylate kinase in Escherichia coli [Kaji et al. (1990) Biol. Chem. Hoppe-Seyler 371, Suppl., 145-150]. After cyanogen bromide cleavage of the fused protein expressed in E. coli, the cystatin portion could be readily isolated. The inhibitory activity of the obtained variant (Cyst A (2-98)) was found to be almost identical with that of the wild type, and thereafter a mutation was introduced into this variant (Ctst A(2-98)), called the standard variant. To elucidate the role of the Gly-4 residue, which is completely conserved in all cystatin species, this residue was substituted with 17 other amino acids by means of cassette mutagenesis. Thus 17 variants (Cyst A(2 98)[G4X]) obtained were examined as to their inhibitory activity towards papain. As the side chain of the substituted amino acid residue became more bulky, the inhibitory activity of the variant markedly decreased. Variants whose side chains were bulkier than a Val residue showed almost no inhibitory effect towards papain. Consequently, it was deduced that the large side chain of a substituted amino acid may cause steric hindrance, which may be responsible for the decrease in inhibitory activity. Thus, we could conclude that the 4th (Gly) residue on cystatin A must be small, because amino acids which existed on the N-terminal side of this residue could interact with a papain molecule. PMID- 8690730 TI - Hepatocyte growth factor suppresses the onset of liver cirrhosis and abrogates lethal hepatic dysfunction in rats. AB - Heptic fibrosis/cirrhosis is a common hepatic disease characterized by the hyper accumulation of connective tissue components, and hepatic necrosis. Chronic alcohol ingestion, viral infection, and metabolic disorders are contributing factors and there has been no effective treatment. Hepatocyte growth factor (HGF), originally identified as a potent mitogen for mature hepatocytes, is a long-sought hepatotrophic factor for liver regeneration. Administration of human recombinant HGF into rats with hepatic fibrosis/cirrhosis caused by dimethylnitrosamine (DMN) elicited mitogenic action for hepatocytes, stimulated hepatic collagenase activity, and prevented the onset and progression of hepatic fibrosis/cirrhosis. Accumulation of fibrous tissue components in the liver due to DMN-treatment were markedly decreased in HGF-injected rats. Moreover, HGF completely abrogated death caused by severe hepatic cirrhosis and dysfunction. We postulate that HGF may prove to be an effective treatment for human liver fibrosis/cirrhosis and for chronic hepatic failure. PMID- 8690731 TI - Purification and characterization of the G203T mutant alpha i-2 subunit of GTP binding protein expressed in baculovirus-infected Sf9 cells. AB - We expressed the Gly203-->Thr (G203T) mutant of Gi2alpha, which was expected to show a dominant-negative phenotype in Gi2-mediated signal transduction, in baculovirus-inefected Sf9 cells and purified the mutant alpha subunit for its characterization. The rate of dissociation of GDP from G203T Gi2alpha was 3- to 4 fold faster than that from wild type Gi2alpha, but their kappacat values for GTP hydrolysis were almost the same. The affinities of the two Gi2alpha proteins for the beta gamma subunits of G proteins to form alpha beta gamma timers, which served as substrates for pertussis toxin-catalyzed ADP-ribosylation, were the same. In marked contrast, G203T Gi2alpha was unable to form a tight complex with a non- hydrolyzable analog (GTP[gammaS) of GTP; bound GTP[gammaS] was readily released from the mutant Gi2alpha even in the presence of a high concentration of Mg2+. Its susceptibility to tryptic digestion also revealed that GTP[gammaS] bound G203T Gi2alpha formed a conformation apparently different from that of the GTP[gammaS]-bound form of wild-type Gi2alpha. Both the G203T and wild-type Gi2alpha proteins were capable of coupling with membrane-bound alpha2-adrenergic receptors, resulting in the formation of receptor-G protein complexes with high affinity for agonists. However, GTP[gammaS]-dependent uncoupling from high affinity receptors was markedly attenuated in the case of G203T Gi2alpha. Thus, G203T-mutated Gi2alpha had a unique property in terms of coupling to membrane receptors, in addition to the previously expected defect in the active conformation of the GTP-bound form of Gi2alpha. PMID- 8690732 TI - Molecular cloning and characterization of a third type of N-glycan alpha 2,8 sialyltransferase from mouse lung. AB - AcDNA encoding a new alpha2,8-sialyltransferase (ST8Sia IV), which exhibits activity toward the alpha,2,3-linked sialic acids of N-linked oligosaccharides, was cloned from a mouse lung cDNA library by means of the PCR-based approach. The predicted amino acid sequence of ST8Sia IV showed 15.2, 56.0, and 26% identity with those of so far cloned mouse alpha2,8-sialytransferases, i.e. GD3 synthase (ST8Sia I), STX(ST8Sia II), and Sia(alpha)2,3Galbeta1,4GlcNAc(alpha)2,8-sialyl transferase (ST8Sia III). ST8Sia IV exhibits high amino acid sequence identity (99.2%) with recently cloned hamster polysialyltransferase-1 gene, which is necessary to polysialic acid expression, but no enzymatic activity of the gene product was reported [Eckhardt, M. et al. (1995) Nature 373, 715-718]. The ST8Sia IV gene was strongly expressed in lung, heart, and spleen, but only weak expression of the gene was observed in brain, without remarkable developmental regulation. The activity of mouse ST8Sia IV was specific toward sialylated glycoproteins. The linage-specific sialidase treatment of glycoproteins as well as N-linked oligosaccharides from the glycoproteins revealed that ST8Sia IV exhibits an alpha2,8-sialytransferase activity toward alpha2,3-linked sialic acids of N-linked oligosaccharides. ST8Sia IV can synthesize polysialic acid chain in vitro without any initiator sialytransferase. PMID- 8690733 TI - An affinity of human replication protein A for ultraviolet-damaged DNA. AB - Replication protein A (RPA), a heterotrimeric protein of 70-, 32-, and 14-kDa subunits, is an essential factor for DNA replication. Biochemical studies with human and yeast RPA have indicated that it is a DNA-binding protein that has higher affinity for single-stranded DNA. Interestingly, in vitro nucleotide excision repair studies with purified protein components have shown an absolute requirement for RPA in the incision of UV-damaged DNA. Here we use a mobility shift assay to demonstrate that human RPA binds a UV damaged duplex DNA fragment preferentially. Complex formation between RPA and the UV-irradiated DNA is not affected by prior enzymatic photo-reactivation of the DNA, suggesting an affinity of RPA for the (6-4) photoproduct. We also show that Mg2+ in the millimolar range is required for preferential binding of RPA to damaged DNA. These findings identify a novel property of RPA and implicate RPA in damage recognition during the incision of UV-damaged DNA. PMID- 8690734 TI - A naturally occurring point mutation confers broad range tolerance to herbicides that target acetolactate synthase. PMID- 8690735 TI - Purification, primary structures, and antibacterial activities of beta-defensins, a new family of antimicrobial peptides from bovine neutrophils. PMID- 8690736 TI - Vertebrate unconventional myosins. PMID- 8690738 TI - Impact of migration, environment and socioeconomic conditions on the physique of Sikhs. AB - This study is based on a cross-sectional sample of 459 Sikh adults, male and female, from three castes representing three levels of socioeconomic affluence. The sedentes group stayed all their lives in the native state of Punjab, India; the migrant group completed their active physical growth in the Punjab and left for the UK at around 20 years of age. The pattern of stature, weight, BMI and skinfolds in both groups reflects their level of socioeconomic affluence in their native Punjab. In the migrants, the caste differences in the mass measures largely disappear, but the differences in the skeletal dimensions remain. Both male and female migrants are heavier than their sedente counterparts and the male migrants have substantially higher amounts of subcutaneous fat. The change in weight, BMI and skinfolds in the migrants is inversely proportional to the original values of these variables in the native settings. Male sedentes and migrants are not statistically significantly different in stature, but the female migrants are taller than their sedente peers in all three castes. In a multivariate analysis, caste remains the most significant factor in the skeletal variables; in the mass characters, both caste and migration are statistically significant factors; age explains very little of the variation. PMID- 8690739 TI - Influence of social class on the correlation of stature of adult children with that of their mothers and fathers. AB - Studies of parent-child correlations in stature require data which can be viewed as random samples of some general population and which are large enough to allow partition of the variable and evaluation of non-genetic and genetic influences. In a sample of 4336 individuals drawn from a cohort of all persons born in England, Scotland and Wales in 1 week in 1958, the correlation of statures of the males with their fathers, the females with their fathers, the males with their mothers and the females with their mothers were 0.36, 0.43, 0.41 and 0.47 respectively at age 16 of the offspring and 0.41, 0.41, 0.47 and 0.46 respectively at age 23. Allowance for the occupational social class of the fathers lowers the correlations, but in no case by more than 5%. Allowance for the occupational class achieved by the offspring by age 23 has little effect on the correlations. PMID- 8690737 TI - Determinants of contraceptive use in Morocco: stopping behaviour in traditional populations. AB - The determinants of modern contraceptive use in traditional populations are analysed in married women aged 30-44 living in the province of Marrakech (Morocco). Women who have never used contraception have smaller family sizes than those who do: the number of live children (or live births) is the variable with maximum predictive power on contraceptive use, while child mortality is the main inhibiting factor. The probability of contraceptive use increases with female age at marriage and decreases with the woman's age, indicating a generational change in reproductive behaviour. The socioeconomic variables education, employment and residence, have no significant independent predictive character on contraceptive use, although the interaction between education and residence does. The paper evaluates the hypothesis that traditional populations in the initial phase of their demographic transition resort to modern contraception in order to stop childbearing, when they have reached a desired number of children, rather than to space births or reduce their fertility. PMID- 8690740 TI - Influence of socioeconomic factors on basic competencies of children in Bangladesh. AB - The effects of selected socioeconomic factors on basic competencies of children in Bangladesh were studied using primary data on 2520 children from all over the country. The residence of the child, years of schooling, parental education and economic status of the household were found to be important determinants of basic competencies of children. PMID- 8690741 TI - Is fertility falling in Zimbabwe? AB - With an unequalled contraceptive prevalence rate in sub-Saharan Africa, of 43% among currently married women in Zimbabwe, the Central Statistical Office (1989) observed that fertility has declined sharply in recent years. Using data from several surveys on Zimbabwe, especially the birth histories of the Zimbabwe Demographic and Health Survey, this study examines fertility trends in Zimbabwe. The results show that the fertility decline in Zimbabwe is modest and that the decline is concentrated among high order births. Multivariate analysis did not show a statistically significant effect of contraception on fertility, partly because a high proportion of Zimbabwean women in the reproductive age group never use contraception due to prevailing pronatalist attitudes in the country. PMID- 8690742 TI - The male versus female perspective on family planning: kinshasa, zaire. AB - Males have often been neglected in both family planning programmes and in surveys used to design and evaluate such programmes. A 1988 study on fertility, family planning and AIDS in Kinshasa, Zaire, provides comparable data on 3140 men and 3485 women of reproductive age which served as the basis for analysing male/female differences. The study indicated a fair degree of similarity in the attitudes, beliefs, knowledge levels and practices of men and women regarding fertility and family planning. Where they differed (e.g. on expected or ideal number of children, the desire for more children at parity 7 or above), men tended to be more pronatalist than women. The implications of the findings for future family planning programmes are discussed. Programmes should target males because of their role as decision makers within Zairian society. PMID- 8690743 TI - Fertility norms and son preference in Morocco and Tunisia: does women's status matter? AB - This paper investigates the normative and behavioural dimensions of son preference in Morocco and Tunisia, using data from the Demographic and Health Surveys of the two countries. It considers three measures of son preference: (1) mothers' ideal number of children, and any preference for having more sons than daughters; (2) the desire for additional children, given their existing family; (3) reported use of contraception in relation to the existing number of children of each sex. The analyses indicate a moderate preference for sons in both countries, and suggest that this preference is somewhat stronger in Tunisia. These findings are interpreted within the cultural context of the two countries, and in particular societal notions of women's status. PMID- 8690744 TI - Racial differences in the relationship between infant mortality and socioeconomic status. AB - This paper presents an ecological analysis of the relationship between infant mortality and economic status by race in metropolitan Ohio, using census data on mother's residence, and economic status determined by the percentage of low income families living in each area. White-non-white comparisons for total infant mortality are examined for the US censuses of 1960, 1970, 1980 and 1990; and more detailed period- and broad cause-specific rates are presented for 1990. A pronounced inverse association is found between income status and infant mortality for whites, but not for non-whites. Non-white post-neonatal death rates were higher for the lowest income area, but for neonatal mortality, total infant deaths, and exogenous and endogenous cause-specific death rates, there was no discernible socioeconomic differential. It is concluded that low income whites and non-whites at all income levels have infant mortality rates that are substantially higher than the overall rate for the population. Policy implications are discussed. PMID- 8690745 TI - Geographical variation and evolution of tertiary sexual equilibrium in the province of Jujuy (Argentina). AB - The tertiary sex ratio, as measured by the masculinity index, was examined in four regions of the Province of Jujuy in north-west Argentina over a period from 1869 to 1991. The results showed that inter-regional, as well as age group differences in MI existed which could be related to changing social and economic conditions in this area over the last two centuries. PMID- 8690746 TI - Family formation patterns among migrant women in Sydney. AB - A demographic survey among a probability sample of 980 married migrant women was carried out in Sydney in 1988. The sample included 507 Lebanese, 250 Turkish and 223 Vietnamese women. The study revealed differences in family formation patterns within and between the three groups and between them and the general population. Family size had declined among all three groups compared with their family of origin, and it was clear that the younger women would not achieve the same family sizes as the older women. Migrant women tended to marry earlier than the general population and to start their families earlier. While they showed a strong preference for their children to marry within their own ethnic and religious group, nearly one-third said it was up to the choice of the individual. Overall, the future family size of younger migrant women is expected to converge towards the Australian norm. Migrant families are in a state of transition between two cultures which needs to be recognised by health and family planning service providers. PMID- 8690747 TI - Clinical practice guidelines in oncology: pros and cons. PMID- 8690749 TI - Metastatic models of human liver cancer in nude mice orthotopically constructed by using histologically intact patient specimens. AB - In this study of orthotopic implantation of histologically intact surgical specimens, the authors constructed metastatic models of human hepatocellular carcinoma (HCC) in nude mice. Histologically intact human liver cancer specimens, derived from patients, were implanted directly into the liver of nude mice, and their orthotopic growth and metastases were observed. The transplantability and metastatic rate of two specimen groups (primary and metastatic lesions) were analysed. alpha-Fetoprotein (AFP) was also determined in transplanted tumours by an immunohistochemical method. Orthotopic growth was observed in 14 of 30 transplanted specimens and formation of metastases in 7 cases, which exhibited the variety of clinical behaviours seen in patients with HCC. These behaviours included local growth, regional invasion, spontaneous intrahepatic, lymph node and lung metastasis and peritoneal seeding. In two groups the growth rate of metastatic lesions following implantation was clearly higher than that of primary tumours. Chromosome analysis from locally growing tumours confirmed their morphologically human origin. An immunohistochemical study showed that implanted tumours originating from AFP-positive specimens maintained AFP expression. These results indicated that the animal models should prove valuable for developing new treatment modalities and studying the mechanism of metastasis of human HCC. PMID- 8690748 TI - The future of antihormone therapy: innovations based on an established principle. AB - Endocrine therapy of mammary and prostate cancer has been established for decades. The therapies available to block sex-hormone-receptor-mediated tumor growth are based on two principles: (i) ligand depletion, which can be achieved surgically, by use of luteinizing-hormone-releasing hormone analogues or inhibitors of enzymes involved in steroid biosynthesis or by interfering with the feedback mechanisms of sex hormone synthesis at the pituitary/hypothalamic level; (ii) blockade of sex hormone receptor function by use of antihormones. The antiestrogen tamoxifen, which is the compound of choice for the treatment of mammary carcinoma, has the drawback of being a partial agonist. A complete blockade of estrogen receptor (ER) function can be achieved by a new class of compounds, pure antiestrogens. In contrast to aromatase inhibitors, pure antiestrogens are able to block ER activation by ligands other than estradiol and can also interfere with ligand-independent ER activation. In addition to estradiol, progesterone has a strong proliferative effect in mammary carcinomas. Antiprogestins are promising new tools for clinical breast cancer therapy. These compounds clearly need a functionally expressed progesterone receptor to block tumor growth, but there is strong experimental evidence that their tumor inhibition is based on more than just progesterone antagonism. The ability of these compounds to induce tumor cell differentiation that leads to apoptosis is unique among all other endocrine therapeutics. In prostate tumors that have relapsed from current androgen-ablation therapies the androgen receptor (AR) is still expressed and, compared to the primary tumors, its level is often even enhanced. Mutated AR that can be activated by other compounds such as adrenal steroids, estrogens, progestins and even antiandrogens have been detected in recurrent tumors. Thus, relapse of tumors under the selective pressure of common androgen-ablation therapies can be caused by acquired androgen hypersensitivity and AR activation by ligands other than (dihydro-)testosterone. There is a clinical need for future compounds that produce a complete blockade of AR activity even in recurrent tumors. Preclinical experiments indicate that combination therapy as well as the extension of endocrine treatments to several other tumor entities are promising approaches for further developments. Examples are the combination of antiestrogens and antiprogestins for breast cancer treatment, or the treatment of prostate carcinomas with antiprogestins. PMID- 8690750 TI - Modulation of multidrug resistance with dexniguldipine hydrochloride (B8509-035) in the CC531 rat colon carcinoma model. AB - The chemosensitizing potency of dexniguldipine hydrochloride (B8509-035) on epidoxorubicin was assessed in a multidrug-resistant (MDR) tumour model, the intrinsic MDR rat colon carcinoma CC531. In vitro in the sulphorhodamine B cell viability assay the cytotoxicity of epidoxorubicin was increased approximately 15 fold by co-incubation with 50 ng/ml dexniguldipine. In vivo concentrations of dexniguldipine 5 h after a single oral dose of 30 mg/kg were 72 (+/- 19 SD) ng/ml in plasma and 925 (+/- 495 SD) ng/g in tumour tissue. Levels of the metabolite of dexniguldipine, M-1, which has the same chemosensitizing potential, were 26 (+/- 6 SD) ng/ml and 289 (+/- 127 SD) ng/g respectively. The efficacy of treatment with 6 mg/kg epidoxorubicin applied intravenously combined with 30 mg kg-1 day-1 dexniguldipine administered orally for 3 days prior to epidoxorubicin injection was evaluated on tumours grown under the renal capsule. Dexniguldipine alone did not show antitumour effects in vivo. Dexniguldipine modestly, but consistently, potentiated the tumour-growth-inhibiting effect of epidoxorubicin, reaching statistical significance in two out of four experiments. In conclusion, these experiments show that dexniguldipine has potency as an MDR reverter in vitro and in vivo in this solid MDR tumour model. PMID- 8690751 TI - Preferential cytotoxic effect of Newcastle disease virus on lymphoma cells. AB - Susceptibility of lymphoma cells (Daudi, HD-Mar) to Newcastle disease virus toxicity was found to be higher than that of lymphoblastoid cells (Milstein) and of resting peripheral blood lymphocyte (PBL). Phytohemagglutinin- and/or pokeweed mitogen-activated PBL however, exhibited, elevated sensitivity, similar to that of lymphoma cells. The level of cytotoxicity was monitored by cell viability, inhibition of DNA synthesis and release of 51Cr. When Daudi cells were mixed with PBL they were significantly more sensitive to the killing effect of the virus (70% mortality compared to 30% 30 h after infection, P < 0.05). The degree of sensitivity to viral cytotoxicity was unrelated to the efficacy of adsorption, which was similar for all cell lines as shown by immunofluorescent staining and flow cytometry. Also an influenza strain A/PR/8/34 (H1N1) adsorbed but did not affect the viability of any of the cells tested. Our results demonstrate that New castle disease virus caused preferential damage to lymphoma cells as compared to non-cancerous normal cells. PMID- 8690752 TI - Luteinizing hormone pulsatility and computer-assisted analysis of sperm features in patients with Hodgkin's disease. AB - The aim of this work was to characterize further the impairment of the reproductive function reported in untreated male patients with Hodgkin's disease. We evaluated the pattern of luteinizing hormone pulsatility and unconventional sperm features by computer-assisted sperm analysis (CASA) in 20 adult patients affected by biopsy-proven Hodgkin's disease before they were submitted to any therapeutic approach. Changes of luteinizing hormone pulsatility were documented and consisted mainly in an increase in pulse number in comparison with control subjects (P < 0.05). On CASA, 1/3 of the patients showed a reduction in the sperm number but, when motility, velocity and linearity of progression were evaluated, the number of patients with seminal alterations rose to 2/3. Sperm velocity and linearity were already impaired in stages I and II, whereas sperm number was reduced only in stage III. Symptomatic patients, regardless of the stage, showed a significant deterioration of all parameters. Our study supports the view that in Hodgkin's disease, before any treatment, a disorder of the reproductive system is present, both at hypothalamic/hypophysial and the gonadal level, having a pathogenesis that deserves to be elucidated by further study. PMID- 8690754 TI - Bcl-2 expression and allelic loss of the p53 gene in gastric carcinomas. AB - In order to clarify the association between bcl-2 protein (Bcl-2) expression and genetic alteration, we investigated p53 and DCC (deleted in the colon carcinoma gene locus) gene abnormalities in Bcl-2-positive and -negative gastric carcinomas using a polymerase chain reaction/loss of heterozygosity (LOH) assay. Bcl-2 immunoreactivity was found in 25 of 178 (14%) gastric carcinoma cases. With these 25 positive cases, the proportion 18/87 (20.6%) of the total in early stages demonstrating invasion of the mucosa and/or submucosa was significantly greater (P = 0.013) than the 7/91 (7.7%) found for advanced tumors exhibiting invasion into or through the muscularis propria. However, there was no statistically significant variation between the proportions for differentiated (17/98 cases, 17.3%) and undifferentiated (8/80 cases, 10%) lesions. Sixteen Bcl-2-positive cases (9 cases were not studied because of insufficient specimen material to allow extraction of DNA) and 31 cases randomly selected from a Bcl-2-negative group were analyzed for the presence of p53-LOH or DCC-LOH and for p53 by immuno histochemistry. The minority of the Bcl-2-positive group had p53-LOH and were immunopositive for p53 (P = 0.033, P = 0.028 respectively), while no association was found in the Bcl-2-negative category. In contrast, there was no correlation at all between Bcl-2 expression and DCC-LOH although the number of informative cases analyzed was too small to allow definite conclusions. These results indicate that Bcl-2 may be predominantly expressed at an early stage in gastric carcinomas, possibly in negative association with p53 gene abnormalities. PMID- 8690753 TI - Intraarterial hepatic chemotherapy with fluorouracil, fluorodeoxyuridine, mitomycin C, cisplatin or methotrexate as single-agent anticancer drugs for a transplanted experimental liver tumor in rats. AB - A prospective, controlled and standardized animal experiment was performed to study the influence of various anticancer drugs. The Novikoff hepatoma transplanted into male Sprague-Dawley rats was treated with fluorouracil (FUra), mitomycin C, methotrexate, cisplatin and fluorodeoxyuridine (FdUrd) at equi effective dosage, in terms of side effects (weight loss), in comparison to a control group (0.9% saline solution) by locoregional application via the hepatic artery. The tumor multiplication factor (TMF = tumor volume day 12/tumor volume day 5) served as the parameter to compare the tumor growth of the various groups. All drugs showed a significant (P < 0.05) effect on the tumor growth. In comparison to the control group (mean TMF 9.66), FdUrd (3.78) and FUra (3.03) only limited the tumor growth, mitomycin C (0.96) produced stable tumor, cisplatin (0.64) and methotrexate (0.15) significantly reduced (P < 0.01) the tumor size. We suggest that, in addition to the established (FUra, FdUrd, mitomycin C) drugs, methotrexate and cisplatin should be considered in further studies of the treatment of primary and secondary liver malignancies. PMID- 8690755 TI - Differential expression of jackfruit-lectin-specific glycoconjugates in metastatic adenocarcinoma and reactive mesothelial cells-a diagnostic aid in effusion cytology. AB - Distinguishing reactive mesothelial cells from adenocarcinoma cells in serous effusions on the basis of morphological criteria alone is often difficult. Interest has therefore been focused on identifying reliable methods to supplement the conventional cytological techniques. Plant lectins have been reported as diagnostic markers for malignant cells. We studied 51 aspirated samples of benign and malignant effusions using horseradish-peroxidase-conjugated jackfruit lectin. No significant difference was observed between the cells of pleural and peritoneal fluids. The reactively proliferated mesothelial cells of benign effusions showed a predominance of mild staining while moderate and intense staining was predominant in malignant effusions. Intense and irregular lectin binding was observed in macrophages irrespective of the cause of effusion. The lectin staining method therefore appears to have some clinical significance as an additional diagnostic aid for use in effusion cytology. PMID- 8690757 TI - Identification of common functional configurations among molecules. AB - A new algorithm for identifying three-dimensional configurations of chemical features common to a set of molecules is described. The algorithm scores each configuration based both on the degree to which it is common to the input set and its estimated rarity. The algorithm can be applied to molecules with large (several hundred) conformational models. Results from the application of this algorithm to three data sets are discussed: PAF antagonists, HIV reverse transcriptase inhibitors, and HIV protease inhibitors. Of particular interest is a common configuration identified for a set of HIV reverse transcriptase inhibitors; this configuration is shared by two new, potent inhibitors that were recently described in the literature. PMID- 8690756 TI - Analysis of thrombocytopenia due to carboplatin combined with etoposide in elderly patients with lung cancer. AB - Thrombocytopenia induced by carboplatin combined with etoposide for elderly lung cancer patients was analyzed in relation to the predicted thrombocytopenia by the equations advocated by Egorin et al. and Taguchi et al. The thrombocytopenia actually observed was strongly correlated with and significantly more severe than that predicted if carboplatin had been administered as a single agent. The AUC (area under the curve) of carboplatin predicted by Calvert's equation significantly affected the degree of thrombocytopenia. These data suggested that dosing of carboplatin should be determined individually on the basis of renal function, as recommended earlier. The reason for the enhancement of thrombocytopenia is yet to be determined in future trials. PMID- 8690758 TI - Rapid, small scale purification of rice hoja blanca and Echinochloa hoja blanca tenuivirus ribonucleoprotein. AB - Highly purified tenuivirus ribonucleoprotein was obtained from small amounts of leaf tissue by sedimenting the ribonucleoprotein particles from debris-free plant extract into a 30% sucrose cushion, in 1.5-mL microfuge tubes. Using this protocol, significant size differences were discovered in the double-stranded forms of the viral genomic RNAs of rice hoja blanca tenuivirus and a tenuivirus isolated from Echinochloa colonum, a common weed of rice cultivation. PMID- 8690759 TI - Detection of airborne cytomegalovirus in hospital rooms of immunocompromised patients. AB - Human cytomegalovirus (CMV) is a major pathogen in immunocompromised patients. Transmission in this population is known to occur by fomites, but the potential for airborne spread is unknown. In this study, air from the rooms of two immunosuppressed patients with CMV pneumonia and one patient with latent infection was filtered and examined by a polymerase chain reaction assay. CMV-DNA was easily detected in the rooms of the patients with pneumonia and a weak positive signal was detected in the room of the patient with latent CMV infection. This technique permits the detection of aerosolized CMV-DNA and could possibly be adapted to detect other airborne pathogens. PMID- 8690760 TI - Consensus oligonucleotide primers for the detection of GB virus C in human cryptogenic hepatitis. AB - Recently, sequences from a putative member of the Flaviviridae, GB virus C (GBV C), were isolated from the serum of patients with cryptogenic hepatitis. These sequences were 83-99% identical at the nucleotide level. Because of the divergence between these GBV-C isolates, it is likely that the PCR-based detection assay yields false negatives, underestimating dramatically the true prevalence of GBV-C in human hepatitis. We report the design of a GBV-C consensus oligonucleotide primer pair that is superior to those originally described. These primers identify GBV-C sequences in cases of cryptogenic hepatitis, allowing a better estimation of the prevalence of this virus in human populations. PMID- 8690761 TI - Hepatitis B core antibody screening in a high prevalence group: comparison of three enzyme immunoassays using receiver operating characteristic analysis. AB - Selected sera from 296 homosexual men were screened by 3 commercially available anti-HBc enzyme immunoassays (EIA). All patients could be classified either as non-immune to hepatitis B, or with current or previous hepatitis B infection. Using the cut-off optical density values (O.D. values) recommended by the respective manufacturers, the results from these three assays were identical for 83% of the serum samples. For anti-HBc reactivity, the ratio (percentage) was calculated using O.D. sample x 100 divided by the O.D. cut-off value. Employing these ratios, sensitivities and specificities for the three assays were compared. All assays performed well when analyzed by receiver operating characteristic curves with area under the curves of 96-97%. A higher specificity, with only a marginal loss of sensitivity could be achieved by lowering the cut-off to 55% for the Enzygost EIA, to 85% for the Enzygost-monoclonal EIA and to 60% for the Corzyme EIA. Using the modified cut-off values, the results with the three assays agreed for 93% of the serum samples. PMID- 8690762 TI - Detection of Tospovirus species by RT-PCR of the N-gene and restriction enzyme digestions of the products. AB - Tomato spotted wilt is a serious disease that affects several economically important crops. From the epidemiological point of view and for the development of a successful plan for transgenic resistance plants, the four known Tospovirus species must be discriminated at the molecular level. A RT-PCR assay using primers complementary to the N gene was used to detect and differentiate fourteen Argentinian isolates of Tospovirus from different crops and geographical areas. Extracts were reverse transcribed using a thermo-resistant reverse transcriptase and PCR reactions were performed for 30 min in a capillar thermo-cycler. The products were digested with restriction enzymes and three of the four described species were identified. Additionally, the results were confirmed by DAS-ELISA. The method described here is rapid and reliable. PMID- 8690763 TI - Determination of hepatitis A antibody response to vaccination by an enzyme immunoassay. AB - The quantitative responses to vaccination with hepatitis A vaccine was determined in 113 volunteers using a commercially available enzyme-linked immunosorbent assay for total antibodies to hepatitis A. Administration of vaccine or control preparation was carried out according to two regimens; at 0, 1 and 12 months (regimen I) and at 0, 0.5 and 12 months (regimen II). Seroconversion rates (concentrations of HAV antibodies > 50 IU/l) were between 94 and 97% at month 1 for regimen I and regimen II, respectively. The geometric mean titres (GMTs) fell gradually by month 12, and increased rapidly 10-100 fold 1 month after the booster dose at month 12. The GMTs of the groups receiving the control preparation remained below 50 IU/l. No significant differences were found between the antibody responses after regimen I or regimen II. It is concluded that the antibody test (Hepanostika HAV Antibody) can be used safely and adequately for quantitation of responses to hepatitis A immunisation. PMID- 8690764 TI - Comparison of a DNA probe assay with the plaque reduction assay for measuring the sensitivity of herpes simplex virus and varicella-zoster virus to penciclovir and acyclovir. AB - A DNA probe assay was compared with the plaque reduction assay to determine the sensitivity of clinical isolates of herpes simplex virus (HSV) and varicella zoster virus (VZV) to penciclovir and acyclovir in MRC-5 cells. In both assays, penciclovir and acyclovir shared comparable activity against cell-free virus (CFV) preparations of VZV and herpes simplex virus type 1 (HSV-1) isolates, whilst acyclovir was significantly more active than penciclovir against herpes simplex virus type 2 (HSV-2) isolates in both the DNA probe assay (P < or = 0.01) and the plaque reduction assay (P < or = 0.01). However, the 50% effective concentrations (EC50s) were generally lower in the DNA probe assay and the correlation between the plaque reduction and DNA probe assays was poor for either compound. Six acyclovir-resistant strains of HSV-1 derived in cell culture were also tested for susceptibility to penciclovir and acyclovir, in the DNA probe and plaque reduction assays. The relative susceptibilities of these strains were comparable, for example, one ACV-resistant strain was susceptible to penciclovir in both assays. Further comparisons of the assay methods were made using cell associated VZV (CAV). As with CFV the EC50s were significantly lower in the DNA probe assay than the plaque reduction assay for penciclovir (P < or = 0.01) and acyclovir (P < or = 0.01). In the DNA probe assay there was no significant difference in the EC50s for either penciclovir or acyclovir when comparing CAV with CFV. However, in the plaque reduction assay the EC50s for CAV were significantly higher than those for CFV for both penciclovir (P < or = 0.01) and acyclovir (P < or = 0.01). Overall the DNA probe assay is objective, does not require prior titration of isolates and provides opportunities for automation. It is more suitable for sensitivity testing of large numbers of clinical isolates than the well-established plaque reduction assay. PMID- 8690765 TI - Sensitive method for the detection of infectious HIV in semen of seropositive individuals. AB - The aim of the study was to develop a sensitive culture method for the detection of HIV in semen. Antimicrobials were evaluated to suppress bacterial and fungal contamination of HIV cultures. Toxicity of seminal plasma was reduced using a short incubation of seminal fluid with culture cells. The detection rate was determined by adding known amounts of diluted primary virus isolates to uninfected cells. The sensitivity of the method was determined in a cohort of 33 HIV seropositive men. The use of a virus transport medium with high doses of antibiotics reduced contamination of HIV cultures. Toxicity of seminal plasma on culture cells was limited when seminal fluid was incubated with culture cells for only 90 min. Detection levels for cell-associated virus and cell-free virus from semen were 12 infected cells per ejaculate and 100 infectious units per milliliter of seminal fluid, respectively. Cell-associated HIV could be recovered from 18 semen samples of 33 HIV positive men (55%). Recovery of cell-free virus from seminal fluid was infrequent. It is concluded that the method is highly sensitive for the detection of HIV from semen. However, the recovery rate of infectious cell-free virus in seminal fluid from clinical samples is infrequent. PMID- 8690766 TI - Multiplex polymerase chain reaction for adenovirus and herpes simplex virus in eye swabs. AB - Adenoviruses and herpes simplex virus (HSV) can cause clinically indistinguishable episodes of acute eye disease. Adenovirus infection is associated with nosocomial outbreaks and HSV may result in episodes of recurrent ocular inflammation. In a comparison of multiplex PCR for the two viral DNAs and virus isolation in cell culture, identical results were obtained for 18 of 20 specimens (positive for adenovirus in 5, HSV in 5, and negative in 8). One specimen was falsely negative for each viral DNA. Inclusion of human beta-globin primers in the adenovirus-HSV reaction was precluded by a consequential 10--100 fold reduction in sensitivity for the two viral targets and by the failure of beta-globin DNA amplification at the annealing temperature (45 degrees C) required to ensure detection of adenoviruses of serotypes 7 and 11 with the selected adenovirus primers. A single-target beta-globin PCR gave positive results with 19 of the 20 specimens prepared by treatment with proteinase K lysis buffer, indicating the effectiveness of this simple DNA extraction procedure. Nonetheless, the availability of effective antiviral therapy for HSV made monitoring for extraction failure using human primers crucial to avoid false negative results for HSV DNA. Adenovirus-HSV PCR has considerable potential for the rapid diagnosis of viral eye disease particularly if beta-globin primers can be included in the reaction. PMID- 8690767 TI - Detection and differentiation of epizootic haemorrhagic disease of deer and bluetongue viruses by serogroup-specific sandwich ELISA. AB - A serogroup specific sandwich ELISA was developed for the detection of epizootic haemorrhagic disease of deer viruses (EHDV) in infected insects and tissue culture preparations. Polyclonal rabbit antiserum against purified EHDV core particles was used to capture viral antigen and specific binding detected using guinea pig antisera against EHDV core particles followed by anti-guinea pig immunoglobulin enzyme-labelled conjugate. The assay is EHDV specific and detects all 8 serotypes. No cross-reactions were found with related viruses such as bluetongue (BTV), Palyam, Tilligery or African horse sickness virus (AHSV). A similar serogroup specific sandwich ELISA was also developed for BTV. The assays showed a similar sensitivity in detecting the respective EHDV or BTV antigens in a pool of 500 midges where only 2 were infected. These assays allow a simple and rapid means of detecting and differentiating members of these closely related serogroups. The sensitivity of the tests will allow more extensive studies on vector competence and virus/vector distribution. PMID- 8690768 TI - A general strategy for cloning viroids and other small circular RNAs that uses minimal amounts of template and does not require prior knowledge of its sequence. AB - Two PCR-based methods are described for obtaining clones of small circular RNAs of unknown sequence and for which only minute amounts are available. To avoid introducing any assumption about the RNA sequence, synthesis of the cDNAs is initiated with random primers. The cDNA population is then PCR-amplified using a primer whose sequence is present at both sides of the cDNAs, since they have been obtained with random hexamers and then a linker with the sequence of the PCR primer has been ligated to their termini, or because the cDNAs have been synthesized with an oligonucleotide that contains the sequence of the PCR primer at its 5' end and six randomized positions at its 3' end. The procedures need only approximately 50 ng of purified RNA template. The reasons for the emergence of cloning artifacts and precautions to avoid them are discussed. PMID- 8690769 TI - Improved membrane preservation of flavivirus-infected cells with cryosectioning. AB - Ultra-cryomicrotomy and electron microscopy were used to investigate membranous structures in dengue virus-infected mammalian and insect cells. The cryo sectioned samples displayed ultrastructure comparable to their resin-embedded counterparts with all previously identified virus-induced structures being observed. Structures not previously identified were also found. In particular, membrane-bound packets of vesicles, 100-200 nm in diameter were seen distributed throughout areas of virus-induced membrane proliferation. These packets were clearly distinct from virion arrays. Small smooth membrane vesicles, previously found to contain thread-like enclosures (M.L. Ng, J. Gen. Virol. 68 (1987) 577 582), were frequently observed to contain dense staining material, however the exact nature of this material remains unclear. Virus-induced modification of golgi-like and/or ER membranes was also observed and may represent early events in the generation of the smooth membrane vesicles seen during infection. We suggest that cryosectioning is the method of choice to investigate membrane rearrangement induced by this family of viruses and that a diamond knife and modified staining techniques, as utilised in this report, be employed to enhance morphology and section preservation. PMID- 8690770 TI - Non-radioactive assay of natural killer cell-mediated cytotoxicity against cytomegalovirus-infected fibroblasts by DNA fragmentation ELISA. AB - Cell-mediated cytotoxicity against cytomegalovirus (CMV)-infected fibroblasts (FS 4 cells) was investigated by a non-radioactive assay, and by DNA fragmentation ELISA and LDH release assay and the assays were compared to the standard chromium release assay. Fragmentation of DNA and LDH activity were detected in the supernatant of CMV-infected FS-4 cells cultured with non-adherent peripheral blood mononuclear cells (PBMC). The DNA fragmentation ELISA was most sensitive to cytotoxicity against CMV-infected FS-4 cells and showed excellent correlation with the standard chromium release assay. DNA fragmentation of CMV-infected FS-4 cells by non-adherent PBMC was reduced markedly by treatment with anti-leu 11b plus complement. Thus, the present DNA fragmentation ELISA is non-radioactive, highly sensitive and a useful method for detecting natural killer cell-mediated cytotoxicity against CMV-infected fibroblasts. PMID- 8690771 TI - A blinded comparison of two methods of viral susceptibility testing: plaque reduction assay versus microplate in situ ELISA. AB - Viral susceptibility testing has been shown to have a role in the management of patients with herpes simplex infections. In this study, 25 isolates of herpes simplex virus representing a broad spectrum of acyclovir-susceptible and resistant phenotypes were tested using a microplate in situ enzyme-linked immunosorbent assay (MISE). This method is objective and more rapid than the traditional plaque reduction assay (PRA). The previously derived PRA results were not known at the time of testing with the MISE method. The correlation coefficient between PRA and MISE was 0.85. Agreement on sensitive or resistant was reached for 21 of 25 isolates. The standardised microplate in situ ELISA was found to be an acceptable alternative to the plaque reduction assay. PMID- 8690772 TI - Rapid cloning of uncharacterised tobacco rattle virus isolates using long template (LT) PCR. AB - A rapid method was developed using long template (LT)-PCR to amplify the complete RNA2 of isolates of TRV for which no sequence data are available. The amplification makes use of a 5' terminal oligonucleotide which contains degeneracies corresponding to the sequences of several different TRV isolates, and a 3' oligonucleotide which is complementary to a sequence present in all known isolates. This method was used to show the high degree of sequence homology existing in the terminal regions of two uncharacterised TRV isolates (TPO3 and PAY4), and revealed the deletion of an 80-nucleotide sequence in the 5' terminal region of TPO3 RNA2. PMID- 8690773 TI - Supernatant rescue assay vs. polymerase chain reaction for detection of wild type adenovirus-contaminating recombinant adenovirus stocks. AB - The certification of recombinant adenoviruses prepared for clinical use requires the exclusion of contaminating, replication-competent adenovirus (wild type virus). Polymerase chain reaction (PCR)-based detection assays have been developed that detect the presence of viral sequences present only in wild type adenoviruses. As an alternative, this report describes a novel bioassay, designated the 'supernatant rescue assay', that detected minimal amounts of wild type virus mixed with high numbers of recombinant adenoviruses. This assay is based on the observation that minimal numbers of wild type adenovirus can be rescued from the supernatants of cells exposed to high multiplicities of infection (mois) of recombinant virus mixed with a known, minimal number of wild type virions. This assay was highly reproducible and routinely detected the presence of a single wild type virus mixed within 10(9) recombinant viruses. Under the experimental conditions employed, the supernatant rescue assay was significantly more sensitive than all three different PCR-detection assays. PMID- 8690774 TI - Frequency of donor cytotoxic T cell precursors does not correlate with occurrence of acute graft-versus-host disease in children transplanted using unrelated donors. AB - Bone marrow transplantation (BMT) from unrelated volunteers is frequently associated with both increased incidence and increased severity of acute graft versus-host disease (GVHD). In the last years, it has been suggested that the analysis of the frequency of cytotoxic T lymphocyte precursors (CTLp) of unrelated HLA-matched donors can be used to detect disparity for HLA class I antigens and as a predictive test for development of severe GVHD. In this report, we summarized our experience regarding 20 pediatric patients affected by various hematological disorders, receiving allogeneic BMT from unrelated donors. HLA class I and II antigens of donor/recipient pairs were determined by means of serological typing, whereas molecular typing of HLA-class II antigens of patients and their potential donors was performed using PCR-SSP and PCR-fingerprinting techniques. CTLp values, estimated using limiting dilution analysis, were high (range, 1:7000-1:40,000) in 9 of 20 patients, while the other 11 children had low or undetectable levels (< 1:100,000) of CTL precursors. CTLp frequency was compared with the incidence and severity of GVHD observed after BMT. Our data demonstrate that the frequency of donor CTLp does not statistically correlate either with the occurrence of clinically significant acute GVHD or with disparity for HLA-class II molecular typing between donor and recipient. In particular, 4 of the 10 evaluable patients with an undetectable CTLp frequency developed grade IV, III, II, and IV acute GVHD, respectively. Although the limited number of subjects studied does not allow us to draw any firm conclusion, our data suggest a certain caution in considering this test suitable for the selection of potential donors. PMID- 8690776 TI - Therapeutic potential for blockade of the CD40 ligand, gp39. PMID- 8690775 TI - Cross-reactive T-cell proliferative responses to V3 peptides corresponding to different geographical HIV-1 isolates in HIV-seropositive individuals. AB - We have investigated the proliferative response of peripheral blood mononuclear cells from individuals infected with human immunodeficiency virus type 1 (HIV-1) to synthetic peptides from the third variable loop region (V3) in the envelope protein gp120. We tested a total of 14 peptides, corresponding to 14 HIV-1 isolates belonging to four geographical locations (clades U, A, B, and D). Although differences in relative level of responses exist between individual peptides and patients, the proliferation in response to all 14 V3 peptides was significantly greater than that to unrelated control peptides. Additionally, we observed that proliferative responses of blood cells from the 10 HIV-seropositive individuals studied from the clade B region to peptides from within clades U, A, B, and D were not significantly different, indicating the cross-reactive nature of the V3-specific cell-mediated immune responses. Even though the majority of patients also exhibited antibody responses against several V3 peptides, serum samples from 50% of clade B patients exhibited antibody cross-reactivity, while proliferative responses to V3 peptides from more than one clade were observed in 80% of patients. Importantly, in two patients, decreased CD4+ cell numbers, an important surrogate marker of disease progression, significantly correlated with loss of V3 peptide-specific proliferative responses but not antibody responses. These results have important implications toward evaluating the utility of V3 peptides for designing therapeutic and/or vaccine reagents against HIV-1. PMID- 8690777 TI - Class I MHC presentation of exogenous antigens. AB - Class I MHC (MHC-I) molecules present primarily endogenous antigens, i.e. antigens that are present in the cytosol and are subject to the cytosolic processing mechanisms that comprise the conventional MHC-I processing pathway. However, exogenous antigens can also be present by MHC-I molecules in certain circumstances, particularly in the case of particulate antigens. Recently, considerable attention has been focused on mechanisms that may contribute to alternate MHC-I processing pathways. Divergent results in several different systems have suggested that more than one alternate processing mechanism may exist. After phagocytic or endocytic uptake, some exogenous antigens can escape the vacuolar system and penetrate into the cytosol, accessing the conventional MHC-I antigen processing mechanisms. In other cases, MHC-I molecules present antigens that have no clear ability to actively escape the vacuolar system. Some results indicate that certain alternate processing mechanisms are quite distinct from the conventional MHC-I pathway and are not dependent on compartments, protein, or mechanisms that are necessary for the conventional pathway, including the endoplasmic reticulum, the transporter for antigen presentation (TAP) and proteasomes. In vivo, alternate MHC-I processing mechanisms may be expressed primarily by phagocytic antigen presenting cells, i.e., macrophages, and perhaps dendritic cells, although other cell types may contribute in certain circumstances. These mechanisms may play important roles in generating CD8 T cell responses, especially to antigens expressed by vacuolar microorganisms. In addition, they provide a potential avenue for therapeutic immunization to achieve protective CD8 T cell responses with nonviable vaccine preparations, in the absence of the endogenous antigen synthesis that is provided by live viral vaccine preparations. PMID- 8690778 TI - Relationships between antibodies against human soluble complement receptor 1 (hsCR1) from various species. AB - The relationships between antibodies against human soluble complement receptor 1 (hsCR1) were studied in rodents, dogs, nonhuman primates, and humans. An antibody response occurred in all species except humans. The anti-hsCR1 antibodies from the various species were characterized to determine if they recognize similar epitopes on the hsCR1 molecule. Dog and monkey sera, positve for hsCR1 binding, were used as blocking antibodies against mouse anti-hsCR1 monoclonal antibodies as well as mouse and rat anti-hsCR1-positive sera. Human sera (blood group antisera: anti-Knops, anti-McCoy, anti-Knops/McCoy, anti-Swain-Langley) and serum from one burn patient (who became seropositive despite ever receiving treatment with hsCR1) were also used to test blocking of mouse, rat, dog, and monkey anti hsCR1. Characterization of anti-hsCR1 antibodies from different species demonstrated that hsCR1 causes divergent antibody responses among animals. While mouse, rat, and dog antibodies cross inhibit binding by approximately 50%, monkey antibodies recognize primarily different epitopes of the hsCR1 molecule. Moreover, human antibodies binding hsCR1 are completely different from the animal antibodies, including monkey. This study indicates that although hsCR1 is immunogenic in animals, there is a difference in response between species, particularly between nonprimates and primates, and finally, that this antibody response is not predictive for humans. PMID- 8690779 TI - The continuing saga of complement receptor type 3 (CR3) PMID- 8690780 TI - Acute graft versus host disease due to T lymphocytes recognizing a single HLA DPB1*0501 mismatch. AB - Analysis of a large number of unrelated bone marrow transplantations (BMT) has shown that HLA-DP incompatibility did not detectably influence the risk for acute graft-versus-host disease (aGVHD). Accordingly, it was proposed that HLA-DP determinants did not function as transplantation antigens in the same way as HLA A, -B, or -DR. We have previously shown that HLA-DP (as well as HLA-A, -B, -DQ, or -DR)-specific T cells could be isolated from skin biopsies of patients who developed an aGVHD after semiallogeneic BMT. Nevertheless, whether a single HLA DP mismatched allele could induce a detectable allo-specific reaction in vivo after BMT remained to be established. To directly address this issue we studied one patient who presented aGVHD after receiving purified CD34+ bone marrow (BM) cells from an unrelated donor with a single HLA-DP mismatch in the GVHD direction. To characterize the immunological events associated with GVHD, we analyzed the peripheral T cell repertoire, the T cell receptor Vbeta diversity, and the specificity of T cells invading a skin biopsy at the onset of GVHD. Our results demonstrated that a large fraction of skin-infiltrating lymphocytes, which expressed diverse T cell receptors, were reactive against this single HLA DPB1 *0501 mismatch and consequently that a single HLA-DP mismatch between BM donor and recipient can activate a strong T cell response in vivo. PMID- 8690782 TI - Bioactivity of glomerular ultrafiltrate during heavy proteinuria may contribute to renal tubulo-interstitial lesions: evidence for a role for insulin-like growth factor I. AB - Clinical and experimental data have indicated that heavy proteinuria in renal glomerular diseases is associated with the formation of tubulo-interstitial fibrosis and contributes to the progression of renal failure. Albumin in glomerular ultrafiltrate does not appear to cause this sequelae, rather than compounds that are associated with ultrafiltered plasma proteins. One such protein-bound factor could be insulin-like growth factor I (IGF-I). The present studies show that in nephrotic rats, IGF-I is ultrafiltered in conjunction with IGF-binding protein-2 and is present in proximal tubular fluid at 1.35 nM. Proximal tubular fluid from nephrotic rats autophosphorylates IGF-I receptors in cultured proximal tubular cells. Nephrotic, but not control, rat proximal tubular fluid increases the [3H]thymidine incorporation in cultured tubular cells, and neutralizing IGF-I-receptor antibodies partially inhibit this activity. Incubation of cultured proximal tubular cells with an extract that was prepared from nephrotic rat urine increases the secretion of collagen types I and IV. Secretion of the two collagens is in part ameliorated by neutralizing IGF-I receptor antibody. In concert, these findings suggest that the IGF-I present in nephrotic rat tubular fluid is bioactive and may contribute to the development of tubulo-interstitial fibrosis in chronic nephrotic glomerular diseases. PMID- 8690781 TI - Intracellular lactate- and pyruvate-interconversion rates are increased in muscle tissue of non-insulin-dependent diabetic individuals. AB - The contribution of muscle tissues of non-insulin-dependent diabetes mellitus (NIDDM) patients to blood lactate appearance remains undefined. To gain insight on intracellular pyruvate/lactate metabolism, the postabsorptive forearm metabolism of glucose, lactate, FFA, and ketone bodies (KB) was assessed in seven obese non-insulin-dependent diabetic patients (BMI = 28.0 +/- 0.5 kg/m2) and seven control individuals (BMI = 24.8 +/- 0.5 kg/m2) by using arteriovenous balance across forearm tissues along with continuous infusion of [3-13C1]-lactate and indirect calorimetry. Fasting plasma concentrations of glucose (10.0 +/- 0.3 vs. 4.7 +/- 0.2 mmol/liter), insulin (68 +/- 5 vs. 43 +/- 6 pmol/liter), FFA (0.57 +/- 0.02 vs. 0.51 +/- 0.02 mmol/liter), and blood levels of lactate (1.05 +/- 0.04 vs. 0.60 +/- 0.06 mmol/liter), and KB (0.48 +/- 0.04 vs. 0.29 +/- 0.02 mmol/liter) were higher in NIDDM patients (P < 0.01). Forearm glucose uptake was similar in the two groups (10.3 +/- 1.4 vs. 9.6 +/ 1.1 micromol/min/liter of forearm tissue), while KB uptake was twice as much in NIDDM patients as compared to control subjects. Lactate balance was only slightly increased in NIDDM patients (5.6 +/- 1.4 vs. 3.3 +/- 1.0 micromol/min/liter; P = NS). A two compartment model of lactate and pyruvate kinetics in the forearm tissue was used to dissect out the rates of lactate to pyruvate and pyruvate to lactate interconversions. In spite of minor differences in the lactate balance, a fourfold increase in both lactate- (44.8 +/- 9.0 vs. 12.6 +/- 4.6 micromol/min/liter) and pyruvate-(50.4 +/- 9.8 vs. 16.0 +/- 5.0 micromol/min/liter) interconversion rates (both P < 0.01) were found. Whole body lactate turnover, assessed by using the classic isotope dilution principle, was higher in NIDDM individuals (46 +/- 9 vs. 21 +/- 3 micromol/min/kg; P < 0.01). Insights into the physiological meaning of this parameter were obtained by using a whole body noncompartmental model of lactate/pyruvate kinetics which provides a lower and upper bound for total lactate and pyruvate turnover (NIDDM = 46 +/- 9 vs. 108 +/- 31; controls = 21 +/- 3 - 50 +/-13 micromol/min/kg). In conclusion, in the postabsorptive state, despite a trivial lactate release by muscle, lactate and pyruvate-interconversion rates are greatly enhanced in NIDDM patients, possibly due to concomitant impairment in the oxidative pathway of glucose metabolism. This finding strongly suggest a major disturbance in intracellular lactate/pyruvate metabolism in NIDDM. PMID- 8690783 TI - Effect of prior exercise on the partitioning of an intestinal glucose load between splanchnic bed and skeletal muscle. AB - Exercise leads to marked increases in muscle insulin sensitivity and glucose effectiveness. Oral glucose tolerance immediately after exercise is generally not improved. The hypothesis tested by these experiments is that after exercise the increased muscle glucose uptake during an intestinal glucose load is counterbalanced by an increase in the efficiency with which glucose enters the circulation and that this occurs due to an increase in intestinal glucose absorption or decrease in hepatic glucose disposal. For this purpose, sampling (artery and portal, hepatic, and femoral veins) and infusion (vena cava, duodenum) catheters and Doppler flow probes (portal vein, hepatic artery, external iliac artery) were implanted 17 d before study. Overnightfasted dogs were studied after 150 min of moderate treadmill exercise or an equal duration rest period. Glucose ([14C]glucose labeled) was infused in the duodenum at 8 mg/kg x min for 150 min beginning 30 min after exercise or rest periods. Values, depending on the specific variable, are the mean +/- SE for six to eight dogs. Measurements are from the last 60 min of the intraduodenal glucose infusion. In response to intraduodenal glucose, arterial plasma glucose rose more in exercised (103 +/- 4 to 154 +/- 6 mg/dl) compared with rested (104 +/- 2 to 139 +/- 3 mg/dl) dogs. The greater increase in glucose occurred even though net limb glucose uptake was elevated after exercise (35 +/- 5 vs. 20 +/- 2 mg/min) as net splanchnic glucose output (5.1 +/- 0.8 vs. 2.1 +/- 0.6 mg/kg x min) and systemic appearance of intraduodenal glucose (8.1 +/- 0.6 vs. 6.3 +/- 0.7 mg/kg x min) were also increased due to a higher net gut glucose output (6.1 +/- 0.7 vs. 3.6 +/- 0.9 mg/kg x min). Adaptations at the muscle led to increased net glycogen deposition after exercise [1.4 +/- 0.3 vs. 0.5 +/- 0.1 mg/(gram of tissue x 150 min)], while no such increase in glycogen storage was seen in liver [3.9 +/- 1.0 vs. 4.1 +/- 1.1 mg/(gram of tissue x 150 min) in exercised and sedentary animals, respectively]. These experiments show that the increase in the ability of previously working muscle to store glycogen is not solely a result of changes at the muscle itself, but is also a result of changes in the splanchnic bed that increase the efficiency with which oral glucose is made available in the systemic circulation. PMID- 8690784 TI - Evidence of oxidant-induced injury to epithelial cells during inflammatory bowel disease. AB - Evidence of in vivo oxidant-induced injury in inflammatory bowel disease (IBD) is largely indirect. Colon epithelial crypt cells (CEC) from paired specimens of histologically normal and inflamed bowel from IBD patients with active disease were examined for altered protein thiol redox status as an indicator of oxidative damage. When CEC preparations from 22 IBD patients were labeled with the reduced thiol-specific probe [14C]-iodoacetamide (IAM), there was decreased labeling of a number of proteins indicating oxidation of thiol groups in CEC from inflamed mucosa compared to paired normal mucosa, especially the loss of thiol labeling of a 37-kD protein which was almost completely lost. The loss of reduced protein thiol status for the 37-kD band was paralleled by loss of epithelial cell glyceraldehyde-3-phosphate dehydrogenase (GAPDH, EC 1.2.1.12) enzyme activity, an enzyme known to contain an essential reduced cysteine (Cys149) at the active site. The identity of the 37-kD protein as GADPH monomer was confirmed by NH2 terminal amino acid sequence analysis. To examine whether this type of in vivo injury could be attributed to biologically relevant oxidants produced by inflammatory cells, CEC prepared from normal mucosa were exposed to H2O2, OCl-, nitric oxide (NO), and a model chloramine molecule chloramine T (ChT) in vitro. Dose-dependent loss of IAM labeling and GAPDH enzyme activity was observed. The efficacy (IC50) against IAM labeling was OCl- >> ChT > H2O2 > NO (52 +/- 3, 250 +/- 17, 420 +/- 12, 779 +/- 120 microM oxidant) and OCl- >> ChT > NO > H2O2 (89 +/- 17, 256 +/- 11, 407 +/- 105, 457 +/- 75 microM oxidant), respectively, for GAPDH enzyme activity. This study provides direct evidence of in vivo oxidant injury in CEC from inflamed mucosa of IBD patients. Oxidation and inhibition of essential protein function by inflammatory cells is a potential mechanism of tissue injury that may contribute to the pathogenesis of the disease and supports the exploration of compounds with antioxidant activity as new therapies for IBD. PMID- 8690785 TI - Proadrenomedullin NH2-terminal 20 peptide inhibits the voltage-gated Ca2+ channel current through a pertussis toxin-sensitive G protein in rat pheochromocytoma derived PC 12 cells. AB - The effect of proadrenomedullin NH2-terminal 20 peptide (PAMP) on the voltage gated Ca2+ channel current was investigated using the perforated whole-cell clamp technique on NGF-treated PC12 cells. PAMP inhibited the Ba2+ current through N type Ca2+ channels in a concentration dependent manner. Injection of GDPbetaS into the cell abolished the inhibition while injection of GTPgammaS into the cell made the inhibition irreversible, indicating that the PAMP-induced inhibition of the voltage-gated Ca2+ channel was mediated by a G protein. The inhibition was abolished by pretreating the cells with pertussis toxin, indicating that a pertussis toxin-sensitive G protein was involved in the signal transduction mechanism of PAMP. The present study revealed that the inhibition of catecholamine secretion from sympathetic nerve endings by PAMP could be explained by the inhibition of N-type Ca2+ channels, which was mediated by pertussis toxin sensitive G protein. PMID- 8690786 TI - A novel mechanism of glucocorticoid-induced immune suppression: the inhibiton of T cell-mediated terminal maturation of a murine dendritic cell line. AB - Working with the murine epidermal-derived dendritic cell (DC) line XS52, we have observed previously that antigen-specific interaction with T cells stimulates their "terminal maturation" into fully professional DC. In this study we examined the impact of dexamethasone (DEX) on this T cell-induced event. When added to cocultures of XS52 DC and the KLH-specific Th1 clone HDK-1 in the presence of antigen, DEX at relatively low concentrations (10(-9)-10(-7) M) prevented substantially or completely each of the changes that typify terminal maturation, including (a) secretion of relatively large amounts of IL-1beta, IL-6, and TNFalpha; (b) loss of CD115 (colony-stimulating factor-1 receptor) expression and proliferative responsiveness to colony-stimulating factor-1; and (c) elevated expression of CD86 (B7-2). XS52 cells also underwent terminal maturation upon exposure to lipopolysaccharide alone, and DEX also inhibited effectively each of the same changes, indicating that DC can serve as the direct target of DEX. By contrast, DEX inhibited XS52 DC-stimulated IL-2 secretion by HDK-1 T cells, but not other changes that accompany T cell activation, including the secretion of IFNgamma and TNFalpha and the elevated expression of CD25, CD28, and CD44. These results reveal a new immunosuppressive mechanism of glucocorticoid action, that is, direct inhibition of T cell-mediated terminal maturation by DC. PMID- 8690787 TI - Chromogranin A processing and secretion: specific role of endogenous and exogenous prohormone convertases in the regulated secretory pathway. AB - Chromogranins A and B and secretogranin II are a family of acidic proteins found in neuroendocrine secretory vesicles; these proteins contain multiple potential cleavage sites for proteolytic processing by the mammalian subtilisin-like serine endoproteases PC1 and PC2 (prohormone convertases 1 and 2), and furin. We explored the role of these endoproteases in chromogranin processing in AtT-20 mouse pituitary corticotropes. Expression of inducible antisense PC1 mRNA virtually abolished PC1 immunoreactivity on immunoblots. Chromogranin A immunoblots revealed chromogranin A processing, from both the NH2 and COOH termini, in both wild-type AtT-20 and AtT-20 antisense PC1 cells. After antisense PC1 induction, an approximately 66-kD chromogranin A NH2-terminal fragment as well as the parent chromogranin A molecule accumulated, while an approximately 50 kD NH2-terminal and an approximately 30 kD COOH-terminal fragment declined in abundance. Chromogranin B and secretogranin II immunoblots showed no change after PC1 reduction. [35S]Methionine/cysteine pulse-chase metabolic labeling in AtT-20 antisense PC1 and antisense furin cells revealed reciprocal changes in secreted chromogranin A COOH-terminal fragments (increased approximately 82 kD and decreased approximately 74 kD forms, as compared with wild-type AtT-20 cells) indicating decreased cleavage, while AtT-20 cells overexpressing PC2 showed increased processing to and secretion of approximately 71 and approximately 27 kD NH2-terminal chromogranin A fragments. Antisense PC1 specifically abolished regulated secretion of both chromogranin A and beta-endorphin in response to the usual secretagogue, corticotropin-releasing hormone. Moreover, immunocytochemistry demonstrated a relative decrease of chromogranin A in processes (where regulated secretory vesicles accumulate) of AtT-20 cells overexpressing either PC1 or PC2. These results demonstrate that chromogranin A is a substrate for the endogenous endoproteases PC1 and furin in vivo, and that such processing influences its trafficking into the regulated secretory pathway; furthermore, lack of change in chromogranin B and secretogranin II cleavage after diminution of PCl suggests that the action of PC1 on chromogranin A may be specific within the chromogranin/secretogranin protein family. PMID- 8690788 TI - Atrial natriuretic peptide inhibits mineralocorticoid receptor function in rat colonic surface cells. AB - Atrial natriuretic peptide (ANP) inhibits and aldosterone (ALDO) stimulates Na conductive transport. Therefore, the effects of ANP and its second messenger cGMP on mineralocorticoid receptor (MR) function in rat colon surface and crypt cells were examined. 100 nM 8-Br-cGMP decreased surface [3H]ALDO binding by 42 +/- 4% but increased crypt [3HvALDO binding by 52+/-16%. ANP decreased surface [3H]ALDO binding by approximately 50% after a 2.5-h lag period but had no effect on crypt ALDO binding. ANP and cGMP rapidly (< 15 min) inhibited surface cell ALDO-induced MR nuclear translocation but did not affect crypt MR nuclear translocation. Inhibition of cGMP-dependent protein kinase with KT5823 blocked the inhibitory effects of ANP and 8-Br-cGMP on surface cell ALDO binding and MR nuclear translocation. In crypt, KT5823 increased baseline [3H]ALDO binding but did not inhibit the stimulatory effect of exogenous cGMP. DEAE-cellulose chromatography and gel mobility shift assay showed that ANP did not inhibit surface MR activation. ANP inhibited ALDO stimulated short circuit current in distal colon. These data demonstrate cell-specific regulation of MR function. In surface cells, ANP rapidly inhibits MR nuclear translocation and ALDO-induced short circuit current. ANP inhibition of MR function may be an additional mechanism of ANP antagonism of Na reabsorption. PMID- 8690790 TI - The effect of a subnormal vitamin B-6 status on homocysteine metabolism. AB - Homocysteine, an atherogenic amino acid, is either remethylated to methionine or metabolized to cysteine by the transsulfuration pathway. The biochemical conversion of homocysteine to cysteine is dependent upon two consecutive, vitamin B-6-dependent reactions. To study the effect of a selective vitamin B-6 deficiency on transsulfuration, we performed oral methionine load tests on 22 vitamin B-6-deficient asthma patients treated with theophylline (a vitamin B-6 antagonist) and 24 age- and sex-matched controls with a normal vitamin B-6 status. Both groups had normal circulating vitamin B-12 and folate concentrations. Methionine loading resulted in significantly higher increases in circulating total homocyst(e)ine (P < 0.01) and cystathionine (P < 0.05) concentrations in vitamin B-6-deficient patients compared with controls. 6 wk of vitamin B-6 supplementation (20 mg/d) significantly (P < 0.05) reduced post methionine load increases in circulating total homocyst(e)ine concentrations in deficient subjects, but had no significant effect on the increase in total homocyst(e)ine concentrations in controls. The increases in post-methionine load circulating cystathionine concentrations were significantly (P < 0.01) reduced in both groups after vitamin supplementation. It is concluded that a vitamin B-6 deficiency may contribute to impaired transsulfuration and an abnormal methionine load test, which is associated with premature vascular disease. PMID- 8690789 TI - Myofibrillar calcium sensitivity of isometric tension is increased in human dilated cardiomyopathies: role of altered beta-adrenergically mediated protein phosphorylation. AB - To examine the role of alterations in myofibrillar function in human dilated cardiomyopathies, we determined isometric tension-calcium relations in permeabilized myocytesized myofibrillar preparations (n = 16) obtained from left ventricular biopsies from nine patients with dilated cardiomyopathy (DCM) during cardiac transplantation or left ventricular assist device implantation. Similar preparations (n = 10) were obtained from six normal hearts used for cardiac transplantation. Passive and maximal Ca2+-activated tensions were similar for the two groups. However, the calcium sensitivity of isometric tension was increased in DCM compared to nonfailing preparations ([Ca2+]50=2.46+/-0.49 microM vs 3.24+/ 0.51 microM, P < 0.001). In vitro treatment with the catalytic subunit of protein kinase A (PKA) decreased calcium sensitivity of tension to a greater degree in failing than in normal preparations. Further, isometric tension-calcium relations in failing and normal myofibrillar preparations were similar after PKA treatment. These findings suggest that the increased calcium sensitivity of isometric tension in DCM may be due at least in part to a reduction of the beta adrenergically mediated (PKA-dependent) phosphorylation of myofibrillar regulatory proteins such as troponin I and/or C-protein. PMID- 8690791 TI - Adenosine modulates vasomotor tone in outer medullary descending vasa recta of the rat. AB - Adenosine is generated within the renal medulla under hypoxic conditions and is known to induce net vasoconstriction within the renal cortex while increasing medullary blood flow and oxygenation. To test the hypothesis that vasoconstriction of outer medullary descending vasa recta (OMDVR) is modulated by adenosine, we examined the effects of adenosine and adenosine Al and A2 receptor subtype agonists on in vitro perfused control and preconstricted rat OMDVR. Constriction with angiotensin II (ANG II, 10(-9) M) was attenuated by adenosine in a concentration-dependent manner (EC50 = 2.0 x 10(-7)M, P < 0.05). Similarly, an adenosine A2 agonist (CGS-21680, 10(-7) M), but not an adenosine Al agonist (cyclohexyladenosine, 10(-6) M), attenuated ANG II-induced vasoconstriction. Under control conditions, ablumenal application of adenosine (10(-12) to 10(-5) M) elicited a biphasic response. Additionally, cyclohexyladenosine (10(-6) M) caused vasoconstriction and CGS-21680 (10(-6) M) had no effect on untreated vessels. Finally, an influence of ANG II receptor stimulation on adenosine Al receptor-mediated vasoconstriction could not be shown. These data suggest that OMDVR possess both Al and A2 adenosine receptors and that they mediate constriction and dilatation, respectively. We conclude that adenosine is a potent modulator of OMDVR vasomotor tone and that its net effect is dependent upon local concentrations. PMID- 8690792 TI - Evidence that the fibrinogen binding domain of Apo(a) is outside the lysine binding site of kringle IV-10: a study involving naturally occurring lysine binding defective lipoprotein(a) phenotypes. AB - It is now established that the lysine binding site (LBS) of apo(a) kringle IV-10, and particularly Trp72, plays a dominant role in the binding of lipoprotein(a) [Lp(a)] to lysine. To determine the role of the LBS in the binding of Lp(a) to fibrinogen, we examined the binding to plasmin-modified (PM) fibrinogen of human and rhesus monkey Lp(a) species classified as either Lys' or Lys- based on their capacity to bind lysine Sepharose and to have Trp or Arg, respectively, in position 72 of the LBS of kringle IV-10. We also examined the free apo(a)s obtained by subjecting their corresponding parent Lp(a)s to a mild reductive procedure developed in our laboratory. Our results show that both Lyst and Lys- Lp(a)s and their derived apo(a)s, bound to PM-fibrinogen with similar affinities (Kds: 33-100 nM), whereas the B(max) values were threefold higher for apo(a)s. Both the lysine analog epsilon-aminocaproic acid and L-proline inhibited the binding of Lp(a) and apo(a) to PM fibrinogen. We conclude that the LBS of kringle IV-10 is not involved in this process and that apo(a) binds to PM-fibrinogen via a lysine-proline-sensitive domain located outside the LBS and largely masked by the interaction of apo(a) with apoB100. The significant difference in the PM fibrinogen binding capacity also suggests that apo(a) may have a comparatively higher athero-thrombogenic potential than parent Lp(a). PMID- 8690793 TI - Efficacy of treatment with the iron (III) complex of diethylenetriamine pentaacetic acid in mice and primates inoculated with live lethal dose 100 Escherichia coli. AB - The iron (III) complex of diethylenetriamine pentaacetic acid (DTPA iron [III]) protected mice and baboons from the lethal effects of an infusion with live LD100 Escherichia coli. In mice, optimal results were obtained when DTPA iron (III) was administered two or more hours after infection. Prevention of death occurred in spite of the fact that the adverse effects of TNF-alpha were well underway in the mouse model. The half-life of DTPA iron (III) was 51 +/- 9 min in normal baboons; primary clearance was consistent with glomerular filtration. In septic baboons, survival was observed after administration of two doses of DTPA iron (III) at 2.125 mg/kg, the first one given before, or as late as 2 h after, severe hypotension. Administration of DTPA iron (III) did not alter mean systemic arterial pressure, but did protect baboons in the presence of high levels of TNF alpha and free radical overproduction. Furthermore, exaggerated production of nitric oxide was attenuated. The mechanism of protection with DTPA iron (III) is not obvious. Because of its ability to interact in vitro with free radicals, its poor cell permeability, and its short half-life, we postulate that DTPA iron (III) and/or its reduced form may have protected the mice and baboons by sequestration and subsequent elimination of free radicals (including nitric oxide) from their systems. PMID- 8690794 TI - Competency in mismatch repair prohibits clonal expansion of cancer cells treated with N-methyl-N'-nitro-N-nitrosoguanidine. AB - The phenomenon of alkylation tolerance has been observed in cells that are deficient in some component of the DNA mismatch repair (MMR) system. An alkylation-induced cell cycle arrest had been reported previously in one MMR proficient cell line, whereas a MMR-defective clone derived from this line escapes from this arrest. We examined human cancer cell lines to determine if the cell cycle arrest were dependent upon the MMR system. Growth characteristics and cell cycle analysis after MNNG treatment were ascertained in seven MMR-deficient and proficient cell lines, with and without confirmed mutations in hMLH1 or hMSH2 by an in vitro transcription/translation assay. MMR-proficient cells underwent growth arrest in the G2 phase of the cell cycle after the first S phase, whereas MMR-deficient cells escaped an initial G2 delay and resumed a normal growth pattern. In the HCT116 line corrected for defective MMR by chromosome 3 transfer, the G2 phase arrest lasted more than five days. In another MMR-proficient colon cancer cell line, SW480, cell death occurred five days after MNNG treatment. A competent MMR system appears to be necessary for G2 arrest or cell death after alkylation damage, and this cell cycle checkpoint may allow the cell to repair damaged DNA, or prevent the replication of mutated DNA by prohibiting clonal expansion. PMID- 8690796 TI - Genetically selected cardiomyocytes from differentiating embronic stem cells form stable intracardiac grafts. AB - This study describes a simple approach to generate relatively pure cultures of cardiomyocytes from differentiating murine embryonic stem (ES) cells. A fusion gene consisting of the alpha-cardiac myosin heavy chain promoter and a cDNA encoding aminoglycoside phosphotransferase was stably transfected into pluripotent ES cells. The resulting cell lines were differentiated in vitro and subjected to G418 selection. Immunocytological and ultrastructural analyses demonstrated that the selected cardiomyocyte cultures (> 99% pure) were highly differentiated. G418 selected cardiomyocytes were tested for their ability to form grafts in the hearts of adult dystrophic mice. The fate of the engrafted cells was monitored by antidystrophin immunohistology, as well as by PCR analysis with primers specific for the myosin heavy chain-aminoglycoside phosphotransferase transgene. Both analyses revealed the presence of ES-derived cardiomyocyte grafts for as long as 7 wk after implantation, the latest time point analyzed. These studies indicate that a simple genetic manipulation can be used to select essentially pure cultures of cardiomyocytes from differentiating ES cells. Moreover, the resulting cardiomyocytes are suitable for the formation of intracardiac grafts. This selection approach should be applicable to all ES derived cell lineages. PMID- 8690795 TI - Ceruloplasmin gene expression in the murine central nervous system. AB - Aceruloplasminemia is an autosomal recessive disorder resulting in neurodegeneration of the retina and basal ganglia in association with iron accumulation in these tissues. To begin to define the mechanisms of central nervous system iron accumulation and neuronal loss in this disease, cDNA clones encoding murine ceruloplasmin were isolated and characterized. RNA blot analysis using these clones detected a 3.7-kb ceruloplasmin-specific transcript in multiple murine tissues including the eye and several regions of the brain. In situ hybridization of systemic tissues revealed cell-specific ceruloplasmin gene expression in hepatocytes, the splenic reticuloendothelial system and the bronchiolar epithelium of the lung. In the central nervous system, abundant ceruloplasmin gene expression was detected in specific populations of astrocytes within the retina and the brain as well as the epithelium of the choroid plexus. Analysis of primary cell cultures confirmed that astrocytes expressed ceruloplasmin mRNA and biosynthetic studies revealed synthesis and secretion of ceruloplasmin by these cells. Taken together these results demonstrate abundant cell-specific ceruloplasmin expression within the central nervous system which may account for the unique clinical and pathologic findings observed in patients with aceruloplasminemia. PMID- 8690797 TI - Regulation of cellular proliferation and intimal formation following balloon injury in atherosclerotic rabbit arteries. AB - Injury to atherosclerotic arteries induces the expression of growth regulatory genes that stimulate cellular proliferation and intimal formation. Intimal expansion has been reduced in vivo in nonatherosclerotic balloon-injured arteries by transfer of genes that inhibit cell proliferation. It is not known, however, whether vascular cell proliferation can be inhibited after injury in more extensively diseased atherosclerotic arteries. Accordingly, the purpose of this study was to investigate whether expression of recombinant genes in atherosclerotic arteries after balloon injury could inhibit intimal cell proliferation. To test this hypothesis, we examined the response to balloon injury in atherosclerotic rabbit arteries after gene transfer of herpesvirus thymidine kinase gene (tk) and administration of ganciclovir. Smooth muscle cells from hyperlipidemic rabbit arteries infected with adenoviral vectors encoding tk were sensitive to ganciclovir, and bystander killing was observed in vitro. In atherosclerotic arteries, a human placental alkaline phosphatase reporter gene was expressed in intimal and medial smooth muscle cells and macrophages, identifying these cells as targets for gene transfer. Expression of tk in balloon injured hyperlipidemic rabbit arteries followed by ganciclovir treatment resulted in a 64% reduction in intimal cell proliferation 7 d after gene transfer (P = 0.004), and a 35-49% reduction in internal area 21 d after gene transfer, compared with five different control groups (P < 0.05). Replication of smooth muscle cells and macrophages was inhibited by tk expression and ganciclovir treatment. These findings indicate that transfer of a gene that inhibits cellular proliferation limits the intimal area in balloon-injured atherosclerotic arteries. Molecular approaches to the inhibition of cell proliferation in atherosclerotic arteries constitute a possible treatment for vascular proliferative diseases. PMID- 8690799 TI - Metal transport and unsafe sanctuary sites. PMID- 8690798 TI - Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia. AB - Elevated plasma homocyst(e)ine may predispose to complications of vascular disease. Homocysteine alters vasomotor regulatory and anticoagulant properties of cultured vascular endothelial cells, but little is known about effects of hyperhomocyst(e)inemia on vascular function in vivo. We tested the hypothesis that diet-induced moderate hyperhomocyst(e)inemia is associated with vascular dysfunction in cynomolgus monkeys. Plasma homocyst(e)ine increased from 4.O +/- O.2 microM when monkeys were fed normal diet to 10.6 +/- 2.6 microM when they were fed modified diet (mean +/- SE; P = 0.02). Vasomotor responses were assessed in vivo by quantitative angiography and Doppler measurement of blood flow velocity. In response to activation of platelets by intraarterial infusion of collagen, blood flow to the leg decreased by 42 +/- 9% in monkeys fed modified diet, compared with 14 +/- 11% in monkeys fed normal diet (P = 0.008), Responses of resistance vessels to the endothelium-dependent vasodilators acetylcholine and ADP were markedly impaired in hyperhomocyst(e)inemic monkeys, which suggests that increased vasoconstriction in response to collagen may be caused by decreased vasodilator responsiveness to platelet-generated ADP. Relaxation to acetylcholine and, to a lesser extent, nitroprusside, was impaired ex vivo in carotid arteries from monkeys fed modified diet. Thrombomodulin anticoagulant activity in aorta decreased by 34 +/- 15% in hyperhomocyst(e)inemic monkeys (P = 0.03). We conclude that diet-induced moderate hyperhomocyst(e)inemia is associated with altered vascular function. PMID- 8690800 TI - Increased IL-6-production by cells isolated from the fibrous bone dysplasia tissues in patients with McCune-Albright syndrome. AB - McCune-Albright syndrome (MAS) is characterized by cafe-au-lait spot, multiple endocrine hyperfunction, and polyostotic fibrous dysplasia. A somatic point mutation of Gsalpha protein was reported to decrease GTPase activity, leading to increase in the GSalpha-associated hormone actions via cAMP. IL-6 is known to stimulate osteoclast formation and in the IL-6 promoter, a cAMP responsive element has been identified. In this paper, we investigated the role of IL-6 in the bone lesions of MAS, using the isolated fibrous cells from the polyostotic fibrous dysplasia tissues in bones of the two patients with MAS. Bone biopsy specimen revealed the increased osteoclast in number. In both patients, a GSalpha mutation (Arg201 -> His) was identified in the cultured fibrous cells. Intracellular cAMP content and IL-6 secretion by the patient cells were increased. Rp-8Br-cAMP significantly inhibited IL-6 production in the patient cells, while it had no effect on normal control. The addition of dibutyryl cAMP significantly increased the synthesis of IL-6 in normal control cells. In contrast, no effect of dibutyryl cAMP on IL-6 synthesis was observed in the cells from one of the MAS patients. These data suggest that IL-6 is, at least, one of the downstream effectors of cAMP and that the increased IL-6 synthesis has a pathogenic role in the bone lesions of MAS patients via increasing the number of osteoclasts. These results may provide a new strategy for the therapy of MAS patients. PMID- 8690801 TI - Effects of 17beta-estradiol on cytokine-induced endothelial cell adhesion molecule expression. AB - One of the earliest events in atherosclerosis is interaction of circulating mononuclear leukocytes and the endothelium. Endothelial cell (EC) activation by cytokines results in expression of adhesion molecules and production of chemotactic factors, augmenting leukocyte adhesion and recruitment, respectively. The incidence of atherosclerosis in premenopausal women is significantly less than that observed in age-matched males with similar risk profiles. Because estrogen has gene regulatory effects, we investigated whether 17beta-estradiol (E2) can inhibit cytokine-mediated EC adhesion molecule transcriptional activation. Cultured human umbilical vein EC (estrogen receptor-positive) were propagated in gonadal hormone-free medium and were E2-pretreated for 48 h before IL-1 activation. Detected by FACS analysis, E2 strongly (60-80%) inhibited IL-1 mediated membrane E-selectin and vascular cell adhesion molecule-1 induction, and intercellular adhesion molecule-1 hyperinduction. 17alpha-estradiol (an inactive E2 stereoisomer) had no effect. This inhibition correlated with similar reductions in steady state-induced E-selectin mRNA levels, and was abrogated by the E2 antagonist ICI 164,384, demonstrating a specific, estrogen receptor mediated effect. Nuclear run-offs confirmed suppression at the transcriptional level. The implications of these results for the cardiovascular protective role of estrogen are discussed. PMID- 8690802 TI - Acute regulation by insulin of phosphatidylinositol-3-kinase, Rad, Glut 4, and lipoprotein lipase mRNA levels in human muscle. AB - We have investigated the acute regulation by insulin of the mRNA levels of nine genes involved in insulin action, in muscle biopsies obtained before and at the end of a 3-h euglycemic hyperinsulinemic clamp. Using reverse transcription competitive PCR, we have measured the mRNAs encoding the two insulin receptor variants, the insulin receptor substrate-1, the p85alpha subunit of phosphatidylinositol-3-kinase, Ras associated to diabetes (Rad), the glucose transporter Glut 4, glycogen synthase, 6-phosphofructo-l-kinase, lipoprotein lipase, and the hormone-sensitive lipase. Insulin infusion induced a significant increase in the mRNA level of Glut 4 (+56 +/- 13%), Rad (+96 +/- 25%), the p85alpha subunit of phosphatidylinositol-3-kinase (+92 +/- 18%) and a decrease in the lipoprotein lipase mRNA level (-49 +/- 5%), while the abundance of the other mRNAs was unaffected. The relative expression of the two insulin receptor variants was not modified. These results demonstrate an acute coordinated regulation by insulin of the expression of genes coding key proteins involved in its action in human skeletal muscle and suggest that Rad and the p85alpha regulatory subunit of phosphatidylinositol-3-kinase can be added to the list of the genes controlled by insulin. PMID- 8690803 TI - The oxidant stress of hyperhomocyst(e)inemia. PMID- 8690804 TI - Soluble beta-glucan polysaccharide binding to the lectin site of neutrophil or natural killer cell complement receptor type 3 (CD11b/CD18) generates a primed state of the receptor capable of mediating cytotoxicity of iC3b-opsonized target cells. AB - When phagocyte CR3 binds to iC3b on bacteria or yeast, phagocytosis and degranulation are triggered because of simultaneous recognition of iC3b via a CD11b I-domain binding site and specific microbial polysaccharides via a lectin site located COOH-terminal to the I-domain. By contrast, when phagocyte or natural killer (NK) cell CR3 adheres to iC3b on erythrocytes or tumor cells that lack CR3-binding membrane polysaccharides, neither lysis nor cytotoxicity are stimulated. This investigation showed that soluble CR3-specific polysaccharides such as beta-glucan induced a primed state of CR3 that could trigger killing of iC3b-target cells that were otherwise resistant to cytotoxicity. Anti-CR3 added before sugars prevented priming, whereas anti-CR3 added after sugars blocked primed CR3 attachment to iC3b-targets. Polysaccharide priming required tyrosine kinase(s) and a magnesium-dependent conformational change of the I-domain that exposed the CBRM1/5 activation epitope. Unlike LPS or cytokines, polysaccharides did not up-regulate neutrophil CR3 expression nor expose the mAb 24 reporter epitope representing the high affinity ICAM-1-binding state. The current data apparently explain the mechanism of tumoricidal beta-glucans used for immunotherapy. These polysaccharides function through binding to phagocyte or NK cell CR3, priming the receptor for cytotoxicity of neoplastic tissues that are frequently targeted with iC3b and sparing normal tissues that lack iC3b. PMID- 8690805 TI - Glucose metabolism distal to a critical coronary stenosis in a canine model of low-flow myocardial ischemia. AB - Myocardial regions perfused through a coronary stenosis may cease contracting, but remain viable. Clinical observations suggest that increased glucose utilization may be an adaptive mechanism in such "hibernating" regions. In this study, we used a combination of 13C-NMR spectroscopy, GC-MS analysis, and tissue biochemical measurements to track glucose through intracellular metabolism in intact dogs infused with [1-13C]glucose during a 3-4-h period of acute ischemic hibernation. During low-flow ischemia [3-13C]alanine enrichment was higher, relative to plasma [1-13C]glucose enrichment, in ischemic than in nonischemic regions of the heart, suggesting a greater contribution of exogenous glucose to glycolytic flux in the ischemic region (approximately 72 vs. approximately 28%, P < 0.01). Both the fraction of glycogen synthase present in the physiologically active glucose-6-phosphate-independent form (46 +/- 10 vs. 9 +/- 6%, P < 0.01) and the rate of incorporation of circulating glucose into glycogen (94 +/- 25 vs. 20 +/- 15 nmol/gram/min, P < 0.01) were also greater in ischemic regions. Measurement of steady state [4-13C)glutamate/[3-13C]alanine enrichment ratios demonstrated that glucose-derived pyruvate supported 26-36% of total tricarboxylic acid cycle flux in all regions, however, indicating no preference for glucose over fat as an oxidative substrate in the ischemic myocardium. Thus during sustained regional low-flow ischemia in vivo, the ischemic myocardium increases its utilization of exogenous glucose as a substrate. Upregulation is restricted to cytosolic utilization pathways, however (glycolysis and glycogen synthesis), and fat continues to be the major source of mitochondrial oxidative substrate. PMID- 8690806 TI - Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-beta1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. AB - Oral administration of antigen is a long recognized method of inducing systemic immune tolerance. In animals with experimental autoimmune disease, a major mechanism of oral tolerance triggered by oral administration of antigen involves the induction of regulatory T cells that mediate active suppression by secreting the cytokine TGF-beta 1. Multiple sclerosis (MS) is a presumed T cell-mediated Th1 type autoimmune disease. Here, we investigated whether in MS patients oral myelin treatment, containing both myelin basic protein (MBP) and proteolipid protein (PLP), induced antigen specific MBP or PLP reactive T cells that either secreted IL4, TGF-beta1, or alternatively did Th1 type sensitization occur as measured by IFN-gamma secretion. Specifically, 4,860 short-term T cell lines were generated to either MBP, PLP, or tetanus toxoid (TT) from 34 relapsing-remitting MS patients: 17 orally treated with bovine myelin daily for a minimum of 2 yr as compared to 17 nontreated patients. We found a marked increase in the relative frequencies of both MBP and PLP specific TGF-beta1-secreting T cell lines in the myelin treated MS patients as compared to non-treated MS patients (MBP P < 0.001, PLP P < 0.003). In contrast, no change in the frequency of MBP or PLP specific IFN-gamma or TT specific TGF-beta1 secreting T cells were observed. These results suggest that the oral administration of antigens generates antigen specific TGF beta1 secreting Th3 cells of presumed mucosal origin that represent a distinct lineage of T cells. Since antigen-specific TGF-beta1 secreting cells localize to the target organ and then suppress inflammation in the local microenvironment, oral tolerization with self antigens may provide a therapeutic approach for the treatment of cell-mediated autoimmune disease which does not depend upon knowledge of the antigen specificity of the original T cell clone triggering the autoimmune cascade. PMID- 8690810 TI - Clinical pharmacology and first-time-in-man studies: the FDA levels the playing field. PMID- 8690811 TI - Treating elevated cholesterol levels: the great Satan in perspective. AB - The purpose of this review is to provide perspective on the developments leading to the recognition of high cholesterol levels as a risk factor for coronary heart disease (CHD). Another objective is to consider the unfolding controversies regarding the relative value of cholesterol-lowering drug therapy in primary and secondary prevention. Should physicians use lipid-lowering drugs to treat patients with elevated cholesterol levels but no clinical evidence of coronary disease, or limit intervention to patients with a previous history of angina, coronary angioplasty, coronary artery bypass surgery, or myocardial infarction? This review finds inadequate data to support a recommendation for screening large populations for the presence of elevated cholesterol levels or for primary prevention in those known to have high cholesterol. On the other hand, there is mounting evidence to support vigorous intervention in those with known coronary disease. Further study is needed to determine whether a subset of patients with one or more well-defined risk factors would benefit from primary prevention. PMID- 8690807 TI - Oxidized low density lipoprotein inhibits lipopolysaccharide-induced binding of nuclear factor-kappaB to DNA and the subsequent expression of tumor necrosis factor-alpha and interleukin-1beta in macrophages. AB - A large body of evidence suggests that oxidized LDL (oxLDL) has a role in atherogenesis. One effect is the impact on macrophage function. We have studied the effects of oxLDL and oxysterols on the binding of the transcription factors nuclear factor (NF)-kappaB and AP-1 to DNA. These transcription factors are involved in the regulation of several genes and expressed during activation of macrophages, for example by endotoxin (LPS). OxLDL did not induce binding of NF kappaB. However, the LPS-induced response to NF-kappaB was substantially reduced after preincubation with oxLDL. Medium and highly oxidized LDL also decreased the constitutive DNA-binding of AP-1. Similar effects on AP-1-binding were seen with the oxysterols, 7beta-hydroxycholesterol, 24- hydroxy-, 25-hydroxy-, and 27 hydroxy-cholesterol. Our data therefore suggest an effect of oxLDL on the DNA binding of AP-1, which might be mediated by the oxysterol content of oxLDL. A decreased LPS-induced TNF-alpha and IL-1beta mRNA and protein expression were found in macrophages incubated with oxLDL before LPS-exposure. These observations suggest that macrophages that internalize extensively oxidized LDL are suppressed in their response to inflammatory stimulation. PMID- 8690808 TI - Neuronal constitutive nitric oxide synthase is involved in murine enteric inhibitory neurotransmission. AB - Mice lacking neuronal nitric oxide synthase gene (ncNOS) were used to determine the enzymatic source of nitric oxide (NO) and its relationship with other putative inhibitory neurotransmitters. Inhibitory junction potentials (IJP) of circular smooth muscle of gastric fundus were studied. The IJP in the wild-type mice consists of overlapping components, the fast and slow IJPs. NOS inhibitor L NA or VIP receptor antagonist VIP(10-28), blocks the slow IJP but not the fast IJP. The fast UP is blocked by alpha-beta methylene ATP tachyphylaxis, by reactive blue 2, and by apamin. The IJP in the ncNOS-deficient [ncNOS(-)] mutant is of short duration and is abolished by blockers of the fast IJP, but is unaffected by blockers of the slow UP. Exogenous VIP produces membrane hyperpolarization in strips from wild-type but not ncNOS(-) mice. The hyperpolarizing action of VIP is resistant to nifedipine but is sensitive to omega-conotoxin GVIA. IN CONCLUSION: (a) NO derived from ncNOS is an inhibitory neurotransmitter rather than a postjunctional mediator; (b) VIP is a prejunctional neurotransmitter that causes release of evanescent NO; and (c) ATP acts in parallel with the VIP/NO pathway. PMID- 8690812 TI - Crossover trials with a binary response: a powerful method despite the carryover effect. AB - The two-period crossover trial has the evident advantage that, by use of within patient comparisons, the usual large between-patient variability is not used as a measure to compare treatments. A prerequisite, however, is that the order of the treatments does not substantially influence the outcome of the treatment. Crossover studies with a binary response (such as yes/no or present/absent), although widely used for initial screening of new compounds, have not previously been studied for such order effects. This study uses a mathematical model based on standard statistical tests to study to what extent such order effects, here identical to carryover effects, may reduce the power of detecting a treatment effect. It is concluded that, despite large carryover effects, the crossover study with a binary response remains a powerful method and that testing for carryover effects makes sense only if the null hypothesis of no treatment effect cannot be rejected. PMID- 8690809 TI - Evidence for a catabolic role of glucagon during an amino acid load. AB - Despite the strong association between protein catabolic conditions and hyperglucagonemia, and enhanced glucagon secretion by amino acids (AA), glucagon's effects on protein metabolism remain less clear than on glucose metabolism. To clearly define glucagon's catabolic effect on protein metabolism during AA load, we studied the effects of glucagon on circulating AA and protein dynamics in six healthy subjects. Five protocols were performed in each subject using somatostatin to inhibit the secretion of insulin, glucagon, and growth hormone (GH) and selectively replacing these hormones in different protocols. Total AA concentration was the highest when glucagon, insulin, and GH were low. Selective increase of glucagon levels prevented this increment in AA. Addition of high levels of insulin and GH to high glucagon had no effect on total AA levels, although branched chain AA levels declined. Glucagon mostly decreased glucogenic AA and enhanced glucose production. Endogenous leucine flux, reflecting proteolysis, decreased while leucine oxidation increased in protocols where AA were infused and these changes were unaffected by the hormones. Nonoxidative leucine flux reflecting protein synthesis was stimulated by AA, but high glucagon attenuated this effect. Addition of GH and insulin partially reversed the inhibitory effect of glucagon on protein synthesis. We conclude that glucagon is the pivotal hormone in amino acid disposal during an AA load and, by reducing the availability of AA, glucagon inhibits protein synthesis stimulated by AA. These data provide further support for a catabolic role of glucagon at physiological concentrations. PMID- 8690813 TI - Lack of diurnal variation in glomerular filtration rates in the elderly. AB - The present study was undertaken to examine the effect of age on diurnal variation in glomerular filtration rate (GFR). The GFR, as estimated by creatinine clearance (Clcr), was determined during a 24-hour period in 10 younger (mean +/- SD age 42 +/- 9 years) and 10 older (mean age 75 +/- 4 years) patients with hypertension. Significant diurnal variations in Clcr were observed in the younger patients, with a peak during the day and trough during the night. Such were not observed in the older patients, however. These results suggest that diurnal variation in GFR is affected by age. Chronopharmacologic profiles of drugs, which are mainly excreted in urine by glomerular filtration, might be altered in these patients. PMID- 8690814 TI - Pharmacokinetics of ondansetron in patients with hepatic insufficiency. AB - Ondansetron is primarily eliminated via hepatic metabolism; thus, liver disease may affect its clearance. The pharmacokinetics of ondansetron in patients with different degrees of hepatic insufficiency (N = 12 with hepatic impairment, as categorized by Pugh's classification method) were assessed and the results compared with results for age- and gender-matched control subjects with normal liver function (n = 12). A secondary objective was to correlate the Pugh method of assessing hepatic impairment and quantitative metabolic markers used to assess hepatic function (antipyrine clearance and indocyanine green clearance) with changes in the pharmacokinetics of ondansetron. This was an open-label study in which 8 mg ondansetron was given orally and intravenously, following a randomized crossover design. Clearance of ondansetron was lower among patients with hepatic impairment that control subjects. After a single, oral dose of ondansetron, mean absolute bioavailability increased markedly with increased hepatic insufficiency (approaching 100% in the group with severe hepatic impairment versus 66% for control subjects). These data suggest that there is a reduced first-pass effect in patients with liver disease resulting in a higher AUC0-infinity. A correlation existed between clearance of ondansetron and decreased antipyrine clearance; a smaller correlation existed between ondansetron clearance and indocyanine green clearance. Mean percent of ondansetron bound to plasma proteins was significantly lower in patients with liver disease than in control subjects. None of the patients experienced any severe adverse reactions attributed to ondansetron. A reduction in the clearance of ondansetron is associated with increasing degrees of hepatic insufficiency; therefore, patients with severe hepatic impairment (Pugh score of > 9) should have their daily dose of ondansetron limited to 8 mg (or 0.15 mg/kg). PMID- 8690815 TI - Pharmacodynamics and pharmacokinetics of two dose regimens of befloxatone, a new reversible and selective monoamine oxidase inhibitor, at steady state in healthy volunteers. AB - The pharmacodynamic equipotency of 2 dose regimens (5 mg twice daily versus 10 mg once daily) of befloxatone, a new reversible and selective monoamine oxidase A (MAO-A) inhibitor, after single and multiple doses for 6 days was examined in a randomized, double-blind, three-way crossover, placebo-controlled trial of 12 healthy volunteers. Plasma levels of the deaminated metabolite 3-4 dihydroxyphenylglycol (DHPG), as measured by high-performance liquid chromatography (HPLC) with coulometric electrochemical detection, were used as an index of MAO inhibition. A single dose of befloxatone produced a significant dose related reduction in plasma DHPG levels, as shown by the decrease in the 24-hour area under the concentration-time curve (AUC0-24) of DHPG, which peaked 2 hours after administration and persisted over 24 hours. Both dose regimens provided equipotent extent and duration of MAO-A inhibition at steady state, suggesting a once daily dosage should be sufficient for most patients. The pharmacokinetic bioavailability at steady state of both dose regimens was also similar. The concentration-time effect curve after a single dose revealed a hysteresis corresponding to the delay necessary to elicit MAO inhibition and/or elimination of DHPG. The relationship between plasma levels of DHPG and/or elimination of plasma concentrations of DHPG and befloxatone after a single dose can be modeled using the Emax model with a mean EC50 of 4.75 ng/mL, and suggests the presence of a maximal response from the single dose. This model permits prediction of steady state levels of DHPG. PMID- 8690816 TI - Explaining variable absorption of a hypolipidemic agent (CGP 43371) in healthy subjects by gamma scintigraphy and pharmacokinetics. AB - The gastrointestinal absorption of a hypolipidemic agent (CGP 43371) was investigated using an external scintigraphy technique in six healthy men. After an overnight fast, subjects received a single 800-mg oral dose of CGP 43371 (4 capsules of 200 mg each) and one capsule of radioactive samarium-153 oxide (100 130 microCi) as a nonabsorbable marker of gastrointestinal transit and fecal recovery for CGP 43371. In vivo gastrointestinal transit of samarium-153 was monitored via gamma scintigraphy for 48 hours after administration to coincide with blood sampling. Samarium-153 content in whole fecal samples was determined by external gamma scintigraphy, and CGP 43371 content in both fecal and plasma samples was determined using high-performance liquid chromatography (HPLC). The results of fecal analysis indicated that transit of the two compounds in the gastrointestinal tract were similar, and bioavailability of CGP 43371 was calculated to be 9% based on the difference between the cumulative amounts of the nonabsorbable radioactive marker and CGP 43371 found in the feces. The onset of drug absorption occurred 4 hours after administration when radioactive samarium 153 was in the distal small bowel, and peak plasma drug level occurred 6 hours after administration, which corresponded with the arrival of samarium-153 in the terminal ileum and ileal/cecal junction. This observation supported the concept that primary absorption of this compound was in the distal to terminal portion of the ileum. Although the onset of drug absorption was delayed, it was curious that the rate of gastric emptying also affected the extent of absorption. A positive correlation (r = 0.91) between area under the drug curve (AUC) and area under the transit curve (AUTC) of the gastric emptying showed that longer gastric residence improved oral absorption of CGP 43371. PMID- 8690817 TI - Effect of food on the relative bioavailability of oral ganciclovir. AB - The steady-state pharmacokinetics of oral ganciclovir in the fasting versus fed state were studied in 20 patients infected with human immunodeficiency virus and with a seropositive test result for cytomegalovirus in a two-way crossover study. Patients received oral ganciclovir at a dose of 1000 mg every 8 hours for 8 days. On days 4 and 8, subjects were randomly assigned to receive the morning dose either after an overnight fast or after a standardized 602-calorie, high-fat (46.5%) breakfast. Serial blood samples were obtained over the 8-hour morning dose interval. The mean time to maximum concentration (tmax) was increased from 1.8 hours in the fasting state to 3.0 hours in the fed state. Mean maximum serum concentration (Cmax) and area under the concentration-time curve from time 0 to 8 hours (AUC0-8) of ganciclovir were significantly higher in the fed state than after an overnight fast. Because food could potentially increase the bioavailability of oral ganciclovir, patients should be instructed to take each dose of oral ganciclovir with food. PMID- 8690818 TI - Effect of age and gender on pharmacokinetics of atorvastatin in humans. AB - Atorvastatin is a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor that reduces plasma cholesterol by inhibiting cholesterol synthesis and increasing cellular uptake of low density lipoproteins. The effects of age and gender on the pharmacokinetics of atorvastatin after administration of single 20 mg tablets of atorvastatin were studied in 16 young and 16 elderly volunteers (8 men and 8 women in each age group). Plasma equivalent concentrations of atorvastatin were quantitated by a validated enzyme inhibition bioassay. Atorvastatin was well tolerated by the participants. The equivalent maximum concentration (Cmax) of atorvastatin was 42.5% higher in elderly participants (age, 66-92 years) than in young participants (age, 19-35 years) and 17.6% higher in women than in men. In addition, mean area under the concentration-time curve (AUC0-infinity) and half-life (t1/2) were 27.3% greater and 36.2% longer, respectively, in elderly adults than in young adults and 11.3% lower and 19.9% shorter, respectively, in women than in men. Because the primary site of action for HMG-CoA reductase inhibitors is the liver and atorvastatin is subject to extensive first-pass hepatic metabolism, it is unclear whether these age- and gender-related differences in the pharmacokinetics of atorvastatin will be clinically important. Results of subsequent safety and efficacy trials should help clarify the clinical significance of these pharmacokinetic differences. PMID- 8690819 TI - The effects of epoprostenol on drug disposition. I: A pilot study of the pharmacokinetics of digoxin with and without epoprostenol in patients with congestive heart failure. AB - The influence of epoprostenol on the pharmacokinetics of drugs administered concurrently to patients with congestive heart failure (CHF) receiving epoprostenol was evaluated as a secondary objective of a Phase II pilot study. A total of 278 blood samples were collected from 30 patients with end-stage CHF receiving conventional therapy alone or conventional therapy plus epoprostenol. Estimates of oral clearance (Cl), volume of distribution, and absorption rate constant of digoxin were generated from plasma digoxin concentrations using nonlinear mixed effects modeling, and the effect of epoprostenol on Cl of digoxin was evaluated by univariate analysis. Additional factors that were evaluated by univariate analysis included age, obesity, time since study entry, cardiac output, concomitant use of angiotensin-converting enzyme (ACE) inhibitor, concomitant dobutamine, and estimated creatinine clearance. Backward elimination was used to arrive at a final model that included concomitant epoprostenol as a covariate. The final model revealed an approximate 15% decrease in Cl of digoxin in response to short-term administration of epoprostenol that was no longer apparent by the end of the 12-week treatment phase. Simulations revealed that this effect, although statistically significant, would not be clinically significant in most patients; however, the potential exists for short-term elevation of digoxin concentrations in response to concurrent administration of epoprostenol. PMID- 8690820 TI - The effects of epoprostenol on drug disposition. II: A pilot study of the pharmacokinetics of furosemide with and without epoprostenol in patients with congestive heart failure. AB - The effect of epoprostenol on the pharmacokinetics of furosemide was investigated in 23 patients with end-stage congestive heart failure (CHF) receiving conventional therapy alone or conventional therapy plus epoprostenol. Estimates of the apparent oral clearance, volume of distribution, and absorption rate constant for furosemide were generated from 198 serum furosemide concentrations using nonlinear mixed effects modeling (NONMEM). Univariate analyses were performed to assess the effects of patient factors on the apparent oral clearance of furosemide. The final multivariate model determined by backwards elimination included concomitant digoxin therapy. When concomitant epoprostenol therapy was included in the final model, there was a 13% decrease in the apparent oral clearance of furosemide in response to short-term administration of epoprostenol. However, the effect of concomitant epoprostenol therapy was not statistically significant and was no longer apparent by the end of the 12-week study. These data suggest that epoprostenol may have a slight short-term effect on the pharmacokinetics of furosemide; the interaction between epoprostenol and furosemide is not clinically significant, however. PMID- 8690821 TI - Pharmacodynamics of torsemide administered as an intravenous injection and as a continuous infusion to patients with congestive heart failure. AB - The natriuretic and diuretic effects of a 100-mg dose of torsemide administered as a continuous infusion of torsemide and as a single bolus were compared in a group of patients with stable mild-to-moderate congestive heart failure (CHF). Patients received in random order 100 mg of torsemide as an intravenous bolus and as a 75-mg infusion over 24 hours started simultaneously with a 25-mg loading bolus. Administration of torsemide to patients with CHF as a continuous infusion was an effective dosing regimen, resulting in 24-hour diuresis and natriuresis that was numerically but not statistically greater than that observed with bolus administration. The response with continuous infusion occurred with less torsemide in the urine, resulting in a significantly greater efficiency of torsemide with this regimen. The effectiveness of torsemide as a continuous infusion does not mean that this mode of administration should be used in all patients. The response to 100 mg of torsemide in patients with mild-to-moderate CHF is the same whether administered as an intravenous bolus, a continuous intravenous infusion, or by mouth. This is consistent with the high bioavailability demonstrated in previous studies. The mode of therapy used should be dictated by each individual patient's needs. This study shows that continuous infusion is a viable option for administration of torsemide, and dosing guidelines for use of such a strategy are presented. PMID- 8690822 TI - No evidence of a direct venodilatory effect of furosemide in healthy human subjects. AB - The present study was undertaken to examine whether furosemide, a loop diuretic, has a direct venodilatory effect in healthy male subjects. Furosemide, or amrinone, an inotropic agent with a vasodilatory action, was infused into a dorsal hand vein that had been preconstricted by phenylephrine. The diameter of the vein was measured by a linear variable differential transformer. Venodilation was observed during the infusion of amrinone, but such a response was not detected with furosemide. These findings do not support the hypothesis that furosemide has a direct venodilatory effect in healthy human subjects. PMID- 8690823 TI - Effects of dihydropyridine calcium antagonists on albuminuria in patients with diabetes. AB - The present study was designated to assess the effects of two different dyhydropyridine calcium antagonists (DHPCAs) on proteinuria in patients with noninsulin-dependent diabetes mellitus (NIDDM). The hypothesis that similar levels of blood pressure reduction with two different DHPCAs produce similar degrees of proteinuria reduction was tested. In a prospective randomized study, 14 patients with NIDDM, hypertension, proteinuria, and renal insufficiency were given either isradipine (n = 7) or nifedipine XL (n = 7) for 6 months. After a 2 week washout period, patients were crossed over to the other drug and observed for an additional 6 months. Drugs were titrated to lower arterial pressure to < 140/90 mmHg. Patients also instructed to follow a low-sodium diet at the initial visit. Blood pressure and 24-hour urine values for creatinine clearance, albuminuria, proteinuria, and sodium were assessed monthly. At the end of the initial and crossover treatment periods, there were no significant reductions in the level of albuminuria from baseline with either drug. Sodium excretion was < 110 mEq/L with each drug tested. The results of this study support the concept that DHPCAs do not reduce proteinuria in patients with type II diabetes. This failure to reduce albuminuria and proteinuria occurred despite adequate blood pressure reduction and an effort at dietary sodium restriction. PMID- 8690824 TI - Drug interactions, cardiac toxicity, and terfenadine: from bench to clinic? PMID- 8690825 TI - Inhibition of terfenadine metabolism in vitro by azole antifungal agents and by selective serotonin reuptake inhibitor antidepressants: relation to pharmacokinetic interactions in vivo. AB - Biotransformation of the H-1 antagonist terfenadine to its desalkyl and hydroxy metabolites was studied in vitro using microsomal preparations of human liver. These metabolic reactions are presumed to be mediated by Cytochrome P450-3A isoforms. The azole antifungal agent ketoconazole was a highly potent inhibitor of both reactions, having mean inhibition constants (Ki) of 0.037 and 0.34 microM for desalkyl- and hydroxy-terfenadine formation, respectively. Itraconazole also was a potent inhibitor, with Ki values of 0.28 and 2.05 microM, respectively. Fluconazole, on the other hand, was a weak inhibitor. Six selective serotonin reuptake inhibitor antidepressants tested in this system were at least 20 times less potent inhibitors of terfenadine metabolism than was ketoconazole. An in vitro-in vivo scaling model used in vitro Ki values, typical clinically relevant plasma concentrations of inhibitors, and presumed liver:plasma partition ratios to predict the degree of terfenadine clearance impairment during coadministration of terfenadine with these inhibitors in humans. The model predicted a large and potentially hazardous impairment of terfenadine clearance by ketoconazole and, to a slightly lesser extent, by itraconazole. However, fluconazole and the six selective serotonin reuptake inhibitors (SSRIs) at usual clinical doses were not predicted to impair terfenadine clearance to a degree that would be of clinical importance. Caution is nonetheless warranted with the coadministration of SSRIs and terfenadine when high doses of SSRIs (particularly fluoxetine) are administered. Also, some individuals may be unusually susceptible to metabolic inhibition for a variety of reasons. PMID- 8690826 TI - Fluvoxamine maleate in the treatment of depression: a single-center, double blind, placebo-controlled comparison with imipramine in outpatients. AB - The efficacy and safety of fluvoxamine maleate, a selective serotonin reuptake inhibitor, was compared with placebo and imipramine in patients with major depressive disorder. Previous literature has cited a dose range of 100 to 300 mg/day of fluvoxamine maleate for the treatment of major depression; however, this study demonstrates that a dose range of 50 to 150 mg/day is as effective as imipramine (80-240 mg/day). After a 1- to 2-week, single-blind, placebo washout phase, 150 depressed outpatients were randomized to double-blind treatment with fluvoxamine maleate (50-150 mg/day), imipramine (80-240 mg/day), or placebo for 6 weeks. Fluvoxamine produced a significant therapeutic benefit over placebo (p < or = 0.05) as assessed by the total score on the Hamilton Rating Scale for Depression; imipramine (80-240 mg/day) produced similar results. The secondary outcome variables (i.e., Clinical Global Impression severity of illness item and 56-Item Hopkins Symptom Checklist depression factor) also showed significant differences between fluvoxamine maleate and placebo during three of the four final weeks of the study. Both fluvoxamine maleate and imipramine appeared to be safe and well tolerated by the majority of patients. As expected from the pharmacology of these agents, the imipramine groups reported more anticholinergic effects (dry mouth, dizziness, and urinary retention) and electrocardiographic effects, whereas the fluvoxamine group reported more nausea, somnolence, and abnormal ejaculation. The majority of these adverse events were mild to moderate and, with the exception of dry mouth (imipramine) and abnormal ejaculation (fluvoxamine), were transient. The data clearly demonstrate the antidepressant activity and tolerability of fluvoxamine maleate (50-150 mg/day) as compared with placebo; it is also as effective as the tricyclic antidepressant imipramine (80 240 mg/day) in patients with major depressive disorder. PMID- 8690827 TI - Fluvoxamine versus clomipramine for obsessive-compulsive disorder: a double-blind comparison. AB - The efficacy and tolerability of fluvoxamine (100-300 mg/day) and clomipramine (100-250 mg/day) were compared in a randomized, double-blind, parallel-group study of 79 patients with obsessive-compulsive disorder (OCD) without coexisting major depression. After a 2-week placebo lead-in period, patients were randomized to fluvoxamine (37 patients) or clomipramine (42 patients) for 10 weeks. Efficacy was evaluated with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the National Institute of Mental Health Obsessive-Compulsive scale, and Patient and Clinical Global Improvement scales. Hamilton Rating Scale for Depression scores and somatic symptoms were also assessed. Seventy-eight percent of fluvoxamine patients and 64% of clomipramine patients completed the study. At the end of treatment, 56% of fluvoxamine patients were classified as responders (> or = 25% decrease in Y-BOCS score), compared with 54% of clomipramine patients. Both groups showed steady improvement throughout the study; no statistically significant differences were observed between the groups for any efficacy variable at any time. A similar percentage of patients in both groups withdrew because of adverse events. No serious adverse events related to drug occurred with either drug. Insomnia, nervousness, and dyspepsia were more statistically frequent with fluvoxamine; dry mouth and postural hypotension were more frequent with clomipramine. In this study, fluvoxamine and clomipramine were equally effective in reducing OCD symptoms over a 10-week treatment period but displayed different side effect profiles. PMID- 8690828 TI - Adverse events and tolerability of the combination of fluoxetine/lithium compared with fluoxetine. AB - Data from an intensive observational drug utilization study were analyzed to determine whether patients who received the combination of fluoxetine and lithium had more and different adverse events as compared with those receiving fluoxetine alone. In a matched cohort control design, we compared 110 patients per group. Results showed no significant difference in side effects between groups. Also, the incidence of "serotonergic" adverse events showed no significant differences between groups during the 7-week study period. In conclusion, the results show that the combination of fluoxetine/lithium is generally well tolerated in spite of a somewhat increased rate of minor side effects. PMID- 8690829 TI - Cardiovascular variability in major depressive disorder and effects of imipramine or mirtazapine (Org 3770). AB - Spectral analysis of fluctuations in heart rate (HR) and blood pressure (BP) was applied to assess sympathetic and parasympathetic cardiovascular control mechanisms in patients with unipolar affective disorder before and after treatment with imipramine (IMI) or mirtazapine (MIR). In a double-blind randomized study, 10 patients received treatment with IMI and 10 patients received treatment with MIR. Cardiovascular parameters were studied before and after 4 weeks of treatment: HR and BP (Finapres) were recorded continuously during supine rest (SR) and orthostatic challenge (OC; 60-degrees head-up tilting). During SR and OC, power spectra were calculated for HR and systolic BP. Spectral density was assessed for three frequency bands: low (0.02-0.06 Hz), mid (0.07-0.14 Hz), and high (0.15-0.50 Hz). Before treatment, the depressed patients (N = 20) differed from age-matched controls (N = 20) only in their response to OC: the depressed patients showed more suppression of HR variability (both mid- and high-frequency band fluctuations), indicating stronger vagal inhibition, and a reduced increase of BP variability (mid-frequency band fluctuations), indicating reduced sympathetic activation. After 4 weeks of treatment, patients treated with either antidepressant drug showed significant changes of HR (increase) and HR variability (decrease) during SR and OC; the suppression of mid and high-frequency fluctuations of HR was larger for IMI than for MIR. The increase in HR and decrease in HR variability may be attributed to the anticholinergic properties of IMI (strong) and MIR (weak), resulting in cardiac vagal inhibition. Whereas MIR had no effect on BP or BP variability, IMI specifically reduced mid-frequency band fluctuations of BP as the result of a suppression of central sympathetic activity. Our data confirm and extend previous observations on the presence of autonomic dysfunctions in unmedicated depressed patients: spectral analysis of HR and BP fluctuations suggested that both parasympathetic and sympathetic mechanisms are involved, specifically during OC. The preexisting autonomic cardiovascular dysfunctions were not normalized by antidepressant drugs. In fact, some of the components of the cardiovascular autonomic dysfunction were further aggravated, depending on the pharmacologic profile of the drug under investigation. PMID- 8690830 TI - Zolpidem, triazolam, and temazepam: behavioral and subject-rated effects in normal volunteers. AB - Zolpidem is an imidazopyridine hypnotic that is biochemically distinct from classic benzodiazepine agonists in that it may be selective for the BZ1 receptor subtype and shows a different pattern of distribution of binding sites. The present study compared the learning, recall, performance, subject-rated and observer-rated effects of zolpidem, triazolam, and temazepam in 11 healthy humans. Placebo, zolpidem (5, 10, and 20 mg/70 kg), triazolam (0.125, 0.25, and 0.50 mg/70 kg), and temazepam (15, 30, and 60 mg/70 kg) were administered orally in a randomized, double-blind, cross-over design. Zolpidem, triazolam, and temazepam produced orderly dose- and time-related impairment of learning, recall, and performance, and increased subject- and observer-rated estimates of strength of drug effect. The absolute magnitude of these effects at peak effect were comparable across the three compounds. The time to maximal drug effect was faster with zolpidem (0.5-1.0 hours) than with triazolam (1.5-2.0 hours) or temazepam (2 3 hours). These results suggest that despite the somewhat unique benzodiazepine receptor-binding profile of zolpidem, its behavioral and subject-rated effects are similar to those of benzodiazepine hypnotics (i.e., triazolam and temazepam). PMID- 8690831 TI - ICI 204,636, an atypical antipsychotic: efficacy and safety in a multicenter, placebo-controlled trial in patients with schizophrenia. U.S. SEROQUEL Study Group. AB - ICI 204,636 is a new, potentially atypical antipsychotic. In early phase II trials, the antipsychotic was well tolerated and results suggested efficacy in the treatment of the positive and negative symptoms of schizophrenia. The efficacy and safety of ICI 204,636 were evaluated on a larger scale in a 6-week, multicenter, double-blind trial. Hospitalized patients who met DSM-III-R criteria for chronic or subchronic schizophrenia with acute exacerbation, as well as other criteria, were randomized to ICI 204,636 (75 to 750 mg daily) (N = 54) or placebo (N = 55). Patients were assessed weekly by use of the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS), and Clinical Global Impression Scale (CGI) for efficacy and the Simpson Scale and Abnormal Involuntary Movement Scale for extrapyramidal side effects (EPS). Significant differences (p < or = 0.05) between treatment groups, which favored ICI 204,636, were identified throughout the trial. Endpoint differences were significant (by analysis of covariance) for BPRS factor IV (activation) and SANS scores and were marginally significant for total BPRS, BPRS factor III (thought disturbance), BPRS positive-symptom cluster, and CGI Severity of Illness item scores (p = 0.07, 0.09, 0.06, and 0.09, respectively). ICI 204,636 was well tolerated, although it was associated with mild transient increases in alanine aminotransferase and a higher incidence of somnolence and anticholinergic effects compared with placebo. In the dose range studied, treatment with ICI 204,636 did not induce EPS as determined by analysis of Simpson Scale total scores and lack of treatment emergent acute dystonic reactions. Furthermore, ICI 204,636 did not produce sustained levels of prolactin; the mean change from baseline at endpoint (-7.2 micrograms/L) was comparable (p = 0.44) to that for placebo (-8.2 micrograms/L). These findings distinguish ICI 204,636 from standard antipsychotics and confirm preclinical predictions that ICI 204,636 is an atypical antipsychotic. PMID- 8690832 TI - Subject selection biases in clinical trials: data from a multicenter schizophrenia treatment study. AB - To evaluate subject selection biases in clinical trials, demographic characteristics (gender, race, and age) of subjects at different phases of evaluation for a multicenter maintenance trial in schizophrenia were examined. Six thousand twelve diagnostically appropriate subjects were screened for the study; of these, 1,320 met eligibility criteria and 528 (9% of the screened sample) entered the study. Women, blacks, and older subjects were more likely not to meet eligibility criteria; women and older subjects were more likely and blacks were less likely to refuse study participation. Overall, compared with the screened population, the sample of subjects who entered the study contained proportionately fewer women (33 vs. 43%), more blacks (48.5 vs. 41%), and fewer older subjects (mean age of the entered sample was 29.4 +/- 7.4 vs. 34.8 +/- 11.3 years for the screened population). Having identified these selection factors, a second goal was to assess the potential clinical relevance of selection biases of these magnitudes on clinical trials using models of hypothetical studies with different degrees of selection bias. These showed that selection biases would rarely change overall study outcomes to a clinically relevant degree. However, in our models, selection biases did limit the ability to make inferences about results for select small subgroups of the study population. Investigators should consider collecting data on the recruitment process to allow estimation of the effects of selection biases on the generalizability of their findings. PMID- 8690834 TI - Serotonin, psilocybin, and body dysmorphic disorder: a case report. PMID- 8690833 TI - Pharmacokinetics of clozapine and risperidone: a review of recent literature. AB - The current literature describing the pharmacokinetics of the atypical antipsychotics clozapine and risperidone is reviewed, and discussion on the clinical significance of these data is presented. These drugs are well absorbed when taken orally but are poorly bioavailable because of presystemic elimination. They are highly cleared by hepatic metabolism involving specific P450 isozymes. Risperidone elimination produces a potent active metabolite. Neither of the drugs has received extensive study related to drug-drug interactions, but several are potentially important because a purported therapeutic plasma concentration range is proposed for clozapine and a possible curvilinear dose response relationship has been reported for risperidone. The current clinical pharmacokinetic database for these atypical antipsychotics suggests that much can be learned with additional study that would be of value in individualizing their dosage regimens. PMID- 8690835 TI - A toxic reaction from combining fluoxetine and phentermine. PMID- 8690836 TI - Vigabatrin and posttraumatic stress disorder. PMID- 8690837 TI - Update to "Over-the-counter hypnotics and chronic insomnia in the elderly" (guest editorial, J Clin Psychopharmacol 1995;15:383-6) PMID- 8690838 TI - Neuroleptic malignant syndrome with risperidone. PMID- 8690839 TI - Clozapine levels after clozapine discontinuation. PMID- 8690840 TI - I have heard that buspirone regularly affects various blood tests. Is this so? PMID- 8690841 TI - Differences in motor control in the bronchus and extrathoracic trachea. AB - The motor control of the bronchus and extrathoracic trachea was evaluated by continuously measuring bronchial diameter and tracheal muscle tension as well as phrenic nerve activity in decerebrated, paralyzed, artificially ventilated dogs. Spontaneous rhythmic changes in bronchial diameter and tracheal muscle tension occurred in phase with phrenic burst during mechanical ventilation and during apnea induced by disconnecting the ventilator. There was a small but consistent difference in the timing of their rhythmic activities; bronchial constriction started at mid-inspiration, whereas tracheal contraction began just prior to the end of inspiration. Both were active in the post-inspiratory phase. Both hypercapnia and apnea caused an enhanced rhythmic constriction of the bronchus, while evoking a tonic contraction of the trachea. Intermittent electric stimulation of the efferent vagus nerves revealed that repetitive stimulation with a short intermission was necessary to evoke a sustained constriction of the bronchus, and that the bronchus could maintain the sustained constriction only transiently. These results indicate that the motor control of the bronchus and extrathoracic trachea are distinct. The central nervous system may contribute to the difference in timing of the contraction between tracheal and bronchial smooth muscle. However, the difference in response to electric stimulation of the nervus vagus may be attributed to the peripheral neuromuscular system. PMID- 8690842 TI - Functional sudomotor responses to cholinergic agonists and antagonists in the mouse. AB - This study evaluates the functional activity of the mouse sweat glands in response to cholinergic agonists and antagonists using the silicone imprint technique. In intact mice the response to acetylcholine, methacholine and pilocarpine did not differ significantly from control saline injection, indicating that immobilization induces high levels of sweating, masking the effects of cholinergic stimulation. Plantar emotional sweating was completely abolished by local anesthesia at the ankle. Under these conditions, administration of acetylcholine only provoked detectable sweating when injected locally into the sole skin. Methacholine activated an increasing number of sweat glands in a dose-dependent manner between 0.5 and 10 mg/kg; the response was maximal after 5-10 min of administration and decreased subsequently. With pilocarpine the maximum number of reactive sweat glands was observed at a dose of 2.5 mg/kg. The response was stable for 45 min with doses 2.5 and 5 mg/kg, but decreased exponentially with higher doses. The subtype of sweat gland muscarinic receptor was characterized by determining the inhibitory effect of different cholinergic antagonists on pilocarpine response. Atropine and 4-DAMP were equally potent inhibitors, showing a dose-related effect from 0.05 mg/kg. Pirenzepine only showed inhibitory effects with doses 10-times higher, whereas gallamine and hexamethonium did not induce inhibition at any of the doses tested. These findings suggest that the mouse eccrine sweat gland muscarinic receptors are predominantly M3. PMID- 8690843 TI - Neural influences on the iris of diabetic rats and effect of oculomotor nerve crush. AB - Using an animal model where the pupil diameter of the eye in anaesthetized and dark-adapted rats serves as a parameter of autonomic function, we studied the functional recovery of the parasympathetic nerve fibres in the oculomotor nerve after a crush lesion in rats with streptozotocin-induced diabetes compared with normal controls. Prior to the crush lesion, diabetic rats develop significantly (P < 0.001) smaller pupils compared with controls, and this occurs early in the course of the diabetes mellitus. As the difference in pupil diameter between control and diabetic rats persists immediately after the crush lesion, when the nervous control of the pupil is entirely due to sympathetic nerves, we suggest that the reduction in pupil diameter is due to a sympathetic neuropathy. Furthermore, we show that the functional recovery of the parasympathetic input to the iris after a crush lesion of the oculomotor nerve is not as good in diabetic rats as it is in normal control rats. PMID- 8690845 TI - Autonomic mediation of short-term cardiovascular oscillations after acute hemorrhage in conscious rats. AB - The role of the autonomic and the renin-angiotensin (R-A) activities in short term cardiovascular control during the bradycardic phase following severe hemorrhage was investigated in conscious rats. Spectral analysis of beat-to-beat fluctuations of the R-R interval (RRI), systolic (SBP) and diastolic (DBP) blood pressure in the 0.01-5-Hz range was carried out under control conditions and following a bleeding of 30% of total blood volume, with and without i.v. injection of atropine (2 mg/kg), prazosin (2 mg/kg), propranolol (5 mg/kg) or captopril (7 mg/kg). The bradycardic stage was characterized by: (i) an increase of the three oscillatory components exhibited by RRI variability which appears driven by vagal activity and buffered by beta-adrenergic activity, while the increase of the slower LF (0.01-0.2 Hz) oscillations seems driven by the slow alpha-adrenergic control; (ii) a decrease of SBP and DBP oscillations and absence of SBP-RRI correlation in the MF band (0.2-0.6 Hz) possibly related to a decrease in the sympathetic drive of SBP-MF and DBP-MF oscillations and in RRI baroreflex control; (iii) an increase in LF oscillations of SBP and even more of DBP that seems driven by the slow alpha-and beta-adrenergic control and buffered by the R A control, responses possibly related to an increase of LF oscillations of peripheral resistance; (iv) the persistence of high SBP-RRI correlation in the LF band and in the respiratory band (1-3 Hz); the former seem to reflect the existence of a slow baroreflex control mediated by beta-adrenergic activity, the latter appears to be caused by feedforward mechanical effects of RRI changes on SBP. PMID- 8690844 TI - Different modes of sensory neuropeptides and nitric oxide involvement in relaxation of guinea-pig vessels. AB - This study investigated involvement of calcitonin-gene-related peptide (CGRP), substance P (SP) and nitric oxide (NO) in transmural nerve stimulation (TNS) induced non-adrenergic, non-cholinergic (NANC) relaxation in isolated guinea pig anterior mesenteric artery (AMA) and posterior caval vein (PCV). Effects of cyclo oxygenase-generated eicosanoids were blocked with indomethacin (10(-5) M) and so were adrenergic and cholinergic responses with phentolamine (3 x 10(-6) M), propranolol (10(-6) M) and atropine (10(-6) M). In both vessels precontracted by U-46619, TNS induced relaxation, which was almost completely abolished by capsaicin pretreatment (10(-6) M, 15 minutes). In AMA, a CGRP1 receptor antagonist (human CGRP8-37, 10(-5) M) significantly attenuated the relaxation, while did both human CGRP8-37 (10(-5) M) and neurokinin-1 receptor antagonists (spantide, 2 x 10(-5) M and FK888, 3 x 10(-6) M) in PCV. NG-nitro-L-arginine methyl ester (10(-4) M) did not significantly attenuate either the NANC-or CGRP induced relaxation in AMA. However, it significantly did attenuate both the NANC and SP-induced relaxation, and it also considerably attenuated CGRP-induced relaxation although insignificantly, in PCV. Thus, CGRP could be significantly responsible for the NO-independent NANC relaxation in AMA, whereas both CGRP and SP could additionally relax PCV in a NO-dependent manner. PMID- 8690846 TI - Assessment of autonomic function in myotonic dystrophy by spectral analysis of heart-rate variability. AB - We analyzed by means of autoregressive spectral analysis the spontaneous beat-to beat heart-rate variability (HRV) of 10 myotonic dystrophy (MD) patients (4 men and 6 women, aged 37-53 years) and 10 age- and sex-matched healthy, sedentary humans (control) at rest in the supine position. All MD patients had no cardiac conduction disturbances (i.e., atrioventricular or intraventricular conduction defects) on 12-lead electrocardiogram and were able to walk and perform daily activities. In the MD group, the total power, the power of the low-frequency component (a marker of sympathetic and vagal modulation of heart rate) and that of the high-frequency component (a marker of vagal modulation of heart rate) were smaller than those in the control group (P < 0.01, P < 0.05 and P < 0.05, respectively). The results of this study suggest that the cardiovascular autonomic nervous system contributing to the HRV may be disturbed even in the MD patients who can walk and perform daily activities. Therefore, one must give careful consideration to the cardiovascular autonomic dysfunction, as well as the cardiac conduction disturbance in the MD patients. PMID- 8690847 TI - Transcription and translation of two glutamate decarboxylase genes in the ileum of rat, mouse and guinea pig. AB - gamma-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter, synthesised from glutamate by glutamate decarboxylase (GAD), in the central nervous system. Two forms of GAD, designated GAD 65 and GAD 67, are encoded by distinct genes and have been demonstrated in the mammalian brain. GABA has been postulated to be synthesised in neurons of the enteric nervous system (ENS), but evidence for its role as an enteric neurotransmitter is equivocal. We therefore aimed to determine whether GAD 65 and GAD 67 messenger RNAs (mRNAs) and proteins were expressed in the ileum of mice, rats and guinea pigs. Using an RNase protection assay, both GAD 65 and GAD 67 mRNAs were detected in the rodent small intestine. Antisera specific for GAD 65 or GAD 67, used in immunoblot analyses, revealed GAD 65-like and GAD 67-like immunoreactivity in rat and guinea pig ileum. Anti-GAD 65 antisera detected a major band of 65 kDa. Anti-GAD 67 antisera detected a major band of 55 kDa, which probably represented a breakdown product, and a minor band of 67 kDa. Analysis of immunoblot extracts of rat and guinea pig ileum revealed more GAD 67-like than GAD 65-like immunoreactivity. GAD enzymatic activity was high in the rat and guinea-pig brain, and low in the whole and dissected ileum. These results demonstrate that both GAD 65 and GAD 67 genes are transcribed and translated in the ileum of three rodent species and lend indirect support to the postulate that GABA is synthesised by neurons of the ENS and intestinal endocrine cells. PMID- 8690848 TI - Preliminary observations on the use of midodrine in treating orthostatic hypotension in familial dysautonomia. AB - Midodrine, a peripheral alpha-adrenergic agonist, was evaluated in 7 female and 2 male patients with familial dysautonomia (FD), a disorder characterized by decreased sympathetic innervation. Prior to and after three months of midodrine treatment, each patient's response to postural change was assessed by arteriosonde readings of blood pressure and heart rate, corrected QT-interval measurements, Doppler evaluation of renal blood flow and circulating atrial natriuretic peptide (ANP) levels. The initial midodrine dose (2.5 mg three times daily) was raised until subjective symptoms improved. Doses were reduced if patients felt jittery or developed erect hypertension (systolic > 180 mmHg or diastolic > 110 mmHg). Midodrine, at an average dose of 0.25 mg/kg per day, improved subjective symptoms in all patients. With treatment, magnitude of blood pressure responses was variable. Although mean erect blood pressure did not increase significantly for the aggregate, it did increase in six of nine patients. In addition, the QTc interval normalized and erect renal perfusion improved. Changes in supine mean blood pressure and supine circulating ANP correlated directly. We judge midodrine to be useful in management of orthostatic hypotension in patients with familial dysautonomia. PMID- 8690849 TI - Neural control of penile erection in the rat. AB - The role of autonomic and somatic neural pathways involved in the control of penile erectile tissue was investigated in an in vivo rat model. Intracavernous pressure (ICP) changes were recorded during single or combined electrical stimulation of peripheral nerves in anesthetized rats. Stimulation of the pelvic and cavernous nerves elicited similar ICP increases. Ganglionic blockade abolished the response to pelvic nerve stimulation. Stimulation of the hypogastric nerve, the sensory or motor branches of the pudendal nerve, or the paravertebral sympathetic chain at L4-L5 by themselves did not produce any change in ICP. Stimulation of some of these nerves caused changes in ICP when combined with cavernous nerve stimulation. Stimulation of the paravertebral sympathetic chain reduced the ICP increases elicited by cavernous nerve stimulation. A decrease in ICP in response to cavernous nerve stimulation was also elicited by stimulation of the peripheral cut end of the sensory branch of the pudendal nerve or in paralyzed rats, the motor branch of the pudendal nerve. After sectioning the two branches of the pudendal nerve, stimulation of the sympathetic chain still reduced the ICP increase in response to cavernous nerve stimulation. Stimulation of the motor branch of the pudendal nerve during erection elicited by cavernous nerve stimulation was responsible for an additional ICP increase, which reached suprasystolic values. The present study confirms a proerectile role for parasympathetic pathways. Sympathetic fibers conveyed in both branches of the pudendal nerve exert an antierectile role in the rat. We identified an antierectile sympathetic outflow, originating in the caudal sympathetic chain, the anatomical arrangement of which remains unknown. In this model, penile erection appeared to be dependent on the recruitment of sacral parasympathetic outflow. Additional recruitment of efferent somatic fibers present in the motor branch of the pudendal nerve could participate in more rigid erection. This study provides new information about the organization of the pathways through which the rat penis is innervated, and would be of interest to investigators in the field of male sexual function. PMID- 8690850 TI - Pupillary and cardiovascular responses to the cold-pressor test. AB - Little is known about the structures and mechanisms involved in the autonomic response to sensory and nociceptive stimulation. In this study, we recorded simultaneously pupil diameter, blood pressure, heart rate and pain levels during a cold-pressor test in 10 healthy subjects. The aim was to evaluate the different components of the Autonomic Nervous System involved in the response to a thermal painful stimulus. A biphasic pupillary response was observed: an initial, short lasting mydriasis, followed by a miotic phase, this latter characterized by rhythmic fluctuations of pupil diameter. The blood pressure response was monophasic with a moderate increase observed from the second minute of the test. Pain intensities remained stable on medium-high levels throughout the test. The topical application of thymoxamine and homatropine clarified some aspects of the pupillary response. The systemic administration of naloxone suggested a role of opiates in the modulation of pupillary and cardiovascular response to the cold pressor test. PMID- 8690851 TI - Excitatory amino-acid receptors contribute to carotid sinus and vagus nerve evoked excitation of neurons in the nucleus of the tractus solitarius. AB - To determine the role of excitatory amino-acid (EAA) receptors in afferent evoked excitation of neurons in the nucleus of the solitarius (NTS), responses of NTS neurons to activation of visceral afferent inputs were examined before and during iontophoretic application of the broad spectrum EAA receptor antagonist kynurenate (KYN). Iontophoretic application of KYN, at doses which attenuated glutamate but not substance P or acetylcholine evoked discharge, inhibited carotid sinus nerve (CSN) and vagus nerve evoked discharge. KYN attenuation of evoked responses was similar whether the evoked input was monosynaptic (CSN evoked discharge reduced by 50 +/- 6% (mean +/- SE; n = 5); vagus nerve evoked discharge reduced by 45 +/- 4%, n = 6) or polysynaptic (CSN evoked discharge reduced by 48 +/- 6%, n = 6; vagus nerve evoked discharge reduced by 43 +/- 3%, n = 8). Spontaneous action potential discharge rate was reduced during KYN iontophoresis in 6 cells (1.8 +/- 0.4 spikes/s vs. 0.7 +/- 0.2 spikes/s). Iontophoretic application of a structural analogue of KYN which has no EAA receptor antagonist properties, xanthurenic acid, had no effect on glutamate, CSN or vagus nerve evoked discharge. Iontophoretic application of KYN reduced the action potential discharge evoked by activation of the carotid body chemoreceptors by 52 +/- 2% in 5 cells tested. The results demonstrate that excitatory amino-acid receptors are involved in visceral afferent evoked activation of NTS neurons. Furthermore, since both mono- and poly-synaptic inputs were attenuated, these receptors appear to be utilized at multiple levels of afferent integration within NTS. PMID- 8690852 TI - The relation of emotional behavior to plasma catecholamines, cortisol and ventricular arrhythmia. AB - Hypothalamic stimulation applied through chronically implanted electrodes elicits several kinds of emotional behavior in conscious cats. We chose 3 kinds of emotional behavior, i.e., restlessness, threat and searching-biting. Under lightly anesthetized condition, we examined the changes of E, NE, DA and cortisol levels in arterial plasma and the cardiovascular responses (changes of systolic and diastolic blood pressure, heart rate and the occurrence of poststimulus ventricular arrhythmia) associated with electrical stimulation of specific sites within the hypothalamus. Both in restlessness and threat groups, elevation in systolic blood pressure was significantly greater and also the occurrence of ventricular arrhythmia and elevation in diastolic blood pressure tended to be greater than in the searching-biting group. Plasma E, NE, DA and cortisol increased significantly in restlessness and threat groups but remained unchanged in searching-biting and control groups. The ratios of changed values in catecholamines: delta E/delta NE, delta E/delta DA or delta NE/delta DA were not significantly different between any groups of emotional behavior. Furthermore, in the restlessness group, delta E, delta NE and delta DA all showed significant correlation with both the number of ventricular arrhythmia and changes of diastolic blood pressure; and the number of ventricular arrhythmia showed significant correlation with both the changes of diastolic blood pressure and heart rate. None of these correlations was observed in the threat or searching biting group. These results suggested that restlessness and threat behaviors were more closely related to stress response than searching-biting behavior in cats. The differences in the endocrine and cardiovascular responses between restlessness and threat behavior were also discussed in the paper. PMID- 8690853 TI - The N-methyl-D-aspartate receptor pathway is involved in hypoxia-induced c-Fos protein expression in the rat nucleus of the solitary tract. AB - Immediate early genes, like c-fos, are believed to be involved in triggering the expression of other genes such as those involved in the synthesis of neurochemicals. Exposure of unanesthetized rats to oxygen deprivation induces activation of the c-fos gene within the nucleus tractus solitarius, resulting in expression of fos-like immunoreactive protein (Fos). Prior administration of MK 801, a nonselective antagonist of the N-methyl-D-aspartate (NMDA)-sensitive glutamate receptor (1 or 2 mg/kg), significantly attenuated but did not completely block hypoxia-induced Fos expression. However, blockade of muscarinic receptors by atropine sulfate (2, 10 or 25 mg/kg) had no measurable effects on Fos expression induced by oxygen deprivation. These results suggest that an NMDA receptor signalling pathway is partly involved in programming the expression of early response genes that regulate various aspects of the response to oxygen deprivation. PMID- 8690854 TI - 'Aortic baroreceptor' neurons in the nucleus tractus solitarius in rats: convergence of cardiovascular inputs as revealed by heartbeat-locked activity. AB - Rat aortic depressor nerve (ADN) contains only baroreceptor afferents. We identified 'aortic baroreceptor' neurons in the nucleus tractus solitarius (NTS) as those responding to electrical stimulation of the ADN and attempted to demonstrate convergence of cardiovascular mechanoreceptor inputs in these 'baroreceptor' neurons. In chloralose-urethane-anesthetized rats, ADN stimulation evoked either short or long latency responses (SLR, LLR) in 193 neurons of the NTS. 28 (SLR, 15; LLR, 13) demonstrated ongoing activities with cardiac rhythm despite the fact that the ADN had been cut peripherally. In 12 (SLR, 5; LLR, 7) of the 28 neurons, heartbeat-locked activity was abolished by carotid occlusion (CO), and augmented by methoxamine-induced blood pressure elevation, indicating that the heartbeat-locked activity originated from carotid sinus baroreceptors (CSB). In 11 neurons (SLR, 6; LLR, 5), the heartbeat-locked activity was not affected by CO but was abolished by topical application of lidocain on the ipsilateral cervical vagus, suggesting that the heartbeat-locked activity originated mostly from cardiac mechanoreceptors. The origin of the heartbeat locked activity of the remaining 5 neurons could not be determined. The onsets, as well as peaks of the heartbeat-locked activity of vagal origin appeared significantly earlier than those of CSB origin. In conclusion, NTS neurons receive converging projection not only from the two major arterial baroreceptors but also from the arterial baroreceptors and cardiac mechanoreceptors, thereby integrating sensory information of vascular and cardiac origins. PMID- 8690855 TI - Periodicity, amplitude and width of synchronized cardiac sympathetic nerve activity in anaesthetized cats. AB - Using a recently developed method, we studied periodicity, amplitude and width of synchronized cardiac sympathetic nerve activity (CSNA) at various intervals of periodic baroreceptor input in anaesthetized cats. ECG, aortic pressure and CSNA were recorded when cardiac interval was changed by artificial pacing, or when the aortic nerve was stimulated after baroreceptor denervation. The periodicity of synchronized CSNA showed mainly two modes: one was 8-14 Hz rhythmicity (Tc) and the other was related to cardiac cycle (Tb). The Tc mode was almost constant and independent of cardiac interval or stimulation. The probability of the Tc mode increased as pacing interval increased. The Tb mode reflected the interval of inhibition in CSNA due to pulsatile baroreceptor input. The mode of inhibitory rhythm (Ts) related to the stimulation of the aortic nerve was almost constant and independent of the stimulation interval. The probability of the Ts mode was highest at a 250-ms interval and decreased with increase in stimulus interval. The mean peak height or mean peak width did not changed significantly during pacing the heart at various intervals nor after baroreceptor denervation. The peak height and peak width had a significant linear relationship at any cardiac interval or after baroreceptor denervation, whereas no relationship between the peak-to-peak interval and the peak height or peak width was found. These results indicate that the cardiac-related rhythm is produced by inhibition of transmission of the fundamental rhythm by periodic baroreceptor input. Our results suggest also that the amplitude and periodicity of synchronized CSNA are separately regulated. PMID- 8690856 TI - Postvagotomy changes in neurogenic plasma extravasation in rat bronchi. AB - The present study was carried out to test if plasma extravasation induced by capsaicin (90 micrograms/kg) in the bronchi of Sprague-Dawley rats could be reduced 10-30 min (0 day), 20-24 h (1 day), 3, 7 or 14 days after unilateral midcervical vagotomy. The second aim of this study was to demonstrate if substance P (3 micrograms/kg) could intensify neurogenic plasma extravasation in the bronchi in which sensory innervation was partially deprived by vagotomy. In the rats 0 days after vagotomy (0 days postvagotomy) that received capsaicin, plasma extravasation in the mainstem and secondary bronchi ipsilateral to vagotomy did not decrease. Capsaicin-evoked plasma extravasation in the secondary bronchi ipsilateral to vagotomy decreased significantly 1, 3, 7 and 14 days after vagotomy as compared with that of 0 days postvagotomy. Differences in extravasation between the secondary bronchi of the two sides were usually significant in animals 3, 7 or 14 days postvagotomy. The effect of unilateral vagotomy on plasma extravasation in the mainstem bronchi was variable. Plasma extravasation produced by substance P in the mainstem and secondary bronchi of rats 0 days postvagotomy was similar to that of unoperated rats receiving either capsaicin or substance P. Unilateral vagotomy did not decrease the amount of substance-P-induced plasma extravasation in the mainstem or secondary bronchi ipsilateral to vagotomy in rat groups 1, 3, 7 or 14 days postvagotomy as compared with that of their contralateral bronchi. This study suggests that the secondary bronchi were the chief location of the bronchial tree that could be desensitized after unilateral cervical vagotomy to stimulation by the irritant capsaicin. This desensitization developed within 1 day after vagotomy, therefore the capsaicin evoked neurogenic inflammation in the bronchi of the vagotomized side was reduced. Exogenous substance P resulted in mucosal edema and degranulation of goblet cells in the bronchi of both vagotomized and opposite sides. The number of mediator-sensitive blood venules did not decrease following vagotomy operation. It is suggested that substance P was insufficient after vagal denervation, but substance-P receptors on the endothelial cells and goblet cells in the denervated regions were still operative. PMID- 8690857 TI - c-Fos expression in brain in response to hypotension and hypertension in conscious rats. AB - Hypotension- and hypertension-evoked expression of the protein product, Fos, of the immediate early gene c-fos was assessed throughout the rat brain as an approach for describing the neuronal populations that respond to alterations in arterial blood pressure. Conscious, chronically catheterized rats were treated with the vasoconstricting drug phenylephrine or the vasodilatating drug hydralazine to increase or decrease, respectively, arterial pressure by approx. 40 mm Hg for 90 min. Rats were then anesthetized, fixed by vascular perfusion, and sections representing the entire brain were processed for the immunocytochemical localization of Fos. In control rats treated with isotonic saline, few Fos-positive neurons were observed. In contrast, phenylephrine and hydralazine treatments resulted in different, yet reproducible, patterns of Fos expression in the brain, with hydralazine evoking Fos expression in more brain regions than phenylephrine. Brain regions containing Fos-positive neurons in rats treated with hydralazine included nucleus tractus solitarius, area postrema, caudal ventrolateral medulla, rostral ventrolateral medulla, bed nucleus of the stria terminalis, amygdala, paraventricular nucleus, supraoptic nucleus, subfornical organ and the Islands of Calleja. The nucleus tractus solitarius, paraventricular nucleus and the amygdala also contained Fos-positive neurons in phenylephrine-treated rats, although the number of Fos-positive neurons was always less than that noted in the hydralazine-treated rats and the location of Fos-positive neurons within these regions tended to differ between treatments. These results generally fit within an emerging understanding of brain circuitry underlying cardiovascular regulation. PMID- 8690858 TI - [Perinatal risk factors and motor deficiency due to cerebral palsy]. AB - Despite improvement in perinatal care, the prevalence of cerebral palsy has not decreased in France, Sweden, the United Kingdom or Australia. Based on a review of recent publications, the course of cerebral palsy can be partially explained by the increase in risk among very low birthweight and very pre-term infants whose survival is now better. Until recently, many publications have supported the hypothesis that asphyxia at birth was the major cause of cerebral palsy. However, these results have been widely questioned; the role of asphyxia remained unclear. In 1993 and 1994, several publications showed that there is a significant relationship between asphyxia and cerebral palsy, but that the role of asphyxia was overestimated in the past. The role of maternal and antenatal risk factors must also be taken into account. The prevention of cerebral palsy must be undertaken very early in pregnancy. PMID- 8690859 TI - [Role of the histologic examination in the diagnosis of cervical intraepithelial cancer]. AB - AIM: Retrospective analysis of preoperative histology examinations in patients with intra-epithelial cancer of the cervix. PATIENTS AND METHODS: Histological examination in 501 cases of cervical dysplasia leading to excision therapy. CONCLUSION: The major contribution of the histological examination is to confirm dysplasia suspected on the basis of cytology and/or colposcopy examinations. It also gives the stage of the dysplasia to orient treatment. However, the choice of a therapy cannot be based on the results of the preoperative histology examination alone. Decisions must be made after comparing all the colposcopy and histology findings. In advanced stage intra-epithelial cancer of the cervix or when the cytology and colposcopy examination give conflicting results, excision would be the preferred choice. These observations confirm the importance of the colposcopic examination. PMID- 8690860 TI - [Value of ultrasonography in utero-vaginal aplasia]. AB - The usefulness of pelvic ultrasound in the diagnosis of Rokitansky-Kuster-Hauser syndrome was evaluated retrospectively in 44 patients. Ultrasonography confirmed the diagnosis in 32%, however was wrong in 68% as a uterus was found, though generally described as hypoplasic. The reasons for the low sensitivity of ultrasonography are discussed. PMID- 8690861 TI - [Biology of solid cancers: breast cancer as an example. First part: genetic systems implicated in carcinogenesis]. AB - There are two main categories of genes involved in cancer: protoconcogenes and tumor suppressor genes. The development of cancer can require the production of several successive gene accidents within a given cell. Most of these alterations appear to be somatic changes. Only one of these two steps would involve germinal processes and only in hereditary tumors. When altered, these genes, implicated in cell proliferation, differentiation and normal cell death, contribute to the initiation and/or the progression of tumors. Other genes have an indirect effect on the malignant transformation and thus complete the action of oncogenes and suppressor genes at certain stages of cancerogenesis. The genes implicated in individual susceptibility to cancer is an example (genes coding for DNA repair enzymes and for proteins which inactivate exogenous cancerogenenic agents. Others are genes coding for growth factors and angiogenic factors, genes involved in metastatic dissemination including those which code for proteases and adherence proteins, and finally genes affecting chemoresistance. PMID- 8690862 TI - [Biology of solid cancers: breast cancer as an example. Second part: gene disregulation in breast cancer]. AB - Several studies have been conducted to identify and determine the nature of genetic anomalies leading to breast cancer. The most frequent genetic anomalies observed in breast cancer are genetic amplification of proto-oncogenes, and mutations and deletions which inactivate suppressor genes. Abnormal protein expression has also been detected. All these modifications of the cell genome could be useful in screening, diagnosis and prognosis of breast cancer, and in the long-term, in developing new therapeutic strategies. PMID- 8690863 TI - [Epidemiology of fetal deaths in the Seine-Saint-Denis perinatal survey]. AB - OBJECTIVE: To analyse the epidemiological characteristics of antepartum stillbirths. DESIGN: A population based cases-cohort study in a limited geographical area, the department of Seine-Saint-Denis, France. Prospective collection of cases and controls between the 1989-10-01 and 1992-09-30, and retrospective collection of data. SUBJECTS: All antepartum stillbirths of 28 weeks gestation of greater, except lethal malformations and multiple pregnancies. RESULTS: 273 antepartum stillbirths were collected during the 3-year study period (52, 2% of the perinatal deaths). The causes were mainly, abruptio placenta and cordonal causes; however, unexplained antepartum stillbirth was the most important group (38, 8%). Hypotrophy was present for 49.5% of cases versus 10.1% of controls (p < 0.001). It was associated with death whatever cause or gestational age, particularly in unexplained antepartum death (54.7%). In univariate analysis, the usual risk factors including obstetrical history, socio economic characteristics, obstetric care and country of birth were associated with death. But, in multivariate analysis, only "no pregnancy declaration", "deficient obstetric care", "history of stillbirth", "born in Black Africa" and "born in DOM-TOM" were significantly associated with death. CONCLUSION: More than one half of perinatal deaths concern antepartum stillbirth; the causes have remained unchanged for twenty years and unexplained antepartum stillbirth remains the most important group. The principal risk factor is fetal hypotrophy. The other significant risk factors after multivariate analysis are deficient obstetric care and birth in Black Africa or in the DOM-TOM. To propose prevention actions, progress is necessary in in utero diagnostic of hypotrophy and in the understanding in the risk associated with country of origin. PMID- 8690864 TI - [Maternal corticotherapy . Pharmacology and effect on the fetus]. AB - There are many indications for steroids in pregnant women including asthma, chronic inflammatory diseases and disseminated lupus erythematosus. Prednisone and prednisolone, the preferred drugs, are inactivated by the placenta so that fetal exposure is minimal. The effect of corticosteroids on the fetus has been studied by a number of workers. The earliest studies in the sixties reported various adverse effects (prematurity, intra-uterine growth retardation), but cannot always be used to analyze the effect of steroid drugs, often used at uneffective doses versus that of the underlying pathology. In the more recent studies conducted since 1980, steroids were given at effective doses and show that maternal-targeted corticosteroids are more beneficial than detrimental for the fetus. Indeed, steroid drugs have no teratogenic effect in man and carry no risk of fetal intoxication at therapeutic doses. The long-term risk remains to be evaluated. PMID- 8690865 TI - [Mass screening of gestational diabetes using O'Sullivan's test in a hospital consultation. Experience in Rennes]. AB - The aim of this work was to study the predictive value of 50 gram glucose O'Sullivan test for systematic screening of gestational diabetes. To confirm the diagnostic the test positivity was controlled by a 100 g, 3 hours oral glucose tolerance test. During a 12-month period, 751 women were included in the 7th month pregnancy consultation. The O'Sullivan test was positive in 18% of cases. The oral glucose tolerance test confirmed the diagnostic in 14% of these positive tests. The frequency of gestational diabetes was about 2.5% in this population. We compared then the results of the test with the other available screening modes. For this purpose, we analysed retrospectively 50 gestational diabetes diagnosed during the same time in the entire pregnant population of the clinic. In our experience, the O'Sullivan's test is a reliable and useful test. It is easy to perform. Less women are selected than in analysis of risk factors (18% versus > 30%), and with better sensitivity. PMID- 8690866 TI - [Prolactinoma and pregnancy. Six cases and review of the literature]. AB - Prolactinoma is the most frequent of secreting pituitary adenomas. It is often discovered among women of childbearing-age presenting an association of amenorrhea and galactorrhea. Data in the literature from large series indicate the current risks of interaction between prolactinoma and pregnancy. Risks have been overestimated in the past and it is now recognized that pregnancy can be allowed providing strict follow-up is assured. Dopaminergic drugs have no teratogenic side-effects and are known to allow tumoral control and recovery of fertility in the majority of cases. The use of these medications explains the reduction of indications for surgery. Microprolactinomas are highly influenced by pregnancy and can even lead to tumor retrogression. Macroprolactinomas give complications more often, and require a good tumor control and a rigorous follow up. PMID- 8690868 TI - [Does asymptomatic amniotic infection in the second trimester really exist?]. AB - OBJECTIVE: Our purpose was to evaluate the incidence of asymptomatic amniotic fluid infection. STUDY DESIGN: One hundred fifty-four amniotic fluid samples obtained at the second trimester between 14 and 27 weeks gestation were studied by Gram stain with bacteriological cultures and detection of mycoplasm species and Chlamydiae trachomatis. Transabdominal amniocentesis for caryotyping were carried out in 151 health patients with intact membranes and without preterm labor or signs of infectious (3 dizygotic twin pregnancies). RESULTS: One hundred forty-seven complete microbiologic examinations were performed (Gram stain examination white-cell count, quantitative aerobic and anaerobic cultures). Commercial texts for Mycoplasma hominis, Ureaplasma urealyticum and Chlamydiae trachomatis were negative. Three patients had rare microorganisms, coagulase negative staphylococcus (30 and 50 bacteria per ml) and alpha-hemolytic streptococcus (5 x 10(2) bacteria per ml). White cell count on amniotic fluids in 50 cases (32%) was less than 30 per ml. CONCLUSION: These findings appear to be in contradiction with recent data, suggesting the existence of intraamniotic infection in the early phase of the second trimester. Our data confirm the need for a cut-off level for white cell count to improve test sensibility. PMID- 8690867 TI - [Myasthenia and pregnancy. Two case reports]. AB - OBJECTIVE: Assess obstetrical care in rare cases of pregnant women with myasthenia. METHOD: Two personal cases led to a brief recall of the disease process and the literature and an assessment of proposed optimal care. RESULTS: Both pregnancies were carried to term without aggravation of the myasthenia. According to the data in the literature, pregnancy has a variable effect on myasthenia (1/3 stability, 1/3 improvement, 1/3 aggravation). The risk of decompensation during expulsion is great and the patient's efforts should be limited, although cesarian section is not required (excepting classical surgical indications). Peridural anaesthesia is not required (excepting classical surgical indications). Peridural anaesthesia is recommended because it reduces patient fatigue and facilitates instrumental extraction. Nursing is authorized except in case of severe episodes with a major rise in antibody levels. Pre-eclampsia was reported in only 5 cases: both maternal and fetal risk is high in such cases requiring intensive care. Fetal risks include rare neuro-muscular disease in which prognosis is poor and in 15 to 20% of the cases, neonatal myasthenia. CONCLUSION: Myasthenia is an autoimmune disease rarely occurring in young women of childbearing age. Care for pregnant women with myasthenia requires close collaboration between the different specialists. PMID- 8690870 TI - [Severe preeclampsia. Principal management modalities before patient transfer]. AB - Preeclampsia is relatively frequent during pregnancy. The occurrence of complications implies referral to a specialized center for optimal care of both mother and fetus. The transfer of these patients is very critical with risk of worsening the mother's status. Management before referral aims to stabilize material clinical status, requiring precise clinical assessment, treatment of severe hypertension or pulmonary edema, and prevention or treatment of eclampsia. The management of oliguria and the tracheal intubation are associated with specific problems. Fetal wellbeing is assessed before and during emergency treatments of maternal disorders. PMID- 8690869 TI - [Severe preeclampsia. Analysis of a case with fatal outcome]. AB - We report a case of preeclampsia presenting initially as a moderate hypertension, and complicated over a ten-day period by eclampsia, retinal hemorrhage, cerebral and hepatic subcapsular hematomas, HELLP syndrome, disseminated intravascular coagulation and renal failure. Fatal outcome was related to cerebral death and rupture of the liver hematoma. The case analysis points out inaccurate initial management: probable misdiagnosis of epigastric pain related to subcapsular hematoma, ineffective antihypertensive therapy, aspiration of the gastric content after benzodiazepine treatment of eclampsia, transfer of the patient without stabilisation of her clinical status. PMID- 8690872 TI - [Term abdominal pregnancy with delivery of a living child. Two case reports]. AB - The lack of antenatal care and the growing number of genital infections make ectopic pregnancy a current unrecognized pathology in areas with few physicians. Such pregnancies exceptionally reach term but delivery of a live infant is rare. We report two cases in which echographic diagnosis of abdominal pregnancy was followed by the delivery of a live child. In both cases, fetal hypotrophy led to neonatal death. Maternal outcome was however favorable with surgery to reduce the risk of hemorrhage. Safe childbearing requires improved preventive measures and better maternal sanitary conditions and education, particularly important for subjects living in areas poorly provided with health facilities. PMID- 8690871 TI - [Fetal and neonatal immune thrombocytopenias]. AB - Fetal and neonatal immune thrombocytopenias with platelet count less than 150.10(9)/l, result from transplacental passage of maternal platelet-specific antibodies. The main risk of these diseases is severe brain damage or death due to intracranial hemorrhage. Prevention and screening are difficult because of the lack of predicting factors. Only some women are at high risk of fetal thrombocytopenia (HLA DRW 52a HPA-la negative women or women with a previous history of immune thrombocytopenic purpura and having platelet-specific autoantibodies). Antenatal diagnosis and therapy have altered the natural course of fetal alloimmune thrombocytopenia. No prenatal treatment has proved to be effective in autoimmune thrombocytopenia and prenatal diagnosis by fetal blood sampling is controversial. A better knowledge of the pathogenesis of gestational incidental thrombocytopenia in otherwise healthy pregnancies, could define a group at high risk of fetal thrombocytopenia. PMID- 8690873 TI - [Break and loss of the parietal wall suture needle. A rare complication of laparoscopic surgery]. PMID- 8690875 TI - Pathways linking parental divorce with adolescent depression. AB - This article examines the intervening pathways linking parental divorce with adolescent depression, using both cross-sectional and prospective data from a study of high school students in the Boston metropolitan area. Overall, findings reveal that parental divorce is linked with adolescent depression in two ways: (1) it is a source of numerous secondary problems and stresses that are causally related to depression, and (2) it alters youths' reactivity to these stresses, in some cases enhancing, but in other cases mitigating, their depressive effects. Analyses demonstrated the central role of economic hardship in linking family status with depression, with the strength of this indirect pathway partly attributable to the greater vulnerability of youths in single-parent families to financial stresses. In contrast, family conflict did not account for the distress of youths in single-parent families, largely because of their immunity to the effects of such conflict. Finally, prospective data failed to support the hypothesis that differences between youths in single-parent and intact families predate the divorce. PMID- 8690874 TI - The effects of psychiatric disorders on the probability and timing of first marriage. AB - While studies of psychopathology have begun to consider social consequences of psychiatric disorders during the past decade, marriage has received little attention, despite evidence that it influences life quality. The present paper examines the effects of clinically significant psychiatric disorders on the probability and timing of first marriage and whether the relationships between psychiatric disorders and marriage differ by type of disorder, gender, and birth cohort. Psychiatric disorders are found to have substantial effects on entry into first marriage. These effects are the same for men and women across all cohorts. Individual psychiatric disorders have similar effects on entry into first marriage. Psychiatric disorders are positively associated with early first marriage, which is strongly related to adverse consequences, and negatively associated with on-time and late first marriage, which are related to benefits such as financial security and social support. These results highlight the importance of early interventions for psychiatric disorders-if not for the purposes of primary prevention, then for the purposes of preventing the cumulation of adversities that occur secondarily through early marriage. PMID- 8690876 TI - Caregiving as reciprocal exchange in families with seriously mentally ill members. AB - Caregiving for people with chronic illnesses, including serious mental illnesses, has generally been seen as support that a care provider gives to a dependent receiver. In contrast, this research views caregiving as a process of mutual exchange. It tests the hypothesis that how much support a mentally ill family member receives depends on how much support they provide to other family members. We also examine whether or not reciprocity depends on the role relationship between recipients and providers of care, the level of patient symptomatology, coresidence, and several sociodemographic characteristics. The sample includes 66 patients who have at least one sampled parent or sibling. The results indicate that the amount of support patients give parents and siblings is very strongly associated with how much support they receive from family members. In comparison to the other variables considered here, patient support provision is by far the best predictor of the amount of family support. These results indicate that it is worthwhile to examine caregiving in families with a member who is seriously mentally ill as a process of mutual exchange. PMID- 8690877 TI - Physicians' discourses on malpractice and the meaning of medical malpractice. AB - Recent analyses of the professions have considered the question of the changing nature of professional power. This study is an interpretive analysis of the meaning of physicians' discourse in the face of a perceived challenge to the traditional boundaries of clinical practice from malpractice suits. The data for this analysis were drawn from interviews with physicians from three specialties and from documents produced by the AMA/Specialty Society. Four modes of discourse were observed: (1) affective lament; (2) rejection of tort law; (3) complaints about a deterioration in the culture of clinical practice; and (4) a call for active campaigning. Analysis of the modes of discourse highlights both the ways in which professional power is subjected to challenge and the forms of political, financial, and cultural struggle that professional organizations and individuals engage in to resist such challenges. PMID- 8690878 TI - Changes in physicians' attitudes toward AIDS during residency training: a longitudinal study of medical school graduates. AB - Understanding the impact of training on the development of physicians' attitudes toward AIDS is important to furthering our knowledge of the mechanisms through which socialization affects professional outlook, as well as promoting an adequate supply of providers to treat people with AIDS (PWAs). This prospective panel study collected data on 383 physicians at two critical stages: as fourth year medical students and as third-year residents. Aspects of residency training (e.g., residents' morale and positive faculty role models) were the most powerful predictors of increase in willingness to treat PWAs. Decline in willingness was primarily a product of negative social attitudes-homophobia and IVDU-phobia (aversion to intravenous drug users). Cynicism toward patient care acted as a trigger, activating the negative effects of IVDU-phobia; having an acquaintance who is HIV positive mediated the negative impact of homophobia. Notably, cynicism was associated with basic aspects of training (specific characteristics of the faculty and of the educational milieu). The findings support a view of socialization as a pervasive process implicating intrinsic aspects of training and having an impact on a broad spectrum of outlooks. Accordingly, interventions must address structural characteristics that transcend AIDS-specific concerns. PMID- 8690879 TI - Asian immigrants and the stress process: a study of Koreans in Canada. AB - The stress process paradigm is one of the most widely held perspectives in the sociology of mental health. While this model has been applied to a large number of research problems, relatively little work has examined whether the paradigm can assist in understanding the link between socially induced stressors and their consequences for the mental health of immigrants. In this paper, we employ a stress process formulation to examine the interplay among stressors, psychological and social resources, and psychological distress among a large sample of Korean immigrants living in Toronto, Canada. Data from a longitudinal study of over 600 respondents indicate that the stress process paradigm provides a useful perspective for understanding how chronic stressors associated with the immigration experience manifest themselves in psychological distress. Our results suggest that social and psychological resources have important deterrent effects on the experience of stressors and their subsequent distressful consequences. Ethnic social support and mastery are especially important factors in this process. PMID- 8690880 TI - Burn infection studies. PMID- 8690881 TI - The Second National Prevalence Survey of infection in hospitals--overview of the results. AB - This study was designed to assess the overall prevalence of infection among the patients in hospitals in the UK and the Republic of Ireland. Patient data were collected and entered directly into a portable Olivetti (A12 notebook) computer with a custom-designed program (Epi-Info version 5.01). The statistical analysis was performed using the Statistical Package for Social Sciences software (SPSS). In all, 37,111 patients from 157 centers were studied, and a mean hospital acquired infection (HAI) prevalence rate of 9.0% (range 2-29%) was calculated. HAI rates were higher in teaching hospitals (11.2%) than in non-teaching hospitals (8.4%) P < 0.001. Four major sites of infections--infections of the urinary tract (23.2%), surgical-wound infections (10.7%), lower-respiratory tract (22.9%) and skin infections (9.6%)--accounted for 66.5% (2559 of 3848) of the total infections identified. PMID- 8690882 TI - Kitchens as a source of Aspergillus niger infection. AB - In this study we investigated the epidemiology of a cluster of cutaneous infections owing to Aspergillus niger, which occurred in neutropenic patients in a bone marrow transplant unit. Heavy environmental contamination with the mould was found in the ward kitchen adjacent to the unit. The clinical and environmental isolates were typed by random amplification of polymorphic DNA (RAPD), which showed one of the patients was infected with the same strain as that isolated repeatedly from the kitchen area. In another case, contaminated stockinette material was implicated as the source of infection. Thorough cleaning of the ward kitchen resulted in no further cases on the unit. This highlights the fact that aspergilli may spread to patients by air, food or other vehicles, and underlines the importance of searching for a source and ensuring high levels of hospital hygiene are maintained. PMID- 8690883 TI - Tracheal colonization with Sphingomonas paucimobilis in mechanically ventilated neonates due to contaminated ventilator temperature probes. AB - Sphingomonas paucimobilis was isolated from tracheal secretions of a total of 85 mechanically ventilated babies in a neonatal intensive-care unit (NICU) during a two-year-period. None of the neonates developed pneumonia or sepsis. After each increase in the fluctuating number of S. paucimobilis isolates, extra attention was paid to hand hygiene and to the maintenance of the ventilation equipment. This resulted in a reduction of the frequency of isolation each time. Cultures of all liquids in use and of the ventilation equipment were negative on several occasions. Fifteen months after the start of the outbreak, the NICU was moved to another building, and some older ventilation equipment was abandoned. After a period of six weeks without problems, S. paucimobilis was isolated in association with at least four ventilators. A new investigation showed that the ventilator temperature probes were the source of contamination. Once effective sterilization procedures for the temperature probes were introduced no new cases appeared, until a spare ventilator with an unautoclaved temperature probe was accidentally used and this caused contamination of one child. After correction, no further cases have occurred to date. The clonal relatedness of the outbreak isolates from patients and from ventilator temperature probes was documented by fingerprinting with the arbitrarily primed polymerase chain reaction. PMID- 8690884 TI - An unusual source for an outbreak of methicillin-resistant Staphylococcus aureus on an intensive therapy unit. AB - During a four-month period, six patients on an intensive therapy unit became colonized or infected with methicillin-resistant Staphylococcus aureus (MRSA). Four of these patients were colonized by the Epidemic MRSA strain 15 (EMRSA 15). The outbreak was characterized by the fact that all four of these patients were nursed in the same bed on the unit before acquisition of the organism. Investigation of the outbreak led the authors to believe that the source of the MRSA may have been the exhaust ducting of the adjacent isolation room ventilation system which allowed the organisms to enter the unit via a partially open window positioned above that particular bed. The cycle was broken once the ventilation system was repaired and the window above the bed was properly sealed. PMID- 8690885 TI - Coagulase-negative Staphylococci in Danish blood cultures: species distribution and antibiotic susceptibility. AB - The distribution and antibiotic susceptibility of coagulase-negative staphylococci (CoNS) isolated from blood cultures was examined in samples from hospitals covering most of Denmark. A total of 499 CoNS isolates were detected in 477 blood cultures from 340 patients and speciated as Staphylococcus epidermidis, 285; Staphylococcus hominis, 61; Staphylococcus haemolyticus, 43; Staphylococcus warneri, 12; Staphylococcus cohnii, 7; Staphylococcus saprophyticus, 4; Staphylococcus capitis, 2 and Staphylococcus lugdunensis, 1. Seventy-eight isolates could not be identified to species level and six were Micrococcus spp. In 108 (22.6%) blood culture sets, more than one CoNS strain were found, as detected by species identification, antibiogram and biotyping. Significantly more blood cultures from patients in university hospitals were drawn from central venous catheters. Comparing university and non-university hospitals, the overall antibiotic susceptibility among CoNS was only slightly different, except for methicillin and amikacin. The prevalence of methicillin-resistant strains was 35.1% in the university hospital strains vs. 25.3% in the non-university hospital strains. The overall prevalence of methicillin resistance was 32%. Great geographic variation in both species distribution and antibiotic resistance was observed. The high prevalence of S. epidermidis makes subtyping of this species important. PMID- 8690887 TI - Diagnostic value of Clostridium difficile cytotoxin assay. PMID- 8690886 TI - Varicella exposure in a neonatal intensive care unit: emergency management and control measures. AB - We describe an exposure of varicella zoster virus in our neonatal intensive-care unit and the emergency procedures instituted to prevent an outbreak. Fifty-seven infants and 129 staff members were exposed but none developed chickenpox. The measures included rapid identification of varicella antibody status in all neonates and those staff members with uncertain history of varicella infection; cohorting of exposed infants according to immune status; and prompt administration of varicella zoster immunoglobulin to susceptible patients. The recommendation of the American Academy of Pediatrics did not accurately predict the immune status of preterm infants, as only one of the eight susceptible infants would have qualified for immunoglobulin prophylaxis if their guidelines had been followed. Mass screening of all exposed infants using the varicella zoster enzyme linked immunosorbent assay (ELISA) test was the only reliable means of determining the immune status. Of the four risk factors evaluated for the prediction of antibody status: gestational age, postnatal age, birthweight and episodes of blood transfusion, only postnatal age was found to independently predict the immune status of our patients. Because varicella zoster susceptible staff members are difficult to identify on the basis of history, we suggest that prospective screening of staff in high-risk units be undertaken and vaccination with live varicella vaccine be offered to susceptibles. PMID- 8690888 TI - From thymic lineages back to hematopoietic stem cells, sometimes using homing receptors. PMID- 8690889 TI - Leukophysin: an RNA helicase A-related molecule identified in cytotoxic T cell granules and vesicles. AB - Leukophysin (LKP) is a 28-kDa protein of CTL and U937 monocytic cells that is located in the membrane of high density granules as well as lighter cytoplasmic granules or vesicles. mAbs to KLP were used to clone a full length cDNA clone with an open reading frame coding for a 235-amino acid polypeptide with a molecular mass of 24.3 kDa and two potential transmembrane regions. The nucleotide sequence was highly homologous to the 3' end of human RNA helicase A. Expression of the LKP was confirmed as a reverse transcriptase-PCR product that may be an alternately spliced product of RNA helicase A. The cDNA contained a repetitive motif that was similar to synaptophysin 1, a protein that is important for synaptic vesicle exocytosis. A polyclonal Ab directed against the 17 carboxyl terminal amino acids of LKP detected the same 28-kDa granule membrane protein as the D545, one of the mAbs used to clone the cDNA. In addition, the D545 mAb reacted strongly with the GST fusion protein of the bacterially expressed LKP cDNA. In confocal immunofluorescence studies, the anti-LKP peptide Ab reacted with granzyme A-negative granules and vesicles in CD8+ CTL lymphocytes from normal and Chediak-Higashi patients. Thus, based on the expression of the C terminal LKP epitope, vesicular structures an granules have been detected in CTL that are distinct from classical granzyme-containing cytolytic granules. PMID- 8690890 TI - Deficient CD4+ T cell proliferation in the class 1 MHC-restricted 2C TCR transgenic mouse. AB - A comparative study of immune function and marker expression of CD4+ T cells from MHC class 1-restricted 2C TCR-transgenic (2C+) and control transgene-negative littermate (2C-) mice was performed. While 2C+CD4+ T cells resembled memory T cells on the basis of CD44highCD45RBlow expression, the majority of 2C-CD4+ T cells were of the CD44lowCD45RBhigh naive phenotype. Slightly lower levels of TCR beta and CD3 were found on 2C+CD4+ T cell than 2C-CD4+ T cells. Vigorous proliferation by 2C-CD4+ T cells was observed upon stimulation with 1) anti-CD3 mAb presented through the FcR of macrophages; 2) immobilized (plate-bound) anti CD3 + anti-CD28 mAbs; and 3) PMA + ionomycin. In marked contrast, all three mitogenic stimuli stimulated highly deficient proliferative responses by 2C+CD4+ T cells. However, significant IL-2 production was detected both in anti-CD3 and in PMA + ionomycin-stimulated cultures of 2C+CD4+ T cells. While intracellular calcium in 2C-CD4+ T cells rapidly increased following anti-CD3 addition, no such increase was observed for similarly stimulated 2C+CD4+ T cells. Anti-CD28, PMA, and coculture with 2C-CD4+ T cells each failed to significantly correct the deficient 2C+CD4+ T cells proliferation as induced by anti-CD3. In addition, IL 2, IL-4, and IL-7 supplements also failed to reverse the deficient proliferation of 2C+CD4+ T cells despite expression of IL-2R component alpha-, beta-chains and the gamma-chain common also to IL-4R and IL-7R. Thymus CD4+8- T cells from the 2C transgenic mouse were similarly deficient in proliferation as spleen CD4+ T cells. A small subpopulation of CD4+ T cell from the 2C-transgenic mouse expressed the transgenic TCR alpha:beta heterodimer as detected by the 1B2 anti 2C clonotypic mAb; both 1B2+ and 1B2- subpopulations proliferated poorly in response to anti-CD3 and to PMA + ionomycin. These results raise the possibility that TCR engagement with MHC class 1 molecules during early intrathymic development can result in the emergence of CD4+ T cells characterized by unusual marker expression and function. PMID- 8690891 TI - Differential activation of phospholipase C-gamma 1 and mitogen-activated protein kinase in naive and antigen-primed CD4 T cells by the peptide/MHC ligand. AB - In this study, we determined the functional and biochemical differences in naive and primed CD4 T cells that expressed a TCR specific for the pigeon cytochrome c (pcc) peptide presented by I-Ek MHC class II molecules. Naive CD4 T cells expressing the transgenic TCR were isolated from the peripheral lymphoid organs of transgenic mice and stimulated with pcc peptide and IL-2 for 10 to 14 days. After this culture period, the Ag-primed cells were quiescent, as judged by the lack of expression of the early activation marker CD69, low expression of CD25 (IL-2R), and failure to incorporate thymidine. The primed cells required 10-fold less peptide than naive cells to achieve the same degree of proliferation and for the induction of CD69. Primed cells also mobilized calcium more efficiently with regard to Ag dose and magnitude of the response. The biochemical signal transduction events in naive and primed T cells were compared by stimulating them with different concentrations of pcc peptide presented by adherent Ek-transfected fibroblasts. It was found that tyrosine phosphorylation and activation of mitogen activated protein kinase (MAPK) in primed cells required 10-fold less Ag and occurred more rapidly and intensively. Interestingly, peptide stimulation induced tyrosine phosphorylation of phospholipase C (PLC)-gamma 1 exclusively in primed cells. RasGAP was also more efficiently tyrosine phosphorylated in primed cells. By contrast, Shc was tyrosine phosphorylated to the same extent in naive and primed cells. PI3Kp85 was not tyrosine-phosphorylated in naive and primed cells either before or after peptide stimulation. We propose that the higher sensitivity of the primed cells to Ag stimulation is most likely dependent, at last in part, on the more efficient activation of PLC-gamma 1, MAPK, and calcium dependent pathways. PMID- 8690892 TI - Antigen receptors on immature, but not mature, B and T cells are coupled to cytosolic phospholipase A2 activation: expression and activation of cytosolic phospholipase A2 correlate with lymphocyte maturation. AB - The Ag receptors on mature B and T cells are not coupled to the activation of cytosolic phospholipase A2 (cPLA2) and arachidonic acid release. Moreover, phorbol esters such as PMA, which can activate cPLA2 via mitogen-activated protein (MAP) kinase in most cell types, also failed to induce the release of arachidonate from mature cells, suggesting that the cPLA2 pathway may not be functional in mature lymphocytes. Interestingly, Western blot analysis revealed that cPLA2, which had previously been thought to be expressed ubiquitously, is not expressed in mature B or T cells and that cytosolic phospholipase A2 expression could not be up-regulated in lymphocytes following culture with a range of cytokines most likely to be involved in an immune response such as IL-1 alpha, IL-3, or TNF-alpha. In contrast, cPLA2 was shown to be expressed and activated in thymocytes and immature B cells under conditions in which ligation of the Ag receptors led to growth arrest and/or apoptosis. Taken together, these data suggest that cPLA2 does not play a role in Ag receptor-mediated lymphocyte activation, but may be involved in the molecular mechanisms underlying lymphocyte maturation and/or self tolerance by clonal deletion. PMID- 8690893 TI - Uncoupling IL-2 production from apoptosis and TNF production by changing the signal through the TCR. AB - T cells may discriminate between stimuli in a variety of ways, including the presence of cytokines or other costimulatory signals, the type of Ag (peptide, superantigen, or allorecognition), or the magnitude of the signal through the TCR. We have used anti-CD3 stimulation of T hybridomas to examine signals generated through the TCR in the absence of exogenous APCs. Soluble whole anti CD3, but not F(ab')2 anti-CD3, was able to stimulate the T hybridomas to produce IL-2. Plastic-bound anti-CD3, in contrast, stimulated TNF production, G1 arrest, and apoptosis by the T hybridoma. Engagement of the CD4 coreceptor on these cells had no effect on the overall pattern of signaling observed. Although TNF production was correlated with apoptosis, anti-TNF treatment did not prevent cell death or G1 arrest. The response of the T hybridoma to both forms of anti-CD3 included significant IL-2 production even at the lowest dose tested. However, soluble anti-CD3 at the highest dose tested elicited only minor apoptosis, while plastic-bound anti-CD3 elicited significant apoptosis even at the lowest dose. The difference in response was not evident at the level of phosphotyrosine proteins two min after cross-linking of the TCR. PMID- 8690894 TI - Evidence for the expression of HLAA-C class I mRNA and protein by human first trimester trophoblast. AB - In this study, evidence is provided that normal human first trimester extravillous trophoblast expresses class I HLA-C molecules in addition to HLA-G. cDNA from highly purified trophoblast cells obtained by flow cytometric sorting was amplified by reverse-transcriptase PCR using HLA locus-specific primers. The identity of the product was confirmed by Southern blotting and hybridization by a second HLA-C-specific oligonucleotide. HLA-C mRNA was clearly demonstrated in all trophoblast samples as well as in JEG-3 and BeWo choriocarcinoma cells. JAR choriocarcinoma cells did not express HLA-C. The presence of HLA-C protein in extravillous trophoblast was investigated using a panel of Abs: L31 is specific for heavy chains of all HLA-C alleles; Q1/28 reacts with all HLA class I products except HLA-G; HC-10 has preferential reactivity with HLA-B and HLA-C heavy chains. We performed 35S metabolic and 125I surface labeling of normal first trimester trophoblast and found abundant HLA-C intracellularly together with low levels of expression of both the beta 2m-associated forms and free heavy chains on the surface. Flow cytometric analysis of normal trophoblast confirmed the expression of a class I HLA molecule distinct from HLA-G by positive reactivity with Q1/28. Immunohistologic studies of first trimester placenta and the implantation site clearly showed expression of HLA-C in all extravillous trophoblast populations. Our results demonstrate the presence of two HLA class I molecules, HLA-G and HLA-C, on the surface of extravillous trophoblast. These results have implications in understanding how maternal uterine lymphocytes, notably the abundant NK-like cells, might recognize the implanting placenta. PMID- 8690895 TI - Frequency of VH81x usage during B cell development: initial decline in usage is independent of Ig heavy chain cell surface expression. AB - B cell development is marked by changes in the pattern of VH segment utilization. B cell precursors characteristically utilize a restricted set of VH segments, while mature B cell populations use a wide range of VH segments. VH81x is an example of a VH segment that is highly utilized in B cell precursors, but rarely utilized in mature B cells. We have developed an assay that allows us to determine the proportion of VDJH rearrangements that utilize the VH81x segment in DNA from selected populations of developing B cells. Consistent with previous observations, it was found that VH81x is utilized at a remarkably high frequency in primary B cell progenitors. The extent of overutilization was found to be identical during fetal and adult B cell development. Phenotypic analyses demonstrated that the decline in VH81x utilization begins at a stage before the expression of IgM on the cell surface and continues through later stages of B cell development. Strikingly, mutant mice that cannot express Ig heavy chain on the cell surface displayed a drop in VH81x utilization during both fetal and adult B cell development. Together, these data suggest that mechanisms other than cellular selection play an important role in determining the shift in VH segment utilization during B cell development. PMID- 8690896 TI - Accelerated immune response in transgenic mice expressing rat CD44v4-v7 on T cells. AB - Splice variants of the glycoprotein CD44 (CD44v) that confer metastatic behavior to noninvasively growing rat tumor cells are transiently expressed on lymphocytes during activation. A mAb directed against an epitope encoded by CD44 exon v6 blocks both metastasis formations and lymphocyte activation, implicating CD44v in normal immune function. To explore the nature of this function of CD44v, transgenic mice were generated that constitutively express rat CD44v4-v7 on thymocytes and peripheral T cells. The number of lymphocytes as well as the distribution of lymphocyte subpopulations were similar in nontransgenic and rat CD44v4-v7 transgenic mice. T cells of the transgenic mice, however, responded faster to activating stimuli, particularly during primary stimulations with T cell mitogens and T-dependent Ags in vivo and in vitro. This accelerated response depended on the expression of the transgene product, since a rat CD44v6-specific Ab reverted the response profiles of the transgenic mice to those of nontransgenic mice. Since the transgene gained in vivo and in vitro functional activity only upon antigenic stimulation, it is likely that CD44 variant isoforms are involved in the process of signal transduction during lymphocyte activation. PMID- 8690897 TI - Chemokines and T lymphocyte activation: I. Beta chemokines costimulate human T lymphocyte activation in vitro. AB - While chemokines primarily promote chemotaxis, it is apparent that these cytokines also modulate a number of other biologic activities, including adhesion, degranulation, cytotoxicity, and enzyme release. We demonstrate here that the beta chemokines, recombinant human macrophage inflammatory protein-1 alpha and -1 beta, RANTES (regulated upon activation, normally T cell expressed and secreted), and macrophage chemotactic peptide-1, are capable of directly costimulating purified human T cell and human T cell clone proliferation and IL-2 production in the presence of anti-CD3 mAb, but not phorbol esters, in vitro. This costimulatory activity was dose and donor dependent and required the presence of free extracellular calcium as well as endogenously produced IL-2. Chemokine treatment of human T cells in vitro increased the level of cell surface CD25 and soluble CD25. In addition, these chemokines enhanced both Ag- and alloantigen-specific T cell and T cell clone proliferation. This activity was further augmented in the presence of the CD28 ligand, B7-1. Neutralization analyses using chemokine-specific Abs revealed that endogenously produced chemokines are important costimulatory mediators in human T cell activation. Together, these results suggest that chemokines not only play an important role in lymphocyte recruitment to inflammatory sites, but also participate in T cell activation. PMID- 8690898 TI - Chemokines and T lymphocyte activation: II. Facilitation of human T cell trafficking in severe combined immunodeficiency mice. AB - Previous studies from this laboratory have demonstrated that the chemokines RANTES (recombinant human regulated upon activation, normally T cell expressed and presumably secreted), macrophage chemotactic peptide-1, recombinant human macrophage inflammatory protein-1 alpha (rhMIP-1 alpha) IL-8, and IP-10 are capable of inducing human T cell infiltration into the injection site of severe combined immunodeficiency (SCID) mice reconstituted with human PBL. However, the ability of these chemokines to facilitate T cell homing into various lymphoid tissues has not been examined. Initial studies focused on the ability of rhMIP-1 beta to induce human T cell infiltration into injection sites in human PBL-SCID mice. SCID mice received s.c. injections of rhMIP-1 beta or PBS (1 microgram/injection) in the hindflank for 4 h or sequential injections for 3 days. Biopsies of the MIP-1 beta injection site revealed the presence of significant mononuclear cell accumulation 72 h after injection. Immunohistologic evaluation determined that significant numbers of human CD3+ T cells were recruited in response to MIP-1 beta injections, and this infiltration could be specifically blocked by co-administration of anti-MIP-1 beta antiserum. We subsequently examined these chemokine-injected mice for the effect of trafficking of human T cells to peripheral lymphoid organs. Flow cytometric analysis of the thymus in human PBL-SCID mice revealed that treatment with rhMIP-1 beta or rhRANTES, but not platelet factor-4, resulted in improved thymic homing of the human T cells after 72 h. This trafficking effect was shown to be direct, as pretreatment of the human T cells with the chemokines in vitro also improved peripheral lymphoid trafficking of the human cells. In addition, co-injection of rhMIP-1 beta with anti-1 beta antiserum abrogated the increase in T cell homing to the thymus. These data demonstrate that MIP-1 beta and RANTES directly augment human T cell trafficking to peripheral murine lymphoid tissues. Chemokines may, therefore, under either isogeneic or xenogeneic conditions, play a role in normal lymphocyte recirculation and homing, and may be of potential clinical use in promoting immune cell trafficking and function. PMID- 8690899 TI - The role of CD28 costimulation in immune-mediated responses against mouse mammary tumor viruses. AB - Infectious mouse mammary tumor viruses (MMTV) encode superantigens (SAg) which, when presented in association with permissive class II MHC molecules, are recognized by those T cells that express appropriate TCRs. Recent findings have indicated that expression of a permissive MHC class II product and of a specific TCR are also critical to susceptibility of newborn mice to infection with milk borne MMTV, suggesting that SAg-mediated T cell activation may play a facilitating role in viral infection. Because effective Ag-specific T cell activation can require costimulatory signals in addition to TCR-mediated recognition, the role of the CD28 costimulatory receptor was analyzed in responses of neonatal and adult mice to MMTV challenge. Mice that were deficient in CD28 expression as a result of gene targeting were compared with CD28-intact littermates. In response to parenteral challenge with MMTV, CD28-deficient adult mice exhibited reduced expansion of MMTV SAg-reactive T cells in draining LNs, decreased cytokine production, and decreased B cell activation and Ig secretion. These results indicate that optimal T and B cell responses to MMTV challenge, as reflected in the parameters measured, are CD28 dependent. In contrast, CD28 absence did not impair TCR-V beta-specific clonal deletion induced by neonatal exposure to MMTV. Further, analysis of susceptibility to viral infection in neonatally exposed mice revealed that CD28 deficiency did not interfere with SAg dependent MMTV infection. Failure to identify CD28 dependence of MMTV infection suggests either the absence of a costimulatory requirement in the events that lead to viral infection or a redundancy in costimulatory signals that support infection. PMID- 8690900 TI - IL-10 inhibits nuclear factor-kappa B/Rel nuclear activity in CD3-stimulated human peripheral T lymphocytes. AB - IL-10 markedly reduces nuclear factor (NF)-kappa B/Rel nuclear activity induced in PBMC by stimulation with the anti-CD3 mAb OKT3. The inhibition is exerted specifically on the NF-kappa B/Rel activation induced by mAb OKT3, and not that produced by PMA. As judged by supershifting the DNA-protein complexes with Abs recognizing specific components of the NF-kappa B/Rel protein family, the p50/p65 (Rel A) heterodimeric form of NF-kappa B is primarily affected. The maximal effect is observed at the IL-10 concentration of 20 U/ml. IL-10 inhibitory activity is exerted on T lymphocytes and is mediated by monocytes. Indeed, monocytes pretreated with IL-10 are able so inhibit NF-kappa B nuclear activity in purified T lymphocytes stimulated with OKT3. Soluble factors do not appear to be involved in the mechanism of inhibition. On the other hand, the up-regulation of CD80 Ag, found on monocytes obtained from PBMC incubated with OKT3, is not detected after addition of IL-10, and the anti-CD28 mAb CLB-CD28/1 restores the NF-kappa B/Rel nuclear activity in IL-10-inhibited lymphocytes. Therefore, the NF kappa B/Rel inhibition might be ascribed to a lack of cooperation between accessory cells and T lymphocytes, resulting from down-regulation of a costimulatory molecule, such as CD80, produced by IL-10 on activated monocytes. Our results demonstrate that IL-10 can inhibit the induction of NF-kappa B/Rel nuclear activity in CD3-stimulated T lymphocytes. Since inappropriate activation of kappa B-driven genes has a physiopathologic role in a number of diseases, such as HIV infection, our findings support the possibility of using this cytokine to suppress an undesirable activation of these transcription factors. PMID- 8690901 TI - A combination of IL-10 and direct contact with plasma cell tumors decreases CD23 expression on splenic B cells. AB - We and others have previously found that splenic B cells from plasma cell tumor bearing mice exhibit decreased CD23 expression. In the present study we further examined the mechanism of CD23 down-regulation by plasma cell tumors. We show here that although direct contact is required between the tumor cells and B cells, it is not sufficient, since fixed tumor cells do not induce the same reduction in CD23 expression. We have identified IL-10, a cytokine produce by the tumors, as the sole soluble factor that contributes to decreased CD23 expression on B cells induced by plasma cell tumors because 1) Abs to IL-10 prevent the loss of CD23 induced by plasma cell tumors both in vitro and in vivo; 2) engineered IL 10 negative variants of these tumors are reduced in their ability to down regulate CD23 expression; 3) rIL-10 alone induces partial, but significant, decreases in CD23 expression on normal splenic B cells; and 4) the addition of IL 10 and fixed tumor cells to cultures of normal splenocytes decreases CD23 expression to levels similar to those in cocultures with live tumor cells. Collectively, these results demonstrate that plasma cell tumors down-regulate CD23 expression on B cells by a coordinate mechanism of IL-10 plus contact mediated events and reveal a novel role for IL-10 in the regulation of CD23 expression on B cells that is suggestive of host B cell activation in the presence of the tumor. PMID- 8690902 TI - Phenotype and function of CD4+ T cells in mice lacking invariant chain. AB - Mice bearing a targeted disruption of the gene encoding the invariant chain (Ii) have provided a deeper understanding of the critical role that Ii plays in the assembly, transport, and peptide occupancy of MHC class II molecules. In this study, we have investigated the consequence of the altered class II expression in Ii-deficient (Ii zero) mice on the phenotype and function of their CD4+ T cells. As seen by others, these mice show a sharp reduction in the CD4+8- subset in the thymus and periphery. Furthermore, a large proportion of the peripheral CD4+, but not CD8+, T cells in Ii zero mice exhibit decreased surface TCR-alpha beta levels and express markers of T cell activation. Although the CD4+ T cells respond to mitogens, anti-CD3 mAbs, and alloantigens, they respond poorly to the bacterial superantigen staphylococcal enterotoxin B and do not respond to peptide and protein Ags. Analysis of reciprocal radiation bone marrow chimeras constructed using Ii zero and wild-type mice indicate that the lack of Ii in the thymus is responsible for the phenotype of the CD4+ T cells in mutant mice. These results suggest that the altered thymic peptide repertoire displayed by class II molecules in the absence of Ii has a dramatic impact on the selection of CD4+ T cells and their phenotype in the periphery. PMID- 8690904 TI - Defective interactions between TCR chains and CD3 heterodimers prevent membrane expression of TCR-alpha beta in human T cells. AB - The human TCR complex is composed of two clonotypic polypeptide chains, TCR-alpha and TCR-beta (or TCR-gamma and TCR-delta) associated with CD3 gamma-, delta-, and epsilon-chains and zeta 2 homodimers. All six polypeptide chains are indispensable for TCR membrane expression and signaling function. In the present paper is described the analysis of a new TCR membrane-negative Jurkat T cell variant: E6.R3. The defect in this variant bears on the interaction between TCR and CD3 chains. E6.R3 cells have deleted three nucleotides in the TCR-alpha transmembrane (TM) region, which consequently lacks a leucine. This defect causes 1) lack of association between TCR alpha-chains and CD delta epsilon heterodimers; 2) lack of formation of disulphide-linked, fully glycosylated TCR alpha beta heterodimers; and 3) lack of interaction between TCR-alpha beta/CD3 complexes and zeta-chains. Despite these defective interactions, TCR alpha-chains appear to become fully glycosylated, i.e., they are not retained in the endoplasmic reticulum but are further processed in the Golgi apparatus without such interactions. The defect may be due to the observation that in the E6.R3 TCR alpha- chains TM region, the two charged amino acids are situated on the same side of the alpha-helix; these two amino acids are exposed on opposite faces of the TM alpha-helix in normal TCR alpha-chains, possibly allowing TCR alpha-chains to interact with both CD3 delta- and CD3 epsilon-chains. Further possible consequences of the leucine deletion in the E6.R3 TCR-alpha TM region are discussed. PMID- 8690903 TI - Regulation of B cell survival in xid mice by the proto-oncogene bcl-2. AB - CBA/N mice carry an X-linked immunodeficiency (xid) due to a point mutation in the Bruton's tyrosine kinase (btk) gene. xid mice have a smaller peripheral B cell pool than normal animals, lack CD5+ B cells (B1), and are hyporesponsive to mitogenic anti-Igs and thymus-independent type 2 Ags. The proto-oncogene bcl-2 affects B cell homeostasis by suppressing programmed cell death. We hypothesized that reduced bcl-2 expression could enhance programmed cell death in xid B cells, directly causing poor peripheral B cell survival and indirectly affecting Ag responsiveness. We measured and compared levels of endogenous Bcl-2 protein and spontaneous apoptosis in xid and normal B cells, and determined the effect of a human bcl-2/Ig minigene on B cell survival and Ag responsiveness in bcl-2 transgenics. The amount of endogenous Bcl-2 was reduced fivefold in freshly isolated xid B cells compared with that in normal cells, but was equal in xid and normal T cells. Attrition by spontaneous apoptosis was significantly higher in cultured xid B cells. Expression of the bcl-2 transgene suppressed apoptosis equally in normal and xid B cells, prolonged in vitro survival, and markedly expanded in vivo the follicular B cell population normally reduced in xid mice. However, most xid defects persisted; xid/bcl-2 mice remained deficient in B1 cells and hyporesponsive to anti-Igs, thymus-independent type 1 Ags, and thymus independent type 2 Ags. The data suggest that signal transduction pathways using Btk independently regulate B cell survival and Ag responsiveness. PMID- 8690905 TI - The sheep Ig variable region repertoire consists of a single VH family. AB - Nine germ-line Ig heavy chain variable (VH) segments (including three pseudogenes) were isolated from a genomic DNA library, and the other six were obtained by PCR, using 5'and 3' primers deduced from the first three. They appear to belong to a homogeneous VH gene family, with >80% sequence identity. This sheep VH gene family is related to the human VH4 family and to the murine VH1 subgroup (clan II). Southern blot analysis shows a maximum of 10 positive restriction fragments; therefore, the nine VH genes isolated probably constitute the major part of the repertoire. Thirty-one expressed mu variable regions (and one gamma 1 variable region) were obtained from adult spleen by either cDNA cloning or anchored reverse transcriptase-PCR; they are >80% similar to each other (in their leader to framework 3 regions) and to the germ-line sequences as well. The sheep VH repertoire thus seems to derive from a small (approximately 10 members) germ-line gene family, and its diversification must rely chiefly on junctional (D and/or N regions) diversity and somatic hypermutations. PMID- 8690906 TI - Allele-specific motifs characterize HLA-DQ interactions with a diabetes associated peptide derived from glutamic acid decarboxylase. AB - Polymorphic residues of HLA class II molecules influence immune activation in part by determining specific structural constraints for binding antigenic peptides. We identified a peptide from glutamic acid decarboxylase, a diabetes associated autoantigen that preferentially bound to HLA-DQ3.2 molecules, one of the HLA determinants highly associated with insulin-dependent diabetes. We analyzed interactions of specific HLA-DQ residues with modified peptide analogues and found a pattern of permissive site-specific amino acids that accommodated allele-specific binding. Four anchor residues constrain binding to different DQ alleles; limited variation at two of these sites, residues 4 and 9, accounts for the unique pattern of peptide binding to HLA-DQ3.1 or HLA-DQ3.2. PMID- 8690907 TI - Residues near the amino and carboxyl termini of staphylococcal enterotoxin E independently mediate TCR V beta-specific interactions. AB - Previous studies identified three COOH-terminal residues in staphylococcal enterotoxin E (SEE; Asp200, Pro206, and Asp207) that in part mediate TCR V beta recognition. We have identified an additional three residues near the NH2 terminus of SEE (Arg20, Asn21, and Ser24 that are needed in conjunction with these COOH-terminal residues to fully restore native levels of V beta-specific T cell proliferation. A staphylococcal enterotoxin A SEA-SEE hybrid molecule containing the NH2-terminal V beta determinants of SEE to activate alone exhibited V beta specificities of both SEA and SEE, indicating that these residues of SEE independently contribute to V beta recognition and do not obscure the native V beta determinants of SEA. These findings suggest that the ability of SEE to activate certain V beta-specific T cell subsets may result from multiple interactions with a single TCR beta-chain or perhaps by cross-linking two TCR. High affinity binding to HLA-DR1, a property of native SEA, was not altered in the SEA-SEE hybrid enterotoxins containing amino acid substitutions in regions 20 to 24 and 200 to 207, indicating that residues comprising the V beta determinants of SEE are separate from residues that contribute to HLA-DR1 binding affinity. Computer models of the predicted structure of SEE revealed that the V beta determinants of SEE are located on two adjacent solvent-exposed loops. Thus, the residues of SEE that mediate V beta recognition may coalesce to form a TCR binding site with specificities for multiple TCR beta-chains. PMID- 8690908 TI - Identification of a contact region for peptide on the TAP1 chain of the transporter associated with antigen processing. AB - The transporter associated with Ag processing (TAP) translocates cytosolic peptides into the endoplasmic reticulum for presentation by MHC class 1 molecules. Recently, the actual peptide translocation step has been suggested to be preceded by binding of the peptide to TAP. In this study, we investigated the peptide binding site of TAP and its relevance for peptide selection by cross linking of translocatable peptides. Our data demonstrate, first, that for a TAP heterodimer containing the rat TAPu allelic product, which selects peptides on basis of their C terminus, the translocation efficiency correlates with the peptide binding efficiency. Second, peptides having the cross-linker at different positions all label both the TAP1 and the TAP2 subunit after binding to the heterodimer, indicating that both TAP subunits contribute directly to the peptide binding site and contact most or all amino acids of a bound peptide. Third, by enzymatic digestion and the use specific antisera, we identified a domain of human TAP1 that contributes to the peptide binding site. This domain contains the two hydrophobic and thus putative transmembrane regions closest to the ATP binding sites. We conclude that the peptide binding site controls the selectivity of TAP and is composed of domains of both TAP1 and TAP2, which each contact the bound peptide over all or most of its length. Moreover, the major contact site(s) for peptide on TAP1 are located within or close to the two putative transmembrane regions adjacent to the ATP binding site. PMID- 8690909 TI - Variation in HLA-DM expression influences conversion of MHC class II alpha beta:class II-associated invariant chain peptide complexes to mature peptide bound class II alpha beta dimers in a normal B cell line. AB - The maturation of invariant chain (Ii):MHC class II complexes into peptide-loaded alpha beta dimers occurs by proteolytic removal of Ii chain and binding of antigenic peptides derived from exogenous and endogenous Ags. A fragment of the Ii chain (class II-associated invariant chain peptide (CLIP) remains associated with class II alpha beta and is an intermediate in this process. Conversion of alpha beta:CLIP complexes into alpha beta:peptide complexes is facilitated by HLA DM. Two unique mAbs, specific for I-Ab bound to human CLIP and I-Ab bound to DR alpha peptide, were used to assess the formation of these peptide:class II complexes in a human B lymphoblastoid cell line (B-LCL) (Swei) transfected with I A(b). In multiple independent Swei:I-Ab transfectants, the amount of human CLIP (hCLIP):I-Ab expressed was inversely proportional to the amount of DR alpha 52 68:I-Ab; quantitative differences in HLA-DM expression accounted for this phenotype. In the low DM transfectant, a substantial proportion of I-Ab, but not DR molecules, was altered structurally and unable to present native protein Ags. Addition of DM transgenes to the DM-low cells resulted in an increase in DR alpha 52-68:I-Ab coupled with a decrease in hCLIP:I-Ab complexes and restoration of exogenous protein Ag presentation. The DR5 molecules in Swei cells, which have a lower affinity for hCLIP than I-Ab, were not affected by low DM expression, suggesting that the amount of DM required for conversion of CLIP:class II to peptide:class II may depend on the affinity of the class II molecules for CLIP or DM. PMID- 8690911 TI - Response of a gamma delta+ T cell receptor invariant subset during bacterial infection. AB - Murine gamma delta T cells can be divided into subsets based on the TCR gamma chains they express. Most of these subsets have variable TCR junctions, but two, both associated with epithelia, express invariant TCRs. The absence of receptor variability in these cells implies uniformity of their ligands. This was previously taken as evidence to suggest that gamma delta T cells recognize host derived, stress-induced ligands. We now demonstrate, for the first time, the response of a gamma delta TCR invariant subset during bacterial infection, a potential cause of stress. After infection with Listeria monocytogenes, absolute numbers of all T cells in the liver, including alpha beta and gamma delta T cell subsets, increased markedly. However, responses of a gamma delta T cell subset varied. We noted a decrease in the relative frequency of V delta 6.3+ cells, which are, for the most part, included in the V gamma 1+ subset. In contrast, cells bearing the invariant V gamma 6/V delta 1 TCR increased substantially in proportion to other gamma delta T cells, as determined by PCR analysis of liver T cell RNA and by comparing liver gamma delta T cell hybridomas made from normal mice to those from mice infected with Listeria. V gamma 6/V delta 1+ cells have been previously reported as a TCR invariant intraepithelial subset in the female reproductive tract and tongue. We show here that V gamma 6/V delta 1+ cells reactive in Listeria-infected liver are polyclonally derived, but still bear TCR chains with invariant junctional sequences, identical with those of the female reproductive tract. Although the Ag that stimulates these cells is unknown, our results indicate that only diverse, but also invariant, gamma delta T cell subsets can become involved in the host response to a bacterial infection. PMID- 8690910 TI - Specificities and functions of CD4+ HLA class II-restricted T cell clones against a human sarcoma: evidence for several recognized antigens. AB - CD4+ T cells play an important role for tumor immunity in animal tumor models, yet there are few reports about the role of CD4+ HLA class II-restricted T cells in the immune response against human tumors. Against a human sarcoma exclusively CD4+, T cell clones could be established. These T cell clones were cytotoxic and secreted TNF and additional cytokines in response to the IFN-gamma-treated, HLA class II-positive autologous sarcoma cells. Several Ags were recognized by representative T cell clones: an Ag presented by HLA-DR and specific for the sarcoma; Ags presented by both HLA-DR alleles of the sarcoma, HLA-DR4 and -15, and shared by allogenic HLA-DR matched cell lines of different tissue lineages, including B cell blasts; and a sarcoma Ag presented by HLA-DP or DQ. Cytokine profiles of sarcoma-reactive T cell clones were dependent on the cytokine environment present during establishment of the T cell clones. The addition of exogenous IL-4 shifted the cytokine patterns of sarcoma-reactive T cell clones from Th1-like patterns to Th0/Th2-like patterns and decreased IL-10 production. TNF, IFN-gamma, IL-4, and supernatants of T cell clones induced HLA-DR expression on the sarcoma cells and, thus, were able to enhance Ag presentation. This autologous T cell response to a human sarcoma represents a new model for HLA class II-restricted T cell responses to human tumors. PMID- 8690912 TI - Protection against lethal Escherichia coli bacteremia in baboons (Papio anubis) by pretreatment with a 55-kDa TNF receptor (CD120a)-Ig fusion protein, Ro 45 2081. AB - Fusion proteins of the human 55-kDa TNF receptor extracellular domain with hinge and C2/C3 constant domains of human IgG1 or IgG3 heavy chains were tested in a primate sepsis model. Twenty-four baboons received 4.6, or 0.2 mg/kg of TNFR5 G1,3, or placebo, before the administration of a lethal dose of live Escherichia coli. Treatment with TNFR5-G1,3 decreased 5-day mortality from 88% in the placebo group to 12% in the TNFR5-G1,3-treated animals (p < 0.01 by Fisher's exact test). Treatments with TNR5-G1 and TNFR5-G3 in doses from 0.2 to 4.6 mg/kg were efficacious. Free plasma TNF was neutralized by all treatments, but inactive TNF/TNFR5-G1,3 complexes remained in circulation for prolonged periods. TNFR5-1,3 treatments attenuated the hemodynamic disturbances, reduced fluid requirements, and decreased the systemic IL-1 beta, IL-6, and IL-8 responses. In addition, TNFR5-G1,3 treatment shortened the granulocytopenia and reduced the loss of cellular TNF receptors from granulocytes. The decrease in fibrinogen concentrations and increase in prothrombin and partial thromboplastin times were significantly attenuated by TNFR5-G1,3 treatment. TNFR5-G1,3 treatment markedly attenuated the rise in plasma lactate concentration. Histologic studies of TNFR5 G1,3 revealed dose-dependent protection against tissue injury by Escherichia coli administration. PMID- 8690913 TI - Local suppression of IFN-gamma in hepatic granulomas correlates with tissue specific replication of Leishmania chagasi. AB - BALB/c mice are susceptible to infection with the visceralizing species of Leishmania, Leishmania chagasi. The parasite load initially rises in the liver and spontaneously subsides, whereas parasite multiplication begins later and remains lower in the spleen. To investigate whether this organ-specific multiplication of L. chagasi correlates with localized immune responses, we compared cytokine production by splenic vs hepatic immune cells. Livers from infected mice contained granulomas harboring intracellular L. chagasi amastigotes, whereas few amastigotes were present in the spleen. FACS analysis granuloma cells showed granuloma lymphocytes expressed a memory/effector phenotype. Granuloma cells cultured in vitro produced IL-10 and IL-6 but no detectable IFN-gamma, IL-4 or IL-5. In contrast, splenocytes from the same animals secreted IFN-gamma, IL-4, IL-6, and IL-10. T cells were depleted from granuloma cells by immune lysis, and the results indicated that IL-10 and IL-6 were derived at least in part from a non-T cell compartment. Paradoxically, FACS purified Thy-1+ granuloma lymphocytes were able to produce IFN-gamma in the absence of other granuloma cells, suggesting IFN-gamma production might usually be inhibited by a granuloma-associated non-T cell element. Coculture of splenocytes with either granuloma cells or supernatants from granuloma cultures inhibited the usual splenocyte production of IFN-gamma and IL-4 but not IL-10. Thus, there may be a unique granuloma-associated suppressive factor accounting for the absence of IFN-gamma in hepatic granuloma cultures. It may be the absence of IFN-gamma in the liver and presence in the spleen that allows or inhibits parasite survival, respectively, in these different locations. PMID- 8690914 TI - LPS-dependent cyclooxygenase-2 induction in human monocytes is down-regulated by IL-13, but not by IFN-gamma. AB - We investigated the effects of Th2 cell-associated cytokines, IL-4, IL-10, and IL 13, on prostaglandin (PG) production by human peripheral blood monocytes (HPBM) in terms of four parameters: PGE2 synthesis; cyclooxygenase activity; protein; and mRNA of two cyclooxygenase isozymes (cyclooxygenase-1 and cyclooxygenase-2). LPS-stimulated PGE2 synthesis and cyclooxygenase activity were suppressed by IL 4, IL-10, or IL-13. Furthermore, the LPS-dependent increase of cyclooxygenase activity in HPBM was attributable to cyclooxygenase-2 because it was inhibited by NS-398 (a cyclooxygenase-2-specific inhibitor). Western and Northern blot analyses revealed that the LPS-induced increases in cyclooxygenase-2 protein and mRNA were attenuated by the addition of IL-4, IL-10, or IL-13. In contrast, cyclooxygenase-1 protein and mRNA were hardly detected in monocytes that were incubated with or without LPS in the presence or absence of IL-4, IL-10, and IL 13. These results suggest that the reduction of LPS-induced PGE2 synthesis and cyclooxygenase activity by IL-4, IL-10, and IL-13 in HPBM are mainly due to the down-regulation of cyclooxygenase-2 selectively induced by LPS. Conversely, IFN gamma, a Th1 cell-associated cytokine, did not affect PGE2 production and cyclooxygenase activity. These data suggest a mechanism for modulation of inflammation by the anti-inflammatory Th2 cell-associated cytokines but not a Th1 cell-associated cytokine. PMID- 8690915 TI - Identification and characterization of complement C3 receptors on human astrocytes. AB - Astrocytes express C components and have been implicated as a major source of intrathecal C. To ascertain the effects of C activation on these cells, we have evaluated the expression of CR1, CR2, and CR3 (CD35, CD21, and CD11b/CD18) in primary fetal astrocytes and astrocyte cell lines. None of the astrocyte cells tested expressed CR3, whereas primary astrocytes and one of four astrocyte cell lines expressed CR1 (220 kDa), as assessed at the protein and mRNA level. Primary fetal astrocytes and all four astrocyte cell lines expressed CR2 (155 kDa). Expression of CR2 by astrocytes was confirmed at mRNA level by reverse transcriptase PCR, using different combinations of seven specific CR2 oligonucleotides, and by partial sequencing of the astrocyte CR2 cDNA. Astrocyte CR2 cDNA presented 100% homology with the lymphocyte CR2 cDNA between the position 181 bp to 600 bp and position 1017 bp to 1347 bp. An alternative splicing pattern of exon 11, reported previously in B cells, was observed in astrocyte CR2 cDNA. Astrocyte CR2 was functional, in that it specifically bound C3d and the EBV surface protein gp340, and the binding was blocked specifically with polyclonal anti-CR2. Scatchard analysis of membrane expression of CR2 on astrocytes revealed 2000 functional sites per cell with a Kd (3 x 10(-7) M) identical with that of CR2 on B cell (Raji). PMID- 8690916 TI - A physiologic anti-inflammatory pathway based on thrombomodulin expression and generation of activated protein C by human mononuclear phagocytes. AB - The endothelial molecule thrombomodulin (TM) regulates hemostasis by binding thrombin and promoting conversion of protein C to activated protein C (aPC). Apart from its anticoagulant actions, aPC modulates mononuclear phagocyte (M phi) activation, including TNF-alpha production, indicating interrelationships of the coagulation and immune systems. While the endothelium is considered to be the prime regulator of aPC generation, TM recently has been identified M phi and neutrophils. This study analyzes TM membrane expression by human blood monocytes, alveolar macrophages, and U937 cells cultured in the presence of various stimuli. All except U937 cell expressed high levels of surface TM. Surprisingly, stimulation with LPS or TNF-alpha further up-regulated TM expression by M phi, whereas cultured endothelial cells (EC) showed decreased TM expression. However, noninflammatory stimuli induced qualitatively similar changes in M phi and EC; all-trans retinoic acid and prostaglandin E up-regulated surface TM, and PMA decreased TM expression. Changes in M phi TM expression were accompanied by alteration in functional activity. Thus, LPS increased the TM cofactor activity of THP-1 cells by 27 +/- 6.9% (p < 0.05), and PMA decreased their cofactor activity by 53.2 +/- 11.5% (p < 0.05).In addition, in vivo relevance was demonstrated by the presence of TM on intragraft inflammatory M phi during cardiac rejection, whereas adjacent EC lacked TM expression. These studies demonstrate that expression of TM on human M phi is regulated differently to EC with respect to inflammatory stimuli, suggesting the potential for extravascular M phi to promote local production of aPC. PMID- 8690917 TI - Lipoxin A4 and B4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells. AB - Lipoxins are bioactive eicosanoids that are generated within the vascular lumen by leukocytes and transcellular biosynthetic routes during multicellular responses. Polymorphomuclear neutrophils (PMN) and endothelial cells express high affinity receptors for lipoxins, engagement of which invokes profiles of signaling events that differ from other lipid mediators. In this work, we report that lipoxins are potent inhibitors of PMN-endothelial cell interactions triggered by leukotrienes via dual-pronged actions with PMN and endothelial cells. Both lipoxin A4(LXA4) and B4(LXB4) blocked PMN migration stimulated by leukotriene B4 (LTB4), a well established agonist for PMN recruitment, a transmigration assay in vitro. Lipoxins were almost as effective in this regard as the pharmacologic LTB4 receptor antagonist, ONO 4057, and the blocking anti CD18 mAb, R15.7. LXA4 and LXB4 blunted PMN transmigration, in part by inhibiting beta 2 integrin-dependent PMN adhesion. These modulatory actions of lipoxins were evident at subnanomolar concentrations, rapid in onset, and attenuated by prior exposure of PMN to a tyrosine kinase inhibitor, genistein. The peptidoleukotrienes, leukotriene C4 (LTC4) and leukotriene D4 (LTD4) also provoked PMN-endothelial cell adhesion, but via a different mechanism than LTB4. Both LTC4 and LTD4 enhanced endothelial adhesiveness for PMN, in part, by stimulating mobilization of P-selectin from intracellular Weibel-Palade bodies. LXA4 and LXB4, but not other lipoxygenase products, blocked P-selectin mobilization induced by peptidoleukotrienes and attenuated P-selectin-mediated PMN-endothelial cell adhesion. These results indicate that lipoxins attenuate PMN endothelial cell interactions supported by selectins and beta 2 integrins in vitro, and are potential endogenous lipid-derived modulators of PMN trafficking in host defense, inflammation, and other vascular events. PMID- 8690918 TI - Feedback modulation of ligand-engaged alpha L/beta 2 leukocyte integrin (LFA-1) by cyclic AMP-dependent protein kinase. AB - Rapid interconversion between a firmly adherent and a nonadherent, circulating phenotype is a distinctive feature of mature leukocytes and is thought to be essential for efficient immune surveillance. Leukocyte adhesion is a finely regulated process controlled in part by reversible, activation-dependent up regulation of beta 1- and beta 2- integrin function. To investigate the molecular basis of such reversibility in human T lymphocytes, we developed a model of alpha L/beta 2 (LFA-1)-dependent adhesion that uses a heterologous cell line expressing human intercellular adhesion molecule-1 as a selected ligand. We show here that intracellular cAMP elevation, followed by cAMP-dependent kinase activation, promotes T cell deadhesion by disassembling the actin-based cytoskeleton, thus dissociating LFA-1 from cytoskeletal anchoring proteins that normally connect the adhesion receptor to F-actin in lymphocytes engaged in intercellular adhesion. Cells costimulated via the CD3 and LFA-1 receptors by specific Abs or by binding to intercellular adhesion molecule-1 display gradual and persistent intracellular cAMP elevations due to the synergistic induction of a protein kinase C-dependent adenylyl cyclase isoform. On the basis of these findings, we propose a feedback model for short term regulation of leukocyte integrins, involving sequential, integrin-dependent activation of the protein kinase C and adenylyl cyclase/cAMP dependent kinase enzymatic pathways and leading to disengagement of the adhesion receptor from its specific ligand. PMID- 8690919 TI - Apoptosis associated with ex vivo down-regulation of Bcl-2 and up-regulation of Fas in potential cytotoxic CD8+ T lymphocytes during HIV infection. AB - In this study, we have investigated whether the enhanced apoptosis of CD4+ and CD8+ T lymphocytes throughout HIV infection was controlled by the bcl-2 proto oncogene, an inhibitor of programmed cell death (PCD) in mammals. We have analyzed the intracellular expression of the Bcl-2 protein by flow cytometry in freshly isolated peripheral T cells from HIV-infected and noninfected individuals. While no decrease in Bcl-2 expression was detected in the CD4+ T cell subset from the seropositive donors, a reduced level of Bcl-2 was found in a fraction of CD8+ T lymphocytes, with the proportion of these cells increasing as HIV infection progressed. We show that the low Bcl-2-expressing CD8+ T cells were highly susceptible to spontaneous apoptosis upon short term culture. Interestingly, PCD significantly increased when these lymphocytes were cultured in the presence of a Fas-specific mAb, which was related to the high expression of the Fas Ag on their surface. The low Bcl-2 CD8+ subpopulation displayed activation markers CD45RO, HLA-DR, and CD38 and expressed TIA-1-positive, but perforin-negative, granules, while lacking the CD28 Ag. These observations suggest that such low Bcl-2 CD8+ T cells correspond to either immature or end staged anergic CTLs. Moreover, they indicate that down-regulation of Bcl-2 and up regulation of Bcl-2 and up-regulation of Fas in CD8+ T lymphocytes, associated with the chronic stimulation of these cells during HIV infection, might render them sensitive to Fas-mediated PCD. Such a Bcl-2/Fas-regulated apoptosis could be responsible for the disappearance of both memory CD45RO+ T cell response and HIV specific cytotoxic activity occurring in the course of HIV infection and could contribute to AIDS pathogenesis. PMID- 8690921 TI - T cells bound by vascular cell adhesion molecule-1/CD106 in synovial fluid in rheumatoid arthritis: inhibitory role of soluble vascular cell adhesion molecule 1 in T cell activation. AB - Elevated levels of soluble vascular cell adhesion molecule-1 (sVCAM-1)/CD106 have been reported in synovial fluid (SF) from patients with rheumatoid arthritis (RA). In the present study, VCAM-1-positive lymphocytes were found in SF from RA patients. The data strongly suggest that sVCAM-1 might be bound to lymphocytes in SF. rsVCAM-1 in the fluid phase can bind to both SF lymphocytes and IL-2 dependent T cell lines with up-regulated expression and binding activity of VLA 4. Furthermore, proliferative responses of SF mononuclear cells (SFMC) with PHA, immobilized anti-CD3, or anti-CD2 and PMA were inhibited to various extents in the presence of rsVCAM-1, but only PMA-induced proliferative response of PBMC from normal individuals was inhibited notably in the presence of rsVCAM-1. rsVCAM 1 also drastically reduced IL-2 production of Jurkat leukemic T cells possessing high affinity VLA-4 with the stimulation of anti-CD3 and PMA, suggesting that the T cell hyporesponsiveness induced by rsVCAM-1 might stem from impairment of IL-2 production. These results indicate that sVCAM-1 provides a negative signal to T cell activation, probably by affecting the pathway of protein kinase C activation. Thus, binding of sVCAM-1 to SF lymphocytes might partly explain the anergic state of these lymphocytes. PMID- 8690920 TI - The in vivo mechanism of action of CTLA4Ig. AB - A single dose of CTLA4Ig, an inhibitor of CD28-mediated T cell costimulation, given 2 days after transplantation induces specific unresponsiveness to alloantigens in vivo. However, the mechanisms responsible are unknown. Using pigeon cytochrome c as a model Ag, we monitored the effect of CTLA4Ig on the fate of Ag-reactive T cells in normal mice and on pigeon cytochrome c-specific TCR transgenic cells adoptively transferred into congenic mice. CTLA4Ig significantly inhibits immunization with pigeon cytochrome c. In particular, ELISA and ELISPOT assays indicate an 80 to 90% reduction in Th1 (i.e, IL-2 and IFN-gamma) cytokine production and in the numbers of cytokine-producing cells. Interestingly, despite this profound reduction in cytokine-producing cells, Ag-reactive T cells expand in CTLA4Ig-treated animals, although the degree of expansion is reduced by 50% compared with that in control Ig-treated animals. Thus, loss of Th1 cytokine production in CTLA4Ig-treated animals is not fully explained by the decreased expansion of Ag-specific T cells. These results suggest two mechanisms of action for CTLA4Ig in vivo: inhibition of expansion of Ag-reactive cells and induction of anergy in the residual population. PMID- 8690922 TI - Molecular bases for inherited human complement component C6 deficiency in two unrelated individuals. AB - Deficiency of the sixth component of complement (C6D) is frequently associated with recurrent neisserial infections, especially meningitis caused by Neisseria meningitidis. We here report the molecular bases of C6D in two unrelated subjects, one African American (case 1) and the other Japanese (case 2). Screening all 17 exons of the C6 gene and their boundaries by exon-specific PCR/single strand conformation polymorphism demonstrated aberrant single stranded DNA fragments in exon 12 of case 1 and exon 2 of case 2. Nucleotide sequencing of the amplified DNA fragments revealed a homozygous single-base deletion (G1936) in exon 12 case 1 and a heterozygous single base deletion (C291/C292/C293/C294) in exon 2 of case 2. Both mutations resulted in frame shifts and premature termination of the C6 polypeptide. Sequence-specific oligonucleotide probe hybridization and direct sequencing of exon 12 amplified from genomic DNA further supported the homozygosity of the mutation in case 1. Case 2 is apparently compound heterozygote, but the putative mutation in the other allele of the C6 gene remains unknown. Both case 1 and case 2 were homozygous for the C6A allotype. These data indicate that at least three distinct mutational events can cause C6D, single nucleotide deletions in exons 2 and 12, and a mutation yet unidentified. Thus, similar to other complement protein deficiencies, the pathogenesis of C6D appears to be heterogeneous. PMID- 8690923 TI - Retrovirus-mediated transfer of viral IL-10 gene prolongs murine cardiac allograft survival. AB - A murine heterotopic, nonvascularized cardiac allograft model was used to examine the effects of the immunosuppressive cytokine, viral IL-10 (vIL-10), delivered by gene transfer on graft rejection. Retroviral-mediated gene transfer and expression of vIL-10 significantly prolonged allograft survival, without conventional systemic immunosuppression, from 12.1 +/- 0.8 days to 39.4 +/- 2.5 days (p < 0.0001). The effect was specific, dose dependent, and restricted to the site of transplantation. PCR analysis demonstrated specific expression of the transferred gene within the allograft. Analysis of the cellular infiltrate in the allografts showed a reduction in T cells and alloantigen-specific cytotoxic T cells and IL-2 producing helper T cells. Thus, the transient local expression of a gene encoding an immunosuppressive protein within a graft can generate local immunosuppression, making gene therapy a viable approach for facilitating transplantation. PMID- 8690924 TI - IL-7 up-regulates HIV-1 replication in naturally infected peripheral blood mononuclear cells. AB - We have investigated the effect of exogenous IL-7 on replication of HIV-1 in PBMCs isolated from asymptomatic, chronically infected donors. We show that IL-7 induced virus replication and increased proviral DNA levels in CD8- PBMC cultures. IL-7 also increased the levels of doubly spliced HIV-1 tat RNA in these cultures. In comparison, IL-2 induced lower levels of virus production than IL-7, but had a more pronounced effect on cell proliferation. The IL-7-mediated increase in virus replication was not inhibited by neutralizing mAbs to IL-1 beta, IL-2, IL-6, or TNF-alpha, and was only partially dependent on ligation of the T cell accessory molecule CD28. CD8+ cells inhibited the increase in viral replication following IL-7 stimulation, but did not prevent virus replication following ligation of CD3 in the presence of IL-7. The data shows that IL-7 regulates HIV-1 replication in naturally infected PBMCs. PMID- 8690925 TI - Increased frequency of abnormal gamma delta T cells in blood of patients with inflammatory bowel diseases. AB - We have previously reported a preferential usage of V delta 1/V gamma 8 on TCR gamma-delta-bearing intraepithelial lymphocytes of the normal human intestine as well as in the inflamed synovial tissue of patients with rheumatoid arthritis. The aim of the present study was to analyze V gene segment usage by gamma delta T cells of the intestine and peripheral blood (PB) from patients with inflammatory bowel disease. Freshly isolated lymphocytes were analyzed by flow cytometry using a panel of V gene subset-specific mAbs. The relative proportion of PB TCR-gamma delta+ cells was increased in patients with Crohn's disease as compared with controls. Interestingly, an increased proportion of PB gamma delta T cells of patients with ulcerative colitis or CrD expressed V delta and V gamma genes typically used by intraepithelial lymphocytes. Thus, increased proportions of V delta 1+ and V gamma 8+ cells were found in the PB of both patient groups. The majority of TCR-gamma delta+ intraepithelial lymphocytes (IEL) in inflamed and noninflamed intestine expressed V delta 1/V gamma 8, and a substantial proportion of V gamma(2,3,4)+ cells were found. These observations suggest a disease associated appearance of "gut-like" gamma delta T cells in the periphery. Moreover, two patients had a large proportion of gamma delta T cells in their PB of which the majority expressed two distinct V gamma proteins. Both of these patients had a short duration of disease (1 and 10 mo, respectively) and the relative proportion of gamma delta T cells decreased in concert with stabilization of disease. Interestingly, one of the patients had a clonal expansion of a V gamma dual-expressing gamma delta T cell in the PB. PMID- 8690926 TI - Simple determination of polysaccharide specific antibodies by means of chemically modified ELISA plates. AB - A new ELISA technique using Nunc CovaLink NH microtiter plates has been developed to measure anticapsular polysaccharide specific antibodies. Capsular polysaccharide (PS) of Haemophilus influenzae type b (PRP) and pneumococcal antigens types 3, 6, 8, 14, 19, 23 were immobilized on CovaLink NH. These are modified plates with secondary amino groups bound to their surface which, in the presence of a water-soluble carbodiimide as coupling reagent, facilitate the direct binding of polysaccharides. We compared the binding characteristics of PS antigens to CovaLink NH and a conventional polystyrene ELISA plate. Checkerboard titration of PS antigens between 0.04-30 micrograms/ml clearly demonstrated that with Covalink NH optimal binding of a pooled serum from immunized donors was achieved for all PS antigens tested at a concentration of 1 microgram/ml, while binding of PS to the conventional plate was rather poor even at concentrations of 30 micrograms/ml. The CVs for the ELISA ranged from 1.1 to 2.8% for intra-assay comparisons and from 3.6 to 7.3% for inter-assay comparisons. In addition, when PRP-IgG antibodies were determined with the CovaLink NH ELISA and compared with the Farr assay an acceptable correlation ( r = 0.89, p < 0.0001) was obtained. The technique described provides a simple and sensitive tool for evaluating specific immunity to PS antigens. PMID- 8690927 TI - Selective isolation of transiently transfected cells from a mammalian cell population with vectors expressing a membrane anchored single-chain antibody. AB - We present here a novel technology for the rapid selection of transiently transfected cells from total populations in culture. This system utilizes recombinant antibody technology to produce a 'molecular hook' by displaying a hapten-binding single-chain antibody (sFv) on the surface of transfected cells. Mammalian cell lines from several origins were transiently transfected with a plasmid (pHook-1) that encodes an sFv fused with a transmembrane anchor and found to express and display the functional hapten-binding sFv on their membranes. Transfected cells were selected from total populations in culture by virtue of their ability to bind to hapten-coated magnetic beads. Some cell lines were able to display sFv sufficient for selection as early as 2 h post-transfection. SK-BR 3 human breast carcinoma cells were co-transfected with pHook-1 and pCR31acZ (expresses beta-galactosidase), selected, and assayed for beta-galactosidase activity. The positive correlation between sFv and beta-galactosidase expression in these cells (95% of selected cells also expressed beta-galactosidase activity) suggests that pHook-1 will be useful in isolating cells co-expressing an exogenous gene of interest. Another vector was constructed in which a gene of interest may be expressed from the same plasmid as the sFv 'hook'. This construct (pHook-2) allows the selection of a homogenous population of cells expressing exogenous genes without co-transfection or the generation of stable transfectants. In experiments where the lacZ gene was co-expressed with the sFv 'hook' from this single plasmid, 100% of 293 human kidney cells and 100% of SK-BR 3 cells selected with antigen-coated magnetic beads stained positively for beta galactosidase activity. We propose that this system will be a valuable tool for studying the acute and chronic effects of the expression of a variety of wild type and mutant proteins. PMID- 8690928 TI - DNA vector constructs that prime hepatitis B surface antigen-specific cytotoxic T lymphocyte and antibody responses in mice after intramuscular injection. AB - We tested the efficiency of induction of immune responses to the small hepatitis B surface antigen (HBsAg) in mice by intramuscular DNA immunization using different vector constructs that allow high levels of HBsAg expression in mouse cells. The HBsAg-specific responses of class I-restricted cytotoxic T lymphocytes (CTL) and of B cells (serum antibody titers) were measured. Following the intramuscular inoculation of 'naked' DNA, five different vector constructs of 4-8 kb, that contained or did not contain an intron and/or the neo gene, in which HBsAg expression was driven by promoter sequences derived from the immediate early region of HCMV, the SV40 enhancer/promoter region, or a retroviral 3' LTR efficiently primed responses of class I-restricted CD8+ CTL precursors. In contrast, the constructs in which HBsAg expression was driven by HCMV-derived promoter sequences stimulated significantly higher levels of HBsAg-specific serum antibody titers after intramuscular DNA injection than the SV40 or MPSV vector constructs. Large (15 kb) episomal vector constructs did not stimulate CTL or antibody responses. The data demonstrate that: (i) intramuscular DNA immunization represents an efficient technique for priming CTL and antibody responses to HBsAg; (ii) many vectors can be constructed that express an immunogenic product after intramuscular inoculation of 'naked' DNA; (iii) the efficiency of the tested vector constructs to prime after DNA immunization, either a CTL response, or an antibody response, differs. PMID- 8690929 TI - In vivo induction of cytotoxic T lymphocytes specific for a single epitope introduced into an unrelated molecule. AB - Cytotoxic T lymphocytes (CTLs) recognise antigenic peptides in the context of major histocompatibility complex (MHC) class I molecules on virus-infected cells. The formation and transportation of antigenic peptides to class I MHC in the cells are multi-step reactions known as antigen processing. In order to design a good DNA vaccine, it is important to dissect the specificity of antigen processing. Here we describe the construction of an epitope-based plasmid vector as a device to investigate antigen processing in transfected cells. The epitope based plasmid vector was constructed by insertion of an epitope-encoding minigene into the lacZ gene. We used a CTL epitope on influenza A virus nucleoprotein (NP366-374 epitope) as a model. Upon transfection, the epitope-based plasmid vector induced the expression of NP epitope antigenically as well as immunogenically. Immunization of mice with plasmid-transfected cells was able to induce NP epitope-specific CTLs in vivo. Moreover, the plasmid vector functioned as a gene vaccine; NP epitope-specific CTLs were primed in vivo upon transfection of the vector into dermis by electroporation. The results suggest that this epitope-based DNA delivery system may provide a new strategy for in vivo induction of epitope-specific CTLs to investigate antigen processing and presentation. PMID- 8690930 TI - Highly sensitive amperometric enzyme immunoassay for alpha-fetoprotein in human serum. AB - A sandwich amperometric enzyme immunoassay with flow injection for alpha fetoprotein in human serum has been developed with alkaline phosphatase as the enzyme label. p-Hydroxyphenyl phosphate was used as the substrate for alkaline phosphatase. The hydrolysis product, hydroquinone, was detected by oxidative amperometry in a flow injection system. The amperometric wall jet detector was fitted with a glassy carbon working electrode held at 350 mV vs. Ag/AgCl. The detection limit of hydroquinone in 30 mM borate buffer pH 9.5 was 1.2 x 10(-10) M (linearity range: 10(-9)-5.12 x 10(-6 M). A detection limit for free alkaline phosphatase of 1.2 x 10(-15) M (linearity range: 10(-15)-10(-13) M), or about 36 000 molecules, was observed (same borate buffer and incubations of 10 min at 25 degrees C). These conditions were maintained for the amperometric alpha fetoprotein immunoassay. For comparison purposes, a photometric detection system was set up, with p-nitrophenyl phosphate as enzyme substrate and the same pair of antibodies and incubation conditions. The detection limit for alpha-fetoprotein obtained by amperometry, 0.07 ng/ml (linearity range = 5-500 ng/ml), was 14 times lower than by photometry. The amperometric enzyme immunoassay correlates well with a commercial colorimetric immunoassay (r = 0.986, slope = 0.967, n = 240). PMID- 8690931 TI - Expression of biologically active mouse and human CD95/APO-1/Fas ligand in the baculovirus system. AB - CD95L (CD95/APO-1/Fas ligand) is a type II transmembrane glycoprotein that induces apoptosis in sensitive target cells. CD95L can be proteolytically cleaved from the membrane by a metalloprotease and occurs in a soluble form. Thus CD95L may act as a cytotoxic effector molecule at a distance from the producer cell. In order to develop an expression system yielding large quantities of CD95L, we expressed mouse and human CD95L tagged with a FLAG sequence in insect cells (Sf9) infected with recombinant baculovirus. CD95L expressed by Sf9 cells was detected with rabbit antibodies directed against the carboxy-terminal region of CD95L (which is highly conserved between mouse and human CD95L) and with an anti-FLAG monoclonal antibody. Immunoblotting showed that recombinant mouse and human CD95L expression was associated with the presence of 40 kDa and 32-33 kDa proteins. CD95L released into the supernatant of infected Sf9 cells specifically induced apoptosis in sensitive target cells, thus indicating that recombinant mouse and human CD95L were functional. The presence of the amino-terminal FLAG sequence did not modify this biological activity. Infection of Sf9 cells with recombinant baculoviruses may thus provide an efficient system for the expression of biologically active recombinant CD95L. PMID- 8690932 TI - An improved isolation method for murine migratory cutaneous dendritic cells. AB - Dendritic cells are highly specialized accessory cells for the initiation of primary immune responses. They occur as trace populations in non-lymphoid and lymphoid organs. Therefore, the isolation and enrichment of primary dendritic cells is difficult and time-consuming. This applies also to dendritic cells from skin, i.e. epidermal Langerhans cells and dermal dendritic cells. Recently introduced skin organ cultures serve as a convenient source for primary cutaneous dendritic cells. We report here a refinement of such cultures in which cutaneous dendritic cells emigrate spontaneously into the culture medium. Murine ear skin is cultured for a total of 3 days in three sequential 24 h steps. This simple modification doubles or triples the yields of dendritic cells that can be obtained and up to 30,000 dendritic cells can be recovered from one ear half. This represents 50-70% (range 30-80%) of all viable cells. The cells are mature dendritic cells that possess potent T cell stimulatory function. Compared to the classical methods of preparing epidermal Langerhans cells by trypsinization this technique is easier and quicker; it does not require enzymes such as trypsin, and it yields similar numbers of mature dendritic cells. It should prove useful for further studies of dendritic cells of the skin. PMID- 8690933 TI - Isolation and characterization of murine Kupffer cells and splenic macrophages. AB - A method is described using counterflow centrifugation elutriation to isolate macrophages from murine liver and spleen. In this study three, size fractionated, macrophage populations were collected. Isolation resulted in a high yield of pure Kupffer cells (total of 10 x 10(6) /g liver) and enrichment of splenic macrophages to 20%. In addition to standard methods such as non-specific esterase staining, the isolated macrophages were also characterized by flow cytometry using specific monoclonal antibodies. In addition, a rapid flow cytometry method was introduced to determine the percentage of macrophages based on autofluorescence. A strong correlation was found between the percentages of macrophages found by non-specific esterase staining and autofluorescence. Functional tests revealed differences between the isolated macrophages in terms of tumor necrosis factor-alpha (TNF-alpha) production, oxygen metabolism and the production of nitric oxide. However, no significant differences in phagocytic activity was observed between the fractions. After two weeks of culture without the addition of antibiotics the cells still exhibited the above mentioned functions. PMID- 8690934 TI - Serological diagnosis of visceral leishmaniasis by a dot-enzyme immunoassay for the detection of a Leishmania donovani-related circulating antigen. AB - Field medicine in tropical areas needs laboratory assays which are inexpensive and easy to perform. To meet this need a semi-quantitative dot-enzyme immunoassay (EIA) was developed for the detection of an L. donovani-related circulating antigen and tested for clinical relevance in the diagnosis of visceral leishmaniasis (VL). The dot-EIA probes serum spotted on nitrocellulose for the presence of the antigen using a monoclonal antibody raised against L. donovani promastigotes, a peroxidase-conjugated rabbit anti-mouse immunoglobulin antiserum and chloronaphthol as peroxidase substrate. The intensity of dot staining by chloronaphthol is read by eye and scored. The dot-EIA was used to test the following groups: 69 patients with VL from Brazil, Kenya, China and France, nine patients with cutaneous leishmaniasis, 38 patients with tropical diseases other than VL, five patients with rheumatoid arthritis and 40 health blood donors. The specificity of the assay was 96.7% (3/92 false positive) and the sensitivity 98.5% (1/69 false negative). A quantitative EIA for the detection of serum antibodies which makes use of a crude, soluble L. infantum promastigote extract as capture antigen and which was used as the reference method, proved to be more specific (98.9%) but similarly sensitive (98.5%). It should be possible to produce a kit, suitable for large scale application at low cost in order to facilitate routine use of the dot-EIA in the diagnosis of VL. PMID- 8690935 TI - Apoptosis of macrophages induced by liposome-mediated intracellular delivery of clodronate and propamidine. AB - Liposomes can be used as vehicles for intracellular delivery of drugs into phagocytic cells. Clodronate and propamidine, delivered into macrophages in this way, will kill these cells as a result of intracellular accumulation and irreversible metabolic damage. The so-called liposome-mediated macrophage 'suicide' approach, which is based on this principle, is now frequently applied in studies aimed at unravelling macrophage function. In the present study, the mechanism of phagocytic cell death induced by liposome encapsulated drugs was investigated 'in vitro'. Peritoneal macrophages and macrophages of the RAW 264 cell line were cultured in the presence of the liposome encapsulated drugs clodronate, propamidine and several forms of ethylenediaminetetraacetic acid (EDTA). The results obtained suggest that apoptotic death is induced in phagocytic cells both by liposomally delivered clodronate and by liposomally delivered propamidine. Although intracellular EDTA did induce apoptosis in a minority of the experiments, the results support earlier findings that EDTA does not deplete macrophages as effectively as clodronate and propamidine. PMID- 8690936 TI - Implications for the assay and biological properties of interleukin-3. Results of a WHO international collaborative study. AB - Five preparations of interleukin-3 (IL-3) have been evaluated by 28 laboratories in 12 countries for their suitability to serve as an international standard for this material in a joint international collaborative study for IL-3 and interleukin-4 (IL-4). The preparations were assayed in a wide range of in vitro bioassays and immunoassays. It is clear from the biological assays contributed to this study that different recombinant preparations of IL-3 can have very different biological specific activities, including those from the same source (i.e., E. coli). Biological assays of IL-3 were significantly more consistent in their estimates of levels of IL-3 than the immunoassays, suggesting an unusual pattern of epitope recognition amongst the antibodies included in the immunoassays. This study also illustrates the point that the level of cytokine measured by immunoassay does not necessarily reflect the biological potency of the cytokine. On the basis of results reported here, with the agreement of the participants of the study and with the authorisation of the Expert Committee on Biological Standardization (ECBS) of the World Health Organization (WHO) the preparation of IL-3 (91/510) was established as the international standard for interleukin-3 with an assigned unitage of 1700 IU/ampoule. PMID- 8690937 TI - Implications for the assay and biological activity of interleukin-4. Results of a WHO international collaborative study. AB - Five ampouled preparations of interleukin-4 (IL-4) have been evaluated by 36 laboratories in 14 countries for their suitability to serve as an international standard for this material in a joint international collaborative study for interleukin-3 (IL-3) and IL-4. The preparations were assayed in a wide range of in vitro bioassays and immunoassays. It is clear from the study that different recombinant preparations of IL-4 can have very different biological specific activities, including those from the same source (i.e., E. coli). In addition, immunoassay estimates of IL-4 levels did not correlate with those of bioassays, illustrating the fact that immunoassays do not necessarily measure biologically active cytokine. It is of interest that the estimates provided by the different bioassays were less variable than those produced by the immunoassays, suggesting that bioassays can be as accurate, if not more so, than immunoassays. The large reduction in the variability of estimates with the inclusion of a single reference preparation clearly illustrates the need for a single standard to assay IL-4. On the basis of the results reported here, with the agreement of the participants of the study and with the authorisation of the Expert Committee on Biological Standardization (ECBS) of the World Health Organization (WHO) the preparation of IL-4 (88/656) was established as the international standard for interleukin-4 with an assigned unitage of 1000 IU/ampoule. PMID- 8690938 TI - Application of reversed-phase high-performance liquid chromatography in the purification of major allergens from grass pollen. AB - Group 1 and 5 allergens of different grasses possess similar physicochemical parameters (molecular weight, pI) and therefore separation with conventional chromatographic methods (gel filtration, ion exchange chromatography) is difficult or impossible to achieve. In this paper we describe the isolation of biologically active group 1 and 5 allergens from extracts of Lolium perenne and Phleum pratense by means of reverse phase chromatography on HPLC. The chromatograms showed very different retention times for group 1 (Rt 19.1-20.5 min) and group 5 (Rt 24.3-26.3 min) containing fractions. In addition, this technique is suitable for the separation of group 5 allergens into 5a and 5b subgroups and for the estimation of the amounts of allergen (groups 1 and 5) in the different extracts. PMID- 8690939 TI - Isolation and characterization of highly purified rat intestinal intraepithelial lymphocytes. AB - The study of intestinal intraepithelial lymphocytes (IEL) has been hindered by the difficulty of isolating a population of lymphocytes which is free of epithelial cell or lamina propria cell contaminants and representative of the in vivo population of IEL in both phenotype and function. We describe an improved technique for the extraction and purification of IEL from the proximal small intestine of the rat. This technique rapidly and reproducibly isolates 5-10 x 10(6) IEL/rat with 90-95% purity and viability without the use of enzymes which affect lymphocyte function. The resulting cell population, which is 75% alpha beta T cell receptor (TCR)+, 70% CD8+, and 33% CD4+ T cells, and only 5% B cells and 2% macrophages, is of suitable purity to allow for flow cytometric analysis of the entire population of cells without requiring gating on lymphocytes. IEL are comprised of a unique T cell repertoire in that 27% of cells co-express the CD4 and CD8 molecules, but only 11% of CD4+ cells co-express CD45RC. All CD4+ cells express the alpha beta TCR, but 9% of IEL are CD8+ CD4- alpha beta TCR-. The adhesion molecules alpha 4 integrin and L-selectin are expressed on 57% and less than 1% of IEL, respectively. The isolated IEL population contains mRNA for IL-1 alpha, IL-1 beta, IL-1R, IL-1RA, IL-2, IL-6R, IFN-gamma, TGF-alpha, TGF-beta 1, and TNF-alpha. Mesenteric lymph node cells (MLNC) were examined in parallel. This technique allows for the isolation of rat IEL appropriate for phenotypic analysis by flow cytometry and for cytokine analysis by reverse transcription/polymerase chain reaction. PMID- 8690940 TI - A simplified procedure for studies of intestinal immunity in rabbits. AB - As interest in the development of oral vaccines continues to rise, alternative animal models for studies of mucosal immunity are needed. The present study examines a simplified procedure for delivering antigen to rabbit Peyer's patches via an indwelling cannula. The cannula was placed 3-4 cm proximal to the Peyer's patch, and was used to deliver four weekly doses of the potent mucosal immunogen, cholera toxin (CT). Anti-CT specific fecal secretory IgA (S-IgA), serum IgG and serum IgA were found in essentially equal amounts in rabbits with cannulas and in rabbits fitted with Thiry-Vella (T-V) isolated ileal loops. In contrast to animals with T-V loops, the intestinal flora of animals with cannulas contained less bacterial overgrowth with Pseudomonas sp. Further, the villus architecture remained histologically normal in appearance and there were fewer post-surgical complications associated with this technique than with T-V loops. This simplified technique should allow wider use of rabbits in studies of mucosal immunity. PMID- 8690941 TI - An automated high capacity data capture and analysis system for the in vitro assessment of leukocyte adhesion under shear-stress conditions. AB - Parallel-plate flow chambers have been used to model the vascular microcirculation and study the in vitro dynamic adhesive interactions of leukocytes and human umbilical vein endothelial cells (HUVECs). We describe here a high capacity system which can simultaneously monitor the adhesive interaction of neutrophils and HUVECs in ten flow chambers. Automated data collection was achieved with an image analyzer controlling the autostage and autofocus attachments of an inverted microscope. Images from the flow chambers were captured via phase-contrast microscopy using a video camera and laser videodisk recorder. The images were downloaded off-line into an image analyzer for automated counting of rolling and adherent cells. Neutrophils were detected by their "phase bright' characteristics. An automated optimization procedure allowed the computer to choose the best setting for the selective detection of neutrophils. In addition, a method which utilized image averaging was used to distinguish between rolling and adherent cells. A comparison of the results obtained from the manual and automated counting methods revealed linear relationships for the counting of both adherent (r = 0.98) and rolling cells (r = 0.96) with counting efficiencies of 59% and 46%, respectively. The utility of the system was demonstrated by its ability to measure the adhesive interaction between neutrophils and HUVEC in response to stimulus such as interleukin-1 alpha (IL-1 alpha), histamine, or formyl-1-methionyl-1-leucyl-1-phenylalanine (fMLP). In conclusion, we have developed an automated assay which combines the capacity of ten flow chambers with a computerized data analysis system; the result is an efficient and reproducible assay which minimizes operator associated errors and biological variability. PMID- 8690943 TI - Typing of murine major histocompatibility complex with a microsatellite in the class II Eb gene. AB - Two DNA-based assays were developed for identification of the H2 alleles present in the 12 standard mouse MHC haplotypes H2b, H2d, H2f, H2j, H2k, H2p, H2q, H2r, H2s, H2u, H2v and H2z. The assays utilized polymerase chain reaction (PCR) amplification of a short stretch of genomic DNA including a highly polymorphic microsatellite from the second intron of the class II Eb gene within the murine major histocompatibility complex. The H2 Eb alleles were discerned by restriction fragment length polymorphism (RFLP) and heteroduplex analyses. For RFLP analysis amplified DNAs were digested with the restriction endonuclease Fnu4HI which delineated seven of the 12 alleles. A distinct pattern was obtained for the haplotypes H2d, H2j, H2k and H2p, whereas a group specific but distinct pattern was obtained for each of the three groups H2b, H2r and H2v, H2f, H2q and H2s, H2u and H2z. Heteroduplex analysis using a pair of haplotypes at a time helped further discriminate H2q from H2f or H2s. More importantly, heteroduplexing was quite informative in delineating the identity or disparity between two given haplotypes in a single step of PCR amplification. Both the RFLP and heteroduplex analyses are extremely sensitive and simple to operate, and since the target is genomic DNA, they can be carried out using any cell or tissue type. PMID- 8690942 TI - Tissue digestion with dispase substantially reduces lymphocyte and macrophage cell-surface antigen expression. AB - Dispase was used to digest central nervous system (CNS) tissue for isolation of the fixed tissue macrophage population (CNS microglia) and other leucocytes present. An apparent reduction in expression of some leucocyte cell surface markers was investigated further by addition of CD45b allotype-marked post activated CD4+ T cells of known phenotype to CNS tissue preparations derived from a CD45a-expressing rat strain, before enzymatic treatment. Assessment of these T cells for expression of a range of surface molecules after completion of the isolation procedure revealed almost complete loss of expression of CD4 and CD25 and reduced expression of a number of other surface antigens. PMID- 8690944 TI - The application of epitope mapping in the development of a new serological test for Helicobacter pylori infection. AB - Epitope mapping was applied to the derived amino acid sequences of the urease A and urease B genes of Helicobacter pylori. This identified 15 epitopes of which five were the most immunodominant. These were LTPKELD (Ure A), FISP, QIPTAF, EVGKVA and SIP (Ure B). Peptide 1 representing LTPKELD and peptide 2 representing EVGKVA were used to develop ELISA procedures for detecting antibody specific to H. pylori infection. The sensitivity, specificity and efficiency values for peptide 1 reactive IgM were 31.6, 92.8 and 52.5% and for peptide 1 IgG were 52.6, 35.7 and 45.4%. The corresponding values for peptide 2 IgM were 31.6, 100 and 60.6% and for peptide 2 IgG were 63.2, 71.4 and 66.6% respectively. When the tests were combined so that a positive for either peptide was counted as a positive overall the figures for IgM were 52.6, 92.8 and 69.6%. Thus epitope mapping delineated peptides against which specific IgM was produced in active H. pylori infection. PMID- 8690945 TI - Immunophenotyping of lymphocytes obtained by bronchoalveolar lavage: description of an all-purpose tricolor flow cytometric application. AB - A tricolor flow cytometric application is described which permits the determination of total T lymphocytes, T helper lymphocytes and cytotoxic T lymphocytes, natural killer cells and activated T lymphocytes under the same experimental conditions. Even when the lymphocyte count is low, when there is contamination by dust particles or when the cells are damaged the method works with high specificity and reliability. Lymphocytes are identified on the basis of their expression of the pan-leucocyte marker CD45, their side scatter, and plasma membrane integrity, assessed using the fluorescent DNA dye LDS 751. When lymphocyte subsets assessed by flow cytometry were compared with the standard immunoperoxidase method, a strong correlation was found for the CD3+, CD4+ and CD8+ cells. A weak correlation was found for CD25+ cells (r = 0.5). No correlation was seen for CD56+ cells. The high specificity of the procedure suggests that it could be used routinely for the analysis of lymphocytes in bronchoalveolar lavage fluid (BALF), especially when the BALF is contaminated by inorganic particles. Furthermore the application may contribute to the evaluation of lymphocyte subset analysis in the presence of low cell counts. PMID- 8690946 TI - [Peripheral lymphocyte subset of patients with pancreatic diabetes mellitus- about a decreased ratio of T-LGL and ability of host defense]. AB - Patients with diabetes mellitus (DM) often suffer from various and severe infection. Patients with pancreatic DM have malnutrition due to chronic pancreatitis. Therefore it is believed that patients with pancreatic DM have a lower ability of host defence to infectious diseases than normal subjects. We examined the primpheral lymphocyte subsets (T cell, B cell, NK cell, CD3+ 56+ T) of eighteen patients (males, age = 52.8 +/- 12.7 years old, mean +/- SD) with pancreatic DM by two color flow-cytometry to evaluate the lymphocyte function. Ratios of T cell (T%, 66.9 +/- 9.3%, mean +/- SD). B cell (B%, 13.1 +/- 5.8%) and NK cell (Nk%, 19.3 +/- 8.7%) to total peripheral lymphocytes of patients with pancreatic DM were not significantly different from those (T% = 66.4 +/- 7.8%, B% = 13.5 +/- 6.7%, NK% = 19.9 +/- 9.1%) of thirteen normal subjects (males, age = 51.2 +/- 13.1). CD3+56+ T cell % (4.1 +/- 1.9%) of patients with pancreatic DM was lower than that (6.0 +/- 3.0%) of normal subjects (p < 0.05). CD3+56+ T cells have cytotoxic activity and it is likely that this activity is similar to that of NK cells. These results suggested that a decrease in peripheral CD3+56+ T cell % is a factor showing a weak host defense mechanism to infectious diseases in patients with pancreatic DM. PMID- 8690947 TI - [Drug-resistance patterns and biological properties of MRSA isolated from different geographical areas of Japan]. AB - One hundred isolates of methicillin-resistant Staphylococcus aureus (MRSA) collected from hospitals located in different geographical areas of Japan were used in the present study. The susceptibilities of the strains to gentamicin (GM), erythromycin (EM), tetracycline (TC) and ofloxacin (OFLX) were determined and classified into twelve groups according to their differences in the patterns of the resistance to the four drugs. Of the 100 strains tested, 75 belonging to the main four groups were investigated for the relationships between their patterns of the drug-resistance and biological properties such as coagulase, enterotoxin and phage types, TSST-1 and beta-lactamase producibilities, and percentages of the strains carrying plasmids of large size (> or = 20,000 bp). The main four patterns of drug resistance of the 75 strains were as follows: the first group (33 strains resistant to GM, EM, TC and OFLX), the second group (15 strains resistant to EM, TC and OFLX), the third group (11 strains resistant to GM, EM and OFLX) and the fourth group (16 strains resistant to EM and OFLX) and the remaining 25 strains were divided into further groups. A considerable number of the strains in the third group differed markedly in some biological properties from those in the other groups; coagulase typing (III type-50%: the other groups II type), enterotoxin typing (64%-non-production: the other groups-C type), TSST 1 producibility (36%-production: the other groups-76 to 88%-production) and phage typing (55%-non-typable: the other groups-80 to 97%-non-typable). In beta lactamase and plasmids of large size, the first group consisted of the strains with beta-lactamase producibility at the ratio of 50:50, but the other groups consisted of most of the strains with the beta-lactamase producibility. Most of the strains belonging to the second and fourth groups carried large size of plasmids, but 36 and 46% of those belonging to the first and third groups did not carry them. On the other hand, our results of the susceptibility test for the 100 strains showed that a considerable number of strains were susceptible to GM (35%) and TC (42%) at therapeutically significant concentrations. PMID- 8690948 TI - [Follow-up of HIV carriers by a laboratory method. I: Virus isolation is useful for prognostication of the onset of symptoms]. AB - We followed 54 HIV-1 carriers (44 asymptomatic carriers and 10 AIDS patients) by virus isolation and immunological examination and evaluated their usefulness for prognostication of the onset of symptoms. From 37 carriers (27 asymptomatic carriers and 10 symptomatic), 132 HIV-1 strains were isolated; the virus isolation rate was 60% in the asymptomatic carriers (AC) but 100% in the symptomatic. In the AC, the isolation rate was 54.5% in the group showing stable in the CD4+ level but 95.5% in the group showing a decrease in the CD4+ level. With progression of the disease, the culture time required for virus isolation was shortened, and the percentage of isolates showing infectivity to the T-cell line (MT-4 cells) increased. These findings suggest that the virus in the body is changed with progression of the disease to that showing rapid replication, T-cell tropic, and high pathogenicity. Indeed, progression of the disease was observed in all carriers in whom a highly pathogenic virus was detected; some developed the disease within 1 year, some showed temporary recovery in the CD4+ level after AZT administration followed by progression to ARC, and others showed a rapid decrease in the CD4+ level. In contrast, in carriers with only slightly pathogenic virus, the CD4+ level was maintained for a long period. These results suggest that the detection of a highly pathogenic virus is one of the most reliable marker for the prognostication of the onset of the disease. The detection of HIV-1 antigen in the plasma and a decrease in the gag antibody were also associated with the progression of the disease. However, the reliability of these markers seems to be lower than that of virus isolation. PMID- 8690949 TI - [Prognosis and evaluation of drug therapy by V3 and RT gene analysis of HIV-1]. AB - We have reported on the investigation of 54 HIV-1 patients concerning the isolation and clinical marker in the preceding paper. We have attempted the analysis of the V3 and RT genes. HIV-1 from a patient who had rapidly taken a turn for the worse had basic amino acid at position 11 (Arg) and lost an acidic amino acid at position 25 (Gln) of V3. This sequence pattern was a distinguished feature of a virus with a rapid-high, syncytium inducing (SI) and T-cell-line tropic phenotype. In contrast, patients with no or mild clinical symptoms had sequences characterized as slow-low, non-synsytium inducing (NSI) and macrophage tropic. We then investigated the appearance of resistant to AZT and ddI. It was shown that the virulent virus obtained drug resistant variants faster than the wild type by analysis of the RT gene. We consider that these data concerning virus isolation and gene analysis are useful for prognosis and strategy for clinical therapy. PMID- 8690951 TI - [Evaluation of a new rapid detection system for mycobacteria using an oxygen sensitive fluorescent sensor]. AB - A comparison of the rate of recovery and time for detection of mycobacteria from clinical specimens of the newly developed Mycobacteria Growth Indicator Tube (MGIT), the biphasic Septi-Chek, and the egg-based Ogawa medium was made. From the 305 sputum specimens processed, a total of 83 mycobacterial isolates were detected. From these 80 (84.3%) isolates were detected with both the MGIT and Septi-Chek systems, respectively, and 50 (60.2%) were detected by the Ogawa egg method. The difference in the percentages of positive cultures between the two systems based on liquid media and the Ogawa egg method was significant (p < 0.001). The mean time for the detection of the Mycobacterium tuberculosis complex were 16.3 days with the MGIT system, 25.6 days with the Septi-Chek, and 21.5 days with Ogawa egg method. These results indicate that the MGIT system is efficient for the recovery of mycobacteria. PMID- 8690950 TI - [Relation between nutrition of patients and methicillin-resistant Staphylococcus aureus (MRSA)]. AB - We respectively evaluated the nutritional state of 31 patients who isolated Methicillin-resistant Staphylococcus aureus (MRSA) was isolated from January to November in 1993. Because 4 of 31 isolates were not considered to be a causative bacteria, we evaluated the rest 27 cases. Fifteen of 27 cases were diagnosed as MRSA infection and 12 (44%) MRSA colonization. We evaluated the nutritional state of patients with infection and colonization. There was significance (p < 0.01) between two groups as for serum total protein were 5.52 g/dl in infection group and 6.65 g/dl in colonization group. Furthermore there were significance (p < 0.05) for mean serum albumin were 3.04 g/dl v.s. 3.58 g/dl and total cholesterol were 122.3 mg/dl v.s. 162.5 mg/dl. Thus, MRSA was colonized in respiratory patients who were in better nutritional state, suggesting that importance of nutritional improvement for prevention and therapy against MRSA infection. We obtained similar results on Methicillin-sensitive Staphylococcus aureus (MRSA). PMID- 8690952 TI - [A case of infective endocarditis with purpura and macroscopic hematuria as initial manifestations]. AB - A 44-year-old female admitted to our hospital because of fever, purpura and macroscopic hematuria. She had been diagnosed as having ventricular septal defect (VSD). She noticed purpura with pain on bilateral legs and macroscopic hematuria since September 18, 1994. Three weeks later she also manifested a fever. Physical examination of admission revealed numerous purpura and leg edema. Laboratory data showed macroscopic hematuria, marked anemia (Hb 3.3 g/dl), leukocytosis, azotemia (Cr 2.7 mg/dl) and positive acute phase reactants. Increased serum immune complex level and hypocomplementemia were also found. The diagnosis of allergic purpura was made initially, but positive blood culture of Streptococcus mitis and the detection of vegetation attached to the right ventricular wall near the ostium of the VSD made the definite diagnosis of infective endocarditis (IE). Chemotherapy with PCG was started for two weeks but with no effect. The chemotherapy was altered to panipenem/betamipron with a daily dose of 3 g, Then, her fever fell and purpura, macroscopic hematuria and renal failure gradually disappeared. In this case, the cause of renal manifestations was considered to be immune complex glomerulonephritis. This is the first report of IE with macroscopic hematuria due to immune complex glomerulonephritis. PMID- 8690953 TI - [A case of psoas abscess associated in the elderly]. AB - A case of psoas abscess associated with diabetes mellitus in the elderly is reported. A 81-year-old male who had been followed for cerebral thrombosis, diabetes mellitus and basal cell carcinoma was admitted to our hospital because of high fever. Leukocytosis, a positive CRP test and pyuria were seen. Proteus mirabilis and Escherichia coli were detected by urine and blood culture, respectively. He was treated with antibiotic therapy for urinary tract infection and sepsis. After starting treatment, a low grade fever continued. On the twenty first hospital day he developed pyrexia again, and a large abscess was demonstrated in the right psoas muscle by pelvic couputed tomography. The abscess was drained and a specimen from it yielded E. coli on culture. Treatment with antibiotics and drainage resulted in symptomatic improvement. In Japan, 82 cases of psoas abscess have been reported from 1990 to 1994. Four cases of these reports were above eighty years old. The experience with this case indicates the necessity of adequate care in cases of elderly diabetes complicated by psoas abscess. PMID- 8690954 TI - [A family outbreak of Chlamydia psittaci infection]. AB - A family outbreak (3 cases) of Chlamydia psittaci infection was reported. The first case, a 56-year-old man was admitted with fever and general fatigue. Chest X-ray film revealed a consolidation in the right lower lung. One month before admission he had purchased 2 parakeets (chick) and one parakeet died. On learning of his history of contact with the chick, psittacosis was suspected. After administration of fixation (CF) antibody titer against chlamydia rose to 1:128 and IgA titer against Chlamydia psittaci by microimmunofluorescence antibody technique (MAF) rose to 1:128 in 21 days after admission. The second case, the wife of the first, a 53-year-old woman had a fever and a cough about two weeks before the admission of the first case. At the time of her husband was admitted, she attended the outpatient department. The chest CT X-ray film showed a ground glass appearance in both lower lung fields. The third case, the daughter of the first, didn't have any signs. Chest X-ray film was normal. But IgM titer against Chlamydia psittaci by MAF rose to 1:16 and IgA titer against Chlamydia psittaci by MAF rose to 1:128. This case was considered as inapparent infection. PMID- 8690955 TI - [A case of empyema caused by Salmonella enteritidis in a patient with sequela of pulmonary tuberculosis]. AB - A 69-year-old male was admitted to our hospital on Jan. 10, 1995 complaining of bloody sputum, left back pain and fever of 39 degrees C. He had a history of pulmonary tuberculosis 45 years ago. His chest X-ray and CT showed the presence of air-fluid level in the left pleural cavity with thickening and calcification of the pleura. Salmonella Enteritidis was isolated from the sputum, bronchoalveolar lavage fluid and stool. He was diagnosed as suffering from Salmonella-empyema with an internal fistula. Based on the in vitro sensitivity test, sulfamethoxazole/trimethoprim was started. However, the efficacy of the antimicrobia was not sufficient. He then underwent left pleuropneumonectomy. Salmonella was cultured also from the specimen obtained at the operation. His course after operation was uneventful. Thus, although Salmonella Enteritidis is known as a common pathogen of food poisoning, it can cause empyema, especially in a case with an impaired host defence system. PMID- 8690956 TI - [Detection of hepatitis A virus in serum by PCR method]. PMID- 8690957 TI - Pilot project on functional outcome in stroke. AB - The purpose of this pilot project was to compare the outcome of stroke survivors cared for on an Acute Stroke Unit (ASU) to those who received care on a routine medical-surgical unit. The sample included a total of 88 patients, 68 admitted to an acute stroke unit and 20 admitted to a medical-surgical unit. The Functional Index Measure was used to assess in-hospital functional gains in the two groups. There appeared to be a trend toward increased functional gains in the group of stroke patients cared for on the Acute Strike Unit as compared to the group of patients cared for on medical-surgical units. These findings provide a foundation for neuroscience nurses and other health care professionals to study functional gains after stroke. PMID- 8690958 TI - How to have a stroke at an early age: the effects of crack, cocaine and other illicit drugs. AB - Illicit drugs have rapidly become one of the most frequent causes of stroke in the under 45 years of age group. Stroke and death can occur for either the first time or long-term user due to the pharmacologic actions of the drugs. The neuroscience nurse needs to be aware of the potential for stroke that can occur with illicit drugs and be prepared to intervene appropriately. PMID- 8690959 TI - Understanding central post-stroke pain. AB - Almost a century ago, two French neurologists described an unusual pain syndrome following stroke. This so-called "thalamic" pain of Dejerine-Roussy exists today, affecting approximately 30,000 survivors of stroke in the United States (US) alone. Lesions involving the neospinothalamocortical tract are thought to cause thalamic pain, but the exact pathogenesis is unclear. Pharmacotherapeutic and surgical approaches offer pain relief in selected patients. Although definitive relief of central post-stroke pain (CPSP) may not be achievable for all at this time, intelligent and informed examination of the full range of options offers every sufferer a real potential for relief and mastery of pain. It is hoped that information provided herein will foster "intelligent caring" and facilitate informed decision making by consumers and caregivers alike. PMID- 8690960 TI - Brain attack: a body of knowledge, a coalition of support. PMID- 8690961 TI - Neurodevelopmental treatment: application to nursing and effects on the hemiplegic stroke patient. AB - Nursing care of the hemiplegic stroke patient is based on a traditional approach, using compensatory rehabilitative principles. However, during recent years, the neurodevelopmental treatment (NDT) approach, based on the noncompensatory rehabilitative principles and focused on activating the affected side of the hemiplegic stroke patient, is increasingly begin applied to neuroscience nursing. Until recently, little evidence existed to support the superiority of the NDT approach. The NDT approach requires considerable investment in education and training. Therefore, benefit of the NDT approach in comparison to the traditional approach must be assessed and interventions applied accordingly. PMID- 8690962 TI - Assessment and management of hypertension in the acute ischemic stroke patient. AB - The assessment and treatment of hypertension in the patient with acute ischemic stroke is a controversial issue in the overall management of such patients. The primary physiologic and pathologic concepts at the core of the issue are autoregulatory failure and shift, cytotoxic and vasogenic edema, vascular pathology and hemorrhage. Clues about the interrelationships of these factors to hypertension in the acute stroke patient are available to the nurse. By integrating pathophysiologic concepts with knowledge gained during assessment of stroke onset, patient history and clinical presentation, the nurse is better prepared to monitor and provide care for the acute stroke patient. PMID- 8690963 TI - Medical futility and life-sustaining treatment decisions. AB - By focusing our attention on the questions of "what are we trying to achieve" and "are we able to do it", the discussion of medical futility has contributed an important dimension to the ethics of treatment decision making near the end of life. It is not simply enough to ask and answer the question of what the patient wants. Healthcare professionals have a responsibility to offer only those life sustaining efforts that have a reasonable chance of being beneficial. Futility policies should permit treatment-limiting decisions to be made without the agreement of the patient or surrogate at times, but such policies should also provide opportunities to challenge a judgement of futility. Above all, such policies should not be used as a reason to avoid communication. Patients or surrogates need to be informed about what treatments are options and what are not. The futility criterion for limiting treatment should be recognized as a means of contributing to communication and discussion regarding benefits, harms and medical goals. It should not be permitted to bypass such discussions. The recognition of the significance of the concept of futility means that discussion needs to continue at another level as well. The questions of "what are we trying to achieve" and "are we able to do it" are not easily answered. It is especially important, we think, that those who are experienced in working with patients with neurological impairments contribute to the on-going reflection on what constitutes benefit or what is the appropriate use of life-sustaining interventions for such patients. PMID- 8690964 TI - Asymptomatic patients benefitting from endarterectomy. PMID- 8690965 TI - Is snoring a risk factor for stroke? PMID- 8690966 TI - Opening of stroke prevention in African-American study. PMID- 8690967 TI - Selective decrease of M. leprae-specific IgG1 and IgG3 antibodies in leprosy patients associated with ENL. AB - Erythema nodosum leprosum (ENL) is a serious complication of lepromatous leprosy. Because of the similarities with the Arthus-type reaction, ENL is presumed to be due to immune complex formation and their deposition in tissues. The aim of this study was to dissect the antibody response at the IgG subclass level to ascertain differences in IgG subclasses in nonreactional lepromatous/borderline lepromatous (LL/BL) patients and reactional (ENL) lepromatous patients. The ENL group showed significantly lower serum antibody levels for the four subclasses compared to the LL/BL group of patients using the Mann-Whitney U test (IgG1, p = 0.0001; IgG2, p = 0.0009; IgG3, p = 0.0001; IgG4, p = 0.03). Since the majority of ENL patients (54 of 67) had received leprosy chemotherapy for varying durations of time, LL/BL patients were also compared with 19 ENL patients who had received < or = 2 weeks of chemotherapy. In this group only IgG1 (p = 0.048) and IgG2 (p = 0.001) antibodies showed significantly lower concentrations. Immunoblotting analysis demonstrated that in ENL patients IgG1 showed a selective disappearance of several antigenic bands recognized by the LL/BL serum pool; while most of the antigens recognized by IgG3 antibodies in the LL/BL serum pool were not detected in the ENL serum pool or in the sera of pretreated individual ENL patients. These results suggest that IgG1 and IgG3 may be the most pathogenic IgG subclass antibodies during ENL, and their deposition in tissues could initiate the complement-mediated inflammatory pathway resulting in the clinical disease associated with ENL. PMID- 8690968 TI - Alterations in serum lipids in lepromatous leprosy patients with and without ENL reactions and their relationship to acute phase proteins. AB - The concentrations of serum lipids were measured in patients with lepromatous (LL/BL) leprosy and erythema nodosum leprosum (ENL). The relationships between serum lipid levels and serum amyloid A (SAA) and C-reactive protein (CRP) were also examined in these patients. LL/BL patients had significantly higher serum triglyceride and lower HDL-cholesterol concentrations compared to the endemic controls. ENL patients had significantly lower total, HDL- and LDL-cholesterol levels compared to the endemic controls. The levels of all lipid metabolites also were significantly lower in ENL patients compared to LL/BL patients. The concentrations of SAA and CRP were markedly elevated in ENL patients but were not statistically different in LL/BL patients compared to control subjects. There was a significant negative correlation between SAA and HDL-cholesterol levels in both stable lepromatous and reactional (ENL) patients; there was no statistically significant correlation between CRP and HDL-cholesterol levels. SAA levels also had a significant negative correlation with total and LDL-cholesterol levels. Our results indicate that serum lipids are significantly altered in patients with lepromatous disease and ENL reaction. Our results also suggest that an increase in SAA levels may divert the metabolism of lipoproteins from hepatocytes toward macrophages, resulting in a decrease in serum lipoprotein levels. PMID- 8690969 TI - Fixed-duration therapy (FDT) in multibacillary leprosy; efficacy and complications. AB - The World Health Organization (WHO) recommended a multidrug therapy (MDT) regimen for multibacillary (MB) leprosy patients in 1982 which was to be administered for a minimum period of 2 years or until a skin smear was negative for acid-fast bacilli, whichever was later. This regimen contains rifampin, dapsone and clofazimine. A single dose of rifampin was shown to effect a high degree of bacterial killing (99.9%). The combined therapy administered for 2 years may be adequate to bring about "total" bacterial killing and to prevent the emergence of drug resistance and persisters. In this study, 360 smear-positive and previously untreated MB leprosy patients were treated with WHO/MDT for 2 years; 22.8% of these MB patients developed lepra reaction during therapy and 10.7% during surveillance. The bacterial index continued to decline even after termination of fixed-duration therapy. None of these patients relapsed during 886 person-years of surveillance. PMID- 8690970 TI - Effectiveness of MDT in multibacillary leprosy. AB - The study on the use of World Health Organization multidrug therapy (WHO/MDT) under field conditions was initiated in December 1981, and included 1067 multibacillary (MB) patients treated with two MDT regimens. The first was a THELEP-recommended regimen which consisted of 600 mg of rifampin (RFP) and 600 mg of clofazimine (CLO) given under supervision on two consecutive days monthly and 225 mg of diacetyl diaminodiphenylsulfone (DADDS) bimonthly plus dapsone (DDS) 100 mg daily unsupervised. The second regimen was the conventional MDT: patients received RFP 600 mg and CLO 300 mg supervised once a month, daily 100 mg of DDS and 50 mg of CLO unsupervised. A zero relapse rate was obtained after more than 10 years (a total of 8244 person-years) of follow up. Both regimens were well tolerated with few complications and a high acceptability, even among women. The fall in the bacterial index (BI) was 0.5 - 1.0+ in positive patients. CLO discoloration began to decrease after 3 months and disappeared within 1 year after it was discontinued. Seventy-two patients (67%) developed reactions during the treatment period; a further 12 patients developed post-treatment reactions during the surveillance period. This study vindicates MDT treatment for MB patients as recommended by WHO under field conditions. PMID- 8690971 TI - Absence of relapse within 4 years among 34 multibacillary patients with high BIs treated for 2 years with MDT. AB - Thirty-four multibacillary patients with a bacterial index (BI) of 3+ or more were treated with 2 years of WHO multidrug therapy (WHO/MDT). Treatment was then stopped and the patients followed for a minimum of 4 years. The rate of fall in the BI in this group without further treatment was similar to the rate of fall in the BI in an earlier group of similar patients treated with MDT until skin-smear negativity. No relapses have been seen. PMID- 8690972 TI - Drug resistance in Nepali leprosy patients. AB - Although multidrug therapy (MDT) was introduced into Nepal in 1983, the MDT coverage only recently exceeded 67%. In view of the large number of patients who were still receiving dapsone monotherapy, it is relevant to investigate the current levels of dapsone and rifampin resistance. The study was undertaken at a leprosy referral hospital near Kathmandu. Over a 5 1/2-year period, 157 leprosy patients with a bacterial index (BI) > or = 2.0 were investigated for drug resistance according to the method of Rees. Among previously untreated cases, 6% of 88 isolates showed low-dose dapsone resistance; among previously treated patients with a presumed relapse, 47% of 34 isolates demonstrated dapsone resistance. In the remaining 35 cases there was no growth in control mice. Rifampin resistance was not confirmed in any case. PMID- 8690973 TI - Determination of the minimal effective dosages of ofloxacin and sparfloxacin against M. leprae in the mouse foot pad system. AB - The minimal effective dosages (MEDs) of ofloxacin (OFLO) and sparfloxacin (SPFX) against 10 isolates of Mycobacterium leprae were measured in the mouse foot pad system. The drugs were administered either by gavage or by incorporation into the mouse diet in a range of concentrations. The results demonstrated that the MEDs of OFLO were 4 to 5 times higher than those of SPFX, thus confirming that, on a weight-to-weight basis, the anti-M. leprae activity of SPFX was significantly greater than that of OFLO. The MEDs of OFLO/SPFX measured by gavage were 20 times lower than those measured by incorporating the drug into the mouse diet. PMID- 8690974 TI - Infection of distal peripheral nerves by M. leprae in infected armadillos; an experimental model of nerve involvement in leprosy. AB - Mechanisms of localization of Mycobacterium leprae to the peripheral nerves and of subsequent nerve injury are not understood. No experimental animal model has been available for use in examining the pathogenesis of M. leprae-induced nerve injury. A detailed dissection was, therefore, done of the major peripheral nerves in the extremities of six M. leprae-inoculated armadillos, three of which had developed characteristic disseminated infection. All of the animals with disseminated infection had extensive involvement of the peripheral nerves, increasing in intensity as the nerve was followed distally. No M. leprae were found in the animals without disseminated infection. The degree of infection was greater in epineural tissues than in the intraneural compartment (i.e., Schwann cells) at all levels. The infection of nerves by M. leprae was associated with focal interstitial, mononuclear cell infiltration of involved nerves. These results suggest that: 1) armadillos offer a model for the study of neural involvement in leprosy, since the pattern of neural distribution in susceptible armadillos is comparable to the pattern of nerve involvement in man; 2) early localization of M. leprae may be to the epineural tissues, including lymphatic and vascular structures and extracellular matrix; 3) Schwann cell involvement may be a late event; and 4) mechanisms involving the endothelium of epineural and perineural tissues may be important in the selective localization of M. leprae to peripheral nerves. PMID- 8690975 TI - Evolution of lymphocyte populations in armadillos (Dasypus novemcinctus) inoculated with M. leprae. AB - In human leprosy patients there are changes in the percentages of T and B lymphocytes in peripheral blood, and there is a correlation with the clinical characteristics or manifestations of the disease. These phenomena still require clarification regarding the triggering mechanism involved that may lead to one or the other clinical entities. Much has yet to be learned about the intricacies of whether the changes in subpopulations of T and B lymphocytes are a causative factor or an effect attributable to the microorganism itself. The armadillo is an excellent animal model to study how Mycobacterium leprae spread, turning into an established infection. The application of modifications in percentages of the subpopulations of B and T lymphocytes in armadillos may well lead to extrapolation of the results obtained in this animal model in an attempt to be able to manipulate the course of the disease in humans. The purpose of the study was to evaluate changes in the percentages of rosette-forming and sIgM+ mononuclear cells during a full year in groups of armadillos: five randomly chosen animals formed the control group and 11 armadillos were inoculated with M. leprae obtained from a human leproma at the onset of the 12-month period of the study. Of the 11 randomly selected armadillos that were inoculated, only five developed an active and disseminated infection. The percentage of rosette-forming cells did not show statistically significant variations during the first 6 months of the study. However, at months 8 and 12 a significant increment in this parameter was observed (p < 0.05) in the animals with active infection. In regard to the variations in the numbers of sIgM+ cells, significant changes occurred in the armadillos with active infection at month 2. However, results returned to normal and no changes were seen at later times. No significant changes occurred in the group of animals inoculated but not developing active infection compared with the other groups. The results are considered sufficiently interesting to encourage further study on the cell-mediated immune system of the armadillo and the changes that occur during the development and dissemination of an inoculated infection with M. leprae. Since this mammal is of great value as an effective animal model in the experimental research of M. leprae, there is an urgent need to obtain, as quickly as possible, a thorough understanding of the cellular branch of its immune system and, thereby, be in a position to extrapolate immune modulation to benefit human leprosy patients. PMID- 8690976 TI - Ultrastructure of normal armadillo epidermis. AB - In view of the importance of the nine-banded armadillo (Dasypus novemcinctus) in leprosy research, we studied the ultrastructure of the normal epidermis of this species. The three basic cell types of human epidermis were identified in armadillo skin: keratinocytes, melanocytes, and Langerhans' cells. The role of Langerhans' cells in the human cell-mediated immune system and the description of changes in the number and structure of Langerhans' cells in human leprosy make detailed observations of these cells in the armadillo highly relevant. Clear cells with ultrastructural features typical of Langerhans' cells were observed in normal armadillo epidermis in all areas of skin sampled (abdomen, chin, ear, and thigh), but are fewer than in human skin. These baseline findings are valuable for further studies on Langerhans' cells and the cell-mediated immune function in armadillos with naturally acquired or experimental leprosy. PMID- 8690977 TI - Discoid lupus erythematosus and lepromatous leprosy. PMID- 8690978 TI - Changes of autonomic nerve function in the first two weeks of acute neuritis in a patient with borderline leprosy. PMID- 8690979 TI - Leprosy and AIDS in the Amazon basin. PMID- 8690980 TI - TT leprosy: does it indicate percutaneous infection? PMID- 8690981 TI - Results of a surveillance system for adverse effects in leprosy's WHO/MDT. AB - The implementation of the World Health Organization's multidrug therapy (WHO/MDT) in Brazil began slowly and gradually in 1986, and in 1991 it was adopted officially by the Brazilian Ministry for Health. After 1991, during the intensive phase of WHO/MDT implementation, there was some concern about the number of cases of renal failure observed in several Brazilian states, including some fatalities. This was the motive behind the state of Sao Paulo's Health Department's decision to carry out a study that would evaluate not only the incidence rate of adverse effects of rifampin in relation to kidney function but also in relation to the use of WHO/MDT in general. Due to the existence in the state of Sao Paulo of health services with a program for the control of Hansen's disease and an organized and stratified system of epidemiological surveillance, it was possible to elaborate a subsystem for data collecting. During the period from July 1991 to December 1993, 20,667 patients were treated with WHO/MDT. Among this group there were 127 notifications considered as adverse effects, mainly: "flu"-like syndrome (54), acute renal failure (20), cutaneous reactions (15), toxic hepatitis (15), gastrointestinal complaints (8), hemolytic anemia (6), methemoglobinemia (4), thrombocytopenic purpura (2), hypotension (2) and disseminated intravascular coagulation (1). There was a predominance of adverse effects among multibacillary (MB) patients and the majority of the reactions occurred before the 6th dose; 82.7% of MB patients had had previous treatment with dapsone and rifampin and, due the fact that most severe reactions were related to rifampin, a booster mechanism could be an explanation for this occurrence. So far, there are seven published reports on renal failure in the world, and in Brazil only in the state of Soao Paulo there were 20 cases reported among 20,667 patients under WHO/MDT treatment, This striking difference deserves a better explanation, but in no way do these reports undermine the positive aspects of WHO/MDT. However, the authors believe that a world alert about its possible serious side effects is not only necessary but ethically required. PMID- 8690982 TI - [A review for the past 20 years in spine and spinal cord injuries]. PMID- 8690983 TI - [Pathogenesis and treatments for hallux valgus]. PMID- 8690984 TI - [Interview of the orthopaedics]. PMID- 8690985 TI - [New paradigm of medical science]. PMID- 8690986 TI - [Study of cancers as genetic diseases]. PMID- 8690987 TI - [Current status and future estimation of patients with cancers in Japan]. PMID- 8690988 TI - [Ectopic cytokine syndrome]. PMID- 8690989 TI - [Three-dimensional image diagnosis of neoplasms]. PMID- 8690990 TI - [Drug therapy of hematologic malignancy]. PMID- 8690992 TI - [Progress on the treatment of tumors--present status and future of bonemarrow and peripheral hematopoietic stem cell transplantation]. PMID- 8690991 TI - [Chemotherapy of solid tumor]. PMID- 8690993 TI - [Present status of gene therapy in cancer]. PMID- 8690994 TI - [Cancer patient care--informed consent and disease notification]. PMID- 8690995 TI - [Cancer patient care--management of intractable pain in patients with cancers]. PMID- 8690996 TI - [Palliative care of patients with neoplasm]. PMID- 8690997 TI - [Malignancy associated with hypercalcemia]. PMID- 8690998 TI - [Topics on diagnosis and therapy of thyroid diseases]. PMID- 8690999 TI - [Diabetes and pregnancy]. PMID- 8691000 TI - [Clinical study of spinal cord diseases]. PMID- 8691001 TI - [Electrophysiological diagnosis and therapy of peripheral nerve demyelinating diseases]. PMID- 8691002 TI - [Diagnosis and therapy of juvenile muscular atrophy of distal upper extremity]. PMID- 8691003 TI - [Primary biliary cirrhosis and ursodeoxycholic acid therapy]. PMID- 8691004 TI - [Physiopathology and therapy of alcoholic liver disease]. PMID- 8691005 TI - [Ulcerative colitis and Crohn disease]. PMID- 8691006 TI - [Recent topics on collagen diseases]. PMID- 8691007 TI - [Recent view on drug therapy of bronchial asthma]. PMID- 8691008 TI - [Characteristic and therapy of hypertension in the aged]. PMID- 8691009 TI - [Autonomic nervous systems and cardiovascular diseases]. PMID- 8691010 TI - [Recent trend on study of therapy and pathophysiology of ischemic heart diseases]. PMID- 8691011 TI - [Clinical study of HIV infections]. PMID- 8691012 TI - [Molecular biology of lung neoplasms--progress of the basic understandings of solid tumors in general and the application to clinical study]. PMID- 8691013 TI - [Recent trends in the treatment and physiopathology of bronchial asthma]. PMID- 8691014 TI - [Present status of peripheral hematopoietic stem cell transplantation]. PMID- 8691015 TI - [Procedure of diagnosis and therapy of myelodysplastic syndrome]. PMID- 8691016 TI - [Early diagnosis and therapy of diabetic nephropathy]. PMID- 8691017 TI - [Physiopathology and therapy of IgA nephropathy]. PMID- 8691018 TI - In vitro rejoining of double-strand breaks in cellular DNA by factors present in extracts of HeLa cells. AB - We described previously a cell-free assay, that could be employed to study the rejoining of radiation-induced DNA double-strand breaks (dsb) in agarose embedded nuclei by activities present in an extract prepared from exponentially growing HeLa cells. Here, we extend the study and present an in vitro assay for rejoining of radiation-induced DNA dsb that employs 'naked' DNA prepared from agarose embedded cells as a substrate and extract of HeLa cells as an enzyme source. There is no detectable residual protein on substrate DNA after extensive lysis with ionic detergents and treatment with proteases, as determined by SDS-PAGE and silver staining. We demonstrate that rejoining of dsb is absolutely dependent on cell extract and that, under optimal reaction conditions, it proceeds to an extent and with kinetics similar to those observed in intact cells. Dsb rejoining in this assay requires Mg 2+ and is inhibited by high concentrations of either K+ or Na+. This assay complements the nuclei assay for DNA dsb repair previously developed, and may be preferable to the latter in the purification of factors involved in DNA dsb repair, as it employs as substrate DNA deprived of proteins. PMID- 8691019 TI - Induction of DNA double-strand breaks by ionizing radiation at the c-myc locus compared with the whole genome: a study using pulsed-field gel electrophoresis and gene probing. AB - Ionizing radiation-induced double-strand breaks (dsb) in a human colon carcinoma derived cell line COLO320HSR were determined from the fragment size distribution of non-specifically labelled DNA and Sfi I restriction enzyme-digested DNA uniformly labelled with a c-myc probe. The dose-effect relation for the induction of DNA dsb was linear with no significant difference between slopes for the curves in the whole genome (7.2 +/- 0.3 x 10(-9) dsb/bp/Gy) and in the 130 kbp restriction fragments containing c-myc (6.5 +/- 0.5 x 10(-9) dsb/bp/Gy). The size distribution of the c-myc fragments showed deviations from the random-breakage model, indicating heterogeneity of dsb induction at this locus. PMID- 8691020 TI - Cell-cycle variation in DNA migration in pulsed-field gel electrophoresis. AB - Pulsed-field electrophoresis is being used extensively in the gene mapping studies and in the analysis of DNA strand breakage by ionizing radiation. We have evaluated the relationship between the fraction of S phase DNA in a cell population and its ability to modify the migration of DNA in pulsed-field gel electrophoresis. We have shown that increasing the proportion of S phase DNA reduced the effective rate of migration of MGH-U1 cellular DNA. This effect was observed after treatment with ionizing radiation or the restriction enzyme Not I. However, when radiation-induced damage was studied using intact cells, only the DNA with 70 percent S phase showed apparent differences in damage induction. These studies therefore provide data to indicate the percentage of S phase cells at which overall DNA migration might be affected significantly. PMID- 8691021 TI - Chromosome analysis in X-irradiated primary cells of a human squamous cell carcinoma by fluorescence in situ hybridization. AB - Chromosomes in primary tumour cells derived from a squamous cell carcinoma of the gingival mucosa were analysed. The ploidy of individual chromosomes and the frequencies of reciprocal translocations in unirradiated and irradiated cells were assessed by the method of fluorescence in situ hybridization. Hybridization probes for whole chromosomes 1, 2, 3, 4, 9 and 12 were used. The analysis was carried out in early (1st-3rd) passage cells and for comparison, in late (25th 30th) passage cells. A radiation-induced polyploidy of all analysed chromosomes was observed in irradiated (D = 4 Gy) early as well as late passage cells, with the exception of chromosome 4 in late passage cells. Ploidy of chromosomes 1 and 4 was studied at lower doses (1-3 Gy), too. Polyploidy was observed for doses >2 Gy. Some of the analysed chromosomes showed a high 'spontaneous' translocation frequency in both types of cells. The frequencies of radiation-induced translocations were similar in early and late cells and these frequencies were not always proportional to the length of the chromosomes studied. The radiosensitivity of individual chromosomes was not correlated with the level of spontaneous translocation frequency. PMID- 8691022 TI - Comparison of the yields of translocations and dicentrics measured using conventional Giemsa staining and chromosome painting. AB - Inconsistent results have been reported regarding the yields of translocations and dicentrics measured using chromosome painting. This inconsistency may be due to mis-scoring of dicentrics as translocations because painting is unsuited to identify centromere positions. In the present study, chromosome aberrations exclusively in the first mitosis after irradiation were analyzed using human peripheral lymphocytes. When identical metaphases were analyzed by both painting and conventional Giemsa staining, which is the most reliable method to locate centromeres, equal frequencies of translocations and dicentrics were observed. PMID- 8691023 TI - Malignant transformation of human fibroblasts by ionizing radiation. AB - As one step in developing an assay for quantifying the induction of malignant transformation of human cells by ionizing radiation, we exposed cells from a non tumorigenic, infinite life span, near-diploid fibroblast strain MSU-1.1 to 4.35 Gy 60Co radiation and assayed them for focus formation. The mean frequency of foci in the irradiated population was 6 x 10(-7) cells assayed. No foci were found in the control cells. Of four focus-derived cell strains studied in detail, two produced malignant tumours within 3-7 weeks. The other two did not produce tumours during the 12-month period of study. The tumours from one strain were classified as sarcomas composed exclusively of spindle-shaped cells. Tumours from the other strain were sarcomas consisting of a mixed population of round and spindle cells. Immunoprecipitation analysis of the status of the p53 gene in the focus-derived strains, using a mutant-specific anti-body (Pab240) and an antibody that recognizes both mutant and wild-type p53 protein (Pab421), showed that the tumorigenic strains were completely devoid of p53 protein. One non-tumorigenic strain expressed wild-type p53 protein, and the other expressed a lower molecular weight form of the protein. Karyotypic analysis showed that the tumour-derived cells from one tumorigenic strain had lost one copy of chromosome 6, 14, 16 and 17. The tumour-derived cells from the second strain had lost one copy of chromosome 7, 13, 14 and 17 and part of chromosome 6, as well as part of the other copy of chromosome 7 and 17. These results suggest that the common loss of one copy of chromosome 14, 17 and part of 6 plays a causal role in the malignant transformation of these cells. Furthermore, the results indicate that it will be possible to develop a system that uses near-diploid human fibroblasts to quantify radiation-induced malignant transformation. PMID- 8691024 TI - Evaluation of a modified micronucleus assay. AB - The relationship between ionizing radiation-induced cell killing and DNA damage measured by the micronucleus assay was determined in three established cell lines (L929, HL-60, and Chang). Our data revealed a dose-dependent increase of cells bearing multiple micronuclei. Cells with the same number of micronuclei were counted separately up to 50 h after irradiation. The counts of these subsets showed a parallel increase and decrease throughout the study. In order to transform the peak of the micronucleus frequency, occurring over only a brief time period into a less time dependent value, we calculated ratios between the different subsets of micronucleated cells. These ratios converged to values which were almost constant beyond 30 h after irradiation. The values showed correlations with cell survival (clonogenic assay) and radiation dose which were comparable with the correlations with the peak of the micronucleus frequency (maximum micronucleus yield) when utilizing the conventional evaluation of the micronucleus assay performed without cytochalasin B. This means that large-scale time kinetics and additional drugs like cytochalasin B can be avoided by changing the evaluation procedure of the conventional micronucleus assay. The modified assay described in this manuscript revealed apoptosis-induced limitations as recently detected for the maximum micronucleus yield assay. PMID- 8691025 TI - Inactivation of V79 cells by low-energy protons, deuterons and helium-3 ions. AB - Previous work by ourselves and by others has demonstrated that protons with a linear energy transfer (LET) about 30 keVmum(-1)are more effective at killing cells than doubly charged particles of the same LET. In this work we show that by using deuterons, which have about twice the range of protons with the same LET, it is possible to extend measurements of the RBE of singly charged particles to higher LET (up to 50 keVmum(-1). We report the design and use of a new arrangement for irradiating V79 mammalian cells. Cell survival measurements have been made using protons in the energy range 1.0-3.7 MeV, deuterons in the energy range 0.9-3.4MeV and 3He2+ ions in the energy range 3.4-6.9 MeV. This corresponds to volume-averaged LET (within the cell nucleus) between 10 and 28 keVmum(-1) for protons, 18-50 keVmum(-1) for deuterons, and 59-106 keVmum(-1) for helium ions. Our results show no difference in the effectiveness of protons and deuterons matched for LET. However, for LET above about 30 keVmum(-1) singly charged particles are more effective at inactivating cells than doubly-charged particles of the same LET and that this difference can be understood in terms of the radial dose distribution around the primary ion track. PMID- 8691026 TI - A microdosimetric-kinetic model of cell death from exposure to ionizing radiation of any LET, with experimental and clinical applications. AB - A model of mammalian cell death and survival following exposure to ionizing radiation that combines a kinetic description of repair and injury processes with a microdosimetric description of radiation energy deposition is presented. With reduction of one of the defining kinetic equations from quadratic to linear form, relations are obtained that describe the results of commonly performed variations of the cell survival experiment. These include single-dose survival of linear quadratic form, survival after split-dose treatment and after post-irradiation change ill culture conditions and survival after exposure to continuously administered irradiation at low constant dose-rate. The effect of the inhomogeneous deposition of radiation energy inherent in exposure to radiation of significantly non-zero LET is included in these relations which apply to radiation of any LET. The values of the kinetic rate and time constants for repair and the processes that lead to cell death postulated in the model, which compose the alpha and beta parameters of the linear-quadratic survival relation, are estimated from cell survival experiments and DNA double-strand break measurements from the literature. A relation for estimating the daily fractional dose equivalent to continuous irradiation as employed in low dose-rate brachytherapy cancer treatment is presented. PMID- 8691027 TI - G2 arrest following fractionated irradiation in the mouse jejunal crypt. AB - A G2 block is a well-known response to irradiation, showing a delay time that depends on the given single dose. Our question was whether the division delay time is the same after multiple doses as after a single dose. We therefore studied mitosis in the mouse jejunal crypt using a quantitative approach. Three radiation schedules with a fraction size of 2 Gy were compared: a single dose and twice-daily irradiation at a 4-h interval, for 1 or 3 days. With the single dose, mitotic figures disappeared at 0.5 h and reappeared after 2 h. At the end of each multiple-dose regimen, significant numbers of mitoses could be observed at 0.5 and 1 h but a trough was seen at 2 h, with numbers then increasing again. Calculated average division delays after the single dose and repeated doses for 1 and 3 days were 1.5, 1.3 and 1.7 h respectively. In summary, most crypt cells treated with multiple fractions remain susceptible to G2 arrest, showing the same delay time as with the single dose. PMID- 8691028 TI - Changes in keratinocyte differentiation during accelerated repopulation of the irradiated mouse epidermis. AB - Epidermal stem cells accelerate their repopulation rate during fractionated irradiation. To study the changes in keratinocyte differentiation associated with radiation-induced repopulation, we investigated the expression of a panel of 14 monoclonal or polyclonal antibodies against keratins, involucrin and others, as well as the expression of 15 lectins in the irradiated mouse leg skin. Tissue samples were collected after 1, 2, and 3 weeks of daily irradiation with 3 Gy per fraction. Abnormal morphological appearance of the irradiated epidermis suggested disturbed terminal differentiation. Keratin 16 (K16) was negative in normal epidermis but intense staining was observed in the irradiated epidermis. Involucrin was expressed in the outmost suprabasal layers only in the normal epidermis but extended to the lower layers in the irradiated epidermis. The lectin binding patterns for agglutinins from Soybean, Dolichos biflorus, and Helix pomatia showed differences between the normal and the irradiated epidermis. From these characteristic changes in staining patterns we concluded that accelerated repopulation of the epidermis during fractionated irradiation is associated with a deficiency in terminal squamous differentiation. PMID- 8691029 TI - Direct effects of gamma-radiation on 2'-deoxycytidine in frozen aqueous solution. AB - The isolation and characterization of the main stable diamagnetic products formed upon exposure of frozen aqueous solutions of 2'-deoxycytidine at 196 K to 60 Co gamma-rays are described. The initial formation of the radical pi-anion of 2' deoxycytidine is strongly indicated by the formation of 5,6-dihydro-2' deoxyuridine and 5,6-dihydrouracil. The formation of radical centres within the sugar moiety is clearly implied. As reported previously, the observed formation of 5',6-cyclo-5,6-dihydro-2'-deoxyuridine indicates hydrogen atom abstraction at the C5' position. The release of cytosine, and 2-deoxy-D-ribono-1,4-lactone may result from deprotonation of a pristine radical pi-cation at C1' or from direct hydrogen abstraction at this position. In general, the structures of the final products correlate well with those of the primary radicals identified from ESR studies by other workers. PMID- 8691030 TI - Treatment with 3,4,3-LIHOPO of simulated wounds contaminated with plutonium and americium in rat. AB - The effect of a siderophore analogue 3,4,3-LIHOPO has been investigated in rat after intramuscular injection of 238Pu, 239Pu and 241Am simulating puncture wounds. Various treatment regimens were used to remove the radioactivity from its injection site and to reduce its retention in body tissues. The local deposits could be reduced to 9% of that in untreated controls by a single local injection of 30 mumol kg-1 3,4,3-LIHOPO administered 1 day after the actinides. Tissue retention of radioactivity was most effectively reduced (to 3% of controls) by continuous subcutaneous infusion of 3,4,3-LIHOPO (3 mumol kg-1 day-1), starting immediately after the injection of actinides and continuing for 2 weeks. The administration of 3,4,3-LIHOPO in drinking water was least effective. Treatment efficacy was substantially higher with 238Pu than with an equal activity of 239Pu (the 238Pu mass, however, was almost 300 times lower than that of 239Pu). Accordingly, the biokinetics and removal of 241Am changed when it was injected with 239Pu instead of 238Pu. Continuous infusion of 3,4,3-LIHOPO (3 mumol kg-1 day-1), starting 4 and 30 days after intramuscular injection of 238Pu and 241Am reduced their femoral retention after 1 month to 20 and 60% of controls respectively; whole-body retention of 241Am was reduced to 20 and 70% of controls respectively. PMID- 8691031 TI - HPRT mutations in V79 Chinese hamster cells induced by accelerated Ni, Au and Pb ions. AB - Mutation induction by accelerated heavy ions to 6-TG resistance (HPRT system) in V79 Chinese hamster cells was investigated with Ni (6-630 Me V/u), Au (2.2, 8.7 Me V/u) and Pb ions (11.6-980 Me V/u) corresponding to a LET range between 180 and 12895 ke V/microns. Most experiments could only be performed once due to technical limitations using accelerator beam times. Survival curves were exponential, mutation induction curves linear with fluence. From their slopes inactivation- and mutation-induction cross-sections were derived. If they are plotted versus LET, single, ion-specific curves are obtained. It is shown that other parameters like ion energy and effective charge play an important role. In the case of Au and Pb ions the cross-sections follow a common line, since these ions have nearly the same atomic weight, so that they should have similar spatial ionization patterns in matter at the same energies. Calculated RBEs were higher for mutation induction than for killing for all LETs. PMID- 8691032 TI - Repair of chromosome and DNA breaks versus cell survival in Chinese hamster cells. AB - Clonogenic and non-clonogenic parameters of cell survival were compared in irradiated Chinese hamster cells. Clonogenic survival, chromatid break and repair kinetics, as well as DNA damage and repair, were assessed in synchronized cells in different parts of the cell cycle. C2 chromatid damage and repair was examined in metaphase chromosomes of cells irradiated during S and G2 phase, treated with or without inhibitors of DNA repair. Bromodeoxyuridine labelling of S phase cells starting at the time of irradiation made it possible to determine precisely, while scoring metaphase chromosomes, whether cells were irradiated in mid S, late S, or G2 phases of the cycle. The results showed that chromatid breaks induced in S phase are efficiently repaired until the moment cells progress into G2, when repair stops abruptly. Chromatid damage in G2 phase is not repaired. On the other hand, DNA double-strand breaks are repaired in all phases of the cycle, even during G2 phase which has no concurrent chromatid break repair. Finally, there is no consistent correlation between chromatid damage and repair, DNA damage and repair, and cell survival, thus indicating that the interaction of different parameters of radiosensitivity must be better understood for them to be useful predictors of cell survival. PMID- 8691033 TI - Comparative study of the repair kinetics of chromosomal aberrations and DNA strand breaks in proliferating and quiescent CHO cells. AB - Repair kinetics observable at the level of exchange-type chromosomal aberrations (dicentric chromosomes), using fractionation and delayed-plating techniques, have been compared with repair kinetics of radiation-induced DNA double-strand breaks, measured with PFGE, and with repair kinetics of all strand breaks, measured with the alkali-unwinding technique. Only data from quiescent or proliferating CHO K1 cells obtained in the same laboratory were used. We determined repair kinetics in terms of the time constant tau (equal to half-time/log(e)2). The repair kinetics (tau approximately 11-14 min) observed in the split-dose formation of dicentric chromosomes agrees with fast repair kinetics of double-strand breaks (tau approximately 11-13 min), thus permitting us to identify the latter as the 'primary lesions' whose pairwise interaction leads to the beta D2 yield term of the aberrations. The repair kinetics observed for dicentric chromosomes formed under delayed-plating conditions (tau approximately 75 min), which mainly affects the alpha D yield term, is attributed to an intermediate interchromosomal product temporarily existing in the course of aberration formation; it is suggested that this product is mechanistically correlated with the slow repair kinetics of 'clustered damage' to DNA seen with the applied molecular methods (tau approximately 90 min). PMID- 8691034 TI - Influence of gestational age at exposure on the prenatal effects of gamma radiation. AB - The abdominal region of pregnant Swiss albino mice was exposed to single dose of 0.5 Gy gamma-radiation at gestation days from 1.5 to 17.5 days post-coitus (p.c). The animals were sacrificed on day 18 p.c. and foetuses were examined for resorption and embryonic death, foetal death, growth retardation, small head, low brain weight, micro-phthalmia and any other gross morphological abnormalities. The period of maximum sensitivity for each effect varied. The only demonstrable effect of irradiation during the pre-implantation period was an increase in prenatal mortality. Resorptions were maximal after exposure between days 2 and 4 p.c. The pre-implantation irradiated embryos which survived did not show any major foetal abnormalities. These results confirm earlier mouse studies using higher doses of X-rays. Small head, low brain weight and microphthalmia were prominent after exposure during the late organogenesis period, especially between days 9 and 13 p.c. But no other externally visible anomalies were detected. These findings demonstrate that mouse organogenesis is very sensitive to radiation induced retardation of development, even at doses < 1 Gy. One exencephaly, one cleft palate and two cases of open eyelids were observed in the foetuses exposed on days 14.5 and 15.5 p.c.; the number of these cases was too small to indicate a causal relationship with exposure. PMID- 8691035 TI - In utero exposure to low-doses of ionizing radiation decelerates neuronal migration in the developing rat brain. AB - In order to elucidate the possible mechanisms for the effects of low doses of ionizing radiation on the developing rat cerebral cortex we studied how neuronal migration can be affected by prenatal in utero irradiation. We have demonstrated an effect of ionizing radiation on neuronal migration at doses as low as 15 cGy together with a changing pattern of expression of the neural cell adhesion molecule N-CAM. After a dose of 15 cGy or more there was a reduction in N-CAM immunoreactivity in the matrix cell zone which became apparent about 24 h after exposure and continued until 48 h after exposure. Normal reactivity occurred 3 days after exposure to radiation. However, there was no obvious change in the immunoreactivity for L1, MAP2, tau protein or neurofilament. Our findings suggest the possible role of N-CAM in neuronal migration and also suggest the presence of a threshold in terms of the effects of small radiation doses on the developing cerebral cortex. PMID- 8691036 TI - Changes in myocardial and circulating atrial natriuretic peptide following thorax irradiation in rat. AB - The effect of thoracic irradiation on plasma and myocardial atrial natriuretic peptide (ANP) was studied in rat. The animals were irradiated with a dose of 20 Gy to the heart. After, 1, 12, 26 and 52 weeks, plasma ANP concentration and ANP in atrial and ventricular myocardium were determined. Plasma ANP levels were increased to 140% of control values from 3 months onwards and remained elevated for the next 9 months. Atrial ANP concentrations remained unaltered in the first 6 months post-treatment, but became reduced after 1 year to 37% of control values. Ventricular ANP concentration in irradiated rats rose 20-fold within 3 months, remained at that level up to 6 months and fell to six times control values at 1 year. An inverse relationship between plasma and atrial ANP concentration was found, while plasma and ventricular ANP concentrations were positively correlated. The results obtained in the present study suggest that in radiation-induced heart disease, plasma ANP concentration can be used as a marker for early stage cardiac dysfunction. PMID- 8691037 TI - Ionizing radiation modulates the spread of an apathogenic rabies virus in mouse brain. AB - Ionizing radiation has been shown to affect a broad range of viral diseases including neurotropic infections through an immunosuppression mechanism. In the present study we have investigated the effect of ionizing radiation on the characteristics of neurotropic infection by rabies virus, which has the unusual feature of infecting almost exclusively neurons. In order to analyze better the effect produced, the study concerned the spread of an apathogenic rabies virus variant in mouse brain. Irradiation was shown to increase both the intensity and duration of the infection in a reversible and dose-dependent manner and was effective in whole-body irradiation and in head-protected body irradiation, whereas cephalic irradiation had no effect. These results underline the role played by the immune system in the regulation of neurotropic virus infections in the brain and show that phenomena such as viral clearance and time-course of a neurotropic viral infection may be significantly modified by ionizing radiation, even for viruses whose infection involves only neurons. PMID- 8691038 TI - Repair of semi-oxidized 3,5-diiodotyrosine: radiation chemical studies in the presence of oxygen, ascorbate and superoxide anion. AB - Reactions of semi-oxidized radicals derived from 3,5-diiodotyrosine (I2TyOH, a thyroid hormone precursor) have been studied using radiation chemical techniques. In buffered, aqueous medium at room temperature, molecular oxygen reactivity towards the phenoxyl radical (I2TyO.) is low, the average bimolecular rate constant, k being 1.7 +/- 0.22 x 10(6) dm3 mol-1s-1. On the other hand, superoxide anion (O2-) reactivity towards I2TyO. is close to the diffusion controlled limit, the k being 5 +/- 1 x 10(9) dm3 mol-1s-1. The major reaction channel in this case (approximately 60%) leads to the reformation of the parent compound by one-electron transfer. Under similar experimental conditions, ascorbate (As-) completely reduces I2TyO. to the parent compound with k = 3 +/- 0.5 x 10(9) and < or = 1 x 10(9) dm3 mol-1s-1 at pH 7.4 and 12 respectively. The propensity of these reactions are not dependent on the primary .OH/.O- or secondary N3. radicals used. These results suggest that the superoxide anion may actively interact at the cellular level, in the Thyroid during the course of I2TyOH oxidation, and the observed in vitro reaction mechanism implies its participation in a new role. PMID- 8691039 TI - Ascorbic acid is not clastogenic and does not modify the effect of extended low dose-rate gamma-irradiation in mouse bone marrow. AB - Ascorbic acid was given to CBA mice in drinking water (5%) a week before and during 35-day exposure to gamma-radiation from 137 Cs at a very low dose-rate (44 mGy/day). The frequency of micronucleated normochromatic erythrocytes (fMNCE) in peripheral blood was monitored by repeated sampling during the exposure. The analyses were made with flow cytometry giving a high resolution because of the large number of cells analysed, about 10(6) for each dose group and sampling occasion. Ascorbic acid in the drinking water did not modify the increase of fMNCE in the gamma-irradiated groups of mice, nor did ascorbic acid influence the fMNCE in the non-irradiated groups of mice. PMID- 8691040 TI - Evidence for curvilinearity in the cancer incidence dose-response in the Japanese atomic bomb survivors. AB - The recently released data on cancer incidence in the Japanese atomic bomb survivors are analysed using a variety of relative risk models which take account of errors in estimates of dose to assess the dose-response at low doses. For all solid cancers analysed together there is a significant positive dose-response (at the one-sided 2.5% significance level) if all survivors who received < 0.5 Sv are considered, but the significance vanishes if doses of < 0.2 Sv are considered. If a relative risk model with a threshold (the dose-response being assumed linear above the threshold) is fitted to the solid cancer data, a threshold of more than about 0.2 Sv is inconsistent with the data, whereas these data are consistent with there being no threshold. Linear-quadratic models and linear-quadratic models with an exponential cell-sterilization term provide no better fit than the linear model. For the three main radiation-inducible leukaemia subtypes analysed together (acute lymphatic leukaemia, acute myeloid leukaemia and chronic myeloid leukaemia) there is a significant positive dose-response (at the one-sided 2.5% significance level) if all survivors who received < 0.5 Sv are considered, but the significance vanishes if doses of < 0.2 Sv are considered. If a relative risk model with a threshold (the dose-response being assumed linear above the threshold) is fitted to the leukaemia data, a thresh-old of more than about 0.3 Sv is inconsistent with the data. In contrast with the solid cancer data, the best estimate for the threshold level in the leukaemia data is significantly different from zero, even when allowance is made for a possible quadratic term in the dose-response, albeit at borderline levels of statistical significance (p = 0.04). There is little evidence for curvature in the leukaemia dose-response from 0.2 Sv upwards. However, the possible underestimation of the errors in the estimates of the dose threshold as a result of confounding and uncertainties not taken into account in the analysis, together with the lack of biological plausibility of a threshold, makes the interpretation of this finding questionable. PMID- 8691042 TI - Immunomodulation: role of intravenous immunoglobulins. Symposium proceedings. Boston, Massachusetts, October 1988. PMID- 8691041 TI - Chromosome aberration analysis in atomic bomb survivors and Thorotrast patients using two- and three-colour chromosome painting of chromosomal subsets. AB - Chromosomal translocations in peripheral lymphocytes of three healthy Hiroshima atomic (A)-bomb survivors, as well as three Thorotrast patients and two non irradiated age-matched control persons from the German Thorotrast study were studied by two- and three-colour fluorescence in situ hybridization (chromosome painting) with various combinations of whole chromosome composite probes, including chromosomes 1, 2, 3, 4, 6, 7, 8, 9 and 12. Translocation frequencies detected by chromosome painting in cells of the A-bomb survivors were compared with results obtained by G-banding. A direct comparison was made, i.e. only those cells with simple translocations or complex aberrations detected by G-banding were taken into consideration which in principle could be detected also with the respective painting combination. The statistical analysis revealed no significant differences from a 1:1 relationship between the frequencies of aberrant cells obtained by both methods. The use of genomic translocation frequencies estimated from subsets of chromosomes for biological dosimetry is discussed in the light of evidence that chromosomes occupy distinct territories and are variably arranged in human lymphocyte nuclei. This territorial organization of interphase chromosomes implies that translocations will be restricted to chromatin located at the periphery of adjacent chromosome territories. PMID- 8691043 TI - Regulation of human IgE synthesis. AB - Allergic diseases result from the interaction with IgE bound to cell surface receptors. Therefore, rational therapeutic approaches to allergic diseases would be aimed at decreasing IgE and/or at blocking the binding of IgE to effector cells such as mast cells and monocytes. Our investigation of the mechanism of IgE synthesis in man shows that IgE synthesis by peripheral blood mononuclear cells (PBMC) absolutely requires the presence of IL-4 and requires endogenous IL-6, because antibody to IL-6 inhibits IgE production completely. IgE synthesis requires T/B cell contact and involves interactions between B cell surface MHC Class II molecules and T cell surface receptors, as antibodies to both of these cell surface molecules inhibit IgE synthesis. Furthermore, alloreactive T cell clones which are unable to engage the B cell MHC Class II molecules fail to induce IgE synthesis in spite of their ability to secrete IL-4. Studies on the immunoglobulin sites that are involved in IgE binding to high affinity receptors on mast cells and basophils have used recombinant fragments of IgE to block mast cell binding. These studies suggest that a stretch of 76 amino acids which straddles the C epsilon 2 and C epsilon 3 domains is essential for this binding. Parallel studies on IgE binding to low affinity receptors on monocytes and B cells suggest that sequences within C epsilon 3 are involved in this binding. Peptides or analogues that inhibit IgE binding to its cellular receptors may be useful in the treatment of allergic diseases. PMID- 8691044 TI - The molecular origin of regulatory idiotypes. AB - A complete immunochemical and molecular profile was generated for a group of hybridoma and myeloma antibodies bearing the A48 regulatory idiotype (RI). These A48 RI+ antibodies were derived from normal or idiotypically manipulated mice and were selected either for utilization of a VHX24 VH gene or expression of the A48 RI. Among the hybridomas selected for VHX24 VH utilization a variety of antibody specificities were seen with the fructosan specificity occurring least frequently and the N-acetylglucosamine specificity occurring most frequently. A variety of Vk families were used with a bias for the Vk1 family by the antibodies deriving from untreated mice. The A48RI was expressed by only 3 of these antibodies, none of which were fructan specific. Two used the canonical VHX24-Vk10 combination utilized by the A48 and UPC 10 prototypes, and one used the VHX24-Vkl combination. This demonstration of A48 RI expression ny non-fructan specific, non VHX24+Vk10+ antibodies was extended by showing expression of this Id by two monoclonal antibodies specific for the Sm self-antigen, one rheumatoid factor and two monoclonal antibodies specific for influenza virus hemagglutinin molecule. They used different VH-VL combinations. Among the monoclonal antibodies selected for A48 RI expression all exhibited fructan binding activity and the vast majority used the VHX24-Vk10 association. A collective analysis of the VH and VL sequences of all these A48RI+ antibodies showed idiotype expression was not associated with any particular germline VH or VL gene. D, Jk or JH sequence. Three positions on the light chain and one on the heavy chain were identified which could represent the structural correlates for the A48 regulatory idiotype. PMID- 8691045 TI - Auto-anti-idiotypy, autoimmunity and some thoughts on the structure of internal images. AB - Application of principles proposed by N.K. Jerne has led to the development of an auto-anti-idiotypic protocol for the preparation of monoclonal antibodies specific for receptors for acetylcholine, adenosine (A1), TSH, glucocorticoids and aldosterone. The properties of these antibodies are described with reference to their behavior as internal images of auto-antibodies found in patients with autoimmune disease or of ligands of the various receptors. The molecular basis of "internal imagery" is discussed in the context of specific antibodies and, in particular, with respect to the hemoglobin-myoglobin family of proteins. We venture the conclusion that immunoglobulins that mimic other biologically active polypeptides need not share primary sequence homologies. PMID- 8691046 TI - The major rheumatoid factor cross-reactive idiotype in rheumatic disease. AB - The major rheumatoid factor cross-reactive idiotype (RCRI), a tertiary structure formed by both light and heavy chains, is found on 60% of all monoclonal IgM kappa RFs. To determine if the RCRI is expressed in patients with rheumatic disease, we used polyclonal rabbit anti-idiotypic antibodies to detect RCRI in sera and in pokeweed mitogen cultures of blood mononuclear cells (PBM) from patients with rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA). We detected increased expression of RCRI+, plasma cells in PWM cultures, and in sera from these patients. We have determined that some 7S IgM molecules from RF+RA patients are RCRI+, and can bind IgG in a sensitive RF ELISA. We have also observed that the CD5+ B cell subset, which is responsible for autoantibody production, generates RCRI+ antibodies. We review these data and discuss the relationship of the idiotypic network of interacting antibodies with rheumatic disease. PMID- 8691047 TI - Properties of a system of public idiotypes of lupus autoantibodies. AB - We can conclude from the properties of the Id-16/6 system that a relatively restricted group of B cell clones is activated in systemic lupus erythematosus. Whether this is a property of the immunogenic stimulus that causes the diseases (if indeed there is one), or whether the observations are due to an idiotypic network that favors the selection of Id-16/6-expressing B cells is not known. These alternatives are under investigation. Apart from these theoretical considerations, the high frequency of Id-16/6(+) autoantibodies, including pathogenic autoantibodies, in systemic lupus erythematosus may point to targets amenable to the specific therapy of the disease. PMID- 8691048 TI - Anti-idiotypes against autoantibodies to procoagulant factor VIII (VIII:C) in intravenous immunoglobulins. PMID- 8691049 TI - Human Fc receptors for IgG. AB - Human lymphocytes bear at least three different classes of Fc gamma R, which are different in cellular distribution, structure, and function. This review deals with recent advances in understanding the complexity of huFc gamma R. In particular, studies demonstrating the presence of alternate phosphatidyl inositol glycan-anchored and transmembrane-anchored forms of huFc gamma RIII (CD16) are discussed. PMID- 8691050 TI - Down regulation of Fc receptors by IVIgG. AB - IVIgG preparations are now widely applied for immune modulatory treatment in various forms of autoimmune and immune complex diseases. Several controlled studies clearly demonstrated the clinical efficacy of this type of treatment; the underlying pathophysiological mechanisms, however, have yet to be elucidated. Among the mechanisms suggested to play a role in this context is the interaction of gamma globulin with Fc gamma receptors (Fc gamma R) expressed in the membrane of immunocompetent cells. Our studies concentrated on these aspects and focused on possible functional consequences of IgG-Fc gamma R interaction. By using the peripheral blood monocyte as a model system for an Fc gamma R-bearing cell, we confirmed previous reports by showing differences in Fc gamma R binding and Fc gamma R modulation induced by IgG in its various forms (monomeric IgG, Polymeric IgG, immune complexes). As biological consequences of Fc gamma R modulation, changes in effector and accessory function of these cells were observed. The results presented in this brief review emphasize especially the difference between ligand-oriented Fc gamma R diffusion (induced by surface-bound IgG) and true long-term down-modulation of Fc gamma R (mediated by fluid-phase IgG polymers) and show that only the down-modulation of Fc gamma R correlated with impaired functions of the affected cell. PMID- 8691051 TI - Idiopathic thrombocytopenic purpura (ITP): immunomodulation by intravenous immunoglobulin (IVIg). AB - ITP is a destructive thrombocytopenia. Platelets are coated with antibodies and these opsonized platelets are rapidly removed by phagocytes. On the other hand, therapeutic application of antibody concentrates (IVIg) rapidly raise platelet counts, and in some patients, sustained platelet recovery has been observed. The mechanism of action of IVIg is far from being clear. Several possible mechanism of action of IVIg treatment have been described. The immediate effect of IVIg seems to be a decrease in (unspecific) Fc mediated mononuclear phagocytosis, the long term effect might be a change in the complex network of the regulatory function of the immune response. Both types of interactions seem to play a keyrole in the immunomodulation. The various possible modes of actions evoke investigation of IVIg in a wide range of diseases with similar ineffective immune response. Controlled clinical studies have to be done to prove or disapprove the use of IVIg in other indications. PMID- 8691052 TI - Feedback inhibition of B cell differentiation by monomeric immunoglobulin. AB - Polyspecific monomeric immunoglobulin (Ig) isolated from either a commercial source (pooled, > 2000 donors), or an autologous donor was capable of inhibiting both B cell proliferation, induced by T dependent mitogens or T cell factors and B cell differentiation, induced by similar stimuli. These effects appear to be directed at the B cell itself since inhibition of differentiation is detectable when monomeric Ig is added to cultures of B cell lines in the presence of B cell differentiation factor (BCDF). The inhibition of B cell differentiation does not appear to relate to inhibition of B cell proliferation, as no detectable change is seen in thymidine incorporation or cell number in these cultures. Furthermore, the effect of monomeric lg appears to relate to an early event in B cell differentiation, as there is no effect of IgSRK on spontaneously secreting B cell lines and maturation to cytoplasmic Ig containing cells is markedly impaired. Therefore, monomeric Ig secreted by B cells may serve as an immunoregulator of further Ig secretion. PMID- 8691053 TI - The immunologic effects of IVIG in Kawasaki disease. AB - Kawasaki disease (KD) is an acute febrile illness of early childhood that is associated with the development of coronary artery aneurysms in 15-25% of the cases. The acute phase of KD is characterized by a deficiency of suppressor T cells, marked activation of the immune system and increased secretion of cytokines by immune effector cells. Evidence that this immune activation contributes to the vascular endothelial cell damage in KD is suggested by the observation that patients in the acute phase of KD have circulating antibodies lytic for vascular endothelial cells activated with gamma interferon, IL-1 or tumor necrosis factor. In contrast, sera from these patients do not lyse unstimulated endothelial cells. High dose intravenous gammaglobulin (IVGG) treatment is effective in preventing the occurrence of coronary artery abnormalities in KD. Patients treated with IVGG have a significant increase in T suppressor cells, a decrease in circulating activated T helper cells, and a decrease in spontaneous IgG and IgM synthesis. These observations suggest that IVGG reduces the vasculitis in KD by suppressing the marked immune activation associated with this disease. PMID- 8691054 TI - Current concepts of B cell modulation. AB - Three interleukins with distinct functions, IL-4, IL-5 and IL-6, are involved in the regulation of B cell response into antibody producing cells. The studies with recombinant interleukins, however, demonstrated that the activities of these interleukins were not restricted to B lineage cells but showed a wide variety of biological functions on various tissues and cells. One of the most typical example of multifunctional interleukins is IL-6. It acts not only on B cells as B cell differentiation factor but also on T cells, hematopoietic stem cells, hepatocytes, nerve cells and myeloma cells. Deregulation of the expression of these interleukins was shown to be responsible for various diseases, such as i) IL-4 vs. immediate type hypersensitivity and ii) IL-6 vs. autoimmunity and multiple myelomas. PMID- 8691055 TI - The legal treatment of recovered memories of child sexual abuse. PMID- 8691056 TI - Involuntary transfers and discharges of nursing home residents under federal and state law. AB - When, as projected, nearly one out of every four Americans is age sixty-five or more, one out of every four Americans over sixty-five will spend time in a nursing home, and caregiver families scarcely exist, we will no longer be able to avert our eyes from the grim options faced by our senior citizens. Nor will we be able to continue to operate under the comforting but often false illusion that our convenient dispositions are actually serving the best interests of the elderly. PMID- 8691057 TI - Lung cancer latency and asbestos liability. PMID- 8691058 TI - Treating children by faith. Colliding constitutional issues. PMID- 8691059 TI - Transforming growth factor-beta1-deficient mice: identification of isoform specific activities in vivo. AB - A remarkable range of activities has been ascribed to the family of proteins known as transforming growth factor-beta (TGF-beta). Each plays an important role in development and homeostasis, influencing mesenchymal-epithelial interactions, regulating cellular differentiation, and maintaining control of cell proliferation. Although in vitro comparisons of activity demonstrate a high degree of functional similarity, recent studies of mice with a targeted deletion of the TGF-beta1 gene reveal that true isoform-specific activities do exist in vivo and that the three mammalian isoforms are not functionally redundant. This approach has defined a unique role for TGF-beta1 in the establishment and maintenance of normal immune function, shed new light on the relevance of endogenous TGF-beta1 to the normal wound healing process, and expanded the list of known mechanisms of TGF-beta1 activity to include endocrine functions. Thus, the TGF-beta1-deficient mouse allows the definition of isoform-specific activities, providing an invaluable window through which to view the principal functions of TGF-beta1 in vivo. PMID- 8691060 TI - The role of calcium in the regulation of apoptosis. AB - The recognition that apoptosis is regulated by an evolutionarily conserved set of polypeptides from the nematode Caenorhabditis elegans to humans suggests that a conserved set of biochemical mechanisms may also he involved in the response. Work from a number of independent laboratories suggests that alterations in cytosolic Ca2+ homeostasis represent one such candidate mechanism, and molecular targets for Ca2+ are now being identified. This review will summarize what is known about the role of Ca2+ in the regulation of apoptosis and discuss how Ca2+ might interact with some of the other biochemical signals implicated in cell death. PMID- 8691061 TI - Membrane phospholipid asymmetry: host response to the externalization of phosphatidylserine. AB - Membrane phospholipid asymmetry is an important regulator of cellular function and homeostasis. The activities of lipid transporters are contributing factors to the regulation of membrane lipid composition over the lifespan of the cell. Alterations in the activities of these proteins result in the movement of phosphatidylserine to the cell's outer leaflet. This promotes several physiologic responses including initiation of the coagulation cascade and cell recognition by the reticuloendothelial system. PMID- 8691062 TI - Regulation of leukocyte adhesion and signaling in inflammation and disease. AB - Cell adhesion molecules provide the foundation for cell communication, trafficking, and immune surveillance central to host defense. These adhesion molecules which include selectins, integrins and members of the Ig superfamily, provide a recognition system between leukocytes, endothelial cells and matrix molecules. Leukocyte-endothelial interactions initiate recruitment at sites of injury, infection and inflammation. Cell-cell and cell-matrix interactions also influence leukocyte phenotype and function. Dysregulation of these adhesion and signal transduction pathways can contribute to continued recruitment and persistent leukocyte activation with unresolved inflammation. Based on the pivotal role adhesive interactions play, the adhesion molecules provide potential targets for intervention. Selected synthetic fibronectin peptides, which inhibit leukocyte integrin binding and signal transduction in vitro, block recruitment and activation to limit inflammation in vivo. PMID- 8691063 TI - Activation of nitric oxide synthase gene for inhibition of cancer metastasis. AB - The process of cancer metastasis consists of multiple sequential and highly selective steps. The vast majority of tumor cells that enter the circulation die rapidly and only a few survive and proliferate to form distant metastases. This survival is not random. Metastases are clonal in origin and are produced by specialized subpopulations of cells that preexist in a heterogeneous primary tumor. Metastatic cells of the murine K-1735 melanoma survive in the circulation to produce experimental lung metastases, whereas nonmetastatic cells do not. After incubation with different cytokines or LPS, nonmetastatic cells exhibit a high level of inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) production, whereas metastatic cells do not. To provide direct evidence for the inverse correlation between the production of endogenous NO and the ability of K-1735 cells to produce metastasis in syngeneic mice, highly metastatic clone 4 cells (C4.P), which express low levels of iNOS, were transfected with a functional iNOS (C4.L8), inactive mutated iNOS (C4.S2), or neomycin resistance (C4.Neo) genes in medium containing 3 mM NMA. C4.P, C4.Neo3, and C4.S2.3 cells were highly metastatic, whereas C4.L8.5 cells were not. Moreover, C4.L8.5 cells produced slow-growing subcutaneous tumors in nude mice, whereas the other three cell lines produced fast-growing tumors. In vitro studies indicated that the expression of iNOS in C4.L8.5 cells was associated with apoptosis. Multiple intravenous injections of liposomes containing a synthetic lipopeptide upregulated iNOS expression in murine M5076 reticulum sarcoma cells growing as hepatic metastases. The induction of iNOS was associated with the complete regression of the lesions. Collectively, these data demonstrate that the expression of iNOS in tumor cells is associated with apoptosis, suppression of tumorigenicity, abrogation of metastasis, and regression of established hepatic metastases. PMID- 8691064 TI - Enhanced expression and production of monocyte chemoattractant protein-1 in inflammatory bowel disease mucosa. AB - Peripheral blood monocytes are recruited to the inflamed mucosa of inflammatory bowel disease but the specific chemotactic signals responsible for their attraction are not known. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine with potent monocyte attracting and activating properties and the aim of this study was to examine its expression and production in inflammatory bowel disease. In situ hybridization demonstrated mRNA for MCP-1 in macrophages, some of which had been recently recruited from the circulation as demonstrated by their co-expression of the monocyte marker CD 14, as well as in smooth muscle and endothelial cells in inflamed mucosa. Immunohistochemical studies showed a corresponding distribution of MCP-1 protein production by macrophages, smooth muscle, and endothelial cells. By contrast minimal MCP-1 mRNA expression and protein were found in histologically normal mucosa. Macrophages isolated from surgically resected inflammatory bowel disease colons and examined by Northern analysis expressed MCP-1 mRNA significantly more frequently (15/24 vs. 0/19, P< 0.0001) than macrophages from histologically normal mucosa from colon cancer resections. Blood monocytes stimulated by lipopolysaccharide and treated with hydrocortisone, 5-aminosalicylic acid, or cyclosporin A showed reduced MCP-1 expression and production in the presence of these agents. This study demonstrates increased expression of MCP-1 mRNA and protein and cells of origin of MCP-1 in inflamed intestinal mucosa. Together with the demonstrated influence of therapeutic agents on monocyte MCP-1 production the findings suggest a role for MCP-1 in monocyte attraction to the mucosal lesion of inflammatory bowel disease. PMID- 8691065 TI - Soluble versus cell-bound CD4, CD8 from bronchoalveolar lavage: correlation with pulmonary diagnoses in human immunodeficiency virus-infected individuals. AB - Identification and assessment of cell populations in bronchoalveolar lavage (BAL) specimens may he used to follow the course of a disease state or response to specific therapy. Beyond cellular assessment, there are indications that the presence and quantity of soluble surface antigens released from activated cells may lead to improved understanding and facilitated diagnosis of a number of disease states. This study evaluated soluble markers (sCD4 and sCD8) in BAL and serum from HIV-infected individuals undergoing diagnostic bronchoscopy, and compared these values to flow cytometry-quantified BAL and peripheral blood cell CD4 and CD8. Patient pulmonary diagnosis (based on cytology and microbiology) was compared with patient blood and BAL-soluble and cell-bound CD4 and CD8 to determine the relationship of these markers to disease states in this population. Serum sCD8 in patients with fungal infections was significantly elevated above sCD8 in patients with Pneumocystis carinii or pulmonary bacterial infections, p = 0.0001. BAL sCD4/sCD8 ratio was also significantly different in patients with bacterial vs. fungal pulmonary infections, p = 0.01. These findings suggest that soluble markers, particularly elevated sCD8, may be an important indication of pulmonary disease progression in these HIV+ patients with fungal infections. PMID- 8691067 TI - Diamine oxidase-gold ultrastructural localization of histamine in isolated human lung mast cells stimulated to undergo anaphylactic degranulation and recovery in vitro. AB - A new enzyme-affinity-gold ultrastructural method makes use of the affinity of the enzyme, diamine oxidase coupled to gold, for its substrate, histamine, for localization of histamine in isolated human lung mast cells (HLMCs). The method works with routinely prepared ultrastructural samples, thereby allowing precise identification of ultrastructural structures that contain histamine. We used this method to identify the release of histamine from granule stores in anti immunoglobulin-E (IgE)-stimulated HLMCs and the replacement of histamine in secretory granules of HLMCs during recovery from anaphylactic degranulation in vitro. The findings show that electron-dense granules in unstimulated HLMCs, maintained up to 24 h in culture, and in responding anti-IgE-stimulated HLMCs, over the same time period in vitro, contained histamine. Alteration of granules, resulting in decreased electron density of their contents, was associated with decreased label for histamine. Electron-lucent intracytoplasmic degranulation chambers were devoid of histamine. Recovering HLMCs developed new granule stores of histamine by a mixture of conservation, synthetic, and endocytotic mechanisms. PMID- 8691066 TI - Colony stimulating factor-1 expression is developmentally regulated in the mouse. AB - Colony stimulating factor-1 (CSF-1) regulates the survival, proliferation, and differentiation of mononuclear phagocytes. To determine whether CSF-1 plays a role in the perinatal development of these cells, CSF-1 protein and mRNA expression in tissues and serum from fetal/neonatal mice and their mothers was analyzed. As fetal/neonatal age increased, CSF-1 concentrations rose in liver, kidney, and lung, declined in brain and serum, and did not change in intestine and heart. Concurrently, fetal/neonatal CSF-1 concentrations were higher in liver, kidney, and serum and lower in lung, brain, intestine, and heart than maternal tissue/serum concentrations, which showed no correlations with gestational or postpartum stage. CSF-1 mRNA was detected in all tissues examined and its expression increased in lung and heart and decreased in brain with increasing fetal/neonatal age. The developmental regulation of mouse CSF-1 expression appears to he important for mononuclear phagocyte development during this period. PMID- 8691068 TI - Inhibition of apoptosis in polymorphonuclear neutrophils from burn patients. AB - Normal human polymorphonuclear neutrophils (PMN) undergo rapid apoptosis during in vitro culture. In contrast, apoptosis is inhibited in PMN from patients with severe burns. This inhibition is not an inherent property of the cells but is caused by thermolabile factors present in the plasma. Endotoxin and the proinflammatory cytokines interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) do not appear to be directly responsible. The ability of burn plasma to inhibit apoptosis was reduced by neutralizing antibodies to human granulocyte macrophage colony-stimulating factor (GM-CSF). GM CSF levels could not be detected in the burn plasma. However, the incubation of burn-derived or normal leukocyte populations consisting primarily of PMN in burn plasma induced the production of GM-CSF. The results suggest that activation of GM-CSF synthesis by factor(s) in burn plasma may play a role in regulating inflammation by the inhibition of apoptosis. PMID- 8691070 TI - Synthesis of 5-oxo-6,8,11,14-eicosatetraenoic acid by human monocytes and lymphocytes. AB - We recently demonstrated that the arachidonate metabolite 5(S)-hydroxy-6,8,11,14 eicosatetraenoic acid (5-HETE) is converted by a highly specific dehydrogenase in human neutrophils to 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), which is a potent stimulator of these cells. The objective of this study was to determine whether 5-oxo-ETE is also formed by monocytes and lymphocytes. Human monocytes (74 +/- 2% pure) and lymphocytes (86 +/- 1% pure) were prepared by successive centrifugations of leukocytes over Ficoll-Paque and Percoll. Both cell types converted 5-HETE to a single major product, which was identified as 5-oxo-ETE. The formation of 5-oxo-ETE was stimulated about twofold by phorbol myristate acetate (PMA; 30 nM). Dehydrogenase activity in monocyte fractions did not appear to be due to platelet contamination, since depletion of platelets did not reduce enzyme activity. The dehydrogenase was localized in membrane fractions from monocytes and required NADP+ as a cofactor. It was specific for eicosanoids containing a 5S-hydroxyl group followed by a 6-trans double bond. We also investigated the formation of 5-oxo-ETE from endogenous arachidonic acid by monocytes. 5-Oxo-ETE, 5-HETE, and leukotriene B4 (LTB4) were present in comparable amounts after incubation of these cells with A23187. PMA (EC50 approximately 4 nM) stimulated the formation of 5-oxo-ETE and 5-HETE and, to a lesser extent, LTB4. Although monocytes released considerably less 5-HETE and LTB4 than neutrophils, they released comparable amounts of 5-oxo-ETE. Unlike neutrophils, monocytes did not convert any of these substances to detectable amounts of omega-oxidation products. Although lymphocytes were capable of converting 5-HETE to 5-oxo-ETE, they released little or no 5-lipoxygenase products in response to A23187. We conclude that monocytes have a high capacity to synthesize 5-oxo-ETE and that its formation is stimulated by activation of protein kinase C. PMID- 8691069 TI - Novel actions of aspirin and sodium salicylate: discordant effects on nitric oxide synthesis and induction of nitric oxide synthase mRNA in a murine macrophage cell line. AB - Aspirin and sodium salicylate each inhibit to a similar extent the production of nitric oxide (NO) in the RAW 264.7 murine macrophage cell line following stimulation by either lipopolysaccharide (LPS) or interferon-gamma (IFN-gamma). The similar potencies of aspirin and sodium salicylate indicate that acetylation of cellular macromolecules is not essential for the observed effects. The failure of added prostaglandin E2 to overcome the effects of aspirin or sodium salicylate indicates that these effects are not simply the result of inhibition of prostaglandin synthesis. The inhibition of NO production occurs irrespective of the effect of these agents on induction of nitric oxide synthase (iNOS) mRNA by LPS or IFN-gamma. Aspirin and sodium salicylate inhibit iNOS mRNA induction in LPS-stimulated cells but enhance iNOS mRNA induction in IFN-gamma-stimulated cells. In contrast, these agents consistently inhibit induction of argininosuccinate synthetase mRNA in both LPS- and IFN-gamma-stimulated cells. Concentrations of aspirin in the 3-10 mM range inhibit induced NO production and expression of iNOS protein without inhibiting induction of iNOS mRNA. Discordances between effects on NO synthesis and induction of iNOS mRNA indicate that aspirin and sodium salicylate have multiple sites of action in their effects on pathways that are involved in the production of NO by stimulated RAW 264.7 cells. PMID- 8691071 TI - Inhibition of neutrophil-endothelial cell adhension by a neutrophil product, cathepsin G. AB - In the present study we investigated the modulation of the polymorphonuclear neutrophil (PMN)-endothelial cell adhesion process by the two main proteinases released from activated PMN during their adhesion to endothelium. Our results showed that, in contrast with elastase, cathepsin G was a powerful inhibitor of PAIN adhesion to interleukin-1 (IL-1)-treated human umbilical vein endothelial cells. This inhibitory effect was linked to the enzymatic activity of the proteinase and was selectively directed against PMN. Because the viability and the reactivity of PMN were not modified by cathepsin G, we looked for a possible effect on adhesion molecules. L-selectin was not cleaved by cathepsin G, whereas it was by chymotrypsin, a closely related proteinase. Cathepsin G blocked PMN adhesion to activated endothelial cells, but also to serum- or fibrinogen-coated plates, three adhesion processes mediated by CD11b/CD18. However, by FACScan analysis or by immunoprecipitation, we failed to find evidence of modifications of CD11b/CD18 expression. Although the precise molecular target(s) of cathepsin G remain(s) to be defined, these data indicate that this proteinase, which is known as an inflammatory mediator, can also be considered as a potential down-regulator of adhesion reactions involved in the inflammatory process. PMID- 8691072 TI - Paradoxical effects of colchicine on the activation of human neutrophilis by chemotactic factors and inflammatory microcrystal. AB - Neutrophil activation by chemotactic factors and by inflammatory microcrystals is accompanied by increases in protein tyrosine phosphorylation and by the activation of the NADPH oxidase. The addition of colchicine inhibited both responses induced by triclinic monosodium urate or calcium pyrophosphate crystals. On the other hand, colchicine enhanced the tyrosine phosphorylation of specific protein in neutrophils stimulated by chemotactic factor and augmented the production of superoxide anions induced by these same agonists. The effects of colchicine were shared by other anti-microtubule agents (nocodazole and vinblastine) but not by its inactive analogue beta-lumicolchicine, trimethylcolchicinic acid, indomethacin, or phenylbutazone. Furthermore, the (enhancing as well as inhibitory) effects of colchicine on tyrosine phosphorylation and superoxide anion production were reversed by taxol. Finally, in human cytoplasts colchicine again inhibited microcrystal-stimulated tyrosine phosphorylation but did not change chemotactic factor-stimulated phosphorylation. These data strongly support the hypothesis that microtubule-related mechanisms are involved in the modulation of the tyrosine phosphorylation response in human neutrophils, and suggest that a relationship may exist between the augmentation of tyrosine phosphorylation and of the stimulation of the NADPH oxidase induced by chemotactic factors. PMID- 8691073 TI - Induction of homotypic lymphocyte aggregation: evidence for a novel activation state of the beta1 integrin. AB - Intercellular adhesion of Jurkat lymphocytic cells was investigated by use of monoclonal antibodies 33B6 and 18D3, which bind to the beta1 integrin receptor. 33B6 induced homotypic aggregation of Jurkat cells, whereas 18D3 inhibited this aggregation. Jurkat cells could he induced to aggregate at low 33B6 concentrations corresponding to 5% beta1 integrin site occupancy, and the rate of aggregation was maximum at 30% occupancy. Simultaneous addition of mAb 18D3 and 33B6 demonstrated that the two antibodies mediate changes in the beta1 integrin activation state that are competitive in nature. Aggregation through beta1 integrin induced by 33B6 was reversed by subsequent addition of 18D3. To further examine the mechanism by which 33B6 and 18D3 affect cell adhesion function, we explored the binding of monoclonal antibody (mAb) 15/7. This mAb recognizes an activation epitope of the beta1 integrin and has been shown to sustain cell adhesion to vascular cell adhesion molecule 1 (VCAM-1) and fibronectin. Activation of Jurkat cells with Mn2+ caused a 2.5-fold increase in 15/7 binding but did not increase binding of 33B6. 33B6 partially blocked 15/7 binding to beta1 integrin on unstimulated and Mn2+-activated Jurkat cells. 18D3 did not affect mAb 15/7 binding. These results indicate that 33B6 and 18D3 modulated homotypic aggregation by inducing a novel activation state of the very late activation integrin distinct from the state recognized by 15/7, which supports cell binding to VCAM-1 and fibronectin. PMID- 8691074 TI - Cooperation between CR1 (CD35) and CR3 (CD 11b/CD18) in the binding of complement opsonized particles. AB - We analyzed the binding of sheep erythrocytes bearing C3b (EC3b) to cells transfected with human complement receptors. EC3b bound avidly to cells expressing CR1 but failed to bind to cells expressing CR3. In the presence of factor I, the binding of EC3b, to CR1 was transient. Primary monocytes and cotransfected cells expressing both CR1 and CR3 mediated a stable resetting of EC3b, even in the prolonged presence of factor I. This stable adhesion was dependent on the presence of CR3, because blocking CR3 with mAb resulted in the factor I-dependent release of erythrocytes from these cells. A model is proposed in which these two complement receptors cooperate in a unique manner. These results suggest that the stable adhesion of complement-opsonized particles to cells expressing CR1 and CR3 is actually a dynamic molecular process in which an important function of leukocyte CR1 is to generate the ligands for CR3. PMID- 8691075 TI - A CD66a-specific, activation-dependent epitope detected by recombinant human single chain fragments (scFvs) on CHO transfectants and activated granulocytes. AB - Antibodies to CD66 recognize at least five members (CD66a-e) of the carcinoembryonic antigen (CEA) family. Recombinant human single-chain Fv fragments (scFvs) that bind specifically to CD66a (biliary glycoprotein) were obtained from a naive human scFv library. The scFvs bound to the N-domain of CD66a on Chinese hamster ovary (CHO) transfectants but did not bind to freshly isolated peripheral granulocytes or to dimethylsulfoxide-treated HL-60 cells. In contrast, scFvs bound well to granulocytes that were short-term activated with N formyl-Met-Leu-Phe or phorbol 12-myristate 13-acetate and to human HL-60 cells that were treated with all-trans-retinoic acid to induce granulocytic differentiation. Quantification of antigenic sites showed that the activation dependent CD66a epitopes were expressed on nearly all of the CD66a molecules on CHO-biliary glycoprotein transfectants, but they were detected only on a portion of the molecules on activated polymorphonuclear neutrophils and differentiated HL 60 cells. Binding of CD66a scFvs to their neoepitopes on prestimulated PMNs induced respiratory burst, suggesting that CD66a is capable of delivering transmembrane signals in these cells. PMID- 8691076 TI - Killing of phagocytosed Staphylococcus aureus by human neutrophils requires intracellular free calcium. AB - The mobilization of intracellular calcium plays an important role in regulating neutrophil activation. With this in mind we investigated the effect of intra- and extracellular calcium on the ability of human neutrophils to kill complement opsonized Staphylococcus aureus. We found that a rise in intracellular calcium is necessary for efficient killing of phagocytosed S. aureus. In the presence of extracellular calcium, killing of ingested bacteria in calcium-buffered neutrophils compared with normal cells was slightly reduced. Calcium buffering had no effect on phagocytic uptake by the neutrophils, but did decrease the generation of toxic oxygen metabolites, measured as chemiluminescence (CL). In nondepleted and calcium-depleted cells, removal of extracellular calcium did not affect ingestion but did cause a marked decrease in the ability to kill the bacteria. In parallel, the CL response was substantially reduced or completely blocked. These data show that calcium is not a prerequisite for phagocytosis of S. aureus by human neutrophils, but does play a vital role in the post-ingestion killing of the bacteria by regulating the generation of toxic oxygen metabolites. PMID- 8691077 TI - Nitric oxide production by peritoneal macrophages of Mycobacterium bovis BCG infected or non-infected mice: regulatory role of T lymphocytes and cytokines. AB - Infection with Mycobacterium bovis bacillus Calmette-Guerin (BCG) confers mice with strong abilities to produce nitric oxide (NO) and cytokines. Because the peritoneal macrophages taken from the mice immunized with live or heat-killed BCG can produce NO without any accessory cells and stimulants, it is difficult to clarify the immune regulation on NO production by manipulating the macrophages. Therefore, we investigated the participation of immune T cells and cytokines in NO production by using in vitro co-cultures of macrophages from non-immune mice with T cells prepared from BCG-infected mice in the presence or absence of a mycobacterial antigen, purified protein derivative (PPD). Although the non-immune thioglycollate (TGB)-elicited macrophages could not produce any detectable NO in the presence of PPD, supplementation of the macrophage cultures with CD4+ T cells prepared from BCG-infected mice enabled the macrophages to produce NO. Immunocytostaining showed that the macrophages, hut not the immune T cells, expressed inducible NO synthase (iNOS), indicating that they were NO producers. PPD could only induce NO production if there was cell-cell contact of the CD4+ T cells in the immune cells and antigen-presenting macrophages were required for the NO production in response to PPD; this interaction led to the production of soluble mediators that induced NO production by the TGB macrophages. NO production by the co-cultured cells was abrogated by adding either anti interferon-gamma(IFN-gamma) or anti-tumor necrosis factor alpha (TNF-alpha) antibody. Furthermore, the roles of immune T cells and PPD could be replaced by adding recombinant IFN-gamma together with TNF-alpha to the macrophage cultures, but neither alone was sufficient to induce NO production by the macrophages. Our present data indicate that TNF-alpha produced by PPD-stimulated macrophages and IFN-gamma produced by cell-cell interaction of BCG-immune T cells and antigen engulfed macrophages together activate the macrophages to produce NO. PMID- 8691078 TI - Altered monocyte chemotactic and activating factor gene expression in human glioblastoma cell lines increased their susceptibility to cytotoxicity. AB - A cDNA encoding for human monocyte chemotactic and activating factor (MCAF) was ligated into the retroviral vector pLXSN. These pMCAF-LXSN and antisense p antiMCAF-LXSN vectors were transfected into HBT20 and HBT28 human brain tumor cells. HBT28 cells constitutively express high amounts of MCAF, whereas HBT20 cells express much less MCAF. HBT20 cells transfected with pMCAF-LXSN (HBT20 MCAF) showed significantly higher MCAF mRNA expression and MCAF protein production than the HBT20-parent or HBT20 cells transfected with control vector (HBT20-LXSN). In contrast, supernatant from HBT28 cells transfected with p antiMCAF-LXSN (HBT28-antiMCAF) contained less MCAF than HBT28-parent, HBT28-LXSN, and HBT28-MCAF cells. Activated human monocytes killed HBT20-MCAF cells more efficiently compared with HBT20-parent, HBT20-LXSN, and HBT20-antiMCAF cells (P< 0.02), whereas HBT28-antiMCAF cells were killed more efficiently by activated monocytes compared with HBT28-parent, HBT28-LXSN, and HBT28-MCAF cells (P< 0.05). Cultured supernatants from activated monocytes plus HBT20-MCAF cells or from activated monocytes plus HBT28-antiMCAF cells inhibited the growth of HBT20 and HBT28 cells, respectively. Altered MCAF expression can therefore enhance the ability of activated monocytes to kill brain tumor cells. This increased cytotoxicity is partially dependent upon the basal state of MCAF in the individual tumor cells. PMID- 8691079 TI - Recombinant natural killer enhancing factor augments natural killer cytotoxicity. AB - Natural killer enhancing factor (NKEF) was originally identified and studied because of its ability to enhance NK cytotoxicity in vitro. After cloning the two genes responsible for NKEF proteins, NKEF-A and -B, we found that they belong to a newly described and highly conserved antioxidant gene family. We have now produced recombinant proteins of both genes and used them to test for their ability to promote NK cytotoxicity. Although recombinant NKEF (rNKEF)-A and -B have similar levels of antioxidant function, only the reduced form of rNKEF-A can enhance NK cytotoxicity. These results indicate that both the antioxidant and NK enhancing functions of rNKEF-A and -B probably involve the cysteine residues of the proteins but are mediated by separate domains of the molecules. We pretreated both effector cells and target cells to investigate which population was influenced by rNKEF-A, and determined that the protein must be present during the cytotoxicity assay to enhance the activity. Despite the similarities between NK cytotoxicity and lymphokine-activated killer (LAK) cytotoxicity, rNKEF-A is not effective in augmenting LAK cytotoxicity. Therefore, rNKEFs can be useful tools in not only protecting cells from oxidative damage, but also in selectively promoting NK cytotoxicity against certain tumor cells. PMID- 8691080 TI - The heavy metal lead modulates the expression of both TNF-alpha and TNF-alpha receptors in lipopolysaccharide-activated human peripheral blood mononuclear cells. AB - It has been shown that lead (Pb) potentiates lipopolysaccharide (LPS) lethality in animals by increasing the secretion and uptake or reactivity of tumor necrosis factor-alpha (TNF-alpha). Herein we report that PbCl2 increased TNF-alpha secretion from LPS-treated human peripheral blood mononuclear cells (PBMC) in a concentration- and time-dependent manner. PbCl2 also increased total cellular TNF alpha levels but had no effect on the steady-state levels of TNF-alpha mRNA. PbCl2 decreased membrane-associated TNF-alpha (mTNF-alpha) on LPS-treated monocytes, whereas PbCl2 increased TNF-alpha receptor (TNF-R) p55 surface expression, and had no effect on TNF-R p75 surface expression by LPS-treated monocytes. Overall, the results suggest that PbCl2 increases TNF-alpha expression by posttranscriptional mechanisms in human PBMC, and enhances the reactivity and uptake of TNF-alpha by increasing the surface expression of TNF-R p55. PMID- 8691081 TI - Oxidized LDL potentiates LPS-induced transcription of the chemokine KC gene. AB - Oxidized low-density lipoprotein (LDL) has been shown to modulate the expression of multiple gene products associated with inflammation in several different cell types including mononuclear phagocytes. The reported effects vary dramatically, however, depending upon cell type, stimulus, and degree of LDL oxidation. In the present report, oxidized LDL has been found to markedly potentiate expression of the KC chemokine gene in lipopolysaccharide (LPS)-stimulated macrophages. Pretreatment of elicited mouse peritoneal macrophages with oxidized LDL but not native LDL produced a significant enhancement of LPS-induced KC mRNA expression, whereas levels of IP-10 mRNA, another CXC chemokine, were altered in opposite fashion. The alteration in KC mRNA expression was dependent upon the dose, exposure time, and extent of LDL oxidation. Oxidized LDL selectively prolonged the expression of KC mRNA. Surprisingly this was not a consequence of altered mRNA stability, but rather of prolonged transcription. These effects on KC gene transcription were in marked contrast to previous reports demonstrating inhibitory effects of oxidized LDL on LPS-induced macrophage chemokine expression. Thus extensively oxidized LDL acts on the transcriptional control process in macrophages in both positive and negative fashion on separate members of the same gene family. PMID- 8691082 TI - On the changing concept of evolutionary population stability as a reflection of a changing point of view in the quantitative theory of evolution. AB - Eighteen different terms, currently employed to define various concepts of evolutionary stability in population dynamics are mentioned in this paper. Most of these terms are used in different connotations and even different meanings by different authors. On the other hand, different terms are often employed by different authors to define quite the same concept. Twenty-five years ago there was only one, well-defined, concept of stability, universally recognized in the field. In this paper I will try to relate the recent confusion, concerning concepts of population stability, with a more serious, though not that well recognized, confusion in the modern analytic approach to population dynamics and quantitative evolution. Concepts of population stability will be examined in relation to each other on the one hand and, on the other hand, in relation to two dichotomies regarding the dynamic processes to which they correspond: Short-term versus long-term processes and processes concerning phenotypic changes versus process concerning genotypic changes. A hopefully more consistent use of the current terminology is suggested. PMID- 8691083 TI - Darwinian adaptation, population genetics and the streetcar theory of evolution. AB - This paper investigates the problem of how to conceive a robust theory of phenotypic adaptation in non-trivial models of evolutionary biology. A particular effort is made to develop a foundation of this theory in the context of n-locus population genetics. Therefore, the evolution of phenotypic traits is considered that are coded for by more than one gene. The potential for epistatic gene interactions is not a priori excluded. Furthermore, emphasis is laid on the intricacies of frequency-dependent selection. It is first discussed how strongly the scope for phenotypic adaptation is restricted by the complex nature of 'reproduction mechanics' in sexually reproducing diploid populations. This discussion shows that one can easily lose the traces of Darwinism in n-locus models of population genetics. In order to retrieve these traces, the outline of a new theory is given that I call 'streetcar theory of evolution'. This theory is based on the same models that geneticists have used in order to demonstrate substantial problems with the 'adaptationist programme'. However, these models are now analyzed differently by including thoughts about the evolutionary removal of genetic constraints. This requires consideration of a sufficiently wide range of potential mutant alleles and careful examination of what to consider as a stable state of the evolutionary process. A particular notion of stability is introduced in order to describe population states that are phenotypically stable against the effects of all mutant alleles that are to be expected in the long run. Surprisingly, a long-term stable state can be characterized at the phenotypic level as a fitness maximum, a Nash equilibrium or an ESS. The paper presents these mathematical results and discusses - at unusual length for a mathematical journal - their fundamental role in our current understanding of evolution. PMID- 8691084 TI - Genetic versus phenotypic models of selection: can genetics be neglected in a long-term perspective? AB - Game theoretical concepts in evolutionary biology have been criticized by populations geneticists, because they neglect such crucial aspects as the mating system or the mode of inheritance. In fact, the dynamics of natural selection does not necessarily lead to a fitness maximum or an ESS if genetic constraints are taken into account. Yet, it may be premature to conclude that game theoretical concepts do not have a dynamical justification. The new paradigm of long-term evolution postulates that genetic constraints, which may be dominant in a short-term perspective, will in the long run disappear in the face of the ongoing influx of mutations. Two basic results (see Hammerstein; this issue) seem to reconcile the dynamical approach of long-term population genetics with the static approach of evolutionary game theory: (1) only populations at local fitness optima (Nash strategies) can be long-term stable; and (2) in monomorphic populations, evolutionary stability is necessary and sufficient to ensure long term dynamic stability. The present paper has a double purpose. On the one hand, it is demonstrated by fairly general arguments that the scope of the results mentioned above extends to non-linear frequency dependent selection, to multiple loci, and to quite general mating systems. On the other hand, some limitations of the theory of long-term evolution will also be stressed: (1) there is little hope for a game theoretical characterization of stability in polymorphic populations; (2) many interesting systems do not admit long-term stable equilibria; and (3) even if a long-term stable equilibrium exists, it is not at all clear whether and how it is attainable by a series of gene substitution events. PMID- 8691085 TI - Evolutionary dynamics of predator-prey systems: an ecological perspective. AB - Evolution takes place in an ecological setting that typically involves interactions with other organisms. To describe such evolution, a structure is needed which incorporates the simultaneous evolution of interacting species. Here a formal framework for this purpose is suggested, extending from the microscopic interactions between individuals--the immediate cause of natural selection, through the mesoscopic population dynamics responsible for driving the replacement of one mutant phenotype by another, to the macroscopic process of phenotypic evolution arising from many such substitutions. The process of coevolution that results from this is illustrated in the context of predator-prey systems. With no more than qualitative information about the evolutionary dynamics, some basic properties of predator-prey coevolution become evident. More detailed understanding requires specification of an evolutionary dynamic; two models for this purpose are outlined, one from our own research on a stochastic process of mutation and selection and the other from quantitative genetics. Much of the interest in coevolution has been to characterize the properties of fixed points at which there is no further phenotypic evolution. Stability analysis of the fixed points of evolutionary dynamical systems is reviewed and leads to conclusions about the asymptotic states of evolution rather different from those of game-theoretic methods. These differences become especially important when evolution involves more than one species. PMID- 8691086 TI - The dynamical theory of coevolution: a derivation from stochastic ecological processes. AB - In this paper we develop a dynamical theory of coevolution in ecological communities. The derivation explicitly accounts for the stochastic components of evolutionary change and is based on ecological processes at the level of the individual. We show that the coevolutionary dynamic can be envisaged as a directed random walk in the community's trait space. A quantitative description of this stochastic process in terms of a master equation is derived. By determining the first jump moment of this process we abstract the dynamic of the mean evolutionary path. To first order the resulting equation coincides with a dynamic that has frequently been assumed in evolutionary game theory. Apart from recovering this canonical equation we systematically establish the underlying assumptions. We provide higher order corrections and show that these can give rise to new, unexpected evolutionary effects including shifting evolutionary isoclines and evolutionary slowing down of mean paths as they approach evolutionary equilibria. Extensions of the derivation to more general ecological settings are discussed. In particular we allow for multi-trait coevolution and analyze coevolution under nonequilibrium population dynamics. PMID- 8691087 TI - Long-term evolution of multilocus traits. AB - We analyze monomorphic equilibria of long-term evolution for one or two continuous traits, controlled by an arbitrary number of autosomal loci and subject to constant viability selection. It turns out that fitness maximization always obtains at long term equilibria, but in the case of two traits, linkage determines the precise nature of the fitness measure that is maximized. We then consider local convergence to long term equilibria, for two multilocus traits subject to either constant or frequency dependent selection. From a model of long term dynamics near an equilibrium we derive a criterion of local long-term stability for 2-dimensional equilibria. It turns out that mutation can be a decisive factor for stability. PMID- 8691089 TI - Evolutionary dynamics for bimatrix games: a Hamiltonian system? AB - We review some properties of the evolutionary dynamics for asymmetric conflicts, give a simplified approach to them, and present some new results on the stability and bifurcations occurring in these conservative systems. In particular, we compare their dynamics to those of Hamiltonian systems. PMID- 8691088 TI - Inclusive fitness arguments in genetic models of behaviour. AB - My purpose here is to provide a coherent account of inclusive fitness techniques, accessible to a mathematically literate graduate student in evolutionary biology, and to relate these to standard one-locus genetic models. I begin in Sect. 2 with a general formulation of evolutionary stability; in Sect. 3 and Sect. 4 I interpret the basic stability conditions within genetic and inclusive fitness models. In Sect. 5 I extend these concepts to the case of a class-structured population, and in Sect. 6 I illustrate these notions with a sex ratio example. In Sect. 7 I give a proof of the result that under additive gene action and weak selection, an inclusive fitness argument is able to verify an important stability condition (2.5) for one-locus genetic models. Most of these results have been published. PMID- 8691090 TI - Recent advances in molecular histochemical techniques: in situ hybridization and southwestern histochemistry. AB - Over the past decade, considerable efforts to understand the states of specific gene expression at cellular and/or subcellular levels have been made. For this particular purpose, nonradioactive in situ hybridization to localize mRNAs has been developed and improved substantially, and it is now recognized as a powerful, established light-microscopical technique. In this review, we focus on the recent advances in the technological aspects of nonradioactive in situ hybridization including the use of synthetic oligodeoxynucleotide probes, the progress in analysis of signals, and the application to electron microscopy. Also, southwestern histochemistry, a relatively new method of localizing transcription regulatory proteins by utilizing haptenized DNA with responsive element sequences is described. Then we discuss what we can see by combining these molecular histochemical methods which were brought about by the merger of molecular biology and structural biology. PMID- 8691091 TI - Microinfusion method using barium sulfate for visualization of embryonic blood vessels with light and scanning electron microscopy. AB - An X-ray contrast medium commonly used for clinical examination of the gastrointestinal tract was purified and applied as an injectant for the observation of the blood vasculature maturing in an early embryonic stage of the mouse. The embryos were perfused with the injectant through the umbilical cord and were processed for light and scanning electron microscope (LM and SEM) observations. When infused, the vessels turned white, the color of barium sulfate, thereby the adequate injection pressure and the amount of the injectant were readily controlled. The whole vasculature of the embryo was elucidated with an SEM in great detail at 9.5 days of the embryonic stage, four days earlier than previously achieved with a resin injection. The back scattered electron image of the lung alveolar capillaries containing barium sulfate was successfully obtained with an SEM in the 17.5 day embryo. The backscattering image and the secondary electron image of the identical area were compared to elucidate the spatial relationship between the capillaries and their circumferential cells such as type I and type II alveolar cells. The vascular injection with barium sulfate introduced may facilitate the systemic study of the blood vasculature and may provide useful information as to the relationship vascular formation and organogenesis occurring in an early embryonic stage. PMID- 8691092 TI - Preparation of liposomes that mimic the membrane of endoplasmic reticulum of rat hepatocytes. AB - To examine the interaction between biomembranes and membrane-bound proteins, large unilamellar liposomes have been required. In the present study, we prepared liposomes from a mixture of phospholipids having a phospholipid composition similar to that in the endoplasmic reticula (microsomes) of rat hepatocytes by eight different methods. The resulting liposomes were examined by a combination of the freeze-fracture-replica procedure with biochemical methods. The freeze thawing method of Pick (1981) gave the best results; large unilamellar liposomes that mimic the membrane of endoplasmic reticulum were obtained. Liposomes made by this method are thus suitable for analysis of the interaction between the endoplasmic reticulum membrane and membrane-bound proteins. PMID- 8691093 TI - The role of IGFBP-3 in the regulation of IGFBP-4 proteolysis. AB - The biological effects of insulin-like growth factors (IGFs) are mediated by cell surface receptors but their bioavailability is regulated by IGF binding proteins (IGFBPs) which bind IGF with higher affinity than the receptor. Proteolytic cleavage of the binding proteins reduces their affinity for IGF making the IGF more available to the cell receptor. In the current study we have examined the regulation of IGFBP-4 protease produced by cultured human dermal fibroblasts. IGF I and the analogs of IGF-I (LR3 and Des[1-3]) induced a dose dependent increase in both proliferation and IGFBP-3 production. Low concentrations of IGF-I induced a marked loss of IGFBP-4 by Western ligand blotting (WLB). This effect was confirmed by the ability of media collected from cells exposed to increasing concentrations of IGF-I to fragment recombinant IGFBP-4, an effect blocked by EDTA. IGFBP-4 proteolysis was observed when cells were exposed to Des[1-3] (albeit at higher concentrations) but not with LR3. Both analogs bind to the IGF receptor but do not bind to IGFBP-4 and have reduced (Des[1-3]) or no (LR3) affinity for IGFBP-3. This demonstrated that neither receptor activation nor ligand binding directly to IGFBP-4 was necessary for IGF induced proteolysis. Protease activity correlated with affinity for IGFBP-3 suggesting a role for IGFBP-3 in the regulation of IGFBP-4 proteolysis. This was confirmed by the ability of excess recombinant IGFBP-3 to inhibit the IGF-I and Des[1-3] induced proteolysis of IGFBP-4. Addition of IGF-I to media from cells unexposed to IGF induced IGFBP-4 proteolysis but this was not seen with LR3 which does not bind to IGFBP-3. Fragmentation occured at higher concentrations of Des[1-3] consistent with its reduced affinity for IGFBP-3. This data suggests that IGFBP-4 proteolysis is regulated in a novel manner by IGFBP-3 which is dependent on the relative proportions of the different binding proteins and the levels of IGFs. PMID- 8691094 TI - Involvement of IGF-II in human cancer. AB - IGF-II is a regulatory peptide which appears to be involved significantly in the progression of many tumors, while minimally involved in post-fetal non-tumor tissue. Interruption of IGF-II pathways therefore offers the possibility of tumor control with a high therapeutic index. Investigators should continue to evaluate tumors for the involvement of IGF-II as well as investigate clinically relevant means of disrupting those pathways. PMID- 8691095 TI - Progress towards gene therapy for Duchenne muscular dystrophy. PMID- 8691096 TI - Characterization of serum-derived and recombinant rat IGF-I and their use for measuring true concentrations of IGF-I in rat plasma. AB - While numerous researchers have used rat models to investigate the in vivo actions of IGF-I, interpretation of the results in terms of true concentrations of rat IGF-I (rIGF-I) in plasma has been hampered by the absence of homologous reference standards. In order to overcome this we have produced recombinant rIGF I (rrIGF-I) from Escherichia coli using procedures similar to those we have previously described for the production of other recombinant IGFs. The rrIGF-I is indistinguishable from serum-derived rIGF-I when characterized in a number of in vitro assays including ability to stimulate protein synthesis and inhibit protein degradation in cultured rat cells, as well as in interactions with the rat type-1 IGF receptor and with rat IGF-binding proteins. Moreover, both the serum-derived and the recombinant rat proteins are similar to recombinant human IGF-I (rhIGF-I) in these assays. However, differences between the human and rat IGFs are apparent when tested in immunoassays using some antibodies raised against rhIGF-I. Furthermore, the differences between rhIGF-I and rrIGF-I are even greater when rhIGF-I is used as the competing radiolabel in these assays, a situation that can lead to a two- to threefold underestimation of the actual concentration of IGF-I in rat plasma. These results indicate that, while immunoassays employing antibodies raised against rhIGF-I and rhIGF-I reference standards reliably indicate trends in IGF-I concentrations in rat plasma, the true amounts of rIGF-I present can only be assured in an assay using homologous tracer and reference peptides. PMID- 8691097 TI - Functional characterisation of an ovine endometrial oxytocin receptor cDNA transiently expressed in Cos-7 cells. AB - The entire coding region of an ovine endometrial oxytocin receptor (OTR) cDNA was generated by PCR, subcloned into the SV40 major late promoter expression vector pSVLJ and transiently expressed in Cos-7 cells. A specific OTR antagonist, 125I labelled d(CH2)5 [Tyr(Me)2,Thr4,Tyr-NH2(9)]-vasotocin (OTA), was used to describe the binding kinetics of the expressed receptor which had a Kd of 4.5 nM and Bmax of 2.4 nM/mg protein (6.8 x 10(5) receptor molecules/transfected cell). The functional properties of the expressed OTR were determined by measuring oxytocin induced phosphoinositide (PI) hydrolysis. Oxytocin increased PI turnover in OTR transfected cells fourfold in excess of residual endogenous activity, and stimulated phospholipase C (PLC) activity in a dose- and time-dependent manner, confirming that the expressed OTR cDNA was functional. Arginine vasopressin also stimulated PI turnover in a dose-dependent manner; thresholds of responses to oxytocin and arginine vasopressin were 10(-9) M and 10(-7) M respectively. OTA did not increase PI turnover and competitively inhibited the oxytocin-induced response. Direct activation of the pathway by aluminium fluoride and guanosine (3'-O-thio)-triphosphate (GTP gamma S) confirmed that the OTR was G-protein linked. Co-incubation of GTP gamma S with oxytocin shifted the PI-response threshold from 10(-7) M to 10(-9) M and significantly increased the level of response, suggesting that maximum PI turnover was agonist-dependent. The G protein involved in mediating the signal transduction pathway was pertussis toxin insensitive and, therefore, probably a member of the Gq subfamily. The PLC inhibitor, U73122, had no effect on oxytocin-induced PI turnover, consistent with the response in endometrial tissue. These data suggest that the signalling pathway mediated by expressed OTR is similar to that attributed to OTR occupancy in ovine endometrium. PMID- 8691098 TI - Cortisol decreases IGF-I mRNA levels in human osteoblast-like cells. AB - Excess levels of glucocorticoids are known to cause osteoporosis. It is speculated that the effect of glucocorticoids could be mediated via regulation of IGF-I. The aims of the present study were to detect and quantify the expression of IGF-I and/or IGF-II mRNA transcripts in human osteoblast-like cells and to investigate whether glucocorticoids regulate the expression of IGF-I mRNA transcripts in human osteoblast-like cells. Cultures of human osteoblast-like cells from trabecular bone were established. The IGF-IA and IGF-IB transcripts were detected in human osteoblast-like cells from seven out of nine patients while the IGF-II transcript was detected in human osteoblast-like cells from eight out of nine patients, as determined by RT-PCR assays. Human osteoblast-like cells, as well as human muscle tissue, expressed approximately 1/10 of the IGF-I mRNA levels found in liver, as determined by RNase protection solution hybridization assay. The IGF-I mRNA levels did not decrease with age in the human osteoblast-like cells and no difference was seen between males and females. However, cortisol (10(-6) mol/l) decreased IGF-I mRNA levels. In summary, the present study has shown that human osteoblast-like cells express IGF-I and IGF-II mRNA transcripts and that cortisol down-regulates the IGF-I mRNA levels, indicating that some of the inhibitory effect of glucocorticoids on bone formation in humans is mediated via a reduced autocrine/paracrine expression of IGF-I. PMID- 8691099 TI - Expression of collagenase-3 in the rat ovary during the ovulatory process. AB - We have examined the expression of the murine counterpart of human collagenase-3, a matrix metalloproteinase produced by breast carcinomas, in the course of processes which involve extensive tissue remodeling. By using Northern blot analysis, we have found that collagenase-3 is expressed in the rat ovary, but not in the remaining analyzed tissues including brain, kidney, liver, lung, mammary gland, uterus, bladder, heart, intestine, prostate, spleen, testis and thymus. Collagenase-3 mRNA was detected at high levels in rat ovaries at proestrus and estrus, was at a minimum at metestrus and started to increase during diestrus through to proestrus. In addition, collagenase-3 was also detected on day 21 of pregnancy, which is approximately one day before parturition. However, no significative expression was detected in RNA from ovaries taken immediately after parturition, or on days 1, 5 or 30 postpartum. Northern blot analysis also revealed that collagenase-3 was not expressed at significant levels, compared with ovarian expression, in the uterus or in the mammary gland during pregnancy or after parturition. When follicular granulosa cells were separated from residual ovarian tissue and their RNA was analyzed by Northern blot, it was seen that collagenase-3 was not expressed by the granulosa cells but was present in the residual tissue containing interstitial and thecal tissues, growing follicles and corpora lutea. Immunohistochemical studies also confirmed, at the protein level, the localization of collagenase-3 in rat ovary. Gonadotropic stimulation of ovulation in immature rats by priming with pregnant mare's serum gonadotropin and stimulation with human chorionic gonadotropin failed to induce the expression of collagenase-3, suggesting that additional factors which are not present in the immature stimulated rats are needed for completely effective induction of the expression of this matrix metalloproteinase. On the basis of these results, together with the comparative analysis of expression of different matrix metalloproteinases in the rat ovary, we propose that collagenase-3 is a major ovarian metalloproteinase potentially involved in ovarian function during the reproductive cycle. PMID- 8691101 TI - Differential release of interleukin-6 from human gestational tissues in association with labour and in vitro endotoxin treatment. AB - In this study, we quantified interleukin-6 (IL-6) concentrations in amniotic fluid at term and preterm labour, and determined the gestational tissue source of IL-6. In addition, aspects of the regulatory mechanisms involved in IL-6 release at the time of term labour and in response to bacterial endotoxin, lipopolysaccharide (LPS), have been established. IL-6 concentrations were 2-fold higher in amniotic fluid collected at term compared with preterm gestation, with an additional 2-fold increase in association with term labour. IL-6 was released from all choriodecidual and placental explants but was detected in only 33% of amniotic explant cultures of tissues obtained before labour onset. In contrast, IL-6 was detected in all amniotic, choriodecidual and placental cultures of tissues obtained after term labour onset and delivery, and the mean IL-6 release was significantly higher than that measured in explant cultures of both amniotic (80-fold increase, P < 0.0001) and choriodecidual (3-fold increase, P < 0.02) but not placental explants taken at the time of elective Caesarean section at term before labour onset. LPS significantly (P < 0.05) increased the release of IL-6 from human choriodecidual and placental explants but not amniotic explants, in a time- and dose-dependent manner. IL-6 is a physiological constituent of amniotic fluid and its production by gestational tissues is differentially regulated by LPS and spontaneous labour onset and delivery. PMID- 8691100 TI - Hormonal regulation of IGF-binding protein-2 expression in proliferating C2C12 myoblasts. AB - No studies have investigated the hormonal regulation of IGF-binding protein-2 (IGFBP-2) secretion and mRNA expression in myoblasts. In this study, cells of the C2C12 mouse myoblast cell line were used to examine the effects of various agents on the hormonal regulation of IGFBP-2. Conditioned medium (CM) was collected and cells were harvested at 2, 4, 6, 15 and 24 h after exposure to treatment media containing porcine insulin (pINS) or recombinant human IGF-I (rhIGF-I), and at 6, 15 and 24 h after exposure to treatment media containing dexamethasone (DEX) or prostaglandin E2 (PGE2). Relative abundance of a single 1.8 kb IGFBP-2 mRNA transcript was determined by Northern analysis using total cellular RNA and a labeled cDNA specific for rat IGFBP-2. IGFBP-2 was detected in CM by probing Western blots with 125I-IGF-I (ligand blot analysis). We have previously shown by immunoblot analysis that the predominant 32,000 M(r) protein on ligand blots is IGFBP-2. Treatment with 10(-9) or 10(-6) M pINS led to a rapid reduction (P < 0.01) in relative IGFBP-2 mRNA abundance and protein secretion relative to controls. Treatment with 7 x 10(-10) or 7 x 10(-9) M (5 or 50 ng/ml) rhIGF-I increased IGFBP-2 mRNA abundance and protein secretion (P < 0.01). Cultures treated with 10(-8) M DEX exhibited significantly increased (P < 0.001) IGFBP-2 mRNA and protein. IGFBP-2 secretion was not affected by 10(-6) M PGE2 but mRNA levels were higher than controls at 24 h (P < 0.01). These findings suggest that multiple factors, including growth factors and metabolic hormones, are involved in regulating IGFBP-2 expression in C2C12 myoblasts. PMID- 8691102 TI - Osmotic and volaemic regulation of atrial and ventricular natriuretic peptide secretion in conscious eels. AB - The effects of acute manipulation of plasma osmolality and blood volume on plasma atrial and ventricular natriuretic peptide (ANP and VNP) levels were examined in conscious freshwater eels, Anguilla japonica. A bolus injection of hypertonic NaCl (0.85 M and 1.7 M, 2.5 ml/kg body weight) through a catheter into the ventral aorta produced increases in plasma Na concentration and osmolality with parallel concentration-dependent, transient increases in plasma ANP and VNP levels. Plasma ANP and VNP levels also increased after injection of 1.7 M mannitol solution which produced an increase in plasma osmolality but a decrease in plasma Na concentration. However, injection of a 2.0 M solution of urea, which does not cause cellular dehydration in mammals, produced only small increases in plasma ANP and VNP levels, although plasma osmolality increased. A bolus injection of 10 or 25 ml/kg isotonic saline supplemented with 2% dextran for colloidal osmotic pressure, which theoretically increased blood volume by 29% or 71%, produced volume-dependent, transient increases in plasma ANP and VNP levels without changes in plasma Na concentration and osmolality. Similar volume expansion with dialysed eel plasma caused greater increases than with dextran saline. However, these increases were much smaller than those after osmotic stimuli. These results indicate that secretion of ANP and VNP is regulated by two receptor mechanisms: osmo-receptors activated by cellular dehydration, not specifically by hypernatraemia, and volume or stretch receptors activated by hypervolaemia. The relative importance of the osmoreceptive mechanism is greater in eels than in mammals where volaemic regulation dominates over osmotic regulation for ANP secretion. PMID- 8691103 TI - GnRH-induced calcium mobilisation and inositol phosphate production in immature and mature rat ovarian granulosa cells. AB - In rat ovarian granulosa cells the effects of GnRH are determined by the state of granulosa cell development with mainly inhibitory actions in immature cells and stimulatory actions in differentiated mature cells. These developmentally related effects of GnRH may arise from changes in either one or more of the signal transduction pathways activated by GnRH. The present study therefore measured downstream signalling events associated with the activation of the phospholipase C (PLC) signal transduction pathway in both mature and immature rat ovarian granulosa cells. Results showed that GnRH produced similar total inositol phosphate and intracellular calcium ([Ca2+]i) responses in both immature and mature granulosa cells. In contrast to the biphasic GnRH-induced [Ca2+]i response in pituitary gonadotropes, stimulation of the endogenously expressed GnRH receptor in both immature and mature granulosa cells produced a prompt monophasic rise in [Ca2+]i. This calcium transient was abolished by pretreating either cell type with a potent GnRH receptor antagonist or the PLC inhibitor U73122, demonstrating a GnRH receptor-specific activation of PLC. Similarly, pretreatment of cells with the [Ca2+]i antagonists thapsigargin or cyclopiazonic acid abolished the GnRH-induced calcium transient, whereas EGTA and nifedipine, a voltage-operated calcium channel (VOCC) antagonist, had no effect. These results suggest that in either immature or mature granulosa cells GnRH mobilises calcium from thapsigargin/cyclopiazonic acid-sensitive [Ca2+]i stores but does not involve the influx of extracellular calcium through VOCCs. We conclude that GnRH induced stimulation of the PLC signal transduction pathway is independent of the stage of granulosa cell maturity and that alternative mechanisms account for the opposite effects of GnRH on gonadotrophin-induced steroidogenesis in mature and immature rat granulosa cells in vitro. PMID- 8691104 TI - Temperature and non-aromatizable androgens: a common pathway in male sex determination in a turtle with temperature-dependent sex determination? AB - This study addressed the hypothesis that, in the red-eared slider turtle, Trachemys scripta, non-aromatizable androgens are the physiological equivalent of temperature in determining male development. In the first experiment, eggs were treated in the middle of the temperature-sensitive period with 1.0 or 10.0 micrograms androsterone, 5 alpha-dihydrotestosterone, 3 alpha-androstanediol, or 3 beta-androstanediol, while at an all-male, male-biased, or one of two female biased incubation temperatures. In the second experiment, eggs were treated with the same dosages of dihydrotestosterone at different stages of embryonic development while at a male-biased, threshold, or a female-biased incubation temperature. Results of experiment one indicated that hormone-induced masculinization is specific to non-aromatizable androgens. Results of experiment two indicated that the sensitivity to dihydrotestosterone corresponds to the temperature-sensitive window during development. Further, there is a dose response relationship but no apparent synergism between exogenous dihydrotestosterone and incubation temperature. When considered with other research, it is suggested that non-aromatizable androgens and their products are involved in the initiation of male sex determination whereas oestrogens and their aromatizable androgen precursors are involved in the initiation of female sex determination. PMID- 8691105 TI - Differential effects of malnutrition, bile duct ligation and galactosamine injection in young rats on serum levels and gene expression of IGF-binding proteins. AB - Hepatic gene expression and circulating levels of IGF-binding proteins (IGFBP)-1 to -4 were examined in two rat models of liver disease employing acute hepatitis or chronic structural damage. The study comprised four groups: group 1 (n = 6) was injected intraperitoneally with saline and food was available ad libitum (AL), group 2 (n = 6) underwent bile duct ligation (BDL), group 3 (n = 6) was injected with 400 mg galactosamine (GAL), group 4 (n = 6) was sham-operated and pair-fed to group 2 (PF). All were killed by decapitation at day 7. Serum IGF-I, by RIA, was significantly (P < 0.05) lower in the BDL group (458 +/- 37 micrograms/l) and PF group (451 +/- 51 micrograms/l) compared with the AL group (643 +/- 77 micrograms/l) and GAL group (720 +/- 67 micrograms/l). Immunoblotting showed raised IGFBP-2 levels in all groups compared with AL (BDL, 167 +/- 14% of AL; GAL, 173 +/- 13%; PF, 149 +/- 9%). IGFBP-3 was decreased in the GAL (56 +/- 11%) and PF groups (66 +/- 5%) but increased in the BDL group (154 +/- 29%). IGFBP-4 was decreased in the GAL (76 +/- 11%) and PF groups (47 +/- 5%) but unchanged in the BDL group (90 +/- 10%). By Northern analysis, IGFBP-1 mRNA expression was increased in the GAL (321 +/- 51%) and PF groups (263 +/- 12%) but reduced in the BDL group (68 +/- 8%). IGFBP-2 expression increased in all groups (PF, 836 +/- 19%; BDL, 683 +/- 121%; GAL, 372 +/- 68%) and was highest in the BDL and PF groups. IGFBP-3 expression was reduced in all groups (BDL, 57 +/- 16%; GAL, 52 +/- 12% PF, 51 +/- 13%). IGFBP-4 expression was reduced in the GAL (30 +/ 4%) and PF (28 +/- 5%) groups but unchanged in the BDL group (76 +/- 9%). Marked changes in gene expression of IGFBPs occurred in both models of liver disease, together with serum changes, which were different from each other and from malnutrition alone. PMID- 8691106 TI - A possible role for D8/PSF-A-like sequences in lactotroph versus somatotroph expression of the human prolactin gene. AB - The transcription factor GHF-1/Pit-1 is essential for the expression of GH and prolactin (PRL) by somatotrophs and lactotrophs respectively. However, PRL is not expressed in mature somatotrophs despite the presence of GHF-1/Pit-1. A possible mechanism is the presence of a somatotroph-specific repressor in the 5'-flanking sequences of the PRL gene. The region -3500/-1750 of the human (h) PRL gene is associated with negative regulatory activity and contains an element, designated D8, that resembles repressor PSF-A sequences which are located in the distal upstream region of placental members of the human GH family. An internal deletion of D8 sequences resulted in a significant stimulation of promoter activity in somatotroph GC (P < 0.005) and somatolactotroph-like GH3 and GH4C1 cells (P < 0.05), but not lactotroph-like 235-1 cells after gene transfer. However, D8 binding was observed by nuclease protection with lactotroph- as well as somatotroph-like cell nuclear protein. Although proteins that bind to the D8 element appear ubiquitous, this element does yield tissue-specific complexes in mobility shift assays. Further, competition studies do not suggest an interaction between GHF-1/Pit-1 and D8 proteins. The hPRL D8 element was inserted upstream of a thymidine kinase promoter and used to transfect pituitary and non-pituitary HeLa cells, to assess intrinsic repressor activity and/or promoter specificity. Although no repression was observed, a significant ninefold increase in expression was observed in HeLa cells (P < 0.001) which was at least twofold greater than observed in any of the pituitary cell lines tested. These results implicate D8 in the somatotroph-specific repression of hPRL; however, they also suggest that D8 can act as a stimulator as well as a repressor, depending on the interaction of a ubiquitous D8 factor forming promoter and cell-specific complexes with other elements/factors. PMID- 8691107 TI - Acquired and naturally occurring resistance of thyroid follicular cells to the growth inhibitory action of transforming growth factor-beta 1 (TGF-beta 1). AB - While the multifunctional proteins of the transforming growth factor-beta (TGF beta) family have a potent antiproliferative effect on thyroid follicular cell growth, increased expression of TGF-beta in proliferating thyroid cells and in thyroid tumours has recently been described, suggesting a secondary counter regulatory role of these proteins. We have studied further this apparent paradox in vitro using FRTL-5 cells, 5 continuous cell strains from feline multinodular goitres (MNG) and 29 primary cultures prepared from human MNG. While dose dependent inhibition of FRTL-5 cell growth was confirmed, a variable fraction of these cells was naturally resistant towards TGF-beta 1, thus explaining the large interassay variability of growth inhibition (36 to 98% within 2 days, n = 19). After 40 days of continuous exposure, FRTL-5 cells became fully refractory towards TGF-beta 1 inhibition, due to the selective growth of naturally resistant subclones, as demonstrated for example by microscopic observation of three dimensionally growing collagen-embedded cell clusters. The refractoriness could still be demonstrated even after several cell passages. In addition, 2 out of 5 feline thyroid cell strains obtained from feline MNG and 18 out of 29 primary cultures from human MNG showed a high degree of refractoriness towards TGF-beta. We conclude that constitutively TGF-beta resistant cells may occur in thyroid glands and that persistent TGF-beta refractoriness may secondarily be acquired. Resistant cells may escape regular growth control mechanisms and hence may contribute to the notorious heterogeneity of thyroid growth and to nodular transformation. PMID- 8691108 TI - New insights into zonal differentiation of adrenal autotransplants in the rat: an immunohistochemical study. AB - Adrenal gland autotransplantation, an interesting model of adrenal regeneration, provides the reconstruction of distinct functional and morphological zonae. An immunohistochemical study of the adrenal gland of adult male rats after autotransplantation and endothelin-1 (ET-1) stimulation was carried out. The technique involved total adrenalectomy and immediate autotransplantation of small adrenal pieces under the skin of the dorsal region. The animals were killed 90 days after the autotransplantation and 1 h after intravenous ET-1 administration. Sections of recovered adrenal grafts were incubated with IZAb, a monoclonal antibody which interacts with an antigen (IZAg) predominantly found in rat adrenal inner zones. Saline-treated control autotransplanted animals showed IZAb immunostaining in almost all adrenocortical tissue, with the exception of small clusters of cells beneath the capsule. ET-1-treated animals exhibited an extended zone devoid of immunostaining and located in the subcapsular area. In addition, ET-1-stimulated animals showed significant increases in aldosterone as well as corticosterone concentrations in plasma. These results revealed that ET-1 stimulated the development of an extended subcapsular zone lacking IZAg expression, an effect that suggests its role in zona glomerulosa induction in these animals. PMID- 8691109 TI - Selective toxic effects of tamoxifen on osteoclasts: comparison with the effects of oestrogen. AB - We investigated the actions of the trans- and cis-isomers of tamoxifen on the function of neonatal rat osteoclasts in vitro. Both compounds inhibited resorption pit formation by osteoclast-containing mixed bone cell cultures incubated for 24 h on cortical bone slices. Cell counts revealed that the inhibition was closely related to a cytotoxic effect, to which osteoclasts appeared particularly sensitive. Partial inhibition of resorption was seen in the presence of 2 microM trans-tamoxifen, whereas complete abolition of resorption and osteoclast viability occurred with 10 microM trans-tamoxifen; survival of mononuclear cells was unimpaired at either concentration. Cis-tamoxifen appeared to be slightly more toxic, with significant inhibitions of osteoclast viability and thus resorption pit formation at a concentration of 2 microM, and also of mononuclear cell numbers at 10 microM. Time-lapse video observations indicated that osteoclast death occurred rapidly (within 2-3 h) following exposure to 10 microM of either trans-tamoxifen or cis-tamoxifen. The morphological appearance of the dying cells was consistent with apoptosis. These results may help to explain the anti-resorptive action of tamoxifen seen in vivo in rats and humans. In contrast, oestradiol-17 beta consistently exerted no significant effects on resorption pit formation by rat osteoclasts over 24 h, even at grossly supraphysiological concentrations (up to 10 microM). PMID- 8691110 TI - Changes in the binding characteristics of the mu, delta and kappa subtypes of the opioid receptor in the hypothalamus of the normal cyclic ewe and in the ovariectomised ewe following treatment with ovarian steroids. AB - The mu, delta and kappa opioid receptor subtypes were measured across the oestrous cycle of the ewe and in ovariectomised (OVX) ewes treated with oestrogen and/or progesterone. We have used a subtype-specific opioid receptor binding assay, in which [3H]diprenorphine non-preferentially labelled each receptor subtype in the presence of blocking concentrations of site-specific opioid analogues. The density and affinity of each receptor subtype was measured in the preoptic area (POA) of the hypothalamus and the mediobasal hypothalamus (MBH). Normally cycling ewes were killed during the luteal phase of the oestrous cycle and at various times after an injection of a synthetic prostaglandin (cloprostenol) to synchronise the onset of the follicular phase. OVX ewes were either untreated as controls (n = 4) or treated with oestrogen (n = 4), progesterone (n = 4) or oestrogen and progesterone combined (n = 4). The total number of opioid receptors did not alter across the oestrous cycle or with steroid hormone treatment. In the POA, the mean (+/- S.E.M.) number of delta receptors was significantly (P < 0.05) greater during the luteal phase than 24 h into the follicular phase (133 +/- 45 vs 35 +/- 8 fmol/mg protein). A significantly (P < 0.05) greater number of delta receptors was also found in the OVX progesterone-treated ewes compared with the control animals (172 +/- 9 vs 39 +/- 4 fmol/mg protein). In the MBH, the number of delta receptors was significantly (P < 0.01) greater in ewes killed 56 h after prostaglandin than luteal-phase ewes (184 +/- 40 vs 51 +/- 7 fmol/mg protein). The number of mu receptors in both the POA and the MBH was also significantly (P < 0.05) higher in the 56-h group than in the 12-h group. A similar trend was also observed in the steroid-treated animals, although differences did not reach statistical significance. The delta:mu ratio in the POA was significantly (P < 0.05) higher in the luteal-phase animals than any of the other groups killed after a cloprostenol injection that causes luteolysis. Similarly the ratio of delta receptor density to mu receptor density was greater (P < 0.05) in the OVX progesterone-treated ewes than in the OVX control ewes. No differences were found in the kappa receptor density across the cycle or with different steroid treatments. These data suggest that the relative proportions of the delta and mu subtypes of the opioid receptor in the hypothalamus change during the oestrous cycle. Regulation appears to be due to the feedback effects of ovarian steroids with progesterone altering the delta:mu ratio. In the MBH, there was a general increase in both delta and mu subtypes during the follicular phase of the oestrous cycle. This may explain, in part, how the responsiveness of the GnRH/LH axis to opioid peptides and antagonists changes across the cycle. PMID- 8691111 TI - Interaction between insulin-like growth factor-I and insulin-like growth factor binding proteins in TC-1 stromal cells. AB - IGF-I and -II play an important role in regulating bone formation. Bone marrow stromal cells, particularly those with osteoblast-like features, may act in concert with osteoblasts to increase IGF-I and -II levels in the bone microenvironment. Local bioavailability of IGFs, however, is modulated by IGF binding proteins (IGFBPs). We have previously demonstrated that murine TC-1 stromal cells constitutively secrete IGF-I and IGFBPs. In the present study, we determined the phenotype of these cells and used them as a model to explore the effect of IGFBPs on IGF-I-induced mitogenesis. The effect of IGF-I on IGFBPs expressed by TC-1 was also determined. When grown under conditions that promote osteogenic differentiation, TC-1 cells showed high alkaline phosphatase activity and mRNA levels, weakly expressed osteocalcin mRNA, and formed mineralized bone like nodules. TC-1 cells expressed IGF-I and IGF-II mRNAs, while other stromal phenotypes preferentially expressed IGF-I. IGF-I stimulated TC-1 DNA synthesis in a dose-dependent manner and this effect was inhibited by recombinant IGFBP-1 and 4. Since IGF-I may regulate IGFBP production, the effect of IGF-I on IGFBPs expressed by TC-1 cells was determined. IGF-I increased the abundance of IGFBP-3, -4 and -5 in TC-1 conditioned medium; this correlated with induction of IGFBP-3 mRNA, but not with that of IGFBP-4 or -5 mRNAs. The findings demonstrate that most stromal cells express IGF-I which may act in an autocrine and/or paracrine fashion. The local effects of IGF-I, however, may be blocked by IGFBP-1 or -4. IGF-I regulates the relative abundance of IGFBPs in stromal cells which, in turn, may influence IGF-I-mediated effects on bone remodeling. PMID- 8691112 TI - The effect of ovarian arterial infusion of human recombinant inhibin and bovine follicular fluid on ovarian hormone secretion by ewes with an autotransplanted ovary. AB - Recombinant human inhibin A (rhInh) or steroid-free bovine follicular fluid (bFF) were infused into the ovarian artery of anoestrous ewes with ovarian autotransplants induced to ovulate with a pulsatile regimen of GnRH applied after a 10-day pretreatment with progestagen sponges. In the period 12-24 h after sponge withdrawal ewes received ovarian arterial infusions of saline (n = 6), 0.3 micrograms rhInh/h (n = 5), 1.6 micrograms rhInh/h (n = 5) or 25 microliters bFF/h (n = 4). Controls had a normal follicular phase with an LH surge 43 +/- 3 h after sponge withdrawal which resulted in ovulation (six out of six). Both doses of rhInh increased ovarian venous inhibin concentrations in a dose-related fashion (P < 0.05) but resulted in depressions (P < 0.05) in FSH concentrations of similar magnitude. Both doses of rhInh acutely inhibited ovarian oestradiol and androstenedione secretion (P < 0.01) but at the end of rhInh infusion oestradiol secretion was quickly re-established without a corresponding increase in FSH. LH surges were detected in five out of five and three out of five ewes infused with low and high doses of rhInh respectively, and progesterone concentrations during the subsequent luteal phase were depressed (P < 0.05). Infusion of bFF had no effect on inhibin or FSH concentrations but resulted in acute inhibition (P < 0.01) of ovarian oestradiol, androstenedione and inhibin secretion, a delay (P < 0.05) in the time to the LH surge and a depression (P < 0.05) in luteal-phase progesterone concentrations. In conclusion, while the depression in FSH induced by rhInh cannot be excluded as a cause for the inhibitory effects of rhInh treatment on ovarian function, such a mechanism cannot fully explain the ovarian responses obtained to rhInh infusion. These results therefore support a direct ovarian role for inhibin in the modulation of ovarian function in addition to its indirect role in controlling FSH. This conclusion is supported by the demonstration that bFF can induce similar inhibitory effects on ovarian function without changing FSH. PMID- 8691113 TI - Elastic and length-force characteristics of the gastrocnemius of the hopping mouse (Notomys alexis) and the rat (Rattus norvegicus). AB - The aim of this study was to compare the contractile and series elastic properties of terrestrial mammals that use bipedal versus quadrupedal gaits. The gastrocnemius muscle of the hopping mouse (body mass 30.2 +/- 2.4 g, mean +/- S.D.) and the rat (313 +/- 10.7 g) were compared with data from the literature for the wallaby and the kangaroo rat to distinguish scaling effects and locomotion-related effects on muscle properties. Contractile length-force properties and series elastic stiffness were measured in situ during maximal tetanic contractions. The rat had a larger muscle-fibre-to-tendon-length ratio. The rat and hopping mouse showed similar normalised length-force characteristics of the gastrocnemius. Normalised stiffness in the hopping mouse was higher. The hopping mouse showed a higher capacity to store elastic energy per unit of contractile work capacity, as well as per unit of body mass. Accounting for body size differences, the rat had a smaller relative muscle mass and thus smaller work capacity than the three hopping animals considered. This is an agreement with a quadrupedal versus bipedal locomotion style. The differences in contractile and elastic properties of the gastrocnemius of the rat and hopping mouse seem to be closely related to locomotion patterns. Small animals seem to be able to utilise the storage and release of elastic energy to a far lesser extent than larger animals. However, even in animals as small as hopping mice, the storage and utilisation of elastic energy during locomotion is of functional significance and probably depends on locomotor behaviour. PMID- 8691114 TI - An increase in activity of serotonergic Retzius neurones may not be necessary for the consummatory phase of feeding in the leech Hirudo medicinalis. AB - During the consummatory phase of feeding, in which blood is ingested, medicinal leeches display a characteristic set of behaviours: they extend their jaws, are less responsive to sensory input, produce mucus, relax the body wall and exhibit waves of peristalsis that can run the length of the body. Earlier reports suggested that this pattern of behaviour is orchestrated by serotonin released from Retzius cells in response to the appropriate sensory stimulation of the lip. We have developed a semi-intact preparation in which only the nervous system in the posterior half of the leech was exposed. The front half of the leech was free to explore, bite through and feed until satiated from a blood-filled sausage casing while continuous intracellular and extracellular recordings were made from identified cells and the nerve roots of the exposed segments. Prior to attachment of the animal to the feeding device, the firing frequency of the Retzius cell increased transiently during spontaneous movements or tactile stimuli to its front or posterior end. In contrast, Retzius cell activity decreased after the anterior sucker attached to the membrane of the feeding device at about the time when ingestion was initiated. Increased activity of Leydig cells, which are known to modulate several circuits in the leech, was also associated with exploration. However, unlike that of Retzius cells, the activity of Leydig cells increased significantly following the onset of consumption. These results suggest that increased activity of Retzius cells in midbody ganglia is not a prerequisite for the consummatory phase of feeding and raises questions regarding the role of serotonin in regulating this behaviour. PMID- 8691115 TI - Mapping motor neurone activity to overt behaviour in the leech: internal pressures produced during locomotion. AB - Several behaviour patterns have been studied in the leech at both the kinematic and neuronal levels. However, very little is known about how patterns of motor neurone activity map to actual movements. Internal pressure is an essential biomechanical property in this process, being responsible for producing the rigidity and posture that allow the directed delivery of forces produced by muscle contraction. To obtain a better understanding of the biomechanical processes involved in movement of the leech, we have measured the internal pressure of the animal by placing catheters through the body wall and into the gut of intact animals showing normal patterns of behaviour. Each type of behaviour had a characteristic pressure waveform. The elongation phase of crawling produced a rapid increase in pressure that peaked when midbody segments were maximally elongated. The pressure produced during the contraction phase of crawling depended on the type of crawl, only inchworm crawling producing a second peak. Whole-body shortening in response to a head poke also produced a pressure peak, but it had a faster rise time. Swimming produced the largest pressure, which was marked by a large sustained increase that fluctuated phasically with undulations of the body. Dual pressure recordings using two catheters demonstrated that pressure was not uniform along the length of the leech, indicating that the body cavity is functionally compartmentalised. Injecting fluid into the gut via a recording catheter allowed us to determine the effects of increasing internal volume on pressure. In line with previous predictions made using an abstract biomechanical model of the leech hydroskeleton, we found that an increase in the volume caused a reduction in the pressure. We are in the process of constructing a more realistic biomechanical model of the leech, based on actual data reported elsewhere. The results in this paper will provide key tests for refining these models. PMID- 8691116 TI - The mechanism of cardiac shunting in reptiles: a new synthesis. AB - The mechanism of cardiac shunting in reptiles is controversial. Recent evidence suggests that a right-to-left shunt in turtles results primarily from a washout mechanism. The mechanism that accounts for left-to-right (L-R) shunting is unresolved. This study used haemodynamic analysis and digital subtraction angiography to determine the mechanism of L-R cardiac shunting in the turtle Trachemys (Pseudemys) scripta. Animals were instrumented with ultrasonic blood flow probes (Transonic Systems, Inc.) for the measurement of total pulmonary blood flow and total systemic blood flow. In addition, catheters were inserted into the common pulmonary artery (PA), the systemic arteries, the left atrium and right atrium. These catheters were used for the measurement of blood pressure or for the infusion of radio-opaque material. Haemodynamic conditions were altered by electrical stimulation of the afferent (VAF) or efferent vagal nerves or by infusion of vasoactive drugs. Under control conditions, the peak systolic pressure in the systemic arteries was slightly higher than that in the PA (30.6 versus 28.3 mmHg; 4.08 versus 3.77 kPa), whereas diastolic pressure in the PA was significantly less than that in the systemic arteries (9.8 versus 24.4 mmHg; 1.31 versus 3.25 kPa). During VAF stimulation, the peak systolic pressures in the PA and aortae almost doubled. Diastolic pressure in the systemic arteries also doubled, but it increased by only 45% in the PA. Ejection of blood into the PA preceded that into the left aorta by 53 ms under control conditions. This difference increased (by as much as 200 ms) as the difference in the diastolic pressures between the two circulations increased during VAF stimulation. This resulted in the development of a large net L-R shunt. Under these conditions, digital subtraction angiography showed that the L-R shunt resulted from a combination of both washout and pressure mechanisms. PMID- 8691117 TI - Children's sensitivity to syllables, onsets, rimes, and phonemes. AB - It has been argued that children's performance on phonological awareness tasks varies with the linguistic level that is tapped by the task. For example, tasks that involve syllables are thought to be easier than tasks that involve lower level linguistic units, and tasks that tap the level of onsets are thought to be easier than tasks that require access to single phonemes. In previous research, however, the linguistic status of a unit has often been confounded with its size. Five experiments were carried out in an attempt to disentangle these variables and so to provide a better test of the linguistic status hypothesis. In the first study, preschoolers and kindergartners more readily judged that two stimuli shared a beginning sound when that sound was an onset on its own than when it was part of a cluster onset. In two additional experiments, there was an advantage for syllables over rimes in kindergarten and first-grade children when the shared units occurred in the middle syllables of trisyllabic stimuli. The superiority for syllables was largely masked in two other studies in which the stimuli that shared a unit rhymed. This latter result suggests that children's familiarity with rhyme can override the syllable advantage. Overall, the results support the linguistic status hypothesis by indicating that effects of linguistic level on phonological sensitivity cannot always be reduced to effects of unit size. PMID- 8691118 TI - Age and gender differences in the nature, meaning, and function of cherished possessions for children and adolescents. AB - Age and gender differences were examined concerning the nature (types of objects considered special), meaning (person/nonperson, past, present, and future associations), and function (emotional, social, identity development, and play) of cherished possessions. One hundred twenty subjects in six age categories (6, 9, 11, 14, 16, and 18 years), with 10 males and 10 females comprising each age group, were interviewed. Results indicated significant age, gender, and age by gender interactions. For example, younger children were egocentric in the meanings assigned to their cherished possessions, while older children held social relationships meaningful; females favored items to be contemplated while males favored action items; possessions which were meaningful for the "enjoyment" they provided decreased after age 6 years in females, but persisted in males throughout the ages studied. The findings have theoretical implications for cognitive, emotional, and social development from childhood through adolescence. PMID- 8691119 TI - The effect of repeated reactivations on memory specificity in infancy. AB - The cues that reactivate forgotten memories of young infants are highly specific. At the time of initial reminding, if either the cue or context differs from that originally present during encoding, then the memory is not recovered. In three experiments, we asked whether this specificity decreases over repeated reactivations. Three-month-old infants, trained in the mobile conjugate reinforcement paradigm with a particular cue in a particular context, received multiple reactivation treatments after their training memory was forgotten; either the cue or the context was changed during the final reminder. For a given age of the memory, context specificity was eliminated after fewer retrievals than cue specificity, and the number of retrievals required to eliminate specificity interacted with the age of the memory. These results confirm that different memory attributes become inaccessible at different rates and that repeatedly retrieved and older memories are likely to be less detailed. This transformation may underlie reconstructive memory in linguistic individuals. PMID- 8691120 TI - Sex differences in the effectiveness of elaborative strategy use: knowledge access comparisons. AB - Dual-task procedures-elaborative strategy use and finger-tapping-were used to examine both recall and mental effort demands of elaboration strategy use with equal numbers of boys and girls at grades two and three. Knowledge-base access was examined by comparing different item types in the associative learning list: masculine, feminine, and mixed. Results showed that boys and girls did not differ in their recall of arbitrarily paired items (e.g., mixed pairs). A Sex by Item Type (masculine vs feminine) interaction, however, revealed that for feminine pairs girls recalled more than boys, whereas for masculine pairs no sex difference was observed. Finger tapping interference scores indexed mental effort. Similar to the recall findings, results indicated that the elaboration of feminine pairs required less mental effort by girls in contrast to boys. Elaboration of masculine pairs was not associated with a sex difference. The results were discussed in terms of sex differences in knowledge-base access. PMID- 8691121 TI - Children's analogical problem solving: the effects of superficial, structural, and procedural similarity. AB - Two experiments with children between 5 and 8 years of age were designed to determine the effects of different types of similarity on analogical problem solving and to explore the cognitive components responsible for these effects. Three dimensions of similarity shared by the source and target problems were manipulated, and children's problem-solving performance was assessed with multiple measures. The results indicate that superficial and structural similarity facilitated the process of drawing analogies. More importantly, the present research demonstrated that procedural similarity influenced the process of applying analogues. The results also indicate that children as young as 5 and 6 years of age are capable of detecting and utilizing similarities in superficial features, structural relations, and procedural operations. Theoretical implications are discussed. PMID- 8691122 TI - Models of T cell anergy: is there a common molecular mechanism? PMID- 8691123 TI - Activation protein 1-dependent transcriptional activation of interleukin 2 gene by Ca2+/calmodulin kinase type IV/Gr. AB - The Ca2+/calmodulin-dependent protein kinase (CaMK) type IV/Gr is selectively expressed in T lymphocytes and is activated after signaling via the T cell antigen receptor (TCR), indicating that it mediates some of the Ca(2+)-dependent transcriptional events that follow TCR engagement. Here we show that CaMKIV/Gr induces the transcription factor activation protein 1 (AP-1) alone or in synergy with T cell mitogens and with the p21ras oncoprotein. CaMKIV/ Gr signaling is associated with transcriptional activation of c-fos but is independent of p21ras or calcineurin. AP-1 is an integral component of the nuclear factor of activated T cells (NFAT) transcriptional complex, which is required for interleukin 2 gene expression in T cells. We demonstrate that CaMKIV/Gr reconstitutes the capacity of the cytosolic component of NFAT to direct transcription from NFAT sites in non T cells. These results reveal a central role for CaMKIV/Gr as a Ca(2+)-regulated activator of gene transcription in T lymphocytes. PMID- 8691125 TI - Use of combinatorial peptide libraries to construct functional mimics of tumor epitopes recognized by MHC class I-restricted cytolytic T lymphocytes. AB - Identification of cytolytic T lymphocyte (CTL) epitopes presented by major histocompatibility complex (MHC) class I molecules on tumor cells is critical for the design of active immunotherapy. We describe the use of combinatorial peptide libraries with defined amino acids in two MHC anchor positions to search for epitopes that are recognized by H-2Db- and Kb-restricted CTL specific for the mouse lymphoma EL4. An iterative strategy was used for screening libraries in which 16 amino acids were divided into 3 groups and 3 subgroups: alpha (AL, VT, FY); beta (GS, P, DE); gamma (KR, H, NQ). The proportions of each group and subgroup at individual peptide positions were changed in the library synthesis, and the effect of these changes on CTL activity was measured in a sensitive RMA-S cell assay. A single H-2Db epitope mimic was deduced from the original library that contained > 2 x 10(8) potential peptides and was at least 9 logs more potent than the original library. Immunization of syngeneic mice with this peptide elicited CTL that lysed EL4 cells as well as RMA-S cells pulsed with peptides isolated from Db molecules of EL4 cells, indicating functional similarity between the mimicking peptide and the naturally processed CTL epitope. Furthermore, adoptive transfer of such a CTL line had a therapeutic effect in mice with EL4 established as an ascites tumor. Two H-2Kb-restricted epitope mimics of the same tumor were also identified. Our method represents a novel approach for the construction of MHC class I-restricted targets that can serve as immunogens for active immunotherapy of cancer. PMID- 8691124 TI - Activation mediated by RP105 but not CD40 makes normal B cells susceptible to anti-IgM-induced apoptosis: a role for Fc receptor coligation. AB - Signals through the B cell antigen receptor lead to a variety of cellular events such as activation, anergy, and apoptosis. B cells select these outcomes to establish and maintain self-tolerance, and to mount adequate antibody responses. However, it is not fully understood how one and the same signal causes such different consequences. In the present study, we have studied the effect of activation signals on the outcome of responses to antigen receptor ligation. Two distinct growth-promoting signals were used to activate B cells. Ligation of either RP105, a newly discovered B cell surface molecule, or the CD40 molecule, drove B cells to proliferate. Resultant blastic cells were then exposed to anti immunoglobulin M (IgM). Blast cells that had been stimulated with anti-RP105 ceased growing and underwent apoptosis after cross-linking of surface IgM. Coligation of the Fc gamma receptor IIB with surface IgM augmented, rather than aborted, this response. In contrast to RP105-activated B cells, blast cells that had been activated by CD40 ligation were unaltered by anti-IgM. On the other hand, CD40-activated B cells became extremely susceptible to Fas-mediated apoptosis, whereas RP105-activated B cells were much less sensitive. Anti-IgM induced apoptosis in RP105 blasts was independent of Fas, because it was demonstrable with Fas-deficient MRL-lpr/lpr mice. These results demonstrate that the nature of an initial activation signal has a great influence on the fate of activated B cells after (re)engagement of the antigen receptor. RP105, as well as CD40, may be important in this life/death decision. PMID- 8691126 TI - A role for CD4+ NK1.1+ T lymphocytes as major histocompatibility complex class II independent helper cells in the generation of CD8+ effector function against intracellular infection. AB - Major histocompatibility complex (MHC) class II (A beta) knockout mice were vaccinated with ts-4, an attenuated mutant strain of Toxoplasma gondii, which in normal animals induces strong T cell immunity mediated by interferon gamma (IFN gamma). After challenge with the lethal parasite strain RH, the knockout mice displayed decreased resistance consistent with absence of CD4+ effectors. Nevertheless, these animals generated CD8+ lymphocyte effectors capable of mediating partial protection through IFN-gamma secretion. Moreover, in vivo neutralization experiments indicated that the development of resistance in knockout mice depends on CD4+ cells as well as interleukin 2 (IL-2). The identity of the IL-2-producing protective cell population was further characterized as CD4+, NK1.1+ by in vitro depletion studies and reverse transcriptase-PCR analysis of fluorescence-activated cell sorter (FACS)-purified CD4+ NK1.1+ T lymphocytes. These results demonstrate that in the absence of conventional MHC class II restricted CD4+ T lymphocytes, CD8 priming persists and mediates partial protective immunity to T. gondii. Moreover, the data argue that CD4+, NK1.1+ cells, previously implicated in the initiation of T helper cell 2 (Th2) responses through their production of IL-4, can also play a role as alternative IL-2 secreting helper cells in Th1-mediated host resistance to infection. PMID- 8691127 TI - Mechanisms of transactivation by nuclear factor of activated T cells-1. AB - Nuclear factor of activated T cells-family proteins (NFAT1/NFATp, NFATc, NFAT3, and NFAT4/NFATx/NFATc3) play a key role in the transcription of cytokine genes and other genes during the immune response. We have defined the mechanisms of transactivation by NFAT1. NFAT1 possesses two transactivation domains whose sequences are not conserved in the other NFAT-family proteins, and a conserved DNA-binding domain that mediates the recruitment of cooperating nuclear transcription factors even when it is expressed in the absence of other regions of the protein. The activity of the NH2-terminal transactivation domain is modulated by an adjacent regulatory region that contains several conserved sequence motifs represented only in the NFAT family. Our results emphasize the multiple levels at which NFAT-dependent transactivation is regulated, and predict significant differences in the architecture of cooperative transcription complexes containing different NFAT-family proteins. PMID- 8691128 TI - Partial signaling by CD8+ T cells in response to antagonist ligands. AB - Structural variants of an agonist peptide-major histocompatibility complex (MHC) molecule ligand can show partial agonist and/or antagonist properties. A number of such altered ligands appear to act as pure antagonists. They lack any detectable ability to induce T cell effector function and have been described as unable to induce calcium transients and turnover of inositol phosphates. This has been interpreted as an inability of these ligands to initiate any T cell receptor (TCR)-dependent signal transduction, with their antagonist properties ascribed to competition with offered agonist for TCR occupancy. Yet antagonists for mature CD8+ T cells can induce positive selection of thymocytes, implying active induction of T cell differentiation events, and partial agonists or agonist/antagonist combinations elicit a distinctive pattern of early TCR associated tyrosine phosphorylation events in CD4+ T cells. We have therefore directly examined proximal TCR signaling in a CD8+ T cell line in response to various related ligands. TCR engagement with natural peptide-MHC class I agonist resulted in the same pattern of early TCR-associated tyrosine phosphorylation events as seen with CD4+ cells, including accumulation of both the p21 and p23 forms of phosphorylated zeta, phosphorylation of CD3 epsilon, and association of phosphorylated ZAP-70 with the TCR. Two antagonists that lacked the ability to induce any detectable CTL effector response (cytolysis, esterase release, gamma interferon secretion, interleukin-2 receptor alpha upregulation) were nevertheless found to also induce TCR-dependent phosphorylation events. In these cases, there was preferential accumulation of the p21 form of phospho-zeta without net phosphorylation of CD3 epsilon, as well as the association of nonphosphorylated ZAP-70 kinase with the receptor. These data show that variant ligands induce similar TCR-dependent phosphorylation events in CD8+ T cells as first observed in CD4+ cells. More importantly, they demonstrate that some putatively pure antagonists are actually a subset of partial agonists able to induce intracellular biochemical changes through the TCR. This delivery of a partial signal by antagonists raises the possibility that antagonism in some cases may result from active interference with stimulation of effector activity by agonist in mature T cells, while the same variant signal could selectively trigger intracellular events that allow positive without negative selection in thymocytes. PMID- 8691129 TI - Translational control of interleukin 2 messenger RNA as a molecular mechanism of T cell anergy. AB - T cell stimulation by triggering through the T cell receptor (TCR) in the absence of costimulatory signals or by calcium ionophore induces unresponsiveness in T cells to further stimulation, a phenomenon known as anergy. In freshly isolated T cells, calcium ionophore induces expression of interleukin (IL)-2 messenger (mRNA), but this mRNA is not translated and not loaded with ribosomes. In addition, while plate-bound anti-CD3 stimulation of resting T cells leads to IL-2 mRNA expression and IL-2 secretion, in cells pretreated with calcium ionophore before anti-CD3 stimulation, the IL-2 mRNA remains polysome unloaded and no IL-2 is produced. These observations show that IL-2 expression is controlled at the translational level, by differential ribosome loading. Furthermore, our data suggest that translational control of IL-2 mRNA may be a molecular mechanism by which anergy is attained. PMID- 8691130 TI - A human tumor necrosis factor p75 receptor agonist stimulates in vitro T cell proliferation but does not produce inflammation or shock in the baboon. AB - Tumor necrosis factor (TNF) is a potentially useful adjunct to anticancer therapies. However, the clinical utility of TNF has been limited by generalized toxicity and hypotension. Recently, studies have begun to dissect the individual proinflammatory and immunologic responses that result from TNF binding to its two cellular receptors, p55 and p75, in an attempt to develop TNF receptor agonists with reduced systemic toxicity. To evaluate a p75 receptor selective TNF mutant (p75TNF), TNF and p75TNF were administered to healthy anesthetized baboons. Intravenous infusion of the p75TNF produced none of the hemodynamic changes seen after the infusion of TNF. Infusion of p75TNF also failed to induce the plasma appearance of interleukins 6 and 8. However, p75TNF enhanced in vitro baboon thymocyte proliferation to concanavalin A, and infusion of p75TNF resulted in increased soluble p55 and p75 receptor plasma concentrations. Local skin necrosis and tissue neutrophil infiltration were seen after subcutaneous injections of TNF and p55TNF. Subcutaneous injection of p75TNF did not result in skin necrosis but did result in a modest dermal infiltration of lymphocytes and macrophages. The findings suggest that p75TNF may stimulate T cell proliferation without the systemic and local toxicity seen with TNF. PMID- 8691131 TI - Activation and homologous desensitization of human endothelial cells by CD40 ligand, tumor necrosis factor, and interleukin 1. AB - We have reported previously that activation of human umbilical vein endothelial cells (HUVECs) through CD40, using a recombinant soluble form of trimerized CD40 ligand, leads to induction of E-selectin, vascular cell adhesion molecule-1 (VCAM 1), and intercellular adhesion molecule-1 (ICAM-1). Here, we compare the effects of CD40 ligand with those of tumor necrosis factor (TNF) and interleukin 1 (IL 1). All three ligands induce transient increases in E-selectin (peak 4 h) and VCAM-1 (peak 8-24 h), as well as sustained increases in ICAM-1 (plateau 24 h). Quantitatively, TNF is more potent than IL-1, which is much more potent than CD40 ligand. The same hierarchy is observed for transcriptional activation of an E selectin promoter reporter gene construct in transiently transfected HUVECs. TNF and CD40 ligand each induced activation of the transcription factors NF-kappa B, IRF-1, and ATF-2/c-Jun, measured by electrophoretic mobility shift assays, but this response appeared quantitatively similar. All three agents transiently (peak 30 min) activated Jun NH2-terminal kinase (JNK), which has been implicated in transcription of E-selectin through its actions on ATF-2/c-Jun. Activation of JNK again showed a hierarchy of potency (TNF > IL-1 >> CD40 ligand), although the time course of induction was similar for all three agents. After 44 h of pretreatment, TNF, IL-1, and CD40 ligand each display homologous desensitization for reinduction of surface expression of E-selectin. A similar pattern of homologous desensitization for reactivation of JNK was observed. We conclude that TNF, IL-1, and CD40 ligand all activate similar responses in ECs, and that homologous desensitization of JNK may explain the inability of individual cytokines to reinduce E-selectin expression. PMID- 8691132 TI - T cell responses affected by aminopeptidase N (CD13)-mediated trimming of major histocompatibility complex class II-bound peptides. AB - Endocytosed protein antigens are believed to be fragmented in what appears to be a balance between proteolysis and MHC-mediated epitope protection, and the resulting peptide-MHC complexes are transported to the surface of the antigen presenting cells (APC) and presented to T cells. The events that lead to antigenic peptide generation and the compartments where antigen processing takes place remains somewhat enigmatic. The importance of intracellular antigen processing has been well established; however, it is unclear whether additional processing occurs at the APC surface. To follow antigen processing, we have identified a pair of T cell hybridomas that recognize a long vs. a short version of the same epitope. We have used prefixed APC and various protease inhibitors to demonstrate that the APC surface has a considerable potential for antigen processing. Specific antibodies further identified the exopeptidase Aminopeptidase N (APN, CD13) as one of the enzymes involved in the observed cell surface antigen processing. The NH2-terminal end of the longer peptide could, even while bound to major histocompatibility complex (MHC) class II molecules, be digested by APN with dramatic consequences for T cell antigen recognition. This could be demonstrated both in cell-free systems using purified reagents and in cellular systems. Thus, MHC class II and APN may act in concert to generate the final T cell epitopes. PMID- 8691133 TI - Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. AB - Human CD4+ T cells, activated by allogeneic monocytes in a primary mixed lymphocyte reaction in the presence of exogenous interleukin (IL) 10, specifically failed to proliferate after restimulation with the same alloantigens. A comparable state of T cell unresponsiveness could be induced by activation of CD4+ T cells by cross-linked anti-CD3 monoclonal antibodies (mAbs) in the presence of exogenous IL-10. The anergic T cells failed to produce IL-2, IL-5, IL-10, interferon gamma, tumor necrosis factor alpha, and granulocyte/macrophage colony-stimulating factor. The IL-10-induced anergic state was long-lasting. T cell anergy could not be reversed after restimulation of the cells with anti-CD3 and anti-CD28 mAbs, although CD3 and CD28 expression was normal. In addition, restimulation of anergized T cells with anti-CD3 mAbs induced normal Ca2+ fluxes and resulted in increased CD3, CD28, and class II major histocompatibility complex expression, indicating that calcineurin-mediated signaling occurs in these anergic cells. However, the expression of the IL-2 receptor alpha chain was not upregulated, which may account for the failure of exogenous IL-2 to reverse the anergic state. Interestingly, anergic T cells and their nonanergic counterparts showed comparable levels of proliferation and cytokine production after activation with phorbol myristate acetate and Ca2+ ionophore, indicating that a direct activation of a protein kinase C-dependent pathway can overcome the tolerizing effect of IL-10. Taken together, these data demonstrate that IL-10 induces T cell anergy and therefore may play an important role in the induction and maintenance of antigen-specific T cell tolerance. PMID- 8691135 TI - The Ets protein Spi-B is expressed exclusively in B cells and T cells during development. AB - Spi-B and PU.1 are hematopoietic-specific transcription factors that constitute a subfamily of the Ets family of DNA-binding proteins. Here we show that contrary to previous reports, PU.1 and Spi-B have very different expression patterns. PU.1 is expressed at high levels in B cells, mast cells, megakaryocytes, macrophages, neutrophils, and immature erythroid cells and at lower levels in mature erythrocytes. PU.1 is completely absent from peripheral T cells and most T cell lines based on sensitive RT-PCR assays. In contrast, Spi-B is expressed exclusively in lymphoid cells and can be detected in early fetal thymus and spleen. In situ hybridizations of adult murine tissues demonstrate Spi-B mRNA in the medulla of the thymus, the white pulp of the spleen, and the germinal centers of lymph nodes. Spi-B expression is very abundant in B cells and both Spi-B mRNA and protein are detected in some T cells. In situ hybridization and Northern blot analysis suggest that Spi-B gene expression increases during B cell maturation and decreases during T cell maturation. Gel-retardation experiments show that Spi B can bind to all putative PU.1 binding sites, but do not reveal any preferred Spi-B binding site. Finally, both PU.1 and Spi-B function as transcriptional activators of the immunoglobulin light-chain enhancer E lambda 2.4 when coexpressed with Pip (PU.1-interaction partner) in NIH-3T3 cells. Taken together, these data suggest that differences in patterns of expression between Spi-B and PU.1 distinguish the function of each protein during development of the immune system. PMID- 8691134 TI - Platelet-activating factor exerts mitogenic activity and stimulates expression of interleukin 6 and interleukin 8 in human lung fibroblasts via binding to its functional receptor. AB - Platelet-activating factor (PAF) is a potent proinflammatory phospholipid mediator of the lung. In this study, we demonstrate that PAF receptor mRNA and protein is expressed by human lung fibroblasts. Interaction of PAF with its specific receptor resulted in increases of tyrosine phosphorylation of several intracellular proteins, indicating that the PAF-receptor might be functionally active. PAF-induced transcription of protooncogenes c-fos and c-jun as well as of interleukin (IL)-6 and IL-8 genes in human fibroblasts. Transcription of the interleukins was followed by secretion of the respective proteins. Moreover, PAF enhanced proliferation of fibroblasts in a concentration-dependent manner. Using signaling inhibitors, we demonstrate that PAF-induced transcription of the c-fos, IL-6, and IL-8 genes, as well as proliferation, require activation of pertussis toxin-sensitive G proteins, tyrosine kinases, and protein kinase C (PKC). In contrast, transcription of c-jun was blocked by pertussis toxin, but not by inhibitors for tyrosine kinases or PKC. These data suggest that PAF stimulates distinct signaling pathways in human lung fibroblasts. In addition, the activation of human fibroblasts by PAF leads to enhanced proliferation and to the expression of proinflammatory cytokines, which may contribute to the pathophysiological changes in pulmonary inflammation. PMID- 8691136 TI - Cell adhesion and migration are regulated at distinct stages of thymic T cell development: the roles of fibronectin, VLA4, and VLA5. AB - T cell development in the thymus requires the establishment of stable interactions with cell-selecting elements such as the cortical epithelium followed by a regulated movement of selected progenitors to the medulla. Cell adhesion and migration are mediated by integrins in a number of biological systems though little is known regarding their function in the thymus. We demonstrated previously that immature CD3loCD69lo double positive human thymocytes adhere avidly to FN via the integrin, VLA4. We now demonstrate that the interaction of mature CD3hiCD69hi thymic subsets with FN triggers migration rather than firm adhesion. Migration requires the engagement of VLA4 in cooperation with VLA5 and both receptors regulate the persistence and directionality of movement. While migration capability is linked to maturation state, ligand concentration determines the efficiency of migration. In fact, FN and the alternatively spliced CS1 site are predominant in the thymic medulla, suggesting an instructive role of this ECM protein in vivo. Our studies identify a novel VLA4 and VLA5/FN-mediated pathway likely to be involved in regulating cell traffic between the cortex and medulla of the thymus. Moreover, the data provides evidence that VLA4 exists in at least two functional states at distinct stages of T cell development. While different states of VLA4 activation have been described on cell lines, this represents the first evidence supporting a biological significance for this integrin property. PMID- 8691137 TI - An anti-platelet-endothelial cell adhesion molecule-1 antibody inhibits leukocyte extravasation from mesenteric microvessels in vivo by blocking the passage through the basement membrane. AB - Platelet-endothelial cell adhesion molecule-1 (PECAM-1, CD31) plays an active role in the process of leukocyte migration through cultured endothelial cells in vitro and anti-PECAM-1 antibodies (Abs) inhibit accumulation of leukocytes into sites of inflammation in vivo. Despite the latter, it is still not clear at which stage of leukocyte emigration in vivo PECAM-1 is involved. To address this point directly, we studied the effect of an anti-PECAM-1 Ab, recognizing rat PECAM-1, on leukocyte responses within rat mesenteric microvessels using intravital microscopy. In mesenteric preparations activated by interleukin (IL)-1 beta, the anti-PECAM-1 Ab had no significant effect on the rolling or adhesion of leukocytes, but inhibited their migration into the surrounding extravascular tissue in a dose-dependent manner. Although in some vessel segments these leukocytes had come to a halt within the vascular lumen, often the leukocytes appeared to be trapped within the vessel wall. Analysis of these sections by electron microscopy revealed that the leukocytes had passed through endothelial cell junctions but not the basement membrane. In contrast to the effect of the Ab in mesenteric preparations treated with IL-1 beta, leukocyte extravasation induced by topical or intraperitoneal administration of the chemotactic peptide formyl-methionyl-leucyl-phenylalanine was not inhibited by the anti-PECAM-1 Ab. These results directly demonstrate a role for PECAM-1 in leukocyte extravasation in vivo and indicate that this involvement is selective for leukocyte extravasation elicited by certain inflammatory mediators. Further, our findings provide the first in vivo indication that PECAM-1 may have an important role in triggering the passage of leukocytes through the perivascular basement membrane. PMID- 8691138 TI - T helper cell 1-type CD4+ T cells, but not B cells, mediate colitis in interleukin 10-deficient mice. AB - Mice rendered deficient in the production of interleukin 10 (IL-10-/-) develop a chronic inflammatory bowel disease (IBD) that predominates in the colon and shares histopathological features with human IBD. Our aim was to identify which cell type(s) can mediate colitis in IL-10-/- mice. We detected an influx of immunoglobulin-positive cells into the colon and the presence of colon-reactive antibodies in the serum of IL-10-/- mice. To assess a pathogenic role for B cells, we generated a B cell-deficient (B-/-) strain of IL-10-/- mice. B-/-IL-10 /- mice acquired a severe colitis analogous to that IL-10-/- mice, implying that B cells were not the primary mediator of IBD in this model. A series of cell transfer experiments was performed to assess a pathogenic role for T cells. When IL-10-/- T cell-enriched lamina propria lymphocytes (LPL) or intraepithelial lymphocytes (IEL) were transferred into immunodeficient recombinase-activating gene (RAG)-2-/- recipients, a mild to severe colitis developed, depending on the cell number transferred. Lymphocytes recovered from the colon of transplanted RAG 2-/- mice with colitis were predominantly alpha beta TCR+CD4+, including a large proportion of CD4+CD8 alpha + cells. These cells were also CD45RB-/low and CD44+, indicative of an activated/memory population. Individual populations of CD4+CD8 alpha-, CD4+CD8 alpha + and CD4-CD8 alpha + T cells were then isolated from the lamina propria compartment of IL-10-/- mice and transferred into RAG-2-/- recipients. Only IL-10-/- CD4-expressing LPL, including both the CD4+CD8 alpha- and CD4+CD8 alpha + populations, induced colitis in recipient mice. Interferon gamma, but little to no IL-4, was produced by CD4+CD8 alpha- and CD4+CD8 alpha + LPL recovered from the inflamed colons of RAG-2-/- recipients implicating alpha T helper cell 1 (TH1)-mediated response. We thus conclude that colitis in IL-10-/- mice is predominantly mediated by TH1-type alpha beta TCR+ T cells expressing CD4 alone, or in combination with the CD8 alpha molecule. PMID- 8691139 TI - T cell receptor (TCR) recognition of MHC class I variants: intermolecular second site reversion provides evidence for peptide/MHC conformational variation. AB - We investigated mechanistic differences in antigen presentation between murine MHC class I variants H-2K(b) and H-2K(bm)8. H-2K(bm)8 differs from H-2K(b) by four residues at the floor of the peptide-binding site, affecting its B pocket which interacts with the second (P2) residue of the peptide. The rest of the molecule, including the T cell receptor (TCR)-contacting residues, is identical to H-2K(b). Due to this variation, CTLs that recognize the ovalbumin 257-264 and HSV gB 498-505 peptides on H-2K(b) cannot recognize them on H-2K(bm)8. This could be due to impaired peptide binding or an altered peptide: K(bm)8 conformation. Peptide binding studies ruled out the first explanation. Molecular modeling indicated that the most obvious consequence of amino acid variation between peptide/H-2K(b) and peptide/H-2K(bm)8 complexes would be a loss of the conserved hydrogen bond network in the B pocket of the latter. This could cause conformational variation of bound peptides. Intermolecular second-site reversion was used to test this hypothesis: P2-substituted OVA and HSV peptides, engineered to restore the hydrogen bond network of the B pocket, were the only ones which restored CTL recognition. These results provide a molecular understanding of peptide/MHC conformational variation. PMID- 8691140 TI - Defective Peyer's patch organogenesis in mice lacking the 55-kD receptor for tumor necrosis factor. AB - Lymphotoxin alpha (LT-alpha) may form secreted homotrimers binding to p55 and p75 tumor necrosis factor (TNF) receptors or cell surface-bound heterotrimers with LT beta that interact with the LT-beta receptor. Genetic ablation of LT-alpha revealed that mutant mice have no detectable lymph nodes or Peyer's patches and that the organization of the splenic white pulp in T and B cell areas is disturbed. In this report we describe a novel function for the p55 TNF receptor during ontogeny and demonstrate that mice deficient for p55 completely lack organized Peyer's patches. In contrast, lymph nodes and spleen are present in p55 deficient mice and lymphocytes segregate normally into B and T cell areas in these organs. Lamina propria and intraepithelial lymphocytes of the small intestine were detected in normal number and distribution in p55 mutant mice. Lymphocytes and endothelial cells from p55-deficient mice express normal levels of adhesion molecules considered important for lymphocyte migration to mucosal organs; this indicates that the lack of Peyer's patches does not result from a defect in lymphocyte homing. In summary, the p55 receptor for TNF selectively mediates organogenesis of Peyer's patches throughout ontogeny, suggesting that the effects of LT-alpha on the development of lymphoid organs may be mediated by distinct receptors, each functioning in an organ-specific context. PMID- 8691141 TI - Humoral and cell-mediated autoimmunity in allergy to Aspergillus fumigatus. AB - A cDNA encoding an allergenic protein was isolated from an Aspergillus fumigatus (A. fumigatus) cDNA library displayed on the surface of filamentous phage. Serum immunoglobulin E (IgE) from A. fumigatus-sensitized individuals was used to enrich phage-expressing gene products binding to IgE. One of the cDNAs encoded a 26.7-kD protein that was identified as a manganese superoxide dismutase (MnSOD) sharing 51.5% identity and 67.2% homology to the corresponding human enzyme. Both human and A. fumigatus MnSOD coding sequences were expressed in Escherichia coli as [His]6-tagged fusion proteins and purified by Ni(2+)-chelate affinity chromatography. The two recombinant MnSODs were both recognized by IgE antibodies from subjects allergic to the A. fumigatus MnSOD and elicited specific immediate type allergic skin reactions in these individuals. Moreover, both human and A. fumigatus MnSOD induced proliferation in peripheral blood mononuclear cells of A. fumigatus-allergic subjects who showed specific IgE responses and reacted in skin tests to MnSOD. These observations provide evidence for autoreactivity to the human MnSOD in allergic persons sensitized to an environmental allergen from A. fumigatus who share a high degree of sequence homology to the corresponding human enzyme. PMID- 8691142 TI - A role for stem cell factor (SCF): c-kit interaction(s) in the intestinal tract response to Salmonella typhimurium infection. AB - Cholera toxin (CT) has been shown to induce stem cell factor (SCF) production in mouse ligated intestinal loops. Further, SCF interaction(s) with its receptor (c kit) was shown to be important for the intestinal tract secretory response after CT exposure. In this study, we have investigated whether SCF production is induced in the intestinal tract after exposure to Salmonella typhimurium and whether this production could be an important intestinal tract response to Salmonella infection. Using a mouse ligated intestinal loop model, increased levels of SCF mRNA were detected at 2-4 h post-Salmonella challenge. Intestinal fluid obtained from Salmonella-challenged loops contained high levels of SCF by ELISA. Human and murine intestinal epithelial cell lines were also shown to have increased levels of SCF mRNA after exposure to Salmonella. Inhibition of Salmonella invasion of epithelial cells was shown to be one potentially important role for SCF:c-kit interactions in host defense to Salmonella infection. Pretreatment of human or murine intestinal cell lines with SCF resulted in a cellular state that was resistant to Salmonella invasion. Finally, mice having mutations in the white spotting (W) locus, which encodes the SCF-receptor (c kit), were significantly more susceptible to oral Salmonella challenge than their control littermates. Taken together, the above results suggest that an important intestinal tract response to Salmonella infection is an enhanced production of SCF and its subsequent interactions with c-kit. PMID- 8691143 TI - B cell differentiation and isotype switching is related to division cycle number. AB - The mature, resting immunoglobulin (Ig) M, IgD+ B lymphocyte can be induced by T cells to proliferate, switch isotype, and differentiate into Ig-secreting or memory cells. Furthermore, B cell activation results in the de novo expression or loss of a number of cell surface molecules that function in cell recirculation or further interaction with T cells. Here, a novel fluorescent technique reveals that T-dependent B cell activation induces cell surface changes that correlate with division cycle number. Furthermore, striking stepwise changes are often centered on a single round of cell division. Particularly marked was the consistent increase in IgG1+ B cells after the second division cycle, from an initial level of < 3% IgG1+ to a plateau of approximately 40% after six cell divisions. The relationship between the percentage of IgG1+ B cells and division number was independent of time after stimulation, indicating a requirement for cell division in isotype switching. IgD expression became negative after four divisions, and a number of changes centered on the sixth division, including the loss of IgM, CD23, and B220. The techniques used here should prove useful for tracking other differentiation pathways and for future analysis of the molecular events associated with stepwise differentiation at the single cell level. PMID- 8691144 TI - The Kaposi sarcoma-associated herpesvirus (KSHV) is present as an intact latent genome in KS tissue but replicates in the peripheral blood mononuclear cells of KS patients. AB - Short DNA sequences have been identified, originally in association with Kaposi's sarcoma (KS) biopsies, that are highly homologous to oncogenic, lymphotropic herpesviruses. Recently a virus, Kaposi sarcoma associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8), bearing these sequences has been identified in a cell line derived from a body cavity-based lymphoma. In this report, we show that the same sequences are present in KS biopsies as DNA molecules of a form and size characteristic of latent herpesviruses-large, covalently closed, circular episomes. The genomes migrate with an apparent size larger than the herpesvirus Epstein-Barr virus (172 kb). This form of the viral genome was found in four of four biopsies and three of five peripheral blood samples from KS patients. Linear forms of the viral genome, characteristic of viral replication, were not detected in the biopsies, but were present in the peripheral blood of three out of five patients. The sequences for KSHV/HHV-8 were also detected in the blood of four of five allograft patients and three of five healthy donors without KS suggesting that the virus is widespread throughout the human population. PMID- 8691145 TI - Interleukin-7 receptor alpha is essential for the development of gamma delta + T cells, but not natural killer cells. AB - Mice that lack a functional gamma c subunit of the receptors for interleukin (IL) 2, IL-4, IL-7, IL-9, and IL-15 display profound defects in lymphoid development. The IL-7/IL-7R system represents a critical interaction for conventional T and B cell development. In this report, the role of IL-7R alpha in the development of lymphoid lineages other than conventional T and B cells was examined. We demonstrate that gamma delta + T cells were absent in IL-7R alpha-deficient mice, whereas the development and function of natural killer cells were normal. Thus, IL-7R alpha function is required for the development of gamma delta + T cells but not natural killer cells. PMID- 8691146 TI - Phosphotyrosines in the killer cell inhibitory receptor motif of NKB1 are required for negative signaling and for association with protein tyrosine phosphatase 1C. AB - NKB1 is one member of a growing family of killer cell inhibitory receptors (KIR). It is expressed on natural killer (NK) cells and T cells, and has been shown to inhibit cytolytic functions of these cells upon interacting with its ligand, HLA B (Bw4). We demonstrate here that the cytoplasmic region of NKB1 is capable of inhibiting T cell activation in Jurkat cells. The tyrosine phosphorylation of the NKB1 KIR consensus motif, YxxL(x)26 YxxL, induces an association with the protein tyrosine phosphatase 1C (PTP1C). Importantly, mutation of both tyrosines in the motif abolished the inhibitory functions of NKB1 and abrogated PTP1C association. Mutational analysis of the individual tyrosines suggest that the membrane proximal tyrosine may play a crucial role in mediating the inhibitory signal. These results demonstrate that KIR can not only inhibit cytolytic activity, but can also negatively regulate T cell receptor activation events that lead to downstream gene activation, and further supports a model that implicates PTP1C as a mediator in the KIR inhibitory signal. PMID- 8691147 TI - A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2. AB - Defects in the gene encoding Bruton's tyrosine kinase (Btk) result in a disease called X-linked agammaglobulinemia, in which there is a profound decrease of mature B cells due to a block in B cell development. Recent studies have shown that Btk is tyrosine phosphorylated and activated upon B cell antigen receptor (BCR) stimulation. To elucidate the functions of this kinase, we examined BCR signaling of DT40 B cells deficient in Btk. Tyrosine phosphorylation of phospholipase C (PLC)-gamma 2 upon receptor stimulation was significantly reduced in the mutant cells, leading to the loss of both BCR-coupled phosphatidylinositol hydrolysis and calcium mobilization. Pleckstrin homology and Src-homology 2 domains of Btk were required for PLC-gamma 2 activation. Since Syk is also required for the BCR-induced PLC-gamma 2 activation, our findings indicate that PLC-gamma 2 activation is regulated by Btk and Syk through their concerted actions. PMID- 8691148 TI - Interaction of CD31 with a heterophilic counterreceptor involved in downregulation of human T cell responses. AB - CD31 is a 130-kD glycoprotein of the immunoglobulin (Ig) superfamily expressed on the surface of endothelial cells, platelets, and several leukocyte subsets. Previous reports indicated that CD31 can mediate intercellular adhesion via both homophilic and heterophilic interaction mechanisms. Using a soluble recombinant CD31-Ig fusion protein (CD31 receptor globulin [Rg]), we demonstrate here that human CD31- T lymphocytes and CD4+CD31- T cell clones express a heterophilic CD31 ligand that is upregulated 18 h after activation. Interaction of CD31Rg with CD31 T helper cell (Th) clones was divalent cation independent but could be blocked by heparin, thus indicating that the CD31 counterreceptor on T cells can be distinguished from the ligands identified on other cell types. Moreover, a single chain protein of 120 kD was precipitated by CD31Rg from the lysates of CD31- Th clones. CD31Rg completely downregulated the proliferative response and cytokine production (interleukin-4, interferon-gamma, and tumor necrosis factor-alpha) of CD31- Th clones when the cells were maximally stimulated via immobilized CD3 monoclonal antibody. These results suggest that interaction of CD31 with a heterophilic counterreceptor on T lymphocytes can interfere with a positive regulatory pathway of T cell activation, or directly signal T cells to downregulate immune function. PMID- 8691149 TI - Net inflammatory capacity of human septic shock plasma evaluated by a monocyte based target cell assay: identification of interleukin-10 as a major functional deactivator of human monocytes. AB - We have developed a functional assay to study the inflammatory capacity of plasma collected from patients with severe gram-negative septic shock. In this assay, elutriation-purified, cryo-preserved human monocytes from one healthy donor are combined with plasma from patients with severe persistent septic shock for 5 h. Subsequently, the plasma is removed, medium added, and procoagulant activity (PCA) and secretion of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) measured after 18-h incubation. Plasma from 10 patients (6 died) infected with Neisseria meningitidis previously shown to contain high levels of native lipopolysaccharide (LPS) (median 2,700 pg/ml), TNF-alpha, IL-6, IL-8, and complement activation products, had a low net spontaneous inflammatory capacity on the monocytes. The median levels of PCA, TNF-alpha, and IL-6 were 5, 0, and 4%, respectively, of the monocyte activities induced by normal plasma boosted with purified N. meningitidis (Nm)-LPS (2,500 pg/ml; net LPS-boosted capacity, 100%). The levels of PCA, TNF-alpha, and IL-6 obtained with plasma from shock patients were not different from those induced by plasma from 10 meningococcal patients without shock or with plasma from healthy persons. Boosting shock plasma with 2,500 pg/ml Nm-LPS had little effect on the monocyte activities since the median values of PCA, TNF-alpha, and IL-6 revealed a minimal increase from 5, 0, and 4% to 9, 2, and 6%, respectively. The shock plasmas revealed a strong LPS inhibitory capacity that was largely absent in plasmas from 10 meningococcal patients without shock since the median levels of PCA, TNF-alpha, and IL-6 increased from 5, 0, and 0% to 135, 51, and 73%, respectively, after boosting with 2,500 pg/ml Nm-LPS. The LPS-inhibitory capacity was closely associated with the levels of IL-10. The median levels of IL-10 were 19,000 pg/ml in nine shock patients vs. 22 pg/ml in nine nonshock patients with systemic meningococcal disease. Removal of native IL-10 by immunoprecipitation restored the capacity of plasmas to induce monocyte activation either by native LPS or by boosting with Nm LPS. IL-4 and TGF-beta were not detected in shock plasmas. In 24 patients with detectable meningococcal LPS ( > 10 pg/ml, 0.1 endotoxin units/ml), the levels of IL-10 were correlated to the levels of LPS (r = 0.79, P < 0.001). IL-10 declined from initiation of antibiotic therapy and paralleled the levels of native LPS. Decreasing levels of IL-10 in serially collected shock plasmas were directly related to increasing monocyte responsiveness after Nm-LPS boosting. These results suggest that IL-10 plays a major role in containing activation of monocytes and possibly other LPS-responsive cells during overwhelming meningococcemia. PMID- 8691150 TI - The transcription factor PU.1 is involved in macrophage proliferation. AB - PU.1 is a tissue-specific transcription factor that is expressed in cells of the hematopoietic lineage including macrophages, granulocytes, and B lymphocytes. Bone marrow-derived macrophages transfected with an antisense PU.1 expression construct or treated with antisense oligonucleotides showed a decrease in proliferation compared with controls. In contrast, bone marrow macrophages transfected with a sense PU.1 expression construct displayed enhanced macrophage colony-stimulating factor (M-CSF)-dependent proliferation. Interestingly, there was no effect of sense or antisense constructs of PU.1 on the proliferation of the M-CSF-independent cell line, suggesting that the response was M-CSF dependent. This was further supported by the finding that macrophages transfected with a sense or an antisense PU.1 construct showed, respectively, an increased or a reduced level of surface expression of receptors for M-CSF. The enhancement of proliferation seems to be selective for PU.1, since transfections with several other members of the ets family, including ets-2 and fli-1, had no effect. Various mutants of PU.1 were also tested for their ability to affect macrophage proliferation. A reduction in macrophage proliferation was found when cells were transfected with a construct in which the DNA-binding domain of PU.1 was expressed. The PEST (proline-, glutamic acid-, serine-, and threonine-rich region) sequence of the PU.1 protein, which is an important domain for protein protein interactions in B cells, was found to have no influence on PU.1-enhanced macrophage proliferation when an expression construct containing PU.1 minus the PEST domain was transfected into bone marrow-derived macrophages. In vivo, PU.1 is phosphorylated on several serine residues. The transfection of plasmids containing PU.1 with mutations at each of five serines showed that only positions 41 and 45 are critical for enhanced macrophage proliferation. We conclude that PU.1 is necessary for the M-CSF-dependent proliferation of macrophages. One of the proliferation-relevant targets of this transcription factor could be the M CSF receptor. PMID- 8691151 TI - Transfection of Syk protein tyrosine kinase reconstitutes high affinity IgE receptor-mediated degranulation in a Syk-negative variant of rat basophilic leukemia RBL-2H3 cells. AB - Aggregation of the high affinity receptor for immunoglobulin E (Fc epsilon RI) on mast cells results in rapid tyrosine phosphorylation and activation of Syk, a cytoplasmic protein tyrosine kinase. To examine the role of Syk in the Fc epsilon RI signaling pathway, we identified a variant of RBL-2H3 cells that has no detectable Syk by immunoblotting and by in vitro kinase reactions. In these Syk deficient TB1A2 cells, aggregation of Fc epsilon RI induced no histamine release and no detectable increase in total cellular protein tyrosine phosphorylation. However, stimulation of these cells with the calcium ionophore did induce degranulation. Fc epsilon RI aggregation induced tyrosine phosphorylation of the beta and gamma subunits of the receptor, but no increase in the tyrosine phosphorylation of phospholipase C-gamma 1 and phospholipase C-gamma 2 and no detectable increase in intracellular free Ca2+ concentration. By transfection, cloned lines were established with stable expression of Syk. In these reconstituted cells, Fc epsilon RI aggregation induced tyrosine phosphorylation of phospholipase C-gamma 1 and phospholipase C-gamma 2, an increase in intracellular free Ca2+ and histamine release. These results demonstrate that Syk plays a critical role in the early Fc epsilon RI-mediated signaling events. It further demonstrates that Syk activation occurs downstream of receptor phosphorylation, but upstream of most of the Fc epsilon RI-mediated protein tyrosine phosphorylations. PMID- 8691154 TI - Tyrosine phosphorylation of a human killer inhibitory receptor recruits protein tyrosine phosphatase 1C. AB - Natural killer (NK) cells express killer inhibitory receptors that mediate negative regulation of NK cell cytotoxicity upon binding to MHC class I molecules on target cells. Unrelated inhibitory receptors on B cells have recently been shown to function through recruitment of phosphotyrosine phosphatase 1C (PTP-1C). Here, we show that a human killer inhibitory receptor specific for HLA-C also recruits PTP-1C after phosphorylation induced either by the pharmacological agent phenylarsine oxide or by conjugation with target cells. This recruitment is mediated by the binding of specific cytoplasmic phosphotyrosine-containing sequences to PTP-1C. These results implicate PTP-1C as a cytosolic component of the negative signaling pathway through NK cell inhibitory receptors. PMID- 8691155 TI - Conditioned antisickness: heat as an internal stimulus in conditioning taste aversion and aversion failure in rats. AB - Heat was found to be effective as a conditional stimulus in the aversion failure procedure (S. Revusky, H. K. Taukulis, L. A. Parker, & S. Coombes, 1979) and was also found to be effective as an unconditional stimulus using a taste aversion procedure in which rats exposed to high ambient temperature following saccharin consumption showed robust saccharin aversions relative to unpaired and unheated controls. The antisickness and taste aversion conditioning evidence force reexamination of the view that toxic heat effects are referred to the external environment. Together with other recent evidence from this laboratory, these data support the hypothetical antisickness mechanism of aversion failure, which requires that toxic heat serve as an internal stimulus. PMID- 8691153 TI - Positive and negative selection invoke distinct signaling pathways. AB - During T cell development, interaction of the T cell receptor (TCR) with cognate ligands in the thymus may result in either maturation (positive selection) or death (negative selection). The intracellular pathways that control these opposed outcomes are not well characterized. We have generated mice expressing dominant negative Ras (dnRas) and Mek-1 (dMek) transgenes simultaneously, either in otherwise normal animals, or in animals expressing a transgenic TCR, thereby permitting a comprehensive analysis of peptide-specific selection. In this system, thymocyte maturation beyond the CD4+8+ stage is blocked almost completely, whereas negative selection, assessed using an in vitro deletion protocol, is quantitatively intact. This suggests that activation of the mitogen activated protein kinase (MAPK) cascade is necessary for positive selection, but irrelevant for negative selection. Generation of gamma/delta and of CD4-8- alpha/beta T cells proceeds normally despite blockade of the MAPK cascade. Hence, only cells that mature via conventional, TCR-mediated repertoire selection require activation of the MAPK pathway to complete their maturation. PMID- 8691152 TI - Interleukin 4 or oncostatin M induces a prolonged increase in P-selectin mRNA and protein in human endothelial cells. AB - During acute inflammation, P-selectin is transiently mobilized from Weibel-Palade bodies to the surface of histamine-activated endothelial cells, where it mediates rolling adhesion of neutrophils under hydrodynamic flow. During chronic or allergic inflammation, sustained expression of P-selectin on the endothelial cell surface has been observed. We found that the cytokines interleukin 4 (IL-4) or oncostatin M (OSM) induced a five- to ninefold increase in P-selectin messenger RNA (mRNA) in human umbilical vein endothelial cells (HUVEC) that persisted as long as 72 h. IL-4 elevated P-selectin mRNA by increasing its transcription rate rather than by prolonging its already long half-life. Stimulation of P-selectin transcription by IL-4 or OSM required new protein synthesis and tyrosine phosphorylation of cellular proteins. Tumor necrosis factor alpha, IL-1 beta, lipopolysaccharide, or IL-3 did not increase P-selectin mRNA in HUVEC, and did not augment the IL-4-induced increase in P-selectin transcripts. IL-4 or OSM increased P-selectin protein on the cell surface as well as in Weibel-Palade bodies. Under flow conditions, neutrophils rolled on P-selectin expressed by IL-4 treated HUVEC, and even more neutrophils rolled on P-selectin after IL-4-treated HUVEC were stimulated with histamine. These data demonstrate that IL-4 or OSM stimulates endothelial cells to synthesize more P-selectin over prolonged periods. The increased expression of P-selectin may facilitate the emigration of leukocytes into sites of chronic or allergic inflammation. PMID- 8691157 TI - Effect of US signal value on blocking of a CS-US association. AB - When an unconditioned stimulus (US) signals the delivery of a second US, there is poor conditioned responding to a conditioned stimulus (CS) that signals the second US. Using an appetitive conditioning preparation with rats, 3 experiments examined the factors that contribute to this poor conditioned responding. In Experiment 1, conditioned responding was improved when US-alone presentations came before, but not after, CS training. Experiment 2 showed that the effect in Experiment 1 was not due to context extinction, and Experiment 3 showed that context-US associations do not significantly contribute to responding in the US US training procedure. The results show that poor conditioned responding is an acquisition deficit, arising from US, rather than context, signal value. PMID- 8691156 TI - Pavlovian aversive context conditioning using carbon dioxide as the unconditional stimulus. AB - Four experiments were conducted to examine the utility of carbon dioxide (CO2) as an aversive unconditioned stimulus (US) in a Pavlovian context conditioning paradigm. Experiment 1 demonstrated that rats exposed to CO2 in a distinctive context showed elevated levels of freezing relative to controls. Experiment 2 replicated this basic effect with a modified conditioning procedure and additionally demonstrated conditioned analgesia. Experiment 3 demonstrated a positive monotonic relationship between US duration and resistance to extinction of freezing behavior as well as conditioned analgesia. Experiment 4 demonstrated extinction and an extinction-related phenomenon, renewal. These studies clearly demonstrate the utility of CO2 as a Pavlovian US. PMID- 8691158 TI - Impact of shock on pain reactivity: II. Evidence for enhanced pain. AB - Shocked rats (Rattus norvegicus) often exhibit longer tail withdrawal latencies to radiant heat, which suggests that exposure to shock reduces pain. But at the same time, rats appear hyperreactive to shock, suggesting than pain is enhanced. Experiment 1 replicated these findings and showed that when tail movement was monitored, shocked rats were less responsive to heat and hyperreactive to shock even when the same behavioral criteria were used. When latency to vocalize was measured, shocked rats appeared hyperreactive to both test stimuli (Experiments 2 and 3). Prior exposure to shock also enhanced the acquisition of conditioned fear in a different context (Experiment 4) and the speed with which rats learned a response to avoid a thermal stimulus (Experiment 5). The results suggest that exposure to shock enhances pain. PMID- 8691159 TI - Second-order excitation mediated by a backward conditioned inhibitor. AB - Conditioned suppression studies with rats explored the informational content of a backward conditioned inhibitor. Pairings of an unconditioned stimulus (US) and Stimulus 1 (US-->S1) established S1 as an inhibitor in Experiment 1. Pairing the inhibitor S1 with a novel S2 (S2-->S1) promoted excitatory second-order conditioning (SOC) to S2, which suggested S1 was well associated with the US. Degrading presumed S1-US associations in Experiment 2 by S1- (extinction) treatment eliminated S2's excitation while preserving S1's inhibition. Experiments 3 and 4 converged in showing that S2 was not an excitor when Pavlovian conditioned inhibition (CI) was the inhibitory treatment prior to the SOC phase, but instead acted as a second-order inhibitor. Results are discussed in relation to the temporal coding hypothesis, the SOP ("sometimes opponent process") and Rescorla-Wagner models of conditioning, and the associative structure of SOC. Also, the data suggest that backward inhibition is special and that not all forms of CI are equal. PMID- 8691161 TI - Speeding up an internal clock in humans? Effects of click trains on subjective duration. AB - Four experiments investigated the effect of trains of clicks (usually 5 s long and at 5 or 25 Hz) on subjective duration in humans, as previous research had suggested that such a manipulation would speed up the pacemaker of an internal clock by increasing participants' arousal. The four experiments used temporal generalization, pair comparison of duration, verbal estimation, and production of short durations. In all cases, preceding the durations to be judged by clicks changed their subjective length in a manner broadly consistent with the idea that pacemaker speed was increased, by an average of about 10%. PMID- 8691160 TI - Sign tracking versus goal tracking in the sexual conditioning of male Japanese quail (Coturnix japonica). AB - Pairings of a conditioned (CS) and unconditioned (US) stimulus can result in approach to either the CS (sign tracking) or the US (goal tracking). Increasing the spatial or temporal separation between the CS and a US food has been reported to results in a decline in sign tracking and an increase in goal tracking. In the present experiments, sign tracking was the predominant response of male quail (Coturnix japonica) to a CS that was presented up to 91 cm from the door through which a female was presented as the US (Experiment 1). Contrary to reported results with food reinforcement, goal tracking was not facilitated by increasing the spatial separation between the CS and US (Experiment 2) or by introducing a trace interval between them (Experiment 3). The preponderance of sign tracking may reflect an adaptive specialization of sexual conditioning or may be related to the absence of magazine training and the use of a moving US in the sexual conditioning procedures. PMID- 8691162 TI - Latent inhibition: a neural network approach. PMID- 8691163 TI - Judging relative duration: the role of rule and instructional variables. AB - Humans compared 2 durations according to different rules. Some judged which duration lasted longer, some judged whether the duration ratio was less or greater than 3:1, and others judged according to a same-different rule. Under each condition, 1/2 of the participants had advance knowledge of the rule, whereas the others acquired the discrimination solely on the basis of informative feedback. Discrimination was affected by both factors. Same-different and ratio comparisons were less accurate than ordinal comparisons. Rule knowledge affected the ratio and same-different comparisons but did not affect judgment about which duration lasted longer. Debriefing of uninformed participants revealed that most guessed that the rule involved judging which duration lasted longer. These results highlight the role of linguistic variables in humans' relational comparisons of duration. PMID- 8691164 TI - Acetaminophen hepatotoxicity. PMID- 8691165 TI - Sustained partnerships. PMID- 8691166 TI - Computerized medical information systems. PMID- 8691167 TI - Computerized medical information systems. PMID- 8691168 TI - A common thread through family medicine. PMID- 8691169 TI - Prostaglandin gel for cervical ripening. PMID- 8691170 TI - Treatment of croup with nebulized dexamethasone. PMID- 8691171 TI - Heparin and thrombolysis in acute MI. PMID- 8691172 TI - Self-management of asthma. PMID- 8691173 TI - Estrogen for postnatal depression. PMID- 8691174 TI - Diagnosing acute sinusitis. PMID- 8691175 TI - Managing rupture of membranes at term. PMID- 8691176 TI - History of abuse among women with GI complaints. PMID- 8691177 TI - Separating fad from fact: family medicine, primary care, and the role of health services research. PMID- 8691178 TI - Medicare costs in urban areas and the supply of primary care physicians. AB - BACKGROUND: The supply of primary care physicians may be important determinants of health care costs. We examined the association between primary care physician supply and geographic location with respect to variation in Medicare Supplementary Medical Insurance (Part B) reimbursement. METHODS: We performed an analysis of data from all US metropolitan counties. Physician supply data were derived from the American Medical Association Masterfile. Medicare Part B reimbursements and enrollment data came from the Health Care Financing Administration. Physician supply was calculated for family practice, general internal medicine, and non-primary care specialties. Linear regression was used to test the association of physician supply and Medicare costs and to adjust for potential confounding variables. RESULTS: The average Medicare Part B reimbursement per enrollee was $1283. After adjusting for local price differences and county characteristics, a greater supply of family physicians and general internists was significantly associated with lower Medicare Part B reimbursements. The reduction in reimbursements between counties in the highest quintile of family physician supply and the lowest quintile was $261 per enrollee. In contrast, a greater supply of general practitioners and non-primary care physicians was associated with higher reimbursements per enrollee. CONCLUSIONS: These results add to the evidence than an increased supply of primary care physicians is associated with lower health care costs. If this association is causal, it supports the theory that increasing the number of primary care physicians may lower health care costs. PMID- 8691179 TI - The effect of first-contact care with primary care clinicians on ambulatory health care expenditures. AB - BACKGROUND: A study was undertaken to examine the relationship between first contact care, an essential feature of primary care, and expenditures for frequent ambulatory episodes of care in a nationally representative sample. METHODS: A nonconcurrent cohort study was conducted using data from the 1987 National Medical Expenditure Survey. Ambulatory claims data of respondents with an identified primary care source were used to develop 20,282 episodes of care for 24 preventive and acute illness conditions. The study examined the relationship of first-contact care, defined as the use of an identified primary care source for the first visit in an episode, and ambulatory episode-of-care expenditures. RESULTS: Episodes that began with visits to an individual's primary care clinician, as opposed to other sources of care, were associated with reductions in expenditures of 53% overall ($63 vs 134, P<.001), 62% for acute illnesses ($62 vs $164, P<.001), and 20 for preventive care ($64 vs $80, P<.001). For 23 of the 24 health problems studied, first-contact care was associated with reductions in expenditures. Multivariate regression analyses that controlled for sociodemographic characteristics, health status, case-mix, length of the episode, and number of visits to the emergency room did not substantively alter these results. CONCLUSIONS: First-contact care was associated with reductions in ambulatory episode-of-care expenditures of over 50% in a nationally representative sample. These findings suggest that systems of care may reduce ambulatory expenditures. PMID- 8691180 TI - Cancer occurrence and screening in family practice. A 20-year experience. AB - BACKGROUND: This article is a sequel to a previously published article describing the occurrence of cancer in a rural family practice and the contribution of screening to the diagnosis of breast, colorectal, and cervical cancer. Together, the two articles describe a 20-year family practice experience in diagnosing and screening for cancer. METHODS: The study is a retrospective chart review of all cancers diagnosed in a family practice from January 1985 through December 1994. Records of a regional tumor registry were reviewed to validate and ensure completeness of the cancer diagnoses. RESULTS: One hundred twenty-one cancers were identified during the 10-year study period in a population of approximately 4000 patients. Screening by fecal occult blood testing identified 11 of 20 colorectal cancers, mammography and physician examination identified 9 of 12 breast cancers, and a program of biannual Papanicolaou smears resulted in the diagnosis of 3 of 3 cervical cancers. Only 3 melanomas, 3 ovarian cancers, and 1 testicular cancer were diagnosed in this practice during the entire 20 years of the combined studies. CONCLUSIONS: The five most common cancers--skin, colorectal, lung, breast, and prostate--accounted for 71% of the cancers diagnosed. A high rate of provider and patient compliance with screening was achieved. Screening detected a majority of breast and colorectal cancers. Annual Papanicolaou smear screening would have provided no incremental benefit over the biannual screening used in this practice. PMID- 8691181 TI - Antibiotics and respiratory infections: are patients more satisfied when expectations are met? AB - BACKGROUND: Antibiotics are frequently prescribed for respiratory infections, even though most of these infections are viral. To understand why physicians do so, we studied patients' and physicians' expectations for antibiotics and the effects of the patient-physician interaction on patient satisfaction. METHODS: Patients with a respiratory infection were asked to complete a questionnaire before and after visiting with physicians at three family medicine centers. Physicians completed a questionnaire following the visit. RESULTS: Sixty-five percent of the 113 patients with respiratory infection expected antibiotics. Physicians had some ability to perceive this expectation and frequently prescribed antibiotics for patients who expected them. Antibiotics were prescribed to over 75% of patients with sinusitis or bronchitis and to 18% of those diagnosed with only viral infections. No association was found between a prescription for antibiotics and patient satisfaction; however, patient satisfaction did correlate with the patients' report that they understood the illness and that the physician spent enough time with them. CONCLUSIONS: Physicians frequently prescribe antibiotics for upper respiratory infections when they believe patients expect it, but receiving a prescription for antibiotics is not in and of itself associated with increased patient satisfaction. PMID- 8691182 TI - Hip, knee, and foot pain during pregnancy and the postpartum period. AB - BACKGROUND: Although much has been written about low back pain during pregnancy, there are few studies regarding leg, foot, and hip pain. The purpose of this study was to investigate the prevalence and characterize the nature of lower extremity pain in women of child-bearing age and to assess the impact of recent pregnancy on these symptoms. METHODS: In this case-control study, 107 consecutive postpartum women (case subjects) and 91 nulliparous women (controls) completed a questionnaire regarding hip, knee, and foot pain and potentially influencing factors. RESULTS: Postpartum subjects had more symptoms of leg and foot pain than did the controls (56% vs 37%; odds ratio [OR]=2.3; 95% confidence interval [CI], 1.2 to 4.7). A significant majority of pain (82%, P<.05) began during the second and third trimesters. Postpartum subjects also had a significantly higher prevalence of hip pain (38% vs 23%; OR=3.2; 95% CI, 1.4 to 7.0) and foot pain (31% vs 22%; OR=2.2; CI, 1.1 to 4.5). History of previous pain complaints also were found to be risk factors for lower extremity pain during pregnancy for case subjects and in the past year for controls. There was a trend toward older age as a risk factor as well. Multiple pain complaints were more common among case subjects than among controls. CONCLUSIONS: Lower extremity pain is common in women of childbearing age. Pregnant and postpartum women are more likely to develop new lower extremity symptoms than are nulliparous women. The timing of symptom onset in mid- to late pregnancy may suggest that biomechanical factors play a larger role than hormonal influences. Regular exercise appears to be neither protective against nor a risk factor for lower extremity pain during pregnancy. PMID- 8691183 TI - Current concepts in postmenopausal hormone replacement therapy. AB - As more women are living longer, there is an increasing need for women to discuss hormone replacement therapy (HRT) with their physicians. This task is complicated by areas of scientific uncertainty and evolving data concerning the risks and benefits of HRT. Benefits of HRT that are supported by strong scientific evidence include relief from menopausal symptoms such as hot flashes, prevention of osteoporosis, cardioprotective effects, relief of urogenital atrophy, and decreased urinary incontinence. Benefits supported by observational evidence include improvement of emotional lability and depression, improved sense of well being in patients with rheumatoid arthritis, increased dermal and total skin thickness, improved verbal memory skills, and decreased risk of colon cancer. Risks to consider include a possible increase in the incidence of breast cancer and an increase in endometrial cancer in women who have an intact uterus and do not receive a progestin. Women in various risk groups, such as those at risk for coronary artery disease, osteoporosis, or breast cancer, must consider the risk to-benefit ratio for their own individual circumstances. PMID- 8691184 TI - Colocutaneous fistula as a complication of PEG tube placement. AB - Individuals with prolonged swallowing difficulties may require enteral supplementation to maintain a healthy nutritional status. Until the advent of the percutaneous endoscopic gastrostomy (PEG) tube in 1980, feeding was usually accomplished by a nasogastric feeding tube. The initial insertion of a PEG tube requires endoscopic or radiologic guidance but has the advantages of being easy to care for and being a permanent or temporary access site for enteral nutrition. Complications associated with PEG tube placement are relatively infrequent. We present a case of a percutaneous fistula as a rare complication associated with reinsertion of a PEG tube. PMID- 8691185 TI - Carpal tunnel syndrome: a case of median nerve injection injury and a safe and effective method for injecting the carpal tunnel. AB - The carpal tunnel syndrome is a compressive neuropathy of the median nerve at the wrist. The local injection of corticosteroid is an effective treatment modality in properly selected cases; however, this usually efficacious and safe procedure may result in serious complications if insufficient attention is paid to technique. A recent case of severe median nerve injury secondary to local steroid injection at the wrist prompted this report. We present a safe and effective method for injection of the carpal tunnel syndrome. PMID- 8691186 TI - Antemortem diagnosis of human rabies. AB - Human rabies is a rare but fatal disease. In the United States, the majority of people infected with rabies contract the disease by being bitten by a wild animal, most commonly bats. Because rabies is so rarely seen, it is often not diagnosed until after death, at which time exposed health care workers will require rabies prophylaxis. We describe a case for which the diagnosis was made before death. The prompt consideration of this diagnosis allowed early isolation of the patient and prevented unnecessary risk to health care workers. PMID- 8691187 TI - Carboxy-terminal CVLS-sequence-specific protein farnesyltransferase from the eyes of the shrimp Penaeus japonicus: purification and characterization. AB - Protein farnesyltransferase from the eyes of Penaeus japonicus farnesylates predominantly H-ras-specific carboxyl termini, with the sequence CVLS, but not the K-ras-specific sequence CVIM or the protein geranylgeranyltransferase specific sequence CAIL. The purified protein farnesyltransferase from shrimp was found by immunoblotting and polyacrylamide gel electrophoresis under denaturing conditions to consist of subunits of Mr 49,000 and Mr 48,000. Since the active protein farnesyltransferase was found to have a relative mass of 100,000, the purified enzyme was deduced to be a heterodimer. The enzyme had an optimal pH of 6 and a K(m) of 14 +/- 1 microM with the synthetic peptide RTRCVLSH as the substrate. The enzyme was activated by Mn+2 and Mg+2 but inhibited by Ca+2 ions. PMID- 8691188 TI - Descriptive and functional characterization of variation in the Fundulus heteroclitus Ldh-B proximal promoter. AB - Variation in enzyme expression may be an important mechanism for physiological and evolutionary adaptation. The Ldh-B locus in the teleost fish Fundulus heteroclitus is one of a very few loci for which an evolutionary difference in transcription rate between populations has been demonstrated. To begin to understand the molecular modifications that are responsible for altering transcription, we have characterized the Ldh-B proximal promoter using a combination of sequence analysis, transient transfection, and in vivo footprinting. The Ldh-B gene has several transcription start sites and a TATA less, Inr (initiator of transcription motif) containing promoter with multiple Sp1-like motifs. Transfection experiments reveal that Sp1 sites, TCC repeats, and Inrs are functional components of the proximal promoter. We find substantial sequence variation between populations within the proximal promoter (250 bp from the transcription start sites) and footprinting analysis indicates that some of this sequence variation is associated with differential protein binding to the apparent TFIID binding site and Sp1 sites. Together, these data suggest that variation in the Ldh-B proximal promoter may play a role in the observed difference in transcription rates between northern and southern populations of F. heteroclitus. PMID- 8691189 TI - Bicarbonate absorption in eel intestine: evidence for the presence of membrane bound carbonic anhydrase on the brush border membranes of the enterocyte. AB - Bicarbonate absorptive fluxes through the isolated intestine of the European eel (Anguilla anguilla) were evaluated by the pH-stat method under short-circuited conditions. It was found that bicarbonate absorptive flux was dependent on the luminal Na+ and was inhibited by luminal 4-acetamido-4' stilbene-2-2' disulfonic acid (SITS; 2.5 x 10(-4) M) and luminal acetazolamide (10(-4) M), while luminal amiloride (1 mM) was without effect. Furthermore, by using brush border membrane vesicles (BBMV) isolated from eel intestine, the existence of two carbonic anhydrase (CA) isoforms, one tightly associated to the brush border membrane (BBM) and the other soluble in the cytosol, was demonstrated. The membrane-bound CA differs from the cytoplasmic isoform in that 1) it is relatively resistant to treatment with 0.045% lauryl sulfate sodium salt (SDS); 2) it is less inhibitable by ethoxzolamide and sulfanilamide; and 3) its Kmapp is significantly lower than that of the cytoplasmic isoform. These results suggest that a BBM-bound CA isozyme would play an important role in bicarbonate absorption from the lumen, facilitating the HCO3- transfer through the luminal membrane of the eel enterocyte most likely via a Na+ (HCO3-) or (OH-) cotransport system. PMID- 8691190 TI - Microscopic and biochemical analysis of the viability and permeability of guinea pig amnion and chorion leave in vitro. AB - Tissue viability and permeability of guinea pig amnion and chorion leave were analyzed microscopically and biochemically. The vital dyes T1111 and fluorescein diacetate were used to locate and determine the integrity of cell plasma membranes in early and late tissue in vitro using confocal laser scanning microscopy and scanning electron microscopy. Early amnion and chorion laeve were each found to contain a single epithelial cell layer, composed of membrane-intact cells. In contrast, plasma membrane lesions were present throughout the epithelium of late amnion. Late chorion laeve contained both regions of intact and damaged epithelial cells on its maternal side. There was also a layer of membrane-intact squamous cells on the fetal side of late chorion laeve. ATP measurements confirmed that early fetal membranes were viable after incubation in isotonic salt solutions at physiological pH. Late amnion was depleted of ATP stores while late chorion laeve retained its capacity for generating energy. These viability markers indicate that late guinea pig amnion is not a viable tissue in vitro, while late chorion laeve is a viable but probably degenerating tissue. Confocal X-Z scans were used to trace the movement of T1111 through the tissue as an indication of permeability to free solutes. Whereas dye will permeate across the main thickness of early amnion and chorion leave, it did not pass between cells, but was blocked, presumably by a line of tight junctions. Late amnion was characterized by the complete permeability to T1111. Late chorion leave contained regions where solute migration was blocked, but overall was a permeable tissue. These results provide an important context for the interpretation of molecular movement across fetal membranes. PMID- 8691191 TI - Mental disorder and criminality. Male alcoholism. AB - This study investigated the lifetime prevalence of criminal behavior in a population of 360 Research Diagnostic Criteria alcoholics. The same number of control subjects were drawn from the general population of the same catchment area and matched with the patients with regard to sex, age, marital status, occupational level, and community size. The full account of conviction records in a criminal register was used as a measure of criminal behavior. Altogether, 68% of patients vs. 37% of controls had any criminal record. Higher rates were found for alcoholics than for controls for all types of crime; differences were especially pronounced in crimes against property and in violent crimes. We conclude that alcoholism contributes to criminal behavior to a considerable degree, independently of sociodemographic factors. PMID- 8691192 TI - Evidence for response set effects in structured research interviews. AB - The Addiction Severity Index and NIMH Diagnostic Interview Schedule data of 20 methadone-maintained subjects with "fake bad" invalid profiles on the Personality Assessment Inventory, 15 methadone-maintained subjects with "fake good" invalid profiles, and 158 methadone-maintained subjects with valid profiles were compared. The findings revealed a number of significant group differences on both measures with the highest scores for the fake bad subjects and lowest scores for the fake good subjects. These findings suggest that the response sets exhibited in response to the Personality Assessment Inventory questionnaire extended to performance during the two semi-structured interviews. There was no indication that interviewers were aware of misrepresentation. The limitations of the findings and alternative interpretations of the data are considered. PMID- 8691193 TI - Performance of subclinical compulsive checkers on putative tests of frontal and temporal lobe memory functions. AB - Previous research suggests that compulsive checking is associated with a deficit in memory for actions. In addition, evidence indicates frontal lobe involvement in both obsessive-compulsive disorder and in the monitoring of self-ordered actions. We examined the relationship between compulsive checking and performance on tests putatively related to frontal and temporal lobe memory functions. Subjects consisted of two groups of 14 university students identified as checkers or noncheckers according to the checking subscale of the Maudsley Obsessional Compulsive Inventory. Checkers demonstrated significantly poorer ability to monitor their responses on the frontal task and a trend toward better long-term visuospatial memory. When the effect of trait anxiety was controlled for, the frontal effect was reduced to a trend, but the visuospatial memory advantage was enhanced. Although both a frontal deficit and enhanced long-term visuospatial memory may contribute to compulsive checking, trait anxiety seems to play a moderating role. PMID- 8691194 TI - An estimate and comparison of MMPI and MMPI-2 concurrent validity. Predicting DSM III-R diagnoses among college students. AB - The ability of the MMPI and MMPI-2 to identify persons who were either free or not free from DSM-III-R-defined psychopathology was assessed and compared. University students completed either the MMPI (N = 388) or the MMPI-2 (N = 302) along with a computerized version of the Diagnostic Interview Schedule, which was scored according to the criteria of the DSM-III-R. MMPI profiles were categorized with several different rules as being within normal limits or not. DSM-III-R status served as the criterion variable, and 189 (27%) study participants met criteria for a current axis I disorder. Although MMPI profiles were more elevated than MMPI-2 profiles, the proportion of profiles categorized as either normal or abnormal did not differ. Both the MMPI and MMPI-2 demonstrated a statistically reliable degree of relation with the broadly applied DSM-III-R standard of current disorder or not. Predictive relationships were modest. The variance in DSM-III-R-measured psychopathology accounted for by MMPI or MMPI-2 categorizations averaged gamma 2 = .12. Contrary to hypotheses, our results did not demonstrate improved MMPI-2 discrimination. PMID- 8691195 TI - The descriptive assessment for psychiatric art. A new way of quantifying paintings by psychiatric patients. AB - This pilot study reports the development of a coding system for quantitative analysis of paintings produced by psychiatric patients. Color, color intensity, quality of line, space covered, and subjectively judged emotional tone as characteristics of paintings were recorded in each section of a grid superimposed over the picture. A sample of 39 psychiatric patients were classified into 4 groups using ICD-10 criteria: depression, psychosis, brain injury, and drug abuse. Six independent raters achieved excellent reliability across all scales on each of eight pictures. Analysis of variance results show that each diagnostic group differed on 4 of 13 variables: yellow, orange, color intensity, and line (p < .02). The prospects for further research are discussed. PMID- 8691196 TI - The prevalence of psychiatric disorders in veterans with spinal cord injury: a controlled comparison. PMID- 8691197 TI - Seasonal depression in patients with dissociative disorders. PMID- 8691198 TI - Subclinical stress responses in noncombatants. PMID- 8691199 TI - Reactive attachment disorder: usefulness of a new clinical category. PMID- 8691200 TI - Dually diagnosed homeless veterans in residential treatment: service needs and service use. PMID- 8691201 TI - Panic disorder cases of Westerners in Japan. PMID- 8691202 TI - Demoralization and unexplained illness in two cohorts of American soldiers overseas. PMID- 8691203 TI - Antitumor activity and stereochemistry of acetylenic alcohols from the sponge Cribrochalina vasculum. AB - Antitumor bioassay-guided fractionation of the organic extract of the marine sponge Cribrochalina vasculum resulted in the isolation of several closely related cytotoxic acetylenic alcohols [1-8], the structures of which were assigned on the basis of chemical and spectral studies. 3-Hydroxyeicos-(4E)-en-1 yne[1], 3-hydroxydocosa-(4E,15Z)-dien-1-yne[2], 3-hydroxy-16-methyleicos-(4E)-en 1-yne[3], 3-hydroxy-19-methyleicos-(4E)-en-1-yne[4], 3-hydroxy-21-methyldocosa (4E,15Z)-dien-1-yne [5], and 3-hydroxy-14-methyldocosa-(4E)-en-1-yne [6] are enantiomers of known compounds, while 3-hydroxyheneeicos-(4E)-en-1-yne [7] and 5 hydroxy-16-methyleicos-(3Z)-en-1-yne [8] are new metabolites isolated as minor components. The absolute configuration of C-3 in 1-7 and C-5 in 8 has been assigned as S using the modified Mosher's method. Compounds selected from this series showed selective in vitro antitumor activity against the H-522 non-small cell lung line and the IGROV-1 ovarian line. Synthetic racemic 1 demonstrated a modest dose-related therapeutic activity in a preliminary in vivo xenograft assay based on the latter cell line. PMID- 8691204 TI - L-735,334, a novel sesquiterpenoid potassium channel-agonist from Trichoderma virens. AB - A novel oleic acid ester of the carotane sesquiterpene 14-hydroxy CAF-603 was isolated from Trichoderma virens grown in a solid brown rice-based medium, a solid millet-based medium, or a mannitol-based liquid medium. Its structure was determined on the basis of ms and nmr analysis. It retains distinct biological activity on the high conductance calcium-activated potassium channel, unlike its analogues 14-hydroxy CAF-603, CAF-603 3-oleate, or CAF-603 3-linoleate. PMID- 8691205 TI - Synthesis and evaluation of 3',5'-di-tert-butyl-4'-hydroxyflavones as potential inhibitors of low density lipoprotein (LDL) oxidation. AB - The novel flavones 6-28, which display structural analogies with the two well known lipid peroxidation inhibitors, probucol [1] and butylated hydroxytoluene [2], were synthesized and studied in vitro for their ability to inhibit the copper sulfate or endothelial cell-induced lipid peroxidation of human low density lipoprotein (LDL). Most of the flavones were active in the range of 0.1-1 microM. PMID- 8691206 TI - Majapolene A, a cytotoxic peroxide, and related sesquiterpenes from the red alga Laurencia majuscula. AB - Seven new sesquiterpenes, majapolenes A [1] and B [2], majapolone [3], and majapols A [4], B [5], C [6], and D [7], were isolated from a Philippine collection of Laurencia majuscula. With the exception of majapolene B [2], all compounds were isolated as inseparable diastereomeric mixtures. Structure elucidation was achieved by spectroscopic methods. Majapolene A [1], a dioxabicyclo[2.2.2]-alkene, displayed modest activity in the NCI 60-cell line cytotoxicity screen. Majapolene A was also found as a major component of a Philippine collection of Laurencia caraibica. PMID- 8691207 TI - Makaluvamines H-M and damirone C from the pohnpeian sponge Zyzzya fuliginosa. AB - Seven new pyrroloiminoquinone alkaloids, makaluvamines H-M [19-24] and damirone C[25], together with the known compounds, makaluvamines C[13], D[14], and G[17], were isolated from the sponge Zyzzya fuliginosa collected at Nahpali Island, Pohnpei, Micronesia. The structures of the new compounds were elucidated by interpretation of spectral data. The chemotaxonomic relationships involving the makaluvamines and related pyrroloiminoquinone alkaloids are discussed. PMID- 8691208 TI - An improved source of bryostatin 10, Bugula neritina from the Gulf of Aomori, Japan. AB - Bryostatins have been isolated from diverse Japanese coastal specimens of Bugula neritina guided by inhibitory activity against fertilized sea urchin egg cell division. B. neritina from the Gulf of Aomori, Japan, has been found to contain bryostatin 10 [1b] in high yield (10(-3)%) for this class of compounds. The 1H- and 13C-nmr signals of bryostatin 10 [1b] were reassigned by 2D nmr techniques. The conformation of bryostatin 10 [1b] in solution was revealed by nmr studies. This compound also exhibited activity in a steroidogenesis assay by increasing the production of adrenocortical hormones nearly twofold. PMID- 8691209 TI - Metabolism of daidzein and genistein by intestinal bacteria. AB - The isoflavones daidzein [1] and genistein [2] were fermented with human fecal bacteria under anaerobic conditions. Dihydrodaidzein [3], benzopyran-4,7-diol,3 (4-hydroxyphenyl) [4], and equol [5] were isolated from the fermentation broth of 1. Only one metabolite, dihydrogenistein [6], was isolated and characterized from the fermentation broth of 2. Metabolites 3-6 were identified by spectral methods. PMID- 8691210 TI - Metabolites of daidzein and genistein and their biological activities. AB - A number of metabolites of daidzein and genestein have been synthesized and their biological activities determined. Equol [3], 5,7,4'-trihydroxyisoflavan [5], 4,7,4'-trihydroxyisoflavan [6], dihydrodaidzein [8], and dihydrogenistein [9] were synthesized either from daidzein [1] or genistein [2] by hydrogenation. Similarly, the derivatives 4, 7, and 11 were synthesized from 3, 6, and 10, respectively. During acetylation and nmr experiments, 9 was converted to a novel enol intermediate [10]. Antifungal, antibacterial, mosquitocidal, nematocidal, and topoisomerase inhibition activities of these compounds were evaluated, with equol [3] being the most active of the compounds tested against topoisomerase I. PMID- 8691211 TI - Two new taxoids from the stem bark of Taxus baccata. AB - Two new taxoids, 13-deoxo-13 alpha-acetyloxy-7 beta,9 alpha-diacetyl-1,2 dideoxytaxine B[1] and 7 beta-xylosyl-10-deacetyltaxol D [7], were isolated from the stem bark of Taxus baccata cv. stricta. Their structures were elucidated using spectroscopic methods and their bioactivity was evaluated using an in vitro microtubule assembly assay. PMID- 8691212 TI - Bruceanols G and H cytotoxic quassinoids from Brucea antidysenterica. AB - Two new quassinoids, bruceanols G [1] and H [4], were isolated from Brucea antidysenterica, and their structures were elucidated by spectral evidence and chemical transformation. Bruceanol G exhibited significant cytotoxicity against the COLO-205 and KB neoplastic cell lines with ED50 values of 0.44 and 0.55 microM, respectively. PMID- 8691213 TI - Novel antiplatelet naphthalene from Rhamnus nakaharai. AB - A new naphthalene derivative, isotorachrysone [1], was isolated from the stem bark of Rhamnus nakaharai along with several known compounds. The antiplatelet effects of isotorachrysone [1], isotorachrysone peracetate [2], 6 methoxysorigenin [3], quercetin 3-O-methyl ether [4], and quercetin 3-O-methyl ether peracetate [5] were studied using washed rabbit platelets. Of the compounds tested, 1, 2, 4, and 5 showed potent antiplatelet effects on arachidonic acid (AA ) and collagen-induced platelet aggregation. Compound 5 also showed potent antiplatelet effects on platelet-activating factor-(PAF-) induced platelet aggregation. Isotorachrysone [1] and its peracetate [2] were also studied for antiplatelet activity in human platelet-rich plasma (PRP) and both showed potent inhibition of the secondary aggregation induced by epinephrine. The antiplatelet effects of 1 and 2 are due partially to an inhibitory effect on thromboxane formation. PMID- 8691214 TI - Chemical constituents of halophilic facultatively anaerobic bacteria, 1. AB - Two new nitrotyramine derivatives, 1 and 2, along with five known aromatic compounds, were isolated from the culture broth of a facultatively anaerobic, halophilic bacterium isolated from a sediment from the Great Salt Plains, Alfalfa County, Oklahoma. The structures of the new compounds were determined from spectral data and were confirmed by synthesis from tyramine hydrochloride. Compound 1 showed cytotoxicity against the murine leukemia P-388 cell line (IC50 3 micrograms/ml). PMID- 8691215 TI - Isolation and structure identification of an active DNA strand-scission agent, (+)-3,4-di-hydroxy-8,9-methylenedioxypterocarpan. AB - A new pterocarpan, (+)-3,4-dihydroxy-8,9-methylenedioxypterocarpan [1], was isolated from the flowers of Petalostemon purpureus by a DNA strand-scission assay-guided fractionation procedure. Compound 1 demonstrated activity in a standard in vitro DNA strand-scission assay, and cytotoxicity toward a KB tumor cell line. Two other related pterocarpans [2, 3] isolated from same plant were found to be moderately active for KB cells, but were inactive in the DNA strand scission assay. (+)-4-Hydroxy-3-methoxy-8,9-methylenedioxypterocarpan [2] has not been reported previously as a natural product, while (+)-maackiain [3] has been isolated only as an optically inactive racemate along with its optical antipode, the (-)-isomer. PMID- 8691216 TI - Murrayanolide, an unusual C21 tetracyclic terpenoid lactone from the marine bryozoan Dendrobeania murrayana. AB - A novel tetracyclic terpenoid lactone possessing an unusual C21 skeleton was isolated from a marine bryozoan and the structure was established by spectral methods. PMID- 8691217 TI - Polytolypin, a new antifungal triterpenoid from the coprophilous fungus Polytolypa hystricis. AB - Polytolypin [1], a new pentacyclic triterpenoid exhibiting antifungal and antibiotic activity, has been isolated from cultures of Polytolypa hystricis (JS189), a fungal colonist of porcupine dung. Two known compounds [2 and 3] were also isolated. Polytolypin was obtained by chromatographic fractionation of the EtOAc extract of P. hystricis liquid cultures, and the structure was assigned on the basis of 2D nmr and hrms data. PMID- 8691218 TI - The future of epidemiology. PMID- 8691219 TI - Interpretation of change scores in ordinal clinical scales and health status measures: the whole may not equal the sum of the parts. AB - The objective of this study was to analyze the problem of interpreting change scores of ordinal health status measures for clinical research or practice. Methods used included exploration of the generation of change scores in the physical ability scale of the SF-36, one of the most widely used generic health status instruments. Resulting data are presented as the ranking of items according to baseline score; a percentage of patients with severe difficulty and Rasch analysis provided the same rank order of item difficulty. On the interval scale provided by the Rasch model a concentration of items reflecting moderate difficulty occurred. This "inflates" numerical gains for patients with moderate disability compared to patients with very severe or minor physical disability. Calibration of change scores using patient perception of the level of change in function showed important variation of numerical gains with baseline. We conclude that numerically equal gains may differ in their meaning depending on baseline health status. It is recommended that distribution of baseline health status measures and distribution of responders by baseline status be reported in evaluative studies. PMID- 8691220 TI - Repeatability and validity of the Rose questionnaire for angina pectoris in the Atherosclerosis Risk in Communities Study. AB - Angina pectoris (AP) as determined by the Rose questionnaire was assessed in nearly 16,000 black and white men and women participating in the Atherosclerosis Risk in communities Study, a population study of cardiovascular disease in four communities. The questionnaire was administered at yearly intervals and estimates of repeatability were made. Validity was assessed indirectly by comparing Rose AP to risk factors, prevalent heart disease, medication use, and thickness of carotid artery walls as measured by B-mode ultrasound. Using kappa statistics for agreement of positive Rose AP determinations taken 1 year apart, white men show a higher level of agreement than white women (average kappa 0.36 for white men, 0.30 for white women), and whites show a higher level of agreement than blacks (average kappa 0.23 and 0.22 for black men and women, respectively). Rose AP that persists for more than one determination is associated with thicker carotid artery walls, greater amounts of cigarette smoking, greater prevalence of reported heart attack, and greater use of chest pain medications. A single determination of severe Rose AP is also associated with thicker carotid artery walls. These data suggest that multiple reports and the more severe grading of Rose AP (pain reported while walking on the level) are likely to indicate more severe disease; however, a single report using the Rose questionnaire appears valid, i.e., moderately associated with disease and risk factors, and appropriate for use in epidemiological studies. PMID- 8691221 TI - Probability of having hypertension: effects of sex, history of hypertension in parents, and other risk factors. AB - The objective of the present study was to determine whether paternal and maternal history of hypertension contributes to the probability of an individual having hypertension before and after other measured traits, including sex, are considered. A cross-sectional sample of 217 men and 196 women was selected from the general Caucasion population of Rochester, Minnesota without respect to the hypertension status of subjects and their parents. Logistic regression analyses indicated that when no other information was considered, paternal history of hypertension contributed to the probability of having hypertension in men (chi 2 = 4.14, df = 1, p = 0.042) and in women (chi 2 = 4.12, df = 1, p = 0.042). The odds ratio associated with paternal history of hypertension was 2.80 in men (95% confidence interval [CI] = 1.0-8.0); the odds ratio was 4.11 in women (95% CI = 0.9-19.3). Maternal history of hypertension provided a marginally significant contribution to the prediction of probability of having hypertension in men (chi 2 = 3.86, df = 1, p = 0.049 in men), and less so in women (chi 2 = 3.31, df = 1, p = 0.068). The odds ratios associated with maternal history of hypertension were 2.85 in men (95% CI = 0.9-8.8) and 3.60 in women (95% CI = 0.8-16.9). A stepwise selection algorithm was used to select other predictors of hypertension in men and women. Other predictors of hypertension identified in men were age and sodium lithium countertransport level. After these other predictors were considered, paternal but not maternal history of hypertension contributed to the probability of having hypertension in men. In a model that contained these other predictors, the partial odds ratio associated with paternal history of hypertension was 3.38 (95% CI = 1.1 = 10.1). Other predictors identified in women were age, apolipoprotein (apo) B, and apo B squared. After these other predictors were considered, neither paternal nor maternal history of hypertension made a statistically significant contribution to the probability of having hypertension in women. These results suggest that evaluation of the hypertension risk of an individual depends on the sex of the individual, the sexes of the individual's hypertensive parents, and the values of other measured risk factor traits. PMID- 8691222 TI - The importance of work-up (verification) bias correction in assessing the accuracy of SPECT thallium-201 testing for the diagnosis of coronary artery disease. AB - Noninvasive testing is often evaluated by the sensitivity and specificity in comparison with a more invasive, but more definitive "gold" standard. However, work-up or verification bias, which occurs when the results of a noninvasive test impact the decision to perform the gold standard invasive test, increases the "observed" sensitivity and decreases the "observed" specificity of the noninvasive test. Most large clinical studies utilizing a noninvasive technique to diagnose coronary artery disease have biases, particularly work-up bias. To obtain more accurate measurements of sensitivity and specificity, we determined the observed sensitivity and specificity of stress (exercise and dipyridamole) single photon emission computed tomographic (SPECT) thallium testing for the detection of coronary artery disease by angiography, and then applied previously published equations to correct for work-up bias. From a computerized data base, reports of 4354 stress SPECT thallium studies from January 1, 1986 through December 31, 1992 were reviewed. All patients with a known history of myocardial infarction or prior coronary angiography were excluded, leaving 2688 patients. From this total, 471 patients underwent coronary angiography within 90 days following stress SPECT thallium testing. Coronary artery disease was defined as a visually assessed stenosis of a coronary artery or a major branch > 50%. Of the 2688 stress SPECT thallium studies, 1265 were normal and 1423 were abnormal. For the 471 patients who underwent catheterization within 90 days following stress SPECT thallium testing. the "observed" sensitivity and specificity were 98 and 14%, respectively. After correction for work-up bias, the corrected sensitivity and specificity were 82 +/- 6% and 59 +/- 2%, respectively. Most studies utilizing noninvasive technologies for the detection of coronary artery disease include patients with known coronary artery disease and have work-up bias as well. By knowing the thallium results of patients with and without catheterization, we were able to correct for work-up bias. These data provide better estimate of the sensitivity and specificity of stress SPECT thallium testing. PMID- 8691223 TI - Prediction of survival of critically ill patients by admission comorbidity. AB - The objective of this study was to determine how well the Charlson index of comorbidity would predict mortality of critically ill patients; and how the predictive ability of the index would compare with that of the comorbidity component (Chronic Health Points) of the APACHE II system. This prospective cohort study included in its setting an intensive care unit (ICU) and intermediate ICU (IICU) in a teaching hospital. Patients included a previously assembled inception cohort of 201 patients consecutively admitted to either unit, followed until death or discharge from the hospital, excluding patients admitted after coronary artery bypass grafting, for planned dialysis, or transferred to the IICU from another intensive care unit. Main outcome measures were recorded as death in hospital versus survival at discharge. For each patient we had prospectively obtained all data necessary to predict the probability of in hospital death using the APACHE II system, and to classify comorbidity using the Charlson index. The Charlson index had significant ability to discriminate between patients who would live and who would die (ROC curve area = 0.67, SE = 0.05). The Chronic Health Points component of APACHE II had no significant discriminating ability (ROC area = 0.57, SE = 0.05), although the full APACHE II system was an excellent predictor (area = 0.87, SE = 0.04). Logistic regression analyses suggested that the Charlson index could contribute significant (p = 0.03) prognostic information to that obtained from the components of APACHE II other than Chronic Health, i.e., acute physiological derangement, age, and reason for admission, but the Chronic Health Points component of APACHE II could not so contribute to the rest of APACHE II (p = 0.19). Our conclusion is that use of the detailed information about comorbidity captured by the Charlson index could improve prognostic predictions even for critically ill patients. PMID- 8691225 TI - The Glasgow Coma Scale: a critical appraisal of its clinimetric properties. AB - The Glasgow Coma Scale is a commonly used instrument in clinical practice. This article examines the published evidence to assess whether the scale possesses the requisite clinimetric properties. Articles describing and using the scale were located through a MEDLINE search. The clinimetric properties of the scale were appraised using the methodological principles of sensibility, reliability, validity, and responsiveness. The scale has a good sensibility and reliability (intraclass correlation coefficient, 0.8 to 1 for trained users). It has a well established cross-sectional construct validity. Its predictive validity in traumatic coma, when combined with age and brainstem reflexes, is good in the generating sample (sensitivity, 79 to 97%; specificity, 84-97%) but has not been tested in an external validation sample. Its longitudinal construct validity has not been studied adequately. Thus, the scale is an established discriminative instrument but its validity as a predictive and an evaluative instrument has not yet been studied adequately. PMID- 8691224 TI - Rating the quality of evidence for clinical practice guidelines. AB - This article describes the system for rating the quality of medical evidence developed and used during creation of the Agency for Health Care Policy and Research-sponsored heart failure guideline. Previous approaches to rating evidence were not designed for use in the setting of clinical practice guidelines. The present system is based on the tenet that flaws in research design are serious to the extent they threaten the validity of the results of studies. A taxonomy of major and minor flaws based on that tenet was developed for randomized controlled trials and for cohort and medical registry studies. The use of the system is described in the context of two difficult clinical issues considered by the Panel: the role of coronary artery revascularization and the use of metoprolol. PMID- 8691226 TI - Rainbow reviews. VII: Recent publications of the National Center for Health Statistics. AB - In this article, selected recent publications of the National Center for Health Statistics (NCHS) are reviewed. In particular, data from a recent NCHS report on hearing loss were found to be consistent with a prediction made in a preview article in this series that there would be an increase in high-tone hearing loss among persons who were exposed to loud music as teenagers and young adults, beginning in the late 1960s, although the data were not specific enough to be considered proof. In addition, the article discusses: (1) recent data on home health care, (2) new insights on how people remember and report on preventive examinations and tests, (3) a comparison of vital statistics in the United States and the Russian Federation, and (4) trends in births to unmarried women. PMID- 8691227 TI - Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990-1992): structure and results of a population-based registry. AB - The severe skin reactions erythema exsudativum multiforme majus (EEM with mucosal involvement, EEMM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) are difficult to study as they are very rare diseases with an incidence of about two cases per 1 million inhabitants per year. We report on the structure of a registry with the aim of ascertaining all hospitalized cases of EEMM, SJS, and TEN in western Germany and Berlin. The registry is structured as an intensive reporting system, regularly contacting more than 1500 departments including 100% of the burn units (n = 34), departments of pediatrics (n = 241), departments of dermatology (n = 106), and 100% of all internal medicine departments in hospitals with intensive care facilities or with more than 200 beds (n = 1161). With a coverage rate up to 95% based on the number of responding departments between April 1, 1990 and December 31, 1992, from a total of 767 reported cases 353 patients with EEMM, SJS, and TEN were finally included in the registry. Most of these patients were directly reported to the registry; only 2.54% (9 of 353) were primarily registered by the German spontaneous reporting systems. Assuming an average population of 64.5 million for western Germany and Berlin an incidence up to 1.89 per 1 million inhabitants per year could be calculated for SJS and TEN. PMID- 8691228 TI - The meaning of kappa: probabilistic concepts of reliability and validity revisited. AB - A framework--the "agreement concept"--is developed to study the use of Cohen's kappa as well as alternative measures of chance-corrected agreement in a unified manner. Focusing on intrarater consistency it is demonstrated that for 2 x 2 tables an adequate choice between different measures of chance-corrected agreement can be made only if the characteristics of the observational setting are taken into account. In particular, a naive use of Cohen's kappa may lead to strikingly overoptimistic estimates of chance-corrected agreement. Such bias can be overcome by more elaborate study designs that allow for an unrestricted estimation of the probabilities at issue. When Cohen's kappa is appropriately applied as a measure of chance-corrected agreement, its values prove to be a linear--and not a parabolic--function of true prevalence. It is further shown how the validity of ratings is influenced by lack of consistency. Depending on the design of a validity study, this may lead, on purely formal grounds, to prevalence-dependent estimates of sensitivity and specificity. Proposed formulas for "chance-corrected" validity indexes fail to adjust for this phenomenon. PMID- 8691230 TI - Referral bias among health workers in studies using hospitalization as a proxy measure of the underlying incidence rate. AB - Contacts with health services like hospitals or general practitioners are usually the only available proxy measure of incidence of disease in studies based on secondary data and differential referrals or care-seeking behavior often bias such proxy measures. In former analyses based on the Occupational Hospitalization Register in Denmark assisting nurses had high Standardized Hospitalization Ratios for many diseases. It was, however, suspected that it fully or partly was due to a referral bias or self-selection to hospital treatment rather than exposures to occupational hazards. The aim of the present study is to evaluate the referral bias hypothesis by comparing hospitalization and mortality data for health workers for a disease category with a high mortality. Cohorts of all gainfully employed 20- to 59-year-old Danes were formed in order to compare Standardized Mortality Ratios and Standardized Hospitalization Ratios of ischemic heart disease (IHD) in occupational groups. The follow-up period was 10 years. For most of the investigated occupational groups a similar disease pattern was found whether hospitalization or death was used as the outcome measure. In "nurse assistants" a statistically significant higher risk was, however, found using hospitalization due to IHD as the end point rather than mortality. Additional analysis did not support the hypothesis that the finding could be explained by differentiated hospitalization due to social factors. The true incidence rates of the disease need not be equally well described by proxy measures such as hospitalization diagnosis or death diagnosis in all occupational groups. Differential access to medical treatment in some groups may lead to bias when hospital data are used as proxy measures for the underlying incidence rates. PMID- 8691229 TI - Healthy volunteer effect in a cohort study: temporal resolution in the Adventist Health Study. AB - The healthy volunteer effect was studied by comparing 6 years of mortality data for 31,124 participants from the Adventist Health Study (AHS) who responded to both a relatively brief census questionnaire (CQ) in 1974 and a detailed life style questionnaire (LQ) in 1976 (responders), to mortality data for 8,762 individuals who did not respond to the second questionnaire. The rate ratio (RR) comparing LQ nonresponders to responders for all cause mortality decreased from 2.5 (2.2-2.9) in 1977 to 1.4 (1.2-1.7) in 1982 (p for trend = 0.02); for ischemic heart disease mortality from 2.3 (1.8-3.0) to 1.3 (1.0-1.7); and for all sites cancer mortality from 1.8 (1.3-2.5) to 1.5 (1.1-2.0). The death rate decreased markedly among nonresponders and increased slightly among responders during the study. Similar results were seen for age and gender subgroups. Multivariate analysis controlling for confounding variables confirms these results, except that the apparent effect of education is probably due to effect modification by age. The RR decreased to about one after 3 years of follow-up in young subjects but remained elevated (> 2) in older subjects. Available sociodemographic information reveals that a higher proportion of responders are married, have college education, are SDA church members, and use medical services less than nonresponders during the previous year. Because the risk remains elevated at the end of the study in some but not all subgroups, it seems reasonable that the elevated risk in nonresponders may be due in part to a less healthy life style and in part to exclusion of individuals who did not feel well during enrollment. The results suggest that for internal comparisons no bias is likely to occur; but descriptive statistics for certain subgroup comparisons, and external comparisons, may be biased by the healthy volunteer effect. PMID- 8691231 TI - The relationship between plasma cholesterol concentration and minor psychiatric disturbance in the Department of the Environment Study. AB - We examined the hypothesis that low plasma cholesterol concentration was associated with minor psychiatric disturbance in a cross-sectional study of 410 male and 138 female civil servants. Psychiatric disturbance was measured using the 30-item General Health Questionnaire (GHQ). Mean GHQ score did not vary significantly with quartile of total cholesterol concentration. After adjustment for confounding variables a significant trend of increasing mean GHQ with increasing cholesterol concentration emerged. In a logistic regression analysis subjects in the highest quartile of cholesterol concentration had an adjusted odds ratio for being a "psychiatric case" of 2.0 (95% confidence interval, 1.1 2.5) compared with those in the lowest quartile. This relationship reversed when using a higher cutoff point to define more severe cases, although the trend was not statistically significant. PMID- 8691232 TI - An alternative explanation for the apparent elevated relative mortality and morbidity risks associated with exposure to environmental tobacco smoke. AB - Insofar as industrial and other blue collar workers are more likely to bring home toxic materials on their person, and also are more likely to smoke than those in other occupations, members of a household are more likely to be subject to paraoccupational exposure and belong to lower socioeconomic strata if the household contains a smoker than if the household does not contain a smoker. Thus observed differences in risk of mortality or morbidity ascribed to ETS on the basis of a comparison of households with and without smokers may be partly or entirely due to differences in paraoccupational exposure and socioeconomic strata. Similarly, differences in mortality and morbidity ascribed to paraoccupational exposure may be partly or entirely due to differences in ETS exposure that are also related to social class and to types of occupation. Unfortunately, there are no data now in existence that could help determine separately the effects of these major confounded variables. There exists, then, a situation in which two explanations are advanced for respiratory diseases among members of a household, each based on similar study populations but focused on different major risk variables: ETS on the one hand, socioeconomic status and paraoccupational exposure on the other. Properly focused investigations need to be initiated. PMID- 8691233 TI - The incidence of depression in new users of beta-blockers and selected antihypertensives. AB - We studied the occurrence of depression in new users of propranolol (n = 704), other beta-blockers (n = 587), angiotensin-converting enzyme inhibitors (n = 976), calcium channel blockers (n = 742), and diuretics (n = 773) in the Harvard Community Health Plan population. The period of the study was from April 1988 to June 1991. All study subjects were followed for new or newly recurrent depression for up to 6 months after receiving their first study prescription. Case status was confirmed by blinded medical record review. We found 10 cases of depression that met DSM-III-R criteria ("major depression") and an additional 18 cases that had one or more symptoms consistent with depression ("minor depression"). Rates of major depression in users of beta-blockers and users of non-beta-blocker study drugs were 5.8 per 1000 person-years of exposure and 9.6 per 1000 person-years, respectively. None of the cases of major depression was propranolol associated. Rates of major or minor depression (combined) in users of beta-blockers and users of non-beta-blockers were 20.2 per 1000 person-years and 25.2 per 1000 person years, respectively. The age- and sex-adjusted relative risk of major or minor depression associated with the use of beta-blockers compared to non-beta-blockers was 0.8 (95% CI, 0.3-1.9). The relative risk associated with propranolol compared to non-beta-blockers was also 0.8 (95% CI, 0.1-2.7). Therefore, depression occurred no more frequently in beta-blocker users than in other members of the study base. PMID- 8691234 TI - Regression coefficients and scoring rules. PMID- 8691235 TI - Monoclonal antibody scan holds promise for prostate cancer staging. PMID- 8691236 TI - The need to improve continuing medical education. PMID- 8691237 TI - HMPAO SPECT to assess neurologic deficits during balloon test occlusion. AB - The purpose of this study was to determine if one could objectively and preoperatively predict the safety of permanent occlusion of an internal carotid artery with 99mTc-HMPAO brain SPECT. METHODS: Twenty-four patients underwent balloon test occlusion of the internal carotid arteries because of neck and skull base tumors. We assessed the uptake of both middle cerebral artery territories before and during balloon test occlusion with 99mTc-HMPAO brain SPECT using the semiquantitative analysis. The results were compared with other factors, including neurologic examination, arterial stump pressure and electroencephalogram. RESULTS: Nineteen patients experienced no neurological deterioration or any problem during balloon test occlusion. The comparative uptake of their middle cerebral artery territories was 95%-101% of the pre balloon test occlusion state. The remaining five patients showed severe neurologic symptoms, such as transient hemiplegia and unconsciousness. The comparative uptake of their middle cerebral artery territories was 77%-85% of the pre-balloon test occlusion state and was well matched with other factors. CONCLUSION: Technetium-99m-HMPAO brain SPECT before and during balloon test occlusion seems to be a simple and objective method for predicting permanent neurologic deficits when the comparative uptake of middle cerebral artery territories during balloon test occlusion is less than 85% of that before balloon test occlusion. PMID- 8691238 TI - Dopamine transporters decrease with age. AB - Postmortem studies have documented degeneration of dopamine cells with age, but the changes that occur in healthy aging individuals is less clear. The purpose of this study was to evaluate the extent to which age-induced changes in dopamine transporters occur in subjects with no evidence of motor impairment. METHODS: We evaluated 23 right-handed healthy volunteers (age range 20-74 yr) using PET and [11C]d-threo-methylphenidate. The ratio of the distribution volume for [11C]d threo-methylphenidate in striatum to that in cerebellum was used as model parameter for dopamine transporter availability (Bmax/Kd + 1). RESULTS: Dopamine transporter availability was significantly lower in subjects > 40 yr of age than in those < 40 yr. Estimates of dopamine transporter availability showed a significant negative correlation with age both for the putamen (r = -0.72, p < 0.0001) and the caudate (r = -0.74, p < 0.0001). Dopamine transporter availability was higher in the left than in the right putamen but did not differ between the left and right caudate. CONCLUSION: This study documents a 6.6% decrease per decade of life in striatal dopamine transporters of healthy volunteers. PMID- 8691239 TI - Gender differences in cerebral blood flow as a function of cognitive state with PET. AB - This study explored the role of cognitive states in gender-based differences in brain function. METHODS: We used the 15O-water bolus method to measure cerebral blood flow (CBF) in 14 young normal volunteers with PET. Each subject was scanned six times, three during different neuropsychological tasks linked to the prefrontal cortex and three others during customized sensorimotor control tasks. The prefrontal tasks were the Wisconsin Card Sorting (WCS) Test, Delayed Alternation task (DA) and Spatial Delayed Response task (DR). RESULTS: A significant main influence of sex on global CBF (ml/min/100g) was seen, with higher values in women, as viewed across all six conditions (means: 60.9 versus 53.2, ANOVA F = 9.35, p < 0.01). Post-hoc contrasts, however showed that this finding was not uniform in all conditions. Differences between men and women were seen during performance of the frontal lobe tasks, but not during the sensorimotor control tasks. Even within the three frontal lobe tasks, results tended to vary: the differences between the sexes were most significant during the DA and just reached traditional levels of significance during the WCS. Therefore, if we had utilized a single task condition to determine whether men and women have different global CBFs, disparate conclusions would have reached depending upon the task chosen. CONCLUSION: Although clear sex differences in global CBF can be demonstrated, the cognitive state of the subjects must be controlled and considered when interpreting the differences. Also, variations in the cognitive state might explain some of the discrepancies in gender studies in the rCBF and cerebral glucose metabolism literature. PMID- 8691240 TI - Double phase parathyroid technetium-99m-MIBI scintigraphy to identify functional autonomy in secondary hyperparathyroidism. AB - Double-phase 99mTc-methoxyisobutylisonitrile (MIBI) parathyroid scintigraphy has been proposed to detect hyperplastic parathyroid tissue, but the clinical usefulness of this technique in secondary hyperparathyroidism is still debated. METHODS: Technetium-99m-MIBI parathyroid scintigraphy associated with parathyroid echography and [99mTc]pertechnetate thyroid scans were performed on 38 patients with chronic renal failure (CRF) and secondary hyperparathyroidism. In all patients, serum calcium, phosphorus, FT3, FT4, TSH, calcitonin and intact PTH (iPTH) were determined. Nine patients eventually underwent neck exploration and 28 parathyroid glands were removed. RESULTS: Thyroid diseases were excluded in all patients. Echography revealed parathyroid enlargement in 22/38 (58%) patients, while MIBI scintigraphy was positive in 28/38 (74%), including 5 ectopic glands. Mean serum iPTH concentration was significantly higher in MIBI positive glands compared to MIBI-negative glands, but several discrepancies were observed in single patients. A significant positive correlation between serum iPTH and gland size was observed when MIBI-positive, but not MIBI-negative, parathyroids were considered. A paradoxical positive correlation between serum calcium and iPTH concentrations was found in MIBI-positive patients. CONCLUSION: Double-phase 99mTc-MIBI scintigraphy is positive in the majority of patients with uremic hyperparathyroidism. Comparison of scintigraphic data with morphological and functional data strongly suggests that 99mTc-MIBI scans do not reveal simple parathyroid enlargement but rather, identify the presence of hyperfunctioning (autonomous) parathyroid tissue suggestive of tertiary hyperparathyroidism. PMID- 8691241 TI - Patient stratification by cardiopulmonary status in the diagnosis of pulmonary embolism. AB - The purpose of this investigation is to provide further evidence in support of the interpretation of ventilation/perfusion (V/Q) lung scans on the basis of criteria dependent on whether or not the patient has prior cardiopulmonary disease (CPD). METHODS: Data are from the collaborative PIOPED study. We evaluated the original PIOPED database to obtain the consensus probability estimates of pulmonary embolism (PE) among patients stratified according to the presence or absence of prior CPD. RESULTS: Among patients with no prior CPD, nuclear physicians consistently underestimated the probability of PE (odds ratio 1.62, 95% confidence interval 1.10-2.38, p = .014). CONCLUSION: Past experience guided nuclear physicians into correctly estimating the probability of acute PE on V/Q scans of patients with prior CPD. The criteria they subjectively used was inadequate for estimating the probability of acute PE in patients with no prior CPD. Different criteria, therefore, apply to the interpretation of V/Q scans in these two groups. PMID- 8691242 TI - Myocardial metabolic changes in hypertrophic cardiomyopathy. AB - We evaluated myocardial blood flow, glucose and oxygen metabolism using PET in hypertrophic cardiomyopathy (HCM). METHODS: PET studies using 18F fluorodeoxyglucose (FDG) and 11C-acetate were performed at rest in patients with HCM and normal subjects as a control group. The metabolic rate of glucose (MRGlu), K mono value as a marker of oxidative metabolism, and myocardial blood flow were estimated from serial dynamic FDG and 11C-acetate PET studies. RESULTS: Myocardial blood flow (%) did not differ significantly in hypertrophic and nonhypertrophic myocardium (90.3 +/- 3.1 versus 91.7 +/- 3.4). The MRGlu in hypertrophic myocardium, however, was lower than that of hypertrophic and normal myocardium (0.44 +/- 0.10 versus 0.52 +/- 0.15 and 0.53 +/- 0.15 mumole/min/g, respectively, p < 0.05). The K mono values were also lower in hypertrophic myocardium than in nonhypertrophic and normal myocardium (0.05 +/- 0.010 versus 0.066 +/- 0.0011 and 0.065 +/- 0.017 per min, respectively, p < 0.05). The %FDG/%perfusion values in hypertrophic myocardium did not differ significantly from those in nonhypertrophic myocardium (0.96 +/- 0.10 versus 1.02 +/- 0.07). CONCLUSION: Myocardial ischemia at rest is observed less frequently in patients with HCM. Impairment of oxidative and glucose metabolism may precede decreased blood flow. Primary metabolic impairment is considered to be dominant in hypertrophic myocardium. PMID- 8691243 TI - Evaluation of individual criteria for low probability interpretation of ventilation-perfusion lung scans. AB - The purpose of this investigation was to identify characteristics or combinations of characteristics of the ventilation-perfusion (V/Q) scan in patients with suspected acute pulmonary embolism (PE) can be used for a "very low probability" interpretation ( < 10% positive predictive value). METHODS: Data were culled from individual lungs of 532 patients in the randomized arm of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study and 205 patients in the referred arm. All patients had a < 20% consensus probability estimate of PE based on V/Q scan results, and all underwent pulmonary angiography. RESULTS: Nonsegmental perfusion abnormalities, perfusion defects smaller than opacities on the chest radiograph, a combination of these types of perfusion abnormalities, and matched V/Q abnormalities in two or three zones of a single lung had a positive predictive value < 10%. These criteria can therefore be used for a very low probability interpretation. A matched V/Q defect in only one zone of the lung had a positive predictive value greater than 10% and is not a criterion for low probability. Perfusion defects associated with small pleural effusions (obliteration of the costophrenic angle) had a positive predictive value of 25% 33%, depending on the group studied, and are a criterion for intermediate probability. CONCLUSION: Criteria appropriate for a very low probability ( < 10% positive predictive value) interpretation of V/Q scans in patients with suspected acute PE have been identified. PMID- 8691244 TI - The low probability V/Q lung scan: can its credibility be enhanced? PMID- 8691245 TI - Radiation pneumonitis imaged with indium-111-pentetreotide. AB - Early recognition of radiation pneumonitis enables adequate treatment with a reasonable chance to prevent late sequelae. The feasibility of 111In pentetreotide in detecting this condition was explored in this study. METHODS: The degree of lung uptake of 111In-pentetreotide, evaluated both visually and quantitatively by irradiated-to-nonirradiated area ratios (INIA ratio) from planar images after 24 hr, was analyzed in relation to the radiation field and compared with ventilation/perfusion (V/Q) images and chest radiographs or CT in 11 patients who had received radiotherapy to the mediastinum or to the internal mammary nodes, 10 of whom were suspected of having clinical radiation pneumonitis. Additional SPECT studies were used to map lung uptake distribution. RESULTS: Indium-111-pentetreotide scans were positive in nine symptomatic patients examined 2-5 mo after radiotherapy; strongly or moderately positive in eight patients, one of whom was receiving steroid therapy without clinical response; and weakly positive in one patient with good steroid response. Indium 111-pentetreotide studies were negative in one asymptomatic patient examined 1 mo after radiotherapy and in one symptomatic patient, with subsequent diagnosis of aspecific viral pneumonitis, examined 4 mo after irradiation. Positive 111In pentetreotide scans delineated areas of radiation pneumonitis that adequately correlated with areas of decreased ventilation/perfusion and x-ray abnormalities. INIA ratios varied from 1.01 to 2.16 and, in irradiated areas with visible uptake, the lowest value was 1.29. SPECT showed lung uptake in both superficial and deep lying areas in patients with mantle irradiation fields whereas distribution was limited to anterior areas in internal mammary lymph node chain irradiation. CONCLUSION: Indium-111-pentetreotide can detect radiation pneumonitis and may have a role in both the differential diagnosis of patients who have complaints after radiotherapy, and when supported by quantification in the monitoring of response to steroid therapy. PMID- 8691246 TI - Measurement of renal function with technetium-99m-MAG3 in children and adults. AB - A single-injection, single-sample procedure for measuring 99mTc-MAG3 clearance is presented that incorporates scaling for patient size and is valid for both children and adults. METHODS: The procedure is based on an empirical formula in which all measurements are expressed in dimensionless combinations. The formula was obtained by fitting data collected from 122 adults and 80 children at several centers. RESULTS: All results were scaled to standard adult surface area and are presented in units of ml/min/1.73 m2. For adult subjects, the residual standard deviation (r.s.d.) calculated from a single sample at 45 min was found to be 23, using the plasma clearance calculated from a multi-sample clearance curve as a reference. This did not differ significantly from the value of 22 obtained with our previous formula, which was valid for adults only. For pediatric subjects, an r.s.d. of 24 was calculated by the new formula from a single sample at 35 min; a comparable value of 33 was found using a pediatric formula previously published. CONCLUSION: The new clearance formula is recommended as a replacement for the formula we previously published, since it is based on a larger and more diverse subject population, and since it now holds for children as well, with no loss of accuracy for adult subjects. PMID- 8691247 TI - Stenosis and renographic characteristics in renovascular disease. AB - This study was designed to determine the degree of renal artery stenosis (RAS) which produces changes in renographic parameters. METHODS: The angiographic severity of luminal narrowing in RAS was compared to 131I-hippuran renographic characteristics in 72 patients who have been selected for renal angiography because of suspected renovascular hypertension. RESULTS: Significant differences in Tmax, T1/2 and counts under the curve to Tmax were apparent at 30% of arterial luminal narrowing when stenotic and nonstenotic kidneys were compared. In patients with unilateral RAS, the difference in counts under the Tmax curve between pairs of kidneys was also significantly different at 30% of stenosis. Patients with bilateral stenosis, on the other hand, could not be differentiated well from patients with essential hypertension because the Tmax value on either side or the difference of Tmax between the two kidneys and the values of the other parameters were similar, except for the difference in counts to Tmax. Based on these findings it seems that bilateral RAS does not "mimic" unilateral stenosis in renographic terms, but rather, resembles a normal situation. CONCLUSION: Significant renographic changes can occur at 30% of arterial luminal narrowing in renal artery disease. PMID- 8691248 TI - Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma. AB - We assessed the therapeutic benefits of 131I treatment in patients with distant metastases of differentiated thyroid carcinoma. METHODS: Of 2200 patients treated for differentiated thyroid carcinoma at our institution, 394 had lung and/or bone metastases. RESULTS: Two-thirds of the patients had 131I uptake in their metastases, but only 46% achieved a complete response. Prognostic factors for complete response were: younger age, presence of 131I uptake in the metastases and small extent of disease. The survival rate was 33% at 15 yr. As shown by multivariate analysis, favorable prognostic factors for survival were: younger age and time of metastases detection, well-differentiated histologic type of the thyroid tumor, presence of 131I type uptake in the metastases, small extent of the disease and year of discovery of metastases. CONCLUSION: In terms of survival, the benefits of 131I therapy cannot be demonstrated by prospective controlled studies. The present study clearly demonstrates, however, that treatment with 131I is one of the factors which accounts for survival; patients whose metastases concentrated 131I and who could be treated with radioiodine had higher survival rates. Patients who achieved complete response following treatment of distant metastases had a 15-yr survival rate of 89%, while those who did not achieve complete response had a survival rate of only 8%. The survival rate improved with the year of discovery of distant metastases, after 131I total body imaging and serum thyroglobulin measurements were routinely used. PMID- 8691249 TI - Exposure to radioactive iodine-131 for scintigraphy or therapy does not preclude pregnancy in thyroid cancer patients. AB - Radiation is known to be mutagenic. The aim of the present study was to ascertain whether exposure to 131I induces genetic damage, as assessed by pregnancy outcomes and the health status of offspring of women previously exposed to 131I during thyroid carcinoma treatment. METHODS: Data on 2113 pregnancies were obtained by interviewing female patients treated for thyroid carcinoma who had not received any significant external radiation to the ovaries. RESULTS: The incidence of miscarriages was 11% before any treatment for thyroid cancer; this number increased slightly after surgery for thyroid cancer, both before (20%) and after (20%) 131I, but did not vary with the cumulative 131I dose. Miscarriages were more frequent (40%) in the ten women who were treated with 131I [mean dose: 3.8 GBq (108 mCi)] during the year preceding conception. Incidences of stillbirth, preterm birth, low birth weight, congenital malformation and death during the first year of life were not significantly different before or after 131I therapy. The incidence of thyroid disease and nonthyroidal malignancy was similar in children born either before or after their mothers were exposed to 131I. CONCLUSION: With the exception of miscarriages, there is no evidence that exposure to radioiodine affects the outcome of subsequent pregnancies and offspring. The question of whether an increased incidence of miscarriages within 1 yr of 131I administration relates to gonadal irradiation or to insufficient control of hormonal thyroid status remains to be established. PMID- 8691250 TI - Genetic risk assessment after iodine-131 exposure: an opportunity and obligation for nuclear medicine. PMID- 8691251 TI - Investigations of breast tumors with fluorine-18-fluorodeoxyglucose and SPECT. AB - METHODS: We designed a prospective study to investigate the feasibility of combined FDG-SPECT and whole-body acquisition in the diagnostic work-up of breast tumors applying visual analysis. We studied 50 patients with breast tumors of unknown histology. RESULTS: All malignant diseases were accurately detected in tumors > 2.3 cm, while the smallest FDG-positive lesion was 1.4 cm. In a subgroup of these patients, quantitative evaluation (tumor-to-back-group ratios) was added, which improved the sensitivity. Lymph node metastases were accurately indicated in 9 of 13 patients, while the detection of distant metastases depended on the location and size. False-positive FDG scans were observed in inflamed tissue, in a rapidly growing phylloides tumor and in supposedly healthy breasts. CONCLUSION: These results are comparable with prior investigations of other groups using PET. Therefore, FDG-SPECT and whole-body acquisition may be an adequate and less expensive technique to meet the increasing demand of FDG examinations. PMID- 8691252 TI - Dynamic indium-111-pentetreotide scintigraphy in breast cancer. AB - The efficacy of imaging breast cancer with 111In-pentetreotide (somatostatin receptor scintigraphy) was evaluate before surgery. METHODS: Seventy-one whole body scintigrams in 24 patients with known breast cancer and 24 whole-body scintigrams in 8 controls were obtained at 0.5, 5 and 24 hr after intravenous injection of 110 MBq 111In-pentetreotide. Anterior and posterior projection images were acquired simultaneously. SPECT of the thorax was performed at 5 or 24 hr after injection in all breast cancer patients. The specimens were imaged immediately after surgery and the distribution of pentetreotide was assessed qualitatively and quantitatively. RESULTS: Somatostatin receptor-positive tumors were found in 18/24 patients with breast cancer. Pentetreotide uptake was significantly greater in breast cancer patients compared to control patients. In all patients with positive images, the early scintigram (0.5 hr) showed abnormal uptake. It was possible to delineate three different dynamic patterns. Increased uptake was visually most distinct at each time (9 patients). Moreover, bilaterally increased pentetreotide uptake was observed in 10/18 true-positive patients (in 8 at each time and in 2 patients only at 5 hr), but only one patient had a known bilateral tumor. CONCLUSION: We found higher incidence of somatostatin receptors in patients with breast cancer than in the control group. Moreover, bilaterally increased pentetreotide uptake in clinically unilateral disease was an unexpected finding. PMID- 8691253 TI - Technetium-99m-MIBI scintimammography for suspicious breast lesions. AB - The aim of this study was to evaluate the diagnostic accuracy of scintimammography with 99mTc-MIBI in patients with suspected primary breast cancer as monitored by SPECT or planar imaging. METHODS: Patients with a suspect lesion detected by palpation or mammography were entered in the study. Excisional biopsy was performed on all patients and a mammography was performed within three weeks prior to scintigraphy. All patients received intravenously 740 MBq 99mTc MIBI in the arm, contralateral to the suspicious breast, and were subsequently examined in a prone position. At 5-10 min postinjection, planar images were obtained in both the lateral and anterior views with an acquisition time of 10 min. After planar imaging, SPECT imaging was performed using a two-head high resolution gamma camera. RESULTS: In the total patient group of 54 patients, 40 lesions were palpable and 14 were nonpalpable but were detected by mammography. Breast cancer was confirmed in 24 of the patients and 20 of the palpable masses were found to be carcinomas. The tumor size ranged from 6 to 90 mm in diameter. In scintigraphic studies, the overall sensitivity was 88% for planar imaging and 83% for SPECT. Specificity was 83% and 80%, respectively. Sensitivity for palpable lesions was 100%. The smallest detectable tumor measured was 9 mm in diameter and could only be visualized in the planar scintigram. CONCLUSION: Scintigraphy with 99mTc-MIBI is extremely sensitive for the detection of primary breast cancer in patients with a palpable mass. SPECT, however, did not improve the diagnostic accuracy over planar scintimammography. PMID- 8691254 TI - Technetium-99m-methoxyisobutylisonitrile in localization of ectopic parathyroid adenoma. AB - Preoperative localization of ectopic parathyroid lesions is crucial for the correct treatment of patients with primary hyperparathyroidism. Invasive and noninvasive procedures, including selective venography, ultrasound, CT and MRI provide limited sensitivity in the detection of ectopic lesions. We report three patients in whom 99mTc-MIBI scintigraphy accurately detected ectopic parathyroid adenomas and was instrumental in the cure for these patients. Technetium-99m-MIBI scintigraphy provides a simple and accurate noninvasive test for the detection of ectopic parathyroid adenomas. PMID- 8691255 TI - Disseminated bone marrow metastases of insular thyroid carcinoma detected by radioiodine whole-body scintigraphy. AB - We present 131I scintigraphic findings in a patient with insular carcinoma of the thyroid showing diffuse abnormal uptake throughout the skeleton. The scintigraphy closely resembled the pattern of [131I]MIBG distribution in children with bone marrow metastases of neuroblastoma. The extent of involvement was underestimated by bone scintigraphy and radiography. Insular carcinoma of the thyroid in the bone marrow was subsequently demonstrated by biopsy. The patient was treated with 242 mCi 131I given in two courses, which led to severe myelosuppression and died as a result of progressive disease and severe pancytopenia 10 mo after initial therapy. PMID- 8691256 TI - Pleuroperitoneal migration of intraperitoneal phosphorus-32-chromic phosphate therapy for stage I ovarian carcinoma. AB - A patient with postoperative Stage I ovarian carcinoma received 15 mCi of 32P chromic phosphate suspension in normal saline intraperitoneally as part of her therapy. The following day, a portion of the infused radiopharmaceutical and normal saline had passed transdiaphragmatically into the patient's right pleural cavity. Thoracentesis removed as much fluid as possible and this fluid contained radioactive material. In the ensuing 4 yr, the patient has not manifested any detectable pleural or pulmonary abnormalities attributable to the radioactivity. Retrospective review of 100 consecutive patients receiving 32P-chromic phosphate intraperitoneal therapy resulted in 43 patients in whom the hemithoraces could be evaluated scintigraphically. Three of the 43 patients (7%) had right pleural fluid radioactivity. This is similar to the percentages reported in patients with cirrhosis with ascites in whom hepatic hydrothorax is identified. PMID- 8691257 TI - Intestinal leakage of technetium-99m-MDP in primary intestinal lymphangiectasia. AB - We present a case in which a patient with primary intestinal lymphangiectasia demonstrated abnormal intestinal accumulation of tracer during 99mTc-methylene diphosphonate (MDP) skeletal scintigraphy. Early intestinal leakage with gradual colonic migration and concentration was confirmed by repeat bone scan with serial acquisitions. The mechanism for the intestinal localization of 99mTc-MDP seen in this patient is not clear. Thus, intestinal lymphangiectasia can be a cause for extra-osseous localization of bone scan agents in the intestine. PMID- 8691258 TI - Fulminant hepatic failure monitored by technetium-99m-DTPA-galactosyl-human serum albumin scintigraphy. AB - We describe a 43-yr-old woman with fulminant hepatic failure whose progress was monitored scintigraphically using 99m-Tc-galactosyl-human serum albumin (99mTc GSA). On admission, the liver was atrophic and the heart was delineated distinctly by scintigraphy with 99m-Tc-GSA. The receptor index, calculated by dividing the radioactivity of the liver region of interest by the radioactivity of the liver plus heart regions of interest at 15 min post-tracer injection, was very low. As the patient's condition improved, the right lobe of the liver enlarged while the left lobe became atrophic; after 4 mo, the left lobe almost completely disappeared. Delineation of the heart gradually became less distinct, and the receptor index slowly increased. Hepatic receptor imaging with 99m-Tc-GSA can define both the hepatic functional reserve and morphological changes of the liver, so it is useful for the diagnosis and follow-up study of fulminant hepatic failure. PMID- 8691259 TI - Positive technetium-99m-red blood cell gastrointestinal bleeding scan after barium small-bowel study. AB - A 53-yr-old man with hepatic insufficiency and portal hypertension was hospitalized and underwent a work-up for gastrointestinal bleeding requiring multiple transfusions. The initial evaluation included a negative upper and lower endoscopy and a barium exam of the small bowel. Both studies failed to demonstrate any pathology to explain the bleeding. Immediately following the barium study, the patient had active bleeding. Because of the significant amount of intestinal barium, angiography was deferred. Technetium-99m-red blood cell (RBC) scintigraphy was undertaken to identify the site of bleeding. Despite intestinal barium, the 99m-Tc-RBC scan demonstrated an active bleeding site in the small bowel in the left abdomen. Therefore, 99mTc-RBC scintigraphy can be of clinical utility for identification of gastrointestinal bleeding, despite the presence of intestinal barium. PMID- 8691260 TI - Tumoricidal cytokines enhance radioiodine uptake in cultured thyroid cancer cells. AB - We explored whether the stimulation of iodine uptake by interferons seen in rat thyroid cell line is reproducible in human thyroid cancer and thus applicable to enhance the efficacy of radioiodine therapy. METHODS: Surgical specimens from 12 papillary and 2 follicular adenocarcinomas were minced and seeded in culture trays. After 14-16 days in a medium supplemented with 5% calf serum, we measured cellular uptake of 125I during a 40-min incubation period. RESULTS: In 8 of 12 papillary and all 2 follicular carcinomas, interferon-gamma significantly stimulated iodine incorporation. The four nonresponder tumors had lower basal iodine uptake and relatively less differentiation of histologic features. The effect was dose dependent (0-100 U/ml), and the average maximum increase in responding cases was 35.1% over basal values. Tumor necrosis factor-alpha alone did not alter uptake, but at 300 U/ml it further enhanced the effect of interferon-gamma in the two follicular tumors. In addition to the pure cytokines, supernatant from lymphocyte culture conditioned with a bacterial immunostimulator also boosted radioiodine trapping in thyroid cancer cells. CONCLUSION: These in vitro results warrant animal experiments to test potential usefulness of tumoricidal cytokines in radioiodine therapy. PMID- 8691261 TI - Brain acetylcholinesterase activity: validation of a PET tracer in a rat model of Alzheimer's disease. AB - We developed three radioactive acetylcholine analogs--N[14C]methyl-4-piperidyl acetate ([14C]MP4A), propionate ([14C]MP4P) and isobutyrate ([14C]MP4IB)--as radiotracers for measuring brain acetylcholinesterase (AchE) activity in vivo. The principle of our method is that the lipophilic analog diffuses into the brain where it is metabolized by AchE to produce a hydrophilic metabolite, which is trapped at the site of its production. The purpose of this study was to examine whether the tracers would have the sensitivity needed for early diagnosis of Alzheimer' disease using rats with a unilateral lesion in the nucleus basalis magnocellularis (NBM), an animal model of the cholinergic deficit in Alzheimer's disease. METHODS: Rats with a unilateral NBM lesion were prepared, and the N[14C]methyl-4-piperidyl esters and N-Isopropyl-p-[123I]iodoamphetamine([123I]IMP were injected intravenously 30 and 2 min, respectively, before the rats were killed. Uptake of 14C and 123I and AchE activity in the lesioned and unlesioned (control) sides of the cortex were measured simultaneously. RESULTS: The NBM lesion showed reduced cortical AchE activity by 30%-50%, with no side-to-side differences in [123I]MP uptake. Autoradiographic studies showed that uptake of 14C from [14C]MP4A and [14C]MP4P was significantly lower in the lesioned than unlesioned side of the cortex, which agreed well with the AchE histochemical staining patterns. Tissue dissection studies showed different uptake changes for the three compounds when AchE activity in the lesioned side of the cortex was reduced by 50%: 14C uptake from [14C]MP4P, [14C]MP4A and [14C]MP4IB was reduced by 27%, 21% and 7.3%, respectively. Theoretical analysis of the observed sensitivities of the tracers in relation to their in vitro enzymatic properties indicated that tracer sensitivity was highly dependent on the enzymatic hydrolysis rate of the tracer. CONCLUSION: The [14C]MP4A and [14C]MP4P esters had sufficient sensitivity to enable AchE activity changes in the rat cortex of less than 50% to be detected, indicating that the present method is applicable to PET diagnosis of Alzheimer's disease. PMID- 8691262 TI - Biodistribution of indium-111-labeled antibody directed against intercellular adhesion molecule-1. AB - We examined the biodistribution in normal rats of an 111In-labeled mouse monoclonal antibody to rat intercellular adhesion molecule-1 (111In-alCAM-1), as a potential detector of inflammation. METHODS: Indium-111-alCAM-1 or 111In labeled normal mouse polyclonal immunoglobulin G (111In-nmIgG) was injected into rats. Groups of three to four rats were killed up to 18 hr after injection, and activity was measured in various tissues. Rats were also imaged at 1 and 18 hr after injection. RESULTS: Uptake of 111In-alCAM-1 was greatest in the lung (approximately 10% injected dose [ID]/g at 15 min) and then declined steadily (to approximately 2% ID/g at 18 hr). Lung uptake of 111In-nmIgG was eightfold less than that for 111In-alCAM-1 and did not change throughout the 18 hr. At all time points, blood activity for 111In-alCAM-1 was only 30% to 40% of that for 111In nmIgG, whereas the percent injected dose per gram was increased more than twofold in the major organs. Compared with 111In-nmIgG, the 111In of alCAM-1 was shifted from the blood and was distributed among the lung kidney, spleen and liver. CONCLUSION: Indium-111-alCAM-1 may be useful as an early inflammation detection agent. Intercellular adhesion molecule-1 upregulation is a very early event in inflammation and rapid removal from the blood of this antibody provides low background in contrast to the usual high background with whole antibodies. PMID- 8691263 TI - HMPAO as a regional cerebral blood flow tracer at high flow levels. AB - HMPAO is being used extensively to image rCBF during focal seizures in humans. It is, however, theoretically possible that back-diffusion of tracer causes retention to fall as flow rises at high levels. METHODS: We used a double label 99mTc-HMPAO/14C-IAP autoradiographic technique to compare HMPAO retention and regional cerebral blood flow in penicillin induced focal seizures in rats. RESULTS: Using this protocol, flows of up to 717 ml/100 g per min were observed. The same pattern of uptake was seen on IAP and HMPAO autoradiographs, with the exception of relatively high HMPAO uptake in the choroid plexus, in the fissures and, in one animal only, the supramammilary nucleus. Correlation of HMPAO retention and blood flow showed a linear relationship up to 200 ml/100 g per min all animals. HMPAO retention then showed a falloff in its rise with blood flow, but was still increasing, even at the highest flows seen. At 700 ml/100 g/min, HMPAO retention was 20% of that expected from a linear relationship. CONCLUSION: HMPAO is a suitable tracer of rCBF at high flows and is unlikely to produce anomalous images in human focal seizures. PMID- 8691264 TI - Local concentration of folate binding protein GP38 in sections of human ovarian carcinoma by in vitro quantitative autoradiography. AB - Folate binding protein (FBP) GP38 is a membrane-associated glycoprotein that mediates the intracellular transport of folates. The enhanced expression of FBP in ovarian carcinomas provided a rational basis for clinical studies with specific monoclonal antibodies and some newly synthesized antifolate drugs. Because the outcome of these clinical studies ultimately depends on the degree of FBP expression, we measured the local concentration of FBP using 125I-MOv18 monoclonal antibody and quantitative autoradiography. METHODS: Tissue sections from 37 specimens of ovarian carcinoma and 13 nonmalignant ovaries were incubated with increasing concentrations of 125I-MOv18 with and without an excess of unlabeled antibody. Tissue-bound radioactivity was measured by quantitative autoradiography. RESULTS: Folate binding protein was found to be overexpressed in 91% of nonmucinous ovarian carcinomas, with local concentrations ranging between 1.14 and 82.84 pmole/g. Adjacent tumor sections simultaneously studied with 125I MOv18 and a 125I-labeled folic acid derivative showed matching and superimposable regional distributions of bound radioactivity of the two radioligands, indicating that the antigen, specifically recognized by 125I-MOv18 in nonmucinous ovarian carcinomas, is capable of binding folates. Nonmalignant ovaries did not contain measurable amounts of antigen when assayed with 125MOv18 but showed a limited and specific binding of the 125I-folic acid derivative to tissue sections. The autoradiographic findings were confirmed by testing sections from mixtures of antigen-positive and antigen-negative cells, by immunoperoxidase staining with MOv18 on tumor sections and by biochemical identification of FBP in membrane fractions from tissue samples. CONCLUSION: Folate binding protein is overexpressed up to 80-90-fold in nonmucinous ovarian carcinomas compared with nonmalignant ovaries. Quantitation of FBP may provide a useful tool in the design of clinical studies with specific monoclonal antibodies and certain antifolate drugs that enter the cell through FBP. PMID- 8691265 TI - Technetium-99m-white blood cell-specific imaging agent developed from platelet factor 4 to detect infection. AB - We have developed a leukocyte-avid, 99mTc-labeled peptide (P483H) as a potential imaging agent for infection. P483H contains the heparin-binding region of platelet factor-4 (PF-4) and a lysine-rich sequence for rapid renal clearance. Technetium-99m-P483H was evaluated for its ability to selectively label white blood cells (WBCs) in vitro and to detect focal E. coli infections in rabbits. METHODS: Technetium-99m-P483H was incubated with citrated whole human blood, layered onto WBC isolation media and subjected to density gradient centrifugation to measure WBC-associated radioactivity. Indium-111-WBCs and 99mTc-gluceptate were used as controls. In the in vivo model, E. coli infected rabbits were imaged and necropsied 4 hr after administration of 99mTc-P483H. Infected and contralateral control muscles were evaluated for %ID, %ID/g, Imax (muscle sample showing the highest uptake, i.e., %ID/g) and Imax-to-blood and Imax-to-control muscle ratios. Indium-111-WBCs, 111In-DTPA, 131I-albumin (HSA), 99mTc nanocolloid, 67Ga and 99mTc-gluceptate were evaluated as in vivo controls. RESULTS: Technetium-99m-P483H associated predominantly with WBCs in vitro, and 99m-Tc-P483H provided high contrast images of infection in vivo. In vitro, 73% of 99mTc-P483H radioactivity was associated with WBCs. Technetium-99m-P483H outperformed 111In-WBCs, 111In-DTPA, 131I-albumin, 99mTc-nanocolloid, 67Ga citrate and 99mTc-gluceptate with an infection Imax average of 0.062 %ID/g (+/- 0.029; n = 48). Technetium-99m-P483H also outperformed all controls, including 111In-WBCs, 111In-DTPA, 131I-albumin, 99mTc-nanocolloid, 67Ga-citrate and 99mTc gluceptate. The Imax-to-blood and Imax-to-control muscle ratios for 99mTc-P483H averaged 3.1 (+/- 2.4) and 26.8 (+/- 16.8), respectively, and again outperformed all controls. CONCLUSION: Technetium-99m-P483H associates predominantly with WBCs in vitro and identified focal infections in vivo within 4 hr versus conventional imaging agents. Additionally, the agent showed rapid blood clearance and exclusive renal excretion, which provides a clear abdominal field for imaging abdominal infections. PMID- 8691266 TI - Dual-tracer autoradiography with thallium-201 and iodine-125 metaiodobenzylguanidine in experimental myocardial infarction of rat. AB - Dual-isotope scintigraphic studies with 201Tl and radioiodinated metaiodobenzylguanidine (MIBG) suggest that acute myocardial infarction causes extensive regional myocardial denervation beyond the infarcted area. We therefore investigated the histopathological and biochemical significance of the discrepancy between 201Tl and 125I-MIBG distribution determined by dual-tracer autoradiography in experimental myocardial infarction. METHODS: Left coronary arteries of 12 male Wistar rats were ligated for 30 min followed by reperfusion. Dual-tracer autoradiography of infarcted heart sections was performed with 201Tl and [125I]MIBG 4 hr or 2 days after coronary reperfusion, followed by immunohistochemical staining with myoglobin monoclonal antibody to determine the area of myocardial infarction. Ultrastructural alterations and myocardial norepinephrine (NE) content in the region determined by dual-tracer autoradiography and myglobin immunostaining were studied. RESULTS: Thirty-minute coronary ligation with 4-hr reperfusion produced myocardial infarction associated with discrepant region in the peri-infarcted myocardium characterized by decreased [125I]MIBG uptake and normal 201Tl distribution (discrepant region), as determined by dual-tracer autoradiography. In the discrepant region, which disappeared after 2 days, the nerve terminals showed loss of granular cores, with normal structures between normal myocytes. The mean myocardial NE level in the discrepant region was significantly lower than that in the nonischemic region (255.2 +/- 85.9 versus 549.5 +/- 82.5 ng/mg). CONCLUSION: The uptake discrepancy of 201Tl and [125I]MIBG observed in the infarcted heart represents a transient functional denervation of the regional cardiac sympathetic nerve terminals in the noninfarcted myocardium. PMID- 8691267 TI - A robust edge detection method for gated radionuclide ventriculograms. AB - We present a myocardial edge detection technique that was developed for fast, reproducible measurements of left ventricular ejection fraction in the clinical setting. METHODS: This myocardial edge detection method compares three edge parameters--count amplitude and first and second count derivatives--in three consecutive locations along a radius to a predetermined template of these values. Each of the radii, defined at 10-degree intervals, has different template values that permit accurate edge detection even though adjacent structures, such as the left atrium and the right ventricle, alter edge parameters. The template for edge detection is based on either the average edge parameters determined from manually defined edges in 15 patients (automatic method) or an operator-defined edge in the first frame (semiautomatic method). RESULTS: The edge detection methods were tested in 100 patients, and intraobserver variabilities as well as comparison with clinically obtained ejection fractions were calculated. The standard error of the estimate was less than 3.1% for all observer comparisons. In 15 patients with both high-count (400,000 counts per image) and low count (50,000 counts per image) studies, the mean absolute difference in ejection fraction was 2.6% for intraobserver comparisons. CONCLUSION: A robust myocardial edge detection technique was developed that is applicable for routine clinical use. PMID- 8691268 TI - Effect of smoothing during transmission processing on quantitative cardiac PET scans. AB - The effects of attenuation in cardiac PET are large and are produced by varied and inhomogeneous attenuating media. Although a measured attenuation correction can potentially provide an exact correction for attenuation, it introduces noise into the attenuation-corrected emission scan. Transmission smoothing reduces this noise but can introduce error of its own. This study investigates these errors in absolute and relative quantitation and estimates their magnitude in a clinical setting. METHODS: Fluorodeoxyglucose cardiac PET scans of 24 subjects were processed using measured attenuation correction with different levels of transmission smoothing. Mean activity concentrations were determined in septal, anterior and lateral regions of the left ventricle at each level of transmission smoothing. A theoretical derivation of the effects of transmission smoothing is presented, so that the observed effects could be compared with theory-based predictions. RESULTS: In addition to the reduction of noise, transmission smoothing produced two further effects: (a) a previously unreported reduction in noise-induced bias, which is beneficial and (b) introduction of errors due to bad estimates of attenuation correction factors resulting from smoothing over regions where attenuation changes. The first effect was observed over all regions of the left ventricle, whereas the second reduced counts primarily in the lateral wall. Twenty-millimeter smoothing reduced noise-induced bias by an average of 4% (compared with 6-mm smoothing). This same smoothing caused an additional 9% decrease in the lateral wall as a result of the adjacent lung-lateral wall boundary. CONCLUSION: Transmission smoothing reduces both noise and noise-induced bias, but near transitions between differently attenuating media (e.g., lung myocardial borders) may produce errors in absolute and relative quantitation. The data presented here document the magnitudes of these effects, permitting one to ensure that artifactually introduced inhomogeneities are kept small. PMID- 8691269 TI - Bone marrow dosimetry: regional variability of marrow-localizing antibody. AB - In radiolabeled antibody therapy, imaging and biopsy-based methods are used to estimate marrow activity concentration when the administered antibody localizes to the marrow. Absorbed dose estimates obtained using such measurements may be subject to large variability due to the potential for regional differences in marrow activity concentration. This variability was examined in ten patients with leukemia after administration of 131I-labeled HuM195 antibody. METHODS: Regions of interest were drawn around the head and neck of the humerus and femur (both sides) and around lumbar vertebra 3 (L3) and 4 (L4) on a series of planar images collected at multiple times postadministration of the antibody. A single exponential fit to each attenuation-corrected, time-activity curve was obtained to estimate clearance half-life and the back-extrapolated percent injected activity. RESULTS: The activity concentration in the femoral head and neck (mean and s.d. = 0.04 +/- 0.02 %ID/g) was not significantly different than that measured in L3 and L4 (0.06 +/- 0.02% ID/g) but was not significantly lower than the concentrations measured in the humeral head and neck regions (0.07 +/- 0.03 %ID/g, p < 0.05). Although half-life estimates differing by more than a factor of 2 were observed in half-life between regions overall. S-factors were used for individual marrow regions to determine the mean absorbed dose to marrow in the femoral and humeral heads and the lumbar vertebrae (L3 and L4) which were 0.66 +/ 0.3, 1.0 +/- 0.3 and 2.2 +/- 0.5 mGy/MBq (2.4, 3.8 and 8.3 rad/mCi), respectively. CONCLUSION: A single value is generally quoted for the absorbed dose delivered to the red marrow following marrow-localizing radiolabeled antibody administration. These results suggest that the regional marrow dose may differ significantly from the mean. PMID- 8691270 TI - Modeling alternatives for cerebral carbon-11-iomazenil kinetics. AB - The in vivo binding kinetics of [11C]iomazenil, a central benzodiazepine antagonist, were analyzed using PET and compartmental modeling. This method is of interest because it allows validation of the SPECT tracer [123I]iomazenil. METHODS: The experimental protocol consisted of serial PET imaging following a single bolus injection of the serial PET imaging following a single bolus injection of the radioligand. Imaging was performed on five healthy young volunteers over 106 min. The tissue time-activity curves of various brain regions were analyzed with models consisting of two (K1, k2") and three (K1, k2', k3', k4) compartments. Some of the methods use simultaneous fitting of the data from multiple brain regions coupled with common parameters. Distribution volumes and k3-based parameters [(K1/k2') k3' and k3')] were chosen to represent receptor density. Goodness of fit was assessed with F-test statistics and chi-square analysis. RESULTS: Compared with the two-compartment model, goodness of fit was significantly improved by all three-compartment configurations. Of the three compartment models, goodness of fit was similar for the configurations with K1/k2', k4 or no parameter coupled, and slightly worse when both parameters were coupled. The most reliable estimates of receptor density were obtained from the specific distribution volumes (DVs) calculated with the three-compartment model, and the coupling of k4 or both k4 and K1/k2'. Due to oversimplification of the kinetics, the DV values calculated with the two-compartment model were underestimated. CONCLUSION: Reliable quantitative information regarding benzodiazepine receptor density following bolus injection of iomazenil is best obtained by tracer kinetic modeling that uses a three-compartment model and parameter coupling. PMID- 8691271 TI - Differentiation of infected from noninfected rapidly progressive neuropathic osteoarthropathy. PMID- 8691272 TI - Primary care for women. Management of common problems of the head and neck. AB - As the companion article to Part I of the Journal of Nurse-Midwifery (JNM) series on "Primary Care for Women: Comprehensive Assessment of the Head and Neck", the pertinent primary care management steps involved in the prevention and treatment of problems of the head and neck in women are addressed. Emphasis is placed on the diagnosis and management of the most common head and neck illnesses; less common diagnoses that may be acute, seasonal, and/or life-threatening are also presented. Collaborative roles in the management of women with problems of the head and neck are discussed, and emphasis is placed on the importance of both preventive strategies and coordination of referrals. PMID- 8691273 TI - Primary care for women. Assessment and management of headache. AB - Headache is the seventh leading presenting complaint for ambulatory care encounters in the United States, which accounts for 18.3 million, or 43.2 per 1000, outpatient visits per year. Headache disorders have historically been difficult to tract and study. This problem has been greatly ameliorated since the development, in 1988, of the international headache classification of the International Headache Society. Tension-type headache and migraine headache predominantly affect women, whereas cluster headache predominantly affects men. Advances both in diagnosis and in treatment modalities such as prophylactic treatments, stress reduction and biofeedback, and the use of sumatriptan, have helped to make the management of headache appropriate for nurse-midwives in the primary care setting. PMID- 8691274 TI - Primary care for women. Comprehensive assessment and management of common mental health problems. AB - This article emphasizes the importance of the role of the certified nurse-midwife (CNM) in the primary care assessment of, and appropriate referral for women with mental health problems, especially in cases of psychiatric emergencies. Essential aspects of assessment, diagnosis, and treatment of the more common psychiatric problems are included, and the treatment modalities that are considered when referral results in psychiatric intervention are reviewed. In addition, the overall prevalence of mental health problems in women, the frequency with which primary care providers may encounter mental health problems, and issues of mental health care utilization are discussed. PMID- 8691275 TI - Primary care for women. Management of common respiratory problems. AB - This article reviews the clinical management of common respiratory illness that primary care providers encounter in an outpatient setting. The latest recommendations from the American Thoracic Society, the National Heart, Lung, and Blood Institute, and the Centers for Disease Control and Prevention are summarized. The article discusses the causative organisms and antibiotics of choice for community-acquired pneumonia, and how to determine which patients require hospitalization. The appropriate use of asthma medications is described in detail, along with strategies for reducing aeroallergen exposure and for educating patients. An extensive section covers the interpretation of tuberculin skin tests and use of prophylactic isoniazid for prevention therapy of latent tuberculous infection, as well as the treatment of active tuberculosis. Controversies regarding antibiotics for both acute and chronic bronchitis are discussed along with other treatment options including over-the-counter medications, bronchodilators, and non-pharmacologic interventions. Finally, a strategy for dealing with the complaint of chronic cough is outlined. Although many of these conditions require active comanagement by collaborating physicians, the nurse-midwife will be better able to communicate with an advocate for her clients if she possesses expanded and current knowledge of treatment strategies. PMID- 8691276 TI - Primary care for women. Management and treatment of gastrointestinal disorders. AB - This article outlines the clinical management of common gastrointestinal disorders encountered in the primary care setting. The general assessment of a woman presenting with a gastrointestinal concern is reviewed. Diagnosis and management of acute and chronic diarrhea, constipation, irritable bowel syndrome, and anorectal disorders are covered with emphasis on client education. Gastroesophageal reflux disease and peptic ulcer disease is discussed with the latest treatment recommendations for Helicobacter pylori infection outlined. Diagnosis of gallbladder disease and gallstones with alternative treatment options is reviewed. Finally, the diagnosis and management of viral hepatitis is outlined. A case study is given to illustrate the basic principles needed by the nurse-midwife in the assessment, diagnosis, and management of a woman with a gastrointestinal concern. PMID- 8691277 TI - Primary care for women. Management of common musculoskeletal disorders. AB - This article provides a review of common adult musculoskeletal disorders including diagnosis and treatment guidelines to assist certified nurse-midwives in their role as primary care providers. Disorders requiring referral as well as signs and symptoms indicating potentially serious underlying problems are emphasized. PMID- 8691278 TI - Primary care for women revisited. Nurse-midwifery management of common health problems. PMID- 8691279 TI - Primary care for women. Health assessment, health promotion, and disease prevention services. AB - This report describes the health assessment, health promotion, and disease prevention practices of certified nurse-midwives (CNMs) working in ambulatory care settings. Survey questionnaires were sent to a stratified systematic random sample of American College of Nurse-Midwives (ACNM) members. Respondents were asked to identify the proportion of clients in their practices for whom certain health assessments and health promotion activities were routinely provided. Sixty six percent of the targeted sample were eligible providers of ambulatory care and returned a completed questionnaire. Results indicate that CNMs meet or approach current national targeted goals for many health assessment and health promotion services. Areas for further improvement are discussed. PMID- 8691280 TI - Primary care for women. Cultural competence in primary care services. AB - The assessment of cultural competence in providing primary care services for women is addressed. Emphasis is placed on the ways in which cultural competency attainment can ensure the availability of key primary care components to all women, especially those from certain vulnerable populations and those who have specific primary health care needs. A cultural competence continuum is described that will assist providers in an assessment of their own cultural competency levels, as well as those of the service settings in which they practice. Six scenarios are provided, describing experience at each level of the continuum that may hinder the development and delivery of effective primary care service interventions. Examples of ways in which nurse-midwives can provide leadership in the area of cultural competence in women's primary care are also included. PMID- 8691281 TI - The difficult patient: prevalence, psychopathology, and functional impairment. AB - OBJECTIVE: To determine the proportion of primary care patients who are experienced by their physicians as "difficult," and to assess the association of difficulty with physical and mental disorders, functional impairment, health care utilization, and satisfaction with medical care. DESIGN: Survey. SETTING: Four primary care clinics. PATIENTS: Six-hundred twenty-seven adult patients. MEASUREMENTS: Physician perception of difficulty (Difficult Doctor-Patient Relationship Questionnaire), mental disorders and symptoms (Primary Care Evaluation of Mental Disorders, [PRIME-MDI]), functional status (Medical Outcomes Study Short-Form Health Survey [SF-20]), utilization of and satisfaction with medical care by patient self-report. RESULTS: Physicians rated 96 (15%) of their 627 patients as difficult (site range 11-20%). Difficult patients were much more likely than not-difficult patients to have a mental disorder (67% vs 35% [corrected], p < .0001). Six psychiatric disorders had particularly strong associations with difficulty: multisomatoform disorder (odds ratio [OR] = 12.3. 95% confidence interval [CI] = 5.9-26.8), panic disorder (OR = 6.9, 95% CI = 2.6 18.1), dysthymia (OR = 4.2, 95% CI = 2.0-8.7), generalized anxiety (OR = 3.4, 95% CI = 1.7-7.1), major depressive disorder (OR = 3.0, 95% CI = 1.8-5.3), and probable alcohol abuse or dependence (OR = 2.6, 95% CI = 1.01-6.7). Compared with not-difficult patients, difficult patients had more functional impairment, higher health care utilization, and lower satisfaction with care, whereas demographic characteristics and physical illnesses were not associated with difficulty. The presence of mental disorders accounted for a substantial proportion of the excess functional impairment and dissatisfaction in difficult patients. CONCLUSIONS: Difficult patients are prevalent in primary care settings and have more psychiatric disorders, functional impairment, health care utilization, and dissatisfaction with care. Future studies are needed to determine whether improved diagnosis and management of mental disorders in difficult patients could diminish their excess disability, health care costs, and dissatisfaction with medical care, as well as the physicians experience of difficulty. PMID- 8691282 TI - The inability of physicians to predict the outcome of in-hospital resuscitation. AB - OBJECTIVE: To measure the accuracy, reliability, and discrimination of physicians' predictions of the outcome of in-hospital cardiopulmonary resuscitation (CPR), using a large series of detailed clinical vignettes of patients with known outcomes. DESIGN: Faculty and resident physicians at three university-affiliated generalist training programs were given one-page summaries of admission data for patients who later underwent in-hospital CPR. These summaries included all pre-arrest variables known to be related to the outcome of CPR. Physicians were asked to estimate the probability that patients would survive the resuscitation long enough to be stabilized, and the probability of survival to discharge. SETTING: Patient cases were derived from a consecutive series of patients undergoing CPR at two urban teaching hospitals in Detroit, Michigan. PARTICIPANTS: Faculty members and residents at a university-based department of internal medicine and two university-based departments of family medicine were surveyed. INTERVENTIONS: Accuracy of the physician predictions was assessed by comparing the mean predicted probability of survival with the percentage of patients who actually survived. The reliability of probability estimates of survival was evaluated by assessing the numerical proximity of the estimates to the actual outcome of the resuscitative effort. The ability to discriminate between survivors and nonsurvivors was measured by comparing the mean predicted probability of survival for those patients who survived CPR with that for those who did not, and by stratifying physician predictions and measuring the area under a receiver operating characteristic (ROC) curve. MEASUREMENTS AND MAIN RESULTS. Physicians (n = 51) made a total of 713 estimates, and showed poor accuracy, reliability, and discrimination in predicting the outcome of in-hospital CPR. The mean predicted probability of survival to discharge did not differ between patients who actually survived to discharge and those who did not (29.5% vs 26.4%, z = 0.35, p = .73). Similarly, the mean predicted probabilities of surviving resuscitation were the same for patients who actually survived long enough to be stabilized and those who did not (37.8% vs 39.9%, z = 0.55, p = .58). Accounting for type of physician and institution by analysis of variance did not change this finding. The area under the ROC curve for the prediction of arrest survival was 0.476, which is not significantly different from 0.5, and is consistent with an ability to discriminate between survivors and nonsurvivors that is no better than random choice. CONCLUSIONS: Physicians were no better at identifying patients who would survive resuscitation than would be expected by chance alone. Further work is needed to establish which variables are used by physicians in the decision-making process, and to design educational interventions that will make physicians more accurate prognosticators. PMID- 8691283 TI - Using severity measures to predict the likelihood of death for pneumonia inpatients. AB - OBJECTIVE: To see whether predictions of patients, likelihood of dying in hospital differed among severity methods. DESIGN: Retrospective cohort. PATIENTS: 18,016 persons 18 years of age and older managed medically for pneumonia; 1,732 (9.6%) in-hospital deaths. METHODS: Probability of death was calculated for each patient using logistic regression with age, age squared, sex, and each of five severity measures as the independent variables: 1) admission MedisGroups probability of death scores; 2) scores based on 17 admission physiologic variables; 3) Disease Staging's probability of mortality model; the Severity Score of Patient Management Categories (PMCs); 4) and the All Patient Refined Diagnosis-Related Groups (APR-DRGs). Patients were ranked by calculated probability of death; 5) rankings were compared across severity methods. Frequencies of 14 clinical findings considered poor prognostic indicators in pneumonia were examined for patients ranked differently by different methods. RESULTS: MedisGroups and the physiology score predicted a similar likelihood of death for 89.2% of patients. In contrast, the three code-based severity methods rated over 25% of patients differently by predicted likelihood of death when compared with the rankings of the two clinical data-based methods [MedisGroups and the physiology score]. MedisGroups and the physiology score demonstrated better clinical credibility than the three severity methods based on discharge abstract data. CONCLUSIONS: Some pairs of severity measures ranked over 25% of patients very differently by predicted probability of death. Results of outcomes studies may vary depending on which severity method is used for risk adjustment. PMID- 8691284 TI - Comparing comorbid-illness indices assessing outcome variation: the case of prostatectomy. AB - OBJECTIVE: We investigated and compared the effects of three different comorbid indices on selection of procedure and outcome variation to determine which, if any, could be used for interpreting outcomes data. DESIGN: Retrospective cohort study. SETTING: Large multispecialty group practice. PATIENTS: Patients (aged 55 85 years) with residence in the United States who underwent a first-time prostatectomy for benign prostatic hyperplasia: 302 total; 253 transurethral procedures (TURF) versus 49 open procedures (OP). MEASUREMENTS AND MAIN RESULTS: The following indices were used to assess comorbid disease: Charison index (CI), index of coexistent disease (ICED), and Kaplan-Feinstein index (KFI). The main outcome measure was the five-year mortality rate. The unadjusted five-year mortality rates were 16% (40/ 253) for TURP and 4% (2/49) for OP; survival analysis revealed this difference to be marginally significant at the p = -05 level. In an effort to control for the effect of comorbidity, CI, ICED, and KFI were independently assessed: together with age, they each had similar effects in rendering the risk of death associated with procedure type insignificant. However, comorbidity, as derived with ICED (not CI or KFI), was identified as a confounding variable when assessing the five-year mortality rate after prostatectomy as ICED was associated with the procedure type (predictor variable) and the five-year mortality (outcome variable). CONCLUSION: Differences in the composition and scoring of comorbid indices may have important implications for interpreting outcomes data. Nevertheless, these results, together with those of previous studies, suggest that the reported increased mortality for patients undergoing TURP is probably due to case-mix differences. PMID- 8691285 TI - The exclusion of non-English-speaking persons from research. AB - OBJECTIVE: We sought to determine how often non-English-speaking (NES) persons are excluded from medical research. DESIGN. Self-administered survey. PARTICIPANTS: A Medline search identified all original investigations on provider patient relations published in major U.S. journals from 1989 through 1991, whose methodologies involved direct interaction between researcher and subject (N = 216). Each study's corresponding author was surveyed; 81% responded. MEASUREMENTS AND MAIN RESULTS: Of the 172 respondents, 22% included NES persons; among these includers, 16% had not considered the issue during the study design process, and 32% thought including the NES had affected their study results. Among the 40% who excluded the NES (excluders), the most common reason was not having thought of the issue (51%), followed by translation issues and recruitment of bilingual staff. The remaining 35% (others) indicated that there were no NES persons in their study areas. CONCLUSIONS: NES persons are commonly excluded from provider patient communication studies appearing in influential journals, potentially limiting the generalizability of study findings. Because they are often excluded through overnight, heightened awareness among researchers and granting institutions, along with the development of valid instruments in varied languages, may increase representation of non-English-speaking subjects in research. PMID- 8691286 TI - Identifying domestic violence in primary care practice. AB - OBJECTIVE: To improve detection of domestic violence as a problem for women seeking primary care, we compared the addition of a single question about domestic violence on an existing self-administered health history form, to discretionary inquiry alone. We studied 689 consecutive new women patients in an internal medicine practice. Domestic violence identification rose from 0% in the control group with discretionary inquiry alone to 11.6% (95% confidence interval 8.8-14.4%) when the health history form included the following question: "At any time has a partner ever hit you, kicked you, or otherwise physically hurt you?" The addition of a single question can increase identification of domestic violence as a problem in patients' lives. PMID- 8691287 TI - Cytomegalovirus polyradiculopathy in HIV-infected patients. AB - Cytomegalovirus polyradiculopathy, a late complication of HIV infection, is characterized by lower extremity weakness, urinary retention, and sacral dysesthesias. We describe four patients (mean CD4 T-cell count = 25 cells/mm3) who developed this "infectious cauda equina syndrome." The characteristic cerebrospinal fluid (CSF) findings, notably atypical for a viral infection, included polymorphonuclear leukocytosis (mean white blood cell count = 1512 cells/mm3, 72% polymorphonuclear leukocytes), elevated protein level (mean = 370 mg/dl), and hypoglycorrhacia (mean = 28 mg/dl). Physicians who treat patients with HIV should be familiar with this syndrome because early intervention, prior to microbiologic confirmation, provides the best hope for improving neurologic function. PMID- 8691288 TI - Strategies in writing for a physician audience. PMID- 8691290 TI - Non-English-speaking patients a challenge to researchers. PMID- 8691289 TI - Psychiatric problems in primary care patients. PMID- 8691291 TI - Hiccups: a curious phenomenon. PMID- 8691292 TI - The impact of media coverage on practice. PMID- 8691293 TI - Inflating physicians' expectations. PMID- 8691294 TI - New paradigms for disease management. PMID- 8691295 TI - The prevalence of mental disorders in rural office practice. AB - OBJECTIVE: To determine the prevalence of mental disorders in rural primary care office practice. DESIGN: Patient interview; chart review. SETTING: Two rural primary care office practices. PATIENTS: Three hundred-fifty scheduled or walk-in patients age 18 years or older. MEASUREMENTS: Medical Outcomes Study 36-Item Short-Form Health Survey (MOS SF-36), the Primary Care Evaluation of Mental Disorders (PRIME-MD), physical health using Greenfield's index of coexistent disease (ICED), and health care utilization using the number of office visits and total office and laboratory charges six months before until six months after the interview. RESULTS: Of these patients 34% met criteria for one or more of the 18 mental disorders evaluated by the PRIME-MD; 19% met criteria for specific disorders according to criteria from the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R). Mood disorders were most common (21.7%), followed by anxiety disorders (12.3%), somatoform disorders (11.1%), probable alcohol abuse or dependence (6.0%), and eating disorders (2.0%). By logistic regression, there was an association of age, sex, race (black), and education with lower prevalence of various mental disorder categories. Even after adjustment for demographic variables and physical health (ICED score), those with PRIME-MD diagnoses had significantly lower function as measured by the eight MOS SF-36 scales and higher utilization of office services (p < .001). CONCLUSIONS: The prevalence of mental disorders in rural primary care office practice is as high as in urban office practice. PMID- 8691296 TI - Whose home health care? PMID- 8691297 TI - Health maintenance organizations in Oklahoma. PMID- 8691298 TI - G. Rainey Williams, MD. The importance of doing it right. PMID- 8691299 TI - Successful urgent cerclage in a quadruplet gestation. AB - Pregnancies complicated by quadruplets are rare but at high risk for premature cervical dilation, premature deliveries, and increased perinatal mortality. This report presents a case of a patient carrying quadruplets whose cervix became 4 cm dilated at 21 weeks even though there were no reported uterine contractions. Despite bed rest and combination tocolytic therapy, the cervix dilated to 6 cm and the membranes protruded. Described here are refinements of an Olatunbosun technique to successfully perform the cerclage. Labor occurred at 32 weeks, and a cesarean delivery was performed before the transvaginal removal of the cerclage. The four appropriately-grown fetuses adjusted well in the intensive care nursery. PMID- 8691300 TI - OSDH nutrition program successful in reducing childhood anemia rate. PMID- 8691301 TI - [Twenty-one cases of malignant tumor of the external auditory canal or middle ear]. AB - Between 1982 and 1994, 21 patients with malignant tumors of the external auditory canal and middle ear were treated at the Department of Otolaryngology, Niigata University. Eleven patients with tumors of the external auditory canal and 10 tumors of the middle ear were registered. There were 9 males and 12 females, and their ages ranged from 10 to 80 years (median: 61). Otalgia, otorrhea or bloody otorrhea were the chief complaints of most patients with external auditory canal of middle ear tumors. Pathological examination revealed squamous cell carcinoma in 16 patients, adenoid cystic carcinoma in 3 patients, and basal cell carcinoma and rhabdomyosarcoma in 1 patient each. External auditory canal tumors were surgically excised, while radical mastoidectomy and subsequent irradiation were performed for the middle ear tumors. The five-year survival rate determined by the Kaplan-Meier method, was 77.8% for patients with external auditory canal tumors and 40% for those with middle ear tumors. PMID- 8691302 TI - [Patency of the ostium of the frontal sinus after endoscopic endonasal surgery for chronic sinusitis]. AB - We examined the patency of the ostium of the frontal sinus after endoscopic endonasal surgery for chronic sinusitis. This study involved one hundred and seventy-two nasal sides of ninety cases who underwent surgery in this unit in the preceding three-year period by the designated three surgeons. All patients were followed up for more than one year after surgery. We obtained a high postoperative patent rate of 90.1%. However, communication between the frontal and ethmoidal sinus could not be confirmed in 9.9% of the cases due to the presence of polyp or adhesion in the middle meatus. Cases with preoperative severe lesion of the frontal sinus showed significantly lower rates of patent than cases with preoperative mild and/or no lesion. In cases where the opening of the ostium could not be sufficiently widened during surgery because the size around the ostium was already small, lower patent rates resulted. However, even in such cases, scraping or curetting of the surrounding bone should be avoided, because it may cause postoperative narrowing of the ostium due to new bone formation. Cases with unsatisfactory results caused by pathological changes in the middle meatus showed significantly lower patent rates than cases with satisfactory postoperative results. It is recommended that accurate cleaning of the ethmoid sinus and adequate postoperative treatment be considered important. Endoscopic endonasal opening of the ostium of the frontal sinus is shown to be a safe and reliable procedure, which can be performed with clear visualization. PMID- 8691304 TI - [Middle ear cholesteatoma caused by cannonball foreign bodies impacted in the bony eustachian tube: a case report]. AB - We present a 76-year-old male patient with adhesive-type cholesteatoma and with metal foreign bodies which were shown to be located in the bony eustachian tube by computed tomography. He sustained a burn injury of the left tympanic membrane when he was struck by a bomb 52 years ago, during World War II. The cannonball fragments that entered the tympanic cavity were apparently transported to and stuck in the eustachian tube isthmus by mucociliary action after spontaneous closure of the tympanic membrane perforation. Persistent tubal obstruction due to the impacted foreign bodies and surrounding granulation tissue seems to have caused chronic adhesive otitis, leading to cholesteatoma which developed in the attic and mastoid antrum. No foreign bodies became visible after cholesteatoma removal by an intact canal wall technique in conjunction with anterior tympanotomy for wide exposure of the supratubal recess and the tympanic osteum of the eustachian tube. Therefore, anterior tympanotomy was further extended anteriorly to open the enlarged bony eustachian tube, allowing visualization and safe removal of two cannonball-fragments firmly impacted within it. We call this surgical approach to the bony eustachian tube "extended anterior tympanotomy". The transmastoidal accessibility of the bony eustachian tube produced by this technique should be assessed by preoperative computed tomography. PMID- 8691303 TI - [Treatment of bilateral neck metastases in laryngeal cancer]. AB - Laryngeal cancer is one of the most curable malignancies. One of the reasons is that most of them are in the early stage. However, the prognosis of advanced bilateral neck metastases is still poor. Based on loco-regional failure and cause of death, the effective procedure of neck dissection and the efficacy of postoperative irradiation were investigated retrospectively. A total of 1022 patients with laryngeal squamous cell carcinoma were registered in our hospital between 1979 and 1991, 58 of them (5.7%) had bilateral neck metastases. Clinical N2c cases accounted for 52% (32/58). In the other patients, the metastatic nodes were revealed by elective neck dissection for a clinically negative neck. The T stages of the 58 cases were as follows; T2 in 14 cases, T3 in 22 and T4 in 22. Forty-nine of the patients treated curatively by bilateral neck dissection were analyzed, 48 with total laryngectomy and 1 with partial laryngectomy. The remaining 9 patients were excluded because of radical irradiation in 3, distant metastases found the diagnosis in 3, unresectable recurrent neck metastases treated in other hospitals in 2 and no treatment because of severe myocardial infarction in 1. Cumulative crude and cause-specific 5-year survival rates for the 49 patients were 32.2% and 52.2%, respectively. Nineteen patients died of their disease; 10 of them of an uncontrolled neck lesion. From a comparison of the surgery alone group (28 cases) with a surgery plus irradiation group (21 cases) which consisted of preoperative irradiation in 2 and postoperative in 19, addition of irradiation may be effective for loco-regional control. Eight patients died of an uncontrolled neck lesion in the surgery alone group, while there were only 2 deaths in the postoperative irradiation group. Nevertheless there were no significant differences in survival: the cumulative crude and cause specific 5-year survival rates in the surgery alone group were 34.4% and 56.2%, respectively, while those in the surgery plus irradiation group were 28.6% and 46.3%, respectively. It is obvious that the procedure of neck dissection influenced the loco-regional control. Excluding the recurrence-free patients who died of intercurrent diseases within 2 years, recurrence in the ipsilateral neck was found in 1 of 12 patients with radical neck dissection (RND), in 1 of 3 with modified radical neck dissection (MRND), in 2 of 15 with lateral neck dissection (lateral ND) and in 9 of 11 with regional neck dissection (regional ND). Recurrence is the contralateral neck were found in none of 2 with RND, of 3 with MRND and of 20 with lateral ND, but in 6 of 16 with regional ND. These results suggest that regional ND was insufficient to accomplish loco-regional control in those patients and that lateral ND or MRND or RND may be required bilaterally. Since 1986, all patients except 1 were treated by more extensive maneuvers than lateral ND bilaterally, so that loco-regional recurrence was found in only 1 case, in spite of the fact that the surgery alone group accounted for 73% (19/26). Cumulative crude and cause-specific 5-year survival rates for the patients prior to 1985 (23 cases) were 26.1% and 32.6%, respectively, while those for the patients since 1986 (26 cases) were 38.5% and 76.9%, respectively. There was no significant difference (p = 0.73) in cumulative crude 5-year survival rates between the 2 groups, but the difference in their cause-specific 5-year survival rates was statistically highly significant (p = 0.0032). It was concluded that lateral ND, MRND or RND should be required bilaterally for the patients with bilateral neck metastases and that addition of irradiation is not always indispensable for patients treated by curative neck dissection, such as lateral ND, MRND or RND. PMID- 8691305 TI - [Clinical characteristics of chronic sinusitis with different lower respiratory tract diseases]. AB - We determined the clinical characteristics of chronic sinusitis in patients with different lower respiratory tract diseases. Sinusitis was divided into three groups. The first group was sinusitis with bronchial asthma. The second group was sinusitis with chronic bronchitis, bronchiectasis or diffuse panbronchiolitis. This type of sinusitis is generally called sinobronchial syndrome (SBS). The third group was sinusitis without lower respiratory tract disease. Because the pathogenesis of these lower respiratory tract diseases differs with the diseases, the pathogenesis of sinusitis accompanied by these lower respiratory tract diseases also may be different. Clinical and laboratory examinations used in this study were rhinoscopy, X-ray examination of the paranasal sinuses, cytological study of nasal secretion and the saccharin test for the muco-ciliary function of the nasal mucosa. By rhinoscopic examination, no difference was found in the size of the nasal polyp among three groups. The results of other examinations were as follows. X-ray examination: Involvement of the ethmoid sinuses was greater than that of the maxillary sinuses in the patients with sinusitis with bronchial asthma. In contrast, involvement of the maxillary sinuses in SBS patients was greater than that of the ethmoid sinuses. Cytology of nasal secretion: Dominant inflammatory cells in the patients with sinusitis with bronchial asthma were eosinophils, while neutrophil were more frequently found in the SBS patients. Saccharin test: Most of the patients with bronchial asthma showed normal responses. In the SBS patients, however, only a few patients showed a normal response and the others showed prolonged responses. Clinical characteristics of the patients with sinusitis without lower respiratory diseases were more similar to those of the SBS patients. In conclusion, there were distinct differences in these clinical characteristics between sinusitis with bronchial asthma and SBS. These results suggest that the pathogenesis or the inflammatory process of sinusitis is heterogeneous and whether the inflammation is allergic or not may be important. PMID- 8691306 TI - [Clinical investigations of five patients with intracranial lesions presenting tinnitus]. AB - We investigated 5 patients with intracranial lesions. The initial complaint was tinnitus with normal hearing or sight sensorineural hearing loss. The lesions were 2 cerebello-pontine angle meningiomas, 1 cerebello-pontine angle epidermoid cyst, 1 supratentorial falx meningioma and 1 dural arteriovenous malformation at the temporal bone. Because of pulsatile or severe persistent tinnitus, we performed CT and MRI to determine the presence of intracranial lesions. Some patients had an episode of cerebral infarction and the complaint of headache or head heaviness. Quantitative measurement of tinnitus showed a low-frequency character in a pitch-match examination and moderate loudness in loudness balance. In the patients with falx meningioma and dural arteriovenous malformation, the tinnitus character was pulsatile and abnormal blood flow might have affected the peripheral auditory system. On the other hand, in the patients with a cerebello pontine angle tumor, the tinnitus character was non-pulsatile and compression on the central auditory system by the tumor might have caused the tinnitus. PMID- 8691307 TI - [A case report of congenital stapes fixation accompanied by symphalangism and hypermetropia]. AB - A 32-year-old female with bilateral congenital stapes fixation accompanied by bilateral proximal symphalangism and bilateral hypermetropia is reported. This is the 19th case of congenital stapes fixation and symphalangism in Japan. Hypermetropia was speculated to be one of the cardinal symptoms of the disease based on the present case and cases previously reported. In this case hypermetropia was due to pure microphthalmos and this was the first report that revealed the cause of hypermetropia in the syndrome. Bilateral stapedotomy were carried out and her hearing loss was improved to the satisfactory level. PMID- 8691308 TI - [Immunohistochemical study on subpopulations of B cells in the nasal mucosa]. AB - The subpopulations of B-lymphocytes in the inferior turbinates of 12 patients with allergic rhinitis and 3 patients with nonallergic nasal disease were studied by immunohistochemical procedures. The specimens were frozen at -70 degrees C and sliced at 4 microns with a cryostat. The LSAB method with monoclonal antibodies (CD4, CD8, CD20, CD40) was used to detect subpopulations of T-lymphocytes and B lymphocytes. In every subject the number of CD4 (+) cells dominated over that of CD8 (+) cells in the lamina propria. CD20 (+) cells were seen mainly in the border between the subepithelial layer and the nasal gland layer. CD40 (+) cells were found among the epithelial cells, the gland cells and the round mononuclear cells. In the serial sections CD20 (+) CD40 (+) cells were found in the inferior turbinates. We did not observe any difference in the distribution of CD20 (+) cells and expression of CD40 between allergic patients and nonallergic patients. Further study seems to be necessary to elucidate the relationship between CD20 (+) CD40 (+) cells and T-lymphocytes and some cytokines. PMID- 8691309 TI - [Acoustic trauma and development of endolymphatic hydrops among the personnel in the self defense forces]. AB - An investigation was carried out among the military personnel in the Self Defense Forces to assess acoustic trauma in association with the onset of endolymphatic hydrops (ELH). Four hundred seventy servicemen were offered general physical examinations in an inpatient setting prior to their discharge from the SDF for mandatory age retirement. A questionnaire on the history of intense acoustic exposure and of dizzy spells was given to the same individuals. A routine ENT examination and audiography were performed for each of them. The following results were noteworthy: five men had a history of Meniere's disease, and 32.5 percent of those questioned had experienced dizzy spells. Hearing thresholds in those who reported that they had had dizzy spells were considerably higher than those who had not had such spells. Although a quantitative analysis as well as a well-established control study seems necessary to implicate acoustic trauma as one of the etiological factors of ELH, this study strongly suggests a relationship between acoustic trauma and development of ELH among the SDF personnel examined. PMID- 8691310 TI - [Imaging and functional diagnosis of acoustic neuroma (CT, MRI, ABR)]. PMID- 8691311 TI - CD 105 and angiogenesis. PMID- 8691312 TI - Lymphoid aggregates in bone marrow trephines: new approaches to a continuing problem. PMID- 8691313 TI - Molecular pathobiology and immunology of malignant mesothelioma. PMID- 8691314 TI - Positive correlation between apoptotic and proliferative indices in gastrointestinal lymphomas of mucosa-associated lymphoid tissue (MALT). AB - To understand the role of deregulation of apoptosis in the pathogenesis of gastrointestinal MALT lymphoma, apoptosis has been quantitatively studied in paraffin sections from 40 cases (19 low grade, 21 high grade). The extent of apoptosis was correlated with histological grade, proliferative activity as measured by immunostaining of Ki67 proliferation antigen, and the expression of bcl-2 and p53 oncoproteins, which are known to participate in the regulation of apoptosis. Both apoptotic and proliferative indices were significantly (P < 0.00001) higher in high-grade than in low-grade tumours. Overall, apoptotic indices were negatively correlated with bcl-2 expression, particularly in low grade tumours in which both strong bcl-2 expression and low levels of apoptosis were observed. Thus, the slow expansion of low-grade MALT lymphoma may partly result from a prolonged life-span of tumour cells, due to bcl-2-mediated blockage of apoptosis. No difference in apoptotic indices was found between p53-positive and p53-negative cases. Furthermore, correlation analysis revealed a significantly positive association between apoptotic and proliferative indices. This supports the current belief that the mechanisms controlling apoptosis and proliferation are both activated during the cell cycle and whether a cell enters the proliferation cycle or the apoptotic process depends on survival factors. PMID- 8691315 TI - Distinctive adhesion pathways are involved in epitheliotropic processes at different sites. AB - Intraepithelial migration of lymphoid cells (epitheliotropism) is a biological process that can be observed under various physiological and pathological conditions. Recently, epitheliotropism was proposed to be a multi-step process, involving interactions of lymphoid cells with both epithelial basement membrane (EBM) and epithelial cells. In the present study we analysed by immunohistochemistry the adhesion mechanisms that are potentially involved in epitheliotropism of lymphoid cells in various disorders, such as tonsillar hyperplasia, coeliac disease, malignant lymphomas of mucosa-associated lymphoid tissue (MALTomas), and mycosis fungoides (MF). The combinations of adhesion molecules expressed on the participating lymphoid and epithelial cells varied among these disorders. These findings suggest that the adhesion pathways utilized in epitheliotropism may be associated with the nature of the lymphoid cell (reactive or neoplastic/B or T) and/or the site of the epithelium involved. In some cases the specificity of the process was determined by the adhesion mechanism involved in the lymphocyte-EBM interaction, as in the case of alpha 3 beta 1 integrin/laminin-5 in MF, and in others by the adhesion mechanisms involved in the interaction between lymphoid and epithelial cells, such as alpha 4 integrin/VCAM-1 in tonsillar hyperplasia and alpha E beta 7/E-cadherin in coeliac disease. PMID- 8691316 TI - Expression of Bcl-2 protein in hyperplastic polyps, adenomas, and carcinomas of the colon. AB - The proto-oncogene Bcl-2 encodes a protein that protects cells from programmed cell death (apoptosis). The protein is expressed in the proliferative compartment of several normal tissues, including normal colonic crypts. The aim of this study was to test Bcl-2 expression in colorectal neoplasms, assuming that, as a regulator of apoptosis, it might be involved in the progression from adenoma to carcinoma. To this end, Bcl-2 reactivity was tested by immunohistochemistry in hyperplastic polyps, colonic adenomas, and carcinomas and its expression was compared with staining for the proliferation-associated Ki-67 antigen, using the MIB-1 antibody. Bcl-2 expression occurred in 2 out of 10 hyperplastic polyps and in 31 out of 35 (tubular, villous, and tubulovillous) adenomas, irrespective of their degree of dysplasia. Of ten carcinomas, only three were focally Bcl-2 positive, all moderately to well differentiated. In two of four carcinomas in Bcl 2-positive adenomas, no Bcl-2 staining was observed. High numbers of MIB-1 positive cells were found in all hyperplastic and neoplastic lesions, without apparent correlation between proliferation and Bcl-2 expression. These findings suggest that in the pathogenesis of hyperplastic polyps, increased crypt cell proliferation is primarily involved, but in some lesions decreased apoptosis may play a role. Furthermore, the increased Bcl-2 expression in adenomas but not in the majority of the carcinomas suggests either that decreased apoptosis is not usually involved in the pathogenesis of these lesions or that the regulation of apoptosis in colorectal epithelia involves additional regulatory factors. PMID- 8691317 TI - Lung tumours immunoreactive for parathyroid hormone related peptide: analysis of serum calcium levels and tumour type. AB - Secretion by tumours of parathyroid hormone-related peptide (PTHrP) in quantities sufficient to raise circulating levels results in the syndrome of humoral hypercalcaemia of malignancy (HHM). Since HHM is commonly associated with squamous carcinoma of lung and rarely with adenocarcinoma or lung neuroendocrine tumours, immunopositivity was related to tumour type, to assess whether this difference was due to a low general incidence of PTHrP expression in the latter two groups. Seventy-six of 82 tumours were immunopositive: 22 of 22 squamous carcinomas, 21 of 25 small cell lung carcinomas, 14 of 15 carcinoids, and 19 of 20 adenocarcinomas. These data confirm and extend previous observations on squamous and neuroendocrine tumours but are in contrast with previous findings in adenocarcinoma, which have suggested that only a small proportion of cases express the peptide. They suggest that the differences in incidence of HHM in the various tumour types are due to patterns of secretion, rather than differences in expression of PTHrP. The second aim of this study was therefore to assess whether tumours immunopositive for PTHrP, but not associated with HHM, might secrete PTHrP at levels which might result in more subtle changes in calcium metabolism. Preoperative calcium levels were analysed in a series of 56 patients with immunopositive lung tumours of all types. One small cell carcinoma was associated with hypercalcaemia, but there was no evidence of any other alteration in serum calcium. These data indicate that the majority of tumours expressing PTHrP do not secrete it in amounts sufficient to alter calcium metabolism. PMID- 8691318 TI - Prognostic value of MIB-1 in neuroendocrine tumours of the lung. AB - The spectrum of neuroendocrine lung tumours ranges from highly aggressive small cell carcinomas (SCLC) to carcinoid tumours (CD) of low malignant potential. Between these two extremes, the 'well-differentiated neuroendocrine carcinomas' (WDNEC) form a transitional group with uncertain biological behaviour. This study investigated the prognostic value of the proliferation marker MIB-1 (paraffin Ki 67) in 59 neuroendocrine lung tumours (32 SCLC, 13 WDNEC, 14 CD) by immunostaining of routinely processed paraffin sections. Morphometric evaluation was done by semi-automatic image analysis. The results were compared with survival data (mean follow-up: 42 months). The proliferation rates of the tumours as determined by MIB-1 immunoreactivity (MIB-1-PR) were significantly different between the tumour types (SCLC > WDNEC > CD) and showed a strong inverse correlation with survival time. In CD, the percentage of MIB-1-labelled nuclei never exceeded 1.1 per cent; higher values would therefore favour the diagnosis of WDNEC over that of CD. Among WDNEC, MIB-1 was able to differentiate a subgroup with excellent prognosis (MIB-1-PR: 0.3-3.4 per cent) from another subgroup with a death rate of 50 per cent (MIB-1-PR: 7.3-20.3 per cent). Within each tumour type, all patients without distant metastases at diagnosis survived when MIB-1-PR was < or = 9.4 per cent, suggesting a potential threshold for prognosis. Although the status of metastases are complementary prognostic indicators and are best used in combination to characterize the biological behaviour of neuroendocrine lung tumours. PMID- 8691319 TI - Interphase fluorescence in situ hybridization detection of t(2;13)(q35;q14) in alveolar rhabdomyosarcoma--a diagnostic tool in minimally invasive biopsies. AB - The identification of t(2;13)(q35;q14) is a useful aid in the accurate diagnosis of rhabdomyosarcoma, distinguishing it from other small round cell tumours and supporting the distinction between alveolar and embryonal forms. Cytogenetic analysis is difficult and with the increased use of minimally invasive biopsy methods and primary chemotherapy, adequate tumour material is not always available. To overcome these difficulties, two-colour interphase fluorescence in situ hybridization (FISH) to detect t(2;13)(q35;q14) was developed and its utility in assessing minimally invasive biopsies was investigated. Two cosmid clones which mapped proximal or distal to the breakpoint region 13q14 and one yeast artificial chromosome clone that mapped distal to the 2q35 breakpoint were identified. In interphase cells containing t(2;13)(q35;q14), the configuration of cosmid and yeast artificial chromosome signals demonstrated the presence of the translocation. Five cases of rhabdomyosarcoma were analysed by interphase FISH. The t(2;13)(q35;q14) was detected in all four alveolar tumours and was confirmed by cytogenetics in two cases, but was absent in one embryonal tumour. This sensitive detection method is applicable to minimal amounts of fresh or frozen tumour. PMID- 8691320 TI - p53 gene alterations and p53 protein in oral epithelial dysplasia and squamous cell carcinoma. AB - To examine the expression of p53 protein and gene alterations in oral epithelial lesions including epithelial dysplasias and primary squamous cell carcinomas, immunohistochemical and temperature gradient gel electrophoresis (TGGE) methods were applied to formalin-fixed and paraffin-embedded tissues. Morphologically normal mucosal epithelium stained negatively for p53 protein. Three out of 11 (27.3 per cent) epithelial dysplasias and 19 out of 57 (33.3 per cent) primary squamous cell carcinomas stained positively for p53 protein. Although more than half of the cases were positive for p53 protein in stage I, the positive cancer cases were found at other stages with variable frequency. Immunoreactive products were localized in the nucleus, especially in the basal and suprabasal layers. The analysis by TGGE revealed gene alterations in exons 5-8 in 3 out of 3 epithelial dysplasias and 17 out of 19 (89.5 per cent) primary squamous cell carcinomas which were immunohistochemically positive for p53 protein. These results suggest that p53 gene mutation may be involved in carcinogenesis in the oral squamous epithelium even in the early stage of the dysplasia-carcinoma sequence. PMID- 8691321 TI - The localization of p34cdc2 in the cells of normal, hyperplastic, and malignant epithelial and lymphoid tissues of the oral cavity. AB - The expression of p34cdc2 has been examined in normal, hyperplastic, and malignant oral epithelia and lymphoid tissues. Four monoclonal antibodies were prepared against Xenopus p34cdc2, three of which react specifically with human p34cdc2 and not with p33cdk2. These produced similar patterns of staining in both fixed and frozen sections of human material. Staining occurred mainly in the proliferative compartments of normal and hyperplastic tissues. In normal oral epithelia, parabasal and basal cells were the most strongly stained, with lighter cytoplasmic staining in lower prickle cells. In tonsillar germinal centres, a high proportion of cells was stained, with fewer positive cells in interfollicular zones, a distribution in keeping with the known pattern of cell proliferation. In normal cells, the intracellular location of p34cdc2 was cytoplasmic until early prophase, but in oral squamous cell carcinomas and lymphomas, it was located in both cytoplasm and nucleus during interphase and a larger fraction of cells was positive than in the equivalent normal tissues. Higher-grade neoplasms showed both a higher intensity of staining and a higher proportion of p34cdc2-positive cells. PMID- 8691322 TI - Immunohistochemical study of overexpression of fibroblast growth factor-1 (FGF 1), FGF-2, and FGF receptor-1 in human malignant salivary gland tumours. AB - Fibroblast growth factor-1 (FGF-1) and FGF-2 are broad spectrum mitogens. The expression of FGF-1, FGF-2, and their receptor, FGF receptor-1 (FGFR-1), was examined in malignant salivary gland tumours and normal salivary glands, using immunohistochemical methods. In seven cases of adenoid cystic carcinoma (ACC), both duct-like cells and modified myoepithelial cells were apparently immunopositive for FGF-1, FGF-2, and FGFR-1. In five cases of mucoepidermoid carcinoma (MC), all three types of tumour cells including epidermoid cells, and intermediate cells expressed immunoreactive FGF-1, FGF-2, and FGFR-1. In these malignant salivary gland tumours, increased expression of FGFR-1 correlated with the intensity of both FGF-1 and FGF-2 immunoreactivity. In contrast to malignant salivary gland tumours, eight cases of normal salivary gland showed negative immunostaining for FGF-1, FGF-2, and FGFR-1 while four cases were weakly immunoreactive for FGF and its receptor. These results demonstrate that malignant salivary gland tumours overexpress FGF-1, FGF-2, and FGFR-1 compared with normal salivary glands and suggest that these growth factors may play an important role in facilitating neoplastic progression in human salivary glands. PMID- 8691323 TI - Ki67 labelling index: an independent predictor of progression in prostate cancer treated by radical prostatectomy. AB - The clinical course of prostate cancer is highly variable and cannot satisfactorily be predicted by histological criteria alone. Both tumour cell proliferation and neuroendocrine differentiation have been suggested as additional prognostic parameters, neuroendocrine differentiation being considered to enhance tumour cell proliferation. This study investigated the prognostic value of tumour cell proliferation [Ki67 labelling index (LI), MIB 1] and neuroendocrine differentiation and their relationship to each other. One hundred and thirty-seven paraffin-embedded radical prostatectomy specimens were examined. Neuroendocrine differentiation was found in 58 per cent of cases, but was not associated with pTN stage, Gleason score, Ki67 LI, or tumour progression. Ki67 LI was not significantly associated with pTN stage or with Gleason score. High grade (P = 0.0005), advanced local stage (P = 0.0004), positive lymph nodes (P = 0.02), and high Ki67 LI (P = 0.0203) were predictors of tumour progression if univariate analysis was performed, but Cox stepwise regression showed that only advanced local stage (P = 0.0025) and Ki67 LI (P = 0.0105) were independent predictors of tumour progression, the relative risk being 3.6 and 2.5, respectively. It is concluded that Ki67 is an important prognostic marker in prostate cancer with a potential for routine application. PMID- 8691324 TI - RT-PCR detection of cytokine transcripts in a series of cultured human meningiomas. AB - The expression of cytokine transcripts has been investigated in a series of cultured human meningiomas using reverse transcriptase linked polymerase chain reaction (RT-PCR), which allowed simultaneous analysis of a range of cytokines. The main histological subgroups of meningioma were investigated; these included transitional, fibroblastic, and syncytial as well as atypical meningiomas. Meningiomas from each of the different histological subgroups were subjected to a standard tissue culture regime. Total RNA was extracted from representative cultures and reverse-transcribed to yield cDNA. PCR was performed using oligonucleotide primers designed to detect interleukin (IL)-1 alpha/beta to IL-8, transforming growth factor (TGF)beta 1-3, tumour necrosis factor (TNF)alpha/beta, and interferon (IFN)gamma. Transcripts for IL-3, IL-6, IL-8, and TGF beta 3 were detected in all cultures. Transcripts for the three isomers of TGF beta were expressed in the transitional and fibroblastic meningioma cells. TGF beta 2 and TGF beta 3 transcripts were expressed in the syncytial and TGF beta 1 and TGF beta 3 in the atypical meningioma cells. IL-1 beta transcripts were expressed in fibroblastic and atypical cultures and TNF beta transcripts were expressed in syncytial and transitional cultures only. Transcripts for IL-1 alpha, IL-2, IL-4, IL-5, IL-7, TNF alpha, or IFN gamma were not detected in any of the meningioma cultures. This investigation using cells cultured from a small number of tumours from each of the classic histological subtypes suggests that there is a distinct pattern of cytokine mRNA expression linked with histological classification. PMID- 8691325 TI - Three-dimensional reconstruction of benign lymphoid aggregates in bone marrow trephines. AB - Distinguishing between deposits of low-grade non-Hodgkin's lymphoma and benign lymphoid aggregates in bone marrow trephine sections is a recognized problem in haematopathology. To test the hypothesis that benign lymphoid aggregates do not make contact with a trabecular surface, three-dimensional models were constructed of five serially sectioned bone marrow trephines, containing a total of 19 lymphoid aggregates known to be benign. The computer-generated images showed that benign lymphoid aggregates were located in the central marrow space and did not become paratrabecular. This suggests that a paratrabecular location may help in some cases to distinguish deposits of low-grade non-Hodgkin's lymphoma from benign lymphoid aggregates. PMID- 8691326 TI - Anti-DNA autoantibodies stimulate the release of interleukin-1 and interleukin-6 from endothelial cells. AB - The pathogenetic mechanism of vasculitis in systemic lupus erythematosus (SLE) remains a subject of debate. Evidence for a direct pathogenetic role of anti double-stranded DNA antibodies (anti-dsDNA) is not strong. Supernatant concentrations of interleukin-1 beta and interleukin-6, and mRNAs encoding for interleukin-1 alpha and interleukin-1 receptor-1 were determined in cultured human umbilical vein endothelial cells (HUVEC), incubated with control IgG (n = 18), anti-dsDNA (n = 18), or IgG from the same lupus patient depleted of anti dsDNA by affinity chromatography (anti-dsDNA-dep-IgG). Compared with control IgG, there was a significant increase of supernatant interleukin-1 beta and interleukin-1 alpha mRNA in endothelial cells incubated with anti-dsDNA. The supernatant interleukin-1 beta and interleukin-6, and mRNAs encoding for interleukin-1 alpha and interleukin-1 receptor-1, were significantly elevated in endothelial cells incubated with anti-dsDNA, compared with those incubated with anti-dsDNA-dep-IgG. Pretreating HUVEC with native DNA before incubating with anti dsDNA did not result in an additive effect. These in vitro studies suggest that anti-dsDNA plays an important pathogenetic role in inducing inflammatory injury of vascular endothelium in SLE. PMID- 8691327 TI - The effect of various forms of heparin on the release of immune complexes from the surface of cultured mesangial cells. AB - Heparin is capable of enhancing the rate of release of antigen from nephritic rat kidneys. It also interferes with the binding of immune complexes by cultured glomerular mesangial cells. Postulating that these two effects might be related, we sought to determine what basic aspects of the molecular structure of heparin are responsible for the interference with binding in vitro. After cultured mesangial cells had bound radiolabelled synthetic immune complexes, heparin or a variety of structurally related molecules were added to the supernatant. De-N sulphated heparin, heparan sulphate, low molecular weight heparin, and low molecular weight dextran sulphate had no effect on immune complex binding. High molecular weight dextran sulphate was able, like heparin, to dislodge immune complexes from mesangial cells, suggesting that high molecular weight and high sulphation are required. These results differ from previous findings in vivo, suggesting that the effect of heparin in vivo is not due to interaction at the mesangial cell surface. Alternative explanations for the effect of heparin in the intact animal include destabilization of the immune complex structure or, more probably, an effect at the boundary between the immune complex deposit and the basement membrane. PMID- 8691328 TI - Cloning of the mouse fibronectin V-region and variation of its splicing pattern in experimental immune complex glomerulonephritis. AB - Increased mRNA and protein expression of extracellular matrix (ECM) components, including fibronectin, occurs during the development of glomerulonephritis and glomerulosclerosis in immunologically mediated kidney diseases. However, in addition to these quantitative changes in ECM expression, qualitative changes in these molecules may contribute to malformations in the composition of the glomerular matrix. These qualitative changes may include alterations in the splicing pattern of the V-region of fibronectin, since this region plays a role in its accumulation. The splicing patterns of this region have been studied in chronic graft-versus-host disease (GvHD) in mice, a model of lupus nephritis, and in chronic serum sickness (CSS) in rats, a model of immune complex nephritis. Cloning of the mouse fibronectin V-region from kidney tissue revealed 96.1 per cent homology with the corresponding domain in rat fibronectin. PCR (polymerase chain reaction) analysis of RNA from isolated glomeruli revealed three isoforms of this region in both mouse and rat fibronectin, namely inclusion or exclusion of the whole region, or exclusion of only the CS1 domain. In both models, increased exclusion of the V-region was observed early in the disease. However, in GvHD the splicing pattern returned to normal, whereas in CSS the shift persisted during the course of the experiment. Differentiated expression of fibronectin isoforms may exert an important effect on the structure and biological function of the glomerulus and may thus play a role in the development of glomerulonephritis and glomerulosclerosis. PMID- 8691329 TI - Hepatotoxicity and absorption of extrahepatic acetaldehyde in rats. AB - Acetaldehyde, the first metabolite of ethanol oxidation, has been proposed as a major initiating factor in ethanol-induced liver injury. The aims of this study were to examine whether acetaldehyde is absorbable from the digestive tract and whether, when delivered chronically in drinking water, it is capable of inducing liver injury in rats. Acetaldehyde concentrations in the rat portal and peripheral blood were measured by head space gas chromatography after intragastric (5 ml) and intracolonic (3 ml) administration of 20 mM acetaldehyde solution. In the hepatotoxicity study, rats were exposed to acetaldehyde (20 and 120 mM) delivered in drinking water for 11 weeks and histopathological changes in the liver were morphometrically assessed. Peak blood acetaldehyde levels were found at 5 min after acetaldehyde infusion and were 235 +/- 11 microM (mean +/- SE) after intragastric and 344 +/- 83 microM after intracolonic infusion of 20 mM acetaldehyde solution. The exposure of rats to 120 mM acetaldehyde solution for 11 weeks resulted in the development of fatty liver and inflammatory changes. Morphometric analysis showed significantly more fat accumulation in rats receiving 120 mM acetaldehyde solution (85 +/- 2 per cent of hepatocytes occupied by fat) than in rats receiving 20 mM acetaldehyde solution (38 +/- 11 per cent) or in controls (36 +/- 10 per cent). The dose of extrahepatic acetaldehyde (500 mg/kg per day) producing liver injury corresponds to only around 3 per cent of that derived from hepatic ethanol oxidation in animals receiving an ethanol containing totally liquid diet (15 g/kg per day). These results indicate that acetaldehyde delivered via the digestive tract can reach the liver by the portal circulation and that acetaldehyde of extrahepatic origin appears to be more hepatotoxic than acetaldehyde formed during ethanol oxidation within the liver. PMID- 8691330 TI - The sequential accumulation of genetic alterations characteristic of the colorectal adenoma-carcinoma sequence does not occur between gastric adenoma and adenocarcinoma. PMID- 8691331 TI - Regulation of apoptosis by Bcl-2 and its related proteins: immunochemical challenges and therapeutic implications. PMID- 8691332 TI - Early expression of bcl-2 protein in the adenoma-carcinoma sequence of colorectal neoplasia. AB - bcl-2 was originally identified as an oncogene involved in follicular lymphomas as a result of chromosomal translocation (14;18). It is now believed that bcl-2 is implicated in the regulation of cell death by inhibiting apoptosis and that its expression is not restricted to haematopoietic cells, but is also present in many epithelial and mesenchymal tissues. Recent studies have analysed the expression of this molecule in a variety of non-lymphoid malignancies including lung, breast, prostate, and nasopharyngeal carcinomas and neuroblastoma. In the present study, 50 colorectal adenomas, 10 hyperplastic polyps, and 142 carcinomas, including 25 arising from pre-existing adenomas, were examined using an antibody detecting the bcl-2 protein product. In non-neoplastic mucosa, bcl-2 was expressed in the crypt cells only, whilst the more differentiated surface epithelial cells lacked any demonstrable bcl-2. Forty-one of the 50 adenomas (82 per cent) and 48 of the 142 carcinomas were positive for bcl-2 expression. All hyperplastic polyps were negative. A reciprocal relationship was found between bcl-2 reactivity and p53 overexpression, as detected by DO7 antibody, in approximately 65 per cent of the cases. The bcl-2-positive/p53-negative subgroup showed a strong correlation (P = 0.0056) with negative lymph node status (Dukes' A and B), implying a less aggressive pathway of neoplastic transformation. PMID- 8691333 TI - Endotoxin- and cytokine-mediated effects on liver cell proliferation and lipid metabolism after partial hepatectomy: a study with recombinant N-terminal bactericidal/permeability-increasing protein and interleukin-1 receptor antagonist. AB - This study was performed to clarify the mechanisms underlying post-resection changes in liver cell proliferation and metabolism. To assess the role of gut derived endotoxaemia and endogenous cytokines in these changes, the effects of peri-operative treatment with either the lipopolysaccharide-neutralizing bactericidal/permeability-increasing protein or interleukin-1 receptor antagonist were investigated at 24 h after two-thirds hepatectomy in rats. Peri-operative treatment with either agent caused enhanced expression of proliferating cell nuclear antigen (PCNA) and reduced lipid accumulation. Activity of the hexose monophosphate shunt was significantly decreased after partial hepatectomy and restored by interleukin-1 receptor antagonist only. After partial hepatectomy, bile canalicular alkaline phosphatase activity was significantly increased in pericentral zones and redistributed to both bile canalicular and sinusoidal membranes of hepatocytes. These effects were not significantly influenced by either treatment. It is concluded that endotoxin restricts liver cell proliferation and leads to lipid accumulation following partial hepatectomy, and that interleukin-1 is a principal mediator in these processes. Furthermore, interleukin-1 mediates a repression of the pentose phosphate pathway. These changes may be of significance with respect to liver function, at least in the early phase after partial hepatectomy. PMID- 8691334 TI - Cells of the mononuclear phagocyte series differentiate into osteoclastic lacunar bone resorbing cells. AB - Although the osteoclast shares several features with other cells of the mononuclear phagocyte system (MPS), its precise cellular ontogeny is unknown, and its membership of the MPS is controversial. This study examined whether various cells of the MPS can be induced to differentiate into cells capable of the highly specialized osteoclastic function of lacunar bone resorption. We isolated mouse and rat monocytes, mouse (liver, peritoneal, alveolar, brain) tissue macrophages, and spleen and marrow haemopoietic cells, as well as foreign body macrophages and macrophage polykaryons derived from subcutaneous granulomas formed by implantation of latex beads and coverslips in mice. When these cells were incubated with UMR106 osteoblast-like cells on glass coverslips and human cortical bone slices in the presence of 1,25-dihydroxy vitamin D3 [1,25(OH)2D3] for 7 and 14 days, numerous tartrate-resistant acid phosphatase-positive cells formed in these co-cultures and scanning electron microscopy revealed extensive lacunar resorption of the bone surface. Bone resorption was seen as early as 4 days after monocytes were co-cultured with UMR106 cells. With the exception of bone marrow-derived cells, lacunar resorption was not seen in the absence of UMR106 cells. These findings show that a bone-derived stromal cell element is necessary for differentiation of monocytes and tissue and inflammatory macrophages into osteoclast-like cells capable of extensive lacunar bone resorption, and would argue in favour of osteoclast membership of the MPS. PMID- 8691335 TI - Ultrastructural change of the glomerular basement membrane in rats with Heymann nephritis revealed by ultrahigh resolution scanning electron microscopy. AB - To assess the relationship between the glomerular injury induced by immune complex deposition and proteinuria, ultrastructural changes of the glomerular basement membrane (GBM) were investigated in Heymann nephritis. Active Heymann nephritis was induced in rats by injecting them with tubular brush border antigen, known as Fx1A, emulsified in complete Freund's adjuvant (CFA). Measurement of urinary protein excretion and histological examinations were carried out for up to 15 weeks after immunization. Proteinuria developed in rats within 10 weeks of immunization and coincided with the development of subepithelial deposits with minimal spike-like basement membrane protrusion. Acellular glomeruli were prepared by detergent treatment and were subjected to tannic acid-osmium conductive staining prior to examination with an ultrahigh resolution scanning electron microscope (HSEM). HSEM of the acellular GBM prepared from control rats injected with CFA alone revealed a meshwork structure, with pores of about 9 nm in diameter. Proteinuric rats immunized with Fx1A showed a loosened meshwork structure, with pores of about 15 nm in the acellular GBM adjacent to the deposits. The newly formed GBM overlying the deposit consisted of a meshwork structure associated with unorganized thin fibrils. Ultrastructural changes were never seen in GBM devoid of deposits. These findings indicate that subepithelial deposits are closely involved in the development of proteinuria by injuring the size selectivity of the GBM. PMID- 8691336 TI - Practical histological microdissection for PCR analysis. AB - Recovery of cells by histological microdissection is increasingly used for analysis by polymerase chain reaction (PCR) or microchemical techniques. This paper describes techniques of histological microdissection. Sections of archival formalin-fixed, paraffin-embedded tissue up to 15 years old were mounted on plain glass slides. Sections 6-7 microns in thickness stained with toluidine blue were dissected under proteinase K buffer solution, using an electrolytically sharpened tungsten needle in a bacteriological loop-holder and a Leitz mechanical micromanipulator (model M). Detached cell groups were recovered in a silicone coated pipette tip for PCR analysis after digestion in 25-50 microliters of proteinase K (500/ml) in TRIS-HCl buffer (pH 8.3). Consistent amplification and analysis of microsatellite loci were obtained from 2 microliters of crude lysate using 28-30 cycles of PCR incorporating a 32P 5'-end-labelled primer, electrophoresis under denaturing conditions on 6 per cent polyacrylamide gels, and autoradiographic detection. PMID- 8691337 TI - Detection of herpes simplex virus DNA in spontaneous abortions from HIV-positive women using non-isotopic in situ hybridization. PMID- 8691338 TI - Genomic instability in colorectal carcinomas: comparison of different evaluation methods and their biological significance. AB - In order to demonstrate the relationship between microsatellite instability and other types of genomic instability, a series of 56 sporadic colorectal carcinomas was investigated by flow cytometrical ploidy analysis, oligonucleotide fingerprinting, and microsatellite polymerase chain reaction (PCR). Stabilization of the p53 gene product was analysed by immunohistochemistry and proliferative activity was determined flow cytometrically and by silver staining of nucleolar organizer regions (AgNORs). Of the 56 carcinomas, 11 (19 per cent) exhibited microsatellite instability; 33 of the cases were aneuploid (59 per cent) and 29 (52 per cent) showed alterations of the oligonucleotide fingerprints. There was a significant correlation of microsatellite instability with localization of these tumours proximal to the splenic flexure, diploid DNA content, and less frequent p53 stabilization. A solid growth pattern, mucinous differentiation, and a Crohn's-like lymphoid infiltrate were also characteristic for those tumours. The results demonstrate for the first time a significantly lower proliferative activity in tumours with microsatellite instability. Data obtained from DNA flow cytometry or from oligonucleotide fingerprinting did not correlate with such tumour characteristics. It is proposed that the use of microsatellite PCR facilitates specifically the detection of a group of colorectal cancers which may differ in pathogenesis and perhaps prognosis. PMID- 8691339 TI - Familial giant hyperplastic polyposis predisposing to colorectal cancer: a new hereditary bowel cancer syndrome. AB - A mother and five of her ten offspring developed colonic cancers, the mother and one of the offspring being younger than 50 years of age at diagnosis. Despite fulfilling the Amsterdam criteria for hereditary non-polyposis colorectal cancer (HNPCC), several features pointed towards the possibility that this represented a different syndrome of familial cancer. Most notable was the presence of large, multiple hyperplastic polyps and mixed polyps in four of the subjects whose pathology was available for review. In addition, three of the four subjects had cancers that were negative for DNA replication errors (RER-). The subject with an RER+ cancer had a second RER+ cancer and three adenomas, one in contiguity with the second cancer. This subject also had multiple, large hyperplastic polyps, thereby combining hyperplastic polyposis and a proneness to multiple RER+ tumours. One of the hyperplastic polyps was also RER+. Two of five young asymptomatic descendants have been found to harbour multiple colorectal polyps. It is suggested that giant hyperplastic polyposis is a new familial syndrome predisposing to colorectal cancer. PMID- 8691340 TI - BCL-2 immunoreactivity increases with severity of CIN: a study of normal cervical epithelia, CIN, and cervical carcinoma. AB - The presence of the BCL-2 protein, a marker for inhibition of programmed cell death, was studied in a series of routinely processed cervical tissues, consisting of normal endocervical (n = 40) and ectocervical epithelium (n = 27), squamous metaplastic epithelium (n = 30), CIN (cervical intraepithelial neoplasia) lesions (n = 32), and cervical carcinomas (n = 13). BCL-2 was strongly expressed in the basal cell compartment of normal ectocervical squamous epithelium and in nearly all reserve cells, while in endocervical columnar cells it was moderately expressed. In immature squamous metaplastic epithelium, BCL-2 expression varied. Half of the cases showed only basal cell staining, while the other half showed staining also in suprabasal layers. BCL-2 could be detected in all premalignant lesions, showing a striking increase in the number of positive cells with increasing severity of CIN, in combination with a mild increase in staining intensity. All adenocarcinomas were positive (n = 5), while five of eight squamous cell carcinomas expressed BCL-2. Based on these results, it is hypothesized that both the larger number of cells staining with BCL-2 in higher grades of CIN and the increase in staining intensity imply an increasing protection of these neoplastic conditions against programmed cell death. This protection facilitates not only continuing proliferation, but also the induction of genetic instability in dysplastic epithelial cells; it may thus reflect the greater capacity of the more severe CIN lesions to evolve into cervical carcinoma. PMID- 8691341 TI - Prognostic significance of the co-expression of p53 and c-erbB-2 proteins in breast cancer. AB - The immunohistochemical expression of p53 and c-erbB-2 gene proteins was examined in a series of 130 breast adenocarcinomas. This study intended to investigate whether the frequency of the altered expression of the tumour suppressor gene p53 and the overexpression of the oncogene c-erbB-2 in breast cancer tissue cells correlated with other variables known to affect the biological behaviour of these tumours and the overall survival of the patients (median follow-up time: 6 years). The expression of p53 protein and c-erbB-2 gene product was evaluated immunohistochemically. Expression of p53 protein was detected in 30 (23 per cent) of the neoplasms examined, while 26 (20 per cent) out of the 130 cases demonstrated positive c-erbB-2 immunoreactivity. There was a statistically significant association between p53 protein expression and primary tumour size, lymph node involvement, and oestrogen receptor positivity. The incidence of c erbB-2 positivity was significantly correlated with high tumour grade, axillary node invasion, large tumour size, and the absence of steroid receptors. p53 immuno-expression was clearly associated with c-erbB-2 protein overexpression. Concomitant p53 and c-erbB-2 positive immunolabelling, which emerged in 14 out of the 130 cases (10.7 per cent), was clearly associated with high grade, large size, positive nodal status, ductal infiltrating (NOS) histological type, and low values of progesterone receptors. Overall survival of patients was not significantly related to the immunoreactivity of either p53 or c-erbB-2 considered separately, whereas there was a clearly significant trend to worse overall prognosis in cancers with double p53/c-erbB-2 positive phenotype. The simultaneous immunodetection of p53/c-erbB-2 appears to have greater negative prognostic relevance than their separate expression. PMID- 8691342 TI - In situ analysis of tissue dynamics and p53 expression in human gastric mucosa. AB - In situ tissue dynamics were studied in 12 cases of human gastric mucosa, including normal gastric body mucosa and gastric glands with intestinal metaplasia, obtained from gastrectomy specimens of adenocarcinoma. Cell proliferation was determined by Ki67 immunoreactivity. DNA fragmentation was studied in situ by TdT-mediated dUTP-biotin nick end labelling (TUNEL). In addition, p53 expression was examined by both immunohistochemistry and mRNA in situ hybridization. In the oxyntic gastric glands, Ki67 immunoreactivity was observed exclusively in the proliferative zone and TUNEL-positive cells were present predominantly in the surface foveolar epithelium. In the gastric glands with complete intestinal metaplasia, Ki67-positive cells were present in the lower portion of the glands and TUNEL-positive cells in the superficial epithelium. In the gastric glands with incomplete intestinal metaplasia, TUNEL positive cells were detected in the lower gastric glands adjacent to cells immunoreactive for Ki67; the proportion of these gastric glands with TUNEL positive cells (40 out of 108 glands) was significantly higher than for oxyntic glands (94 out of 620 glands) or for glands with complete metaplasia (31 out of 254 glands). Relatively strong p53 immunoreactivity and mRNA hybridization were also observed in the proliferative and apoptotic areas of gastric glands with incomplete intestinal metaplasia. These results indicate that incomplete intestinal metaplasia is associated with increased cell turnover and p53 overexpression, possibly in response to various noxious or DNA-damaging stimuli. PMID- 8691343 TI - Extracorporeal gall bladder lithotripsy--a review of tissue and cellular effects. PMID- 8691344 TI - Decreased expression of galectin-3 is associated with progression of human breast cancer. AB - Galectin-3, a member of the beta-galactoside-binding lectin family, is involved in several biological events including binding to the basement membrane glycoprotein laminin. Although the exact role of galectin-3 during the interactions between cells and laminin is not yet known, it has recently been observed that its expression is down-regulated at both the protein and the mRNA level in colon cancer tissues in correlation with progression of the disease. This study investigated the possibility that breast cancer cells might also exhibit decreased galectin-3 expression in association with their aggressiveness. The expression of galectin-3 was examined by immunoperoxidase staining, using a polyclonal antibody raised against recombinant galectin-3, in a collection of 98 human breast lesions including 12 fibroadenomas, 15 fibrocystic disease lesions, 22 in situ carcinomas, and 49 infiltrating ductal carcinomas, 19 of which had positive axillary lymph nodes. Normal breast tissue adjacent to the lesions was present in 59 biopsies. Normal breast tissue expressed high levels (3+) of galectin-3. High expression (2+ to 3+) was also found in most benign lesions examined. The expression of galectin-3 was significantly decreased in in situ carcinoma and this down-regulation was more pronounced in invasive ductal carcinoma, particularly when associated with infiltration of axillary lymph nodes. These data constitute the first observation that galectin-3 is down regulated in breast cancer and suggest the decreased expression of this galactoside-binding lectin is associated with the acquisition of the invasive and metastatic phenotype. PMID- 8691345 TI - Splenic marginal zone expansion in B-cell lymphomas of gastrointestinal mucosa associated lymphoid tissue (MALT) is reactive and does not represent homing of neoplastic lymphocytes. AB - It has been suggested that lymphocytes of mucosa-associated lymphoid tissue (MALT) arise from marginal zone cells and that MALT-derived lymphomas may spread to other extra-nodal sites by homing to marginal zones in different tissues. Marginal zone expansion has been observed in spleens removed during surgery for gastrointestinal MALT lymphoma, which was sufficiently extreme in some cases to suggest neoplastic involvement. To investigate this phenomenon, polymerase chain reaction (PCR) amplification of immunoglobulin heavy chain gene fragments was performed to demonstrate B-cell clonality in gastrointestinal MALT lymphomas and spleens from 11 patients. Monoclonal PCR products were obtained from 9 of the 11 gastrointestinal tumours but from none of the accompanying spleens. One additional spleen, for which the accompanying gastric lymphoma tissue was unavailable for review, yielded a monoclonal product. However, obvious lymphoma deposits were present in this specimen, in addition to marginal zone enlargement. It is concluded that splenic marginal zone expansion accompanying gastrointestinal MALT lymphoma is correctly interpreted as being reactive. Splenic involvement by MALT lymphoma is uncommon and does not show preferential colonization of the marginal zone to suggest homing of MALT-derived cells to this site. PMID- 8691346 TI - Phenotypic modulation of Hodgkin and Reed-Sternberg cells by Epstein-Barr virus. AB - Expression of the Epstein-Barr virus (EBV) gene product LMP1 is found in tumour cells in varying proportions of Hodgkin's disease (HD) cases. It is not clear which cellular genes are influenced by EBV in HD. A total of 387 HD cases were tested for differences among LMP1-positive and -negative cases with respect to age, sex, histotype and immunophenotypic parameters (CD2, CD3, CD4, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD30, CD43, CD45RA, CD45R0, CD70, HLA-DR, T-cell receptor beta-chain, and p53 expression). Comparison of patient age and sex as well as distribution of histotype and tumour cell immunophenotype with published data suggests that the cases in this study are representative of the spectrum of HD in developed countries. LMP1 expression was found in 131/387 HD cases (36.4 per cent) with non-homogeneous distribution among HD histotypes, the mixed cellularity type (HDmc) being most frequently EBV-associated (71/129 cases, 55 percent). No relationship was found to age and sex. Significant phenotypic differences were restricted to the HDmc histotype, where the tumour cells expressed the activation marker CD30 in a larger proportion, and CD20 in a smaller proportion, when harbouring EBV. These results suggest that EBV may influence the tumour cell phenotype in HD. PMID- 8691347 TI - Monokine expression in Langerhans' cell histiocytosis and sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) AB - Langerhans' cell histiocytosis (LCH) is a clonal proliferation of Langerhans cells (LC) showing histologically an abundant reactive infiltrate composed of macrophages and lymphocytes, as well as eosinophilic and neutrophilic granulocytes. Rosai-Dorfman disease (RDD) shows a sinusoidal accumulation of large histiocytic cells with an immunophenotype similar to LC of LCH. The histological picture of LCH is reminiscent of an inflammatory disorder and LC may produce cytokines and are influenced by these soluble factors. This study set out to establish the monokine expression pattern in LCH in comparison with those of RDD; dermatopathic lymphadenopathy, which also shows a proliferation of S100 positive dendritic cells; and LC in normal skin specimens. Isotopic in situ hybridization was used for the detection of transcripts of tumour necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1 beta, in some cases combined with immunohistology for the S100 protein or CD68. In all 11 tissue samples from eight patients, LC of LCH expressed TNF-alpha; in two cases IL-1 beta transcripts were additionally noted in some LC, whereas IL-6 was found in reactive cells. Large histiocytic cells of RDD expressed all three monokines, whereas minimal or no expression of these cytokines could be detected in interdigitating reticulum cells in dermatopathic lymphadenopathy. In two out of five normal skin samples, only TNF-alpha specific signals were observed in LC. These data suggest that histologically different lesions of the histiocytic/dendritic cell system display distinct cytokine profiles. The expression of monokines, which have been demonstrated to influence various functions of epidermal LC, may play a role in the pathogenesis of LCH. Systemic symptoms in RDD may be related to enhanced production of monokines in these lesions. PMID- 8691348 TI - Expression of CD44 splice variants in squamous epithelia and squamous cell carcinomas of the head and neck. AB - Splice variants of the adhesion molecule CD44 have been described as essential for the lymphatic spread of rat tumour cells and are claimed to be involved in the metastatic spread of several human tumours. Immunohistochemistry has been used to analyse the expression pattern of CD44 standard (CD44s) and variant (CD44v) isoforms in normal and dysplastic squamous epithelia, as well as in primary and metastatic squamous cell carcinomas (SCCs), which spread predominantly by way of the lymphatic system. Frozen sections of squamous epithelia and of squamous cell carcinomas were stained with a panel of monoclonal antibodies recognizing epitopes of CD44s as well as of the variant exons v5, v6, v7, v7-v8, and v10. The stratum basale and stratum suprabasale of squamous epithelia stained with all antibodies; the stratum spinosum stained with anti CD44v5, anti-CD44v6, anti-CD44v7-8 and anti-CD44v10; the lower layers of the stratum corneum stained with anti-CD44v5. This expression profile was seen in epithelia of the lip, the tongue, the gingiva, the hard palate, the floor of the mouth, the buccal mucosa, and the pharynx. The same pattern of expression was also noted in dysplastic epithelia, but expression of the variant exons v7, v8, and v10 was significantly downregulated in primary squamous cell carcinomas and was not detected at all in the majority of metastasis-derived specimens. Expression of CD44v5 and CD44v6, on the other hand, was mainly unaltered. Thus, epithelial cell layers representing different stages of differentiation express distinct sets of CD44 variant isoforms, where especially exons v8-v10 might be required for the maintenance of the structural integrity of squamous epithelium. Downregulation of these exons on tumour cells could indicate that they are irrelevant for tumour progression or may even hamper infiltration of surrounding tissue or of lymphatics. PMID- 8691349 TI - CD44 is expressed in hepatocellular carcinomas showing vascular invasion. AB - CD44 and its variant isoforms are a group of transmembrane glycoproteins which play important roles in immune recognition, in lymphocyte trafficking, and in cell-cell and cell-matrix interactions. Although CD44 is expressed by some normal human epithelial and mesenchymal cells, upregulation of CD44 expression has been related to the metastatic potential of some malignant tumours. In this study of 27 hepatocellular carcinomas (HCCs), an indirect immunohistochemical method was used to investigate the distribution of CD44 in normal liver and to determine whether expression of the standard form of CD44 (CD44s), or two of its variant isoforms (CD44-v3 and CD44-v6), correlated with tumour grade, proliferation indices, or histological evidence of vascular invasion. Fifteen of the tumours were Edmondson grade II, four were grade III, and eight were grade IV. Liver cell dysplasia was present in adjacent liver parenchyma in three cases and vascular invasion was observed in ten HCCs. Vascular invasion was found to be more frequent in high grade HCCs and a significant correlation was observed between tumour proliferation indices and vascular invasion. CD44s was not expressed by epithelial cells of normal liver but was expressed by tumour cells in six HCCs; vascular invasion was present in five of these HCCs. Three CD44s-positive cases also expressed CD44-v3 and two of these also expressed CD44-v6. CD44 was not expressed in areas of hepatocyte dysplasia. There was a significant correlation between CD44 expression and the presence of vascular invasion, but not between CD44 expression and tumour grade or tumour proliferation indices. It is concluded that upregulation of cell surface CD44 expression on malignant hepatocytes is related to their tendency to vascular invasion and may have implications relating to metastasis and prognosis in patients with HCCs. PMID- 8691350 TI - Prognostic value of angiogenesis in operable non-small cell lung cancer. AB - Tumour angiogenesis is an important factor for tumour growth and metastasis. Although some recent reports suggest that microvessel counts in non-small cell lung cancer are related to a poor disease outcome, the results were not conclusive and were not compared with other molecular prognostic markers. In the present study, the vascular grade was assessed in 107 (T1,2-N0,1) operable non small cell lung carcinomas, using the JC70 monoclonal antibody to CD31. Three vascular grades were defined with appraisal by eye and by Chalkley counting: high (Chalkley score 7-12), medium (5-6), and low (2-4). There was a significant correlation between eye appraisal and Chalkley counting (P < 0.0001). Vascular grade was not related to histology, grade, proliferation index (Ki67), or EGFR or p53 expression. Tumours from younger patients had a higher grade of angiogenesis (P = 0.05). Apart from the vascular grade, none of the other factors examined was statistically related to lymph node metastasis (P < 0.0001). A univariate analysis of survival showed that vascular grade was the most significant prognostic factor (P = 0.0004), followed by N-stage (P = 0.001). In a multivariate analysis, N-stage and vascular grade were not found to be independent prognostic factors, since they were strongly related to each other. Excluding N-stage, vascular grade was the only independent prognostic factor (P = 0.007). Kaplan-Meier survival curves showed a statistically significant worse prognosis for patients with high vascular grade, but no difference was observed between low and medium vascular grade. These data suggest that angiogenesis in operable non-small cell lung cancer is a major prognostic factor for survival and, among the parameters tested, is the only factor related to cancer cell migration to lymph nodes. The integration of vascular grading in clinical trials on adjuvant chemotherapy and/or radiotherapy could substantially contribute in defining groups of operable patients who might benefit from cytotoxic treatment. PMID- 8691351 TI - Immunohistochemical loss of thyroid peroxidase in papillary thyroid carcinoma: strong suppression of peroxidase gene expression. AB - It is believed that qualitative changes in thyroid peroxidase (TPO) cause decreased enzyme activity in differentiated thyroid carcinoma. To re-evaluate TPO expression in thyroid cancer, TPO mRNA expression was compared with TPO protein expression in 38 samples of thyroid tissue obtained from patients with various thyroid diseases. In Northern blot studies, while TPO mRNA was highly expressed in tissues from all 18 benign lesions, it was strongly suppressed in 14 tumours, including 12 out of 12 papillary carcinomas, one of seven follicular carcinomas, and one medullary carcinoma. TPO mRNA was not detected in six carcinomas, of which four were papillary, one follicular, and one medullary, by the usual Northern blot method. The 14 cases with strong underexpression of TPO mRNA were very weakly stained with anti-TPO monoclonal antibody 38E, whereas all 18 benign tissues were strongly stained. Moreover, a comparative study of TPO expression by Northern blot and immunohistochemical analysis revealed a positive correlation between TPO mRNA expression and the staining intensity of TPO protein. These results suggest that strong suppression of TPO mRNA transcription causes low TPO activity in papillary carcinoma; immunohistochemical loss of TPO may be a useful diagnostic marker. TPO mRNA expression in differentiated thyroid carcinomas did not always correlate with the mRNA expression of thyroglobulin, thyroid stimulating hormone receptor, and thyroid transcription factor 1. PMID- 8691352 TI - Type-1 plasminogen activator inhibitor in human renal cell carcinoma. AB - In experimental models, plasminogen activator-mediated degradation of the extracellular matrix is inhibited by type-1 plasminogen activator inhibitor (PAI 1). PAI-1 has also been shown to protect tumour stromal tissue from autoproteolytic activities and may thus substantially promote tumour growth and metastasis formation. Human renal cell carcinoma (RCC) cells express significant amounts of plasminogen activator activity. In the present study, the expression of its specific inhibitor PAI-1 has been investigated in 32 cases of RCC and compared with adjacent non-tumour renal tissues. RCC tissue exhibited higher levels of PAI-1, determined at both the antigen and the mRNA level by ELISA and Northern blot analysis respectively. Immunohistochemical analysis showed that PAI 1 antigen was primarily confined to tumour cells and vascular endothelium, a distribution similar to that previously reported for plasminogen activator activity in RCC. The close co-localization with endogenous plasminogen activator activity may be important in the regulation of RCC-associated proteolysis. The increased expression of PAI-1 and its predominant localization within the tumour may help to conserve tumour tissue integrity and may thus promote RCC progression and metastasis formation. PMID- 8691353 TI - Slow fluorescent indicators of membrane potential: a survey of different approaches to probe response analysis. AB - Basic tenets related to the use of three main classes of potentiometric redistribution fluorescent dyes (carbocyanines, oxonols, and rhodamines) are discussed in detail. They include the structure/function relationship, formation of nonfluorescent (H-type) and fluorescent (J-type) dimers and higher aggregates, probe partitioning between membranes and medium and binding to membranes and intracellular components (with attendant changes in absorption and emission spectra, fluorescence quantum yield and lifetime). The crucial importance of suitable probe-to-cell concentration ratio and selection of optimum monitored fluorescence wavelength is illustrated in schematic diagrams and possible artifacts or puzzling results stemming from faulty experimental protocol are pointed out. Special attention is paid to procedures used for probe-response calibration (potential clamping by potassium in the presence of valinomycin, use of gramicidin D in combination with N-methylglucamine, activation of Ca-dependent K-channels by A23187, the null-point technique). Among other problems treated are dye toxicity, interaction with mitochondria and other organelles, and possible effects of intracellular pH and the quantity of cytosolic proteins and/or RNA on probe response. Individual techniques using redistribution dyes (fluorescence measurements in cuvettes, flow cytometry and microfluorimetry of individual cells including fluorescence confocal microscopy) are discussed in terms of reliability, limitations and drawbacks, and selection of suitable probes. Up-to date examples of application of slow dyes illustrate the broad range of problems in which these probes can be used. PMID- 8691354 TI - Impairment of phagocytic cell respiratory burst by UVA in the presence of fluoroquinolones: an oxygen-dependent phototoxic damage to cell surface microvilli. AB - Fluoroquinolones are widely used clinically as broad-spectrum antimicrobial agents. One of their side effects is UVA-dependent photosensitivity, observed after the skin is exposed to sunlight. We have investigated five fluoroquinolones and have found that their phototoxicity is oxygen dependent. Human phagocytic leucocytes were stimulated with serum opsonized zymosan to produce superoxide radical (O2-) (respiratory burst) in the presence of a sensitive O2(-)-specific cypridina luciferin analogue, 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazol (1,2-alpha) pyrazin-one hydrochloride (MCLA), as chemiluminescence reagent with which O2- can react to induce photon emission. The photon count was used as a measure of respiratory burst activity. When leucocytes were irradiated with UVA for 10 min in the presence of 3 micrograms ml-1 lomefloxacin, ciprofloxacin or norfloxacin, a marked decrease in respiratory burst activity was observed; in this respect, ofloxacin and tosufloxacin were weak. Scanning electron microscopy revealed that the cell surface microvilli were destroyed. The phototoxicity of fluoroquinolones could be abolished if oxygen in the tests was replaced by nitrogen or if the aminothiol DL-cysteine (1.5 mg ml-1) was added prior to irradiation. It is suggested that an oxygen species derived from UVA-excited drug molecules and oxygen mediates the phototoxicity of these fluoroquinolones. PMID- 8691355 TI - Phytochrome regulates phosphorylation of a protein with characteristics of a nucleoside diphosphate kinase in the crude membrane fraction from stem sections of etiolated pea seedlings. AB - The molecular mechanism of light signal perception via phytochrome was analysed using the third internodes of etiolated pea seedlings irradiated with red or red followed by far-red light. A crude membrane fraction prepared from the tissue was labelled by [gamma-32P]ATP at 4 x 10(-8) M for 15 s at 0 degree C, and the proteins were separated by two-dimensional gel electrophoresis. The phosphorylation of a protein with a molecular mass of about 15 kDa in the crude membrane fraction increased with an increase in the intensity of red light irradiation (10, 50 and 100 mumol m-2 s-1) for 20 s. Successive irradiation with red light (100 mumol m-2 s-1 for 20 s) and subsequent irradiation with far-red light reduced the phosphorylation of the protein, depending on the intensity of the far-red light (from 0.1 to 8 mumol m-2 s-1 for 180 s). A plasma membrane purified from the crude membrane fraction from red light irradiated tissue showed a rapid phosphorylation of the 15 kDa protein by 4 x 10(-8) M [gamma-32P]ATP at 0 degree C for 7 s, and subsequent addition of ATP, GTP, ADP or GDP at 10(-5) or 10(-6) M efficiently removed the phosphoryl group of the 15 kDa protein. The 15 kDa protein was autophosphorylated in the gel following separation by sodium dodecylsulphate (SDS) polyacrylamide gel electrophoresis. The partially purified 15 kDa protein included nucleoside diphosphate kinase (NDP kinase) activity, as well as cross-reactivity with an antibody specific to rat NDP kinase as assayed by immunostaining and crossreactivity with an antibody specific to ricet NDP kinase as assayed by immunoprecipitation. PMID- 8691356 TI - Effects of Photofrin on in vivo skin reflectivity. AB - Skin reflection spectra were measured before and 24 h after administration of Photofrin to nevoid basal-cell carcinoma syndrome patients. The presence of the drug reduced the reflectivity of uninvolved skin and increased the reflectivity of erythematous basal cell cancers. Data analysis with diffusion approximation and Monte Carlo simulation were employed to estimate the optical constant changes and localized drug concentration. PMID- 8691357 TI - Beta-carotene serum levels in patients with erythropoietic protoporphyria on treatment with the synthetic all-trans isomer or a natural isomeric mixture of beta-carotene. AB - The all-trans-beta-carotene serum level of patients suffering from erythropoietic protoporphyria increases substantially during continuous treatment with beta carotene (either with the synthetic all-trans compound or with beta-carotene from a natural source consisting of a cis-trans isomeric mixture). On continuous daily ingestion, the beta-carotene serum level rose from day 0 to day 30, and no further increase was observed between day 30 and day 150. Slightly lower beta carotene steady state serum levels were observed with the natural isomeric mixture than with synthetic beta-carotene. Higher levels of 13-cis-beta-carotene, in some cases up to 10% of the total beta-carotene, were detected after ingestion of the synthetic compound. The level of 9-cis-beta-carotene was below or close to the limit of quantification in all samples, even when the isomeric mixture containing high amounts of 9-cis-beta-carotene was applied. PMID- 8691358 TI - A cost-effectiveness analysis of anthelminthic intervention for community control of soil-transmitted helminth infection: levamisole and Ascaris lumbricoides. AB - A study to compare effects of mass, targeted, and selective chemotherapy with levamisole as an intervention for the control of Ascaris lumbricoides was carried out in 3 communities in rural Oyo State, Nigeria. Selective treatment was applied in 1 village by treating the most heavily infected 20% of the inhabitants, targeted treatment in the second village involved children aged 2-15 yr, whereas mass treatment was offered to all inhabitants in the third village, excluding infants under 1 yr and pregnant women. Intensity (eggs per gram,) of A. lumbricoides infection was determined immediately before and 3 mo after the period of intervention as a means of assessing the relative efficacy of the treatment regimes. During the field study, information on resource use was also collected for a retrospective cost analysis of the 3 strategies Resources used included manpower, materials, drugs, and transport. The results of the parasitological evaluation on the effect of treatment on egg intensity were then combined with the cost analysis to provide an overall measure of the cost effectiveness of mass, targeted, and selective interventions. The results were expressed in terms of the cost per 1,000 egg reduction in intensity and the cost per person treated. The results showed the mass and targeted approach to be considerably more cost effective than the selective approach. PMID- 8691359 TI - Alteration of host stage distribution by parasitic water mites of the species Hydrachna virella (Acari: Hydrachnidae). AB - The effect of a parasitic water mite, Hydrachna virella, on the stage distribution (the proportion of the host population represented by a stage) of its aquatic insect host, Buenoa scimitra, was studied using a stage-based matrix model. Despite killing members of several stages, the mite increased the stage distribution values of those stages. This effect seems to result from a lag in the rate of development of parasitized hosts; parasitized hosts remain in a stage longer. Consequently, a stage with parasitized individuals would represent a larger proportion of the host population than would the same stage with only unparasitized individuals. Parasites that delay host development can bias field estimates of prevalence or proportion of a host population (or stage) parasitized. PMID- 8691360 TI - Variations in microsatellite sequences provide evidence for population differences and multiple ribosomal gene repeats within Trichinella pseudospiralis. AB - Enzymatic amplification of expansion segment 5 sequences within domain IV of the large subunit ribosomal DNA generated distinct results among geographical isolates of Trichinella pseudospiralis from Russia, North America, and Australia from both avian and mammalian hosts. Discrete, multiple DNA fragments ranging in approximate size from 285 to 360 bp were observed within and among each of the isolates tested. Polymerase chain reaction performed on individual adult parasites from each isolate resulted in multiple DNA fragments that were comparable to those generated from pooled genomic DNA. Sequence analysis of cloned, representative amplified fragments demonstrated that fragment length variation resulted primarily from the dinucleotide (TG)n and trinucleotide (TGC)n microsatellite repeats present within the expansion segment. Results are consistent with both population differences within the species as well as the presence of multiple alleles of the large subunit ribosomal RNA genes within individual parasites. PMID- 8691361 TI - Rapid internalization and degradation of surface-bound antibodies by Tritrichomonas foetus. AB - Tritrichomonas foetus is a protozoan parasite of cattle that can be cultured axenically. Three monoclonal antibodies specific for surface antigens of T. foetus were found to be rapidly internalized and degraded by these cells after binding. Degradation was not due to secreted or artificially liberated proteases but depended on targeting to internal degradative compartments. Radiolabeled catabolites of the antibodies were subsequently incorporated into the parasite's own proteins. Antibody degradation could be inhibited by certain protease inhibitors or lowered temperatures; a sharp reduction in degradation between 20 C and 15 C was similar to a well documented block in endocytic transport to degradative compartments of mammalian cells. Growth and proliferation of T.foetus in the continuous presence of the antibodies appeared unhindered, but there was a general shift toward expression of both more and less of each epitope among cells within each population. Subclones of these populations always exhibited striking variability in epitope expression levels, with patterns similar to the parent cultures. These findings may lead to a better understanding of how T. foetus resists host immune responses. PMID- 8691363 TI - Schistosoma mansoni: in vitro and in vivo excretion of CAA and CCA by developing schistosomula and adult worms. AB - In this study we describe the excretion patterns of circulating anodic (CAA) and cathodic antigen (CCA) by freshly transformed and developing Schistosoma mansoni schistosomula and adult worms. In vitro, CAA and CCA were excreted by the parasites immediately after transformation. During the first days of development CAA and CCA levels were similar, but after 1 wk more CCA was excreted. Neither feeding the schistosomula with red blood cells nor addition of colchicine influenced the rates of antigen excretion. Female worms produced more antigen than males. In heavily infected mice CCA was the first antigen detectable from the third week of infection onward. A few days later, CAA showed a steep increase, becoming the predominant antigen during the course of infection. In urine samples, obtained at the time of perfusion (7 wk), CCA was the predominant antigen. In conclusion, although CAA and CCA levels in serum and urine generally correlate well with worm burden (as determined by egg output), the present study and a literature review show that the actual quantities produced by the worms and detected in the host circulation or excreta may depend on many factors, e.g., host and parasite species, clearance rates, or duration and intensity of infection. PMID- 8691362 TI - Effect of Brugia malayi on the growth and proliferation of endothelial cells in vitro. AB - Athymic mice (C3H/HeN) parasitized by Brugia malayi develop massively dilated lymphatics. The lymphatic endothelial lining is perturbed, and numerous mononuclear and giant cells are closely apposed to the endothelium. The hyperplastic endothelial cells and low opening pressure of the lymphatics suggest abnormal multiplication of these cells may be important in the dilation. We studied the in vitro growth rate of human umbilical vein endothelial cells cultured with adult worms and microfilariae of B. malayi. The tetrazolium salt reduction assays were used to quantify possible direct mitogenic or inhibitory effects. The growth factor-induced proliferation of endothelial cells was significantly suppressed by 44-51% on day 1, 46-81% on day 3, and 45-79% on day 5 in cultures containing adult female worms, which had greater suppressor activity on endothelial cell proliferation than male worms, microfilariae, or soluble adult worm extract. Culture supernatant containing female worm excretory secretory products significantly inhibited the growth and multiplication of cells, suggesting that adult female worms release antigens or proteins that have inhibitory activity on growth factors necessary for endothelial cell proliferation in vitro. Excess human recombinant epidermal growth factor and bovine brain extract partly reversed the inhibitory activity of worms in culture and restored the endothelial cell proliferation when incubated with worm culture supernatant. Indomethacin and BW 775Hcl failed to restore normal endothelial proliferation in the presence of female worms, suggesting that parasite-derived prostanoids and cyclooxygenase products did not cause the inhibition. Lymph from dilated lymphatics, but not serum from infected mice, increased the proliferation of cells in vitro. Together, these data demonstrate that excretory-secretory products of B. malayi parasites suppress vascular endothelial proliferation in vitro. Furthermore, increases in the number of these cells in vitro in the presence of lymph suggest that parasite-induced host factors may be important in modulating the degree of proliferation. PMID- 8691364 TI - The genus Hepatozoon (Apicomplexa: Adeleina). AB - Hemogregarines of the genus Hepatozoon are intraerythrocytic apicomplexan parasites that have been described from all groups of tetrapod vertebrates. Gametogenesis, fertilization, and sporogonic development, which culminates in the formation of polysporocystic oocysts, occur in the gut or hemocoel of a hematophagous arthropod definitive host. Merogonic development occurs in the internal organs of vertebrate hosts after they ingest these infected arthropods. The presence of cystic stages, observed for many Hepatozoon species, increases life cycle complexity and exploits the feeding behavior of vertebrate hosts. The inconsistency of morphological characteristics of these parasites, especially those associated with gamont structure, coupled with low host specificity of the parasites for their invertebrate and vertebrate hosts, have rendered species differentiation difficult. A systematic review of the hemogregarine complex has resulted in the expansion of the genus Hepatozoon to include all members of the genus Haemogregarina that infect amphibians, snakes, lizards, crocodilians, birds, and mammals. PMID- 8691365 TI - Purification and characterization of SM 37: a fucosyllactose determinant-bearing glycoprotein probed by a Biomphalaria alexandrina lectin on adult male schistosomes. AB - Utilizing a Biomphalaria alexandrina-derived lectin (BaSII) of proven specificity to a Schistosoma mansoni-associated fucosyllactose [(Fuc alpha 1-2)Gal beta 1-4 Glc] determinant, a 37-kDa determinant-bearing glycoprotein (Sm 37) was identified selectively on adult male schistosomes. Sm 37 was purified to homogeneity from extracts of adult male worms metabolically radiolabeled with [35S] methionine by BaSII affinity chromatography followed by separation on an HPLC column. Treatments with endoglycosidases, alkaline borohydride, as well as serial lectin affinity chromatography and analysis on 2-dimensional gels indicated that Sm 37 is synthesized as a 33-kDa polypeptide backbone that expresses the fucosyllactose determinant on the outer chain of a single N-linked complex-type glycan unit of either the biantennary or, to a lesser extent, the tri- or tetra-antennary types. The distinct structures of the complex oligosaccharides accounted for the expression of 2 isomorphs of Sm 37. the glycoprotein lacks other conventional high mannose-type or O-linked oligosaccharides and, as deduced from the N-terminal amino acid sequence, the Sm 37 polypeptide may be distinct from other schistosome polypeptides of known sequence. Based on the structural relatedness of the Sm 37-associated fucosyllactose determinant to the antigenic blood group H trisaccharide, these observations may have implications for mechanisms of these host-parasite interactions. PMID- 8691366 TI - Immune and inflammatory responses to reproductive tract infection with Tritrichomonas foetus in immunized and control heifers. AB - Histopathologic changes and local antibody responses were studied in immunized and control heifers after intravaginal challenge with 10(6) Tritrichomonas foetus. Animals were given 3 intramuscular inoculations of immunoaffinity purified superficial antigen, TF 1.17, in 2 different adjuvant combinations (incomplete Freund's adjuvant or dextran sulfate plus IFA-8 animals each) or adjuvant alone at 3-wk intervals and were challenged with T. foetus 2 wk later. Histologically, a nonsuppurative endometritis with nodular lymphoid aggregates in the stratum spongiosum was present in 9 of 24 heifers. Twice as many control heifers as immunized had moderate to severe endometritis at 10 wk and the rate of clearance of the organism was significantly faster in immunized than in control heifers. Furthermore, time of clearance was statistically correlated with severity of endometritis at 10 wk postinfection, when necropsies were done (P < 0.02). Because 9-10 wk postinfection is thought to be the critical period for determining fetal loss associated with endometritis, this correlation with early clearance is important to protection against disease. In heifers with moderate to severe infiltration of mononuclear cells in the endometrium, lymphoid nodules and some secondary follicles were detected. In the subgroup of 12 animals from which uterine secretions were collected. IgA antibody responses to antigen were detected by 6 wk in infected animals with increases in mean responses at 8 and 10 wk, but not in uninfected animals. A rationale is presented for consideration of the lymphoid nodules as a possible inductive site for this local antibody response to T. foetus. PMID- 8691367 TI - Schistosoma mansoni induces in the Kenyan baboon a novel intestinal pathology that is manifestly modulated by an irradiated cercarial vaccine. AB - Light and scanning electron microscopic study of intestines of 5 baboons (Papio anubis) in a state of acute schistosomiasis mansoni after exposure to 800 cercariae was made. In addition to overt granulomatous inflammation in the mucosa of the colon and ileum, more subtle microscopic lesions consisting of smooth muscle hypertrophy and villous atrophy were present. The intensity and distribution of these lesions were less marked in 5 baboons previously vaccinated with 40,000 30-krad-attenuated cercariae and presenting a 39% mean protection level measured as a percent reduction in adult worms recovered from mesenteric vasculature at perfusion. No similar lesions were observed in 2 normal uninfected and nonvaccinated baboons. These results are comparable to what has been reported in mice infected by Schistosoma mansoni. The data indicate that villous atrophy, hypertrophy of muscularis mucosa, nd goblet cell hyperplasia are important pathological changes to be included in the evaluation of the efficacy of schistosomiasis vaccines in the baboon model, together with the routine adult worm recovery from mesenteric blood vessels and the overt liver and bowel pathology. PMID- 8691368 TI - Fetal loss in BALB/C mice infected with Neospora caninum. AB - The suitability of mice as a model for reproductive loss due to Neospora caninum infection was investigated. Groups of mice were infected with 2 x 10(6) N. caninum before pregnancy (10 days) and during pregnancy (days 5 and 10 of gestation). In mice infected before and during early pregnancy, fetal loss was evaluated throughout gestation, and pregnancy loss was evaluated by enumeration of fetal resorptions and total fetuses. In mice infected before pregnancy, no difference was present in resorptions between infected and control mice, although litter size was decreased in the infected mice (P < 0.05). In mice infected during early pregnancy (day 5 gestation) and examined temporally throughout gestation, resorptions were increased in the infected mice compared to the control mice (P < 0.05). In mice infected at 5 days gestation and examined at one time point (day 14 of gestation), the resorption rate for infected mice was 33% and 12% for controls (P < 0.05). Routine histopathologic examination and immunohistochemistry using N. caninum-specific antisera did not identify tachyzoites in placental and fetal tissues during the pre- and early pregnancy infections. In mice infected late midgestation (day 10), N. caninum tachyzoites were identified in placenta and fetal muscle and neural tissue. In the placenta, there was multifocal necrosis and hemorrhage with intralesional tachyzoites. Tachyzoites in fetal tissues were not associated with pathologic changes. No reproductive loss was associated with mice infected late in gestation. These data demonstrate that mice can be used as a model for the study of fetal resorption and congenital infection associated with N. caninum. PMID- 8691369 TI - Comparison of two methods for recovering migrating Ascaris suum larvae from the liver and lungs of pigs. AB - Nine groups of 5 pigs were inoculated with Ascaris suum eggs on day 0. Groups 1, 2, and 3 were inoculated with 100 eggs, groups 4, 5, and 6 with 1,000 eggs, and groups 7, 8, and 9 with 10,000 eggs. On day 3, groups 1, 4, and 7 were slaughtered, on day 7 groups 2, 5, and 8, and on day 10 groups 3, 6, and 9. The liver (days 3 and 7) and lungs (days 3, 7, and 10) were removed and 2, 25% samples of both organs were collected. Larvae were recovered from 1 sample by the Baermann method and from the other by an agar-gel method. Overall there were no significant differences in the liver larval recovery between the 2 methods. The use of the agar-gel method resulted in a very clean suspension of larvae and thereby reduced the sample counting time by a factor of 5-10 compared to the Baermann method. With both methods larval recovery from the lungs resulted in a clean larval suspension that was easy to count, and there were overall no significant differences between the 2 methods, although there was a tendency toward the Baermann method recovering more larvae from the lungs than the agar gel method. The tissue sample dry weight did not significantly influence larval recovery by the agar-gel method, and the time interval from slaughtering to start of incubation on day 3 (interval 51-92 min), day 7 (interval 37-114 min), and day 10 (interval 50-129 min) had no significant effect on recovery by either method. PMID- 8691370 TI - Phylogeny of the Haplosporidia (Eukaryota: Alveolata) based on small subunit ribosomal RNA gene sequence. AB - The phylogenetic position of the phylum Haplosporidia was investigated with the complete small subunit rRNA gene sequences from 5 species in the phylum: Haplosporidium nelsoni and Haplosporidium costale, parasites of the eastern oyster Crassostrea virginica; Haplosporidium louisiana, a parasite of the mudcrab Panopeus herbstii; Minchinia teredinis, a parasite of shipworms (Teredo spp.) and Urosporidium crescens, a hyperparasite found in metacercariae of the trematode Megalophallus sp. in the blue crab, Callinectes sapidus. Multiple alignments of small subunit rRNA gene sequences included the 5 haplosporidian taxa and 14 taxa in the alveolate phyla Ciliophora, Dinoflagellida, and Apicomplexa. Maximum parsimony analysis placed the phylum Haplosporidia as a monophyletic group within the alveolate clade, as a taxon of equal rank with the other 3 alveolate phyla, and as a sister taxon to the clade composed of the phyla Dinoflagellida and Apicomplexa. Transversionally weighted parsimony placed the haplosporidians as a sister taxon to the ciliates. A separate analysis focused on the relationships of species in the genus Haplosporidium. Analyses were conducted with the haplosporidians as a functional ingroup, using each of the alveolate phyla individually as functional outgroups. The results indicated that species in the genus Haplosporidium do not form a monophyletic assemblage. As such, the present morphological criteria for distinguishing the genera Haplosporidium and Minchinia are insufficient. PMID- 8691371 TI - Coccidia of the collared peccary (Tayassu tajacu) in southern Texas with descriptions of three new species of Eimeria (Apicomplexa: Eimeriidae). AB - In February 1993, fresh fecal samples were collected from 47 collared peccaries (Tayassu tajacu) killed by hunters at the Chaparral Wildlife Management Area, southern Texas, USA. Five species of coccidia (Eimeria chaparralensis n. sp. [9/47, 19%], Eimeria dicotylensis n. sp. [21/47, 21%], Eimeria pecari n. sp. [2/47, 4%], Eimeria sp. [1/47, 2%], and Klossia sp. [1/47, 2%]) were observed. Measurements are in micron. Sporulated oocysts of E. chaparralensis are rough walled, elongate ovoidal, 43.3 x 28.5 (37-52 x 26-35); sporocysts are elongate ellipsoidal 21.8 x 9.0 (16-27 x 7-12); micropyle (approximately 4.9), Stieda, and substieda body are present; sporocyst residuum is present in newly sporulated oocysts; polar granule and oocyst residuum are absent. Sporulated oocysts of E. dicotylensis are smooth-walled, ovoidal, 25.7 x 20.1 (23-29 x 17-23); sporocysts are ellipsoidal 13.0 x 6.9 (11-17 x 6-9); micropyle and oocyst residuum are absent; polar body sometimes present; Stieda body and sporocyst residuum always present. Sporulated oocysts of E. pecari are smooth-walled, elongate ellipsoidal, 26.8 x 18.1 (22-31 x 15-21); sporocysts are elongate ellipsoidal 16.4 x 5.9 (13 22 x 4-7); micropyle (approximately 5.8) with collar, Stieda body, substieda body, and sporocyst residuum are present; polar granule and small oocyst residuum sometimes present. There were no sex or age differences in prevalences of infection, and there were no positive or negative associations between any species of eimerian. The majority of hosts were infected with a single species of Eimeria. Overall prevalence of infection with eimerians was 23/47 (49%). PMID- 8691372 TI - Cryptosporidiosis of the conjunctiva in SIV-infected rhesus monkeys. AB - Cryptosporidium was found on the conjunctiva of 6 SIV-infected immunodeficient rhesus monkeys. Some affected membranes were inflamed. The conjunctiva is a newly recognized site for disseminated Cryptosporidium infection in spontaneously infected immuno-deficient mammals, and clinicians and investigators should be aware of its possible presence in immunodeficient patients with disseminated cryptosporidiosis. PMID- 8691373 TI - Kinetics of entry of virulent and avirulent strains of Leishmania donovani into macrophages: a possible role of virulence molecules (gp63 and LPG). AB - Specific receptors may be involved in the process of attachment of Leishmania donovani promastigotes to macrophage surfaces and their subsequent internalization. Two virulent strains of Indian L. donovani (AG83 and GE-I) were found to enter into macrophages much faster than the avirulent ones (UR6). These virulent promastigotes express surface glycoprotein (gp63) and lipophosphoglycan (LPG) to a greater extent than avirulent strains. We examined their interaction with macrophages as a function of time by preblocking the macrophage receptors with the exogenous addition of gp33 or LPG. In experiments where gp63 was used as the blocking agent, the entry of one virulent strain (GE-I) was affected. In other experiments where LPG was used, the entry of another virulent strain (AG83) was affected. Entry of the avirulent strain (UR6) was unaffected by either of these treatments. Exposed LPG or gp63 on the surface of promastigotes thus appear to expedite their recognition and entry into the host cell. To assess the role of gp63 further in the entry of Leishmania into the macrophages, an avirulent UR6 strain was transfected with the gp63 gene cloned from L. amazonensis. The transfected UR6 as expected expressed more GP63 at a faster rate and entered into the macrophages like the virulent strain when compared to the nontransfected UR6 or UR6 transfected with vector alone. Thus, the expression of the gp63 gene is involved in the recognition and intracellular entry of visceral Leishmania into the macrophages in addition to the cutaneous species demonstrated previously. PMID- 8691374 TI - Wistar rat-Plasmodium berghei model does not approximate human congenital malaria. AB - Until recently, congenital malaria was thought to be rare. Now, several reports suggest that more than 10% of newborns in some settings are parasitemic. The pathophysiology of transplacental transmission of Plasmodium is not well understood, and no animal model of congenital malaria exists. A rodent model of malaria in pregnant females, however, has been developed. In an effort to test the usefulness of this model in the study of congenital malaria, Wistar rats were injected intraperitoneally with approximately 10(6) NYU-2 strain Plasmodium berghei-infected erythrocytes at various times relative to conception. Perinatal maternal and neonatal blood was tested for the presence of parasites. Two rats infected preconceptually, 1 at 29 and the other at 11 days prior to mating, delivered aparasitemic pups. Fourteen rats were inoculated during gestation. Five of 5 rats infected on the fifth gestational day succumbed prior to delivery; 1 fetus was parasitemic. Offspring of females infected on the 9th, 10th, 12th, and 14th days of gestation were aparasitemic at birth. Four rats conceived after an initial Plasmodium infection had waned and were reinfected during pregnancy; none of their pups showed evidence of parasitemia. Thus, though rare, transplacental passage of malaria parasites can occur in rats. The Wistar rat-P. berghei model of gestational malaria, however, does not seem to be useful for the study of congenital malaria. PMID- 8691375 TI - Efficacy of serine protease inhibitors against Cryptosporidium parvum infection in a bovine fallopian tube epithelial cell culture system. AB - The anticryptosporidial potential of the protease inhibitors alpha-1-antitrypsin (AAT), antipain, aprotinin, leupeptin, methoxysuccinyl-ala-ala-pro-valine chloromethylketone (MAAPVCK), soybean trypsin inhibitor (SBTI), and phenylmethylsulfonyl fluoride (PMSF) was evaluated in a bovine fallopian tube epithelial (BFTE) cell culture system. Protease inhibitor concentrations of 5, 10, 50, 100, and 500 micrograms/ ml (PMSF at 1, 2, and 3 mM) in RPMI medium were mixed with Cryptosporidium parvum oocysts and used to inoculate BFTE cell monolayers. At 24 hr postinoculation (candlejar/37 C), cells were rinsed with RPMI medium, fixed in methanol, and stained with Giemsa. Parasites were enumerated in cell monolayers by brightfield microscopy. The mean number of parasites counted in each protease inhibitor treatment group was expressed as a percentage of the mean number of parasites counted in an infection control group. Leupeptin and SBTI reduced parasite numbers to 40-50% of the control mean at 500 micrograms/ml: AAT, antipain, and aprotinin reduced parasite numbers to 10-15% at the same concentration. PMSF reduced parasite numbers to 40% of the control mean at 3 mM. MAAPVCK did not significantly inhibit cryptosporidial infection. These findings suggest that a protease component of C. parvum may be essential for host cell infection. PMID- 8691376 TI - Detection of canine erythrocytes infected with Babesia gibsoni by flow cytometry. AB - Peripheral blood samples from dogs infected with Babesia gibsoni were analyzed by flow cytometry for parasitized erythrocytes after staining with hydroethidine. Cells identified as positive by flow cytometry were erythrocytes infected with B. gibsoni. Analysis of 26 samples by flow cytometry for % parasitemia revealed a correlation coefficient of 0.97 in comparison to the conventional method of light microscopy. PMID- 8691377 TI - Differentiation between the human hookworms Ancylostoma duodenale and Necator americanus using PCR-RFLP. AB - There are 2 major species of hookworms that infect humans. Ancylostoma duodenale and Necator americanus. Although traditionally considered to be identical for treatment purposes, there are significant life history differences between the species that must be considered for the rational design of chemotherapeutic and immunoprophylactic control strategies. However, identification of the species infecting a particular population has been problematic, as the eggs of the 2 species cannot be reliably differentiated by classical parasitological methods. A PCR-based technique for the differentiation of hookworm species that infect humans is reported. A fragment of the 3' untranslated region of the cAMP dependent protein kinase catalytic subunit gene was amplified from A. duodenale and N. americanus genomic DNA using primers derived from the corresponding A. caninum cDNA. Digestion of the amplified DNA with the restriction enzymes HpaII, MboI, TaqI, and ThaI generated specific restriction fragment patterns unique to each species. The technique can distinguish between pure and mixtures of hookworm DNA and can amplify DNA from a single egg. The primers also amplify the fragment from the DNA of several other species of hookworms that infect humans and other animals. The technique is fast, simple, and hookworm specific and represents a considerable savings in time over current methods used for distinguishing between human hookworm infections. PMID- 8691378 TI - A human case of Plagiorchis muris (Tanabe, 1922: Digenea) infection in the Republic of Korea: freshwater fish as a possible source of infection. AB - A Korean man was found infected with Plagiorchis muris and 2 other intestinal trematodes, Echinostoma hortense and Metagonimus takahashii. No complaint of gastrointestinal discomfort due to these fluke infections was noted. The patient had a history of eating various kinds of freshwater fish caught from a small stream near his village. Freshwater fish collected from the stream were examined for trematode metacercariae by an artificial digestion technique. Unidentified metacercariae collected were administered to a Sprague-Dawley rat. One P. muris adult was recovered from the small intestine of the rat on day 8 postinfection. Thus, freshwater fish of the genera Liobagrus, Puntungia, and Odontobutis are a probable source of infection for this patient. PMID- 8691379 TI - Attempts to immunize chickens with Cryptosporidium baileyi oocyst extract. AB - In order to study the possibility of immunization against Cryptosporidium baileyi with extracted crude antigen, Arbor Acres chickens were injected intramuscularly with 80 micrograms of C. baileyi oocyst-derived proteins (uninfected immunized, UI) or inoculated orally with 8 x 10(5) viable C. baileyi oocysts (infected control, IC) at 1 wk of age. The immunization was repeated in the UI group at 2 wk of age. Uninfected (UC) birds served as controls. All animals in UI, IC, and UC groups were challenged orally with 8 x 10(5) C. baileyi oocysts at the age of 4 wk. Blood samples were collected when birds were 4 and 6 wk of age, and sera were examined by enzyme-linked immunosorbent assay for the presence of antibodies against C. baileyi. Total oocyst output of UI chickens was about 60% of that of UC birds after challenge, and the prepatent and patent periods were nearly identical in the latter 2 groups. In contrast, IC birds developed complete resistance to challenge infections. These results suggest that immunization with the oocyst extract of C. baileyi may confer some degree of protection against oral challenge; however, the protection is less effective than that induced by primary oral infection. The lack of significant difference between the antibody responses of IC and UI animals to C. baileyi at 2 wk of age suggests that serum antibodies play little role in acquired resistance to challenge infection. PMID- 8691380 TI - Trypanosoma cruzi downregulates the production of interleukin-2, interferon gamma, interleukin-4 and interleukin-5 by activated human lymphocytes. AB - The intracellular levels of interleukin (IL)-2, IL-4, IL-5 and interferon-gamma (IFN-gamma) produced by mitogen-stimulated normal human blood lymphocytes were found to be markedly reduced in cultures containing purified Trypanosoma cruzi trypomastigotes. This was evidenced by marked decreases in the proportion of lymphocytes whose cytoplasm was stained with fluorochrome-conjugated monoclonal antibodies specific for the selected cytokines and a somewhat small but systematically demonstrable reduction in the mean fluorescence intensity of the stained lymphocytes relative to values obtained with parasite-free cultures. The percentage of activated CD3+ cells containing both IL-2, IL-4, i.e., THO-like cells, was also much smaller in the cultures containing trypomastigotes, indicating that T. cruzi can concomitantly inhibit the production of more than 1 cytokine by individual activated T lymphocytes. These results evidence the ability of T. cruzi to down-regulate the production of several important cytokines and raise the possibility of a direct role for this parasite in altering cytokine production during infection. PMID- 8691381 TI - Prevalence of Neospora caninum and Toxoplasma gondii antibodies in coyotes (Canis latrans) and experimental infections of coyotes with Neospora caninum. AB - Antibodies to Neospora caninum were detected in 5 (10%) of 52 coyotes from Texas. Antibodies to Toxoplasma gondii were detected in 32 (62%) of 52 samples from these same coyotes. Four (80%) of the 5 coyotes that were seropositive for N. caninum also had antibodies to T. gondii. Nineteen (37%) of the coyotes did not have antibodies to either parasite. Three coyote pups were inoculated with the brains from mice infected with 3 strains of N. caninum originally isolated from dogs. None of the pups developed neosporosis or excreted N. caninum oocysts in their feces. The pups developed anti-N. caninum antibody titers of > or = 1:800 but did not develop antibodies to T. gondii. Results of this study indicate that antibodies to T. gondii are more common than antibodies to N. caninum in coyotes. Additionally, young coyotes appear to be resistant to experimental N. caninum infection. PMID- 8691382 TI - Four isolates of Giardia lamblia cultivated axenically in China and the restriction endonuclease analysis of their DNA. AB - Axenic culture of 4 Giardia lamblia isolates, 3 from humans and 1 from a rabbit, have been established in China for the first time. The trophozoites of Giardia used for the initial cultivation were obtained from the purified cysts excysted in suckling gerbil (Meriones unguiculatus) and BALB/c mice. Modified TYI-S-33 medium was used in establishment of the culture. DNA banding patterns were compared using restriction-endonuclease analysis and then followed by Southern blot analysis with genomic DNA as a probe. The 4 isolates showed identical banding patterns after being digested with Hind III, Bgl II, Pts I, Hae III, and Hinf. Two different banding patterns were observed after further digestion with Alu I and southern blot analysis. This indicated that isolates of human and rabbit origins do not have strict host specificity and that cross transmission may occur between humans and rabbits. PMID- 8691383 TI - The effects of light intensity on hatching of Echinostoma caproni Miracidia. AB - Egg cultures of Echinostoma caproni were exposed to 25-W incandescent light at control intensities (9.7 mumol s-1 m-2) and reduced intensities (1.0, 0.5, 0.25, 0.125, 0.06, 0.03, and 0.01 mumol s-1 m-2). Low intensities of light did not affect the diurnal hatching rhythm of the miracidia, with maximum hatching occurring from 1200 to 1300 hr. However, at 0.5, 0.25, and 0.125 mumol s-1 m-2, hatching was delayed 2 days at each interval. From 0.06 to 0.01 mumol s-1 m-2, hatching still occurred, but at 17 days of development rather than at the 11.3 day average found under illumination with a 25-W incandescent light. No appreciable hatching was observed in cultures kept in the dark. PMID- 8691384 TI - Gammarus lacustris harboring Polymorphus paradoxus show altered patterns of serotonin-like immunoreactivity. AB - The pattern of serotonin-like immunoreactivity in the central nervous system of individuals of the amphipod Gammarus lacustris harboring polymorphid cystacanths was compared to the pattern seen in individuals not infected with acanthocephalans. Ventral nerve cords from both parasitized and nonparasitized amphipods showed the same bilateral pair of immunoreactive cell bodies in the third thoracic ganglion. Significant differences were noted in the fine structure of these cell bodies, with nerve cords from Polymorphus paradoxus-parasitized amphipods showing a greater number of bright spots or localized points of storage of serotonin. The results of this study indicate that infection of G. lacustris by cystacanths of P. paradoxus, but not P. marilis, is correlated with changes in the anatomy of the serotonergic neurons of the amphipod's central nervous system. PMID- 8691385 TI - Ticks and fleas of shrews in Appalachian Georgia and North Carolina. AB - Ticks (Acari: Ixodidae) and fleas (Insecta: Siphonaptera) were recovered from 8 smoky shrews, Sorex fumeus Miller, and 9 northern short-tailed shrews, Blarina brevicauda (Say), trapped at elevations of 720-1,310 m in Macon and Jackson counties in western North Carolina and Union County in northern Georgia from April 1994 to August 1995. The ticks Ixodes angustus Neumann and Ixodes woodi Bishopp, and the flea Corrodopsylla curvata (Rothschild), were recovered from smoky shrews. The same 2 tick species, in addition to the fleas, Ctenophthalmus pseudagyrtes Baker and Doratopsylla blarinae Fox, were recovered from northern short-tailed shrews. New state records for I. angustus from Georgia and I. woodi from North Carolina are established. PMID- 8691386 TI - The amphipod Gammarus fossarum as a natural true intermediate host of the nematode Raphidascaris acus. AB - A single third-stage larva of the fish nematode Raphidascaris acus (Bloch, 1779) (body length 1.77 mm) was found in 1 of 775 gammarids Gammarus fossarum Koch examined from the Jihlava River, Czech Republic. This is the first confirmed record of the advanced L, of this species from an invertebrate host, showing that an invertebrate may serve as true intermediate host of this nematode, in addition to lower aquatic vertebrates. Until now, invertebrates have generally been considered as paratenic hosts of the second-stage larvae of R. acus. PMID- 8691387 TI - Refeeding activity of immature ticks of Ixodes persulcatus and transmission of Lyme disease spirochete by partially fed larvae. AB - The refeeding activity of immature ticks of Ixodes persulcatus was studied under laboratory conditions. BALB/c mice were used as blood sources. Feeding larvae and nymphs spontaneously detached themselves from parasitized mice when the mice were killed 1 or 2 days after tick exposure. Partially fed ticks were reexposed on other mice. Both larvae and nymphs were able to refeed on mice. The resultant engorged ticks normally molted to the next developmental stages. We also examined the transmission of the Lyme disease spirochete, Borrelia garinii, by bites of partially fed ticks. Larvae that had fed on infected mice for 1 or 2 days transmitted the spirochete to mice by refeeding. PMID- 8691388 TI - Does Aponomma varanensis (Acari: Ixodida: Ixodidae) occur on the Taiwanese mainland? AB - On 15 July 1976, teams from the U.S. Naval Medical Research Unit No. 2, Taipei, Taiwan, made 3 collections of ticks from beneath the dorsal scales of the Taiwan stink snake, Elaphe carinata, at Makung in the Penghu Islands, which lie astride the Tropic of Cancer in the Taiwan Strait between southern mainland China and Taiwan proper. These ticks were later determined to be Aponomma varanensis (Supino, 1897), but this discovery was never published, and no member of the genus Aponomma has heretofore been reported from Taiwan or any of its outlying islets. Because suitable hosts, including E. carinata, are abundant on Taiwan and because A. varanensis is widely distributed in tropical Asia, it is argued that this or a related species of Aponomma will one day be found on the Taiwanese mainland. PMID- 8691389 TI - Emergence of cercariae of Echinostoma trivolvis from Helisoma trivolvis under different conditions. AB - Release of Echinostoma trivolvis cercariae from naturally infected Helisoma trivolvis snails maintained under different laboratory conditions was studied. Infected snails were isolated for 1 hr in Stender dishes containing 5 ml of artificial spring water and the number of cercariae released during this time was recorded. Of the conditions tested, i.e., light versus dark, day versus night, volume of water, snail maintenance temperature prior to isolation, temperature during isolation, food versus no food, aeration of water, disturbance of water, and isolation in snail conditioned water, the only significant factors in the emergence of E. trivolvis cercariae were temperature related. Observations on cercariae released in vitro from isolated rediae maintained in Locke's solutions were in accord with the in vivo results. PMID- 8691390 TI - Patterns of haemogregarine load, aggregation and prevalence as a function of host age in the lizard Lacerta vivipara. AB - Patterns of haemogregarine load, aggregation, and prevalence as a function of host age in the lizard Lacerta vivipara were investigated. These parameters may provide evidence for the potential effect of parasites on host survival. The predictions of theoretical models concerning the shape of parasite load, parasite aggregation, and parasite prevalence across host age were used to test if parasites are a significant source of host mortality. Both age-intensity and age aggregation curves were found to be peaked, whereas the age-prevalence curve increased with host age, reaching high levels (> 80% of infected hosts). These findings of humped age-aggregation and age-intensity curves are in good agreement with the predictions of the Anderson and Gordon (1982) model and suggest that haemogregarines may influence age-dependent host mortality in this population of L. vivipara. PMID- 8691391 TI - Giardia duodenalis: exposure to metronidazole inhibits competitive interactions between isolates of the parasite in vitro. AB - The competitive interactions of genetically distinct isolates of Giardia duodenalis with different growth rates were studied in vitro. Electrophoretic analysis of mixed cultures showed that competition between 2 cloned isolates occurs under normal in vitro culture conditions, with faster-growing isolates outcompeting those with slower growth rates. The addition of sublethal concentrations of metronidazole to clonal mixtures in vitro prevented the competitive exclusion, which was seen in normal culture. This apparently occurred because the drug reduced the growth rate of the faster-growing but not the slower growing clone. PMID- 8691392 TI - [Analysis of calcium ion concentration in cells by confocal microscopy]. PMID- 8691393 TI - [Problems on medical statistic processing--special reference to incorrect application]. PMID- 8691394 TI - [Thermodynamics of biophysical system: basics of network thermodynamics]. PMID- 8691395 TI - Identifying problems in community health promotion: an illustration of the Nominal Group Technique in AIDS education. AB - Recognition of the extent and consequences of HIV/AIDS in Africa has resulted in many large scale health promotion programmes. These programmes usually provide information about how to avoid contracting HIV as well as information to dispel false beliefs about the virus. However there also exist anti-health promotion ideas about HIV/AIDS which often challenge the very premises on which health promotion messages are based. Such anti-health promotion ideas may represent reassuring benefits and these are likely to vary not only across cultures but also between different communities and 'at risk' groups within the same culture. The Nominal Group Technique (NGT) is a participative exercise which can be used with small groups to achieve a consensus concerning which anti-health promotion ideas are most influential in terms of encouraging people to ignore health promoting messages. The application of the NGT is illustrated with a group of Malawian students. PMID- 8691396 TI - Public health in the 1990s: time for a change of approach. PMID- 8691397 TI - High prevalence of smoking in young patients with acute myocardial infarction. AB - Of 35 patients with acute myocardial infarction (AMI) at the age of 40 years or less, 32 (91%) smoked and only three patients were non-smokers. The age at AMI related significantly to the extent of smoking (p < 0.001, Kruskall-Wallis test). Five patients with AMI at the age < 30 years smoked more heavily than the 30 with AMI at the age of 30-40 years (p = 0.04, Mann Whitney U test). Heavy smoking men > 30 years at the AMI had a Q-wave infarction as often (11 of 13 (85%)) as those with multivessel disease or a coronary artery occlusion (8 of 9 (89%) and 14 of 16 (88%) respectively) on coronary arteriography after the infarction. Smoking may be the most important modifiable risk factor in young patients with AMI. PMID- 8691398 TI - Doctors at risk of hepatitis B and HIV infection from patients in Nigeria. AB - The aim of this study was to assess the degree of residents' concern about acquiring hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infection from their patients at the University College Hospital, Ibadan, Nigeria. We surveyed 149 resident doctors. The response was 89%. Nine per cent of the resident doctors reported percutaneous exposures to needles contaminated with blood of patients infected with HBV or HIV. Eighty per cent of the residents experienced moderate to major concern about contracting these viral infections from their patients. The majority of the doctors (54-64%) indicated that they should be allowed to decide for themselves whether to treat the infected patients. A substantial proportion of them (46-49%) believed that refusing to take care of the patient was not unethical. About 86-96% of the doctors believed that the hospital as well as the Residency Training Programme administrators were not concerned about the risk of acquiring the viruses from their patients. In general, the results demonstrate a major degree of concern about acquiring HBV and HIV infections among resident doctors. Moreover, there is a need for the hospital and Residency Training Programme administrators to formally address these concerns so as to motivate well and reassure these doctors. No such study exists that exclusively address this important and topical subject in doctors in tropical Africa. PMID- 8691399 TI - Generalised obesity and regional adiposity in adult white and migrant Muslim males from Pakistan in Peterborough. AB - A comparative study was made of generalised obesity (body mass index; BMI) and the regional distribution of adiposity (measured as circumferences and circumference ratios) in adult White and migrant Muslim males from Pakistan in Peterborough. No significant difference in the prevalence of obesity as measured by the BMI was observed between Whites and Pakistani migrants. Although the mean BMI values were similar in both groups, they had distinctly different body fat patterning. Whites had significantly more upper body, central body and lower body adiposity compared with Pakistani migrants. They also had significantly more total fat as well as upper body:lower body, upper body:central body, and upper body: total fat indices. Within the central body, Whites had significantly more adiposity in the waist region relative to abdomen region (Waist:Abdomen ratio). However, Pakistani migrants had significantly more abdominal adiposity relative to total adiposity (Abdomen:Sum of All Circumferences ratio) than Whites. These preliminary results clearly indicate that there is a tendency for accumulation of adiposity in the abdominal region in Asian men of Pakistani origin compared with White men irrespective of the level of generalised adiposity. The health implications of body fat patterning on non-insulin-dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD) are well-known. The pattern of fat distribution observed in migrant Pakistani males in this study may exist in other migrant groups originating from the Indian sub-continent and could be one of the risk factors predisposing migrant Asians (persons originating from the Indian sub continent) in Britain to develop NIDDM and CHD irrespective of their generalised (BMI) obesity. Future epidemiological studies should lay more emphasis on morphological fat patterning instead of BMI in Asian migrants in Britain. PMID- 8691400 TI - Assessment of job motivational factors by Malawian health inspectors. PMID- 8691401 TI - Life after birth. PMID- 8691402 TI - Nomenclature of health care organisations: the extent of public understanding. AB - Health care systems in many parts of the world are undergoing organisational change. In Britain, the establishment of new organisations following the National health Service (NHS) reforms of 1990 has led to a change and a greater diversity in the nomenclature of health bodies. An important but often overlooked consequence of such change is the extent to which the public, as consumers of services, can recognise health organisations by their names. We investigated this in a study in the North east of England in early 1994. Eleven hundred respondents were asked to identify their local health authority, acute hospital and community health service provider. Mean scores for correct identification were: health authorities (or consortia of health authorities) 32%; acute hospitals 36%; community units 19%. Worst performing organisations scored very high 'don't know' responses: worst performing health authority 52%; acute hospitals 59%; community unit 48%. This survey demonstrates that the names chosen for themselves by health care organisations can convey little meaning to the public. This is an area which needs attention if health care systems are to create a culture in which they regard their patients as informed consumers. PMID- 8691403 TI - Nurses and commissioning. PMID- 8691404 TI - Managing regulations--for profit. PMID- 8691405 TI - Veterinary wildlife research and its role in community development. AB - Veterinarians, biologists and administrators attended a workshop 'Veterinary science and wildlife utilisation for the benefit of community development' which was held during March 1995 as part of the Veterinary Science Research Programme of the Foundation for Research Development. The workshop was the first step in the establishment of a veterinary wildlife research forum which aims to integrate veterinary research with that of other disciplines in addressing issues that have an impact on wildlife. Initially, discussions covered a broad perspective of worldwide approaches towards the conservation of the environment and the upliftment of rural communities. Thereafter the dialogue focused upon the objectives of the workshop which were: (1) to identify areas in wildlife and nature conservation where veterinary research is needed; (2) to identify specific projects within these areas. Seven areas were identified in which veterinary research was needed: the promotion of the free flow of products and animals; extensive husbandry; intensive husbandry; pharmacology and toxicology; public health; ethical issues; forensic and diagnostic techniques. A steering committee was elected to coordinate veterinary wildlife research; establish relevant data bases; to facilitate cooperation between researchers; and to organise regular contact through annual workshops. PMID- 8691406 TI - Differences in the oral bioavailability of three rafoxanide formulations in sheep. AB - The bioavailability of a modified rafoxanide oral suspension was compared to the original innovator product and a generic formulation in a single dose, randomised, parallel design study in sheep (n = 30). The area under the rafoxanide plasma concentration versus time curve (AUC), AUC extrapolated to infinity, and maximum plasma rafoxanide concentrations (Cmax), were used to compare the extent of absorption of the formulations. All 3 parameters were significantly (p < or = 0.01) smaller for both the modified and generic formulations relative to the original product. There were no significant (p > 0.05) differences between the modified and generic formulations. The mean point ratio % of the modified to original and modified to generic formulations for the 3 parameters were 36.4%, 35%, 45.9% and 70.9%, 70%, 79.7%, respectively. In terms of the calculated 90% confidence t-intervals of the mean % ratios, the modified and generic formulations were not bioequivalent to the original product, since they were substantially below the accepted range of 80-125%. No significant differences (p > 0.05) were noted for the time to Cmax and Cmax/AUC, both measurements of rate of absorption. A lag period before absorption of rafoxanide for all formulations of c 5 h was observed. The differences in oral bioavailability of rafoxanide and related anthelmintic formulations have implications for the efficacy and registration of generic products. PMID- 8691407 TI - A molecular epidemiological study of porcine rotaviruses. AB - Diarrhoea in the piglet can lead to stunted growth and neonatal death, with important implications for the pig farmer. During 1993, a pilot study was initiated to monitor the epidemiology of rotavirus infection in piglets with diarrhoea. Bimonthly diarrhoeal faecal specimens were collected from scouring piglets less than 6 weeks of age on a pig farm in the Northern Transvaal. The stool specimens were examined by a commercial enzyme-linked immunosorbent assay (Rotavirus EIA, IDL, Jerusalem). In total, rotavirus antigen was detected in 24% of the litters by the ELISA, which is directed at the group A rotavirus antigen. Rotavirus was found to occur throughout the year and predominantly in piglets 4 weeks old. Polyacrylamide electrophoretic analysis of the viral RNA genomes showed the presence of four distinct strains of Group A rotaviruses circulating on this farm. This study highlights the natural diversity of rotavirus strains circulating on a single farm and may indicate the importance of rotavirus infection in piglets with diarrhoea in South Africa. PMID- 8691408 TI - Macromineral composition of kikuyu herbage relative to the requirements of ruminants. AB - A 2-year study was conducted to determine the macromineral status of kikuyu grass pastures growing on representative soils in the KwaZulu-Natal Midlands. Herbage samples were collected at 25 to 35 day intervals during the growing season from 12 rotationally-grazed camps located on 3 sites. Seasonal mean herbage Ca and P concentrations were within the ranges 0.22 to 0.33% and 0.27 to 0.39%, respectively, while seasonal mean Ca:P ratios ranged from 1.1:1 to 0.63:1. Calcium concentrations and the Ca:P ratios were lowest in the midsummer months, while P concentrations increased in midsummer. In terms of the requirements of various classes of sheep and cattle, Ca concentrations and Ca:P ratios were frequently well below published critical limits. This finding, coupled with reports of kikuyu containing high levels of oxalate which reduce Ca absorption by ruminants, implies a major Ca insufficiency for animals pastured on kikuyu. Herbage Mg concentrations (seasonal mean range: 0.25 to 0.35%) were adequate in terms of the requirements of most classes of ruminants; however, K concentrations (seasonal mean range: 2.64 to 4.46%) were well in excess of animal requirements, and Mg absorption could be severely inhibited by the oversupply of K. In most camps the K:Ca+Mg ratio exceeded the reported safety threshold for grazing animals of 2.2, suggesting a high hypomagnesaemic tetany potential for animals on kikuyu pastures. Sodium concentrations in kikuyu were found to be largely inadequate in terms of animal requirements. PMID- 8691409 TI - The arterial oxygen status of clinically healthy dogs at an altitude of 1250 metres. AB - The blood-gas, acid-base, and arterial oxygen status of 6 healthy blood donor dogs was studied at an altitude of 1250 metres on 2 occasions 3 days apart. The values, and repeatability, of a number of derived variables that describe oxygen status, including oxygen extraction tension (Px), extractable oxygen concentration (Cx), and oxygen compensation factor (Qx) were established in clinically healthy dogs. The Oxygen Status Algorithm computer programme which was developed for use in humans was used to calculate these derived variables. 2,3 Bisphosphoglycerate concentrations were measured spectrophotometrically and compared with 2,3-bisphosphoglycerate concentrations calculated by the Oxygen Status Algorithm. This study revealed that there were no significant differences between the means of any of the variables used to describe oxygen status on the two occasions. The mean Px of 38.74 mmHg, Cx of 4.38 ml/dl, and Qx of 1.2 were similar to those reported for man. PMID- 8691410 TI - Electrophoretic separation of canine haemoglobin in dogs with babesiosis. AB - Venous blood was collected from clinically healthy (n = 5) and B. canis (n = 5) infected dogs. Parasitised red blood cells were not removed from blood samples prior to preparation. The erythrocytes were washed, lysed, the haem ring removed from the haemoglobin molecule and the globin chains denatured by breaking disulphide linkages between amino acids. These haemolysates were then subjected to electrophoresis in polyacrylamide gels containing acid, urea and the non-ionic detergent Triton X-100. In all 5 B. canis infected dogs a protein band was observed above the beta chain of haemoglobin. This band was absent in all 5 healthy dogs. It is postulated that this band represents a fragment of the globin chain that remains after proteolysis caused by the B. canis parasite. Further study is needed to exclude the possibility that the electrophoretic band might be of parasitic origin. PMID- 8691411 TI - Artificial transmission of Bolo disease in woolled sheep and attempted characterisation of the causative unclassified Corynebacterium sp. AB - Bacterial isolates (n = 38) previously cultured from sheep with Bolo disease were compared bacteriologically with known Corynebacterium spp. and Actinomyces spp. The isolates did not conform to any previously described species but closely resembled C. pseudodiptheriticum and C. urealyticum. More comprehensive tests are needed to classify this Corynebacterium sp. Bacterial cultures of this unclassified Corynebacterium sp. were used artificially to induce Bolo disease in Dohne Merino sheep (n = 20). Ten sheep were kept at Middelburg in the Cape Midlands (Northern Cape) under arid conditions and another 10 at Queenstown in the Eastern Cape in a more humid climate. Two suspensions containing 2.8 x 10(5) Corynebacterium sp. (inoculum A) and 2.8 x 10(9) Corynebacterium sp. (inoculum B) respectively were used to infect each sheep on 9 different sites on the skin. One sheep died during the course of the experiment. Corynebacterium sp. established itself on 81 out of 171 inoculation sites of the remaining sheep and caused typical lesions of Bolo disease, clinically and pathologically. Bolo disease lesions developed slowly over 175 days at Middelburg and 287 days at Queenstown. Weather conditions were unfavourable to the development of fleece-rot and mycotic dermatitis. No difference was seen in lesion development between rams and ewes or between sheep with 5 months' wool growth and those which were shorn before inoculation. More lesions developed with the higher concentration of inoculum B (49 sites positive) as compared to inoculum A (32 sites positive). PMID- 8691412 TI - The effect of melatonin treatment on reproductive efficiency in an accelerated lambing system. AB - A trial, which involved 917 ewes, was conducted to examine whether reproductive traits could be improved in an accelerated lambing system with 3 lambing seasons per year by subcutaneous melatonin treatment. Fertility (ewes lambed per ewes put to the ram), litter size and the interval between melatonin application date and lambing date were not affected by treatment. However, in the first lambing season (15 February to 15 March), fertility was 16% higher in melatonin-treated ewes compared to untreated ewes (P > 0.05). Season or month of application therefore seems to be an important factor with regard to the response. It is concluded that melatonin treatment in accelerated lambing systems is further complicated by the presence of pregnant and lactating ewes, which makes the value of commercial use thereof doubtful. PMID- 8691413 TI - Evaluation of calving date and calving interval as measures of reproductive efficiency in beef cows. AB - Five hundred and thirty-five calving records were analysed to determine the relationship and factors influencing calving date (CD) and calving interval (CI) so as to determine which of the two is the best measure of reproductive efficiency in beef cows mated during a restricted breeding season. Effects included in the model for the analysis of effects of CD and CI were: age of dam, year, previous sex of calf (PSex), previous calving date (PCD), previous calf birthmass (PBM) and previous calf weaning mass (PWM) and the interactions PBM x PSex and PWM x PSex. PCD and year had a highly significant influence on CD and CI. PCD had a significantly larger influence on calving interval than on calving date as evidenced by the larger mean square associated with calving interval. It was found that cows that calved earliest during the calving season had the longest calving intervals, whilst cows that calved latest had the shortest calving intervals. Calving interval was found to be reduced by 0.61 +/- 0.05 days for each one day delay in PCD, whilst CD was delayed by 0.09 +/- 0.07 days for each one day delay in PCD. It was concluded, since calving date was influenced to a smaller extent than calving interval by previous calving date, that calving date is a more reliable reproductive measure where restricted mating is practised. PMID- 8691414 TI - Measurement of maximal oxygen consumption of thoroughbred horses at an altitude of 1250m using open-circuit flow-through calorimetry. AB - This study determined the maximal O2 uptake (VO2max) of Thoroughbred horses acclimatised to mild hypobaric conditions using a standard exercise test on a treadmill inclined at a 7% slope. The O2 uptake (VO2) versus speed relationship was linear below the exercise intensity required to attain VO2max. The VO2max of individual horses ranged from 143.5 to 172.6 ml/kg/min. The proportion of total variance for the VO2 versus speed relationship was greater than 0.992, and the coefficients of variation in repeated tests in individual horses ranged between 0.07 and 1.54%. The VO2 versus speed relationship attained a plateau at speeds above the VO2max, which ranged from 9.3 to 12.0 m/s. When work intensity was increased above that of the VO2max, there was no further increase in VO2, thus showing that a maximum had been attained. PMID- 8691415 TI - Diagnosis, distribution and prevalence of Stilesia globipunctata (Rivolta 1874) in sheep in the Overberg region of the southern western Cape Province. AB - Stilesia globipunctata infections were found in sheep from the area east and south of Bredasdorp in the Overberg region of the southern Cape Province. The prevalence of infection on these farms ranged from 5.1 to 65%. In an abattoir survey 4 of the 6 lots of 4 to 5 year old sheep and only 1 of the 9 lots of sheep under the age of 1 year were infected with S. globipunctata. None of the sheep examined in the Overberg region were infected with Stilesia hepatica. A modified sedimentation technique proved to be the most reliable for the coprological diagnosis of S. globipunctata in sheep. PMID- 8691416 TI - The incidence of canine babesiosis amongst sick dogs presented to the Onderstepoort Veterinary Academic Hospital. AB - The number of sick dogs with and without canine babesiosis, a potentially fatal tick-borne disease, presented to the Onderstepoort Veterinary Academic Hospital situated north of Pretoria is reported from counts extracted from the records of the Outpatients clinic for the 6 years 1988 to 1993. The average percentage of sick dogs diagnosed as positive for canine babesiosis is 11.69%, of which 31.4% were admitted to the small animal medicine clinic for more intensive treatment. The correlation between the number of monthly babesiosis cases and meteorological data is poor. PMID- 8691417 TI - The influence of stress on the adrenals of the springbok (Antidorcas marsupialis). AB - The absolute and relative adrenal mass as well as histological sections of the adrenals of springbok (Antidorcas marsupialis) (n = 76; 36 ewes and 39 rams) were studied over a period of 12 months. No significant difference was found in the absolute mass of the adrenals of rams and ewes. However, a significant difference (p < 0.01) was found in the relative masses (adrenal mass in terms of carcass mass), in that relative masses in males were greater than females. The zona fasciculata was found to be enlarged during the dry season (February and March), and showed increased activity in both sexes. The zona fasciculata of the ewes showed an additional increase in activity during September (late pregnancy) and October (lactation). In rams increased activity of the zona fasciculata was seen during the mating season in April and May. It appears that stressful events during reproduction and during the dry season cause an increase in adrenal mass and activity. PMID- 8691418 TI - Aortic thromboembolism associated with traumatic reticuloperitonitis in a downer cow. AB - A large thrombus was found at the ileal bifurcation on post mortem examination of a 6-year-old Jersey cow which presented clinically with a history of acute onset recumbency, hind limb paresis and skin necrosis over the sacral area. Other significant findings on post mortem were traumatic reticuloperitonitis accompanied by mural thrombosis of the left ventricle associated with a purulent sinus tract through the ventricular wall, fibrous adhesions between the pericardium, diaphragm and liver, and multiple infarcts in both kidneys. PMID- 8691419 TI - Death of a dog attributed to the cyanobacterial (blue-green algal) hepatotoxin nodularin in South Africa. AB - A bull terrier died after drinking water at the margin of Zeekoevlei near Cape Town. At the time, Zeekoevlei, a hypertrophic coastal lake, contained a bloom of the cyanobacteria Nodularia spumigena and Microcystis aeruginosa. The circumstances of the incident, clinical signs of poisoning and histopathology, which mainly revealed extensive liver damage, were consistent with cyanobacterial poisoning. The cyanobacterial bloom material contained 3.47 micrograms mg-1 dry weight of the pentapeptide hepatotoxin nodularin. It is inferred that the dog died of cyanobacterial hepatotoxicosis due to the ingestion of nodularin. PMID- 8691420 TI - Cyanobacterial (blue-green algae) poisoning of livestock in the western Cape Province of South Africa. AB - Three outbreaks of cyanobacterial (blue-green algae) poisoning involving cattle and sheep are described. In 2 of these acute mortality was followed by photodermatitis in some of the surviving animals. In all 3 outbreaks the hepatotoxicity of the water collected from the dams where the animals had been drinking was confirmed following the intraperitoneal administration to mice. Nodularia spumigena was the dominant cyanobacterium in the first 2 outbreaks, and Microcystis aeruginosa in the third. The presence of the heptapeptide toxin microcystin-LR in the third outbreak was demonstrated by high pressure liquid chromatography. PMID- 8691421 TI - Boomslang envenomation in a dog. AB - This case report describes a young male German Shepherd dog that presented with bleeding from the lip 24 hours after being bitten by a boomslang (Dispholidus typus). Bites from this snake are infrequently encountered in dogs due to the shy habits of the snake. The boomslang venom is a potent procoagulant causing a consumption coagulopathy with resultant profuse haemorrhage. The only effective treatment is the administration of specific antiserum. Antiserum administration in this patient resulted in cessation of bleeding within one hour after administration. The article also discusses treatment options if antiserum is unavailable. This is the first recorded case of boomslang envenomation in the dog. PMID- 8691422 TI - 2-Phenyl-4-quinolinecarboxamides: a novel class of potent and selective non peptide competitive antagonists for the human neurokinin-3 receptor. PMID- 8691423 TI - 4-(Phenylamino)pyrrolopyrimidines: potent and selective, ATP site directed inhibitors of the EGF-receptor protein tyrosine kinase. AB - Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGF-R protein tyrosine kinase (PTK), 4-(phenylamino)-7H pyrrolo[2,3-d]pyrimidines have been identified as a novel class of potent EGF-R protein tyrosine kinase inhibitors. In an interactive process, this class of compounds was then optimized. 13, 14, 28, 36, 37, and 44, the most potent compounds of this series, inhibited the EGF-R PTK with IC50 values in the low nanomolar range. High selectivity toward a panel of nonreceptor tyrosine kinases (c-Src, v-Abl) and serine/threonine kinases (PKC alpha, PKA) was observed. Kinetic analysis revealed competitive type kinetics relative to ATP. In cells, EGF-stimulated cellular tyrosine phosphorylation was inhibited by compounds 13, 36, 37, and 44 at IC50 values between 0.1 and 0.4 microM, whereas PDGF-induced tyrosine phosphorylation was not affected by concentrations up to 10 microM. In addition, these compounds were able to selectively inhibit c-fos mRNA expression in EGF-dependent cell lines with IC50 values between 0.1 and 2 microM, but did not affect c-fos mRNA induction in response to PDGF or PMA (IC50 >100 microM). Proliferation of the EGF-dependent MK cell line was inhibited with similar IC50 values. From SAR studies, a binding mode for 4-(phenylamino)-7H-pyrrolo[2,3 d]pyrimidines as well as for the structurally related 4-(phenylamino)quinazolines at the ATP-binding site of the EGF-R tyrosine kinase is proposed. 4 (Phenylamino)7H-pyrrolo[2,3-d]pyrimidines therefore represent a new class of highly potent tyrosine kinase inhibitors which preferentially inhibit the EGF mediated signal transduction pathway and have the potential for further evaluation as anticancer agents. PMID- 8691424 TI - Synthesis and biological activities of flavonoid derivatives as A3 adenosine receptor antagonists. AB - A broad screening of phytochemicals has demonstrated that certain flavone and flavonol derivatives have a relatively high affinity at A3 adenosine receptors, with Ki values of > or = 1 microM (Ji et al. J. Med. Chem. 1996, 39, 781-788). We have further modified the flavone structure to achieve a degree of selectivity for cloned human brain A3 receptors, determined in competitive binding assays versus [125I]AB-MECA[N6-(4-amino-3-iodobenzyl)adenosine-5'-(N-methylur onamide)]. Affinity was determined in radioligand binding assays at rat brain A1 and A2a receptors using [3H]-N6-PIA ([3H]-(R)-N6-phenylisopropyladenosine) and [3H]CGS21680 [[3H]-2-[[4-(2-carboxyethyl)phenyl]ethylamino]-5'-(N ethylcarbamoyl++ +)adenosine], respectively. The triethyl and tripropyl ether derivatives of the flavonol galangin, 4, had Ki values of 0.3 - 0.4 microM at human A3 receptors. The presence of a 5-hydroxyl group increased selectivity of flavonols for human A3 receptors. The 2',3,4',7-tetraethyl ether derivative of the flavonol morin, 7, displayed a Ki value of 4.8 microM at human A3 receptors and was inactive at rat A1/A2a receptors. 3,6-Dichloro-2'-(isopropyloxy)-4' methylflavone, 11e, was both potent and highly selective (approximately 200-fold) for human A3 receptors (Ki = 0.56 microM). Among dihydroflavonol analogues, the 2 styryl instead of the 2-aryl substituent, in 15, afforded selectivity for human A3 vs rat A1 or A2A receptors. The 2-styryl-6-propoxy derivative, 20, of the furanochromone visnagin was 30-fold selective for human A3 receptors vs either rat A1 or A2A receptors. Several of the more potent derivatives effectively antagonized the effects of an agonist in a functional A3 receptor assay, i.e. inhibition of adenylyl cyclase in CHO cells expressing cloned rat A3 receptors. In conclusion, these series of flavonoids provide leads for the development of novel potent and subtype selective A3 antagonists. PMID- 8691425 TI - Structural and stereoelectronic requirements for the inhibition of mammalian 2,3 oxidosqualene cyclase by substituted isoquinoline derivatives. AB - 2,3-Oxidosqualene lanosterol-cyclase (OSC; EC 5.4.99.7) is an attractive target for the design of compounds that block hepatic cholesterol biosynthesis. (4a alpha, 5 alpha, 6 beta, 8a beta)-Decahydro-5,8a-dimethyl-2-(1,5,9-trimethyldecyl) 6- isoquinolinol (1) and simplified analogs have been devised to inhibit this enzyme by mimicking the postulated pro-C-8 high-energy intermediary carbocation occurring during the cyclization-rearrangement pathway. In order to gain an understanding into the mechanism by which these types of molecules inhibit OSC, we have synthesized a series of substituted isoquinoline derivatives 3 and investigated the structural and stereoelectronic requirements, and their stringency, that make 3 potential high-energy intermediate analogs of OSC. Determination of the IC50 values of the different compounds with rat liver microsomal cyclase, allowed the study of the relative importance of (i) the nature and the stereochemistry of the nitrogen side chain, (ii) the presence of methyl groups at C-5 and C-8a (ring junction), (iii) the presence and stereochemistry of the C-6 hydroxyl group, (iv) the nature of the ring junction, and (v) the absolute configuration of the bicyclic system. The resulting structure-activity relationships seem to validate the mechanism of action of these inhibitors as analogs of a pro-C-8 high-energy intermediate and delineate the minimal requirements for the design of efficient isoquinoline-based, or simplified, OSC inhibitors. PMID- 8691426 TI - Synthesis and structure-activity relationships of 2-substituted D-tryptophan containing peptidic endothelin receptor antagonists: importance of the C-2 substituent of the D-tryptophan residue for endothelin A and B receptor subtype selectivity. AB - Continuing studies on modifications of potent cyclic pentapeptide endothelin (ET) receptor antagonists, represented by BQ-123, and potent linear tripeptide derivative ET receptor antagonists, represented by BQ-788, are described herein. The introduction of D-tryptophan analogues with C-2 substituents in these peptidic ET antagonists resulted in potent ET receptor antagonists with various ETA/ETB subtype selectivity. Combined ETA/ETB receptor antagonists were found in both cyclic pentapeptide and linear tripeptide series with 2-halo- and 2-methyl-D tryptophans. In contrast, compounds with 2-cyano-D-tryptophan were ETB receptor selective antagonists. The C-2 substituent of the D-tryptophanyl residue appeared to be very important for the discrimination of ETA/ETB subtype selectivity of the antagonists. The potent ET receptor antagonists with various ETA/ETB subtype selectivity synthesized in this study may be useful tools for elucidating the physiological and pathophysiological roles of ET and ET receptors. PMID- 8691427 TI - Ryanodine action at calcium release channels. 1. importance of hydroxyl substituents. AB - Ryanodine (1) and dehydroryanodine (2) have a polar face formed by cis-hydroxyls at C-2, C-4, C-6, and C-12. The importance of the hydroxyls to the action of 1 and 2 at the ryanodine receptor (ryr) of calcium release channels is examined at [3H]-1 binding sites in brain and skeletal muscle and in heart membranes relative to cardiac contractility, a pharmacologic response which appears to be mediated by the ryr. Five types of changes are considered: blocking the 4- and 6-hydroxyls as cyclic borates and boronates; blocking the 10- and 12-hydroxyls as cyclic phosphates, phosphonates, and phosphoramidates; methylation at nitrogen or hydroxyls at C-4 and C-10; dehydration of the C-2 hydroxyl; additional data for a 4,12-oxygen-bridged series. The first change has little effect on potency possibly due to the lability of the boron protective groups whereas the cyclic phosphorus compounds have reduced activity. Methylation reduces potency the least at nitrogen and the C-4 hydroxyl. Dehydration of 1 to 2-deoxy-2(13)-dehydro-1 allows the restoration of oxygen at C-2 by conversion to epoxides or a diol. One of the epoxides and 2-deoxy-2(13)-dehydro-2 retain 8-31% of ryanodine's potency in the ryr assays and 81% in the cardiac contractility system. In the 4,12-oxygen bridged series, high potency at the receptor and cardiac muscle is retained in the 4-hydroxy ketal. PMID- 8691428 TI - Ryanodine action at calcium release channels. 2. relation to substituents of the cyclohexane ring. AB - Ryanodine (1) and dehydroryanodine (2) are equipotent probes for the ryanodine receptor (ryr) of calcium release channels and differ only in 9eq-methyl for 1 and 9,21-methylene for 2. Ryanoids 1 and 2 are used here to prepare novel modifications of the cyclohexane substituents to determine their effects on ryr activity and selectivity. 10-Oxo-1 when reacted with carbonyl and other reagents gave 13 C-10 derivatives including the epi-amine and epi-4-azidobenzoyl hydrazide as a candidate affinity probe. Four derivatives of 2 including the delta 8-10 hydroxy and delta 8-10-oxo compounds. Defunctionalization of the cyclohexane ring of 2 or its 4,6-ethylboronate was achieved in part by controlled periodate oxidation of the 9,21-diol to the 21-nor-9-oxo compounds. These in turn provided access to the 9ax- and 9eq-hydroxy derivatives and to the 21-nor-10-deoxy-9-oxo compound which was converted to 21-nor-10-deoxy-1 and 10-deoxy-2 along with the epimeric 10-deoxy-9-hydroxy compounds. Ryanoids of similar potency to 1 as inhibitors of [3H]-1 binding in mouse brain, rabbit skeletal muscle, and canine ventricle ryr preparations and in rat cardiac contractility assay (inhibition of mechanical response to electrical stimulation) are epi-1 and the 10-epi-amino, 10 epi-methoxyamino, and 10-epi-azidobenzoyl hydrazide derivatives and 10 deoxydehydroryanodine. With a few exceptions the potency of the ryanoids at the cardiac ryr correlates well with their inhibition of cardiac contractility, indicating that the activity is associated with stabilizing the calcium release channel in a subconducting state, thereby uncoupling the excitation-contraction process. PMID- 8691429 TI - Aristeromycin-5'-carboxaldehyde: a potent inhibitor of S-adenosyl-L-homocysteine hydrolase. AB - In an earlier study, Liu et al. (Bioorg. Med. Chem. Lett. 1992, 2, 1741-1744) showed that both the E and Z isomers of 4',5'-didehydro-5'-fluoroaristeromycin were very potent irreversible inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase. However, it was unclear from a mechanistic standpoint whether these vinyl fluorides were themselves type-I mechanism-based inhibitors causing reduction of enzyme-bound NAD+ or whether they were prodrug for aristeromycin-5' carboxaldehyde, which was the ultimate type-I inhibitor. To elucidate this mechanism of enzyme inhibition, (4'S)- and (4'R)-aristeromycin-5'-carboxaldehydes (1a,b) were synthesized in this study and shown to be potent type-I mechanism based inhibitors of AdoHcy hydrolase with k2/Ki values of 4.4 x 10(6) and 8.2 x 10(4)M-1min-1, respectively. However, Using 19F NMR and HPLC, it was shown that (4'S)-4,5'-dedehydro-5'-fluoraristeromycin in the presence of AdoHcy hydrolase did not release fluoride ion or generate aristeromycin-5'-carboxaldehyde (1a,b). These results suggest that the E and Z isomers of 4',5'-didehydro-5' fluoroaristeromycin are inactivating AdoHcy hydrolase by directly reducing NAD+ to NADH and not using the hydrolytic activity of the enzyme to generate aristeromycin-5'-carboxaldehyde. PMID- 8691430 TI - Inhibitors of acyl-CoA:cholesterol O-acyltransferase. synthesis and pharmacological activity of (+/-)-2-dodecyl-alpha-phenyl-N-(2,4,6 trimethoxyphenyl)-2H-tetrazole-5- acetamide and structurally related tetrazole amide derivatives. AB - A series of tetrazole amide derivatives of (+/-)-2-dodecyl-alpha-phenyl-N-(2,4,6 trimethoxyphenyl)-2H-tetrazole-5- acetamide (1) was prepared and evaluated for their ability to inhibit acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and to lower plasma total cholesterol in vivo. For this series of compounds, our objective was to systematically replace substituents appended to the amide and tetrazole moieties of 1 with structurally diverse functionalities and assess the effect that these changes have on biological activity. The ensuing structure activity relationship (SAR) studies identified aryl (7b) and heteroaryl (7f,g) replacements for 2,4,6-trimethoxyphenyl that potently inhibit liver microsomal and macrophage ACAT in vitro and exhibit good cholesterol lowering activity (56 66% decreases in plasma total cholesterol at 30 mg/kg), relative to 1, when compared in the acute rat model of hypercholesterolemia. Replacement of the alpha phenyl moiety with electron-withdrawing substituents (13e-h), however, significantly reduced liver microsomal ACAT inhibitory activity (IC50 > 1 microM). This is in contrast to electron-donating substituents (13ij,m-q), which produce IC50 values ranging from 5 to 75 nM in the hepatic microsomal assay. For selected tetrazole amides (1, 7b, 13n,o), reversing the order of substituents appended to the 2- and 5-positions in the tetrazole ring (36a-d), in general, improved macrophage ACAT inhibitory activity and provided excellent cholesterol lowering activity (ranging from 65% to 77% decreases in plasma total cholesterol at 30 mg/kg) in the acute rat screen. The most potent isomeric pair in this set of unsubstituted methylene derivatives (13n and 36a) caused adrenocortical cell degeneration in guinea pigs treated with these inhibitors. In contrast, adrenal glands taken from guinea pigs treated with the corresponding alpha-phenyl substituted analogs (7b and 36c) were essentially unchanged compared to untreated controls. Subsequent evaluation of 7b and 36c in a rabbit bioassay showed that both compounds and/or their metabolities were present in plasma after oral dosing. Unlike 7b and 36c, compound 1 and related 2,4,6-trimethoxyanilides (13j, 30c,d) showed poor oral activity in the rabbit bioassay. Nevertheless, in cholesterol-fed rabbits, both systemically available (7b, 36c) and poorly absorbed inhibitors (1, 36d) were more effective in lowering plasma total cholesterol than the fatty acid amide CI-976. PMID- 8691431 TI - Mapping the aspartic acid binding site of Escherichia coli asparagine synthetase B using substrate analogs. AB - Novel inhibitors of asparagine synthetase, that will lower circulating levels of blood asparagine, have considerable potential in developing new protocols for the treatment of acute lymphoblastic leukemia. We now report the indirect characterization of the aspartate binding site of Escherichia coli asparagine synthetase B (AS-B) using a number of stereochemically, and conformationally, defined aspartic acid analogs. Two compounds, prepared using novel reaction conditions for the stereospecific beta-functionalization of aspartic acid diesters, have been found to be competitive inhibitors with respect to aspartate in kinetic studies on AS-B. Chemical modification experiments employing [(fluorosulfonyl)benzoyl]adenosine (FSBA), an ATP analog, demonstrate that both inhibitors bind to the aspartate binding site of AS-B. Our results reveal that large steric alterations in the substrate are not tolerated by the enzyme, consistent with the failure of previous efforts to develop AS inhibitors using random screening approaches, and that all of the ionizable groups are placed in close proximity in the bound conformation of aspartate. PMID- 8691432 TI - New prolyl endopeptidase inhibitors: in vitro and in vivo activities of azabicyclo[2.2.2]octane, azabicyclo[2.2.1]heptane, and perhydroindole derivatives. AB - A series of potent and selective prolylendopeptidase (PEP) inhibitors of the alpha-keto heterocyclic type has been obtained by replacing the classical central proline of 1-[1-(4-phenylbutanoyl)-L-prolyl]pyrrolidine (SUAM 1221,3) by non natural amino acids PHI, ABO, and ABH. These 4-phenylbutanoyl side-chain containing inhibitors exhibited potent in vitro inhibitory potencies with IC50 around 30 nM (compounds 24 and 25). Modulation of the side chain by replacement of the terminal phenyl ring by the dicyclopropyl moiety afforded derivatives 30 and 32 with improved potencies (IC50 between 10 and 20 nM). Furthermore, replacing the linear 4-phenylbutanoyl side chain by the (2 phenylcyclopropyl)carbonyl entity provided potent inhibitors with IC50 culminating at 0.9 nM on a rat cortex enzymatic preparation (compound 70). The configuration of the cyclopropyl ring had to be R,R in order to obtain not only a strong PEP inhibition in vitro but also a good activity in vivo, exemplified by inhibitor 68, which gave ID50 ip and po of 0.3 and 1 mg/kg, respectively. Finally, demonstration of the cognition-enhancing properties of compound 54 was given in the passive avoidance test using scopolamine-induced amnesia in the rat, where it dose dependently inhibited the scopolamine-induced decrease in avoidance response. PMID- 8691433 TI - New neplanocin analogues. 6. Synthesis and potent antiviral activity of 6' homoneplanocin A1. AB - The design, synthesis, and antiviral activities of 6'-homoneplanocin A (HNPA, 3) and its congeners having nucleobases other than adenine, such as 3-deazaadenine (4), guanine (5), thymine (6), and cytosine (7), were described. Starting from the known cyclopentenone derivative 8, the optically active (mesyloxy)cyclopentene derivative 15 was prepared, which was condensed with nucleobases then deprotected to give target compounds 3-7. Of these compounds, HNPA showed an antiviral activity spectrum that was comparable to, and an antiviral specificity that was higher than, that of neplanocin A. HNPA proved particularly active against human cytomegalovirus, vaccinia virus, parainfluenza virus, vesicular stomatitis virus, and arenaviruses, which is compatible with an antiviral action targeted at S-adenosylhomocysteine hydrolase. HNPA appears to be a promising candidate drug for the treatment of these viruses. PMID- 8691434 TI - Structure-based design of novel HIV protease inhibitors: sulfonamide-containing 4 hydroxycoumarins and 4-hydroxy-2-pyrones as potent non-peptidic inhibitors. AB - The low oral bioavailability and rapid biliary excretion of peptide-derived HIV protease inhibitors have limited their utility as potential therapeutic agents. Our broad screening program to discover non-peptidic HIV protease inhibitors previously identified compound I (phenprocoumon, Ki = 1 microM) as a lead template. Structure-based design of potent non-peptidic inhibitors, utilizing crystal structures of HIV protease/inhibitor complexes, provided a rational basis for the previously reported carboxamide-containing 4-hydroxycoumarins and 4 hydroxy-2-pyrones. The amino acid containing compound V (Ki = 4 nM) provided an example of a promising new series of HIV protease inhibitors with significantly improved enzymatic binding affinity. In this report, further structure-activity relationship studies, in which the carboxamide is replaced by a sulfonamide functionality, led to the identification of another series of nonamino acid containing promising inhibitors with significantly enhanced enzyme binding affinity and in vitro antiviral activity. The most active diastereomer of the sulfonamide-containing pyrone XVIII (Ki = 0.5 nM) shows improved antiviral activity (IC50 = 0.6 nM) and represents an example of a new design direction for the discovery of more potent non-peptidic HIV protease inhibitors as potential therapeutic agents for the treatment of HIV infection. PMID- 8691435 TI - Retinoic acid receptor beta,gamma-selective ligands: synthesis and biological activity of 6-substituted 2-naphthoic acid retinoids. AB - In search for retinoic acid receptor (RAR) selective ligands, a series of 6 substituted 2-naphthoic acid retinoids were synthesized and evaluated in vitro in a transactivation assay and a competition binding assay for all RARs. These derivatives, in general, showed RAR beta,gamma selectivity. Among these naphthoic acids, oxime derivative 12 was identified as a potent RAR gamma-selective retinoid, while olefinic derivative 11 was found to be comparable to retinoic acid and slightly RAR beta,gamma selective. For the bioassays, a general correlation was observed between the binding affinity of the ligand to the receptors and the potency of the compounds in the transactivation assay. The structure-activity relationship of these naphthoic acids will be discussed. PMID- 8691436 TI - Chemical synthesis of benzamide adenine dinucleotide: inhibition of inosine monophosphate dehydrogenase (types I and II). AB - Treatment of 3-(2,3-O-isopropylidene-beta-D-ribofuranosyl)benzamide (6) with POCl3 in (EtO)3-PO afforded only little phosphorylation product (8, 5%), but the major product was 5'-chlorobenzamide riboside (7, 85%). Reaction of 6 with 2 cyanoethyl N,N-diisopropylchlorophosphoramidite followed by 2 cyanoethanol/tetrazole treatment and oxidation with tert-butyl peroxide gave a 1:1 mixture of the desired 5'-O-bis(2-cyanoethyl) phosphate 9 and the chloro derivative 7. This mixture was treated with methanolic ammonia and partitioned between CHCl3 and water. The 2',3'-O-isopropylidenebenzamide mononucleotide (8) was obtained in 21.2% overall yield from the aqueous layer. Compound 8 was then converted into the corresponding imidazolide 11b which, upon coupling with 2',3' O-acetonide of AMP, afforded the acetonide of benzamide adenine dinucleotide (15) in 94% yield together with small amounts of symmetrical pyrophosphates P1,P2 bis(2',3'-O-isopropylideneadenosin-5'-yl)pyrophosphate (13, 3%) and P1,P2 bis(2',3'-O-isopropylidene-3-(carbamoylphenyl)-5'-ribosyl)py rophosphate (14, 2%). Deprotection of 15 with Dowex 50/H+ in water afforded the desired benzamide adenine dinucleotide (BAD) in 93% yield. BAD inhibits inosine monophosphate dehydrogenase type I (IC50 = 0.78 microM) and type II (IC50 = 0.88 microM) with same degree of potency. PMID- 8691437 TI - Synthesis and potent anti-HIV-1 activity of novel 6-benzyluracil analogues of 1 [(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. AB - Ethyl 2-alkyl-4-aryl-3-oxobutyrates were synthesized from the corresponding arylacetonitriles and 2-bromo esters. Condensation of the butyrates with thiourea followed by treatment with chloroacetic acid afforded the 5-alkyl-6 (arylmethyl)uracils. Condensation of the uracils with acetals using trimethylsilyl triflate (TMS triflate) as a catalyst gave acyclic 5-alkyl-6 (arylmethyl)uracil derivatives. 6-Benzyl-5-ethyluracil was also condensed with methyl 5-O-(tert-butyldiphenylsilyl)-2-deoxy-3-O-(phenoxythiocarbonyl+ ++) alpha,beta-D-erythro-pentofuranoside, followed by Barton reduction and deprotection, to give the anomers of 6-benzyl-5-ethyl-2',3'-dideoxyuridine. Alkylation of the uracils with alkyl chloromethyl sulfides gave new thio analogues of HEPT. All new N1-substituted uracils were tested for activity against HIV-1, and the thio analogues were found extremely potent. PMID- 8691438 TI - (S)-(-)-4-[4-[2-(isochroman-1-yl)ethyl]-piperazin-1-yl] benzenesulfonamide, a selective dopamine D4 antagonist. PMID- 8691439 TI - First examples of peptidomimetic inhibitors of interleukin-1 beta converting enzyme. PMID- 8691440 TI - Synthesis of potent cyclic hexapeptide NK-1 antagonists. Use of a minilibrary in transforming a peptidal somatostatin receptor ligand into an NK-1 receptor ligand via a polyvalent peptidomimetic. AB - The endogenous peptides somatostatin (SRIF) and substance P comprise very different structures. Although both bind G-protein-coupled receptors, the SRIF receptors (SSTR 1-5) recognize SRIF and related peptides which retain its beta turn such as the potent cyclic hexapeptide SRIF agonist L-363,301 (6a), but not substance P. Conversely the NK-1 receptor binds substance P but not the above ligands. In contrast, the beta-D-glucosides 1 and 2, designed to mimic the beta turn of 6a, bind both receptors. This observation led us to attempt the conversion of 6a into the first potent, selective cyclic hexapeptide ligand for the NK-1 receptor. To this end, we combined design with a minilibrary approach. The goal was accomplished with surprising ease, leading to the NK-1 receptor antagonist 9 (IC50 2.0 +/- 0.4 nM). This demonstrates that peptidomimetics, incorporating in this case the promiscuous beta-D-glucose scaffold, can provide valuable clues about receptor similarities not revealed by their endogenous ligands. In addition, this work suggests that the use of libraries and rational design need not be mutually exclusive approaches to lead discovery. PMID- 8691441 TI - Topographical amino acid substitution in position 10 of glucagon leads to antagonists/partial agonists with greater binding differences. AB - The role of position 10 in the beta-turn region of glucagon was investigated by substituting chiral constrained amino acids and other modifications in the N terminal region. A series of glucagon analogues have been designed and synthesized by incorporating beta-methylphenylalanine isomers (2S,3S, 2S,3R, 2R,3R, and 2R,3S) at position 10 in order to explore the structural and topographical requirements of the glucagon receptor, and, in addition, utilizing previous studies which indicated that antagonism could be enhanced by modifications (des-His1, Glu9) and a bulky group at position 5. The structures of the new analogues are as follows: [des-His1,-Tyr5,Glu9]glucagon-NH2 (II), [des His1,Tyr5,Glu9,Phe10]glucagon-NH2 (III), [des-His1,Tyr5,Glu9,-Ala10]glucagon-NH2 (IV), [des-His1,Tyr5,Glu9,(2S,3R)-beta-MePhe10]glucagon-NH2 (V), [des-His1, Tyr5,Glu9,(2S,3S)-beta-MePhe10]glucagon-NH2 (VI), [des-His1,Tyr5,Glu9,D Tyr10]glucagon-NH2 (VII), [des-His1,Tyr5,Glu9,D-Phe10]glucagon-NH2 (VIII), [des His1,Tyr5,Glu9,D-Ala10]glucagon-NH2 (IX), [des-His1,Tyr5,Glu9,(2R,3R)-beta MePhe10]glucagon-NH2 (X), and [des-His1,Tyr5,Glu9,(2R,3S)-beta-MePhe10]glucagon NH2 (XI). These analogues led to dramatically different changes in in vitro binding affinities for glucagon receptors. Their receptor binding potencies IC50 values (nM) are 2.3 (II), 4.1 (III), 395.0 (IV), 10.0 (V), 170.0 (VI), 74.0 (VII), 34.5 (VIII), 510.0 (IX), 120.0 (X), and 180.0 (XI). Analogues II, III, V, VI, and XI were found to be weak partial agonists/partial antagonists with maximum stimulation between 5%-9%, while the other compounds (IV and VII-X) were antagonists unable to activate the adenylate cyclase system even at concentrations as high as 10(-5) M. In competition experiments, all of the analogues caused a right shift of the glucagon-stimulated adenylate cyclase dose response curve. The pA2 values were 6.60 (II), 6.85 (III), 6.20 (IV), 6.20 (V), 6.10 (VI), 6.50 (VII), 6.20 (VIII), 5.85 (IX), 6.20 (X), and 6.00 (XI). Putative topographical requirements of the glucagon receptor for the aromatic side chain conformation in position 10 of glucagon antagonists are discussed. PMID- 8691442 TI - Effects of modifications of residues in position 3 of dynorphin A(1-11)-NH2 on kappa receptor selectivity and potency. AB - Tyrosine1 and phenylalanine4 in dynorphin A (Dyn A) have been reported to be important residues for opioid agonist activity and for potency at kappa receptors. The glycine residues in the 2 and 3 positions of dynorphin A may affect the relative orientation of the aromatic rings in positions 1 and 4, but their flexibility precludes careful analysis. To examine these effects on dynorphin A, we previously have synthesized the linear analogues [D-Ala3]Dyn A(1 11)-NH2 (2) and [Ala3]Dyn A(1-11)-NH2 (3) and reported their biological activities. Analogues 2 and 3 displayed affinities for the central kappa opioid receptor (IC50 = 0.76 and 1.1 nM, respectively) similar to that of Dyn A(1-11) NH2 (1) (IC50 = 0.58 nM) and greatly enhanced selectivities for kappa vs mu and kappa vs delta receptors (IC50 ratios of 350 and 1300 for 2, and 190 and 660 for 3, respectively). These results suggest that the structure and lipophilicity of the amino acid present in position 3 of Dyn A(1-11)-NH2 as well as the conformational changes they induce in the message sequence of dynorphin have important effects on potency and selectivity for kappa opioid receptors. To further investigate structure-activity relationships involving the residue at the 3 position of Dyn A(1-11)-NH2, a series of Dyn A analogues with aromatic, charged, and aliphatic side chain substitutions at the 3 position was designed, synthesized, and evaluated for their affinities for kappa, mu, and delta opioid receptors. It was found that analogues with lipophilic amino acids at the 3 position of Dyn A(1-11)-NH2 generally displayed higher affinity but similar selectivities for the kappa receptor than analogues with charged residues at the same position. It is suggested that the structural, configurational, and steric/lipophilic effects of amino acids at position 3 of Dyn A(1-11)-NH2 may play an important role in potency and selectivity for the kappa receptor. PMID- 8691443 TI - Metabolically programmed polyamine analogue antidiarrheals. AB - The design, synthesis, and testing of a novel class of antidiarrheal drugs based on a tetraamine pharmacophore are reported. While N1,N14-diethylhomospermine (DEHSPM) (5 mg/kg) completely prevents diarrhea in rodents, tissue distribution studies demonstrated that the principal metabolite of DEHSPM, homospermine (HSPM), accumulates and persists in tissues for a protracted period of time. This accumulation accounts for a large part of the chronic toxicity of DEHSPM. Thus a major objective was to develop a metabolically labile analogue of DEHSPM which retained the desirable biological properties of the parent drug. Hydroxyl groups, sites vulnerable to further metabolic transformation, were introduced into the external aminobutyl segments providing N1,N14-diethyl-(3R),(12R) dihydroxyhomospermine [(HO)2-DEHSPM]. The design concept was assisted by molecular modeling, which predicted that (HO)2DEHSPM would have a Ki for polyamine transport essentially identical with that of DEHSPM. The experimentally measured Ki and also the observed values of other biological properties of (HO)2DEHSPM were in fact identical with those of DEHSPM, including IC50 against L1210 cells, impact on the NMDA receptor, and impact on L1210 native polyamine pools. Most significantly, however, there was no accumulation of the dideethylated metabolite in tissues from mice treated chronically with (HO)2DEHSPM, and (HO)2DEHSPM was 3-fold less toxic than DEHSPM. Finally, (HO)2DEHSPM completely prevented diarrhea in the castor oil-treated rat model at a dose of 5 mg/kg, just as did DEHSPM. PMID- 8691444 TI - Antiretroviral agents as inhibitors of both human immunodeficiency virus type 1 integrase and protease. AB - The human immunodeficiency virus type one integrase (HIV-1 integrase) is required for integration of a double-stranded DNA copy of the viral RNA genome into a host chromosome and for HIV replication. We have previously reported that phenolic moieties in compounds such as flavones, caffeic acid phenethyl ester (CAPE), tyrphostins, and curcumin confer inhibitory activity against HIV-1 integrase. We have investigated the actions of several recently described protease inhibitors, possessing novel structural features, on HIV-1 integrase. NSC 158393, which contains four 4-hydroxycoumarin residues, was found to exhibit antiviral, antiprotease, and antiintegrase activity. Both the DNA binding and catalytic activities (3'-processing and strand transfer) of integrase were inhibited at micromolar concentrations. Disintegration catalyzed by an integrase mutant containing only the central catalytic domain was also inhibited, indicating that the binding site for these compounds resides in the central 50-212 amino acids of HIV-1 integrase. Binding at or near the integrase catalytic site was also suggested by a global inhibition of the choice of attacking nucleophile in the 3' processing reaction. NSC 158393 inhibited HIV-2, feline, and simian immunodeficiency virus integrases while eukaryotic topoisomerase I was inhibited at higher concentrations, suggesting selective inhibition of retroviral integrases. Molecular modeling studies revealed that the two hydroxyls and two carbonyl moieties in NSC 158393 may represent essential elements of the pharmacophore. Antiviral efficacy was observed with NSC 158393 derivatives that inhibited both HIV protease and integrase, and the most potent integrase inhibitors also inhibited HIV protease. Hydroxycoumarins may provide lead compounds for development of novel antiviral agents based upon the concurrent inhibition of two viral targets, HIV-1 integrase and protease. PMID- 8691446 TI - Structural differences between the free and bound states of the DNA bisintercalating peptide YSPTSPSY. AB - The YSPTSPSY peptide is a DNA-bisintercalator that can adopt nonrandom conformations in solution. Strategies based on random conformational search and energy minimizations have been applied to generate populations of conformers characterizing YSPTSPSY. Subsequent analysis based on statistical methods and clustering allowed to determine the existence of four classes of conformers containing beta- and/or gamma-turns. NMR spectra of YSPTSPSY in solution provide evidence for such structures. Employing a Monte Carlo-based docking procedure, the YSPTSPSY peptide was docked in a DNA double-helical fragment with the sequence [d(GACGTC)]2. The peptide binds on the minor groove of DNA stacking the central CG base pairs, in a manner similar to that observed in complexes of triostin A with DNA. Upon binding, the structure of the C-terminal segment is modified into a type I beta-turn. Five intermolecular hydrogen bonds are observed, but the van der Waals interactions constitute the major stabilization factor for the complex. NMR chemical shifts, coupling constants, and NOESY connectivities are in agreement with the molecular model. PMID- 8691445 TI - Chiral pyrrolo[2,3-d]pyrimidine and pyrimido[4,5-b]indole derivatives: structure activity relationships of potent, highly stereoselective A1-adenosine receptor antagonists. AB - A series of 33 novel, mostly chiral pyrrolo[2,3-d]pyrimidine and pyrimido[4,5 b]indole derivatives has been synthesized and investigated in radioligand binding assays at the high-affinity adenosine receptor (AR) subtypes A1 and A2a. The compounds can be envisaged as adenine and hypoxanthine analogs lacking the nitrogen in the 7-position (7-deazaadenines and 7-deazahypoxanthines). 7 Deazaadenines were much more potent than 7-deazahypoxanthines at AR with A1AR affinities in the low-nanomolar range, extraordinarily high selectivity for the rat brain A1AR versus the A2aAR (several thousandfold), and high stereoselectivity (up to 96-fold). Pyrimido[4,5-b]indoles were more potent A1AR antagonists compared to pyrrolo[2,3-d]pyrimidines. Compound 34a (APEPI) is one of the most potent and most selective nonxanthine A1AR antagonists known to date (Ki = 2.8 nM, > 2000-fold A1-selective). A new class of very potent A1AR antagonists has been identified, namely, 2-phenyl-7-deazaadenines bearing a substituent at the exocyclic amino group (N4-substituted pyrrolo[2,3-d]pyrimidines). (R)-N- (1 Phenylethyl)-4-amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin e (DPEAP, 17a) showed a Ki value of 6.7 nM at A1AR and > 4000-fold A1 selectivity. Different binding modes are postulated for the N4-substituted 4-aminopyrrolo[2,3 d]pyrimidines (e.g., 17a) and the 7-substituted derivatives (e.g., 1a), based on a comparison of steric, electronic, and hydrophobic properties of the two classes of compounds. Water solubility and lipophilicity have been determined for selected compounds. 4-Amino-5,6-dimethyl-2-(3-chlorophenyl)-7H-pyrrolo[2,3 d]pyrimidine (4a) showed the highest water solubility/A1AR affinity ratio of 368 in the present series, over 2000-fold A1 selectivity, and 64-fold stereoselectivity (R > S). Therefore, 4a should be an interesting compound for in vivo evaluation. PMID- 8691447 TI - Synthesis and X-ray crystal structure of trans,cis-[Pt(OAc)2I2(en)]: a novel type of cisplatin analog that can be photolyzed by visible light to DNA-binding and cytotoxic species in vitro. AB - An original approach intended to facilitate the intratumoral activation of Pt(IV) diamines by illumination with visible light to form photolysis products that irreversibly bind to DNA and are cytotoxic to human cancer cells is reported. The novel Pt(IV) complex trans,cis-[Pt(OAc)2I2-(en)] was prepared by the acetylation of trans,cis-[Pt(OH)2I2(en)] with acetic anhydride in CH2-Cl2; trans,cis [Pt(OH)2I2(en)] was synthesized by oxidation of [PtI2(en)] with 30% aqueous H2O2. trans,cis-[Pt(OAc)2I2(en)] crystallized from methanol as deep-red needles with a = 9.029(4) A, b = 11.443(2) A, c = 12.822(2) A, beta = 95.48(3) degrees, monoclinic space group Cc, and Z = 4. The conformation of the acetato groups around the O-Pt-O axis deviated significantly from the conformation of the acetato groups in the X-ray crystal structure reported for the cis-dichloro analog, which may explain the very different aqueous solubilities of the two compounds. trans,-cis-[Pt(OAc)2I2(en)] and trans,cis-[Pt(OH)2I2(en)] displayed broad ligand-to-metal charge-transfer bands centered at lambda = 389 and 384 nm, respectively (epsilon = 1372 and 1425 M-1 cm-1, respectively), with tailing out to ca. 550 nm. When trans,cis-[Pt(OAc)2I2(en)] was incubated with calf thymus DNA in the absence of light, no covalent binding of Pt to DNA was measurable after 6 h; however, irradiation with light of wavelengths > 375 nm resulted in 63 +/- 13% of the platinum being covalently bound to DNA after 6 h, suggesting that a photoreduction to Pt(II) species took place. Although trans,cis-[Pt(OH)2I2(en)] was also labile to visible light, only 10 +/- 2% DNA platination was observed after 6 h of illumination; however, covalent binding of Pt to DNA took place quantitatively when a reducing agent such as glutathione was added to the photolyzed incubations. These results provide evidence that the photolysis of the trans-dihydroxo analog resulted predominately in the substitution of the iodide ligands for water rather than a reduction of Pt(IV) to Pt(II). When protected from light, trans,cis-[Pt(OAc)2I2-(en)] and trans,cis-[Pt(OH)2I2(en)], both at a concentration of 10 microM, had half-lives of 6.6 +/- 0.5 and 46.8 +/- 8.8 h, respectively, at 37 degrees C in Eagle's minimum essential medium (EMEM) containing 5% fetal calf serum. When irradiated with light lambda(irr) > 375 nm, the half-lives were decreased by 24- and 53-fold for the diacetato- and dihydroxoplatinum(IV) complexes, respectively. Compared to the "dark" control, the in vitro treatment of TCCSUP human bladder cancer cells with trans,cis [Pt(OAc)2I2(en)] resulted in 35% greater growth inhibitory activity when during the first 1.5 h of drug exposure the cells were irradiated with light lambda irr > 375 nm. The photolysis of trans,cis-[Pt(OH)2I2(en)] with visible light resulted in a 22% enhancement of antiproliferative activity. PMID- 8691448 TI - Hypoxia-selective antitumor agents. 13. Effects of acridine substitution on the hypoxia-selective cytotoxicity and metabolic reduction of the bis-bioreductive agent nitracrine N-oxide. AB - A series of nuclear-substituted derivatives of nitracrine N-oxide (2; a bis bioreductive hypoxia-selective cytotoxin) were prepared and evaluated, seeking analogues of lower nitroacridine reduction potential. Disubstitution with Me or OMe groups at the 4- and 5-positions did not provide analogues with one-electron reduction potentials significantly lower than those of the corresponding monosubstituted derivatives (E(1) ca. -350 mV for both the 4-OMe and 4,5-diOMe compounds). This appears not to be due to a concomitant raising of the acridine pKa but to a lack of direct electronic effect of substituents in the ring not bearing the nitro group. Conversely, placing two OMe groups in the nitro-bearing ring does result in a substantial further lowering of reduction potential (the 2,4-diOMe analogue has an E(1) of -401 mV). The mono- and disubstituted N-oxides have substantially lower cytotoxicities than the parent nitracrine N-oxide 2 but generally retain very high hypoxic selectivity. The OMe-substituted N-oxides all showed greater metabolic stability than 2 in hypoxic AA8 cell cultures, and the 4 OMe compound 6 had improved activity in EMT6 multicellular spheroids suggesting that this metabolic stabilization may allow more efficient diffusion in tumor tissue. The parent compound 2 was selectively toxic to hypoxic cells in KHT tumors in vivo and clearly superior to nitracrine itself (although only at doses which would eventually be lethal to the host). The analogues of lower E(1), including 6, were not superior to 2 in vivo, indicating that metabolic stabilization of the nitro group is not alone sufficient to improve therapeutic utility. PMID- 8691449 TI - Hypoxia-selective antitumor agents. 14. Synthesis and hypoxic cell cytotoxicity of regioisomers of the hypoxia-selective cytotoxin 5-[N,N-bis(2 chloroethyl)amino]-2,4-dinitrobenzamide. AB - A series of regioisomers of the novel hypoxia-selective cytotoxin (HSC) 5-[N,N bis(2-chloroethyl)-amino]-2,4-dinitrobenzamide (2a) have been prepared by displacement of the chloro group from methyl chlorodinitrobenzoates or the corresponding carboxamides with diethanolamine, followed by dimesylation and mesylate displacement with LiCl. The compounds fall into two classes, where the two nitro groups have either a meta or an ortho (or para) disposition to each other. The four meta derivatives had one-electron reduction potentials in the range -340 to -375 mV, similar to that of the known isomer 2a, while the other isomers had much higher values (-262 to -285 mV). The meta derivatives were much less cytotoxic to AA8 cells under aerobic conditions (IC50s from 75 to 470 microM) than were the other compounds (IC50s from 1.6 to 20 microM). However, the ratios of IC50s of the compounds in repair-proficient (AA8) and repair-deficient (UV4) cell lines varied, indicating differing contributions of DNA alkylation to aerobic toxicity between the isomers, with no clear relationship between this and nitro group disposition. The hypoxic selectivities of the (dimethylamino)ethylcarboxamide analogues for each isomer were determined by clonogenic assay against both AA8 and UV4 cells. With one exception, the meta derivatives showed excellent hypoxic selectivities (ca. 45-115-fold) against UV4 cells, while the ortho or para isomers had little selectivity (ca. 2-7-fold). A possible reason may be that the latter compounds, with higher reduction potentials, undergo rapid bioreduction even under aerobic conditions. None showed hypoxic selectivities greater than 2-3-fold against AA8 cells. The 3-[N,N-bis(2 chloroethyl)amino]-2,6-dinitrobenzamide isomer (5b), which showed the highest hypoxic selectivity for UV4 cells in this series, was active against both hypoxic and aerobic cells in KHT tumors in mice at well-tolerated doses, and showed superior in vivo activity to the previously studied 2,4-dinitro isomer 2b. PMID- 8691450 TI - Synthesis and biological evaluation of new imidazole, pyrimidine, and purine derivatives and analogs as inhibitors of xanthine oxidase. AB - Several derivatives of 4,5-disubstituted imidazole, 2,4,5-trisubstituted pyrimidine, 2-substituted purine, thiazolo[3,2-alpha]purine, [1,3]thiazino[3,2 alpha]purine, thiazolo[2,3-i]purine, [1,3]thiazino-[2,3-i]purine, and 6 substituted pyrazolo[3,4-d]pyrimidine were synthesized and tested as inhibitors of the xanthine oxidase enzyme. Of those, some 4-(acylamino)-5 carbamoylimidazoles and 2-thioalkyl-substituted purines exhibited very good inhibitory activity, being at least 500 times more effective than allopurinol. The ineffectiveness of 6-n-alkylpyrazolo[3,4-d]pyrimidines is imputable to the alkyl chain which could hinder the coordination with molybdenum according to the known mechanism for the binding of the inhibitor allopurinol; the effectiveness of imidazole derivatives, by contrast with the ineffectiveness of 4,5-diamino-2 (thioalkyl)-6-hydroxypyrimidines, indicates the relative importance of the five membered ring in the interaction with the enzyme. Moreover, the marked effectiveness of the angularly-cyclized [1,3]thiazino[2,3-i]purinones, which constitute an interesting new class of inhibitors, together with the weak activity of linearly-cyclized derivatives, allowed us to characterize more precisely the lipophilic region of the enzyme facing the N(1)-C(2) positions of the substrate hypoxanthine. PMID- 8691452 TI - Molecular modeling and site-directed mutagenesis studies of a phorbol ester binding site in protein kinase C. AB - The protein kinase C (PKC) binding site used by PKC activators such as phorbol esters and diacylglycerols (DAGs) has been characterized by means of molecular modeling and site-directed mutagenesis studies. Based upon a NMR-determined solution structure of the second cysteinerich domain of PKC alpha, molecular modeling was used to study the structures of the complexes formed between the PKC receptor and a number of PKC ligands, phorbol esters, and DAGs. Site-directed mutagenesis studies identified a number of residues important to the binding of phorbol esters to PKC. Analysis of the molecular modeling and mutagenesis results allows the development of a binding model for PKC ligands for which the precise binding nature is defined. The calculated hydrogen bond energies between the protein and various ligands in this binding model are consistent with their measured binding affinities. The binding site for phorbol esters and DAGs is located in a highly conserved, hydrophobic loop region formed by residues 6-12 and 20-27. For the binding elements in phorbol esters, the oxygen at C20 contributes most to the overall binding energy, and that at C3 plays a significant role. The oxygen atom at C12 is not directly involved in the interaction between phorbol esters and PKC. Our results also suggest that the oxygens at C9 and C13 are involved in PKC binding, while the oxygen at C4 is of minimal significance. These results are consistent with known structure-activity relationships in the phorbol ester family of compounds. Comparisons with the X ray structure showed that although the X-ray data support the results for oxygens at C3, C12, and C20 of phorbol esters, they suggest different roles for oxygens at C4, C9, and C13. Several factors which may contribute to these discrepancies are discussed. PMID- 8691451 TI - Synthesis and biological evaluation of N alpha-(4-amino-4-deoxy-10-methylpteroyl) DL-4,4-difluoroornithine. AB - N alpha-(4-Amino-4-deoxy-10-methylpteroyl)-DL-4,4-difluoroornithi ne (AMPte-DL 4,4-F2Orn, 4) was synthesized and evaluated as an inhibitor of human folypoly gamma-glutamate synthetase (FPGS), dihydrofolate reductase (DHFR), and cell growth. Synthesis of 4 involved the use of a protected form of DL-4,4 difluoroornithine 9 which was derived from DL-4,4-difluoroglutamic acid. Biological activities of 4 were compared directly to those of the corresponding nonfluorinated compound N alpha-(4-amino-4-deoxy-10-methylpteroyl)-L-ornithine (AMPte-L-Orn, 3). Although the fluorinated analogue is a potent inhibitor of DHFR, it is a poor inhibitor of FPGS. However, the compound is transported across the cell membrane and inhibits cell growth, presumably due to the inhibition of DHFR. The data obtained with the fluorinated analogue are in contrast to those of the corresponding nonfluorinated compound 3, which is a potent inhibitor of both FPGS and DHFR but shows very low cytotoxicity due to poor transport. PMID- 8691453 TI - Synthesis of 3 beta-aryl-8-azabicyclo[3.2.1]octanes with high binding affinities and selectivities for the serotonin transporter site. AB - A novel entry to tropane analogs of cocaine was developed based on the reaction of rhodium-stabilized vinylcarbenoids with pyrroles. These analogs were tested in binding to dopamine, serotonin (5-HT), and norepinephrine transporters in membranes from rat striatum and frontal cortex. In all the analogs, the aryl group at the 3 position was directly bound to the tropane ring and an ethyl ketone moiety was present at the 2 position. By appropriate modification of the aryl and nitrogen substituents, highly potent and 5-HT selective tropanes were prepared. The most potent and selective compound was 3 beta-[4-(1 methylethenyl)phenyl]-2 beta-propanoyl-8-azabicyclo[3.2.1]octane (13b) which had a Ki of 0.1 nM at 5-HT transporters and was 150 times more potent at 5-HT vs dopamine transporters and almost 1000 times more potent at 5-HT vs norepinephrine transporters. PMID- 8691454 TI - Novel 3,7-diheterabicyclo[3.3.1]nonanes that possess predominant class III antiarrhythmic activity in 1-4 day post infarction dog models: X-ray diffraction analysis of 3-[4-(1H-imidazol-1-yl)benzoyl]-7-isopropyl-3,7 diazabicyclo[3.3.1]nona ne dihydroperchlorate. AB - Several 3,7-diheterabicyclo[3.3.1]nonanes (DHBCNs) were prepared and screened in the Harris dog model for their ability to abolish pace-induced and sustained ventricular tachycardia (SVT) or prevent induction of ventricular tachycardia. In addition, an electrophysiological examination was made in the infarcted hearts of each animal to determine if more than one class activity was present. The examples exhibited predominately class III antiarrhythmic activity via a prolongation of the ventricular effective refractory period (VERP) in the models, although there may well be an underlying class Ib action present as exemplified by the ability of several of the agents to slow conduction in the myocardial infarcted dog hearts. 3-[4-(1H-Imidazol-1-yl)benzoyl]-7-isopropyl-3,7 diazabicyclo[3.3.1]nonan e dihydroperchlorate displayed powerful class III activity in the model systems while several other DHBCNs exhibited various degrees of class III action. An X-ray diffraction analysis revealed that this compound has a 3,7-diazabicyclo[3.3.1]nonane bicyclic unit in a chair-chair conformation. PMID- 8691455 TI - 4-[4-[(2-Hydroxybenzoyl)amino]phenyl]butyric acid as a novel oral delivery agent for recombinant human growth hormone. AB - A series of N-acetylated, non-alpha, aromatic amino acids was prepared and shown to promote the absorption of recombinant human growth hormone (rhGH) from the gastrointestinal tract. Seventy compounds in this family were tested in vivo in rats. Of the compounds tested, 4-[4-[(2-hydroxybenzoyl)amino]phenyl]butyric acid was identified as a preclinical candidate and was used to demonstrate the oral delivery of rhGH in primates. A significant positive correlation was found between the relative log k' of the delivery agents, as determined by HPLC on an immobilized artificial membrane (IAM) column, and serum rhGH concentrations following oral or colonic dosing in rats. Structure-activity relationships have also been developed on the basis of electronic effects and hydrogen-bonding characteristics of the aromatic amide substituents. PMID- 8691456 TI - Esters and amides of 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid as inhibitors of alpha-chymotrypsin: significance of the "aromatic" nature of the novel ester-type coumarin for strong inhibitory activity. AB - A series of esters and amides of 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3 carboxylic acid were synthesized and evaluated in vitro for their inhibitory activity toward bovine alpha-chymotrypsin and human leukocyte elastase. Both series behaved as time-dependent inhibitors of alpha-chymotrypsin, but ester-type coumarins were clearly more efficient than the corresponding amides in inactivating the serine proteinase. The best inactivations were observed with "aromatic" esters, in particular with meta-substituted phenyl esters such as m chlorophenyl 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylate, which appears to be one of the most powerful inactivators of alpha-chymotrypsin yet reported (kinact/KI = 760,000 M-1 S-1 at pH 7.5 and 25 degrees C). Usually, the coumarin derivatives failed to inhibit significantly human leukocyte elastase. As a result, the reported series of aromatic coumarinic esters behaves as a new chemical family of selective alpha-chymotrypsin inhibitors. PMID- 8691457 TI - Synthesis and biological activity of 3- and 5-amino derivatives of pyridine-2 carboxaldehyde thiosemicarbazone. AB - A series of 3- and 5-alkylamino derivatives, as well as other structurally modified analogues of pyridine-2-carboxaldehyde thiosemicarbazone, have been synthesized and evaluated as inhibitors of CDP reductase activity and for their cytotoxicity in vitro and antineoplastic activity in vivo against the L1210 leukemia. Alkylation of 3- and 5-amino-2-(1,3-dioxolan-2-yl)pyridines (1, 2) resulted in corresponding 3-methylamino, 5-methylamino, 3-allylamino, 5 ethylamino, 5-allylamino, 5-propylamino, and 5-butylamino derivatives (5, 6, and 11-15), which were then condensed with thiosemicarbazide to yield the respective thiosemicarbazones (7, 8, and 16-20). Oxidation of 3,5-dinitro-2-methylpyridine (21) with selenium dioxide, followed by treatment with ethylene glycol and p toluenesulfonic acid, produced the cyclic ethylene acetal, 23. Oxidation of 2 (1,3-dioxolan-2-yl)-4-methyl-5-nitropyridine (26) with selenium dioxide, followed by sequential treatment with sodium borohydride, methanesulfonyl chloride, and morpholine afforded the morpholinomethyl derivative 30. Catalytic hydrogenation of 23 and 30 with Pd/C yielded the corresponding amino derivatives 24 and 31. Catalytic hydrogenation of 5-cyano-2-methylpyridine (33) with Raney nickel, followed by treatment with acetic anhydride, gave the amide derivative 35. N Oxidation of 35, followed by rearrangement with acetic anhydride, produced the acetate derivative, 5-[(acetylamino)methyl]-2-(acetoxymethyl)pyridine (37). Repetition of the N-oxidation and rearrangement procedures with compound 37 yielded the diacetate derivative 39. Condensation of compounds 24, 31, and 39 with thiosemicarbazide afforded the respective 3,5-diaminopyridine-, 4-(4 morpholinylmethyl)-5-aminopyridine-, and 5-(aminomethyl)pyridine-2-carboxaldehyde thiosemicarbazones (25, 32, and 40). The most biologically active compounds synthesized were the 5-(methylamino)-, 5-(ethylamino)-, and 5 (allylamino)pyridine-2-carboxaldehyde thiosemicarbazones (8, 17, and 18), which were potent inhibitors of ribonucleotide reductase activity with corresponding IC50 values of 1.3, 1.0, and 1.4 microM and which produced significant prolongation of the survival time of L1210 leukemia-bearing mice, with corresponding optimum % T/C values of 223, 204, and 215 being obtained when administered twice daily for six consecutive days at dosages of 60, 80, and 80 mg/kg, respectively. PMID- 8691458 TI - Design of orally active dual inhibitors of neutral endopeptidase and angiotensin converting enzyme with long duration of action. AB - Mercaptoacyl dipeptides, containing a glycine linked to a C-terminal 5 phenylproline, have been synthesized in order to obtain new highly efficient dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), which are involved in the control of blood pressure and fluid homeostasis. These compounds have been designed (i) to fit optimally the ACE pharmacophore previously described (Fournie-Zaluski, M. C.; et al. J. Med. Chem. 1994, 37, 1070-1083), through interaction with the S1, S1', and S2' subsites of this enzyme, (ii) and to interact with the S1' and S2' subsites of NEP with the 5-phenylproline moiety outside the catalytic domain (Coric, P.; et al. J. Med. Chem. 1996, 39, 1210-1219). Replacement of Gly by Ala in these mercaptoacyl dipeptides induced an about 100-fold decrease in ACE inhibition. This shows that, in agreement with molecular modeling studies, a steric constraint as weak as a methyl group hinders optimal ACE active site recognition. Among these compounds, the dual inhibitor 26 (RB 106) (Ki, ACE = 0.35 nM; NEP = 1.6 nM) showed excellent pharmacokinetic properties with an almost complete in vivo inhibition of NEP and ACE for more than 4 h after oral administration in mice of a low dose (2.6 x 10(-5) mol/kg) of the inhibitor. Moreover, RB 106 remained active 12 h after oral administration. In spontaneous hypertensive rats, a chronic treatment of orally administered RB 106 (25 mg/kg/day) induced a prolonged hypotensive effect (-28 mmHg) still significant 2 days after the end of the treatment. In DOCA salt rats, a hypotensive response and a significant natriuresis were observed after i.v. administration. RB 106, which is one of the most potent dual inhibitors described to date, could have interesting clinical applications in long term treatment of congestive heart failure and myocardial ischemia. PMID- 8691459 TI - Alkyl and alkoxyethyl antineoplastic phospholipids. AB - Two series of phosphodiester ether lipid analogs with (N-methylmorpholino)ethyl or (N-methylpiperidino)ethyl polar head groups and long aliphatic or alkoxyethyl chains in the nonpolar portion of the molecule were synthesized as potential antineoplastic agents. The cytotoxic activity of these compounds (9-19) was evaluated in vitro against a panel of six human tumor xenografts and in two biochemical, mechanism-based screens (cdc2 kinase and cdc25 phosphatase). Analogs 13, 14, 17, and 19 showed activity in the in vitro tests. Specifically, 14 and 17 were more active than the reference compound hexadecylphosphocholine (Miltefosine, He-PC) while 13 and 19 possessed activity similar to that of the control. Of the analogs tested the one with the highest potency and least toxicity (17) has an N-methylpiperidino head group and a C16 alkyl chain. In the mechanism-based tests 11 showed weak inhibitory activity in the cdc25 phosphatase screen. PMID- 8691460 TI - Carbocyclic nucleosides as inhibitors of human tumor necrosis factor-alpha production: effects of the stereoisomers of (3-hydroxycyclopentyl)adenines. AB - A series of four structurally related carbocyclic nucleosides (6a, 6b, 10a, and 10b) were synthesized and evaluated for their ability to inhibit tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL 6) production from human primary macrophages. These compounds had little effect on the production of IL-1 beta and IL-6. It was determined that compound 10a was the most potent inhibitor of TNF-alpha production (IC50 = 10 microM), having 2-5 fold more activity compared to its enantiomer 10b or its diastereomers 6a and 6b. In addition, these compounds were also tested for their ability to protect mice against lethal challenges of lipopolysaccharide (LPS) and D-galactosamine (D Gal). Compound 10a showed superior protective effects (100% protection) compared to its enantiomer 10b or its diastereomers 6a and 6b when it was administered to mice which were challenged with 3 times the LD100 dose of LPS. PMID- 8691461 TI - Thermodynamic aspects of hydrophobicity and the blood-brain barrier permeability studied with a gel filtration chromatography. AB - It has been said that the selective permeability across the blood--brain barrier depends on several physicochemical properties of drugs such as hydrophobicity, molecular weight, and hydrogen-bonding potential. In order to investigate quantitatively the relationship between the blood--brain barrier permeability and the hydrophobicity of drugs, we have measured the micelle/water partition properties (Pmic) by the MLC (micellar liquid chromatography) method using a gel filtration version and compared with the blood--brain barrier permeability. The thermodynamic aspects of partition were derived by separating the micelle/water partition coefficient (log Pmic) into the enthalpy term PH and the entropy term PS. It was found that the PH shows a good correlation to the permeability, although log Pmic fails to do so. The result means that PH, which is easily obtained from the in vitro experiment, can be used as an excellent standard in discussing the transport phenomena through the blood--brain barrier. PMID- 8691462 TI - 2-substituted piperazines as constrained amino acids. Application to the synthesis of potent, non carboxylic acid inhibitors of farnesyltransferase. PMID- 8691463 TI - Active site directed inhibition of estrone sulfatase by nonsteroidal coumarin sulfamates. PMID- 8691464 TI - Geranylgeranyl diphosphate-based inhibitors of post-translational geranylgeranylation of cellular proteins. AB - A novel series of stable analogs of geranylgeranyl diphosphate (GGdP) are described in which the biologically labile diphosphate moiety of GGdP is replaced by portions that can act as stable isosters. The compounds inhibited the geranylgeranyltransferase activity in whole PC-3 prostate cancer cells, as determined by the inhibition of post-translational isoprenylation of the small GTP-binding protein p21rap 1 and the accumulation of unprocessed p21rap 1 in the cytosolic fraction. However, the compounds did not affect the farnesylation of p21ras, as shown by protein immunoprecipitation after whole cell labeling with [3 H]-(R,S)-mevalonolactone. Despite the absence of effects of post-translational processing of p21ras, these compounds proved to be cytotoxic for prostate cancer cells, with half-maximal inhibition of cell growth obtained in the range 18.5 35.1 microM. The GGdP analogs described in the this study are novel, non-peptidic inhibitors of geranylgeranylation that may be active as antitumor agents. PMID- 8691465 TI - Ligand interactions with E-selectin. Identification of a new binding site for recognition of N-acyl aromatic glucosamine substituents of sialyl Lewis X. AB - Several N-acylglucosamine derivatives of sialyl Lewis X (1-3) were prepared using a combined chemical enzymatic approach and evaluated as an inhibitor of E selectin-mediated cellular adhesion. Compounds with aromatic functionality, 1 and 2, were found to be 3-10 times more potent than the N-acetyl derivative (14) in an ELISA E-selectin cell adhesion assay. Conformational analysis with NMR indicated that the sialyl Lewis x domain of 1 retained the conformation of the N acetyl derivative (14) despite the presence of the N-naphthamido group. The dramatic order of magnitude increase in potency of these monovalent structures can be utilized to design more potent selectin-based cell adhesion inhibitors. PMID- 8691466 TI - Somatostatin receptor-binding peptides labeled with technetium-99m: chemistry and initial biological studies. AB - The synthesis of peptides which possess a high affinity for the somatostatin receptor and contain a chelator for the radionuclide technetium-99m is described. The target compounds were designed such that they would form stable, oxotechnetium(V) chelate complexes in which the Oxorhenium(V) chelate complexes of these peptides were prepared as nonradioactive surrogates for the technetium complexes. Peptide oxorhenium complexes and Tc-99m complexes eluted closely upon HPLC analysis. The receptor-binding affinities of both the free and rhenium coordinated species were measured in vitro. The binding affinities of the free peptides (Ki's in the 0.25 - 10 nM range) compared favorably with [DTPA]octreotide (Ki = 1.6 nM), which, as the indium-111 complex, is already approved for somatostatin receptor (SSTR)-expressing tumor imaging in the United States and Europe. Furthermore, the rhenium-coordinated peptides had binding affinities which, in many cases, were higher than those of the corresponding free peptides, with several complexes having a Ki's of 0.1 nM. Some of the more potent SSTR-binding peptides were labeled with technetium-99m and assessed in an in vivo study with tumor-bearing rats. The 99m Tc-labeled peptides prepared in this study should be useful as SSTR-expressing tumor-imaging agents due to their high SSTR binding affinities, ease of preparation, and, because they are low molecular weight peptides, expected pharmacokinetics characterized by rapid tracer excretion from the body resulting in high-contrast images. PMID- 8691467 TI - Thrombus imaging using technetium-99m-labeled high-potency GPIIb/IIIa receptor antagonists. Chemistry and initial biological studies. AB - Platelet-specific compounds which are radiolabeled with gamma-emitting radionuclides may be particularly useful for the noninvasive in vivo detection of thrombi. The synthesis of peptides which are potent inhibitors of platelet aggregation and which contain a chelator for the radionuclide technetium-99m are described. The target compounds were designed such that stable, oxotechnetium(V) species could be prepared where the site of metal coordination was well defined. A strategy was employed where the pharmacophore-Arg-Gly-Asp-(RGD), or RGD mimetic, was constrained in a ring which was formed by the S-alkylation of a cysteine residue with an N-terminal chloroacetyl group. Binding affinities were enhanced by the replacement of arginine with the arginine mimetics S-(3 aminopropyl)cysteine and 4-amidinophenylalanine. Further enhancements could be obtained by the synthesis of oligomers which contained two or more rings containing receptor binding regions. The increase in binding affinity seen was more than that expected from a simple stoichiometric increase of pharmacophore. The most potent compounds described had IC50s of approximately 0.03 microM for the inhibition of human platelet aggregation. Two of the more potent peptides (P280 and P748) were labeled with technetium-99m and assessed in a canine thrombosis model. The 99m Tc complexes of the peptides prepared in this work hold promise as thrombus imaging agents due to their high receptor binding affinity, ease of preparation, and expected rapid pharmacokinetics. PMID- 8691468 TI - Antitumor agents. 163. Three-dimensional quantitative structure-activity relationship study of 4'-O-demethylepipodophyllotoxin analogs using the modified CoMFA/q2-GRS approach. AB - Analogs of 4'O-demethylepipodophyllotoxin are considered as potential anticancer agents. We have applied comparative molecular field analysis (CoMFA) and a novel CoMFA/q2-GRS technique recently developed in our group to identify the essential structural requirements for increasing the ability of these compounds to form cellular protein-DNA complex. In addition, a new method to incorporate different types of probe atoms as part of q2-GRS routine has been developed. The best final model with 101 compounds using a combination of four different sets of probe atoms and charges [C (sp3, +1), C (sp3, 0), H (+1), and O (sp3, -1)] yielded a q 2 of 0.584 and the standard error of prediction of 0.660 at 5 principal components. The steric and electrostatic contour plots of the final model were compared with the DNA phosphate backbone environment of the DNA-4'O demethylepipodophylltoxin analog complex, which was generated using the X-ray structure of the DNA-nogalamycin complex. The comparison reveals that the CoMFA steric and electrostatic fields are compatible with stereochemical properties of the DNA backbone. The results obtained from this study shall guide our future synthetic efforts. PMID- 8691469 TI - Antitumor agents. 164. Podophenazine, 2'',3''-dichloropodophenazine, benzopodophenazine, and their 4 beta-p-nitroaniline derivatives as novel DNA topoisomerase II inhibitors. AB - We report here the synthesis and biological evaluation of novel DNA topoisomerase II inhibitors, podophenazine (8), 2'',3'' "-dichloropodophenazine (9), and benzopodophenazine (10), and their 4beta-p-nitroaniline derivatives 13-15. Among these, 4'-0-demethyl-4beta-(4'''- nitroanilino)-4-desoxypodophenazine (13) and 4' O-demethyl-2'',3''-dichloro-4beta-(4-'''-nitroanilino)-4- desoxypodophenazine (14) were found to inhibit KB cells at sub-micromolar concentrations (IC50 = 0.11 +/- 0.03 and 0.48 +/- 0.17 microM, respectively. Against KB/7d cells (a pleiotrophic multiple drug-resistant subclone selected with etoposide which has reduced level of topoisomerase II), only compound 13 out of a target series maintained activity in the sub-micromolar concentration range with a IC 50 value of 0.56 +/- 0.13 mu M. The differential toxicity ratio for 13 [IC 50 (KB/7d)/IC 50 (KB)] was approximately 5. Unlike etoposide and its congeners, compounds 13 and 14 were found to be weak inhibitors of the catalytic activity of topoisomerase II (IC100 = > 100 and > 150 microM, respectively). In vitro protein linked DNA complex formation assay revealed that 13 and 14, respectively, induced marginal response (13 at 1 microM, 320.3 +/- 124.5 cpm; 13 at 50 microM, 308.8 +/ 139.9 cpm; 13 at 100 mu M, 446.0 +/- 153.5 cpm) and no response (14 at 1 microM, 104.9 +/- 52.6 cpm; 14 at 50 microM, 103.3 +/- 42.6 cpm; 14 at 100 microM, 101.4 +/- 35.2 cpm) compared to the enzyme control. On the basis of these results, we conclude that the mechanism of enzyme inhibition of these compounds is distinct from that of etoposide and its congeners. We are currently investigating the mechanism(s) of action of compounds 13 and 14 as well as synthesizing other derivatives in order to better characterize structure-activity relationships of this series of compounds. PMID- 8691470 TI - Nucleoside analogs. 14. The synthesis of antitumor activity in mice of molecular combinations of 5-fluorouracil and N-(2-Chloroethyl)-N-nitrosourea moieties separated by a three-carbon chain. AB - 5-fluorouracil (5-FU) seco-nucleosdies having as the "sugar" moiety a two-carbon (C2) side chain carrying a N-(2-chloroethyl)-N-nitrosourea group were designed as molecular combinations of antimetabolite and alkylating agent, but hydrolytic release of free 5-FU was not fast enough for significant contribution to the high activity they showed against colon and breast tumors in mice. In the present study of the synthesis of the more reactive C3 seco-nucleosides, it emerged that, of various groups attached to the aldehydic center in the precursor phthalimides, only the alkoxy/uracil-1-yl type was conveniently obtained by the standard method. The methylthio/uracil-1-yl analog required relatively large amounts of reagent methanethiol, and exploration of alternatives involving alpha chlorination of alkyl methyl sulfide or Pummerer rearrangement of its S-oxide, or successive hydrolysis and methylation of isothiouronium bromide, gave disappointing yields. For successful preparation of the alkoxy/uracil-3-yl compounds, the route used for C2 homologs required considerable experimental modification. In addition to these O,N- and S,N-acetals, some N,N-acetals bearing two 5-FU residues were prepared. The new drugs have been tested against a panel of experimental tumors in mice. Although it is evident from a parallel study that even these C3 seco-nucleosides release free 5-FU too slowly in vivo, several of them have shown impressive anticancer activity. Reviewing their performance in comparison with earlier molecular combinations, a short list of seven [B.4152 (6), B.4015 (5), B.4030 (10), B.3999 (4), B.3995 (2), B.4083 (3), and B.3996 (the N 3-substituted analog of 1)] should be investigated further. This is particularly appropriate in light of the present understanding of the mode of action of chloroethylating agents. Following a prolonged period of clinical impatience with nitrosoureas because of limited selectivity action, a new era is confidently anticipated as these powerful drugs are increasingly studied in combination with O6-benzylguanine and other more efficient inhibitors of repair enzymes like O6-alkylguanine-DNA-alkyltransferase now being developed. PMID- 8691471 TI - The squalestatins: inhibitors of squalene synthase. Enzyme inhibitory activities and in vivo evaluation of C3-modified analogues. AB - Squalestatin analogues modified at C3 were prepared and evaluated for their ability to inhibit rat liver microsomal squalene synthase in vitro. While the 4,6 dimethyloctenoate ester group at C6 was maintained, a number of modifications to the C3 carboxylic acid were well tolerated. However, in the absence of the C6 ester group, similar modifications to the C3 carboxyl group caused loss of activity. Selected compounds were evaluated for their ability to inhibit cholesterol biosynthesis in vivo in rats 1 and 6 h postadministration. Analogues of squalestatin 1 (S1) modified at C3 were found to possess a shorter duration of effect in vivo which is reflected in their substantially reduced ability to lower serum cholesterol levels in marmosets. Significant cholesterol lowering (up to 62%) for the C3 hydroxymethyl analogue 1b was observed only when this compound was dosed three times a day for 3 days. PMID- 8691472 TI - Acyl-CoA:Cholesterol O-acyltransferase (ACAT) inhibitors. 2. 2-(1,3-Dioxan-2-yl) 4,5-diphenyl-1H-imidazoles as potent inhibitors of ACAT. AB - The second in this series of papers concerns our further investigations into the search for a potent bioavailable acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor suitable for the treatment of atherosclerosis. The design, synthesis, and structure-activity relationship for a series of ACAT inhibitors based on the 2-(1,3-dioxan-2-yl)-4,5-diphenyl-1H-imidazole pharmacophore are described. Compounds such as 13a bearing simple alkyl or hydroxymethyl substituents at the 5 position of the 1,3-dioxane ring are potent bioavailable inhibitors of the rat hepatic microsomal enzyme in vitro (IC50 < 100 nM) but are only weak inhibitors of the human hepatic enzyme. We have found however that 1,3-dioxanes substituted at the 5-cis position with pyrazolylalkyl or aminoalkyl groups are potent inhibitors in vitro of human macrophage ACAT, the potency depending on the nature of the terminal heterocycle and the length of the alkyl chain. An ex vivo bioassay herein demonstrates that potent inhibitors such as 13t (IC50 = 10 nM) which contain lipophilic terminal heterocycles do not appear to be systematically available. Less potent but more water soluble compounds such as 13h (IC50 = 60 nM) and 13n (IC50 = 70 nM) are absorbed following oral dosing and achieve plasma levels significantly in excess of their IC50 for ACAT inhibition. These compounds are therefore possible candidates for further investigation as oral antiatherosclerotic agents. PMID- 8691473 TI - Synthesis and hypolipidemic activities of novel 2-[4 [diethoxyphosphoryl)methyl]phenyl]quinazolines and 4(3H)-quinazolinones. AB - The novel compound NO-1886, 4-[(diethoxyphosphoryl)methyl]-N-(4-bromo-2 cyanophenyl)-ben zamide, is a hypolipidemic agent, which appears to increase lipoprotein lipase activity in rats. Various analogs of NO-1886 were synthesized to study the structure-activity relationship of this hypolipidemic drug. A novel series of quinazolines and 4(3H)-quinazolinones were prepared by cyclization of NO-1886 derivatives. Derivatives bearing a 4-[(diethoxyphosphoryl)-methyl]phenyl] group at the 2-position were found to lower triglyceride and total cholesterol levels. In accord with the decrease in log P*, quinazolines and 4(3H) quinazolinones showed good absorption and hypolipidemic activity. When the quinazolinone ring system is substituted at positions 6 and 7 with methoxy groups, increased hypolipidemic activity was observed. The highest hypolipidemic activity was observed when the 3-position was substituted by a methyl or benzyl group. PMID- 8691474 TI - 2,4-diamino-5-deaza-6-substituted pyrido[2,3-d]pyrimidine antifolates as potent and selective nonclassical inhibitors of dihydrofolate reductases. AB - Fifteen novel nonclassical and two classical 2,4-diamino-6 (benzylamino)pyrido[2,3-d]pyrimidine antifolates were synthesized as potential inhibitors of Pneumocystis carinii, (pc) Toxoplasma gondii, (tg) rat liver (rl), and human (h) recombinant dihydrofolate reductases (DHFR). These analogues lack a 5-methyl substitution which has been shown to be important for increased hDHFR inhibitory activity. In addition, they contain a reversal of the C9-N10 bridge present in folates and most antifolates. The synthesis of the compounds involved the reaction of 2,4,6-triaminopyrimidine with the sodium salt of nitromalonaldehyde to afford the key intermediate 2,4-diamino-6-nitropyrido[2,3 d]pyrimidine (7), in a single step. Reduction of 7 to the 2,4,6 triaminopyrido[2,3-d]pyrimidine (8), followed by reductive amination with the appropriate benzaldehydes or phenylacetaldehydes afforded the target compounds. N9 methylation of these analogues was carried out using formaldehyde and sodium cyanoborohydride. The analogues demonstrated significant inhibition of pcDHFR and tgDHFR. N9 methylation significantly increased DHFR inhibitory potency. Compound 11, the 3'4'5'-trimethoxy-substituted analogue with a selectivity ratio of 9.4 for tgDHFR (compared to rlDHFR) was the most selective analogue of the nonclassical series. Compound 22, the N9 methyl 2'5'-dimethoxy-substituted analogue was the most potent analogue against tgDHFR (IC 50 = 6.3 nM) and was the second most selective analogue for tgDHFR (compared to rlDHFR) in the nonclassical series. The naphthyl-substituted analogues 23-25 were generally more potent against rlDHFR than against pcDHFR and tgDHFR. Selected analogues were also evaluated against Streptococcus faecium (sf) DHFR, Escherichia coli (ec) DHFR, Lactobacillus casei (lc) DHFR and tgDHFR with hDHFR as the mammalian reference, under slightly different assay conditions than those employed for rlDHFR. Analogues 11 and 22 had selectivity ratios of greater than 100 for tgDHFR (compared to hDHFR). Analogue 22 in particular, was the most selective analogue of the nonclassical series against tgDHFR (selectivity ratio = 303.5) with excellent potency (28 nM). Analogue 11, also displayed significant selectivity for sfDHFR (selectivity ratio = 4902). Compound 22 was evaluated in vivo for the inhibition of the growth of T.gondii trophozoites in mice, where at 50 mg/kg orally, it demonstrated distinct prolongation of survival without toxicity. Compounds 11, 12 and 21-23 were evaluated as antitumor agents in the National Cancer Institutes preclinical in vitro screening program. Compounds 12, 22, and 23 showed GI50s for tumor growth inhibition in the 10 -6 - 10 -7 M range. PMID- 8691475 TI - Synthesis and cytotoxicity of 1,2-disubstituted naphth[2,3-d]imidazole-4,9-diones and related compounds. AB - As part of our continuing search for potential anticancer drug candidates that are selective against slowly growing solid tumors, we have synthesized several series of 1- and 2-substituted derivatives of the lead structure, 1-ethyl-2 methylnaphth[2,3-d]imidazole-4,9-dione (5). Their cytotoxic activity in the National Cancer Institute's in vitro cancer cell line panel is reported. In general, substitution of various alkyl, phenyl, or benzyl moieties did not improve activity, and compound 5 remains the most active naphth[2,3-d]imidazole 4,9-dione derivative. However, high levels of activity and selectivity were found with several related 2-(acylamino)-3-chloro-1,4-naphthoquinones (2f-j). Compound 2i, 2-[(2-fluorophenyl)acetamido]-3-chloro-1,4-naphthoquinone, has been selected for further in vivo testing and as an additional lead compound for further structural modification. PMID- 8691476 TI - Synthesis and DNA interactions of benzimidazole dications which have activity against opportunistic infections. AB - Considerable evidence now indicates that DNA is the receptor site for dicationic benzimidazole anti-opportunistic infections agents (Bell, C.A.; Dykstra, C.C.; Naiman N.A.I.; Cory, M.; Fairley, T.A.; Tidwell, R.R. Antimicrob. Agents Chemother. 1993, 37, 2668-2673. Tidwell R.R.; Jones, S.K.; Naiman, N.A.; Berger, I.C.; Brake, W.R.; Dykstra, C.C.; Hall, J.E. Antimicrob. Agents Chemother. 1993, 37, 1713-1716). To obtain additional information on benzimidazole-receptor complexes, the syntheses and DNA interactions of series of symmetric benzimidazole cations, linked by alkyl or alkenyl groups, have been evaluated. Biophysical techniques, thermal denaturation measurement (deltaTm), kinetics, and circular dichroism (CD) have been used in conjunction with NMR and molecular modeling to evaluate the affinities, binding mode, and structure of complexes formed between these compounds and DNA. All the compounds bind strongly to DNA samples with four or more consecutive AT base pairs, and they bind negligibly to GC rich DNA or to RNA. Spectral and kinetics characteristics of the benzimidazole complexes indicate that the compounds bind in the DNA minor groove at AT sequences. NMR and molecular modeling of the complex formed between an ethylene linked benzimidazole derivative, 5, and the self-complementary oligomer d(GCGAATTCGC) have been used to establish structural details for the minor groove complex. These results have been used as a starting point for molecular mechanics calculations to refine the model of the minor groove-benzimidazole complex and to draw conclusions regarding the molecular basis for the effects of substituent changes on benzimidazole-DNA affinities. PMID- 8691477 TI - N6,C8-distributed adenosine derivatives as partial agonists for adenosine A1 receptors. AB - The synthesis and biological evaluation of N6, C8-disubstituted derivatives of adenosine as potential partial agonists for adenosine receptors is described. Via three routes, two series of compounds were prepared, viz., N6 cyclopentyladenosine derivatives 3a-e and C8-(cyclopentylamino)adenosine analogs 3e and 9a-d, respectively. The X-ray structure determination of one of these compounds, N6-ethyl-8(cyclopentylamino)adenosine (9b), was carried out (orthorhombic, space group P2(1)2(1)2(1) (No. 19) with a = 11.039(3), b = 8.708(2), and c = 24.815(12) angstrom, Z=4,R1=0.0974,R2(W) = 0.2455). Due to intramolecular hydrogen bonding, the ribose moiety of this compound is in an anti conformation. The compounds were tested in vitro in radioligand binding studies, yielding their affinities for A1 and A2a adenosine receptors. All compounds appeared A1 selective, with affinities in the high nanomolar, low micromolar range. On A1 receptors the so-called GTP shift was also determined, i.e., the ratio between the affinities measured in the presence and absence of 1 mM GTP. All GTP shifts (values between 1.1 and 3.8) were lower than the GTP shift for CPA (6.0). This GTP shift appeared indicative for partial agonism in vivo, since the N6-cyclopentyladenosine derivatives showed lower intrinsic activities than the prototypic full agonist N6-cyclopentyladenosine on the decrease in heart rate in conscious, normotensive rats. PMID- 8691478 TI - Bradykinin receptor antagonists containing N-substituted amino acids: in vitro and in vivo B(2) and B(1) receptor antagonist activity. AB - We report a systematic probing of the structural requirements of the bradykinin (BK) type 2 (B(2)) receptor for antagonist activity by incorporating N-alkyl amino acid residues at positions 7 and 8 of a potent antagonist sequence. Compound 1 (D-Arg(0)-Arg(1)-Pro(2)-Hyp(3)-Gly(4)-Thi(5)-Ser(6)-D-Tic(7)-N-Chg (8) Arg(9), CP-0597)(1,2) is a potent (pA(2) = 9.3, rat uterus; pK(i) = 9.62, binding, human receptor clone) B(2) receptor antagonist devoid of in vitro B(1) antagonist activity (rabbit aorta). Compound 1 exhibits high potency (ED(50) = 29.2 pmol/kg/min, iv, rabbit) and duration of action when tested in models for in vivo B(2) antagonist activity. Although devoid of activity in a classic B(1) isolated tissue assay, B(1) antagonist activity for 1 was demonstrated in vivo, in a LPS-treated, inducible BK(1) receptor rabbit blood pressure model (ED(50) = 1.7 nmol/kg/min). D-Arg(0) of 1 can be formally replaced by an achiral arginine surrogate, without significant loss in antagonist potency on rat uterus (compound 11, B(2) pA(2) = 9.1). Antagonist 13 (Hyp(2), Nchg(8)), pK(i) = 10.2, and agonist 4 (N-methylcyclohexyl-Gly(8)), pK(i) = 10.1, also exhibited substantial binding to guinea pig ileum membrane receptors as well as a human B(2) receptor clone. Very minor structural changes in the N-alkyl amino acid residues in positions 7 and 8 can modify the activity of this class of compounds from being extremely potent antagonists to tight binding partial or full agonists. These studies have resulted in a series of compounds containing inexpensive amino acid residues but which produce broad spectrum BK receptor blocking potency and exceptional in vivo duration of action. PMID- 8691479 TI - trans-2-Aryl-N,N-dipropylcyclopropylamines: synthesis and interactions with 5 HT(1A) receptors. AB - Twelve N,N-dipropyl-substituted derivatives of trans-2-arylcyclopropylamine have been prepared and assayed for their ability to displace [(3)H]-8-OH-DPAT from rat brain 5-HT(1A) receptors. The new derivatives include phenyl (7a), bromo- (7b) and fluorophenyl (7c-e), 2-methoxy-5-fluorophenyl (7h), and 2-hydroxy-5 fluorophenyl (7l) as well as trifluoromethylphenyl (7f) and 2,3-dichlorophenyl (7g) analogues. In the present series of compounds, electron-withdrawing substituents in the phenyl ring appear to decrease the affinity for 5-HT(1A) receptors. In contrast, electron-rich aryl groups, such as 2- or 3-thienyl (7j and 7k, respectively), provide compounds with high affinity. The additional bulk produced by the aromatic moiety in the 2-benzothienyl derivative 7i appears to be detrimental to 5-HT(1A) receptor affinity. The racemic mixtures of the interesting 7j and 7l were resolved into the enantiomers; 7j and 7l exhibited a high enantiomeric 5-HT(1A) receptor affinity ratio (75-fold and 100-fold, respectively). The enantiomers of 7j and 7l were evaluated in vivo by use of biochemical and behavioral tests in rats. Compound (1R,2R)-7j behaved as a partial agonist whereas (1R,2S)-7l appeared as an efficacious 5-HT(1A) receptor agonist, stimulating both autoreceptors and postsynaptic receptors. PMID- 8691480 TI - Influence of glutathione on the oxidation of 1-methyl-6-hydroxy-1,2,3,4 tetrahydro-beta-carboline: chemistry of potential relevance to the addictive and neurodegenerative consequences of ethanol use. AB - Recent evidence suggests that intraneuronal metabolism of ethanol by catalase/H2O2 and an ethanol-inducible form of cytochrome P450 together generate acetaldehyde and oxygen radicals including the hydroxyl radical (HO.). Within the cytoplasm of serotonergic neurons, these metabolic processes would thus provide acetaldehyde, which would react with unbound 5-hydroxytryptamine (5-HT) to give 1 methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline (1), known to be formed at elevated levels in the brain following ethanol drinking, and HO. necessary to oxidize this alkaloid. In this study, it is demonstrated that the HO.-mediated oxidation of 1 at physiological pH yields 1-methyl-1,2,3,4-tetrahydro-beta carboline-5,6-dione (8) that reacts avidly with free glutathione (GSH), a significant constituent of axons and nerve terminals, to give diastereomers of 8 S-glutathionyl-1-methyl-1,2,3,4-tetrahydro-beta-carboline-5,6-dione (9A and 9B). In the presence of free GSH, ascorbic acid, other intraneuronal antioxidants/reductants, and molecular oxygen diastereomers, 9A/9B redox cycle in reactions that generate H2O2 and, via trace transition metal ion catalyzed decomposition of the latter compound, HO.. Further reactions of 9A/9B with GSH and/or HO. generate several additional glutathionyl conjugates that also redox cycle in the presence of intraneuronal reductants and molecular oxygen forming H2O2 and HO.. Thus, intraneuronal formation of 1 and HO. as a consequence of ethanol drinking and resultant endogenous synthesis of 8,9A, and 9B would, based on these in vitro chemical studies, be expected to generate elevated fluxes of H2O2 and HO. leading to oxidative damage to serotonergic axons and nerve terminals and the irreversible loss of GSH, both of which occur in the brain as a consequence of ethanol drinking. Furthermore, deficiencies of 5-HT and loss of certain serotonergic pathways in the brain have been linked to the preference for and addiction to ethanol. PMID- 8691481 TI - Synthesis and evaluation of N-(phenylacetyl)trifluoromethanesulfonamides as anticonvulsant agents. AB - A series of N-(phenylacetyl)trifluoromethanesulfonamides (3a-g) was prepared according to the Topliss scheme in order to determine if aryl substituents would influence anticonvulsant activity. In initial (phase I) screening and quantitative (phase II) evaluation, all seven compounds exhibited significant activity against MES- and scMet-induced seizures. N (Phenylacetyl)trifluoromethanesulfonamide (3a) was then advanced through five additional testing phases (phases III-VII). Compound 3a displayed good oral bioavailability, low toxicity, and a larger protective index in mice than the prototype drugs, phenytoin, phenobarbital, valproate, and ethosuximide. Additionally, 3a exhibited a longer time to peak effect in all tests and a greater 24-h margin of safety (HD(50)/ED(50)) than the prototypes. Compound 3a blocked picrotoxin-induced seizures but was ineffective against seizures induced by bicuculline or strychnine. In vitro receptor binding studies revealed that 3a did not displace [(3)H]-labeled gamma-aminobutyric acid or [(3)H]-labeled flunitrazepam, and tolerance did not develop during a 5-day chronic administration. PMID- 8691482 TI - A structure-activity relationship study of novel phenylacetamides which are sodium channel blockers. AB - A structure-activity relationship study of a series of novel Na(+) channel blockers, structurally related to N-[3-(2,6-dimethyl-1-piperidinyl)propyl]-alpha phenylbenzeneacetamide (1, PD85639) is described. The diphenylacetic acid portion of the molecule was left unchanged throughout the study, while structural features in the amine portion and the amide alkyl linkage of the molecule were modified. The compounds were tested for inhibition of veratridine-stimulated Na(+) influx in CHO cells expressing type IIA Na(+) channels. Several derivatives show a trend toward more potent Na+ channel blockade activity with increasing lipophilicity of the amine portion of the molecule. The presence of a phenyl ring near the amine increases inhibitory potency. A three-carbon spacer between the amide and amine is optimal, and a secondary amide linkage is preferred. PMID- 8691483 TI - Evolutionary optimization in quantitative structure-activity relationship: an application of genetic neural networks. AB - A new hybrid method (GNN) combining a genetic algorithm and an artificial neural network has been developed for quantitative structure-activity relationship (QSAR) studies. A suitable set of molecular descriptors are selected by a genetic algorithm. This set serves as input to a neural network, in which model-free mapping of multivariate data is performed. Multiple predictors are generated that are superior to results obtained from previous studies of the Selwood data set, which is used to test the method. The neural network technique provides a graphical description of the functional form of the descriptors that play an important role in determining drug activity. This can serve as an aid in future design of drug analogues. The effectiveness of GNN is tested by comparing its results with a benchmark obtained by exhaustive enumeration. Different fitness strategies that tune the evolution of genetic models are examined, and QSARs with higher predictiveness are found. From these results, a composite model is constructed by averaging predictions from several high-ranking models. The predictions of the resulting QSAR should be more reliable than those derived from a single predictor because it makes greater use of information and also permits error estimation. An analysis of the sets of descriptors selected by GNN shows that it is essential to have one each for the steric, electrostatic, and hydrophobic attributes of a drug candidate to obtain a satisfactory QSAR for this data set. This type of result is expected to be of general utility in designing and understanding QSAR. PMID- 8691484 TI - A possible involvement of solvent-induced interactions in drug design. AB - We propose to study a new factor in designing new drugs. Most approaches to the drug design problem focus on the direct interactions between the drug and the corresponding target. We propose to study specific solvent-induced effects that can contribute to the binding Gibbs energy between the drug and its target. We estimate that these indirect effects will contribute significantly to the binding affinity and hopefully improve the clinical efficiency of the drugs. PMID- 8691485 TI - Synthesis and evaluation of a boronated nitroimidazole for boron neutron capture therapy. AB - We postulated that nitroimidazoles, previously used for radiosensitizing solid tumors, may be interesting templates as carriers of 10B for boron neutron capture therapy. To test this hypothesis, we synthesized a 10B-enriched nitroimidazole, 1 2[(undecahydro-closo-dodecaborato)thio]ethyl]-2- methyl-5-nitroimidazole (imidocaptate), by coupling the Cs salt of BSH (Cs2-10B12H11SH) with 1-(2 bromoethyl)-2-methyl-5-nitroimidazole followed by purification of the adduct. Imidocaptate was taken up by V-79 cells in culture and showed no inherent toxicity under euoxic conditions up to 1.05 mM (126 micrograms of 10B/mL of culture medium). Imidocaptate showed a dose-dependent decrease in D0 when the treated cells were irradiated with a thermal neutron beam. At the highest dose tested (126 micrograms of 10B/mL of culture medium), the ratio of control to sample D0 values was 2.6 for both linear quadratic and single-hit multitarget models. At 33 micrograms of 10B/mL, imidocaptate showed a control/treated D0 ration (1.5) equal to that observed with the disulfide form of BSH at 28 micrograms of 10B/mL. Compared to BSH and its disulfide, the reduced toxicity and equipotency of imidocaptate suggest that this agent may be useful for boron neutron capture therapy of cancer. PMID- 8691486 TI - Synthesis and evaluation of the antiproliferative effects of 1-O-hexadecyl-2-O methyl-3-O-(2'-acetamido-2'-deoxy-beta-D- glucopyranosyl)-sn-glycerol and 1-O hexadecyl-2-O-methyl-3-0- (2'-amino-2'-deoxy-beta-D-glucopyranosyl)-sn-glycerol on epithelial cancer cell growth. AB - Two ether glucosyl diglyceride analogs were synthesized, and their antiproliferative activity against four epithelial cancer cell lines was evaluated. 1-O-Hexadecyl-2-O-methyl-3-O-(2'-acetamido-2'-deoxy-beta-D- glucopyranosyl)-sn-glycerol (4) was synthesized by reaction of 2-acetamido-2 deoxy-3,4,6-tri-O-acetyl-alpha-D-glucopyranosyl chloride with 1-O-hexadecyl-2-O methyl-sn-glycerol followed by deacetylation by methanolic hydrolysis. The N acetyl group of 4 was removed by hydrolysis with ethanolic potassium hydroxide to form 1-O-hexadecyl-2-O-methyl-3-O-(2'-amino-2'-deoxy-beta-D-glucopyranosyl)- sn glycerol (5). Compounds 4 and 5 inhibited the proliferation of MCF-7, A549, A427, and T84 cancer cell lines. The IC(50) values for 5 ranged from 6.5 to 12.2 microM, whereas 4 was more effective against A549 cells (IC(50) 9 microM) than against MCF-7 (IC(50) 17 microM) and A427 (IC(50) 25 microM) cells and was inactive against T84 cells. Under identical incubation conditions, compounds 4 and 5 were potent inhibitors of the proliferation of OVCAR-3 cells with IC(50) values of 12 and 4 microM, respectively, whereas ET-18-OCH(3), hexadecylphosphocholine, and erucylphosphocholine had IC(50) values of 24, >30, and >30 microM, respectively. The cell-inhibitory profile of these ether-linked glucosyl diglycerides strengthens the hypothesis that such glycolipids represent a distinct group of antitumor ether lipids, having antineoplastic activities that differ from the well-known alkylphosphocholines and alkyllysophospholipids. PMID- 8691487 TI - Inhibition of human glutathione reductase by 10-arylisoalloxazines: crystalline, kinetic, and electrochemical studies. AB - A series of newly synthesized N(10)-arylisoalloxazines--some of which are known to be antimalarial agents--were studied as inhibitors of human glutathione reductase (GR;NADPH + GSSG + H(+) <==> NADP(+) + 2GSH). The flavoenzyme was inhibited with IC(50) values between or = 40 years about the need for cancer prevention. Articles also were printed in the monthly HMO newsletters to providers about the benefits of using these early detection methods. A review of provider claims from 574 women showed that baseline utilization rates for screening mammograms and pap smears before the intervention in year 1 (1990) were 14% and 16.4%, respectively. After the intervention, in years 2 and 3, mammograms had increased to 41% and pap smears to 38% for both years, indicating a levelling off effect of the intervention by year 3. These data show that while a significant improvement in screening behaviors was achieved, the intervention impact was limited to only about one third of the sample on the long term. Further, data do not indicate whether behavioral change was initiated as the member or provider level. More research is needed to increase overall screening behavior among the indigent and their physicians. The results reported here provide a baseline against which more intensive interventions can be measured in this setting. PMID- 8691501 TI - Acute epididymitis: a work-related injury? AB - Occupational medicine physicians frequently are presented with requests by employers to determine the work-relatedness of medical illnesses or injuries. Occasionally, this involves a sudden onset of acute epididymitis in the male employee after strenuous activity in the workplace. Because the vast majority of acute epididymitis cases have an underlying sexually transmitted disease component, this poses a real dilemma for the consulting physician. This article discusses the etiology and pathogenesis of acute epididymitis along with its epidemiologic significance and reviews workers' compensation and its possible legal interpretation when acute epididymitis occurs at the worksite. PMID- 8691502 TI - Etiology of diverticular disease with classic illustrations. AB - Diverticulosis is a common colonic disorder and often is found incidentally on colonic endoscopy and contrast enema radiographs. Theories relating to the etiology of the pathologic processes are commonly quoted, although the actual anatomic features are rarely seen during colonoscopic examinations. Here we show classic illustrations that support the widely held theories regarding the etiologies of diverticular diseases. PMID- 8691503 TI - Prolonged amenorrhea associated with total nodal irradiation for Hodgkin's disease. AB - Pelvic irradiation in the treatment of Hodgkin's disease, including total nodal irradiation, may result in substantial radiation to the ovaries unless oophoropexy and central pelvic shielding is used. Despite such precautions, temporary or permanent amenorrhea may result due to direct or scattered radiation. This article describes a 32-year-old patient who underwent oophoropexy followed by total nodal irradiation for Hodgkin's disease. The patient became amenorrheic for 14 consecutive months. Spontaneous recovery of ovarian function with resumption of menses then occurred and has remained normal to date. The occurrence of prolonged but temporary amenorrhea should be recognized after pelvic radiotherapy for the treatment of Hodgkin's disease. PMID- 8691504 TI - Proteinases in renal cell death. AB - The role of proteinases in renal proximal tubule (RPT) cellular death was examined using specific inhibitors of proteinases. Rabbit RPT suspensions were incubated with antimycin A for 1 h or tetrafluoroethyl-L-cysteine (TFEC) for 4 h in the absence or presence of the specific cysteine proteinase inhibitor L-trans epoxysuccinyl-leucylamido (4-guanidino)butane (E-64), the serine proteinase inhibitors N-p-tosyl-L-lysine chloromethyl ketone (TLCK) or 3,4 dichloroisocoumarin (DCS), the serine and cysteine proteinase inhibitors leupeptin or antipain, or the aspartic proteinase inhibitor pepstatin. E-64 and pepstatin decreased lactate dehydrogenase (LDH) release, a marker of cell death, from RPT exposed either to antimycin A or TFEC. TLCK, DCS, leupeptin, or antipain did not decrease antimycin A- or TFEC-induced cell death. Bromohydroquinone- or t butylhydroperoxide-induced cell death was not decreased by any of the proteinase inhibitors. Loss of lysosomal membrane potential, indicated by neutral red release, occurred prior to the onset of antimycin A-induced cell death. Extensive inhibition of lysosomal cathepsins B and L by E-64 was correlated with cytoprotection. However, E-64 was only protective after some cell death had occurred. These results suggest that lysosomal cysteine and aspartic proteinases, but not serine proteinases, play a role in RPT cell death induced by antimycin A or TFEC. The observation that E-64 was only protective after some cell death had occurred suggests that lysosomal cathepsins are released from dying cells and subsequently attack the remaining viable cells. PMID- 8691505 TI - Mechanism of nephrotoxicity induced by repeated administration of cadmium chloride in rats. AB - To explore the mechanism of Cd nephrotoxicity, CdCl2 was subcutaneously injected to rats, at 3 mg Cd/kg body weight once a day, for 8 d. In the liver, Cd bound to metallothioneins (MTs-Cd) rose from d 1 after the initiation of CdCl2 administration, and reached a plateau after the administration ceased. In the plasma, MTs-Cd rose from d 4, peaked on d 8, and gradually fell thereafter. In the kidneys, leucine aminopeptidase (LAP) and N-acetyl beta-D-glucosaminidase (NAG) fell during d 6-20, and Cd bound to cellular membranes (Mem-Cd) rose from d 1 and reached a plateau during d 6-20. The Mem-Cd levels were significantly correlated with the reduction in the LAP and NAG activity; the values of MTs-Cd plus Mem-Cd were almost equivalent to those of total Cd. These findings showed that the hepatic synthesis of MTs-Cd occurred followed by its release into plasma; the extent of renal injury was aggravated as the plasma level of MTs-Cd rose; and a greater part of the renal Cd distributed intracellularly as the MTs binding form, while the residual Cd distributed as the cellular membrane-binding form. Also, it was suggested that Cd that occurred as the cellular membrane- binding form in the kidneys was involved in manifestation of renal injury. PMID- 8691506 TI - Evaluation of urinary D-glucaric acid excretion in workers exposed to butyl glycol. AB - The biological follow-up of subjects exposed to butyl glycol (BG) is generally accomplished using a standard blood count that is not sensitive enough to reveal early intoxication by this molecule. For this reason we have used an indirect test for evaluating the induction of hepatic enzymes, the measurement in urine of D-glucaric acid (DGA), which reflects the activity of the glucuronic acid enzyme pathway. This study was performed on 17 foundry workers exposed to BG emissions coming from paints used in cataphoresis. The airborne concentration of BG was less than 0.3 times the average limit exposure value. This study shows that BG emissions at low concentrations are able to increase the activity of the enzymes of the glucuronic acid pathway. DGA urinary excretion increased by 165% in winter (p < .01) and by 85% (p < .05) in summer when the doors are open and the BG concentration lower. DGA urinary excretion is significantly higher in smoking than in nonsmoking exposed workers. None of these workers had a perturbed blood count. This study shows that the urinary level of DGA provides a good test for the follow-up of exposure to BG in the electrophoresis painting plant, and that the exposed smoking workers seem to be more sensitive to BG exposure than do the nonsmokers. In conclusion, the measurement of urinary DGA might be considered as a useful test for the surveillance of subjects exposed to vapors containing BG. PMID- 8691507 TI - Induction of c-myc and c-jun proto-oncogene expression in rat L6 myoblasts by cadmium is inhibited by zinc preinduction of the metallothionein gene. AB - Certain proto-oncogenes transfer growth regulatory signals from the cell surface to the nucleus. These genes often show activation soon after cells are exposed to mitogenic stimulation but can also be activated as a nonmitogenic stress response. Cadmium (Cd) is a carcinogenic metal in humans and rodents and, though its mechanism of action is unknown, it could involve activation of such proto oncogenes. Metallothionein (MT), a metal-inducible protein that binds Cd, can protect against many aspects of Cd toxicity, including genotoxicity and possibly carcinogenesis. Thus, the effects of Cd on expression of c-myc and c-jun in rat L6 myoblasts, and the effect of preactivation of the MT gene by Zn treatment on such oncogene expression, were studied. MT protein levels were determined by the Cd-heme assay, and MT, c-myc, and c-jun mRNA levels were measured using oligonucleotide hybridization and standardized to beta-actin levels. Cd (5 microM CdCl2, 0-30 h) stimulated both c-myc and c-jun mRNA expression. An initial peak of activation of c-myc expression occurred 2 h after initiation of Cd exposure, and levels remained elevated throughout the assessment period. Zn pretreatment markedly reduced the activation of c-myc expression by Cd compared to cells not receiving Zn pretreatment. Cd treatment increased c-jun mRNA levels by up to 3.5 fold. Again, Zn pretreatment markedly reduced Cd-induced activation of c-jun expression as minimal increases occurred with Cd exposures of < or = 1 h, but otherwise the Zn pretreatment prevented activation of c-jun. The Zn pretreatment elevated MT protein levels > 5-fold over control at the point of Cd exposure, but Cd exposure did not further elevate these Zn-induced MT levels. Similarly, Zn pretreatment did not result in increased relative MT mRNA levels above Cd exposure alone at various time points after Cd exposure. Therefore, Zn pretreatment, possibly by providing elevated MT protein levels at the point of Cd exposure, inhibited the Cd-induced c-myc and c-jun proto-oncogene expression. The extent of Cd-induced proto-oncogene activation thus may be limited by the presence of cellular MT. PMID- 8691508 TI - Effects of mycotoxins on cytokine production and proliferation in EL-4 thymoma cells. AB - The thymoma cell line EL4.IL-2 (EL-4) was used as a T-cell model to assess the immunotoxic effects of several mycotoxins produced by the Aspergillus-Penicillium and the Fusarium groups. EL-4 cells were stimulated with phorbol 12-myristate 12 acetate (PMA) in the presence of mycotoxins at various concentrations for 5 d and culture supernatants were analyzed for interleukins (IL) IL-2 and IL-5 by enzyme linked immunosorbent assay (ELISA). The cytokine effects were further related to proliferation and cell viability using the MTT [3-(4,5-dimethylthiazol-2-yl) 2,5 diphenyltetrazolium bromide] assay with absorbance at 570 nm (A570) as the endpoint indicator. IL-2 and IL-5 levels were dramatically increased by cyclopiazonic acid at 50-1000 ng/ml, whereas IL-2 was significantly decreased at 10 microgram/ml. Proliferation was slightly increased at 100-1000 ng/ml cyclopiazonic acid but markedly depressed at 5 and 10 microgram/ml. When EL-4 cells were exposed to 5 and 10 microgram/ml of ochratoxin A, IL-2 production was markedly increased while IL-5 production was significantly decreased. The A570 was significantly decreased by ochratoxin A at 10 microgram/ml. IL-2 and Il-5 production was almost totally suppressed by patulin at concentrations > or = 500 ng/ml and by T-2 toxin at > or = 5 ng/ml. These effects occurred concurrently with marked depression of A570 in the MTT assay. Although A570 was unaffected by either zearalenone or alpha-zearalenol exposure, both IL-2 and IL-5 levels were significantly elevated by these toxins at 5 or 10 microgram/ml. IL-2 and IL-5 production were not affected in EL-4 cells cultured with either the Aspergillus Penicillium toxins aflatoxin B1 and secalonic acid or the Fusarium toxins wortmannin, fumonisin B1, or fusaric acid at concentrations up to 10 microgram/ml. In total, the EL-4 culture studies indicated that cyclopiazonic acid, ochratoxin A, zearalenone, and alpha-zearalenol could stimulate cytokine production whereas patulin and T-2 toxin were inhibitory. Cytokine dysregulation was not always related directly to perturbations in proliferation. The results suggest that the EL-4 thymoma cell line could be a simple and effective in vitro model for evaluating immunotoxicity of various classes of environmental chemicals. PMID- 8691509 TI - Catecholamine concentrations and contractile responses of isolated vessels from hens treated with cyclic phenyl saligenin phosphate or paraoxon in the presence or absence of verapamil. AB - Blood samples and vascular segments from the ischiadic artery of hens treated with either cyclic phenyl saligenin phosphate (PSP; 2.5 micrograms/kg, im) or paraoxon (PXN; 0.1 micrograms/kg, im) in the presence or absence of verapamil, a calcium channel antagonist (7 micrograms/kg, im, given 4 consecutive days beginning the day before PSP or PXN administration), were examined 1, 3, 7, and 21 d after PSP or PXN administration in order to determine the contribution of catecholamines and peripheral blood vessel physiology and morphology to organophosphorus-induced delayed neuropathy (OPIDN). The levels of plasma catecholamines were measured by high-performance liquid chromatograpy (HPLC) and indicated a different effect with PSP, which causes OPIDN, and PXN, which does not. PSP treatment elevated the levels of norepinephrine and epinephrine throughout the study, while PXN treatment depressed the levels of these catecholamines. Verapamil treatment attenuated the OP response by approximately 50% for both compounds. Ischiadic vessel segments were isolated from OP-treated hens and perfused at a constant flow rate of 12 ml/min, then examined for their response to potassium chloride (KCl, 3 x 10(-3) M), acetylcholine (ACh), phenylephrine (PE), an alpha 1 adrenergic agonist, and salbutamol (SAL), a beta 2 adrenergic agonist. Agents were delivered in concentrations of 10(-8) to 10(-3) M. Vascular segments did not respond to ACh or SAL at any concentration used. Vessels displayed a significant reduction in contractile response to both KCl (3 x 10(-3) M) and PE (10(-8) to 10(-3) M) 3 and 21 d after exposure to either PSP or PXN. This reduced response was not altered by the presence of verapamil. Innervation of the peripheral vasculature was unchanged after OP treatment. This study indicates that plasma catecholamine levels could be differentially altered by treatment with OPs that do and do not cause OPIDN and suggests that the alterations involve intracellular calcium. In contrast, vascular response of the ischiadic artery was altered following OP treatment, but the effect was not specific for the neuropathy-inducing OP, PSP, and response was not mediated by Ca 2+, nor was it the result of autonomic nerve deterioration. PMID- 8691510 TI - Correlation between biochemical parameters and susceptibility of freshwater fish to malathion. AB - Acute toxicity (96-h LC50) of malathion was tested using five species of freshwater fish, namely, topmouth gudgeon (Pseudorasbora parva), goldfish (Carassius auratus), nile tilapia (Tilapia nilotica), mosquitofish (Gambusia affinis), and rainbow trout (Salmo gairdneri). Correlation was found between susceptibility and biochemical parameters such as activity of brain acetylcholinesterase (AChE) and in vitro resistance of the enzyme to inhibition (IC50) of malaoxon (a major metabolite of malathion). The in vitro study also showed that malaoxon instead of malathion was the main inhibitor of AChE. Susceptibility to malathion was considerably changed as the fish was pretreated with piperonyl butoxide (PB, a P-450 inhibitor) and triphenyl phosphate (TPP, an inhibitor of carboxylesterase), respectively. Toxicity of malathion was significantly increased by TPP, but the responses of fish to PB were quite different among species. This suggested that both carboxylesterase and monooxygenase played an important role in susceptibility determination, and great variations existed among species in activity of monooxygenase. PMID- 8691511 TI - Remembrance of things past--New England surgeons and infrainguinal reconstruction. PMID- 8691512 TI - Intraoperative autotransfusion in aortic surgery: comparison of whole blood autotransfusion versus cell separation. AB - OBJECTIVE: Differences concerning alteration of hemostatic, hemolysis, and hematologic parameters after transfusion of blood from a cell-separation (CS) device or whole blood autotransfusion (WBA) were prospectively evaluated during major aortic surgery. METHOD: Thirty-two patients were randomly selected to receive autologous retransfusion by using either WBA or a CS device. Coagulation and hematologic parameters and levels of hemolytic degradation products (HDP) were assessed in the retransfused blood and in the patients' plasma preoperatively and until 24 hours after autologous retransfusion, respectively. RESULTS: Mean volume of retransfused blood was 1072 +/- 473 ml in the WBA group and 556 +/- 504 in the CS group. Level of HDP (bilirubin, free hemoglobin [free HB], and lactic dehydrogenase [LDH] and hemostatic disturbances (d-dimer value, fibrin degradation products) were significantly higher in the WBA device compared with the CS blood. Blood samples taken from the WBA group revealed significantly higher level of HDP (free HB, LDH) and of d-dimer values after autotransfusion compared with the CS group. CONCLUSION: Levels of HDP and the degree of hemostatic disturbances were significantly higher in retransfused whole blood compared with CS blood. Hemostatic disturbances and levels of HDP were significantly pronounced in the patients' plasma after WBA compared with CS. CS retransfused blood seems to be of superior quality compared with WBA and the degree of hemolysis and hemostatic disturbances is minor after CS retransfusion. PMID- 8691513 TI - Carotid endarterectomy with homologous vein patch angioplasty: a review of 1006 cases. AB - PURPOSE: Because homologous vein is rarely used in vascular reconstructions, we evaluated the homologous vein as a patch for the reconstruction of the carotid bifurcation after endarterectomy. METHODS: Excess vein harvested during open heart operations was either refrigerated in saline solution or cryopreserved in a solution of 10% dimethyl sulfoxide. Donors were tested for transmissible infections, and the veins were cultured for common pathogens. Data were analyzed from 837 consecutive patients (1006 cases) who underwent carotid endarterectomy with homologous vein patch angioplasty between 1981 and 1993. RESULTS: The perioperative mortality rate was 0.8% (eight patients). Two deaths (0.2%) were attributed to ipsilateral strokes. Ischemic strokes occurred in 12 patients (1.2%; 10 ipsilateral), and ipsilateral transient ischemic attacks occurred in three patients (0.3%). Follow-up data were obtained for 482 patients (56%; mean follow-up time, 61 months; range, 1 to 132 months). Ipsilateral recurrent symptoms occurred in eight patients (1.7%; seven strokes, one transient ischemic attack). Of the 63 late deaths (13%), the majority (25 patients; 40%) were caused by complications of coronary artery disease. The 10-year overall survival rate was 76% +/- 3.2%, and the 10-year rate of freedom from late ipsilateral morbidity was 96% +/- 1.4%. The 10-year rate of freedom from late stenosis (a reduction in diameter of > or = 20%) in the 220 arteries (22%) that were studied by duplex scan was 84% +/- 2.3%. CONCLUSIONS: The postoperative mortality and neurologic morbidity rates of carotid endarterectomy with homologous vein patch angioplasty are similar to those in the best series with all types of closure. The existing long-term follow-up data indicate that the homologous vein is a durable patch that behaves like other patches used in the same location. PMID- 8691514 TI - Influence of patient-related variables on the outcome of carotid endarterectomy. AB - PURPOSE: Variability in outcome after carotid endarterectomy is well recognized. This study examines the importance of patient-related factors in determining outcome. METHODS: Four hundred and sixty consecutive patients undergoing carotid endarterectomy for symptomatic severe (60% to 99%) internal carotid stenosis performed by one vascular surgeon have been studied prospectively. Patients were followed-up at 3, 6, 9, and 12 months and then yearly. Pre-, intra-, and perioperative details and follow-up information were entered on a database. RESULTS: Multiple logistic regression identified a number of factors significantly associated with death and stroke. A history of crescendo transient ischemic attacks (TIAs) (p = 0.003, p = 0.0002) and being female (p = 0.03, p = 0.0001) were associated with both perioperative death and stroke within 30 days of operation, respectively. Deaths between 1 and 36 months were associated with ischemic heart disease (p = 0.03) and diabetes (p = 0.04), whereas stroke was associated with small internal carotid diameter (p = 0.02). The importance of symptoms at presentation on outcome was further emphasized by life-table analysis. In 98% of patients with amaurosis fugax, only 67% of those with crescendo TIAs were alive at 18 months (p < 0.01). The survival of patients with amaurosis was significantly better than those with TIAs (p < 0.01), transient stroke (p < 0.01), and progressive, stroke (p < 0.05). Similarly, postoperative stroke was significantly more common for patients with crescendo TIAs than those with amaurosis (p < 0.01), established stroke (p < 0.05), and TIA (p < 0.05). Transient stroke was associated with a poor outcome, with only 66% of patients being alive in 36 months and 14% having suffered a stroke (p < 0.05 compared with established stroke). CONCLUSION: Presenting symptoms significantly predict outcome after carotid endarterectomy. This should be considered both in patient selection and comparison of patient series. PMID- 8691515 TI - Activated forms of MMP2 and MMP9 in abdominal aortic aneurysms. AB - PURPOSE: This consistent observation of a reduction of the elastin concentration in abdominal aortic aneurysms (AAAs) has led us to investigate in AAA specimens two metalloproteinases that display elastase activity, MMP2 (gelatinase A/72kDa) and MMP9 (gelatinase B/92 kDa). METHODS: Samples of full-thickness aortic wall, adherent thrombus, and serum were collected in 10 patients with AAAs. Samples of normal aortic wall and serum were taken from 6 age-matched control patients. Quantitative gelatin-zymography and gelatinolytic soluble assays after acetyl phenyl mercuric acid activation were performed on serum and tissue extracts, and the results were expressed in units on a comparative wet-weight basis. Histologic analysis was performed in parallel to score the inflammatory infiltrate. RESULTS: The luminal and parietal parts of the thrombus contained, respectively, 20- and 10-fold more gelantinolytic activity than the serum. The predominate form was MMP9. Although the total gelatinolytic activity was in the same range both in AAAs and in normal walls, a significantly higher proportion of MMP9 was found in the aneurysmal aortic walls. Furthermore, a significant proportion of MMP9 was under its processed active form, which was never observed in normal samples. A significantly higher proportion of MMP2 was also present as processed active form in AAA wall. This latter parameter positively correlated with the inflammatory score. CONCLUSIONS: The presence of activated MMP9 and MMP2 might contribute to the degradation of the extracellular matrix proteins that occurs during the development of aneurysms. PMID- 8691517 TI - The Society for Vascular Surgery: a look at the future. PMID- 8691516 TI - Complementary distal arteriovenous fistula and deep vein interposition: a five year experience with a new technique to improve infrapopliteal prosthetic bypass patency. AB - PURPOSE: In an attempt to improve graft patency results of prosthetic bypasses to infrapopliteal arteries, we used a new type of adjunctive technique that combines an arteriovenous fistula and vein interposition (AVF/VI). METHODS: Over the past 5 years, 68 such reconstructions were performed in 62 patients with critical ischemia in whom a totally autogenous vein bypass was not feasible. Forty-seven patients (76%) had one or more failed ipsilateral infrainguinal bypasses. The AVF/VI was performed by transposing the central portion of the adjacent deep vein onto the side of the recipient artery. The distal end of a 6-mm polytetrafluoroethylene (PTFE) ringed graft then was anastomosed to the hood of the AVF. The segment of vein interposed between the PTFE graft and the recipient artery widened the anastomosis and improved the compliance mismatch. Simultaneous pressure measurements of the radial artery and the distal portion of the graft were obtained in all cases. RESULTS: Significant pressure gradients ranging from 35 to 70 mm Hg were detected in 26 bypasses (38%), which led to banding of the venous outflow that decreased the gradient to within 20 mm Hg. A gradient < or = 30 mm Hg was found in 28 bypasses (41%), and no banding was required if the absolute intragraft systolic pressure was > or = 100 mm Hg. Only 14 bypasses (21%) had no detectable pressure gradients. Twenty-six bypasses originated from femoral arteries, 34 from iliac arteries, and 8 from patent proximal grafts. The recipient arteries were the anterior tibial artery in 33 cases, posterior tibial in 17, peroneal in 15, dorsalis pedis in 2, and lateral plantar in 1. All patients began a regimen of heparin 6 to 8 hours after surgery and continued to receive chronic anticoagulation. Cumulative, 3-year assisted primary graft patency rates were 78%, 70%, and 62%, respectively. Cumulative 3-year AVF patency rates were 65%, 57%, and 46%, respectively. The 3-year limb salvage rate was approximately 78%. CONCLUSION: Adjunctive AVF/VI significantly improves infrapopliteal PTFE graft patency and limb salvage rates. The combination of a decreased compliance mismatch at the distal anastomosis and the abolishment of a large pressure gradient at the distal anastomosis while maintaining higher graft flow rates may have contributed to the improved results. PMID- 8691518 TI - Vascular Gene Transfer: Models of Disease and Therapy. Symposium. Bethesda, Maryland, March 7-8, 1996. Abstracts. PMID- 8691520 TI - Simple percutaneous arteriovenous graft ligation. PMID- 8691519 TI - Evaluation of carotid artery stenosis: is duplex ultrasonography sufficient? AB - PURPOSE: The purpose of this study was to compare the results of duplex ultrasonography and magnetic resonance angiography in the evaluation of carotid artery stenosis to determine whether ultrasonography alone is sufficient for preoperative evaluation. METHODS: This study consisted of a retrospective review of 33 patients who underwent 35 carotid endarterectomies. A total of 66 vessels were studied by both duplex ultrasonography and magnetic resonance angiography, and an overall correlation between the two studies was determined. RESULTS: A high correlation was found between duplex and magnetic resonance angiography with an r coefficient equal to 0.87 (Pearson's correlation coefficient) and kappa = 0.75. Discrepancies between the two studies or the presence of intracranial disease did not alter surgical decision making. CONCLUSION: Duplex ultrasonography alone can accurately determine the degree of internal carotid artery stenosis and when paired with careful clinical evaluation is a reliable and cost-effective method for evaluating surgical carotid disease. PMID- 8691521 TI - Increasing the sensitivity of the diagnosis of chronic venous obstruction. PMID- 8691522 TI - Compression of the descending duodenum after reconstruction of infrarenal aortic aneurysm. PMID- 8691523 TI - Necrotizing venulitis and in situ saphenous vein bypass. PMID- 8691525 TI - Defining the limitations of measurements from Doppler spectral recordings. AB - PURPOSE: The purpose of this study was to determine whether Doppler measurements of peak velocity and four other quantitative measures of spectral shape are affected significantly by the site of the Doppler recording in relation to the location of the maximum stenosis. METHOD: Continuous-wave and pulsed Doppler recordings were made distal to a 70% (area reduction or 45% diameter reduction) asymmetric stenosis in an in vitro flow model under steady and pulsatile flow conditions. Recordings were taken at six different locations proximal and distal to the stenosis. A photochromic dye technique was used to visualize the actual flow field in the model. RESULTS: Distal to the stenosis, the flow visualization results demonstrated a strong radial and axial variation of the velocity field and thus explained why the Doppler measurements of peak frequency and spectral broadening were strongly dependent on the recording site. The peak frequency was maximum within the throat of the stenosis and returned to the prestenotic value five tube diameters distal to the stenosis. Other measurements of spectral broadening and spectral shape varied greatly depending on the location of the recording site in the poststenotic region. Higher order spectral moments such as the coefficient of kurtosis were found to exhibit large temporal variability, which makes them inappropriate as diagnostic indicators. CONCLUSIONS: Because of the complex nature of the poststenotic flow field, these results clearly demonstrate that no single Doppler measurement can accurately quantify the severity of a stenosis. Of the Doppler measurements only peak velocity is related to the severity of stenosis. Reproducible peak velocity measurements are obtained only if the Doppler sample volume is positioned at or very near the throat of the stenosis and at an appropriate radial site that may not necessarily be at the center of the vessel. PMID- 8691524 TI - Extracellular matrix proteins are potent agonists of human smooth muscle cell migration. AB - PURPOSE: Extracellular matrix proteins can stimulate smooth muscle cell (SMC) migration by three distinct mechanisms: chemokinesis (nondirected migration in the presence of soluble protein), chemotaxis (directed migration toward soluble protein), and haptotaxis (directed migration toward insoluble, substrate-bound protein). This study investigates the effects of four prevalent extracellular matrix proteins (collagen types I and IV, fibronectin, and laminin), and platelet derived growth factor (PDGF) on haptotaxis, chemotaxis, and chemokinesis of human SMCs. The role of large guanosine triphosphate-binding proteins (G-proteins) in the signaling mediating these effects is also evaluated. METHODS: Human saphenous vein SMCs were used in all migration studies. Chemokinesis, chemotaxis, and haptotaxis to each of the matrix proteins were measured and compared with PDGF through the use of a 48-well microchemotaxis chamber. The role of G-proteins in matrix-induced SMC migration was studied with the modulators of G-protein function, cholera and pertussis toxins. RESULTS: For all matrix proteins the relative strength of the various stimuli for migration was haptotaxis > chemotaxis > chemokinesis (p < 0.05). For all three stimuli collagen I and IV produced the most significant migration followed by fibronectin > PDGF-AB > laminin (p < 0.05). Pertussis toxin completely inhibited chemotaxis and partially inhibited haptotaxis by laminin but did not affect migration by other matrix proteins, whereas cholera toxin abolished migration in response to all four matrix proteins. CONCLUSION: Matrix proteins, with the exception of laminin, provide a more significant stimulus for SMC locomotion than does the prototypical agonist, PDGF-AB. Of the three mechanisms by which migration can be stimulated, haptotaxis elicits the most profound effect. The importance of G-proteins as second messengers for migration varies with each matrix protein and with the mechanism of stimulation. PMID- 8691526 TI - A prospective study of the incidence of deep venous thrombosis in hospitalized children. AB - PURPOSE: It is commonly believed that the incidence of deep venous thrombosis (DVT) in hospitalized children is less than in adults. However, it is possible that the disease is significantly underdiagnosed in children because the index of suspicion of pediatric practitioners is low, a substantial number of patients may have no symptoms, and DVT screening is not routinely performed. We therefore undertook a prospective study to define the incidence of DVT in hospitalized children with no symptoms. METHODS: Patients included in the study were those younger than 18 years of age who were hospitalized for more than 72 hours and were identified to have two or more risk factors for the development of DVT and had at least one screening duplex scan. Risk factors for the development of DVT considered were a history of DVT or pulmonary embolism, recent operation, immobilization, trauma, stroke or acute neurologic deficit, the presence of cancer, sepsis, greater than 150% ideal body weight, a hypercoagulable state, and the presence of a femoral venous catheter. RESULTS: Over the 9-month period ending December 1994, 1997 patients 17 years of age and younger were admitted to the hospital, and 59 patients including 19 girls and 40 boys were enrolled in the study. The one patient with DVT was a 17-year-old boy hospitalized after a motor vehicle accident with blunt head trauma and a neurologic deficit who underwent multiple orthopedic and neurosurgical procedures. CONCLUSIONS: The development of acute DVT in children is unusual. As a result, DVT prophylaxis and screening is unnecessary in young children with only two risk factors for the development of the disease. Young age appears to be an important protective risk factor for the prevention of DVT. PMID- 8691527 TI - Matrix-specific effect of endothelial control of smooth muscle cell migration. AB - PURPOSE: Smooth muscle cell (SMC) migration is a critical element in the development of intimal hyperplasia. The effect of endothelial cells (ECs) on SMC migration and the modulation of this cell-to-cell interaction by extracellular matrix is not well understood. METHODS: To examine this relationship SMCs and ECs were cocultured on opposite sides of a semipermeable membrane and were compared with SMCs cultured alone. To assess migration SMCs were plated at confluent density into the center of the membrane with a steel fence. After the fence was removed, SMCs were treated for 2 hours with mitomycin C (20 micrograms/ml) to assess migration independent of proliferation. Cell migration was measured with morphometry. Experiments were performed on plastic and membranes coated with fibronectin or type I collagen (n > or = 8/group). Cell adhesiveness was quantitated by cell attachment and spreading assays. RESULTS: ECs stimulated SMC migration by 187% when compared with SMCs cultured alone on plastic and by 160% when cultured on fibronectin (p < 0.01). Type I collagen stimulated migration of SMCs cultured alone and prevented EC stimulated migration in cocultured SMCs (p < 0.01). Cell adhesiveness was significantly increased in cocultured SMCs compared with SMCs cultured alone regardless of whether cells were cultured on plastic (EC/SMC, 13.5 +/- 0.6 SMCs/high power field vs SMC, 8.9 +/- 0.5, p < 0.01), fibronectin (16.3 +/- 0.8 vs 12.3 +/- 0.7, p < 0.01) or type I collagen (15.5 +/- 1.0 vs 12.4 +/- 0.6, p < 0.01). ECs increased SMC cell spreading on plastic and fibronectin when compared with SMCs cultured alone. No difference in SMC cell spreading was seen in the presence or absence of ECs when cells were cultured on type I collagen. EC-SMC contact was not required; EC-conditioned media alone increased SMC migration by 75% when compared with SMCs cultured alone. Our data suggest that ECs increase SMC migration by a diffusable molecule that may also alter SMC adhesion molecule expression. Extracellular matrix composition can attenuate these effects. PMID- 8691528 TI - Simultaneous carotid endarterectomy and coronary bypass: perioperative risk and long-term survival. AB - PURPOSE: The purpose of this article is to examine the outcome of simultaneous coronary bypass-carotid endarterectomy (CABG-CEA) and to compare it with the outcome of endarterectomy alone (CEA alone) in patients at high cardiac risk. METHODS: A retrospective review of the records and follow-up data for 100 consecutive patients who had undergone CABG-CEA and were at high risk and 114 patients who had undergone CEA, had overt coronary artery disease (angina, previous infarct, or ischemic electrocardiographic abnormalities), but had not undergone CABG was carried out. RESULTS: Our CABG-CEA group had a high incidence of symptomatic carotid disease (57%) and contralateral occlusion (28%) when compared with patients in other reports. Patients in the CABG-CEA group were older (67.9 +/- 8.3 years vs 63.6 +/- 15.7 years, p = 0.01) and more often smokers (81% vs 52.6%, p = 0.01) than patients in the CEA alone group. Perioperative mortality was 8% for the CEA-CABG group and for 1.8% for the CEA alone group (p = 0.035). Perioperative stroke morbidity was 9% for the CEA-CABG group and 2.6% for the CEA alone group (p = 0.05). Life table survival at 1,3, and 5 years was 90%, 82%, and 73% versus 96%, 84%, and 76% for the CABG-CEA and CEA alone groups, respectively (p = 0.30). CONCLUSIONS: Selection criteria for CABG-CEA greatly influence perioperative risk. Despite the greater age and more advanced coronary artery disease in the CABG-CEA group, long-term outcome differences are accounted for entirely by differences in perioperative morbidity and mortality. Prospective trials of strategies such as staged CEA and CABG to reduce perioperative risk are needed. PMID- 8691529 TI - Infrapopliteal bypasses to severely calcified, unclampable outflow arteries: two year results. AB - PURPOSE: Although severe, circumferential calcification of distal outflow vessels is frequently encountered, its effect on bypass graft patency rates has not been well established. METHODS: Using a computerized vascular registry database, we conducted a retrospective review of 1957 bypass grafts with distal anastomoses to infrapopliteal vessels performed at a single institution between 1990 and 1995. Of these cases, 101 procedures involved outflow arteries classified by the operating surgeon as severely calcified and unclampable (requiring intraluminal occluders for vascular control), whereas in 105 cases the outflow arteries had no calcification present at the distal anastomotic site. The remaining cases had varying intermediate degrees of calcification and were not analyzed. Indication for bypass procedure was limb-threatening ischemia in 90% of severe calcification cases and in 84% of cases without calcification. Atherosclerotic risk factors were similar except for the presence of diabetes (92% vs 74%, p < 0.001), creatinine level > 2.0 mg/dl (21% vs 8%, p < 0.01), and dialysis dependency (17% vs 3%, p < 0.001), all of which were more prevalent in the severe calcification group. Infrapopliteal distal anastomotic location and type of conduit ( > 90% autogenous vein) were comparable between groups. RESULTS: Primary patency, secondary patency, and foot salvage rates at 24 months were 60%, 65%, and 77% for the severe calcification group and 74%, 82%, and 93% for the no calcification group, respectively. With secondary procedures comprising 26% of cases in each group, data from the 150 primary procedures were reanalyzed separately. In this primary procedure group, 24-month primary patency, secondary patency, and foot salvage rates were 66%, 69%, and 77% for the severe calcification group and 84%, 90%, and 96% for the no calcification group, respectively. Although patency and salvage rates were consistently lower for the severe calcification group in all analyses, these differences did not achieve significance by log-rank life-table analysis at 2-year follow-up. Perioperative 30-day mortality (0.99% severe calcification vs 0.95% no calcification) and 24-month survival rates (84% severe calcification vs 83% no calcification) were also similar between groups. CONCLUSION: These data suggest that effective techniques exist to perform infrapopliteal bypasses to severely calcified, unclampable outflow arteries with results comparable with those obtained with clampable, uncalcified vessels. The finding of severe, circumferential calcification of outflow target arteries should not dissuade vascular surgeons from distal bypass for limb salvage indications. PMID- 8691530 TI - Functional outcome after surgical treatment for intermittent claudication. AB - PURPOSE: Although patency data for lower extremity bypass grafts are readily available, few reports have focused on patients' satisfaction after surgical reconstruction for claudication. We reviewed our experience with surgical treatment for claudication, focusing on late outcome from the patients' perspective to further refine surgical decision making in patients with intermittent claudication. PATIENTS AND METHODS: From February 1987 through April 1994, 114 consecutive patients underwent surgical bypass for intermittent claudication. Nine patients were lost to follow-up, leaving the study cohort composed of 105 patients with a mean age of 63 years (range 42 to 82 years). Sixty-two percent of the procedures were inflow reconstructions, and the remainder were infrainguinal bypasses. Clinical and demographic data were gathered from record review, and late follow-up was obtained by return visit or telephone interview. Patient satisfaction and level of function were assessed by a simple five-point questionnaire administered by a research nurse. Actuarial methods were used to calculate late graft patency and survival. Cox regression analysis was used to identify clinical and anatomic factors predictive of late survival and favorable outcome. RESULTS: Cardiac risk assessment revealed that 75% of patients either had no clinical markers for cardiac disease or had been treated with previous coronary artery bypass grafting or percutaneous transluminal angioplasty; despite this 61% of patients underwent specific preoperative cardiac testing. Most (68%) inflow procedures were aortobifemoral bypass grafts, and 93% of outflow procedures were femoropopliteal bypass grafts. Two thirds of infrainguinal grafts were performed with autogenous conduits, with prosthetic femoropopliteal bypass grafts performed only to the above-knee popliteal artery. Early graft failure with successful immediate revision occurred in 5% of patients. No operative deaths or early or late amputations occurred. At a mean follow-up of 4.5 years 96% of surviving patients had a patent graft. However, primary unassisted patency at 4 years was superior for inflow (92% +/- 4%) versus outflow (81% +/- 6%) procedures (p = 0.009). Late readmission for cardiac-related events occurred in 12%, and late cardiac-related death occurred in 5%. Actuarial survival at 5 years was 80% +/- 5%, with diabetes being the only negative survival predictor (risk ratio 2.6, 95% confidence interval 1 to 7, p = 0.049); 60% of late deaths were cancer-related. Satisfactory late results were reported by 82% of patients, with age < or = 70 years (odds ratio 4.01, 95% confidence interval 1.2 to 13.7, p = 0.026) and normalization ( > or = 0.85) of ankle/brachial index (odds ratio 5.7, 95% confidence interval 1.6 to 20, p = 0.008) being powerful independent predictors of patient satisfaction. CONCLUSIONS: After considering cardiac-related short- and long-term prognosis, we conclude that lower extremity bypass grafting for intermittent claudication will produce optimal results when restricted to younger ( < 70 years) nondiabetic patients in whom near normalization of the postoperative ankle/brachial index can be anticipated. PMID- 8691531 TI - Improvement in results of repair of type IV thoracoabdominal aortic aneurysms. AB - PURPOSE: Although management of extensive type I and II thoracoabdominal aortic aneurysms (TAA) remains a formidable challenge, results of repair of TAA originating in the distal thoracic aorta (type IV) appear to have improved significantly. To quantitate this perceived improvement, the following retrospective study was undertaken to examine the results of type IV TAA repair at the Brigham & Women's Hospital over the past 18-year period. METHODS: From July 1977 to September 1994, nonruptured atherosclerotic type IV TAAs were repaired in 58 patients. The mean age was 70 years, and associated risk factors included smoking (91%), hypertension (86%), coronary artery disease (52%), and previous aortic surgery (38%). Mean follow-up was 2.4 years (median 2 years). RESULTS: Overall 30-day mortality was 5.3% (two deaths). Morbidity included stroke (3.5%), paraplegia (1.8%), permanent paraparesis (1.8%), myocardial infarction (7%), pneumonia (8.8%), gastrointestinal bleeding (11%), intestinal ischemia (5.3%), wound infection (7.0%), peripheral ischemia (5.3%), in-hospital dialysis (8.8%), and permanent dialysis (1.9%). Overall 5-year survival was 50%. With univariate analysis, survival was positively correlated with more recent year of operation (p = 0.002), smaller volume of intraoperative blood transfusion (p = 0.02), decreased supraceliac ischemia time (p = 0.04), and the use of the retroperitoneal approach (p = 0.09). Multiple regression analysis revealed that the year of operation was the only independent predictor of survival (p = 0.003). Subgroup analysis of patients who underwent operation between 1977 and 1987 (n = 13) and 1988 and 1994 (n = 45) revealed statistically significant improvements in length of hospital stay (46 +/- 12 vs 21 +/- 4 days, p = 0.02), postoperative dysrhythmia (50% vs 16%, p = 0.03), postoperative maximum serum glutamic oxaloacetic-transaminase (516 +/- 234 vs 319 +/- 139 mg%, p = 0.04), incidence of hemorrhage requiring reexploration (33% vs 0%, p = 0.002), 30-day mortality (23% vs 0%, p = 0.009), and in-hospital mortality (39% vs 2.2%, p = 0.002). CONCLUSIONS: The modern mortality, morbidity, and survival of surgical repair of type IV TAA in our institution approaches that of infrarenal abdominal aortic aneurysm. PMID- 8691532 TI - Increased synthesis of matrix metalloproteinases by aortic smooth muscle cells is implicated in the etiopathogenesis of abdominal aortic aneurysms. AB - PURPOSE: The objective of this study was to identify the metalloproteinases elaborated by medial smooth muscle cells (SMCs) isolated from abdominal aortic aneurysm (AAA) and control arterial tissues and to ascertain if the levels produced by AAA SMCs were elevated. METHODS: SMC monolayers cultured from the outgrowth cells of tunica media explants were established, and their identity was determined by fluorescent microscopy by using a fluorescein isothiocyanate conjugated anti-SMC alpha-actin antibody. Matrix metalloproteinases (MMPs) produced by SMC monolayers in serum-free culture were examined by gelatin zymography and Western blotting with monoclonal antibodies to MMP-2, 3, and 9. RESULTS: Serum-free media from AAA SMCs contained metal-dependent elastolytic activity that cleaved the synthetic substrate succinyl trialanyl 4-nitroanilide (pH optima 7.2) and also 14C-insoluble elastin. The level of proteolytic activity found in these cultures was significantly greater than from control SMC media. Zymography established that AAA SMC media samples contained metal-dependent gelatinases of 50 to 64 and 92 kDa, which were identified respectively as MMP-2 and 9 by Western blotting by using monoclonal antibodies to these proteases. CONCLUSION: Medial SMCs isolated from AAA tissue produce significantly higher levels of MMP-9 and 2 than SMCs from control arterial tissues. These proteinases have the capacity to degrade elastin and a range of extracellular matrix proteins. From these data, we suggest SMCs may be involved in the abnormal degradation of the aortic wall in AAA through the excessive metalloproteinase activity produced by SMCs. PMID- 8691533 TI - Incidence and histologic characteristics of blebs in patients with abdominal aortic aneurysms. AB - PURPOSE: Aortic blebs-focal outpouchings within aortic aneurysms-may contribute to their eventual rupture. In this study we determine the incidence of aortic blebs and describe their microscopic features. METHODS: Computed tomographic scans of the abdominal aorta were obtained in 188 patients with aortic diameters measuring > or = 3 cm and were independently evaluated by a radiologist. The number and location of blebs were recorded, and each was measured with calipers. Sixteen blebs, with an adjacent uninvolved aneurysmal segment of aorta, and tissue from two patients with ruptured aneurysms were examined by light microscopy and immunohistochemical analysis. Specimens from six blebs and five aneurysms were examined for alpha 1 (I) procollagen messenger RNA by in situ hybridization. RESULTS: Twenty blebs, ranging in size from 5 to 30 mm (mean, 12 +/- 7 mm), were detected in 11% (20 of 188) of computed tomographic scans. Blebs were observed in 10% (11 of 111) of patients with aortic diameters between 3.0 and 4.9 cm, 10% (6 of 61) of patients with aneurysms between 5.0 and 6.9 cm, and 19% (3 of 16) of patients with aortic diameters > or = 7 cm. Histologically, the major difference between the aneurysmal aortic wall and blebs was found in the media. In aneurysmal aortas, the media consisted of multiple layers of fragmented elastic lamellae, whereas the number of elastic tissue elements along the circumference of the blebs progressively decreased; only a few isolated fragments of elastic tissue were present at the apices. Histologic evidence of rupture was evident in two specimens. A chronic inflammatory cell infiltrate composed of T and B lymphocytes, plasma cells, and macrophages, common to both the aneurysmal and the blebs, was most prominent in the adventitia of aneurysmal tissue, but involved both the media and adventitia of the blebs. In situ hybridization demonstrated the presence of alpha 1 (I) procollagen messenger RNA in four of the five aneurysm segments that were evaluated, compared with only one of six blebs. CONCLUSIONS: Blebs were discovered in aneurysms of all sizes; their frequency appeared to be unrelated to aneurysm size. The presence of inflammatory cell infiltrates and absence of alpha 1 (I) procollagen messenger RNA in five of six blebs suggest that a local imbalance of matrix degradation and repair plays a role in the cause of these lesions. Attenuation of the aortic wall accompanying the formation of blebs may predispose these sites to rupture. PMID- 8691534 TI - A piece of my mind. Welcome to Stone Harbour Mansion. PMID- 8691535 TI - Can researchers use new drugs to push HIV envelope to extinction? PMID- 8691536 TI - Views of reason for mad cow disease vary widely. PMID- 8691537 TI - Even as new options emerge, gynecologists urge women to find older contraceptives user-friendly. PMID- 8691538 TI - From the Food and Drug Administration. PMID- 8691539 TI - Blastomycosis--Wisconsin, 1986-1995. From the Centers for Disease Control and Prevention. PMID- 8691540 TI - Treatment for obesity. PMID- 8691541 TI - Mammographic screening of elderly women. PMID- 8691542 TI - What do we learn from disciplined practice learning? PMID- 8691543 TI - What do we learn from disciplined practice learning? PMID- 8691545 TI - Airway management during active compression-decompression CPR. PMID- 8691544 TI - Clinical practice guidelines for smoking cessation. PMID- 8691546 TI - Hepatitis A vaccines. PMID- 8691547 TI - Another standard of care--the patient. PMID- 8691548 TI - Patient vs physician follow-up for melanoma: a clarification. PMID- 8691549 TI - Should we screen for gestational diabetes? PMID- 8691550 TI - Charles Bonnet syndrome in a centenarian. PMID- 8691551 TI - Date of delivery in multifetal pregnancies. PMID- 8691552 TI - Self-perceived health status and health-related quality of life of extremely low birth-weight infants at adolescence. AB - OBJECTIVES: To estimate and to compare the self-assessed health status and health related quality of life of extremely low-birth-weight (ELBW) and control infants during adolescence. DESIGN: Prospective, observational study of an inception cohort with a concurrent control group. SETTING: Geographically defined region in central-west Ontario. PARTICIPANTS: We interviewed 141 (83 percent) of 169 ELBW survivors born between 1977 and 1982 and 124 (86 percent) of 145 controls aged between 12 and 16 years. In addition, proxy responses obtained from parents were used for 9 severely impaired teenagers. MAIN OUTCOME MEASURES: Assessments of health status (6 attributes), measured with the Health Utilities Index Mark 2 classification system, and health-related quality of life (utilities), quantified with 2 preference measurement techniques, were used to quantify each participants self-reported, subjectively defined health state and 4 preselected hypothetical health states. RESULTS: Adolescents who were ELBW infants reported a higher number of attributes affected, as well as more complex and severe limitations in cognition, sensation, self-care, and pain, compared with controls. Statistically significant differences for the teenagers' health-related quality of life were noted between ELBW and control teenagers in the mean utility scores (0.87 +/- 0.26 vs 0.93 +/- 0.11; P=.02 on a conventional scale where O=dead and 1.00=perfect health). However, a similar percentage of ELBW and control teenagers (71 percent vs 73 percent) gave utility ratings of more than 0.95 for their health status. CONCLUSIONS: Direct measures of self-reported health status and utility scores indicated that, as a cohort, adolescents who were ELBW infants suffer from a greater burden of morbidity and rate their health-related quality of life as significantly lower than control teenagers. Nevertheless, the vast majority of ELBW respondents view their health-related quality of life as quite satisfactory and are difficult to distinguish from controls. PMID- 8691553 TI - Ambulatory visits to hospital emergency departments. Patterns and reasons for use. 24 Hours in the ED Study Group. AB - OBJECTIVES: To characterize the reasons ambulatory patients use hospital emergency departments (EDs) for outpatient care and to determine the proportion of ED patients who initially are assessed as having nonurgent conditions, but subsequently are hospitalized. DESIGN: Cross-sectional survey during a single 24 hour period of time. SETTING: Fifty-six hospital EDs nationwide. PATIENTS OR OTHER PARTICIPANTS: Consecutive ambulatory patients presenting for care. Patents who arrived by ambulance were excluded. RESULTS: Of 6441 ambulatory patients (79 percent of all ED visits) who were eligible for study, interviews were obtained from 6187 (96 percent). A total of 5323 patients (86 percent) had clinical reasons or preferences for seeking care at an ED, including 2799 (45 percent) who thought they had an emergency or an urgent condition or were too sick to go elsewhere. Nineteen percent (n=1199) reported that they were sent to the ED by a health care professional. Patients with a regular clinician or with insurance cited similar reasons for seeking care at an ED. A total of 3062 patients (50 percent) cited 1 or more nonfinancial barriers to care as an important reason for coming to the ED, and 949 (15 percent) cited financial considerations. A total of 3045 patents (49 percent of ambulatory patients and 37 percent of total ED visits) were assessed at triage as having a nonurgent condition; 166 of them (5.5 percent; 95 percent confidence interval, 4.7 percent-6.3 percent) were admitted to the hospital. CONCLUSIONS: Most ambulatory patients seek care in an ED because of worrisome symptoms or nonfinancial barriers to care. Although many ambulatory patients appear to have nonurgent conditions based on triage classification, a small but disturbing percentage of nonurgent patients are hospitalized. PMID- 8691554 TI - Reversible membranous nephropathy associated with the use of nonsteroidal anti inflammatory drugs. AB - OBJECTIVE: To investigate the frequency of membranous nephropathy associated with nonsteroidal anti-inflammatory drug (NSAID) use and identify associated clinical characteristics. DESIGN: Retrospective chart review. SETTING: A large group practice that staffs 2 large teaching hospitals. PATIENTS: All patients diagnosed as having stage I or early stage II membranous nephropathy by renal biopsy between January 1975 and May 1995. MAIN OUTCOME MEASURES: Nephrotic syndrome was said to be associated with NSAID use if patients developed nephrotic syndrome while taking an NSAID and if other causes of membranous nephropathy were excluded and a rapid remission of the nephrotic syndrome followed withdrawal of the drug. RESULTS: Of 125 patients identified with early membranous nephropathy, 29 were taking NSAIDs at the time symptoms of nephrotic syndrome developed. Thirteen of these patients met the criteria for NSAID-associated membranous nephropathy. None of these patients had any evidence of renal insufficiency or significant proteinuria after follow-up periods ranging from 5 months to 13 years. In addition to diclofenac and fenoprofen, which have previously been implicated, ibuprofen, nabumetone, naproxen, and tolmetin were found to be associated. CONCLUSIONS: Nephrotic syndrome due to membranous nephropathy should be recognized as an idiosyncratic drug reaction to many NSAIDS. Because withdrawal of the drug may result in prompt and complete recovery of normal renal function, a history of NSAID intake should be sought in patients with membranous nephropathy. PMID- 8691555 TI - Temporal lobectomy for refractory epilepsy. AB - OBJECTIVE: To examine the long-term effectiveness of anterior temporal lobectomy for refractory epilepsy with regard to seizure control and related medical and psychosocial measures and to determine how patterns of early seizure recurrence relate to long-term prognosis. DESIGN: A cohort of patients prospectively followed up for 5 years after surgery. SETTING: Tertiary care comprehensive epilepsy center. PATIENTS: Eighty-nine patients with medically refractory epilepsy who were consecutively treated with anterior temporal lobectomy between 1986 and 1990. All patients had noninvasive preoperative evaluations, and 31 were evaluated with intracranial electrodes prior to surgery. MAIN OUTCOME MEASURES: Postoperative seizure frequency, neuropsychologic function, mortality, and postoperative employment status. RESULTS: Five years after surgery, 62 patients (70 percent) were seizure free, 8 (9 percent) had seizures on fewer than 3 days per year or exclusively had nocturnal seizures, 10 (11 percent) had greater than 80 percent reduction in seizure frequency, 5 (6 percent) had less than 80 percent reduction in seizure frequency, and 4 (4 percent) died of causes unrelated to surgery. The proportion of patients in each outcome class remained stable throughout the 5-year period. Fifty-five percent of seizure recurrences happened within 6 months of surgery, and 93 percent occurred within 2 years after surgery. Outcome at 1 year related only moderately well to outcome at 5 years. No significant cognitive or linguistic deficits occurred. All patients who died had persistent seizures after surgery. Underemployment and unemployment declined significantly after surgery, with improvement noted in seizure-free patients. CONCLUSIONS: Temporal lobectomy provides sustained seizure relief over 5 years to most patients who have surgery. Outcome at 2 years predicts long-term outcome. A seizure-free state is associated with reduced mortality and increased employment. Mere reduction in seizure frequency is not associated with improvement in those measures. PMID- 8691556 TI - Health system reform and quality. PMID- 8691557 TI - Should survivors of myocardial infarction with low ejection fraction be routinely referred to arrhythmia specialists? AB - Because survivors of myocardial infarction are at risk for ventricular arrhythmias and sudden death, physicians must decide whether to refer these patients to specialists for arrhythmia assessment and therapy. However, this decision is complex as few randomized data are available concerning either diagnostic or therapeutic options. Therefore, we modeled the potential impact of current arrhythmia detection and management strategies on mortality in survivors of myocardial infarction with reduced left ventricular function who are managed in a contemporary manner. Based on recent data we estimated that the mortality for myocardial infarction survivors with left ventricular ejection fraction less than 0.40 is 20 percent over 3.5 years and that half of the deaths are sudden. The sensitivity and specificity of a Holter electrocardiogram (ECG), a signal averaged ECG, and an invasive electrophysiology study for predicting sudden death were obtained from a literature review of trials published after 1990 that included more than 300 patients. A series of models were constructed to predict mortality achieved by different arrhythmia management strategies that reduced sudden death by 50 percent and 75 percent--reductions estimated to be within the range for amiodarone and implantable defibrillators. We found that, when routinely applied to all infarct survivors with depressed ventricular function, a therapy that reduces sudden death by 50 percent with 1 percent fatal adverse effects (potentially amiodarone) saves approximately 1 life for every 25 patients treated. Therapy that reduces sudden death by 75 percent with 2 percent fatal adverse effects (potentially implantable defibrillators) saves 1 life for every 14 patients treated. Using Holter ECG recordings, a signal-averaged ECG, or an invasive electrophysiology study to select higher-risk groups, 1 life can be saved for every 4 to 11 patients treated, and the negative impact of adverse effects can be reduced. However, to achieve this benefit, additional and potentially invasive arrhythmia testing must be applied to 28 to 47 patients for each life saved. Thus, with contemporary management of acute myocardial infarction, the risk of sudden death for survivors is sufficiently low that broad application of available antiarrhythmic therapies has limited potential for further improving survival, particularly if therapy also has significant adverse effects. Thus, routine referral to arrhythmia specialists is not warranted for the majority of infarct survivors and should be largely reserved for patients with serious, symptomatic arrhythmias. PMID- 8691558 TI - A 76- year-old woman considering total hip replacement. PMID- 8691559 TI - A 47-year-old woman with ductal carcinoma in situ, 1 year later. PMID- 8691560 TI - Progress in assessing the long-term outcome of extremely low-birth-weight infants. PMID- 8691561 TI - Triage of ambulatory patients. PMID- 8691562 TI - Breaking bad news. A review of the literature. AB - OBJECTIVE: To review the literature on breaking bad news while highlighting its limitations and describing a theoretical model from which the bad news process can be understood and studied. DATA SOURCES: Sources were obtained through the MEDLINE database, using "bad news" as the primary descriptor and limiting the sources to English-language articles published since 1985. STUDY SELECTION AND EXTRACTION: All articles dealing specifically with bad news were examined. These works included letters, opinions, reviews, and empirical studies. Recommendations from these articles were examined, sorted into discrete categories, and summarized. DATA SYNTHESIS: The 13 most consistently mentioned recommendations (eg, delivering the news at the patient's pace, conveying some hope, and giving the news with empathy) were examined. CONCLUSION: Although much has been written on the topic of breaking bad news, the literature is in need of empirical work. Research should begin with the simple question of whether how the news is conveyed accounts for variance in adjustment before moving to more specific questions about which aspects of conveying bad news are most beneficial. It is suggested that the bad news process can be understood from the transactional approach to stress and coping. PMID- 8691563 TI - [Clinical significance of soluble interleukin-2 receptor in multiple myeloma]. AB - Increased levels of soluble interleukin-2 receptor (sIL-2R) have been noted in the sera of patients with various diseases such as adult T cell leukemia, malignant lymphoma and autoimmune diseases. Using an enzyme-linked immunoabsorbent assay, we assessed sIL-2R levels in the sera of 16 patients with multiple myeloma (MM) and 27 normal subjects. There was a significant increase in the levels of sIL-2R in the patients with myeloma (963 +/- 523 U/ml) compared to normal subjects (213 +/- 80 U/ml). The levels of sIL-2R corresponded well with the clinical stage, M-protein, serum IL-6 and serum beta 2 microglobulin levels. Taking the evidence that the CD4/CD8 ratio decreased as the disease worsened into consideration, the increase in the serum sIL-2R levels of the patients with MM is considered to have some correlation with B and T cell activation through various cytokines including IL-6. Furthermore such evidence would support the role of sIL 2R as a disease monitor of MM. PMID- 8691564 TI - [Carrier detection and prenatal diagnosis for hemophilia A using the inversion analysis of the factor VIII gene]. AB - Hemophilia A is an X-linked hemorrhagic disorder caused by heterogeneous mutations in the factor VIII gene. Recently, it was reported that approximately 50% of the cases of severe hemophilia A may be caused by a common inversion in the factor VIII gene. In this study, we analyzed 33 Japanese patients with severe hemophilia A for the presence of this inversion mutation using the non-RI Southern blotting, and detected inversion mutations of the factor VIII gene in 12 patients (36.4%). We also showed that the inversion analysis of the factor VIII gene was useful for carrier detection and prenatal diagnosis in a hemophilia A family, which we had not been able to diagnose by the analysis of restriction fragment length polymorphisms (RFLPs) of the factor VIII gene. The detection of inversion mutations in the factor VIII gene using non-RI Southern blotting analysis appears to be very useful for the genetic counseling for severe hemophilia A. PMID- 8691565 TI - [Efficacy of early administration of G-CSF after intensive chemotherapy in acute leukemia: a randomized controlled trial. Tokai Infection Study Group on Hematological Disorders]. AB - The effect of granulocyte colony-stimulating factor (G-CSF) on neutropenia and infection was studied in a randomized trial in patients receiving intensive chemotherapy for acute leukemia. Fifty seven patients with acute leukemia (35 cases of refractory acute myeloid leukemia, 19 cases of acute lymphoblastic leukemia and 3 cases of blast crisis of chronic myeloid leukemia) were given G CSF under either of the following two conditions; 1) Group A: starting G-CSF (200 micrograms/m2iv) administration 24 hrs after chemotherapy. 2) Group B: the same dose of G-CSF administration after a febrile episode of 38 degrees C with neutropenia (less than 1,000/microliters). Five patients were excluded from the study. Group A (27 patients) showed a shorter febrile period (2.15 +/- 2.98 days) than the 25 patients of Group B (3.40 +/- 4.78 days), but the difference was not statistically significant. Compared to Group B, Group A showed significantly early recovery of neutrophil counts as well as early recovery from documented infections. There was no evidence that early administration of G-CSF accelerates the growth of leukemic cells nor causes early relapse of acute leukemia. PMID- 8691566 TI - [A quantitative parameter of ineffective erythropoiesis deduced by canonical discrimination and axis rotation on the basis of ferroerythrokinetic data]. AB - Ferroerythrokinetic data including erythron transferrin uptake (ETU) calibration of 134 cases of control, hemolytic anemia, hypoplastic anemia and ineffective erythropoiesis (IEP) were subjected to canonical discrimination analysis. Axis rotation was then performed for the second variate so as to be parallel to the long axis of distribution ellipsoid of IEP group. The process yielded three variates. The first one, V-1, was assumed to represent the amount of effective erythropoiesis, the second one, V'-2, its efficiency ratio and the third one, V' 3, the rate of peripheral hemolysis. A definite correlation (r = -0.872) was obtained in IEP group between V'-2 and ETU, i.e. reduction in efficiency and compensatory hyperplasia in erythropoiesis. On the plane with concised parameters of V-1 and V'-2, an ellipse of 95 percent confidence of IEP group and three discrimination lines delineated five areas representing five patterns of ferroerythrokinetics, i.e. IEP, hemolytic, hypoplastic, IEP combined with hemolytic or with hypoplastic ones. This method is considered to be useful for application to those erythropoietic disorders having partial or complicated factors described above, where routine ferroerythrokinetic parameters may, be indecisive. PMID- 8691567 TI - [Varicella pneumonia with multiple nodular shadows after allogeneic bone marrow transplantation in chronic myeloid leukemia]. AB - A 30-year-female with chronic myelogenous leukemia received allogeneic bone marrow transplantation (BMT). On day 104, low-grade fever, cough, and general malaise developed, resulting in hospitalization 10 days later. Chest X ray revealed diffuse infitrates, suggesting cytomegalovirus interstitial pneumonia. Ganciclovir (DHPG) was given daily and all symptoms disappeared three days later. However, a very few vesicular lesions appeared on her trunk and her two children had chickenpox at that time. Chest CT was taken and disclosed diffuse nodular shadows. Clinical course and chest CT suggested varicella pneumonia. DHPG administration was stopped and acyclovir PO started to be given. She was discharged in excellent condition. In this report, we show a rare case of varicella pneumonia after allogeneic BMT and efficacy of DHPG for the treatment of varicella pneumonia. PMID- 8691568 TI - [Treatment with bolus methylprednisolone for pure red cell aplasia after ABO incompatible bone marrow transplantation in a patient with chronic myelocytic leukemia]. AB - Pure red cell aplasia (PRCA) was found in a male patient with chronic myelocytic leukemia after major ABO incompatible bone marrow transplantation (BMT). He had blood group O, and received BMT from an HLA identical sibling (blood group A). Erythrocyte-depleted marrow was transplanted. Methotrexate for short time and cyclosporine (CyA) were used for graft versus host disease (GVHD) prophylaxis. Engraftment of neutrophils and platelets were observed on day 14 and 22, respectively. The Ph1 chromosome disappeared on day 133. However engraftment of erythrocytes was not observed on day + 280. Bone marrow puncture revealed depletion of erythrocyte precursors. Anti-A isoagglutinin was persisted. There was no evidence of acute or chronic GVHD. Administration of prednisolone, discontinuance of CyA and subcutaneous infusion of recombinant human erythropoietin failed to improve PRCA. Bolus methylprednisolone (m-PSL) therapy started on day 284 resulted in rapid increase in reticulocyte counts within 6 days, which was followed by normal hemoglobin concentrations. We conclude that bolus m-PSL may be one treatment for PRCA after BMT. PMID- 8691569 TI - [Myelofibrosis complicated by T-cell lymphoma followed by leukemic transformation]. AB - A 37-year-old man was admitted because of pancytopenia with leukoerythroblastosis and anisocytosis in January 1986. Bone marrow aspiration resulted in a dry tap and biopsy showed marked myelofibrosis. Three months after admission, generalized lymph node swelling and multiple skin tumors were recognized. A biopsied lymph node revealed lymphoblastic lymphoma. The surface markers of lymphoma cells showed an immature T-cell phenotype, whereas T-cell receptor beta and gamma chain genes showed germ line configuration. The patient was treated with combination chemotherapy in June 1986. A month later, he developed leukemic transformation with features of acute myelocytic leukemia and he died of pneumonia. Autopsy disclosed extramedullary hematopoiesis in the liver and spleen. Primary myelofibrosis complicated by T-cell lymphoma is extremely rare. PMID- 8691570 TI - [Hematological stability under ubenimex monotherapy in a patient with acute myelogenous leukemia developing marrow karyotypic changes during the course]. AB - We encountered a 71-year-old female with acute myelogenous leukemia (AML, M1), who maintained a steady hematological state for 22 months under ubenimex monotherapy. At the first medical examination in our hospital, the marrow cellularity was approximately 40% containing leukemic myeloblasts of 41.4% in the total nucleated cells, and the marrow cytogenetic study revealed 47, XX, + 8 in 13 of 20 cells analyzed. Nineteen months later, the bone marrow showed definite hypoplasia with leukemic blasts of 39.8% and chromosome finding of 46, XX, ins (10;?) (q11;?) in all cells analyzed. During the course, the patient has been doing well without transfusion of red blood cells or platelets. PMID- 8691571 TI - [Philadelphia chromosome-negative chronic myelogenous leukemia with trisomy 13]. AB - Trisomy 13, as a sole karyotypic abnormality in acute leukemia, has been reported in several cases. However, in chronic myelogenous leukemia (CML), only two cases with this abnormality were reported so far. We describe herein a 68-year-old case with Philadelphia chromosome-negative CML and trisomy 13. Leukocytosis was pointed out during the treatment for other diseases. After 7 months, abrupt increase in leukocyte count (108,000/microliters) and splenomegaly developed. Decreased neutrophil alkaline phosphatase activity and morphological features fulfilled the diagnostic terms for CML. However, the karyotypic analysis revealed trisomy 13 instead of Philadelphia chromosome, and the BCR gene rearrangement was not detected. In cases with acute leukemia accompanied by trisomy 13, malignant transformation of an immature hematopoietic precursor cell has been suggested by the expression of antigens characteristic of both the myeloid and lymphoid lineage. In a few cases with myelodysplastic syndrome, a multipotent stem cell disorder, trisomy 13 has also been reported. From these standpoints, there might be a possibility that trisomy 13 as a sole abnormality in hematologic disorders would be related to tumorigenesis in the levels of multipotent stem cells. PMID- 8691572 TI - [Erythroblastic transformation of chronic myelogenous leukemia associated with an additional chromosome abnormality translocation (6;9]. AB - A 57-year-old female was diagnosed being in the blastic phase of chronic myelogenous leukemia (CML) on her second admission in May 1993. The patient was previously treated with vincristine and prednisolone in the accelerated phase of CML in December 1991 without improvement. Other chemotherapeutic agents such as BHAC-DMP (enocitabine, daunorubicin, mercaptopurine, prednisolone), interferon, mercaptopurine and ranimustine were also administered. After the second chronic phase was achieved, she was treated with busulfan as an outpatient. On her second admission, the diagnosis of erythroblastic transformation was made, and cytogenetic study revealed t(9;22) (q34;q11) with the additional chromosomal abnormalities, t(6;9) (p23;q34). This karyotype rearrangement has been reported neither in Ph-positive CML nor in blastic crisis. PMID- 8691574 TI - [Chylothorax in a patient with 9-year remission of malignant lymphoma]. AB - We describe a 69-year-old man who developed chylothorax after a 9-year remission of malignant lymphoma. The patient was admitted to our hospital and received exploratory laparotomy for ileus in February 1986. Bulky masses in the posterior mediastinum and the retroperitoneum, and also a jejunal tumor were observed. Fibrosis of the liver was also observed. The jejunal tumor was removed and histological findings revealed diffuse large B-cell malignant lymphoma. He was treated by combination chemotherapy and remission was achieved. He was discharged in June and remained in remission, but was readmitted for right pleural effusion in October 1994. Effusion was chylous and the chylomicron level was estimated to be 181 mg/dl. Liver cirrhosis also developed but there was no chylous ascites. Chylorrhea disappeared after continuous aspiration, but recurred in December. Continuous aspiration was ineffective, therefore 10 KE of OK-432 was administered twice into the pleural cavity, and chylorrhea again disappeared. No findings suggestive of malignant lymphoma were not detected by computerized tomography and gallium scintigram. He was discharged in March 1995 and chylothorax has not recurred since. These findings suggest that the fragility of the thoracic duct which had been infiltrated by malignant lymphoma might increase, resulting in rupture, even if in remission. PMID- 8691573 TI - [Long-term selective beta 1-blockade therapy for a patient with anthracycline induced cardiomyopathy]. AB - A 44 year-old woman with acute myeloid leukemia (AML, FAB, M4E) developed heart failure during treatment with anthracyclines for AML. She had not experienced heart disease and her left ventricular ejection fraction (LVEF) was 59% at the end of a successful remission induction therapy. Because her LVEF decreased to 33% after early consolidation therapy, the chemotherapy for AML was discontinued. The cumulative dose of daunorubicin, aclarubicin and mitoxantrone was 486 mg/m2, 135 mg/m2 and 55 mg/m2, respectively. In October 1990, four months after the end of the chemotherapy, heart failure (class III, NYHA) developed and did not improve by treatment consisting of dobutamin, digoxin and diuretics. Anthracycline cardiomyopathy was histologically confirmed by endomyocardial biopsy. Then we administered selective beta 1-antagonist, metoprolol (Seloken), with an initial dose of 5 mg/day which was doubled 3 times every 4 or 8 weeks to 40 mg/day, according to the treatment schedule of dilated cardiomyopathy. She recuperated satisfactorily (Class I, NYHA), and was discharged on February '91. Her LVEF gradually improved and it has been maintained at above 50% on an outpatient basis. The patient has been in complete hematological remission during this period. It seems that low dose selective beta 1-antagonist therapy has a potential to improve myocardial function in some patients with anthracycline cardiomyopathy. PMID- 8691575 TI - [Reactive hemophagocytic syndrome responded to combination chemotherapy with steroid pulse therapy]. AB - A 66-year-old male was admitted to our hospital because of persistent fever. Laboratory data revealed leukopenia, thrombocytopenia, marked elevation of serum lactic acid dehydrogenase and ferritin levels, as well as disseminated intravascular coagulophathy (DIC). Bone marrow aspiration showed increased numbers of mature histiocytes with hemophagocytosis and a diagnosis of reactive hemophagocytic syndrome was made. In the broad spectrum of this syndrome, we suspected virus-associated hemophagocytic syndrome (VAHS) but no causative viral infection was detected. Since DIC is known to be a poor prognostic factor, he was given combination chemotherapy containing VP-16 in addition to pulse therapy of methylprednisolone. He completely recovered after the treatment. Chemotherapy is one option in the treatment of adult onset reactive hemophagocytic syndrome. PMID- 8691576 TI - [PUVA therapy for cutaneous acute graft-versus-host disease--a case report]. AB - We performed 8-methoxypsolaren and ultraviolet A (PUVA) therapy as a second line treatment for stage +3 cutaneous acute graft-versus-host disease (GVHD) in a 10 year-old girl who had undergone unrelated bone marrow transplantation. Although prednisolone as first line therapy was not effective, the cutaneous lesion began to improve after several times of PUVA treatment and completely disappeared following 11 times of irradiation without additive systemic immunosuppressive therapy. PUVA therapy was considered as a useful treatment for cutaneous acute GVHD. PMID- 8691577 TI - [Assessment of cardiac toxicity by 123I-MIBG myocardial SPECT in elderly non Hodgkin lymphoma patients treated with COP-BLAM and G-CSF]. AB - COP-BLAM chemotherapy with concomitant G-CSF was performed on patients 65 or older with non-Hodgkin's lymphoma (NHL), and cardiac sympathetic disorders due to the chemotherapeutic agents were studied using 123I-MIBG (metaiodobenzylguanidine) myocardial SPECT (single photon emission CT). The results showed no correlation between the ejection fraction due to echocardiography and the total dose of adriamycin (ADR). However, there was a positive correlation between the total dose of ADR and the washout rate, and the possibility of cardiac sympathetic disorders caused by ADR was suggested. PMID- 8691578 TI - [Aplastic anemia associated with ovarian bleeding]. AB - A 22-year-old female was admitted on June 19, 1993 with pancytopenia. Aplastic anemia was diagnosed and she was treated with anti-thymocyte globulin. After one month, she started to feel abdominal pain. Her platelet count was 1.3 x 10(4)/microliters at that time. Computed tomography revealed vast accumulation of blood in the abdomen and pelvis. A total of 1,000 ml blood was obtained from the right ovarium and she underwent right partial oophorectomy. Although ovarian bleeding is rarely reported in aplastic anemia, we should always keep in mind this possibility when abdominal pain occurs in a female patient. PMID- 8691579 TI - [Shear-induced platelet aggregation (SIPA) monitoring of hemostatic effect during platelet transfusion in a patient with Glanzmann's thrombasthenia: a comparison between SIPA and conventional platelet aggregation]. AB - Shear-induced platelet aggregation (SIPA) in a patient with Glanzmann's thrombasthenia was examined during platelet infusion therapy. Prior to platelet infusion, SIPA measured with the modified cone-and-plate type viscometer, as well as ADP-and collagen-induced platelet aggregation measured with the conventional platelet aggregometer, were absent. The patient's SIPA after multiple infusions of platelet, in parallel with the bleeding time and the clinical hemostatic effect, improved to the normal level, while ADP-and collagen-induced platelet aggregation remained abnormal. These observations imply that SIPA is physiologically more relevant than the conventional agonist-induced platelet aggregometry in this type of the disease. PMID- 8691580 TI - Intracellular pharmacodynamics in leukemia therapy. PMID- 8691581 TI - [Mechanism of action of antileukemic agents in leukemia chemotherapy]. PMID- 8691582 TI - [Mechanism of cell proliferation of adult T cell leukemia (ATL) cells]. PMID- 8691583 TI - [Tumor suppressor genes in hematopoietic tumors]. PMID- 8691584 TI - [Genetic abnormalities in B cell neoplasms: special reference to diffuse large cell lymphoma]. PMID- 8691585 TI - [Mantle cell lymphoma and related lesions]. PMID- 8691586 TI - [IBL-like T cell lymphoma. The relationship between cytokine production and histopathogenesis]. PMID- 8691587 TI - [So-called NK cell lymphoma]. PMID- 8691588 TI - [Identification of a t(2;5)-associated novel chimeric protein p80 and its clinicopathological significance in anaplastic large cell lymphoma]. PMID- 8691589 TI - [Hodgkin's disease: the origin of HRS (Hodgkin and Reed-Sternberg) cells]. PMID- 8691590 TI - [Mast cell leukemia evolved from RAEB-T (5q-syndrome) in a 12 year-old girl]. AB - A 12-year-old, female 5q- syndrome case of refractory anemia with excess of blasts in transformation (RAEB-T) evolving to mast cell leukemia is described. This case was admitted because of general fatigue, when her peripheral blood count revealed anemia and leukocytosis with basophil-like cells. RAEB-T was diagnosed based on the laboratory findings of her peripheral blood and bone marrow aspiration, which revealed over 10% peripheral blast cells and dysmyelopoietic changes in all three lineages. Chromosomal analysis of the bone marrow cells showed 46, XX, 5q-. Six months later, the RAEB-T phase evolved to acute leukemia, despite prednisolone, vitamin D3, oxymetholone and low-dose cytosine arabinoside treatment. She had remarkable pancytopenia, hemorrhage, and hepatosplenomegaly, which were not responsive to daunomycin, enocitabine, etoposide, and 6-mercaptopurine, and eventually died. This case was unique in that her karyotype changed to normal; 46, XX, and her blast cells were mast cell lineage during the overt leukemic phase. Interestingly, some blasts were intermediate cells possessing the ultrastructural features typical of both basophils and mast cells. PMID- 8691591 TI - [High activity of antistreptolysin-O in a case of IgM myeloma]. AB - A 56-year-old man was admitted to our hospital in November, 1991 because of hyperproteinemia and anemia. Total protein showed 12 g/dl and serum immunoglobulins were as follows; IgG 974 mg/dl, IgA 142 mg/dl, IgM 9270 mg/dl. M component was identified as IgM-kappa with immunoelectrophoresis and serum viscosity indicated 6.9. Although the patient had no history of severe streptococcal infection, his serum showed very high activity of ASLO (6890 IU/ml). Bence Jones protein was detected in the urine and determined to be of kappa-type. Plasma cells occupied 43% of bone marrow nucleated cells and their cytoplasms were stained with FITC-labeled anti-IgM and anti-kappa antibodies. X ray examination disclosed punched out lesions in the skull. Consequently, the patient was diagnosed as having IgM-myeloma. At first, VCAP regimens were given after plasmapheresis, but had no effect. Therefore, the patient was treated with CHOP protocol and the serum IgM decreased in amount and the proportion of bone marrow myeloma cells got down to 17%. ASLO titer also decreased in parallel with IgM. These findings suggest that IgM in this case had ASLO activity. PMID- 8691592 TI - [Sinus bradyarrhythmia during administration of all-trans retinoic acid in a patient with acute promyelocytic leukemia]. AB - A case of acute promyelocytic leukemia (APL) complicated by sinus bradyarrhythmia during the course of all-trans retinoic acid (ATRA) administration is reported. A 3-year-old boy was admitted for evaluation of petechiae and APL was diagnosed. He was initially treated with 45 mg/m2 of ATRA without success, and a complete remission was achieved when the dose was increased to 135 mg/m2. Sinus bradyarrhythmia was first recognized 3 days after the induction therapy with ATRA. It did not disappear even when the patient stopped taking the medication. However, the arrhythmia tended to be augmented whenever he received ATRA again. Close observation of his cardiac condition was mandatory to continue ATRA as an integral part of the therapy for APL, combined with multidrug chemotherapy including anthracyclines, which themselves are potentially toxic to myocardium. In conclusion, the present case revealed the possibility that ATRA therapy induces sinus node arrhythmia, or that it can potentiate preexisting node dysfunctions. PMID- 8691593 TI - [Therapy-related AML(M2) with t(8;21) that developed three years after chemotherapy for hepatocellular carcinoma]. AB - A 60-year-old male with hepatocellular carcinoma was treated by repeated intra arterial injection of epirubicin, carboplatin and doxorubicin. Subsequently, radiotherapy and intravenous administration of etoposide were also carried out. Thirty-three months later he developed AML (M2). The chromosome analysis revealed 45, X, -Y, t (8;21) (q22;q22), which suggested that this leukemia was induced by topoisomerase II targeting agents. He was treated with low dose BHAC and G-CSF and achieved complete remission. This leukemia may be caused by synergic effect of topoisomerase II inhibitors and carboplatin together with radiotherapy. This may be the first report of therapy-related leukemia following chemotherapy for hepatocellular carcinoma. PMID- 8691594 TI - [Immunohistochemical detection of tumor marker antigens by using monoclonal antibodies and its clinical application]. PMID- 8691595 TI - [Definition and classification of tumor marker]. PMID- 8691596 TI - [Historical aspect and present status of tumor marker studies]. PMID- 8691597 TI - [Perspectives for tumor marker research]. PMID- 8691598 TI - [Kinds of cancer-associated antigens and their properties]. AB - Although a number of substances have been reported to be tumor markers, no substance can be completely cancer-specific, but only a cancer-associated antigen (CAA). Now, CAA is considered to be a substance by which malignancies are distinguishable by a quantitative increase or qualitative change, even though it may be present or be produced in small quantities in normal cell as well. The following is a classification of CAAs chiefly on the basis of their origins. Group 1: ectopic CAA that is produced in a large amount in cancer cell, but can also be present or be produced in small amounts in its original normal cell. Group 2: ectopic CAA that is not present in the original normal cell, but can be produced by its carcinogenesis, though it can exist or be produced in other organs as well. Group 3: heterophile CAA that is not present in the human normal cell, but is produced by its carcinogenesis, though it can exist in other species. Group 4: fetal CAA that can be expressed in the fetal stage of the normal cell and vanishes after birth, but reappears with its carcinogenesis. This group includes oncofetal proteins, and carbohydrate antigens of which most are referred to as differentiation or developmental antigens. Based on the above classification, properties of each CAA are reviewed and discussed. PMID- 8691599 TI - [Clinical application of oncogene and antioncogene as a tumor marker]. AB - Since it is generally accepted that neoplasm is developed by accumulation of abnormalities in oncogenes and antioncogenes, these genetic analysis would be useful as new tumor markers. The present clinical applications of genetic analysis of oncogenes are as follows, 1) diagnosis of neoplasm (early detection, differential diagnosis for borderline lesion), 2) speculation of the prognosis of a cancer patient and prediction of chemosensitivity and, 3) establishment of high risk group of cancer. In regard to clinical practice, a medical doctor take care of scientific interpretation of genetic examinations as well as ethical problems. PMID- 8691600 TI - [Carcino-fetal antigens]. AB - Among various kinds of tumor markers, alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) are very important and widely used in the clinical medicine. AFP is a specific marker for diagnosis of hepatocellular carcinoma (HCC). AFP is a glycoprotein composed of 590 amino acid residues and has one asparagine-linked sugar chain at the 232nd position from N-terminal of the AFP molecule. A difference exists between the sugar chain of HCC AFP and the chain from a cirrhotic patient. This difference is easily detected by a lectin-binding analysis using LCA or PHA-E4. This technique enabled us to predict a risk of tumor occurrence in patients with a high probability of HCC development. Exciting progress in molecular biology has been made in the field of AFP and CEA research. The gene structures and the regulatory mechanism of synthesis of AFP and CEA has been elucidated successively. These results may provide a clue to the solution of the mechanism of carcinogenesis and may provide more sensitive tools for detection of tumors as well as practical therapies. PMID- 8691601 TI - [Isoenzyme]. AB - Expression of cancerous isoenzymes in various malignant tumors has been extensively studied using different biochemical techniques. Cancerous alkaline phosphatase (ALP) isoenzymes, such as placental ALP and variant ALP, are detected from sera of patients with various malignant diseases. Variant ALP is a specific tumor marker for hepatocellular carcinoma (HCC). The positive rate of each ALP isoenzyme is, however, low except for a high positivity of placental ALP in seminoma. Novel gamma-glutamyltranspeptidase (gamma-GTP) isoenzyme is specifically found in about 60% of the sera from patients with HCC but in only 3% of those from patients with benign liver diseases, suggesting a high specificity for HCC. Thus, cancerous isoenzymes are available for diagnosis of various malignant tumors. PMID- 8691602 TI - [Peptide hormone]. AB - Clinical studies have confirmed the efficacy of peptide hormone as a routine tumor marker in the diagnosis, monitoring, and assessment of the prognosis of patients with endocrine tumors. However, in a large number of cancer patients, including those with ectopic hormone-producing tumors, the peptide hormone has limited clinical use as a routine tumor marker because of its poor specificity for tumor tissue and its low concentration in the patient sera. A new analysis product, ProGRP, is a specific and reliable serum tumor marker for small cell lung carcinoma (SCLC). It is useful not only in the evaluation of prognosis but also in the detection of SCLC at an early stage. On the other hand, recently, the RET proto-oncogene has been identified as a gene responsible for multiple endocrine neoplasia (MEN) syndromes: MEN 2A and MEN 2B. In the future, serum peptide hormone markers and molecular genetic markers may be useful in the diagnosis of endocrine tumors. PMID- 8691603 TI - [Amines and pteridines]. AB - Polyamines (putrescine, spermidine and spermine) play important roles in cell proliferation and differentiation, and have been established as tumors markers. We and other workers have confirmed that N1-acetylspermidine in tumor tissues, spermidine and spermine in erythrocytes, and N1,N12-diacetylspermine in urine might be the most sensitive indicators for various forms of tumors. Neopterin is a marker of cell-mediated immunostimulation, and may be a helpful marker in monitoring cancer patients. HPLC and immunological assays of neopterin, biopterin, and N2-(3-aminopropyl)biopterin(oncopterin) in urine might be useful in the clinical study of pteridines, as cancer markers. Serum 5-S-cysteinyldopa level is a useful and specific biochemical marker for malignant melanoma. PMID- 8691604 TI - [Expression of EGF receptor subfamily in tumor]. AB - The members of EGF receptor subfamily are transmembrane glycoproteins with tyrosine kinase activity. Once EGF or EGF-related peptides binds to the receptors, they undergo autophosphorylation and binding to the SH2 protein, which in turn activates the intracellular signaling cascade. In the squamous carcinoma of head and neck, esophagus and lung, the EGF receptor gene amplification and EGF receptor hyperproduction are frequently observed. In the adenocarcinoma of pancreas, breast and stomach, hyperproduction of the EGF receptor subfamily is common, suggesting the involvement of these growth factor receptors in the tumorigenesis. The prognostic value of EGF receptor hyperproduction appears considerable when combined with other factors. EGF receptor subfamily members are useful targets for the immunotoxin therapy and immunogene therapy. PMID- 8691605 TI - [Viral tumor markers]. AB - Viruses can contribute to the development of human tumors by different mechanisms: directly by altering host cellular gene expression by viral products or by viral DNA integration; indirectly by modifying the host cell genome co operated with other factors. Human cancer associated with hepatitis B virus (HBV), hepatitis C virus (HCV), human T cell leukemia virus (HTLV-I), papillomavirus (HPV) and Epstein-Barr virus (EBV) infections are responsible for liver cancer (HBV and HCV), adult T cell leukemia (HTLV-I), cervical cancer (HPV) and malignant lymphoma (EBV) respectively. Based on the clinical and experimental knowledge, viral tumor markers are thought of not as diagnostic markers, but as most important risk factors for various tumorigenesis. PMID- 8691606 TI - [Leukocyte surface antigen]. AB - Leukemic cells as well as normal blood cells possess several antigens on their cell surfaces. By detecting these cell-specific molecules using monoclonal antibodies and flow cytometry, these immunological methods can be applied to both clinical and basic tumor studies. The analysis of cell surface markers has been applied in the diagnosis and the management of hematological disorders such as leukemias and lymphomas and it has become to be utilized as the routine work in many laboratories. Such analysis has been particularly useful in lymphocytic leukemias due to the ability of this method to classify lymphocyte subtypes, as well as specify their developmental origin. Importance is that, with this information, it is possible to determine expected clinical prognosis, to recommend treatment options and to judge treatment efficacy. PMID- 8691607 TI - [Intermediate filaments]. AB - The antibodies for intermediate filaments, including keratin, vimentin, desmin, GFAP and neurofilaments, have been much useful in routinely-processed immunohistochemical study for identifying characteristics of tumor cells or making the definite diagnosis. In general, when neoplastic transformation has taken place, the affected cells would reveal to some extent alterated immunolocalization of intermediate filaments in the cytoplasm. Whether the tumor cells are of epithelial or non-epithelial origin is significant from diagnostic points of view when utilizing those intermediate filaments as tumor markers. But there are many "exceptional" cases of epithelial tumors with expression of vimentin, or those of non-epithelial tumors with expression of keratin, indicating some "variants". Immunohistochemical application of the intermediate filaments is indispensable not only as "a diagnostic tool for surgical pathologists", but also a method for analyzing relationship between morphological changes and functional aspects of the tumor cells. PMID- 8691608 TI - [Biological function of cancer-associated carbohydrate antigens]. AB - An important outcome of the monoclonal antibody approach for cancer-associated antigens is that cell-surface carbohydrates have been shown to be very important cancer-associated antigens. These antigens are currently classified into several groups. The first group has the sugar determinant carried by so-called type 1 chain carbohydrates, with a backbone structure composed of the Gal beta 1- >3GlcNAc beta repeating unit. The antigens in this group are utilized mainly for the diagnosis of cancers in the pancreas, biliary tract and other digestive organs. This group includes the well-known serum tumor marker, the 2 -->3 sialyl Le(a) antigen, which is detected by N19-9 and other antibodies. This group also includes DU-PAN-2, which was recently confirmed to be the sialyl Lec. The second group has the polysaccharide determinant carried by so-called type 2 chain carbohydrates, the characteristic feature of which is a backbone structure composed of the Gal beta1 -->4GlcNAc beta repeating unit. This group includes the tumor markers, sialyl SSEA-1, CSLEX-1 or sialyl Lewis X, and is used for the diagnosis of cancers originating in the lung, ovary and digestive organs. The third group has the antigenic determinant carried by the innermost core structures in O-linked carbohydrate side chains. The example of this group is the sialyl Tn antigen, which is detected in ovarian cancers. This group also includes the recently described carbohydrate determinant called Fl alpha antigen, which is frequently expressed in gastric cancer cells. Some of the antigens in the first and second groups such as sialyl Le(a) and sialyl Le(x), serve as ligands for E selectin, a cell adhesion molecule expressed on activated human endothelial cells, and play significant roles in hematogenous metastasis of cancer. PMID- 8691610 TI - [Clinical implication of tumor marker expressions suggesting biological characters of malignancies]. AB - One of the potential utilities of tumor markers is to recognize the biological characters of malignancies. These biological characters include cell lineage, cell differentiation, cell growth activity, metastatic risk, drug sensitivity or precancerous involvements. So it is very important for the clinical management of cancer patients to detect such tumor marker expressions. The major aim of this brief overview has been to provide an update on the such tumor markers. Expression of some phenotype markers recognized by monoclonal antibodies against cancer cells suggests cell lineage or cell differentiation. Neuroendocrine property can be diagnosed by tumor markers such as GRP, 1-DDC, NSE or CR-BB. Cancer cell nuclear DNA patterns are highly associated with cell growth activity. Expression of E-selectin suggests high risk of cancer metastasis. Detection of MDR protein or GST-pi is correlated with anticancer drug resistance. Precancerous involvement such as atrophic gastritis can been screened by the serum pepsinogen level. These tumor markers were discussed on the basis of our research or literatures. PMID- 8691609 TI - [Regulation of tumor marker gene expression]. AB - Tumor marker is a group of proteins that specifically expressed in association with carcinogenic processes. Thus, studies of regulation mechanisms of the tumor marker genes are important for understanding the possible alteration of gene expression during neoplastic transformation. In this article, we described the molecular mechanisms of the regulation of two major tumor marker genes, i.e. human alpha-fetoprotein (AFP) gene and rat glutathione transferase P(GST-P) gene. Positive and negative mechanisms of each gene regulations are discussed. PMID- 8691611 TI - [Detection of tumor markers by genetic diagnostic methods and its clinical application]. AB - Since the development of the polymerase chain reaction (PCR) method of DNA amplification in 1985, numerous improvements, modifications, and novel applications of PCR have been devised. These developments eventually made it possible to examine minute clinical samples. It has become clear that cancer arise and progress through the accumulation of various genetic alterations. Certain genetic changes are now considered to be molecular markers useful not only for early diagnosis but also for predicting the behavior of cancer and the clinical outcome of patients. Some molecular markers are also useful for diagnosis of inherited cancer and susceptibility to cancer. We describe the latest improvements of detecting these molecular markers and clinical application of them in digestive cancer. PMID- 8691612 TI - [Molecular microheterogeneity of tumor marker substances and its significance of biological recognition]. AB - It has been well known that molecular microheterogeneity of tumor marker substances have occasionally a big impact on the laboratory determination of tumor marker in sera. These includes molecular heterogeneity due to delicate difference of peptide or carbohydrate chain structures(CEA, AFP), the difference of epitope (CA19-9, CA125), the difference of combination of subunits(NSE) or the difference of combed other substances(PA). This paper reviewed such instances in terms of the definite data from our works or literatures. PMID- 8691613 TI - [Sensitivity and specificity of tumor markers in cancer diagnosis]. AB - Each serum tumor marker has its own sensitivity and specificity. The sensitivity is the true positive rate in malignant cases, and the specificity is the true negative rate in benign cases. We should ascertain various benign diseases or triggers which tend to show false-positivity, especially in the measuring of CA19 9, CA125, and acute phase reactants, such as, IAP and TPA. Cancer-specificity is high in sialyl-stage-specific embryonic antigen-I, sialyl-Tn antigen, and NCC-ST 439, etc. Organ-specificity is considerably high in the case of some markers, such as, alpha-fetoprotein, elastase-I, and neuron-specific enolase, etc. On the other hand, the organ-specificity of carcinoembryonic antigen is low. Therefore, the combination of different categories of tumor markers is of great importance. Recently, molecular diagnosis of cancer is being developed. However, even K-ras oncogene mutations at codon 12 are not absolutely specific to pancreatic cancer from genetic analysis of pancreatic juice endoscopically aspirated from patients with pancreatic diseases. Improvement of sensitivity and specificity is still one of the most important issues in the research and development of tumor markers. PMID- 8691614 TI - [Organ specificity of tumor markers and its application for clinical diagnosis]. AB - Several tumor markers are produced by the limited organ and have the advantage for the determination of the origin. However, many tumor markers are produced by various organs and are not specific to cancer but associated with cancer. therefore, combination assays using different categories of tumor markers are necessary to increase the efficacy of cancer-diagnosis and to determine the origin of tumor. PMID- 8691615 TI - [Role of tumor marker in the presymptomatic diagnosis of hereditary malignant tumors]. AB - Oncogene is not categorized as a tumor marker in a strict sense, however, cancer related oncogens play an important role as a biomarker in hereditary malignant tumors in a wide sense. Various suppressor oncogenes have been identified in the autosomal dominant hereditary diseases such as APC, in familial adenomatous polyposis, p53 in Li-Fraumeni syndrome and BRACA 1 and 2 in breast cancer. By identifying the mutation site or deletions of germ line, it is possible to make a presymptomatic diagnosis of those hereditary malignant tumors. There is splendid progress in understanding of DNA repair mechanism. Recently, the mismatch repair genes were cloned as a causing gene of HNPCC. There are another group of genes called nucleotide excision repair genes which are causative genes of various autosomal recessive hereditary diseases such as xeroderama pigmentation. Pro and cons of presymptomatic diagnosis of familial adenomatous polyposis were discussed in a series of 72 patients among 42 family trees. PMID- 8691616 TI - [Methodology and clinical usefulness of radioimmunoimaging using radiolabeled monoclonal antibodies]. AB - Radioimmunoimaging is a functional diagnostic radiology mainly using radiolabeled monoclonal antibodies. The radioimmunoimaging may offer the specific targeting of human malignant tumors. Presently available radiolabeled monoclonal antibodies clinically yield an average sensitivity of more than 70% with an average specificity of more than 80% in colorectal and ovarian cancers. The radioimmunoscintigraphy has been demonstrated to be more accurate than methods based on the morphological imaging for the detection of local recurrence in the pelvis. A combination of functional (radioimmunoimaging) and morphological (CT, MRI, etc) images are expected to offer the early detection of recurrent and metastatic diseases. PMID- 8691617 TI - [Usefulness and limitation of serum tumor markers in diagnosis of lung cancer]. AB - In the clinical practice of lung cancer, serum tumor markers are important laboratory tests and their use is wide spread. Among the various markers for lung cancer, the usefulness of CEA, SLX, SCC and NSE has been firmly established. These markers cannot be used routinely to screen for lung cancer but may be used as complementary tools for diagnosing the tumor. Elevated levels of these markers also appear to be useful for monitoring the response to therapy and tumor progression. CYFRA21-1 and ProGRP, new tumor markers with relatively high sensitivity and specificity to lung cancer, were recently developed. These tumor markers may be useful tools for early detection of lung cancer. PMID- 8691618 TI - [Tumor markers: neoplasmas in digestive organs]. AB - Because they show high levels in hepatocellular carcinoma, alpha-fetoprotein and des-gamma-carboxyprothrombin are clinically useful tumor markers for differentiating hepatocellular carcinoma from other hepatic diseases. The two are useful complementary markers of hepatocellular carcinoma because they do not correlate with each other. A typical marker of pancreatic cancer is carbohydrate antigen (CA) 19-9. Over a period of more than 10 years, many markers resembling CA19-9 have been identified, but none are markedly superior to CA19-9, and the sensitivity of these markers in pancreatic cancer is only 65%-80%. Tumor markers are not useful for the early diagnosis of either hepatocellular carcinoma or pancreatic cancer. They are, however, considered to be useful for monitoring after treatment. PMID- 8691619 TI - [Tumor markers in lymphoproliferative disorders]. AB - The tumor markers detected in patients' peripheral blood with lymphoproliferative disorders, especially malignant lymphomas were reviewed and classified as follows: I) Biochemical marker and reactive protein, II) Cytokine and soluble cytokine receptor, III) Soluble form of tumor-surface marker, IV) Circulating tumor and V) Others. They were reported to be useful to predict the prognosis, to monitor the effects of the treatment, to detect minimum residual disease and to diagnose early relapse. At present clinical practice, non-specific tumor markers such as LDH, ESR, CRP and beta 2-MG are generally used. In the future when the convenient methods of biological assays including molecular biology-technique are developed, it will be possible to detect the specific tumor markers in clinical setting. PMID- 8691620 TI - [Neoplasias in hematopoietic tissues]. AB - Leukemia-specific chromosomal aberrations are the most reliable tumor markers. Although chromosome analysis is a powerful diagnostic tool, some aberrations like monosomy 7 in AML, 15; 17 translocation in APL and trisomy 12 in CLL are not adequately detected. Fluorescence in situ hybridization is a recent method to detect specific genetic alteration in both interphase and mitoic cells and overcomes the disadvantages of conventional cytogenetics, Southern blotting and RT-PCR. In this manuscript, the advantages and limitations of the methods used for detecting leukemia/lymphoma specific chromosomal markers were discussed. PMID- 8691621 TI - [Tumor markers in urological malignancies]. AB - Present status of tumor markers in urological malignancies for diagnosis and follow-up was reviewed. Although many researches have been performed, specific tumor markers in kidney, urothelium and penis cancers have not identified. In testicular tumors, AFP and beta-subunit of HCG are widely used. Especially, using biological half time, these substances are very useful in the judgement of presence of residual tumor or tumor recurrence. In prostate cancer, the determination of PSA has been confirmed to be the most useful tumor marker in solid tumor. World standardization of PSA assays and evaluation of PSA subtypes are necessary. PMID- 8691622 TI - [Gynecologic malignancies]. AB - Clinical Value of tumor markers in gynecologic malignancies is discussed with regard to their possible role in the future. Generally, the first choices of tumor markers include SCC antigen for squamous cell carcinoma and CA125 for adenocarcinoma and uterine sarcoma. Also, recent data regarding the biological function of some tumor markers, e.g., inhibition of cysteine protease by SCC antigen, have provided new information for understanding the malignant behavior of tumor cells, which would be useful for setting up new diagnostic and therapeutic modalities against malignant tumor in the future. PMID- 8691623 TI - [Current advancement of assay of tumor markers and the perspective in future]. AB - Cancer has ranked first as regards the cause of death with the longest average life span. So the early cancer detection is very important to prevent cancer death. Tumor-secreted fetal antigens are already part of routine diagnosis of cancer and play an important role in the detection of cancers. However, the present methods for measurement of tumor markers don't have adequate sensitivity to detect early stage of cancer owing to their frequent elevation in benign disease and absence in some cases of malignancy. A cancer screening system with blood samples was devised for purposes of detecting unspecified various cancers. Namely, a modified combination assay with five tumor markers (AFP, CEA, CA19-9, CA125 or PAP, DUPAN-2, and cancer risk factors, pepsinogens (PG) I and II and I/II) was investigated in 50 patients with various cancers. The sensitivity of combination assay with these five tumor markers was 68% but that of modified combination assay with tumor markers and risk factors was as high as 87%. In particular its sensitivity to detect cancer of gastro-intestinal tract was highly improved. It was indicated as a subject of future studies that the sensitivity of modified combination assay could be improved further by the exchange and addition of new adequate tumor markers like as CYFRA 21-1 or ProGRP. So I described here the current advancement of assays of tumor markers and the perspective in future. PMID- 8691624 TI - [Cut-off values and grey-zone of tumor markers in blood]. AB - Cut-off values and grey-zone of tumor markers in blood were described. Cut-off values are a little different from reference intervals, and can discriminate tumor status from non-tumor status. Cut-off values are commonly determined by ROC (receiver operating characteristic) curve, that can show us the diagnostic efficiency of the test. The patients of control group used in ROC curve must be selected from benign diseases whose conditions are similar to those of tumors. Grey-zone is defined as the range between cut-off value from healthy subjects and that from benign diseases. Cost-efficiency must be considered when cut-off values and grey-zone of tumor markers in blood were set up. PMID- 8691625 TI - [How to determine the best combination assay by several tumor markers?]. AB - Combination assay by several tumor markers provides more precise diagnosis of malignancy than using a single tumor marker. The best combination assay by two tumor markers is determined as follows. MINIMIZE RFP (1-SpAorB(CA, CB)) + RFN(1 SnAorB(CA, CB)), where RFP, RFN denote the loss of false positive and false negative, respectively. SpAorB (CA, CB), SnAorB (CA, CB) are specificity and sensitivity of the combination assay by tumor markers A, B with cut-off values CA, CB. PMID- 8691626 TI - [The combination assay of tumor markers by multivariate analysis for improvements of the diagnostic precision in malignancies]. AB - Since 1987, we have been trying to develop a computer-aided multivariate pattern analysis system (CAMPAS) with the focus on ovarian tumors using a discriminant analysis, which is one of multivariate analysis, to raise specificity while retaining sensitivity of combination assay as high as possible. We applied this CAMPAS which was developed in collaboration with SRL (Tokyo, Japan) under the guidance of Prof. Em. Terashima, Y.(The Jikei University School of Medicine, Tokyo, Japan). CAMPAS OV-2, which is the newest one, based on 2 discriminant formulas with 6 tumor markers, ie, cancer antigen 125 (CA125), immunosuppressive acidic protein (IAP), tissue polypeptide antigen (TPA), alkaline phosphatase (ALP), albumin and iron (Fe), was developed and practised prospectively as a pretherapeutic serological diagnostic means to distinguish epithelial ovarian carcinomas from benign ones tumors. The sensitivity and specificity reached 87.1% and 82.9%, respectively in CAMPAS OV-2. PMID- 8691627 TI - [Applications of tumor markers to the screening of endometrial and ovarian cancers]. AB - Several new trials, using tumor markers in the screening for gynecological malignancies, have been conducted. For assisting the cytological diagnosis of uterine endometrial cancers, the new EIA method using cytological specimens and the monoclonal antibody against endometrial cancer cells, MSN-1, was developed. This method could help to discriminate between cancer and normal cells, so this would result in decrease the numbers of suspicious cases on cytological diagnosis. For ovarian cancers, especially to identify high-risk groups, two carbohydrate-related antigens, CA602 and CA546, were employed. The combined use of these two markers showed a high potentiality to detect ovarian cancers. GAT (galactosyltransferase associated with tumor), an isoform of galactosyltransferase, could rescue the false-positive cases with endometriotic cysts. These new methods with tumor markers are supposed to be handy tools in the screening for gynecological malignancies. PMID- 8691628 TI - [Application of tumor marker for immunotargeting therapy of cancer]. AB - For many years, attempts have been made to utilize the monoclonal antibody against tumor markers for diagnostic purposes. On the other hand, studies with various form of immunoconjugate have demonstrated some therapeutic promise. In this paper, the ideal tumor marker for immunotargeting therapy will be discussed. Results of clinical trials of radioimmunoconjugates, immunotoxin and chemoimmunoconjugates will be reviewed and prospects of these new approaches for the treatment of cancer patients will be presented. PMID- 8691629 TI - [Selection of drugs for chemotherapy based on drug resistance marker]. AB - There is no appropriate tumor marker for the selection of anti cancer drug. Some agents can be selected for the reversal of anti cancer drug resistance. For example, verapamil or cyclosporin A may be useful for p-glycoprotein related multidrug resistance, and amphotericin B, docosahexaenoic acid or 8-chloro cAMP can be used for the modification of cisplatin-resistance. Recently, bcl-2 or mutated p53 gene are demonstrated to be important markers for drug resistance. More studies are necessary to identify an appropriate markers for drug resistance and overcome it. PMID- 8691630 TI - [Assessment of response to chemotherapy by tumor marker in solid neoplasms]. AB - The points at issue in the assessment of response to chemotherapy by tumor marker are discussed, and our guideline is proposed. In cancer clinics, many paradoxical movements of tumor marker are usually recognized in the situations such as heterogeneity changes of neoplasms, acute tumor cytolysis, non-peculiar rise of tumor marker, low level rise of markers near the basal level, which show paradoxical movements apart from clinical response to treatment. Then the guidelines must be settled based under the consideration of these phenomena and tumor marker kinetics. Partial response > = 65% decrease over 4 weeks; No change within < 65% decrease or < 40% increase over 8 weeks; Progressive disease > = 40% increase over 8 weeks. CR must not be defined. PMID- 8691631 TI - [Biology and clinical relevance of multidrug resistance associated antigen]. AB - Multidrug resistance (MDR) is a main obstacle to cancer chemotherapy. P glycoprotein(P-gp) is the first antigen discovered to be linked to MDR, and is a energy dependent plasma membrane efflux pump, which actively transports a variety of drugs and substances out of cells. P-gp can be detected by immunological or biochemical (molecular) methods, but both methods have some limitations with respect to sensitivity and specificity. Some studies have demonstrated the adverse prognostic factor of P-gp and some others have not. The discrepancy between various studies is considered to be due to the limitation of methodology for detecting P-gp and the existence of other MDR antigens, for example multidrug resistance associated protein. The clinical roles of MDR reversing agents have not yet been confirmed. PMID- 8691632 TI - [Endoscopic treatment of gastrointestinal cancers--indication and limitation]. AB - Recently, endoscopic treatments have been applied for the curative treatment of early gastrointestinal cancers and for the palliative treatment of end-stage gastrointestinal cancers. As a curative treatment for early gastric cancers, the endoscopic Nd-YAG laser therapy was initially applied and a satisfactory results were obtained. However, the endoscopic mucosal resection (EMR) is evaluated as the reliable endoscopic treatment for early gastric cancers because curability can be histologically detected by resected specimen. EMR technique is also applied for early esophageal cancers and early flat or depressed colon cancers. EMR-L (EMR with the use of Ligating device) developed by us is mainly practiced in our department. By the use of EMR-L technique. Resectability has been improved compared with 2 channel EMR technique. As the palliation of end-stage gastrointestinal cancers endoscopy recanalization of malignant esophageal stenosis is very effective to improve the patient's QOL. The memorial metallic stent for esophageal stenosis is very useful to keep cavity for a long term after endoscopic recanalization. PEG (percutaneous endoscopic gastrostomy) is also very effective to reduce the symptoms of the patients with peritonitis carcinoma or ileus. In this paper, the present status of curative and palliative endoscopic treatment for gastrointestinal cancers was reported. In recent future, endoscopy will be more widely applied as a less invasive therapeutic procedure for gastrointestinal cancers. PMID- 8691633 TI - [Gene structure of the human MHC region]. AB - The human major histocompatibility complex (MHC) encodes the highly polymorphic human leukocyte antigens (HLA) responsible for antigen presentation to T cells. The HLA gene complex is located on the short arm of chromosome 6 within 6p21.3 and covers a distance of about 4,000 kb that has arisen through repeated gene duplication and conversion during evolution. The HLA class I region is about 2,000 kb in size, while the class II region is about 1,000 kb. The remainder comprises the HLA class III region. There are presently 19 HLA or HLA-like expressed genes and about 80 non-HLA expressed genes as well as 27 pseudogenes or gene fragments localized within the HLA region, although the function of most of these genes is still uncertain. This paper provides a comprehensive overview of non-HLA genes as well as HLA genes which are so far identified in this region. PMID- 8691634 TI - [Positional cloning of the putative gene responsible for transient abnormal myelopoiesis and that for multiple cartilaginous exostoses]. AB - Positional cloning of the putative gene responsible for transient abnormal myelopoiesis (TAM) and that for multiple cartilaginous exostoses (MEX) is described. TAM is a leukemoid reaction occurring frequently in Down syndrome (DS) newborn infants and they often develop true leukemia several years later. The previous findings of "disomic homozygosity in trisomic cells" and tentative mapping of the TAM gene to 21q11.1, and an encounter of a unique DS-associated TAM patient with inv(21) (q11.1q22.13) let us start positional cloning of the TAM gene. One type of MEX is an autosomal dominant disorder and patients with MEX sometimes develop chondrosarcoma. The MEX gene has been mapped to 8q24. We encountered a sporadic case of MEX with de novo t(8q; 13q). Thus, we hypothesized that in both patients, the TAM and the MEX genes are disrupted by the structural chromosome abnormalities. For TAM, we first mapped the proximal breakpoint of inv(21) between 2 STSs using 7 cosmid clones as FISH probes that were isolated on the basis of STS markers at the 21q11.1 region, isolated their corresponding YACs, and then analyzed them. However, since YACs corresponding to 2 other STSs between the two markers could not be isolated, we carried out a chromosome walking to construct a cosmid contig between the 2 STSs. Southern analysis with a cosmid clone within the contig detected EcoRI-/HindIII extra bands on the patient's DNA. The cDNA screening and exon trapping to isolate a gene from the region are underway. Similarly, in the MEX patient we mapped the 8q breakpoint between 2 cosmid markers, then isolated YACs and cosmid subclones. By exon trapping after detection of a cosmid covering the breakpoint, an exon-like sequence was isolated. The 3'-RACE/5'-RACE revealed a novel transcript from this cosmid. Whether the transcript is the MEX gene remains to be determined. PMID- 8691635 TI - [Clinical classification of adult T-cell leukemia and its complications]. AB - Since human lymphotropic virus, type 1(HTLV-1) associated adult T-cell leukemia (ATL) has various clinical appearances and courses, it is difficult for the clinician to differentiate acute disease which needs immediate treatment from chronic disease which can be observed with no specific treatment. The Lymphoma Study Group of Japan (1984-87) proposed four clinical subtypes: (1) smoldering type; more than 5% of abnormal T-lymphocytes with less than 4000/microliters of lymphocytes in peripheral blood and few abnormal blood chemistry profiles and ATL infiltration, (2) chronic type; absolute lymphocytosis with T-lymphocytosis of more than 4000/microliters, LDH < 2 times the normal upper limit and no hypercalcemia with possible lymph-node, liver, spleen, skin and lung involvement, (3) lymphoma type; no lymphocytosis with less than 1% of abnormal T-lymphocytes, and histologically-proven lymph-node enlargement, and (4) acute type; the patients not classified into any of the above 3 types. The median survival time (MST) was 6.2 months for acute type, 10.2 months for lymphoma type, and 24.3 months for chronic type; 62.8% of smoldering type was still alive up to 4 years. ATL has a poor prognosis because of life-threatening complications including infections and hypercalcemia. Among infectious complications, cytomegalovirus (CMV) is frequently encountered in autopsy patients. It is important to make an early diagnosis since an anti-CMV agent, ganciclovir is now available for clinical use. It takes 10-14 days to culture CMV in vitro, but now rapid diagnosis can be made by direct immunoperoxidase staining with human monoclonal antibodies against an immediate-early antigen. Another major complication is hypercalcemia. The patients' serum and tumor tissues are found to have parathyroid hormone related protein (PTHrP) associated with hypercalcemia. Serum PTHrP (1-34) is determined by radioimmunoassay and its values seem to be correlated with hypercalcemia and the disease activity. There are still many problems to solve for ATL, but recent advances have been made in clinical subtypes and the above 2 complications. PMID- 8691636 TI - [Malignant lymphoma and EBV]. AB - Epstein-Barr virus (EBV), a DNA virus of the herpes virus family can infect and transform resting human B lymphocytes in vitro. EBV was originally considered to be a possible causative agent of African Burkitt's lymphoma and nasopharyngeal lymphoepithelioma. Recently, using highly sensitive methods, such as the polymerase chain reaction (PCR) and in situ hybridization (ISH), EBV has been found to be also present in numerous human lymphoproliferative disorders, including Hodgkin's disease, anaplastic large cell lymphoma, B cell lymphoma in immunocompromised patients, peripheral T cell lymphoma, adult T cell leukemia/lymphoma, nasal lymphoma, AILD-T cell lymphoma, pyothorax-associated pleural lymphoma, and angiocentric T/NK cell lymphoma. However, the EBV infection pattern and the role of EBV in each disease is not the same. We introduce the relationship between EBV and each disease found in our department, using Southern blot analysis, PCR, ISH and immunological staining. PMID- 8691637 TI - [The cell cycle and the tumor suppressor genes]. AB - Cell cycle progression is controlled by cyclin-dependent kinases (CDKs) at the transition of both G1 to S and G2 to M phases. The activities of CDKs are negatively regulated by CDK inhibitors. Deregulation of CDK activity at the G1-S transition allows an aberrant progression of the cell cycle in tumor cells. Recent developments on cell cycle control have revealed a signal transducing pathway of tumor suppressor genes, p53 and pRb, concerning CDK and CDK inhibitors. CDK inhibitor p21 is a target of p53. p53 binds a promoter of the p21 gene and activates the transcription of p21. Consequently, cell cycle progression is blocked at the G1 phase through the suppression of CDK activity. pRb is a substrate of CDK. pRb functions to suppress cell cycle progression at the G1 phase associated with the E2F transcription factor. Phosphorylated pRb by CDK releases an active E2F, which promotes the expression of genes whose products may play a crucial role in controlling G1-S progression. These findings have deepened our understanding on the molecular mechanisms of tumor growth suppression. PMID- 8691638 TI - [Clinicopathological study on primary lung cancer--immunohistochemical expression of p53 suppressor gene and bcl-2 oncogene in relation to prognosis]. AB - Two hundred and eleven surgically resected primary lung tumors were studied immunohistochemically. According to histologic type, they were 129 adenocarcinomas, 56 squamous cell carcinomas, 4 small cell carcinomas, 8 large cell carcinomas, 8 adenosquamous cell carcinomas, 5 so-called carcinosarcomas and 2 other tumors. Immunohistochemical expression of p53 and bcl-2 was studied in relation to the disease-free survival. Among the 211 patients with lung cancer, 109 were positive for p53 expression, and there was no significant relationship between p53 expression and sex, or clinicopathological stage and size of the tumor, although the patients with squamous cell carcinoma had a significantly higher frequency of p53 expression than those with adenocarcinomas. The frequency of p53 expression was significantly higher in the patients with poorly differentiated adenocarcinomas than in those with other histologic types. Seventy four of the 211 patients were positive for bcl-2 expression and bcl-2 expression was higher in the stage I patients and patients with small lung tumors 2cm or less in diameter than in the other patients. The patients with adenocarcinoma had a higher frequency of expression than those with squamous cell carcinoma but no difference was found in the histological differentiation of the tumor. The 5-year survival of patients positive for p53 expression was poorer than that of those with negative expression and the survival rate was higher in the patients positive for bcl-2 expression than in those with negative expression. These findings suggested that the expression of p53 and bcl-2 is a useful marker of follow-up and prognosis, but will require more data concerning the mechanism of carcinogenesis. Seven cases of primary lung cancer were examined for genetic abnormality of the p53 gene. cDNA was synthesized from total RNA of primary tissues of lung cancer using oligo (dT) primer and reverse transcriptase and polymerase chain reaction (RT-PCR), and PCR-single strand conformation polymorphism (SSCP) analysis were performed. Five patients gave a positive result upon PCR-SSCP analysis of the p53 gene. To confirm the results of PCR-SSCP analysis, their nucleotide sequences were further analyzed and four of them had point mutations at different codons (154, 176, 207, 236) and one had deletion of one nucleotide (245) in exon 5 and 8. Fifteen percent of 26 patients with small peripheral lung adenocarcinomas less than 2cm in diameter were already advanced in stage and various factors such as vascular invasion, pleural involvement and degree of scar grade were higher than in patients with clinicopathological stage I. In advanced cases, the frequencies of p53 expression was higher than in stage I cases. Concerning the relationship of the degree of scar grade to PDGF-B expression, we demonstrated the production of PDGF-B protein immunohistochemically and the expression of PDGF-B-mRNA by In situ hybridization in the adenocarcinoma cells and macrophages of the lung tumors. However, no significant correlation was observed between the degree of PDGF-B expression and collagen production in the fibrotic focus. PMID- 8691639 TI - [CD26/dipeptidyl peptidase IV and thyroid peroxidase as molecular markers for differentiated thyroid carcinoma]. AB - Differential expression of two enzymes, dipeptidyl peptidase IV (CD26/DPP IV) and thyroid peroxidase (TPO), in neoplastic thyroid tissues was studied by Northern blot analysis and histochemical analysis using 31 thyroid tissue specimens of various thyroid diseases. On Northern blot analysis, all 16 differentiated carcinomas (12 papillary and 4 follicular carcinomas) overexpressed CD26/DPP IV mRNA, whereas all 14 benign tissue specimens (4 normal thyroid, 4 Graves' disease, 2 adenomatous goiters and 4 follicular adenomas) showed faint expression of CD26/DPP IV mRNA. All 14 benign tissues expressed high levels of TPO mRNA, whereas all 12 papillary carcinomas strongly underexpressed TPO mRNA. A medullary carcinoma did not show any mRNA expression of either enzyme. TPO mRNA expression in differentiated carcinomas did not always correlate with mRNA expression of thyroglobulin, thyroid stimulating hormone receptor, and thyroid transcription factor-1. Northern blot analysis also revealed that CD26/DPP IV is a more specific marker of differentiated carcinoma than three proto-oncogenes previously reported to increase mRNA expression in thyroid carcinomas: c-met, c-erbB-2, and EGF-R. Histochemically, all 14 benign tissues were CD26/DPP IV negative and strongly TPO positive, while all 12 papillary carcinomas were strongly CD26/DPP IV positive and TPO negative. Three of 4 follicular carcinomas were histochemically positive for the two enzymes. These findings suggest that the differential expression of these two enzymes can be applied to study the thyroid tumorigenesis. PMID- 8691640 TI - [Separation of methotrexate-polyglutamates by capillary electrophoresis and its application to the measurement of gamma-glutamyl hydrolase activity in human leukemia cells in culture]. AB - We have applied capillary electrophoresis to the separation of methotrexate (MTX) polyglutamates, and gamma-glutamyl hydrolase (GGH) activities in tumor cells were measured by using this new analytical method. MTX-polyglutamates were sufficiently separated in 15min by capillary electrophoresis with silica fused capillary (phi 50 microns x 75cm), being electrophoresed at 25kV and 30 degrees C in a buffer which contained 20mM sodium tetraborate, 20mM SDS and adjusted pH to 9.5. MTX-polyglutamates eluted were detected at 300nm UV. Cellular extracts obtained from the sensitive and antifolate-resistant human leukemia cell lines, MOLT-3 and K562, were incubated with MTX-glu5 at 37 degrees C for 1, 2 and 4 hr, and the amounts of the degradation products (glu1-glu4) were measured for GGH activity by capillary electrophoresis. There was no significant difference in the production of the metabolites between MOLT-3 and K562 cells (867 +/- 109 vs 799 +/- 56 pmol products/min/1 x 10(7) cells), however, the MTX-resistant MOLT-3 cells with a diminished polyglutamation of folates (MOLT-3/MTX.P-17) and the ZD1694-resistant K562 cells with the impaired membrane transport for reduced folates/MTX/ZD1694 (K562/ZD1694.C) showed decreased activities of GGH (519 +/- 52 and 680 +/- 99 pmol products/min/1 x 10(7) cells, respectively), suggesting the down-regulation of the enzyme in these antifolate-resistant cells concomitant with the intracellular substrate depletion. This study indicates that capillary electrophoresis is a rapid, cost-efficacious method with a sufficient reproducibility in the measurement of GGH activity and must be more suitable for the analysis of clinical samples than HPLC method which requires a large volume of the material. PMID- 8691641 TI - [Plasma fibrin monitor level in DIC patients with a hematopoietic malignancy]. AB - The Plasma level of soluble fibrin monomer (sFM) was measured in 218 patients with a hematopoietic malignancy. Of them, 198 were diagnosed with disseminates intravascular coagulation (DIC), 20 with Pre-DIC, and 20 with Non-DIC. Pre-DIC was retrospectively defined as the condition at least 1 week before the onset of DIC. The plasma levels of sFM, thrombin-anti-thrombin III complex (TAT), plasmin alpha 2-antiplasmin inhibitor complex (PIC), and FDP-D-dimer were significantly higher in patients with DIC than in those with Non-DIC. These levels were significantly higher in patients with Pre-DIC than in those with Non-DIC. Among these hemostatic parameters, the plasma sFM showed the highest sensitivity and specificity for DIC or Pre-DIC. These findings suggests that sFM is the most valuable marker hemostatic for the diagnosis of DIC and Pre-DIC. PMID- 8691642 TI - [Comparative studies on the time course of proliferating cell nuclear antigen and bromodeoxyuridine staining pattern in regenerating rat liver cells]. AB - Immunohistochemical staining pattern of proliferating cell nuclear antigen (PCNA) was examined in regenerating rat liver specimens fixed under the various conditions (10% buffered formalin for 6hr, 1% paraformaldehyde for 6hr, 100% methanol for 4hr, 70% ethanol for 6hr). Time course of PCNA staining pattern after hepatectomy in the specimens fixed with 100% methanol or 70% ethanol coincided closely with that of bromodeoxyuridine (BrdU) staining pattern, which is known to be standard marker of cell proliferation. Similar result was obtained in fixation with 10% buffered formalin (10% BF) or 1% paraformaldehyde (1% PFA) when only granular staining pattern of PCNA was evaluated. These findings suggest that granular immunostaining of PCNA in tissue specimens fixed with 100% methanol, 70% ethanol, 10% BF or 1% PFA is useful for evaluating the extent of cell proliferation. PMID- 8691643 TI - [Colorimetric broth microdilution for antifungal susceptibility testing]. AB - A colorimetric broth microdilution modification of the National Committee for Clinical Laboratory Standards (NCCLS) for antifungal susceptibility testing was developed and evaluated. The test method modification includes; air-dried microdilution trays, in which serial two-fold dilutions of three antifungal agents, amphotericin B (AMPH), flucytosine (5-FC) and fluconazole (FCZ) were first prepared and evaporated, then reconstituted by adding 100 microliters of yeast inocula, and an oxidation-reduction color indicator (sodium resazurin, Sigma) added to RPMI 1640 medium buffered to pH7.0 with 0.165M morpholinepropanesulfonic acid. The trays were incubated in air at 35 degrees C and were inspected after 24 and 48hr of incubation. The MICs were defined as the lowest concentration of the respective agents; no color change (blue) for AMPH, and slight color change (blue to purple) for 5-FC and FCZ. The MICs of AMPH, 5-FC and FCZ were determined for four reference strains and 100 clinical isolates, in comparison with the NCCLS macrodilution method. The four reference strains were tested seven times each by macrodilution method (MACRO) and 14 times each against all three antifungal agents by microdilution method (MICRO). Overall, 100% of MICs determined by MACRO, 96% of those determined at 24hr incubation by MICRO, and 93% of those determined at 48hr incubation by MICRO fell within the 3-log2 dilutions, although 20 to 33% were out of the acceptable MIC ranges of the NCCLS M27-P proposal. Excellent reproducibility in determining growth endpoint by color change was also demonstrated, giving 99 to 100% agreements in duplicated dilutions. When the MICs determined for 100 clinical isolates against three antifungal agents were compared, those determined at 24hr incubation by MICRO gave 61.7% of agreement within the 3-log2 dilutions of the NCCLS MACRO, and those determined at 48hr incubation by MICRO were 86.2%. The MICRO read at 24hr trended to the lower MICs, except for 5-FC. While the MICs of MICRO read at 48hr were mostly comparable (78 to 97% agreement) to those of MACRO, especially against 5 FC (97%) and AMPH (85%), but the discrepant MICs of Candida tropicalis against FCZ were noted. With these results, it can be concluded that the resazurin colorimetric broth microdilution method is easy to perform and highly precise, and may provide MICs comparable to those determined by the reference NCCLS macrodilution method. PMID- 8691644 TI - [A predictive and prognostic study on two cases of transient hyperphosphatasemia of infancy]. AB - We presented two cases with transient hyperphosphatasemia (TH) of infancy, whose serum alkaline phosphatase (EC 3.1.3.1, ALP) activity showed markedly increased and the atypical isoenzyme fractions were seen by electrophoresis. These isoenzymes migrated into normal bone ALP region (alpha 2-beta globulin fraction) and fast liver ALP region (fast alpha 2 globulin fraction). From various investigation such as, heat stability, inhibition test by amino acid, neuraminidase treatment and Triton X-100 treatment, former fraction seemed to derive from bone ALP and later fraction from liver ALP. From our study, increment of the activity of alpha 2-beta gl fraction was in advance one month before maximum ALP activity stage, and fast alpha 2 gl fraction followed increasing 3 weeks after that. On the other hand, decreasing of fast alpha 2 gl fraction showed a shorter delay than alpha 2-beta gl fraction. These results suggest that a differential exchange of sugar chain or an impaired clearance of the enzyme from circulation was possibly occurred. It seemed to be important to increase a study of such a predictive and prognostic change of ALP activity and isoenzyme fraction in TH cases. PMID- 8691645 TI - [Case of adult T-cell leukemia without antibodies for HTLV-I but with for pX gene region]. AB - A 76-year-old woman had lymphocytosis with lymphocytes having convoluted or lobulated nuclei. These abnormal lymphocytes (leukemic cells) were positive for CD4, and some expressed IL-2R (CD25) and CD3 molecules, respectively. These morphologic and phenotypic features were compatible with adult T-cell leukemia, but serum antibodies to human T-cell lymphotropic virus type I (HTLV-I) were not detected by the particle aggregation method and an enzyme-linked immunosorbent assay. The polymerase chain reaction showed that the LTR, gag, pol, and env regions of HTLV-I proviral DNA had not been incorporated into the leukemic cells. Only the pX region was detected in these leukemic cells. PMID- 8691646 TI - [Markedly elevated serum fructosamine in a non-diabetic patient with IgA-kappa type multiple myeloma]. AB - We reported a non-diabetic patient with IgA-kappa multiple myeloma whose serum fructosamine value was markedly elevated. The M-protein from this patient was shown to be conjugated to serum albumin confirmed by immunoelectrophoresis and immunofixation. The fructosamine activity was shown in the high molecular weight fraction by S-300 superfine gel chromatography. Although serum fructosamine values of other three non-diabetic patients with IgA type multiple myeloma were elevated, patients with IgG type multiple myeloma and primary macroglobulinemia had low or normal serum fructosamine values. These findings suggested that glycation of monoclonal IgA of multiple myeloma was much more increased than that of other types of immunoglobulins and monoclonal IgA in this patient was conjugated to serum albumin resulting in the elevated serum fructosamine. PMID- 8691647 TI - [Usefulness of PCR-SSCP using non-RI coloration method as a routine genetic analysis]. AB - The polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis is considered as one of useful routine genetic analyses. However, that PCR-SSCP has been analyzed using radioisotope (RI) such as [32P] labeled compounds. So that, it was difficult to use this method routinely at clinical laboratories. In this paper, we compared with an RI mediated and a non-RI coloration mediated PCR-SSCP analysis regarding to those of sensitivity, time and money cost, respectively. The coloration method had enough sensitivity to detect one of cholesteryl ester transfer protein gene mutations. The time and money cost of non-RI coloration mediated method were more advantageous than the RI mediated one. Therefore, it is shown that the non-RI coloration mediated PCR-SSCP analysis is very useful for the routine genetic analysis at clinical laboratories. PMID- 8691648 TI - Measurement of ABH blood group substances in human saliva by immunoassay using artificial antigens as standard substances. AB - Introducing artificial antigens (trisaccharide-albumin complexes for A, B and H activities) as reference substances for immunoassay, blood group substances, A, B, and H in human saliva were measured. A good correlation between hemagglutination inhibition titers and concentrations of A, B, and H in saliva was demonstrated. Since the anti-H 1E3 used showed the specificity for both H type 1 and H type 2 chains and anti-H 224 for H type 2 chain, we measured H type (1 and 2) and H type 2 separately, and found 10- to 20-fold higher concentration of H type (1 and 2) compared with that of H type 2 in human saliva. The H type 2 was not found in all the saliva samples from nonsecretors irrespective of ABO subtypes. The results suggest that about 90% of A and B blood group substances in human saliva is also type 1 chain. PMID- 8691649 TI - Application of the Triage panel for drugs of abuse to forensic blood samples. AB - A simple and rapid screening procedure with Triage has been developed to detect 7 classes of drugs of abuse, phencyclidine (PCP), benzodiazepines (BZO), cocaine metabolite (COC), amphetamines (AMP), cannabinoids (THC), opiates (OPI), and barbiturates (BAR), in hemolyzed blood. A clear supernatant was obtained by mixing the blood with sulfosalicylic acid. The supernatant was neutralized with ammonium acetate and then screened using Triage. The lower limits of detection of the Triage screening method for PCP, diazepam, benzolyecgonine, methamphetamine, morphine, 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH), phenobarbital, and secobarbital were 50 ng/mL, 900 ng/mL, 1,000 ng/mL, 600 ng/mL, 900 ng/mL, and 900 ng/mL, respectively. The sensitivity of Triage for THC-COOH in deproteinized blood samples was much lower than that in urine samples. No false positive reactions were observed for the 6 classes of the drugs of abuse with the exception of AMP when the blood was decomposed. Phenethylamine, a putrefactive amine, gave positive results for AMP at concentrations over 5,000 ng/mL. The method was applied to 9 hemolyzed blood samples and 3 turbid urine samples from 12 forensic autopsy cases suspected of drug misuse. Among these, 5 were positive for AMP, 1 for OPI, and 4 for BAR. The presence of methamphetamine is only one of the 5, codeine in 1, and phenobarbital in 4 was confirmed by gas chromatography. All 4 samples which were false positive for AMP contained phenethylamine at relatively high concentrations because of moderate to heavy putrefaction. This method, although disadvantageous to test for AMP and THC, is helpful for the forensic toxicologist because any kind of bloody fluid can be tested rapidly with Triage to detect toxic levels of PCP, BZO, COC, OPI, and BAR. PMID- 8691650 TI - Analysis and classification of nasopharyngeal electroencephalogram in "brain death" patients. AB - Nasopharyngeally-derived electroencephalogram (EEG) was recorded and digitized in 12 "brain death" subjects with flat-line scalp EEG and loss of auditory brain stem response. The nasopharyngeal EEGs of these cases were classified into three types: Type Ia with complete flat-line, Type Ib with almost but incomplete flat line EEG, and Type II with low-amplitude slow fluctuations. Digitization of the nasopharyngeal EEG showed that equivalent electric potentials in low frequency bands (delta and/or theta 1) remained within the values of healthy volunteers in Types Ib and II. These results suggested that the tissue in or around the brain stem still functioned in Type 1b and II "brain death" patients. The origin of nasopharyngeal EEG was also discussed in this paper. PMID- 8691651 TI - Morphological and morphometric investigation of cardiac lesions after chronic administration of methamphetamine in rats. AB - The effects of chronic administration of methamphetamine on myocardium were morphologically and morphometrically studied in experimental models. Methamphetamine (1 mg/kg/day) was subcutaneously injected to five-week-old male Wistar Kyoto rats (WKY) for 8 weeks. Age- and sex-matched WKY served as controls. In light microscopy, scattered cytomyolysis, vacuolization, contraction bands and disarray of myofibers were prominent in methamphetamine-treated group; the electron microscopy showed degenerated mitochondria with disrupted cristae, myofibrillar hypercontraction and dissolution. Morphometric analysis was carried out using electron photographs and an image analyzer. The sizes of mitochondria and the number of mitochondria per unit area (100 microns2) in methamphetamine treated group were significantly smaller than in the controls. No statistically significant difference was found regarding the percentage of myofibrillar area in cytoplasm between methamphetamine-treated and control groups. These findings show that chronic administration of methamphetamine can cause serious cardiac lesions and decrease in mitochondrial function. PMID- 8691652 TI - Brain death diagnosed by forensic analysis of drug distribution in human tissues II--Distribution of caffeine in brain dead patients. AB - Caffeine concentrations in human tissues of 6 brain death cases as well as 5 non brain death cases were examined in order to assess the possibility of diagnosing brain death based on an analysis of this compound. Concentrations of caffeine in human tissues were determined using gas chromatography/mass spectrometry. The tissue-to-blood concentration ratios were used to evaluate the distribution pattern in each case. In non-brain death cases, the ratios in all examined tissues were similar, and the values were close to 1 in all tissues except adipose, of which the value was near 0.3. In brain death cases, the ratios in all tissues except brain and adipose were similar to those in non-brain death cases. The ratios in the brain were higher than those of non-brain death cases, in 5 brain death cases, and lower in 1 brain death case to whom blood transfusion was done in a hospital. The ratios in the adipose were slightly higher in brain death cases than those in non-brain death cases. The discorded distribution of caffeine in brain death cases was presumably related to cessation of cerebral blood circulation at the time of brain death. Therefore, comparing caffeine concentrations in the brain with those in the other tissues can be useful for a forensic diagnosis of brain death. PMID- 8691653 TI - Two deficiency cases of disputed paternity: sibling or half-sibling? AB - We report briefly the results of DNA analysis in two cases of disputed paternity where the alleged father and the mother were dead and only the children were available. In one case, half-sibship was established by minisatellite typing with a multi-locus probe and microsatellite FGA typing. In the other case, Y27H39 typing revealed that the fathers of the two male children were different. DNA polymorphisms, especially at microsatellite loci, provide useful information to solve such paternity cases. PMID- 8691654 TI - Microsatellite typing in a paternity case against a deceased man whose two brothers were available for testing. AB - To resolve a deficiency case of disputed paternity, we examined the mother, child, and two sibs of the deceased alleged father. In all of the 11 conventional marker systems and three microsatellite systems (ACTBP2, FGA, and D11S488) applied, the child and the paternal sibs had alleles is common. We deduced first the possible ACTBP2 genotypes of the deceased parents of the two sibs from their test results. Next, from all the combinations of the deduced genotypes, we estimated the frequencies of the possible genotypes of the alleged father and, with Bayes' theorem, calculated the probabilities of the alleged father having the genotypes compatible with paternity. Using these probabilities, we worked out the probability of the child's genotype resulting from the mating of the mother with the alleged father. Meanwhile, we calculated the probability of the child's genotype being expected of the mating of the mother with an unrelated random man. Finally, applying Bayes' theorem again, we obtained a probability of paternity of 0.992 for the ACTBP2 locus alone. Inclusion of the FGA locus in the probability calculations brought the overall probability of paternity to 0.998. The present study demonstrates that testing for hypervariable microsatellite loci greatly facilitates the solution of a deficiency case that would be difficult or time consuming to solve by conventional marker typing. PMID- 8691655 TI - Death caused by undiagnosed acute pancreatitis. AB - A fatal case of acute pancreatitis is reported. On account of difficulty in eating caused by persistent dysphagia and heartburn, the clinical condition of a 39-year-old man who had been a heavy drinker deteriorated rapidly. He was taken to a hospital in an ambulance in an unconscious state. Based on the endoscopic examination and blood chemistry data, the diagnosis of hemorrhagic esophagitis and hepatic failure was made. Treatment including fluid infusion was unsuccessful and he died on the second hospital day. Based on a strong suspicion that the pathologic change in the esophagus may have been chemical esophagitis caused by corrosives of some type, the police ordered an administrative autopsy. The postmortem examination revealed marked necrosis in the pancreas and in the abdominal fatty tissue including the omentum and the mesentery. The necrotic areas in the pancreas were accompanied by only a slight degree of hemorrhage. The cause of death was diagnosed as acute pancreatitis. The pathologic change in the esophagus was identified as Candida esophagitis. Alcohol abuse and malnutrition caused by esophagitis were both considered to be factors which lead to the acute fatal pancreatitis. PMID- 8691656 TI - An autopsy case of abandoned infant body with severe destruction. AB - One case of infanticide and abandonment by the natural mother is presented. The body was extensively damaged, evidently by a fox. Fortunately, since the body showed less advanced putrefaction due to cold weather, it was possible to narrow down the cause of death and to detect the drug which had been forced down the victim's throat before the crime. However, our estimates of age and postmortem interval were erroneous. We comment as to why we were misled. Pathological problems associated with "aspiration of vomitus" are also discussed. PMID- 8691657 TI - [Epidemiologic survey of pleural plaques among inhabitants of Matsubase exposed to asbestos]. AB - A high prevalence of pleural plaques (41.5%, 148/357) was found during a mass screening for lung cancer in Matsubase town in 1988. The inhabitants of this town were carefully studied each year from 1988 to 1993. The vast majority (81.2%) of inhabitants over the age of 20 years underwent chest roentgenography at least once during this period. Pleural plaques were detected by CT in 938 subjects, which is 17.3% of those studied and 4.1% of the total population. A total of 89 had an occupational history of asbestos exposure, 64 (71.9%) of whom had pleural plaques. However, these subjects with occupational exposure accounted for only 6.8% of the 938 subjects, and therefore most of the pleural plaques seemed to have been caused by general environmental exposure. The incidence of plaques was greater in older subjects: among those in the seventh decade of life it was more than eight times higher than among those in the fourth decade of life. Anthophyllite was detected in the main asbestos mill. The concentrations of asbestos fibers in the air and water near the old asbestos mills and factories were not high. The death rates and the adjusted mortality rates due to lung cancer in Matsubase were lower than in surrounding towns and lower than in Kumamoto prefecture as a whole. These results indicate that there is now no environmental contamination by asbestos fibers in Matsubase town. No cases of malignant mesothelioma have been confirmed in this town during the past 17 years. PMID- 8691658 TI - [Death due to pulmonary tuberculosis--a comparison between 1984-88 and 1989-93]. AB - Pulmonary tuberculosis (TB) remains the single leading cause of death from any single infectious agent in the world. We reviewed the case records and chest radiographs of patients with pulmonary tuberculosis who died between 1984 and 1993. Of 2333 patients discharged from National Nishi-Niigata Hospital, 86 (3.7%) died during that period. Comparison between the data for 1984-88 and for 1989-93 showed an increase in the number of elderly patients, TB-related deaths, and complication of TB by malignancy. Thirty-nine of the 86 patients died within 2 months of admission: a spread of TB over a wide region and low performance scores were noted in these patients. Multiple-drug-resistant Mycobacterium tuberculosis was often the cause of death. These results encourage us to pursue early detection in elderly people, to improve management during initial treatment such as with steroids, and to develop new and more effective drugs to treat TB. PMID- 8691659 TI - [Effects of pulmonary rehabilitation in patients with chronic respiratory failure]. AB - To evaluate the effects of pulmonary rehabilitation in patients with chronic respiratory failure, 43 patients with stable chronic respiratory failure were enrolled in a pulmonary rehabilitation program. The program included education, instruction in diaphragmatic breathing, respiratory muscle training, and exercise training (walking and riding a stationary bicycle). Patients were divided into 2 groups by the lowest SpO2 during a 12-minute-walk test done before rehabilitation: lowest SpO2 < 90% (Group A, 32 patients) and lowest SpO2 > or = 90% (Group B, 11 patients). In group A, SpO2 during exercise training was maintained over 90% by O2 inhalation, by load reduction, or by maintaining a slower walking speed. During 2 months of rehabilitation, the distance walked in 12 minutes and the maximum distance walked with an SpO2 > or = 90% significantly increased in both groups, but PaO2, VC, and FEV1 increased only in group A. In group A, the patients with chronic obstructive pulmonary disease had significant increases in PaO2, VC, and FEV1, but those with old tuberculosis sequelae had significant increases in PaO2 only. Pulmonary rehabilitation in patients with chronic respiratory failure may not only increase exercise tolerance but may also improve arterial oxygenation and pulmonary function. PMID- 8691660 TI - [Levels of alpha-elastin and of desmosine as indexes of elastase-induced lung injury in rats]. AB - Two markers of elastin degradation, alpha-elastin and desmosine levels, were measured in sera from rats after single tracheal instillations of porcine pancreatic elastase (PPE). Biochemical and pathophysiological changes in the lung were also studied. Male Wistar rats were divided into three groups. The control group received one intratracheal dose of saline (0.3 ml). The PPE 60 group received one intratracheal dose of 60 U of PPE. The PPE 120 group received one intratracheal dose of 120 of PPE. Blood samples were collected 0, 1, 3, 5, 7, 14, 28, and 56 days after the intervention, and levels of alpha-elastin and desmosine were measured by enzyme-linked immunosorbent assay. At the end of the study (day 56), lung volumes and static pressure-volume curves were measured by body pletysmography. Then the rats were killed and the mean linear intercept was measured as defined by Thurlbeck. The serum alpha-elastin level in the PPE 120 group on day 7 was significantly higher (p < 0.05) than those in other groups. Desmosine values on day 1 in the PPE 60 group and on days 1 and 7 in the PPE 120 group were significantly higher (p < 0.05) than those in the control group. Functional and morphometric analyses revealed that the PPE 120 group had more emphysematous changes than the control group (p < 0.01) and more than the PPE 60 group (p < 0.05). These results suggest that levels of alpha-elastin and of desmosine reflect changes that occur in the early stages of lung injury, and that these changes are related to abnormalities found in rat lungs on day 56. PMID- 8691661 TI - [Abnormalities in pulmonary perfusion scans after transcatheter arterial embolization of the liver]. AB - Thirteen patients with hepatocellular carcinoma who underwent transcatheter arterial embolization (TAE) were studied to evaluate the incidence of pulmonary embolism and methods for diagnosing this complication. Pulmonary perfusion scans and changes in indexes of coagulation and of fibrinolysis, and in the partial pressure of oxygen in arterial blood were evaluated as possible signs of pulmonary embolism complicating TAE. In 3 out of 13 patients (23%), perfusion lung scans showed perfusion defects. These 3 patients were asymptomatic and their perfusion defects had disappeared by 4 weeks later. TAE was followed by significant decreases in platelet counts (p < 0.01) and in serotonin levels (p < 0.05); and by increases in A-aDO2 (p < 0.01), in levels of fibrinogen in plasma (p < 0.01), and in levels of thrombin-antithrombin III complex (TAT) (p < 0.05), with no significant increase in levels of D-dimer in plasma. Similar hematologic changes were observed in patients without perfusion defects after TAE. In 3 patients with perfusion defects, plasma levels of TAT before TAE were significantly higher than the levels in patients without perfusion defects (p < 0.01). Perfusion defects that occur after TAE may be caused by pulmonary thromboemboli, by pulmonary fat emboli, and by microatelectasis or discoid atelectasis, and the most common cause is probably pulmonary thromboemboli. We conclude that the risk of pulmonary embolism complicating TAE is higher in patients with hepatocellular carcinoma who have high levels of TAT in plasma. PMID- 8691662 TI - [Lymphocyte subsets in bronchoalveolar lavage fluid from patients with idiopathic interstitial pneumonia]. AB - Lymphocyte activation may be involved in interstitial inflammatory processes in the lungs. We analyzed lymphocytes in bronchoalveolar lavage fluid obtained from 15 patients with idiopathic interstitial pneumonia (IIP) and from 7 controls. Clinical criterial were used to divide the patients with IIP into two groups: acute (n = 5) and chronic (n = 10). Lymphocytes in the bronchoalveolar lavage fluid were analyzed with a flow-cytometric two-color system. Differential cell counts showed that percentages and numbers of lymphocytes were significantly higher in patients with acute IIP (44.2 +/- 25.2%, 12.3 +/- 8.18 x 10(4)/ml) than in controls (8.31 +/- 3.66%, 0.69 +/- 0.39 x 10(4)/ml, p < 0.05) and in patients with chronic IIP (8.44 +/- 6.11%, 1.58 +/- 1.08 x 10(4)/ml, p < 0.05). In particular, percentages and numbers of CD8+ S6F1+ lymphocytes, which are regarded as activated cytotoxic T lymphocytes were markedly higher in patients with acute IIP (32.3 +/- 16.0%, 39.6 +/- 37.1 x 10(3)/ml), than in controls (6.31 +/- 1.69%, 0.42 +/- 0.25 x 10(3)/ml, p < 0.05) and in patients with chronic IIP (10.6 +/- 6.16%, 1.88 +/- 1.42 x 10(3)/ml, p < 0.05). These data suggest that patients with acute IIP differ from those with chronic IIP in the percentage and the number of lymphocytes in bronchoalveolar lavage fluid, and that activated cytotoxic T lymphocytes may play an important role in the pathogenesis of acute IIP. PMID- 8691663 TI - [Polyangiitis overlap syndrome with multiple pulmonary aneurysms and renal vascular hypertension]. AB - A 37-year-old man with multiple nodules on a chest X-ray film, hypertension, and proteinuria was admitted to our hospital in September, 1993. Thirteen years earlier, he had been admitted to another hospital because of bloody sputum, fever, and dyspnea. He also had slight oral aphthae and slight iridocyclitis. A chest X-ray film at that time showed bilateral diffuse reticular shadows, and his illness was diagnosed as acute interstitial pneumonitis. Since that time, he had been continuously receiving tapering doses of prednisolone. His chest symptoms were relieved, and the findings on the chest X-ray film resolved with that treatment. In 1993, he also had positive tests for HBs antigen and for HLA-B51, and he was found to have renal vascular hypertension. Chest CT films and a pulmonary angiogram showed multiple aneurysms and occlusions of pulmonary arteries. A renal angiogram showed multiple intraparenchymal aneurysms of renal arteries. A specimen taken by open-lung biopsy showed healed endoarteritis obliterans of muscular arteries and no alveolitis. His illness was diagnosed as polyangiitis overlap syndrome, because of the unclassified systemic necrotizing vasculitis. PMID- 8691665 TI - [Exacerbation of idiopathic interstitial pneumonia after lobectomy for lung cancer]. AB - A 51-year-old man was found to have cancer in the left lung during treatment for idiopathic interstitial pneumonia. He underwent a left upper lobectomy because pulmonary function was judged to be adequate and because the interstitial pneumonia was not severe. After the operation, acute exacerbation of interstitial pneumonia occurred, and respiratory failure developed. Immediate steroid therapy alleviated his condition. Acute exacerbations of idiopathic interstitial pneumonia after pulmonary resection are usually fatal, and cases such as this are very rare. PMID- 8691664 TI - [Diffuse panbronchiolitis with P-ANCA-positive arteritis and necrotizing glomerulitis]. AB - A 53-year-old man was admitted to our hospital with a skin eruption, a high fever, and diplopia in April of 1992. He had been given a diagnosis of diffuse panbronchiolitis in 1981. After administration of erythromycin began in 1987, symptoms and chest roentgenographic findings gradually improved. Arteritis of peribronchial muscular arteries with medial destruction was seen in lung biopsy specimens, and periglomerular granulomatous inflammation and necrotizing glomerulitis were seen in renal biopsy specimens. P-ANCA was found, but a test for cytoplasmic ANCA (which is the most specific antigen of Wegener's granulomatosis) was negative. Chronic pulmonary infection due to diffuse panbronchiolitis might have formed ANCA, which may have caused the vasculitis in this patient. PMID- 8691666 TI - [Intralobar pulmonary sequestration with an aberrant artery originating from the celiac artery and communicating with the pulmonary artery]. AB - A 13-year-old boy underwent a right lower lobectomy for removal of an intralobar pulmonary sequestrum with a very rare type of aberrant artery. The aberrant artery originated from the celiac artery and communicated with the pulmonary artery. Angiographic and histologic findings led us to the following hypothesis regarding the origin of the sequestrum in this patient: There was a hypoplastic bronchus and an aberrant artery that originated from the celiac artery. Infection caused obstruction of the hypoplastic bronchus, which resulted in formation of the sequestrum. Another possibility is that high systemic pressure in the aberrant artery caused destruction of alveoli and led to the formation of cysts in the lung and to sequestration. Finally, the aberrant artery and the pulmonary artery communicated due to chronic inflammation in the sequestrum. PMID- 8691667 TI - [Bronchial asthma complicated by myasthenia gravis]. AB - A 52-year-old woman had a 14-year history of stridor attacks. Pulmonary function tests revealed reversible airway obstruction, and bronchial asthma was diagnosed. She also has bilateral ptosis, diplopia, and moderate weakness of all four limbs; a positive edrophonium test confirmed the diagnosis of myasthenia gravis. Although the parasympathetic system plays an important role in the regulation of bronchial tone, in this patient the edrophonium test did not provoke an asthmatic attack or exacerbate pulmonary function, except for increases in sputum production and in frequency of cough. The general weakness was usually worse in the afternoon. The decrease in grip strength and the shortening of arm elevation time also occurred after asthma attacks, which means that general muscle fatigue was caused by the work of breathing. Furthermore, dyspnea increased and pulmonary function worsened when an anti-cholinesterase inhibitor was discontinued, probably because of respiratory muscle weakness. Accordingly, the clinical status of bronchial asthma seemed to change in parallel with that of the myasthenia gravis. PMID- 8691668 TI - [Tuberculous aneurysm of the descending aorta--successful surgical treatment]. AB - A 62-year-old woman visited her primary physician because of high fever and vomiting. From a chest roentgenogram miliary tuberculosis was diagnosed. Anti tuberculosis drugs were prescribed. Mycobacterium tuberculosis was cultured from samples of sputum. Although she took drugs for 3 months, her symptoms did not resolve and back pain developed. A chest roentgenogram showed an egg-sized mass in the posterior part of the mediastinum. Examination of a chest CT scan showed that the mass was an aortic aneurysm. A graft replacement was done, and histologic examination of the resected specimen showed that it was a tuberculous aneurysm of the descending aorta. Her symptoms disappeared, and she recovered fully. Tuberculous aneurysms are rare: they account for only 0.3% of all aneurysms. This is only the 9th reported case of tuberculous aneurysm successfully treated with surgery in Japan. We must realize that aneurysms are life-threatening complication of miliary tuberculosis. PMID- 8691669 TI - [Invasive pulmonary aspergillosis in a patient with acute leukemia--the role of neutrophil elastase in in cavity formation]. AB - A 47-year-old man complaining of common cold-like symptoms was admitted to our hospital. Acute myelogenous leukemia was diagnosed and the patient was treated with induction chemotherapy. During granulocytopenia caused by induction chemotherapy, a nodular lesion appeared in the right upper lobe. The nodular lesion changed to a cavitary lesion after the recovery of peripheral white blood cell counts. A transbronchial biopsy specimen obtained from the right B3b showed Aspergillus. Oral itraconozole, flucytosine, and intravenous amphotericin B were given. The cavitary lesion in the right upper lobe regressed after anti-fungal therapy was started. During granulocytopenia caused by consolidation chemotherapy, the nodular lesion enlarged again. Thereafter, as bone marrow recovered, it changed to a cavitary lesion with a lung ball inside. In both episodes, a nodular lesion appeared during granulocytopenia, and changed to a cavitary lesion after bone marrow recovery. In addition, the level of neutrophil elastase reached its maximum at the time of the bone marrow recovery. These findings suggest that white blood cells of the host as well as neutrophil elastase play an important role in cavitation in pulmonary aspergillosis. PMID- 8691670 TI - [Hard metal lung with diffuse small nodular shadows]. AB - A 32-year-old woman was admitted to Niigata University Hospital with dyspnea and a non-productive cough. She had been exposed to hard metal dust for 4 years in a metal-polishing factory. Chest X-ray and CT films showed diffuse small nodular shadows in both lung fields and pulmonary-function tests revealed severe restrictive impairment. Specimens obtained by thoracoscopic lung biopsy showed fibrosis in the centers of lobules and in peribronchiolar regions. Giant-cell interstitial pneumonia-like findings were also noted. Tungsten carbide and cobalt were detected in these specimens, with an X-ray microanalyzer. Hard metal lung was diagnosed. By 1 year after she changed her place of work and began corticosteroid treatment her symptoms and pulmonary function had improved remarkably, although shadows on chest X-ray films remained to some extent. PMID- 8691671 TI - [Thymic carcinoid associated with ectopic ACTH syndrome]. AB - A 63-year-old man was admitted to Sendai Red Cross Hospital complaining of chest and back pain associated with Cushing's syndrome. Based on the abnormally high levels of ACTH, cortisol, and CRH in plasma the patient was suspected of having ectopic ACTH syndrome. Histological examination of an extirpated rib and pleural tumor led to the diagnosis of atypical carcinoid tumor, with ribbon and festoon formation, immunoreactivity to ACTH, NSE, Chg-A, and argyrophilia in the tumor cells. Anti-cancer chemotherapy was not effective, and the patient died within a year after the onset of Cushing's syndrome. An autopsy revealed that the patient had an ACTH- and CRH-producing thymic carcinoid with metastases to many organs. The pituitary was atrophic with Crooke's hyaline change. There were many CRH positive cells in the paraventricular nuclei of the hypothalamus, where no remarkable pathologic changes were seen. PMID- 8691672 TI - [Increased CA19-9 level in serum and bronchoalveolar lavage fluid from a patient with pulmonary tuberculosis]. AB - A 66-year-old woman was admitted to the hospital because of general malaise and loss of appetite. Laboratory examination revealed an abnormally high level of CA19-9 in serum and a chest roentgenogram revealed soft reticular shadows in the right mid-lung field. An extensive examination revealed no malignant disease. Bronchoalveolar lavage fluid obtained from the right B5 contained an abnormally high level of CA19-9. Immunochemical staining for CA19-9 was positive in the epithelial cells of respiratory bronchioles. The level of CA19-9 decreased during anti-tuberculosis therapy. This case suggests that the CA19-9 level can reflect the activity of pulmonary tuberculosis. PMID- 8691673 TI - [Bronchial cyst in a patient with a high serum CA19-9 concentration that fluctuated with the cyst fluid volume]. AB - A 44-year-old woman was found to have an abnormally high concentration of CA19-9 in serum. Five years later, she underwent a right upper lobectomy for an abnormal shadow on a chest roentgenogram, because it was thought to indicate a malignant tumor. A chest CT scan revealed a cyst with fluid in the right upper lobe. During the 5 years before the lobectomy, the serum CA19-9 concentration rose when the cyst fluid volume increased, and fell when the cyst fluid volume decreased. Before the operation, the serum CA19-9 concentration was very high and the cyst was swollen. The cyst wall was found to be lined with ciliated columnar epithelial cells and to contain hyaline cartilage and smooth muscle, which led to the diagnosis of bronchial cyst. The surface epithelium and cyst fluid were positively stained by a monoclonal antibody against CA19-9. The serum CA19-9 concentration decreased and was within the normal range 3 months after the operation. PMID- 8691674 TI - [Pulmonary tuberculosis manifesting predominantly as ileus secondary to peritoneal tuberculosis in a young man]. AB - A 27-year-old man was admitted to our hospital because of abdominal pain and vomiting. A radiograph of the chest revealed widening of the right superior part of the mediastinum, and an abdominal radiograph showed many air-fluid levels. A computed tomographic scan of the chest revealed a solitary nodule in the right anterior lobe of the lung, and right paratracheal lymphadenopathy. Ileus was diagnosed and a nasogastric tube was inserted. The patient's condition gradually worsened, and on hospital day 17 a laparotomy was performed. Operative findings were significant for numerous, white nodules all over the peritoneum, omentum, and mesentery, which ranged from miliary to rice grain-sized. Examination of an omental specimen revealed noncaseating granulomas with Lang hans' giant cells. The polymerase chain reaction was used to examine fluid from the nasogastric tube used before surgery, and on hospital day 40 that fluid was found to be positive for Mycobacterium tuberculosis. M. tuberculosis was also cultured from the fluid. From these findings, we concluded that this was a case of pulmonary tuberculosis manifesting predominantly as ileus secondary to tuberculous peritonitis. Anti tuberculosis therapy consisting of isoniazid, rifampin, and ethambutol was started postoperatively. On repeat laparoscopy 224 days later, no white nodules were seen. A computed tomographic scan of the chest revealed that the right paratracheal lymphadenopathy was markedly reduced, and the solitary nodule in the right anterior lobe of the lung was almost gone. Few cases of young people with pulmonary tuberculosis manifesting primarily as ileus have been reported. Tuberculosis should be included in the differential diagnosis in patients presenting with ileus. PMID- 8691675 TI - [Pulmonary typical carcinoid with metastases to pulmonary hilar, and mediastinal lymph nodes]. AB - A 50-year-old woman was admitted to our hospital complaining of recurrent bloody sputum and hemoptysis. Chest X-ray films showed an infiltrative shadow in the left lower lung field. Chest computed tomograms showed a nodular tumor shadow near the left B8 and this tumor shadow was found between A8 and A9 by pulmonary arteriography. Bronchoscopic examination revealed a red coagulum in the left B8 and cytologic examination of broncho alveolar lavage fluid revealed atypical squamous cells. With a clinical diagnosis of squamous cell carcinoma of the lung, a left lower lobectomy with hilar and mediastinal lymph node dissection was done. A milk-white tumor was found in the lower lobe of the resected lung. The pathological diagnosis of the resected tissue specimen was carcinoid, accompanied by pulmonary, hilar, and mediastinal lymph node metastases. Reduced immunofluorescence by Chromogranin A and serotonin staining were further evidence that the tumor was atypical. This case is very interesting in that the tumor metastasized to the lung and lymph nodes, even-though it was pathologically typical. PMID- 8691676 TI - [Late pericardial effusion after open-heart surgery: usefulness of pericardiocentesis under echocardiographic guidance]. AB - Late pericardial effusion (PE) after open heart surgery has a potential for serious complications, including tamponade necessitating urgent drainage. From October 1990 to March 1995 moderate to massive PE developed following 9 of 359 (2.5%) cardiac procedures between 11 and 55 days postoperatively (mean, 18.6 days). Only one of these nine patients had evidence of cardiac tamponade; the other 8 patients had moderate symptoms including malaise, weight gain, and dyspnea on exertion. All patients except one were being treated with warfarin and anti-platelet agents. Echocardiography detected posterior PE of variable magnitude in all 9 patients; anterior PE was present in only one of these patients. Pericardiocentesis under echocardiographic guidance using an echo transducer with a built in puncture needle was performed in all patients. A flexible catheter was left in place for 24 to 72 hours for suction. In each case, 300 to 712 ml of old bloody fluid (mean, 475 ml) was evacuated, with relief of symptoms. Despite continuing anticoagulant therapy, there was no recurrence of pericardial effusion. The technique we have described simplifies pericardiocentesis and helps to avoid complications in this procedure. PMID- 8691677 TI - [Two operated cases of synchronous double cancer of the lung and digestive tract in patients over 80 years old and genetical diagnosis]. AB - Synchronous double cancer of the lung and gastrointestinal organ was successfully resected by an one-step approach in two aged patients over 80 years. An 81-year old man was clinically diagnosed as having a right lung cancer (S3) along with a sigmoid colon cancer. The pathological cell types of these cancers were squamous cell carcinoma and adenocarcinoma respectively. Right upper lobectomy and sigmoidectomy were performed at the same time because he had no risks for the operation. An-80-year-old woman was diagnosed as having a left lung cancer (S8-9) along with a stomach cancer. The cell types of these cancers were both highly differentiated adenocarcinoma. Left lower lobectomy and subtotal gastrectomy were performed at the same time, too. We limited lymph nodes dissection to shorten the operation time and no postoperative complications occurred in both patients. It is suggested that simultaneous operation for double cancer in aged patients can be safely performed in selected cases. In the latter patient, pathological cell type of the lung cancer was similar to that of stomach cancer. So we applied polymerase chain reaction (PCR) for making a diagnosis of double cancer postoperatively, and it was proved that the lung and gastric cancers were different from each other in genetical natures. Application of the genetical technique to clinical field which greatly contribute to making a diagnosis of double cancer is expected. PMID- 8691678 TI - [Surgical experiences of fenestrated total cavopulmonary connection in patients under four year of age]. AB - The fenestrated Fontan operation is an interim steps for patients who considered to be at high risk for one step Fontan procedure. We performed total cavopulmonary connection with baffle fenestration in five patients under four year of age (33 month of mean age at operation). All patients previously underwent palliative surgery (Blalock shunt in 3, PA banding in 2). Three patients weighed less than 10 kg. Pulmonary vascular resistance index (PARI) were 2.03 +/- 0.18 U/BSA and exceeded 2 U/SQm in 3 patients. Nakata's indice were ranged from 282 to 644 (mean 394) mm2/BSA. Bidirectional cavopulmonary shunt was considered to be alternative pathway for three patients in staged Fontan strategy. Postoperative hemodynamics were relatively stable in all patients and weaned from mechanical ventilation within 5 days with various arterial oxygen saturation. There was no pleural effusion lasting longer than 1 week. One patient died of ileus caused from congenital malrotation. Follow up catheter examination at 1 year showed 83 to 96% of SaO2 and survived patients were doing well. Fenestrated TCPC can be applied safely in younger patients who are considered to need surgical treatments in staged Fontan strategy. Whether fenestration should be closed has to be wait further studies. PMID- 8691679 TI - [Sleeve pulmonary arterial resection for bronchogenic carcinoma]. AB - Two cases of bronchogenic carcinoma undergone left upper lobectomy (R 3) with bronchoplasty and sleeve pulmonary arterial resection via mid-sternotomy were reported. Both cases were squamous cell carcinoma originated in the orifice of the left upper lobe. Case 1 was stage IIIB (T2N3M0) bronchogenic carcinoma, its postoperative course was uneventful and died of distant lymphatic metastasis thirty-three months after operation. Case 2 was stage II (T2N1M0) bronchogenic carcinoma and its postoperative management was laborious because of hard expectoration of the sputum but is doing well fifteen months after operation. In order to preserve adequate pulmonary function and to maintain reasonable quality of life (QOL) for the patients with impaired pulmonary function, this angioplastic procedure seems to be acceptable. It is still under discussion to perform this procedure for the patients who would be able to withstand undergoing pneumonectomy, therefore we adopt this method only for every patient for whom it is difficult to maintain desirable QOL after pneumonectomy. Namely, for the patient whose predicted one second forced expiratory volume (FEV1.0) after pneumonectomy is less than 900 ml/m2, we'll be likely to try this angioplastic procedure at first. PMID- 8691680 TI - [Evaluation of blood absorption, hemostatic ability and purity of a polyepoxy compound cross-linked cotton type collagen hemostat]. AB - A polyepoxy compound cross-linked cotton type collagen hemostat (CCH) made of highly purified atelocollagen in a fine filament shape was developed. To evaluate blood absorption, hemostatic ability and purity of the CCH, Avitene and Oxycel were used for comparison. Blood absorption speed of the CCH was faster than Avitene and Oxycel. The handling characteristics of the CCH were much better than those of Avitene and Oxycel. Hemostatic ability was better in the CCH compared to Avitene in a canine study. The purity of the CCH was better than in Avitene which contained albumin and other proteins. Those results suggest that the developed hemostat with excellent blood absorption, handling characteristics, hemostatic ability and purity, could be useful in clinicals. PMID- 8691681 TI - [A successful repair of aortic regurgitation and right ventricular aneurysm long after correction of tetralogy of Fallot]. AB - Twenty-seven years after correction of tetralogy of Fallot, a 35-year-old man, suffered from dyspnea on effort and palpitations, underwent repair of aortic regurgitation and right ventricular aneurysm. Aortic regurgitation was due to a perforation at the base of the right coronary cusp, probably caused during the initial VSD patch closure, and it was repaired by suture. The right ventricular aneurysm was excised and the defect was closed directly. After operation, only slight aortic regurgitation was observed and premature ventricular contractions, presumably related to right ventricular aneurysm, were decreased markedly. His postoperative course has been uneventful and satisfactory for these 15 months. PMID- 8691682 TI - [Coronary artery bypass grafting surgery without cardiopulmonary bypass in a patient with calcified aorta]. AB - Coronary artery bypass surgery in a 67-year-old male with severe calcified ascending aorta was performed without cardiopulmonary bypass under beating heart, utilizing the left internal thoracic artery graft. No neurological complication was observed and postoperative angiogram showed good graft patency. We think coronary revascularization without cardiopulmonary bypass can be one of the safe and reliable methods to avoid complications associated with aortic cross clamping and aortic cannulation with severely calcified aorta. PMID- 8691683 TI - [Mobile right atrial thrombus: a case report of surgical removal]. AB - A 71-year-old man was admitted due to brain infarction. An abnormal floating mass was found in the right atrium by echocardiography. The mass was assumed to be a thrombus. The patient was failed to be in danger of pulmonary embolism, so it was decided to remove surgically. The thrombus was removed under cardiopulmonary bypass including the atrial wall where it was attached, because it was difficult to rule out the possibility of cardiac tumor macroscopically. The tumor showed pathological findings of thrombus. Postoperative course was uneventful. PMID- 8691684 TI - [A case of infective aortic valve endocarditis with splenic abscess]. AB - A 47-year-old woman was admitted to our hospital with high fever, exertional dyspnea and left flank pain. Echocardiography revealed vegetations attached to the aortic valve and moderate aortic regurgitation. Streptococcus anginosus was identified by blood culture examination. Abdominal CT scan showed a low density area in the spleen. The diagnosis of infective aortic valve endocarditis with splenic abscess was obtained. The splenectomy and the aortic valve replacement were performed simultaneously after the treatment with antibiotics. The postoperative clinical course was uneventful. In the case of infective endocarditis with splenic abscess, the splenectomy concomitant with valve surgery should be performed for removing all of the infected tissues. PMID- 8691685 TI - [Traumatic tricuspid regurgitation: a case report and a review of operated cases in Japan]. AB - A 48-year-old male was admitted with chief complaints of fatigue and palpitation. He had a past history of closed chest trauma without rib fracture due to an automobile accident 7 years ago. He had been complaining of a gradual increase of palpitation since 4 years after the accident. A two-dimensional and transesophageal Doppler echocardiography revealed severe tricuspid regurgitation due to ruptured chorda tendinea of the tricuspid anterior leaflet. Cardiac catheterization revealed an elevated right atrial v wave (16 mmHg). At open heart surgery, complete tear of a chorda tendinea of the anterior leaflet and elongation of chordae tendineae of the posterior leaflet were observed. The valve was replaced with a 31 mm Carpentier-Edwards bioprosthesis. His post operative course was uneventful. A brief review of the reported surgical cases of traumatic tricuspid regurgitation in Japan is also described in this paper. PMID- 8691686 TI - [Coronary artery bypass grafting in a patient with severe coronary disease due to Kawasaki disease: a case report]. AB - A 14-year-old girl with severe coronary artery disease due to mucocutaneous lymph node syndrome, "Kawasaki disease", admitted to our hospital. Though she had no angina on any effort in her daily life, coronary angiography (CAG) demonstrated 90% stenosis and a large aneurysm of left main trunk. Based on the CAG findings, we determined to do the coronary artery bypass grafting (CABG) to left anterior descending artery (LAD) and 1st diagonal branch (D1) to prevent the occurrance of fatal acute myocardial infarction. We attempted to use bilateral internal thoracic arteries (ITAs) at the beginning of this surgery. While LAD was grafted with left one, D1 was done with saphenous vein (SV) because of difficulty of harvesting right one. The weaning from cardiopulmonary bypass was easy and the postoperative course was of no event. A month later, CAG showed the good patency of both left ITA and SV graft. PMID- 8691687 TI - [Surgical correction of total anomalous pulmonary venous drainage: an adult case of successful repair]. AB - Total anomalous pulmonary venous drainage (TAPVD) is a rare congenital cardiac anomaly. It occurs in only 1.5% of children born with congenital heart defects. But, it is one of the most common lesions necessitating intracardiac operation in the neonatal period. We have experienced a 33-year-old man with supracardiac type TAPVD who was operated upon successfully. Cardiac catheterization showed 0.35 in Pp/Ps, 3.33 in Qp/Qs and 0.11 in Rp/Rs. The left to right shunt ratio was 77%, while the right to left shunt ratio was 23%. The operation was composed of anastomosis between the left atrium and the common pulmonary vein, patch closure of the atrial septal defect, ligation of the vertical vein and tricuspid annuloplasty. The posterior approach was adopted in anastomosis between the left atrium and the common pulmonary vein. The association of a normal pulmonary vascular resistance, a large interatrial communication and absence of a pulmonary venous obstruction was considered as factors of a favorable result. PMID- 8691688 TI - [So-called carcinosarcoma of the lung: A case report]. AB - A 50-year-old male was admitted to our hospital because of an abnormal shadow in chest X-ray films. The diagnosis of adenocarcinoma was obtained by transbronchial brushing cytology. Right lower lobectomy with hilar and mediastinal lymph node dissection was performed. Histological examinations of the resected specimen showed that the tumor was composed predominantly of spindle-shaped cells containing scattered islands of moderately differentiated adenocarcinoma. Immunohistochemically, the spindle cells were positively stained by vimentin, keratin and epithelial membrane antigen, suggesting sarcomatous transformation of adenocarcinoma cells. PMID- 8691689 TI - [A case of bronchogenic carcinoma associated with pulmonary infarction which showed a tumorous shadow]. AB - The patient was 69-year-old male with bronchogenic carcinoma associated with another abnormal shadow in the same left lower lobe. Its shadow was considered whether obstructive pneumonia or intrapulmonary metastasis before thoracotomy. Pathological examination revealed that this lesion was pulmonary infarction. It may be rare that bronchogenic carcinoma is associated with pulmonary infarction showing tumorous shadow. The staging and operative indication of lung cancer should be carefully determined which associate with abnormal shadow on the same lung field. PMID- 8691690 TI - [Recurrence of AL type primary localized pulmonary amyloidosis]. AB - A 52-year-old female, who was diagnosed primary pulmonary amyloidosis by left open lung biopsy 11 years ago, has been pointed out chest abnormal shadow in the opposite lung for 9 years. Two masses situated in the right S3a and S4 have been growing gradually with suspicion of malignancy. The right open lung biopsy revealed amyloidosis by frozen section and wedge resections were performed. Microscopic findings were compatible with AL type amyloid protein. We reported a rare case of recurrence of localized primary pulmonary amyloidosis. PMID- 8691691 TI - [Surgical treatment for ascending aortic aneurysm using a transthoracic left ventricular venting]. AB - Three patients with ascending aortic aneurysms underwent graft replacement using deep hypothermic circulatory arrest with continuous retrograde cerebral perfusion. In all three cases, preoperative radiographic examination revealed that the aneurysm was large, thin, and adherent to the back of the sternum. For this reason, left ventricular venting was performed through a left thoracotomy before median sternotomy, to decrease both the risk of rupture of the aneurysm and the difficulty of cannulation. This new method, called transthoracic left ventricular venting, was very useful for performing a median sternotomy under hypotensive and hypothermic conditions adequate to reduce the risk of rupture and to manage any rupture immediately through deep hypothermic circulatory arrest. PMID- 8691692 TI - [Thoracoscopic extended thymectomy in conjunction with a collar incision of the neck for cases of myasthenia gravis]. AB - Extended thymectomy in conjunction with a collar incision of the neck was performed thoracoscopically for a 64-year-old women with myasthenia gravis. Although this patient had Osserman type II B myasthenia gravis not associated with a thymoma, the clinical symptoms were alleviated after the surgery. Although this surgical procedure has the disadvantage such as of being time-consuming, it also has various advantages such as: 1) extended thymectomy can be performed without a midsternotomy, 2) the wound is small and not prominent, 3) surgical invasiveness is slight, and 4) postoperative pain is mild. This method was considered to be an extremely useful surgical method which should be used in future for cases of myastenia gravis not associated with a thymoma. PMID- 8691694 TI - [Basic study in the natural history of benign prostatic hyperplasia: biology of prostatic growth]. PMID- 8691693 TI - [A case of ACTH-producing thymic carcinoid tumor with Cushing syndrome]. AB - ACTH-producing thymic carcinoid tumor with Cushing syndrome in a 41-year-old male was reported. Plasma ACTH and cortisol was high, and chest X-ray film and CT scan revealed a tumor mass in the anterior mediastinum. Extended thymectomy with pretracheal lymph node dissection was performed. The microscopic findings revealed that the mass was carcinoid tumor with metastasis of anterior mediastinal lymph node. ACTH and cortisol were restored to normal range 1 week after operation. Unfortunately, he admitted seven months later because of high level of ACTH and right supraclavicular lymph nodes swelling. He underwent right neck dissection. Pathological examination proved metastatic carcinoid tumors in the dissected nodes. It is important to perform supraclavicular lymph node dissection together with extended thymectomy for thymic carcinoid tumor. PMID- 8691695 TI - [Efficacy of the chemosensitivity test using collagen gel matrix-supported culture system for urogenital tumors]. AB - BACKGROUND: We evaluated the usefulness of in vitro tumor culture system using a specialized collagen gel matrix (CGM assay) as a chemosensitivity test. PATIENTS AND METHODS: Chemosensitivity results of CGM assay were compared with other in vivo and in vitro assays on an implantable murine bladder tumor cell line (MBT 2). In addition we investigated the possibility of the clinical use of CGM assay using clinical specimens obtained from urogenital malignant tumor patients by comparing the result with that of the other chemosensitivity test, SDI testing using single cells (conventional SDI test). Methods of CGM assay were as follows. Tumor tissues on the collagen gel matrices were incubated under the existence of anticancer drugs following 4 days preculture. Drug sensitivities were evaluated by counting the number of viable cells adjusted to the tumor weight. RESULTS: Inhibition rates in MBT-2 were high in the order of mitomycin C, cisdiamminedichloroplatinum (II), (2"R)-4'-0-tetrahydropyranyl adriamycin. Four of 6 anticancer drugs were decided as chemosensitive drugs. These results corresponded to the results of the antitumor effects on subcutaneously transplanted MBT-2 in vivo, moreover was correlated well with those of the conventional SDI test. Twenty of 22 cases, including 11 of 13 bladder cancer cases, 1 of 3 renal cancer cases, 2 of 3 testicular cancer cases and 1 of 1 adrenal cortical cancer cases, were evaluable in the clinical study of the CGM assay. Corresponding rates between the results of the CGM assay and those of the conventional SDI test performed simultaneously in 12 cases were excellent for each anticancer drug. CONCLUSION: This CGM assay can serve as an effective tool for chemosensitivity testing because of its convenience and high evaluable rate. PMID- 8691696 TI - [Clinical experience with laparoscopy-assisted live donor nephrectomy]. AB - PURPOSE: Laparoscopic nephrectomy has become widely performed because of its minimally invasive nature. We have performed laparoscopic nephrectomies for non functioning kidneys and laparoscopy-assisted radical nephrectomies for renal carcinomas. Recently, we have successfully performed laparoscopy-assisted transperitoneal living related donor nephrectomy for kidney transplantation. To determine the efficacy of laparoscopy-assisted live donor nephrectomy, we investigated the clinical results of 2 patients operated upon with this new operation. PATIENTS: Case 1 was a 64-year-old healthy male and the left kidney was removed for his son who had a history of 4 months hemodialysis. Case 2 was 67 year-old healthy female who decided to donate her left kidney for her son with the history of 3 years and 2 months hemodialysis. METHODS: An upper abdominal midline incision of approximately 10 cm in length was made. Two retractors were attached to either side of the midline incision. The abdominal wall was raised by suspending these retractors from a special hanger. Then three trocars were introduced. The Gerota's fascia was incised and the kidney was suspended by grasping the perirenal fatty tissues. The renal artery and vein were carefully isolated without any manipulations of the kidney (non-touch method). After the transection of the ureter, the renal artery was ligated with a free tie of 1-0 silk and a suture ligature of 3-0 silk and the renal vain was clamped with a Satinski forceps. Immediately after the transection of the renal pedicle, the kidney was irrigated and transplanted to the right iliac fossa of the recipient in the usual fashion. A pen-rose drain was placed in the retroperitoneal space and the posterior peritoneal membrane was completely closed with 3-0 silk interrupted sutures. RESULTS: The mean operating time was 298 minutes and the mean blood loss was minimal. The average time of warm ischemia and cold ischemia of the graft were 4.5 minute and 37 minutes, respectively. There were no complications during either the operation or the postoperative period in both patients. The donors began oral intake and ambulation within 48 hours and resumed their normal daily activities by postoperative day 6.5 on average. Postoperative recovery of the patients were far faster than that of the patients receiving open donor nephrectomy. The graft functions were also excellent. The serum creatinine concentration of the recipients fell down to 0.82 mg/dl and 1.02 mg/dl at the third postoperative day. CONCLUSION: Laparoscopy-assisted live donor nephrectomy might be advantageous for kidney transplantation because of its minimally invasive procedure. PMID- 8691697 TI - [Tumor size and DNA ploidy changes in renal cell carcinomas--flow cytometric analysis of DNA content in renal cell carcinomas associated with von Hippel Lindau disease]. AB - BACKGROUND: Renal cell carcinomas (RCCs) develop in 8-63% of von Hippel-Lindau disease (VHL) patients, and loss of 3p segments, chromosome aberrations found in 90% of sporadic RCCs, has also been observed in RCCs associated with VHL. In fact, comparative analysis showed that the chromosome aberrations in RCCs associated with VHL are similar to those found in sporadic RCCs. VHL patients have the whole spectrum of tumors from small early lesions to large ones in the same kidney, providing a unique opportunity to analyze tumors in different stages of development. Subsequently deoxyribonucleic acid (DNA) content in RCCs of VHL patients was examined and correlated to their tumor size to gain some insight in the progression of sporadic RCCs. METHODS: From 1988 to 1991, we have experienced 6 cases of RCCs associated with VHL who underwent partial or radical nephrectomy. A total number of 52 paraffin-embedded samples from 33 RCCs from 6 patients with VHL was analyzed by flow cytometry. RESULTS: The sizes of tumors ranged from 0.2 to 8.2 cm. DNA aneuploid patterns demonstrated in none of 9 tumors less than 1.6 cm, 4 of 14 tumors (29%) as large as 1.6 to 2.5 cm, and 5 of 10 tumors (50%) larger than 2.5 cm (p < 0.05). Twelve tumors less than 1.8 cm showed DNA diploid, so the smallest size of aneuploid tumors was 1.8 cm. CONCLUSION: These data suggest that DNA ploidy change (diploid to aneuploid) in RCCs probably takes place as tumors grow approximately 1.8 cm in size. PMID- 8691698 TI - [A clinical study of radial prostatectomy]. AB - BACKGROUND: The objective of this study is to evaluate the efficacy of radical prostatectomy for patients with organ-confined prostate cancer. METHODS: From 1990 to 1994, a total of 50 patients with prostate cancer underwent radical retropubic prostatectomy. RESULTS: Eleven patients were in state A2, 34 in stage B and 5 in stage C according to clinical stage. Extended disease was observed pathologically in 45%, and 59% of patients in clinical stages A2 and B, respectively. Preoperative serum PSA levels were closely correlated with pathological extension of the disease. The disease-free rates for organ-confined disease, extended disease without lymph node metastasis and stage D1 disease were 75% (3 years), 82% (2 years) and 80% (3 years), respectively. Four patients had rectal injuries, and three of these underwent temporary colostomy diversion. Two patients had bladder neck contracture and received internal urethrotomy. Urinary incontinence improved in 60% of patients during the first 6 post-operative and in 90% of patients within 12 post-operative months. Urinary incontinence tended to improve earlier in patients with nerve-sparing than those without it. The erectile capacity in nerve sparing patients recovered good. CONCLUSION: Our results indicate that radical prostatectomy is a safe and temporarily satisfactory treatment for the patient with organ-confined prostate cancer. PMID- 8691699 TI - [Nephron sparing surgery for synchronous and asynchronous bilateral renal cell cancer. A procedure using intraoperative ultrasonography, argon beam coagulator and fibrin glue]. AB - BACKGROUND: Bilateral renal cell cancer (RCC) is an imperative indication of nephron sparing surgery (NSS). In the present study, we examined a new modality for NSS; intraoperative ultrasonography, argon beam coagulator (ABC) and fibrin glue. PATIENTS AND METHODS: We performed NSS against 7 kidneys in 5 patients, including 3 with synchronous and 2 with asynchronous tumors. Radical nephrectomy was performed on the contralateral kidney in 2 patients including one with asynchronous and the other with synchronous RCC. RESULTS: To examine satellite lesions and exact tumor extent within the kidney, intraoperative ultrasound scan was performed for all cases. Intraoperative ultrasound scan was shown to be useful for the above mentioned purposes because of its high resolving power. After clamping of the renal artery and surface cooling, dissection of the kidney was done by knife holder or by ultrasonic aspirator. Hemostasis was made by figure eight sutures with chromic catgut or poliglecaprone 25 monofilament, followed by coagulation using ABC, and with fibrin glue. Duration of arterial clamp ranged 20 approximately 78 min under surface cooling. Major complication did not occur except urinary fistula in one case caused by inadequate placement of a double J ureteral catheter. Postoperative renal functions were well preserved and any additional therapy for daily life was not needed in each patient. CONCLUSION: For performing NSS, the use of intraoperative ultrasound scan, ultrasonic aspirator, ABC and fibrin glue seemed to be useful, encouraging us to widespread its indication. PMID- 8691701 TI - [Eighteen cases of multicystic kidney: natural history and renal function of the contralateral kidney]. AB - PURPOSE: The objective of this study is to evaluate natural history of multicystic kidney (MCK) and renal function of the contralateral kidney. METHODS: We analyzed 18 children (7 boys and 11 girls) with unilateral MCK. The sizes of cysts were investigated by ultrasonography. Urinary beta 2-microgloblin (beta 2 m), alpha 1-microgloblin (alpha 1 m) and N-acetyl-beta-D-glucosaminidase (NAG) and albumin were determined as markers of tubular and glomerular damage. The renal function was evaluated by 99m Tc-dimercaptosuccinic acid (99 m Tc-DMSA) renal uptake rate. RESULTS: Nephrectomy was performed in 2 children. In 14 (87.5%) of 16 cases who were followed conservatively, the size of cysts was spontaneously reduced by 1-18 months (mean 6.4). Neither hypertension nor malignancy from the affected kidney has been observed in follow-up periods of 6 63 months. One patient had minor degree of contralateral ureteral dilatation which resolved spontaneously. Lower DMSA uptake rate of contralateral kidney was demonstrated in 63% (10/16). Markers of tubular damage were abnormally high in these patients. CONCLUSION: From these results, the most appropriate management of MCK is conservative with ultrasonic monitoring. Long-term follow-up testings with special care on contralateral renal function will be necessary because the overload to the contralateral healthy kidney may have already occurred during infancy and cause focal glomerulosclerosis and renal failure in future. PMID- 8691700 TI - [A clinical and pathological study of radical prostatectomy for prostate cancer]. AB - BACKGROUND: Thirty-one patients with prostate cancer underwent radical prostatectomy and simultaneous pelvic lymphadenectomy at Matsumoto National Hospital between 1988 and 1994. Prognostic factors are discussed from their clincopathological findings. METHODS: The patients ranged from 54 to 80-year-old, with an average age of 69.9 years. The median follow-up period was 44 months. The diagnosis was confirmed by needle biopsy or transurethral resection of the prostate. All the patients received short-term endocrine therapy preoperatively, and only noncuratively resected patients underwent adjuvant therapy postoperatively. At initial diagnosis, the tumor grades were well, moderately, and poorly differentiated adenocarcinoma in 9, 12, and 10 patients, respectively. The clinical stage was defined as A2, B, C, D1, and D2 in 12, 4, 6, 3, and 6 patients, respectively. RESULTS: A difference of tumor grade was found between the initial diagnosis and the final diagnosis based on the resected prostate in 8 patients (26%), with 7 of them (88%) showing an increase in grade in the final diagnosis. Also revealed was that 11 of the 25 patients (44%) in stage A2, B, C, or D1 had been understaged preoperatively. The five-year actuarial survival rates were 100%, 92%, and 51% for patients with well, moderately, and poorly differentiated adenocarcinoma, respectively, with a significant difference noted between well and poorly differentiated adenocarcinoma (p = 0.03). Recurrence only developed in patients with pathological stage D tumors. However, the presence or absence of lymph node metastasis did not affect the crude 5-year survival rate. Several stage D patients were successfully treated by radical prostatectomy and adjuvant therapy, achieving long survival. CONCLUSION: These results indicate that patients in clinical stage C have tumors which exhibit differing biological behavior. These patients should be analyzed and classified more precisely so that the most appropriate therapy can be chosen. PMID- 8691702 TI - [Comparison of hormone therapy alone and in combination with chemotherapy of cisplatin and methotrexate in newly diagnosed patients with stage D2 prostatic cancer]. AB - BACKGROUND: Prognosis of hormone-refractory prostatic cancer is dismal. We evaluated the efficacy of cytotoxic chemotherapy in combination with hormone therapy in patients with newly diagnosed metastatic prostatic cancer. METHODS: From February 1984 to March 1992, 39 newly diagnosed patients with stage D2 prostatic cancer were randomized to orchiectomy plus diethylistilbestrol diphosphate or orchiectomy plus diethylstilbestrol diphosphate plus combination chemotherapy with cisplatin and methotrexate. RESULTS: There was not significant difference in survival or progression-free survival between the two groups. CONCLUSION: Chemotherapy has not been proved to prolong survival or progression free survival in patients who received hormone therapy. PMID- 8691704 TI - [Usefulness of bladder auto-augmentation in neurogenic bladder: a case report]. AB - A 41-year-old male with myelomenigocele underwent a bladder auto-augmentation and endoscopic collagen injections. He has been performing self intermittent catheterization for 10 years but urinary incontinence remained unchanged. Furthermore, he suffered from recurrent pyelonephritis due to the left vesicoureteral reflux. A preoperative fluoroscopic urodynamic study showed a poorly compliant bladder with the maximal bladder capacity of 200 ml at 60 cmH2O. The left vesicoureteral reflux was observed at 10 cmH2O. The low compliant bladder was treated with the bladder autoaugmentation and the left vesicoureteral reflux was treated with the endoscopic subureteral injection of collagen 5 months after the previous operation. A fluoroscopic urodynamic study 6 months postoperatively showed the increase of the maximal bladder capacity of 300 ml at 18 cmH2O and the reflux disappeared completely. The endoscopic periurethral injections of collagen improved his persisting urinary incontinence. In patient with neurogenic bladder having a lot of clinical problems, bladder auto augmentation is less invasive and offers many advantages over enterocystoplasy. PMID- 8691703 TI - [Development of a new technique to detect the laterality of microscopic hematuria by means of gas cystoscopy]. AB - BACKGROUND: We developed a new technique to determine the laterality of microscopic hematuria by means of gas cystoscopy. METHODS: An originally designed catheter system consisted of two catheters. On the tip of an inner catheter, a urine dipstick for blood was attached, with a cap on the tip of an outer catheter to keep the dipstick dry. In order to react a dipstick with the urine coming out from a ureteral orifice in the bladder, CO2 was insufflated into the bladder through a cystoscope (gas cystoscopy). The laterality of microscopic hematuria was determined in the bladder, based on the color reaction on the dipstick. RESULT: This technique was performed successfully in 14 (88%) of 16 cases with microscopic hematuria. The laterality of microscopic hematuria was determined to be ipsilateral in 6 patients, which coincided with the side of a urological upper urinary tract disorder. In contract, bilateral microscopic hematuria was confirmed in 8 patients with glomerular disorders. CONCLUSION: The diagnostic process in patients with microscopic hematuria remains unsolved for urologists and nephrologists. This technique may provide a new approach in diagnosing microscopic hematuria. PMID- 8691706 TI - [Comparison of symptom degree and frequency to quantity the lower urinary tract symptoms]. AB - (BACKGROUND). To evaluate urinary symptoms, the International Prostate Symptom Score (I-PSS), which queries about frequency of symptoms, has been recently used in a clinical setting. However, there are men who are not satisfied with their voiding conditions in spite of a low symptom score. In such cases, their dissatisfaction may not be appropriately expressed by querying about frequency of the symptoms alone. We investigated whether the degree or the frequency of the obstructive symptoms correlated with the symptom-related problems. (METHODS). We analyzed obstructive symptoms in 739 males 40 years old and older who participated in a field survey for prostatic diseases. (RESULTS). Although not only frequency but degree of "hesitancy", "intermittency during urination", "strain or pushing" or "weak stream" correlated with the trouble, the correlations were higher in frequency than in degree. However, since some participants felt bothered when they expressed some degree of the symptoms alone but not frequency of the symptoms, evaluation of symptom degree may be helpful to identify such participants. Of the participants who answered "none" for frequency of the symptoms, some reported "having a mild symptom" in degree. This indicated that in recognition of symptoms degree may precede frequency. If the obstructive symptoms are very mild, men may express the symptoms as changes in degree, but not as changes in frequency. (CONCLUSIONS). These results suggested that evaluation of symptom degree is necessary for some participants. PMID- 8691705 TI - [Extraperitoneal laparoscopic adrenalectomy: the initial 9 cases]. AB - (PURPOSE). To determine the efficacy of extraperitoneal laparoscopic adrenalectomy for patients with adrenal tumor, the clinical results of 9 patients treated with this procedure were analysed. (PATIENT AND METHOD). Between July 1994 and March 1995, we have performed extraperitoneal laparoscopic adrenalectomy using the modified Gaur technique of balloon dilatation of the retroperitoneum in 4 men and 5 women with unilaterla small adrenal tumor who were 30 to 79 years old (mean age 56 years). Preoperative diagnosis was primary aldosteronism in 2, 18 hydroxycorticosterone producing adnoma in 1, pre-Cushing syndrome in 5, and nonfunctioning adrenal tumor in 1 patient. The operations were performed with the patients on lateral position and 4 torocars were positioned. The retroperitoneal space was first dissected bluntly by the index finger and a balloon dissector through a small skin incision, and the retroperitoneal space was insufflated with carbon dioxide at the pressure of 10 to 12 mmHg. After the dissection of the adrenal gland, adrenal vein was clipped and transected. The completely freed adrenal gland was enclosed in an entrapment sack and removed en bloc through the open laparoscopy wound. (RESULTS). All 9 procedures were successfully performed. The mean estimated blood loss and the mean operating time were 53 ml and 168 min respectively. There was no intraoperative complication. A postoperative retroperitoneal hematoma was observed in one patient, however it spontaneously resolved without surgical management. (CONCLUSION). In open adrenalectomy, the benefit of the extraperitoneal approach (excluding patients with pheochromocytoma or bilateral lesions) have already been established elsewhere. Although the working space is smaller than that of peritoneal approach, and the surgical techniques are slightly more difficult, extraperitoneal laparoscopic adrenalectomy promises to be safe and a minimally invasive treatment for patients with unilateral small adrenal tumors except for pheochromocytoma. PMID- 8691708 TI - [Role of serum E-selectin (ELAM-1) and inflammatory parameters in patients with renal cell carcinoma]. AB - (BACKGROUND). E-selectin is an adhesion molecule expressed on IL-1 activated endothelial cells and it binds to carbohydrate ligands such as sialy Lewis A antigen (SLeA) or Lewis X antigen (SLeX) on cancer cells. This mechanism is supposed to play an important role during hematogenous metastasis. Some of renal cell carcinomas (RCC) are known to produce inflammatory cytokines such as IL-1 beta and IL-6 and clinical evidence shows that the prognosis of this type of tumor is generally poor. We investigated whether this adhesion molecule was involved in hematogenous metastasis. (METHOD). In the present study, soluble E selectin level was measured in the sera of 89 patients with RCC prior to nephrectomy or IFN treatment using sanwich ELISA method. (RESULTS). The results indicated that high E-selectin concentration in the patients' sera was correlated with low incidence of metastasis and consequently correlated with good prognosis of RCC patients. Inflammatory serum parameters, such as serum C reactive protein (CRP), immunosuppressive acid protein (IAP) and erythrocyte sediment rate (ESR) were also assessed and these parameters were revealed to be negatively correlated with the serum level of E-selectin. In order to investigate this mechanism, we performed in vitro study on RCC cell/endothelial cell adhesion. IL-1 beta enhanced adhesion of 2 RCC cell lines and this adhesion was partially inhibited by adding exogenous E-selectin into the culture medium. Expression of SLeA and SLeX were demonstrated on the cell surface of 2 RCC cell lines by flowcytometric analysis. (CONCLUSION). The results suggested that E-selectin and SLeX/SLeA interaction was involved in the adhesion between RCC and endothelial cells and also inflammatory cytokine production by RCC cells was a risk factor for metastasis through E-selectin induction. Although expression of E-selectin on endothelial cells facilitates metastasis, excessive production of E-selectin into the serum was suggested to have inhibitory effect against metastasis. PMID- 8691707 TI - [Evaluation of Ki67 antigen using MIB1 antibody as a prognostic factor in renal pelvic and ureteral cancer]. AB - (PURPOSE). Recently, several reports showed that immunohistochemistry using MIB-1 antibody, which recognizes Ki-67 antigen, is one of the useful methods to determine the proliferative activity in various cancer. To evaluate the prognostic usefulness of the MIB-1, antibody we assessed the cell proliferation immunohistochemically in urothelial cancer. (METHODS). The proliferative activity of thirty cases of renal pelvic and ureteral cancer has been investigated immunohistochemically using MIB-1 antibody, which recognizes Ki-67 antigen, a human nuclear antigen expressed in proliferating cells. (RESULTS). The Ki-67 index correlated with prognostic factors such as pathological stage and histological grade. The patients with early stage or low grade tumors had lower Ki-67 indices. And the Ki-67 index significantly correlated with recurrence and prognosis. The tumors of patients with recurrence or cancer death had higher Ki 67 indices. When the patients were suggrouped according to Ki-67 indices (more than 22%) had significantly worse prognosis even in the same grade. Especially in the grade 2 group, all the four patients in the higher Ki-67 index subgroup had recurred and died of cancer, whereas, in the subgrouped patients with tumors of lower Ki-67 indices, only three patients had bladder cancer recurrence, and no patients had died of cancer, except one case with advanced tumor (T4, N3, M0) resected incompletely. (CONCLUSIONS). These results indicate that the Ki-67 index is a useful prognostic factor and may enhance the prognostic accuracy determined by conventional morphological grading systems. PMID- 8691709 TI - [Experience of 143 cases of laparoscopic surgery in urology--clinical outcome in comparison to open surgery]. AB - (BACKGROUND). The clinical outcome of laparoscopic surgery performed in 143 patients, including laparoscopic adrenalecotmy, nephrectomy, pelvic lymph node dissection (PLND) and varicocele ligation is reported. (METHODS). In patients who underwent laparoscopic adrenalectomy (32 cases), laparoscopic nephrectomy (7) or PLND (44), the following parameters were evaluated and compared to those obtained in patients undergoing the same surgeries but by conventional open procedure; operation time, hospital stay, pain killer doses and the time necessitated for ambulation. (RESULTS). The operation was successful in 95.8% (137/143). Open laparotomy was necessitated in 4 patients to control bleeding (two in adrenalectomy and two for PLND) and in one nephrectomy case due to massive adhesion with the descending colon. The major complication occurred in 4.2% of the cases, but without mortality. The laparoscopic adrenalectomy, nephrectomy and PLND had an average operating time of 260, 304 and 139 minutes, respectively, while the open surgery for each procedure required 251, 212 and 128 minutes, respectively (p = 0. 24 approximately 0.82). Likewise, the total dose of pain killer was 0.8, 1.8 and 0.9 for the former, whereas it was 3.2, 6.0 and 3.9 for the latter, respectively (p < 0.01). The average hospital stay for laparoscopic surgery was 4.9, 6.4 and 4.7 days in the same order, whereas open adrenalectomy or nephrectomy required about 14 days (p < 0.001). Convalescence was completed within significantly shorter term in patients with laparoscopic surgery. Potential complications of laparoscopic surgery included not only those unique to pneumoperitoneum (8.1%), but also those which may be encountered during any endoscopic operation such as compartment syndrome in the lower extremities. The physiologic changes accompanying increased intra-abdominal pressure affected renal function, characterized by a significant decrease in urinary output (p < 0.02), which, however, resumed to normal range within several hours after the operation without causing permanent renal dysfunction. (CONCLUSION). These results suggest that the laparoscopic surgery in certain area in urology has less morbidity and equal accuracy compared with conventional open surgery. PMID- 8691710 TI - [A study of the relation between clinical prognostic factors and the estimated tumor growth speed in superficial bladder cancer]. AB - (BACKGROUND). We studied the dynamic estimation of biological activity to evaluate stage progression using clinical findings of the superficial bladder cancer. (METHODS). From 1983 to 1993, 111 patients who underwent transurethral resection initially. 54 (48.6%) cases showed tumor recurrences at least once were estimated the tumor growth speed, dividing the total amount of tumor volume of summing all tumors at a certain recurrence with the duration between recurrences, and which was compared with various prognostic factors of the superficial bladder cancer. The Prognostic factors included age, sex, frequency of recurrences, tumor's number, tumor's size, stage, histological grade, shape, intravesical treatment and duration to recurrence from the last transurethral resection. (RESULTS). Seven (13%) cases showed disease progression in the sense of tumor stage (T2 < ) out of 54 recurrent patients. The tumor growth speed during one episode of recurrence was not statistical different between any factors. However, the average of tumor growth speed, which was calculated based on all episodes of recurrences, was statistically different (the cases with stage progression versus without : P < 0.05) between the cases with and without stage progression. (CONCLUSION). The results suggested that the dynamic estimation of biological activity of the superficial bladder cancer has a potential to be an important prognostic factor to determine the stage progression of the disease. PMID- 8691713 TI - [A case of secondary leukemia in anaplastic seminoma patient treated with long term chemotherapy]. AB - A 46-year-old man had received a long-term induction plus salvage chemotherapy for anaplastic seminoma with stage IV disease. Chemotherapy regimens and cycles included the following; four cycles of bleomycin plus vinblastine plus cisplatin (BVP); eight cycles of cyclophosphamide, vincristine, and cisplatin (COP); three cycles of etoposide plus cisplatin (EP); thirteen cycles of etoposide with ifosfamide and cisplatin (VIP). The total cumulative dose of etoposide was 4250 mg/m2. Severe and persistent pancytopenia developed 32 months after starting etoposide-based salvage chemotherapy. Bone marrow examination showed hypercellular marrow containing 68% myeloblasts but peroxidase reaction was negative. CD-13 was 30.1% which meant that leukemia was myelogenous. Therefore, he was diagnosed as acute myelogenous leukemia. French-American-British classification was MO. Chromosome analysis revealed a t (8; 21)(q22;q22) cytogenetic abnormality. This case may be compatible with the clinical and cytogenetic characters of epipodophyllotoxin-related leukemia. We conclude that high doses of etoposide seem to be leukemogenic. To our knowledge, this is the first reported case in the literature relevant to epipodophyllotoxin-related secondary leukemia in testicular tomor in Japan. PMID- 8691712 TI - [Significance of macrophage and cytokines in expression of stone matrix]. AB - (BACKGROUND). Urinary calculus consists of inorganic substances as a major component and organic substances as a minor component. In this study, the organic substances playing an important role in the formation of calculus, such as osteopontin, calprotectin, macrophage and cytokines, are investigated for their significance in the calculus formation mechanism. (METHODS). Using renal tissues of rats having intraperitoneal glyoxylic acid-induced calculus, mode of the expression of osteopontin was examined by in situ hybridization method, immunohistological staining and northern blot method. Then human renal tissues obtained from the nephrectomy specimen conducted for a renal calculus were subjected to immunohistological staining by an enzyme antibody method using antibodies against osteopontin, calprotectin, macrophage and cytokines. (RESULTS). In rats, while the expression of osteopontin mRNA was observed in renal distal tubular cells, no expression was observed in glomerulus or renal interstitial tissues. The level of osteopontin mRNA expression in calculus forming rats was higher than in control rats by northern blot method. In human tissues, all of osteopontin, calprotectin, macrophage exhibited positive results in the renal distal tubular cells and in the calculus nucleus in the renal distal tubular cavity. Calprotectin and macrophage exhibited positive result also in the renal interstitial tissues. Cytokines exhibited positive results for interleukin 1,6, tumor necrosis factor alpha and transforming growth factor beta. Cytokines exhibited positive results in the distal tubular cells. Negative results were observed for interleukin-2,4 and 5. (CONCLUSION). Based on the findings described above, it is concluded that accumulation of macrophage in the renal interstitial tissues takes place and then one type of cytokines sensitive to macrophage is secreted. Subsequently, in the renal distal tubular cells stimulated with macrophage and cytokines, the expression of osteopontin and calprotectin takes place, and these organic substances bind to calcium, whereby forming the calculus nucleus. PMID- 8691711 TI - [The long-term effect and outcome of preoperative chemotherapy combined with radiation therapy for bladder cancer]. AB - (BACKGROUND). The object of this study is to evaluate the efficacy of preoperative chemotherapy combined with radiation therapy for bladder cancer. (METHOD). A total of 44 patients with bladder cancer were treated by preoperative chemotherapy combined with radiation therapy between October, 1981 and December, 1986. Of the 44 patients, ranging in age from 40 to 82, with an average age of 65.8, 34 were male and 10 were female. Clinical stages included 4 patients in Ta, 25 in T1, 11 in T2, and 4 in T3. Each patient was treated twice with 15 gray of radiation to the small pelvic cavity and a chemotherapy combination of adriamycin, cis-platinum, tegaful, and peplomycin. The average observation time after the therapy was 83 month, with the maximum being 146 months. (RESULTS). Complete remission was included in 5 patients, partial remission in 27, and no change in 12. Thus, the overall effective rate was 72.8%. Operations, selected by the results of the preoperative therapy, included transurethral resection on 28 patients, transurethral fulguration on 2, partial cystectomy on 4, resection of tumor on 4, and total cystectomy on 3. Operations were not performed on 2 patients and not allowed on 1 patient. The outcome during the long-term follow-up included cancer related deaths in 4 patients, and death resulting from other disorders in 9. The 5-year survival rates for superficial and invasive bladder cancer were 92.4%, and 83.9%, respectively. The 10-year survival rates for superficial and invasive bladder cancer were also 92.4% and 83.9%, respectively. The 3-year and 5-year non-recurrence rates for superficial bladder cancer were 75.8%, and 66.9% respectively, according to the Kaplan-Meier method. On the other hand, the 3-year and 5-year non-recurrence rates for invasive bladder cancer were both 73.8%. During the follow-up between 9 and 11 years, 3 upper tract tumor were diagnosed (2 ureteral cancer, and 1 renal pelvic cancer). (CONCLUSION). We concluded that preoperative chemotherapy combined with radiation therapy may be effective for the treatment of bladder cancer. PMID- 8691714 TI - Parenteral strobilar development of Echinococcus multilocularis in scid mice. AB - Parenteral strobilation of Echinococcus multilocularis was observed in acid (severe combined immuno-deficient) mice after intracerebral, subcutaneous and intraperitoneal inoculation with protoscoleces. Evaginated protoscoleces and segmented worms were obtained at the inoculated sites. Most worms recovered from peritoneal cavity of scid mice were encapsulated by connective tissue and granulocytes but showed a maximum of 3 proglottids, elongation of genital primordia and vesiculation. Viability of worms recovered from the subcutaneous tissue and peritoneal cavity of scid mice were higher (69.1-91.4%) than those from the immunologically normal C.B-17 (4.0-48.0%) control mice. However, viabilities of worms from the cerebrum of both scid and C.B-17 were almost the same (87.7-94.4%). Worms recovered from scid mice showed further development of reproductive organs when transplanted into the small intestine of prednisolone treated golden hamster. These findings suggest that the parenteral milieu of scid mice allows adult development of E. multilocularis protoscoleces. PMID- 8691715 TI - Peptide hormone action on renal phosphate handling. PMID- 8691716 TI - Regulation of rat renal Na/Pi-cotransporter by parathyroid hormone: immunohistochemistry. PMID- 8691717 TI - New aspects of adaptation of rat renal Na-Pi cotransporter to alterations in dietary phosphate. PMID- 8691718 TI - Role of renal handling of extracellular nucleotides in modulation of phosphate transport. PMID- 8691719 TI - Mechanism of renal phosphate retention during growth. AB - We have previously demonstrated that the retention of phosphate required for growth is due to a a high Vmax of the Na(+)-Pi cotransport system located in the brush border membrane of the proximal tubule. Because of this and other similarities between adaptation of the kidney to a high Pi demand (growth) and that to low Pi supply, we measured the levels of NaPi-2 mRNA and cDNA present in kidney cortex of 3- and > 12-week-old rats. Like in Pi depletion, Western blots revealed that a 80 to 85 kDa protein recognized by a polyclonal antibody directed against the N-terminal region of the NaPi-2 protein was 2.3-fold more abundant in renal microvilli of the young than of adult animals. However, unlike in Pi depletion, Northern blot analysis failed to reveal a significant difference between mRNA levels at the two ages. Furthermore, suppression of NaPi-2 mRNA activity by annealing with antisense oligomers, or removal of the NaPi-2 transcripts by subtractive hybridization did not affect the rate of Na(+)-Pi cotransport induced in oocytes by polyA RNA of rapidly growing animals, while abolishing the ability of the renal cortical polyA RNA of adult rats to encode for Na(+)-Pi cotransport. RT-PCR of subtracted polyA RNA using primers specific for a region conserved in NaPi type II (Pi modulated) cotransporters yielded a product that was 98% homologous with that region, despite the absence of NaPi-2 cDNA. The results of these experiments demonstrate that the polyA RNA from kidneys of young animals contains unique mRNA transcripts able to encode for a NaPi protein homologous to, but distinct from NaPi-2. PMID- 8691720 TI - Renal Na(+)-phosphate cotransporter gene expression in X-linked Hyp and Gy mice. AB - The X-linked Hyp and Gy mutations are murine homologues of X-linked hypophosphatemia (XLH), a dominant disorder of phosphate (Pi) homeostasis characterized by growth retardation, rickets, hypophosphatemia and decreased renal tubular maximum for Pi reabsorption relative to glomerular filtration rate (Tmp/GFR). In Hyp and Gy mice, the decrease in Tmp/GFR is associated with a reduction in renal brush-border membrane (BBM) Na(+)-Pi cotransport that can be ascribed to a decrease in renal-specific, Na(+)-Pi cotransporter (NPT2) mRNA and protein abundance. Although renal NPT2 gene expression is reduced in Hyp and Gy mice, the NPT2 gene does not map to the X chromosome. These findings exclude NPT2 as a candidate gene for murine and human X-linked hypophosphatemias and suggest that genes at the Hyp, Gy and XLH (HYP) loci are involved in regulation of NPT2 gene expression. Both Hyp and Gy mice respond to low Pi diet with an increase in BBM Na(+)-Pi cotransport, NPT2 mRNA and protein. The increase in NPT2 protein in Pi-depleted mice far exceeds the increase in NPT2 mRNA, suggesting that translational or post-translational mechanisms are involved in the adaptive process. NPT2 protein is localized to the apical surface of the proximal tubule, where immunostaining in both normal and Hyp mice is increased in response to low Pi diet. Pi-deprived Hyp and Gy mice fail to show an increase in Tmp/GFR, indicating that adaptation at the BBM is not sufficient for the overall increase in Tmp/GFR in response to low Pi diet. PMID- 8691721 TI - Positional cloning of the HYP gene: a review. PMID- 8691722 TI - Regulation of the Na+/H+ exchanger isoform NHE1: role of phosphorylation. PMID- 8691723 TI - A cloned extracellular Ca(2+)-sensing receptor: molecular mediator of the actions of extracellular Ca2+ on parathyroid and kidney cells? PMID- 8691724 TI - G-protein-coupled receptor kinases. AB - beta-Adrenergic receptors are prototypes of the many G-protein-coupled receptors. Activation and inactivation of these receptors are regulated by multiple mechanisms which can affect either their function or their expression. The most obvious changes of such receptor systems are induced by activation of the receptors themselves by their respective agonists, and this process is called receptor desensitization. One of these mechanisms of desensitization is due to the actions of specific receptor kinases, termed the G-protein-coupled receptor kinases (GRKs). These kinases specifically phosphorylate only the agonist occupied form of such receptors. This phosphorylation is then followed by binding of inhibitor proteins, called arrestins, to the receptors. Binding of arrestins results in displacement of the G-proteins from the receptors and hence causes uncoupling of receptors and G-proteins. Recent data indicate that the function and subcellular distribution of GRKs is itself subject to regulation. Various mechanisms have evolved to anchor the different GRKs to the plasma membrane. In addition, recent data indicate that GRKs can also associate with intracellular membranes where they may exert as yet unknown functions. A pathophysiological role for GRKs can be inferred from recent studies on heart failure as well as the observation that chronic treatment with various agonists or antagonists for G protein-coupled receptors results in alterations of GRK expression. PMID- 8691725 TI - Immunochemical study of a transforming growth factor-alpha-related protein in the chicken kidney. AB - A number of polypeptides are involved in renal growth and physiology. Both transforming growth factor-alpha (TGF-alpha) protein and mRNA are expressed in kidney cells during embryonic and adult stages, and exert mitogenic activity on kidney cells in culture. We studied the immunolocalization of a TGF-alpha-related protein at the ultra-structural level and found it in the basolateral membranes of dark cells from distal tubules of the chicken kidney. By Western blotting techniques, we identified a protein complex composed of a least two TGF-alpha immunoreactive subunits of 40 and 88 kDa, respectively. Both subunits were sensitive to elastase digestion, and released TGF-alpha immunoreactive products. In addition, TGF-alpha immunoreaction was found in primary culture of chicken kidney cells. These findings suggest that the TGF-alpha-related protein complex plays a very specific role in proliferation and/or differentiation of kidney cells. PMID- 8691726 TI - Anti-Fas antibodies induce cytolysis and apoptosis in cultured human mesangial cells. AB - Death of renal cells often occurs during the acute and resolution phases of some forms of glomerulonephritis. The apoptotic Fas protein belongs to a recently described family of cytokine receptors with similarities to tumor necrosis factor (TNF) receptors, and may contribute to the necrobiology of renal cells. Fas transduces a signal for apoptosis in sensitive cells after binding by specific antibodies or following contact with natural Fas ligand. We have studied Fas in cultured human mesangial cells. Cytoflurography demonstrated Fas expression on the surface of human mesangial cells that was increased by stimulation with interferon gamma (IFN gamma). Agonistic anti-human Fas antibodies were cytotoxic to these cells. Cytotoxicity was time- and dose-dependent, and was modulated by pre-stimulation of the mesangial cells with IFN gamma and/or by co-treatment with actinomycin-D. Mesangial cell death following exposure to anti-Fas antibodies has features consistent with apoptosis, such as internucleosomal DNA fragmentation, nuclear shrinkage and condensation, and decreased DNA content. These data suggest that Fas and its ligand could play a mechanistic role in human glomerular cell injury. PMID- 8691727 TI - Characterization of insulin-like growth factor binding proteins and regulation of IGFBP3 in human mesangial cells. AB - IGF-I regulates renal growth and development. Insulin-like growth factor binding proteins (IGFBPs) are synthesized by the kidney and may modulate the local autocrine and/or paracrine actions of IGF-I. We have previously demonstrated that mesangial cells (MC) release IGF-I and IGF-binding activity; however, the specific IGFBPs produced by these cells and the factors involved in their regulation are unknown. We examined MC for expression of IGFBP-1 to -6 mRNAs and proteins. RNase protection assays using total RNA demonstrated that MC express all of the IGFBPs. [125I]IGF-I Western ligand blot of conditioned medium demonstrated that MC release IGFBPs of 24, 29, 32 kDa, and a doublet at 46 kDa, consistent with IGFBP-4, -5, -2 and -3, respectively. IGFBP species of 28 and 34 kDa were also detected. Since IGF-I and TGF-beta are implicated in glomerular hypertrophy and matrix expansion, we tested their effect on IGFBPs released by MC. IGF-I (100 ng/ml), TGF-beta (2 ng/ml) and forskolin (10(-5) M) differentially regulated the abundance of IGFBPs released in the conditioned medium in a time dependent manner. IGF-I and TGF-beta were potent inducers of the release of IGFBP3 protein; however, TGF-beta, but not IGF-I, increased IGFBP3 mRNA levels. Recombinant IGFBP3 was tested for its effect on IGF-I-induced mitogenesis. IGFBP3 inhibited IGF-I-stimulated DNA synthesis in a dose-dependent manner with a peak effect observed at 50 nM IGFBP3. Although TGF-beta is a potent inhibitor of IGF-I stimulated DNA synthesis, this effect is not mediated via IGFBPs. Expression of IGFBP-1 to -6 by MC suggests that these proteins may modulate IGF-I bioavailability in the glomerulus. IGF-I itself, TGF-beta and cAMP agonists may indirectly modulate the effects of IGF-I via the release of IGFBPs by MC. PMID- 8691728 TI - Effects of high glucose on the production of heparan sulfate proteoglycan by mesangial and epithelial cells. AB - Changes in heparan sulfate metabolism may be important in the pathogenesis of diabetic nephropathy. Recent studies performed on renal biopsies from patients with diabetic nephropathy revealed a decrease in heparan sulfate glycosaminoglycan staining in the glomerular basement membrane without changes in staining for heparan sulfate proteoglycan-core protein. To understand this phenomenon at the cellular level, we investigated the effect of high glucose conditions on the synthesis of heparan sulfate proteoglycan by glomerular cells in vitro. Human adult mesangial and glomerular visceral epithelial cells were cultured under normal (5 mM) and high glucose (25 mM) conditions. Immunofluorescence performed on cells cultured in 25 mM glucose confirmed and extended the in vivo histological observations. Using metabolic labeling we observed an altered proteoglycan production under high glucose conditions, with predominantly a decrease in heparan sulfate compared to dermatan sulfate or chondroitin sulfate proteoglycan. N-sulfation analysis of heparan sulfate proteoglycan produced under high glucose conditions revealed less di- and tetrasaccharides compared to larger oligosaccharides, indicating an altered sulfation pattern. Furthermore, with quantification of glomerular basement membrane heparan sulfate by ELISA, a significant decrease was observed when mesangial and visceral epithelial cells were cultured in high glucose conditions. We conclude that high glucose concentration induces a significant alteration of heparan sulfate production by mesangial cells and visceral epithelial cells. Changes in sulfation and changes in absolute quantities are both observed and may explain the earlier in vivo observations. These changes may be of importance for the altered integrity of the glomerular charge-dependent filtration barrier and growth-factor matrix interactions in diabetic nephropathy. PMID- 8691729 TI - L-arginine depletion inhibits glomerular nitric oxide synthesis and exacerbates rat nephrotoxic nephritis. AB - Nitric oxide (NO) synthesis is induced in glomeruli in glomerulonephritis; its role in the pathogenesis of glomerular injury is unknown. Interpretation of its role using the currently available analogues of L-arginine as in vivo inhibitors of NO is complicated by their lack of specificity for inducible NO synthase (iNOS). As NO synthesis by iNOS depends on extracellular L-arginine, we have here examined effects of L-arginine depletion on glomerular NO synthesis and the course of accelerated nephrotoxic nephritis (NTN). Arginase, which converts L arginine to urea and L-ornithine, was used to achieve L-arginine depletion. A single dose of i.v. arginase produced complete depletion of plasma arginine for four hours. Two forms of NTN were induced in preimmunised rats by nephrotoxic globulin: (1) the systemic form of the model by intravenous nephrotoxic globulin; or (2) the unilateral form of model by left kidney perfusion with nephrotoxic globulin, which avoids the complications of systemic administration of nephrotoxic globulin. Arginase reduced plasma arginine levels and the synthesis of nitrite (the stable end-product of NO) by NTN glomeruli (95% inhibition). Proteinuria was exacerbated. There was no effect on early (24 hr) leukocyte infiltration. In the systemic form of the model arginine depletion by i.v. arginase increased glomerular thrombosis at 24 hours, and the severity of histological changes at four days, accompanied by systemic hypertension. In the unilateral form of the model, where i.v. arginase did not induce hypertension, there was no increase in thrombosis or histological severity of nephritis. These results show that arginine depletion, which inhibits glomerular NO synthesis in NTN, leads to increased proteinuria. Where injury is severe, or accompanied by systemic hypertension, the disease is further exacerbated by glomerular thrombosis. These results suggest that NO has an important role in limiting acute glomerular injury. PMID- 8691731 TI - Assessment of excess fluid distribution in chronic hemodialysis patients using bioimpedance spectroscopy. AB - Sodium and water homeostasis is abnormal in hemodialysis (HD) patients, however, the distribution of the excess fluid (extracellular vs. intracellular) has not been fully characterized. We studied the distribution of fluid using bioimpedance spectroscopy to determine if HD patients have an excess of fluid in any specific compartment relative to controls. Dual-energy x-ray absorptiometry was used to measure lean body mass and bone mineral content. The resistive index (RI) for extracellular water volume (RIECW), was significantly increased in patients pre HD when corrected for bone mineral content (RIECW:BMC) (pre-HD, 19.0 +/- 3.3; controls, 15.8 +/- 1.7 cm2-ohms(-1)-kg -1; P < 0.01). This value decreased to the control range following HD (15.2 +/- 2.5 cm2-ohms(-1)-kg(-1). The intracellular water volume to bone mineral content (RIICW:BMC) was not different between controls and HD patients. These data suggest that hemodialysis patients carry their excess fluid volume primarily in the extracellular compartment and that bioimpedance spectroscopy coupled with a stable measure of lean tissue such as bone mineral content can determine the degree of relative excess hydration. PMID- 8691730 TI - Interleukin-1 beta up-regulates the plasminogen activator/plasmin system in human mesangial cells. AB - The plasminogen activators (PA), which are regulated by their specific inhibitor, PAI-1, convert the zymogen plasminogen to plasmin, a protease involved in fibrinolysis and extracellular matrix turnover. Interleukin 1 beta (IL-1) is a key cytokine released from infiltrating monocytes/macrophages during the initial stages of glomerular injury. We investigated the effects of IL-1 on the production of tissue-type plasminogen activator (t-PA), urokinase (u-PA) and PAI 1 by glomerular cells. IL-1 significantly increased the synthesis of t-PA by mesangial cells and glomerular epithelial cells (P < 0.005 for both cell types), while u-PA production was unaltered. PAI-1 in mesangial cell supernatants was significantly lower when cultured in the presence of IL-1 (p < 0.008), and the synthesis decreased in a time and dose dependent manner. The effects of IL-1 were eliminated by anti-IL-1 neutralizing antibodies. The PAI-1 sequestered in the extracellular matrix of mesangial cells was also decreased. No significant change in PAI-1 synthesis by epithelial cells was observed with exogenous IL-1. Northern blot analysis paralleled the protein results, demonstrating an increase in t-PA and a decrease in PAI-1 mRNA of mesangial cells after 6 and 24 hours stimulation with 10 U/ml IL-1. These studies suggest a role for IL-1 in regulating localized proteolysis by mesangial cells during acute inflammation. PMID- 8691732 TI - Delayed treatment with enalapril halts tubulointerstitial fibrosis in rats with obstructive nephropathy. AB - Tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) is driven by increased levels of angiotensin II (Ang II). In this study, we examined the time course of the fibrotic process in rats with UUO and explored the effect of delayed administration of an angiotensin converting enzyme (ACE) inhibitor, enalapril, on the tubulo-interstitial fibrosis of obstructive uropathy. Rats were sacrificed at 3, 5, 8, or 10 days after UUO was initiated. Some rats did not receive treatment, whereas others were treated with enalapril from day 4 to day 8 or from day 6 to day 10 after the onset of UUO. The levels of mRNA for transforming growth factor beta 1 (TGF-beta 1), collagen type IV (collagen IV), and tissue inhibitor of metalloproteinase (TIMP-1) were measured at each time point by reverse transcription-polymerase chain reaction (RT-PCR). The relative volume of the tubulointerstitium (Vv) was measured by a point-counting method. Monocyte/macrophage infiltration and collagen IV protein deposition were examined histologically using specific antibodies. There were significant increases in TGF beta 1, TIMP-1, and collagen IV mRNAs in the obstructed kidney. Treatment with enalapril on day 4 through day 8 or on day 6 through day 10 significantly reduced the elevated mRNA levels of these compounds in the obstructed kidney. Histological studies showed augmented Vv, monocyte/macrophage infiltration, interstitial alpha-smooth muscle actin expression, and collagen IV protein deposition on days 3, 5, 8, or 10 of UUO; enalapril treatment from day 4 to 8 or from day 6 to 10 halted and to an extent reversed these increases. These data suggest that enalapril administration after several days of UUO is an effective means of preventing the progression of tubulointerstitial fibrosis of obstructive uropathy. PMID- 8691733 TI - Quantification of glomerular TGF-beta 1 mRNA in patients with diabetes mellitus. AB - Transforming growth factor-beta 1 (TGF-beta 1) is a primary determinant of the mesangial expansion observed in diabetic nephropathy. In this study, we quantitated the levels of intraglomerular TGF-beta 1 mRNA in patients with diabetes mellitus using a competitive polymerase chain reaction (PCR) method. Renal biopsy specimens were obtained from 29 patients with non-insulin-dependent diabetes mellitus. Total RNA was extracted from the glomeruli and reverse transcribed into cDNA with reverse transcriptase. To prepare samples containing identical amounts of beta-actin cDNA (8 pg), we performed competitive PCR by co amplifying mutant templates of beta-actin with a unique EcoRI site. We also used this competitive PCR method to measure TGF-beta 1 cDNA by co-amplifying mutant templates of TGF-beta 1. We observed higher expression of TGF-beta 1 mRNA in glomeruli of patients with diabetic nephropathy as compared with normal glomeruli. Intraglomerular TGF-beta 1 mRNA was elevated, even in the early stage of diabetic nephropathy. Moreover, levels of intraglomerular TGF-beta 1 mRNA correlated with values of HbA1c. These data suggest that hyperglycemia induces intraglomerular TGF-beta 1 mRNA expression in vivo, and that TGF-beta 1 overproduction may be associated with the progression of diabetic nephropathy. PMID- 8691734 TI - Autoreactive T-cells in Goodpasture's syndrome recognize the N-terminal NC1 domain on alpha 3 type IV collagen. AB - Goodpasture's syndrome is mediated by immunopathogenic autoantibodies to the alpha 3 NC1 domain of type IV collagen. It is not known whether collaborating T cells participate in this autoreactive response. Here we describe the first T cell clone isolated from a Goodpasture patient autoreactive to alpha 3 type IV collagen of glomerular basement membrane. To investigate cellular autoreactivity, T-cells from Goodpasture patients or controls were isolated and stimulated by purified native or recombinant type IV collagen proteins and synthetic oligopeptides. Cell surface markers, the T-cell receptor repertoire, and MHC restriction were analyzed. T-cell clones specific for the alpha 3 (IV) NC1 domain were established in two Goodpasture patients, but not in controls. One of the three CD8+ T-cell clones was characterized further. It was MHC class I restricted (HLA-A11) and expressed the T-cell receptor V beta 5.1. chain. This clone specifically recognized a motif at the N-terminal area of the alpha 3 (IV) NC1 domain (AA 51 to 59: GSPATWTTR). We conclude that autoreactive T-cells exists in Goodpasture patients and may play a crucial role in the inflammatory process. T cell clones are autoreactive to the alpha 3 (IV) NC1 domain. At least for one of the clones, the T-cell epitope is different from the putative antibody-binding site. PMID- 8691735 TI - Pharmacokinetics of insulin-like growth factor-1 in advanced chronic renal failure. AB - Information regarding the impact of chronic renal failure (CRF) on IGF-1 serum clearance is limited. Thus we evaluated the pharmacokinetics of insulin-like growth factor-1 (IGF-1) in six normal adults and six adults with advanced CRF (serum creatinine 7 +/- 0.8 mg/dl). All subjects were given 80 micrograms/kg recombinant human IGF-1 s.c. and blood was sampled over 48 hours. Baseline total serum IGF-1 levels were similar in both groups, but peak levels were elevated significantly in CRF; this was apparently related to the reduced distribution volume in CRF subjects. CRF did not affect the metabolic clearance rate (MCR) of total serum IGF-1. Immunoreactive IGF binding protein-3 (IGFBP-3) levels were greater in CRF. Western immunoblots revealed that the apparent increase in IGFBP 3 was largely due to an increase in immunoreactive fragments. IGFBP-3 protease activity was not increased. Thus IGFBP fragment accumulation likely reflects reduced fragment clearance. Western ligand blots revealed elevated 30 and 34 kDa IGFBP levels and IGFBP products in CRF serum. Serum acid labile subunit levels were unchanged in CRF. Peak free IGF-1 levels and the MCR of free IGF-1 did not differ between groups. In both groups the MCR of free IGF-1 exceeded the MCR of total IGF-1 by approximately 30-fold. These data suggest that in CRF patients receiving s.c. IGF-1: (a) total serum IGF-1 levels are increased as a result of elevated circulating IGFBPs that may restrict the distribution of IGF-1 beyond plasma; (b) serum free IGF-1 levels are not altered; and (c) the IGF-1 MCR is unchanged in CRF. Thus, in advanced CRF, apart from a reduction in the total IGF 1 volume of distribution the pharmacokinetics of IGF-1 are largely unaltered. PMID- 8691737 TI - A device and a method for rapid and accurate measurement of access recirculation during hemodialysis. PMID- 8691736 TI - Role of transforming growth factor-beta 1 in experimental chronic cyclosporine nephropathy. AB - The pathogenesis of fibrosis in chronic cyclosporine (CsA) nephropathy remains unknown. Since TGF-beta 1 plays a key role in the fibrogenesis of a number of renal diseases, we studied a salt-depleted rat model of chronic CsA nephropathy which shows similarity to the structural and functional lesions described in patients. Pair fed rats were treated with either CsA (15 mg/kg/day s.c.) or an equivalent dose of olive oil and sacrificed at 7 and 28 days. Characteristic histologic changes of proximal tubular injury, tubulointerstitial fibrosis and arteriolopathy developed in CsA-treated rats at day 28. They were accompanied by physiologic changes of increased serum creatinine, decreased creatinine clearance, increased enzymuria and decreased concentrating ability. CsA-treated rats showed a progressive increase in mRNA expression of TGF-beta 1 and matrix proteins at days 7 and 28. Most of the changes were in the tubulointerstitial and vascular compartments by immunofluorescence with a predominant involvement of the medulla as compared to cortex. The mRNA expression of plasminogen activator inhibitor, a protease inhibitor stimulated by TGF-beta 1, followed TGF-beta 1 and matrix proteins, suggesting that the fibrosis of chronic CsA nephropathy likely involves the dual action of TGF-beta on matrix deposition and degradation. PMID- 8691738 TI - Vascular access stenosis: prospects for prevention and therapy. PMID- 8691739 TI - Forefronts in Nephrology: Phosphates. Symposium proceedings. Seelisberg, Switzerland, September 24-27, 1995. PMID- 8691740 TI - Phosphate metabolism: contribution of different cellular compartments. PMID- 8691741 TI - Atomic basis of the exquisite specificity of phosphate and sulfate transport receptors. AB - We have determined, by the method of x-ray crystallography, the 1.7 A resolution three-dimensional structures of the ligand-bound form of the phosphate receptor as well as the sulfate receptor. These protein structures provide an unprecedented atomic-level understanding of the mechanism governing the exquisite specificity of each receptor. Although they lack amino acid sequence homology, both receptors have very similar three-dimensional structure. The structure consists of two globular domains separated by a deep cleft which contains the ligand-binding site. The bound phosphate and sulfate are totally devoid of water of hydration. The bound phosphate is tightly held in place by 12 hydrogen bonds, 11 with donor and 1 with acceptor groups. The acceptor group (an Asp carboxylate side chain) plays three key roles. It confers specificity by directly recognizing one proton of either the monobasic or dibasic phosphate. It also assists in the recognition of another proton of the monobasic phosphate. Finally, because of charge repulsion, it disallows binding of fully ionized sulfate. The sulfate bound to the sulfate receptor makes seven hydrogen bonds with uncharged polar groups exclusively. The absence of an acceptor group in the binding site of the sulfate receptor is not conducive to phosphate binding. PMID- 8691742 TI - Structural and functional aspects of the phosphate carrier from mitochondria. AB - The paper reviews the major structural and functional aspects of the phosphate carrier from the inner mitochondrial membrane in comparison to other mitochondrial carrier proteins. The mitochondrial phosphate carrier catalyzes the transport of inorganic phosphate from the cytosol into the mitochondrial matrix and is thus essential for the energy metabolism of the cell. The phosphate carrier from beef and pig heart, from rat liver and from yeast mitochondria has been purified by chromatographic methods and functionally reconstituted in proteoliposomes. The primary sequence of the phosphate carrier from several different species has been determined. The carrier protein of Mr 33 to 34 kDa most likely acts as a dimer in the membrane. The phosphate carrier has been characterized with respect to transport kinetics, energy dependence and carrier mechanism mainly after functional reconstitution into artificial bilayers (liposomes). Three different modes of action were elucidated, namely homologous phosphate/phosphate antiport, heterologous phosphate/proton symport or phosphate/hydroxyl antiport, respectively, as well as unphysiological uniport (efflux) after modification of essential SH-groups. Both with respect to its primary structure and its functional (kinetic) properties, the phosphate carrier is a member of the well-defined mitochondrial carrier protein family. PMID- 8691743 TI - Endoplasmic reticulum phosphate transport. AB - The major role of the liver endoplasmic reticulum phosphate/pyrophosphate transport proteins is the regulation of blood glucose levels. The glucose-6 phosphatase enzyme is an endoplasmic reticulum enzyme system which hydrolyzes glucose-6-phosphate to glucose and phosphate. Glucose-6-phosphatase is the terminal step of both gluconeogenesis and glycogenolysis. The glucose-6 phosphatase enzyme is a very hydrophobic membrane protein and its active site is inside the lumen of the endoplasmic reticulum. The substrates and products of the enzyme therefore have to cross the endoplasmic reticulum membrane. The glucose-6 phosphatase enzyme is associated with a calcium binding protein (SP). There are also transport proteins for the substrate glucose-6-phosphate (T1) and the products phosphate (T2) and glucose (T3). There appear to be at least two different liver endoplasmic reticulum proteins that can transport phosphate. One of the proteins T2b can also transport pyrophosphate and carbamyl phosphate which are also substrates for the glucose-6-phosphatase enzyme. The metabolic regulation, genetic deficiencies, ontogeny and tissue distribution of the endoplasmic reticulum T2 proteins will be described. PMID- 8691744 TI - Identification and characterization of a widely expressed phosphate transporter/retrovirus receptor family. AB - The cell-surface receptors for gibbon ape leukemia virus (Glvr-1; [1]) and rat amphotropic virus (Ram-1; [2]) were recently demonstrated to serve normal cellular functions as sodium-dependent phosphate transporters [3, 4]. These transporters, called PiT-1 and PiT-2, respectively, are approximately 59% identical in amino acid sequence and are members of a gene family distinct from the renal type I and type II NaPi sodium-dependent phosphate transporters. Both PiT-1 and PiT-2 are widely distributed in many tissues including kidney, brain, heart, liver, muscle, and bone marrow. Expression of both transporters is increased by phosphate deprivation. The distinct structural and functional properties of these molecules establishes them as members of a new family of phosphate transporters which may play a major role in phosphate uptake in a wide variety of cell types. PMID- 8691745 TI - Signal transduction in the control of phosphate-regulated genes of Escherichia coli. PMID- 8691746 TI - Phosphate transport in osteoclasts: a functional and immunochemical characterization. AB - Osteoclasts are polarized cells involved in bone resorption. They are exposed to high ambient concentrations of inorganic phosphate (Pi) during the active process of bone resorption. We hypothesize that osteoclasts may possess specific Pi transport system(s) for transcellular movement of Pi released from bone into the resorption cavity. We have previously reported the existence of a Na-dependent Pi cotransporter in the avian osteoclast, which provides a model culture system for the fully differentiated phenotype capable of bone resorption. In whole cell Pi uptake studies, the rate of Pi transport was sensitive to both ouabain and 2,4 DNP, an inhibitor of aerobic ATP production. When these osteoclasts were exposed to bone particles, there was an immediate stimulation of Pi transport, independent of de novo protein synthesis. The stimulatory effect of bone particles was inhibited by peptides with the Arg-Gly-Asp-Ser (RGDS) motif, an effect which implicates integrins and cell-matrix interaction in the regulation of Pi transport. We performed Western blots on both whole cell lysates and membrane fractions using a polyclonal antibody to the N-terminal of NaPi-2 (the rat variant) and found a single approximately 100 kDa protein; the non-immune serum was used as control. Immunofluorescence studies using the same N-terminal antibody to NaPi-2 detected the protein in discrete vesicles. There was an induction of the protein in membrane fractions isolated from osteoclasts cultured in the presence of bone particles. Our preliminary studies indicate that a Na-Pi cotransporter may exist in the avian osteoclast, immunologically related to the NaPi-2 family, and which may be regulated through integrin-mediated pathways in the presence of bone. We also hypothesize that there may be a redistribution of vesicular pools containing the Na-Pi cotransporter toward discrete plasma membrane sites on the polarized osteoclast for transcellular movement of Pi during active bone resorption. PMID- 8691747 TI - Characteristics and regulation of Pi transport in osteogenic cells for bone metabolism. AB - Inorganic phosphate (Pi) is an essential element in the development of osteogenic cells. The translocation of Pi from the systemic to the skeletal extracellular compartment appears to be an important function of osteoblastic cells. The plasma membrane of osteogenic cells is endowed with a sodium-dependent Pi transport system that is regulated by osteotropic factors such as parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP), insulin-like growth factor-1 (IGF-1), platelet-derived growth factor (PDGF) and fluoride. A similar Pi transport system has been recently identified in matrix vesicles derived from the plasma membrane of osteogenic cells, such as epiphyseal chondrocytes or osteoblastic cells. Matrix vesicles are extracellular structures which are considered to play an important role in endochondral and membranous calcification. Pi transport appears to be the driving force responsible for the accumulation of mineral inside the matrix vesicles and thereby can be considered as a pivotal determinant in the induction of the calcification process. Furthermore, modulation of the activity of the Pi transport at the level of the plasma membrane of osteogenic cells by osteotropic factors is transferred to the matrix vesicles derived from these cells. This notion implies that hormonal and other environmental factors, such as Pi itself and calcium, which have a direct impact on the Pi transport activity of osteogenic cells can also influence the capacity of the matrix vesicles to initiate the mineralization of the bone matrix. The cellular mechanisms involved in the regulation of Pi transport by osteotropic factors have been recently investigated. For the PTH/PTHrP regulatory effect, cAMP appears to be the main mediator and the response does not require the de novo synthesis of proteins. For the effects of IGF-1, PDGF and fluoride, tyrosine phosphorylation processes are involved and responses are dependent upon the de novo synthesis of proteins. The molecules responsible for activation of these signaling pathways are currently under investigation. Such an investigation may improve our understanding of the mechanisms underlying the differentiation processes of osteogenesis such as the calcification of the extracellular matrix. PMID- 8691748 TI - Renal Na/Pi-cotransporters. AB - Two non-homologous proximal tubular apical Na/Pi-cotransport systems (type I and type II) have been identified thus far by expression cloning. Subsequent studies provided evidence that the type II Na/Pi-cotransporter represents a target for the physiological and pathophysiological regulation of proximal reabsorption of phosphate. The exact role of the type I Na/Pi-cotransporter in proximal Pi reabsorption and eventually also in the renal handling of other substrates, such as organic anions, is currently less clear and needs further investigation. Evidence was obtained that acute changes of brush border membrane Na/Pi cotransport involves endo- and exocytic movement of type II Na/Pi-cotransporters. In particular, we elucidated if and how phosphorylation reactions are involved and defined the intracellular structures of the endo/exocytic apparatus involved. At the level of the gene it will be necessary to elucidate its organization in order to understand the mechanisms involved in chronic regulations of Na/Pi cotransport related to the type II Na/Pi-cotransporter. Furthermore, for structural investigations of these integral membrane proteins, they have to be isolated in sufficient quantities. Thus far the type II cotransporter (NaPi-2) has been expressed in Sf9 insect cells [20], which may eventually allow a purification of this protein. PMID- 8691749 TI - Electrophysiological insights of type I and II Na/Pi transporters. PMID- 8691750 TI - Simultaneous occlusion of Na+ and phosphate by the intestinal brush border membrane Na+/phosphate cotransporter. AB - The molecular mechanism of Na+ and phosphate transport by the intestinal brush border membrane Na+/phosphate cotransporter was examined using anion and cation exchange columns interfaced to a light-activated microsecond timer. The nature of ion:cotransporter interaction was examined for sensitivity to itself versus non substrates, and sensitivity to amino acid specific reagents. Two possible ion:cotransporter interactions were examined. (a) ion bound, where ion exchanges rapidly with medium ion but not non-substrates, and (b) ion occluded, where ion exchanges slowly with medium ion. The Na+/phosphate cotransporter was found to occlude Na+ or Na+ and H2PO4, but not H2PO4 alone or HPO4. Phosphate occlusion had an absolute requirement for Na+ with K+ or Cs+ unable to substitute. Phosphate occlusion distinguished between phosphate and sulfate. Deocclusion from the fully loaded cotransporter was consistent with the release of 2 Na+'s prior to phosphate. These results predict two ternary cotransporter conformations differing in the Na+ sensitivity of their phosphate affinity. PMID- 8691751 TI - Epithelial phosphate transport in ruminants, mechanisms and regulation. PMID- 8691752 TI - Modulation of renal Na-Pi cotransport by hormones acting via genomic mechanism and by metabolic factors. AB - The renal Na-Pi cotransport is subject to multiple regulatory inputs, such as endocrine, paracrine and intracrine. Among lipophilic, long-acting hormones that act via genomic mechanism, thyroid hormones, calcitriol, all-trans-retinoic acid stimulate, whereas glucocorticoids and estradiol inhibit the rate of Na-Pi cotransport across the brush border membrane of proximal tubules in vivo and/or across apical membrane of renal epithelial cells in vitro. Some findings suggest that these hormones may also influence Na-Pi cotransporter by modification of membrane microenvironment. It should be considered that Na-Pi cotransport can be modulated by lipophilic hormones by non-genomic signaling mechanisms such as sphingomyelin-ceramide pathway, NAD-cyclic ADP-ribose-Ca2+i pathway or by Ca2+ influx. Recent studies outline a basis for the putative intracrine signaling mechanisms that utilize Ca(2+)-releasing nucleotides, cyclic ADP-ribose, and nicotinic acid adenosine dinucleotide phosphate (NAADP), as novel second messengers for regulation of Na-Pi cotransport in response to changes of intermediary metabolic processes: gluconeogenesis, pentose phosphate pathway, polyamines and metabolism of fatty acids. PMID- 8691753 TI - [Longitudinal sternotomy--a method for the surgical option in pulmonary and hepatic echinococcosis]. AB - Emphasis is laid on the utilization of longitudinal sternotomy as an operative method of choice, practicable in echinococcosis with bilateral pulmonary location, eventually associated with liver involvement. Experience had with performing longitudinal sternotomy in some of the patients operated in the clinic of thoracic surgery of the Higher Medical Institute--Sofia and in other surgical units throughout the country, covering the period 1985 through 1990, is shared. A clinical case of interest concerning bilateral lung echinococcosis, partially complicated, and associated with hydatid disease of the liver, is described. A new and rational treatment tactics yielding a very good outcome is introduced, namely--single-stage longitudinal sternotomy with right-side frenotomy and echinococcotomy of the lung and liver cysts according to well-established surgical tenets, with ensuing plastic reconstruction of the disrupted right hemidiaphragm integrity and osteosynthesis of the sternum. PMID- 8691754 TI - [Plasmacytomas of the upper respiratory tract]. AB - Nine cases of plasmocytoma of the upper airways in the current biopsy material are studied over a three-year period (1991-1993). Initially, all nine cases are clinically diagnosed as neoplasms: hemangiofibroma--one, chondrosarcoma--one, suspected carcinoma--five, and unspecified diagnosis--two. "Plasmocytoma" diagnosis is made on the ground of histological investigation of the material, supported histochemically and electron-microscopically. Some diagnostic problems (differential diagnosis inclusive) are discussed, as well as issues relating to the clinical and morphological evolution of the disease, and predilected gender and age groups. PMID- 8691755 TI - [Endoscopic prosthesis in malignant stenoses of the esophagus and the cardioesophageal junction]. AB - The palliative treatment results in 41 patients presenting intractable malignant stenosis of the esophagus--carcinomas among which one carcinoid and three branchial carcinomas--following endoscopic implantation of a plastic prosthesis (tubus) are analyzed. It is stressed that it is a matter of a palliative method, promptly eliminating the nutritional passage impairment; in case of tracheoesophageal fistula is a method of choice, but leads to a comparatively high incidence of serious complications-perforations of the esophagus (7.3 per cent) all with lethal outcome. PMID- 8691756 TI - [Pneumatic balloon dilatation with a Rigiflex dilator in the treatment of patients with achalasia]. AB - In a clinical series including 32 patients with achalasia an assessment is done of the possibilities afforded by palliative management using the method of pneumatic balloon dilatation with Rigiflex dilatator. Emphasis is laid on the simplicity and efficacy of this endoscopic procedure, seldom giving rise to serious complications--one esophageal perforation only (3.1 per cent) out of the total of 32 patients treated over a 10-year period. Application of the method is recommended in all cases presenting achalasia, and more particularly in patients with achalasia I and II stage. PMID- 8691757 TI - [The endoscopic therapy of benign stenoses of the esophagus and cardioesophageal junction using Eder-Puestow instrumentation]. AB - The results of palliative endoscopic treatment by bougienage using Eder-Puestow instrumentation, performed in a limited contingent of patients presenting benign esophageal strictures, are analyzed. It is underscored that the method is readily carried out and effective, and seldom leads to noteworthy complications, such as esophageal perforations--one patient alone presenting cicatricial stricture out of the total of 42 cases given treatment with bougienage over a 10-year period. The commonest cause of benign strictures of the esophagus in the series being examined is reflux (peptic) esophagitis against the background of hiatus hernia. PMID- 8691758 TI - [The therapeutic approach in combined post-corrosive esophageal strictures]. PMID- 8691759 TI - [The diagnosis and treatment of breast cancer (from the experience of the Surgical Clinic of the District Hospital, Sofia)]. AB - Based on a survey of literature reports dealing with mammary gland cancer, the up to-date views on the problems related are highlighted. The different stages of the diagnostic and treatment process along with the prognostic trends are discussed. The experience with diagnosing and treating breast cancer, accumulated in the surgical clinic of the District Hospital-Sofia, is analyzed against the background of current concepts and trends along this line. The study covers a 7 year period (1986 through 1993) during which a total of 1,433 patients are treated--192 with benign conditions and 1,241 with malignant disease of the mammary gland; of the total 1,352 are subjected to operation. Emphasis is laid on the successful diagnostic activity in the mammology department of the hospital. The diverse types of operative interventions in breast cancer are discussed, with a special attention focused on organ-salvaging procedures. The postoperative results are evaluated in 359 cases subjected to follow-up study over a period ranging from 1 to 5 years. The clinical case material is discussed with a special reference to the indications for operative tactics, and combined radio-, chemo- and hormonotherapy, pointing out the probable underlying causes of post-operative relapses. The latter group includes patients operated on elsewhere also. The inferences reached summarize the author's views and recommendations concerning the diagnostic and therapeutic approach to mammary gland cancer. PMID- 8691760 TI - [The use of low-frequency ultrasound in surgical practice in thoracic surgery]. AB - To gain better insight into the intimate mechanisms of action of low-frequency ultrasound in surgical practice, and to establish the indications for its practical implementation in concrete cases, the preliminary results in patients operated in the clinic of thoracic surgery of the State Institute Hospital of Pulmonary Diseases "St. Sofia"--Higher Medical Institute, Sofia, are reported. For the purpose the Russian ultrasound apparatus URSK-7N-18 is successfully employed. Following a concise technical characterization of the URSK-7N-18 parameters of action, clinical cases are described where ultrasound treatment with the apparatus is successfully used for the purpose of prophylaxis against pulmonary carcinoma recurrences, and serious purulent complications (mediastinitis, pleural empyema, subphrenic abscess). The method of intraoperative ultrasound treatment with the apparatus does not imply special qualification of the surgeon. The only requirement is to secure gradual filling of the respective cavity with normal serum, simultaneously with the ultrasound treatment, effected from the cavity bottom to its borders over a 10-minute period. PMID- 8691761 TI - [Acute abdominal complications after thoracic-pulmonary operations]. AB - Serious abdominal complications occurring after chest and lung operations are discussed. The most common abdominal complications include acute dilatation of the stomach, paralytic ileus, gastrointestinal tract hemorrhage, as well as perforations of hollow abdominal organs. An interesting case presenting perforation of the small intestine after lung resection for pulmonary carcinoma is reported. The attention of surgeons is called to severe surgical complications, such as profuse hemorrhages from the gastrointestinal tract, and perforations of hollow abdominal organs, first and foremost. PMID- 8691762 TI - [Spontaneous perforation of the small intestine in primary lung carcinoma]. PMID- 8691763 TI - [The morphological characteristics of the changes in spontaneous pneumothorax. Thorascopic observation]. AB - The results obtained by thoracoscopy in 58 patients with spontaneous pneumothorax for the period 1990-1992 were discussed. The distribution of the patients by sex was: male--46 (79.31%); female--12 (20.69%). The mean age was 36.5 and the most patients was between 36-45 years (37.95%). The procedure was performed under local anesthesia with neuroleptanalgesia. Right localisation of the pneumothorax we found in 67.24% and left--in 32.76% of the cases. According to the degree of the collapse of the lung the distribution was: total pneumothorax--in 72.41% and partial pneumothorax--in 27.59% of the patients. Thoracoscopy in recidivist pneumothorax was performed in 18.5% from the followed up group of patients. The most often found causes for developing of spontaneous pneumothorax are: bullous emphysema--79.31%; pleural adhesions-in 15.52% and idiopathic pneumothorax--in 5.17%. PMID- 8691764 TI - [A case of osteogenic sarcoma of the breast]. PMID- 8691765 TI - [A rare case of traumatic rupture of the diaphragm]. PMID- 8691766 TI - [Our procedure with patients with spontaneous pneumothorax]. AB - Experience hitherto accumulated with the treatment of spontaneous hemopneumothorax (SHPT) is shared. The successful treatment of the condition is largely dependent on the promptly made diagnosis and hemorrhage control. Four patients are subjected to emergency thoracotomy, two are operated according to routinely planned surgery, and the remainder are treated by effecting closed pleural drainage following trocar thoracentesis. There are no postoperative complications, and postoperative lethality is nil. PMID- 8691767 TI - [5th Workshop on quantification and regulation of ocular perfusion. Ulm, January 27-28, 1995]. PMID- 8691768 TI - [Current views on pathogenesis, diagnosis and treatment of reflux esophagitis]. PMID- 8691769 TI - [New data on heliotropic dystrophy of the liver]. AB - The outbreak of heliotropic dystrophy (HD) in Khalton region of Tadzhikistan registered in 1992 caused 3096 cases. Of them 83 cases underwent thorough examination. Liver biopsy performed in the patients showed primarily vascular lesion rather than inflammation. This makes more logical to denote the above disorder as heliotropic hepatoangiopathy. Foci of bleeding in the liver manifested ultrasonically in the form of previously unobserved silent zones. Metabolism investigations discovered activation of lipid peroxidation, subnormal zinc and elevated copper concentrations in plasma. Nitrogenous metabolism was characterized by high levels of medium-size molecular peptides (markers of endogenous intoxication), oxyprolin, amino nitrogen and sialic acid, reduced urea formation. The serum contained increased quantities of low density lipoproteins, TH, low content of high density lipoproteins, cholesterol, PL indicating membranous impairment of endoplasmic network and disintegration of lipid-lipid and lipid-protein complexes on its surface. PMID- 8691770 TI - [Difficulties in diagnosis of thyrotoxicosis in internal medicine]. AB - Misdiagnosis of hyperthyroidism is explained first of all by errors in symptoms analysis, absence of ophthalmopathy, thyroid enlargement, predominant lesion of one system, atypical onset, various clinical masks (ischemic heart disease, active rheumatic fever with mitral and aortic defects, endogenic depression, obesity, gastrointestinal and hepatic diseases). PMID- 8691771 TI - [Kidney lesions in non-insulin dependent diabetes mellitus]. AB - Because little is known about disordered metabolism of uric acid as a pathogenetic mechanism of renal damage in non-insulin-dependent diabetes mellitus (NIDDM) it was studied in 75 NIDDM and 48 IDDM patients. Clinical examination of the patients included evaluation of purin metabolism according to serum uric acid, diurnal urine excretion, uric acid clearance. Hyperuricemia occurred more frequently in NIDDM. Positive correlation was observed between hyperuricosuria and the severity of diabetic nephropathy which was more pronounced in IDDM. PMID- 8691772 TI - [Visceral manifestations of Wilson-Konovalov disease (analysis of 22 cases)]. AB - Twenty-two patients with Wilson-Konovalov disease (WKD) had not only hepatic but also visceral symptoms: renal affection, cutaneous vasculitis, arthralgias, endocrine disorders, etc. In 8 of these 22 patients extrahepatic symptoms appeared 10 years before hepatic signs. The latter were distinguished by the frequency of edematic-ascitic syndrome, hemolytic episodes, hemorrhagic syndrome; low activity of serum aminotransferase. Initial neurological symptoms were registered in 6 patients only. 12 patients benefited from copper-eliminating therapy. 4 patients had advanced process which caused death. To detect WKD early, special diagnostic tests should be conducted in all subjects under 45 with hepatic symptoms or WKD-specific visceral manifestations. Examination of the patients' sibs is also desirable. PMID- 8691773 TI - [Diagnostic significance of erythrocyte carbohydrate metabolism indicators in chronic subclinical HBsAG carrier state]. AB - Erythrocytic activity of H-6-PDG and alpha-HPDG was studied in 32 chronic carriers of HBsAg free of any clinical or biochemical signs of viral hepatitis B. Puncture biopsy of the liver discovered chronic persistent hepatitis (CPH) in 25 patients. 7 cases had no changes of hepatic tissue. In these patients alpha-HPDG activity remained normal while in all the HBsAg carriers with latent CPH it was very high. For H-6-PDG, the activity was enhanced in 28 and 72% of HBsAg carriers, respectively. The above biochemical tests may serve markers of latent liver involvement in subclinical HBsAg carriers. PMID- 8691774 TI - [CNS lesions in generalized herpetic infection in adults]. PMID- 8691775 TI - [Action of drugs based on native DNA against RNA and DNA containing viruses]. PMID- 8691776 TI - [Pathogenesis of cerebral edema-swelling in bacterial meningoencephalitis]. AB - Nuclear-absorption spectrometry was used to measure concentration of some metals in cerebrospinal liquid (CSL) of 70 patients with bacterial meningoencephalitis and in different brain compartments of 10 dead patients. Estimation of the difference between dry and wet tissue mass provided the picture of watering for different brain parts. A correlation analysis demonstrated a quantitative relationship between metals and water in different brain compartments. Quantitative determination of CSL metals (potassium, sodium, magnesium, manganese, copper, zinc) enables diagnosis of brain swelling and prognosis of the inflammation outcome. PMID- 8691777 TI - [Rare and atypical manifestations of infectious endocarditis]. AB - Along with typical clinical symptoms in present-day infectious endocarditis atypical picture may arise: impairment of CNS and cardiac muscle with psychosis, arrhythmia, defective cerebral circulation, heart failure. In the absence of typical manifestations diagnosis of infectious endocarditis presents difficulties. PMID- 8691778 TI - [Thrombocytic vascular hemostasis in patients with infectious endocarditis]. PMID- 8691779 TI - [Isolated lymphadenopathy as manifestation of the early stage of Lyme borreliosis]. AB - The paper reports 4 cases of early Lyme borreliosis which presented as lymphadenopathy at the site of the tick bite. Erythema migrans and dissemination of infection were absent. The diagnosis was verified via diagnostic titer of antibodies to Borrelia. Administration of antibiotics at the stage of lymphadenopathy contributed to better prognosis. One patient did not receive antibacterial treatment in acute disease and had progression with infection dissemination. Regional lymphadenopathy may serve a clinical marker of early Lime borreliosis. PMID- 8691780 TI - [Use of alpha-tocopherol acetate and nicotinamide at the onset of insulin dependent diabetes mellitus]. PMID- 8691781 TI - [Treatment with thymogen and myelopid of patients with bronchial asthma]. AB - The authors studied the effect of alpha-tocopherol acetate and nicotinamide on lipid peroxidation and antioxidant enzyme defense (AED) in red cell membranes of 61 patients with new-onset insulin-dependent diabetes mellitus. Lipid peroxidation products were found in excessive quantities, whereas enzymes of the cell antioxidant defense were on the decrease. Combination of tocopherol with nicotinamide as adjuvants to conventional insulin therapy promoted normalization of lipid peroxidation and AED, improving beta-cell function. It is believed justified to introduce antioxidant treatment early in the disease onset to prevent toxic damage to beta-cells and vascular endothelium induced by lipid peroxidation products. PMID- 8691782 TI - [Effectiveness of mexitil-depot in patients with chronic ventricular arrhythmia]. AB - Bacterial bronchial asthma provokes development of secondary immunodeficiency. In addition to conventional treatment 90 asthmatics were given standard doses of timogen and myelopid alone and in combination. Routine clinical and immunological tests show that the above medication corrects immunodeficiency and advances the efficacy of the basic treatment. In combination, timogen and myelopid displayed the highest efficacy. PMID- 8691783 TI - [Experience in the use of ofloxacin in the prevention and treatment of wound infection in burns]. AB - Ofloxacin has been used for prevention and treatment of burn infection in 40 burnt subjects. Clinical response and microbiological efficacy reached 82.5 and 83%, respectively. The highest efficacy was observed in patients with burnt body surface area not more than 25%. The drug is recommended as a prophylactic modality in acute burn toxemia. PMID- 8691784 TI - [Extrahepatic syndromes (vascular manifestations) in patients HCV infection]. AB - The authors report 4 cases with hepatitis C infection running with vascular disorders: Raynaud syndrome (3 cases), mixed cryoglobulinemia (1 case), primary pulmonary hypertension (1 patient). Whether hepatitis C virus contributes to vascular disturbances is discussed and relevant literature is reviewed. PMID- 8691785 TI - [Plasmapheresis in the treatment of diphtheritic polyneuropathy]. PMID- 8691786 TI - [Familial vitamin D poisoning]. PMID- 8691787 TI - [Effectiveness of vermox in the treatment of helminthiasis]. PMID- 8691788 TI - [A case of diagnosis of Ewing's sarcoma in a patient with pseudotuberculosis]. PMID- 8691789 TI - [Traumatic anastomosis of the aorta and pulmonary artery]. PMID- 8691790 TI - [Teaching of laboratory diagnosis in the course of treatment]. PMID- 8691791 TI - [Computer screening in the determination of groups at risk for postvagotomy syndromes]. PMID- 8691792 TI - [Analysis of fatal outcomes in meningococcal infections]. PMID- 8691793 TI - [Character of surgical interventions in patients with stomach cancer in non oncologic institutions]. PMID- 8691794 TI - [Duodenogastric reflux in pathogenesis of peptic ulcer recurrence after conservative surgery with vagotomy]. PMID- 8691795 TI - [Diagnosis of chorea gravidarum]. PMID- 8691796 TI - [Clinical effectiveness of ciprofloxacin in a female patient with peptic ulcer associated with Helicobacter infection]. PMID- 8691797 TI - [Clinico-pathogenetic variants of chronic alcoholic gastritis]. PMID- 8691798 TI - [Indications for surgical treatment of patients with hiatal hernia]. PMID- 8691799 TI - [Creative longevity of scientist physicians]. PMID- 8691800 TI - [Humanism, charitable and patriotic activities of the community physician K. A. Zil'bernik]. PMID- 8691801 TI - [So-called functional diseases]. PMID- 8691802 TI - [Chronic viral hepatitis]. PMID- 8691803 TI - [Comments on the article by I. N. Sidel'nikov, G. S. Kovalskii and G. A. Sivoraksh, "Pulmonary edema in patients with hemorrhagic fever with renal syndrome"]. PMID- 8691804 TI - [Evolution in research on chronic bronchitis]. PMID- 8691805 TI - [From the job of guarding the patients to the nursing profession. I. From dependence to professionalism]. PMID- 8691806 TI - [Who will be the professionals of tomorrow?]. PMID- 8691807 TI - [Campaign: "living with cancer without pain". Why do you let me suffer?]. PMID- 8691808 TI - [Patient's joint control of diabetes. Puzzles that help to learn]. PMID- 8691810 TI - [Nobody remains untouched: laughter is contagious]. PMID- 8691809 TI - [With planned care against immobilizing behavior. Pathways out of learned helplessness]. PMID- 8691811 TI - [Prevention project EIGER. Health nurses care for frail elderly]. PMID- 8691812 TI - [Reply to "So the itch remains bearable" 10/95. Treatment of eczema--the Bernese version]. PMID- 8691813 TI - [To find a common language]. PMID- 8691814 TI - [In Lausanne the children meet the clown. Interview by Scarlet Huissoud]. PMID- 8691815 TI - Benefits from a teen pregnancy program: neonatal outcomes potential cost savings. AB - These data demonstrated that participants in our teen pregnancy program had better birth outcomes than comparable teens who did not participate in the program. Based on number of NICU admissions and lengths of stay, we estimate that this program provided, through the reduction of poor birth outcomes, potential cost savings of $890,000 over four years. PMID- 8691816 TI - Removal of a 130 pound ovarian neoplasm. PMID- 8691817 TI - The Kiva project. AB - The treatment program for patients involved in the Kiva Project was individualized. Growth was reinforced and regression was accepted as a natural part of the treatment process. Discharge was never discussed until the patient indicated readiness to leave the hospital and willingness to undertake a particular placement opportunity in the community. Rehospitalization, if it occurred was considered a part of the process and the staff continued to be supportive of the patient regardless of whether or not they remained in the Department of Mental Health system. As of March, 1993, 21 patients had been successfully discharged to the community. Eleven of these patients have been out of the hospital for more than a year, and three for as long as six years. In financial terms, this means a savings in the long-term institutional care of these patients as opposed to more cost-effective outpatient services. The Project currently serves 17 patients. It continues to be a viable treatment modality for the Division of Psychiatric Rehabilitation. PMID- 8691818 TI - Dr. William Harleston Huger: physician to the Charleston Orphan House, 1854-1906. PMID- 8691819 TI - Kiva: making a difference. PMID- 8691820 TI - 50 years ago. PMID- 8691821 TI - Alzheimer's disease and managed care: challenges and strategies. PMID- 8691822 TI - Prostate biopsies: optimized cancer detection and staging. PMID- 8691823 TI - Latex allergy: an emerging crisis in health care. AB - Concomitant with the increase in latex glove use in the mid 1980s, the spectrum and severity of latex-associated allergic reactions has become well recognized and the number of affected individuals has mushroomed. Reactions range from annoying rashes to life-threatening anaphylaxis but are none-the-less unpredictable. More and more workers are affected and claiming 100 percent disability and, while I am unaware of any cost analysis of this issue, with five percent of the health care field at risk, the costs will be staggering. Latex sources must be clearly identified and eliminated if possible. Similarly, at risk individuals must be identified, advised on prevention and be prepared for possible exposure. PMID- 8691824 TI - Euthanasia: a personal perspective. PMID- 8691825 TI - At the interface of cultures: multiethnic/multiracial high school and college students. AB - Data from 2 studies conducted in the United States--1 with high school students and 1 with college students--are reported. Two hundred forty-one multiethnic/multiracial youths (also termed biethnic/biracial, mixed ethnic/mixed racial, and interracial) were selected using 2 large surveys and compared with 1,041 of their monoethnic peers. Although more than 10% of the students across both studies were multiethnic, less than one third of these respondents labeled themselves as such. Ethnic self-labels varied with setting, type of question, and parental ethnicity. Multiethnic youths did not differ from monoethnics regarding self-esteem. In some cases, multiethnic students had more positive attitudes toward other groups than monoethnics did. PMID- 8691826 TI - Demographic differences in coping with uncertainty about the future. AB - Age, gender, and regional differences in the responses of a Dutch population to the Prediction of Future Events Scale (Tobacyk, Nagot, & Mitchell, 1989) were explored. The factor structure of the scale was found to be identical to that in the U.S. study of Tobacyk et al., although the latter study accounted for 40.6% of the variance, whereas the present study accounted for 63.1% of the variance. Only 3 of the 7 factors could be considered reliable. Age appeared to be an important factor; the younger groups had more confidence than the older groups did in all methods of predicting the future. The scores for the western part of the Netherlands were systematically and significantly lower than those of the other regions, for all scales, and the women's scores for methods of prediction involving psi were higher than those of the men. PMID- 8691827 TI - Predictors of health behavior from an behavior-analytic orientation. AB - The frequencies of American college students' positive self-talk, emotional reactions, and other positive thoughts for engaging in five health behaviors were assessed and found to be highly correlated; they then were combined into a composite measure. A similar composite resulted for negative self-talk, emotional reactions, and other negative thoughts for engaging in unhealthy alternative behaviors. Effortfulness and pleasantness of the health behaviors were also assessed. One or (in some cases) both composites, effortfulness, and pleasantness were substantially related to vigorous exercise, use of seat belts, and avoidance of alcoholic beverages. Mild exercise and avoidance of junk food were less well predicted. PMID- 8691828 TI - Collective identity and intergroup prejudice among Jewish and Arab students in the United States. AB - Relationships between indicators of collective identity (collective self-esteem, religious involvement, and involvement in ethnic organizations) and prejudice toward the other-group were examined in a sample of Jewish and Arab students in the United States. Contrary to expectations, collective identity variables were largely unrelated to prejudice among the Jewish students, although the Jewish students who expressed the least amount of anti-Arab sentiment were those who were the most religious. As expected, the Arab students who (a) had low public collective self-esteem and (b) were highly involved in religious and ethnic organizations tended to be the most prejudiced. The findings for Arab students, in particular, contradict findings obtained in the laboratory, using the minimal intergroup paradigm, and suggest that individuals who are highly involved in in group activities but believe their group is not viewed favorably by others may derogate the members of a salient out-group in an attempt to acquire a more positive social identity. PMID- 8691829 TI - The effects of audience laughter on men's and women's responses to humor. AB - Forty participants (20 men and 20 women) listened individually to a recording of a radio comedy show under one of two conditions: an experimental condition, with audience laughter present, or a control condition, with laughter absent. While the participants were listening to the tape, their spontaneous responses were covertly videotaped so that the frequency of laughter and smiling could be measured. After listening to the program, the participants rated the material for funniness and enjoyment. Those participants who listened with laughter present gave significantly higher ratings of the funniness and enjoyability of the recording. Moreover, they laughed and smiled more in the experimental condition, although the score for the difference in smiling failed to reach significance. In contrast with some published studies, no differences between men and women were found--a result that is attributed to the greater ecological validity of the context and to the stimuli used in the present study. PMID- 8691830 TI - Height and risk of suicide. PMID- 8691831 TI - Effect of sex role identity on academic achievement of late adolescents in India. PMID- 8691832 TI - Rape myth acceptance among Scottish and American students. PMID- 8691833 TI - The relationship between eating disorders and depression. PMID- 8691834 TI - Ovarian cancer--1996. PMID- 8691835 TI - Serum tumor markers in colorectal cancer staging, grading, and follow-up. AB - Early diagnosis of colorectal cancer, a frequent neoplasia in industrialized countries, permits curative surgery. In this study we assessed the clinical role of serum tumor markers determination in diagnosing, staging, and grading colorectal cancer; the role of carcinoembryonic antigen (CEA), CA 19-9, tissue polypeptide antigen (TPA) and CA 72-4 in colorectal cancer follow-up was also assessed. In 114 patients with colorectal cancer, the oncofetal antigen CEA was compared with the membrane-associated glycoproteins CA 19-9, CA 242, and CA 72-4 and with the cytokeratins TPA, tissue polypeptide-specific antigen (TPS) and tissue polypeptide monoclonal antigen (TPM). Overall, the most sensitive indices were TPA and TPS (67% and 70%, respectively). Tumor stage influenced the levels of CEA, CA 19-9, and TPA, but not those of TPS, while tumor grade influenced CEA and TPS, but not CA 72-4, TPA, and TPM. TPA was the most sensitive index in identifying early or well-differentiated colorectal cancers. The sensitivity was enhanced when this marker was determined in combination with CEA, in diagnosing both advanced and early colorectal tumors. Seventy-seven patients were followed up after therapy for at least 18 months. CEA was the most sensitive index of recurrence (58%); however, this sensitivity is too low to consider tumor markers useful in colorectal cancer follow-up. PMID- 8691836 TI - Occurrence of monocytoid B lymphocytes in lymph nodes of patients treated by chemotherapy. AB - Occurrence of monocytoi B lymphocytes (MBL) in the lymph nodes of patients receiving preoperative chemotherapy for cancer was examined and compared to lymph nodes in controls who had not received chemotherapy. Number of patients receiving and not receiving preoperative chemotherapy were 3 and 10 cases in ovarian cancer, 7 and 11 in testicular cancer, and 22 and 8 in lung cancer, respectively. Chemotherapeutic agents for ovarian, testicular, and lung cancer consisted of cisplatin, Adriamycin, and cyclophosphamide; cisplatin, vinblastine, and bleomycin; and cisplatin, vindesin, and mitomycin, respectively. MBL were defined morphologically as having abundant pale cytoplasm with distinct cell borders and small nucleus. Immunohistochemistry revealed a B-cell nature of these cells, i.e., CD20+ and/or MB-1+ together with negative reactivity for antibodies for T lymphocytes (CD43, CD45RO, OPD4) and macrophages (KP-1, PGM-1). Monocytoid cells in two cases showed a positive reactivity for CD43 together with CD20. The occurrence rate of MBL in patients with ovarian, lung, and testicular cancer receiving and not receiving chemotherapy was 67% (2/3) and 10% (1/10), 59% (13/22) and 75% (6/8), and 43% (3/7) and 9% (1/11), respectively. The occurrence rate in the total patients receiving chemotherapy (56%) was significantly higher than for those not receiving chemotherapy (28%) (P < 0.05). These findings suggest that chemotherapy-induced depressed immune function is causative for the occurrence of MBL in the lymph nodes. MBL might be found more frequently in nodes from patients who have received chemotherapy in certain settings. PMID- 8691837 TI - Endobronchial metastatic disease: analysis of 32 cases. AB - Endobronchial metastasis (EM) from nonpulmonary tumors is uncommon. A 9-year retrospective study at the University Hospital Vall d'Hebron (Barcelona, Spain) identified 32 patients with EM. All but four cases were diagnosed by fiberoptic bronchoscopy with bronchial biopsy. Primary tumors included the following types: breast cancer (20), colorectal cancer (3), melanoma (2), gastric cancer (1), neuroblastoma of the olfactory nerve (1), abdominal leiomyosarcoma (1), hypernephroma (1), endometrial carcinoma (1), papillary thyroid cancer (1), and hepatocarcinoma (1). Median age at diagnosis of EM was 58.7 years and median interval from the diagnosis of the primary tumor to the diagnosis of EM was 50.4 months. Seventeen patients (53%) had evidence of other metastatic sites at endobronchial relapse. The more common clinical manifestations included cough (37.5%), haemoptysis (28%), dyspnea (18.7%), and recurrent pulmonary infections (6.2%). Eight patients (25%) had no symptoms. There appears to be a predilection for metastatic involvement of the right and left upper lobe bronchus. Treatment was instituted in 20 patients, and their median survival was 11 months, in comparison with the 3 months found in 12 patients who received only palliative therapy because of advanced disseminated disease. Breast cancer is the most common tumor causing EM. The prognosis of patients with EM depends on the type of the primary tumor and the presence of other metastatic sites. Treatment must be individualized. PMID- 8691838 TI - Immunohistochemical staining for the p53 protein and proliferating cell nuclear antigen in familial clustering of gastric cancer. AB - Purpose of this study was to assess the role of p53 gene and tumor proliferating activity in familial clustering of gastric cancer. MATERIALS AND METHODS: Among 344 patients who underwent resections for gastric cancer, 10 patients had two or more gastric cancer-affected, first-degree relatives. We classified them as the group of gastric cancer with family history (FGC). Eighty-seven patients with gastric cancer who had no relatives with any malignant neoplasm were classified as the sporadic group. The paraffin-embedded specimens were stained immuno histochemically using monoclonal antibodies against the p53 product and proliferating cell nuclear antigen (PCNA). RESULTS: There was no significant difference in any clinicopathologic factor and the PCNA labeling index between the two groups. Staining for the p53 product was positive in 80% of the FGC group and in 38% of the sporadic group (P < 0.05). CONCLUSION: Our study suggests that overexpression of p53 protein is one of the familial factors that correlates with carcinogenesis in the stomach. PMID- 8691839 TI - Long-term benefits of aggressive treatment for primary colorectal cancer. AB - The long-term follow up of 128 colorectal cancer patients is reported. Seventy nine percent (101/128) of the patients had curative resections: 70 patients had radical lymphadenectomies with wide removal of tumor-adjacent nodes, and 31 patients had standard resections. The 5-year overall survival rates for Dukes' stage B and C patients and for all rectosigmoid cancer patients significantly favored radical resection (60% vs. 38%, 57% vs. 29%, respectively, P < 0.05). Tumor-free survival rates were also higher after radical lymphadenectomy but did not reach statistical significance. Eleven percent (14/128) of the patients required multiorgan resections, and/or preoperative radiation to render fixed cancers resectable, and these patients had a 10-year tumor-free survival rate of 45%, compared to zero % 5-year survival for the 27 patients who underwent palliative procedures (P < 0.01). These results confirm that many colorectal cancer patients will be cured with aggressive treatment and they support the need for a controlled trial for evaluation of lymphadenectomy for this disease. PMID- 8691840 TI - Preliminary results of phase I/II study of high-dose-rate intraoperative radiation therapy for pediatric tumors. AB - Ten children with locally advanced or recurrent tumors were treated on a Phase I/II study to assess the feasibility and toxicity of intraoperative radiotherapy (IORT) for primary and recurrent pediatric solid malignancies at high risk for local recurrence. Eligible patients include all primary and recurrent pediatric solid tumors that are amenable to resection and have residual microscopic or gross disease after surgery. In all cases, after a gross tumor resection was performed, a flexible, transparent, multichannel applicator was placed and secured within the tumor bed. Once the position of the applicator was optimized, the applicator catheters were attached to the cables of a high-dose-rate remote afterloader, and 1,200 cGy prescribed to 0.5-1.0 cm from the applicator was delivered to the tumor bed via the remote afterloader. One patient with a malignant teratoma developed a peri-rectal abscess 1 month after treatment; no other complications were noted. The 2-year actuarial local recurrence-free and distant metastases-free survival were 80% and 59%, respectively, with a median follow-up of 12 months (range: 3-18 months). The preliminary results suggest that high-dose-rate IORT is a safe and feasible modality for pediatric tumors at high risk for local recurrence. Longer follow-up will be needed to assess fully the toxicity and efficacy of this approach. PMID- 8691841 TI - Totally implanted device for long-term intravenous chemotherapy: experience in 123 adult patients with solid neoplasms. AB - Vascular access in patients receiving prolonged chemotherapy is a difficult problem. This led to the introduction of a totally implanted device. We intend to assess the efficacy of this device in a subset of oncologic patients. Between May 1989 and November 1992, 129 devices were placed in 123 adult patients with solid neoplasms. Most of the catheters were inserted by cut-down of the external jugular vein. Follow-up period ranged from 28 to 70 months. Early complications occurred in 4 of 129 implants, all in percutaneously inserted catheters. Infection was the most frequent late complication. By March 1995, 113 devices had been removed, 15 (13.3%) because of complications. Mean life of the explanted systems was 512 days. Totally implanted devices provide safe and efficient long term venous access. Implantation should be performed by experienced surgeons, by cut-down whenever possible. Infection is the most serious complication and may be prevented by careful management. PMID- 8691842 TI - P53 protein expression in pancreatic tumors and its relationship to clinicopathological factors and prognosis. AB - We examined the expression of p53 protein by immunohistochemical method in a series of pancreatic tumors and evaluated its relationships to the clinicopathological factors and prognosis. The study involved 108 cases of pancreatic tumors (79 ductal carcinomas, 1 acinar cell carcinoma, 14 endocrine tumors, 6 solid cystic tumors, 8 benign ductal tumors) and 8 chronic pancreatitides. Thirty-nine cases of pancreatic ductal carcinoma (49.4%) were positive for p53 protein. Analysis of the Cox hazards model identified p53 positivity and stage at the initial operation as an independent prognostic factor. Patients with p53 positive ductal carcinomas had a greater risk of death compared to p53 negative cases (P < 0.05). There was, however, no statistically significant correlation between p53 protein expression and other clinicopathological factors. Cases of stage III and IVb with positive p53 showed a bleak prognosis compared to p53 negative cases (P < 0.05). Our results suggest that p53 expression is common in invasive pancreatic ductal carcinomas and may have a prognostic value. PMID- 8691843 TI - Early carcinoma of the gallbladder: an elusive disease. AB - Prognosis of carcinoma of the gallbladder can be improved by diagnosing the disease in the early stages. Records of 14 patients with early (UICC AJCC TNM stages I and II) carcinoma of the gallbladder were analyzed. Clinical presentation in all these patients was like benign biliary disease. Ultrasonography could diagnose carcinoma of the gallbladder in only five patients; in the remaining nine patients, even the ultrasonographic diagnosis was benign biliary disease. All patients were operated; carcinoma of the gallbladder was diagnosed at operation in two more patients, but it was first detected only after histological examination in seven patients. All patients except four had associated gallstones. Preoperative diagnosis of early carcinoma of the gallbladder is difficult. The only way to diagnose early carcinoma of the gallbladder is by early surgical treatment of patients with clinical features of benign biliary disease. PMID- 8691844 TI - Characterization of F3II, a sarcomatoid mammary carcinoma cell line originated from a clonal subpopulation of a mouse adenocarcinoma. AB - We characterized a new mammary tumor cell line, F3II, previously established in vitro from a clonal subpopulation of the BALB/c transplantable mammary adenocarcinoma M3, moderately metastatic to lung. The F3II cell line has been passaged > 50 times. It has grown as elongated cells adherent to the bottom of the flask. Cytogenetic studies showed that F3II cultures were nearly triploid. Tumor cells expressed fibronectin and showed high levels of cell-surface urokinase, a key protease in invasion and metastasis. F3II cells grew as poorly differentiated, spindle-cell carcinoma tumors (sarcomatoid carcinomas) with a prominent local invasiveness, a high angiogenic response, and a 90-100% incidence of lung metastases when inoculated s.c. into syngeneic mice. Ultrastructural and immunocytochemical analysis revealed characteristic features of carcinomas. Our data suggest that F3II is less differentiated and more aggressive than the original tumor line, supporting the notion that mammary carcinomas are heterogeneous neoplasms and contain subpopulations with diverse biologic behavior. The F3II mouse mammary sarcomatoid carcinoma line is a suitable model to examine antiinvasive, antiangiogenic, and antimetastatic agents. PMID- 8691845 TI - A new guiding device for safer introduction of the blunt-ended stapler from the anus in low anterior anastomosis. PMID- 8691846 TI - Psychoactive constituents of the genus Sceletium N.E.Br. and other Mesembryanthemaceae: a review. AB - The use by the Khoisan of South Africa of Sceletium plants in psychoactive preparations has often been alluded to in the literature. However, much of it is fragmentary and contradictory. The current review reassembles the historical data recorded over a 300-year period, describes techniques for the preparation and use of "kougoed' from plants of Sceletium and documents the subjective experiences of a number of contemporary users. Apart from chewing the dried product, after "fermentation', there are reports of uses as tinctures for sedation and analgesia, chewing the material directly and smoking the residue after chewing. The symbolic connections of Sceletium with eland antelopes, the "trance animals' par excellence of the San hunter-gatherers is noted. Observations by Paterson (1789) and reports of contemporary users indicate a synergism and potentiation with smoked Cannabis. There is no evidence to support the view that "kougoed' or Sceletium alkaloids are hallucinogenic. The alkaloid distribution in Sceletium and other members of the family Mesembryanthemaceae are considered. Chemical studies have indicated as many as nine alkaloids in Sceletium which fall into three distinct structural categories. Mesembrine, the alkaloid first isolated and named is not the dominant constituent of plants and is weakly narcotic. Evidence is assembled to suggest that traditional and contemporary methods of preparation serve to reduce levels of potentially harmful oxalates, which are found in Sceletium and other Mesembryanthemaceae. It is concluded that there is a need for further pharmacological studies on these alkaloids, based on their narcotic anxiolytic properties, strong synergism with other psychomimetics, moderate toxicity and anti-cancer activity. PMID- 8691847 TI - The neuroprotective properties of the Ginkgo biloba leaf: a review of the possible relationship to platelet-activating factor (PAF). AB - Ginkgo biloba (Ginkgoaceae) is an ancient Chinese tree which has been cultivated and held sacred for its health-promoting properties. There is substantial experimental evidence to support the view that Ginkgo biloba extracts have neuroprotective properties under conditions such as hypoxia/ischemia, seizure activity and peripheral nerve damage. Research on the biochemical effects of Ginkgo biloba extracts is still at a very early stage. One of the components of Ginkgo biloba, ginkgolide B, is a potent platelet-activating factor (PAF) antagonist. Although the terpene fraction of Ginkgo biloba, which contains the ginkgolides, may contribute to the neuroprotective properties of the Ginkgo biloba leaf, it is also likely that the flavonoid fraction, containing free radical scavengers, is important in this respect. Taken together, the evidence suggests that Ginkgo biloba extracts are worthy of further investigation as potential neuroprotectant agents. PMID- 8691848 TI - Some ethnopharmacological notes on African hallucinogens. AB - This paper provides a short overview of ritual African hallucinogens. In addition to examples already listed by Schultes and Hofmann in their classic text books, Boophane disticha, Alchornea floribunda, Monadenium lugardae, Mostuea spp. and Voacanga bracteata are identified as African botanicals with proven or alleged hallucinogenic potential. PMID- 8691849 TI - The ethnopharmacopoeia of Rotuma. AB - The traditional Rotuman herbal pharmacopoeia consists of many plants, each of which is used in a specific way for specific disease states. The practitioners of traditional medicine are specialists recognized by the culture as having spiritual power to promote health. These individuals have been interviewed in order to determine which plants are presently in use. The healers interviewed represent a disappearing tradition which is not being passed on to the next generation. An effort has been made to record all of the plants used by all of the healers which remain in the Rotuman culture (on the island). This information is presented as a table of plant species and their respective indications. PMID- 8691850 TI - Drug leads from the Kallawaya herbalists of Bolivia. 1. Background, rationale, protocol and anti-HIV activity. AB - Aqueous, organic and alcoholic extracts of over 100 samples of 60 species of Kallawaya medicinal herbs representing 30 plant families were assayed to compare their toxicity and ability to protect MT-2 T-lymphoblastoid cells from the cytopathic effect of human immunodeficiency virus (HIV). The results are reported as a therapeutic index (TI) which was > 25 for eighteen species, including seven > 50 and one > 100. The anti-HIV activity resided primarily in the aqueous rather than in the organic extracts and was concentrated in plants used in ethnomedicine to treat lung and liver diseases. PMID- 8691851 TI - Antiamoebic activity of Piper longum fruits against Entamoeba histolytica in vitro and in vivo. AB - The fruits of Piper longum used in traditional remedies against intestinal distress have been tested for their efficacy against experimental caecal amoebiasis of rats. The ethanolic extract, hexane fraction, n-butanol soluble fraction exerted in vitro amoebicidal action at 1000 micrograms/mL and the chloroform fraction at 500 micrograms/mL. The ethanolic extract and piperine, a pure compound, from this plant material cured 90% and 40% of rats with caecal amoebiasis, respectively. PMID- 8691852 TI - Midterm results of the rotation-advancement flap method for correction of partial anomalous pulmonary venous drainage into the superior vena cava. AB - Since 1986, a rotation-advancement flap method has been used in 11 patients with partial anomalous pulmonary venous drainage into the superior vena cava. This method consists of atrial partitioning, enlargement of the superior vena cava, and protection of the sinus node. The midterm postoperative sinus node function and hemodynamic changes were examined in this study. Postoperative angiograms showed normal pulmonary venous pathway and no stenosis in the superior vena cava. Cardiac rhythm was normal and no clinical symptoms appeared. PMID- 8691853 TI - Preservation of endothelium-dependent vasodilation with low-potassium University of Wisconsin solution. AB - University of Wisconsin solution has provided excellent myocardial preservation. However, the high potassium content of the currently available University of Wisconsin solution has been implicated in coronary artery endothelial damage. We placed 16 neonatal (age 1 to 3 days) Duroc piglet hearts on an isolated nonworking perfusion circuit. Endothelium-dependent and endothelium-independent vasodilation were tested by measuring coronary blood flow after intracoronary infusion of bradykinin (10(-6) mol/L) and nitroprusside (10(-6) mol/L), respectively. In addition, nitric oxide levels were measured after bradykinin infusion. The hearts were then arrested blindly with either a modified University of Wisconsin solution (group 1; n = 8, K+ = 25 mEq/L) or standard University of Wisconsin solution (group 2; n = 8, K+ = 129 mEq/L) by infusion of cardioplegic solution every 20 minutes for a total of 2 hours. After bradykinin infusion, the mean coronary blood flow increased by 237.1% +/- 14.0% of baseline valves before arrest and by 232.8% +/- 16.0% after arrest in group 1 (p = not significant). As in the first group, the mean coronary blood flow in group 2 increased by 231.1% +/- 13.7% before arrest; however, the increase in mean coronary blood flow after arrest was significantly attenuated (163.3% +/- 12.8%, p < 0.01). The loss of endothelium-dependent coronary blood flow response in group 2 correlated with a decreased capacity to release nitric oxide after arrest (prearrest 8.25 +/- 2.30 nmol/min per gram versus postarrest -2.46 +/- 2.29 nmol/min per gram, p < 0.01). Endothelium-independent vasodilatory response revealed no significant difference between groups before and after arrest. These results suggest that the low potassium University of Wisconsin solution provides superior protection of the endothelium by preserving the endothelium-dependent vasodilatory response to nitric oxide release. PMID- 8691854 TI - Euro-Collins solution exacerbates lung injury in the setting of high-flow reperfusion. AB - Single-lung transplantation has been abandoned for the treatment of pulmonary hypertension by many centers because of overperfusion of the graft following implantation. Euro-Collins solution is currently used for lung preservation despite the vasoconstrictive effect of this intracellular-type solution. We hypothesized that high-flow reperfusion, alone or in combination with Euro Collins-induced vasoconstriction, may cause lung dysfunction. Twenty-eight New Zealand White rabbit lungs were harvested and studied in an isolated, blood perfused model of lung function after 4 hours of cold ischemia. Control lungs were preserved with 50 ml/kg cold saline solution flush and reperfused at either normal flow (60 ml/min) or high flow (120 ml/min). Experimental lungs were preserved with 50 ml/kg cold Euro-Collins solution and reperfused at normal or high flow rates. The arteriovenous oxygen gradient at the end of the 30-minute reperfusion period was significantly lower in the high-flow versus the low-flow experimental group (31.1 +/- 4.2 vs 130.6 +/- 41.6 mm Hg, p < 0.05). The pulmonary vascular resistance was increased in the high-flow groups and the experimental groups, with a statistically significant difference between low-flow experimental and control groups (64374.4 +/- 5722.6 vs 37041.5 +/- 2110.9 dynes x sec x cm(-5), p < 0.001). The percentage decrease in dynamic airway compliance in the high-flow experimental group was markedly different from that in the high flow control group (-51% +/- 13.3% vs -10.15% +/- 3.4%, p < 0.05). Similarly, the wet/dry ratio of the lungs in the high-flow experimental group (13.92 +/- 2.32) was significantly greater than that in the low-flow experimental group (6.27 +/- 0.19, p < 0.01) and than that in the high-flow control group (5.88 +/- 0.23, p < 0.001). These data demonstrate that high-flow reperfusion and preservation with Euro-Collins solution are deleterious to lung function, both individually and in combination, in an ex vivo rabbit lung model. Lung preservation with Euro-Collins solution may not be optimal when high-flow reperfusion is anticipated, as in the setting of unilateral lung transplantation for pulmonary hypertension. PMID- 8691855 TI - Pulmonary function and postoperative complications after wedge and flap reconstructions of the main bronchus. AB - Between 1980 and 1989, 8 wedge and 17 flap main bronchoplasties were done in 24 patients (4 carcinoid tumors, 4 benign lesions, 17 carcinomas). Bronchial anastomotic stenoses, pulmonary function, and survival were evaluated. Preoperative ventilation/perfusion scans with preoperative and postoperative spirometry were done in all patients except two who underwent a wedge bronchoplasty. Postoperative bronchoscopy was done in all patients. Follow-up was complete for the patients with carcinoma (N = 17). In the wedge group bronchial anastomotic stenoses occurred in three (38%) of eight patients. All three patients had serious postoperative complications (persistent atelectasis in one, prolonged ventilatory support in two); one patient died and the other two had impaired postoperative pulmonary function. Complete function recovery occurred in only three (38%) of eight patients who underwent wedge bronchoplasty. In the flap group, bronchostenosis occurred in 3 (18%) of 17 patients. The associated complications (mucus retention, minor atelectasis, partial lobar torsion) were mild. Complete pulmonary function recovery occurred in 13 (76%) of 17 patients who had flap bronchoplasty. Actuarial survival, for the patients with carcinoma, was 88%, 47%, and 41% after 1, 3, and 5 years, respectively. The local recurrence rate was 25% (4/16). In our series, flap main bronchoplasties were effective for the resection of bronchial tumors with local involvement of the adjacent main bronchus. Wedge main bronchoplasties, however, were associated with substantial postoperative complications. PMID- 8691856 TI - Esophageal tracheobronchoplasty for diseases of the central airway. AB - Three infants with congenital tracheal stenosis and three adults with various diseases of the central airway underwent esophageal tracheobronchoplasty to repair long-segment stenoses and defects. The primary operative goal was enlargement of the stenosis (n = 4), repair of the defect (n = 1), or both (n = 1). Cardiopulmonary support was required in two cases. All three infants were operated on for generalized congenital tracheal stenoses. There was one postoperative death on the fifth day. Another infant died of pneumonia 3 months after operation. Tracheal patency was excellent in two infants. One infant is well without symptoms 6 years after the operation, although balloon dilation was required three times during the first postoperative year. In the three adult patients, the primary diseases were congenital tracheal stenosis, iatrogenic injury associated with relapsing polychondritis, and malignant mediastinal tumor involving the trachea. All lesions involved both the trachea and main stem bronchi. Postoperative airway patency was excellent in all three adults, although expandable metallic stents had to be inserted in one patient. Postoperative pulmonary function was improved, particularly forced expiratory volume in 1 second and peak expiratory flow rate. Although the postoperative mortality rate was still high, especially among the infants, and prolonged postoperative ventilatory support was required for five of the six patients, long-term patency and postoperative pulmonary functional improvement are encouraging. PMID- 8691857 TI - Comparison of prevalence and resection rates in patients with esophageal squamous cell carcinoma and adenocarcinoma. AB - Since 1987 we have observed a predominance of adenocarcinoma in patients undergoing esophagectomy because of carcinoma at our institution. To discover whether this observation represented an actual change in the prevalence of adenocarcinoma, the Johns Hopkins Hospital pathology records were reviewed for the years 1959 to 1994. Overall, esophageal squamous cell carcinoma was the most common histologic type with 817 cases identified versus 284 cases of adenocarcinoma. The number of patients with squamous cell carcinoma rose slowly from 1959 to 1992 but since 1992 has decreased. Whereas adenocarcinoma was uncommon before 1978, its frequency has since increased markedly, exceeding that of squamous cell carcinoma in 1994. The number of patients with adenocarcinoma who underwent surgical resection has equaled or exceeded the number of those treated nonoperatively for all recorded years. Therefore the predominance of adenocarcinoma in patients undergoing esophageal resection for carcinoma appears to result from two factors: an overall increase in the prevalence of adenocarcinoma since 1978 and an increased likelihood of resection for patients with these tumors. PMID- 8691858 TI - Improved sternal fixation in the transsternal bilateral thoracotomy incision. AB - The success of bilateral sequential single-lung transplantation has led to the rebirth of the transsternal bilateral thoracotomy incision. Despite the multiple advantages of this incision over a median sternotomy for this operation, one distinct disadvantage is the high prevalence of sternal disruption at the transverse sternotomy site, which is traditionally closed with sternal wires. This disruption rate is between 20% and 40% in most institutions and can lead to significant pain and deformity in addition to slowing the postoperative recovery and increasing the risk of sternal infection. To overcome this problem we have designed and manufactured a device that provides a sound method of fixating the sternum. The device is composed of two plates, one anterior and one posterior to the sternum, that are fixed to each other and to the sternum by means of screws into internally threaded posts positioned in predrilled holes through the bone on either side of the sternotomy. All components of the device are made from titanium and a range of post lengths are available to accommodate variability in sternal thickness. The structure of the device is demonstrated. The device has now been inserted into a total of 20 patients after bilateral lung transplantation and the preliminary results suggest this is a superior technique for closure of a transverse sternotomy and support continued and routine use. PMID- 8691859 TI - Ten-year experience with surgical treatment of partial atrioventricular septal defect: risk factors in the early postoperative period. AB - Partial atrioventricular septal defects are electively repaired with good results. However, recent reports suggest that such repair is potentially a high risk surgical procedure. Our aim was to determine the risk factors of adverse outcome early after surgical treatment of atrioventricular septal defects in our hospital. A retrospective study was done in 100 consecutive patients from 2 months to 50.6 years old (median 3.6 years) who underwent surgical correction between January 1984 and December 1993. An intermediate form of the lesion was noted in 31% of cases. Congestive heart failure occurred in 50% of cases. Preoperative left atrioventricular valve incompetence (moderate to severe) was present in 63% of patients. Severe abnormalities of left subvalvular apparatus were noted in 28% of patients. The cleft of the left atrioventricular valve was closed in 76% of cases. The study was done to determine risk factors associated with hospital mortality (13%), postoperative residual left atrioventricular valve incompetence (23%), and early reoperation (14%) within the first 30 postoperative days. Univariate analysis showed that age at the date of operation and cleft closure were not related to an early adverse outcome. A stepwise logistic regression with variables selected by univariate analysis identified infections and severe abnormalities of left subvalvular apparatus as predictive factors of early death (odds ratio, 28.07 and 6.18, respectively), preoperative left atrioventricular valve regurgitation as a predictive factor of residual postoperative left atrioventricular valve regurgitation (odds ratio, 5.34), and severe abnormalities of left subvalvular apparatus as a predictive factor of early reoperation (odds ratio, 5.27). These results emphasize the importance of the severity of the morphologic features of the left subvalvular apparatus, the occurrence of early postoperative infections, and the presence of residual left atrioventricular valve regurgitation as risk factors in the early period after surgical correction of partial atrioventricular septal defects. PMID- 8691860 TI - The effect of preoperative methylprednisolone on pulmonary function and pain after lung operations. AB - Thirty-six patients undergoing elective thoracotomy with pulmonary resection with the use of combined epidural and general anesthesia were randomized into a double blind study to receive a single intravenous preoperative dose of methylprednisolone 25 mg/kg body weight or a placebo (saline solution). Postoperative pain relief consisted of epidural morphine 4 mg and paracetamol 1 gm three times a day for 4 days. Postoperative pulmonary function (peak expiratory flow rate, forced expiratory volume in first second, forced vital capacity) was evaluated on days 1, 2, 3, 4, and 7 and after 1 month. The value obtained after 1 month served as the control value. Pain score at rest and during cough was evaluated after 4 and 8 hours and on days 1, 2, 3, and 4. Pulmonary function was reduced after operation to the same degree in the steroid and placebo group: 42% versus 41% for forced expiratory volume in first second and 38% versus 39% for forced vital capacity, compared with control values after 1 month. Pain score was reduced in the steroid group after 4 hours and on day 1 during rest and after 4 and 8 hours and on day 2 during cough, compared with results in the placebo group (p < 0.05). In the steroid group three patients underwent reoperation because of leakage through the chest wall incision. In conclusion, administration of a single preoperative dose of methylprednisolone did not affect the postoperative reduction in pulmonary function after thoracotomy despite attenuated pain response, and the results do not warrant steroid administration before lung operation. PMID- 8691862 TI - Measurement of heparin concentration in whole blood with the Hepcon/HMS device does not agree with laboratory determination of plasma heparin concentration using a chromogenic substrate for activated factor X. AB - Measurement of circulating heparin concentration has been suggested to optimize anticoagulation during cardiopulmonary bypass. The Hepcon/HMS device (Medtronic HemoTec, Inc., Parker, Colo.) uses heparin/protamine titration to quantitatively determine heparin concentration. Extensive validation of this instrument is still lacking. METHODS: Agreement between heparin concentrations measured by the Hepcon/HMS system and by laboratory determination was evaluated in 16 patients undergoing cardiac operations. For laboratory determinations, plasma heparin concentration was derived from the measure of anti-Xa activity by means of chromogenic substrate technique. The Hepcon/HMS instrument and cartridges measured whole blood heparin concentration. Samples were analyzed 5 minutes after administration of heparin, 15 and 30 minutes after the start of cardiopulmonary bypass, 5 minutes after aortic unclamping, at the end of cardiopulmonary bypass, and after administration of protamine. Data were plotted and interpreted according to the method of Bland and Altman: First, a difference less than 1.4 U/ml (i.e., +/- 0.7 U/ml) was chosen as acceptable, because it would not cause major difficulties in clinical interpretation; second, the difference between the two measurement techniques was plotted against the mean of the two measures. RESULTS: The mean difference (bias) between heparin concentrations derived by the Hepcon/HMS device and those obtained by laboratory determination was as expected for measures performed on whole blood versus plasma (1.45 U/ml). Nevertheless, heparin concentrations derived by the Hepcon/HMS device may be as much as 2.76 U/ml above or 6.17 U/ml below the concentrations measured in the laboratory, differences well outside the predetermined limits of agreement and clearly unacceptable for clinical purposes. CONCLUSION: We conclude that heparin concentrations determined with the Hepcon/HMS instrument do not agree with laboratory determination of heparin concentration. Monitoring of heparin concentrations during bypass with the Hepcon/HMS device cannot be recommended. PMID- 8691861 TI - Resection of single brain metastasis in non-small-cell lung cancer: prognostic factors. AB - Combined resection of primary non-small-cell lung cancer and single brain metastasis is reportedly superior to other treatments in prolonging survival and disease-free interval. To identify prognostic factors that influenced survival we reviewed clinical records and follow-up data of 52 consecutive patients with non small-cell lung cancer and single brain metastasis who had been evaluated for combined lung and brain operation: 19 had synchronous and 33 metachronous non small-cell lung cancer and single brain metastasis. Seven patients were excluded from combined operation because of either early brain relapse after craniotomy or single brain metastasis localization in deep brain structures. Forty-one of the 45 patients who underwent combined operation had complete remission of neurologic symptoms. Actuarial 5-year survival from the second surgical intervention was 16% (median 19 months, range 1 to 104 months). N0 status and lobectomy were the only variables associated with longer survival. Actuarial 5-year survivals in patients with synchronous and metachronous presentation were 6.6% and 19%, respectively. In patients with metachronous presentation the length of survival was significantly associated with N0 status, lobectomy, and interval between lung and brain operation equal to or longer than 14.5 months. The subset of patients with N0 status and interval between operations longer than 14.5 months had a 61% 5 year survival. None of the patients with N1-2 disease and shorter interval between operations was alive at 20 months. These data indicate that prognostic factors may help to identify subsets of patients with markedly different outcomes after combined lung and brain operation. PMID- 8691863 TI - The routine use of fresh frozen plasma in operations with cardiopulmonary bypass is not justified. AB - BACKGROUND: The negative influence of cardiopulmonary bypass on hemostasis has been documented. Although abnormalities in platelet function are reported as the major cause of postoperative blood loss related to this hemostasis defect, fresh frozen plasma is often used in operations with cardiopulmonary bypass because it is thought to contribute to the reduction of postoperative bleeding complications. This study was designed to evaluate the effect of the administration of fresh frozen plasma after cardiopulmonary bypass on blood loss, transfusion requirements, and a number of coagulation parameters. METHODS: In a prospective, randomized, double-blind clinical trial 50 patients (mean age 63 years; 35 men/15 women) undergoing elective operation with cardiopulmonary bypass were randomly assigned to one of two groups: group I (n = 24) received 3 units of fresh frozen plasma after operation and group II (n = 26) received an equal amount of Gelofusine plasma substitute. At seven points before, during, and after operation hemoglobin concentration, hematocrit level, thrombocyte count, and coagulation parameters were analyzed. Study endpoints were the volume of blood loss and the transfusion requirement. RESULTS: There were no significant differences between the two study groups in blood loss, transfusion requirement, coagulation parameters, or thrombocyte counts. CONCLUSION: The routine use of fresh frozen plasma in operations with cardiopulmonary bypass cannot be recommended. PMID- 8691864 TI - Nitric oxide mediates fluid accumulation during cardiopulmonary bypass. AB - Fluid accumulation during cardiopulmonary bypass may be related to the production of endogenous vasoactive substances. We investigated the role of nitric oxide in mediating fluid accumulation during cardiopulmonary bypass. Normothermic cardiopulmonary bypass was carried out for 3 hours in male Sprague-Dawley rats with constant, nonpulsatile flow and hemodilution. Fluid accumulation (rate of change of external reservoir volume) was measured under three experimental conditions: saline solution control (n = 8), L-arginine infusion (n = 6), and N nitro-L-arginine methyl ester infusion (n = 6). At the end of the experiments, body weight and organ wet/dry ratios were examined. Percentage weight gain was 77% greater in the N-nitro-L-arginine methyl ester group and 23% less in the L arginine group compared with control values. Fluid accumulation was increased with N-nitro-L-arginine methyl ester after 30 minutes (p < 0.01) and reduced with L-arginine after 120 minutes (p < 0.01) compared with control animals. Water content was significantly decreased in the heart, lung, skin, muscle and peritoneum in rats receiving L-arginine. These data suggest that endogenous nitric oxide plays an important role in minimizing fluid accumulation during cardiopulmonary bypass. PMID- 8691866 TI - Median sternotomy for prolonged resuscitation in neonatal tetralogy of Fallot with absent pulmonary valve. PMID- 8691865 TI - Developmental differences in cytosolic calcium accumulation associated with surgically induced global ischemia: optimization of cardioplegic protection and mechanism of action. AB - OBJECTIVE: The effect of cardioplegic solutions with high concentrations of potassium or magnesium (or both) on cytosolic calcium accumulation was investigated with fura-2 in isolated perfused mature (n = 24) and aged (n = 24) rabbit hearts. METHODS: We compared cytosolic calcium accumulation before ischemia (control), during 30 minutes of ischemia and 30 minutes of reperfusion under global ischemia, or after treatment with potassium (20 mmol/L), magnesium (20 mmol/L), or both. RESULTS: Cytosolic calcium accumulation was increased during global ischemia in the mature heart (from 178.7 +/- 24.2 in the control group to 393.6 +/- 25.5 nmol/L; p < 0.005) and in the aged heart (from 187.4 +/- 18.7 in the control group to 501.0 +/- 46.1 nmol/L; p < 0.005). Potassium reduced cytosolic calcium accumulation during ischemia in both the mature and aged hearts (300.9 +/- 23.2 and 365.2 +/- 27.7 nmol/L, respectively; p < 0.05 vs global ischemia). Magnesium and potassium/magnesium completely controlled cytosolic calcium accumulation in the mature heart (198.7 +/- 27.5 nmol/L; p < 0.01 vs global ischemia and p < 0.05 vs potassium: 182.3 +/- 22.7 nmol/L; p < 0.05 vs global ischemia and potassium, respectively). Magnesium and potassium/magnesium attenuated cytosolic calcium accumulation in the aged heart (261.3 +/- 26.7, 262.3 +/- 25.2 nmol/L, respectively; p < 0.01 vs global ischemia). These changes in cytosolic calcium accumulation correlated with improved post-ischemic ventricular function. To investigate the mechanism(s) of magnesium-supplemented cardioplegic inhibition of cytosolic calcium accumulation, we performed parallel studies (n = 43) using nifedipine, ryanodine, and dimethylthiourea. Nifedipine with or without ryanodine reduced cytosolic calcium accumulation. Dimethylthiourea did not alter cytosolic calcium accumulation during global ischemia. Our results suggest that cytosolic calcium accumulation during global ischemia was mainly increased via the sarcolemmal 1-type calcium channel and the sarcoplasmic reticulum calcium-release channel. The modulating action of potassium/magnesium cardioplegia on cytosolic calcium accumulation during ischemia would appear to act through the inhibition of the myocardial 1-type calcium channel and the sarcoplasmic reticulum calcium-release channel. CONCLUSION: Senescent cardiac dysfunction correlates with increased ischemia induced cytosolic calcium accumulation. Magnesium-supplemented potassium cardioplegia ameliorates this age-related phenomenon at normothermia and may have important implications in myocardial protection in the elderly population. PMID- 8691867 TI - Severe left ventricular outflow tract obstruction despite sliding leaflet technique for repair of the mitral valve. PMID- 8691868 TI - Thoracoscopic release of tracheopexy stitch causing phrenic nerve paralysis in an infant. PMID- 8691869 TI - Cine computed tomography for evaluation of tumors invasive to the thoracic aorta: seven clinical experiences. PMID- 8691870 TI - Aprotinin use in patients with dialysis-dependent renal failure undergoing cardiac operations. PMID- 8691871 TI - Transatrial and transmitral approach for left ventricular myectomy and mitral valve plication for diffuse-type hypertrophic obstructive cardiomyopathy: a novel approach. PMID- 8691872 TI - A nonnarrowing technique for implantation of the Duran flexible ring. PMID- 8691873 TI - Intraoperative monitoring of pressure-volume loops of the left ventricle in pericardectomy for constrictive pericarditis. PMID- 8691874 TI - Transaortic video-assisted excision of a left ventricular papillary fibroelastoma. PMID- 8691875 TI - Cardioprotection by adenosine: is it a question of effective dose, timing, or the target compartment? PMID- 8691876 TI - Perfusion pressure and coronary bypass. PMID- 8691877 TI - Mitral valve repair. PMID- 8691878 TI - A simple switching technique from cardiopulmonary bypass to a long-term extracorporeal life support system. PMID- 8691879 TI - Aortic and aortic-mitral annular enlargement. PMID- 8691880 TI - Cardioprotective effects of ischemic preconditioning. PMID- 8691881 TI - Failure of devices used for closure of atrial septal defects: mechanisms and management. AB - Various devices for transcatheter ASD closure are undergoing clinical trials. Each new device claims advantages in terms of safety and efficacy over earlier devices. We report three cases in which a new investigational device--the Das angel wings--failed. Emergency operations were necessary for device retrieval and defect closure. The possible mechanisms of the event and the options in management are discussed with a review of literature on all devices. PMID- 8691882 TI - A new technique of arterial switch operation with in situ coronary reallocation for transposition of great arteries. AB - Coronary artery translocation is the most important step in achieving a successful result in arterial switch operations. Although a few centers have reported excellent results, coronary artery transfer requires a high technical expertise. We report a new technique of arterial switch operation without coronary translocation. By creating flaps in the proximal great arteries, the coronaries are transferred to the neoaorta without distortion of their original anatomic position. This technique avoids problems related to coronary translocation. Because coronary buttons are not excised, there is no need for nonviable material to be used in reconstruction of neopulmonary artery. Arterial wall is sutured to arterial wall, so postoperative bleeding is lessened. This technique can be used for any type of coronary anomaly and great arterial relationship. Coronary perfusion is well maintained. Two patients with transposition variants and ventricular septal defects have been operated on successfully with this technique. Postoperative investigations showed good coronary perfusion, without right or left ventricular outflow obstruction or leakage through the semilunar valves. This technique achieves anatomic correction for transposition of the great arteries, just as a conventional arterial switch operation does, but it avoids problems related to coronary artery translocation. We believe that it is a much simpler, more reliable, and more reproducible operation than others in current use, and it can be carried out by many cardiac surgeons with acceptable results. The early results are encouraging, although longer follow-up and more cases are essential. PMID- 8691883 TI - Short-term effect of monocuspid valves on pulmonary insufficiency and clinical outcome after surgical repair of tetralogy of Fallot. AB - In the surgical repair of tetralogy of Fallot, monocuspid valves are sometimes inserted within a transannular patch to prevent pulmonary insufficiency. To determine whether this monocuspid valve prevents short-term postoperative pulmonary insufficiency and improves clinical outcome, we reviewed clinical data and preoperative and postoperative echocardiographic variables from 61 patients who underwent one of three different procedures for repair of tetralogy of Fallot between August 1992 and March 1994. We compared features from 24 patients who had undergone transannular patch repair with a monocuspid valve (patch-valve) with those from 17 patients who had undergone patch repair without a monocuspid valve (patch) and 20 patients who had undergone repair without a transannular patch (no patch). We used the ratio of pulmonary valve insufficiency jet width to pulmonary artery diameter, as measured by color-flow Doppler flowmetry, as an index of severity of pulmonary insufficiency. Moderate to severe pulmonary insufficiency was arbitrarily defined as a ratio of at least 0.50. We found no significant differences in ratios among the patch-valve group (0.73 +/- 0.25, mean +/- standard deviation), the patch group (0.79 +/- 0.20), and the no patch group (0.59 +/- 0.23). The percentages of patients with moderate to severe pulmonary insufficiency did not differ among the three groups (patch-valve 80%, patch 90%, no patch 64%). Clinical data (including mortality, number of reoperations, intensive care unit and hospital lengths of stay, and postoperative hemodynamics) were similar in the three groups. We conclude that insertion of a monocuspid valve in repair of tetralogy of Fallot does not prevent short-term postoperative pulmonary insufficiency and does not improve immediate postoperative outcome for these patients. PMID- 8691884 TI - Predictors of low cardiac output syndrome after coronary artery bypass. AB - The purpose of this study was to identify patients at risk for the development of low cardiac output syndrome after coronary artery bypass. Low cardiac output syndrome was defined as the need for postoperative intraaortic balloon pump or inotropic support for longer than 30 minutes in the intensive care unit to maintain the systolic blood pressure greater than 90 mm Hg and the cardiac index greater than 2.2 L/min per square meter. The preoperative patient characteristics that were independent predictors of low cardiac output syndrome were identified among 4558 consecutive patients who underwent isolated coronary artery bypass at The Toronto Hospital between July 1, 1990, and December 31, 1993. The overall prevalence of low cardiac output syndrome was 9.1% (n = 412). The operative mortality rate was higher in patients in whom low cardiac output syndrome developed than in those in whom it did not develop (16.9% versus 0.9%, p < 0.001). Stepwise logistic regression analyses identified nine independent predictors of low output syndrome (percent frequency in parentheses) and calculated the factor-adjusted odds ratios associated with each predictor: (1) left ventricular ejection fraction less than 20% (27%, odds ratio 5.7); (2) repeat operation (25%, odds ratio 4.4); (3) emergency operation (27%, odds ratio 3.7); (4) female gender (16%, odds ratio 2.5); (5) diabetes (13%, odds ratio 1.6); (6) age older than 70 years (13%, odds ratio 1.5); (7) left main coronary artery stenosis (12%, odds ratio 1.4); (8) recent myocardial infarction (16%, odds ratio 1.4); and (9) triple-vessel disease (10%, odds ratio 1.3). Low cardiac output syndrome is a clinical outcome that may result from inadequate myocardial protection or perioperative ischemic injury. Patients at high risk for the development of low cardiac output syndrome should be the focus of trials of new techniques of myocardial protection to resuscitate the ischemic myocardium. PMID- 8691885 TI - Changing flow pattern of the internal thoracic artery undergoing coronary bypass grafting: continuous-wave Doppler assessment. AB - Surgeons have limited ability to evaluate intraoperatively the patency of internal thoracic artery graft as a bypass for coronary artery revascularization. We used continuous-wave Doppler ultrasonography to study the velocity of the internal thoracic artery before harvesting and after grafting (scanning probe, 8 MHz). Systolic and diastolic frequency shift (in kilohertz) and systolic frequency/diastolic frequency index were analyzed. Twenty four internal thoracic artery grafts in 15 patients were studied. Fourteen internal thoracic artery grafts were anastomosed to the left anterior descending artery, one to a diagonal artery, and nine to the circumflex artery. The mean systolic frequency before harvesting was 1.19 +/- 0.40 KHz and no significant differences were found between the right and the left internal thoracic artery (right, 1.17 +/- 0.37; left, 1.19 +/- 0.42 KHz). There was a 40% drop in systolic frequency related to the harvesting. Mean systolic frequency decreased after grafting (1.19 +/- 0.40 versus 0.87 +/- 0.32 KHz; p < 0.01) whereas mean diastolic frequency doubled (0.32 +/- 0.12 versus 0.83 +/- 0.4 KHz; p < 0.001) and mean diastolic frequency/systolic frequency index increased from 28% +/- 11% to 101% +/- 39% (p < 0.001), indicating an increased myocardial vascularization during diastole. No significant difference was found between grafted arteries (left anterior descending versus circumflex). All patients had an uneventful postoperative course and no perioperative myocardial infarction was reported. Doppler flow quantification of internal thoracic artery bypasses may give the surgeon an opportunity to evaluate intraoperatively the physiologic features and patency of the internal thoracic artery before and after coronary artery bypasses. PMID- 8691886 TI - Clinical experience with the CarboMedics valve: early results with a new bileaflet mechanical prosthesis. AB - Between January 1989 and August 1992, 612 CarboMedics mechanical prostheses (CarboMedics, Inc., Austin, Tex.) (295 mitral, 308 aortic, and 9 tricuspid) were implanted in 504 patients: 189 patients had isolated mitral valve replacement, 209 had isolated aortic valve replacement, and 106 had multiple valve replacement. The total follow-up was 1182 patient-years. The hospital mortality rate was 7.4% for mitral valve replacement, 5.3% for aortic valve replacement, and 13.2% for multiple valve replacement. Linearized rates for the different complications for mitral valve replacement, aortic valve replacement, and multiple valve replacement (in events per 100 patient-years) were, respectively, as follows: late mortality, 2.6 +/- 0.8, 1.5 +/- 0.5, and 3.9 +/- 1.3; thromboembolism [correction of thromboembolim], 3.7 +/- 0.9, 3.1 +/- 0.8, and 3.9 +/- 1.3; valve thrombosis, 0.5 +/- 0.3 for mitral valve replacement and 0.4 +/- 0.4 for multiple valve replacement; anticoagulant-related hemorrhage, 2.8 +/- 0.8, 1.9 +/- 0.6, and 2.6 +/- 1.1; nonstructural dysfunction, 1.6 +/- 0.6, 0.8 +/ 0.4, and 3.5 +/- 1.2; and reoperation, 1.1 +/- 0.5, 0.4 +/- 0.3, and 3.1 +/- 1.1. Actuarial estimates of freedom from the different complications for mitral valve replacement, aortic valve replacement, and multiple valve replacement (at 5 years of follow-up for mitral valve replacement and aortic valve replacement and 4.5 years for multiple valve replacement) were, respectively, as follows: overall death, 83% +/- 4%, 89% +/- 2%, and 76% +/- 4%; thromboembolism or valve thrombosis, 88% +/- 3%, 91% +/- 2%, and 86% +/- 5%; anticoagulant-related hemorrhage, 89% +/- 3%, 95% +/- 2%, and 90% +/- 5%; nonstructural dysfunction, 97% +/- 1%, 98% +/- 1%, and 91% +/- 3%; and reoperation, 96% +/- 2%, 99% +/- 1%, and 87% +/- 5%. There were no instances of prosthetic structural dysfunction. The performance of the CarboMedics valve is satisfactory at 5 years of follow-up but thromboembolic and hemorrhagic phenomena are still serious complications of mechanical prostheses. PMID- 8691887 TI - Different clinical outcome in coronary artery bypass with single and sequential vein grafts: a fifteen-year follow-up study. AB - OBJECTIVE: In trying to answer the question about the controversial use of sequential grafts, we determined the long-term clinical outcome of patients in whom coronary artery bypass was done with different types of vein grafts. METHODS: A total of 428 consecutive patients who underwent isolated coronary artery bypass with vein grafts between April 1, 1976, and April 1, 1977, were prospectively observed. In these patients three groups could be defined with single grafts only, sequential grafts only, and combined single and sequential grafts. Follow-up was 99.8% complete and averaged 15.4 years for the survivors. The Kaplan-Meier method and multivariate analysis done with the Cox regression model were used for survival, myocardial infarction, reintervention, and "any event." RESULTS: Perioperative mortality and perioperative myocardial infarction rate were not statistically different among the three groups. During follow-up more myocardial infarctions (hazard ratio: 2.06; 95% confidence interval: 1.08 to 3.93; p = 0.0293) or any events (hazard ratio: 1.54; 95% confidence interval; 1.01 to 2.36; p = 0.0450) occurred in patients with sequential grafts only than in patients with single grafts only. CONCLUSION: Although more complete revascularization was obtained in patients with sequential vein grafts only, more events during a 15-year follow-up occurred in these patients than in patients with single vein grafts only. PMID- 8691888 TI - External stenting reduces early medial and neointimal thickening in a pig model of arteriovenous bypass grafting. AB - The long-term clinical success of coronary artery bypass grafting with autologous saphenous vein is limited by progressive medial and neointimal thickening in the graft and superimposed atherosclerosis. We sought to reduce wall thickening by applying an external stent to experimental grafts in pigs. The diameter of the stent was designed to allow unrestricted initial expansion of the vein in response to arterial pressure and the stent material was highly porous so as to minimize adventitial [correction of advential] disruption. Four weeks after graft implantation, stented grafts had a larger lumen (11.2 +/- 6.2 [standard deviation] mm2 versus 7.6 +/- 3.4 mm2, p < 0.05, n = 9) and an almost fourfold thinner media (0.14 +/- 0.08 versus 0.49 +/- 0.22, p < 0.001) and neointima (0.10 +/- 0.07 versus 0.35 +/- 0.24, p < 0.001) than paired unstented grafts in the same animals. Cell proliferation was also greatly reduced by stenting in the neointimal and medial layers. The stenting procedure devised here is readily applicable to clinical coronary bypass grafts. PMID- 8691889 TI - Chronic hypoxia induces adaptive metabolic changes in neonatal myocardium. AB - The effect of chronic hypoxia on neonatal myocardial metabolism remains undefined. With a new neonatal piglet model, we determined changes in myocardial metabolism during global ischemia after chronic hypoxia. Five-day-old piglets (N = 30) were randomly assigned to two groups and exposed to an atmosphere of 8% oxygen or to room air for 28 days before they were killed. Left ventricular myocardium was then analyzed at control and at 15-minute intervals during 60 minutes of global normothermic ischemia to determine high-energy phosphate levels, glycogen stores, and lactate accumulation. Time to peak ischemic myocardial contracture was measured with intramyocardial needle-tipped Millar catheters as a marker of the onset of irreversible ischemic injury. Results showed an initially greater level of myocardial adenosine triphosphate in the hypoxic group (27 +/- 1.2 vs 19 +/- 1.8 micromol/gm dry wt, p = 0.001) and a delay in adenosine triphosphate depletion during 60 minutes of global ischemia compared with the control group. Initial energy charge ratios (1/2 adenosine diphosphate + adenosine triphosphate/adenosine monophosphate + adenosine diphosphate + adenosine triphosphate) were also greater in the hypoxic group (0.96 +/- 0.01 vs 0.81 +/- 0.04, p = 0.01) and remained so throughout global ischemia. Initial glycogen stores were greater in the hypoxic group (273 +/- 13.3 vs 215 +/- 14.7 micromol/gm dry weight, p = 0.02) when compared with the control group. Lactate levels in the hypoxic group were initially higher (19.1 +/- 6.4 vs 8.9 +/- 3.1 micromol/gm dry weight, p = 0.001) compared with control levels and remained elevated throughout 60 minutes of ischemia. Time to peak ischemic contracture was prolonged in the hypoxic group (69.5 +/- 1.8 vs 48.9 +/- 1.4 minutes, p = 0.001) compared with the controls group. These data show that chronic hypoxia results in significant myocardial metabolic adaptive changes, which in turn result in an improved tolerance to severe normothermic ischemia. These beneficial effects are associated with elevated baseline glycogen storage levels and an accelerated rate of anaerobic glycolysis during ischemia. PMID- 8691890 TI - Effects of inflation volume during lung preservation on pulmonary capillary permeability. AB - The degree of lung allograft inflation during harvest and storage may affect posttransplantation function. High volume ventilation causes pulmonary vascular injury and increased pulmonary capillary permeability. However, the effect of lung inflation on pulmonary capillary permeability after hypothermic flush and storage is unknown. The current study was designed to examine the effects of hyperinflation and hypoinflation during preservation on pulmonary vascular permeability. METHODS: An isolated, ex vivo rabbit lung gravimetric model without the confounding effects of reperfusion was used to determine post pulmonary capillary filtration coefficients (Kf). New Zealand White rabbits (2.75 to 3.15 kg) were intubated and lungs ventilated with room air (tidal volume 25 ml). After sternotomy and heparinization, the pulmonary artery was flushed with low potassium dextran-1% glucose solution (200 ml). The heart-lung block was then excised. Two studies were conducted. For measurement of changes in airway pressure and lung volume during preservation, lungs were inflated to one of four storage volumes (12, 25, 40, 55 ml) with room air, 100% O2, or 100% N2 and stored at 10 degrees C in a sealed container filled with saline solution. During preservation, lung volume and airway pressure were measured at 3, 6, 12 and 24 hours. In the Kf study, lungs were inflated with 100% O2, 50% O2 (with 50% N2), or room air and preserved. After 24 hours of preservation at 10 degrees C, the heart-lung block was suspended from a strain-gauge force transducer and the lungs were ventilated with room air. The pulmonary artery was connected to a reservoir of hetastarch solution (6% hetastarch with 0.9% saline solution). Lung weight gain, airway pressure, pulmonary artery pressure, and left atrial pressure were measured continuously. After a brief flush with hetastarch solution, the reservoir was then elevated to achieve 1.0 to 1.5 mm Hg increments in pulmonary artery pressure. RESULTS: The slope of subsequent steady-state lung weight gain was used to determine the Kf. The current study demonstrated the following: (1) changes in lung volume and airway pressure during storage increased with intraalveolar O2 concentration, (2) irrespective of inflation, fraction of inspired oxygen, hyperinflation during lung preservation increased the Kf in a volume-dependent fashion; (3) Kf was increased in lungs stored hypoinflated with room air; and (4) at any inflation volume, the Kf was significantly increased with 100% O2 inflation after 24 hours of preservation. CONCLUSION: These results suggest that storage at high lung volume or high inspired oxygen fraction increases pulmonary capillary permeability. PMID- 8691891 TI - Hyperinflation of canine lung allografts during storage increases reperfusion pulmonary edema. AB - The optimal state of inflation for lung allografts during preservation is not known. We previously showed that hyperinflation of canine lung allografts during storage improved posttransplant graft function as measured during 10 minutes of contralateral pulmonary artery occlusion. However, we have also shown that hyperinflation during storage increases pulmonary capillary permeability. It is possible that short-term total cardiac perfusion through the transplanted left lung (for assessment) may not adequately reproduce the clinical situation. The purpose of this study was to assess the effects of hyperinflation during storage in a canine left single-lung transplantation model in which all perfusion was continuously directed to the graft after implantation. Twenty canine left single lung transplants were done. The lungs of donor animals were ventilated at a tidal volume of 750 ml and an inspired oxygen fraction of 100%. Donor lungs were flushed with modified Euro-Collins solution and the trachea occluded at end inspiration. For donors in groups I and III, the trachea was sealed at that postinflation volume. In groups II and IV, 200 cc of air was withdrawn from the endotracheal tube under positive pressure and the trachea sealed at the lower tidal volume. Lungs were then extracted and stored at 1 degree C for 12 hours. After the preservation period, left lung transplants were performed. After implantation in all groups, the right pulmonary artery was ligated. In groups I and II, the right bronchus was ligated and in groups III and IV the right bronchus was kept open. Subsequent allograft gas exchange and hemodynamics were assessed during a 6-hour period of reperfusion. After assessment, both lungs were excised, wet/dry lung weight ratio was calculated, and histologic examination was done. During the 6-hour assessment, lungs stored in a state of hyperinflation (groups I and III) showed rapid deterioration of gas exchange. At the final assessment, arterial oxygen tension and alveolar-arterial oxygen gradient of groups I and III were significantly worse than those of groups II and IV (group I versus group II: arterial oxygen tension 87.5 +/- 15.0 versus 373.8 +/- 65.5 mm Hg, alveolar-arterial oxygen gradient 564.4 +/- 13.2 versus 298.6 +/- 69.3 mm Hg, p < 0.05; group III versus group IV: arterial oxygen tension 245.4 +/- 33.0 versus 543.6 +/- 41.8 mm Hg, alveolar-arterial oxygen gradient 392.5 +/- 35.6 versus 120.5 +/- 34.7 mm Hg, p < 0.01). We conclude that donor lung hyperinflation during storage does not provide better posttransplant allograft function when perfusion is limited only to the allograft. PMID- 8691892 TI - Hostility predicts restenosis after percutaneous transluminal coronary angioplasty. AB - OBJECTIVE: To investigate the "toxic" total (potential for) hostility component of the type A behavior pattern (assessed by means of the structured interview) as it relates to prediction of restenosis after percutaneous transluminal coronary angioplasty (PTCA). DESIGN: Patients with single vessel or multivessel coronary artery disease in whom PTCA had been scheduled or done were administered the structured interview by one trained interviewer prospectively or retrospectively (blinded to angiographic endpoints). MATERIAL AND METHODS: A total of 41 patients underwent 53 initial balloon dilations on native arteries by 1 of 5 participating cardiologists. Inclusion criteria for this study were a successful initial PTCA and post-PTCA recatheterization if a patient complained of ischemic symptoms possibly related to restenosis. RESULTS: Of the 41 patients, 15 (36.6%) had restenoses at a total of 18 previous angioplasty sites. Patients with high total (potential for) hostility ratings were almost 2.5 times more likely to have restenosis than those with low total (potential for) hostility scores (95% confidence interval = 1.03 to 5.32). Logistic regression revealed that total (potential for) hostility scores predicted post-PTCA restenosis overall as well as when adjusted for gender and race. Total (potential for) hostility scores were also positively associated with the number of arteries restenosed (P = 0.01). CONCLUSION: This is the first report of type A total (potential for) hostility behavior conferring an increased risk for restenosis after PTCA. Its modification may be effective in reducing recurrent cardiac events. A coronary-prone behavior modification program for patients with persistent, same-site restenosis after PTCA has been initiated. PMID- 8691893 TI - Ventricular remodeling after orthotopic cardiac transplantation. AB - OBJECTIVE: To determine quantitative changes in ventricular chamber volumes and left ventricular mass after orthotopic cardiac transplantation. MATERIAL AND METHODS: Right ventricular and left ventricular chamber volumes and left ventricular muscle mass were quantified by electron beam computed tomography in 10 patients at 1 month and 12 months after orthotopic cardiac transplantation. RESULTS: During the study period, the mean right ventricular end-diastolic volumes increased from 117 +/- 26.1 cc to 143 +/- 25.3 cc (P < 0.005), and the mean left ventricular end-diastolic volumes increased from 90 +/- 20.6 cc to 117 +/- 27.3 cc (P < 0.001). Left ventricular stroke volume increased from 63 +/- 16.5 cc at 1 month to 78 +/- 19.8 cc by 12 months (P < 0.005). These changes were associated with a concurrent reduction in global left ventricular muscle mass from 168 +/- 25.2 g to 145 +/- 16.3 g (P < 0.01). The left ventricular end diastolic volume/mass ratio, an index of wall tension, was abnormally low at 1 month but was in the normal range by 12 months (P < 0.0005). Both left ventricular and right ventricular ejection fractions were normal at all times and not significantly changed between the 1-month and 12-month studies. CONCLUSION: Significant right and left ventricular remodeling occurs between 1 month and 12 months after orthotopic cardiac transplantation, with progressive cavity dilatation but reduction in global left ventricular muscle mass. These adjustments, especially in the left ventricle, tend to reduce the volume/mass ratio by 1 year and are compatible with normalization of ventricular wall tension between the early and late scan dates. Routine clinical measurements of ejection fraction alone mask the almost parallel increases in stroke volume and end diastolic volume during the first 12 months after orthotopic cardiac transplantation. PMID- 8691894 TI - Changing referral patterns for surgical treatment of ulcerative colitis. AB - OBJECTIVE: To determine whether referral patterns for surgical treatment among patients with chronic ulcerative colitis have changed in recent years, especially in view of the introduction of a new operation, the ileal pouch-anal anastomosis (IPAA). MATERIAL AND METHODS: Between January 1976 and December 1986, 981 patients underwent proctocolectomy at Mayo Clinic Rochester. Brooke ileostomy (N = 300), colectomy with ileorectal anastomosis (N = 33), proctocolectomy with Kock pouch (N = 180), or ileal pouch-anal anastomosis (IPAA) (N = 468) was performed. The indications for surgical intervention were categorized as emergent or elective, the latter including intractability, cancer, and cancer prophylaxis. For analysis, the duration from diagnosis of disease to operation, indications for surgical treatment, and types of operation were subdivided into pre-IPAA era (before 1981) and post-IPAA era (from 1981 onward) for the entire group and for distant versus local patients. RESULTS: More continence-preserving operations were done in 1981 and thereafter (76%) than before 1981 (46%). In the later segment of the study period in comparison with before 1981, fewer operations were done for emergent reasons (4% versus 8%) and a greater percentage of operations were done for elective indications, especially intractability (74% versus 61%). With the advent of IPAA in 1981, patients underwent operation sooner after the diagnosis was made (7.4 years versus 8.6 years before 1981). A smaller proportion of patients underwent operation for cancer prophylaxis during 1981 through 1986 (19%), however, than before 1981 (28%). CONCLUSION: Referral patterns for surgical treatment of patients with ulcerative colitis have changed in recent years--patients are being referred for operation sooner, before complications develop that necessitate emergent procedures. Although the changed referral pattern may be due to the availability of IPAA, other factors may also have a role. PMID- 8691895 TI - Comparison of surgical treatment of ulcerative colitis associated with primary sclerosing cholangitis: ileal pouch-anal anastomosis versus Brooke ileostomy. AB - OBJECTIVE: To compare the operative risks, operative complications, and late outcome of two homogeneous groups of patients with chronic ulcerative colitis (CUC) and primary sclerosing cholangitis (PSC) who underwent either Brooke ileostomy or ileal pouch-anal anastomosis (IPAA). MATERIAL AND METHODS: Between 1970 and 1990, 72 patients with CUC and PSC underwent proctocolectomy with either Brooke ileostomy (group I; N = 32) or IPAA (group II; N = 40). Postoperative data included operative mortality, need for blood transfusion, general postoperative complications, liver-related complications, and proctocolectomy-related complications. RESULTS: Eight group I patients and nine group II patients had a total of 12 and 11 general complications, respectively. Liver-related complications were diagnosed in 16% and 10% of group I and group II patients, respectively. Proctocolectomy-specific complications occurred in 34% of group I and 20% of group II patients. The overall need for blood transfusion was 94% in group I and 47% in group II (P < 0.001). The cumulative probability of proctocolectomy-related complications at 5 years was 23% for group I and 64% for group II patients (P < 0.002). The difference, however, was primarily due to the high frequency of pouchitis after IPAA, estimated at 57% at 4 years. The cumulative 5-year risk of liver-related complications was 37% and 28% for group I and group II, respectively. Peristomal varices and bleeding occurred in eight group I patients but in none of group II. CONCLUSION: Because IPAA avoids bleeding problems, it is the surgical treatment of choice in patients with PSC and CUC. PMID- 8691896 TI - Effect of corrective rearfoot orthotic devices on ground reaction forces during ambulation. AB - OBJECTIVE: To determine the quantitative effects of a corrective rearfoot orthotic device on the vertical, anteroposterior, and mediolateral ground reaction forces (GRFs) during ambulation. DESIGN: We conducted a prospective, randomized, single-blinded study of 25 subjects during ambulation with and without a rearfoot orthotic device. MATERIAL AND METHODS: Thirteen men and 12 women were enrolled in the study; the inclusion criteria included asymptomatic pes planus (5 to 10 degrees of calcaneal eversion). Each subject walked across a standard force plate in 10 trials without an orthotic device. The force plate was used to quantify the effect of a semirigid functional rearfoot orthotic device on GRFs and the center of pressure versus a standard shoe with no device. The observer was blinded, trials were completed in random order, and the paired t test was used for statistical analysis. RESULTS: No evidence suggested the presence of a significant difference in mediolateral GRFs and in the center of pressure exerted at 10%, 20%, 50%, and 80% of stance phase with and without the orthotic device. Significant reductions were noted in vertical GRFs per newton of body weight exerted at 10% (P = 0.0009) and 20% (P = 0.0383) of stance phase and in anteroposterior GRFs exerted at 10% (P = 0.0009) and 50% (P = 0.0033) of stance phase when ambulation was compared with and without the orthotic device. CONCLUSION: These results indicate that a rearfoot orthotic device reduces vertical and anteroposterior GRFs in the early stages of the stance phase during the gait cycle. We found no evidence to suggest a significant difference at any of the percent stance phases when comparisons were made of mediolateral GRFs exerted with and without the orthotic device. These data are contrary to current hypotheses about use of orthotic devices, and further studies would be helpful to reproduce these findings and to determine whether these changes are related to clinical improvement in symptomatic pes planus. PMID- 8691897 TI - Pharmacologic treatment options for non-insulin-dependent diabetes mellitus. AB - Non-insulin-dependent diabetes mellitus (NIDDM) is a major health concern for clinicians who are responsible for the care of an aging population. The relationship between hyperglycemia and the chronic complications of retinopathy, nephropathy, and neuropathy has been established in patients with insulin dependent diabetes mellitus, and it is extremely likely that such a relationship exists in patients with NIDDM as well. Diet and exercise are the cornerstone for the management of NIDDM. The assessment of glycemic control should determine which patients with NIDDM need more aggressive intervention to control hyperglycemia. Pharmacologic treatment options include oral administration of the sulfonylureas, a biguanide, and an alpha-glucosidase inhibitor and subcutaneous administration of insulin. Extensive education about diabetes and self-monitoring of blood glucose levels are important components in maximizing glycemic control. Additional pharmacologic treatment options are necessary when adequate individualized treatment goals are not attained. The goal of therapy is to prevent the onset or progression of long-term microvascular and macrovascular complications. In this review, we present the therapeutic options and outline our approach to the pharmacologic treatment of NIDDM. Relevant medical literature on each treatment modality is reviewed, and the cost of therapy with use of each medication is provided. PMID- 8691898 TI - The role of endothelin in coronary atherosclerosis. AB - During the evolution of coronary atherosclerosis, growth factors, cytokines, and other molecules are involved in cell recruitment, migration, and proliferation. Endothelin is an endothelial-derived vasoconstrictor peptide that possesses mitogenic properties. In this review, current evidence is provided that suggests that endothelin fulfills proposed criteria to be considered an atherogenic peptide because of its mitogenic and proliferative properties, as well as its inter-actions with known atherogenic factors. In addition, a proposed role of endothelin in the evolution of atherosclerosis is outlined. PMID- 8691899 TI - Selection of antiepileptic drugs: a practical approach. AB - The selection of antiepileptic drugs (AEDs) is increasingly more complex as new agents become available. We discuss an individualized approach to selection of an AED that is tailored to each patient's needs by considering the following six factors: effectiveness of the drug in controlling seizures, adverse effects profile, pharmacokinetic properties, special or unique patient situations, drug interactions, and cost of treatment. When these factors are considered, treatment complications and failure can be minimized by anticipating incompatibilities among drugs or between the drugs and the patient's condition. We emphasize the concept that the best AED therapy is dependent on optimal seizure control and absence of unacceptable side effects. In the current environment of medical practice, the cost of treatment has also become a major concern. With rare exceptions, no single factor dictates the choice of an AED. In the long term, the most cost-effective treatment will be the one that provides the most therapeutic benefit with the fewest complications and maximal patient satisfaction. PMID- 8691900 TI - Generalized convulsive status epilepticus. AB - Generalized convulsive status epilepticus (GCSE) is a medical emergency that may be associated with severe neuronal injury. The mortality attributable to GCSE ranges from 3 to 35%. The disorder occurs most frequently in the young and the old extremes of the population. GCSE commonly occurs in patients with no history of seizures or epilepsy. The morbidity associated with status epilepticus is related to the underlying precipitating factors, age of the patient, and duration of seizure activity. Morbidity and mortality are highest in elderly patients and those with acute symptomatic seizures--for example, GCSE related to anoxia or cerebral infarction. Mortality is lowest among pediatric patients and patients with unprovoked seizures or GCSE related to low antiepileptic drug levels. Intravenously administered diazepam or lorazepam and phenytoin remain the first line therapy for GCSE. More than half the patients will respond to initial treatment. Patients with refractory status epilepticus require a physician with expertise in epilepsy. Treatment options include pentobarbital, high-dose phenobarbital, or inhalation anesthetic agents. PMID- 8691901 TI - Thoracic duct-cutaneous fistula in a patient with cirrhosis of the liver: successful treatment with a transjugular intrahepatic portosystemic shunt. AB - Patients with cirrhosis of the liver have increased hepatic and gastrointestinal lymph flow that may contribute to the formation of ascites and pleural effusions. Increased lymph flow, which is due to postsinusoidal portal hypertension, causes a high rate of flow through the thoracic duct. Because of the high flow rates, disrupted lymphatic vessels in patients with cirrhosis of the liver may fail to close, a situation that results in chylous ascites, pleural effusions, or chylous fistulas. Chylous fistulas deplete proteins, fluid, and lymphocytes and thus lead to volume depletion and coagulopathy. Herein we describe an unusual case in which a high-output traumatic thoracic duct-cutaneous fistula developed in a patient with cirrhosis and led to volume depletion and coagulopathy. Correction of the portal hypertension with placement of a transjugular intrahepatic portosystemic shunt led to closure of the fistula and normalization of accompanying metabolic abnormalities. PMID- 8691902 TI - Psychogenic coma after use of general anesthesia for ethmoidectomy. AB - Failure of a patient to awaken promptly after use of general anesthesia may be due to various causes, including medication-related effects, neurologic insults, or metabolic disturbances. Herein we describe a 49-year-old woman with a history of depression, for which she was receiving treatment, who did not awaken promptly after use of general anesthesia for ethmoidectomy. Results of neurologic examinations were normal, as were laboratory tests and radiologic studies. Six hours after completion of the operation, the patient spontaneously awakened. We hypothesize that she underwent a transient, self-limited period of dissociation related to unresolved grief due to the recent death of a family member. PMID- 8691904 TI - 60-year-old man with respiratory distress and confusion. PMID- 8691903 TI - Glucose modulation of ischemic brain injury: review and clinical recommendations. AB - Ischemic brain injury is the third-leading cause of death among Americans and the leading cause of serious disability. Based on studies of animal models, a substantial amount of experimental evidence shows that hyperglycemia at the onset of brain ischemia worsens postischemic neurologic outcome. Consistent with these observations, hyperglycemia also is associated with a worsening of postischemic brain injury in humans. In humans, however, data are often difficult to interpret because of problems in determining the timing of hyperglycemia relative to a critical ischemic event and in elucidating the effect of coexisting pathophysiologic processes (for example, a stress response) on outcome. Glucose modulation of neurologic injury is observed when ischemia is either global (for example, that accompanying cardiac arrest or severe systemic hypotension) or focal (for example, that accompanying thrombotic or embolic stroke). Toxicity is probably the result of an intracellular lactic acidosis. Specifically, the associated hydrogen ions are injurious to neurons and glia. On the basis of these factors, we recommend diligent monitoring of blood glucose concentrations in patients who are at increased risk for new-onset, ongoing, or recurring cerebral ischemia. In such patients, the use of fluid infusions, corticosteroid drugs, and insulin, as well as stress management, should be tailored to treat preexisting hyperglycemia and prevent new-onset hyperglycemia. Maintenance of normoglycemia is recommended. When one attempts to treat preexisting hyperglycemia, care should be taken to avoid rapid fluid shifts, electrolyte abnormalities, and hypoglycemia, all of which can be detrimental to the brain. PMID- 8691905 TI - Identification and treatment of psychosocial risk factors for coronary artery disease. PMID- 8691906 TI - Recommendations of the American Academy of Neurology for Evaluation of Dementia. PMID- 8691907 TI - Patient-doctor communication in cross-national perspective. A study in Mexico. AB - The authors assessed the cross-national replicability previously used to study medical encounters in the United States by adapting them to Mexico. The main research questions focused on information-giving, gender and social class differences in communication, and attention to socioemotional concerns in primary encounters. Sixty-two primary care encounters were audiotaped. Questionnaires were translated into Spanish, then translated back into English. Coding and transcription techniques were taught to Spanish-speaking researchers. Measures of communication were treated as dependent variables and were related by nonparametric statistical analyses to characteristics of physicians, patients, and clinical settings. Doctors in Mexico spent an average of 2.1 minutes (+/- 1.7 standard deviation [SD]), or 16.7% (+/- 10.7 SD) of total interaction time, in information-giving. Mexican doctors asked an average of 27.3 questions per encounter (+/- 18.0 SD), whereas patients asked an average of 1.5 questions (+/- 2.0 SD). Substantial interphysician variability was observed in total time of interaction (Kruskal-Wallis analysis of variance, chi-square = 27.2, P = 0.000), physician time in information giving (chi-square = 16.4, P = 0.022), and physician questions (chi-square = 36.7, P = 0.000). Patient characteristics associated with physician information-giving included male gender (chi-square = 4.1, P = 0.04) and age (Kendall's tau-b = .17, P = 0.05) but not education (tau-b = .08, P = 0.41). Information-giving in public clinics did not differ from that in private practices (chi-square = 0.0, P = 0.91). A bootstrap approach to multiple nonlinear regression permitted additional analysis of physicians', patients', and situational characteristics in explaining measures of patient doctor communication; this analysis further demonstrated the importance of interphysician variability in communicative behavior. Previous methods for studying patient-doctor communication can be adapted and replicated in a non English-speaking society. With certain exceptions, findings from Mexico were similar to those obtained in the United States. PMID- 8691908 TI - [The handicaps and the need for services among the aged detected in the health survey OARS-Vigo]. AB - BACKGROUND: In populational studies the standardized questionnaires of multidimensional functional evaluation, particularly the Older Americans Resources and Services Program-Multidimensional Functional Assessment Questionnaire (OARS), have shown to be the most adequate tools to evaluate the elderly persons living within the community. METHODS: A health care survey was performed by personal interview in the homes of a stratified randomized sample of people over the age of 65 years in Vigo, Galicia, Spain obtained from the Municipal Inhabitants Patronage (n = 841) using complete validated versions of OARS in the Spanish and Gallician languages. RESULTS: The prevalence of severe/absolute handicap in the basic functional areas among this population over 65 years was 7.7% in physical health, 6.2% in mental health, 5.2% in economic resources, 6.7% in social work, and 9.5% in daily life activities (DLA). Twenty two percent of the population presented severe/absolute handicaps in at least one of the dimensions. One point nine percent of the population studied required institutionalization: 2.6% required economic aid, 1.4% required home help for the instrumental DLA and 1.1% required help for both the basic and the instrumental DLA although these were not being provided. One point three percent were found to be ideal candidates for a telealarm/teleaid program. CONCLUSIONS: The use of the OARS questionnaire in Spain is useful to obtain information to be applied in the planning of health care services directed at elderly people. PMID- 8691909 TI - [DTP vaccine and infant sudden death syndrome. Meta-analysis]. AB - BACKGROUND: At the beginning of 1994, five cases of sudden infant death syndrome after DTP immunization appeared in Spain. In order to study a causal relationship a meta-analysis of the different studies that assess this possibility has been conducted. METHODS: The selection criteria was epidemiological study, case control or cohort, assessing risk of sudden infant death syndrome in immunized versus non-immunized infants or risk of sudden infant death syndrome in recently immunized infants versus immunized infants beyond 30 days. Pooled risk ratios were calculated from adjusted risk ratios, when available, of the different studies, by a meta-analysis according the method described by Greenland. RESULTS: One cohort and four case-control studies were selected. Pooled risk ratio for immunized versus non-immunized infants was 0.67 (95% CI = 0.60-0.75). When comparing risk of sudden death syndrome in up to 30 days immunized infants versus more than 30 days immunized infants, the pooled risk ratio was 1.00 (95% CI = 0.84-1.20). CONCLUSIONS: DTP-immunization does not seem to increase the risk of sudden infant death syndrome. The risk of sudden infant death syndrome is not greater in the first thirty days following immunization. These data indicate a lack of association between DTP immunization and sudden infant death syndrome. PMID- 8691911 TI - [Aquaporins: membrane protein water channels]. PMID- 8691910 TI - [Pneumology residents trained in Catalonia (1989-1993)]. AB - BACKGROUND: The aim of this study was to analyze the outcome of the latest groups of pneumologists trained in hospitals in Catalonia, Spain, and to compare these results with international estimate rates on the need for pneumologists. METHODS: Information was collected by a self-administered closed response questionnaire which was filled out during the first trimester of 1994 by the pneumologists trained in hospitals in Catalonia from 1989 to 1993. RESULTS: One hundred percent response to the questionnaire was achieved (48 pneumologists). The first job following completion of resident training period consisted in being grant holders in the same department in 27 cases (56%), 15 (31%) received a contract as pneumologists, 2 (4%) as non-pneumologists physicians and 4 (8%) became unemployed. When the periods of 1989-1990 and 1992-1993 were compared, in the latter only 2/26 pneumologists directly obtained a contract on termination of training versus 13/22 from the former period (p < 0.0003). Half of the new pneumologists (24/48) performed other complementary labor activities, the most frequent being the work in medical emergency areas. CONCLUSIONS. Despite the importance of the respiratory diseases in health care, there is an increase in the number of pneumologists with difficulties in working in his specialty. This situation shows the need for searching for secondary professional activities. This fact, together with the scarce of promotion of specialized medical care, may enhance the risk of health care quality in respiratory diseases not improving to the desired level. PMID- 8691912 TI - [Cancer and AIDS: an odd couple]. PMID- 8691913 TI - [Bronchogenic carcinoma in patients with human immunodeficiency virus infection]. AB - The diagnosis of bronchogenic carcinoma (BC) in patients with HIV infection is infrequent. Five cases are described and the existing references reviewed. The incidence, risk factors, clinical manifestations, histology, age of onset, diagnosis and survival in HIV positive patients with BC were analyzed. The clinical histories of 2,586 patients with HIV infection seen in the authors' center were reviewed. Five cases in whom BC was detected were found. Sixty-nine cases published in the international literature were collected in a reference search by the MEDLINE system between 1982-1994. The patients with BC and HIV infection have an early age of presentation (mean age: 42 years) and a lower survival with respect to those without infection. No differences were observed with regard to the smoking habit, procedures for achieving diagnosis or clinical manifestation. The predominant histologic subtype was adenocarcinoma. A higher incidence of BC was observed in patients with HIV infection with respect to the control groups on elimination of the bias for age and risk factors for BC. Given its low incidence, BC should be considered in the differential diagnosis of pulmonary disease in patients with HIV infection in cases presenting a history of smoking, once the most common opportunistic infections have been discarded. PMID- 8691914 TI - [Drug surveillance within the pharmaceutical industry: present and future]. PMID- 8691915 TI - [Dyspnea, cough and interstitial radiological changes in an 18-year-old woman]. PMID- 8691916 TI - [The cost of antihypertensive drug combinations]. PMID- 8691917 TI - [Autoimmune hemolytic anemia associated with Castleman's disease. Response of both diseases to glucocorticoid treatment]. PMID- 8691918 TI - [Sabbatical leave: vacation or work?]. PMID- 8691919 TI - [Coexistence of cholesterol tophi and calcium pyrophosphate deposit disease]. PMID- 8691920 TI - [The dawn of therapy of meningococcal disease]. PMID- 8691921 TI - Emergent management of acute asthma. AB - In almost no other field is the gap between diagnostic and therapeutic knowledge and its general application so great as it is in asthma. As previously mentioned, most asthma deaths are preventable. Identification of high-risk patients, intensive education about asthma (purpose of each medication; necessity of compliance, particularly with inhaled corticosteroids; proper use of inhalers and spacer devices; home use of PEFR meter), self-treatment of mild or moderate attacks with oral corticosteroids, and written crisis plan for severe attacks explicitly telling the patient what to do and whom to call are necessary. In addition, all potential exacerating factors should be eliminated (external triggers, medication, gastroesophageal reflux, allergic rhinitis, and sinusitis). High doses of inhaled corticosteroids should be provided to all those patients, and referral to a specialist is highly recommended for such high-risk patients. PMID- 8691922 TI - HIV: a war still to be won. PMID- 8691923 TI - Final height of short normal children treated with growth hormone. AB - BACKGROUND: Short-term studies have demonstrated acceleration of growth rate following administration of biosynthetic human growth hormone (r-hGH) to short normal children. We describe the effect of such treatment on final height. METHODS: This was an open study of consecutive referrals to a growth disorder clinic from which 16 short children (height standard deviation score [SDS] -2.17 [range -1.8 to -3.3]; height velocity SDS -0.44 [0.33]; peak serum GH response to stimulation 27.9 mU/L [9.2] were treated with r-hGH, and 7 short children who declined treatment (height SDS -2.34 [0.61]; height velocity SDS -0.36 [0.28]; peak serum GH response 28.2 mU/L [6.8]) acted as an observation group. Subcutaneous r-hGH dose ranged between 12.2 and 21.0 U/m2 per week (0.02-0.04 mg/kg per day) for the first 2 years of treatment and 20 U/m2 per week thereafter, 3 untreated children were lost to long-term follow-up. FINDINGS: r hGH significantly increased the difference in final height compared with pretreatment predicted height (+0.42 SDS [0.79], p = 0.03) but this change was not significantly greater than that of the observation group (+0.16 SDS [0.20]). Treatment had no effect on the timing of puberty. Boys progressed slightly faster through puberty, associated with an acceleration in bone-age maturation. No untoward effects on glucose metabolism were observed. Long-term therapy did not alter body-fat distribution or blood pressure. INTERPRETATION: Long-term therapy in this group of children appears safe but the small increment in final height, approximately 2.8 cm in boys and 2.5 cm in girls, does not justify the widespread use of r-hGH for short normal children. PMID- 8691924 TI - Randomised controlled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevention of leprosy and tuberculosis in Malawi. Karonga Prevention Trial Group. AB - BACKGROUND: Repeat BCG vaccination is standard practice in many countries for prevention of tuberculosis and leprosy, but its effectiveness has not been evaluated. The addition of Mycobacterium leprae antigens to BCG might improve its effectiveness against leprosy. A double-blind, randomised, controlled trial to evaluate both these procedures was carried out in Karonga District, northern Malawi, where a single BCG vaccine administered by routine health services had previously been found to afford greater than 50% protection against leprosy, but no protection against tuberculosis. METHODS: Between 1986 and 1989, individuals lacking a BCG scar were randomly assigned BCG alone (27,904) or BCG plus killed M leprae (38,251). Individuals with a BCG scar were randomly allocated placebo (23,307), a second BCG (23,456), or BCG plus killed M leprae (8102). Incident cases of leprosy and tuberculosis were ascertained over the subsequent 5-9 years. FINDINGS: 139 cases of leprosy were identified by May, 1995; 93 of these were diagnostically certain, definitely postvaccination cases. Among scar-positive individuals, a second BCG vaccination gave further protection against leprosy (about 50%) over a first BCG vaccination. The rate ratio for all diagnostically certain, definitely postvaccination cases, all ages, was 0.51 (95% CI 0.25-1.03, p = 0.05) for BCG versus placebo. This benefit was apparent in all subgroups, although the greatest effect was among individuals vaccinated below 15 years of age (RR = 0.40 [95% CI 0.15-1.01], p = 0.05). The addition of killed M leprae did not improve the protection afforded by a primary BCG vaccination. The rate ratio for BCG plus killed M leprae versus BCG alone among scar-negative individuals was 1.06 (0.62-1.82, p = 0.82) for all ages, though 0.37 (0.11-1.24, p = 0.09) for individuals vaccinated below 15 years of age. 376 cases of postvaccination pulmonary tuberculosis and 31 of glandular tuberculosis were ascertained by May, 1995. The rate of diagnostically certain tuberculosis was higher among scar positive individuals who had received a second BCG (1.43 [0.88-2.35], p = 0.15) than among those who had received placebo and there was no evidence that any of the trial vaccines contributed to protection against pulmonary tuberculosis. INTERPRETATION: In a population in which a single BCG vaccination affords 50% or more protection against leprosy, but none against tuberculosis, a second vaccination can add appreciably to the protection against leprosy, without providing any protection against tuberculosis. PMID- 8691925 TI - The SWORD of Damocles. PMID- 8691926 TI - Does growth-hormone supplementation affect adult height in Turner's syndrome? AB - BACKGROUND: By comparison with historical controls, the effect of treatment with growth hormone on adult height in Turner's syndrome was initially reported as uniformly and strongly positive. Because randomised controlled trials are not near completion, we report our experiences in an open study. METHODS: We examined adult height, projected and attained, in 31 patients (17 treated with subcutaneous recombinant human growth hormone, up to 15 mg a week, outside of a controlled trial and 14 untreated contemporaries). FINDINGS: Contingency table analysis of attained versus projected height showed significantly higher values in treated patients although only 4 of 17 had final heights of 5 cm or more over projection. Patients' and treatment variables (height, bone-age delay, oestrogen replacement) that interfere with adult height projection confounded the analysis of adult height data. INTERPRETATION: Girls with Turner's syndrome should be counselled cautiously about the expectation of a strongly positive effect of treatment on adult height. Completion of the randomised controlled trials to adult height is needed to establish the effect of growth-hormone supplementation on adult height in Turner's syndrome and the psychological effect of treatment. PMID- 8691927 TI - Growth and adrenal suppression in asthmatic children treated with high-dose fluticasone propionate. AB - BACKGROUND: Fluticasone propionate was introduced in 1993 in the UK as a potentially safer inhaled corticosteroid than those already in use. The efficacy and safety of fluticasone has been established at recommended doses of 200 micrograms/day, but not at higher doses that are often used. METHODS: Growth retardation was observed in six severely asthmatic children after introduction of high-dose fluticasone propionate treatment (dry powder). Assessment of cortisol response was by insulin-induced hypoglycaemia in three cases, by short tetracosactrin test in two, and by low-dose tetracosactrin and 24-hour urinary cortisol/creatinine ratio in one. FINDINGS: Six children with growth retardation noted after treatment with high-dose fluticasone propionate were found to have adrenal suppression. In one case the growth rate and cortisol response returned to normal 9 months after the fluticasone dose was reduced to 500 micrograms/day. INTERPRETATION: When high doses of fluticasone propionate are used, growth may be retarded and adrenal suppression may occur. PMID- 8691928 TI - Jury still out on growth hormone for normal short stature and Turner's syndrome. PMID- 8691929 TI - Suspected sexual abuse in a 10-year-old girl. PMID- 8691930 TI - HIV as the cause of AIDS. AB - The two known types of HIV are members of a family of primate lentiviruses. HIV, like other retroviruses, contains a virus capsid, which consists of the major capsid protein, the nucleocapsid protein, the diploid single-stranded RNA genome, and the viral enzymes protease, reverse transcriptase, and integrase. HIV isolates show extensive genetic variability, resulting from the relatively low fidelity of reverse transcriptase in conjunction with the extremely high turnover of virions in vivo. These features of HIVs may have strong implications for vaccine development. Simian immunodeficiency viruses from naturally infected animals differ from HIV in one fundamental respect: they do not cause disease in their natural hosts. Study of these viruses may therefore lead to information about the interaction between lentiviruses and host immune response that could be exploited to combat AIDS. PMID- 8691931 TI - Survey of British clinicians' views on management of patients in persistent vegetative state. AB - BACKGROUND: The best care and management of patients in persistent vegetative state (PVS) has been the subject of sustained moral and legal debate for a number of years. However, the views of clinicians in the UK involved in caring for patients in PVS are largely unknown. METHODS: A postal questionnaire was sent to 1882 consultant members of the British Association of Orthopaedic Surgeons, the Association of British Neurologists, the Society of British Neurosurgeons, and the British Society of Rehabilitation Medicine. Their views were sought on various aspects of the management and care of PVS, in particular the appropriateness of a decision not to treat and a decision to withdraw artificial nutrition and hydration (ANH). FINDINGS: 1027 doctors responded (55%) of whom 558 (54%) had experience of managing patients in PVS. Over 90% of responding doctors considered that it could be appropriate not to treat acute infections and other life-threatening conditions. 65% of doctors considered that withdrawal of ANH could be appropriate. About two-thirds of doctors who thought treatment-limiting decisions could be appropriate thought that such decisions could be considered with the first 12 months of the patient being in PVS. Despite recent case law, less than half the doctors responding to the survey thought that an advance directive made by the patient should have a decisive influence in determining treatment-limiting decisions. Most doctors would like decisions about withdrawing ANH to be made in conjunction with family members and in accordance with agreed guidelines but without the need to go to court. INTERPRETATION: There is a broad consensus among doctors that treatment-limiting decisions are sometimes appropriate for patients in PVS, irrespective of whether they have experience of the condition or of the specialty to which they belong. However, two thirds of doctors said that such decisions can be considered at a time earlier than that recommended by the British Medical Association. It is not clear why some doctors thought a decision not to treat could be appropriate while a decision to withdraw ANH would not be. PMID- 8691932 TI - Repercussions of the Karonga prevention trial for tuberculosis control. PMID- 8691933 TI - Raised ESR in polymyalgia rheumatica no longer a sine qua non? PMID- 8691934 TI - Testing for drug abuse. PMID- 8691935 TI - New guidelines set for occupational HIV exposure. PMID- 8691936 TI - Kampo medicine, a source of drugs waiting to be exploited. PMID- 8691937 TI - Court rules that tainted-blood commissioner can investigate misconduct. PMID- 8691938 TI - US states must cover protease inhibitors. PMID- 8691939 TI - Spontaneous spongiform encephalopathy in a young adult rhesus monkey. PMID- 8691940 TI - Failure to transmit bovine spongiform encephalopathy to marmosets with ruminant derived meal. PMID- 8691941 TI - Prion protein gene analysis in new variant cases of Creutzfeldt-Jakob disease. PMID- 8691942 TI - Statins and coronary heart disease. PMID- 8691943 TI - Statins and coronary heart disease. PMID- 8691944 TI - Statins and coronary heart disease. PMID- 8691945 TI - Methylenetetrahydrofolate reductase and neural tube defects. PMID- 8691946 TI - Mediastinal cyst masquerading as left atrial tumour. PMID- 8691947 TI - Use of intracytoplasmic sperm injection in severe male factor infertility. PMID- 8691948 TI - HIV-1 infection and the female genital tract. PMID- 8691949 TI - Treatment of blepharospasm with nicotine nasal spray. PMID- 8691950 TI - Experimentally induced hypoglycaemia. PMID- 8691951 TI - Experimentally induced hypoglycaemia. PMID- 8691953 TI - Medicine and the media. PMID- 8691952 TI - Medicine and the media. PMID- 8691954 TI - Medicine and the media. PMID- 8691955 TI - Need for liver transplantation. PMID- 8691956 TI - Execution by lethal injection. PMID- 8691957 TI - Effect of fluticasone on growth in children with asthma. PMID- 8691958 TI - Long-term toxicity of intravenous mercury injection. PMID- 8691959 TI - High blood pressure and dementia. PMID- 8691960 TI - High blood pressure and dementia. PMID- 8691961 TI - Alzheimer's disease, Down's syndrome, and chromosome segregation. PMID- 8691962 TI - Limited role for PCR-based diagnosis of Whipple's disease from peripheral blood mononuclear cells. PMID- 8691963 TI - Non-O1 Vibrio cholerae bacteraemia without diarrhoea. PMID- 8691964 TI - Maternal folate status and risk of neural tube defects. PMID- 8691965 TI - HLA and inflammatory bowel disease. PMID- 8691966 TI - Informed consent for observational research in children. PMID- 8691968 TI - Retraction: familial Alzheimer's disease associated with S182 codon 286 mutation. PMID- 8691967 TI - Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. AB - BACKGROUND: Left ventricular dysfunction after myocardial infarction is associated with an increased risk of death. Other studies have suggested that a potassium-channel blocker might reduce this risk with minimal adverse effects. We investigated whether d-sotalol, a pure potassium-channel blocker with no clinically significant beta-blocking activity, could reduce all-cause mortality in these high-risk patients. METHODS: Patients with a left ventricular ejection fraction of 40% or less and either a recent (6-42 days) myocardial infarction or symptomatic heart failure with a remote (> 42 days) myocardial infarction were randomly assigned d-sotalol (100 mg increased to 200 mg twice daily, if tolerated) or matching placebo twice daily. FINDINGS: After 3121 of the planned 6400 patients had been recruited, the trial was stopped. Among 1549 patients assigned d-sotalol, there were 78 deaths (5.0%) compared with 48 deaths (3.1%) among the 1572 patients assigned placebo (relative risk 1.65 [95% CI 1.15-2.36], p = 0.006). Presumed arrhythmic deaths (relative risk 1.77 [1.15-2.74], p = 0.008) accounted for the increased mortality. The effect was greater in patients with a left ventricular ejection fraction of 31-40% than in those with lower ( 90%) and elevated levels of serotonin. In this model, SIB is precipitated by DA agonists via activation of D1 DA receptors which are in turn linked to an induction of tachykinin biosynthesis and release. The data taken together suggest that (a) a substantial reduction of DA accompanied by an increase in serotonin turnover may be essential conditions that are conducive to the occurrence of SIB, and (b) this phase is either superimposed with, or followed by a D1 and/or D2 DA receptor-linked activation of striatonigral tachykinin neurons resulting in enhanced tachykinin biosynthesis and release that may sustain the SIB. Thus, a dynamic interplay between DA, serotonin and tachykinin neuronal systems of the basal ganglia appear to influence the genesis and/or expression of SIB. PMID- 8691982 TI - Diclofenac inhibits endothelial cell adhesion molecule expression induced with lipopolysaccharide. AB - Stimulation of cultured human umbilical vein endothelial cells (HUVEC) with lipopolysaccharide (LPS) induces adherence for human promyelocytic cell line HL60. Adherence of HL60 cells to HUVEC stimulated with LPS for 4 hr and for 24 hr were completely inhibited by pretreatment with diclofenac. While some other nonsteroidal antiinflammatory drugs (NSAIDs), such as ketoprofen, phenylbutazone, indomethacin, ibuprofen and acetylsaticylic acid, did not inhibit. The mechanism whereby diclofenac inhibits the adhesiveness of HUVEC was investigated. Pretreatment of diclofenac inhibited LPS-induced expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in HUVEC, determined by flow cytometry and a cellular enzyme-linked immunosorbent assay (cell-ELISA). The inhibitory activity was concentration dependent between 15.6 and 250 micrograms/ml. Diclofenac also inhibited LPS induced increases in E-selectin, ICAM-1 and VCAM-1 mRNAs, indicating that the action of diclofenac is to inhibit synthesis of these molecules. These data demonstrate that diclofenac is capable of inhibiting the expression of E selectin, ICAM-1 and VCAM-1 in HUVEC. PMID- 8691983 TI - Decrease in plasma phenylalanine and tyrosine after phenylalanine-tyrosine free amino acid solutions in man. AB - After an overnight fast, 5 male healthy subjects ingested increasing amounts of a solution containing a fixed proportion of seven essential amino acids (L isoleucine, 13.3%; L-leucine, 21.0%; L-lysine, 15.2%; L-methionine, 21.0%; L threonine, 9.5%; L-tryptophan, 4.8% and L-valine, 15.2%) and lacking phenylalanine and tyrosine. The solutions caused a rapid fall in plasma phenylalanine and tyrosine which was proportional to the total amount of amino acids ingested. Following the highest dose administered (31.5 g) plasma phenylalanine and tyrosine fell to a minimum of, respectively, 12.7% and 29.8% the initial levels and remained markedly reduced at 6 hours after treatment. The decrease of tyrosine and phenylalanine levels was associated with a decrease of systolic and diastolic arterial pressure. PMID- 8691984 TI - The effect of propofol on CA1 pyramidal cell excitability and GABAA-mediated inhibition in the rat hippocampal slice. AB - An in vitro paired-pulse orthodromic stimulation technique was used to examine the effects of propofol on excitatory afferent terminals, CA1 pyramidal cells and recurrent collateral evoked inhibition in the rat hippocampal slice. Hippocampal slices 400 microns thick were perfused with oxygenated artificial cerebrospinal fluid, and electrodes were placed in the CA1 region to record extracellular field population spike (PS) or excitatory postsynaptic potential (EPSP) responses to stimulation of Schaffer collateral/commissural fibers. Gamma-aminobutyric acid (GABA)-mediated recurrent inhibition was measured using a paired-pulse technique. The major effect of propofol (7-28 microM) was a dose and time dependent increase in the intensity and duration of GABA-mediated inhibition. This propofol effect could be rapidly and completely reversed by exposure to known GABAA antagonists, including picrotoxin, bicuculline and pentylenetetrazol. It was also reversed by the chloride channel antagonist, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). It was not antagonized by central (flumazenil) or peripheral (PK11195) benzodiazepine antagonists. Reversal of endogenous inhibition was also noted with the antagonists picrotoxin and pentylenetetrazol. Input/output curves constructed using stimulus propofol caused only a small enhancement of EPSPs at higher stimulus intensities but had no effect on PS amplitudes. These studies are consistent with propofol having a GABAA-chloride channel mechanism causing its effect on recurrent collateral evoked inhibition in the rat hippocampal slice. PMID- 8691985 TI - Effect on nociception of intracerebroventricular administration of low doses of neuropeptide Y in mice. AB - The present study shows further evidence about the implication of neuropeptide Y (NPY) in nociception. The effect of NPY (1-36), when intracerebroventricularly administered, has been studied using two physical models of acute pain (hot plate test and electrical tail stimulation) and the formalin test. The animal response to these three pain models has been shown to be integrated at different levels in the CNS. A decrease in pain threshold was exhibited in both the hot plate test (10, 30, 60, 120 and 480 pmol of NPY i.c.v.) and the electrical tail simulation test (10, 30 and 60 pmol of NPY i.c.v.), while in the formalin test (10, 30, 60 and 120 pmol of NPY icv) the licking response decreased in phase I but not in phase 2. In these three tests NPY showed hyperalgesic or analgesic effects when administered at low doses, while at high doses it failed to induce any effect. Results show that the effect of NPY on nociception is clearly test-dependent and is only observed at low doses. PMID- 8691986 TI - An experimental model for studying passive cigarette smoking effects on gastric ulceration. AB - Cigarette smoking is associated with gastric mucosal damage in humans. For this study, a smoke chamber was designed to investigate the effects of passive smoking on gastric ulceration. Different concentrations of cigarette smoke (0%, 1%, 2%, and 4%) were perfused into a chamber for one hr in which conscious rats were placed. This one-hr smoke exposure potentiated ethanol (70%, v/v, p.o.)-induced gastric mucosal damage and increased serum nicotine levels; however, it did not affect the blood pH, pCO2, pO2, and HCO3 concentrations, or the systemic blood pressure and heart rate. Under these experimental conditions, exposure to cigarette smoke produced no significant changes in the blood acid/base balance and stress in the animals but significantly potentiated ethanol-induced gastric mucosal damage. The present experimental model is suitable for studying the adverse interactions between passive smoking and alcohol drinking in gastric ulcer formation in rats. PMID- 8691988 TI - Characterization of the oxidation reactions catalyzed by CYP2D enzyme in rat renal microsomes. AB - Monooxygenase activities in rat renal microsomes were determined with the substrates of hepatic CYP2D enzymes. Seven kinds of CYP2D-mediated monooxygenase activities and immunochemically determined CYP2D contents in kidneys corresponded to approximately 3% of those in livers. Debrisoquine 4-hydroxylase and bunitrolol 4-hydroxylase in renal microsomes were inhibited almost completely by the antibody against a CYP2D enzyme purified from rat liver. A marked strain difference (Wistar > Dark Agouti) in these activities was observed in kidney like in liver. The two hydroxylases were inhibited stereoselectively by quinine and quinidine both in renal and hepatic microsomes. Substrate stereoselectivity in (+)- and (-)-bunitrolol 4-hydroxylase activities in kidneys was also consistent with that in livers. These results suggested that the CYP2D enzyme(s) was expressed in the kidney at levels much less than in the liver but had similar functions to those in the liver. PMID- 8691987 TI - Biphasic changes in the density of muscarinic and beta-adrenergic receptors in cardiac atria of rats treated with diisopropylfluorophosphate. AB - Chronic treatment with organophosphate inhibitors of cholinesterases is known to bring about down-regulation of muscarinic acetylcholine receptors in the heart while its effect on the functionally antagonistic beta-adrenergic receptors is not known. We describe experiments in which rats were exposed to daily injections of diisopropylflurophosphate (DFP) and the density of muscarinic and beta adrenergic binding sites in their cardiac atria was measured according to the binding of (3H)quinuclidinyl benzilate ((3H)QNB) and (-)-4-(3-tert-butylamino-2 hydroxy)-propoxy-(5,7-3H) benzimidazol-2-one ((3H)CGP 12177) as subtype non specific muscarinic and beta-adrenergic ligands, respectively. Biphasic course of changes was discovered with both ligands. With the dosage scheme applied, the density of beta-adrenoceptors was augmented 24 h after the first dose of DFP and decreased to about one half of control values after 5 days of treatment with DFP. The density of muscarinic receptors was augmented after two days of treatment with DFP and decreased to about one half of control values after 5 days of treatment. Comparatively small changes in the heart rate were observed during the treatment, they reflected changes in the muscarinic and beta-adrenergic receptor density. The finding of DFP-induced changes in the binding of (3H)CGP 12177 suggests that the mechanisms responsible for the control of the density of muscarinic and beta-adrenergic receptors in the heart cells are interconnected but potential roles of other factors involved in in vivo experiments deserve further analysis. The transient increase in the density of muscarinic receptors after two days of DFP treatment appears related to published data on transient stimulation by cholinergic agonists of the transcription of mRNAs for muscarinic receptors. PMID- 8691989 TI - Importance of the Glu 160 and Glu 189 residues to the various biological activities of the ribosome inactivating protein trichosanthin. AB - Site-directed mutagenesis of trichosanthin (TCS), a ribosome inactivating protein with a broad spectrum of biological activities, was carried out to ascertain the importance of the Glu 160 and Glu 189 residues to the protein synthesis inhibitory, antiproliferative, immunosuppressive and embryotoxic activities of TCS. Replacement of Glu 160 with alanine and with aspartate produced muteins, designated [E160A] and [E160D] respectively, with considerably attenuated protein synthesis-inhibitory, antiproliferative, immunosuppressive and embryotoxic activities, indicating that Glu 160 in TCS plays a role in its biological activity. [E160A] was, however, more potent than [E160D] because in the former mutein, Glu 189 constitutes a back-up of the carboxylate group but in the latter mutein, the negative charge from Asp is at a suboptimal position. The mutein [E160A, E189A] formed by mutation of both Glu 160 and Glu 189 retained considerable embryotoxic activity, suggesting that other amino acids in the active site were able to partially replace the role of Glu 160 and Glu 189. The TCS muteins also exhibit higher toxicity toward cultured embryos than cultured cells (spleen cells and tumor cells). PMID- 8691990 TI - Melatonin inhibits DNA synthesis in MCF-7 human breast cancer cells in vitro. AB - The aim of the present work was to study whether physiological doses of melatonin (1nM) modified DNA synthesis in MCF-7 human breast cancer cells. Exponentially growing MCF-7 cells were incubated for 24 h with thymidine (2mM) for blocking mitosis and synchronizing the cell division cycle. Synchronization was assessed by a flow cytometry study which showed that after release from excess thymidine, 82.3% of the cells were in phase G1. Lots of these synchronized cells were pulsed for 1h with [3H]deoxythymidine ([3H]dThy) or [3H]dThy + melatonin, at 0,3,6,9,12,15 or 24 h from the release of the mitotic arrest. The exposition of these synchronized MCF-7 cells to melatonin for only 1h, significantly inhibited [3H]dThy incorporation when it was at 6 or 9 h. after release from mitotic block, at a time when DNA precursor incorporation was the highest and the number of cells in S phase was maximum. We conclude that, at least in part, melatonin antiproliferative effects on MCF-7 cells could be mediated by a reduction of DNA synthesis. PMID- 8691991 TI - Consent--Scots law and the patient's right to know. AB - Four cases highlight interesting points in relation to the legal considerations, in Scotland, of consent to medical treatment. MOYES sets the broad parameters and deals with the situation or risk established but a reasonable warning given of that risk. INGRAM and COSGROVE are cases where the risk averred to exist was not proved to exist. GOORKANI brings together risk, a causal link between the risk and the injury, and negligent failure to warn of the risk. And it has the interesting twist of the nature of the loss which had to be compensated--not infertility but the loss of the opportunity to adjust to the prospect of infertility. PMID- 8691992 TI - Mental hospital regime in England and Wales. AB - Although non-private conventional mental hospitals in England and Wales have been in existence for about two centuries, the literature on the actual regimes in those hospitals is not enormous. Since Goffman's Asylums, things have changed in North America, the United Kingdom and elsewhere. However, not much has been written about the present position. This article (based on qualitative data collected over 12 months) describes the regimes in three conventional mental hospitals in S.E. England. It covers hospital policy on the admission of a patient, daily ward routine, the open-door policy, fire precautions, close observation, seclusion, search of patients and their belongings and the handling of patients' correspondence. It concludes that the regimes are reasonable. PMID- 8691993 TI - The use of non-mental health professionals volunteers in a psychiatric hospital. AB - Volunteers' activities in psychiatric institutions is becoming a widespread phenomenon in Israel with different modalities and approaches implemented in a variety of settings. This paper presents and discusses the historical roots of volunteering, its potentialities and also some of the characteristics of existing programs. PMID- 8691994 TI - Bromocriptine related atypical vascular accidents postpartum identified through medicolegal reviews. AB - Recent literary case reports indicate that bromocriptine mesylate, when used for the suppression of lactation in the puerperium, can cause serious and even lethal side effects. The untoward sequelae are attributed to generalized or focal vasospasm affecting the cardiac and/or cerebral bold vessels. Apart from pre existing hypertension and use in association with other ergot derivatives, the factors predisposing to such complications have not been elucidated, The authors present three atypical bromocriptine related postpartum accidents which may expand the understanding both of the predisposing factors and the potential consequences of bromocriptine related severe side effects. One of the cases raises the suspicion that the manifestations of hyperthyroidism may be aggravated by this method of pharmacologic ablactation. Another observation appears to imply that the drug may trigger the onset of chronic hypertension in women so predisposed. The development of cerebral infarcts, identified by MRI, in a clinically asymptomatic woman, exemplifies the threat of recurrent seizure activity in cases of bromocriptine related stroke. PMID- 8691995 TI - Occupational handicap in victims of limb injuries. AB - The authors analysed 115 victims of limb injuries due to traffic accidents, to compare the medico-legal assessment by the rate of permanent disability (PD) with a tridimensional evaluation of the damage (lesion, function and situation), from a professional aspect. There was a high correlation between PD and lesional and functional sequelae. However, in professional situations only with those who were working full-time was there a high correlation with PD. PD gives only a lesional assessment. The authors propose a professional damage evaluation which considers the handicap of the individual in her/his ordinary work besides the lesion and function, as long as the assessment is personal and it is meant to reintegrate the victim completely in her/his professional life. PMID- 8691996 TI - Malingering a challenge for the forensic examiner. AB - After pointing out that spoken and non-verbal language are the primary means of communication in interpersonal dialogue, and especially in a forensic criminological examination, the authors present malingering in a legal context from an historical and psychodynamic- ontogenetic point of view. Diagnostic characteristics of malingering are reported in a review of previous studies. Latest psychological testing is presented. The authors express their professional opinion that malingering in a criminological forensic setting should be divested of the aura of deviousness and manipulation acquired throughout the past years. They propose that it is a defensive reaction to which a person charged with a crime resorts when under the stress of facing the legal consequences of wrongdoing. They view malingering in a forensic setting as regressive behavior to a childhood or adolescent stage, not to condone or justify it, but in an attempt to bring about better communication between examiner and examinee. PMID- 8691997 TI - 'Wrongful conception', 'wrongful birth' and 'wrongful life': the first South African cases. AB - Internationally case law has developed in regard to actions which in due course were given the following labels. "Wrongful pregnancy" or "wrongful conception" for cases where a healthy but unwanted child is born, following negligent contraceptive advice by a doctor or a negligent sterilization or abortion procedure, and the parents claim damages; "wrongful birth" where such a claim is brought by the parents of an abnormal or disabled child; "wrongful life" where a claim is brought by or on behalf of the abnormal or disabled child itself. The first judgments in South Africa were handed down during the past seven years and are discussed in this article. PMID- 8691999 TI - Medico-legal aspects of brachial plexus injury: the obstetrician's point of view. AB - The author reviews the obstetric literature with regard to factors predisposing to or predicting the occurrence of brachial plexus injury in the newborn. Based on the evaluated data, it is concluded that, whereas there are identifiable predisposing factors for shoulder dystocia, to which the occurrence of brachial plexus injury is widely attributed, the predictive power of the various identifiable factors is generally low. The writer also quotes literary data which suggest that injury to the brachial plexus may occur in utero before labor and, thus, unrelated to arrest of the shoulders during the process of delivery. The contemporary literature contains diverse and often contradictory opinions which do not provide clear-cut guidelines for the practicing obstetrician for the prevention of brachial plexus injury. In some parts of the world a disproportionately large number of malpractice claims against obstetricians derive from such injuries. Therefore, the formulation of a consensus concerning the definition of shoulder dystocia, the identification of preventive measures to be utilized to avoid its occurrence and the required clinical management in case of arrest of the shoulders are unresolved problems that the medical profession needs to address. PMID- 8691998 TI - Trial by jury; a pilot study of juror perception of mental health professional testimony in NGRI pleas for first degree international homicide. AB - The authors present a pilot statistical study of the way in which jurors perceived psychiatric/psychological expert testimony in ten court trials for first degree intentional homicide in which a plea of not guilty by reason of mental disease or defect had been entered. The reader is offered a short history of the insanity defense, of the trial by jury, and a discussion of the desired professional and personality prerequisites looked for in choosing a mental health expert. The study is based on a detailed protocol devised by two of the authors- a forensic psychiatrist and a psychologist--assessing various parameters of the professionality and demeanor of the experts on the basis of a statistically valid number of juror responses to the questionnaire. The results show that the jurors perceived the expert testimony as a useful, but not determinant factor when reaching their verdict. This is consonant with the definition of the rationale for using expert testimony as given by the Federal Rules of Evidence. PMID- 8692000 TI - Use and abuse of medicolegal and forensic scientific expert testimony in the courtroom. PMID- 8692001 TI - The testimonial value of the statements of minors in a criminal trial. AB - There is no doubt that a child is capable of making statements just as any other person is, nevertheless, in addition to the need, which takes priority in some cases, of knowing how to correctly understand his way of expressing himself in order to avoid distorted interpretations, one cannot ignore the fact that his testimony may often imply delicate psychological problems for which the law must bear responsibility, on one hand to adequately protect the emotional integrity of the child and on the other to safeguard the defendant from accusations that could be the result of imagination or biased knowingly or unknowingly by third parties, particularly from within the family circle. PMID- 8692002 TI - Informed consent: the nurse's dilemma. AB - The author builds upon the concept of informed consent whereby the patient agrees to undergo experimental medical procedures. Ideally, the doctor will inform the patient fully on the proposed treatment so as to assure the patient's right to participate intelligently and freely in the decisions regarding his treatment. The nurse is drawn into the doctor-patient relationship in cases where the patient seeks her counsel because he feels insufficiently informed by the doctor, or because the nurse becomes aware of inadequacies in the information-giving process. She is then faced by the nurse's dilemma: a conflict between the loyalties she owes to her patient and to her physician team mate. A work sheet is presented which can help the nurse decide upon the proper course of action in solving this dilemma, guided by her personal and professional beliefs and by specific ethical concepts in the Code for Nurses. Solution of the dilemma and attainment of informed consent requires willing cooperation between doctor and nurse. Both can develop the skills for imparting information to the patient under difficult conditions and for verifying its comprehension by the patient. Both must learn to respect the patient's decision and to temper their professional skills with sensitivity, a strong moral sense and a deep respect for their fellow human beings. PMID- 8692003 TI - Selective abortion after prenatal diagnosis. AB - This paper deals with the main arguments in Europe against selective abortion after prenatal diagnoses and against using prenatal diagnoses as a whole from an ethical point of view. The different experiences from the Eastern and the Western parts of Germany are used as examples. The paper suggests that using ethics could promote multicultural experiences and different strategies of decision-making. PMID- 8692004 TI - Self-determination for life and death. PMID- 8692005 TI - Organ donation consanguinity or universality. AB - 1. Neither the "Diseased Persons" nor the "Genetic Relations" provide an answer to "trading" in human body parts. 2. Live human body constitutes a vital source of supply of organs and tissues and the possibilities of optimum utilisation should be explored. 3. There is no scope for dogmatic postures and open mindedness should be the approach while dealing with the issue of Organ Transplantation. 4. Society owes a duty to save the file of a dying man and in the event of failure to do so, it is absolutely immoral to interfere with his own arrangements by making unrealistic laws. No immorality is involved if an individual disposes of his spare body parts for a valid consideration to a needy person. 5. The scarcity needs to be urgently overcome otherwise unwarranted trade and crime are liable to thrive. 6. Families are not unconnected or antagonistic fragments of humanity. After thousands of years of continuous efforts the individuals on this earth have attained the stage of organic and functional integration. Atomisation of society on the basis of consanguineous proximities amounts to reversing this holistic trend. Organ transplantation is a functional expression of a highly evolved pursuit with inherent and intimate interaction in the form of organic exchange at the individual level, independent of consanguineous inducements or motivations. As such there is absolutely no scope for restricting organ donations by strangers. 7. Commercialisation should be curbed by making the enforcement agencies more efficient and not by depriving a needy person of his genuine requirements. Legislative craftsmanship lies in providing an answer without curtailing the freedom of the people. PMID- 8692006 TI - Trypsin-like protease activity of Porphyromonas gingivalis as a potential virulence factor in a murine lesion model. AB - Porphyromonas gingivalis possesses a large number of enzymatic activities which might be important in the virulence of this putative periodontopathogen. The purpose of this study was to examine these enzymatic activities in vivo in a murine model to assess their role in soft tissue destruction. Whole cells of P. gingivalis strains whether grown on blood agar plates or in broth exhibited high levels of alkaline phosphatase (ALPase), a trypsin-like protease (TLPase), acid phosphatase (ACPase), N-acetyl beta-glucosaminidase (Na beta-Gase) enzymes and collagenolytic activities. P. gingivalis W50 treated with 2 mM Na-P-tosyl-L lysine chloromethyl ketone (TLCK)/phenylmethylsulfonyl fluoride (PMSF) prior to subcutaneous infection of mice failed to induce a phlegmonous abscess and lethality characteristic of animals challenged with untreated P. gingivalis. Comparison of wild type P. gingivalis strain 3079.03 with its protease-deficient (TLPase-negative) mutant NG4B19 revealed the mutant to be avirulent (no lesion and no death) in this model. P. gingivalis BEI and SW5 mutants (parent W50), which partially lacked TLPase enzyme activity produced only localized lesions, and no death. Thus, the TLPase enzyme appears to be correlated with the lesion type (spreading or localized), lesion size, and death in this mouse abscess model. Therefore, the enzymatic activities of P. gingivalis and specifically the TLPase enzyme could play an important role in periodontal disease by enhancing bacterial spread and degrading gingival tissues. PMID- 8692007 TI - Construction of recombinant aroA salmonellae stably producing the Shigella dysenteriae serotype 1 O-antigen and structural characterization of the Salmonella/Shigella hybrid LPS. AB - The TN501 mercury resistant transposon containing the rfp and rfb loci encoding biosynthesis of the O-antigen of Shigella dysenteriae serotype 1 lipopolysaccharide (LPS) was constructed and introduced into aroA mutants of Salmonella typhimurium and Salmonella dublin. In five recombinant strains, both homologous LPS and hybrid LPS, consisting of Salmonella lipid A-core and Shigella O-antigen, were produced. All derivatives but one (SL3235) stably inherited the new trait. Immunofluorescence microscopy, using mixtures of differentially labelled antibodies specific for either the Salmonella or the Shigella O-antigen, demonstrated that individual bacteria produced both types of LPS. Qualitative and quantitative analysis of polysaccharides obtained by mild hydrolysis of purified LPS was carried out by methylation analysis and NMR spectroscopy, and revealed that the ratio of Salmonella to Shigella O-antigen repeating units in the high molecular weight fraction of isolated polysaccharides varied from 1.3: 1 to 8.4:1 as based on the relative proportions of 1,4,5-tri-O-acetyl-2,3-di-O-methyl-L- rhamnitol (Salmonella repeating unit) and 1,3,5-tri-O-acetyl-2,4-di-O-methyl-L rhamnitol (Shigella repeating unit). The attachment site of the Shigella O antigen to the Salmonella core was investigated by construction of a mutant rfp rfb gene cluster encoding the synthesis of only one repeat unit of the Shigella dysenteriae type 1 O-antigen, and its introduction into a rough Salmonella strain. This hybrid organism produced a polysaccharide with the following structure, [formula: see text] demonstrating that the Shigella dysenteriae type 1 O-antigen is linked at position O-4 of the subterminal D-glucose unit in the Salmonella core. PMID- 8692008 TI - Accelerated development of genital Chlamydia trachomatis serovar E in McCoy cells grown on microcarrier beads. AB - Chlamydia trachomatis serovar E is a major cause of bacterially-acquired sexually transmitted infections. Stock cultures of these obligate intracellular bacteria are often propogated in McCoy cells. We recently reported that greater infectious titers of chlamydiae could be obtained if the McCoy cells were cultured on collagen-coated microcarrier beads versus plastic flasks, although the reason for the difference in efficiency was not clear. This study analyzed the development of C. trachomatis grown in McCoy cells by the two methods. Transmission electron microscopy analysis revealed an accelerated chlamydial development, with maturation of reticulate bodies into elementary bodies sooner in McCoy cells grown on the porous substratum. Comparison of particle counts versus infectivity titers indicated the production of fewer numbers of elementary bodies but which were highly infectious sooner from the infected McCoy cell-microcarrier bead cultures than from duplicate infected McCoy cell cultures grown in plastic tissue culture flasks. PMID- 8692009 TI - Molecular characterization of a surface-exposed superoxide dismutase of Mycobacterium avium. AB - Mycobacterium avium is an intracellular pathogen capable of growing inside the phagosomal compartment of macrophages. In this work, we characterized the superoxide dismutase of M. avium, as a putative candidate to resist the oxidative stress. The gene sodA encoding superoxide dismutase (SOD:EC1.15.1.1) from Mycobacterium avium TMC724 was cloned and sequenced. It encodes a 23 kDa protein (207 aminoacids) showing identity with the Mycobacterium leprae SOD (91%) and the M. tuberculosis SOD (83%). This enzyme was functionally expressed in both Escherichia coli and Mycobacterium smegmatis, and identified as a manganese (Mn) SOD on the basis of sequence comparison with other MnSODs from different organisms, and by activity inhibition studies. By indirect immunogold labeling of M. avium with a mAb directed against M. leprae SOD, the enzyme was found to be exposed at the cell surface of M. avium. It was also shown that SOD was released in supernates of M. avium TMV724 during exponential growth, suggesting a role of this enzyme during interactions with the environment. When SOD was expressed in the non-pathogenic M. smegmatis, it was also exposed at the surface of bacteria and released in supernates, but this was not sufficient to protect this recombinant mycobacterium from the killing mechanisms of macrophages. PMID- 8692010 TI - Deletion in the 190 kDa antigen gene repeat region of Rickettsia rickettsii. AB - The 190 kDa outer membrane protein of Rickettsia rickettsii is a major immunodominant protective antigen which contains 13 tandem nearly identical repeating sequences. We have identified a deletion in the 190 kDa antigen gene of R. rickettsii strain Smith maintained in the laboratory. The deletion occurred within the repeat region of this gene and the mutated repeat region corresponded to one repeating unit in size. PMID- 8692011 TI - The effect of physical activity on serum total and low-density lipoprotein cholesterol concentrations varies with apolipoprotein E phenotype in male children and young adults: The Cardiovascular Risk in Young Finns Study. AB - Apolipoprotein E (apo E) determines serum total (TC) and low-density lipoprotein (LDL-C) cholesterol concentrations and is thus associated with coronary heart disease (CHD) risk. We studied if the effect of physical activity (PA) on serum TC and LDL-C concentrations varies with apo E phenotype in a population-based sample of children and young adults with regular PA. The study cohort consisted of subjects aged 9, 12, 15, 18, 21, and 24 years in 1986 (N = 1,498) participating in a large multicenter study of cardiovascular risk factors in children and young adults. Serum lipid concentrations were determined enzymatically, and apo E phenotypes by isoelectric focusing and immunoblotting. The composition of the diet was determined by a 48-hour recall method, and a PA index was calculated on the basis of frequency, intensity, and duration of activity assessed by a questionnaire. LDL-C (P = .0082), TC (P = .014), and the high-density lipoprotein cholesterol (HDL-C)/TC ratio (P = .0004) responses to exercise varied with apo E phenotype. The effect of PA on LDL-C, TC, or HDL/TC was not found in apo E phenotype E4/4. A moderate inverse effect of PA on TC and LDL-C and a positive effect on HDL/TC was found in subjects with E4/3 and E3/3 phenotypes. Similar but stronger associations were found between these variables within the group of E3/2 males. The effect of PA on serum lipid levels was strongest within the phenotype E3/2. These associations were not explained by dietary habits. Apo E phenotype partly determines the effect of PA on serum TC and LDL-C in Finnish male children and young adults with regular PA. PMID- 8692012 TI - Low erythrocyte Na/K-pump activity and number in northeast Thailand adults: evidence suggesting an acquired disorder. AB - Healthy northeastern Thais have a higher erythrocyte sodium concentration and a lower erythrocyte membrane Na,K-adenosine triphosphatase (ATPase) activity than central Thais. To elucidate whether the defect is hereditary or acquired, we studied plasma sodium and potassium and erythrocyte sodium, potassium, Na,K ATPase activity, and ouabain-binding sites (OBS) in the following groups: healthy newborns of ethnic central Thais (group 1), healthy newborns of ethnic northeast Thais (group 2), healthy adults of central Thailand ethnicity who lived in the rural central region (group 3) or in Bangkok (group 4), healthy adults of northeast Thailand ethnicity who lived in the rural northeast region (group 5) or who migrated to work in Bangkok for at least 1 year (group 6). Erythrocyte Na was higher in group 2 than in group 1. Group 3 had lower erythrocyte Na,K-ATPase activity than group 4, and it was lower in group 5 than in group 6. Among all groups, group 5 had the highest erythrocyte Na (11.6 mmol/L,F < 0.0001) and the lowest Na,K-ATPase activity (63 mmol Pi/mg x h, F < 0.0001) and erythrocyte OBS (397 sites per cell, F < 0.05) than the other adult groups. There was a positive correlation between erythrocyte Na,K-ATPase and erythrocyte OBS (r = .416, P < .0001). Multiple regression analysis demonstrated a correlation between erythrocyte Na as a dependent variable and erythrocyte OBS, plasma potassium, erythrocyte potassium, and erythrocyte Na,K-ATPase (r = .517, P < .0001). The erythrocyte Na,K-ATPase/OBS ratio, an expression of Na,K-ATPase activity equalized for the number of Na,K-pump units, was lowest among rural adults of the central region (group 3) and the northeast region (group 5) (F < 0.0002). Our data suggest that rural dwellers in Thailand tend to have lower erythrocyte Na,K ATPase activity than urban dwellers and that this is probably acquired after birth. It was more severe among those from the northeast versus the central region, and was less severe among those who migrated to an urban area. This defect in northeast rural dwellers was probably associated with low numbers of Na,K-pump units and a defect of the pump to express activity, whereas in central rural dwellers it was probably associated with the latter condition. We postulate that there might be circulating Na,K-pump inhibitors and metabolic disturbances that cause attenuation of Na,K-ATPase function and synthesis in the northeast Thailand rural population, and that such substances may have an environmental origin. There may be a relationship between these abnormalities and sudden unexpected deaths. PMID- 8692013 TI - Effect of physical training on mitochondrial function in skeletal muscle of normal and diabetic rats. AB - The study was designed to assess the impact of physical training on the oxidative phosphorylation rate (OPR) in mitochondria isolated from two different skeletal muscles of rats with or without chronic diabetes mellitus. Diabetes was induced by an intravenous injection of streptozotocin (50 mg/kg), and only animals with a blood glucose level between 14 and 22 mmol/L 1 week later were kept in the protocol. Exercise training was performed on a treadmill with a progressive 10 week program. Rats were killed by decapitation at the end of the training program, and mitochondria were isolated from the gastrocnemius and the red vastus lateralis muscles. When the data were expressed as per milligrams of protein, OPR was significantly depressed by diabetes mellitus in the mitochondria from each muscle; a similar negative impact also appeared to be produced by physical training in mitochondria isolated from the red vastus lateralis muscle. However, due to changes in mitochondrial protein yield between groups, the capacity to oxidize pyruvate and malate was also calculated per gram of muscle. Adenosine triphosphate (ATP) production rate appeared to be unaffected by diabetes but significantly increased by training in both muscles of diabetic and nondiabetic rats. This effect of training was not associated with any improvement in plasma glucose or insulin levels in diabetic animals. However, the large increase in plasma levels of beta-hydroxybutyric acid in sedentary diabetic rats was partly reversed by training (1,079 +/- 472 v 3,424 +/- 618 micromol, P < .001). These results suggest that the training-induced increase in the capacity of skeletal muscles to oxidize substrates and generate energy may also contribute to reduce the elevated plasma beta-hydroxybutyric acid levels observed in a state of insulin deficiency. This may have clinical relevance, since ketoacidosis remains a life-threatening event in insulin-dependent diabetic subjects. PMID- 8692014 TI - In vivo measurement of plasma cholesterol and fatty acid synthesis with deuterated water: determination of the average number of deuterium atoms incorporated. AB - Fractional lipid synthesis can be measured using the incorporation of deuterium from deuterated water. The calculations require knowledge of the maximum incorporation number (N) of deuterium atoms in the molecules synthesized. For both tissue palmitate and cholesterol, N values have been found to be higher during in vivo versus in vitro experiments. We determined the N values to be used for measuring the fractional synthesis of plasma cholesterol and of palmitate triglycerides (TG). Rats were given drinking water enriched (7% to 10%) with deuterated water, and N was determined from the mass isotopomer distributions of plasma cholesterol and plasma TG palmitate and the deuterium enrichment of plasma water. We found N to be 21 for palmitate and 27 for cholesterol. These values agree with those reported for tissue palmitate and cholesterol in vivo, and are higher than values found in vitro. We also found large deuterium enrichments in plasma glucose and in liver lactate and pyruvate. We suggest that, compared with in vitro studies, in vivo metabolism of these compounds leads to an additional pathway of incorporation of deuterium into lipids through deuterium-labeled acetyl coenzyme A (CoA). This could explain why N values are higher in vivo than in vitro. PMID- 8692015 TI - Changes in glycerophospholipid profile in experimental nephrotic syndrome. AB - We investigated changes in the glycerophospholipids in kidney tissue and its various intracellular fractions in rats with nephrotic syndrome induced by puromycin aminonucleoside. The ethanolamine plasmalogen, 1-O-alk-1'-enyl-2-acyl GPE (EP), was increased in kidney tissue obtained from the puromycin-treated animals. A similar increase was found in the mitochondria and endoplasmic reticulum (microsomes) of this tissue. These increases were not found in the liver. Since platelet-activating factor (PAF) is known to be produced in increased amounts in inflammatory disorders, it is suggested that the higher plasmalogen found in rat kidneys during experimental nephrotic syndrome might be derived from increased levels of this autacoid. The increase in PAF may also result in the elevation of plasma PAF-acetylhydrolase (AH) activity observed in these animals. PMID- 8692016 TI - Postprandial reduction in high-density lipoprotein cholesterol concentrations in postmenopausal women: improvement by 17beta-estradiol. AB - The aim of the study was to characterize postprandial high-density lipoprotein (HDL) cholesterol metabolism in postmenopausal women and to evaluate the effect of replacement therapy with 17beta-estradiol. Sixteen healthy normolipidemic (plasma cholesterol, 5.39 +/- 0.68 mmol/L; plasma triglycerides [TGds], 1.24 +/- 0.55 mmol/L) postmenopausal women received an oral vitamin A fat tolerance test (50 g fat with 60,000 IU vitamin A/m2 body surface area). Various blood samples were taken before the test, at hourly intervals up to 8 hours, and 24 hours after ingestion of the fat load for determination of HDL cholesterol, HDL TG, and HDL apolipoprotein (apo) A-I concentrations. TG and vitamin A concentrations were also measured. A subgroup of six women were treated with 2 mg micronized 17beta estradiol orally each day for 6 weeks, after which the oral vitamin A fat tolerance test was repeated. A reduction in plasma HDL cholesterol concentrations was observed 3 to 8 hours after ingestion of the fat load, and the minimal postprandial HDL cholesterol concentration was, on average, 31.7% (P = .04) lower than the fasting HDL cholesterol concentration. HDL cholesterol had returned to the initial value 24 hours after the fat load. The decrease in postprandial HDL cholesterol concentrations was attenuated by treatment with 17beta-estradiol. The area under the curve (AUC) for the postprandial reduction in HDL cholesterol improved substantially by 66% during 17beta-estradiol (-2.4 +/- 2.6 mmol x h x L( 1) before 17beta-estradiol and - 1.1 +/- 1.2 mmol x h x L(-1)_ during 17beta estradiol, P = .038). In conclusion, HDL cholesterol concentrations decreased by 32% in the postprandial state in normolipidemic postmenopausal women, indicating that HDL cholesterol must be measured in the fasting state. Replacement therapy with 17beta-estradiol reduced the postprandial decrease in HDL cholesterol by 66%. This effect of 17beta-estradiol can be beneficial in reducing the risk of coronary artery disease. PMID- 8692017 TI - No influence of proinsulin and insulin on plasma levels of plasminogen activator inhibitor type 1 and tissue plasminogen activator in young women before and during intake of contraceptive steroids. AB - Clinical observations in patients predisposed to cardiovascular disorders and recent experimental observations suggest that proinsulin and insulin participate in the regulation of fibrinolysis in vivo. In the present study, we examined if proinsulin and insulin affect the constitutive (fasting) secretion of plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA) in young healthy women (N = 17). We also measured the antigen concentrations of PAI 1 and t-PA during slow and fast changes in proinsulin and insulin levels induced by oral (OGTT) and intravenous (IVGTT) glucose tolerance tests. The assessments were performed before and after 6 months of treatment with contraceptive steroids, which have a well-defined influence on the fibrinolytic variables. We observed no consistent correlations between fasting values of proinsulin, insulin, PAI-1, and t-PA either before or during hormonal treatment. Before hormonal treatment, PAI-1 and t-PA antigen levels decreased (P < .05) during the hyperproinsulinemia and hyperinsulinemia induced by the OGTT and IVGTT. After hormonal intake for 6 months, a decrease only in t-PA concentrations during the OGTT was observed despite similar proinsulin and insulin responses to the glucose loads. Our findings suggest that proinsulin and insulin have no influence on the regulation of plasma levels of PAI-1 and t-PA in young healthy women, irrespective of intake of contraceptive steroids. PMID- 8692018 TI - Magnesium deficiency and glucose metabolism in rat adipocytes. AB - We examined the effect of reducing ambient and intracellular free Mg ion ([Mg]i) concentrations on insulin action in epididymal adipocytes from male Sprague Dawley rats in terms of (1) cellular transport of nonmetabolizable 2 deoxyglucose, (2) [U-14C]glucose oxidation to CO2, and (3) D-[3H]glucose incorporation into triglycerides. There were no significant differences in basal or insulin-stimulated transport of 2-deoxyglucose between adipocytes cultured in physiologic (1.24 mmol) or low (0.16 mmol) Mg for up to 24 hours. In contrast, insulin-stimulated but not basal [U-14C]glucose oxidation to CO2 was significantly reduced in adipocytes cultured in low versus physiologic Mg (P < .05 to .01). Similarly, there were no differences in basal glucose incorporation into triglycerides between cells cultured in low or physiologic Mg media for up to 24 hours. However, long-term (24-hour) but not short-term (2-hour) exposure of cells to low Mg was associated with a significant 30% reduction in insulin stimulated D-[3H]glucose incorporation into triglycerides. When adipocytes incubated in low Mg were reincubated in high Mg (1.24 or 5 mmol) for 30 minutes, normal insulin-stimulated D-[3H]glucose incorporation into triglycerides was restored. Incubation of adipocytes in low Mg (0.16 mmol) for 24 hours resulted in a significant decrease in [Mg]i (264 +/- 89 v 437 +/- 125 micromol/cell [mean +/- SEM]) as compared with cells incubated in physiologic Mg (1.24 mmol; P < .01). These data support a role for intracellular Mg deficiency in the development of insulin resistance and suggest that the effect occurs at a site(s) distal to glucose entry into the cell. The effect of Mg deficiency on insulin action appears to be reversible. PMID- 8692019 TI - The effects of anabolic androgenic steroids on serum ubiquinone and dolichol levels among steroid abusers. AB - We measured serum ubiquinone and dolichol concentrations in 13 men while they abused anabolic androgenic steroids (AAS) and during the following withdrawal period. Serum total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol and triglycerides were also determined. AAS administration increased serum ubiquinone by 68% (P < .001) and decreased serum dolichol by 30% (P < .002). Both nonsterol isoprenoid levels in plasma correlated with the AAS dose, ubiquinone positively (P < .001) and dolichol negatively (P < .002). When the subjects were taking steroids, the ubiquinone to LDL ratio was 42% higher than during the withdrawal period. In conclusion, our study suggests that AAS have an influence on the by-products of the mevalonate pathway. PMID- 8692020 TI - Reduced splenocyte metabolism and immune function in rats implanted with the Morris Hepatoma 7777. AB - Although the immune system is important in antitumor defense, little is know about the immune response during progressive tumor growth. Sprague-Dawley rats (171 +/- 3g) of the Buffalo strain were implanted with the Morris Hepatoma 7777 ([MH 7777] a poorly differentiated, rapidly growing tumor) and killed either 2 (T2) or 3 (T3) weeks postimplantation when the tumor weighed 3.0 +/- 0.4 and 14 +/- 1 g, respectively. Splenocytes were isolated and their phenotypes, metabolism (metabolite production from glucose and glutamine), proliferative response ([3H]thymidine incorporation in response to polyclonal mitogens), and natural killer (NK) cytotoxicity (lysis of YAC-1 cells) were determined. Five rats were killed with the T2 group to serve as non-tumor-bearing controls (T0). Food intake and nontumor body weight decreased (P < .01) 14 days after tumor implantation. There was a progressive decrease (T3 < T2 < T0) in splenic mitogen responses (P < .05) and plasma essential and nonessential amino acid concentrations (P < .05). Compared with T0, NK cytotoxic activity was significantly (P < .05) lower at T2 and higher at T3. The presence of the tumor at both T2 and T3 resulted in lower production of metabolites from glucose and glutamine by splenocytes. The proportion of CD8+ cells was lower (P < .05) and the proportion of B cells and macrophages higher (P < .05) in spleens from tumor-bearing rats. In conclusion, the presence of even a small tumor burden (1.4% of body weight) significantly altered the host's immune function and metabolism. A larger tumor burden (6% of body weight) increased NK cytotoxic activity and further reduced cell-mediated immune function. PMID- 8692021 TI - Effects of pancreas transplantation on distribution and composition of plasma lipoproteins. AB - In type I (insulin-dependent) diabetic patients, peripheral hyperinsulinemia due to subcutaneous insulin treatment is associated with increased high-density lipoprotein (HDL) cholesterol, and also with an altered surface composition of HDL. Pancreas grafts also release insulin into the systemic rather than into the portal venous system, giving rise to pronounced peripheral hyperinsulinemia. We hypothesized that if peripheral hyperinsulinemia is responsible for high HDL cholesterol and/or altered surface composition of HDL in diabetic subjects, similar changes in the lipid profile should be present in pancreas-kidney transplant recipients (PKT-R). Using zonal ultracentrifugation, we isolated HDL2, HDL3, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) from fasting plasma of 14 type I diabetic PKT-R, eight nondiabetic kidney transplant recipients (KT-R), and 14 healthy control subjects and determined the level and composition of the above lipoproteins. HDL2 cholesterol was increased in PKT-R as compared with KT-R and healthy controls (both P < .05), whereas HDL3 cholesterol was unchanged. However, an altered lipoprotein surface composition was evident in PKT-R: HDL2, HDL3, and LDL were enriched in unesterified cholesterol ([UC] PKT-R v KT-R, P=.13, P < .005, and P < .05, respectively; PKT-R v controls, all P < .005); HDL2 was enriched in phospholipids; and LDL was depleted of phospholipid. KT-R, in contrast, showed no changes in lipoprotein surface composition but a substantial triglyceride enrichment of HDL2 as compared with PKT-R and healthy controls (both P < .05). LDL size as determined by gradient gel electrophoresis was increased in PKT-R compared with controls (P < .005). The plasma concentration of cholesteryl ester (CE) transfer protein (CETP), involved also in phospholipid transfer, was increased in both transplant groups compared with healthy controls (both P < .05). Insulin concentrations in fasting plasma were directly related to CETP levels and to the weight-percentage of UC in HDL3, and inversely to the weight percentage of phospholipids in LDL (all P < .05). We explain the increase in HDL2 cholesterol and LDL size in PKT-R by their high lipoprotein lipase (LPL) activity conferring an excellent capacity to clear chylomicron triglycerides. Effective handling of postprandial triglycerides, high HDL2 cholesterol, and predominance of LDL pattern A, respectively, are established indicators of a low risk of atherosclerosis. However, it is presently unclear what effects the compositional changes on the surface of HDL and LDL may have on cardiovascular risk in clinically stable PKT-R. PMID- 8692022 TI - Detection of an amino acid polymorphism in hormone-sensitive lipase in Japanese subjects. AB - Hormone-sensitive lipase (HSL) plays an important role in energy metabolism by controlling the hydrolysis of triglycerides stored in adipose tissue. To investigate whether mutations in the HSL gene are associated with non-insulin dependent diabetes mellitus (NIDDM), we screened for mutations of this gene using single-stranded conformation polymorphism (SSCP) in 35 Japanese subjects with NIDDM. SSCP analysis identified a variant pattern in axon 4, and the sequence showed that this variant pattern resulted from amino acid polymorphism (Arg309Cys). Subsequent study showed that this polymorphism was found in 18 of 151 NIDDM patients and 10 of 97 nondiabetic subjects, but allele frequency was not significantly different between the two groups (P = .7). Body mass index, serum triglyceride, and high-density lipoprotein (HDL) cholesterol were not different in subjects with and without the polymorphism. But serum total cholesterol was higher in subjects with the polymorphism than in subjects without it (P = .0005). These data indicate that this HSL polymorphism is not associated with NIDDM, obesity, and serum triglyceride level. However, an effect of the polymorphism to elevate serum total cholesterol has not been excluded, although further study is necessary to resolve its association with cholesterol metabolism. PMID- 8692023 TI - Acetyl-L-carnitine deficiency as a cause of altered nerve myo-inositol content, Na,K-ATPase activity, and motor conduction velocity in the streptozotocin diabetic rat. AB - Defective metabolism of long-chain fatty acids and/or their accumulation in nerve may impair nerve function in diabetes by altering plasma or mitochondrial membrane integrity and perturbing intracellular metabolism and energy production. Carnitine and its acetylated derivatives such as acetyl-L-carnitine (ALC) promote fatty acid beta-oxidation in liver and prevent motor nerve conduction velocity (MNCV) slowing in diabetic rats. Neither the presence nor the possible implications of putative ALC deficiency have been definitively established in diabetic nerve. This study explored sciatic nerve ALC levels and the dose dependent effects of ALC replacement on sciatic nerve metabolites, Na,K-ATPase, and MNCV after 2 and 4 weeks of streptozotocin-induced diabetes (STZ-D) in the rat. ALC treatment that increased nerve ALC levels delayed (to 4 weeks) but did not prevent nerve myo-inositol (MI) depletion, but prevented MNCV slowing and decreased ouabain-sensitive (but not -insensitive) ATPase activity in a dose dependent fashion. However, ouabain-sensitive ATPase activity was also corrected by subtherapeutic doses of ALC that did not increase nerve ALC or affect MNCV. These data implicate nerve ALC depletion in diabetes as a factor contributing to alterations in nerve intermediary and energy metabolism and impulse conduction in diabetes, but suggest that these alterations may be differentially affected by various degrees of ALC depletion. PMID- 8692024 TI - Effects of insulin administration on beta-cell function in subjects at high risk for type I diabetes mellitus. AB - The aim of the study was to determine the appropriate dose of subcutaneous insulin to induce "beta-cell rest" without any hypoglycemic risk, as the first stop in the investigation of its potential effect in preventing or delaying clinical diabetes mellitus onset in high-risk subjects. Four subjects at high risk for type I diabetes mellitus (first-degree relatives, islet cell antibodies (ICA)-positive, and with diminished first-phase insulin secretion) were compared with four healthy individuals. After hospitalization, urinary C-peptide excretion (UCP) and 24-hour serum profiles for glucose were measured before and after administration of NPH insulin 0.1, 0.2, and 0.3 U x kg body weight per day subcutaneously in a single dose on 4 consecutive days. After insulin 0.1 U x kg body weight, a significant inhibition of endogenous insulin secretion was observed in high-risk subjects, but not in control subjects. There was no further inhibition when a higher insulin dose (0.2 and 0.3) was administered. A sustained beta-cell rest was obtained after 3, 6, and 12 months of treatment with 0.1 U x kg body weight per day as outpatient therapy in high-risk subjects. With this dose, no subject developed hypoglycemia (plasma glucose <50 mg/dL), whereas this adverse effect was detected after 0.2 and 0.3 U x kg body weight in both groups. In conclusion, our results indicate that administration of NPH insulin 0.1 U x kg bodyweight per day induces beta-cell rest without the undesirable effect of hypoglycemic episodes. This is a preliminary study to investigate the potential beneficial effect of insulin in preventing or delaying type I diabetes mellitus in subjects at high risk for the disease. PMID- 8692025 TI - Plasma oxidizability in Mexican-Americans and non-Hispanic whites. AB - Several lines of evidence support an atherogenic role for oxidized low-density lipoprotein (LDL). Previous studies have suggested that although Mexican Americans have an increased rate of diabetes, obesity, elevated triglyceride levels, and low high-density lipoprotein (HDL) cholesterol levels, their rates of coronary heart disease (CHD) are similar or possibly lower than in non-Hispanic whites. Mexican-Americans have smaller, denser LDL than non-Hispanic whites. On the basis of this latter observation, we postulated that lipid peroxide (LPO) levels would be increased in Mexican-Americans. We examined the oxidizability of plasma in 50 Mexican-Americans and 50 non-Hispanic whites from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease, at baseline and after coincubation with a metal-independent system (2'2'-azobis-2 amidinopropane hydrochloride [AAPH]) and a metal-dependent system (Fe2+/H2O2) of oxidation. LPO levels were measured by a modified fluorimetric assay. Vitamin E and plasma fatty acid composition were also determined. We found significantly higher LPO levels at baseline and after AAPH coincubation in Mexican-Americans than in non-Hispanic whites (baseline, 2.75 +/- .09 v 2.07 +/- .09 micromol/L, P < .001; post-AAPH, 5.49 +/- .14 v 5.07 +/-. .04 micromol/L, P = .037). However, no significant ethnic differences were seen after coincubation with Fe2+/H2O2. Diabetes and cigarette-smoking were also associated with higher LPO levels. Mexican-Americans also had lower levels of vitamin E (the predominant lipid soluble antioxidant in plasma) than non-Hispanic whites, although these differences only partially explained the differences in susceptibility to oxidation. Plasma fatty acids were similar in Mexican-Americans and non-Hispanic whites, suggesting only small differences in diet composition. We conclude that LPO levels are higher in Mexican-Americans than in non-Hispanic whites, and that these results are only partially related to differences in vitamin E levels. PMID- 8692026 TI - Plasma high-density lipoprotein cholesterol but not apolipoprotein A-I is a good correlate of the visceral obesity-insulin resistance dyslipidemic syndrome. AB - Apolipoprotein (apo) A-I is a major component of high-density lipoproteins (HDLs), and it has been suggested that measurement of apo A-I may provide additional information in the assessment of coronary heart disease (CHD) risk. In the present study in a sample of 111 men (age [mean +/- SD], 35.3 +/- 6.6 years), we determined whether a low apo A-I concentration is associated with the cluster of metabolic abnormalities that characterize the visceral obesity-insulin resistance dyslipidemic syndrome. For this purpose, the first and fourth quartiles of apo A-I and HDL cholesterol (HDL-C) concentrations were compared in relation to body fat distribution, glucose tolerance, and plasma insulin and lipoprotein levels. Men in the first quartile (< the 25th percentile) of HDL-C, as compared with men in the fourth quartile (> the 75th percentile), were characterized by an elevated visceral adipose tissue (AT) accumulation (P < .05), as well as by increased plasma levels of triglycerides ([TGs] P < .0001), apo B (P < .0005), and insulin (P < .01). These differences were not found when the first and fourth quartiles of plasma apo A-I concentrations were compared. These results suggest that plasma levels of HDL-C are more closely associated with the various features of the visceral obesity-insulin resistance syndrome than plasma apo A-I. PMID- 8692027 TI - Estrogen increases low-density lipoprotein receptor-independent catabolism of apolipoprotein B in hyperlipidemic rabbits. AB - Estrogen has been reported to increase the catabolism of low-density lipoprotein (LDL) apolipoprotein (apo) B by increasing LDL receptor activity. To determine the effect of estrogen on LDL receptor-independent pathways, paired turnover studies of native LDL and chemically modified LDL (methyl-LDL) were performed before and during estrogen administration in female New Zealand rabbits consuming a diet containing 0.5% (wt/wt) cholesterol. Rabbits were matched by plasma cholesterol concentration and assigned randomly to receive estrogen (estradiol cypionate 0.5 mg/kg/wk) or placebo. The residence time of both the native LDL apo B tracer and the methyl-LDL apo B tracer in plasma was decreased by estrogen but not by placebo. Multicompartmental modeling of the paired, double-labeled turnover studies indicated that an increase in fractional catabolic rate (FCR) of the fast-turnover pool, a kinetically distinct LDL subpopulation in plasma, accounted for the observed decrease in residence time in plasma for both tracers. These data support the hypothesis that, in addition to any effect on the LDL receptor, estrogen promotes the activity of LDL receptor-independent pathways. PMID- 8692028 TI - Measuring glycerol turnover, gluconeogenesis from glycerol, and total gluconeogenesis with [2-13C] glycerol: role of the infusion-sampling mode. AB - Mass isotopomer distribution analysis (MIDA) of glucose during infusion of [2 13C]glycerol is a new method for measuring total gluconeogenesis (GNG). Since this method relies on calculation of the isotopic enrichment (IE) of hepatic triose phosphates (TP), the results should be independent of the sites of tracer infusion and blood sampling. Postabsorptive and starved rats were infused with [2 13C]glycerol and sampled either in the arterial-venous (A-V) or venous-arterial (V-A) modes. Blood was also sampled from the portal vein. In both postabsorptive and starved rats, glycerol turnover rate (Rt) and the percent contribution of glycerol to total glucose production were higher in the A-V mode than in the V-A mode (P < .05). Glycerol IE in portal venous blood was intermediate between IE values observed in peripheral arterial and venous blood. Its use for calculating the contribution of glycerol to glucose production reconciled the results obtained with the two infusion-sampling modes in both postabsorptive and starved rats; this contribution was increased by starvation (P < .01). In postabsorptive rats, total GNG calculated from MIDA of glucose accounted for approximately 50% of glucose production whatever the infusion-sampling mode (A-V, 48.8% +/- 4.7%; V A, 52.2% +/- 3.9%). This contribution increased to 90% in starved rats, again, with no difference between A-V (95.2% +/- 1.8%) and V-A (89.2% +/- 1.3%) modes. In conclusion, during infusion of [2-13C]glycerol, total GNG measured from MIDA of glucose is independent of the infusion-sampling mode, contrary to calculations of Rt and GNG from glycerol. Measurement of glycerol IE in portal venous blood reconciles the results obtained with the two modes with respect to the contribution of glycerol to GNG. PMID- 8692029 TI - The effects of acetyl-L-carnitine and sorbinil on peripheral nerve structure, chemistry, and function in experimental diabetes. AB - Nerve conduction velocity (NCV) increased with age in nondiabetic male Wistar rats for the first 26 weeks of life. The NCV of animals made hyperglycemic at age 6 weeks by administration of streptozotocin (STZ) also increases, but at a slower rate. Animals with 4 weeks of hyperglycemia and reduced NCV treated with an aldose reductase inhibitor (sorbinil) or a short-chain acyl-carnitine (acetyl-L carnitine [ALC]) daily for 16 weeks showed an improvement in NCV. Morphometric studies of tibial nerves collected from animals after 20 weeks of hyperglycemia (age 26 weeks) showed a consistent reduction in the width of the myelin sheath and little change in axon area. The number of large myelinated fibers (>6.5 microns) found in nerves collected from hyperglycemic animals was less than the number found in nondiabetic animals. Treatment of hyperglycemic rats with either sorbinil or ALC was associated with increased NCV, myelin width, and large myelinated fibers. The apparent metabolic effect of these agents was similar for fatty acid metabolism, but different for polyol pathway activity. We conclude that in animals hyperglycemic long enough to slow NCV, sorbinil and/or ALC treatment reduces the functional, structural, and biochemical changes associated with hyperglycemia that occur in the myelin sheath. PMID- 8692030 TI - Insulin resistance syndrome in adolescents. AB - To explore whether the so-called insulin resistance syndrome can be identified in adolescents, serum insulin level was measured in 842 healthy Swedish adolescents (462 boys and 380 girls) and the values were related to current serum lipoprotein and apolipoprotein values (triglyceride [TG], total cholesterol [TC], high density lipoprotein cholesterol [HDL-C), low-density lipoprotein cholesterol [LDL C], apolipoprotein [apo] A-I, apo B, and lipoprotein(a)), blood pressure (BP), and anthropometric measurements and previous physical growth. Mean serum insulin values were higher in 14-year-olds as compared with 17-year-olds and were highest in midpuberty. Adolescents with a high serum insulin had a higher attained height and weight during infancy and childhood. Obesity (body mass index [BMI] > 30 kg/m2) was found in 1% of both boys and girls, and hypertensive BP levels were found in 3% of the boys and 1% of the girls. Controlling for age, serum insulin correlated positively with BMI (r = .36 and .25 in boys and girls, respectively), TG (r = .32 and .14), LDL-C (r = .17 and .24), and apoB (r = .23 and .23) and negatively with HDL-C (r = -.13 and -.21). High serum insulin, TG, LDL-C, and BP and low HDL-C clustered in adolescents with high BMI. In conclusion, the findings of this study indicate that features typical of the insulin resistance syndrome are already present in adolescents. PMID- 8692031 TI - Effects of carbohydrate (CHO) and fat supplementation on CHO metabolism during prolonged exercise. AB - The aim of the study was to examine carbohydrate (CHO) utilization in subjects receiving CHO or CHO + medium-chain triglycerides (MCT) supplements during 180 minutes of exercise at 50% maximal aerobic work rate ([Wmax] 57% maximal oxygen consumption [VO2max]). In a double-blind crossover design, nine trained athletes cycled four times. Subjects received a bolus of 4 mL x kg(-1) at the start and 2 mL x kg(-1) every 20 minutes during exercise of either a 150-g x L(-1) CHO solution (CHO trial), an equicaloric 70 energy% (en%) CHO-30 en% MCT suspension containing 29 g MCT (CHO + MCT trial), or a 150-g x L(-1) CHO (high-CHO [HCHO]) solution plus 20 g MCT (HCHO + MCT trial). A fourth trial consisted of a 13C background control trial (CON). The four trials were randomized. Before and after the exercise bout, muscle biopsies were taken from the quadriceps muscle and muscle glycogen levels were determined. During exercise, breath samples were collected for estimation of exogenous and endogenous CHO oxidation. No significant differences were detected in glycogen breakdown among the trials (277 +/- 14 mmol x kg dry weight(-1) CHO, 249 +/- 20 CHO + MCT, and 240 +/- 18 HCHO + MCT) or in the respiratory exchange ratio during exercise. Mean exogenous CHO oxidation rates during the final hour of exercise were 0.79, 0.63, and 0.73 g x min(-1), respectively. No differences were observed between the trials regarding exogenous or endogenous CHO oxidation. Plasma free fatty acid (FFA) concentrations were elevated during exercise to a level of approximately 500 micromol x L(-1) and were comparable in all trials, whereas plasma ketone concentrations significantly increased after MCT ingestion as compared with the CHO trial. It is concluded that 29 g MCT co-ingested with CHO during 180 minutes of exercise does not influence CHO utilization or glycogen breakdown. PMID- 8692032 TI - Cancer and stress. AB - Chronic stress in humans can cause psychological and physiological reactions. Emotional withdrawal may be accompanied by biochemical changes in a cell that turns it to anaerobic metabolism instead of aerobic respiratory metabolism. These are both aquatic defence mechanisms which whales, as well as humans, can use as part of the diving reflex to escape from stress. The cell now metabolizes anaerobically in the presence of adequate oxygen (the Warburg effect, present in virtually all cancer cells). The oxygen is toxic and causes DNA damage. An ATPase enzyme, normally useful in phosphorylation of sugar, reverts to its former function as part of the SOS 'error-prone' DNA repair system and attempts to repair the damaged DNA by sending in new DNA that causes such mutations in the chromosomes that the cell acts like an anaerobic microbe, reproducing immortally and eventually metastasizing. Chronic stress can be lessened in the treatment of cancer. PMID- 8692033 TI - Fish oil may impede tumour angiogenesis and invasiveness by down-regulating protein kinase C and modulating eicosanoid production. AB - Inhibition of angiogenesis shows considerable promise as a strategy for treating solid malignancies. Induction of collagenase by protein kinase C plays an important role in the angiogenic process as well as in metastasis. Lipoxygenase products are required for endothelial cell mitosis, and also promote collagenase production. By down-regulating hormonal activation of protein kinase C and modulating eicosanoid metabolism, ingestion of omega-3-rich fish oils may impede angiogenesis and reduce tumor invasiveness-thus rationalizing the growth retardant and anti-metastatic effects of fish oil feeding almost invariably seen in animal tumour models. Certain other anti-inflammatory agents-including cromolyn (an inhibitor of protein kinase C activation) and gamma-linolenic acid (which indirectly inhibits lipoxygenase) may have analogous tumour-retardant activity. Clinical application of supplemental fish oil in cancer therapy is long overdue. PMID- 8692034 TI - Inversion-subversion of short DNA sequences by a nuclear vesicle on a kinked chromatid. AB - The paper discusses a mechanism whereby symmetry group actions synergised by a nuclear vesicle and a kink yield either single or double inversions and/or other misorientations of relatively short DNA sequences and genes on small chromatid sections. PMID- 8692036 TI - Can evolutionary principles help resolve the acquired immune deficiency syndrome crisis? AB - The population of retroviruses inside each infected host can quickly adapt its genes in response to survival threats. For this reason, therapeutics attempting to eliminate or inhibit the human immunodeficiency virus have been unsuccessful. However, it may be possible to apply evolutionary principles to the problem of human immunodeficiency virus infection/acquired immune deficiency syndrome. The rapid evolution capabilities of this pathogen might assist researchers in evolving human immunodeficiency virus toward the goal of virus-host coexistence. In this relationship, infecting viruses do not harm their host. Two different examples illustrate the theoretical application of evolutionary principles to this problem. First, by viewing the virus as a new gene of the immune system, it is possible to evolve this gene toward the goal of improving immune function. Second, the retroviral population of each host is maladapted for long-term survival. Retroviral genes could be evolved with respect to continued existence in the host. PMID- 8692035 TI - Hyperglycemia-induced latent scurvy and atherosclerosis: the scorbutic-metaplasia hypothesis. AB - Latent scurvy is characterized by a reversible atherosclerosis that closely resembles the clinical form of this disease. Acute scurvy is characterized by microvascular complications such as widespread capillary hemorrhaging. Vitamin C (ascorbate) is required for the synthesis of collagen, the protein most critical in the maintenance of vascular integrity. We suggest that in latent scurvy, large blood vessels use modified LDL--in particular lipoprotein(a)--in addition to collagen to maintain macrovascular integrity. By this mechanism, collagen is spared for the maintenance of capillaries, the sites of gas and nutrient exchange. The foam-cell phenotype of atherosclerosis is identified as a mesenchymal genetic program, regulated by the availability of ascorbate. When vitamin C is limited, foam cells develop and induce oxidative modification of LDL, thereby stabilizing large blood vessels via the deposition of LDL. The structural similarity between vitamin C and glucose suggests that hyperglycemia will inhibit cellular uptake of ascorbate, inducing local vitamin C deficiency. PMID- 8692037 TI - IGHG3 G and the pathogenesis of hyperreactive malarious splenomegaly. AB - Hyperreactive malarious splenomegaly is an aberrant response to chronic malarial infection, defined by persistent gross splenomegaly and elevated serum IgM and IgG. The populational and familial patterns of this disorder suggest genetically based, immune incompetence. In Papua New Guinea, the disease occurs among populations characterized by high frequencies of IGHG3 G haplotypes. Elsewhere, the distribution and prevalence of hyperreactive malarious splenomegaly is consistent with the distributions of IGHG3 alleles. Drawing upon this relationship, I suggest that expression of the G3M G phenotype is a necessary precondition for hyperreactive malarious splenomegaly, consistent with the pathogenesis of malaria and the functions of the immune system. PMID- 8692038 TI - Role of gangliosides in tumour progression: a molecular target for cancer therapy? AB - In a number of patients with tumours of either neuroectodermal or epithelial origin, polysialylated gangliosides (e.g. GD3) are over-expressed. The mechanism of ganglioside over-expression may be different for the two classes of tumour and could represent distinct secondary genetic mutations or epigenetic changes affecting the enzymes (transferases and/or hydrolases) controlling the metabolic interconversions of these gangliosides. Tumour cells of neuroectodermal origin (e.g. melanomas and brain tumours) are known to produce and shed polysialylated gangliosides, whereas paracrine signal(s) from tumour cells of epithelial origin (e.g. carcinomas of cervix, lung, prostate, breast, head and neck, colon and ovary) may stimulate over-expression and shedding from tumour infiltrating mesenchymal cells (e.g. macrophages and/or fibroblasts). This cellular membrane over-expression and shedding of acidic glycosphingolipids into the interstitial spaces and blood of cancer patients may play a central role in increased tumour cell growth, lack of immune cell recognition and neovascularization and could represent a molecular target for cancer therapy. PMID- 8692039 TI - Natural course of growth hormone hypersecretion in insulin-dependent diabetes mellitus. AB - High growth hormone levels in patients with insulin-dependent diabetes were recognised 25 years ago. For many years this has been explained as an epiphenomenon of poor metabolic control. The natural course of the disease is characterised by gradual loss of residual beta-cell function and parallel elevations of plasma growth hormone and can be divided into three consecutive phases. It appears that the hormonal changes observed are determined by the IGF-1 generating capacity of the liver which, in turn, is dependent on the synergistic stimulating action of growth hormone and portal insulin. The first (initial) phase of insulin-dependent diabetes mellitus is characterised by the absence of insulin, high growth hormone levels and low plasma IGF-1. The pituitary growth hormone response to exercise and other stimuli is pathological. The second phase of disease ('C-peptide positive phase') is characterised by the return of some residual beta-cell insulin secretion, increased levels of growth hormone compared to non-diabetic subjects, physiological IGF-1 levels and near normal pituitary growth hormone responses to different agents. The third phase of the disease is characterised by complete loss of endogenous insulin secretion, very high plasma growth hormone levels, low normal plasma IGF-1 but impaired hepatic IGF-1 generating capacity. The control mechanisms of pituitary growth hormone secretion (long loop negative feedback and auto-feedback), are disturbed. PMID- 8692040 TI - Does ozone therapy normalize the cellular redox balance? Implications for therapy of human immunodeficiency virus infection and several other diseases. AB - The role of ozone on earth is controversial, as in the stratosphere it is protective against excessive ultra violet irradiation, and in the troposphere it is toxic for animals and plants. The effectiveness of ozone against pathogens is well recognized and ozone appears to be the best agent for sterilization of water. In spite of this, the use of ozone in medicine has been overlooked or despised, mostly because it has been either misused or used without appropriate controls. Studies carried out in our laboratory have revealed that ozone can display relevant biological effects and that, having defined its therapeutic index, can become an important and reliable drug for the treatment of several diseases. An exciting new aspect is that ozone, being a strong oxidizer, can stimulate the increase of cellular anti-oxidant enzymes, eventually inhibiting the oxidative stress. PMID- 8692041 TI - Non-ischemic hypoxia of the arterial wall is a primary cause of atherosclerosis. AB - The response-to-injury hypothesis has been the dominant model of atherosclerosis for 20 years. However, it does not explain the experimental role of oxygen in atherogenesis, does not explain many of the clinical features of atherosclerosis, and has failed to provide useful countermeasures. I propose that arterial wall hypoxia results from risk factors for atherosclerosis. The primary mechanism is decreased oxygen delivery by a microcirculatory derangement resulting from impaired erythrocyte deformability. As in a healing wound, hypoxia causes growth factor release within the arterial media. Diffusion of these factors causes intimal proliferation and atheroma formation. This hypothesis implies that simple inexpensive oxygenation regimens might prevent the morbidity and mortality of atherosclerosis. Despite demonstrated effectiveness in experimental models, such treatments have not been extensively studied in clinical atherosclerosis because they conflict with the dominant model. This dogma needs to be re-examined. PMID- 8692042 TI - Sudden infant death syndrome: orthostatic intolerance and disordered antigravity postural mechanisms. PMID- 8692044 TI - Organ/body weight loss with aging: evidence for co-ordinated involution. AB - Loss of body weight, during later stages of aging, is a phenomenon recognized in all human populations studied. Reduction of body weight is accompanied by a loss of internal organ weight and volume. The usual approach is to describe organ weight versus age. However, organ weight can be related to overall body weight, by means of the allometric equation. This general expression can be used to relate the weight of each of several organs to that of the body, and offered a good description of data for a reported Japanese autopsy study on males and females over the age of 60 years. The equations were also used in describing the ratio of organ weights (such as the spleen/liver weight). A further extension was in examining the terms of the allometric equation (a constant and an exponent for each organ), and noting a close coupling between male and female values. The allometric description of organ weights versus body weight, suggests a 'co ordinated involution', and appears worthy of further investigation. PMID- 8692043 TI - Mycobacterial infections: are the observed enigmas and paradoxes explained by immunosuppression and immunodeficiency? AB - The enigmas and paradoxes observed in tuberculous patients, in Bacille Calmette Guerin-vaccinated people and in Bacille Calmette-Guerin-treated cancer patients have been examined, in an attempt to explain them through the mechanisms of immunodeficiency and immunosuppression. A dual effect is postulated: an immunosuppression induced by the infecting mycobacteria that adds to a pre existing or emerging state of immunodeficiency of the infected individual. The immunological cellular and humoral anergies observed at the beginning of a tuberculous therapy are usually lifted after the first two weeks of treatment. This restoration of immune responsiveness may be attributed to the destruction or to the growth inhibition of immunosuppressive mycobacteria. The observation that drugs cytocidal in vitro do not always sterilize the patients under treatment whereas bacteriostatic drugs do, may find an explanation in the dual immunosuppression induced by cytocidal drugs and mycobacteria. The fact that Bacille Calmette-Guerin applied as an immunotherapy to residual cancer has either a favorable or an unfavorable action may be due to the immunosuppressive activity attached to some Bacille Calmette-Guerin strains and to some cancers. The variable protective activity of Bacille Calmette-Guerin vaccines may be due to the immunological status of the vaccinated people and the compositional differences between strains. The protective activity of subunit vaccines in experimental models can be attributed to the elimination of immunosuppressive factors present in whole killed mycobacteria. PMID- 8692045 TI - The rise and fall of the chronic fatigue syndrome as defined by Holmes et al. AB - This paper is a sequel to my monograph on neurocirculatory asthenia and chronic fatigue syndrome. It pays special attention to the nature of chronic fatigue syndrome, to the forms of neurocirculatory asthenia, and above all to the 6th form in which profound fatigue is the dominant symptom. All forms including the 6th are characterized by the presence of concomitant symptoms due to dysfunction of the autonomic nervous system. Chronic fatigue syndrome as defined by Holmes et al is devoid of these symptoms. Up till the present day no case histories of it have been published. It is argued that chronic fatigue syndrome sensu Holmes et al does not exist, the 6th form of neurocirculatory asthenia having to take up its place. PMID- 8692046 TI - Multiple sclerosis: sunlight, diet, immunology and aetiology. AB - Multiple sclerosis is more common in temperate latitudes, and migration studies indicate the involvement of an aetiological environmental factor in pre-pubertal life; the precise nature of this factor has never been identified and may perhaps have been overlooked. Here we suggest a simple explanation for the latitude gradient of multiple sclerosis, i.e. that it can be explained by the immunosuppressant effects of sunlight mediated via suppression of the secretion of the immunostimulatory neurohormone melatonin from the pineal gland. The effects of dietary fatty acids in multiple sclerosis also indicate the involvement of anti-inflammatory eicosanoids in its pathogenesis. We further suggest that the exceptions to the latitude gradient (e.g. Japan), which have previously been attributed to genetic factors, may in fact have a dietary basis. Since sunlight also influences the metabolism of fatty acids in the retina, it may also influence the development of retrobulbar optic neuritis-a common antecedent of multiple sclerosis. We suggest a re-examination of the epidemiology of multiple sclerosis based on an understanding of the immunological consequences of illumination of the retina by sunlight. PMID- 8692047 TI - Short note: towards re-interpretation of the standard model of the immune system- the saver system subset--and a very simple test. AB - Assembling pieces of the standard model of the immune system, a saver system subset is proposed, comprising a continuously active circulating subsystem of saver cells and saver bodies which inspect every cell and antigen and saves/interrupts from self attack. PMID- 8692048 TI - Chromium and other insulin sensitizers may enhance glucagon secretion: implications for hypoglycemia and weight control. AB - Increased pancreatic beta-cell secretory activity usually is associated with decreased alpha-cell activity; stimulated beta-cells release gamma-aminobutyric acid, which hyperpolarizes alpha-cells, inhibiting glucagon release. Thus, insulin secretion and glucagon secretion are usually inversely coupled. This suggests that chromium and other insulin-sensitizing modalities, by down regulating beta-cell activity, may increase glucagon secretion. Such an effect might play a role in the documented therapeutic activity of supplemental chromium and biguanides in reactive hypoglycemia, and might also be of benefit to dieters. PMID- 8692049 TI - Gene competition and the possible evolutionary role of tumours. AB - The evolutionary role of tumours might consist of providing the conditions for the expression of evolutionary new genes and thus in providing the material for the origin of new cell types. To approach this concept the principle of gene competition is essential. With an increase in gene number in the genomes of the evolving multicellular organisms the enforcement of gene competition should take place. Therefore, the pre-existing cell types possess limited possibilities for the expression of evolutionary new genes. Like evolutionary new genes originated from extra copies (duplicates) of old genes, evolutionary new cell types had to originate from extra cells which were not functionally necessary to the organism. Tumours could have supplied the evolving multicellular organisms with extra cells for the expression of originating evolutionary new genes. Of course, on the basis of this proposal only tumours at the earlier stages of progression are considered to be meaningful, or some kind of tumour-like processes, but not malignant tumours at late stages of progression. The evolutionary new genes originate in the DNA of germ line cells but not in DNA of tumour cells. Until the moment of their expression in the tumour cells these genes could stay silent. After the expression of these genes tumour cells should acquire the function in the organism, differentiate and lose their previous autonomy. The organisms with a new cell type should then be selected against their fitness and competitive abilities. PMID- 8692050 TI - The etiology of male homosexuality. AB - This hypothesis agrees with Le Vay's suggestion that the two phenomena of childhood behavior and adult sexuality are induced by separate events rather than being two events in a single chain. However, it differs from Le Vay in that it includes the postnatal period, as being of crucial importance in the development of adult sexuality. Male homosexuality is portrayed as a biological variation of human sexuality and the hormonal changes which may produce it are described. It is postulated that sexual preference is dictated by testosterone action on the brain possibly commencing prenatally but certainly continuing during a critical postnatal period. It is proposed that reduction in testosterone action results in reduced proliferation of hypothalamic nuclei, which play a vital role in psycho sexual orientation. The cause of this reduction in testosterone is the prolongation of hyperprolactinemia during this critical postnatal period, which is deemed to be secondary to prolactin microadenomata stimulated to secrete prolactin by high estrogen levels at the end of pregnancy and failing to turn off this secretion until after this critical postnatal period. It is postulated that there is a temporal dissociation between the development of masculine behaviour and psycho-sexual orientation, but that hormonal influences may overlap these periods. Hyperprolactinemia, caused by stress upon the infant, may also influence psycho-sexual orientation. PMID- 8692051 TI - Complementary vascular-protective actions of magnesium and taurine: a rationale for magnesium taurate. AB - By a variety of mechanisms, magnesium functions both intracellularly and extracellularly to minimize the cytoplasmic free calcium level, [Ca2+]i. This may be the chief reason why correction of magnesium deficiency, or induction of hypermagnesemia by parenteral infusion, exerts antihypertensive, anti atherosclerotic, anti-arrhythmic and antithrombotic effects. Although the amino acid taurine can increase systolic calcium transients in cardiac cells (and thus has positive inotropic activity), it has other actions which tend to reduce [Ca2+]i. Indeed, in animal or clinical studies, taurine lowers elevated blood pressure, retards cholesterol-induced atherogenesis, prevents arrhythmias and stabilizes platelets--effects parallel to those of magnesium. The complex magnesium taurate may thus have considerable potential as a vascular-protective nutritional supplement, and might also be administered parenterally, as an alternative to magnesium sulfate, in the treatment of acute myocardial infarction as well as of pre-eclampsia. The effects of magnesium taurate in diabetes deserve particular attention, since both magnesium and taurine may improve insulin sensitivity, and also may lessen risk for the micro- and macrovascular complications of diabetes. PMID- 8692052 TI - Screening for colorectal cancer, 1996. AB - Screening average-risk people aged 55 to 70 years for colorectal cancer is now a public health priority in Australia. Pilot studies of faecal occult blood testing are required to find ways of achieving optimal compliance and cost efficiency in the Australian health care setting. Flexible sigmoidoscopy probably should be used as complementary screening but further trials are needed. High-risk groups (family history of colorectal cancer, or previous ulcerative colitis, adenomas or cancer) should already be in surveillance programs. PMID- 8692053 TI - Emerging issues in sleep-disordered breathing. AB - Community studies of problems with breathing during sleep suggest that sleep disordered breathing is a better general term than sleep apnoea. Male sex, increasing age and increasing neck size are the main factors differentiating people with from those without sleep-disordered breathing. The contribution of sleep-disordered breathing to morbidity has not been established. Future research should address the possible cardiovascular associations of sleep-disordered breathing, its impact on sleepiness in the community, and the cost-effectiveness of treatment. PMID- 8692054 TI - Further reflections on the NHMRC recommendations for alcohol consumption. PMID- 8692055 TI - Risks of self-injection therapy for impotence. PMID- 8692056 TI - Medicine and the community--the euthanasia debate. PMID- 8692057 TI - Severe stroke: a carer's viewpoint. PMID- 8692058 TI - If it's the virus why aren't we measuring it? PMID- 8692059 TI - Protecting Australian overseas travellers. PMID- 8692060 TI - Screening--sensitivity, specificity and hepatitis C. PMID- 8692061 TI - Screening for colorectal cancer: too early to be dogmatic. PMID- 8692062 TI - Down on the farm: health and safety in Australian agriculture. PMID- 8692064 TI - World population day. PMID- 8692063 TI - Compensation and recovery from injury. PMID- 8692065 TI - Flexible sigmoidoscopy screening for colorectal cancer in average-risk subjects: a community-based pilot project. AB - OBJECTIVE: To test a pilot screening program for colorectal cancer. DESIGN: Subjects, chosen at random and recruited by mail, were examined by flexible sigmoidoscopy. PARTICIPANTS AND SETTING: Normal-risk, asymptomatic men and women aged 55-59 years recruited from the community, July to December, 1995. MAIN OUTCOME MEASURES: Number of polyps detected and cancers diagnosed, and compliance with screening. RESULTS: Letters of invitation were sent to 3500 subjects; of these, 2881 were eligible for inclusion in the study and 342 (12%) consented to participate. A further 3.5% of non-compliant subjects attended the screening program after a telephone survey assessing reasons for non-attendance. Common reasons for non-attendance were a lack of interest (30%) or a lack of time, mainly due to work commitments (28%). A third of subjects had polyps and 46% of these were adenomas. Three subjects were found to have adenocarcinoma: in two the cancer was confined to a polyp and treated with polypectomy, and one subject underwent anterior resection (overall prevalence of cancer, 0.9%). The median depth of insertion achieved with flexible sigmoidoscopy was 55 cm (range, 25-100 cm). Median pain level (on a scale of 0 = no pain to 10 = worst pain imaginable) was 2 (range, 0-8.5), and 99% of the subjects would have the test again if required. CONCLUSIONS: Flexible sigmoidoscopy was well tolerated and had an acceptable detection rate of adenomatous polyps and early cancer. Subject compliance emerged as a major issue which requires further evaluation to maximise participation in future programs. PMID- 8692067 TI - The effect of workers' or third-party compensation on return to work after hand surgery. AB - OBJECTIVES: To investigate the role of compensation in recovery from scaphoid internal fixation. DESIGN: Retrospective review of patients who had had scaphoid internal fixations performed by one surgeon between 1 September 1981 and 31 December 1994 with a minimum follow-up of six months. SETTING: Private practice of a specialist hand surgeon. PATIENTS: 202 patients who attended for the minimum of six months' follow-up, and for whom accurate details of return-to-work time were available. INTERVENTION: Internal fixation of scaphoid fractures using the Herbert bone screw without postoperative immobilisation. MAIN OUTCOME MEASURES: Return-to-work time and compensation status. RESULTS: Overall, patients receiving compensation took more than twice as long as privately insured individuals to return to work after scaphoid internal fixation (7.3 v. 3.3 weeks). There was no difference for clerical workers, but for manual workers compensable individuals took significantly longer (P < 0.001) to return to work. Compensation status did not affect bony union, postoperative wrist function, pain or patient satisfaction. CONCLUSIONS: Compensation encourages a slower return to work after surgery. The current compensation system could save millions of dollars each year by incorporating incentives to return to work without sacrificing good surgical results. PMID- 8692066 TI - Alzheimer's disease and apolipoprotein E genotype in Western Australia: an autopsy-verified series. AB - OBJECTIVE: To determine the relationship between the apolipoprotein E epsilon 4 allele and autopsy-verified Alzheimer's disease (AD) in an Australian population. DESIGN: Retrospective case-control study. SETTING: Royal Perth Hospital, Perth, Western Australia (a tertiary referral hospital). SUBJECTS: 50 subjects with "definite" AD (according to the histological and clinical criteria of the Consortium to Establish a Registry for Alzheimer's Disease [CERAD]) and 30 control subjects who had died from a non-neurological disease were randomly selected from the hospital's neuropathology register. OUTCOME MEASURES: Histological grading of brain sections stained with the modified Bielschowsky stain according to the criteria of CERAD; number (burden) of neuritic plaques; apolipoprotein E genotype (APOE). RESULTS: Frequency of the epsilon 4 allele was significantly higher in the AD group (37%) than in the control group (2%) (chi 2 = 25.8; P < 0.00001). In the AD group, 50% of subjects were heterozygous for the epsilon 4 allele and 12% were homozygous, while in the control group one subject was heterozygous for the allele and none were homozygous. No association was seen between the epsilon 4 allele and neuritic plaque burden in the hippocampus, entorhinal cortex, middle frontal gyrus or inferior parietal lobule in subjects with AD. CONCLUSIONS: Our findings confirm an association between the epsilon 4 allele and autopsy-verified AD. The epsilon 4 allele may be an important risk factor for susceptibility to AD in the general Australian population. PMID- 8692068 TI - Mother-to-baby transmission of hepatitis G virus. AB - A mother tested positive for hepatitis G virus (HGV) by reverse transcription polymerase chain reaction (RT-PCR) before and at delivery. Her baby tested HGV negative by RT-PCR at birth but serum samples at four and six weeks of age were HGV positive, suggesting transmission of HGV from mother to baby. PMID- 8692069 TI - Managing HIV. Part 7: Professional issues. 7.1 HIV infection control in medical practice. AB - Reports of cross-infection with HIV and hepatitis C during routine surgery in Sydney have refocused attention on preventing transmission of HIV and other blood borne viruses in the health care setting. This review examines the risks of transmission in medical practice, summarises infection control measures and examines issues regarding the HIV-infected health care worker. PMID- 8692070 TI - Managing HIV. Part 7: Professional issues. 7.2 HIV and confidentiality. PMID- 8692071 TI - Managing HIV. Part 7: Professional issues. 7.3 What do people with HIV, their carers and families want of their medical carers? PMID- 8692072 TI - Photosensitivity. PMID- 8692073 TI - Interferon beta-1A for relapsing multiple sclerosis. PMID- 8692075 TI - Drugs past their expiration date. PMID- 8692074 TI - Dexfenfluramine for obesity. PMID- 8692076 TI - Choice of lipid-lowering drugs. PMID- 8692077 TI - [Ethics in psychopharmaceutical research]. AB - This paper deals with deontological considerations, especially with ethical aspects of examining drug effects in psychiatric institutions. These observations are based on the author's ten-year research experience. PMID- 8692078 TI - [Factors affecting the efficiency (sensitivity, specificity) of diagnostic procedures for the detection of Chlamydia trachomatis infections of the male and female genital tract]. AB - This paper presents and analyzes some factors which may exert influence on the outcome of the diagnostic procedure in establishing male and female genital tract infections with Chlamydia Trachomatis. On the basis of this study it has been suggested that diagnostic procedures used nowadays should be used selectively, either individually or as a group within defined optimal conditions. PMID- 8692079 TI - [The future of psychiatric hospitals]. AB - We are of the opinion that it is less important whether a large mental hospital is regionalized or not, but whether it is possible to realize the principle of universal psychiatric protection as a "unity of responsibilities of all subjects who take part in the protection of mental health and the society in the whole" by improvement and advancement of the existing system. We accept the opinion that the internal organization of mental hospitals has to be changed by organizing hospitals wards with 30-50 beds. We consider that in a perspective organization of psychiatric protection of all institutions (large hospitals, clinic, psychiatric wards of general hospitals, dispensaries and health centers) have their role and that the achieved level of the protection greatly depends on socio economic level and possibilities. PMID- 8692080 TI - [Nervous system plasticity in the recovery of patients after cerebrovascular stroke]. AB - Plasticity is a very important characteristic of the nervous system structures, due to which it alliterates the functioning way, recompenses deranged function and adapts to new conditions caused by damage. Deranged brain circulation is very frequently caused by the arteriosclerosis which can finally cause stroke. Stroke usually appears at the age of 60-69 years, but in persons of different ages as well. The aim of rehabilitation is to ensure quality of life as much as possible. In young persons recovery after stroke is usually successful, whereas the plasticity of the nervous system is completely preserved. PMID- 8692081 TI - [Sociodemographic and epidemiologic characteristics of hospitalized alcoholics in Vojvodina]. AB - Using the Register of hospitalized alcoholics in Vojvodina we analyzed data on sociodemographic and epidemiologic characteristics of the alcoholic disease. This retrospective study, using longitudinal and anamnestic data during a three-year period (1991-1993) deals with all patients treated for Alcohol Dependency Syndrome (according to the International classification of diseases, IX revision) treated at neuropsychiatric institutions in Vojvodina and living on this territory. The sample consisted of 4783 examinees. The gathered results indicate that there is a decrease in number of patients treated for alcoholic disease, that is in incidence, prevalence and risk of morbidity in regard to the population of the examined territory. As this decrease is associated with a decreased number of registered psychiatric, neurologic, and somatic complications of the alcoholic disease, the authors may conclude that the intensity of actual social pathology and social disorders, which are characteristic for the above mentioned period resulting in the decrease of production and consumption of alcohol, decreases alcoholism and its complications. PMID- 8692082 TI - [MEDLINE on compact disk as an information source at the Medical School Library in Novi Sad]. AB - The transformation of the Library at the Medical Faculty of Novi Sad into a modern information center necessitated the introduction of an up-to-date technology and enforced the use of the latest information sources among which MEDLINE medical database is the most famous one. In the studied period, January 1993-current, 200 searches have been performed on the basis of which the following parameters were analyzed: institution, occupation, and degree of the user, purpose and accuracy of the order, relevant period, number and format of the references, assessment of the search quality and the quality of the library staff services. The analysis proved the initial belief that MEDLINE is a remarkably valuable data base necessary for medical libraries. PMID- 8692083 TI - [Basic characteristics of bacterial meningitis in patients treated at the Clinic for Infectious Diseases in Novi Sad during a 2-year period]. AB - Although known for centuries, bacterial meningitis is a disease which still causes death and invalidity no matter there are modern diagnostic methods and therapeutic modalities. Our investigation included 45 patients treated for a purulent meningitis during a two-year period at the Clinic for Infectious Diseases in Novi Sad. Most patients suffered from meningococcal meningitis. The onset of the disease was sporadic, during winter and spring, and there were no contact cases. Most patients were 2-3 and 8-15 years of age. Patients with pneumococcal meningitis had the most serious clinical picture, course of the disease, laboratory results, as well as outcome of the disease. PMID- 8692084 TI - [Systemic diseases: evaluation of important laboratory parameters in 3 cases with unusual skin changes]. AB - A whole spectrum of various clinical and laboratory disorders in patients with skin changes, may present systemic disease manifestations. Serological parameters correlate with the progression of the disease. Authors present cases with unusual skin lesions and abnormal laboratory findings, that were presumed to be manifestations of the systemic disease progression. The first case is a report of a patient age 44, female with dermatomyositis that started suddenly from full health with generalized linear bluish dark erythematous lesion like excoriations, periocular heliotrope violaceous to dusky erythematous rash with edema in a symmetrical distribution involving periorbital skin with no pruritus, diagnosed on admission as the case of acute urticarica. In the second report, a 17-year old female was referred to us because of a spread up linear sclerodermia followed by high immunological disturbances. Our third case was a 21-year old female with a systemic lupus erythematous--Rowell syndrome, with skin lesions of erythema multiforme type with some similarities to dermatitis herpetiformis on the first examination. PMID- 8692085 TI - [Identification and rehabilitation of high-risk patients in the prevention of atherosclerotic ulceration]. AB - From the medicosocial point of view, arteriosclerosis obliterans is important not only because of the increased number of the diseased, but also because of being more and more prominent in the mortality of cardiovascular diseases. This paper presents a case report which points to the importance of synchronized diagnostic and therapeutic process--on time identification of the II clinical stage of arteriosclerosis obliterans (electromyoneurography, US-Doppler, perfusion pressure), and application of physiotherapeutic measures which can contribute to effective therapy and rehabilitation. Using vasotrain apparatus (hyper-hypo-baric effect) and other therapeutic measures in the patient with arteriosclerosis obliterans, diabetic polyneuropathy and compression traumatic radiculopathy, regression from the IIB to IIA clinical stage was achieved as well as of features of diabetic polyneuropathy. In this way the III clinical stage of arteriosclerosis obliterans can be delayed. PMID- 8692086 TI - [Respiratory tract hemorrhage]. AB - Bleeding from the respiratory tract can be met in everyday clinical practice. The number of patients with bleeding is not small, which implies that every physician should have adequate knowledge in order to react promptly, when needed. We have underlined the causes and the accessory factors which promote bleeding, localization--upper and lower respiratory tract, diagnostic methods which are available, prevention and treatment of bleeding. PMID- 8692087 TI - [Etiopathogenesis of obesity]. PMID- 8692088 TI - [Calcification in atherosclerotic plaque as one of the types of complicated atherosclerotic lesions]. AB - Calcifications of the atherosclerotic plaque is the form of a complicated atherosclerotic lesion. It is characterized by granular or massive deposits of calcium chloride inside the atherosclerotic plaque. It was found in at least one of the three main coronary arteries in 43 (86.00%) out of 50 autopsy cases. In all three, coronary arteries calcifications were found in 8 (18.60%) cases, in two coronary arteries in 19 (44.19%), and one coronary artery in 16 (37.21%) cases. Calcifications of atherosclerotic changes which contain fats were statistically significantly more frequently established than those which did not contain fats. In three fourths of cases calcifications were present in segments with significant narrowing of the arterial lumen (group 3 and 4). In 59.61% of calcificated atherosclerotic changes the residual lumen was of eccentric shape, in 20.51% of concentric shape, in 7.69% it was semilunar, and in 12.18% a few lumens were detected (channeled and organized thrombi). Granular deposits of calcium were established 63.46%, while massive in 36.54% of segments of atherosclerotic lesions, but no statistically significant difference in distribution of these two types of calcifications was established in regard to the type of atherosclerotic change. PMID- 8692090 TI - [The importance of medical psychology]. PMID- 8692089 TI - [Fertility in men after mumps infection without manifestations of orchitis]. AB - The study presents results of an investigation on male fertility after mumps infection without clinically manifested mumps orchitis. The study included 30 patients, but 10 were excluded because of other ethnologic factors connected to male infertility. Out of 20 patients 12 were fertile, while 8 were subfertile. All of these 8 subfertile patients were with asthenospermia, that is with decreased sperm motility. PMID- 8692091 TI - [Response of pancreatic polypeptide to a protein test meal in the evaluation of diabetic autonomic neuropathy]. AB - In normal subjects, the early human pancreatic polypeptide increase induced by food is mainly dependent on vagal activity. Parasympathetic function and plasma human pancreatic polypeptide response to a protein rich meal were evaluated in 105 insulin nondependent diabetic patients: 20 only with autonomic neuropathy (group A), diagnosed by clonidin test and tests of cardiovascular reflexes, 35 patients with neurophysiological evidence of polyneuropathy (group B), 30 patients with autonomic neuropathy and polyneuropathy (group C) and 20 patients without any sign of neuropathy (group D). Plasma human pancreatic polypeptide levels were determined by radioimmunoassay using an anti-human pancreatic polypeptide antiserum. Blood was taken at 0, 45 and 60 minutes after the beginning of the meal. In groups A and C, the meal induced human pancreatic polypeptide increase was significantly lower than in group D (45. min:, 65.8 + 16.2(A), 54.0 + 19.2 pg/ml (C) in regard to 130.0 + 27.6 pg/ml (D); 60, min: 55.2 + 15.6 (A), 37.0 + 11.2 pg/ml (C) in regard to 121.7 + 15.4 pg/ml (D). In group B patients had a marked increase of peptide, similar to that in diabetics without neuropathy. These results suggest that diabetic autonomic neuropathy is associated with the dysfunction of human pancreatic polypeptide secretion and that evaluation of his response to test meal may be a sensitive and simple method for the assessment of parasympathetic impairment in diabetics. PMID- 8692092 TI - [Changes in ocular refraction after tamponade with silicone oil]. AB - In order to study refractive changes caused by a intravitreal silicone oil injection we retrospectively analyzed 25 eyes after vitreoretinal surgery combined with silicone oil tamponade. In all cases the postoperative visual acuity was 0.1 or better. Mean difference in refraction after silicone oil tamponade in phakic eyes was +5.07 Dsph (+2.0 to +8.0 Dsph). Mean refractive change in the aphakic silicone oil filled eyes was - 6.63 Dsph (-4.0 to -9.0 Dsph). Silicone oil extraction induced a greater refractive change (myopic shift, mean -5.57 Dsph) than silicone oil injection. After silicone oil extraction from the aphakic eyes refractive changes (shift towards hypermetropia, mean +5.86 Dsph) were less manifest than after silicone oil injection. The disparity could be explained by eye elongation after cerclage performed during primary vitreoretinal surgery. PMID- 8692093 TI - [Clinical use of hematopoietic growth factors--general principles]. AB - Biology of haematopoietic growth factors in the process of haematopoiesis is well known, but their clinical utilization started with production of recombinant preparations. Today only preparations of Erythropoietin, GM-CSF and G-CSF are commercially at disposal. Absolute indications for utilization of haematopoietic growth factors are states caused by decreased production of certain classes of blood cells as a consequence of shortage of a growth factor necessary for production of a certain class. As these states are very rare, relative indications spread to other states characterized by a decreased number of blood cells or necessity for stimulation of haematopoiesis due to any other reason. This paper contains results of clinical researches only for those growth factors which are not commercially utilized.: M-CSF, Interleukin 3, PIXY321, SCF, Interleukin 6, Interleukin 11, Interleukin 1, Interleukin 2 and Thrombopoietin. Our institution utilizes only the preparations of Erythropoietin (Eprex) and G CSF (Neuprogen) in 38 patients. PMID- 8692094 TI - [New findings on the etiopathogenesis and clinical manifestations of Epstein-Barr virus infections]. AB - Epstein-Barr virus is an ubiquitous member of the human herpes virus family. A specific antigen structure of the Epstein-Barr virus was discovered in the last decade. It was possible to diagnose some unusual clinical manifestations of EBV infections and its clinical course by different serologic analyses (immunofluorescent tests, immunoenzyme assay and polymerase chain reaction). This is very important in cases of atypical primary infections (hepatitis, meningoencephalitis), chronic mononucleosis and lymphoproliferative disorders and nasopharyngeal carcinoma. Famciclovir, a new antiviral agent (peroral form of penciclovir) may play an important role in the therapy of these infections. PMID- 8692095 TI - [Isotretinoin in dermatologic practice]. AB - In dermatology Isotretinoin has been used for 16 years in cases of serious clinical forms of acne resistant to common therapy. This paper presents actual knowledge on pharmacokinetics of isotretinoin, mechanisms of its action, side effects, the newest clinical indications for its application in acne therapy and other possible indications in the contemporary dermatology. PMID- 8692096 TI - [Evaluation of ejection fraction and end-diastolic volume using one-dimensional and two-dimensional echocardiography]. AB - A group of 30 healthy persons and 120 coronary patients were investigated by one and two-dimensional echocardiography and digital subtraction angiography. End diastolic volume and ejection fraction were estimated. Patients with coronary disease had greater volumes than healthy persons and smaller ejection fraction as well. The correlation of the given values showed that data gathered by two dimensional echocardiography have greater coefficient in comparison to digital subtraction angiography (end-diastolic volume index r = 0.86, ejectional fraction r = 0.88, p < 0.01) than the same data estimated by one-dimensional technique. Two-dimensional echocardiography is a reliable noninvasive method for evaluation of these significant indicators of left ventricle function. PMID- 8692097 TI - [Early aggressive treatment in severe craniocerebral injuries]. AB - A series of 33 severely head injured patients, Glasgow Coma Scala score 8 or less, was studied prospectively. All patients were treated by the same protocols and by the physician. Intracranial pressure was monitored in all patients by ventricular puncture. Some degree of increased intracranial pressure (more than 10mmHg) was present at admission to the intensive care unit in 52% of cases. Increases in over 20mmHg during the monitoring period were seen in 15 patients (45%). In 5 patients (15%) he was over 20mmHg, but controlled in intensive care unit with combination of dexamethasone, hyperventilation, normothermia, furosemide and mannitol. In this group mortality rate was 80%. In 10 patients (30%) intracranial hypertension was uncontrollable despite intensive measures, in this group all patients died. The mortality rate in patients with intracranial pressure less than 20mmHg during the monitoring period was significantly lower, 25%. Uncontrollable intracranial hypertension is a serious prognostic sign; all affected patients in our series died. Even intracranial pressure more than 20mmHg, which could be controlled, was associated with high mortality rate (80%). By early aggressive treatment based on intracranial pressure monitoring we can diminish the incidence of intracranial hypertension and reduce overall mortality rate in patients with severe head injury. PMID- 8692098 TI - [Characteristics of persons killed by firearms and examined at the Institute of Forensic Medicine in Novi Sad 1989-1993]. AB - Gunshot wounds present an actual medical problem today. This research deals with a group of deceased persons murdered by firearms examined at the Institute of Forensic Medicine Novi Sad during the period 1989 - 1993 (402 persons). The analysis included sex and age structure as well as forensic medical categories connected to characteristics of gunshot wounds and wounds by explosion. Out of the total number of examined persons murdered during the analyzed period 11.92% of cases were deadly injured by firearms. There is an evident increase of those who die by firearms. During the same period of time correlations among homicides, suicides and accidents changed in favor of homicides. The average increase of homicides in 1991, 1992 and 1993 was 61.28% in regard to the average values of the first two years of the 5-year period. PMID- 8692099 TI - [The role and significance of sagittal abdominal diameter in the determination of adipose tissue distribution]. AB - Up-to-now trials have pointed out the importance of determining the type of obesity because the central type of obesity is joined with glucose tolerance disturbance, hyperinsulinemia and insulin resistance. The sagittal abdominal diameter proved to be the method of choice in routine clinical practice for visceral fat tissue detection. We examined a group of 60 females in whom, apart from standard measures (body weight, height, body mass index, perimeters of waist and hips), the sagittal abdominal diameter was measured by means of specially constructed caliper (Holtain Kahn Abdominal Caliper). Gathered parameters were compared with the results of an examination performed on 30 healthy females of normal body weight (control group). Results show a statistically significant higher sagittal abdominal diameter in females with central type of obesity in comparison to the control group, which points to greater quantity of visceral fat tissue in this type of obesity. PMID- 8692100 TI - [Postoperative infection as an indication for hysterectomy after cesarean section]. AB - Even today infection is the most important cause of morbidity and mortality after cesarean section. The aim of this paper is to point to the significance of hysterectomy in treatment of puerperal infection in the contemporary obstetrics. During a 15- year period (1981 - 1995) 85231 deliveries were performed at the Clinic for Gynecology and Obstetrics in Novi Sad (Yugoslavia). There were 8609 (10.10%) cesarean sections. Hysterectomy was performed in 16 cases (0.186%) of women undergoing cesarean section due to dehiscence of uterine suture, endometritis, diffuse peritonitis or sepsis. Infection during delivery was diagnosed in 3 (18.75%) cases, the delivery itself began by amnion rupture in 5 (31.25%) cases, it lasted more than 12 hours in 6 (37.50%) cases. Elective cesarean section was performed in 3 (18.75%) cases, cesarean section during delivery in 13 (81.25%) and iterative cesarean section in 5 (31.25%) cases. Total hysterectomy was performed in 9 (56.25%) cases and subtotal in 7 (43.75%) cases. Postoperative treatment by antibiotics was carried out in all cases. There were postoperative complications after hysterectomy in 7 (43.75%) cases. According to results of microbiologic analyses in 7 (43.75%) cases one cause was determined, while in 9 (56.25%) cases two or more causes were determined. Gram-negative bacteria were the most common cause (68.75%). PMID- 8692101 TI - [Congenital leukemia--personal experience]. AB - Congenital leukemia is a very rare form of acute leukemia and up to now more than 100 well documented cases have been published. Symptoms and signs of the disease may be faintly differentiated and be a differential diagnostic problem for a long period of time in comparison to other common diseases of the newborn. This is a case report on two newborns with congenital leukemia. It was an acute non lymphoblastic leukemia in the first case, and acute lymphoblastic leukemia in the second. In both cases there were nonspecific manifestations of the disease (no weight gaining, hemorrhagic enterocolitis). In both cases polyhemotherapeutic protocols were performed. In the first case only partial remission occurred and death occurred during the hemathologic recidive of the disease. In the second case, 15 months after the diagnose of congenital leukemia has been established, complete remission is in course. PMID- 8692102 TI - [Systemic necrotizing vasculitis: case report]. AB - Systemic vasculitis presents a group of clinically pathologic syndromes with acute inflammatory process in its basis which commonly occurs on small blood vessels destroying their walls with fibrinoid necrosis. It often occurs on several organs and systems depending on the form, size and number of the diseased blood vessels. This paper is a case report on a female patient suffering from a serious systemic necrotizing vasculitis with clinically demonstrated ulceronecrotizing skin changes and purpura together with appearance of coronary ischemia; rhythmic disorders of heart rate and gastrointestinal bleeding and cardiac arrest in one moment. It contains a description of the course of the disease and a good result after application of immunosuppressive therapy with high doses of corticosteroids, cyclosporin A and plasmaphereses. PMID- 8692103 TI - [Behcet's disease--clinical picture and treatment]. AB - Behcet's disease is a systemic inflammatory disease of unknown etiology which usually occurs as a trait of symptoms: aphatous stomatitis, genital ulcerations and eye disease. Characteristic manifestations are frequent: erythema nodosum, arthralgias, arthritis, myalgias, phlebothrombosis and nervous system disorders as well as disorders of other organs and systems. Behcet's disease was discovered in 1937 for the first time by dermatovenerologist Hulusi Behcet (1889 - 1948) after whom it was named Behcet's disease or Behcet's syndrome. At the beginning of the disease the diagnosis is uncertain because of different schedule of certain manifestations and a long period up to the full clinical picture manifestation. As it is well known, the main changes occur at the buccal mucosa in a form of a recidivant aphthous and herpetiformis lesions. Genital ulcerations are present in 64 to 87% of patients. Changes which occur on eyes may be present in 28 - 80% of patients and may dominate the clinical picture. The skin is affected in about 50% of patients. Manifestations on joints occur at major joints of the lower limbs. Sometimes gastrointestinal manifestations occur as enterocolitis and ulcerous colitis. Nervous system lesions have poor prognosis. The treatment involves: acute exacerbations with multisystemic manifestations by utilization of non-steroid anti-inflammatory drugs and immunosuppressive preparations. Corticosteroids are used in severe cases. PMID- 8692104 TI - [Newly manifested type IIb diabetes presents with significant hyperinsulinemia]. AB - BACKGROUND: Data concerning the insulin status in the early phase of NIDDM are controversial. PATIENTS AND METHOD: Since this has therapeutical implications, ten patients were identified with new-onset type 2 diabetes, defined by fasting blood glucose concentrations below 120 mg/dl, no previous history of diabetes and venous blood glucose concentrations at 120 min of an oral glucose tolerance test above 200 mg/dl (x 262 +/- 15 mg/dl) ("diabetic glucose tolerance"). Ten subjects with normal glucose tolerance and no familial history of NIDDM, who were matched for gender, age (n: 56 +/- 2 years, D: 61 +/- 5) and BMI (n: 28 +/- 1, D: 28 +/- 1), served as control group. Serum insulin was measured using a double-antibody sandwich-test (no cross-reaction with proinsulin and C-peptide) at 0, 30 and 120 min of an oGTT. RESULT: In the diabetic group, basal insulin levels were found to be elevated 1.7-fold (n: 7.9 +/- 1.4 uU/ml, D: 13.3 +/- 1.4, p = 0.03), 30 min values were the same in both groups and the 120 min value was 4.6-fold higher in the diabetic group (n: 33.9 +/- 8.7, D: 156.2 +/- 27.4, p = 0.0008). CONCLUSION: Thus, in new-onset diabetes, in the early phase of an oGTT (30 min) both insulin secretion and action are reduced, in the second phase (120 min) severe insulin resistance predominates at maximally stimulated secretion. These findings underline the therapeutical strategy in these patients, to reduce postprandial blood glucose increments and improve insulin resistance by diet and, if necessary, pharmacologically. PMID- 8692105 TI - [Paraproteins and lymphoma in HIV positive patients]. AB - BACKGROUND AND AIM: Compared to healthy subjects there is a higher incidence of monoclonal immunoglobulins (= paraproteins = PP) in patients infected with the human immunodeficiency virus (HIV). High-grade B-cell non-Hodgkin's lymphomas (NHL) are the second most common neoplasms in these patients. Our aim was to determine whether paraproteins would be of diagnostic significance regarding an underlying or developing NHL. PATIENTS AND METHODS: The sera of 202 HIV-positive patients were tested for the presence of monoclonal or oligoclonal bands by using high-resolution-electrophoresis (HRE) and immunofixation (IFX). We also examined immunoglobulin concentrations, leucocyte count, lymphocyte count, CD4 lymphocyte count and CD4/CD8-ratio and collected clinical data. RESULTS: Paraproteins were detected in 26 (12.8%) of the patients. 84.6% of PP were IgG, in 80.7% associated with a kappa light chain. Patients with monoclonal or oligoclonal bands developed NHL significantly more often compared to those without PP (16.7% and 2.8%, respectively (p < 0.05%)). The CD4 count was significantly higher in patients with PP. There was no difference in levels of immunoglobulins, leucocyte count, lymphocyte count and CD4/CD8-ratio. The prevalence of PP was equally distributed in patients at different CDC-stages of HIV-infection. Common acute systemic infections like pneumocystis carinii pneumonia (PCP), toxoplasmosis, mycobacteriosis or cytomegalovirus (CMV) infection were not associated with paraproteins. CONCLUSION: We conclude that paraproteins could indicate the presence of a non-Hodgkin's-lymphoma. PMID- 8692106 TI - [Epithelioid cell granulomatosis with bilateral extensive superficial lung shadows]. PMID- 8692107 TI - [Endocrinology update. II]. PMID- 8692108 TI - [First steps in clinical gene therapy]. PMID- 8692109 TI - [Immunotherapy of hemato-oncologic diseases]. PMID- 8692110 TI - [Sex hormone substitution in hormone-dependent neoplasms--oil into the fire?]. PMID- 8692111 TI - [Ethical decisions in medical treatment]. PMID- 8692112 TI - [Adjuvant chemotherapy in colorectal carcinoma. An error of omission?]. PMID- 8692113 TI - [Results and perspectives in hematology and oncology. Symposium proceedings. Hannover, 16 June 1995]. PMID- 8692114 TI - [Therapy of chronic myeloid leukemia with interferon-alpha. A decade of experiences]. AB - PATIENTS AND RESULTS: One hundred and fifty-nine patients with chronic myelogenous leukemia have been treated in six studies during 10 years at Hannover Medical School University Center. The prognosis of 111 patients without pretreatment has been improved compared to conventional therapy with a median survival of 5.7 years. Cytogenetic remissions have been induced in all studies followed for a longer time. The most pronounced improvement of prognosis has been observed in these patients. CONCLUSIONS: Several conclusions can be drawn on the basis of the results on the different treatment concepts: 1. Patients with pretreatment have an unfavourable response to interferon. 2. There is a likely effect of the dose of Interferon alpha on the frequency of cytogenetic remissions. 3. The combination of Interferon alpha and interferon gamma has been toxic and ineffective in a pilot study. 4. The combination of interferon and cytosine arabinoside has a positive impact on the frequency of cytogenetic remissions. A continuous parallel application of both drugs seems to be most effective in this respect. An ongoing trial has been initiated to compare a fixed combination of Interferon alpha and cytosine arabinoside and with hydroxyurea respectively. Additionally the feasibility of autologous peripheral blood stem cell transplantation will be studied in patients with insufficient response to the interferon treatment. PMID- 8692116 TI - [10 years transplantation of bone marrow and hematopoietic stem cells in adults at the Hannover Medical School]. AB - PATIENTS AND METHODS: From January 1986 until August 1995 230 adult patients received an allogeneic or autologous transplantation of bone marrow or hematopoietic blood stem cells. The conditioning and myeloablative treatment regimens were chosen according to the underlying disease and type of transplant. RESULTS: The observation period comprises 1 to 115 months after transplantation. After allogeneic transplantation from HLA-identical family donors, the probabilities of disease-free survival were for acute myeloid leukemia in first complete remission (CR) (n = 35) 77%, for acute lymphoid leukemia in 1st CR (n = 7) 72% and in 2nd CR (n = 10) 40%, in first chronic phase of chronic myeloid leukemia (n = 34) 50% and in severe aplastic anemia (n = 7) 100%. Following myeloablative therapy and autologous transplantation the probabilities of disease free survival were 47% in relapsed Hodgkin's disease (n = 22) and 42% for relapsed high-grade non-Hodgkin's lymphoma (n = 12). Eight of 10 patients with acute myeloid and 7 of 8 with acute lymphoid leukemia suffered a leukemic relapse after autologous bone marrow transplantation. Three of 8 patients with relapsed testicular cancer survived relapse-free. Treatment failures were due to more advanced acute graft versus host disease after allogeneic transplantation and caused by relapse after autologous transplantation. Current protocols evaluate the allogeneic transplantation of enriched CD34+ blood stem cells. In chronic myeloid leukemia the autologous transplantation of blood stem cells after myeloablative therapy is being studied. PMID- 8692115 TI - [Intensive post-remission therapy in acute myeloid leukemia. Results of a prospective comparative study by the South Germany Hemoblastosis Group]. AB - BACKGROUND: To study intensive postremission therapy in adult patients with acute myeloid leukemia myeloablative therapy followed by allogeneic or unpurged autologous bone marrow transplantation (BMT) was compared with high-dose cytosine arabinoside/daunorubicin (HDAC) consolidation. PATIENTS AND METHODS: 148 de novo AML patients of maximum 50 years (median 36 years, range 16 to 50) were enrolled in the trial. Following induction and early consolidation chemotherapy consisting of daunorubicin, cytosine-arabinoside and VP-16 (DAV), patients with an HLA identical sibling underwent allogeneic BMT. The other patients received (by randomization or patient's decision) either HDAC or high-dose busulfan plus cyclophosphamide followed by autologous BMT. RESULTS: Hundred and five 105 (70.9%) patients achieved a complete remission. The event-free survival rates after intensive postremission therapy after 72 months were: after BMT (24 patients) 62% (95% confidence interval +/- 19%), after HDAC (44 patients) 36 +/- 16% and after autologous BMT (12 patients) 18 +/- 22%. Thus allogeneic BMT was superior to autologous BMT (p = 0.04), as was HDAC compared to autologous BMT, although not significantly so (p = 0.15). Patients receiving 2 cycles of HDAC had a better 6-year event-free survival rate (47%) and a lower relapse rate (50%) than patients who received only 1 course (29% and 70% respectively). CONCLUSIONS: High-dose busulfan/cyclophosphamide followed by unpurged autologous BMT early after achieving CR had no advantage over high-dose ara-c/daunorubicin. Two cycles of HDAC yielded better results than 1 cycle. The highest event-free survival rate was reached with myeloablative therapy followed by allogeneic BMT. PMID- 8692117 TI - [Progress in development of chemotherapy of colorectal carcinoma]. AB - BACKGROUND: Despite its low antineoplastic activity 5-fluorouracil remains the most active compound for the treatment of patient with metastatic colorectal cancer. PATIENTS AND METHODS: Within 5 consecutive trials (2 were randomized) 174 patients have been treated with bolus 5-FU 600 mg/m2 plus folinic acid 300 mg/m2 day 2 to 4 with or without dipyridamole 3 x 75 mg p.o. day 1 to 5; 74 patients with bolus 5-FU 300 to 350 mg/m2, folinic acid 200 mg/m2 and interferon 5 x 109 U/m2 s.c. day 1 to 5; 18 patients with PALA 250 mg/m2, MTX 250 mg/m2 day 1 and bolus FU 600 mg/m2 day 2 q day 14 and 86 patients with FU 2.6 g/m2 given as 24-h infusion plus interferon 3 x 10(9) Ul s.c. and 133 patients with FU 2.6 g/m2 given as 24-h infusion, folinic acid 500 mg/m2 as 2-h infusion with or without interferon 3 x 10(9) U s.c. RESULTS: The response rate was 11 to 14% for the i.v. push schedules and 21 to 36% for the 24-h continuous infusion regimens. The responses lasted for a median of 4.5 months and 12 months, respectively, if bolus or infusion schedules were applied. Median time to tumor progression was 4.5 months and 7 months for continuous infusion. The median patient survival was 10 to 12.7 months (bolus regimens) and 13 to 15 months for infusional 5-FU schedules. CONCLUSION: By weekly high dose infusional 5-FU the response rate, response duration, time to tumor progression and patient survival may be prolonged especially when modulated by folinic acid compared to modulated bolus regimens. This retrospective comparison however needs to be confirmed by the intergroup trial of AIO (#1/95) and EORTC (#40952). PMID- 8692118 TI - [Interleukin 2 based ambulatory therapy of metastatic renal cell carcinoma]. AB - BACKGROUND: In metastatic renal cell carcinoma, strictly immunomodulatory maneuvers using systemic interleukin-2 have produced objective tumor remissions and led to an effective palliation. The goals of an improved cost effectiveness and therapeutic index of interleukin-2 require the design of risk factor adapted individual therapeutic strategies for the outpatient setting. PATIENTS AND METHODS: In 215 consecutive single institution patients with advanced metastatic renal cell carcinoma, the efficacy and tolerance of different subcutaneous recombinant interleukin-2 (rIL-2) based home therapies was assessed. Independent risk factors at pre-treatment level were identified and patient survival was compared between risk groups and therapies. Treatment consisted of s.c. rIL-2 alone and s.c. rIL-2 in combination with recombinant interferon-alpha 2 (rIFN alpha 2), with or without intravenous 5-fluorouracil (5-FU). RESULTS: Overall objective response rate in 215 patients was 33% (95% confidence interval, 26 to 39%). Among patients receiving rIL-2 alone (n = 16), there was 1 partial remission (overall response, 6%). In patients on rIL-2 and rIFN-alpha 2 in combination (n = 79), 6 complete and 16 partial remissions occurred (overall response, 28%). Of 120 patients receiving a combination of rIL-2, rIFN-alpha 2 and 5-FU, 13 patients achieved a complete and 34 a partial remission (lung, liver, local relapse, bone, adrenal, pleural, and thyroid metastases; overall response 39%). Duration of complete and partial remissions ranged from 10 to 55+ months, and 3 to 32 months, respectively, in rIL-2/rIFN-alpha 2 treated patients, and from 8+ to 47+ months and from 3 to 31+ months, respectively, in rIL-2/rIFN alpha/5-FU treated patients. Of all patients 5% achieved long-lasting remissions and remain disease-free. In the majority of patients, systemic toxicity of s.c. rIL-2 based protocols was limited to grade 1 or 2 constitutional symptoms i.e., fever, chills, malaise, and anorexia; this allowed for an outpatient therapy. No life-threatening toxicity and no toxic deaths occurred. CONCLUSIONS: The present outpatient rIL-2 triple drug combination protocol was as effective as the most aggressive i.v. rIL-2 regimen available; it substantially improved the therapeutic index and cost effectiveness of rIL-2 therapy in metastatic renal cell carcinoma stratified for risk. PMID- 8692119 TI - [Chemo-/immunotherapy in advanced malignant melanoma: carboplatin and DTIC or cisplatin, dtic, bcnu and tamoxifen followed by immunotherapy with interleukin 2 and interferon alpha-2a]. AB - BACKGROUND: Polychemotherapy and immunomodulating treatment using IL-2 and/or IFN alpha produce objective responses in a proportion of advanced malignant melanoma patients. PATIENTS AND METHODS: In 2 consecutive phase II trials in a total of 85 patients, we assessed the potential synergism between both modalities i.e., chemo and immunotherapy. Treatment consisted of intravenous carboplatin (CBDCA, 400 mg/m2) and dacarbazine (DTIC, 750 mg/m2) given twice at a 3-week interval, or 4 cycles of DTIC (220 mg/m2 i.v. x 3 days), cisplatin (DDP 35 mg/m2 i.v. x 3 days), carmustine (BCNU 150 mg/m2 i.v., cycles 1 and 3) and tamoxifen (TAM 20 mg/per os x 5 days) at a 3-week interval. Chemotherapy was followed by immunotherapy with combined subcutaneous interleukin-2 and (rIL-2) and s.c. interferon-alpha 2a (rIFN-alpha). RESULTS: Among 40 patients who received a full cycle of chemotherapy with CBDCA/DTIC and sequential immunotherapy, there were 3 (7.5%) complete remissions (CR) with durations of 13 to 26+ months. Partial remissions (PR) were noted in 11 (27.5%) patients with a median response duration of 8 (range 5 to 14) months. Among 45 patients who received DTIC/DDC/DDP/BCNU and TAM and sequential rIL-2/rIFN-alpha 2a there were 5 (11%) complete remissions and 17 (38%) partial remissions. Duration of complete and partial remissions ranged from 8+ to 24+ months (median 12+) and 5+ to 17 months (median 8+), respectively. Chemotherapy produced mostly moderate toxicity. Thrombocytopenia was common with the nadir after a median time of 17 days following start of the chemotherapy. 19 patients required transfusion of thrombocytes. Nausea and vomiting due to chemotherapy were well tolerated using concomitant ondansetrone (8 mg i.v.). Immunotherapy was self-administered at home with mild to moderate side-effects; malaise, fever, chills, nausea/vomiting, diarrhea, anorexia and arthralgias were most frequent (70% to 100%), but spontaneously reversible after ending the immunotherapy. A mean of 87% (trial I) to 89% (trial II) of the projected doses of rIL-2 and rIFN-alpha were administered on either protocol. There were no life threatening complications and no treatment-related deaths. CONCLUSION: The sequential combination of chemotherapy and immunotherapy had at least additive therapeutic activity against metastatic malignant melanoma. Both schedules produced long-lasting remissions and were overall well tolerated. These trials substantiate a potential role for low to intermediate dose immunotherapy in maintaining and consolidating therapeutic effects of chemotherapy in metastatic melanoma. PMID- 8692121 TI - [Late damage of curative oncologic therapy. Results of a patient sample with Hodgkin's disease and testicular tumors at the Hannover Medical School]. AB - BACKGROUND: The present analysis deals with 2 main problems among therapy associated late toxicities in patients after curative treatment for malignant tumors, such as Hodgkin's disease and testicular cancer: gonadal late toxicities in young patients after treatment for lymphomas and the risk of secondary neoplasia after curative treatment for malignant male germ cell tumors. PATIENTS/RESULTS: In 66 patients with Hodgkin's disease and 24 patients with non Hodgkin's lymphomas ( < 45 years), who were in complete remission for more than 2 years after chemo- and/or radiotherapy, gonadal damages were analysed based on hormone levels (FSH, LH, testosterone, estrogen), clinical examination and patients' histories. 50% of female patients with Hodgkin's disease suffered from premature ovarian failure and 65% of men were either sub- or infertile. In contrast, only 18% of patients treated for non-Hodgkin's lymphoma showed signs of gonadal toxicity. The risk for gonadal toxicity in patients with Hodgkin's disease was related to the use of procarbacine as a part of the COPP-regimen and to infradiaphragmatic radiotherapy. Sperm conservation should be offered to male patients prior to therapy. In female patients with Hodgkin's disease hormone levels should be evaluated after therapy and substitution should be initiated early in order to avoid osteoporosis, an increased cardiovascular risk and psychological problems. In patients with testicular cancer it could be demonstrated that current therapeutic strategies are associated with a small but identifiable risk for secondary neoplasia: radiotherapy causes a 2- to 3-fold increased risk for solid cancers and chemotherapy, particularly the use of etoposide-based regimens, is associated with secondary leukemias. However, a risk benefit analysis shows that cure rates above 80% for patients with metastatic disease will outweigh the risk of secondary neoplasia. CONCLUSION: The investigation of therapy-associated late toxicities will remain an important issue even with the use of new treatment approaches such as high-dose therapy. Prospective evaluation of late toxicities needs to be incorporated into new studies for the curative treatment of malignant tumors. PMID- 8692120 TI - [Ex vivo increase in hematopoietic progenitor cells for clinical use]. AB - BACKGROUND: The clinical use of ex vivo expanded hematopoietic progenitor cells is currently explored. MATERIAL AND METHODS: In this study the culturing of G-CSF mobilized and purified CD34+ blood cells was investigated. The interleukins IL-1 beta, IL-3 and IL-6 (each at a dose of 300 U/ml) and stem cell factor (25 ng/ml) without or with erythropoietin (1 U/ml) were used. Cells of 10 healthy sibling donors and 10 patients with solid tumors were incubated under small-scale (n = 15, 2 ml) and large-scale (n = 7, 50 ml) culture conditions at 37 degrees C for 5 and 4 weeks, respectively. The cell density was adjusted to about 1 x 10(5) cells/ml. RESULTS: The nucleated cell counts increased approximately 7-fold and 10- to 70-fold after 1 and 2 weeks of incubation. Numbers of CD34+ cells doubled to triplicated within this time interval, without any significant changes in their clonogenicity (CFU-GM and BFU-E output). Thereafter a depletion of the CD34+ cell pool was noticed. However the numbers of CD34+/CD38(-)- or CD34+/ HLA DR(-)- cells were reduced to a lesser extent. The expanded cells generated predominantly myeloid and almost no lymphoid cells. More glycophorin-A+ cells were produced when erythropoietin was added. Replacement of non-human additives with heat-inactivated autologous plasma had no influence on cell growth. Almost no proliferation was obtained with a 10-fold higher cell density (1.7 x 10(6)/ml in 100 ml), but the cells maintained their viability for 13 to 16 days. CONCLUSIONS: This study suggests, that the chosen culture conditions might be feasible for a large-scale ex vivo expansion of hematopoietic progenitor cells for clinical application. The impact of the ex vivo generated cells on hematopoietic regeneration after chemotherapy is currently under clinical investigation. PMID- 8692122 TI - [Clinical phase I studies in oncology and hematology. Concepts, implementation and ethical considerations]. PMID- 8692123 TI - [Responsibilities and goals of the Hannover Tumor Center: prospects of medical telecommunication]. PMID- 8692124 TI - [Prognosis and therapy of Hodgkin's disease]. PMID- 8692125 TI - [Therapy of germ cell tumors. Model for interdisciplinary treatment approach]. PMID- 8692126 TI - [Perioperative therapy in esophageal and stomach carcinoma]. PMID- 8692127 TI - [Uncertainty of prognosis in patient education--communication on the way to diagnosis]. PMID- 8692128 TI - Managed care ethics. A delicate balance. PMID- 8692129 TI - Mode of inquiry. PMID- 8692130 TI - How valuable is prostate-specific antigen screening? PMID- 8692131 TI - Don't let managed care cost-cutting carve out psychiatry entirely. PMID- 8692132 TI - Avoiding the ethical pitfalls of managed care. PMID- 8692133 TI - The ethical challenge of managed care. A critique of the AMA's stance. PMID- 8692134 TI - Physician detection of family violence. Do buttons worn by doctors generate conversations about domestic abuse? AB - Family violence is ubiquitous in our society and, thus, is encountered in all medical practices. The purpose of this study was to ascertain whether physicians wearing buttons with an anti-abuse message have more conversations about violence compared with physicians not wearing such buttons. Six of 11 family practice residents wore Minnesota Medical Association buttons that invited conversations about abuse. For four weeks, all 11 residents recorded daily the number of conversations about violence that occurred in the medical setting. Analyses comparing the two groups showed that the physicians wearing buttons had significantly more conversations than those not wearing buttons (c2 = 9.040, p < 0.005). Physicians wearing buttons had a higher percentage of days with conversations about domestic violence than physicians without buttons (c2 = 7.695, p < 0.01). From the significant p-values documented, we conclude that wearing the buttons increases conversations about family violence and makes physicians more consistent in talking about violence with patients. PMID- 8692136 TI - Elusive managed care ethics. PMID- 8692135 TI - Why patients bypass rural health care centers. AB - Many rural health care facilities are financially strained and in danger of closing. One reason is that some patients bypass their local facilities and travel longer distances to urban medical centers for care. We surveyed the residents of two rural Minnesota communities to investigate the factors that draw rural residents to larger urban medical centers. Patient perceptions that bigger is better and that smaller, rural medical facilities are unable to keep up with technology appear to be at the heart of the issue. We asked about residents' attitudes and perceptions of their local health care systems as compared with an urban system. Most rural residents perceive rural primary care physicians as more compassionate and accessible than their urban colleagues; however, many feel rural physicians are less qualified. PMID- 8692137 TI - Cutting school absenteeism. PMID- 8692138 TI - Protecting patients & profits. PMID- 8692139 TI - [Genetic alterations in stomach cancer]. AB - The scenario of multistep of stomach carcinogenesis differs depending on the two histological types, well differentiated adenocarcinoma and poorly differentiated adenocarcinoma, because the two types may have different genetic pathways. Genetic instability, reactivation of telomerase and abnormal transcript of CD44 including intron 9 are common events of both well and poorly differentiated type carcinomas. These occur at early stage of carcinogenesis, even in precancerous lesions such as intestinal metaplasia and adenoma. Inactivation of APC, activation of K-ras, amplification of c-erbB2, and allelic loss of DCC locus are associated with well differentiated type, while amplification of K-sam and functional loss of cadherin/catenin are characteristics of poorly differentiated type. HGF/c-met system plays a pivotal role in morphogenesis of both histological types through interaction with cell-cell adhesion molecules. Reactivation of telomerase or genetic instability may be an initial event for accumulation of multiple genetic alterations during the progression of stomach carcinogenesis. PMID- 8692140 TI - [Helicobacter pylori and gastric cancer]. AB - H. pylori has been included as a definite biological carcinogen by WHO/ IARC. H. pylori is thought to play a role in the gastritis-metaplasia-carcinoma sequence by inducing atrophic gastritis. Clinical and epidemiological studies have shown a close association between H. pylori infection and gastric cancer. Yet, experimental evidence is equivocal. Epidemiological evidence also suggests that there are significant variable(s) other than H. pylori infection in gastric carcinogenesis. Clearly many questions regarding the role of H. pylori in gastric carcinogenesis have been left for further study. The authors have summarized these aspects together with their experimental results. PMID- 8692141 TI - [Comparative study on biological difference between gastric cancer and colorectal cancer]. AB - In this study, we investigated the clinico-pathologic characteristics of patients with adenocarcinoma of the stomach and those with colorectal carcinoma to compare early progression patterns of both tumors. Histologically, gastric and colorectal adenocarcinomas showed similar progression patterns, including the incidence of submucosal invasion, lymphatic infiltration and lymph node metastasis. One striking finding was in gross appearance in born tumors. In contrast to most gastric well differentiated adenocarcinoma (DTA), which showed superficial growth, colorectal DTAs mainly showed polypoid growth. However, the superficial type colorectal DTAs invaded the submucosal layer more frequently than did polypoid DTAs and gastric DTAs. These findings indicate that superficial-type colorectal DTAs grow more rapidly and aggressively than do polypoid DTAs and gastric DTAs. In order to elucidate growth rates between gastric cancer and colorectal cancer with hepatic metastasis doubling time was measured by exponential growth of tumor marker (CEA or AFP). The doubling time of liver metastases calculated from tumor markers was 26.6 +/- 10.8 days for stomach cancer and 57.8 +/- 35.4 days for colorectal cancer; accordingly doubling time for gastric cancer was approximately half of that for colonic cancer. However, there were no other factors (age, sex, site, histologic type in stomach, tumor marker production, etc.) influencing doubling time. PMID- 8692142 TI - [Modified surgery for early gastric cancer]. AB - Based on the sufficiently accumulated results of early gastric cancer (EGC), particularly the diagnostic accuracy regarding the depth of cancerous involvement in the gastric wall, lymph node metastasis, pattern of recurrence etc., the modified surgery has been induced for the treatment of EGC since late 1970's. The modification is as follows depending on the depth and location of EGC: constriction of size of gastric resection; narrowing of the extent of lymphadenectomy; preserving omentum, pancreas, spleen, pylorus, vagal nerve, lower esophageal sphincter etc; sparing thoracotomy. This kind of surgery has resulted in remarkable reduction of blood loss during surgery, reduced operation time and hospital stay, which have brought improved QOL to the patients as well as satisfactory survival rate after surgery. PMID- 8692143 TI - [Endoscopic mucosal resection (EMR) for early gastric cancer]. AB - The treatment of early gastric cancer using an endoscopy, namely, endoscopic mucosal resection (EMR), has been employed in the world, especially in Japan from the beginning of 1980s. It has the advantage of enabling histopathological exploration of the resected specimen. This study involved of patients with solitary early gastric cancer who underwent a radical operation at the department of surgery, School of Medicine, Kitasato University. They selected from a retrospective study of the presence of lymph node metastasis based on histopathological findings. It was found that the early gastric cancer with negative lymph node appeared as an elevated tumor with the diameter of 2.5 cm or less; or concave tumor with the diameter of 2.0 cm or less and without concomitant ulcer in the lesion. Moreover, histologically differentiated adenocarcinoma and the invasion depth of m were desirable conditions for EMR. The above mentioned conditions were defined as the indications for EMR in a broad sense. This study redefined the size of a tumor that could be completely removed by one EMR. It has become clear that, based on our experience, the conditions should be strictly revised as follows; elevated tumors with the diameter of 2.0 cm or less and concave tumors with the diameter of 1.0 cm or less (absolute indications). If EMR is first selected for early gastric cancers under these strict conditions, it would promise the same favorable long-term survival rate as we experienced. PMID- 8692144 TI - [Laparoscopic surgery for early gastric cancer]. AB - We have successfully treated 40 patients with early gastric cancer by using two different laparoscopic procedures since March 1992, which are laparoscopic wedge resection of the stomach using a lesion-lifting method (n = 25) and laparoscopic intragastric mucosal resection (n = 15). The indication is as follows; 1) mucosal cancer, 2) < 25 mm, if the lesion is protruded type, 3) < 15 mm and U1 (-), if the lesion is depressive type. All patients were discharged within 4-8 days uneventfully. The resected specimens were 66 +/- 16 mm and 48 +/- 8 mm in diameter respectively, and had a sufficient surgical margin horizontally (16 +/- 5 mm, 8 +/- 4 mm) and vertically. Histology revealed they were all curative surgeries except one case in whom an additional gastrectomy with lymph node dissection by laparotomy was required one month after surgery because lymphatic invasion had been revealed by pathology. In conclusion, these laparoscopic procedures are curative and minimally invasive treatment for early gastric cancer. PMID- 8692145 TI - [Vagus-saving D2 procedure for early gastric carcinoma]. AB - To improve quality of life in patients who had an aggressive lymph nodes dissection (D2) for early gastric carcinoma, we developed a novel procedure, nerve-saving D2 (VS-D2), in 1991. This procedure constitutes D2 and saving of hepatic and celiac branches of the vagus nerve, whereas conventional D2 consists of D2 and preserving hepatic branches alone of the vagus nerve. Thirty-nine patients between 1991 and 1994 who received VS-D2 and included 3 cases with nodal involvement had no operative death and no recurrence. The occurrence rate of postoperative diarrhea in patients with VS-D2 significantly lower than that in patients with conventional D2 (3% versus 28%, p < 0.01). Postoperative incomplete weight regain (less than 95% of preoperative weight) was also relatively lesser in patients with VS-D2 than those with conventional D2 (64% versus 84%, p = 0.08). The incidence of formation of gallstone also was relatively low in patients with VS-D2 compared that in those with conventional D2 (3% versus 13%) though the difference was not statistically significant. These results suggest that VS-D2 keeps curability of conventional D2 and improves quality of life in patients following surgery for early gastric carcinoma. PMID- 8692146 TI - [Pylorus-preserving gastrectomy for early gastric cancer]. AB - Pylorus-preserving gastrectomy (PPG) was originally proposed by Maki et al for gastric ulcer. Recently this operation with lymph node dissection has been adopted for patients with early gastric cancer locating at antrum and body of the stomach in Japan. But standard procedure of this operation has not been established yet. Grade of lymph node dissection, preservation of pyloric branch and indication criteria are fairly dependent on each surgeon when PPG is applied for gastric cancer. Although the results of this operation is not accumulated enough, it is considered that this operation may have benefits for decrease of postoperative chronic morbidity with acceptable cancer curativity as compared to conventional distal gastrectomy, Billroth-I procedure. PMID- 8692147 TI - [Treatment of advanced gastric carcinoma based on histologic type]. AB - It is well known that clinicopathological characteristics in gastric carcinoma are different according to its histologic type, intestinal type or diffuse type. Multivariate analysis of advanced gastric carcinoma revealed that the histologic type significantly related to the type of recurrence, hematogenous metastasis or peritoneal dissemination. Therefore, we introduced a prospective randomized trial for treatment of advanced gastric carcinoma based on histologic type of carcinoma. Intraoperatively, 10 mg of mitomycin C was given via portal system in the intestinal type and given in peritoneal cavity in the diffuse type. As results, in the intestinal type, survival rate in patients with the chemotherapy was longer than that without the chemotherapy, but this did not reach to a significant difference. On the contrary, in the diffuse type, patients with the chemotherapy showed a significant longer survival rate compared to those without the chemotherapy. These results suggests the availability of treatment based on histologic type of carcinoma. Much more selective and effective improvements in this type of treatment will be required. PMID- 8692148 TI - [Clinico-pathological studies and problems on para-aortic lymph node dissection- D4 dissection]. AB - The advantage or disadvantage of para-aortic lymph node dissection was studied from the viewpoint of clinicopathological findings and their prognosis. No 16 lymph node dissection was performed in 427 cases, and metastasis was observed in 100 (23%). The metastatic rate increased with the depth of cancer. High metastatic rates were seen in type 3 and 4, and in the histologically undifferentiated type. Five year survival rate of patients with No. 16 metastasis (PoHo) was 14%. The n3 (-) group among cases with n4 showed a significantly better outcome than the n3 (+) group. Concerning total gastrectomy with pancreato splenectomy procedure, blood loss was greater and length of surgery was longer in the D4 group than D2 group. The exudate volume was much higher in D4 and serum albumin significantly decreased in D4 than D2. Almost the same findings were seen in D4 with subtotal gastrectomy. Postoperative complications in D4 group were the same as D2 excluding abscess around pancreatic stump which was higher in D4. In conclusion, D4 dissection does not have an obvious disadvantage for the patients. Randomized clinical trials between D4 and D2 should be done in order to clarify an efficacy of the D4 dissection. PMID- 8692149 TI - [Prophylaxis and treatment of peritoneal metastasis from gastric cancer]. AB - Between 1976 and 1984, 234 patients with advanced gastric cancer (pT3, pT4) were curatively gastrectomized and intraperitoneal free cancer cells which were detected by lavave of the Douglas cavity were recognized in 17.8% of the patients with pT3 and 25.0% of those with pT4. Even if curative surgery was performed for patients with free cancer cells, their five-year survival rate was very poor. The five-year survival rate was very poor. The five-year survival of patients with curatively operated gastric cancer without free cancer cells was 49.3%, whereas that of patients with free cancer cells was significantly lower (15.4%). Then the results of treatment for patients with free cancer cells were analyzed in regard to the effect of continuous hyperthermic peritoneal perfusion (CHPP) as prophylaxis of peritoneal metastasis. Five-year survival rate in the patients treated with CHPP was 33.3% and it was only 4.2% in the controls. In patients without intraperitoneal free cancer cells, however, no difference was observed in the five-year survival rates between those patients who had been treated with CHPP and the controls. Therefore, it is reasonable to assume that CHPP can be effective in preventing peritoneal recurrence of resected gastric cancer that is positive for free cancer cells in the peritoneal cavity and peritoneal micrometastasis. PMID- 8692150 TI - [Adjuvant chemotherapy for advanced gastric cancer]. AB - For recent 40 years, many authors reported the results of adjuvant chemotherapy for advanced gastric cancer including 5-fluorouracil, uracil and tegafur, mitomycin C, cytosine arabinoside. OK-432 adriamycin, methotrexate, and cis pltatin in solitary use of combinations. It is difficult to find a standard effective adjuvant chemotherapy for advanced gastric cancer in these reports. The reasons of this unclearness were as follows; (1) In phase III studies, surgery alone was not a control group in some reports. (2) The number of patients was too small to evaluate statistically. (3) Inter-institutional differences had important roles in the results of multicenter study in the other studies. For the future plans on adjuvant chemotherapy, it is important to make a simple designed protocol, and perform it as a multicenter study including institutions with minimum inter-institutional differences. PMID- 8692151 TI - [Therapy for the gastric cancer in the near future]. AB - Through the review of recent Japanese literatures, anticipated ways of the treatments for the gastric cancer in the near future were discussed. Most hopefully, no surgical intervention with the prevention and early diagnosis of initiation or promotions of the cancer development by genom analyses in individuals who may have high risk gene mutations will be expected. In the near future periods, however, vigorous molecular biological investigations for purpose will be required to clarify the mechanisms and each biological characteristics of the cancer developments. Further improvements of endoscopic ultrasonography and electron endoscopy will be needed for "early" detection of the lesions in the high risk group patients. More finely defined minimally invasive or extended operative procedures will still be challenged for molecular-biologically identified malignancies of the disease. Immuno-chemotherapy and chemotherapy aided by gene therapy will be the greatest hoperfull ways to conquer the disease. Direct concerns at the moment, however, cancer developments in the stomach with benign "ulcer" infected with Helicobacter Pylori must be urgently integrated for the prevention of the disease. Post-operative disorders after any type of surgery will still be one of the great issue in this until the complete achievements of above mentioned future tasks. PMID- 8692152 TI - [A case of bronchiolo-alveolar carcinoma with high production of carbohydrate antigen (CA19-9)]. AB - A 75-year-old female had loss of appetite, left hypochondrial and back pain. An X ray and a computed tomogram of both lungs showed multiple small granular shadows. By Tc-labelled bone scintigram, multiple uptakes were found. Since high serum CA19-9 was obtained, pancreatic or bile duct cancer with multiple lung and bone metastasis was suspected. The autopsy revealed, small nodules in both lungs were well-differentiated adenocarcinoma, bronchiolo-alveolar type, and immunohistologically, tumor cells were stained positively for CA19-9. Since CA19 9 exists in normal bronchial glands and bronchiole, high level of serum CA19-9 in our patient may be derived from the neoplastic bronchiolar epithelium. PMID- 8692153 TI - Breast cancer and family history: a multivariate analysis of levels of tumor HER2 protein and family history of cancer in women who have breast cancer. AB - BACKGROUND: The HER2 gene, located on the long arm of chromosome 17, codes for a protein with the characteristics of a growth factor receptor. In a preliminary study, we reported that high levels of tumor HER2 (erbB-2/neu) protein are associated with a family history of breast cancer (that is, one or more female blood relatives with breast cancer). METHODS: We have now collected a larger number of subjects (94) and performed a multivariate analysis of the independent variables family history of breast cancer, tumor estrogen receptor, age, and tumor DNA index. Family history of breast cancer was assessed by questioning the patient, in many cases by telephone. RESULTS: HER2 levels were significantly higher in women with a family history of breast cancer (p = 0.015, two-tailed t test). The 27 women with family history were predominantly postmenopausal, mean age 61 +/- 2.3 (mean +/- SEM), versus a mean age of 56 +/- 1.7 for the 67 women with no family history. Of the 27 women with a family history of breast cancer, 13 had a first-degree relative (mother or sister) with the disease. The remaining 14 women had other relatives (grandmothers, aunts, cousins, or a niece) with breast cancer. The results of multiple linear regression analysis, with HER2 as the dependent variable, showed that family history of breast cancer was significantly associated with elevated HER2 levels in the tumors (p = 0.0038), after controlling for the effects of age, tumor estrogen receptor, and DNA index. CONCLUSIONS: The association of family history of breast cancer and elevated tumor HER2 protein suggests that postmenopausal familial breast cancer may be associated with altered HER2 expression. PMID- 8692154 TI - Breast cancer and family history: levels of lipid-associated sialic acid in plasma and absent family history of breast cancer in women who have breast tumors. AB - BACKGROUND: Breast cancer has a strong genetic component, and at least two breast cancer genes exist. But these genes probably play little role in most breast cancers. Other factors, such as environmental estrogens and diet, may cause the genetic changes involved in the genesis of sporadic breast cancer. A method of observing genetic changes indirectly might be to measure tumor markers known to be associated with breast cancer. METHODS: We measured, by biochemical extraction and partition, lipid-associated sialic acid in plasma (LASA-P), a circulating tumor marker, in a group of 239 women with benign or malignant breast tumors. RESULTS: The concentration of LASA-P was elevated in women with both benign and malignant tumors and no family history of breast cancer (p = 0.046, one-way ANOVA). Because LASA-P levels rise with age and number of pregnancies, we analyzed our data using multiple linear regression. Benign versus malignant character of the tumor, family history of breast cancer, number of pregnancies, and age were the independent variables. Family history of breast cancer had a significant effect on LASA-P levels (p = 0.0146) independent of the effects of age (p = 0.011), number of pregnancies (0.012), and whether the tumor was benign or malignant (p = 0.31). CONCLUSIONS: We hypothesize that elevated LASA-P in women with breast tumors and no family history of breast cancer is a result of the genetic changes occurring in nonfamilial breast cancer. These genetic changes, possibly related to environmental estrogens or other environmental factors, are distinct from the changes due to mutations of BRCA1 or other familial breast cancer genes. Moreover, the elevation of LASA-P suggests that the surface membranes of breast cancer may differ in composition. Further study may lead to exact characterization of the genetic and cell membrane changes associated with familial and nonfamilial breast tumors, and perhaps to better methods of breast cancer prevention and treatment. PMID- 8692155 TI - Mortality in hospitalized patients with hypoglycemia and severe hyperglycemia. AB - BACKGROUND: We designed a study to determine the incidence, cause, and implications of hypoglycemia (< or = 2.7 mmol/L, 49 mg/dL) and severe hyperglycemia (> or = 22.2 mmol/L, 400 mg/dL) in in-patients at an urban tertiary medical center. METHODS: A daily computer search of the Laboratory Information System identified all hospitalized patients with hypoglycemia and severe hyperglycemia during a 49-day period. Chart review was used to assess demographic information, risk factors, and epidemiologic variables. The eventual outcome of the hospitalization was obtained by follow-up. RESULTS: The incidence of hypoglycemia was 1.5%, and of hyperglycemia, 1.9%. Seventy-six percent of the hypoglycemic patients and 16% of the hyperglycemic patients had no prior history of diabetes. The mortality rate for hypoglycemic patients was 22.2%; for hyperglycemic patients it was 11.1%. For all other hospitalized patients it was 2.3% (p < 0.0001). Mortality rates for the black and Hispanic patients who were hypoglycemic (30% and 46%) were significantly higher than for white patients (6%, p < 0.01). CONCLUSIONS: Hypoglycemia and severe hyperglycemia are not uncommon in hospitalized patients and serve as metabolic markers for patients at increased risk for inhospital mortality. Early identification of at-risk patients and the impact of aggressive treatment of their underlying disease processes should be evaluated in future studies. PMID- 8692156 TI - Pharmaceutical industry support for continuing medical education programs: a review of current ethical guidelines. AB - Ethical relationships between physicians and the drug industry require guidelines to maintain the integrity of the medical profession. The acceptance of gifts and subsidies for the cost of continuing-medical-education conferences is considered ethically acceptable provided the gifts are of minimal value and that the control of content and the selection of presenters and moderators for industry-supported CME programs rest solely with the CME-sponsoring institution. Current ethical guidelines for pharmaceutical industry support of CME programs are reviewed in this essay. PMID- 8692157 TI - Pelvic exenteration in gynecologic oncology: Experience at the Mount Sinai Center, 1975-1992. AB - Thirty-nine patients underwent pelvic exenteration for gynecologic malignancies at The Mount Sinai Medical Center between 1975 and 1992. Surgical techniques, morbidity, survival, and other variables for patients so treated in two periods, 1975-1984 and 1985-1992, were compared. The primary cancer included squamous cell carcinoma of the cervix, 27; adenocarcinoma of the cervix, 1; squamous cell carcinoma of the vagina, 4; adenocarcinoma of the endometrium, 4; squamous cell carcinoma of the vulva, 2; and adenocarcinoma of the rectum, 1. Median survival was 23.1 months, with a median follow-up of 18 months. Survival was significantly related to status of the lymph nodes (p 0.0004) and surgical margins (p 0.0038). There were two postoperative mortalities, one due to pulmonary embolus and another to myocardial infarction. The ability in the second period analyzed, 1985 1992, to integrate a continent urinary reservoir and supralevator exenteration without colostomy yet not induce increased morbidity or decreased survival, has not been previously reported. PMID- 8692158 TI - Central neurocytoma: An unusual intraventricular tumor. AB - A case of central neurocytoma occurring in a 22-year-old man is presented. This tumor is generally considered to be benign in appearance, nonrecurrent, and amenable to surgical resection. However, this particular neurocytoma demonstrated anaplastic features, raising the issue of malignancy and the need for additional modes of treatment. Implicated factors and possible optimal treatment for this tumor are discussed. PMID- 8692159 TI - Neurocysticercosis: Report of fifteen cases. AB - BACKGROUND: Neurocysticercosis (NCC), which is caused by the encysted larvae of the porcine tapeworm Taenia solium, is uncommon in developed countries. METHODS: Fifteen cases were reviewed retrospectively from the medical records of patients admitted to Queens Hospital Center, a 550-bed acute care municipal hospital in New York City, from 1986 through 1992. All patients were immigrants from Central and South America. Nine were men and six were women; age range was 11-80 years, mean 33.8 years. Thirteen of the 15 patients (86%) were admitted with seizures. One patient had a strokelike syndrome with transient slurred speech and confusion. RESULTS: Diagnosis was based on clinical findings, CT or MRI studies (100%), and ELISA titers (81%). Cerebrospinal fluid abnormalities were noted in 5 of 7 samples obtained. Twelve adult patients with NCC were treated with praziquantel and steroids, and their courses were uncomplicated, except for one patient who required ventricular shunt placement for hydrocephalus. CONCLUSIONS: NCC should be suspected in immigrants from Central and South America who have seizures; it may complicate the differential diagnosis of various central nervous system syndromes. Available therapies entail risks and uncertainties. The ultimate approach is prevention of infestation. PMID- 8692160 TI - Cough induced by angiotensin-converting-enzyme inhibitors: Airway responses to inhalation of methacholine in patients who have essential hypertension. AB - We investigated whether patients with cough due to angiotensin-converting-enzyme inhibitors have a common pattern of airway responses to methacholine inhalation. Studies assessing only presence or absence of hyperresponsiveness to this agent have produced conflicting results. Spirometric testing before and after methacholine was performed in 14 hypertensive patients at least two weeks after discontinuation of these inhibitors, when cough had abated or disappeared. Subjects were predominantly female (86%) nonsmokers (93%), with high prevalence of respiratory atopic illnesses (57%) probably due to ethnic background (72% Hispanic). Premethacholine spirometric values were normal. Postmethacholine bronchoconstriction of varying degrees was observed in seven patients, but reached the level of hyperresponsiveness in only one patient with asthma. The other seven subjects exhibited no bronchoconstriction. The two groups did not differ in age, concomitant illnesses (e.g., atopy) and medications, or blood pressure reduction. We conclude that airway responses to cholinergic stimulation do not exhibit a common pattern and are randomly distributed in hypertensive patients who develop cough induced by angiotensin-converting-enzyme inhibitors. PMID- 8692161 TI - The nature of rheumatogenic streptococci. PMID- 8692162 TI - The emergence of "emerging diseases": a lesson in holistic epidemiology. AB - The term "emerging diseases" is a loosely defined category of entities comprising resurgent or recurrent old diseases (usually caused by "new" or mutated previously known agents), diseases truly new to man, but caused by preexisting ("old") zoonotic agents, and syndromes newly defined by the discovery of new agents through advances in biotechnology. Identification and solution of these problems depends, first, on recognition of their differences, and then upon tailoring appropriate strategies for their control. Thus, new influenza viruses appear each year to challenge immunity to their antecedents, but evoke the unchanged and centuries old symptom complex of influenza. Tuberculosis, is resurgent because of mycobacterial mutation to antibiotic resistance, immunosuppression by AIDS, and laxity in public health surveillance. Parvovirus B19 and herpesvirus 6 were revealed as cryptic infectors of white blood cells in studies of hepatitis B and AIDS, but since have been shown to be important causes of childhood rashes, aplastic anemia, and neurologic disease. The encroachment of human habitation on wilderness perimeters (ecosystem change) has increased contact with vectors of zoonotic viruses and bacteria, as evidenced by Lyme disease, Ebola virus infection, and the hemorrhagic fevers. The term "holistic epidemiology" embraces all these problems, from the molecular to the macroenvironmental level. Humans, parasites, and their environment will continue their ancient, fluctuating, dynamic relationship in the future, and new diseases will continue to emerge. PMID- 8692163 TI - Research in psychodynamic psychotherapy. PMID- 8692164 TI - Renal biopsy: why and when. AB - The purpose of this paper is to emphasize the importance of information obtained by renal biopsy in the diagnosis, prognosis, and therapy of patients with renal disease. Because controversy persists regarding the value of renal biopsy as an aid in determining prognosis and in choosing appropriate therapy, there has been some reluctance to use it early after the onset of obvious signs, symptoms, and laboratory findings indicative of renal disease with or without involvement of other organs. Although all such patients may not benefit from the information provided by a proper biopsy, we will illustrate some of the characteristic histologic details found in specific circumstances in our experience where the biopsy has been particularly helpful in reaching a diagnosis, in assessing prognosis, and in choosing therapy. PMID- 8692165 TI - A history of immunosuppressive drugs in the treatment of inflammatory bowel disease: origins at the Mount Sinai Hospital. AB - If the cause of Crohn's disease and ulcerative colitis turns out to be some immunopathologic mechanism, many of the steps leading to such an understanding of their pathogenesis can be attributed to concepts that originated at The Mount Sinai Hospital. Perhaps immodestly, we can claim a role in the acceleration and the acceptance of these concepts; however, many contributions were made by others, including Moschkowitz, Klemperer, Otani, Crohn, Ginzburg, Oppenheimer, Marshak, and Janowitz. This does not mean that clinicians and researchers from other institutions did not contribute to this understanding. As happens so often in medical history, elucidation of many disease processes are serendipitous. The concept of autoimmune diseases was introduced when we were house officers at Mount Sinai. The early days of transplant surgery soon followed along with the introduction by Hitchings and Elion of azathioprine to inhibit rejection. The concept of immunosuppression slowly evolved into possible treatment of any disease thought to be caused by autoimmunity, including those diseases of the bowel, seen so frequently at The Mount Sinai Hospital: ileitis, granulomatous colitis, ileocolitis, and ulcerative colitis. Although most of the world called granulomatous disease of the bowel Crohn's disease, it was only after the deaths of Drs. Crohn, Ginzburg, and Oppenheimer that we accepted this single eponym. However, we will always pay tribute to all three Mount Sinai physicians who wrote the original paper that described the disease. PMID- 8692166 TI - Pathogenesis of inflammatory bowel disease: evolving concepts. PMID- 8692168 TI - Meta-analysis: an update. AB - A fairly new type of research, termed meta-analysis, attempts to analyze and combine the results of previous reports. In 1992 we updated our 1987 survey of 86 meta-analyses of randomized control trial reports in the english language literature with an additional 78. We evaluated the quality of these meta-analyses using a scoring method that lists 23 items in six major areas: study design, combinability, control of bias, statistical analysis, sensitivity analysis, and application of results. Of the 23 individual items, the mean number satisfactorily addressed was 7.63 +/- 2.84 (mean +/- S.D.) for 40 papers published from 1955 through 1982, 6.80 +/- 3.86 for 66 papers published from 1983 through 1986, and 11.91 +/- 4.79 for 58 papers published from 1987 through 1990 (F = 31.3, p < .001). We noted that methodology has definitely improved since our first survey of meta-analyses, but an urgent need still exists for a better search of the literature, quality evaluation of trials, and a synthesis of the results. Recently, meta-analysis has expanded to cover non-randomized studies, including evaluation of diagnostic tests and pooling of epidemiologic studies. There is growing concern for standards, and several methodologic issues remain unresolved. PMID- 8692167 TI - Calcification of elastic fibers in pseudoxanthoma elasticum. AB - Pseudoxanthoma elasticum is an inherited disorder of connective tissue that is characterized by calcification of elastic fibers with associated abnormalities of the skin, ocular, and cardiovascular systems. The genetic defect causing pseudoxanthoma elasticum has not been determined and the diagnosis relies on clinical recognition of skin lesions and histologic demonstration of calcification of elastic fibers that are clumped and fragmented in the dermis. The role of connective tissue components in the etiology of pseudoxanthoma elasticum is reviewed and includes changes in collagen, elastin, glycosaminoglycans, fibronectin, microfibrillar proteins, modifying enzymes of extracellular matrix proteins, fibroblasts, and fibrillins. PMID- 8692169 TI - Hemophilia: yesterday, today, and tomorrow. AB - Hemophilia is an ancient disease which was not defined until the 1940s. Marked advances in management have altered the lifestyle of these patients and extended their life. The use of human-derived blood products had brought devastating viral infections to hemophiliacs. New products and creative interventions offer new patients safer and longer life, prophylaxis, continuous infusion, and gene therapy offer a bright future. Inhibitor induction and its management remain a significant challenge, but financial underwriting of care for this chronic disease remains the major uncertainty regarding fulfillment of the scientific and clinical gains. PMID- 8692170 TI - Prevention into the 21st century. AB - Prevention in the United States has suffered because of the use of a traditional "medical" model rather than a "health" model. Financing, medical education, and research support have favored a focus on disease rather than prevention, although the greatest gains in man's physical well-being have come from preventive rather than curative activities. Although prevention has not been a major focus within medicine to date, despite its significant contributions, it appears that major changes will take place in the twenty-first century that will markedly change this situation. Mount Sinai, because of its meaningful role in studying the health of groups and in health service delivery, and its founding as a medical school with a focus on populations, has made, and will make, contributions to preventive activities in the future. PMID- 8692171 TI - Using standardized patients for assessing clinical performance: an overview. AB - Standardized patients are being used increasingly worldwide to assess the clinical skills and competencies of medical students, residents, and physicians; plans are now underway for the use of standardized patients in licensure and certification examinations. The Morchand Center for Clinical Competence was established at Mount Sinai School of Medicine for the purpose of assessing clinical performance with the use of standardized patients, and currently all students in the eight medical schools in the New York City Consortium are tested at The Morchand Center. This paper presents an overview of standardized-patient assessment, a description of the assessment program at The Morchand Center, and a summary of research on this assessment approach including research at The Morchand Center. PMID- 8692172 TI - Breast cancer chemotherapy after fifty years: more cures and less mutilation. PMID- 8692173 TI - Hypertension: a personal odyssey. AB - This is a brief history of my personal experiences at the Mount Sinai Hospital and Medical School, preceding and interlaced with the research that eventually involved hypertension. My research on the hearts, kidneys, and lungs of animals was followed by work on clubbing of the fingers, hypertrophic osteoarthropathy, and myocardial infarction. This finally led to studying vascular resistance and reactivity in hypertension and other vascular diseases. I investigated and treated special causes of hypertension and developed proper testing and effective treatment of "essential" hypertension. We established the hypertension clinic and laboratory to accomplish these objectives. As for etiology, hereditary and environmental factors have become better defined, especially in "essential" hypertension. Study of the spontaneously hypertensive rat may clarify some hereditary factors in hypertension, although its relationship to human essential hypertension remains questionable. In addition, basic work on the physiology and molecular biology of uterine and vascular smooth muscle has shed some light on the complexities of restenosis after angioplasty, arteriosclerosis, left ventricular hypertrophy, and hypertension. The help and encouragement of teachers and colleagues throughout the years has made all this effort possible. PMID- 8692174 TI - History of the Department of Dermatology of the Mount Sinai Hospital. AB - The Department of Dermatology at Mount Sinai has a long, distinguished history. Founded in 1891, the department started in an era of keen diagnosticians and clinicians. By the middle of the twentieth century, it had evolved as both a clinical and investigational department at the forefront of both dermatology and syphilology. Today, it excels in both clinical and research areas and is on the cutting edge in dermatologic surgery. PMID- 8692175 TI - Vena cava filters: available devices and current practices. AB - Deep venous thrombosis and pulmonary embolus are significant clinical problems. Although anticoagulation remains first-line therapy for thromboembolic disease, the placement of inferior vena cava filters plays an important role as alternative or supplemental therapy. Initial filters were high-profile devices intended to be placed via surgical cutdown. Concerns about the size of the delivery systems prompted development of low-profile systems intended specifically for percutaneous placement. The placement of filters has progressively become a percutaneous procedure performed by interventional radiologists outside of the operating room. This article reviews the currently available devices that have been approved by the Food and Drug Administration, their indications, efficacy, and complications. Experimental temporary filter designs are discussed as well. PMID- 8692176 TI - Mammalian DNA damage-inducible genes associated with growth arrest and apoptosis. AB - Mammalian cells are exposed to a wide variety of genotoxic stresses from both endogenous and exogenous sources. Cells typically exhibit cell cycle delays, or checkpoints, in response to acute genotoxic stress. Other types of cellular responses to DNA damage include apoptosis and probably increases in DNA repair levels. These response pathways are altered in cancer cells, by genetic alterations such as overexpression or mutation of oncogenes, or loss of tumor suppressor gene functions. As cancer chemotherapy relies primarily on the selective killing of cancer cells by DNA-damaging agents, genetic alterations affecting cellular stress response pathways may affect the outcome of cancer treatment. PMID- 8692178 TI - Tetracycline reduces fluoroquinolones-induced bleaching of Euglena gracilis. AB - Inhibitory activity of tetracycline against ofloxacin- and fleroxacin-induced bleaching of green and etiolated Euglena gracilis was examined. Tetracycline hydrochloride in concentrations of 83-2079 microM in the light partially inhibited the bleaching activity of 83 microM ofloxacin and of 162 microM fleroxacin. In the dark, the TC inhibition of the fluoroquinolones-induced bleaching activity was most obvious, the white colony counts were all decreased. The total inhibition of bleaching was observed in 43 microM ofloxacin and 81 microM fleroxacin both in light and darkness. Cell growth was not significantly influenced by ofloxacin, fleroxacin and tetracycline in the light or darkness. Cell growth was not significantly influenced by ofloxacin, fleroxacin and tetracycline in the light or darkness. Inhibition of ofloxacin-induced Euglena bleaching by tetracycline was more effective in etiolated cells. TC at 0-416 microM did not influence the growth of ofloxacin (2.15 microM)-induced Salmonella typhimurium revertants. PMID- 8692177 TI - Genetic, cytogenetic, and carcinogenic effects of radon: a review. AB - Radon exposure has been linked to lung carcinogenesis in both human and animal studies. Studies of smoking and nonsmoking uranium miners indicate that radon alone is a risk factor for lung cancer at the levels encountered by these miners, although the possibility exists that other substances in the mine environment affect the radon-induced response. The relevance of data from mines to the lower exposure home environment is often questioned; still, a recent study of miners exposed to relatively low radon concentrations demonstrated a statistically significant increase for lung and laryngeal cancer deaths. In two major series of experiments with rats, the primary carcinogenic effect found was respiratory tract tumors, and evidence for an inverse exposure-rate effect was also noted. Although this inverse dose-rate effect also has been described in underground miner studies, it may not similarly apply to radon in the home environment. This observation is due to the fact that, below a certain exposure, cells are hit once or not at all, and one would not expect any dose-rate effect, either normal or inverse. Because some chromosome aberrations persist in cycling cells as stable events, cytogenetic studies with radon are being performed to help complete the understanding of the events leading to radon-induced neoplasia. Radon has been found to induce 13 times as much cytogenetic damage (as measured by the occurrence of micronuclei) than a similar dose of 60Co. A wide variety of mutation systems have demonstrated alpha-particle mutagenesis; recent investigations have focused on the molecular basis of alpha-induced mutagenesis. Gene mutations are induced by radon in a linear and dose-dependent fashion, and with a high biological effect relative to low-LET irradiation. Studies of the hprt locus show that approximately half of the alpha-induced mutations arise by complete deletion of the gene; the remaining mutations are split between partial deletions, rearrangements, and events not detectable by Southern blot or PCR exon analysis. Although other mutation systems do not show the same spectra as observed in the hprt gene (suggesting that the gene environment affects response), DNA deletions or multilocus lesions of various size appear to be predominant after radon exposure. As data emerge regarding radon-induced changes at the chromosomal and molecular level, the mechanisms involved in radon carcinogenesis are being clarified. This information should increase the understanding of risk at the low exposure levels typically found in the home. PMID- 8692179 TI - Achievements by CSGMT/JEMS.MMS: the Collaborative Study Group for the Micronucleus Test in the Mammalian Mutagenesis Study Group of the Environmental Mutagen Society of Japan. AB - The Collaborative Study Group for the Micronucleus Test (CSGMT) is one of the task groups in the Mammalian Mutagenesis Study Group (MMS) of the Environmental Mutagen Society of Japan (JEMS). It was established in 1982 and has made efforts to understand what the micronucleus test is, what are the advantages and disadvantages of the test as an in vivo detection system for mutagens/carcinogens, and to establish a standard protocol applicable to numerous chemicals. Members of the CSGMT have published more than 75 papers as part of collaborative studies and have contributed to the understanding of the nature of the micronucleus test and to setting guidelines for testing of medicinal and other chemicals. The CSGMT held some workshops to share up-to-date knowledge and techniques on the micronucleus test. Through workshops and collaborative studies, the CSGMT contributed to the maintaining of a high standard of knowledge and techniques among Japanese researchers of the micronucleus test. This paper reviews achievements made by the CSGMT until now. PMID- 8692181 TI - A re-evaluation of the cytogenetic effects of styrene. PMID- 8692180 TI - A comparison of the 8-hydroxydeoxyguanosine, chromosome aberrations and micronucleus techniques for the assessment of the genotoxicity of mercury compounds in human blood lymphocytes. AB - We compared the mechanism of action of micronuclei (MN), unstable chromosome aberrations, and 8-hydroxydeoxyguanosine (8-OHdG) levels to evaluate the genotoxicity of methyl mercuric chloride (CH3HgCl) and mercuric chloride (HgCl2) in human peripheral lymphocytes. The chromosome aberrations in human peripheral lymphocytes exposed to various concentrations of CH3HgCl or HgCl2 increased in a concentration-dependent manner and were significantly higher than the control when the cells were incubated with 1 x 10(-5) M (HgCl2) or 2 x 10(-6) M (CH3HgCl). The increase in the incidence of micronucleated lymphocytes was significant among the exposed groups, being 2 x 10(-5) M (HgCl2) and 5 x 10(-6) M (CH3HgCl) compared with the control. CH3HgCl was about 4-fold more potent than HgCl2. We determined the 8-OHdG levels in human peripheral blood mononuclear cells(PBMC) and found that they were significantly higher in the exposed groups at 1 x 10(-5) M (HgCl2) and 5 x 10(-6) M (CH3HgCl) compared with the control. A detectable (p < 0.05) increase in the level of 8-OHdG was induced by CH3HgCl at a concentration that was about 50% of the amount of HgCl2 required to produce a similar response. The data confirmed the value of the MN and/or chromosome aberration assays for assessing of HgCl2- and/or CH3HgCl-induced genotoxicity, and indicated that they are about the same concentration as the 8-OHdG assay. The presence of genotoxic effects in peripheral blood lymphocytes exposed to the mercuric compounds indicated by the chromosome aberrations and the MN assays could be partly due either to the disturbance of the spindle mechanism, or to the elevated level of 8-OHdG brought by the generation of reactive oxygen species. PMID- 8692182 TI - Optimization of the Salmonella/mammalian microsome assay for urine mutagenesis by experimental designs. AB - Assessing urine mutagenicity with the Salmonella mutagenicity test is often limited by the volumes of the samples. Optimization of the assay was performed with factorial and Doehlert designs. Two fractional factorial designs 2(3-1) (3 factors, 4 experiments) were used to estimate the main effects of the percent S9 in the mix, the time of liquid incubation, the inoculum size and the growth conditions. A Doehlert design (3 factors, 13 experiments) was used to study the main effects and the interactions of the NADP, G6P and S9 in the mix. The positive markers were benzo[a]pyrene (BaP, 0.3 microgram/plate) and a pool of smokers' urine (SU, 1.25 ml equivalent/plate). The response was limited to the induction factor (IF, number of induced revertants/number of spontaneous revertants) with Salmonella typhimurium TA98. The optimal conditions for BaP were: a 60 min period of liquid incubation and a volume of 0.1 ml (approx. 10(8) cells/plate) of an overnight culture grown in 50 ml of Nutrient Broth No. 2 from a 250 ml flask. The S9 mix (0.1 ml, final volume) included 1.5% of S9, 1.0 mM NADP and 4.4 mM G6P. The maximal IF was 15.79. The optimal conditions for SU were: a 60 min period of liquid incubation and a volume of 0.1 ml (approx. 10(8) cells/plate) of an overnight culture grown in 7 ml of Nutrient Broth No. 2 from a 20 x 180 mm tube. The S9 mix (0.1 ml, final volume) included: 4% S9, 4.2 mM NADP and 5.2 mM G6P. The maximal IF was 10.95. These optimal conditions did not modify the spontaneous frequencies of the tester strains: TA97a, TA98, TA100 and TA102. The dose-response curves of mutagenic urine samples were found to be non-linear. This micromethod required 8-fold less urine sample and 12.5-fold less liver homogenate as compared to the standard plate incorporation assay and was from 6.2 to 11.8-fold more sensitive to evaluate urine mutagenicity. The sensitivity of this technique was found to be limited to individuals smoking more than approx. 5 cigarettes/day by the standard extraction-concentration procedure. PMID- 8692183 TI - DNA adducts in human carcinogenesis: etiological relevance and structure-activity relationship. AB - Sensitive methods for quantifying DNA adducts from (i) benzo[a]pyrene (BP), (ii) alkylation exposure, and (iii) etheno(epsilon)-DNA adduct-forming chemicals were developed and applied to humans and animal models. The aims were to identify hitherto unknown sources and mechanisms of exogenous and endogenous DNA damage, to examine the effect of drug polymorphism on BP adduct levels, and to develop QSAR between tumorigenic potency, heritable genetic damage and structural elements of alkylating carcinogens (Vogel and Nivard (1994) Mutation Res., 395, 13-32). (i) BP-DNA adducts: An HPLC/fluorimetry assay suitable for measuring (+) anti-BP-diol-epoxide (BPDE) adducts in human tissues and white blood cells (WBC) was developed (Alexandrov et al. (1992) Cancer Res., 52, 6248-6253). In smokers, a positive correlation was found between pulmonary CYP1A1-related catalytic activity (AHH) and the level of lung BPDE-DNA adducts. In coke oven workers, an enhancing effect of smoking on BPDE-adduct levels in WBC was demonstrated (Rojas et al. (1995) Carcinogenesis, 16, 1373-1376). (ii) 3-Alkyladenines (3-alkAde): Alkylating carcinogens form 3-alkAde adducts in DNA which depurinate to yield 3 alkAde in urine, for which a detection method was developed (Friesen et al. (1991) Chem. Res. Toxicol., 4, 102-106; Prevost et al. (1990) Carcinogenesis, 11, 1747-1751), using immunoaffinity purification and GC-MS analysis. The usefulness of 3-alkAde analysis for the determination of the whole-body dose of alkylating agents derived from exogenous and endogenous sources was demonstrated. (iii) Etheno-DNA adduct-forming agents: Etheno(epsilon)-DNA base adducts (epsilon A, epsilon dC, epsilon dG) are promutagenic DNA lesions that are formed by occupational (vinyl halides) and environmental (urethane) carcinogens. An ultrasensitive detection method was developed (Nair et al. (1995) Carcinogenesis, 16, 613-617), based on immunoaffinity purification and 32P-postlabelling of epsilon-nucleoside 3'-monophosphates. Liver DNA from unexposed rats, mice and from human samples contained background levels of epsilon dA and epsilon dC (Bartsch et al. (1994) Drug. Metab. Rev., 26, 349-371). As formation of epsilon dA and epsilon dC adducts by lipid peroxidation products was demonstrated (El Ghissassi et al. (1995) Chem. Res. Toxicol., 8, 278-283), they may serve as markers for oxidative stress. Results from testing this hypothesis are presented. PMID- 8692184 TI - Chemical structure and genotoxicity: studies of the SOS chromotest. AB - Analyses of a data base consisting of 461 chemicals tested in the SOS chromotest with MULTICASE resulted in the development of an SAR model that displayed a highly significant concordance (87.3%) between experimental and predicted results of chemicals not included in the model. An analysis of the nature of the biophores and their modulators revealed that electrophilicity and structural features affecting: (a) accessibility of the electrophile to the nucleophilic site on the DNA; and (b) the bulkiness of the DNA adduct were factors determining the probability that a chemical would induce DNA error prone repair and if so the extent of this activity. Additional analyses indicated that there were significant mechanistic similarities between the SOS chromotest and mutations in Salmonella as determined in the standard ('Ames') assay. PMID- 8692185 TI - Genetic toxicology of four commonly used benzodiazepines: a review. AB - Benzodiazepines are a group of drugs which have been extensively used for their activities as an anti-anxiety, sedative, muscle relaxant and anti-convulsant. Benzodiazepines at present are the most commonly prescribed drugs. Some of these drugs are teratogenic and also carcinogenic in experimental animals. The wide human exposure to this group of drugs throughout the world is of great concern for human health. In the present review, we have attempted to evaluate and update the mutagenic and genotoxic effects of four of the most commonly used benzodiazepines, i.e., chlordiazepoxide (CDZ), diazepam (DZ), nitrazepam (NZ) and oxazepam (OZ) based on available literature. PMID- 8692186 TI - A STEP forward for European environmental mutagenesis research. AB - This article introduces a special issue of Mutation Research which contains final synthesis reports of eight multi-national research projects in the STEP (Science and Technology for Environmental Protection) Research Programme of the European Commission. In addition to sketching the scientific, policy and historical background to the research, the contents of the eight reports are summarised and the broader issue of environmental research and its links to chemicals control, risk assessment, and regulation in the European Union is discussed. PMID- 8692187 TI - Development of new molecular procedures for the detection of genetic alterations in man. AB - The Restriction Site Mutation (RSM) procedure is a DNA-based method for detecting mutations at any unselected locus. Mutations are identified as alterations of the DNA sequence at a chosen restriction site. DNA from cells exposed to mutagenic treatment is exhaustively digested with the restriction enzyme (RE). Sequences containing the mutated target site are specifically amplified using the polymerase chain reaction (PCR), whereas DNA without mutations at this site will have been cleaved and can not therefore provide a substrate for PCR. We have developed this procedure using both bacterial and mammalian cells. With bacteria, in plasmid reconstruction experiments we were able to detect mutations at a frequency of 10(-6) at an EcoRI site in the AraA locus of Salmonella typhimurium. The detection limit with an RsaI site in the lacI gene of Escherichia coli was 10(-5), and we were able to detect DNA damage and repair after treatment with N methyl-N-nitrosourea (MNU). With mammalian cells, we have detected mutations induced by ethyl methanesulphonate (EMS) at a TaqI site in the aprt gene of Chinese hamster cells. In extensive studies with normal and repair-deficient human cells, we have detected and sequenced mutations induced by UV-C or UV-B in fibroblasts and lymphoblastoid cells from repair-deficient xeroderma pigmentosum (XP) donors. Similar results were obtained at TaqI sites in three genes, hprt, c Ha-rasI and p53. These results demonstrate that the system is able to detect and analyse mutations induced at high frequencies. In our extensive attempts to extend the work to conditions of lower mutation frequencies, we have encountered several obstacles, the most serious being false-positive mutant DNA in totally untreated cells. This appeared to be a cell-line specific phenomenon, which we have not been able to eliminate by altering conditions. We propose therefore that, at present, RSM is a suitable method for studying high mutation frequencies at different loci and could be used for mutagen testing with repair-deficient cells. As yet, however, its sensitivity and specificity is not sufficient for population monitoring. PMID- 8692188 TI - The detection and evaluation of aneugenic chemicals. AB - Although aneuploidy makes a significant contribution to both somatic and inherited disease the mechanisms by which environmental chemicals may induce numerical chromosome aberrations are only poorly defined. The European Union Project was aimed to further our understanding of those chemical interactions with the components of the mitotic and meiotic cell division cycle which may lead to aneuploidy and to characterise the parameters such as cellular metabolism which may influence the activity of aneugenic chemicals. C-mitosis can be induced by the highly lipophilic polychlorinated biphenyl and the completion of mitosis and cleavage can be modified by agents which deplete cellular levels of reduced glutathione. Modifications of the fidelity of chromosome segregation were produced by inhibiting the functioning of topoisomerase II during chromatid separation. In contrast, the modification of centromere integrity resulted in chromosome breakage as opposed to disturbance of segregation. Modifiers of tubulin assembly and centriolar functioning in somatic cells such as acrylamide, vinblastine and diazepam reproduced their activity in rodent bone marrow and male germ cells. The analysis of chromosome malsegregation in Aspergillus nidulans by a structurally related series of halogenated hydrocarbons was used to develop a QSAR model which had high predictive value for the results of fungal tests for previously untested related chemicals. Metabolic studies of potential aneugens in genetically engineered human lymphoblastoid cells demonstrated the detoxification of the aneugenic activity of chloral hydrate and the activation of 2,3 dichlorobutane, 1,1,2-trichloroethane and trichloroethylene by Phase I biotransforming enzymes. Cell transformation studies in Syrian hamster dermal cultures using a panel of 22 reference and or potential aneugens indicated that 15 of the 22 produced positive results following single exposures. Five of the aneugens which were negative following single exposures produced positive results where cultures were continuously exposed for up to 6 weeks to low concentrations following a single non-transforming exposure to the mutagen dimethyl sulphate. The transformation studies indicate that a significant proportion of chemical aneugens are potential complete carcinogens and/or co-carcinogens. To optimise the enumeration of chromosomes following exposure to potential chemical aneugens whole chromosome paints and centromere specific probes suitable for use in fluorescence in situ hybridisation (FISH) were developed for the rat, mouse and Chinese hamster and selected human probes evaluated for their suitability for routine use. Molecular chromosome probes were used to develop protocols for enumerating chromosomes in metaphase cells and centromeres and micronuclei in interphase cells. The analysis of segregation of specific centromeres in binucleate cells following cytochalasin B treatment was shown to be a potentially valuable system for characterising non-disjunction following chemical exposure. Whole chromosome paints and centromere specific probes were used to demonstrate the presence of dose-response thresholds following treatment with a reference panel of spindle inhibiting chemicals. These data indicate that the FISH technology is suitable for evaluating the relative hazards of low-dose exposures to aneugenic chemicals. PMID- 8692189 TI - Molecular dosimetry of chemical mutagens. Relationship between DNA adduct formation and genetic changes analyzed at the molecular level. AB - This is a review of the work carried out by 16 collaborating institutes within a project which was part of the European Programme: Science and Technology for Environmental Protection (STEP). The purpose of the project was to investigate the relationship between the exposure to genotoxic chemicals and the induction of DNA damage and genetic effects as determined in in vitro and in vivo assays under laboratory conditions. Two types of investigation were performed: (i) determination of the relationship between the extent of exposure to a genotoxic chemical and the frequency of DNA adducts formed in the test organism and (ii) identification of those DNA adducts which are responsible for the biological effects of genotoxic chemicals. The research was carried out with a series of alkylating agents which all induce similar types of DNA damage but for which the proportions of the different types of adducts vary. The frequency of this type of DNA damage was also modulated by base excision repair processes. In addition, a number of genotoxic agents which cause DNA damage recognized by nucleotide excision repair were investigated. The consequences of DNA adduct formation, i.e., the induction of gene mutations, were analyzed at the DNA sequence level, generating mutational spectra. These investigations of the mutational specificities of carcinogens contributed to our understanding of the molecular mechanisms which are involved in cancer induction by genotoxins. PMID- 8692190 TI - Development and validation of alternative metabolic systems for mutagenicity testing in short-term assays. AB - We present here the results obtained within the framework of an EU funded project aimed to develop and validate alternative metabolic activating systems to be used in short-term mutagenicity assays, in order to reduce the use of laboratory animals for toxicology testing. The activating systems studied were established cell lines (Hep G2, CHEL), genetically engineered V79 cell lines expressing specific rat cytochromes P450, erythrocyte-derived systems, CYP-mimetic chemical systems and plant homogenates. The metabolically competent cell lines were used as indicator cells for genotoxic effects as well as for the preparation of external activating systems using other indicator cells. The following endpoints were used: micronuclei, chromosomal aberrations and sister chromatid exchanges, mutations at the hprt locus, gene mutations in bacteria (Ames test), unscheduled DNA synthesis and DNA breaks detected in the comet assay. All metabolic systems employed activated some promutagens. With some of them, promutagens belonging to many different classes of chemicals were activated to genotoxicants, including carcinogens negative in liver S9-mediated assays. In other cases, the use of the new activating systems allowed the detection of mutagens at much lower substrate concentrations than in liver S9-mediated assays. Therefore, the alternative metabolizing systems, which do not require the use of laboratory animals, have a substantial potential in in vitro toxicology, in the basic genotoxicity testing as well as in the elucidation of activation mechanisms. However, since the data basis is much smaller for the new systems than for the activating systems produced from subcellular liver preparations, the overlapping use of both systems is recommended for the present and near future. For example, liver S9 preparations may be used with some indicator systems (e.g., bacterial mutagenicity), and metabolically competent mammalian cell lines may be used with other indicator systems (e.g., a cytogenetic endpoint) in a battery of basic tests. PMID- 8692191 TI - DNA damage and repair in mutagenesis and carcinogenesis: implications of structure-activity relationships for cross-species extrapolation. AB - Previous studies on structure-activity relationships (SARs) between types of DNA modifications and tumour incidence revealed linear positive relationships between the log TD50 estimates and s-values for a series of mostly monofunctional alkylating agents. The overall objective of this STEP project was to further elucidate the mechanistic principles underlying these correlations, because detailed knowledge on mechanisms underlying the formation of genotoxic damage is an absolute necessity for establishing guidance values for exposures to genotoxic agents. The analysis included: (1) the re-calculation and further extension of TD50 values in mmol/kg body weight for chemicals carcinogenic in rodents. This part further included the checking up data for Swain-Scott s-values and the use of the covalent binding index (CBI); (2) the elaboration of genetic toxicity including an analysis of induced mutation spectra in specific genes at the DNA level, i.e., the vermilion gene of Drosophila, a plasmid system (pX2 assay) and the HPRT gene in cultured mammalian cells (CHO-9); and (3) the measurement of specific DNA alkylation adducts in animal models (mouse, rat, hamster) and mammalian cells in culture. The analysis of mechanisms controlling the expression of mammalian DNA repair genes (alkyltransferases, glycosylases) as a function of the cell type, differentiation stage, and cellular microenvironment in mammalian cells. The 3 classes of genotoxic carcinogens selected for the project were: (1) chemicals forming monoalkyl adducts upon interaction with DNA; (2) genotoxins capable of forming DNA etheno-adducts; and (3) N-substituted aryl compounds forming covalent adducts at the C8 position of guanine in DNA. In general, clear SARs and AARs (activity-activity relationships) between physiochemical parameters (s-values, O6/N7-alkylguanine ratios, CBI), carcinogenic potency in rodents and several descriptors of genotoxic activity in germ cells (mouse, Drosophila) became apparent when the following descriptors were used: TD50 estimates (lifetime doses expressed in mg/kg b.wt. or mmol/kg b.wt.) from cancer bioassays in rodents; the degree of germ-cell specificity, i.e., the ability of a genotoxic agent to induce mutations in practically all cell stages of the male germ-cell cycle of Drosophila (this project) and the mouse (literature search), as opposed to a more specific response in postmeiotic stages of both species; the Mexr /Mexr+ hypermutability ratio, determined in a repair assay utilizing Drosophila germ cells; mutation spectra induced at single loci (the 7 loci used in the specific-locus test of the mouse (published data), and the vermilion gene of Drosophila); and doubling doses (DD) in mg/kg (mmol/kg) for specific locus test results on mice. By and large, the TD50 values, the inverse of which can be considered as measures of carcinogenic potency, were shown to be predictable from knowledge of the in vivo doses associated with the absorbed amounts of the investigated alkylators and with the second-order constant, kc, reaction at a critical nucleophilic strength, nc. For alkylating agents kc can be expressed as the second-order rate constant for hydrolysis, kH2O, and the substrate constant s:kH2OTD50 is a function of a certain accumulated degree of alkylation, here given as the (average) daily increment, ac, for 2 years exposure of the rodents. The TD*50 in mmol/kg x day) could then be written: [formula: see text] This expression would be valid for monofunctional alkylators provided the reactive species are uncharged. This is the case for most SN2 reagents. Although it appears possible to predict carcinogenic potency from measured in vivo doses and from detailed knowledge of reaction-kinetic parameter values, it is at present not possible to quantify the uncertainty of such predictions. One main reason for this is the complication due to uneven distribution in the body, with effects on the dose in target tissues. The estimation can be impro PMID- 8692192 TI - Nongenotoxic carcinogens: development of detection methods based on mechanisms: a European project. AB - While the accumulation of genetic changes in a somatic cell is considered essential for the genesis of a cancer, it has become clear that not all carcinogens are genotoxic, suggesting that some carcinogens indirectly participate in the generation of genetic changes during carcinogenesis. A European project funded by the European Community was thus conceived to study mechanisms of nongenotoxic aspects of carcinogenesis. Two main strategical approaches were adapted: (i) to study whether and how Syrian hamster embryo (SHE), Syrian hamster dermal (SHD) and BALB/c 3T3 cell transformation systems simulate in vivo carcinogenesis, and to examine whether they can detect nongenotoxic carcinogens; (ii) to study, refine and validate mechanisms-based end points for detection of nongenotoxic carcinogens. For mechanisms-based research, the proposed end-points included gap junctional intercellular communication (GJIC) inhibition, altered expression of critical genes, immortalization and aberrant cell proliferation. We also selected model compounds commonly usable for various endpoints. Our major results can be summarized as follows: (1) SHE and BALB/c 3T3 transformation systems reflect both genotoxic and nongenotoxic carcinogenic events; they detect not only genotoxic but also many although not all, nongenotoxic carcinogens. This is further supported by the fact that both genotoxic and nongenotoxic carcinogens were able to immortalize SHD cells. (2) Many nongenotoxic carcinogens, although not all, inhibit GJIC in vitro as well as in vivo. Mechanistic studies suggest an important role of blocked GJIC in carcinogenesis and that different mechanisms are involved in inhibition of the communication by different agents used. However, inhibition of GJIC is not a prerequisite for the enhancement (or induction) of transformation of SHE or BALB/c 3T3 cells. (3) Among compounds examined, there was a good correlation between induction of micronuclei and cell transformation in SHE cells while no such correlation was found between the induction of cell transformation and ornithine decarboxylase activity. (4) Two transgenic mouse mutation assays (lacI and lacZ) were established and validated. The genotoxin dimethylnitrosamine was shown to be mutagenic to the liver in both assays. Ortho-anisidine, a bladder specific carcinogen that was inactive in standard rodent genetic toxicity assays was uniquely mutagenic to the bladder of the transgenic mice. The peroxisome proliferator methyl clofenipate was established as nonmutagenic to the liver of both transgenic mice. That eliminated DNA damage as a cause of the liver tumours produced by this chemical and weakened the idea that induced cell division leads to mutation induction. (5) With an in vitro DNA replication model, it was found that DNA damage induced by genotoxic agents can be responsible for inhibition of DNA replication, while certain nongenotoxic agents such as phorbol esters increase DNA replication. (6) An attempt to use structure-activity relationship for subfamilies of nongenotoxic carcinogens, e.g., receptor-mediated carcinogens, has been initiated with some promising results. Our results support the idea that there are multiple nongenotoxic mechanisms in carcinogenesis, and that working hypothesis-oriented approaches are encouraged rather than simple screening of chemicals in developing test systems for the detection of nongenotoxic carcinogens. PMID- 8692194 TI - Somatic recombination, gene amplification and cancer. AB - The principle objective of this research programme, to analyse chemical induction of somatic recombination and related endpoints, i.e., mobilization of transposing elements and gene amplification, has been approached by means of several assay systems. These have included Drosophila, Saccharomyces and mammalian cell cultures. 6.1. Screening assays for mitotic recombination. A large number of chemicals have been investigated in the three Drosophila assay systems employed- the multiple wing hair/flare wing spot system developed by Graf et al., 1984, the white-ivory system developed by Green et al., 1986 and the white/white+ eye spot assay developed by Vogel (Vogel and Nivard, 1993). Particularly the screening of 181 chemicals, covering a wide array of chemical classes, by the last mentioned assay has shown that measurement of somatic recombination in Drosophila constitutes a sensitive and efficient short-term test which shows a remarkably good correlation with the agent score of 83 short-term tests analysed by ICPEMC (Mendelsohn et al., 1992; Table 2) as well as the assay performance in international collaborative programmes measuring carcinogen/non-carcinogens (de Serres and Ashby, 1981; Ashby et al., 1985, 1988). Also the wing spot assay has gained wide international recognition as a similarly sensitive test. These two assay systems in Drosophila measure both intrachromosomal events and interchromosomal recombination. The white-ivory system on the other hand is based on the loss of a tandem duplication in the white locus, the mechanism of which is less known, but probably involves intrachromosomal recombination. The difference in the mechanism between this assay and the former two was indicated by the lack of response to methotrexate in the white-ivory assay, while this compound was strongly recombinogenic in both the wing spot and white/white+ assays. The use of different strains of Drosophila with the white/white+ assay demonstrated the importance of the background genotype for the outcome of the test. Up to a 60 fold variation was found between the different genotypes in the response to procarcinogens, evidently dependent on differences in the metabolic activation of procarcinogens. In 1989 Schiestl presented results on intrachromosomal recombination in the strain RS112 of Saccharomyces, which indicated a capability to detect a range of chemical carcinogens, which gave negative results in Ames Salmonella assay. Such a test system, which could identify a larger range of potential carcinogens than conventional short-term tests evidently would be of great value and it therefore seemed of importance to follow up the observations by Schiestl. However, studies within this programme on the same strain of Saccharomyces, as well as the strains D7 (measuring intragenic recombination, intergenic recombination, and point mutation) and JD1 (measuring intragenic recombination at two loci) could not support the observations and interpretation by Schiestl (1989). The Drosophila white-ivory system, which presumably responds primarily by intrachromosomal recombination, did not give positive results with these Salmonella-negative agents either. One system to measure mitotic recombination in mammalian cell cultures was developed in the present programme. It was based on heterozygous mutations in both alleles of the adenosine deaminase gene (ADA). The system selects for proficient recombinants generated by the deficient cells. So far only pilot experiments, indicating that this experimental system operates as planned, have been performed. 6.2 Mechanisms of mitotic recombination The induction of mosaic spots in the wing spot and the white/white+ assays is predominantly dependent on interchromosomal recombination. This is evident from the fact that heterozygous inversions reduce the frequency of spots. A relationship between the length of inversions and the reduction of spots was demonstrated in the white/white+ assay--the long inversion ln(l)sc4L PMID- 8692193 TI - Synthesis report of the step project detection of germ cell mutagens. AB - The project 'Detection of Germ Cell Mutagens' was designed with three major goals: (1) Detection and characterization of germ-cell mutagens; (2) standardization and validation of new germ-cell tests; and (3) development of a data base on germ-cell mutagenicity. All three goals were achieved. The classical germ-cell tests were applied to characterize the genetic effects of acrylamide (AA), 1,3-butadiene (BD), trophosphamide (TP) and urethane (UR). All but UR were found to cause heritable genetic damage. The experimental data obtained for AA and BD were the basis for genetic risk evaluations during the EC/US Workshop on Risk Assessment 'Human Genetic Risk from Exposure to Chemicals, Focusing on the Feasibility of the Parallelogram Approach'. Nine chemicals were employed to validate the spermatid micronucleus assay with mice and rats: AA, BD and its metabolites 1,2-epoxybutene-3 and 1,2:3,4-diepoxybutane, chlorambucil, mitomycin C, methylnitrosourea, TP and UR. The spermatid micronucleus test was combined with micronucleus tests in somatic cells such as bone marrow or peripheral blood erythrocytes, and splenocytes which allowed a comparison of effects in somatic and germinal cells. Improvements of the spermatid micronucleus test included BrdU labelling of premeiotic S-phase for the determination of stage sensitivity and fluorescence in situ hybridization with pancentromeric DNA-probes to distinguish between clastogenic and aneugenic events. The results indicate that the spermatid micronucleus test with its improvements is an adequate procedure to detect germ cell clastogenicity and to compare the activity of chemicals in different tissues and between species, i.e., rats and mice. Other germ cell methods under study were the flow cytometric measurement of testicular sperm DNA and the cytogenetic analysis of preimplantation embryos for chromosomal aberrations and micronuclei. The collection of a reliable germ-cell data base was accomplished through a critical evaluation of the literature and with the data obtained in the present project. Remarkable concordance between responses of germ cell tests to chemical mutagens was the most striking conclusion to be drawn from the present data base. PMID- 8692195 TI - Micronuclei kinetics of exfoliated urothelial cells. AB - Micronuclei observed in exfoliated cells result from DNA-damage of basal epithelium's cells by mutagens. Exfoliated urothelial cells can be collected by non-invasive procedure and may be used as target site to identify genotoxic effects of chemicals. Kinetic studies are important for any biomarker, especially those in which tissue differentiation and maturation processes will heavily influence the time between induction of damage and collection of damaged cells for analysis. This manuscript details the result of a longitudinal study of micronuclei induction in cells isolated from urine samples of 4 healthy women over 6 consecutive days. Three of them were former smokers. Results suggested that micronucleated cell rates were not influenced neither by the day nor by the time of sampling. PMID- 8692196 TI - Low mutagenic effects of mitomycin C in undifferentiated embryonic P19 cells are correlated with efficient cell cycle control. AB - Pluripotent undifferentiated embryonic carcinoma cells of line P19 and their differentiated progeny, epithelioid ectoderm-like EPI-7 cells, showed different responses to mitomycin C (MMC) with respect to induction of micronuclei, mutations at the HPRT-locus and cell cycle control. Cytotoxic effects of MMC after a 5-h treatment were lower in undifferentiated P19 cells than in differentiated EPI-7 cells with IC50 values of 1.3 and 0.25 microM for P19 and EPI-7 cells, respectively. MMC did not induce 6-thioguanine-resistant mutants in P19 cells but significantly increased the mutation frequency in EPI-7 cells with concentrations of 0.25, 0.5 and 1.0 microM MMC. Micronuclei determined by flow cytometry were induced by MMC in both cell lines at equitoxic concentrations of 4.5 (P19) and 0.75 (EPI-7) microM, reducing the viability in both cell lines to 10%. Whereas the induction of micronuclei in P19 cells was maximal 28 h after treatment and declined thereafter, micronucleus induction peaked 48 h post treatment in EPI-7 cells and remained significantly increased even 67 h after the treatment. Flow-cytometric determination of the distribution of MMC-treated P19 and EPI-7 within the cell cycle revealed a distinct G2/M-block in P19 cells, whereas EPI-7 cells showed normal progression through S-phase and a negligible G2/M-block. Therefore, we conclude that the lower effectivity of MMC to induce gene mutations and micronuclei in P19 cells seemed to be correlated with a more efficient cell cycle control in undifferentiated compared to differentiated EPI-7 cells. PMID- 8692197 TI - Instability of repeated dinucleotides in bacteriophage T7 genomes. AB - The ligase gene of bacteriophage T7 was interrupted with an insert of synthetic DNA that included a series of dinucleotide repeats which altered the reading frame of the gene and prevented the phage from growing on a host deficient in Escherichia coli ligase. The insert was designed so that gain of an additional copy of the repeat would restore the reading frame and produce ligase positive T7. It was found that a pair of nucleotides was gained at a frequency of 1.4 x 10(-3) and a dinucleotide was lost from this sequence at a frequency of 1 x 10( 4). The same measurements were made using T7 with a DNA polymerase without the 3' --> 5' exonuclease function. This mutant DNA polymerase lacks proofreading edit function and is more processive than its wild-type counterpart. Phage without the edit function gained or lost a dinucleotide repeat significantly more frequently than wild-type T7. Thus, the frequency of two base frameshifting is very high during DNA replication. Proofreading activity attenuates the frequency of two base frameshifts. Inactivation of the 3' --> 5' exonuclease of T7 DNA polymerase had essentially no effect on the frequency of deletion of one member of a pair of 10 bp tandem repeats. PMID- 8692198 TI - Alterations of c-fos gene methylation in the processes of aging and tumorigenesis in human liver. AB - The state of DNA methylation in the c-fos gene was examined in human livers of different ages, cirrhosis and hepatocellular carcinoma. The degree of methylation in the intron 1 to exon 4 region increased with age, whereas all of the 10 cirrhosis samples revealed a decrease in methylation when compared to normal livers of similar ages. The 11 hepatocellular carcinomas showed varied alterations suggesting that the alteration of the c-fos gene methylation is related to aging as well as to early-step of hepatocarcinogenesis. PMID- 8692199 TI - Chromosome changes caused by alterations of p53 expression. AB - It has been proposed that p53 tumor-suppressor plays a key role in maintaining genome integrity in mammalian cells. We analyzed karyotype alterations in human and murine cell sublines expressing various exogenous human mutant (His175, Trp248, His273) or wild-type (wt) p53 cDNAs. In human pseudodiploid LIM1215 cells that contain two endogenous wt-p53 gene alleles, p53 mutants caused both an increase in the frequency of chromosome breaks and an emergence of hyperdiploid cells. Murine T12-/- and 10(1) fibroblasts lacking endogenous p53 expression have very unstable karyotypes and show a strong tendency to increase their ploidy levels during growth in culture. Transduction of a wt-p53 construct into p53 deficient cells inhibited an accumulation of highly polyploid cell variants. Transduction of mutant p53 did not show such an effect. Modification of endogenous and exogenous p53 expression by caffeine, which interferes with normal induction of p53 in response to DNA damage, showed no correlation between the induction of chromosome breaks and heteroploidy. We conclude that the caffeine- or mutant p53-induced increase in the frequency of chromosomal breaks in dividing LIM1215 cells is assonated with inactivation of wt-p53 function(s) responsible for control of G1 checkpoint and/or DNA repair, while numerical chromosome changes in these cells may be a result of elimination or modification of a separate p53 function, or due to gain-of-function activities of p53 mutants. p53 modifications may therefore cause chromosome instability by different pathways: (1) through changes in the system(s) preventing proliferation of cells with genomic alterations; and (2) by increasing the probability of events, such as chromosome non-disjunction and/or endoreduplication that can lead to chromosome gains. PMID- 8692200 TI - Evidence for an effect of exposure to low levels of alpha particle irradiation in larval cells of Drosophila as measured in the wing-spot test. AB - Larvae of Drosophila were exposed to a range of concentrations of alpha particles from 3 to 318 mRad, and genetic effects measured in the wing-spot test. The results were positive, and evidence of a linear relationship between exposure and response observed. The induction of chromosome breakage is suggested by the significantly higher frequency of twin spots in the treated series compared with controls. PMID- 8692201 TI - Erratum to Mutation spectrum of 2-chloroethyl methanesulfonate in Drosophila melanogaster premeiotic germ cells' [Mutation Res. 331 (1995) 213-224]. AB - The 2-chloroethyl methanesulfonate (2CIEMS)-induced alcohol dehydrogenase (Adh) null germline mutation frequency in treated Drosophila melanogaster second instar larval gonia was two orders of magnitude greater than the spontaneous mutation frequency. DNA sequence analysis of 83 Adh null mutations showed that 40 mutations of independent origin were at 23 sites in the Adh gene. The mutation spectrum contained only GC --> AT transitions with 35 mutations (87.5%) at the middle or 3' guanine. In addition, characteristics of glutathione (GSH)-mediated bioactivation were determined for 2CIEMS in vitro. Rates of GSH-mediated conjugation, catalyzed by purified rat liver glutathione-S-transferase (GST), and binding of [35S]GSH-mediated conjugation products to calf thymus DNA were determined for 2CIEMS, 1,2-dichloroethane (EDC) and 1,2-dibromoethane (EDB). The relative rates of GSH-mediated conjugation were the following: 5 mM EDB > 40 mM 2CIEMS > 40 mM EDC. A similar trend was observed for DNA binding of the [35S]GSH mediated conjugation products when differences in mutagen concentration were considered: EDB > 2CIEMS > EDC. The ratios of DNA binding to GSH conjugation calculated for EDB, EDC and 2CIEMS were 6.8 x 10(-5), 9.3 x 10(-5) and 19.1 x 10( 5), respectively. A narrow range, less than a 3-fold difference, in the ratios of DNA binding to GSH conjugation indicates that the bioactivation of 2CIEMS is mediated by the same mechanism as EDB and EDC. Consequently, 2CIEMS, EDC and EDB may induce a specific mutation in premeiotic germ cells. PMID- 8692202 TI - Spontaneous immortalization of cultured skin fibroblasts obtained from a high dose atomic bomb survivor. AB - Two immortal fibroblastic cell strains (substrains) were established by culturing healthy skin cells obtained from a high-dose atomic bomb survivor (female, age 76 years, 5.14 Gy) for more than 4 years. Designated FM-U and FM-M, the two substrains share the same marker chromosome, t(5q-;6p+), but are karyotypically different, possessing hypodiploid chromosome numbers (39-43) in the former and hypertriploid (69-76) in the latter. Thus far, the two strains have passed through 117 and 156 subcultures or more than 230 and 310 cumulative population doublings, respectively, each passage requiring 4-6 days in the former and 3-4 days in the latter. In the process of immortalization, sequential rearrangement among various chromosomes presumably due to telomeric and interstitial telomeric fusions took place following the telomere shortening, particularly in the senescence and postsenescence phase cells. Of particular interest is the fact that loss of heterozygosity (LOH) of the p53 gene was demonstrated in these immortalized cell populations. In addition, the allelic patterns of the LOH of p53 differed. Further evidence indicative of infinite proliferation was demonstrated in both strains, such as the telomere elongation and the significantly low frequency of cells possessing dicentric chromosomes. PMID- 8692203 TI - Evidence for association of mitochondrial DNA sequence amplification and nuclear localization in human low-grade gliomas. AB - Gliomas are tumors which have been found to exhibit consistent genetic changes. Recent studies have shown mitochondrial DNA is also altered in these tumors, and include large deletions and gene amplification. Other studies of the mitochondrial genome in cancer have revealed a variety of different alterations, including the localization and insertion of mitochondrial DNA into the nucleus and nuclear genome in HeLa cells and diethylnitrosurea-induced hepatoma cells. Whether these changes are ontogenically early in the multistep pathway to the development of malignancy, or if this phenomenon occurs in human glial tumors is unknown. I sought to study these questions in a panel of unselected primary glial tumors of pathologically low grade. Fifteen tumors were assessed with a mitochondrial cDNA probe with homology to positions 1679-1948, and 2017-2057. All low-grade tumors revealed increases in copy number when compared to a normal brain control. Nuclear suspensions of these tumors were evaluated by fluorescent in situ hybridization (FISH), using the entire mitochondrial genome as a probe after labeling with rhodamine. All tumors showed evidence of mitochondrial sequence localization within the nuclei. A corresponding glioblastoma and two normal brain specimens were also evaluated which did not have amplification of the mitochondrial genome; FISH with the mitochondrial probe revealed minimal hybridization signal within the nuclei of these samples. Mitochondrial DNA nuclear localization can be found in primary low-grade brain neoplasms, and is correlated to increases in mitochondrial DNA. PMID- 8692204 TI - Quantitation of the allelic imbalance provides evidence on tumour heterogeneity: a hypothesis. AB - The observation of loss of heterozygosity (LOH) in tumours represents a useful clue to the presence of tumour suppressor genes (TSGs). However, analysis of this phenomenon is often complicated by tumour heterogeneity and the presence of DNA from adjacent normal tissues. The present study suggests a quantitative approach for measurement of LOH which may help to distinguish between these possibilities and to provide clues for the heterogeneous process of tumour progression. We applied this methodology to a laryngeal tumour with LOH at markers D9S171, D9S157, D8S87 and THRA1 and found that LOH at D9S171 is the commonest aberration among the tumour cells, while LOH at the THRA1 marker is present in only a small subset of the tumour cells. It is likely that LOH at D9S171 occurs early uin tumour development while LOH at the rest of the markers tested occurred later resulting in the generation of heterogeneous cell populations. PMID- 8692205 TI - Estimation of mutation rates from parentage exclusion data: applications to STR and VNTR loci. AB - Nonpaternity is a common source of bias in estimating mutation rates when they are obtained from family data showing discordance of parental and children's genotypes. With the availability of hypervariable DNA markers, this source of bias can be largely eliminated. However, the proportion of cases where parentage exclusion is caused by presumed mutation(s) of parental alleles must be adjusted to obtain a valid mutation rate estimate. The present work derives the basis of this adjustment factor, called the proportional bias. This proportional bias depends upon the allele frequency distribution at the locus. The maximum and minimum bounds of the proportional bias depend on the number of alleles at the locus. Using data from Caucasian populations at tandem repeat loci commonly used for parentage testing and forensic identification purposes, we show that when mutation rates are estimated at these loci, the proportional bias is generally very close to the maximum possible value for the observed number of alleles (or binned fragment sizes) at each locus. The expected proportional bias decreases with increasing mutation rate at a locus. For the short tandem repeat loci, without bias correction, the direct count method can result in an underestimation of up to 60% of their true value. In contrast, for the minisatellite VNTR loci, even with crude measurements on allele sizes, we show that the absolute proportional bias is generally below the coefficient of variation of the direct estimates. PMID- 8692206 TI - Analysis of micronuclei induced by 1,3-butadiene and its metabolites using fluorescence in situ hybridization. AB - In our previous study, micronuclei (MN) were induced in bone marrow cells of mice following inhalation exposure to 1300 ppm of 1,3-butadiene (BD) for 6 h per day on 5 consecutive days, and in splenocytes of mice and rats treated intraperitoneally with 80 mg/kg 1,2-epoxybutene (EB) and 30 mg/kg 1,2,3,4 diepoxybutane (DEB), respectively. In the present study, the nature of MN induced by BD, EB and DEB was analyzed by means of fluorescence in situ hybridization (FISH) using mouse minor satellite DNA and rat satellite I DNA as probes. Percentages of MN with centromere signals (MN+) measured following exposures to BD, EB and DEB indicate that these agents are predominantly clastogens. Frequencies of MN+ per 1000 cells suggest that BD, EB and DEB are not only strong clastogens, but also weak aneugens in mice. The weak aneugenic effect of EB and DEB was not observed in rats. Analysis of the number of centromere signals in individual MN, and the size distribution of MN with centromere signals in EB- and DEB-treated animals, and in animals exposed to the positive controls diethylstilbestrol (DES) and mitomycin C (MMC) led to the following conclusions: (1) analysis of MN for the number of centromere signals may be a useful indicator for identifying chemicals with aneugenic properties; (2) there is no correlation between the size of MN and their origin (i.e., chromosome loss/gain or fragment). PMID- 8692207 TI - Co-recombinogenic and anti-mutagenic effects of diethylhexylphthalate, inactiveness of pentachlorophenol in the spot test with mice. AB - In in vivo experiments using the spot test with mice, diethylhexylphthalate (DEHP) was co-recombinogenic and anti-mutagenic. In two independent experiments, DEHP was able to increase in combination with ethylnitrosourea (ENU) the frequency of animals with spots of genetic relevance from about 12% (ENU alone) to about 15% (ENU+DEHP). This enhancement can be exclusively attributed to an enhancement of recombination. In historical as well as in current experiments, with astonishing accuracy, about 8% of all spots induced with ENU alone are black, near-white or twin spots, i.e., presumed products of reciprocal recombination. Under the influence of DEHP, about 20% of all colored spots were black, near-white or twin spots. These co-recombinogenic effects are very strong, considering that the low frequency of twin spots with 0.3% (historical ENU control) or 0.6% (current ENU control) after ENU treatment alone has been enhanced up to a frequency of 3%. While ENU alone induces about 14% light brown colored spots, depending exclusively on gene mutations, under the influence of DEHP the frequency was only 7%, i.e., DEHP was anti-mutagenic. Pentachlorophenol was ineffective in enhancing or reducing recombination or mutations. There was no difference between ENU and ENU+PCP treatment. Since a number of "non-genotoxic' carcinogens with tumor-promoting activities like D-limonene, 12-O-tetradecanoyl phorbol-13-acetate (TPA) and 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) have shown similar effects in the spot test, it is suggested that DEHP may have tumor promoting activity in carcinogenicity tests. PMID- 8692208 TI - Hydroxyurea induces recombination in dividing but not in G1 or G2 cell cycle arrested yeast cells. AB - Hydroxyurea, a chemotherapeutic and radiosensitizing agent, inhibits ribonucleotide reductase, arrests cells in the S-phase and is mutagenic and recombinagenic. In this paper we investigated whether the recombinagenic activity of hydroxyurea is due to the same activity that leads to arrest in the S-phase or to a more direct action on DNA. The effect of hydroxyurea on intrachromosomal and interchromosomal recombination was investigated in dividing and in G1 or G2 cell cycle-arrested cells of the yeast Saccharomyces cerevisiae. Treatment of dividing cells with hydroxyurea resulted in a large increase in recombination frequencies, even at low non-toxic doses. In contrast, in cells arrested in the G1 or G2 phase, hydroxyurea failed to induce recombination, even at 60-fold higher toxic doses. The presence of metabolic activation (S9 mix) did not change the effects of hydroxyurea on recombination. The data suggest that the recombinagenic activity of hydroxyurea may not be due to any direct effect of hydroxyurea on DNA, but may be linked to the inhibition of ribonucleotide reductase causing inhibition of DNA synthesis leading to S-phase arrest and possibly causing recombinagenic lesions. PMID- 8692209 TI - Do human lymphocytes exposed to the fallout of the Chernobyl accident exhibit an adaptive response? III. Challenge with bleomycin in lymphocytes from children hit by the initial acute dose of ionizing radiation. AB - In the present paper, we report data on the possible adaptive response, induced in vivo by exposure to ionizing radiation to a challenge treatment with the radiomimetic glycopeptide bleomycin (BLM). Lymphocytes from children living in Pripjat at the time of the Chernobyl accident, and thus hit by the initial acute dose of ionizing radiation, were treated for the last 5 h of culture with 0.004 U/ml BLM. Significantly lower chromosome damage was found only in lymphocytes from children who, independently of the initial acute exposure to ionizing radiation, still showed a 137Cs internal contamination, due to persistent continuous exposure to low doses of radiation. The present results indicate that past exposure to acute high dose of ionizing radiation does not interfere with resistance to BLM which is related to internal contamination. PMID- 8692210 TI - Decreased sensitivity to the cytogenetic effects of bleomycin in individuals occupationally exposed to ionizing radiation. AB - In the present work, 12 individuals occupationally exposed to ionizing radiation and 11 unexposed ones were studied to determine the cytogenetic effect of a challenge dose of bleomycin on their phytohemagglutinin stimulated lymphocytes. After bleomycin treatment, the frequencies of chromatid breaks and gaps were significantly lower in the exposed population (p < 0.025 for both types of chromatid alterations). These results could indicate that occupational exposure to ionizing radiation can induce an adaptive response that can be detected by a subsequent treatment with bleomycin. PMID- 8692212 TI - Possible factors leading to a misjudgement of mutant frequencies in HPRT assay. AB - Interactions between cloning efficiency (CE) and mutant frequency (MF) in the HPRT clonal assay in in vitro study were analysed. In 12 separate reconstruction experiments with independent pairs of wild type (WT) and mutant (HPRT-) clones, the CE of WT cells (Group 1) and the recovery of mutant cells in absence (Group 2), as well as in the presence of non-irradiated (Group 3), or irradiated (Group 4) WT cells (10(4) cells/well) was determined. The plating of mutant cells with irradiated WT cells improved their CEs by almost 30%. In contrast, the presence of non-irradiated WT cells led to a slight decline (10%) in CE of mutant cells, resulting in a significant difference between groups (p = 0.0083). The extent of decline in survival of mutant cells in the presence of non-irradiated WT cells negatively correlated (r = 0.3496, p < 0.05) with the initial CE of WT cells. The data suggest that the presence of WT cells in the selection plates may suppress the recovery of mutants in HPRT assay, and this negative effect is stronger in samples with high CE. These findings indicate a possible source for a serious underestimation of mutant frequencies (3-fold in the range of CEs from 10% to 60%) in the HPRT assay and may be useful for the interpretation of results from studies on exposure to mutagens in humans. PMID- 8692211 TI - Inhibition of RNA and DNA synthesis in UV-irradiated normal human fibroblasts is correlated with pyrimidine (6-4) pyrimidone photoproduct formation. AB - UV-irradiation of living cells results in an inhibition of RNA and DNA synthesis. The purpose of this study was to determine whether specific photoproducts or the total combined yield of lesions were responsible for these effects. Asynchronously dividing human fibroblasts from normal donors were irradiated with UVC (254 nm), broad spectrum UVB (290-320 + nm, Westinghouse FS20 lamp) or narrow spectrum UVB (310-315 nm, Philips TL01 lamp) at fluences which induce known yields of cyclobutane pyrimidine dimers, pyrimidine (6-4) pyrimidone photoproducts or Dewar isomers. DNA synthesis was approximately 3-4 times more sensitive to both UVC and UVB irradiation than RNA synthesis. The immediate inhibition of RNA and DNA synthesis was correlated with (6-4) rather than overall photoproduct formation suggesting that the (6-4) photoproduct is the mediator of these inhibitory effects. In support of this suggestion we found that photoreactivation of cells cultured from the marsupial, mouse Sminthopsis crassicaudata, resulted in removal of 70% of pyrimidine dimers from the overall genome, but had only a slight effect on the recovery of RNA synthesis. PMID- 8692213 TI - Specificity of spontaneous and t-butyl hydroperoxide-induced mutations in delta oxyR strains of Escherichia coli differing with respect to the SOS mutagenesis proficiency and to the MutY and MutM functions. AB - Mutations induced by oxidative DNA damage appear to occur by two pathways, differing in their dependence on SOS mutagenesis. We have analysed the specificity of mutations produced by each pathway. Base substitutions generating extragenic suppressors were characterized in Trp+ revertants of Escherichia coli strains carrying the trpE65 ochre mutation, which were hypersensitive to oxidative mutagenesis due to a deletion of the oxyR gene. In strain IC3821, containing MucA/B proteins and therefore proficient for SOS mutagenesis, the more frequently scored base substitutions, either spontaneous or induced by t-butyl hydroperoxide (BuOOH), were T:A-A:T transversions, followed by G:C-A:T transitions, while the frequency of G:C-T:A transversions was lower. This SOS dependent mutability could be promoted by abasic sites. In strains IC3894 (mutY) and IC3981 (mutY mutM), lacking mutagenesis proteins, SOS-independent revertants arose almost exclusively via G:C-T:A transversions probably derived from oxidatively damaged 8-oxoguanine/adenine mispairs. Formation of these mispairs in IC3894 and IC3981 would be enhanced by BuOOH treatment since it caused a significant increase in the revertant number. Strains IC3894 and IC3981 could have a complementary role to that of IC3821 to analyse the mutagenicity and the mutational specificity of oxidants. PMID- 8692216 TI - Chromosome aberrations in humans in relation to site of residence. AB - Baseline frequencies of chromosome aberrations (CAs) were assessed in three samples of healthy individuals, 60 living in a rural area (Po Delta), 134 in Pisa downtown and 116 in Cascina, a small town near Pisa, Italy. The three groups were similar for average age, sex ratio, smoking, drinking habit, and occupation. Multifactor ANOVA showed that CA frequencies increased significantly with age (p < 0.0001 excluding and including gaps), and with smoking habit (p = 0.0045 including gaps; p = 0.04 excluding gaps). Gender, drinking habit and occupation exerted no statistically significant effects. Multifactor ANOVA showed also a significant effect of the site of residence on the frequency of the CA, including gaps (p = 0.0003) and excluding gaps (p = 0.03). The CA frequency of the Pisa samples was statistically significantly higher than that of the Po Delta samples. Air pollution was considered to be a possible factor in determining the observed differences among the sites of residence, as levels of air pollutants (SO2 and TSP, total suspended articles) were more elevated in Pisa and Cascina than in the Po Delta. In addition, respiratory symptoms used as indirect indicators of air pollution at individual level were significantly more frequent in the Pisa population than in Cascina or in the Po Delta. These findings might support the hypothesis that air-pollution levels, even within E.E.C. (European Economic Community) air-quality standards, may influence baseline CA frequencies. PMID- 8692215 TI - The mutagenicities of alkaloids and N-nitrosoguvacoline from betel quid. AB - In Taiwan, betel quid is a natural masticatory, which is composed of fresh green areca fruit, Piper betle and slaked lime paste. Areca fruit contains some alkaloids, of which arecoline is the major one. N-Nitrosoguvacoline (NG), one of the N-nitrosation products of arecoline, is the only one N-nitrosamine found in Taiwanese betel quid chewing saliva. The mutagenic studies in Ames Salmonella microsome test showed that crude alkaloid extracts of areca fruit and arecoline were active in Salmonella typhimurium TA100, and NG was weakly active in TA98 and TA100. The activities in both arecoline and NG decreased further in the presence of rat liver S9 mix. Nitrite was significantly consumed during the N-nitrosation of arecoline and sodium nitrite at acidic condition (pH 3), whereas the formation of NG was favored at neutral condition (pH 7). Crude phenolic extracts of leaf and inflorescence of Piper betle inhibited the formation of NG by blocking the nitrite. However, a high amount of crude phenolic extracts of areca fruit enhanced the formation of NG. PMID- 8692214 TI - Protective role of soybean feeding against the cytogenetical and histopathological effects of dibutylamine and sodium nitrate on bone marrow and liver of mice. AB - The protective role of soybean feeding against the cytogenetic and histopathologic effects of the nitrosamine precursors sodium nitrate and dibutylamine was evaluated. Treated animals were killed every 3 months, over a period of 15 months, and bone marrow cells were prepared for cytogenetic studies and livers for histopathological observations. Structural chromosomal aberrations and mitotic indices increased after treatment with the nitrosamine precursors for all tested times. Livers were within the normal appearance during the first 6 months. After that a mild, moderate, marked dysplasia with lymphocytic infiltration, fatty vacuolation and liver atrophy was observed. Soybean coadministered with the nitrosamine precursors reduced the number of structural chromosomal aberrations. Mitotic indices decreased at all tested groups but still higher than the control level. A marked reduction in dysplastic features in the liver cells was observed. In conclusion, the cytogenetic and histopathologic results of this study strongly support the protective role of soybean against the genotoxic and carcinogenic action of nitrosomine formed in vivo from its precursors. PMID- 8692218 TI - Chlorophyll and chromosome breakage. AB - Increased consumption of green vegetables in the diet has been associated with protection against carcinogenic effects and related mutagenic and clastogenic (chromosome breaking) activity of genotoxic agents. Chlorophyll, present in all green plant parts, has been suggested to be a major protective factor in the process. We have, however, observed that while a crude aqueous extract of Indian spinach leaf significantly reduced genotoxic effects, chlorophyll alone was ineffective. On the other hand, chlorophyll, both as an aqueous extract from the leaf and in a purified commercial form, induced a significantly high frequency of chromosome breaks in bone marrow cells of mice on oral administration. The crude aqueous extract of the leaf was non-toxic. The protective activity of the crude leaf extract may be attributed to the total effect of the interaction between different components, in which the clastogenicity of chlorophyll has been neutralized. PMID- 8692217 TI - Stable expression of human CYP2E1 in Chinese hamster cells: high sensitivity to N,N-dimethylnitrosamine in cytotoxicity testing. AB - Involvement of human CYP2E1 expressed in genetically engineered cells in the metabolic activation of promutagens and procarcinogens was studied. An expression plasmid containing an insert of CYP2E1 cDNA and SR alpha promoter was constructed and transfected into the cultured cell line CR-119 which had previously been established by introducing a cDNA coding for NADPH-cytochrome P450 reductase. Among newly established cell lines, ER-181 showed the highest expression of CYP2E1 mRNA. Production of the CYP2E1 protein was confirmed by Western blot analysis using anti-rat CYP2E1 antibodies. Assay of 7-ethoxycoumarin O-deethylase activity demonstrated that ER-181 cells acquired the catalytic function of CYP2E1. ER-181 cells showed higher sensitivity to N,N-dimethylnitorosamine (DMN) in cytotoxicity assays as compared to parental CR-119 cells. Hypersensitivity to DMN of ER-181 cells was completely suppressed by 3-amino-1,2,4-triazole, a known inhibitor of CYP2E1. These results indicate that ER-181 cells which express human CYP2E1 are a useful tool to investigate toxicological functions of the cytochrome. PMID- 8692220 TI - 25th Annual meeting of the European Environmental Mutagen Society. Noordwijkerhout, the Netherlands, 18-23 June 1995. Abstracts. PMID- 8692219 TI - The alkaline comet test on plant cells: a new genotoxicity test for DNA strand breaks in Vicia faba root cells. AB - The alkaline comet assay (single cell gel electrophoresis assay) is a sensitive method for the detection of DNA damage. This paper describes the first application of this assay to plant cells for genotoxicological assessment. Germinating Vicia faba (field bean) seedlings were kept in water with either methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), mitomycin C (MMC), cycloheximide (CH), cadmium chloride (CdCl2), potassium dichromate (K2Cr2O7), or chromium trichloride (CrCl3). Nuclei were isolated from the root cells and evaluated for the extent of DNA migration. With the exception of cycloheximide, all agents induced a significant increase in DNA migration. These results indicate that the comet assay may be a valuable tool for monitoring DNA damage in plant systems. However, there was a significant heterogeneity in the extent of DNA migration within and between seedlings, which may be intrinsic to the assay or indicative of sampling problems. PMID- 8692221 TI - Genotoxicity of dihydroabikoviromycin, a secondary metabolite of Streptomyces anulatus. AB - The potential genotoxicity of dihydroabikoviromycin was assessed in bacterial and sister-chromatid exchange (SCE) test systems. Direct cytotoxicity was also assayed using bioluminescence methods to screen for differences in cell viability among different tumour cell lines following exposure to the drug. Differential killing tests with Escherichia coli WP2 and its repair-deficient derivative CM871 indicated that a functional DNA repair system was protective against the action of dihydroabikoviromycin, implying that this compound causes some form of DNA damage and is almost certainly therefore genotoxic. Dose-dependent reversion from His- to His+ with dihydroabikoviromycin was observed in the Ames test with Salmonella typhimurium TA100, but not in frameshift tester strain TA98. Dihydroabikoviromycin also induced the sfiA gene, as indicated by beta galactosidase induction in an SOS-chromotest with E. coli PQ37 strain. A dose related increase in SCEs by dihydroabikoviromycin was observed in CHO cells. Growth of tumour cells was also suppressed by dihydroabikoviromycin at a dose of 10 micrograms/ml. PMID- 8692222 TI - Squalene inhibits sodium arsenite-induced sister chromatid exchanges and micronuclei in Chinese hamster ovary-K1 cells. AB - Arsenic, widely distributed throughout our environment, is a well-established human carcinogen. We report here that squalene, a natural fish oil, is a potential agent in the reduction of sodium arsenite-induced sister chromatid exchange (SCE) and micronuclei in Chinese hamster ovary (CHO-K1) cells. Squalene dose-dependently inhibited sodium arsenite-induced SCE. At the highest concentration (160 microM), squalene reduced the SCE frequency from 8.85 to 6.47 SCEs per cell which is very close to the background level (5.82 SCEs per cell). Sodium arsenite dose-dependently induces micronuclei in CHO-K1 cells, and squalene at 80 microM significantly inhibits arsenite-induced micronuclei. However, squalene did not eliminate the killing effects of arsenite on the cells and only slightly decreased intracellular accumulation of arsenic. PMID- 8692223 TI - The evaluation of waste, surface and ground water quality using the Allium test procedure. AB - The bulbs of Allium cepa were grown in test liquids of various pollution levels as follows: undiluted industrial and municipal waste water; biological treatment plant output water; water from the Drava river upstream and downstream of the city of Maribor; and non-chlorinated drinking water as a negative control test. The paper presents the response of the Allium cepa genetic material to the presence of potential cytotoxic and genotoxic substances in test liquids and the suitability of the Allium cepa testing procedure as a method for short-term determination of water pollution level. The suitability of the Allium test procedure as a system for environmental monitoring is presented. The influence of water pollution on macroscopic and cytologic parameters of the common onion by application of the biological testing method was examined. The macroscopic parameter was inhibition of root growth. The cytological parameters were: aberrant cells in metaphase and anaphase, index of micronuclei appearance and inhibition of cell division. The possibility of categorization the different polluted test liquids into quality classes is presented according to the influence of the test liquids on macroscopic and cytologic parameters. Test liquids are divided into 8 quality classes: the first class is the least polluted surface waters, the second and the third classes are more polluted surface water, the fourth and the fifth classes are biological treatment plant output waters, the sixth till the eighth quality classes are untreated waste waters. The most polluted test liquids (untreated industrial and municipal waste waters) caused sublethal and even lethal effects. The most polluted tested liquids cause the inhibition of root growth over 50% (even up to 74%), decrease of mitotic index over 36% (even up to 66%), increase of presence of interphase cells with micronuclei over 3% and increase of presence of aberrant cells for more than 10 times in comparison to control test. PMID- 8692224 TI - Genotoxicity of dental materials. AB - This study was performed to characterize the (possible) DNA-damaging properties of dental materials and to identify specific compounds that contribute to this genotoxicity. For screening, three tests that assay for different aspects of genotoxicity (i) the bacterial umu-test; (ii) the eucaryotic DNA synthesis inhibition test; and (iii) the in vivo alkaline filter elution technique were chosen. This investigation gives several lines of evidence that most dental materials tested (14 chemical monosubstances present in dental devices and 7 extracts of dental materials) yield 'positive' results in at least one of the genotoxicity tests, however, with effects ranging from 'borderline' to 'strong positive'. The extracts of the widely used dental materials Vitrebond and AH26 elicited clear concentration-related genotoxic responses in all test systems. On the basis of these data and public concern, more attention has to be given to local or systemic complications which may be associated with the use of dental materials. PMID- 8692225 TI - Urinary mutagenicity and thioethers in nonsmokers: role of environmental tobacco smoke (ETS) and diet. AB - The urinary excretion of mutagens and thioethers was investigated in a controlled diet study and in two field studies. A diet containing charcoal-broiled meat and other items rich in mutagenic compounds increased the urinary mutagenicity as assessed in Salmonella typhimurium strain TA98 with metabolic activation approximately 46-fold compared to a diet low in mutagens. The excretion of thioethers after ingestion of the diet rich in mutagens also increased significantly when compared to the diet low in mutagens. The increase was associated with the content of preformed thioethers in the diet. In the first field study with 21 nonsmokers, urinary mutagenicity as assessed in Salmonella typhimurium strain TA98 and excretion of thioethers showed no relation to either the self-reported exposure to environmental tobacco smoke (ETS) or to serum cotinine concentrations used as an objective marker for ETS exposure. In the second field study, urinary mutagenicity was determined with a tobacco-smoke sensitive Salmonella typhimurium strain YG1024 with metabolic activation. No correlation was found between the mutagenic activity in urine and ETS exposure duration, nicotine on the personal sampler, cotinine in saliva and cotinine in urine. Our results suggest that real-life ETS exposure does not measurably increase either urinary mutagen or urinary thioether excretion. Furthermore, diet seems to be the most important source for both urinary mutagen and thioether excretion in nonsmokers. PMID- 8692226 TI - Sister-chromatid exchanges (SCE) induction by inhibitors of DNA topoisomerases in cultured human lymphocytes. AB - The induction of sister-chromatid exchanges (SCE) in cultured human lymphocytes by four inhibitors of DNA topoisomerases: m-amsacrine, camptothecin, etoposide and nalidixic acid has been evaluated. Although the four compounds apparently increase the frequency of SCE, the effect of nalidixic acid is weak because only a statistically significant positive response was found in one donor at the highest concentration (500 microM). The other compounds tested act as SCE inducers in both donors, camptothecin being the most effective. In addition, the influence of these four topoisomerase inhibitors on the SCE frequency induced by MMC was also analysed. The results reveal that less than additive SCE effect was induced by the combined treatments which could suggest that the process leading to SCE induction by MMC and the four inhibitors of DNA topoisomerases are not totally independent. PMID- 8692227 TI - Benzene-induced genotoxicity in mice in vivo detected by the alkaline comet assay: reduction by CYP2E1 inhibition. AB - The myelotoxic and genotoxic effects of benzene have been related to oxidative DNA damage after metabolism by CYP2E1. Single cell gel electrophoresis (alkaline comet assay) detects DNA damage and may thus be a convenient method for the study of benzene genotoxicity. Benzene exposure to NMRI mice as a single oral gavage at 40, 200 or 450 mg/kg resulted in dose-related DNA damage indicated by an increased comet tail length of peripheral blood lymphocytes and bone marrow nucleated cells sampled 6 h after exposure. After a dose of 40 mg/kg, there was a 1.6-fold increase of 'tail length' in bone marrow nucleated cells in comparison with the control (p < 0.01). There was no significant increase in DNA damage in peripheral blood lymphocytes in the same animals. At 200 mg/kg, the tail length was 4.8-fold and 4.0-fold increased in the two cell types, respectively (p < 0.01). At 450 mg/kg, the tail length was further increased to 5.4-fold and 6.6 fold of the control values, respectively (p < 0.01). Pretreatment with propylene glycol (5 microliters/g b.wt., twice with a 60-min interval), a selective CYP2E1 inhibitor, reduced the increase in the tail length by about half at all doses in both cell types (p < 0.01). By comparing our data with those from genotoxicity studies on benzene using other methods, we conclude that the 'alkaline comet assay' is a sensitive method to detect DNA damage induced by benzene. We also infer that CYP2E1 contributes, at least partly, to the formation of the 'comet' inducing metabolites in the chosen cell types. PMID- 8692228 TI - Modulation of the mutagenicity and metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by phenolic compounds. AB - NNK is a potent environmental carcinogen generated during tobacco processing and smoking. The carcinogenic response to tobacco smoking is modulated by nutritional factors. In this study, liver microsomes from phenobarbital and beta naphthoflavone-treated or control hamsters were used to assay the mutagenicity (Salmonella typhimurium TA1535) of NNK. Western analysis of these microsomal preparations revealed an increased expression of protein recognized by polyclonal antibodies specific for P-450 1A2 in beta-naphthoflavone-induced microsomes and P 450 2B1/2B2 in phenobarbital-induced microsomes. Both inducers significantly increased the mutagenicity of NNK. Metabolism of NNK by the three microsomal preparations was compared. Metabolites formed by methyl-hydroxylation of NNK by microsomes from control animals were significantly greater than those formed by alpha-methylene hydroxylation. Phenobarbital treatment had the greatest effect on alpha-methylene hydroxylation while beta-naphthoflavone had the greatest effect on methyl hydroxylation. The antimutagenic action of the polyphenolic compounds ellagic acid, esculetin and propyl gallate correlated with an inhibition of the metabolism of NNK. There were, however, differences in the effects of these compounds on specific pathways of NNK metabolism depending upon the microsomal enzyme induction treatment. This suggests that phenolic compounds have selective affinity for specific P-450 isozymes activating NNK. PMID- 8692229 TI - Detection of DNA damage induced by human carcinogens in acellular assays: potential application for determining genotoxic mechanisms. AB - Positive outcomes of in vitro genotoxicity tests may not always occur as a consequence of direct reaction of a compound or a metabolite with DNA. To follow up positive responses in in vitro tests, we developed two supplemental, cell-free assays to examine the potential of compounds and metabolites to directly damage DNA. Calf thymus DNA was used as the target for the direct detection of adducts by 32P-postlabeling/TLC and electrochemical detection, and alkaline gel electrophoresis was used to detect single-strand breakage of bacteriophage lambda DNA. To show that these assays would detect damage from relevant compounds, we examined nine human carcinogens (aflatoxin B1, busulfan, chlorambucil, cyclophosphamide, diethylstilbestrol, melphalan, 2-naphthylamine, phenacetin and potassium chromate). Each of the nine compounds produced a positive result for one or both endpoints. Using multifraction contact-transfer TLC, we detected 32P labeled DNA adducts produced by aflatoxin B1, chlorambucil, diethylstilbestrol, melphalan, 2-naphthylamine, and potassium chromate (plus hydrogen peroxide). Aflatoxin B1, diethylstilbestrol and 2-naphthylamine required metabolic activation (induced rat liver S9) to generate DNA adducts. Although potassium chromate alone induced a slight increase in the content of 8 hydroxydeoxyguanosine (a promutagenic adduct produced by reactive oxygen species), addition of hydrogen peroxide greatly increased 8-hydroxydeoxyguanosine levels. The damage to lambda DNA by each human carcinogen (or metabolites), except diethylstilbestrol, was sufficient to generate single-strand breaks after neutral thermal hydrolysis at 70 degrees C. Chromate was a weak inducer of DNA fragmentation, but adding hydrogen peroxide to the reaction mixtures dramatically increased the DNA strand breakage. Our data suggest that these non-routine, acellular tests for determining direct DNA damage may provide valuable mechanistic insight for positive responses in cell-based genetic toxicology tests. PMID- 8692230 TI - Cytogenetic effects of piperonyl butoxide and safrole in CHO-K1 cells. AB - Recently, hepatocarcinogenicity in rats and mice was reported with regard to the methylenedioxyphenyl compound, piperonyl butoxide (PB), which is used as a synergist for pyrethrins and related insecticides. Induction of sister-chromatid exchanges (SCEs) and chromosomal aberrations (CAs) due to PB were investigated using CHO-K1 cells with or without rat liver S9 fraction (S9); at the same time, the effects of safrole (SF), a methylenedioxyphenyl compound and a weak hepatocarcinogen, were also examined. PB (0.25 and 0.3 mM) and SF (0.8 mM) caused a slight but significant increase in SCEs followed by a cell-cycle delay in the 3 h treatment without S9. In the presence of S9 (4.5%), the cytotoxicity of PB or SF was weakened greatly or slightly, the top dose capable of cell division was raised to 0.6 mM (2-fold) or 1 mM, respectively. PB with S9 induced SCE at doses of 0.4 and 0.5 mM, and caused endoreduplications (ERDs, 7%) at a dose of 0.6 mM, while SF caused a dose-related significant increase in SCE at all doses used (0.4 1 mM) with S9. Genotoxicity of the metabolites of PB or SF was cleared by changing the dose of S9 (1.5-9%) while holding the dose of each chemical constant. In the case of SF (0.6 mM), induction of SCE, ERD and cell-cycle delay intensified almost in a dose-effect relationship, and CAs and a high level of ERD (14%) were caused by a 9% dose of S9. The concentration of unchanged SF in the incubated medium was certainly in inverse proportion to the dose of S9. This strongly suggests that the metabolites of SF are genotoxic. In the case of PB (0.3 mM), no positive responses were produced in the cultures, even with a high level of S9, though the amount of unchanged PB left in the incubated medium was very slight. This indicates that the metabolites of PB may not be genotoxic. In conclusion, PB and SF are possible to somewhat induce SCE at high dose(s) in the absence of S9, and the genotoxic effects of SF are more intensified in the presence of S9 than in its absence, while PB is probably no genotoxic in the presence of sufficient metabolic activation. PMID- 8692231 TI - Lack of mutagenicity of diethylstilbestrol metabolite and analog, (+/-) indenestrols A and B, in bacterial assays. AB - Indenestrol A (IA), one of metabolites of the indanyl group of diethylstilbestrol, has a stronger binding affinity for the estrogen receptor and also a weaker uterotropic activity than endogenous estradiol. We tested the microbial mutagenicity of structural isomers of indenestrol A and indenestrol B (IB) in Salmonella typhimurium TA100 and TA98 and in Escherichia coli WP2 uvrA to investigate whether the interaction of diethylstilbestrol or IA with genomic DNA has any part in their carcinogenicity and other biological activities. In the absence of S9 mix, (+/-)-IA was cytotoxic at higher doses (1 and 10 mumol/plate), and both (+/-)-IA and (+/-)-IB were non-mutagenic at lower doses (0.1-100 nmol/plate). In the presence of S9 mix, (+/-)-IA was cytotoxic at higher doses (0.5 and 1 mumol/plate), and at the other doses, (+/-)-IA and (+/-)-IB did not show any distinct increase in revertants. Although (+/-)-IA and (+/-)-IB showed a slight increase in the revertants in strain TA100 by the preincubation method without S9 mix, these results were considered to be negative, because no reproducible dose-revertants relationship necessary for a chemical to be determined as mutagenic was obtained. The S9 fraction interacted with (+/-)-IA or (+/-)-IB enzymatically or non-enzymatically, and weakened its cytotoxicity, so that the toxic dose was higher in the presence of S9 mix than in its absence. Both the plate incorporation and preincubation methods were used with a wide range of concentrations of (+/-)-IA and (+/-)-IB in the present experiment. No clear positive mutagenic data were obtained. These results are the first reports on the mutation assays of (+/-)-IA and (+/-)-IB, and suggest that they were non mutagenic towards the bacterial strains tested. The study revealed that the cytotoxic activity of (+/-)-IA and (+/-)-IB did not correlate with DNA interaction, but was the result of a direct effect on microtubule polymerization, although indenestrols are known to have strong binding affinities for estrogen receptors. PMID- 8692232 TI - Assessment of a possible genotoxic environmental risk in sheep bred on grounds with strongly elevated contents of mercury, arsenic and antimony. AB - A part of Northern Palatinate country (Germany) was formerly influenced by mercury mining. Today, in many cases agricultural and housing areas are placed onto or near to former dump grounds of rubble. In the soil of these areas the concentration of mercury, arsenic and antimony was found ranging from basic natural contents up to strongly elevated levels. In a biomonitoring project, sheep bred on grounds contaminated with mercury (range 1-435 mg Hg/kg dry matter), arsenic (range 17-147 mg As/kg dry matter) and antimony (range 2-15 mg Sb/kg dry matter) were taken as example on the uptake of these elements from the environment and for possible effects of this exposure. Significantly elevated mercury levels were found in wool of one collective of exposed sheep (0.107 mg/kg mean vs. 0.048 mg/kg mean, p < 0.001, U-test). Surprisingly, the arsenic content of wool taken from sheep bred in the urban referential area was approx. 10 times higher than that of the sheep bred on the grounds contaminated with arsenic (0.57 mg/kg mean vs. 0.051 mg/kg mean, p < 0.001, U-test). In general, element concentrations in the examined blood samples were low and the differences between the collectives were small: mercury was found in concentrations ranging from 0.9 microgram/l up to 2.0 micrograms/l (means), arsenic and antimony were generally found in concentrations below 1 microgram/l. Neither in the alkaline elution technique nor in the sister chromatid exchange (SCE) analysis significant increases in the rate of DNA-damaging effects between the different sheep collectives were detected. This indicates that the transfer rate of genotoxic compounds of mercury, arsenic or antimony from the environment is too low to register effects with AFE and SCE although the soil was highly contaminated. PMID- 8692233 TI - Comparative synchronous fluorescence spectrophotometry and 32P-postlabeling analysis of PAH-DNA adducts in human lung and the relationship to TP53 mutations. AB - Polycyclic aromatic hydrocarbon (PAH)-DNA adducts were studied in human lung from 39 lung cancer patients by synchronous fluorescence spectrophotometric (SFS) and 32P-postlabeling assays. Regression analysis of the samples failed to detect any correlation between benzo[a]pyrene-diolepoxide (BPDE)-DNA adducts detected by SFS and the BPDE co-migrating spot detected by 32P-postlabeling. We have also analyzed the relationship between adduct levels and TP53 mutations. By postlabeling diagonal radioactive zone (DRZ) adducts were detected in 37 of 39 (95%) lung tissues from lung cancer patients and the adduct level ranged from 6.81 to 108.50 adducts/10(8) nucleotide. Thirty-three of 39 (85%) had detectable levels of BPDE-DNA adducts (> 1 adduct/10(9) nucleotide). Current heavy smokers (> 20 cigarettes/day) have significantly higher DRZ adduct levels compared to individuals smoking less than 20 cigarettes/day. By SFS combined with immunoaffinity column (IAC), 11 of 39 (28%) samples had detectable adduct levels, and 6 of 11 (55%) were detectable by SFS following purification of benzo[a]pyrene (BP)-tetrols by high pressure liquid chromatography (HPLC). Six of 33 (18%) samples were positive for BPDE-DNA adducts by both postlabeling and HPLC/SFS. No correlation was observed between the SFS and 32P-postlabeling assays for the detection of BPDE-DNA adducts. However, there was a good correlation between adduct levels detected by IAC/SFS and HPLC/SFS. We found a weak association between total PAH-DNA adduct levels in lung tissue and TP53 mutations. PMID- 8692234 TI - Mutagenicity and contents of polycyclic aromatic hydrocarbons in used and recycled motor oils. AB - Thirteen samples of used motor oil and 33 recycled fractions, obtained in the laboratory by means of a recovery process similar to that currently used in Italy (vacuum distillation followed by thermal clay treatment) were examined. The Ames test (standard and modified version according to Blackburn) was used to determine the mutagenicity of the extracts and their contents of polyaromatic fraction (PAF) (IP346/80 method) and polycyclic aromatic hydrocarbons (PAH) (Grimmer's method). Used motor oils are mutagenic, both directly and indirectly. The highest values have been found in used oils from motor vehicles using leaded petrol (up to 118.8 revertants/mg). Samples from vehicles using unleaded petrol or diesel fuel are less mutagenic (up to 31.1 and 16.4 rev/mg, respectively). The enrichment in mutagens due to the use of oil in the three types of engine ranges from mean values of 6.2, 1.1 and 0.4 rev/mg per 1000 km, respectively. Recycled oils are almost completely devoid of direct mutagenic activity (33 samples: mean +/- SD = 1.6 +/- 1.5 rev/mg). Most recycled distillates show considerable mutagenic activity in the presence of microsomial enzymes (up to 82.5 rev/mg), although this is reduced with respect to the original oils (recycled, mean +/- SD = 13.8 +/- 15.5 rev/mg; original oils, mean +/- SD = 30.7 +/- 35.2, Mann-Whitney U-test, z = 1.793, p < 0.05). Both PAF and PAH contents are high in used oils from the two types of petrol engine but not in those from diesel engines. Recycling reduces PAF contents only in used oils from petrol engines, from a mean value of 13.91 +/- 7.32 to 4.23 +/- 2.90% (comparison with original used oils, Mann-Whitney U-test, U = 8, p < 0.01). The light distilled fractions have greater concentrations of indirect mutagens, PAF and PAH than the others. The increase in PAH in light recycled products with respect to the original used oils is significant (Wilcoxon's t-test, z = 2.306, p < 0.05). Benzo[a]pyrene (BaP) is found in appreciable quantities (> 10 ppm) in all used oils from petrol engines and in most of their recycled products. Recycling generally recovers 50% of mutagens and PAF and about 80% of PAH. Considered together, recycled products have in any case contents of mutagens and PAF which are significantly lower than those in the parent oils, but not of PAH (Wilcoxon's t-test; mutagens, z = 2.935, p < 0.01; PAF, z = 3.145, p < 0.01; PAH, z = 1.397, not significant). Lastly, many recycled oils have PAH concentrations which are equal to or higher than those of the original used oils. The health risks linked to professional exposure to these types of oils and the inadequate recycling process currently used (redistillation and thermal clay treatment) in reducing mutagenic and cancerogenic substances from used motor oils are stressed. PMID- 8692236 TI - Induction of micronuclei by low doses of azidothymidine (AZT). AB - The dideoxynucleoside azidothymidine (AZT; Zidovudine) was assessed for its ability to induce micronuclei in mouse erythrocytes at a low (therapeutic) dosage. Specifically, male and female BALB/c mice were treated via intraperitoneal injection 5 days a week for 2 weeks with saline or 17 mg AZT/kg body weight per day. Each animal was monitored for chemical-induced micronucleus formation over the course of the treatment regimen through the flow cytometric analysis of one million pre-dosing and one million post-dosing peripheral blood erythrocytes. No significant change in micronucleus frequencies was observed for the vehicle control group as micronuclei continued to enter the peripheral blood pool at background levels. Conversely, the AZT-treated mice exhibited a statistically significant net increase in micronucleated cells over the course of dosing as erythrocytes with a high incidence of micronuclei entered the peripheral blood pool. The advantages of high throughput scoring protocols utilizing flow cytometry are discussed. PMID- 8692235 TI - Evaluation of the ability of paracetamol to produce chromosome aberrations in man. AB - The ability of paracetamol to induce structural chromosome aberrations in human peripheral blood lymphocytes in vivo was evaluated in volunteers who had been administered a single oral dose of 3 g paracetamol, in patients who had received 2 g of propacetamol by intravenous infusion every 6 h for at least 7 days, and in self-poisoned patients who, for suicidal reasons, had ingested more than 15 g paracetamol. In addition to the in vivo observations, the effectiveness of paracetamol to interfere with fusorial microtubule polymerisation was assayed in vitro in order to detect a possible effect of paracetamol on the distribution of chromosomes during cell division. The negative results obtained in all those assays strongly suggest that paracetamol has no mutagenic properties in human. There was, indeed, no significant difference in the percentage of abnormal cells before and after application of paracetamol in volunteers (0.2% before ingestion of 3 g paracetamol, 0.12% after 24 h, 0.04% after 72 h and 0.04% after 168 h) and in patients (0.5% of abnormal cells before treatment versus 0.44% after intravenous infusion of a total of 28 g paracetamol). Moreover, the yield of abnormal cells was not modified in self-poisoned persons (0.24%), in spite of an important decrease in the mitotic index of the PHA stimulated lymphocytes. In the in vitro assay, no inhibition of microtubule polymerisation was detected with concentrations of 2.5, 5 and 10 mM paracetamol. PMID- 8692237 TI - Fate of unfertilized ova in male rodent dominant lethal assays: extension of the studies by Kratochvilova. AB - Kratochvilova has described a technique whereby ova can be recovered from mated mice and their stage of division determined. This is of value to determine if reduced total implantations in a male dominant lethal (DL) germ cell mutation assay are due to pre-implantation loss of embryos, a presumed mutagenic event, or to chemically induced male infertility. Kratochvilova was not specific about the fate of unfertilized ova, but it was implied that they undergo a process of fragmentation that might be confused with the regular cleavage of fertilized ova. It became important for us to draw a firm distinction between ova fragmentation and regular ova cleavage in the rat. We therefore repeated the ova analyses of female mice mated with males exposed to iso-propyl methanesulphonate (iPMS), as described by Kratochvilova. Following that calibration study the technique was extended to the rat via ova cleavage analysis in mated female rats, coupled to a study of the normal decay of ova in virgin rats. Unfertilized ova are shown to undergo irregular fragmentation that can be clearly distinguished from normal cell division. It is concluded that the individual or combined incidences of single celled ova and fragmented ova (dependent on the cleavage stage of the concurrent control embryos) can provide a measure of male infertility as it relates to reduced implantations in DL assays. This ability to regard two morphological classifications of unfertilized ova as providing evidence for male infertility will simplify the conduct of ova analyses in both the mouse and the rat. PMID- 8692238 TI - Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. AB - BACKGROUND: Recently, a cluster of patients was observed in France in whom primary pulmonary hypertension developed in patients exposed to derivatives of fenfluramine in appetite suppressants (anorexic agents), which are used for weight control. We investigated the potential role of anorexic agents and other suspected risk factors for primary pulmonary hypertension. METHODS: In a case control study, we assessed 95 patients with primary pulmonary hypertension from 35 centers in France, Belgium, the United Kingdom, and the Netherlands and 355 controls recruited from general practices and matched to the patients' sex and age. RESULTS: The use of anorexic drugs (mainly derivatives of fenfluramine) was associated with an increased risk of primary pulmonary hypertension (odds ratio with any anorexic-drug use, 6.3; 95 percent confidence interval, 3.0 to 13.2). For the use of anorexic agents in the preceding year, the odds ratio was 10.1 (95 percent confidence interval, 3.4 to 29.9). When anorexic drugs were used to a total of more than three months, the odds ratio was 23.1 (95 percent confidence interval, 6.9 to 77.7). We also confirmed an association with several previously identified risk factors: a family history of pulmonary hypertension, infection with the human immunodeficiency virus, cirrhosis, and use of cocaine or intravenous drugs. CONCLUSIONS: The use of anorexic drugs was associated with the development of primary pulmonary hypertension. Active surveillance for this disease should be considered, particularly since their use is expected to increase in the near future. PMID- 8692239 TI - Images in clinical medicine. Intraventricular rupture of a cerebral abscess. PMID- 8692240 TI - Endometrial carcinoma. PMID- 8692241 TI - Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 27-1996. A 31-year-old woman with lumbar and abdominal pain, hypertension, and a retroperitoneal mass. PMID- 8692242 TI - Olestra and the FDA. PMID- 8692243 TI - Olestra and the FDA. PMID- 8692244 TI - Olestra and the FDA. PMID- 8692245 TI - Olestra and the FDA. PMID- 8692246 TI - Unfractionated versus low-molecular-weight heparin for deep venous thrombosis. PMID- 8692247 TI - Unfractionated versus low-molecular-weight heparin for deep venous thrombosis. PMID- 8692248 TI - Growth hormone in the treatment of dilated cardiomyopathy. PMID- 8692249 TI - Growth hormone in the treatment of dilated cardiomyopathy. PMID- 8692250 TI - Auto-PEEP and electromechanical dissociation. PMID- 8692251 TI - Renal tubular acidosis. PMID- 8692252 TI - Transmission of tuberculosis during a long airplane flight. PMID- 8692253 TI - Transmission of tuberculosis during a long airplane flight. PMID- 8692254 TI - Box of bones 'clinches' identity of Piltdown palaeontology hoaxer. PMID- 8692255 TI - 'Unrealistic' misconduct plans under fire. PMID- 8692256 TI - US coalition counters breast gene patents. PMID- 8692257 TI - Bidding heats up for protein database. PMID- 8692258 TI - Japan needs centre of excellence for brain research, council says. PMID- 8692259 TI - IQ and censorship. PMID- 8692260 TI - Planning of US AIDS research. PMID- 8692261 TI - Morgagni and the impact factor. PMID- 8692262 TI - Errors in protein structures. PMID- 8692263 TI - Mobile genetic elements. Inside an intron invasion. PMID- 8692264 TI - Energy metabolism. Creatine kinase shapes up. PMID- 8692265 TI - Visual illusion from running. PMID- 8692266 TI - Learning improved by arts training. PMID- 8692267 TI - A complete skeleton of the giant South American primate Protopithecus. AB - A complete skeleton of a large-bodied New World monkey has been found in Pleistocene cave deposits in the Brazilian state of Bahia. It demonstrates an unprecedented combination of body size, locomotor and cranial morphology. Skeletal features indicate an animal of approximately 25 kg, more than twice the mass of any living South American monkey. We refer the specimen to Protopithecus brasiliensis Lund, 1838, a large Pleistocene primate originally represented by only a proximal femur and distal humerus. The skeleton resembles species of two distinct New World monkey lineages. The cranium is modified for an enlarged vocal sac typical of living howler monkeys, and the postcranium includes suspensory and brachiating components of locomotion as seen in living spider and woolly spider monkeys. This skeleton confirms that adaptive diversity in neotropical primates was greater in the recent past, and that current interpretations of how their distinctive adaptations evolved should be revised. PMID- 8692268 TI - Specification of the wing by localized expression of wingless protein. AB - Limb development in Drosophila depends on subdivision of the limb primordia into functional units called compartments. Cell interactions across compartment boundaries establish pattern-organizing centres that control growth and specify cell fates along the anteroposterior (AP) and dorsoventral (DV) axes of the limbs. AP subdivision of the disc primordia is inherited from the embryonic ectoderm. DV subdivision of the wing disc occurs during the second larval instar through localized expression of the apterous protein (Apterous) in dorsal cells. A third major subdivision of the wing disc into wing and body-wall compartments also occurs in the second instar. Here we show that specification of the wing primordium in early second instar depends on activity of the AP patterning system but not the DV system. These results define two distinct roles for the wingless gene: a primary role in specifying the wing primordium, and a subsequent role mediating the patterning activities of the DV compartment boundary. PMID- 8692269 TI - Function of the Eph-related kinase rtk1 in patterning of the zebrafish forebrain. AB - Early during its development, the vertebrate brain is subdivided into regions that have distinct fates and correlate with the expression domains of regulatory genes, but little is known about the cell-cell interactions that establish this spatial pattern. Candidates for regulating such interactions are the Eph-related receptor tyrosine kinases (RTKs) which have spatially restricted expression in the developing brain. These RTKs may mediate cell-contact-dependent signalling by interacting with membrane-bound ligands, and have been implicated in axon repulsion and the segmental restriction of gene expression in the hindbrain, but nothing is known regarding their function in the rostral neural epithelium. Here we use a dominant-negative approach in the zebrafish embryo to interfere with the function of Rtk1, an Eph-related RTK expressed in the developing diencephalon. We find that expression of a truncated receptor leads to expansion of the eye field into diencephalic territory and loss of diencephalic structures, indicating a role for Rtk1 in patterning the developing forebrain. PMID- 8692270 TI - Multiple spike-initiation zones in single neurons revealed by voltage-sensitive dyes. AB - The primary function of the nerve cell is to process electrical signals. Over the past fifteen years there has been renewed interest in the detailed spatial analysis of signalling in individual neurons owing to experimental evidence that the regional electrical properties of neurons are complex. Thus the behaviour of many nerve cells cannot be understood on the basis of microelectrode measurements from the soma. Regional electrical properties of neurons have been studied using sharp microelectrode and patch-electrode recordings from neuronal processes, high resolution multisite optical recordings of Ca2+ concentration changes and by using models to predict the distribution of membrane potential in the entire neuronal arborization. Additional direct evidence about electrical signalling in neuronal processes in situ can now be obtained by recording membrane potential changes using voltage-sensitive dyes. Here I demonstrate the existence of multiple action potential trigger zones in separate regions of the neuronal arborization of an identified molluscan neuron. PMID- 8692271 TI - Regulation of B-lymphocyte negative and positive selection by tyrosine phosphatase CD45. AB - Elimination of self-reactive B cells must be balanced against the need for B-cell diversity for antibody responses to pathogens. To analyse factors that determine the extent of B-cell negative selection, we crossed CD45-deficient mice with mice carrying immunoglobulin transgenes specific for hen egg lysozyme (HEL). CD45 positively regulates antigen-receptor signalling and CD45-deficient HEL-specific B cells gave diminished signalling in response to HEL. Significantly, few mature CD45-/- B cells accumulated, despite normal immature B-cell production. Circulating HEL autoantigen mediates negative selection of mature CD45+/+ HEL binding B cells but, in striking contrast, the autoantigen positively selected CD45-/- HEL-binding B cells, promoting their accumulation as long-lived IgD(hi) cells. These findings are consistent with a signal-threshold model for B-cell selection and demonstrate that changes in antigen receptor signalling can cause high-affinity self-reactive B cells to be actively retained instead of eliminated, thus revealing a potential mechanism for inherited susceptibility to autoimmune disease. PMID- 8692272 TI - Effects on NF-kappa B1/p105 processing of the interaction between the HTLV-1 transactivator Tax and the proteasome. AB - The viral Tax protein, which is encoded by human T-cell leukaemia virus HTLV-I, activates nuclear translocation of the NF-kappa B/Rel transcription factors and relieves cytoplasmic sequestration of RelA and Rel by heterodimerization with NF kappa B1/p1O5 (refs 1,2). Proteolytic maturation of this precursor protein is performed by the proteasome complex. Here we show that Tax binds specifically to two subunits of the 20S proteasome, HsN3 and HC9. This interaction is weakened with HsN3 and lost for HC9 when a mutant of Tax is substituted that is selectively defective for NF-kappa B activation. Immunoprecipitation shows that p1O5 binds weakly to HC9 and that this interaction is reinforced by Tax. No bridging function of Tax between p1O5 and HsN3 was observed. From these results, we propose that Tax accelerates the proteolytic maturation of P105 by favouring its anchorage to the proteasome. PMID- 8692273 TI - Efficient integration of an intron RNA into double-stranded DNA by reverse splicing. AB - Some group II introns are mobile elements as well as catalytic RNAs. Introns aI1 and aI2 found in the gene COX1 in yeast mitochondria encode reverse transcriptases which promote site-specific insertion of the intron into intronless alleles ('homing'). For aI2 this predominantly occurs by reverse transcription of unspliced precursor RNA at a break in double-strand DNA made by an endonuclease encoded by the intron. The aI2 endonuclease involves both the excised intron RNA, which cleaves the DNA's sense strand by partial reverse splicing; and the intron-encoded reverse transcriptase which cleaves the anti sense strand. Here we show that aI1 encodes an analogous endonuclease specific for a different target site compatible with the different exon-binding sequences of the intron RNA. Over half of aI1 undergoes complete reverse splicing in vitro, thus integrating linear intron RNA directly into the DNA. This unprecedented reaction has implications for both intron mobility and evolution, and potential genetic engineering applications. PMID- 8692275 TI - Structure of mitochondrial creatine kinase. AB - Creatine kinase (CK, EC 2.7.3.2), an enzyme important for energy metabolism in cells of high and fluctuating energy requirements, catalyses the reversible transfer of a phosphoryl goup from phosphocreatine to ADP. We have solved the structure of the octameric mitochondrial isoform, Mib-CK, which is located in the intermembrane compartment and along the cristae membranes. Mib-CK consumes ATP produced in the mitochondria for the production of phosphocreatine, which is then exported into the cytosol for fast regeneration of ATP by the cytosolic CK isoforms. The octamer has 422 point-group symmetry, and appears as a cube of side length 93 angstrom with a channel 20 angstrom wide extending along the four-fold axis. Positively charged amino acids at the four-fold faces of the octamer possibly interact with negatively charged mitochondrial membranes. Each monomer consists of a small alpha-helical domain and a large domain containing an eight stranded antiparallel beta-sheet flanked by seven alpha-helices. The conserved residues of the CK family form a compact cluster that covers the active site between the domains. PMID- 8692274 TI - X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. AB - THE Bcl-2 family of proteins regulate programmed cell death by an unknown mechanism. Here we describe the crystal and solution structures of a Bcl-2 family member, Bcl-xL (ref. 2). The structures consist of two central, primarily hydrophobic alpha-helices, which are surrounded by amphipathic helices. A 60 residue loop connecting helices alpha1 and alpha2 was found to be flexible and non-essential for anti-apoptotic activity. The three functionally important Bcl-2 homology regions (BH1, BH2 and BH3) are in close spatial proximity and form an elongated hydrophobic cleft that may represent the binding site for other Bcl-2 family members. The arrangement of the alpha-helices in Bcl-xL is reminiscent of the membrane translocation domain of bacterial toxins, in particular diphtheria toxin and the colicins. The structural similarity may provide a clue to the mechanism of action of the Bcl-2 family of proteins. PMID- 8692276 TI - Careers and recruitment. Flexibility the key for neuroscientists. PMID- 8692277 TI - The view from Europe. PMID- 8692278 TI - Antagonists that differentiate between alpha 2A-and alpha 2D-adrenoceptors. AB - Four antagonists were examined for their ability to differentiate alpha 2A-from the orthologous alpha 2D-adrenoceptors. The antagonists were (2S,12bS)1',3' dimethylspiro(1,3,4,5',6,6',7,12b-octah ydro-2H- benzo[b]furo[2,3-a]quinolizine) 2,4'-pyrimidin-2'-one (MK912), 2-[2-(methoxy-1,4-benzodioxanyl)imidazoline (RX 821002), efaroxan and benoxathian. The alpha 2-autoreceptors in rabbit brain cortex were chosen as alpha 2A-and the alpha 2-autoreceptors in guinea-pig brain cortex as alpha 2D-adrenoceptors. Slices of the brain cortex were preincubated with 3H-noradrenaline and then superfused and stimulated electrically by brief pulse trains (4 pulses, 100 Hz) that led to little, if any, alpha 2 autoinhibition. 5-Bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) was used as an alpha 2-adrenoceptor agonist. UK 14, 304 decreased the stimulation evoked overflow of tritium. The antagonists shifted the concentration-inhibition curve of UK 14, 304 to the right in an apparently competitive manner. Dissociation constants of the antagonists were calculated from the shifts. MK 912, RX 821002 and efaroxan had markedly higher affinity for (guinea-pig) alpha 2D-adrenoceptors (pKd values 10.0, 9.7 and 9.1, respectively) than for (rabbit) alpha 2A-adrenoceptors (pKd 8.9, 8.2 and 7.6, respectively). Benoxathian had higher affinity for alpha 2A-(pKd 7.4) than for alpha 2D-adrenoceptors (pKd 6.9). Ratios calculated from the Kd values of the four compounds differentiated between alpha 2A and alpha 2D up to 100 fold. It is concluded that MK 912, RX 821002, efaroxan and benoxathian are antagonists with high power to differentiate alpha 2A-from alpha 2D-adrenoceptors. PMID- 8692279 TI - Functional characterization of adenosine A2 receptors in Jurkat cells and PC12 cells using adenosine receptor agonists. AB - The effect of several adenosine analogues on cyclic AMP accumulation was examined in the rat phaeochromocytoma cell PC12 and in the human T-cell leukaemia cell Jurkat, selected as prototypes of cells predominantly expressing adenosine A2A or A2B receptors. Using the reverse transcription-polymerase chain reaction it was, however, demonstrated that the Jurkat cell and the PC12 cell express both A2A and A2B receptor mRNA, albeit in different relative proportions. In PC12 cells the concentration required for half-maximal response (EC50) for the full agonist 5'-N ethyl-carboxamidoadenosine (NECA) was 30 times lower than in Jurkat cells. There was no significant difference in the pA2 for the antagonist 5-amino-9-chloro-2-(2 furanyl)- 1,2,4-triazolo(1,5-C)quinazolinemonomethanesulphonate (CGS 15943) between the two cell types. In the presence of forskolin (1 microM in PC12 cells; 10 microM in Jurkat cells) the EC50 value for NECA was reduced two-to sixfold. Forskolin also increased the maximal cAMP accumulation twofold in PC12 cells and sevenfold in Jurkat cells. A series of 2-substituted adenosine analogues CV 1808 (2-phenylamino adenosine), CV 1674 [2-(4-methoxyphenyl)adenosine], CGS 21680 ?2 [p-(2-carbonylethyl)phenylethylamino]-5'-N-ethyl- carboxamido adenosine?, and four 2-substituted isoguanosines, SHA 40 [2-(2-phenylethoxy)adenosine; PEA], SHA 91 [2-(2-cyclohexylethoxy)adenosine; CEA], SHA 118 ?2-[2-(p methylphenyl)ethoxy]adenosine; MPEA?, and SHA 125 (2-hexyloxyadenosine; HOA), all raised cAMP accumulation in PC12 cells, but had minimal or no effect in Jurkat cells. In the PC12 cells the addition of forskolin (1 microM) reduced the EC50 by a factor of 2(CV 1808) to 12 (SHA 125). In Jurkat cells all the analogues gave a significant, but submaximal, cAMP response in the presence of forskolin (10 microM), but they were essentially inactive in its absence. The results show that a series of 2-substituted adenosine analogues can be used to discriminate between A2A and A2B receptors. The two receptor subtypes appear to coexist, even in clonal cells selected for typical pharmacology. A2 receptor pharmacology can therefore be complex. PMID- 8692280 TI - Evidence for high-affinity binding sites for the adenosine A2A receptor agonist [3H] CGS 21680 in the rat hippocampus and cerebral cortex that are different from striatal A2A receptors. AB - The binding of the adenosine A2A receptor selective agonist 2-[4-(2-p carboxyethyl)phenylamino] -5'-N-ethylcarboxamidoadenosine (CGS 21680) to the rat hippocampal and cerebral cortical membranes was studied and compared with that to striatal membranes. [3H] CGS 21680, in the concentration range tested (0.2-200 nM), bound to a single site with a Kd of 58 nM and a Bmax of 353 fmol/mg protein in the hippocampus, and with a Kd of 58 nM and a Bmax of 264 fmol/mg protein in the cortex; in the striatum, the single high-affinity [3H] CGS 21680 binding site had a Kd of 17 nM and a Bmax of 419 fmol/mg protein. Both guanylylimidodiphosphate (100 microM) and Na+ (100 mM) reduced the affinity of [3H] CGS 21680 binding in the striatum by half and virtually abolished [3H] CGS 21680 binding in the hippocampus and cortex. The displacement curves of [3H] CGS 21680 binding with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), N6 cyclohexyladenosine (CHA), 5'-N-ethylcarboxamidoadenosine (NECA) and 2 chloroadenosine (CADO) were biphasic in the hippocampus and cortex as well as in the striatum. The predominant [3H]CGS 21680 binding site in the striatum (80%) had a pharmacological profile compatible with A2A receptors and was also present in the hippocampus and cortex, representing 10-25% of [3H]CGS 21680 binding. The predominant [3H]CGS 21680 binding site in the hippocampus and cortex had a pharmacological profile distinct from A2A receptors: the relative potency order of adenosine antagonists DPCPX, 1,3-dipropyl- 8-?4-[(2 aminoethyl)amino]carbonylmethyl- oxyphenyl? xanthine (XAC), 8-(3 chlorostyryl)caffeine (CSC), and (E)-1,3-dipropyl-8-(3,4-dimethoxystyryl)- methylxanthine (KF 17,837) as displacers of [3H] CGS 21680 (5 nM) binding in the hippocampus and cerebral cortex was DPCPX > XAC >> CSC approximately KF 17,837, and the relative potency order of adenosine agonists CHA, NECA, CADO, 2-[(2 aminoethylamino)carbonylethylphenylethylamino]-5'-N- ethylcarboxamidoadenosine (APEC), and 2-phenylaminoadenosine (CV 1808) was CHA approximately NECA > or = CADO > APEC approximately CV1808 > CGS 21680. In the presence of DPCPX (20 nM), [3H] CGS 21680 (0.2-200 nM) bound to a site (A2A-like) with a Kd of 20 nM and a Bmax of 56fmol/mg protein in the hippocampus and with a Kd of 22 nM and a Bmax of 63fmol/mg protein in the cortex. In the presence of CSC (200 nM), [3H]CGS 21680(0.2-200 nM) bound to a second high-affinity site with a Kd of 97 nM and a Bmax of 255 fmol/mg protein in the hippocampus and with a Kd of 112 nM and a Bmax of 221 fmol/mg protein in the cortex. Two pharmacologically distinct [3H]CGS 21680 binding sites were found in synaptosomal membranes of the hippocampus and cortex and in the striatum, one corresponding to A2A receptors and the other to the second high-affinity [3H]CGS 21680 binding site. In contrast, the pharmacology of [3H]CHA binding was similar in synaptosomal membranes of the three brain areas. The present results establish the existence of at least two high-affinity [3H]CGS 21680 binding sites in the CNS and demonstrate that the [3H]CGS 21680 binding site predominant in the hippocampus and cerebral cortex has different binding characteristics from the classic A2A adenosine receptor, which predominates in the striatum. PMID- 8692281 TI - Inhibition of noradrenaline release via presynaptic 5-HT1D alpha receptors in human atrium. AB - In segments of human right atrial appendages preincubated with [3H]noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone, we determined the effects of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on tritium overflow evoked by transmural electrical stimulation (2 Hz). Tritium overflow was inhibited by 5-HT, 5 carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT), 5-methoxy-3(1,2,3,6 tetrahydro-4-pyridinyl)-1H indole succinate (RU 24969) and sumatriptan. Yohimbine and oxymetazoline (in the presence of idazoxan) also inhibited tritium overflow. The inhibitory potency of the drugs was significantly correlated with their affinity for 5-HTID receptors in human brain and for cloned human 5-HT1D alpha and 5-HT1D beta receptors, but not with their affinity for 5-HT1B, 5-HT1E, 5 HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5A, 5-HT5B and 5-HT7 receptors. The potency order 5-CT > 5-HT > 5-MeOT is opposite to the order of affinities reported for 5-HT6 binding sites. The preferential 5-HT1A receptor agonist 8 hydroxy-2-(di-n-propylamino)tetraline (up to 0.3 microM) and the selective 5-HT4 receptor agonist cisapride (up to 1 microM) failed to inhibit tritium overflow. L 694,247, a potent 5-HT1D beta receptor agonist, did not inhibit tritium overflow, but counteracted the inhibitory effect of 5-HT. Ketanserin at a concentration which should block 5-HT1D alpha but not 5-HT1D beta receptors and methiothepin at a concentration which may be assumed to block both 5-HT1D alpha and 5-HT1D beta receptors antagonized the inhibitory effect of 5-HT. Propranolol and ondansetron did not modify the 5-HT-induced inhibition of release. In conclusion, noradrenaline release in human right atrial appendages is inhibited via 5-HT receptors which are located on the noradrenergic axon terminals. These inhibitory presynaptic 5-HT receptors belong to the 5-HT1D subfamily. The ability of ketanserin to antagonize the inhibitory effect induced by activation of these receptors suggests that they can be subclassified as 5-HT1D alpha. PMID- 8692282 TI - Evidence for presynaptic location of inhibitory 5-HT1D beta-like autoreceptors in the guinea-pig brain cortex. AB - The effects of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on tritium overflow evoked by high K+ were determined in superfused synaptosomes and slices, preincubated with [3H]5-HT, from guinea-pig brain cortex. In addition, we estimated the potencies of 5-HT receptor ligands in inhibiting specific [3H]5-HT binding (in the presence of 8-hydroxy-2(di-n-propylamino)tetralin and mesulergine to prevent binding to 5-HT1A and 5-HT2C sites) to guinea-pig cortical synaptosomes and membranes. 5-HT receptor agonists inhibited the K(+)-evoked tritium overflow from synaptosomes and slices. In synaptosomes the rank order of potencies was 2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl] -1H indole-3-yl] ethylamine (L-694,247) > 5-carboxamidotryptamine (5-CT) > oxymetazoline (in the presence of idazoxan) > or = 5-HT > sumatriptan > or = 5 methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (RU 24969). The potencies of the agonists in inhibiting tritium overflow from slices correlated with those in synaptosomes, suggesting that the same site of action is involved in both preparations. In synaptosomes the nonselective antagonist at cloned human 5-HT1D alpha and 5-HT1D beta receptors, methiothepin, shifted the concentration-response curve for 5-CT to the right (apparent pA2: 7.87). In contrast, ketanserin at a concentration which should block the 5-HT1D alpha, but not the 5-HT1D beta, receptor did not alter the inhibitory effect of 5-CT on tritium overflow. In cortical synaptosomes and membranes, [3H]5-HT bound to a single site with high affinity. In competition experiments, 5-HT receptor agonists and antagonists inhibited specific [3H]5-HT binding. In synaptosomes the rank order was L-694,247 > methiothepin > 5-CT > 5-methoxytryptamine > 5-HT > or = sumatriptan > or = oxymetazoline > RU 24969 > ketanserin > ritanserin. A very similar rank order was obtained in cerebral cortical membranes. The potencies of the 5-HT receptor agonists in inhibiting tritium overflow from synaptosomes and slices correlated with their potencies in inhibiting [3H]5-HT binding to synaptosomes and membranes. In conclusion, the 5-HT receptors mediating inhibition of 5-HT release in the guinea-pig cortex are located on the serotoninergic axon terminals and, hence, represent presynaptic inhibitory autoreceptors. The [3H]5-HT binding sites in cerebral cortical synaptosomes and membranes exhibit the pharmacological properties of 5-HT1D receptors. The correlation between the functional responses and the binding data confirms the 5-HT1D character of the presynaptic 5-HT autoreceptors. According to the results of the interaction experiment of ketanserin and methiothepin with 5-CT on 5-HT release, the presynaptic 5-HT autoreceptors can be subclassified as 5-HT1D beta-like. PMID- 8692284 TI - 8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate (TMB-8) acts as a muscarinic receptor antagonist in the epithelial cell line HT29. AB - 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) is a widely used pharmacological tool to investigate the involvement of intracellular Ca2+ stores in cellular responses. In this study we investigate the effect of TMB-8 as a putative inhibitor of "Ca2+ signalling" in single fura-2 loaded HT29 colonic epithelial cells stimulated by ATP, carbachol (CCH) and neurotensin (NT). TMB-8 effectively inhibited the CCH-induced (100 mumol/l intracellular Ca2+ ([Ca2+]i) transient with an IC50 of 20 mumol/l. However, [Ca2+]i transients induced by other phospholipase C coupled agonists ATP (10 mumol/l, n = 4) and NT (10 nmol/l, n = 4) remained unaffected by TMB-8 (50 mumol/l). The agonist-induced [Ca2+]i transients remained equally unaffected by 100 mumol/l TMB-8 when the stimulatory concentration was reduced to 0.5 mumol/l for ATP (n = 4) or 1 nmol/l for NT (n = 4). The competitive nature of the TMB-8-induced inhibition of the CCH-induced [Ca2+]i transient was demonstrated by examining the agonist at various concentrations in absence and presence of the antagonist. High TMB-8 concentrations (100 mumol/l) alone induced a small [Ca2+]i increase (delta[Ca2+]i: 40 +/- 5 nmol/l, n = 7). We assume that this increase is a consequence of a TMB-8 induced intracellular alkalinization (delta pH: 0.1 +/- 0.02, n = 7) occurring simultaneously with the increase in [Ca2+]i. From these results we draw the following conclusions: (1) In sharp contrast to a large number of other studies, but in agreement with studies in other types of cells, these results substantially challenge the value of the "tool" TMB-8 as an "intracellular Ca2+ antagonist"; (2) TMB-8 acts a muscarinic receptor antagonist at the M3 receptor; (3) TMB-8 does not influence the release of Ca2+ from intracellular stores when IP3 signal transduction is activated by ATP or NT; (4) TMB-8 as a weak organic base alkalinizes the cytosol at high concentrations; and (5) TMB-8 induces small [Ca2+]i transients at higher concentrations. PMID- 8692283 TI - The moderate affinity of clozapine at H3 receptors is not shared by its two major metabolites and by structurally related and unrelated atypical neuroleptics. AB - We determined the affinity and/or potency of two metabolites of clozapine (clozapine-N-oxide and N-desmethylclozapine) and of five atypical neuroleptics, chemically related (olanzapine) or unrelated to clozapine (remoxipride, risperidone, thioridazine, zotepine), at H3 receptors. The specific binding of 3H N alpha-methylhistamine to rat brain cortex homogenates was inhibited by the seven compounds; the pKi values were: N-desmethylclozapine (5.33); clozapine-N oxide (4.18); olanzapine (5.45); thioridazine (4.91); zotepine (4.75); remoxipride (4.51) and risperidone (4.43). Three compounds were examined in a functional H3 receptor model as well. The electrically evoked tritium overflow from superfused mouse brain cortex slices, which represents quasi-physiological noradrenaline release, was not affected by N-desmethylclozapine (3.2 and 10 microM), clozapine-N-oxide (3.2-100 microM) and olanzapine (3.2-32 microM). On the other hand, the three compounds shifted to the right the concentration response curve of histamine for its inhibitory effect on the evoked overflow; the apparent pA2 values were 5.84, 4.21 and 5.80, respectively. The present study shows that five atypical neuroleptics of different chemical classes and the two major metabolites of clozapine possess a lower affinity and/or antagonistic potency at H3 receptors than clozapine itself (pKi 6.15, pA2 6.33; Kathmann M, Schlicker E, Gothert M (1994). Psychopharmacology 116: 464-468). PMID- 8692285 TI - Opposing effects on blood pressure following the activation of metabotropic and ionotropic glutamate receptors in raphe obscurus in the anaesthetized rat. AB - The microinjection of L-glutamate (1-6 nmol/rat) and N-methyl-D-aspartate (NMDA 1 10 nmol/rat), ionotropic glutamate receptor (iGluR) agonists, into the nucleus raphe obscurus caused a concentration -dependent increase of arterial blood pressure. In contrast, (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t ACPD, 14-42 nmol/rat), a metabotropic glutamate receptor (mGluRs) agonist, caused a concentration-dependent decrease in blood pressure. Pretreatment with D,L-2 amino-phosphono valeric acid (2-APV, 5 nmol/rat) a selective NMDA iGluR antagonist, and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b] cyclohepten-5,10-imine hydrogen maleate (MK801, 0.9 nmol/rat), a noncompetitive NMDA iGluR antagonist, blocked both the glutamate and NMDA pressor responses, while pretreatment with (+)-alpha-methyl-4-carboxyphenylglycine (MCPG, 0.05 nmol/rat), a mGluR1 antagonist, increased the glutamate-induced pressor effects and blocked the fall in blood pressure induced by t-ACPD. 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX, 0.4 nmol/rat) a non-NMDA iGluR antagonist, did not affected the glutamate-induced hypertension. These observations indicate opposing roles for ionotropic and metabotropic receptors in the glutamate-induced blood pressure changes elicited from the nucleus raphe obscurus. Moreover, we suggest that the glutamate-induced hypertension may be due to the activation of NMDA ionotropic receptor subtypes and the metabotropic receptors may influence this activation through a reduction of excitability at level of synapses. PMID- 8692286 TI - Thermodynamics and kinetics of t-butylbicyclophosphorothionate binding differentiate convulsant and depressant barbiturate stereoisomers acting via GABAA ionophores. AB - The temperature dependence of [35S]-t-butylbicyclophosphorothionate (TBPS) binding to the convulsant sites of the GABAA receptor complex was studied in membrane preparations of rat forebrain. Although specific [35S]TBPS binding was maximal around 20 degrees C, the rate constants of dissociation decreased monotonously between 37 degrees C and 2 degrees C. The displacing potencies of the convulsant S(+) enantiomer of 1-methyl-5-phenyl-5-propyl-barbituric acid (MPPB) (IC50 = 1250 +/- 30 microM) and the depressant R(-) MPPB (IC50 = 310 +/- 5 microM) did not show significant changes between 19 degrees C and 37 degrees C. Therefore barbiturate binding seems to be driven by entropic, rather than enthalpic changes. An excess of MPPB enantiomers elicited accelerated and polyphasic dissociations of [35S]TBPS as compared to the monophasic dissociation by TBPS. Arrhenius analysis was applied to the measurable initial rate constants of dissociation. Arrhenius plots were linear between 2 degrees C and 37 degrees C. Activation parameters were similar when [35S] TBPS dissociation was triggered by the convulsants TBPS and S(+) MPPB. It can be attributed to similar conformations of the closed ionophore complex. In contrast, the depressant R(-) MPPB strongly decreased the activation energy of TBPS dissociation from the open ionophore ternary complex. In whole-cell patch-clamp experiments R(-) MPPB, but not S(+) MPPB, elicited chloride currents in rat primary cortical cultures with an EC50 value of 560 +/- 30 microM and a Hill coefficient of 2.9 +/- 0.2. These currents were similar to those elicited by GABA and blocked by TBPS. A kinetic scheme is proposed for the dissociation of TBPS and to explain the different effects of MPPB enantiomers. Submillimolar R(-) MPPB is supposed to bind to (about three) barbiturate sites on GABAA-ionophores and to open them in a cooperative manner to result in a decreased activation energy for accelerated displacement of convulsant binding. PMID- 8692287 TI - Effects of noradrenaline and neuropeptide Y on rat mesenteric microvessel contraction. AB - We have studied the contractile effects of the sympathetic transmitter noradrenaline and its cotransmitter neuropeptide Y (NPY) given alone and in combination on isolated rat mesenteric resistance vessels (200-300 microns diameter). Noradrenaline and NPY each concentration-dependently contracted rat mesenteric microvessels (EC50 approximately equal to 800 nM and 10 nM, respectively), but noradrenaline caused considerably greater maximal effects than NPY (14.3 mN vs. 3.5 mN). A low antagonistic potency of yohimbine indicated that the response to noradrenaline did not involve alpha 2-adrenoceptors, and the subtype-selective antagonists 5-methylurapidil, tamsulosin and chloroethylclonidine indicated mediation via an alpha 1A-adrenoceptor. Shallow Schild regressions for prazosin and 5-methylurapidil indicated that an alpha 1 adrenoceptor subtype with relatively low prazosin affinity might additionally be involved. Studies with the NPY analogues PYY, [Leu31, Pro34] NPY and NPY18-36 demonstrated that NPY acted via a Y1 NPY receptor. In addition to its direct vasoconstricting effects NPY also lowered the noradrenaline EC50 but did not appreciably affect maximal noradrenaline responses indicating possible potentiation. The potentiating NPY response occurred with similar agonist potency as the direct contractile NPY effects and also via a Y1 NPY receptor. The Ca2+ entry blocker nitrendipine (300 nM) reduced direct contractile responses to noradrenaline and NPY but did not affect the potentiation response to NPY. PMID- 8692288 TI - Effects of different congestion pressures on the diameter of the dorsal hand vein and on its apparent sensitivity to noradrenaline. AB - We have measured the diameter of the human dorsal hand vein (DHV) in situ and compared the venoconstrictor dose-response curves to locally infused noradrenaline at different venous congestion pressures using the DHV compliance technique. Congestion pressure was defined as the inflation pressure of a sphygmomanometer cuff on the ipsilateral upper arm. Male healthy volunteers (20 45 years) participated in two experimental sessions. In Session I, DHV diameter was measured at congestion pressures of 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 mmHg. In Session II, venoconstrictor dose-response curves to six doses (0.1 33.33 ng min-1) of (-)noradrenaline acid tartrate were established at congestion pressures 30 and 45 mmHg. DHV diameter increased as a function of congestion pressure. The rate of increase in DHV diameter (mm/5 mmHg) declined at higher values of congestion pressure (e.g. 0.14 mm/5 mmHg between 20 and 45 mmHg, and 0.04 mm/5 mmHg between 45 and 70 mmHg). Noradrenaline was less potent at 45 mmHg than at 30 mmHg. Mean log ED50 was significantly greater at 45 mmHg than at 30 mmHg congestion pressure, while mean E(max) did not differ at the two congestion pressures. The geometric mean ED50 was approximately 195% greater at 45 mmHg than at 30 mmHg. These results show that DHV diameter is positively related to congestion pressure, and that as the congestion pressure increases, the apparent sensitivity of the vein to the venoconstrictor effect of noradrenaline decreases. This latter finding is consistent with the physiological antagonism between congestion-induced venodilatation and noradrenaline-evoked venoconstriction. It is recommended that a standard congestion pressure is used in order to facilitate the comparison of results obtained in different laboratories. PMID- 8692289 TI - Expression of the extraneuronal monoamine transporter (uptake2) in human glioma cells. AB - Tritiated methylphenylpyridinium ([3H]MPP+), a substrate of the neuronal and extraneuronal noradrenaline transporter (uptake1 and uptake2, respectively) and of the organic cation transporter (OCT1), was used to characterize the amine transport system of the established human glioma cell line SK-MG-1. Uptake of [3H]MPP+ (25 nM) into SK-MG-1 cells increased linearly with time for up to 15 min. Selective uptake1 inhibitors (e.g. (+)oxaprotiline) or omission of Na+ or Cl ions did not affect [3H]MPP+ uptake, whereas uptake2 inhibitors such as O-methyl isoprenaline (OMI) or corticosterone as well as depolarizing concentrations of K+ or Ba2+ strongly reduced [3H]MPP+ uptake. Initial rates of OMI(100 microM) sensitive [3H]MPP+ uptake were saturable, with a K(m) of about 17 microM and a maximal rate of about 50 pmol/(min x mg protein). IC50 (or Ki) values for inhibition of [3H]MPP+ uptake by substrates and inhibitors of uptake2 or OCT1 were highly significantly correlated with published IC50 values for inhibition of uptake2 but not with corresponding values for inhibition of OCT1. The results presented here clearly demonstrate that human glioma cells express an uptake2 transporter. Thus, glial cells in the human central nervous system endowed with this transporter are likely to contribute to the inactivation of neuronally released noradrenaline. PMID- 8692290 TI - Voltage-dependent suppression of calcium current by caffeine in single smooth muscle cells of the guinea-pig urinary bladder. AB - The suppressive action of caffeine on L-type Ca current (Ica) in smooth muscle cells of the guinea-pig urinary bladder was investigated using the whole-cell patch clamp technique. Caffeine (5-30 mM) suppressed Ica, the effect having two phases: a rapid and transient suppression of Ica, which was followed by a sustained suppression. When intracellular Ca2+ was strongly buffered by the Ca2+ chelator EGTA (20 mM) or BAPTA (5 mM) in the patch pipette, the transient suppression of Ica was abolished, whereas the sustained effect remained. Similarly, inclusion of both 10 mM procaine and 1 mg/ml heparin in the patch pipette blocked the transient suppression of Ica, but did not block the sustained effect. The degree of the sustained effect of caffeine on Ica was dose-dependent with a kd of 20 mM. Application of the cyclic AMP analogue, 8-bromo-cyclic AMP (100 microM) or forskolin (10 microM) to the bath failed to mimick the sustained suppression of Ica, suggesting that inhibition of phosphodiesterase activity was not involved in the caffeine action. The steady-state activation curve remained unchanged by 10 mM caffeine but the steady-state inactivation curve was significantly shifted in the negative direction by 15.6 mV in 1.8 mM Ca2+ solution or by 10 mV in 1.8 mM Ba2+ solution. From these results it appears that caffeine inhibits L-type Ica via two mechanisms: (1) it releases Ca2+ from an internal store causing a transient Ca2+ -mediated inactivation of the Ca channel; (2) it inhibits Ca channel via a mechanism that does not require such a Ca2+ release. It is possible that caffeine suppresses Ica through a preferential binding to the inactivated state of L-type Ca channel. PMID- 8692291 TI - Effects of basic fibroblast growth factor and ganglioside GM1 on neuronal survival in primary cultures and on eight-arm radial maze task in adult rats following partial fimbria transections. AB - The effects of basic fibroblast growth factor (bFGF) and ganglioside GM1 (GM1) were evaluated alone and simultaneously in two types of experiments. First, the neuronal survival of primary culture neurons from fetal rat brain was measured. Then, performance on radial maze task in adult male rats following bilateral partial Fimbria-Fornix transections (F-F lesion) was tested. In primary culture neurons, bFGF (1-10 ng/ml) supported the neuronal survival from three regions (hippocampus, cortex and septum) of embryonic rat brain. However, GM1 (0.1-10 micrograms/ml) did not support the neuronal survival from any regions. Survival of cultured neurons was not supported by addition of 0.1 ng/ml bFGF, but when bFGF (0.1 ng/ml) and GM1 (0.1, 1 microgram/ml) were given to the cultured neurons simultaneously, the number of surviving neurons increased significantly. In the eight-arm radial maze task, where only the same four arms were baited, F-F lesion produced substantial memory impairment. In this task, administration of bFGF (10 micrograms/ml) or GM1 (1 mg/ml) alone did not produce any effects. However, when they were given simultaneously, the number of working memory errors decreased significantly, in spite of no amelioration for hippocampal choline acetyl transferase (ChAT) depletion. These findings indicate that actions of bFGF may be potentiated by the addition of GM1 in both primary neuronal cultures and radial maze task performance. These results suggest that the combination of bFGF and GM1 may synergistically improve spatial memory deficits. PMID- 8692292 TI - Correlation between brain nitric oxide synthase activity and opiate withdrawal. AB - The opiate withdrawal induced by administration of naloxone to morphine-dependent mice correlates with an increment of calcium- dependent nitric oxide synthase (NOS) activity in the cerebellum. L-NAME, an irreversible competitive inhibitor of NOS (0.5, 5, 25, 50 mg/kg) injected sc. 45 min. prior to naloxone significantly reduced the number of escape jumps and other motor symptoms of abstinence. In addition, L-NAME also decreased NOS activity in cerebellum. L arginine, but not D-arginine, when coadministered with L-NAME, prevented both the inhibition of NOS activity and the reduction of withdrawal symptoms induced by L NAME in morphine-withdrawn animals. These results demonstrate a hyperactivity of the L-arginine: NO pathway in opiate withdrawal and suggests the possibility of a therapeutic use of NOS inhibitors in this state. PMID- 8692293 TI - Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on neuropeptide metabolism in the rat brain. AB - The effect of a novel prolyl endopeptidase (PEP) inhibitor, (S)-2-[[(S)-2 (hydroxyacetyl)-1-pyrrolidinyl] carbonyl]-N-(phenylmethyl)-1-pyrrolidine carboxamide (JTP-4819), on neuropeptide metabolism was investigated in the rat brain. JTP-4819 exhibited a strong in vitro inhibitory effect on cortical and hippocampal PEP activity, with the IC50 values being approximately 0.58 +/- 0.02 and 0.61 +/- 0.06 nM, respectively. JTP-4819 also inhibited the in vitro degradation of substance P (SP), arginine-vasopressin (AVP), and thyrotropin releasing hormone (TRH) by rat brain supernatants, with the IC50 values being respectively 3.4, 2.1, and 1.4 nM in the cerebral cortex and 3.3, 2.8, and 1.9 nM in the hippocampus. Oral administration of JTP-4819 at doses of 1 and 3 mg/kg increased SP-like immunoreactivity (LI) and AVP-LI in the cerebral cortex. JTP 4819 also increased hippocampal SP-LI and AVP-LI at doses of 1 and 3 mg/kg, as well as hippocampal TRH-LI at a dose of 3 mg/kg. These findings suggest that JTP 4819 inhibited the degradation of SP, AVP, and TRH in the rat brain secondary to the inhibition of PEP, and thus increased cortical and hippocampal SP-LI and AVP LI as well as hippocampal TRH-LI. PMID- 8692294 TI - Tolerance to nitrates and simultaneous upregulation of platelet activity prevented by enhancing antioxidant state. AB - We analysed the induction of tolerance to nitrates both in the vasculature (in vivo) and platelets (ex vivo). Simultaneously, we tested mechanisms underlying the induction of tolerance and interventions to prevent or overcome this phenomenon. For this purpose nitroglycerin (GTN 1.5 micrograms/kg per min i.v.), alone or in combination with ascorbate (55 micrograms/kg per min i.v.) as antioxidant, was infused continuously for a period of 5 days into chronically instrumented dogs. Along with haemodynamic parameters, ex vivo platelet function was continuously monitored. Following the start of GTN infusions there was a maximal coronary dilator response (245 +/- 15 microm) and, as an index of venodilation, a fall of left ventricular end-diastolic pressure (by 2.3 +/- 0.4 mmHg). Both responses declined progressively and disappeared during the infusion period. However, in combination with ascorbate as antioxidant the dilator responses were maintained fully throughout the infusion period. With GTN alone there was a progressive, unexpected upregulation of platelet activity demonstrated by enhanced thrombin-stimulated intracellular Ca2+ levels and increases in the microviscosity of platelet membranes (indicating enhanced receptor expression) associated with a progressive impairment in basal, unstimulated cGMP levels. These changes could also be prevented completely by i.v. co-administration of ascorbate. From these results it is concluded that vascular tolerance is closely reflected by simultaneous changes in platelet function and further, that both can be prevented completely by appropriate antioxidants such as ascorbate. PMID- 8692295 TI - [Placed in the wrong bed with a broken leg]. PMID- 8692296 TI - [Wrong beds and wrong care]. PMID- 8692297 TI - [Vascular complications in diabetes mellitus: role of endothelial dysfunction]. PMID- 8692298 TI - [Parent and child care: medical efficacy]. PMID- 8692299 TI - [Malaria: under-notification and risk assessment for travelers to the tropics]. AB - OBJECTIVE: To define the risk of contracting malaria for travellers to malaria endemic areas and to calculate the under-notification under the current notification system. DESIGN: Retrospective epidemiological analysis. SETTING: Agricultural University Wageningen, The Netherlands. METHODS: Risks of contracting malaria were estimated by calculating the incidence per 100,000 travellers. This incidence was found using an estimated under-notification calculated on the basis of data from the "SIG Zorginformatie' (hospital cases) and the Medical Health Inspectorate (notified cases). RESULTS: The average under notification in the Netherlands was at least 59% in the period January 1988 to June 1993 inclusive and increased by 10% each year. Judging by this estimation at least 3170 travellers returned to the Netherlands with malaria in this period. The risk in Africa appeared to be decreasing. In Asia the malaria incidence increased slightly in recent years while no trend was found for America. The imported malaria was mainly caused by Plasmodium falciparum. CONCLUSION: In order to improve the malaria notification system in the Netherlands a notification obligation for all microbiological laboratories should be introduced as almost all malaria is diagnosed there. PMID- 8692300 TI - [Diagnosis and course of early arthritis; study in a specialized clinic for early arthritis]. AB - OBJECTIVE: To investigate the occurrence, diagnosis and course of all new inflammatory arthropathies seen in a special Early Arthritis Clinic (EAC). DESIGN: Prospective cohort study. SETTING: Academic Medical Hospital, Leiden, The Netherlands. METHODS: An Early Arthritis Clinic (EAC) was started in the outpatient clinic of rheumatology of Leiden University Hospital for diagnostic work-up according to protocol of patients with recent-onset arthritis. Inclusion criteria were: active arthritis with onset < 2 years without traumatic aetiology and no referral for a second opinion. RESULTS: In the first 18 months 276 patients were sent to the EAC, 212 met the inclusion criteria. After 2 weeks the following diagnoses were made: rheumatoid arthritis (RA) (58; 28%), psoriatic arthritis (8; 4%), reactive arthritis (11; 5%) sarcoidosis (9; 4%), crystal arthritis (30; 14%), osteoarthritis (8; 4%), other diagnosis (18; 8%). The remaining 70 patients (33%) were classified as arthritis e causa ignota (e.c.i.). After follow-up, the first diagnoses changed in 27 (12%) patients, of whom 20 patients originally had had the diagnosis of arthritis e.c.i. Persistent arthritis was found in 90% of RA and in 35% of arthritis e.c.i. Other forms of arthritis seldom showed persistent activity. CONCLUSION: In the EAC, RA, arthritis e.c.i. and crystal arthritis were seen most often. Almost all RA patients showed persistent arthritis, as against only a third of those with arthritis e.c.i. Because of the early diagnosis treatment could start early in patients with joint disease entailing irreversible joint destruction. PMID- 8692301 TI - [CO2 laser treatment; an effective and minimally disruptive endoscopic therapy for small glottic laryngeal carcinomas]. AB - OBJECTIVE: To evaluate endoscopic CO2 laser vaporization as a treatment of small glottic laryngeal carcinomas selected by means of video laryngo-stroboscopy. DESIGN: Prospective. SETTING: ENT department, University hospital, Free University Amsterdam. METHODS: Patients with a small glottic laryngeal carcinoma (stage Tis or T1a), were selected by means of video-laryngo-stroboscopy for a single stage endoscopic CO2 laser vaporization treatment as an alternative for radiotherapy. They were followed up for at least 24 months. RESULTS: Three of the 46 patients (6%) developed a local recurrence within 2 years; one of these could be treated once more with the CO2 laser, the other two were irradiated. None of these patients developed metastases in cervical lymph nodes or distant metastases. Most patients (41, 89%) assessed their voices after CO2 laser vaporization as normal or almost normal. Slight dysphonia was reported by five patients (11%). No serious dysphonia or aphonia occurred. CONCLUSION: Endoscopic CO2 laser vaporization, compared with radiotherapy or more extensive surgery, constitutes an adequate treatment for selected patients with small glottic laryngeal carcinomas. As a result of this treatment, it will be possible to preserve the larynx in more patients. PMID- 8692303 TI - [Malaria prevention: recommendations adapted once more. Work Group Malaria Prophylaxis]. PMID- 8692302 TI - [2 patients with diarrhea caused by Cyclospora cayetanensis following a trip to the tropics]. AB - A 58-year-old man and his 60-year-old wife returned from a journey through Indonesia with complaints of persisting diarrhoea. In the stools of both patients we found oocysts of the parasite Cyclospora cayetanensis. We treated them with co trimoxazole which resulted in fast clinical improvement. An infection with the parasite C. cayetanensis should be considered in travellers returning from tropical countries with persisting diarrhoea. Despite the self-limiting nature of the infection treatment with co-trimoxazole 960 mg 2 dd for 7 days may be considered in cases with a protracted course. PMID- 8692304 TI - [Didactic and educational schooling of instructors in medicine]. PMID- 8692305 TI - [Fecal analysis for occult blood obsolete]. PMID- 8692306 TI - [Recovery processes in interrupted peripheral nerves]. PMID- 8692307 TI - [Toxic encephalopathy; occupational disease as a result of organic solvents]. PMID- 8692308 TI - [100 years radiology in The Netherlands. III. Radiodiagnosis, a historical overview]. PMID- 8692309 TI - [Effect of the formulation of information on side effects on patients' interpretation and on reported side effects]. PMID- 8692310 TI - [Pre-eclampsia in the first half of pregnancy: an unknown problem?]. PMID- 8692311 TI - [Extensive lymph node dissection in stomach cancer? Initial results of the Dutch Stomach Cancer Study]. AB - The five-year survival rate after curative resection for gastric cancer is higher in Japan (62%) than in the Netherlands (30%). In Japan, extensive D2 resection surgery is performed, in the Netherlands D(1) resection in which only the perigastric lymph nodes are removed. In a large prospective randomised trial, surgical departments of 80 Dutch hospitals compared the results of both resection types. A Japanese surgeon gave instruction in the D2 technique. D2 patients suffered more complications than D(1) patients and hospital mortality was 10% as against 4%. Demographic characteristics and concomitant morbidity might explain these differences. A change in current therapy is not advised at present. However, the surgical protocols and standards developed in connection with the trial reduced the overall death rate and morbidity of surgical treatment of gastric cancer in the Netherlands. PMID- 8692312 TI - [Treatment of Helicobacter pylori infection]. PMID- 8692313 TI - [Clinical judgment and decision making in clinical practice. A patient with fever and splenomegaly]. PMID- 8692314 TI - [No difference in frequency of family practitioner consultation by Turkish, Surinam and Moroccan 0-14-year-old children from Dutch children, but difference in reason for contact]. AB - OBJECTIVE: To determine whether consultation behaviour of Turkish, Surinam and Moroccan children (0-14 years old) with a GP differs from that of a comparable group of Dutch children. DESIGN: Cohort study with comparison of matched groups. SETTING: 103 general practices in the Netherlands. METHODS: Data on 63.753 children collected in the Dutch National Survey were used. 161 GPs registered all contacts between patient and practice during 1 year (in 4 parts of each 3 months). Sociodemographic characteristics of all 103 practice populations were gathered. For each Turkish, Surinam and Moroccan child a Dutch child was selected with similar age, gender, socio-economic status, degree of urbanisation, season of registration and sickness insurance coverage. Consult frequency, number of encounters per episode of care, morbidity presented, duration of encounter and percentages of encounters during evening, night and weekend were registered. RESULTS: There were no significant differences in consult frequency between the three ethnic groups and their Dutch reference group, nor were there any differences in number of encounters during an episode of care. The morbidity presented did vary compared with Dutch children. Turkish children consulted the GP more often for gastrointestinal problems (relative risk (RR): 1,81) and respiratory problems (RR: 1,27), but less often for ear problems (RR: 0,54). Surinam children consulted the GP less often for musculoskeletal problems (RR: 0,65), but more often for respiratory problems (RR: 1,20). Moroccan children consulted the GP less often for ear problems (RR: 0,51). For a larger percentage of ethnic children the duration of encounter was less than ten minutes. CONCLUSION: Turkish, Surinam and Moroccan children do not consult a GP more often than a comparable group of Dutch children. The morbidity presented differed. PMID- 8692315 TI - [Continent ileostomy following discontinuation of ileoanal anastomosis with ileum reservoir; good results in 7 patients]. AB - OBJECTIVE: To study the results of constructing a continent ileostomy in cases of problems with a former ileoanal pouch operation. DESIGN: Retrospective and questionnaire study. SETTING: Onze Lieve Vrouwe Gasthuis, department of General Surgery, Amsterdam, the Netherlands. METHOD: The operations of 7 patients in the period 1988 to 1993 were analysed for indication and postoperative results; the long term functioning was determined by means of a questionnaire. Indications for removal of the ileoanal pouch were septic problems in the true pelvis, untreatable inflammation of the pouch with high defecation frequency and incontinence. RESULTS: The results in all 7 patients were good. No postoperative complications were observed. However, supra-anal sinus problems developed in the next 2 years in 6 out of the 7 patients and in 4 had to be treated by operation. The follow-up after 5 years on average showed that functioning was good in all patients. Because the continent ileostomy gave minimal trouble in work, sport and social life, the patients' satisfaction was high. CONCLUSION: The continent ileostomy should be considered a good alternative to a terminal ileostomy, notably for patients in whom resection of a dysfunctioning ileoanal pouch will be performed. Continence can be preserved in this way, which is of great importance to the patient. PMID- 8692316 TI - [Squamous esophageal papillomas]. AB - In three patients, two women of 37 and 58 and a man of 68 years, a papillomatous lesion was incidentally detected in the distal part of the oesophagus. Microscopically a squamous papilloma was seen with parakeratosis and in two patients poikilocytosis, indicating an infection with human papilloma virus (HPV). The lesions were removed endoscopically, in one patient with laser photocoagulation. Squamous papillomas of the oesophagus are benign tumours with a very low incidence. The pathogenesis still remains unclear. Some authors suggest local irritation as a possible mechanism. On the other hand there is growing evidence of an aetiological role of HPV. In several studies the presence of viral antigen or DNA has been demonstrated. These papillomas may undergo malignant transformation, which means that they are best removed preventively. PMID- 8692317 TI - [Ethics and medical technology assessment]. PMID- 8692318 TI - [Problems in weaning of artificial ventilation: motor-neuron disease]. PMID- 8692319 TI - [Calcium antagonists: safe or unsafe?]. PMID- 8692320 TI - [Acute colectomy in toxic colitis: better too much than too little...]. PMID- 8692321 TI - [Optimal treatment with oral anticoagulants]. PMID- 8692322 TI - [Bone density measurement and prevention of fractures: who should be eligible?]. PMID- 8692323 TI - [Growth hormone and bone metabolism]. PMID- 8692324 TI - [Hereditary prostate carcinoma. National Work Group Hereditary Urological tumors. Foundation Tracing Hereditary Tumors]. PMID- 8692325 TI - [Multiple drug use by the elderly in need of care and nursing and possibility of reducing this practice]. AB - OBJECTIVE: To determine and evaluate the simultaneous use of multiple drugs in elderly people (aged > or = 65 years). DESIGN: Cohort study. SETTING: Region Rijnstreek, the Netherlands. METHOD: In 200 consecutive persons who were evaluated for admission to a hospice or a nursing home, and who used > or = 5 drugs simultaneously, the drug use was determined and evaluated according to published guidelines and on the premise that the use of drugs ought to be reduced. RESULTS: A total number of 1131 persons (mean age: 80.4 years (SD: 6.4)) were evaluated in two study periods (January 1993-February 1994 and March-October 1994). The 200 selected patients (17.7%) used a mean of 6.9 drugs (SD: 1.9). Evaluation of these pharmacotherapeutic regimens, abolishing drugs deemed redundant, interaction screening and checks on dosage showed a number of opportunities for improvement although only a slight reduction in the number of drugs could be achieved (to 5.3 (SD: 1.9)). CONCLUSION: In practice, systematic re-evaluation of actual pharmacotherapeutic regimens on a regular basis is necessary. The increasing possibilities for self-medication should be taken into consideration. PMID- 8692326 TI - [Phantom pain following leg amputation: retrospective study of incidence, therapy and the effect of preoperative analgesia]. AB - OBJECTIVE: Evaluation of (a) the incidence of phantom limb pain after a lower limb amputation, (b) the influence of either general or epidural anaesthesia on the incidence, and (c) the different kinds of therapies applied. DESIGN: Retrospective. SETTING: Department of Anaesthesiology, Academic Hospital, Vrije Universiteit, Amsterdam, the Netherlands. METHOD: All 45 patients who had undergone a lower limb amputation in the period 1985-1994, and whose amputation had taken place at least 6 months earlier received a questionnaire. The level of the phantom limb pain was measured using a Visual Analogue Scale. RESULTS: 33 Patients returned the questionnaire. 85% suffered from phantom limb pain; 20 patients were still suffering at the time of replying to the questionnaire. The pain sensation was mostly characterized as "cramping'. The physicians told 42% of the patients that nothing could be done to relieve the pain. Other patients were given all different kinds of therapies. The type of anaesthesia, general or regional anaesthesia, did not influence the incidence of phantom limb pain. CONCLUSION: After lower limb amputations there was a high incidence of long lasting phantom limb pain. Therapy showed a large variability and a considerable failure rate. Further research into prevention and treatment of phantom pain is urgently needed. PMID- 8692327 TI - [Myiasis caused by Dermatobia hominis]. AB - In two patients, a woman of 35 and a man of 62 years old, myiasis caused by the larvae of the fly Dermatobia hominis was diagnosed. Both patients had recently returned from a visit to Central America. This ectoparasitosis is found in Central and South America. Patients present themselves with an insect bite which fails to heal. If the clinical presentation is unknown, the disease may well be mistaken for furunculosis. The condition may be easily treated by applying vaseline to the insect bite, which causes extrusion of the larva. PMID- 8692328 TI - [From Dees to Borst: from modification to codification?]. PMID- 8692329 TI - [Quality improvement project 'Laboratory diagnosis by family physicians' leads to substantial reduction in number of laboratory analyses]. PMID- 8692330 TI - [Quality improvement project 'Laboratory diagnosis by family physicians' leads to substantial reduction in the number of laboratory analyses]. PMID- 8692331 TI - [Consensus 'Basic resuscitation' from the Nederlandse Reanimatie Raad]. PMID- 8692332 TI - [Consensus 'Basic Resuscitation' from the Nederlandse Reanimatie Raad]. PMID- 8692333 TI - [Hereditary diseases are family diseases]. PMID- 8692334 TI - [Neonatal osteomyelitis: a separate category as far as clinical picture and course are concerned]. PMID- 8692335 TI - [For the present Duchenne' disease should not be treated with prednisone]. PMID- 8692337 TI - [First aid in asphyxia]. PMID- 8692336 TI - [Role of chemotherapy in non-small cell lung carcinoma]. PMID- 8692338 TI - [Low incidence of non-Hodgkin lymphoma but high seroprevalence of HTLV-I in Curacao]. AB - OBJECTIVE: To determine whether the low incidence of non-Hodgkin's lymphoma (NHL) in Curacao has changed in comparison with the increase in incidence in many western countries, and to investigate the role of the HTLV-I infection that is endemic in the Caribbean area. DESIGN: Retrospective. SETTING: Curacao, Netherlands Antilles. METHOD: Retrospective file analysis in the only hospital in Curacao. RESULTS: During the period 1987-1992, 31 patients had a histologically confirmed diagnosis of NHL resulting in an annual incidence rate of 4.9/100,000 adults. There was a strong age-related increase in NHL incidence rate (0.5 for patients < 30 years to 17.8 for patients > or = 70 years), with a male to female ratio of I. (In the western world the incidence is 12-14, in the seventies it was 4.5 in Curacao.) Seven of 12 patients (58%) tested were seropositive for HTLV-I. Median survival was 6 months, despite conventional therapy. CONCLUSION: While HTLV-I infection can often be demonstrated in NHL patients in Curacao, NHL incidence has remained low over the past 25 years. PMID- 8692339 TI - [Relationship between duodenal diverticuli, gallstones and duodenal and pancreaticobiliary disorders]. AB - OBJECTIVE: To determine the relationship between duodenal diverticula and the prevalence of bile duct stones, and between duodenal diverticula and pancreatic pathology and/or duodenal inflammation. DESIGN: Retrospective descriptive study. SETTING: Department of Internal medicine, Division of Gastroenterology/Hepatology, University Hospital Maastricht. METHODS: The medical records were reviewed of 273 consecutive patients in whom an endoscopic retrograde cholangiopancreatography (ERCP) had been performed for the first time during the period 1991-1992. Clinical data such as previous history of cholecystectomy and ERCP findings such as presence of a duodenal diverticulum, its location (juxtapapillary or circumpapilary), and possible concomitant pancreaticobiliary disorders and/or duodenal inflammation were evaluated. RESULTS: Duodenal diverticula were present in 49 out of 273 patients (18%(: 30 patients with a juxtapapillary, 18 patients with a circumpapillary duodenal diverticulum and one patient with both types. A history of cholecystectomy was not reported more frequently in patients with a diverticulum than in those without. At the time of ERCP investigation, gallbladder stones were not diagnosed more frequently in diverticulum patients. A significantly higher prevalence of common bile duct stones was found in diverticulum patients than in those without (53% versus 22%, p = 0.001). Pancreatic pathology was not related to the presence of duodenal diverticula (p = 0.441). Furthermore. duodenitis and duodenal ulcers were significantly more prevalent in diverticulum patients than in those without (18% versus 7% for duodenitis, p = -0.049; 14% versus 2% for duodenal ulcers, p = 0.001). CONCLUSIONS: Duodenal diverticula were not only associated with common bile duct stones, but were also related to duodenitis and duodenal ulcers. Pancreatic pathology appeared not to be related to duodenal diverticula. PMID- 8692341 TI - [Choking due to 'flippos']. PMID- 8692340 TI - [Acanthamoeba keratitis]. AB - Three patients, women aged 69, 25 and 30 years, with refractory keratitis were found to have a rare infection with Acanthamoeba. All wore soft contact lenses. The frequency of Acanthamoeba keratitis increased in recent years. At present, an efficacious antiprotozoal therapy is available, for instance in the form of polyhexamethylene biguanide and propamidine. In cases of refractory keratitis, the possibility of an Acanthamoeba infection should be taken into account. PMID- 8692342 TI - [Basic subjects: a base for what?]. PMID- 8692343 TI - [Deep venous thrombosis: does recently improved knowledge lead to real advances in direct patient care?]. PMID- 8692344 TI - [Deep venous thrombosis: does recently improved knowledge lead to real advances in direct patient care?]. PMID- 8692345 TI - [Incidence of fever convulsions in 3-72-month-old children]. PMID- 8692346 TI - [Clinical judgment and decision making in clinical practice. A patient with diarrhea]. PMID- 8692347 TI - [Incarcerated inguinal hernia in a child: reduce it first]. PMID- 8692348 TI - [Hypophyseal growth hormone and Creutzfeldt-Jakob disease in The Netherlands. Ad hoc Commission Creutzfeldt-Jakob-disease of the Dutch Growth Foundation]. PMID- 8692349 TI - [Current regulations for reporting of side effects in The Netherlands after 1995]. PMID- 8692350 TI - [Drug monitoring]. PMID- 8692351 TI - [Post-polio syndrome; the limit of neuromuscular adaptation?]. PMID- 8692352 TI - [Clinical judgment and decision making. A patient with tetany]. PMID- 8692353 TI - [The Dutch poliomyelitis epidemic 1992/'93; invalidity and rehabilitation]. AB - OBJECTIVE: To describe epidemiologic characteristics and neurological and functional recovery of the victims of the 1992/'93 Dutch poliomyelitis epidemic compared to the 1971 and 1978 epidemics. DESIGN: Descriptive research. SETTING: Rehabilitation Centre 'De Hoogstraat', Utrecht, The Netherlands. METHODS: Two written questionnaires were sent out: one to the doctors attending the 71 registered patients five months after the end of the epidemic, the second 30 months after the end of the epidemic to the doctors of the patients with initial neurological impairments. Once every three months, muscular strength (MRC criteria), activities of daily life (ADL; using the Functional Independence Measure) and mobility (according to Hoffer) were assessed for 13 adult patients with moderately severe and severe disabilities. RESULTS: The questionnaire response was 100%. The median age increased from 5-9 years in 1971 to 10-14 years in 1978 to 20 years old in 1992/'93. Due to the 1992/'93 epidemic adults ( > or = 20 years) had more moderately severe and severe sequelae than people below 20 years of age (p < 0.00I). In the 1978 epidemic these differences were not significant. Muscular strength improved until 30 months after the onset of the disease although no improvement was seen in 10/13 patients after 18 months. The ability to cope independently with the ADL improved until 18 months; ten patients became almost independent. Mobility improved until 12 months. Three patients remained wheelchair bound, 1 became an exercise walker, 5 household walkers and 4 community walkers. CONCLUSION: Poliomyelitis is no longer a paediatric disease in the Netherlands. In future epidemics it should be borne in mind that most disablement probably will occur among adults. After an attack of acute poliomyelitis, muscular strength can continue to improve for up to two and a half years, while ADL usually remain stable after one and a half years and mobility after one year. PMID- 8692354 TI - [Many chronic problems in CVA patients at home]. AB - OBJECTIVE: To find out what the late implications of a stroke were for patients and relatives and whether specific requests for help existed. DESIGN: Cross sectional study. SETTING: Academic Hospital Nijmegen, department of Neurology and Sint Maartenskliniek (rehabilitation centre), The Netherlands. METHOD: Patients who had sustained a cerebrovascular accident (CVA) in the last five years were asked, using the sickness impact profile (SIP), about their subjective functioning and the effect of the CVA on daily life. They were also asked about the degree to which they experienced their complaints as a problem, and whether they needed help. RESULTS: In this study 165 patients and their close relatives filled out the SIP. Stroke had a very high impact on everyday functioning as indicated by a total SIP score of 20. The results further showed that psychosocial problems arise independently of the degree of physical problems, that these problems were chronic, and that psychosocial problems hindered 52% of the patients often to always. The physical problems hindered 60% of them often to always. A third of the patients wanted help for their physical problems, a quarter for their psychosocial problems. CONCLUSION: The impact of stroke on both patients and their relatives was extensive and appeared chronic. There was need for physical and psychosocial help in a third or quarter of the cases. PMID- 8692355 TI - [Pustular dermatitis in veterinarians following delivery in domestic animals; an occupational disease]. AB - OBJECTIVE: To assess the prevalence of contact dermatitis after deliveries in cattle or sheep among veterinarians. DESIGN: Retrospective. SETTING: Provinces of Groningen, Friesland and Drenthe, The Netherlands. METHODS: By means of a short inquiry 31O veterinarians were asked whether and how often they had experienced pustular dermatitis after deliveries in cattle and sheep and what course the dermatitis had run. They were also asked about details of the deliveries (type of animal, condition of the foetus, course of the partus), about microbiological investigation, preventive measurements and therapy. RESULTS: The response to the questionnaires was 24.5%. One or more episodes of pustular dermatitis on an arm after a delivery in cattle or sheep was noticed by 6(2) (81.5%) of the 7(6) respondents. Sometimes it was associated with secondary symptoms like headache, fever and lymphadenitis. Listeria monocytogenes (7 times out of 13) and Salmonella dublin (4/13) were the agents cultured most often. CONCLUSION: Contact dermatitis after deliveries in cattle or sheep occurs frequently as an occupational disease of veterinarians. PMID- 8692356 TI - [A patient with Creutzfeldt-Jakob disease following treatment with human growth hormone]. AB - In a 39-year old woman Creutzfeldt-Jakob disease was diagnosed. More than twenty years prior to the first clinical symptoms she had been treated with human pituitary growth hormone. After four months of illness she died of Creutzfeldt Jakob disease, as was shown by the post-mortem finding of spongiform encephalopathy immunochemically positive for abnormal prion protein. The patient represented the first case of Creutzfeldt-Jakob disease associated with the use of human growth hormone in the Netherlands. PMID- 8692357 TI - [Further use of human tissues: toward a balanced regulation]. PMID- 8692358 TI - [Post-marketing surveillance]. PMID- 8692359 TI - [Post-marketing surveillance]. PMID- 8692360 TI - [Post-marketing surveillance]. PMID- 8692361 TI - [Dog bites: publications on risk factors, infections, antibiotics and primary wound closure]. PMID- 8692362 TI - [Cause of death of Amsterdam children who died abroad 1992-1993; possibilities for prevention]. PMID- 8692363 TI - Physician assisted suicide, or be careful in which state you vacation in the next 12 months. PMID- 8692364 TI - Managed care: a view from the consumer. PMID- 8692365 TI - Cat bites in primary care: a case report. PMID- 8692366 TI - [Clinical application of functional mapping; the present state of the art and its future prospects: (series 4) noninvasive functional mapping of the brain with near-infrared spectroscopy]. PMID- 8692367 TI - [Lumbar discectomy: anatomical review and surgical techniques]. PMID- 8692368 TI - [Establishment of the criteria to evaluate intraoperative changes of brainstem auditory evoked potentials during microvascular decompression and acoustic neurinoma excision]. AB - Although monitoring of brainstem auditory evoked potentials (BAEP) is helpful to preserve hearing during operations in the cerebellopontine angle such as microvascular decompression and excision of an acoustic neurinoma, criteria for what and when changes in BAEP should be communicated to the surgeon have not been well established. An exhaustive review was, therefore, conducted of the English and Japanese literature on this topic. Analysis of the results of this literature review led to the conclusion that during a microvascular decompression procedure, the surgeon should be warned as soon as progressive prolongation of the latency of wave V of the BAEP exceeds 1.5 msec. It is reasonable to apply stricter criteria in acoustic neurinoma excision; prolongation of wave V latency even less than 0.5 msec should be regarded as the warning sign to the surgeon who is trying to preserve hearing. Whenever BAEP monitoring is performed, it is crucial that changes in the BAEP are evaluated in light of the particular surgical procedure in progress and that the person who evaluates these changes is well versed in the conduct of the surgical procedure. PMID- 8692369 TI - [Necessity for searching for cerebral aneurysm in thunderclap headache patients who show no evidence of subarachnoid hemorrhage: investigation of 8 minor leak cases on operation]. AB - The study included 562 patients with headache who visited our clinic from January 1988 to December 1993. In these patients, the possibility of subarachnoid hemorrhage was denied from CT findings and color of cerebrospinal fluid by lumbar puncture. Cerebral aneurysm was found in 52 out of 562 patients (9.3%), and minor leak was found during 46 surgery cases in 8 patients with cerebral aneurysm. These 8 patients (32-51 years old, 5 males and 3 females, period from onset to hospital visit; 1-6 days) were examined concerning characteristics of headache and concomitant symptom, cerebrospinal fluid and operative findings. Headache attack occurred at rest in 6 patients (75%) and suddenly in all patients. It continued over 24 hours in 7 patients (87.5%). All patients felt that they had never experienced such a headache. Pulsating headache was observed in 5 patients (62.5%). Nausea and vomiting were complications in all patients. The site of headache was in the forehead region, and circumorbital pain was a complication in four patients. Six patients (75%) had unilateral pain, and 5 patients (62.5%) had headache at the same side as the cerebral aneurysm. Increase of cell count ( > or = 10/mm3) in cerebrospinal fluid was found in 4 patients (50%). In all cases, lymphocytes were dominant. Arachnoid adhesion and hypertrophy with hemorrhage were found during surgery in 4 patients (50%). In these patients, the period from onset to surgery (average 16.5 days) was longer than that of the patients with hemorrhage alone (average 6 days). The site of the hemorrhage was located in the cistern of the cerebral aneurysm in all cases. In patients suffering sudden headache, screening for cerebral aneurysm should be thoroughly performed though early findings on CT and cerebrospinal fluid indicated no abnormalities. PMID- 8692370 TI - [Vertebral artery dissection without subarachnoid hemorrhage studied by serial angiography]. AB - We presented six cases we have encountered of vertebral artery dissection without subarachnoid hemorrhage followed by serial angiography. All six patients suffered from severe headache and/or nuchal pain at onset. Pain was acute at onset, with severe intensity and sharp quality and was located unilaterally on the dissection side. Only two patients showed neurological deficits. CT scan disclosed no abnormalities in any of the cases and angiography performed at the acute stage showed varied findings. The so-called pearl and string sign, which has been considered the most common finding of this disorder, was observed in only two cases. The definite diagnosis was able to be finally made by serial angiography. During the first few months after onset, dynamic changes of angiographical findings were demonstrated in all cases. During these periods, although transient deterioration of the angiographical findings was shown in four cases, spontaneous healing or improvement was finally recognized in all cases except one which progressed to total occlusion. In contrast to this, in the chronic stage, no changes of angiographical findings occurred in any of the cases. All six patients were treated non-surgically. All showed almost total recovery from symptoms and returned to their previous life styles. There were no cases of recurrent deterioration of symptoms in spite of the changes indicated by the angiographical findings. Our experience with these patients suggests that the actual incidence of vertebral artery dissection without subarachnoid hemorrhage may be much higher than is usually thought, and that the natural course of this disorder seems to be usually favorable. However, longer follow-up study and an analysis of a larger number of cases are required to identify the true incidence and the natural course of this disorder. In addition, we would like to emphasize that accurate diagnosis is most important. If it is clinically suspected, careful investigations including serial angiography should be carried out for the diagnosis of this disorder. PMID- 8692371 TI - [Traumatic atlanto-occipital dislocation: a case report with survival]. AB - We reported a case of a patient who survived anterior atlanto-occipital dislocation. A seven-year-old girl was admitted to our hospital due to disturbed consciousness after being involved in a traffic accident. With gradual improvement of consciousness, she showed bilateral abducens nerve palsy, quadriparesis and cervical instability. Lateral plain film showed anterior atlanto-occipital dislocation. MRI showed severe compression of the cervical cord and disruption of supporting ligaments of the cervicomedullary junction. After 4 months, cervical instability continued and posterior fixation was carried out with bone grafts. Her postoperative course was uneventful. PMID- 8692372 TI - [Posterior fossa dural arteriovenous fistula with progressive disorder of cerebellar circulation; case report]. AB - A rare case of posterior fossa dural arteriovenous fistula with cerebellar circulation disorder is reported. A 64-year-old male was admitted to a hospital with complaints of nausea, vertigo and mild headache. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed cerebellar infarction. Then, he was sent to our hospital. He had complaints of cerebellar signs and nystagmus. Cerebral angiography showed dural AVF of the posterior fossa and occlusion of the left transverse-sigmoid sinuses. Because his condition deteriorated, embolization of the left middle meningeal artery, ascending pharyngeal artery and occipital artery was performed selectively on August 18. Subsequently, isolation of dural AVF was performed on August 19. After the operation he improved and was able to walk with a stick. Controlled angiography revealed the disappearance of dural AVF. This case suggested that AV shunt is essential for the progression of venous infarction. PMID- 8692373 TI - [A case of Jefferson fracture treated with the Sof'wire cable system method of fixation]. AB - Jefferson fracture is a very rare disease which occurs in only 2-13% of all cervical spinal fracture cases and in only 1.3% of total spinal fracture cases. A combination of an atlas-axis fracture occurs relatively frequently and with a higher incidence of neurological morbidity than isolated fractures. However, a Jefferson fracture, which is an isolated C-1 fracture, occurs very rarely. A 58 year-old woman was involved in a traffic accident and admitted to our hospital. She had a large scalp laceration in the parietal region and complained of nuchal pain. Neurological examination revealed nothing abnormal. A cervical x-p (lateral view) revealed no abnormal findings, but an open-mouth view revealed an 8 mm displacement (in total) in the lateral mass of the atlas. A cervical CT revealed a Jefferson fracture. Crutchfield traction was performed for 9 days followed by external immobilization with a halo-vest to allow the patient to be ambulatory quickly. A posterior occipitocervical fusion was performed with an iliac bone autograft using the Sof'wire Cable system for late cervical stability and reducing the period of rigid external immobilization. The postoperative state was uneventful. The halo-vest was removed 10 weeks after surgery. An x-p obtained 3 months postoperatively showed good stability of the cervical spine. The Sof'wire Cable system proved to be very useful. PMID- 8692374 TI - [A case of metastatic choriocarcinoma associated with cerebral thrombosis and aneurysmal formation]. AB - A rare case of metastatic choriocarcinoma with cerebral thrombosis and subsequent neoplastic aneurysm formation and rupture is reported. Three months after normal pregnancy and normal delivery, a 16-year-old woman was admitted with the chief complaints of speech disturbance and paresthesia of her right upper extremity on June 4, 1992. Both CT and MRI demonstrated cerebral infarction in the left insula. A cerebral angiogram revealed that the left middle cerebral artery (about 2 mm in diameter) was occluded in the distal M2 segment. On the 34th day, a follow up angiogram demonstrated a fusiform aneurysm at the same point of the arterial occlusion that had been already recanalized. On the 37th day, she suddenly had severe headaches and consciousness disturbance. CT showed subarachnoid hemorrhage. Resection of the aneurysm and left STA-MCA anastomosis were performed. Histological examination revealed that the aneurysmal walls were invaded by choriocarcinoma. On the 60th day, she was transferred to the department of obstetrics and gynecology for chemotherapy. On the 65th day and the 71st day, the patient suffered from intracerebral hemorrhage in the left basal ganglia, which originated from a different point of aneurysmectomy. She died because of the rapid growth of liver metastases 7 months after initial admission. Because chest CT and roentgenogram detected no lesion in the lungs, neoplastic embolus was unlikely as a cause of occlusion of the cerebral artery of about 2 mm in diameter. It would be more reasonable to believe that choriocarcinoma metastasized to the cerebral arterial walls initially and formed a thrombus which occluded the artery. As the neoplastic invasion weakened the arterial wall, a fusiform aneurysm was formed when the vessel was recanalized. There has been no case reported in the literature of neoplastic aneurysms of choriocarcinoma in which the course from aneurysmal formation to rupture was followed angiographically. PMID- 8692375 TI - [A case of de novo aneurysm of the distal posterior inferior cerebellar artery with intraventricular hemorrhage]. AB - A case is presented of a de novo aneurysm of the distal posterior inferior cerebellar artery with intraventricular hemorrhage. A 67-year-old woman was admitted to our hospital with sudden onset of severe headache and loss of consciousness. Computed tomography (CT) scans showed subarachnoid hemorrhage. Angiography demonstrated three aneurysms: an aneurysm of the right vertebral posterior inferior cerebellar artery, an aneurysm of the bifurcation of the basilar artery, and an aneurysm of the left middle cerebral artery. Considering the distribution of the hemorrhage on CT scans, we concluded that the cause of the hemorrhage was rupture of the vertebral-posterior inferior cerebellar aneurysm. The vertebral-posterior inferior cerebellar aneurysm and the middle cerebral aneurysm were successfully clipped, postoperative angiograms showing the complete clippings. At that time, however, there were no abnormal findings in the left posterior inferior cerebellar artery. Six years later, she was readmitted to our hospital because of sudden onset of headache, nausea, and vertigo. CT scans showed an intraventricular hemorrhage, especially in the fourth ventricle, although subarachnoid hemorrhage was not clearly found. Angiography revealed an aneurysm of the left distal posterior inferior cerebellar artery. She underwent clipping of the aneurysm verified by postoperative angiograms. However she had bacterial meningitis and died from pneumonia and disseminated intravascular coagulopathy. De novo aneurysms of the anterior circulation have often been reported. Carotid, ligation, smoking, the use of oral contraceptives, congenital anomalies and hypertension are major risk factors in the formation of aneurysms. A de novo aneurysm of the distal posterior inferior cerebellar artery is, however, extremely rare. In this case, the right posterior inferior cerebellar artery disappeared when the de novo aneurysm was found. So it is supposed that hemodynamic changes caused by the clipping of the right vertebral-posterior inferior cerebellar aneurysm and the left middle cerebral aneurysm had contributed to the formation of the de novo aneurysm of the left distal posterior inferior cerebellar artery. In the present study, we review the literature on the aneurysm at the distal posterior inferior cerebellar artery and on the de novo aneurysm of the vertebrobasilar artery, and discuss the radiological findings and features. PMID- 8692376 TI - [A case of pituitary adenoma progressing to pituitary apoplexy on the occasion of cerebral angiography]. AB - A case of pituitary adenoma which had progressed from subclinical pituitary apoplexy to subacute pituitary apoplexy on the occasion of cerebral angiography is reported. A 29-year-old man, complaining of bitemporal hemianopsia, was admitted to our department. Plain skull X-p revealed enlargement and double floor of the sella turcica. No abnormal calcification was revealed. CT demonstrated an isodensity mass with a diameter of 4 x 4 cm, and with ring enhancement in the suprasellar region. The mass extended from the intrasellar region to the suprasellar region and had a signal of high intensity on T1-weighted images. Endocrinological examination revealed hyperprolactinemia with a serum level of 422 ng/ml and normal reaction of anterior pituitary hormones. On 3rd March, digital subtraction angiography with 5F catheter was performed with the patient under sedation. The contrast medium was ioxaglic acid (Hexabrix 320). A volume of 6 ml with a speed of 4 ml per second was injected for the internal carotid angiogram. A total volume of 60 ml was used. Serum saline with 10 unit per ml of heparin sodium was also used for flushing. During angiography, the patient's blood pressure was 125/60-115/60mm Hg. DSA revealed upward displacement of the proximal portion of the anterior cerebral artery, pocket formation, and staining of the tumor capsule. Six hours later, he complained of retroorbital headache. Next morning, he noticed complete lack of left visual acuity. On 7th March, right visual acuity degenerated to blindness. CT revealed that the mass had increased its density. With bifrontal osteoplastic craniotomy, the tumor with marked intratumoral hemorrhage was resected. Its histology was chromophobe adenoma. The patient's right visual acuity improved rapidly. On the occasion of cerebral angiography, we could observe that subclinical pituitary apoplexy deteriorated to subacute pituitary apoplexy. Rosenbaum postulated that injection of contrast media increased intravascular pressure leading to pituitary apoplexy. At present, we cannot postulate increased intravascular pressure with 5F catheter and DSA. We cannot rule out that, with underlying subclinical pituitary apoplexy, hemorrhagic infarction due to contrast media and the anti-coagulate effect of heparin sodium accelerated the intratumoral bleeding. Subclinical pituitary apoplexy is a vulnerable state because of its aggravation to symptomatic apoplexy under mild stress. We emphasize that an operation should be performed as early as possible in the case of subclinical pituitary apoplexy. PMID- 8692377 TI - [Usefulness of neoadjuvant brachytherapy in the treatment of pineoblastoma: a case report]. AB - The treatment strategy and prognosis of pineal cell tumors are still subjects of debate because of their rarity and the mixture of pineoblastoma and pineocytoma as components. Pineoblastoma is believed to be the more malignant tumor and total gross resection of this tumor is very difficult because of its invasive tendency and location. Although the effectiveness of external irradiation and chemotherapy has been reported, the outlook for patients with this tumor is extremely poor. We treated a case of pineoblastoma with a single total resection nine months after interstitial irradiation and chemotherapy. In this case, brachytherapy was successful as neoadjuvant therapy for decreasing the tumor's volume and clarifying its boundary. The patient was a 36-year-old woman who had complained of occipital headache for about a month. On admission, neurological examination revealed bilateral papilloedema but, otherwise, there were no deficits. A magnetic resonance image (MRI) showed a homogeneously enhanced tumor in the pineal region and obstructive hydrocephalus. Two weeks after ventriculo peritoneal shunting, a stereotactic needle biopsy was performed using a BRW MRI guided stereotactic apparatus, and three catheters for interstitial brachytherapy were implanted into the tumor through the biopsy tract. Iridium-192 seeds were inserted through the catheters and kept there for 8 days to irradiate 40 Gy at the tumor periphery. Four courses of chemotherapy with carboplatin (400 mg/m2) and VP-16 (400 mg/m2) were administered after brachytherapy. Repeat MRI scans every month showed a gradual regression of tumor volume. However, the tumor did not disappear and no further decrease in tumor volume was observed 8 months after brachytherapy. A suboccipital craniotomy was performed 9 months after brachytherapy and en bloc tumor resection was achieved readily via an infratentorial supracerebellar approach. After receiving another course of chemotherapy and external irradiation at 40 Gy, the patient was discharged without any symptoms and no residual tumor or recurrence was observed for 24 months after brachytherapy and 15 months after surgery. The clinical course of this case suggests that a combination of stereotactic biopsy and brachytherapy with chemotherapy followed by surgery may be a good strategy for the treatment of pineal cell tumors regardless of their histopathological features. PMID- 8692378 TI - [A case report of chronic encapsulated intracerebral hematoma]. AB - Chronic encapsulated intracerebral hematoma is a rare clinicopathological entity. The authors reported a case of a 52-year-old male who presented with progressive sensory disturbance of the left extremities three weeks prior to admission. Plain CT and MRI scans revealed a subcortical mass in the right temporal lobe associated with extensive peritumoral edema and intratumoral hemorrhage (mixed intensity on T1WI, low intensity on T2WI). There was a ring-like enhancement with GdDTPA. These findings strongly suggested metastatic melanoma associated with intratumoral hemorrhage. During the operation, the mass appeared partly at the surface of the brain and was easily extirpated totally. Histologically, the specimen showed chronic encapsulated hematoma with a thick, fibrous capsule and there was no evidence of neoplasm. The postoperative course was uneventful and follow up CT scan showed disappearance of the mass and the surrounding edema. The relevant literature was reviewed, and the pathogenesis of this entity was discussed. PMID- 8692379 TI - The Richard C. Schneider Lecture. New dimensions of neurosurgery in the realm of high technology: possibilities, practicalities, realities. AB - Fueled by a buoyant economy, popular attitudes and demands, and parallel progress in transferable technical and biological areas, neurosurgery has enjoyed a remarkable quarter of a century of progress. Developmental trends in the discipline have included the following: 1) a refinement of preoperative definition of the structural substrate, 2) miniaturization of operative corridors, 3) reduction of operative trauma, 4) increased effectiveness at the target site, and 5) incorporation of improved technical adjuvants and physical operative tools into treatment protocols. In particular, the computer has become a formidable ally in diagnostic and surgical events. Trends in technical development indicate that we are entering an exciting era of advanced surgery of the human cerebrum, which is heralded by the following: 1) current developments in areas of imaging, sensors, and visualization; 2) new devices for localization and navigation; 3) new capabilities for action at the target point; and 4) innovative concepts related to advanced operative venues. Imaging has provided structurally based surgical maps, which now are being given the new dimension of function in complex and integrated formats for preoperative planning and intraoperative tactical direction. Cerebral localization and navigation based on these advances promise to provide further refinement to the field of stereotactic neurosurgery, as linked systems are superseded by more flexible nonlinked methodologies in functionally defined volume-oriented navigational databases. Target point action now includes not only ablative capabilities through micro operative methods and the use of stereotactically directed high-energy forms but also the emergence of restorative capabilities through applications of principles of genetic engineering in the areas of molecular and cellular neurosurgery. Complex, dedicated, and self-contained operative venues will be required to optimize the emergence and development of these computer-oriented micro/stereotactic capabilities, which appear to be unavoidably required as locales for the practice and development of virtual reality-based stations for operative rehearsal, simulation, training, and, ultimately, enhancement of operative events through robotic interfaces. Primary impetus for progress has relied upon new combinations of technologies, disciplines, and industries. Philosophical and practical problems include the spectrum of availability of these methods to the population at large, the training of individuals to properly administer these methods, defining the acceptable envelope of expertise, and maintaining suitable delivery and progress while containing spiraling costs. Advanced neurological surgery and the use and development of high-technology adjuvants require a robust economy that has a populace willing to invest in the luxury of such developments. The current socioeconomic situation is fragile from the standpoint of both economics and attitudes of the patients and health care providers, with diversion of economic resources, redistribution of funding bases, modification of patient referrals, practice styles, and service attitudes undermining progress. Economic pressures have brought high-technology methods under great scrutiny regarding their effectiveness and cost-effectiveness. Reform proposals have specifically targeted technology-oriented services, and the Office of Technology Assessment has recommended increasing the use of managed care providers who look to information on cost-effectiveness and clinical practice guidelines to establish efficient management strategies and issue "report cards." Although the premise is laudable and "gimmickry" needs to be identified, it might be argued that such scrutiny and control might be overbearing and overused, impeding appropriate delivery and progress. PMID- 8692380 TI - Computer-assisted interactive three-dimensional planning for neurosurgical procedures. AB - We have used three-dimensional reconstruction magnetic resonance imaging techniques to understand the anatomic complexity of operative brain lesions and to improve preoperative surgical planning. We report our experience with 14 cases, including intra- and extra-axial tumors and a vascular malformation. In each case, preoperative planning was performed using magnetic resonance imaging based three-dimensional renderings of surgically critical structures, such as eloquent cortices, gray matter nuclei, white matter tracts, and blood vessels. Simulations, using the interactive manipulation of three-dimensional data, provided an efficient and comprehensive way to appreciate the anatomic relationships. Interactive three-dimensional computer-assisted preoperative simulations provided otherwise inaccessible information that was useful for the surgical removal of brain lesions. PMID- 8692381 TI - Hemorrhage risk after stereotactic radiosurgery of cerebral arteriovenous malformations. AB - To analyze the effect of stereotactic radiosurgery on the hemorrhage rate of arteriovenous malformations (AVMs), we reviewed the clinical and angiographic characteristics of 315 patients with AVMs before and after radiosurgery. One hundred ninety-six patients sustained 263 bleeds in 10,939 patient-years before radiosurgery, for an annual nonfatal hemorrhage rate of 2.4%. Clinical follow-up after radiosurgery was available in 312 patients (mean, 47 +/- 20 mo); follow-up > or = 24 months was obtained in 295 patients (94%). Twenty-one patients had AVM bleeds at a median of 8 months (range, 1-60 mo) after radiosurgery. Two additional patients had three aneurysmal bleeds (at 5, 27, and 32 mo, respectively) for a 7.4% total risk of hemorrhage per patient. The actuarial hemorrhage rate until AVM obliteration was 4.8% per year (95% confidence interval, 2.4-7.0%) during the first 2 years after radiosurgery and 5.0% per year (95% confidence interval, 2.3-7.3%) for the third to fifth years after radiosurgery. Multivariate analysis of clinical and angiographic factors demonstrated that the presence of an unsecured proximal aneurysm was associated with an increased risk of postradiosurgical hemorrhage (relative risk, 4.56; 95% confidence interval, 1.77-11.70%; P < 0.001). No AVM hemorrhages were observed after radiosurgery in seven patients with intranidal aneurysms. No protective effect against hemorrhage was observed in patients who received an "optimal" radiation dose (> or = 25 Gy to the AVM margin) compared with patients who received < 25 Gy to the AVM margin (P = 0.36). No patient suffered a hemorrhage after angiography had confirmed complete obliteration (n = 140) or suffered from an early draining vein without residual nidus (n = 19). Stereotactic radiosurgery was not associated with a significant change in the hemorrhage rate of AVMs during the latency interval before obliteration. No protective benefit was conferred on patients who had incomplete nidus obliteration in early (< 60 mo) follow-up after radiosurgery. AVM patients with unsecured proximal aneurysms should have aneurysms obliterated either before radiosurgery or at the time of surgical resection of their AVMs. PMID- 8692382 TI - Growth, subsequent bleeding, and de novo appearance of cerebral cavernous angiomas. AB - In a series of 145 patients with brain cavernous angiomas treated at our hospital in the last 16 years, the angiomas of 18 patients exhibited aggressive biological behavior characterized by recurrent overt bleeding, growth, or de novo appearance. The cavernomas were in the cerebellum in three patients, in the brain stem in one, in the thalamus in four, in the caudate nucleus in two, in the diencephalon in one, and in the white matter of the cerebral hemispheres in seven. Three of these patients suffered from the familial or multiple form of the disease, two were pregnant, three had previously been irradiated for other tumors, and one had been treated by radiosurgery in the past. Overall, new cavernous malformations not previously shown were discovered in six patients. In 10 patients (3 male and 7 female) presenting with recurrent hemorrhages, the mean period of time between bleedings was 11 months (range, 1 wk-3 yr). Eleven patients were treated by definitive surgery, and seven were conservatively treated. One patient with a diencephalic cavernoma died from progressive hypothalamic dysfunction; three patients in the nonsurgical group had repeated symptoms and were left with additional neurological deficits. The outcome of the surgical group was the same (seven patients) or improved (four patients). Risk factors favoring an aggressive behavior included pregnancy, familial or multiple form of the disease, previous whole brain or stereotactic radiotherapy, incomplete removal, brain location, and associated venous malformation. The female preponderance (female to male ratio, 13:5) may also suggest some role of hormonal factors in influencing the biological behavior of cavernous malformations. PMID- 8692383 TI - Treatment of scalp arteriovenous malformation. AB - We report seven patients with scalp arteriovenous malformations, including two patients with lesions > 10 cm in diameter, who were successfully treated. The principal complaint of each patient was a deforming mass. Each of four patients had a history of blunt traumatic injury. The lesions, each consisting of the nidus, feeders, and draining veins, evolved in all patients. The nidus consisted of fistulae, which exhibited various angioarchitectures as revealed by angiography. A hemangiomatous component was histologically recognized in one patient. In five patients, in whom the lesions were relatively small and whose nidi included only large fistulae, the malformations were remedied by surgical intervention alone or were cured with embolization alone using liquid adhesives. In the two patients with lesions > 10 cm, the nidi consisted of numerous large fistulae and plexiform fistulae in one patient and plexiform fistulae and a hemangiomatous component in the other patient. These patients were treated with a combination of transarterial embolization and surgical intervention. Preoperative embolization greatly reduced blood loss during resection. Total excision and scalp reconstruction using a soft tissue expander were performed in both patients. The cosmetic results were excellent in all of the patients, and no recurrence has been recognized during the follow-up period, which ranges from 31 to 99 months. The treatment of scalp arteriovenous malformations should strive to improve deforming features and to attain a permanent cure. Because each nidus includes a variety of anomalous angioarchitectural features, there should be different means and a combination of treatments for each patient. Embolization alone could be adequate treatment in relatively small lesions, the nidi of which consist only of several large fistulae. For malformations with more extensive, large fistulae or with anomalous components other than large fistulae, a combined endovascular and surgical approach and scalp reconstruction seems to be the best treatment. PMID- 8692384 TI - Functional cortex and subcortical white matter located within gliomas. AB - Some neurosurgeons state that intra-axial tumors may be resected with a low risk of neurological deficit if the tumor removal stays within the confines of the grossly abnormal tissue. This is thought to be so even when the lesion is presumably located in a functional area, providing that the adjacent normal appearing cortex and subcortical white matter are not disturbed. This retrospective analysis presents evidence that this view is not always correct, because functioning motor, sensory, or language tissue can be located within a grossly obvious tumor or the surrounding infiltrated brain. Intraoperative stimulation mapping techniques identified 28 patients, ranging in age between 22 and 73 years, who showed evidence of functional tissue within the boundaries of infiltrative gliomas, as identified by correlation with computed tomography and magnetic resonance imaging scans, intraoperative ultrasound, gross visualization, and histological confirmation. Direct stimulation mapping of cortical and subcortical portions of the tumor during resections identified motor, sensory, naming, reading, or speech arrest function. Nineteen patients had new or worsened neurological deficits immediately after the operation, but after 3 months, only 6 continued to show new deficits whereas 18 showed no deficits and 2 improved. These results demonstrate that regardless of the degree of tumor infiltration, swelling, apparent necrosis, and gross distortion by the mass, functional cortex and subcortical white matter may be located within the tumor or the adjacent infiltrated brain. Therefore, to safely maximize glioma resection in these functional areas, intraoperative stimulation mapping may be used to identify functional cortical or subcortical tissue within, as well as adjacent to, the tumor, thus avoiding permanent injury. PMID- 8692385 TI - Recurrence of hemifacial spasm after microvascular decompression. AB - The success of medical and surgical treatment for hemifacial spasm, and involuntary paroxysmal unilateral contraction of the facial muscles, has been mixed. Although microvascular decompression has the greatest reported success, symptom recurrence affects many patients in whom treatment was initially successful. In this study, we report the results of 34 patients who underwent microvascular decompression of the facial nerve from 1976 to 1989 as well as review the literature concerning the incidence and timing of recurrence in more than 600 patients who underwent microvascular decompression. In this series, 94% of 34 patients had continuous relief of spasm after surgical treatment (mean duration, > 6 yr). Of those patients whose spasms were completely initially relieved, 10.3% developed some degree of recurrent spasm; however, no patient developed a recurrence after 24 months without spasm. Our review of the literature discloses that 86% of all recurrences occurred within 2 years of surgery. Patients who have no recurrence of symptoms 2 years after surgical treatment have only a 1% chance of developing recurrent hemifacial spasm. We also comment on possible causes of treatment failure and recurrence of hemifacial spasm after surgical treatment. PMID- 8692386 TI - Surveillance imaging in children with primitive neuroectodermal tumors. AB - Controversy surrounds the benefits of routine surveillance magnetic resonance or computed tomographic imaging for monitoring children after resection of primitive neuroectodermal tumors. A recent study suggested that serial imaging studies detect only a small minority of tumor recurrences in patients with symptoms. The authors concluded that even in patients with recurrence documented by imaging, no patient with a recurrence survived long (average, 5 mo) and that surveillance scanning is of little clinical value in children with primitive neuroectodermal tumors. We reviewed our experience with 25 patients (28% of our total series) who presented to the Children's Hospital Los Angeles, Los Angeles, CA, from 1985 to 1993 with recurrent tumors after surgery and adjuvant therapy. Recurrent tumors were detected on routine imaging in 19 asymptomatic patients (76%) and in 6 symptomatic patients (24%). Recurrences were documented 15 months (mean) after the initial diagnosis in asymptomatic children and 5 months (mean) after the initial diagnosis in children with symptoms of recurrent tumor (P < or = 0.01). Asymptomatic patients with recurrence documented on serial imaging had prolonged survival when compared with those who were symptomatic (P < or = 0.05). The surviving patients with recurrence remained alive for more than 24 months after documentation of recurrence. Early detection of local tumor recurrence by surveillance scanning may provide a critical therapeutic window for successful treatment with aggressive or novel therapies. PMID- 8692387 TI - Stereotactic radiosurgery for glial neoplasms of childhood. AB - We evaluated the role of stereotactic radiosurgery (SRS) in 25 children with surgically incurable brain tumors of glial origin. Histological diagnoses were obtained at the time of craniotomy and attempted removal (n = 20) or by stereotactic biopsy (n = 5). Thirteen children had tumors with benign histological characteristics (pilocytic and low-grade astrocytomas), whereas 12 children had tumors with malignant characteristic (malignant astrocytomas and ependymomas). Eleven (10 with malignant tumors) of the 25 children had received fractionated irradiation before SRS. Radiosurgical doses (range to margin, 11-20 Gy) were calculated on the basis of tumor volume and location, with consideration given to prior radiation dose. Follow-up for the 13 children with benign tumors ranged from 6 to 48 months (median, 21 mo). Eleven of the 13 children with "benign" glial neoplasms had tumor control with SRS alone (no evidence of tumor, n = 4; decreased tumor, n = 5; and unchanged tumor, n = 2), and all 13 remain alive. Five children with malignant tumors are alive at 12, 45, 50, 72, and 72 months after radiosurgery. The other seven children with malignant tumors are dead, with a median survival of 6 months after radiosurgery. Three of 12 children with malignant glial neoplasms had tumor control after SRS. Two of these three children received fractionated irradiation as an adjunct to SRS. Complications occurring in four children were transient, associated with peritumoral edema, and responsive to oral glucocorticoids. There was no relationship between tumor volume and local control after radiosurgery. Radiosurgery alone is a safe and effective treatment modality for unresectable benign gliomas of childhood. Radiosurgery may have a role in the adjuvant management of unresectable malignant glial neoplasms of childhood if other therapies (irradiation or chemotherapy) are available. PMID- 8692388 TI - The effect of early craniocervical decompression on functional outcome in neonates and young infants with myelodysplasia and symptomatic Chiari II malformations: results from a prospective series. AB - The indications for hindbrain decompression in neonates and young infants with spinal dysraphism who experience brain stem dysfunction in association with Chiari II malformations have remained controversial. This largely reflects the fact that the postoperative outcome in such patients has often been poor, which has supported the belief that much of the brain stem compromise in these patients is congenital and inherently irreversible. However, in a previous retrospective review of our operative results between 1975 and 1989, we noted that a significant component of the brain stem dysfunction in these children was an acquired phenomenon that potentially was reversible with prompt operative intervention. Accordingly, we hypothesized that with early craniocervical decompression, excellent functional outcome could be achieved in a majority of neonates and young infants with symptomatic Chiari II malformations. On the basis of this premise, we prospectively treated all such patients since 1989 with urgent brain stem decompression after other potential causes for brain stem dysfunction, such as progressive hydrocephalus, had been ruled out. All children underwent limited suboccipital craniectomies, cervical laminectomies extending beneath the inferior extent of the cerebellar tissue, and dural decompressions. The outcome in these patients has been favorable in comparison with previous studies. Ten of the 13 children treated according to this protocol recovered normal or nearly normal brain stem function shortly after decompression; 1 child had mild residual unilateral lower cranial nerve paresis. None of these children required a tracheostomy for ventilatory support, and only one required a temporary gastrostomy. The other three children all exhibited bilateral vocal cord paralysis and severe central hypoventilation by the time decompression was performed and failed to have any meaningful recovery of function. We conclude that early recognition of the symptoms of brain stem compromise in neonates and young infants with spinal dysraphism coupled with urgent evaluation and decompression are effective in producing prompt resolution of the brain stem dysfunction in most affected patients. Conversely, the prognosis for recovery is poor in children who exhibit bilateral vocal cord paralysis by the time of decompression. PMID- 8692389 TI - Predictors of ability to walk after selective dorsal rhizotomy in children with cerebral palsy. AB - Serial evaluations were completed after selective dorsal rhizotomy on 90 children with spastic cerebral palsy to analyze whether age, the preoperative gait score, voluntary dorsiflexion at the ankle, the diagnosis (quadriplegia or diplegia), or the length of follow-up correlated with the ability to walk after rhizotomy. The preoperative gait score (P < 0.0001), the diagnosis (diplegia versus quadriplegia, P < 0.0001), unilateral dorsiflexion (P = 0.0029), and bilateral dorsiflexion (P < 0.0001) were significant predictors of the maximal postoperative gait score in the univariate regression analysis, but only the preoperative gait score (P < 0.0001) and the diagnosis (P = 0.0015) retained significant predictive power in the multivariate analysis. These data suggest that the preoperative gait score and the diagnosis are the strongest predictors of ability to walk after selective dorsal rhizotomy. Dorsiflexion demonstrated predictive power only in the univariate model, suggesting that it might have some prognostic value but less than the preoperative gait score or the diagnosis. PMID- 8692390 TI - Percutaneous radiofrequency upper thoracic sympathectomy. AB - Between June 1979 and May 1994, I performed 148 unilateral or bilateral sympathectomies on 247 limbs in 110 patients using a percutaneous radiofrequency technique, usually on an outpatient surgery basis. Patient ages ranged from 10 to 81 years, with 45 male and 65 female patients. Four patients had unsuccessfully undergone prior open surgical sympathectomy. Patients suffered from hyperhidrosis, vascular occlusion, Raynaud's disease or other chronic vasculopathies, painful causalgia or reflex sympathetic dystrophy, or Prinzmetal's angina. The sympathectomy technique has evolved over this 15-year period and is currently in its third phase. Changes in the procedure were based on anatomic and clinical/radiographic correlations and careful patient follow-up. Current modifications have reduced the frequency of both early and late failures. The present technique (Phase III) relies on neuroleptanalgesia with superficial local anesthesia only and does not require general anesthesia, intubation, or lung collapse. Two 18-gauge radiofrequency TIC needle electrodes (Radionics, Burlington, MA) are used. A series of three lesions is rostrocaudally made at each of the ganglion sites selected in an attempt to destroy the entire fusiform ganglion. Lesion sites are targeted by C-arm fluoroscopy and electrical stimulation, which produces a threshold of sensory awareness of > 1.0 V. Lesion effectiveness is monitored by bilateral finger plethysmography and hand skin temperature measurement. With the Phase III technique, the sympathetic activity in 96% of operated limbs after 2 years and in 91% of operated limbs after 3 years continues to be completely or largely interrupted. By comparison, I achieved similar success in 83 and 72% operated limbs with the Phase I technique and in 77 and 71% with the Phase II technique. Symptomatic pneumothorax, in six patients, has been the only serious complication. When necessary, a subsequent operation can easily be performed and is effective. PMID- 8692391 TI - Use of intracranial pressure monitoring in the management of childhood hydrocephalus and shunt-related problems. AB - Although the clinical and radiological diagnosis of hydrocephalus in children is usually straightforward, there exists a minority of patients in whom the decision to shunt can be extremely difficult. Similarly, although the diagnosis of shunt malfunction usually presents little difficulty in the context of an acute blockage, a child can present with a confusing and unpredictable constellation of symptoms that might be caused by conditions separate from shunt malfunction. Continuous intraparenchymal intracranial pressure (ICP) monitoring was used to assess 41 patients with hydrocephalus, either as part of the initial diagnostic evaluation of ventriculomegaly (18 patients) or in the assessment of presumed shunt malfunction (23 patients). In 9 of 18 patients with ventriculomegaly, the ICP was within normal limits and surgical insertion of shunts was avoided. Of the 23 patients being assessed for shunt malfunction, the change in ICP profile indicated a siphoning or overdrainage process in 13. In no patient was there significant attendant morbidity, and the process was well tolerated and simple to perform. Clinical and radiological criteria alone can afford insufficient information in the initial evaluation and the subsequent management of the child with hydrocephalus. ICP monitoring provides a safe means of investigating such patients and provides valuable information upon which to base surgical management. PMID- 8692392 TI - The significance of artificial cerebrospinal fluid as perfusate and endoneurosurgery. AB - To compare the benefits of physiological saline solution and artificial cerebrospinal fluid (CSF) as perfusates, we investigated 12 patients with presumed symptomatic aqueductal stenosis by clinical course and CSF analysis. In all patients, endoneurosurgical third ventriculostomy and cine magnetic resonance imaging confirmed the patency of ventriculostomy. After endoneurosurgery, patients who received the saline solution experienced high fever, headaches, and elevated cell count in lumbar CSF. Saline solution provoked a striking inflammatory reaction in the CSF. In contrast, the artificial CSF reduced these conditions to a minimum. Artificial CSF used as a physiological perfusate during endoneurosurgery can suppress host reactions within the CSF pathway and is also available for routine neurosurgical procedures. PMID- 8692393 TI - Microendoscopy of the internal auditory canal in vestibular schwannoma surgery. AB - Intraoperative microendoscopy was performed for eight patients to access the fundus of the internal auditory canal after retrosigmoid transmeatal surgery of vestibular schwannomas. The transmeatal procedure is usually limited laterally by the labyrinth block. The restricted opening of the internal auditory canal bears a potential risk of incomplete tumor resection. For eight patients with vestibular schwannomas, intraoperative microendoscopy was performed after tumor resection to expose the "blind" area of the internal auditory canal fundus. An excellent view of the fundus contents was obtained, including Cranial Nerves VII and VIII and the crista transversa. Tumor remnants were not observed in this series. Microendoscopy was shown to be an ideal adjunct to hearing-preserving transmeatal surgery of vestibular schwannomas, enabling the removal of intracanalicular tumors with direct control of the lateral intracanalicular nerve portions. PMID- 8692394 TI - Postoperative magnetic resonance imaging with titanium implants of the thoracic and lumbar spine. AB - Within recent years, the technologies of radiological imaging and spinal instrumentation have exponentially increased. New methods of preoperative imaging, that is, magnetic resonance imaging (MRI) and computed tomography, have allowed for a better understanding of surgical pathology. Such an understanding is likely to lead to a more successful surgical experience, which certainly is the case with spine surgery with instrumentation. However, after implantation of most instrumentation, imaging is greatly impaired. Metallurgic advancements in titanium were sought to reduce postoperative imaging problems. The purpose of this study is to assess the presence and extent of artifacts seen on postoperative MRI scans in patients with titanium spinal implants. Six patients, four with degenerative spine disease and two with neoplasms, had thoracic and/or lumbar spinal fixation performed with titanium instrumentation. All patients underwent postoperative conventional MRI with the use of T1-weighted, T2 weighted, and gradient-echo sequences. The scans and individual sequences were then analyzed for image quality. A progressive and significant increase in imaging artifact related to the titanium spinal instrumentation was observed on the T1-weighted, T2-weighted, and gradient-echo sequences. Titanium spinal instruments do not allow optimal postoperative imaging on conventional MRI scanners. PMID- 8692395 TI - Increasing volume of distribution to the brain with interstitial infusion: dose, rather than convection, might be the most important factor. AB - The volume of distribution in tissue (Vt) that can be achieved by direct interstitial infusion of therapeutic agents into brain is limited. The maintenance of a pressure gradient during interstitial infusion to establish fluid convection has been shown to increase the Vt of small, medium, and large molecules. We have used monocrystalline iron oxide nanocompounds, superparamagnetic particles of sizes the same order of magnitude as virions, to investigate the effect of dose, the volume of infusate, and the time of infusion on the distribution of large molecules in rodent brain. Our initial study in rats (n = 6) replicated the results of a previously described report of convection enhanced delivery in cats. At a constant rate and concentration, the Vt increased in a linear fashion, proportional to the increases in time, volume, and dose. When using a constant rate and a constant concentration, however, it is unclear which variable or variables (dose, volume, infusion time) have the greatest influence on this effect. Therefore, we assessed each variable independently (n = 12). When the iron dose was increased from 5.3 to 26.5 micrograms, there was a three- to fivefold increase in the Vt, depending on the volume and time of infusion (2 Microliters/20 min, 24 microliters/20 min, or 24 microliters/120 min) (P < 0.001). When the volume of infusate was increased from 2 to 24 microliters, at an infusion time of 20 minutes and a dose of either 5.3 or 26.5 micrograms, there was a 43 or 52% decline in the Vt, respectively (P = 0.018). When the time for the infusion of 24 microliters was increased from 20 to 120 minutes, there was a 79% increase in the Vt at a dose of 26.5 micrograms but no change in the Vt at a dose of 5.3 micrograms. The effect associated with infusion time was not significant (P = 0.113). Magnetic resonance imaging was performed to document the distribution of monocrystalline iron oxide nanocompounds in vivo, and histochemical staining for iron was used to document the distribution of monocrystalline iron oxide nanocompounds in tissue sections. The Vt for both methods was calculated by computer image analysis, and the correlation between magnetic resonance and histological volumes was determined (r2 = 0.93). On the basis of this model, we suggest that dose, rather than convection, might be the most important variable in maximizing the Vt and improved distribution might be achieved by administering an increased concentration of agent. PMID- 8692396 TI - Migration of human glioma cells on myelin. AB - Histoanatomically invading astrocytoma cells appear to migrate along distinct structures within the brain. Astrocytoma invasion may occur along extracellular matrix (ECM) protein-containing structures, such as blood vessels, but most frequently occurs along tracts of myelinated fibers. This behavior most likely is a consequence of the use of constitutive extracellular ligands expressed along the pathways of preferred dissemination. Enzymatic modification of the extracellular space or deposition of ECM by the tumor cells may also create a more permissive environment. Established human glioma cell lines and two preparations of primary cells isolated from glioblastoma biopsies were studied with the use of cell adhesion and monolayer migration assays to investigate whether crude human central nervous system myelin extracts present specific cell adhesion ligands that promote glioma attachment and cell migration. Two cell lines showed high levels of adhesion and migration on central nervous system myelin similar to levels of migration on the ECM protein merosin, which has previously been shown to be a highly permissive substrate for cultured astrocytoma cells. Two other cell lines showed lower but specific migratory response; one cell line did not attach or specifically migrate on crude myelin extracts. For both glioblastoma primary cell preparations, myelin and merosin were the most permissive substrates for attachment and migration. Other ECM proteins (collagen type IV, fibronectin, and vitronectin) were moderate or nonpermissive substrates. Our findings indicated that astrocytoma cells may be able to use oligodendrocyte membrane-associated ligands as well as ECM proteins of the basement membranes for invasion of normal brain. PMID- 8692397 TI - p53 expression in pituitary adenomas and carcinomas: correlation with invasiveness and tumor growth fractions. AB - Although most pituitary tumors are well differentiated, histologically benign neoplasms, their clinical behavior is known to vary greatly. These lesions are relentlessly aggressive in some instances yet biologically indolent in others, but these prognostically relevant differences in behavior are not reflected in their histopathological appearance. As a means of identifying intrinsically aggressive pituitary tumors, we evaluated 70 pituitary adenomas and 7 primary pituitary carcinomas for their expression of the p53 gene product, a nuclear phosphoprotein whose immunohistochemical accumulation has served as an unfavorable prognostic factor for a wide range of human neoplasms. All tumors were fully classified by immunohistochemistry and electron microscopy; adenomas were further stratified on the basis of their invasion status, the latter being defined as gross operatively or radiologically apparent infiltration of dura or bone. Conclusive nuclear immunopositivity for p53 was identified in a total of 12 tumors, all being either invasive adenomas or primary pituitary carcinomas. A clear and highly significant association was evident between p53 expression and tumor behavior, as the proportion of p53-positive cases among noninvasive adenomas, invasive adenomas, and pituitary carcinomas was 0, 15.2, and 100%, respectively (chi 2 = 44.72; degrees of freedom, 2; P << 0.001). A comparison of previously reported growth fraction data with p53 expression indicated that the mean Ki-67-derived growth fraction of p53-positive tumors was significantly higher than that of p53-negative tumors (10.41 +/- 2.20 versus 2.51 +/- 0.28%) (+/- standard error of the mean, two-sample t test for independent samples, P = 0.004). There was no apparent relationship between the functional status of the tumor and p53 expression; positivity was observed among somatotroph, lactotroph, corticotroph, and clinically nonfunctioning pituitary tumors. These data indicate that p53 expression, when conclusively present in pituitary tumors, may be of some diagnostic usefulness as a marker of biologically aggressive behavior. PMID- 8692398 TI - Time-related ultrastructural changes in an experimental model of whole brain irradiation. AB - To stimulate therapeutic irradiation, we exposed rats to conventional fractionation (200 +/- 4 cGy/d, 5 d/wk; total dose, 4000 cGy). The effects of this regimen were assessed by electron microscopic examinations of brain microvascular and parenchymal cells 15 and 90 days after irradiation. Studies of the transendothelial passage of horseradish peroxidase provided information about the functional status of the blood-brain barrier. At 15 days after irradiation, there was an increased vesicular transport of horseradish peroxidase across the intact endothelium without opening of the tight junctions, and without evidence of structural alterations of neuropil, neuronal bodies, and astrocytes. Ninety days after irradiation, well-defined ultrastructural alterations were observed, involving the microvasculature, the neuropil, the neuronal bodies, and astrocytes. The main ultrastructural feature of cortical microvessels was their collapsed aspect, associated with perivascular edema containing cell debris. Altered neurons and reactive activated astrocytes were also noticeable. These data suggest a possible association, not necessarily causal, between damage of the microvascular/glial unit of tissue injury and development of radiation induced brain toxicity. PMID- 8692399 TI - Intracellular calcium, myosin light chain phosphorylation, and contractile force in experimental cerebral vasospasm. AB - It remains unknown what proportion of delayed arterial narrowing after subarachnoid hemorrhage depends on ongoing metabolic activity within arterial smooth muscle cells versus changes in the passive structural properties of the arterial wall. To determine this, vasospasm was induced by the double subarachnoid hemorrhage model. Anterior spinal artery segments were harvested from control dogs and from dogs with vasospasm. The segments were suspended in a force transducer and stretched to an optimal length for contraction. The difference in tension between 37 and 0 degrees C was defined as the intrinsic tone, and the residual tension at 0 degrees C was defined as the passive tension. The segments taken from dogs with vasospasm had increased intrinsic tone and passive tension (the differences were 3.8 kN/m2 [P < 0.05] and 14.8 kN/m2 [P < 0.025], respectively). Hence, the passive component accounted for 79.6% of the increased tension in vasospastic arterial segments. The intracellular calcium concentration was measured in these segments, using the luminescent calcium indicator, aequorin. The vasospastic segments had increased basal intracellular calcium concentration (398 versus 258 nmol/L, P < 0.025). In parallel experiments, control and vasospastic vessels were immediately excised when the animals were killed, and the vessels were quick-frozen. Subsequently, using two dimensional gel electrophoresis to measure percent myosin light chain phosphorylation, vasospastic vessels were found to have increased myosin light chain phosphorylation (37 versus 2%, P < 0.05). The increased intracellular calcium concentration and increased percent myosin light chain phosphorylation in vasospastic segments implicate a role for the Ca(2+)-dependent pathway of smooth muscle cell contraction in vasospasm. PMID- 8692400 TI - Immunohistochemical detection of intracranial vasa vasorum: a human autopsy study. AB - The existence of intracranial vasa vasorum supplying the larger vessels of the circle of Willis has long been debated. Much of this debate results from contradictory findings of microanatomic studies in a variety of nonprimate species. Recently, however, a growing body of evidence seems to suggest that in certain pathological situations, such as human intracranial atherosclerosis, vasa vasorum are present. In an effort to determine whether intracranial vasa vasorum are present in humans without clinical evidence of intracranial vascular disease, we studied the circle of Willis in five autopsy specimens using immunohistochemistry. Antiserum to the endothelial-specific antigen, Factor VIII, revealed staining of 10- to 20-microns vascular channels in the outer media and adventitial layers. Staining was present in the proximal carotid, middle cerebral (M1), and anterior cerebral (A1) arteries but could not be detected in M2 or A2 segments. Hematoxylin and eosin staining was additionally helpful in identifying the nuclear morphology of the endothelial cells lining these channels, as well as the presence of erythrocytes within them. We conclude that in nonpathological settings, endothelial-lined channels exist in the proximal intracranial vessels of humans. These vessels might represent intracranial vasa vasorum, which in turn might play a role in pathological conditions, such as atheroma formation, intracranial dissection, and vasospasm. PMID- 8692401 TI - A history of neurological surgery at the University of California, San Francisco. AB - Over a span of 80 years and four chairmanships, and now beginning the fifth chairmanship, the Department of Neurological Surgery at the University of California, San Francisco has held a position of renown among academic institutions serving neurological surgery. This article attributes this reputation to the qualities of the chairmen, an unforgettable group including Howard Naffziger, Edwin Boldrey, John Adams, and Charles Wilson. Some of their accomplishments are described. PMID- 8692402 TI - Management of a pediatric hypothalamic mass. PMID- 8692403 TI - High cervical split cord malformation and neurenteric cyst associated with congenital mirror movements: case report. AB - A 48-year-old woman with congenital mirror movements of the hands presented with a high cervical split spinal cord malformation and a ventrally located neurenteric cyst. The clinical, radiological, and surgical features are presented. A brief discussion of the literature and embryology pertaining to split cord malformations and mirror movements is included. To our knowledge, this is the first case of radiographically and surgically proven split cord malformation associated with either mirror movements or a neurenteric cyst presenting in an adult. PMID- 8692404 TI - Spontaneous resolution of a large spinal epidural hematoma: case report. AB - Spontaneous spinal epidural hematoma is a rare condition that usually requires surgical evacuation of the hematoma. We report a case of spontaneous spinal epidural hematoma that was probably associated with aspirin intake. The initial clinical signs and symptoms included sharp, left-sided neck pain and weakness of the left arm. The initial magnetic resonance image showed a spinal epidural hematoma extending from C2 to C6, with compression of the myelon. This case is remarkable for dramatic clinical improvement within 12 hours and the magnetic resonance imaging documentation of complete resolution within 3 days. For each patient with a stable or improving neurological status, conservative management monitored by magnetic resonance imaging might be the treatment of choice. PMID- 8692405 TI - Midcervical flexion myelopathy after posterior fossa surgery in the sitting position: case report. AB - Midcervical Quadriplegia is a well-known complication of posterior fossa surgery performed with the patient in the sitting position. The case of a 24-year-old man with a fourth ventricular choroid plexus papilloma is described. The patient developed reversible quadriparesis after surgery in the sitting position; postoperative magnetic resonance imaging demonstrated a hyperintense area within the cervical cord at C5-C6 on T2-weighted images, which was considered to represent "midcervical flexion myelopathy." It is suggested that the prolonged stretch and compression of the cervical cord is the pathogenesis of this serious complication. PMID- 8692406 TI - Pleomorphic xanthoastrocytoma: case report and analysis of the literature concerning the efficacy of resection and the significance of necrosis. AB - The case of a patient with a pleomorphic xanthoastrocytoma (PXA), a low-grade glioma of adolescence, is presented. A literature review of 79 patients with PXAs is described and confirms a favorable prognosis in 80% of patients. The sex ratio in the reported cases was almost equal, and the median age at time of diagnosis was 14 years. Seventy-nine percent of the patients presented with seizures. Nine of the 15 deaths from PXA are associated with histological evidence of necrosis at initial presentation or in a recurrent tumor, confirming the poor prognosis associated with the presence of necrosis in these neoplasms. Survival curves confirm that the optimal treatment for PXAs without necrosis is primary surgical resection with subsequent operation for recurrent tumor. The roles of surgery or radiotherapy in necrotic PXA are not clear from the literature. PMID- 8692407 TI - Burr hole neuroendoscopic fenestration of quadrigeminal cistern arachnoid cyst: technical case report. AB - Arachnoid cysts of the quadrigeminal cistern have been managed by cyst shunting and craniotomy with cyst fenestration. Two children are presented who underwent successful burr hole neuroendoscopic fenestration of symptomatic quadrigeminal plate cysts. The literature is reviewed with regard to the treatment of quadrigeminal arachnoid cysts, and the neuroendoscopic management of these cysts is described. PMID- 8692408 TI - Magnetic resonance angiographic screening for asymptomatic intracranial aneurysms: the problem of false negatives: technical case report. AB - To emphasize the limitations of magnetic resonance angiographic screening for intracranial aneurysms, we present the case of a patient with a false-negative screening result, unfortunately advancing to rupture of the aneurysm. An asymptomatic woman underwent magnetic resonance angiographic screening in an investigational setting. Three years later, she had an onset of sudden headache, after which her condition rapidly deteriorated. Severe subarachnoid hemorrhage and an intracerebral hematoma were diagnosed. Conventional angiography detected a small ruptured middle cerebral artery trifurcation aneurysm and two very small aneurysms. There are still limitations in the ability of magnetic resonance angiography to detect small or very small aneurysms. Even small-probability findings should always be confirmed or excluded by conventional angiography. PMID- 8692409 TI - SecureStrand cable system. PMID- 8692410 TI - Fedor Krause (1857-1937). PMID- 8692411 TI - Aggressive papillary middle ear tumors: a report of two cases with review of the literature. PMID- 8692412 TI - Resolution of chronic cluster headache after resection of a tentorial meningioma: case report. PMID- 8692413 TI - Perspectives in neurosurgery: neurosurgery in Greece. PMID- 8692414 TI - Frontal lobe changes after severe diffuse closed head injury in children: a volumetric study of magnetic resonance imaging. PMID- 8692415 TI - Association between peridural scar and recurrent radicular pain after lumbar discectomy: magnetic resonance evaluation. ADCON-L European Study Group. AB - The purpose of this study was to investigate the presence of any correlation between recurrent radicular pain during the first six months following first surgery for herniated lumbar intervertebral disc and the amount of lumbar peridural fibrosis as defined by MR imaging. 197 patients who underwent first time single-level unilateral discectomy for lumbar disc herniation were evaluated in a randomized, double-blind, controlled multicenter clinical trial. Clinical assessments, performed by physicians blinded to patient treatment status, were conducted preoperatively and at one and six months postoperatively. The enhanced MR images of the operative site utilized in the analysis were obtained at six months postoperatively. Radicular pain was recorded by the patient using a validated visual analog pain scale in which 0 = no pain and 10 = excruciating pain. The data obtained at the 6 month time point were analyzed for an association between amount of peridural scars as measured by MR imaging and clinical failure as defined by the recurrence of radicular pain. The results showed that the probability of recurrent pain increases when scar score increases. Patients having extensive peridural scar were 3.2 times more likely to experience recurrent radicular pain than those patients with less extensive peridural scarring. In conclusion, this prospective, controlled, randomized, blinded, multicenter study has demonstrated that there is a significant association between the presence of extensive peridural scar and the occurrence of recurrent radicular pain. PMID- 8692416 TI - Cerebral oxygen and glucose metabolism and blood flow in mitochondrial encephalomyopathy: a PET study. AB - Cerebral blood flow (CBF), oxygen metabolism (CMRO2), and glucose metabolism (CMRGlc) were measured using positron emission tomography in five patients diagnosed as having mitochondrial encephalomyopathy. The molar ratio between the oxygen and glucose consumptions was reduced diffusely, as CMRO2 was markedly decreased and CMRGlc was slightly reduced. The CBF showed less changes. The CBF increase on hypercapnia was smaller than normal, though this was not significant. CBF with hypocapnia demonstrated a significant reduction compared with the normal. These results suggest that oxidative metabolism is impaired and anaerobic glycolysis relatively stimulated, due to a primary defect of mitochondrial function, and that mild lactic acidosis occurs in brain tissue because of impaired utilisation of pyruvate in the TCA cycle. As these findings appear to indicate directly a characteristic of this disease, such measurements may be a useful tool for assessment of the pathophysiology and for diagnosis of mitochondrial encephalomyopathy. PMID- 8692417 TI - Registration and display of brain SPECT and MRI using external markers. AB - Accurate anatomical localisation of abnormalities observed in brain perfusion single-photon emission computed tomography (SPECT) is difficult, but can be improved by correlating data from SPECT and other tomographic imaging modalities. For this purpose we have developed software to register, analyse and display 99mTc-hexamethylpropyleneamine oxime SPECT and 1.0 T MRI of the brain. For registration of SPECT and MRI data external skin markers containing 99mTc (220 kBq) in 50 microliters of coconut butter were used. The software is coded in the C programming language, and the X Window system and the OSF/Motif standards are used for graphics and definition of the user interface. The registration algorithm follows a noniterative least-squares method using singular value decomposition of a 3 x 3 covariance matrix. After registration, the image slices of both data sets are shown at identical tomographic levels. The registration error in phantom studies was on average 4 mm. In the two-dimensional display mode the orthogonal cross-sections of the data sets are displayed side by side. In the three-dimensional mode MRI data are displayed as a surface-shaded 3 D reconstruction and SPECT data as cut planes. The usefulness of this method is demonstrated in patients with cerebral infarcts, brain tumour, herpes simplex encephalitis and epilepsy. PMID- 8692418 TI - Magnetisation transfer ratios of contrast-enhancing and nonenhancing lesions in multiple sclerosis. AB - Magnetisation transfer (MT) is a recently introduced technique for assessing the water content of tissues in vivo and its relationship to macromolecules or membranes. It has been suggested that MT could provide indirect evidence of the characteristics of multiple sclerosis (MS) lesions (oedema, demyelination, or gliosis). Our aims were to characterise brain MS lesions and to compare the magnetisation transfer ratio (MTR) values of lesions with different patterns of contrast enhancement. In patients with MS we measured the MTR of 65 gadolinium enhancing and 292 nonenhancing lesions. Using the equation published by Dousset et al. we studied 29 patients with clinically definite MS and 10 healthy controls. Lesions had significantly lower MT than the normal-appearing white matter of the patients or the normal white matter of healthy controls. There was no difference in the MTR of enhancing and nonenhancing lesions. Enhancement was homogeneous in 45 and ring-like in 20 lesions; MTR values were lower in the latter. These findings are presumably related to the differences in pathological features of enhancing (different amounts of proteins and inflammatory cells, oedema and demyelination) and nonenhancing (gliosis, demyelination and axonal loss) lesions. PMID- 8692419 TI - MRI in patients with general paresis. AB - Few cases of MRI in neurosyphilis have been reported. We examined the value of MRI in patients with general paresis; MRI was performed on four HIV-negative patients with parenchymatous neurosyphilis. It demonstrated frontal and temporal atrophy, subcortical gliosis and, in one patient, increased ferritin in the basal ganglia. The progression of the lesions on MRI correlated well with the neuropsychiatric disturbances. The MRI findings correlated with the well-known neuropathological findings. This combination of pathological findings in neurosyphilis has not been described before and we suggest that MRI is of prognostic value in patients with general paresis. PMID- 8692420 TI - Ill-defined focal low attenuation in the posterior internal capsule: a normal CT finding. AB - Although many pathological changes in the internal capsule may lead to neurological deficits, we often encounter ill-defined focal low attenuation in the posterior limb of the internal capsule (PIC) on CT in patients with no neurological disturbance. Brain CT studies of 141 patients without neurological deficits were reviewed to investigate the position of the focal low attenuation by analysis of a profile density curve. Nine patients with lacunar infarcts only within the posterior internal capsule were also studied. The focal low attenuation areas were ill-defined and bilaterally symmetrical, without mass effect. They were seen consistently within the posterior limb of the posterior internal capsule. Correlation between the distribution of these foci and the position of lacunar infarcts in the posterior internal capsule in nine patients with neurological deficits suggests that they may be related to the corticospinal tract. PMID- 8692421 TI - Atypical MRI findings in treatment-related leukoencephalopathy: case report. AB - A patient with acute myeloblastic leukaemia showed atypical findings on MRI following combination therapy including intrathecal methotrexate and radiation. MRI findings not previously been reported are ring as well as patchy enhancement, marked mass effect and lesions extending to the putamen and corpus callosum. PMID- 8692422 TI - MRI and angiographic diagnosis of lupus cerebral vasculitis. AB - The authors present a patient with striking angiographic findings of systemic lupus erythematosus (SLE) cerebral vasculitis. Although lupus is often cited as part of the differential diagnosis for angiographically apparent cerebral vasculitis, true SLE cerebral vasculitis is rare in pathological and radiological series. The clinical spectrum and pathological findings of CNS lupus with particular attention to cerebral vasculitis are briefly discussed. PMID- 8692423 TI - MRI demonstration of a reversible lesion in cerebral deep white matter in thrombotic thrombocytopenic purpura. AB - We report a 75-year-old woman with thrombotic thrombocytopenic purpura (TTP) whose MRI showed diffuse abnormal signal in the deep white matter. She was successfully treated, and this abnormal signal disappeared. This finding indicates that the deep white matter is involved in TTP; the lesion may reflect reversible microangiopathy and brain oedema. PMID- 8692424 TI - Imaging in phaeohyphomycosis of the brain: case report. AB - A case of multiple, conglomerated brain abscesses due to Xylohypha bantiana, with unique imaging features, is presented. This is the first culture-proven case of brain infection due to this fungus in the neuroimaging literature. PMID- 8692425 TI - Two-dimensional MRI at 1.5 and 0.5 T versus CT myelography in the diagnosis of cervical radiculopathy. AB - A prospective comparison was made of standard two-dimensional MRI sequences, at both high and midfield strength, with CT myelography in 23 patients with cervical spondylosis. MRI is adequate for assessment of cord compression, where high field strength is superior to midfield strength. MRI using 4-mm sections is inadequate for presurgical assessment of root compression. It remains to be proven whether thin-section white-CSF volume sequences or gadolinium-enhanced volume studies can replace CT myelography. PMID- 8692426 TI - Morphological analysis of the cervical spinal canal, dural tube and spinal cord in normal individuals using CT myelography. AB - To verify the conventional concept of "developmental stenosis of the cervical spinal canal", we performed a morphological analysis of the relations of the cervical spinal canal, dural tube and spinal cord in normal individuals. The sagittal diameter, area and circularity of the three structures, and the dispersion of each parameter, were examined on axial sections of CT myelograms of 36 normal subjects. The spinal canal was narrowest at C4, followed by C5, while the spinal cord was largest at C4/5. The area and circularity of the cervical spinal cord were not significantly correlated with any parameter of the spinal canal nor with the sagittal diameter and area of the dural tube at any level examined, and the spinal cord showed less individual variation than the bony canal. Compression of the spinal cord might be expected whenever the sagittal diameter of the spinal canal is below the lower limit of normal, that is about 12 mm on plain radiographs. Thus, we concluded that the concept of "developmental stenosis of the cervical spinal canal" was reasonable and acceptable. PMID- 8692427 TI - An unusual spinal intradural arachnoid cyst. AB - Spinal intradural arachnoid cysts are seen most frequently in the thoracic region, particularly near the midline posteriorly. A thoracic intradural arachnoid cyst in this typical location is reported, with the additional unusual finding of herniation of the spinal cord through an anterior defect in the dura matter. The MRI findings are described. PMID- 8692428 TI - Idiopathic spinal cord herniation. AB - Idiopathic spinal cord herniation is a rare disease, few cases having been reported. We encountered a case of idiopathic spinal cord herniation presenting with severe spasticity in the right leg and urinary dysfunction. The spinal cord was herniated into a cavity created by duplication of the dura mater and resection of the inner layer improved the neurological deficits. MRI, myelography, and CT myelography were useful for diagnosing this disease. Four radiological signs of spinal cord herniation are described. PMID- 8692429 TI - Herniation of the spinal cord 38 years after childhood trauma. AB - We report an unusual post-traumatic spinal cord herniation, which became symptomatic 38 years after the trauma. A 44-year-old man presented with a 2-year history of increasing impotence, neuropathic bladder dysfunction and dissociated sensory loss below the level of T6. At the age of 6 years he had a severe blunt spinal injury with transient paraparesis. MRI revealed right lateral and ventral displacement of the spinal cord at the T5/6 level. The spinal cord was surgically exposed and found to herniate through a ventral defect of the arachnoid membrane and the dura mater. As there were no other events that could have precipitated spinal cord herniation the reported blunt trauma in childhood is the most likely cause for the spinal cord herniation in this patient. PMID- 8692430 TI - Intramedullary lipoma. PMID- 8692431 TI - MRI of spinal cord and vertebral body infarction in the anterior spinal artery syndrome. PMID- 8692432 TI - Langerhans cell histiocytosis in monocygote twins: case reports. AB - Langerhans cell histiocytosis includes three clinical forms of histiocytosis X. We describe a disseminated form of Langerhans cell histiocytosis (Letterer-Siwe disease) in monozygotic twins. The twins showed simultaneous onset of disease, almost identical clinical follow-up and findings on cranial CT. The cause of this phenomenon remains unknown. PMID- 8692433 TI - Imaging in the trilateral retinoblastoma syndrome. AB - The medical records, CT, and MRI of ten children with trilateral retinoblastoma were reviewed. The intracranial pathology consisted of eight pineal neoplasms and two parasellar lesions, at least seven of the which were calcified. Two lesions demonstrated calcification only (no soft tissue mass) at initial presentation. Hydrocephalus was seen in eight cases, and concurrent or subsequent subarachnoid dissemination was documented in seven. Only one patient is known to be alive at the present time. The imaging features of the midline intracranial tumors mirror those of the ocular neoplasm. As calcification may be the only clue to the presence of the intracranial malignancy, close surveillance of high-risk patients with retinoblastoma with initial CT and follow-up MRI is suggested. PMID- 8692434 TI - Imaging in optic nerve coloboma. PMID- 8692435 TI - Rhinoscleroma with orbital extension: CT and MRI. AB - We describe the MRI features of a rhinoscleroma with orbital extension. This benign bacterial and granulomatous lesion of the paranasal sinuses gave homogeneous low intensity on T2-weighted images and enhanced with gadolinium. It could simulate a malignant sinonasal tumour or a fungal sinusitis; the diagnosis must be considered in patients from endemic areas. PMID- 8692436 TI - Adenocarcinoma of the endolymphatic sac: imaging features and preoperative embolization. AB - Adenocarcinoma arising from the endolymphatic sac is very rare. Its imaging features are nonspecific and the differential diagnosis involves mainly paraganglioma or aggressive meningioma. In our case, the blood supply to the tumor was identical to that found in glomus jugulotympanicum tumors and the patient benefitted from preoperative embolization. PMID- 8692437 TI - Lys-plasminogen as an adjunct to local intra-arterial fibrinolysis for carotid territory stroke: laboratory and clinical findings. AB - To improve the efficacy of local intraarterial fibrinolysis (LIF), we compared different fibrinolytic drugs in a cerebral circulation model in the laboratory. The technical efficacy of fibrinolysis, defined as the clot volume lysed per unit time, was found to be optimal with r-tissue plasminogen activator (TPA) activated lys-plasminogen (= plasmin). Subsequently, 20 patients with stroke due to carotid artery territory occlusion were treated by local intraarterial fibrinolysis using the plasmin regimen. The angiographic data and clinical outcome of these patients were compared with those of 40 patients who received plasminogen activators (urokinase or r-TPA) only. Laboratory and clinical data confirmed that plasmin lysis is superior to treatment using only plasminogen activators. PMID- 8692438 TI - Endovascular treatment of bacterial intracranial aneurysms. AB - We report three patients with bacterial intracranial aneurysms treated by the endovascular approach: two presented with sudden severe neurological deficits after a diagnosis of endocarditis; the other had suspected vasculitis. CT showed an intracerebral haematoma in all cases; angiography revealed bacterial aneurysms of distal branches of the middle cerebral artery in one. Because of the patients' condition and the location of the aneurysms, endovascular treatment was considered the fastest and safest treatment. Hyperselective catheterisation of the parent branch, close to the aneurysm, was performed with a microcatheter. A small amount of glue was injected to occlude both the aneurysm and a short segment of the diseased vessel. Follow-up angiography revealed occlusion of the aneurysm in all cases. One patient recovered completely; one recovered over some months, with neurological deficit due to the haematoma. The third patient suddenly worsened and died 9 days after treatment for a contralateral haematoma, due to rupture of a new bacterial aneurysm of the middle cerebral artery. Endovascular occlusion of the aneurysm and parent vessel may be an alternative to surgery in selected, severe cases of deep or distal bacterial intracranial aneurysms. PMID- 8692439 TI - Dancing with the devil: fighting the tobacco war in New Jersey. PMID- 8692440 TI - Interview with Anthony P. Caggiano, Jr, MD. Interview by Bill Berlin. PMID- 8692441 TI - The minor side of smoking. AB - Richie T. is a teenager from an affluent family in Westfield, where he attends the local high school. His grades are good and he expects to go to a major out-of state university next year. Richie hangs out with different cliques, drinks occasionally at weekend parties, and likes a girl who does not seem to notice him. Richie started smoking Marlboros last year. He likes the taste of tobacco and says that his friends who smoke are "cool" and "interesting." He sees a lot of adults who smoke, and he is certain he could quit whenever he feels like it. Richie does not think about the health effects of smoking, and apparently he is not alone. PMID- 8692442 TI - Clinical strategies for work-related carpal tunnel syndrome. PMID- 8692443 TI - Radiology/pathology conference: mesenteric cystic lymphangioma. PMID- 8692444 TI - Chest radiographs in patients with community-acquired pneumonia. PMID- 8692445 TI - Management and disposal of medical waste. PMID- 8692446 TI - Managing the rise of managed care in New Jersey. PMID- 8692447 TI - Should the proposed FDA rules on tobacco regulation be adopted? PMID- 8692448 TI - Diabetes and its complications in New Zealand: an epidemiological perspective. PMID- 8692450 TI - Changes in payments for general practice consultations 1989-93. AB - AIMS: Information generated by the computer systems of general practitioners was examined to determine whether general practitioners fee structures during 1993 were different from those reported in 1989. METHODS: Copies of the general medical services (GMS) claims and actual consultation charges to patients were examined to determine whether patients had been charged the doctors' regular fee or an amount greater or less than this, in 1993. These data were compared with results from a previous study describing charging data in 1989. RESULTS: Information on 59,215 consultations was collected in 1993 and compared with information on 97,869 consultations collected in 1989. The proportion of consultations which resulted in a regular fee being charge had reduced from 47.0% in 1989 to 34.1% in 1993 (p < 0.001). The proportion of cases in which a less than normal fee was charged had risen 7.9 times from 3.5% in 1989 to 27.5% in 1993 (p < 0.001). The contribution of Accident Compensation (ACC) funding for general practitioner consultations had reduced from 17.5% of consultations in 1989 to 10.1% of 1993 consultations (p < 0.001). Excluding consultations in which a maternity or immunisation claim was made, 19.4% of consultations in 1993 generated no fee to the patient. CONCLUSION: In the 4 years between these two data collections, changes in the contribution of different agencies funding general practice care is marked. Public agencies have diminished input and both patients and practitioners are carrying more of the financial burden for access to primary care. PMID- 8692449 TI - Management of acute myocardial infarction in Auckland. AB - AIM: To analyse the utilisation of therapies in coronary care units for patients with acute myocardial infarction. METHODS: An evaluation form was completed prospectively by a designated nurse in each coronary care unit of the four Auckland hospitals in 1993. RESULTS: One thousand and eighty one patients who were admitted with definite or probable acute myocardial infarction had a coronary care unit stay of 63.4 (SD 49.3) hours, and hospital stay of 7.3 (5.1) days. The mortality for definite myocardial infarction was 13.7% (< 70 years 7.1%). Coronary angiography was performed on 10% of patients during their hospital admission, and 4.9% underwent revascularisation. Thrombolytic therapy was administered to 52% (495/948) of patients with definite infarction and 4% had contraindications. Patients aged > or = 70 years (47% vs 55% p = 0.02) or diabetics (46% vs 56%, p = 0.04) were less likely to receive thrombolysis. The utilisation of aspirin and oral beta-blockers was 86% and 40%, respectively, in patients with definite infarction and both were used less frequently in patients > or = 70 years. Intravenous beta-blockers were administered to < 1% of patients. Angiotensin converting enzyme (ACE) inhibitors were prescribed in 21%, intravenous or long acting nitrates in 41% and calcium antagonists in 14%; the latter two therapies were used more frequently in patients > or = 70 years. There was no evidence of gender or ethnic bias for either investigation or treatment. CONCLUSION: On the basis of results of recent clinical trials, there may be under utilisation of some treatments for acute myocardial infarction including aspirin, thrombolytic therapy, beta-blockers and ACE inhibitors, while calcium antagonists may be over used. PMID- 8692451 TI - Out-of-hours attendance and outcomes for asthmatic patients at two primary care services. AB - AIM: To describe patients who choose different primary care services for asthma care at Wellington general practitioner run After-hours Medical Centre (AMC) and Wellington hospital emergency department (WED). METHOD: Two month prospective study of patients attending out-of-hours. RESULTS: Eighteen percent of 249 AMC patients and 47% of 126 WED patients had a community services card and 6% and 7% respectively had high user health cards (p < 0.0001). AMC patients were more likely to:- be younger (mean age 19.3 vs 24.9 years, p < 0.006), live further from the service mean distance 5.3 km vs 4.1 km, p < 0.003), be given a repeat prescription for asthma medication (20% vs 3%, p < 0.0001), and be sent back to their GP (67% vs 25%, p < 0.0001). AMC patients were less likely to be referred by a GP (4% vs 9%, p < 0.05) and be admitted (1% vs 30%, p < 0.0001). 22.5% of patients admitted for asthma had seen a general practitioner prior to admission. CONCLUSION: Asthmatic patients had different outcomes at the two services which reflects different management policies at the two services. More research is needed on access factors influencing attendance for asthma such as the direct cost to the patient, the distance services are located from patients homes, and the time when services are convenient for patients. PMID- 8692452 TI - Stroke audit in a New Zealand hospital. AB - AIMS: This study was designed to test the Royal College of Physicians Stroke Audit Package in a general hospital in New Zealand, to identify the strengths and weaknesses of the package and to determine its applicability to the New Zealand environment. A secondary aim was to identify strengths and weaknesses in the process of stroke care at Hutt Hospital. METHODS: A retrospective case-note review of 50 consecutive discharges with a diagnosis of stroke or intracerebral haemorrhage. RESULTS: The Royal College of Physicians (RCP) Stroke Audit Package proved easy to use. The hospital audit revealed significant weaknesses in evaluation of stroke patients with inadequate documentation in the medical notes of important items including heart rate and rhythm (58%), blood pressure (74%), visual field assessment (33%), ability to swallow (2%) and conscious level (68%). CONCLUSIONS: The RCP Stroke Audit Package is a simple, validated and potentially valuable tool for stroke audit in New Zealand hospitals. Using it, deficiencies in the process of stroke care can be readily identified, improvements made, and the results re-audited to demonstrate change. PMID- 8692453 TI - Sickle cell anaemia in a Cook Island child. PMID- 8692455 TI - Chloroform in extemporaneous preparations. PMID- 8692454 TI - Otitis media with effusion. PMID- 8692456 TI - Older adults and healthy lifestyle issues: results of a community study. PMID- 8692457 TI - Selective serotonin reuptake inhibitors prescriptions. PMID- 8692458 TI - Humor doesn't cut it. PMID- 8692459 TI - Trends in endodontic instruments and materials. AB - It is the skill and knowledge of the clinician using the technique or material that determines success. This article provides an overview of some current trends in endodontic instruments and materials. PMID- 8692460 TI - New techniques for removing separated root canal instruments. AB - Minimizing accidental fracture of root canal instruments through preventive measures is good practice. Having the right techniques and armamentarium to remove instrument fragments can greatly increase chances for success. Use of the operating microscope minimizes loss of tooth structure and reduces the need for surgery. Three cases are presented. PMID- 8692462 TI - Contract analysis. A guide to participating provider agreements. AB - Dentists need to be able to make informed decisions about the contracts they are considering. Knowledge of participation agreements and typical provisions provides means for evaluating the potential impact of individual contracts on a dental practice. PMID- 8692461 TI - A dual approach to bleaching. AB - A procedure is presented which combines the walking bleach and the external thermocatylitic bleaching technique. This maximizes the bleaching potential of each and minimizes the possibility of subsequent external root resorption. PMID- 8692463 TI - An advertising conundrum. PMID- 8692464 TI - Dentistry at the millenium. Politics and public policy. PMID- 8692465 TI - DSSNY, managed care and antitrust laws. A marriage of necessity. PMID- 8692466 TI - UK nuclear medicine survey. PMID- 8692468 TI - Results of three-phase bone scintigraphy and radiography in 20 cases of neonatal osteomyelitis. AB - Neonatal osteomyelitis, a rare, potentially crippling disease, requires early diagnosis and effective therapy. This study of 20 neonates analysed the diagnostic value of three-phase bone scintigraphy (motivated by its controversial role), plain radiography and local clinical signs in neonatal osteomyelitis and complicating septic arthritis. The sensitivities for detecting focal skeletal involvement were as follows: bone scintigraphy 90%, radiography 65%, clinical local signs 20%. Reliable scintigraphic signs were localized hyperperfusion (phase I), vasodilation (phase II) and hot or cold lesions on 3-h images. Radionuclide angiography definitely increased the validity of bone scintigraphy. During follow-up, the reduction or normalization in focal hyperperfusion was the first and most sensitive sign of an adequate response to antibiotic treatment; persistence (or recurrence) of focal hyperperfusion, increasing relative uptake ratios and the appearance of new foci of bone involvement indicated escape from antibiotic therapy. Radiography revealed no pathological signs in 35% of cases, soft tissue changes in 20% and effusion of the hip joint in 45%. Local clinical signs were not a reliable predictor of scintigraphic or radiographic findings. We consider bone scintigraphy in neonatal osteomyelitis to be a successful, efficient and cost-effective diagnostic modality, not only for early diagnosis, but also during follow-up. PMID- 8692467 TI - Limited value of stress electrocardiographic changes in predicting late 201Tl reversibility: do all patients need reinjection? AB - The aim of this study was to assess the relationship between the exercise electrocardiogram (ECG) and late thallium-201 (201Tl) reversibility in a series of 72 consecutive patients with undiagnosed chest pain and an initial persistent perfusion defect on conventional stress/4-h redistribution imaging. We wished to establish the diagnostic accuracy of the exercise ECG in predicting the outcome of late 201Tl reversibility. All 72 patients, of whom 44 (61%) had had a previous myocardial infarction (MI), underwent quantitative planar 201Tl stress redistribution imaging followed by resting 201Tl imaging 1-4 days later. Fifty (69%) patients showed exercise ECG changes during conventional stress redistribution imaging, of whom 30 (42%) had a history of previous MI and 20 (28%) had suspected coronary artery disease (CAD). The overall diagnostic accuracy of the exercise ECG in predicting 201Tl reversibility was 83% (60/72 patients): 75% (21/28 patients) in patients with suspected CAD and 87% (39/44 patients) in patients with previous MI. Only the patients with a previous MI and a negative exercise ECG showed 100% accuracy (n = 14). We conclude that reinjection of 201Tl might be withheld in patients with a previous MI and a negative exercise ECG. For patients with previous MI and a positive exercise ECG, and for patients with suspected coronary artery disease regardless of the result of their exercise ECG, reinjection of 201Tl should be strongly considered if the redistribution images are abnormal, because of the suboptimal diagnostic accuracy of the exercise ECG in these patients. PMID- 8692469 TI - Scintigraphic diagnosis of subclinical Cushing's syndrome in patients with adrenal incidentalomas. AB - Adrenal scintigraphy has been shown to be a useful procedure for the characterization of incidentally discovered adrenal tumours. The functional evaluation of these patients is controversial. This paper describes the biochemical and pathological findings in five patients with asymptomatic adrenal masses and unilateral concordant adrenocortical scintigraphic uptake. All the patients were diagnosed as having subclinical Cushing's Syndrome, without clinical or biochemical adrenocortical dysfunction. Scintigraphy is the most sensitive method for detecting an adrenal adenoma in the subclinical setting when the disease is not yet demonstrable by biochemical methods. PMID- 8692470 TI - UK nuclear medicine survey, 1992-93. AB - A postal survey of UK nuclear medicine departments was undertaken to collate information on equipment, numbers of procedures and staffing levels for the years 1992 and 1993. It was estimated that there are 235 sites undertaking nuclear medicine, the total number of procedures performed being some 490,000 in 1993 compared with 430,000 in 1989. Informal investigation suggests that the increase is due to greater usage of myocardial perfusion and lung ventilation/perfusion studies. Wide variations were noted in staffing levels, with only 22% of departments having medical cover of half-time equivalent or better: over 30% of departments have less than one consultant session per week. Approximately 20% of departments claimed to have no physics input, with a further 20% having less than one session per week. PMID- 8692471 TI - Lung perfusion scintigraphy in patients with congenital heart disease: sensitivity and important pitfalls. AB - The lung perfusion scans requested over a 5-year period for children with known congenital heart disease were reviewed retrospectively. Altogether, 102 lung perfusion scans were performed and comparable pulmonary arteriograms were available in 63 cases. There was agreement between scintigraphy and angiography in 50 (79%) cases and discrepancy in 13 (21%) cases. Scintigraphy was more sensitive in detecting small perfusion defects, particularly those seen only on oblique views. Pulmonary arteriography was more specific in identifying the cause of the perfusion abnormalities. The two techniques yield complementary information about lung perfusion. Perfusion scintigraphy is safe in children with congenital heart disease even with known pulmonary to systemic shunting. Many pitfalls could be avoided by careful choice of injection site, by knowledge of previous surgery and comparison with relevant angiograms. PMID- 8692472 TI - Alpha- and beta-emitting radiolanthanides in targeted cancer therapy: the potential role of terbium-149. AB - The efficacy of systemic cancer therapy rests on the ability of a toxin to be preferentially located in cancer cells, so that cancer cell kill is maximized and normal tissue spared. This requires that the lifetime of the toxin be less than the lifetime of the carrier in the body, effectively ruling out chemical toxins, as they remain effective until excreted from the body. The requirement of localization of dose to the cancer cell makes radioactive beta-emitting radionuclides unattractive. Alpha-emitting radionuclides are much more appropriate toxins, as their efficacy depends on the high energy and short range of the alpha particles, and terbium-149 is shown to be the most efficacious of these. However, the merit of various alpha- and beta-emitting radionuclides depends on the stage and type of cancer. Recommendations are made with respect to the matching of the target cancer with required properties of the radiolabel and carrier. PMID- 8692473 TI - Cerebral perfusion abnormalities in therapy-resistant epilepsy in childhood: comparison between EEG, MRI and 99Tcm-ECD brain SPET. AB - We performed 99Tcm-ethyl cysteinate dimer (ECD) interictal single photon emission tomography (SPET) in 26 children with severe therapy-resistant epilepsy. All the children underwent a detailed clinical examination, an electroencephalogram (EEG) investigation and brain magnetic resonance imaging (MRI). In 21 of the 26 children, SPET demonstrated brain blood flow abnormalities, in 13 cases in the same territories that showed EEG alterations. MRI showed structural lesions in 6 of the 26 children, while SPET imaging confirmed these abnormalities in only 5 children. The lesion not detected on SPET was shown to be 3 mm thick on MRI. Five symptomatic patients had normal SPET. In one of these patients, the EEG findings were normal and MRI revealed a small calcific nodule (4 mm thick); in the others, the EEG showed non-focal but diffuse abnormalities. These data confirm that brain SPET is sensitive in detecting and localizing hypoperfused areas that could be associated with epileptic foci in this group of patients, even when the MRI image is normal. PMID- 8692474 TI - 99Tcm-HIG accumulates in the synovial tissue of rats with adjuvant arthritis by binding to extracellular matrix proteins. AB - Our objective was to investigate the mechanism of accumulation of 99Tcm-labelled non-specific polyclonal human immunoglobulin (99Tcm-HIG) in inflamed synovial tissue (ST) in an experimental animal model of arthritis. Following 99Tcm-HIG scintigraphy, the in vivo localization of 99Tcm-HIG in the ST of knee joints of rats with adjuvant arthritis was studied using immunohistochemical techniques. In addition, the in vitro binding of 99Tcm-HIG to extracellular matrix proteins was analysed by means of immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). After 99Tcm-HIG scintigraphy, 99Tcm-HI was detected in the ST of rats with adjuvant arthritis. 99Tcm-HIG was diffusely distributed and not bound to cells. In vitro incubation of 99Tcm-HIG on the ST of rats with adjuvant arthritis revealed binding of 99Tcm-HIG to inflamed, but not to non-inflamed, ST. In addition, specific binding of 99Tcm-HIG to fibronectin, fibrin, collagen type I and III was demonstrated by ELISA. We conclude that the accumulation of 99Tcm-HIG in inflamed ST can be explained by the binding of 99Tcm-HIG to extracellular matrix proteins. PMID- 8692475 TI - Discrepant pattern of solid and liquid gastric emptying in Chinese patients with type II diabetes mellitus. AB - While abnormal gastric emptying has been widely reported in patients with diabetes, its clinical relevance is still uncertain. We conducted scintigraphic gastric emptying studies in patients with Type II diabetes mellitus who had symptoms suggestive of delayed gastric emptying in an attempt to evaluate the incidence of abnormal gastric emptying and to assess the clinical parameters of the different patterns of gastric emptying. Seventy male diabetic patients were included in the study. The patients were divided into four groups according to the results of liquid and solid gastric emptying: group 1, normal liquid and solid emptying (n = 22); group 2, normal liquid but delayed solid emptying (n = 30); group 3, delayed liquid but normal solid emptying (n = 7); group 4, delayed liquid and solid gastric emptying (n = 11). To assess clinical significance, we compared duration of disease, status of blood sugar control, presence or absence of vascular complications and of peripheral neuropathy among the four groups. Of the 70 patients, 18 (25.7%) showed delayed liquid gastric emptying and 41 (58.6%) delayed solid gastric emptying. There were no significant differences in the clinical parameters of the four groups, except that patients with good sugar control were likely to have normal liquid gastric emptying. Based on the results of this study, delayed solid gastric emptying is more common than liquid gastric emptying in symptomatic Type II diabetes mellitus patients. Of the different patterns of gastric emptying, delayed liquid gastric emptying with normal solid gastric emptying is the most unusual. For Type II diabetic patients with symptoms suggestive of delayed gastric emptying, both liquid and solid gastric emptying studies should be performed. PMID- 8692476 TI - Protein labelling via deoxyribonucleic acid hybridization. AB - A novel method of radiolabelling antibodies and other proteins is described. A small single-stranded DNA was covalently conjugated to an antibody and labelled by hybridization following the addition of the complementary single-stranded DNA labelled with technetium-99m (99Tc(m)) or indium-111 (111In). Antibody labelling efficiencies were 100% in about 1 h at room temperature with specific activities of up to 30 microCi micrograms-1 of IgG for 99Tc(m). Both diester and thioate DNAs were used. Both the diester- and thioate-labelled antibodies showed complete label stability in 37 degrees C saline. After 24 h in 37 degrees C serum, however, about 40% of the label in the case of the diester antibody was on low molecular weight species--probably labelled catabolites from nuclease degradation of the phosphodiester DNA. In contrast, the 99Tc(m) label on the thioate antibody was immediately and quantitatively bound to serum proteins--probably due to non specific binding through the sulphur groups. Biodistribution studies in normal mice reflect these in vitro observations: 99Tc(m) on the diester antibody was rapidly cleared through the kidneys, probably as low molecular weight catabolite, while on the thioate antibody, the 99Tc(m) label was predominately deposited in the liver. In conclusion, by modifying with a single-stranded DNA, proteins may be readily labelled with a variety of radionuclides by DNA hybridization. The properties of the radiolabel are strongly influenced by the nature of the DNA. PMID- 8692477 TI - A comparative study of 99Tcm-d,l-HMPAO and 99Tcm-d,l-CBPAO as leukocyte-labelling agents. AB - An attempt was made to use 99Tcm-d,l-cyclobutylpropylene amine oxime (99Tcm-d,l CBPAO) to label leukocytes. The radiochemical purity of 99Tcm-d,l-CBPAO, labelling efficiency of leukocytes, cell viability of labelled leukocytes and stability of 99Tcm-d,l-CBPAO-labelled leukocytes were calculated. In comparison with the commercial cell-labelling agent 99Tcm-d,l-hexamethylpropylene amine oxime (99Tcm-d,l-HMPAO), (1) the radiochemical purity of 99Tcm-d,l-CBPAO was higher than that of 99Tcm-d,l-HMPAO immediately after and 1, 2, 4, 6, 8 and 24 h after 99Tcm labelling; (2) the labelling efficiency of 99Tcm-d,l-CBPAO-labelled leukocytes was lower than that of 99Tcm-d,l-HMPAO; (3) the viability of labelled white blood cells was high for both agents; and (4) the stability of 99Tcm-d,l CBPAO-labelled leukocytes was better than that of 99Tcm-d,l-HMPAO after 1, 2, 4, 6, 8 and 24 h. In conclusion, although the labelling efficiency of 99Tcm-d,l CBPAO is lower, it is more stable than 99Tcm-d,l-HMPAO and provides greater stability of 99Tcm-d,l-CBPAO-labelled leukocytes. Therefore, 99Tcm-d,l-CBPAO has the potential to replace 99Tcm-d,l-HMPAO as a commercial leukocyte-labelling agent. PMID- 8692478 TI - A software application to estimate exposure around 131I cancer and hyperthyroid patients. AB - A Windows-based software application (IDOSE) has been developed to estimate time dependent radiation exposure around patients who receive 131I-sodium iodide (NaI) for hyperthyroidism or thyroid cancer therapy. This application is based on radiation exposure associations which relate pharmacokinetically such factors as administered dose, distance from patient, directional projection and time. The software was tested by comparing its predictability with that obtained with a survey meter in-house as well as at neighbouring hospitals for a total of 74 patients who were administered 131I(NaI). The latter surveys were performed at the patient's surface, at 30 cm and at 100 cm, from 0.25 to 56 h post administration for a total of 133 data points. Statistical testing showed r coefficients of > 0.9 and paired t-test values of > 0.39 between the predicted and measured survey values for all distances surveyed. The versatility of IDOSE lies in its ability to predict radiation exposure to others who come into contact with the patient relative to projection, time and distance. The latter is based on patient- and literature-generated default values at administration for three distances: surface, 30 cm and 100 cm. Thereafter, IDOSE predicts exposures at the default distances as a function of time. User-generated survey values at administration are an input option. IDOSE will never take the place of an actual survey. Its potential lies with estimating such information at times when surveys are not possible. Hypothetical 131I(NaI) patients are followed to illustrate the multifaceted nature of IDOSE. This paper describes the development, implementation and efficacy of a user-friendly Windows-based software application for predicting radiation exposure around 131I(NaI) patients. PMID- 8692479 TI - Radiochemical and radioimmunological data of 99Tcm-anti-CEA labelled by two diverse methods. AB - The aim of this study was to make a comparative evaluation of a direct and an indirect method for the labelling of anti-CEA with technetium-99m (99Tcm). With the direct method, disulphide bridges were cleaved by the use of 2 mercaptoethanol as reductant, whereas with the indirect method, the antibody was coupled to 2-iminothiolane. In both cases, a preformed intermediate chelate was used for 99Tcm exchange. The radiochemical and radiobiological behaviour of the 99Tcm-labelled species were studied. Furthermore, the influence of the labelling systems on the integrity of monoclonal antibodies, as well as the ability of 99Tcm-anti-CEA to tag onto human cancer cells, was investigated for the two labelling systems. Both methods showed a high labelling yield and resulted in immunoreactive and stable derivatives. However, detailed electrophoretical and radiochemical data, as well as the cysteine challenge trial, indicated relatively greater stability for the 2-mercaptoethanol reduction procedure. PMID- 8692480 TI - Question of the month--October. PMID- 8692481 TI - The future of nuclear medicine. PMID- 8692482 TI - Imaging in lung cancer. PMID- 8692483 TI - A review of renal scarring in children. AB - It is now widely accepted that children with a proven urinary tract infection should undergo some form of diagnostic imaging to assess the presence of, or the potential to develop, renal scarring. The type of investigation which should be performed is controversial. Some centres still perform intravenous urography, others rely on ultrasound alone, while others believe that a 99Tc(m) dimercaptosuccinic acid (99Tc(m)-DMSA) scan is essential. This review discusses the advantages and disadvantages of these techniques by drawing from the extensive literature currently available. The consensus view is that a DMSA scan is the most sensitive method of detecting renal scarring and of highlighting the kidney at risk of developing scarring. It is hoped that wider early use of DMSA scintigraphy will lead to a fall in the number of children who develop end-stage renal disease. PMID- 8692484 TI - Somatostatin receptor scintigraphy in the staging of small cell lung cancer. AB - The aim of this study was to evaluate somatostatin receptor scintigraphy (SRS) in the staging of patients with small cell lung cancer. Prior to chemotherapy, 20 patients were investigated up to 24 h following an injection of 200 MBq 111In octreotide. Following chemotherapy and restaging, four patients were re evaluated. Primary tumour was detected in 18 of 23 studies, which exhibited increasing target-to-back-ground ratios over time. Lymph node metastases and distant metastases were detected in 7 of 27 and 8 of 31 sites, respectively. Thus, the overall sensitivity for detecting metastases was less than 26%. SRS did not result in any upstaging of patients. We conclude that in patients with small cell lung cancer, functional imaging by SRS has no impact on clinical decision making. PMID- 8692485 TI - FDG-PET screening for cerebral metastases in patients with suspected malignancy. AB - 2-(18)F-Fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) is increasingly being used in the evaluation of patients with malignancy. Recently, imaging protocols have incorporated ?whole-body' views acquired over multiple steps. However, with this strategy, brain metastases can potentially go undetected. The aim of this study was to determine whether a supplementary 10-min brain 18F-FDG scan provides additional clinically useful information. Accordingly, we reviewed the studies of 273 patients with various malignancies in whom both whole-body and brain images were performed. Whole-body and regional attenuation-corrected 18F-FDG images were obtained approximately 60 min post injection. A separate 10-min scan of the brain was subsequently performed. All studies were performed using a standard PET scanner with the images being interpreted by consensus of at least two experienced observers. Altogether, 119 studies were reported as normal (n = 96) or showing anatomic or normal variants (n = 23). Abnormalities involving extracranial organs were identified in 149 (55%) patients. Cerebral metastases were reported in 4 (1.5%) patients, only two of which (0.7%) were unsuspected prior to the PET scan. Incidental pathology (encephalopathy, infarct) was reported but unconfirmed in two further patients (0.7%). We conclude that routine ?screening' for cerebral metastases in patients with suspected malignancy has a low yield and may not be clinically useful. PMID- 8692487 TI - Serial changes in regional blood flow in the cerebrum and cerebellum of stroke patients imaged by 99Tcm-HMPAO SPET. AB - Luxury perfusion is a well-known phenomenon that can mask ischaemic lesions in patients with cerebral infarction, thus making diagnosis difficult. In this study, we evaluated the incidence of luxury perfusion over a 3-week period following a stroke episode. The usefulness of crossed cerebellar diaschisis (CCD) as a complementary feature in the diagnosis of cerebral infarction was also evaluated using 99Tcm-hexamethylpropyleneamine oxime (99TcmHMPAO) brain single photon emission tomography (SPET). Twelve patients diagnosed as having a hemispheric ischaemic stroke of the middle cerebral arterial territory were enrolled in the study. Each patient underwent a total of four 99Tcm-HMPAO brain SPET examinations, 1 day, 1 week, 2 weeks and 3 weeks following the stroke episode. Our results show that the incidence of luxury perfusion was 67% (8/12) after 1 week, 75% (9/12) after 2 weeks and 83% (10/12) after 3 weeks. The incidence of CCD was 33% (4/12) after 1 day, 50% (6/12) after 1 week, 42% (5/12) after 2 weeks and 33% (4/12) after 3 weeks. We conclude that the detection of cerebral infarction is difficult 2 weeks or more after a stroke episode. The interval between the stroke episode and examination must be considered when reading the 99Tcm-HMPAO image. In addition, CCD may be helpful for the diagnosis of cerebral infarction within the first week after a stroke episode, especially in cases of an unidentified ischaemic region on the 99Tcm-HMPAO hemispheric image. However, the value of CCD is limited 2 weeks or more following the stroke episode. PMID- 8692488 TI - Comparison of a corticopelvic transfer index with renal transit times. AB - The aim of this study was to compare a simple measure obtained visually from serial images, the corticopelvic transfer index (CPI), with renal transit times obtained by deconvolution. The CPI was defined as the time interval between the appearance of the tracer in the renal cortex to its appearance in the renal pelvis. Four groups of subjects as determined by clinical data and renal transit times were investigated retrospectively: 86 normal kidneys, 20 kidneys with renovascular disorder, 17 kidneys with obstructive nephropathy and 26 kidneys with dilated pelves without obstructive nephropathy. There were good correlations only between the CPI and mean parenchymal transit time (MPTT; r = 0.6) and the whole kidney transit time index (WKTTI; r = 0.8). It was concluded that in centres where gamma-camera studies with deconvolution analysis are not possible, the CPI could be a useful parameter in renal radionuclide scintigraphy for suspected renovascular disorders. PMID- 8692486 TI - What is the role of 1100 MBq (< 30 mCi) radioiodine 131I in the treatment of patients with differentiated thyroid cancer? AB - Based on pre-therapy whole-body 131I scintiscans showing only residual thyroid, 64 patients with differentiated thyroid cancer were treated with 1100 MBq ( < 30 mCi) 131I as out-patients. A follow-up whole-body scan with uptake measurements was made 6-12 months later. An uptake of 10%, this fell to 59%. A serum TSH > 10 microU ml-1 at the time of the first scan was associated with ablation (i.e. an uptake of < or = 0.3% on the follow-up scan) in 93% of patients. We recommend measurement of TSH and a whole-body scan to exclude regional or distant metastases, plus calculation of uptake in the neck to determine whether out patient therapy with 1100 MBq is appropriate. PMID- 8692489 TI - Head-to-head comparison of 201Tl rest-redistribution scintigraphy and stress immediate reinjection scintigraphy in the detection of myocardial viability. AB - Reinjection imaging with thallium-201 (201Tl) provides a reliable method of identifying viable myocardium. Reinjection of 201Tl immediately after completing the stress images followed by imaging 1 h after reinjection shortens the examination time to a maximum of 2.5 h and provides an alternative imaging approach in patients with coronary artery disease. In this study, we investigated whether immediate 201Tl reinjection imaging provides adequate information on myocardial viability compared with separate-day 201Tl rest or rest-redistribution imaging. In 23 patients with anterior or anteroseptal wall infarction first documented more than 3 months previously, we performed 201Tl stress-immediate reinjection, separate-day 201Tl rest imaging and rest-stress radionuclide angiography. In 13 patients, 201Tl rest scintigraphy was followed by redistribution imaging 3 h later. On the three-view planar 201Tl images, eight myocardial segments were analysed visually and quantitatively. Stress 201Tl images were compared with 201Tl reinjection images, 201Tl rest images and 201Tl 3 h redistribution images after rest injection. When comparing the stress images both with the immediate reinjection images and the rest images, concordant scintigraphic classification was found in 181 of 184 myocardial segments (kappa = 0.97). Comparing the stress images both with the immediate reinjection images and with the 3-h redistribution images following 201Tl injection at rest, concordant scintigraphic classification was found in 102 of 104 myocardial segments (kappa = 0.97). In 16 of 23 (70%) patients, 201Tl stress-immediate reinjection scintigraphy and radionuclide angiography provided concordant information on myocardial viability. In 6 (26%) patients, we observed a function-perfusion mismatch (i.e. 201Tl uptake in dyskinetic/adyskinetic regions) indicative of jeopardized but viable myocardium, demonstrating the additional value of 201Tl as a marker of viability. We conclude that stress-immediate 201Tl reinjection images provide information on myocardial viability and ischaemia in patients with previous myocardial infarction in addition to that obtained regarding wall motion abnormalities as assessed by rest-stress radionuclide angiography. PMID- 8692490 TI - Simultaneous assessment of regional adrenergic activity and perfusion with 123I MIBG and 201Tl in congestive heart failure. AB - Simultaneous assessment of regional adrenergic activity and perfusion with 123I meta-iodobenzylguanidine (123I-MIBG) and 201Tl in various organs was performed in 13 patients with congestive heart failure (CHF) and 13 subjects without heart failure. In order to reduce the crosstalk of 201Tl to the 123I energy window to less than 5%, a dose of 123I-MIBG more than five times greater than that of 201Tl was administered following 201Tl scintigraphy. Regional uptake of 201Tl (%dose) was significantly increased in the heart (left ventricle) and lung (both P < 0.01) in the patients with CHF. The increased global cardiac uptake could have been related to the enlarged left ventricle. The patterns of regional uptake of 123I-MIBG (% dose) at 15 min were similar to those of 201Tl, suggesting that early 123I-MIBG uptake could in part depend on regional perfusion in both groups. At 3 h, regional uptake of 123I-MIBG was significantly increased in the heart, lung and kidney (all P < 0.01) in the patients with CHF. The delayed 123I-MIBG uptake indicates the degree of neuronal accumulation of the tracer, and therefore reflects adrenergic activity. Interestingly, the cardiac 123I-MIBG (adrenergic activity) to 201Tl (unit of perfusion) ratio decreased significantly in the heart (P < 0.01) but increased significantly in the kidney (P < 0.01) in the patients with CHF compared with the control group. Cardiac 123I-MIBG washout was also significantly increased in the CHF patients. Moreover, the cardiac 123I MIBG:201Tl ratio was negatively correlated with plasma norepinephrine concentration (r = -0.74, P < 0.01), but positively correlated with LVEF (r = 0.60, P < 0.01). These data suggest that there may be impairment of both the neuronal uptake function and the vesicular storage function in the failing heart, and an increment in neuronal uptake function in the kidneys in patients with CHF. We suggest that dual-tracer scintigraphy is a useful non-invasive method for the simultaneous assessment of adrenergic activity and perfusion in various organs in patients with heart failure. PMID- 8692491 TI - The correlation of bone scintigraphy and histological findings in patellar tendinitis. AB - Patellar tendinitis is a chronic overuse injury causing pain and tenderness over the proximal insertion of the patellar tendon. Its management is usually conservative, but in intractable cases surgery is effective. Bone scintigraphy has been suggested as a useful investigation in these patients, although we are aware of no large series supporting this. Thirty-four patients with intractable symptoms of patellar tendinitis were treated surgically. The operative specimens were graded histologically and compared with preoperative radionuclide bone scans. The histological findings confirmed tendon and or tendon sheath abnormalities in all the samples. The predominant abnormalities were increased vascularity, fibroblast proliferation, acid mucopolysaccharide and haemosiderin deposition. Bone scintigraphy showed 24 (71%) patients to have abnormalities on the delayed images, 8 with diffusely increased activity in the patella and 16 with increased activity localized to the lower pole. Patients with abnormal bone scans had significantly more severe histological changes in their tendons. These findings support the use of radionuclide bone scans in the pre-operative assessment of patellar tendinitis correlating well with histopathological severity of the disease process. The 10 false-negative cases (29%), however, suggest that bone scans are unhelpful in the routine diagnosis and management of this condition. PMID- 8692492 TI - Liver uptake function measured by IODIDA clearance rate in liver transplant patients and healthy volunteers. AB - Hepatobiliary scintigraphy with 99Tc(m)-diethyl-iodo-HIDA (IODIDA), an iminodiacetic acid derivative, is used to assess hepatocyte function and to visualize the hepatobiliary system. The aim of this study was to evaluate whether it is possible to describe liver function by calculating the clearance rate of IODIDA from the blood. Clearance rate was evaluated in 18 liver transplant patients (28 studies) and 11 healthy volunteers (11 studies). Two different clearance rates were calculated: the clearance of IODIDA from the blood due to liver uptake and the total clearance of IODIDA from the blood due to all possible routes of elimination. Both for the healthy controls and the liver transplant patients, there was an excellent correlation between these two methods (r = 0.92 and r = 0.93, respectively), indicating that the liver is the only essential pathway for elimination of IODIDA from the blood. The difference in clearance rate between healthy controls and liver transplant patients was highly significant (P < 0.01), corresponding to the clinical condition of the two groups. We conclude that the clearance rate of IODIDA, based on a simple measurement from the time-activity curve derived from a blood pool region of interest, is a reliable test of liver function. PMID- 8692493 TI - Gallbladder visualization in 99Tcm-HMPAO autologous white cell scintigraphy. AB - The appearance of the gallbladder in images of patients undergoing 99Tcm hexamethylpropylene amine oxime (99Tcm-HMPAO) autologous white cell scans (AWCSs) was compared before and after the introduction of fasting in the white cell scan protocol in our department. Before February 1995, when fasting was not required as a condition of the test, gallbladders were identified in 10 and 13% of 128 patients at 1 and 3 h, respectively. After February 1995, when fasting was imposed for the duration of the AWCS procedure, gallbladders were identified in 44 and 58% of 139 patients undergoing an AWCS at 1 and 3 h, respectively (P < 0.01). While further studies are required to show that fasting affects the false positive rate, the results suggest that the degradation products of 99Tcm-HMPAO may be retained in the biliary system longer during fasting. Fasting should therefore be included in the protocol for an AWCS, particularly in the evaluation of inflammatory bowel disease (IBD) when 99Tcm-HMPAO is the cell label used. PMID- 8692494 TI - Pregnancy-related mortality in the United States, 1987-1990. AB - OBJECTIVE: To use data from the Centers for Disease Control and Prevention's (CDC) Pregnancy-Related Mortality Surveillance System to examine trends in pregnancy-related mortality and risk factors for pregnancy-related death. METHODS: In collaboration with ACOG and state health departments, the Pregnancy Related Mortality Surveillance System has collected information on all deaths caused by pregnancy since 1979. Multiple data sources were used, including national death files, state health departments, maternal mortality review committees, individuals, and the media. As part of the initiation of the Pregnancy-Related Mortality Surveillance System in 1987, CDC staff contacted state health department personnel and encouraged them to identify and report pregnancy-related deaths. Data were reviewed and coded by experienced clinicians. Pregnancy-related mortality ratios (pregnancy-related deaths per 100,000 live births) were calculated. RESULTS: After decreasing annually after 1979, the reported pregnancy-related mortality ratio increased from 7.2 in 1987 to 10.0 in 1990. This increase occurred among women of all races. A higher risk of pregnancy related death was found with increasing maternal age, increasing live-birth order, no prenatal care, and among unmarried women. The leading causes of pregnancy-related death were hemorrhage, embolism, and hypertensive disorders of pregnancy. During the periods 1979-1986 and 1987-1990, the cause-specific pregnancy-related mortality ratios decreased for deaths due to hemorrhage and anesthesia, whereas pregnancy-related mortality ratios due to cardiomyopathy and infection increased. The leading causes of death varied according to the outcome of the pregnancy. CONCLUSION: Increased efforts to identify pregnancy-related deaths have contributed to an increase in the reported pregnancy-related mortality ratio. More than half of such deaths, however, are probably still unreported. Adequate surveillance of pregnancy-related mortality and morbidity is necessary for interpreting trends, identifying high-risk groups, and developing effective interventions. PMID- 8692495 TI - Bone turnover and mineral metabolism in the last trimester of pregnancy: effect of multiple gestation. AB - OBJECTIVE: To test the hypothesis that maternal bone turnover and mineral stress are greater in multiple pregnancy than in singleton pregnancy. METHODS: We measured serum markers of bone turnover and mineral stress in 17 multiple and 30 singleton pregnancies during the third trimester. RESULTS: Serum 25(OH) vitamin D, a marker of vitamin D intake, was higher (61 +/- 5 versus 39 +/- 2 ng/mL, P < .001), and 1,25(OH)2 vitamin D was lower (50 [95% confidence interval (CI) 24 102] versus 64 pg/mL [95% CI 30-135], P = .03) in multiple than in singleton pregnancy. Carboxyterminal telopeptide of type I collagen, a marker of bone resorption, increased with gestational duration and was higher in multiple gestation (5.8 [95% CI 3.3-10.1] versus 4.4 ng/mL [95% CI 2.5-7.8], P = .005). Carboxyl-terminal propeptide of type 1 procollagen, a marker of bone formation, increased with gestational duration and was not different between groups (110 [95% CI 36-337] versus 99 ng/mL [95% CI 34-286], P = .5). Calcitonin increased with gestational duration and was not different between groups (7.0 [95% CI 3.7 13.0] versus 7.8 pg/mL [95% CI 4.0-15.4], P = .37). Parathyroid hormone was not different between groups and decreased with increasing maternal age. CONCLUSION: Bone turnover indices increased with gestational duration. The bone resorption index was greater in multiple than in singleton gestation. Serum 25(OH) vitamin D was greater and 1,25(OH)2 vitamin D was lower in multiple gestation, presumably because of greater consumption of vitamin D and minerals by women carrying more than one fetus. PMID- 8692497 TI - Comparison of age distribution of umbilical cord erythrocytes in preeclampsia versus uncomplicated pregnancy. AB - OBJECTIVE: To evaluate the age distribution of umbilical cord (fetal) erythrocytes in preeclamptic women. METHODS: Prospective evaluation of density distribution of erythrocytes was performed using the density distribution of cells method. Ten consecutive patients having preeclampsia in the third trimester and ten matched controls were studied. Maternal blood samples were taken during the latent phase of labor. Umbilical cord samples were taken immediately after the umbilical cord was cut. An additional control group that consisted of nonpregnant women (n = 30) was determined from our previously published studies. RESULTS: The erythrocyte population of umbilical cord blood of preeclamptic women has a younger age distribution than the erythrocyte population of umbilical cord blood of women with a normal pregnancy. CONCLUSION: The shift in age distribution of erythrocytes in umbilical cord blood of preeclamptic women could be attributed to a shorter life span of erythrocytes compared with that of uncomplicated pregnancy. PMID- 8692496 TI - Immunolocalization of eicosanoid enzymes and growth factors in human myometrium and fetoplacental tissues in failed labor inductions. AB - OBJECTIVE: To investigate the correlation between myometrial-derived eicosanoids and growth factors during the onset of parturition. METHODS: Myometrial samples were obtained from patients who were delivered by cesarean for failed induction or abnormal fetal heart rate tracings but who experienced normal labor progression until the occurrence of the abnormal tracing. Placentas and fetal membranes were obtained from patients with normal labor, no labor, and failed labor progression. The tissues were processed and sections were immunostained for cyclooxygenases, prostacyclin synthetase (PGI2-S), thromboxane A2 synthetase (TXA2-S), 5-lipoxygenase, epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), and EGF receptor, using specific antibodies directed against these molecules. RESULTS: Myometrial and fetoplacental tissues from women with normal labor, no labor, and failed labor contain immunoreactive cyclooxygenases, 5-lipoxygenase, TXA2-S, PGI2-S, EGF, TGF-alpha, and EGF receptor. However, their immunostaining intensity, with the exception of EGF receptor, decreased substantially in myometrium from women with failed labor induction compared with those having normal labor progression. No difference was noted in the immunostaining intensity of growth factors and eicosanoid enzymes in the fetoplacental membranes from these patients, except for cyclooxygenases, which were prominent in fetal membranes from normal labor compared with failed labor and no labor. CONCLUSION: Myometrial-derived eicosanoids and growth factors may be important in processes of parturition because reduction in their production in the myometrium is correlated with failed labor induction. Because of the regulatory action of growth factors in eicosanoid biosynthesis in uterine and fetoplacental tissues, EGF/TGF-alpha may indirectly influence the process of parturition by regulating eicosanoid production in the myometrium. PMID- 8692498 TI - Brain ionized magnesium and calcium levels during magnesium supplementation and deficiency in female Long-Evans rats. AB - OBJECTIVE: To examine the effect of changes in the state of magnesium balance on ionized magnesium and ionized calcium in serum and brain tissue of female rats. METHODS: Forty-two mature rats were used in the study. To induce hypermagnesemia, 12 rats received 270 mg/kg of magnesium sulfate intraperitoneally, followed every 20 minutes for 2 hours with 27 mg/kg magnesium sulfate. Ten control rats received an equal volume of saline. To induce hypomagnesemia, ten rats were placed on a magnesium-deficient diet for 4 (n = 5) or 8 (n = 5) days. Ten control rats were placed on basal diets of equal duration. Following treatment, rats were euthanized and serum and brain tissue were analyzed for ionized magnesium and calcium content. RESULTS: Hypermagnesemia produced a significant increase in serum ionized magnesium (P < .05) and calcium (P < .05). In addition, brain levels of ionized magnesium were significantly increased (P < .05), whereas calcium levels significantly decreased (P < .05) particularly in the hippocampus, parietal cortex, and cerebellum. Hypomagnesemia induced by 4 days on a magnesium deficient diet led to decreased serum ionized magnesium (P < .01) and total magnesium (P < .05) but did not affect brain magnesium levels. Brain levels remained unaltered even after 8 days of hypomagnesemia. Serum and brain ionized calcium were not affected during peripheral magnesium deficiency. CONCLUSION: During peripheral magnesium deficiency, brain levels of ionized magnesium and ionized calcium are tightly regulated and appear unaffected. However, central levels of these electrolytes are altered under hypermagnesemic conditions. Thus, magnesium administration may change biologically active portions of magnesium and calcium in the brain. PMID- 8692499 TI - Excess males in preterm birth: interactions with gestational age, race, and multiple birth. AB - OBJECTIVE: To confirm an excess of males among preterm births and study its interaction with other risk factors to better understand its potential etiologic significance. METHODS: Fetal gender was analyzed in 1,781,960 white and 103,329 black singleton births, and in 37,429 white twin births using vital statistics data from the six New England states for 1977-1988. RESULTS: A 7.2% excess of males was found among white singleton preterm births. There was only a 2.8% excess among comparable blacks, a highly significant difference between the races (P < .001). The effect was roughly constant for 20-37 weeks' gestation. Being married increased the effect for white, but not black, women, and was also found among white fetal deaths. Among white twins, male excess in preterm births occurred only in 20-33 week's gestations. CONCLUSIONS: Male fetal gender is associated with singleton preterm birth, an effect most evident in white women, particularly if married. Among preterm white twins, there is also a male excess, limited to gestations under 34 weeks. The excess of males in selected groups suggests the existence of a mechanism of preterm birth influenced by fetal gender. Preterm births in blacks and in twin gestations greater than 33 weeks may be more often due to alternative mechanisms that are independent of fetal gender. PMID- 8692501 TI - Doppler study of the fetal cardiac function in prolonged pregnancies. AB - OBJECTIVE: To evaluate the association between fetal cardiac function and amniotic fluid index (AFI) in postterm fetuses, and to determine if changes in fetal cardiac function precede the occurrence of nonreassuring intrapartum fetal heart rate (FHR) patterns. METHODS: Forty-five otherwise low-risk pregnant women between 41 and 43 weeks' gestation were studied longitudinally. Gestational age was confirmed in all patients by ultrasound before 20 weeks' gestation. Each subject had two or three tests performed every 3-4 days, including a non-stress test, a biophysical profile, and Doppler studies of the aortic and pulmonic outflow tracts. Aortic and pulmonic artery flow velocity waveforms were recorded slightly distal to the valves. Peak velocity, velocity time integral, and heart rate were calculated from the flow velocity waveforms we obtained. The change in AFI and aortic and pulmonic peak velocity and [velocity time integral] x [heart rate] were calculated for each fetus. RESULTS: Labor was induced at 42 weeks' gestation in 20 patients, and 17 entered labor spontaneously. Changes in AFI, observed during the follow-up period, correlated significantly with changes in aortic peak velocity (r = 0.54, P < .01) and with aortic outflow [velocity time integral] x [heart rate] (r = 0.60, P < .001) but not with pulmonic peak velocity and [velocity time integral] x [heart rate]. The decrease in aortic peak velocity and aortic and pulmonic [velocity time integral] x [heart rate] was significantly higher (P < .01) in eight fetuses that developed a nonreassuring intrapartum FHR (reduced FHR variability, late decelerations, and severe variable decelerations) than in those who had an uneventful labor. CONCLUSION: In prolonged pregnancies, cardiac function deteriorates in fetuses that develop a nonreassuring intrapartum FHR, and the changes in the left cardiac function correlate with changes in AFI. PMID- 8692500 TI - Perinatal outcome in growth-restricted fetuses: do hypertensive and normotensive pregnancies differ? AB - OBJECTIVE: To test the hypothesis that fetal growth restriction (FGR) associated with a maternal hypertensive disorder results in worse perinatal outcome than FGR in pregnancies without maternal hypertension. METHODS: All consecutive, singleton, nondiabetic, small for gestational age (SGA) deliveries (birth weight at or below the tenth percentile for gestational age) in a 15-year computerized data base were analyzed for pregnancy outcome. Perinatal outcome was compared after stratification by presence or absence of hypertensive disorders and by gestational age at delivery. RESULTS: Eleven thousand two hundred twenty-seven SGA pregnancies were analyzed. The morbidity and mortality profiles differed between hypertensive and normotensive pregnancies delivered preterm and those delivered at term. Perinatal mortality was significantly higher in the normotensive than in the hypertensive group in preterm deliveries (30.3 versus 18.7%, odds ratio [OR] 1.9 [confidence interval (CI) 1.3-2.9]). At term, hypertensive pregnancies demonstrated significantly higher mortality than normotensive pregnancies (4.6 versus 1.9%, OR 2.42 [95% CI 1.7-3.4]). In both preterm and term gestations, cesarean rates were significantly higher in hypertensive pregnancies than in normotensive pregnancies. Using logistic regression analysis, hypertension was independently associated with a 39% reduction in risk of perinatal mortality preterm, compared with a twofold increased risk of perinatal mortality at term. CONCLUSION: Before term, FGR in normotensive women resulted in significantly higher perinatal mortality than FGR in hypertensive women. In contrast, at term, FGR in pregnancies complicated by hypertension had poorer perinatal outcomes than FGR in normotensive women. PMID- 8692502 TI - Second-trimester minor ultrasound anomalies: impact on the risk of aneuploidy associated with advanced maternal age. AB - OBJECTIVE: To determine the impact of the presence or absence of minor ultrasound anomalies for the risk of aneuploidy in patients already at high risk because of advanced maternal age. METHODS: Eleven hundred forty-four women having amniocentesis for advanced maternal age were divided into those with minor ultrasound anomalies (n = 62) and those without (n = 1082). Two hundred fifty nine women younger than 35 years but with minor anomalies on ultrasound were also included. RESULTS: Fetal aneuploidy was found in six of 62 (9.7%) women of advanced maternal age with minor ultrasound anomalies, in five of 1082 (0.5%) women older than 35 years with normal ultrasound results, and in five of 259 (1.9%) women younger than 35 years with minor ultrasound anomalies. CONCLUSION: Minor ultrasound anomalies increase considerably the risk of aneuploidy in women older than 35 years, and their absence lowers that risk slightly. Minor ultrasound anomalies in the fetuses of women younger than 35 raises their risk to that of a 39-year-old women in her second trimester. Ultrasound can be used to modify genetic risks at counseling and may help patients in their decision to have invasive testing. PMID- 8692503 TI - Determination of fetal RhD status from uncultured amniocytes. AB - OBJECTIVE: To determine the accuracy of DNA analysis for fetal RhD status using polymerase chain reaction (PCR) on uncultured amniocytes. METHODS: Three hundred forty-seven amniotic fluid (AF) samples obtained for a variety of clinical indications were tested for fetal RhD status using PCR and primers specific for the genes coding for D and Cc/Ee. Fetal RhD status was confirmed by serologic methods on neonatal cord blood obtained at the time of delivery. RESULTS: In 346 of 347 cases (99.7%), the PCR results of AF were in agreement with the serologic RhD blood type. The single error was in an RhD-negative fetus (misidentified as RhD-positive) whose AF was contaminated with blood from an RhD-positive mother. The likelihood of an erroneous result was 0.3%. CONCLUSION: Polymerase chain reaction-based analysis of fetal RhD status using uncultured amniocytes and established primers appears to be highly accurate. PMID- 8692504 TI - Prolonged labor in nulliparas: lessons from the active management of labor. AB - OBJECTIVE: To define factors causing prolonged labor in nulliparous women undergoing active management of labor. METHODS: We included all nulliparas delivered during 1990-1994 with spontaneous onset of labor lasting more than 12 hours, singleton gestation, cephalic presentation, and labor at greater than 37 weeks. Each patient was matched with the next nulliparous woman who delivered with a labor lasting less than 12 hours and who fulfilled the same inclusion criteria. Subjects were managed according to the previously described active management of labor protocol from The National Maternity Hospital, Dublin. RESULTS: In the 5-year period, 9018 nulliparas met inclusion criteria, with 147 (1.6%) having prolonged labor. Prolonged labor was due to inefficient uterine action in 65%, persistent occipitoposterior position in 24%, and cephalopelvic disproportion in 11% of cases. Univariate analysis showed statistically significant (P < .05) differences in maternal body mass index, cervical dilation on admission, oxytocin use, epidural use, placement of epidural at less than 2 cm of dilation, and birth weight between these study groups. On multivariate conditional logistic regression analysis, the following were significant independent predictors for having a prolonged labor (odds ratios with 95% confidence intervals presented): 3.1 (1.3-7.3) for cervical dilation less than 2 cm on admission, 42.7 (7.5-242.0) for early epidural placement, 5.1 (1.9-13.7) for epidural placement at greater than or equal to 2 cm, and 10.2 (3.6-29.4) for birth weight greater than 4000 g. CONCLUSION: Less-advanced cervical dilation on admission and epidural use, especially when placed early, are strongly associated with prolonged labor. PMID- 8692505 TI - Meconium-stained amniotic fluid-associated infectious morbidity: a randomized, double-blind trial of ampicillin-sulbactam prophylaxis. AB - OBJECTIVE: To evaluate the efficacy of intrapartum prophylactic administration of ampicillin-sulbactam in reducing intraamniotic infection and postpartum endometritis in patients with meconium-stained amniotic fluid (AF). METHODS: Patients with intrapartum meconium-stained AF were randomized to receive either ampicillin-sulbactam or normal saline (placebo) intravenously at the time of diagnosis of meconium and every 6 hours until delivery. The outcomes of the two groups were compared with respect to intra-amniotic infection and postpartum endometritis. RESULTS: During the study period, 332 patients with meconium stained AF were approached for participation, and 120 patients met inclusion criteria and were enrolled. Patient demographics, labor, and delivery characteristics were similar. Ampicillin-sulbactam reduced the incidence of intra amniotic infection from 23.3 to 6.7%, (P = .02; relative risk [RR] 0.48, 95% confidence interval [CI] 0.22-0.98). The incidence of postpartum endometritis was also reduced, but the difference was statistically nonsignificant (8.3 versus 16.7%, P = .16; RR 0.64, 95% CI 0.30-1.33). CONCLUSION: Prophylactic intravenous ampicillin-sulbactam significantly reduces intra-amniotic infection in patients with meconium-stained AF. PMID- 8692506 TI - Induction of ovulation in clomiphene-resistant polycystic ovary syndrome with pulsatile GnRH. AB - OBJECTIVE: To determine the efficacy of pulsatile GnRH alone and in combination with clomiphene citrate or gonadotropins in a stepwise approach for inducing ovulation in women with clomiphene-resistant polycystic ovary syndrome (PCOS). METHODS: Eighty women with clomiphene-resistant anovulatory infertility and PCOS were given subcutaneous pulsatile GnRH (15 micrograms every 90 minutes) using a portable infusion pump. If no follicular development was seen, clomiphene citrate (100 mg/day for 5 days) was given concurrently with the hormone in the next cycle of treatment. Those who still failed to ovulate regularly were treated with combined pulsatile GnRH with intramuscular gonadotropins (one ampule per day for 5-7 days). RESULTS. Sixty-six of 131 (50%) pulsatile GnRH cycles, 94 of 142 (66%) pulsatile GnRH with clomiphene cycles, and 48 of 69 (70%) pulsatile GnRH with gonadotropin cycles were ovulatory. Monofollicular response (one follicle at least 14 mm on the day of ovulation) occurred in 80.6, 83.9, and 53.6% of cycles, and multifollicular response occurred in 4.8, 3.1, and 21.6% of cycles in the three groups, respectively. Mild ovarian hyperstimulation occurred in one of the 342 cycles. The cumulative conception rate was 30% after three cycles, 60% after six cycles, and 73% after nine cycles. The miscarriage rate was 22% (ten of 45 pregnancies), and 35 women (78%) had live births (33 singletons and two sets of twins). CONCLUSION: The use of subcutaneous pulsatile GnRH alone and in combination with clomiphene citrate or gonadotropins for induction of ovulation in clomiphene-resistant PCOS in a stepwise approach produces a high cumulative conception rate associated with a low rate of multiple pregnancy and ovarian hyperstimulation syndrome. PMID- 8692507 TI - Experiences of injectable contraceptive users in an urban setting. AB - OBJECTIVE: To examine method-related experiences and acceptability of depot medroxyprogesterone acetate (DMPA) among women using this contraceptive for the first time. METHODS: Five hundred thirty-six women who received an injection of DMPA from any of seventeen clinical settings in southeast Texas, United States, were followed for 1 year. At each follow-up visit, patients were asked about their experiences with DMPA during the past 3 months and their plans to use this method in the future. RESULTS: Amenorrhea, irregular bleeding, and weight gain were the conditions reported most frequently. Reports of amenorrhea, weight gain, and acne or skin problems increased over time, but complaints of longer periods decreased (P < .001). Two pregnancies occurred during the study period. However, of these, one existed before the first injection. Depot medroxyprogesterone acetate's continuation rate at 1 year was 28.6%. Heavier and more frequent bleeding, increased cramping, amenorrhea, weight gain, headaches, depression, and nervousness were more frequent complaints of women who discontinued DMPA (P < .05), whereas lighter and less frequent bleeding were reported more often by those who continued to use this method (P <.05). Women who discontinued use of DMPA were more likely to be married and have a concern about injectable contraceptives than those who continued to use this method. CONCLUSION: Intolerable side effects and changes in menstrual pattern are the most frequently indicated reasons for discontinuing DMPA use. Our results suggest that DMPA's 1 year continuation rate may be lower than previously reported. PMID- 8692508 TI - Natural cytotoxicity and GnRH agonist administration in advanced endometriosis: positive modulation on natural killer activity. AB - OBJECTIVE: To investigate the effects of pharmacologic suppression of ovarian function on the immune system, with respect to the clinical outcome of endometriosis and the possibility of an immunoendocrine combined treatment. METHODS: After informed consent, 25 of 37 patients with revised American Fertility Society stage III and IV endometriosis who underwent postoperative medical treatment were selected and enrolled for this immunoendocrine longitudinal study. Medical treatment consisted of tryptorelinum depot injection, 3.75 mg/month for 24 weeks. Blood samples were collected before the first injection in the early follicular phase, day 2-3 of the cycle, and during medical treatment (every 4 weeks) and follow-up (every 6 months). At the end of the study, we had ten blood samples per patient to evaluate the cytotoxic activity, the number of natural killer cells, and the serum levels of estradiol. Natural killer activity was determined against the K562 cell line by target cell retention of the fluorescent dye carboxyfluorescein diacetate. RESULTS: A positive immunomodulating effect was observed during GnRH agonist administration. In particular, a significant progressive increase in natural killer cell activity was defined within the first 12 weeks of medical treatment; after three injections, we observed the highest values of cytotoxicity, with a median of 7.1 lytic units (range 0.3-14.0; P = .02). Natural cytotoxicity then decreased toward a plateau, which persisted during therapy completation and follow-up, with slight fluctuations. In patients who had recurrence, the values of natural killer cell activity were constantly lower than those in patients with disease-free follow up, particularly within the first 12 weeks of medical treatment. PMID- 8692509 TI - Economic evaluation of hysteroscopic endometrial ablation versus vaginal hysterectomy for menorrhagia. AB - OBJECTIVES: To estimate society's expenses and benefits of hysteroscopic endometrial ablation and vaginal hysterectomy for the treatment of women with menorrhagia. METHODS: Between June 1992 and July 1993, 40 women with menorrhagia underwent vaginal hysterectomy by five surgeons in one hospital. These patients were compared retrospectively with the first 40 patients having had endometrial ablation for menorrhagia during the same period by the senior author (GAV). The age, parity, weight of patients, and uterine size were similar in both groups. Measurable variables that would incur costs included surgical time, procedure time (anesthetist and resource use in operating room), length of hospital stay, convalescence (value of patient time), and indirect costs associated with subsequent surgical procedures. Measurable benefits included reduction in blood loss and complications, and effectiveness of procedure. RESULTS: The total cost per episode of care was estimated to be $5373 and $2279 (1995 Canadian dollars) for vaginal hysterectomy and hysteroscopic endometrial ablation, respectively, a mean savings of $3094. The benefits derived from both procedures were comparable. Vaginal hysterectomy eliminated bleeding in 100% of patients and had a complication rate of 41%. Endometrial ablation eliminated or improved bleeding in 90% of patients (amenorrhea 46%, hypomenorrhea 35%, eumenorrhea 9%, no significant change 10%), was associated with no complications, and resulted in 82% patient satisfaction. CONCLUSION: Endometrial ablation is 82% effective and 58% less expensive than vaginal hysterectomy for the treatment of women with menorrhagia. PMID- 8692510 TI - Clinical and pathologic characteristics of women undergoing hysterectomy after tubal sterilization. AB - OBJECTIVE: To examine differences in clinical and pathologic characteristics between women undergoing hysterectomy who had had prior tubal sterilization and those who had not. METHODS: One thousand eight hundred fifty-one women undergoing hysterectomy were enrolled as part of a multicenter, prospective cohort study. We used logistic regression to describe the association between prior tubal sterilization and patient characteristics at hysterectomy. RESULTS: Although sterilized women were not more likely than nonsterilized women to have a menstrual disorder as a presenting complaint, they were more likely to have a primary discharge diagnosis of menstrual disorder (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2-2.0). After adjustment for menstrual indices, sterilized women had an increased probability of having normal findings on pathologic examination, which differed by age (women less than 30 years: OR 3.4, 95% CI 2.0-5.8; women 30 years of age and older: OR 1.7, 95% CI 1.3-2.3). CONCLUSION: Differences in clinical and pathologic characteristics between sterilized and nonsterilized women suggest that nonbiologic factors may influence decision making regarding hysterectomy among sterlized women. PMID- 8692511 TI - Comparison of Burch and lyodura sling procedures for repair of unsuccessful incontinence surgery. AB - OBJECTIVE: To assess the effectiveness and late postoperative morbidity of the Burch procedure and the sling procedure for the treatment of recurrent urinary stress incontinence after vaginal hysterectomy and anterior repair. METHODS: Clinical, urodynamic, and sonographic examinations were done on 77 women suffering with recurrent urinary stress incontinence. The women were randomized to two groups, modified Burch colposuspension and lyophilized dura mater sling surgery; 72 women were reexamined 32-48 months after these procedures. RESULTS: The cure rate at 32-48 months' follow-up was 86% for the Burch procedure and 92% for the sling. Women who had had the sling procedure demonstrated a clear decrease in maximal bladder capacity, from 330 to 240 mL (P < .05). In both groups, stress profiles demonstrated a shift of maximal pressure point toward the proximal urethra and a significant improvement in pressure transmission (P < .05). The post-operative patients who had persistent incontinence were found to have insufficient elevation of the bladder neck (less than 10 mm). The uroflow examination showed an increase of urination time in both groups. The incidence of bladder problems was 10% with the Burch procedure and 29% with the sling procedure; however, 13% of the Burch group developed rectoceles. CONCLUSION: Both procedures offer a high rate of success. We believe that the sling surgery should be used only in certain special cases because of its higher rate of complications, but that posterior vaginal repair should be considered after modified Burch colposuspension because of the possibility of rectocele and enterocele. PMID- 8692512 TI - Absence of papillomavirus DNA in normal tissue adjacent to most cervical intraepithelial neoplasms. AB - OBJECTIVE: To determine if human papillomavirus (HPV) DNA is present in the normal mucosa adjacent to cervical intraepithelial neoplasia (CIN). METHODS: Serial sections of 28 CIN lesions were studied. Lesional and normal epithelia and stroma were microdissected; the DNA was extracted and amplified by polymerase chain reaction (PCR) using primers designed to amplify both HPV late (L1) and human beta-globin sequences. Human papillomavirus was typed by restriction fragment length polymorphism analysis following digestion of PCR products. RESULTS: Twenty-five of 28 (89%) lesional epithelia scored positive for HPV nucleic acids. In' four of 25 (16%) HPV-positives, the normal squamous epithelium scored positive for HPV nucleic acids, two of which (8%) also scored positive in the stroma. Repeat microdissection and PCR analysis of three of these cases was performed and all were negative in both normal epithelium and stroma, suggesting laboratory contamination. CONCLUSION: Human papillomavirus nucleic acids are present uncommonly in normal-appearing squamous epithelium adjacent to CIN. This does not exclude occult infection in the natural history of CIN but indicates that when lesions develop, occult infection is not normally maintained in the normal mucosa. This is consistent with the low recurrence rates following ablation as well as low indices of HPV positivity in normal cervices during follow-up. This finding should be taken into consideration when counseling patients and is relevant to the concept of HPV testing during follow-up after cone biopsy. PMID- 8692513 TI - Short-term fluctuations in the detection of cervical human papillomavirus DNA. AB - OBJECTIVE: To obtain point and cumulative prevalence estimates of cervical human papillomavirus (HPV) infection using two HPV DNA detection methods with different end point sensitivities; compare cervical swab and cervicovaginal lavage specimen collection methods for subsequent evaluation by polymerase chain reaction (PCR); and evaluate potential effects of the menstrual cycle on HPV DNA detection. METHODS: Seventy-two college women participated in a 10-week follow-up study. Cervical samples were obtained for HPV DNA detection and typing at each clinic visit, and information was collected concerning menstrual cycle and sexual and hygienic behaviors. Human papillomavirus DNA was detected by the ViraPap HPV DNA dot-blot assay and a broad-spectrum PCR HPV DNA amplification system. RESULTS: On a weekly basis, point prevalence for HPV infection by the ViraPap assay ranged from 4.2 to 9.7%, and the cumulative prevalence was 13.9%. Point prevalence by the broad-spectrum PCR assay ranged from 20.8 to 47.2%, and the cumulative HPV prevalence was 58.3%. Using cervicovaginal lavage specimens, we found lower cervical HPV prevalence estimates when compared with cervical swab specimens in the HPV PCR-based assay. No correlation between HPV DNA detection and phase of menstrual cycle was observed. CONCLUSION: Short-term HPV DNA detection is highly variable within individuals; therefore, single-point measurements of cervical HPV have limitations when assessing an individual's HPV status. The relationship between short-term and long-term HPV DNA persistence profiles may prove relevant to determining the risk of developing cervical intraepithelial neoplasia. PMID- 8692514 TI - Characteristics of women with AIDS and invasive cervical cancer. AB - OBJECTIVE: To characterize women reported with AIDS and invasive cervical cancer in the first year of the expanded AIDS surveillance case definition. METHODS: Using X2 testing and logistic regression, we compared women with invasive cervical cancer with those having other AIDS-defining illnesses. RESULTS: Of the 16,794 women 13 years old or older and reported with AIDS in 1993, 217 (1.3%) had invasive cervical cancer and 9113 (54.3%) had other opportunistic illnesses; the remaining 7464 (44.4%) had no opportunistic illnesses and were reported based on immunologic criteria. Women with invasive cervical cancer were more likely to have had AIDS diagnosed before 1993 (73 and 56%, respectively; P < .01), to be younger (median age 33 and 35 years; P < .001), to be white (31 and 21%; P < .01), and to reside in the south (41 and 34%; P < .05). Among women reported with CD4+ counts, the median value was higher in 149 women with invasive cervical cancer than in the 5993 with other opportunistic illnesses (153 and 50 cells/microL, respectively). Women with invasive cervical cancer were more likely to report injection drug use (57 and 48%; P < .05). In multivariate analysis, Hispanic women were 0.6 times less likely to be reported with invasive cervical cancer than were white women (P < .05). Among women infected through injecting drug use, black women were 0.5 times less likely to be reported with invasive cervical cancer (P < .001). CONCLUSION: Hispanic and black women infected with HIV were less likely to be reported with invasive cervical cancer, a finding that may be associated with inadequate access to health care services. Women with invasive cervical cancer were less severely immunosuppressed than women with other AIDS opportunistic illnesses. PMID- 8692515 TI - Risk factors for recurrence in patients with stage IB, IIA, and IIB cervical carcinoma after radical hysterectomy and postoperative pelvic irradiation. AB - OBJECTIVE: To identify risk factors for cancer recurrence in patients with stage IB, IIA, and IIB cervical carcinoma after abdominal radical hysterectomy with pelvic lymph node dissection and postoperative pelvic irradiation. METHODS: One hundred and eighty-seven patients with cervical carcinoma stage IB (n = 63), IIA (n = 43), and IIB (n = 81) disease who received abdominal radical hysterectomy with pelvic lymph node dissection and postoperative pelvic irradiation were followed-up for 2-10 years. The histologic type, grade, lymphovascular tumor emboli, tumor size, invasion sites, deep cervical stromal invasion, and pelvic lymph node metastases were assessed for correlation with cancer recurrence. RESULTS: Recurrence occurred in 45 cases (24%), of whom 40 had died of the disease at the 5-year follow-up period. Univariate proportional hazards analysis revealed that the significant risk factors were adenocarcinoma, bulky tumor size (4 cm or greater), lymphovascular tumor emboli, deep cervical stromal invasion, and lymph node metastases, especially iliac nodal metastases and bilateral nodal metastases. Multivariate proportional hazards analysis showed that bulky tumor size (hazard ratio 2.34), tumor emboli (hazard ratio 2.74) and iliac nodal metastases (hazard ratio 5.31) remained significant risk factors. In contrast, no deaths occurred in the other 142 cases who did not have recurrence. CONCLUSION: This retrospective study suggests that stage IB, IIA, and IIB cervical carcinoma cases with the above-mentioned pathologic factors are at higher risk of recurrence after abdominal radical hysterectomy with pelvic lymph node dissection and postoperative pelvic irradiation. PMID- 8692516 TI - Pelvic lymph node metastasis in endometrial cancer with no myometrial invasion. AB - OBJECTIVE: To analyze the incidence of pelvic lymph node metastasis in endometrial carcinoma with no myometrial invasion. METHODS: Between 1971 and 1995, 684 women with stage I endometrial carcinoma underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph-adenectomy. The incidence of pelvic lymph node metastases in 100 cases without myometrial invasion was examined. RESULTS: Histologic examination of the surgical specimens revealed a single pelvic lymph node metastasis in each of four cases. The incidence of pelvic lymph node metastasis was four of 83 in grade 1, zero of 13 in grade 2, and zero of four in grade 3 tumors. CONCLUSION: Pelvic lymph node metastasis in endometrial cancer with no myometrial invasion is not rare, even with grade 1 tumors. Lymphadenectomies may be necessary in all patients with endometrial cancer, except when clinical or operative factors increase the procedure's risk of morbidity. PMID- 8692517 TI - Color and pulsed Doppler sonography, gray-scale imaging, and serum CA 125 in the assessment of adnexal disease. AB - OBJECTIVE: To compare color and pulsed Doppler sonography with gray-scale ultrasound imaging and serum CA 125 levels in establishing accurate preoperative diagnoses of adnexal masses. METHODS: Medical records of 109 patients referred with preexisting adnexal lesions were reviewed retrospectively by comparing preoperative ultrasonic data (gray-scale imaging and color and pulsed Doppler findings) with serum CA 125 levels. RESULTS: Eighty-three masses were removed surgically, confirming seven malignancies and 76 benign tumors, and 26 masses were followed; 15 regressed and 11 persisted. Color and pulsed Doppler sonography showed the highest sensitivity, followed by gray-scale imaging, whereas serum CA 125 levels revealed the highest specificity in distinguishing malignant from benign adnexal tumors. All three methods had high negative predictive values (96 100%), whereas only serum CA 125 had a positive predictive value greater than 50%. CONCLUSION: Color and pulsed Doppler sonography, which demonstrate a tumor angiogenic activity, are as accurate as gray-scale imaging in the assessment of adnexal lesions. Together with serum CA 125 marker levels, they produce high negative predictive values, providing reassurance that an adnexal mass is benign. PMID- 8692518 TI - Infertility treatment dropout and insurance coverage. AB - OBJECTIVE: To assess early patient dropout rates during infertility treatment as a potential measure of wasted resources. METHODS: The study involved multifaceted population cohorts, including a prospectively observed captive health maintenance organization (HMO) population and retrospectively selected preferred provider organization (PPO) patients. One hundred twenty-eight HMO couples were followed prospectively for 6 months. The insurance carrier retroactively selected 96 couples from their PPO population who were believed to be infertility patients. They were matched by date, age, and time of hysterosalpingography to infertility patients in the carrier's HMO population. Patients were considered treatment dropouts if they either requested their provider to abandon further work-up or treatment, or if they failed to return for an appointment for 3 months. RESULTS: Forty-six of 128 (36%) HMO patients followed prospectively discontinued care within 180 days, with only eight (6.3%) providing defined reasons. Preferred provider organization patients uniformly demonstrated significantly higher dropout rates than HMO patients, a finding already apparent at 60 days (P < .002; odds ratio [OR] 3.67, 95% confidence interval [CI] 1.47-9.97) and 120 days of treatment (P = .002; OR 2.87, 95% CI 1.39-6.06). Among PPO patients, dropout rates were especially pronounced if infertility care was provided by generalists. At billing levels of at least $2000, HMO patients also demonstrated less dropout than PPO patients (P < .001; OR 6.14, 95% CI 2.72-14.79), with generalists again demonstrating a significantly larger patient loss than infertility specialists (P < .001; OR 0.18, 95% CI 0.66-0.49). CONCLUSION: Infertility patients demonstrate a surprisingly large early dropout rate, which is significantly larger if patients receive infertility care from generalists rather than specialists. Newly presenting infertility patients should be carefully evaluated, especially in indemnity situations, before expensive diagnostic and therapeutic interventions are ordered. PMID- 8692519 TI - Transvaginal bladder neck suspension to Cooper's ligament: a modified Pereyra procedure. AB - We describe a modified Pereyra procedure with fixation of the bladder neck to Cooper's ligament. The anterolateral attachments of the paraurethral tissue to the inferior pubic ramus are exposed through a vaginal incision. Sutures are placed in the detached endopelvic fascia together with vaginal wall without epithelium and passed suprapubically through small ipsilateral skin and fascial incisions made slightly lateral to and at the level of the pubic symphysis, allowing visualization of Cooper's ligament. The sutures are passed through Cooper's ligament and tied to suspend the bladder neck. All ten women in whom we have done this operation have been subjectively cured of stress incontinence. Five have had long-term urodynamic follow-up. Four of these were dry by objective criteria, after a mean follow-up time of 18 months (range 15-23). The other patient was subjectively dry but had urodynamic evidence of recurrent stress incontinence. PMID- 8692520 TI - Student doctors and women in labor: attitudes and expectations. AB - OBJECTIVE: To compare the attitudes and expectations that obstetric patients and medical students bring to the student-patient relationship in intrapartum care. METHODS: Written questionnaires were distributed to obstetric patients who had students assist in their labor and delivery care and to medical students who had completed their clinical clerkship year. Responses of 222 patients and 67 students were analyzed for differences in expectations of student participation and assessment of skills. RESULTS: Responses of medical students and patients were significantly different in all attitudes and expectations studied. One hundred thirty-six (61%) patients compared with 27 (40%) students identified the patients' wish to contribute to the education of students as the most important reason for agreeing to student participation. All patients felt that student participation should be requested rather than assigned, with 194 (87%) patients but only 30 (45%) students wishing to have the student absent from the room at the time of the request. Mean ratings of different student skills tended to be higher from patients (1.3-1.8 on a seven-point Likert scale) than from the students themselves (range 1.6-2.4). Although students' expectations of participation in patient care were high, patients indicated expectations of fairly low levels of student involvement in communication, examination, labor support, and procedures. CONCLUSION: Students have high expectations for their active involvement in intrapartum care and tend to under-estimate the sense of altruism that motivates patients to allow student participation. Patients have low expectations of levels of student participation in their care, but are overall quite satisfied with the skills of the students. These differences highlight the need for the development of educational objectives that clarify student roles in clinical clerkships and the process of informed consent for student participation. PMID- 8692521 TI - Adjunctive antibiotic treatment in preterm labor and neonatal morbidity: a meta analysis. AB - OBJECTIVE: To estimate the effect of prophylactic antibiotics on neonatal mortality and morbidity in patients with preterm labor, based on a meta-analysis of seven published randomized clinical trials. DATA SOURCES: We searched 18 medical data bases, including MEDLINE from 1964 and EMBASE from 1974, to identify all literature included under preterm or premature labor and antibiotics. We scanned all abstracts from the computer printouts, the retrieved full-text reports, the references from each retrieved report, and review articles to determine whether studies met our inclusion criteria. METHODS OF STUDY SELECTION: The following criteria were used to select studies for inclusion: article original published report written in English; study design-randomized controlled trial; population-patients with preterm labor, defined as labor before 37 weeks' gestation; intervention-antibiotic treatment; and one or more of the following outcomes-neonatal mortality, sepsis, pneumonia, respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis. TABULATION, INTEGRATION AND RESULTS: We analyzed study patients and methods, and abstracted quantitative outcome data. For each outcome, both odds ratio (OR) and 95% confidence interval (CI) were calculated. Seven trials, published between 1989 and 1995 included a total of 795 patients. Adjunctive antibiotic therapy appeared to reduce the risk of pneumonia (OR 0.45, 95% CI 0.12-1.72) and necrotizing enterocolitis (OR 0.38, 95% CI 0.14-1.08) and to increase the risk of neonatal mortality (OR 3.25, 95% CI 0.93-11.38), but it had no effect on neonatal sepsis (OR 0.98, 95% CI 0.34-2.83), respiratory distress syndrome (OR 0.93, 95% CI 0.54 1.87), and intraventricular hemorrhage (OR 1.01, 95% CI 0.20-5.10). None of the effects observed reached a significance level of P < .05. CONCLUSION: The results of this meta-analysis do not support the routine use of adjunctive antibiotic treatment in patients with preterm labor diagnosed on the basis of subjective uterine contractions and the resulting cervical changes. PMID- 8692522 TI - Placental abruption and its association with hypertension and prolonged rupture of membranes: a methodologic review and meta-analysis. AB - OBJECTIVE: To conduct a meta-analysis of published studies on placental abruption to examine its incidence, recurrence, and association with hypertensive disorders (chronic hypertension and preeclampsia) and prolonged rupture of membranes (PROM) in pregnancy. DATA SOURCES: We reviewed studies on placental abruption published since 1950, based on a comprehensive literature search using MEDLINE, and by identifying studies cited in the references of published reports. METHODS OF STUDY SELECTION: We identified 54 studies, excluding case reports on placental abruption and studies relating to placenta previa and vaginal bleeding of unknown origin. We also restricted the search to articles published in English. TABULATION, INTEGRATION, AND RESULTS: Studies chosen for the meta-analysis were categorized based on their study design (case-control or cohort), where they were conducted (United States or other countries), source of the data (vital records versus other sources), and magnitude of risk (risk of abruption greater or less than 1.0%). We used both fixed- and random-effects analysis to identify sources of heterogeneity in results among studies. There were striking differences in the incidence of placental abruption between cohort (0.69%) and case-control (0.35%) studies. United States-based studies found a somewhat higher incidence both for cohort (0.81%) and case-control (0.37%) studies compared with studies conducted outside the U.S. (0.60% and 0.26%, respectively). Abruption was more than ten times more common in pregnancies preceded by a pregnancy with abruption. Chronically hypertensive patients were more than three times as likely to develop placental abruption (odds ratio [OR] 3.13, 95% confidence interval [CI] 2.04 4.80) as normotensive patients. The OR for placental abruption was 1.73 (95% CI 1.47-2.04) for patients with preeclampsia. Similarly, women with pregnancies complicated by PROM were more than three times as likely to develop placental abruption (OR 3.05, 95% CI 2.16-4.32). United States-based studies, case-control studies, and studies with an incidence of abruption greater than 1% demonstrated stronger associations between abruption and hypertension and PROM. CONCLUSION: Risk of abruption is strongly associated with chronic hypertension, PROM, and especially abruption in a prior pregnancy, and somewhat more modestly with preeclampsia. The criteria for the diagnosis of placental abruption, hypertensive disorders, and PROM may have introduced variability among the results of these studies. More standardized definitions of these pregnancy complications would improve the comparability of the study results. PMID- 8692523 TI - The length of active labor in normal pregnancies. PMID- 8692524 TI - Why don't racing associations provide hearing protection? PMID- 8692525 TI - Proper fall protection training. PMID- 8692526 TI - Wipe out slips and falls. PMID- 8692527 TI - Head protection for industrial and construction applicants. PMID- 8692528 TI - Preoperative interleukin-2 subcutaneous immunotherapy may prolong the survival time in advanced colorectal cancer patients. AB - It has been demonstrated that surgery may induce immunosuppression. This finding could influence the clinical course of surgically treated cancer patients. Moreover, preliminary experimental studies have shown that a preoperative injection of IL-2, whose importance in generating the antitumor immune response is well known, may neutralize surgery-induced immunosuppression. At present, however, it is still unknown whether preoperative IL-2-induced immune improvement in the postoperative period may influence the prognosis of surgically treated cancer patients. The present study was performed to evaluate the prognostic impact of IL-2 presurgical therapy in advanced colorectal cancer patients. The study included 50 colorectal cancer patients, Dukes' stage D, who were randomized to be treated with or without IL-2 preoperatively (18.10(6) IU/day subcutaneously for 3 consecutive days). After surgery, all patients underwent chemotherapy with 5-FU and folates until disease progression. Postoperative mean numbers of lymphocytes, T lymphocytes, natural killer cells and activated lymphocytes were significantly higher in IL-2-treated patients than in controls. Moreover, the percent of lymphocytic and/or eosinophilic tumor infiltration was significantly higher in IL-2 group than in controls. Finally, both survival curve and the percent of survival at 1 year were significantly greater in patients pretreated with IL-2 than in controls. This clinical trial demonstrates that preoperative IL 2-induced neutralization of postoperative lymphocytopenia is associated with a prolonged survival time in advanced colorectal cancer patients. PMID- 8692529 TI - Epidoxorubicin and double biochemical 5-fluorouracil modulation with folinic acid and human lymphoblastoid interferon in advanced gastric carcinoma: a multicentric phase II study of the Southern Italy Oncology Group (GOIM). AB - In our previous randomized trial of advanced gastric cancer patients, the addition of epirubicin (EPI) to 5-fluorouracil (FU) with folinic acid (FA) resulted in an improved response rate and survival in the responder patients. Preclinical studies also showed an enhancement of FU and anthracyclines with interferon. To evaluate the possibility of human lymphoblastoid interferon (IFN) to enhance the therapeutic activity of the FA-FU + EPI combination regimen, 39 advanced gastric cancer patients received: FU at 375 mg/m2 i.v. immediately after FA (l-isomer form) at 100 mg/m2 i.v. for 5 consecutive days; EPI at 60 mg/m2 i.v. on day 1, and IFN 3 MU s.c. for 7 consecutive days, starting 2 days before the FA FU administration. Thirty-seven patients were evaluable for response and toxicity. Twelve partial responses were observed with an overall response rate of 32% (95% CI, 17-48%). The median response duration was 6 months, and the median survival time was 8 months. Toxicity was mild and no grade 4 side effects or treatment-related deaths were observed. However, the addition of IFN to the FA-FU + EPI regimen did not improve response, duration of response or survival. PMID- 8692530 TI - Bone-specific alkaline phosphatase in plasma as tumour marker for osteosarcoma. AB - The levels of bone-specific alkaline phosphatase (BALP) in plasma and tumour tissue samples of 20 Chinese patients with osteosarcoma in Hong Kong were measured by the wheat germ lectin precipitation technique. The plasma BALP levels in these patients were significantly higher than those of the normal subjects (p < 0.001), and also significantly higher than those of patients with benign bone tumor and those of patients with malignant tumor metastasized to the bone (p < 0.0001). Considering the prognostic value of BALP for osteosarcoma, the plasma BALP levels at the time of diagnosis were found to be significantly related to the rate of disease recurrence (p < 0.05). Furthermore, at the time of relapse, the plasma BALP levels in the group of recurrent osteosarcoma patients were significantly higher than those of osteosarcoma patients showing no recurrence (p < 0.05). When ALP was assayed in the tumor tissue, the BALP levels were also significantly higher than those of the control cortical bone extracts in the same group of patients (p < 0.05). We conclude that plasma BALP is a sensitive and specific biochemical parameter in the diagnosis and the subsequent monitoring of osteosarcoma. PMID- 8692531 TI - Intravesical bacillus Calmette-Guerin versus epirubicin in the prophylaxis of recurrent and/or multiple superficial bladder tumours. AB - A prospective, randomized trial was conducted to evaluate and compare the effects of modified adjuvant intravesical bacillus Calmette-Guerin (BCG) and epirubicin regimens in patients with superficial bladder cancer. One hundred thirty-two individuals with recurrent and/or multiple neoplasms, i.e. at high risk for tumour recurrence and progression, were enrolled. After complete transurethral resection of their tumours, the patients received a 6-week course of BCG instillations or an early 4-week course of epirubicin instillations as their initial therapy. Those with stage Ta and grade 1 neoplasms who remained free of recurrences received maintenance therapy consisting of single quarterly instillations. However, for those with stage T1 cancer of any grade or stage Ta of grade 2 or 3 neoplasms who also remained free of recurrences, the treatment schedules were modified: they received, instead of single maintenance doses, 3 weekly instillations of epirubicin at months 3 and 6 of follow-up, or a 3-week course of BCG at month 6 of follow-up. The recurrence-free rates did not differ significantly between the two study groups (44% for epirubicin versus 55% for BCG), for an identical median follow-up of 43 months. However, in terms of relative risk of recurrences, disease-free intervals and recurrence rate per 100 patient-months, a significant benefit in favour of BCG when compared with epirubicin was demonstrated in patients who had stage T1 or grade 3 neoplasms. PMID- 8692532 TI - Dose intensity of standard adjuvant CMF with granulocyte colony-stimulating factor for premenopausal patients with node-positive breast cancer. AB - The effects of granulocyte colony-stimulating factor (G-CSF) on total dose and dose intensity of standard oral adjuvant CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) chemotherapy were studied in premenopausal patients with node positive breast cancer. Treatment consisted of standard CMF and locoregional radiotherapy (on indication). G-CSF was administered if the leukocyte count recovery was insufficient. Fifty-one patients required no G-CSF ("no cytopenia'), and 50 patients received G-CSF ("G-CSF). Twenty-two patients, however, received no G-CSF support despite insufficient leukocyte recovery ("control'). Following G CSF, leukocyte recovery was adequate in 83% of the chemotherapy cycles. The proportion of the patients who had a dose intensity > or = 85% was 90% in the "no cytopenia' group, 74% in the "G-CSF' group, and 45% in "control' group (p < 0.05). Leukocyte recovery was adequate in 87% of the chemotherapy cycles in the patients who received radiotherapy as compared with 92% of those in the patients without radiotherapy (p < 0.05). In conclusion an adequate leukocyte recovery after G-CSF was found in 83% of all chemotherapy cycles. The dose intensity of the G-CSF group was higher as compared with controls. The impact of radiotherapy on hematological recovery was significant, but not dependent on G-CSF. PMID- 8692533 TI - Assessing psychological distress in cancer patients: validation of a self administered questionnaire. AB - BACKGROUND: Screening for psychological distress in cancer patients is important, considering the high prevalence of psychiatric disorders responsive to treatment. The aim of this study is to test the psychometric properties of the Psychological Distress Inventory (PDI), a 13-item self-administered questionnaire developed to measure psychological distress in cancer patients. PATIENTS AND METHODS: The PDI was tested in three samples of 434 cancer patients. In the first sample (n = 102) it was administered with the State Trait Anxiety Inventory (STAI) and with the Eysenck Personality Questionnaire (EPQ). Its validity as a screening method for psychiatric disorders was evaluated through a clinical interview in the second sample (n = 107). The third sample (n = 225) provided information on the ability of the PDI to discriminate among patients in different clinical phases of disease and allowed an estimate of the prevalence of psychiatric disorders in these groups of patients. RESULTS: A 0.88 alpha coefficient was obtained in the whole study sample. The correlations with the STAI scales were > 0.70. A positive correlation with neuroticism (r = 0.59) and a negative correlation with extroversion (r = -0.34) was observed. In the second sample, 67 patients (62.6%) received a psychiatric diagnosis according to the ICD-X criteria. The mean PDI scores were significantly lower for the 40 patients with no psychiatric diagnosis (mean 24.5) as compared with the 49 patients with adjustment disorders (mean 36.4) and with the 12 patients with depressive disorders (mean 40.8). The area under curve, estimated through a Receiver-Operating Characteristics analysis, was 0.88. A cut-off of 29 was associated with a 75% sensitivity and a 85% specificity. In the third sample, the lowest PDI scores were in patients with no evidence of disease (mean 24.7, 95% CL 23.0-26.4) as compared to patients undergoing antineoplastic treatment (mean 30.9, 95% CL 28.9-32.9) and to patients under palliative therapy (mean 36.0, 95% CL 34.0-37.9). The estimated prevalence of patients with psychiatric disorders in these three groups were respectively 5.0, 56.6 and 98.8%. CONCLUSIONS: Our results suggest that the PDI is a reliable and valid tool for measuring psychological distress in cancer patients and to detect psychiatric disorders through a screening procedure. PMID- 8692534 TI - Mucinous carcinoma of the ovary. Clinicopathologic analysis. AB - Since the incidence of mucinous carcinoma of the ovary is relatively low, with only small numbers of cases at any institution, detailed clinicopathologic studies on the prognosis and the care of patients with mucinous carcinoma are missing. Forty-four patients with mucinous carcinoma were histopathologically subclassified into endocervical (n = 8) and intestinal types (n = 36), and studied for clinical manifestations. All tumors of the endocervical type were stage I, whereas 14 intestinal-type tumors were stage II or higher (p < 0.05). Stromal invasion was not observed in 14 of 44 tumors, 13 of which were stage I. Analysis of prognostic factors disclosed that the clinical stage, maximum residual tumor diameter, volume of ascites, stromal invasion, and preoperative CA125 and CA19-9 levels significantly affected prognosis. However, multivariate analysis (stepwise regression) showed that the only significant factor was clinical stage (p < 0.004). In conclusion it is believed that, pathologically, the endocervical-type mucinous carcinoma is not as aggressive as the intestinal type cancer. The clinical stage was found to be a significant prognostic factor even by multivariate analysis, and the prognosis at stages III and IV was unfavorable compared to stages I and II. PMID- 8692535 TI - p53 and MDM2 expression in oral squamous cell carcinoma. AB - The p53 tumor suppressor gene is the most commonly mutated gene in human cancer and is a frequent abnormality in oral squamous cell carcinoma and its precancerous lesions. MDM2 (murine double minute-2), a new proto-oncogene, may be associated with p53 gene products and may negatively affect the transcriptional activating function of p53. The purpose of this study was to investigate the incidence of MDM2 and its relationship to the expression of p53 in oral squamous cell carcinoma and precancerous lesions. Overexpression of p53 and MDM2 proteins was detected in 52 and 40% of oral squamous cell carcinomas, respectively. p53 gene mutation, absent in normal oral epithelium was observed in 31% of the carcinoma cases. Our finding suggested that MDM2 protein may be an alternative mechanism causing p53 protein dysfunction in oral squamous cell carcinoma. PMID- 8692536 TI - Cisplatin versus cisplatin plus D-Trp-6-LHRH in the treatment of ovarian cancer: a pilot trial to investigate the effect of the addition of a GnRH analogue to cisplatin. AB - Thirty-four patients with histologically confirmed ovarian cancer were entered into a pilot study. Patients were randomized to receive cisplatin alone or cisplatin plus D-Trp-6-LHRH(decapeptyl). Objective response (complete and partial response) was documented in 9 of 14 patients on cisplatin and in 12 of 18 patients on cisplatin plus decapeptyl. Median time to treatment failure and median survival times were the same in the two treatment regimens. Toxicities were similar in the two treatment arms, except for hot flashes which only occurred in patients on cisplatin plus decapeptyl. PMID- 8692537 TI - Late recurrence of small-cell lung cancer: treatment and outcome. AB - The 2-year survival of patients with small-cell lung cancer (SCLC) with limited disease is about 25% and the survival curve continues to decline after 2 years. We reviewed 34 cases of survivors of SCLC who had been free of disease for 2 years and who constituted 12.2% of the 278 patients with SCLC newly diagnosed at our institution from 1977 to 1991. The cancer had recurred in 13 patients, 10 of whom were treated with chemotherapy and/or radiotherapy, and 1 complete and 1 partial response were obtained. Three patients received only supportive care because of poor performance status. The median survival after recurrence in the 13 patients was 7.4 months (range 0-39 months). A second primary cancer was noted in 5 patients, but 3 of them died from recurrence of SCLC. The prognosis of patients with late recurrence of SCLC was relatively good, and it seems that adequate treatment in such cases may lead to long-term survival. PMID- 8692538 TI - Antitumor and antitumor-promoting actions of macrophages and their relationship with estrogen. AB - Silica provides, in fact, a remarkable example of selective toxicity for macrophage by a substance of simple chemical composition and low chemical reactivity. Intraperitoneal injection of silica resulted in an increase of growth rate of subcutaneously implanted mouse sarcoma 180 (S180) in female BALB/c mice and of tumor incidence of two-stage mouse skin carcinogenesis in female ICR mice, but did not show any significant effects on tumor growth and carcinogenesis in male mice. In contrast, local administration of homologous macrophages led to the decrease of growth rate of subcutaneously implanted mouse S180 in female BALB/c mice and of tumor incidence of two-stage mouse skin carcinogenesis in female ICR mice. On the other hand, estradiol, estradiol plus macrophages or a large number of macrophages alone inhibited the tumor growth in male mice. It should be noted that estradiol plus macrophages had the most potent antitumor action among them. These results suggest that macrophages, especially estrogen-activated macrophages, may play an important role in antitumor and antitumor-promoting actions of organisms. PMID- 8692539 TI - Pentoxifylline potentiates the antitumor effect of cisplatin and etoposide on human lung cancer cell lines. AB - The effect of pentoxifylline (PENT) on the sensitivity of two human lung adenocarcinoma cell lines, PC-9 and PC-14, to cisplatin (CDDP) and etoposide (ET) was studied. PENT at 0.5 and 1 mM enhanced the cytotoxicity of CDDP and ET on PC 14 and PC-9, respectively. Isobologram analyses of IC50 data, as well as combination index calculations, revealed that PENT had an additive or a synergistic effect when applied in combination with CDDP or ET, respectively. PENT potentiated the antitumor effect of ET in a nude-mouse xenograft model using PC-14 cells, when PENT was administered at 150 mg/kg subcutaneously for 6 days. Flow cytometry revealed that PENT decreased the accumulation of cells in the G2+M phase caused by CDDP when using PC-9 cells. However, PENT did not remarkably alter the accumulation of cells in G2+M caused by ET. These results suggest that PENT enhanced the antitumor effects of CDDP additively and those of ET synergistically. The enhancement mechanism probably differs between CDDP and ET. PENT needs more study to elucidate its potency as a new agent for combination chemotherapy. PMID- 8692540 TI - In vitro and in vivo growth inhibition of SC-M1 gastric cancer cells by retinoic acid. AB - Retinoids are differentiating agents that have been used successfully for the treatment of acute promyelocytic leukemia. When combined with interferons, they are active in preventing second malignancies in patients with head and neck cancer. Our previous studies have demonstrated cytostatic effects of alltrans retinoic acid (tRA) on SC-M1 gastric cancer cells in vitro. The activity of tRA and 13-cis-retinoic acid (cRA) on SC-M1 cells was compared both in vitro and in vivo in this study. Measurement of total cellular DNA was used to determine cell growth in vitro. The effect of retinoic acid on tumor growth was evaluated by implanting sustained release tRA or cRA pellets into athymic nude mice. The results showed that tRA was more potent than cRA in suppressing the growth of SC M1 gastric cancer cells in vitro. Both tRA and cRA were effective in suppressing the growth of SC-M1 tumors in athymic nude mice. No change in the differentiation status and cell cycle phase distribution in excised tumors was observed. Side effects such as bone fractures and weight loss were observed in mice of both treatment groups. The results suggest that retinoic acid may provide therapeutic advantages for the treatment of gastric cancer. PMID- 8692541 TI - Inhibitory effect of taraxastane-type triterpenes on tumor promotion by 12-O tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin. AB - Two taraxastane-type hydroxy triterpenes, taraxasterol and faradiol, isolated from the flowers of Compositae plants Cynara scolymus (artichoke) and Chrysanthemum morifilolium (chrysanthemum), respectively, showed strong inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in mice. At 2.0 mumol/mouse, these compounds inhibited markedly the tumor-promoting effect of TPA (1 microgram/mouse) on skin tumor formation following initiation with 7,12-dimethylbenz[alpha]anthracene (50 micrograms/mouse). PMID- 8692542 TI - Hypouricemia and cancer. A study of the mechanisms of renal urate wasting in two cases. AB - Two cases of hypouricemia in association with malignant diseases are presented. One patient had metastatic breast cancer and the other an undifferentiated retroperitoneal sarcoma of the childhood. Uric acid renal handling was studied with the pyrazinamide and benzbromarone tests. Both patients had reduced postsecretory reabsorption of uric acid. The increase of serum uric acid levels in both patients, after a partial response to chemotherapy, indicates the possible paraneoplastic origin of hypouricemia. Our results are discussed and compared with other reports in the literature. PMID- 8692543 TI - Mechanisms and Management of Nausea and Emesis Associated with Cancer Therapy. Symposium proceedings. Marlow, United Kingdom, October 13-14, 1994. PMID- 8692544 TI - Mechanisms and management of nausea and emesis. PMID- 8692545 TI - Towards understanding the aetiology and pathophysiology of the emetic reflex: novel approaches to antiemetic drugs. AB - The introduction of 5-HT3 antagonists, such as ondansetron, as antiemetic agents has transformed the management of patients receiving chemotherapy or radiation therapy. Studies in animal models with NK1 antagonists suggest that these represent a new class of antiemetic agents having a broader spectrum of activity than 5-HT3 antagonists. Compounds of this class may prove to be more effective in man against delayed emesis induced by cisplatin, post-operative nausea and vomiting and motion sickness. Thus, they have the potential to complement 5-HT3 antagonists and so provide a further advance in the management of nausea and vomiting. PMID- 8692546 TI - Serotonin mechanisms in chemotherapy-induced emesis in cancer patients. AB - Emesis is a common side effect of chemotherapeutic drugs. Cisplatin, nitrogen mustard and dacarbazine induce increases in urinary 5-hydroxyindoleacetic acid (5 HIAA) in parallel with the development of the period of emesis which is sensitive to 5-HT3 receptor antagonists ('acute emesis'). It is suggested that these cytotoxics release serotonin from enterochromaffin cells, which then acts on 5 HT3 receptors to trigger the emetic response. Cyclophosphamide, on the other hand, induces a modest emetic response, partly sensitive to 5-HT3 receptor antagonists, but not associated with increases in urinary 5-HIAA. It is suggested that cyclophosphamide-induced emesis is not mediated by the release of serotonin from enterochromaffin cells. Although after high-dose cisplatin most emesis is sensitive to 5-HT3 receptor antagonists, patients often present a milder, although more prolonged form of emesis which is mostly resistant to 5-HT3 receptor antagonists (also known as 'delayed emesis'). This form of emesis is not associated with increases in urinary 5-HIAA (not due to serotonin released from the enterochromaffin cells). Treatment with p-chlorophenylalanine (a serotonin synthesis inhibitor) inhibited cisplatin-induced emesis and cisplatin-induced increases in urinary 5-HIAA excretion. In summary, these results indicate that in human patients, serotonin plays a fundamental role in chemotherapy-induced emesis. Serotonin released from enterochromaffin cells seems to mediate emesis sensitive to 5-HT3 receptor antagonists induced by cisplatin, dacarbazine and nitrogen mustard. Emesis sensitive to 5-HT3 receptor antagonists associated with cyclophosphamide treatment, is not mediated by the release of serotonin from enterochromaffin cells by the cytotoxic. Therefore, cyclophosphamide could induce serotonin release either from enteric serotonin nerves or from the CNS. Cisplatin induced emesis resistant to 5-HT3 receptor antagonists ('delayed emesis') is not mediated by serotonin released from enterochromaffin cells. PMID- 8692547 TI - The severity and pattern of emesis following different cytotoxic agents. AB - Different cytotoxic drugs induce different patterns of emesis. This is relevant to clinical practice since we often see in the medical literature oversimplifications in the recommendation for management of chemotherapy-induced emesis, so that the same guidelines are given for cisplatin and non-cisplatin containing chemotherapy. In particular, cisplatin induces a biphasic pattern of emesis which is characterized by an acute immediate phase and a delayed phase. These two phases are clearly different, especially when cisplatin is given in short i.v. administration (e.g. over 20 min to 1 h) and in high doses (1000-120 mg/m2). On the other hand, cyclophosphamide and carboplatin induce a quite different pattern of emesis, characterized by a monophasic curve which although more intense in the first 24 h, may continue for a number of days. The antiemetic response to 5-HT3 receptor antagonists on days 2-5 is good in the case of carboplatin and cyclophosphamide and poor in the case of cisplatin (delayed emesis after cisplatin). This firmly suggests that the pathogenesis of cisplatin induced emesis may differ from that induced by other cytotoxic drugs, especially in the delayed phase of emesis. We think that we should reserve the term 'delayed emesis' for the late emesis induced by cisplatin, while 'prolonged emesis' could be a better denomination for the late emesis induced by cyclophosphamide and carboplatin. The main clinical implication of these observations is that 5-HT3 receptor antagonists should be administered over 3-5 days in the case of carboplatin and cyclophosphamide, while a short treatment during the first day could be sufficient to control the acute phase of cisplatin-induced emesis. PMID- 8692548 TI - Optimal control of cyclophosphamide-induced emesis. AB - Cyclophosphamide induces moderate to severe emesis. The severity of emesis is dependent on the dose of cyclophosphamide and on the addition of other cytotoxic drugs. A review of the literature dividing studies according to the dose of cyclophosphamide and the specific cytotoxic combination shows that ondansetron plus dexamethasone provides optimal antiemetic therapy in patients receiving standard or high-dose cyclophosphamide (> or = 450 mg/m2). These studies also show that it is important to give antiemetic therapy to cover the prolonged duration emesis and nausea induced by these regimens, e.g. intravenous CMF/(F)AC/(F)EC. For continuous 'oral' (low-dose) CMF chemotherapy, oral ondansetron or oral metoclopramide plus intravenous (or possibly oral) dexamethasone are effective antiemetic therapies. PMID- 8692550 TI - Models, mechanisms and management of anticipatory nausea and emesis. AB - Anticipatory nausea and vomiting (ANV) are learned responses to chemotherapy that develop in up to 25% of patients by the fourth treatment cycle. Post-treatment nausea and emesis must occur before development of ANV can take place. Certain patient characteristics and other responses to chemotherapy can also be used to predict their occurrence. Once they develop, ANV cannot be controlled by pharmacologic means including use of new 5-HT3 receptor antagonists. By contrast, behavioral therapies involving relaxation, most notably systematic desensitization, can be used to effectively treat ANV. Clinic personnel including oncologists and oncology nurses as well as behavioral psychologists can effectively administer systematic desensitization to chemotherapy patients. PMID- 8692549 TI - Management of cyclophosphamide-induced emesis over repeat courses. AB - This paper describes the only published study to date which prospectively evaluates the efficacy of a 5-HT3 receptor antagonist over repeated courses of cyclophosphamide chemotherapy. The combination of ondansetron and dexamethasone was significantly superior to metoclopramide and dexamethasone over 6 courses of chemotherapy given for the treatment of breast cancer. Importantly, patients given ondansetron benefited from a superior quality of life over the six courses of treatment. A Markov chain statistical model has been applied to these data. This model assumes that the results over subsequent courses is dependent on the efficacy of the anti-emetic therapy and the results obtained during the previous course of chemotherapy. This model successfully predicts the actual results obtained in the clinical study. Using this model it is possible to hypothesise on the results obtained following different treatment strategies. These data emphasise that it is important to give optimal anti-emetic therapy from the first course of chemotherapy as this will facilitate good control during subsequent courses. PMID- 8692552 TI - Management of other non-cisplatin-induced emesis. AB - A number of non-cisplatin cytotoxic regimens induce moderate to severe nausea and emesis. Moreover, the majority of these regimens are given to outpatients where an effective, well-tolerated anti-emetic therapy is particularly important to maintain patients' well-being. This review focuses on the management of nausea and emesis induced by non-cisplatin chemotherapy particularly regimens that do not contain cyclophosphamide or carboplatin, as these are reviewed elsewhere in this volume. For patients receiving highly emetogenic cytotoxic therapy such as dacarbazine, total body irradiation or hemi-body irradiation, a 5-HT3 receptor antagonist plus a corticosteroid may provide optimal control of emesis and nausea. High-dose single-fraction and fractionated radiotherapy to the upper abdomen induces moderate emesis. Traditional anti-emetics prevent emesis in approximately 50% of patients; 5-HT3 receptor antagonists provide a more effective anti-emetic therapy for these patients. Studies evaluating anti-emetics in specific chemotherapy regimens will give clear guidelines for the management of emesis in different patient populations. PMID- 8692551 TI - Pathophysiology, severity, pattern, and risk factors for carboplatin-induced emesis. AB - Carboplatin has proven efficacy in the treatment of ovarian cancer and has been proven to be less toxic compared to the parent compound cisplatin. Nevertheless, emesis is still a major problem associated with carboplatin-containing chemotherapy. Several investigators have focussed on the understanding of the pathophysiology and pattern of cisplatin-induced emesis. Data describing both the pathomechanisms and pattern of carboplatin-induced emesis are still lacking. This paper combines data from the literature with our own experience with the pattern and control of carboplatin-induced emesis, and presents data contributing to the understanding of the underlying pathomechanisms. Carboplatin induces a significant increase in urinary 5-HIAA excretion, the main metabolite of serotonin. 5-HIAA excretion levels remain elevated over 3 days following chemotherapy. Carboplatin-induced emesis is observed in about 40% of patients despite anti-emetic prophylaxis with 5-HT3 antagonists. Vomiting after carboplatin extends over days 1-3 with an equal distribution regarding the severity on each day. Analysis of the pattern of emesis revealed that delayed emesis (> 24 h after chemotherapy) is a major problem associated with carboplatin therapy. Description of the pattern of emesis as 'prolonged emesis' seems to be appropriate. 5-HT3 receptor antagonists such as ondansetron seem to be efficacious both in the control of acute and prolonged emesis following carboplatin chemotherapy, but randomly controlled data comparing ondansetron with other anti-emetic regimens have not yet been published. Univariate analysis reveals gender and combination therapy containing carboplatin and cyclophosphamide and/or anthracyclines as risk factors for emesis. PMID- 8692553 TI - Optimal control of acute cisplatin-induced emesis. AB - A survey by Coates and co-workers in 1983 revealed that patients ranked nausea and vomiting as the most distressing side effects of chemotherapy. In the last decade the use of high-dose metoclopramide and, especially, the introduction of the 5-HT3 receptor antagonists, have been major leaps forward in the control of chemotherapy-induced emesis. Nevertheless, since patients still consider nausea and vomiting to be the most distressing side effect of their chemotherapy there is clearly a need for further improvements. Acute emesis, which is the topic of this review, can now be controlled in the majority of patients during their first course of chemotherapy. Future focus should be on better control of emesis during subsequent courses of chemotherapy as well as on better control of delayed emesis. PMID- 8692554 TI - Control of acute cisplatin-induced emesis over repeat courses of chemotherapy. Italian Group for Antiemetic Research. AB - There have been few studies to determine whether the efficacy of antiemetics is maintained over repeated courses of cisplatin chemotherapy. Two large controlled studies have been undertaken by our group to address this issue. A comparison of the standard high-dose regimen of metoclopramide plus methylprednisolone versus a higher dose regimen of metoclopramide plus dexamethasone and diphenhydramine showed that the latter regimen was significantly more efficacious with regard to complete control of nausea and vomiting in chemotherapy-naive patients. However, this difference was not maintained over repeated courses of chemotherapy. A comparison of metoclopramide and dexamethasone plus diphenhydramine with ondansetron plus dexamethasone showed that the ondansetron regimen provided even greater control of vomiting, which was maintained over subsequent cycles of chemotherapy. Various factors were analysed in both studies to determine whether they had any effect on treatment outcome. In general, age < 50 years, female gender, and higher doses of cisplatin were associated with an increased risk of emesis. However, the most significant prognostic factor was emesis response in the previous cycle. It is therefore important to aim for good antiemetic control in the first cycle of cisplatin chemotherapy. PMID- 8692555 TI - Management of cisplatin-induced delayed emesis. AB - High-dose cisplatin chemotherapy induces a biphasic pattern of emesis. Following the initial peak of emesis, which occurs during the first 8 h after cisplatin, there is a reduction in the occurrence of symptoms with a further increase in the incidence of nausea and emesis which are most severe 48-72 h following cisplatin administration. This latter phase of emesis is defined as delayed emesis and is distinct from the prolonged emesis which occurs after non-cisplatin chemotherapy such as cyclophosphamide. The incidence and severity of delayed emesis is influenced by the dose of cisplatin, being particularly severe in patients receiving doses > 100 mg/m2. Patients who have good control of acute emesis experience less delayed emesis. For this reason, clinical trials designed to evaluate antiemetics for delayed emesis should be carefully designed; ideally patients should be randomized to different treatments after the first 24 h. Studies which have used this design have shown that metoclopramide plus dexamethasone is an effective treatment. However, approximately 50% of patients may experience delayed emesis despite this treatment. The efficacy of the 5-HT3 receptor antagonists in the control of cisplatin-induced delayed emesis in phase II studies has been equivocal and large well-controlled studies with these agents are needed to establish their role in this setting. PMID- 8692556 TI - 5-HT3 receptor antagonists in the control of cisplatin-induced delayed emesis. AB - Two large randomized, double-blind, placebo-controlled studies with an appropriate study design have been conducted to fully evaluate the efficacy of ondansetron in the control of cisplatin-induced delayed emesis. These studies show that ondansetron and particularly ondansetron plus dexamethasone have moderate efficacy in the control of cisplatin-induced delayed emesis and nausea. The benefit of ondansetron, with or without dexamethasone, may be greatest in patients with incomplete control of acute emesis. The efficacy of ondansetron in this setting compared to its greater efficacy during the acute phase of emesis induced by cisplatin and the more prolonged phases of acute emesis induced by cyclophosphamide and carboplatin indicates that non-5-HT3-mediated emetic mechanisms maybe are relatively more important in the delayed phase of emesis following cisplatin. PMID- 8692557 TI - Mechanisms of chemotherapy/radiotherapy-induced emesis in animal models. AB - Animal models of chemotherapy/radiotherapy-induced emesis successfully predicted the clinical efficacy of the 5-HT3 receptor antagonists for the control of acute emesis. Further studies in animals have provided valuable information relating to the pathophysiology of emesis and the mechanism of action of 5-HT3 receptor antagonists. These agents inhibit emesis by blocking the action of 5-HT at 5-HT3 receptors on the vagus nerve in the gastrointestinal tract and in the hindbrain vomiting system. 5-HT is hypothesized to be released from enterochromaffin cells following cytotoxic therapy or radiation. The mechanism by which 5-HT is released from enterochromaffin cells is unknown and, although various mechanisms have been proposed, none of these have provided convincing supportive evidence. In collaboration with scientists at Glaxo we have pioneered two models of cisplatin induced acute and delayed emesis [Rudd et al., 1994]. In the first model, ferrets are given a low dose of cisplatin (5 mg/kg i.p.) and observed for 3 days. A pattern of emesis similar to that seen in the clinic has been observed with two distinct phases of emesis. Ondansetron, and particularly ondansetron plus high dose dexamethasone, are effective in reducing the emetic response over days 1-3. The second model uses a higher dose of cisplatin (10 mg/kg i.p.) and an observation period of 24 h. Part of the emetic response over this time is resistant to 5-HT3 receptor antagonism. Studies into the mechanism of the emesis induced in both models may give an insight into cisplatin-induced emesis in man that is not controlled with 5-HT3 receptor antagonists. PMID- 8692558 TI - Cisplatin and emesis: aspects of treatment and a new trial for delayed emesis using oral dexamethasone plus ondansetron beginning at 16 hours after cisplatin. AB - The marked progress in controlling emesis caused by cisplatin characterizes the current status of antiemetic treatment for all chemotherapy. Cisplatin has provided a model for antiemetic studies. Strategies for controlling cisplatin induced emesis are at least as successful when applied to other chemotherapy and persistent problems such as delayed emesis and the emesis associated with consecutive-day chemotherapy are also similar to or less severe than those observed with cisplatin. The purpose of this report is twofold: first to outline briefly therapy for cisplatin-induced emesis as illustrated by several new studies, and, second, to report on a new trial that incorporates some different strategies in the control of delayed emesis after cisplatin. PMID- 8692559 TI - Quality of life studies in chemotherapy-induced emesis. AB - Health-related quality of life (HQL) was assessed before and after either moderately or highly emetogenic chemotherapy. When the pretreatment HQL in patients who did not vomit after chemotherapy (n = 203) was compared to those who vomited (n = 230), it was found that patients who did not vomit had better physical, role, and social function scores as well as a better global quality of life score than did patients who had one or more episodes of vomiting. Furthermore, in patients who did not vomit, the pretreatment fatigue and anorexia scores were better than in patients who did vomit. Thus, pretreatment HQL scores appear to have value in predicting which patients will experience chemotherapy induced emesis. In the week following chemotherapy, HQL change scores from prechemotherapy values for cognitive function, global quality of life, fatigue, anorexia, insomnia and dyspnea were significantly worse in the group experiencing emesis than in the group who remained completely free of emesis. There were no differences in physical, role, emotional and social function attributable to chemotherapy-induced vomiting. PMID- 8692560 TI - Antiemetic study methodology: recommendations for future studies. AB - The methodology of future antiemetic studies will reflect the need to address the problems identified in current studies. New preclinical information on the mechanisms of emesis and antiemetic action will allow more rational clinical study design. Prior to large randomized studies, phase I and II trials should define the minimum effective dose of an antiemetic which may differ according to the strength of the emetic stimulus. The most convenient route of administration and schedule should also be sought in early phase trials. New endpoints such as cost-effectiveness should be incorporated into phase III studies, which should also serve as vehicles for further studies of prognostic factors. Problem areas such as delayed emesis should be specifically targeted in future trials. Patients must evaluate the overall benefit of a new antiemetic regimen. PMID- 8692561 TI - Epidemiology of blindness and eye disease. PMID- 8692563 TI - [Elbow arthrodesis and its alternative]. AB - Significant functional impairment, increasing pain or joint infection are the indications for arthrodesis of the elbow joint. Six patients underwent a compression arthrodesis with internal and external fixation and an additional bone graft in our institution between 1987 and 1993. Out of this series only one patient developed a non-union due to a fall on the extremity. In a series of nine patients treated with external fixation alone between 1978 and 1987, four patients developed a non-union. Unlike other joints, there is no optimal position for arthrodesis of the elbow and the functional deficit cannot be compensated by the other joints of the upper extremity. Therefore, it should be useful to know if an interposition arthroplasty is possible. With this technique a joint infection can be healed. Ten patients treated with this technique between 1987 and 1993 had no recurrent infection. Two patients had instability. The best results were achieved in post-traumatic joint stiffness. Permanent instability and post-traumatic arthritis are indications for an allo-arthroplasty. Contraindications are a previous joint infection and intensive bone loss, as well as ipsilateral shoulder ankylosis and neuropathic joint disorders. In younger patients, resection arthroplasty is better due to a high loosening rate of the prostheses. PMID- 8692562 TI - [Arthrodesis of the shoulder joint]. AB - If strict indications are adhered to, shoulder arthrodesis is a valuable method in the operative treatment of restoring function to a chronically painful joint in a physically hard-working patient. Functional failure, especially because of rotation loss occurs often and is frequently the cause of unsatisfactory results. The main problem is the position of the arthrodesis. After numerous contradictory proposals, the most favorable approach is an abduction of 20-25 degrees and flexion of 30 degrees with an internal rotation of 45 degrees. Of all of the previous methods of fixation, today compression arthrodesis with one or two AO plates is preferred. PMID- 8692564 TI - [Arthrodesis of the wrist in arthritis]. AB - The AO technique of wrist arthrodesis with an embedded iliac crest bone graft is a stable kind of fixation that allows early range of motion. Solid fusion with correction of the deformity and relief of pain can be achieved. A correct position in dorsal extension and ulnar abduction will improve hand function, but a decrease in grip strength must be expected. PMID- 8692565 TI - [Arthrodesis of the rheumatoid wrist]. AB - In rheumatoid wrists surgical procedures are not indicated before non surgical measures have failed to restore comfortable function or even severe instability and joint disorganisation have developed. Primarily synovectomies and stabilisation measures have to be done. Arthrodesis of the rheumatoid wrist is not indicated as often. In case arthrodesis is required in the rheumatoid wrist quality of bones and soft tissues should be taken carefully into consideration. The arthrodesis of the wrist according to Mannerfelt has been proven as a simple and safe method. PMID- 8692566 TI - [Hip joint arthrodesis using the cobra plate. Indication, technique, outcome]. AB - In the era of successful total hip replacement, hip arthrodesis has become an infrequent surgical procedure. Current indications are severe deterioration of the hip joint with a painful, reduced range of motion in young patients, such as disorders subsequent to sepsis of the hip joint, slipped capital epiphysis, Perthes' disease and trauma with contraindications for a total joint replacement. Another important indication is paralysis or musculature loss. From 1980 to 1990, 20 consecutive patients underwent a hip arthrodesis with a cobra plate and were evaluated. None of the patients was lost for follow-up; complications occurred in 5 out of 25 cases (20%). All patients had radiographic evidence of union, 2 patients required re-osteosynthesis and bone grafting. In two cases infection occurred. In one case the position of the fused join went into abduction. Thirteen patients were able to walk free of pain; however, 5 patients were disappointed with the arthrodesis result because of the handicap involved with a fused hip. Hip arthrodesis using the cobra plate is a technically demanding operation, but immediate mobilization and partial weight bearing are facilitated. There is little risk of non-union compared to other surgical procedures. If the technique is correct functional problems will be rare. PMID- 8692567 TI - [New technique for a hip arthrodesis using an anterior approach and a ventral plate]. AB - The authors present a new technique for fusion of the hip joint through an anterior approach (Smith-Petersen) with the use of a ventral plate and a lateral compression screw. The indications for fusion of the hip joint are discussed and some cases are presented. The advantages of this technique are that strong bone stock for fixation is used on the pelvic side, that the abductor muscles and vascularization of the femoral head are left intact, and that no external fixation (cast) is routinely used for after-treatment. PMID- 8692568 TI - [Primary arthrodesis of the knee joint]. AB - Because of progressive development in the field of knee arthroplasty, currently there are fewer indications for primary knee arthrodesis. Primary knee arthrodesis is indicated in acute or chronic infections in which conservative treatment has failed, monoarticular arthritis in young patients if total knee replacement is not suitable, unstable knee joints caused by poliomyelitis or other neuromuscular disease, neuropathic joint disease, in salvage of the extremities with tumors of the distal femur and proximal tibia, and to obtain length in femur dysplasia. The operation technique with a modified Charnley compression fixator is described. Fifteen patients (100%) treated by this double frame fixator have had a solid arthrodesis 13.6 weeks after surgery. We found 5 pin infections and had to reset 2 Steinmann pins. PMID- 8692569 TI - [Arthrodesis following revision of a knee endoprosthesis. Literature review 1984 1994]. AB - Two percent of primary and 8% of revision total knee replacements are followed by arthrodesis. Today knee arthrodesis is the most important salvage procedure after failed total knee arthroplasty, resection arthroplasty and above-the-knee amputation being the only alternatives. Analysis of the literature between 1984 and 1994 revealed 533 cases treated with arthrodesis of the knee; 403 were done after failed total knee arthroplasty. The fusion rate was 74%. External fixation, intramedullary nail, plates and combinations of these are currently used for fixation. The literature and an analysis of our own patients from 1988 to 1994 showed that arthrodesis after failed arthroplasty is a difficult procedure, and complications often occur. Bone loss of the distal femur and proximal tibia is the one most important prognostic factor. A new classification system for bone loss is presented. PMID- 8692570 TI - [Arthrodesis of the ankle joint]. AB - Arthrodesis of the ankle joint is still an important operation in the treatment of painful arthrosis, chronic infection, and malalignment instability when these cases have been treated unsuccessfully with other therapeutic procedures. To date, prosthetic replacement of the ankle joint has been an alternative only in rheumatoid patients. Concerning the long-term results, ankle arthrodesis is much better than alloarthroplasty. Because of the good functional results achievable by arthrodesis when done in the right position, there is less often a need for prosthetic replacement than in the hip or knee joint. A patient with a fused ankle joint is only limited when running. Compression arthrodesis is possible at present with various operative techniques utilizing external fixators, ring fixators and open reduction internal fixation with plates and screws. The last procedure can be carried out arthroscopically. With these techniques, fusion of the ankle joint in the correct position is possible in nearly all situations, e.g., infection, malalignment, osteoporosis, soft tissue damage. The main complication of ankle arthrodesis is pseudarthrosis (up to 35%) and postoperative infection (3%-25%). An important late sequela is arthrosis in the joints adjacent to the fused ankle joint (10-60%). PMID- 8692571 TI - [Screw arthrodesis of the ankle joint. Technique and outcome]. AB - In ankle arthrodeses several clinical and biomechanical studies have shown the superiority of the screw technique over external fixation. As a maximum of stability is a major goal, especially for functional after-treatment or in patients with poor bone stock, the arthrodeses technique at Hannover Medical School is performed with four screws. Two parallel anterior/posterior screws are placed from the tibia to the talus, providing anterior stabilization. One screw posteriomedial has a posterior tension-wiring effect and one screw placed through the fibula to the talus acts against rotational and sagittal translation. From May 1975 to May 1995, 225 ankle arthrodeses with internal or external fixation technique were performed. Complications were found in 47% in the external fixation treatment group (n = 44) and in 10% the patients stabilized with the screw technique (n = 181). Fifty of these 225 patients had a follow-up evaluation after an average of 7.4 years (external fixation, n = 22; screw fixation, n = 28). All patients were examined and scored with three different scoring systems: (1) MHH Score, (2) Clinical Rating System according to Kitaoka et al. (1994) and (3) Outcome Questionnaire for evaluating the overall outcome. The results from the questionnaire were compared to the clinical scores. Retrospective analysis revealed a higher rate of complications for arthrodeses performed by external fixation. The overall results of all three different scoring systems showed a trend in favor of the screw-fixation technique without reaching statistical significance (P > 0.05). The results of the Outcome Questionnaire are statistically as valid as the two clinical scoring systems. PMID- 8692572 TI - [Hindfoot arthrodesis]. AB - Arthrodesis of the hindfoot is indicated in congenital foot deformity of young adults, in posttraumatic arthrosis of the subtalar joint following calcaneus fractures, in idiopathic, isolated arthroses of hindfoot joints, in rheumatoid arthritis and in deformities of the longitudinal arch of the foot. Common and useful combinations are the triple-arthrodesis and the arthrodesis of the subtalar and the calcaneocuboid joint, in particular if both joints are affected by calcaneus fractures. Arthrodesis of the subtalar and the talonavicular joint are often performed as isolated procedures. The three-dimensional structure of the hindfoot articulations may impede perfect contact of the bone surfaces in combined arthrodeses. Various fixation methods are in use. Follow-up examination of 52 arthrodeses after 11.1 years revealed good, symptomatic improvement in most patients. However, complete bony union was achieved in only 47 percent, and this was due to insufficient stabilization of the arthrodesis in many cases. In view of comparable rates of pseudarthroses in the literature, we advocate stable internal fixation with screws or bone staples. PMID- 8692574 TI - [Arthrodesis]. PMID- 8692573 TI - [Arthrodesis of the metatarsophalangeal joint of the large toe]. AB - Arthrodesis of the first metatarsophalangeal joint is the procedure of choice in hallux rigidus with advanced destruction of the joint surfaces. It is also indicated after failed resection arthroplasty in hallux valgus. A dorsal skin incision is used. Flat osteotomy surfaces are created at the first metatarsal head and at the proximal phalanx with a saw. The angle between the great toe and the bottom of the foot should be ten to 15 degrees of dorsal extension. The great toe should be aligned in ten degrees of valgus relative to the first metatarsal bone, and in neutral rotation. Fixation with a dorsal one-third or one-quarter tubular plate and an interfragmentary lag screw is most stable. Interposition of a bone graft may be necessary in cases of undue shortening of the great toe, as in revision surgery following resection arthroplasty. Full weightbearing in a postoperative shoe with a rigid sole is allowed immediately postoperatively. Results with this technique are good and excellent in approximately 80 percent. The incidence of pseudarthroses is between three and 13 percent, depending on the operative technique. Symptomatic degeneration of the interphalangeal joint occurs in approximately 10 percent of patients at long-term follow-up. PMID- 8692575 TI - [Significance of arthrodeses]. PMID- 8692576 TI - [Biomechanics of arthrodesis of the major joints of the extremities]. AB - Insufficient movement after an arthrodesis must be compensated for by other joints. Arm movements with an ankylotic shoulder joint can be executed by rotation and tilting of the scapula. The trapezius muscle plays an important role in these movements. Arthrodesis of the hip joint requires an extended range of movement in the intact contralateral joint and sufficient mobility of the lumbar spine. Moreover, every ankylotic joint is stressed by bending because compensation of the torque due to the weight of the corresponding part of the body by the balancing muscles is no longer necessary. The architecture of the spongy bone is adapted to that bending stress. Characteristic examples are anatomic specimens of ankylotic hip and knee joints. PMID- 8692577 TI - To sign, or not to sign: evaluating networks from Timbuktu. PMID- 8692578 TI - Kill the CAT fund? Elimination of fund would be costly to providers. PMID- 8692579 TI - Computerized records security: problems of policy, not technology. AB - As computer-based medical records systems become more common, both physicians and their patients worry about two questions: Who should have access to medical information? How can unauthorized access be prevented? If you and your staff can answer the first question clearly, you can probably find answers to the second. PMID- 8692580 TI - Whither the roles of rifater and rifamate? PMID- 8692581 TI - Medical savings accounts: physicians are key. PMID- 8692582 TI - Developmental dysplasia of the hip. AB - The essential points regarding screening for and detection of developmental dysplasia of the hip are emphasized. Background information is provided to understand why this entity presents in a variable fashion. This article is not intended to comprehensively cover treatment methodology for the orthopedic surgeon. Instead, the information provided is meant to aid the primary care practitioner in identification of the problem and in supporting the family during the treatment process when an abnormality is detected. PMID- 8692583 TI - Limb length discrepancy. AB - The surgical management of LLD has gradually evolved from a time when patients were bedridden in traction for prolong periods of time to the point at which much of the treatment time is spent in mobility. Improved surgical techniques, such as percutaneous epiphysiodesis and distraction osteogenesis, have contributed greatly to the success of surgery for LLD. Factors affecting outcome and patient satisfaction must be weighed carefully before selecting treatment for LLD. PMID- 8692584 TI - Torsional and angular deformities. AB - A general understanding of the cause and natural history of rotational and angular malalignment of the lower extremity allows accurate differentiation between pathologic and physiologic conditions. One can then educate the involved and often concerned family and proceed with observational management of physiologic conditions as spontaneous improvement of alignment can be expected. Aside from treatment for resistant metatarsus adductus, other forms of treatment, such as special shoes, casts, or braces, are rarely beneficial and have no proven efficacy. Persistent deformity beyond skeletal maturity is unusual and rarely causes significant functional disability. In rare cases of severe residual deformity, operative correction is the only effective treatment. PMID- 8692585 TI - Spinal deformity. AB - Spinal deformity in children has a wide range of causes. The most common entities are idiopathic scoliosis, postural roundback, and Scheuermann's kyphosis. The pediatrician, primary care physician, and orthopedic surgeon can optimally treat these disorders with close observation, attention to detail, initiation of bracing when indicated, and surgery on patients who have an appropriate indication. A careful, well-planned approach to these conditions results in the successful treatment of spinal deformities with minimal complications. The physiologic and psychological sequelae of these entities can then be minimized, preserving the overall health of the child. PMID- 8692587 TI - Orthopedic conditions of the cervical spine and shoulder. AB - Orthopedic conditions of the cervical spine and shoulder can range from benign to life threatening. A careful history and examination are crucial to evaluate these children, and additional investigations may be necessary. The signs and symptoms in these conditions and the indications for referral are discussed. PMID- 8692586 TI - Back pain in children and adolescents. AB - Back pain in children is a common problem that is infrequently reported to physicians. Persistent back pain in children is serious, and most conditions can be diagnosed with relatively simple tests, including diagnostic plain radiographs and bone scans. Many cases, including strains and sprains, are relieved with rest and decreased activity. If persistent back pain, increasing pain, fever, or neurologic deficit is present, referral to the orthopedic surgeon should be swift until a specific cause can be found and treated. PMID- 8692588 TI - Pediatric bone and joint infections. Diagnosis and antimicrobial management. AB - Bone and joint infections in children provide unique clinical challenges. When evaluating children with suspected bone and joint infection, the differential diagnosis is broad. Consideration must be given to possible neoplastic and traumatic causes. Appropriate imaging and diagnostic techniques should be initiated without delay. Orthopedic consultation for surgical evaluation should be made early. Prolonged use of antibiotics is often warranted. Treatment often is continued in the outpatient setting, requiring frequent follow-up with appropriate serial laboratory studies to monitor side effects of antimicrobial agents. PMID- 8692589 TI - Benign pediatric bone tumors. Evaluation and treatment. AB - Several recent significant advances have been made in the evaluation and treatment for bone lesions in children. Most advances have come as a result of better imaging of these lesions, namely with magnetic resonance imaging. When a child presents with a bone lesion, several aids allow the treating physician to develop a differential diagnosis. Both recent advance and newer techniques in the diagnosis and treatment of children with benign bone lesions are discussed. PMID- 8692590 TI - Malignant bone tumors of childhood. AB - Improvements in diagnosis and treatment have increased survival for many children with malignant bone tumors. New molecular genetic discoveries are providing insights into the mechanisms of tumorigenesis and may provide novel therapeutic modalities based on interfering with aberrant transcriptional activation by hybrid transcripts. PMID- 8692591 TI - [Tick-borne diseases]. AB - In Poland since 1992 there is a rapid increase in the incidence of Lyme borreliosis and arboviral encephalitis. The role of ticks in spread of this diseases is discussed. The clinical picture, diagnosis and treatment of the Lyme disease, tick encephalitis tularemia and babesiosis are discussed. PMID- 8692592 TI - [Evolution of viral hepatitis B markers in children infected with HBV in the first two years of life]. AB - Circumstances of acquiring an infection, spontaneous evolution of markers during 6 years of follow-up, laboratory findings and results of liver biopsies were analysed in 51 children infected with HBV during the first two years of life; 76.5% of them developed chronic carrier state. ALAT values were periodically increased in 34 children (66.6%) and elimination of HBeAg i HBsAg occurred in 17 (33.3%) and 12 children (23.5%), respectively, during the first year of follow up. Seroconversion was observed only in a few cases in the subsequent years. Anti HBc IgM antibodies were detectable for a mean period of less than 7 months (p < 0.02) after diagnosis of infection. PMID- 8692594 TI - [Long-term efficacy of hepatitis B vaccine in children with chronic renal failure]. AB - The aim of the study was to determine the duration of post vaccination immunity and antibody persistence in children in different stages of chronic renal failure. The study was performed in 25 children and time of observation was 12-36 months. After completing vaccination seroprotection rate was 92% in non-dialysed children and 77% in dialysed. After 36 months of observation seroprotection was found in 90% of patients, none of them was infected by HBV. We conclude that in case of decrease in antibody titer below 100 mIU/ml the booster dose of vaccine is indicated. PMID- 8692593 TI - [Efficacy of passive and active immunization against HBV infection in children with neoplastic diseases]. AB - The efficacy of 3 schemes of passive and active prevention of HBV infection was evaluated in 47 children with haematologic proliferative diseases. Twenty-six children suffering from leukemia (group I) received passive immunisation (hepatitis B immunoglobulin) in six week intervals during intensive chemotherapy and were vaccinated on maintenance therapy. Thirteen children with Hodgkin or B non-Hodgkin lymphoma (group II) received active immunisation from the beginning of intensive chemotherapy with two doses of immunoglobulin. Eight children who had completed their therapy (group III) were vaccinated only. Among children who completed vaccinations, 5/8 in group I, 4/7 in group II and 5/5 in group III produced protective anti-HBs levels. Passive/active prophylaxis was successful in most patients suffering from neoplastic diseases and reduced the endemy of HBV infection in our department from 43.3% to 2.56% infected subjects. Among 7 patients vaccinated from the beginning of treatment (group II), 4 of them produced protective levels of anti,-HBs, despite intensive chemotherapy. PMID- 8692595 TI - [Interferon alpha in the treatment of chronic hepatitis B in children]. AB - Nine children suffering from chronic hepatitis due to hepatitis B virus (HBV) infection were treated with recombinant IFN-alpha-2C for 16 weeks. Replication of HBV was inhibited in 5 cases while a decreased inflammatory process in the liver was attained in 3. The treatment was very well tolerated in all of the studied children. A significant increase of ALT activity in the fourth week of treatment seems to be a positive prognostic factor. PMID- 8692596 TI - [Chronic hepatitis C and interferon alpha treatment]. AB - The authors discuss some of the aspects of chronic hepatitis C infection e.g. interferon alpha treatment. They describe the current state of knowledge on HCV pathophysiology: liver pathology, immunological phenomena, autoimmunity. Attention is paused on development of hepatitis C serodiagnosis which enables patient monitoring during infection and therapy: detection of serum anti-HCV antibodies with third and fourth generation ELISA kits; the polymerase chain reaction (PCR), which enables detection of viral nucleic acid (HCV-RNA). Some differences in interferon therapy in children are also described. PMID- 8692597 TI - [Successful treatment with alpha-interferon of HBV and HDV coinfection. Case report of a 4-year-old boy]. AB - The authors present a case of chronic active hepatitis due to HBV and HDV coinfection. Because of high biochemical and histopathological activity with coexisting hepato- and splenomegaly, treatment with alpha interferon was initiated. HBe/anti-HBe seroconversion and normalisation of biochemical and patomorphological paramethers were achieved. PMID- 8692598 TI - [Wilson disease with HCV infections]. AB - In this paper we describe liver-related Wilson's disease in two sisters. The elder died of liver failure. Our patient, a 13-year old girl has hepatitis C coinfection. Gradual improvement was observed after Cuprenil, Zincteral and interferon (Intron A). PMID- 8692599 TI - [Giant-cell hepatitis in a 10-year-old boy]. AB - In this paper we present a 10-year-boy with viral giant-cell hepatitis with a immune component. We observed clinical, biochemical and histological improvement after treatment. PMID- 8692601 TI - [CMV infection and cytomegalovirus disease in immunodepressed patients]. PMID- 8692600 TI - [HIV infection: a case report]. AB - A case is presented of HIV-infection in a child born to an HIV(+) mother belonging to a high-risk group. The diagnosis was determined through multiple identification of anti-HIV-antibodies by means of the ELISA and Western blot tests in a child with lymphopenia, depressed CD4 lymphocyte count and diminished CD4 and CD8 index. Retrovir, among others, has been used in treatment. At present the child is 3.5 years-old and is developing normally. Persistent insignificant enlargement of all groups of lymphnodes, the liver and the spleen is present Full blown AIDS has not developed yet. PMID- 8692602 TI - [Child with epilepsy in the family]. PMID- 8692603 TI - [Hemoglobin concentration, hematocrit and leukocyte distribution pattern in children with Down's syndrome]. AB - Sixty-two children with Down's syndrome and twenty-five healthy children, aged 3 months to 10 years, were studied. It was found that the hematocrit values and concentrations of hemoglobin in Down's syndrome were insignificantly higher than in healthy children, while their leukocyte count was slightly lower. The leukocyte distribution patterns in children with Down's syndrome, aged 3 months to 3 years, were similar to those in healthy children. However, children aged 3.5 10 years with Down's syndrome had a slightly higher percentage of neutrophiles and a significantly lower percentage of lymphocytes. The percentage of E-rosette forming cells and count of T-lymphocyte forming these rosettes in Down's syndrome were significantly lower than in healthy children. PMID- 8692604 TI - [Metal content in children from Katowice and Rabka. I. Magnesium in blood and hair]. AB - The authors determined the magnesium content in the blood and hair by atomic mass absorption. The studied material included preschool children from a kindergarten situated in the center of Katowice (n = 60) and their older teenage brothers and sisters (n = 10). The control group was made up to 24 preschool children from Rabka (a health resort in the mountains). It was found that the majority (over 60%) of preschool children in Katowice had a magnesium deficit. The magnesium content in teenagers was significantly higher than in their preschool siblings. Children from Rabka had much more favorable results. PMID- 8692605 TI - [The circulatory system in children with cutaneous forms of scleroderma. The results of routine as well as 24-hour ECG and physical performance test]. AB - Thirty-four children suffering from so-called cutaneous forms of scleroderma were studied (physical examination, routine and 24-hour ECG, and physical performance test). Physical development was significantly impaired in 5 cases. Congenital heart malformations with left-to-right shunt were detected in 3 children. These children underwent surgery with good results. Heart murmur was found during physical examination in 14 cases. In 30 subjects routine ECG was described as abnormal or doubtful. Abnormal Holter monitoring results were found in 13 children. The authors were not able to detect inferior physical performance test results in the studied children as compared to the control group (when the children suffering from congenital heart malformations and resting tachycardia were excluded from the study). It is suggested that children suffering from so called cutaneous forms of scleroderma should remain under constant cardiological care. PMID- 8692606 TI - [Acceleration of physical development in children and adolescents in the city of Poznan in 1880-1990]. AB - Height and weight measurements taken from children and adolescents in the last century in Poznan show that physical development has accelerated. This is manifested by earlier attainment of larger final body dimensions. This tendency has markedly decreased in the last ten years. PMID- 8692607 TI - [Trends and intensity of height and weight changes in children and adolescents in the city of Poznan over the last century]. AB - The directions and intensity of accelerated development of children and adolescents from the city of Poznan during the last century are analyzed. Periods of increased (the fifties and seventies) and decreased intensity (the sixties and eighties) can be distinguished, as well as a period of deceleration (corresponding to the second world war). PMID- 8692608 TI - [Late infantile neuronal ceroid-lipofuscinosis: clinical symptoms and investigations]. PMID- 8692609 TI - [Bacterial meningitis caused by the strains of Haemophilus influenzae type B resistant to most penicillins and cephalosporins]. AB - In recent years bacterial meningitis caused by Haemophilus influenzae appears to have occurred more frequently in Poland. In this paper the author presents three specific cases treated in one typical month at the Department of Neuroinfections at John Paul the II Hospital, Krakow. Each of the cases in question proved difficulty to treat because the strains of bacteria encountered were resistant to the most of penicilins and cephalosporins. PMID- 8692610 TI - [Psychogenic polydipsia in infants due to the wrong parental behavior]. AB - Three infants with symptoms of diabetes insipidus are described. Psychogenic polydipsia, which rarely occurs in infancy, was diagnosed. It was caused by mistakes made by the parents in bringing up these children. PMID- 8692611 TI - [A case of porphyria cutanea tarda in an 11-year-old boy]. AB - A rare case of porphyria cutanea tarda (PCT) in an 11-year-old boy is presented. The clinical manifestations were typical. Results of porphyrin analyses of urine and serum with a fluorescence emission maximum around 398 nm revealed a pattern consistent with PCT. PMID- 8692612 TI - [Tracheal hemangioma]. PMID- 8692613 TI - The evolution of therapy for dehydration: should deficit therapy still be taught? AB - OBJECTIVE: To describe the evolution of rehydration therapy for cholera and diarrheal dehydration from its beginning in 1832 to the present. To reaffirm the central role for extracellular fluid (ECF) expansion and question the continued teaching of deficit therapy in many current pediatric texts. METHODOLOGY: I reviewed the rationale underlying three treatment strategies: rapid parenteral infusions of saline solutions to restore ECF; deficit therapy to replace specific electrolyte and water losses; and oral rehydration therapy (ORT) to effect both. I used crude mortality rates as the measure of outcomes. RESULTS: (1) Beginning in 1832 for cholera and 1918 for infant diarrheal dehydration, parenteral saline infusions were infused to replace losses of salt and water; they were very effective in salvaging moribund dehydrated patients by quickly restoring ECF volume and renal perfusion. Mortality rates dropped from more than 60% to less than 30%. (2) Deficit therapy as it evolved in the 1950s defined potassium and other fluid and electrolyte deficits and replaced them using specific but complicated fluid and electrolyte replacement regimens. Mortality rates dropped to single digits. (3) ORT, with intravenous expansion of ECF volume when indicated, rapidly corrected specific fluid and electrolyte disorders with a very simple therapeutic regimen. Mortality rates dropped to less than 1%. CONCLUSIONS: The simpler, more effective ORT regimen should be taught as standard therapy for diarrheal dehydration. Principles of body fluid physiology should be taught in their own right. PMID- 8692614 TI - Assuring quality of care for children with special needs in managed care organizations: roles for pediatricians. AB - Increasing numbers of children with special health care needs are enrolling in managed care programs. Although managed care may improve service coordination and use of primary care, it may also threaten health outcomes for these children by potentially decreasing access to the range of needed services, eroding progress in developing community-based service systems, and failing to assure quality of care. To date, few frameworks have been proposed to assess quality of care for this population of children in managed care organizations. In this article, we adapt the Institute of Medicine's definition of quality and identify six key components: content of service delivery systems, the nature of desired health outcomes, risks associated with service delivery, constraints of care, interpersonal dimensions, and attention to developmental issues. These components can be assessed at three levels: the individual, the health plan, and the community. Pediatricians and other child health professionals have critical roles to play in assuring that policies and practices within managed care organizations promote a high quality of care for this vulnerable population of children. PMID- 8692615 TI - Practice variations by population: training significance. AB - OBJECTIVE: This study sought to examine variations in the frequency of procedures performed and patterns of care of sick infants and older children by general pediatricians in different sized communities. The results of the study will be considered in developing relevant educational experiences for postgraduate trainees. METHODOLOGY: Questionnaires were sent to 1412 Texas pediatricians requesting frequency information for 29 procedures and whether they provided various levels of care to sick infants and older children. Responses were tabulated by the size of the community in which each pediatrician practiced. RESULTS: Fifty-four percent of the questionnaires were returned. The proportion of pediatricians performing each procedure was significantly different for all but 8 of the 29 procedures between communities of less than 100,000 and more than 100,000 population. For all procedures with significant differences, the proportion of physicians performing the procedures was significantly greater for pediatricians practicing in communities of less than 100,000 population. No significant difference was found between the proportion of pediatricians providing newborn level II and III care; however, more than 65% of both groups provided level II care. Physicians in communities of less than 100,000 population were more likely to provide intermediate and intensive care beyond the newborn period. CONCLUSION: The general practice rotation in the community setting will not provide adequate training experiences for many of the procedures currently being performed by general pediatricians. PMID- 8692616 TI - A cohort study on childhood asthma admissions and readmissions. AB - BACKGROUND: Admissions to hospitals for childhood asthma seem to be increasing, even though admissions for other childhood conditions are decreasing. We studied admissions and readmissions for childhood asthma in Ontario in an attempt to uncover factors relating to the admission patterns. METHODS: Using the hospital discharge data from the Canadian Institute for Health Information, 28,646 children with diagnoses of asthma were identified from April 1, 1989, to March 31, 1992. RESULTS: The admission rates for asthma among children in Ontario showed a 14.8% decrease from 1987 to 1992. This decline was observed primarily in 5- to 17-year-olds. Younger children had a fourfold risk of hospital admission for asthma. In the 4 years studied, 10,427 children (36.4%) were readmitted at least once, representing 22,114 readmissions, 16,196 (73.2%) of which were for asthma. The 6-month probabilities of readmission for asthma were 20.0% (0- to 4 year-olds) and 11.7% (5- to 17-year-olds). The estimated relative risks (RRs) indicated that younger children had a significantly higher risk of readmission for asthma (RR, 1.38; 95% confidence interval, 1.30 to 1.46) or asthma-related causes (RR, 5.02; 95% confidence interval, 4.16 to 6.05). CONCLUSIONS: The observed increasing trend in admissions for asthma among children in the 1970s and 1980s leveled off in the early 1990s. The declining admission rates were largely caused by the lower admission rates among school-aged children from 5 to 17 years. The relatively high admission and readmission rates of preschool children are still a concern. Further research is necessary to examine factors that influence admissions for asthma among young children. PMID- 8692617 TI - Influenza vaccination of children during acute asthma exacerbation and concurrent prednisone therapy. AB - OBJECTIVES: The influenza vaccination rate is very low among children with moderate to severe asthma. This may be partly because of poor patient motivation and failure to visit clinics for vaccination. Another important factor may be health care providers' deferral of vaccination because of concern about the efficacy and safety of influenza vaccination during asthma exacerbations and concurrent prednisone therapy. We therefore examined the safety and immunogenicity of influenza vaccination during acute asthma exacerbation with concomitant prednisone therapy. SETTING: A pediatric allergy and pulmonology clinic and a pediatric emergency department. DESIGN: Children (n = 109) with a known diagnosis of asthma 6 months to 18 years of age were recruited. All participating patients, 59 without asthma symptoms (no prednisone, control group) and 50 with acute asthma exacerbation requiring prednisone burst therapy (prednisone group) received trivalent subvirion influenza vaccine. Fifteen children in the control group and 12 in the prednisone group received a booster dose according to American Academy of Pediatrics guidelines. Serum antibody titers to influenza A/Beijing/32/92 (H3N2), influenza A/Texas/36/91 (H1N1), and influenza B/Panama/45/90 were measured before and 2 weeks after vaccination. Adverse effects noted within 48 hours after vaccine dose were ascertained during the follow-up visit. RESULTS: The antibody response was analyzed by comparing mean postvaccine titers, the percentage of patients achieving protective antibody levels (> or = 5log2), and the percentage of patients achieving rises in titers of 2log2 or greater. Antibody responses to influenza A/Beijing/32/92 (H3N2) and influenza A/Texas/36/91 (H1N1) in the prednisone-treated and control groups were not different. A significantly better response to the influenza B/Panama/45/90 antigen was seen in the prednisone group for all three parameters. Children who received a booster dose and the subgroup of children with low prevaccination titers (< or = 3log2) showed similar patterns. Adverse effects, including asthma exacerbation, local swelling at the injection site, fever, rash, and headache, were not different in the two groups. CONCLUSIONS: Influenza vaccination can be given safely and effectively to asthmatic children regardless of asthma symptoms or concurrent prednisone therapy when necessary. Vaccination of all moderate to severe asthmatic patients visiting clinics or emergency departments would improve the overall vaccination rate significantly. PMID- 8692618 TI - Serum leptin in children with obesity: relationship to gender and development. AB - BACKGROUND: The identification of the ob gene and its adipocyte-specific protein leptin has provided the first physiologic links to the regulatory system controlling body weight. In adults, elevations of serum leptin concentrations were closely correlated with the percentage of body fat. This study investigated whether leptin concentrations were elevated in obese children and the relationship between leptin concentrations and gender, pubertal stage, and race. METHODS: Seventy-seven children (44 girls and 33 boys), mean age, 11.3 years, with a body mass indices (BMIs) greater than 95% for age, race, and gender (mean BMI, 34.4) constituted the obese group. Thirty children (20 girls and 10 boys), mean age, 13.3 years, with BMIs less than 85% for age, race, and sex formed the control group. Radioimmunoassay for serum leptin was performed on a blood sample collected from each child after an overnight fast. RESULTS: The mean serum concentration of leptin in the obese group was 38.6 (SD, 21) ng/mL compared with 7.8 (SD, 6.5) ng/mL in the control group. Serum leptin concentrations were highly correlated with BMI (r = .88). Analysis of covariance revealed a main effect for Tanner stage and gender. CONCLUSIONS: As in adults, obese children have high concentrations of serum leptin, which were highly correlated with arm fat and BMI. Increased adipose tissue in children is associated directly with serum leptin concentration. Leptin concentrations were found to vary with Tanner stage independent of adiposity. Compared with boys, girls had increased leptin concentrations independent of adiposity. It was hypothesized that children manifest a relative "leptin resistance" to support increased growth and development of reproductive capacity. PMID- 8692619 TI - A controlled trial of dexamethasone to prevent bronchopulmonary dysplasia in surfactant-treated infants. AB - BACKGROUND: Surfactant therapy now has a well-established role in the treatment of neonates with respiratory distress syndrome but has failed to reduce the incidence of bronchopulmonary dysplasia (BPD). We conducted a double-blind, placebo-controlled trial to test the hypothesis that dexamethasone therapy given during the first 12 days of life to very low birth weight infants would be synergistic to surfactant in preventing BPD. METHODS: Seventy surfactant pretreated infants (700-1500 g) who had severe respiratory distress syndrome (a/A ratio, 0.18 +/- 0.10; mean airway pressure, 11.1 +/- 1.9 cm H2O; fraction of inspired oxygen, 0.81 +/- 0.22) were enrolled to receive a 12-day course of dexamethasone (n = 36) or saline placebo (n = 34) starting within the first 12 hours after birth. The starting dose of dexamethasone was 0.5 mg/kg per day, and it was tapered progressively. RESULTS: Ventilator variables at 5 to 14 days were significantly improved in those infants who received dexamethasone compared with those who received the placebo. The effect seem to be more marked in infants weighting less than 1250 g at birth. Significantly more infants could be extubated by 14 days of age in the dexamethasone group (26 of 32 vs 14 of 32). Dexamethasone therapy reduced the incidence of BPD at 28 days (odds ratio, 0.1; 95% confidence interval, 0.03 to 0.3) and eliminated BPD at 36 weeks' postconceptional age. Dexamethasone-treated infants had greater weight loss at 14 days (12.9 +/- 6.4% vs 3.7 +/- 8.6%, respectively) and higher blood pressures from days 3 to 10. However, no differences were seen in time to regain birth weight, hypertension (1 infant in each group), or incidence of intraventricular hemorrhage. CONCLUSIONS: We found an additive effect between dexamethasone and surfactant in improving pulmonary status and reducing the incidence of BPD. Compared with the placebo, dexamethasone therapy was more effective in reducing the incidence of BPD in surfactant-pretreated very low birth weight infants. PMID- 8692620 TI - Clinical and virologic features of hepatitis C virus infection associated with intravenous immunoglobulin. AB - OBJECTIVE: To characterize the clinical features of hepatitis C virus (HCV) infection associated with the administration of intravenous immunoglobulin (IVIG) in patients with varied immunodeficiencies. DESIGN: Prospective collection of clinical and virologic data in patients determined to have HCV exposure associated with Gammagard. SETTING: Outpatient department of Children's Hospital, Boston. PATIENTS: Twenty-one patients with evidence of HCV infection were identified during a screening program initiated to detect infection in exposed individuals. They ranged from 5 to 53 years of age; 14 were children under age 18. RESULTS: Six patients presented with severe clinical hepatitis before detection by screening, 13 were detected by screening only, and 2 were first detected by screening and subsequently developed symptomatic hepatitis. Follow-up is available on 20 patients; 4 without viremia at identification have remained clinically well. Hepatitis and viremia have resolved in 2, 2 additional subjects have developed normal alanine aminotransferase (ALT) values with persistent viremia, and 13 have biochemical and/or virologic evidence of chronic hepatitis. Eight patients (7 children) have undergone liver biopsies; 7 have histologic findings of chronic hepatitis, 5 have mild fibrosis, and 2 have moderate fibrosis. HCV genotypes 1a and 1b were observed with equal frequency in this group. CONCLUSIONS: Some HCV infections associated with IVIG had a more severe, acute course than is ordinarily described. This may be attributable to host factors, such as immunodeficiencies, or virologic factors, such as inoculum or genotype. Although a large percentage (87.5%) of these individuals developed chronic infection, the natural history is not as yet completely defined. PMID- 8692621 TI - The risk of seizure recurrence after a first unprovoked afebrile seizure in childhood: an extended follow-up. AB - OBJECTIVE: To assess the long-term recurrence risks after a first unprovoked seizure in childhood. METHODS: In a prospective study, 407 children who presented with a first unprovoked seizure were then followed for a mean of 6.3 years from the time of first seizure. RESULTS: One hundred seventy-one children (42%) experienced subsequent seizures. The cumulative risk of seizure recurrence was 29%, 37%, 42%, and 44% at 1, 2, 5, and 8 years, respectively. The median time to recurrence was 5.7 months, with 53% of recurrences occurring within 6 months, 69% within 1 year, and 88% within 2 years. Only 5 recurrences (3%) occurred after 5 years. On multivariable analysis, risk factors for seizure recurrence included a remote symptomatic etiology, an abnormal electroencephalogram (EEG), a seizure occurring while asleep, a history of prior febrile seizures, and Todd's paresis. In cryptogenic cases, the risk factors were an abnormal EEG and an initial seizure during sleep. In remote symptomatic cases, risk factors were a history of prior febrile seizures and age of onset younger than 3 years. Risk factors for late recurrences (after 2 years) were etiology, an abnormal EEG, and prior febrile seizures in the overall group and an abnormal EEG in the cryptogenic group. These are similar to the risk factors for early recurrence. CONCLUSIONS: The majority of children with a first unprovoked seizure will not have recurrences. Children with cryptogenic first seizures and a normal EEG whose initial seizure occurs while awake have a particularly favorable prognosis, with a 5-year recurrence risk of only 21%. Late recurrences do occur but are uncommon. PMID- 8692622 TI - Parental availability for the care of sick children. AB - OBJECTIVE: Parents have always played a critical role in the care of sick children. Although parents' roles remain crucial to children's health, parental availability has declined during the past half century. The percentage of women with preschool children who work has risen almost fivefold in 45 years from 12% in 1947 to 58% in 1992. The percentage of women in the paid work force with school-aged children has almost tripled in the same period, from 27.3% to 75.9%. Research has examined the effects of a variety of parental work conditions on children. However, past research has not examined how working conditions affect the ability of parents to care for their sick children. In this article, we examine how often the children of working parents get sick and whether parents receive enough paid leave to care for their sick children. METHODOLOGY: This analysis makes use of two national surveys, which provide complementary information regarding the care of sick children. The National Longitudinal Survey of Youth is a longitudinal survey of a nationally representative probability sample of 12,686 men and women; the National Medical Expenditure Survey is a panel survey of 34,459 people. First, we estimated the family illness burden. Second, we looked in detail at the number of days of sick leave mothers had. Third, we examined whether mothers who had sick leave had it consistently during a 5-year period. Finally, we conducted a logistic regression to determine what factors were significant predictors of both lacking sick leave. RESULTS: More than one in three families faced a family illness burden of 2 weeks or more each year. Yet, 28% of mothers had sick leave none of the time they were employed between 1985 and 1990. Employed mothers of children with chronic conditions had less sick leave than other employed mothers. Thirty-six percent of mothers whose children had chronic conditions had sick leave none of the time they were employed. Although 20% of working parents who did not live in poverty lacked sick leave, 38% of parents who did live in poverty lacked sick leave. The problem is also more marked for nonwhite parents. Although 23% of working white parents lacked paid sick leave, 31% of nonwhite parents lacked sick leave. One in six families that lacked sick leave had to cover for more than 4 weeks of family illness during the year. CONCLUSION: In 1993, the US Congress passed the Family and Medical Leave Act (FMLA). However, by limiting the medical leave to the care of major illnesses, primarily those requiring hospitalization, the FMLA does not address the majority of children's sick care needs. For the common childhood illnesses that are not covered by the FMLA, employed parents often must rely on their sick leave if they are to care for their sick children themselves. Yet, we found that many employed parents lack sick leave. This is particularly true of parents of children with chronic conditions and poor and minority families. PMID- 8692623 TI - Neonatal mortality and length of newborn hospital stay. AB - OBJECTIVE: To investigate the effect of hospital discharge time on neonatal mortality of term newborns. DESIGN: Infants who were discharged home at 5 days of age of younger and who subsequently died were compared with control infants using a retrospective case-control design. Descriptive information was collected from records of infants who were not discharged home from the hospital of birth (because of death or transfer to a tertiary care hospital) to determine the age at which their illnesses presented. METHODS: We reviewed death certificates for all infants with birth weights of 2500 g or greater born at 37 weeks' gestational age or greater who died in the first 28 days of life and who were born in one of four Utah counties (1985 through 1989). Of the 109,256 eligible births, 115 infants were found who had died in the neonatal period. Eighty-four infants had not been discharged home from the hospital of birth, 5 infants had had hospital stays of more than 5 days, 9 records could not be located, 17 presumed healthy infants were discharged from the hospital at 5 days of age or younger. These 17 infants were each matched with 3 control infants. Newborn nursery charts were reviewed to determine hospital discharge times for case and control infants. Descriptive information regarding the time of presentation of illness was collected for the other 89 infants. RESULTS: The mean age of hospital discharge was 43 +/- 21 hours for the 17 case infants and 47 +/- 25 hours for the 51 control infants. The odds ratio for neonatal mortality for discharge at less than 24 hours was 1.65 (95% confidence interval, 0.42 to 3.34) and for discharge at less than 48 hours was 1.16 (95% confidence interval, 0.4 to 3.34). Of the 84 infants who were not discharged home from the hospital of birth, 93% had been symptomatic by 12 hours of age, and 99% were symptomatic by 18 hours. CONCLUSIONS: Most full-term infants who die in the neonatal period are symptomatic within the first 18 hours after birth. We could not demonstrate an association between early hospital discharge and neonatal mortality in those infants who died after discharge home. PMID- 8692624 TI - Maternal risks for very low birth weight infant mortality. AB - OBJECTIVE: To determine whether known maternal risk factors for low birth weight directly contribute to infant mortality among very low birth weight infants. DESIGN: Retrospective population-based, case-control study. SETTING: Four hospitals in the Oakland, California, area: one community, two private, one health maintenance organization. PARTICIPANTS: All live-born singleton very low birth weight ( < 1500 g) infants born to Oakland residents over a 3-year period. Cases were infants who died before their first birthday, identified by computerized linkage of birth and death certificates. For each case, a surviving control was selected to match for birth weight, sex, and race. Forty matched pairs were identified in total. OUTCOME MEASURES: Prevalence of maternal risk factors among cases versus controls. RESULTS: After controlling for other factors known to influence either birth weight or infant mortality, maternal cocaine use (odds ratio [OR] = 5.43), prior infant death (OR = 27.14), and planned pregnancy (OR = 6.33) were significantly associated with the survival of very low birth weight infants. CONCLUSIONS: Some maternal risk factors for low birth weight confer a survival advantage to very low birth weight infants. Our data reveal that maternal cocaine use is independently associated with survival among this subset of infants. Prior research supports the observed relationship as well as the scientific plausibility of a cocaine-mediated survival advantage among premature infants. Our study also showed both planned pregnancy and prior infant death to be independently associated with infant survival among this subset of infants, suggesting that maternal behaviors may play a role in determining birth weight-specific mortality. These data should be systematically evaluated to better define their relationship to infant mortality. PMID- 8692625 TI - Rapid placement of transpyloric feeding tubes: a comparison of pH-assisted and standard insertion techniques in children. AB - OBJECTIVE: To compare transpyloric feeding tube placement using a pH-assisted placement technique versus a standard placement technique in pediatric patients requiring enteral nutrition. METHODS: Critically ill children younger than 4 years were prospectively and randomly assigned to either a pH-assisted or a standard feeding tube placement group. Identical pH-assisted feeding tubes were used in both groups; however, feeding tubes in the standard group were not attached to a portable pH meter. Successful transpyloric placement was confirmed by radiography before beginning feedings. If placement was not successful, a second placement attempt was made after metoclopramide administration. Information regarding tube placement success, number of radiographs, time to initiation of feedings, and daily caloric intake was collected. A cost comparison between the two groups was performed. RESULTS: Thirty-four patients were enrolled in the pH-assisted group, and 34 were enrolled in the standard feeding tube group. Ninety-seven percent of patients in the pH-assisted group had successful placement after the first attempt, compared with 53% of patients in the standard group. The average time to successful placement of pH-assisted feeding tubes was 6 minutes. All patients in the pH-assisted group had successful placement after the second attempt, compared with 78% of patients in the standard group. A pH of greater than 5.6 accurately predicted transpyloric placement in 97% (33 of 34) of individuals in the pH-assisted group. Children in the pH-assisted group required significantly fewer radiographs than those in the standard group. Hospital costs were $114 per patient in the pH-assisted group and $135 per patient in the standard group. CONCLUSIONS: Our findings indicate that bedside transpyloric placement of pH-assisted feeding tubes can be accomplished rapidly and with a high success rate. This method is associated with decreased radiation exposure and economic savings when compared with a standard placement technique. PMID- 8692627 TI - Renal bicarbonate excretion in extremely low birth weight infants. AB - OBJECTIVE: To test the hypothesis that due to the immaturity of their kidneys extremely low birth weight infants lose large amounts of bicarbonate in their urine. METHODS: Urine and blood samples collected every 8 to 12 hours for the first 4 days of life from 22 preterm infants 23 to 29 weeks' gestation weighing 540 to 982 g at birth were prospectively studied. RESULTS: As described previously, three phases of fluid homeostasis were identified. The first phase (prediuresis) was a period of low urine output followed by a period of spontaneous diuresis/natriuresis (diuretic phase) and then by a phase when urine output varied according to fluid intake (postdiuresis). Sodium, potassium, chloride, and bicarbonate excretion rates and bicarbonate balance (bicarbonate or acetate infused minus bicarbonate excreted) were calculated for each of the three phases. Urinary excretion of sodium, potassium, chloride, and bicarbonate increased from the prediuretic to the diuretic phase and decreased from the diuretic to the postdiuretic phase. During the diuretic phase 88% of renal sodium excretion was accompanied by excretion of chloride. Bicarbonate balance was positive in all three fluid phases. Cumulative renal bicarbonate loss over the first 4 days of life was 1.9 +/- 0.5 meq/kg (SD) and the cumulative bicarbonate balance was +4.4 +/- 4.1 meq/kg (SD). The glomerular filtration rate, filtered load of bicarbonate, and absolute tubular reabsorption of bicarbonate significantly increased from the prediuretic to the diuretic phase, while fractional reabsorption of sodium and chloride decreased between these two phases. The fractional reabsorption of bicarbonate did not change from prediuresis to diuresis, but increased from diuresis to postdiuresis and consequently from prediuresis to postdiuresis. CONCLUSIONS: Contrary to our original hypothesis, the total renal bicarbonate excretion of extremely low birth weight infants in the first 4 days of life is low and the net bicarbonate balance is positive. The anion predominantly accompanying the excretion of sodium in all three phases is chloride and not bicarbonate. Bicarbonate excretion appears to be independent of sodium excretion during these phases. The increase in renal tubular bicarbonate reabsorption during the first week of life may be associated with extracellular volume contraction. PMID- 8692626 TI - Psychosocial function during treatment for familial hypercholesterolemia. AB - OBJECTIVE: To determine whether children treated for familial hypercholesterolemia (FH) have greater psychosocial dysfunction compared with their peers. CHILDREN: Children were 86 boys and 66 girls 7-16 years of age attending a lipid clinic. They were screened and instructed to follow a diet low in saturated fat and cholesterol 18 months to 9 years earlier (mean, 4 years), and their mean dietary intake, estimated by a quantitative food frequency questionnaire, was within recommended limits. One-fourth had lost a parent or had a parent who had had cardiovascular disease due to FH (parental disease group). METHODS: Results of the Child Behavior Checklist, Teacher's Report Form, and Youth Self-Report were compared with a population sample. A semistructured interview, the Child Assessment Schedule, was administered to the children with FH and a well-functioning comparison group from the population (epidemiologic cohort; n = 62). RESULTS: Psychosocial scores were similar in the children with FH and the population sample. The Child Assessment Schedule showed that, compared with the epidemiologic cohort, children with FH did not have increased symptoms in any area of function, and scores for family, mood, and expression of anger were lower (less symptomatic). The prevalence of psychiatric diagnoses was 10%, which was not greater than expected. Children from the parental disease group had higher symptom scores in the areas of school and expression of anger than the rest of the children with FH. Their mean Children's Global Assessment Score (CGAS, which gives average children scores of 70-79) was slightly lower (77 vs 79). Belonging to the parental disease group predicted a lower CGAS in multivariate regression analyses, as did male sex, parental divorce, and low parental educational level. These factors explained up to 19% (95% confidence interval, 9%-31%) of the variance in CGAS. CONCLUSIONS: We found that the prevalence of psychosocial dysfunction was not greater than expected in children treated for FH. Psychosocial function within the group was associated with the usual demographic characteristics and with the loss or disease of a parent, beyond the period of bereavement or immediately after the event. PMID- 8692628 TI - Male adolescents involved in pregnancy: associated health risk and problem behaviors. AB - OBJECTIVE: Little is known about male high school students who have been involved in a pregnancy. This study was undertaken to determine whether male involvement with a pregnancy during adolescence is associated with other risk and problem behaviors. METHODS: The 1993 Massachusetts Youth Risk Behavior Survey was conducted on a random sample of 3054 9th- through 12th-grade students. The use of tobacco, alcohol, and other drugs, early and multiple sexual experiences, fighting resulting in injury, and demographic variables were compared between sexually active young men who reported being involved in pregnancy (n = 82) and their counterparts who reported not ever causing a pregnancy (n = 537). Associations were measured using chi 2 analyses and Kruskal-Wallis analysis of variance. Stepwise logistic regression was used to further analyze those variables significantly associated with involvement with a pregnancy. RESULTS: Based on logistic regression, older age and earlier ages of onset of cocaine use, initial sexual intercourse, and regular use of cigarettes were associated with being involved with a pregnancy. An increased lifetime frequency of cocaine use, lifetime frequency of alcohol use, and an increased number of lifetime sexual partners were also associated with having caused a pregnancy. Those who reported involvement with a pregnancy reported a higher frequency of being injured in a fight during the past year, drinking while driving, and having multiple sexual partners during the previous 30 days than those who had not gotten someone pregnant. CONCLUSIONS: A history of being involved with a pregnancy clustered with other health risk and problem behaviors to form a "risk behavior syndrome." These findings suggest that when risk behaviors are encountered during the routine comprehensive screening of male adolescents, strategies for pregnancy prevention among young men should also be emphasized. PMID- 8692629 TI - African-American adolescents residing in high-risk urban environments do use condoms: correlates and predictors of condom use among adolescents in public housing developments. AB - OBJECTIVE: African-American adolescents living in high-risk inner-city environments have been disproportionately affected by the epidemics of human immunodeficiency virus (HIV) and other sexually transmitted diseases. Understanding the factors that influence the use of condoms by adolescents is critical for developing effective behavioral interventions. The present study examined the demographic, psychosocial, and behavioral correlates of condom use among African-American adolescents residing in public housing developments in an HIV epicenter (San Francisco) and prospectively evaluated the stability of these significant cross-sectional variables to predict consistent condom use. DESIGN: A prospective study. SETTING: Two public housing developments in San Francisco. PARTICIPANTS: African-American adolescents and young adults between 12 and 21 years of age were recruited though street outreach and completed a theoretically derived research interview assessing HIV-related knowledge, attitudes, and behaviors. After a 6-month period, adolescents completed a follow-up interview similar to the baseline measure. Among adolescents reporting sexual activity in the 6 months before completing the baseline interview (n = 116), logistic regression analysis evaluated the influence of demographic, psychosocial, and behavioral factors on consistent condom use. RESULTS: Adolescents who had high assertive self-efficacy to demand condom use (adjusted odds ratio [OR], 11), perceived peer norms as supporting condom use (OR, 4.2), had greater impulse control (OR, 3.7), were male (OR, 4.7), and were younger (OR, 2.9) were more likely to report consistent condom use. Frequency of sexual intercourse was inversely related to condom use; adolescents with higher numbers of sexual episodes were less likely to use condoms consistently. Prospective analyses identified the baseline level of condom use as the best predictor of condom use at the 6-month follow-up. Adolescents who were consistent condom users at baseline were 7.4 times as likely to be consistent condom users during the follow up period. Of those adolescents changing their frequency of condom use during the follow-up interval, significantly more engaged in risky behavior; 33.3% changed from consistent to inconsistent condom use, whereas 20.6% changed from inconsistent to consistent use (OR, 1.6). CONCLUSIONS: The findings suggest that HIV prevention programs need to be implemented early, before high-risk behaviors are established and may be more difficult to modify. PMID- 8692631 TI - Why use homeopathic doses of phototherapy? PMID- 8692630 TI - Growth hormone increases breast milk volumes in mothers of preterm infants. AB - AIMS: To determine the galactopoietic response to recombinant human growth hormone (hGH) in mothers of premature infants with inadequate lactation. STUDY DESIGN: Prospective placebo-controlled, double-blind trial. SUBJECTS: Twenty healthy mothers on no concurrent medication, with infants born between 26 and 34 weeks' gestation with insufficient milk production for their infants' needs. INTERVENTIONS: Ten mothers received hGH, .2 IU/kg/day subcutaneously to a maximum of 16 IU/day, for 7 days, while 10 mothers received the same volume of placebo. One mother from each group withdrew from the study. OUTCOME MEASURES: Maternal milk production and plasma concentrations of insulin-like growth factor-1 (IGF 1), insulin-like growth factor binding protein-3 (IGFBP-3), and growth hormone (GH) were determined before starting treatment and 1 day after stopping therapy. A nurse measured the amount of milk expressed (5 to 6 times daily) plus, if the infant was suckling, weighed the infant before and after feeding. RESULTS: The mothers were enrolled 35 +/- 26 days after birth; at this time the infants weighed 1.89 +/- .64 kg. Milk production in hGH-treated mothers increased from 139 +/- 49 mL/day to 175 +/- 46 mL/day after 7 days of treatment (a rise of 31%). Placebo-treated mothers showed no significant change from 93 +/- 50 mL/day to 102 +/- 69 mL/day (a rise of 7.6%, not significant). Milk production increased in all treated mothers but decreased in 4 of 9 placebo mothers. Plasma concentrations of IGF-1 and IGFBP-3 increased in hGH-treated mothers but not placebo-treated mothers; there was no change in plasma GH levels in either group. No adverse effects were seen with hGH treatment in the mothers or infants. CONCLUSIONS: hGH therapy in mothers with lactational insufficiency can improve breast milk volumes. PMID- 8692632 TI - Children in orphanages: Newt Gingrich is not Daddy Warbucks. PMID- 8692633 TI - Brain injury in a healthy child one year after periureteral injection of Teflon. AB - This report presents the case of a previously healthy 6-year-old girl who had an ischemic injury corresponding to the territory perfused by the lateral branches of the lenticulostriate arteries of the middle cerebral artery. Stroke in childhood is rare, and the specific causes are identified in only half the cases. Our patient was carefully studied for any hereditary or acquired risk factors for stroke, but we found only one, an endoscopic injection of Teflon performed 1 year before to correct vesicoureteral reflux. This suggests the risk of potential migration of Teflon particles to the brain, where they can block the microcirculation. PMID- 8692634 TI - Gastric fluid analysis for determining gestational cocaine exposure. PMID- 8692635 TI - Ketorolac-induced acute renal failure in a previously healthy adolescent. PMID- 8692636 TI - Health supervision for children with fragile X syndrome. American Academy of Pediatrics Committee on Genetics. PMID- 8692637 TI - Medication for children with attentional disorders. American Academy of Pediatrics Committee on Children With Disabilities and Committee on Drugs. AB - Increasing numbers of children with attentional difficulties have been treated with medication, especially during the last 25 years, and now adolescents and adults are also being recognized with attentional difficulties. This policy statement provides information on the role and the pharmacology of medications used to treat children with attention deficit disorders. Indications and use of medications are discussed and recommended drugs and dose levels are outlined. Information on adverse effects and common side effects is presented. PMID- 8692638 TI - Testing for drugs of abuse in children and adolescents. American Academy of Pediatrics Committee on Substance Abuse. AB - The American Academy of Pediatrics (AAP) recognizes the abuse of psychoactive drugs as one of the greatest problems facing children and adolescents and condemns all such use. Diagnostic testing for drugs of abuse is frequently an integral part of the pediatrician's evaluation and management of those suspected of such use. "Voluntary screening" is the term applied to many mass non-suspicion based screening programs, yet such programs may not be truly voluntary as there are often negative consequences for those who choose not to take part. Participation in such programs should not be a prerequisite to participation in school activities. Involuntary testing is not appropriate in adolescents with decisional capacity-even with parental consent-and should be performed only if there are strong medical or legal reasons to do so. The AAP reaffirms its position that the appropriate response to the suspicion of drug abuse in a young person is the referral to a qualified health care professional for comprehensive evaluation. PMID- 8692639 TI - The role of the pediatrician in prescribing therapy services for children with motor disabilities. American Academy of Pediatrics Committee on Children With Disabilities. AB - Pediatricians are often called upon to prescribe physical and occupational therapy service for children with motor disabilities. This statement defines the context in which rehabilitation therapies should be prescribed, emphasizing the identification and enhancement of the child's function and abilities. The statement encourages the pediatrician to work with teams including the parents, child, teachers, therapists, and other physicians. PMID- 8692640 TI - Protective eyewear for young athletes. American Academy of Pediatrics Committee on Sports Medicine and Fitness and American Academy of Ophthalmology Committee on Eye Safety and Sports Ophthalmology. PMID- 8692641 TI - Comments from another student of Gamble and Darrow on fluids. PMID- 8692642 TI - Need for bedtime dose of ritalin. PMID- 8692643 TI - Pinhole occluder. PMID- 8692644 TI - Streptococcus and varicella. PMID- 8692645 TI - The interface between dysmorphology and epidemiology in the "diagnosis" and surveillance for fetal alcohol effects. PMID- 8692646 TI - Survival < or = 800 grams!? PMID- 8692647 TI - [The discovery of X-rays and their introduction to Japan at the end of the 19th century]. AB - The discovery of X-rays was first reported in Japan on February 29, 1896 by the TOKYO IJISHINPOU, a widely distributed medical journal, which translated Jastrowitz's presentation on the newly discovered X-rays at the meeting of the Berliner Gesellschaft fur Innere Medizin on January 6, 1896. The most important early report on X-rays from Germany was that of H. Nagaoka, who had attended the festival of das 50 jahrige Bestehen der Berliner Physikalischen Gesellschaft on January 4, 1896. The report with a roentgenograph of a human hand (not that of Mrs Roentgen) appeared in the TOUYOU GAKUGEI ZASSHI, issued on March 25, 1896. Physicists in a few institutes in Tokyo were said to have carried out successful roentgenography by the middle of March 1896. The first booklet containing a roentgenograph of a human hand taken by Japanese researchers was published on May 15, 1896. PMID- 8692648 TI - [Evaluation of the retrosternal space and the retrocardiac space on normal left lateral radiographs of the chest]. AB - Left lateral chest radiographs with normal studies were evaluated in 100 Japanese (50 females and 50 males) to compare the radiolucency of the retrosternal space (RSS) with that of the retrocardiac space (RCS) and to measure the RSS. In 56 (56%) cases, the RSS was equally radiolucent to the RCS. In 40 (40%) cases, the RSS was less radiolucent than the RCS (33 of 50 females and 7 of 50 males). The difference between the sexes was statistically significant (p = 0.0001). The RSS was more radiolucent than the RCS in only 4 (4%) males. Frontal chest radiographs of 50 females were classified into one of three groups (Small, Medium, or Large) depending on the size of soft tissue opacity of the breast. The differences between the radiolucency of the RSS and RCS were statistically significant between the Small and Medium and the Small and Large groups (both p < 0.0001). The strength of the relationship between the radiolucency and body-to-fat ratio was statistically significant (p = 0.0028). Results of data comparison between females and males remained significant when adjusted for differences in body-to fat ratio (p < 0.0001). The distance on the chest radiograph from the sternum to the most anterior aortic border (the distance of RSS) could be measured on only 37 (37%) lateral chest radiographs, and the averages and standard deviations were as follows: 2.2 +/- 0.5 in all cases, 2.0 +/- 0.5 in females, and 2.4 +/- 0.5 in males. The difference between the sexes was statistically significant (p < 0.05). In conclusion, an RSS that is more opaque (less radiolucent) than the RCS is a frequent normal finding because of the opacity of the breast and fat tissue, especially in females, and the length of the RSS is shorter in females than in males. PMID- 8692649 TI - [Quantitative flow measurement of the vertebro-basilar circulation for positional vertigo by using 2D phase contrast technique]. AB - Quantitative measurements of blood flow in the vertebral and basilar arteries were obtained by the 2D phase contrast (2D PC) technique. In phantom study, flow velocity measured with 2D PC correlated well with actual flow velocity. Sixty-six patients were neurologically normal and 20 had positional vertigo due to vertebrobasilar insufficiency (VBI). Mean velocities (MV) were measured by using a transverse plane in the vertebral arteries at the level of C3 and in the basilar arteries at the level of the sella floor. Volume flow rates (VFR) were calculated as the product of MV and the area of the arteries whose diameters were measured on the basis of pixel counting in the histogram of the signal intensity profile. In the normal group, MV of the left vertebral artery and MV and VFR of the basilar artery showed significant declines as age progressed. In the vertigo group, MV and VFR of the basilar artery were significantly lower than in the normal group. It is concluded that 2D PC technique appears to be fast and easy to handle without cardiac gating to assess blood flow in vessels surrounded by bone tissues. PMID- 8692650 TI - [Evaluation of renal function using Gd-DTPA dynamic MR imaging]. AB - To establish a new method for evaluating renal function using MRI, we performed dynamic Gd-DTPA enhanced MR imaging at 1.5 T in 68 subjects (71 examinations), including 23 normal volunteers, 19 patients with chronic renal failure, 22 with hydronephrosis, and 7 with renal vascular disorders. Thirty GRASS images [35/9/20 degrees /1 (TR/TE/Flip Angle/NEX)] were obtained after a bolus injection of Gd DTPA (0.2 mmol/Kg) in each case, and were evaluated in the following respects. (1) Whether or not the initial signal increase and/or the following signal drop in cortex was observed. (2) Whether or not the signal drop in medulla and/or calyces was observed. (3) Time between initial signal increase in cortex and signal drop in medulla (Ta). (4) Time between signal drop in medulla and calyces (Tb). (5) Time between signal increase in cortex and signal drop in calyces (Tc). (6) Maximum ratio of signal intensity between cortex and medulla (Max. C/M). In normal subjects, the initial signal increase and the following signal drop in cortex, and the signal drop in medulla and calyces were observed. In patients with abnormal renal function, the characteristic signal changes described above were not seen clearly or disappeared in many cases. In normal subjects, Ta, Tb, Tc, and Max. C/M were 41.9 +/- 6.9 sec, 53.2 +/- 10.6 sec, 95.0 +/- 9.5 sec, and 1.10 +/- 0.05, respectively. In the patients, time parameters were significantly larger than those of normal subjects and C/M ratios were lower. This study suggested that dynamic Gd-DTPA renal MR imaging can serve as a new method for the evaluation of renal function. PMID- 8692651 TI - [Quantitative analysis of clinical usefulness of CRT monitor diagnosis by using previous and current chest images with simulated lung nodules]. AB - We quantitatively evaluated the clinical usefulness of CRT diagnosis by using previous and current chest images with simulated lung nodules. Sixty normal chest X-ray films consisting of previous and current chest images were digitized. Simulated nodules prepared by a computer workstation were added on lung fields of the 30 current images. Observer performance tests were carried out with six radiologists to evaluate the detection of simulated lung nodules in CRT and hard copy film with previous and current images, and with only current films. ROC analyses indicated that the detection accuracy in CRT diagnosis with current and previous images was greater than that in CRT diagnosis with only a current image. In addition, there was no statistically significant difference between CRT and hard copy film diagnoses if current and previous images were employed for the diagnosis of simulated lung nodules. We believe that CRT diagnosis is as useful as hard copy film diagnosis for the evaluation of pulmonary nodules by using previous and current chest images. PMID- 8692652 TI - [An assessment of the thalamocortical sensory pathway based on small infarcts in the corona radiata on CT]. AB - Although lacunar syndrome is relatively commonly encountered in patients with a lacunar infarct in the deep cerebral white matter, the responsible lesions are often unidentified. By examining eight patients with lacunar syndrome who had small infarcts in the deep cerebral white matter, an attempt was made to determine the position and distribution of the sensory pathway on brain CT at the level of the splenium of the corpus callosum. When the distance from the frontal crista to the superior saggital sinus sulcus was defined as 1.0, the position of the corticospinal tract was located in the portion from 0.45 to 0.49 and that of the sensory pathway in the portion from 0.49 to 0.53. These data indicated that the position of the sensory pathway was just behind the corticospinal tract and the distribution was very narrow at this level. The results of this assessment revealed that lacunar infarcts in the deep cerebral white matter were liable to cause sensorimoter syndrome more than pure sensory stroke. PMID- 8692653 TI - [Stage IIIa endometrial carcinoma: MR findings]. AB - [PURPOSE]: An attempt was made to evaluate the ability of magnetic resonance (MR) imaging to diagnose stage IIIa endometrial carcinoma. [MATERIALS AND METHODS]: Thirty-three patients with endometrial carcinoma underwent MR imaging and surgery. Surgical staging was classified as I in 21 patients, II in 3 patients and III in 9 patients. The MR images of each patient were retrospectively reviewed by three radiologists. Only the clinical diagnosis of endometrial carcinoma was previously notified. Segmental disruption of the full thickness of the myometrium was considered serosal invasion. Intraperitoneal metastasis was diagnosed according to three criteria (intraperitoneal solid mass of isointensity compared with endometrial lesion, cystic mass excluding benign ovarian cysts, ascites). These evaluations were compared with the surgical findings and analyzed by the kappa statistic. [RESULTS]: The rates of sensitivity and positive predictive value (PPV) for serosal invasion were 33% and 6%, respectively. False positive evaluation frequently occurred when thickness of the intact myometrium was less than 5mm. The rates of sensitivity and PPV for intraperitoneal metastasis were 86% and 72%, respectively. The reason for false negative evaluation was small foci of intraperitoneal metastasis. Overall, sensitivity and PPV for stage IIIa were 86% and 69%, respectively. [CONCLUSION]: MRI was useful in detecting intraperitoneal metastasis of endometrial carcinoma with the exception of diagnosing serosal invasion. It is difficult to detect small foci of peritoneal metastasis. It is necessary to differentiate adnexal metastasis from benign adnexal masses. PMID- 8692654 TI - [Clinical study of pneumoconiosis featuring small nodules and without large opacities on high-resolution CT]. AB - High-resolution CT (HRCT) was performed in 25 patients with pneumoconiosis diagnosed as category 1 or 2 according to the ILO radiographic classification. The small opacities shown on HRCT images were classified as small branching structures (SBS) or small rounded opacities (SRO). Patients in these two groups were compared with respect to the distribution of small nodules, pulmonary function, arterial blood gas analysis, degree of exertional dyspnea, and alteration ratio of the lung field CT numbers between maximum inspiration and maximum expiration (%(I-E)). The small nodules in all patients of the SBS group were classified as type p. SBS were distributed evenly throughout the lungs, while SRO were mainly localized in the upper middle lobe. Pulmonary emphysema was observed in patients with SBS and was particularly common among patients in this group with an irregular septum (IS). No emphysematous lesions were detected in the SRO group. RV/ TLC was higher and exertional dyspnea was more severe in the SBS group than in the SRO group. It was considered that an increase of RV/TLC resulted in worsening of exertional dyspnea in the patients with SBS. The % (I-E) value was significantly lower in the SBS group than in the SRO group. PMID- 8692655 TI - [A clinical study on optimization of dose distribution in 60Co RALS for carcinoma of the uterine cervix using X-ray CT images]. AB - From 1983 to 1992, 248 patients with carcinoma of the uterine cervix were treated with intracavitary radiation therapy using the 60Co remotely controlled high dose rate afterloading system apace (RALS). Five-year survival rates were 92,8 +/- 7 % for Stage I, 72.4 +/- 5% for Stage II and 52.1 +/- 4% for Stage III. The relations among the sequelae in surrounding organs, local control rates and the calculated dose in the rectum, sigmoid colon, bladder and small intestine were evaluated using X-ray CT images. The patients were treated with intracavitary radiation of 6 Gy/fraction at point A. A total of 5 fractions were delivered once a week. The dose calculation was performed by, and dose distribution shown on, a system developed in our hospital with a personal computer. The average values of maximum dose at certain points of the walls of the rectum and sigmoid colon were similar to point A dose. The incidence of late sequelae increased significantly in the group receiving a maximum dose to the rectum and sigmoid colon higher than 8 space Gy/fraction. This report describes the program for automatic optimization of dose distribution by modifying the hot spot (higher than 8 space Gy/fraction) and the cold spot (lower than 6 space Gy/ fraction). PMID- 8692656 TI - [Time, dose and volume factors in interstitial brachytherapy combined with external irradiation for oral tongue carcinoma]. AB - This is a retrospective analysis of 136 patients with squamous cell carcinoma of stages I and II of the oral tongue who were treated with interstitial brachytherapy alone or in combination with external irradiation between 1976 and 1991. Control of the primary lesion and the occurrence of late complications were analyzed with respect to dose, time and tumor size with the Cox hazard model. The 5-year survival rates for stages I and II were 84.5% and 75.6%. The 5-year primary control rate was 91.3% for stage I and 77.3% for stage II (p < 0.05). Local control and survival rates were comparable with those of other modalities. The significant factor in local control was stage. For lesions more than 30 mm in diameter, local control was rather poor in the group given only brachytherapy compared with the group given combined therapy. After 30 Gy of external irradiation, local control was better at a brachytherapy dose > 50 Gy compared with a brachytherapy dose < = 50 Gy. Mucosal ulcer, occurred frequently with increasing total dose and tumor volume. Bone necrosis increased significantly with increasing external irradiation dose. We suggest that external irradiation of 30 Gy followed by brachytherapy of 52 Gy is a better choice for T2 lesions > 30 mm. Late complications should be reduced by using a spacer, improvements in dental and oral hygiene, and a sophisticated implant method. PMID- 8692657 TI - [Quantitative evaluation of 99mTc-GSA for fatty liver and ischemia-reperfusion injury in rats]. AB - 99mTc-GSA (GSA) liver scintigraphy was performed in rats with fatty liver and ischemia-reperfusion injury to study the usefulness of GSA in evaluating these pathological processes. Fatty liver was produced by feeding rats a choline deficient diet. The rats with fatty liver were divided into five groups according to the length of the diet (controls, two weeks, six weeks, 10 weeks, and 12 weeks). In the rats dieted for two weeks and six weeks, regional hepatic ischemia was also induced by clamping the left hepatic artery and the left portal vein for 10 minutes, then reperfusion was performed for 15 minutes. GSA was administered via the IVC.t90, or the time at which the liver time activity curve reached ninety percent of its peak value, was used as an index of GSA hepatic uptake, Ku and Kd, determined by two compartment analysis, were also used as indices. In rats of the fatty liver group, we confirmed microscopically that various degrees of fatty infiltration existed according to the diet period, and t90 became significantly longer according to the severity of fatty infiltration. Ku and Kd also decreased according to the severity of fatty infiltration. In the rats with fatty infiltration and ischemia-reperfusion injury, t90 also increased according to the severity of fatty infiltration, becoming longer than in the rats without ischemia-reperfusion injury. Quantitative analysis of GSA liver scintigraphy was useful for evaluating fatty liver and ischemia-reperfusion injury. PMID- 8692658 TI - [Attempt of helical CT densitometry for assessing regional pulmonary ventilation]. AB - Pulmonary dynamic CT densitometry during steady-state breathing was recorded and analyzed using helical CT scan in 14 patients with obstructive disorders involving small and large airways, and 2 with restrictive lung disease. The data set of 7-second, continuous helical scan at constant table position were reconstructed as 35 one-second temporarily overlapping images at 0.2- second intervals over 2-3 respiratory cycles, and regional CT densitometry was displayed. Normal lungs (5 volunteers) showed a regular sinusoidal curve, and maximal lung density change (LDC) was greater independent lungs than in independent lungs, with an average difference of 29.5 HU, indicating the gravitational effect In contrast, a regular sinusoidal curve was not shown in obstructive disorders, and a significant reduction in maximal LDC (33.7 +/- 22.6 HU) compared with the normal lungs (60.8 +/- 25.9 HU) (P < 0.001) was indicated. In contrast, no marked reduction in maximal LDC (53.7 +/- 28.6 HU) was shown in restrictive disorders. This method is fast and easy, and appears useful for the detection of ventilation abnormalities in obstructive lung disorders. PMID- 8692659 TI - [The usefulness of three-dimensional helical CT for the detection of abnormalities of the auditory ossicles]. AB - To evaluate the usefulness of three-dimensional (3D) helical CT for the detection of abnormalities of the auditory ossicles, 3D helical CT of the middle ear was performed in seven patients with hearing disorder. It revealed that 4 patients had congenital deficiency of the auditory ossicles, 2 patients with chronic otitis media had shortening of the incus and one patient with head injury had doubtful fracture of the incus. This study indicated that 3D helical CT of the middle ear can represent the auditory ossicles objectively and can offer detailed diagnosis. PMID- 8692660 TI - [Portal embolization using lipiodol-gelatin sponge]. AB - Gelatin sponge moistened with lipiodol was prepared for use in portal embolization to improve percutaneous transhepatic portal embolization as preoperative management of patients undergoing extensive liver resection. For one sheet of gelatin sponge (20 x 60 x 7mm)0.5ml of lipiodol was used. Five sheets cut to 2mm square pieces and mixed with physiological saline solution were injected into the right portal vein. This embolic material proved safer and more reliable than gelatin sponge mixed with water-soluble contrast medium, because it provided sufficient opacification to grasp the extent of embolization and prevented back flow. PMID- 8692661 TI - [Fat suppressed dynamic MR imaging of breast cancer: radiologic-pathologic correlation]. AB - Fat-suppressed spoiled gradient-echo imaging was performed on 35 preoperative patients with breast cancer. Whole breast images using coronal sections were obtained immediately after bolus injection of Gd-DTPA. The images were reviewed regarding detectability of the lesion, irregularity of its margin, homogeneity of contrast enhancement and detectability of intraductal spread. The results were correlated with the histopathologic findings. All breast tumors were identified on dynamic MRI. The existence of mastopathy and lactating change obscured the lesion border. Scirrhous carcinomas exhibited speculation. They showed inhomogeneous enhancement, and time-intensity curves variety might be due to different amounts of fibro-connective tissue within the tumor. Solid-tubular and papillotubular carcinomas showed well-defined borders. They exhibited septum and rim enhancement corresponding to fibrous stroma. The peak of their time-intensity curves was within 3 minutes. Fifty-five percent of cases of intraductal spread were visualized on dynamic MRI. Those lesions had large numbers of cancer cells in the ducts and also showed periductal inflammation. The histologic type of breast cancer was well reflected in the enhancement pattern. The ability of dynamic MRI to detect all intraductal components of breast cancer was limited. PMID- 8692662 TI - [Color Doppler sonographic assessment of intrahepatic hemodynamics and shunt patency after transjugular intrahepatic portosystemic shunt (TIPS)]. AB - The usefulness of color Doppler sonography for the assessment of intrahepatic hemodynamics and shunt patency was evaluated in a total of eight patients in whom the intrahepatic hemodynamics before and after transjugular intrahepatic portosystemic shunt (TIPS) could be serially examined by color Doppler sonography. In six of these patients the serial sonographic examinations could be followed for more than one year after TIPS creation. Within one month after TIPS creation, Vmax in the shunt was ranged from 87 cm/sec to 242 cm/sec (mean: 142.5 cm/ sec), and the flow direction in the right anterior portal vein was reversed in all patients. More than 70% stenosis of the shunt could be diagnosed by color Doppler sonography. When the shunt was confirmed by angiography to be more than 70% stenotic or occluded, Vmax in the shunt was decreased to less than 50 cm/sec and the blood flow in the right anterior portal vein become hepatopetal. From three months before stenosis or occlusion of the shunt, it was confirmed that Vmax in the shunt was less than 70 cm/sec or the blood flow of right anterior portal vein was hepatopetal. Color Doppler sonography was useful for the assessment of intrahepatic hemodynamics, and shunt patency and prediction of shunt stenosis or occlusion following TIPS creation. PMID- 8692663 TI - [MR appearance of fat distribution in ovarian teratoma: pathologic correlation]. AB - Magnetic resonance (MR) imaging was performed in 45 patients with 52 surgically proved ovarian teratomas. MR findings of these tumors were classified into three types depending on the degree of fatty proportions in the tumor. The majority of teratomas were filled with fatty tissue in the cystic cavity (n = 43, 82.7%). In 5 tumors (9.6%), fatty tissue was seen at the edge or within the cyst wall. Fatty tissue could not be seen in any part of the tumor in 4 cases (7.7%). The tumors without a fatty component on MR images tend to have fewer sebaceous glands and less fatty tissue within the cyst wall than tumors with an abundant fatty component. Demonstration of fatty tissue is pathognomonic for these tumors. However, tumors with a small amount of fatty tissue may be indistinguishable from cystic ovarian tumors on MR images. PMID- 8692664 TI - [Evaluation of data compression in gastrointestinal examinations using computed radiography]. AB - The purpose of this study was to evaluate the clinical utility of Type III irreversible data compression of computed radiography (CR) in gastrointestinal examinations. Simulated gastric lesions created on a specially made phantom gastric mucosa as well as normal and abnormal cases selected from upper gastrointestinal radiographic examinations and barium enemas were used. Twenty five sets of original and compressed CR images were obtained for each category of normal and abnormal cases. Visual ranking and a receiver operating characteristic (ROC) study using these images were carried out by 5 radiologists. By visual ranking, deterioration of image quality on the compressed images was recognized in 32.8 to 58.4% of the phantom gastric mucosa images, 23.2 to 75.2% of the upper gastrointestinal examinations, and 21.6 to 81.6% of the barium enemas. However, this deterioration was subtle and the analysis of ROC curves revealed no significant difference in detectability of the lesion between original and compressed images. It is concluded that this Type III irreversible data compression is clinically applicable and useful in gastrointestinal examinations using CR. PMID- 8692665 TI - [MR imaging of cerebral palsy]. AB - We evaluated 35 patients with cerebral palsy on the basis of MR imaging findings in the brain. The types of palsy were spastic quadriplegia (n = 11), spastic diplegia (n = 9), spastic hemiplegia (n = 2), double hemiplegia (n = 1), athetosis (n = 10) and mixed (n = 2). Of all patients, 28 (80%) generated abnormal findings. In spastic quadriplegia, although eight cases revealed severe brain damage, two cases showed no abnormal findings in the brain. One of the three had cervical cord compression caused by atlanto-axial subluxation. In spastic diplegia, the findings were divided according to whether the patient was born at term or preterm. If the patient had been born prematurely, the findings showed periventricular leukomalacia and abnormally high intensity in the posterior limbs of the internal capsule on T2-weighted images. MR imaging in spastic hemiplegia revealed cerebral infarction. In the athetoid type, half of all cases showed either no abnormal findings or slight widening of the lateral ventricle. Three cases showed abnormal signals of the basal ganglia. The reason why athetoid-type palsy did not show severe abnormality is unknown. We believe that MR imaging is a useful diagnostic modality to detect damage in the brain in cerebral palsy and plays an important role in the differentiation of cerebral palsy from the spastic palsy disease. PMID- 8692666 TI - [Methodological study of hemodynamic analysis of lung mass by contrast enhanced dynamic CT]. AB - We investigated a method of analyzing the hemodynamics of the lung mass by contrast enhanced dynamic computed tomography (dynamic CT) to determine the difference in vascular supply between the pulmonary artery and bronchial artery using an experimental model. Our experimental model consisted of two injectors connected to two tubes, representing the pulmonary artery and bronchial artery, which were further connected to a chamber representing the lung mass. Following infusion of contrast medium into each tube with some delay time, dynamic CT scans were performed to obtain time density curves of the two tubes and the chamber. Using the time-density curve of contrast passage, flow rates from the two tubes into the chamber were calculated by the curve fitting method. Calculated values correlated well with the adopted flow rates of fluid from the injectors (r = 0.893) in the experiment. The results indicate our method of individually measuring flow rates of dual-input blood flow, i.e., from the pulmonary artery and bronchial artery, into the lung mass is applicable clinically to determine blood flow by the two arteries supplying the lung mass. PMID- 8692667 TI - [Dynamic study of the liver with helical scanning: determination of hepatic contrast enhancement in routine studies]. AB - Helical CT makes possible imaging of the entire liver in as few as 20 seconds during a single breath hold. This method is thus superior to conventional dynamic CT. In this study, optimal late scanning time and optimal volume of contrast medium in the liver were determined with helical CT in routine studies. (1) Optimal late scanning time In 50 cases, CT images of the liver were obtained at various times following the administrations of contrast medium (1.4 ml/kg). Scanning was started at 60,90,120,150 and 180 seconds after injection. Enhancement of the liver and detection of hepatic and portal veins were best at 60 seconds, followed at 90 seconds. However, a scanning delay of 60 seconds still had an effect on the arterial phase. The optimal late scanning time was thus concluded to be at 90 seconds. (2) Optimal volume of contrast medium In 40 cases, CT images of the liver were obtained following the administration of various amounts of contrast medium (1.0 ml, 1.2 ml, 1.4 ml, 1.6 ml/kg) to determine the optimal volume. No significant difference was found between 1.6 ml/kg compared and 1.4 ml/kg of administered contrast medium. It is evident from the present data that a scanning delay of 90 seconds appears to be optimal and a contrast medium volume of 1.4 ml/kg (body weight) is best for conducting helical dynamic CT on the liver. PMID- 8692668 TI - [Determination of optimal technical factors for the single breath-hold pulmonary MR angiography and its clinical applications]. AB - To optimize pulmonary MR angiography for the noninvasive evaluation of pulmonary vasculature, six healthy volunteers were examined using the fast radiofrequency spoiled gradient echo sequence (Fast SPGR) and standard body coil of a commercial 1.5T MR imaging system. The examinations by 2D Fast SPGR were performed under various TR, flip angles and slice thicknesses within the time of a single breath hold, and those by 3D Fast SPGR were performed under various flip angles and slab thicknesses. The most satisfactory results were obtained by 2D Fast SPGR with the parameters of TR 60 msec, TE 2.1 msec, flip angle 20 degrees slice thickness 10 mm, FOV 30-40 cm, matrix 256 x 192 and NEX1. For 3D Fast SPGR, TR 10 msec, TE 1.9 msec, flip angle 10 degrees, slab thickness 60mm (12 partitions), FOV 30-40 cm, matrix 256 x 128 and NEX1 were best. Concomitant injection of Gd-DTPA provided higher resolution of peripheral vessels. The MIP images showed pulmonary vasculature with resolution of vessels beyond 4 th order branches in 2D Fast SPGR and 5 th order branches in 3D Fast SPGR. 3D Fast SPGR with contrast enhancement was applied to patients with primary lung cancer in the hilum, malignant mediastinal tumor, pulmonary embolism, pulmonary arteriovenous fistula, pulmonary varix, and round atelectasis. Pulmonary MR angiography is considered to be a noninvasive and effective method not only for the evaluation of the tumor invasion to the central pulmonary vessels but also for the demonstration of other pulmonary vascular pathology. PMID- 8692669 TI - [Efficacy of respiratory-triggered fast spin echo MR cholangiopancreatography on intermediate MR imaging]. AB - MR cholangiopancreatography (MRCP) using a respiratory-triggered fast spin-echo technique was performed on intermediate MR imaging in 26 patients with suspected biliary disease. In almost all of 12 patients without dilated biliary tract, the hilum of the liver and extrahepatic bile duct were clearly visualized. All of 11 cases of cholelithiasis were demonstrated. In all 4 cases of obstructive jaundice, dilatation and obstruction of the bile ducts were clearly demonstrated. Respiratory-triggered fast spin-echo MRCP is a non-invasive technique for visualization of the biliary tract and biliary disease on intermediate MR imaging. PMID- 8692670 TI - [A preliminary study of percutaneous ethanol injection therapy for hepatocellular carcinoma: evaluation of the ethanol diffusion area by the ethanol mixed with gadolinium]. AB - To evaluate the ethanol diffusion area after Lipoidalization in 3 patients with advanced HCC treated by Lipoidalization-PEIT combination therapy, 99.9% ethanol mixed with Gadolinium was used for PEIT (Gd-PEIT). T1-weighted MR images wear obtained 1 hr after Gd-PEIT. The area of homogeneous hyperintense change on T1 weighted MR images was taken to be the ethanol diffusion area. In all 3 patients, homogeneous hyperintensity throughout the tumor over the capsule was recognized on T1-weighted MR images after treatment. The results suggests that T1-weighted MR images after Gd-PEIT provide a valuable tool by which to directly evaluate the ethanol diffusion area for advanced HCC treated by Lipoidalization followed by PEIT. PMID- 8692671 TI - [Can we know the frequency of true late adverse reactions to nonionic contrast media?: Late adverse reactions due to factors other than contrast media]. AB - We investigated the frequency and causative factors of symptoms unrelated to contrast media (false late adverse reactions) among patients who were evaluated as having late adverse reactions to contrast media. The nature and frequency of complaints stated by each 200 of patients who underwent plain CT scans and enhanced CT scans were evaluated. In the plain CT group, three patients showed false late adverse reactions. The frequency was 2.6% among respondents and 1.5% in the population. These symptoms encompassed psychological effects and diseases that developed after CT scanning. It is difficult to detect only true late adverse reactions, because of survey bias. PMID- 8692672 TI - [Perioperative fractionated high dose rate brachytherapy in bone and soft-tissue tumors]. AB - The 13 lesions of 11 patients with bone and soft-tissue tumors (four primary and nine recurrent lesions) were treated with surgery and postoperative fractionated high dose rate (HDR) brachytherapy started on the 6-7th day after surgery. The total dose was 40-50 Gy/7-10 fr/6-7d(bid) at 5 mm from the source. Local control was achieved in eight of 13 lesions (62%). Four of the five uncontrolled lesions had macroscopic residual tumor after the surgery. There was one peripheral nerve damage as a side effect. This study indicates that the use of perioperative fractionated HDR brachytherapy is feasible and well tolerated. PMID- 8692673 TI - [Ulcer treatment--an ever present but neglected field]. PMID- 8692674 TI - [Current ulcer treatment]. AB - Patients with wounds and cutaneous ulcers have been a costly but low priority group. During recent years, greater attention has been focused on wound problems, partly as the result of the formation of interest groups and the establishment of wound treatment centres, e.g. in Britain and the USA. In June this year, the first wound treatment centre in Scandinavia is to open in Copenhagen. Research and education in this field give promise of modernised treatment for patients with chronic non-healing wounds and ulcers. PMID- 8692675 TI - [Venous leg ulcer. Management, care , quality of life]. AB - The treatment of patients with chronic leg ulcers should always be based on aetiological diagnosis and tailored to the individual patient. In a Swedish study, medical staff responsible for such treatment were found to have been unsure of the aetiological diagnosis in as many as 40 per cent of the cases. Large gains, both to the patients and to the community, can be made by systematic treatment by an interdisciplinary team that consistently evaluates the effect of treatment. Treatment should include causal therapy, topical wound treatment, and treatment of oedema and eczema, and the focus should be on such aspects of quality of life as pain, sleep, nutrition and physical activity. PMID- 8692676 TI - [Reduced frequency of amputation in diabetic patients]. AB - The number of major amputations performed for vascular disease in Bispebjerbx Hospital, Copenhagen, has decreased from 122 to 29 per year during the period 1981 to 1994. In diabetic patients the frequency decreased from 25.5/100,000 to 5.5/100,000, i.e. a reduction of 78 percent, and in non diabetics it decreased from 42.2/100,000 to 14.6/100,000, i.e. a reduction of 65 percent. During the period vascular surgery has become a surgical specialty (1983), bypass to infra popliteal arteries (from 1988) and graft surveillance by colour duplex scanning (from 1983) has become routine and in 1993 a diabetic foot center was established. Initial experience with a diabetic foot center in a vascular surgery unit is reported. PMID- 8692677 TI - [Asthma symptoms and anti-asthma drugs in 4 Scandinavian countries]. AB - A study of the occurrence of asthma in six areas in four Nordic countries showed 18-25 percent of the populations investigated to have had wheezing or whistling in the airways during the previous 12-month period, and 2-3 percent to have had asthma attacks. The use of anti-asthmatics was found to have differed from one to another of the areas included in the study, and the result suggest the difference to depend upon corresponding differences in the extent to which an active approach to treatment was adopted for the care of patients with asthmatic problems. PMID- 8692678 TI - [Technology-deprived hospitals]. PMID- 8692679 TI - [Regulated working time and guaranteed leisure time for Finnish physicians?. Interview by Eva Oldinger]. PMID- 8692680 TI - [EU regulations for the protection of pregnant and breast-feeding employees]. PMID- 8692681 TI - [Health care in sparsely populated areas--border cooperation in northern Sweden]. PMID- 8692682 TI - Molecular cloning of the three base restriction endonuclease R.CviJI from eukaryotic Chlorella virus IL-3A. AB - R.CviJI is unique among site-specific restriction endonucleases in that its activity can be modulated to recognize either a two or three base sequence. Normally R.CviJI cleaves RGCY sites between the G and C to leave blunt ends. In the presence of ATP R.CviJI* cleaves RGCN and YGCY sites, but not YGCR sites. The gene encoding R.CviJI was cloned from the eukaryotic Chlorella virus IL-3A and expressed in Escherichia coli. The primary E.coli cviJIR gene product is a 278 amino acid protein initiated from a GTG codon, rather than the expected 358 amino acid protein initiated from an in-frame upstream ATG codon. Interestingly, the 278 amino acid protein displays the normal restriction activity but not the R.CviJI* activity of the native enzyme. Nine restriction and modification proteins which recognize a central GC or CG sequence share short regions of identity with R.CviJI amino acids 144-235, suggesting that this region is the recognition and/or catalytic domain. PMID- 8692683 TI - G/C-modified oligodeoxynucleotides with selective complementarity: synthesis and hybridization properties. AB - Modified oligodeoxyribonucleotides (ODNs) that have unique hybridization properties were designed and synthesized for the first time. These ODNs, called selective binding complementary ODNs (SBC ODNs), are unable to form stable hybrids with each other, yet are able to form stable, sequence specific hybrids with complementary unmodified strands of nucleic acid. To make SBC ODNs, deoxyguanosine (dG) and deoxycytidine (dC) were substituted with deoxyinosine (dI) and 3-(2'-deoxy-beta-D-ribofuranosyl)pyrrolo-[2,3-d]-pyrimidine-2-(3H)-one (dP), respectively. The hybridization properties of several otherwise identical complementary ODNs containing one or both of these nucleoside analogs were studied by both UV monitored thermal denaturation and non-denaturing PAGE. The data showed that while dI and dP did form base pairs with dC and dG, respectively, dI did not form a stable base pair with dP. A self-complementary ODN uniformly substituted with dI and dP acquired single-stranded character and was able to strand invade the end of a duplex DNA better than an unsubstituted ODN. This observation implies that SBC ODNs should effectively hybridize to hairpins present in single-stranded DNA or RNA. PMID- 8692684 TI - The telomeric GGGTTA repeats of Trypanosoma brucei contain the hypermodified base J in both strands. AB - We have previously shown that nuclear DNA of bloodstream from Trypanosoma brucei contains a novel base beta-glucosyl-hydroxymethyluracil, called J. Base J is enriched in minichromosome fractions but not in the minichromosome internal repeats, suggesting the association of J with telomeric DNA. To test whether J is present in the long telomeric (GGGTTA)n repeat arrays, which are 2-26 kb in T.brucei, we have purified these arrays both by hybrid selection and by isolating 2-26 kb fragments from DNA digested with multiple restriction enzymes. We find that in purified telomeric repeats approximately 13% of T is replaced by J, compared to 0.8% in total DNA, and we estimate that approximately 50% of the total J is in these repeats. Highly purified complementary strands of the repeats were obtained by alkaline CsCl equilibrium centrifugation. In the (TAACCC)n strand 14% of T was replaced by J. In the (GGGTTA)n strand approximately 36% of the second T was replaced by J; the first T was not detectably replaced. Modified bases have not been found in telomeric repeats before. How the bulky base J affects telomere function and structure in bloodstream form trypanosomes remains to be determined. PMID- 8692685 TI - A new class of genome rare cutters. AB - Although significant efforts have been directed at developing efficient techniques for rare and super rare genome cutting, only limited success has been achieved. Here we propose a new approach to solve this problem. We demonstrate that peptide nucleic acid 'clamps' (bis-PNAs) bind strongly and sequence specifically to short homopyrimidine sites on lambda and yeast genomic DNAs. Such binding efficiently shields methylation/restriction sites which overlap with the bis-PNA binding sites from enzymatic methylation. After removing the bis-PNA, the genomic DNAs are quantitatively cleaved by restriction enzymes into a limited number of pieces of lengths from several hundred kbp to several Mbp. By combining various bis-PNAs with different methylation/restriction enzyme pairs, a huge new class of genome rare cutters can be created. These cutters cover the range of recognition specificities where very few, if any, cutters are now available. PMID- 8692686 TI - The helix-hairpin-helix DNA-binding motif: a structural basis for non-sequence specific recognition of DNA. AB - One, two or four copies of the 'helix-hairpin-helix' (HhH) DNA-binding motif are predicted to occur in 14 homologous families of proteins. The predicted DNA binding function of this motif is shown to be consistent with the crystallographic structure of rat polymerase beta, complexed with DNA template primer [Pelletier, H., Sawaya, M.R., Kumar, A., Wilson, S.H. and Kraut, J. (1994) Science 264, 1891-1903] and with biochemical data. Five crystal structures of predicted HhH motifs are currently known: two from rat pol beta and one each in endonuclease III, AlkA and the 5' nuclease domain of Taq pol I. These motifs are more structurally similar to each other than to any other structure in current databases, including helix-turn-helix motifs. The clustering of the five HhH structures separately from other bi-helical structures in searches indicates that all members of the 14 families of proteins described herein possess similar HhH structures. By analogy with the rat pol beta structure, it is suggested that each of these HhH motifs bind DNA in a non-sequence-specific manner, via the formation of hydrogen bonds between protein backbone nitrogens and DNA phosphate groups. This type of interaction contrasts with the sequence-specific interactions of other motifs, including helix-turn-helix structures. Additional evidence is provided that alphaherpesvirus virion host shutoff proteins are members of the polymerase I 5'-nuclease and FEN1-like endonuclease gene family, and that a novel HhH-containing DNA-binding domain occurs in the kinesin-like molecule nod, and in other proteins such as cnjB, emb-5 and SPT6. PMID- 8692688 TI - Proofreading in trans by an aminoacyl-tRNA synthetase: a model for single site editing by isoleucyl-tRNA synthetase. AB - Editing of errors in amino acid selection by an aminoacyl-tRNA synthetase prevents attachment of incorrect amino acids to tRNA, thereby greatly enhancing accuracy of translation of the genetic code. Editing of the non-protein amino acid homocysteine, a frequent type of an error-correcting process, involves reaction of the side chain sulfhydryl group of homocysteine with its activated carboxyl group forming a cyclic thioester, homocysteine thiolactone. Here, it is shown that isoleucyl-tRNA synthetase (IleRS), which occasionally misactivates homocysteine in vitro and in vivo, catalyzes reactions of activated isoleucine with organic thiols (analogues of the side chain of homocysteine). That these enzymatic reactions occur between Ile-tRNAIle or Ile-AMP (bound in the synthetic sub-site) and a thiol (an analogue of the side chain of homocysteine, bound in the editing sub-site), indicates that the two sub-sites are physically close on the surface of IleRS, forming a single synthetic/editing active site of the enzyme. Although IleRS.Val-AMP undergoes thiolysis as efficiently as do IleRS.Ile AMP and IleRS.Ile-tRNAIle, IleRS.Val-tRNAIle does not react with thiols. These and other data suggest that the mischarged valine residue in IleRS.Val-tRNAIle is, most likely, positioned off the enzyme. PMID- 8692687 TI - Dominant negative mutator mutations in the mutL gene of Escherichia coli. AB - The mutL gene product is part of the dam-directed mismatch repair system of Escherichia coli but has no known enzymatic function. It forms a complex on heteroduplex DNA with the mismatch recognition MutS protein and with MutH, which has latent endonuclease activity. An N-terminal hexahistidine-tagged MutL was constructed which was active in vivo. As a first stop to determine the functional domains of MutL, we have isolated 72 hydroxylamine-induced plasmid-borne mutations which impart a dominant-negative phenotype to the wild-type strain for increased spontaneous mutagenesis. None of the mutations complement a mutL deletion mutant, indicating that the mutant proteins by themselves are inactive. All the dominant mutations but one could be complemented by the wild-type mutL at about the same gene dosage. DNA sequencing indicated that the mutations affected 22 amino acid residues located between positions 16 and 549 of the 615 amino acid protein. In the N-terminal half of the protein, 12 out of 15 amino acid replacements occur at positions conserved in various eukaryotic MutL homologs. All but one of the sequence changes affecting the C-terminal end of the protein are nonsense mutations. PMID- 8692689 TI - Genetic regulation of delta-aminolevulinate dehydratase during erythropoiesis. AB - In an effort to understand how the heme biosynthetic pathway is uniquely regulated in erythroid cells, we examined the structure of the gene encoding murine delta-aminolevulinate dehydratase (ALAD; EC4.2.1.24), which is the second enzyme of the pathway. The gene contains two first exons, named 1A and 1B, which are alternatively spliced to exon 2, where the coding region begins. Each first exon has its own promoter. The promoter driving exon 1A expression is TATA-less and contains many GC boxes. In contrast, the exon 1B promoter bears regulatory sequences similar to those found for beta-globin and other erythroid-specific genes. Tissue distribution studies reveal that ALAD mRNA containing axon 1A is ubiquitous, whereas mRNA containing axon 1B is found only in erythroid tissues. This finding, together with our further observation that GATA-1 mRNA levels increase 3-fold during maturation of murine erythroid progenitor cells, may help explain simultaneous 3-fold increases in exon 1B expression. The unexpected result that axon 1A expression also increases 3-fold during CFU-E maturation may be attributable to the action of NF-E2, since there is a potential binding site in a position analogous to the NF-E2 site in the locus control region of the beta globin gene cluster. PMID- 8692690 TI - A new efficient gene disruption cassette for repeated use in budding yeast. AB - The dominant kanr marker gene plays an important role in gene disruption experiments in budding yeast, as this marker can be used in a variety of yeast strains lacking the conventional yeast markers. We have developed a loxP-kanMX loxP gene disruption cassette, which combines the advantages of the heterologous kanr marker with those from the Cre-lox P recombination system. This disruption cassette integrates with high efficiency via homologous integration at the correct genomic locus (routinely 70%). Upon expression of the Cre recombinase the kanMX module is excised by an efficient recombination between the loxP sites, leaving behind a single loxP site at the chromosomal locus. This system allows repeated use of the kanr marker gene and will be of great advantage for the functional analysis of gene families. PMID- 8692691 TI - Preference for guanosine at first codon position in highly expressed Escherichia coli genes. A relationship with translational efficiency. AB - The variation in base composition at the three codon sites in relation to gene expressivity, the latter estimated by the Codon Adaptation Index, has been studied in a sample of 1371 Escherichia coli genes. Correlation and regression analyses show that increasing expression levels are accompanied by higher frequencies of base G at first, of base A at second and of base C at third codon positions. However, correlation between expressivity and base compositional biases at each codon site was only significant and positive at first codon position. The preference for G-starting codons as gene expression level increases is discussed in terms of translational optimization. PMID- 8692692 TI - MoMuLV proviral integrations identified by Sup-F selection in tumors from infected myc/pim bitransgenic mice correlate with activation of the gfi-1 gene. AB - Infecting mice with a mutant Moloney murine leukemia virus which contains the bacterial suppressor tRNA supF in its LTR allows rapid cloning of proviral integration sites from genomic tumour DNA. In a previous study Emu pim-1/Emu L myc bitransgenic mice had been inoculated neonatally with MoMuLV supF virus. The retroviral infection led to acceleration of lymphomagenesis indicating the proviral activation of further oncogenes cooperating with myc and pim-1 in tumour development. Using a functional supF screen for analysis of genomic mouse tumour DNA libraries which had been constructed in the phage vector EMBL3A, a common proviral integration site on mouse chromosome 5 was cloned and found to be identical to the proviral integration site evi-5 which has recently been identified in an AKXD T-cell lymphoma and which is located 18 kb upstream of the gfi-1 gene. Tumours bearing evi-5 integrations showed an enhanced gfi-1 expression level suggesting that gfi-1 is the target gene for insertions at the evi-5 locus. Together with three other previously described Moloney integration clusters all responsible for enhanced gfi-1 expression the number of tumours from infected double transgenic Emu L-myc/Emu pim-1 transgenic mice with retrovirally activated gfi-1 added up to 53% underscoring the role of GFI-1 as an effective collaborator for MYC and PIM-1 in the process of lymphomagenesis. PMID- 8692693 TI - The human hnRNP-M proteins: structure and relation with early heat shock-induced splicing arrest and chromosome mapping. AB - With anti-hnRNP monoclonal antibody 6D12 we previously showed in HeLa cells that as early as 10 min after the onset of a heat shock at 45 degrees C, a 72.5-74 kDa antigen doublet leaves the hnRNPs and strongly associates with the nuclear matrix, the effect being reversed after a 6 h recovery at 37 degrees C. cDNA cloning and sequencing enabled us to identify these antigens as hnRNP-M proteins and further to show that the correct sequence differs by an 11 amino acid stretch from the originally published sequence. We also show that monoclonal antibodies raised against synthetic hnRNP-M peptides can directly inhibit in vitro splicing. Furthermore, stressing cells at 45 degrees C for 10 min is sufficient to abolish the splicing capacity of subsequently prepared nuclear extracts which, interestingly, do not contain the hnRNP-M proteins any more. Taken together, our data suggest that these proteins are involved in splicing as well as in early stress-induced splicing arrest. Further in situ hybridization assays located the hnRNP-M encoding gene on human chromosome 19. PMID- 8692694 TI - Related enhancers in the intron of the beta1 tubulin gene of Drosophila melanogaster are essential for maternal and CNS-specific expression during embryogenesis. AB - Expression of the beta1 tubulin gene of Drosophila melanogaster is under complex developmental control. For high levels of transcription in the embryonic central nervous system (CNS) different modules dispersed over 3 kb have to co-operate. Combination of a core promoter with either far upstream localized enhancer elements or, alternatively, with an enhancer from the intron results in expression limited to only a few neuronal cells. Cooperation of all three modules, however, leads to high level expression in most neuronal cells of the CNS. In the intron, we identified a 6 bp core element which is essential for transcription in the CNS, as well as an 8 bp element required for maternal expression. Interestingly, both motifs are quite similar, with CAAAAT as the CNS core and CAAAAAT as the maternal enhancer core. Specific binding of proteins from nuclear extracts to the CNS-specific element could be demonstrated. We suggest that the beta1 tubulin gene represents an ideal marker gene to elucidate connections between pro-neural or neurogenic genes and downstream target genes throughout the CNS. PMID- 8692695 TI - XPC and human homologs of RAD23: intracellular localization and relationship to other nucleotide excision repair complexes. AB - The xeroderma pigmentosum syndrome complementation group C (XP-C) is due to a defect in the global genome repair subpathway of nucleotide excision repair (NER). The XPC protein is complexed with HHR23B, one of the two human homologs of the yeast NER protein, RAD23 (Masutani at al. (1994) EMBO J. 8, 1831-1843). Using heparin chromatography, gel filtration and native gel electrophoresis we demonstrate that the majority of HHR23B is in a free, non-complexed form, and that a minor fraction is tightly associated with XPC. In contrast, we cannot detect any bound HHR23A. Thus the HHR23 proteins may have an additional function independent of XPC. The fractionation behaviour suggests that the non-bound forms of the HHR23 proteins are not necessary for the core of the NER reaction. Although both HHR23 proteins share a high level of overall homology, they migrate very differently on native gels, pointing to a difference in conformation. Gel filtration suggests the XPC-HHR23B heterodimer resides in a high MW complex. However, immunodepletion studies starting from repair-competent Manley extracts fall to reveal a stable association of a significant fraction of the HHR23 proteins or the XPC-HHR23B complex with the basal transcription/repair factor TFIIH, or with the ERCC1 repair complex. Consistent with a function in repair or DNA/chromatin metabolism, immunofluorescence studies show all XPC, HHR23B and (the free) HHR23A to reside in the nucleus. PMID- 8692696 TI - Functional interaction between TFIIB and the Rpb9 (Ssu73) subunit of RNA polymerase II in Saccharomyces cerevisiae. AB - Recessive mutations in the SSU71, SSU72 and SSU73 genes of Saccharomyces cerevisiae were identified as either suppressors or enhancers of a TFIIB defect (sua7-1) that confers both a cold-sensitive growth phenotype and a downstream shift in transcription start site selection. The SSU71 (TFG1) gene encodes the largest subunit of TFIIF and SSU72 encodes a novel protein that is essential for cell viability. Here we report that SSU73 is identical to RPB9, the gene encoding the 14.2 kDa subunit of RNA polymerase II. The ssu73-1 suppressor compensates for both the growth defect and the downstream shift in start site selection associated with sua7-1. These effects are similar to those of the ssu71-1 suppressor and distinct from the ssu72-1 enhancer. The ssu73-1 allele was retrieved and sequenced, revealing a nonsense mutation at codon 107. Consequently, ssu73-1 encodes a truncated form of Rpb9 lacking the C-terminal 16 amino acids. This Rpb9 derivative retains at least partial function since the ssu73-1 mutant exhibits none of the growth defects associated with rpb9 null mutants. However, in a SUA7+ background, ssu73-1 confers the same upstream shift at ADH1 as an rpb9 null allele. This suggests that the C-terminus of Rpb9 functions in start site selection and demonstrates that the previously observed effects of rpb9 mutations on start site selection are not necessarily due to complete loss of function. These results establish a functional interaction between TFIIB and the Rpb9 subunit of RNA polymerase II and suggest that these two components of the preinitiation complex interact during transcription start site selection. PMID- 8692698 TI - Obligatory activator-polymerase addition order at promoters. AB - The kinetics of open complex formation were measured by migration retardation assay and DNase I footprinting at the activator-dependent promoters ara P1, lac P1 and gal P1. In each case, the rate of open complex formation was significantly faster if the activator, AraC for ara and CAP for lac and gal, had been added before RNA polymerase. The results indicate that complexes of transcriptional activators, RNA polymerase and promoter can exist in two states, one which can form open complexes rapidly and one which cannot. PMID- 8692697 TI - Assessment of major and minor groove DNA interactions by the zinc fingers of Xenopus transcription factor IIIA. AB - Zinc finger proteins of the Cys2His2 class are DNA sequence-specific transcription factors. Previous structural studies of zinc finger protein-DNA complexes have shown that amino acids in the finger tip and alpha-helix regions within individual finger domains make base-specific contacts with the major groove of DNA. The nine finger protein transcription factor IIIA (TFIIIA) from Xenopus oocytes binds a 43 base pair region of the 5S RNA gene through major groove interactions with two sets of three fingers (fingers 1-3 and 7-9) and with finger 5. Previous studies have suggested that zinc fingers 4 and 6 each bind in or across the minor groove to bridge these major groove-binding zinc fingers. Here it is shown that a polypeptide containing zinc fingers 1-5 (zf1-5) binds oligonucleotides with modifications in the major groove of the finger 4 binding site with wild-type affinity. Mutagenesis and binding site selection studies were performed to determine whether high affinity DNA binding by zf1-5 requires a particular sequence in the binding site for finger 4. Several mutations in this region of the 5S gene reduced the DNA-binding affinity of zf1-5; however, selection and amplification binding assays did not recover the wild-type finger 4 binding site sequence from a pool of mixed sequence oligonucleotides. Rather, a purine-rich sequence on the top strand was highly selected within the finger 4 binding site. We suggest that high affinity DNA binding by zinc finger 4 may be dictated by a sequence-specific DNA structure rather than by a unique DNA sequence. Deletion of finger 4 from zf1-5 results in a protein with poor binding affinity, demonstrating the importance of finger 4 in proper alignment of neighboring fingers with the DNA, and/or the importance of correct protein protein interactions between fingers. PMID- 8692699 TI - The CtBP binding domain in the adenovirus E1A protein controls CR1-dependent transactivation. AB - The adenovirus E1A-243R protein has the ability to force a resting cell into uncontrolled proliferation by modulating the activity of key targets in cell cycle control. Most of these regulatory mechanisms are dependent on activities mapping to conserved region 1 (CR1) and the non-conserved N-terminal region of E1A. We have previously shown that CR1 functions as a very patent transactivator when it is tethered to a promoter through a heterologous DNA binding domain. However, artificial DNA binding was not sufficient to convert full-length E1A 243R to a transactivator. Thus, an additional function(s) of the E1A-243R protein modulates the effect of CR1 in transcription regulation. Here we demonstrate that a 44 amino acid region at the extreme C-terminus of ElA inhibited transactivation by a Gal4-CR1 fusion protein. Inhibition correlated with binding of the nuclear 48 kDa C-terminal binding protein (CtBP), which has been implicated in E1A mediated suppression of the metastazing potential of tumour cells. This might suggest that CtBP binding can regulate E1A-mediated transformation by modulating CR1-dependent control of transcription. PMID- 8692701 TI - Detection of multiple conformations of the E-domain of 5S rRNA from Escherichia coli in solution and in crystals by NMR spectroscopy. AB - NMR spectroscopy of the E-domain fragment of Escherichia coli 5S rRNA indicates that this molecule exists in solution as either a stem-loop or as a duplex with two U-U base pairs in the bulge region. At temperatures below 27 degrees C, interconversion between the monomeric and dimeric forms in solution occurs on a time scale of weeks and allows the preparation of samples on which NMR structure determinations can be carried out on predominantly monomeric or dimeric species. The NMR results obtained provide comparison data for the distinction between A- and B-form E.coli 5S rRNA and for the possible kinetics of conversion between these forms. NMR evidence is presented that the duplex form also exists in crystals and suggestions are made for means to obtain stem-loop conformations of E-domain and other small RNA stem-loop sequences in crystals. PMID- 8692700 TI - The Schizosaccharomyces pombe pla1 gene encodes a poly(A) polymerase and can functionally replace its Saccharomyces cerevisiae homologue. AB - We have isolated the poly(A) polymerase (PAP) encoding gene pla1 [for poly(A) polymerase] from the fission yeast Schizosaccharomyces pombe. Protein sequence alignments with other poly(A) polymerases reveal that pla1 is more closely related to Saccharomyces cerevisiae PAP than to bovine PAP. The two yeast poly(A) polymerases share significant sequence homology not only in the generally conserved N-terminal part but also in the C-terminus. Furthermore, pla1 rescues a S. cerevisiae PAP1 disruption mutant. An extract from the complemented strain is active in the specific in vitro polyadenylation assay. In contrast, recombinant PLA1 protein can not replace bovine PAP in the mammalian in vitro polyadenylation assay. These results indicate a high degree of conservation of the polyadenylation machinery among the evolutionary diverged budding and fission yeasts. PMID- 8692702 TI - Comparative and functional analysis of the AP2 promoter indicates that conserved octamer and initiator elements are critical for activity. AB - AP-2 is a developmentally-regulated transcription factor expressed in ectodermal cell lineages. The AP-2 protein is essential for neural tube, craniofacial and body wall morphogenesis and has been implicated in oncogenesis. Here we report the isolation of the AP-2 promoter from human, mouse and chicken. The initiation sites for the human gene have been mapped in a variety of cell lines, including several derived from breast tumours. Initiation occurs just upstream of an IR3 like repetitive element, present in the human and mouse genes, but absent in chicken. The cis-acting elements responsible for promoter activity in human HeLa cells have been mapped both in vivo and in vitro. The proximal promoter contains binding sites for transcription factors AP-2, NF-1 and octamer proteins, but lacks a TATA box motif. Functional analysis demonstrates that the octamer binding site is the critical component of basal promoter activity. In addition, the promoter relies on an initiator element for efficient start site utilization. There is an excellent correlation between the requirement for the initiator and octamer elements in transcription assays and the conservation of these cis-acting sequences between chicken, mouse and human. PMID- 8692703 TI - Triplex formation by oligonucleotides containing novel deoxycytidine derivatives. AB - Homopurine sequences of duplex DNA are binding sites for triplex-forming oligodeoxyribopyrimidines. The interactions of synthetic duplex DNA targets with an oligodeoxyribopyrimidine containing N4-(6-amino-2-pyridinyl)deoxycytidine (1), a nucleoside designed to interact with a single C-G base pair interruption of the purine target tract, was studied by UV melting, circular dichroism spectroscopy and dimethylsulfate alkylation experiments. Nucleoside 1 supports stable triplex formation at pH 7.0 with formation of a 1-Y-Z triad, where Y-Z is a base pair in the homopurine tract of the target. Selective interaction was observed when Y-Z was C-G, although A-T and, to a lesser extent, T-A and G-C base pairs were also recognized. The circular dichroism spectra of the triplex having a 1-C-G triad were similar to those of a triplex having a C(+)-G-C triad, suggesting that the overall structures of the two triplexes are quite similar. Removal of the 6-amino group from 1 essentially eliminated triplex formation. Reaction of a triplex having the 1-C-G triad with dimethylsulfate resulted in a 50% reduction of methylation of the G residue of this triad. In contrast, the G of a similar triplex containing a U-C-G triad was not protected from methylation by dimethylsulfate. These results are consistent with a binding mode in which the 6 amino-2-pyridinyl group of 1 spans the major groove of the target duplex at the 1 C-G binding site and forms a hydrogen bond with the O6 of G. An additional stabilizing hydrogen bond could form between the N4 of the imino tautomer of 1 and the N4 amino group of C. PMID- 8692704 TI - DOP-vector PCR: a method for rapid isolation and sequencing of insert termini from PAC clones. PMID- 8692705 TI - AFLP-based mRNA fingerprinting. PMID- 8692706 TI - Fractionation of nucleic acids into single-stranded and double-stranded forms. PMID- 8692707 TI - High efficiency, long-term clinical expression of cottontail rabbit papillomavirus (CRPV) DNA in rabbit skin following particle-mediated DNA transfer. AB - The ability of skin to support long lasting expression of genes delivered with a particle-mediated system was evaluated in rabbits inoculated with cottontail rabbit papillomavirus (CRPV) DNA. The optimal delivery force for maximal gene expression in rabbit skin was determined in transient beta-galactosidase assays. Forty-five sites in four rabbits were then inoculated at 350-400 p.s.i. with CRPV DNA. All sites (100%) formed papillomas with multiple papillomas at most sites. These results support the feasibility of using a particle-mediated delivery system for gene therapy and suggest that some papillomavirus features, such an origin of replication, may be well suited for use in vectors to target long term expression to skin. PMID- 8692708 TI - PicoGreen quantitation of DNA: effective evaluation of samples pre- or post-PCR. PMID- 8692709 TI - The histopathological spectrum of type A gastritis. AB - It has been recently shown that type A gastritis can be histologically diagnosed in the preatrophic stage. In order to evaluate whether parietal cell atrophy in AG might correlate with other histopathological findings in the antral and body mucosa, we retrospectively investigated 171 consecutive cases of histologically diagnosed preatrophic (active) or atrophic type A gastritis (H&E, Warthin Starry). The prevalences of intestinal metaplasia (75% vs 44.4%) and micronodular hyperplasia (86.1% vs 52.4%) of endocrine cells in the oxyntic mucosa were significantly higher of parietal cell atrophy was present (p < 0.001 and p < 0.0001, respectively), whereas the prevalence of nodular lymphoid aggregates (77.8% vs 48.1%) and of Helicobacter pylori (14.3% vs 1.9%) in the oxyntic mucosa was significantly higher if parietal cell atrophy could not be detected (p < 0.001 and p < 0.01, respectively). In the antral mucosa, altered patterns of the inflammatory reaction could be demonstrated independent of the parietal cell mass possibly caused by impaired gastric acid production. Our data support the notion that the development of parietal cell atrophy in type A gastritis represents a stepwise process including initial pseudohypertrophy of these cells. PMID- 8692710 TI - Morphometric techniques in the evaluation of pulmonary vascular changes due to congenital heart disease. AB - Open lung biopsy is performed in patients with congenital heart disease to determine the suitability for surgical correction. Controversy exists as to whether arterial density can be graded with certainty. We studied the influence on the grading (Heath-Edwards) of two morphometric techniques. Lung tissue from 14 controls and biopsy specimens from 80 patients with atrial septal defect (n=10) ventricular septal defect (n=27), complete atrioventricular canal (n=27), miscellaneous lesions (n=8) and tetralogy of Fallot (n=8) were analyzed with a planimetric method. Additionally, wall thickness was determined in 52 patients by distance measurements. The ratio of alveoli/arteries per area of lung tissue was measured. Medial thickness was "increased" on distance measurements in 15% of the cases where planimetric data showed normal wall thickness. The ratio of alveoli/arteries varied up to 43% from the mean. Hemodynamic data obtained at a median (range) time of 2 months (1 day to 18 months) before the operation did not correlate with morphologic findings. In 27 patients hemodynamic data were recorded at a median time of 1 year (3 days to 44 months) after the operation. Intimal fibrosis occupying more than 10% of the vessel lumen was associated with persistent high pulmonary vascular resistance. We conclude that morphometric techniques are useful to determine the degree of fibrosis in advanced vascular lesions. Arterial density cannot be determined in biopsy specimens with adequate certainty. PMID- 8692711 TI - Biophenotypes of breast carcinoma in situ defined by image analysis of biological parameters. AB - In 50 in situ breast cancers an immunohistochemical study, evaluating estrogen (ER) and progesterone (PR) receptors, Proliferation Index (PI), c-erbB-2/Neu and p53 expression was performed. According to histopathological diagnosis, cases were classified as follows: 14 comedo, 8 solid, 5 micropapillary, 6 lobular, 3 papillary, 1 apocrine and 12 mixed in situ carcinomas. The quantitation of immunohistochemical results was obtained with an image analysis computerized system (CAS 200) with a lesion-field method; tumors were subdivided in fields (1177) histologically homogeneous, with 40 x microscopic objective. For ER, PR, Neu and p53, 10% of the positive area was used as cut-off value; 13% was used for PI. Cribriform and lobular types showed a higher positivity for ER (92.1% and 95.5% of the fields); cribriform and papillary a higher for PR (92.6% and 93.9%). Comedo variant demonstrated the higher PI (52.7%), Neu and p53 expression (67.7% and 43%). A cluster analysis performed on 608 fields, defined two groups according to biological homogeneous criteria. The results obtained identify the different biophenotypes of in situ carcinomas, suggesting the possibility of multiple cancerogenetic ways with a different weight of biological events. PMID- 8692712 TI - Microvessel quantitation in breast ductal invasive carcinoma. Correlation with proliferative activity, hormonal receptors and lymph node metastases. AB - To investigate the correlation between tumor angiogenesis with axillary metastasis in breast cancer, we analyzed a series of 130 cases of infiltrating ductal carcinoma N.O.S. Tissue sections were stained with factor VIII-RA and microvessel quantitation was performed at x 400 magnification in the most vascular areas and expressed in vessels per mm2. Other variables such as tumor size, histologic grade, mitotic count, tumor necrosis, vascular invasion, skin involvement, anti-P.C.N.A. (proliferative cell nuclear antigen) and estradiol and progesterone receptors measured by an immunohistochemical method were determined. Statistical analysis of variance (AN-OVA) and Pearson's correlation coefficient were applied. The average of vessels per mm2 in tumors with metastases (n = 70) was 82.0 (median 74, SD 37.5), whereas in tumors without metastases (n = 60), it was 67.1 (median 64, SD 28.1). The difference was statistically significant (p < 0.01). However, the significance was lost when tumor size was introduced as a co factor in a multifactorial analysis of variance. The number of vessels was unassociated with menopausal status, histologic grade, mitotic count, tumor necrosis, vascular invasion, skin involvement, estradiol and progesterone receptors and proliferative activity measured with anti-P.C.N.A. We conclude that in breast ductal invasive carcinoma, when tumor size is taken into consideration, angiogenesis is not associated with axillary lymph node metastases. PMID- 8692713 TI - Evaluation of non-isotopic in situ hybridization for mRNA in reactive and neoplastic lymphoid cells. AB - An evaluation of nonisotopic in situ hybridization (NISH) for mRNA in archival lymphoid tissue was carried out and an analysis of factors affecting the final outcome was performed. A modification of the in situ reverse transcription method for RNA preservation assessment has been used and described. We have shown that, for frozen samples mRNA detection is optimal within 3 months of the biopsy being taken, while preservation declines after 1 year of storage. PMID- 8692714 TI - The calcium binding protein calretinin is a selective marker for malignant pleural mesotheliomas of the epithelial type. AB - In a series of 23 cases of mesothelioma of either the epithelial, sarcomatoid or the mixed type, the expression of three calcium-binding proteins (calretinin, parvalbumin and calbindin-D28k) was studied using immunohistochemical techniques on paraffin sections. The results show that calretinin is expressed in mesotheliomas of the epithelial type (papillary, adenomatous or solid) and by the epithelial component of the mixed tumours. The immunohistochemical reaction is specific and reproducible. The tissues of the pulmonary parenchyma and of the pleura are negative for calretinin except for the rare fibroblasts and some skeletal muscle fibres situated in the interstices of, or near the epithelial tumour mass. The sarcomatoid mesotheliomas and the sarcomatoid component of the mixed tumours do not express calretinin. Parvalbumin and calbindin-D28k are expressed neither in mesotheliomas nor in normal lung tissue. Primary adenocarcinomas of the lung are negative for all three calcium binding proteins cited. Thus, calretinin seems to represent a selective marker for mesotheliomas of the epithelial type and allows their differentiation from metastases of lung adenocarcinomas. PMID- 8692715 TI - Mandibular osteosarcoma with unusual expression of alpha-actin smooth muscle antibody. AB - Mandibular osteosarcoma is a rare neoplasm, appearing in young adults as a mass often accompanied by pain, occasionally with paraesthesias, gingival haemorrhages and mobility of teeth, and rarely with ulceration of the skin or mucosa. Roentgenological lytic and/or sclerotic findings are non-specific. Some patients have a previous history of Paget's disease, antecedent radiation treatment, or fibrous dysplasia. Malignant osteoid production can be minimal, resulting in diagnostic difficulties. We report a case of a 33 year-old woman, who, in the absence of a clinical soil associated with the condition, was presented with advanced disease. Immunohistochemical study using alpha-actin smooth muscle antibody disclosed bizarre tumor cells with "dendritic" appearance, to our knowledge, never described thus far. This report draws attention to this uncommon neoplasm and reviews the pertinent literature related to this entity. PMID- 8692716 TI - Human papillomavirus infection and transitional cell carcinoma of the bladder. Immunohistochemistry and in situ hybridization. AB - The aim of the present research was to investigate human papillomavirus (HPV) infection by means of immunohistochemistry and in situ hybridization in 76 bladder cancer specimens. A biotinylated DNA probe that recognizes HPV 6/11, HPV 16/18 and HPV 31/33/35 was used for in situ hybridization. A polyclonal antibody recognizing HPV capsid antigen (HPVcAg) was used for immunohistochemistry. In situ hybridization and immunohistochemistry were developed by alkaline phosphatase and immunogold-silver techniques respectively. Our results showed that 25 (32.8%) out of 76 bladder carcinoma specimens reacted with HPVcAg. Twelve (15.7%) out of 76 cases were positive for HPV 16/18-DNA using non-isotopic in situ hybridization. Sixteen cases had koilocytosis. No positive signals were found for HPV 6/11 or 31/33/35-DNA probes. PMID- 8692717 TI - Primary malignant lymphoma of the bladder. Report of three cases. AB - Primary malignant lymphoma of the bladder is a rare tumour. In a recent literature search only 70 cases have been found since 1885. Most of these tumours were low grade B-cell non Hodgkin's lymphomas and only 20% were high grade neoplasms. This tumour usually appears in women between 20 and 85 years (median 64 yr.) of age. 20% of them have antecedents of chronic cystitic. Some authors have considered that some of the primary malignant lymphomas of the bladder arise from the mucosa-associated lymphoid tissue (MALT), therefore acting like MALT lymphomas which affect the gastrointestinal tract, the salivary glands or the thyroid. We report three additional cases of primary malignant lymphoma of the bladder, two of high grade, and discuss the histological criteria that support their MALT nature. PMID- 8692718 TI - Pseudolymphoma of the thyroid gland. A case report. AB - An unusual case of pseudolymphoma of the thyroid gland is presented. A well demarcated whitish mass measuring 1.0 cm in diameter was found in the upper center of the right lobe of the thyroid gland. Microscopically, the lesion was composed of hyperplastic lymphoid tissues with many follicular centers and mixed infiltration of plasma cells and macrophages. The immunostain revealed a similar distribution of T-and B-lymphocytes to reactive lymph node and a polyclonal nature of the plasma cell infiltrates. No lymphoepithelial lesion was associated. The adjacent thyroid tissues showed chronic lymphocytic thyroiditis. This finding suggests that the lesion is a pseudolymphoma of the thyroid gland. This condition is rare, but it should be considered during the differential diagnosis of lymphoproliferative lesions occurring in the thyroid gland, especially with low grade malignant lymphoma of the thyroid gland. PMID- 8692719 TI - A case of myospherulosis occurring in the perirenal adipose tissue. AB - The authors report a case of spontaneous myospherulosis that developed in the right perirenal adipose tissue, presented like an abscess, in an 82-year old man of the A, Rh+ blood group. The patient had a history of chronic lymphocytic leukaemia. Fine needle aspiration and histological examination of the renal cyst allowed the observation of 4- to 7-micron spherules (or endobodies) enclosed in saccular structures (or parent bodies) and accompanied by a foreign body-type response. The walls of the parent bodies were negative for PAS, Gomori's methenamine silver and Giemsa's stain. Immunohistochemical study was positive with anti A antibody specific of A1/A2 blood group and with anti glycophorin A antibody. The authors reviewed the literature concerning this rare lesion: it usually occurs in subcutaneous fat or in the paranasal sinuses, nose and middle ear but, up to now, no previous case has ever been reported in the urinary tract. The only case of visceral myospherulosis previously reported occurred in a cystic teratoma of the ovary. The reported case is also peculiar by the unusual thickness of the parent bodies. The authors also discuss the mechanism of the disease and suggest that, in the present observation, myospherulosis could have been induced by the rupture of a preexisting cyst in the perirenal adipose tissue. PMID- 8692720 TI - Hepatic Morphological alterations induced by zidovudine (ZDV) in an experimental model. AB - Zidovudine (AZT) inhibits HIV replication. Many studies have demonstrated its toxic myopathic effect in both HIV-positive patients treated with the drug and experimental animal models. So far hepatic lesions induced by AZT have not been reported. In our study, an experimental rat model was used in which the rats were administered AZT (1 mg/ml) in drinking water; histological and ultrastructural alterations were observed in the liver of treated animals and compared with the findings in control animals. The histological alterations detected were turbid swelling, vacuolar degeneration and microvacuolar fatty degeneration of panlobular distribution; these lesions were progressively greater as the duration of treatment increased. The ultrastructural alterations detected involved the mitochondria (similar to those described in cardiac muscle), smooth and rough endoplasmic reticulum (SER and RER), and the accumulation of fat and glycogen in the hepatocytes of treated animals. The histopathological and ultrastructural findings in our experimental model suggest hepatotoxicity induced by AZT or its catabolites in treated, as compared to control animals. PMID- 8692721 TI - Low concentrations of actinomycin D potentially cause therapeutic differentiation in human rhabdomyosarcoma cell line RD. AB - Neoplastic transformation may be an alteration in the process of cell maturation that leads to an infinite capacity for proliferation. Because the cytodestruction caused by most drugs available for cancer chemotherapy is often accompanied by significant morbidity and poor response, the induction of differentiation has been proposed as an alternative approach to conventional anticancer therapy. We used human rhabdomyosarcoma cell line RD to analyze the differentiation process induced by actinomycin D, a drug of choice in the conventional treatment of rhabdomyosarcomas. Low concentrations of actinomycin D induced a terminal process of morphological and ultrastructural myogenic differentiation in rhabdomyosarcoma cells, which concluded with cell death. However, this potential therapeutic effect cannot be considered complete because of the presence of tumoral cells that are heterogeneous with respect to actinomycin D chemosensitivity. This heterogeneity led to the appearance of foci of resistant cells which, despite their greater degree of differentiation in comparison with the parental cell line, escaped from terminal myogenic differentiation. This subgroup of tumoral cells may be responsible for the failure of cytotoxic treatment. PMID- 8692722 TI - The teaching of pathology in European undergraduate programs in medicine: quality assurance. Discussion of the validity and reliability of various forms of examination. PMID- 8692723 TI - Lipophilicity in molecular modeling. AB - PURPOSE: The molecular lipophilicity potential (MLP) offers a three-dimensional representation of lipophilicity, a molecular property encoding intermolecular recognition and intramolecular interactions. METHOD: The interest and applications of the MLP in molecular modeling are varied, as illustrated here. RESULTS: The MLP is a major tool to assess the dependence of lipophilicity on conformation. As a matter of fact, the MLP combined with an exploration of the conformational space of a solute reveals its "chameleonic" behavior, i.e. its capacity to adapt to its molecular environment by hydrophobic collapse or hydrophilic folding. Another successful application of the MLP is its concatenation into 3D-QSAR (Comparative Molecular Field Analysis, CoMFA). CONCLUSION: Work is in progress to expand the MLP into a docking tool in the modeling of ligand-receptor interactions. PMID- 8692724 TI - Targeted drug delivery for boron neutron capture therapy. AB - PURPOSE: Boron neutron capture therapy (BNCT) is a form of radiochemotherapy that is becoming increasingly important for the treatment of malignant gliomas, malignant melanomas and other forms of cancer. Targeted delivery of boron to tumors is a critical prerequisite for successful BNCT. METHODS: Strategies that involve synthetic chemical approaches and biochemical and biophysical approaches are employed to meet this requirement. Compounds developed for targeting to tumors include borocaptate sodium (BSH) and p-boronophenylalanine (BPA) which are currently in clinical use. RESULTS: Boronated porphyrins, nucleosides, nucleotides and other boronated compounds show potentials as targeting molecules. Conjugation of boron compounds to macromolecules such as monoclonal antibodies, epidermal growth factor and dextran is also employed for active or passive tumor targeting. CONCLUSIONS: Boron delivery via microparticulate carriers such as liposomes, high density lipoproteins and microcapsules is also attractive for its potential application in BNCT. PMID- 8692725 TI - Preparation and characterization of doxorubicin-loaded sterically stabilized immunoliposomes. AB - PURPOSE: To compare the performance of sterically stabilized, doxorubicin-loaded liposomes with and without surface attached specific antibodies (D-SSIL and D SSL, respectively). METHODS: Small (< or = 120 nm) unilamellar liposomes were prepared composed of hydrogenated soy phosphatidylcholine, hydrogenated phosphatidylethanolamine (HPE), cholesterol, and 2000Da polyethylene glycol (2000PEG) attached to the primary amino group of distearoyl phosphatidylethanolamine. Doxorubicin was remote-loaded into these liposomes by an ammonium sulfate gradient to form the D-SSL. Monoclonal IgG3 NI32/2 antibodies directed against a polyoma virus tumor-associated antigen expressed on A9 ctc 102 murine fibrosarcoma cells were attached to the D-SSL HPE via a thioether bond to form the D-SSIL-32/2. A control of nonspecific D-SSIL was prepared by attaching nonspecific IgG3-enriched immunoglobulins to D-SSL. All liposomes were physically and chemically characterized and then tested in vitro for tumor cell binding, specificity, and uptake by macrophages; and in vivo for the drug plasma pharmacokinetics after intravenous administration in mice. RESULTS: (i) The attachment of antibodies to D-SSL did not impair their chemical or physical stability and had a minimal effect on their size and level of loaded drug. (ii) The combination of specific antibodies and 2000PEG grafted in the liposomes improved the specific binding to relevant target cells by reducing the level of unspecific binding to nonrelevant cells. (iii) D-SSIL retained the prolonged circulation and slow clearance typical of SSL lacking the antibodies. CONCLUSIONS: Sterically stabilized immunoliposomes exhibited stability, ability to recognize target cells, and prolonged circulation time. This study also shows that it is feasible to prepare them in pharmaceutically acceptable dosage form. Thus, further investigation for tumor targeting and efficacy is warranted. PMID- 8692726 TI - A novel method of preparing PLGA microcapsules utilizing methylethyl ketone. AB - PURPOSE: To substitute dichloromethane with a safer solvent, a solvent extraction process using methylethyl ketone (MEK) was developed to prepare poly(d,l-lactide co-glycolide) microcapsules. METHODS: The MEK dispersed phase containing PLGA and progesterone was emulsified in the MEK-saturated aqueous phase (W1) to make a transient oil-in-water (O/W1) emulsion. It was then transferred to a sufficient amount of water (W2) so that MEK residing in polymeric droplets could be extracted effectively into the continuous phase. RESULTS: This solvent extraction process provided the encapsulation efficiency for progesterone ranging from 77 to 60%. The amount of MEK predissolved in W1, as well as the degree of progesterone payload, influenced the encapsulation efficiency. The leaching profile of MEK analyzed by GC substantiated that, upon dispersion of O/W1, to W2, MEK quickly diffused into the continuous phase. Such a rapid diffusion of MEK from and the ingression of water into polymeric droplets produced hollow microcapsules, as evidenced by their SEM micrographs. CONCLUSIONS: When solvent extraction/evaporation techniques are employed for preparing PLGA microcapsules, water-immiscibility of a dispersed phase is not an absolute prerequisite to the successful microencapsulation. Adjustment of an initial extraction rate of MEK and formation of a primary transient O/W1 emulsion are found to be very crucial not only for the success of microencapsulation but also for the determination of microcapsule morphology. PMID- 8692727 TI - Development of a polymeric surgical paste formulation for taxol. AB - PURPOSE: To develop and characterize a biodegradable polymeric sustained release surgical paste formulation for taxol. METHODS: Taxol was incorporated into poly(epsilon-caprolactone) (PCL) or blends of PCL with methoxypolyethylene glycol, MW 350 (MePEG). The surgical pastes were characterized using gel permeation chromatography, thermal analysis, scanning electron microscopy, and a tensile strength tester. In vitro release data for taxol from the surgical paste formulations was carried out at 37 degrees C in phosphate buffered saline, pH 7.4, using an HPLC assay for taxol. Antiangiogenic activity of the formulations were assessed using a chick chorioallantoic membrane assay (CAM). RESULTS: The addition of up to 30% MePEG in PCL decreased the melting point of PCL by 5 degrees C and the tensile strength by 152.7 N/cm2 to 26.7 N/cm2 but increased the degree of PCL crystallinity from 42% to 51%. Taxol showed a biphasic in vitro release profile composed of a burst phase lasting 1 or 2 days followed by a period of slow sustained drug release. There was no significant difference in the release profiles of taxol from two different sources of PCL. The addition of MePEG increased the amount of water taken up by the polymer blends but decreased the rate of taxol release. The formulations were shown to have antiangiogenic activity by the CAM assay at levels as low as 0.1% taxol using 3 mg surgical paste pellets. CONCLUSIONS: Our surgical paste formulations for taxol give sustained release while having physical properties which can be adjusted using additives. PMID- 8692729 TI - Determination of tablet coating distribution by deconvolution of uncoated and coated tablet weight distributions. AB - PURPOSE: The purpose of this research is to obtain the tablet coating distribution from weight distributions of uncoated and coated tablets. METHODS: The method of deconvolution with digital smoothing was used to calculate the distribution of coating applied to a tablet population from separate random measurements of individual uncoated and coated tablets. RESULTS: It was demonstrated that the calculated coating weight distribution agrees well with the measured distribution. The effect of the smoothing factor on the solution is illustrated. CONCLUSIONS: This method can be used during development to facilitate process scale-up/optimization. In routine production, the method can assess the reproducibility and consistency of a coating process. PMID- 8692728 TI - Structure and behavior in hydrophilic matrix sustained release dosage forms: 4. Studies of water mobility and diffusion coefficients in the gel layer of HPMC tablets using NMR imaging. AB - PURPOSE: The purpose of this study was to characterise the water mobility in the gel layer of hydrating HPMC tablets. Water mobility in the gel layer of different HPMCs was studied. METHODS: NMR imaging, a non-invasive technique, has been used to measure the spatial distribution of self-diffusion coefficient (SDC) and T2 relaxation times across the gel layer. RESULTS: It has been shown that there is a water mobility gradient across the gel layer of HPMC tablets. Although SDC and T2 relaxation times in the outer parts of the gel layer approached that of free water, in the inner parts they decreased progressively. Water mobility and SDC in the gel layer of different HPMCs appeared to vary with degree of substitution of the polymer and the lowest values were obtained across the gel layer of K4M tablets. CONCLUSIONS: Water mobility varies across the gel layer of hydrating HPMC tablets and it is dependent on the degree of substitution of the polymer. PMID- 8692730 TI - Relationship between drug percolation threshold and particle size in matrix tablets. AB - PURPOSE: Since a previous qualitative study carried out by us showed the existence of an important influence of the particle size on the percolation thresholds and taking into account that the existing theoretical models can only provide qualitative explanation to this influence, the purpose of this work is to carry out the first quantitative study of the influence of the particle size over the drug percolation thresholds. METHODS: Matrix tablets have been elaborated using potassium chloride as drug model and Eudragit RS-PM as matrix forming material. Five different KCl particle size fractions have been employed whereas the Eudragit RS-PM particle size was kept constant. In-vitro release assays were carried out for all the elaborated lots. The drug percolation thresholds were estimated following the method proposed by Bonny and Leuenberger. RESULTS: A linear relationship has been found between the drug particle size and the corresponding drug percolation threshold. CONCLUSIONS: This finding confirms the results previously obtained in our qualitative study and has important repercussions in the design of pharmaceutical solid dosage forms. If this linear behaviour is general, the percolation threshold can soon become a useful preformulation parameter. PMID- 8692731 TI - A cascade impactor entry port for MDI sprays with collection characteristics imitating a physical model of the human throat. AB - PURPOSE: This work was performed in order to compare and contrast results obtained from cascade impactor measurements on metered dose inhalers (MDIs) using a variety of inlet ports. METHODS: The collection characteristics of four cascade impactor ports (a physical model of the human throat, a simplified geometry intended to mimic the physical model, and two currently-used ports) were measured on a variety of MDI formulations. RESULTS: The portion of the MDI spray which collects on the entry port depends in a complicated fashion on the characteristics of the formulation; in these studies the fraction of the total dose which was collected on the port ranged between about 20% and 90% of the total emitted dose. The collection characteristics of the simplified geometry closely corresponded to the physical model. The length of the flow path between the port and the impactor was varied, and found not to have a strong effect on the measured size distribution passing the port. CONCLUSIONS: Ranking of various MDI formulations according to performance criteria as measured with a cascade impactor should be expected to depend on the particular inlet port which is used. PMID- 8692732 TI - The simultaneous estimation of the influx and efflux blood-brain barrier permeabilities of gabapentin using a microdialysis-pharmacokinetic approach. AB - PURPOSE: To determine the apparent bidirectional permeabilities of gabapentin (GBP) across the blood-brain barrier (BBB) using a novel microdialysis pharmacokinetic approach. METHODS: Rats were administered intravenous infusions of [14C]GBP to achieve clinically relevant steady-state plasma concentrations. Microdialysis was used to monitor GBP concentration in brain extracellular fluid (ECF) in conscious animals. Brain tissue GBP concentration was measured at termination. The BBB influx (CL1) and efflux (CL2) permeabilities of GBP were estimated with a hybrid pharmacokinetic model assuming that transport between intra- and extracellular space was more rapid than transport across the BBB. The time course of GBP concentration in brain tissue was determined independently to validate the model assumption. RESULTS AND CONCLUSIONS: Simulations of the concentration-time course of GBP in brain tissue based on this modeling correlated well with the time-course of brain tissue concentrations determined after intravenous bolus administration and validated this pharmacokinetic microdialysis approach for estimation of BBB permeabilities. The values for CL1 and CL2 were 0.042 (0.017) and 0.36 (0.16) ml/min.g-brain, respectively, indicating that GBP was more efficiently transported from brain ECF to plasma. The total brain tissue concentration of GBP was significantly higher than the ECF concentration at steady-state due to intracellular accumulation and tissue binding, that if not considered, will lead to underestimated efflux BBB permeability using the tissue homogenate-pharmacokinetic approach. PMID- 8692734 TI - Transdermal drug delivery using low-frequency sonophoresis. AB - PURPOSE: Application of therapeutic ultrasound (frequency: 1-3 MHz and intensity: 0-2 W/cm2) enhances transdermal drug transport, although typically by a factor of less than 10. In this paper, we show that application of ultrasound at 20 KHz induces transdermal transport enhancements of up to 1000 times higher than those induced by therapeutic ultrasound. METHODS: In vitro (human cadaver epidermis) as well as in vivo (hairless rat skin) permeation experiments were performed to assess the effect of low-frequency ultrasound on transdermal transport. RESULTS: Application of low-frequency ultrasound (20 KHz, 125 mW/cm2, 100 msec pulses applied every second) enhanced transdermal transport of several permeants, including estradiol, salicylic acid, corticosterone, sucrose, aldosterone, water, and butanol, across human cadaver skin by a factor in the range of 3 to 3000 and that of salicylic acid across hairless rat skin in vivo by a factor of up to 300. Low-frequency ultrasound did not induce a long-term loss of the barrier properties of the skin (in vitro) or damage to living skin of hairless rats. At a mechanistic level, it is hypothesized that application of low-frequency ultrasound enhances transdermal transport through aqueous channels in the SC generated by cavitation-induced bilayer disordering. Support for this hypothesis is provided using experimental and theoretical analyses of low-frequency sonophoresis. CONCLUSIONS: Low-frequency ultrasound enhances transdermal transport of drugs more effectively than that induced by therapeutic ultrasound. PMID- 8692735 TI - Non steady-state descriptions of drug permeation through stratum corneum. I. The biphasic brick-and-mortar model. AB - PURPOSE: The diffusion equation should be solved for the non-steady-state problem of drug diffusion within a two-dimensional, biphasic stratum corneum membrane having homogeneous lipid and corneocyte phases. METHODS: A numerical method was developed for a brick-and-mortar SC-geometry, enabling an explicit solution for time-dependent drug concentration within both phases. The lag time and permeability were calculated. RESULTS: It is shown how the barrier property of this model membrane depends on relative phase permeability, corneocyte alignment, and corneocyte-lipid partition coefficient. Additionally, the time-dependent drug concentration profiles within the membrane can be observed during the lag and steady-state phases. CONCLUSIONS: The model SC-membrane predicts, from purely morphological principles, lag times and permeabilities that are in good agreement with experimental values. The long lag times and very small permeabilities reported for human SC can only be predicted for a highly-staggered corneocyte geometry and corneocytes that are 1000 times less permeable than the lipid phase. Although the former conclusion is reasonable, the latter is questionable. The elongated, flattened corneocyte shape renders lag time and permeability insensitive to large changes in their alignment within the SC. Corneocyte/lipid partitioning is found to be fundamentally different to SC/donor partitioning, since increasing drug lipophilicity always reduces both lag time and permeability. PMID- 8692733 TI - Evaluation of adjuvants that enhance the effectiveness of antisense oligodeoxynucleotides. AB - PURPOSE: A factor limiting the effectiveness of antisense (AS) deoxyoligonucleotides (ODNs) is inefficient transport to their sites of action in the cytoplasm and in the nucleus. The extent of ODN transfer from endosomes to cytosol seems to be an important determinant of ODN effects. Consequently, the development of compounds (adjuvants) that enhance endosome to cytosol transfer may be vital in AS ODN therapeutics. METHODS: In this report, we evaluated compounds for their potential to enhance the effects of phosphorothioate ODNs. The test system used a CHO cell line expressing the enzyme chloramphenicol acetyl transferase (CAT) under the control of an inducible promoter. Several potential endosomal disrupting adjuvants were screened, including: (a) fusogenic peptides; (b) a pH sensitive polymer; (c) polymeric dendrimers, (d) cationic liposomes and (e) a pH sensitive surfactant N-dodecyl 2-imidazole-propionate (DIP). ODN effects were evaluated at the protein level by quantitating levels of CAT. RESULTS: The use of AS ODN in co-incubation with the GALA peptide, cationic liposomes or 5th generation dendrimers resulted in a 35-40% reduction in CAT expression. The mis matched ODN had no effect on CAT expression. Only modest effects were observed with the other adjuvants. DIP did not increase ODN activity by itself; however, when the liposomal form was used a significant reduction (48%) in CAT activity was seen. CONCLUSIONS: We found the fusogenic peptide GALA, dendrimers, as well as the liposomal form of DIP, could significantly enhance the effects of ODNs. PMID- 8692736 TI - Theoretical design of prodrug-enhancer combination based on a skin diffusion model: prediction of permeation of acyclovir prodrugs treated with 1 geranylazacycloheptan-2-one. AB - PURPOSE: A theoretical design of percutaneous penetration enhancement in which prodrug derivation and enhancer application are combined is proposed based on the skin diffusion model and it is experimentally verified. METHODS: Employing acyclovir as a model drug, the hypothesis was tested by synthesis of its prodrugs and evaluation of their in vitro permeation in the rat skin, with or without a penetration enhancer, 1-geranylazacycloheptan-2-one(GACH). RESULTS: Among five acyclovir prodrugs, those with higher lipophilicities (propionate, butyrate, valerate, and hexanoate prodrugs) showed greater skin penetration than those of hydrophilic prodrugs (acetate), when administered in combination with GACH. Furthermore, the observed enhancement ratios were in good agreement with those predicted by theoretical consideration. CONCLUSIONS: Thus, skin permeation of prodrugs applied with an enhancer can be predicted and optimized by model analysis. PMID- 8692737 TI - Effect of nonionic surfactant on transport of model drugs in emulsions. AB - PURPOSE: To investigate the influence of excess surfactant on transport kinetics in emulsions, using phenylazoaniline (PAA), benzocaine, benzoic acid and phenol as model drugs. Mineral oil was chosen as the oil phase and the nonionic surfactant, polyoxyethylene oleyl ether (Brij 97) as the emulsifier. METHODS: Model drug transport in emulsions was investigated using side by side diffusion cells mounted with hydrophilic dialysis or hydrophobic membranes. A novel method, involving a combination of a membrane equilibrium technique and surface tension measurement (Wilhelmy plate method), was developed to determine surfactant critical micelle concentration (CMC) in the presence of O/W emulsions. Emulsion stability was determined by droplet size analysis as a function of time, temperature and dilution using photon correlation spectroscopy and a light blockage technique. Model drug mineral oil/water partition coefficients and aqueous solubilities were determined in the presence of surfactant. RESULTS: The emulsion CMC value was used to calculate micellar phase concentration. The transport rates of PAA and benzocaine in emulsions increased with increase in Brij 97 micellar concentrations up to 1.0% w/v and then decreased at higher surfactant concentrations. The transport rates of the more hydrophilic compounds, benzoic acid (ionized form, pH 7.0) and phenol, were not affected by the presence of micellar phase. CONCLUSIONS: Excess surfactant affected the transport rates of the model drugs in the emulsions depending on drug lipophilicity. Transport rates measured using side by side diffusion cells appeared to be governed by model drug partitioning rates from the oil to the continuous phases and by membrane type. PMID- 8692738 TI - Effect of food on the bioavailability of SDZ DJN 608, an oral hypoglycemic agent, from a tablet and a liquid-filled capsule in the dog. AB - PURPOSE: The effect on food on the bioavailability of SDZ DJN 608, a D phenylalanine derivative, was investigated in three mature, male beagle dogs. METHODS: Each dog received, under fasting and postprandial conditions, a 30 mg oral dose as a tablet (T) and a liquid-filled capsule (LC). Additionally, a 5 mg intravenous dose was given in the fasting state. Doses in the same dog were separated by 1-week washout periods. Serial plasma samples were collected for 24 h postdose and analyzed for SDZ DJN 608 using HPLC. Model-independent pharmacokinetic parameters were compared between treatments by 3-way ANOVA: In vitro dissolution profiles of T and LC were generated using the USP paddle method. In addition, the transport of SDZ DJN 608 through a Caco-2 cell monolayer was examined at concentrations of 0.1 and 1 mM, in the absence and presence of an aromatic amino acid, L-alpha-methyldopa, the transport of which is mediated by the large neutral amino acid (LNAA) carrier. RESULTS: In the dog, SDZ DJN 608 was rapidly absorbed. The peak plasma concentration (Cmax) averaged higher, and the peak time (tmax) shorter, after LC than T, though the differences were not statistically significant. This finding is consistent with in vitro dissolution data showing that, at both pH 1.2 and pH 6.8, the dissolution rate of LC was faster than that of T. No significant difference in the area under curve (AUC) was observed between LC and T, the absolute bioavailability of both being complete in the fasting state. Whereas the presence of food showed little effect on the tmax and Cmax of either dosage form, it significantly reduced the AUC, the effect (ca -20%) being not different between LC and T. In the Caco-2 model, the mucosal-to-serosal permeability of SDZ DJN 608 was independent of concentration and unaffected by L-alpha-methyldopa, suggesting passive diffusion of the former. CONCLUSIONS: Food had little effect on the absorption rate but significantly reduced the bioavailability of SDZ DJN 608 regardless of the dosage form. This effect is unlikely to be caused by inhibition of the transepithelial transport of SDZ DJN 608 by amino acids in the diet. PMID- 8692739 TI - Pharmacokinetics, bioavailability, and safety of montelukast sodium (MK-0476) in healthy males and females. AB - PURPOSE: The safety, tolerability, and pharmacokinetics of intravenous *i.v.) montelukast sodium (Singulair, MK-0476), and the oral bioavailability of montelukast sodium in healthy males and healthy females were studied. METHODS: This was a two-part study. Part I was a four-period study in males of rising i.v. doses of montelukast sodium (3, 9, and 18 mg) administered as 15-minute constant rate i.v. infusions (Periods 1-3), followed by a 10-mg oral tablet dose of montelukast sodium (Period 4) under fasting conditions. Part II was a four-period study in females of i.v. montelukast sodium (9 mg) infused over 15 and 5 minutes (Periods 5 and 6, respectively) or injected as a bolus over 2 minutes (Period 7), followed by a 10-mg oral tablet dose of montelukast sodium (Period 8). Plasma samples were collected and analyzed by HPLC. RESULTS: In males (N = 6), as the i.v. dose of montelukast sodium increased from 3 to 18 mg, the area under the plasma concentration-time curve of montelukast sodium from time 0 to infinity (AUC) increased proportionately. The mean values of plasma clearance (CL), steady state volume of distribution (Vss), plasma terminal half-life (t1/12), and mean residence time in the body (MRTi.v.) of montelukast sodium were 45.5 ml/min, 10.5 1, 5.1 hr, and 3.9 hr, respectively, and remained essentially constant over the i.v. dosage range. Following oral administration of a 10-mg tablet of montelukast sodium, the AUC, maximum plasma concentration (Cmax), time when Cmax occurred (Tmax), apparent t1/12, mean absorption time (MAT), and bioavailability (F) of montelukast sodium averaged 2441 ng.hr/ml, 385 ng/ml. 3.7 hr, 4.9 hr, 3.4 hr, and 66%, respectively. Following i.v. administration of 9 mg of montelukast sodium to females (N = 6), the values of CL, Vss, t1/2, and MRT i.v. averaged 47.6 ml/min, 9.6 1, 4.5 hr, and 3.6 hr, respectively. Following oral administration of a 10-mg tablet to females, the mean AUC, Cmax, Tmax, apparent t1/2, MAT and F were 2270 ng.hr/ml, 350 ng/ml, 3.3 hr, 4.4 hr, 2.6 hr, and 58%, respectively. These parameter values were similar to or slightly smaller than those in healthy males receiving the same i.v. and oral doses. CONCLUSIONS: The disposition kinetics of montelukast sodium were linear. Gender had little or no effect on the kinetics of montelukast sodium. Safety results from this study indicate that intravenous doses of montelukast sodium from 3 to 18 mg and a 10-mg oral dose are well tolerated. PMID- 8692741 TI - Absorption rate vs. exposure: which is more useful for bioequivalence testing? AB - PURPOSE: The goals were to evaluate the usefulness of Cmax/AUClqc, ratio of the maximum plasma drug concentration to the area under the plasma concentration-time curve to the time of the last quantifiable concentration, in bioequivalence testing and to explore the use of exposure as a replacement for the concepts of rate and extent of drug absorption. METHODS: The bioequivalence of products differing in both rate (ka) and extent (F) of absorption was assessed under conditions similar to those encountered in a typical trial. A one-compartment model drug with first-order absorption (rate constant = ka) and eliminations was used. Variability was introduced in all model parameters using Monte Carlo techniques. The results were expressed in terms of the probability of declaring bioequivalence in a cross-over trial with 24 subjects using Cmax/AUClqc, AUClqc, and Cmax as bioequivalence measures. RESULTS: The outcome of a bioequivalence trial was shown to depend on the measure. Cmax/AUClqc reflected changes in ka, but not in F. AUClqc showed dependence on F, but virtually no dependence on ka. For Cmax, a 3- to 4-fold increase in ka and a concomittant 20% decrease in F, as well as corresponding changes in the opposite directions, resulted in bioequivalent outcomes. CONCLUSIONS: It was concluded that use of Cmax/AUClqc should be discouraged and that defining bioequivalence in terms of rate and extent of absorption has major problems. The goal of bioequivalence trials should be to assure that the shape of the concentration-time curve of the test product is sufficiently similar to that of the reference product. To this end, the use of "exposure" rather than "rate and extent of absorption" concepts is encouraged. PMID- 8692740 TI - The effect of probenecid on the pharmacokinetics of zalcitabine in HIV-positive patients. AB - PURPOSE: The purpose of this study was to determine the potential effect of probenecid on the pharmacokinetics of zalcitabine in HIV-positive patients. METHODS: Twelve patients received single oral 1.5 mg doses of zalcitabine alone and during probenecid treatment (500 mg at 8 and 2 hours before and 4 hours after zalcitabine dosing) in an open-label, randomized two-way crossover study with a one-week washout period between treatments. Serial blood and urine samples were collected over a 24 hour period and assayed for zalcitabine by a modified GC/MS method. RESULTS: Coadministration of probenecid with zalcitabine resulted in a decrease in mean (%CV) renal clearance of zalcitabine from 310 (28%) ml/min when zalcitabine was given alone to 180 (22%) ml/min with probenecid and a prolonged half-life from 1.7 hours to 2.5 hours. Mean AUCs increased from 59 ng.h/ml when zalcitabine was given alone to 91 ng.h/ml when given with probenecid. Considering the short half-life of zalcitabine (1-3 hours) relative to its dosing schedule, the pharmacokinetic changes observed in this study are not expected to result in significant accumulation during chronic dosing. CONCLUSIONS: The results of this study show that co-administration of probenecid with zalcitabine results in a moderate decrease in renal clearance of zalcitabine due to inhibition of renal tubular secretion and a 50% increase in drug exposure. Although well tolerated in this single-dose study, patients taking this combination should be monitored closely for signs of toxicity and dosage reduction should be considered if warranted. PMID- 8692742 TI - Nicanartine improves in vitro resistance of lipoproteins to oxidation. AB - PURPOSE: The aim of this study is to investigate the plasma protein binding of nicanartine and to measure its antioxidant effect on lipoproteins. METHODS: The blood binding was studied with an erythrocyte partitioning method and the lipoprotein oxidation with the conjugated dienes method. RESULTS: Nicanartine was 24.7% LDL (low density lipoprotein)-bound and 29.2% AAG(alphal-acid glycoprotein) bound. Nicanartine delayed but did not stop the oxidation of the three density classes of lipoprotein HDL (high density lipoprotein), LDL, VLDL (very low density lipoprotein). The addition of AAG to LDL in the conjugated dienes method decreased the nicanartine fraction bound to LDL and decreased its antioxidant effect. The decrease of nicanartine LDL-bound fraction and the decrease in antioxidant effect were not parallel. CONCLUSIONS: This suggested that (a) AAG bound nicanartine dissociated to equilibrate the decrease in LDL-bound nicanartine consumed by oxidation, or (b) the oxidation conditions could involve chemical modifications of nicanartine and therefore modify its affinity for AAG. PMID- 8692743 TI - Differences in lipoprotein concentration and composition modify the plasma distribution of free and liposomal annamycin. AB - PURPOSE: The purpose of these studies were to determine the distribution of a lipophilic antineoplastic agent, annamycin (Ann), and its liposomal counterpart (LAnn) in plasma which had been altered in its lipoprotein concentration and lipid composition. METHODS: Ann, LAnn, and doxorubicin (a hydrophilic control) were incubated in human plasma for 1 hour at 37 degrees C. Following incubation plasma samples were assayed by fluorimetry for drug in each of the lipoprotein and lipoprotein-deficient plasma (LPDP) fractions. To assess the influence of modified lipoprotein concentrations and lipid composition on plasma distribution of Ann and LAnn, either Ann or LAnn were incubated in human plasma which had been supplemented with very low density lipoproteins (VLDL) or low density lipoproteins (LDL). RESULTS: When unbound Ann or doxorubicin was incubated in plasma for 1 hour at 37 degrees C, the majority of drug was found in the LPDP fraction. However, when Ann was incorporated into liposomes composed of dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol (LAnn) the majority of Ann was recovered in the high-density lipoprotein (HDL) fraction. Elevation of plasma LDL-cholesterol or VLDL-triglyceride concentrations increased the amounts of Ann and LAnn associated with these lipoprotein classes. Alterations in HDL composition decreased the amount of Ann, but increased the amount of L-Ann within the HDL fraction. Lipid transfer protein (LTP) activity did not significantly modify the plasma distribution of Ann and LAnn in short term experiments, but the modified lipoprotein composition that LTP facilitates in long-term incubations reduced the capacity of VLDL and LDL to accept drug. CONCLUSIONS: These findings suggest that lipoprotein concentration and composition alter the plasma distribution of Ann and LAnn and may help to explain the discrepancies observed in the pharmacokinetics of Ann and LAnn when they are administered to healthy versus cancer patients. PMID- 8692744 TI - Derivatives of dexanabinol. II. Salts of amino acid esters containing tertiary and quaternary heterocyclic nitrogen with increased water-solubility. AB - PURPOSE: Amino acid esters containing tertiary or quaternary nitrogen heterocycles were synthesized for dexanabinol (1) and evaluated as water-soluble prodrugs or congeners. METHODS: Syntheses were performed by conventional methods; stability studies in water, blood (rat, dog, human) and assay-media were performed by HPLC; NMDA receptor binding was determined by [3H] MK-801 displacement; neuroprotection and neurotoxicity studies were performed in cortical cell cultures. RESULTS: 7-morpholino and N-methylpiperazino acetates and butyrates and the respective N-methylmorpholinium and piperazinium iodides as well as a 3'-N-methyl morpholino butyrate and the corresponding N-methyl quaternary type derivative were synthesized. All compounds were relatively soluble in water or 10% aqueous ethanol. The examined derivatives were stable in water and generally less stable in blood and assay media. Quaternary derivatives of dexanabinol were found to hydrolyze faster. All examined compounds inhibited NMDA receptor and protected neurons against NMDA induced toxicity. Neuroprotection (with one exception) is however attributed to the parent 1 released by hydrolysis during the assay. CONCLUSIONS: Some of the examined derivatives could be further evaluated as prodrugs on congeners of 1. PMID- 8692745 TI - Anti-inflammatory and antishock water-soluble polyesters of glucocorticoids with low level systemic toxicity. AB - PURPOSE: The objective of this study was to evaluate the pharmacological activity of glucocorticoid hormones incorporated into the structure of water-soluble carbochain polymers via the esterified 21-CH2OH group. METHODS: Polymer analogs of glucocorticoids were prepared by radical copolymerization of 1-vinyl-2 pyrrolidone with cortisol or dexamethasone 21-crotonates and crotonic acid or 2 (diethylamino) ethylcrontonate which served as ionogenic comonomers. Anti inflammatory, immunosuppressive and catabolic activities for ionogenic tertiary copolymers and previously prepared non-ionogenic binary copolymers were evaluated in standard animal models. The antishock activity of some of the copolymers was evaluated using the "declamping shock" model. RESULTS: Water-soluble tertiary copolymers with a steroid content up to 14 mol% and an intrinsic viscosity up to 0.30 dl/g in ethanol were synthesized. It was shown that the copolymers were stable in aqueous solutions at pH 5.2-7.3. All of the polymers studied suppressed inflammatory reactions at the level of free hormones when administered interperitoneally. The antishock activity was considerably higher compared to free steroids. The copolymers, unlike unmodified glucocorticoids, did not influence the physical development of young animals. They also caused much lower thymus hypotrophy than free hormones. No clear effect of the presence and nature of ionogenic units in copolymers on the pharmacological performance of the copolymers was detected. CONCLUSIONS: The water-soluble polymers bearing glucocorticoid 21-residues in the side chains retain the anti-inflammatory activity of free steroids and exhibit a higher antishock, a lower immunosuppressive and no catabolic effect. PMID- 8692746 TI - Characterization of the salts of a cyclic RGD peptide. PMID- 8692747 TI - pH-sensitive nanoparticles: an effective means to improve the oral delivery of HIV-1 protease inhibitors in dogs. PMID- 8692748 TI - [20 years of lumbar chymonucleolysis]. AB - If correct indications and rigorous technique are applied, nucleolysis with chymopapain can be an effective cure for herniated nucleus pulposus in patients who do not respond to adequate medical treatment. Pain relief is obtained in approximately 75% of the patients. In case of failure, secondary surgery may be proposed with a success rate similar to primary surgery. The risk of complications is lower than for surgery. Initial satisfactory results are usually maintained at long term. The main inconveniences include a possible painful reaction in 30-40% of the patients and in certain cases progressives rather than rapid pain relief. Cost analysis shows a 40% gain over surgery. After 20 years of experience, chemonucleolysis for herniated nucleus pulposus has been shown to be an effective therapeutic technique which should be part of an overall management strategy including medical treatment and surgery. PMID- 8692749 TI - [Community-acquired and nosocomial septicemias in patients with human immunodeficiency virus infection]. AB - OBJECTIVES: Study the characteristics of community and nosocomial-acquired bacteremia in HIV-infected patients in order to improve curative, and if possible, preventive therapy. METHODS: We analyzed retrospectively 47 cases of community-acquired and 31 cases of nosocomial bacteremia identified in 63 of 436 patients hospitalized between January 1992 and December 1993 with HIV infection (53 men, 10 women, mean age 34.3 years, stage A: 1, stage B: 20, stage C: 42). The portal was identified for 68 episodes (40 in the community acquired and 28 in the nosocomial groups). The main portal was pulmonary infection (42.5% vs 17.8%; p = 0.03) and digestive tract infection due to Streptococcus pneumoniae (70%) and Salmonella spp (60%). Nosocomial bacteremia following intravenous infusions included Staphylococcus epidermidis (oxacillin-resistant in 57%) and Staphylococcus (oxacillin-sensitive) infections. Bacteremia was the immediate cause of death in 18% of the deaths occurring in the 436 patients hospitalized during the study period. CONCLUSION: These findings confirm the gravity of community-acquired and nosocomial bacteremia in advanced stage HIV-infected patients. Antibiotics should be adapted on the basis of probability of the infectious agent obtained from epidemiologic data and the effectiveness of prophylaxis measures validated. PMID- 8692750 TI - [Thrombopenia induced by heparin: treatment with Org 10172. Tolerability and efficacy]. AB - OBJECTIVES: Heparin-induced thrombocytopenia is a relatively common and potentially serious adverse complication of heparin treatment. After heparin withdrawal initiation of an alternative anticoagulant is often indicated. Org 10172 or Orgaran is a mixture of several non-heparin low molecular weight glycosaminoglycans with proven antithrombotic efficacy. Unlike low molecular weight heparins, Org 10172 has a low cross reaction rate (about 10%) with the heparin-dependent antibody. METHODS: We present nine patients with heparin induced thrombocytopenia. Org 10172 was prescribed to treat or to prevent a thromboembolic event. RESULTS: Seven patients required further parenteral anticoagulant at diagnosis of heparin-induced thrombocytopenia. Org 10172 was given at prophylactic doses for three patients with a high thrombosis risk and at therapeutic doses for four patients who presented either a venous or an arterial thrombosis related to thrombocytopenia. Two patients presented heparin-induced thrombocytopenia four to six years earlier and needed a parenteral anticoagulation treatment in a post-operative period. CONCLUSION: For the nine patients, Org 10172 was a safe and effective antithrombotic treatment. However, strict monotoring of the platelet count is absolutely mandatory during Org 10172 therapy. PMID- 8692751 TI - [Anticoagulant therapy with recombinant hirudin in patients with thrombopenia induced by heparin]. AB - OBJECTIVES: Heparin-induced thrombocytopenia is an uncommon and severe complication of heparin therapy. Both venous and arterial thromboembolic events can occur, requiring withdrawal of the heparin therapy. When anticoagulant therapy is mandatory, recombinant hirudin can be used. METHODS: We used recombinant hirudin (HBW 023) in 6 patients with heparin induced thrombocytopenia. In case of venous thromboembolism, an initial intravenous bolus (0.07 mg/kg) was followed by continuous infusion (0.05 mg/kg/h); for arterial thromboembolism the initial bolus was 0.7 mg/kg and infusion rate 0.15 mg/kg/h. When possible oral anticoagulants were started and hirudin withdrawn when the INR ratio reached 3. RESULTS: The clinical course was uneventful in all 6 patients. There was no recurrent thromboembolism. Cephalin-activated coagulation time (patient/control) varied between 1.8 and 3.5 (median 2.4) during hirudin administration. Platelet count rose to the nadir (median 70 x 10(9)/l, range 15 90) reaching over 100 x 10(9)/l in all patients between the third and sixth day (median 5 days) after stopping heparin. CONCLUSION: Intravenous administration of hirudin provides effective immediate anticoagulation in patients with heparin induced thrombocytopenia, thus allowing conversion to oral anticoagulants without risking recurrent thromboembolism. PMID- 8692752 TI - [Nicotine: a psychoactive drug, a doping agent?]. AB - A 43-year-old high-level athlete used nicotine gum to stop his smoking habit. Later, use of nicotine gum was directly related to improved sports performance. It is suggested that nicotine might be added to the official list of prohibited drugs in athletes. PMID- 8692753 TI - [Alzheimer disease: hypotheses implicating apolipoproteins E]. AB - The most promising discovery in the study of Alzheimer's disease (AD) markers is undoubtedly the implication of apolipoprotein E (apoE). The gene of this apoliprotein is located on chromosome 19 and is characterized by three common alleles epsilon 2, epsilon 3 and epsilon 4 giving raise to 6 genotypes and 6 protein phenotypes. ApoE is well known for its role in cholesterol transport. Different studies have been performed, giving major arguments in favor of an important role of apoE in the pathophysiology of AD. These include the discovery of the relationship between the epsilon 4 allele and AD, the ability of this protein to form complexes with beta amyloid protein (A beta) in seniles plates, its presence in neurofibrillary tangles and in vessels of AD patients. Another important finding is the differential interaction between the different isoforms of apoE and tau protein. Some of the hypotheses implicate the role of different apoE isoforms on the growth and extension of neurones, perhaps by a receptor mediated pathway. It has been suggested that apoE acts as a pathological chaperone protein, or alternatively that it protects neurons by regulation of the cell membrane and modifying calcium homeostasis. It is clear that apoE genotype determination alone cannot be used for diagnosis of AD. The presence of epsilon 4 allele is only one of several risk factors for the development of the disease. Other factors may also be implicated and are the subject of ongoing research. PMID- 8692755 TI - [Porphyria cutanea tarda in Languedoc-Roussillon. Epidemiological study in 24 years]. PMID- 8692754 TI - [Glucocorticoid receptor anomalies in asthma]. AB - Asthma is an inflammatory disease sensitive to glucocorticoids as has been demonstrated by several studies on the mechanisms of action of these drugs both in vitro and in vivo. The cellular and molecular targets of glucocorticoids have however not been identified. The best candidates are lymphocytes and the glucocorticoid receptors, although other cells and other transcription factors which interact with glucocorticoids may also be involved. Qualitative and quantitative abnormalities in glucocorticoid receptor binding to glucocorticoids and desoxyribonucleic acid have been described in the lymphocytes of patients with corticosteroid-resistant asthma. The chances of observing an abnormality in the mechanism of action of glucocorticoids would be greatest in these patients. Indeed, such deficits might also participate in the pathogenesis of corticosteroid-dependent asthma or in asthma in general. We recall here the mechanisms of action of glucocorticoids and their effect in asthma. PMID- 8692756 TI - [Life expectancy of patients with human immunodeficiency virus infection with CD4 lymphocytes below or equal to 50 microliter. Retrospective study with 91 treated patients]. PMID- 8692757 TI - [Pseudotumoral pelvic actinomycosis]. PMID- 8692759 TI - Blastocystosis or Zierdt-Garavelli disease. PMID- 8692758 TI - [Bone and bone marrow metastases of prostatic adenocarcinoma: the serum level of prostate-specific antigen may be normal]. PMID- 8692760 TI - [Non-hospitalization orders for subjects with presumed alcoholic intoxication]. AB - OBJECTIVES: French law requires all persons in an apparent state of alcoholic intoxication taken into police custody to be examined at hospital to determine whether medical observation is necessary. A do-not-hospitalize order is required to return the person to police custody. We attempted to ascertain the number of orders delivered and the quality of medical management of these persons. METHODS: Over a one-month period, 140 persons in an apparent state of alcoholic intoxication and under police custody were seen at the University Hospital emergency ward at Tours, France. Do-not-hospitalize orders were delivered for 131 of them who were returned to police custody. Among the 66 other persons admitted for acute intoxication, 4 were also returned to police custody. Nurse and physician reports were assessed. RESULTS: The 135 persons, accounting for 12.7% of all emergency ward activity, were predominantly men (96%) and young (mean age 33 years). Many were aggressive (12.7%) and 80% arrived between 6 p.m. and 6 a.m. Nurse records revealed care was less rigorous at night and for the more aggressive subjects. Reasons for delivery of the do-not-hospitalize order were not sufficiently explicit in the physician records. CONCLUSION: The large volume of activity involved in caring for these persons and the difficulty encountered in correct medical management, together with legal implications, suggest that medical and paramedical teams need better training for the management of persons in an apparent state of alcoholic intoxication. PMID- 8692761 TI - [Prognosis of systemic diseases diagnosed in intensive care units]. AB - OBJECTIVES: The aims of this study were to evaluate the prognosis of patients with systemic rheumatic disease diagnosed in medical intensive care unit (MICU) and to determine whether the outcome is different for patients with systemic rheumatic disease previously known hospitalized in MICU. METHODS: Retrospective evaluation, over a ten-year period, of 88 cases of systemic rheumatic disease selected in two groups: group I: diagnosed in MICU, group II: previously known and treated. RESULTS: Group I: 18 patients with necrotizing vasculitis (n = 6), extra-intestinal manifestations of inflammatory bowel disease (n = 4), systemic lupus erythematosus (n = 3), miscellaneous (n = 5). Group II: 70 patients with rheumatoid arthritis (n = 31), necrotizing vasculitis (n = 12), systemic lupus erythematosus (n = 12), polymyositis (n = 4), extra-intestinal manifestations of inflammatory bowel disease (n = 5), miscellaneous (n = 6). The main admission diagnoses were infectious diseases (p < 0.005) or iatrogenic complications in the group II (p < 0.01) and acute exacerbation of systemic rheumatic disease in the group I (p < 0.0001). Age; simplified acute physiologic score (SAPS); number of acute organ system failure; number of patients requiring mechanical ventilation, haemodialysis or right heart catheterization were not different between the two groups. The durations of mechanical ventilation and stay in the MICU were shorter in the group II (p < 0.005). MICU mortality rate was higher in the group II (p < 0.05), with a five years cumulative proportion of surviving statistically lower (p < 0.05). Mortality rate of the entire population (37.5%) was similar to that of a non-selected population with comparable SAPS. Multivariate analysis showed that SAPS, number of acute organ system failure and iatrogenic complications were the main prognostic factors (p = 0.05). CONCLUSIONS: The prognosis was better for patients with systemic rheumatic disease diagnosed in MICU. Infectious diseases were the main cause of death, probably in relation with immunosuppressive treatments. PMID- 8692762 TI - [Intrahepatic portasystemic shunt as a salvage treatment of uncontrolled hemorrhage caused by rupture of esophageal varices in patients with liver cirrhosis]. AB - OBJECTIVES: Patients who continue to bleed despite standard treatment including sclerotherapy have a poor prognosis with a mortality up to 90%. TIPS has been used as salvage therapy for ruptured oesophageal varices refractory to all conventional treatments. METHODS: During a period of 3 years, 65 cases of variceal rupture in cirrhotic patients were treated at our center and a salvage TIPS was performed in 15 patients (23%) for active uncontrolled hemorrhage despite standard medical and endoscopic treatment (Child A, 2; B, 1; C, 12). The procedure was technically successful in all cases and hemorrhage was controlled in 11/15 cases (73%). RESULTS: Three patients died of persistent bleeding and liver failure; one case of moderate and persistant hemorrhage was controlled by transfusions until bleeding ceased. This patient was transplanted 3 months after TIPS and is alive 3.5 years later. Two patients had early recurrence of hemorrhage due to TIPS thrombosis. These 2 cases of thrombosis were deobstructed but both patients died of liver failure despite bleeding control. Overall, 7 patients died within 60 days of TIPS by hemorrhage and/or liver failure. One patient died of liver failure 7 months after TIPS following surgery for aortic aneurysm. None of the 8 survivors after 60 days had bleeding recurrence or encephalopathy. Actuarial survival was 42.7 +/- 14% at 1 and 2 years. CONCLUSION: TIPS is currently the alternative of choice for persistant bleeding refractory to standard management. However despite control of hemorrhage, operative mortality remains high due to the underlying severe cirrhosis. PMID- 8692763 TI - [Pregnant women with HIV infection: medical decision]. AB - The aim of this study was to review current knowledge of mother-to-fetus transmission of human immunodeficiency virus (HIV) and attempt to determine a rationale for decision making in infected women. The risk of transmission to the fetus varies from 20% for women with stage II infection to 50% in stage IV patients. The risk can be reduced to 8% with zidovudine (in stage II patients). Knowledge of the prevalence of HIV infection in women in different risk groups and geographic areas is important in evaluating risk; currently 80 to 500 infants are contaminated annually in France. Although clinical signs and laboratory results may be suggestive of late transmission, neither the mechanism nor the precise period of transmission are known. HIV-infection has no effect on the natural course of pregnancy. Screening tests should be performed for all pregnant women, but are not mandatory. A positive test should always be announced by the physician. The decision to continue the pregnancy must be based on several factors: term, disease severity and socioeconomic situation. If the pregnancy is continued, zidovudine (5 x 100 mg) should be prescribed through delivery. To date, there is no evidence favoring cesarean rather than vaginal delivery. Two steps are required for the infants: zidovudine for 6 weeks and artificial feeding. Social and psychological obstacles hinder progress in limiting disease transmission from mother to infant. PMID- 8692764 TI - [Neuronal ceroid lipofuscinosis. An unknown overload disease]. AB - Neuronal ceroid lipofuscinosis comprises a group of lysosomal diseases transmitted by autosomal recessive inheritance. Often unrecognized, this disease should be evoked in children or adolescents with blindness due to retinal pigmentation, dementia and myoclonal seizures. Retinal pigmentation is lacking in adults. The characteristic feature is an accumulation of fluorescent lipopigments deposited within cells, especially neurons. Histology examination gives the diagnosis based on the ultrastructure of skin biopsies and identification of the disease-specific lysosomal inclusions. The disease can also be identified in children by identification of mutations on genes CLN1, CLN3 and CLN5. The pathophysiology of these diseases remains unknown and treatment is limited to symptomatic care. PMID- 8692765 TI - [Nebulization for basic treatment of asthma in adults]. AB - Many different forms of nebulizer treatment for asthma have been developed over the last few years, including several which have reached international concensus. Nevertheless, there are no widely recognized recommendations concerning the role of nebulization in the treatment of asthma in adults. We present here the main elements on the pathophysiological basis of nebulization treatment of asthma, the physical and chemical parameters of nebulization, the different nebulizers and the substances which can be administered and their costs. The indications for home nebulizer treatment of asthma in adults include asthma with chronic sinusitis or nasosinus polyposis, asthma with hypersecretion with or without bronchial dilatation, severe poorly controlled asthma, corticodependent asthma. The aim of this discussion on nebulizer administration is to reduce the amount of systemic corticosteroid delivery and underline the need for quality research in this area. PMID- 8692766 TI - [Common bile duct stenosis: clinical and diagnostic aspect]. PMID- 8692767 TI - [Is thrombocytopenia in primary antiphospholipid syndrome a contraindication for aspirin?]. PMID- 8692768 TI - [Serum assay of soluble CD23: value in chronic lymphoid B-cell leukemia]. PMID- 8692769 TI - [Spinal extradural hematoma after anticoagulants. 5 cases]. PMID- 8692770 TI - [Intravenous use of nitroglycerin in obstetrical emergencies. 9 cases of version by internal manipulations]. PMID- 8692771 TI - Endometrial carcinoma presenting with massive chylous ascites. PMID- 8692772 TI - [[Therapeutic perspectives in multiple sclerosis]. AB - Numerous clinical trials have been performed during the last 5 years in multiple sclerosis patients. Some of the results have been encouraging. However, clinical benefit remains limited. Corticosteroids are indicated during the course of severe relapses but have not proven any long term benefit. Immunosuppressive agents may be of some help during very active stages of the disease. Results of interferon beta-1b trial in relapsing multiple sclerosis have shown a moderate decrease in the frequency of relapses. The same effect has recently been reported with interferon beta-1a. In addition, an effect on disability progression have been suggested with the latter interferon. In France, interferon beta-1b is now authorized in the relapsing forms of the disease. Initial results with copolymer I also suggest an effect on the frequency of relapses. Despite these major therapeutical efforts, further trials, possibly using new therapeutical approaches, are still needed. PMID- 8692773 TI - [Angiography of coronary arteries by nuclear magnetic resonance]. AB - OBJECTIVES: Evaluate magnetic resonance imaging of the coronary arteries. METHODS: The study was conducted in 18 healthy volunteers (mean age 26 years, range 22-32). A superconducting magnet operating at 1.5 Tesla was used with an in phase matrix surface coil. Images were obtained with 2D acquisition with flow compensation on ultra-rapid echo gradient sequences coupled with the electrocardiogram and segmentation of the Fourier plane. A coronary image was obtained during a 15 to 20 sec apnea. Frontal slices were used to identify cardiac structures before selecting axial slices starting from the origin of the aorta to the coronary ostia. Orthogonal, oblique and radial slices were then obtained starting from the axial slices. Slice thickness was 3 to 5 mm separated by 0.5 mm with a 30 degrees angle and a 320 mm field. Echo times were 5.8 and 10.3 msec with 2 excitations. Heart rate varied from 59 to 85 sec giving 15 to 18 ms repetition and 96 to 144 msec time resolution. RESULTS: The proximal, middle and disatal segments of the right coronary artery were seen in 100% of the subjects, the common left coronary artery in 100%, the proximal anterior interventricular artery in 83% and the proximal circumflex artery in 80%. All the coronary arteries were visualized on at least two slices with different incidences. The proximal measurements were: common trunk 3.75 +/- 0.66 mm; anterior interventricular 3.25 +/- 0.43 mm; circumflex 2.62 +/- 0.48; right coronary 3.37 +/- 0.51. CONCLUSION: Magnetic resonance angiography provides good visualization of the coronary arteries. PMID- 8692774 TI - [Painful rib syndrome (or Cyriax syndrome). Study of 100 patients]. AB - OBJECTIVE: To analyse clinical expression and outcome of painful rib syndrome in a large series of 100 cases. METHODS: From 1978 to 1993, 100 consecutive patients with chronic anterior chest pain or supramesocolic abdominal pain of unknown origin underwent complete physical examination, laboratory tests and complementary explorations as required. RESULTS: Among the first 100 patients the sex ratio was 3.34 and mean age 50.6 years (21-80). Chronic pain had persisted for an average 41.2 months (15 days-30 years), predominantly on the right (81%) and exceptionally bilaterally (1%). No evidence of a cause could be identified from laboratory tests or complementary explorations. A past history of direct trauma was found in 71 patients and indirect trauma in 21. Seventy-three patients were given 1% lidocaine infiltrations (20 to 40 ml) including 14 who received 2 or 3 infiltrations. Six patients underwent surgical resection of a luxated cartilage with curative effect in 5. CONCLUSION: The diagnosis of painful rib syndrome is based solely on the presence of pain upon applying pressure to the anteroinferior border of the rib cage and is related to often neglected or forgotten trauma. PMID- 8692775 TI - [Liver transplantation after exertion-induced heat stroke associated with fulminant liver failure]. AB - OBJECTIVES: Describe the course of fulminant liver failure after exertional heat stroke. CASE REPORT: A 30-year-old man acclimated to the tropical climate, collapsed and became comatose with hyperthermia during a commando march in Gabon. Thirty-six hours later, the biological examination revealed moderate rhabdomyolysis and fulminant liver failure. An orthotoptic liver transplantation was performed at the 48th hour. Acute renal failure with severe rhabdomyolysis developed on the 4th day post-surgery while the patient was perfectly alert. His condition thereafter deteriorated and he died of chronic rejection 11 months after liver transplantation. DISCUSSION: In its most serious forms exertional heat stroke is a multiple organ dysfunction syndrome of poorly understood pathogenesis. The reported case suggests that exertional heat stroke can cause fulminant liver failure, resulting either from the direct effect of heat on the hepatic parenchyma, or from acute hepatic ischemia due to blood redistribution made worse by the hypersecretion of antidiuretic hormone, a potent portal vasoconstrictor, which occurs in the heat acclimated subject. PMID- 8692776 TI - [Secretion of thyrotropin during states of wakefulness and sleep. Physiological data and clinical applications]. AB - Rhythmic hormone secretion appears to be a common characteristic of several endocrine systems. Alterations in these secretions are associated with the pathophysiology of certain diseases. Thyrotropin (TSH) exhibits a nocturnal surge in normal subjects. The time and the amplitude of the surge depend on the waking or the sleeping state. The TSH surge is decreased or abolished in various pathological conditions. Assessment of the surge is of particular interest for the early detection of central (pituitary) hypothyroidism, and in the exploration of isolated decreased TSH to predict further evolution toward hyperthyroidism. However, the characterization of the TSH surge needs simplification and standardization before this index could be used for the practical evaluation of thyroid function. PMID- 8692777 TI - [Inclusion body myositis]. AB - Inclusion body myositis has been recently recognized as a clinical entity although its exact definition remains uncertain. Initially considered to be an inflammatory dermatomyositis, inclusion body myositis can actually take on three specific forms: disseminated muscle atrophy and weakness, pseudopolymyositis, or pseudo-degenerative disease. Inclusion body myositis is different from non inflammatory neuromuscular diseases with vacuoles. Abnormal deposits are seen within the muscle fiber may contain amyloid substance, beta-amyloid precursor, ubiquitin, antichymotrypsin, protein tau, apolipoprotein E and even prions. The signification of these deposits is unknown. Deletions in mitochondrial DNA have been demonstrated but do not appear to play a causal role. More and more hereditary forms are being recognized and certain may be related to an abnormality in chromosome 9. PMID- 8692778 TI - [Intracytoplasmic injection of spermatozoa (ICSI). Ethical requirements and assessment]. AB - There is no doubt that the clinical application of intracytoplasmic sperm injection (ICSI) has been a major breakthrough in the treatment of extremely severe male-factor infertility. We analyzed the impact of ICSI on medically assisted reproduction practices. The potential of risks ICSI, whether related to abnormalities associated with male infertility, penetration within the ovocyte or the risk of introducing foreign material, should not be neglected. With ICSI, a situation of human experimentation has been created without adequate prior animal experimentation and research has been conducted without the approval of ethics committees as required by the Huriet Law in France. When first introduced, ICSI was not accompanied by an evaluation protocol to follow the biological risks and societal impact. We thus believe that meeting the requirements of the following ethical criteria deserves discussion. ICSI should still be considered as an experimental clinical procedure. Risk should be evaluated with animal models since all forms of spermatozoa can now be injected into mouse oocytes. Complete independence is needed for biological and genetic assessment, pediatric follow-up on children born and societal and health care impact. Scientific personnel as well as patients and the society in general should be continuously informed of the status of the evaluation work. As for any experimental therapy, the process of obtaining informed consent takes on special significance. Careful explanation of the procedure is needed so the patients can be in a position to determine what level of risk is acceptable. PMID- 8692779 TI - [Fetomaternal hemorrhage after cordocentesis]. PMID- 8692781 TI - [Myocardial infarction during amphetamine poisoning]. PMID- 8692780 TI - [Lipid pneumonia after aerosol therapy with gomenol in a 4-month-old child]. PMID- 8692782 TI - [Myopericarditis during hepatitis A]. PMID- 8692783 TI - [Mixed cryoglobulinemia caused by hepatitis C virus: how to treat it?]. PMID- 8692784 TI - [Urologic complications of multiple sclerosis. 180 cases]. AB - OBJECTIVES: The aim of this study was to assess frequency and importance of urological complications in multiple sclerosis. METHODS: A total of 180 patients with multiple sclerosis (115 women, 64 men; mean disease duration 13.4 years) underwent the following examinations: neuroperineal examination, bladder and kidney echography, intravenous pyelography, creatinine assay, urodynamic investigation and sphincter electromyography. RESULTS: Detrusor hyperreflexia (70%) and areflexia (15%) were the commonest findings on cystometry and correlated with clinical data (urinary incontinence in 62% and retention in 18%). Urologic complications were noted in 56% with benign lesions in 37% (diverticula, urinary infections) and serious lesions in 19% (hydronephrosis, pyelonephritis, renal reflux). No correlations were found between complications and dyssynergia, overactivity and urinary retention. CONCLUSIONS: The presence of these complications suggests the need for frequent urodynamic and radiologic controls in patients with multiple sclerosis. PMID- 8692785 TI - [Audit of the management of postoperative pain]. AB - OBJECTIVE: The aim of this study was to assess the incidence and severity of postoperative pain in patients undergoing operations in various surgery clinics in the Assistance Publique des Hopitaux de Paris (AP-HP) and to evaluate management of pain during the 24 hours following surgery. METHODS: Data from surgical and anesthesia observation sheets and from patient complaints collected in a one-day external audit were obtained for 96 surgery clinics in the AP-HP. RESULTS: At the time of surgery, most patients were receiving opioids, especially fentanyl: low dose ( < 1 microgram/kg/h) was given in 17.1% of the patients and regional anesthesia was used in 13%. In 95% of the cases, postoperative orders were written by anesthesiologists. Initial orders were modified according to patient response in 11.8% of the cases. "On demand" prescriptions were used in 10% of the orders. Patient controlled analgesia and regional analgesia were not routine techniques (2 and 0% respectively). Finally, 37.8% of the patients were given a single prescription of a step-1 drug (e.g. propacetamol i.v.), 25.9% a step-2 drug either alone or in combination with a step-1 drug, and 28.9% of the patients were given strong opioids at least once. CONCLUSIONS: For all types of drugs, dosage level was considered as correct in 86.5% of the cases. For approximately 10% of the opioid prescriptions, an ineffective dose was used. The interval between doses was too long in 54.1% of the prescriptions for at least one drug (e.g. for peripheral analgesia with propacetamol). The incidence of severe pain was 46.4%, especially after abdominal, high urologic and back surgery. PMID- 8692786 TI - [Decreasing incidence of HIV infection in intravenous drug users in Aquitaine: 1985-1993]. AB - OBJECTIVE: To describe trends in the incidence of HIV infection diagnosis since 1985 in different at-risk groups in Aquitaine, south-west France. METHODS: We analyzed the data from two regional surveillance systems on HIV infection: the hospital-based system of the Groupe d'Epidemiologie Clinique du SIDA en Aquitaine (GECSA) and the laboratory-based system of the Observatoire Regional de la Sante d'Aquitaine (ORSA). The number of intravenous drug users (IVDUs) in Aquitaine was estimated from two sources: a study performed by the GECSA in IVDUs treatment centers (1990-1991 data) and the annual surveys undertaken by the Ministry of Health (SESI) in all the health facilities and social services of the region from 1988 to 1993. RESULTS: As of December 31st, 1993, 3478 HIV-infected patients had been reported to the GECSA, including 3031 Aquitaine residents. Among those, 1096 were IVDUs without any other at-risk behavior (36.2%), the largest transmission category. The annual incidence of HIV diagnoses has steadily and considerably changed over time for IVDUs: 175 new cases diagnosed in 1985, 218 in 1987, then falling to 38 in 1993. During the same period, there was no marked decrease for homosexuals and the incidence of diagnoses of heterosexually-acquired HIV infections increased. Between 1989 and 1993, the number of HIV tests performed by the laboratories involved in the ORSA surveillance system increased steadily from 80,310 to 176,250 per year, when the number of first positive tests in Aquitaine residents decreased from 744 to 319 per year (-57%). This decrease was greater for IVDUs (-80%) than for the other groups. The survey performed by the GECSA estimated that 990 IVDUs were followed annually by treatment centres in Aquitaine in 1990-1991. This figure was stable and in agreement with the results of the SESI surveys performed throughout the period. CONCLUSION: The incidence of new diagnoses of HIV infection has been decreasing in Aquitaine since 1988, particularly among IVDUs, suggesting that the epidemic is slowing down. It is essential to maintain these systems of epidemiological surveillance as a component of the HIV prevention program. PMID- 8692787 TI - [Immunoprophylaxis of rabies: current recommendations]. AB - Pre-exposure rabies vaccination should comprise 3 injections (day 0, day 7, day 28) followed by boosters 1 year later then every 5 years. Populations who are particularly exposed due to occupation, regular contact with animals in endemic areas during leisure activities or holidays should be vaccinated, especially if access to post-exposure treatment is difficult. Post-exposure treatment should comprise 5 injections (day 0, day 3, day 7, day 14, day 28) which must be given with specific immunoglobulins on day 0 if there are penetrating wounds. In persons whose prior vaccination status is well-documented and correctly maintained, post-exposure treatment may be limited to 2 injections on day 0 and day 3. The vaccine is given is intramuscular injection in the deltoid region. Immunoglobulins are used at the dose of 20 IU/kg for human immunoglobulins and at 40 IU/kg for horse immunoglobulins. The injections are infiltrated around the lesions and the remaining quantity injected in the gluteus muscle. Seroconversion must be monitored by assaying neutralizing antibodies (titre > or = 0.5 IU/ml with the RFFI Test) in vaccinated populations who regularly exposed. Monitoring can also be useful after post-exposure treatment in certain specific cases (immunosuppressed subjects, treatment protocol incorrectly or incompletely applied). An antibody titre under 0.5 IU/ml requires an immediate vaccine injection. PMID- 8692788 TI - [Presentation by the GRECO group of the French adaptation of a cognitive assessment scale used in Alzheimer type dementia]. AB - A consensus group on cognitive evaluation in clinical research, the GRECO, carried out a French adaptation of the American ADAS. This "unique and consensual" version answers the purposes of the original version, taking into account the constraints and customs of the French language. After presenting the ADAS-cog rating scale, the principles underlying its design, and its various items, a review of the literature is proposed. This review deals with the ADAS as a diagnosis and assessment tool to evaluate both spontaneous evolution of dementia of Alzheimer's type and drug efficacy in clinical trials. PMID- 8692789 TI - [Mechanisms and treatment of primary type I hyperoxaluria]. AB - Type I primary hyperoxaluria is an uncommon disease related to alanine glyoxylate aminotransferase (AGT) deficiency, an exclusively hepatic enzyme. AGT deficiency leads to an overproduction of oxalate in the liver and consequent hyperoxalemia and massive hyperoxaluria with renal failure. The diagnosis is confirmed by needle biopsy of the kidney showing the exact nature of the enzyme deficiency. When terminal renal failure has developed there are two therapeutic possibilities: kidney graft or a double liver-kidney graft. Kidney graft alone is often insufficient and carries the risk of recurrent disease in the graft since the liver disorder has not been corrected. Inversely, combined liver-kidney graft can not only replace the destroyed kidneys but also correct the metabolic disorder through the effect of the AGT in the donor liver. Although this approach may be successful, it is a very aggressive procedure with high mortality. PMID- 8692790 TI - [Aneurysm developed at the level of a femoropopliteal bypass with ex-situ venous graft 10 years later]. PMID- 8692792 TI - [Memory consultation without medical prescription]. PMID- 8692791 TI - [Autotransfusion using erythropoietin in patients under chronic hemodialysis. 2 cases]. PMID- 8692793 TI - [Toxic dermatitis caused by heparin]. PMID- 8692795 TI - Role of recombination enzymes in mammalian cell survival. PMID- 8692794 TI - Reflections on STAT3, STAT5, and STAT6 as fat STATs. PMID- 8692796 TI - Archaeal ubiquity. PMID- 8692797 TI - Defective STAT signaling by the leptin receptor in diabetic mice. AB - Leptin and its receptor, obese receptor (OB-R), comprise an important signaling system for the regulation of body weight. Splice variants of OB-R mRNA encode proteins that differ in the length of their cytoplasmic domains. We cloned a long isoform of the wild-type leptin receptor that is preferentially expressed in the hypothalamus and show that it can activate signal transducers and activators of transcription (STAT)-3, STAT-5, and STAT-6. A point mutation within the OB-R gene of diabetic (db) mice generates a new splice donor site that dramatically reduces expression of this long isoform in homozygous db/db mice. In contrast, an OB-R protein with a shorter cytoplasmic domain is present in both db/db and wild-type mice. We show that this short isoform is unable to activate the STAT pathway. These data provide further evidence that the mutation in OB-R causes the db/db phenotype and identify three STAT proteins as potential mediators of the anti obesity effects of leptin. PMID- 8692798 TI - Targeted disruption of the Rad51 gene leads to lethality in embryonic mice. AB - The mouse Rad51 gene is a mammalian homologue of the Escherichia coli recA and yeast RAD51 genes, both of which are involved in homologous recombination and DNA repair. To elucidate the physiological role of RAD51 protein, the gene was targeted in embryonic stem (ES) cells. Mice heterozygous for the Rad51 null mutation were intercrossed and their offspring were genotyped. There were no homozygous (Rad51-/-) pups among 148 neonates examined but a few Rad51-/- embryos were identified when examined during the early stages of embryonic development. Doubly knocked-out ES cells were not detected under conditions of selective growth. These results are interpreted to mean that RAD51 protein plays an essential role in the proliferation of cell. The homozygous Rad51 null mutation can be categorized in cell-autonomous defects. Pre-implantational lethal mutations that disrupt basic molecular functions will thus interfere with cell viability. PMID- 8692799 TI - A psychrophilic crenarchaeon inhabits a marine sponge: Cenarchaeum symbiosum gen. nov., sp. nov. AB - Archaea, one of the three major domains of extant life, was thought to comprise predominantly microorganisms that inhabit extreme environments, inhospitable to most Eucarya and Bacteria. However, molecular phylogenetic surveys of native microbial assemblages are beginning to indicate that the evolutionary and physiological diversity of Archaea is far greater than previously supposed. We report here the discovery and preliminary characterization of a marine archaeon that inhabits the tissues of a temperate water sponge. The association was specific, with a single crenarchaeal phylotype inhabiting a single sponge host species. To our knowledge, this partnership represents the first described symbiosis involving Crenarchaeota. The symbiotic archaeon grows well at temperatures of 10 degrees C, over 60 degrees C below the growth temperature optimum of any cultivated species of Crenarchaeota. Archaea have been generally characterized as microorganisms that inhabit relatively circumscribed niches, largely high-temperature anaerobic environments. In contrast, data from molecular phylogenetic surveys, including this report, suggest that some crenarchaeotes have diversified considerably and are found in a wide variety of lifestyles and habitats. We present here the identification and initial description of Cenarchaeum symbiosum gen. nov., sp. nov., a symbiotic archaeon closely related to other nonthermophilic crenarchaeotes that inhabit diverse marine and terrestrial environments. PMID- 8692800 TI - Dynamic contrast-enhanced magnetic resonance imaging reveals stress-induced angiogenesis in MCF7 human breast tumors. AB - The mechanism of contrast enhancement of tumors using magnetic resonance imaging was investigated in MCF7 human breast cancer implanted in nude mice. Dynamic contrast-enhanced images recorded at high spatial resolution were analyzed by an image analysis method based on a physiological model, which included the blood circulation, the tumor, the remaining tissues, and clearance via the kidneys. This analysis enabled us to map in rapidly enhancing regions within the tumor, the capillary permeability factor (capillary permeability times surface area per voxel volume) and the fraction of leakage space. Correlation of these maps with T2-weighted spin echo images, with histopathology, and with immunohistochemical staining of endothelial cells demonstrated the presence of dense permeable microcapillaries in the tumor periphery and in intratumoral regions that surrounded necrotic loci. The high leakage from the intratumoral permeable capillaries indicated an induction of a specific angiogenic process associated with stress conditions that cause necrosis. This induction was augmented in tumors responding to tamoxifen treatment. Determination of the distribution and extent of this stress-induced angiogenic activity by contrast-enhanced MRI might be of diagnostic and of prognostic value. PMID- 8692801 TI - Structural analysis of p185c-neu and epidermal growth factor receptor tyrosine kinases: oligomerization of kinase domains. AB - The epidermal growth factor receptor (EGFR) and p185c-neu proteins associate as dimers to create an efficient signaling assembly. Overexpression of these receptors together enhances their intrinsic kinase activity and concomitantly results in oncogenic cellular transformation. The ectodomain is able to stabilize the dimer, whereas the kinase domain mediates biological activity. Here we analyze potential interactions of the cytoplasmic kinase domains of the EGFR and p185c-neu tyrosine kinases by homology molecular modeling. This analysis indicates that kinase domains can associate as dimers and, based on intermolecular interaction calculations, that heterodimer formation is favored over homodimers. The study also predicts that the self-autophosphorylation sites located within the kinase domains are not likely to interfere with tyrosine kinase activity, but may regulate the selection of substrates, thereby modulating signal transduction. In addition, the models suggest that the kinase domains of EGFR and p185c-neu can undergo higher order aggregation such as the formation of tetramers. Formation of tetrameric complexes may explain some of the experimentally observed features of their ligand affinity and hetero-receptor internalization. PMID- 8692802 TI - Fatal embryonic bleeding events in mice lacking tissue factor, the cell associated initiator of blood coagulation. AB - Tissue factor (TF) is the cellular receptor for coagulation factor VI/VIIa and is the membrane-bound glycoprotein that is generally viewed as the primary physiological initiator of blood coagulation. To define in greater detail the physiological role of TF in development and hemostasis, the TF gene was disrupted in mice. Mice heterozygous for the inactivated TF allele expressed approximately half the TF activity of wild-type mice but were phenotypically normal. However, homozygous TF-/- pups were never born in crosses between heterozygous mice. Analysis of mid-gestation embryos showed that TF-/- embryos die in utero between days 8.5 and 10.5. TF-/- embryos were morphologically distinct from their TF+/+ and TF+/- littermates after day 9.5 in that they were pale, edematous, and growth retarded. Histological studies showed that early organogenesis was normal. The initial failure in TF-/- embryos appeared to be hemorrhaging, leading to the leakage of embryonic red cells from both extraembryonic and embryonic vessels. These studies indicate that TF plays an indispensable role in establishing and/or maintaining vascular integrity in the developing embryo at a time when embryonic and extraembryonic vasculatures are fusing and blood circulation begins. PMID- 8692803 TI - Probing the interaction between two single molecules: fluorescence resonance energy transfer between a single donor and a single acceptor. AB - We extend the sensitivity of fluorescence resonance energy transfer (FRET) to the single molecule level by measuring energy transfer between a single donor fluorophore and a single acceptor fluorophore. Near-field scanning optical microscopy (NSOM) is used to obtain simultaneous dual color images and emission spectra from donor and acceptor fluorophores linked by a short DNA molecule. Photodestruction dynamics of the donor or acceptor are used to determine the presence and efficiency of energy transfer. The classical equations used to measure energy transfer on ensembles of fluorophores are modified for single molecule measurements. In contrast to ensemble measurements, dynamic events on a molecular scale are observable in single pair FRET measurements because they are not canceled out by random averaging. Monitoring conformational changes, such as rotations and distance changes on a nanometer scale, within single biological macromolecules, may be possible with single pair FRET. PMID- 8692804 TI - Retinal engineering: engrafted neural cell lines locate in appropriate layers. AB - A major question in central nervous system development, including the neuroretina, is whether migrating cells express cues to find their way and settle at specific locations. We have transplanted quail neuroretinal cell lines QNR/D, a putative amacrine or ganglion cell, and QNR/K2, a putative Muller cell into chicken embryo eyes. Implanted QNR/D cells migrate only to the retinal ganglion and amacrine cell layers and project neurites in the plane of retina; in contrast, QNR/K2 cells migrate through the ganglion and amacrine layers, locate in the inner nuclear layer, and project processes across the retina. These data show that QNR/D and QNR/K2 cell lines represent distinct neural cell types, suggesting that migrating neural cells express distinct address cues. Furthermore, our results raise the possibility that immortalized cell lines can be used for replacement of specific cell types and for the transport of genes to given locations in neuroretina. PMID- 8692805 TI - Disruption of the MacMARCKS gene prevents cranial neural tube closure and results in anencephaly. AB - MacMARCKS is a member of the MARCKS family of protein kinase C (PKC) substrates. Biochemical evidence demonstrates that these proteins integrate calcium and PKC dependent signals to regulate actin structure at the membrane. We report here that deletion of the MacMARCKS gene prevents cranial neural tube closure in the developing brain, resulting in anencephaly. This suggests a central role for MacMARCKS and the PKC signal transduction pathway in the folding of the anterior neural plate during the early phases of brain formation, and supports the hypothesis that actin-based motility directs cranial neural tube closure. PMID- 8692806 TI - A melanoma-specific VH antibody cloned from a fusion phage library of a vaccinated melanoma patient. AB - The human antimelanoma antibody V86 was cloned from a single-chain Fv molecule (scFv) fusion phage library displaying the heavy chain variable domain (VH) and light chain variable domain (VL.) repertoire of a melanoma patient immunized with genetically-modified autologous tumor cells. Previous ELISA tests for binding of the V86 fusion phage to a panel of human metastatic melanoma and carcinoma cell lines and primary cultures of normal melanocytes, endothelial, and fibroblast cells showed that measurable binding occurred only to the melanoma cells. In this communication, the strict specificity of V86 for melanoma cells was confirmed by immunohistochemical staining tests with cultured cells and frozen tissue sections. The V86 fusion phage stained melanoma cell lines but did not stain carcinoma cell lines or cultured normal cells; V86 also stained specifically the melanoma cells in sections of metastatic tissue but did not stain any of the cells in sections from normal skin, lung, and kidney or from metastatic colon and ovarian carcinomas and a benign nevus. An unexpected finding is that V86 contains a complete VH domain but only a short segment of a VL, domain, which terminates before the CDR1 region. This VL deletion resulted from the occurrence in the VL cDNA of a restriction site, which was cleaved during construction of the scFv library. Thus V86 is essentially a VH antibody. The effect of adding a VI. domain to V86 was examined by constructing scFv fusion phage libraries in which V86 was coupled to Vlambda or Vkappa domains from the original scFv library of the melanoma patient and then panning the libraries against melanoma cells to enrich for the highest affinity antibody clones. None of the V86-Vlambda clones showed significant binding to melanoma cells in ELISA tests; although binding occurred with most of the V86-Vkappa clones, it was generally weaker than the binding of V86. These results indicate that most of the VL domains in the original scFv library reduce or eliminate the affinity of V86 for melanoma cells. Accordingly, VH libraries could provide access to anti-tumor antibodies that might not be detected in scFv or Fab libraries because of the incompatibility of most randomly paired VH and VL, domains. PMID- 8692807 TI - Assembly and movement of a plant virus carrying a green fluorescent protein overcoat. AB - Potato virus X (PVX) is a filamentous plant virus infecting many members of the family Solanaceae. A modified form of PVX, PVX.GFP-CP which expressed a chimeric gene encoding a fusion between the 27-kDa Aequorea victoria green fluorescent protein and the amino terminus of the 25-kDa PVX coat protein, assembled into virions and moved both locally and systemically. The PVX.GFP-CP virions were over twice the diameter of wild-type PVX virions. Assembly of PVX.GFP-CP virions required the presence of free coat protein subunits in addition to the fusion protein subunits. PVX.GFP-CP virions accumulated as paracrystalline arrays in infected cells similar to those seen in cells infected with wild-type PVX The formation of virions carrying large superficial fusions illustrates a novel approach for production of high levels of foreign proteins in plants. Aggregates of PVX.GFP-CP particles were fluorescent, emitting green light when excited with ultraviolet light and could be imaged using confocal laser scanning microscopy. The detection of virus particles in infected tissue demonstrates the potential of fusions between the green fluorescent protein and virus coat protein for the non invasive study of virus multiplication and spread. PMID- 8692808 TI - Gene gun-mediated skin transfection with interleukin 12 gene results in regression of established primary and metastatic murine tumors. AB - Particle-mediated (gene gun) in vivo delivery of the murine interleukin 12 (IL 12) gene in an expression plasmid was evaluated for antitumor activity. Transfer of IL-12 cDNA into epidermal cells overlying an implanted intradermal tumor resulted in detectable levels (266.0 +/- 27.8 pg) of the transgenic protein at the skin tissue treatment site. Despite these low levels of transgenic IL-12, complete regression of established tumors (0.4-0.8 cm in diameter) was achieved in mice bearing Renca, MethA, SA-1, or L5178Y syngeneic tumors. Only one to four treatments with IL-12 cDNA-coated particles, starting on day 7 after tumor cell implantation, were required to achieve complete tumor regression. This antitumor effect was CD8+ T cell-dependent and led to the generation of tumor-specific immunological memory. By using a metastatic P815 tumor model, we further showed that a delivery of IL-12 cDNA into the skin overlying an advanced intradermal tumor, followed by tumor excision and three additional IL-12 gene transfections, could significantly inhibit systemic metastases, resulting in extended survival of test mice. These results suggest that gene gun-mediated in vivo delivery of IL 12 cDNA should be further developed for potential clinical testing as an approach for human cancer gene therapy. PMID- 8692809 TI - A bacterial artificial chromosome-based framework contig map of human chromosome 22q. AB - We have constructed a physical map of human chromosome 22q using bacterial artificial chromosome (BAC) clones. The map consists of 613 chromosome 22 specific BAC clones that have been localized and assembled into contigs using 452 landmarks, 346 of which were previously ordered and mapped to specific regions of the q arm of the chromosome by means of chromosome 22-specific yeast artificial chromosome clones. The BAC-based map provides immediate access to clones that are stable and convenient for direct genome analysis. The approach to rapidly developing marker-specific BAC contigs is relatively straightforward and can be extended to generate scaffold BAC contig maps of the rest of the chromosomes. These contigs will provide substrates for sequencing the entire human genome. We discuss how to efficiently close contig gaps using the end sequences of BAC clone inserts. PMID- 8692810 TI - A new isoleucine substitution of Val-20 in transthyretin tetramers selectively impairs dimer-dimer contacts and causes systemic amyloidosis. AB - The most frequent form of inherited amyloidoses is associated with mutations in the transthyretin (TTR) gene coding for 127-amino acid residues of four identical, noncovalently linked subunits that form a pair of dimers in the plasma protein complex. Amyloid fibrils containing the variant and to a lesser extent the wild-type form of the TTR molecule are deposited in various organs, including peripheral nerves and the myocardium, with polyneuropathy and cardiomyopathy as major clinical manifestations. So far, more than 40 distinct amino acid substitutions distributed throughout the TTR sequence over 30 positions have been found to be correlated with an increased amyloidogenicity of TTR. Most of these amyloidogenic amino acid substitutions are suspected to alter the conformation and stability of the monomer. Here we identify and characterize by protein and DNA analysis a novel amyloidogenic Val-20 to Ile mutation in a German three generation family. The index patient suffered from severe amyloid cardiomyopathy at the age of 60. Conformational stability and unfolding behavior of the Ile-20 monomer in urea gradients was found to be almost indistinguishable from that of wild-type TTR. In contrast, tetramer stability was significantly reduced in agreement with the expected change in the interactions between the two opposing dimers via the side chain of Ile-20. Our observations provide strong evidence for the view that amyloidogenic amino acid substitutions in TTR facilitate the conversion of tetrameric TTR complexes into those conformational intermediates of the TTR folding pathway that have an intrinsic amyloidogenic potential. PMID- 8692811 TI - Structural basis for selectivity of the isoquinoline sulfonamide family of protein kinase inhibitors. AB - A large family of isoquinoline sulfonamide compounds inhibits protein kinases by competing with adenosine triphosphates(ATP), yet interferes little with the activity of other ATP-using enzymes such as ATPases and adenylate cyclases. One such compound, N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide (CK17), is selective for casein kinase-1 isolated from a variety of sources. Here we report the crystal structure of the catalytic domain of Schizosaccharomyces pombe casein kinase-1 complexed with CK17, refined to a crystallographic R-factor of 17.8% at 2.5 angstrom resolution. The structure provides new insights into the mechanism of the ATP-competing inhibition and the origin of their selectivity toward different protein kinases. Selectivity for protein kinases versus other enzymes is achieved by hydrophobic contacts and the hydrogen bond with isoquinoline ring. We propose that the hydrogen bond involving the ring nitrogen-2 atom of the isoquinoline must be preserved, but that the ring can flip depending on the chemical substituents at ring positions 5 and 8. Selectivity for individual members of the protein kinase family is achieved primarily by interactions with these substituents. PMID- 8692812 TI - Cell cycle regulation and cell type-specific localization of the FtsZ division initiation protein in Caulobacter. AB - Many genes involved in cell division and DNA replication and their protein products have been identified in bacteria; however, little is known about the cell cycle regulation of the intracellular concentration of these proteins. It has been shown that the level of the tubulin-like GTPase FtsZ is critical for the initiation of cell division in bacteria. We show that the concentration of FtsZ varies dramatically during the cell cycle of Caulobacter crescentus. Caulobacter produce two different cell types at each cell division: (i) a sessile stalked cell that can initiate DNA replication immediately after cell division and (ii) a motile swarmer cell in which DNA replication is blocked. After cell division, only the stalked cell contains FtsZ. FtsZ is synthesized slightly before the swarmer cells differentiate into stalked cells and the intracellular concentration of FtsZ is maximal at the beginning of cell division. Late in the cell cycle, after the completion of chromosome replication, the level of FtsZ decreases dramatically. This decrease is probably mostly due to the degradation of FtsZ in the swarmer compartment of the predivisional cell. Thus, the variation of FtsZ concentration parallels the pattern of DNA synthesis. Constitutive expression of FtsZ leads to defects in stalk biosynthesis suggesting a role for FtsZ in this developmental process in addition to its role in cell division. PMID- 8692813 TI - Molecular cloning of violaxanthin de-epoxidase from romaine lettuce and expression in Escherichia coli. AB - Plants need to avoid or dissipate excess light energy to protect photosystem II (PSII) from photoinhibitory damage. Higher plants have a conserved system that dissipates excess energy as heat in the light-harvesting complexes of PSII that depends on the transthylakoid delta pH and violaxanthin de-epoxidase (VDE) activity. To our knowledge, we report the first cloning of a cDNA encoding VDE and expression of functional enzyme in Escherichia coli. VDE is nuclear encoded and has a transit peptide with characteristic features of other lumen-localized proteins. The cDNA encodes a putative polypeptide of 473 aa with a calculated molecular mass of 54,447 Da. Cleavage of the transit peptide results in a mature putative polypeptide of 348 aa with a calculated molecular mass of 39,929 Da, close to the apparent mass of the purified enzyme (43 kDa). The protein has three interesting domains including (i) a cysteine-rich region, (ii) a lipocalin signature, and (iii) a highly charged region. The E. coli expressed enzyme de epoxidizes violaxanthin sequentially to antheraxanthin and zeaxanthin, and is inhibited by dithiothreitol, similar to VDE purified from chloroplasts. This confirms that the cDNA encodes an authentic VDE of a higher plant and is unequivocal evidence that the same enzyme catalyzes the two-step mono de epoxidation reaction. The cloning of VDE opens new opportunities for examining the function and evolution of the xanthophyll cycle, and possibly enhancing light stress tolerance of plants. PMID- 8692814 TI - Inhibitors of HIV-1 replication [corrected; erratum to be published] that inhibit HIV integrase. AB - HIV-1 replication depends on the viral enzyme integrase that mediates integration of a DNA copy of the virus into the host cell genome. This enzyme represents a novel target to which antiviral agents might be directed. Three compounds, 3,5 dicaffeoylquinic acid, 1-methoxyoxalyl-3,5-dicaffeoylquinic acid, and L-chicoric acid, inhibit HIV-1 integrase in biochemical assays at concentrations ranging from 0.06-0.66 microgram/ml; furthermore, these compounds inhibit HIV-1 replication in tissue culture at 1-4 microgram/ml. The toxic concentrations of these compounds are fully 100-fold greater than their antiviral concentrations. These compounds represent a potentially important new class of antiviral agents that may contribute to our understanding of the molecular mechanisms of viral integration. Thus, the dicaffeoylquinic acids are promising leads to new anti-HIV therapeutics and offer a significant advance in the search for new HIV enzyme targets as they are both specific for HIV-1 integrase and active against HIV-1 in tissue culture. PMID- 8692815 TI - Primary structure and expression of a pathogen-induced protease (PR-P69) in tomato plants: Similarity of functional domains to subtilisin-like endoproteases. AB - A 69-kDa proteinase (P69), a member of the pathogenesis-related proteins, is induced and accumulates in tomato (Lycopersicon esculentum) plants as a consequence of pathogen attack. We have used the polymerase chain reaction to identify and clone a cDNA from tomato plants that represent the pathogenesis related P69 proteinase. The nucleotide sequence analysis revealed that P69 is synthesized in a preproenzyme form, a 745-amino acid polypeptide with a 22-amino acid signal peptide, a 92-amino acid propolypeptide, and a 631-amino acid mature polypeptide. Within the mature region the most salient feature was the presence of domains homologous to the subtilisin serine protease family. The amino acid sequences surrounding Asp-146, His-203, and Ser-532 of P69 are closely related to the catalytic sites (catalytic triad) of the subtilisin-like proteases. Northern blot analysis revealed that the 2.4-kb P69 mRNA accumulates abundantly in leaves and stem tissues from viroid-infected plants, whereas the mRNA levels in tissues from healthy plants were undetectable. Our results indicate that P69, a secreted calcium-activated endopeptidase, is a plant pathogenesis-related subtilisin-like proteinase that may collaborate with other defensive proteins in a general mechanism of active defense against attacking pathogens. PMID- 8692816 TI - The precursor of PsaD assembles into the photosystem I complex in two steps. AB - The present study addresses the assembly in the chloroplast thylakoid membranes of PsaD, a peripheral membrane protein of the photosystem I complex. Located on the stromal side of the thylakoids, PsaD was found to assemble in vitro into the membranes in its precursor (pre-PsaD) and also in its mature (PsaD) form. Newly assembled unprocessed pre-PsaD was resistant to NaBr and alkaline wash. Yet it was sensitive to proteolytic digestion. In contradistinction, when the assembled precursor was processed, the resulting mature PsaD was resistant to proteases to the same extent as endogenous [correction of endogeneous] PsaD. The accumulation of protease-resistant PsaD in the thylakoids correlated with the increase of mature-PsaD in the membranes. This protection of mature PsaD from proteolysis could not be observed when PsaD was in a soluble form-i.e. not assembled within the thylakoids. The data suggest that pre-PsaD assembles to the membranes and only in a second step processing takes place. The observation that the assembly of pre-PsaD is affected by salts to a much lesser extent than that of mature-PsaD supports a two-step assembly of pre-PsaD. PMID- 8692818 TI - Construction of an improved mycoinsecticide overexpressing a toxic protease. AB - Mycoinsecticides are being used for the control of many insect pests as an environmentally acceptable alternative to chemical insecticides. A key aim of much recent work has been to increase the speed of kill and so improve commercial efficacy of these biocontrol agents. This might he achieved by adding insecticidal genes to the fungus, an approach considered to have enormous potential for the improvement of biological pesticides. We report here the development of a genetically improved entomopathogenic fungus. Additional copies of the gene encoding a regulated cuticle-degrading protease (Pr1) from Metarhizium anisopliae were inserted into the genome of M. anisopliae such that Pr1 was constitutively overproduced in the hemolymph of Manduca sexta, activating the prophenoloxidase system. The combined toxic effects of Pr1 and the reaction products of phenoloxidase caused larvae challenged with the engineered fungus to exhibit a 25% reduction in time of death and reduced food consumption by 40% compared to infections by the wild-type fungus. In addition, infected insects were rapidly melanized, and the resulting cadavers were poor substrates for fungal sporulation. Thus, environmental persistence of the genetically engineered fungus is reduced, thereby providing biological containment. PMID- 8692817 TI - Cystic fibrosis gene encodes a cAMP-dependent chloride channel in heart. AB - cAMP-dependent chloride channels in heart contribute to autonomic regulation of action potential duration and membrane potential and have been inferred to be due to cardiac expression of the epithelial cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. In this report, a cDNA from rabbit ventricle was isolated and sequenced, which encodes an exon 5 splice variant (exon 5-) of CFTR, with >90% identity to human CFTR cDNA present in epithelial cells. Expression of this cDNA in Xenopus oocytes gave rise to robust cAMP-activated chloride currents that were absent in control water-injected oocytes. Antisense oligodeoxynucleotides directed against CFTR significantly reduced the density of cAMP-dependent chloride currents in acutely cultured myocytes, thereby establishing a direct functional link between cardiac expression of CFTR protein and an endogenous chloride channel in native cardiac myocytes. PMID- 8692819 TI - Long-term functional recovery from age-induced spatial memory impairments by nerve growth factor gene transfer to the rat basal forebrain. AB - Nerve growth factor (NGF) stimulates functional recovery from cognitive impairments associated with aging, either when administered as a purified protein or by means of gene transfer to the basal forebrain. Because gene transfer procedures need to be tested in long-term experimental paradigms to assess their in vivo efficiency, we have used ex vivo experimental gene therapy to provide local delivery of NGF to the aged rat brain over a period of 2.5 months by transplanting immortalized central nervous system-derived neural stem cells genetically engineered to secrete NGF. By grafting them at two independent locations in the basal forebrain, medial septum and nucleus basalis magnocellularis, we show that functional recovery as assessed in the Morris water maze can be achieved by neurotrophic stimulation of any of these cholinergic cell groups. Moreover, the cholinergic neurons in the grafted regions showed a hypertrophic response resulting in a reversal of the age-associated atrophy seen in the learning-impaired aged control rats. Long-term expression of the transgene lead to an increased NGF tissue content (as determined by NGF-ELISA) in the transplanted regions up to at least 10 weeks after grafting. We conclude that the gene transfer procedure used here is efficient to provide the brain with a long lasting local supply of exogenous NGF, induces long-term functional recovery of cognitive functions, and that independent trophic stimulation of the medial septum or nucleus basalis magnocellularis has similar consequences at the behavioral level. PMID- 8692820 TI - Targeted deletion in astrocyte intermediate filament (Gfap) alters neuronal physiology. AB - Glial fibrillary acidic protein (GFAP) is a member of the family of intermediate filament structural proteins and is found predominantly in astrocytes of the central nervous system (CNS). To assess the function of GFAP, we created GFAP null mice using gene targeting in embryonic stem cells. The GFAP-null mice have normal development and fertility, and show no gross alterations in behavior or CNS morphology. Astrocytes are present in the CNS of the mutant mice, but contain a severely reduced number of intermediate filaments. Since astrocyte processes contact synapses and may modulate synaptic function, we examined whether the GFAP null mice were altered in long-term potentiation in the CA1 region of the hippocampus. The GFAP-null mice displayed enhanced long-term potentiation of both population spike amplitude and excitatory post-synaptic potential slope compared to control mice. These data suggest that GFAP is important for astrocyte-neuronal interactions, and that astrocyte processes play a vital role in modulating synaptic efficacy in the CNS. These mice therefore represent a direct demonstration that a primary defect in astrocytes influences neuronal physiology. PMID- 8692821 TI - IA-2, a transmembrane protein of the protein tyrosine phosphatase family, is a major autoantigen in insulin-dependent diabetes mellitus. AB - IA-2 is a 105,847 Da transmembrane protein that belongs to the protein tyrosine phosphatase family. Immunoperoxidase staining with antibody raised against IA-2 showed that this protein is expressed in human pancreatic islet cells. In this study, we expressed the full-length cDNA clone of IA-2 in a rabbit reticulocyte transcription/translation system and used the recombinant radiolabeled IA-2 protein to detect autoantibodies by immunoprecipitation. Coded sera (100) were tested: 50 from patients with newly diagnosed insulin-dependent diabetes mellitus (IDDM) and 50 from age-matched normal controls. Sixty-six percent of the sera from patients, but none of the sera from controls, reacted with IA-2. The same diabetic sera tested for autoantibodies to islet cells (ICA) by indirect immunofluorescence and glutamic acid decarboxylase (GAD65Ab) by depletion ELISA showed 68% and 52% positivity, respectively. Up to 86% of the IDDM patients had autoantibodies to IA-2 and/or GAD65. Moreover, greater than 90% (14 of 15) of the ICA-positive but GAD65Ab-negative sera had autoantibodies to IA-2. Absorption experiments showed that the immunofluorescence reactivity of ICA-positive sera was greatly reduced by prior incubation with recombinant IA-2 or GAD65 when the respective antibody was present. A little over one-half (9 of 16) of the IDDM sera that were negative for ICA were found to be positive for autoantibodies to IA-2 and/or GAD65, arguing that the immunofluorescence test for ICA is less sensitive than the recombinant tests for autoantibodies to IA-2 and GAD65. It is concluded that IA-2 is a major islet cell autoantigen in IDDM, and, together with GAD65, is responsible for much of the reactivity of ICA with pancreatic islets. Tests for the detection of autoantibodies to recombinant IA-2 and GAD65 may eventually replace ICA immunofluorescence for IDDM population screening. PMID- 8692822 TI - Dynamic methylation adjustment and counting as part of imprinting mechanisms. AB - Monoallelic expression in diploid mammalian cells appears to be a widespread phenomenon, with the most studied examples being X-chromosome inactivation in eutherian female cells and genomic imprinting in the mouse and human. Silencing and methylation of certain sites on one of the two alleles in somatic cells is specific with respect to parental source for imprinted genes and random for X linked genes. We report here evidence indicating that: (i) differential methylation patterns of imprinted genes are not simply copied from the gametes, but rather established gradually after fertilization; (ii) very similar methylation patterns are observed for diploid, tetraploid, parthenogenic, and androgenic preimplantation mouse embryos, as well as parthenogenic and androgenic mouse embryonic stem cells; (iii) haploid parthenogenic embryos do not show methylation adjustment as seen in diploid or tetraploid embryos, but rather retain the maternal pattern. These observations suggest that differential methylation in imprinted genes is achieved by a dynamic process that senses gene dosage and adjusts methylation similar to X-chromosome inactivation. PMID- 8692823 TI - A point mutation in the HIV-1 Tat responsive element is associated with postintegration latency. AB - Study of the mechanism of HIV-1 postintegration latency in the ACH2 cell line demonstrates that these cells failed to increase HIV-1 production following treatment with exogenous Tat. Reasoning that the defect in ACH2 cells involves the Tat response, we analyzed the sequence of tat cDNA and Tat responsive element (TAR) from the virus integrated in ACH2. Tat cDNA sequence is closely related to that of HIV LAI, and the encoded protein is fully functional in terms of long terminal repeat (LTR) transactivation. Cloning of a region corresponding to the 5'-LTR from ACH2, however, identified a point mutation (C37 -> T) in TAR. This mutation impaired Tat responsiveness of the LTR in transient transfection assays, and the measured defect was complemented in cells that had been treated with tetradecanoyl phorbol acetate or tumor necrosis factor type alpha (TNF-alpha). A compensatory mutation in TAR (G28 -> A), designed to reestablish base pairing in the TAR hairpin, restored wild-type Tat responsiveness. When the (C37 -> T) mutation was introduced in an infectious clone of HIV-1, no viral production was measured in the absence of TNF-alpha, whereas full complementation was observed when the infection was conducted in the presence of TNF-alpha or when a compensatory mutation (G28 -> A) was introduced into TAR. These experiments identify a novel mutation associated with HIV-1 latency and suggest that alterations in the Tat-TAR axis can be a crucial determinant of the latent phenotype in infected individuals. PMID- 8692824 TI - Positive genetic feedback governs cAMP spiral wave formation in Dictyostelium. AB - The aggregation stage of the life cycle of Dictyostelium discoideum is governed by the chemotactic response of individual amoebae to excitable waves of cAMP. We modeled this process through a recently introduced hybrid automata-continuum scheme and used computer simulation to unravel the role of specific components of this complex developmental process. Our results indicated an essential role for positive feedback between the cAMP signaling and the expression of the genes encoding the signal transduction and response machinery. PMID- 8692825 TI - Phenotypic analysis of mice expressing exclusively apolipoprotein B48 or apolipoprotein B100. AB - Apolipoprotein (apo)-B is found in two forms in mammals: apo-B100, which is made in the liver and the yolk sac, and apo-B48, a truncated protein made in the intestine. To provide models for understanding the physiologic purpose for the two forms of apo-B, we used targeted mutagenesis of the apo-B gene to generate mice that synthesize exclusively apo-B48 (apo-B48-only mice) and mice that synthesize exclusively apo-B100 (apo-B100-only mice). Both the apo-B48-only mice and apo-B100-only mice developed normally, were healthy, and were fertile. Thus, apo-B48 synthesis was sufficient for normal embryonic development, and the synthesis of apo-B100 in the intestines of adult mice caused no readily apparent adverse effects on intestinal function or nutrition. Compared with wild-type mice fed a chow diet, the levels of low density lipoprotein (LDL)-cholesterol and very low density lipoprotein- and LDL-triacylglycerols were lower in apo-B48-only mice and higher in the apo-B100-only mice. In the setting of apo-E-deficiency, the apo B100-only mutation lowered cholesterol levels, consistent with the fact that apo B100-lipoproteins can be cleared from the plasma via the LDL receptor, whereas apo-B48-lipoproteins lacking apo-E cannot. The apo-B48-only and apo-B100-only mice should prove to be valuable models for experiments designed to understand the purpose for the two forms of apo-B in mammalian metabolism. PMID- 8692827 TI - A new extinct primate among the Pleistocene megafauna of Bahia, Brazil. AB - A nearly complete skeleton of a robust-bodied New World monkey that resembles living spider monkeys was recovered from undisturbed Pleistocene deposits in the Brazilian state of Bahia. The skeleton displays the highly specialized postcranial pattern typical of spider and woolly spider monkeys and shares cranial similarities to the spider monkey exclusively. It is generically distinct on the basis of its robustness (>20 kg) and on the shape of its braincase. This new genus indicates that New World monkeys nearly twice the size of those living today were part of the mammalian biomass of southern Amazonia in the late Pleistocene. The discovery of this specimen expands the known adaptive diversity of New World monkeys and demonstrates that they underwent body size expansion in the terminal Pleistocene, as did many other types of mammals. PMID- 8692826 TI - 31P NMR magnetization transfer study of the control of ATP turnover in Saccharomyces cerevisiae. AB - 31P NMR magnetization transfer measurements have been used to measure the steady state flux between Pi and ATP in yeast cells genetically modified to overexpress an adenine nucleotide translocase isoform. An increase in Pi -> ATP flux and apparent ratio of moles of ATP synthesized/atoms of oxygen consumed (P:O ratio), when these cells were incubated with glucose, demonstrated that the reactions catalyzed by the translocase and F1F0 ATP synthase were readily reversible in vivo. However, when the same cells were incubated with ethanol alone, translocase overexpression had no effect on the measured Pi -> ATP flux or apparent P:O ratio, suggesting that the synthase was now operating irreversibly. This change was accompanied by an increase in the intracellular ADP concentration. These observations are consistent with a model proposed for the kinetic control of mitochondrial ATP synthesis, which was based on isotope exchange measurements with isolated mammalian mitochondria [LaNoue, K. F., Jeffries, F. M. H. & Radda, G. K. (1986) Biochemistry 25, 7667-7675]. PMID- 8692828 TI - Radiation target analysis of RNA. AB - Ribozymes are polynucleotide molecules with intrinsic catalytic activity, capable of cleaving nucleic acid substrates. Large RNA molecules were synthesized containing a hammerhead ribozyme moiety of 52 nucleotides linked to an inactive leader sequence, for total lengths of either 262 or 1226 nucleotides. Frozen RNAs were irradiated with high energy electrons. Surviving ribozyme activity was determined using the ability of the irradiated ribozymes to cleave a labeled substrate. The amount of intact RNA remaining was determined from the same irradiated samples by scanning the RNA band following denaturing gel electrophoresis. Radiation target analyses of these data revealed a structural target size of 80 kDa and a ribozyme activity target size of 15 kDa for the smaller ribozyme, and 319 kDa and 16 kDa, respectively, for the larger ribozyme. The disparity in target size for activity versus structure indicates that, in contrast to proteins, there is no spread of radiation damage far from the primary site of ionization in RNA molecules. The smaller target size for activity indicates that only primary ionizations occurring in the specific active region are effective. This is similar to the case for oligosaccharides. We concluded that the presence of the ribose sugar in the polymer chain restricts radiation damage to a small region and prevents major energy transfer throughout the molecule. Radiation target analysis should be a useful technique for evaluating local RNA:RNA and RNA:protein interactions in vitro. PMID- 8692829 TI - A novel homeobox gene PV.1 mediates induction of ventral mesoderm in Xenopus embryos. AB - The formation of ventral mesoderm has been traditionally viewed as a result of a lack of dorsal signaling and therefore assumed to be a default state of mesodermal development. The discovery that bone morphogenetic protein 4 (BMP4) can induce ventral mesoderm led to the suggestion that the induction of the ventral mesoderm requires a different signaling pathway than the induction of the dorsal mesoderm. However, the individual components of this pathway remained largely unknown. Here we report the identification of a novel Xenopus homeobox gene PV.1 (posterior-ventral 1) that is capable of mediating induction of ventral mesoderm. This gene is activated in blastula stage Xenopus embryos, its expression peaks during gastrulation and declines rapidly after neurulation is complete. PV.1 is expressed in the ventral marginal zone of blastulae and later in the posterior ventral area of gastrulae and neurulae. PV.1 is inducible in uncommited ectoderm by the ventralizing growth factor BMP4 and counteracts the dorsalizing effects of the dominant negative BMP4 receptor. Overexpression of PV.1 yields ventralized tadpoles and rescues embryos partially dorsalized by LiCl treatment. In animal caps, PV.1 ventralizes induction by activin and inhibits expression of dorsal specific genes. All of these effects mimic those previously reported for BMP4. These observations suggest that PV.1 is a critical component in the formation of ventral mesoderm and possibly mediates the effects of BMP4. PMID- 8692830 TI - Targeted mutation of Ncam to produce a secreted molecule results in a dominant embryonic lethality. AB - The neural cell adhesion molecule (NCAM) is a membrane-associated member of the immunoglobulin superfamily capable of both homophilic and heterophilic binding. To investigate the significance of this binding, a gene targeting strategy in embryonic stem (ES) cells was used to replace the membrane-associated forms of NCAM with a soluble, secreted form of its extracellular domain. Although the heterozygous mutant ES cells were able to generate low coat color chimeric mice, only the wild-type allele was transmitted, suggesting the possibility of dominant lethality. Analysis of chimeric embryos with high level of ES cell contribution revealed severe growth retardation and morphological defects by E8.5-E9.5. The second allele was also targeted, and embryos derived almost entirely from the homozygous mutant ES cells exhibited the same lethal phenotype as observed with heterozygous chimeras. Together, these results indicate that dominant lethality associated with the secreted NCAM does not require the presence of membrane associated NCAM. Furthermore, the data indicate that potent bioactive cues or signals can be generated by NCAM. PMID- 8692832 TI - Studies on the biosynthesis of taxol: the taxane carbon skeleton is not of mevalonoid origin. AB - A cell culture of Taxus chinensis was established to produce the diterpene 2alpha,5alpha,10beta,14beta-tetra-acetoxy4 ++ +(20),11-taxadiene (taxuyunnanine C) in 2.6% (dry weight) yield. The incorporation of [U-13C6]glucose, [1 13C]glucose, and [1,2-13C2]acetate into this diterpene was analyzed by NMR spectroscopy. Label from [1,2-13C2]acetate was diverted to the four acetyl groups of taxuyunnanine C, but not to the taxane ring system. Label from [1-13C]glucose and [U-13C6]glucose was efficiently incorporated into both the taxane ring system and the acetyl groups. The four isoprenoid moieties of the diterpene showed identical labeling patterns. The analysis of long-range 13C13C couplings in taxuyunnanine C obtained from an experiment with [U-13C6]glucose documents the involvement of an intramolecular rearrangement in the biosynthesis of the isoprenoid precursor. The labeling patterns are inconsistent with the mevalonate pathway. The taxoid data share important features with the alternative pathway of isoprenoid biosynthesis operating in certain eubacteria Rohmer, M., Knani, M., Simonin, P., Sutter, B. & Sahm, H. (1993) Biochem. J. 295, 517-524]. PMID- 8692831 TI - Whole body positron emission tomography imaging of simian immunodeficiency virus infected rhesus macaques. AB - Pathogenesis of simian immunodeficiency virus (SIV) infection in rhesus macaques begins with acute viremia and then progresses to a distributed infection in the solid lymphoid tissues, which is followed by a process of cellular destruction leading to terminal disease and death. Blood and tissue specimens show the progress of infection at the cellular level but do not reveal the pattern of infection and host responses occurring throughout the body. The purpose of this investigation was to determine whether positron emission tomography (PET) imaging with intravenous 2-18F-2-deoxyglucose (FDG) could identify activated lymphoid tissues in a living animal and whether this pattern would reflect the extent of SIV infection. PET images from SIV-infected animals were distinguishable from uninfected controls and revealed a pattern consistent with widespread lymphoid tissue activation. Significant FDG accumulation in colon along with mesenteric and ileocaecal lymph nodes was found in SIV infection, especially during terminal disease stages. Areas of elevated FDG uptake in the PET images were correlated with productive SIV infection using in situ hybridization as a test for virus replication. PET-FDG images of SIV-infected animals correlated sites of virus replication with high FDG accumulation. These data show that the method can be used to evaluate the distribution and activity of infected tissues in a living animal without biopsy. Fewer tissues had high FDG uptake in terminal animals than midstage animals, and both were clearly distinguishable from uninfected animal scans. PMID- 8692833 TI - The crystal structure of the immunity protein of colicin E7 suggests a possible colicin-interacting surface. AB - The immunity protein of colicin E7 (ImmE7) can bind specifically to the DNase type colicin E7 and inhibit its bactericidal activity. Here we report the 1.8 angstrom crystal structure of the ImmE7 protein. This is the first x-ray structure determined in the superfamily of colicin immunity proteins. The ImmE7 protein consists of four antiparallel alpha-helices, folded in a topology similar to the architecture of a four-helix bundle structure. A region rich in acidic residues is identified. This negatively charged area has the greatest variability within the family of DNase-type immunity proteins; thus, it seems likely that this area is involved in specific binding to colicin. Based on structural, genetic, and kinetic data, we suggest that all the DNase-type immunity proteins, as well as colicins, share a "homologous-structural framework" and that specific interaction between a colicin and its cognate immunity protein relies upon how well these two proteins' charged residues match on the interaction surface, thus leading to specific immunity of the colicin. PMID- 8692834 TI - Human MutSalpha recognizes damaged DNA base pairs containing O6-methylguanine, O4 methylthymine, or the cisplatin-d(GpG) adduct. AB - Bacterial and mammalian mismatch repair systems have been implicated in the cellular response to certain types of DNA damage, and genetic defects in this pathway are known to confer resistance to the cytotoxic effects of DNA methylating agents. Such observations suggest that in addition to their ability to recognize DNA base-pairing errors, members of the MutS family may also respond to genetic lesions produced by DNA damage. We show that the human mismatch recognition activity MutSalpha recognizes several types of DNA lesion including the 1,2-intrastrand d(GpG) crosslink produced by cis diamminedichloroplatinum(II), as well as base pairs between O6-methylguanine and thymine or cytosine, or between O4-methylthymine and adenine. However, the protein fails to recognize 1,3-intrastrand adduct produced by trans diamminedichloroplatinum(II) at a d(GpTpG) sequence. These observations imply direct involvement of the mismatch repair system in the cytotoxic effects of DNA methylating agents and suggest that recognition of 1,2-intrastrand cis diamminedichloroplatinum(II) adducts by MutSalpha may be involved in the cytotoxic action of this chemotherapeutic agent. PMID- 8692835 TI - Targeting of nitric oxide synthase to endothelial cell caveolae via palmitoylation: implications for nitric oxide signaling. AB - The membrane association of endothelial nitric oxide synthase (eNOS) plays an important role in the biosynthesis of nitric oxide (NO) in vascular endothelium. Previously, we have shown that in cultured endothelial cells and in intact blood vessels, eNOS is found primarily in the perinuclear region of the cells and in discrete regions of the plasma membrane, suggesting trafficking of the protein from the Golgi to specialized plasma membrane structures. Here, we show that eNOS is found in Triton X-100-insoluble membranes prepared from cultured bovine aortic endothelial cells and colocalizes with caveolin, a coat protein of caveolae, in cultured bovine lung microvascular endothelial cells as determined by confocal microscopy. To examine if eNOS is indeed in caveolae, we purified luminal endothelial cell plasma membranes and their caveolae directly from intact, perfused rat lungs. eNOS is found in the luminal plasma membranes and is markedly enriched in the purified caveolae. Because palmitoylation of eNOS does not significantly influence its membrane association, we next examined whether this modification can affect eNOS targeting to caveolae. Wild-type eNOS, but not the palmitoylation mutant form of the enzyme, colocalizes with caveolin on the cell surface in transfected NIH 3T3 cells, demonstrating that palmitoylation of eNOS is necessary for its targeting into caveolae. These data suggest that the subcellular targeting of eNOS to caveolae can restrict NO signaling to specific targets within a limited microenvironment at the cell surface and may influence signal transduction through caveolae. PMID- 8692836 TI - Targeting of proteins to granule subsets is determined by timing and not by sorting: The specific granule protein NGAL is localized to azurophil granules when expressed in HL-60 cells. AB - The mechanism of protein targeting to individual granules in cells that contain different subsets of storage granules is poorly understood. The neutrophil contains two highly distinct major types of granules, the peroxidase positive (azurophil) granules and the peroxidase negative (specific and gelatinase) granules. We hypothesized that targeting of proteins to individual granule subsets may be determined by the stage of maturation of the cell, at which the granule proteins are synthesized, rather than by individual sorting information present in the proteins. This was tested by transfecting the cDNA of the specific granule protein, NGAL, which is normally synthesized in metamyelocytes, into the promyelocytic cell line HL-60, which is developmentally arrested at the stage of formation of azurophil granules, and thus does not contain specific and gelatinase granules. Controlled by a cytomegalovirus promoter, NGAL was constitutively expressed in transfected HL-60 cells. This resulted in the targeting of NGAL to azurophil granules as demonstrated by colocalization of NGAL with myeloperoxidase, visualized by immunoelectron microscopy. This shows that targeting of proteins into distinct granule subsets may be determined solely by the time of their biosynthesis and does not depend on individual sorting information present in the proteins. PMID- 8692837 TI - Mitochondria are selective targets for the protective effects of heat shock against oxidative injury. AB - Heat shock (HS) proteins (HSPs) induce protection against a number of stresses distinct from HS, including reactive oxygen species. In the human premonocytic line U937, we investigated in whole cells the effects of preexposure to HS and exposure to hydrogen peroxide (H2O2) on mitochondrial membrane potential, mass, and ultrastructure. HS prevented H2O2-induced alterations in mitochondrial membrane potential and cristae formation while increasing expression of HSPs and the protein product of bcl-2. Protection correlated best with the expression of the 70-kDa HSP, hsp70. We propose that mitochondria represent a selective target for HS-mediated protection against oxidative injury. PMID- 8692838 TI - Complementation of an Escherichia coli adhE mutant by the Entamoeba histolytica EhADH2 gene provides a method for the identification of new antiamebic drugs. AB - The pathogenic protozoan parasite Entamoeba histolytica, the cause of amebic dysentery and amebic liver abscess, is an obligate anaerobe, and derives energy from the fermentation of glucose to ethanol with pyruvate and acetyl coenzyme A as intermediates. We have isolated EhADH2, a key enzyme in this pathway, that is a NAD+- and Fe2+-dependent bifunctional enzyme with acetaldehyde dehydrogenase and alcohol dehydrogenase activities. EhADH2 is the only known eukaryotic member of a newly defined family of prokaryotic multifunctional enzymes, which includes the Escherichia coli AdhE enzyme, an enzyme required for anaerobic growth of E. coli. Because of the critical role of EhADH2 in the amebic fermentation pathway and the lack of known eukaryotic homologues of the EhADH2 enzyme, EhADH2 represents a potential target for antiamebic chemotherapy. However, screening of compounds for antiamebic activity is hampered by the cost of large scale growth of Ent. histolytica, and difficulties in quantitating drug efficacy in vitro. To approach this problem, we expressed the EhADH2 gene in a mutant strain of E. coli carrying a deletion of the adhE gene. Expression of EhADH2 restored the ability of the mutant E. coli strain to grow under anaerobic conditions. By screening compounds for the ability to inhibit the anaerobic growth of the E. coli/EhADH2 strain, we have developed a rapid assay for identifying compounds with anti EhADH2 activity. Using bacteria to bypass the need for parasite culture in the initial screening process for anti-parasitic agents could greatly simplify and reduce the cost of identifying new therapeutic agents effective against parasitic diseases. PMID- 8692839 TI - Microsatellite spreading in the human genome: evolutionary mechanisms and structural implications. AB - Microsatellites are tandem repeat sequences abundant in the genomes of higher eukaryotes and hitherto considered as "junk DNA." Analysis of a human genome representative data base (2.84 Mb) reveals a distinct juxtaposition of A-rich microsatellites and retroposons and suggests their coevolution. The analysis implies that most microsatellites were generated by a 3'-extension of retrotranscripts, similar to mRNA polyadenylylation, and that they serve in turn as "retroposition navigators," directing the retroposons via homology-driven integration into defined sites. Thus, they became instrumental in the preservation and extension of primordial genomic patterns. A role is assigned to these reiterating A-rich loci in the higher-order organization of the chromatin. The disease-associated triplet repeats are mostly found in coding regions and do not show an association with retroposons, constituting a unique set within the family of microsatellite sequences. PMID- 8692840 TI - Telomerase activity in the regenerative basal layer of the epidermis inhuman skin and in immortal and carcinoma-derived skin keratinocytes. AB - Cellular senescence is defined by the limited proliferative capacity of normal cultured cells. Immortal cells overcome this regulation and proliferate indefinitively. One step in the immortalization process may be reactivation of telomerase activity, a ribonucleoprotein complex, which, by de novo synthesized telomeric TTAGGG repeats, can prevent shortening of the telomeres. Here we show that immortal human skin keratinocytes, irrespective of whether they were immortalized by simian virus 40, human papillomavirus 16, or spontaneously, as well as cell lines established from human skin squamous cell carcinomas exhibit telomerase activity. Unexpectedly, four of nine samples of intact human skin also were telomerase positive. By dissecting the skin we could show that the dermis and cultured dermal fibroblasts were telomerase negative. The epidermis and cultured skin keratinocytes, however, reproducibly exhibited enzyme activity. By separating different cell layers of the epidermis this telomerase activity could be assigned to the proliferative basal cells. Thus, in addition to hematopoietic cells, the epidermis, another example of a permanently regenerating human tissue, provides a further exception of the hypothesis that all normal human somatic tissues are telomerase deficient. Instead, these data suggest that in addition to contributing to the permanent proliferation capacity of immortal and tumor derived keratinocytes, telomerase activity may also play a similar role in the lifetime regenerative capacity of normal epidermis in vivo. PMID- 8692841 TI - Isolation and characterization of two human transcription factor IIH (TFIIH) related complexes: ERCC2/CAK and TFIIH. AB - Transcription factor IIH (TFIIH) is a multisubunit protein complex essential for both the initiation of RNA polymerase class II (pol II)-catalyzed transcription and nucleotide excision repair of DNA. Recent studies have shown that TFIIH copurifies with the cyclin-dependent kinase (cdk)-activating kinase complex (CAK) that includes cdk7, cyclin H, and p36/MAT1. Here we report the isolation of two TFIIH-related complexes: TFIIH* and ERCC2/CAK. TFIIH* consists of a subset of the TFIIH complex proteins including ERCC3 (XPB), p62, p44, p41, and p34 but is devoid of detectable levels of ERCC2 (XPD) and CAK. ERCC2/CAK was isolated as a complex that exhibits CAK activity that cosediments with the three CAK components (cdk7, cyclin H, and p36/MAT1) as well as the ERCC2 (XPD) protein. TFIIH* can support pol II-catalyzed transcription in vitro with lower efficiency compared with TFIIH. This TFIIH*-dependent transcription reaction was stimulated by ERCC2/CAK. The ERCC2/CAK and TFIIH* complexes are each active in DNA repair as shown by their ability to complement extracts prepared from ERCC2 (XPD)- and ERCC3 (XPB)-deficient cells, respectively, in supporting the excision of DNA containing a cholesterol lesion. These data suggest that TFIIH* and ERCC2/CAK interact to form the TFIIH holoenzyme capable of efficiently assembling the pol II transcription initiation complex and directly participating in excision repair reactions. PMID- 8692843 TI - Chemical basis of courtship in a beetle (Neopyrochroa flabellata): cantharidin as precopulatory "enticing" agent. AB - Male Neopyrochroa flabellata have a natural affinity for cantharidin (Spanish fly). They are attracted to cantharidin baits in the field and feed on the compound if it is offered to them in the laboratory. Males that ingest cantharidin secrete cantharidin from a cephalic gland. Females sample secretion from this gland during courtship and mate preferentially with males that had fed on cantharidin. Cantharidin-unfed males can be rendered acceptable to females if cantharidin is added to their cephalic gland. PMID- 8692842 TI - Human cyclin-dependent kinase-activating kinase exists in three distinct complexes. AB - Transcription factor IIH (TFIIH) is a multisubunit complex required for transcription and for DNA nucleotide excision repair. TFIIH possesses three enzymatic activities: (i) an ATP-dependent DNA helicase, (ii) a DNA-dependent ATPase, and (iii) a kinase with specificity for the carboxyl-terminal domain of RNA polymerase II. The kinase activity was recently identified as the cdk (cyclin dependent kinase) activating kinase, CAK, composed of cdk7, cyclin H, and MAT-1. Here we report the isolation and characterization of three distinct CAK containing complexes from HeLa nuclear extracts: CAK, a novel CAK-ERCC2 complex, and TFIIH. CAK-ERCC2 can efficiently associate with core-TFIIH to reconstitute holo-TFIIH transcription activity. We present evidence proposing a critical role for ERCC2 in mediating the association of CAK with core TFIIH subunits. PMID- 8692844 TI - Chemical basis of courtship in a beetle (Neopyrochroa flabellata): Cantharidin as "nuptial gift". AB - The amount of cantharidin (Spanish fly) that the Neopyrochroa flabellata male presents to the female as a glandular offering during courtship represents only a small fraction of the total cantharidin the male accumulates systemically following ingestion of the compound. A major fraction of the acquired cantharidin is stored by the male in the large accessory glands of the reproductive system. At mating, the male transfers this supply, presumably as part of the sperm package, to the spermatheca of the female. The female in turn allocates the gift to the eggs. Eggs endowed with cantharidin proved relatively invulnerable to attack by a predaceous beetle larva (Coleomegilla maculata). PMID- 8692845 TI - An abundant cell-surface polypeptide is required for swimming by the nonflagellated marine cyanobacterium Synechococcus. AB - Certain marine unicellular cyanobacteria of the genus Synechococcus exhibit a unique and mysterious form of motility characterized by the ability to swim in liquid in the absence of flagella. An abundant cell-surface-associated polypeptide that is required for swimming motility by Synechococcus sp. strain WH8102 has been identified, and the gene encoding it, swmA, has been cloned and sequenced. The predicted SwmA protein contains a number of Ca2+-binding motifs as well as several potential N-glycosylation sites. Insertional inactivation of swmA in Synechococcus sp. strain WH8102 results in a loss of the ability to translocate, although the mutant strain, Swm-1, generates torque. This suggests that SwmA functions in the generation of thrust. PMID- 8692846 TI - Reduction of two functional gamma-globin genes to one: an evolutionary trend in New World monkeys (infraorder Platyrrhini). AB - Nucleotide sequences were determined for the gamma1- and gamma2-globin loci from representatives of the seven anciently separated clades in the three extant platyrrhine families (Atelidae, Pitheciidae, and Cebidae). These sequences revealed an evolutionary trend in New World monkeys either to inactivate the gamma1 gene or to fuse it with the gamma2 gene, i.e. to have only one functional fetally expressed gamma gene. This trend is clearly evident in six of the seven clades: (i) it occurred in atelids by deletion of most of the gamma1 gene in the basal ancestor of this clade; (ii-iv) in pitheciid titi, saki, and cebid capuchin monkeys by potentially debilitating nucleotide substitutions in the proximal CCAAT box of the gamma1 promoters and (v and vi) in cebid owl and squirrel monkeys by crossovers that fused 5' sequence from gamma1 with 3' sequence from gamma2. In the five clades with gamma1 and gamma2 loci separated by intergenic sequences (the fifth clade being the cebid marmosets), the gamma2 genes retained an unaltered proximal CCAAT motif and their gamma2 promoters accumulated fewer nucleotide substitutions than did the gamma1 promoters. Thus, phylogenetic considerations indicate that the stem platyrrhines, ancestral to all New World monkeys, had gamma2 as the primary fetally expressed gamma gene. A further inference is that when the earlier stem anthropoid gamma gene duplicated, gamma2 (at its greater downstream distance from epsilon) could evade embryonic activation by the locus control region but could be fetally activated once released by regulatory mutations from fetal repressors. PMID- 8692847 TI - Development of Valpha4+ NK T cells in the early stages of embryogenesis. AB - The majority of T lymphocytes start to develop at around day 15 of gestation (d15)-d17 in the thymus and comprise the peripheral repertoire characterized by the expression of polymorphic T-cell antigen receptors (TCRs). Contrary to these conventional T cells, a subset of T cells, called natural killer (NK) T cells (most of them expressing an invariant TCR encoded by the Valpha14Jalpha281 gene with a 1-nt N-region), preferentially differentiates extrathymically and dominates the peripheral T-cell population at a high frequency (5% in splenic T cells and 40% in bone marrow T cells). Here, we investigated the development of NK T cells and found that the invariant Valpha14+ TCR transcripts and the circular DNA created by Valpha14 and Jalpha281 gene rearrangements can be detected in the embryo body at d9.5 of gestation and in the yolk sac and the fetal liver at d11.5-d13.5 of gestation, but not in the thymus, whereas T cells with Valpha1+ TCR expression, a major population in the thymus, were not observed at these early stages of gestation. Fluorescence-activated cell sorter analysis also demonstrated that there exist CD3+ alpha beta+ T cells, almost all of which are Valpha14/Vbeta8+ NK+ T cells, during early embryogenesis. To our knowledge, this demonstrates for the first time that a T lymphocyte subset develops in extrathymic tissues during the early stages of embryogenesis. PMID- 8692848 TI - In vitro reconstitution of human replication factor C from its five subunits. AB - Replication factor C (RFC, also called Activator I) is part of the processive eukaryotic DNA polymerase holoenzymes. The processive elongation of DNA chains requires that DNA polymerases are tethered to template DNA at primer ends. In eukaryotes the ring-shaped homotrimeric protein, proliferating cell nuclear antigen (PCNA), ensures tight template-polymerase interaction by encircling the DNA strand. Proliferating cell nuclear antigen is loaded onto DNA through the action of RFC in an ATP-dependent reaction. Human RFC is a protein complex consisting of five distinct subunits that migrate through SDS/polyacrylamide gels as protein bands of 140, 40, 38, 37, and 36 kDa. All five genes encoding the RFC subunits have been cloned and sequenced. A functionally identical RFC complex has been isolated from Saccharomyces cerevisiae and the deduced amino acid sequences among the corresponding human and yeast subunits are homologous. Here we report the expression of the five cloned human genes using an in vitro coupled transcription/translation system and show that the gene products form a complex resembling native RFC that is active in supporting an RFC-dependent replication reaction. Studies on the interactions between the five subunits suggest a cooperative mechanism in the assembly of the RFC complex. A three-subunit core complex, consisting of p36, p37, and p40, was identified and evidence is presented that p38 is essential for the interaction between this core complex and the large p140 subunit. PMID- 8692849 TI - Glutamate is required to maintain the steady-state potassium pool in Salmonella typhimurium. AB - In many bacteria, accumulation of K+ at high external osmolalities is accompanied by accumulation of glutamate. To determine whether there is an obligatory relationship between glutamate and K+ pools, we studied mutant strains of Salmonella typhimurium with defects in glutamate synthesis. Enteric bacteria synthesize glutamate by the combined action of glutamine synthetase and glutamate synthase (GS/GOGAT cycle) or the action of biosynthetic glutamate dehydrogenase (GDH). Activity of the GS/GOGAT cycle is required under nitrogen-limiting conditions and is decreased at high external ammonium/ammonia ((NH4)+) concentrations by lowered synthesis of GS and a decrease in its catalytic activity due to covalent modification (adenylylation by GS adenylyltransferase). By contrast, GDH functions efficiently only at high external (NH4)+ concentrations, because it has a low affinity for (NH4)+. When grown at low concentrations of (NH4)+ (< or = 2 mM), mutant strains of S. typhimurium that lack GOGAT and therefore are dependent on GDH have a low glutamate pool and grow slowly; we now demonstrate that they have a low K+ pool. When subjected to a sudden (NH4)+ upshift, strains lacking GS adenylyltransferase drain their glutamate pool into glutamine and grow very slowly; we now find that they also drain their K+ pool. Restoration of the glutamate pool in these strains at late times after shift was accompanied by restoration of the K+ pool and a normal growth rate. Taken together, the results indicate that glutamate is required to maintain the steady-state K+ pool -- apparently no other anion can substitute as a counter-ion for free K+ -- and that K+ glutamate is required for optimal growth. PMID- 8692850 TI - Complex dynamics of multilocus systems subjected to cyclical selection. AB - Earlier we have shown that oscillations with a long period ("supercycles") may arise in two-locus systems experiencing cyclical selection with a short period. However, this mode of complex limiting behavior appeared to be possible for narrow ranges of parameters. Here we demonstrate that a multilocus system subjected to stabilizing selection with cyclically moving optimum can generate ubiquitous complex limiting behavior including supercycles, T-cycles, and chaotic like phenomena. This mode of multilocus dynamics far exceeds the potential attainable under ordinary selection models resulting in simple behavior. It may represent a novel evolutionary mechanism increasing genetic diversity over long term time periods. PMID- 8692851 TI - Circular RNAs from transcripts of the rat cytochrome P450 2C24 gene: correlation with exon skipping. AB - The cytochrome P450 2C24 gene is characterized by the capability to generate, in rat kidney, a transcript containing exons 2 and 4 spliced at correct sites but having the donor site of exon 4 directly joined to the acceptor site of exon 2 (exon scrambling). By reverse transcriptase-PCR analysis, it is now shown that the only exons present in the scrambled transcript are exons 2, 3, and 4 and that this molecule lacks a poly(A)+ tail. Furthermore, the use of PCR primers in both orientations of either exon 2 or exon 4 revealed that the orders of the exons in the scrambled transcript are 2-3-4-2 and 4-2-3-4, respectively. These results, combined with the observation that P450 2C24 is a single-copy gene, with no duplication of the exon 2 to exon 4 segment, suggest that the scrambled transcript has properties consistent with that of a circular molecule. In line with this is the observation of an increased resistance of the transcript to phosphodiesterase I, a 3'-exonuclease. Moreover, an alternatively processed cytochrome P450 2C24 mRNA, lacking the three scrambled exons and having exon 1 directly joined to exon 5, has been identified in kidney and liver, tissues that express the scrambled transcript. This complete identity of the exons that are absent in the alternatively processed mRNA but present in the scrambled transcript is interpreted as indicative of the possibility that exon scrambling and exon skipping might be interrelated phenomena. It is therefore proposed that alternative pre-mRNA processing has the potential to generate not only mRNAs lacking one or more exons but also circular RNA molecules. PMID- 8692852 TI - The dynamics of hepatitis B virus infection. AB - We consider a cellular model of infection by the hepatitis B virus and describe how it may be used to account for two important features of the disease, namely (i) the wide variety of manifestations of infection and the age dependence thereof, and (ii) the typically long delay before the development of virus induced liver cancer (primary hepatocellular carcinoma). The model is based on the assumption that the liver is comprised of both immature and mature hepatocytes, with these two subpopulations of cells responding contrastingly upon infection by the virus. PMID- 8692853 TI - Gestational drive and the green-bearded placenta. AB - A "green beard" refers to a gene, or group of genes, that is able to recognize itself in other individuals and direct benefits to these individuals. Green-beard effects have been dismissed as implausible by authors who have implicitly assumed sophisticated mechanisms of perception and complex behavioral responses. However, many simple mechanisms for genes to "recognize" themselves exist at the maternal fetal interface of viviparous organisms. Homophilic cell adhesion molecules, for example, are able to interact with copies of themselves on other cells. Thus, the necessary components of a green-beard effect -- feature, recognition, and response -- can be different aspects of the phenotype of a single gene. Other green-beard effects could involve coalitions of genes at closely linked loci. In fact, any form of epistasis between a locus expressed in a mother and a closely linked locus expressed in the fetus has the property of "self-recognition." Green beard effects have many formal similarities to systems of meiotic drive and, like them, can be a source of intragenomic conflict. PMID- 8692854 TI - In vitro motility from recombinant dynein heavy chain. AB - The dyneins are a class of motor protein involved in ciliary and flagellar motility, organelle transport, and chromosome segregation. Because of their large size and subunit complexity, relatively little is known about their mechanisms of force production and regulation. We report here on the expression and analysis of the entire rat cytoplasmic dynein heavy chain (Mr 532,000). Full-length cDNAs were constructed from a series of partial clones and tagged at the C terminus with either a FLAG-epitope tag or a His6-tag. The recombinant polypeptides were expressed either in insect cells by baculovirus infection or in COS-7 cells by transient transfection. The recombinant protein was mostly soluble and showed good microtubule binding. It exhibited a broad sedimentation profile, indicative of the formation of dimers as well as higher order multimers. Good microtubule gliding motility activity was observed in assays of heavy chain expressed in either insect or COS-7 cells. Average microtubule gliding velocities of 1.2-1.8 microm/sec were observed, comparable with the rates determined for calf brain cytoplasmic dynein. These results represent the first indication that recombinant heavy chain alone is capable of force production, and should lead to rapid progress in defining the dynein motor domain. PMID- 8692855 TI - Protonatable residues at the cytoplasmic end of transmembrane helix-2 in the signal transducer HtrI control photochemistry and function of sensory rhodopsin I. AB - Neutral residue replacements were made of 21 acidic and basic residues within the N-terminal half of the Halobacterium salinarium signal transducer HtrI [the halobacterial transducer for sensory rhodopsin I (SRI)] by site-specific mutagenesis. The replacements are all within the region of HtrI that we previously concluded from deletion analysis to contain sites of interaction with the phototaxis receptor SRI. Immunoblotting shows plasmid expression of the htrI sopI operon containing the mutations produces SRI and mutant HtrI in cells at near wild-type levels. Six of the HtrI mutations perturb photochemical kinetics of SRI and one reverses the phototaxis response. Substitution with neutral amino acids of Asp-86, Glu-87, and Glu-108 accelerate, and of Arg-70, Arg-84, and Arg 99 retard, the SRI photocycle. Opposite effects on photocycle rate cancel in double mutants containing one replaced acidic and one replaced basic residue. Laser flash spectroscopy shows the kinetic perturbations are due to alteration of the rate of reprotonation of the retinylidene Schiff base. All of these mutations permit normal attractant and repellent signaling. On the other hand, the substitution of Glu-56 with the isosteric glutamine converts the normally attractant effect of orange light to a repellent signal in vivo at neutral pH (inverted signaling). Low pH corrects the inversion due to Glu-56 -> Gln and the apparent pK of the inversion is increased when arginine is substituted at position 56. The results indicate that the cytoplasmic end of transmembrane helix 2 and the initial part of the cytoplasmic domain contain interaction sites with SRI. To explain these and previous results, we propose a model in which (i) the HtrI region identified here forms part of an electrostatic bonding network that extends through the SRI protein and includes its photoactive site; (ii) alteration of this network by photoisomerization-induced Schiff base deprotonation and reprotonation shifts HtrI between attractant and repellent conformations; and (iii) HtrI mutations and extracellular pH alter the equilibrium ratios of these conformations. PMID- 8692856 TI - Nucleator-dependent intercellular assembly of adhesive curli organelles in Escherichia coli. AB - Bacterial adhesion to other bacteria, to eukaryotic cells, and to extracellular matrix proteins is frequently mediated by cell surface-associated polymers (fimbriae) consisting of one or more subunit proteins. We have found that polymerization of curlin to fimbriae-like structures (curli) on the surface of Escherichia coli markedly differs from the prevailing model for fimbrial assembly in that it occurs extracellularly through a self-assembly process depending on a specific nucleator protein. The cell surface-bound nucleator primes the polymerization of curlin secreted by the nucleator-presenting cell or by adjacent cells. The addition of monomers to the growing filament seems to be driven by mass action and guided only by the diffusion gradient between the source of secreted monomer and the surface of monomer condensation. PMID- 8692857 TI - Expression of a candidate cadherin in T lymphocytes. AB - Cadherins are homotypic adhesion molecules that classically mediate interactions between cells of the same type in solid tissues. In addition, E-cadherin is able to support homotypic adhesion of epidermal Langerhans cells to keratinocytes (Tang, A., Amagai, M., Granger, L. G., Stanley, J. R. & Udey, M. C. (1993) Nature (London) 361, 82-85) and heterotypic adhesion of mucosal epithelial cells to E cadherin-negative intestinal intraepithelial T lymphocytes. Thus, we hypothesized that cadherins may play a wider role in cell-to-cell adhesion events involving T lymphocytes. We searched for a cadherin or cadherins in T lymphocytes with a pan cadherin antiserum and antisera against alpha- or beta-catenin, molecules known to associate with the cytoplasmic domain of cadherins. The anti-beta-catenin antisera coimmunoprecipitated a radiolabeled species in T-lymphocyte lines that had a molecular mass of 129 kDa and was specifically immunoblotted with the pan cadherin antiserum. Also, the pan-cadherin antiserum directly immunoprecipitated a 129-kDa radiolabeled species from an 125I surface-labeled Jurkat human T-cell leukemic cell line. After V8 protease digestion, the peptide map of this pan cadherin-immunoprecipitated, 129-kDa species exactly matched that of the 129-kDa species coimmunoprecipitated with the beta-catenin antiserum. These results demonstrate that T lymphocytes express a catenin-associated protein that appears to be a member of the cadherin superfamily and may contribute to T cell-mediated immune surveillance. PMID- 8692858 TI - The binding site of karyopherin alpha for karyopherin beta overlaps with a nuclear localization sequence. AB - By using proteolysis, recombinant mutant proteins, or synthetic peptides and by testing these reagents in liquid phase binding or nuclear import assays, we have mapped binding regions of karyopherin alpha. We found that the C-terminal region of karyopherin alpha recognizes the nuclear localization sequence (NLS), whereas its N-terminal region binds karyopherin beta. Surprisingly, karyopherin alpha also contains an NLS. Thus, karyopherin alpha belongs to a group of proteins that contain both a ligand (NLS) and a cognate receptor (NLS recognition site) in one molecule with a potential for autologous ligand-receptor interactions. The NLS of karyopherin alpha overlaps with the binding site of karyopherin alpha for karyopherin beta. Hence, binding of karyopherin beta to karyopherin alpha covers the NLS of karyopherin alpha. This prevents autologous ligand receptor interactions and explains the observed cooperative binding of karyopherin alpha to a heterologous NLS protein in the presence of karyopherin beta. PMID- 8692859 TI - Genetic interactions affecting touch sensitivity in Caenorhabditis elegans. AB - At least 13 genes (mec-1, mec-2, mec-4-10, mec-12, mec-14, mec-15, and mec-18) are needed for the response to gentle touch by 6 touch receptor neurons in the nematode Caenorhabditis elegans. Several, otherwise recessive alleles of some of these genes act as dominant enhancer mutations of temperature-sensitive alleles of mec-4, mec-5, mec-6, mec-12, and mec-15. Screens for additional dominant enhancers of mec-4 and mec-5 yielded mutations in previously known genes. In addition, some mec-7 alleles showed allele-specific, dominant suppression of the mec-15 touch-insensitive (Mec) phenotype. The dominant enhancement and suppression exhibited by these mutations suggest that the products of several touch genes interact. These results are consistent with a model, supported by the known sequences of these genes, that almost all of the touch function genes contribute to the mechanosensory apparatus. PMID- 8692860 TI - Separation of the transcriptional coactivator and antirepression functions of transcription factor IIA. AB - Human transcription factor IIA (TFIIA) is composed of three subunits (alpha, beta, and gamma). TFIIA interacts with the TATA-box binding protein and can overcome repression of transcription. TFIIA was found to be necessary for VP16 mediated transcriptional activation through a coactivator function. We have separated the coactivator and antirepression activities of TFIIA. A TFIIA lacking the alpha subunit was isolated from HeLa cells. This "mini-TFIIA" interacts with the TATA-box binding protein and can overcome repression of transcription, but it is defective in transcriptional coactivator function. PMID- 8692862 TI - Skin wounds and severed nerves heal normally in mice lacking tenascin-C. AB - A large number of functions have been demonstrated for tenascin-C by antibody perturbation assays and in vitro cell culture experiments. However, these results contrast sharply with the lack of any apparent phenotype in mice with a genetic deletion of tenascin-C. A possible explanation for the lack of phenotype would be expression of some altered but functional tenascin-C in the mutant. We report the generation of an independent tenascin-C null mouse and conclude that the original tenascin-C knockout, which is genetically very similar to ours, is also a true null. As found previously, the absence of tenascin-C has no influence on development, adulthood, life span, and fecundity. We have studied in detail two models of wound healing. After axotomy, the regeneration of the sciatic nerve is not altered without tenascin-C. During healing of cutaneous wounds, deposition of collagen I, fibulin-2, and nidogen is identical in mutant and wild-type mice. In contrast. fibronectin appears diminished in wounds of tenascin-C-deficient mice. However, the lack of tenascin-C together with the reduced amount of fibronectin has no influence on the quality of the healing process. PMID- 8692861 TI - The yeast and mammalian isoforms of phosphatidylinositol transfer protein can all restore phospholipase C-mediated inositol lipid signaling in cytosol-depleted RBL 2H3 and HL-60 cells. AB - The mammalian phosphatidylinositol transfer proteins (PITP) and the yeast Saccharomyces cerevisiae PITP (SEC14p) that show no sequence homology both catalyze exchange of phosphatidylinositol (PI) between membranes compartments in vitro. In HL-60 cells where the cytosolic proteins are depleted by permeabilization, exogenously added PITPalpha is required to restore G protein mediated phospholipase Cbeta (PLCbeta) signaling. Recently, a second mammalian PITPbeta form has been described that shows 77% identity to rat PITPalpha. We have examined the ability of the two mammalian PITPs and SEC14p to restore PLC mediated signaling in cytosol-depleted HL-60 and RBL-2H3 cells. Both PITPalpha and PITPbeta isoforms as well as SEC14p restore G protein-mediated PLCbeta signaling with a similar potency. In RBL-2H3 cells, crosslinking of the IgE receptor by antigen stimulates inositol lipid hydrolysis by tyrosine phosphorylation of PLCgamma1. Permeabilization of RBL cells leads to loss of PLCgamma1 as well as PITP into the extracellular medium and this coincides with loss of antigen-stimulated lipid hydrolysis. Both PLCgamma1 and PITP were required to restore inositol lipid signaling. We conclude that (i) because the PI binding/transfer activities of PITP/SEC14p is the common feature shared by all three transfer proteins, it must be the relevant activity that determines their abilities to restore inositol lipid-mediated signaling and (ii) PITP is a general requirement for inositol lipid hydrolysis regardless of how and which isoform of PLC is activated by the appropriate agonist. PMID- 8692863 TI - Deciphering the mechanism for the assembly of aromatic polyketides by a bacterial polyketide synthase. AB - Aromatic polyketides are assembled by a type 11 (iterative) polyketide synthase (PKS) in bacteria. Understanding the enzymology of such enzymes should provide the information needed for the synthesis of novel polyketides through the genetic engineering of PKSs. Using a previously described cell-free system [B.S. & C.R.H. (1993) Science 262, 1535-1540], we studied a PKS enzyme whose substrate is not directly available and purified the TcmN polyketide cyclase from Streptomyces glaucescens. TcmN is a bifunctional protein that catalyzes the regiospecific cyclization of the Tcm PKS-bound linear decaketide to Tcm F2 and the 0 methylation of Tcm D3 to Tcm B3. In the absence of TcmN, the decaketide formed by the minimal PKS consisting of the TcmJKLM proteins undergoes spontaneous cyclization to form some Tcm F2 as well as SEK15 and many other aberrant shunt products. Addition of purified TcmN to a mixture of the other Tcm PKS components both restores and enhances Tcm F2 production. Interestingly, Tcm F2 but none of the aberrant products was bound tightly to the PKS. The results described support the notion that the polyketide cyclase, not the minimal PKS, dictates the regiospecificity for the cyclization of the linear polyketide intermediate. Furthermore, because the addition of TcmN to the TcmJKLM proteins results in a significant increase of the total yield of decaketide, interactions among the individual components of the Tcm PKS complex must give rise to the optimal PKS activity. PMID- 8692864 TI - Effect of deletion of 5'HS3 or 5'HS2 of the human beta-globin locus control region on the developmental regulation of globin gene expression in beta-globin locus yeast artificial chromosome transgenic mice. AB - To analyze the function of the 5' DNase I hypersensitive sites (HSs) of the locus control region (LCR) on beta-like globin gene expression, a 2.3-kb deletion of 5'HS3 or a 1.9-kb deletion of 5'HS2 was recombined into a beta-globin locus yeast artificial chromosome, and transgenic mice were produced. Deletion of 5'HS3 resulted in a significant decrease of epsilon-globin gene expression and an increase of gamma-globin gene expression in embryonic cells. Deletion of 5'HS2 resulted in only a small decrease in expression of epsilon-, gamma-, and beta globin mRNA at all stages of development. Neither deletion affected the temporal pattern of globin gene switching. These results suggest that the LCR contains functionally redundant elements and that LCR complex formation does not require the presence of all DNase I hypersensitive sites. The phenotype of the 5'HS3 deletion suggests that individual HSs may influence the interaction of the LCR with specific globin gene promoters during the course of ontogeny. PMID- 8692865 TI - Gadolinium(III) texaphyrin: a tumor selective radiation sensitizer that is detectable by MRI. AB - Gadolinium(III) texaphyrin (Gd-tex2+) is representative of a new class of radiation sensitizers detectable by magnetic resonance imaging (MRI). This porphyrin-like complex has a high electron affinity [E1/2 (red.) approximately = 0.08 V versus normal hydrogen electrode] and forms a long-lived pi-radical cation upon exposure to hydrated electrons, reducing ketyl radicals, or superoxide ions. Consistent with these chemical findings, Gd-tex2+ was found to be an efficient radiation sensitizer in studies carried out with HT29 cells in in vitro as well as in in vivo single and multifraction irradiation studies with a murine mammary carcinoma model. Selective localization of Gd-tex2+ in tumors was confirmed by MRI scanning. PMID- 8692866 TI - Transcription activation by phage phi29 protein p4 is mediated by interaction with the alpha subunit of Bacillus subtilis RNA polymerase. AB - Regulatory protein p4 from Bacillus subtilis phage phi29 activates transcription from the viral late A3 promoter by stabilizing sigmaA-RNA polymerase at the promoter as a closed complex. Activation requires an interaction between protein p4 and RNA polymerase mediated by the protein p4 carboxyl-end, mainly through residue Arg-120. We have obtained derivatives of B. subtilis RNA polymerase alpha subunit with serial deletions at the carboxyl-end and reconstituted RNA polymerase holoenzymes harboring the mutant alpha subunits. Protein p4 promoted the binding of purified B. subtilis RNA polymerase alpha subunit to the A3 promoter in a cooperative way. Binding was abolished by deletion of the last 15 amino acids of the alpha subunit. Reconstituted RNA polymerases with deletions of 15 to 59 residues at the alpha subunit carboxyl-end could recognize and transcribe viral promoters not activated by protein p4, but they had lost their ability to recognize the A3 promoter in the presence of protein p4. In addition, these mutant reconstituted RNA polymerases could not interact with protein p4. We conclude that protein p4 activation of the viral A3 promoter requires an interaction between the carboxyl-end of protein p4 and the carboxyl-end of the alpha subunit of B. subtilis RNA polymerase that stabilizes the RNA polymerase at the promoter. PMID- 8692867 TI - Interaction of the two cytosolic domains of mammalian adenylyl cyclase. AB - Adenylyl cyclase activity can be reconstituted by simple mixture of the two cytosolic domains of the enzyme after their independent synthesis in Escherichia coli. We have synthesized and purified the C1a domain of type I adenylyl cyclase and the C2 domain of the type II enzyme to assess their interactions with each other and with the activators Gsalpha and forskolin. In the absence of an activator, the fragments associate with low affinity and display low catalytic activity. This basal activity can be stimulated more than 100-fold by either forskolin or activated Gsalpha. Further, the addition of these activators increases the apparent affinity of the fragments for each other. Stimulation of catalysis by Gsalpha and forskolin is synergistic. These data suggest a model wherein either Gsalpha or forskolin enhances association of the other activator with adenylyl cyclase, as well as facilitating the interaction between the C1 and C2 domains of the enzyme. PMID- 8692869 TI - Taste receptor-like cells in the rat gut identified by expression of alpha gustducin. AB - The alpha-subunit of the trimeric G-protein complex specific for taste receptor cells of the tongue, alpha-gustducin, is described here to be also expressed in the stomach and intestine. The alpha-gustducin-containing cells were identified as brush cells that are scattered throughout the surface epithelium of the gut and share structural features of taste receptor cells of the tongue. These findings provide clues to the long-sought molecular and cellular basis for chemoreception in the gut. PMID- 8692868 TI - A human axillary odorant is carried by apolipoprotein D. AB - The characterization of the source of the odor in the human axillary region is not only of commercial interest but is also important biologically because axillary extracts can alter the length and timing of the female menstrual cycle. In males, the most abundant odor component is known to be E-3-methyl-2-hexenoic acid (E-3M2H), which is liberated from nonodorous apocrine secretions by axillary microorganisms. Recently, it was found that in the apocrine gland secretions, 3M2H is carried to the skin surface bound to two proteins, apocrine secretion odor-binding proteins 1 and 2 (ASOB1 and ASOB2) with apparent molecular masses of 45 kDa and 26 kDa, respectively. To better understand the formation of axillary odors and the structural relationship between 3M2H and its carrier protein, the amino acid sequence and glycosylation pattern of ASOB2 were determined by mass spectrometry. The ASOB2 protein was identified as apolipoprotein D (apoD), a known member of the alpha2mu-microglobulin superfamily of carrier proteins also known as lipocalins. The pattern of glycosylation for axillary apoD differs from that reported for plasma apoD, suggesting different sites of expression for the two glycoproteins. In situ hybridization of an oligonucleotide probe against apoD mRNA with axillary tissue demonstrates that the message for synthesis of this protein is specific to the apocrine glands. These results suggest a remarkable similarity between human axillary secretions and nonhuman mammalian odor sources, where lipocalins have been shown to carry the odoriferous signals used in pheromonal communication. PMID- 8692870 TI - A novel function for Myc: inhibition of C/EBP-dependent gene activation. AB - We have investigated the effect of the v-Myc oncoprotein on gene expression in myelomonocytic cells. We find that v-Myc dramatically down-regulates the expression of myelomonocytic-specific genes, such as the chicken mim-1 and lysozyme genes, both of which are known targets for C/EBP transcription factors. We present evidence that Myc downregulates these genes by inhibiting the function of C/EBP transcription factors. Detailed examination of the inhibitory mechanism shows that amino-terminal sequences of v-Myc, but not its DNA-binding domain, are required for the suppression of C/EBP-dependent transactivation. Our findings identify a new function for Myc and reveal a novel mechanism by which Myc affects the expression of other genes. PMID- 8692872 TI - Copy-choice recombination mediated by DNA polymerase III holoenzyme from Escherichia coli. AB - Formation of deletions by recombination between short direct repeats is thought to involve either a break-join or a copy-choice process. The key step of the latter is slippage of the replication machinery between the repeats. We report that the main replicase of Escherichia coli, DNA polymerase III holoenzyme, slips between two direct repeats of 27 bp that flank an inverted repeat of approximately equal 300bp. Slippage was detected in vitro, on a single-stranded DNA template, in a primer extension assay. It requires the presence of a short (8 bp) G+C-rich sequence at the base of a hairpin that can form by annealing of the inverted repeats. It is stimulated by (i) high salt concentration, which might stabilize the hairpin, and (ii) two proteins that ensure the processivity of the DNA polymerase III holoenzyme: the single-stranded DNA binding protein and the beta subunit of the polymerase. Slippage is rather efficient under optimal reaction conditions because it can take place on >50% of template molecules. This observation supports the copy-choice model for recombination between short direct repeats. PMID- 8692871 TI - Restricted expression of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genes in Kaposi sarcoma. AB - Kaposi sarcoma (KS) is the leading neoplasm of HIV-infected patients and is also found in several HIV-negative populations. Recently, DNA sequences from a novel herpesvirus, termed KS-associated herpesvirus (KSHV), or human herpesvirus 8 (HHV 8) have been identified within KS tissue from both HIV-positive and HIV-negative cases; infection with this agent has been proposed as a possible factor in the etiology or pathogenesis of the tumor. Here we have examined the pattern of KSHV/HHV-8 gene expression in KS and find it to be highly restricted. We identify and characterize two small transcripts that represent the bulk of the virus specific RNA transcribed from over 120 kb of the KSHV genome in infected cells. One transcript is predicted to encode a small membrane protein; the other is an unusual polyadenylylated RNA that accumulates in the nucleus to high copy number. This pattern of viral gene expression suggests that most infected cells in KS are latently infected, with lytic viral replication likely restricted to a much smaller subpopulation of cells. These findings have implications for the therapeutic utility of currently available antiviral drugs targeted against the lytic replication cycle. PMID- 8692873 TI - Infectivity of chimeric human T-cell leukemia virus type I molecular clones assessed by naked DNA inoculation. AB - Two human T-cell leukemia virus type I (HTLV-I) molecular clones, K30p and K34p were derived from HTLV-I-infected rabbit cell lines. K30p and K34p differ by 18 bp with changes in the long terminal repeats (LTRs) as well as in the gag, pol, and rex but not tax or env gene products. Cells transfected with clone K30p were infectious in vitro and injection of the K30p transfectants or naked K30p DNA into rabbits leads to chronic infection. In contrast, K34p did not mediate infection in vitro or in vivo, although the cell line from which it was derived is fully infectious and K34p transfectants produce intact virus particles. To localize differences involved in the ability of the clones to cause infection, six chimeric HTLV-I clones were constructed by shuffling corresponding fragments containing the substitutions in the LTRs, the gag/pol region and the rex region between K30p and K34p. Cells transfected with any of the six chimeras produced virus, but higher levels of virus were produced by cells transfected with those constructs containing the K30p rex region. Virus production was transient except in cells transfected with K30p or with a chimera consisting of the entire protein coding region of K30p flanked by K34p LTRs; only the transfectants showing persistent virus production mediated in vitro infection. In vivo infection in rabbits following intramuscular DNA injection was mediated by K30p as well as by a chimera of K30p containing the K34p rex gene. Comparisons revealed that virus production was greater and appeared earlier in rabbits injected with K30p. These data suggest that several defects in the K34p clone preclude infectivity and furthermore, provide systems to explore functions of HTLV-I genes. PMID- 8692874 TI - Variegated transgene expression in mouse mammary gland is determined by the transgene integration locus. AB - Mice carrying an ovine beta-lactoglobulin (BLG) transgene secrete BLG protein into their milk. To explore transgene expression stability, we studied expression levels in three BLG transgenic mouse lines. Unexpectedly, two lines exhibited variable levels of transgene expression. Copy number within lines appeared to be stable and there was no evidence of transgene rearrangement. In the most variable line, BLG production levels were stable within individual mice in two successive lactations. Backcrossing demonstrated that genetic background did not contribute significantly to variable expression. Tissue in situ hybridization revealed mosaicism of transgene expression within individual mammary glands from the two variable lines; in low expressors, discrete patches of cells expressing the transgene were observed. Transgene protein concentrations in milk reflected the proportion of epithelial cells expressing BLG mRNA. Furthermore, chromosomal in situ hybridization revealed that transgene arrays in both lines are situated close to the centromere. We propose that mosaicism of transgene expression is a consequence of the chromosomal location and/or the nature of the primary transgene integration event. PMID- 8692875 TI - Loss of oncogenic ras expression does not correlate with loss of tumorigenicity in human cells. AB - ras oncogenes are mutated in at variety of human tumors, which suggests that they play an important role in human carcinogenesis. To determine whether continued oncogenic ras expression is necessary to maintain the malignant phenotype, we studied the human fibrosarcoma cell line, HT1080, which contains one mutated and one wild-type N-ras allele. We isolated a variant of this cell line that no longer contained the mutated copy of the N-ras gene. Loss of mutant N-ras resulted in cells that displayed a less transformed phenotype characterized by a flat morphology, decreased growth rate, organized actin stress fibers, and loss of anchorage-independent growth. The transformed phenotype was restored following reintroduction of mutant N-ras. Although loss of the oncogenic N-ras drastically affected in vitro growth parameters, the variant remained tumorigenic in nude mice indicating that mutated N-ras expression is not necessary for maintenance of the tumorigenic phenotype. We confirmed this latter observation in colon carcinoma cell lines that have lost activated K-ras expression via targeted knockout of the mutant K-ras gene. PMID- 8692876 TI - A distribution of tumor size at detection and its limiting form. AB - A distribution of tumor size at detection is derived within the framework of a mechanistic model of carcinogenesis with the object of estimating biologically meaningful parameters of tumor latency. Its limiting form appears to be a generalization of the distribution that arises in the length-biased sampling from stationary point processes. The model renders the associated estimation problems tractable. The usefulness of the proposed approach is illustrated with an application to clinical data on premenopausal breast cancer. PMID- 8692877 TI - Alpha-helical, but not beta-sheet, propensity of proline is determined by peptide environment. AB - Proline is established as a potent breaker of both alpha-helical and beta-sheet structures in soluble (globular) proteins. Thus, the frequent occurrence of the Pro residue in the putative transmembrane helices of integral membrane proteins, particularly transport proteins, presents a structural dilemma. We propose that this phenomenon results from the fact that the structural propensity of a given amino acid may be altered to conform to changes imposed by molecular environment. To test this hypothesis on proline, we synthesized model peptides of generic sequence H2N-(Ser-LyS)2-Ala- Leu-Z-Ala-Leu-Z-Trp-Ala-Leu-Z-(Lys-Ser)3-OH (Z = Ala and/or Pro). Peptide conformations were analyzed by circular dichroism spectroscopy in aqueous buffer, SDS, lysophosphatidylglycerol micelles, and organic solvents (methanol, trifluoroethanol, and 2-propanol). The helical propensity of Pro was found to be greatly enhanced in the membrane-mimetic environments of both lipid micelles and organic solvents. Proline was found to stabilize the alpha-helical conformation relative to Ala at elevated temperatures in 2-propanol, an observation that argues against the doctrine that Pro is the most potent alpha-helix breaker as established in aqueous media. Parallel studies in deoxycholate micelles of the temperature-induced conformational transitions of the single-spanning membrane bacteriophage IKe major coat protein, in which the Pro-containing wild type was compared with Pro30 --> Ala mutant, Pro was found to protect the helix, but disrupt the beta-sheet structure as effectively as it does to model peptides in water. The intrinsic capacity of Pro to disrupt beta-sheets was further reflected in a survey of porins where Pro was found to be selectively excluded from the core of membrane-spanning beta-sheet barrels. The overall data provide a rationale for predicting and understanding the structural consequences when Pro occurs in the context of a membrane. PMID- 8692878 TI - Different functions for the interleukin 8 receptors (IL-8R) of human neutrophil leukocytes: NADPH oxidase and phospholipase D are activated through IL-8R1 but not IL-8R2. AB - Two monoclonal antibodies, anti-IL8R1 and anti-IL8R2, raised against both interleukin 8 receptors (IL-8R) of human neutrophils, IL-8R1 and IL-8R2, were used to study individual receptor functions after stimulation with IL-8, GRO alpha, or NAP-2. Efficacy and selectivity of the antibodies were tested in Jurkat cells transfected with cDNA coding for one or the other receptor. The binding of 125 I labeled IL-8 and IL-8-induced changes of the cytosolic free Ca2+ concentration were inhibited by anti-IL8RI in cells expressing IL-8R1 and by anti IL8R2 in cells expressing IL-8R2. In human neutrophils, release of elastase was observed after stimulation with IL-8 or GRO alpha. The response to IL-8 was inhibited slightly by anti-IL8R1 and more substantially when both monoclonal antibodies were present, while the response to GRO alpha was inhibited by anti IL8R2 but was not affected by anti-IL8R1. These results indicate that both IL-8 receptors can signal independently for granule enzyme release. Superoxide production, a measure of the respiratory burst, was obtained with increasing concentrations of IL-8 with maximum effects at 25 to 50 nM, but no response was observed upon challenge with GRO alpha or NAP-2 up to 1000 nM. The superoxide production induced by IL-8 was inhibited by anti-IL8R1, but was not affected by anti-IL8R2. Stimulation of neutrophils with IL-8, in contrast to GRO alpha or NAP 2, also elicited phospholipase D activity. The effect of IL-8 was again inhibited by anti-IL-8R1 but not by anti-IL8R2, indicating that this response, like the respiratory burst, was mediated by IL-8R1. Taken together, our results show that IL-8R1 and IL-8R2 are functionally different. Responses, such as cytosolic free Ca2+ changes and the release of granule enzymes, are mediated through both receptors, whereas the respiratory burst and the activation of phospholipase D depend exclusively on stimulation through IL-8R1. PMID- 8692879 TI - An alpha-mercaptoacrylic acid derivative is a selective nonpeptide cell-permeable calpain inhibitor and is neuroprotective. AB - Overactivation of calcium-activated neutral protease (calpain) has been implicated in the pathophysiology of several degenerative conditions, including stroke, myocardial ischemia, neuromuscular degeneration, and cataract formation. Alpha-mercaptoacrylate derivatives (exemplified by PD150606), with potent and selective inhibitory actions against calpain, have been identified. PD150606 exhibits the following characteristics: (i) Ki values for mu- and m-calpains of 0.21 microM and 0.37 microM, respectively, (ii) high specificity for calpains relative to other proteases, (iii) uncompetitive inhibition with respect to substrate, and (iv) it does not shield calpain against inactivation by the active site inhibitor trans-(epoxysuccinyl)-L-leucyl-amido-3-methylbutane, suggesting a nonactive site action for PD150606. The recombinant calcium-binding domain from each of the large or small subunits of mu-calpain was found to interact with PD150606. In low micromolar range, PD15O6O6 inhibited calpain activity in two intact cell systems. The neuroprotective effects of this class of compound were also demonstrated by the ability of PD150606 to attenuate hypoxic/hypoglycemic injury to cerebrocortical neurons in culture and excitotoxic injury to Purkinje cells in cerebellar slices. PMID- 8692880 TI - Pattern of gp120 sequence divergence linked to a lack of clinical progression in human immunodeficiency virus type 1 infection. AB - Differential rates of AIDS development and/or T4 lymphocyte depletion in HIV-1 infected individuals remain unexplained. The hypothesis that qualitative differences in selection pressure in vivo may account for different rates of disease progression was addressed in nine eligible study participants from a cohort of 315 homosexual men who have been followed since 1985. Disproportionately fewer changes in variable regions and more in C3 of gp12O were found to be significantly associated with slower disease progression. Our finding provides the first example to demonstrate that differential selection pressure related to the emergence of HIV-1 variants is associated with long term nonprogression. Candidate vaccines that elicit strong selection pressure on C3 of gp120 are likely to provide better protection than those targeting variable regions. PMID- 8692881 TI - Efficient and specific ribozyme-mediated reduction of bovine alpha-lactalbumin expression in double transgenic mice. AB - Transgenic mice carrying a bovine alpha-lactalbumin (alpha-lac) specific ribozyme gene under the transcriptional control of the mouse mammary tumor virus long terminal repeat were generated and cross-bred with animals that highly express a bovine alpha-lac transgene (0.4 mg of alpha-lac/ml(-1) of milk). The ribozyme contains the hammerhead catalytic domain, flanked by 12-nt sequences complementary to the 3' untranslated region of bovine alpha-lac transcript. High level expression of the ribozyme gene was detected by Northern blot analysis in the mammary gland of 7-8 day lactating transgenic mice, from 3 of 12 lines analyzed. Heterozygous expression of the ribozyme resulted in a reduction in the levels of the target mRNA to 78, 58, and 50% of that observed in the nonribozyme transgenic littermate controls for three independent lines. The ribozyme-mediated reduction in the levels of the bovine protein paralleled that observed for the mRNA, and was positively correlated with the level of expression of the ribozyme. In nonribozyme expressing transgenic mice, the level of bovine alpha-lac mRNA and protein was not affected. The specificity of this activity is demonstrated by the absence of a reduction in the levels of the endogenous murine alpha-lac mRNA or protein. These results demonstrate the feasibility of ribozyme-mediated down regulation of highly-expressed transcripts in transgenic animals. PMID- 8692882 TI - Simultaneous assessment of loss of heterozygosity at multiple microsatellite loci using semi-automated fluorescence-based detection: subregional mapping of chromosome 4 in cervical carcinoma. AB - Detection of loss of heterozygosity (LOH) by comparison of normal and tumor genotypes using PCR-based microsatellite loci provides considerable advantages over traditional Southern blotting-based approaches. However, current methodologies are limited by several factors, including the numbers of loci that can be evaluated for LOH in a single experiment, the discrimination of true alleles versus "stutter bands," and the use of radionucleotides in detecting PCR products. Here we describe methods for high throughput simultaneous assessment of LOH at multiple loci in human tumors; these methods rely on the detection of amplified microsatellite loci by fluorescence-based DNA sequencing technology. Data generated by this approach are processed by several computer software programs that enable the automated linear quantitation and calculation of allelic ratios, allowing rapid ascertainment of LOH. As a test of this approach, genotypes at a series of loci on chromosome 4 were determined for 58 carcinomas of the uterine cervix. The results underscore the efficacy, sensitivity, and remarkable reproducibility of this approach to LOH detection and provide subchromosomal localization of two regions of chromosome 4 commonly altered in cervical tumors. PMID- 8692883 TI - Conformational transitions monitored for single molecules in solution. AB - Phenomena that can be observed for a large number of molecules may not be understood if it is not possible to observe the events on the single-molecule level. We measured the fluorescence lifetimes of individual tetramethylrhodamine molecules, linked to an 18-mer deoxyribonucleotide sequence specific for M13 DNA, by time-resolved, single-photon counting in a confocal fluorescence microscope during Brownian motion in solution. When many molecules were observed, a biexponential fluorescence decay was observed with equal amplitudes. However, on the single-molecule level, the fraction of one of the amplitudes spanned from 0 to unity for a collection of single-molecule detections. Further analysis by fluorescence correlation spectroscopy made on many molecules revealed a process that obeys a stretched exponential relaxation law. These facts, combined with previous evidence of the quenching effect of guanosine on rhodamines, indicate that the tetramethylrhodamine molecule senses conformational transitions as it associates and dissociates to a guanosine-rich area. Thus, our results reveal conformational transitions in a single molecule in solution under conditions that are relevant for biological processes. PMID- 8692884 TI - Multivalent DNA-binding properties of the HMG-1 proteins. AB - HMG-I proteins are DNA-binding proteins thought to affect the formation and function of transcription complexes. Each protein contains three DNA-binding motifs, known as AT-hooks, that bind in the minor groove of AT tracts in DNA. Multiple AT-hooks within a polypeptide chain should contact multiple AT tracts, but the rules governing these interactions have not been defined. In this study, we demonstrate that high-affinity binding uses two or three appropriately spaced AT tracts as a single multivalent binding site. These principles have implications for binding to regulatory elements such as the interferon beta enhancer, TATA boxes, and serum response elements. PMID- 8692885 TI - The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation. AB - TRAF1 and TRAF2 form an oligomeric complex that associates with the cytoplasmic domains of various members of the tumor necrosis factor (TNF) receptor superfamily. TRAF2 action is required for activation of the transcription factor NF-kappaB triggered by TNF and the CD40 ligand. Here we show that TRAF1 and TRAF2 interact with A20, a zinc finger protein, whose expression is induced by agents that activate NF-kappaB. Mutational analysis revealed that the N-terminal half of A20 interacts with the conserved C-terminal TRAF domain of TRAF1 and TRAF2. In cotransfection experiments, A20 blocked TRAF2-mediated NF-kappaB activation. A20 also inhibited TNF and IL-1-induced NF-kappaB activation, suggesting that it may inhibit NF-kappaB activation signaled by diverse stimuli. The ability of A20 to block NF-kappaB activation was mapped to its C-terminal zinc finger domain. Thus, A20 is composed of two functionally distinct domains, an N-terminal TRAF binding domain that recruits A20 to the TRAF2-TRAF1 complex and a C-terminal domain that mediates inhibition of NF-kappaB activation. Our findings suggest a possible molecular mechanism that could explain A20's ability to negatively regulate its own TNF-inducible expression. PMID- 8692886 TI - An archaebacterial homologue of the essential eubacterial cell division protein FtsZ. AB - Life falls into three fundamental domains--Archaea, Bacteria, and Eucarya (formerly archaebacteria, eubacteria, and eukaryotes,. respectively). Though Archaea lack nuclei and share many morphological features with Bacteria, molecular analyses, principally of the transcription and translation machineries, have suggested that Archaea are more related to Eucarya than to Bacteria. Currently, little is known about the archaeal cell division apparatus. In Bacteria, a crucial component of the cell division machinery is FtsZ, a GTPase that localizes to a ring at the site of septation. Interestingly, FtsZ is distantly related in sequence to eukaryotic tubulins, which also interact with GTP and are components of the eukaryotic cell cytoskeleton. By screening for the ability to bind radiolabeled nucleotides, we have identified a protein of the hyperthermophilic archaeon Pyrococcus woesei that interacts tightly and specifically with GTP. Furthermore, through screening an expression library of P. woesei genomic DNA, we have cloned the gene encoding this protein. Sequence comparisons reveal that the P. woesei GTP-binding protein is strikingly related in sequence to eubacterial FtsZ and is marginally more similar to eukaryotic tubulins than are bacterial FtsZ proteins. Phylogenetic analyses reinforce the notion that there is an evolutionary linkage between FtsZ and tubulins. These findings suggest that the archaeal cell division apparatus may be fundamentally similar to that of Bacteria and lead us to consider the evolutionary relationships between Archaea, Bacteria, and Eucarya. PMID- 8692887 TI - Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. AB - The Ah receptor (AHR) is a ligand-activated transcription factor that mediates a pleiotropic response to environmental contaminants such as benzo[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. In an effort to gain insight into the physiological role of the AHR and to develop models useful in risk assessment, gene targeting was used to inactivate the murine Ahr gene by homologous recombination. Ahr-/- mice are viable and fertile but show a spectrum of hepatic defects that indicate a role for the AHR in normal liver growth and development. The Ahr-/- phenotype is most severe between 0-3 weeks of age and involves slowed early growth and hepatic defects, including reduced liver weight, transient microvesicular fatty metamorphosis, prolonged extramedullary hematopoiesis, and portal hypercellularity with thickening and fibrosis. PMID- 8692888 TI - Expression of galectin-3 modulates T-cell growth and apoptosis. AB - Galectin-3 is a member (if a large family of beta-galactoside-binding animal lectins. It has been shown that the expression of galectin-3 is upregulated in proliferating cells, suggesting a possible role for this lectin in regulation of cell growth. Previously, we have shown that T cells infected with human T-cell leukemia virus type I express high levels of galectin-3, in contrast to uninfected cells, which do not express detectable amounts of this protein. In this study, we examined growth properties of human leukemia T cells transfected with galectin-3 cDNA, and thus constitutively overexpressing this lectin. Transfectants expressing galectin-3 displayed higher growth rates than control transfectants, which do not express this lectin. Furthermore, galectin-3 expression in these cells confers resistance to apoptosis induced by anti-Fas antibody and staurosporine. Galectin-3 was found to have significant sequence similarity with Bcl-2, a well-characterized suppressor of apoptosis. In particular, the lectin contains the NWGR motif that is highly conserved among members of the Bcl-2 family and shown to be critical for the apoptosis suppressing activity. We further demonstrated that galectin-3 interacts with Bc1 2 in a lactose-inhibitable manner. We conclude that galectin-3 is a regulator of cell growth and apoptosis and it may function through a cell death inhibition pathway that involves Bcl-2. PMID- 8692889 TI - The human multidrug resistance-associated protein functionally complements the yeast cadmium resistance factor 1. AB - A Saccharomyces cerevisiae strain with a disrupted yeast cadmium resistance factor (YCF1) gene (DTY168) is hypersensitive to cadmium. YCF1 resembles the human multidrug resistance-associated protein MRP (63% amino acid similarity), which confers resistance to various cytotoxic drugs by lowering the intracellular drug concentration. Whereas the mechanism of action of YCF1 is not known, MRP was recently found to transport glutathione S-conjugates across membranes. Here we show that expression of the human MRP cDNA in yeast mutant DTY168 cells restores cadmium resistance to the wild-type level. Transport of S-(2,4-dinitrobenzene) glutathione into isolated yeast microsomal vesicles is strongly reduced in the DTY168 mutant and this transport is restored to wild-type level in mutant cells expressing MRP cDNA. We find in cell fractionation experiments that YCF1 is mainly localized in the vacuolar membrane in yeast, whereas MRP is associated both with the vacuolar membrane and with other internal membranes in the transformed yeast cells. Our results indicate that yeast YCF1 is a glutathione S conjugate pump, like MRP, and they raise the possibility that the cadmium resistance in yeast involves cotransport of cadmium with glutathione derivatives. PMID- 8692890 TI - Amyloid beta-peptide disrupts carbachol-induced muscarinic cholinergic signal transduction in cortical neurons. AB - Cholinergic pathways serve important functions in learning and memory processes, and deficits in cholinergic transmission occur in Alzheimer disease (AD). A subset of muscarinic cholinergic receptors are linked to G-proteins that activate phospholipase C, resulting in the liberation of inositol trisphosphate and Ca2+ release from intracellular stores. We now report that amyloid beta-peptide (Abeta), which forms plaques in the brain in AD, impairs muscarinic receptor activation of G proteins in cultured rat cortical neurons. Exposure of rodent fetal cortical neurons to Abeta25-35 and Abeta1-40 resulted in a concentration and time-dependent attenuation of carbachol-induced GTPase activity without affecting muscarinic receptor ligand binding parameters. Downstream events in the signal transduction cascade were similarly attenuated by Abeta. Carbachol-induced accumulation of inositol phosphates (IP, IP2, IP3, and IP4) was decreased and calcium imaging studies revealed that carbachol-induced release of calcium was severely impaired in neurons pretreated with Abeta. Muscarinic cholinergic signal transduction was disrupted with subtoxic levels of exposure to AP. The effects of Abeta on carbachol-induced GTPase activity and calcium release were attenuated by antioxidants, implicating free radicals in the mechanism whereby Abeta induced uncoupling of muscarinic receptors. These data demonstrate that Abeta disrupts muscarinic receptor coupling to G proteins that mediate induction of phosphoinositide accumulation and calcium release, findings that implicate Abeta in the impairment of cholinergic transmission that occurs in AD. PMID- 8692891 TI - Postembryonic segregation of the germ line in sea urchins in relation to indirect development. AB - The four small micromeres of the sea urchin embryo contribute only to the coelomic sacs, which produce major components of the adult body plan during postembryonic development. To test the proposition that the small micromeres are the definitive primordial germ cell lineage of the sea urchin, we deleted their 4th cleavage parents, and raised the deleted embryos through larval life and metamorphosis to sexual maturity. Almost all of the experimental animals produced functional gametes, excluding the possibility that the germ cell lineage arises exclusively and obligatorily from descendants of the small micromeres; rather, the germ cell lineage arises during the postembryonic development of the rudiment. A survey of the literature indicates that there is no known case of an embryonic primordial germ cell lineage in a bilaterian species that displays maximal indirect development. PMID- 8692893 TI - Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury. AB - Besides synthesizing nitric oxide (NO), purified neuronal NO synthase (nNOS) can produce superoxide (.O2-) at lower L-Arg concentrations. By using electron paramagnetic resonance spin-trapping techniques, we monitored NO and .O2- formation in nNOS-transfected human kidney 293 cells. In control transfected cells, the Ca2+ ionophore A23187 triggered NO generation but no .O2- was seen. With cells in L-Arg-free medium, we observed .O2- formation that increased as the cytosolic L-Arg levels decreased, while NO generation declined. .O2- formation was virtually abolished by the specific NOS blocker, N-nitro-L-arginine methyl ester (L-NAME). Nitrotyrosine, a specific nitration product of peroxynitrite, accumulated in L-Arg-depleted cells but not in control cells. Activation by A23187 was cytotoxic to L-Arg-depleted, but not to control cells, with marked lactate dehydrogenase release. The cytotoxicity was largely prevented by either superoxide dismutase or L-NAME. Thus, with reduced L-Arg availability NOS elicits cytotoxicity by generating .O2- and NO that interact to form the potent oxidant peroxynitrite. Regulating arginine levels may provide a therapeutic approach to disorders involving .O2-/NO-mediated cellular injury. PMID- 8692892 TI - Mutation of Pro-258 in transmembrane domain 6 constitutively activates the G protein-coupled alpha-factor receptor. AB - The alpha-factor pheromone receptor stimulates MATa yeast cells to undergo conjugation. The receptor contains seven transmembrane domains that function in ligand binding and in transducing a signal to the cytoplasmic receptor sequences to mediate G protein activation. A genetic screen was used to isolate receptor mutations that constitutively signal in the absence of alpha-factor. The Pro-258- >Leu (P258L) mutation caused constitutive receptor signaling that was equivalent to about 45% of the maximum level observed in wild-type cells stimulated with alpha-factor. Mutations of both Pro-258 and the adjacent Ser-259 to Leu increased constitutive signaling to > or = 90% of the maximum level. Since Pro-258 occurs in the central portion of transmembrane domain 6, and since proline residues are expected to cause a kink in alpha-helical domains, the P258L mutation is predicted to alter the structure of transmembrane domain 6. The P258L mutation did not result in a global distortion of receptor structure because alpha-factor bound to the mutant receptors with high affinity and induced even higher levels of signaling. These results suggest that sequences surrounding Pro-258 may be involved in ligand activation of the receptor. Conformational changes in transmembrane domain 6 may effect a change in the adjacent sequences in the third intracellular loop that are thought to function in G protein activation. Greater than 90% of all G protein-coupled receptors contain a proline residue at a similar position in transmembrane domain 6, suggesting that this aspect of receptor activation may be conserved in other receptors. PMID- 8692894 TI - The kinesin walk: a dynamic model with elastically coupled heads. AB - Recently individual two-headed kinesin molecules have been studied in in vitro motility assays revealing a number of their peculiar transport properties. In this paper we propose a simple and robust model for the kinesin stepping process with elastically coupled Brownian heads that show all of these properties. The analytic and numerical treatment of our model results in a very good fit to the experimental data and practically has no free parameters. Changing the values of the parameters in the restricted range allowed by the related experimental estimates has almost no effect on the shape of the curves and results mainly in a variation of the zero load velocity that can be directly fitted to the measured data. In addition, the model is consistent with the measured pathway of the kinesin ATPase. PMID- 8692895 TI - A mammalian 2-5A system functions as an antiviral pathway in transgenic plants. AB - Resistance to virus infections in higher vertebrates is mediated in part through catalysis of RNA decay by the, interferon-regulated 2-5A system. A functional 2 5A system requires two enzymes, a 2-5A synthetase that produces 5' phosphorylated, 2',5'-linked oligoadenylates (2-5A) in response to double stranded RNA, and the 2-5A-dependent RNase L. We have coexpressed these human enzymes in transgenic tobacco plants by using a single plasmid containing the cDNAs for both human RNase L and a low molecular weight form of human 2-5A synthetase under control of different, constitutive promoters. Expression of the human cDNAs in the transgenic plants was demonstrated from Northern blots, by specific enzyme assays, and by immunodetection (for RNase L). Infection of leaves, detached or in planta, of the coexpressing transgenic plants by tobacco mosaic virus, alfalfa [correction of alfafa] mosaic virus, or tobacco etch virus resulted in necrotic lesions. In contrast, leaves expressing 2-5A synthetase or RNase L alone and leaves containing the plasmid vector alone produced typical systemic infections. While alfalfa mosaic virus produced lesions only in the inoculated leaves regardless of the concentration of virus in the inoculum, high, but not low, levels of tobacco etch virus inoculum resulted in escape of virus to uninoculated leaves. Nevertheless, there was a substantial reduction of tobacco etch virus yield as measured by ELISA assay in the coexpressing transgenic plants. These results indicate that expression of a mammalian 2-5A system in plants provides resistance to virus infections. PMID- 8692896 TI - Negative electrostatic surface potential of protein sites specific for anionic ligands. AB - Determination of the crystal structure of an "open" unliganded active mutant (T141D) form of the Escherichia coli phosphate receptor for active transport has allowed calculation of the electrostatic surface potential for it and two other comparably modeled receptor structures (wild type and D137N). A discovery of considerable implication is the intensely negative potential of the phosphate binding cleft. We report similar findings for a sulfate transport receptor, a DNA binding protein, and, even more dramatically, redox proteins. Evidently, for proteins such as these, which rely almost exclusively on hydrogen bonding for anion interactions and electrostatic balance, a noncomplementary surface potential is not a barrier to binding. Moreover, experimental results show that the exquisite specificity and high affinity of the phosphate and sulfate receptors for unions are insensitive to modulations of charge potential, but extremely sensitive to conditions that leave a hydrogen bond donor or acceptor unpaired. PMID- 8692897 TI - Monophyletic origin and unique dispersal patterns of domestic fowls. AB - With the aim of elucidating in greater detail the genealogical origin of the present domestic fowls of the world, we have determined mtDNA sequences of the D loop regions for a total of 21 birds, of which 12 samples belong to red junglefowl (Gallus gallus) comprising three subspecies (six Gallus gallus gallus, three Gallus gallus spadiceus, and three Gallus gallus bankiva) and nine represent diverse domestic breeds (Gallus gallus domesticus). We also sequenced four green junglefowl (Gallus varius), two Lafayette's junglefowl (Gallus lafayettei), and one grey junglefowl (Gallus sonneratii). We then constructed a phylogenetic tree for these birds by the use of nucleotide sequences, choosing the Japanese quail (Coturnix coturnix japonica) as an outgroup. We found that a continental population of G. g. gallus was the real matriarchic origin of all the domestic poultries examined in this study. It is also of particular interest that there were no discernible differences among G. gallus subspecies; G. g. bankiva was a notable exception. This was because G. g. spadiceus and a continental population of G. g. gallus formed a single cluster in the phylogenetic tree. G. g. bankiva, on the other hand, was a distinct entity, thus deserving its subspecies status. It implies that a continental population of G. g. gallus sufficed as the monophyletic ancestor of all domestic breeds. We also discussed a possible significance of the initial dispersal pattern of the present domestic fowls, using the phylogenetic tree. PMID- 8692898 TI - Expression of calbindin-D28K in motoneuron hybrid cells after retroviral infection with calbindin-D28K cDNA prevents amyotrophic lateral sclerosis IgG mediated cytotoxicity. AB - Calbindin-D28K and/or parvalbumin appear to influence the selective vulnerability of motoneurons in amyotrophic lateral sclerosis (ALS). Their immunoreactivity is undetectable in motoneurons readily damaged in human ALS, and in differentiated motoneuron hybrid cells [ventral spinal cord (VSC 4.1 cells)] that undergo calcium-dependent apoptotic cell death in the presence of ALS immunoglobulins. To provide additional evidence for the role of calcium-binding proteins in motoneuron vulnerability, VSC 4.1 cells were infected with a retrovirus carrying calbindin-D28K cDNA under the control of the promoter of the phosphoglycerate kinase gene. Differentiated calbindin-D28K cDNA-infected cells expressed high calbindin-D28K and demonstrated increased resistance to ALS IgG-mediated toxicity. Treatment with calbindin-D28K antisense oligodeoxynucleotides, which significantly decreased calbindin-D28K expression, rendered these cells vulnerable again to ALS IgG toxicity. PMID- 8692899 TI - Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors. AB - Histamine H2 receptors transfected in Chinese hamster ovary (CHO) cells are time- and dose-dependently upregulated upon exposure to the H2 antagonists cimetidine and ranitidine. This effect appears to be H2 receptor-mediated as no change in receptor density was observed after H1 or H3 antagonist treatment or after incubation with the structural analogue of cimetidine, VUF 8299, which has no H2 antagonistic effects. By using transfected CHO cells expressing different densities of wild-type H2 receptors or an uncoupled H2Leu124Ala receptor, the histamine H2 receptor was found to display considerable agonist-independent H2 receptor activity. Cimetidine and ranitidine, which both induce H2 receptor upregulation, actually functioned as inverse agonists in those cell lines displaying spontaneous agonist-independent H2 receptor activity. Burimamide, on the other hand, was shown to act as a neutral antagonist and did as expected not induce H2 receptor upregulation after long-term exposure. The displayed inverse agonism of H2 antagonists appears to be a mechanistic basis for the observed H2 antagonist-induced H2 receptor upregulation in transfected CHO cells. These observations shed new light on the pharmacological classification of the H2 antagonists and may offer a plausible explanation for the observed development of tolerance after prolonged clinical use. PMID- 8692900 TI - Molecular cloning of the first metazoan beta-1,3 glucanase from eggs of the sea urchin Strongylocentrotus purpuratus. AB - We report the molecular cloning of the first beta-1,3 glucanase from animal tissue. Three peptide sequences were obtained from beta-1,3 glucanase that had been purified from eggs of the sea urchin Strongylocentrotus purpuratus and the gene was cloned by PCR using oligonucleotides deduced from the peptide sequences. The full-length cDNA shows a predicted enzyme structure of 499 aa with a hydrophobic signal sequence. A 3.2-kb message is present in eggs, during early embryogenesis, and in adult gut tissue. A polyclonal antibody to the native 68 kDa enzyme recognizes a single band during early embryogenesis that reappears in the adult gut, and recognizes a 57-kDa fusion protein made from a full-length cDNA clone for beta-1,3 glucanase. The identity of this molecule as beta-1,3 glucanase is confirmed by sequence homology, by the presence of all three peptide sequences in the deduced amino acid sequence, and by the recognition of the bacterial fusion protein by the antibody directed against the native enzyme. Data base searches show significant homology at the amino acid level to beta-1,3 glucanases from two species of bacteria and a clotting factor from the horseshoe crab. The homology with the bacteria is centered in a 304-aa region in which there are seven scattered regions of high homology between the four divergent species. These four species were also found to have two homologous regions in common with more distantly related plant, fungal, and bacterial proteins. A global phylogeny based on these regions strongly suggests that the glucanases are a very ancient family of genes. In particular, there is an especially deep split within genes taken from the bacterial genus Bacillus. PMID- 8692901 TI - Radioimmunotherapy with a 64Cu-labeled monoclonal antibody: a comparison with 67Cu. AB - 67Cu (t1/2 = 62 h) has demonstrated potential as a radionuclide for radioimmunotherapy, but limited availability severely restricts its widespread use. 64Cu (t1/2 = 12.8 h) has been shown to have comparable effectiveness in vitro and in vivo. The present study was undertaken to examine the therapeutic potential of 64Cu- and 67Cu-bromoacetamidobenzyl-1,4,8,11-tetraazacyclotetradeca ne-N, N',N",N"'-tetraacetic acid (BAT)-2-iminothiolane (2IT)-1A3 (1A3 is a mouse anti-human colorectal cancer mAb) for treatment of GW39 human colon carcinoma carried in hamster thighs. Hamsters were injected with 64Cu- or 67Cu-BAT-2IT-1A3 or Cu-labeled nonspecific IgG (MOPC) or saline. Hamsters were killed 6-7 months after therapy or when tumors were > or = 10 g. Of the hamsters with small tumors (mean weight 0.43 +/- 0.25 g), 87.5% were disease-free 7 months after treatment with 2 mCi (1 Ci = 37 GBq) of 64Cu-BAT-2IT-1A3 or 0.4 MCi of 67Cu-BAT-2IT-1A3. The mean tumor doses at these activities of 64Cu- and 67Cu-BAT-2IT-1A3 were 586 and 1269 rad (1 rad = 0.01 Gy), respectively. In contrast, 76% of hamsters treated with 2 mCi of 64Cu-BAT-2IT-MOPC or 0.4 mCi of 67Cu-BAT-2IT-MOPC had to be killed before 6 months because of tumor regrowth. When hamsters with larger tumors (mean weight 0.66 +/- 0.11 g) were treated with 64Cu- or 67Cu-BAT-2IT-1A3, survival was extended compared with controls, but only one animal remained tumor free to 6 months. These results demonstrate that 64Cu- and 67Cu-BAT-2IT-1A3 given in a single administered dose can eradicate small tumors without significant host toxicity, but additional strategies to deliver higher tumor doses will be needed for larger tumors. PMID- 8692902 TI - Cloning and characterization of cDNAs for matrix metalloproteinases of regenerating newt limbs. AB - Matrix metalloproteinases (MMPs) of regenerating urodele limbs have been suggested to play crucial roles in the process of the dedifferentiation of cells in the damaged tissues and the ensuing blastema formation because the activation of MMPs is an early and conspicuous event occurring in the amputated limb. MMP cDNAs were cloned as products of the reverse transcription-PCR from cDNA libraries of newt limbs, and their structures were characterized. Three cDNAs encoding newt MMPs (2D-1, 2D-19, and 2D-24) have been cloned from second day postamputation regenerating limbs, and a cDNA (EB-1) was cloned from early bud stage regenerating limbs. These cDNAs included the full-length coding regions. The deduced amino acid sequences of 2D-1, 2D-19, 2D-24, and EB-1 had a homology with mammalian MMP9, MMP3/10, MMP3/10, and MMP13, respectively. The basic motif of these newt MMP genes was similar to mammalian counterparts and contained regions encoding a putative signal sequence, a propeptide, an active site with three zinc-binding histidine residues, a calcium-binding domain, a hemopexin region, and three key cysteine residues. However, some unique molecular evolutionary features were also found in the newt MMPs. cDNAs of 2D-19 and 2D-24 contained a specific insertion and deletion, respectively. The insertion of 2D-19 is threonine-rich, similar to the threonine cluster found in the collagenase-like sea urchin hatching enzyme. Northern blot analysis showed that the expression levels of the newt MMPs were dramatically increased after amputation, suggesting that they play an important role(s) in tissue remodeling of the regenerating limb. PMID- 8692903 TI - Surface antigen cross-linking triggers forced exit of a protozoan parasite from its host. AB - We used the common fish pathogen Ichthyophthirius multifiliis as a model for studying interactions between parasitic ciliates and their vertebrate hosts. Although highly pathogenic, Ichthyophthirius can elicit a strong protective immune response in fish after exposure to controlled infections. To investigate the mechanisms underlying host resistance, a series of passive immunization experiments were carried out using mouse monoclonal antibodies against a class of surface membrane proteins, known as immobilization antigens (or i-antigens), thought to play a role in the protective response. Such antibodies bind to cilia and immobilize I. multifiliis in vitro. Surprisingly, we found that passive antibody transfer in vivo caused rapid exit of parasites from the host. The effect was highly specific for a given I. multifiliis serotype. F(ab)2 subfragments had the same effect as intact antibody, whereas monovalent Fab fragments failed to protect. The activity of Fab could, nevertheless, be restored after subsequent i.p. injection of bivalent goat anti-mouse IgG. Parasites that exit the host had detectable antibody on their surface and appeared viable in all respects. These findings represent a novel instance among protists in which protective immunity (and evasion of the host response) result from an effect of antibody on parasite behavior. PMID- 8692904 TI - Neural plasticity in adults with amblyopia. AB - Amblyopia is a neuronal abnormality of vision that is often considered irreversible in adults. We found strong and significant improvement of Vernier acuity in human adults with naturally occurring amblyopia following practice. Learning was strongest at the trained orientation and did not transfer to an untrained task (detection), but it did transfer partially to the untrained eye (primarily at the trained orientation). We conclude that this perceptual learning reflects alterations in early neural processes that are localized beyond the site of convergence of the two eyes. Our results suggest a significant degree of plasticity in the visual system of adults with amblyopia. PMID- 8692905 TI - Antifreeze glycoproteins inhibit leakage from liposomes during thermotropic phase transitions. AB - Antifreeze glycoproteins (AFGPs), found in the blood of polar fish at concentrations as high as 35 g/liter, are known to prevent ice crystal growth and depress the freezing temperature of the blood. Previously, Rubinsky et al. [Rubinsky, B., Mattioli, M., Arav, A., Barboni, B. & Fletcher, G. L. (1992) Am. J. Physiol. 262, R542-R545] provided evidence that AFGPs block ion fluxes across membranes during cooling, an effect that they ascribed to interactions with ion channels. We investigated the effects of AFGPs on the leakage of a trapped marker from liposomes during chilling. As these liposomes are cooled through the transition temperature, they leak approximately 50% of their contents. Addition of less than 1 mg/ml of AFGP prevents up to 100% of this leakage, both during chilling and warming through the phase transition. This is a general effect that we show here applies to liposomes composed of phospholipids with transition temperatures ranging from 12 degrees C to 41 degrees C. Because these results were obtained with liposomes composed of phospholipids alone, we conclude that the stabilizing effects of AFGPs on intact cells during chilling reported by Rubinsky et al. may be due to a nonspecific effect on the lipid components of native membranes. There are other proteins that prevent leakage, but only under specialized conditions. For instance, antifreeze proteins, bovine serum albumin, and ovomucoid all either have no effect or actually induce leakage. Following precipitation with acetone, all three proteins inhibited leakage, although not to the extent seen with AFGPs. Alternatively, there are proteins such as ovotransferrin that have no effect on leakage, either before or after acetone precipitation. PMID- 8692906 TI - Identifying functional domains within terpene cyclases using a domain-swapping strategy. AB - Cyclic terpenes and terpenoids are found throughout nature. They comprise an especially important class of compounds from plants that mediate plant- environment interactions, and they serve as pharmaceutical agents with antimicrobial and anti-tumor activities. Molecular comparisons of several terpene cyclases, the key enzymes responsible for the multistep cyclization of C10, C15, and C20 allylic diphosphate substrates, have revealed a striking level of sequence similarity and conservation of exon position and size within the genes. Functional domains responsible for a terminal enzymatic step were identified by swapping regions approximating exons between a Nicotiana tabacum 5-epi aristolochene synthase (TEAS) gene and a Hyoscyamus muticus vetispiradiene synthase (HVS) gene and by characterization of the resulting chimeric enzymes expressed in bacteria. While exon 4 of the TEAS gene conferred specificity for the predominant reaction products of the tobacco enzyme, exon 6 of the HVS gene conferred specificity for the predominant reaction products of the Hyoscyamus enzyme. Combining these two functional domains of the TEAS and HVS genes resulted in a novel enzyme capable of synthesizing reaction products reflective of both parent enzymes. The relative ratio of the TEAS and HVS reaction products was also influenced by the source of exon 5 present in the new chimeric enzymes. The association of catalytic activities with conserved but separate exonic domains suggests a general means for generating additional novel terpene cyclases. PMID- 8692907 TI - Chromosome manipulation: a systematic approach toward understanding human chromosome structure and function. PMID- 8692908 TI - Probing the oligomeric structure of an enzyme by electrospray ionization time-of flight mass spectrometry. AB - Electrospray ionization time-of-flight (ESI-TOF) mass spectrometry was used to study the quaternary structure of 4-oxalocrotonate tautomerase (EC 5.3.2; 4OT), and four analogues prepared by total chemical synthesis. Wild-type 4OT is a hexamer of 62 amino acid subunits and contains no cysteine residues. The analogues were: (desPro1)4OT, a truncated construct in which Pro1 was deleted; (Cpc1)4OT in which Pro1 was replaced with cyclopentane carboxylate; a derivative [Met(O)45]4OT in which Met45 was oxidized to the sulfoxide; and an analogue (Nle45)4OT in which Met45 was replaced with norleucine. ESI of (Nle45)4OT, (Cpc1)4OT, and 4OT from solution conditions under which the native enzyme was fully active (5 mM ammonium bicarbonate buffer, pH 7.5) gave the intact hexamer as the major species detected by TOF mass spectrometry. In contrast, analysis of [Met(O)45]4OT and (desPro1)4OT under similar conditions yielded predominantly monomer ions. The ESI-TOF measurements were consistent with structural data obtained from circular dichroism spectroscopy. In the context of kinetic data collected for 4OT and these analogues, ESI-TOF mass spectrometry also provided important evidence for the structural and mechanistic significance of the catalytically important Pro1 residue in 4OT. PMID- 8692910 TI - Ferulate-5-hydroxylase from Arabidopsis thaliana defines a new family of cytochrome P450-dependent monooxygenases. AB - The fah1 mutant of Arabidopsis is defective in the accumulation of sinapic acid derived metabolites, including the guaiacyl-syringyl lignin typical of angiosperms. Earlier results indicated that the FAH1 locus encodes ferulate-5 hydroxylase (F5H), a cytochrome P450-dependent monooxygenase (P450) of the general phenylpropanoid pathway. We have cloned the gene encoding this P450 by T DNA tagging and have confirmed the identity of the cloned gene by complementation of the mutant phenotype. F5H shows 34% amino acid sequence identity with the avocado ripening-induced P450 CYP71A1 and 32% identity with the flavonoid-3',5' hydroxylases of Petunia hybrida. In contrast, it shares much less homology with cinnamate-4-hydroxylase, a P450 that catalyzes the hydroxylation of cinnamic acid three steps earlier in the general phenylpropanoid pathway. Since the highest degree of identity between F5H and previously sequenced P450s is only 34%, F5H identifies a new P450 subfamily that has been designated CYP84. PMID- 8692911 TI - Molecular mechanics calculations of the riboacetal internucleotide linkage in double and triple helices. AB - Structures of Watson-Crick base paired 15-nucleobase oligomer strands in A-type or B-type conformation in which one strand [a strand of alternating nucleotide and riboacetal thymidine nucleoside (RT) units, RP] is DNA and the other is composed of alternating nucleotides and riboacetal nucleosides have been studied by molecular mechanics. Analogously, oligomer strands of RNA in place of DNA have been modeled. The calculations indicate that the RP strand is more stable when complexed in an A-type duplex relative to a B-type form and that this conformational preference is presumably due to the more uniform nature of the former. Nearly planar ribose rings were more commonly observed in the minimized structures of the B-type DNA.RP duplexes as compared with A-type duplexes, despite the fact that planar ribofuranose rings are known to be energetically unfavorable in oligonucleotides. Computed relative stabilities of all duplexes containing the RP strand suggest that such heteroduplexes are less stable than the corresponding double-stranded DNA and double-stranded RNA species. These findings are in agreement with experimental results which show, when equivalent sequences were compared, that a DNA.RNA control forms a more stable duplex than RP hound to a complementary single-stranded RNA strand. In contrast, molecular mechanics studies of complementary triple-helical (DNA)2.RP, (DNA)2.DNA, and (DNA)2.RNA structures indicate that the binding of RP as a Hoogsteen strand stabilizes the underlying duplex to a greater extent compared with native oligonucleotides. These calculations suggest that puckering of the ribose ring in the riboacetal linkage leads to a more favorable interaction with a complementary nucleic acid target than the proposed planar geometry and that this puckering may account for the enhanced binding of RP to a double-stranded target. PMID- 8692909 TI - Differential display of intestinal mRNAs regulated by dietary zinc. AB - Regulation of gene expression by zinc is well established, especially through the metal response elements of the metallothionein genes; however, most other aspects of the functions of zinc in gene expression remain unknown. We have looked for intestinal mRNAs that are regulated by dietary zinc status. Using the reverse transcriptase-PCR method of mRNA differential display, we compared intestinal mRNA from rats that were maintained for 18 days in one of three dietary groups: zinc-deficient, zinc-adequate, and pair-fed zinc-adequate. At the end of this period, total RNA was prepared from the intestine and analyzed by mRNA differential display. Under these conditions, only differentially displayed cDNA bands that varied in the zinc-deficient group, relative to the zinc-adequate groups, were selected. Utilizing two anchored oligo-dT3' PCR primers and a total of 27 arbitrary decamers as 5' PCR primers, our results yielded 47 differentially displayed cDNA bands from intestinal RNA. Thirty were increased in zinc deficiency, and 17 were decreased. Nineteen bands were subcloned and sequenced. Eleven of these were detectable on Northern blots, of which four were confirmed as regulated. Three of these have homology to known genes: cholecystokinin, uroguanylin, and ubiquinone oxidoreductase. The fourth is a novel sequence as it has no significant homology in GenBank. The remainder of those cloned included novel sequences, as well as matches to reported expressed sequence tags, and functionally identified genes. Further characterization of the regulated sequences identified here will show whether they are primary or secondary effects of zinc deficiency. PMID- 8692912 TI - High mobility group I(Y)-like DNA-binding domains on a bacterial transcription factor. AB - The bacterium Myxococcus xanthus responds to blue light by producing carotenoids. It also responds to starvation conditions by developing fruiting bodies, where the cells differentiate into myxospores. Each response entails the transcriptional activation of a separate set of genes. However, a single gene, carD, is required for the activation of both light- and starvation-inducible genes. Gene carD has now been sequenced. Its predicted amino acid sequence includes four repeats of a DNA-binding domain present in mammalian high mobility group I(Y) proteins and other nuclear proteins from animals and plants. Other peptide stretches on CarD also resemble functional domains typical of eukaryotic transcription factors, including a very acidic region and a leucine zipper. High mobility group yI(Y) proteins are known to bind the minor groove of A+T-rich DNA. CarD binds in vitro an A+T-rich element that is required for the proper operation of a carD-dependent promoter in vivo. PMID- 8692913 TI - Conservation and diversification in homeodomain-DNA interactions: a comparative genetic analysis. AB - Nearly all metazoan homeodomains (HDs) possess DNA binding targets that are related by the presence of a TAAT sequence. We use an in vitro genetic DNA binding site selection assay to refine our understanding of the amino acid determinants for the recognition of the TAAT site. Superimposed upon the conserved ability of metazoan HDs to recognize a TAAT core is a difference in their preference for the bases that lie immediately 3' to it. Amino acid position 50 of the HD has been shown to discriminate among these base pairs, and structural studies have suggested that water-mediated hydrogen bonds and van der Waals contacts underlie for this ability. Here, we show that each of six amino acids tested at position 50 can confer a distinct DNA binding specificity. PMID- 8692914 TI - Mutational analysis of NM23-H2/NDP kinase identifies the structural domains critical to recognition of a c-myc regulatory element. AB - NM23-H2, a presumed regulator of tumor metastasis in humans, is a hexameric protein with both enzymatic (NDP kinase) and regulatory (transcriptional activation) activity. While the structure and catalytic mechanisms have been well characterized, the mode of DNA binding is not known. We examined this latter function in a site-directed mutational study and identified residues and domains essential for the recognition of a c-myc regulatory sequence. Three amino acids, Arg-34, Asn-69, and Lys-135, were found among 30 possibilities to be critical for DNA binding. Two of these, Asn-69 and Lys-135, are not conserved between NM23 variants differing in DNA-binding potential, suggesting that DNA recognition resides partly in nonconserved amino acids. All three DNA-binding defective mutant proteins are active enzymatically and appear to be stable hexamers, suggesting that they perform at the level of DNA recognition and that separate functional domains exist for enzyme catalysis and DNA binding. In the context of the known crystal structure of NM23-H2, the DNA-binding residues are located within distinct structural motifs in the monomer, which are exposed to the surface near the 2-fold axis of adjacent subunits in the hexamer. These findings are explained by a model in which NM23-H2 binds DNA with a combinatorial surface consisting of the "outer" face of the dimer. Chemical crosslinking data support a dimeric DNA-binding mode by NM23-H2. PMID- 8692915 TI - The stress response to ionizing radiation involoves c-Abl-dependent phosphorylation of SHPTP1. AB - c-Abl is a nonreceptor tyrosine kinase that is activated by certain DNA-damaging agents. The present studies demonstrate that nuclear c-Abl binds constitutively to the protein tyrosine phosphatase SHPTP1. Treatment with ionizing radiation is associated with c-Abl-dependent tyrosine phosphorylation of SHPTP1. The results demonstrate that the SH3 domain of c-Abl interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that c-Abl phosphorylates C terminal Y536 and Y564 sites. The functional significance of the c-Abl-SHPTP1 interaction is supported by the demonstration that, like c-Abl, SHPTP1 regulates the induction of Jun kinase activity following DNA damage. These findings indicate that SHPTP1 is involved in the response to genotoxic stress through a c-Abl-dependent mechanism. PMID- 8692916 TI - Crystal structure of the catalytic domain of Pseudomonas exotoxin A complexed with a nicotinamide adenine dinucleotide analog: implications for the activation process and for ADP ribosylation. AB - The catalytic, or third domain of Pseudomonas exotoxin A (PEIII) catalyzes the transfer of ADP ribose from nicotinamide adenine dinucleotide (NAD) to elongation factor-2 in eukaryotic cells, inhibiting protein synthesis. We have determined the structure of PEIII crystallized in the presence of NAD to define the site of binding and mechanism of activation. However, NAD undergoes a slow hydrolysis and the crystal structure revealed only the hydrolysis products, AMP and nicotinamide, bound to the enzyme. To better define the site of NAD binding, we have now crystallized PEIII in the presence of a less hydrolyzable NAD analog, beta-methylene-thiazole-4-carboxamide adenine dinucleotide (beta-TAD), and refined the complex structure at 2.3 angstroms resolution. There are two independent molecules of PEIII in the crystal, and the conformations of beta-TAD show some differences in the two binding sites. The beta-TAD attached to molecule 2 appears to have been hydrolyzed between the pyrophosphate and the nicotinamide ribose. However molecule 1 binds to an intact beta-TAD and has no crystal packing contacts in the vicinity of the binding site, so that the observed conformation and interaction with the PEIII most likely resembles that of NAD bound to PEIII in solution. We have compared this complex with the catalytic domains of diphtheria toxin, heat labile enterotoxin, and pertussis toxin, all three of which it closely resembles. PMID- 8692917 TI - Mutational analysis and molecular modeling of the nonapeptide hormone binding domains of the [Arg8]vasotocin receptor. AB - To identify determinants that form nonapeptide hormone binding domains of the white sucker Catostomus commersoni [Arg8]vasotocin receptor, chimeric constructs encoding parts of the vasotocin receptor and parts of the isotocin receptor have been analyzed by [(3,5-3H)Tyr2, Arg8]vasotocin binding to membranes of human embryonic kidney cells previously transfected with the different cDNA constructs and by functional expression studies in Xenopus laevis oocytes injected with mutant cRNAs. The results indicate that the N terminus and a region spanning the second extracellular loop and its flanking transmembrane segments, which contains a number of amino acid residues that are conserved throughout the nonapeptide receptor family, contribute to the affinity of the receptor for its ligand. Nonapeptide selectivity, however, is mainly defined by transmembrane region VI and the third extracellular loop. These results are complemented by a molecular model of the vasotocin receptor obtained by aligning its sequence with those of other G-protein coupled receptors as well as that of bacteriorhodopsin. The model indicates that amino acid residues of transmembrane regions II-VII that are located close to the extracellular surface also contribute to the binding of vasotocin. PMID- 8692918 TI - The structure of bovine F1-ATPase complexed with the antibiotic inhibitor aurovertin B. AB - In the structure of bovine mitochondrial F1-ATPase that was previously determined with crystals grown in the presence of adenylyl-imidodiphosphate (AMP-PNP) and ADP, the three catalytic beta-subunits have different conformations and nucleotide occupancies. Adenylyl-imidodiphosphate is bound to one beta-subunit (betaTP), ADP is bound to the second (betaDP), and no nucleotide is bound to the third (betaE). Here we show that the uncompetitive inhibitor aurovertin B binds to bovine F1 at two equivalent sites in betaTP and betaE, in a cleft between the nucleotide binding and C-terminal domains. In betaDP, the aurovertin B pocket is incomplete and is inaccessible to the inhibitor. The aurovertin B bound to betaTP interacts with alpha-Glu399 in the adjacent alphaTP subunit, whereas the aurovertin B bound to betaE is too distant from alphaE to make an equivalent interaction. Both sites encompass betaArg-412, which was shown by mutational studies to be involved in binding aurovertin. Except for minor changes around the aurovertin pockets, the structure of bovine F1-ATPase is the same as determined previously. Aurovertin B appears to act by preventing closure of the catalytic interfaces, which is essential for a catalytic mechanism involving cyclic interconversion of catalytic sites. PMID- 8692919 TI - Evidence for a novel DNA damage binding protein in human cells. AB - We describe a novel DNA damage binding activity in nuclear extracts from a normal human fibroblast cell strain. This protein was identified using electrophoretic mobility shift assays of immunopurified UV-irradiated oligonucleotide substrates containing a single, site-specific cyclobutane pyrimidine dimer or a pyrimidine (6-4) pyrimidinone photoproduct. Compared with the (6-4) photoproduct, which displayed similar levels of binding in double and single-stranded substrates, the protein showed somewhat lower affinity for the cyclobutane dimer in a single stranded oligonucleotide and negligible binding in double-stranded DNA. The specificity and magnitude of binding was similar in cells with normal excision repair (GM637) and repair-deficient cells from xeroderma pigmentosum groups A (XP12RO) and E (XP2RO). An apparent molecular mass of 66 kDa consisting of two subunits of approximately 22 and approximately 44 kDa was determined by Southwestern analysis. Cell cycle studies using centrifugal cell elutriation indicated that the binding activity was significantly greater in G1 phase compared with S phase in a human lymphoblast cell line. Gel supershift analysis using an anti-replication protein A antibody showed that the binding protein was not antigenically related to the human single-stranded binding protein. Taken together, these data suggest that this activity represents a novel DNA damage binding protein that, in addition to a putative role in excision repair, may also function in cell cycle or gene regulation. PMID- 8692920 TI - Activation of the Raf-1/MAP kinase cascade is not sufficient for Ras transformation of RIE-1 epithelial cells. AB - The potent transforming activity of membrane-targeted Raf-1 (Raf-CAAX) suggests that Ras transformation is triggered primarily by a Ras-mediated translocation of Raf-1 to the plasma membrane. However, whereas constitutively activated mutants of Ras [H-Ras(61L) and K-Ras4B(12V)] and Raf-1 (DeltaRaf-22W and Raf-CAAX) caused indistinguishable morphologic and growth (in soft agar and nude mice) transformation of NIH 3T3 fibroblasts, only mutant Ras caused morphologic transformation of RIE-1 rat intestinal cells. Furthermore, only mutant Ras expressing RIE-1 cells formed colonies in soft agar and developed rapid and progressive tumors in nude mice. We also observed that activated Ras, but not Raf 1, caused transformation of IEC-6 rat intestinal and MCF-10A human mammary epithelial cells. Although both Ras- and DeltaRaf-22W-expressing RIE-1 cells showed elevated Raf-1 and mitogen-activated protein (MAP) kinase activities, only Ras-transformed cells produced secreted factors that promoted RIE-1 transformation. Incubation of untransformed RIE-1 cells in the presence of conditioned medium from Ras-expressing, but not DeltaRaf-22W-expressing, cells caused a rapid and stable morphologic transformation that was indistinguishable from the morphology of Ras-transformed RIE-1 cells. Thus, induction of an autocrine growth mechanism may distinguish the transforming actions of Ras and Raf. In summary, our observations demonstrate that oncogenic Ras activation of the Raf/MAP kinase pathway alone is not sufficient for full tumorigenic transformation of RIE-1 epithelial cells. Thus, Raf-independent signaling events are essential for oncogenic Ras transformation of epithelial cells, but not fibroblasts. PMID- 8692921 TI - ATP-dependent uptake of natural product cytotoxic drugs by membrane vesicles establishes MRP as a broad specificity transporter. AB - MRP is a recently isolated ATP-binding cassette family transporter. We previously reported transfection studies that established that MRP confers multidrug resistance [Kruh, G. D., Chan, A., Myers, K., Gaughan, K., Miki, T. & Aaronson, S. A. (1994) Cancer Res. 54, 1649-1652] and that expression of MRP is associated with enhanced cellular efflux of lipophilic cytotoxic agents [Breuninger, L. M., Paul, S., Gaughan, K., Miki, T., Chan, A., Aaronson, S. A. & Kruh, G. D. (1995) Cancer Res. 55, 5342-5347]. To examine the biochemical mechanism by which MRP confers multidrug resistance, drug uptake experiments were performed using inside out membrane vesicles prepared from NIH 3T3 cells transfected with an MRP expression vector. ATP-dependent transport was observed for several lipophilic cytotoxic agents including daunorubicin, etoposide, and vincristine, as well as for the glutathione conjugate leukotriene C4 (LTC4). However, only marginally increased uptake was observed for vinblastine and Taxol. Drug uptake was osmotically sensitive and saturable with regard to substrate concentration, with Km values of 6.3 microM, 4.4 microM, 4.2 microM, 35 nM, and 38 microM, for daunorubicin, etoposide, vincristine, LTC4, and ATP, respectively. The broad substrate specificity of MRP was confirmed by the observation that daunorubicin transport was competitively inhibited by reduced and oxidized glutathione, the glutathione conjugates S-(p-azidophenacyl)-glutathione (APA-SG) and S-(2,4 dinitrophenyl)glutathione (DNP-SG), arsenate, and the LTD4 antagonist MK571. This study establishes that MRP pumps unaltered lipophilic cytotoxic drugs, and suggests that this activity is an important mechanism by which the transporter confers multidrug resistance. The present study also indicates that the substrate specificity of MRP is overlapping but distinct from that of P-glycoprotein, and includes both the neutral or mildly cationic natural product cytotoxic drugs and the anionic products of glutathione conjugation. The widespread expression of MRP in tissues, combined with its ability to transport both lipophilic xenobiotics and the products of phase II detoxification, indicates that the transporter represents a widespread and remarkably versatile cellular defense mechanism. PMID- 8692922 TI - Increased accommodation of nascent RNA in a product site on RNA polymerase II during arrest. AB - RNA polymerases encounter specific DNA sites at which RNA chain elongation takes place in the absence of enzyme translocation in a process called discontinuous elongation. For RNA polymerase II, at least some of these sequences also provoke transcriptional arrest where renewed RNA polymerization requires elongation factor SII. Recent elongation models suggest the occupancy of a site within RNA polymerase that accommodates nascent RNA during discontinuous elongation. Here we have probed the extent of nascent RNA extruded from RNA polymerase II as it approaches, encounters, and departs an arrest site. Just upstream of an arrest site, 17-19 nucleotides of the RNA 3'-end are protected from exhaustive digestion by exogenous ribonuclease probes. As RNA is elongated to the arrest site, the enzyme does not translocate and the protected RNA becomes correspondingly larger, up to 27 nucleotides in length. After the enzyme passes the arrest site, the protected RNA is again the 18-nucleotide species typical of an elongation competent complex. These findings identify an extended RNA product groove in arrested RNA polymerase II that is probably identical to that emptied during SII activated RNA cleavage, a process required for the resumption of elongation. Unlike Escherichia coli RNA polymerase at a terminator, arrested RNA polymerase II does not release its RNA but can reestablish the normal elongation mode downstream of an arrest site. Discontinuous elongation probably represents a structural change that precedes, but may not be sufficient for, arrest by RNA polymerase II. PMID- 8692923 TI - Lack of the DNA repair protein O6-methylguanine-DNA methyltransferase in histologically normal brain adjacent to primary human brain tumors. AB - Exposure to exogenous alkylating agents, particularly N-nitroso compounds, has been associated with increased incidence of primary human brain tumors, while intrinsic risk factors are currently unknown. The DNA repair protein O6 methylguanine-DNA methyltransferase (MGMT) is a major defense against the carcinogenicity of N-nitroso compounds and other alkylators. We report here that in 55% (64/117) of cases, histologically normal brain tissue adjacent to primary human brain tumors lacked detectable MGMT activity [methyl excision repair defective (Mer-) status]. The incidence of Mer- status in normal brain tissue from brain tumor patients was age-dependent, increasing from 21% in children 0.25 19 years of age to 75% in adults over 50. In contrast, Mer- status was found in 12% (5/43) of normal brain specimens from patients operated for conditions other than primary brain tumors and was not age-dependent. The 4.6-fold elevation in incidence of Mer- status in brain tumor patients is highly significant (chi2 = 24; p < or = 0.001). MGMT activity was independent of age in the lymphocytes of brain tumor patients and was present in lymphocytes from six of nine tumor patients whose normal brain specimen was Mer-. DNA polymerase beta, apurinic/apyrimidinic endonuclease, and lactate dehydrogenase activities were present in all specimens tested, including Mer- specimens from brain tumor patients. Our data are consistent with a model of carcinogenesis in human brain in which epigenetically regulated lack of MGMT is a predisposing factor and alkylation-related mutagenesis is a driving force. PMID- 8692924 TI - BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional repressor. AB - Approximately 40% of diffuse large cell lymphoma are associated with chromosomal translocations that deregulate the expression of the BCL6 gene by juxtaposing heterologous promoters to the BCL-6 coding domain. The BCL6 gene encodes a 95-kDa protein containing six C-terminal zinc-finger motifs and an N-terminal POZ domain, suggesting that it may function as a transcription factor. By using a DNA sequence selected for its ability to bind recombinant BCL-6 in vitro, we show here that BCL-6 is present in DNA-binding complexes in nuclear extracts from various B-cell lines. In transient transfectin experiments, BCL6 can repress transcription from promoters linked to its DNA target sequence and this activity is dependent upon specific DNA-binding and the presence of an intact N-terminal half of the protein. We demonstrate that this part of the BCL6 molecule contains an autonomous transrepressor domain and that two noncontiguous regions, including the POZ motif, mediate maximum transrepressive activity. These results indicate that the BCL-6 protein can function as a sequence-specific transcriptional repressor and have implications for the role of BCL6 in normal lymphoid development and lymphomagenesis. PMID- 8692925 TI - Interactions between tRNA identity nucleotides and their recognition sites in glutaminyl-tRNA synthetase determine the cognate amino acid affinity of the enzyme. AB - Sequence-specific interactions between aminoacyl-tRNA synthetases and their cognate tRNAs both ensure accurate RNA recognition and prevent the binding of noncognate substrates. Here we show for Escherichia coli glutaminyl-tRNA synthetase (GlnRS; EC 6.1.1.18) that the accuracy of tRNA recognition also determines the efficiency of cognate amino acid recognition. Steady-state kinetics revealed that interactions between tRNA identity nucleotides and their recognition sites in the enzyme modulate the amino acid affinity of GlnRS. Perturbation of any of the protein-RNA interactions through mutation of either component led to considerable changes in glutamine affinity with the most marked effects seen at the discriminator base, the 10:25 base pair, and the anticodon. Reexamination of the identity set of tRNA(Gln) in the light of these results indicates that its constituents can be differentiated based upon biochemical function and their contribution to the apparent Gibbs' free energy of tRNA binding. Interactions with the acceptor stem act as strong determinants of tRNA specificity, with the discriminator base positioning the 3' end. The 10:25 base pair and U35 are apparently the major binding sites to GlnRS, with G36 contributing both to binding and recognition. Furthermore, we show that E. coli tryptophanyl-tRNA synthetase also displays tRNA-dependent changes in tryptophan affinity when charging a noncognate tRNA. The ability of tRNA to optimize amino acid recognition reveals a novel mechanism for maintaining translational fidelity and also provides a strong basis for the coevolution of tRNAs and their cognate synthetases. PMID- 8692926 TI - Ceramide-binding and activation defines protein kinase c-Raf as a ceramide activated protein kinase. AB - Interleukin 1 is the prototype of an inflammatory cytokine, and evidence suggests that it uses the sphingomyelin pathway and ceramide production to trigger mitogen activated protein kinase (MAPK) activation and subsequent gene expression required for acute inflammatory processes. To identify downstream signaling targets of ceramide, a radioiodinated photoaffinity labeling analog of ceramide ([125I] 3-trifluoromethyl-3-(m-iodophenyl)diazirine-ceramide) was employed. It is observed that ceramide specifically binds to and activates protein kinase c-Raf, leading to a subsequent activation of the MAPK cascade. Ceramide does not bind to any other member of the MAPK module nor does it bind to protein kinase C-zeta. These data identify protein kinase c-Raf as a specific molecular target for interleukin 1 beta-stimulated ceramide formation and demonstrate that ceramide is a lipid cofactor participating in regulation of c-Raf activity. PMID- 8692928 TI - Linker histones affect patterns of digestion of supercoiled plasmids by single strand-specific nucleases. AB - The effect of histone H1 binding on the cleavage of superhelical plasmids by single-strand-specific nucleases was investigated. Mapping of P1 cleavage sites in pBR322, achieved by EcoRI digestion after the original P1 attack, showed an intriguing phenomenon: preexisting susceptible sites became "protected," whereas some new sites appeared at high levels of H1. Similar results were obtained with another single-strand-specific nuclease, S1. Disappearance of cutting at preexisting sites and appearance of new sites was also observed in a derivative plasmid that contains a 36-bp stretch of alternating d(AT) sequence that is known to adopt an altered P1-sensitive conformation. On the other hand, H1 titration of a dimerized version of the d(AT)18-containing plasmid led to protection of all preexisting sites except the d(AT)18 inserts, which were still cut even at high H1 levels; in this plasmid no new sites appeared. The protection of preexisting sites is best explained by long-range effects of histone H1 binding on the superhelical torsion of the plasmid. The appearance of new sites, on the other hand, probably also involves a local effect of stabilization of specific sequences in Pl-sensitive conformation, due to direct H1 binding to such sequences. That such binding involves linker histone N- and/or C-terminal tails is indicated by the fact that titration with the globular domain of H5, while causing disappearance of preexisting sites, does not lead to the appearance of any new sites. PMID- 8692927 TI - Molecular characterization of a FKBP-type immunophilin from higher plants. AB - Immunophilins are intracellular receptors for the immunosuppressants cyclosporin A, FK506, and rapamycin. In addition to their use in organ transplantation, these natural products have been used to investigate signaling pathways in yeast, plant, and mammalian cells. We have recently described the identification of an immunosuppressant-sensitive signaling pathway in and the purification of several immunophilins from Vicia faba plants. We now report the molecular characterization of a 15 kDa FK506- and rapamycin-binding protein from V. faba (VfFKBP15). The amino acid sequence deduced from the cDNA starts with a signal peptide of 22 hydrophobic amino acids. The core region of VfFKBP15 is most similar to yeast and mammalian FKBP13 localized in the endoplasmic reticulum (ER). In addition, VfFKBP15 has a carboxyl-terminal sequence that is ended with SSEL, a putative ER retention signal. These findings suggest that VfFKBP15 is a functional homolog of FKBP13 from other organisms. Interestingly, two distinct cDNAs corresponding to two isoforms of FKBP15 have been cloned from Arabidopsis and also identified from rice data base, suggesting that pFKBP15 (plant FKBP15) is encoded by a small gene family in plants. This adds to the diversity of plant FKBP members even with the same subcellular localization and is in contrast with the situation in mammalian and yeast systems in which only one FKBP13 gene has been found. Like the mammalian and yeast FKBP13, the recombinant VfFKBP15 protein has rotamase activity that is inhibited by both FK506 and rapamycin with a Ki value of 30 nM and 0.9 nM, respectively, illustrating that VfFKBP15 binds rapamycin in preference over FK506. The mRNA of VfFKBP15 is ubiquitously expressed in various plant tissues including leaves, stems, and roots, consistent with the ER localization of the protein. Levels of VfFKBP15 mRNA are elevated by heat shock, suggesting a possible role for this FKBP member under stress conditions. PMID- 8692930 TI - Binding site size limit of the 2:1 pyrrole-imidazole polyamide-DNA motif. AB - Polyamides containing N-methylimidazole (Im) and N-methylpyrrole (Py) amino acids can be combined in antiparallel side-by-side dimeric complexes for sequence specific recognition in the minor groove of DNA. Six polyamides containing three to eight rings bind DNA sites 5-10 bp in length, respectively. Quantitative DNase I footprint titration experiments demonstrate that affinity maximizes and is similar at ring sizes of five, six, and seven. Sequence specificity decreases as the length of the polyamides increases beyond five rings. These results provide useful guidelines for the design of new polyamides that bind longer DNA sites with enhanced affinity and specificity. PMID- 8692929 TI - The C-terminal domain of the largest subunit of RNA polymerase II interacts with a novel set of serine/arginine-rich proteins. AB - Although transcription and pre-mRNA processing are colocalized in eukaryotic nuclei, molecules linking these processes have not previously been described. We have identified four novel rat proteins by their ability to interact with the repetitive C-terminal domain (CTD) of RNA polymerase II in a yeast two-hybrid assay. A yeast homolog of one of the rat proteins has also been shown to interact with the CTD. These CTD-binding proteins are all similar to the SR (serine/arginine-rich) family of proteins that have been shown to be involved in constitutive and regulated splicing. In addition to alternating Ser-Arg domains, these proteins each contain discrete N-terminal or C-terminal CTD-binding domains. We have identified SR-related proteins in a complex that can be immunoprecipitated from nuclear extracts with antibodies directed against RNA polymerase II. In addition, in vitro splicing is inhibited either by an antibody directed against the CTD or by wild-type but not mutant CTD peptides. Thus, these results suggest that the CTD and a set of CTD-binding proteins may act to physically and functionally link transcription and pre-mRNA processing. PMID- 8692931 TI - Processing of the leader mRNA plays a major role in the induction of thrS expression following threonine starvation in Bacillus subtilis. AB - The threonyl-tRNA synthetase gene, thrS, is a member of a family of Gram-positive genes that are induced following starvation for the corresponding amino acid by a transcriptional antitermination mechanism involving the cognate uncharged tRNA. Here we show that an additional level of complexity exists in the control of the thrS gene with the mapping of an mRNA processing site just upstream of the transcription terminator in the thrS leader region. The processed RNA is significantly more stable than the full-length transcript. Under nonstarvation conditions, or following starvation for an amino acid other than threonine, the full-length thrS mRNA is more abundant than the processed transcript. However, following starvation for threonine, the thrS mRNA exists primarily in its cleaved form. This can partly be attributed to an increased processing efficiency following threonine starvation, and partly to a further, nonspecific increase in the stability of the processed transcript under starvation conditions. The increased stability of the processed RNA contributes significantly to the levels of functional RNA observed under threonine starvation conditions, previously attributed solely to antitermination. Finally, we show that processing is likely to occur upstream of the terminator in the leader regions of at least four other genes of this family, suggesting a widespread conservation of this phenomenon in their control. PMID- 8692932 TI - Kinetics of photo-induced electron transfer from high-potential iron-sulfur protein to the photosynthetic reaction center of the purple phototroph Rhodoferax fermentans. AB - The kinetics of photo-induced electrontransfer from high-potential iron-sulfur protein (HiPIP) to the photosynthetic reaction center (RC) of the purple phototroph Rhodoferarfermentans were studied. The rapid photooxidation of heme c 556 belonging to RC is followed, in the presence of HiPIP, by a slower reduction having a second-order rate constant of 4.8 x 10(7) M(-1) x s(-1). The limiting value of kobs at high HiPIP concentration is 95 s(-1). The amplitude of this slow process decreases with increasing HiPIP concentration. The amplitude of a faster phase, observed at 556 and 425 nm and involving heme c-556 reduction, increases proportionately. The rate constant of this fast phase, determined at 425 and 556 nm, is approximately 3 x 10(5) s(-1). This value is not dependent on HiPIP concentration, indicating that it is related to a first-order process. These observations are interpreted as evidence for the formation of a HiPIP-RC complex prior to the excitation flash, having a dissociation constant of -2.5 microM. The fast phase is absent at high ionic strength, indicating that the complex involves mainly electrostatic interactions. The ionic strength dependence of kobs for the slow phase yields a second-order rate constant at infinite ionic strength of 5.4 x 10(6) M(-1) x s(-1) and an electrostatic interaction energy of -2.1 kcal/mol (1 cal = 4.184 J). We conclude that Rhodoferar fermentans HiPIP is a very effective electron donor to the photosynthetic RC. PMID- 8692933 TI - Ice as a matrix for IR-matrix-assisted laser desorption/ionization: mass spectra from a protein single crystal. AB - Lasers emitting in the ultraviolet wavelength range of 260-360 nm are almost exclusively used for matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) of macromolecules. Reports about the use of lasers emitting in the infrared first appeared in 1990/1991. In contrast to MALDI in the ultraviolet, a very limited number of reports on IR-MALDI have since been published. Several matrices have been identified for infrared MALDI yielding spectra of a quality comparable to those obtained in the ultraviolet. Water (ice) was recognized early as a potential matrix because of its strong O-H stretching mode near 3 microm. Interest in water as matrix derives primarily from the fact that it is the major constituent of most biological tissues. If functional as matrix, it might allow the in situ analysis of macromolecular constituents in frozen cell sections without extraction or exchanging the water. We present results that show that IR-MALDI of lyophilized proteins, air dried protein solutions, or protein crystals up to a molecular mass of 30 kDa is possible without the addition of any separate matrix. Samples must be frozen to retain a sufficient fraction of the water of hydration in the vacuum. The limited current sensitivity, requiring at least 10 pmol of protein for a successful analysis needs to be further improved. PMID- 8692934 TI - Structure of the ripple phase in lecithin bilayers. AB - The phases of the x-ray form factors are derived for the ripple (Pbeta') thermodynamic phase in the lecithin bilayer system. By combining these phases with experimental intensity data, the electron density map of the ripple phase of dimyristoyl-phosphatidylcholine is constructed. The phases are derived by fitting the intensity data to two-dimensional electron density models, which are created by convolving an asymmetric triangular ripple profile with a transbilayer electron density profile. The robustness of the model method is indicated by the result that many different models of the transbilayer profile yield essentially the same phases, except for the weaker, purely ripple (0,k) peaks. Even with this residual ambiguity, the ripple profile is well determined, resulting in 19 angstroms for the ripple amplitude and 10 degrees and 26 degrees for the slopes of the major and the minor sides, respectively. Estimates for the bilayer head head spacings show that the major side of the ripple is consistent with gel-like structure, and the minor side appears to be thinner with lower electron density. PMID- 8692935 TI - X-ray structure determination of a metastable state of carbonmonoxy myoglobin after photodissociation. AB - The x-ray structure of carbon monoxide (CO)-ligated myoglobin illuminated during data collection by a laser diode at the wavelength lambda = 690 nm has been determined to a resolution of 1.7 A at T = 36 K. For comparison, we also measured data sets of deoxymyoglobin and CO-ligated myoglobin. In the photon-induced structure the electron density associated with the CO ligand can be described by a tube extending from the iron into the heme pocket over more than 4 A. This density can be interpreted by two discrete positions of the CO molecule. One is close to the heme iron and can be identified to be bound CO. In the second, the CO is dissociated from the heme iron and lies on top of pyrrole ring C. At our experimental conditions the overall structure of myoglobin in the metastable state is close to the structure of a CO-ligated molecule. However, the iron has essentially relaxed into the position of deoxymyoglobin. We compare our results with those of Schlichting el al. [Schlichting, I., Berendzen, J., Phillips, G. N., Jr., & Sweet, R. M. (1994) Nature 317, 808-812], who worked with the myoglobin mutant (D122N) that crystallizes in the space group P6 and Teng et al. [Teng, T. Y., Srajer, V. & Moffat, K. (1994) Nat. Struct. Biol. 1, 701-705], who used native myoglobin crystals of the space group P2(1). Possible reasons for the structural differences are discussed. PMID- 8692936 TI - Three quaternary structures for a single protein. AB - The structure of a multisubunit protein (immunoglobulin light chain) was solved in three crystal forms, differing only in the solvent of crystallization. The three structures were obtained at high ionic strength and low pH, high ionic strength and high pH, and low ionic strength and neutral pH. The three resulting "snapshots" of possible structures show that their variable-domain interactions differ, reflecting their stabilities under specific solvent conditions. In the three crystal forms, the variable domains had different rotational and translational relationships, whereas no alteration of the constant domains was found. The critical residues involved in the observed effect of the solvent are tryptophans and histidines located between the two variable domains in the dimeric structure. Tryptophan residues are commonly found in interfaces between proteins and their subunits, and histidines have been implicated in pH-dependent conformation changes. The quaternary structure observed for a multisubunit protein or protein complex in a crystal may be influenced by the interactions of the constituents within the molecule or complex and/or by crystal packing interactions. The comparison of buried surface areas and hydrogen bonds between the domains forming the molecule and between the molecules forming the crystals suggest that, for this system, the interactions within the molecule are most likely the determining factors. PMID- 8692937 TI - Direct measurement of oligonucleotide binding stoichiometry of gene V protein by mass spectrometry. AB - The binding stoichiometry of gene V protein from bacteriophage f1 to several oligonucleotides was studied using electrospray ionization-mass spectrometry (ESI MS). Using mild mass spectrometer interface conditions that preserve noncovalent associations in solution, gene V protein was observed as dimer ions from a 10 mM NH4OAc solution. Addition of oligonucleotides resulted in formation of protein oligonucleotide complexes with stoichiometry of approximately four nucleotides (nt) per protein monomer. A 16-mer oligonucleotide gave predominantly a 4:1 (protein monomer: oligonucleotide) complex while oligonucleotides shorter than 15 nt showed stoichiometries of 2:1. Stoichiometries and relative binding constants for a mixture of oligonucleotides were readily measured using mass spectrometry. The binding stoichiometry of the protein with the 16-mer oligonucleotide was measured independently using size-exclusion chromatography and the results were consistent with the mass spectrometric data. These results demonstrate, for the first time, the observation and stoichiometric measurement of protein oligonucleotide complexes using ESI-MS. The sensitivity and high resolution of ESI-MS should make it a useful too] in the study of protein-DNA interactions. PMID- 8692938 TI - The N-terminal domain of Escherichia coli enzyme I of the phosphoenolpyruvate/glycose phosphotransferase system: molecular cloning and characterization. AB - The bacterial phosphoenolpyruvate/glycose phosphotransferase system (PTS) comprises a group of proteins that catalyze the transfer of the phosphoryl group from phosphoenolpyruvate (PEP) to sugars concomitant with their translocation. The first two steps of the phosphotransfer sequence are PEP <--> Enzyme I (EI) <- > HPr (the histidine-containing phosphocarrier protein). We have proposed that many functions of the PTS are regulated by EI, which undergoes a monomer/dimer transition. EI monomer (63.5 kDa) comprises two major domains: a flexible C terminal domain (EI-C) and a protease-resistant, structurally stable N-terminal domain (EI-N) containing the active site His. Trypsin treatment of Salmonella typhimurium EI yielded EI-N, designated EI-N(t). Homogeneous recombinant Escherichia coli EI-N [i.e., EI-N(r)], has now been prepared in quantity, shows the expected thermodynamic unfolding properties and, similarly to EI-N(t), is phosphorylated by phospho-HPr, but not by PEP. In addition, binding of EI-N(r) to HPr was studied by isothermal titration calorimetry: K/a = 1.4 x 10(5) M(-1) and delta H = +8.8 kcal x mol(-1). Both values are comparable to those for HPr binding to intact EI. Fluorescence anisotropy [dansyl-EI-N(r)] and gel filtration of EI-N(r) show that it does not dimerize. These results emphasize the role of EI C in dimerization and the regulation of intact EI. PMID- 8692939 TI - The Mos/mitogen-activated protein kinase (MAPK) pathway regulates the size and degradation of the first polar body in maturing mouse oocytes. AB - Mos is an upstream activator of mitogen-activated protein kinase (MAPK) and, in mouse oocytes, is responsible for metaphase II arrest. This activity has been likened to its function in Xenopus oocytes as a component of cytostatic factor. Thus, Mos-deficient female mice (MOS-/-) are less fertile and oocytes derived from these animals fail to arrest at metaphase II and undergo parthenogenetic activation [Colledge, W. H., Carlton, M. B. L., Udy, C. B. & Evans, M. J. (1994) Nature (London) 370, 65-68 and Hashimoto, N., Watanabe, N., Furuta. Y., Tamemoto, B., Sagata, N., Yokoyama, M., Okazaki, K., Nagayoshi, M., Takeda, N., Ikawa, Y. & Aizawa, S. (1994) Nature (London) 370, 68-71]. Here we show that maturing MOS-/- oocytes fail to activate MAPK throughout meiosis, while p34cdc2 kinase activity is normal until late in metaphase II when it decreases prematurely. Phenotypically, the first meiotic division of MOS-/- oocytes frequently resembles mitotic cleavage or produces an abnormally large polar body. In these oocytes, the spindle shape is altered and the spindle fails to translocate to the cortex, leading to the establishment of an altered cleavage plane. Moreover, the first polar body persists instead of degrading and sometimes undergoes an additional cleavage, thereby providing conditions for parthenogenesis. These studies identify meiotic spindle formation and programmed degradation of the first polar body as new and important roles for the Mos/MAPK pathway. PMID- 8692941 TI - bcl-2 overexpression reduces apoptotic photoreceptor cell death in three different retinal degenerations. AB - Apoptosis of photoreceptors occurs infrequently in adult retina but can be triggered in inherited and environmentally induced retinal degenerations. The protooncogene bcl-2 is known to be a potent regulator of cell survival in neurons. We created lines of transgenic mice overexpressing bcl-2 to test for its ability to increase photoreceptor survival. Bcl-2 increased photoreceptor survival in mice with retinal degeneration caused by a defective opsin or cGMP phosphodiesterase. Overexpression of Bcl-2 in normal photoreceptors also decreased the damaging effects of constant light exposure. Apoptosis was induced in normal photoreceptors by very high levels of bcl-2. We conclude that bcl-2 is an important regulator of photoreceptor cell death in retinal degenerations. PMID- 8692940 TI - The glucose sensor protein glucokinase is expressed in glucagon-producing alpha cells. AB - Expression of glucokinase in hepatocytes and pancreatic 6-cells is of major physiologic importance to mammalian glucose homeostasis. Liver glucokinase catalyzes the first committed step in the disposal of glucose, and beta-cell glucokinase catalyzes a rate-limiting step required for glucose-regulated insulin release. The present study reports the expression of glucokinase in rat glucagon producing alpha-cells, which are negatively regulated by glucose. Purified rat alpha-cells express glucokinase mRNA and protein with the same transcript length, nucleotide sequence, and immunoreactivity as the beta-cell isoform. Glucokinase activity accounts for more than 50% of glucose phosphorylation in extracts of alpha-cells and for more than 90% of glucose utilization in intact cells. The glucagon-producing tumor MSL-G-AN also contained glucokinase mRNA, protein, and enzymatic activity. These data indicate that glucokinase may serve as a metabolic glucose sensor in pancreatic alpha-cells and, hence, mediate a mechanism for direct regulation of glucagon release by extracellular glucose. Since these cells do not express Glut2, we suggest that glucose sensing does not necessarily require the coexpression of Glut2 and glucokinase. PMID- 8692942 TI - Rfc5, a small subunit of replication factor C complex, couples DNA replication and mitosis in budding yeast. AB - The inhibition of DNA synthesis prevents mitotic entry through the action of the S phase checkpoint. In the yeast Saccharomyces cerevisiae, an essential protein kinase, Spk1/Mec2/Rad53/Sad1, controls the coupling of S phase to mitosis. In an attempt to identify genes that genetically interact with Spk1, we have isolated a temperature-sensitive mutation, rfc5-1, that can be suppressed by overexpression of SPK1. The RFC5 gene encodes a small subunit of replication factor C complex. At the restrictive temperature, rfc5-1 mutant cells entered mitosis with unevenly separated or fragmented chromosomes, resulting in loss of viability. Thus, the rfc5 mutation defective for DNA replication is also impaired in the S phase checkpoint. Overexpression of POL30, which encodes the proliferating cell nuclear antigen, suppressed the replication defect of the rfc5 mutant but not its checkpoint defect. Taken together, these results suggested that replication factor C has a direct role in sensing the state of DNA replication and transmitting the signal to the checkpoint machinery. PMID- 8692943 TI - Brush border myosin-I truncated in the motor domain impairs the distribution and the function of endocytic compartments in an hepatoma cell line. AB - Myosins I, a ubiquitous monomeric class of myosins that exhibits actin-based motor properties, are associated with plasma and/or vesicular membranes and have been suggested as players for trafficking events between cell surface and intracellular membranous structures. To investigate the function of myosins 1, we have transfected a mouse hepatoma cell line (BWTG3) with cDNAs encoding the chicken brush border myosin-I (BBMI) and two variants truncated in the motor domain. One variant is deleted of the first 446 amino acids and thereby lacks the ATP binding site, whereas the other is deleted of the entire motor domain and lacks the ATP and actin binding sites. We have observed (i) that significant amounts of the truncated variants are recovered with membrane fractions after cell fractionation, (ii) that they codistribute with a compartment containing alpha2-macroglobulin internalized for 30 min as determined by fluorescent microscopy, (iii) that the production of BBMI-truncated variants impairs the distribution of the acidic compartment and ligands internalized for 30 min, and (iv) that the production of the truncated variant containing the actin binding site decreases the rate of alpha2-macroglobulin degradation whereas the production of the variant lacking the ATP binding site and the actin binding site increases the rate of a2-macroglobulin degradation. These observations indicate that the two truncated variants have a dominant negative effect on the distribution and the function of the endocytic compartments. We propose that an unidentified myosin-I might contribute to the distribution of endocytic compartments in a juxtanuclear position and/or to the regulation of the delivery of ligands to the degradative compartment in BWTG3 cells. PMID- 8692944 TI - Nuclear protein import: Ran-GTP dissociates the karyopherin alphabeta heterodimer by displacing alpha from an overlapping binding site on beta. AB - The alpha subunit of the karyopherin heterodimer functions in recognition of the protein import substrate and the beta subunit serves to dock the trimeric complex to one of many sites on nuclear pore complex fibers. The small GTPase Ran and the Ran interactive protein, p10, function in the release of the docked complex. Repeated cycles of docking and release are thought to concentrate the transport substrate for subsequent diffusion into the nucleus. Ran-GTP dissociates the karyopherin heterodimer and forms a stoichiometric complex with Ran-GTP. Here we report the mapping of karyopherin beta's binding sites both for Ran-GTP and for karyopherin alpha. We discovered that karyopherin beta's binding site for Ran-GTP shows a striking sequence similarity to the cytoplasmic Ran-GTP binding protein, RanBP1. Moreover, we found that Ran-GTP and karyopherin alpha bind to overlapping sites on karyopherin beta. Having a higher affinity to the overlapping site, Ran GTP displaces karyopherin alpha and binds to karyopherin beta. Competition for overlapping binding sites may be the mechanism by which GTP bound forms of other small GTPases function in corresponding dissociation-association reactions. We also mapped Ran's binding site for karyopherin beta to a cluster of basic residues analogous to those previously shown to constitute karyopherin alpha's binding site to karyopherin beta. PMID- 8692945 TI - Bcl-2 interacting protein, BAG-1, binds to and activates the kinase Raf-1. AB - The Bcl-2 protein blocks programmed cell death (apoptosis) through an unknown mechanism. Previously we identified a Bcl-2 interacting protein BAG-1 that enhances the anti-apoptotic effects of Bcl-2. Like BAG-1, the serine/threonine protein kinase Raf-1 also can functionally cooperate with Bcl-2 in suppressing apoptosis. Here we show that Raf-1 and BAG-1 specifically interact in vitro and in yeast two-hybrid assays. Raf-1 and BAG-1 can also be coimmunoprecipitated from mammalian cells and from insect cells infected with recombinant baculoviruses encoding these proteins. Furthermore, bacterially-produced BAG-1 protein can increase the kinase activity of Raf-1 in vitro. BAG-1 also activates this mammalian kinase in yeast. These observations suggest that the Bcl-2 binding protein BAG-1 joins Ras and 14-3-3 proteins as potential activators of the kinase Raf-1. PMID- 8692946 TI - Matrix metalloproteinase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1. AB - Recent studies have demonstrated the existence of a soluble fibroblast growth factor (FGF) receptor type 1 (FGFR1) extracellular domain in the circulation and in vascular basement membranes. However, the process of FGFR1 ectodomain release from the plasma membrane is not known. Here we report that the 72-kDa gelatinase A (matrix metalloproteinase type 2, MMP2) can hydrolyze the Val368-Met369 peptide bond of the FGFR1 ectodomain, eight amino acids upstream of the transmembrane domain, thus releasing the entire extracellular domain. Similar results were obtained regardless of whether FGF was first bound to the receptor or not. The action of MMP2 abolished binding of FGF to an immobilized recombinant FGFR1 ectodomain fusion protein and to Chinese hamster ovary cells overexpressing FGFR1 The released recombinant FGFR1 ectodomain was able to bind FGF after MMP2 cleavage, suggesting that the cleaved soluble receptor maintained its FGF binding capacity. The activity of MMP2 could not be reproduced by the 92-kDa gelatinase B (MMP9) and was inhibited by tissue inhibitor of metalloproteinase type 2. These studies demonstrate that FGFR1 may be a specific target for MMP2 on the cell surface, yielding a soluble FGF receptor that may modulate the mitogenic and angiogenic activities of FGF. PMID- 8692947 TI - Hypoxia enhances stimulus-dependent induction of E-selectin on aortic endothelial cells. AB - In many diseases, tissue hypoxia occurs in conjunction with other inflammatory processes. Since previous studies have demonstrated a role for leukocytes in ischemia/reperfusion injury, we hypothesized that endothelial hypoxia may "superinduce" expression of an important leukocyte adhesion molecule, E-selectin (ELAM-1, CD62E). Bovine aortic endothelial monolayers were exposed to hypoxia in the presence or absence of tumor-necrosis factor alpha (TNF-alpha) or lipopolysaccharide (LPS). Cell surface E-selectin was quantitated by whole cell ELISA or by immunoprecipitation using polyclonal anti-E-selectin sera. Endothelial mRNA levels were assessed using ribonuclease protection assays. Hypoxia alone did not induce endothelial E-selectin expression. However, enhanced induction of E-selectin was observed with the combination of hypoxia and TNF alpha (270% increase over normoxia and TNF-alpha) or hypoxia and LPS (190% increase over normoxia and LPS). These studies revealed that a mechanism for such enhancement may be hypoxia-elicited decrements in endothelial intracellular levels of cAMP (<50% compared with normoxia). Addition of forskolin and isobutyl methyl-xanthine during hypoxia resulted in reversal of cAMP decreases and a loss of enhanced E-selectin surface expression with the combination of TNF-alpha and hypoxia. We conclude that endothelial hypoxia may provide a novel signal for superinduction of E-selectin during states of inflammation. PMID- 8692948 TI - 17p (p53) allelic losses, 4N (G2/tetraploid) populations, and progression to aneuploidy in Barrett's esophagus. AB - Increased 4N (G2/tetraploid) cell populations have been postulated to be genetically unstable intermediates in the progression to many cancers, but the mechanism by which they develop and their relationship to instability have been difficult to investigate in humans in vivo. Barrett's esophagus is an excellent model system in which to investigate the order in which genetic and cell cycle abnormalities develop relative to each other during human neoplastic progression. Neoplastic progression in Barrett's esophagus is characterized by inactivation of the p53 gene, the development of increased 4N (G2/tetraploid) cell fractions, and the appearance of aneuploid cell populations. We investigated the hypothesis that patients whose biopsies have increased 4N (G2/tetraploid) cell fractions are predisposed to progression to aneuploidy and determined the relationship between inactivation of p53 and the development of 4N abnormalities in Barrett's epithelium. Our results indicate that increased 4N (G2/tetraploid) populations predict progression to aneuploidy and that the development of 4N abnormalities is interdependent with inactivation of the p53 gene in Barrett's esophagus in vivo. PMID- 8692949 TI - Bootstrap confidence levels for phylogenetic trees. AB - Evolutionary trees are often estimated from DNA or RNA sequence data. How much confidence should we have in the estimated trees? In 1985, Felsenstein [Felsenstein, J. (1985) Evolution 39, 783-791] suggested the use of the bootstrap to answer this question. Felsenstein's method, which in concept is a straightforward application of the bootstrap, is widely used, but has been criticized as biased in the genetics literature. This paper concerns the use of the bootstrap in the tree problem. We show that Felsenstein's method is not biased, but that it can be corrected to better agree with standard ideas of confidence levels and hypothesis testing. These corrections can be made by using the more elaborate bootstrap method presented here, at the expense of considerably more computation. PMID- 8692950 TI - Does behavior reflect phylogeny in swiftlets (Aves: Apodidae)? A test using cytochrome b mitochondrial DNA sequences. AB - Swiftlets are small insectivorous birds, many of which nest in caves and are known to echolocate. Due to a lack of distinguishing morphological characters, the taxonomy of swiftlets is primarily based on the presence or absence of echolocating ability, together with nest characters. To test the reliability of these behavioral characters, we constructed an independent phylogeny using cytochrome b mitochondrial DNA sequences from swiftlets and their relatives. This phylogeny is broadly consistent with the higher classification of swifts but does not support the monophyly of swiftlets. Echolocating swiftlets (Aerodramus) and the nonecholocating "giant swiftlet" (Hydrochous gigas) group together, but the remaining nonecholocating swiftlets belonging to Collocalia are not sister taxa to these swiftlets. While echolocation may be a synapomorphy of Aerodramus (perhaps secondarily lost in Hydrochous), no character of Aerodramus nests showed a statistically significant fit to the molecular phylogeny, indicating that nest characters are not phylogenetically reliable in this group. PMID- 8692951 TI - Naturally occurring variation in copia expression is due to both element (cis) and host (trans) regulatory variation. AB - Significant differences in levels of copia [Drosophila long terminal repeat (LTR) retrotransposon] expression exist among six species representing the Drosophila melanogaster species complex (D. melanogaster, Drosophila mauritiana, Drosophila simulans, Drosophila sechellia, Drosophila yakuba, and Drosophila erecta) and a more distantly related species (Drosophila willistoni). These differences in expression are correlated with major size variation mapping to putative regulatory regions of the copia 5' LTR and adjacent untranslated leader region (ULR). Sequence analysis indicates that these size variants were derived from a series of regional duplication events. The ability of the copia LTR-ULR size variants to drive expression of a bacterial chloramphenicol acetyltransferase reporter gene was tested in each of the seven species. The results indicate that both element-encoded (cis) and host-genome-encoded (trans) genetic differences are responsible for the variability in copia expression within and between Drosophila species. This finding indicates that models purporting to explain the dynamics and distribution of retrotransposons in natural populations must consider the potential impact of both element-encoded and host-genome-encoded regulatory variation to be valid. We propose that interelement selection among retrotransposons may provide a molecular drive mechanism for the evolution of eukaryotic enhancers which can be subsequently distributed throughout the genome by retrotransposition. PMID- 8692952 TI - Evolutionary changes in the expression pattern of a developmentally essential gene in three Drosophila species. AB - The hypothesis that morphological evolution may largely result from changes in gene regulation rather than gene structure has been difficult to test. Morphological differences among insects are often apparent in the cuticle structures produced. The dopa decarboxylase (Ddc) and alpha-methyldopa hypersensitive (amd) genes arose from an ancient gene duplication. In Drosophila, they have evolved nonoverlapping functions, including the production of distinct types of cuticle, and for Ddc, the production of the neurotransmitters, dopamine and serotonin. The amd gene is particularly active in the production of specialized flexible cuticles in the developing embryo. We have compared the pattern of amd expression in three Drosophila species. Several regions of expression conserved in all three species but, surprisingly, a unique domain of expression is found in Drosophila simulans that does occur in the closely related (2-5 million years) Drosophila melanogaster or in the more remote (40-50 million years) Drosophila virilis. The "sudden" appearance of a completely new and robust domain of expression provides a glimpse of evolutionary variation resulting from changes in regulation of structural gene expression. PMID- 8692953 TI - Selection for genes encoding secreted proteins and receptors. AB - Extracellular proteins play an essential role in the formation, differentiation, and maintenance of multicellular organisms. Despite that, the systematic identification of genes encoding these proteins has not been possible. We describe here a highly efficient method to isolate genes encoding secreted and membrane-bound proteins by using a single-step selection in yeast. Application of this method, termed signal peptide selection, to various tissues yielded 559 clones that appear to encode known or novel extracellular proteins. These include members of the transforming growth factor and epidermal growth factor protein families, endocrine hormones, tyrosine kinase receptors, serine/threonine kinase receptors, seven transmembrane receptors, cell adhesion molecules, extracellular matrix proteins, plasma proteins, and ion channels. The eventual identification of most, or all, extracellular signaling molecules will advance our understanding of fundamental biological processes and our ability to intervene in disease states. PMID- 8692954 TI - A change of ploidy can modify epigenetic silencing. AB - A silent transgene in Arabidopsis thaliana was reactivated in an outcross but not upon selfing of hemizygous plants. This result could only be explained by assuming a genetic difference between the transgene-free gametes of the wild-type and hemizygous transgenic plants, respectively, and led to the discovery of ploidy differences between the parental plants. To investigate whether a change of ploidy by itself can indeed influence gene expression, we performed crosses of diploid or tetraploid plants with a strain containing a single copy of a transgenic resistance gene in an active state. We observed reduced gene expression of the transgene in triploid compared with diploid hybrids. This led to loss of the resistant phenotype at various stages of seedling development in part of the population. The gene inactivation was reversible. Thus, an increased number of chromosomes can result in a new type of epigenetic gene inactivation, creating differences in gene expression patterns. We discuss the possible impact of this finding for genetic diploidization in the light of widespread, naturally occurring polyploidy and polysomaty in plants. PMID- 8692955 TI - Stabilization of diverged tandem repeats by mismatch repair: evidence for deletion formation via a misaligned replication intermediate. AB - A functional methyl-directed mismatch repair pathway in Escherichia coli prevents the formation of deletions between 101-bp tandem repeats with 4% sequence divergence. Deletions between perfectly homologous repeats are unaffected. Deletion in both cases occurs independently of the homologous recombination gene, recA. Because the methyl-directed mismatch repair pathway detects and excises one strand of a mispaired duplex, an intermediate for RecA-independent deletion of tandem repeats must therefore be a heteroduplex formed between strands of each repeat. We find that MutH endonuclease, which in vivo incises specifically the newly replicated strand of DNA, and the Dam methylase, the source of this strand discrimination, are required absolutely for the exclusion of "homeologous" (imperfectly homologous) tandem deletion. This supports the idea that the heteroduplex intermediate for deletion occurs during or shortly after DNA replication in the context of hemi-methylation. Our findings confirm a "replication slippage" model for deletion formation whereby the displacement and misalignment of the nascent strand relative to the repeated sequence in the template strand accomplishes the deletion. PMID- 8692956 TI - Mini-chromosomes derived from the human Y chromosome by telomere directed chromosome breakage. AB - We have used telomeric DNA to break two acrocentric derivatives of the human Y chromosome into mini-chromosomes that are small enough to be size- fractionated by pulsed-field gel electrophoresis. One of the mini-chromosomes is about 7 Mb in size and sequence-tagged site analysis of this molecule suggests that it corresponds to a simple truncation of the short arm of the Y chromosome. Five of the mini-chromosomes are derived from the long arm, are all rearranged by more than a simple truncation, and range in size from 4.0 Mb to 9 Mb. We have studied the mitotic stabilities of these mini-chromosomes and shown that they are stably maintained by cells proliferating in culture for about 100 cell divisions. PMID- 8692957 TI - Double-strand break repair in the absence of RAD51 in yeast: a possible role for break-induced DNA replication. AB - In wild-type diploid cells of Saccharomyces cerevisiae, an HO endonuclease induced double-strand break (DSB) at the MAT locus can be efficiently repaired by gene conversion using the homologous chromosome sequences. Repair of the broken chromosome was nearly eliminated in rad52delta diploids; 99% lost the broken chromosome. However, in rad51delta diploids, the broken chromosomes were repaired approximately 35% of the time. None of these repair events were simple gene conversions or gene conversions with an associated crossover, instead, they created diploids homozygous for the MAT locus and all markers in the 100-kb region distal to the site of the DSB. In rad51delta diploids, the broken chromosome can apparently be inherited for several generations, as many of these repair events are found as sectored colonies, with one part being repaired and the other part being lost the broken chromosome. Similar events occur in about 2% of wild-type cells. We propose that a broken chromosome end can invade a homologous template in the absence of RAD51 and initiate DNA replication that may extend to the telomere, 100 or more kb away. Such break-induced replication appears to be similar to recombination-initiated replication in bacteria. PMID- 8692958 TI - CHD1 is concentrated in interbands and puffed regions of Drosophila polytene chromosomes. AB - Previously, we reported on the discovery and characterization of a mammalian chromatin-associated protein, CHD1 (chromo-ATPase/helicase-DNA-binding domain), with features that led us to suspect that it might have an important role in the modification of chromatin structure. We now report on the characterization of the Drosophila melanogaster CHD1 homologue (dCHD1) and its localization on polytene chromosomes. A set of overlapping cDNAs encodes an 1883-aa open reading frame that is 50% identical and 68% similar to the mouse CHD1 sequence, including conservation of the three signature domains for which the protein was named. When the chromo and ATPase/helicase domain sequences in various CHD1 homologues were compared with the corresponding sequences in other proteins, certain distinctive features of the CHD1 chromo and ATPase/helicase domains were revealed. The dCHD1 gene was mapped to position 23C-24A on chromosome 2L. Western blot analyses with antibodies raised against a dCHD1 fusion protein specifically recognized an approximately 210-kDa protein in nuclear extracts from Drosophila embryos and cultured cells. Most interestingly, these antibodies revealed that dCHD1 localizes to sites of extended chromatin (interbands) and regions associated with high transcriptional activity (puffs) on polytene chromosomes from salivary glands of third instar larvae. These observations strongly support the idea that CHD1 functions to alter chromatin structure in a way that facilitates gene expression. PMID- 8692959 TI - ECA39, a conserved gene regulated by c-Myc in mice, is involved in G1/S cell cycle regulation in yeast. AB - The c-myc oncogene has been shown to play a role in cell proliferation and apoptosis. The realization that myc oncogenes may control the level of expression of other genes has opened the field to search for genetic targets for Myc regulation. Recently, using a subtraction/coexpression strategy, a murine genetic target for Myc regulation, called EC439, was isolated. To further characterize the ECA39 gene, we set out to determine the evolutionary conservation of its regulatory and coding sequences. We describe the human, nematode, and budding yeast homologs of the mouse ECA39 gene. Identities between the mouse ECA39 protein and the human, nematode, or yeast proteins are 79%, 52%, and 49%, respectively. Interestingly, the recognition site for Myc binding, located 3' to the start site of transcription in the mouse gene, is also conserved in the human homolog. This regulatory element is missing in the ECA39 homologs from nematode or yeast, which also lack the regulator c-myc. To understand the function of ECA39, we deleted the gene from the yeast genome. Disruption of ECA39 which is a recessive mutation that leads to a marked alteration in the cell cycle. Mutant haploids and homozygous diploids have a faster growth rate than isogenic wild type strains. Fluorescence-activated cell sorter analyses indicate that the mutation shortens the G1 stage in the cell cycle. Moreover, mutant strains show higher rates of UV-induced mutations. The results suggest that the product of ECA39 is involved in the regulation of G1 to S transition. PMID- 8692960 TI - The activation of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation. AB - Human gene MAGE-1 encodes tumor-specific antigens that are recognized on melanoma cells by autologous cytolytic T lymphocytes. This gene is expressed in a significant proportion of tumors of various histological types, but not in normal tissues except male germ-line cells. We reported previously that reporter genes driven by the MAGE-1 promoter are active not only in the tumor cell lines that express MAGE-1 but also in those that do not. This suggests that the critical factor causing the activation of MAGE-1 in certain tumors is not the presence of the appropriate transcription factors. The two major MAGE-1 promoter elements have an Ets binding site, which contains a CpG dinucleotide. We report here that these CpG are demethylated in the tumor cell lines that express MAGE-1, and are methylated in those that do not express the gene. Methylation of these CpG inhibits the binding of transcription factors, as seen by mobility shift assay. Treatment with the demethylating agent 5-aza-2'-deoxycytidine activated gene MAGE 1 not only in tumor cell lines but also in primary fibroblasts. Finally, the overall level of CpG methylation was evaluated in 20 different tumor cell lines. It was inversely correlated with the expression of MAGE-1. We conclude that the activation of MAGE-1 in cancer cells is due to the demethylation of the promoter. This appears to be a consequence of a genome-wide demethylation process that occurs in many cancers and is correlated with tumor progression. PMID- 8692962 TI - Stepwise assembly of the lipid-linked oligosaccharide in the endoplasmic reticulum of Saccharomyces cerevisiae: identification of the ALG9 gene encoding a putative mannosyl transferase. AB - The core oligosaccharide Glc3Man9GlcNAc2 is assembled at the membrane of the endoplasmic reticulum on the lipid carrier dolichyl pyrophosphate and transferred to selected asparagine residues of nascent polypeptide chains. This transfer is catalyzed by the oligosaccharyl transferase complex. Based on the synthetic phenotype of the oligosaccharyl transferase mutation wbp1 in combination with a deficiency in the assembly pathway of the oligosaccharide in Saccharomyces cerevisiae, we have identified the novel ALG9 gene. We conclude that this locus encodes a putative mannosyl transferase because deletion of the gene led to accumulation of lipid-linked Man6GlcNAc2 in vivo and to hypoglycosylation of secreted proteins. Using an approach combining genetic and biochemical techniques, we show that the assembly of the lipid-linked core oligosaccharide in the lumen of the endoplasmic reticulum occurs in a stepwise fashion. PMID- 8692961 TI - Apolipoprotein B RNA editing enzyme-deficient mice are viable despite alterations in lipoprotein metabolism. AB - RNA editing in the nucleus of higher eukaryotes results in subtle changes to the RNA sequence, with the ability to effect dramatic changes in biological function. The first example to be described and among the best characterized, is the cytidine-to-uridine editing of apolipoprotein B (apo-B) RNA. The editing of apo-B RNA is mediated by a novel cytidine deaminase, apobec-1, which has acquired the ability to bind RNA. The stop translation codon generated by the editing of apo-B RNA truncates the full-length apo-B100 to form apo-B48. The recent observations of tumor formation in Apobec-1 transgenic animals, together with the fact that Apobec-1 is expressed in numerous tissues lacking apo-B, raises the issue of whether this enzyme is essential for a variety of posttranscriptional editing events. To directly test this, mice were created with a null mutation in Apobec-1 using homologous recombination in embryonic stem cells. Mice, homozygous for this mutation, were viable and made apo-B100 but not apo-B48. The null animals were fertile, and a variety of histological, behavioral, and morphological analyses revealed no phenotype other than abnormalities in lipoprotein metabolism, which included an increased low density lipoprotein fraction and a reduction in high density lipoprotein cholesterol. These studies demonstrate that neither apobec-1 nor apo-B48 is essential for viability and suggest that the major role of apobec 1 may be confined to the modulation of lipid transport. PMID- 8692963 TI - Heterodimer formation and activity in the human enzyme galactose-1-phosphate uridylyltransferase. AB - One of the fundamental questions concerning expression and function of dimeric enzymes involves the impact of naturally occurring mutations on subunit assembly and heterodimer activity. This question is of particular interest for the human enzyme galactose-l-phosphate uridylyl-transferase (GALT), impairment of which results in the inherited metabolic disorder galactosemia, because many if not most patients studied to date are compound heterozygotes rather than true molecular homozygotes. Furthermore, the broad range of phenotypic severity observed in these patients raises the possibility that allelic combination, not just allelic constitution, may play some role in determining outcome. In the work described herein, we have selected two distinct naturally occurring null mutations of GALT, Q188R and R333W, and asked the questions (i) what are the impacts of these mutations on subunit assembly, and (ii) if heterodimers do form, are they active? To answer these questions, we have established a yeast system for the coexpression of epitope-tagged alleles of human GALT and investigated both the extent of specific GALT subunit interactions and the activity of defined heterodimer pools. We have found that both homodimers and heterodimers do form involving each of the mutant subunits tested and that both heterodimer pools retain substantial enzymatic activity. These results are significant not only in terms of their implications for furthering our understanding of galactosemia and GALT holoenzyme structure-function relationships but also because the system described may serve as a model for similar studies of other complexes composed of multiple subunits. PMID- 8692964 TI - Interleukin 7 receptor-deficient mice lack gammadelta T cells. AB - The interleukin 7 receptor (IL-7R) plays a crucial role in early B- and T-cell development. It consists of a unique a chain and a common gamma chain [IL-2 receptor gamma chain (IL-2Rgamma)]. Gene inactivation of IL-7, IL-7R, and IL 2Rgamma resulted in severe impairment of B and T lymphopoiesis in mice. In addition, IL-2Rgamma-deficient mice lack gammadelta T cells in the skin and have the impaired development of natural killer (NK) cells and intraepithelial lymphocytes. To explore the role of IL-7/IL-7R system in gammadelta T- and NK cell development, we have generated and analyzed IL-7R-deficient mice. gammadelta T cells were absent from skin, gut, liver, and spleen in the deficient mice. In contrast, alphabeta T and B cells were detected in reduced, but certain, numbers, and NK cells developed normally. The gammadelta T-cell development in fetal and adult thymus was also completely blocked. These results clearly demonstrate that the signal from IL-7R is indispensable for gammadelta T-cell development in both thymic and extrathymic pathways. On the contrary, it is suggested that NK-cell development requires cytokine(s) other than IL-7. PMID- 8692965 TI - Direct binding of a soluble natural killer cell inhibitory receptor to a soluble human leukocyte antigen-Cw4 class I major histocompatibility complex molecule. AB - Natural killer (NK) cells expressing specific p58 NK receptors are inhibited from lysing target cells that express human leukocyte antigen (HLA)-C class I major histocompatibility complex molecules. To investigate the interaction between p58 NK receptors and HLA-Cw4, the extracellular domain of the p58 NK receptor specific for HLA-Cw4 was overexpressed in Escherichia coli and refolded from purified inclusion bodies. The refolded NK receptor is a monomer in solution. It interacts specifically with HLA-Cw4, blocking the binding of a p58-Ig fusion protein to HLA-Cw4-expressing cells, but does not block the binding of a p58-Ig fusion protein specific for HLA-Cw3 to HLA-Cw3-expressing cells. The bacterially expressed extracellular domain of HLA-Cw4 heavy chain and beta2-microglobulin were refolded in the presence of a HLA-Cw4-specific peptide. Direct binding between the soluble p58 NK receptor and the soluble HLA-Cw4-peptide complex was observed by native gel electrophoresis. Titration binding assays show that soluble monomeric receptor forms a 1:1 complex with HLA-Cw4, independent of the presence of Zn2+. The formation of complexes between soluble, recombinant molecules indicates that HLA-Cw4 is sufficient for specific ligation by the NK receptor and that neither glycoprotein requires carbohydrate for the interaction. PMID- 8692966 TI - Covalent assembly of a soluble T cell receptor-peptide-major histocompatibility class I complex. AB - We used stepwise photochemical cross-linking for specifically assembling soluble and covalent complexes made of a T-cell antigen receptor (TCR) and a class I molecule of the major histocompatibility complex (MHC) bound to an antigenic peptide. For that purpose, we have produced in myeloma cells a single-chain Fv construct of a TCR specific for a photoreactive H-2Kd-peptide complex. Photochemical cross-linking of this TCR single-chain Fv with a soluble form of the photoreactive H-2Kd-peptide ligand resulted in the formation of a ternary covalent complex. We have characterized the soluble ternary complex and showed that it reacted with antibodies specific for epitopes located either on the native TCR or on the Kd molecules. By preventing the fast dissociation kinetics observed with most T cell receptors, this approach provides a means of preparing soluble TCR-peptide-MHC complexes on large-scale levels. PMID- 8692967 TI - Reduction in the level of Gal(alpha1,3)Gal in transgenic mice and pigs by the expression of an alpha(1,2)fucosyltransferase. AB - Hyperacute rejection of a porcine organ by higher primates is initiated by the binding of xenoreactive natural antibodies of the recipient to blood vessels in the graft leading to complement activation. The majority of these antibodies recognize the carbohydrate structure Gal(alphal,3)Gal (gal epitope) present on cells of pigs. It is possible that the removal or lowering of the number of gal epitopes on the graft endothelium could prevent hyperacute rejection. The Gal(alpha1,3) Gal structure is formed by the enzyme Galbeta1,4GlcNAc3-alpha-D galactosyltransferase [alpha(1,3)GT; EC 2.4.1.51], which transfers a galactose molecule to terminal N-acetyllactosamine (N-lac) present on various glycoproteins and glycolipids. The N-lac structure might be utilized as an acceptor by other glycosyltransferases such as Galbeta1,4GlcNAc 6-alpha-D-sialyltransferase [alpha(2,6)ST], Galbeta1,4GlcNAc 3-alpha-D-Sialyltransferase [alpha(2,3)ST], or Galbeta 2-alpha-L-fucosyltransferase [alpha(1,2)FT; EC 2.4.1.691, etc. In this report we describe the competition between alpha(1,2)FT and alpha(1,3)GT in cells in culture and the generation of transgenic mice and transgenic pigs that express alpha(1,2)Fr leading to synthesis of Fucalpha,2Galbeta- (H antigen) and a concomitant decrease in the level of Gal(alpha1,3)Gal. As predicted, this resulted in reduced binding of xenoreactive natural antibodies to endothelial cells of transgenic mice and protection from complement mediated lysis. PMID- 8692968 TI - Treatment of experimental autoimmune encephalomyelitis by feeding myelin basic protein conjugated to cholera toxin B subunit. AB - Oral administration of autoantigens can prevent and partially suppress autoimmune diseases in a number of experimental models, Depending on the dose of antigen fed, this approach appears to involve distinct yet reversible and short-lasting mechanisms (anergy/deletion and suppression) and usually requires repeated feeding of large (suppression) to massive (anergy/deletion) amounts of autoantigens to be effective. Most importantly, this approach is relatively less effective in animals already systemically sensitized to the fed antigen, such as in animals already harboring autoreactive T cells and, thus, presumably also in humans suffering from an autoimmune disorder. We have previously shown that feeding a single dose of minute amounts of antigens conjugated to cholera toxin B subunit (CTB) can effectively suppress delayed-type hypersensitivity reactions in systemically immune animals. We now report that feeding small amounts of myelin basic protein (MBP) conjugated to CTB either before or after disease induction protected rats from experimental autoimmune encephalomyelitis. Such treatment was as effective in suppressing interleukin 2 production and proliferative responses of lymph node cells to MBP as treatment involving repeated feeding with much larger (50- to 100-fold) doses of free MBP. Different from the latter treatment, which led to decreased production of interferon-gamma in lymph nodes, low-dose oral CTB-MBP treatment was associated with increased interferon-gamma production. Most importantly, low-dose oral CTB-MBP treatment greatly reduced the level of leukocyte infiltration into spinal cord tissue compared with treatment with repeated feeding of large doses of MBP. These results suggest that the protection from experimental autoimmune encephalomyelitis achieved by feeding CTB-conjugated myelin autoantigen involves immunomodulating mechanisms that are distinct from those implicated by conventional protocols of oral tolerance induction. PMID- 8692969 TI - Critical contribution of beta chain residue 57 in peptide binding ability of both HLA-DR and -DQ molecules. AB - Position 57 in the beta chain of HLA class II molecules maintains an Asp/non-Asp dimorphism that has been conserved through evolution and is implicated in susceptibility to some autoimmune diseases. The latter effect may be due to the influence of this residue on the ability of class II alleles to bind specific pathogenic peptides. We utilized highly homologous pairs of both DR and DQ alleles that varied at residue 57 to investigate the impact of this dimorphism on binding of model peptides. Using a direct binding assay of biotinylated peptides on whole cells expressing the desired alleles, we report several peptides that bind differentially to the allele pairs depending on the presence or absence of Asp at position 57. Peptides with negatively charged residues at anchor position 9 bind well to alleles not containing Asp at position 57 in the beta chain but cannot bind well to homologous Asp-positive alleles. By changing the peptides at the single residue predicted to interact with this position 57, we demonstrate a drastically altered or reversed pattern of binding. Ala analog peptides confirm these interactions and identify a limited set of interaction sites between the bound peptides and the class II molecules. Clarification of the impact of specific class II polymorphisms on generating unique allele-specific peptide binding "repertoires" will aid in our understanding of the development of specific immune responses and HLA-associated diseases. PMID- 8692970 TI - Cellular mechanisms for the formation of a soluble form derivative of T-cell receptor alpha chain by suppressor T cells. AB - Upon stimulation with anti-CD3, suppressor T-cell (Ts) hybridomas and homologous transfectants of T-cell receptor a (TCRalpha) cDNA in the T-cell hybridoma formed a 55-kDa TCRalpha chain derivative that bound both the monoclonal anti-TCRalpha chain and polyclonal antibodies against glycosylation inhibiting factor (GIF). The peptide is a subunit of antigen-specific suppressor T-cell factor (TsF), and is considered to be a posttranslationally-formed conjugate of TCRalpha chain with GIF peptide. The TCRalpha derivative is synthesized by the transfectant after stimulation with anti-CD3, and not derived from TCR present on the cell surface. Stimulation of the stable homologous transfectants with anti-CD3 induced translocation of the 13-kDa GIF peptide into endoplasmic reticulum (ER). When a helper Ts hybridoma or a stable transfectant of the same TCRalpha cDNA in a helper cell-derived TCRalpha- clone was stimulated with anti-CD3, translocation of GIF peptide was not detected, and these cells failed to secrete a TCRalpha derivative. However, further transfection of a chimeric cDNA encoding a procalcitonin-GIF fusion protein into the helper cell-derived stable transfectant of TCRalpha cDNA resulted in translocation of the GIF protein and formation of bioactive 55-kDa GIF. The results indicated that translocation of GIF peptide through ER is unique for Ts cells, and that this process is essential for the formation/secretion of the soluble form derivative of TCRalpha chain by T cells. PMID- 8692971 TI - DNA vaccine for hepatitis B: evidence for immunogenicity in chimpanzees and comparison with other vaccines. AB - Vaccination of two chimpanzees against hepatitis B virus (HBV) by intramuscular injection of plasmid DNA encoding the major and middle HBV envelope proteins induced group-, subtype- and preS2-specific antibodies. These were initially of IgM isotype, and then they were of IgG (predominantly IgGl) isotype. The chimpanzee injected with 2 mg of DNA attained >100 milli-international units/ml of anti-HBs antibody after one injection and 14,000 milli-international units/ml after four injections. A smaller dose (400 microg) induced lower and transient titers, but a strong anamnestic response occurred 1 year later. Comparison with responses in 23 chimpanzees receiving various antigen-based HBV vaccines suggests that the DNA approach is promising for prophylactic immunization against HBV. PMID- 8692972 TI - U1 small nuclear RNA chimeric ribozymes with substrate specificity for the Rev pre-mRNA of human immunodeficiency virus. AB - The in vivo effectiveness of ribozymes strongly depends on the correct choice of the vector molecule. High levels of expression, stability, active conformation, and correct cellular localization are the most important features for a ribozyme vector. We have exploited the utilization of the U1 small nuclear RNA (snRNA) as a vector for specifically targeting a ribozyme into the nucleus. The Rev pre-mRNA of human immunodeficiency virus type 1 was chosen as target for testing the activity of the Ul-ribozyme. The catalytic core of the hammerhead motif, plus the recognition sequences, substituted the stem-loop III of the U1 snRNA. The resulting construct displays efficient cleavage activity in vitro. In addition, in the in vivo system of Xenopus laevis oocytes, the Ul-chimeric ribozyme accumulates in large amounts in the nucleus and produces a considerable reduction of Rev pre-mRNA levels. The Rev-specific ribozyme was also inserted in a derivative of the Ul snRNA mutated in the region of pairing with the 5' splice site, such as to match it with the suboptimal splice junction of the Rev precursor. This construct shows more efficient reduction of Rev pre-mRNA in vivo than the wild-type U1 vector. PMID- 8692973 TI - Correction of diabetic alterations by glucokinase. AB - Hyperglycemia is a common feature of diabetes mellitus. It results from a decrease in glucose utilization by the liver and peripheral tissues and an increase in hepatic glucose production. Glucose phosphorylation by glucokinase is an initial event in glucose metabolism by the liver. However, glucokinase gene expression is very low in diabetic animals. Transgenic mice expressing the P enolpyruvate carboxykinase/glucokinase chimeric gene were generated to study whether the return of the expression of glucokinase in the liver of diabetic mice might prevent metabolic alterations. In contrast to nontransgenic mice treated with streptozotocin, mice with the transgene previously treated with streptozotocin showed high levels of both glucokinase mRNA and its enzyme activity in the liver, which were associated with an increase in intracellular levels of glucose 6-phosphate and glycogen. The liver of these mice also showed an increase in pyruvate kinase activity and lactate production. Furthermore, normalization of both the expression of genes involved in gluconeogenesis and ketogenesis in the liver and the production of glucose and ketone body by hepatocytes in primary culture were observed in streptozotocin-treated transgenic mice. Thus, glycolysis was induced while gluconeogenesis and ketogenesis were blocked in the liver of diabetic mice expressing glucokinase. This was associated with normalization of blood glucose, ketone bodies, triglycerides, and free fatty acids even in the absence of insulin. These results suggest that the expression of glucokinase during diabetes might be a new approach to the normalization of hyperglycemia. PMID- 8692974 TI - Mass vaccination to control chickenpox: the influence of zoster. AB - The impact of transmission events from patients with shingles (zoster) on the epidemiology of varicella is examined before and after the introduction of mass immunization by using a stochastic mathematical model of transmission dynamics. Reactivation of the virus is shown to damp stochastic fluctuations and move the dynamics toward simple annual oscillations. The force of infection due to zoster cases is estimated by comparison of simulated and observed incidence time series. The presence of infectious zoster cases reduces the tendency for mass immunization to increase varicella incidence at older ages when disease severity is typically greater. PMID- 8692975 TI - Increased liposome extravasation in selected tissues: effect of substance P. AB - We have used a pharmacologic mediator to open intercellular connections in selected vessels to allow liposomes to escape from the blood stream and to extravasate into tissues that have appropriate receptors. We have examined the effects of substance P (SP), a peptide known to increase vascular permeability in selected tissues, such as trachea, esophagus, and urinary bladder in rats. We used quantitative fluorescence analysis of tissues to measure two fluorescent markers, one attached to the lipid (rhodamine-phosphatidylethanolamine) and another, doxorubicin (an anti-tumor drug), encapsulated within the aqueous interior. We have also examined the deposition of liposomes microscopically by the use of encapsulated colloidal gold and silver enhancement. Analysis of the biochemical and morphological observations indicate the following: (i) Injection of SP produces a striking increase in both liposome labels, but only in tissues that possess receptors for SP in postcapillary venules; (ii) liposome material in these tissues has extravasated and is found extracellularly near a variety of cells beyond the endothelial layer over the first few hours; (iii) 24 h following injection of liposomes and SP, liposome material is found in these tissues, localized intracellularly in both endothelial cells and macrophages. We propose that appropriate application of tissue-specific mediators can result in liposome extravasation deep within tissues that normally do not take up significant amounts of liposomes from the blood. Such liposomes are able to carry a variety of pharmacological agents that can be released locally within selected target tissues for therapeutic purposes. PMID- 8692976 TI - Suppression of diet-induced atherosclerosis in low density lipoprotein receptor knockout mice overexpressing lipoprotein lipase. AB - Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. Conflicting results have been reported concerning its role in atherogenesis. To determine the effects of the overexpressed LPL on diet-induced atherosclerosis, we have generated low density lipoprotein receptor (LDLR) knockout mice that overexpressed human LPL transgene (LPL/LDLRKO) and compared their plasma lipoproteins and atherosclerosis with those in nonexpressing LDLR knockout mice (LDLRKO). On a normal chow diet, LPL/LDLRKO mice showed marked suppression of mean plasma triglyceride levels (32 versus 236 mg/dl) and modest decrease in mean cholesterol levels (300 versus 386 mg/dl) as compared with LDLRKO mice. Larger lipoprotein particles of intermediate density lipoprotein (IDL)/LDL were selectively reduced in LPL/LDLRKO mice. On an atherogenic diet, both mice exhibited severe hypercholesterolemia. But, mean plasma cholesterol levels in LPL/ LDLRKO mice were still suppressed as compared with that in LDLRKO mice (1357 versus 2187 mg/dl). Marked reduction in a larger subfraction of IDL/LDL, which conceivably corresponds to remnant lipoproteins, was observed in the LPL/LDLRKO mice. LDLRKO mice developed severe fatty streak lesions in the aortic sinus after feeding with the atherogenic diet for 8 weeks. In contrast, mean lesion area in the LPL/LDLRKO mice was 18-fold smaller than that in LDLRKO mice. We suggest that the altered lipoprotein profile, in particular the reduced level of remnant lipoproteins, is mainly responsible for the protection by LPL against atherosclerosis. PMID- 8692977 TI - Viral dynamics in vivo: limitations on estimates of intracellular delay and virus decay. AB - Anti-viral drug treatment of human immunodeficiency virus type I (HIV-1) and hepatitis B virus (HBV) infections causes rapid reduction in plasma virus load. Viral decline occurs in several phases and provides information on important kinetic constants of virus replication in vivo and pharmacodynamical properties. We develop a mathematical model that takes into account the intracellular phase of the viral life-cycle, defined as the time between infection of a cell and production of new virus particles. We derive analytic solutions for the dynamics following treatment with reverse transcriptase inhibitors, protease inhibitors, or a combination of both. For HIV-1, our results show that the phase of rapid decay in plasma virus (days 2-7) allows precise estimates for the turnover rate of productively infected cells. The initial quasi-stationary phase (days 0-1) and the transition phase (days 1-2) are explained by the combined effects of pharmacological and intracellular delays, the clearance of free virus particles, and the decay of infected cells. Reliable estimates of the first three quantities are not possible from data on virus load only; such estimates require additional measurements. In contrast with HIV-1, for HBV our model predicts that frequent early sampling of plasma virus will lead to reliable estimates of the free virus half-life and the pharmacological properties of the administered drug. On the other hand, for HBV the half-life of infected cells cannot be estimated from plasma virus decay. PMID- 8692978 TI - Surface-epitope masking and expression cloning identifies the human prostate carcinoma tumor antigen gene PCTA-1 a member of the galectin gene family. AB - The selective production of monoclonal antibodies (mAbs) reacting with defined cell surface-expressed molecules is now readily accomplished with an immunological subtraction approach, surface-epitope masking (SEM). Using SEM, prostate carcinoma (Pro 1.5) mAbs have been developed that react with tumor associated antigens expressed on human prostate cancer cell lines and patient derived carcinomas. Screening a human LNCaP prostate cancer cDNA expression library with the Pro 1.5 mAb identifies a gene, prostate carcinoma tumor antigen 1 (PCTA-1). PCTA-1 encodes a secreted protein of approximately 35 kDa that shares approximately 40% sequence homology with the N-amino terminal region of members of the S-type galactose-binding lectin (galectin) gene family. Specific galectins are found on the surface of human and marine neoplastic cells and have been implicated in tumorigenesis and metastasis. Primer pairs within the 3' untranslated region of PCTA-1 and reverse transcription-PCR demonstrate selective expression of PCTA-1 by prostate carcinomas versus normal prostate and benign prostatic hypertrophy. These findings document the use of the SEM procedure for generating mAbs reacting with tumor-associated antigens expressed on human prostate cancers. The SEM-derived mAbs have been used for expression cloning the gene encoding this human tumor antigen. The approaches described in this paper, SEM combined with expression cloning, should prove of wide utility for developing immunological reagents specific for and identifying genes relevant to human cancer. PMID- 8692979 TI - Cloning and expression of human deoxyguanosine kinase cDNA. AB - A human cDNA sequence homologous to human deoxycytidine kinase (dCK; EC 2.7.1.74) was identified in the GenBank sequence data base. The longest open reading frame encoded a protein that was 48% identical to dCK at the amino acid level. The cDNA was expressed in Escherichia coli and shown to encode a protein with the same substrate specificity as described for the mitochondrial deoxyguanosine kinase (dGK; EC 2.7.1.113). The N terminus of the deduced amino acid sequence had properties characteristic for a mitochondrial translocation signal, and cleavage at a putative mitochondrial peptidase cleavage site would give a mature protein size of 28 kDa. Northern blot analysis determined the length of dGK mRNA to 1.3 kbp with no cross-hybridization to the 2.8-kbp dCK mRNA. dGK mRNA was detected in all tissues investigated with the highest expression levels in muscle, brain, liver, and lymphoid tissues. Alignment of the dGK and herpes simplex virus type 1 thymidine kinase amino acid sequences showed that five regions, including the substrate-binding pocket and the ATP-binding glycine loop, were also conserved in dGK. To our knowledge, this is the first report of a cloned mitochondrial nucleoside kinase and the first demonstration of a general sequence homology between two mammalian deoxyribonucleoside kinases. Our findings suggest that dCK and dGK are evolutionarily related, as well as related to the family of herpes virus thymidine kinases. PMID- 8692980 TI - Antisense RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cells in vivo. AB - Prostate carcinoma is the second leading cause of death from malignancy in men in the United States. Prostate cancer cells express type I insulin-like growth factor receptor (IGF-IR) and prostate cancer selectively metastazises to bone, which is an environment rich in insulin-like growth factors (IGFs), thereby supporting a paracrine action for cancer cell proliferation. We asked whether the IGF-IR is coupled to tumorigenicity and invasion of prostate cancer. When rat prostate adenocarcinoma cells (PA-III) were stably transfected with an antisense IGF-IR expression construct containing the ZnSO4-inducible metallothionein-1 transcriptional promoter, the transfectants expressed high levels of IGF-IR antisense RNA after induction with ZnSO4, which resulted in dramatically reduced levels of endogenous IGF-IR mRNA. A significant reduction in expression both of tissue-type plasminogen activator and of urokinase-type plasminogen activator occurred in PA-III cells accompanying inhibition of IGF-IR. Subcutaneous injection of either nontransfected PA-III or PA-III cells transfected with vector minus the IGF-IR insert into nude mice resulted in large tumors after 4 weeks. However, mice injected with IGF-IR antisense-transfected PA-III cells either developed tumors 90% smaller than controls or remained tumor-free after 60 days of observation. When control-transfected PA-III cells were inoculated over the abraded calvaria of nude mice, large tumors formed with invasion of tumor cells into the brain parenchyma. In contrast, IGF-IR antisense transfectants formed significantly smaller tumors with no infiltration into brain. These results indicate an important role for the IGF/IGF-IR pathway in metastasis and provide a basis for targeting IGF-IR as a potential treatment for prostate cancer. PMID- 8692981 TI - Cytotoxic analogs of luteinizing hormone-releasing hormone containing doxorubicin or 2-pyrrolinodoxorubicin, a derivative 500-1000 times more potent. AB - Doxorubicin (DOX) and its daunosamine-modified derivative, 2-pyrrolino-DOX, which is 500-1000 times more active than DOX, were incorporated into agonistic and antagonistic analogs of luteinizing hormone-releasing hormone (LH-RH). The conjugation of DOX with LH-RH analogs was performed by using N-(9 fluorenylmethoxycarbonyl)-DOX-14-O-hemiglutarate, a dicarboxylic acid ester derivative of DOX. Coupling this derivative covalently to the epsilon-amino group of the D-Lys side chain of agonist [D-Lys6]LH-RH or antagonistic analog AC-D Nal(2)-D-Phe(4Cl)-D-Pal(3)-Ser-Tyr-D-Lys-Leu-Arg-Pro-D-Ala-NH 2 [where Nal(2) = 3 (2-naphthyl)alanine, Pal(3) = 3-(3-pyridyl)alanine, and Phe(4CI) = 4 chlorophenylalanine] was followed by the removal of the 9 fluorenylmethoxycarbonyl protective group to yield cytotoxic derivatives of LH-RH analogs containing DOX. From these DOX containing LH-RH hybrids, intensely potent analogs with daunosamine-modified derivatives of DOX can be readily formed. Thus, cytotoxic LH-RH agonist containing DOX (AN-152) can be converted in a 66% yield by a reaction with a 30-fold excess of 4-iodobutyraldehyde in N,N dimethylformamide into a derivative having 2-pyrrolino-DOX (AN-207). Hybrid molecules AN-152 and AN-207 fully preserve the cytotoxic activity of their radicals, DOX or 2-pyrrolino-DOX, respectively, in vitro, and also retain the high binding affinity of the peptide hormone portion of the conjugates to rat pituitary receptors for LH-RH. These highly potent cytotoxic analogs of LH-RH were designed as targeted anti-cancer agents for the treatment of various tumors that possess receptors for the carrier peptide. Initial in vivo studies show that the hybrid molecules are much less toxic than the respective cytotoxic radicals incorporated and significantly more active in inhibiting tumor growth. PMID- 8692982 TI - Costimulatory protein B7-1 enhances the cytotoxic T cell response and antibody response to hepatitis B surface antigen. AB - There is a need for more effective therapy for chronic virus infections. A principle natural mechanism for elimination of virus-infected host cells is activation of viral antigen-specific cytotoxic T lymphocytes (CTL). In an effort to develop methods of inducing virus-specific CTL responses that might be utilized in therapy of virus infections, we have investigated the effect of B7, a costimulatory factor for T-cell activation. In this study we show that delivery of genes encoding human B7-1 and a viral antigen in the same recombinant viral vector to cells of mice induces a greater viral antigen-specific CTL response than does similar delivery of the viral antigen gene alone. Two recombinant adenovirus vectors were constructed with the foreign genes inserted in the early region 3. One of them (Ad1312) directed expression of the surface antigen gene of hepatitis B virus (HBS); the other (Ad1310) directed coexpression of HBS and human B7-1 (CD80) by means of an internal ribosomal entry site placed between the two coding sequences. When inoculated into BALB/c mice, both vectors induced a viral surface antigen-specific CTL response. The response induced by Ad1310 was stronger than that by Adl312 as measured by a chromium release assay for CTL activity and limiting dilution analysis for CTL precursor frequency, indicating that the B7-1 gene co-delivered with the HBS gene had an enhancing effect on the CTL response against surface antigen. Ad1310 also induced a higher titer of antibody against surface antigen than did Ad1312. This result suggests that expression of a costimulatory protein and a viral antigen in the same cells in vivo induces stronger immune responses than expression of the antigen alone. This could be a novel strategy for development of both preventive and therapeutic vaccines against infectious agents. PMID- 8692983 TI - Circumventing tolerance to generate autologous monoclonal antibodies to the prion protein. AB - Prion diseases are disorders of protein conformation and do not provoke an immune response. Raising antibodies to the prion protein (PrP) has been difficult due to conservation of the PrP sequence and to inhibitory activity of alpha-PrP antibodies toward lymphocytes. To circumvent these problems, we immunized mice in which the PrP gene was ablated (Prnp 0/0) and retrieved specific monoclonal antibodies (mAbs) through phage display libraries. This approach yielded alpha PrP mAbs that recognize mouse PrP. Studies with these mAbs suggest that cellular PrP adopts an unusually open structure consistent with the conformational plasticity of this protein. PMID- 8692984 TI - Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide. AB - The islet in non-insulin-dependent diabetes mellitus (NIDDM) is characterized by loss of beta cells and large local deposits of amyloid derived from the 37-amino acid protein, islet amyloid polypeptide (IAPP). We have hypothesized that IAPP amyloid forms intracellularly causing beta-cell destruction under conditions of high rates of expression. To test this we developed a homozygous transgenic mouse model with high rates of expression of human IAPP. Male transgenic mice spontaneously developed diabetes mellitus by 8 weeks of age, which was associated with selective beta-cell death and impaired insulin secretion. Small intra- and extracellular amorphous IAPP aggregates were present in islets of transgenic mice during the development of diabetes mellitus. However, IAPP derived amyloid deposits were found in only a minority of islets at approximately 20 weeks of age, notably after development of diabetes mellitus in male transgenic mice. Approximately 20% of female transgenic mice spontaneously developed diabetes mellitus at 30+ weeks of age, when beta-cell degeneration and both amorphous and amyloid deposits of IAPP were present. We conclude that overexpression of human IAPP causes beta-cell death, impaired insulin secretion, and diabetes mellitus. Large deposits of IAPP derived amyloid do not appear to be important in this cytotoxicity, but early, small amorphous intra- and extracellular aggregates of human IAPP were consistently present at the time of beta-cell death and therefore may be the most cytotoxic form of IAPP. PMID- 8692985 TI - Characterization of promoters and stable transfection by homologous and nonhomologous recombination in Plasmodium falciparum. AB - Genetic studies of the protozoan parasite Plasmodium falciparum have been severely limited by the inability to introduce or modify genes. In this paper we describe a system of stable transfection of P. falciparum using a Toxoplasma gondii dihydrofolate reductase-thymidylate synthase gene, modified to confer resistance to pyrimethamine, as a selectable marker. This gene was placed under the transcriptional control of the P. falciparum calmodulin gene flanking sequences. Transfected parasites generally maintained plasmids episomally while under selection; however, parasite clones containing integrated forms of the plasmid were obtained. Integration occurred by both homologous and nonhomologous recombination. In addition to the flanking sequence of the P. falciparum calmodulin gene, the 5' sequences of the P. falciparum and P. chabaudi dihydrofolate reductase-thymidylate synthase genes were also shown to be transcriptionally active in P. falciparum. The minimal 5' sequence that possessed significant transcriptional activity was determined for each gene and short sequences containing important transcriptional control elements were identified. These sequences will provide considerable flexibility in the future construction of plasmid vectors to be used for the expression of foreign genes or for the deletion or modification of P. falciparum genes of interest. PMID- 8692986 TI - Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives. AB - So324 is a 2',3'-dideoxy-2',3'-didehydrothymidine-5'-monophosphate (d4T-MP) prodrug containing at the phosphate moiety a phenyl group and the methylester of alanine linked to the phosphate through a phosphoramidate linkage. So324 has anti HIV activity in human CEM, MT4, and monocyte/macrophage cells that is superior to that of d4T. In contrast to d4T, So324 is also able to inhibit HIV replication in thymidine kinase-deficient CEM cells. After uptake of So324 by intact human lymphocytes, d4T-MP is released and subsequently converted intracellularly to d4T TP. In addition, accumulation of substantial amounts of a novel d4T derivative has been found. This d4T metabolite has been characterized as alaninyl d4T-MP. The latter metabolite accumulates at approximately 13- to 200-fold higher levels than d4T-TP depending the experimental conditions. Alaninyl d4T-MP should be considered as an intra- and/or extracellular depot form of d4T and/or d4T-MP. These findings may explain the superior anti-retroviral activity of So324 over d4T in cell culture. PMID- 8692988 TI - Formation of stable cationic lipid/DNA complexes for gene transfer. AB - Stable cationic lipid/DNA complexes were formed by solubilizing cationic liposomes with 1% octylglucoside and complexing a DNA plasmid with the lipid in the presence of detergent. Removal of the detergent by dialysis yielded a lipid/DNA suspension that was able to transfect tissue culture cells up to 90 days after formation with no loss in activity. Similar levels of gene transfer were obtained by mixing the cationic lipid in a liposome form with DNA just prior to cell addition. However, expression was completely lost 24 hr after mixing. The transfection efficiency of the stable complex in 15% fetal calf serum was 30% of that obtained in the absence of serum, whereas the transient complex was completely inactivated with 2% fetal calf serum. A 90-day stability study comparing various storage conditions showed that the stable complex could be stored frozen or as a suspension at 4 degrees C with no loss in transfection efficiency. Centrifugation of the stable complex produced a pellet that contained approximately 90% of the DNA and 10% of the lipid. Transfection of cells with the resuspended pellet and the supernatant showed that the majority of the transfection activity was in the pellet and all the toxicity was in the supernatant. Formation of a stable cationic lipid/DNA complex has produced a transfection vehicle that can be stored indefinitely, can be concentrated with no loss in transfection efficiency, and the toxicity levels can be greatly reduced when the active complex is isolated from the uncomplexed lipid. PMID- 8692987 TI - Molecular cloning of a rat chromosome putative recombinogenic sequence homologous to the hepatitis B virus encapsidation signal. AB - Previously, we reported that a 61-bp subgenomic HBV DNA sequence (designated as 15AB, nt 1855-1915) is a hot spot for genomic recombination and that a cellular protein binding to 15AB may be the putative recombinogenic protein. In the present study, we established the existence of a 15AB-like sequence in human and rat chromosomal DNA by Southern blot analysis. The 15AB-like sequence isolated from the rat chromosome demonstrated a 80.9% identity with 5' CCAAGCTGTGCCTTGGGTGGC-3', at 1872-1892 of the hepatitis B virus genome, thought to be the essential region for recombination. Interestingly, this 15AB-like sequence also contained the pentanucleotide motifs GCTGG and CCAGC as an inverted repeat, part of the chi known hot spot for recombination in Escherichia coli. Importantly, a portion of the 15AB-like sequence is homologous (82.1%, 23/28 bp) to break point clusters of the human promyelocytic leukemia (PML) gene, characterized by a translocation [t(15;17)], and to rearranged mouse DNA for the immunoglobulin kappa light chain. Moreover, 15AB and 15AB-like sequences have striking homologies (12/15 = 80.0% and 13/15 = 86.7%, respectively) to the consensus sequence for topoisomerase II. Our present results suggest that this 15AB-like sequence in the rat genome might be a recombinogenic candidate triggering genomic instability in carcinogenesis. PMID- 8692989 TI - Highly stable expression of a foreign gene from rabies virus vectors. AB - A reverse genetics approach was applied to generate a chimeric nonsegmented negative strand RNA virus, rabies virus (RV) of the Rhabdoviridae family, that expresses a foreign protein. DNA constructs containing the entire open reading frame of the bacterial chloramphenicol acetyltransferase (CAT) gene and an upstream RV cistron border sequence were inserted either into the nontranslated pseudogene region of a full-length cDNA copy of the RV genome or exchanged with the pseudogene region. After intracellular T7 RNA polymerase-driven expression of full-length antigenome RNA transcripts and RV nucleoprotein, phosphoprotein and polymerase from transfected plasmids, RVs transcribing novel monocistronic mRNAs and expressing CAT at high levels, were recovered. The chimeric viruses possessed the growth characteristics of standard RV and were genetically stable upon serial cell culture passages. CAT activity was still observed in cell cultures infected with viruses passaged for more than 25 times. Based on the unprecedented stability of the chimeric RNA genomes, which is most likely due to the structure of the rhabdoviral ribonucleoprotein complex, we predict the successful future use of recombinant rhabdovirus vectors for displaying foreign antigens or delivering therapeutic genes. PMID- 8692990 TI - A chromosomal locus required for copper resistance, competitive fitness, and cytochrome c biogenesis in Pseudomonas fluorescens. AB - A chromosomal locus required for copper resistance and competitive fitness was cloned from a strain of Pseudomonas fluorescens isolated from copper-contaminated agricultural soil. Sequence analysis of this locus revealed six open reading frames with homology to genes involved in cytochrome c biogenesis in other bacteria, helC, cycJ, cycK, tipB, cycL, and cycH, with the closest similarity being to the aeg-46.5(yej) region of the Escherichia coli chromosome. The proposed functions of these genes in other bacteria include the binding, transport, and coupling of heme to apocytochrome c in the periplasm of these Gram negative bacteria. Putative heme-binding motifs were present in the predicted products of cycK and cycL, and TipB contained a putative disulfide oxidoreductase active site proposed to maintain the heme-binding site of the apocytochrome in a reduced state for ligation of heme. Tn3-gus mutagenesis showed that expression of the genes was constitutive but enhanced by copper, and confirmed that the genes function both in copper resistance and production of active cytochrome c. However, two mutants in cycH were copper-sensitive and oxidase-positive, suggesting that the functions of these genes, rather than cytochrome c oxidase itself, were required for resistance to copper. PMID- 8692991 TI - A family of lysozyme-like virulence factors in bacterial pathogens of plants and animals. AB - We describe a conserved family of bacterial gene products that includes the VirB1 virulence factor encoded by tumor-inducing plasmids of Agrobacterium spp., proteins involved in conjugative DNA transfer of broad-host-range bacterial plasmids, and gene products that may be involved in invasion by Shigella spp. and Salmonella enterica. Sequence analysis and structural modeling show that the proteins in this group are related to chicken egg white lysozyme and are likely to adopt a lysozyme-like structural fold. Based on their similarity to lysozyme, we predict that these proteins have glycosidase activity. Iterative data base searches with three conserved sequence motifs from this protein family detect a more distant relationship to bacterial and bacteriophage lytic transglycosylases, and goose egg white lysozyme. Two acidic residues in the VirB1 protein of Agrobacterium tumefaciens form a putative catalytic dyad, Each of these residues was changed into the corresponding amide by site-directed mutagenesis. Strains of A. tumefaciens that express mutated VirB1 proteins have a significantly reduced virulence. We hypothesize that many bacterial proteins involved in export of macromolecules belong to a widespread class of hydrolases and cleave beta-1,4 glycosidic bonds as part of their function. PMID- 8692992 TI - Dimorphism and haploid fruiting in Cryptococcus neoformans: association with the alpha-mating type. AB - Cryptococcus neoformans is a major opportunistic fungal pathogen in AIDS and other immunosuppressed patients. We have shown that wild-type haploid C. neoformans can develop an extensive hyphal phase under appropriate conditions. Hyphae produced under these conditions are monokaryotic, possess unfused clamp connections, and develop basidia with viable basidiospores. The ability to undergo this transition is determined by the presence of the alpha-mating type locus and is independent of serotype. The association of the hyphal phase with the alpha-mating type may explain the preponderance of this mating type in the environment and the nature of the infectious propagule of C. neoformans. PMID- 8692993 TI - Localization of alpha type II calcium calmodulin-dependent protein kinase at glutamatergic but not gamma-aminobutyric acid (GABAergic) synapses in thalamus and cerebral cortex. AB - The alpha subunit of type II calcium/calmodulin-dependent protein kinase (CAM II kinase-alpha) plays an important role in longterm synaptic plasticity. We applied preembedding immunocytochemistry (for CAM II kinase-alpha) and postembedding immunogold labeling [for glutamate or gamma-aminobutyric acid (GABA)] to explore the subcellular relationships between transmitter-defined axon terminals and the kinase at excitatory and inhibitory synapses in thalamus and cerebral cortex. Many (but not all) axon terminals ending in asymmetric synapses contained presynaptic CAM II kinase-alpha immunoreactivity; GABAergic terminals ending in symmetric synapses did not. Postsynaptically, CAM II kinase-alpha immunoreactivity was associated with postsynaptic densities of many (but not all) glutamatergic axon terminals ending on excitatory neurons. CAM II kinase-alpha immunoreactivity was absent at postsynaptic densities of all GABAergic synapses. The findings show that CAM II kinase-alpha is selectively expressed in subpopulations of excitatory neurons and, to our knowledge, demonstrate for the first time that it is only associated with glutamatergic terminals pre- and postsynaptically. CAM II kinase-alpha is unlikely to play a role in plasticity at GABAergic synapses. PMID- 8692994 TI - Selective expression of m2 muscarinic receptor in the parvocellular channel of the primate visual cortex. AB - Visual information in primates is relayed from the dorsal lateral geniculate nucleus to the cerebral cortex by three parallel neuronal channels designated the parvocellular, magnocellular, and interlaminar pathways. Here we report that m2 muscarinic acetylcholine receptor in the macaque monkey visual cortex is selectively associated with synaptic circuits subserving the function of only one of these channels. The m2 receptor protein is enriched both in layer IV axons originating from parvocellular layers of the dorsal lateral geniculate nucleus and in cytochrome oxidase poor interblob compartments in layers II and III, which are linked with the parvocellular pathway. In these compartments, m2 receptors appear to be heteroreceptors, i.e., they are associated predominantly with asymmetric, noncholinergic synapses, suggesting a selective role in the modulation of excitatory neurotransmission through the parvocellular visual channel. PMID- 8692995 TI - Genetic construction and properties of a diphtheria toxin-related substance P fusion protein: in vitro destruction of cells bearing substance P receptors. AB - We have genetically replaced the native receptor binding domain of diphtheria toxin with an extended form of substance P (SP): SP-glycine (SP-Gly). The resulting fusion protein, DAB389SP-Gly, is composed of the catalytic and transmembrane domains of diphtheria toxin genetically coupled to SP-Gly. Because native SP requires a C-terminal amide moiety to bind with high affinity to the SP receptor, the precursor form of the fusion toxin, DAB389SP-Gly, was converted to DAB389SP by treatment with peptidylglycine-alpha-amidating monooxygenase. We demonstrate that following conversion, DAB389SP is selectively cytotoxic for cell lines that express either the rat or the human SP receptor. We also demonstrate that the cytotoxic action of DAB389SP is mediated via the SP receptor and dependent upon passage through an acidic compartment. To our knowledge, this is the first reported use of a neuropeptide as the targeting ligand for a fusion toxin; and the first instance in which an inactive precursor form of a fusion toxin is converted to the active form by a posttranslational modification. PMID- 8692996 TI - Ciliary neurotrophic factor protects striatal output neurons in an animal model of Huntington disease. AB - Huntington disease is a dominantly inherited, untreatable neurological disorder featuring a progressive loss of striatal output neurons that results in dyskinesia, cognitive decline, and, ultimately, death. Neurotrophic factors have recently been shown to be protective in several animal models of neurodegenerative disease, raising the possibility that such substances might also sustain the survival of compromised striatal output neurons. We determined whether intracerebral administration of brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3, or ciliary neurotrophic factor could protect striatal output neurons in a rodent model of Huntington disease. Whereas treatment with brain-derived neurotrophic factor, nerve growth factor, or neurotrophin-3 provided no protection of striatal output neurons from death induced by intrastriatal injection of quinolinic acid, an N-methyl-D-aspartate glutamate receptor agonist, treatment with ciliary neurotrophic factor afforded marked protection against this neurodegenerative insult. PMID- 8692997 TI - Detection of JC virus DNA sequence and expression of the viral oncoprotein, tumor antigen, in brain of immunocompetent patient with oligoastrocytoma. AB - We describe molecular and clinical findings in an immunocompetent patient with an oligoastrocytoma and the concomitant presence of the human papovavirus, JC virus (JCV), which is the etiologic agent of the subacute, debilitating demyelinating disease, progressive multifocal leukoencephalopathy. Histologic review revealed a glial neoplasm consisting primarily of a moderately cellular oligodendroglioma with distinct areas of a fibrillary astrocytoma. Immunohistochemical analysis revealed nuclear staining of tumor cells with antibodies against the viral oncoprotein [tumor antigen (T antigen)], the proliferation marker (Ki67), and the cellular proliferation regulator (p53). Using primers specific to the JCV control region, PCR yielded amplified DNA that was identical to the control region of the Mad-4 strain of the virus. PCR analysis demonstrated the presence of the genome for the viral oncoprotein, T antigen, and results from primer extension studies revealed synthesis of the viral early RNA for T antigen in the tumor tissues. The presence of viral T antigen in the tumor tissue was further demonstrated by immunoblot assay. To our knowledge, this is the first report of the presence of JCV DNA, RNA, and T antigen in tissue in which viral T antigen is localized to tumor cell nuclei and suggests the possible association of JCV with some glial neoplasms. PMID- 8692998 TI - Interocular transfer in perceptual learning of a pop-out discrimination task. AB - The specificity of the improvement in perceptual learning is often used to localize the neuronal changes underlying this type of adult plasticity. We investigated a visual texture discrimination task previously reported to be accomplished preattentively and for which learning-related changes were inferred to occur at a very early level of the visual processing stream. The stimulus was a matrix of lines from which a target popped out, due to an orientation difference between the three target lines and the background lines. The task was to report the global orientation of the target and was performed monocularly. The subjects' performance improved dramatically with training over the course of 2-3 weeks, after which we tested the specificity of the improvement for the eye trained. In all subjects tested, there was complete interocular transfer of the learning effect. The neuronal correlate of this learning are therefore most likely localized in a visual area where input from the two eyes has come together. PMID- 8692999 TI - Isoform-specific interaction of the alpha1A subunits of brain Ca2+ channels with the presynaptic proteins syntaxin and SNAP-25. AB - Presynaptic Ca2+ channels are crucial elements in neuronal excitation-secretion coupling. In addition to mediating Ca2+ entry to initiate transmitter release, they are thought to interact directly with proteins of the synaptic vesicle docking/fusion machinery. Here we report isoform-specific, stoichiometric interaction of the BI and rbA isoforms of the alpha1A subunit of P/Q-type Ca2+ channels with the presynaptic membrane proteins syntaxin and SNAP-25 in vitro and in rat brain membranes. The BI isoform binds to both proteins, while only interaction with SNAP-25 can be detected in vitro for the rbA isoform. The synaptic protein interaction ("synprint") site involves two adjacent segments of the intracellular loop connecting domains II and III between amino acid residues 722 and 1036 of the BI sequence. This interaction is competitively blocked by the corresponding region of the N-type Ca2+ channel, indicating that these two channels bind to overlapping regions of syntaxin and SNAP-25. Our results provide a molecular basis for a physical link between Ca2+ influx into nerve terminals and subsequent exocytosis of neurotransmitters at synapses that have presynaptic Ca2+ channels containing alpha1A subunits. PMID- 8693000 TI - Alternative splicing of agrin regulates its binding to heparin alpha dystroglycan, and the cell surface. AB - Agrin is a basal lamina molecule that directs key events in postsynaptic differentiation, most notably the aggregation of acetylcholine receptors (AChRs) on the muscle cell surface. Agrin's AChR clustering activity is regulated by alternative mRNA splicing. Agrin splice forms having inserts at two sites (y and z) in the C-terminal region are highly active, but isoforms lacking these inserts are weakly active. The biochemical consequences of this alternative splicing are unknown. Here, the binding of four recombinant agrin isoforms to heparin, to alpha-dystroglycan (a component of an agrin receptor), and to myoblasts was tested. The presence of a four-amino acid insert at the y site is necessary and sufficient to confer heparin binding ability to agrin. Moreover, the binding of agrin to alpha-dystroglycan is inhibited by heparin when this insert is present. Agrin binding to the cell surface showed analogous properties: heparin inhibits the binding of only those agrin isoforms containing this four-amino acid insert. The results show that alternative splicing of agrin regulates its binding to heparin and suggest that agrin's interaction with alpha-dystroglycan may be modulated by cell surface glycosaminoglycans in an isoform-dependent manner. PMID- 8693001 TI - Targeted disruption of the mouse beta1-adrenergic receptor gene: developmental and cardiovascular effects. AB - At least three distinct beta-adrenergic receptor (beta-AR) subtypes exist in mammals. These receptors modulate a wide variety of processes, from development and behavior, to cardiac function, metabolism, and smooth muscle tone. To understand the roles that individual beta-AR subtypes play in these processes, we have used the technique of gene targeting to create homozygous beta 1-AR null mutants (beta 1-AR -/-) in mice. The majority of beta 1-AR -/- mice die prenatally, and the penetrance of lethality shows strain dependence. Beta l-AR -/ mice that do survive to adulthood appear normal, but lack the chronotropic and inotropic responses seen in wild-type mice when beta-AR agonists such as isoproterenol are administered. Moreover, this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice. These findings occur despite persistent cardiac beta 2-AR expression, demonstrating the importance of beta 1-ARs for proper mouse development and cardiac function, while highlighting functional differences between beta-AR subtypes. PMID- 8693002 TI - High affinity type I interleukin 1 receptor antagonists discovered by screening recombinant peptide libraries. AB - Two families of peptides that specifically bind the extracellular domain of the human type I interleukin I (IL-1) receptor were identified from recombinant peptide display libraries. Peptides from one of these families blocked binding of IL-lalpha to the type I IL-1 receptor with IC50 values of 45-140 microM. Affinity selective screening of variants of these peptides produced ligands of much higher affinity (IC50 approximately 2 nM). These peptides block IL-1-driven responses in human and monkey cells; they do not bind the human type II IL-1 receptor or the murine type I IL-1 receptor. This is the first example (that we know of) of a high affinity peptide that binds to a cytokine receptor and acts as a cytokine antagonist. PMID- 8693004 TI - Adjacent pore-lining residues within sodium channels identified by paired cysteine mutagenesis. AB - The pores of voltage-gated ion channels are lined by protein loops that determine selectivity and conductance. The relative orientations of these "P" loops remain uncertain, as do the distances between them. Using site-directed mutagenesis, we introduced pairs of cysteines into the P loops of micro1 rat skeletal muscle sodium channels and sought functional evidence of proximity between the substituted residues. Only cysteinyl residues that are in close proximity can form disulfide bonds or metal-chelating sites. The mutant Y401C (domain I) spontaneously formed a disulfide bond when paired with E758C in the P loop of domain II; the same residue, when coupled with G1530C in domain IV, created a high-affinity binding site for Cd2+ ions. The results provide the first specific constraints for intramolecular dimensions of the sodium channel pore. PMID- 8693006 TI - Self-recognition and abstraction abilities in the common chimpanzee studied with distorting mirrors. AB - The reactions of chimpanzees to regular mirrors and the results of the standard Gallup mark test have been well documented. In addition to using the mark test to demonstrate self-recognition in a regular mirror, we exposed six female chimpanzees to mirrors that produced distorted or multiplied self-images. Their reactions to their self-images, in terms of mirror-guided self-referenced behaviors, indicated that correct assessment of the source of the mirror image was made by each subject in each of the mirrors. Recognition of a distorted self image implies an ability for abstraction in the subjects in that the distortion must be rationalized before self-recognition occurs. The implications of these results in terms of illuminating the relative importance of feature and contingency of movement cues to self-recognition are discussed. PMID- 8693003 TI - Creation of a reversible on/off system for site-specific in vivo control of exogenous gene activity in the renal glomerulus. AB - Using genetically engineered glomerular mesangial cells, an in vivo gene transfer approach was developed that specifically targets the renal glomerulus. By combining this system with a tetracycline (Tc)-responsive promoter, the present study aimed to create a reversible on/off system for site-specific in vivo control of exogenous gene activity within the glomerulus. In the Tc regulatory system, a Tc-controlled transactivator (tTA) encoded by a regulator plasmid induces target gene transcription by binding to a tTA-responsive promoter located in a response plasmid. Tc inhibits this tTA-dependent transactivation via its affinity for tTA. In double-transfected cells, therefore, the activity of a transgene can be controlled by Tc. Cultured rat mesangial cells were cotransfected with a regulator plasmid and a response plasmid that introduces a beta-galactosidase gene. In vitro, stable double-transfectant MtTAG cells exhibited no beta-galactosidase activity in the presence of Tc. However, following withdrawal of Tc from culture media, expression of beta-galactosidase was induced within 24 h. When Tc was again added, the expression was rapidly resuppressed. Low concentrations of Tc were sufficient to maintain the silent state of tTA-dependent promoter. MtTAG cells were then transferred into the rat glomeruli via renal artery injection. In the isolated chimeric glomeruli, expression of beta-galactosidase was induced ex vivo in the absence of Tc, whereas it was repressed in its presence. When Tc-pretreated MtTAG cells were transferred into the glomeruli of untreated rats, beta-galactosidase expression was induced in vivo within 3 days. Oral administration of Tc dramatically suppressed this induction. These data demonstrate the feasibility of using mesangial cell vectors combined with the Tc regulatory system for site-specific in vivo control of exogenous gene expression in the glomerulus. PMID- 8693005 TI - Hypothalamic integration of body fluid regulation. AB - The progression of animal life from the paleozoic ocean to rivers and diverse econiches on the planet's surface, as well as the subsequent reinvasion of the ocean, involved many different stresses on ionic pattern, osmotic pressure, and volume of the extracellular fluid bathing body cells. The relatively constant ionic pattern of vertebrates reflects a genetic "set" of many regulatory mechanisms--particularly renal regulation. Renal regulation of ionic pattern when loss of fluid from the body is disproportionate relative to the extracellular fluid composition (e.g., gastric juice with vomiting and pancreatic secretion with diarrhea) makes manifest that a mechanism to produce a biologically relatively inactive extracellular anion HCO3- exists, whereas no comparable mechanism to produce a biologically inactive cation has evolved. Life in the ocean, which has three times the sodium concentration of extracellular fluid, involves quite different osmoregulatory stress to that in freshwater. Terrestrial life involves risk of desiccation and, in large areas of the planet, salt deficiency. Mechanisms integrated in the hypothalamus (the evolutionary ancient midbrain) control water retention and facilitate excretion of sodium, and also control the secretion of renin by the kidney. Over and above the multifactorial processes of excretion, hypothalamic sensors reacting to sodium concentration, as well as circumventricular organs sensors reacting to osmotic pressure and angiotensin II, subserve genesis of sodium hunger and thirst. These behaviors spectacularly augment the adaptive capacities of animals. Instinct (genotypic memory) and learning (phenotypic memory) are melded to give specific behavior apt to the metabolic status of the animal. The sensations, compelling emotions, and intentions generated by these vegetative systems focus the issue of the phylogenetic emergence of consciousness and whether primal awareness initially came from the interoreceptors and vegetative systems rather than the distance receptors. PMID- 8693007 TI - Structure of murine and human renal type II Na+-phosphate cotransporter genes (Npt2 and NPT2). AB - Na+-phosphate (Pi) cotransport across the renal brush border membrane is the rate limiting step in the overall reabsorption of filtered Pi. Murine and human renal specific cDNAs (NaPi-7 and NaPi-3, respectively) related to this cotransporter activity (type II Na+-Pi cotransporter) have been cloned. We now report the cloning and characterization of the corresponding mouse (Npt2) and human (NPT2) genes. The genes were cloned by screening mouse genomic and human chromosome 5 specific libraries, respectively. Both genes are approximately 16 kb and are comprised of 13 exons and 12 introns, the junctions of which conform to donor and acceptor site consensus sequences. Putative CAAT and TATA boxes are located, respectively, at positions -147 and -40 of the Npt2 gene and -143 and -51 of the NPT2 gene, relative to nucleotide 1 of the corresponding cDNAs. The translation initiation site is within exon 2 of both genes. The first 220 bp of the mouse and human promoter regions exhibit 72% identity. Two transcription start sites (at positions -9 and - 10 with respect to nucleotide 1 of NaPi-7 cDNA) and two polyadenylylation signals were identified in the Npt2 gene by primer extension, 5' and 3' rapid amplification of cDNA ends (RACE). A 484-bp 5' flanking region of the Npt2 gene, comprising the CAAT box, TATA box, and exon 1, was cloned upstream of a luciferase reporter gene; this construct significantly stimulated luciferase gene expression, relative to controls, when transiently transfected into OK cells, a renal cell line expressing type II Na+ -Pi cotransporter activity. The present data provide a basis for detailed analysis of cis and trans elements involved in the regulation of Npt2/NPT2 gene transcription and facilitate screening for mutations in the NPT2 gene in patients with autosomally inherited disorders of renal Pi reabsorption. PMID- 8693008 TI - Pollen specific expression of maize genes encoding actin depolymerizing factor like proteins. AB - In pollen development, a dramatic reorganization of the actin cytoskeleton takes place during the passage of the pollen grain into dormancy and on activation of pollen tube growth. A role for actin-binding proteins is implicated and we report here the identification of a small gene family in maize that encodes actin depolymerizing factor (ADF)-like proteins. The ADF group of proteins are believed to control actin polymerization and depolymerization in response to both intracellular and extracellular signals. Two of the maize genes ZmABP1 and ZmABP2 are expressed specifically in pollen and germinating pollen suggesting that the protein products may be involved in pollen actin reorganization. A third gene, ZmABP3, encodes a protein only 56% and 58% identical to ZmABP1 and ZmABP2, respectively, and its expression is suppressed in pollen and germinated pollen. The fundamental biochemical characteristics of the ZmABP proteins has been elucidated using bacterially expressed ZmABP3 protein. This has the ability to bind monomeric actin (G-actin) and filamentous actin (F-actin). Moreover, it decreases the viscosity of polymerized actin solutions consistent with an ability to depolymerize filaments. These biochemical characteristics, taken together with the sequence comparisons, support the inclusion of the ZmABP proteins in the ADF group. PMID- 8693009 TI - Psychophysical evidence for fast region-based segmentation processes in motion and color. AB - Theories of image segmentation suggest that the human visual system may use two distinct processes to segregate figure from background: a local process that uses local feature contrasts to mark borders of coherent regions and a global process that groups similar features over a larger spatial scale. We performed psychophysical experiments to determine whether and to what extent the global similarity process contributes to image segmentation by motion and color. Our results show that for color, as well as for motion, segmentation occurs first by an integrative process on a coarse spatial scale, demonstrating that for both modalities the global process is faster than one based on local feature contrasts. Segmentation by motion builds up over time, whereas segmentation by color does not, indicating a fundamental difference between the modalities. Our data suggest that segmentation by motion proceeds first via a cooperative linking over space of local motion signals, generating almost immediate perceptual coherence even of physically incoherent signals. This global segmentation process occurs faster than the detection of absolute motion, providing further evidence for the existence of two motion processes with distinct dynamic properties. PMID- 8693010 TI - [Hypothesis of the standard level of care for patients with acute myocardial infarct]. PMID- 8693011 TI - [Let us talk again about Virginia Henderson]. PMID- 8693012 TI - [Nursing assistance for patients with tumor pathology: a project for nursing education. 2]. PMID- 8693013 TI - [Competences of professional nurses in transfusion: medico-legal aspects]. AB - This paper explains the regulations in force in our Country about the competences of the nurse during the blood transfusion and the blood astraction. Successively it underlines how it is important for the nurse to be conscious of belonging to a medical team, considering also the ethical point of view suggested, by the care activity, to all the operators. Finally the paper notices the independence of the nurse's work compared with the other medical professional figures, and the following liabilities. It points out especially the role of the nurse in handling the information and the consent for the operating action, to the entrusted patient. PMID- 8693014 TI - [Diagnosis related groups: an instrument for the future]. PMID- 8693015 TI - [Nursing service in Great Britain. Experience with an apprenticeship in Wales]. PMID- 8693016 TI - [The law from 2/9/1992, #104: towards a new paradigm of assistance to the handicapped]. AB - In 1992 Italian Parliament promulgated the first constitutional law for handicap. This law is a change, because it brings up a new idea about the assistance in Italy. The hospital treatment, che schools assistance and so on must have the aim introducing the handicap into society and into normal job. Above all the hospital treatment must be joined to social and school assistance so the handicap can enter in friendly relations and it must offer as possible a normal life. PMID- 8693017 TI - Island hopping in Drosophila: patterns and processes. AB - Radiation of Drosophila along the Hawaiian archipelago has resulted in an astounding array of diversity. The speciation in this group corresponds well to the geological history of the region and colonization events appear to have been a major contributing factor. Although much less impressive in terms of diversity, Drosophila have also radiated throughout the Caribbean islands. In contrast to the pattern exhibited in Hawaii, major changes that distinguish the species in the Caribbean are not always coupled to colonization events. The patterns of speciation for these two island groups are compared and contrasted in light of founder effect speciation models. PMID- 8693018 TI - The maintenance of genetic polymorphism in small island populations: large mammals in the Hebrides. AB - Conventionally, small populations living on islands are expected to lose genetic variation by drift. Fluctuations in population size, combined with polygynous mating systems, are expected to contribute to the process by increasing sampling effects on genetic variation. However, in individually monitored populations of Red deer on Rum and Soay sheep on St. Kilda, which experience fluctuations in population size, two processes have been identified which mitigate loss of genetic variation. First, in a number of examples, population reductions are associated with selection. Selection may be in favour of heterozygotes, or, as we have documented in several cases, it may fluctuate in direction temporally. Second, in Soay sheep, in which mortality over population crashes is male-biased, ostensibly leading to low effective numbers of males, molecular studies show that there are systematic changes in the reproductive success of young males, and in variance in male success, that broaden genetic representation compared with expectation. PMID- 8693019 TI - Small mammal differentiation on islands. AB - The reason for the distinctiveness of small mammals on islands has traditionally attracted some imaginative story-telling, usually invoking isolation (as a relict) followed by adaptation and/or random genetic changes. Studies of voles on Orkney, long-tailed field mice on the Hebrides and Shetland, and house mice on the Faroe archipelago show that the main factor in differentiating island races from their mainland ancestors is the chance genetic composition of the founding animals. Subsequent change has necessarily to be based on the genes and frequencies carried by this colonizing group. Probably most post-colonization change is adaptive, although possibly limited in extent both by the initial paucity of variation and by the conservative effect of intragenomic interactions. It is probably helpful to recognize that the 'founder effect' or principle commonly invoked in discussions about evolution on islands involves a founder 'event', followed by founder 'selection'. Island differentiation is not necessarily a precursor to speciation, although the wide occurrence of island endemics suggests that founder effects should not be rejected as a driving force initiating speciation. Notwithstanding, island forms provide a valuable 'laboratory' for testing new genetic combinations, a small proportion of which may prove evolutionarily exciting. Only more empirical studies will uncover their evolutionary importance. PMID- 8693020 TI - Natural selection and random genetic drift as causes of evolution on islands. AB - The evolutionary processes responsible for adaptation and speciation on islands differ in several ways from those on the mainland. Most attention has been given to the random genetic drift that arises when a population is founded from just a few colonizing genomes. Theoretical obstacles to "founder effect speciation' are discussed, together with recent proposals for avoiding them. It is argued that although certain kinds of epistasis can facilitate the evolution of strong reproductive isolation, this favours divergence by selection as much as by random drift. PMID- 8693021 TI - Mitochondrial phylogeography of rock-dwelling cichlid fishes reveals evolutionary influence of historical lake level fluctuations of Lake Tanganyika, Africa. AB - The East African Lakes Tanganyika, Malawi and Victoria each harbour hundreds of endemic invertebrate and vertebrate species. Inferences about the ecological and evolutionary processes responsible for the origin of these species flocks will only be possible when they are made within historical and comparative frameworks. Specifically, the relative importance of intrinsic characteristics and extrinsic factors may offer information about the processes that drive diversification and speciation in these species. We investigated the sequence variation of a segment of the mitochondrial DNA control region of 32 populations representing all four nominal species in the three genera of eretmodine cichlids from Lake Tanganyika. Based on a phylogenetic analysis of these data we attempted to evaluate the importance of major lake level fluctuations on patterns of intralacustrine speciation. The geography of genetic variation reveals a high degree of within lake endemism among genetically well-separated lineages distributed along the inferred shore lines of three historically intermittent lake basins. Seismic data indicate that extreme lowering of water levels in the Pleistocene caused the single Lake Tanganyika basin to split into three isolated ones. The strong phylogeographic structure of the Eretmodini, and the observation that some closely related populations occur on opposite shores of the lake, agree with this geological scenario. The three-clade-three-basin phylogeographic pattern was repeated twice within this tribe of cichlids. The phylogeographic pattern of eretmodine cichlids suggests that major fluctuations in the level of the lake have been important in shaping their adaptive radiation and speciation. The mitochondrially defined clades are in conflict with the current taxonomy of the group and suggest that there has been convergent evolution in trophic morphology, particularly in the shapes of oral teeth, taxonomically the most diagnostic characters of the three genera. PMID- 8693023 TI - A positive selection vector for the analysis of structural plasmid instability in Bacillus subtilis. AB - A system for the positive selection of structural plasmid rearrangements in Bacillus subtilis was developed. Random deletions removing a transcription terminator structure in the assay plasmid, designated pGP100, resulted in expression of the cat-86 gene, under control of a constitutive bacteriophage promoter. The resulting chlorampenicol-resistant colonies were analyzed for plasmid contents and were shown, by restriction analysis, to contain initially both the intact parental plasmid and a deletion variant. Sequence analysis of deletion derivatives revealed a consensus target site (5'-A-T-T-A-A/T-3') at or near deletion termini, which resembles topoisomerase I target sites. Endpoints on one side of the deletions were found to be clustered in the promoter region of the tetracycline resistance gene present on pGP100, the gene product of which is an integral membrane protein. Furthermore, deletion of the genes encoding the ATP dependent exonuclease, AddAB, severely reduced the structural stability of pGP100. The data indicate that similar mechanisms underlie deletion formation in pGP100, and a different plasmid-based system, pGP1, which we have analyzed previously. PMID- 8693022 TI - Conditionally replicative and conjugative plasmids carrying lacZ alpha for cloning, mutagenesis, and allele replacement in bacteria. AB - We describe several new cloning vectors for mutagenesis and allele replacement experiments. These plasmids have the R6K gamma DNA replication origin (oriR(R6K gamma) so they replicate only in bacteria supplying the pi replication protein (encoded by pir), and they can be maintained at low or high plasmid copy number by using Escherichia coli strains encoding either wild-type or mutant forms of pi. They also carry the RP4 transfer origin (oriT(RP4)) so they can be transferred by conjugation to a broad range of bacteria. Most of them encode lacZ alpha for blue-white color screening of colonies for ones with plasmids carrying inserts, as well as the f1 DNA replication origin for preparation of single stranded DNA. Particular plasmids are especially useful for allele replacement experiments because they also encode a positive counterselectable marker. One set carries tetAR (from Tn10) that allows for positive selection of plasmid-free segregants as tetracycline-sensitive (TetS) recombinants. Another set carries sacB (from Bacillus subtilis) that allows selecting plasmid-free segregants as sucrose-resistant (SucR) ones. Accordingly, derivatives of these plasmids can be introduced into a non-pir host (via conjugative transfer, transformation, or electroporation), and integrants with the plasmid recombined into the chromosome via homologous sequences are selected using a plasmid antibiotic resistance marker. Plasmid-free segregants with an allele replacement can be subsequently selected as TetS or SucR recombinants. A number of additional features (including the presence of multiple cloning sites flanked by T3 and T7 RNA polymerase promoters) make these plasmids useful as general cloning vectors as well. PMID- 8693024 TI - An inverted repeat in the Tn21 integron determines the production of stem-loop DNA. AB - A 580-bp-long stem-loop DNA (sl-DNA) molecule was produced by a recombinant plasmid containing complete int and aadA genes from the transposon Tn21 cloned in the vector pUC18. A 50-bp-long inverted repeat found near the int gene stop codon could be involved in the generation of the sl-DNA molecule. cloning of the dhfrII gene between the plasmid replication origin and this IR produced an extended sl DNA including the dhfrII gene. Tn21 recombination hot spot 2 was also able to direct the production of sl-DNA. PMID- 8693025 TI - Positive selection, cloning vectors for gram-positive bacteria based on a restriction endonuclease cassette. AB - Lactococcus lactis contains numerous restriction and modification (R/M) systems of different specificities. A novel IIS type R/M system encoded by the LlaI operon has previously been characterized from the L. lactis conjugative plasmid pTR2030. The LlaI operon is composed of six genes: First, a small regulatory gene llaIC precedes the methylase gene llaIM. The following three genes, llaI.1, llaI.2, llaI.3, are all essential for restriction endonuclease activity and are designed as the restriction cassette llaIR. The forth open reading frame of unknown function follows the llaIR gene cassette. We have successfully subcloned the three llaIR genes, llaI.1, llaI.2, and llaI.3, without llaIM, as a suicide cassette into the three shuttle vectors pTRKL2, pTRKH2, and pBV5030. A promoter (P6) from Lactobacillus acidophilus ATCC4356, which is functional in E. coli, lactococci, and lactobacilli (Djordjevic and Topisirovic, unpublished) was cloned upstream of the three gene cassette. Restriction activity was evaluated in Escherichia coli and several gram-positive bacteria. The llaIR restriction cassette was not functional in E. coli, but its presence was lethal to L. lactis, Lactobacillus gasseri, Lactobacillus plantarum, Lactobacillus johnsonii, Lactobacillus acidophilus, Carnobacterium pisicola, Enterococcus faecalis, Bacillus subtilis, and Leuconostoc gelidum. Several novel, positive selection cloning vectors were developed that can exploit unique cloning sites within the llaIR cassette. Insertions in llaI.1 resulted in complete inactivation of restriction activity and provided unconditional selection for recombinant plasmids in surviving transformants. These positive selection cloning vectors are the first for gram-positive bacteria that are based on a restriction endonuclease cassette. Functional activity of the llaIR genes in various gram-positive bacteria would also enable use of these cloning vectors for positive selection of promoters, terminators, and regulatory sequences across these genera. PMID- 8693026 TI - Identification and characterization of the genes of Enterococcus faecalis plasmid pCF10 involved in replication and in negative control of pheromone-inducible conjugation. AB - The prgB gene of the Enterococcus faecalis pheromone-inducible conjugative plasmid pCF10 encodes the surface protein Asc10. This protein mediates cell aggregation and its expression results in high-frequency transfer of the plasmid from donor to recipient. To identify the minimum region necessary for negative regulation of prgB expression, target plasmids were constructed containing a recently identified positive control region and a prgB::lacZ transcriptional fusion; expression of prgB in cells carrying these plasmids was thus verified by beta-galactosidase assay. The target plasmids were used in genetic studies with compatible plasmids containing cloned pCF10 genes supplying putative negative control functions to define the minimum region of pCF10 required for shutdown of prgB expression in the absence of exogenous pheromone. The minimum segment required for negative control, as indentified by deletion analysis, was a 6.9-kb region extending from the 5' end of a gene called prgN, through a previously identified gene, prgX. The DNA in this region, which had not been previously characterized (2.85 kb), was sequenced, and several potential regulatory genes and plasmid replication genes were identified. Genetic analysis indicated that the prgN, -Y, and -X genes are involved in negative control; prgW may also play a role in negative control, since it appeared to be required for expression of prgY. prgX, or a closely adjacent DNA sequence, acted in cis. The region of pCF10 containing negative control genes was also shown to function as an autonomous replicon in E. faecalis. PMID- 8693027 TI - Use of a DNA polymerase III bypass mutant of Escherichia coli, pcbA1, to isolate potentially useful mutations of a complex plasmid replicon. AB - The essential replicon region of plasmid pCU1 has, within 1.2 kb, two origins of replication that can function in the absence of Escherichia coli DNA polymerase I and one that requires this polymerase. To isolate mutants in the replicon pathway that uses the PolI-dependent origin in the presence of the two other origins, we examined the feasibility of exploiting E. coli strains carrying a polymerase c bypass mutation (pcbA) and which can survive and form colonies with the polymerase activity of polC inactivated at 42 degrees C. The selection scheme that is described was successful and resulted in the isolation of a mutant replicon that is not maintained at 42 degrees C in a PcbA-PolC+tsPolA+ strain. Nucleotide sequencing indentified the mutated region to be within the origin (OriV) that was known to be polA-dependent. Electron microscopy of mutant plasmid molecules replicating in a Pcb+ strain confirmed that OriV is inactivated. PMID- 8693028 TI - Electrotransformation of highly DNA-restrictive corynebacteria with synthetic DNA. AB - Highly DNA-restrictive Corynebacteria can be transformed with DNA made in vitro by PCR amplification of a sequence that contains the replication origin of pBL1, a plasmid common to many Corynebacteria. In all strains examined, the transformation efficiencies of PCR-synthetized DNA equal or improve the performances of heterologous DNA extracted from wild-type and dam(-)-dcm-strains of Escherichia coli. The transformation efficiencies obtained with PCR-made DNA may be high enough to permit its general application to experiments of gene integration. PMID- 8693029 TI - Plasmid pDGO100 contains a second integron with the trimethoprim resistance gene dfrA7 as the inserted cassette. AB - Southern hybridization analysis of the IncC plasmid pDGO100 showed that, in addition to the well-characterized integron In7, there is a second integron which is located on a 3.6-kb BamHI fragment. This integron also possesses the qacE delta l and sulI genes typically found as part of the 3'-conserved segment of integrons. The 3.6-kb BamHI fragment, when cloned into pUC19 to form pDGO301, conferred resistance to trimethoprim as well as sulfamethoxazole. The DNA sequence of the trimethoprim resistance gene in pDGO301 was determined and it was shown that the gene was precisely inserted as a cassette in an integron with 100% identity to the trimethoprim resistance gene dfrA7. PMID- 8693030 TI - Marine natural products research: current directions and future potential. AB - Natural products research is increasingly turning to marine animals, plants, and microbes as source organisms. Several marine natural products are currently in preclinical and clinical evaluation, others show promising biological activities in in vitro and in vivo assays. Investigations of biological and chemical ecological phenomena in the marine world will contribute to a better understanding of marine habitats, and also provide a more founded basis regarding the search for pharmaceutically useful marine natural products. PMID- 8693031 TI - In vitro anticancer activity of fruit extracts from Vaccinium species. AB - Fruit extracts of four Vaccinium species (lowbush blueberry, bilberry, cranberry, and lingonberry) were screened for anticarcinogenic compounds by a combination of fractionation and in vitro testing of their ability to induce the Phase II xenobiotic detoxification enzyme quinone reductase (QR) and to inhibit the induction of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis, by the tumor promoter phorbol 12-myristate 13-acetate (TPA). The crude extracts, anthocyanin and proanthocyanidin fractions were not highly active in QR induction whereas the ethyl acetate extracts were active QR inducers. The concentrations required to double QR activity (designated CDqr) for the ethyl acetate extracts of lowbush blueberry, cranberry, lingonberry, and bilberry were 4.2, 3.7, 1.3, and 1.0 microgram tannic acid equivalents (TAE), respectively, Further fractionation of the bilberry ethyl acetate extract revealed that the majority of inducer potency was contained in a hexane/chloroform subfraction (CDqr = 0.07 microgram TAE). In contrast to their effects on QR, crude extracts of lowbush blueberry, cranberry, and lingonberry were active inhibitors of ODC activity. The concentrations of these crude extracts needed to inhibit ODC activity by 50% (designated IC50) were 8.0, 7.0, and 9.0 micrograms TAE, respectively. The greatest activity in these extracts appeared to be contained in the polymeric proanthocyanidin fractions of the lowbush blueberry, cranberry, and lingonberry fruits (IC50 = 3.0, 6.0, and 5.0 micrograms TAE, respectively). The anthocyanidin and ethyl acetate extracts of the four Vaccinium species were either inactive or relatively weak inhibitors of ODC activity. Thus, components of the hexane/chloroform fraction of bilberry and of the proanthocyanidin fraction of lowbush blueberry, cranberry, and lingonberry exhibit potential anticarcinogenic activity as evaluated by in vitro screening tests. PMID- 8693032 TI - Antiperoxidative components in Thymus vulgaris. AB - A biphenyl compound, 3,4,3',4'-tetrahydroxy-5,5'-diisopropyl-2,2' dimethylbiphenyl (1), and a flavonoid, eriodicytol (2), were isolated as antioxidative components from the leaves of Thymus vulgaris by bioassay-directed fractionation. These compounds inhibited superoxide anion production in the xanthine/xanthine oxidase system. Mitochondrial and microsomal lipid peroxidation induced by Fe(III)-ADP/NADH or Fe(III)-ADP/NADPH were also inhibited by these compounds. Compound 1 is an extremely potent antioxidant; complete inhibition was observed at 1 microM against both microsomal and mitochondrial peroxidation. Furthermore, compound 1 protected red cells against oxidative hemolysis. These phenolic compounds were shown to be effective to protect biological systems against various oxidative stresses. PMID- 8693033 TI - Inhibition of bacterial mutagenesis by Citrus flavonoids. AB - The antimutagenicity of the Citrus flavonoids naringin, hesperidin, nobiletin, and tangeretin against the mutagens benzo[a]pyrene, 2-aminofluorene, quercetin, and nitroquinoline N-oxide was investigated in the Salmonella/microsome assay. Naringin and hesperidin showed a weak antimutagenic activity against benzo[a]pyrene. Tangeretin was antimutagenic against all indirectly-acting mutagens tested, but in general a large molar excess was necessary. Liquid preincubation increased the antimutagenicity of tangeretin against 2 aminofluorene. Nobiletin acted as an antimutagen against benzo[a]pyrene, but it enhanced the mutagenicity of 2-aminofluorene. However, in a liquid preincubation assay nobiletin also exhibited antimutagenicity against 2-aminofluorene. Both tangeretin and nobiletin inhibited the mutagenicity of quercetin. Quercetin itself acted as an antimutagen against 2-aminofluorene in a Salmonella strain (TA1538) where its mutagenicity was not expressed. Quercetin should not merely be regarded as a genotoxic risk factor in the human diet, since its mutagenicity may be inhibited by accompanying compounds including other flavonoids, and since quercetin itself also exhibits an antimutagenic action. Because of the antimutagenic properties the Citrus flavonoids tested, especially tangeretin and nobiletin, might play a role in the chemoprevention of cancer. PMID- 8693034 TI - Chelidonium majus L.: components with in vitro affinity for the GABAA receptor. Positive cooperation of alkaloids. AB - The influence of an ethanolic dry extract of Chelidonii herba on the GABAA receptor has been studied in vitro. In the presence of 90 micrograms/assay a positive cooperation was induced for [3H]muscimol accompanied by an increase of the specific binding (115%) while 160 micrograms/assay exerted a 50% inhibition of the specific binding of the radioligand [3H]muscimol. The quantitative determination of the Chelidonium alkaloids by HPLC together with the evaluation of the radioreceptor assays of the pure alkaloids revealed that the allosteric modulation of the GABAA receptor is mainly due to protopine. The small amounts of allocryptopine and stylopine assumingly support the action of protopine. Protopine, stylopine, and allocryptopine do not influence the specific binding of [3H]flunitrazepam. Thus, the positive cooperative modulation of the GABAA receptor is not based on an interaction of these alkaloids with the benzodiazepine receptor. The specific [3H]muscimol binding was inhibited only by chelerythrine and sanguinarine with IC50 values of 25 microM and 39 MicroM, respectively. The content of chelerythrine and sanguinarine in the ethanolic dry extract of Chelidonii herba is 500 or even 1000 times too low to account for the observed interference with GABAA receptor activity. Thus, the alkaloids are not responsible for the inhibitory action on the GABAA receptor at higher concentrations of the ethanolic dry extract. PMID- 8693035 TI - Anti-inflammatory and analgesic activity of Baccharis trimera: identification of its active constituents. AB - The butanolic fraction (BT-II) derived from the aqueous crude extract was prepared from aerial parts of Baccharis trimera and assessed in anti inflammatory, analgesia, and ulcerogenesis models. Intraperitoneal pretreatment with lyophilized BT-II, at doses ranging from 40 to 100 mg/kg, markedly inhibited carrageenan- and dextran-induced inflammation (70.4-90.8% and 25.7-71.3%, respectively) and weakly decreased C16-paf- and arachidonic acid-induced swelling (24.9-36.7% and 0-30.6%, respectively). No effect was observed, at the same doses, on zymosan-induced edema. The intraperitoneal examination indicates that the anti-phlogistic action of BT-II was not due to an irritating effect at the injection site. Besides, BT-II reduced abdominal constrictions in mice following injection of acetic acid: at 50 mg/kg, it gave 67.4% inhibition and, at 100 mg/kg, 95.1%. The ulcerogenic assay showed that the incidence of ulcers after BT II i.p. treatment was 2/6 at 50 mg/kg and 6/6 at 100 mg/kg. Ulcerogenic indices were 1.3 +/- 0.5 and 2.7 +/- 0.8, respectively. These results indicate that B.trimera shows strong anti-inflammatory and analgesic properties which seem to be due, at least partly, to the inhibition of prostaglandin biosynthesis. The chromatographic separation of BT-II monitored by bio-assay (carrageenan-induced edema test in mice) was carried out. The active constituents were found to be mainly saponins in which echinocystic acid (or its enantiomer) is the major aglycone, and also rutin. PMID- 8693036 TI - Non-phenolic linear diarylheptanoids from Curcuma xanthorrhiza: a novel type of topical anti-inflammatory agents: structure-activity relationship. AB - The topical anti-inflammatory activity of three non-phenolic linear 1,7 diarylheptanoids, previously isolated from a Thai medicinal plant, Curcuma xanthorrhiza (Zingiberaceae) and four new semi-synthetic derivatives of the naturally occurring compounds were assessed in the murine model of ethyl phenylpropiolate-induced ear edema. The naturally occurring compound 1E,3E,1,7 diphenylheptadien-5-one (6) exerted the most potent anti-inflammatory activity, with an ID50 value of similar magnitude to that of the reference drug oxyphenbutazone (67 vs. 46 micrograms/ear, respectively). None of the semi synthetic diarylheptanoids was more active than 6. The chemical structures and pharmacological data of the natural and semi-synthetic derivatives identified a distinct structure-activity relationship. The degree of unsaturation in positions 1 and 3, and the nature of the oxygenated functional group in position 5 of the C7-chain were found to play significant roles in determining the observed in vivo activity. Based on these findings, the non-phenolic linear 1,7-diarylheptanoids are proposed to represent a novel class of topical anti-inflammatory agents. PMID- 8693037 TI - Antiviral and antiphlogistic activities of Hamamelis virginiana bark. AB - A crude hydroalcoholic extract from Hamamelis virginiana bark was subjected to ultrafiltration (UF) with a cut-off limit of 3 kDa to obtain a higher and a lower molecular weight fraction. Characterisation of the fractions was attempted with TLC, HPLC, acidic hydrolysis, and chromatography over Sephadex LH-20. The UF concentrate was shown to consist mainly of oligomeric to polymeric proanthocyanidins (PA). This fraction was found to exhibit significant antiviral activity against Herpes simplex virus type 1 (HSV-1). In addition, the UV concentrate displayed radical scavenging properties, inhibited alpha-glucosidase as well as human leukocyte elastase (HLE), and exhibited strong antiphlogistic effects in the croton oil ear edema test in the mouse. With the exception of the antioxidant potential and the inhibition of HLE-action the lower molecular fraction possessed weaker activities and contained mainly hamamelitannin, catechin, and further, unidentified constituents. PMID- 8693038 TI - Lack of calcium-antagonizing activity of dehydroevodiamine on the chronotropic and inotropic activities of mouse isolated atria. AB - Dehydroevodiamine (DeHE) was reported to induce bradycardia and to have calcium antagonizing activity besides other actions. The purpose of the present study was to investigate if DeHE could act as a calcium antagonist on the chronotropic and inotropic activities of mouse isolated atria. The data showed that DeHE induced bradycardia but did not decrease the contraction amplitude of the right atrium. Moreover, DeHE did not attenuate the contraction amplitude of the electrically driven left atrium and, in the presence of 1 x 10(-4) M DeHE, the contraction amplitude of left atrium was increased when the calcium concentration in Krebs solution was further increased. Since calcium antagonists are known to inhibit chronotropic and inotropic activities, it seems unlikely that DeHE acts as a calcium antagonist on the chronotropic and inotropic activities of mouse isolated atria. PMID- 8693039 TI - Anthelmintic properties of alpha-sanshool from Zanthoxylum liebmannianum. AB - The decoction of the stem bark of Zanthoxylum liebmannianum (Engelm.) P. Wilson (Rutaceae) decreased the count of intestinal nematode eggs in naturally infected sheep. In addition, the chloroformic extract was toxic to Ascaris suum. Fractionation of the organic extract guided by the Ascaris suum lethality test led to the isolation of alpha-sanshool (LC50 = 83.4 x 10(-5)M) as the only active compound. On the other hand, alpha-sanshool induced tonic-clonic seizures when it was injected intraperitoneally to mice. This finding could be a warning regarding the potential toxicity of this plant. PMID- 8693040 TI - Prevention of hydrogen peroxide damage by soybean saponins to mouse fibroblasts. AB - Soybean saponin is one of several soybean glycosides. Recently, new soybean saponins which possess the DDMP (2,5-dihydroxy-6-methyl-2,3-dihydro-4H-pyran-4 one) moiety have been detected. Soyasaponin beta g of these new soybean saponins was shown to inhibit hydrogen peroxide damage to mouse fibroblast cells. Not only the new saponin but also soyasaponin I, which has lost the DDMP moiety from soyasaponin beta g, was tested and showed higher inhibition in this assay. In order to investigate the relationship between the effect and chemical structure, glycyrrhizin, which has a similar chemical structure to soyasaponin I, was also tested and exhibited the same effect as soyasaponins beta g and I. Soyasaponin Ab, a major authentic bisdesmosidic saponin that exists only in the soybean hypocotyl, was also tested and exhibited the highest inhibition of hydrogen peroxide damage among the four saponins. It was concluded that water-soluble soybean saponins protected the cells from damage by hydrogen peroxide. PMID- 8693041 TI - Antibacterial and antifungal polyine compounds from Glehnia littoralis ssp. leiocarpa. AB - Glehnia littoralis F. Schmidt ssp. leiocarpa (Mathias) Hult. (Apiaceae), a species of ethnopharmacological interest in British Columbia, has antibacterial and antifungal properties. Antibacterial and antifungal compounds include two hitherto unreported polyine compounds, (9Z)1,9-heptadecadiene-4,6-diyne-3,8,11 triol and (10E)1,10-heptadecadiene-4,6-diyne-3,8,9-triol. PMID- 8693042 TI - Determination of wogonin in rat plasma by liquid chromatography and its pharmacokinetic application. AB - A high-performance liquid chromatographic method has been developed for the determination of wogonin in the rat plasma. After addition of an internal standard (clomipramine), plasma was deproteinized by acetonitrile and centrifuged for sample clean-up. The supernatant was separated by a reversed-phase column chromatography, identified by a photodiode-array detector, and quantified by ultraviolet detection at a wavelength of 275 nm. Acetonitrile-water-diethylamine (50:50:0.1, v/v/v, pH 3.0 adjusted by orthophosphoric acid) was used as the mobile phase. The method was applied to the pharmacokinetic study of wogonin in rats after a dose of mg/kg by intravenous administration. A biphasic phenomenon with a rapid distribution followed by a slower elimination phase was observed from the plasma concentration time profile. PMID- 8693043 TI - A competitive enzyme immunoassay for the pyrrolizidine alkaloids of the senecionine type. AB - We developed an immunoassay with antibodies against retrorsine to detect the closely related senecionine, the main alkaloid in various Asteraceae. Sensitivity is about 23 pg (68 fmol) for senecionine. Cross reactivity of monocrotalin, retrorsine N-oxide, senkirkine (< 0.1%), and seneciphylline (3.6-34.5%) was resolved. The alkaloid content in leaves of Petasites hybridus (Asteraceae) was determined to be 3.86 ppm, calculated as senecionine, which was far less than in rhizomes (104.8 ppm). Additionally, we proved specificity by taking immunograms from different parts of Petasites hybridus. The test is a suitable tool for assessing the toxic potential of medicinal plants containing senecionine. PMID- 8693044 TI - Isolation of vasodilatory active flavonoids from the traditional remedy Satureja obovata. AB - In the course of screening natural products for smooth muscle relaxant properties, the effects of constituents of Satureja obovata var. obovata (Lamiaceae) on vascular reactivity experiments were studied. Bioassay-guided fractionation led to pure vasodilator compounds, identified by spectroscopic methods as the flavonoids: naringenin, eriodictyol, and luteolin. The relaxant effects induced by different extracts and fractions obtained on KCl (80 mM) and noradrenaline (NA) (10(-6) M) induced contractions on isolated rat aorta were selected as bioassay procedures. The sustained contraction induced by NA (10(-6) M) and K+ (80 mM) were relaxed by luteoline (98.7 +/- 0.7%; 40.30 +/- 2.4%), naringenin (12.41 +/- 1.8%; 3.05 +/- 0.3%), and eriodictyol (67.48 +/- 3.3%; 17.93 +/- 2.1%) each at the dose of 5 x 10(-5)M, respectively. PMID- 8693046 TI - Isolation of aurantiamide acetate from Arisaema erubescens. AB - Aurantiamide acetate (N-benzoyl-1-phenylalanyl-1-pheylalaninol acetate) has been isolated by chromatographic separation of a methanol extract of Arisaema erubescens and its structure confirmed by synthesis. PMID- 8693045 TI - Comparison of antimicrobial properties of monoterpenes and their carbonylated products. AB - Some monoterpenes and their carbonylated products were evaluated for their antibacterial and antifungal properties. The carbonylation of tested monoterpenes was shown to increase the bacteriostatic and fungistatic activities specifically by the contact method. Concerning the killing effects, only (1R,2S,5R) isopulegol, its carbonylated products, and (R)-carvone showed significant bactericidal activities, particularly against Enterococcus faecium and Escherichia coli above a concentration of 10 microliters/ml. A fungicidal efficiency of (1R,2S,5R)-isopulegol and (R)-carvone against Aspergillus niger was also noted. It seems that the presence of an oxygenated function in the framework increases the antimicrobial properties. However, monoterpenes were more active using a micro-atmosphere method. PMID- 8693047 TI - Picroliv protects against alcohol-induced chronic hepatotoxicity in rats. AB - Daily administration of ethyl alcohol (3.76 g/kg, p.o.) for 45 days resulted in significant changes in several biochemical parameters of the liver and serum of albino rats. After exposure to alcohol for 30 days when Picroliv (12 mg/kg, p.o.), an iridoid glycoside fraction of Picrorhiza kurroa, was administered for 15 days along with alcohol, the degree of change in most of the parameters was reduced. PMID- 8693048 TI - The effect of some 2-substituted quinolines isolated from Galipea longiflora on Plasmodium vinckei petteri infected mice. AB - We have evaluated the in vivo antiplasmodial activity of six 2-substituted quinolines and a total alkaloidal extract of Galipea longiflora. BALB/c mice infected with Plasmodium vinckei petteri were treated orally at single dose of 50 mg/kg with quinolines or extract. Contrary to the previous results obtained with the Leishmania murine infection, 2-n-pentylquinoline showed activity against P. vinckei petteri. This result seems to confirm the antimalarial efficacy of infused stem bark of G. longiflora. PMID- 8693049 TI - Displacement in depth: representational momentum and boundary extension. AB - Memory for targets moving in depth and for stationary targets was examined in five experiments. Memory for targets moving in depth was displaced behind the target with slower target velocities (longer ISIs and retention intervals) and beyond the target with faster target velocities (shorter ISIs and retention intervals), and the overall magnitude of forward displacement for motion in depth was less than the overall magnitude of forward displacement for motion in the picture plane. Memory for stationary targets was initially displaced away from the observer, but memory for smaller stationary targets was subsequently displaced toward the observer and memory for larger stationary targets was subsequently displaced away from the observer; memory for the top or bottom edge of a stationary target was displaced inside the target perimeter. The data are consistent with Freyd and Johnson's (1987) two-component model of the time course of representational momentum and with Intraub et al.'s (1992) two-component model of boundary extension. PMID- 8693051 TI - Action planning during the presentation of stimulus sequences: effects of compatible and incompatible stimuli. AB - Experimental designs that require the simultaneous perception and reproduction of a stimulus sequence could help to clarify the relationship between perception and action. This contribution examines a specific stimulus-response compatibility with the reproduction of simple stimulus sequences. In the procedure a response just prepared or one to be prepared is confronted with a new incoming stimulus that is compatible or incompatible with the response. Interference is predicted from a framework in which stimulus perception and action control are assumed to share common codes. Five arrows were successively presented at 1-s intervals. The arrows pointed either to the left or to the right with equal probability. One of the five arrows was accompanied by a randomly presented go signal. Subjects then had to reproduce the sequence by pressing corresponding left or right keys while the stimulus presentation continued. Reaction-time latencies and reaction intervals within a sequence were analyzed in six experiments. Results showed increasing reaction-time latencies the later the go signal was presented--that is, the longer the sequence to be reproduced was. In contrast to previous findings, this effect interacted with the compatibility between the arrow displayed together with the go signal and the first reaction. It is argued that the go signal initiates a transfer of a cognitive action plan to a peripheral motor program and that this process is subject to interference the more the current stimulus is at odds with one of the first parameter specification. PMID- 8693050 TI - A dotted line assimilates in visibility to a solid line. AB - This study tested the theory that a context-produced increase in visibility of a target is due to its assimilation in visibility to the context. A context + target and a context are discriminated better than are a target and background. This occurs for two different context + targets in which the context is a solid line and the target is a dotted line. But it does not occur when solid lines replace these dotted lines. The dotted lines are much less visible than the solid lines. Therefore, the dotted lines increase in similarity in visibility to the solid lines, which is assimilation, but for visibility, rather than for a typical part. Assimilation does not occur between perceptually equal parts. Consequently, the reason why the two context + targets with only solid lines do not result in increases in visibility may be that these lines are sufficiently equal in visibility that assimilation in visibility is precluded. So, the theory is supported. This theory is consistent with evidence that one group (phenomenal whole) is associated with both assimilation and an increase in visibility. Accordingly, a stimulus with a relatively large distance between its solid and dotted lines is apprehended as a relatively weak group, and does not result in an increase in visibility. PMID- 8693053 TI - The effect of enactment on memory for order. AB - The effect of enactment on memory for serial order was investigated in two experiments. In both experiments a reconstruction task was used to separate order from item information. In Experiment 1 enactment and test information was manipulated between groups. For subjects who had not been informed about the reconstruction test, performance of verbal and motor groups was similar with regard to both serial-position curves and overall performance. For subjects who knew beforehand that they would be tested for memory of the order of the action events, performance in the verbal condition was significantly better than in the motor condition. In Experiment 2, the reversed enactment effect for test-informed subjects was replicated with a within-subjects design. The results agree with Engelkamp and Zimmer's (1984, 1994) position that enactment serves exclusively to enhance item information, and indicate that subjects have less control over the encoding processes when they are enacting than during verbal encoding (cf. Cohen, 1981). PMID- 8693052 TI - Adaptation of a reaching model to handwriting: how different effectors can produce the same written output, and other results. AB - This report shows how a model initially developed for the control of reaching can be adapted for the control of handwriting. The main problem addressed by the model is how people can produce essentially the same written output with different effectors (e.g., the preferred or nonpreferred hand, the foot, or even the mouth). The model is based on the assumption that writers strive for invariant graphic outputs when they write with different effectors, when they write on surfaces with different orientations, or when they write large or small script; such output invariance is an essential requirement for later recognition of the written result. Given this assumption, the question is how the motor system enables the relevant effectors to generate the necessary pen strokes. The adapted model provides one possible answer to this question. It is first fully working model of multijoint activity underlying writing and related graphic tasks. We describe how the model differs from other models developed in the past, and we review the model's strengths and weaknesses. PMID- 8693054 TI - [In which specialty periodicals have current faculty chair/specialty representatives for psychosomatic medicine and psychotherapy published?]. PMID- 8693055 TI - ["Filtered normality": psychological causes and sequelae of specific retinal diseases]. AB - Until now there is a lack of investigation in psychological aspects of retinopathy in patients of the middle ages. The few studies have been found, focused on an old-fashioned psychopathology. Medical treatment, f.e. laser therapy is only partially available, constant visual loss to blindness is possible. Life events, coping strategies, social support, and symptomatic distress of patients with presumed ocular histoplasmosis (group 1) and patients with retinopathy centralis serosa (group 2) were compared with another and with a comparison group. Group 1 scored higher on the Schedule of Recent Experiences (Holmes and Rahe 1967) and showed better social support. Group 2 scored higher on the Brief Symptom Inventory (Derogatis and Melisaratos 1983) and showed low social support. Additionally gender differences were discussed. PMID- 8693056 TI - [Family emotional climate of pain patients]. AB - Personal clinical experiences in an interdisciplinary pain clinic and their integration into family interaction theories led to a concept of an explorative study of chronic pain patients. Therefore 32 patients and their spouses were investigated with the "family-environment-scale" (by Moos and Moos 1981, adapted by Schneewind et al. 1985). Most of the couples showed agreement with regard to familial solidarity, combined with few expressions of anger and conflict and low achievement orientation. The typical profile of these factors led to one group with the "positive-emotional family climate", in contrast to one group with the "normative-authoritative family climate". In addition, a potentially new factor was described as a so-called "symbiotic family climate". The latter constellation was on the one hand quite similar compared to the "positive-emotional climate", but differed on the other hand because of the small amount of structural control. The interference of these family climate profiles with the process of chronification for pain patients is discussed. PMID- 8693057 TI - [Therapeutically relevant effects by transcendental meditation?]. AB - In two longitudinal studies the Freiburger Personality Inventory (FPI) was administered to beginners of Transcendental Meditation (TM), using pre-post-test intervals of 8 weeks (study 1) and 14 months (study 2). TM-beginners showed a typical psychologically moderately stressed FPI-profile including a considerably reduced domineering tendency. Meditators in study 2 exhibited significantly greater improvements after 14 months compared to dropout-controls with 7 of the 12 FPI-factors. Before starting TM, controls showed significantly greater extraversion compared to successful meditators. Significantly reduced openness compared to the norm was found at the time of the second testing in study 1 and with 47% of the participants in a cross section study including 360 TM practitioners (study 3). The uncritically reserved TM-practitioners within study 3 described themselves as remarkably positive; however, no effects correlating with length of practice could be distinguished in this group. In the same study the open meditators and several selected subgroups drawn from them--subjects with no treatment, subjects with any medical treatment and psychosomatically treated subjects--showed different focal points of generally constructive hypothetical effects resulting from long-term TM-practice for each group. In consequence, for meditating successfully a sufficiently self-critical and open attitude has to be required as a prerequisite. Subjects scoring clearly above average in extraversion should be discouraged starting TM because of the increased probability of abandoning the TM-routine early. PMID- 8693058 TI - [Physical complaints and stress of caregiving family members providing home nursing for long-term disabled patients]. AB - A study of 128 caregivers caring for a person in need of constant nursing care at home showed them to suffer from a range of somatic symptoms (Giessen Symptom List) which lay significantly above the average for their age and sex. However, this was only true of those caregivers who perceived their task as a burden (moderate to severe burden, Burden Scale for Family Caregivers). The aspects which were seen to be most burdensome were lack of free-time and opportunities for respite as well as the fate of the person receiving care. The mean score of subjective burden did not linearly increase according to the degree of nursing care needed. The mean score was a maximum in cases where the degree of nursing care required is not intensive. PMID- 8693059 TI - The evolution of endometrial cycles and menstruation. AB - According to a recent hypothesis, menstruation evolved to protect the uterus and oviducts from sperm-borne pathogens by dislodging infected endometrial tissue and delivering immune cells to the uterine cavity. This hypothesis predicts the following: (1) uterine pathogens should be more prevalent before menses than after menses, (2) in the life histories of females, the timing of menstruation should track pathogen burden, and (3) in primates, the copiousness of menstruation should increase with the promiscuity of the breeding system. I tested these predictions and they were not upheld by the evidence. I propose the alternative hypothesis that the uterine endometrium is shed/resorbed whenever implantation fails because cyclical regression and renewal is energetically less costly than maintaining the endometrium in the metabolically active state required for implantation. In the regressed state, oxygen consumption (per mg protein/h) in human endometria declines nearly sevenfold. The cyclicity in endometrial oxygen consumption is one component of the whole body cyclicity in metabolic rate caused by the action of the ovarian steroids on both endometrial and nonendometrial tissue. Metabolic rate is at least 7% lower, on average, during the follicular phase than during the luteal phase in women, which signifies an estimated energy savings of 53 MJ over four cycles, or nearly six days worth of food. Thus the menstrual cycle revs up and revs down, economizing on the energy costs of reproduction. This economy is greatest during the nonbreeding season and other periods of amenorrhea when the endometrium remains in a regressed state and ovarian cycling is absent for a prolonged period of time. Twelve months of amenorrhea save an estimated 130 MJ, or the energy required by one woman for nearly half a month. By helping females to maintain body mass, energy economy will promote female fitness in any environment in which fecundity and survivorship is constrained by the food supply. Endometrial economy may be of ancient evolutionary origin because similar reproductive structures, such as the oviducts of lizards, also regress when a fertilized egg is unlikely to be present. Regression of the endometrium is usually accompanied by reabsorption, but in some species as much as one third of the endometrial and vascular tissue is shed as the menses. Rather than having an adaptive basis in ecology or behavior, variation in the degree of menstrual bleeding in primates shows a striking correlation with phylogeny. The endometrial microvasculature is designed to provide the blood supply to the endometrium and the placenta, and external bleeding appears to be a side effect of endometerial regression that arises when there is too much blood and other tissue for complete reabsorption. The copious bleeding of humans and chimps can be attributed to the large size of the uterus relative to adult female body size and to the design of the microvasculature in catarrhines. PMID- 8693060 TI - Sex chromatin in lepidoptera. AB - Like mammals, Lepidoptera possess female-specific sex chromatin. In a compilation of new and published data, 81% of the 238 investigated Lepidoptera species display one or more heterochromatin bodies in female somatic interphase cells, but not in male cells. In contrast with the similar phenomenon in mammals, this sex-specific heterochromatin does not function as a dosage compensation mechanism. Most Lepidoptera have a WZ/ZZ sex chromosome mechanism, and the sex chromatin is derived from the univalent W sex chromosome. Sex chromatin is regarded as an indicator of an advanced stage of W chromosome evolution. In species with a Z/ZZ sex chromosome mechanism, loss of the W chromosome is accompanied by loss of the female-specific heterochromatin. Since sex chromatin can be discerned easily in interphase nuclei, and especially so in the highly polyploid somatic cells, it is a useful marker for diagnosing chromosomal sex of embryos and larvae, and of identifying sex chromosome aberrations in mutagenesis screens. All species with sex chromatin belong to the Ditrysia, the main clade of Lepidoptera that contains more than 98% of all extant species. Sex chromatin has not been reported for clades that branched off earlier. The nonditrysian clades share this character with Trichoptera, a sister group of the Lepidoptera. We propose that Lepidoptera originally had a Z/ZZ sex chromosome mechanism like Trichoptera; the WZ/ZZ sex chromosome mechanism evolved later in the ditrysian branch of Lepidoptera. Secondary losses of the W chromosome account for the sporadically occurring Z/ZZ sex chromosome systems in ditrysian families. The lepidopteran sex chromatin, therefore, appears to mirror the full evolutionary life cycle of a univalent sex chromosome from its birth through heterochromatinization to sporadic loss. PMID- 8693061 TI - A novel DNA repair response is induced in human cells exposed to ionizing radiation at the G1/S-phase border. AB - We have discovered a novel DNA repair response which is induced in cells irradiated with gamma rays at the G1/S-phase border. The induction of this repair response occurs at a stage in the cell cycle when overall levels of excision repair are reduced compared to cells irradiated in either S phase, G2/M phase or exponential growth. The induced repair is characterized by the formation of very long excision repair patches (VLERP) containing at least 150 nucleotides compared to the constitutive repair patches that are 3-5 nucleotides. These VLERP appear to be produced in response to a DNA lesion specific to ionizing radiation since they were not observed in cells irradiated with UV radiation at G1/S phase. The formation of VLERP requires both the nucleotide excision repair pathway, since they are absent in irradiated xeroderma pigmentosum group A cells, and the synthesis of new protein and mRNA. The time course for the induction of the VLERP shows an initial delay of 2 h, followed by a steady increase for up to 12 h after irradiation. By comparison, the production of the constitutive short repair patches shows an initial rapid production which levels out after 4 h. PMID- 8693062 TI - Induction of multilocus mutations at the Tk1 locus after X irradiation of L5178Y cells at different times in the mitotic cycle. AB - TK1+/- L5178Y-R16 cells were separated into G1, S and G2/M-phase populations by centrifugal elutriation and were treated with 1.5 Gy X radiation. Cells irradiated in the G1 and G2/M phases were most sensitive to the cytotoxic effects of radiation, while cells irradiated in the G2/M phase showed the highest mutant frequency at the thymidine kinase (Tk1) locus. DNA isolated from independent TK1 /- mutants was analyzed for loss of heterozygosity (LOH) at the Tk1 locus and two microsatellites, D11Mit48 and D11Nds7. Homogenates of each mutant were assayed for activity of galactokinase (GLK), the product of the galactokinase (Glk) gene neighboring the Tk1 gene on chromosome 11. Irradiated G1-phase cells had the highest percentage of mutants showing no LOH. The frequency of mutants with LOH at both Tk1 and D11Nds7 with no loss of GLK activity was high in all cell populations: There was no significant difference in the observed frequency of these mutants between the populations. The frequency of mutants losing GLK activity was low, particularly in cells irradiated in the S or G2/M phases. The possibility that the loss of GLK activity is not indicative of LOH at the Glk gene under the conditions of the present experiments is discussed. PMID- 8693063 TI - Attenuation of G2-phase cell cycle checkpoint control is associated with increased frequencies of unrejoined chromosome breaks in human tumor cells. AB - To test the hypothesis that attenuation in G2-phase checkpoint control leads to elevated frequencies of unrejoined chromosome breaks in mitosis, the relationship between G2-phase cell cycle checkpoint control and unrejoined chromosome break frequencies after radiation exposure was examined in cells of 10 human tumor cell lines: 8 squamous cell carcinoma cell lines and 2 lymphoblastoid cell lines. Most of the delay in progression through the cell cycle seen in the first cell cycle after radiation exposure in these cell lines was due to blocks in G2 phase, and there were large cell line-dependent variations in the length of the G2-phase block. There was a highly significant inverse correlation between the length of G2-phase delay after radiation exposure and the frequency of induced unrejoined chromosome breaks seen as chromosome terminal deletions in mitosis. This observation supports the hypothesis that the signal for G2-phase delay in mammalian cells is an unrejoined chromosome break and that attenuation of G2 phase checkpoint control allows cells with unrejoined breaks to progress into mitosis. Attenuation in G2-phase checkpoint control was not associated with alterations in the frequency of induced chromosome rearrangements, suggesting that most chromosome rearrangements develop prior to G2 phase, and there was no significant relationship between the length of G2-phase delay and inherent radiation sensitivity, suggesting that unrejoined chromosome breaks are not the primary toxic lesion induced by radiation in mammalian cells. PMID- 8693064 TI - Ultrasoft 1.5 keV aluminum K X rays are efficient producers of complex chromosome exchange aberrations as revealed by fluorescence in situ hybridization. AB - The electron pairs generated by ultrasoft 1.5 keV aluminum K X-ray photons deposit their energy in tracks of length < 70 nm and provide an ideal tool for analyzing the spatial distribution of breaks and misrepair processes. We have undertaken the analysis of changes in chromosome structure produced by aluminum K X rays in untransformed HF12 human fibroblasts in G1 phase using fluorescence in situ hybridization (FISH). Multicolored chromosome-specific DNA probes for chromosomes 1 and 2 and an alpha-satellite pan-centromeric probe were used to examine in vitro radiation-induced chromosome-type exchange aberrations. After mean doses of 0.37-2.93 Gy the relative frequencies of complex exchanges, derived from three or more breaks in two or more chromosomes, ranged from 15-35%. For the classic break-age-and-rejoining theory to hold, very large interaction distances are needed to account for this high frequency of multibreak interactions, unless many sites pre-exist where several different chromosomes come very close together. Alternatively, damaged DNA may be able to interact with adjacent undamaged DNA, obviating the need for large rejoining distances. PMID- 8693065 TI - DNA and chromosome breaks induced by iodine-123-labeled estrogen in Chinese hamster ovary cells. AB - The effects of the Auger electron-emitting isotope 123I, covalently bound to estrogen, on DNA single- and double-strand breakage and on chromosome breakage was determined in estrogen receptor-positive Chinese hamster ovary (CHO-ER) cells. Exposure to the 123I-labeled estrogen induced both single- and double strand breaks with a ratio of single- to double-strand breaks of 2.8. The corresponding ratio with 60Co gamma rays was 15.6. The dose response was biphasic, suggesting either that receptor sites are saturated at high doses, or that there is a nonrandom distribution of breaks induced by the 123I-labeled estrogen. The 123I-labeled estrogen treatment induced chromosome aberrations with an efficiency of about 1 aberration for each 1000 disintegrations per cell. This corresponds to the mean lethal dose of 123I-labeled estrogen for these cells, suggesting that the lethal event induced by the Auger electron emitter bound to estrogen is a chromosome aberration. Most of the chromosome-type aberrations were dicentrics and rings, suggesting that 123I-labeled estrogen-induced chromosome breaks are rejoined. The F ratio, the ratio of dicentrics to centric rings, was 5.8 +/- 1.7, which is similar to that seen with high-LET radiations. Our results suggest that 123I bound to estrogen is an efficient clastogenic agent, the cytotoxic damage produced by 123I bound to estrogen is very like damage induced by high-LET radiation, and the 123I in the estrogen receptor-DNA complex is probably in proximity to the sugar-phosphate backbone of the DNA. PMID- 8693066 TI - Measurements of relative biological effectiveness of the 70 MeV proton beam at TRIUMF using Chinese hamster V79 cells and the high-precision cell sorter assay. AB - Measurements of relative biological effectiveness (RBE) have been made on the range-modulated 70 MeV proton beam at TRIUMF using a precise cell sorting survival assay. In this study, Chinese hamster V79-WNRE cells were suspended in medium containing liquid gelatin at 37 degrees C in irradiation tubes and the gel was allowed to solidify by cooling to 4 degrees C. Complete cell survival responses were measured at 11 positions with 2 mm spacing within a proton stopping peak width of approximately 2 cm. Survival responses after proton irradiation were compared with responses to 60Co gamma rays measured at the same time, and RBE values were determined as a function of both dose and depth. Above doses of 4 Gy, the average RBE for these cells throughout the modulated proton stopping distribution was 1.21 +/- 0.05, measured at a survival of 1%. However, we also observed that, within the spread-out Bragg peak, the RBE increased with increasing depth, from approximately 1.2 at the proximal part to > 1.3 at the distal part of the peak. At the distal edge of the stopping distribution, the RBE value increased significantly, to an extent that may be of concern when this region of the treatment volume is close to sensitive tissues. Below 4 Gy, the RBE value was also dependent on radiation dose, increasing significantly to values of approximately 1.37 and 1.56 at 2 and 1 Gy, respectively. Our results illustrate that the use of a single RBE value in different irradiation protocols can be an oversimplification, and argues for the use of "proton gray doses" rather than "gamma-ray equivalent grays." PMID- 8693067 TI - The biological effects of radium-224 injected into dogs. AB - A life-span study was conducted in 128 beagle dogs to determine the biological effects of intravenously injected 224Ra chloride. The 224Ra chloride was prepared by the same method used for intravenous injections in humans who were treated for ankylosing spondylitis and tuberculosis. Thus the results obtained from dogs can be compared directly to the population of treated humans, both for the elucidation of the effect of exposure rate and for comparison with other radionuclides for which data for humans are unavailable. Using equal numbers of males and females, the dogs were injected with one of four levels of 224Ra resulting in initial body burdens of approximately 13, 40, 120 or 350 kBq of 224Ra kg-1 body mass. A control group of dogs was injected with diluent only. All dogs were divided further into three groups for which the amount of injected 224Ra (half-life of 3.62 days) or diluent was given in a single injection or divided equally into 10 or 50 weekly injections. As a result of these three injection schedules, the accumulation of dose from the injected 224Ra was distributed over approximately 1, 3 or 12 months. Each injection schedule included four different injection levels resulting in average absorbed alpha particle doses to bone of 0.1, 0.3, 1 and 3 Gy, respectively. The primary early effect observed was a hematological dyscrasia in the dogs receiving either of the two highest injection levels. The effect was most severe in the dogs receiving a single injection of 224Ra and resulted in the death of three dogs injected at the highest level. The late-occurring biological effects were tumors. Bone tumors were the most common followed by tumors in the nasal mucosa. The occurrence of bone tumors was highest in the dogs given the highest dose in 50 injections. The age-specific incidence rate for mammary tumors was increased in all three injection groups. The results of this study revealed two important exposure-rate effects. Hematological dyscrasia was amplified by delivery of relatively high doses at a high exposure rate. In contrast, bone tumors were amplified by delivery of relatively high doses at a lower exposure rate (i.e. dose delivered over 1 year rather than 1-3 months). There was a dose-response relationship for the induction of nasal mucosal tumors and mammary tumors. These findings in dogs are similar to those in humans injected with 224Ra, except for the nasal tumors. The calculated risk of developing a bone tumor was about 40 times higher in dogs than reported for humans. PMID- 8693068 TI - Effect of chronic exposure to ultraviolet radiation and photoreactivation on life span and tumor development in the marsupial Monodelphis domestica. AB - The effect of exposure to chronic ultraviolet (UV) radiation on life span was examined in Monodelphis domestica, which is capable of photoreactivation repair of UV-radiation-induced pyrimidine dimers. Shaved Monodelphis were exposed to 500 J/m2 UV radiation, 500 J/m2 UV radiation then 90 min of photoreactivating light (PRL), or 90 min of PRL three times weekly for 104 weeks. Opossums were weighed weekly; samples for serum chemistry and hematology testing were obtained periodically. Complete postmortem examinations revealed a primary cause of death for each opossum. Meaningful differences among the groups in weight gain, serum chemistry values or hematology values were not seen. Significant life-shortening due to UV-radiation exposure was found for females but not males. Photoreactivation prolonged life only in the females exposed to UV radiation. Exposure to UV radiation was not associated with accelerated development of degenerative disease. Significant treatment-related mortality occurred in both male and female opossums exposed to UV radiation. Photoreactivation reduced the relative risk of skin tumors but not eye tumors in Monodelphis exposed to UV radiation. Eye and skin tumors were less likely to be a cause of death in UV radiation-exposed opossums subsequently exposed to PRL than in opossums exposed to UV radiation alone. Females exposed only to UV radiation had an increased risk of skin tumor development relative to males. PMID- 8693069 TI - Single-strand breaks in double-stranded DNA irradiated in anoxic solution: contribution of tert-butanol radicals. AB - Yields of single-strand breaks induced by 60Co gamma or pulse irradiation in double-stranded calf thymus DNA have been measured in N2O-saturated aqueous solution as a function of the concentration of tert-butanol. The yields were found to be dependent on dose rate. The experimental data were analyzed using a theoretical model based on non-homogeneous scavenging kinetics. It is concluded from this analysis that after 60Co gamma irradiation in the absence of oxygen, aside from breaks caused by hydroxyl radicals, additional breaks occur which are initiated by hydrogen atoms and secondary radicals of tert-butanol. The efficiency of hydrogen atoms in causing single-strand breaks in double-stranded calf thymus DNA was determined to be 2.3%, while the rate constant for the reaction of tert-butanol radicals with DNA and their efficiency in causing single strand breaks was determined to be 4.1 x 10(3) dm3 mol-1 s-1 and 2%, respectively. PMID- 8693070 TI - Transport of aminothiol radioprotectors into mammalian cells: passive diffusion versus mediated uptake. AB - Water:n-octanol partition coefficients (KD) were determined for a series of radioprotective thiols to ascertain whether these could be used to estimate reliably their rates of uptake into mammalian cells by passive diffusion. Values of KD determined for thiols in 0.1 M potassium phosphate, pH 7.4, at 22 degrees C were: N-(2-mercaptoethyl)-1,3-diaminopropane (WR-1065, WRSH), 2.0 x 10(3); dithiothreitol, 1.4; 2-mercaptoethanol, 1.7; cysteamine, 180; 3-mercaptopropanoic acid, 450; mercaptosuccinic acid, 5 x 10(6) (extrapolated value). Predictions of uptake rates by passive diffusion into mammalian cells using these values and values for the membrane diffusion rate derived from empirical evaluation of appropriate values from the literature for erythrocyte permeability paralleled the experimental rates for WR-1065 and dithiothreitol but were about threefold lower. Although the utility of KD values for quantitative prediction of uptake rates is limited, the analysis clearly indicated that uptake of aminothiols having three or more ionized amino groups will not occur at useful rates by passive diffusion. Studies of WR-1065 import by Chinese hamster V79-171 cells at micromolar levels of WR-1065 revealed an uptake that could not be explained by passive diffusion. This uptake was not inhibited by substrates for common amino acid transport systems but was inhibited by polyamines and by 1 mM DTT, which suggested that WR-33278 (WRSSWR) formed by oxidation of WRSH was being transported by a polyamine transport system. This was confirmed by showing that WRSSWR is imported efficiently by V79-171 cells treated with D,L-2 difluoromethylornithine to deplete intracellular polyamines and hence enhance their transport. Spermine inhibited uptake of WRSSWR and WRSSWR inhibited uptake of [14C]spermine, confirming that a common system is involved in the uptake of these similar molecules, both having +4 charge. It was shown that after import WRSSWR is reduced to WRSH and that uptake at low micro-molar concentrations of WRSSWR results in marked cellular concentration of the drug. These results indicate that the spermidine/spermine transport system may also provide a feasible route for import of radioprotective aminothiols bearing net charges of +3 or +4 into mammalian cells. PMID- 8693071 TI - Uptake of indium-111-labeled platelets and indium-111 oxine by murine kidneys after total-body irradiation. AB - Radiation nephropathy is a well-known late manifestation of renal irradiation in human beings and experimental animals. Its pathogenesis is unclear, but vascular injury may play a role. Endothelial cells have been demonstrated to manifest a variety of abnormalities within hours of exposure to radiation. In the present experiments mice were exposed to lethal doses of whole-body radiation, and the distribution of 111In-labeled platelets was evaluated during the first week after irradiation. The purpose was to determine if early abnormalities of endothelial cells would be manifested by altered sequestration of platelets in kidneys and other organs. It was found that the indium accumulated in the kidneys of irradiated mice to a greater extent than in nonirradiated mice, supporting the possibility of early vascular injury. In control experiments, administration of 111In-oxine was also followed by excessive accumulation of radioactivity in kidneys of irradiated mice, but the pattern of accumulation differed from that seen after injection of radiolabeled platelets. Renal hyperemia was not demonstrable with 51Cr-labeled red cells, renal vascular permeability was not detected with 125I-labeled albumin, and the pattern of renal uptake of plasma proteins labeled with 59Fe or 111In did not coincide with that seen from 111In administered as labeled platelets or oxine. Renal uptake of 111In-oxine was not associated with alterations in urinary or fecal excretion or an increase in total body retention of the radioisotope. The findings are consistent with the notion that renal vascular injury at the time of irradiation results in accumulation of platelets or platelet constituents during the first week after total-body irradiation of mice. PMID- 8693072 TI - Prevalence of skin neoplasms among the atomic bomb survivors. AB - About 7,000 atomic bomb (A-bomb) survivors from Hiroshima and Nagasaki who participate in the Radiation Effects Research Foundation (RERF) Adult Health Study (AHS) were examined to define the relationship between skin neoplasms and exposure to ionizing radiation. Careful clinical inspection of the skin was undertaken to detect not only skin cancer but precancerous lesions such as senile keratosis. Five cases of basal cell carcinoma, five cases of senile keratosis and one case of Bowen's disease were confirmed histologically among 5955 A-bomb survivors for whom Dosimetry System 1986 (DS86) dose estimates are available. The relationship between the combined prevalence of skin cancer and precancerous lesions and DS86 dose was examined together with other factors that might affect skin neoplasms including occupational exposure to ultraviolet (UV) rays, age, sex and city. The prevalence of basal cell carcinoma and senile keratosis increased as the DS86 dose increased. The prevalence of skin cancer and senile keratosis among persons engaged in work involving frequent exposure to UV rays was higher than among those who were not engaged in such work. Sex and city were not significantly related to those skin diseases. Odds ratios of skin neoplasm for a 1-Gy dose, occupational exposure to UV rays and age at time of examination (in 10 year increments) are 1.7, 5.9 and 1.9, respectively. PMID- 8693073 TI - Evaluation of nitrone spin-trapping agents as radioprotectors. AB - The focus of this investigation was to determine whether the nitrone spin trapping compounds alpha-phenyl-N-tert-butylnitrone (PBN), 5,5-dimethyl-1 pyrroline-N-oxide (DMPO) and alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) are radioprotectors. Two methods were used to assess for radioprotection: measurement of oxidative damage to DNA bases and mammalian cell survival assays. Oxidative damage to DNA was quantified by measuring the relative amounts of 8 hydroxy-2'-deoxyguanosine (8-OH-dG) produced by the reaction of hydroxyl radicals (OH.) with 2-deoxyguanosine (dG) after irradiation. PBN, DMPO and POBN, when dissolved in aqueous solutions of either dG or naked salmon sperm DNA, reduced the formation of 8-OH-dG by 137Cs gamma irradiation significantly. The spin trapping agents, especially PBN at lower concentrations, were more effective in preventing radiation-induced formation of 8-OH-dG in naked DNA than in free dG. These data suggest that PBN, DMPO and POBN act as free radical scavengers which may associate with DNA and afford protection against gamma rays. However, no enhancement of survival was observed when Chinese hamster ovary (CHO) cells were exposed to high non-toxic concentrations of PBN or POBN prior to and during irradiation with 60Co gamma rays and scored for clonogenic survival. DMPO provided only minimal protection from radiation-induced cell killing. PMID- 8693074 TI - Radiation-induced cell killing is highly dependent upon buffer treatment (filtration compared to autoclaving) due to metal-catalyzed formation of hypochlorite: a cautionary note. AB - Buffer solutions used in experiments in radiation biology may be sterilized by either autoclaving or filtration. We show here that for phosphate-buffered saline such differences in buffer treatment may result in widely differing dose-effect curves for cell killing. The temperature-dependent transformation of monophosphate ions into di- or polyphosphate evidently proceeds to an appreciable extent upon autoclaving the buffers at 120 degrees C for 10 to 20 min. This increases the capability of the buffer to chelate spurious metal contaminations and, as a consequence, to reduce the amount of cytotoxic hypochlorite being produced. Depending on conditions of buffer treatment we have observed dose modification factors for the colony-forming ability of yeast cells up to the order of 3. Thus effects due to buffer treatment might easily outweigh the effect which the experiment was originally designed to determine. We strongly advise, therefore, that results of parallel sets of experiments in which different methods of buffer sterilization have been used should not be compared directly. PMID- 8693075 TI - Comment on the ratio of chromosome-type dicentric interchanges to centric rings for track-clustered compared with random breaks. AB - Evidence has been published suggesting that the ratio of chromosome-type dicentric interchanges to centric rings (D/R or F) is significantly lower for neutrons than for X or gamma rays, and it is proposed that a low D/R could be used as a "fingerprint" for high-LET radiations. One explanation offered for this observation is that the closely spaced, clustered breaks confined to linear tracks will favor intrachanges, as opposed to interchanges, leading to a lower D/R, while the more scattered, random breaks of low-LET radiations will favor the reverse situation and elevate the D/R. We have tested this suggestion empirically by constructing various modeled tracks and grids of breaks which satisfy the proposed conditions. These have then been superimposed, in random orientation, on an array of hexagons, representing a planar section through the interphase arm domains of 14 polarized, metacentric, G1-phase chromosomes, and the D/R computed from the interaction of break clusters with the arms. The ratios recovered were essentially the same for the four different break distributions tested, and we conclude that, for this simple model, the determinant of the D/R is the arm arrangement in the array, rather than the disposition of the breaks. PMID- 8693076 TI - Comments on "Comment on the ratio of chromosome-type dicentric interchanges to centric rings for track-clustered compared with random breaks" by Savage and Papworth (Radiat. Res. 146, 236-240, 1996) PMID- 8693077 TI - Retraction of "In vitro split-dose recovery of glioblastoma multiforme" by Taghian et al. (Radiat. Res. 134, 16-21, 1993) PMID- 8693078 TI - [History of diagnostic imaging in the area of the head-neck]. AB - The head and neck region is a limited anatomical area in radiological diagnostics. Nevertheless, head and neck radiology has a long and interesting history with excellent scientists involved in its development. Before the discovery of X-rays, no information about the head and neck could be obtained without surgery or even autopsy. Therefore, conventional radiograms and special projections were an important step forward. During the 1950s, a second diagnostic breakthrough was achieved by the introduction of tomographic techniques. Film tomography was the first step in this important development. Computed tomography and magnetic resonance imaging yielded astonishing and unforeseen results. Especially in the field of magnetic resonance imaging, the technical development has not yet come to an end. Scientific research and continuing education are required in order to achieve further advances in head and neck radiology, and European cooperation is on the way. PMID- 8693079 TI - [Clinical differential diagnosis of the mouth and oropharynx]. AB - In the present paper, common disorders of the oral cavity and oropharynx are described with special emphasis on differential diagnostic aspects. The first part of this presentation covers different inflammatory diseases, mainly focusing on complications like peritonsillar, para- and retropharyngeal abscesses, and Ludwig's angina. These clinical entities can lead to further life-threatening complications, including deep neck infections and mediastinitis. The diagnostic value and necessity of modern imaging in these cases are emphasized. In the second part, the author reports on the incidence, etiology and clinical course of tumors of the oral cavity and oropharynx with special regard to malignancies. Tumors in these areas have been increasing in number over the past decades mainly due to changes in alcohol and nicotine consumption in the developed countries. Diagnostic management includes a thorough clinical evaluation as well as modern imaging for tumor delineation and possible bone infiltration, depending on the site of the original tumor. In addition, therapeutic considerations are discussed, focusing on surgical tumor removal and soft tissue replacement using different pedicled flaps and free flaps. It is also emphasized that postoperative radiotherapy is mandatory in most malignant tumors in this area. PMID- 8693080 TI - [Diagnostic imaging for therapy planning of orofacial malformations]. AB - Two-dimensional conventional X-rays and computer tomographic imaging systems contribute to the diagnosis and surgical planning of patients with orofacial malformations. The ability to reformat CT scans into three-dimensional osseous and soft tissue surface images has a significant impact on the diagnosis and management of orofacial malformations. Cephalometric evaluation with teleradiography provides precise insight into both the skeletal structures and the soft parts, enabling the radiologist to assess the relationship among the different parts in a given subject, at any given time and in relation to the normal. PMID- 8693081 TI - [Computerized tomography of malignancies of the oral cavity, the oropharynx and hypopharynx and invasiveness]. AB - Carcinomas of the oral cavity, oropharynx and hypopharynx represents 5% of all malignant neoplasms. The vast majority, over 90%, are squamous cell carcinomas; less common are lymphomas and tumors of the minor salivary glands. In general, the clinical findings already suggest the presence of a tumor. Therefore, the role of imaging is precise tumor localisation and staging of the malignancy. CT is still the gold standard, although MRI is gaining more importance. We present the CT appearance of most frequent malignancies of the oral cavity, oro- and hypopharynx, discussing briefly the pertinent anatomy. PMID- 8693082 TI - [Value of fat signal suppression MRI pulse sequences for diagnosis of malignant tumors in the area of the head-neck]. AB - PURPOSE: Evaluation of frequency-selective fat saturation (FS) and short-tau inversion recovery (STIR) fat suppression (FU) in MRI of patients with malignant head and neck tumors. METHODS: Forty-five patients with biopsy-proven carcinomas of the extracranial head and neck were examined with MRI at 1.0 T. A T2-weighted TSE sequence with and without STIR-FU and a T1-weighted SE sequence with and without FS were compared in axial slices. RESULTS: STIR-FU was successful in all and FS in 85-88% of the head examinations (nasopharynx, sinuses, oropharynx, and oral cavity) and 33-46% of the neck examinations (hypopharynx and larynx). When visualization and delineation of tumors were ranked on a four-point scale (0-3), respective mean values for images with/without FU or FS were 2.6/1.9 for T2-TSE in all examinations, 2.2/1.7 (nasopharynx and sinuses) and 1.3/1.4-1.6 (oropharynx, oral cavity, hypopharynx, and larynx) for T1-SE without contrast media administration (CM) and 2.3/2.1 (nasopharynx and sinuses) and 2.4-2.5/1.9 2.0 (oropharynx, oral cavity, hypopharynx, and larynx) with CM. CONCLUSIONS: STIR T2-TSE was a technically reliable pathfinder for localization and extension of both tumors and lymph nodes. FS-T1-SE was technically unreliable in examinations of the hypopharynx and larynx. With CM, FS-T1-SE was most useful for MRI of carcinomas of the oral cavity and oropharynx. In the nasopharynx and sinuses, T1 SE with CM and FS-T1-SE with or without CM were equal for tumor visualization and delineation. PMID- 8693083 TI - [Ultrasound diagnosis in primary staging of head-neck tumors]. AB - The radiologic imaging methods play an important role in the precise staging as basic requirement for an effective concept of tumor therapy. The accuracy of ultrasound in the primary staging according to the TNM-classification (UICC) was therefore prospectively investigated in 260 patients with head and neck tumors of the clinical stages T1N0 to T4N3. The clinically (C1) and sonographically (C2) evaluated pretherapeutic stages were compared to the postoperative histopathologic tumor classifications. The clinical staging was correct in 75.0%, high in 7.7%, low in 17.3%, the N-stages were correct in 59.2%, high in 17.7%, low in 23.1%. The sonographic staging was apparently superior with the T classifications correct in 92.3%, high in 7.7%, low 0.0%. The N-stages were correct in 89.6%, high in 9.2%, low in 1.2%. The accuracy of combined TN classification rose from clinical 46.5% to 84.6% by sonography. Accompanying inflammations, foregoing biopsies and tooth extractions were the main reasons for incorrect staging. Therefore, the thorough sonographic investigation performed after the clinical examination and before invasive procedures, due to little patient discomfort, good availability and high accuracy, is an excellent sectional imaging method for staging, therapy-planning and follow up of tumors of the head and neck especially of the orofacial regions. PMID- 8693084 TI - [CT and MRI of small intestine interposition after oropharyngeal tumor resection]. AB - Freely transplanted, microvascularly anastomosed jejunal patches can be used to cover soft tissue defects in the oral cavity or oropharynx after the resection of malignant tumors. Even a patch without complications or alteration from tumor recurrence is morphologically diverse. Therefore it is difficult to distinguish between malignant and benign alterations, and knowledge of the possible morphological spectrum and the significance of an alteration is of practical interest. Computed tomography (CT; n = 30) and magnetic resonance imaging (MRI; n = 13) were used for follow-up examinations in patients who had an operative reconstruction with a jejunal patch. Three parts of a patch were differentiated with both imaging modalities: the region of the anastomosis, the mesenterial fatty tissue and the intestinal wall. The morphology of the patches correlated with clinical findings in the following cases. The patches were identified satisfactorily by CT and MRI. The appearance of patches without complications was influenced by a variable degree of fibrosis and by persistent intestinal folds. Recurrent tumors only infiltrated the margins of the patches. Destructive alterations in the patches were always less severe than those in the original orofacial soft tissue. Postoperative follow-up examinations with CT and MRI are particularly important when tumor recurrences spread under a patch, since these tumors are invisible in the clinical examinations. CT was advantageous in demonstrating osseous alterations and showed less loss of image quality in patients for whom the implantation of multiple metallic hardware during the operation had been necessary. PMID- 8693085 TI - [Computerized tomography of the alveolar process]. AB - In addition to the conventional radiological methods used in odontology, computed tomography (CT) provides superposition-free images of the mandible and maxilla. Its value has been proved not only in cases of malignancy but also in many other problems. If an examination is performed with a slice thickness of less than 1.5 mm, the form and position of retained teeth in the alveolar bone, as well as subsequent lesions of neighboring permanent teeth, can be visualized so that early treatment can be planned. If the parodontal space of a retained tooth is visible, orthodontic intervention is possible. Precise assessment of horizontal or vertical bone loss is essential in inflammatory dental diseases. The morphology and extent of benign cystic lesions are also shown by CT. With CT surgical strategy of an intended implant therapy can take into account the remaining bone substance and the exact position of nerves and foramina. If such therapy is possible, the location, form and number of implants are easily defined. PMID- 8693086 TI - [Functional studies of swallowing with electron beam computerized tomography]. AB - Functional evaluation of swallowing disorders requires rapid imaging modalities. Videofluorography and cinematography are the gold standard, but they have their limitations: no transverse plane imaging is achieved and structural resolution for exact topographic analysis is limited. Three cases preselected by videofluorography were studied to evaluate whether electron beam tomography (EBT) permits more detailed dynamic imaging of swallowing disorders focusing on the mesonasopharyngeal segment, the hypopharynx and the upper esophageal sphincter (UES). Immediately after videofluorographic examination of the oropharyngeal deglutition, EBT is performed. The patient is in a supine position and while the patient swallows a 20 ml bolus of water or diluted iodine containing contrast agent, a sequence of 20 images per level is scanned. The levels, which are determined by using the scout view, are oriented parallel to the hard palate either at the level of the hard palate to image the mesonasopharyngeal segment or just above the hyoid bone to focus on the hypopharynx or at the location of the UES. The scan technique is a single-slice cinemode with a slice thickness of 3 mm (exposure time 100 ms, interscan delay 16 ms, 130 kV, 620 mA). The following structural interactions that we have so far been unable to image can be clearly demonstrated with EBT: (1) during normal swallowing, the mesonasopharyngeal segment is completely and symmetrically closed by the soft palate and Passavant's cushion; (2) lateral hypopharyngeal pouches can be located more precisely; and (3) disorders of the UES can be differentiated into functional or morphologically caused disorders (e.g., goiter or cervical osetophytes). Videofluorography and cinematography are still the gold standard in functional evaluation of swallowing disorders. However, EBT permits dynamic imaging of pharyngeal deglutition in a preselected transverse plane and can give useful additional information concerning functional anatomical changes in the pharynx during swallowing. Further clinical evaluation is needed. PMID- 8693087 TI - [Value of dental CT for the implant specialty in mouth, jaw and facial surgery]. AB - The importance of dental CT in comparison to conventional OPT in implantation diagnostics is demonstrated in specific indication groups (atrophy of upper and lower jaw, patient after tumor and reconstructive surgery). The application of radiological techniques is illustrated in relation to diagnostic information quality, radiation exposure and cost effectiveness regarding clinical routine use. PMID- 8693088 TI - [Initial results with MRI-controlled laser-induced interstitial thermotherapy of head and neck tumors]. AB - Laser-induced interstitial thermo-therapy (LITT) was introduced as a minimally invasive form of therapy for tumors in different anatomic regions. However, in the orofacial region, it has not been used so far for inoperable T4 carcinomas. Since vascular and neural structures are often close to the tumor or are even involved, online monitoring of LITT is necessary. The aim of our study was to establish a method of monitoring LITT with MRI (magnetic resonance imaging) in the orofacial region. Five patients with T4 carcinomas of the orofacial region underwent LITT under anesthesia. A 1.5 T whole-body imager with a circular polarized head coil was used. Before and after the intervention, the region of interest was studied using T1- and T2-weighted sequences in axial and coronal planes, with and without contrast enhancement (intravenous Gd-DTPA). Temperature distribution was monitored with a T1-weighted 2D-FLASH (fast low angle shot) sequence. The positioning of the optical fibers was monitored with MRI. Nd:YAG laser equipment was used for laser application. The necrosis was best seen on contrast-enhanced MRI. Immediately after LITT, the outcome could be determined by MRI. We proposed that MRI-guided LITT be used for neoplasms in the orofacial region at advanced stages. PMID- 8693089 TI - [Functional MRI of the pharynx in obstructive sleep apnea using rapid 2D FLASH sequences]. AB - Functional imaging of the pharynx used to be the domain of cineradiography, CT and ultrafast CT. The development of modern MRI techniques led to new access to functional disorders of the pharynx. The aim of this study was to implement a new MRI technique to examine oropharyngeal obstructive mechanisms in patients with obstructive sleep apnea (OSA). Sixteen patients suffering from OSA and 6 healthy volunteers were examined on a 1.5 T whole-body imager ("Vision", Siemens, Erlangen Medical Engineering, Germany) using a circular polarized head coil. Imaging was performed with 2D flash sequences in midsagittal and axial planes. Patients and volunteers were asked to breathe normally through the nose and to simulate snoring and the Mueller maneuver during magnetic resonance imaging (MRI). Prior to MRI, all patients underwent an ear, nose and throat (ENT) examination, functional fiberoptic nasopharyngoscopy and polysomnography. A temporal resolution of 6 images/s and an in-plane resolution of 2.67 x 1.8 mm were achieved. The mobility of the tongue, soft palate and pharyngeal surface could be clearly delineated. The MRI findings correlated well with the clinical examinations. We propose ultrafast MRI as a reliable and non-invasive method of evaluating pharyngeal obstruction and their levels. PMID- 8693090 TI - [Experimental evaluation of contrast medium enhanced high resolution MR angiography in the animal model. Gd-DTPA compared with Gd-DTPA-polylysine]. AB - PURPOSE: To evaluate the qualitative and quantitative efficacy of Gd-DTPA and Gd DTPA polylysine for contrast-enhanced high resolution MRA (CMRA) of the abdominal vessels. MATERIALS AND METHODS: In ten anesthesized rabbits (average weight 4.3 kg) MR angiography was performed using a 1.5 T MR unit (Magnetom SP 63; Siemens Erlangen) and a CP head coil. Arterial MRA (FISP 3D TONE, TR/TE = 33/8, Flip 20 degrees) and venous MRA (FLASH 2D, TR/TE = 37/10, Flip 60 degrees) was performed before and after administration of the paramagnetic contrast agents Gd-DTPA (n = 5) or Gd-DTPA polylysine (n = 5) at a dosage of 0.1 mmol/kg. In all studies the single sections and the MIP reconstructions were evaluated quantitatively by measuring and calculating signal intensity, percentage enhancement, signal-to noise and contrast-to-noise ratios. All studies were assessed qualitatively for visualization and distinction of the arterial and venous vessel system by three independent observers before and after the administration of contrast agent. RESULTS: Gd-DTPA-enhanced arterial FISP 3D tone led to a percentage enhancement of 30% for the kidneys, 12% for the superior mesenteric artery, 18% for the deep circumfluent iliac artery, and 7% for the internal iliac artery. In FLASH 2D sequences Gd-DTPA led to a good C/N only for venous abdominal vessels like the left renal vein (2.59) and internal iliac vein (1.66); the percentage enhancement of these structures was between 16 and 21%. Qualitative comparison also showed no significant improvement after injection of Gd-DTPA. In FISP 3D TONE sequences Gd DTPA polylysine led to a strong percentage enhancement of right and left kidney (21 and 40%) and deep circumfluent iliac artery (17%). Qualitative evaluation showed improved delineation and contrast of low-diameter vessels, while the soft tissue was only slightly enhanced and did not impair vessel visualization. CONCLUSION: CMRA using Gd-DTPA and Gd-DTPA polylysine significantly improved the delineation of abdominal vessels, with Gd-DTPA polylysine being superior. PMID- 8693091 TI - [Rare fracture of the atlas after hyperextension trauma]. PMID- 8693092 TI - Current recommendations for the anticoagulation of patients with atrial fibrillation. AB - Atrial fibrillation (AF) is the most commonly encountered cardiac rhythm disorder and is strongly associated with stroke. The risk of stroke and the benefit of anticoagulant therapy in patients with AF associated with mitral stenosis has been well accepted. Until recently the risk of stroke and the role of anticoagulant therapy in patients with nonrheumatic AF was unclear. Over the past decade studies have shown an approximate fivefold increase in the risk of stroke in patients with nonrheumatic AF. The results of large clinical trials have shown a benefit of treatment with anticoagulants and, to a lesser extent, aspirin for both the primary and secondary prevention of thromboembolic complications. Other than patients with a low risk of thromboembolic complications (primarily young patients without clinical risk factors), current guidelines recommend anticoagulation of most patients with AF. The studies that form the basis for these recommendations and the currently published guidelines are reviewed. PMID- 8693093 TI - Transesophageal echocardiography-guided approach to cardioversion of atrial fibrillation. AB - In patients with atrial fibrillation, electrical cardioversion is often performed to relieve symptoms, to improve left ventricular function, and to decrease thromboembolic risks. However, cardioversion of atrial tachyarrhythmias is associated with an increased embolic risk, with an event rate of up to 5.6%. The American College of Chest Physicians recommend 3 weeks of systemic anticoagulation before elective cardioversion and 4 weeks of systemic anticoagulation afterwards. Expulsion of preexisting left atrial (LA) thrombi with resumption of sinus rhythm has traditionally been considered the mechanism for this increased embolic risk associated with cardioversion. The advent of transesophageal echocardiography (TEE) has allowed accurate detection of LA thrombus. Moreover, recent studies using TEE have identified a state of atrial "stunning" immediately after cardioversion, which is considered a thrombogenic milieu in which new thrombus formation and increased or de novo appearance of LA spontaneous echocardiographic contrast have been observed. Furthermore, embolic events have been reported after cardioversion despite exclusion of preexisting LA thrombus by TEE. These studies strongly suggest an alternative mechanism for embolism after cardioversion, ie, atrial stunning with worsened atrial appendage function and enhanced thrombogenesis. Recent studies have shown the safety of a TEE-guided anticoagulation approach in which exclusion of preexisting LA thrombus by TEE enables early cardioversion without the need for the standard 3 weeks of systemic anticoagulation. The importance of maintaining therapeutic anticoagulation has been further emphasized. Although preliminary observational studies of TEE-guided cardioversion are encouraging, there has been no prospective, randomized trial comparing the two strategies of anticoagulation management. The Assessement of Cardioversion Utilizing Transesophageal Echocardiography (ACUTE) pilot study randomized 126 patients from 10 sites and showed the feasibility and safety of the larger scale study. A larger multicenter, prospective randomized trial is now underway and is expected to randomize a total of 3,000 patients. The results of the ACUTE study will definitively establish the safest and the most cost-effective way to manage anticoagulation for elective cardioversion. PMID- 8693094 TI - Atrial anatomy and function postcardioversion: insights from transthoracic and transesophageal echocardiography. AB - Echocardiography provides a valuable tool for the evaluation and assessment of atrial function in patients with atrial fibrilation (AF). Atrial morphology after restoration of sinus rhythm is dynamic, with a decrease in atrial size if sinus rhythm is maintained and atrial growth among those with sustained AF. Restoration of electrocardiographic sinus rhythm is frequently accompanied by relatively depressed atrial mechanical function, with recovery that appears to be related to multiple factors, including the duration of AF before cardioversion and the mode of cardioversion. Such delay appears to confer ongoing risk for thrombus formation and thromboembolism in the days after cardioversion and argues strongly for the need to maintain therapeutic anticoagulation during the pericardioversion and postcardioversion period. PMID- 8693095 TI - In vivo and in vitro studies on the mechanism and clinical significance of spontaneous echocardiographic contrast in patients with atrial dysrhythmias. AB - The pathogenesis of spontaneous echocardiographic contrast (SEC) is complex and multifactorial. Although originally described in low-flow state situations such as in the left atrium of patients with mitral stenosis or in the false lumen of patients with aortic dissection, its detection is highly dependent on technical factors such as the frequency of the transducer used. Multiple blood components have been implicated in SEC formation and erythrocyte aggregation currently appears to be the most likely mechanism. SEC is related to atrial fibrillation and is commonly found in patients with thrombus or prior history of thromboembolism. In addition, it may represent a prognostic marker for patients with atrial fibrillation because patients with SEC have a higher incidence of subsequent thromboembolic events. Therapeutic options include anticoagulation and, perhaps, antiplatelet therapy. Further prospective studies are necessary to better define SEC pathogenesis and treatment. PMID- 8693096 TI - Stratification of thromboembolic risk of atrial fibrillation by transthoracic echocardiography and transesophageal echocardiography: the relative role of left atrial appendage function, mitral valve disease, and spontaneous echocardiographic contrast. AB - The role of transesophageal echocardiography (TEE) in thromboembolic risk stratification in atrial fibrillation (AF) has not been established. Left atrial appendage contractile dysfunction in patients with AF predisposes to thrombus formation. The extent of blood stasis and propensity for thrombus can be assessed during TEE by measurement of the peak Doppler velocity of blood outflow from the appendage. Spontaneous echocardiographic contrast (SEC) is a swirling pattern of blood echogenicity that may be detected by TEE in the left atrium in patients with AF. The presence of SEC reflects left atrial blood stasis and a prothrombotic state. SEC is associated with an increased risk of systemic thromboembolic events. Parameters derived from TEE may provide additional prognostic data to clinical history and transthoracic echocardiography in thromboembolic risk stratification in AF. PMID- 8693097 TI - Risk of thromboembolism in new onset or transient atrial fibrillation. AB - Atrial fibrillation (AF), potentially serious cardiac arrhythmia, occurs in 2% to 4% of persons greater than 60 years of age. The risk of systemic thromboembolism from chronic AF has long been recognized. Little is known about the thromboembolic risk of new onset AF. However, the results of prior studies support a significant risk of thromboembolism because of recent onset or paroxysmal AF. The mechanism of thrombus formation, embolization, and resolution in AF is ill-defined, particularly that of new onset. The traditional concept holds that atrial thrombus forms only after greater than 2 days of AF and embolizes by dislodgement from increases in shear forces. This prevailing concept further proposes that newly formed atrial thrombus, in the setting of AF, organizes over a span of 14 days. The results of recent transesophageal echocardiographic studies have given insight into the temporal sequence of atrial thrombus formation, embolization, and resolution in AF and have expanded the traditional concept of thromboembolism in AF. Namely, left atrial thrombus may form before the onset of AF in the face of sinus rhythm. Conversion to sinus rhythm may increase the thrombogenic millieu of the left atrium. Importantly, atrial thrombus may form in the acute phase of AF. Lastly, thrombus may require more than 14 days to become immobile or to resolve. On the basis of these emerging insights by transesophageal echocardiography, it appears appropriate to consider anticoagulation in patients presenting with new onset or acute AF. PMID- 8693098 TI - Reimbursement for radiotherapy treatment in the EU countries: how to encourage efficiency, quality and access? AB - In this paper, the radiotherapy reimbursement systems actually used in the EU countries are compared. From this overview, it is concluded that up to date health care policy makers have not yet tapped all opportunities to encourage efficient, accessible radiotherapy delivery of high quality, through the reimbursement system. Therefore, some recommendations are given on how the reimbursement system can be designed in order to promote efficiency, accessibility and/or quality. PMID- 8693099 TI - A palliative accelerated irradiation regimen (PAIR) for advanced non-small-cell lung cancer (NSCLC). AB - In order to avoid overtreatment in advanced NSCLC we developed a palliative accelerated irradiation regimen (PAIR) applying a total dose of 32 Gy in 10 days with two daily fractions of 2 Gy. This paper reports on a 1-year pilot study carried out in preparation of a randomised trial. Data for the 34 patients receiving PAIR were compared to 179 conventionally irradiated historical controls selected from a pre-existing database according to identical inclusion criteria. Statistical analysis showed that PAIR patients had a significantly longer survival than controls (P = 0.0029). Median survival was 11.8 and 5.8 months, respectively, while 1-year survival was 45.6% vs. 21.2%. Compared to the subgroup of controls who had received the full planned dose of 60 Gy (n = 104) PAIR patients showed no significant difference in survival. In order to adjust for possible imbalances we used a comprehensive blinded prognostic rating design creating one score value per patient out of several known prognostic factors. After adjustment for the resulting prognostic score by means of the Cox proportional hazards model PAIR patients still showed significantly longer survival. We conclude that in advanced NSCLC survival after a palliative short term regimen appears to be at least equivalent to that following conventional high-dose irradiation. PMID- 8693100 TI - Complications of combined intraoperative radiation (IORT) and external radiation (ERT) of the upper abdomen: an experimental model. AB - An experimental model in the rabbit is presented which is suitable for analysis of clinically relevant, early side-effects of combined upper abdominal IORT and ERT. Fractionated ERT alone given through an upper abdominal a.-p. field including the entire stomach caused gastric ulcerations within < or = 58 days. Latent times decreased with increasing dose and the ED50 for occurrence of ulcers was 39 +/- 3.3 Gy. Single doses of IORT of 20-40 Gy alone administered through a 2-cm diameter field localized on the coeliac axis and carefully excluding any intestinal mucosa caused neither gastric ulcerations nor other clinical symptoms. When ERT with 40 Gy was preceded by IORT with 20-40 Gy or by sham IORT, 13 out of 15 animals developed ulcers after latent times which in a life-table analysis were shown to be significantly shorter than after ERT alone. However, a statistically significant IORT dose-dependence of latent time or incidence of ulcers could not be demonstrated in the present experiment. The most significant histological changes were observed in the areas of gastric ulcers. Already during ERT, the mucosal epithelium was depleted and regenerative activity was evident in spite of ongoing fractionated irradiation. However, profound irregularities in glandular structure and distribution, as well as number of proliferating epithelial cells were still present in healed ulcers at 80 days. In summary, IORT to the coeliac artery did precipitate the development of gastric ulcers induced by subsequent ERT. On the one hand, the data indicate that the surgical procedure of IORT did contribute to this effect. On the other hand, IORT to the coeliac artery could cause transient, functional alterations in blood supply to the depending organs, i.e. the stomach, and could thus precipitate the development of radiation-induced ulcers. PMID- 8693101 TI - Urethrography and ischial intertuberosity line in radiation therapy planning for prostate carcinoma. AB - We analyzed our urethrography procedure regarding the validity of using the ischial tuberosity line (ITL) as the caudal margin of treatment portals for prostate carcinoma. The distances of the external urethral sphincter and the lowest margin of the opacified urinary bladder were analyzed in one hundred fifteen consecutive urethrograms. None showed the urethral sphincter to be caudal to the ITL. Ten percent of the sphincters were located less than 1.0 cm cephalad to the ITL, yielding inadequate treatment coverage if the ITL was relied on. Arbitrarily considering 2.0 cm or more of the urethral irradiation to be excessive, the use of the ITL would then have resulted in unnecessary normal tissue irradiation of 42.5%. The ITL should not be used as the caudal margin for prostate treatment portals. Variation in sphincter position, as also seen on lateral projections, reveal a need for urethrography as a necessary supplement to computed tomography to plan radiation portals for prostate cancer. PMID- 8693102 TI - Reproducibility of conformal radiation therapy in localized carcinoma of the prostate without rigid immobilization. AB - The reproducibility of 3-dimensional (3D) conformal therapy in localized prostate cancer was studied in 14 patients, based on retrospective analysis of 196 anteroposterior-posteroanterior (AP/PA) and lateral portal images. The patients were treated supine without rigid immobilization using six isocentric coplanar conformal fields. Three different observers independently compared the portal and simulation images, determining the deviation of each portal film from the corresponding simulation film. No significant deviations were observed in the cephalo-caudal or lateral axes (0 mm median values). However, a systematic median shift of 5 mm (0 to + 10, range) was observed in the anteroposterior direction, presumably as a consequence of a sagging in the treatment couch under the patient's weight. After modification of the treatment couch, no further systematic anteroposterior shifts have been observed. These results demonstrate that the daily setup of conformal prostate irradiation fields can be performed with acceptable reproducibility without the use of special immobilization devices. PMID- 8693103 TI - How can the co-ordinate transformation method of beam matching be extended to include separately labelled collimators? AB - The problem of matching radiation beams was tackled by Siddon in 1980 using co ordinate transformations. Since then, the need to distinguish between individual collimators in prescriptions of treatment set-up, brought about by the widespread use of 3-D treatment planning systems and asymmetric fields, as well as a reversal of the rotation sense in the turntable co-ordinate system proposed by the International Electrotechnical Commission, have made it necessary to revisit this particular problem. This paper builds upon Siddon's general equations for the particular case of matching beams, and derives expressions for calculating treatment-unit settings which may be used in a computer program without the need to perform matrix manipulation. The expression treat the individual collimator jaws separately. PMID- 8693105 TI - Increasing the work speed of radiographers: the effect on the accuracy of a set up of a complex shaped cranial field, part of a matched cranio spinal junction. AB - Simulator port films of 22 set-ups of a complex cranial field positioned by radiographers working either at normal or at increased pace were compared with a control film. Analysis showed that accuracy decreased for set-ups achieved at an increased speed, demonstrating risks to treatment outcomes incurred by increasing working speed to meet workload demands. PMID- 8693104 TI - Matching wedge field characteristics on different treatment machines. AB - A method is presented for matching wedge field dose distributions on different treatment units, simplifying the transfer of patients between machines during machine failure or scheduled downtime and avoiding the need for a full re-plan in most cases. Differences in wedge field characteristics between machines are accounted for and differences in energy are easily accommodated. PMID- 8693106 TI - Calibration of semiconductor detectors for dose assessment in total body irradiation. AB - The aim of this paper is to discuss the measurements carried out to implement 'in vivo dosimetry' with EDP-30 diodes in total body irradiation (TBI) techniques. Exit calibrations and calibrations behind cerrobend protection blocks showed the importance of calibrating diodes in all relevant clinical conditions. Special attention was given to calibration of diodes behind cerrobend blocks. Dependence of the calibration factors on the thickness of the shielding blocks was, therefore, studied. This dependence was again studied after adding a wax cap to the diode and when the ionisation chamber was placed at the same depth as the measuring point of the diode. Temperature dependence in diode sensitivity and dependence on accumulated dose for diodes response and for temperature correction factors were also examined. PMID- 8693107 TI - Total body irradiation with translation method. AB - Total body irradiation (TBI) using translation method has been applied in 20 patients prior to bone marrow transplantation (BMT). This paper describes the technique of irradiation as well as the results of in vivo dosimetry in patients undergoing TBI. According to our experience, the translation technique is comfortable for patient and provides homogeneous dose distribution over the whole body. PMID- 8693108 TI - Late renal function following whole abdominal irradiation. AB - Sixty patients treated with whole abdominal radiotherapy who had remained disease free since completion of treatment participated in a study to assess the late clinical and biochemical effects of bilateral renal irradiation. Minimum follow up was 5 years with a maximum of 20 years and a median of 9 years. Fifty-two patients in the study group were treated for primary ovarian cancer. Seven had non-Hodgkins lymphoma arising in the gastrointestinal tract and one patient had a carcinoid tumour arising in small bowel. None of the patients received chemotherapy. Abdominal radiation was given using an open beam technique to a mean dose of 22.92 Gy (range 6.68-27.54 Gy) in 1.02 to 1.25 Gy fractions treated once daily. Posterior kidney shields were used in order to limit the renal dose to < 20 Gy. Mean radiation dose to both kidneys (retrospectively calculated) was 19.28 Gy (range 6.68-22.99 Gy). Patients ranged in age from 32-81 years with a median of 61 years. No patient had clinical evidence of renal impairment. Nine patients were hypertensive prior to radiotherapy and a further five patients became hypertensive after treatment. Serum creatinine values ranged from 44-123 mumol/l, with a mean of 87 mumol/l. Creatinine clearance ranged from 0.61-2.38 ml/s (mean 1.28 ml/s). Tubular function tests revealed one borderline high 24-h protein excretion and normal 24-h phosphorous and uric acid. Using a multiple linear regression analysis with creatinine clearance as the endpoint, age was the only significant variable (P < 0.00001) and renal dose and interval from treatment were not independently significant. There was no evidence of late renal toxicity more than 5 years after whole abdominal radiotherapy delivered with this technique and dose/fractionation schedule, and using the clinical and biochemical endpoints assessed in this study. PMID- 8693109 TI - Combined teletherapy and intracavitary brachytherapy boost for the treatment of nasopharyngeal carcinoma. AB - For the non-metastatic nasopharyngeal carcinoma, external beam radiation therapy (median dose 64 Gy) and a boost of intracavitary irradiation (ICRT) has been given. Caesium-137 pellets of 40 mCi were used at a dose rate of 3-3.5 Gy/h, 1 cm from the sources. The median dose was 8.5 Gy. Overall 5-year actuarial survival for the 48 studied patients was 60.4% and LRFS was 64%. The procedure was well tolerated by our patients. PMID- 8693110 TI - Estimation of the radiation dose delivered to any point outside the target volume per patient treated with external beam radiotherapy. AB - The methodology we have developed to study dose distribution outside the target volume during external beam radiotherapy allows us to determine the dose received by the patient arising from leakage radiation and scattered radiation from both the head of the treatment machine and from the treatment room. It also allows us to evaluate the dose due to photon scattering in the patient by means of a dedicated 3-D algorithm permitting computations for the whole body of the patient and taking into account height, sex and anatomical data at the time of the treatment, dosimetric data and lung heterogeneity parameters. This methodology offers solid criteria for recommendations concerning radiation protection. PMID- 8693111 TI - [Greetings from the president of the SIRM]. PMID- 8693112 TI - [Radioactivity: its first centennial. Retrospective digression from medicine to history and folklore]. PMID- 8693113 TI - [Fast Spin Echo sequences in neuroradiology: technical features, semiology, and applications]. PMID- 8693114 TI - [The "cardiac lung": radiology correlations with respiratory physiopathology and clinical features]. PMID- 8693115 TI - [Bone callus: possible assessment with color Doppler ultrasonography. Normal bone healing process]. AB - Conventional US demonstrates bone callus dimensions and structure, which permits to monitor the bone healing process. January, 1993, through May, 1995, we examined 108 patients with simple fractures of humerus, femur and tibia; all the fractures had been treated with an external or intramedullary metallic fixator. All the patients were submitted to conventional and color-Doppler US of the fracture focus on all possible scanning planes. We considered morphological parameters (the presence/absence of vessels, their number and shape) and functional parameters (the resistive index and the presence of a telesystolic notch). Color-Doppler US and the spectral analysis allowed us to add functional data, on bone callus and newly formed bone vascularization, to morphological studies. In the patients with positive fracture evolution, the caliber of afferent vessels progressively increased, their number decreased and branches appeared. The RI progressively increased, up to similar values to those of nutrient vessels (.36 to .90). Within the second month of fracture, a telesystolic notch appears: this indicates a muscular tunic in the vessel wall, meaning a mature, and no longer a newly formed, vessel. The normal evolution of bone healing may be interrupted by several mechanical and biohumoral factors which reportedly act in a similar way by reducing the number of vessels and increasing peripheral resistance in residual vessels because of fibrosclerotic involution of bone healing. Color-Doppler US permits noninvasive, repeatable and nearly real-time monitoring of bone fracture healing, which suggests this technique could be used: -to assess the results of treatment changes (e.g., loading, external fixator adjustments); -to study the definitive callus; -for the medicolegal assessment of delayed bone healing and of pseudoarthrosis; -for real time treatment planning, according to color-Doppler findings, and to monitor treatment results. PMID- 8693117 TI - [Dynamic study of the distal radioulnar joint with computerized tomography]. AB - The authors describe a CT technique which allows the dynamic study of the inferior radioulnar joint. The examination consists of 4 CT slices, three of them acquired at the same level-i.e., the radioulnar joint- in the prone, intermediate and supine positions, respectively. The last slice is acquired, with the patient in the prone position, at the base of the styloid process where the triangular fibrocartilage is demonstrated. The distal radioulnar ligaments are not directly visible. Nineteen patients complaining of painfully impaired pronation and supination because of previous trauma (11 Colles fractures, 7 distortions and 1 Galeazzi lesion) were examined with this technique. In all patients, both wrists were studied to obtain normal parameters. The radioulnar joint was evaluated superimposing a draft on the dynamic images, which demonstrated that, in healthy limbs, during movement the ulnar epiphysis is always contained between two parallel lines drawn on the volar and dorsal surfaces of the radial epiphysis, respectively. It was also confirmed that supination is possible up to 110-135 degrees from the support plane. CT demonstrated different causes of impaired movements in the affected joints: in 12 cases some fibrous density tissue was seen at the ulnar epiphysis on the volar aspect and considered to be the evolution of a traumatic hematoma; 6 patients presented dorsal subluxation of the ulna during movement; finally, volar subluxation was detected only in one case. In 6 patients the triangular fibrocartilage was detached; in 1 patient an intraarticular fluid collection was demonstrated. In 3 patients CT detected no abnormalities. The fibrous tissue is responsible for impaired movements and causes the detached triangular fibrocartilage to shrink. The authors believe that this simple CT technique can yield useful pieces of information for accurate surgical planning. PMID- 8693116 TI - [Biomechanical changes in and lesions of the lumbosacral spine in horse riding. Magnetic resonance assessment]. AB - Spinal injuries account for 5-15% of sport-related traumas. Equestrian sports are considered, together with rugby, motor sport and diving, the riskiest sport for severe spinal injuries. We investigated the biomechanical changes and repeated microtraumas in equitation. We examined with MR the lumbar spines of 12 professional horsewomen and horsemen, 18-51 years old (mean: 33.4 years), belonging to F.I.S.E. (the Italian Federation for Equestrian Sports) and classified as Olympic riders, Senior and Young European riders. An 0.3-T resistive and an 0.2-T permanent magnets with dedicated surface coils were used. We also examined a control group of non-professional healthy volunteers homogeneous by age. MR findings were classified as follows: 1) changes in normal bending and angles of the lumbar spine; 2) injuries and changes in lumbar disks; 3) changes in spinal ligaments; 4) vertebral body injuries. MR was very sensitive in the assessment of all lumbosacral components in all the athletes; besides yielding useful findings to integrate with clinical results, MR also has a predictive value relative to both the continuation of sports activity and the possible damage at the end of it. PMID- 8693118 TI - [Calcaneal fractures: guidelines for the diagnosis with computerized tomography]. AB - We report on 31 cases of calcaneal fractures studied with CT according to the latest classification by the Italian Surgical Society of the Foot. Of the utmost importance is the radiologic assessment of the posterior facet and of the underlying bone, which make up the so-called talamus which bears most of the body weight. In our series, talamus fractures were the most frequent ones (26/31 cases): they are characterized by a main sagittal line, running obliquely and dividing the posterior surface and the bone into an anteromedial, or substentacular, fragment and a posterolateral, or tuberosity, fragment. According to fracture severity, the first differential criterion is the presence/absence of displacement and depression (type I fractures the latter, 6 cases in our series, and (types II and III the former, 20/26 cases in our series). Based on the degree of displacement and depression, fractures as classified as type II (10/26 cases) when only the lateral portion of the talamus is displaced and depressed, or as type III (10/26 cases) when the whole talamus is fragmented, displaced and depressed. Moreover, other worsening factors must be considered and B subgroups differentiated in types II and III fractures; these factors are: calcaneus-cuboid facet involvement, lateral wall fragmentation, posterior facet comminution, a small sustentacular fragment and a secondary frontal fracture interrupting the plantar cortex. Extra-talamic fractures, defined as such when isolated, rarely occur. Relative to the anterior apophysis, radiologic attention must be focused on fractures of the dorsal prominence, or beak, which are very often misdiagnosed. As regards the posterior tuberosity, its lateral dislocation must be studied because it may account for calcaneofibular impingement. CT exhibits excellent potentials, provided that slices are thin, acquired on the axial and coronal planes and that, as far as possible, sagittal reconstructions are used, the latter being very useful to depict talamic surface. PMID- 8693119 TI - [Occult post-traumatic osteochondral changes in the knee. Assessment with magnetic resonance]. AB - Occult posttraumatic osteochondral injuries of the knee are bone and/or cartilage abnormalities which cannot be detected on plain radiographs. This study was aimed at investigating MR capabilities in the detection and characterization of occult bone and/or cartilage injuries in symptomatic patients with previous musculoskeletal trauma of the knee. We retrospectively selected 60 patients (45 men and 15 women; mean age: 33.1 +/- 16.3 years; range: 12-70 years) from our patients submitted to MRI of the knee during a 3-year period. These patients had a history of previous acute musculoskeletal trauma, negative conventional radiographs and MR signal intensity changes of the osteochondral structures. MR protocol included: SE T1-, PD and T2-weighted images and GRE T2-weighted images; imaging planes were the sagittal, the axial and the coronal planes. Plain radiographs and MR images were interpreted by three experienced readers in musculoskeletal radiology. Our reviewers confirmed normal conventional radiographic findings in all the patients enrolled in the study. According to morpho-topographic and signal intensity patterns, we identified three types of occult posttraumatic injuries: bone contusions or bone bruises or occult subcortical fractures (n 30), osteochondral injuries (n 26) and chondral injuries (n 4). A bone contusion was defined as a typical subcortical area of signal loss, with various shapes, on T1-weighted images and increased signal intensity on T2 weighted images. The cortical bone and articular cartilage below were normal in all cases. On the contrary, osteochondral lesions presented an association of cartilage and bone injuries with the same M(R) signal abnormalities. Thinning and focal interruptions of the cortical bone were demonstrated in all cases. Chondral lesions were characterized by a sudden discontinuity and irregularity of cortical bone outline and by small high-intensity spots in cartilage thickness on T2 weighted images, in the absence of any subchondral bone abnormality. Finally, 42 of 60 patients (70%) had an anterior cruciate ligament tear and 28 (45%) had a medial meniscus tear. In conclusion, MRI appears a very useful tool in the detection and characterization of the different types of occult bone and/or cartilage injuries of the knee in the patients with previous acute trauma. Moreover, the correct and early diagnosis of an osteochondral lesion does affect prognosis. PMID- 8693120 TI - [Magnetic resonance imaging in tendon and ligament injuries of the ankle. Our personal experience]. AB - While Magnetic Resonance Imaging (MRI) has become a routine diagnostic method in knee studies, little has been published about ankle injuries. This is probably due to the anatomic complexity of the bone and ligament structures of this joint. Our study was aimed at assessing the yield of MRI of the ankle with a cost effective, compact, low-field (0.2 T) M(R) system (Artoscan, Esaote). January, 1994, to August, 1995, 148 ankle examinations were carried out in a series of patients whose age ranged 7 to 75 years. In 56.7% of cases the exam was performed because of acute joint strain and in 43.3% for pain and chronic ankle instability. In 16.2% of cases the exam was negative; in 41.2% osteochondral injuries were found (which are not considered in this paper) and in 62.1% of cases ligament and tendon injuries were demonstrated. As for the latter, 46 patients had anterior talofibular rupture, 3 associated anterior talofibular and calcaneofibular ligament injuries, 9 tenosynovitis of extensor or flexor tendons, 2 tendon rupture and 17 Achilles tendon conditions (10 chronic tendinitis, 2 bone metaplasia and 5 tendon rupture cases). Three tarsal tunnel syndromes and 3 accessory soleus muscles were also observed. Surgical correlation was available only in 17 patients; after radiography and MRI, the vast majority of patients was treated nonoperatively. Nevertheless, a good correlation was demonstrated between M(R) and intraoperative findings or clinical and US findings. The authors believe that low-field MRI can be a very useful diagnostic tool in the study of ankle tendon injuries and to assess the severity of ligament injuries, for better treatment planning. PMID- 8693121 TI - [Clinico-radiologic correlations in common neck pain]. AB - Patients with spontaneous neck pain, headache, dizziness and/or pain to the upper limbs are frequently observed. Common cervicodynia, due to the involvement of arthromuscular structures of the cervical spine, was diagnosed in the patients with these symptoms in the absence of trauma or neurologic signs. The authors investigated the clinical-radiologic correlation in a series of 130 symptomatic patients and considered it a metameric disorder. The frequent association of many radiographic signs at the same level often prevents single radiographic signs from being assessed individually; therefore, the authors selected some patients with just one radiographic change per functional unit, to assess its relationship with clinical symptoms. The patients underwent anteroposterior, lateral and functional (flexion-extension) radiographs of the cervical spine. Vertebral rotation, detected on antero-posterior views as a spinous process deviation, was the most frequent isolated sign (79/130 cases) per metameric level, with strong clinical correlation (70/79 cases). Vertebral rotation was probably due to unilateral muscular stiffness. Other single radiologic signs per functional unit with strong clinical correlation follow: atloaxial rotation (13/130 with clinical radiologic agreement of 12/13), functional blockage (13/130 with clinical radiologic agreement of 11/13), angular flexion (21/130 with clinical-radiologic agreement of 19/21) and overall disc space thinning (12/130 with clinical radiologic agreement of 10/12). Atloaxial rotation is represented as an asymmetry of the spaces between the odontoid and the lateral masses of the atlas; functional blockage consists of insufficient or lacking physiological width of the occipito-atlantoid or interspinous space in functional tests. Angular flexion consists of a single flexion angle of the cervical spine in functional tests; two or more angles indicate normal flexion of the cervical spine. This study confirmed the poorer clinical impact of degenerative changes, mostly interapophyseal arthrosis, than of other radiologic signs. Interapophyseal arthrosis alone was isolated in single functional units in 46/130 patients, mostly at C7-D1, with clinical-radiologic agreement in 19/46 patients. Clinical radiologic correlation proved the high diagnostic value of anteroposterior, lateral and functional radiographs of the cervical spine in common cervicodynia, which make them a valuable tool for the clinician. PMID- 8693122 TI - [Power Doppler in breast diseases: preliminary results]. AB - Since 1993, a new technique called power Doppler or color Doppler energy, based on Doppler signals, has been used to study the vascularization of various organs. Since power Doppler appears to permit better assessment of slow flow than color Doppler, we used this technique to study the vascularization of breast lesions. Seventy-five patients (age range: 33-81 years, mean: 53 years) were examined: 28 had simple or complex cysts, 4 cysts with internal echoes, 1 fibrocystic disease, 3 nodular fibrocystic disease, 12 fibroadenoma, 3 benign microcalcifications, 10 cancer, 3 scarring, 1 recurrent cancer, 7 axillary nodes; 3 young patients with no breast disease were also examined as a control group. All the patients were examined first with B-mode and then with color power Doppler; both during the exam and later on, in the study of similar sections, power Doppler signals were stronger and, in many cases, more numerous. Particularly, with power Doppler, in similar sections, 1-3 more signals were demonstrated in healthy women and 1-4 more signals in fibroadenomas with rich vascularization and in neoplasms, while in 2 cysts perilesional signals were demonstrated only with power Doppler. Color Doppler semiology of breast lesions was confirmed. Thus, since the signals were stronger with power Doppler, we believe it to be a promising tool in the study of the vascularization of breast lesions which can provide useful diagnostic information as to lesion nature, the results of local treatment and the response to primary medical therapy, as well as in the study of axillary lymph nodes. PMID- 8693123 TI - [Breast scintigraphy with technetium 99m sestamibi, as support to radiologic methods in the study of breast lesions]. AB - Our study was aimed at investigating the efficacy of scintigraphy with 99mTc Sestamibi (MIBI) as a support to mammography and US in the diagnosis and staging of breast cancer. Twenty-seven women with breast lesions were examined: the masses, detected at mammography and US, ranged in diameter 0.7 to 2.5 cm; mass features suggested a benign lesion in 5 patients, a malignant lesion in 9 patients and a questionable diagnosis in 13 patients. 99mTc-MIBI scintigraphic images were analyzed blind by two observers and the pattern was considered positive when tracer uptake was demonstrated at the lesion. In neoplastic lesions, tracer uptake was looked for also in the axilla. All the patients were submitted to surgery and, in case of malignancy, lymphadenectomy was also performed. MIBI scintigraphy was negative in 14/16 benign lesions and positive in 9/11 malignant lesions. Tracer uptake in the axilla was observed in 3 of 5 patients with nodal involvement. Scintigraphy had 82% sensitivity, 87% specificity and 85% accuracy in the diagnosis of breast cancers. PMID- 8693124 TI - [Diagnostic imaging of phyllodes tumors: preliminary observations]. AB - Phyllodes tumors are rare fibro-epithelial neoplasms; they may be classified as benign, borderline and malignant according to their histologic features of mitotic index, stroma pleomorphism and lesion outline. Their epidemiology is rather different from that of other breast neoplasms, since these lesions most frequently affect white Latin women 45 to 49 years old. The incidence of metastases is strictly correlated with the degree of histologic aggressiveness, although even small lesions, either borderline or with low malignancy, may metastasize. To assess the incidence of this neoplasm and its metastases and to investigate the role of diagnostic imaging, we retrospectively reviewed 8000 mammograms, 2000 sonograms, 1000 color-Doppler sonograms and 4500 CT scans of the chest; 7 phyllodes tumors and 2 metastases were detected. This neoplasm showed no specific characteristics either at mammography or at sonography, whereas rich neovascularization with venous flow and low resistance arterial flow were shown at color-Doppler US. Secondary lesions, first diagnosed at radiography and then studied with CT for number, size and lymph node involvement were: a large solitary mass with no involvement of mediastinal nodes, which was observed 36 months after surgical ablation of the primary lesion and multiple small lesions, involving both lungs, with no mediastinal metastases, diagnosed 42 months after surgical removal of the primary lesion. In both cases the primary neoplasm was histologically classified as borderline and responded to adjuvant therapy. Therefore, our work confirms the polymorphic nature of this condition which is rather difficult to diagnose and whose prognosis is unpredictable. However, even though color-Doppler US may open new diagnostic perspectives, the reliability of conventional radiography and CT in the follow-up of these lesions is nowadays a matter of fact. In our opinion, every case should be followed-up, regardless of the histologic classification of the primary tumor. PMID- 8693125 TI - [Computerized tomography in the surgical planning of supraglottic carcinoma: analysis of cost-effectiveness in 69 patients]. AB - This study was aimed at investigating the role of CT in the surgical planning (partial vs. total laryngectomy) of supraglottic laryngeal carcinoma. Sixty-nine patients affected with supraglottic cancers were reviewed to assess the accuracy and the clinical role of CT and laryngoscopy. The detection rates of tumor spread to the glottis, to thyroid and arytenoid cartilages, pyriform sinus and base of the tongue were compared and correlated with surgical and pathologic data. Thirty one patients underwent supraglottic laryngectomy and 38 had total laryngectomy. Endoscopy correctly assessed the glottis in 54/69 patients (78.2%) and CT in 52/69 (75.3%). The two techniques were in agreement in 47/69 patients: 42/47 (89.4%) had a correct diagnosis. Sensitivity, specificity, accuracy, positive and negative predictive values in assessing neoplastic invasion at the glottic level were, respectively, 68.4%, 90.3%, 78.2%, 89.6%, 94.1% and 86.6% when endoscopy and CT were in agreement. In deciding the feasibility of supraglottic laryngectomy, the results of endoscopy alone did not differ significantly from those of CT and endoscopy in agreement (X2 = 3.255, p > 0.05), whereas the negative predictive value of CT was significantly lower than that of the two techniques in agreement (X2 = 4.55, 0.05 > p > 0.025). In our experience, CT did not significantly change the surgical treatment planned on the basis of endoscopic findings. Therefore, when assessing the feasibility of partial laryngectomy for supraglottic carcinoma, CT cannot be considered a cost-effective tool. Nine of 33 (27.2%) patients treated with total laryngectomy had local recurrences at the hypopharynx, probably because the primary tumor was underestimated at both preoperative staging and during surgery. PMID- 8693126 TI - [Diagnostic impact of ultrasonography in abdominal diseases]. AB - The diagnostic accuracy of conventional radiography and ultrasound (US) in patients with acute or chronic abdominal pain was investigated by the authors in two prospective studies to assess the capabilities of the two imaging techniques. 262 patients (135 men and 127 women, age range: 25-83 years) were entered into the study within 8 months. The patients were divided into different groups according to clinical presentation (80 patients with acute and 182 with chronic pain) and to the referring physician (a hospital clinician for 127 patients and a general practitioner for 135 patients). For each technique the presence (positive result) or the absence (negative result) of abnormal imaging features related to clinical symptoms was recorded and the agreement of conventional radiography and US findings was assessed. Statistical analysis showed similar sensitivity of conventional radiography and US in the examination of acute hospitalized patients (54.3% positive results), chronic hospitalized patients (28.1% negative results) and chronic nonhospitalized patients (47.2% negative results). The results of our prospective studies showed poor diagnostic accuracy of the two techniques and clearly evidenced the improper use of diagnostic imaging methods by referring physicians, with a technical-oriented attitude in imaging examination requests. In the authors' opinion, a clinical-based approach by referring physicians with accurate patient selection might improve diagnostic accuracy, the cost/benefit ratio and the clinical effectiveness of imaging techniques. PMID- 8693127 TI - [Computerized tomography and magnetic resonance in the diagnosis of recurrent rectal neoplasms: comparison of reliability and errors of both methods]. AB - Our work was aimed at assessing the accuracy of CT and MRI in the early identification of postoperative recurrences of rectosigmoid cancer, quantifying false positive and false negative ratios and questionable findings. A homogeneous series of 50 patients submitted to surgery for primary rectosigmoid carcinoma was studied with both CT and MRI and followed-up for up to 2 years: local recurrences were observed in 15 patients (30%) which occurred within the first year of surgery in 67% of cases and were in extraluminal site in 86% of cases. CT appeared to be a reliable and highly sensitive screening method, with 82% sensitivity: only 2 false negatives were observed, which were nevertheless followed-up because CT had yielded questionable, and not negative, findings. In contrast, CT had only 78% specificity, being unable to differentiate fibrosis, displaced normal structures and recurrences in 7 cases; its positive predictive value (PPV) was 66%, with 89% negative predictive value (NPV) and 80% accuracy. MRI had a complementary role to CT, because of its capabilities in discriminating all the questionable CT cases and in identifying all CT false positives, thanks to its higher specificity (100%). MRI had 74% sensitivity, which was lower than that of CT; MRI yielded 2 false negatives which, however, had been previously diagnosed with CT. MRI had 100% PPV, 89% NPV and 92% accuracy. Therefore, for the early detection of rectal cancer recurrences, the following diagnostic protocol is suggested: CT should be performed first, as a screening method, within 2-4 months of surgery, and repeated every 6-8 months during the first 2 years together with CEA values monitoring. MRI should be reserved to the patients in whom CT findings were positive, questionable, or in disagreement with clinical symptoms and/or with increasing CEA values. If MRI fails to solve the diagnostic doubt, a CT-guided biopsy of the mass should be performed. PMID- 8693128 TI - [Single-contrast enema after colon lavage in the elderly patient]. AB - Double-contrast enema is often unsuccessful in elderly patients because of their poor cooperation and colon cleaning. This work was aimed at showing that a well done single-contrast exam with simple colon lavage can make a very good alternative to double-contrast enema in elderly patients. Thus, 66 consecutive elderly patients (age range: 70-90 years) were submitted, over a 6-month period (June-December, 1994), to single-contrast enema, after colon cleaning with oral whole-gut lavage, using an osmotically balanced electrolyte solution (Isocolan, Bracco) containing polyethylenglycol (PEG 4000). We examined, in each patient: a) the tolerance to and effectiveness of bowel cleaning, according to the liquid volume drunk by each subject, needed to obtain clear diarrhea; b) radiograph quality. Successful colon cleaning was achieved with a mean (2.5-3 liters) and a large (3.5-4 liters) amount of solution, in 80% and 20% of our patients, respectively. Tolerance was good in the whole series except for 3 patients with emesis. Moreover, radiograph quality was good in 85% of the subjects. Finally, barium enema results, compared with endoscopic results, yielded 27 true positives, 3 false negatives (small neoplastic lesions) and 1 false positive. Therefore, in our opinion, these results confirm the role of single-contrast enema, combined with gut lavage, in elderly patients. PMID- 8693129 TI - [Usefulness of color echo Doppler with power Doppler in the diagnosis of hypoechoic thyroid nodules: work in progress]. AB - The aim of this study was twofold: first, to improve the predictive value of ultrasonography (US) in differentiating benign from malignant thyroid nodules and, second, to investigate whether color Doppler and power Doppler can distinguish different morpho-hemodynamic patterns of hypoechoic thyroid nodules according to their vascularity. Twenty-nine patients with hypoechoic thyroid nodule(s) were entered into this work in progress. Three typical power Doppler patterns were recorded and compared with color Doppler patterns and with cytologic and/or histologic findings. Power Doppler patterns were classified as follows: type A, a perilesional vascular halo; type B, a peri- and intralesional vascular halo, subdivided into: 1) with moderate intralesional vascularization, homogeneous structure and regular vessel caliber and 2) with rich intralesional vascularization, anarchical structure and winding vessel caliber and flow; type C, a perilesional vascular halo with a characteristic peripheral large afferent vessel characterized by winding caliber and flow. Of 29 patients, 21 had type A power Doppler (benign nodular goiter at cytology, in 4 of them with regressive phenomena); seven patients had type B power Doppler patterns-4 had a subtype 1 pattern (3 with nodular hyperplasias and 1 with a papillary adenoma), 3 had a subtype 2 (two had a follicular adenoma and one had a final diagnosis of angioinvasive follicular carcinoma). The patient with undifferentiated carcinoma had a type C power Doppler pattern. In conclusion, according to our early results, PD seems to be more sensitive and reliable than CD in the screening of thyroid nodules, and to yield better vascular information. PMID- 8693130 TI - [Implementation of a server World Wide Web of radiology accessible by Internet]. AB - Internet is an international computer network that uses standard communication protocols for the exchange of information. This facilitates the retrieval of multimedia data through a "web" of servers distributed in the whole world. Among Internet users, Radiologists are a potentially important segment, due to the inherent multimedia characteristics of the discipline, which requires a continuous international update of information. The Department of Radiology of the University of Pisa has an Internet access through the metropolitan area network which was installed in the framework of the CNR Telecomunicazioni Project. The Internet access allowed the implementation of a World Wide Web server made public on Internet in March, 1994, being the first European server specifically oriented to radiology. This server can be accessed at the following address: http:@www.rad.unipi.it:7080/IRMosaicHome.html . On the server, 3 hypermedia papers are present, a list of international servers containing radiological information, a questionnaire, and statistics concerning the number of users who accessed the server. In the first 18 months of public access through Internet (April 1, 1994-September 30, 1995) 16,166 users accessed the server, retrieving 127,349 documents, corresponding to 1,279.7 MByte of information. The mean amount of information retrieved in each access to the server in the considered quarters ranges from 72 to 85.8 kByte. The geographic distribution of the users who accessed the server is the following: United States, 7,158, Italy, 2,466; other European countries, 3,813; other extra-European countries, 2,729. The increasingly diffuse knowledge of Internet services had a substantial impact on the rise in number of the servers and of the users who can access them. It is likely that in the future this technology will be used with increasing interest by Radiologists, since it provides easier "navigation" through multimedia information, consisting of text and several images, without the inherent limitations of the printed paper. PMID- 8693131 TI - [Locally advanced carcinoma of the cervix uteri (stage IIB-IIIB TNM-UICC): radiotherapy combined with simultaneous daily low-dose platinum. Phase II study]. AB - A prospective, single arm, phase-II trial was performed to assess the efficacy and local toxicity of the combination of low doses of platin and pelvic radiotherapy in patients with locally advanced carcinoma of the cervix. January, 1993, through August, 1994, twenty-three previously untreated patients with squamous carcinoma (stages IIB-IIIB UICC) entered the study. All patients were examined by a gynecologist and by a radiation oncologist and then submitted to conventional pretreatment staging procedures. Nine patients were classified as stage IIB and 14 patients as stage IIIB. Radiotherapy consisted of 60 Gy external beam irradiation (46 Gy to pelvis + 14 Gy boost to cervix uteri and parametria) plus one low dose rate intracavitary treatment to a dose of 8 Gy to point A. Cisplatin (3 mg/m2/day) or carboplatin (12 mg/m2/day) was also given for 6 weeks starting on radiotherapy day 1. The treatment was well tolerated and no patient required radiotherapy discontinuation. With a median follow-up time of 20 months, complete response was seen in 74% (17/23) of the patients. One of the 17 patients who achieved a complete remission, during follow-up, relapsed in the pelvis and one developed lung metastases. Total failure rate in the pelvis was 30.5% (7/23). Distant metastases were observed in 17.5% (4/23) of the patients. Actuarial overall and disease-free survival rates at 33 months were 69.1% and 65.2%, respectively. Late gastrointestinal toxicity (grade 3) occurred in 8.6% (2/23) of patients, with one patient developing a rectal ulcer-which was submitted to colostomy- and one patient a vaginal necrosis. The combination of platin and radiotherapy appears to be an effective regimen for the patients with locally advanced carcinoma of the cervix and caused a relatively low rate of late gastrointestinal complications. PMID- 8693132 TI - [Palliative intraluminal brachytherapy of tumors of the extrahepatic biliary tract. Experience with a new naso-biliary catheter]. PMID- 8693133 TI - [Development of a software for estimating skeletal age based on the TW2 method]. PMID- 8693134 TI - [A computer software for assessing single critical organ doses in conventional radiodiagnostic studies in accordance with articles 111 and 114 of the legislative decree of March 17, 1995, n. 230]. PMID- 8693135 TI - [Osteosclerotic myeloma. Report of a case]. PMID- 8693136 TI - [Mesenteric panniculitis: computerized tomography features. Report of 5 cases]. PMID- 8693137 TI - [Radiologic assessment of Boerhaave's syndrome: report of a case]. PMID- 8693138 TI - [A case of pyloric stenosis diagnosed at the time of ileo-colic intussusception]. PMID- 8693139 TI - [Ultrasonography and computerized tomography findings in a case of enterolith in Meckel's diverticulum]. PMID- 8693141 TI - [Computed tomography assessment of Spigelian hernia. Report of 2 cases]. PMID- 8693140 TI - [A rare case of leiomyosarcoma of the jejunum and review of the literature]. PMID- 8693142 TI - [Epidermoid carcinoma of the gallbladder. Report of a rare case]. PMID- 8693143 TI - [Role of computerized tomography (CT) in the diagnosis and treatment of primary lymphoma of the cervix uteri: report of 2 cases]. PMID- 8693144 TI - [A case of ischemic stenosis of the colon-sigmoid treated with self-expandable uncoated metallic prosthesis]. PMID- 8693145 TI - [Policy of the Health Ministry on anti-retroviral therapy]. PMID- 8693146 TI - [Treatment of bacterial infections in patients with AIDS]. PMID- 8693147 TI - [Treatment of fungal infections in patients with AIDS]. PMID- 8693148 TI - [Opportunistic viral infections]. PMID- 8693149 TI - [Opportunistic protozoal infections]. PMID- 8693150 TI - Experience with stavudine (D4T). PMID- 8693152 TI - Antiretroviral therapy in the future. PMID- 8693151 TI - [Anti-retroviral monotherapy with nucleoside analogues]. PMID- 8693153 TI - [Resistance and combined use of anti-HIV drugs]. PMID- 8693154 TI - Epidemiology, risk assessment, and public policy: restoring epistemic warrants. PMID- 8693155 TI - Comment on "An approach for balancing health and ecological risks at hazardous waste sites". PMID- 8693156 TI - Response to Dr. Barry's article on Environmental tobacco smoke/regarding Mr. Wilson's letter. PMID- 8693157 TI - Using time intervals between expected events to communicate risk magnitudes. AB - Because members of the public have difficulty understanding risk presented in terms of odds ratios (e.g. 1 in 1000) and in comparing odds ratios from different hazards, we examined the use of time intervals between expected harmful events to communicate risk. Perceptions of the risk from a hypothetical instance of naturally-occurring, cancer-causing arsenic in drinking water supplies was examined with a sample of 705 homeowners. The risk was described as either 1 in 1000 or 1 in 100,000 and as present in a town of 2000 people or a city of 200,000 people. With these parameters, the time intervals ranged from 1 expected death in 3500 years (1 in 100,000 risk, small town) to 1 death every 4 months (1 in 1000 risk, city). The addition of time intervals to the odds ratios significantly decreased perceived threat and perceived need for action in the small town but did not affect response for the city. These framing effects were nearly as large as a 100-fold difference in actual risk. Instances when this communication approach may be useful are discussed. PMID- 8693158 TI - On-site storage of high level nuclear waste: attitudes and perceptions of local residents. AB - No public policy issue has been as difficult as high-level nuclear waste. Debates continue regarding Yucca Mountain as a disposal site, and-more generally-the appropriateness of geologic disposal and the need to act quickly. Previous research has focused on possible social, political, and economic consequences of a facility in Nevada. Impacts have been predicted to be potentially large and to emanate mainly from stigmatization of the region due to increased perceptions of risk. Analogous impacts from leaving waste at power plants have been either ignored or assumed to be negligible. This paper presents survey results on attitudes of residents in three counties where nuclear waste is currently stored. Topics include perceived risk, knowledge of nuclear waste and radiation, and impacts on jobs, tourism, and housing values from leaving waste on site. Results are similar to what has been reported for Nevada; the public is concerned about possible adverse effects from on-site storage of waste. PMID- 8693159 TI - Small parts aspiration, ingestion, and choking in small children: findings of the small parts research project. AB - Obtaining information on current child injury trends and their associated issues is an important factor in developing products that meet or surpass acceptable toy safety boundaries. Understanding these boundaries helps determine safe product design characteristics that reduce the risk of product-related injury. Inchcape Testing Services developed a Small Parts Aspiration, Ingestion, and Choking Hazards Research Project, independent of an ongoing consumer Product Safety Commission (CPSC) project. The project's purpose was to determine, independent of CPSC, whether a more stringent small parts regulatory standard was necessary and, if so, to ensure that the standard was determined objectively. This article reports on the project's findings relating to critical characteristics (size, shape, and consistency) relative to the victim's age, of objects responsible for child choking injuries and fatalities. PMID- 8693160 TI - A general model for exposure and uptake from consumer products. AB - To assess exposure to and uptake of chemical compounds from consumer products, a general model framework is proposed. The model framework separates exposure into the components contact, potential exposure, and potential uptake rate, and establishes the relation between the three. It adds a contact function and a spatial component to other exposure modeling concepts. Before the model framework can be used, its components need to be specified. A simple diffusional model is built as an example of specifying functions for exposure and uptake. A case study of 1,1,1 trichloroethane in some shoe impregnating product, partly based on the diffusional uptake model, illustrates the inclusion of the contact component. In the latter example, the exposure is calculated for the user and then, by only modifying the contact component, for a nonuser randomly walking in the house. PMID- 8693161 TI - Systemic uptake and clearance of chloroform by hairless rats following dermal exposure. I. Brief exposure to aqueous solutions. AB - The systemic uptake of chloroform from dilute aqueous solutions into live hairless rats under conditions simulating dermal environmental exposure was studied. Whole blood was sampled during a 30-min immersion of an animal within water containing a known concentration of chloroform and then for 5.5 h following its removal from the bath. The amount of chloroform systemically absorbed was determined by comparing the AUCs of the blood concentration vs. time plots from dermal exposure to that obtained after i.v. infusion (for a period of 30 min) of an aqueous solution containing a known amount of chloroform (positive control). Although dermal data implied two-compartment disposition characteristics, i.v. infusion data fit best to a three-compartment disposition. Linear pharmacokinetics was observed both by i.v. administration and percutaneous absorption at the dose levels studied. Chloroform was detected in the rat blood as early as 4 min following exposure. Our findings suggest that about 10.2 mg of chloroform was systemically absorbed after dermal exposure of a rat to an aqueous solution of 0.44 mg/ml. This amount is substantially higher than the predictions of mathematical risk-models put forth by some investigators. However, when expressed as the "effective" permeability coefficient (Kpeff), close agreement was noticed between our value and those estimated by others using physiologically based pharmacokinetic (PBPK) models. Also, in terms of Kpeff, reasonable agreement existed between our and another investigator's past estimates of uptake based on depletion of bath level of chloroform and the actual uptake measured in our current experiments. The estimated onset of systemic entry seen here is entirely consistent with our estimate of how long it takes to establish the diffusion gradient across the stratum corneum based on tape stripping. PMID- 8693162 TI - The effects of exposure to "synthetic" chemicals on human health: a review. AB - This article examines how scientists use human, animal, and bacterial evidence to develop policy recommendations about the health consequences of human exposure to modern chemicals. Human evidence is limited because many epidemiological studies are contaminated with selection effects or unobserved heterogeneity. Changes in the aggregate incidence of morbidity (such as cancer) in the population over time are not a substitute for the lack of good individual-level data because incidence data are contaminated by the medicalization of cancer. Animal tests are also problematic because the expense of conducting experiments leads researchers to use only enough animals to allow detection of large differences in cancer incidence between controls and experimental animals that can only arise if the exposure doses are large. Predictions about the cancer incidence that would result in humans at much lower exposure levels, thus, require statistical inferences that implicitly make choices between false positive and false negative inference errors. Policy recommendations about carcinogens, therefore, are as much the product of value choices as "scientific" knowledge. PMID- 8693163 TI - Uncertainties in the link between global climate change and predicted health risks from pollution: hexachlorobenzene (HCB) case study using a fugacity model. AB - Industrial societies have altered the earth's environment in ways that could have important, longterm ecological, economic, and health implications. In this paper, we examine the extent to which uncertainty about global climate change could impact the precision of predictions of secondary outcomes such as health impacts of pollution. Using a model that links global climate change with predictions of chemical exposure and human health risk in the Western region of the United States of America (U.S.), we define parameter variabilities and uncertainties and we characterize the resulting outcome variance. As a case study, we consider the public health consequences from releases of hexachlorobenzene (HCB), a ubiquitous multimedia pollutant. By constructing a matrix that links global environmental change both directly and indirectly to potential human-health effects attributable to HCB released into air, soil, and water, we define critical parameter variances in the health risk estimation process. We employ a combined uncertainty/sensitivity analysis to investigate how HCB releases are affected by increasing atmospheric temperature and the accompanying climate alterations that are anticipated. We examine how such uncertainty impacts both the expected magnitude and calculational precision of potential human exposures and health effects. This assessment reveals that uncertain temperature increases of up to 5 degrees C have little impact on either the magnitude or precision of the public health consequences estimated under existing climate variations for HCB released into air and water in the Western region of the U.S. PMID- 8693164 TI - A simple upper limit for the sum of the risks of the components in a mixture. AB - Natural or manufactured products may contain mixtures of carcinogens and the human environment certainly contains mixtures of carcinogens. Various authors have shown that the total risk of a mixture can be approximated by the sum of the risks of the individual components under a variety of conditions at low doses. Under these conditions, summing the individual estimated upper bound risks, as currently often done, is too conservative because it is unlikely that all risks for a mixture are at their maximum levels simultaneously. In the absence of synergism, a simple procedure is proposed for estimating a more appropriate upper bound of the additive risks for a mixture of carcinogens. These simple limits also apply to noncancer endpoints when the risks of the components are approximately additive. PMID- 8693165 TI - A simulation study of the influence of study design on the estimation of benchmark doses for developmental toxicity. AB - The benchmark dose (BMD)4 approach is emerging as replacement to determination of the No Observed Adverse Effect Level (NOAEL) in noncancer risk assessment. This possibility raises the issue as to whether current study designs for endpoints such as developmental toxicity, optimized for detecting pair wise comparisons, could be improved for the purpose of calculating BMDs. In this paper, we examine various aspects of study design (number of dose groups, dose spacing, dose placement, and sample size per dose group) on BMDs for two endpoints of developmental toxicity (the incidence of abnormalities and of reduced fetal weight). Design performance was judged by the mean-squared error (reflective of the variance and bias) of the maximum likelihood estimate (MLE) from the log logistic model of the 5% added risk level (the likely target risk for a benchmark calculation), as well as by the length of its 95% confidence interval (the lower value of which is the (BMD). We found that of the designs evaluated, the best results were obtained when two dose levels had response rates above the background level, one of which was near the ED05, were present. This situation is more likely to occur with more, rather than fewer dose levels per experiment. In this instance, there was virtually no advantage in increasing the sample size from 10 to 20 litters per dose group. If neither of the two dose groups with response rates above the background level was near the ED05, satisfactory results were also obtained, but the BMDs tended to be more conservative (i.e., lower). If only one dose level with a response rate above the background level was present, and it was near the ED05, reasonable results for the MLE and BMD were obtained, but here we observed benefits of larger dose group sizes. The poorest results were obtained when only a single group with an elevated response rate was present, and the response rate was much greater than the ED05. The results indicate that while the benchmark dose approach is readily applicable to the standard study designs and generally observed dose-responses in developmental assays, some minor design modifications would increase the accuracy and precision of the BMD. PMID- 8693166 TI - Citizen perceptions of risks associated with moving radiological waste. AB - Much has been written about public support or opposition to the siting of hazardous waste facilities and more generally about concern for radioactive contamination. Much less has been written about the perceived risks of citizens' specific concerns about the transportation of radiological waste to temporary or permanent sites. This study reviews the existing literature in the area and presents new data on the subject from an Idaho survey. The new data indicates: (1) age, gender, and knowledge are the key variables predicting opposition to the transportation of such waste, (2) the primary concern among the opposing and unsure public is the planned use of trucks to move the TRU waste, and (3) respondents have high degrees of trust in officials who make decisions based on technical knowledge, are charged with the safety of transporting TRU waste, and who respond to mishaps. These attitudes need to be understood by policymakers and administrators when designing and implementing waste-transportation programs. PMID- 8693167 TI - [Ectopic pregnancy: factors related to ovum anomalies?]. AB - Identified risk factors for ectopic pregnancy (prior pelvic inflammatory disease, smoking at the time of conception, intrauterine device, obstetrical and surgical history) explain from 60 to 65% of the cases. Egg anomalies may also be a risk factor as it is likely that the transport of an abnormal egg along the uterine tube is less efficient than a normal one. We tested this hypothesis with data from two case-control studies with the same design covering a total of 1955 women. The risk of ectopic pregnancy increased specifically with age, which is compatible with our hypothesis. We also studied the associations with spontaneous abortion, considered to be a marker of the risk of pregnancies involving chromosomal malformations. We observed an association between ectopic pregnancy and spontaneous abortions (especially recurrent abortions), not explained by other known risk factors. Although our data do not supply a single definitive demonstration, our results converge to suggest that egg chromosomal anomalies may play a part in ectopic pregnancy aetiology. PMID- 8693168 TI - [Estimation of need for obstetrical interventions in Morocco. An approach based on the spatial analysis of deficits]. AB - One of the indicators of health system effectiveness with regard to maternal health is the maternal mortality ratio. Measuring this ratio in developing countries is, however, not an easy task since reliable information on mortality is rarely available. An alternative to the maternal mortality ratio measurement, as an indicator of effectiveness, is the assessment of the coverage of obstetrical intervention needs. The authors chose to restrict the notion of "needs" to the obstetrical interventions carried out in order to save a mother's life. Using data from a survey by the Ministry of Health of the Moroccan Kingdom on all the obstetrical interventions carried out in 1989, obstetrical intervention rates for "absolute maternal indications" are analysed according to the mother's origin, by province and urban/rural environment. The spatial analysis of these rates showed large variations in each of the environments (0 to 2.14 % of the expected births in urban areas and 0 to 1.25 % in rural areas) and a significative difference between the rural and urban distributions (median 0.80 % in urban areas versus 0.30 % in rural areas). Applying a reference rate of 1 %, deficits between the expected numbers of needed obstetrical interventions and the observed numbers were calculated for every province in both urban and rural areas. In the whole of Morocco, intervention rates are markedly below what is expected. The spatial analysis of the deficits helps to identify the provinces where the problem is the most prominent in terms of numbers of women whose intervention needs have to be covered. The authors discuss the validity of the reference rate and suggest several strategies to solve the problem. They conclude that the deficits map is a useful tool to decide on priorities for planning and monitoring of strategies to be implemented. The spatial analysis of obstetrical intervention deficits seems to be an instrument both cheaper and more relevant than a maternal mortality estimates survey. PMID- 8693169 TI - [Level of cardiovascular risk factors in the urban and rural populations of Cap Bon: Tunisia]. AB - Cardiovascular risk factors were studied in a random sample from the urban and rural population of the Cap-Bon, including 692 men and women, aged 35-50 years. In this sample, including 56 % urban dwellers, the mean total cholesterol was higher in urban areas (4.64 mmol/l) than in rural areas (4.16 mmol/l). In urban areas 10.2 % of the subjects had values above 6.2 mmol/l compared with 6.6 % in rural areas. Obesity was much more frequent among women (35.2 % versus 26.3 %) but less frequent among men (16.0 % versus 5.4 %) in urban and rural areas. Diabetes was found in 8.8 % of men and 10.4 % of women in urban areas, and only 0.8 % and 3.9 % in rural areas. Hypertension was found in 13.8 % of women and 11.6 % of men in urban areas, 13.3 % and 4.0 % in rural areas (13.3 %). Cigarette smoking was found in 60.7 % of men in urban areas and 75.8 % in rural areas (p < 0.05). PMID- 8693170 TI - [Comparative study of the costs for two hematopoietic cell specimen collections: cytapheresis and bone marrow collection]. AB - The aim of this study, carried out at the Institut Paoli-Calmettes (Marseille France), was to compare, in terms of monetary and non monetary costs, alternate procedures for hematopoietic stem cells collection i.e. peripheral blood stem cells collection (PBSCC) and bone marrow collection (BMC) used in cancer therapies. Monetary costs have been evaluated by calculating the direct costs of the two types of procedures and non monetary costs by comparing anxiety, discomfort and pain of cancer patients submitted to PBSCC or BMC. Patients, randomized (7/1993-2/1994), in view of autologous transplantation, to receive the first procedure or the second one received three self-administered questionnaires to complete before, during and after the procedure. Pain was assessed using visual analogical scale and McGill Pain questionnaire. Anxiety was evaluated by means of State-Trait Anxiety Inventory. Results showed that, under some conditions, presently realized in the current practice, direct costs of PBSCC (10,140 to 13,780 FF) were lower than BMC ones (16,509 FF) and that anxiety and pain experienced by patients submitted to PBSCC, with or without femoral catheter, were significantly less severe than in other group patients (State anxiety, before procedure : p < 0.01 ; pain related to the procedure assessed on VAS : p < 0.001 and total McGill score : p < 0.00001). These findings justify the substitution of bone marrow transplantation by peripheral blood stem cells transplantation, provided there is a demonstration of similar medical efficacy for cancer therapy. PMID- 8693171 TI - [Decision analysis of congenital toxoplasmosis in the absence of exact knowledge of the treatment benefits and secondary effects]. AB - Decision analysis seemed the appropriate method to bring out the interest of toxoplasmosis serology in children born from mothers who seroconverted during pregnancy. In particular it provides the possibility to choose between IgA serology, recently introduced in hospital practice, and IgM serology that is the reference test. We study a series of 96 children suspected of having congenital toxoplasmosis who were followed up until the age of one. A decision analysis is thereafter conducted by synthesizing data about clinical efficacy with the RBNCN ratio that is the net benefit of treating an affected person divided by the net cost of treating an unaffected person; these costs and benefits are clinical. The effectiveness of the treatment (sulphonamides in most cases) was not quantified. Therefore, we used the fact that the RBNCN ratio is equal to the number of healthy children likely to be treated unnecessarily in order not to leave untreated a contaminated child. Although data available in the literature and data from our study still remain insufficient to draw a final conclusion, IgA antibodies are significantly more sensitive than IgM antibodies (p < 0.01). Conversely, IgA antibodies are significantly less specific than IgM antibodies (p < 0.001). The sensitivity analysis shows that the IgA test is preferred to the IgM test if the mother is contaminated during the third trimester. On the other hand, for low prevalences, as observed in the first trimester, the IgM serology is more useful. PMID- 8693172 TI - Trends in mortality from bronchial asthma in Switzerland, 1969-1993. AB - Several unfavourable trends and epidemics of fatal asthma have been registered in various developed countries of Europe, the United States and New Zealand over the last three decades. These have been related to problems in the treatment of the disease, following the introduction and/or inappropriate utilization of selected beta-agonist treatments. Thus, trends in mortality rates from bronchial asthma have been analyzed in Switzerland, where the Eighth Revision of the International Classification of Diseases has been in operation from 1969 to 1993. Overall age standardized mortality rates (world standard) declined, from 4.3/100,000 males in 1969-73 to 2.8 in 1989-93, and from 2.0 to 1.5/100,000 females. The declines were consistent in both sexes for the age group 35 to 64 years, and some downward trend was observed also above age 65, particularly in males. Asthma mortality trends were inconsistent in children and young adults ( < 35 years), with some increase in males aged 15 to 34 after 1983, in the absence however of any significant linear trend in rates. Thus, trends in asthma mortality in Switzerland showed a moderate and steady decline in rates, particularly in middle aged males, in the absence of any systematic upward trend or epidemic peak. Still, the trends were only moderately favourable, and in the early 1990's about 250 deaths per year were attributed in Switzerland to bronchial asthma, i.e. an avoidable, in principle, cause of death. PMID- 8693173 TI - [Objective and subjective determinants in the benefits of home help services for the elderly]. AB - In this paper, we analyze the factors related to the allocation of home help services, a main component for maintaining elderly at home. The study is based on a random sample of 889 people aged 65 and over, living at home in the areas of Lunel and Pezenas (Herault, France). The factors taken into account were disabilities, income, social support, and subjective health assessed through the Nottingham Health Profile (NHP). A logistic model allowed to bring out the factors related to the delivery of home help services. Positive statistical correlations were found for age (OR = 1.6 per 10-year age groups), disabilities for instrumental activities of daily living (OR = 3.8) and for the notion of mobility assessed through the NHP (OR = 3.3); negative statistical correlations were found for the level of income (OR = 0.3), as well as for disabilities for activities of daily living (physical dependency) (OR = 0.5). These results show that the main criterion for allocating home help services is not severe disability and that subjective aspects play an important part. Accordingly, current practices should be modified to obtain a better targeting of home help services for disabled elderly at home. PMID- 8693174 TI - Training of opinion leaders in family planning in India: does it serve any purpose? AB - Community leaders are known to play a crucial role in the diffusion of innovations. The government of India started an ambitious programme for the training of opinion leaders in family planning, so as to provide a boost to its National Family Planning (Welfare) Programme. The present study attempts to analyse the knowledge, attitudes and practices of opinion leaders who had been trained in such Orientation Training Camps, vis a vis their untrained counterparts from the same geopolitical region. There was a highly significant difference between the knowledge of the two groups (p < 0.001) and a minor difference in their attitudes towards family planning (p = 0.18), but the practices of opinion leaders from both the groups were identical, thus pointing to a significant KAP-gap in the trained group. Opinion leaders from both the groups were engaged in minimal or negligible motivational work among their followers for acceptance of contraception, and only a very limited few from both the groups had themselves adopted any method of modern contraception. PMID- 8693175 TI - [About the article "Maternal mortality and birth distribution: a possible explanation of overmortality in France"]. PMID- 8693176 TI - [Computer assisted instruction in statistics and epidemiology]. PMID- 8693177 TI - [A new generation of oral contraceptives and venous thromboembolic diseases: unexpected results!]. PMID- 8693178 TI - [Changes in the incidence and mortality of breast cancer in England and Wales since the introduction of screening]. PMID- 8693179 TI - [Research using communication networks: ageing as an example]. PMID- 8693180 TI - [Hannover Functional Questionnaire in ambulatory diagnosis of functional disability caused by backache]. AB - This paper describes conceptual and clinimetric aspects as well as fields of application of the Hannover Functional Ability Questionnaire for measuring back pain-related disability (FFbH-R). The FFbH-R belongs to a series of short self administered questionnaires for the assessment of functional limitations in activities of daily living among patients with musculoskeletal disorders. In addition to the FFbH-R, a specific version is available for patients with polyarticular diseases (the FFbH-P), as well as a combined version of both questionnaires. A new questionnaire for patients with osteoarthritis is currently being developed. Data from various studies indicate that the FFbH-R meets the relevant psychometric criteria of acceptability, reliability, validity, and sensitivity to change. It has been successfully applied in (observational and controlled) clinical studies, in epidemiologic surveys, and in compensation disability evaluation. PMID- 8693181 TI - [Prof. Dr. med. K.-A. Jochheim, promoter of rehabilitation--an interview. Interview by H. Stroebel]. PMID- 8693182 TI - [Quality development--quality assurance--quality management]. AB - Business and industry, legislators, service providers, people with disabilities, all expect the facilities involved in rehabilitation to engage in quality management. What does this imply? Which regulations exist? How much does it cost? The issues involved in implementation of quality assurance systems in production and human service sectors are discussed on the example of the workshops for the disabled. PMID- 8693183 TI - [Assessment of capacity and job requirements at the interface between medical and occupational rehabilitation]. AB - The article deals with the development, nationally and internationally, of assessment systems permitting parallel appraisal of an individual's abilities and the requirements presented by the working conditions at hand. By comparison of abilities and requirements, these assessments are aimed at concretizing individual need for intervention as well as prompt practical implementation in view of occupational placement of people with disabilities. The course of development is of special interest in this context as the description of abilities starts out from the basic concepts of the ICIDH while description of the working conditions is based on ergonomic concepts. Uniting these different developments in an integrated system for assessing abilities and requirements, has been achieved by ERTOMIS Foundation, with effective support on the part of K. A. Jochheim, through an empirically-practically oriented approach, whereas a corresponding multidisciplinary research project funded by the Federal Ministry of Labour, in light of its scientific-theoretical background gave preference to a hierarchical-modular structural concept. At a European level as well, both the European Council (partial agreement) and the European Union Helios II working groups have exclusively acknowledged assessment systems of this kind as providing an important bridge between the field of rehabilitation and the world of work. PMID- 8693184 TI - [Sports therapy and rehabilitation sports--a health policy responsibility of rehabilitation]. AB - From a demographic and health policy perspective, movement and sports are gaining increased importance in terms of their preventive, therapeutic and rehabilitative potential. Successful use of sports therapy and rehabilitation sports in rehabilitating paraplegics, breast cancer patients, and patients with total hip replacement have provided convincing proof of their positive physical, mental and social impact, hence of the substantial contributions they are able to make towards enhancing specific parameters of the quality of life. It is assumed that movement and sports are conducive in particular in chronic conditions, in line with the principle of "rehabilitation taking priority over care". Whether reduced health care spending will ensue, will in the final analysis have to be determined through controlled longitudinal studies, which have not been embarked upon as yet. Successful rehabilitation in this domain presupposes adequately qualified staffing in movement therapy-focussed rehabilitation facilities, both in- and out patient, availability of an uninterrupted rehabilitation chain as well as appropriate follow-up for evaluation. PMID- 8693185 TI - [Early neurologic-neurosurgical rehabilitation--on the epidemiology of the need for early rehabilitation beds by adult patients exemplified by the Bremen federal district]. AB - Early neurological rehabilitation means starting rehabilitation of brain damaged patients already during the acute phase of the trauma or illness. It meanwhile is commonly accepted that early onset of specific neurological rehabilitation interventions will enhance medical improvement and social reintegration potential. On the other hand, the number of treatment places required for adequate early neurological rehabilitation remains a controversial, and as yet unresolved, issue in Germany. In the present study, an evaluation was undertaken for the first time to determine the local demand for early rehabilitation beds in the well-defined region of the federal state of Bremen, based on retrospective analysis of all adults treated for severe brain disease in the major Bremen clinics over a period of 22 months, i.e., between January 1992 and October 1993. A total of 146 early rehabilitation treatments was found, which is equivalent to 80 treatments a year. These results are compared with the figures and recommendations given by Kuratorium ZNS. Also, our findings document the apparent deficits in neurological rehabilitation at the time in the Land Bremen, which undoubtedly jeopardize our daily objectives, the progress and successes achieved in early intensive care. PMID- 8693186 TI - [Group work in neuropsychological therapy]. AB - The section "Psychology in the Neurological Department" at the Hardtwaldklinik I, of Bad Zwesten, can look back at 18 years of experience with neuropsychological group therapy within the neurological rehabilitation setting. The functions of the psychological section can be subdivided into diagnostic tasks on the one hand, and therapeutical interventions concerning cognitive and emotional aspects on the other, with psychotherapy having a mediating function, depending on the individual indication at hand. Depending on the kind and degree of the neurological impairment present, and based on detailed diagnostics, the patients are treated in the field of cognitive performance either individually or in groups. There are groups with different degrees of difficulty in line with type and extent of the selective disorders present. Experiences have shown that neuropsychological group therapy in particular is aimed at a holistic approach to the pattern of interference and the patient's personality. The possibilities for intervention and therapy are diverse, and range from play material to computer based individual or group therapy. In the framework of internal quality assurance, experiences have shown that the effects of neuropsychological group therapy are not easily validated. In this respect, the subjective estimates of therapist and patient are the predominant, if not the only, criteria in terms of improved mental functioning. PMID- 8693187 TI - [Mentally handicapped and learning disordered co-workers in the occupational environment]. AB - Attention is drawn to the specific issues faced--in contrast to other disability groups--in the vocational rehabilitation of persons with mental retardation and learning disorders. Current practice serves as a background for pointing out specific desiderations and outlining possible solutions. In particular posited is the need for a more tangible definition of modularized occupational qualifications as well as upgrading and refinement of flexible, community-based supports to be made available at the special/general labour market interface. PMID- 8693188 TI - [Innovative ways of occupational integration of handicapped patients--results of the European Community Initiative HORIZON]. AB - A European Commission programme aimed at occupational integration of disabled, disadvantaged and migrant persons, the HORIZON Community initiative had been implemented in the Federal Republic of Germany between 1991 and 1994. Along with an overview of project participants, exemplary innovative approaches to and potential for integrating disabled persons in employment are presented that have been developed and implemented under the programme. Also, the labour market effects achieved for the disability target group are set out. PMID- 8693189 TI - [Follow-up of rehabilitation after stroke--the practical work of an interdisciplinary team of an acute clinic for geriatrics]. AB - The treatment course in a 66 year old female stroke patient serves to describe the cooperation among various professions in a geriatric acute-care clinic. The treatment challenges, entailed by the multifaceted stroke sequels, are concretized, and an effort towards interdisciplinary team decision-making is set out, with cooperation among team members offering support and respite. The approach outlined clearly testifies to the need for ongoing team supervision in this field of work. PMID- 8693190 TI - [Effects of mastectomy on dimensions of psychological and psychosocial experience and behavior of affected women]. AB - The present study deals with the issue of how mastectomy will impact selected dimensions of psychological and psychosocial experience and behaviour in the women concerned. The study had comprised 21 women, mean age 55. 73 years, with a breast cancer diagnosis given between 1 and 21 years ago. Data collection was carried out using a 17-item questionnaire standardized for this purpose. Factor analyses produced four clearly interpretable factors. Study findings suggest that breast cancer surgery will not inevitably result in impaired sexual behaviour and experience in the affected women, whereas it is sure to impact, to varying degrees, on the factors and dimensions of "body image and self-image", "psychological and psychosomatic complaints" as well as anticipated "performance capacity and social relationships". Intercorrelations among questionnaire items are set out. It has further been found that the variables "time of breast removal" and "life age" had exercised only negligible influence on the women's questionnaire response, and that the psychosocial support experienced post surgery was reported to have primarily come from the circle of family and friends, and less so been extended by self-help groups or medial staff. Concluding, the need for integrated rehabilitative measures is pointed out. PMID- 8693191 TI - [International Classification of Impairments, Disabilities and Handicaps ICIDH- results and problems]. AB - Published by the World Health Organization in 1980, the International Classification of Impairments, Disabilities, and Handicaps (ICIDH) provides a conceptual framework for information by enabling classification, and hence description, of the three dimensions of the phenomenon of "disablement" (as a consequence of disease, injury or congenital condition). The ICIDH permits a highly complex issue to be easily grasped to a certain extent, and has gained almost worldwide recognition as a valuable tool in the perception of the problem of disablement, in describing this problem and developing solutions for this problem. With modern definitions in rehabilitation using its basic terms, the ICIDH will before long also be established as a tool for purposes of documentation, evaluation and treatment planning in the field of rehabilitation. Notwithstanding its successes, the ICIDH not only raises practical problems but theoretical ones as well. The points of criticism relate to the consequences of disease model, the definitions of the basic terms, and the overlap of basic term extensions. In order to overcome the definitional and overlap problems it is suggested, for one, to clearly distinguish between the phenomena and their symptoms and, for the other, to eliminate any overlap that may exist in the formulation of the concepts the definitions of the basic terms build on. The ICIDH model of disease consequences may be viewed as a preliminary step towards developing a theory of disablement. Such a theory would in particular be designed to enable explanation and prognosis of disablement creation processes as well as development of causally founded methods of intervention in rehabilitation. It should moreover include a theory of the etiologic processes involved in disablement as well as a theory of rehabilitative intervention. The crucial future tasks of the rehabilitation sciences will include the further development of a theory of disablement enabling provision of assistance to persons with disablement, or at risk of being disabled, in a more purposeful and causally founded manner than has been the case so far. PMID- 8693192 TI - [Comment on the legal proposal for modifying SGB VI law. German Society for Rehabilitation of Handicapped]. PMID- 8693194 TI - [REHA 95 International: rehabilitation--help--care for handicapped persons, October 1995 in Dusseldorf]. PMID- 8693193 TI - [Membership meeting and 10th Asian-Pacific Regional Conference of International Rehabilitation in Jakarta, September 1995]. PMID- 8693196 TI - [Rheumatoid arthritis in the cricoarytenoid joint]. AB - We present a female patient of 42 years with hoarseness, irradiation of pain into the ear and feeling of fullness in the throat when speaking and swallowing. The symptoms lasted about 9 months and intensively last 10 days. The edema and redness as well as adduction of vocal cords was conformed by laryngoscopy. It was sure rheumatoid arthritis of the cricoarythenoid joint which reacted relatively good on prednisolone therapy. PMID- 8693195 TI - [Changes in thyroid function in systemic lupus erythematosus, progressive systemic sclerosis and rheumatoid arthritis]. AB - According to frequent thyroid function disorders in systemic connective tissue diseases a group of 380 patients were analysed - 70 with systemic erythematous lupus (SLE), 31 with progressive systemic scleris (PSS) and 270 with rheumatoid arthritis (RA). Thyroxine (T4) and triodothyronine (T3) were measured by radioimmunoassay technique and thyroid stimulating hormone (TSH) chronologically by monoclonal antibody technique and thereafter by fluoroimmunoassay. Thyreopahty was found at 15 patients with SLE (21.43%), 11 patients with PSS (35.48%) and 35 patients with RA (12.54%). Our results pointed out the significant frequency of thyroid function disorders in these diseases and imply the necessity of the routine thyroid function follow up, therefore to take adequate cure in due time. PMID- 8693197 TI - [The effect of an antimalarial agent (chloroquine) on acute phase reactants in patients with rheumatoid arthritis]. AB - The effect of chloroquine on acute phase reactants and clinical features in rheumatoid arthritis patients was evaluated. The patients had also one of nonsteroid antiinflammatory drugs therapy. Following acute phase reactans were evaluated: erythrocyte sedimentation rate and haptoglobin. The number of swollen and painful joints were also evaluated. All parameters were evaluated before the beginning of the therapy and each 3 months of medication during 9 months. The patients were analyzed by therapy effect and they were divided in 3 groups: all patients, only the patients who responded and the patients who did not respond on antimalarials. Assessed clinical and laboratory parameters were most improved in patients who responded on therapy. Acute phase reactants are markers of activity of illness, better CRP and less other haptoglobin and other parameters erythrocyte sedimentation rate and haemoglobin. PMID- 8693198 TI - [Antineutrophil cytoplasmic autoantibodies (ANCA)--in patients with connective tissue diseases]. AB - Antineutrophil cytoplasmic autoantibodies (ANCA) attack primary cytoplasmic granules of neutrophil leukocytes and lysosomes of monocytes. Indirect immunofluorescence technique distinguished two types of ANCA: genuine of cytoplasmic (c-ANCA) and perinuclear (p-ANCA). ANCA were followed up at patients with systemic connective tissue diseases who underwent a treatment at Department of Rheumatology and Clinical Immunology of Clinical Hospital Osijek. p-ANCA were found at 15 patients. Its titre dependent upon the stage of the disease. This very finding pointed out the importance of ANCA not only as a valid additional diagnostic factor but as a strong prognostic marker in particular systemic connective tissue diseases as well. PMID- 8693199 TI - [Arthrosis of the hand: epidemiologic and clinical characteristics]. AB - The trial included 641 subjects, 200 (31.2%) of whom were found to have hand arthrosis. There were 135 (33.1%) women and 65 (27.9%) men with an average age of 54 (ranging from 35 to 75 years). Interphalangeal arthrosis was found in 33.1% of women and 25.8% of men, and rhisarthrosis in 8.3% of women and 7.3% of men. No significant differences in sex and age was found between these two groups of subjects (P = 0.45, P = 0.70). The relative incidence of arthrosis of the right hand was slightly higher than that of the left hand, but this difference was not significant because it was below 5% and 3.7%, respectively. Distal interphalangeal joints were more than three times more frequently affected than proximal interphalangeal joints. Pain and functional inability were found in two thirds of patients with rhisarthrosis and in one third of patients with interphalangeal arthrosis, and were closely correlated with the menopause. A significant correlation was found between the onset of menopause and clinical symptoms (r = 0.87, P = < 0.001). PMID- 8693200 TI - [The effect of pregnancy on the course of ankylosing spondylitis]. AB - Twenty-five of our patients were married women (71.4 percent), 23 had given birth once or twice and 20 of our patients gave birth after the onset of the disease. The average age at the time of the analysis was 34 years. The course of the disease showed exacerbation once or twice in the course of pregnancy in most of our patients. Improvement of their condition was seen in 11 patients with a duration of approximately 5.4 months on the average and in individual cases even for a duration of 7 or 8 months. Remission during the puerperium period lasted somewhat over 4 months in only 2 of our patients. Pregnancy and the puerperium had no significant effect on the course of the disease. PMID- 8693201 TI - [Rheumatoid arthritis and ankylosing spondylitis]. AB - A case of a patient having ankylosing spondylitis of 16 years duration is presented. Eight years ago developed a clinical picture with symptoms which completely fulfill criteria for diagnosing rheumatoid arthritis with exception of rheumatoid factor. As a conclusion we can say that in our patient there have been developed ankylosing spondylitis and rheumatoid arthritis as a coexistence of two diseases. PMID- 8693202 TI - [Incipient pericardial tamponade as the first symptom of systemic lupus erythematosus in 2 children]. AB - Two patients (a boy and a girl), with systemic lupus erythematosus (SLE), in which pericarditis with threatening tamponade was an initial symptom of disease, are presented. Pericardial tamponade is very rare initial manifestation, described in only 1-3% of all the cases of SLE. The typical clinical features of tamponade are described (tachycardia, hypotension, venous congestion) and the importance of echocardiography in early diagnosis of pericarditis and pericardial tamponade is pointed out. Therefore, the echocardiography is considered as the complementary method in diagnosis of SLE. PMID- 8693203 TI - [Epidemiologic study of uricemia in healthy persons 1 to 20 years of age]. AB - We investigated the frequency of hyperuricaemia in scoliotic subjects age 1 to 20 years. Concentration of uric acid was determined by Acc-Uric test in which the normal values are 200 to 420 mumol/L in males and 140 to 340 mumol/L in females. Hyperuricaemia was found in 49 of 400 subjects (18.5%), in 12 males (6%) and 37 females (18.5%). Hyperuricaemia was found in 10 of 49 subjects age of 2 years (20.4%), more often in females than in males. Frequency of hyperuricaemia was equal in all groups except in age of 5, 15, 16 and 20 years. PMID- 8693204 TI - [The mode of onset of rheumatoid arthritis and seasonal variations]. AB - The aim of the study was to establish age and sex distribution, seasonal variations, and mode, of onset in a sample of patients with rheumatoid arthritis. One hundred eighty nine patients (146 women and 43 men), whose age ranged from 18 to 77 yrs. (mean age 49.1, SD 12.93) were included in the survey. In majority of patients the disease started between 31-50 years, whereas in the age group from 21-30 it occurred more frequent in women, and in the age group from 51-60 in men. The onset of rheumatoid arthritis was in almost equal proportions acute or insidious, regardless sex. No difference was found concerning onset of the disease and seasonal variations. However there was a statistically significant correlation between mode of the onset and seasonal variations (P < 0.05). Rheumatoid arthritis started abruptly more often in springtime, and more insidiously in autumn, whereas in summer and winter there was an equal number of patients with acute or insidious onset of the disease. PMID- 8693205 TI - [Chloroquine in the treatment of psoriatic arthritis]. AB - In 30 patients (20 males and 10 females) wih psoriatic arthritis chloroquine was administered in a dosage of 250 mg daily per os. After 12 months of monitoring decreased number of swollen and painfully tender joints were found as well as shortening in duration of morning stiffness. As for laboratory parameters lowering of the average values of ESR and alpha-2 globulins were found whilst there were no changes of ceruloplasmin, haptoglobin and CRP. Worsening of skin lesions was observed in only 2 patients (6.5%). These results suggest that synthetic antimalarials (chloroquine) can be successfully used in the treatment of psoriatic arthritis with special care. PMID- 8693206 TI - Management of peptic ulcer disease in general practice. PMID- 8693207 TI - Development of a postal health status questionnaire to identify people with dyspepsia in the general population. AB - OBJECTIVE: To develop and validate a postal health status questionnaire which will identify people with dyspepsia in the general population. DESIGN: Validation against telephone interview and post re-post determination of reliability. SETTING: A general practice population in the north of England. SUBJECTS: A random sample of adults aged 20-69 years inclusive chosen from the general population. MAIN OUTCOME MEASURES: Validity has been checked against telephone interview. A kappa statistic has been calculated for each question and clinical category. RESULTS: Compared with interview the questionnaire is a valid, comprehensive and easily understood record of symptomatology. The kappa statistics (mean value 0.92) indicate a very reliable questionnaire. CONCLUSION: The questionnaire accurately and reliably identifies people with dyspeptic symptoms. PMID- 8693208 TI - The Finnmark general practitioner hospital study. Patient characteristics, patient flow and alternative care level. AB - OBJECTIVES: In a study assessing the role of general practitioner hospitals (GPHs) in the health service two main questions were addressed: 1) Are general practitioner beds used for short-term medical observations, or as a supplement for long-term geriatric care? 2) What are the alternatives to stays in GPHs? DESIGN: In a prospective design GPH stays during 8 weeks were recorded. SETTING: 15 GPH units in Finnmark county in Norway. SUBJECTS: 395 completed stays were recorded. MAIN OUTCOME MEASURES: The patients' sex, age and diagnosis, flow of patients, length of stays, bed occupancy rate, and doctors' assessments of alternative level of care. RESULTS: 60% of the patients were admitted from and discharged to their home after a mean stay of 6.8 days. The 19% who were transferred to higher level hospitals stayed significantly shorter than the rest (3.6 days), while 9% transferred from hospital stayed significantly longer (22.3 days). Of the 395 patients discharged 61% were assessed as candidates for higher level hospitals, if GPHs did not exist. 45% of the GPH stays seem to replace higher level hospital admissions. CONCLUSION: The GPHs have a pre-hospital "buffer" function by preventing patients with acute symptoms from being unnecessarily admitted to general hospitals through short-term observation stays. A post-hospital function was also demonstrated, since GPHs allow for long-term follow up stays for patients transferred from general hospitals. PMID- 8693209 TI - The economic cost of a streptococcal tonsillitis episode. AB - OBJECTIVE: To estimate the cost of a streptococcal tonsillitis episode from the data of a questionnaire. SETTING: Five primary health centres in the west of Sweden. PARTICIPANTS: 101 consecutive patients treated for streptococcal tonsillitis. MAIN OUTCOME MEASURE: The cost estimation included costs for physician visit and drug, travel costs to and from the primary health centre, cost of lost production resulting from the patient's or the guardian's absence from work for physician visit or sick-leave, and cost of telephone consultation with a physician or nurse. RESULTS: The period of illness was on average seven days, time to recovery after treatment five days, and the mean period of sick leave 2.5 days. The total cost of a tonsillitis episode was about SEK 3,300 (385 USD). Of this sum, the cost for the antibiotic accounted for only 3% and loss of production for 75%. CONCLUSION: Differences in the cost of drugs only have a minor influence on the total cost, while factors causing loss of production, such as efficacy and side effects of the drug, have a greater influence. Economic evaluation of pharmaceuticals will be more relevant in the future, and in the search for the most effective treatment, cost effective studies will be integrated with clinical trials. PMID- 8693210 TI - Bronchial airflow limitation and chest findings in adults with respiratory infection. AB - OBJECTIVE: To study the predictive value of clinical chest findings for bronchial airflow limitation in patients with respiratory tract infection. DESIGN: Associations were analysed between FEV1 (forced expiratory volume in one second) in % of predicted and physical chest findings. SETTING: The Municipal Emergency Clinic in Tromso, Norway. PARTICIPANTS: 398 adult patients with respiratory tract infection and 40 general practitioners. OUTCOME MEASURES: Mean FEV1% predicted and frequency of FEV1 < 80% predicted according to chest findings. Regression coefficients of the findings with FEV % predicted as outcome variable. RESULTS: Mean FEV1% predicted was 87 (range 25-129). Pathological chest findings were recorded in 127 patients (32%) and in 22 of the 24 patients (92%) with FEV1% predicted less than 60. The 78 patients with wheezes had a mean FEV1% predicted of 74 (range 29-120), significantly lower than those without wheezes (p < 0.0001), and 63% had FEV1% predicted less than 80. Prolonged expiration or strenuous respiration was recorded in 49 patients. The 29 patients with wheezes in this subgroup had a significantly lower mean FEV1% predicted, 65, than the 20 patients without wheezes (p < 0.005). By multiple regression wheezes and strenuous respiration were the most significant predictors of FEV1% predicted, together with patients' statement of very annoying dyspnoea. CONCLUSION: When predicting the degree of bronchial obstruction in a patient with respiratory infection, the doctor may take into account wheezes heard by auscultation, an impression of strenuous respiration, and the patient's statement about severe dyspnoea. PMID- 8693211 TI - Oral anticoagulant treatment in a medical care district--a descriptive study. AB - OBJECTIVE: To describe how oral anticoagulant therapy is performed in a defined catchment area in order to improve the quality of care. DESIGN: Two study periods of 8 weeks were compared with reference to monitoring sites, i.e. hospital departments and primary health care centres. SETTING: The health care district of Umea in northern Sweden, with 125,300 inhabitants. PARTICIPANTS: Patients on oral anticoagulant therapy at the department of Internal Medicine, Umea University Hospital, in 1987 (n = 243) were compared with all patients treated in 1990 at health centres (n = 175) and at the department of Internal Medicine (n = 290) in the Umea district. MAIN OUTCOME MEASURES: The prevalence of treatment failures and complications was calculated per patient year, as well as the relative frequencies of patients within treatment recommendations. RESULTS: 80-83% of the patients were within treatment recommendations. Treatment failures were 3.6% of hospital patients, and 2.6% of primary care patients. Corresponding figures for bleeding complications were 8.9% and 5.1%, respectively. The differences are partly explained by differences in the studied groups, e.g. age, indications for treatment, and concomitant diseases. PMID- 8693212 TI - Smoking behaviour in young families. Do parents take practical measures to prevent passive smoking by the children? AB - OBJECTIVE: To investigate smoking behaviour in young families. DESIGN: Cross sectional study. SETTING: Mother and child health centres in Oslo, Norway. SUBJECTS: The families of 1,046 children attending the health centres for 6-weeks , 2- or 4- year well child visits. MAIN OUTCOME MEASURES: Daily smoking, smoking quantity and practical measures taken by the parents to prevent passive smoking among the children as assessed by parental reports. RESULTS: In 48% of the families at least one adult was smoking. 33% of the smoking parents smoked more than ten cigarettes per day. 47% of the smoking families reported that they did not smoke indoors. CONCLUSIONS: The parents were less likely to smoke if they were more than 35 years of age, had a child aged less than one year, had a spouse/co-habitee or had a long education. Smoking parents smoked less if they had a spouse/co-habitee, had a child aged less than one year or had few children. Smoking parents were more often careful and did not smoke indoors if they had a child aged less than one year, had a spouse/co-habitee, did not have a smoking spouse/co-habitee or smoked a low number of cigarettes per day. PMID- 8693213 TI - Antidepressant treatment in general practice--an interview study. AB - OBJECTIVE: To elucidate potential problems concerning the use of antidepressants (AD) in general practice. DESIGN: Cross-sectional, descriptive interview study. SETTING: General practices, Odense, Denmark. SUBJECTS: Random sample consisting of 98 AD users from 12 general practices. MAIN OUTCOME MEASURES: Indication for AD treatment, justification of the treatment, duration of AD treatment, daily dose of AD, side effects, Hamilton depression rating, WONCA score. RESULTS: The primary indication for AD treatment was depression (72 patients), partly regular depression (therapeutic/prophylactic treatment) (n = 39), partly depressive tendencies (n = 32) (1 unknown). Median treatment duration was 3 years; 25% had been in treatment for more than 10 years. The general practitioners judged the treatment problematic/unacceptable in 23 cases, largely because of uncertain indication or because other or no treatment was considered better for the patient. The daily doses of AD were generally low. Side effects were modest. The patients often had a relatively high depression score and poor status according to the WONCA-scale. CONCLUSIONS: The use of low doses, long duration of treatment, and uncertainty about the relevance of the treatment are important features of the use of AD by general practitioners. There seems to be a discrepancy between the use of AD in general practice and the scientifically based recommendations. PMID- 8693215 TI - Predictors for recurrent falls among the home-dwelling elderly. AB - OBJECTIVE: Scant attention has been paid to the risk factors for recurrent falls among the home-dwelling elderly, although there are remarkable age and sex differences according to whether or not the falls recur. In this report we describe and analyse the risk factors for recurrent falls by selected clinical variables and the history of falling during the previous year. DESIGN: A community-based prospective study covering two years. SETTING: All home-dwelling persons (N = 1016) aged 70 years or older living in five municipalities in northern Finland. OUTCOME MEASURES: The risk factors of recurrent falling by selected clinical variables using cross-tabulations and multivariate analyses. RESULTS: Previous falls, peripheral neuropathy, use of psychotropic medication and slow walking speed were independent risk factors for recurrent falling. The risk of recurrent falling increased with an increasing number of previous falls. CONCLUSIONS: Early preventive measures should be taken among the elderly persons who are prone to falling. In order to reduce the risk of recurrent falls among the elderly, the attending physician should take a critical view of the use of psychotropic medications, and attempts should be made to treat conditions underlying peripheral neuropathies and abnormal gait. PMID- 8693214 TI - Outcomes of referrals from general practice. AB - OBJECTIVE: To investigate hospital referrals by general practitioners, subsequent hospital events, and discharge letters. DESIGN: Audit of 340 referrals written by 29 general practitioners, hospital case records, discharge letters, and primary care case records. SETTING: Salo Area Health Authority in southern Finland (population 43,000). MAIN OUTCOME MEASURES: Referral rates, reasons for referrals, distribution according to specialty, number of hospital days, visits to outpatient-departments, laboratory and radiological examinations, therapeutic procedures, changes in medication and/or diagnosis and availability of discharge letters. RESULTS: The mean referral rate was 4.5% and varied from 1.6-10.0 per cent. The referring physician's age, sex, and workload did not significantly explain the variation of referral rates between individual general practitioners. A third of all hospital referrals from general practitioners led to a single visit at the hospital outpatient department. Discharge letters were received for 33% of all referrals. A change in medication or diagnosis did not substantially affect the rate of discharge information supplied by the hospital. CONCLUSIONS: The variation of the referral rates between the individual general practitioners was large. The small number of participating general practitioners (n = 29) did not permit valid explanations for this variation. The referring general practitioner rarely receives discharge letters from secondary care providers. PMID- 8693216 TI - Salt and public health--policies for dietary salt in the Nordic countries. AB - OBJECTIVE: To review current knowledge about excess dietary salt as a risk factor for diseases and to compare and discuss the national policies for dietary salt in the Nordic countries. DESIGN: Literature review, questionnaire and interviews. Nordic comparative study. SETTING: The Medline bibliographic system and authorities responsible for the national nutritional policies in the Nordic countries. SUBJECTS: Scientific articles published since 1988 concerning the impact of excess dietary salt on health and key persons with responsibilities for the formulation of national recommendations about dietary salt in each of the five Nordic countries. MAIN OUTCOME MEASURES: Articles dealing with (i) epidemiological observations, (ii) sensitive groups, (iii) underlying biological mechanisms concerning the contents of the latest national recommendations and the wording of legislation and decrees about salt in food-stuffs in the Nordic countries. RESULTS: The impact of excess dietary salt on health mainly concerns hypertension, gastric cancer, osteoporosis and bronchial hyperreactivity. The national policy for dietary salt in Finland differs from the other Nordic countries. In Finland salt is a food additive and a variety of special regulations exist. Finland has chosen a more active way to achieve the existing Nordic recommendation of 5 g salt per day. The daily intake is about 10 g per day in all the Nordic countries. CONCLUSIONS: There is need for further epidemiological studies of the relationship between excess dietary salt and gastric cancer, osteoporosis, and bronchial hyperreactivity. The knowledge of the relationship between dietary salt and raised blood pressure is sufficient to put force behind the implementation of existing Nordic recommendations. PMID- 8693217 TI - Role of Danish general practitioners in AIDS prevention. AB - OBJECTIVE: To describe Danish general practitioners' perception of their own role and to register their actual behaviour in the prevention of HIV/AIDS. DESIGN: Data collection was carried out by a) questionnaire and b) prospective registration of consultations dealing with HIV/AIDS in a two-week period in September 1992. SETTING: General practice, Denmark. SUBJECTS: One thousand general practitioners (GPs), selected at random, were asked to participate. The study population comprised 352 GPs who returned the questionnaire and participated in the prospective registration. RESULTS: Most of the GPs (94%) were of the opinion that GPs should play a central part in the prevention of HIV; 96% found that their knowledge was sufficient to advise on the prevention of HIV, and 90% thought that the GP should take the initiative to talk about HIV. The median number of consultations dealing with HIV was two during ten working days (range 0 18), and more than half the GPs (56%) had not themselves initiated a conversation concerning the problem. CONCLUSION: There was discrepancy between the GPs' vision of their role in HIV prevention and the activities in practice. It is recommended that initiatives are taken to strengthen the GPs' role in AIDS prevention. PMID- 8693218 TI - [How I treat... A Type 2 diabetic patient who has become insulin-dependent]. PMID- 8693219 TI - [Clinical case of the month. Physiopathology, symptoms, complications and treatment of alcoholic ketoacidosis: apropos of a fatal case]. PMID- 8693220 TI - [Hematopoietic stem cell transplantation ("Bone marrow graft"): indications, methods and risks]. PMID- 8693221 TI - [Therapeutic approach in pediatric oncology]. PMID- 8693222 TI - [Abnormal hair, anthology of pilary dysplasias]. PMID- 8693223 TI - [Strangulated hernia of the groin in adults]. PMID- 8693225 TI - [General interpretation of so-called alternative practices]. PMID- 8693224 TI - [Circulatory support. I. Indications and description of systems]. PMID- 8693226 TI - [Doctor Rene Mouchet's contribution to the study of neonatal jaundice]. PMID- 8693227 TI - [How I examine... positron-emission tomography in suspected bronchopulmonary cancer]. PMID- 8693228 TI - [Is alcohol healthy?]. PMID- 8693229 TI - [Electronic expert system in medicine. For example ILIAD]. AB - Expert systems are knowledge data bases founded on patient data, literature searches and opinions of experts. With these systems it is for instance possible to test or to take clinical decisions. ILIAD, USA version 4.2, an adaptable software using probabilistic strategies, was investigated. This system is, among other uses, employed for quality assurance and documentation, as a teaching instrument as well as a knowledge base. It comprises the ICD-9 index of diagnoses and a selected and commented up-to-date review of the literature from 'Mosby's Year Book of Medicine'. The features of ILIAD are presented, and the possibilities and limitations of its use as well as that of expert systems in general are discussed. PMID- 8693230 TI - [Tumor staging and follow-up care in rectosigmoid carcinoma: colonoscopic endosonography compared to CT, MRI and endorectal MRI]. AB - BACKGROUND AND STUDY AIMS: Endosonography has become the best available method for local staging of primary rectal cancer and diagnosing recurrent local tumor. The aim of this prospective study is to compare the accuracy of endoscopic ultrasound (EUS), using an echo colonoscope (CF-UM 3, CF-UM 20, Olympus optical) to computed tomography (CT), body coil magnetic resonance imaging (MRI) and endorectal coil magnetic resonance imaging (EMRI). PATIENTS AND METHODS: From February 1991 to July 1993 90 patients with primary rectosigmoidal tumors (n = 32: 9 women, 23 men, mean age 68 years [range 37 to 84]) or follow-up examinations for recurrent local cancer (patients: n = 58, examinations: n = 93; 41 women, 52 men, mean age 61 years [range 31 to 84]) were investigated. The results of preoperative examinations were compared to histopathological findings regarding T and N stages. RESULTS: In T staging, accuracy of EUS (78%) was superior to CT (50%) and equivalent to both MRI (75%) and EMRI (80%). The accuracy of EUS (84%) in assessing transmural tumor infiltration was superior to CT, MRT and EMRT (50%, 75% and 80%, resp.); however, CT (77%) and MRI (86%) were more accurate than EUS (64%) and EMRI (33%) in assessing N stages. Recurrent local cancer was found in 22 patients. All but one were detected by EUS. Sensitivity, specificity and accuracy in follow-up examinations for recurrent disease for EUS were 95%, 94% and 95%, for CT 75%, 73% and 74%, for MRI 57%, 100% and 70%, and for EMRI 83%, 100% and 90% resp. CONCLUSIONS: Endoscopic ultrasound proved to be a safe and accurate method of preoperative staging and early diagnosis of recurrent rectal cancer and was superior or at least equivalent to CT, MRI and EMRI. PMID- 8693231 TI - [A case of acute sarcoidosis]. AB - Upper respiratory tract involvement occurs in 1 to 6% of all patients with sarcoidosis. Dry cough, hoarseness, dyspnea and dysphagia are the main symptoms. The diagnosis is established by biopsy demonstrating granulomatous lesions. We report the case of a 22-year-old woman who presented with erythema nodosum, arthralgias and granulomatous lesions of the trachea, larynx and bronchi. Although the biopsies of the lesions were nondiagnostic, the diagnosis of acute sarcoidosis was made, and a steroid therapy was initiated. The patient recovered rapidly, and the lesions disappeared. The features and differential diagnosis of upper respiratory tract sarcoidosis are discussed. PMID- 8693232 TI - [Febrile status and exanthema following a trip to the jungle]. AB - A 30-year-old female entered the emergency room for medical advice because of progressive deterioration of general health with headache, arthralgias, myalgias and fever after a vacation of three weeks in Malaysia and Hong Kong. Because of persistent fever, lymphadenopathy, slight leuco- and thrombocytopenia and only insignificantly elevated humoral signs of an inflammatory process, the patient was treated symptomatically after exclusion of malaria. A viral disease was suspected. Two days later, an exanthema erupted suddenly on the trunk. Pinhead sized livid, flat macules, increasing in size within hours and spreading to the extremities, were observed. Further investigations revealed a significantly elevated titer of IgG directed against rickettsia conorii, leading to the diagnosis of Mediterranean spotted fever. Under antibiotic treatment with tetracycline, the aforementioned findings regressed within few days, and the patient recovered completely. PMID- 8693233 TI - [A case from practice (348). Systemic juvenile chronic arthritis, Adult-onset Still's disease]. PMID- 8693234 TI - [Gene therapy--a new form of drug administration]. PMID- 8693235 TI - [Osteosarcoma and Ewing's sarcoma. Improved recovery chances in the past 25 years according to the experience of Balgrist Hospital]. AB - At the Balgrist hospital 38 patients with osteosarcoma and 18 patients with Ewing sarcoma were treated from 1970 through 1992; a follow-up of at least three years is available for all patients. Disease-free survival in this period of time has increased from 20% (Ewing sarcoma) and 30% (osteosarcoma) to over 75%. While systemic tumor control was improved by systematic chemotherapy, local tumor control was improved by appropriate biopsy techniques, and amputations have been replaced by local resections, in most cases with reconstruction (arthrodesis, rotation plasty, endoprosthesis, allografts), which require further improvements. With respect to cure of the neoplastic disease, the currently available methods have been used to their maximum potential, and a steady state has been reached regarding survival. Further improvement of survival will therefore depend on the introduction of completely new modalities. PMID- 8693236 TI - [Quality management and quality assurance: terminology of a structural change in medicine]. AB - The topic of quality assurance and management gains increasing interest by society, medical professionals, carriers of health expenses and government. In this review the most important terms borrowed from industry and management will be critically explained to persons employed in Health Systems in particular. Beside numerous novel quality terms, closer attention is paid to the Donabedian model, extended by indicational quality, audits, tracer systems, ISO models, technology assessment, total quality management, new control mechanisms in health care and costs. In the context of structural changes in society and medicine the new aspects of quality are featured as a real chance for a 'healthy' Public System and not as a threat. PMID- 8693237 TI - [Sudden death following bypass surgery]. PMID- 8693238 TI - [Episodic headache, diminished performance and depressive mood]. AB - By the example of two case reports, typical signs of caffeine withdrawal like headache, increased irritability, decreased performance and disturbed concentration are described. These symptoms occurred two times within one week in two healthy nonsmoking individuals volunteering in a scientific study including periods of 24 hours with standardized caffeine-free-diet. The two volunteers were used to a regular coffee consumption of eight cups per day (about 600 mg/day). Since caffeine obviously represents the most common psycho-stimulant worldwide and since even moderate coffee consumption may lead to dependence, withdrawal symptoms induced by sudden reduction of consumption or withdrawal of caffeine may occur more often than usually assumed. PMID- 8693239 TI - [A case from practice. Fibromyalgia]. PMID- 8693240 TI - [What is your diagnosis? Idiopathic dilatation of the right atrium with dilatation of the tricuspid valve and consecutive medium-severe tricuspid insufficiency. (Normocardial atrial flutter, anamnestic transient ischemic attacks with right-sided arm weakness)]. PMID- 8693241 TI - [Hematopoietic stem cell transplantation: principles and practice]. AB - This article describes the basic definitions, indications and complications of hematopoietic stem cell transplantation. The different modes of transplantation (autologous, allogeneic-related and allogeneic-unrelated transplantation) are explained with regard to the underlying immunological processes and consequences for duration of treatment, distribution of age, complications, lethality, and for the family of the patient. In our department, the duration of the hospital stay was (median) 44 days for autologous BMT, 45 days for allogeneic-related BMT and 66 days for allogeneic-unrelated BMT. Six to twelve years old children showed a peak for allogeneic related transplantations; these children were treated mainly for relapse of acute lymphoblastic or myeloid leukemias. Patients over 15 years old showed a peak for autologous transplantations; due to the research focus of our center, Ewing's sarcoma was the main underlying disease in this age group. Allogeneic-unrelated transplantations were uniformly distributed over the whole age range from nine months to 24 years. PMID- 8693242 TI - [Bone marrow transplantation: role of radiation therapy]. AB - Conditioning regimes before bone marrow transplantation serve a dual purpose. Firstly they have to destroy the host immune system sufficiently to allow permanent engraftment, secondly they have to eliminate the abnormal tumor cells. The special aim of total body irradiation is to eradicate those cells, which escape chemotherapy. The effectiveness of TBI is influenced by: delivered dose, fraction size and dose rate. Dose escalation improves the results of TBI. The seven year survival probability is 74%, if more than 9,9 Gy are administered and only 38% under 9,9 Gy. Combining TBI and chemotherapy promotes the outcome in patients with acute leukaemia and allogeneic bone marrow transplantation. The two year relapse rate is 16% with and 37% without TBI. Side effects are distinctly determined by fraction size and dose rate. PMID- 8693243 TI - [Wilms' tumor]. AB - Today the prognosis in children with nephroblastoma is excellent. With the combination of surgery, chemotherapy and radiation more than 80% of children can be cured. Because of acute toxicity and late effects of treatment (scoliosis, cardiotoxicity, fertility problems and second malignancies) a major issue in the management of children with this kind of malignancy is the reduction of chemotherapy and radiation. This is done in prospective multicenter studies. In 1989 the GPOH did join the SIOP 9 study for the treatment of Wilms' Tumors. All the SIOP studies mainly investigated the preoperative treatment. With the introduction of a centralized radiodiagnostic center in Germany (Prof. Troger, Heidelberg) a high certainty in making the right diagnosis preoperatively without histological proof could be achieved. It could be shown in SIOP 9, that four weeks of preoperative chemotherapy with actinomycin-D and vincristine is as effective as eight weeks. 60% of patients with a localized nephroblastoma will have stage I disease at the time of surgery. The response to preoperative chemotherapy is of prognostic value. As a result of the NWTS and SIOP studies the postoperative stage and histological subtype are very important regarding prognosis. By reducing the dose of actinomycin-D to 2/3 in children under 12 kg of body weight problems with venous occlusive disease could be minimized. In the now ongoing study SIOP 93-01/GPOH postoperative treatment for patients with stage I disease and intermediate malignancy is randomized to a short and a long branch. PMID- 8693244 TI - [Conservative strategy in primary lymphomas of the stomach]. AB - Surgery is no longer necessary for pathologic diagnosis and staging of gastric lymphoma because of improved endoscopic biopsy and modern imaging techniques. At least equal results may be achieved compared to surgery by wide-field megavoltage radiotherapy and polychemotherapy without prior resection. PMID- 8693245 TI - [Radiotherapy of primary non-Hodgkin lymphoma of the stomach]. AB - Primary gastric non Hodgkin's lymphoma is a localized disease, which tends to local recurrences. Local treatment by surgery and/or radiotherapy is adequate for small low malignant primary gastric lymphomas of stages IE and IIE. Larger tumors should be resected before radiotherapy and systemic treatment. Chemotherapy alone has its impact in high grade lymphomas and as adjuvant treatment for tumors < 5 cm. Prospective randomized studies are underway to establish the respective role of the treatment modalities. The radiotherapeutic technique for gastric lymphomas is outlined. The risk of blocking part of the tumor volume by shielding the kidneys is mentioned. PMID- 8693246 TI - [Pediatric anesthesia: introduction]. PMID- 8693247 TI - [Characteristics of anatomy and physiology in the pediatric population]. PMID- 8693248 TI - [Pediatric anesthesia. Induction, sustaining, awakening]. PMID- 8693249 TI - [What is new in pediatric loco-regional anesthesia?]. PMID- 8693250 TI - [Postoperative analgesia in children: what is new?]. PMID- 8693251 TI - [Anesthesia for ambulatory surgery in children]. PMID- 8693252 TI - [Labor and delivery in twin pregnancy]. PMID- 8693253 TI - [Hemorrhage during the third stage of labor and the postpartum period]. PMID- 8693254 TI - [Pre-eclampsia and HELLP syndrome]. PMID- 8693256 TI - [Uterine inversion]. PMID- 8693255 TI - [Uterine rupture: literature review and Genevan experience (1980-1994)]. PMID- 8693257 TI - [Injury and pregnancy]. PMID- 8693258 TI - [Emergencies in obstetrics. Pulmonary embolism]. PMID- 8693259 TI - [Amniotic fluid embolism]. PMID- 8693260 TI - [Psychiatric emergencies and pregnancy]. PMID- 8693261 TI - [Rational use of analgesics]. PMID- 8693262 TI - [Melatonin: a fashion hormone for not very Cartesian reasons]. PMID- 8693263 TI - [Vaccines]. PMID- 8693264 TI - [3rd Rolle meeting: inhalation treatments]. PMID- 8693265 TI - [Inhalation techniques]. PMID- 8693266 TI - [Bronchodilator drugs]. PMID- 8693267 TI - [Inhalation treatment: glucocorticoids]. PMID- 8693268 TI - [Bronchial mucolytic agents]. PMID- 8693269 TI - [Antibiotics in aerosols]. PMID- 8693270 TI - [Gene therapy of mucoviscidosis]. PMID- 8693271 TI - [Infectiology: is there need of a new subspecialty? Committee of the Society of Infectiology]. PMID- 8693272 TI - [Brief survival guide in a hostile environment: molecular mechanisms in the recognition of infectious agents]. PMID- 8693273 TI - [Pathogenesis of HIV infection. Therapeutic implications]. PMID- 8693274 TI - [Nosocomial infections: a problem in ambulatory practice]. PMID- 8693275 TI - [Clinical presentation of primary cytomegalovirus infection in a non immunodepressed adult]. AB - In the immunocompromised patients and during foetal life an acute infection due to the cytomegalovirus (CMV) causes great morbidity. In adults without predisposing factors the acute infection with CMV is rarely symptomatic, but can also provoke fever, fatigue, headache and anorexia for weeks. The peripheral blood smear shows big atypical lymphocytes within a relative lymphocytosis. The suspicion of the CMV infection is confirmed by the serological evidence of IgM anti-CMV antibodies. There is no etiological treatment, the evolution is spontaneously favorable most of the time. Establishing the diagnosis is reassuring for the patient and for the physician and avoids unnecessary analyses and treatments. We describe a series of 11 adults without predisposing factors who contracted an acute cytomegalovirus infection. PMID- 8693276 TI - [Extracerebral toxoplasmosis in immunodepressed subjects. Case report of a case of pulmonary toxoplasmosis in an HIV-positive patient and literature review]. PMID- 8693277 TI - [Extrapulmonary tuberculosis: 2 cases with hepatic, splenic, peritoneal and cerebral involvement]. AB - Two cases of unusual extrapulmonary tuberculosis are presented. One patient was suffering of a pulmonary tuberculosis involving the brain, liver, spleen and peritoneum, with headaches, ascites, weight loss and night sweats. The other patient had lymph nodes and nodular liver tuberculosis and complained of fever, right upper quadrant pain, anorexia and weight loss. This tuberculosis form is extremely rare; only 23 cases were reported between 1950 and 1990. Furthermore, a drug-induced hepatitis developed in a liver already damaged by the tuberculosis and a chronic active C hepatitis. These two cases remind us that the diagnosis of extrapulmonary tuberculosis may be extremely difficult. It must be suspected mostly in patients that are immuno-depressed or whose origins are not caucasian. Other diagnoses are often wrongly suggested, such as tumors, inflammatory diseases or other infectious diseases. As a result, the correct diagnosis or other infectious diseases. As a result, the correct diagnosis is often delayed. If cultures are negative and the chest roentgenogram is normal, procedures such as transbronchial, liver, bone marrow or lymph node biopsies may help to properly identify the disease. PMID- 8693278 TI - [Acute lumbago: infectious traps]. PMID- 8693280 TI - [Position raised by Dr. Patrick Haenni's article entitled "Medical practitioner's attitude in case of suspected pulmonary embolism", No. 116, pp. 107-109, 1966]. PMID- 8693279 TI - [Urinary infections and the role of quinolones]. PMID- 8693281 TI - Proliferation markers as a tool in oncological neuropathology. AB - Unique character of brain tumors and problems inherent in different concepts of histological classification are impediments to effective histoprognosis. Large place for subjectivity may be diminished by integration of kinetics data into evaluation of tumor samples. Methods of measuring cell proliferation include immunohistochemical detection of halogenated or tritiated pyrimidine analogues after intravenous injection and nuclear antigens associated with the cell cycle, other methods are selective silver staining and modified flow cytometry. In this study, the literature concerning the use of proliferation markers in neurooncology is reviewed and the problems consisting in used methods are pointed out. The most reliable markers and techniques are recommended and situations of special importance for the cell proliferation markers use specified. PMID- 8693282 TI - Cultivation of neural EGF-responsive precursor cells. AB - We demonstrated that proliferation of dissociated neural E14 and E19 rat precursor cells could be induced by Long-EGF. Dividing EGF-responsive neural progenitor cells stimulated by Long-EGF formed spherical multicellular clusters (neurospheres) which may reach macroscopical size. We have studied the inner organization of cells in semithin sections and revealed that the cell population within the neurosphere is not uniform. These are original findings as other researchers did not process neurospheres histologically. Cells located in a central area possessed neuron-like morphology whereas peripheral cells where differentiated to a lesser degree. Generally, we have observed several apoptotic cells or apoptotic bodies per section. Moreover, the central portion of the neurosphere contained degenerating cells that probably die from worsened nutrition conditions in the large neurosphere. After plating the neurosphere in serum-supplemented medium, cells began to migrate radially from the edge of the neurosphere and differentiate. The cells lying in the vicinity to the cluster mimicked radial glia whereas the cells located at the periphery of the colony took morphology of astroglial cells. These observations suggest EGF-responsive neural precursor cells retained their ability to produce both neuronal and glial phenotypes after prolonged cultivation period. PMID- 8693283 TI - Epilepsy associated with low-grade brain glial neoplasms. AB - In 1991-1993, 52 patients underwent surgery for low-grade supratentorial glioma. In 37 of them (astrocytoma 22, oligodentrocytoma 12, oligodendroglioma 2) seizures, often refractory to drug therapy, appeared as the first symptom. These cases were retrospectively analyzed. The patients had partial seizures: simple, complex, or secondarily generalized (preoperative duration: from 3 days to 17 years (mean 2 years); frequency: between 1 and 2/year and over 10/day). Neurological examination either revealed slight focal changes or was normal. Conventional craniotomy and resection of a tumor, without intraoperative electrocorticography, was performed. Partial resection was performed in 73%, subtotal in 5%, "total" in 22% of the cases. Postoperatively, 27 patients had focal radiotherapy, 3 of them in combination with chemotherapy. Two patients were reoperated. Out of 33 alive (89%), about two-thirds appear normal by neurological examination and are seizure-free at present (mean follow-up period 28 months). Most remain on antiepileptic drugs at lower doses. Histological and immunohistochemical analyses of resected tissue together suggest that the peripheral zone of cortical tumor infiltration may participate on epileptogenesis. PMID- 8693284 TI - Breathlessness perception in asthmatic patients--clinical implications. AB - Dyspnoea perception in patients with asthma bronchiale varies considerably in the course of their disease intra- and interindividually. The variability tends to be age dependent, elderly patients being less aware of even severe obstruction. Blunted perception of progressive airway narrowing has been identified, as an independent risk factor of severe asthma attacks or even asthma induced death. Such patients should be provided with a peak flow meter for home objective monitoring of airway obstruction. Simultaneously, a written action plan of how to manage an impending asthma attack should be available. A small number of asthmatics has been shown demonstrate excessive dyspnoea perception when no or minor airway obstruction could be established objectively. These patients could also profit from offering them a home peak flow meter due to the calming of their distress when no airway obstruction was measured and avoiding them of drug overuse. PMID- 8693285 TI - Fc gamma RII-mediated regulation of human B cells. AB - Recent studies have provided considerable insight into the mechanism of BCR mediated B-cell activation, but the inhibitory signals transferred by Fc gamma Rs leading to down-regulation of BCR-activated B lymphocytes are not clarified yet. In the present paper the authors give an overview on new findings regarding BCR structure and signal transduction mechanisms induced by the B-cell antigen receptor complex and outline, partly based on their own observations, the possible mechanisms resulting in Fc gamma R-mediated inhibition of B cells. PMID- 8693286 TI - Cloning of a partial cDNA for rat interleukin-12 (IL-12) and analysis of IL-12 expression in vivo. AB - Experimental models of autoimmunity in the rat may feature selective activation of either the Th1 or Th2 subset of helper T cells. Interleukin-12 (IL-12) is a key cytokine in the development of Th1 responses. In order to study IL-12 in the rat we used polymerase chain reaction (PCR) primers based on murine IL-12 to amplify a partial cDNA from rat tissue. The product was cloned and sequenced: it shows 94% nucleotide identity with the murine gene and 94% identity of predicted amino acid sequence. Primers based on the rat IL-12 sequence were used to analyse IL-12 expression in vivo using semi-quantitative PCR. We studied RNA from lymphoid tissues of two rat strains which differ in their response to mercuric chloride (HgCl2): Brown Norway (BN) rats develop autoimmunity with a predominant Th2 response; Lewis rats are resistant. Interleukin-12 expression was higher in Lewis than BN, and higher in spleen than lymph node. After HgCl2, IL-12 expression increased in BN towards the time when the autoimmune response autoregulates. Variation in baseline levels of IL-12 expression may account for the Th2 predisposition of BN rats compared to Lewis rats; IL-12 may play a role in the autoregulation of the Th2 response induced by HgCl2. PMID- 8693287 TI - The effect of anti-oestrogens on cytokine production in vitro. AB - Oestrogens can regulate immune functions, and due to this females have more effective immune responses than males. Oestrogens and anti-oestrogens enhance T cell-dependent antibody production of B cells in vitro. The cytokine mediators which are behind oestrogen and anti-oestrogen induced effects are not yet known. The authors studied whether anti-oestrogens (tamoxifen and toremifene) can regulate PMA-induced cytokine production of B-, T- or myeloid cell lines. Anti oestrogens, tamoxifen and toremifene, stimulated overall cytokine production on a B-cell line (Ball), whereas on a T-cell line (Molt-4) tamoxifen stimulated IL-1 beta, IL-6 and IFN-gamma production and toremifene inhibited it. Anti-oestrogens did not have any significant effect on cytokine production of myeloid cells. PMID- 8693288 TI - T helper-independent activation of human CD8+ cells: the role of CD28 costimulation. AB - The concept that activation of MHC class I-restricted CD8+ cells entirely depends on help from MHC class II-restricted CD4+ T cells has recently been supplemented with an alternative model in which CD8+ cells can directly be activated by MHC class I-expressing professional antigen-presenting cells (APC), which are able to deliver an accessory signal. The authors analysed the role of CD28-mediated costimulation for T helper cell-independent activation of purified human CD8+ T cells in two different in vitro models. Freshly isolated CD8+ cells could be activated (proliferation, IL-2 production and cytotoxic activity) by anti-CD3 presenting Fc gamma R+ mouse cells transfected with the human CD28 ligand, CD80, as the only accessory signal. On the other hand, activation of CD8+ cells by allogeneic MHC class I on EBV-transformed B cells, which express two different CD28 ligands, CD80 and CD86, also proceeded very efficiently (proliferation, cytotoxic activity and CD25 expression), but was either not, or only partially, blocked by anti-CD80 and anti-CD86 MoAb or CTLA-4Ig. This indicates that other costimulatory signals are also effective, and that CD28 triggering is not absolutely required for initial T-cell activation. CsA and CD80/CD86-blocking agents were synergistic in completely inhibiting activation of CD8+ cells in the MLR with allogeneic B-cell lines. This combination also induced non responsiveness of CD8+ cells upon restimulation in the absence of blocking agents. Therefore, although professional APC can apparently provide multiple costimulatory signals for direct activation of CD8+ T cells, the signal derived from CD80/CD86 is unique in providing CsA-resistance. PMID- 8693289 TI - The human mast cell line HMC-1 expresses C5a receptors and responds to C5a but not to C5a(desArg). AB - The expression of the receptor for the anaphylatoxin C5a (C5aR, CD88) on the human mast cell line HMC-1 was studied with four anti-C5aR monoclonal antibodies directed to the N-terminal domain of the receptor. All antibodies bound to the human mast cell line HMC-1. The binding could be blocked by recombinant C5a and by peptide EX-1 representing amino residues 1-31 on the N-terminal domain of the C5aR. In addition, FITC-labelled C5a bound to HMC-1, and this binding could be blocked by unlabelled C5a or C5aR antibodies. C5aR-specific mRNA was detected in HMC-1 cells by RT-PCR which confirmed the expression of the C5aR gene made by these cells. Lymphocyte-conditioned medium, interferon-gamma or phorbol esters which have been shown to induce a down-regulation of C5aR on myeloid cells did not influence the expression of C5aR on HMC-1. C5a led to a transient mobilization of intracellular calcium in HMC-1 which could be inhibited by pre incubation of C5a with a C5a-specific antibody. In contrast to findings with granulocytes, HMC-1 did not respond to C5a(desArg), confirming previous findings with human skin mast cells. The findings show that (i) although HMC-1 differ from granulocytes in their responsiveness to C5a(desArg), they express similar C5aR and (ii) HMC-1 cells resemble skin mast cells in the expression and function of C5aR and may therefore serve as a model in future studies addressing the biology of this anaphylatoxin receptor on skin mast cells. PMID- 8693290 TI - CD45 engagement induces L-selectin down-regulation. AB - The CD45 glycoprotein isoforms exhibit a receptor-like composition and display intracellular protein tyrosine phosphatase (PTPase) activity. The present study links CD45 to the regulation of L-selectin (CD62L), a leucocyte glycoprotein important for extravasation and homotypic aggregation. Monoclonal antibodies (MoAbs) IOL1b and AICD45.2, but not GAP8.3, all of which are directed against common CD45 epitopes, were found to elicit lymphocyte L-selectin down-regulation. Lymphocyte L-selectin down-regulation in response to anti-CD45 MoAbs was enhanced by high cell density and partially antagonized by the protein tyrosine kinase (PTK) inhibitor, herbimycin A. The MoAbs IOL1b, AICD45.2 and GAP8.3 recognized granulocyte-expressed CD45 but did not induce loss of L-selectin expression of granulocytes. In contrast, the CD45 PTPase inhibitor, vanadate, induced L selectin down-regulation both in lymphocytes and granulocytes. The PTPase activation by nitric oxide (NO) or the NO-generating compound, sodium nitroprusside, did not affect L-selectin surface expression. Increased concentrations of soluble L-selectin were detected after anti-CD45 or vanadate induced down-regulation of L-selectin surface expression. While activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) induces rapid L selectin down-regulation of L-selectin surface expression in both lymphocytes and granulocytes, the PKC inhibitor, H 7, was also found to down-regulate lymphocyte and granulocyte L-selectin surface expression. The inhibitor H 7 synergized with vanadate in down-regulating lymphocyte L-selectin surface expression, but partially inhibited vanadate-induced granulocyte L-selectin down-regulation. The results suggest that in a cell type-specific fashion the PKC system and tyrosine phosphorylation and dephosphorylation cascades are involved in the regulation of L-selectin surface expression. PMID- 8693291 TI - Persistent CD3-crosslinking down-regulates interleukin-2 responsiveness in interleukin-2-competent cloned T cells: the possible involvement of protein kinase C. AB - To investigate the regulation of interleukin-2 (IL-2) responsiveness of T cells, a human CD4+ T-cell clone with constitutive expression of IL-2 receptors was stimulated with recombinant IL-2 (rIL-2) in the presence or absence of immobilized anti-CD3 monoclonal antibodies (alpha CD3imm MoAb). Incubation of T cells with alpha CD3imm MoAb decreased IL-2-induced proliferation which could not be ascribed to the modulation of IL-2 receptor expression nor to cell death. Phorbol-myristate-acetate (PMA), an activator of protein kinase C (PKC), also induced down-regulation of IL-2 responsiveness. The alpha CD3sol MoAb, inducing Ca(2+)-mobilization without activating PKC, did not inhibit IL-2 responsiveness whereas cyclosporine A (CsA), a drug that inhibits the Ca(2+)-dependent activation pathway, did not prevent the induction of IL-2 hyporesponsiveness induced by alpha CD3imm MoAb. It is concluded that modulation of IL-2 responsiveness of T cells via the T-cell receptor/CD3 complex (TCR/CD3) may be mediated by a PKC-activating signal. PMID- 8693292 TI - Characterization of a human basophil-like cell line (LAMA-84). AB - LAMA-84, a human leucocytic cell line, which upon establishment was described as having megakaryocytic, erythroid and granulocytic characteristics, was analysed for expression of various differentiation markers. In addition to some of the previously described phenotypic characteristics, this cell line was found to express mRNA for several proteins characteristic for basophilic leucocytes and mast cells. The authors show that LAMA-84 cells express mRNA for the mast cell tryptase, the proteoglycan core protein, carboxypeptidase A and the alpha and beta chains of the high affinity IgE receptor (Fc epsilon RI). The authors examined the potential of LAMA-84 to differentiate in serum-free medium or after DMSO or PMA treatment. Depending on the inducing factor, surface expression of the Fc epsilon RI alpha-chain was increased from 20% to 35-50% of the cells and mRNA levels for tryptase were increased in serum-free medium and after DMSO treatment. LAMA-84 was found to express CD13, CDw17, CD29, CD33, CD40, CD45 and CD117. Furthermore, mRNA for the eosinophil/basophil markers Charcot-Leyden crystal (CLC) protein and the major basic protein (MBP), as well as the erythrocyte differentiation marker alpha-globin, was detected. However, the authors observed only trace amounts of mRNA for another erythroid differentiation marker (glycophorin), trace amounts of the megakaryocytic marker GPIIIa, and no detectable level of GPIb alpha. By comparing the expression pattern of a panel of differentiation markers in LAMA-84, and a second human cell line (KU812) expressing a basophil phenotype, it is evident that these cell lines, which presently are the only two cell lines identified with basophilic characteristics, share a large number of phenotypic characteristics. PMID- 8693293 TI - Decreased number of CD73 (ecto-5'-nucleotidase) molecules on lymphocytes from patients with primary immunoglobulin deficiencies. Correlation between number of CD73 molecules and T-lymphocyte function in vitro. AB - CD73 is a bifunctional glycosyl phosphatidylinositol anchored leucocyte differentiation antigen which has specific ecto-5'-nucleotidase (ecto-5'-NT) activity and is an accessory T-lymphocyte activation molecule. The aim of the present study was to investigate the CD73 expression on blood mononuclear cells (BMC) from a group of patients with primary immunoglobulin deficiency (IGD). This group of patients had both significantly decreased levels of ecto-5'-NT on BMC (P = 0.002) and decreased numbers of CD73 molecules per CD73+ lymphocyte (P = 0.01). Five of the 10 patients had a decreased percentage of CD73+ lymphocytes. Among B lymphocytes the patients had normal percentages of CD73+ cells but four of the 10 patients had numbers of CD73 molecules per CD73+ B-lymphocyte below the normal range. Among CD4-lymphocytes three out of 10 patients had percentages of CD73+ below the normal range and four out of 10 patients had decreased percentages of CD73+ CD8-lymphocytes. Significant correlations were found between in vitro proliferative responses to mitogens and the number of CD73 molecules per CD73+ lymphocyte (rs = 0.60, P < 0.01) and per CD73+ CD8-lymphocyte (rs = 0.64, P < 0.02). In addition, a positive correlation was found between ability to proliferate and level of ecto-5'-NT on BMC (rs = 0.53, P < 0.05). Furthermore the ability of BMC to synthesize ecto-5'-NT was studied. During 2 days culture ecto 5'-NT activity increased markedly on BMC from both patients and healthy donors. The level of activity on BMC from all patients attained levels higher than on freshly isolated BMC from healthy donors. This shows that the decreased levels of ecto-5'-NT found on freshly isolated BMC from patients with IGD is due to defective regulation of the enzyme activity in vivo. PMID- 8693294 TI - Bacteria-specific T-cell clones are selective in their reactivity towards different enterobacteria or H. pylori and increased in inflammatory bowel disease. AB - In the present study the authors investigated the T-cell response to different enterobacteria or Helicobacter pylori and tested the hypothesis that the frequency of bacteria-specific T cells is increased in the intestine of patients with active inflammatory bowel disease (IBD), i.e. Crohn's disease (CD) and ulcerative colitis (UC). The analysis of a large panel of T-cell clones (Tc) (n = 888) from peripheral blood, non-inflamed and inflamed intestine from IBD patients and control individuals shows that both peripheral blood and intestinal T-cell clones were selectively stimulated by either Salmonella typhimurium, Yersinia enterocolitica 03, Escherichia coli or Helicobacter pylori sonicates, that only < 3% of all bacteria-reactive Tc were crossreactive and that proliferation to bacterial sonicates was inhibited by anti-MHC class II antibody. In addition, bacteria-specific Tc from IBD patients were more frequently isolated from inflamed intestine than from peripheral blood (P = 0.0039) or non-inflamed intestine. These data, from a large number of T-cell clones, are the first systematic analysis describing the response of individual T cells towards different bacterial species (ssp.). They show that T cells with specificity for distinct antigens or superantigens that are characteristic for a defined bacteria ssp. are present in normal, and increased in inflamed, IBD-intestine. These bacteria-specific Tc may play a role in IBD pathogenesis. PMID- 8693295 TI - Co-stimulation-induced release of pro-inflammatory cytokine interleukin-8 by allergen-specific T cells. AB - Chemokines, which include interleukin (IL)-8, are a family of pro-inflammatory molecules with potent chemoattractant activity on neutrophils, as well as other cell types. IL-8 can be recovered from many inflammatory sites. To test the hypothesis that Th2-type allergen-specific T cells, known to be the main cell type governing the allergic inflammation, are a source of IL-8 and to investigate whether IL-8 release is influenced by the nature of the in vitro mitogenic or co mitogenic stimulation, cypress-specific T-cell clones (TCC) were generated from five allergic subjects during in vitro seasonal exposure to the allergen. Purified cypress extract was produced directly from freshly collected pollen and used for in vitro stimulation of PBMC bulk cultures. After 5 days priming and a further 7 day period of IL-2-driven cell expansion, monoclonal antibodies to CD3, CD2 and CD28 were adopted for in vitro restimulation of allergen-specific cell lines or, subsequently, secondary established TCC. The induction of apoptosis was detected by propidium iodide (PI) cytofluorimetric assay. Basal and co stimulation-induced IL-8 production was measured by an ELISA method. Both cypress specific T-cell lines and TCC secreted appreciable amounts of IL-8. By cross linking T-cell lines or Th2 CD4+ TCC with CD3, CD2 or CD28 MoAbs, the authors observed a great stimulation-induced IL-8 secretion, preferentially after CD2 or combined CD2/CD28 stimulation. In addition, CD4+ clones released large amounts of IL-8 into culture supernatants after CD2 stimulation while undergoing programmed cell death (30-40% hypodiploid DNA profile of PI-stained cells). In contrast, CD3 crosslinking was unable to determine the release of IL-8 or the induction of apoptosis. Taken together, these results suggest that incomplete TcR engagement by allergen may lead to the secretion of pro-inflammatory cytokines with a contemporary induction of apoptosis in a significant number of target cells. This phenomenon may represent an additional way for local recruitment of neutrophils and basophils. PMID- 8693296 TI - Signals leading to the activation of NF-kappa B transcription factor are stronger in neonatal than adult T lymphocytes. AB - The molecular background of the defects in the immune reactivity of human neonates has not been fully elucidated. As the NF-kappa B transcription factor has a central role in the control of transcription of several genes involved in immune and inflammatory responses, the authors have analysed the activation of NF kappa B in human umbilical cord T lymphocytes. The activity was tested by quantitating the nuclear proteins binding to an oligonucleotide containing the consensus kappa B binding sequence (electrophoretic mobility shift assay). The data obtained demonstrate that phorbol dibutyrate/calcium ionophore A23187 (PDBu/iono) combination induced a clearly higher nuclear translocation of NF kappa B in neonatal than adult T cells. This higher NF-kappa B activity was restricted to the CD4+ T-cell subset. Analysis of the nuclear extracts with antibodies directed against the major components of NF-kappa B the p50 and RelA (p65) proteins, indicated that the composition of NF-kappa B was similar in neonatal and adult cells. These results suggest that neonatal T cells are exposed to oxidative stress-inducing signals during delivery and/or are inherently more sensitive to NF-kappa B activating signals than adult T cells. PMID- 8693297 TI - Early B-cell factor (EBF) down-regulates immunoglobulin heavy chain intron enhancer function in a plasmacytoma cell line. AB - The immunoglobulin heavy chain intron enhancer contains two potential binding sites for early B-cell factor (EBF). To investigate the functional properties of these, EBF was expressed in the EBF non-expressing S194 plasmacytoma cell line and found to down-regulate the activity of a co-transfected immunoglobulin heavy chain intron enhancer reporter construct. The expression of an unrelated reporter construct was unaltered. Dividing the immunoglobulin heavy chain intron enhancer into two subregions showed that the EBF mediated down-regulation of expression was mediated by at least two independent sites. These data indicate a role for EBF in the regulation of immunoglobulin gene expression. PMID- 8693298 TI - [Beta-blockers in cardiac insufficiency. Time to reconsider?]. PMID- 8693299 TI - [Acute overdose of Zolpidem (Stilnox)]. AB - Zolpidem (Stilnox), an imidazopyridine derivative, is a strong sedative with minor myorelaxant and anticonvulsant properties which exhibits high-affinity binding at a benzodiazepine-receptor subtype. Although the structure of zolpidem differs from the benzodiazepines, the acute toxicity of zolpidem has generally been compared to triazolam (Halcion) and midazolam (Dormicum). 5 years after introduction of zolpidem to the Swiss market we have therefore retrospectively analyzed 91 well documented cases of acute zolpidem intoxication reported to the Swiss Toxicological Information Center. Furthermore, 54 single-drug poisonings with zolpidem were compared with 53 triazolam and 55 midazolam intoxications observed over the same time period. 0.01-0.02 g of zolpidem is the recommended therapeutic dose. But only mild symptoms were observed in acute single-drug poisonings with zolpidem up to 0.6 g. Patients mainly suffered from somnolence. Only one anorectic patient became comatose after ingestion of 0.6 g zolpidem. The acute toxicity of zolpidem was markedly less pronounced than that of the short acting benzodiazepines triazolam and midazolam. With forty-fold the therapeutic dose no severe symptoms occurred in patients with zolpidem single-drug poisonings, while coma was encountered in 4 cases with triazolam (11% of patients) and 4 cases with midazolam (10%). While only the patient mentioned above was reported to be comatose after overdosing with zolpidem, 6 (11%) and 8 (15%) comatose patients were observed in triazolam and midazolam single-drug poisonings, respectively. On the other hand, in combined intoxications with other CNS active drugs or ethanol a zolpidem dose as low as 0.1-0.15 s induced coma in some patients, even if the amount of the additionally ingested drugs in itself would not have caused a comatose state. Flumazenil (Anexate) was an effective antidote in mono- and combined intoxications involving zolpidem. In conclusion, our results indicate that zolpidem single-drug poisonings are generally benign and require no specific therapeutic measures. In combined intoxications, however, patients may develop coma at relatively low zolpidem doses and should therefore be monitored for approximately 24 hours. If necessary, disturbances of consciousness can be successfully treated with flumazenil. PMID- 8693300 TI - [Adult form of GM2-gangliosidosis: a man and 2 sisters with hexosaminidase-A and B deficiency (Sandhoff disease) and literature review]. AB - Three adult siblings had atypical progressive spinal muscular atrophy of the limb girdle type, predominantly sensory polyneuropathy and cerebellar ataxia. Hexosaminidase A and B activity was profoundly decreased in serum, leukocytes and cultured fibroblasts. GM2-gangliosidosis, variant O (Sandhoff disease) was diagnosed. Mechano-allodynia was the presenting symptom in two of the patients. After 50 years of disease evolution, the patients led an independent life and were intellectually normal. The literature on the adult form of GM2 gangliosidosis is reviewed. PMID- 8693301 TI - [African histoplasmosis in a patient with HIV-2 infection]. AB - 9 months after immigration into Switzerland, a 38-year-old male patient from Liberia/West Africa developed granulomatous and subsequently ulcerative nodules in the face. The heterosexual patient, with no history of i.v. drug abuse, tested positive for HIV-2. Histology of a skin biopsy revealed superficial colonization by numerous fungal elements described as spores and hyphae that were compatible with the initial isolation of Candida parapsilosis. The definite diagnosis of African histoplasmosis was established 3 weeks later after review of the PAS stained direct smear and after cultures had grown a cream-colored mold subsequently identified as Histoplasma capsulatum var. duboisii. There were no signs of disseminated disease. The lesions cleared under therapy with itraconazole (200 mg q 24h for 2 weeks, subsequently 100 mg q 24h) as well as ketoconazole and Aqua Dalibour (A. zinco-cuprica) locally for 2 months. Follow-up was not possible. Despite alarmingly increasing numbers of HIV-positive patients in Africa, the general incidence of African histoplasmosis seems to be stable with only a few cases per year. To our knowledge only four cases of disseminated African histoplasmosis have been reported in HIV-positive patients; localized cutaneous infection as in our patient, seems to be the exception. The low incidence of this infection is in contrast to the substantial number of HIV positive patients with disseminated histoplasmosis by H. capsulatum var. capsulatum in the United States. PMID- 8693302 TI - [Food allergy: definition, diagnosis, epidemiology, clinical aspects]. AB - Contrary to the lay and media perception, adverse reactions to foods (and food additives) occur less often than believed by the patients. The term food intolerance (FI) is widely misused as a cause of all sorts of symptoms and diseases. This diagnosis is often based on "alternative" techniques. Food allergy (FA) is the correct diagnosis if the symptoms resulting from the ingestion of a food (or an ingredient) are due to an immune mechanism. This diagnosis is seldom difficult in the case of a severe reaction immediately after ingestion of the food and when skin prick tests and/or IgE antibodies to the incriminated food are clearly positive. However, the best way to establish FA/FI is-apart from exclusion from the diet, which tends to have a marked placebo effect-the performance of proper double-blind, placebo-controlled food challenges (DBPCFC). Evidently, there are difficulties in conducting studies of this nature in a large population sample, and so far only three prevalence studies in Dutch and English adults have been based on DBPCFC. The reported prevalences of FA/FI (questionnaire answers) were 12% to 19%, whereas the confirmed prevalences varied from 0.8% to 2.4%. For additive intolerance the prevalence varied between 0.01 to 0.23%. The consequences of mistaken perception of FA/FI, which can have a major social impact in financial and health terms, require an information campaign for doctors, lay and media in connection with these problems. PMID- 8693303 TI - [Greatness and hazards of medicine]. AB - A critical and constructive discussion of the Janus-face of modern medicine is presented. Its image of the human being and of the physician are viewed as a source of grandeur as well as a threat. After sidelights on the grandeur of modern medicine and its impressive advances, attention is focused on the threats hanging over it: the predominance of patriarchal norms with corresponding neglect of matriarchal paradigms, headlong technologic progress with atrophy of the spiritual dimension, and the dangers of inflated knowledge and specialization. Finally, an attempt is made to look ahead to a humane future medicine which has evolved in three ways: a bridge has been thrown between the scientifico technologic and spiritual culture; it has broadened its present predominantly pathogenetic view into a restorative view, and it has also broadened the image of the physician. PMID- 8693304 TI - Prevention of gastrointestinal cancer--the potential role of NSAIDs in colorectal cancer. AB - Gastrointestinal cancers are among the leading sites of cancer and leading causes of cancer-related deaths. Gastrointestinal cancers are often at an advanced stage at the time of diagnosis, and are highly resistant to non-surgical therapy. Thus early diagnosis and prevention are approaches that are under active investigation. Screening and surveillance are considered secondary prevention. Primary prevention is the use of dietary or environmental modification or chemopreventive agents. This written review will emphasize the potential role of acetylsalicylic acid and other non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention of gastrointestinal cancer, and specifically colorectal cancer. Cell culture and animal studies have shown that NSAIDs possess anti-proliferative and anti-neoplastic effects. Recent epidemiologic surveys also suggest that individuals who regularly take NSAIDs, particularly acetylsalicylic acid, have about a 50% decrease in colorectal cancer incidence and mortality. However, in the only interventional trial of aspirin (and beta-carotene), a retrospective analysis had inadequate statistical power to demonstrate any protective effect against colorectal cancer. About a dozen small prospective intervention studies have been done in a total of about a hundred patients with familial adenomatous polyposis to test the efficacy of NSAIDs, particularly sulindac. All human trials have shown substantial partial and some complete regression of colorectal and perhaps also duodenal adenomatous polyps. But virtually all patients had regrowth of adenomatous polyps after sulindac was stopped. In addition, sulindac and other NSAIDs result in occasional adverse events such as gastrointestinal bleeding. Thus sulindac cannot be recommended for routine use outside of a study setting. One valid current approach to the prevention of gastrointestinal cancer, and colorectal cancer in particular, is the adoption of a healthy lifestyle and appropriate screening and surveillance. Screening and surveillance guidelines have been developed by several public agencies and their recommendations should be adopted. In addition, we should adopt a healthy lifestyle and diet, which consists of low fat ( < 30% to total calories), and high fiber (> 3 daily servings of fruits/vegetables), with the avoidance of red meats ( < 3 weekly servings) and alcohol ( < 2 drinks daily), and the absolute avoidance of tobacco smoking. PMID- 8693305 TI - [Gastrointestinal lymphomas: ultrasonic aspects]. AB - The importance of ultrasound for the diagnosis of gastrointestinal malignant lymphoma is explained by the fact that ultrasound is the first radiologic procedure after clinical examination which is used in diagnostic workup. The main sonographic findings are based on the radiologic appearance of the bowel wall and differentiation of its layers, starlike configuration of the narrowed echogenic center and hypoechoic wall thickening of varying extent. Typically, malignant lymphoma of the gastrointestinal wall shows as hypoechoic circumferential intestinal infiltration. Other findings such as exclusive mucosal involvement, transmural segmental infiltration or bulky tumor are rare. Characteristically, peristalsis is unaffected until a late stage in patients with gastrointestinal malignant lymphoma. These sonographic findings in patients with gastrointestinal lymphoma are not alone specific for the disease, but the combinations of various abnormalities found by ultrasound are helpful in selecting appropriate radiologic, endoscopic and biopsy procedures in the further diagnostic workup. PMID- 8693306 TI - Endoscopic ultrasonography in gastric lymphoma. AB - Endoscopic ultrasonography (EUS) was performed in 82 patients with primary gastric lymphoma. EUS correctly diagnosed lymphoma in 76/82 patients, with a sensitivity of 93%. Positive predictability was 91%, specificity 98%, and negative predictability 98%. Diagnostic accuracy was 97%. In the evaluation of lymphoma, depth invasion EUS was correct in 87% of cases. EUS disclosed metastatic perigastric lymph nodes in 15/27 patients, with a sensitivity of 56%. Positive predictability was 100%, specificity 100%, and negative predictability 82%. Diagnostic accuracy was 85%. Differential diagnosis with EUS among lymphoma, linitis plastic and Menetrier's disease was difficult. Large particle biopsy must be considered when EUS diagnosis of these diseases remains uncertain. PMID- 8693307 TI - [Helicobacter pylori infection and gastrointestinal lymphomas]. AB - Primary gastric lymphoma of the MALT (mucosa-associated lymphoid tissue) is nowadays considered a distinct entity with specific morphological, biological and clinical characteristics. In the pathogenesis of gastric MALT lymphoma, Helicobacter pylori infection plays an important conditioning role, In the case of low grade gastric lymphoma of stage E I, eradication of Helicobacter pylori offers a promising therapeutic option. PMID- 8693308 TI - [Radiodiagnosis of gastrointestinal lymphomas]. AB - Radiological synopsis of primary gastrointestinal lymphoma depends on the growth direction and dynamism of the tumor, i.e. grade of malignancy and stage of the pathological processes at diagnosis. Initial nodal-polypoid lesions, because of their mucosal/submucosal aggregation, in combination with more or less pathological small bowel relief, are successfully diagnosed by conventional barium studies. Progressive ulcerous and narrowing destruction of the gut wall, as a result of the advanced mural infiltration, increases the success rate of tomographic examination. Tomographic imaging, particularly computed tomography, is considered the primary method, alongside the selective small bowel double contrast study for demonstration of diffuse tumor infiltration. PMID- 8693309 TI - [Role of surgery in gastrointestinal lymphomas]. AB - The role of surgery in primary gastrointestinal non-Hodgkin lymphoma is still controverted. The author reviews the advantages of surgery, which alone allows diagnosis in emergencies, serves to assess the extent of the disease, offers a means of preventing complications chemotherapy and radiotherapy, and has a therapeutic function. He also assesses the drawbacks of surgery and provides exact surgical indications depending on the circumstances and localization of the lymphoma. In an area which has seen rapid changes in 1995, surgery still retains an important role in the therapeutic arsenal. PMID- 8693310 TI - [MALT-type low-grade B-cell lymphomas of the stomach and Helicobacter pylori]. AB - From January 1 1994 to March 1 1995 we observed 6 patients with gastric low-grade B-cell lymphoma of MALT type in association with Helicobacter pylori infection. Endoscopically only 3 of the 6 patients presented with pathological findings. All but one patient with metastatic carcinoma received antibiotic therapy for Helicobacter pylori. Follow-up was not possible in one patient who died unexpectedly. In all 4 patients followed-up, eradication of Helicobacter pylori resulted in regression of the malignant lymphoma. During the median follow-up time of 7 months (2-13 months) no relapse of lymphoma was observed. Our results confirm that gastric low-grade B-cell lymphoma of MALT type can regress after eradication of Helicobacter pylori. PMID- 8693311 TI - [Molecular genetic diagnosis and deletion analysis in Type I-III spinal muscular atrophy]. AB - Autosomal recessive spinal muscular atrophy (SMA) is, after cystic fibrosis, the second most common fatal monogenic disorder. The disease is characterized by degeneration of anterior horn cells leading to progressive paralysis with muscular atrophy. Depending on the clinical type (Werdnig-Hoffmann = type I, intermediate form = type II, Kugelberg-Welander = type III), SMA causes early death or increasing disability in childhood. The SMA-critical region on the long arm of chromosome 5q13.1 contains many duplicated genes and polymorphisms. Recently, two presumptive SMA genes (survival motoneuron gene = SMN, and neuronal apoptosis inhibitory protein = NAIP) have been identified. Deletions involving critical regions of these genes are very often associated with SMA, and the extent of the deletions seems to correlate in part with disease severity. We have evaluated the diagnostic and prognostic value of molecular analysis in a large number of SMA patients. 57 patients and 78 healthy relatives were molecularly screened for deletions in the SMA critical region. We demonstrated homozygous deletions removing the SMN genes in over 90% of patients, whereas nearly 45% of patients exhibited NAIP gene deletions. Large deletions involving both genes on each chromosome are generally found in patients with severe SMA (Werdnig-Hoffman cases), while mildly affected Kugelberg-Welander cases frequently show only deleted SMN genes. Molecular classification based on combined deletion sizes, however, seems not to be exact, especially for the group with chronic SMA (type II and III). Direct DNA testing of patients in whom SMA is suspected is a highly reliable, fast, and noninvasive method. The ability to detect homozygous gene deletions in a high percentage of typical SMA patients will much improve genetic counselling and prenatal diagnosis in affected families. PMID- 8693312 TI - [Lausanne experience in radiofrequency percutaneous ablation of the slow pathway in nodal tachycardia]. AB - Atrioventricular nodal reentrant tachycardia (AVNRT) is the most frequent paroxysmal supraventricular tachycardia and results from reentry in the atrioventricular nodal region via slow and fast pathways. The curative treatment of choice consists of selective radio-frequency catheter ablation of the slow pathway. In this retrospective study we report our experience of 73 consecutive patients suffering from AVNRT treated by selective slow pathway ablation and also review some features of AVNRT. AVNRT appeared for the first time at the age of 29 +/- 15 years and lasted for 17 +/- 13 years. In 37% of the patients AVNRT recurred at least weekly, 10% presented with syncope and 15% were admitted to hospital more than 5 times. On average, 2.5+/-1.6 drugs were prescribed to 66 of the 73 patients and 83% of them were drug-refractory. Selective slow pathway ablation was successfully performed in 65 patients (89%). The procedure, although effective, was complicated by atrioventricular block in 2 patients (2.7%) and failed in 6 patients. In 5 of them, fast pathway ablation was attempted and was successful in 2 cases, resulted in atrioventricular block in one case and failed in 2 cases. The complications, apart from atrioventricular block necessitating a pacemaker in all cases, were one pulmonary embolism and 2 pneumothorax. The mean follow-up for the 70 patients for whom ablation was effective (with or without atrioventricular block) is 12.7+/-7.3 months. AVNRT relapsed in 5 patients (7%); all of them underwent a second ablation with 4 successes (slow pathway) and one atrioventricular block (fast pathway after failed slow pathway ablation). 11 patients (16%) developed palpitations: in one case they were due to atrial fibrillation and in 10 cases they remained of unknown origin. The palpitations were of short duration and well tolerated, and these patients nevertheless felt an improvement after the ablation. Therefore, at medium term, 62 patients (85%) remained free from symptoms or only slightly symptomatic and without a pacemaker, and 51 of them (70%) remained completely asymptomatic and without a pacemaker. AVNRT can result in considerable morbidity and antiarrhythmic drugs are frequently ineffective. Slow pathway ablation is a safe and effective treatment for AVNRT. In our opinion, if AVNRT or medical treatment diminish the quality of life, ablation is indicated. When AVNRT presents with hemodynamic collapse, ablation is mandatory. Fast pathway ablation after failed slow pathway ablation is associated with a high incidence of atrioventricular block and is targeted only at very symptomatic patients who accept the possibility of definitive pacemaker implantation. PMID- 8693313 TI - [Menstruation-associated (catamenial) pneumothorax and catamenial hemoptysis]. AB - We report on 2 patients with catamenial pneumothorax and one patient with catamenial hemoptysis. The pathogenesis of these diseases is not clear, and intrathoracic endometriosis is often assumed. Catamenial pneumothorax is rare and differs from primary spontaneous pneumothorax in its prevalence in the fourth decade and in mainly multiparous women, its recurrent and almost exclusively right-sided occurrence within 72 hours of the beginning of menstruation, and the generally small size of the pneumothorax. About 5% of women under 50 presenting with primary pneumothorax have catamenial pneumothorax. Prevention of recurrence is difficult, as the recurrence rate is high, treatment duration is potentially long, and residual thoracic pain during menstruation is sometimes seen. The combination of medication (Gn-RH analogues, danazol, possibly hormonal contraceptive drugs or progestagens) with efficient pleurodesis (e.g. thoracoscopic talc application preferentially performed during menstruation) seems so far to be the most efficient, although no controlled studies have yet been performed. Catamenial hemoptysis is very rare and hormonal treatment alone is frequently successful in the long term. In the event of relapse, resection of the implicated endometriotic or angiomatous lesion localized by computed tomography can be performed. PMID- 8693315 TI - [The sense of smell: primitive and neglected?]. PMID- 8693316 TI - [The power of odors--pathogenic or unpleasant]. AB - Modern toxicological studies have prompted us to rethink the role of olfaction and odours in our world. Our sense of smell is able to discriminate between an almost unlimited number of compounds of different chemical composition at extremely low threshold levels. Olfaction is classified as a chemical sense because of the bimolecular excitation process between the stimulant and receptor molecule. Receptor molecules of the olfactory epithelium have a variable region of the molecule which can differentiate between an unlimited number of aromatics. The sense of smell--the oldest phylogenetic sense--is therefore in very intensive contact with the "chemical" environment. Virtually all of the aromatic products which we are exposed to are highly complex chemical mixtures of numerous individual components which have a toxic potential little investigated to date. The perception of odours can be interpreted as a warning--a protective mechanism necessary for survival. At the same time, however, the exaggerated use of perfumes is held to be indicative of a highly cultured status. Unlike any other sense, that of smell is directly connected to archaic areas of the paleocortex region of the cerebral hemisphere, so that an odour will fill us with joy or abhorrence outside of our control. Odours cannot, therefore, be analyzed rationally without eliciting instinctive reactions, positive or negative, which result in acceptance or rejection. The highly developed memory for odour types is believed to be coupled to the route of the olfactory tract. The use of olfactometry today enables odours to be reliably quantified and characterized in a reproducible manner. PMID- 8693317 TI - [Time loss in the therapy of acute heart infarct]. AB - As part of the ISIS study, the prehospitalization phase in 570 patients with acute myocardial infarction was evaluated and protocolled in 34 Swiss hospitals. The aim was to assess whether the time lapse between onset of pain symptoms and start of treatment could be shortened. It was felt that, particularly in the case of lethal cardiac arrhythmias, rapid intervention could secure reversal or controlled relief of symptoms and/or conduction disorders. The study protocol recorded the specific time lapses between onset of symptoms and notification of the physician, notification of the physician and hospital admission, and between hospital admission and therapeutic action. The longest time lapse observed was the patient's delay (57%). Delay by the patient was shortened when pain symptoms (a) occurred during daytime, (b) were preceded by symptoms in the week before the infarction, (c) occurred at work, and (d) occurred during exercise, particularly in the company of unknown persons. The longest time lapse observed in hospital was associated with the night shift. The time lost through delay in contacting a doctor, the main factor in delaying therapeutic action in acute myocardial infarction, is very difficult to influence since the target group for a public information campaign is hard to identify. On the other hand, the "door to needle" time lapse observed in hospital can be reduced by the introduction of clear-cut guidelines. PMID- 8693318 TI - [Supraventricular tachycardias: mechanism, diagnosis and therapy]. AB - Most of the paroxysmal forms of supraventricular tachycardia are reentry tachycardias in origin with either an AV-nodal reentry (AVNRT; approx. 50%) or an AV reentry circuit via accessory pathway (AVRT; approx. 30%) as the anatomical basis of tachycardia. The therapeutic options include either drug therapy or transcatheter radiofrequency ablation. In asymptomatic patients, where supra ventricular tachycardia or WPW syndrome was documented incidentally, an expectative approach without therapy is usually recommended. However, if frequent tachycardia recurrences or severe clinical symptoms (syncope, pre-syncope make treatment mandatory, medical therapy with either betablockers, calcium antagonists or digoxin should be tried if AV-nodal reentry tachycardia is the mechanism (no evidence of WPW syndrome on the 12-lead ECG). In patients with symptomatic WPW syndrome or drug refractory AV-nodal reentry tachycardia, transcatheter radiofrequency ablation with its good results and low complication rate is the therapy of choice. The treatment modality is particularly indicated in young patients who otherwise would need lifelong drug therapy. In contrast, supraventricular tachycardias with badly defined anatomical substrate, such as multifocal atrial tachycardias or atrial fibrillation, should in the first place be treated medically and not by radiofrequency ablation. PMID- 8693314 TI - [Drug therapy of cardiac insufficiency: status 1995]. AB - Congestive heart failure is a frequent disorder with an estimated prevalence of 0.4-2% in the general population. Despite recent advances in our understanding of the pathophysiology of this disorder and new developments in its treatment, the prognosis of heart failure remains poor. All patients with heart failure should undergo diagnostic evaluation to determine the type of cardiac dysfunction, establish its etiology and orient treatment. Angiotensin converting enzyme (ACE) inhibitors, diuretics and digoxin are the standard therapy for chronic congestive heart failure caused by systolic dysfunction. ACE inhibitors are indicated in all stages of heart failure, even in asymptomatic patients. Diuretics should be added in the presence of fluid retention. Digoxin remains an important component in the management of refractory symptoms and atrial fibrillation. Symptomatic improvement and reduced morbidity have been shown with all these drugs. However, improved survival has been documented for ACE inhibitors only. Currently, numerous drugs with different mechanisms of action are being evaluated in ongoing clinical trials. Promising results have been published, mainly with beta-receptor blockers and newer positive inotropic substances. Rapidly growing evidence from basic research will advance our understanding of heart failure and hopefully pave the way for new preventive and therapeutic strategies in the near future. PMID- 8693319 TI - Paying attention. The controversy over ADHD and the drug Ritalin is obscuring a real look at the disorder and its underpinnings. PMID- 8693320 TI - Patient, smell thyself. PMID- 8693321 TI - Lethal accidents, 1979-1992. PMID- 8693322 TI - Mouse to father rat? Renewable reproductive cells could transform fatherhood. PMID- 8693323 TI - Magnet on the brain. Safer neurosurgery with magnetically steered implants. PMID- 8693324 TI - Gradients that organize embryo development. PMID- 8693325 TI - Ring bubbles of dolphins. PMID- 8693327 TI - Biocides: mechanisms of antifungal action and fungal resistance. PMID- 8693326 TI - Gaining on fat. PMID- 8693328 TI - Egg proteins: what are their functions? AB - The principal functions so far attributed to egg proteins are: (i) provision of nutrient for the developing embryo; (ii) protection of the egg from microbial attack; and (iii) transport of nutrients into the developing embryo. All the proteins contribute to the nutrient role in the form of the amino acid residues they contain. Some also contribute to the phosphate reserves. Protection is provided by a variety of means, including the physical barrier of albumen with its high viscosity, and the chemical barriers in the form of protease inhibitors, nutrient sequesters, a lytic enzyme, and antibodies. Various proteins are involved in nutrient uptake, either by acting as carriers or in the form of membrane receptors. PMID- 8693329 TI - The Samaritans. PMID- 8693330 TI - Monitoring of chronic disease registers. PMID- 8693331 TI - Registers--a public health view. PMID- 8693332 TI - Use of drugs at 'raves'. AB - Widespread use of drugs at the currently popular 'raves' has caused concern principally because of an increasing number of cases of serious toxicity and even death. The availability and use of drugs at raves, mainly in the Edinburgh area, have been investigated and self-reported use of drugs compared with results of urine screening. Use of Ecstasy and LSD have been confirmed and there is evidence to support the use of Khat. A new preparation, Herbal Ecstasy, is readily available at Edinburgh raves and appears to be widely used. All urines tested positive for one or more drugs or drug metabolites and in general analytical results correlated well with self-reported use of drugs. PMID- 8693333 TI - Feasibility of reducing L-thyroxine dose in patients with a suppressed serum TSH. AB - A total of 748 patients on L-thyroxine with a suppressed serum TSH were requested to reduce their dose and this was achieved in 601 patients. Thyroxine dosage was reduced by 25 or 50 micrograms of L-thyroxine and patients were reviewed six months later. Of all 601 patients, 54.4% remained with a suppressed serum TSH despite dose reduction and in 5.8% an elevated serum TSH resulted. 25 micrograms reductions and 50 micrograms reductions were equally likely to result in an detectable but non-elevated serum TSH (42.8% vs 34.1% ns) but 25 micrograms reductions were less likely to result in an elevated serum TSH (3.8% vs 10.0% p < 0.01). Only 7/601 patients in the study (1.2%) appeared to require a dose of over 150 micrograms. If dose reduction is thought to be necessary for patients with a suppressed serum TSH, we would recommend 50 micrograms reductions if the original dose is 200 micrograms or more, and 25 micrograms reductions if the original dose is 175 micrograms or less. PMID- 8693334 TI - Psychosis and substance abuse: cause, effect or coincidence? AB - An association between substance abuse and major psychiatric illness is increasingly well recognised, but most studies have been conducted in the USA and have focussed upon patients with schizophrenia rather than other disorders. We conducted a survey of 38 consecutively admitted patients with DSM-III-R functional psychoses. A semi-structured substance abuse interview was administered and a urine specimen for drug metabolite screening requested. The prevalence of cigarette smoking (63%) and current illicit drug use (26%) were higher than general population norms. The 16 subjects with schizophrenia and related disorders were more likely to smoke cigarettes than the 22 patients with an affective disorder (p = 0.008, odds ratio 8.4, 95% Cl 1.3-69.6), and showed tendencies to more illicit drug and alcohol consumption. Illicit drug users were more likely to have a forensic history and less likely to have entered further education. Substance abuse is common among patients with psychoses, particularly in those with schizophrenia and related disorders. All psychotic patients should have a detailed drug history taken, and therapeutic attempts made to reduce consumption. PMID- 8693335 TI - Cyclical etidronate and calcium carbonate (with citrate) supplementation for osteoporosis unmasking primary hyperparathyroidism. AB - An 88 year old lady undergoing cyclical etidronate and calcium carbonate (with citrate) therapy for vertebral osteoporosis was found to be symptomatically hypercalcaemic at the end of the first cycle of treatment. She had been previously asymptomatic and normocalcaemic, but was subsequently found to have primary hyperparathyroidism. This condition is most prevalent in postmenopausal females--the same patient group at risk of osteoporosis. Serum calcium should be measured after commencing cyclical etidronate and calcium carbonate. If hypercalcaemia is detected primary hyperparathyroidism should be excluded as an underlying, cause. PMID- 8693336 TI - The use, efficacy and monitoring of artificial nutritional support in a teaching hospital. AB - The implementation of circulated guidelines has been audited, by assessing the extent to which nutritional goals were set and achieved and recording the levels of morbidity as a result of complications. Adults receiving artificial nutritional support were studied over a six month period. Nutritional assessment was used to determine adequacy of prescription and efficacy of the support. Energy requirements were retrospectively calculated and compared with prescriptions and actual intakes. Complications and interruptions to the regimens which resulted in lost feeding time were recorded, as were patient outcomes. Nutrient prescriptions were inadequate, delivery of prescriptions was incomplete and thus nutrient supply inadequate. PMID- 8693338 TI - On metaphor. PMID- 8693337 TI - A Scottish doctor's association with the discovery of the plague bacillus. AB - Plague killed at least a quarter of the population of Europe in 1348. This was the first wave of the epidemic known as 'The Black Death' which continued for two years and then recurred sporadically till the late 17th Century. In London in 1603, 22.6% of the population died from plague and in the outbreak known as The Great Plague of London in 1694 there were over 70,000 deaths out of a population of 460,000. Many English villages were completely wiped out at this time. Marseilles suffered severely in 1720. The next serious outbreak was in Canton in China in 1894, the disease spreading to Hong Kong. 80,000 died, the great majority of these being in China. A Scottish doctor played an important part in the management of this epidemic when it reached the British colony, and by chance found himself on the periphery of the controversy about who first discovered Yersinia Pestis, the Gram negative bacillus that causes plague. PMID- 8693339 TI - Leprosy (Hansen's disease) in South Dakota. AB - Worldwide Hansen's disease is an important and relatively common disease, but is still very rare in South Dakota. Two patients are described to help demonstrate the wide variety of clinical manifestations associated with Hansen's disease. Since the clinical appearance of Hansen's disease is highly variable, the following six forms of Hansen's disease are described: Indeterminate, tuberculoid (TT), borderline tuberculoid (BT), borderline (BB), borderline lepromatous (BL), and lepromatous leprosy (LL). In addition, three well-recognized reactional forms of leprosy are also described: Type 1 (lepra reaction), type 2 (erythema nodosum leprosum), and type 3 (Lucio's phenomenon). While the disease affects primarily the skin and nerves, health care providers of all disciplines should remain alert for this disease which can present with a high degree of clinical variability. PMID- 8693340 TI - Clinical pathway effects on treatment of the alcohol withdrawal syndrome. AB - We investigated whether initiating a clinical pathway, that incorporated the use of an alcohol withdrawal assessment scale, would decrease length of stay (LOS) for and/or amount of benzodiazepine prescribed during uncomplicated alcohol detoxification. We retrospectively reviewed alcohol detoxification admissions on an inpatient unit: 66 admissions before, 56 after, and 75 admissions 1-year after initiation of the pathway. Admissions were grouped into completers and non completers. Comparison of group means before and after pathway implementation demonstrated a significant decrease in LOS for completers of the detoxification service from 7.35 to 4.77 days, and from 6.67 to 4.31 days for all admissions. Similarly, total benzodiazepine exposure decreased to a third of the mg amount given per admission prior to the pathway. There were no increases in the "irregular" discharge rate or complication rate. These findings suggest that a clinical pathway, with an incorporated withdrawal assessment scale, can decrease LOS and benzodiazepine prescribing on an alcohol detoxification unit. PMID- 8693341 TI - Theophylline: taking it to a new level. PMID- 8693342 TI - USDSM all-school symposium on AIDS. PMID- 8693343 TI - Legislation to protect individual confidentiality: the case of cancer registration in Germany. AB - Until 1994, cancer registration in Germany was characterized by non-uniformity. This was caused by different legal requirements for population-based cancer registries in the individual states (or Lander), resulting in either incomplete registration on the one hand, or the impossibility of using the data at the individual level for epidemiologic studies on the other hand. These existing disadvantages can be overcome with the new Act on Cancer Registration that came into effect in 1995. The new Act on Cancer Registration in Germany is discussed as a compromise between the interests of data protection and those of epidemiologic research. PMID- 8693345 TI - Monitoring the worker and the community for chemical exposure and disease: legal and ethical considerations in the United States. PMID- 8693344 TI - Ethical aspects of genetic predisposition to environmentally-related disease. AB - Some individuals are highly susceptible to disease caused by chemical exposures and this hypersusceptibility can be genetically determined. Because biomarker technology for the determination of genetic predisposition is at the disposal of researchers, the capability therefore exists to include genetic screening in epidemiologic studies. The application of this technological advance in population-based research is, however, fraught with ethical tensions heretofore unknown. Moral duties alone are of limited use in resolving these problems. Scientific documentation is almost always insufficient to clarify the exact nature of the ethical implications, and ways to deal with uncertainties arising as a result of information generated from genetic screening studies must be considered. The most important tensions relate to autonomy and the right to privacy, fairness and equality, while balancing potential public interest in paternalistic measures. Because no moral framework has been accepted for dealing with this technological advance, an ethical discourse in an open forum is required with all affected parties. Scientists alone, or any other group in isolation, should not expect to resolve these questions, but they should participate in and facilitate the process. PMID- 8693346 TI - Science, advocacy, human and environmental health. AB - Medicine and public health sciences are applied sciences. The research upon which these are based is mission-oriented and as such they are underlain by advocacy. Ecological sciences, by way of parallel, involve managing ecological systems so they can remain healthy to support productive natural processes and the human population. In any eco-system, however, renewal has associated with it naturally occurring background levels of diseases and death. These are normal in all biological systems. 'Sustainable development' has been focused on commodity based, managed systems where the goal is to ensure that the needs of growing human populations are met, producing healthy people. This objective is deemed by the Ecological Society of America to be too narrow. Priority should rather be given to the sustainability of natural ecosystems, otherwise the biosphere that sustains all life forms is neglected. Epidemiologists concerned with the health of populations need to recognize that human health and the health of natural systems have entwined destinies. Some convictions about limits, about the role of disease, degeneration, and death in healthy, that is, stable and sustainable human ecologies, ought to be embedded into any ethics for epidemiologists. PMID- 8693347 TI - Environmental integrity, racism, health. AB - Environmental degradation seriously affects human health. Thus, a close relationship exists between the protection of ecosystem integrity and wilderness on one hand, and human health on the other. However, there is an overarching, holistic perspective in laws and regulations--as well as morality--to to maintain a healthy relationship between the two. Problem areas focused on in this paper are: (a) climate change and global warming; (b) food production; and (c) global equity. This paper argues for the principle of integrity, which provides an holistic perspective, suggested as a better approach than that of current regulations to mitigate against associated threats to human health. PMID- 8693348 TI - [Prevalence of dental caries, gingivitis and periodontal disease in pregnant diabetic women]. AB - OBJECTIVE: To determine the difference in the prevalence of dental caries, gingivitis, and periodontal disease among non-diabetic, type-II diabetic and pregnant diabetic women. MATERIAL AND METHODS: In the period from June 1993 to January 1994, a cross-sectional study was carried out at the Instituto Nacional de Perinatologia among 160 pregnant women; eighty non-diabetic women were included in the control group, while 40 type-II diabetic and 40 gestational diabetic women conformed the study group. In each patient the following variables were recorded: age, week of pregnancy, the Simplified Oral Hygiene Index, the Decayed, Missing and Filled Teeth Index, the Gingival Index, and the Extent and Severity Index. Statistical analysis was carried out using Analysis of Variance and the Multiple Range Test, with a 95% confidence internal. RESULTS: All of the groups had similar prevalences of dental caries (100%). Type-II diabetic women showed a higher prevalence of gingivitis (42.5%) than non-diabetic (36.25%) and gestational diabetic (10%) women, but the differences were not statistically significant between the non-diabetic and type-II diabetic women. Type-II diabetic women had a statistically significant higher prevalence of periodontal disease (12.5%) than the women in the other groups. CONCLUSIONS: It is very important to establish proper metabolic control and a fitting oral hygiene in pregnant diabetic women, since type-II diabetes was shown to be associated with a higher prevalence of periodontal disease. Besides, gestational diabetes is likely to pose a high risk of periodontal disease in the absence of preventive measures. PMID- 8693349 TI - [Accumulated years of potential productive life lost due industrial accidents in Petroleos Mexicanos]. AB - OBJECTIVE: There are different indicators to give priority to health problems within the area of occupational health; we propose the calculation of accumulated years of potential productive life lost (AYPPLL) to estimate the loss of material and human resources due to work accidents. MATERIAL AND METHODS: A total of 8 638 work accidents were analyzed using this method. Independent variables were: sex, age, place and type of accident, subject's income and work conditions. The dependent variable was permanent disability. RESULTS: Subjects who had some kind of permanent damage were 19.5%; the total number of AYPPLL was 5611, with an average of 3.2 YPPLL per accident. Variables associated with the highest AYPPLL were the sociodemographic variables, male sex, lowest income levels, temporary work contracts and injuries of the hand and wrist. CONCLUSIONS: The AYPPLL method was found to be a valuable indicator of the safety and hygiene of the worksite and a useful tool for planning and evaluating work accident programs. PMID- 8693350 TI - [Safety belt use and severity of injuries in traffic accidents]. AB - OBJECTIVE: To analyze the association between the severity of car accident injuries and the use of safety belts. MATERIAL AND METHODS: The unit of observation and analysis was car drivers in the Mexico-Cuernavaca toll highway. Variables included were those of car drivers, the vehicles and the physical environment at the accident site. Statistical analysis was carried out by means of chi square, odds ratios, 95% confidence intervals and logistic regression. Data was collected in 422 questionnaires for 324 accident events. RESULTS: There were 177 injured people, including 12 deaths, with rates of 67.5 injuries and 4.58 deaths per 10 000 kilometers driven. Variables associated with not using a safety belt (p < 0.05) were: alcohol drinking, vehicle size, night-time and road section. Risk factors for severe injuries were: not using a safety belt (raw OR 4.9, 95% CI 2.2-10.8, adjusted OR 2.94, 95% CI 1.13-7.66); age < 25 years (OR 3.6, 95% CI 1.0-12.7) and > 54 (OR 6.0, 95% CI 1.4-25.0); alcohol drinking (OR 10.8, 95% CI 3.8-30.4); and night time (OR 2.8, 95% CI 1.4-5.8). CONCLUSIONS: Theses findings suggest the need to formulate interventions aimed at enforcing the use of safety belts and prevention of related factors. PMID- 8693351 TI - [The social cost of chronic bronchitis in Mexico City: a pilot study]. AB - OBJECTIVE: To construct a comprehensive model to evaluate the social or overall impact of a chronic disease. MATERIAL AND METHODS: Case studies of a convenience sample of 28 patients seen at secondary and tertiary levels of health care services. Bronchitis was selected for evaluation. Among the variables included in the model are the direct costs of health care for bronchitis, the indirect costs or costs of opportunity, and the intangible costs or loss of quality of life. Information on costs estimated by the home institution was also included. RESULTS: The social costs attributable to this condition are as high as $ 14 761.60 each case per year; 53% of this cost corresponds to case-management at health care services; 5% to household economic costs; 14% to intangible costs and 28% to production costs. CONCLUSIONS: The model allowed the identification of variables necessary to evaluate production, household and intangible costs, which have been seldom utilized in our country. Including these variables results in a more comprehensive economic evaluation of social costs of disease. PMID- 8693352 TI - [Breast cancer. A historical account, present and future]. AB - This essay describes the different theoretical constructions of breast cancer models, such as the biological, hygienist-preventive and epidemiological. An anecdotal account of the Hippocratic model is also presented. This disease will be one of the major challenges posed by noncommunicable diseases in coming years, due to a significant increase of life expectancy and to a decrease of the overall annual growth rate-resulting in the ageing of the population-, as well as to lifestyle changes-particularly the considerable decrease of fertility rates and breastfeeding practices-, and to the poor efficiency and effectiveness of breast cancer screening programs. In this context, one of the main challenges for breast cancer control is to secure the multidisciplinary approach offered by public health. After analyzing the different models, we favor the sociomedical model as the one that incorporates several areas of knowledge to formulate an effective response to breast cancer. PMID- 8693354 TI - [A year of redefinitions at the National Institute of Public Health]. PMID- 8693353 TI - [Comment on the article about teratogenesis due to industrial pollution caused by organic solvents]. PMID- 8693355 TI - [Prevalence of Haemophilus influenzae carrier state in children in Ciudad Nezahualcoyotl, State of Mexico, Mexico]. AB - OBJECTIVE: To determine the prevalence of H. influenzae (Hi) carrier state among children, in Ciudad Nezahualcoyotl, State of Mexico. MATERIAL AND METHODS: A cross-sectional comparative random study was designed. Study subjects were 639 children under 15 years of age, stratified by age and sex. Nasopharyngeal cultures were used to identify Hi and to typify encapsulated strains. Sample size was computed with the software package Epi-Info, using a p value of 0.5%, 95% confidence intervals and a 5% error; statistical analysis was performed using frequencies, means and proportions. Differences were tested by comparison of two proportions from independent populations. RESULTS: Hi was isolated from 136 of 639 pharyngeal cultures (21%). Hi types found were Hi b (n = 6, 4%), Hi a, c, and f (n = 5, 4%), and non-typifiable (NT) Hi (n = 125, 92%). CONCLUSIONS: The prevalence of pharyngeal colonization by Hi found among children under 15 years of age, in Ciudad Nezahualcoyotl, is similar to that reported in the literature. The inverse relation of pharyngeal carriers with age can be accounted for by the progressive development of specific and non-specific immunity against encapsulated and non-encapsulated strains. PMID- 8693356 TI - [Prevalence of risk factors associated with hepatitis C in blood donors in the municipality of Durango, Mexico]. AB - OBJECTIVE: To determine the prevalence of anti-viral hepatitis C antibodies (HCV Ab+) in voluntary blood donors and to identify the main risk factors associated with it. MATERIAL AND METHODS: A case-control study was conducted over a 20-month period beginning in June 1993. A clinical history was obtained from all blood donors seen at the Centro Estatal de la Transfusion Sanguinea (State Blood Transfusion Center) and the Instituto Mexicano del Seguro Social in Durango, Mexico. HCV-Ab+ was determined in 5 915 serum assays using the second generation enzymatic immunoassay (UBI HCV EIA). RESULTS: The prevalence of HCV-Ab+ was 1.47 per 100 donors. The HCV-Ab+ prevalence was similar for urban and rural donors (1.54% and 1.34%) with no history of work migration. The main risk factors associated with HCV were a history of transfusions, (odds ratio -OR- 14.80, 95% confidence interval -CI-4.97-47.17) and sexual promiscuity or intercourse with prostitutes, (OR 6.53, 95% CI 2.61-16.54). CONCLUSIONS: The high prevalence of HCV-Ab+ may be explained by the lack of epidemiological surveillance of the population at risk. These data underscore the need for routine screening of HCV Ab among voluntary blood donors and male or female prostitutes. PMID- 8693358 TI - Psychiatric institutions in decay. PMID- 8693357 TI - Chronic diseases of lifestyle. PMID- 8693359 TI - Evading bad blood. PMID- 8693360 TI - Deaths associated with anaesthesia--a lesson for South Africa. PMID- 8693361 TI - ACE inhibitors in pregnancy--how to avoid the sting in the tail. PMID- 8693362 TI - Impressions of health care systems in the new South Africa. PMID- 8693363 TI - Unity in the medical profession. PMID- 8693364 TI - HIV testing in the workplace. PMID- 8693365 TI - Doctor, your file is open. PMID- 8693366 TI - Implications of the development of managed health care in the South African private health care sector. AB - The South African private health care sector has been looking to managed health care (MHC) to control the unsustainable cost escalations of the last decade. This paper draws on experience of MHC in other countries, particularly the USA, to assess its potential for solving the private sector's difficulties. In addition, it looks at problems which may be associated with MHC in a South African setting. The conclusion reached is that MHC alone cannot be seen as a panacea for the private sector's financial problems, although it may produce a degree of saving and be part of a solution. It is argued that MHC per se seems unlikely to compromise equity, quality of care or the public health care sector, and that it may potentially promote national health policy objectives. However, if MHC's benefits are to be maximised and potential negative effects controlled, ongoing monitoring of MHC, coupled with an appropriate regulatory and incentive environment, will be required. PMID- 8693367 TI - Mortality associated with anaesthesia at Zimbabwean teaching hospitals. AB - OBJECTIVE: To determine and analyse peri-operative mortality with particular emphasis on avoidable factors, in the hope that this information will lead to an improvement in standards. DESIGN: Review of all anaesthetic-associated deaths (AADs) during the year 1992. All available records were scrutinised and further information was obtained from mortality meetings and confidential discussions. SETTING: Harare Central and Parirenyatwa hospitals, which are referral centres. PATIENTS: Out of 34,553 subjects presenting for surgical procedures, there were 89 deaths between 1 January and 31 December 1992. MAIN OUTCOME MEASURES: Incidence of AAD, avoidable mortality rate (AMR) and classification of avoidable surgical, anaesthetic and administrative factors. MAIN RESULTS: The incidence of AAD per 1,000 anaesthetics was 2.58. (AAD was defined as death within 24 hours of anaesthesia or failure of a patient, who was previously conscious, to regain consciousness.) There were avoidable factors in 45 (51%) of the deaths. The overall AMR was 1.34 per 1,000 operations (death classified as avoidable if mismanagement contributed to mortality). The AMR (surgical), AMR (anaesthetic) and AMR (administrative) were 0.80, 0.33 and 0.21 respectively. Scoring in each category of avoidability was done proportionately, with a maximum of one point per death awarded where there were avoidable factors). The commonest avoidable factors (in order of frequency) were uncontrolled haemorrhage, poor postoperative management, poor pre-operative management and anastomotic dehiscence. CONCLUSIONS: This audit reveals that there were avoidable factors in 51% of peri operative deaths. It should be possible to reduce the mortality rate by developing preventive measures. PMID- 8693368 TI - Counting the cost of language services in psychiatry. AB - OBJECTIVE: To document interpreter utilisation at a major South African mental hospital over a 2-month period in 1993. DESIGN: A survey was conducted by requesting clinicians to complete a questionnaire each time they required an interpreter. SETTING: Seven admission wards at a Western Cape mental hospital and an emergency psychiatric service at a general hospital. PARTICIPANTS: Twenty-nine clinical staff members. MAIN OUTCOME MEASURES: Number of patients requiring an interpreter, who provides interpreting services; interpreter availability; and duration of interview. RESULTS: One hundred and forty-eight predominantly Xhosa speaking patients (20-30% of admissions) required interpreting. Interpreter services were available immediately in 69% of cases. Nursing staff provide 67% of the interpreter service, while cleaning staff provide 10%. There were 93.5 documented hours of interpreting. One person employed as an interpreter in 2 wards had longer interviews on average than the other staff members. The opportunity cost of using nurses and cleaners as interpreters amounts to R1 504 for the period of the study. CONCLUSIONS: Psychiatrically educated staff are clearly preferred as interpreters. A significant proportion of patients are being assessed through the use of family members, cleaners and other inappropriate people. The financial burden to the hospitals of not providing an interpreter service is small, but the impact on working conditions and service to patients is considerable. PMID- 8693369 TI - Hepatitis B infection in black children from residential care facilities in KwaZulu-Natal. Implications for adoption and foster care. AB - OBJECTIVES: A study was undertaken to assess the prevalence of hepatitis B infection in selected residential child care facilities in Natal. DESIGN: All residents at three facilities in the Durban and Pietermaritzburg areas of KwaZulu Natal were tested for markers of hepatitis B infection as part of a broader health status assessment. RESULTS: One hundred and ninety-five children between the ages of 3 and 194 months (78 +/- 47) were studied. Overall 66.2% of children had evidence of past exposure to hepatitis B virus. Of these 14.9% were positive for hepatitis B surface antigen, 13.3% for hepatitis B e antigen, 47.7% for hepatitis B surface antibody and 59.5% for hepatitis B core antibody. Relative rates of infection increased with age from 18.2%, 20% and 27.8% in the 1st, 2nd and 3rd years of life respectively to 72.2% and 88.2% in the 4th and 5th years of life. Relative rates of infection increased with duration of stay from 40% by the end of the 1st year to 100% by the end of the 5th year. CONCLUSIONS: This study has demonstrated a very high rate of infection with hepatitis B virus and a high prevalence of hepatitis B surface antigenaemia in residential care facilities. It has also shown that the infection is horizontally transmitted within these facilities, that infection increases with duration of stay, that there is a dramatic increase in infection rates after the 3rd year of life, that the highest carrier rates are occurring in children between the ages of 2 and 4 years, and that the vast majority of carriers are highly infectious. These children are not only at risk themselves for the long-term complications of this disease but also constitute an important reservoir of hepatitis B infection within the larger community. There is an urgent need for uniform national guidelines for the screening and management of children in residential care facilities and children being prepared for adoption or foster care. There is also a need for a wider investigation into conditions at residential care facilities previously designated for black children in this country. PMID- 8693370 TI - Schistosoma mansoni in migrants entering South Africa from Mocambique--a threat to public health in north-eastern KwaZulu-Natal? AB - OBJECTIVES: To identify possible public health consequences of Schistosoma mansoni infections in migrants entering north-eastern KwaZulu-Natal and Mpumalanga and Northern Province from southern Mocambique. DESIGN: (i) Intestinal parasite surveys, one sample per person, within a 4-month period; (ii) temperature recordings and snail collections in an irrigation system. SETTING: North-eastern KwaZulu-Natal and Kruger National Park, Mpumalanga and Northern Province. PARTICIPANTS: Ninety-seven migrants (1-68 years) from north-eastern KwaZulu-Natal and 47 from the Kruger Park (1 - 70 years). MAIN OUTCOME MEASURES: The relatively high S. mansoni prevalence may cause problems on the rice paddy scheme in north-eastern KwaZulu-Natal. Ranges and prevalence rates of other parasites were recorded. RESULTS: S. mansoni prevalence in Mocambicans entering north-eastern KwaZulu-Natal was 14.4%, seven times more than in local residents. S. mansoni is not endemic to this region because most bodies of water become too warm for either the parasite or its snail host, Biomphalaria pfeifferi, to develop. Recordings in paddies suggest, however, that the rice modifies the temperature pattern as it grows and provides a suitable habitat for transmission. Migrants entering the Transvaal lowveld where S. mansoni is endemic may become more severely infected. Thirteen other parasite species were recorded from migrants entering KwaZulu-Natal and 8 from those entering Mpumalanga and Northern Province. CONCLUSIONS: The relatively high S. mansoni prevalence among migrants entering north-eastern KwaZulu-Natal may have public health implications as it could encourage transmission in a non-endemic area. The range of parasites carried by migrants entering KwaZulu-Natal, Mpumalanga and Northern Province was similar to that harboured by local people but prevalence rates were generally lower. PMID- 8693371 TI - Anthropometric, vitamin A, iron and immunisation coverage status in children aged 6-71 months in South Africa, 1994. South African Vitamin A Consultative Group (SAVACG). AB - OBJECTIVE AND DESIGN: To establish the anthropometric, vitamin A, iron and immunisation coverage status of children 6-71 months of age in South Africa by means of a national survey. SETTING: South Africa. PARTICIPANTS: The study population consisted of all children in the country aged 6-71 months. A total of 18,219 households (19,003 families) was selected on the basis of a national probability sample with disproportionate stratification by province. OUTCOME MEASURES: Serum retinol, serum ferritin, haemoglobin, mean corpuscular volume, weight, height and immunisation status. RESULTS: According to international criteria, the national prevalence of marginal vitamin A status found in the survey identifies the country as having a serious public health problem of vitamin A deficiency. Stunting is a major problem in the country and is more prevalent in rural than in urban communities. In terms of anaemia and poor iron status, children in the 6-23-month age group were the most severely affected. A trend for increased immunisation coverage over the past 5 years was evident in every dose and in the percentage of fully immunised children. PMID- 8693372 TI - Hypertension 1996--simplified guidelines for primary care nurses and medical students. PMID- 8693373 TI - Apolipoprotein B levels and related factors in a rural white South African community--the CORIS study. Coronary Risk Factor Study. AB - OBJECTIVE: In a survey of the Coronary Risk Factor Study (CORIS), apolipoprotein B (apoB) levels were determined to ascertain their impact on coronary heart disease (CHD) risk. Other CHD risk factors associated with apoB were also identified. DESIGN: Cross-sectional analytical study, which included CHD risk factor and dietary questionnaires, electrocardiography, anthropometric and blood pressure measurements, and a blood sample for a lipid profile. SETTING AND PARTICIPANTS: The three districts of Riversdale, Robertson and Swellendam in the south-western Cape; a 25% random sample of 1,528 white respondents aged 15-68 years. RESULTS: Men tended to have higher mean apoB levels than women. Classification of CHD risk by apoB levels and total cholesterol (TC) levels did not correspond, as only 61% of men and 58.5% of women were classified in the same risk categories. Respondents in the highest apoB risk category reported a medical history of hypercholesterolaemia and hypertension more frequently than those in lower categories. There was a significant increase from the low to the high apoB risk category of TC, low-density lipoprotein (LDL) cholesterol, triglyceride levels, body mass index and percentage body fat. Using stepwise multiple regression, 84.9% of the variation in apoB of men and 85.8% in apoB of women were accounted for by significantly associated variables. CONCLUSION: Although apoB may be a better predictor of CHD than TC or LDL cholesterol concentrations, its easy approximation with the formula (TC-HDLC)/2 + 20, high cost, measurement variability and an approach in management similar to that for raised TC discourage its routine use in the screening of patients for CHD. PMID- 8693374 TI - Assessment and 2-year follow-up of some factors associated with severity of respiratory infections in early childhood. AB - OBJECTIVE: To assess the effect of some factors on the severity of acute respiratory infection (ARI) in children. DESIGN: In a case control study, children with pneumonia were matched with controls who had upper respiratory infection. They were compared in respect of nutrition, household crowding and smoke pollution, and the presence of current viral respiratory infection. Both cohorts were followed up for 18-24 months to determine if there was a difference in subsequent respiratory sequelae. SETTING: Primary health care-based cohorts of peri-urban township children. PARTICIPANTS: Forty-eight children < 3 years of age with pneumonia (index cases) were matched by age and presentation time with controls who suffered only from upper respiratory infection. All came from underprivileged communities. Index cases were selected as they presented and the study was conducted between February 1988 and June 1991. MAIN OUTCOME MEASURE: Any difference between index cases and controls in respect of the four factors listed under 'Design'. Follow-up home visits determined whether subsequent sequelae of the two grades of ARI were different. RESULTS: The presence of current viral infection at entry to the study was evident in 21 of those with pneumonia and 12 controls (difference between groups = 19.15%, 95% confidence intervals 0.25 - 38.05, P = 0.052). Overcrowding in the home was comparable. Index homes were occupied by a mean of 3.57 (SD 1.54) children and 5.26 (SD 4.84) adults, control homes by 3.51 (SD 1.80) children and 4.36 (SD 2.02) adults. Occupancy of the room in which the child slept was also not significantly different: index group mean 4.23 (SD 1.55) and controls 4.02 (SD 1.38) (mean difference 0.21, 95% Cl 0.378 - 0.798, P = 0.485). Correlation of bedroom crowding with young age (< 1 year) or weight-for-age centiles was not significant in either cohort (r < 0.3 in all). The prevalence of viral infection was not increased by degree of crowding in either group (P = 0.636). Domestic smoke pollution was similar: cigarette smoking occurred in 75% of index homes and 69% of control homes. Wood or coal fires were used in 19% of index and 14% of control homes. The nutritional status of both groups proved to be similar. Fifteen per cent of index children and 12% of controls had weight-for-age centiles < or = 10th centile (difference = 3.26%, 95% Cl -10.72 - 17.24, P = 0.649). Two-year home follow-up visits were completed in 75% of the index and 69% of the control group. The balance were followed up for 18 months. There was no difference between index and control children in the recurrence of respiratory symptoms (P = 0.664) or need to visit a health facility (P = 0.302). CONCLUSIONS: Factors shown elsewhere to contribute to the acquisition or severity of ARI could not be demonstrated as important in this study. The children with pneumonia and their matched controls with upper respiratory infections came from equally overcrowded and smoke-filled homes, had comparable nutritional status which was not markedly poor, and had an equal incidence of current viral infection. Subsequent ill health was not found to be greater in the pneumonia group. PMID- 8693375 TI - 'Neither obscure nor mysterious'--infant mortality and the Kimberley Board of Health, 1898-1977. AB - Annual reports of the Kimberley Board of Health, established in 1883, provide rich insight into public health discourse on infant mortality. Commentaries on the determinants of infant mortality, especially prior to 1950, largely focus on poverty and interracial disparities, issues relevant to current health policy. PMID- 8693376 TI - Cystic fibrosis and 'kwashiorkor'. PMID- 8693377 TI - Preventable death from neonatal tetanus--shortage of tetanus toxoid. PMID- 8693378 TI - Time for diagnosis-related tariffs? PMID- 8693379 TI - Hypertension management guidelines. PMID- 8693380 TI - Hypertension management guidelines. PMID- 8693382 TI - HIV and informed consent. PMID- 8693381 TI - Hypertension management guidelines. PMID- 8693383 TI - Screening for cervical neoplasia--further lessons from Mamelodi. PMID- 8693384 TI - Detection of human papillomaviruses in cancer of the uterine cervix. PMID- 8693385 TI - Discontinuation of Sotazide. PMID- 8693386 TI - Abortion--some further considerations. PMID- 8693387 TI - Abortion--some further considerations. PMID- 8693388 TI - Abortion--some further considerations. PMID- 8693389 TI - Hepatitis B in South African anaesthesiologists. PMID- 8693391 TI - Treating family members. PMID- 8693390 TI - Is diagnostic dilatation and curettage ever necessary? PMID- 8693392 TI - Sleep paralysis accompanied by secondary psychiatric disturbance. PMID- 8693394 TI - 'Translational research', the 'linker laboratory' or a paradigm shift in cancer care? PMID- 8693393 TI - Lifestyle disease changes in urban blacks. PMID- 8693395 TI - Pediatric discharge planning: complications, efficiency, and adequacy. AB - The complications encountered in discharge planning in an acute care pediatric hospital were documented. The cases of 105 children hospitalized on selected units of an acute care, regional, pediatric hospital in the Midwest were studied. The most frequently encountered complications were financial, family unavailability and lack of cooperation, family inability/unwillingness to learn patient care, custody issues, unexpected medical developments, and transportation problems. Team differences in understanding the child's psychosocial situation and custody disputes were associated with delays in discharge. Private insurance, late referral, and lack of family availability were associated with the adequacy of the discharge plan, as rated by the discharge planner at discharge. Results show discharge planning to be a complex process, affected by family, resource, and team work issues. PMID- 8693396 TI - Predictors of patient and proxy satisfaction with discharge plans. AB - If patients are not readily available, family members or others sometimes are used as substitute informants when evaluating consumer satisfaction. Little is known, however, about the extent to which responses of patients and proxies are interchangeable. In this study, patients (N = 225) or significant others (N = 115) provided an overall rating of discharge plans, as well as information on psychosocial, health, and post-hospital service related factors, at 3-4 weeks post-discharge. While no difference was found between mean plan ratings for the two groups, substantial differences were found in factors predicting satisfaction for patients and for proxies. Results indicate that care should be taken in using proxy ratings in the place of patient ratings, particularly when developing strategies for enhancing consumer satisfaction. Findings are discussed as they relate to continuity of care initiatives and programs for enhancement of desirable health utilization behaviors, in the context of managed care. PMID- 8693397 TI - Decisions regarding the order of opening multiple high-risk cases: a pilot study in an urban hospital. AB - Decision making is central to social work practice. Decision making has been extensively researched outside of the field of social work. Within the field some work has been done regarding decision making, but much remains to be done. A pilot study was undertaken to describe how hospital social workers decide to open a specific case when they have to choose among multiple high-risk cases and the guidelines for case openings do not dictate a specific choice. The results indicate that social workers in this setting do not view the various established high-risk factors as equally important. Rather, decisions were based on an integration of explicit and implicit high risk factors developed by workers over time. PMID- 8693398 TI - Problems with public health outreach. AB - Using a case study to illustrate the dilemma, this analysis attempts to offer some possible explanations for the problems with public health outreach by exploring the tendency of society to medicalize the needs of the poor, by highlighting the variation over time in social work's view of work done outside the office and by examining the manner in which individual professionals use discretion when implementing social policy. The implications for social work education involve the recruitment of indigenous workers and the preparation of social work students for the responsibilities and challenges of reaching out to service the poor in need of public health services. PMID- 8693399 TI - What happens to patients after nursing home placement? AB - Follow-up of patients discharged from hospitals to nursing homes is often difficult for the busy practitioner to implement. A one page follow-up telephone questionnaire was designed by a hospital social work department to monitor the outcomes of patient transfers to nursing homes at one and three months post hospital discharge. Time to complete the interviews averaged five minutes. This instrument is designed to inform social workers of the disposition of patient transfers and to monitor client satisfaction. Professional accountability and practice research are addressed in the follow-up process and the implementation of a simple, systematic data gathering instrument. PMID- 8693400 TI - Clinical indicators to assess the quality of social work services in nursing homes. AB - Nursing home social work service providers (n = 209) evaluated a proposed set of clinical indicators developed by an NASW Work Group to use in measuring social work performance in that setting. Practitioners rated all of the indicators highly for clarity, relevance, and meaningfulness to service provision. Problems with feasibility of use were identified for two of the indicators. Perceived difficulties in implementation are identified and addressed. A rationale is presented for the utility for nursing home practice of a uniform, professionally validated set of performance indicators as a component of quality improvement efforts. PMID- 8693401 TI - [Nomenclature of modified fractionation protocols in radiotherapy]. AB - BACKGROUND/AIM: During the last few years a number of new, unconventional fractionation protocols have been established for various biological reasons. Recently specific terms, established for these schedules, have frequently been applied inappropriately in oral presentations as well as in publications. Hence, the present work was initiated in order to clarify definitions and, in addition, to illustrate the respective biological basis for the various fractionation designs. PMID- 8693402 TI - [Radiotherapy of primary extranodal non-Hodgkin's lymphoma of the head and neck region. Results of a prospective multicenter study. Study Group NHL: early studies]. AB - PURPOSE: To evaluate the long-term outcome of patients with limited-stage primary extranodal lymphoma of head and neck treated with definitive radiotherapy in low grade and a combined radio- and chemotherapy in high-grade lymphoma. PATIENTS AND METHODS: Between January 1986 and August 1993, 63 patients with primary extranodal Non-Hodgkin lymphoma of head and neck region, stages IE and IIE were treated with radiotherapy. The histological classification followed the Kiel classification, staging the Ann Arbor classification. PATIENT CHARACTERISTICS: 33 male, 30 female; age 18 to 84 years; tumor localisation: tonsils 26, nasopharynx 7, oropharynx 8, paranasal sinus 11, salivary glands 7, floor of mouth/gingiva 3, larynx 1. Mean follow-up is 74 months. Low-grade lymphoma in stages I and II CS were treated with definitive radiation therapy according to the concepts of epithelial tumors of the same localisation (target volume and technique). The adjuvant dose was 30 Gy and in the tumor volume 40 Gy, 2 Gy daily. 28 patients were registered, 18 in stage I and 10 in stage II. High-grade lymphoma were treated with definitive radiation therapy according to the concepts of epithelial tumors of the same localisation, too. The dose was 40 respectively 50 Gy, followed by 4 courses of adjuvant chemotherapy with CHOP. Thirty-five patients were enrolled, of whom only 10 received chemotherapy. RESULTS: The overall 5-year survival rates were for low-grade 67% and for high grade lymphoma 88%. The corresponding relapse-free survival rates were 54/68%, respectively. Only 1 patient failed within the irradiated target volume. Recurrences occurred at sites distant to the irradiated volume in nodal and extranodal regions. Prognosis was influenced by histologic grade. Significant trends were not observed for other potential pretreatment parameters (age, stage, localisation, bulk). CONCLUSIONS: In stage I or II patients with low malignant non-Hodgkin's lymphoma of the head and neck, initial management with definitive external radiotherapy is appropriate and probably curative. In high-grade lymphoma of clinical stage IE with nonextensive tumor size definitive radiotherapy is possible in curative intention. Primary chemotherapy followed by radiation is probably preferable. PMID- 8693403 TI - [Role of percutaneous radiotherapy in male breast carcinoma]. AB - PURPOSE: Breast cancer in men is a very rare malignancy. Current knowledge about its natural history, diagnostic management and overall prognosis is poor and usually relies on reviews and a few retrospective studies. Herein we report about our past 20-year-clinical experience. PATIENTS AND METHODS: From 1972 to 1993, 21 men with histologically verified tumors were irradiated for operable primary (n = 17) or recurrent (n = 4) breast cancers at our institution. Patients received surgery and post-operative radiotherapy to the chest wall and ipsilateral lymph nodes. Additionally hormones and chemotherapy were applied in only a few cases (n = 5). RESULTS: The follow-up ranged from 18 to 184 months (median 46 months). At last follow-up (11/94), 9 patients were alive and 8 without disease. The median overall survival of all patients was 69 (mean: 106) months and the 5-year survival rate 59%. In univariate analysis, a relapse- and disease-free survival advantage was observed for patients with stage I/II disease, with negative lymph nodes, central tumor location, patients younger than 60 years and short interval (less than 3 months) from first symptoms and diagnostic verification of the malignancy. None of these factors, however, was statistically significant due to the low case number. CONCLUSION: Postoperative adjuvant radiotherapy is an essential part of the treatment strategy of advanced node-negative and node positive cancer of the breast in men. With respect to locoregional tumor control it is a necessary treatment, while it does not influence the rate of distant metastases. The role of adjuvant hormones and chemotherapy management remains unclear from our scarce patient data. PMID- 8693404 TI - [Radiotherapy of plantar heel spurs: indications, technique, clinical results at different dose concepts]. AB - BACKGROUND: In a retrospective study the efficacy of orthovoltage radiotherapy for refractory painful plantar heel spur was analyzed for 3 different radiation dose concepts. PATIENTS AND METHODS: From 1.1 1984 through 1.3.1994, 182 patients with refractory painful heel symptoms and radiologically proven plantar heel spur received radiotherapy. A total of 141 patients and 170 heels (due to double-sided symptoms) were completely documented in long-term follow-up. Clearly defined semi quantitative criteria (9-point score) were used to analyze heel pain and ankle function prior to RT, 6 to 12 weeks post-radiation, and at last follow-up. The treatment outcome, i.e. (un)favourable response, of 3 radiation dose concepts were compared: Group A (n = 72 heels) received 12 Gy total radiation dose in 3 fractions per week and 2 series (6 x 1 Gy per series) separated by 6 weeks; group B (n = 98 heels) received 3 Gy total radiation dose in 10 fractions of 0.3 Gy (n = 50) or 5 Gy (10 x 0.5 Gy) (n = 48) with conventional fractionation in 1 series. RESULTS: Radiotherapy was very effective: at last follow-up 67% (group A) and 71% (group B) remained completely free of pain. The rate of "complete pain relief" (i.e. free of any pain symptoms) was not different between the 3 radiation concepts. However, significant differences were observed with regard to "incomplete or insufficient pain relief", i.e. a subjective pain relief of less than 80%, a delayed pain relief after more than 4 weeks or a relapse of pain symptoms in long-term follow-up. More favourable results were achieved in patients receiving 5 Gy or 12 Gy total dose, while patients with 3 Gy total dose had significantly worse results. Prognostic factors for "complete pain relief" were short duration of pain symptoms and acute pain symptoms prior to radiotherapy; with regard to "in-complete or insufficient pain relief" the total dose was found to be a prognostic parameter. CONCLUSIONS: Patients with refractory heel pain can yield a high response to radiotherapy even after failing various conventional treatments previously. Thus, radiotherapy should not be solely regarded as a last resort due to its low costs and high efficacy at low radiation doses. PMID- 8693405 TI - Development of a fast optimization preview in radiation treatment planning. AB - PURPOSE: Having the capability of fast previewing an expected optimization result for a defined combination of optimization parameters is essential to reach a better optimization result. In order to achieve this goal, the well-tried Cimmino optimization algorithm requires modification. MATERIALS AND METHODS: Usually, the speed of convergence of some iterative algorithms is restricted to a bounded relaxation parameter. Exploiting the special altering behavior of the weighting factors at each step, many iteration steps are avoided by overrelaxing this relaxation parameter. Therefore, the relaxation parameter is increased as long as the optimization result is improved. This can be performed without loss of accuracy. RESULTS: Our optimization technique is demonstrated by the case of a right lung carcinoma. The solution space for this case is 36 isocentric X-ray beams evenly spaced at 10 degree. Each beam is restricted to 23 MV X-ray fields with a planning target volume matched by irregular field shapes, similar to that produced by a multileaf collimator. Four organs at risk plus the planning target volume are considered in the optimization process. The convergence behavior of the optimization algorithm is shown by overrelaxing the relaxation parameter in comparison to conventional relaxation parameter control. CONCLUSION: The new approach offers the ability to get a fast preview of the expected final result. If the clinician is in agreement with the preview, the algorithm is continued and achieves the result proven by the Cimmino optimization algorithm. In the other case, if the clinician doesn't agree with the preview, he will be able to change the optimization parameters (e.g., field entry points) and to restart the algorithm. PMID- 8693406 TI - [High-dose multimodal radiotherapy of confluent destructively growing aggregated keratoacanthoma. 2 case reports]. AB - BACKGROUND: Keratoacanthoma is a fairly common, benign, usually self-resolving skin lesion that arises from the hair follicle. This nodular lesion shows a predilection for areas exposed to light, mainly for the face. We report on the intensive radiation therapy of 2 cases of a rare subset of keratoacanthoma which showed a locally aggressive, seriously destructive growth. PATIENTS AND METHODS: Two female patients with previously treated, confluent-destructive growing keratoacanthoma were treated by multimodal, high-dose radiotherapy. Patient 1 showed a rapid progress of midfacial tumor with destructive infiltration of the left cheek, nasal cartilage, the cribriform plate of ethmoid and congestion of the conjunctiva close to the lacrimal caruncle. This could be shown in clinical and histopathological investigations and CT-scans. The coexistence of cutaneous and conjunctival lesions in locally rapidly enlarging keratoacanthoma of the face is unusual and unreported to our knowledge. One case of simultaneous conjunctival and multiple, eruptive keratoacanthoma of the body has been reported. Patient 2 had received soft X-ray pretreatment because of a large, relapsing keratoacanthoma of the left cheek. RESULTS: Patient 1 underwent a parallel, intensive treatment of the conjunctiva with 90Sr-contact therapy, percutaneous high-dose 60Co-gamma- and megavoltage electron treatment (10 and 18 MeV) of the midfacial lesions. Conjunctiva and caruncle showed a complete remission of keratoacanthoma. In the other facial areas no long-term regression could be reached, despite giving a fully cancericidal, total dose of more than 100 Gy in some regions. Patient 2: Further high dose radiotherapy using megavoltage electron treatment with a total dose of 50 Gy showed a complete remission of the lesion for 5 months. Another relapse of this keratoacanthoma could be operated successfully. There was no more relapse established in follow-up checks. CONCLUSIONS: The 2 case reports show that in treatment of locally destructive growing subsets of keratoacanthoma a sufficient therapy should be initiated in time. Keratoacanthoma and subsets of this lesion that do not respond well to initial treatment, recur early or show seriously aggressive growth should be treated early by combined therapy that takes previous experiences into consideration. PMID- 8693407 TI - [Adjuvant chemotherapy in soft tissue sarcoma: review and meta-analysis of published data of randomized clinical trials]. PMID- 8693408 TI - [Survival after radical retropubic prostatectomy in patients with poorly differentiated prostatic carcinoma]. PMID- 8693409 TI - [Effects of radiotherapy and surgery in early breast carcinoma. A meta-analysis of randomized trials]. PMID- 8693410 TI - Diagnostic test studies: biotechnology assessment. PMID- 8693411 TI - Correlation of soluble interleukin-2 receptor levels with severity of chronic hepatitis C virus liver injury and development of hepatocellular cancer. AB - BACKGROUND: Patients with acute and chronic hepatitis B virus infection have elevated serum levels of soluble interleukin-2 receptor. This study examined patients with chronic hepatitis C virus infection to determine whether serum soluble interleukin-2 receptor levels were elevated and whether the degree of these elevations in serum levels correlated with histologic severity of hepatitis related liver injury. METHODS: Percutaneous liver biopsies were performed on 123 patients with chronic hepatitis C virus infection. Serum levels of soluble interleukin-2 receptor in these 123 patients were measured by means of specific enzyme-linked immunoassay and were compared with levels in 174 subjects in a hepatitis-free control group. RESULTS: Soluble interleukin-2 receptor levels were significantly higher in the patients with hepatitis C than in subjects in a control group (p < 0.0001). A progressive and significant increase occurred in soluble interleukin-2 receptor levels with increasing severity of liver injury (p < 0.001). The highest levels of soluble interleukin-2 receptor occurred in patients who had hepatocellular cancer. CONCLUSIONS: Soluble interleukin-2 receptor levels correlate with the histologic severity of liver damage in patients with chronic hepatitis C virus infection and may be useful as a marker in patients at high risk of getting hepatocellular cancer. PMID- 8693412 TI - Bleeding gastric varices as a result of splenic vein compression by a celiac arterial aneurysm. AB - Celiac arterial aneurysms are very unusual and often lack clinical manifestations. According to our review of the literature, this is the first report of a patient with a large celiac arterial aneurysm who exhibited hematemesis from gastric varices. Arteriography, as well as color Doppler ultrasonography and enhanced computed tomography, contributed to the diagnosis of this aneurysm, which was best exposed by a left thoracoabdominal approach. In this patient the lesion was a false aneurysm with perforation of the celiac artery, so simple closure of the orifice was carried out and the revascularization of the celiac artery was not necessary, but we should take care not to ignore the possible recurrence of vascular lesions. The risk of celiac arterial aneurysm rupture is relatively high, but the operative mortality of unruptured aneurysms is now so low that operation is strongly recommended for all patients with this type of aneurysm. PMID- 8693413 TI - Role of urokinase in the superior mesenteric artery embolism. PMID- 8693414 TI - Localization and resection of an in transit sentinel lymph node by use of lymphoscintigraphy, intraoperative lymphatic mapping, and a hand-held gamma probe. PMID- 8693415 TI - Spontaneous liver rupture in amyloidosis. PMID- 8693416 TI - Split-liver transplantations. PMID- 8693417 TI - Wound closure with human keratinocytes cultured on a polyurethane dressing overlaid on a cultured human dermal replacement. AB - BACKGROUND: Burn excision followed by immediate wound coverage has become the clinical standard for managing extensive burn injuries in much of the world. When sufficient autograft skin to achieve permanent wound closure is unavailable, cell culture technology has made the use of cultured human keratinocyte (HK) sheets clinically feasible. Whereas previous techniques have focused on development of multilayered, differentiated HK sheets, our attention has been drawn to using HK in a highly proliferative, less differentiated state. Time requirements for preparation of multistratified cultured HK are high, and preparatory steps may destroy important integrin adhesion molecules. METHODS: We describe the use of HK cultured to single layer confluence on a polyurethane membrane(HD), with serum free medium. HK-HD grafts were transplanted to full-thickness wounds on athymic mice (n = 31). A second group of mice (DG-HK-HD), n = 28) received a living human dermal replacement containing cultured fibroblasts before placement of HK-HD. Control mice received HD alone (n = 4). Basement membrane proteins on healed wounds and surface integrins on cultured HK were identified by means of immunostaining and direct microscopic visualization. RESULTS: HK cultured just to the confluent state on polyurethane membrane were positive for integrins alpha(5) and alpha(6), major integrins on proliferating HK. Histologic analysis showed epithelialized wounds in all groups after 21 days. Using an anti-human involucrin antibody we demonstrated the presence of HK in 64.5% of the HK-HD group, 61% of the DG-HK-HD group, and 0% in the HD group. Mice that received the living human dermal replacement containing cultured fibroblasts in combination with HK-HD grafts developed a thick, well-vascularized neodermis. Strong laminin and collagen IV staining was observed in wound areas covered with HK. CONCLUSIONS: These data show that full-thickness wounds can be closed by application of a single layer of proliferating HK cultured on a biocompatible polyurethane membrane. This technique is an alternative to the use of multilayered, differentiated HK sheets. Preparation times for HK-HD grafts should be significantly shorter than required for multilayered HK sheets, technical efforts should be less, and more extensive wound areas could be covered. PMID- 8693418 TI - Surgical resection for recurrent hepatocellular carcinoma: prognosis and analysis of risk factors. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is common in Asian countries, and tumor recurrence is the most common cause of treatment failure after curative resection. Repeated hepatectomy is performed only for selected patients because most patients with HCC also have liver cirrhosis and poor liver function reserve. The purposes of this study were to clarify the outcome of the patients after second hepatectomy for recurrent HCC and to evaluate the prognostic factors after second hepatectomy. METHODS: We used retrospective cohort study to examine the disease-free survival, cumulative survival, and possible prognostic factors for recurrence and death in 59 patients who underwent surgical resection for recurrent HCC at the National Taiwan University Hospital from August 1986 to December 1993. Another 64 patients with unresectable recurrent HCC were used as a historical control group. The survival curves between those patients with resectable HCC and those with unresectable HCC were compared. RESULTS: After resection for recurrent HCC, gender and multiplicity (n > 3) of tumor affect recurrence rate (p = 0.046 and 0.021, respectively), whereas gender, age, and tumor invasiveness affect survival rate significantly (p = 0.024, 0.021, and 0.046, respectively). The survival rate of patients with resectable HCC was significantly better than that of those with unresectable HCC. CONCLUSIONS: For recurrent HCC surgical resection is an effective mode of treatment in selected patients. Whether surgery is better than other modes of treatment in the treatment of resectable recurrent HCC demands further investigation. PMID- 8693419 TI - Increased arterial inflow in extremities with chronic venous insufficiency: an important and unappreciated hemodynamic parameter. AB - BACKGROUND: The purpose of this study was to evaluate and analyze arterial inflow (AI) in lower extremities of patients with symptoms of chronic venous insufficiency (CVI) and of members of a healthy control group. METHODS: Foot mercury-in-silicon strain-gauge plethysmography was used to measure AI, venous reflux, and muscle pump efficiency in 388 extremities of 194 patients with symptoms of CVI. Severe stage III symptoms (Society for Vascular Surgery/International Society for Cardiovascular Surgery classification) were present in 84 extremities, moderate stage II symptoms were present in 81 extremities, and mild stage I symptoms were present in 158 extremities. No symptoms, stage 0, were found in 65 contralateral extremities of patients with unilateral symptoms. Identical parameters were measured in 70 extremities of 35 healthy subjects in a control group. AI in each staged group was compared with that of the control group and with that of the other groups with symptoms with the use of Kruskall-Wallis analysis of multiple variances. RESULTS: The mean AI (+/-SD) in milliliters per 100 ml of foot tissue per minute in the extremities in the control group was 0.82 +/- 0.48. In the extremities without symptoms, contralateral to those with symptoms in patients with unilateral disease, the AI was 1.24 +/- 0.88. In extremities with mild symptoms the AI was 1.54 +/- 1.20, in extremities with moderate symptoms it was 2.88 +/- 1.70, and in extremities with severe symptoms it was 6.25 +/- 4.91. The AI was significantly increased in all extremities of patients with CVI (stages 0 to III) when compared with that of patients in the control group. Extremities with stage II and III disease had significantly higher AI than did extremities with stage 0 and stage I disease. The difference in AI between extremities with stage 0 and I disease was not statistically significant, and no significant difference in AI was seen between extremities with stage II and III disease. CONCLUSIONS: When plethysmographic methods are used to evaluate extremities with CVI, high AI, if not considered, can overrepresent the true magnitude of reflux. High AI may indicate presence of primary anatomic arterioventricular fistulas, or it may be the consequence of inflammatory changes and secondary functional arterioventricular shunting. Increased AI in contralateral extremities with no symptoms may point to the role of high flow in the pathogenesis of CVI. Clarification of this question requires further investigation. PMID- 8693421 TI - End results of simultaneous splenectomy in patients undergoing total gastrectomy for gastric carcinoma. AB - BACKGROUND: Splenectomy often is performed simultaneously with total gastrectomy for gastric carcinoma to facilitate dissection of splenic hilar lymph nodes. Splenectomy, however, should be avoided as frequently as possible because of its important role in the reticuloendothelial system and because of its sometimes severe complications. We evaluated the end results of simultaneous splenectomy with total gastrectomy. METHODS: The effect of splenectomy on survival was examined by retrospective analysis of 245 patients undergoing total gastrectomy for gastric carcinoma. Of these, 154 underwent splenectomy, and 91 did not. Prognostic factors for patients undergoing total gastrectomy were determined. The relationship to postoperative complications also was analyzed. RESULTS: No significant differences overall were found between the 5-year survival of the patients undergoing total gastrectomy with or without splenectomy. No correlation to any prognostic factor was seen with splenectomy. In contrast, splenectomy was independently associated with postoperative complications. CONCLUSIONS: In this retrospective study simultaneous splenectomy at total gastrectomy for gastric cancer did not have an effect on the survival rate of patients undergoing total gastrectomy, and it sometimes caused severe complications. PMID- 8693420 TI - Hepatic resection of hepatocellular carcinoma in cirrhotic livers: is it unjustified in impaired liver function? AB - BACKGROUND: Resection for hepatocellular carcinoma in patients with cirrhosis and impaired liver function is usually unjustified because of higher surgical risks and poorer long-term prognosis. METHODS: A retrospective comparison of the background and resectional results of patients with cirrhosis and hepatocellular carcinoma was carried out between those with preoperative indocyanine green 15 minute retention rate of 20% or greater (group A, impaired function group, n = 36) and those with indocyanine green 15-minute retention rate of 10% or less (group B, normal function group, n = 34). RESULTS: The group A patients had significantly lower serum albumin level and higher serum bilirubin level, longer prothrombin time, higher incidence of associated esophageal varices, and poorer Child's classifications for cirrhosis. Although the tumor diameter in both groups was similar (A, 6.9 versus B, 7.1 cm; p = 0.94), the resected liver amount in group B was greater (227.4 versus 473.2 gm; p = 0.038) because of a greater extent of liver resection (p < 0.001) and a wider surgical margin (0.34 versus 1.85 cm; p < 0.0001). The amount of operative blood loss and blood transfusion, operative morbidity, and operative mortality were not different between the two groups. The pathologic characteristics and staging were also comparable. The 5 year disease-free and actuarial survival rates of groups A and B were 30.9% and 29.6% (p = 0.16) and 45.2% and 33.4% (p = 0.11), respectively. CONCLUSIONS: If the amount of resected nontumorous liver parenchyma could be reduced, resection of hepatocellular carcinoma in selected patients with cirrhosis and impaired liver function is still justified in spite of a narrow surgical margin. PMID- 8693422 TI - Comparative p53 mutational analysis of multiple primary cancers of the upper aerodigestive tract. AB - BACKGROUND: Tumors arising in the upper aerodigestive tract (UAT) are often associated with predisposing factors that place the patient at risk for development of multiple synchronous or metachronous tumors. The aim of this study was to evaluate p53 as a susceptibility gene in UAT malignancy. METHODS: Seventeen patients with 41 separate primary tumors involving esophagus (n = 15), larynx (n = 14), pharynx (n = 6), lung (n = 2), mouth (n = 2), and tongue (n = 2) were analyzed for the presence and specific genotype of p53 point mutation. Immunohistochemical staining of p53 and topographic genotyping consisting of polymerase chain reaction amplification and direct sequencing of p53 exons to 5 to 8 were performed. RESULTS: Eleven tumors were metachronous (6 months to 11 years), and 11 were synchronous. We found p53 point mutations in 19 (46.3%) of 41 tumors in exons 8 (n = 11), 7 (n = 4), 5 (n = 3), and 6 (n = 1). Tumors possessed either wild-type p53 or a single type of point mutation. Metastases displayed the identical genotype of its primary tumor in all cases. Most importantly, p53 genotype was found to be completely discordant between separate primary tumors for the same patient. CONCLUSIONS: Complete discordance in p53 genotype between separate primary UAT cancers strongly indicates that p53 is not functioning as a susceptibility gene in this setting. PMID- 8693423 TI - Carotid artery resection for head and neck cancer. AB - BACKGROUND: Carotid artery resection has been shown to yield a chance of cure in patients with advanced head and neck carcinoma involving the carotid artery. However, the criteria for the identification of those who are vulnerable to neurologic injury after resection have not been established. Interposition grafting may minimize the risk of neurologic morbidity, although it is technically difficult when there is involvement of the internal carotid artery close to the skull base. METHODS: We studied 24 patients with head and neck tumor involvement of the carotid artery. We performed carotid artery resection in 16 of them, including 10 in whom the carotid artery was reconstructed with interposition grafts covered with muscle flaps. When it was thought that the reconstruction would be difficult, positron emission tomography was performed during balloon test occlusion of the internal carotid artery to assess the adequacy of hemispheric collateral blood flow before carotid resection. In one patient with interposition graft, carotid rupture occurred as a result of wound infection, but none of the other patients experienced perioperative death, persistent hemiplegia, or delayed stroke. RESULTS: Twelve patients have survived longer than 8 months, and seven (43.8%) were alive without disease at 12 months after resection, whereas all four patients who could not be treated operatively died within 8 months as a result of local primary tumors. CONCLUSIONS: Carotid artery resection is the only therapy offering any potential for cure or palliation. Positron emission tomography is a rapid quantitative means of determining the cerebral blood flow, particularly when resection is planned without reconstruction. PMID- 8693424 TI - Healing characteristics of intraarterial stented grafts: effect of intraluminal position on prosthetic graft healing. AB - BACKGROUND: The purpose of this study was to investigate the effect of complete intraluminal placement on prosthetic graft healing. METHODS: Thirty dogs underwent infrarenal abdominal aorta polytetrafluoroethylene interposition (12) or intraluminal stented (18) grafting. Grafts were removed at 4 and 8 weeks. Length of endothelial ingrowth and intima to media height ratios (IMHRs) were calculated. Perianastomotic endothelial (CD31+, factor VIII [FVIII+]), smooth muscle (actin+), macrophage (CD44+), and proliferating (PCNA+) cell content was determined. RESULTS: In control grafts mean proximal and distal anastomotic endothelial cell ingrowth was 0.42 +/- 0.06 and 0.47 +/- 0.08 cm at 4 weeks and 1.10 +/- 0.24 and 0.94 +/- 0.17 cm at 8 weeks. In intraluminal grafts mean proximal and distal anastomotic endothelial cell ingrowth was 1.57 +/- 0.09 and 1.54 +/- 0.12 cm at 4 weeks and 1.88 +/- 0.06 and 2.11 +/- 0.25 cm at 8 weeks. Endothelial ingrowth was greater in all stented grafts (p < 0.001). Mean proximal anastomosis IMHRs were 1.01 +/- 0.16 for 4-week and 1.42 +/- 0.16 for 8-week control grafts and 0.59 +/- 0.18 for 4-week and 0.50 +/- 0.14 for 8-week stented grafts. Similar IMHR values were present at the distal anastomosis. Lower IMHRs were observed in stented grafts (p < 0.05). Content of CD44+, PCNA+, and FVIII+ cells were reduced both proximally and distally in 4-week stented grafts (p < 0.05). Distal content of CD31+ and actin+ cells was greater in 4-week stented grafts (p < 0.05). At 8 weeks CD44+ cell content decreased in controls (p < 0.05). CONCLUSIONS: Intraluminal location enhances prosthetic graft reendothelialization and attenuates intimal thickening. PMID- 8693425 TI - Decision analysis in surgery. AB - BACKGROUND: The technique of decision analysis is often applied to clinical policy and economic issues in surgery. Because surgeons may be unfamiliar with such work, this article catalogues decision analysis studies in the surgical specialties. METHODS: We reviewed the medical literature (1966 to 1994) to identify surgical decision analysis studies and to assess trends over time. Each article was categorized according to the type of journal (surgical, other clinical, or technical) in which it was published and content, including surgical specialty, clinical topic, article focus (individual patient decision making, clinical policy, or cost-effectiveness), and primary findings. RESULTS: Publication rates of surgical decision analysis have increased dramatically over time. Of the 86 total studies only six were published before 1980. In contrast, 44 studies appeared between 1990 and 1994. Although 77% were published in nonsurgical journals, decision analyses have begun to appear more regularly in surgical forums. Studies addressing all of the surgical specialties were found, although more than one half addressed topics in general surgery (34%) or cardiothoracic surgery (22%). The most frequent topics were gallstones (11 articles), head and neck cancer (five articles), coronary artery disease (four articles), and cerebral arteriovenous malformations (four articles). Articles focusing on clinical policy (i.e., those assessing surgical efficacy for broad groups of patients) now account for large majority of published decision analyses. CONCLUSIONS: The use of decision analysis in surgery is growing steadily. Because decision analysis is being used to influence clinical policy, it is important for surgeons to be aware of these studies and to be able to review them critically. PMID- 8693426 TI - Laparoscopy not recommended for routine appendectomy in men: results of a prospective randomized study. AB - BACKGROUND: Laparoscopic appendectomy has now gained wider acceptance in clinical practice, particularly in the treatment of women with right iliac fossa pain. However, the precise role of laparoscopic appendectomy in men is unclear, and this study was therefore undertaken to examine this specific issue in a prospective randomized trial. METHODS: One hundred men between the ages of 16 and 65 years who had suspected appendicitis were recruited and randomized to undergo either open or laparoscopic appendectomy. Both groups were compared in terms of their clinical parameters, duration of anesthetic and operation times, postoperative pain, duration of ileus, and length of hospital stay. RESULTS: The histologic confirmation of appendicitis was present in 94% of the cases for both groups of patients. Laparoscopic appendectomy required significantly longer anesthetic time (72.5 minutes versus 55 minutes) and actual operating time (45 minutes versus 25 minutes) compared with open appendectomy. Postoperative pain as measured by visual analog scale on postoperative days 1 and 2 were not significantly different between the patients who underwent laparoscopic and open surgery with values of 4.7 versus 4.4 and 2.1 versus 2.2, respectively. Also no significant difference was seen between the laparoscopic and open appendectomy groups in the recovery of bowel function (24.7 hours versus 21 hours) and in the length of hospital stay (4.9 days versus 5.3 days). CONCLUSIONS: The results of this prospective randomized trial showed that there were no significant advantages of laparoscopic appendectomy over open appendectomy for the treatment of male patients with suspected appendicitis. We recommend that the use of laparoscopy be limited to men with atypical pain of uncertain diagnosis and in obese patients. PMID- 8693427 TI - Efficiency of percutaneous core biopsy in pancreatic tumor diagnosis. AB - BACKGROUND: Radiologic diagnosis of pancreatic tumors exhibits limited precision. The aim of this study was to investigate the outcome and complications of pancreatic core biopsy in patients with suspected pancreatic neoplasms. METHODS: One hundred patients underwent ultrasonography-guided core biopsy of 1.2 mm external diameter. Medical charts were examined for biochemical and clinical signs of complications. Final diagnosis was settled by operation, autopsy, and clinical signs of the disease including survival with at least 2.3 years of follow-up. RESULTS: Histopathologic biopsy evaluation showed correct discrimination between exocrine and endocrine tumors and nonneoplastic conditions in 89 patients. No false-positive cancer diagnosis was found, and guidance on nature of primary tumors was obtained for eight of eight metastases. The sensitivity was 91% for exocrine and 87% for endocrine pancreatic tumors, and negative predictive values of these diagnoses were 83% and 97%, respectively. No clinically significant complications were noted. CONCLUSIONS: Core biopsy is an attractive alternative to diagnostic laparotomy in unresectable pancreatic cancer and efficiently provides diagnosis of endocrine tumors and pancreatic metastases in conjunction with rare complications. Benign biopsy findings cannot be used to exclude presence of primary or metastatic pancreatic neoplasms. PMID- 8693428 TI - Actions of acute ethanol intoxication on cardiopulmonary function after an endotoxin challenge. AB - BACKGROUND: This study examined whether acute ethanol (EtOH) intoxication could alter the systemic inflammatory response evoked by endotoxin (lipopolysaccharide, LPS). METHODS: Anesthetized (fentanyl) and mechanically ventilated mongrel pigs were administered 20% EtOH (3 gm/kg) or its vehicle (VEH) by means of gastric lavage. After 60 minutes of equilibration, blood levels were 110 to 130 mg/dl, and LPS (1 microgram/kg per 30 minutes) was infused intravenously to mimic the type of sepsis that might be encountered after a penetrating abdominal injury. RESULTS: LPS caused initial pulmonary vasoconstriction followed by cardiovascular collapse in 7 of 14 pigs with EtOH versus 0 of 14 pigs with VEH (p = 0.0058); survival time averaged 2.4 +/- 0.5 hours for EtOH versus 4.5 +/- 0.3 hours for VEH (p = 0.002). At 3 to 5 hours after LPS infusion the survivors were acidotic (base excess, -5.1 +/- 1.5 versus 0.4 +/- 1.1 mEq/L; p = 0.007) and vasodilated (systemic vascular resistance, 54% +/- 9% versus 111% +/- 9% baseline; p = 0.005). Systemic arterial pressure and cardiac filling pressures were maintained with fluid resuscitation, but more was required for EtOH versus VEH (80 +/- 11 versus 42 +/- 5 ml/kg/hr; p = 0.0034). A diffuse capillary leak was detected with gamma scintigraphy and regional uptake of technetium 99m albumin. With EtOH versus VEH microvascular permeability was higher in abdomen (p = 0.01) and liver (p = 0.06) but not in lung (p = 0.29). These changes were probably mediated in part by leukosequestration: neutrophil counts were initially reduced more than 80% in both groups, but they then rebounded with VEH (p < 0.05) but not EtOH. The early versus late deaths within the EtOH group were distinguished by higher baseline levels of cortisol (1.4 +/- 0.3 versus 0.9 +/- 0.2 micrograms/dl; p = 0.075) and by a 50% decrease evoked by EtOH (p = 0.0042) versus no change in the late death subgroup. After LPS infusion cortisol peaked sooner and then recovered with VEH (p < 0.05), whereas the peak occurred later and there was no decay with EtOH. In addition, at 60 and 90 minutes after LPS infusion tumor necrosis factor was 119 +/- 27 and 240 +/- 40 pg/ml with VEH versus 62 +/- 15 and 95 +/- 23 pg/ml with EtOH (p = 0.041 and p = 0.0030). CONCLUSIONS: By means of a leukocyte mediated mechanism in the splanchnic circulation, acute EtOH impaired host defense, which exacerbated LPS-evoked systemic inflammatory response. In context with our earlier experimental study and two large clinical trials, it appears that acute EtOH can have opposite effects on the vulnerability to posttrauma sepsis, depending on the timing of the septic insult and on the immune status at the time of septic challenge. PMID- 8693429 TI - Glutamine metabolism and neuropathological disorders in experimental hepatic encephalopathy: effect of transplanted hepatocytes. AB - BACKGROUND: Physiopathology of hepatic encephalopathy remains unclear. Recent studies have suggested that ammonia would not act by itself but through an increase in glutamine in the brain. We have previously demonstrated that transplantation of syngeneic hepatocytes into the spleen was able to correct both behavioral deficits and plasma amino acid changes observed in portacaval shunted rats. The aim of the present work was to show a correlation between the correction of chronic hepatic encephalopathy by means of intrasplenic hepatocyte transplantation and two parameters, brain glutamine concentration and ultrastructural aspects of astrocytes. METHODS: Inbred male Wistar Furth rats were divided into three groups: sham-operated rats (n = 10), rats subjected to portacaval shunt (n = 10), and rats subjected to portacaval shunt and intrasplenic hepatocellular transplantation of 10(7) hepatocytes isolated from livers of syngeneic rats (n = 10). Chronic hepatic encephalopathy was quantified 30 and 60 days after operation by means of nose-poke exploration and spontaneous activity. Pathologic examination and measurement of glutamine concentrations in the corpus striatus and in the cerebral cortex were performed 60 days after operation. RESULTS: Portacaval shunt rats showed reduced spontaneous activity and nose-poke exploration scores. After portacaval shunt a significant glutamine increase occurred in the corpus striatus and in the cerebral cortex when compared with sham rats (p < 0.05). Ultrastructural examination showed modification of astrocytes named Alzheimer type II after portacaval shunt. Correction of behavioral abnormalities by means of intrasplenic hepatocyte transplantation was associated with partial correction of striatal glutamine increase and with decrease in astrocyte alterations. Cortex glutamine concentration in portacaval shunt-intrasplenic hepatocyte transplantation group and in portacaval shunt rats did not differ significantly. CONCLUSIONS: These data show that intrasplenic hepatocyte transplantation not only prevents neurologic disorders of hepatic encephalopathy but can also decrease glutamine and ultrastructural alterations in the corpus striatus in an experimental model of chronic liver failure. These data are in favor of the involvement of glutamine in chronic hepatic encephalopathy. These results suggest that intrasplenic hepatocyte transplantation might be of therapeutic interest in chronic liver failure. PMID- 8693430 TI - Discrete clutch sizes, local mate competition, and the evolution of precise sex allocation. AB - Optimal sex allocation under a population structure with local mate competition has been studied mainly in deterministic models that are based on the assumption of continuous clutch sizes; Hamilton's (1967) model is the classic example. When clutch sizes are small, however, this assumption is not appropriate. When taking the discrete nature of eggs into account it becomes critically important whether females control only the mean sex ratio ("binomial" females) or the variance as well ("precise" females). As both types of sex ratio control have been found, it is of interest to investigate their evolutionary stability. In particular, it may be questioned whether perfect control of the sex ratio is always favoured by natural selection when mating groups are small. Models based on discrete clutch sizes are developed to determine evolutionarily stable (ES) sex ratios. It is predicted that when all females are of the binomial type they should produce a lower proportion of daughters than predicted by Hamilton's model, especially when clutch size and foundress number are small. When all females are of the precise type, the ES number of sons should generally be either a stable mixed strategy or a pure strategy, but there are special cases (for two foundresses and particular clutch sizes) where the ES number of sons lies in a trajectory of neutrally stable mixed strategies; the predicted mean sex ratios can be either higher or lower than predicted by Hamilton's model. The existence of ES mixed strategies implies that individual females do not necessarily have to produce sex ratios with perfect precision; some level of imperfection can be tolerated (i.e., will not be selected against). When the population consists of both binomial and precise females, the latter always have a selective advantage. This advantage of precision does not disappear when precision approaches fixation in the population. The latter result contradicts the conclusions of Taylor and Sauer (1980) which is due to their way of expressing selective advantage; they define selective advantage as the between-generation increase per allele, which will always become vanishingly small when an allele reaches fixation, irrespective of fitness differences. PMID- 8693431 TI - Distinguishing migration from isolation using the variance of pairwise differences. AB - Two demographic scenarios are considered: two populations with migration and two populations that have been completely isolated from each other for some period of time. The variance of the number of differences between pairs of sequences in a single sample is studied and forms the basis of a test of the isolation model. The migration model is one possible alternative to isolation. The isolation model is rejected when the proposed test statistic, which involves the variances of pairwise difference within and between populations, is larger than some critical value. The power and realized significance of the test are investigated using simulations, and an example using mitochondrial DNA illustrates its application. PMID- 8693433 TI - Tobacco: the Third World War--advice from General Sun Tzu. PMID- 8693432 TI - Management of lung cancer. PMID- 8693434 TI - Age and the treatment of lung cancer. AB - BACKGROUND: The average age of patients with lung cancer is increasing and there are large numbers of elderly symptomatic patients with this common disease. However, there are few data on how the treatment of this group differs from that of younger patients. METHODS: From 1 January 1990 information was collected for the Southend Lung Cancer Registry on all patients with a diagnosis of lung cancer in a geographically well defined health district of the UK with a population of 325,000. Every effort was made to find new cases from all departments of the hospital, including all clinical diagnoses, histopathological and cytological reports, and necropsies. All death certificates in the district were examined, irrespective of age, for any diagnosis of lung cancer. This therefore included any patient not seen by the hospital services. The differences in initial treatment have been analysed for three age groups: under 65, 65-74 years, and over 75. RESULTS: The 563 cases of lung cancer diagnosed during a 30 month period were included in the study, of whom 240 (43%) were aged over 75 years. The overall mean age was 71 years (range 31-95). The incidence of lung cancer in the general population was 69 per 100,000, but in men over 75 years of age it rose to 751 per 100,000. For all patients the active treatment rate (chemotherapy, surgery, or radiotherapy) was 49%, but for patients not reviewed by a chest physician (n = 86) it was only 21%. There were large differences in initial treatment between age groups. For patients with non-small cell lung cancer (NSCLC) reviewed by a chest physician, surgery was undertaken in 18% of those under 65, 12% of the 65-74 age group, and 2.1% of those over 75. For patients with small cell lung cancer (SCLC) reviewed by a chest physician, 79% of those aged under 65, 64% of the 65-74 age group, and 41% of patients aged over 75 received chemotherapy. In patients with NSCLC reviewed by a chest physician, chemotherapy was given to 21% under 65, 6.4% in the 65-74 age group, and none over 75. If no histological diagnosis was made 37% of patients aged under 75 and only 5.4% of those over 75 received either surgery, radiotherapy, or chemotherapy. Patients not reviewed by a chest physician were less likely to have had a histological diagnosis. Differences in treatment rates with age persisted even after allowing for performance score status at presentation. CONCLUSIONS: Lung cancer is a common disease in the elderly and, in our district, 43% of patients were aged 75 or over at presentation. Age alone appeared to be a major factor in influencing treatment choices, and treatment was more likely if histological confirmation was obtained. Further detailed analysis of the reasons for the differences is needed. Patients referred to chest physicians were more likely to have both histological confirmation and active treatment. This study supports the contention that all patients with a diagnosis of lung cancer, irrespective of age or condition, should be assessed by an accredited chest physician. PMID- 8693435 TI - Management of lung cancer in South East Scotland. AB - BACKGROUND: There are few reports which describe the management of unselected groups of patients with lung cancer. This study was undertaken to audit prospectively the presentation, diagnosis, management, and outcome of patients presenting with lung cancer in South East Scotland. METHODS: Data were recorded on all patients with newly diagnosed lung cancer who presented to a multidisciplinary group of clinicians over a 12 month period. Subsequent follow up data on treatment and survival were collected. RESULTS: Six hundred and twenty two patients were registered, 80% of whom were referred from primary care. There was a considerable variation in the length of history, but the diagnosis was rapidly made after referral (87% within two weeks). In 82% of patients the pathological examination was positive; 70% were treated with palliative intent. Only 36% of patients who underwent surgery had computed tomographic scanning and 55% had sampling of mediastinal nodes. A wide variety of regimens was used for treatment with radiotherapy and chemotherapy, and follow up data were difficult to obtain in these patients. Survival was poor in all patients treated with palliative intent. CONCLUSIONS: This audit confirms the importance of previously noted prognostic factors. Significant variation in referral practice, diagnostic and management evaluation has been shown. The data serve as a useful background for the formation of local management guidelines. PMID- 8693437 TI - Effect of allergen avoidance at high altitude on direct and indirect bronchial hyperresponsiveness and markers of inflammation in children with allergic asthma. AB - BACKGROUND: Improvement of allergic asthma is seen at high altitude partly because of low concentrations of allergen, especially house dust mite. To investigate the effect of a hypoallergenic environment (Davos, 1560 m) on airways inflammation, the changes in bronchial hyperresponsiveness measured with methacholine and adenosine 5'-monophosphate (AMP), blood eosinophils, eosinophil cationic protein (ECP), and serum IgE were studied. METHODS: In 16 allergic asthmatic children tests were performed on admission and after one month. Medication was kept unchanged during the month of investigation and the patients performed peak expiratory flow (PEF) measurements twice daily. RESULTS: After one month at high altitude a considerable improvement was seen in the provocative concentration of AMP causing a 20% fall in forced expiratory volume in one second (PC20 AMP), but not with methacholine. There was also a reduction in total blood eosinophils and ECP. No change in serum IgE was observed. Peak flow variability decreased. CONCLUSIONS: After one month at high altitude a reduction in airways inflammation occurs. The results indicate that AMP responsiveness is a more accurate marker of disease activity in relation to inflammation in asthma than methacholine. The benefits of allergen avoidance at high altitude have important clinical implications for children with allergic asthma. PMID- 8693436 TI - Effect of natural allergen exposure during the grass pollen season on airways inflammatory cells and asthma symptoms. AB - BACKGROUND: Bronchial challenge with allergen causes a specific form of airways inflammation consisting of an influx of neutrophils, eosinophils, and T cells. Because the relevance of the challenge model to clinical asthma is uncertain, the cellular changes that occur in the lungs of asthmatic subjects during natural seasonal allergen exposure were investigated. METHODS: Seventeen grass pollen sensitive asthmatic subjects with previously reported seasonal exacerbations of asthma kept records of symptoms and underwent fibreoptic bronchoscopy with bronchoalveolar lavage (BAL) and endobronchial biopsy before and during the peak of the grass pollen season. The BAL cells were analysed for differential cell counts and by flow cytometry for T cell subsets and surface activation markers. The biopsy samples were processed into glycol methacrylate resin and immunohistochemical analysis was performed for mast cells, activated eosinophils, T cells and interleukin 4 (IL-4), a cytokine with a pivotal role in allergen induced inflammation. RESULTS: In the pollen season there was an increase in T lymphocyte activation in the BAL fluid as identified by increased expression of interleukin 2 receptor (IL-2R). In the submucosa these changes were paralleled by an increase in CD4+ T cells. By contrast, the numbers of metachromatic cells in BAL fluid staining with toluidine blue were reduced, possibly because of degranulation following allergen stimulation. In keeping with mast cell activation, the number of mucosal mast cells staining for secreted IL-4 increased during the season. In comparison with the period shortly before the onset of the season, all but two subjects experienced an asthma exacerbation which followed the rise in pollen counts but, compared with the period preceding the first bronchoscopic examination, asthma symptoms were not increased during the pollen season. CONCLUSIONS: The data suggest that natural allergen exposure, leading to a clinical exacerbation of asthma, may induce an inflammatory response involving T cells, mast cells and eosinophils. The relationship between allergen exposure, cellular infiltration and activation, and clinical symptoms appears to be complex, with factors other than allergen also contributing to asthmatic activity. PMID- 8693438 TI - Effects of prior treatment with salmeterol and formoterol on airway and systemic beta 2 responses to fenoterol. AB - BACKGROUND: Previous studies have shown that both salmeterol and formoterol act as partial beta 2 receptor agonists in terms of antagonising the extrapulmonary responses to fenoterol in normal subjects. The aim of the present study was to extend previous observations in evaluating the effect of prior treatment with salmeterol and formoterol on bronchodilator responses to fenoterol, a full beta 2 receptor agonist, in patients with asthma. METHODS: Ten stable asthmatic patients of mean (SE) age 37 (3.7) years and forced expiratory volume in one second (FEV1) 59.5 (4.1)% of predicted completed the study. One hour after inhaling single doses of placebo, salmeterol 25 micrograms, or formoterol 12 micrograms, dose response curves to repeated doses of inhaled fenoterol were constructed (cumulative doses of 100-3200 micrograms). Measurements of airway and systemic beta 2 receptor mediated responses were made at baseline, after inhalation of placebo, salmeterol, or formoterol, and after each dose of fenoterol. RESULTS: Salmeterol and formoterol produced significant bronchodilation compared with placebo (mean difference and 95% CI compared with placebo): FEV1, salmeterol 0.41 (95% CI 0.13 to 0.69) 1, formoterol 0.47 (95% CI 0.19 to 0.75) 1. Salmeterol and formoterol had no significant effect on systemic responses compared with placebo. There were no significant differences in peak airway responses to fenoterol after treatment with salmeterol or formoterol compared with placebo (mean (pooled SE)): FEV1, placebo 2.84 (0.03) 1, salmeterol 2.87 (0.03) 1, and formoterol 2.88 (0.03) 1. There were no significant differences in the area under the dose-response curve for any of the parameters during the dose-response curve following treatment with salmeterol or formoterol compared with placebo. There was no difference in the slope of the dose-response curves to fenoterol for FEV1 or forced expiratory flow (FEF25-75) after treatment with salmeterol or formoterol compared with placebo, although there was a significant (p < 0.05) attenuation of the slope in the dose-response curve for the peak expiratory flow rate (PEFR). CONCLUSIONS: Prior treatment with low doses of salmeterol or formoterol does not significantly alter bronchodilator dose-response curves to repeated doses of fenoterol in stable asthmatic patients. PMID- 8693439 TI - Evaluation of bronchial responsiveness to exercise in children as an objective measure of asthma in epidemiological surveys. AB - BACKGROUND: Exercise has been proposed as a useful challenge test for the measurement of bronchial responsiveness in community surveys of the prevalence of childhood asthma. This study aimed to develop a standardised exercise challenge in which the sensitivity to detect asthma was increased by inhalation of dry air. METHODS: Sixty four children aged 12-13 years who had reported wheeze in the past 12 months and 70 control subjects were invited to participate in an exercise challenge at school. Subjects performed eight minutes of cycle exercise while breathing dry air at a workload calculated to produce a minute ventilation of 60% maximum voluntary ventilation during the final three minutes. A fall in forced expiratory volume in one second (FEV1) of 10% or more from baseline was considered a positive test. Data on recent asthma symptoms, asthma morbidity, and use of medication were collected by parent completed questionnaires in those subjects who reported wheeze in the past 12 months. Repeatability of the exercise test was determined in a further 13 children with known asthma. RESULTS: Fifty five children (88%) who reported wheeze in the previous 12 months and 54 control subjects (77%) were studied. Nine subjects in whom baseline FEV1 was less than 75% predicted did not perform the exercise test. Technically unsatisfactory tests were obtained in five subjects. Twenty six (57%) subjects who reported wheeze and three controls (6%) had a positive exercise test, giving a sensitivity of 57% (26 of 46) and specificity of 94% (47 of 50). Estimates of the repeatability of the exercise test showed a mean difference in percentage fall in FEV1 for patients with asthma of 3.08% (95% limits of agreement -7.76% to 13.92%). CONCLUSIONS: Despite attempts to maximise the stimulus to bronchoconstriction in this exercise challenge test, its sensitivity and specificity were not improved in comparison with previous epidemiological studies of the prevalence of asthma. PMID- 8693441 TI - Reliability of a commercially available threshold loading device in healthy subjects and in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Threshold loading with the Nickerson and Keens' device is frequently applied in the training and assessment of inspiratory muscles. However, this equipment is not easily applied in clinical practice and training. A study was therefore designed to investigate the accuracy and reliability of the Threshold, a commercially available threshold loading device. METHODS: The resolution (accuracy) of the system was determined by measuring variation of pressure and flow during one minute in an experimental setup. The reproducibility and flow independence were then determined during threshold loading at six different inspiratory loads between 25% and 50% maximal inspiratory pressure (PImax) in 10 patients with chronic obstructive pulmonary disease (COPD) and eight healthy subjects. RESULTS: In the first experiment the mean variation of the sustained pressure for all loads was 1.7%. The mean coefficients of variation for pressure and flow measurements were 0.2% and 3%, respectively. In the second experiment the healthy subjects showed mean coefficients of variation for pressure and flow of 0.8% and 20.5%, respectively, and the patients showed mean coefficients of variation of 0.6% and 14.5%, respectively. CONCLUSIONS: During the in vitro experiment as well as during the experiments in patients with COPD and in healthy subjects only small variations in pressure were observed despite large variations in flow. The Threshold is a reliable and reproducible device for loading inspiratory muscles in patients with COPD as well as in healthy subjects. PMID- 8693440 TI - Effect of inhaled morphine on the development of breathlessness during exercise in patients with chronic lung disease. AB - BACKGROUND: Inhaled morphine has previously been shown to increase exercise endurance in patients with chronic lung disease. A similar study was performed to determine whether inhaled morphine reduces the sensation of breathlessness in this group of patients. METHODS: A randomised double blind study on the effect of nebulised morphine on both exercise induced breathlessness and maximum achievable power output using isotonic saline as a control was performed in 10 patients with stable chronic lung disease. Each subject performed a progressive exercise test (Jones' stage I) on an electrically braked cycle ergometer. The work load was increased by 10 watts per minute and subjects exercised to exhaustion. At the end of each minute of exercise patients were asked to rate their degree of breathlessness according to a modified Borg scale. All subjects were randomised to receive either inhaled morphine sulphate 1 mg/ml (5 ml) or isotonic saline (5 ml) by wet nebulisation. The effect of morphine and saline on the achieved exercise capacity and the development of breathlessness during exercise was tested on separate days. RESULTS: The mean dose of morphine inhaled was 1.24 mg. There was no difference in maximum power output achieved, minute ventilation at maximum power output, nor the degree of breathlessness at maximum power output between the groups treated with morphine and placebo. The degree of breathlessness was related to the power output achieved during exercise by a power function relationship (mean r: morphine = 0.86, saline = 0.87). However, there was a wide variation in the sensation for any given power output in both groups. There was no difference in the group mean slopes (morphine = 1.15, saline = 1.00) or intercepts (morphine = 0.07, saline = 0.15) in this relationship between the morphine and saline treatment groups. CONCLUSIONS: In patients with severe chronic lung disease inhaled morphine in the doses used in this study does not relieve exercise induced breathlessness nor does it increase maximum power output achieved during progressive exercise. PMID- 8693442 TI - Gastric intramural pH in mechanically ventilated patients. AB - BACKGROUND: The hypothesis that gastric intramural pH (pHi) is predictive of outcome in haemodynamically stable, mechanically ventilated patients was tested in 25 patients on assisted mechanical ventilation for respiratory failure. METHODS: Simultaneous samples of arterial blood and gastric juice were obtained from patients on assist control, synchronised intermittent and pressure control ventilation during the first 48 hours of mechanical ventilation. Gastric pHi was calculated from the equation: pHi= 6.1 + log HCO3/(gastric PCO2 X 0.03). The outcome was survival or death due to respiratory or circulatory failure within 45 days of admission. RESULTS: Gastric pHi proved to be a better predictor of outcome than all presently utilised parameters. Although all patients included in this study were haemodynamically stable and were similar for all laboratory indices, the only variable capable of accurately predicting outcome was gastric pHi. Patients with a normal arterial pH but a gastric intramural pH of less than 7.25 had an observed mortality of 66%. Standard severity of illness scores grossly underestimated mortality rates. The sensitivity and specificity of a gastric pHi value of less than 7.25 in predicting death were 86% and 83%, respectively. A receiver operator curve for all variables exaggerates the superiority of gastric pHi as a predictor of outcome. CONCLUSION: Low gastric pHi, a marker of gastrointestinal ischaemia, may occur in the presence of normal haemodynamics and may be used to predict severity of illness and mortality accurately. PMID- 8693443 TI - Role of granulocyte-macrophage colony stimulating factor (GM-CSF) in the pathogenesis of adult pulmonary histiocytosis X. AB - BACKGROUND: Pulmonary histiocytosis X is a disorder characterised by the presence of destructive granulomas preferentially involving distal bronchioles, that contain numerous activated Langerhans' cells. Recent studies have shown that granulocyte-macrophage colony stimulating factor (GM-CSF), which is produced by normal bronchiolar epithelium, may play an important part in the distribution and differentiation of Langerhans' cells. The aim of this study was to evaluate the role of this factor in the pathogenesis of pulmonary histiocytosis X. METHODS: Four patients with pulmonary histiocytosis X were examined by immunohistochemical techniques for GM-CSF and CD1a surface molecules. RESULTS: In early lesions the epithelium of bronchioles affected by the disease was strongly positive for GM CSF and infiltrated by numerous CD1a+ Langerhans' cells organised into granulomas. In contrast, the expression of GM-CSF was substantially lower in bronchioles not affected by the disease, and these bronchioles contained few Langerhans' cells. When destruction by histiocytosis X lesions was more advanced, only remnants of bronchiolar epithelium could occasionally be identified; these remained strongly reactive for GM-CSF. Langerhans' cells within granulomas also moderately expressed this cytokine. CONCLUSIONS: These results support the hypothesis that GM-CSF could be one of the factors responsible for the local accumulation of lymphostimulatory Langerhans' cells in early lesions of pulmonary histiocytosis X. PMID- 8693444 TI - Comparison of cell profiles in separately evaluated fractions of bronchoalveolar lavage (BAL) fluid in children. AB - BACKGROUND: Bronchoalveolar lavage (BAL) has been widely accepted as a routine procedure in the differential diagnosis of respiratory diseases in adults. However, there is only limited information about the value of BAL in children and there is no standardisation of the procedures. METHODS: The difference in cellular profiles of sequential BAL fractions from children was analysed to assess the effect of evaluating bronchial and alveolar fractions separately. Twenty five children (mean age 13.4 years) were examined by fibreoptic bronchoscopy under general anaesthesia, combined with local application of lignocaine. The investigation was part of the clinical evaluation of an infective pulmonary problem. Bronchoalveolar lavage was performed from the right middle lobe using four 20 ml aliquots of normal saline and the four fractions of recovered fluid were evaluated separately. RESULTS: The total cell count was lowest in the first aspirate (1.8 x 10(6)) and increased gradually from fraction 1 to fraction 4. Similarly, the viability of the cells was lowest in fraction 1 and gradually improved from fraction 1 to fraction 4. In the differential count the number of neutrophils decreased from fraction 1 (8.3%) to fraction 4, with fractions 2 (5.4%), 3 (3.4%), and 4 (2.4%) being significantly different from fraction 1. There were no differences in the numbers of eosinophils, lymphocytes, or macrophages between individual fractions. CONCLUSIONS: These results show that the cell profile of the first "bronchial" fraction is different from subsequent samples. It should be evaluated separately while the second and third aliquots may be pooled. PMID- 8693446 TI - Tuberculin testing in two Liverpool social clubs: the effects of a tuberculosis outbreak on background positivity. AB - BACKGROUND: Tuberculin testing remains the standard method for assessing infection due to tuberculosis in the UK. However, there are no data on the incidence of tuberculin positivity among the general adult population in the UK and consequently interpretation of Heaf test results is often difficult. METHODS: During the investigation of an outbreak of tuberculosis in a Liverpool social club 198 members were interviewed and Heaf tested and 171 members of a second social club in Liverpool were similarly screened as a control group. Comparisons between the results from the two populations provided both an estimate of baseline Heaf test positivity in indigenous white adults from a British inner city population, and a measure of the effect on this baseline of recent exposure to tuberculosis. RESULTS: In both club populations the proportion of positive Heaf tests increased with age. Independent of age, the tuberculosis exposed population had a higher proportion of positive Heaf grade results (40.9%) than those in the control group (26.9%). Multivariate analysis confirmed both the differences in Heaf results between clubs and between age groups but identified no other behavioural or medical factors which affected Heaf test results. CONCLUSIONS: Heaf test positivity increases with age at least up to 54 years, and recent exposure to tuberculosis increases the proportion of positive Heaf tests in each age group. Interpretation of positive Heaf tests when assessing the effects of a tuberculosis outbreak should take account of background levels of Heaf positivity. PMID- 8693445 TI - Effect of nebulised recombinant DNase on neutrophil elastase load in cystic fibrosis. AB - BACKGROUND: DNA released by degenerating inflammatory neutrophils contributes to mucous plugging of airways in patients with cystic fibrosis. Neutrophil elastase, a major effector of tissue destruction in the lungs of patients with cystic fibrosis, is a highly cationic molecule which is bound and inhibited by negatively charged polyanions such as mucin and DNA in purulent sputum. Thus, the solubilisation of DNA in the airways by aerosolised recombinant DNase may remove a source of neutrophil elastase inhibition, effectively increasing elastase load. The aim of this study was to assess the effect of rhDNase therapy on neutrophil elastase load in patients with cystic fibrosis. METHODS: Blood and sputum were collected from 15 patients with cystic fibrosis before initiation of nebulised DNase therapy and at 12 weeks following therapy. The long term effects of continuous rhDNase administration were evaluated at 52 weeks for 11 of these patients. Plasma was analysed for neutrophil elastase, interleukin (IL)-8 and neutrophil elastase in complex with alpha 1-protease inhibitor (alpha 1PI). Sputum was assessed for neutrophil elastase, IL-8, and active elastase. At each visit spirometric measurements were carried out. RESULTS: Sputum elastase activity decreased at 12 weeks and was maintained at 52 weeks when a decline in total plasma elastase was also observed. Although, as expected, there was a correlation between plasma levels of total elastase and neutrophil elastase/alpha 1PI complex, the decrease in the levels of the complex at 52 weeks did not reach statistical significance. CONCLUSIONS: This study indicates that prolonged daily administration of rhDNase results in a reduction in elastase load in patients with cystic fibrosis. PMID- 8693447 TI - Exercise-induced bronchospasm at low temperature in elite runners. AB - BACKGROUND: Healthy elite runners often report bronchial symptoms when training in subzero temperatures. The occurrence and causes of exercise-induced bronchospasm after heavy exercise in cold air were investigated in elite runners. METHODS: Thirty two non-asthmatic runners, mostly from Finnish national teams, volunteered to take part in the study. They answered a questionnaire and were subjected at subzero temperature to a heavy exercise challenge test combined with lung function testing. RESULTS: Sixteen of the runners were atopic on skin prick tests. The mean (SD) maximal change in forced expiratory volume in one second (FEV1) after the exercise challenge was -4.8 (7.1)% in the atopic runners, and +2.1 (3.4)% in the non-atopic runners. When the mean maximal change in FEV1 minus 2SD (-4.7%) of the exercise response of the non-atopic runners was taken as the lower limit of a "normal" result, eight of the atopic runners responded abnormally. CONCLUSIONS: Heavy exercise at temperatures below zero causes bronchospasm in a high proportion of elite runners with atopy. Although the changes in lung function are mostly small, they may affect the maximal performance of atopic runners. Non-atopic runners are not affected. PMID- 8693448 TI - Descriptive study of cough, wheeze and school absence in childhood. AB - BACKGROUND: Respiratory symptoms such as cough and wheeze are associated with significant morbidity, including school absenteeism. METHODS: A respiratory questionnaire was sent to the parents of all 5727 children aged 7-9 years of age registered with 95 general practitioners in the Southampton area to determine (a) the prevalence of asthma, cough and wheeze, (b) the effects of respiratory symptoms on school absenteeism, and (c) the use of anti-asthma medication. RESULTS: A total of 4830 parents replied (response rate 86%). The 12 month prevalence of wheeze in the absence of cough was 5.5%, cough in the absence of wheeze was 10.0%, and 7.6% reported cough and wheeze; 15.2% of children had been diagnosed. Of the 4830 who replied, 12.7% were receiving bronchodilators, 0.6% xanthine derivatives, 1.7% sodium cromoglycate, and 4.1% inhaled corticosteroids. In all, 348 (7.2%) children had missed more than five days of schooling in the preceding year for respiratory symptoms, while 43 children (0.9%) had missed more than 20 days of schooling in the preceding year. Of the children who had missed more than five days of schooling, 43% reported cough and wheeze, 33% cough alone, and 16% wheeze alone in the preceding year. Compared with children who coughed, those who wheezed were significantly more likely to be diagnosed as asthmatic and to be receiving bronchodilators or inhaled corticosteroids. CONCLUSIONS: In this study, cough was the most frequently reported symptom amongst children missing more than five days of schooling per year. PMID- 8693449 TI - Byssinosis: a review. PMID- 8693451 TI - Phosphodiesterase inhibitors: Lily the Pink's medicinal compound for asthma? AB - The second messenger cyclic nucleotides, cyclic AMP and cyclic GMP, mediate relaxation of airways smooth muscle and suppression of multiple inflammatory cell functions. The intracellular concentrations of these cyclic nucleotides are regulated by a superfamily of phosphodiesterase (PDE) enzymes which break down cAMP and cGMP and, thereby, affect airway tone and inflammation. Theophylline and other drugs that act through inhibition of PDE are currently the subject of great research interest, since the uncovering of their anti-inflammatory actions suggests a possible additional mode of action in inflammatory diseases such as asthma. The characterisation of multiple families of PDE isoenzymes with distinct tissue distributions has encouraged hope that selective PDE inhibitors can be developed which act at specific targets without exhibiting the side effects of non-selective inhibitors like theophylline. The combination of bronchodilator and anti-inflammatory properties in a single drug by selective inhibition of specific PDE isoenzymes could produce agents most efficacious in every way for asthma therapy. PMID- 8693452 TI - Hypersensitivity pneumonitis induced by a smut fungus Ustilago esculenta. AB - A case of hypersensitivity pneumonitis caused by a smut fungus Ustilago esculenta is presented. PMID- 8693450 TI - New prognostic factors in resectable non-small cell lung cancer. PMID- 8693453 TI - Severe lipoid pneumonia following attempted suicide by mineral oil immersion. AB - Following an attempted suicide by drowning in a vat of mineral oil, a previously fit man survived the usually fatal lipoid pneumonia resulting from total immersion after intensive support and prolonged steroid therapy with recovery of chest radiography and pulmonary function at one year. PMID- 8693454 TI - Pulmonary infiltration after exposure to home renovation dust: histopathology and microanalysis. AB - A subacute self-resolving illness associated with bilateral pulmonary infiltration developed in a patient following renovation in her home. This may have been related to exposure to silicaceous plaster dust which was found in an environmental sample as well as on microanalysis of a transbronchial lung biopsy specimen and bronchoalveolar lavage fluid. PMID- 8693455 TI - Lung bioavailability of generic and innovator salbutamol MDIs. PMID- 8693456 TI - [Regional drug purchasing. Of what significance are equivalent drugs]. PMID- 8693457 TI - [Cardio-reparation--or cardioversion]. PMID- 8693458 TI - [Safety of joint prostheses]. PMID- 8693459 TI - [Quality control of prosthetic replacements of knee, ankle, toe, shoulder, elbow and finger joints in Norway 1994. A report after the first year of registration of joint prostheses in the national registry]. AB - Total hip replacements have been recorded in the Norwegian Arthroplasty Register since 1987, and recording of the other joint arthroplasties was started in January 1994. After 12 months 1,589 primary arthroplasties had been registered; these referred to 962 knees, 11 ankles, 76 toes, 113 shoulders, 69 elbows, 12 wrists, 335 fingers and 11 carpometacarpal 1 joints. Median age of the patients was 70 years. 80% were women. Rheumatoid arthritis was the predominant reason for joint replacement, except in the case of the knees where the dominant cause was osteoarthrosis (71%) and of shoulders, 28% of which were replaced because of fractures. Cement was used in 83% of the primary arthroplasties in knee, ankle, shoulder, and elbow joints. 74% of the cement types used contained antibiotics. 9% were uncemented and 8% hybrids. 97% were given systemic antibiotic prophylaxis, most commonly first generation cephalosporins. 114 reoperations were reported. The reason was aseptic loosening in 56%, and infection in 15%. The cooperation with Norwegian orthopaedic surgeons is good. The Register thus provides a reliable picture of implants of Norway, and a good basis for future follow-up studies. PMID- 8693460 TI - [Clexane (enoxaprin) or Fragmin (dalteparin) for thrombolytic prevention in hip replacement surgery?]. AB - In an attempt to reduce medical costs it was decided that four Oslo hospitals should use the same low molecular weight heparin (LMWH) for thromboprophylaxis. Clexane was chosen because it was slightly cheaper than Fragmin. Experts in haematology stated that a daily dose of 40 mg Clexane was equivalent to 5,000 units of Fragmin in high risk surgery. After changing from Fragmin to Clexane for thromboprophylaxis in connection with total hip replacement, an unacceptable increase in perioperative bleeding complications was experienced. Thus, after being used in 18 patients, use of Clexane was discontinued. We compared the group given Clexane with the last 18 total hip replacement patients who had received Fragmin. The two groups were comparable with regard to base line characteristics. In both groups the thromboprophylaxis was started the evening before the operation. We found a statistically significant increase in postoperative wound and drain-site discharge and in number of days with elevated body temperature in the Clexane group. Even though the Clexane group received an average of 1.5 blood units more, their haemoglobin value at discharge from the department was significantly lower. We conclude that a daily dose of Clexane led to more bleeding than 5,000 units of Fragmin did. PMID- 8693461 TI - [Measurement of ejection fraction after acute myocardial infarction. A comparison of measurements by means of radionuclide technique one week and 8 weeks after the infarction]. AB - Left ventricular ejection fraction was measured in 54 patients by means of radionuclide technique at one week after, and again at eight after acute myocardial infarction that had been treated with streptokinase. In 17 patients (31%) ejection fraction increased and in 15 patients (28%) it decreased > or = 5 ejection fraction units. In 22 patients (41%) ejection fraction remained unchanged. No obvious difference were found between the three groups as regards infarct localization, infarction size (enzyme activity), or level of first ejection fraction measurement. There was a statistically significant (p < 0.05) longer delay from start of chest pain until treatment was started among the patients with increased ejection fraction than among the patients with decreased ejection fraction. PMID- 8693462 TI - [Treatment with ticlodipine after intracoronary stent implantation]. AB - Complications were registered prospectively in 100 patients who had had a successful intracoronary stent implantation as assessed by quantitative angiography. The reference diameter of the vessels was 3.29 +/- 0.52 mm. Instead of the traditional treatment with dextran, heparin, warfarin, acetylsalicylic acid (ASA) and dipyridamol, all patients received the platelet antagonist ticlopidine 250 mg twice daily for 28 days together with ASA 160 mg daily. In the first 50 patients low molecular weight heparin was injected for three days. There was no incidence of stent occlusion within one month after the stent implantation. Only one patient needed surgical repair because of groin haematoma, whereas three patients needed prolonged compression in the groin because of bleeding. Ticlopidine was withdrawn because of side effects in 11 patients. No serious haematological side effect was seen. In the patients who received low molecular weight heparin the stay in hospital was 5.3 +/- 1.0 days, whereas the remaining 50 patients stayed in the hospital for 2.8 +/- 1.9 days. Thus, compared with traditional anticoagulation therapy, treatment with ticlopidine and ASA after stent implantation prevented stent occlusion, groin complications were few, and the need for hospitalization was reduced. PMID- 8693463 TI - [Treatment of hepatitis C]. AB - Hepatitis C virus (HCV) has been a major cause of post transfusion hepatitis, and is still an important cause of chronic liver disease throughout the world. How to treat patients with chronic HCV infection has been brought into focus in recent years, and a substantial amount of data has been obtained about the development of hepatitis C with and without treatment. This survey considers the diagnosis of hepatitis C, and present treatment modalities and their potential. The patients most likely to respond to treatment are described, and the authors finally discuss why treatment of hepatitis C still should take place in controlled studies. PMID- 8693464 TI - [Increased incidence of prostatic cancer. The significance of prostate-specific antigen]. AB - Patients with newly diagnosed prostate cancer who were registered in one hospital during two recent one-year periods were studied with regard to causes and consequences of the diagnosis. 65 new cases were registered in 1991 and 102 in 1994. These constitute about 90% of all new cases in the area served by the hospital, and are representative of the population to this extent. In only one of the 16 patients treated with curative intent was the diagnosis made as a consequence of routine determination of prostate specific antigen (PSA) when he was asymptomatic. On the other hand, PSA-assay in asymptomatic men led to an increasing number of patients being made aware of a disease for which no treatment was recommended. This was partly because most of the patients diagnosed in this manner were elderly (mean age 72). A plea is made to restrict this practice to younger men. PMID- 8693465 TI - [Physicians' own control of their working situation--a myth?]. AB - The idea that physicians have more autonomy than others in regard to their work does not match the physicians' own experience. In 1993, Norwegian physicians experienced less control over their own work than other professionals and employees in Norwegian society did. However, large variations exist between groups of physicians. Hospital doctors report less autonomy than other physicians do. Among specialists, surgeons report the lowest degree of job control. Female physicians report having less autonomy than their male colleagues, regardless of where or with what they work. Job control increases with age, both for female and for male physicians. PMID- 8693466 TI - [Dreading the winter.... Light and winter depression]. PMID- 8693468 TI - [Isolation of Escherichia coli O157:H7 in feces from cattle and uncooked meat products in The Netherlands]. PMID- 8693467 TI - [Veterinary dentistry (12). Discoloration of teeth in companion animals]. AB - Tooth discolouration is frequently seen in companion animal practice. Knowledge of the composition and development of the dental tissues involved in such discolouration and identification of the cause of the discolouration and the consequences for the dentition are essential to provide adequate treatment for the problem. This article provides a practical classification of tooth discolouration in companion animals and discusses the most common discolourations. PMID- 8693469 TI - [Regulation indication contagious animal diseases]. PMID- 8693470 TI - [Reinforcement epidemiologic and economic expertise in health care for animals]. PMID- 8693471 TI - [Project 'Measuring is Knowledge']. PMID- 8693472 TI - [Use of progestagens]. PMID- 8693473 TI - [What clients want from veterinarians following the death of their companion animal. Bobby died, what now?]. AB - The aim of this investigation is to determine whether Dutch people would appreciate support, either from or via veterinarians following the death of a companion animal. In general, clients believe both local practitioners and specialists, even though they might not have seen the animal more than once, should offer some form of support. Being called by the veterinarian in question, a few days after the death of the animal, was the option that was most appreciated. Twenty one respondents (15%) wished to be able to attend a pet loss support group or call a hotline, following the death of their companion animal. The need to have questions answered by the veterinarian and the role the respondents thought the veterinarian should play following pet loss, were significant factors determining whether use would be made of support offered to them. Other factors included in the survey, such as age, sex and social status were not significant. PMID- 8693474 TI - [Lung worm control in calves during the 1996 pasture season]. PMID- 8693475 TI - [Pioneers: veterinarians from earlier times (15). Petrus Camper]. PMID- 8693476 TI - [Health and welfare legislation for animals, what is its status?]. PMID- 8693477 TI - [Bovine spongiform encephalitis (BSE)]. PMID- 8693478 TI - [Anaphylaxis in cattle]. PMID- 8693479 TI - [Mad-cow disease; a strange cow disease]. PMID- 8693480 TI - [Male veterinarians are still slightly ahead, but hot breath of women clearly noticeable]. PMID- 8693481 TI - [Quality guideline precedes legislation]. PMID- 8693482 TI - Immunohistological reaction mechanism of anti-monosialoganglioside monoclonal antibody, MAb 202, showing predominant cytotoxicity for malignant melanoma. AB - Mouse monoclonal IgM antibody (MAb 202) can cause melanoma cell necrosis in vivo. We analysed its immune mechanism in three melanoma patients to whom MAb 202 was administered. After the MAb 202 administration, histopathological analysis showed necrosis of melanoma cells expressing only GM3 in two patients. Another patient carrying both GM3 and GD3 showed infiltration of lymphocytes within the tumor nest but no tumor cells or nest necrosis. Immunohistological examination using anti-mouse IgM antibody revealed MAb 202 bound on the surface of melanoma cells in two patients but not in the third (positive for both GM3 and GD3). In vitro, MAb 202 reacted with the melanoma cells of the same two patients, but not with any other tissues of these individuals. We found no reaction of MAb 202 to non melanoma cells including normal melanocytes and glia cells. Our trials suggest, 1) MAb 202 reacts directly to monosialogangliosides on the melanoma cell surface and then leads to the cytotoxicity reaction, or 2) MAb 202 induces lymphocyte infiltration and possibly then promotes the secretion of some cytokines. PMID- 8693483 TI - Clinical evaluation of polymerase chain reaction DNA amplification method for the diagnosis of pulmonary tuberculosis in patients with negative acid-fast bacilli smear. AB - We evaluated the sensitivity and specificity of polymerase chain reaction (PCR) for the detection of Mycobacterium tuberculosis among 109 patients who were suspected to have active pulmonary tuberculosis (PTB) and showed negative acid fast bacilli (AFB) smears in a total of 393 samples of sputum (169), gastric aspirate (134), and urine (90) which fulfilled different criteria for the positivity of PCR. The patients were subsequently divided into one group of active PTB composed of 15 patients with definite PTB and 43 patients with highly suspected PTB, and another group of 51 non-active PTB patients. The PCR assay using samples of sputum and gastric aspirate proved to be specific for active PTB. The PCR method for diagnosis of active PTB using sputum samples was sensitive (97.8%) but lacked specificity (27.0%) when regarded as PCR positive when at least one positive reaction was obtained among all samples examined. However, the PCR of gastric aspirate demonstrated a sensitivity of 63.4% and a specificity of 76.7%. Our data supports that the PCR method for detecting active PTB in AFB smear negative patients using gastric aspirate shows markedly improved sensitivity over the conventional method (25.9%), although it still lacks specificity. PCR assay for M. tuberculosis using multiple samples of gastric aspirate in conjunction with careful clinical observations for the presence of active infection is essential for the diagnosis of active PTB among patients with negative AFB smear. PMID- 8693484 TI - Effects of alpha-blocker on daily testicular sperm production and sperm concentration, motility, intraluminal pressure and fluid movement in the rat epididymis. AB - This study was undertaken to investigate whether alpha-blocker has an effect on daily testicular sperm production and epididymal sperm parameters, intraluminal pressure and fluid movement in the rat cauda epididymal tubules. Sprague-Dawley rats were given daily oral doses 1 mg/kg, 2 mg/kg, or 10 mg/kg of Bunazosin, which was a selective alpha-blocker, for three months. Intraluminal fluids were collected from the cauda epididymidis using a micropuncture technique. Sperm concentration was determined with a sperm concentration microassay. Motility estimates were made by measurements of linear distance traveled by sperm in the diluent. Epididymal intraluminal pressure was measured through a micropunctured pipette connected to a micropressure transducer. Intraluminal fluid movement was examined by measurement of the distance which Sudan Black stained mineral oil moved along the epididymal tubules. Outside diameters of seminiferous and epididymal tubules were measured by light microscopy. Epididymal sperm concentrations were significantly increased after administration of alpha blocker. Progressive motility of spermatozoa was not significantly altered by alpha-blocker. Intraluminal pressures were significantly reduced and intraluminal fluid movement rates were significantly increased by alpha-blocker. Daily sperm production was significantly increased by alpha-blocker. Outside diameters of seminiferous and epididymal tubules were significantly distended when treated with alpha-blocker. These results demonstrate that alpha-blocker has an effect on spermatogenesis and sperm transport in the rat testis and epididymis. PMID- 8693485 TI - Histological and immunohistochemical changes after transurethral balloon laser hyperthermia in the canine prostate. AB - Transurethral balloon laser hyperthermia (TUBAL-H) for the prostate was performed in a canine model. Eleven normal and hyperplastic prostates were heated at between 40 to 45 degrees C for 30 min. Compared to the pretreatment weight, the prostatic weight significantly increased immediately after treatment and significantly decreased at 4 weeks later, but was not significantly different after 8 weeks. Histologically, shedding of epithelial cells was observed immediately after treatment, although, coagulonecrotic tissue was not seen. After 8 weeks, atrophic changes of epithelial cells were observed at the inner portion of the prostate. By immunohistochemical analysis, epithelial cells expressing apoptosis related antigen (Ley) were observed at the inner portion of the prostate from immediately after treatment until 4 weeks later. The atrophic epithelia and the expression of apoptosis in the prostate gland were pathological changes induced by TUBAL-H. From the present data, it is suggested that TUBAL-H combined with radiation or administration of anti-cancer drugs may be effective for prostate cancer. PMID- 8693486 TI - Changes in plasma vasopressin levels and cardiovascular function due to postural changes in diabetic neuropathy. AB - Decreases in blood pressure are well known to increase the release of vasopressin. Studies were carried out to investigate whether vasopressin responses to postural changes in blood pressure are maintained in diabetic patients with orthostatic hypotension [DM-OH(+)] as well as non-diabetic patients with orthostatic hypotension [nonDM-OH(+)] and these responses were compared with those observed in normal subjects and diabetic patients without orthostatic hypotension [DM-OH(-)]. After 30 min in the supine position, the upright posture for 40 min was maintained and then the supine for 10 min. Blood pressure and heart rate (HR) were measured every 5 min and plasma vasopressin levels (plasma AVP) were determined every 10 min. In normal subjects and DM-OH(-), mean arterial blood pressure (MABP) did not change, but HR increased significantly by the upright position. Plasma AVP did not change in these groups. On the other hand, in DM-OH(+) MABP fell abruptly and remained to decrease during the upright posture. The HR responses in this group, however, were similar to those in normal control and DM-OH(-). Plasma AVP in DM-OH(+) significantly increased only at 30 min during upright. These increases were significantly greater than those in normal and DM-OH(-). There were significant correlation in changes in MABP (delta MAP) and plasma AVP (delta AVP) in DM-OH(+) (delta AVP = -0.13 MABP + 1.5, r = 0.32, p < 0.01). Relationship between delta MABP and delta AVP in nonDM-OH(+) was similar to that in DM-OH(+). It is concluded that AVP responses to orthostatic hypotension in diabetic and non-diabetic neuropathies were attenuated, but heart rate responses in these patients ware well reserved. PMID- 8693487 TI - Establishment of a new extrahepatic bile duct carcinoma cell line, TFK-1. AB - A new human extrahepatic bile duct carcinoma cell line (TFK-1) was established from a surgically resected tumor specimen, which was histologically diagnosed as partly papillary adenocarcinoma and partly differentiated tubular adenocarcinoma. The tumor cells cultured in RPMI-1640 medium supplemented with 10% FBS grew as monolayers showing epithelial-like morphology with a population doubling time of 37 hr during exponential growth at passage 40. Chromosome number was distributed in the range of 72 to 76, with a modal number of 73. Tumor markers (CEA, CA19-9, ST-439, DUPAN-2) were negative in culture supernatant and plasma of SCID mice grafted with TFK-1 cells. Though no point mutation at 12 codon of K-ras was detected, expression of c-erb B-2 product and MUC1 antigen was positive. TFK-1 is the third cell line established from extrahepatic bile duct carcinomas in the world literature, and should provide useful information on various aspects of this type of neoplasm. PMID- 8693488 TI - Role of atrial natriuretic peptide in interleukin 1 beta-induced natriuresis in conscious rats. AB - To assess whether atrial natriuretic peptide (ANP) plays a role in the natriuresis induced by interleukin 1 beta (IL-1 beta), the following experiments were carried out. Experiment (Ex) I: IL-1 beta (7.5 micrograms/kg BW) was given intravenously (i.v.) in conscious hydrated rats (n = 6). Plasma ANP, vasopressin (AVP) osmolality (Posm), Na and K, urine Na (UNa V) and K excretion (UK V), osmolality and flow (UF), and mean arterial blood pressure (MABP) and heart rate were simultaneously determined. In the control group (n = 6), the drug was omitted, and the same protocols were carried out. Ex II: Three mg/kg BW of the specific ANP antagonist, HS-142-1 (HS), was administered i.v. and then, IL-1 beta (7.5 micrograms/kg BW) was given i.v. (n = 6). In the HS alone group (n = 6), IL 1 beta was omitted. The experimental protocols were the same as those in Ex I. IL 1 beta increased significantly plasma ANP and AVP and UNa V, but not UF, accompanied by decreases in Posm and UKV and increases in MABP (ExI). HS inhibited the natriuresis mediated by IL-1 beta, despite increases in plasma ANP and had no influence on plasma AVP and MABP. In the control (ExI) and HS alone (ExII) groups, these parameters did not change, except for decreases in Posm in both groups and increased plasma ANP in the latter. These results suggest that plasma ANP may play an essential role in the IL-1 beta-mediated natriuresis. PMID- 8693489 TI - The secular trend in the incidence of subarachnoid hemorrhage in Miyagi, Japan: 1979-1990. AB - Since 1978, a stroke registry has been carried out in Miyagi Prefecture (2.2 million in population), Japan. Approximately 2,000 cases of stroke were annually registered through 16 hospitals which have cerebrovascular disease units. The incidence of subarachnoid hemorrhage was 17.4 per 100,000 population in 1990. The incidence increased gradually during early 1980's and reached plateau during late 1980's. Further, the trend in the incidence of subarachnoid hemorrhage is compared with those in other communities in other countries as well as Japan. PMID- 8693490 TI - Left ventricular regional wall motion in the early neonatal period. AB - To investigate the changes in regional wall motion of the left ventricle in the early neonatal period, serial echocardiography was performed in normal neonates at 2 and 120 hr after birth. Quantitative analysis of the regional wall motion was performed by the centerline method. We measured right ventricular systolic time intervals, left ventricular stroke volume, flow velocity-time integral of the pulmonary artery, and size of the ductus arteriosus. The ductus arteriosus was 4.5 +/- 0.5 mm at 2 hr but was closed in all subjects by 120 hr. At 2 hr, there was hyperkinesis of the interventricular septum which disappeared by 120 hr. The right ventricular systolic time intervals at 2 hr showed a sign of pulmonary hypertension. At 2 hr, the left ventricular stroke volume was at the highest level and the flow velocity-time intervals of pulmonary artery was at the lowest level. Thus the hyperkinesis of the interventricular septum at 2 hr might reflect the circulatory changes that are characteristic of the early neonatal period. PMID- 8693491 TI - Identification and expression of a missense mutation (Y446C) in the acid sphingomyelinase gene from a Japanese patient with type A Niemann-Pick disease. AB - Types A and B Niemann-Pick disease (NPD), an autosomal recessive lysosomal storage disorder, are caused by deficiency of acid sphingomyelinase (ASM). The recent identification of mutations in ASM gene causing types A and B NPD has led to the investigation of the phenotypic heterogeneity and the ethnic distribution of this disease, especially in Ashkenazi Jewish population. To characterize the mutations causing NPD in Japanese population, we analyzed the genomic sequence of ASM from a Japanese patient with type A NPD by PCR amplification and sequencing. A new mutation, Y446C, was identified. The authenticity of this lesion was demonstrated by the expression of the Y446C allele in COS-1 cells. No residual ASM activity was detected from the expression of the Y446C. PMID- 8693492 TI - Increased regional systolic myocardial stiffness of the left ventricle during coronary artery occlusion in a dog: analysis of the finite element model. AB - (1) We measured the instantaneous systolic transfer function of an isolated canine left ventricle (LV) before and after the ligation of the left anterior descending coronary artery (LAD). The instantaneous transfer function before the ligation of the LAD showed a resonance curve whose peak frequency was 30 to 70 Hz. On the other hand, the transfer function 40 min after the ligation of the LAD showed a divided peak in the resonance curve. (2) We constructed a finite element model of a thick-walled spherical shell with a non-uniform structure. In this model, the myocardial elasticity and viscosity of the ischemic region are different from those of non-ischemic regions. One can calculate the theoretical transfer function using modal analysis and also estimate the elasticity and the viscous coefficient of both non-ischemic and ischemic myocardium by fitting the theoretical transfer function to the experimental one. (3) The estimated elasticity of the ischemic myocardium was three to five times larger than that of the non-ischemic myocardium. The estimated viscous coefficient of the ischemic myocardium was about half that of the non-ischemic myocardium. These results showed that ischemia alters the viscoelastic properties of the myocardium during systole as well as during diastole. PMID- 8693493 TI - Kidney disease in systemic lupus erythematosus (SLE) of children--morphometric analysis of kidneys from autopsy cases. AB - We have investigated the histopathological changes of kidney from 16 autopsy cases of children with systemic lupus erythematosus (SLE) using morphometric and immunohistochemical methods. These 16 cases accounted for 61% of the child autopsy cases with SLE registered in the data base "Annual of the Pathological Autopsy Cases in Japan" during the nine years from 1984 to 1992. Based on the histologic and morphometric findings, we divided the SLE-associated renal disease into three types: glomerular (3 cases), vascular (3 cases) and non-renal (10 cases) types. The glomerular and vascular types had renal lesions, while in the non-renal the main changes were found in extrarenal tissues. Of the 16 cases examined, three showed diffuse proliferative glomerulonephritis, with one of the three having crescentic formations in the glomeruli. Two of the three had wire loop lesions. Recently the crescentic or wire-loop lesions are rarely experienced even in renal biopsy and autopsy of adult cases. The vascular type was characterized by necrotizing angiitis (1 case) and severe intimal thickening of interlobular arteries (2 cases), but they had no advanced glomerular lesion. Morphometric methods allowed us to demonstrate that the severity of arterial lesions, especially intimal thickening, does not correlate with that of glomerular lesions in children. PMID- 8693494 TI - Angiographic determination of left and right ventricular volumes and left ventricular mass in normal infants and children. AB - Left and right ventricular (LV and RV) volumes and LV mass were assessed by angiography in 63 infants and children without major cardiovascular abnormalities. LV and RV end-diastolic volumes (EDV) were excellently expressed as a function of body surface area (BSA) with an exponential equation: LVEDV = 83.7 (BSA)1.29 ml (r = 0.96, p < 0.001), RVEDV = 87.9 (BSA)1.29 ml (r = 0.94, p < 0.001). LV ejection fraction (EF) averaged 64 +/- 6 (mean +/- standard deviation) %, and RVEF 56 +/- 5%, each of which was independent of BSA. LV mass was well expressed as a function of BSA with an exponential equation: LV mass = 75.4 (BSA)1.22 g (r = 0.86, p < 0.001). LV mass/LVEDV was constant, and averaged 0.96 +/- 0.22 g/ml. Thus, the values of LVEDV, RVEDV, and LV mass in infants and children with various heart diseases may be estimated with reasonable accuracy as a percentage of normal values predicted from their BSA by using the above proposed exponential equations. The normal values of LVEF, RVEF and LV mass/LVEDV themselves can be compared with these parameters in pediatric patients with heart diseases because of their independence of BSA. PMID- 8693495 TI - Further studies of HLA-DR antigens on colonic epithelium in ulcerative colitis. AB - The aim of this study was to determine whether HLA-DR antigens are expressed on colonic epithelium in macroscopically involved areas in all cases of ulcerative colitis and whether the expression precedes inflammation (colitis). Thirty-four cases of active ulcerative colitis were studied including two cases in which island-like lesions were observed proximally apart from the main lesion, and three cases in which distal colitis became entire colitis in 8 months or less. Detection of HLA-DR antigens on colonic epithelium was performed with the immunoperoxidase method using anti-HLA-DR monoclonal antibodies. HLA-DR antigens were expressed on colonic epithelium in macroscopically involved areas in all 34 cases. In the macroscopically normal areas, the antigens were modestly expressed in six of 16 specimens (cases) in the presence of microscopic inflammation. The antigens were expressed on colonic epithelium in island-like lesions, but not in the intervening mucosa between the proximal island-like lesions and the distal main lesion. HLA-DR antigens were not expressed on colonic epithelium in the proximal non-inflamed mucosa where colitis later developed. These results lead to the conclusion that HLA-DR antigen expression does not precede, but is associated with the inflammation. PMID- 8693496 TI - Polysplenia syndrome with common atrioventricular canal and persistent truncus arteriosus. AB - A case of an infant with a rare combination of polysplenia syndrome with common atrioventricular canal and persistent truncus arteriosus is presented. In our present case, severe common atrioventricular valve regurgitation was identified, as in previous cases. To our knowledge, echocardiographic and autopsy findings of this association has not been previously reported. The persistent truncus arteriosus is extremely rare in the setting of the polysplenia syndrome, but the present case report demonstrates that these anomalies may, at times, occur. PMID- 8693497 TI - Relation between the stromal volume and liver metastasis in ductal cell carcinoma of the pancreas. AB - In 23 patients with ductal cell carcinoma of the pancreas, the volume density of the stromal area was estimated by morphometry on photomicrographs of cancer tissue taken at surgery. The patients were divided into three groups: those with metachronous liver metastasis (Group A, n = 8), with simultaneous liver metastasis (Group B, n = 4) and those without liver metastasis (Group C, n = 11). The analysis illustrated a significantly lower fraction of stromal element in Groups A and B as compared to Group C at a statistical level of 0.01 (Ryan test). The scirrhous pancreatic carcinoma tended to resist liver metastasis after various therapeutic modalities including pancreatic resection. PMID- 8693498 TI - Significance of the right ventricular free wall in dogs with and without pulmonary constriction. AB - To evaluate the role of the right ventricular (RV) free wall in cardiac function, RV and left ventricular (LV) wall segment lengths were measured by ultrasonic crystals in 10 open chest dogs with the pericardium preserved. Right coronary artery (RCA) was perfused separately by own blood and the flow was reduced stepwise until active shortening (delta L) of the RV segment disappeared or RCA flow became zero (Ischemia). The experiment was repeated with and without pulmonary stenosis (PS). At Ischemia, RV and LV systolic pressures decreased. RV end-diastolic length increased and RV delta L decreased. LV end-diastolic length and LV delta L were reduced. LV stroke volume concurrently fell. These changes became more prominent with PS. The critical level of RCA flow, at which RV delta L began to change, was higher with PS (5.27 +/- 2.85 ml/min, mean +/- S.D.) than without PS (1.44 +/- 1.16, p < 0.01). Based on the relationships between RV delta L and percent changes in RV developed pressure and stroke volume, the degree of the decreases in RV developed pressure and stroke volume at RV delta L of zero were estimated to be about 20%. These results indicate that the RV free wall partly contributes to maintaining the RV function, especially during RV pressure overload. PMID- 8693499 TI - HLA-reduced platelets to overcome platelet refractoriness: can lemons help? PMID- 8693500 TI - How much fresh, low-titer, O-negative blood is available? PMID- 8693501 TI - Infection by hepatitis C virus through contaminated intravenous immune globulin: results of a prospective national inquiry in France. AB - BACKGROUND: A recent hepatitis C virus (HCV) outbreak has been suspected of being caused by an infusion of intravenous immune globulin. STUDY DESIGN AND METHODS: Three laboratories were mandated by the French regulatory agency to prospectively screen on a national scale those persons having received suspected batches: 233 exposed patients were recalled and tested for HCV antibody and for HCV RNA. RESULTS: Nineteen patients (8.1%) were found positive for HCV RNA; 7 of these 19 were positive for the HCV antibody. CONCLUSION: The link between HCV infection and intravenous immune globulin was reinforced by the overrepresentation of the 2b genotype (58%), which contrasts with the low prevalence of this genotype in France (1%). PMID- 8693502 TI - Surveillance for human immunodeficiency virus type 1 group O infections in the United States. AB - BACKGROUND: Reports that the human immunodeficiency virus type 1 (HIV-1) group O variants are not reliably detected by some commercial diagnostic tests have raised concerns about the sensitivity of existing screening tests, especially with regard to blood safety. Although it is unlikely that these divergent strains are prevalent in North America, systematic, continuous surveillance is needed to monitor the potential spread of HIV variants into that region. STUDY DESIGN AND METHODS: Stored serum samples (n = 1072) from both high- and low-risk population groups at several sites in the United States and Puerto Rico were tested by peptide enzyme immunoassays specific for the prototypic HIV-1 group O strains, MVP5180 and ANT70. RESULTS: None of the 1072 samples examined had peptide reactivity that was consistent with HIV-1 group O infection. CONCLUSION: While no evidence of specific HIV-1 group O (MVP5180 or ANT70) infection was found in this study, the sensitivity of current tests has not been fully evaluated against the wide range of genetic variation of HIV. Therefore, it is important to continue active surveillance for HIV-1 and HIV type 2 strains, to characterize any divergent strains, and to judiciously modify tests to correct for any deficiencies in sensitivity. PMID- 8693503 TI - Safety and efficacy of hepatitis C virus antibody screening of blood donors with two sequential screening assays. AB - BACKGROUND: Reactive samples in hepatitis C virus (HCV) antibody screening of blood donors are currently referred for a confirmatory assay. This scheme is not optimally efficient and is expensive because of the lack of specificity and cost of confirmatory tests, as well as the need to discard false-positive donations. As in some human immunodeficiency virus antibody-confirmatory schemes, the safety and efficacy of confirming anti-HCV with two sequential screening assays were evaluated. STUDY DESIGN AND METHODS: Three combinations of two anti-HCV screening assays were used to test 75,874 blood donors. Results were compared with the routine testing scheme and HCV RNA detection in any enzyme immunoassay-repeatably reactive samples. RESULTS: The use of an alternative screening assay for repeat testing decreased the proportion of enzyme immunoassay-positive donors from 0.28 to 0.05 percent. All samples that were "confirmed" as positive by the standard combination of immunoassays and all HCV RNA-positive samples were detected by the sequential screening assays. No samples that had discordant results on primary and secondary screening assays were confirmed by recombinant immunoblot assay or were found to contain detectable HCV RNA. CONCLUSION: The combination of screening assays for anti-HCV confirmation was as safe as, cheaper than, and nearly as efficient as the standard testing scheme. PMID- 8693504 TI - Photochemical inactivation of duck hepatitis B virus in human platelet concentrates: a model of surrogate human hepatitis B virus infectivity. AB - BACKGROUND: Photochemical decontamination of platelet concentrates (PCs) has been demonstrated by the use of 8-methoxypsoralen and ultraviolet A light. Systems for studying the inactivation of blood-borne viruses facilitate the evaluation of photochemical decontamination protocols. STUDY DESIGN AND METHODS: Duck hepatitis B virus (HBV), a model for human HBV, was adapted for the study of hepadnavirus inactivation. A highly specific in vitro infectivity assay used primary duck hepatocyte cultures and was followed by the detection of replicated duck HBV sequences. RESULTS: Duck HBV-infected primary duck hepatocyte cultures produced authentic infectious virus. High-titer (> 10(9) virus genome equivalents/mL) duck HBV-infected sera were completely inactivated in serum or PCs by the use of 100 micrograms per mL of 8-methoxypsoralen and 70 J per cm2 of ultraviolet A light. Intracellular duck HBV (> 4.2 log10) in PCs was also inactivated. Culture results were confirmed by a sensitive duckling infectivity assay that indicated that 6.3 log10 of infectious duck HBV had been inactivated by photochemical decontamination. CONCLUSION: The sensitivity of the culture assay was comparable to that of the duckling assay using polymerase chain reaction gene amplification to detect duck HBV. Duck HBV inactivation in PCs was dependent on the dose of ultraviolet A light and independent of 8-methoxypsoralen concentrations of 100 to 300 micrograms per mL: 100 micrograms per mL 8-methoxypsoralen inactivated 4 to 5 log10 of virus in conjunction with 20 to 40 J per cm2 of ultraviolet A light. The polymerase chain reaction-enhanced duck HBV culture system has utility in optimizing photochemical decontamination protocols. PMID- 8693505 TI - Assignment of the gene(s) governing Froese and Swann blood group polymorphism to chromosome 17q. AB - BACKGROUND: The red cell antigens Fra and Swa were first described in 1978 and 1959, respectively. Despite the fact that these antigens are well defined serologically, information regarding the gene(s) controlling antigenic expression was not known. The present study represents a continued effort to establish the chromosomal location of human blood group genes by family linkage studies. STUDY DESIGN AND METHODS: DNA from members of kindreds segregating for FR and SW was isolated from whole blood and analyzed for restriction fragment length polymorphisms of SLC4A1 and D17S41. RESULTS: Lods for linkage between FR:SLC4A1 and SW:D17S41 were determined. Peak lods of 5.72 for the FR:SLC4A1 pair and of 3.01 for the SW:D17S41 pair were observed; there was no evidence of recombination between either pair. CONCLUSION: Lods for the FR:SLC4A1 and the SW:D17S41 pairs exceed the formal level required to establish linkage. (3.00) It was therefore concluded that the gene(s) governing Froese and Swann blood group polymorphism are located on the long arm of chromosome 17. PMID- 8693506 TI - The red cell chemokine receptor is distinct from the Fy6 epitope. AB - BACKGROUND: Previous studies established an association between the red cell chemokine receptor and Fy6 of the Duffy glycoprotein. The relationship between Duffy system antigens and interleukin 8 binding by red cells was examined. STUDY DESIGN AND METHODS: Interleukin 8 adsorption was measured by using red cells from owl, squirrel, and rhesus monkeys, and human red cells before and after saturation with anti-Fya (anti-Fy1), anti-Fyb (anti-Fy2), or anti-Fy6. The effect of cell saturation with interleukin 8 on Duffy system antigen expression and the effect of enzyme treatment on interleukin 8 adsorption were also examined. RESULTS: Fy:1,-2,6 or Fy:-1,2,6 (owl monkey, squirrel monkey, human) red cells adsorbed interleukin 8 over a wide range of concentrations (125-1000 pg/mL). Human Fy:-1,-2,-6 red cells bound minimal interleukin 8. Human red cells saturated with corresponding antibodies displayed decreased interleukin 8 binding. Saturation of human cells with interleukin 8 failed to interfere with Duffy system antigen expression. Rhesus monkey cells lacking Fy1, Fy2, and Fy6 were able to adsorb interleukin 8 in a manner similar to Fy:1,-2,6 or Fy:-1,2,6 primate cells. Ficin treatment eliminated both Duffy system antigen expression and interleukin 8 adsorption from red cells. CONCLUSIONS: The Duffy glycoprotein binds interleukin 8. Although previous studies suggested that interleukin 8 bound either directly to or close to the Fy6 epitope, the ability of Fy:-1,-2,-6 rhesus monkey cells to adsorb interleukin 8 suggests that the interleukin 8 receptor is distinct from Fy6, Fy1, and Fy2. PMID- 8693507 TI - Genotyping of the human platelet antigen systems 1 through 5 by multiplex polymerase chain reaction and ligation-based typing. AB - BACKGROUND: Platelet-specific antibodies may be involved in refractoriness to platelet transfusions, disorders such as neonatal alloimmune thrombocytopenia, and post-transfusion purpura. Genotyping for the major human platelet antigen (HPA) systems HPA-1 through HPA-5 is of considerable help in establishing the diagnoses of these diseases. STUDY DESIGN AND METHODS: A new genotyping method is described. Alleles of all five systems are amplified in a multiplex polymerase chain reaction. Subsequently, aliquots of the amplification products are thermocycled in the presence of a pair of allele-specific oligonucleotide probes and a heat-stable ligase. After heat denaturation, the probes hybridize adjacent to complementary sequences of the amplification product. In a perfect match, the two probes become covalently joined. Detection of the ligation product is performed with an enzyme-linked immunosorbent assay. RESULTS: Complete concordance of genotypes between the ligation-based typing and established genotyping methods was determined in 54 Austrian (HPA-1, -2, -3, and -5) and 56 Japanese (HPA-4) individuals. Ligation-based genotyping of HPA-1 polymorphism using platelet-derived RNA as starting material gave concordant results in all 15 cases tested. CONCLUSION: Multiplex polymerase chain reaction in combination with ligation-based typing allows fast typing of large numbers of platelet donors and screening for critical antigens in pregnant women. PMID- 8693508 TI - Use of a directly conjugated monoclonal anti-D (BRAD-3) for quantification of fetomaternal hemorrhage by flow cytometry. AB - BACKGROUND: Determination of the volume of fetal D-positive cells in the circulation of D-negative women after delivery is carried out to determine whether additional prophylactic anti-D should be given to the mother. Although the Kleihauer-Betke test is still widely used to calculate the fetomaternal hemorrhage, increasing use is being made of flow cytometry. STUDY DESIGN AND METHODS: A conjugated monoclonal anti-D was prepared by labeling purified BRAD-3 (IgG3) with fluorescein isothiocyanate (FITC-BRAD-3). This reagent was used to label D-positive red cells by a one-step procedure: 5 microL of washed cells were incubated with 50 microL of FITC-BRAD-3 (50 micrograms/mL) at 37 degrees C for 30 minutes; then the cells were washed and 500,000 events were analyzed by flow cytometry. RESULTS: The FITC-BRAD-3 reagent effectively labeled D-positive cells. The percentage of D-positive cells in mixtures containing more than 0.04 percent D-positive cells in D-negative cells was accurately determined by using this reagent and flow cytometry. Although the Kleihauer-Betke test was more accurate than this one-step flow cytometric method at quantifying fetomaternal hemorrhage of < 1 mL, the flow cytometric method was more accurate in the 1- to 7-mL fetomaternal hemorrhage range of 1 to 7 mL (whole-blood equivalents). Analysis of 175 clinical samples for fetomaternal hemorrhage gave consistent quantification results with the three methods used: the Kleihauer-Betke test, flow cytometry with FITC-BRAD-3, and flow cytometry with polyclonal anti-D followed by FITC-anti IgG. CONCLUSION: Labeling of samples with FITC-BRAD-3 was simple and rapid. By flow cytometric analysis, good separation of D-positive from D-negative cells was obtained, and fetomaternal hemorrhage of > 1 mL was quantified accurately. PMID- 8693509 TI - HLA class I-eluted platelets as an alternative to HLA-matched platelets. AB - BACKGROUND: Alloimmunized refractory thrombocytopenic patients often require HLA matched platelet transfusions. As the HLA system is very polymorphic, sufficient HLA-matched donors are not available for every patient. STUDY DESIGN AND METHODS: In vitro elution techniques with citric acid incubation of platelets at pH 3.0 showed that platelets lose expression of HLA, whereas platelet-specific glycoproteins are preserved. This technique was modified for clinical use. Random donor platelet concentrates were incubated with citric acid, subsequently washed, and transfused to two patients. RESULTS: Platelet-specific glycoproteins were unaffected, and HLA expression decreased generally to below 25 percent of the initial expression. One alloimmunized patient who was without compatible donors because of a rare HLA type underwent repeated transfusions with acid-treated platelets. In contrast to the results with random-donor platelet transfusions, posttransfusion increments up to 47 x 10(9) per L were obtained with acid-treated platelets, and profuse gastrointestinal bleeding was stopped, while multiple skin hemorrhages were resolved. No side effects were observed. A second patient developed a severe transfusion reaction without platelet increment after one transfusion with acid-treated platelets expressing 30 percent of the original HLA antigens. Further transfusions were not given. CONCLUSION: Standardization of the acid elution technique and validation of the technique in patients is necessary. The results suggest, however, that HLA-eluted platelets prepared under specified conditions may gain a place in platelet transfusion therapy. PMID- 8693511 TI - All medium starches are not the same: influence of the degree of hydroxyethyl substitution of hydroxyethyl starch on plasma volume, hemorrheologic conditions, and coagulation. AB - BACKGROUND: After the application of high volumes of high-molecular-weight starch (hetastarch), bleeding complications have repeatedly been observed. Later studies showed that the application of medium-molecular-weight starch led to far fewer disturbances of the blood coagulation system. However, the relationships among the degree of hydroxyethyl substitution, the rate of degradation, and the average in vivo molecular weight have not been investigated. STUDY DESIGN AND METHODS: A 10-day hemodilution treatment (n = 20) was carried out using two medium-molecular weight hydroxyethyl starches (HES) with a degree of hydroxyethyl substitution of 0.5 and 0.62, respectively (10% HES 200 was used for a substitution of 0.5 and 6% HES 200 for a substitution of 0.62). After a loading dose of 500 mL was administered, 1000 mL of HES was infused daily for 4 days, and then 500 mL was infused daily for 6 days. RESULTS: The more highly substituted starch was broken down more slowly and eliminated renally. This resulted in a higher intravascular molecular weight than for the less highly substituted HES (120 vs. 84 kDa) and a greater increase in serum concentration (20.3 vs. 9.0 mg/mL). Initially, the more highly substituted 6-percent HES had a lesser effect on plasma volume (p < 0.01). Because of HES accumulation, there was no longer a significant difference between the starches by the end of treatment, even though a higher dose of the 10-percent low-substitution starch was infused. Six-percent HES caused an increase in plasma viscosity (+9%, p < 0.01) that was due to an accumulation of macromolecules. Ten percent HES 200/0.5 had no effect on the coagulation system beyond the dilution effect. Six-percent HES, on the other hand, led to an acquired von Willebrand syndrome during the course of the 10-day therapy. Factor VIII function was reduced by 72.2 percent, von Willebrand ristocetin cofactor by 61.3 percent, and von Willebrand factor antigen by 64 percent (p < 0.01). CONCLUSION: It is the intravascular and not the initial (in vitro) molecular weight that determines the properties of HES. Especially after repeated administration, a high degree of hydroxyethyl substitution leads to an accumulation of macromolecules that affect hemorrheologic measures and the coagulation system just as adversely as high molecular-weight starch does. Depending on the degree of substitution, medium molecular-weight starches can have widely differing properties. PMID- 8693512 TI - Assessment of blood donor privacy during health history interviews. AB - BACKGROUND: Given the personal nature of health history interviews, it is important to provide donors with both visual and auditory privacy. Privacy is affected by variables such as background noise, the use of visual screens, and the loudness of the donor's voice. STUDY DESIGN AND METHODS: In Phase I of this study, an interview station and waiting area were simulated. To measure auditory privacy, a speech intelligibility test was given to subjects with and without the use of a free-standing privacy screen and masking noise device. Phase II was a field trial designed to evaluate screens and masking noise. Background noise was measured during each blood collection operation, and donors completed a survey. RESULTS: In Phase I, speech intelligibility test scores ranged from 78 to 5.1 percent, depending on the type of visual screen and the number of masking noise devices used. In Phase II, with the use of screens, 94 percent of donors rated visual privacy as "good to excellent," compared with 74 percent who did so when no screens were used. At many blood drives, the background noise level exceeded the level of the masking noise. CONCLUSION: The use of visual screens increases donors' perception of visual privacy. The use of masking noise is effective only when the health history interview is conducted under conditions of low background noise levels. PMID- 8693510 TI - Chemokines in stored platelet concentrates. AB - BACKGROUND: Platelets contain several mediators, belonging to a family of proinflammatory cytokines named chemokines, that are stored in the organelles. Release and accumulation of these chemokines during storage of platelet concentrates (PCs) might be responsible for nonhemolytic transfusion reactions. STUDY DESIGN AND METHODS: Analysis was done of pH and the levels of platelet factor 4, beta-thromboglobulin, interleukin 8, RANTES, macrophage-inflammatory protein-1 alpha, lactate dehydrogenase, and serotonin in the supernatant of stored PCs on Days 1, 3, 5, and 8. PCs were prepared by apheresis or from pools of four buffy coats. Buffy coat PCs were filtered before storage. RESULTS: Nonfiltered apheresis PCs, which had a higher white cell contamination (p < 0.01), contained significantly more platelets than did buffy coat PCs (p = 0.02). The pH decreased significantly in apheresis PCs (p = 0.01), whereas there was a significant increase in lactate dehydrogenase (p < 0.001). In buffy coat PCs, pH remained stable and lactate dehydrogenase increased moderately. Concentrations of platelet factor 4 and beta-thromboglobulin increased steadily in both preparations over the storage period (p < 0.001). Macrophage-inflammatory protein 1 alpha was hardly detectable in the supernatant of both PCs, while RANTES levels increased significantly with storage time (p < 0.001). Interleukin 8 was not found in the supernatant of any PCs, with the exception of one apheresis PC with high white cell contamination (> 10(9)/ L). Serotonin levels were higher in apheresis PCs (p = 0.01), but the levels did not correlate with storage time. CONCLUSION: Platelet factor 4, beta-thromboglobulin, and RANTES were released from platelets during storage and accumulated over time in the PCs. These chemokines might play a causative role in nonhemolytic transfusion reactions because of their inflammatory potential, but the clinical effects of the transfusion of PCs with high chemokine contents remain to be investigated. PMID- 8693513 TI - Acute gram-negative urosepsis mimicking an acute hemolytic transfusion reaction. AB - BACKGROUND: The acute hemolytic transfusion reaction (AHTR) is one of the most feared complications of blood transfusion. Over the years, several clinical conditions, as well as errors in blood component preparation and administration, that mimic AHTR have been identified. This report describes a novel variation on the theme of pseudo-AHTR. CASE REPORT: A 47-year-old diabetic man with drug induced pancytopenia suddenly manifested severe shaking chills, flank pain, and back pain during a red cell transfusion. The passage of bright red urine immediately after the transfusion virtually confirmed for the clinicians administering the transfusion that an AHTR had occurred. In the laboratory, the hematuria was shown to be due principally to red cells and not to free hemoglobin. Further posttransfusion work-up showed a urinary tract infection and overwhelming bacterial sepsis with Escherichia coli. CONCLUSION: As a pseudo AHTR, gram-negative bacterial sepsis of urinary tract origin may surpass other forms of sepsis. Urosepsis should be considered in the work-up of a suspected AHTR in a pancytopenic patient with a urinary tract infection. PMID- 8693514 TI - Hemolytic anemia in chronic large granular lymphocytic leukemia of natural killer cells: cytotoxicity of natural killer cells against autologous red cells is associated with hemolysis. AB - BACKGROUND: It has ben suggested that natural killer cells are effectors in some hemolytic transfusion reactions, but a direct mechanism of the destruction of red cells has not been demonstrated. CASE REPORT: Lytic activity of natural killer cells against autologous red cells was found in a patient with large granular lymphocytic leukemia of natural killer cells and hemolytic anemia, with no evidence of immune antibody or complement-mediated hemolysis. Large granular lymphocytes in the blood showed a CD2+ CD3- CD16+ CD57+ phenotype, cytotoxic activity against natural killer cell-sensitive K562 target cells, and no lytic activity against natural killer cell-resistant JY target cells. Cytotoxicity directed against red cells was quantified by a 51Cr-specific release assay with autologous and ABO-identical red cells used as target cells and the patients purified natural killer cells used as effector cells in the presence and absence of autologous serum. The cytotoxic activity of natural killer cells was directed against autologous red cells but not against allogenic red cells, and it was not enhanced by the presence of autologous serum in the medium. Clinical remission was induced by the administration of cyclophosphamide, after which no evidence of cytotoxic activity against the red cells could be found. CONCLUSION: Hemolytic anemia in the presence of a negative direct antiglobulin test can be attributed to a direct cytotoxic mechanism mediated by natural killer cells. PMID- 8693515 TI - Serologic evidence that factor IX inhibitor in the plasma of hemophilia B patients detects factor IX on normal red cells. AB - BACKGROUND: Patients with hemophilia B lack factor IX (F IX). These patients may become alloimmunized after the transfusion of F IX concentrates and may develop F IX inhibitors, which have been characterized as polyclonal IgG4 alloantibodies. Two cases in which F IX inhibitors caused difficulty in compatibility testing and antibody identification were encountered. It was hypothesized that, because F IX is present in normal plasma, it might be adsorbed by red cells in vivo and then be detected during antibody screening tests with serum containing F IX inhibitors. CASE REPORT: Sera from two African American half-brothers with hemophilia B were incompatible with all common and rare red cell phenotypes tested in the anti-human globulin test, but did not react with each other's red cells. The brothers' red cell antibodies were neutralized with both normal plasma and a commercially available F IX concentrate, which indicated that the red cell incompatibility was most probably caused by their F IX inhibitors. Red cells from an unrelated patient with hemophilia B and a very low titer of F IX inhibitor were tested against the half-brothers' sera and did not react. The compatible red cells from one of the half-brothers and the unrelated patient with hemophilia B adsorbed F IX from normal plasma or F IX concentrate after 37 degrees C incubation; this rendered them incompatible with the plasma containing F IX inhibitor from the other half-brother. CONCLUSION: F IX appears to be present on normal red cells and may be detected during compatibility and antibody identification procedures when serum or plasma containing F IX inhibitors is tested. PMID- 8693516 TI - Quality of blood components filtered before storage and at the beside: implications for transfusion practice. PMID- 8693517 TI - Inactivation of human immunodeficiency virus by high hydrostatic pressure. PMID- 8693519 TI - Can the recombinant immunoblot assay generate an erroneous diagnosis of hepatitis C virus infection? PMID- 8693518 TI - A cost-effective and Food and Drug Administration-approved alternative to tissue culture media in cryopreservation. PMID- 8693520 TI - Comparison of second- and third-generation hepatitis C virus enzyme-linked immunosorbent assays in a low-risk blood donor population. PMID- 8693521 TI - Hemolytic disease of the newborn caused by alloanti-D from an R0Har r Rh:33 mother. PMID- 8693522 TI - Inhibition of platelet integrin GPIIbIIIa prolongs survival of discordant cardiac xenografts. AB - The integrin GPIIbIIIa is known to be crucial to the formation of platelet aggregates and potentiates adhesion to subendothelial matrices via fibrin(ogen), von Willebrand factor, and vitronectin. Given the demonstration by us and others of widespread platelet aggregation during xenograft rejection, we hypothesized that platelet thrombi might contribute to graft dysfunction during development of hyperacute rejection (HAR), as well as during what we have termed delayed xenograft rejection (DXR), e.g., as seen in complement-depleted rat recipients of guinea pig cardiac xenografts. We therefore tested the effects of a specific GPIIbIIIa antagonist (SDZ GPI 562) during xenograft rejection. Lewis rats received heterotopic guinea pig cardiac xenografts and were treated with GPI 562 alone (HAR model) or in combination with cobra venom factor (CVF) (DXR model). A high (0.5 mg/kg) or a low dose (0.1 mg/kg) of GPI 562 was administered perioperatively and then given twice daily in the same dose until rejection. CVF was given daily until rejection. Plasma drawn after the first dose of GPI 562 and at the time of rejection was tested for the ability to inhibit ADP-stimulated platelet aggregation in vitro. Rejected grafts were analyzed by immunohistology. Plasma from animals in the high-dose group completely inhibited platelet aggregation in vitro, whereas plasma from the low-dose group resulted in only partial inhibition. Similarly, whereas low-dose GPI 562 failed to prolong graft survival, high-dose GPI 562 showed a statistically significant increase in graft survival in both HAR and DXR groups. Immunohistologic studies of HAR showed little effect of GPI 562 on platelet aggregation or activation and no effect on fibrin deposition. However, the combination of high-dose GPI 562 and CVF resulted in a significant decrease in intragraft platelet aggregation, P-selectin expression, and leukocyte infiltration compared with CVF alone. In conclusion, GPIIbIIIa antagonist therapy can inhibit platelet aggregation in vitro and prolong xenograft survival. The diminution of intragraft platelet microthrombi formation and leukocyte infiltration suggests an important role for platelet dependent mechanisms in leukocyte recruitment during DXR. PMID- 8693523 TI - Removal of terminal alpha-galactosyl residues from xenogeneic porcine endothelial cells. Decrease in complement-mediated cytotoxicity but persistence of IgG1 mediated antibody-dependent cell-mediated cytotoxicity. AB - To determine the role of the terminal alpha-galactosyl residue in the endothelial damage mediated by human xenoreactive natural antibodies (IgM and IgG), we treated porcine endothelial cells in culture with green coffee bean alpha galactosidase. A practically complete removal of terminal alpha-Gal residues (as evaluated by flow cytometry with Bandeiraea simplicifolia isolectin B4) and concomitant exposure of N-acetyllactosamine were obtained without altering cell viability. A dramatic decrease in IgM and IgG binding (from a pool of human sera) was observed, confirming the key role of the alpha-galactosyl residues. The enzyme treatment did not induce any nonspecific immunoglobulin binding sites, but led to the exposure of new epitopes for a minor fraction of IgM. The main residual IgM and IgG binding could be due to xenoantigens other than the alpha galactosyl residues. When alpha-galactosidase-treated endothelial cells were used as targets in cytotoxicity experiments, they were less susceptible than untreated cells to complement-mediated cytotoxicity induced by fresh human serum. In contrast, they did not acquire resistance to human IgG-dependent cellular cytotoxicity, despite the decrease in IgG binding. Because it is known that antibody-dependent cytotoxicity mediated by CD16+ NK cells is dependent on IgG1 and IgG3, and not on IgG2 or IgG4, which was confirmed by blocking experiments, we studied the binding of all four subclasses to intact and alpha-galactosidase treated endothelial cells. Two major subclasses, IgG1 and IgG2, bound to untreated endothelial cells, whereas IgG3 binding was low and IgG4 binding was negligible. A decrease in IgG1, IgG2, and IgG3 binding was observed upon alpha galactosidase treatment, indicating that antibodies belonging to these three subclasses recognize alpha-galactosyl residues. The decrease in IgG2 binding was more pronounced than the decrease in IgG1 binding. Collectively, these data indicate that IgG1 xenoreactive natural antibodies, including those which are not directed at the alpha-galactosyl residues, could play a major role in the early delayed vascular rejection of pig xenografts. PMID- 8693524 TI - Late reflush in clinical renal transplantation. Protection against delayed graft function not observed. AB - Mechanical flushing of cadaveric kidneys with organ preservation fluid immediately before transplantation has been reported to be associated with improved early graft function. We report here the results of a prospective randomized controlled study of cadaveric renal transplantation after late reflush with organ preservation fluid in which no benefit with respect to delayed graft function was observed and, indeed, the protocol may have been harmful. The study was terminated after recruitment of only 18 patients (9 to each arm) because postreperfusion biopsies of reflushed kidneys contained unusual features, including abnormal cellular debris within the tubules or eosinophilic proteinaceous material within Bowman's capsule. These features were not present in the control kidneys. Acute tubular necrosis and biopsy-proven acute rejection episodes were more frequently seen in the reflushed kidneys, but at 1 year there was no significant difference in the function of the surviving grafts. PMID- 8693525 TI - Induction of persistent allograft tolerance in the rat by combined treatment with anti-leukocyte function-associated antigen-1 and anti-intercellular adhesion molecule-1 monoclonal antibodies, donor-specific transfusion, and FK506. AB - We previously reported that a short course of treatment with anti-LFA-1 and anti ICAM-1 monoclonal antibodies (mAbs) led to a persistent acceptance of mouse cardiac allografts, which resulted from the induction of allospecific tolerance. In the present study, we tested the effect of anti-LFA-1 and anti-ICAM-1 mAbs on rat allograft rejection and analyzed the mechanisms underlying allograft tolerance. In sharp contrast to the mouse case, a short course of treatment with anti-LFA-1 and anti-ICAM-1 mAbs led to a persistent acceptance in only half of the treated rats when MHC was compatible but mismatched for minor antigens, and was virtually ineffective when MHC was fully incompatible. However, treatment with these mAbs combined with donor-specific transfusion and FK506 consistently led to a persistent acceptance, even when the MHC was fully incompatible. Donor specific tolerance was induced by this treatment, as estimated by skin challenging. In the tolerant rats, proliferative response and CTL generation against donor-type alloantigen were severely impaired but partially restored by exogenous interleukin-2. Limiting dilution analysis demonstrated that the precursor frequency of CTL was decreased in the tolerant rats, as compared with the naive rats. These results suggest that donor-reactive T cells were partially deleted and rendered anergic in the periphery. PMID- 8693527 TI - Status of microchimerism in recipients 15 years after living related kidney transplantation. AB - To study the relevance of microchimerism to the long-term outcome of renal allografting, we analyzed the frequency of microchimerism in kidney transplant recipients who had stable graft function for 15 years or longer. Among the 104 recipients who underwent kidney transplantation between 1971 and 1980, 27 renal allografts (26%) are still functioning. Among these 27 patients, 13 recipients whose donor was still alive and cooperative were investigated for the presence of microchimerism in the peripheral blood and for their immunological status. Microchimerism was tested using the polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) method. To test the sensitivity of PCP-SSCP, the peripheral blood obtained within 5 weeks after transplantation (four kidney transplants, three liver transplants) was also examined. Microchimerism was detectable in five patients within 5 weeks of transplantation (kidney transplantation, 3/4; liver transplantation 2/3. However, in the patients studied 15 years after transplantation, microchimerism was detected in only one recipient (1/13). In this chimeric patient, mixed lymphocyte response revealed high responsiveness against donor antigen. In contrast, some patients who did not have chimerism showed donor-specific hyporesponsiveness in mixed lymphocyte response assay and did not develop antidonor antibody, according to flow cytometric analysis. Microchimerism is an infrequent state in the long-term survivors of kidney allografting, and this state is irrelevant to donor-specific unresponsiveness. PMID- 8693526 TI - Effect of grapefruit juice on cyclosporine pharmacokinetics in renal transplant patients. AB - This study investigated the effect of grapefruit juice on cyclosporine A (CsA) bioavailability in 10 renal transplant patients. Under CsA steady state conditions, patients were randomly administered their usual dose of CsA with either 8 ounces of grapefruit juice or 8 ounces of water. Using a crossover design, a 12-hr pharmacokinetic study was then conducted. Grapefruit juice increased the area under the concentration versus time curve (4218+/-1497 ng x hr/ml [grapefruit juice] vs. 3415+/-1288 ng x hr/ml [water], P=0.029) and 12-hr trough (244+/-214 ng x ml [grapefruit juice] vs. 132+/-56 ng x ml [water], P=0.09), but it did not change peak concentration (734+/-290 ng x ml [grapefruit juice] vs. 708+/-305 ng x ml [water], P=0.76). In addition, grapefruit juice delayed the time to peak concentration compared with water (5.4+/-3.0 hr [grapefruit juice] vs. 2.8+/-0.8 hr [water], P=0.025). These data suggest that concurrent administration of grapefruit juice with CsA will delay the absorption of CsA and increase the drug exposure of CsA without changing peak concentration. PMID- 8693528 TI - A prospective study on the reliability and cost effectiveness of preoperative ultrasound screening of the "marginal" liver donor. AB - With the growing shortage of available liver donors, many donors with risk factors that would have traditionally precluded liver procurement are now being considered. In this prospective study, we evaluated 50 "marginal" liver donors with pre-procurement abdominal ultrasounds and correlated results with findings at procurement and with subsequent allograft function. The results show that the ultrasounds have a specificity of 96% and a sensitivity of 68% in predicting abnormalities in donor livers that precluded transplantation. In addition, using ultrasound to screen marginal donors would result in significant savings in manpower and hospital resource utilization without "missing" any normal liver organs. Our results also show that, when properly selected, livers from donors with one or more high-risk factors function well with acceptable primary nonfunction rates. PMID- 8693529 TI - Conditioning of liver grafts by donor bolus pretreatment with epoprostenol. AB - Despite improved preservation methods, graft dysfunction after liver transplantation continues to contribute considerably to postoperative morbidity and mortality. In clinical and experimental studies prostaglandin (PG)I2 analogs proved effective in the treatment of liver damage of different origin. Using in vivo fluorescence microscopy in a rat liver transplantation model, we studied the effect of donor bolus pretreatment with the PGI2 analog epoprostenol on hepatic graft revascularization. After epoprostenol bolus pretreatment (group 1: liver transplantation/PGI2), perfusion of liver sinusoids after reperfusion was significantly improved as compared with untreated donor livers (group 2: liver transplantation (95.2+/-0.6% vs. 75.3+/-3.8%, mean +/- SEM; P=0.001) and epoprostenol was found almost in the range of that in normal nontransplanted livers (99.4+/-0.2%). In addition, leukocyte adherence in liver lobules (21.0+/ 3.5 vs. 115+/-11.5 n/lobule; P=0.001) and postsinusoidal venules (23.0+/-3.8 vs. 113+/-11.3 n/mm2 endothelial surface; P=0.002) was significantly reduced in the pretreated grafts. Bile production in the recipient was significantly increased by epoprostenol pretreatment of the donor (1.88+/-0.4 vs. 0.63+/-0.13 g/100 g liver*1 hr; P=0.015), indicating restored liver function. These results suggest that the prostacyclin analog epoprostenol is effective in preconditioning the graft prior to transplantation, i.e., improving preservation and increasing graft resistance to ischemia/reperfusion injury. Thus, favorable effects on early graft function after clinical liver transplantation may be achieved by introducing epoprostenol pretreatment into the harvesting procedure. PMID- 8693530 TI - Continuous venovenous hemofiltration with dialysis in combination with total hepatectomy and portocaval shunting. Bridge to liver transplantation. AB - Children who experience acute liver failure following liver transplantation will have multiple organ failure and a high rate of mortality unless emergency retransplantation can be performed. Transplant hepatectomy with portocaval shunting has been described as a bridge to transplantation in the most severe cases, as well as in patients with fulminant hepatic failure at high risk for mortality who have not undergone liver transplantation. Patients with multiple organ failure who have undergone hepatectomy require renal replacement therapy. Continuous hemofiltration may be used in patients with fulminant hepatic failure to facilitate fluid removal and circulatory and metabolic balance. We used continuous venovenous hemofiltration with dialysis following hepatectomy with portocaval shunting in a patient who remained anhepatic for 66 hr in order to achieve circulatory and metabolic homeostasis as well as stable neurologic function prior to successful retransplantation. PMID- 8693531 TI - Orthotopic liver transplantation from a donor with abdominal situs inversus. AB - The good results reported for liver transplantation have encouraged a much wider application of the procedure, broadening the list of indications and increasing the number of candidates. The shortage of organs for transplantation is a main problem that limits hepatic replacement in the potential recipients. Consequently, the number of contraindications for donor selection has been reduced over the last years. Some factors that were previously thought to preclude successful transplantation have now been relegated to relative contraindications, while others are no longer included. This has frequently led to the use of livers under suboptimal conditions or with anatomical anomalies. This is the case of donors with abdominal situs inversus. In this article, we report an orthotopic liver transplantation using a donor with abdominal situs inversus. Immunosuppressive protocol following surgery was composed of a classic three-drug therapy (cyclosporine, azathioprine, and prednisolone). The modified piggyback technique was performed over the right suprahepatic vein with orthotopic position of the graft. The graft showed good long-term function in the recipient, with a normal hepatic biopsy 5 months after the transplantation. There was no patient readmission or other medical problem after a 2 1/2-year follow-up. PMID- 8693532 TI - Porcine islets for xenotransplantation. AB - Long-term function of isolated porcine islets was investigated in diabetic nude mice. Seven of eight mice that received transplants of porcine islets remained normoglycemic for 1 year with progressive weight gain. Circulating porcine C peptide was detected throughout the study period. Intravenous glucose tolerance tests showed a rapid glucose clearance rate. Together with our recent finding that porcine islets contained within an immunoexclusion device achieved glycemic control in a totally pancreatectomized dog, these results clearly demonstrate that isolated porcine islets are capable of functioning for prolonged periods in xenogeneic hosts and are suitable for long-term use in an immunoexclusion device in a discordant host. PMID- 8693534 TI - The effect of lung preservation on alveolar surfactant. PMID- 8693533 TI - Soluble interleukin-6 receptors in hematology patients undergoing bone marrow transplantation. AB - Soluble interleukin-6 receptor (sIL-6R) has previously been shown to potentiate the activity of interleukin (IL)-6, which may display antitumor activity. We evaluated sIL-6R and IL-6 levels in the sera of 24 patients following transplantation (allogeneic, n=17; autologous, n=7). Five patients developed acute graft-versus-host disease (AGVHD), three had early graft rejection, and three had an early relapse following bone marrow transplantation (BMT). Soluble IL-6R levels were evaluated at day - 10, day 0, day of engraftment, and during BMT-related complications, using IL-6R-specific monoclonal antibodies (mAb) and double-sandwich ELISA. In normal controls, sIL-6R and IL-6 levels were 20+/-3 ng/ml and 0.01+/-0.005 ng/ml, respectively. Soluble IL-6R levels increased in direct correlation with engraftment in the uneventful allogeneic transplants (17.7+/-2.1 ng/ml at day 0 to 49.7+/-2.6 ng/ml at day of engraftment, n=6, P<0.05) as well as in the autologous transplants (26.8+/-2.82 at day 0 to 66.4+/ 12.9 at day of engraftment, n=5, P=0.01). In contrast, IL-6 levels declined with time during the conditioning period and showed only a modest elevation following BMT. Increased levels of sIL-6R and IL-6 were found in the patients who developed AGVHD (23.8+/-4.2 and 0+/-0 ng/ml at day 0 to 79+/-6.9 and 0.26+/-0.04 ng/ml, respectively, at time of AGVHD, n=5, P=0.01). No correlation was found between the severity of AGVHD and sIL-6R levels. In the three patients with early relapse, sIL-6R levels increased from 30+/-0 ng/ml at day 0 to 90 ng/ml (P=0.05) and IL-6 levels increased from 0 to 0.16+/-0 ng/ml, respectively. The mean elevation of sIL-6R in the patients with early relapse and AGVHD was significantly higher than the mean elevation in the patients with the relatively smooth engraftment (P<0.05). Contrary to these findings, in the three patients with graft rejection, sIL-6R levels decreased while IL-6 was found to be elevated. Basic disease, conditioning regimen, type of transplant, GVHD propylaxis, and T cell depletion had no effect on sIL-6R or IL-6 levels. In summary, sIL-6R levels positively correlated with engraftment. Both sIL-6R and IL 6 levels were found to be significantly elevated in patients who developed AGVHD or early relapse following BMT. Therefore, the sIL-6R level may be used as a tool for assessing engraftment and transplant-related complications following BMT. PMID- 8693535 TI - Use of percutaneously placed catheters for venovenous bypass in orthotopic liver transplantation. PMID- 8693536 TI - Reversal of the OKT3-related shivering and chest tightness by intravenous meperidine. PMID- 8693537 TI - Ischemic preconditioning enhances donor heart preservation. AB - Ischemic preconditioning has not been assessed in an experimental model for myocardial preservation during heart transplantation. Using isolated working rat hearts, ischemic preconditioning was investigated as an adjunct to isolated hypothermic (group 1), crystalloid (group 2: University of Wisconsin solution; group 3: St. Thomas' Hospital cardioplegic solution II; group 4: Bretschneiders' cardioplegic solution), and noncrystalloid (group 5: cold blood cardioplegia) preservation during a 10-hr period of global ischemia at 4 degrees C. After acquisition of functional baseline data, ischemic preconditioning was induced with one cycle of 5 min of normothermic ischemia and 5 min of reperfusion before induction of global hypothermic ischemia (n= 10/group). Nonpreconditioned hearts (n= 10/group) were assessed for control. Ischemic preconditioning improved postischemic: functional recovery. Thus, aortic flow after 60 min of reperfusion recovered to 0%, 8%, 0%, 1% and 0% in control groups 1 to 5 without ischemic preconditioning and 21%, 25%, 10%, 8%, and 3% in groups 1 to 5 with ischemic preconditioning. The same pattern of recovery was observed in regard to postischemic maximum developed left ventricular pressure, which recovered to 21%, 56%, 30%, 36%, and 19% in groups 1 to 5 without preconditioning and 46%, 75%, 49%, 40%, and 47% in the corresponding groups with ischemic preconditioning. High energy phosphate contents were not significantly different between preconditioned hearts and corresponding nonpreconditioned control hearts. Creatine kinase leakage during early reperfusion was found to be reduced with ischemic preconditioning. Thus, we have demonstrated that ischemic preconditioning can improve contractile function after global hypothermic ischemia in the isolated rat heart and we have shown that this protection is additive to that of hypothermia-induced protection during global ischemia at 4 degrees C. This endogenous mechanism of cardioprotection was effective regardless of whether preservation was accomplished using cardioplegic solution or topical hypothermia alone. This may have clinical implications in myocardial preservation for heart transplantation. PMID- 8693538 TI - Alloantibody and intragraft cellular response to MHC class I-disparate kidney allografts in recipients tolerized by donor-specific transfusion and cyclosporine. AB - Congenic PVG.RT1u rats rapidly reject Aa class I-disparate kidney allografts from recombinant PVG R8 donors and we recently demonstrated that anti-class I MHC alloantibody plays a critical role in effecting acute rejection in this experimental model. In this article, we show that PVG.RT1u recipients can be rendered permanently and specifically tolerant to R8 kidney allografts by administration of four weekly donor-specific transfusions (DST) combined with a 7 day course of cyclosporine given with the first DST. Tolerance induction correlated with abrogation of a cytotoxic alloantibody response by thymus independent, i.e., peripheral mechanisms; IgM and all IgG subclasses of anti class I alloantibody were abolished. In contrast, nonrejecting kidney allografts in tolerant rats and rejecting grafts from unmodified recipients were similarly infiltrated by mononuclear cells, and intragraft transcripts for interleukin (IL) 2, interferon-gamma, and IL-13 were readily detected by reverse transcriptase polymerase chain reaction with no apparent quantitative difference between the two groups. Messenger RNA for IL-4 and IL-10 was present in rejecting grafts but barely detectable in grafts from tolerant animals. These results suggest that tolerance induction by DST and cyclosporine is, in this experimental model, associated with a selective impairment in humoral alloimmunity. PMID- 8693539 TI - Porcine islet cells of Langerhans are destroyed by human complement and not by antibody-dependent cell-mediated mechanisms. AB - In the near future, xenotransplantation of porcine islets of Langerhans might be an alternative in the treatment of patients with diabetes mellitus. However, xenotransplantation of islets of Langerhans in large animals has been shown to result in an exceedingly short graft survival, which suggests that a humoral immune response might play a major role in islet demise. This study was performed to assess binding human preformed antibodies to isolated porcine islet cells (PIC) and to determine the lysis of PIC using human sera in complement-mediated cytotoxicity (CMC) and antibody-dependent cell-mediated cytotoxicity (ADCC) assays. Ten Dutch Landrace pigs were used for the isolation of PIC. Sera from 30 healthy blood donors (1/10 diluted) were used in a 51Cr release assay to assess CMC. Heat-inactivated normal human sera and fresh sera from patients with agammaglobulinemia were used as controls. Binding of human IgM IgG, and IgA antibodies to PIC was tested in an ELISA using isotype-specific secondary monoclonal antibodies ADCC was tested in a 51Cr release assay using normal human sera and sera from newly diagnosed type I diabetics with peripheral blood mononuclear cells as effector cells and PIC as targets. It was found that PIC were recognized by human IgM and IgG preformed antibodies and that fresh human sera had strong CMC activity inducing a percentage-specific PIC lysis of 61 +/- 10% (mean +/- SD) within 60 min. Agammaglobulinemic sera killed 42 +/- 12% of PIC. No significant cytotoxic activity was found in ADCC assays using normal sera or sera from diabetic patients. These results show that all tested human sera lyse PIC via CMC, even in the absence of human antibodies, as concluded from the use of agammaglobulinemic sera. In pig-to-human transplantation, islets may be hyperacutely rejected by antibody-dependent and antibody-independent activation of complement and not by antibody-dependent cell-mediated mechanisms. PMID- 8693540 TI - Cytomegalovirus antibody status and renal transplantation: 1987-1994. AB - We examined graft and patient survival rates of 47,146 patients in the United Network for Organ Sharing registry following transplants between donors and recipients who were cytomegalovirus (CMV) antibody negative and positive. CMV positivity increased with age to about 80% in patients over 60. Seropositivity was seen in 80% of Asians, 71% of African Americans, and 56% of Caucasians. In all age groups, females had a slightly higher incidence of positivity than males. Transplants involving CMV-positive donors resulted in lower graft survival rates than those with CMV-negative donors. This occurred regardless of whether the recipient was CMV negative or positive. The greatest effect was on patient survival rate, which, in turn, adversely affected graft survival rate. The CMV positive-donor effect was primarily noted in (1) Caucasian recipients, (2) patients with HLA-A,B,DR mismatches, and (3) patients older than 15 years of age. In contrast, CMV-positive donors were not a risk factor for African American and Hispanic patients, CMV-positive Asian patients, patients younger than 16 years of age, and patients with no HLA-A,B,DR antigen mismatches. In conclusion, a kidney from a CMV-positive donor is a risk factor for certain patients and currently yields about a 4% overall lower graft survival rate at 3 years than a kidney from a CMV-negative donor. PMID- 8693541 TI - Half dose of OKT3 is efficient in treatment of steroid-resistant renal allograft rejection. AB - Rejection episodes in renal allograft recipients are usually efficiently treated with high doses of intravenous methylprednisolone. Rejection therapy with OKT3 is often reserved for steroid-resistant episodes. However, the optimal dose of OKT3 in the treatment of steroid-resistant rejection is not known. Therefore, we randomized renal transplant recipients with steroid-resistant rejection to treatment with a standard daily intravenous dose of either 5 mg of OKT3 (n=15) or 2.5 mg of OKT3 (n=15) for 10 days. Circulating T cells (measured as CD2+ cells) were adequately and equally depleted in the two groups. Three grafts were lost due to rejection within the first 3 months following OKT3 administration, one in the 2.5 mg OKT3 group and two in the 5 mg OKT3 group. Two nonimmunologic graft losses occurred in the 2.5 mg OKT3 group. Median serum creatinine values were not different between the two groups, neither at the start (median values: 200 micormol/L in the 5 mg OKT3 group vs. 188 micromol/L in the 2.5 mg group) nor immediately after OKT3 rescue therapy (202 micromol/L vs. 185 micromol/L, respectively). Eight cytomegalovirus infections occurred in each group. Two re rejection episodes occurred in the 5 mg OKT3 group and one occurred in the 2.5 mg OKT3 group. All responded to treatment. Function of the remaining grafts estimated by serum creatinine after a mean long-term follow-up of 18 months (range, 6-36 months) revealed no differences (185 micromol/L in the 5 mg OKT3 group vs. 170 micromol/L in the 2.5 mg OKT3 group). We conclude that OKT3 treatment of steroid-resistant rejections in renal transplant recipients is equally effective in daily doses of 2.5 mg and 5 mg with respect to reversal rate and long-term outcome. PMID- 8693542 TI - Outcome of grafts with long-lasting delayed function after renal transplantation. AB - To assess the impact of long-lasting acute renal failure after renal transplantation on late graft prognosis, we compared the risk factors and outcome in renal allografts with delayed function for >3 weeks after renal transplantation (long-lasting delayed graft function [LLDGF]) (group A, n=64), and in four control groups: group B, initially functioning grafts (n=322); group C, grafts with delayed function for <2 weeks after transplantation (n=110); group D, grafts with delayed function for 14 to 20 days after transplantation (n=57); and group E, never-functioning grafts (n=88). Donor asystolia or instability, stroke as a cause of donor's death, and prolonged cold ischemia and vascular surgical times were some predictors of LLDGF. Overlap was important, but 43% of patients of group A, 15% of group B, 25% of group C, 31% of group D, and 40% of group E (P<0.01) presented two or more risk factors for severe acute tubular necrosis after transplantation. Acute rejection and early complications were very frequent in group A. Also, patient survival was significantly decreased in group A, due to a higher incidence of infectious mortality. Graft survival was moderately (NS) decreased in group A. Serum creatinine was initially higher in patients of group A, but differences disappeared after the second year. However, late proteinuria was more frequent in group A, and there was also a trend for a higher prevalence of hypertension in this group. LLDGF cannot be reliably predicted at the time of renal transplantation. The main consequence of LLDGF is an excess mortality, while the impact on late graft function is less significant. Short-lasting delayed graft function does not seem to have a negative impact on the outcome of renal transplantation. PMID- 8693543 TI - Renal function and glomerular permselectivity late after living related donor transplantation. AB - Living related kidney transplantation is the preferable procedure for renal replacement therapy. The aim of the current study was to determine systemic hemodynamic and intrarenal adaptions in donors and recipients late after living related kidney transplantation. Furthermore, glomerular permselectivity was assessed in these subjects. We studied mean blood pressure (MAP), glomerular filtration rate (GFR), renal plasma flow (RPF), microalbuminuria (MIA), 24-hr urinary protein excretion, and glomerular permselectivity (fractional clearance of neutral dextrans [thetaD] as a marker for size selectivity and fractional clearance of dextran sulfate [thetaDS] to assess charge selectivity) in 22 donors and 22 recipients. MAP was normal in the donor group (102 +/- 4 mmHg), but five patients had blood pressure above 140/90 mmHg. This 18%, however, is lower than the prevalence of hypertension in the age-adjusted general population in Austria. The recipients also had normal MAP at the time of study (99 +/- 3); however, 13 needed antihypertensive therapy. GFR and RPF were lower in recipients than in donors (53 +/- 8 vs. 72 +/- 11 and 314 +/- 74 vs. 412 +/- 86 ml/min respectively). In the donor group, GFR was 137 +/- 45% of the expected age adjusted mean value/kidney due to hyperfiltration. Proteinuria and MIA were higher in the recipients than in the donors (0.39 +/- 0.22 vs. 0.07 +/- 0.04 g/day, 137 +/- 136 vs. 26 +/- 15 mg/day). Nonetheless, five donors had an elevated MIA. A higher need for antihypertensive medication could be observed in recipients with previous rejection episodes, as well as a significantly higher urinary protein excretion and MIA (0.7 +/- 0.42 vs. 0.24 +/- 0.14 g/day, 336 +/- 380 vs. 48 +/- 32 mg/day). ThetaDS was significantly higher in the recipients, whereas thetaDS of the donors was identical to the value obtained from 18 healthy controls (0.7 +/- 0.08 vs. 0.6 +/- 0.06). OD was similar in all groups studied. In conclusion, 76 months after uninephrectomy for renal donation, mild changes in glomerular permselectivity occurred in a subset of donors without affecting renal excretory function. In recipients, proteinuria was due to a defect in glomerular charge selectivity. PMID- 8693544 TI - Selective IgM depletion prolongs organ survival in an ex vivo model of pig-to human xenotransplantation. AB - In the pig-to-primate model, xenograft hyperacute rejection (HAR) is mediated by antibody and complement. Previous studies have implicated xenoreactive IgM natural antibody (nAb) as the predominant immunoglobulin involved in HAR. To further evaluate the role of IgM, we selectively reduced IgM levels in human blood, without changing IgG and IgA levels, and then used this blood to perfuse porcine hearts ex vivo. Specific IgM depletion was accomplished with an immunoabsorption column containing sheep anti-human IgM (mu-chain specific) conjugated to Sepharose beads. Human blood was separated into plasma and cellular components. For control experiments, those components were unmodified and recombined in the perfusion system. For experiments with IgM reduced blood, the plasma was passed through the IgM column. Immunoabsorption resulted in approximately 90% reduction in xenoreactive IgM levels, as measured by ELISA. Porcine hearts perfused with unmodified human blood survived 25 +/- 5.6 min (n=5). Porcine hearts perfused with human blood containing reduced levels of IgM survived 229 +/- 45.2 min (n=4; P<0.01). Organ survival was negatively associated with xenoreactive IgM nAb levels measured immediately before perfusion (r=-0.83; P=0.01), and not with IgG nAb levels (r=-0.21; P=0.62). The ability of plasma from IgM-depleted blood to elicit complement activation, measured by iC3b binding to porcine aortic endothelial cells in vitro, was also strongly associated with IgM xenoreactive nAb levels (r=0.92; P<0.0001). Control hearts perfused with unmodified human blood showed typical widespread histologic features of HAR, while porcine hearts perfused with IgM-reduced blood demonstrated milder and less uniform changes. Immunopathological analysis of heart tissues obtained at the completion of each study showed similar deposition of IgG between groups but markedly less IgM, C3, C4, and C9 in the IgM reduction group. These results suggest that selective IgM reduction delays HAR with prolongation of survival and that xenoreactive IgM may be the predominant immunoglobulin involved in HAR in the pig-to-human combination. PMID- 8693545 TI - A randomized trial comparing safety and efficacy of OKT3 and a monoclonal anti interleukin-2 receptor antibody (BT563) in the prevention of acute rejection after heart transplantation. AB - In a prospective randomized trial, BT563, a murine IgG, anti-interleukin-2 receptor antibody, was compared with OKT3 for use as an early rejection prophylaxis after heart transplantation. Patients received either BT563 (n=31) or OKT3 (n=29) during the first 7 days after transplantation; cyclosporine was started on day 3. Median follow-up was 34 months. A cytokine release syndrome occurred in the majority of patients of the OKT3-treated group but in none of the BT563 recipients. The mean duration of electrical stimulation of the heart in the BT563 group was longer than in the OKT3 group (5.1 vs. 2.1 days). In both groups, one patient required insertion of a permanent pacemaker. Freedom from acute rejection at 3 months was not significantly different between the two groups (BT563: 5/29, 17%; OKT3: 6/29, 21%). In the BT563 group, however, rejection tended to occur earlier after transplantation. There was no difference in the overall incidence of rejection. The incidence of infectious complications was evenly distributed in both groups. Malignancies occurred in two patients, both in the OKT3 group. In conclusion, the use of this anti-interleukin-2 receptor monoclonal antibody in heart transplant recipients is safe and devoid of the side effects that accompany the use of OKT3. OKT3 and BT563 result in a similar freedom from rejection at 3 and 12 months after heart transplantation. PMID- 8693546 TI - Liver dysfunction in allogeneic bone marrow transplantation recipients. AB - Liver dysfunction is common in allogeneic bone marrow graft recipients, but no systematic studies of pre- and posttransplantation liver biopsies have been performed to identify and compare hepatic lesions. This study involved 25 consecutive patients who had undergone serial viral screening tests, liver tests, and pre- and posttransplantation liver biopsy. The aims were to ascertain the origin of liver disorders prior to bone marrow transplantation, to determine the mechanism and severity of liver dysfunction occurring early after transplantation, and to identify a possible relationship between pre-existing liver lesions and the frequency and nature of early liver dysfunction after transplantation. Pretransplantation biochemical liver tests were abnormal in 72% of patients, despite the absence of clinical liver disease. Eleven patients had chronic viral hepatitis B or C. Mild or moderate histological lesions were present in all the patients, with bile duct abnormalities in 48%, central vein abnormalities in 24%, sinusoidal fibrosis in 52%, portal fibrosis in 88%, portal necrosis in 52%, and parenchymal siderosis in 76%. After transplantation, fatal veno-occlusive disease occurred in two patients and biochemical abnormalities occurred in 24. Coded review of needle biopsy specimens failed to provide a single diagnosis. Histological lesions differed between pre- and posttransplantation biopsy specimens only by increased iron overload (96%, P<0.01). We conclude that pretransplant liver lesions contribute to hepatic dysfunction early after bone marrow transplantation, being very similar in nature and degree to lesions observed posttransplantation. PMID- 8693547 TI - Safe use of hepatic allografts from donors older than 70 years. AB - Between March 1991 and August 1995, 36 livers from donors >/=70 years old were transplanted. In donors, we recorded the following risk factors: alanine aminotransferase > 120 and rising, dopamine dose > 15 microg/kg/min, hypotension (systolic blood pressure <80) >1 hr, stay in the intensive care unit >5 days and body mass index >/=27. In 35 recipients, we recorded pretransplant United Network for Organ Sharing (UNOS) status, cold/warm ischemia time, intraoperative blood loss, and occurrence of poor early graft function or primary nonfunction. Mean recipient age was 55 years (range, 25-75 years). Four recipients were UNOS status 1, 19 were UNOS 2, and 12 were UNOS 3. Two livers were used as second grafts for primary graft nonfunction. Mean donor age was 73 years (range, 70-84 years). Intracranial bleeding was the cause of death in the majority of donors. The 36 donors had 40 risk factors; 10 donors had >1 risk factor. Mean cold and warm ischemia times were 9:08 +/- 2:57 hr and 51 +/- 9 min. Mean total operative time was 7.5 hr. Posttransplant mean peak alanine aminotransferase and aspartate aminotransferase levels were 937.3 +/- 703.1 IU/L and 923.3 +/- 708.5 IU/L, respectively. Mean prothrombin time on postoperative day 2 was 14.9 +/- 1.6 sec. Average total bilirubin on postoperative day 5 was 4.9 mg/dl. Median length of stay in the intensive care unit was 4 days. One recipient had poor early graft function; two recipients had primary nonfunction. Mean follow-up was 503 days (range, 110-1714 days). Three-month actual graft and patient survival rates were 85% and 91%, respectively. One-year actuarial graft and patient survival rates were also 85% and 91%, respectively. We conclude that older livers can be used safely. Advanced donor age should not be a contraindication to liver procurement. PMID- 8693548 TI - Comparison of conventional oral cyclosporine and cyclosporine microemulsion formulations in children with a liver transplant. AB - We studied 22 children (mean age: 8.42 years, range: 1.9-15.6 years) with a liver transplant to compare the pharmacokinetics of oral cyclosporine (CsA) microemulsion to the conventional formulation. The CsA treatment (mean dose: 5.9 mg/kg/day, range: 3.0-11.7 mg/kg/day) was converted 1:1 on a milligram-to milligram basis to the microemulsion formulation. Five days after the conversion, the mean peak blood CsA concentration was higher (microemulsion: 963 ng/ml, range: 518-1864 ng/ml; conventional: 431 ng/ml, range: 98-888 ng/ml; P<0.0001) and it was reached faster (median time of peak concentration: 1.6 hr vs. 2.9 hr, range: 1.0-3.0 hr vs. 1.9-4.0 hr; P=0.0009). The absorption lasted on the average 19% longer after the conventional formulation. The area under the concentration versus time curve (AUC) was larger after the microemulsion formulation in all but one patient (P=0.001) by a mean factor of 1.80 (range: 0.72-3.04). The trough CsA level after the microemulsion formulation was more closely related to peak concentration (r2=0.86 vs. 0.45) and AUC (r2=0.84 vs. 0.47); thus, therapeutic drug monitoring may be more useful. After 6 months on the new formulation, the results for the whole group were similar, but in five children the AUC was comparable to the AUC obtained with the conventional formulation. No rejections occurred, and the liver and kidney functions remained unchanged. A 1:1 conversion can be safely performed in children, based on a 6-month follow-up. However, the total drug exposure changes in significant ways, which, on a long-term basis, may improve the immunosuppression in an underimmunosuppressed patient, but may increase the risk for dose-related adverse effects in others. PMID- 8693549 TI - Original extrahilar approach for hepatic portal revascularization and relief of extrahepatic portal hypertension related to later portal vein thrombosis after pediatric liver transplantation. Long term results. PMID- 8693550 TI - Dominance of tissue-restricted cytotoxic T lymphocytes in the response to allogeneic renal epithelial cell lines. AB - Our current knowledge of cytotoxic T lymphocytes (CTL) is largely derived from studies of effector populations generated in allogeneic mixed leukocyte cultures (MLC) and assayed for lytic activity to lymphoid cell (LC) targets. We herein report that the CTL response to allogeneic renal epithelial cell lines (REC) is dominated by effectors that efficiently lyse REC targets but show little cross reactivity with LC targets. In contrast, CTL generated against allogeneic spleen cell stimulators (ie., in MLC) lysed REC and LC targets at comparable levels. Lytic activity in both types of cultures was mediated by CD8+TCRalpha/beta+ cells directed to classical H2 class I alloantigens. Anti-REC effectors cross-reacted with fibroblast and macrophage targets but not with targets commonly used to detect alloreactive CTL, such as lipopolysaccharide- or Con A-stimulated lymphoblasts or lymphoid tumor lines, whereas MLC-elicited effectors efficiently lysed all targets. CTL clones propagated from anti-REC cultures exhibited the same allospecificity and tissue specificity as bulk anti-REC effectors. Individual CTL clones were highly heterogeneous in their capacity to recognize the same class I alloantigen expressed on cells derived from different tissues. These data demonstrate that the cellular environment in which CD8 precursors encounter class I alloantigens can have a profound effect on the cell-type specificity of CTL populations. An important implication of these data is that conventional assays of CTL lytic activity may fail to reveal a significant component of the host response to allogeneic tissues. PMID- 8693551 TI - Secretion of CTLA4Ig by an SV40 T antigen-transformed islet cell line inhibits graft rejection against the neoantigen. AB - In a model of transplantation rejection, we tested whether a graft manipulated to secrete an immunomodulator could protect itself from immune destruction, thus waiving the need for administration of exogenous immunosuppressants to the recipient. An insulinoma cell line, NIT, having the nonobese diabetic (NOD) genotype but also expressing the SV40 large T antigen, was transfected with CTLA4Ig in an attempt to block the CD28/B7 costimulatory pathway between antigen presenting calls and T lymphocytes near the site of the graft. The SV40 T antigen is potent at inducing graft rejection. NIT.CTLA4Ig and control transfectants were transplanted subcutaneously into young NOD mice to determine whether CTLA4Ig secretion would abet the survival of the insulinoma graft. CTLA4Ig protein was secreted abundantly in vitro (3-5 microg/ml) and this phenotype was maintained in vivo. Tumor growth was monitored visibly, by palpation, by measuring blood glucose levels, and by death of the host from hypoglycemia caused by unregulated insulin production of the growing insulinoma. Cell growth was similar for NIT.CTLA4Ig7 and control transfectants in immunodeficient mice (nude, irradiated, or SCID mice), indicating that there was no intrinsic growth advantage of the NIT.CTLA4Ig cells. In immunocompetent NOD mice however, the survival/growth of the NIT.CTLA4Ig graft was significantly better than that of the controls. Histopathology was consistent with this finding. Donor-specific second-set grafts were acutely rejected, indicating that tolerance was not induced. CTLs were generated even when the graft secreted CTLA4Ig; there was no clear difference in in vitro immune responses generated by NIT.CTLA4Ig and control cells. We conclude that blockade of the B7 costimulation pathway by graft manipulation can contribute to transplantation success. PMID- 8693552 TI - Delayed xenograft rejection in the concordant hamster heart into Lewis rat model. AB - The inability to provide an adequate supply of human organs for clinical transplantation has created a strong interest in the use of nonhuman, especially nonprimate, organs. The first biological obstacle confronting such discordant transplantations is a series of violent reactions that result in hyperacute rejection of the xenograft. Significant advances in controlling hyperacute rejection have been achieved recently through the generation of transgenic pig donors bearing human complement regulatory proteins. However, when hyperacute rejection is averted, the xenografts are rejected in 2-70 days in spite of high dose immunosuppression, by a process collectively termed delayed xenograft rejection. Delayed xenograft rejection is characterized by a refractoriness to conventional immunosuppression, extensive xenoreactive antibody deposition, and cellular infiltration that is dominated by macrophages. We have examined the features of extended host and graft response in the concordant hamster-to-rat xenotransplant model, where such features have historically been obscured by early graft destruction. Hamster hearts transplanted into rats do not encounter hyperacute rejection but are rejected within 3-4 days when xenoreactive antibody titers rise exponentially to levels that elicit a classical antibody- and complement-mediated acute xenograft rejection. We have successfully blocked acute xenograft rejection by a combination of immunosuppressive agents, leflunomide, and cyclosporine. Stopping the immunosuppression resulted in graft rejection that is histologically characterized by extensive xenoreactive antibody deposition and cellular infiltration that is predominantly composed of macrophages. We have noted the similarities between the histopathology of rejection of long-surviving concordant xenografts and that described for discordant xenografts and refer to the process of rejection of concordant grafts that have escaped acute xenograft rejection, delayed xenograft rejection. PMID- 8693553 TI - The intragraft CD8+ T cell response in renal allograft rejection in the mouse. AB - To identify the role of donor class I alloantigens in regulating the CD8+ T cell response to a kidney allograft, we analyzed and compared the CD8+ infiltrate in kidney transplants from MHC class I-deficient (class I-) mouse donors and class I+ controls. One week after transplantation, there was a prominent CD8+ infiltrate in control allografts, whereas CD8+ T cells were virtually absent in grafts from class I- donors. In class I+ allografts, infiltrating CD8+ cells utilized a wide range of T cell receptor (TCR) Vbeta families and their Vbeta usage was similar to that of the systemic CD8+ population. However, there was a modest but significant overrepresentation of cells bearing Vbeta8 in the graft compared with the spleen due to an expansion of CD8+ Vbeta8.3+ cells. This could be detected as early as 1 week and became more pronounced by 3 weeks after transplantation. In 3-week allografts, only 52% of CD8+ cells expressed alphabetaTCR. Among T cells isolated from class I+ grafts, the CD8+ Vbeta8+ cells demonstrated allospecific responses that were numerically larger than responses of the CD8+ Vbeta8- population. In contrast to the early (1 week) time point, significant numbers of CD8+ cells could be isolated from class I- grafts by 3 weeks after transplantation and their Vbeta repertoire resembled that seen in controls. While increasing numbers of CD8+ Vbeta8+ were present in the class I- grafts at 3 weeks, this increase was not statistically significant. Thus, expression of class I alloantigens on a kidney graft plays an important role in regulating the rate of accumulation of CD8+ T cells in rejecting kidney grafts. However, the TCR Vbeta repertoire of the CD8+ T cell infiltrate is largely determined by factors that are independent of normal class I expression on the graft. PMID- 8693554 TI - Tropical diabetes? PMID- 8693555 TI - The value of naked eye examination of biopsied lymph nodes in the diagnosis of tuberculous lymphadenitis. AB - Tuberculous lymphadenitis is common in Central Africa, where diagnosis by histological examination of a biopsied node is often delayed. In the present study, the naked eye appearance of the cut surface of 306 consecutive biopsied lymph nodes was compared with the histological diagnosis. One hundred and eight eight nodes showed tuberculosis on histology (including two with coexisting second pathology). One hundred and forty-eight (79%) cases of tuberculous lymphadenitis (including both with coexisting second pathology) showed noncaseating tuberculomata or caseation visible on naked eye examination. Such signs were not seen in other nodes. Other signs were seen in another 18 (10%) tuberculous nodes. It is concluded that naked eye examination of nodes provides useful information for the diagnosis of tuberculous lymphadenitis, pending confirmation by histology. PMID- 8693556 TI - Meconium stained liquor: a view from a district hospital. AB - Meconium stained liquor (MSL) is a common problem in obstetrics, but its management at district level causes some specific questions. Recent literature was reviewed to obtain an insight in the current knowledge about the significance, the related pathology and the possible strategies to prevent adverse fetal outcome. The acquired data were used to propose some recommendations to tackle this problem at district level. PMID- 8693557 TI - Chlamydia pneumoniae (TWAR) infection in Tanzanian children. PMID- 8693558 TI - Microcytosis: guidelines for family doctors. AB - In our studies of microcytosis, the complete blood count (CBC) of 82,830 randomly selected patients was analysed. Of these 34.3% showed microcytosis, and 5.5% were not anaemic. Emphasis was given to study the extent, causes and patterns of non iron deficient microcytosis. Haematological data was adequate to differentiate iron deficient (ID) from non-iron deficient (NID) patients with microcytosis in 285 subjects. Of these 21.4% were found to be NID. A majority (73.8%) had showed a form of haemoglobinopathy, the commonest being beta-thalassaemia minor (60.7%). Of non-invasive investigations, mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), red cell size distribution width (RDW), anisocytosis in blood smears, serum iron (SI) and haemoglobin electrophoresis, the parameter which separated ID from NID patients most effectively was haemoglobin electrophoresis. It showed an abnormal pattern in 82% of NID subjects and normal pattern in 96.4% ID subjects. In the 18% of the NID subjects with a normal pattern, raised serum iron levels characterized 11% additional subjects with NID. PMID- 8693559 TI - Trial of polythene tobacco-wrap in prevention of hypothermia in neonates less than 1500 grams. PMID- 8693560 TI - Prevalence of antibodies to hepatitis C virus among normal blood donors and multi transfused sickle-cell anaemia patients in Nigeria. PMID- 8693561 TI - The value of sharing your skills abroad. PMID- 8693562 TI - Intravenous catheter-related Candida rugosa fungaemia. PMID- 8693563 TI - Acute intravascular haemolysis in glucose-6-phosphate dehydrogenase deficient patients following ingestion of herbal broth containing Acalypha indica. PMID- 8693564 TI - Renal hydatid disease. PMID- 8693565 TI - External intestinal strangulation in anal injury. PMID- 8693566 TI - Re-establishment of patency of the inflation channel in obstructed balloon catheter: safe method of removal. PMID- 8693567 TI - An out-patient audit of the insulin administration technique of patients with diabetes mellitus in Blantyre, Malawi. PMID- 8693568 TI - Cytology and fine needle aspiration biopsy: appropriate technology, quick, safe and cheap. PMID- 8693569 TI - Acid-fast bacilli positivity in buffy coat and bone marrow in pulmonary tuberculosis. PMID- 8693571 TI - Meningitis epidemic in Guinea, West Africa. PMID- 8693572 TI - Completion rates of hospital-based tuberculosis treatment. PMID- 8693573 TI - Infant feeding--knowledge and attitudes in a part of South India. PMID- 8693570 TI - Drug resistant Shigella. PMID- 8693574 TI - Non-compliance with tuberculosis treatment: the Kumasi experience. PMID- 8693575 TI - A cautionery tale for TBA trainers. PMID- 8693576 TI - Foreign bodies and balloon catheters. PMID- 8693578 TI - Managing tropical diabetes mellitus in Pemba, Mozambique: the diet palaver, which way out? PMID- 8693579 TI - The nomenclature of chronic viral hepatitis: 1968-1995. PMID- 8693580 TI - Does Rota virus infection cause persistent diarrhoea in childhood? AB - Rota virus is the commonest agent for infectious diarrhoea in childhood. Whether an acute diarrhoea episode due to Rota virus constitutes a risk factor for persistence of diarrhoeal episode has not been well evaluated. This study aimed at evaluating the role of antecedent Rota virus infection in the causation of persistent diarrhoea. One hundred twenty children with acute watery diarrhoea were investigated for evidence of recent Rota virus infection and were followed up for 2 weeks to determine the proportion developing persistent diarrhoea. Rota virus antigen in stool and IgM class antibodies in serum were detected in 33 (27.5%) of the cases, only 2 (6.06%) of whom developed persistent diarrhoea. On the other hand 11.3% children without evidence for antecedent Rota virus infection developed persistent diarrhoea. The prevalence of Rota virus antigen in stools of children who developed persistent diarrhoea was 16.7%. In another group of 25 children with persistent diarrhoea definite evidence for a Rota virus infection was detected in only 2 (8%) cases. It was therefore concluded that antecedent Rota virus infection does not increase the risk for abnormal prolongation of an episode of acute diarrhoea. PMID- 8693577 TI - The aetiology of anaemia in pregnancy in West Africa. PMID- 8693582 TI - Carcinoid crisis during a partial hepatic resection; lack of essential drugs: a cause for concern in the tropics. AB - We report a patient of carcinoid syndrome with hepatic metastasis (primary lesion in the ileum) who was posted for a right hepatic lobe resection and excision of the primary lesion. The patient developed carcinoid crisis with excessive blood loss due to vasodilation and severe hypotension during surgery. This case highlights the lack of essential drugs in the management of an intraoperative carcinoid crisis in this part of the world. PMID- 8693581 TI - Role of radiation therapy in carcinoma of the gall bladder--a preliminary indian experience. AB - Carcinoma of the gall bladder has a poor prognosis despite surgical resection of the tumour. We prospectively enrolled 21 patients with histologically proven adenocarcinoma of the gall bladder, who were stage III or beyond for post operative radiotherapy. Six month survival was 67% (14 of 21 patients) while one year survival was 33% (7 out of 21 patients) and five year survival was 23% (5 of 21 patients). Those patients who had residual disease or were considered inoperable at surgery had no improvement in survival. The 1 year and 5 year survival in these patients was encouraging with radiotherapy in the present open labelled study of radiotherapy in patients with carcinoma of the gall bladder. PMID- 8693583 TI - Acute pancreatitis in hepatitis A infection. AB - A 13 year old boy who was admitted for acute viral hepatitis due to hepatitis A virus developed acute pancreatitis which resolved completely with conservative treatment. Extensive evaluation did not reveal any other cause of pancreatitis and it was presumed that hepatitis A may result in acute pancreatitis. PMID- 8693584 TI - Clinical and endoscopic features of hereditary hemorrhagic telangiectasia (Osler Weber-Rendu disease) in India. AB - Hereditary hemorrhagic telangiectasis (HHT) is an autosomal dominant disease characterized by recurrent epistaxis and telangiectasia of the skin and mucous membranes. Most reports of HHT are from Europe and N. America. In this report of 7 patients from India we postulate that increased skin pigmentation in Asians and Negroids masks the cutaneous manifestations of the disease but without any discernible effect on mucosal lesions. The median hemoglobin value in these patients was 4 g/dl. Endoscopic lesions in the stomach or duodenum were detected in six patients. Most patients in our report (5/7) presented with a chronic iron deficiency anaemia. The treatment of HHT is mainly supportive although our preliminary data shows that low dose ethinyl estradiol therapy decreases transfusion requirement in these patients. PMID- 8693585 TI - Endoscopic treatment of bile duct stones: is stone extraction necessary after endoscopic sphincterotomy? AB - BACKGROUND: The current treatment for stones in the biliary tree is endoscopic sphincterotomy (ES) followed by stone extraction with the help of balloon catheters or metal baskets. Stone extraction techniques are often associated with complications. Moreover, the balloon catheters break easily which aids to the cost of the procedure. The present study was designed to examine the effectiveness of endoscopic sphincterotomy (ES) alone in allowing spontaneous expulsion of bile duct stones and to determine the circumstances which warrant stone extraction. METHODS: Endoscopic retrograde cholangio-pancreatography (ERCP) was attempted in 68 patients with stones in the common bile duct. The stone size was determined by ultrasound, cholangiography in post cholecystectomy patients with a T-tube or by ERCP. Patients with stone size of 15 mm or less in diameter were treated with ES alone without stone extraction. Patients were discharged from the hospital within 24 hrs and returned for reassessment every week or earlier, if symptomatic, until complete clearance of stones was demonstrated. RESULTS: Endoscopic sphincterotomy was successfully performed in 63 (93%) patients, the procedure was abandoned in the remaining 5 patients for technical reasons. Spontaneous clearance of stones was observed in 55 (87%) patients, usually without any accompanying pain (47.85%). Persistent stones were seen in 8 (13%) patients; extension of the ES resulted in spontaneous stone expulsion in 6 of these patients. Thus, 61 (97%) of the 63 patients with stones of 10 mm or less in size cleared the stones spontaneously and all 8 patients who failed the initial ES, had stones > 10 mm in size. COMMENT: The present study shows that all small stones (< 10 mm) and most of those < 15 mm are expelled spontaneously after an adequate ES. These finding if substantiated by larger studies will reduce considerably the cost of the procedure as well as the morbidity associated with mechanical stone extraction. PMID- 8693586 TI - Partial cholecystectomy in elective and emergency gall bladder surgery in the high risk patients--a viable and safe option in the era of laparoscopic surgery. AB - Partial cholecystectomy was performed in this Institute in fifteen patients in the last 8 years. Three were performed in cirrhotic patients with bleeding diathesis. The other indications were obscure anatomy, intraperitoneal adhesions, Mirizzi syndrome and poor general condition of the patient. None of these had any major morbidity in the immediate postoperative period. Partial cholecystectomy is a safe and viable option in a difficult situation. PMID- 8693587 TI - Cholecystectomy in high risk patients. AB - Two hundred and seventy two patients with one or more associated preoperative high risk factors underwent cholecystectomy in the Department of Surgical Gastroenterology, SGPGIMS, Lucknow, between December 89 and November 95. The identified risk factors were advanced age (> 65 years), cardiac diseases, endocrine disorders, respiratory diseases and others. Fifty patients (18%) had two and 6 patients (2.2%) had three risk factors each. During the same period, 1006 patients with no risk factors had simple cholecystectomy done in the department. The morbidity and mortality of cholecystectomy in the high risk group was 27% and 0.4% respectively, and in the group with no risk factors 14% and 0.2% respectively. The morbidity and mortality in the high risk group was significantly greater than that in the no risk group. It is suggested that with good preoperative evaluation close intraoperative monitoring and intensive postoperative care, these figures could be reduced further. PMID- 8693589 TI - Gene therapy. PMID- 8693588 TI - Prognostic significance of argyrophilic nucleolar organizer regions (AGNOR) in oesophageal cancer. AB - AgNOR (Argyrophilic nucleolar organiser region) has been shown in recent times, to have value in knowing the prognosis of carcinoma oesophagus. We have evaluated the significance of AgNOR in oesophageal cancer with reference to prognosis following treatment. Fifty patients of histologically proven squamous cell carcinoma of the oesophagus were studied. Following oesophagectomy the specimens removed were evaluated for AgNOR number. Of the resected specimens, 25 (50%) had an AgNOR count < or = 3.0, 18 (36%) had an AgNOR count of more than 3 per nucleus and in the remaining 7 cases, AgNOR number was not quantifiable due to the total absence of tumour tissue in the postoperative specimen due to preoperative radiotherapy. When followed up for an average period of 25 months (3 to 47 months), it was seen that patients with AgNOR count of < or = 3.0 per nucleous had a similar mean survival (30.39 +/- 3.29 months) as those with counts > 3.0 per nucleus (27.80 + 3.33 months). The survival in the seven patients in whom no tumour was present following preoperative radiotherapy, was 30.30 +/- 2.42 months. An analysis was done for the presence of change in the AgNOR count before and after radiotherapy in twenty eight case of carcinoma oesophagus treated with preoperative radiotherapy. It was found that the counts on an average were lower in patients after radiotherapy (2.89 +/- 1.04 per nucleus), than before radiotherapy (3.17 +/- 9.69). This was found in 24 cases, while the remaining 4 cases showed no change in count after radiotherapy. This suggested that radiotherapy caused a reduction in AgNOR counts. Mean survival in those with decreased count after radiotherapy was 33.65 (+/- 3.35) months. Since the AgNOR counting is a simple method and can be applied to paraffin embedded section, estimation of the AgNOR number may help in determination of prognosis in patients with oesophageal carcinoma. Preoperative radiotherapy seems to decrease AgNOR count with improved survival. These observations need however, to be reproduced with a larger sample size. PMID- 8693590 TI - Prophylaxis against spontaneous bacterial peritonitis. Is trimethoprim sulfamethoxazole the answer? PMID- 8693591 TI - High-dose chemotherapy for breast cancer: twenty years later. Whom should we treat? And when? PMID- 8693592 TI - Recent advances in prostate cancer metastasis. AB - Prostate cancer in men has now surpassed lung cancer as the most frequent non cutaneous cancer. From a biological perspective, prostate carcinoma is unique among human malignancies in the wide discrepancy that exists between the prevalence of 'latent' cancer, recognizable only histologically, and that of the clinical disease. Histologically detected localized prostate cancers are heterogeneous, with only a small subset having undergone all of the malignant changes required to produce clinically aggressive tumors. Most of these 'latent' carcinoma never become fully malignant and do not threaten the life or well-being of the host. At present, it is not possible to predict which localized cancers will progress to clinically overt disease. Likewise, many patients have underevaluated and unpredictable extent of their prostate carcinoma, thus resulting in inadequate therapeutic strategies. It is clear that we need to identify molecular and/or cellular markers that are able to define the invasive and metastatic potential of prostate cancer on an individual patient basis. Acquisition of metastatic ability is a definitive criterion by which substage localized prostate cancers. Under the light of recent studies designed to identify some of the features associated with the metastatic phenotype of prostate cancer, the authors review recent advances aimed at gaining insight into those factors that may be involved in prostate cancer metastasis. PMID- 8693593 TI - Role of three cancer "master genes" p53, bcl2 and c-myc on the apoptotic process. AB - We review some of the most recent developments concerning three genes involved in human cancer: p53, bcl2 and c-myc. Recent data have demonstrated that the bcl2 gene protects tumor cells from apoptosis induced by a variety of agents, including ionizing radiation, and is thus related to resistance to DNA-damaging therapeutic agents. The p53 tumor suppressor gene, however, has been related with growth arrest, apoptosis and thus with selective sensitivity to the killing effects of ionizing radiation and DNA-damaging drugs. This functional antagonism between the two genes was recently substantiated in molecular terms by demonstration of reciprocal down-regulation due to the presence of a p53 dependent transcription silencer in the untranslated region of the bcl2 gene. Growth arrest in the G1 phase of the cell cycle and induction of apoptosis are two distinct and dissectable functions of p53: bcl2 is able to antagonize the induction of apoptosis by p53, but not the growth arrest in G1. However, coexpression of bcl2 and of the oncogene c-myc efficiently antagonizes effects of p53 on G1 arrest and apoptosis, thus suggesting a cooperation between the two oncogenes. In addition, c-myc disrupts other functions of genetic control in the early G1 phase of the cell cycle including the expression of D1 cyclin. We believe that knowledge of the functional/molecular interactions between these three genes involved in human cancer is a fundamental prerequisite to improve the knowledge on prognosis and to design innovative therapeutic approaches. PMID- 8693594 TI - Colorectal, lung, and breast cancer care during the three years following the diagnosis: a population-based study. AB - AIMS: We evaluated a number of basic parameters of care during hospitalization that contribute to the total cost of therapy during the 3 years after the first diagnosis of cancer. METHODS: The study examined a sample of cases of cancer of the colon-rectum (164 cases), lung (160 cases) and breast (144 cases) diagnosed in 1987, taken from the data base of the Tuscany Cancer Registry. All the information collected by the Registry was examined and the sample was further validated by reviewing original clinical records. The agreement between the two sources was very high, confirming the adequacy of the Registry as a source of information. The parameters evaluated for each patient were the number of cytohistologic examinations, surgery, hospital admissions and days spent in hospital during the 3 follow-up years. RESULTS: The average number of admittances in 3 years was 1.93 for colorectal, 3.39 for lung and 2.15 for breast cancer. The mean number of days spent in hospital in the 3 follow-up years was 39.9 for colorectal, 50.1 for lung and 21.1 for breast cancer. The parameters differed among subjects still alive, those deceased and those in various stages of the illness. CONCLUSIONS: The costs of the time spent in hospital, based on the number of days during the first 3 years of the illness, were higher in cases of lung cancer than of the other sites, and more so for patients diagnosed in an advanced phase of the disease. PMID- 8693595 TI - Survey on the use of questionable methods of cancer treatment. GOCS. Grupo Oncologico Cooperativo del Sur Republica Argentina. AB - BACKGROUND: Despite the improvement of cancer treatments, unproven and useless therapies are widely adopted among cancer patients and their families. Little information is available on the actual magnitude of such a phenomenon. METHODS: Two anonymous, similarly aimed surveys were independently carried out in Italy and Argentina on cancer patients and their families by two research groups. RESULTS: Respectively 563 and 400 questionnaires were distributed. The percentage of patients and/or families involved in unsound care (17%) was similar in both surveys. Of these treatments, 20%-38% were proposed by physicians, but relatives, friends, and mass-media had an equally important role. The costs of such care was difficult to estimate. CONCLUSIONS: Real and exhaustive efforts are needed by Health Care Organizations, which must execute a policy of information and education towards the public and professionals, as well as declare unethical the use of unproven therapies which claim cancer cure but simply create false hopes. All oncologists should be aware of the use of these treatments for cancer patients, even concomitantly with conventional care. PMID- 8693596 TI - Mitogen-induced lymphocyte proliferation and systemic immune activation in cancer patients. AB - AIMS AND BACKGROUND: Proliferative response of lymphocytes to mitogens is known to be decreased in cancer patients. Depressed proliferation of lymphocytes in other disorders has been linked to systemic inflammatory response. METHODS: Lymphocyte proliferation in response to phytohemagglutinin (PHA) and concanavalin A, as well as urinary neopterin, plasma interferon-gamma and interleukin-4, were investigated in 41 patients with solid tumors. RESULTS: The proliferative response to PHA was significantly depressed in cancer patients at most of the concentrations examined. Urinary neopterin and plasma interferon-gamma were significantly elevated in cancer patients, whereas interleukin-4 was undetectable in all the subjects. A negative correlation was observed between urine neopterin and lymphocyte proliferative response to mitogens. CONCLUSIONS: Lymphocyte proliferative response to PHA is significantly diminished in cancer patients, and this depression appears to be partly linked to systemic inflammatory response. Plasma interferon-gamma was significantly increased in cancer patients, whereas interleukin-4 was undetectable. PMID- 8693597 TI - Survival after chemotherapy with cisplatin and infusion of bleomycin prior to local-regional treatment in pyriform sinus cancer. AB - AIMS AND BACKGROUND: The purpose of this study was to retrospectively compare different approaches including neoadjuvant chemotherapy. METHODS: Ninety-six consecutive patients with pyriform sinus squamous cell carcinoma with no distant metastases were entered. The first 48 patients were treated with surgery plus postoperative radiation therapy (50-60 Gy) over cervical lymphatics. The next 48 patients were treated by induction chemotherapy with two courses of cisplatin, 120 mg/m2 i.v. day one, plus bleomycin, 20 mg/m2/day for 5 consecutive days in 24 hr i.v. perfusion followed by definitive surgery and postoperative radiation therapy as in the first therapeutic group. RESULTS: Definitive surgery was performed in 38 control vs 39 neoadjuvant patients. Complete response was observed in 9 (18.7%) and partial response in 32 (66.7%) of 48 chemotherapy treated patients. Partial plus complete response was seen in 41 (85.4%) of the 48 patients. Comparison between controls versus chemotherapy-treated groups showed persistence of the disease in 10 vs 9 patients; local-regional relapses in 21 versus 14 patients; and distant metastases in 4 vs 2 patients. Median survival was 12 vs 40 months. Survival curves were statistically better in neoadjuvants than in controls (P < 0.025). CONCLUSIONS: Multidisciplinary therapy slightly decreases the rate of local-regional relapses and distant metastases and should improve survival in this set of pyriform sinus cancer patients. PMID- 8693598 TI - Continuous non chronomodulated infusion of floxuridine in metastatic renal cell carcinoma (MRCC): report of 17 cases. AB - AIMS AND BACKGROUND: MRCC responds poorly to usual treatments. Recently floxuridine (FUDR) has been administered by chronomodulated infusion, obtaining interesting results. In order to simplify the infusion, we used continuous non chronomodulated infusion. METHODS: We treated 17 patients affected by MRCC with continuous non chronomodulated infusion of FUDR. Toxicity was evaluated according to WHO criteria. Responses were recorded as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). RESULTS: Sixty four courses of therapy were administered; 15/17 patients, treated with a median of 4 cycles, were evaluable for the response. Only 1 patient showed a grade 3 toxicity (mucositis and diarrhoea); 6 patients showed grade 1-2 diarrhoea; 2 grade 1-2 nausea and vomiting; 1 grade 2 anaemia and thrombocytopenia. No patient obtained CR; 2 PR (lasting 7 and 9 months respectively) and 4 SD (lasting 4,5,6 and 9 months) were observed. CONCLUSIONS: In our experience continuous non chronomodulated infusion of FUDR did not show important general toxicity. The observed responses were not good enough. We think that a better selection of patients (good performance status) and the use of FUDR in an earlier stage of disease, can obtain better results. PMID- 8693599 TI - Procarbazine, CCNU, vincristine combination in the treatment of brain tumors. AB - Forty patients with primary malignant brain tumor were treated by combination chemotherapy after prior treatment with surgery and radiotherapy. The chemotherapy schedule consisted of PCV: procarbazine per os, 100 mg/m2, during 14 consecutive days; CCNU, per os, 80 mg/m2 on day 1 and vincristine, intravenously, 1.4 mg/m2 on days 1 and 14. This protocol was planned to be repeated every 45 days for 6 courses. Median 5 courses (range, 2-6) of chemotherapy was administered to patients. The median relapse free (RFS) and overall survival (OS) rates were found to be 28 and 79+ months, respectively. According to univariate analysis, performance status (PS) of patients was an important prognostic factor on RFS and OS where extent of surgery was an additional significant determinant of OS. Multivariate analysis of pretreatment factors revealed the influence of sex, type of histopathology and PS on RFS and that of PS on OS rates (P < 0.05). The toxicity of this regimen was mild to moderate. The major toxicity noted was myelosuppression. Severe (grade III-IV) neutropenia and thrombocytopenia has been observed in 13 (7%) and 6 courses (3.5%), respectively. In general, PCV is well tolerated and the median RFS and OS times elucidated are comparable with particular trials utilizing combination chemotherapy and longer than using radiotherapy alone. PMID- 8693600 TI - Complications with fully implantable venous access systems in oncologic patients. AB - AIMS: To evaluate the complications caused by long-term central venous catheterization in patients with malignant hemopathies or solid tumors. METHODS: Retrospective study from June 1988 to June 1993 in 211 consecutive patients who required 223 venous access devices for long-term use. A consistent analysis was possible only in 161 of these patients. RESULTS: Fourteen catheter systems were removed for complications. Infections were the most common complications, with an overall incidence rate of 9.6%, i.e. 0.033/100 catheter days/patient. A significant difference was noted between the two groups of patients: 10 cases (24%) in malignant hemopathies, 6 cases (4.8%) in solid tumors (P = 0.0002). The main mechanical complication was thrombosis, with an incidence rate of 3%. CONCLUSIONS: Given the cost-benefit ratio, our study indicates that fully implantable venous access systems in oncologic patients are extremely useful. PMID- 8693601 TI - Lung cancer surgery in elderly patients. AB - AIMS AND BACKGROUND: Bronchogenic carcinoma is the major cancer-related cause of death in patients aged 70 years and over, and its incidence is rising. The aim of our study was to compare the incidence and the prognostic effect of the parameters characterizing resected patients with non-small-cell lung cancer (NSCLC) when stratified by age. Of 283 NSCLC patients candidates to a long-term follow-up program and who underwent pulmonary resection in our Unit, 34 (12%) were older than 70 years. METHODS: All patients had been preoperatively selected to exclude those with severe or multiple organ system disease and staged in accordance with the UICC classification. RESULTS: When univariate and multivariate analyses were performed within the elderly group, exclusively epidermoid carcinoma and multiple tumor nodules emerged as independent poor prognostic factors (hazard risk, 5.77 and 7.33, respectively). In comparing the older and younger groups, a higher incidence of previous primary neoplastic disease (P = 0.001), epidermoid carcinoma (P < 0.05) and multiple tumor nodules (P < 0.001) was observed in the elderly. Postoperative death was similar (3% vs 4.8%) in the two age groups, as was survival expectancy when stratified by stage. However, univariate analysis showed that epidermoid carcinoma (P = 0.001) and pneumonectomy (P = 0.00001) had a worse outcome in the older early stage subset than in the younger group. When multivariate analysis was performed in all early stage patients, only lymph node involvement and multiple tumor nodules were independently related to survival (hazard risk, 1.82 and 3.76, respectively) and had a poor prognosis. In more advanced disease, elderly and younger patients had a similar outcome. CONCLUSIONS: Our results confirm that a patient's advanced age is not a risk factor in deciding on pulmonary resection, at least for stage I and II NSCLC, and suggest that in all patients, irrespective of age, stage and histologic cell type, the presence of multiple tumor nodules is the only true prognostic factor with a very low survival rate. PMID- 8693602 TI - Breast cancer necrosis following fine needle aspiration biopsy. AB - Two cases of mammary carcinoma with nearly complete coagulative necrosis following fine needle aspiration biopsy (FNAB) are described. Although this occurrence rarely complicates a fine needle aspiration procedure, it seems to be a real possibility. Final diagnosis can be problematic and rests on the reassessment of the previous aspirate material, on the ghost architecture outlines of the infarct tumorous lesion and on any viable tissue left at the periphery of the lesion. PMID- 8693603 TI - Multiple primary malignant tumors in patients with hepatocellular carcinoma. A review of 29 patients. AB - BACKGROUND: The study of patients with hepatocellular carcinoma (HCC) and multiple primary malignant tumors (MPMTs) is interesting from an etiopathogenetic as well as from a clinical point of view. There are few studies dealing with this topic. METHODS: Smoking habits, alcohol intake, HBsAg status, alpha-feto-protein serum concentration, presence of liver cirrhosis, type of associated cancers, treatment, and survival were evaluated in 29 patients (25 men and 4 women; median age 73 years) with histologically confirmed HCC and MPMTs. All patients were examined between January 1980 and February 1995 at the General Hospital of Monfalcone, in northeastern Italy. In the same period there were 143 patients with HCC. RESULTS: Tumors associated with HCC were located in: prostate (9 cases), colon-rectum (5), bladder (3), lung (3), stomach (2), gallbladder (2), and brain, breast, oesophagus, pancreas, thyroid, larynx, pleura, small intestine, kidney (1 each). In 25 patients there was a single, and in 4 patients two associated malignancies. A diagnosis in vita of the associated malignancy was made in 15 cases. Cirrhosis was present in 90% of patients and HBsAg was positive in 15%. Mean survival time from diagnosis was 5.5 weeks (0-150) in patients with MPMTs and 6.8 weeks (0-221) in patients with HCC only. The cause of death was HCC in 18 patients, the associated tumor in 8, and non-neoplastic diseases in 2. Treatment of the associated tumors was performed in 8 cases. CONCLUSIONS: In this study the prevalence of MPMTs in patients with HCC is high (20.3%) in accordance with other autopsy series. Mean survival time in patients with MPMTs was similar to that in patients with HCC only. From a clinical point of view, attention must be paid to the diagnosis of hepatic lesions in patients affected with cirrhosis and extrahepatic cancer. PMID- 8693604 TI - Gliomas of the conus medullaris. AB - AIMS AND BACKGROUND: Gliomas of the conus medullaris often show characteristic clinical, radiological, and intraoperative features which differ from gliomas involving other parts of the spinal cord. METHODS: Eight patients with histologically verified gliomas of the conus medullaris were diagnosed and studied. RESULTS: There were five men and three women ranging in age from 21 to 59 years. Predominant initial symptoms were back pain (4 cases) and leg weakness (4 cases). The most common findings on admission were flaccid paraparesis with impaired sensation and bladder dysfunction. Postoperative magnetic resonance (MR) images with more than 95% removal of a tumour were defined as "subtotal removal" (noted in 4 of 8 cases), and less than 95% as "partial removal" (4 of 8 cases). All patients had postoperative radiotherapy. During the follow-up period ranging from 3 to 10 years, there was no tumour recurrence or regrowth on MR images. CONCLUSIONS: The postoperative radiotherapy in gliomas of the conus medullaris where total resection is not possible seems provide a beneficial effect on preventing tumour regrowth. PMID- 8693605 TI - Histiocytosis X of the thyroid gland. AB - Histiocytosis X rarely involves the thyroid gland and occurs as one of the unusual manifestations of systemic diseases. Diagnosis is based on the identification of the Langerhans' cells in an appropriate background. We report a case of histiocytosis X confined to the thyroid gland that represents the primary manifestation of the disease. A careful histological, immunohistochemical and ultrastructural study has been performed and problems of differential diagnosis are discussed. PMID- 8693606 TI - Metastasis to intracranial meningioma as first clinical manifestation of occult primary lung carcinoma. AB - Metastasis to an intracranial meningioma was the first clinical manifestation of an occult primary bronchogenic carcinoma. The principles of diagnosis on morphologic and immunohistochemical findings are discussed, particularly as regards the differential diagnosis between a metastasis to meningioma and microcystic or secretory meningioma. PMID- 8693607 TI - A case of small cell carcinoma of the lung associated with hypertrophic pulmonary osteoarthropathy. AB - A 73-year-old man had complained of painful swelling in the upper and lower extremities for several months before detection of small cell lung carcinoma. A bone scan showed abnormal symmetrical accumulations in the extremities, but periosteal proliferation was not demonstrated by X-ray. When a complete remission was obtained by chemoradiotherapy, the joint manifestation also subsided completely. In almost all reported cases, hypertrophic pulmonary osteoarthropathy was observed in all patients with non-small cell lung carcinoma. To our knowledge, this is the first case report of hypertrophic pulmonary osteoarthropathy associated with small cell lung carcinoma published in the English literature. PMID- 8693608 TI - Psoriasis and tamoxifen therapy: a case report. AB - A case of chronic plaque psoriasis in a woman with advanced breast cancer is reported. Treatment of the breast cancer with tamoxifen cleared the psoriatic skin lesions for several months, even after suspension of the hormonal treatment. PMID- 8693609 TI - Chylopericardium following right thoracotomy for lung cancer. AB - A 69-year-old woman underwent the right upper lobectomy, a partial resection of right segment 6 (rt S6) and removal of mediastinal lymph nodes (LN) for adenocarcinoma of the lung (rt S2), stage IIIA (T2N2M0). A chest computerized tomography (CT) taken one month after the operation revealed a pericardial effusion which was milky in color, and contained high levels of triglycerides (TG) of 615 mg/dl (serum, 217 mg/dl). Cytology of effusion for malignant cells was negative. The pericardial effusion gradually decreased in one month by restriction of her fat intake. Chylopericardium following right thoracotomy for lung cancer is extremely rare. PMID- 8693610 TI - Solitary left ventricle metastasis by renal cell carcinoma with sarcomatoid features. AB - A 64 year-old male presented with a mass of the left kidney, 9 cm across. A radical nephrectomy was performed and the pathological examination of the surgical specimen revealed a large papillary renal cell carcinoma (RCC). Five weeks after surgery, the patient died because of progressive cardiac failure. At autopsy, a whitish-gray subendocardial mass, measuring 6 cm in its main diameter, was discovered in the left ventricle. Histologically, the tumour, consisted of interlacing bundles of spindle cells, showing large vesicular nuclei, with prominent nucleoli. Rare gland-like structures lined by neoplastic cells were occasionally found. Neoplastic cells were focally immunoreactive to anti cytokeratin and anti-epithelial membrane antigen antisera. The diagnosis was that of cardiac involvement by RCC with sarcomatoid features. Cardiac metastases by RCC are rare and their incidence ranges from 1.3% to 4.2%. In the present case, the sarcomatoid appearance of the cardiac lesion raises the problem of the differential diagnosis with primary cardiac sarcoma. The clinico-pathological features of this case are discussed and the literature on this topic is reviewed. PMID- 8693611 TI - Postradiation sarcoma of head and neck: report of two cases. AB - AIMS AND BACKGROUND: Post-irradiation sarcoma (PIS) a rare, late side effect of radiotherapy and, consequently, its natural history is not well known. For this reason, two cases treated between 1975 and 1990 are described. CASE REPORTS: The Authors describe one case of malignant fibrous histiocytoma grown in the larynx 111 months after conservative surgery and postoperative radiotherapy, and one case of soft tissue sarcoma developed in the oral cavity 72 months after radical interstitial low dose rate brachytherapy. Both patients had chronic distress of the soft tissues after the primary treatment. The patients are alive and well respectively at 94 and 18 months from salvage surgery. DISCUSSION: The PIS of the head and neck region is a rare event, usually with a bad prognosis. An improvement in results could be possible with early diagnosis, followed by a timely excision, when anatomically possible. As the chronic suffering of the irradiated tissues may increase the risk of PIS, a longer and more frequent follow-up is advisable in these cases. PMID- 8693612 TI - Dermatomyositis and malignancy: case report and review of the Japanese literature. AB - The first reported association of dermatomyositis with malignancy was by Stertz in 1916, who described a patient with proximal muscle weakness, eyelid changes, and evidence of myositis on muscle biopsy as well as a coexisting gastric carcinoma. In the same year, Kankeleit described a patient with dermatomyositis and breast cancer--the seeds of a controversy were thus sewn. We report a female patient with multiple cancer who developed dermatomyositis and review the relevant Japanese literature. Our patient suffered from metachronous bilateral breast cancer and thyroid cancer. She underwent curative resection of all 3 tumors. Our experience suggests that clinicians should perform extensive screening of dermatomyositis patients to salvage those with occult cancer, although the issue of cost effectiveness also has to be considered. PMID- 8693613 TI - Oxyphil cell adenoma (oncocytoma) of the lacrimal caruncle: a case report. AB - The onset of oncocytic neoplasms in the ocular area is exceptional. A rare case of oxyphil cell adenoma of the lacrimal caruncle in an 81-year-old woman is presented. The anatomo-clinical profile of this benign small tumor is drawn up: a slowly growing tumor, generally occurring in the caruncle of elderly women, which is characterized by a uniform population of epithelial cells with eosinophilic finely-granular cytoplasm containing large numbers of mitochondria. The histogenetic problem of this tumor is briefly discussed. PMID- 8693614 TI - Progressive effects of malachite green at varying concentrations on the development of N-nitrosodiethylamine induced hepatic preneoplastic lesions in rats. AB - AIMS AND BACKGROUND: Malachite green (MG) is a triarylmethane textile dye which is banned for use as a food colour. However, despite the ban it is used unscrupulously as a food colouring agent. It is also used extensively for dyeing silk, wool, jute, leather, cotton and also as a laboratory reagent, in view of its multipurpose utility, MG may pose a potential environmental health hazard. The purpose of this study was to evaluate the dose-dependent effects of malachite green on the development of pre-neoplastic lesions during N-nitrosodiethylamine (DEN)-induced hepatocarcinogenesis in comparison with phenobarbitone (PB) in male Wistar strain rats. METHODS: Rats were administered 200 p.p.m. DEN in drinking water for a period of one month. Following an interval of two weeks the animals were given MG at concentrations of 25, 50 and 100 p.p.m. through drinking water for 7 months. PB at a concentration of 500 p.p.m. served as the standard tumour promoter. The dose dependent tumour enhancing effects of MG were monitored on the basis of morphological appearance of the livers, liver weight profile, histological pattern and quantitative GGT activity. RESULTS: MG tested at all the three concentrations and PB were found to enhance liver carcinogenesis to a significant extent when compared to either with their corresponding controls or only the DEN treated animals. CONCLUSIONS: A dose-dependent tumour enhancing effect of MG on DEN-induced hepatic preneoplasia in rats was observed. The enhancing effects at 25, 50 and 100 p.p.m. were found to be comparable with PB at 500 p.p.m. PMID- 8693615 TI - Measure of cancer prevalence with a computerized program: an example on larynx cancer. AB - In spite of the great value from the health planning point of view, only a few Cancer Registries have produced measures of prevalence. PREVAL is a computerized program for personal computers that provides prevalence data expressed as number or proportion. The program calculates prevalence, cross-classified by years from diagnosis and age. PREVAL reads data on the vital status, available from those Cancer Registries that have carried out population-based survival studies. Larynx cancer in males has been used as an example. Analysis has been performed on 15 year follow-up data of 840 incidence cases registered during 1976-1987 period from Lombardy Cancer Registry. In 1987, larynx cancer prevalence proportions are 67.6 per 100,000 for patients with up to 5 years from diagnosis and 108.4 per 100,000 for those with up to 10 years. The Authors will provide PREVAL free of charge upon request. PMID- 8693616 TI - [Treatment of acute pulmonary failure]. PMID- 8693617 TI - [Acute respiratory distress syndrome. Pathogenesis and therapy of acute pulmonary failure]. AB - Adult respiratory distress syndrome (ARDS) is the pulmonary response to systemic inflammation precipitated by local or systemic tissue hypoxia, or ischaemia and reperfusion. ARDS is a dynamic, pathological process with a multifactorial etiology. The main clinical manifestations of ARDS are dyspnoea, non-cardiogenic pulmonary oedema, and hypoxia due to increased pulmonary capillary permeability, pulmonary vasoconstriction and diminished pulmonary vascular reactivity. Eventually this pulmonary pathology results in first, oedema, pulmonary hypertension, and increased ventilation-perfusion inequality and later, pulmonary remodelling and irreversible pulmonary hypertension. The inflammatory mechanisms involved in acute lung injury are complex and include activation of polymorphonuclear neutrophils, endothelial cells, and synthesis of free radicals, predominantly derived from oxygen. Cytokines synthesized by macrophages maintain and regulate the inflammatory host response. Immune-modulating therapy in ARDS is yet experimental. Accordingly, treatment in ARDS is supportive, directed towards pulmonary oedema, pulmonary hypertension and hypoxaemia. The use of low tidal volumes and low inspiratory pressures in mechanical ventilation is established therapy. The goal in haemodynamic monitoring by applying a Swan-Ganz catheter is to obtain a low pulmonary capillary wedge pressure (< 12-15 mmHg) without compromising adequate delivery of oxygen to vital organs. For treatment of pulmonary hypertension nitric oxide is useful. Change of position and inhalation with beta2-agonists are therapeutic possibilities. Steroids may be of benefit in the late proliferative phase of ARDS. PMID- 8693618 TI - [Dopamine D4-receptor variants, schizophrenia and clozapine therapy]. AB - Clozapine is an atypical antipsychotic with a low extrapyramidal side effect profile, and is often useful in the treatment of schizophrenics who do not respond to classical neuroleptics. While the dopamine D2-receptor is believed to be the primary target of classical neuroleptics, clozapine has greater affinity to the dopamine D4-receptor (DRD4). Great variability has been reported for the DRD4 gene and in the receptor itself. It is now possible to investigate if this variation influences individual differences in response to clozapine treatment or in the genetic susceptibility to schizophrenia. Till now the examined variations in the DRD4 gene do not seem to influence response to clozapine treatment or genetic susceptibility to schizophrenia. However, some of clozapine's side effects might be mediated through DRD4 binding. PMID- 8693619 TI - [The effect of salmeterol in the treatment of smokers with chronic obstructive lung disease]. AB - Patients with chronic obstructive pulmonary disease (COPD) may benefit from long term treatment with bronchodilators despite having a modest acute response to these drugs. To investigate the efficacy of salmeterol in smokers with COPD a double blind, randomised, crossover comparison was performed between salmeterol (50 micrograms twice daily) and placebo in 63 patients with stable COPD (mean age 63 yrs); inclusion criteria: aFEV1) < 60% of predicted and FEV1 reversibility < 15% (0.4 mg salbutamol). Patients received four weeks of therapy with each of the treatment regimens. Assessment of efficacy was done by recording morning and evening peak expiratory flow rates (PEF), respiratory symptoms, and use of rescue salbutamol. Morning PEF values were higher during the salmeterol than during the placebo period, although the mean treatment difference was small (12 l/min (95% confidence limits 6 to 17)). No difference in mean evening PEF values was found. Diurnal variation in PEF was more pronounced during the placebo than during the salmeterol period. Compared with placebo, treatment with salmeterol was associated with lower day time and night time symptom scores and less use of rescue salbutamol both during the day and the night. This study shows that, compared with placebo, treatment with salmeterol produces an improvement in respiratory symptoms and morning PEF values in patients with moderate to severe COPD. Treatment with long acting beta(2)-agonists may therefore result in an improvement in functional status, even in patients suffering from apparently non reversible obstructive pulmonary disease. PMID- 8693620 TI - [Mortality and fatal risk factors in 1075 outpatients treated for asthma]. AB - Mortality and markers of risk of death from asthma were studied among 1,075 astmathics attending a chest clinic in Copenhagen between 1974 and 1990; they were compared with a sex- and age-matched group of non-asthmatic patients. Both groups comprised 425 males (mean age 37 yrs (SD 15)) and 650 females (mean age 39 yrs (SD 16)) and the mean follow up period was 8.6 yrs (SD 4.2). Mortality from all causes was significantly increased in the asthmatic subjects (93 deaths) compared to the control group (41 deaths); relative risk (RR) 2.4, (95% confidence interval (CI) 1.6 to 3.4). The predominant cause of excess mortality was obstructive pulmonary disease, that is, status asthmaticus (14 vs. 0 deaths, RR 8.2) and chronic asthma (19 vs. 0 deaths, RR 8.3). Mortality analysis employing the multiple regression model of Cox revealed that age, pack-years of smoking, eosinophilia, level of FEV1% pred and degree of reversibility in FEV1 were significant predictors of death from asthma. In subjects with eosinophilia (> 0.45 mia/l), the risk of dying from asthma was 7.4 (CI 2.8-19.7) greater than in those without eosinophilia. Compared to subjects with 15-24% reversibility in FEV1, the subjects with 25-49% and > 50% reversibility had a 2.7 and 7.0 higher risk of death from asthma, respectively. Mortality was significantly increased in asthmatics compared to matched controls, primarily due to death from acute and chronic asthma. Furthermore, the present findings suggest that eosinophilia and pronounced increase in FEV1 following bronchodilator are strong markers of subsequent risk of death from asthma. PMID- 8693621 TI - [Eosinophil count in asthma. A marker of disease activity in intrinsic and extrinsic asthma]. AB - The relationship between eosinophil count and pulmonary function (FEV1), respiratory symptoms, bronchial responsiveness to histamine and diurnal variation in peak expiratory flow rate (PEF) was studied in a group of asthmatics (n = 70) examined in childhood (mean age 10 yrs) and early adulthood (mean age 21 yrs), of whom 24 had intrinsic and 46 extrinsic asthma. Self-reported symptoms of asthma were graded on a scale from zero to five; histamine responsiveness was analysed by means of the dose-response slope (DRS). In both childhood and adulthood, a direct correlation was found between blood eosinophil count and symptom score (r = 0.69, p < 0.001 and r = 0.58, p < 0.001, respectively), whereas inverse correlations were observed between number of eosinophils and FEV1 expressed as percentage of predicted values (r = -0.75, p < 0.001 and r = -0.80, p < 0.001, respectively). Furthermore, in adulthood, eosinophil count was found to be significantly correlated to histamine responsiveness (logDRS) (r = 0.65, p < 0.001) and diurnal PEF variation (r = 0.81, p < 0.001); these correlations were also noted after dividing the subjects into intrinsic and extrinsic asthmatics. The findings in the present study suggest that the peripheral eosinophil count reflects asthmatic activity, and possibly the degree of inflammation in the airways, in both children and young adults. PMID- 8693622 TI - [Extrinsic and intrinsic asthma from childhood to early adult age. A 10-year follow-up]. AB - The purpose of this study was to describe factors of potential importance for the outcome in children with intrinsic and extrinsic asthma. Of 85 consecutive children, five to 15 years of age, with asthma, 70 (82%) participated in a ten year follow up examination. At the time of referral all children underwent certain tests for asthma (case history, total IgE, skin prick tests, radioallergosorbent tests (RAST) and specific bronchial provocations). On the basis of these tests 24 children had intrinsic asthma and 46 extrinsic asthma. At the follow up examination 60 of the 70 adults (86%; 20 with intrinsic asthma) had current symptoms; 54 of the 60 (90%; 18 with intrinsic asthma) were receiving maintenance therapy. Both FEV1 %pred (from 73% +/- 19% to 92% +/- 17%) and FEV1/FVC (from 75% +/- 13% to 80% +/- 12%) increased significantly from childhood to early adulthood (p < 0.0002 and p < 0.001, respectively); a corresponding amelioration of symptoms was also observed (p < 0.0001). In children with intrinsic asthma the outcome seems to be predicted by a combination of the initial frequency of symptoms (p = 0.04), initial FEV1 (p = 0.001), active smoking (p = 0.001) and age at onset of respiratory symptoms (p = 0.001), whereas the initial FEV1 (p < 0.001) seems to be a strong predictor for the outcome in children with extrinsic asthma. These findings suggest that the pathogenetic mechanisms underlying intrinsic and extrinsic asthma in children may differ. PMID- 8693623 TI - [Pleomorphic adenoma of the trachea]. AB - A case report of a 43 year-old man with an extremely rare pleomorphic adenoma arising from the trachea is presented. Management was successful by bronchoscopic laser resection, which is a relatively harmless procedure compared to open tracheotomy. Tracheal tumors are often overlooked as a cause of pulmonary symptoms, until they give airway obstruction. This case was initially misdiagnosed as asthma. PMID- 8693624 TI - [Cutaneous symptoms after continuous subcutaneous injection of morphine]. AB - We present two cases of patients who developed local swelling and induration after continuous subcutaneous infusion of morphine. Cutaneous complications of repeated subcutaneous injections of pentazocine, meperidine, ketobemidone and methadone are well described. There are few reports of similar reactions after subcutaneous administration of morphine. Both patients were later treated with sufentanil using the subcutaneous route without any reaction. Sufentanil might be an alternative to patients who cannot tolerate morphine. PMID- 8693625 TI - [Carbon monoxide poisoning]. PMID- 8693626 TI - [Nutrition committee in Denmark]. PMID- 8693627 TI - Abdominal repair of vesicovaginal fistula. PMID- 8693628 TI - Erectile dysfunction following minimally invasive treatments for prostate cancer. AB - OBJECTIVES: Cryosurgical ablation of the prostate (CSAP) and interstitial radiotherapy (IR) are relatively new procedures intended to be less invasive than radical prostatectomy for the treatment of prostate cancer. Despite absence of long-term or intermediate data of efficacy, many patients choose one of these therapies because they presume their potency will be maintained. We report our experience with CSAP, IR, and post-procedure erectile dysfunction. METHODS: Global sexual assessments were made in 12 months after therapy in 28 CSAP patients, and at 18 months in 37 IR patients. Each patient was contacted by telephone following his procedure. The patients were asked several questions regarding their sexual function both preoperatively and postoperatively. The questionnaire was administered only to the patient. RESULTS: Twenty-eight of 36 patients who underwent CSAP responded to the questionnaire (78%). Twenty patients were potent preoperatively (71%). The mean age of the potent group was 69 years (range 54 to 82). Following therapy, 2 of these patients (10%) reported potency at 12 months. Thirty-seven of 42 patients who underwent IR responded to the questionnaire (88%). Twenty-seven were potent preoperatively (73%). The mean age of the potent group was 70 years (range 56 to 83). The mean follow-up was 18 months (range 5 to 36). Following therapy, 15 patients reported potency (55%). All of the patients who reported potency felt that the quality of their erections had decreased following radiation. CONCLUSIONS: Our short-term results with IR and CSAP suggest a significant adverse effect on erectile function. Our results suggest that enhanced preservation of potency should not be used as an enticement in the promotion of IR or CSAP. PMID- 8693629 TI - Bias due to observation of different parts of a nonconstant hazard curve over time. AB - OBJECTIVES: Uncontrolled data often have to be used in clinical decision marking and in the planning of clinical trials. When such data are used as a basis for comparing different treatment strategies, they tend to generate sources of bias such as inconsistent patient selection, misrepresentation, and measurement errors. A rational usage of uncontrolled data requires identification and handling of different systematic errors when comparing different treatment strategies. Therefore we sought to define a systematic error that deserves more attention in the clinical literature. METHODS: Using hypothetical examples, we illustrate the bias introduced by variations in "lead time," proportions of so called prevalent/incident cases, and lengths of follow-up between reference and treatment groups. RESULTS: We found these three situations conceptually identical. Bias is introduced because different parts of a nonconstant hazard curve over time are observed. CONCLUSIONS: The systematic error described is potentially important in uncontrolled data provided the hazard rate over time is nonconstant. Thus the seemingly worse outcome after external beam radiation therapy as compared to the outcomes of deferred treatment of radical prostatectomy in compiled patient series of localized prostate cancer may in some part be explained by bias due to observation of different parts of a nonconstant hazard curve over time. PMID- 8693630 TI - Pelvic floor electrical stimulation: a comparison of daily and every-other-day therapy for genuine stress incontinence. AB - OBJECTIVES: To compare the effectiveness of daily and every-other-day electrical stimulation in treating genuine stress incontinence. METHODS: Subjects with genuine stress incontinence were enrolled in a multicenter, prospective, nonrandomized study and underwent daily or every-other-day pelvic floor stimulation treatments for 15 minutes twice a day. Outcome measures assessed were (1) leakage episodes and pad count; (2) leakage amount, and (3) subject subjective assessment and quality of life. Thirteen subjects treated daily and 15 treated every other day completed the 20-week protocol. One-year follow-up data were available for 21 subjects. RESULTS: No significant differences in primary outcome variables were found between the groups. Subjects treated every other day had significant decreases in total leakage episodes (P = 0.04), pad count (P = 0.04), total voids (P = 0.02), and visual analog scale scores, with stress incontinence cured or improved by 50% in 73% (n = 11). Subjects treated every day had significant decreases in urge episodes (P = 0.03), pad count (P = 0.05), and visual analog scale scores, with 62% (n = 8) cured or improved by 50%. Compliance was higher for subjects treated every other day (P = 0.05). Satisfaction with therapy was 75% (n = 10) for daily treatment and 77% (n = 12) for every-other-day treatment. At 1 year, 70% (n = 7) of subjects who continued device use maintained their cure or improvement status. CONCLUSIONS: Both daily and every-other-day therapy with pelvic floor electrical stimulation are effective in treating genuine stress incontinence. Subjects who continue device use maintain a higher curve or improvement rate. PMID- 8693631 TI - Does technique or material used affect bladder tissue reactions when injecting teflon or silicone paste? AB - OBJECTIVES: Submucosal injections of polytetrafluoroethylene (PTFE) and polydimethylsiloxane (PDMS) paste continue to be used for the correction of vesicoureteral reflux and urinary incontinence. Potential distant particle migration and foreign body tissue reactions are thought to be significantly affected by the technique of injection and the paste material used. A study to determine if injection technique, paste material, or pretreatment of the injection site significantly affects local tissue reaction was performed on 44 New Zealand white rabbits. METHODS: Animals were randomly assigned to undergo four distinct injection treatments into the submucosa or bladder muscularis. Prior to injecting 0.1 cc of the PTFE or PDMS paste, some sites were pretreated with 0.1 cc saline to separate tissue planes, epinephrine to cause vasoconstriction, or doxycycline to provide sclerosis. Pretreatment controls were also performed without injecting PTFE or PDMS paste. Animals were killed, and quadrant bladder biopsies were performed at 1 hour (9), 1 day (9), 7 days (10), 1 month (8), and 6 months (8). A single pathologist, blinded to the injection treatments, performed a histologic evaluation to determine bleb location and the degree of inflammation, fibrosis, and epithelial necrosis. RESULTS: Seven of the 12 submucosal PTFE injection treatments were found on biopsy to be primarily within the muscularis, compared to 1 of 9 with PDMS paste. Three of the 24 PTFE injections could not be found at autopsy. Of these, two were injected into the muscularis, and all were discovered at least 1 month following injection. Particles were present in all 22 PDMS injection sites that were retrieved. Pretreatments, especially with doxycycline, resulted in significant epithelial necrosis at 1 and 7 days. At 1 and 6 months there were no differences in inflammation or fibrosis between PTFE and PDMS or any pretreatment combinations with saline or epinephrine. CONCLUSIONS: Correctly injected, silicone (PDMS) paste appears most likely to remain in the submucosal space. Pretreatment injections may cause early epithelial necrosis. PTFE and PDMS elicit similar foreign body reactions over time. PMID- 8693632 TI - Phytotherapy in treatment of benign prostatic hyperplasia: a critical review. AB - Phytotherapeutic agents have enjoyed widespread use, especially in Europe, for the treatment of BPH. With the recent proliferation of nutrition and vitamin stores in the United States, use of these agents has greatly increased. Although SPB extract is the most extensively studied of the phytotherapeutic agents used for BPH, no well-defined mechanism of action has been proposed. Evidence for an antiandrogenic or antiestrogenic effect is conflicting, and there are no clinical data suggesting an effect on 5-alpha-reductase activity. Furthermore, clinical trials with SPB have largely been uncontrolled and are thus of limited value in ascertaining the true clinical impact of this agent. Double-blind, controlled studies with SPB also have limitations in that most were of very short duration (none longer than 3 months) and did not provide entry or exclusion criteria. In addition, standardized symptom scores were not utilized. Only two of seven studies showed an appropriate placebo response, and the results and conclusions of both these studies were contradictory. The best and most convincing study of the efficacy of phytotherapeutic agents (using Harzol) was recently published in the Lancet. This study was rigorous and matched in design and format with pharmaceutical industry trials. A mild but appropriate placebo response was detected, which further validates the study. However, a prior placebo-controlled study showed no efficacy of beta-sitosterol-beta-D-glucoside. This dichotomy of results possibly reflects the different composition of the agents tested. This is a major confounding factor in this field of study, especially because the active ingredients are unknown. Standardization of the compounds is needed to compare and assess accurately the effect of the different extracts. PMID- 8693633 TI - Penile orthoplasty using dermal grafts in the outpatient setting. AB - OBJECTIVES: To review and evaluate our extensive outpatient experience in the use of dermal grafts for the correction of significant residual chordee in patients requiring penile orthoplasty. METHODS: The medical records of all patients requiring surgical correction for severe penile curvature over the past 5 years were reviewed. Among these, 51 patients were identified in whom dermal grafts were used to correct severe residual chordee. Of these patients, 41 had severe hypospadias, 9 had epispadias, and 1 had urethral atresia. Graft harvest and placement technique, any resulting complications, and parental satisfaction with cosmetic and functional results were all evaluated. RESULTS: The dermal grafts were harvested from the hairless skin of the inguinal area, using one of two techniques. All were used to fill a tunical defect created by incising the tunica at the point of maximal penile curvature. No complications or postoperative hospitalizations resulted from any of the orthoplasty procedures. At a mean follow-up of 27 months, all patients had excellent cosmetic and functional results. CONCLUSIONS: In patients with significant residual chordee, a dermal graft is our preferred method of penile orthoplasty. This technique provides a straight phallus with a very minimal complication rate, it can easily and successfully be performed as an outpatient procedure, and it has assured an excellent cosmetic and functional result. PMID- 8693635 TI - High scrotal incision for scrotal pouch orchiopexy. AB - Orchiopexy is one of the most common operations in children. It should be performed meticulously, and the testis should be anchored within the scrotum without undue tension. I present another method for making a pouch in scrotal pouch orchiopexy. PMID- 8693634 TI - The use of an ultrasonic assisted lipectomy device for the treatment of obstructive pelvic lipomatosis. AB - Pelvic lipomatosis is a rare disease of unknown etiology characterized by overgrowth of pelvic fat. We describe a 60-year-old man with pelvic and retroperitoneal lipomatosis causing severe urinary obstruction with massive hydroureteronephrosis. The diagnostic procedure and the management of the patient is described, emphasizing the value of the Ultrasonic Assisted Lipectomy device in performing ureterolysis. PMID- 8693636 TI - Laser-tissue interactions during laser prostatectomy. PMID- 8693637 TI - Atypical findings in a patient with a renal milk-of-calcium cyst. AB - A case of an atypical renal milk-of-calcium cyst is presented. Although this cyst contained a colloidal suspension of calcium crystals, other signs and findings typical for a milk-of-calcium cyst were lacking. No connection of the cyst to the collecting system could be identified, no "half moon" phenomenon was found on upright and cross-sectional radiography, and the biopsies taken from the wall of the cyst showed sclerosis instead of urothelium. From the present case it was concluded that renal milk-of-calcium cysts may sometimes occur in the absence of findings that are typical of this particular entity. Therefore, this disease should be considered in the differential diagnosis of renal calcifications of unknown origin. PMID- 8693638 TI - Renal arterioureteral hemorrhage: a complication of acucise endopyelotomy. AB - The Acucise ureteral catheter is a ureteral cutting balloon device that recently received approval for retrograde endopyelotomy. We report a case of a postoperative lower pole renal arterioureteral hemorrhage after retrograde endopyelotomy requiring interventional radiographic treatment. Significant gross hematuria after Acucise endopyelotomy may indicate a communication between the vasculature and collecting system. Prompt arteriography with embolization should be considered in this clinical situation. PMID- 8693639 TI - Ultrasonographic appearance of necrotizing gangrene: aid in early diagnosis. AB - In 2 seriously ill patients with scrotal swelling of uncertain origin, scrotal and perineal ultrasonography demonstrated gas in the soft tissue before crepitus was detected on physical examination. Necrotizing infections of the scrotum and perineum have characteristic ultrasonographic features that can facilitate earlier diagnosis and treatment. PMID- 8693640 TI - Testicular seminoma originating in an undescended testis in a renal allograft recipient. AB - Immunosuppressed transplant recipients are at significantly increased risk for developing neoplasms than are nonimmunosuppressed individuals. However, only six cases of pure testicular seminoma following renal transplantation have been reported in the English literature. This case report represents the first description of a seminoma arising in an undescended testis post-transplantation. We propose that it may be prudent to remove atrophic undescended testes when lifelong immunosuppressive therapy is anticipated, because accelerated tumor growth can occur. PMID- 8693641 TI - Long-term disease-free survival after plasmacytoma of the urethra: a case report and review of the literature. AB - Plasmacytoma is an unusual soft-tissue collection of neoplastic monoclonal plasma cells. The most common site of presentation is the upper respiratory tract, although any site of disease is theoretically possible. We report the fifth known case of primary urethral plasmacytoma. This case is unique in that the patient received only radiation as definitive treatment and has remained well, without recurrence for more than 12 years. PMID- 8693642 TI - Amebiasis of the penis. AB - Penile amebiasis is rarely a recognized entity because the penis is not the usual site of presentation for amebiasis. Homosexual men have a higher risk of acquiring the lesion. Amebic ulcers resemble cutaneous lesions arising from squamous cell carcinoma, chancroid, primary syphilis, granuloma inguinale, and many other causes. An amebic ulcer should be suspected in a patient with balanoposthitis that resists antibiotic therapy. Biopsy is fundamental to isolate the trophozoites to confirm the diagnosis. Metronidazole and hydrochloric emetine are still the treatment of choice. This diagnosis should especially be considered in cases of lesions detected in patients who practice anogenital sex or who are immunocompromised. PMID- 8693643 TI - Severe injury from neodymium: yttrium-aluminum-garnet laser therapy for penile condylomata acuminata. AB - Laser therapy is widely accepted as a safe and effective means of treating genital condylomata acuminata. In this report, single-session neodymium: yttrium aluminum-garnet laser treatment of extensive condylomata of the penis resulted in deep coagulation necrosis and sloughing of penile shaft skin and urethra. Management of this unfortunate occurrence is also described. PMID- 8693644 TI - Agonist and antagonist activities of hydroxyflutamide and Casodex relate to androgen receptor stabilization. PMID- 8693645 TI - Effect of estramustine, etoposide, and taxol on prostate cancer cell growth in vitro and in vivo. PMID- 8693646 TI - Oral bropirimine immunotherapy of carcinoma in situ of the bladder: results of a phase II trial. AB - OBJECTIVES: Bropirimine is an orally administered immunostimulant that has been shown to have activity against carcinoma in situ (CIS) of the bladder. To further assess this potential activity, bropirimine was administered to 42 patients for bladder CIS in a Phase II trial. METHODS: Patients were treated with bropirimine 3.0 g/day by mouth for 3 consecutive days each week up to 1 year. Cystoscopy with biopsies and bladder wash cytology were performed quarterly. RESULTS: Twenty (61%) of 33 evaluable patients converted malignant biopsies and bladder wash cytology to negative, including 6 (50%) of 12 who failed prior bacillus Calmette Guerin (BCG) immunotherapy, 14 (67%) of 21 who had not received prior BCG therapy, and 12 (80%) of 15 with primary CIS. Median response duration exceeds 21 months. Four of the 20 responders did have a papillary tumor recurrence at 3 to 15 months, all Stage Ta or T1. Mild toxicity (grade I or II) suggestive to interferon induction or administration occurred in one third of patients. Headache, transient hepatic enzyme elevations, skin rash, and arthralgias each occurred in 5% to 14% of the patients, with nausea or emesis in 21%. Grade 1 tachycardia/palpitations or chest pain each were noted in 5%. CONCLUSIONS: Oral bropirimine can induce remission of bladder CIS with acceptable toxicity at 3.0 g/day. Bropirimine may be a valuable alternative to cystectomy for some failures of BCG therapy and may have the potential to replace BCG as front-line therapy because of its ease of administration. PMID- 8693648 TI - Use of a moderated international Internet information exchange in the study of male reproduction. AB - It is clear that modern information technology is having a profound impact on the way researchers and clinicians exchange information. Use of the Internet is one example of how such change can be translated into scientific progress and improved patient care. Androlog, a moderated international information exchange, has proven to be very useful in the transfer of information pertaining to the study and treatment of male reproductive disorders. Allowing instantaneous dispersal of messages to members in 27 countries, this system has become a valuable source of scientific information, as well as an excellent forum for the discussion of a broad range of clinical and laboratory topics. Moderated-user groups such as Androlog are highly applicable to many other areas of urology. Establishment of such an information exchange requires only a modest investment in computer hardware and software and moderators who are willing to perform the necessary tasks of system administration and message review. Given the unique advantages provided by this method of communication, there is little doubt that systems such as Androlog will flourish in the future, providing a valuable tool in the advance of medical science. PMID- 8693647 TI - Bropirimine immunotherapy of upper urinary tract carcinoma in situ. AB - OBJECTIVES: Bropirimine has been shown to be effective in treating approximately 50% of patients with carcinoma in situ (CIS) of the bladder in recent clinical trials. Patients with upper tract CIS were treated with bropirimine to determine whether this oral drug might be effective in that setting. METHODS: Twenty-four patients with negative radiographic findings and positive cytologic evidence for upper tract CIS in one or both ureters received bropirimine (3.0 g/day orally) for 3 consecutive days each week for up to 1 year. Ureteral collection of urine or barbotage for cytologic analysis was performed quarterly thereafter. RESULTS: Ten (48%) of 21 evaluable patients had a negative ureteral cytologic analysis after 12 weeks (5 patients) or 24 weeks (5 patients). Of these 10 patients, 8 continue to have negative cytology for a period of 3 to 30 months (median, more than 9 months). In 2 patients, negative cytology reverted to positive at 6 and 9 months, respectively, during therapy. Twelve (50%) of the 24 patients reported no toxicity. Three patients stopped treatment at 2, 3, and 3 weeks due to pruritic rash, nausea and vomiting, and severe bone pain, respectively. Therapy was stopped in 1 additional patient between 4 and 5 months because of transient liver enzyme elevations, yet this patient has had a continuous negative cytologic analysis for more than 9 months. CONCLUSIONS: Orally administered bropirimine may be effective therapy for CIS of the ureter or renal pelvis, with acceptable toxicity in most patients. Further efforts to better define this activity as well as the possible need for maintenance or intermittent long-term therapy are warranted. PMID- 8693649 TI - Renal oncocytoma: preoperative diagnosis using technetium 99m sestamibi imaging. AB - OBJECTIVES: To determine if 99mTc-sestamibi (technetium 99m methoxyisobutylisonitrile) can be used preoperatively to differentiate renal oncocytomas from other renal masses. METHODS: We performed 99mTc-sestamibi scans on 6 patients with various renal masses, using a standard technique. The diagnosis in each patient was determined either by radiologic methods. RESULTS: There was significantly increased uptake in the patient with the renal oncocytoma, whereas the other lesions had decreased uptake in comparison to normal kidney. This was determined visually and by mean pixel analysis. CONCLUSIONS: Technetium 99m sestamibi scanning appears to have a potential role in the nonoperative diagnosis of renal oncocytomas, in combination with pathologic fine-needle biopsy confirmation. More definitive pathologic experience is required before recommending standard use. PMID- 8693650 TI - Comparison of bladder rupture pressure after intestinal bladder augmentation (ileocystoplasty) and myomyotomy (autoaugmentation). AB - OBJECTIVES: To compare the risk of bladder rupture of bladder augmentation using ileocystoplasty versus that of autoaugmentation with myomyotomy in a rat model. METHODS: Bladder rupture pressure and volume of three groups of female Sprague Dawley rats were determined by cystometry. The first group of 11 rats had undergone ileocystoplasty using a detubularized 1 -cm segment of ileum. A second group of 9 rats had undergone autoaugmentation with myomyotomy. One month after surgery the animals were studied cystometrically to determine the bladder rupture pressure, then killed. A third group, consisting of 10 nonoperated rats, was studied and served as controls. RESULTS: Nonoperated, control rat bladders were able to sustain 154 +/- 43 mm Hg pressure and 2.5 +/- 2.0 mL volume prior to bladder rupture. Conventional ileocystoplasty was noted to increase bladder capacity to 4.0 +/- 1.9 mL, but decrease rupture pressure to 111 +/- 49 mm Hg. Myomyotomy resulted in a mean bladder rupture volume of 1.2 +/- 0.4 mL, with a rupture pressure of 101 +/- 13 mm Hg. The rupture pressure after myomyotomy is significantly lower than that of the native bladder (P < 0.001), whereas the rupture volume after myomyotomy is significantly lower than either after the ileocystoplasty or with the native bladder (P < 0.001). Bladder rupture occurred at the augmented ileal bladder dome in 7 of 11 ileocystoplasty animals and at the anastomotic suture line in 4 animals. Bladder rupture occurred at the area of bladder diverticulum in all 9 myomyotomy animals. Among controls, no specific site pattern of bladder rupture was noted. CONCLUSIONS: Bladder augmentation with myomyotomy increases vulnerability to urinary extravasation, evidenced by a significantly reduced rupture pressure and bladder volume at rupture when compared to the native bladder. PMID- 8693651 TI - Optimized microvessel density analysis improves prediction of cancer stage from prostate needle biopsies. AB - OBJECTIVES: Clinical staging of prostate cancer is inaccurate, often with significant upstaging on final pathologic review. We previously demonstrated the ability to predict extraprostatic extension of cancer by use of the Gleason score and serum prostate-specific antigen (PSA) measurements. Herein we present an interim analysis of data from an ongoing multi-institutional study to determine the predictive power of an enhancement of microvessel density analysis in combination with Gleason score and serum PSA to predict extraprostatic extension. METHODS: We evaluated a total of 186 randomly selected biopsy samples and matched totally embedded radical prostatectomy samples with preoperative PSA concentrations and patient demographics. Gleason score and optimized microvessel density (OMVD) were determined from the needle biopsy samples; pathologic stage was verified by independent review of the radical prostatectomy samples. An automated digital image analysis system measured microvessel morphology and calculated the OMVD in the biopsy samples (Biostage; Bard Diagnostic Sciences, Seattle, Wash). RESULTS: Prediction of extraprostatic extension was increased significantly when OMVD analysis was added to Gleason score and serum PSA concentration (P = 0.003). CONCLUSIONS: Optimized microvessel density analysis significantly increases the ability to predict extraprostatic extension of cancer preoperatively when combined with Gleason score and serum PSA concentration. This method appears to be a useful tool that can assist with treatment decisions in selected patients. PMID- 8693652 TI - Immunoassay and immunohistology studies of chromogranin A as a neuroendocrine marker in patients with carcinoma of the prostate. AB - OBJECTIVES: Neuroendocrine differentiation in carcinoma of the prostate is characterized by the expression of neuroendocrine cell products such as chromogranin A (CgA). We studied serum levels and tissue staining for CgA in prostate cancer to assess their clinical value. METHODS: In 82 patients with prostate cancer, serum specimens were obtained at diagnosis and studied by both CgA and prostate-specific antigen (PSA) immunoassays. In 43 additional patients with prostate cancer, paraffin-embedded tissue from core biopsies or transurethral resections and serum samples were studied, respectively, by immunohistology and immunoassay for CgA. RESULTS: In serum samples from the 82 patients in whom CgA and PSA levels were measured, 26 of 82 (32%) had an elevated CgA (greater than 200 ng/mL), and 36 of 82 (44%) had an elevated PSA (greater than 4.0 ng/mL). Of the patients with Stage D2 cancer, 11 of 18 (61%) had an elevated CgA and 6 of 18 (33%) had an elevated PSA. Four of 5 patients with local recurrence had an elevated CgA, but only 1 patient had an elevated PSA. Of the 43 patients in whom serum and tissue CgA studies were performed, 12 (28%) had elevated serum CgA, and 15 of the 43 (35%) had CgA staining in their prostate tissue. Of the 14 of these patients with D2 disease (distant metastases), 9 (64%) had elevated serum levels of CgA and 6 (43%) had positive staining in their prostate tissue. Of the 9 patients with Stage D2 disease and elevated serum CgA, 6 had a normal serum PSA. CONCLUSIONS: Our studies complement those of others and indicate that CgA has potential as a clinically useful serum and tumor marker for prostate cancer. Serum CgA measurements can identify some patients with advanced disease who do not have elevated serum PSA. However, further studies in larger groups of patients are needed to define the clinical value of CgA as a marker for prostate cancer. PMID- 8693653 TI - Effect of elective prolonged urethral catheterization on serum prostate-specific antigen concentration. AB - OBJECTIVES: To determine the effect of an indwelling catheter on prostate specific antigen (PSA) levels. PSA is an organ (prostate)-specific marker, and its level can be elevated in various pathologies as well as following urologic manipulations. An elevated marker may indicate the presence of prostate cancer. In the presence of an indwelling catheter, our inability to decide whether an elevated PSA value represents genuine pathology or is related to the catheter itself is often of great clinical importance. METHODS: A prospective study was conducted on 21 men with an indwelling catheter inserted electively for major nonurologic abdominal surgery to determine its influence on PSA concentration. Sera were collected before catheter insertion, 2 hours after, and then every day (average, 16 days). Catheters were left in place for an average of 5.5 days. RESULTS: Follow-up data compared to baseline and to the previous day's PSA concentrations revealed no significant change in any of the subjects. In 2 men with elevated preinsertion PSA levels (more than 10.0 ng/mL), the change over time did not differ in magnitude from changes in the other 19 men with normal pretreatment values. CONCLUSIONS: Inserting a urethral catheter and maintaining it for several days does not result in any clinically or statistically significant change in PSA levels. PSA values obtained in patients with an indwelling catheter are reliable and independent of its presence. An elevated level mandates prompt evaluation to exclude prostate cancer. PMID- 8693654 TI - Improving survival for patients with prostate cancer diagnosed in the prostate specific antigen ERA. AB - OBJECTIVES: Although prostate-specific antigen (PSA) screening has not been demonstrated to reduce prostate cancer mortality in the clinical trial or population setting, the use of PSA for screening increased during the early 1990's. A clinical trial is currently underway to test the efficacy of PSA screening; however, the results will not be available for at least 10 years. To address concerns about the effectiveness of PSA screening in the near term, population-based assessments of PSA screenings are needed. To reduce mortality, PSA screening must first produce improved survival. In New Mexico, increased screening was associated with a stage migration from distant to earlier stages and an increase in 5-year relative survival, suggesting that PSA screening may be effective. METHODS: To further investigate early indicators of the effectiveness of PSA screening in New Mexico, we examined temporal trends in survival for the period 1983-1992, using proportional-hazard models to estimate the risk of death by year of diagnosis, adjusted for age, stage, grade, ethnicity, and initial treatment. RESULTS: We found the risk of death following the diagnosis of local or regional-stage prostate cancer decreased in the 1987-1988 (relative-risk [RR] = 0.9 [95% confidence interval (CI) 0.8, 1.1]), 1989-1990 [RR = 0.9 [0.8, 1.0]), and 1991-1992 (RR =0.7 [0.6, 0.9]) periods compared with the 1983-1984 period. Men treated with radical prostatectomy were at increased risk between 1985 and 1990, compared with those treated in the 1983-1984 period. However, for men diagnosed and treated in the 1991-1992 period, risks were lower than in the 1983 1984 period (RR =0.8 [0.4, 1.5]). CONCLUSIONS: The earlier stage at diagnosis and the improved survival during the period of increased PSA screening are consistent with changes expected from an effective screening test and treatment modality. PMID- 8693655 TI - Vaginal approach to vesicovaginal fistula repair. PMID- 8693656 TI - Utility of chest radiography and cystoscopy in the evaluation of patients with localized prostate cancer. AB - OBJECTIVES: Candidates for radical prostatectomy have been frequently evaluated with chest radiography and occasionally with cystoscopy. The utility of these studies was assessed. METHODS: A retrospective review of 236 cases of radical prostatectomy performed over 5 years was conducted. Chest x-ray results were correlated with certain comorbidities believed to be risk factors for radiographic abnormalities, including hypertension, cardiac disease, pulmonary problems, and tobacco use. Cystoscopic findings were analyzed with regard to urologic history and urinalysis results. RESULTS: Chest radiography was normal in 208 (88.1%) and abnormal in 28 (11.9%) patients. All 28 patients with abnormalities had one or more of the aforementioned risk factors. Sixty-two individuals (26.3%) had no risk factors, and chest radiography was uniformly normal in this group. Cystoscopy was performed in 91 patients. State Ta transitional cell carcinoma of the bladder was detected in 6 of these patients (6.6%); these 6 patients all had either a history of this problem or hematuria. One individual had a mild bladder-neck contracture that did not warrant treatment. Endoscopic findings were normal in the remaining patients. CONCLUSIONS: Chest radiography is not routinely needed to evaluate radical prostatectomy candidates. It should only be performed in patients who have or are at risk for cardiopulmonary disease. Cystoscopy is not warranted in this setting unless there is clinical suspicion of other urologic pathology. PMID- 8693657 TI - Single focus of adenocarcinoma in the prostate biopsy specimen is not predictive of the pathologic stage of disease. AB - OBJECTIVES: To determine whether a very small focus of prostate cancer in a needle biopsy specimen correlates with organ-confined disease or with favorable disease parameters. METHODS: Of 598 needle biopsies of the prostate performed from January 1990 through June 1994, 49 specimens (8.2%) contained a microscopic focus (less than 2 mm in length of the entire biopsy core specimen) of adenocarcinoma. For these 49 patients, the clinical and pathologic features were correlated. RESULTS: Of these 49 patients, 27 (55.1%) underwent either radical prostatectomy, with or without pelvic lymph node dissection (26), or pelvic lymph node dissection alone (1). Seven of these 27 patients (25.9%) had extraprostatic disease: lymph node involvement (1), positive surgical margins (5), or seminal vesicle invasion (1). Ten of the 49 patients (20.4%) underwent radiotherapy, and 12 (24.5%) chose hormonal therapy. The pathologic stage for these 22 patients could not be ascertained. However, despite the limited amount of disease in the biopsy specimen, 2 patients treated with radiotherapy suffered a relapse (mean interval to recurrence, 11.5 months), and 3 patients treated with hormonal therapy (early or delayed) had bony metastasis at the time of diagnosis. Overall, 12 of the 49 patients (24.5%) had unfavorable disease (as defined by extraprostatic disease on pathologic specimen, relapse after radiotherapy, or bony metastasis at the time of diagnosis). CONCLUSIONS: These findings suggest that a microscopic focus of prostatic adenocarcinoma in a needle biopsy specimen, per se, does not predict the pathologic stage or the biologic behavior of a tumor. PMID- 8693658 TI - Positive surgical margins with radical prostatectomy: detailed pathological analysis and prognosis. AB - OBJECTIVES: To examine the extent and location of positive surgical margins and their influence on progression. METHODS: Two hundred fifteen consecutive radical prostatectomy specimens, using 2 to 3-mm step-sections, were reviewed. Particular attention was paid to the location and extent of positive margins. Seventy-three patients (34%) with one or more positive margins were subjected to further detailed analysis. Progression was defined as a serum prostate-specific antigen level greater than 0.1 ng/mL and rising. The mean follow-up period was 23.2 months; median 24 months (range 3 to 40). RESULTS: Margin-positive patients had a significantly higher biopsy tumor grape (P = 0.05) than did margin-negative patients. Capsular preforation was present in 75%, seminal vesicle invasion in 33%, and nodal metastases in 10% of margin-positive patients; in contrast, these tumor characteristics were present in 47%, 8%, and 1% of margin-negative patients, respectively. The extent of involvement of linked margins was focal in 22% and extensive in 66%. An equivocal margin identified as surgical incision into the specimen (due to hemostatic staples, surgical dissection, or retraction) was present in 12%. Seventy-one percent of patients had a positive margin at only one location. Of all 99 positive-margin locations, 40% were apical, 10% anterior, 8% bladder neck, 16% posterolateral, and 25% posterior. Thirty-four percent of margin-positive and 7% of the margin-negative patients demonstrated biochemical progression. Of the 36 patients with a positive margin as their only major risk factor for progression (seminal vesicle and lymph node negative, Gleason score less than 8), 25% have progressed. Progression occurred in 2 of 9 patients with an equivocal positive margin, and 5 of 16 with a single focal-positive margin. A multivariate analysis of margin-positive patients identified tumor volume and grade as the most significant predictors, with the location and extent of the positive margin not significant. CONCLUSIONS: Although more frequent at the prostatic apex, tumor at the inked margin at any location is a risk factor for postoperative biochemical progression. PMID- 8693659 TI - Anatomic approach for placement of surgical drains after radical retropubic prostatectomy: long-term effects on postoperative pain. AB - OBJECTIVES: The placement of drains following radical retropubic prostatectomy (RRP) may potentially damage neural and vascular structures within the abdominal wall, leading to postoperative pain and morbidity. In this study, we compare postoperative pain in two groups of men who underwent RRP. The Davol drains were either placed lateral to the rectus muscle (n = 100) or in the medial two thirds of the rectus muscle (n = 100). METHODS: We investigated postoperative pain for an average of 5 months after RRP. Detailed responses were obtained from 89.5% (179 of 200) of the men. The average age was 57 years and the average follow-up 20 weeks. RESULTS: Overall, 33.5% (60 of 179) of the men reported postoperative pain associated with either the incision or drain site. Rated on a scale of 0 to 10 (with 10 representing the most pain), the average pain scale assessment was 1.3 +/- 2.6 (range 0 to 6). Pain was attributable to the incision site only in 9% (16 of 179) and at the drain site only in 24% (42 of 179). We found more pain overall (41%) where the drains were placed lateral to the rectus muscle as compared with men in whom the drains were placed in the medial two thirds of the rectus muscle (26%) (P = 0.03). CONCLUSIONS: Placement of drains in the medial two thirds of the rectus muscles avoids injury to intercostal nerves and results in less pain at the drain sites. PMID- 8693660 TI - Urinary incontinence following external-beam radiotherapy for clinically localized prostate cancer. AB - OBJECTIVES: To determine the incidence of urinary incontinence in men with prostate cancer treated with definitive external-beam radiation therapy and to analyze the impact of various patient and treatment variables on the development of urinary incontinence. METHODS: The records of all 758 men who received definitive external-beam radiation therapy at our institution between October 1986 and December 1994 were reviewed. The development of incontinence was recorded and graded according to the Late Effects Normal Tissues/Radiation Therapy Oncology Group (LENT/RTOG) scoring system. RESULTS: Late grade 2 or higher urinary incontinence developed in 4 of 758 patients (0.5%) (3 grade 2; 1 grade 3). The actuarial urinary incontinence rate was 1.3% at 5 years. Patients with a history of prior transurethral resection of the prostate (TURP) had higher rates of urinary incontinence than patients without prior TURP (prior TURP 3 of 132 [2%] versus 1 of 626 [0.2%]; P = 0.02). CONCLUSIONS: Urinary incontinence following definitive external-beam radiation therapy for clinically localized prostate cancer is a rare event. Previous TURP increases the risk of incontinence, although the risk remains low. There is no evidence that higher doses to the prostate using conformal techniques are associated with an increased risk of urinary incontinence. PMID- 8693661 TI - [The effect of emissions from a mercury-processing metallurgy plant on the intensity of experimental Fasciola hepatica infection in sheep]. AB - A group of 14 improved Valashka lambs, aged 4 months, body weight 14-16 kg, were used in the experiment studying the effect of subchronic heavy metal intoxication on the course of experimental fasciolosis (Fasciola hepatica). The animals were divided into two groups, each of 7 lambs, 3 lambs--ewes and 4 lambs--rams. Each animal in group I was given orally for 27 days gelatinous capsules containing heavy metal emissions of the following composition: 4.5 mg Hg, 2.9 mg Pb, 147.8 mg Cu, 9.8 mg Zn, 0.9 mg Cr and 0.04 mg Cd per animal and day. Group II served as control. On Day 27, when the administration of heavy metals ceased, each animal in both groups received 250 F. hepatica metacercariae. The animals were sacrificed on Day 110 post infection, their liver necropsied and parenchymatous organs and muscles taken to examine the content of heavy metals. The heavy metal concentrations are presented in Tab. I. In the emission-intoxicated group, the maximum permissible reference level of mercury in the kidneys, liver and muscles was exceeded on the average by 1.94, 0.87 and 0.020 mg Hg/kg, respectively. Cu exceeded the reference level only in the liver, with 261.3 mg Cu/kg. In the kidneys and muscles, Cu was below the reference levels. An analogous situation was with Zn, Cr, and Cd. The F. hepatica infection mean intensity in this animal group was 38.3 +/- 3.01 specimens (min. 34 - max. 46 specimens). In control group, the heavy metal levels were several times lower than the reference values and the infection mean intensity was 27 +/- 5.4 (min. 19 - max. 35 specimens). In subchronically intoxicated animals, the reference values for mercury were exceeded and so were partially those of copper in the parenchymatous organs and muscles. The F. hepatica infection mean intensity also increased, compared with control. The results have proved the negative effect of the metal emissions on the animal immune system, which was manifested by the increased infection intensity. PMID- 8693662 TI - [Annual testing of immunity in foxes after oral rabies immunization]. AB - Ten young foxes were orally immunized with a "Rabies vaccine for oral immunization of foxes--LYSVULPEN por. a.u.v.," batch 69 10 93, commercially manufactured by the company Bioveta, s.r.o. at Ivanovice in Hana. The vaccine contained 1.8 x 10 of rabies vaccination virus, strain SAD-Bern, in a vaccination dose. Three foxes were used as control animals without vaccination. Blood samples were taken before the beginning of the experiment in all test foxes, and then in three-month intervals. The last blood samples were taken just before the beginning of a challenge experiment and two months after challenge in the foxes that survived. A challenge test was done in all foxes (vaccinated and nonvaccinated ones) a year after single oral immunization against rabies. Challenge virus was prepared from the salivary gland of a naturally infected fox living in the territory of the Czech Republic. Street virus was applied to each fox i.m. to a great depth to both masticatory muscles (musculus masseter) at a total dose of 10,000 MICLD50. The experimental animals were 60 days under observation. Tab. I shows the titers of virus-neutralizing rabies antibodies after oral immunization against rabies in all experimental foxes. Except fox no. 8, the formation of specific virus-neutralizing rabies antibodies was recorded in all animals after they had eaten vaccination baits. The antibodies were detected throughout the whole year of observation. Tab. II shows the results of challenge test. Out of the nine vaccinated foxes (fox no. 9 died before infection) only fox no. 8 died from rabies, the other treated foxes were protected from rabies (89% rate of protection). Tab. III presents the results of laboratory examination. Tetracycline was demonstrated in all treated foxes (a vaccination proof). Death due to rabies was demonstrated in control animals without vaccination and in fox no. 8. The results achieved in the Czech Republic for oral immunization of foxes against rabies with the vaccination strain SAD-Bern document very good efficacy of the vaccine manufactured by the company Bioveta, s.r.o., in Ivanovice in Hana since 1992. Oral immunization largely improved the infection situation in the Czech Republic. A total of 1,501 cases of rabies infection were recorded at the start of vaccination in 1989 while it was only 221 cases in 1994 (a decrease in then number of foci by 85%). PMID- 8693664 TI - [Czech veterinary publications in international data bases]. PMID- 8693663 TI - The effect of silymarin on concentration and total content of nucleic acids in tissues of continuously irradiated rats. AB - The effect of the hepatoprotective drug silymarin (Flavobion) on the radiation injury of rats continuously irradiated with gamma rays (60Co) was studied. The rats were irradiated during 14 days by the dose rates of 0.2 and 0.6 Gy/day. In the course of irradiation the animals were treated with silymarin twice daily (70 mg/kg p. o. by tube). Silymarin effect was evaluated on the basis of quantitative changes of nucleic acids in the regenerating liver (after 70% hepatectomy), spleen, bone marrow and blood. Silymarin administration in the course of continuous gamma irradiation influenced beneficially the radiation-induced changes of DNA and RNA especially in the bone marrow. PMID- 8693665 TI - Urinary iodine level as an intake indicator in dairy cows. AB - Urinary iodine concentrations were determined in 672 dairy cows of 22 herds. Less than 20 micrograms per L, 20 to 50 micrograms per L, 50 to 100 micrograms per L and more than 100 micrograms per L were found in 27.5, 24.6, 16.8, and 31.3% of the cows, respectively. In terms of the ICCIDD grading, moderate iodine deficiency was recorded in 68.9% and normal iodine intake in 31.3% of the cows. The mean urinary iodine concentrations were 94.8 micrograms per L at the peak of the lactation period (n = 300), 82.3 micrograms per L immediately before drying off (n = 122), 92.5 micrograms per L in the cows fed summer rations (n = 267), and 79.2 micrograms per L in those fed winter rations (n = 405). The differences in mean values were nonsignificant. Urinary iodine concentrations were examined in the herd LOS in cows fed iodine-supplemented (LOS E) or nonsupplemented (LOS C) rations. Mean concentrations were 316.2 micrograms per L for LOS E (n = 46) and 52.3 micrograms per L for LOS C (n = 41). The difference was highly significant (P < 0.01). The status of the group LOS C was classified as a medium iodine deficiency. The mean iodine concentrations at the peak of the lactation period and immediately before drying off were also significantly higher (P < 0.01) in this group. The supplementation of iodine resulted in an increase of urinary iodine concentration and, in terms of ICCIDD, the increase of iodine intake to the normal range. Normal intake and moderate, medium and serious deficits were found in three, two, one, and four herds, respectively. Special attention should be paid to herds showing higher grades of iodine deficiency. PMID- 8693666 TI - [Iodine deficiency in goats as a cause of congenital goiter in kids]. AB - The objective of the paper was to assess the occurrence of congenital struma in kids in relation to the clinical and biochemical finding in their mothers. Observations involved 46 imported goats of Saanen and Alpine breeds in the course of kidding and their kids. Thyroid gland hypertrophy (39 goats) and somewhat worse or even bad state of nutrition were dominant clinical findings in pregnant goats and in goats after kidding. Abortions in the last month of pregnancy were recorded in 14 goats, and 14 goats delivered stillborn kids. Eighteen goats delivered 26 liveborn kids, but 18 out of them died within 12 to 24 hours after birth. Dead kids were hairless, they had skin edema, and very shortened thoracic as well as pelvic limbs. The thyroid gland was well visible and palpable. Surviving kids lagged behind in their growth and often suffered from bronchopneumonia as an additional disease. Iodine concentration in the blood serum of goats (5.58 +/- 2.14 mumol/l) was significantly lower (P < 0.01) in comparison with kids (133.4 +/- 15.61 mumol/l). This state was characterized by adequate T3 and T4 concentrations in the blood serum of goats (1.78 +/- 0.59 and 4.53 +/- 4.44 nmol/l, resp.) and of kids (4.66 +/- 2.26 and 182.93 +/- 2.59 nmol/l, resp.). Iodine content in the thyroid gland of the seven kids that died was 1.86 +/- 0.96 mg/kg fresh tissue. Examination of indicators of the internal environment in the blood serum showed alternate statistical differences (P < 0.01) between adult goats and their kids in erythrocyte counts, hemoglobin, hematocrit value, leucocyte counts, activities of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, alkaline phosphatase, concentrations of total protein, albumin, total immunoglobulins, total lipids, cholesterol, phosphorus, copper, iron and zinc, while the explicit relation to disorders of iodine metabolism and thyroid hormones was not confirmed. The average content of iodine in the examined samples of soil (14.67 mg/kg) and alfalfa hay (0.1 mg/kg) demonstrated that primary deficiency of iodine in goats was the cause of congenital struma in kids. PMID- 8693668 TI - Survival of model bacterial strains and helminth eggs in the course of mesophilic anaerobic digestion of pig slurry. AB - The effect of methanogenesis on the survival of model bacterial strains (Escherichia coli EC 5, Staphylococcus aureus SA 11, Enterococcus faecium CCM 4231) and non-embryonated helminth eggs (Ascaris suum) was investigated in pig slurry. Two pilot-plant experiments were carried out in two anaerobic digesters (800 and 1,000 litre) in a mesophilic thermal range (35-37 degrees C). The mean hydraulic retention time of the digesters was 20 days. The methanogenesis process was monitored by determining the following chemical parameters: pH, N-NH3, total dry matter (kg/day), organic matter (kg/day) production of methane by supplied and degraded organic matter (m3/kg). The results obtained allow us to state that the anaerobic stabilization of pig slurry in the mesophilic temperature range resulted in total devitalization of model bacterial strains E. coli EC 5 and Ent. faecium CCM 4231. St. aureus SA 11 cells, exposed to the above mentioned conditions, were also reduced in their number from 10.04 to 3.27 and from 8.69 to 2.77 log cfu/ml. It is assumed that the longer retention time of excrements in the digester could also result in total devitalization of St. aureus SA 11 cells. From the microbiological point of view, the above mentioned facts indicate a sufficient hygienization effect of the anaerobic fermentation on the contaminated pig excrements. The survival of A. suum eggs was little affected by the 20-day anaerobic mesophilic digestion of pig slurry. Only 17 or 18% (F1, F2) of the non embryonated A. suum eggs were damaged after the 20-day exposure. PMID- 8693667 TI - Enhancement of antibody response to bovine herpesvirus 1 with non-specific immunostimulants. AB - Stimulatory effects of aluminium hydroxide, lipopolysaccharide (LPS), muramyldipeptide (MDP), and empty liposomes on the antigenicity of inactivated bovine herpesvirus 1 were tested in mice. Compared with the standard effect of aluminium hydroxide, stronger antibody responses were observed in mice treated with empty liposomes or LPS alone, or a combination thereof. The strongest antibody response was recorded in mice treated with a combination of inactivated BHV-1, MDP and empty liposomes. PMID- 8693669 TI - Interactions of Lactobacillus spp. and enteropathogenic Escherichia coli under in vitro and in vivo conditions. AB - In the present study, the effect of Lactobacillus spp. against enteropathogenic Escherichia coli 08:K88+Ent+ under in vitro and in vivo conditions has been compared and the effect of inoculation of Lactobacillus spp. upon the colonization of both the jejunum and ileum by enteropathogenic E. coli 08:K88+Ent+ in 9 gnotobiotic pigs has been observed. Under in vitro conditions, the strain Lactobacillus spp. showed the inhibition of 2.1 +/- 0.1 mm against enteropathogenic E. coli 08:K88+Ent+. Two days after the inoculation, the enteropathogenic E. coli 08:K88+Ent+, inoculated to the control group of gnotobiotic pigs (E), colonized the mucosa of both jejunum and ileum of gnotobiotic pigs at counts of 6.41 and 6.08 log 10/cm2, respectively. In experimental group (L-E), the counts of adhered enteropathogenic E. coli in the identical sections of the small intestine, following the inoculation by Lactobacillus spp., amounted to 6.35 and 6.43 log/cm2, respectively. In both groups, numbers of E. coli in the intestinal content of both jejunum and ileum were nearly the same (group E 9.03 and 9.31 log 10/ml; group L-E 8.97 and 9.11 log 10/ml). Two to five days after E. coli inoculation, Lactobacillus spp. counts adhered to the jejunal wall ranged from 5.4 to 6.49 log 10 cm2; in the ileum they ranged from 6.05 to 6.77 log 10 cm2. In the jejunal content, the lactobacilli counts ranged from 6.81 to 8.86 log 10/ml and in the ileum from 8.5 to 898 log 10/ml. Two days after the E. coli inoculation, the concentration of lactic acid in the content of jejunum in gnotobiotic pigs of the groups E and L-E was 16.3 mmol/l and 23.6 mmol/l, respectively. The concentration of acetic acid in the jejunum of the pigs of E and L-E groups was 15.9 mmol/l and 19.6 mmol/l, respectively. Similarly, the higher concentrations of both acids were found also in the ileum of the L-E pigs. The results obtained indicate that the used strain of Lactobacillus spp. which has been preventively inoculated to gnotobiotic pigs, did not prevent the adhesion of enteropathogenic E. coli 08:K88+Ent+ to the mucosa of both jejunum and ileum also despite of the demonstrated inhibitory effect against enteropathogenic E. coli under in vitro conditions and despite good adherent ability in vivo. In both groups of animals, the diseases with pronounced clinical signs as well as losses have occurred. PMID- 8693670 TI - [Immobilization in alginate gels]. AB - Summarization of literary data on immobilization in calcium alginates as published in the last two years. The review focuses on those papers in which the new knowledge of immobilized enzymes, cells and tissues expands their biotechnological applications. PMID- 8693671 TI - LVIs and certification. PMID- 8693672 TI - Comparison of arthroscopy and arthrotomy for the treatment of osteochondritic lesions in the femoropatellar joint of horses. AB - Forty-eight horses with osteochondritic lesions of the femoropatellar joint were treated, 23 of them by an arthrotomy and 25 by arthroscopy. Follow-up information was obtained from either the owner or the referring veterinarian by telephone inquiry. There were no statistical differences between the groups of horses undergoing the two procedures with regard to age, sex, breed, the involvement of one or both limbs, the size of the lesion, and the duration of either the surgery or anaesthesia. However, the horses treated by an arthrotomy spent 14.5 days in hospital after the operation whereas those treated by arthroscopy spent only three days. Nineteen of the horses treated by arthroscopy were able to pursue athletic activities and a further five were expected to enter training in the future, whereas only 12 of the horses treated by an arthrotomy were suitable for their intended use (P < 0.05). When the severity of the lesions was considered, the success rate after an arthrotomy deteriorated with increasing severity, whereas the success rate after arthroscopy remained at a high level. Fourteen of the 16 owners of horses treated by an arthrotomy who replied to the question considered that the horses had a palpable scar, a femoropatellar effusion or both, whereas only two of the horses treated by arthroscopy (8 per cent) were considered to have had a poor cosmetic outcome (P < 0.05). PMID- 8693673 TI - Failure of exit-race teat spraying to control Corynebacterium bovis colonisation. AB - When an automated exit-race teat sprayer replaced a conventional teat dip cup for the application of a disinfectant containing 0.5 per cent iodine, there was an increase in the level of intramammary infection by Corynebacterium bovis at drying off from approximately 25 per cent of quarters to approximately 75 per cent of quarters. When the peak level of infection had been reached half of the clinical mastitis in the herd was caused by C bovis, and these were recurrent and chronic infections. There was some evidence that the increase in C bovis infection increased the bulk milk cell count. There were no changes in the rates of infection by major pathogens or by coagulase-negative staphylococci, another important secondary pathogen. The reintroduction of teat dipping rapidly reduced the rate of mastitis infection and the level of infection was reduced to approximately 20 per cent of quarters in about 12 months. PMID- 8693674 TI - Comparison of topical cyclosporin and dexamethasone for the treatment of chronic superficial keratitis in dogs. AB - Thirty dogs with chronic superficial keratitis (CSK) were randomly assigned to treatment with 0.2 per cent cyclosporin ointment or 0.1 per cent dexamethasone drops. They were treated for six weeks and examined before and after three and six weeks of treatment, and then every three weeks without treatment until the lesions recurred. The regression of the disease during the treatment and the time to a recurrence after the cessation of treatment were determined. Changes in the size of the corneal lesions were measured by image analysis of photographs taken at each examination, and the severity of adnexal changes such as conjunctival hyperaemia was assessed by means of a scoring system. Clinical evaluations suggested that both drugs were equally effective as treatments for CSK and a statistical analysis showed that they had reduced the size of the lesions to the same extent at each examination. There was a significant increase in tear production, measured by the Schirmer tear test, during the treatment with cyclosporin. PMID- 8693675 TI - Persistent activity of ivermectin topical and moxidectin injection against Ostertagia ostertagi and Dictyocaulus viviparus in calves. PMID- 8693676 TI - Antigenic characterisation of avian paramyxoviruses serotype 4 isolated from wild mallard (Anas plathyrinchos) in Israel. PMID- 8693677 TI - Acute encephalopathy and hyperammonaemia in a horse without evidence of liver disease. PMID- 8693678 TI - Development of a rapid screening test to detect beta-agonist residues in bovine eye and hair. PMID- 8693679 TI - Severe foul-in-the-foot and BVD infection. PMID- 8693680 TI - Yeast infection in ferrets. PMID- 8693681 TI - Due recognition. PMID- 8693682 TI - Origin of BSE. PMID- 8693683 TI - Experiences with acute organophosphate poisonings in Crete. AB - Nine human acute poisonings due to intentional ingestion of organophosphorous pesticides are presented. Six of the victims died. Six patients were treated in the Intensive Care Unit (ICU) from 34 h to 45 d, while 3 were found dead by relatives. Two of the patients treated in the ICU fully recovered after 15 and 24 d while the third survivor developed delayed neuropathy. Organophosphate blood levels were determined on admission and during therapy, and in 1 case atropine and pralidoxime levels were also detected. Significant fluctuations of the plasma cholinesterase activity were observed during therapy. Postmortem analysis revealed higher levels of pesticides in organs (eg 23.1 micrograms fenthion/g kidney) and in fat (135.2 micrograms fenthion/g) than in blood (eg 4.8 micrograms fenthion/ml) and vitreous humor. Considerable pesticide was measured in testis (eg 5.8 micrograms fenthion/g, 0.8 micrograms methidathion/g) and uterus (170.5 micrograms malathion/g). Extracorporeal decontamination to enhance pesticide elimination is a therapeutic challenge. PMID- 8693685 TI - Experience with acute paraquat poisoning in Crete. AB - Ten cases of acute paraquat poisonings with lethal (n = 5) and non-lethal (n = 5) outcomes are presented. Paraquat plasma and urine levels of the patients on admission (from 2 to 41 h after ingestion) at the peripheral hospitals varied from 0.4 to 6.0 and 0.5 to 12.8 micrograms/ml, respectively. Besides standard supportive treatment, hemoperfusion/hemodialysis and/or plasmapheresis were performed for therapy, which in 1 case lasted for 28 d. The pharmacokinetic data from patient paraquat elimination confirmed considerable paraquat rebound from tissues to blood circulation and marked the need for continued therapy even with undetectable paraquat plasma levels. Postmortem analysis showed that while paraquat was mainly distributed in kidney (807 micrograms/g), lung (479 micrograms/g) and liver (206 micrograms/g), amounts were also detected in thyroid (64 micrograms/g), testis (21 micrograms/g), vitreous humor (45 micrograms/ml) and cerebrospinal fluid (7.4 micrograms/ml). Paraquat crossed the placenta and concentrated there to higher levels than in the mother's blood. The fetus seemed to tolerate the mother's paraquat intoxication while dependent on placental circulation. PMID- 8693684 TI - Clinical experience in poisonings following exposure to blasticidin S, a curiously strong fungicide. AB - The fungicide blasticidin S has been used against a rice blast disease. Reports on its human toxicity are extremely limited, and irritation to GI tract, eye and skin are the presenting symptoms in most afflicted cases. Fatalities resulting from profuse intestinal fluid loss with subsequent hypotension have also been recorded. In an attempt to delineate the clinical pictures of blasticidin S poisoning, a retrospective study covering an 8.5-y period was then conducted. A total of 28 blasticidin S poisoning exposures, including 24 suicidal ingestions, were recorded. The ingested amounts in most cases were rather large, while 2 cases were found with estimated dosages up to 10 g. The presented symptoms in most cases were immediate vomiting, abdominal pain, diarrhea and sore throat which were resolved after conservative treatment. Nevertheless, hypotension, arrhythmia, acrocyanosis, aspiration, and even coma occurred in severe cases. Fatalities were noted in 5 patients, in whom profound hypotension and severe aspiration pneumonitis were the main features. Poisoning following blasticidin S ingestion remains a challenge to acute health care physicians. Adequate administration of i.v. fluid and careful monitoring of electrolytes have been considered as the mainstay in the treatment of blasticidin S poisoning. Prevention of aspiration and ventilatory support are also crucial for life-saving since poisoning cases might succumb after massive aspiration. PMID- 8693686 TI - Cisapride toxicosis in dogs. AB - Cisapride is an oral prokinetic agent used to facilitate or restore motility in the gastrointestinal tract. The National Animal Control Center has received 17 reports of accidental overexposure of dogs to cisapride since 1994. Doses of 640 mg/kg in dogs were reported to be lethal, but severe clinical signs have been noted at acute exposures as low as 18 mg/kg. The most common signs include diarrhea, muscle tremors and fasciculations, ataxia and incoordination, and hyperthermia. Available treatment is symptomatic and supportive. Activated charcoal is effective in reducing plasma cisapride levels. PMID- 8693687 TI - Medicated oils and severe salicylate poisoning: quantifying the risk based on methyl salicylate content and bottle size. AB - In Hong Kong, medicated oils containing methyl salicylate account for 48% of acute salicylate poisoning cases treated in the general medical ward of the Prince of Wales Hospital. To quantify better the risk to average persons who have intentionally ingested these medicated oils, the methyl salicylate content and bottle size of 7 commonly available formulations were examined. Koong Yick Hung Far Oil had the highest methyl salicylate content (67%) and was available only in 60-ml bottles. If the entire bottle of this product were ingested, the equivalent of 184 adult 300-mg aspirin tablets would have been swallowed. Accidental ingestions of as little as 6 ml of Koong Yick Hung Far Oil by a child can be fatal. Six other products contained 15-40% methyl salicylate and their biggest bottle sizes range from 28-57 ml. Among medicated oils commonly found in Hong Kong, Koong Yick Hung Far Oil poses the greatest threat for severe salicylate poisoning if swallowed because of its high salicylate content and its availability in 60-ml bottles. The threat from medicated oils can probably be reduced by restricting their bottle size and methyl salicylate concentration. Physicians and clinical toxicologists should appreciate the toxic potential of these products. PMID- 8693688 TI - The effect of feeding dried tomato vines to beef cattle. AB - Dried Tomato vines (DTV) are used as a feedstuff in some beef cattle in Israel, despite the literature citation that tomato vines contain potentially harmful steroid alkaloids. A small-scale feeding trial over 42 d examined possible deleterious effects of feeding DTV, compared with wheat straw, in beef cows. No differences in hematological values, serum parameters for body weight were seen between the 2 groups. Steroid alkaloid content of the DTV was not examined, but toxic levels of nitrates were found. The main practical hazard in feeding DTV would appear to be from their potentially high nitrate content. PMID- 8693689 TI - Re-engineering regional poison control center services. AB - In summary, I propose a model of poison control service delivery to replace poison control centers. A handful of financially self-sustaining poison consult centers would remain. All other services would be provided by health plans to their members, including those covered under State-funded managed care. The need for continued fundraising efforts would be eliminated. Rather than devoting large sums of money to consolidate the State's 6 centers into 1 large center, I encourage Blue Cross of California to fund the protocol development process that will drive a true restructuring effort for poison control services. In our hearts, if our goal is to ensure continued service provision, then let's take the initiative to re-engineer the way we do business. The risks of doing nothing more than seek continued funding for the existing service delivery model should be painfully obvious by now. If your individual goals include survival for your center, then there's great news. The demand for call centers providing a wide range of advice services is approaching a critical level. Most health and hospital systems are moving to a managed care environment. Health care delivery is quickly moving out of the hospital to ambulatory services. Telemedicine is here--and growing very quickly. Distance learning technology is knocking at the door. There is plenty to do. With sound strategic development, your center will survive--it just won't look or feel the same as its does today. Survival the way it used to be ...uh, except for the computers and stuff. PMID- 8693691 TI - The effect of 6-aminonicotinamide on testicular development in the rat. AB - 6-Aminonicotinamide (6-AN), a niacin antagonist, was administered sc to pregnant female (1.0, 3.0, or 6.0 mg 6-AN/kg body weight) and neonatal male (1.5, 3.0, 6.0 or 12.0 mg 6-AN/kg body weight) Sprague-Dawley rats on the 15th, 17th and 19th days of gestation or the 5th, 7th and 9th days of life, respectively, to determine the effects of the antimetabolite on testicular morphology and development. In prenatal males, microscopic alterations were present in testes of fetuses from females treated with 6.0 mg 6-AN/kg and consisted of necrosis and loss of gonocytes, and vacuolation of interstitial cells. Histologic changes in testes of neonatal rats treated with 3.0, 6.0 or 12.0 mg 6-AN/kg were qualitatively similar with necrosis and loss of spermatogonia and supporting cells, and increased cross-sectional areas of affected tubules. Quantitation of the number of nuclei/cm2 of seminiferous tubule indicated 6-AN caused a significant reduction in the numbers of supporting cells and spermatogonia/tubular cross-section. PMID- 8693690 TI - Hematological alterations in propylene glycol-dosed female rats are minimal. AB - The effect of a single oral dose of 73 or 294 mg propylene glycol/100 g bw, in Group I or II respectively, on hematological parameters, plasma osmolality and erythrocyte morphology was investigated in groups of 6 female rats each at different time intervals after dosing. A statistically significant and progressive decrease was observed in hemoglobin, packed cell volume and red cell counts for 2 d, which returned to basal values on the 8th day. Reticulocyte counts, plasma hemoglobin and osmolality increased after PG dosing in both the groups, and the changes were more pronounced after 2 d. The osmotic fragility of erythrocytes remained unaffected after PG dosing whereas electron microscope morphology revealed rough cell surface, ruptured membranes and increased cell adherence throughout the observation period, but these features were not marked on the 8th day. These modified red cell surface characteristics could promote removal by the reticulo-endothelial system resulting in the significant increases in spleen weight in both groups. PMID- 8693692 TI - Putative effect of silymarin on sawfly (Arge pullata)-induced hepatotoxicosis in sheep. AB - The prevention of hepatotoxicity from sawfly larvae (Arge pullata) was studied in 8 lambs by using silymarin, a botanical compound isolated from Silybum marianum. Of 2 lambs dosed orally with larvae only, 1 had a marked toxic response whereas the other responded poorly as judged from clinical parameters, blood biochemistry and pathology. Two lambs treated with penicillin, glucose and silymarin 7 and 24 h after larvae dosing were not affected by toxicosis, whereas 2 lambs treated similarly but without silymarin responded intermediate to the other 2 groups. Our study suggests a favorable effect using silymarin in treatment of sawfly larvae induced ruminant hepatotoxicosis. PMID- 8693693 TI - Delay among the general public in telephoning a poison center. AB - Delay in seeking treatment for poisonings can hinder patient recovery. Our study examined delay in notifying a poison center about green tobacco sickness (GTS), a form of nicotine poisoning resulting from dermal contact with tobacco leaves. We conducted a follow-up survey of 55 cases of GTS reported by telephone to the kentucky Regional Poison Center in 1993. The "delay" group (38.2% of the cases) was defined as those callers who stated in the follow-up report that they should have phoned the poison center sooner than they did. Characteristics of the callers who delayed and the GTS patients they reported were compared with characteristics of the "non-delay" group. Delay was associated with callers' awareness of the poison center's expertise in agricultural poisonings and with age and sex of the patient. Our findings point to the need to target groups such as farmers with an educational campaign to make them more aware of the extent of the poison center's services and to encourage timely reporting of occupational poisonings. PMID- 8693694 TI - Iron complexation with oral deferoxamine in a swine model. AB - A controversial therapy in the management of acute iron poisoning is the oral administration of deferoxamine which purportedly complexes unabsorbed iron, exerts protection at the cellular level, and/or enhances the renal elimination of ingested iron. To study the effects of oral deferoxamine on iron absorption, fasted male pigs weighing an average of 10 kg simulated potentially toxic iron overdoses in 12 to 24-mo-old children. A control group of 13 pigs received 60 mg elemental iron/kg via oral gavage followed by 50 ml of distilled water. Serum iron (SI) levels were obtained at 0, 1 2, 4, 6 and 8 h post-iron dosing. The study group of 10 pigs received 60 mg elemental iron/kg po followed by 10 g deferoxamine (1 g/kg). SI levels were obtained at the same intervals. There was no mortality in either group. Statistical differences in SI were noted at 6 and 8 h. Characteristic urine discoloration secondary to deferoxamine was noted at 4 h in the study group. Deferoxamine reduced some peak 51 levels but did not diminish the total absorption of iron. PMID- 8693695 TI - Lithium toxicosis in a cow. AB - A case of lithium toxicosis is described in a cow that had consumed grease. Clinical signs included increased salivation, ataxia, reduced consciousness, seizures and diarrhea. No treatment was instituted. The grease did not contain high concentrations of other heavy metals or minerals. PMID- 8693696 TI - Comparison of performance and mortality in the hybro normal and hybro giant meat poultry breeders and their offspring. AB - The performance and mortality of similarly managed parent flocks of Hybro Normal and Hybro Giant meat poultry was compared. The overall daily egg production at 6 9 months of age was insignificantly greater in the Hybro Normal compared to the Hybro Giant parents (p > 0.05). The Hybro Normal parents had a significantly higher average daily egg production (56.08%) compared to that of the Hybro Giant parents (52.03%) during their sixth month of age, one month before the production peak (p < 0.05). The Hydro Giant parent-males had a significantly higher average daily mortality during the sixth and seventh months of age compared to the parent males of the Hybro Normal breed (p < 0.05); however, the females of the Hybro Normal parents had a significantly higher daily mortality during the sixth month of age compared to the Hybro Giant parent females (p < 0.05). The percentage hatchability was significantly lower in eggs collected from Hybro Giant birds compared to those collected from the Hybro Normal birds during the sixth and ninth months of age. The mean live weights at 45-days old of five flocks of Hybro Normal offspring was 1535 g compared to a mean live weight of 1870 g of five similarly managed flocks of the offspring of the Hybro Giant birds (p < 0.05). The feed conversion by the offspring of both breeds was not significantly different (p > 0.05). The mean percentage lameness in the five flocks of the offspring was 2.34% for Hybro Normal and 9.26% for Hybro Giant (p < 0.05). In summary, the overall performance of the Hybro Normal parent stock was superior to the Hybro Giant breeders regarding egg production and hatchability of their eggs; however, the weight gain of the Hybro Giant broiler flocks was superior to that of the Hybro Normal, but this was associated with a higher incidence of lameness. PMID- 8693697 TI - The early development of mouse embryos in vitro in medium supplemented with different batches of serum and bovine serum albumin. PMID- 8693698 TI - Quantitative capillary reversed passive latex agglutination test for C-reactive protein (CRP) in the dog. AB - A capillary reversed passive latex agglutination test (capillary RPLA) was developed which allows quantification of serum C-reactive protein (CRP) within approximately 15 min. The logarithmic regression line (calibration curve) obtained after measuring each CRP concentration three times in twofold dilutions of a standard canine serum containing 222 micrograms/ml of CRP was y = 6.394 + 0.030x (r = 0.995). Capillary RPLA permitted quantification of CRP in the range 6.9-222 micrograms/ml. The coefficients of variation ranged from 10.28% to 12.40%. The recovery rates (percentage recovery) of CRP by capillary RPLA were within the range 87% to 106%. On measuring the CRP concentrations in sera from 78 dogs by capillary RPLA, single radial immunodiffusion (SRID) and enzyme-linked immunosorbent assay (ELISA), close correlations were demonstrated between SRID and capillary RPLA (y = 7.250 + 1.109x, r = 0.978), between SRID and ELISA (y = 3.042 + 1.059x, r = 0.967), and between capillary RPLA and ELISA (y = 1.778 + 0.929x, r = 0.962). Capillary RPLA may be considered useful as a routine biochemical technique for measurement of serum CRP concentration in the dog. PMID- 8693699 TI - The effects of early-season treatments with doramectin on set-stocked calves naturally exposed to trichostrongyles. AB - A study was carried out to evaluate the effects of strategic early-season treatments with doramectin on first-season grazing calves exposed to trichostrongylid infection on a naturally contaminated pasture. Two groups of cross-bred Limousine/Red Danish calves were turned out in early May on two plots that were similar with respect to size and herbage infectivity. They grazed separately until housing in early October. One of these groups was given doramectin at turnout and 10 weeks later, while the other group served as untreated controls. The results showed that the treatments significantly reduced trichostrongylid loads throughout the season, as evidenced by significant reductions in both their Ostertagia ostertagi burdens and serum pepsinogen levels compared with the controls. Furthermore, the results of herbage larval counts and post-mortem worm counts in tracer animals demonstrated that the treatment had successfully suppressed herbage infectivity on the 'treated' plot. PMID- 8693700 TI - Hepatozoon canis: the prevalence of antibodies and gametocytes in dogs in Israel. AB - A survey for the prevalence of antibodies to Hepatozoon canis and for intraneutrophilic H. canis gametocytes in the peripheral blood neutrophils of dogs in Israel showed that 33.1% were seropositive, while only 1% of the dogs sampled had detectable parasites in their blood smears. Exposure to H. canis is widespread but it appears that most infected dogs undergo a subclinical infection and only a small proportion develop clinical disease. PMID- 8693701 TI - Ruminal, cardiorespiratory and adrenocortical sequelae of Na2EDTA-induced hypocalcaemia in calves. AB - A study was undertaken to provide further information on the ruminal, cardiorespiratory and hypothalamo-pituitary-adrenocortical (HPAC) physiological sequelae of hypocalcaemia in dairy calves. The functional picture observed in standing calves experiencing Na2EDTA-induced progressive hypocalcaemia showed a biphasic pattern. During the first phase (Ca2+ varying between 1.20 +/- 0.09 and 0.64 +/- 0.15 mmol/L, mean +/- SD), the animals became dull and lethargic, shifting their weight from one hind limb to the other, with cool extremities and hypersalivation. Their ventilation was slightly increased but their heart rate, thoracoabdominal pressure, pulmonary mechanics, haemoglobin and temperature remained constant. Conversely, their systemic arterial pressure (SAP) and the amplitude of their ruminal contractions (RCA) were severely decreased. During the second phase (Ca2+ < 0.64 +/- 0.15 mmol/L), there was restlessness, tachycardia, hypertension, polycythaemia and, finally, inability to stay upright. It is suggested that the diminished Ca2+ availability caused smooth-muscle and myocardial dysfunctions which could explain the RCA and SAP changes recorded during the first phase, whereas neural and/or humoral sympathetic discharge probably accounted for the reversal in SAP and heart rate when Ca2+ was decreased further. Serum cortisol increased regularly and remained significantly correlated with Ca2+ in each animal. Moreover, regression of delta cortisol/delta Ca2+ on delta Ca2+/delta Na2EDTA was significant (p < or = 0.001). It was concluded that mild asymptomatic hypocalcaemia severely impairs ruminal function, which will progressively worsen the Ca2+ deficit; that the inability to maintain posture in hypocalcaemia is not due to hypotension; and that the higher the HPAC response to hypocalcaemia, the higher the resistance to its effects. An asymptomatic periparturient cow with barely detectable ruminal activity may merit preventive calcium borogluconate therapy. Also, the physiological role of hypotension in explaining the clinical picture may be less important than other processes, such as neuromuscular failure. Finally, the present results imply a possible HPAC exhaustion in cows with periparturient paretic hypocalcaemia. PMID- 8693703 TI - Clinico-pathological studies on the effect of different anti-neoplastic chemotherapy regimens on transmissible venereal tumours in dogs. AB - Thirty-two dogs affected with transmissible venereal tumour (TVT) were divided into three treatment groups. In group I vincristine sulphate at 0.025 mg/kg body weight, in group II vinblastine sulphate at 0.150 mg/kg body weight, and in group III vinblastine sulphate at 0.100 mg/kg body weight plus methotrexate at 0.35 mg/kg body weight were given intravenously at weekly intervals. Biopsies were performed on days 0, 3, 7 and 14. The tissues were preserved in 10% neutral buffered formalin and processed routinely for haematoxylin and eosin staining. Histopathologically, the untreated TVT was characterized by sheets or bundles of mostly rounded cells having a large, highly basophilic nucleus with a prominent, highly basophilic necleolus. Both vincristine and vinblastine primarily affected the nuclei of neoplastic cells, causing condensation, karyorrhexis and karyolysis within 3 days of chemotherapy. The regressing tumour mass showed marked infiltration by lymphocytes, lymphoblasts and macrophages by day 7. There was nearly complete regression of the tumour by day 14, as shown by the almost complete loss of neoplastic cells, with fibrous tissue substitution. However, in group III, the changes occurred more slowly and more injections were needed for complete regression. In both groups I and II, 11/12 of the animals responded completely to the chemotherapy within 3 weeks, while in group III, 6/8 of the dogs responded to the treatment by 21-28 days. PMID- 8693702 TI - The vasomotor effects of 5-hydroxytryptamine on equine basilar arteries in vitro. AB - The vasomotor effects of 5-hydroxytryptamine (5-HT) on isolated equine basilar arteries were studied. 5-HT induced contractions of equine basilar arteries in a concentration-dependent manner, with a pEC50 value (with 95% confidence limits) of 7.35 (7.08-7.62). Similar results were obtained with endothelium-denuded basilar arteries. Contractions were not competitively inhibited by the 5-HT2 receptor antagonist ketanserin at low concentrations of 5-HT. Conversely, at high concentrations of 5-HT, contractions were inhibited by ketanserin in a concentration-dependent manner, with a pA2 value of 8.91 (8.62-9.20). The 5-HT1 and 5-HT2 receptor antagonist methiothepin shifted the concentration-response curve of 5-HT downwards and to the right in a concentration-dependent manner. In the presence of 10(-6) mol/L ketanserin, however, methiothepin antagonized 5-HT induced contractions competitively with a pA2 value of 7.95 (7.59-8.31). The 5 HT3 receptor antagonist MDL 72222 had no effect on 5-HT-induced contractions. The findings of this study indicate that 5-HT1 and 5-HT2 receptors are located in equine basilar arterial smooth muscle cells, and that stimulation of these receptors results in contraction. PMID- 8693705 TI - The detection of subclinical mastitis in the bactrian camel (Camelus bactrianus) by somatic cell count and California mastitis test. AB - Milk samples (n = 160) from 7 clinically healthy bactrian camels were cultured to detect subclinical udder infection. The samples were assessed by the Californian mastitis test (CMT) and somatic cell count (SCC). Bacteria were recovered from 36 (22.5%) of the milk samples. Staphylococcus aureus and coagulase-negative staphylococci (CNS) were the main organisms found. Infected quarters had significantly higher mean values for the SCC (p < 0.01) and CMT (p < 0.001) than non-infected quarters. All 7 camels were infected with CNS but only 4 with S. aureus. CMT values for S. aureus-infected camels were significantly higher than for those only infected with CNS. The values for SCC and CMT were significantly influenced by the stage of lactation (p < 0.05). No significant difference was found from the effect of the quarters. Both SCC and CMT were of value in predicting the infection status of the udder. PMID- 8693707 TI - [Microalbuminuria in patients with glomerulonephritis in remission]. AB - The authors focused their attention on residual changes in patients with glomerulonephritis who have a zero or only "physiological" proteinuria (under 0.15 g/24 hours), normal or slightly elevated s-creatinine and who do not suffer from hypertension. In these patients microalbuminuria in urine per 24 hours was assessed. Patients with albuminuria under 20 micrograms/min were included in the group with normal albuminuria (13 patients) and patients with albuminuria of more than 20 micrograms/min in the microalbuminuric group (11 patients). The two groups did not differ significantly as to age, sex, duration of the disease, maximum levels of proteinuria and s-creatinine values at the onset of the disease. S-creatinine and blood pressure values at the time of investigation were also comparable. The groups differed, however, significantly as to the period of "absolute" remission which the authors defined as the period during which proteinuria did not exceed the "physiological" limit. This period was in the normoalbuminuric group significantly longer--on average 5.1 years--while in the microalbuminuric group it was 2.1 years (difference at the 1% level of significance). PMID- 8693704 TI - Lymphoid leukosis viruses, their recognition as 'persistent' viruses and comparisons with certain other retroviruses of veterinary importance. AB - Diseases caused by lymphoid leukosis virus (LLV), a retrovirus, take a long time after infection to develop and have a wide variety of pathological manifestations. This long latent period is characteristic of 'persistent virus infections'. Disease produced by LLV infection and its underlying mechanisms is compared with 'persistent' infections caused by other retroviruses in birds and mammals of veterinary importance. The diseases considered for comparison are those caused by reticuloendotheliosis, feline leukaemia, bovine leukosis and equine infectious anaemia viruses. There are significant changes in the immunological status in all diseases caused by these viruses. LLV infections follow this trend with, in manifestations of neoplastic disease, a perturbation of the normal switch that occurs from IgM to IgG synthesis. There are also indications of other immunological disturbances. Factors other than immunological disturbances may contribute to the length of time after infection required for the many forms of LLV infection to appear. Such additional factors may include the operation of 'biological clocks', such as the arrival of sexual maturity, and also the very nature of retroviruses. These factors, like the immunological changes, play major roles in the maintenance and progression of persistent retrovirus infections. PMID- 8693706 TI - [Treatment of hypertension with a fixed combination of bopindolol and chlorthalidone (Sandoretic)]. AB - A multicentric, prospective, 16-week open study evaluated the effectivity and tolerance of the fixed combination of the beta-blocking agent bopindolol with the diuretic chlorthalidone--Sandoretic in 81 patients with mild to moderate hypertension. The combination of these two drugs is appropriate, since both drugs have long-term effects. Sandoretic induced a decrease of the mean sitting initial systolic blood pressure of 162.5 +/- 16.5 mmHg to 134.2 +/- 12.8 mmHg at the end of the study, a decrease of 28.3 mmHg. Diastolic blood pressure decreased after 16 weeks of treatment from the initial value of 103.9 +/- 4.9 mmHg to 85.3 +/- 6.0, a decrease of 18.6 mmHg. Changes of the standing systolic and diastolic blood pressures were of similar magnitude. Sandoretic treatment led to a normalization of the diastolic blood pressure (90 mmHg and lower) in 80.3% of patients. In 49.4% of patients treatment with Sandoretic led even to a diastolic blood pressure of 85 mmHg and lower and 29.6% patients had at the end of treatment diastolic blood pressure 80 mmHg and lower. Tolerance of the drug was excellent in 75.3% patients. Sandoretic induced a mild, however, significant decrease of potassium plasma levels. The increase of the uric acid plasma level was also significant. Monitoring of potassium plasma levels is therefore necessary during the treatment with Sandoretic. In patients showing a decrease of the potassium plasma level, potassium sparing diuretic-amiloride should be added or the dosage of the drug should be halved. PMID- 8693708 TI - [Lactilol (Importal, 10g in powder made by ZYMA) in the treatment of portal systemic encephalopathy]. AB - In a group of 15 patients with portal systemic encephalopathy (PSE) associated with cirrhosis of the liver with portal hypertension and spontaneous systemic shunt of the portal circulation the authors administered Lactitol (Importal, powder a 10 g Zyma), in amounts up to 40 g/day for a period of 56 days. In the course of treatment every patient was repeatedly examined before the onset of treatment and three times during treatment. The grade of PSE was assessed on the basis of the score of the neuropsychiatric examination from which the PSE index was worked out. In the investigated group of patients with PSE the authors found a significant improvement of the PSE index during treatment with Importal Zyma. The mental condition of the patients improved, the NCT period was reduced, asterixis receded, on the EEG the delta and theta activity receded and normal alpha activity developed. The serum ammonia levels declined but did not reach statistical significance. During treatment the authors did not record changes of normal values of glucose, sodium and potassium in serum and did not detect any adverse side effects. Based on the assembled results the authors conclude that lactitol treatment extends possibilities of PSE treatment. PMID- 8693709 TI - [Personal experience with 200mg of micronized fenofibrate (Lipanthyl 200 M) in the treatment of primary dyslipidemias]. AB - Micronized phenofibrate 200 mg was administered in clinical trial to 30 patients with dyslipidaemia. Their average age was 51.9 years (10 with type 2a, 12 with type 2b and 8 with types 4 and 5). After 12 weeks of treatment significant improvement of the whole lipid profile was achieved. The total cholesterol declined in different sub-groups by 16, 17 and 20% resp. LDL cholesterol declined by 20 and 18 per cent in types 2a and 2b, in types 4 and 5 it was not assessed (it was not possible to use Friedewald's equation). Triglycerides declined by 39, 45 and 75%. The HDL concentration increased by 16, 27 and 25%. The atherogenic indexes TCh/HDL-Ch declined by 28, 36 and 32%. LDL-Ch/HDL-Ch dropped by 30 and 34%. The extent of the hypolipidaemic effect depended on the baseline value: the more pathological the baseline value, the more marked the improvement. As to other investigated indicators there was a significant rise of the apolipoprotein AI and Lp AI particle concentration. Apoprotein B declined insignificantly. Uric acid declined significantly by 28%. Fibrinogen dropped significantly only in type 2a. The lipoprotein(a) concentration did not change significantly. The drug was very well tolerated and undesirable effects were minimal. Micronized phenofibrate (Lipanthyl 200 M) due to its comprehensive favourable effect on the entire lipid profile and other risk factors can prove useful in the treatment of all types of dyslipidaemias (with the exception of type I). As compared with Lipanthyl 100, the better pharmacokinetic properties make it possible to reduce the dose from 300 mg/day and it can be administered in a single daily dose. PMID- 8693710 TI - [Analysis of adverse effects of dobutamine stress echocardiography]. AB - Recently in various departments interest in dobutamine stress echocardiography is increasing. Originally this examination was meant for the diagnosis of suspected ischaemic heart disease in patients unable to tolerate a physical load. Clinical applications of this test are constantly expanding and comprise a number of risk patients. The purpose of the submitted paper is to discuss the safety of dobutamine stress echocardiography. The authors submit an analysis of 259 examinations of patients with suspected ischaemic heart disease (46%), after acute myocardial infection (42%) and patients with significant left ventricular dysfunction (12%). 231 examinations (89%) were made up to the defined maximum. The test was terminated prematurely in 12 patients on account of arrhythmia, in 10 because the test was positive, in two because of extracardiac effects, in three instances on account of hypotension and in one patient on account of pressure hyperreaction. Arrhythmias were recorded in 26%, discontinuous ventricular tachycardia was recorded only in two patients (0.7) with severe left ventricular dysfunction. Hypotension was found in 13%, pressure hyperreaction in 2%. Palpitations were noted in 15% of the examined patients and extracardiac side effects in 31%. None of the side-effects called for therapeutic intervention. The authors consider dobutamine stress echocardiography a safe test which is well tolerated by the majority of patients and there is a minimum of side-effects. A higher risk must be foreseen in patients with reduced left ventricular function, hypertrophy of the left ventricle and those with an history of arrhythmias. PMID- 8693711 TI - [Laterality differences in ultrasonic densitometry]. AB - The authors discuss lateral differences between heel bones during ultrasonic bone densitometry using the apparatus Achilles Lunar. While the mean values for the whole group are statistically insignificant (162 patients) in different parameters (SOS, BUA, stiffness) in one quarter of the patients the differences between the two extremities are greater than 9% which may be a source of errors when evaluating the state of the skeleton and when subsequently deciding on treatment. PMID- 8693712 TI - [Unstable Santa Ana hemoglobin or alpha 2 beta 2 88 (F4) Leu-Pro detected in a Slovak girl]. AB - The unstable haemoglobin variant Ana (alpha 2 beta 2 88 (F4) Leu-Pro) was identified to cause haemolysis in a 10-year-old Slovak girl. She was followed for haemolytic anaemia symptoms since two years of age. Clinical signs are hepatosplenomegaly and moderate haemolytic anaemia not requiring blood transfusions. It is the first case of an unstable haemoglobinopathy found in Slovak Republic as far as we know. Hypothesis of 'de novo' origin of the mutation in the propositus is supported by the parents' and brother's laboratory findings. PMID- 8693713 TI - [Recombinant human erythropoietin in the treatment of anemia associated with lymphoproliferative diseases--chronic lymphadenosis and multiple myeloma]. AB - The etiology of anaemia associated with tumours is multifactorial. One of the mechanisms of development of anaemia in tumours are so-called chronic diseases anaemias, the main feature of which is inadequate production of endogenous erythropoietin (EPO). The objective of the investigation was to test the effect of recombinant human erythropoietin (rHuEPO) in the treatment of anaemia (rise of haematocrit, Hb) in patients with chronic lymphatic leukaemia (CLL) and multiple myeloma (MM) and the effect of this treatment on the quality of life. The authors evaluated at the same time the impact of the endogenous EPO level before treatment and its predictive value as regards the therapeutic response. PATIENTS: The investigation comprised a total of 14 patients (6 CLL, 8 MM). The basic criterion for inclusion in the group was a Ht value lower than 0.32 and Hb less than 105 g/l. The examination protocol was focused on elimination of other causes of anaemia. During the 12-week investigation the patients completed a questionnaire "Quality of life" which reflected their subjective evaluation of the effect of treatment. The patients themselves administered r-HuEPO three times a week by the s.c. route--an initial dose of 150 U/kg with the possibility to increase the dose to 300 U/kg. RESULTS: A therapeutic response was obtained in four patients with CLL and eight patients with MM. Respondents with CLL had endogenous EPO values lower than 300 U/l, seven MM respondents lower than 200 U/l, one 400 U/l. The Hb level of the patients rose and the quality of life improved. All patients tolerated treatment very well and the authors did not observe any serious undesirable effects. CONCLUSION: The investigation confirmed the therapeutic effect of r-HuEPO in patients with a lower baseline value of EPO. Subjective evaluation (questionnaire) correlated with objective evaluation (Ht, Hb). Assessment of the endogenous EPO level before treatment is according to the authors one of the important primary predictive parameters and EPO values between 200 and 300 U/l are the upper range where a therapeutic effect can be expected with the highest probability. The authors conclude also that a secondary predictive criterion of the response is evaluation of the therapeutic effect after 4-5 weeks treatment when a rise of Hb by at least 20 g/l is an argument for further treatment. PMID- 8693714 TI - [Evaluation of the cardioprotective effect of bispiperazinedione ICRF-187 (Cardioxane) in patients treated with anthracyclines--an echocardiographic study]. AB - The cardiotoxicity of anthracycline antibiotics is a serious complication of anti tumourous treatment. One of the possible ways how to prevent it or at least restrict it substantially is to use cardioprotective substances. The latter include ICRF-187 bispiperazinedione (dexrazoxan) which is manufactured and supplied by CHIRON Cop. under the name Cardioxane. The authors investigated by echocardiography indicators of systolic and diastolic function of the left ventricle in patients where cumulative doses of 180-240 mg/sq.m of doxorubicin were achieved. In 10 patients to whom Cardioxane was administered no changes of left ventricular function were recorded. In 18 patients treated with boluses of doxorubicin significant deterioration of left ventricular diastolic function developed. The authors provided evidence that relatively small cumulative doses of doxorubicin administered as boluses lead to impaired left ventricular diastolic function. These changes were not recorded in patients who were given the cardioprotective substance ICRF-187 (Cardioxane). PMID- 8693715 TI - [Importance of the expression of the C6 molecule on cells in chronic lymphatic leukemia]. AB - The authors made immunophenotyping analyses of blood cells of 50 patients with the diagnosis of B-CLL. Malignant cells contained in all instances HLA DR and CD24 molecules. The superficial molecule CD5 was expressed on cells in 85.7% molecule CD6 on 66.7% cases. By statistical analysis the relationship between selected clinical parameters and expression of surface molecules CD5, CD6 and CD10 was sought. A statistically significantly higher number of leucocytes was found in patients with expression of molecule CD6. PMID- 8693716 TI - [Treatment of multiple myeloma--melphalan monotherapy after bone marrow transplantation]. AB - Melphalan has brought the first improvement in the therapy of multiple myeloma at the beginning of the sixties. The median of survival was prolonged from several months to three years. In the following three decades new drugs were tested, but no other drug brought better results than melphalan. The comparative studies have proved, that therapy response has been reached more rapidly after polychemotherapy than monotherapy, but none of the treatment modalities differed in the survival parameters. The significance of interferon alpha for the treatment of multiple myeloma has been tested since the beginning of the eighties. Many clinical trials have brought contraverse results. The latest metaanalysis and data published by Ludwig support the indication of interferon alpha for the multiple myeloma maintenance treatment. Important progress in the therapy of multiple myeloma has been done in the nineties. High doses of alkylating cytostatics with the support of autologous peripheral blood stem cells transplantation or bone marrow transplantation enhanced the number of therapy responses and prolonged the survival. The results of autologous transplantations are so favourable, that this procedure can be recommended as the first line treatment in suitable patients. Allogenic bone marrow transplantation is linked with many complications and therefore this method will be performed only in a limited number of patients. Trials dealing with this new therapy-trend are reviewed in this paper. PMID- 8693717 TI - [Erythropoietin in hematology and oncology. I. Chronic anemia in malignant disease and the pharmacology of erythropoietin]. AB - In many patients with malignant haematological and oncological diseases during the disease the haemoglobin concentration declines. Anaemia can be due to blood losses, less frequently to nutritional deficiency. One of frequent causes is the humoral effect of malignant disease on haematopoiesis and the development of anemia of chronic disease. Anemia of chronic disease has a complex etiology. Decreased production of erythropoietin is one of the participating factors and the pharmacological doses of erythropoietin can restore the number of erythrocytes to normal value. The authors present basic information on chronic anaemia of malignant diseases and principles of erythropoietin treatment of these patients. PMID- 8693718 TI - [Angiotensin converting enzyme inhibitors in ischemic heart disease]. AB - Angiotensin formed in the renin-angiotensin system is involved in the genesis and development of atherosclerosis and coronary heart disease. It has a negative impact on the process of ischaemization/reperfusion. The renin-angiotensin system is activated during a new myocardial infarction and has an impact on the process of remodelling of the left ventricle after myocardial infarction which causes its dysfunction and heart failure. ACE inhibitors are one of the important means which influence the formation of angiotensin II and thus prevent its action on heart and vessels. They prevent the development of atherosclerosis, reduce the extent of necroses during myocardial infarction and reduce the extent of left ventricular dysfunction. They diminish also stunning of the heart muscle during ischaemia/reperfusion and significantly prolong the patients life after infarction. They do not influence the development of restenosis after percutaneous transluminal angioplasty. ACE inhibitors have a positive effect on heart failure, they reduce the rate of reinfarctions and the mortality rate. PMID- 8693719 TI - Caregiving and ethnicity. PMID- 8693721 TI - Toward a cross-cultural understanding of family caregiving burden. AB - This article is part of a symposium describing the development of cross culturally relevant instruments to measure familism, caregiver burden, and quality of elder caregiving among Anglo- and Mexican American caregivers. This article explores issues involved in measuring caregiving burden. Caregiving burden is thought to adversely affect family caregiving, but the influence of culture on perceptions of burden has not been explored. Because no research focuses on caregiving burden among Mexican American caregivers, the first step involved reviewing the literature for cultural factors influencing caregiving and using the expertise of the cross-cultural team to identify and compare the meaning of caregiving burden in both groups. Next, two instrumentation studies were done to analyze the items on Poulshock and Deimling's Burden Instrument for comparable meaning and internal consistency within and between groups. The third step involved assessing the validity of Poulshock and Deimling's conceptualization of burden cross-culturally. PMID- 8693720 TI - Toward a cross-cultural perspective of family caregiving. AB - This article is part of a symposium that explores the issues involved in developing cross-culturally equivalent conceptualizations and measures for studying family caregiving. The examples used are from the instrument development phase of an ongoing program of research designed to generate and test a theory that explains the quality of family caregiving for frail elders at home. This article provides the background for the symposium by introducing the symposium's unifying theme: cross-cultural equivalence. The process described is based on the experiences of the cross-cultural research team and Berry's model for developing cross-culturally equivalent research. PMID- 8693722 TI - The relevance of familism in cross-cultural studies of family caregiving. AB - Although familism has been studied in both Mexican American and Anglo families, there is controversy about whether familism in both groups is the same. Research has shown great within-group variability, and in addition, the kinship structure in the two groups is fundamentally different. This article explores the cross cultural issues in conceptualizing familism and its relevance to caregiving among Anglo and Mexican American caregivers. Based on data obtained in an ongoing research program, the process of arriving at similarities and differences in the expression of familism is discussed using Berry's criteria for achieving cultural equivalence. PMID- 8693723 TI - Uncovering the cultural context for quality of family caregiving for elders. AB - This article is part of a symposium exploring issues in developing cross culturally equivalent conceptualizations and measures for a study of elder family caregiving. This article describes the development of an instrument to measure quality of elder family caregiving among Anglo and Mexican American caregivers. Following a review of typical approaches for evaluating quality of caregiving, a cross-cultural standard for excellence in elder caregiving is described. An instrument consistent with the United Nations Universal Declaration of Human Rights, the QUALCARE Scale, is identified as an appropriate cross-cultural instrument for assessing the quality of elder family caregiving. Refinement of the QUALCARE Scale using Berry's model for cross-cultural research, which necessitated identification of appropriate cross-cultural indicators of quality, is described. Examples of this process of indicator clarification are given for several basic human rights, based on the cross-cultural research team members' experiences with Anglo and Mexican American caregivers. PMID- 8693725 TI - A descriptive study of nurse managers and leadership. AB - This descriptive study was designed to examine the leadership activities of nurse managers. Through the use of an open-ended questionnaire, 42 nurse managers were asked to describe how they operationalized seven leadership concepts identified through a literature search: goals, change, influence, power, growth, mentoring, and vision. Findings indicate that the leadership activities described by the nurse managers were congruent with the descriptions in the leadership literature. Given the complex nature of the role of the nurse manager, leadership skills are essential for survival. PMID- 8693724 TI - Pregnancy and delivery practices and beliefs of Ethiopian immigrant women in Israel. AB - This exploratory, qualitative study compared traditional and biomedical pregnancy and delivery practices from the perspective of Ethiopian immigrant women in Israel. Findings documented that certain beliefs, such as the belief that nonmedical factors (i.e., moral behavior, God, and proper nutrition) were responsible for pregnancy outcomes, were relatively unaffected by immigration. After immigration to Israel, Ethiopian women, however, chose to deliver their babies in the hospital rather than import traditional home delivery practices from their homeland. Despite many negative aspects of labor and delivery in Israel, Ethiopian immigrant women felt that it was worth enduring negative Israeli health care practices in order to have "clean," "safe," and expert deliveries. Findings from this study assist health care professionals to provide more culturally sensitive care to this immigrant group. PMID- 8693726 TI - The relationship between education and ethical behavior of nursing students. AB - Based on the cognitive theory of moral development of Kohlberg, refined by the addition of the dimension "ethics of care" and the educational theory of Janssen, the relationship of education and ethical behavior of nursing students was examined. Ethical behavior referred not only to the ethical reasoning of students but also to the relationship between this reasoning and their behavior. This study examined the responses of 2,624 nursing students to five ethical nursing dilemmas included in the Ethical Behavior Test by relating them to four educational variables: students' level of education, level of enrollment, school, and students' perceptions of the educational process. A significant relationship between education and ethical behavior was found. PMID- 8693727 TI - Ridit analysis on ordinal data. PMID- 8693729 TI - Using the Internet to enhance nursing knowledge and practice. PMID- 8693728 TI - Nurturing longitudinal samples. PMID- 8693730 TI - The obesity epidemic of the Caribbean. PMID- 8693731 TI - Breastfeeding prevalence among six-week-old infants at University Hospital of the West Indies. AB - Eight-five (85) mothers attending postnatal and well baby clinics were interviewed at six weeks post-partum regarding breastfeeding. An overall prevalence of 98.8% at six weeks of age was seen, with an exclusive breastfeeding rate of 37.6%. Older maternal age and multiparity favoured exclusive breastfeeding. There was no significant association between pattern of breastfeeding (exclusive versus partial) and employment or union status. Breastfeeding was found to favour good weight gain in normal birthweight babies. Normal birthweight babies who were exclusively breastfed had a higher mean weight gain than the exclusively breastfed low birthweight infants, who in turn had better weight gain when partially breastfed. PMID- 8693732 TI - Disparities in access to family planning services in Jamaica. AB - In order to improve the effectiveness and subtainability of the family planning programme, the National Family Planning Board has devised a strategy to shift users to longer-acting methods and increase the role of the private sector. To design interventions, a better understanding of existing services was thought to be necessary. This study examines the distribution of family planning service delivery points in Jamaica and the services offered by the public and private sectors through an examination of records and questionnaire interviews. The study found that, because of the concentration of private sector providers-the main outlets for longer-acting methods-in urban areas, rural areas had poor access to these methods. Because rural areas are not attractive to private sector providers, the public sector should recognize the need to continue to serve these areas. PMID- 8693733 TI - Trends in admission and case fatality for acute malnutrition (Kingston 1982 1991). AB - The case fatality ratio (CFR) in acute protein-energy malnutrition (PEM) achieved in the Tropical Metabolism Research Unit (TMRU) was compared with that of other tertiary care facilities in Kingston. Trends in admission and fatality rates, case severity and complications were also examined. From ward admission registers for Bustamante Hospital for Children (BHC), the University Hospital of the West Indies (UHWI), children's wards and the TMRU all cases of PEM admitted from 1982 through 1991 were enumerated and there was a docket search for random subsamples. Ten-year mean CFR% for BHC was 8.8 (n = 1948); for UHWI wards 5.5 (n = 658); for TMRU 7.1 (n = 662). BHC has the least restrictions on admission and showed most clearly that the peak time in Kingston for admission of PEM was around 1985, falling to a minimum in 1988-1990 and rising again in 1991; however, the other sites also showed similar trends. BHC had a range of CFR% p.a. of 20.0 to 3.0, with a striking fall in the second half of the decade. There was no temporal CFR trend for the UHWI or TMRU. The latter institution had the highest proportion of admissions with marasmic-kwashiorkor and the lowest proportion with recorded infection. The annual variation in numbers of PEM deaths at BHC was best accounted for by (a) percentage change in consumer price index and (b) percentage change in the US$ value of the Jamaican $, in the preceding year, and (c) annual number of admissions, together. Generally, our findings suggest a minor role for expert in-patient management in reducing deaths from PEM. PMID- 8693734 TI - Use of food expenditure data to estimate household nutrient accessibility. AB - The nutritional status of at-risk groups is usually monitored using health statistics. This approach has limitations as individuals are identified only after they have been afflicted by morbidity. In Jamaica, national surveys are carried out in which expenditure data on all consumption items are collected. We used these data to monitor food accessibility in at-risk groups. The identification of decreases in accessibility levels relative to requirements would enable timely intervention before there is a deterioration in nutritional status. We analysed the data from the survey of 3861 households conducted by Statistical and Planning Institutes of Jamaica in 1989. Using the food expenditure data, per capita energy and protein accessibility levels were determined. The mean energy and protein accessibility levels for the sample were 2170 Cals and 64 g, respectively. The results showed that the per capita accessibility levels of 20% and 9% of the households were less than half of requirements for energy and protein, respectively. The situation was worse in rural areas than in urban centres. However, the accessibility levels may have been underestimated as the data did not include meals bought and consumed away from the home, which may be significant to some households. We believe that the use of data from these surveys is a cost-effective way to monitor nutrient accessibility in Jamaica. PMID- 8693735 TI - Plasma fibronectin kinetics during uncomplicated acute myocardial infarction. AB - Plasma fibronectin (Fbn) was assessed daily in 9 men admitted to the cardiology care unit for uncomplicated acute myocardial infarction (AMI). In a control group of twenty healthy men, plasma Fbn was 0.290 +/- 0.0417 g/l-1 (mean +/- SD). In 6 hypertensive AMI patients, Fbn levels were increased to a maximum of 0.461 +/- 0.0294 g/l-1 at day five (5.5 +/- 0.84 days) and returned to the range of the control group values 56 +/- 32.8 hours afterwards. Three normotensive patients had higher Fbn results without returning to the control group range at the end of the hospitalization (0.734 +/- 0.0209 gl-1). Plasma Fbn could in part be implicated in the repair process and/or in the limitation of the cardiac necrosis extension. Moreover, it seems that a link exists between plasma Fbn kinetics and hypertension and/or normotension during uncomplicated AMI. PMID- 8693736 TI - The prevalence of seat belt use in Jamaica. An observational study. AB - An observational cross-sectional survey showed that 21.1% of private motor vehicle drivers and 13.5% of front seat passengers voluntarily wore seat belts in Kingston, Jamaica, where there is no law requiring this. Rear passenger utilisation was not examined. Compared to males, females were significantly more likely to wear seat belts when driving but not as front seat passengers. Of all motor vehicles examined, 10.1% were not equipped with seat belts. The oldest group of vehicles were mostly not fitted with seat belts. Drivers of older vehicles were significantly less likely to use seat belts even when the vehicles were equipped with belts. Implementation of legislation can reduce mortality, morbidity and costs from road traffic accidents which are relatively frequent in Jamaica. Male drivers, drivers of older vehicles and all passengers may require specific targeting in an educational and enforcement campaign should legislation, which is highly desirable, be implemented. PMID- 8693737 TI - Multicentric angiofollicular lymph node hyperplasia in ulcerative colitis. A case report. AB - Multicentric angiofollicular lymph node hyperplasia (MAFH) is a rare disorder which has been associated with various disease entities. This is the first report of its association with ulcerative colitis. Details of lymph node histology and views on pathogenesis are given. PMID- 8693738 TI - Metastatic carcinoma of the penis. AB - Metastatic carcinoma of the penis is uncommon. The primary tumour is most commonly reported to be in the genitourinary or gastrointestinal tract. A case of metastatic carcinoma of the penis, secondary to a primary carcinoma of the prostate gland, is described. PMID- 8693739 TI - A case of vivax malaria presenting with psychosis. AB - The first case of psychosis due to Plasmodium vivax malaria, imported from India is reported. A 44-year-old Trinidadian male presented with fever, and psychotic episodes in association with vivax malaria. The symptoms of both malaria and psychosis were resolved following the standard chloroquine-primaquine therapy. PMID- 8693740 TI - Heterosexual transmission of HTLV-I. Epidemiological aspects. PMID- 8693741 TI - Characteristics of Jamaicans who smoke marijuana before sex and their risk status for sexually transmitted diseases. AB - Because of the high prevalence of marijuana smoking in Jamaica, it is important to know if this practice is associated with increased risk for STD infections. A national sample of 2 580 randomly selected Jamaicans, aged 15 to 49 years were administered a questionnaire to measure a number of health and behavioural variables. The results indicated that more persons who smoked marijuana before sex had a history of STD infections than non-marijuana smokers, the difference was significant among men (46% vs 26%, p < 0.001) but not among women (19% vs 8%, p = 0.09). There was no difference in age, however, more of the smokers were unmarried, poorly educated and unemployed than persons who did not smoke marijuana before sex. They were also more likely to engage in high risk sex behaviours and other risk taking behaviors than non-smokers. The results of multiple logistic regression analyses indicated that marijuana smoking before sex was an independent risk factor for STDs among men (Odds Ratio = 2.0, p = 0.04). Although it was not possible to determine if the association was causal, the increased risk for STDs among men who smoke marijuana before sex should be incorporated into the Jamaican STD/AIDS control programme by making special efforts to encourage condom use among marijuana smokers. PMID- 8693742 TI - James Joyce (1882-1941): medical history, final illness, and death. PMID- 8693743 TI - 20-year experience with the treatment of gastric cancer since adopting a radical systemic lymph node dissection. PMID- 8693744 TI - Name of the game: a healthy lifestyle. PMID- 8693745 TI - Former Packer physician lends perspective. PMID- 8693746 TI - Pain medications and addiction. PMID- 8693748 TI - Hometown sports medicine: teamwork in action. PMID- 8693747 TI - Rarity of FLP should be noted. PMID- 8693749 TI - Primary care sports medicine: fitting today's patient needs. PMID- 8693750 TI - Former Packer doctor sees growing trend in injuries. PMID- 8693751 TI - Going to bat for sports medicine in Wisconsin. PMID- 8693752 TI - Medical problems of adolescent female athletes. AB - Adolescent female athletes represent unique medical challenges. Although still limited, research and understanding of their particular problems has grown over the past 3 decades as female sports participation has increased dramatically. Despite concerns, however, exercise and athletic activity are safe and beneficial for girls and young women, and may help them develop positive attitudes toward self-image and body satisfaction. Several musculoskeletal injuries fairly common among female athletes may be related to structural development. Iron and calcium deficiencies are frequent nutritional concerns for these girls. Disordered eating, a phenomenon exhibited by many adolescent females, may not be more prevalent in athletes. Amenorrhea is a common problem for female athletes, and may contribute significantly to stress fractures and future osteoporosis. For these and other reasons, physicians must be aware of these issues to better help their female patients safely participate in athletics. PMID- 8693753 TI - Establishing a high-school-based training room clinic. AB - Being a team physician can be a time-consuming commitment. The team physician is responsible for all aspects of the athlete's care and has the final say in all medical matters related to athletic participation. Primary care physicians are well suited to be team physicians. The training room is an outstanding way to increase physician availability to adolescents and underserved population. Setting up a training room must be planned in advance, including funding, supplies and liability. Most legal problems can be avoided with a contract and proper documentation. The school-based training room provides the physician with an excellent opportunity for community service and can be a very rewarding experience. PMID- 8693754 TI - Diagnosis and treatment of common knee injuries in athletes. AB - Knee injuries are an all too common occurrence in athletes. Prompt diagnosis, aggressive treatment and rehabilitation is necessary to minimize time away from athletic activity and to maximize function at a competitive level. This article reviews the latest trends in diagnosing and treating common knee injuries in athletes, including ligamentous and meniscal injuries. PMID- 8693755 TI - Risk factors for anterior cruciate ligament injury. PMID- 8693756 TI - Athletic performance in relation to training load. AB - Athletic performance generally is thought to improve with increases in training load. However, few data exist showing the quantitative relationship between training load and performance. We followed 56 athletes (16 runners; 40 cyclists/speed skaters) during 12 weeks of training. We recorded index performances (3.2 km time trial or 5 or 10 km bicycle ergometry) after 6 weeks of baseline training and 6 weeks of a self-selected training increases. Training load was quantitated as the product of intensity (global rating of perceived exertion (RPE)) and the duration (time) of each training session. Load was expressed as the weekly average over the 6 weeks preceding each index performance. We also recorded the duration of high intensity training (RPE>5, hard) (inten). From 6 to 12 weeks, performance improved 12.95 +/- 3.83 to 12.66 +/- 3.00 min (p < .01). Training time (345 +/- 282 to 355 +/- 273 min/wk) and inten (61 +/- 88 to 71 +/- 91 min/wk) did not change significantly, although RPE (3.8 +/- 0.7 to 4.0 +/- 0.8) and load (1242 +/- 957 to 1386 +/- 978) increased significantly. No strong correlations existed between changes in performance and changes in any training measure (TIME, r = -0.031, RPE, r = -0.039, LOAD, r = 0.29, INTEN, r = 0.025.) Data suggest that improved performance in events of 7-20 minutes duration in response to intensified training is primarily dependent upon increases in total load and overall RPE during training and; that a 10-fold increase in training load may be associated with an approximately 10% improvement in performance. These data suggest the possibility of understanding the training responses of athletes on a quantitative basis. PMID- 8693757 TI - Exercise-induced asthma and the asthmatic athlete. AB - Almost all asthmatics involved in moderate to heavy exercise will experience exercise-induced asthma (EIA). Up to 14% of athletes exhibit EIA, symptoms of which include dyspnea, coughing, chest tightness and wheezing. Education, warm-up exercises and pre-treatment with the appropriate medications can enable an athlete to excel and even win a gold medal in the 1996 Olympic games. PMID- 8693758 TI - The incidence of needlestick and sharps injuries and use of safer devices in Wisconsin hospitals. PMID- 8693760 TI - Don't doctor your records. PMID- 8693759 TI - Heat-related deaths during the summer of 1995, Wisconsin. PMID- 8693761 TI - Telemedicine. PMID- 8693762 TI - Domestic violence: the physician as patient advocate. PMID- 8693763 TI - A word from WIPRO. Hospitals working on improving use of prophylactic antibiotics. PMID- 8693764 TI - [Multiplicity of clinical symptoms and manifestations of unruptured aneurysms of the sinus of Valsalva--3 case reports]. AB - Sinus Valsalva aneurysms belong to the less common congenital or acquired structural cardiac anomalies. However, in patients with known cardiac anomalies and uncertain or uncharacteristic cardiac symptoms the existence of a sinus Valsalva aneurysm must be taken into consideration. A sinus Valsalva aneurysm can be clinically silent as in the case of the 56-year-old patient with an accompanying bacterial endocarditis. An increasing aortic regurgitation after dilatation of a coarctation of the aorta can also proceed with an ecstasy of the ascending aorta and an aneurysm of the sinus Valsalva (case 2). Furthermore, a rapid dilatation of a non-ruptured sinus Valsalva aneurysm can cause a severe compression of coronary arteries with subsequent myocardial infarction, as in the 27-year-old patient with congenital aortic stenosis and acute endocarditis in case 3. PMID- 8693765 TI - [DDD versus DDDR pacemaker stimulation: comparison of cardiopulmonary performance, incidence of atrial arrhythmias and quality of life]. AB - The purpose of this study was to assess cardiopulmonary exercise capacity, variation in heart rate during everyday activities, frequency of atrial arrhythmias and quality-of-life during accelerometer-based rate modulated dual chamber pacing. Nine chronotropically incompetent and 14 chronotropically competent patients (mean age 51 years) were randomly assigned to DDD and DDDR mode and evaluated by a semisupine bicycle exercise testing exceeding the anaerobic threshold, 24-h Holter monitoring and a quality-of-life questionnaire. In the subgroup of patients with chronotropic incompetence, defined by a HR/VO2 ration, 2 beats/ml/kg, during DDDR pacing, compared to DDD, maximum heart rate increased from 83 +/- 13 to 132 +/- 7 beats/min (p < 0.01), maximum oxygen uptake from 12.7 +/- 3.1 to 15.3 +/- 3.2 ml/kg/min ( p < 0.05) and the VO2/WR-ratio from 8.1 +/- 1.0 to 9.0 +/- 0.9 ml/min/watts (p < 0.05). Exercise duration lengthened from 252 +/- 59 to 301 +/- 96 s (p < 0.05). During the 24-h Holter recordings the average maximum heart rate rose form 69 +/- 7 in the DDD mode to 78 +/- 9 beats/min in the DDDR mode significantly (p < 0.05). DDDR pacing did not result in an increased number of atrial salvos (2.6 atrial events/24 h) when compared to DDD pacing (2.5 atrial events/24 h, N.S.). These objective results were confirmed by the quality-of life assessment due to a symptom questionnaire. The symptom score declined from 20 +/- 10 in the DDD mode to 16 +/- 7 in the DDDR mode (p < 0.01). In the patients with chronotropic competence, however, cardiopulmonary exercise capacity did not improve in the DDDR mode: maximum heart rate was 120 +/ 21 versus 130 +/- 24 beats/min (N.S.), maximum oxygen uptake 17.7 +/- 5.9 versus 16.8 +/- 5.9 ml/kg/min (N.S.), The VO2/WR-ratio 9.8 +/- 2.3 versus 9.2 +/- 2.5 ml/min/watts (N.S.) and the exercise duration 407 +/- 159 versus 406 +/- 165 s (N.S.). The average maximum heart rate was 80 +/- 15 in the DDD mode and 83 +/- 16 beats/min in the DDDR mode (N.S.). Significantly more atrial arrhythmias occurred in the DDDR pacing mode: 1.6 atrial salvos per 24 h in the DDD mode versus 4.8 atrial salvos per 24 h in the DDDR mode (p < 0.05). This patient subgroup experienced a significant worsening of his quality-of-life. The symptom score rose from 20 +/- 9 in the DDD mode to 28 +/- 11 in the DDDR mode (p < 0.05). In conclusion, DDDR pacing improved cardiopulmonary exercise capacity, normalized heart rate variation over 24 h and increased quality-of-life in patients with chronotropic incompetence. On the contrary, since the DDDR pacing more could not improve cardiopulmonary exercise capacity, increased atrial arrhythmias and worsened the patient's quality-of-life, patients with chronotropic competence should not be programmed in the DDDR pacing mode. PMID- 8693766 TI - [Transient pacemaker dysfunction and spontaneous arrhythmias in symptomatic and asymptomatic patients with ventricular demand pacemakers]. AB - This prospective cross-sectional study include 100 consecutive patients (56 males, 44 females, 29 to 86 (mean = 67.5 +/- 12.2) years) with ventricular inhibited demand pacemakers 0.1 to 94.7 (mean 23.3 +/- 25.4) months after pacemaker implantation. Fifty-two patients were free of symptoms, whereas 48 patients were still complaining of syncope, dizziness, or palpitations. After history, physical examination, and 12-lead standard ECG all patients underwent 24 h Holter monitoring. A computer-aided analysis of spontaneous arrhythmias was done first. In a second run computed-aided analysis of transient pacemaker dysfunctions was performed with a specially designed pacemaker module. There were no significant differences between asymptomatic and symptomatic patients with regard to the incidence of transient pacemaker dysfunctions, with regard to defined types of pacemaker dysfunctions, spontaneous ventricular arrhythmias, and with regard to supraventricular tachycardias. A significant difference between asymptomatic and symptomatic patients was found, however, regarding the Lown classification of ventricular arrhythmias, because asymptomatic patients showed class 0 and I/II arrhythmias more frequently (p < 0.025). In the 100 patients a total of 6609 pacemaker dysfunctions were observed, 5104 failures to sense and 1505 inappropriate inhibitions. Most patients showed up to 240 pacemaker dysfunctions per 24 h. There were no failures to capture. Different types of pacemaker dysfunctions were found with different clinical implications. Due to the Holter findings in nine patients pacemakers were reprogrammed or replaced. After pacemaker implantation the number of patients with severe symptoms significantly decreased compared to the number of patients before pacemaker implantation. Nonetheless, there was a number of patients still complaining of symptoms after pacemaker implantation. In only a few patients did pacemaker implantation worsen symptoms . Our data show that with use of long-term ECG transient pacemaker dysfunctions and spontaneous arrhythmias are more frequent than patients' history and common standard techniques in the pacemaker clinic may suggest Holter monitoring, therefore, is a useful diagnostic tool, not only in symptomatic, but also in asymptomatic pacemaker patients. It allows to obtain a reliable survey of the real amount of transient pacemaker dysfunctions in the individual patient, which is the base for further therapeutic decisions. PMID- 8693767 TI - [Intermittent atrial fibrillation/flutter: contraindication for implantation of a dual chamber pacemaker?]. AB - The programming of dualchamber pacemakers to DDD(R) mode is not recommended in patients with paroxysmal atrial fibrillation/flutter, because the pacemaker detects atrial fibrillation/flutter and paces the ventricle up to the pacemaker's upper tracking rate. Some newer pacemakers have the feature to switch automatically from DDD(R) to DDIR mode at the onset of atrial tachyarrhythmias. The aim of the study was to assess how many patients who received such a new DDDR pacemaker with automatic mode switch can be programmed to DDD(R) mode during follow-up. The dual-chamber pacemaker Thera DR (Medtronic) was implanted for clinical evaluation in 142 patients (65 +/- 16 years, male n = 86; female n = 56). Paroxysmal atrial fibrillation/flutter was present in 54 patients, with an additional 2nd or 3rd degree AV-block in 13 and no high-degree AV block in 22 cases; an AV node ablation was performed in 19 patients. Pacemakers were programmed to DDD(R) mode at discharge in 52 of 53, at month 1 in 44 of 46, and at month 3 in 28 of 30 cases. In respect to the programming to DDD(R) mode there were no statistically significant differences to patients without paroxysmal atrial fibrillation/flutter. CONCLUSION: Paroxysmal atrial fibrillation/flutter was present in 38% of the studied patients. During follow up more than 90% of the patients were paced in the DDD(R) mode. PMID- 8693768 TI - [Comparison of active and passive fixation of steroid emitting atrial electrodes]. AB - Steroid-eluting screw-in leads (CapSure Fix 4068, Medtronic; n = 14) were compared to the same lead as a J-shaped tined electrode (CapSure SP 4524, Medtronic; n = 27, implanted in the atrium in patients receiving dual-chamber pacemakers. Follow-up were at discharge and after 1 month. Implantation (screw-in lead: 84 +/- 18 min; tined lead: 81 +/-29 min) and fluoroscopy times (screw-in lead: 7.3 +/- 4.9 min; tined lead 9.2 +/- 7.0 min) were similar in the two groups. At implant, P-wave amplitudes were similar with 4.8 +/- 1.6 mV (screw-in lead) and 4.0 +/- 2.6 mV (tinted lead), respectively. Compared to tined leads, the screw-in leads had higher pacing thresholds at 0.5 ms pulse duration (screw in lead: 0.74 +/- 0.32 V; tined lead: 0.55 +/- 0.15 V; p = 0.02) as well as higher impedance (screw-in lead: 566 +/- 93 ohms; tined lead: 470 +/- 99 ohms; p = 0.01). Pulse duration thresholds at 2.5 V pulse amplitude were neither different at discharge (screw-in lead: 0.07 +/- 0.04 ms; tined lead: 0.06 +/- 0.05 ms) nor after 1 month (screw-in lead: 0.09 +/- 0.04 ms; tined lead: 0.06 +/- 0.06 ms). P-wave amplitudes > or = mV were observed at discharge in 14/14 (screw in lead) 21/27 patients (tined lead), respectively, and after 1 month in 13/14 (screw-in lead) and 22/27 (tined lead) patients, respectively. Impedance of the screw-in lead was significantly higher with 693 +/- 84 ohms at discharge and 691 +/- 79 ohms after 1 month compared to the tined lead with 520 +/- 81 and 574 +/- 62 ohms (p = 0.001). No lead dislodgment was reported during follow-up. CONCLUSIONS: For the studied steroid-eluting leads active and passive fixation had neither at implantation nor during 1-month follow up any influence on P-wave amplitude. At similar pulse duration thresholds, impedance of the screw-in lead was significantly higher than for the tined lead. Higher impedance additionally reduces pacing current, if similar pacing impulses are delivered. PMID- 8693769 TI - [Normalization of myocardial perfusion reserve after coronary stent implantation in comparison with balloon angioplasty alone]. AB - Stents scaffold coronary arteries after angioplastic treatment and inhibit elastic recoil resulting in a larger and more circular focal lumen. In 25 patients with significant stenoses of the left anterior descending coronary artery, presenting no collaterals or myocardial infarction, EKG-gated digital subtraction angiograms were recorded at baseline and during hyperemia induced by intracoronary injection of 12 mg papaverine before and after balloon angioplasty, and after adjunct implantation of a single Palmaz-Schatz stent. Densitometric evaluation revealed the time parameters contrast medium appearance time (MCAT) rise time (RT) and mean transit time (MTT) and maximum intensity (Imax). Myocardial perfusion reserve (MPR1) was calculated as the ratio of baseline MCAT and hyperemic MCAT multiplied by the ratio of hyperemic Imax and baseline Imax while MPR2 was calculated as the ratio of baseline RT and hyperemic RT. Maximum flow ratio (MaxFR) was calculated as the ratio of preprocedural hyperemic MTT and postprocedural hyperemic MTT. Post-stenotic MPR1 increased from 1.36 +/- 0.28 to 2.50 +/- 1.20 and to 3.40 +/- 0.58 (ANOVA p < 0.05), while reference MPR1 remained unchanged with 3.40 +/- 0.60. Post-stenotic MPR2 increased from 1.57 +/- 0.14 to 2.59 +/- 0.86 after balloon angioplasty and to 3.10 +/- 0.41 after stenting (ANOVA p < 0.05), while reference MPR2 remained unchanged with 3.10 +/- 0.40. MaxFR was 2.13 +/- 0.53 after balloon angioplasty and 2.83 +/- 0.35 after stenting (p < 0.05). A good correlation was found between minimal stenosis diameter and MPR1 or MPR2 (MPR1: r = 0.94; MPR2: r = 0.87) and between luminal gain and MaxFR (r = 0.75). A negative correlation was measured between recoil, defined as the difference between inflated balloon diameter and resulting minimal stenosis diameter, and MPR1 and MPR2 and MaxFR (MPR1: r = -0.86; MPR2 r = -0.80; MaxFR r = -0.83). In conclusion, adjunct coronary stent implantation normalized post-stenotic myocardial perfusion immediately in contrast to balloon angioplasty alone resulting from a larger postprocedural lumen and a more pronounced inhibition of elastic recoil. PMID- 8693770 TI - [Effect of high insufflation pressures on elastic recoil forces and vascular resistance after balloon dilatation]. AB - In this study, we examined whether percutaneous coronary angioplasty (PTCA) of native coronary arteries with high inflation pressure can improve the immediate postinterventional result in comparison to PTCA with nominal inflation pressure. Using quantitative coronary angiography, we analyzed the coronary angiograms of 24 patients who underwent PTCA with nominal inflation pressure (< 10 atm; group 1) and of 20 patients who underwent PTCA with high inflation pressure (> or = 10 atm; group 2). Only balloon catheters with little compliance were used. The following variables were recorded: 1) minimal luminal diameter (MLD), reference diameter and percent diameter stenosis before and after PTCA, 2) average balloon diameter during PTCA, 3) balloon/artery diameter ratio, 4) acute luminal gain (difference between MLD before and after PTCA), 5) nominal elastic recoil (difference between nominal balloon diameter and MLD after PTCA), 6) actual elastic recoil (difference between average balloon diameter during PTCA and MLD after PTCA). Nominal balloon diameter, reference diameter before and after PTCA and the balloon/artery diameter ratio were similar in both groups. Application of high inflation pressure resulted in a greater average balloon diameter. In group 2 (high inflation pressure), average balloon diameter amounted to 94 +/- 12% of nominal balloon diameter, whereas in group 1 (nominal inflation pressure), it reached only 84 +/- 9% of nominal balloon diameter. Actual elastic recoil was not different between the two groups. Nominal elastic recoil, however, was greater in the cohort which received PTCA with nominal inflation pressure (1.13 +/- 0.35 mm vs. 0.83 +/- 0.28 mm; p < 0.02). After use of high inflation pressure, acute postinterventional luminal gain was significantly increased (1.04 +/- 0.25 mm vs. 0.77 +/- 0.34 mm; p < 0.02) and the postinterventional percent diameter stenosis was significantly lower (12 +/- 10% vs. 24 +/- 13%; p < 0.05). Application of high inflation pressure improves the postinterventional result after PTCA because of a greater acute luminal gain. The stenotic coronary artery is expanded to a greater degree, and actual elastic recoil remains unchanged. PMID- 8693771 TI - [Lumen enlargement in coronary angioplasty: qualitative and quantitative analysis of vascular mechanisms with intravascular ultrasound]. AB - The purpose of this study was to determine the mechanisms by which balloon angioplasty increases luminal patency. Therefore serial examinations with intravascular ultrasound before and after coronary balloon angioplasty were performed. Forty consecutive patients (7 female, 33 male, aged 58 +/- 9 years) with 49 dilated lesions were examined with a 3.5 F, 20 MHz mechanical intravascular ultrasound imaging system before and immediately after coronary balloon angioplasty. Quantitative measurements of lumen area, total arterial area, plaque area and arterial stretch were performed in the dilated vessel segments. Plaque reduction accounted for 65% and vessel wall stretch for 35% of the total increase in luminal patency after angioplasty. In 34/49 (69%) lesions plaque reduction and in 15/49 (31%) arterial stretch contributed most (> 50%) of the overall increase in luminal area post angioplasty. in lesions with an ultrasound area stenosis before PTCA larger than the mean value of the group (> or = 87%) plaque reduction contributed a significantly higher percentage to luminal gain as compared to lesions with an area stenosis < 87% (76.5 +/- 25.0 vs 52.7 +/- 29.9, p < 0.05). Conversely, PTCA resulted in a significantly greater amount of vessel walls stretch in lesions with an area stenosis < 87% (47.3 +/- 29.9 vs. 24.4 +/- 24.2; p < 0.05). In lesions with localized dissections (32/49 (65%)) after PTCA as compared to lesions without dissection a significantly greater relative reduction of stenosis (24% +/- 13% vs. 19% +/- 7%, p < 0.05) was found. Plaque reduction and to a lesser extent vessel wall stretch constitute the principal mechanisms responsible for increased luminal patency after balloon angioplasty. The amount of plaque reduction and vessel wall stretch on the overall luminal gain after PTCA is dependent on the size of area stenosis. The presence of localized dissections after angioplasty correlates favorably with a better result. PMID- 8693772 TI - [What determines disease outcome after PTCA?]. PMID- 8693773 TI - [The effect of stimulation of the medial geniculate body on the motor polarization dominant in rabbits]. AB - We studied the influence of stimulation of the medial geniculate body (MGB) on the course and recovery of the motor polarization dominant created by the action of DC anode on the rabbit's right sensorimotor cortex. Electrical activity of the sensorimotor cortex and MGB was recorded in both cerebral hemispheres as well as mechanograms of both the forelimbs. It was shown that MGB stimulation at the background of the dominant optimum reinforced it eliciting a movement of the "dominant" forelimb. During geniculate stimulation spectral power of the electrical activity of both the structures of the right hemisphere increased in the delta-1 range. Coherence spectra displayed an increase of the mean coherence level in the same delta-1 range. These phenomena were characteristic for the dominant state. On the next after exposure of the cortex to DC, the dominant recovered after application of 7--10 trials of geniculate stimulation. PMID- 8693774 TI - [The interaction of rabbit neocortical neurons during natural feeding motivation]. AB - Interaction between neurons in the visual and sensorimotor, visual and frontal cortical areas of both brain hemispheres was studied by means of cross- and autocorrelation histogram analysis in fed up and hungry rabbits after daily food deprivation. In hungry rabbits as compared with fed up ones the total number of neurons with correlated activity was higher (43 +/- 3 and 32 +/- 3%, respectively), the number of neuronal pairs with the frequency of interaction in the theta-range was higher, and that with interaction frequency in the alpha range was lower. Interhemispheric asymmetry in correlation between the visual and sensorimotor neurons was observed in hungry animals. Most expressed changes were observed in the left hemisphere, where increase in the number of neuronal pairs with correlated activity was the highest and certain order of neuronal activity dominated, i.e., discharges of the sensorimotor neurons were up to 120 msec ahead of those of the visual ones. PMID- 8693775 TI - [The effect of the NMDA-receptor antagonist (+/-)-CPP on the conditioned-reflex activation of an operant reaction in the brain electrical self-stimulation test in rats]. AB - Self-stimulation behaviour was studied in rats with implanted bipolar electrodes in ventral tegmental area (VTA) and guide cannulae in nuclei accumbens septi (NAC). Conditioned activation of the operant response was induced by the stimuli associated with rewarding electrical stimulation of VTA, i.e., light or subthreshold stimulation. Bilateral administration of NMDA receptor antagonist ( +/- )-CPP (2.5 mcg in each cannula) significantly attenuated the facilitating effect of the conditioned stimuli. These data provide evidence for the role of glutamatergic transmission in NAC in realization of responses with conditioned reinforcement. PMID- 8693776 TI - [The molecular basis of dopamine synapse activity in the mechanisms of learning and amnesia]. AB - Neurochemical events underlying the activity of the dopamine synapse during the retrieval of memory and its impairment ("psychogenic" amnesia) are considered in the paper. Physico-chemical parameters of operation of D2 receptor and catechole content were investigated in various brain areas (striatum, neostriatum, hypothalamus, amygdala, frontal cortex, hippocampus, nuclei accumbens, A9, and A10) in intact, learned, and amnestic rats. The impairment in the memory trace retrieval was found to be associated with a significant decrease in activation of synaptic dopamine receptors and a modification of the dopamine transformation pathway. PMID- 8693777 TI - [A comparative analysis of the effects of the systemic and intraventricular administration of serotonin antibodies on the behavioral reactions and nociceptive sensitivity in animals]. AB - The antibodies to serotonin modulate behavioural reactions of animals depending on the mode of administration (intracerebroventricular or intraperitoneal) and the testing time. Intraventricular injection induces inhibition of behavioural activity within 1--2 hours. Systemic injection produces a biphasic effect on the serotoninergic system, i. e., the activation in the early period and the steady inhibition later. Effects of the intraperitoneally injected serotonin antibodies on the CNS are probably mediated either by serotonin binding in blood or by involvement of neurotrophic factors of the immune system. Both ways of administration of the serotonin antibodies result in late hyperalgesia. PMID- 8693778 TI - [Neurochemical research on the behavioral phenomenon of "parasitism" in rats]. AB - Lipid content and free radical processes in brain cortex as well as cAMP content in frontal cortex, hippocampus, hypothalamus, and amygdala were investigated in 20-month old male Wistar rats with different strategies of behaviour in a situation of competition for food and way of its procurance. Four groups of rats were selected in accordance with their strategies, the so-called "workers", "parasites", "inverters", and "lazy rats". Distinctions in brain lipid composition were revealed in animals of different groups. These distinctions were most clearly seen when the cortical lipid extracts from the left and right hemispheres were analysed separately. The content of cAMP was higher in the hypothalamus of "workers" than in this structure of "inverters". However, no intergroup differences were revealed in the content of cAMP in the hippocampus, frontal cortex, and amygdala. Cross-correlation between cAMP levels in the frontal cortex, hippocampus, hypothalamus, and amygdala revealed specific features of correlation of cAMP content in animals with different behavioural strategies. PMID- 8693779 TI - [The characteristics of the coordinated activity of functionally identified hypothalamic neurons under different motivational-emotional states]. AB - Simultaneous impulse activity of pairs of neurons in hypothalamus was analysed in different natural functional states of rats (hunger, satiation after food deprivation, cry of a victim) and those induced by electrical stimulation of the emotionally positive (lateral hypothalamus, lateral preoptic area) and negative (dorso-medial tegmentum) reinforcing hypothalamic structures. Two classes of neurons were separated according to the pattern of their activity determined by the motivational state or reinforcement. Characteristic features were revealed in the patterns of conjugate activity of the functionally identified neurons. They were determined by the dominance of motivational or emotional component in the behaviour of an animal and manifested in a specificity of temporal delays in impulsation of one of the neurons in respect to the other one, in magnitude and number of positive and negative correlations. The results suggest the different ways of realization of the motivational and reinforcing hypothalamic influences mediated by the neurons of the motivational and reinforcing systems, on the cortical processes at different stages of learning which also differ in the balance between the motivational and emotional components of the animal behaviour. PMID- 8693780 TI - [The complex interaction of the hypothalamic suprachiasmatic nuclei with the epiphysis and corpus striatum--a functionally unified system for regulating circadian behavioral fluctuations]. AB - Suprachiasmatic nuclei (SCN) of the hypothalamus are a pacemaker of circadian fluctuations of behaviour. Their signals reach the executive organs by the hormonal and neuronal pathways through the brain messenger structures. It has been demonstrated with relationships between the SCN, the pineal gland and striatum that these communications present the closed and autoregulated functional blocks. PMID- 8693781 TI - [The effect of neurotization after a long period following its termination on the behavior of rats differing by nervous system excitability]. AB - Behaviour of two strains of rats with high and low levels of excitability of the nervous system was studied in 6 months after the end of neurotization and compared with that of the intact (control) rats. Stable disturbances were revealed in behavioural components which were initially characteristic for each strain of rats. In rats with the high threshold of nervous excitability the emotional component of behaviour was disturbed and in those with the low threshold the motor disorders were observed. PMID- 8693782 TI - [The correlation of the behavioral, bioelectrical and cytobiochemical characteristics of the effect of taftsin]. AB - The complex neurophysiological, biochemical, and histochemical investigation carried out in dogs, cats, rabbits, and rats revealed the effects of taftsin (300 mcg/kg) at the macro- and microlevels within different periods (30 and 75 min) after its intraperitoneal injection. It was shown that after taftsin administration the configuration of evoked potentials was modified, especially, in the visual cortex and the nucleus accumbens. The absolute power of EEG spectra increased in a wide range of brain structures under consideration. Catecholaminergic activity was augmented and serotonin activity suppressed in the sensorimotor cortex and caudate nucleus, the indices of the protein metabolism reciprocally changed in the cortical and subcortical structures. Comparison of taftsin effects at different levels suggests that such effects are mainly caused by the interaction between the dopamine-containing brain structures. The consequence of taftsin administration can be probably interpreted as an intervention into the processes of visual perception. PMID- 8693784 TI - [The effect of epiphysectomy and melatonin administration on the catecholamine content of rat hypothalamic and adrenal tissue]. PMID- 8693783 TI - [The role of the brain serotoninergic system in the mechanisms of the effect of kyotorphin on animal behavior]. PMID- 8693785 TI - [The behavioral reactions of anosmic rats to new complex stimuli]. PMID- 8693786 TI - [The effect of unilateral cortical inactivation on the perception of pain vocalizations in rats]. PMID- 8693788 TI - [Computerized methods for studying the sensorimotor reaction time in preschoolers]. PMID- 8693787 TI - [The role of the neurochemical mechanisms of the basolateral amygdaloid nucleus in anxiety states of different aversive origins]. PMID- 8693789 TI - [A method for studying the neurophysiological correlates of the zoosocial relations of the lower monkeys]. PMID- 8693790 TI - [A new method for the automatic recording and analysis of the structure of the motor activity of small animals]. PMID- 8693791 TI - [The behavior of dominant and subordinate female laboratory rats at different stages of their estrous cycles]. PMID- 8693792 TI - [The tradition of observing the laws of nature in making a judgement]. PMID- 8693793 TI - [Negative potentials of the human brain to visual stimuli evoking saccades]. AB - EEG of the frontal and parietal areas (F3, F4, Fz, P3, P4 according to the International 10-20 System) was recorded in 4 healthy subjects aged 20-25 years. The saccades were elicited by the shift of the light stimulus to the peripheral diodes (step or gap stimulation scheme). A complex fast event-related potential was evoked by the visual stimulation prior to the saccade onset. Amplitudes and topography of this potential depended on the saccade latency, stimulation scheme, spatial pattern of stimuli presentation and individual features of a subject. It is suggested that the early negative potentials reflect the processes of sensory processing of the stimuli spatial patterns and perceptive attention. The negative potentials with the intermediate latency may reflect the processes of activation of the cortical structures which participate in programming and triggering the saccades. PMID- 8693794 TI - [In memoriam: Vladimir Sergeevich Rusinov]. PMID- 8693795 TI - [Visual illusions and the alpha-rhythm EEG]. AB - During flicker stimulation with the alpha-rhythm frequency through the closed eyes 11 from 12 subjects clearly saw illusory objects (in order of descending probability, ring, circle, three-dimensional spiral or spiral spring, funnel, curved crossed bars). The individual optimal stimulation frequency for producing an illusion was always within the alpha range and was closely correlated with the individual dominant alpha frequency (r = 0.86). A supposition is discussed that the effect obtained is based on the quasistroboscopic fixation of the spreading cortical excitation wave of the alpha-rhythm due to its summation with the isorhythmic afferent diffuse cortical excitation evoked by flashes. This phenomenon enables "freezing" of the alpha wave at a certain instant of its spreading and makes it "visible". PMID- 8693796 TI - [The activation and suppression by light of human cerebral cortical activity]. AB - EEG rhythm driving was studied in the dark, under action of constant illumination and after its switching off. The intensity of the background illumination influenced frequency-dependent brain reactivity changes. The results testify to the existence of the range of the optimal for brain activity illumination between the moderate (activating) and extra-high (suppressing) background light intensities. A conclusion is drawn on the possibility of application of electrophysiological techniques for revealing the optimal illumination conditions. PMID- 8693797 TI - [Disordered higher mental functions in lesions of different parts of the caudate nucleus]. AB - The relation between deterioration in higher mental functions and localization of the brain pathological process was studied in 22 patients with arteriovenous malformation in the head or/and the body of the caudate nucleus using the methods of multivariate statistics and structurally organized neuropsychological information. It was shown that the lesions in the caudate nucleus body resulted in disturbances of the spatial functions. Pathological foci in the head of the caudate nucleus were associated with memory disorders (the right-side foci were accompanied by deterioration in the visual memory and the left-side ones by that in the audio-verbal memory) and modification of programming and control of voluntary activity. PMID- 8693798 TI - [Acoustically guided behavior in the early ontogeny of the long-eared owl: the characteristics of its feeding behavior and the parameters of the acoustic signal important for its stimulation]. AB - Feeding behaviour of nestlings of long-eared owls (Asio otus) is manifested as a complex of two components, i. e., the vocal reaction (uttering of begging calls) and specific motor response. Exposure to the appropriate acoustic signals resulted in an increase in the number of begging calls and approaching reaction to the source of acoustic signals. The range of monotonal signals effective for eliciting feeding behaviour was 0.2--1.5 kHz, the most effective were the tones of 0.3--0.7 kHz. The approaching reaction to acoustic signals was rather weak up to the 5th day after hatching, clearly pronounced in the 6--11th days, and later on was abruptly substituted for the response of following the visual stimulus provoked by the acoustic stimulation. Specific acoustic afferentation is the sole stimulus for begging in nestlings up to 11 days of age, and it remains a triggering stimulus for feeding behaviour in owl nestlings throughout the period of artificial feeding under laboratory conditions (up to the 40th day after hatching. PMID- 8693799 TI - [Sex dimorphism in the patterns of conditioned-reflex taste aversion and orienting-exploratory and passive-defensive behaviors]. AB - The patterns of conditioned taste aversion (CTA) and of some other types of behaviour were compared in adult male and female Wistar rats. Correlations between the CTA variables, on the one hand, and those of the exploratory and defensive behaviours, on the other, were shown. Females displayed initially less expressed CTA and more rapid its extinction than males. While tested in the open field, in a six-arm radial maze and in a special enclosed cubic chamber with holes in its vertical walls the females demonstrated higher levels of exploratory and locomotor activities with lower levels of emotionality and defensive behaviour than males. Sex differences were revealed in correlations between variables of CTA and behavioural responses under study. Thus, CTA patterns appear to be one of the manifestations of sexual dimorphism in non-reproductive behaviour. PMID- 8693800 TI - [Vector coding and neuronal maps]. AB - The model of vector coding is proposed. The excitation vector generated in a neuronal ensemble simultaneously acts on a map of selective detectors (selectors) producing a local excitation maximum that represents the input stimulus. Vector coding is suggested also to explain associative learning and memory. The output responses in the model are specified by excitation vectors triggered by the command neurons in the ensembles of premotor neurons. PMID- 8693801 TI - [External respiration as an index of the individual physiological characteristics of higher nervous activity in rats]. AB - A special type of external breathing (stressed breathing) of rats has been described which develops spontaneously or is induced by an external factor. This type of behaviour is accompanied by a catatonic "freezing". Rats with stressed breathing significantly differ from those in the normal state in lower open-field activity and rate of the local volume blood flow in the hippocampus and motor cortex. The possibility is discussed of correlation of this type of breathing with the catatonia-like state. PMID- 8693802 TI - [The role of steroid hormones in the sexual and agonistic behaviors of male silver foxes]. AB - Silver fox males were tested for sexual and agonistic behaviour after introduction of a female at different stages of the reproductive cycle. The high level of aggressive interactions between male and female and no mountings were observed out of the reproductive season. During the reproductive season, the introduction of anoestrus female did not affect the aggressive behaviour but increased the number of mountings while introduction of a receptive female reduced aggressive contacts and augmented sexual behaviour in pairs independently of mating. Considerable variations in testosterone and oestradiol but not cortisol plasma levels were observed between different stages of sexual activity. At the beginning of the reproductive season, silver fox males responded to anoestrus females with significant increase in their blood levels of testosterone and oestradiol. Contents of these two hormones did not change in males during the reproductive season when they encountered a receptive female. A female did not elicit any cortisol response in a male during different periods of the reproductive cycle. The data obtained suggest that the sexual behaviour in silver fox males can be facilitated by testosterone and oestradiol while aggressive interactions between male and female occur independently of these hormones. PMID- 8693803 TI - [The participation of the right and left hemispheres in the realization of the maze habit in male mice of the BALB/c strain]. AB - Motor, Searching and alimentary activity of male mice BALB/c as well as spatiomotor asymmetry was studied under conditions of training in symmetrical multi-alternative maze. In the period of realization of the stable optimal habit the right-side spatially motor asymmetry was observed in intact males. In animals with inactivated left or right hemisphere motor and alimentary activity was reduced and the structure of elaborated maze habit was broken. These changes were more expressed in mice with inactivated left hemisphere. Searching activity was augmented during cortical inactivation of the right hemisphere (this was associated with the right-side spatially motor asymmetry) and reduced during inactivation of the left hemisphere (associated with the left-side asymmetry). The left hemisphere was dominant in realization of all main components of elaborated maze habit (including the spatially motor asymmetry) in male mice BALB/c as in female ones. PMID- 8693804 TI - [The similarity of the effects of learning and of serotonin application on the electrical activity of surviving slices of rat hippocampus]. AB - In has been supposed that the enhanced neural activity in hippocampus after conditioning is due to the modification of modulating inputs. The influence of serotonin application on the population spike amplitude in hippocampal slices of rats after conditioning was essentially less expressed than that in the slices prepared from the control rats. The after-effects of serotonin in the control slices were due to frequency facilitation in repetitive stimulation. Frequency facilitation was found in the hippocampal slices of conditioned rats before serotonin application. Serotonin did not influence this process. These findings are evidence in favour of an assumption that serotonin can be at least one of the causes of the frequency facilitation in hippocampus after conditioning. PMID- 8693805 TI - Air pollution and daily mortality in three Swiss urban areas. AB - Particulate air pollution, in association with other common urban air pollutants, has been associated with various measured health endpoints, including the incidence and duration of respiratory symptoms, lung function, absence from work or school due to respiratory illness, hospitalization for respiratory disease, and cardiopulmonary disease mortality. In this study, the association between daily mortality and air pollution was assessed in Zurich, Basle, and Geneva (Switzerland) for the time period 1984 through 1989. Various regression modeling techniques were used to estimate the effect of air pollution on mortality, to control for time trends, seasonal factors, and weather variables, and to assess the sensitivity of the results. A positive, statistically significant association between daily mortality counts and measures of ambient air pollution in all three cities was observed. Mortality was associated with total suspended particulate pollution, sulfur dioxide, and nitrogen dioxide. The strongest association was with a 3-day moving average (including the concurrent day and the preceding 2 days) of these pollutants. The estimated mortality-air pollution effects were not highly sensitive to regression modeling techniques used to control for seasonality, long-term trends, and weather variables. PMID- 8693806 TI - [Availability and quality of necessary data for establishing health assessment in the canton of Geneva: implications for the monitoring of the development of problems and impact of health policies]. AB - The global health assessment of the population of the canton of Geneva, based on the WHO's 38 "Health-for-ALL" targets, shown several gaps in the health information system. The quality of the available data is discussed in regard of various criteria (type of statistics, representativeness, frequency of data collection, diffusion, comparability, concern for validation). Two examples are presented: 1.) The incidence of low birthweight shows how a hospital-based statistics indicator can accurately reflect a trend over time, but provide a biased estimation of a risk level. 2.) The evolution of several indicators concerning drug consumption shows how important it is to validate these indicators in order to allow an adequate interpretation. Such a validation is seldom made. The present situation could be improved by a more efficient structure of the canton's health statistics. PMID- 8693807 TI - Introducing a first AIDS vaccine in Switzerland: a Policy Delphi analysis. PMID- 8693808 TI - [Regional variations in health services: various methodological problems]. AB - Many studies show strong variation of health consumption between regions, suggesting that theses variations are related to the uncertainty of medical practice or to other factors related to health services or patients attitude. However the statistical interpretation of these variations is far from easy: apart from usual and specific information bias, there are statistical problems when observing incidence of events like health care consumption: it is in fact a rare event, which is observed within small population, and among regions with unequal number of person. Therefore, most of the variation reported might be well explained by a purely statistical phenomenon. This paper presents some aspects of this variability for three common indicators of variation, and suggest the use of ad hoc simulation to get statistical criteria. PMID- 8693809 TI - Determinants of stillbirth mortality in Greece. AB - A population-based case-control study of the determinants of stillbirths was conducted in Greece from 1989 to 1991. All reported stillbirths after 28 weeks of pregnancy (N = 2,006) during the three year study period comprised the case group. The control group derived from random sampling of 10% of all livebirths in Greece, during the same period (N = 30,705). The data were analysed by modelling through multiple logistic regression. The adjusted relative risk of stillbirth was significantly higher for males compared to females. A statistically significant monotonic increase in relative risk was observed with shorter gestational age, low maternal education, and older maternal age. Birthweight and parity showed a statistically significant U-shaped association with stillbirth risk, with a higher risk being observed among both low and high birthweight deliveries, as well as among primiparous or multiparous (4+) mothers. Positive associations of stillbirth with multiple births, out-of-wedlock marriage and non Greek-orthodox maternal religion were noted in crude analyses, but these associations almost disappeared in logistic regression model. Maternal urban or rural residence showed no relation to risk. Overall, the prospective risk of stillbirth after the 24th week of gestation in Greece has been estimated to be higher than that in Japan (a more developed country) with more than 40% of stillbirths occurring after the 36th week of pregnancy. PMID- 8693810 TI - [What can family physicians contribute to health promotion in schools?]. AB - Although several German schools have developed and tested concepts of a goal directed health education, a stable and continuous implementation is missing. In this field free-practising physicians can support public health efforts. In the area Bruchsal/Ostringen it is demonstrated, that especially those primary care physicians, who work according to the "Three-Level-Concept of Free-Practising Physicians", can successfully use their geographical and social proximity to schools in their neighbourhood for a log-lasting implementation of recurring health-related activities. Within ten years 1389 students in schools, further ca. 500 outside schools, were directly included in interactive learning in the framework of preventive measures, e.g. during school health days. 10 physicians (4 of them continuously) cooperated in these activities, which had been planned in close collaboration with teachers and parents, considering the different age groups. From the very beginning--although sometimes limited in scale--each activity was evaluated. Pupils in the age group 10-12 years generally showed the highest interest in health-related diet, 17-26% were physically more active. Promising are the results with respect to smoking: one fifth of the smoking students intended to quit as a consequence of the health activities in their schools. PMID- 8693811 TI - Concepts of health and illness in entering medical students; first part of a prospective study. AB - The objective of this prospective study is to assess curriculum-related factors which might influence both concepts of health and illness and health behaviour. A representative sample of 546 freshmen enrolled at the University of Berne, entering medical students and a control group of freshmen in other faculties, were surveyed on their subjective concepts of illness and health. The questionnaire described as "Health and illness concept Scales" (HICS) was mailed out shortly before the beginning of school, and was returned by 70%. The prospective medical view of health and illness before entering professional training, contrary to the hypothesis of "anticipatory socialisation". Their general concept of illness and health was found to be distinctly naturalistic rather than psychosocial in nature. While psychosocial factors were considered to be rather irrelevant by both cohort of students, individual health behaviour and the ability to recognize warning signs of impending hazard to one's health were given high priority. PMID- 8693812 TI - [Knee joint arthroses and work-related factors]. AB - Occupational risk factors for arthrosis of the knee confirmed by x-ray were evaluated in a case-control study comprising 115 male and 86 females cases. Controls (95 men and 87 women) were free of symptoms of the musculoskeletal system. For both sexes age-adjusted odds ratios were calculated. Elevated odds rations were found in men working on their knees (OR 2.2), being exposed to vibrations of the upper limbs (OR 2.8), or adverse climatic conditions--humidity, coldness, or current air (OR 2.0). Men working in the metal industry or in other not further classified blue collar jobs also showed increased odds ratios (OR 3.2 and 3.1). In women odds rations were elevated for working in a standing position (OR 2.1) and for working with heavy tools (OR 6.1). PMID- 8693813 TI - [Exchange of syringes or apprenticeship? The buses of Bienne and Geneva]. AB - In Switzerland, the health ministry (Office Federal de la Sante Publique) has systematically encouraged the evaluation of low threshold services. In this article, we discuss the evaluation of two of these: the buses for syringes exchange in Geneva and Bienne, the implementation of these two services, the success obtained and the contacts established. Even if the design of such an evaluation was relatively complicated, with one monitoring and two specific surveys, the principal aim of this article is not to measure the efficacy as such but to show how an learning process has occurred between the actors: government, administration, police, service's team, drug's users and neighbourhood's inhabitants. The efficacy for a long period of time and the implementation's success are largely linked to such learning processes. PMID- 8693814 TI - [Benefits of low-threshold services for drug addicts exemplified by the city of Zurich]. AB - Low threshold services for drug users are a comparatively new approach in programs for drug users. The authors evaluate the facilities offered in Zurich with special regard to their establishment, concepts and objectives. The change of paradigms from unconditional abstinence towards an accepting attitude is characterized and explained by the notions of conceptualization, differentiation and resubjectivation. The evaluation aims at the assessment of these premises of low threshold programs for drug users. The assessment is scheduled in three stages from January to December 1995. This requires the use of standardized quantitative and guideline based qualitative instruments. In baseline interviews a total of 837 contacts with 655 persons could be achieved. Sociodemographic features, drug career and frequency of use of the different facilities on the sample day are described as initial data. A recontact rate of 60% from the first panel of interviews which ended in January 1995 considered satisfactory. PMID- 8693815 TI - [Evaluation of contact and care centers, a low-threshold daytime source in the city of Zurich]. AB - Contact centres for drug addicts in the city of Zurich exist since 1988 to provide decentralized low threshold meeting places and contact centres for persons who are poor and neglected. The main objective of these survival aids is to counteract further impoverishment of the addicted in order to actively contribute to their subsistence. Since its foundation the project as a whole has been submitted to numerous structural changes which had to be taken into consideration by the evaluation. Subject of the examination was the description of the target group and the staff, the use of the services and their effect on the users as well as the environment. Only quantitative methods were used. The target group of the centers consisted of drug consumers who at the best are partially socially integrated, but usually completely desintegrated. The evaluation revealed that the different contact centers services were extensively used and met the focal needs of their users. However, the high fluctuation of personnel within the project teams turned out to be a permanent problem for the project management and the operators. As main reasons for the fluctuation the authors discuss the great dependency on political decisions and the problematical demanding clientele. Due to these structural turbulences some staff related offers are only accepted to a limited degree, and the contact centers tend to become simple supply services. Therefore the authors endorse the redefinition of long term objectives of the institution under consideration of the necessary framework. PMID- 8693817 TI - [Monitoring of the activities of low-threshold access structures for drug users in Switzerland: distribution of sterile injection equipment, results for 1993 and various cantonal examples]. AB - In Switzerland numerous structures distribute or sell sterile injecting equipment for i.v. drug users, low threshold centres (LTC's) being the major provider. A national survey of these centres was initiated by the UEPP in january 1993, in the context of the global evaluation of the new set of the federal measures to reduce the problems related to illegal drug use. This article concentrates mainly on the results of the monitoring activity of the LTC's, which in 1993 distributed 7.1 millions syringes. This important offer is not, however, uniform across the different regions of the country. Some examples of regional variations are presented, as are fluctuations of demand in many LTC's. The observed variations can be correlated with season (increased demand in summer), but also with the development of LTC's (opening /closing down of centre, change in the structure, opening hours, etc.) and with external events (policy, increased pressure from police, etc.). This type of monitoring is useful not only for researchers in the field of drug addiction and prevention of HIV/AIDS, but also for decision makers and actors in the field of public health. The recommendations based on the first three years of this monitoring suggest that efforts to prevent sexual transmission of HIV among i.v. drug users should be reinforced as well as measures to supply sterile injecting equipment and condoms at low threshold level must be continued and further developed. PMID- 8693816 TI - [Evaluation of a stay and care center for drug addicts in Lucerne]. AB - Between April 1992 and March 1994 a low threshold centre named "Aufenthalts- und Betreuungsraum fur Drogenabhangige (ABfD)" ("Common Care Room for Drug Addicts") was run in the city of Lucerne which intended to help drug addicts to live and survive in terms of harm and risk reduction. The evaluation of the ABfD was conducted by the Institute for Social and Preventive Medicine on behalf of the Federal Office of Health. Combining qualitative and quantitative research methods its structure was evaluated regarding the realization of its own objectives. THE RESULTS: the ABfD was frequented beyond expectation by an average of about 65 male and female drug addicts per evening. All of its facilities were used and appreciated. The clientele of the ABfD was characterized by a great diversity of sociodemographic factors such as age, sex and income as well as housing conditions. The majority were residents of the city (approx. 54%) and the canton of Lucerne (approx. 28%). In general, the ABfD had a positive effect on the physical condition of its user insofar as the distribution of sterile injecting material enabled them to behave more risk consciously. Also, it gave many drug addicts something like a home and the opportunity to experience an atmosphere of solidarity. In spite of isolated criticism the ABfD generally enjoyed great esteem. The evaluation has shown that there is a need for a care center for drug addicts such as the ABfD, that it had been widely made use of, realized many of its objectives and it had no attractive effect on other regions. The researchers concluded by recommending the establishment of an analogous institution within a sensible period of time since with the closing of the ABfD in the Lucerne area the help to live and survive, an important pillar of the drug policy was no longer warranted for. PMID- 8693818 TI - [Evaluation of street facilities I, II and III in Basel]. AB - In June 1991 the city of Basel established the first low threshold centre (LTC) subsidized by the government after various private initiatives of "Live & Survive" aids. This low threshold facility which was supplemented in 1992 by two additional LTCs aimed at harm and risk reduction. The evaluation of LTCs was conducted by the institute for Social and Preventive Medicine of the University of Basel on behalf of the Federal Office of Health. Combining qualitative and quantitative research methods its structure was evaluated regarding the realization of its own objectives. The LTCs reached a great variety of drug addicts which were characterized by a remarkable heterogeneity. The majority of users were aged between 20 and 30, a quarter of them were female. Differences were found in housing conditions, subsistence and the degree of social integration. The facilities of the institutions were extensively used. In 1993 and 1994 a daily average of 250 to 300 visits was recorded in the injecting rooms only. the clientele were mainly residents of the Basel area. This lead to the conclusion that there was no attractive effect on more remote regions. As a consequence of the extensive use of the facilities a movement of the drug scene away from the street into the LTCs could be observed. In general, a stabilization or even an improvement of the physical condition of its users could be noticed. Another important feature was the improvement of the drug addicts' social integration. The main reason for this was the relationship between users and staff. Due to the shortage of personnel this promising base for further psychosocial work could not be adequately developed. The investigators not only concluded that there is a need for continuing maintenance of these facilities but also that additional efforts to improve the psychosocial services would be justified. PMID- 8693819 TI - [Evaluation of "Wallstrasse 16", day facility for the homeless and needy in Basel]. AB - "16, Wallstrasse, Common House for homeless and indigent People" in Basel is a new kind of facility in the range of already existing low threshold institutions of common kitchen, low threshold centre and night's lodging. This daycenter has the objective to offer homeless and indigent persons a place of tranquility rest where they can make new acquaintances and feel at home. In addition, its various facilities meet the sanitary needs of its clientele. The evaluation of the "Wallstrasse" was conducted by the Institute for Social and Preventive Medicine of the Basel University on behalf of the Federal Office of Health. Combining qualitative and quantitative research methods it inquired 1.) to what extent the institution realized its own objectives and 2.) if and how it met the needs of its target group. The evaluation revealed that its clientele mainly consisted of marginalized consumers of illegal drugs exclusively coming from that very area and often living in unstable housing conditions. Thus, the intended target group was reached. Within a year's time the attendance increased from 10 to 80 visitors a day to a high frequency of use. All of the various facilities of the house were used and appreciated. The evaluation stressed the significance as a place of tranquility and rest offering shelter not found in the street. The daycenter fills a gap in the range of low threshold services and contributes to the drug scene remove from the street. It establishes the base for extended social work which however cannot be properly realized due to the shortage of personnel. The evaluation found a good acceptance among the residents as well as a conflict free relationship with the police and a good cooperation with other institutions. PMID- 8693820 TI - [Evaluation of Haus Breitenstein, a low-threshold living facility in the city of Zurich]. AB - Early in 1991 in attended home with 13 rooms was established in the Breitenstein House in Zurich as a low threshold survival aid for most severe drug addicts. After only 17 months, before the end of the two-year pilot phase, the facility was closed for economic reasons. The objective of the project laid emphasis on the furtherance of each resident's initiative and responsibility. Using quantitative as well as qualitative instruments the accompanying evaluation came to the conclusion that the attended low threshold accommodation is a realistic completion and an alternative to already existing aids. The institution enabled the drug addicts to reestablish their damaged autonomy and take a constructive step towards the shaping of their lives. In individual cases a substantial structural change could be initiated. The authors concluded that the Breitenstein House was a successful attempt to develop comprehensive strategies in drug policy. PMID- 8693821 TI - [Evaluation of occupational programs in the city of Zurich]. AB - Occupational and job integration programs are components of low threshold drug policies. Since the mid-eighties many such projects have been realized not least to counteract the increasing pauperization of drug addicts and the spreading of AIDS. Two of these occupational programs, the "job-Bus" and the "Forderband (Conveyor Belt)", were evaluated by the means of two quantitative cross-sectional studies and by a qualitative topic oriented interview in the second phase. The results presented refer to the second phase of the evaluation. The proportion of women in the programs is low with only 10%. The average age of 38.4 is higher than in other institutions for drug users. The work program is well accepted among the participants, and there is a high demand for such programs in the target group. Non-material aspects such as structuring of days, contact opportunities and fulfillment give the institution an additional significance. The author therefore recommends expansion of these programs under occupational and socio-pedagogical aspects in doing so, the underrepresented women and young adults ought to be reached. Furthermore it should be examined whether stable users can be employed permanently. PMID- 8693822 TI - [Drug users outside medical treatment: methodological and practical aspects]. AB - A legal context that classifies the consumption of heroin and cocaine as an illegal act, poses a considerable methodological challenge to research on users of these substances. This is in particular the case for research on those users who are not in treatment and, therefore, cannot be recruited through treatment settings. In a research project on heroin and/or cocaine users outside treatment settings, a sample of 917 individuals was recruited through "Privileged Access Interviewers" in the whole of Switzerland. In the first part of this article, we discuss matters of reliability as well as of validity concerning this method of data collection. In the second part of the article, we discuss the use of low threshold syringe exchange schemes by the user groups represented in the sample. Only intravenous drug users frequent those services - they are however a minority in the sample (n = 238). In several regions of Switzerland syringe exchange schemes do not exist. Where they do exist, they appear to correspond to a need which they are able to cover largely. In the regions without such services, intravenous drug users get their supply of syringes more frequently from pharmacies. However, pharmacies do not compensate the absence of specific syringe exchange schemes. In regions without such schemes, injections with used syringes are more frequent. Thus, regarding Aids-Prevention, there is an urgent need to develop syringe exchange schemes in all parts of the country. PMID- 8693830 TI - Neuronal degeneration in brain stem nuclei in bovine spongiform encephalopathy. AB - In 57% of 151 BSE positive brains of Swiss cattle, degenerating neurons were found in BSE predilection sites, either single scattered (34%) or involving large parts of brain stem nuclei (23%). The lesion consisted of central chromatolysis, shrinkage, karyolysis or nuclear pyknosis. In 43% of the BSE positive brains no neuronal changes besides vacuolation were present. Neuronal degeneration other than vacuolation alone is not pathognomonic for BSE but, according to our findings, seems to be of some importance together with the typical vacuolation of neuropil and neurons. There is no correlation between extent of these degenerative changes and accumulation of PrPSc protein, determined by immunohistochemistry. The significance remains obscure, yet as it had not been seen in cattle brains before the outbreak of BSE in Switzerland in 1990 it certainly is linked to the disease. Possible pathogenetic mechanisms are discussed. PMID- 8693829 TI - Evaluation of seven microsatellite loci in Simmental cattle. AB - Seven microsatellite loci were evaluated for their suitability for parentage control. The polymerase chain reaction (PCR) was used to amplify the short tandem repeat (STR) loci in separate reactions. The microsatellite polymorphisms were visualized by radioisotopic autoradiographic detection. The microsatellite loci showed extensive polymorphism with allele numbers ranging from 4-23 and polymorphism information content (PIC) values in the range of 0.57-0.87. The analysis of these loci also revealed that they have a 99.9% combined probability of exclusion (PE) of erroneous parentage. The results of this study revealed that a very high probability of exclusion could be reached with only four microsatellite loci. PMID- 8693832 TI - The sequelae of fragmented anconeal process (FAP) lesion in pigs: a radiologic, macroscopic and histopathological investigation. AB - The development of the anconeal process its lesions and their sequelae were scrutinized during the follow-up radiographic study (every 5 months) of porcine osteochondrosis of elbow joint bones done in 80 Danish Landrace pigs from day 42 of age to 38 months of age. The anconeal process was observed radiologically to be ossified at the age of between 6 to 7 months. Normally it ossifies by pyramidal extension from the proximal ulna. However, fragmented/ separated anconeal process lesion was demonstrated in 15 pigs (the process was "ununited' with the rest of the proximal ulna). The diagnosis was confirmed in nine pigs at gross post-mortem and microscopically when the pigs were slaughtered due to other reasons than lameness of the front leg. These cases were interpreted as "fragmented/separated anconeal process' (FAP/SAP). This lesion showed a tendency to heal with increasing age. The lesions were healed in all surviving pigs at the age of 25-26 months. PMID- 8693831 TI - Systemic, metastatic, eu- and heterotope tumours of the heart in necropsied dogs. AB - 10,090 dissections of dogs exhibited 2631 neoplastic processes of which 309 involved the heart in the form of eu- and heteropic tumours. The most common primary and/or secondary heart tumour type was hemangiosarcoma (n = 187), followed by paraganglioma (n = 46), carcinoma (n = 33), malignant lymphoma (n = 12), thyroid heart base tumour (n = 9), melanoma (n = 7), mast cell tumour (n = 3) and blastoma (n = 2). The tumour diagnoses were immunohistochemically proved by various antibodies to cytokeratins, vimentin, GFAP, NSE, von Willebrand factor, CD3, CD45RA, S100, thyroglobulin as well as histochemically with argyrophilic, Fontana-Masson and heterochromatic reactions. The odds ratio (OR) for breed and tumour prevalences were determined: German shepherds showed the highest OR for hemangiosarcomas and boxers for paragangliomas. PMID- 8693833 TI - Total blood volume in the normally performing Standardbred trotter: age and sex variations. AB - The purposes of this study were to elucidate the influences of age and sex on the mass specific blood volume parameters: total blood volume (TBV/BW, ml/kg), plasma volume (PV/ BW, ml/kg), total red cell volume (CV/BW, ml/kg) and maximal packed cell volume (PCV, l/l, i.e. after total mobilisation of the splenic red cell reservoir) and to establish reference values for these in normally performing Standardbred trotting race horses. In total 205 horses were studied. They were all, according to their owners and/or trainers, performing satisfactorily in racing or training for shortly impending racing. Blood volume determination was done with the Evans blue dye dilution technique after exercise induced emptying of the spleen. Both age and sex were found to influence variation of these parameters significantly, with the possible exception of PV/BW, whereas the primary variation appeared to be in CV/BW. It was concluded that taking age and sex dependent variations into consideration will render prediction of normal values for the blood volume parameters in the athletic Standardbred trotter more reliable and the detection of abnormal deviations more precise if five age and sex groups are used for comparisons. PMID- 8693834 TI - [Tissue lipid peroxidation in nutritional encephalomalacia of broiler chickens]. AB - The consequences of different dietary fats in combination with two vitamin E levels on peroxidative tissue damage of chicken brain and liver and its meaning for development of nutritional encephalomalacia (NE) were investigated. A feeding experiment was performed with 1-day-old chickens from hens on a vitamin-E-poor diet. The animals received a vitamin-E-deficient basic diet containing 10% fat, rich in either C18:3n3-, C18:2n6- or C18:1n9-fatty acids. The fat was given either fresh or oxidized (peroxidation number: 250) and 0 or 50 ppm alpha tocopherylacetate was added. Typical symptoms of NE occurred mainly in those groups fed with n6-fatty acids beginning on day 7. In order to evaluate oxidative tissue damage, conjugated dienes, fluorescent pigments and TBA-reactive substances were determined in liver, cerebrum and cerebellum. Brain was examined histologically. In liver and cerebrum, the feeding of oxidized fats led to a 20% increase in conjugated dienes. Fluorescent pigments could be determined only in the brain tissues. However, feeding conditions had no effect, although autofluorescence was observed histologically in the affected animals. TBA reactive substances were heightened in cerebrum (30%) and liver (130%) as a result of feeding linolenic acid. Vitamin E deficiency doubled TBA-reactive substances only in the liver. The parameters measured did not show intensified lipid peroxidation in the cerebellum of the animals fed the NE producing diet. Rather, the liver seems to be affected by the oxidative stress. PMID- 8693835 TI - Absence of skeletal muscle lesions after experimental restraint stress induced by pancuronium in normal and stress-susceptible pigs. AB - Stress-susceptible (SS) pigs develop rhabdomyolysis and increased serum levels of muscle enzymes after a 12 min experimental stress induced by the depolarizing myorelaxant succinylcholine. It is suspected that not only the stress situation but also succinylcholine itself contributes to the skeletal muscle lesions. This experiment was performed to study whether rhabdomyolysis occurs after restraint stress when succinylcholine was replaced by the non-depolarizing myorelaxant pancuronium. Four normal and four SS pigs were subjected to restraint stress by intravenous injection of pancuronium. The neuromuscular block was reversed after 12 min by neostigmine. The animals wee necropsied approximately 48 h after stress and 24 skeletal muscle groups were examined pathologically. The severity of acute myofibre lesions were graded, and the results were compared with the results from normal and SS pigs which had been subjected to restraint stress induced by succinylcholine. The serum levels of creatine kinase (CK) and aspartate aminotransferase (ASAT) stayed at the base line level after the stress. The scores for muscle lesions were significantly lower, both in normal and SS pigs, than after restraint stress induced by succinylcholine indicating no rhabdomyolysis after restraint stress induced by pancuronium. Thus succinylcholine is synergistic with stress, exacerbating its effect on skeletal muscle in SS pigs. PMID- 8693837 TI - Intra-articular morphine and saline injections induce release of large molecular weight proteoglycans into equine synovial fluid. AB - Both morphine and physiologic saline injected intra-articularly into healthy equine tarsocrural joints induced a release of large molecular size proteoglycan (PG) subunits into the synovial fluid (SF) analysed 24 h postinjection. High performance liquid chromatography (HPLC) with a size-exclusion column was used to assess the high molecular weight proteoglycans in equine synovial fluid (SF). The PG peaks of SF samples eluated separately from SF hyaluronate and other molecular components of the SF in the HPLC chromatographies indicating no interaction between hyaluronate and PG in the SF. Individual elution profiles varied between joints and horses. The amount of PG release was measured by relative area index from the HPLC chromatograms. The synovial fluid PG content was significantly increased (P < 0.05) after morphine but not in saline injected joints compared with pretreatment but there were no significant differences between the two groups. It was concluded that intra-articular injections of both morphine and physiologic saline are able to elicit a marked PG release into the SF from articular cartilage within 24 h of injection. PMID- 8693836 TI - Endogenous opioids may modulate the activity of the hypothalamus-pituitary adrenocortical axis in domestic fowl. AB - The activity of the hypothalamus-pituitary-adrenocortical (HPA) axis is under complex neuronal, hormonal and peptidergic control. In order to determine the role of the endogenous opioids in the modulation of the HPA axis in hens we have examined the changes of the plasma levels of Met-enkephalin, alpha-neo-endorphin, catecholamines and corticosterone during rest, stress (30 min of overcrowding) and after naltrexone pretreatment. Short overcrowding induced an increase of all parameters, but the time of response and duration of elevation was different. Plasma Met-enkephalin showed a biphasic response: decrease followed by increase at the end of stress. Catecholamines and corticosterone peaked at 30 min of overcrowding and the highest level of alpha-neo-endorphin has been noticed at 20 min after the experiment was started. Naltrexone (2 mg/kg b.w., i.v) diminished the responses to stress of all parameters and did not change their basal levels, except for corticosterone. These results indicate that the endogenous opioids may take part in the mediation of HPA activity in hens during resting and stressful situations. PMID- 8693838 TI - Influence of sample predilution on the sensitivity of prothrombin time in feline plasma. AB - The prothrombin time (PT) is measured in feline plasma usually by means of a method that has been optimized for measurements in human plasma (standard test). In the present study the sensitivity of this test was investigated in comparison to a modified PT using a human placental thromboplastin. In the modified test, 100 microliter sample predilution (1:5, 1:10, and 1:20) were incubated with 100 microliter of a human fibrinogen solution (2 g/l) until 100 microliter Ca thromboplastin was added. When measured in 31 samples with a reduced, and 22 samples with an increased activity of the coagulation factors II, V, VII and/or X the modified test showed an increased sensitivity as well as a correlation between PT and the changes in single factor activity which was distinctly closer compared to the standard test. The highest sensitivity was produced by a 1:10 or 1:20 sample dilution. A test procedure modified in this way, is thus, a more reliable screening test for the extrinsic system in cats and should be used for routine diagnostics. PMID- 8693839 TI - PCR screening for carriers of bovine leukocyte adhesion deficiency (BLAD) and uridine monophosphate synthase (DUMPS) in Argentine Holstein cattle. AB - BLAD (Bovine Leukocyte Adhesion Deficiency) and DUMPS (Deficiency of Uridine Monophosphate Synthase) are monogenic autosomal, recessive inherited diseases of Holstein cattle. Single nucleotide changes (point mutations) responsible for the genetic disorders were detected by polymerase chain reaction coupled with restriction fragment length polymorphism assays (PCR-RFLP). Using oligonucleotide primers, DNA fragments of predicted sizes were amplified, and the products' specificity was assessed by nucleotide sequencing. Mutations were detected in DNA samples from bovine blood and semen by the presence or absence of restriction sites within the PCR amplification products (Taq I, Hae III for BLAD, Ava I for DUMPS). The test included 104 bulls and 950 cows of Argentinean Holstein breed. Defective alleles frequencies were as follows: 2.88% BLAD in bulls used in artificial insemination, 1.79% in cows; 0.96% DUMPS in bulls and 0.11% in cows. PMID- 8693840 TI - Attainment of spermatogenesis in Swedish cross-bred boars. AB - Twenty peripubertal Swedish cross-bred boars were used to study the testicular differentiation and the maturation of spermatozoa (epididymal) between 100 and 180 days of age. In all animals the sex cords were small and solid at 100 days of age. Spermatogenesis started at approximately 115 days of age and was completed, i.e. the cellular organization of the seminiferous tubules indicated a sexually mature testis with normal spermatogenesis, at 180 days of age. By 125 days of age only a few spermatozoa were found in the cauda epididymidis Furthermore, a high frequency of sperm morphological alterations were seen. The sperm concentration in the cauda increased with increasing age, and simultaneously the frequency of abnormal spermatozoa decreased. However, not all boars had a 'mature' semen picture in the cauda epididymis at 180 days of age. PMID- 8693841 TI - Evaluation of additional acetone and urea analyses, and of the fat-lactose quotient in cow milk samples in the herd recording system in Norway. AB - The purpose of this study was to evaluate the use of additional acetone and urea analyses to the established herd recording system (protein, fat, lactose, and somatic cell count) in cow milk samples every second month. Samples were obtained from 43/82 herds (800/1368 cows) in a lowland/highland area. Acetone concentration (mmol/l) were classified into acetone classes 1 (<0.7); 2 (0.7 1.4); and 3 (>1.4). There was an association between increasing acetone class and increasing ketosis incidence in herd (Kendall's Tau-b = 0.13). The highest percentage frequencies of acetone classes 2 and 3 were in weeks 4-6 postpartum. Milk yield, urea, and lactose were significantly lower; milk protein not different, and milk fat was significantly higher in herds with high ketosis incidence and in cows in acetone classes 2 and 3. General linear models, obtained by backward elimination of non-significant variables, showed that milk protein was negatively associated to milk yield and positively associated to milk fat. Milk yield decreased, and milk fat concentration increased with increasing acetone level. Milk fat and milk lactose were negatively associated, and a fat lactose-quotient might be promising in a model to rule out subclinical ketosis cows. PMID- 8693842 TI - Early stages of rabbit haemorrhagic disease virus infection monitored by polymerase chain reaction. AB - In order to define more accurately the initial events that take place during rabbit haemorrhagic disease virus (RHDV) infection, different organs of experimentally infected rabbits were analysed for the presence of the virus and correlated with histopathological observations. A total of 24 rabbits were intranasally inoculated with a viral suspension, and tissue samples were taken from the liver, spleen, kidney, lung, thymus, lymph node and tonsil at different intervals post-inoculation (2, 4, 6, 12, 18, 24, 30, 36, 48, 50, 51, 70 and 72 h). Histopathological observations revealed the presence of the first significant lesions at 30 h post-inoculation (p.i.) in the liver. Using an ELISA and a haemagglutination test (HAT), the virus was detected in the liver at 36 h p.i. The reverse transcriptase-polymerase chain reaction (RT-PCR) showed that the RHDV RNA was present as early as 18 h p.i. in the liver and spleen, whereas thymus, kidney, tonsil and lymph node were found to be positive after more than 36 h p.i. The lungs presented a variable positivity between 0 and 36 h p.i., but remained positive after this time. PMID- 8693843 TI - Seasonal variations in the isolation of Salmonella typhimurium, Salmonella enteritidis, Bacillus cereus and Clostridium perfringens from environmental samples. AB - Calf carcasses contaminated with S. typhimurium, B. cereus and Cl. Perfringens were placed in either a decomposition pit or in a deep burial pit. Salmonella was isolated from the soil around the decomposition pit for 27 weeks and for 15 weeks around the burial site. Salmonella re-appeared in soil samples during cold winter weather after an apparent 9-week absence from the decomposition pit and after 68 weeks in the burial site (a total of 88 weeks after the start of the experiment). There was also an annual rise in the isolation rate of B. cereus from the soil during the colder winter months, but Cl. perfringens appeared to be more prevalent in samples taken during spring of the second year of the study. A similar apparent rise in the prevalence of S. enteritidis during a cold winter period occurred in an empty poultry house that had previously held a naturally infected broiler-breeder flock. PMID- 8693844 TI - Histopathological and immunofluorescent studies on transplacental infection in experimentally induced abortion by equine arteritis virus. AB - Five pregnant mares, at between 6 and 8 months gestation, were experimentally infected with the Bucyrus strain of equine arteritis virus (EAV). Of the five mares, four aborted and one died. The pathogenesis of the abortions was studied, using histopathologic techniques, tissue immunofluorescence and virus isolation. Common microscopic lesions in the maternal reproductive organs indicated myometritis with a degeneration of the myocytes and an infiltration of the mononuclear cells. Epithelial cells of the endometrial gland showed sporadic degeneration. Lesions in the fetal tissue included an atrophy of the lymphoid follicles in the spleen and lymph nodes with degenerated lymphocytes. The placentae were oedematous and degenerated fibroblasts were observed in the subvillous layers. Immunofluorescence detected EAV antigen in the myometrium and the endometrial gland in the dams, in the subvillous layer of the placentae, and in the aborted fetuses. EAV was recovered from the maternal uteri, placentae and fetuses. The placentae yielded the greatest amounts of the virus. Transplacental infection of the fetus was clearly demonstrated in the EAV infection. PMID- 8693845 TI - Use of the polymerase chain reaction for the detection of reticuloendotheliosis virus in Marek's disease vaccines and chicken tissues. AB - Reticuloendotheliosis virus (REV) proviral DNA appears to be a frequent contaminant in Marek's disease (MD) vaccines. A polymerase chain reaction (PCR) was established and evaluated for its ability to detect REV proviral DNA in infected cell cultures and chicken tissues. Deoxynucleotide primers were selected from the highly conserved gag region of the REV genome. The amplification products were identified by electrophoresis, nested PCR and by hybridization with a digoxigenine-labelled oligonucleotide. The PCR results correlated well with the diagnosis obtained by conventional procedures, i.e. virus isolation or indirect immuno-fluorescence test (IIFT). PMID- 8693846 TI - Clinical features of experimentally induced rabies in cattle and sheep. AB - A total of 20 cattle and five sheep out of a larger group of animals that were experimentally challenged with virus as part of the required protocol for a vaccine trial developed clinical signs of rabies. All five sheep and 18 of the cattle tested positive for rabies in a direct fluorescent antibody (FA) test. The remaining two cattle had suspicious FA results. Prospective observations are reported in this study. In the diseased cattle, the average incubation period was 15.1 days and the average morbidity period was 3.7 days. Of those, the naive cattle had significantly shorter incubation and morbidity periods than the test vaccinated cattle. Major clinical signs included excessive salivation (100%), behavioural change (100%), muzzle tremors (80%), vocalization (bellowing; 70%), aggression, hyperaesthesia and/or hyperexcitability (70%), and pharyngeal paresis/paralysis (60%). The furious form of rabies was seen in 70% of the cattle. In the diseased sheep, the average incubation period was 10.0 days and the average morbidity period was 3.25 days. Major clinical signs included muzzle and/or head tremors (80%), aggressiveness, hyperexcitability, and/or hyperaesthesia (80%), trismus (60%), salivation (60%), vocalization (60%) and recumbency (40%). The furious form of rabies manifested in 80% of the sheep. Current rabies vaccines on the market contain higher effective doses than that utilized for the test vaccine and the results of this study do not reflect in any way on commercially available ruminant rabies vaccines. PMID- 8693847 TI - Blastogenic response of lymphocytes from foals infected with Rhodococcus equi. AB - The blastogenic response of lymphocytes from 16 newborn foals naturally infected with Rhodococcus equi was investigated, in order to evaluate the relationship between R. equi infection and depressed host response. Naturally infected foals showed evidence of R. equi infection at 5-6 weeks of age, as determined by clinical, haematological, bacteriological and serological methods. The blastogenic response of lymphocytes against phytohaemagglutinin was significantly depressed (stimulation index < 1.80; P < 0.01, P < 0.05) in R. equi-infected foals at 5-6 weeks of age compared with those of control foals. Serum IgG concentration decreased rapidly after foals reached 1 week of age, and minimum levels of IgG were observed at 5-7 weeks of age in R. equi-infected foals. This study suggests that the onset of R. equi infection may be associated with the depressed immune function of naturally infected foals during the first 5-6 weeks after birth. PMID- 8693848 TI - In vivo interpretation of in vitro effect studies with a detailed analysis of the method of in vitro transcription in isolated cell nuclei. AB - In vitro experimental approaches are of central importance to contemporary molecular and cellular biology and toxicology. However, the scientific value or impact of in vitro results depends on their relevance in vivo. In vitro effect studies address inobservable in vivo phenomena through experiments on analogous in vitro phenomena. We present a theoretical basis developed to evaluate the in vivo relevance of in vitro effect studies. As a case study, the procedure for measuring specific gene transcription in isolated cell nuclei (?nuclear run-off method?) is analyzed. It is concluded that current evidence fails to justify in vivo interpretations of nuclear run-off experiments within the framework of theoretical models of transcription, implying that quantitative in vivo interpretations are unwarranted. Qualitative interpretations of nuclear run-off experiments may be justified by inferring ?the best explanation?, especially when significant in vitro effects follow in vivo perturbations. Elements of a general theory are proposed. It is concluded that quantitative in vivo interpretations are warranted primarily in biochemical quantitation of biomolecules, while studies on biological function should be interpreted qualitatively in terms of causal explanations. Inferences to the best explanations are strengthened through additional evidence and the creation of experimental differences (effects). PMID- 8693849 TI - Some prerequisites for a study of the evolution of cognition in the animal kingdom. AB - A distinction is made between two definitions of animal cognition: the one most frequently employed in cognitive sciences considers cognition as extracting and processing information; a more phenomenologically inspired model considers it as attributing to a form of the outside world a significance, linked to the state of the animal. The respective fields of validity of these two models are discussed along with the limitations they entail, and the questions they pose to evolutionary biologists are emphasized. This is followed by a presentation of a general overview of what might be the study of the evolution of knowledge in animals. PMID- 8693850 TI - Atavisms in homo sapiens: a Bolkian heterodoxy revisited. AB - An atavism is the "..reappearance of a lost character (morphology or behaviour) typical of remote ancestors and not seen in the parents or recent ancestors of the organisms displaying the atavistic character" (Hall, 1984). In humans, hypertrichosis (extensive body hair), the presence of a tail and supernumerary nipples are often quoted as examples (Hall, 1995). However, Louis Bolk (1866 1930) explained these phenomena in another way. He considered human morphology as an unspecialized expression of the mammalian developmental pattern. The latter also encompasses potentialities for unilateral or propulsive development pathways (specializations) that usually remain latent in humans, but can become expressed in other species. According to Bolk, the appearance of so-called atavisms in human results from the occasional expression of these latencies in Homo sapiens; they do not recapitulate ancestral conditions. PMID- 8693852 TI - [Sutures in digestive surgery]. AB - Anastomotic leakage remains the most important cause of morbidity and mortality in digestive surgery. Despite the development of new surgical techniques and devices, intestinal anastomose continue to be complicated by leakage even in the best and most experienced of hands. One may explain the persistence of anastomotic leakage in spite of these technical advances on the basis of the dynamic effect that multiple factors (shock, peritoneal sepsis, inadequate intestinal preparation, advanced age, malignancy, malnutrition, coagulopathy, steroid dependence, uremia, radiation therapy, diabetes, perforation, anemia, fecal soiling and deficiency of vitamin C, iron and zinc) have on the healing of an anastomosis. Awareness of these factors and proper precautions by the surgeon can make a high-risk anastomosis less prone to leakage. Collagen is the essential material for composing an anastomosis and the basis of a good surgical suture. Recognition an correction of factors that compromise collagen synthesis, should be the goal of the surgeon. Over the years, numerous anastomotic techniques have been proposed, but the search for the ideal technical anastomosis goes on. Traditional inverting methods ignore the basic principle of accurately opposing clean-cut tissues, and temporary clamping of the gut and crushing of mucosal tissue by intraluminal sutures may damage the microcirculation. Submucosa should always be included in the formation of an anastomosis because it is the strongest intestinal layer and because the collagen has its origin and its synthesis just in submucosa. Monofilament sutures may be more desirable for anastomosis. Staple sutures have minimum tissue reaction. Single layer extramucosal technique has many of the attributes of an ideal intestinal anastomosis. Single interrupted and continuous sutures are not opposite and both give satisfactory results. PMID- 8693851 TI - A possible contribution of phenomenology to ethology: application to a behaviour pattern in the mouse. AB - Classical ethology encourages a causal approach to animal behaviour, using Tinbergen's four questions concerning evolution, function, mechanism and development of behaviour. It sets aside the study of mental processes, which could otherwise help to unify our picture of the relationships between animal and environment. Here the steps in research focused on the psychological meaning of a peculiar behaviour in the mouse--carrying its tail--and what this implies regarding the mouse's cognitive world are given. Initial empirical observations suggested epistemic choices concerning space and object notions in the mouse; this led us to go beyond the first stage in exploring the significance of this behaviour. Later experiments showed the limitations of an explanation based on a cause-effect relationship. An interpretative model integrating a phenomenological conceptual framework is proposed. PMID- 8693853 TI - [Esophago-visceral anastomosis]. AB - Anastomoses which include oesophagus are still surgical problem. Anastomotic stricture and leakage are the most frequent. Consecutive 1155 patients operated in I surgical clinic KCS from 1968 to 1994 were analysed. Results reviles that precise technique and surgeon experience ware of the most importance. PMID- 8693854 TI - [Complications in esophagojejunal anastomosis]. AB - In the period between January 1, 1982 until December 31 1993, in the Center for Esophageal Surgery, Institute for Digestive Disease - 1 st Surgical clinic in Belgrade, 345 esophago-jejuno anastomosis (EJA) were performed. In 326 pt's EJA, with the Roux-en-Y reconstruction with the segment of the small intestine, was performed after a total gastrectomy due to a malignant disease of stomach or cardia and in 7 due to an extensive corrosive changes of the stomach. In 12 pt's a resection of the distal esophagus due to an undilatable stricture and the reconstruction with the short segment of the small intestine (Merendino) was performed. In all 345 pt's a terminolaternal EJA was performed. In 149 pt's EJA was done mechanically by staplers (e.g., the EEA instrument) and in 196 an interrupted two layer suture was performed. In 326 pt's (operated due to a malignant disease) complications occurred in 29 of them (8.89%) while in the group of patients with benignant disease only in 2 pt's or 10.52%. A dehiscention of EJA occurred only in the group of pt's with malignant disease. Comparing the way of performing EJA a higher percentage of anastomotic leaks was found in the group of hand sewn anastomosis (18/8.16%) while in the group with a stapler performed anastomosis anastomotic leak was found only in 7 pt's (4.69%). In two pt's where a stapler anastomosis was performed there was a hemorrhage from the anastomosis during the operation, and in 8 pt's or 5.36% an unsuccessful anastomosis using a stapler was performed. Overall mortality was 6.66% or 23 pt's. Due to anastomotic leak 13 pt's died (3.76%). In 5 pt's 4 to 14 months after the operation a stenosis of anastomosis developed on EJA that severely compromised EJA and needed further medical treatment. None of the pt's was reoperated. PMID- 8693855 TI - [Advantages and disadvantages of esophagogastroplasty in reconstruction of malignant and benign esophageal stenosis]. AB - Advantageous morphology, sufficient blood supply and good tissue quality predispose use of stomach for ideal substitute in subtotal and total esophagoplasty. Additional advantages are one act surgery and possibility of single anastomosis formation. In an eighteen years' time, since 1976., two hundred nine (209) patients were operated with use of esophagogastroplasty for malignancies and benign diseases of esophagus and hyphopharinx. The esophagogastric anastomosis is most common reconstructive procedure for esophageal and hyphopharingeal malignancies. Anastomosis on pharyngeal level was made in 13 pts., on cervical esophagus level in 168 pts. and on thoracic esophagus level in the rest of 28 pts. Overall postoperative morbidity was 25,36%. Most common complication was anastomotic dehiscence (18,66%), transplant necrosis occurred in 2% of pts., whereas stenosis of the anastomosis was observed in 4,78% of pts. Overall intrahospital mortality was 14,38%, while specific mortality (anastomotic dehiscence and/or transplant necrosis) was 10,04% (21 pts.), whereas nonspecific mortality (predominantly lung insufficiency) was 4,78% (10 pts.). Anastomotic dehiscence is major disadvantage of this method. PMID- 8693856 TI - [Primary suture of the esophagus with reinforcement using autologous tissue in the therapy of perforation of the thoracic esophagus]. AB - Perforations of the esophagus are the serious problem and only promptly diagnosis and treatment with effective operation can change the fatal destiny of this patients. The most effective operations of early diagnosed perforations are the primar suture with buttresses with circumferential wrap of parietal pleura. Authors discuss 15 patients with perforations of thoracic esophagus. In six patients the perforation was only sutured, and in nine patients the suture line was buttressed with Grillo pleural wrap. In this group one patient had a leak at the suture line and died after reoperation. This data indicate that the pleural wrap should be used routinely. PMID- 8693857 TI - [Anastomosis suture technic and complications of esophagocoloplasty in corrosive lesions]. AB - For the reconstruction of the esophagus due to a corrosive stenosis a colon transplant is usually used. In all esophagocoloplastics three anastomosis are necessary: anastomosis that continues the alimentary tract, anastomosis of the distal part of transplant with the stomach or duodenum, and the most important proximal anastomosis of the esophagus (or pharynx) with the transplant. In the period of 29 years (from January 1, 1964 until December 31, 1993) on the Institute for digestive diseases in Belgrade 250 esophagocoloplastics were performed with 750 anastomosis, in the patients with corrosive stenosis of the esophagus. All the anastomosis are sewn in two layers with the interrupted or continuous stitch, except for the anastomosis with the pharynx where due to a structure of the wall a one layer continuous stitch was only possible. From 750 anastomosis in 30 patients or 4% an anastomotic leakage occurred and in only 4 patients or 0.5% it ended lethaly. Stenosis of the anastomosis occurred in 18 patients or 2.4%. PMID- 8693858 TI - [Characteristics of surgical sutures in the duodenum and small intestine]. AB - The particularities of the surgical suture of duodenum and small intestine are exposed. According to the recent experiences from the literature, the best material for the intestinal suture is monofilamentous, with delayed resorption rate, and characterized by the hardness appropriate to the tissue involved. The representatives of these are Polyglactin and Polydioxanon. In the technique of the duodenal suture, inversion of the tissue and placing the sutures in the healthy tissue are more important than mucosal inversion and multiple layers closure. The omental patch must be variable, and not involved directly in sutures. In the small intestinal surgery, one layer sero muscular-extramucosal, or two layers mucomucosal with inversion and seroserosal suture are to be used. For duodenojejunal transition, terminolateral anastomosis is recommendable. Upon lower parts of ileum oblique terminoterminal or latero-lateral anastomosis is to be used. In the cases of luminal disproportion between open ends, terminolateral anastomosis seems to be the best choice. The percentage of duodenal stump dehiscence in the period of 1986-1992. is 2.53% upon 356 emergencies of delayed operations, and the percentage of the intestinal anastomotic dehiscence upon 102 elective and emergency operations is 5.8%. PMID- 8693859 TI - [Sutures in biliopancreatic surgery]. AB - The most important element of surgical intervention is quality of the surgical stitch, meaning of surgical anastomosis. The importance of resorptive surgical stitch in the surgery of hepato-biliary system has been painted out, so that a possibility of delayed stricture and calculus's can be avoided. Principals of the reconstruction of extrahepatic biliary system have been shown together with the types of surgical suture material in the bilio-pancreatic surgery. Review of 486 bilio and pancreaticoenteric derivations or reconstructions in the period from 1989 until 1993 on the First Surgical Clinic is presented. A comparative study has been made comparing postoperative complications due to an anastomotic leak and the mortality in the groups of patients with the reconstruction of benign biliary strictures (119 pt's) and cephalic duodenopancreatectomy (44 pt's) with the other results from the world-wide instructions reported in the literature. In the group with benign biliary strictures temporary bile leakage reached 3.8% and operative mortality was 0.8%. In the group with Whipple operation 11.3% pt's had pancreatic, 4.5% pt's had biliary leakage and operative mortality was 4.5%. We can conclude that our results match the worldwide results concerning this problem. PMID- 8693860 TI - [Sutures in reconstructive procedures in biliopancreatic surgery]. AB - The question of the suture technique in digestive surgery as in reconstructive biliopancreatic surgery remains of interest to all surgeons throughout the world. On the basis of the biochemical process in anastomose healing the author accepted the one-layer operative technique as a routine. The dilemma was only in pancreatic reconstructive surgery, where the two-layer technique was also performed. Minimal postoperative morbidity with no mortality justifies our stand. Our conclusion is based on 241 operated patients in a ten years period. PMID- 8693861 TI - [Sutures in surgery of the colon]. AB - The use of different suture technique in the surgery of colon in the Surgical Clinic KBC Zvezdara Belgrade, was subjected to the retrospective study. The 2 years period of statistical study was performed in 1992/93. The early postoperative results of 143 patients were analysed and divided in four different groups: In the first group are the patients operated by mechanical device technique (12 patients, 8%), the second group of patients are those operated by the double row suture technique (38 patients 26%) the third one are the patients operated by one raw suture technique (37 patients, 25%)) and the fourth one in which the patients were operated by Gambee technique of suture (56 patients, 39%). In all four groups of patients three most important parameters of the postoperative evolution of the reconstructive operations in the surgery of the colon were analysed: anastomotic leakage, leptic temperature over 38 C, and evident wound infection. The best results have been registered in the group operated by mechanical device, without any anastomotic leak, septic state or evident wound infection. Good results have been obtained using the Gambee suture technique with evident anastomotic leakage in 4 patients (7,8%). The worst results were found using the double row suture where we registered 13,5% dehiscencics and in 27% of patients septic fever over 38 C. Based on our experience on the small group of patients we could find the following conclusions: a mechanical suture is the best in the surgery of colon b. in the field of manual suture we prefer the one-row extramucosal suture, c. Gambee suture is a transitional one between one row and double row suture and it presents everywhere good results except in low and extralow anastomosis. PMID- 8693862 TI - [Single-layer anastomosis of the colon]. AB - Presented are the analysis of 134 single-layer colon anastomosis done between years 1983 and 1993. Essential parameters of those are compared with two-layer colon anastomosis - 65, done at the same period, as well as with wider series done in the world in a last couple of years. Main task of the analysis is to point to contemporary developments of suture technique in the world and at home, which is being simplified in technical terms, characterized by time and material savings without affecting anastomosis quality. Those characteristics have been attained due to good preparation of intestines, improved materials, antibiotics and due to finding out that submucosis and subserosis are carriers of suture firmness. On processed material when single-layer suture was used (134) we had average of 8.2% clinically evident fistulas - single-layer individual (78) 3.8% a single-layer continuous (58) 14%. With two-layer suture technique (65) we had 14% clinically evident fistula. Average mortality with both techniques was 4%. PMID- 8693863 TI - [Comparative analysis of sutures and stapling for colorectal anastomosis in resection of the rectum in carcinoma]. AB - In Clinic for general and vascular surgery - Military Medical Academy Belgrade since 1987 to 1993 in treatment of the rectal cancer it was done 326 low anterior resections. In 149 patients anastomosis was done with sutures and in 177 with stapler. Half of them were more then 60 years old, and in 40% of patients carcinoma was staged as Dukes C or D. In group I tumor was localised in the middle or distal third of rectum in 24.8% of patients while in group II this was in 75.7%. Anastomosis related complications where rare in stapler group, clinically evident anastomotic dehiscence was found in 11.4% patients in I group and in 99% in II group. Total mortality was 3.1%; 3.4% in the I group and 2.8% in the II group. In our comparative analysis of early complications after low anterior resection of rectum when colorectal anastomosis was done with suture or stapler technic we have found that stapler technic give opportunity for creating much more low colorectal anastomoses which are safe and with less complications and with the same oncologic control of disease. PMID- 8693864 TI - [Mechanical sutures in resection of the rectum in carcinoma]. AB - In the period between January 1, 1992, and January 1, 1994, on the 3rd Department of the 1st Surgical Clinic, Clinical Center in Belgrade, 116 pt's has been operated due to a rectal carcinoma. In all of these pt's an anterior resection of the rectum and a colorectal stapled anastomosis was performed. Colorectal anastomosis was performed using an American EEA stapler on the different segments of the rectum. Overall, a 30 or 25.86% intraperitoneal anastomosis have been performed, 18 (15.51%) were done on the medium third of the rectum and ultra low anastomosis were performed in 68 pt's (58.63%). In our group there was 6 pt's with the anastomotic leakage and a leakage occurred only in the group of pt's with ultra-low colorectal anastomosis. In three pt's after conservative treatment a spontaneous healing of the anastomosis happened while in the other three pt's an explorative laparatomy with loop ileostomy had to be performed. One patient died during the postoperative treatment. The patient died on the second postoperative day due to a mesenteric thrombosis and gangrene of the intestines. PMID- 8693865 TI - [Anastomosis of the rectum]. AB - The anastomosis between rectal remnant and anal canal with other parts of digestive system, remains a big challenge for surgeons till nowadays. In the years period 173 anastomoses has been done with 21 case (12%) of clinical leaks. According to our experience the technique of continuous extramucosal one layer anastomosis is a good one for high colorectal and ileorectal anastomosis. For low colorectal anastomosis the technique of extramucosal interrupted sutures for posterior and Lembert's suture for anterior wall as single layer have had the lowest incidence of clinical leaks. Low and ultra low anastomoses could be best done with double staptechnique acc. to Knight-Griffen. Our figure of 12% of clinical leaks is rather comparable with published data of others. PMID- 8693866 TI - Rhodococcus equi infection in 3 AIDS patients. AB - Three cases of AIDS complicated by Rhodococcus equi infection are reported. At least one of the patients acquired his Rhodococcus infection in Africa. Despite the fact that the R. equi strains were susceptible to tetracycline, erythromycin, amikacin, co-trimoxazole, rifampicin and vancomycin, these antibiotics were clinically not successful. A clinical improvement was observed in only one patient during teicoplanin and imipenem-cilastatin treatment. Multicentre clinical trials are needed to determine the optimal treatment of R. equi infections in AIDS patients. PMID- 8693867 TI - Granulocytic sarcoma (chloroma): a report of two cases. AB - Granulocytic sarcoma or chloroma is defined as an extramedullary solid tumor, composed of granulocytic precursor cells at various levels of differentiation. Granulocytic sarcoma is mostly associated with acute and chronic leukemia, rarely with polycythemia vera and myelofibrosis. The use of special immuno-histochemical stains is mandatory, because this tumor is often misdiagnosed as malignant lymphoma. We report two cases of granulocytic sarcoma (tonsil and ovary) associated with chronic myelogenous leukemia. We describe the first reported association of atypical CML and granulocytic sarcoma. PMID- 8693868 TI - Cutaneous cryptococcosis in corticosteroid-treated patients without AIDS. AB - Two corticosteroid-treated patients with cutaneous cryptococcal infection are described. One patient had pustulous lesions on the back of his left hand and cellulitis of his left forearm, the other patient had ulcerous lesions of the right forearm and cellulitis of the right lower leg. In both cases diagnosis was suggested by histopathological examination of a biopsy and confirmed by culture. One patient may have had disseminated cryptococcal disease as suggested by a positive cryptococcal capsular antigen test, the other had no evidence of dissemination. Treatment consisted of oral fluconazole for six weeks. One patient died of an unrelated cause after four weeks treatment. Secondary antifungal prophylaxis was not given. Cutaneous cryptococcal infections are described in AIDS patients, but only seldom observed in other immunocompromised patients. Early recognition of the cutaneous lesions is important, as they can be the first sign of disseminated cryptococcosis. Untreated, the mortality of this disease is high. Therapy consists of amphotericin B with or without flucytosine. Fluconazole may be valuable alternative. The optimal treatment regimen and duration are not defined yet. Contrary to AIDS patients with cryptococcal infection, who need life long secondary antifungal prophylaxis in order to prevent relapses, suppressive treatment is not indicated for immunocompromised non-AIDS patients. PMID- 8693869 TI - Progressive mediastinal widening after therapy for Hodgkin's disease. Association of Hodgkins disease with sarcoidosis. PMID- 8693870 TI - Insulin resistance syndrome and atherosclerotic cardiovascular disease. PMID- 8693871 TI - In vitro activity of amoxycillin/clavulanate and ticarcillin/clavulanate compared with that of other antibiotics against anaerobic bacteria: comparison with the results of the 1987 survey. AB - The activity of amoxycillin/clavulanate (Augmentin) and ticarcillin/ clavulanate (Timentin) was tested against 351 strict anaerobic clinical isolates collected from September 1993 to April 1994 in eight Belgian university hospitals and compared with that of 8 other antibiotics using the NCCLS reference agar dilution procedure. Production of beta-lactamase was detected by the nitrocefin test in 48% of the isolates. At NCCLS-recommended breakpoints, more than 90% of isolates were susceptible to amoxycillin/clavulanate, ticarcillin/clavulanate, piperacillin/tazobactam, imipenem, chloramphenicol and metronidazole but only 77%, 72% and 48% to cefoxitin, clindamycin and penicillin, respectively. In comparison with the results of a similar survey conducted in 1987 no major changes in susceptibility were observed except for the susceptibility to clindamycin that declined from 83% to 72% overall, and from 83% to 66% in the B. fragilis group. Furthermore one isolate of Clostridium clostridioforme was found produce beta-lactamase and few B. fragilis group isolates showed reduced susceptibility to metronidazole. PMID- 8693872 TI - The neurobiology of Alzheimer's disease. AB - Significant developments in our understanding of the pathophysiology of Alzheimer's disease have been obtained in the recent years. Diagnostic criteria, based on clinical data, have been proposed and have been validated by clinico pathological correlations. Some neuroimaging techniques and laboratory tests (e.g. dosage in the cerebrospinal fluid) are promising diagnostic avenues. Genetic mutations associated with familial cases of the disease have been identified and the involved genes localized on chromosome 1, 14 or 21. The apolipoprotein E genotype has been discovered to affect the risk of developing the disease, i.e. homozygotes for the apolipoprotein E4 allele are much more prone to develop Alzheimer's disease The definitive diagnosis of the disease still relies on the demonstration of characteristic neuropathological lesions, i.e. neurofibrillary tangles and senile plaques, whose numbers are correlated with the severity of the dementia. Other lesions include neuronal and synaptic loss, amyloid angiopathy, and severe decrease in the level of cortical acetylcholine. Neurofibrillary tangles have been found to be composed of the microtubule-associated protein tau, in highly phosphorylated state. The accumulation of these phosphorylated tau proteins is thought to be associated to disturbances of intracellular transport of molecules and organelles in affected neurones, leading to cell dysfunction and death. An inbalance in the activities of selected protein kinases and phosphatases is also thought to generate these highly phosphorylated tau species. The major component of senile plaques is the A4/beta amyloid peptide, generated by proteolysis of the amyloid peptide precursor, a transmembrane protein. When aggregated into amyloid fibrils, the A4/beta amyloid peptide is thought to be neurotoxic. An abnormal metabolism of the amyloid peptide precursor is often considered as a central physiopathological mechanism of the disease. Although many pharmacological treatments of the disease have been investigated, they have not yet led to sustained and major clinical improvements. PMID- 8693873 TI - Herniation of the left atrial appendage due to partial congenital absence of the left pericardium. AB - Partial congenital absence of the left pericardium is a rare abnormality which may provoke serious complications. We report the case of a young adult, suffering from chest pain due to incarceration of atrial tissue. Based on this case report the clinical, pathophysiological and diagnostic features of this condition are described. PMID- 8693874 TI - Muscular actinomycosis in the back. AB - We present an unusual observation actinomycosis involving muscles of the back and probably of one thigh in a patient with pulmonary lesions. The patient was alcoholic and a heavy smoker and his teeth were in very poor repair. Opportunity is taken to review the literature on the rare cases of muscular actinomycosis. PMID- 8693875 TI - Endoscopic treatment of biliary ascariasis. Report of a case. AB - Ascaris lumbricoides is the most common intestinal parasite to infect humans. The incidence of ascariasis is increasing in our regions, due to world travel and population migration. In one third of cases, the worm can enter the bile duct and cause cholangitis or biliary colics. Diagnosis and treatment of ascariasis are discussed. Endoscopic retrograde cholangio-pancreaticography (ERCP) with endoscopic extraction of the worm, using a Dormia basket, is a safe and effective procedure for the diagnosis and treatment of biliary ascariasis. This technique serves as an effective alternative for surgery. PMID- 8693876 TI - Detection of allele loss on chromosome 16q in DNA isolated from fine needle aspiration specimens of breast tumors. A simulation study using surgically resected specimens. AB - OBJECTIVE: To clarify whether analysis of loss of heterozygosity (LOH) on chromosome 16q is possible using DNA isolated from fine needle aspiration specimens, a simulation study was performed using resected biopsy or mastectomy specimens of 37 breast carcinomas and 3 fibroadenomas. STUDY DESIGN: A highly polymorphic (AC)n repeat region on the D16S305 locus on chromosome 16q24 was amplified in the DNA samples by the polymerase chain reaction (PCR) using 32P labeled oligonucleotide primers, and the PCR products were electrophoresed in denaturing gel for detection of LOH by autoradiography. RESULTS: PCR was successful in 34 cases, and LOH was detected in 10 (71%) of 14 carcinomas but not in the 3 fibroadenomas. These results were almost always compatible with the data obtained by restriction fragment length polymorphism analysis on chromosome 16q using Southern blotting. CONCLUSION: Examination of LOH on 16q by (AC)n polymorphism analysis using fine needle aspiration specimens is suggested as a supportive tool for preoperative diagnosis of breast tumors. PMID- 8693877 TI - Immunohistochemical panel for distinguishing between carcinoma and reactive mesothelial cells in serious effusions. AB - OBJECTIVE: This study was designed to assess whether a new panel of antibodies is a useful adjunct in the differential diagnosis of carcinoma and reactive mesothelial cells. STUDY DESIGN: Complete, one-hour immunohistochemistry using antibodies against cytokeratin (CK), carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA) and fibronectin was applied to cell blocks from 76 pleural and peritoneal fluid specimens. Fifty patients with histologically diagnosed primary carcinomas and 26 without evidence of malignancy were included. The results were correlated with routine cytologic results. RESULTS: The final cytologic diagnoses were 28 malignant effusions and 48 benign effusions. CEA and EMA were present in 25 (89%) and 24 (86%) of 28 carcinoma cases, respectively. These determinants were absent from reactive mesothelial cells. Fibronectin strongly labeled reactive mesothelial cells, with no staining of carcinoma cells. Carcinoma cells expressed at least two antibodies to CK, CEA and EMA and were negative to fibronectin. Reactive mesothelial cells expressed both CK and fibronectin. In 6 of 28 carcinoma cases (21%) the immunohistochemical panel identified carcinoma cells that were not recognized initially on routine cytologic examination. CONCLUSION: A panel of CEA, EMA and fibronectin monoclonal antibodies appears to be suitable for distinguishing between carcinoma cells and reactive mesothelial cells in serous effusions. PMID- 8693878 TI - Value of GCDFP-15 (BRST-2) as a specific immunocytochemical marker for breast carcinoma in cytologic specimens. AB - OBJECTIVE: The diagnosis of metastatic mammary carcinoma by morphologic criteria alone can be difficult, depending on the site of metastasis and state of cell differentiation. Numerous histopathologic studies have shown GCDFP-15 (BRST-2) to be a specific marker for breast cancer in surgical specimens. To date, no studies have been done to evaluate its utility in cytologic preparations. STUDY DESIGN: To evaluate the usefulness of GCDFP-15 as a marker in the cytologic diagnosis of breast carcinoma, we studied 23 cases of mammary carcinoma and compared them with 20 cases of tumors of nonmammary origin (lung, ovary, liver, colon, stomach and bladder). "Bench top" fine needle aspirates from unfixed surgical specimens of breast carcinoma, cytocentrifuge samples from body cavity fluids and cerebrospinal fluids with morphologically proven metastatic carcinoma were studied. RESULTS: Expression of BRST-2 was found in 56.5% of primary and recurrent or metastatic breast carcinomas. All the nonmammary carcinomas studied were negative. Staining was found to be strongly dependent on the means of cell fixation. Slides fixed in 10% formalin and Bouin's solution gave optimal results. Except in two cases, which showed focal immunostaining, all specimens fixed in alcohol were negative. CONCLUSION: Our results support the diagnostic value of GCDFP-15 in recognizing tumors of breast origin and suggest that in clinical situations in which metastatic breast carcinoma is suspected, a portion of the cytologic specimen should be fixed with an optimal fixative for BRST-2 detection. PMID- 8693879 TI - Detection of heterozygosity loss in microdissected fine needle aspiration specimens of breast carcinoma. AB - OBJECTIVE: To use the polymerase chain reaction (PCR) to detect loss of heterozygosity (LOH) in microdissected cells form cytologic smears obtained by fine needle aspiration (FNA) from 20 cases of invasive breast carcinoma. STUDY DESIGN: In each case, histologic sections of the primary tumor were also available. Tumor and nontumor cells were dissected from both the cytologic smear and tissue section in all cases except in three smears that showed only tumor cells. RESULTS: LOH was identified in 10 of 19 informative cases using two polymorphic DNA markers at chromosome 11q13 (INT-2, PYGM). The same results were obtained in both the cytologic and histologic specimens, including three cases that had hypocellular cytologic smears. CONCLUSION: FNA of breast lesions provides adequate samples for direct microdissection of the cytologic smear to detect LOH using PCR amplification. PMID- 8693880 TI - Imprint cytology. A rapid, reliable method of diagnosing breast malignancy. AB - OBJECTIVE: To compare imprint cytology with fine needle aspiration biopsy and histology for the intraoperative diagnosis of breast malignancy. STUDY DESIGN: We evaluated imprint cytology, comparing it with other diagnostic techniques. Three hundred fifty-one cases (180 benign and 171 malignant) were studied by fine needle aspiration cytology, imprint cytology and histopathology. RESULTS: Imprint cytology, as compared to histopathology, had 98.3% accuracy, with 97.1% sensitivity and 99.4% specificity. Aspiration cytology was less accurate than imprint cytology as compared to histopathology (accuracy 94.9%, sensitivity 93.9%, specificity 96.2%). CONCLUSION: These data confirm the value of imprint cytology and suggest that it could be used intraoperatively as an alternative to frozen section if a pathology laboratory is not available. PMID- 8693881 TI - Diagnosis of parasites in fine needle breast aspirates. AB - OBJECTIVE: To document the value of fine needle aspiration cytology (FNAC) in the diagnosis of parasites in breast aspirates. STUDY DESIGN: Review of 8,364 breast aspirates studied over 15 years (1978-1992) for parasitic infections. RESULTS: Eight cases of cysticercosis and nine of filariasis were detected among 4,714 benign breast aspirates. Diagnosis of cysticercosis was based on identification of parts of the parasite in aspirates (seven cases) and excisional biopsy (one case). Among the cases of filariasis in breast aspirates, gravid adult females of Wuchereria bancrofti were seen in three cases and microfilarial larvae in four. In the remaining two cases, an intense, eosinophilic infiltrate was seen in breast aspirates, while microfilariae were identified in aspirates from draining axillary lymph nodes. CONCLUSION: In rare cases, parasitic infections present as breast lumps and can be easily diagnosed by FNAC. PMID- 8693882 TI - Application of plastic embedding to fine needle aspiration biopsy. AB - OBJECTIVE: To explore the possible advantages that plastic embedding offers to fine needle aspiration biopsy (FNAB). STUDY DESIGN: A series of 54 FNABs was fixed in Kryofix (30 cases) and acetone (24 cases), plastic embedded and cut using a rotative microtome. The 2-micron sections obtained were May-Grunwald Giemsa and Papanicolaou stain in all cases; mucicarmine, Alcian Blue, periodic acid-Schiff (PAS), PAS-diastase and Feulgen stain for DNA cytometric evaluation were also applied in five cases. Immunocytochemical staining using the antibodies cytokeratin 1-8, epithelial membrane antigen, vimentin, Ki-67, lysozime, calcitonin and carcinoembryonic antigen was carried out with the immunoalkaline phosphatase method. RESULTS: The fragments in the sections were perfectly two dimensional; the architectural features of the original tissues were preserved. Morphologic details of nuclear membranes, nucleoli and mitotic figures were excellent. Cytochemical and immunocytochemical stains were successful in all cases. Immunostains showed the precise location of the signal (nuclear, nucleolar or cytoplasmic), a clear background and preservation of morphology. CONCLUSION: Plastic embedding can be applied to FNAB to solve the problem of dense cellular groups, to study structural and cellular details, and to capitalize on the diagnostic material available for serial cytochemical, quantitative and immunocytochemical purposes. PMID- 8693883 TI - Detecting structural changes at the molecular level with Fourier transform infrared spectroscopy. A potential tool for prescreening preinvasive lesions of the cervix. AB - OBJECTIVE: To study cervical exfoliated cells with Fourier transform infrared spectroscopy (FTIR). STUDY DESIGN: Consecutive samples from 133 women attending the Dysplasia Clinic, Ottawa Civic Hospital, were collected in balanced electrolyte solution. After centrifugation, two smears were prepared for routine screening. The remainder of the pellet was frozen for FTIR spectroscopic study. RESULTS: In 120 samples, adequate material was available for spectroscopic study. All smears from 17 women with normal spectra were within normal limits (WNL). One hundred three spectra were abnormal. The corresponding smears were interpreted as: 41 low grade squamous intraepithelial lesions, 20 high grade squamous intraepithelial lesions, 6 atypical squamous cells of undetermined significance, 17 cases with benign cellular changes, and 19 WNL. Ten of 17 cases with benign cellular changes had characteristic spectra consistent with inflammatory changes. CONCLUSION: FTIR spectroscopy is a highly sensitive technique for detecting cervical abnormalities and a potential tool for prescreening preinvasive lesions of the cervix. PMID- 8693884 TI - Nongynecologic cytology utilizing the ThinPrep Processor. AB - OBJECTIVE: To assess the utility of the ThinPrep Processor (TP) for nongynecologic cytology. STUDY DESIGN: We reviewed the number of unsatisfactory specimens from the esophagus, common bile duct, hepatic duct, pancreas, gastric, bronchial wang, vertebra, submandibular area and neck over a one-year period, before and after TP implementation. For a one-year period after TP implementation, the cytologic diagnoses of selected TP specimens with corresponding surgical tissue diagnoses were compared, and the TP slides were reviewed in discrepant cases. RESULTS: The number of unsatisfactory specimens was reduced from 17% to 1% after TP implementations. The cytologic diagnoses of 145 TP specimens were in agreement with surgical tissue diagnoses. However, in 43 cases the cytology and tissue diagnoses were discordant. On review of 26 of the discrepant cases, the majority of TP slides were cellular, with good nuclear and cytoplasmic detail. Discrepancies resulted from sampling errors in 19 cases and TP interpretation errors in 7 cases. CONCLUSION: In our laboratory, TP is a reliable processor for nongynecologic specimens. PMID- 8693885 TI - Cytology of grade 1 papillary transitional cell carcinoma. A comparison of cytologic, architectural and morphometric criteria in cystoscopically obtained urine. AB - OBJECTIVE: To assess the diagnostic criteria for grade 1 papillary transitional cell carcinoma (TCC) in cystoscopically obtained urine. STUDY DESIGN: We compared the sensitivity, specificity and positive predictive value of cytologic, architectural and morphometric (primarily architectural) criteria in 177 specimens with corresponding biopsy follow-up. RESULTS: Sensitivities ranged from 22% to 44%, specificities from 69% to 85% and positive predictive values from 59% to 66%. CONCLUSION: The currently described cytologic, architectural and morphometric criteria are inadequate for the identification of grade 1 papillary TCC, and the cytologic diagnosis of grade 1 papillary TCC in cystoscopically obtained urine remains unreliable. PMID- 8693886 TI - Fine needle aspiration cytology in pancreatic pathology. AB - OBJECTIVE: To assess the sensitivity and specificity of pancreatic fine needle aspiration. STUDY DESIGN: Two hundred five fine needle aspirates were obtained from 149 patients over seven years. After excluding 40 patients lacking biopsy or follow-up, 125 aspirates from 109 patients were selected to analyze the accuracy of this method. (male:female ratio, 1.4:1; age range 43-79 years). RESULTS: The cytologic diagnosis was true positive in 50 studies (45.9%), false positive in 0, true negative in 25 (22.9%), false negative in 19 (17.4%) and suspicious for malignancy in 17 (15.6%); 14 aspirations (12.8%) yielded material unsatisfactory for a diagnosis. Of the 17 suspicious studies, 15 were from patients in whom a malignancy was confirmed later. The other two patients had chronic pancreatitis. CONCLUSION: The efficiency was 79.8%, sensitivity 72.5%, and specificity and predictive value of a positive result 100%. Cell blocks provided sufficient material in 96.8% of cases and smears in 90.4%. No major complications were reported after fine needle aspiration. PMID- 8693887 TI - Transthoracic fine needle aspiration biopsy. Sensitivity in relation to guidance technique and lesion size and location. AB - OBJECTIVE: To obtain site- and size-specific data on transthoracic fine needle aspiration (TFNA) and determine the sensitivity in relation to guidance technique and lesion size and location. STUDY DESIGN: Data on 112 patients undergoing TFNA between 1992 and 1993 were analyzed for accuracy rates, stratified according to lesion size and location within the lung. The series included 13 benign lesions, 53 metastatic neoplasms and 46 primary carcinomas. RESULTS: Overall sensitivity was 90%, with 92% specificity. There was a clear relationship between nodule size and sensitivity of TFNA, with a sensitivity of 60% for lesions < 1 cm but 93% sensitivity for nodules > or = 2 cm in diameter. Similarly, lesion location affected sensitivity. Sensitivity was 100% for peripherally located nodules but was as low as 82% for nodules in the centrobasal portion of the lung. Sensitivity was higher for fluoroscopy (97%) than computed tomography (80%). CONCLUSION: The guidance technique as well as lesion location and size affect diagnostic accuracy. PMID- 8693888 TI - Tumor-infiltrating lymphocytes. Cytologic, phenotypic and morphometric analysis. AB - OBJECTIVE: To characterize the cytologic, phenotypic and morphometric features of tumor-infiltrating lymphocytes (TILs). STUDY DESIGN: Morphology and cell size parameters of 50 TILs and five normal donor peripheral blood lymphocyte (PBL) specimens were compared using light microscopy, manual ocular measurements and digital image processing. RESULTS: Cytologically, all TILs demonstrated similar morphologic findings regardless of the initial tumor type. Changes included large; eccentric nuclei, sometimes hyperlobated; clumped chromatin; and prominent nucleoli. The cytoplasm was abundant and basophilic. Mitotic figures were usually evident. In addition, TIL showed significant increases in cell size parameters as compared to PBLs. CONCLUSION: The activated morphology of TILs resembles the appearance of high grade lymphoma. Several cell size parameters are increased; that may help to explain differences in previously reported trafficking patterns between TILs and peripheral blood lymphocytes. PMID- 8693889 TI - Fine needle aspiration cytology of carcinoid tumors. AB - OBJECTIVE: To define the cytomorphologic features of carcinoid tumor. STUDY DESIGN: The study consisted of 19 carcinoid tumors sampled by fine needle aspiration. These included 6 pulmonary carcinoids. 11 intestinal carcinoids and 2 aspirates from a patient with a mediastinal carcinoid. The cytomorphologic features of carcinoid tumor were documented, and, in selected cases, immunocytochemical findings were noted. Additionally, the cytology literature concerning carcinoid tumor was reviewed and summarized. RESULTS: Morphologically, the carcinoid tumors consisted predominantly of loose groups with a background of single cells. A striking degree of cellular and nuclear monomorphism was seen in all cases. Nuclei were small and round to oval, and all exhibited a characteristic finely granular, evenly distributed chromatin pattern. Cytoplasm was minimal to moderate in amount and finely granular in appearance. Necrosis and prominent nucleoli were not seen. Positive staining was noted in all seven cases in which immunostaining for chromogranin was performed. Neuron-specific enolase was positive in four of five cases. CONCLUSION: The cytomorphologic characteristics of carcinoid tumors are distinctive, and appropriate ancillary studies can assist in confirming the diagnosis. PMID- 8693890 TI - Cytology of primary skin tumors. AB - OBJECTIVE: To evaluate the role of fine needle aspiration biopsy (FNAB) in the diagnosis of primary skin and adnexal tumors and to study the cytomorphology of various primary skin and adnexal tumors. STUDY DESIGN: FNAB was routinely done in 18 cases of skin and adnexal tumors, and the cytologic diagnosis, along with detailed cytomorphology, was correlated with subsequent histology. RESULTS: FNAB was done on 15 cases of primary skin tumors and 3 cases of recurrent lesions. FNAB successfully established the benign or malignant nature of skin tumors in 16 of 18 cases (88.9%). However, subtyping was possible in only 12 of 18 cases (66.7%). CONCLUSION: Clinical history and physical findings are essential to the proper diagnosis of adnexal tumors. Knowing the cytologic features of primary skin neoplasms helps distinguish them from tumors metastatic to the skin and more commonly referred for FNAB. PMID- 8693891 TI - Utility of brushing cytology in the diagnosis of Helicobacter pylori infection. AB - OBJECTIVE: We performed brushing cytology during routine gastroendoscopic examinations to evaluate the utility of gastric brushing cytology in the diagnosis of Helicobacter pylori infection. STUDY DESIGN: The brushing cytology materials were obtained from the antrum of the stomach in 107 patients. The urea breath test, biopsy urease test and histology with hematoxylineosin staining were also performed on each patient. We then compared the results of brushing cytology with those of the three other tests (13C urea breath test, biopsy urease test, histology). RESULTS: Fifty-nine of 103 patients (57%) were diagnosed as positive for H pylori organisms using brushing cytology. Using positive or negative results from any two of the other three tests as the gold standard, a true positive result was found in 57 cases, a true negative in 43 cases, a false positive in 2 cases and a false negative in 1 case. The sensitivity and specificity of brushing cytology were 98% and 96%, respectively. CONCLUSION: Gastric brushing cytology provides an accurate, inexpensive and easy technique in the rapid detection of H pylori infection. Brushing cytology also has the advantage of being applicable to diagnostic endoscopy without waiting days for results. PMID- 8693892 TI - Cytomorphology of leprosy across the Ridley-Jopling spectrum. AB - OBJECTIVE: To evaluate the possible role of cytology in classifying leprosy lesions on the Ridley-Jopling scale. STUDY DESIGN: A double-blind, prospective study comparing cytologic assessment of 30 clinically diagnosed cases of leprosy with their histopathology. May-Grunwald-Giemsa and Ziehl-Neelsen stain were done on slit skin smears and fine needle aspiration material. RESULTS: Cytologic subclassification was possible in 23 cases as tuberculoid leprosy (11), midborderline (3), borderline lepromatous (5) and lepromatous leprosy (4). These correlated with histologic subtypes. CONCLUSION: May-Grunwald-Giemsa complements Ziehl-Neelsen stain, yielding information almost comparable to that from histologic examination of skin biopsies. PMID- 8693893 TI - Significance of AgNOR count in differentiating malignant cells from reactive mesothelial cells in serous effusions. AB - OBJECTIVE: To distinguish reactive mesothelial cells from malignant cells in serous effusions using silver staining of nucleolar organizer regions (AgNOR) applied to ethanol-fixed cytologic preparations. STUDY DESIGN: One hundred aspirated samples of benign and malignant effusions were studied using the one step silver staining method. Eight cytologically atypical samples were also included in the study. RESULTS: In malignant cells the mean AgNOR count was 4.72 +/- 0.76 (+/- SD), and the AgNORs were irregular in shape, while in benign mesothelial cells AgNORs were comparatively larger, single dots with a mean count of 1.92 +/- 0.23. Of the cytologically atypical samples, five were in the malignant range. The others were within benign limits. Repeat cytology of the second aspirate confirmed that finding. CONCLUSION: AgNOR study appears to be clinically useful as an additional diagnostic tool for use in ascitic and pleural fluid samples when the cytologic diagnosis is difficult. PMID- 8693894 TI - Extremely well differentiated squamous cell carcinoma of the breast. Report of a case with a comparative study of an epidermal cyst. AB - BACKGROUND: Although the cytologic diagnosis of malignancy by fine needle aspiration is easy in cases of moderately to poorly differentiated squamous cell carcinoma in various organs, it is not always easy in cases of the well differentiated type. CASE: A 46-year-old female presented with a slowly growing mass in the right breast; it was diagnosed as an extremely well differentiated squamous cell carcinoma. The diagnosis of malignancy was initially not established by fine needle aspiration cytology because of minimal cellular atypia. The smear contained many squamous cells, mainly of the superficial type, with little cellular atypia, in a background of horny material. However, neither anuclear superficial cells nor granular cells were found. CONCLUSION: Absence of anuclear keratinized cells and granular cells is probably a helpful finding for distinguishing squamous cell carcinoma from epidermal cyst in the breast region. PMID- 8693895 TI - Apocrine metaplasia in gynecomastia by fine needle aspiration as a possible indicator of anabolic steroid use. A report of two cases. AB - BACKGROUND: The fine needle aspiration finding of apocrine metaplasia in association with the usual cytologic findings of gynecomastia is distinctly unusual. Previous reports do not mention any historical clinical association. CASES: Two otherwise healthy adult males presented for fine needle aspiration (FNA) of new-onset breast masses. Both showed apocrine metaplasia associated with the typical clinical and cytologic features of gynecomastia on FNA. Additional questioning revealed that both patients reported recent anabolic steroid use as part of their body-building routines. CONCLUSION: The fine needle aspiration finding of apocrine metaplasia in association with the usual cytologic and clinical findings of gynecomastia in otherwise healthy adult males without a medication history may be an indicator of illicit anabolic steroid use. Anabolic steroid use often has serious consequences, so its possibility should prompt further evaluation by the patient's clinician. PMID- 8693896 TI - Infarction after fine needle aspiration. A report of four cases. AB - BACKGROUND: Fine needle aspiration (FNA) is a well-established and safe method for the rapid diagnosis of palpable and deep-seated masses. A few clinically important complications, including bleeding, pneumothorax, infection and inflammatory reactions, result from FNA. Little attention has been focused on tissue changes resulting from FNA. In a small number of cases FNA has been followed by varying degrees of necrosis. This has occurred in thyroid nodules, salivary glands, breast fibroadenomas, lymph nodes and renal cell carcinoma. CASES: Four cases of infarction followed FNA biopsy. All 4 (1 papillary carcinoma of the thyroid, 1 pleomorphic adenoma of the parotid gland and 2 fibroadenomas of the breast) were diagnosed by FNA. Subsequent histologic study of the surgical specimens revealed massive necrosis of the neoplasms. CONCLUSION: Necrosis associated with infarction may cause diagnostic problems in two settings. FNA yielding necrotic debris may result in a false negative diagnosis in repeat aspiration. Alternatively, post-FNA infarction may obscure the nature of a neoplasm diagnosed by FNA, making histologic confirmation difficult. PMID- 8693898 TI - Fine needle aspiration cytology of squamous cell carcinoma arising in a thyroglossal duct cyst. A case report. AB - BACKGROUND: Carcinoma arising in a thyroglossal duct cyst is a rare entity. Malignancy generally is revealed only after surgical excision of a thyroglossal duct lesion because of the lack of specific physical findings. CASE: A 68-year old male presented with a squamous cell carcinoma arising in a midline cyst in the neck. The malignancy had been discovered because of an enlarged metastasized lymph node in the left side of the neck. Fine needle aspiration cytology (FNA) showed cells with marked nuclear atypia and keratinizing cells. CONCLUSION: To our knowledge, this is the 10th squamous cell carcinoma reported and, among these, the first case diagnosed preoperatively by FNA cytology. A firm diagnosis at the preoperative stage is important with this neoplasm to plan extensive surgical intervention. PMID- 8693897 TI - Pancreatic oncocytic endocrine tumors. Cytologic features of two cases. AB - BACKGROUND: Oncocytoma designates a usually benign tumor consisting of oncocytes (cells rich in mitochondria). Rarely do endocrine pancreatic tumors show oncocytic transformation, and consequently their liver metastases may resemble a hepatocellular carcinoma. CASES: Case 1, a 36-year-old male, presented with an 8 cm pancreatic mass with multiple liver metastases. Fine needle aspiration (FNA) biopsy was performed on the liver. The cytologic features were highly cellular material; numerous isolated cells and irregular, loose cellular aggregates; rare mitoses; round or polygonal cell shape; rosette formation; and large, granular, eosinophilic cytoplasm (suggestive of poorly differentiated hepatocellular carcinoma). Case 2, a 57-year-old female with hypoglycemia, had a 13-cm pancreatic mass. FNA material showed the same cytologic features as case 1. In situ hybridization to detect albumin mRNA was negative in both cases, while immunocytologic reactions for glandular epithelial cytokeratin and chromogranin A were positive. Case 2 was also positive for insulin. CONCLUSION: Oncocytic transformation in endocrine tumors of the pancreas is a rare occurrence and must be kept in mind in the diagnostic workup of FNA material from tumors of the hepatopancreatic region. PMID- 8693899 TI - Fine needle aspiration diagnosis of intramuscular bacillary angiomatosis. A case report. AB - BACKGROUND: Bacillary angiomatosis (BA) is a localized infectious process that affects primarily patients with the acquired immunodeficiency syndrome. The microorganisms implicated in the pathogenesis of this disease belong to the Rickettsiaceae family. CASE: A 43-year-old, human immunodeficiency syndrome positive male presented with diffuse swelling in the right deltoid area. A neoplastic process was considered in the differential diagnosis. Fine needle aspiration biopsy showed proliferation of blood vessels lined with plump endothelial cells, and the interstitial space was occupied by neutrophilic infiltrate, leukocytoclastic debris and clumps of characteristic amphophilic, granular material. Warthin-Starry stain demonstrated clusters of bacilli diagnostic of bacillary angiomatosis. CONCLUSION: The diagnosis of this entity, made by fine needle aspiration cytology (as the only diagnostic procedure), was instrumental in preventing further surgical manipulation and in initiating appropriate and immediate antibiotic therapy. PMID- 8693900 TI - Sarcomatoid carcinoma of the larynx with neck and distant subcutaneous metastases. A case report with fine needle aspiration cytology. AB - BACKGROUND: Sarcomatoid carcinoma of the upper aerodigestive tract is an unusual neoplasm with divergent cellular differentiation. Typically this carcinoma is a squamous cell carcinoma with spindle and giant cell components and may be misinterpreted as a sarcoma. CASE: A 56-year-old, diabetic male presented with a 2.5-cm, left-sided neck mass. Fine needle aspiration showed a mixture of malignant squamous and spindle cells. A third population of osteoclastlike giant cells was also present. Similar cells were aspirated from a subcutaneous left leg lesion months later. CONCLUSION: The diagnosis of a sarcomatoid carcinoma of the larynx should be considered when malignant epithelial, spindle and giant cells are present in aspirated smear material from the neck. PMID- 8693901 TI - Cartilaginous tumors of the larynx. A report of two cases with definitive diagnosis by fine needle aspiration and computed tomography. AB - BACKGROUND: Cartilaginous tumors of the larynx are rate tumors with an indolent course. In the past they were diagnosed by radiographic or computed tomographic imaging and laryngoscopic or surgical biopsy. The literature contains few examples of fine needle aspiration biopsy of these tumors. CASES: Smears of the fine needle aspirates from two cases of cartilaginous tumors of the larynx consisted of a mucinous background containing chondroid fragments of benign appearing lacunar cells. Cytomorphologic and architectural features of smears and cell block preparations correlated well with histologic sections for subsequent surgical specimens. Both tumors were classified by cytology and histology as low grade cartilaginous tumors. CONCLUSION: Fine needle aspiration biopsy, together with typical computed tomographic images, is adequate for diagnosis, cost effective and safe and can be performed in an outpatient setting. PMID- 8693902 TI - Serous surface papillary carcinoma of the ovary metastatic to a cervical polyp. A case report. AB - BACKGROUND: Malignancies in cervical polyps are rare. In the literature, malignant transformation to adenocarcinoma and squamous cell carcinoma has been described, but metastasis from ovarian tumors has not been reported before. CASE: An asymptomatic female had a serous surface papillary carcinoma of the ovary, metastatic to a cervical polyp and first noticed on a routine vaginal/cervical/endocervical smear. CONCLUSION: The most common sources of adenocarcinoma cells in a cervical/vaginal smear are the endocervix and endometrium, but, as in our case, the tumor may well be metastatic disease, originating in the ovary or even in extragenital sites, such as gastrointestinal tract, breast and lung. The possibility of dual primaries, involving, for instance, both ovary and endocervix, should be considered. PMID- 8693903 TI - Fine needle aspiration cytology of cystic partially differentiated nephroblastoma. A case report. AB - BACKGROUND: Cystic partially differentiated nephroblastoma (CPDN) is an uncommon childhood kidney tumor. CASE: For the first time, in this case report we describe the cytologic features of this entity. Predominant clusters and rows of cells with occasional discrete blastemal cells on cytologic smear along with multiple hypoechoic cystic spaces on radiology suggested CPDN. CONCLUSION: It is essential to diagnose CPDN preoperatively because the tumor needs only nephrectomy for treatment. PMID- 8693904 TI - Fine needle aspiration of basal cell adenocarcinoma of the parotid gland. Report of a case with assessment of DNA ploidy in aspirates and tissue sections by image analysis. AB - BACKGROUND: Basal cell adenocarcinoma of the parotid gland is a low grade malignant neoplasm. It has cytologic features of basal cell adenoma and a histologically infiltrative growth pattern of malignant tumors with perineural and vascular invasion. CASE: Fine needle aspiration biopsy findings of basal cell adenocarcinoma of the parotid gland in a 77-year-old male were supplemented by DNA ploidy analysis. CONCLUSION: No single cytologic feature was found to unequivocally distinguish this lesion from basal cell adenoma and/or solid variant of adenoid cystic carcinoma. Therefore, for diagnostic purposes, we grouped all three lesions under the term basal cell tumor. Evaluation of DNA content of tumor cells revealed diploid histograms in both cytologic material and paraffin-embedded tissue. Infiltrative tumor nests, the histologic basis for differentiating basal cell adenocarcinoma from adenoma, showed the same diploid pattern. Though DNA quantitation may not discriminate basal cell adenoma from basal cell adenocarcinoma, it may prove useful in separating them from adenoid cystic carcinoma, which is considered to be a tumor with high malignant potential. PMID- 8693906 TI - Fetal rhabdomyoma. A case report with the diagnosis suggested by intraoperative cytology. AB - BACKGROUND: Fetal rhabdomyoma is a relatively rare tumor that occurs mainly in the head and neck of toddlers. A similar lesion can occasionally be found in the adult female genital tract. Increased cellularity may be seen in the fetal type and can lead to confusion with the well-differentiated types of rhabdomyosarcoma. CASE: An 8-day-old infant presented with a unilateral, right-sided, postauricular mass. Intraoperative cytology of the mass showed numerous cells with spindled nuclei in a background of myxoid material. A provisional diagnosis of fetal rhabdomyoma was made and subsequently confirmed by histopathologic examination. CONCLUSION: In neonates presenting with cervical swelling, the possibility of fetal rhabdomyoma should always be considered and confirmed by both intraoperative cytology and histopathologic examination of the resected tumor. PMID- 8693907 TI - Fine needle aspiration cytology of adenoma of the nipple. A case report. AB - BACKGROUND: Adenoma (papillary adenoma, florid papillomatosis, subareolar duct papillomatosis, erosive adenomatosis) of the nipple is an uncommon lesion and can be mistaken clinically for Paget's disease and pathologically be misinterpreted as an adenocarcinoma. CASE: A case of adenoma of the nipple was studied by cytology and histopathology. CONCLUSION: Recognition of this benign lesion on cytology will prevent unnecessary radical surgery. Local excision alone suffices. PMID- 8693905 TI - Fine needle aspiration cytology, histology and immunohistochemistry of anaplastic large cell Ki-1-positive lymphoma. A report of three cases. AB - BACKGROUND: Large cell anaplastic Ki-1 lymphoma is a cytologically undifferentiated malignant lymphoma that needs to be distinguished from a variety of other neoplasms using immunohistochemistry. CASES: The cytopathologic, histopathologic and immunohistochemical features of three cases of Ki-1-positive anaplastic large cell lymphoma are presented. The patients comprised two females and one male, ranging in age from 48 to 82 years. Presentation was with peripheral lymphadenopathy. Fine needle aspiration biopsy of an enlarged lymph node in each case revealed single cells and poorly cohesive groups of cells with large, pleomorphic nuclei, many containing prominent nucleoli, and a moderate amount of cytoplasm. Many binucleate and multinucleate tumor cells were present. In each case the cytologic features suggested metastatic anaplastic carcinoma. The histopathologic features of excised nodes were also suggestive of this diagnosis, with cohesive groups of cells and many multinucleate tumor giant cells. In one case malignant cells were confined to subcapsular and medullary sinuses, further highlighting the resemblance to metastatic carcinoma. Immunohistochemical staining of histologic sections confirmed the diagnosis of large cell anaplastic, Ki-1-positive lymphoma, with the tumor cells in the three cases showing diffuse and strong positive staining for Ki-1 antigen. Further immunohistochemistry revealed tumor cells in two cases to be positive for leukocyte common antigen, two cases to express B-cell markers and one case to express T-cell markers. CONCLUSION: The fine needle aspiration biopsy findings confirmed that large cell anaplastic, Ki-1-positive lymphoma should be considered in the cytologic differential diagnosis of anaplastic tumor within a lymph node. The differential diagnosis may include anaplastic carcinoma, malignant melanoma, sarcoma, Hodgkin's disease and histiocytic lymphoma. Immunostaining of fine needle aspiration biopsy material or, preferably, of histologic tissue sections is necessary for confirmation of the diagnosis. PMID- 8693908 TI - 23rd European Congress of Cytology. Arhus, Denmark, September 22-25, 1996. Abstracts. PMID- 8693909 TI - A perspective on modern quality control methods. PMID- 8693910 TI - Unusual plant cell contamination in a vaginal smear. PMID- 8693911 TI - Pitfalls in the diagnosis of germ cell tumors on fine needle aspiration biopsy. PMID- 8693912 TI - Pneumothorax: a complication of fine needle aspiration of breast tumors. PMID- 8693913 TI - Rhinosporidioma of bone: diagnosis by fine needle aspiration. PMID- 8693914 TI - Cytology of tumors of the central nervous system. PMID- 8693915 TI - Intracytoplasmic "negative images" in Gaucher cells. PMID- 8693916 TI - Papillary serous carcinoma of the uterus arising in an adenomyoma. PMID- 8693917 TI - An economizing innovation for immunocytochemistry. PMID- 8693918 TI - Search tasks in human visual perception: relevance to diagnosis of cervical small cell and pale dyskaryosis and other cytologic specimens. PMID- 8693919 TI - A new, stable preservation method for cytologic specimens for immunocytochemical analysis. PMID- 8693920 TI - Flumazenil and midazolam in anaesthesia. AB - Flumazenil, the first benzodiazepine antagonist, is currently used widely as an emergency drug, and has also been utilized in planned procedures, to time arousal intra- or post-operatively. It is known that flumazenil, used at the end of a procedure, causes instant recovery by reversing the residual effects of, for example, midazolam. An agonist-antagonist concept, midazolam-flumazenil, where benzodiazepine sedation or anaesthesia is terminated at will, is, therefore, finding increasing application. In neuroanaesthesia, for example, it facilitates immediate recovery, cardiovascular stabilization and the use of midazolam as an alternative to thiopentone and inhalational agents, and in ear, nose and throat endoscopies, it permits more rapid turnover of patients and is a good choice for haemodynamic stability in patients with a high cardiovascular risk factor. There continues to be debate over the term used to describe the level of sedation remaining after the effects of the antagonist have worn off. 'Resedation' is often used incorrectly to describe what is in reality residual sedation. Given the correct use of midazolam or the exploitation of synergism using opioids, flumazenil will cause arousal, while maintaining the benefit of opioid analgesia. Such a technique may eliminate the need for formal recovery facilities in many ambulatory patients, thereby reducing dependence on trolleys, beds and nurses. This has major implications for health economics, particularly in relation to endoscopy clinics and when co-induction of anaesthesia is employed. PMID- 8693921 TI - The role of flumazenil in the critically ill. AB - Flumazenil is a specific benzodiazepine antagonist. It competitively inhibits the action of benzodiazepines at gamma aminobutyric acid (GABA) receptors in the central nervous system and thus reverses the sedative effects of benzodiazepines. Usually, it is given intravenously as a bolus dose or as an infusion. It has a short duration of action. Flumazenil is extensively metabolized to compounds that have minimal benzodiazepine antagonistic properties. Reversal of sedation can be useful in many conditions that are often encountered in the critically ill. The adverse effects of its use are usually predictable and, with sufficient clinical monitoring, are usually avoidable. These properties make it a useful and safe drug when used appropriately. PMID- 8693922 TI - Pharmacology of flumazenil. AB - Flumazenil, an imidazobenzodiazepine, is the first benzodiazepine antagonist available for clinical use. It is a specific competitive antagonist at benzodiazepine receptors, which are associated with receptors for gamma aminobutyric acid, the most important inhibitory neurotransmitter in the central nervous system. Administered orally, it has a low bioavailability and the preferred route is intravenous. Its usual clinical role is to reverse the effects of benzodiazepine sedation; however, administered before, or with, other benzodiazepines, it modifies their effects, the extent of such modification depending on the dose, duration of effect and relative receptor affinity of the agonist. Flumazenil also reverses adverse physiological effects of benzodiazepines. Its indications include reversal of benzodiazepine-induced sedation, termination of benzodiazepine-induced anaesthesia, return of spontaneous respiration and consciousness in intensive care patients and the treatment of paradoxical reactions to benzodiazepines. Other potential indications include its use in hepatic encephalopathy, alcohol intoxication and coma; however, these claims still require substantiation. Following sedation reversed with flumazenil, minimal residual effects of the agonist can sometimes be detected using psychomotor tests and are due to the relatively short half-life of flumazenil, but are of no clinical consequence. There is concern that flumazenil could precipitate an acute withdrawal syndrome following long-term benzodiazepine administration; however, the available evidence suggests otherwise and that it could be useful in the treatment of benzodiazepine tolerance. The existence of flumazenil is important, with implications for future research and the development of minimally invasive therapy and day-case surgery. With increasing pressures on non-anaesthetically trained practitioners to perform sedation, flumazenil has important implications for safety. PMID- 8693923 TI - Reversal of conscious sedation by flumazenil: current status and future prospects. AB - Flumazenil is safe and highly effective at reversing both benzodiazepine-induced sedation and amnesia. Bolus intravenous injection is the most appropriate technique when the goal is to fully reverse conscious sedation. Currently, the proven effective dose of flumazenil is 0.5 mg. For practical purposes, in this clinical setting, true resedation does not occur, and if the appropriate type and dose of agonist have been used, residual sedation is not a clinical problem. Concerns over acute anxiety reactions and precipitation of acute withdrawal syndrome in chronic benzodiazepine users remain theoretical and unsubstantiated by human data. Further clinical studies are required to determine whether the clinical practice of using flumazenil could include this group of patients. Depression of ventilatory responsiveness induced by benzodiazepines can be reversed effectively and promptly by flumazenil. Flumazenil must be immediately available as an emergency drug in any area where benzodiazepines are used. The clinical and economic benefits of elective and routine use of flumazenil have been demonstrated, but yet to gain widespread acceptance. PMID- 8693924 TI - Genital mutilation of women--is it a concern for gynecologists? PMID- 8693925 TI - Effect of the non-peptide, vasopressin V1a receptor antagonist, SR 49059 and its enantiomer, SR 49770, on isolated human myometrium. AB - BACKGROUND: Vasopressin seems to be an important etiological factor for the myometrial hyperactivity and reduced blood flow in primary dysmenorrhea. Substances which block the action of vasopressin on the uterus are therefore of interest. METHODS: The effect of an orally active, non-peptide vasopressin V1a receptor antagonist, SR 49059, as well as its enantiomer, SR 49770, which is 50 to 100 fold less potent in binding studies, were tested in vitro on myometrium from 14 subjects. Two doses of the compounds, 2 nmol/L and 10 nmol/L, were used for counteracting the contractile effect of arginine vasopressin in a concentration of 0.7 nmol/L. RESULTS: SR 49059, in the lower concentration, significantly decreased the response to arginine vasopressin, measured as area under the recording curve, to 48 per cent of that to the agonist alone, and in the higher dose to 28 per cent. SR 49770 was much less potent in reducing the response to vasopressin. CONCLUSION: The myometrial action of arginine vasopressin is exerted via V1a receptors. The potent stereospecific inhibitory effect of SR 49059 on arginine vasopressin-induced myometrial activity indicates that the compound acts specifically through V1a receptors and may have a therapeutic potential in primary dysmenorrea. PMID- 8693926 TI - Fetal fibronectin and microorganisms in vaginal fluid of healthy pregnant women. AB - OBJECTIVE: To determine fetal fibronectin in vaginal fluid from healthy women during uncomplicated pregnancy and to investigate possible relationships to gestational age and the vaginal microflora. MATERIALS AND METHODS: Samples of vaginal fluid were collected for fetal fibronectin determination and for quantitative aerobic and anaerobic microbiological culture from 22 women followed longitudinally at 12, 28 and 37 weeks gestation cross-sectionally in women at 12 weeks (n = 10), 28 weeks (n = 10), 37 weeks (n = 10), and 39 weeks (n = 30) gestation, respectively. Fetal fibronectin was determined by a quantitative enzyme immunoassay (Adeza Biomedical). RESULTS: There were no significant differences between the concentrations of fetal fibronectin in vaginal secretions at any of the four measurement points (12, 28, 37 and 39 weeks gestation). Women with elevated fetal fibronectin concentration (> or = 0.05 mg/L) had less often hydrogen peroxide-producing facultative lactobacilli (p < 0.0001), and more often bacterial vaginosis (p < 0.02) and Peptostreptococcus species (p < 0.002). Bacterial vaginosis (p < 0.01) and Candida albicans (p < 0.01) were more frequently found in women lacking hydrogen peroxide-producing lactobacilli. CONCLUSION: Fetal fibronectin in vaginal fluid was more associated with the vaginal microflora than with the gestational age of the pregnancy. Presence of hydrogen peroxide-producing lactobacilli seems to be the most important factor for a stable vaginal microflora. PMID- 8693927 TI - Endometrial and fetoplacental markers in pregnancies with fetal congenital nephrosis. AB - OBJECTIVE: Congenital nephrotic syndrome of the Finnish type [CNF] is an autosomal recessive disorder leading to death in early childhood, if treated conservatively without early renal transplantation. Prenatal screening at midtrimester is feasible by measuring maternal serum alpha-fetoprotein [MSAFP], elevated amniotic fluid [AF] AFP being the only diagnostic test in population screening. We studied whether concentrations of other pregnancy-related markers offer any ancillary procedure for screening. METHODS: In a prospective case control study, the concentrations of maternal serum human chorionic gonadotropin [hCG], unconjugated estriol [uE3], human placental lactogen [hPL] and placental protein 14 [pp14] were measured in samples from six singleton pregnancies associated with fetal CNF and from 18 matched controls at 15 weeks of gestation. RESULTS: In the CNF group, mean hCG and pp 14 concentrations were slightly elevated, whereas uE3 and hPL concentrations were within the lower normal range. None of these differences were statistically significant and the distribution of these values was too wide to use them for screening. CONCLUSIONS: Low unconjugated E3 and elevated hCG concentrations were expected, since newborns with CNF are growth-retarded and have large placentas. The extent of these alterations was not sufficient to identify high risk pregnancies. Substantial differences in the maternal serum concentrations of hPL and pp 14 were not observed. Hence, MSAFP screening at midtrimester is the strategy of choice for prenatal detection of CNF. PMID- 8693928 TI - The effect of work activity in pregnancy on the risk of fetal growth retardation. AB - BACKGROUND: The relationship between physical activity at work and risk of fetal growth restriction is controversial. For the most part, previous studies investigated the effect of work activity on birthweight alone. We evaluated the impact of type of occupation and physical effort at work on the risk of ultrasonographically confirmed fetal growth retardation among nulliparous women. METHODS: We compared the characteristics of work and the intensity of occupational fatigue (work posture, weekly working hours, physical effort at work) in 349 patients with ultrasonographically confirmed fetal growth retardation and 698 control pregnancies with appropriate fetal growth. Physical demands at work were evaluated by interview at birth. Logistic regression analysis was used to evaluate the association of employment status, type of occupation, and intensity of occupational fatigue with the risk of fetal growth retardation, correcting for potential confounders (maternal age, pre-pregnancy body mass index, mean weight gain in pregnancy, education, partner's social status, smoking in pregnancy, alcohol use, illicit drug use, time of stopping work, and hypertension). RESULTS: After adjusting for confounding, the risk of fetal growth retardation was similar between unemployed and formally employed women at the beginning of pregnancy (OR = 1.26; 95% confidence interval = 0.86 - 1.83). However, manual workers were at slightly higher risk of IUGR than not formally employed women (OR = 1.81; 95% CI = 1.15 - 2.85). Among formally employed women, standing or walking at work, and working > or = 30 hours a week were not significantly associated with IUGR. Finally, the risk of IUGR was significantly higher (OR = 2.46; 95% CI = 1.36 - 4.21) among women reporting moderate-to-heavy as compared to light physical effort at work. CONCLUSION: Formal employment at the beginning of pregnancy is not associated with an increased risk of IUGR. However, moderate-to-heavy physical effort at work seems to increase the risk of sonographically confirmed fetal growth retardation. PMID- 8693929 TI - Antibiotic prophylaxis in cesarean section. AB - BACKGROUND: To investigate the guidelines for patient selection and drug regimens for application of antibiotic prophylaxis in relation to cesarean section in the maternity clinics in Denmark. METHODS: A questionnaire to all the Danish maternity clinics that perform cesarean section, concerning indications for application of antibiotic prophylaxis and antibiotic regimens to patients undergoing acute and elective cesarean section. RESULTS: All departments (n = 48) returned the questionnaire. Twenty departments (46%) provided written guidelines for antibiotic prophylaxis. Four departments (8%) used antibiotic prophylaxis to elective cesarean sections, 25 departments (52%) applied antibiotics to all emergency sections. In the presence of the rupture of membranes or prolongation of labor (> 12 hrs) 58% and 63% of the departments applied antibiotic prophylaxis, respectively. The most infrequent first choice drug was cefuroxim, employed by 27 departments (56%). Concerning timing, 21 departments (44%) applied antibiotics after cord clamping and 13 departments (27%) before incision. CONCLUSION: We propose a nation-wide prospective investigation on the rate of infections associated with cesarean section to set up rational guidelines for antibiotic prophylaxis. PMID- 8693930 TI - Towards regional equality in family planning: teenage pregnancies and abortions in Finland from 1976 to 1993. AB - BACKGROUND: A major goal of Finnish family planning policy since the 1970s has been to minimize unintended pregnancies by providing equal contraception and abortion services throughout the country. This report looks at how this policy has succeeded among teenagers. METHODS: The data on childbirths, induced abortions and mean populations were collected from the national abortion and population registers. Regional and age-specific rates were calculated for fertility, abortions and pregnancies in girls aged 15-19. RESULTS: In 1993, the teenage pregnancy rate was 20/1000 and the abortion rate 9.5/1000 in the whole country. Although the pregnancy rate had dropped by half since the 1970s, the regional differences were still there: the lowest rate was 18/1000 and the highest 29/1000 (in Lapland) in 1991-93. The abortion rate ranged from 8/1000 to 14/1000. Childbirths decreased, particularly at the beginning of the study period, while abortions declined sharply towards the end of the period. In 1986 88, the abortion ratio exceeded 100 in all provinces except two. In the 1990s, it dropped below 100 again except in the capital province. In 16-17 year-olds, the trends were quite equal in different provinces. In 18-19 year-olds, pregnancies remained more frequent in the north and were more often carried to term, while the choice of abortion was more likely in the south. CONCLUSIONS: Equally declining trends in pregnancies in all provinces suggest that teenage family planning services have a comprehensive coverage. However, regional differences still remain and imply a detailed analysis of their reasons. PMID- 8693931 TI - Central nervous system involvement in gestational trophoblastic neoplasia. AB - BACKGROUND: To review the experience of seven cases of gestational trophoblastic neoplasia with central nervous system involvement. METHODS: Seven patients among 50 cases of malignant gestational trophoblastic neoplasia were analyzed retrospectively in a single institution. RESULTS: The mean age of the patients at diagnosis was 28.7 years (range: 20-34). While five of the patients presented initially with symptoms related to cranial involvement, the remaining two developed cerebral metastases during the therapy. In two patients, the presentation was so similar to a primary cranial pathology that craniotomy and biopsy revealed the trophoblastic involvement. The sites of involvement were the parietal lobe in three, temporal lobe in two and frontal lobe in two patients. Besides central nervous system involvement, four had additional lung and one had pelvic metastases. In terms of therapy, while five patients received methotrexate+actinomycin-D+cyclophosphamide regimen for 3 to 5 courses, only two could be administered additional intrathecal methotrexate. Since one patient exhibited a fulminant clinical course, she could not be delivered a chemotherapy regimen and was lost in two months of initial diagnosis. The other patient was administered modified Bagshawe protocol (5 courses) which was switched to etoposide+methotrexate+actinomycin-D+vincristine+cyclophosphamide (6 courses) due to development of resistance. She was still alive and free of disease after 24 months of initial diagnosis. Six of the patients were also delivered whole-brain irradiation simultaneously with chemotherapy. CONCLUSIONS: The prognosis of brain metastases still seems to be poor despite combination chemotherapy and radiotherapy. Measures should be focused on early diagnosis and prophylaxis. PMID- 8693932 TI - Endometrial stromal sarcoma of twenty cases. AB - BACKGROUND: Endometrial stromal sarcoma is a rare neoplasm. We reviewed twenty cases to study the characteristics of this disease. METHODS: Twenty cases of endometrial stromal sarcoma were treated at our hospital. The clinical stage, treatment and outcome were retrospectively analyzed. RESULTS: Endometrial stromal sarcoma comprised 4.3% of corpus cancers and 46.4% of uterine sarcomas at our hospital. Seven cases were stage I, one was stage II, ten were stage III, and two were stage IV at the time of diagnosis. Histopathologically, seventeen cases were classified as low-grade sarcoma and three were high-grade sarcoma. Seven patients had recurrence and five of them had already died of disease. Among these recurrent patients, one was stage II and six were stage III. All three patients with high-grade sarcoma and four with low-grade sarcoma had recurrence. CONCLUSIONS: We think mitotic count is an important prognostic factor in low grade endometrial stromal sarcoma and high-grade endometrial stromal sarcoma has a poor prognosis even with post-operative adjuvant treatment. PMID- 8693933 TI - HPV-types, cytological and histopathological findings in three groups of women with possible HPV-related disease. AB - OBJECTIVE: The aim of this investigation was to study three groups of women presenting with possible HPV-infection with regard to HPV-types and cervical dysplasia. METHODS: Eighty women were included. Eighteen of them were present partners to men with condylomas, 20 had clinical vulvar HPV-lesions and 42 were referred due to an abnormal PAP-smear. Samples for HPV-analysis by PCR-technique were taken from the vulva, the portio and the cervical canal. A universal HPV primer as well as specific primers for HPV 6/11, 16, 18, 31, and 33 were utilized. PAP-smears were taken as well as biopsies from cervix/portio. RESULTS: Seventy-eight percent had HPV-DNA identified. Sixty-seven percent of those with HPV 16 and/or 18 had dysplasia verified by histopathology and 50% of those with 31 and/or 33. Twenty of 21 women with dysplasia had HPV 16, 18, 31 and/or 33 identified. One woman with dysplasia was HPV-negative. Histopathologically verified CIN were diagnosed in all groups investigated. Women referred for suspicion of CIN significantly more often had HPV detected at the cervix/portio. HPV 6/11 was mostly found in women with condylomas. Apart from this the occurrence of the different HPV types were alike in the three groups. CONCLUSION: Infection with HPV is a process and the usefulness of different diagnostic methods seems to depend on when during the course of the disease they are used. HPV-findings in women with dysplasia were all associated with oncogenic virus types. High-risk virus was often found simultaneously with low-risk virus indicating a covariation in the acquisition of the different HPV-types. PMID- 8693934 TI - Hysteroscopic surgery in postmenopausal women. AB - OBJECTIVE: To assess the efficacy of hysteroscopic surgery in postmenopausal women presenting with abnormal uterine bleeding. DESIGN: A retrospective audit of 102 patients. SETTING: The Department of Obstetrics and Gynecology B, La Conception Hospital, Marseilles, France. PATIENTS: One hundred and two women between the ages of 47-67 years with postmenopausal bleeding or bleeding related to hormone replacement therapy were evaluated by pelvic ultrasound and diagnostic hysteroscopy. A benign organic cause was noted in 87 cases (polyps in 51 and fibroids in 36.) Fifteen patients had no significant disease. INTERVENTIONS: Resection of polyps or fibroids, endometrial ablation. RESULTS: One hundred and seven procedures were performed on 102 patients. Major operative complications were rare and included one perforation and one case of glycine toxicity. Eighty eight patients were satisfied with the results. Six patients were subsequently treated by hysterectomy. Six patients complained of recurrent abnormal bleeding. CONCLUSIONS: This modality of treatment appears to be effective over the long term. The operative criteria should take the causes of bleeding and not just the age of the patient into account. PMID- 8693935 TI - Transcervical resection of endometrium and fibroids: the outcome of 412 operations performed over 5 years. AB - OBJECTIVE: To evaluate the value of transcervical resection of endometrium and fibroids in clinical practice. STUDY DESIGN: A retrospective review of operative details of 412 transcervical resections of endometrium and fibroids and clinical outcome from 387 procedures performed over five years is reported. MATERIAL AND METHODS: Patients referred due to bleeding disturbance, treated with a standard urological resectoscopes, controlled after 6 and 12 months. Subsequent follow up was performed by questionnaire and patient bleeding diary. RESULTS: Operative complications (perforation, hemorrhage, absorption and more than 1500 ml glycine irrigating fluid) arose in 72 patients (18%). In 52 (14.4%) of 366 patients the outcome was not considered acceptable by either ourselves or the patients. This led to a repeat resection procedure being performed in 31 cases (9.0%) with favorable result in 21 (68%) of these cases. Twenty-one patients (6.1%) underwent a hysterectomy because of a persistently poor outcome. A favorable outcome was then reported in subsequent follow up of 335 patients (91%). In addition, pain associated with menstruation was reduced after the procedure and correlates with achieved result on bleeding intensity. CONCLUSION: Endometrial resection is safe and acceptable treatment option for both menorrhagia and metrorrhagia associated with dysmenorrhoea. PMID- 8693936 TI - Preliminary experience in pelviscopic uterine suspension using Webster-Baldy and Franke's method. AB - OBJECTIVE: To find which method gives the best relief from dyspareunia and pelvic pain caused by a retroverted uterus using the two methods mentioned as compared to other methods reported in the medical literature. SUBJECTS: Twenty-five patients, with ages ranging from 25-55 years old, complaining of mild to severe pelvic pain and dyspareunia seeking treatment in our OPD were evaluated and treated in a span of 3 years' time. METHODS: Pelviscopic retrouterine ligament fixation using Webster-Baldy and Franke's method were done after each patient was evaluated as to the uterine position, degree of misalignment of the uterus and severity of adhesion. Pelvic pain and dyspareunia were reproduced by palpation of the retroverted uterus. Ultrasonographies were performed to confirm initial findings and to rule out any ovarian or uterine abnormalities. Orthopedic and psychological consultations were done to rule out any orthopedic disorders or non organic causes of their problem. RESULTS: Of the twenty-five patients treated, 20 patients were treated using Webster-Baldy method and five patients were treated using Franke's method, all the patients (100%) experienced great improvement 6 weeks after the operation. After 6 months, 16 patients (80%) with the Webster Baldy method and four patients (80%) with the Franke's method had complete relief from pelvic pain and dyspareunia. The remaining four patients (20%) with the former method and one patient (20%) with the latter method complained of mild abdominal discomfort. After 6 months to 2 years of follow-up, 17 patients with Webster-Baldy method and five patients with Franke's method (88%) had improved sexual life and the remaining three patients were lost to follow-up. CONCLUSION: When dyspareunia and pelvic pain are caused by a retroverted method, we believe uterine suspension using different procedures will certainly relieve this problem. We have presented and have chosen these two procedures mainly due to their simplicity and the almost nil possibility of bowel intussusception into the anterior cul-de-sac as compared to other methods. PMID- 8693937 TI - Increased use of condoms among female university students: a 5-year follow-up of sexual behavior. AB - OBJECTIVE: To ascertain any changes in sexual behavior and attitudes as an indication of the impact of intensified information activities aiming at decreasing the risk of spread of sexually transmitted diseases among university students. METHODS: In 1989 questionnaires were offered to 275 consecutive female students visiting the Student Health Center. Identical questionnaires were mailed to 200 randomly selected women registered at Uppsala University. The study was repeated in 1994. The study was carried out in Uppsala, a city in Sweden with 27,000 university students. RESULTS: At the Student Health Center 241 (88%) participated in the study in 1989 and 262 (95%) in 1994. Corresponding figures in the postal survey were 137 (69%) in 1989 and 151 (76%) in 1994. Compared with the findings in 1989, in 1994 the sexual behavior was unchanged in terms of mean age at first intercourse (17.6 years), median number of life partners (3-4) and median number of sexual partners during the last 12 months (1), but the awareness of sexually transmitted diseases had increased. Their attitudes to using condoms had become more positive and the actual use of a condom had also increased both at the first intercourse and when changing partner, from 40 to 60%. Concerns about safety of oral contraceptives decreased significantly. CONCLUSIONS: This follow-up shows that awareness of sexually transmitted diseases and condom use had increased between 1989 and 1994, possibly as a result of intensified information efforts. PMID- 8693938 TI - Occurrence of anti-D in RhD-positive mothers and the outcome of the newborns. PMID- 8693939 TI - Incomplete androgen insensitivity (testicular feminization) syndrome: two case reports. PMID- 8693940 TI - Uterine leiomyosarcoma in patient receiving tamoxifen therapy. PMID- 8693941 TI - Multiple giant endometriotic cysts of the pelvic-abdominal cavity. A case report. PMID- 8693942 TI - Ovarian hyperstimulation syndrome (OHSS) in pregnancy not associated with ovulation induction. PMID- 8693943 TI - [Guignol or the comedian's paradox]. AB - Our study is based on a puppet theatre performed with a group of children aged from six to eight who were experiencing a neurotic context. Guignol's playing reveals anguishes and defensive mechanisms as well as, regarding the actors, the ability to experience the comedy with authenticity without forgetting it is imaginary. The puppet theatre has allowed us to progress in a therapeutic process while continuing diagnostic exploration. PMID- 8693944 TI - The management of drug-resistant, persistent and unpleasant auditory hallucinations. AB - This article attempts to give an overview of the main cognitive-behavioral therapeutic approaches in order to reduce persistent, unpleasant and drug resistant auditory hallucinations. These procedures are based on operant conditioning principles and cognitive self-management techniques. A brief case history is reported to illustrate the therapeutic interventions. PMID- 8693945 TI - [Return to work following myocardial infarct. effect of certain socioeconomic factors]. AB - The influence of several socioeconomic factors in return to work following myocardial infarction has been evaluated for 55 male patients. Age, employment status and educational level are among the most determinant factors. Whereas, the financial resources appear less significant as an incentive to resumption of work. PMID- 8693946 TI - [Systemic approach to families dealing with cancer diagnosis, its treatment and its prognosis]. AB - This paper reviews and comments the literature related to the problems families have to deal with when cancer occurs, in a psychological and relational perspective. It addresses, among other topics, communication problems and the specific aspects of the different evolutional phases of the disease, and the subsystems of the family. Considering the dramatic effects of cancer within the family and the interdependency of the patient and his family in their adjustment to the disease, we propose that psychological evaluation and support should be offered to the family system as a whole. PMID- 8693947 TI - [The wolf-man, a borderline case?]. AB - The diagnostic of "borderline" relies on the study of the Ego the refers to the prevalence of imaginary mechanisms, like object splitting. However, it doesn't allow to distinguish neurotic from psychotic structure. In the case of the Wolf Man, the investigation of childhood's material (hallucination of the cut finger) allows to overpass this difficulty. PMID- 8693948 TI - [The future of the concept of depression]. AB - The history of the concept of depression is briefly reviewed. First described under the name of melancholia as a delusional state, then, since Esquirol, as a primary mood disorder, it was subdivided by Kraepelin in diseases characterised by an hypothetical etiology and is considered, since 1980, as a syndrome with many sub-varieties. The nature of the three possible models is discussed. The first two, until now used, which considered depression either as a disease or as a syndrome, are categorical. The first has been provisorily abandoned, due to the insufficiency of scientific proofs about the etio-pathogeny; the second, despite its growing complexity, is obviously not satisfactory. The third model, dimensional, which attracts a growing attention in other field of psychiatric nosology, offers for the time being a possible alternative. PMID- 8693949 TI - [Monoamine oxidase inhibitors and food precautions. A comparison of utilization in Belgian psychiatric education institutes and current findings in the literature]. AB - After an extensive survey of MAOI diets prescribed in different Belgian training institutes, there appears to be a confused situation which can cause obstacle for prescription. Of the diets received, we note that 211 foodstuffs and type of foodstuffs have been recommended for restrictive use. However, a most recent literature overviews shows restrictive recommendations for only 40 foodstuffs and types of foodstuffs. Its systematic analysis allows us to propose to the patient a personalized diet with little restrictions which is explained on an understandable rather than a descriptive basis. The adoption of this kind of diet should facilitate easier access to MAOI's, in case more simple therapy strategies have failed, especially in the atypical depressive disorders and tricyclic's refractory depressive disorders. PMID- 8693950 TI - The effects of variation of an irrelevant dimension on same-different visual judgments. AB - In a series of experiments observers judged whether two visual tachistoscopically presented shapes were the same or different in a relevant dimension, and had to ignore the graded variation on an irrelevant dimension that appeared concurrently with the relevant dimension. Experimental results from judgments in orientation, size and brightness failed to support the normalization hypothesis. The hypothesis predicts a monotonous increase in RTs with the increasing degree of disparity in the irrelevant dimension in same as well as in different comparisons. The results were interpreted in terms of the type of dimensions used to construct the shapes. It was suggested that with separable stimulus dimensions normalization would not be necessary. However, interference might appear when the stimuli to be compared were generated from a combination of more integral dimensions. PMID- 8693951 TI - The role of vision in repetitive circle drawing. AB - In the present experiment the role of vision in the control of repetitive circular movements was examined. Subjects drew circles at a 600 ms per circle rate. During the first nine seconds of the trial subjects moved with full vision and were paced by a metronome. During the latter 15 seconds, vision could be removed and/or the pacing signal could be removed. There were no effects of the pacing signal on the temporal and spatial characteristics of the circle. Withdrawal of vision did not affect the shape of the circle, but did change its scaler quality. The circles became smaller and the center drifted in a systematic fashion. Furthermore, the loss of vision produced an increase in variability in the circle shape, size and location. It is clear that in a simple task such as circle drawing, vision serves not as a source of information about form, but to maintain a stable and consistent form. PMID- 8693952 TI - Visuomotor control when reaching toward and grasping moving targets. AB - Two experiments were conducted to examine the influence of target motion on the control and coordination of reaching and grasping movements. In Experiment 1 all the measures which reflected the transport or reaching phase of prehension (movement time, peak velocity, time to peak velocity, and transport tau margin) were sensitive to the velocity of the target, with subjects moving even slower than during the stationary trials, when the target was moving very slowly. Measures which reflected grasp formation such as the size of maximum aperture and the grasping tau margin were not influenced by target speed. To further investigate this dissociation between grasp and transport, different object sizes and even slower object speeds were introduced in Experiment 2. Transport results similar to those found in the first study were observed. However, in Experiment 2, both size of peak aperture and the grasping tau margin were sensitive to target movement. The results of these two studies are discussed in terms of the limitations of optic variables in the visual regulation of movement, and the independence of control of the reach and grasp phase of prehension. PMID- 8693953 TI - Confidence and accuracy in trait inference: judgment by similarity. AB - We examined the confidence and accuracy with which people make personality trait inferences and investigate some consequences of the hypothesis that such judgments are based on similarity or conceptual relatedness. Given information concerning a target person's standing on three global personality dimensions, American and Israeli subjects were asked to estimate the target's self-ratings of 50 trait adjectives and to express their confidence by setting a 90 percent uncertainty range around each estimate. The estimates were positively correlated with the actual ratings obtained from subjects who had evaluated themselves in terms of the 50 traits, but were far too extreme. Furthermore, confidence was negatively correlated with accuracy: People's estimates were most inaccurate and made with greatest certainty when the trait in question was highly similar to the information provided as a basic for judgment. We suggest that intuitive personality judgments overestimate the coherence of the structure underlying trait constructs. PMID- 8693954 TI - Testing the global-slowing hypothesis: are alcohol's effects on human performance process-specific or task-general? AB - In an interesting recent meta-analysis, Maylor and Rabbitt (1993) suggested that alcohol's effects on human performance may not be process- or stage-specific, but reflect a general, undifferentiated, cognitive slowing. According to this view, performance is globally slowed by a constant multiplicative fraction (b), such that the longer a process takes without alcohol on board (a -), the more it will be slowed by alcohol (a +). In summary: RTa+ = b b (RTa-). In this sense, the effects of alcohol are determined simply by the duration of a process or stage- not by its function or content--and attempts to map the effects of alcohol to specific cognitive operations are essentially futile. This global-slowing hypothesis entails, then, (i) that the function relating RTa+ to RTa- will be linear and increasing; (ii) that the value of b will be significantly greater than 1.0; and (iii) that all experimental factors which increase the complexity (hence, duration) of a task or stage will interact with alcohol. In this study we tested the global-slowing hypothesis directly using fixed set, varied set and concurrent sets item-recognition paradigms. All three tasks showed convincing additivity between alcohol and other key experimental factors which affect response latency (e.g., setsize, response type); there was no hint of any of the spectrum of significant interactions predicted by the global-slowing hypothesis. A meta-analysis of varied set latencies, analogous to Maylor and Rabbitt's, yielded a reasonably linear alcohol/no-alcohol function, but with a slope constant (b) less than 1.0. In all, the data provided little support for the global-slowing hypothesis. PMID- 8693955 TI - Information integration in cross-modal pattern recognition: an argument for acquired modularity. AB - Three experiments addressed the issue of whether modularized operations (Fodor, 1983) in pattern recognition could be acquired. In Experiment 1, blind and sighted individuals were compared in the speech-tactile domain of pattern recognition. The results were inconsistent with the assumptions of the fuzzy logical model of perception (FLMP) (Oden and Massaro, 1978) and with the assumptions of modularized pattern recognition processes, but were consistent with the assumptions of 'penetrability' into non-modularized operations. Experiments 2 and 3 compared sighted individuals across speech-visual and speech tactile domains, revealing fundamentally different patterns of performance that we argue demonstrate modularized and non-modularized FLMP operations in pattern recognition, respectively. PMID- 8693956 TI - [Intracavitary bacillus Calmette-Guerin therapy for upper tract transitional cell carcinoma]. AB - Four patients with upper urinary tract transitional cell carcinoma were treated with bacillus Calmette-Guerin (BCG) via a percutaneous nephrostomy tube or a retrograde ureteral catheter. A 68-year-old female and an 80-year-old male had carcinoma in situ (CIS) in the left upper urinary tract (cases 1 and 2). A man aged 47 had CIS in the left upper urinary tract, bladder, and prostatic urethra (case 3). CIS in the left upper urinary tract was identified in a woman aged 63 with chronic renal insufficiency (case 4). Two patients (cases 1 and 2) responded to this therapy. In the other two patients nephrectomy was performed due to residual tumor. There were extensive tuberculous granulomas in the kidneys. In one resected kidney (case 4) carcinoma had invaded the renal parenchyma. The reviewed literature showed that BCG perfusion therapy was effective in 71% (27 of 38 renal units) for the upper urinary tract tumors and that there were 5 cases of severe complication, including sepsis in 2, high fever in 2, and ureteral stricture in 1. Based on the fact that the kidney receives a profuse blood supply and that the renal pelvis and ureter have a thin wall, careful management is mandatory to prevent severe adverse effects and insidious tumor progression. PMID- 8693957 TI - Intra-arterial chemotherapy for muscle-invasive urinary bladder cancer. AB - A total of 9 patients with muscle-invasive bladder cancer (T3 or T4N0M0) were treated with a modified intra-arterial M-VEC (IA-M-VEC) regimen beginning in October 1992 to evaluate its therapeutic efficacy, and in 3 evaluable patients who subsequently underwent radical cystectomy, the possibility of bladder preservation was assessed. The responses of the 8 evaluable patients were rated as complete response (CRs) in 3, partial response (PRs) in 3 and no change (NCs) in 2. The objective response rate (PR + CR) was 75%. An obvious down-staging (T3 -> pT1b) was confirmed in 2 of the 3 evaluable patients, suggesting the possibility of bladder preservation. Otherwise similar changes to hemorrhagic cystitis with minimal muscular fibrosis were conspicuous in the normal bladder wall. These pathological findings corresponded with those obtained by dynamic single photon emission computed tomography (D-SPECT) using 99mTC-macroaggregate albumin (99mTC-MAA). Besides a buttock-to-perianal erosion with neuralgia on the injection side, mild to moderate sensory disturbance of the sacral plexus was observed. PMID- 8693958 TI - [Prognostic factors in stage D2 prostate cancer: results of univariate and multivariate analyses]. AB - To evaluate prognostic factors in stage D2 prostate cancer, 235 patients who had been treated with endocrine therapy were investigated. With univariate analysis, performance status, hemoglobin concentration, serum alkaline phosphatase, LDH, histological grade, extent of disease (EOD), and response of tumor markers at 3 months were shown to be significant prognostic factors. To compare these 7 factors, multivariate analyses was performed in 196 cases. Cox proportional hazard model demonstrated that LDH, followed by response of tumor markers at 3 months, histological grade, and EOD were significant for predicting prognosis. We concluded that the patients whose serum LDH was above the normal range and/or whose tumor markers were not or had not been normalized 3 months after the onset of endocrine therapy were in the high risk group, and should be given more aggressive treatment. PMID- 8693959 TI - [Prostate cancer screening in total health care check--using serum PSA and AUA score]. AB - From April 1994 to February 1995, we studied prostate cancer screening at Shakaihoken Hazu Hospital and Health Care Center. Among 1,838 men, over 55, who had taken the total health care check, 857 applicants had had prostate cancer screening, using serum PSA (Delia kit; normal range < 11.7 ng/ml) and AUA voiding symptom score and bothersome score. According to the serum PSA level, they were divided into 4 groups, 11 with 8 ng/ml or more indicating requirement of further examination, 29 with 4-8 ng/ml indicating requirement of observation, 100 with less than 4 ng/ml and AUA score (approximately more than 10) indicating voiding disturbance and the other 717 were normal; Of 11 further examined cases, 6 applicants underwent random biopsy. We found 3 with prostate cancer (0.35%). PMID- 8693960 TI - [Determination of free type and complex type prostate-specific antigen (PSA): differences in immunorecognition by Delfia PSA, ACS-PSA and Eiken PA kits]. AB - To study immunorecognition of free type and complex type prostate-specific antigen (PSA) by current commercial PSA assays, sera from 3 patients with stage D2 prostate cancer were separated by Sephacryl S-200 chromatography and determined by Delfia PSA, ACS-PSA and Eiken PA kits. Two antibodies used in the 3 kits are 2 monoclonal, 1 monoclonal and 1 polyclonal and 2 polyclonal antibodies, respectively. Following chromatography, two PSA peaks were obtained in all patients. One was about 100 kDa and the other about 30 kDa. The former was considered to be the complex type PSA (complex with alpha-1 antichymotrypsin) and the latter to be free type PSA. As to free type PSA, the ACS-PSA kit and Eiken PA kit quantitated PSA values approximately 5.1 and 2.5 times higher than the Delfia PSA kit. For complex type PSA, the quantity determined by ACS-PSA kit was approximately 1.3 times higher than that determined by the Delfia PSA kit, while the quantity determined by the Eiken PA kit was about one third of that determined by Delfia PSA kit. The ratio of complex type PSA to total PSA (free type PSA + complex type PSA) was 74.8 +/- 14.9% (mean +/- SD) when determined by Delfia PSA kit, 59.3 +/- 18.4% by ACS-PSA kit and 52.9 +/- 13.8% by Eiken PA kit. The range of this ratio determined by ACS-PSA kit was from 47.3% to 80.5% in the 3 patients. These findings suggest that there are qualitative differences in immunorecognition of free type PSA and complex type PSA among current commercial PSA assays and that there are quantitative differences in the ratio of the 2 forms of PSA in serum among prostatic cancer patients. The measurement and follow up of both free type and complex type PSA might be important for diagnosis and monitoring of prostate cancer. PMID- 8693961 TI - [Classification of patterns of nocturnal penile tumescence with continuous monitoring of penile rigidity: analysis of various factors affecting erection]. AB - In 43 men who required further examination of erectile function, we analyzed the relationship between the various factors including hormone levels, penile blood pressure index (PBPI), shape of the arterial wave, erection period after prostaglandin E1 injection and dynamic cavernosography/metry, as well as the patterns of nocturnal penile tumescence (NPT) with rigidity. Normal, dissociation, short episode, low amplitude and flat trace patterns, which were classified by Kaneko, were observed in 11, 8, 11, 2 and 11 men, respectively. Uncoupling was not observed in any men. There were no differences in the levels of prolactin and LH among the 6 patterns. A high FSH level was seen in men with a flat trace pattern; a low level of free testosterone ( < 12.2 pg/ml) was seen in men with dissociation, low amplitude and flat trace patterns, and low PBPI ( < 0.75) in men with flat trace pattern; and an arteriosclerotic shape of the arterial wave was seen in men with short episode and flat trace patterns. Each erection period immediately after prostaglandin E1 injection in men with dissociation, short episode, low amplitude and flat trace was shorter compared with cases with a normal pattern. Venoocclusive dysfunction was observed in 5 men with a dissociation pattern and 6 men with a flat trace pattern. In conclusion, an integral analysis of pattern of NPT with rigidity and other examinations are useful for differentiating organic impotence from psychogenic impotence and for accurately diagnosing pathophysiological disorders of organic impotence and underlying diseases. PMID- 8693962 TI - Non-refluxing ileal ureter replacement using intussuscepted nipple valve--an experimental study in dogs. AB - Although the vast accumulation of data from the continent urinary reservoir clearly proves that intussusception of the ileum is a reliable procedure for preventing urine reflux, few reports have appeared on the application of this technique to ileal replacement of the ureter. In an effort to determine if the nipple valve created by the intussuscepted ileum can prevent urine reflux in the ileal ureter, an experimental study was done using five dogs. I performed ureteral replacement using a newly developed procedure to secure the nipple valve in place. All dogs were followed for 6 months and evaluated by blood urea nitrogen (BUN), creatinine (Cr), serum electrolyte, urine culture, intravenous urogram (IVU), cystogram, and urodynamic studies. No significant differences were notable between the preoperative and 6-month postoperative values of BUN, Cr, and serum electrolytes in all dogs. Only one of the dogs, which showed extussusception of the nipple valve, demonstrated the reflux. IVUs and Whitaker flow studies did not confirm any urinary outflow obstruction. Furthermore, during the pressure studies, the nipple valve prevented transmission of the increased intravesical pressure to the upper urinary tract. I believe that the intussuscepted ileum can be secured by our procedure and can prevent reflux even though it is incorporated into the urinary system itself. PMID- 8693963 TI - [A case of asymptomatic extra-adrenal pheochromocytoma]. AB - A 46-year-old female first presented to our clinic with a chief complaint of an abdominal mass. A computerized tomographic (CT) scan revealed a 6 cm retroperitoneal mass below the left kidney. Preoperative hormonal examinations showed elevation of catecholamines and vanillymandelic acid (VMA) in her 24-hour urine, although she had no hypertension. Therefore, the tumor was uneventfully removed and histologically diagnosed as pheochromocytoma. It is difficult to preoperatively diagnose normotensive extra-adrenal pheochromocytoma without any considerations of the possibilities. However, it may be hazardous to treat pheochromocytoma surgically without any preparations. In the present case, we emphasized the importance of preoperative accurate diagnosis of extra-adrenal pheochromocytoma and discussed briefly the clinical features in the literature. PMID- 8693964 TI - [Renal cell carcinoma associated with circumferential "ring-like" calcification]. AB - A 37-year-old man was found to have large calcification in the left kidney in a health check. This calcification has not changed in size during 3 years with computerized tomographic (CT) studies. However, a suspicious lesion for a malignant tumor with the calcification was suggested by a magnetic resonance image (MRI) study. Thus, the patient underwent tumor enucleation and the histology showed the mixed typed renal cell carcinoma. Although it remains controversial, partial nephrectomy or tumor enucleation would be considered in a case of renal cell carcinoma with calcification, which is usually considered to have a favorable prognosis compared to that of a tumor without a calcification. PMID- 8693965 TI - [Juxtaglomerular cell tumor: a case report]. AB - We report a case of juxtaglomerular cell tumor. A 17-year-old female complained of headache with severe hypertension, hypokalemia, and elevated level of plasma renin activity. Computerized tomographic (CT) scan revealed a slightly enhanced tumor at middle pole of right kidney. Angiography showed a hypovascular tumor. A renin secreting tumor of the right kidney was diagnosed and right nephrectomy was performed. The pathological findings showed a juxtaglomerular cell tumor. Postoperatively, prompt normalization of blood pressure and decrease of plasma renin activity level were found. This case was incorporated into a review of the 43 cases previously published and we discussed the clinical characteristics of juxtaglomerular cell tumor in this report. PMID- 8693966 TI - [Primary adenocarcinoma of renal pelvis and ureter associated with incomplete ureteral duplication: a case report]. AB - We report a rare case of primary adenocarcinoma of the renal pelvis and ureter in an incomplete duplicated ureter. A 69-year-old male with macroscopic hematuria consulted our hospital. Retrograde pyelography revealed left incomplete duplicated ureter and a filling defect in the lower pole of the ureter. Transurethral ureteroscopy was employed to investigate the filling defect, and a papillary tumor was detected extending into the lower segment of the incomplete duplicated ureter. From these findings, the patient was diagnosed with tumor of renal pelvis and ureter, and left total nephroureterectomy was performed. Pathological diagnosis was adenocarcinoma of the renal pelvis and ureter, INF beta, pT2, pR0, pL0, PV0, PN0. No evidence of either tumor recurrence or metastasis was found on the 3-month postoperative follow up. This case is thought to be the first report of primary adenocarcinoma of the renal pelvis in an incomplete duplicated ureter. PMID- 8693967 TI - [Recurrent and up-grading bladder cancer in a young female: a case report]. AB - We report a case of superficial bladder cancer in a young female, with grade-up tumor after frequent recurrences. A 29-year-old woman complained of gross hematuria on April 25, 1991. Cystoscopic examination revealed a papillary pedunculated tumor and transurethral resection of bladder tumor (TUR-BT) was performed. Pathological examination showed transitional cell carcinoma (TCC) pT1 grade 1. In spite of prophylactic therapy, such as intravesical instillation of anticancer drugs and radiochemohyperthermia, she suffered frequent recurrences. At the 6th recurrence, the tumor deteriorated to grade 3 on September 2, 1992. Total cystectomy was done on February 15, 1993 because of uncontrollable bleeding from bladder cancer. Convalescence was uneventful, and no evidence of recurrence was present 2.8 years postoperatively. PMID- 8693968 TI - [A case of sensitive urethra treated by continent vesicostomy using detrusor tube]. AB - A case of sensitive urethra treated with continent vesicostomy is reported. She suffered from atonic bladder due to a previous pelvic surgery and could not continue clean intermittent self-catheterization because of pain and discomfort, or sensitive urethra. Continent vesicostomy using detrusor tube following Mitrofanoff principle was performed. Postoperatively, the daily life activity improved markedly. Mitrofanoff operation is considered to be applicable to the cases with sensitive urethra after sufficient explanation and consent. PMID- 8693969 TI - [A case of oligozoospermia with marginal hyperprolactinemia due to pituitary microadenoma]. AB - We present an infertility male with prolactin level of 37.5 ng/ml. The patient had pituitary microadenoma detected by Gd-DTPA enhanced magnetic resonance imaging (MRI). After bromocriptine was administrated for 4 months, the size of microadenoma decreased, and sperm density and mortality improved. His wife became pregnant after 6 months. Dynamic MRI is a useful modality for detection of pituitary microadenoma, and bromocriptine is also useful for treatment of oligospermic patients with marginal hyperprolactinemia. PMID- 8693970 TI - Effect of long-term administration of finasteride (MK-906), an inhibitor of 5 alpha-reductase, in patients with benign prostatic hyperplasia. AB - We evaluated the effect of long-term administration of finasteride (MK-906), a potent inhibitor of 5 alpha-reductase in patients with benign prostatic hyperplasia (BPH). The effect of an increase in dose was also assessed. Finasteride was administered to 61 patients with BPH at the dose of 1 mg/day for 48 weeks. Thirty three of these patients subsequently received finasteride at the dose of 5 mg/day for further 24 weeks in an open extension study. Urinary symptoms, urinary flow rate, residual urinary volume, prostatic volume and serum concentrations of dihydrotestosterone and prostate-specific antigen were examined periodically during the treatment. The size of the prostate and total urinary symptom scores decreased progressively during the first 16 weeks of treatment. The patients who received finasteride had a significant increase in the maximal urinary flow rate and a significant decrease in residual urinary volume. After 72 weeks of treatment, finasteride at an increased dose of 5 mg did not provide additional benefit to patients, although the effects of the drug at a dose of 1 mg were well maintained. Treatment with finasteride was well tolerated at both doses. In conclusion, the treatment of BPH with 1 mg of finasteride per day for 48 weeks results in a significant increase in maximal urinary flow rate, and a decrease in prostatic volume, symptoms of obstruction and residual urinary volume, with minimal toxicity. PMID- 8693971 TI - Functional MR of brain activity and perfusion in patients with chronic cortical stroke. AB - PURPOSE: (1) To determine whether functional MR can reliably map functional deficits in patients with stroke in the primary visual cortex; (2) to determine whether functional MR can reliably map perfusion deficits; and (3) to determine whether functional MR can give any additional diagnostic information beyond conventional MR. METHODS: Seven patients who had had a stroke in their primary visual system were examined using two functional MR techniques: (1) dynamic susceptibility contrast imaging, and (2) cortical activation mapping during full field visual stimulation. Maps of relative cerebral blood volume and activation were created and compared with visual field examinations and conventional T2 weighted images on a quadrant-by-quadrant basis in five of these patients. RESULTS: Visual field mapping matched with both T2-weighted conventional images and activation mapping of 16 of 18 quadrants. In two quadrants, the activation maps detected abnormalities that were present on the visual field examination but not present on the T2-weighted images nor on the relative cerebral blood volume maps, which may indicate abnormal function without frank infarction. In addition, the activation maps demonstrated decreased activation in extrastriate cortex and had normal T2 signal and relative cerebral blood volume but was adjacent to infarcted primary cortex, mapping in vivo how stroke in one location can affect the function of distant tissue. CONCLUSION: Functional MR techniques can accurately map functional and perfusion deficits and thereby provide additional clinically useful information. Additional studies will be needed to determine the prognostic utility of functional MR in stroke patients. PMID- 8693973 TI - Improved detection of enhancing and nonenhancing lesions of multiple sclerosis with magnetization transfer. AB - PURPOSE: To determine whether magnetization transfer imaging can improve visibility of contrast enhancement of multiple sclerosis plaques. METHODS: Fifty nine enhancing and 63 nonenhancing lesions in 10 patients with multiple sclerosis were evaluated to calculate contrast-to-noise ratios on conventional T1-weighted and T1-weighted magnetization transfer images. The signal intensity of the lesion and the background (white matter) were measured on precontrast T1-weighted and T1 weighted magnetization transfer images (800/20/1 [repetition time/echo time/excitations]) and on postcontrast T1-weighted and T1-weighted magnetization transfer images. Mean contrast-to-noise ratios was calculated for all lesions. RESULTS: The contrast-to-noise ratio was significantly higher for enhancing and nonenhancing lesions on T1-weighted magnetization transfer images than on conventional T1-weighted images. For enhancing lesions, the contrast-to-noise ratio was significantly higher on postcontrast T1-weighted magnetization transfer images, 32 +/- 2 compared with 21 +/- 2 on conventional T1-weighted images. Fifty of the 59 enhancing lesions were seen on both the T1-weighted and the T1-weighted magnetization transfer images. Nine enhancing lesions were seen only on the postcontrast T1-weighted magnetization transfer images. In addition, of 63 nonenhancing lesions seen on proton-density, T2-weighted, and T1-weighted magnetization transfer images, 16 were not seen on the conventional T1-weighted images. Seven of the 63 nonenhancing lesions and 7 of the 59 enhancing lesions had high signal intensity on the precontrast T1-weighted magnetization transfer images suggestive of lipid signal, a finding not seen on the conventional precontrast T1-weighted images. CONCLUSION: Magnetization transfer improves the visibility of enhancing multiple sclerosis lesions, because they have a higher contrast-to-noise ratio than conventional postcontrast T1-weighted images. High signal intensity on both nonenhancing and enhancing lesions noted only on precontrast T1-weighted magnetization transfer suggests a lipid signal was unmasked. If magnetization transfer is used in multiple sclerosis patients, a precontrast magnetization transfer image is necessary. PMID- 8693972 TI - Functional MR in the evaluation of dementia: correlation of abnormal dynamic cerebral blood volume measurements with changes in cerebral metabolism on positron emission tomography with fludeoxyglucose F 18. AB - PURPOSE: To determine whether magnetic susceptibility functional MR imaging of cerebral blood volumes provides information similar to fludeoxyglucose F 18 positron emission tomography (PET) brain images in patients undergoing evaluation for dementia. METHODS: Ten subjects were studied with both PET and functional MR. Clinical diagnoses included probable Alzheimer disease (n = 5), possible Alzheimer disease (n = 1), Pick disease (n = 2), and primary progressive aphasia (n = 2). The studies were quantitatively evaluated by coregistration of PET and functional MR images followed by regression analyses of corresponding regions of interest. Qualitatively, each brain was categorized into eight regions, and each was classified as normal or abnormal by visual inspection. RESULTS: Correlation coefficients between registered functional MR and PET images were excellent (mean, r = 0.58) in most of the cerebrum. Significant correlations were observed in 72 of 74 brain sections. Qualitatively, 16 brain regions were judged to be abnormal by both MR imaging and PET; 46 regions were normal by both; 10 regions were abnormal by PET only; and 8 regions were abnormal only by functional MR. The concordance between functional MR and PET was 78%, which was highly significant. CONCLUSION: Cerebral blood volumes images derived from magnetic susceptibility (functional MR) provide information similar to fludeoxyglucose F 18 PET images in demented patients undergoing evaluation for dementia. PMID- 8693974 TI - Evaluation of automated MR spectroscopy: application in Alzheimer disease. AB - In a trial involving 21 patients with dementia and 3 healthy control subjects, a comparison between the major cerebral metabolite ratios obtained with an established manually optimized proton MR spectroscopic examination and those obtained with an automated proton MR spectroscopic procedure shows that the two techniques provide very comparable results. PMID- 8693975 TI - MR findings in methanol intoxication. AB - We report the MR and CT findings with pathologic correlation in a case of severe methanol intoxication. There was bilateral hemorrhagic necrosis of the putamen and caudate nuclei and, in addition, extensive subcortical necrosis and symmetric bilateral necrosis of the pontine tegmentum and optic nerves, which may indicate poor prognosis. PMID- 8693976 TI - Erdheim-Chester disease: MR of intraaxial and extraaxial brain stem lesions. AB - A case of Erdheim-Chester disease demonstrates cerebral hemispheric involvement, as well as and intraaxial and extraaxial brain stem involvement in a patient with symptoms of paraparesis, urinary incontinence, visual loss, ataxia, vertigo, proptosis, and nystagmus. Persistent gadopentetate dimeglumine enhancement was noted in the extraaxial cervicomedullary brain stem lesion 23 days after injection. However, the supratentorial lesions fail to show similar persistent enhancement. This case also demonstrates MR features characteristic of retrobulbar infiltration. PMID- 8693977 TI - Angioplasty of the occluded internal carotid artery. AB - PURPOSE: To review patients who have presented with acute strokes from a middle cerebral artery occlusion in whom in addition to the middle cerebral artery thromboembolus, an internal carotid artery occlusion has been present, and in whom angioplasty of these totally occluded internal carotid arteries has bee n successful. METHODS: We reviewed retrospectively our experience in treating a cute stroke patients with intracranial, intraarterial urokinase. Six of 27 patients had internal carotid artery occlusions in addition to middle cerebral artery occlusions. Two patients presented with spontaneous carotid dissections for wh ich no further intervention from the ipsilateral internal carotid artery was attempted. In the remaining four internal carotid artery occlusions secondary to atherosclerotic disease, standard guide wires and catheters were negotiated across the level of the internal carotid artery occlusion, which expedited intracranial catheterization for thrombolysis. Subsequently, angioplasty of the internal carotid artery was performed. RESULTS: All four occluded internal carotid arteries could be traversed. No new neurologic deficits occurred. No vascular injuries occurred. No deaths occurred. Four- to 6-month follow-up showed all four internal carotid arteries remained patent. CONCLUSION: In acute occlusions of the internal carotid artery from atherosclerosis, the occluded vessel can sometimes be recanalized with low morbidity. In addition, endovascular access to the intracranial circulation can be expedited by using the recanalized internal carotid artery. PMID- 8693978 TI - Outcome analysis of preoperative embolization with N-butyl cyanoacrylate in cerebral arteriovenous malformations. AB - PURPOSE: To determine the influence of preoperative N-butyl cyanoacrylate embolization on outcome in the treatment of cerebral arteriovenous malformations. METHODS: Two groups were compared: 30 patients who underwent surgery and embolization versus 41 patients who underwent surgery only. Both groups were categorized by Spetzler-Martin grade and evaluated with the Glasgow Outcome Scale at various intervals. The long-term follow-up in months was, for surgery only, mean of 35 and range of 4 to 59, and for surgery and embolization, mean of 10 and range of 1 to 19). RESULTS: The arteriovenous malformations in the surgery and embolization group had a larger average greatest diameter (4.2 +/- 1.5 cm versus 3.4 +/- 1.8 cm) and were of higher Spetzler-Martin grade (89% versus 68% grade III-V). No significant difference in the preoperative or immediate postoperative (less than 24 hours) Glasgow Outcome Scale was identified between the two groups. At I week after surgery, the surgery and embolization group displayed a significantly better outcome evaluation (70% versus 41% with Glasgow Outcome Scale score of 5). The long-term evaluation continued to favor the surgery and embolization patients (86% versus 66% with Glasgow Outcome Scale score of 5). CONCLUSION: Preoperative N-butyl cyanoacrylate embolization improves postsurgical outcome. PMID- 8693979 TI - Fistula between a posterior communicating artery aneurysm and the cavernous sinus. AB - We report the angiographic appearance of a posterior communicating artery aneurysm with a fistula to the cavernous sinus, which had been misinterpreted as a direct carotid-cavernous fistula, on which endovascular repair was unsuccessfully attempted. PMID- 8693980 TI - Transarterial embolization of cerebral arteriovenous malformations: improvement of results with experience. AB - PURPOSE: To present the treatment outcome after embolization of arteriovenous malformations. METHODS: All patients with cerebral arteriovenous malformations treated in 1987 and 1988 (27 patients, group I) and in 1992 and 1993 (35 patients, group II) were compared regarding treatment results and clinical outcome. RESULTS: Complications of the treatment occurred in 52% of group I and 22% of group II patients. Severe complications occurred in 11 % and 0%, respectively. There were no treatment deaths. Thirty percent of the arteriovenous malformations in the first group were totally occluded or made accessible for gamma knife treatment, compared with 69% of the arteriovenous malformations in the second group. The clinical outcome improved from 56% with an excellent or good outcome in group I, to 89% in group II. The follow-up time is much shorter in group II, 1.5 versus 5.5 years in group I. CONCLUSION: A definite improvement in treatment outcome has been achieved. The clinical outcome seems to have improved as well, although the shorter follow-up time makes this conclusion less certain. PMID- 8693981 TI - Rupture of a cerebral aneurysm during embolization for a cerebral arteriovenous malformation. AB - An aneurysm ruptured during superselective catheterization into the posterior cerebral artery for a left temporal arteriovenous malformation. The rupture may have been caused by stretching and displacement of the basilar and posterior cerebral arteries while the microcatheter with guide wire was advanced. PMID- 8693982 TI - Proton MR spectroscopy of pediatric cerebellar tumors. AB - PURPOSE: To investigate the role of proton MR spectroscopy in pediatric cerebellar tumor diagnosis. METHODS: Single voxel pulse sequences with long echo time (135 or 270 milliseconds, voxel size 8 to 19 cm3), were used to obtain proton spectra of primary pediatric cerebellar tumors. Eleven primitive neuroectodermal tumors (patient age, 2 to 12 years; mean, 7 years), 11 low-grade astrocytomas (age, 2 to 16 years; mean, 9 years), 4 ependymomas (age, 1 to 6 years; mean, 4 years), 1 mixed glioma ependymo-astrocytoma (age, 11 years), 1 anaplastic ependymoma (age, 7 years), 1 ganglioglioma (age, 14 years), and 1 malignant teratoma (age, 6 days) were studied. Control cerebellum spectra were acquired from five patients without abnormality in cerebellum (age, 2 to 15 years; mean, 8 years). The signal intensities from choline-containing compounds (Cho), creatine/phosphocreatine (Cr), N-acetyl-aspartate (NAA), and lactate (Lac) were quantified. The mean and standard deviation of metabolite ratios were calculated. RESULTS: The control spectra ratios (NAA:Cho = 1.49 +/- 0.36, Cr:Cho = 1.13 +/- 0.23) were distinct from the tumor spectra (NAA:Cho = 0.41 +/- 0.27 and Cr:Cho = 0.37 +/- 0.23). Most of primitive neuroectodermal tumors had low NAA:Cho (0.17 +/- 0.09) and Cr:Cho (0.32 +/- 0.19). Compared with primitive neuroectodermal tumors, low-grade astrocytomas and ependymomas had higher NAA:Cho ratio (0.63 +/- 0.19 and 0.39 +/- 0.12). The Cr:Cho ratio was higher for ependymomas (0.60 +/- 0.20) than for astrocytomas (0.27 +/- 0.12) and primitive neuroectodermal tumors. No NAA was found in the malignant teratoma. Lac:Cho ratio was 0.66 +/- 0.40, 0.58 +/- 0.30, and 0.08 +/- 0.12 for astrocytoma, ependymoma, and primitive neuroectodermal tumor, respectively. Lactate was elevated in the mixed glioma ependymo-astrocytoma, ganglioglioma, and teratoma. The NAA and lactate signals were sometimes obscured by lipids in the spectra. Discriminant analysis was carried out using NAA:Cho and Cr:Cho ratios to differentiate the three major tumor types. The sensitivity/specificity values for diagnosing astrocytoma, ependymoma, and primitive neuroectodermal tumor were found to be 0.91/0.84, 0.75/0.92, and 0.82/0.89, respectively, based on this study. CONCLUSION: In many cases, proton MR spectroscopy can be used to help differentiate cerebellar primitive neuroectodermal tumor, low-grade astrocytoma, and ependymoma. PMID- 8693983 TI - MR of childhood-onset dentatorubral-pallidoluysian atrophy. AB - MR findings in a 14-year-old boy with progressive myoclonic epilepsy, who was diagnosed as having dentatorubral-pallidoluysian atrophy by DNA analysis, were compared with those of his father, who had adult-onset dentatorubral pallidoluysian atrophy. Besides showing severe brain atrophy, especially of the brain stem tegmentum and cerebellum, MR showed diffuse periventricular hyperintensity on T2-weighted images. As compared with the proband, the father had a mild case. PMID- 8693984 TI - Profound asphyxia in the premature infant: imaging findings. AB - PURPOSE: To investigate imaging findings in premature infants who had profound asphyxia. METHODS: CT (three patients), MR (three patients), and ultrasonography (four patients) studies of five patients who had profound asphyxia before the postconceptional age of 32 weeks were retrospectively reviewed. The patients ranged from 1 day to 4 months old at the time of the imaging studies. An autopsy report was available in one patient. The results were compared with reports in the literature of patients with similar injuries at similar ages. RESULTS: Abnormalities of the thalami and basal ganglia were present in all infants examined with CT or MR. CT showed low attenuation in the basal ganglia and high attenuation (blood or calcium) in the thalami; thalamic cavitation and low attenuation of the upper brain stem were present in one infant. MR showed T1 and T2 shortening in the thalami in all patients. Variable MR changes were noted in the basal ganglia, ranging from diminished size with normal signal intensity to T1 and T2 shortening with normal size and complete cavitation. T1 and T2 shortening were seen in the dorsal brain stem in one patient. Sonography showed transient or persistent hyperechogenicity in the thalami in three patients and cavitation of the thalami in one patient. Damage to the perirolandic cortex was not present in any patient. CONCLUSION: Profound asphyxia before 32 weeks gestational age shows consistent injury to the thalami, basal ganglia, and brain stem that can be detected by all three imaging modalities. The pattern of injury seems to differ from that of partial asphyxia in premature infants and of profound asphyxia in term infants. PMID- 8693985 TI - Limbic lobe embryology and anatomy: dissection and MR of the medial surface of the fetal cerebral hemisphere. AB - PURPOSE: To facilitate understanding of limbic lobe anatomy by showing embryologic transformations of the medial surface of the cerebral hemisphere. METHODS: Brains from fetal specimens ranging from 13 to 24 weeks of gestational age were dissected. Photographs were made of the medial surface of the cerebral hemisphere. MR images of different fetal specimens of similar age were made for comparison of MR anatomy with dissected material. RESULTS: At 13 weeks, the entire inner limbic arch of the hippocampal formation is visible on the medial surface of the cerebral hemisphere. The hippocampal sulcus extends from frontal lobe to temporal lobe. At 16 weeks, the outer neocortical limbic arch of the subcallosal area, cingulate gyrus, and parahippocampus gyrus is present. Growth of the corpus callosum is associated with reduction in size of the hippocampal formation in the frontal lobe. The sulcus of the corpus callosum is the remnant of the anterior part of the hippocampal sulcus. At 18 weeks, growth of the parahippocampal gyrus begins to conceal the hippocampal formation. The supracallosal gyrus (indusium griseum), hidden from view by the corpus callosum, and the paraterminal gyrus are remnants of the previously larger hippocampal formation. CONCLUSIONS: Analysis of fetal specimens in different developmental stages with dissection and MR provides insight into embryologic transformations responsible for the complex anatomy of the limbic lobe. PMID- 8693986 TI - Selective amygdalohippocampectomy for hippocampal sclerosis: postoperative MR appearance. AB - PURPOSE: To analyze the anatomic consequences of selective amygdalohippocampectomy (AH) in patients with hippocampal sclerosis and to correlate the clinical outcome with the MR appearance. METHODS: Seventeen patients were examined with clinical and neuropsychologic examination and cranial MR after AH (7 transcortical AH, 10 trans-Sylvian AH). The clinical and neuropsychologic outcomes after AH were compared with those of anterior lobectomy (ATL). RESULTS: There was no significant difference in seizure cure between transcortical or trans-Sylvian AH and ATL. However, patients with left AH fared significantly better in terms of verbal IQ and nonverbal memory when compared with those with left ATL. Verbal memory and cognition were not significantly different in the two AH groups. Variable amounts of hippocampal and amygdala remnants were found in both AH groups and did not correlate with seizure cure. White matter change consistent with gliosis probably secondary to wallerian degeneration was demonstrated in the anterior temporal lobe to a mean distance of 4.5 cm after transcortical AH and to a lesser degree as a consequence of trans Sylvian AH. Nine patients (53%) (4 transcortical All, 5 trans-Sylvian AH) demonstrated wallerian degeneration in the optic radiations after surgery. All had incomplete contralateral quadrantanopia. CONCLUSIONS: There is more secondary damage to the temporal lobe after AH than was previously recognized. The extent of hippocampal and amygdala resection in AH do not seem to be directly related to seizure cure. Visual field defects are common in AH because of the anterior but variable course of the optic radiations PMID- 8693987 TI - MR magnetization transfer measurements in temporal lobe epilepsy: a preliminary study. AB - MR magnetization transfer ratio was measured in both hippocampi of three patients with temporal lobe epilepsy, and in two control subjects. The magnetization transfer ratio in each section was significantly lower on the affected side than on the contralateral side and in control subjects. Magnetization transfer ratio measurements are relatively fast and precise, this preliminary study shows that they may provide useful presurgical information. PMID- 8693988 TI - Adaptive changes of autoregulation in chronic cerebral hypotension with arteriovenous malformations: an acetazolamide-enhanced single-photon emission CT study. AB - PURPOSE: To evaluate the relationship among feeding arterial pressure, lesion size, and perfusion in cerebral cortex adjacent to cerebral arteriovenous malformations (AVMs). METHODS: Eleven patients with hemispheric AVMs underwent 99mTc hexamethyl-propyleneamine oxime single-photon emission CT before and after 1 g of acetazolamide was administered intravenously. AVM volume was estimated from MR dimensions and measured according to the method described by Pasqualin. Pressure measurements were obtained in arteries feeding the cortex adjacent to AVMs. Single-photon emission CT regions of interest were defined in cortex adjacent to the AVM and compared with contralateral regions using the Mountz method to estimate a baseline and dynamic (acetazolamide-challenged) perfusion defect volume. RESULTS: Eight of 11 patients had baseline perfusion defects, but these defects were unrelated to feeding artery pressures (y = -.06x + 9.92, r2 = .04) or the dynamic change in defect volume after acetazolamide administration (y = .01x + .02, r2 = .002). However, there was a correlation between AVM volume and the baseline defect volume (y = .75x - 1.9, r2 = .76). Five patients had increased defect volume after acetazolamide administration; 5 patients had either no change in or improvement of perfusion. Dynamic changes in defect volume were related to feeding artery pressures. CONCLUSION: Perilesional baseline perfusion defects appear to be related to lesion size and not to local arterial pressure. Cerebrovascular reserve generally was preserved, and perfusion defects appeared to be more pronounced with lower arterial pressures in feeding vessels. Although vasodilatory testing can unmask hemodynamic failure with severe local hypotension, baseline perfusion defects near the lesion and distant perfusion changes are more likely attributable to other causes such as mass-related or neurogenic changes. PMID- 8693989 TI - Imaging of carotid artery stenosis: clinical efficacy and cost-effectiveness. AB - PURPOSE: To determine the most accurate, safe, and cost-effective imaging protocol for selecting patients for carotid endarterectomy. METHODS: The actual costs of carotid angiography, ultrasound, and MR angiography were calculated. The diagnostic accuracy with different confidence levels was assessed for carotid ultrasound and MR angiography in 45 patients. The cost-effectiveness and theoretical impact on patient outcome of hypothetical screening models were compared. RESULTS: Ultrasound before angiography is more effective and considerably cheaper than performing angiography in all patients presenting with transient ischemic attacks ($25 216 versus $48 708 imaging costs per one prevented stroke). When the more costly MR angiography was used to select patients for angiography the slightly higher diagnostic accuracy did not result in a greater number of prevented strokes. As the only preoperative scrutiny, the combination of ultrasound and MR angiography would have resulted in a greater number of prevented strokes than invasive angiography (27.9 versus 23.3) but at the expense of unnecessary surgery (6.6% of all surgeries). CONCLUSIONS: Ultrasound followed by confirmatory angiography is a cost-effective way to image patients suspected of carotid artery stenosis. MR angiography may become cost effective and lead to a better final patient outcome only when it can reliably replace invasive angiography as the preoperative examination. PMID- 8693990 TI - Spontaneous hemorrhage from a cerebral venous malformation related to thrombosis of the central draining vein: demonstration with angiography and serial MR. AB - A cerebral venous malformation ruptured after acute thrombosis of its central draining venous channel, leading to intracerebral hemorrhage. The CT, MR, and angiographic studies unequivocally demonstrated subsequent progressive recanalization of the malformation, providing proof that venous malformations can spontaneously bleed and that venous thrombosis may be associated with, and perhaps produce, the hemorrhage. PMID- 8693991 TI - Three-dimensional processing of ultrafast CT sialography for parotid masses. AB - PURPOSE: To evaluate the diagnostic potential of three-dimensional image processing of ultrafast CT sialography in comparison with conventional CT sialography in patients with parotid masses. METHODS: In nine patients, CT sialography was done with three-dimensional image processing. The visibility of anatomic details and pathologic findings, derived from three-dimensional images, were graded numerically by three observers and compared with the findings obtained from conventional CT sialograms. Histopathologic specimens were obtained in all cases. RESULTS: Ultrafast CT images showed no motion artifact. Three dimensional CT sialography offered significant improvement in demonstration of ductal anatomy (2.5 +/- 0.2 versus 1.5 +/- 0.1, respectively) and ductal pathology (2.6 +/- 0.1 versus 1.1 +/- 0.2, respectively) over conventional CT sialography. In two cases, the therapeutic regimen was altered substantially. CONCLUSION: Ultrafast CT three-dimensional sialography has the potential to allow more precise presurgical planning and contributes to the diagnosis and therapy planning of parotid masses, especially in patients in whom MR image quality is degraded by motion artifact. PMID- 8693992 TI - A comparison of MR sequences for lesions of the parotid gland. AB - PURPOSE: To compare six MR sequences (plain and gadolinium-enhanced fat suppressed T1-weighted spin echo, T2-weighted standard spin echo, fat-suppressed and non-fat-suppressed T2-weighted fast spin echo, and inversion-recovery T2 weighted fast spin echo) in their ability to detect, delineate, and characterize lesions of the parotid gland. METHODS: Fifty-eight parotid gland lesions imaged on 47 examinations were retrospectively evaluated by three blinded observers. Several outcome-related variables were compared by the above six sequences: imaging time, image quality, anatomic sharpness of parotid space, subjective lesion conspicuity, detected abnormality volume, number of individual lesions or discrete lobulations, conspicuity of invasion into adjacent boundaries and structures, and overall diagnostic value. RESULTS: Differences in the above outcome variables between sequences did not correlate with MR scanner software upgrade level, coil type, or lesion-dependent characteristics. Fat-suppressed fast spin-echo T2-weighted and inversion-recovery fast spin-echo T2-weighted sequences resulted in significantly higher scores for lesion conspicuity, detected abnormality volume, and overall diagnostic value. T1-weighted images resulted in the next highest scores, whereas gadolinium-enhanced T1-weighted and standard spin-echo T2-weighted sequences performed poorly for most parotid lesions. CONCLUSION: MR imaging of the parotid gland should include fat suppressed, long-repetition-time, fast spin-echo T2-weighted, and T1-weighted sequences. Gadolinium-enhanced images need not be obtained routinely. PMID- 8693993 TI - Intracranial tuberculoma: comparison of MR with pathologic findings. AB - PURPOSE: To compare the MR signal intensity patterns and enhancement pattern of intracranial tuberculomas with their histopathologic features. METHODS: MR images of six patients with surgically proved intracranial tuberculoma were reviewed retrospectively and were compared with histologic findings of the resected specimen. Detailed histologic examination was performed to look for the extent and characteristics of caseation necrosis, fibrosis, and inflammatory cellular infiltrates at each area of different signal intensities and at the enhancing areas on MR. Signal intensities for T1- and T2-weighted images were compared with normal gray matter. RESULTS: On T1-weighted images, the granulomas showed a slightly hyperintense rim surrounded by a complete or partial rim of slight hypointensity and central isointensity or mixed isointensity and hyperintensity in five patients and homogeneous isointensity in one patient. Histologically, the zone of central isointensity or mixed intensity corresponded to caseation necrosis plus adjacent cellular infiltrates. The hyperintense and hypointense rims corresponded to the layers of collagenous fiber and the layers of the inflammatory cellular infiltrates, respectively. On T2-weighted images, the entire portion of the granuloma showed slightly heterogeneous isointensity or hypointensity with small markedly hypointense foci in five patients, and a hyperintense center surrounded by a hypointense rim in one patient. Histologic layers were not discriminated on T2-weighted images. On postcontrast T1-weighted images, there were single or multiple conglomerate ring enhancements within a tuberculoma in all six patients, corresponding to the layers of both collagenous and inflammatory cells. CONCLUSION: Combination of the described signal intensity patterns and conglomerate ringlike enhancing appearance of the lesion is characteristic of tuberculoma, and may play an important role in differentiating intracranial tuberculomas from other ring-enhancing brain lesions. PMID- 8693994 TI - Three-dimensional MR of the inner ear with steady-state free precession. AB - PURPOSE: To describe the steady-state free-precession MR sequence and its application to the study of the inner ear. METHOD: The inner ear was imaged with CT and a 0.5-T MR unit in three dimension, to evaluate the various signals from the lumen of the labyrinth. RESULTS: Normally, the signal from the perilymphatic and endolymphatic spaces is homogeneous. However, among our cases of neurosensory deafness, differences of signal and morphology were seen in patients with otosclerosis, ossifying labyrinthitis, and inner ear malformations. CONCLUSION: Three-dimensional MR, used together with routine two-dimensional fast spin-echo, is another diagnostic too]l that can provide new data in the evaluation of the normal and unhealthy inner ear. PMID- 8693995 TI - Esophageal carcinoma metastatic to the brain: clinical value and cost effectiveness of routine enhanced head CT before esophagectomy. AB - PURPOSE: To assess the value of screening enhanced head CT before esophagectomy for carcinoma, identify increased risk factor(s) for brain metastases, and determine metastasis incidence. METHODS: Thoracic surgery files of patients undergoing esophagectomies for squamous carcinomas, adenocarcinomas, and undifferentiated carcinomas between January 1984 and March 1993 were reviewed regarding sex, size (length) of neoplasm, and brain metastases. Surgical pathology and tumor registry files also were reviewed. Records of patients with brain metastases were reviewed in detail. RESULTS: Three hundred thirty-four esophagectomies were performed for 230 adenocarcinomas (202 male, 28 female) and 104 squamous carcinomas (61 male, 43 female). In 9 males and 1 female with adenocarcinomas and 1 male and 1 female with squamous carcinomas, brain metastases developed. Surgical pathology files identified 293 additional esophageal carcinomas, including 2 males with adenocarcinomas metastatic to brain. Tumor registry files identified I additional male with brain metastasis from an undifferentiated esophageal neoplasm. No statistically significant preoperative characteristic of esophageal carcinomas with proneness to brain metastases was found, except large size of primary neoplasm. Preoperative screening head CT done on approximately 240 patients who underwent esophagectomies showed no metastases. CONCLUSIONS: Brain metastases from carcinomas of the esophagus are relatively uncommon (3.6% in the esophagectomy cohort). They tend to occur in patients with large primary neoplasm, probably especially adenocarcinomas involving the esophagogastric junction, and with findings of local invasion and lymph node metastases by CT and/or microscopically. It may be reasonable to obtain head CT as a last preoperative staging procedure in such patients. Routine preoperative head CT for staging is not cost effective. PMID- 8693996 TI - MR evaluation of tuberous sclerosis: increased sensitivity with fluid-attenuated inversion recovery and relation to severity of seizures and mental retardation. AB - PURPOSE: To evaluate the utility and possible increased sensitivity of fluid attenuated inversion recovery (FLAIR) images for the detection of tubers in patients with tuberous sclerosis, compared with standard T2-weighted images, and to evaluate whether the tubers are correlated with neurologic symptoms. METHOD: We examined the number, size, and location of tubers in five tuberous sclerosis patients using T2-weighted and FLAIR images. Their intelligence quotients, ages at the onset of the first seizure, seizure types, and epileptic severity also were studied retrospectively. RESULTS: The number of tubers observed ranged from 4 to 17 on T2-weighted images, and from 10 to 33 on FLAIR images. All the tubers, other than the myelination line on T2-weighted images, were remarkably demonstrated as high-intensity lesions on FLAIR images. No correlation was found between the neurologic outcome and the number, size, or location of tubers on FLAIR images. CONCLUSION: FLAIR images were very sensitive for the detection of tubers, especially small subcortical ones, the number, size, and location of which are not related to the neurologic symptoms. PMID- 8693997 TI - Osseous anatomy of the orbital apex. PMID- 8693998 TI - Imaging of nasopharyngeal atresia. AB - CT and MR revealed a case of nasopharyngeal atresia, a malformation in which the soft palate is not formed, and the hard palate extends posteriorly to fuse with the anterior surface of the clivus, resulting in complete isolation of the nasal and oral cavities and the absence of a nasopharynx. We believe this rare anomaly results from abnormal persistence of the embryologic bucconasal plate and/or anomalous migration of the nasoseptal elements. PMID- 8693999 TI - MR of nonhemorrhagic postpartum pituitary apoplexy. AB - A 30-year-old woman had uterine bleeding and hypotension after delivery. Hyponatremic seizures and a mild headache prompted early neuroimaging, which disclosed an enlarged nonhemorrhagic pituitary gland with subsequent involution consistent with pituitary apoplexy (Sheehan syndrome). Endocrinologic investigation confirmed a partial pituitary insufficiency with subsequent improvement to almost normal status. PMID- 8694000 TI - Transient involuntary movement of the leg (monoballismus) during cerebral angiography. AB - Transient involuntary movement of the leg developed during diagnostic or therapeutic angiography in five patients. The movement was jerky, brisk flexion/extension of the hip and knee joints on the side contralateral to acute ischemia. This movement may occur as a result of thromboembolic cerebral ischemia or as an ischemic complication of angiography. PMID- 8694001 TI - Low-cost method of presenting visual stimuli during MR. PMID- 8694002 TI - Preoperative spinal angiography for lateral extracavitary approach to thoracic and lumbar spine. PMID- 8694003 TI - Annotated bibliography. PMID- 8694004 TI - Magnesium in acute myocardial infarction. PMID- 8694005 TI - Management of acute myocardial infarction: evaluating the past, practicing in the present, elaborating the future. AB - The management of acute myocardial infarction initially focused on treatment and/or prevention of complications. In the prethrombolytic era, therapeutic regimens mainly comprised the use of antianginal and antiarrhythmic drugs. The development of semi-invasive hemodynamically guided treatment concepts led to remarkable improvement in clinical outcome. After the introduction of the "wave front phenomenon," multiple pharmacologic treatment strategies were developed with the goal of infarct size reduction. The use of thrombolytic agents reduced infarct size and improved prognosis of patients with acute myocardial infarction. Acute angioplastic intervention was introduced in specialized centers to achieve rapid restoration of coronary blood flow. The protection of the myocardium from reperfusion injury, however, remains an unresolved issue. Intravenous magnesium administration in conjunction with new and better recanalization techniques could therefore be a promising therapy strategy in patients with acute myocardial infarction. PMID- 8694006 TI - Is there a place for magnesium in the treatment of acute myocardial infarction? AB - Infusions of solutions of magnesium sulfate for patients with acute myocardial infarction were shown by a meta-analysis of seven small studies and a larger study of 2316 patients (LIMIT-2) to have clinical efficacy. However, the ISIS-4 study of 58,050 patients found no improvement in short-term mortality rates with magnesium therapy in patients with acute myocardial infarction. In this article we explore the following four differences between the ISIS-4 study and the earlier studies: (1) Time of initiation of magnesium treatment after acute myocardial infarction and thrombolytic therapy; (2) dosage of magnesium in the first 24 hours after acute myocardial infarction; (3) duration of magnesium infusion after acute myocardial infarction; and (4) differences in patient risks in control and treatment groups. These four differences may explain the different outcomes among these studies and indicate the type of additional studies that are needed to define the clinical utility of magnesium infusion in the treatment of patients with acute myocardial infarction. PMID- 8694007 TI - Acute myocardial infarction, reperfusion injury, and intravenous magnesium therapy: basic concepts and clinical implications. AB - The concept of reperfusion-induced injury has aroused special interest during the past decade as thrombolysis and direct angioplasty were introduced for early restoration of coronary blood flow in patients with acute myocardial infarction. There is experimental and clinical evidence that oxygen-derived free radicals (oxyradical hypothesis), activation of the complement system (complement hypothesis), and disturbance in calcium homeostasis (calcium hypothesis), may account for the development of reperfusion injury. Data from numerous animal experiments and clinical trials suggest that magnesium, a physiologic calcium blocker, may be efficacious for reduction of reperfusion injury. Despite encouraging results from previous clinical trials that revealed beneficial effects of intravenous magnesium therapy with respect to mortality, left ventricular function, and infarct size, a recently published large-scale trial (ISIS-4) provided conflicting data and caused major controversy. Further clinical trials, well-designed and carefully conducted, should elucidate the beneficial effects of magnesium in acute myocardial infarction, especially in conjunction with new and aggressive reperfusion techniques. PMID- 8694008 TI - The rationale of magnesium as alternative therapy for patients with acute myocardial infarction without thrombolytic therapy. AB - Only one third of hospitalized patients with acute myocardial infarction receive thrombolytic therapy despite its proven benefits on outcomes. Elderly patients, for example, have a greater risk of death after myocardial infarction, but studies demonstrate that thrombolytic therapy is less likely to be used in older patients. Intravenous magnesium supplementation, both theoretically and experimentally, has been demonstrated to decrease myocardial damage and reduce the mortality rate in subsets of patients, including the elderly and/or patients not suitable for thrombolysis, if it is administered before reperfusion occurs. The aim of this study is to review the rationale for patients with acute myocardial infarction without thrombolytic therapy. PMID- 8694009 TI - Magnesium in acute myocardial infarction: overview of available evidence. AB - Despite improvements in the outcome of patients with acute myocardial infarction (MI) during the past three decades, room for improvement exists in elderly patients and in patients who are not candidates for thrombolysis. Animal models suggest that magnesium supplementation before reperfusion reduces infarct size. Statistical analysis of the randomized trials of magnesium in MI reveals a gradient of response. When higher risk patients were enrolled, a greater benefit of magnesium was observed; progressively smaller benefits of magnesium occurred as the control group mortality approached 7%, at which point no benefit was detected. Although the ISIS-4 study enrolled more than 58,000 patients, no reduction in mortality was seen, probably as a result of a low control group mortality and relatively late administration of the magnesium. Because the potential benefit of magnesium in MI remains an open question, additional trials are needed before this inexpensive and easily administered therapy is prematurely cast aside. PMID- 8694010 TI - Comparison of five body-composition methods in peritoneal dialysis patients. AB - Body-composition assessment is an important method of evaluating nutritional status in peritoneal dialysis patients. Because body-composition measurement estimates have not been fully validated in this population, we assessed five body composition methods in 30 well-dialyzed peritoneal dialysis patients. The techniques studied included bioelectrical impedance analysis, dual-energy X-ray absorptiometry, total-body potassium counting, and anthropometry by two techniques. The dialysis patients were matched for age, race, sex, height, weight, and body mass index with 29 healthy control subjects in our laboratory database. By 5 x 2 x 2 analysis of variance, significant differences were found between results by modality (P < 0.0001) as well as by sex, with women having an increased percentage of fat (P < 0.0001). However, there was no significant intermethod difference by condition (peritoneal dialysis or control). That is, although significantly different percentage fat values were found between the body-composition techniques, this variability was independent of whether the measurement was made on control or peritoneal dialysis patients. Despite the differences between modalities, all techniques were found to correlate significantly with each other (P < 0.01 or better for men and P < 0.001 or better for women). Our experience shows that these routine techniques for measuring body composition can be readily applied to stable peritoneal dialysis patients. PMID- 8694011 TI - Apolipoprotein E phenotype modifies metabolic and hemodynamic abnormalities related to central obesity in women. AB - Apolipoprotein E (apo E) is a normal constituent of very-low-density lipoproteins and it participates in the metabolism of both low-density lipoproteins (LDL) and apo E-containing lipoproteins. In the present study, the aim was to examine to what extent apo E phenotypes modify central obesity-induced changes in serum lipids, insulin, and blood pressure in obese women. Altogether, 143 middle-aged obese women with a body mass index (in kg/m2) of 28.0-43.0 were examined. Twelve had apo E 3,2 phenotype, 93 had apo E 3,3 phenotype, and 38 had either apo E 4,3 or 4,4 (4,3 + 4,4 group) phenotype. Serum total and LDL cholesterol were lower in the apo E 3,2 group than in other groups, but no significant differences were observed in other lipid variables in this regard. Both systolic and diastolic blood pressure measures tended to be lowest in subjects with apo E 3,2 phenotype and highest in those with apo E 4,3 or 4,4 phenotype (P = 0.08-0.15 for trend). When serum lipids, blood pressure, and insulin were analyzed by waist circumference and apo E phenotype group, it became evident that women who had central obesity and the apo E 4 allele had the highest blood pressures, insulin glucose ratios, and insulin concentrations. These results suggest that apo E phenotype significantly modifies the central obesity-induced changes in metabolic and hemodynamic variables characteristic of insulin resistance. PMID- 8694012 TI - Resting metabolic rate and body composition in stunted and nonstunted children. AB - The resting metabolic rate (RMR) and body composition of 34 stunted children (height-for-age < or = 1.5 SD) aged 7-8 y were compared with that of two groups of nonstunted control subjects (height-for-age > or = -1.0 SD) matched for either age and sex or height and sex. No significant group differences were found in percentage lean body mass (LBM). The RMR of the stunted children (4702 +/- 570 kJ/d) was significantly lower than that of both the age-matched (5802 +/- 616 kJ/d) and height-matched (5269 +/- 663 kJ/d) groups (ANOVA, P < 0.001). However, in a multiple-regression model including sex and LBM, the RMRs of the stunted and age-matched groups were not significantly different, suggesting that the stunted children's smaller LBM accounted for their lower RMR. This suggests that the composition and metabolic activity of the LBM is unaffected by stunting. The younger, height-matched control subjects had significantly higher RMRs than the stunted children after adjustment for LBM (P < 0.001). This may have been due to age-related changes in the composition of LBM. PMID- 8694013 TI - Randomized outcome trial of human milk fortification and developmental outcome in preterm infants. AB - Despite potential benefits, human milk may fail to meet preterm infants' nutrient requirements. We tested the hypothesis that fortified breast milk, fed alone or with preterm formula, would improve neurodevelopment and growth at 18-mo follow up without adverse short-term clinical or biochemical consequences. Two hundred seventy-five preterm infants from two medical centers (birth weight < 1850 g; mean gestation 29.8 +/- 2.7 wk) whose mothers chose to provide breast milk were randomly assigned to receive for a mean of 39 d a multinutrient fortifier or control supplement containing phosphate and vitamins. Breast milk comprised 47.6% and 46.4% of enteral intake in fortified and control groups, respectively; preterm formula supplements were used when insufficient breast milk was available. Overall, there were no significant growth advantages with fortification; although, when breast milk exceeded 50% of intake, fortification promoted faster weight gain (an advantage of 1.6 g.kg-1.d-1; 95% CI: 0.1, 3.1; P < 0.05). Compared with control infants, the fortified group showed 1) higher plasma urea from week 2 (P = 0.04), 2) higher plasma calcium (mean 2.34 +/- 0.01 compared with 2.27 +/- 0.02 mmol/L; P = 0.003), 3) a greater rise in alkaline phosphatase by week 6 (P = 0.04), 4) more clinical infections (suspected plus proven; 43% compared with 31%, P = 0.04), 5) a nonsignificantly increased incidence of necrotizing enterocolitis (5.8% compared with 2.2%, P = 0.12), and 6) higher white cell and platelet counts. Developmental scores at 18 mo were slightly but not significantly higher in the fortified group. This study confirmed that breast milk fortifiers can improve short-term growth (when breast milk intakes are high); but beneficial effects on long-term development remained unproven. Future research is required to evaluate potential adverse consequences and explore more optimal fortification strategies. PMID- 8694014 TI - Medium-chain triacylglycerols in formulas for preterm infants: effect on plasma lipids, circulating concentrations of medium-chain fatty acids, and essential fatty acids. AB - Limited information is available on the metabolic fate of medium-chain triacylglycerols (triglycerides) after intestinal absorption and on their influence on essential fatty acid metabolism. We studied in preterm infants the effect of two infant formulas, one with a high (HMCT) and one with a low (LMCT) medium-chain triacylglycerol content, on plasma fatty acids. The HMCT formula contained 46 mol% 8:0 + 10:0 and the LMCT formula (4.8 mol% 8:0 + 10:0) had approximately twice the amount of long-chain saturated and monounsaturated fatty acids as the HMCT. Both formulas had similar contents of linoleic and linolenic acids. Plasma lipids and fatty acids were determined at birth and on day 24 of life in 20 infants fed the LMCT (n = 12) or HMCT (n = 8) formula. Significant amounts of medium-chain fatty acids were found in the systemic circulation of the infants fed the HMCT formula, mainly in plasma fatty acids and triacylglycerols. Despite striking dietary differences, palmitic and stearic acids were not different between groups, indicating de novo synthesis of long-chain fatty acids with the HMCT formula. Plasma phospholipid docosahexaenoic acid was significantly lower in the HMCT group than in the LMCT infants (1.38 +/- 0.07 compared with 1.73 +/- 0.07 mol%, P = 0.002). Our data indicate that a high MCT intake in preterm infants increases lipogenesis, and dietary nonessential fatty acids interfere with the metabolism of docosahexaenoic acid. PMID- 8694015 TI - Plasma fatty acid responses, metabolic effects, and safety of microalgal and fungal oils rich in arachidonic and docosahexaenoic acids in healthy adults. AB - The effect of dietary supplementation with different amounts of a fungal oil containing arachidonic acid (AA, 20:4n--6) and a microalgal oil containing docosahexaenoic acid (DHA, 22:6n--3), blended to give a ratio of AA to DHA of 1.25:1.00, on plasma lipid AA, DHA, cholesterol, and triacylglycerols was evaluated in healthy men. Subjects (n = 8/group) were given 28.8 g fat/d containing 0 x (0 g AA, 0 g DHA), or 1 x (0.8 g AA, 0.6 g DHA), 3 x (2.2 g AA, 1.7 g DHA), or 5 x (3.6 g AA, 2.9 g DHA) the estimated intake of infants fed human milk with 0.5% AA and 0.4% DHA for 14 d. No clinically significant dose related effects were seen on physical examination or from routine laboratory tests. The microalgal-fungal oil blend resulted in a significant, dose-dependent increase in plasma cholesterol and percentage phospholipid AA and DHA, and a decrease in percentage triacylglycerols and phospholipid linoleic acid. Plasma phospholipid AA and DHA increased approximately 18% and 50%, respectively, with the 1 x dose, similar to that expected at intakes provided by human milk. These oils appear to be safe dietary sources of AA and DHA for healthy adults at intakes equivalent to 0.8 g AA and 0.6 g DHA/d for > or = 2 wk. PMID- 8694016 TI - Acute effect of high-fat meals rich in either stearic or myristic acid on hemostatic factors in healthy young men. AB - Suggestions have been made that saturated fatty acids with 12-18 carbon atoms, stearic acid (18:0) in particular, are prothrombogenic. These suggestions are based mainly on in vitro measurements. In the present study the effect of dietary fats high in stearic or myristic acid (14:0) on plasma triacylglycerol concentrations and key variables of blood aggregation (in vitro and in vivo), coagulation, and fibrinolysis was studied over 24 h in 10 healthy young men. For each dietary fat, two identical high-fat test meals were served: one in the morning (0 h) and one 8 h later, and blood samples were collected at 0, 2, 4, 6, 8, and 24 h. Both fats decreased platelet aggregation compared with fasting values. Stearic fat resulted in a tendency toward lower activity of plasminogen activator inhibitor 1 (PAI-1) than did myristic fat (P < 0.08). PAI-1 was also lower 24 h after consumption of either fat than initially (P < 0.05). Stearic fat, but not myristic fat, tended to cause some increase in factor VII coagulant activity and beta-thromboglobulin after 4 h. In conclusion, an acute prothrombotic effect of fats high in myristic and stearic acid was not confirmed. PMID- 8694017 TI - Evidence of cis-trans isomerization of 9-cis-beta-carotene during absorption in humans. AB - Absorption and metabolism of [13C]9-cis-beta-carotene ([13C]9c beta C) was studied in three subjects after a single oral dose. Subjects given 1.0 mg [13C]beta-carotene (mean: 99.4% 9-cis-beta-carotene, 0.6% all-trans-beta carotene; dose A) had substantial concentrations of [13C]all-trans-beta-carotene ([13C]tr beta C) and [13C]all-trans retinol ([13C]retinol) but very low concentrations of [13C]cis-beta-carotene ([13C]cis beta C) in saponified plasma 5 h after dosing, as determined by HPLC and isotope-ratio mass spectrometry. There was no evidence of appreciable absorption of [13C]9-cis retinol. To determine the proportion of [13C]tr beta C and [13C]retinol derived from [13C]9c beta C, a second set of studies in the same subjects was performed with the same isomeric composition except with 13C labeling only in all-trans-beta-carotene (dose B). The results indicated that > 95% of plasma [13C]tr beta C and [13C]retinol observed after dose A was derived from [13C]9c beta C. The concentrations of [13C]tr beta C observed, in excess of that derived from the trace amounts of [13C]tr beta C in the dose, indicated that a significant proportion of the [13C]9c beta C dose was isomerized to [13C]tr beta C before entering the bloodstream. Although precise quantitative estimates of the extent of isomerization of 9-cis-beta-carotene could not be made, it is apparent that cis trans isomerization of 9-cis-beta-carotene to all-trans-beta-carotene contributed to the near absence of postprandial plasma 9-cis-beta-carotene after its oral administration in humans. The observation of different ratios of beta-carotene to retinol between the two dosing protocols suggests that isomerization did not occur exclusively before uptake by the intestinal mucosa. These results indicate that isomerization of ingested 9-cis-beta-carotene before its secretion into the bloodstream limits the potential supply of 9-cis retinoids to tissues, and increases the vitamin A value of 9-cis-beta-carotene. PMID- 8694018 TI - Intrauterine elimination of pyridoxal 5'-phosphate in full-term and preterm infants. AB - This study addressed the intrauterine elimination of pyridoxal 5'-phosphate (PLP) in 15 preterm and 31 full-term infants, thereby providing estimates of fetal vitamin consumption as well as maternal vitamin requirements during pregnancy. Elimination was calculated as the difference in the plasma PLP concentration between umbilical vein and umbilical artery times the umbilical plasma flow. Plasma flow in the umbilical vein was calculated from pulsed Doppler ultrasonographic determination of blood flow and from the hematocrit value. Plasma PLP concentrations were assayed in maternal and umbilical veins and the umbilical artery; PLP concentrations were similar in preterm and full-term infants (P > 0.05). In both groups of infants the PLP concentration in the umbilical vein (preterm: 100.3 nmol/L; full-term: 63.9 nmol/L) was ninefold higher than in maternal circulation (P < 0.001). In full-term infants, PLP concentrations in maternal and umbilical veins correlated weakly (r = 0.358, P < 0.05), but no significant correlation was found in the preterm group (P > 0.05). The arteriovenous concentration gradient of PLP in cord vessels was higher in preterm infants (15.0 nmol/L) than in full-term infants (2.1 nmol/L), but the difference between groups was not significant (P > 0.05). Preterm infants eliminated 1.7 nmol PLP.kg-1.min-1 in utero, whereas full-term infants eliminated 0.2 nmol PLP.kg-1.min-1 (P < 0.05). The significantly higher plasma flow in preterm infants (116 mL.min-1.kg-1) compared with full-term infants (78 mL.min 1.kg-1) contributed to the higher PLP elimination in preterm infants. PMID- 8694019 TI - Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly. AB - We examined vitamin E and vitamin C supplement use in relation to mortality risk and whether vitamin C enhanced the effects of vitamin E in 11,178 persons aged 67 105 y who participated in the Established Populations for Epidemiologic Studies of the Elderly in 1984-1993. Participants were asked to report all nonprescription drugs currently used, including vitamin supplements. Persons were defined as users of these supplements if they reported individual vitamin E and/or vitamin C use, not part of a multivitamin. During the follow-up period there were 3490 deaths. Use of vitamin E reduced the risk of all-cause mortality [relative risk (RR) = 0.66; 95% CI: 0.53, 0.83] and risk of coronary disease mortality (RR = 0.53; 95% CI: 0.34, 0.84). Use of vitamin E at two points in time was also associated with reduced risk of total mortality compared with that in persons who did not use any vitamin supplements. Effects were strongest for coronary heart disease mortality (RR = 0.37; 95% CI: 0.15, 0.90). The RR for cancer mortality was 0.41 (95% CI: 0.15, 1.08). Simultaneous use of vitamins E and C was associated with a lower risk of total mortality (RR = 0.58; 95% CI: 0.42, 0.79) and coronary mortality (RR = 0.47; 95% CI: 0.25, 0.87). Adjustment for alcohol use, smoking history, aspirin use, and medical conditions did not substantially alter these findings. These findings are consistent with those for younger persons and suggest protective effects of vitamin E supplements in the elderly. PMID- 8694020 TI - Tolerance to small amounts of lactose in lactose maldigesters. AB - In this study we examined whether small doses of lactose induced symptoms in 39 lactose maldigesters and 15 lactose digesters in a randomized, crossover, double blind design. The test doses were 200 mL fat-free, lactose-free milk to which 0, 0.5, 1.5, and 7 g lactose was added. Every third day of a lactose-free diet, after an overnight fast, the subjects drank one of the test milks in random order and registered the occurrence and severity of gastrointestinal symptoms in the next 12 h. During the study, the maldigesters reported significantly more abdominal bloating (P = 0.0003) and abdominal pain (P = 0.006) than the digesters. There was no difference in the mean severity of the reported symptoms between the test milks and the lactose-free milk in the group of lactose maldigesters, of whom one-third did not experience any symptoms from any of the test doses. The same proportion (64%) of the maldigesters experienced symptoms after both the lactose-free milk and the milk with 7 g lactose. However, the symptoms occurred inconsistently with the different test doses in 59% of the maldigesters. Thus, it can be concluded that the gastrointestinal symptoms in most lactose maldigesters are not induced by lactose when small amounts (0.5-7.0 g) of lactose are included in the diet. PMID- 8694021 TI - Dietary fatty acids and progression of coronary artery disease in men. AB - We examined associations between dietary fatty acids and progression of coronary artery disease (CAD) in 50 men receiving a lipid-lowering diet or usual care in the St Thomas' Atherosclerosis Regression Study. Nutrient intake was assessed by dietary history and computerized food tables. Progression of CAD over 39 mo, measured by a decrease in minimum absolute width of coronary segments (MinAWS) on angiography, was highly correlated with intakes of palmitic, stearic (18:0), palmitoleic, and elaidic (t-18:1) acids (P < 0.001); no protective effects were found with polyunsaturates. Total saturates and trans unsaturates explained 20% of variance in CAD progression. After adjustment for plasma cholesterol and other risk factors, change in MinAWS was most closely associated with intakes of 18:0 and t-18:1 fatty acids (P = 0.009). We suggest that progression of CAD in men is strongly related to intakes of both long-chain saturates and trans unsaturates, the effects of 18:0 and t-18:1 possibly being independent of plasma cholesterol concentration. PMID- 8694022 TI - Effect of three sources of long-chain fatty acids on the plasma fatty acid profile, plasma prostaglandin E2 concentrations, and pruritus symptoms in hemodialysis patients. AB - Patients with chronic renal failure exhibit plasma fatty acid patterns indicative of essential fatty acid deficiency. The plasma fatty acid profile of 25 hemodialysis patients with a history of pruritus symptoms indicated lower 20:3n-9 (eicosatrienoic acid), 20:4n-6 (arachidonic acid), and 20:5n-3 (eicosapentaenoic acid) concentrations; a higher 18:1n-9 (oleic acid) concentration; and above normal ranges of prostaglandin E2 (PGE2) compared with 22 subjects chosen from a normal population. No significant difference in 22:6n-3 (docosahexaenoic acid) was shown between the hemodialysis patients and the normal subjects. The dietary intake of 20:5n-3 was higher and that of 18:1n-9 lower in the patients compared with the normal population group. In this 8-wk double-blind study the hemodialysis patients were randomly assigned to receive daily supplements of 6 g ethyl ester of either fish oil, olive oil, or safflower oil. At the end of 8 wk of treatment the fish oil group (FO group) had a greater decrease in 18:1n-9 (P < 0.05), greater increases in 20:5n-3 and 22:6n-3 (P < 0.01), and trends toward a greater decrease in 20:4n-6, a greater increase in PGE2 concentrations, and greater improvement in pruritus scores (0.10 > P > 0.05) compared with the other two groups. The increases in 20:5n-3 and 22:6n-3 in the FO group indicate compliance with fish oil supplementation. Results indicate that hemodialysis patients have abnormal fatty acid profiles and increased PGE2 values. Fish oil intervention changes the fatty acid profile and may improve the symptoms of pruritus. PMID- 8694023 TI - Dietary fish oil decreases low-density-lipoprotein clearance in nonhuman primates. AB - To assess whether fish oil-induced alterations in low-density-lipoprotein (LDL) composition have distinct and important effects on LDL metabolism, we evaluated LDL kinetic behavior in cynomolgus macaques fed an atherogenic diet supplemented with either fish oil (1.6 g n-3 fatty acids; n = 10) or olive oil (n = 9) for > or = 6 mo. LDL from monkeys supplemented with fish oil or olive oil was isolated, labeled with either 125I or 131I, and simultaneously reinjected so that each monkey received its own (autologous injection) and donor (homologous injection) LDL. For LDL injected autologously (monkeys that received their own LDL), the LDL fractional clearance rate (FCR) was reduced in fish oil-supplemented monkeys compared with the olive oil-supplemented controls (0.42 +/- 0.03 compared with 0.56 +/- 0.05 pools/d, P = 0.04). The cholesteryl ester content of fish oil LDL increased compared with olive oil LDL (43 +/- 2% and 36 +/- 3%, respectively, P = 0.03), and the LDL cholesteryl ester content was strongly correlated with autologous LDL clearance (r = -0.76, P = 0.0001). Compared with olive oil LDL, fish oil LDL had a reduced dissociation constant (KD) for binding to the LDL receptor in vitro (KD for fish oil LDL compared with olive oil LDL: 13.9 +/- 1.8 and 7.4 +/- 1.0 mg LDL protein/L, P = 0.03). When both fish oil LDL and olive oil LDL were simultaneously injected into fish oil-supplemented monkeys, the FCR of fish oil LDL was decreased compared with olive oil LDL (0.42 +/- 0.03 and 0.52 +/ 0.04 pools/d, P = 0.006). These data suggest that dietary supplementation with fish oil decreases LDL clearance, and that this effect is mediated, at least in part, by altering LDL structure and reducing the affinity of LDL for its receptor. PMID- 8694024 TI - Importance of colonic support for energy absorption as small-bowel failure proceeds. AB - Digestive processes in the human colon are affected by the bacterial fermentation of malabsorbed carbohydrates and protein to short-chain fatty acids, which are absorbed and supply energy. Energy absorption was measured by assessing fecal bomb calorimetry in 148 patients with extremely different small-bowel lengths. Colectomy increased fecal loss of energy by 0.8 MJ/d and carbohydrate excretion fivefold in patients with a small-bowel length between normal and 150-200 cm. Patients with 100-150 cm small bowel, with and without a colon, excreted 1.3 +/- 0.3 and 4.7 +/- 0.5 MJ/d, respectively (P = 0.002), a difference of 3.4 MJ/d. Patients with < 100 cm small bowel excreted 3.1 +/- 0.4 and 8.0 +/- 1.3 MJ/d, respectively (P = 0.03), a difference of 4.9 MJ/d. Similar and highly significant differences were calculated by linear-regression analysis. Considerably less energy was excreted as carbohydrate than as fat in patients with preserved colonic function, probably because fermentation removed carbohydrate as absorbed short-chain fatty acids, whereas a comparable amount of energy was lost as carbohydrate and fat in patients without colonic function. The correlation between malabsorbed energy and small-bowel length was poor (r = -0.41) but increased when data for patients with and without a colon were separated (r = 0.56 and r = -0.58, respectively). Small-bowel length, however, was still an inaccurate measure of intestinal failure to absorb nutrient energy. In conclusion, colonic digestion may support energy supply with up to approximately 4.2 MJ/d as small-bowel failure proceeds, but it is of minor importance in patients with a small-bowel length > 200 cm or malabsorption < 2.1 MJ/d. PMID- 8694026 TI - Influence of changes in peritoneal fluid on body-composition measurements by dual energy X-ray absorptiometry in patients receiving continuous ambulatory peritoneal dialysis. AB - The effect of the presence of intraabdominal fluid on measurement of body composition by dual-energy X-ray absorptiometry (DXA) was determined by scanning 14 patients who were receiving continuous ambulatory peritoneal dialysis (CAPD) before and after the drainage of peritoneal dialysate, resulting in a mean (+/- SD) weight loss of 1.81 +/- 0.34 kg. DXA showed changes in whole-body soft tissue, which were correctly localized to the trunk region on regional analysis. Changes in DXA estimates of mean total lean tissue, 1.78 +/- 0.94 kg, and trunk lean tissue, 1.87 +/- 0.84 kg, were very similar to the actual change in body weight. However, the DXA estimate of change in total soft tissue, 2.11 +/- 0.44 kg, was significantly greater than the change in body weight by 0.3 kg (P < 0.005); the difference was accounted for by a tendency for a reduction in the estimate of body fat affecting the trunk region after drainage of dialysate. DXA was also less good at detecting changes in individual subjects. Estimates of total and regional bone mineral content and bone mineral density were not affected by the drainage of the dialysis fluid. PMID- 8694025 TI - Colonic adaptation to daily lactose feeding in lactose maldigesters reduces lactose intolerance. AB - We conducted blinded, controlled crossover studies to determine the effect of daily lactose feeding on colonic adaptation and intolerance symptoms. The initial study with nine lactose maldigesters showed a threefold increase in fecal beta galactosidase activity after 16 d of lactose feeding. To determine the effects of this adaptation on breath hydrogen and intolerance symptoms, 20 lactose maldigesting adults were randomly assigned to lactose or dextrose supplementation for 10 d (days 1-10), crossing over to the other period for days 12-21. The sugar dosage was increased from 0.6 to 1.0 g.kg-1.d-1, subdivided into three equal doses, by adjusting the dose every other day. Symptoms during lactose supplementation and comparison of symptoms during the lactose and dextrose feeding periods showed no significant differences. On days 11 and 22, challenge doses of lactose (0.35 g/kg) were administered after an overnight fast, and breath hydrogen and intolerance symptoms (abdominal pain, flatulence, and diarrhea) were carefully monitored for 8 h. Frequency of flatus passage and flatus severity ratings after the lactose challenge decreased 50% when studied at the end of the lactose period compared with the dextrose period. The sum of hourly breath-hydrogen concentrations (1-8 h) was significantly reduced after the lactose feeding period (9 +/- 38 ppm.h) compared with after the dextrose period (385 +/- 52 ppm.h, P < 0.001). We conclude that there is colonic adaptation to regular lactose ingestion and this adaptation reduces lactose intolerance symptoms. PMID- 8694027 TI - Chronic low intakes of vitamin A-rich foods in households with xerophthalmic children: a case-control study in Nepal. AB - Dietary patterns in 81 rural Nepali households with a 1-6-y-old child with a history of xerophthalmia were compared with dietary patterns of 81 households with an age-matched nonxerophthalmic control subject. Weekly food-frequency questionnaires were collected from case and control "focus" children, a younger sibling (if present), and the household 1-2 y after recruitment and treatment of cases. Control households and children were more likely than case households and children to consume vitamin A-rich foods during the monsoon (July-September) and major rice harvesting (October-December) seasons. Cases were less likely to consume preformed vitamin A-rich foods throughout the year [odds ratio (OR) = 1.2 4.5] with the strongest differences observed from October to December (OR = 2.0 4.2). Dietary risks were generally shared by younger siblings of cases, suggesting that infrequent intake of beta-carotene and preformed vitamin-A rich foods begins early in life and clusters among siblings within households, a pattern that is consistent with their higher risk of xerophthalmia and mortality. In developing countries where vitamin A deficiency is endemic, dietary counseling for children with xerophthalmia should be extended to their younger siblings. Moreover, dietary intake of preformed vitamin A may be as, or more, important as carotenoid-containing food consumption in protecting children and other members of households from vitamin A deficiency. PMID- 8694028 TI - Human milk fortification for premature infants. PMID- 8694029 TI - Abdominal symptoms and lactose: the discrepancy between patients' claims and the results of blinded trials. PMID- 8694030 TI - The decisive influence of diet on the progression and reversibility of coronary heart disease. PMID- 8694031 TI - Eliminating jargon, or medicalese, from scientific writing. PMID- 8694032 TI - Intrapartum fetal pulse oximetry: past, present, and future. AB - Oxygen saturation monitoring (pulse oximetry) has markedly improved medical care in many fields, including anesthesiology, critical care, and newborn intensive care. In obstetrics, fetal heart rate monitoring remains the standard for intrapartum assessment of fetal well-being. Fetal heart rate monitoring is sensitive but nonspecific for detecting fetal compromise. Additional clinical information is needed to discern those fetuses not at risk for development of intrapartum acidosis to avoid unnecessary intervention. Fetal oxygen saturation monitoring is a new technique currently under development. This article reviews the evolution of intrapartum fetal oxygen saturation monitoring and proposes directions for future investigation. PMID- 8694033 TI - The standardization of terminology of female pelvic organ prolapse and pelvic floor dysfunction. AB - This article presents a standard system of terminology recently approved by the International Continence Society, the American Urogynecologic Society, and the Society of Gynecologic Surgeons for the description of female pelvic organ prolapse and pelvic floor dysfunction. An objective site-specific system for describing, quantitating, and staging pelvic support in women is included. It has been developed to enhance both clinical and academic communication regarding individual patients and populations of patients. Clinicians and researchers caring for women with pelvic organ prolapse and pelvic floor dysfunction are encouraged to learn and use the system. PMID- 8694034 TI - A randomized, placebo-controlled study on the effect of cyclic intermittent etidronate therapy on the bone mineral density changes associated with six months of gonadotropin-releasing hormone agonist treatment. AB - OBJECTIVE: Our purpose was to determine whether intermittent cyclic etidronate therapy blocks the decline in bone density associated with gonadotropin-releasing hormone agonist therapy. STUDY DESIGN: Thirty-one premenopausal subjects who needed treatment with leuprolide (Lupron) 3.75 mg monthly for 6 months were randomized to etidronate or placebo. Bone turnover was assessed by measurement of serum calcium, phosphorus, alkaline phosphatase, and fasting urinary calcium/creatinine ratios. Bone density was measured by dual energy x-ray absorptiometry. RESULTS: Gonadotropin-releasing hormone treatment produced a significant decrease (4% to 10%) in bone density at the anteroposterior and lateral spine in placebo-treated patients (11). No significant change was demonstrated in etidronate-treated patients (15). Significant increases in serum calcium, phosphorus, alkaline phosphatase, and urinary calcium/creatinine ratios were noted in the placebo group. No significant change in these parameters were evident in the etidronate group. CONCLUSION: Etidronate blocks bone mineral density changes associated with gonadotropin-releasing hormone agonist therapy and normalizes serum and urine indicators of bone turnover. PMID- 8694035 TI - In normal postmenopausal women physiologic estrogen replacement therapy fails to improve exercise tolerance: a randomized, double-blind, placebo-controlled, crossover trial. AB - OBJECTIVE: Our purpose was to test whether estrogen replacement therapy could increase exercise tolerance in postmenopausal women. STUDY DESIGN: A randomized, double-blind, placebo-controlled, crossover study in 31 healthy postmenopausal women who received 12 weeks of physiologic estrogen replacement therapy (micronized estradiol, 2 mg/day) and were evaluated with modified Balke exercise treadmill tests. RESULTS: Serum estradiol levels increased significantly during replacement therapy in this cohort of female volunteers with a mean age of 59 years, and resting heart rate was lower in women receiving estrogen replacement (p < 0.05). However, neither the heart rate nor the blood pressure responses to exercise was different, nor was the total exercise time, rate of oxygen uptake, or maximal oxygen uptake increased after estradiol treatment. Similarly, ventilatory parameters were unaffected by estradiol. The slope of the respiratory exchange ratio was slightly but significantly different (p < 0.05) while volunteers received estrogen replacement therapy. CONCLUSION: Estrogen replacement therapy, which achieves serum estradiol concentrations in the physiologic range for 12 weeks, fails to increase exercise tolerance or improve cardiovascular response to exercise in postmenopausal women. PMID- 8694036 TI - Structural and functional effects of endometrial photodynamic therapy in a rat model. AB - OBJECTIVE: Our purpose was to determine the optical dose required for irreversible endometrial destruction and prevention of implantation by photodynamic therapy with topical 5-aminolevulinic acid. STUDY DESIGN: Three hours after drug application 74 female Sprague-Dawley rats received varying doses of 630 nm of light delivered by an intrauterine cylindric diffusing fiber. RESULTS: A 64 J/cm2 in situ optical dose resulted in long-term irreversible endometrial destruction; 43 J/cm2 damaged endometrial stroma and myometrium but not glandular epithelium 1 day after photodynamic therapy. At this lower light dose endometrium regenerated to full thickness within 3 weeks; however, implantation sacs were significantly reduced. CONCLUSIONS: Photodynamic destruction of glandular epithelium accompanies irreversible endometrial ablation, whereas isolated stromal damage leads to reproductive impairment only. The optical dose required for endometrial ablation is approximately 1.5-fold higher than for reproductive impairment (functional damage) because of differential cell photosensitivity. PMID- 8694037 TI - Presence of cell-free human immunodeficiency virus in cervicovaginal secretions is independent of viral load in the blood of human immunodeficiency virus infected women. AB - OBJECTIVE: The purpose of this study was to establish virologic or molecular criteria for evaluating the rate of transmission of human immunodeficiency virus type 1 and for defining the role of virus burden in the development of gynecologic diseases in human immunodeficiency virus-infected women. STUDY DESIGN: Paired samples of blood and cervicovaginal secretions from 63 human immunodeficiency virus-seropositive women were evaluated for cell-free and cell associated virus load by several methods, including quantitative cultures and reverse transcription polymerase chain reaction. RESULTS: All women showed evidence of virus infection in both blood and cervicovaginal secretions by a combination of in vitro culture and molecular detection methods. The CD4+ cell counts in these women ranged from < 200/microliter to > 500/microliter. Blood plasma of 26% women (12/46) did not show detectable levels of human immunodeficiency virus ribonucleic acid by reverse transcription polymerase chain reaction (< 10(2)/100 microliters). These same women had significant amounts of human immunodeficiency virus in the cell-free cervicovaginal secretions (10(2) to 10(5) copies per 100 microliters). In contrast, 17% (8/46) women with significant quantity of human immunodeficiency virus ribonucleic acid in the blood plasma had negative results for human immunodeficiency virus in the cervicovaginal secretions. Further, treatment of women with the antiviral drug zidovudine did not change the human immunodeficiency virus-1 detection rate in plasma ribonucleic acid but showed significant reduction in the ability to detect human immunodeficiency virus ribonucleic acid in cell-free cervicovaginal secretions (p = 0.036). CONCLUSIONS: We conclude that the replication kinetics of human immunodeficiency virus in the blood and cervicovaginal cells are unrelated, independent events. Further, there is no correlation between the virus load or the CD4+ cell counts in the blood and the presence or absence of quantifiable human immunodeficiency virus in cervicovaginal secretions. PMID- 8694038 TI - Neocolpopoiesis with split-thickness skin graft as a surgical treatment of vaginal agenesis: retrospective review of 201 cases. AB - OBJECTIVES: Our goals were to present a modified Abbe-Mcindoe technique of vaginoplasty with split-thickness skin graft and to analyze 51 years of experience in performing this procedure. STUDY DESIGN: Two hundred one women with vaginal agenesis were diagnosed and operated on by the same surgeon in 51 years (1943 through 1994). The patients' ages ranged from 14 to 41 years with an average of 20.5 years (SD 3.9 years). In most of the cases surgical intervention was performed when the patient desired to begin her sexual experience. The graft was taken from the thigh or gluteal region, followed by dissection of the urethrovesicorectal space. The access in this space was performed through two mutually perpendicular incisions (a modification of the Abbe-Mcindoe technique). A multiholed, rigid plastic mold was inserted during surgery and was replaced after 8 to 10 days with a semirigid silicone mold, which remained in place at least 6 months after operation or until the patient became sexually active. RESULTS: We retrospectively reviewed 201 cases of Mayer-Rokitansky-Kuster-Hauser syndrome in which vaginoplasty was performed. The data were obtained from the personal records of Dan Alessandrescu, MD, PhD, for the 76 cases operated on between 1943 and 1967 and from the medical records in the Polizu Hospital Archive, Bucharest, Romania, for 125 cases operated on between 1968 and 1994. Overall surgical mortality was null. Intraoperative and postoperative complications consisted of two rectal perforations (1%), eight graft infections (4.0%), and 11 infections of graft-site origin (5.5%). Additional information was obtained during follow-up. Sexual satisfaction was investigated with objective (depth of constructed vagina) and subjective (ability to have sexual intercourse, presence or absence of dyspareunia, vaginal lubrication, orgasm) criteria and was analyzed on a qualitative scale. In 12 patients we performed biopsies of the neovaginal wall for histologic evaluation. CONCLUSION: Because of the simplicity, low morbidity, and high success rate, our modified Abbe-Mcindoe technique is a procedure of choice for vaginoplasty. PMID- 8694039 TI - Polymerase chain reaction search for viral etiology of vulvar vestibulitis syndrome. AB - OBJECTIVE: Our purpose was to assess the prevalence of infections by human papillomavirus, herpes simplex virus, and cytomegalovirus among women with severe vulvar vestibulitis. STUDY DESIGN: Eighty-six women referred for dyspareunia and diagnosed as having severe vestibulitis underwent perineoplasty, including surgical removal of the sensitive vestibule. Controls included 25 age-matched patients without dyspareunia undergoing vaginal operations for various benign causes or undergoing repair of an episiotomy. Polymerase chain reaction analysis was carried out to determine the presence of viral genes. RESULTS: The prevalence of herpes simplex virus and cytomegalovirus among the subjects tested was nil, whereas human papillomavirus was detected in 46 cases (54%). The human papillomavirus present was not of types 6, 11, 16, 18, or 33. Only one woman of the 25 asymptomatic controls (4%) had human papillomavirus deoxyribonucleic acid in the vestibule (p < 0.001). CONCLUSION: Our data provide support for the idea that vulvar vestibulitis is associated with human papillomavirus deoxyribonucleic acid in more than half of cases. PMID- 8694040 TI - A prospective randomized evaluation of a hygroscopic cervical dilator, Dilapan, in the preinduction ripening of patients undergoing induction of labor. AB - OBJECTIVE: Our purpose was to investigate the safety and efficacy of a synthetic intracervical hygroscopic dilator, Dilapan (Gynotech, Inc., Middlesex, N.J.), on ripening the cervix before medically indicated induction of labor. STUDY DESIGN: Two hundred forty patients with a Bishop score of < or = 4 were prospectively randomized to receive either preinduction synthetic hygroscopic dilators (n = 112) or no pretreatment (n = 128) before oxytocin induction. RESULTS: Compared with controls, the dilator group exhibited a significant change in median Bishop score, but there was no significant difference in length of labor (dilator 18.8 +/- 12.8 hours vs control 21.7 +/- 14.8 hours) or in the cesarean section rate (dilator 41/112 [36.6%] vs control 49/128 [38.3%]). Relative proportions of nulliparous and multiparous patients, infant weights, and cervical dilation at the time of cesarean section were not significantly different between groups. No adverse maternal or fetal effects could be attributed to use of the device. CONCLUSIONS: Preinduction cervical ripening with hygroscopic dilators does not shorten the length of labor or lower the cesarean section rate in patients undergoing induction of labor. PMID- 8694041 TI - Asthma treatment in pregnancy: a randomized controlled study. AB - OBJECTIVE: Our purpose was to study the effect of inhaled corticosteroids on asthma exacerbations in pregnancy. STUDY DESIGN: We prospectively studied 84 pregnant women with 105 asthma exacerbations. Women were hospitalized if the forced expiratory volume in 1 second was < 70% after sequential bronchodilator therapy. They were randomly assigned to receive either intravenous aminophylline and inhaled beta 2-adrenergic receptor agonist or intravenous methylprednisolone and a beta 2-adrenergic receptor agonist. At discharge women were randomly assigned to receive either inhaled beclomethasone, beta 2-adrenergic receptor agonist, and an oral corticosteroid taper or a beta 2-adrenergic receptor agonist and a corticosteroid taper. RESULTS: Sixty-five (62%) of 105 women with exacerbation required hospitalization. Aminophylline did not shorten response time or decrease hospital stay. Readmission rate was decreased by 55% in women given inhaled beclomethasone (33% vs 12%, p < 0.05, odds ratio 3.63, 95% confidence interval 1.01 to 13.08). Pregnancy-induced hypertension and cesarean delivery were increased over those of the general population. CONCLUSIONS: Intravenous aminophylline offers no therapeutic advantages. Continuous inhaled corticosteroids reduced the need for subsequent admissions. PMID- 8694042 TI - A comparison of the yield of positive antenatal group B Streptococcus cultures with direct inoculation in selective growth medium versus primary inoculation in transport medium followed by delayed inoculation in selective growth medium. AB - OBJECTIVE: Our purpose was to compare the yield of positive group B Streptococcus cultures with standard medium for transport of culture swabs compared with use of selective medium during transport. STUDY DESIGN: Cultures of introitus, perineum, and rectum were obtained on prenatal patients; one was placed in standard transport medium, and the other directly in selective growth medium. Swabs in standard transport medium were plated for routine culture and then transferred to selective growth medium, Todd-Hewitt broth, in the laboratory. RESULTS: A total of 307 of 1222 (25.1%) patients had a positive result by any method. With direct inoculation into selective growth medium at the time of sampling, 4.6% of positive cultures were missed. With delayed inoculation into selective growth medium, 16.3% were missed (p < 0.001). Without use of selective media (routine culture), 31.9% were missed (p < 0.001). CONCLUSIONS: Use of standard transport medium with subsequent transfer into selective growth medium results in a significantly decreased yield of positive group B Streptococcus cultures. PMID- 8694043 TI - A comparison of differing dosing regimens of vaginally administered misoprostol for preinduction cervical ripening and labor induction. AB - OBJECTIVE: Our purpose was to compare two dosing regimens of vaginally administered misoprostol for preinduction cervical ripening and induction of labor. STUDY DESIGN: Five hundred twenty-two patients with indications for induction of labor and unfavorable cervices were randomly assigned to one of two dosing regimens of vaginally administered misoprostol. Twenty-five microgram tablets of misoprostol were placed in the posterior vaginal fornix either every 3 hours to a maximum of eight doses or every 6 hours to a maximum of four doses. The maximal period of cervical ripening was 24 hours regardless of the number of misoprostol doses administered. Medication was not given after either spontaneous rupture of membranes or the beginning of active labor. RESULTS: Among 522 patients enrolled, 261 were randomized to receive misoprostol every 3 hours and 261 to receive misoprostol every 6 hours. The average interval from start of induction to vaginal delivery was shorter in the 3-hour dosing group (1311.74 +/- 785.14 minutes) than in the 6-hour dosing group (1476.96 +/- 805.30 minutes) (p < 0.05). Oxytocin augmentation of labor occurred more commonly in the 6-hour dosing group (51.4%) than in the 3-hour dosing group (41.8%) (p < 0.05) [corrected]. There were no significant differences between routes of delivery. Overall, 108 patients (20.8%) were delivered by cesarean section. There was a slightly higher prevalence of tachysystole (six or more uterine contractions in a 10-minute window for two consecutive 10-minute periods) in the 3-hour group (14.6%) than in the 6-hour group (11.2%), but this difference was not statistically different. There were no significant differences in the frequency of uterine hyperstimulation or hypertonus. There was no significant difference between groups in the frequency of abnormal fetal heart rate tracings, meconium passage, 1- or 5-minute Apgar scores < 7, neonatal resuscitations, or admissions to the neonatal intensive care unit. CONCLUSIONS: Vaginally administered misoprostol is an effective agent for cervical ripening and induction of labor. Patients with the 6-hour dosing schedule had longer intervals to delivery, more frequently required oxytocin augmentation, and had more failed inductions than did patients with 3-hour dosing. Further investigation to characterize the safety of misoprostol is needed. PMID- 8694044 TI - Detection of Chlamydia trachomatis and Trichomonas vaginalis by polymerase chain reaction in introital specimens from pregnant women. AB - OBJECTIVE: We analyzed whether specimens obtained from the vaginal introitus were comparable to endocervical and posterior vaginal vault specimens for detection of Chlamydia trachomatis and Trichomonas vaginalis by polymerase chain reaction. STUDY DESIGN: Introital and endocervical specimens were obtained from 300 women at the first prenatal visit. Specimens from the posterior vaginal vault were also obtained from 219 of these patients. All samples were tested for C. trachomatis and T. vaginalis by polymerase chain reaction. RESULTS: C. trachomatis was identified in the endocervices of 36 women (12.0%); all but one of these women and none of the endocervical-negative women were positive for this organism in the introitus. T. vaginalis was detected in 22 women (10.0%); all but one were also introitus positive for this organism. Compared with endocervical and vaginal polymerase chain reaction, introital testing had a 100% specificity and a 97.2% and 95.5% sensitivity for detecting C. trachomatis and T. vaginalis, respectively. CONCLUSION: Polymerase chain reaction analysis of vaginal introital specimens is highly sensitive and specific in detecting C. trachomatis and T. vaginalis in pregnant women and thus provides an alternative to speculum examination in screening for these pathogens. PMID- 8694045 TI - The effect of specific hormones on fibrinolysis in pregnancy. AB - OBJECTIVE: Plasminogen activator inhibitor-1, the major serum protease inhibitor of fibrinolysis, increases steadily during pregnancy. The study objective was to examine four hormones, namely, estradiol-17 beta, progesterone, prolactin, and hydrocortisone to determine their individual contributions in the production of tissue plasminogen activator antigen, plasminogen activator inhibitor-1 antigen, and plasminogen activator inhibitor-1 activity. STUDY DESIGN: Human umbilical vein endothelial cells were grown with physiologic third-trimester concentrations of the above hormones, and fibrinolytic parameters were measured. RESULTS: Of the four hormones evaluated, only hydrocortisone significantly increased plasminogen activator inhibitor-1 antigen and activity at both concentrations tested (p < 0.001). Estradiol-17 beta significantly increased tissue plasminogen activator antigen and progesterone significantly decreased tissue plasminogen activator antigen, but neither affected the overall fibrinolytic balance. CONCLUSION: Hydrocortisone demonstrated antifibrinolytic properties at physiologic concentrations in pregnancy, suggesting that there may be a role for hydrocortisone in the prothrombotic tendency associated with pregnancy. The overall process of fibrinolysis was unaffected by estradiol-17 beta, progesterone, or prolactin. PMID- 8694046 TI - A comparison of misoprostol with and without laminaria tents for induction of second-trimester abortion. AB - OBJECTIVE: Our purpose was to determine whether intracervical placement of laminaria tents would improve the effectiveness of the prostaglandin analog misoprostol for the elective termination of pregnancies in the second trimester. STUDY DESIGN: Sixty-eight women between 12 and 22 weeks of gestation with either an intrauterine fetal death (n = 40) or medical or genetic indications for pregnancy termination (n = 30) were randomized to receive 200 micrograms of misoprostol administered vaginally every 12 hours with or without intracervical placement of laminaria concurrently with the first dose of misoprostol. RESULTS: The rate of abortion 24 hours after initiation of treatment was 69.7% in the 33 women receiving misoprostol alone and 68.6% in the 35 women treated with misoprostol and laminaria. The abortion rates 48 hours after initiation of treatment were 84.8% and 91.4%, respectively, an insignificant difference. The complete abortion rate was also similar between women receiving misoprostol alone (39.3%) and the group receiving misoprostol and laminaria (37.5%). There were no significant differences in the incidence of fever, vomiting, diarrhea, or pain. The mean interval from initiation of treatment to abortion was also similar, 15.7 hours in those receiving misoprostol alone and 17.4 hours in those treated with misoprostol and laminaria. In both groups women who had live fetuses at the start of the procedure had a higher failure rate of abortion and a longer time interval to abortion than women whose fetus was dead. CONCLUSIONS: Laminaria tents inserted concurrently with the first dose of misoprostol do not significantly improve the abortifacient effect of vaginal misoprostol in the second trimester of pregnancy. PMID- 8694048 TI - Maternal and neonatal outcome of 846 term singleton breech deliveries: seven-year experience at a single center. AB - OBJECTIVE: Our purpose was to evaluate the maternal and neonatal outcome of 846 consecutive term singleton breech deliveries at a single center. STUDY DESIGN: We reviewed the maternal and neonatal charts of all women who delivered singleton breech fetuses between 1984 and 1990 and divided them into two groups: women who fulfilled the criteria for trial of labor (group 1, n = 613) and those who did not meet these criteria and underwent scheduled cesarean section (group 2, n = 233). RESULTS: In group I, 326 women (53.2%) were delivered vaginally. There were no maternal deaths. Febrile morbidity and length of hospitalization were significantly higher in the women who required cesarean section in labor compared with those delivered vaginally. In the total study population there were no stillbirths and eight neonatal deaths, 6 of which had major malformations incompatible with life. The remaining two deaths occurred in group I (0.33% corrected neonatal mortality in group 1). Newborns in Group 1 exhibited a higher rate of trauma with borderline statistical significance (3.0% vs 0.5%, p = 0.052). No significant differences were found in the rates of low Apgar scores, intubation, and intensive care unit admission. CONCLUSION: Although certain short term outcome variables may appear less favorable in term singleton breech infants delivered vaginally, large randomized studies of short- and long-term outcome should be undertaken because current data are not sufficiently conclusive to warrant routine cesarean section for term breech presentation. PMID- 8694047 TI - Cervical fetal fibronectin in patients at increased risk for preterm delivery. AB - OBJECTIVE: This study aimed to evaluate fetal fibronectin concentrations in cervical secretions measured by either a rapid immunoassay or an enzyme-linked immunosorbent assay as a tool for the screening of premature delivery in otherwise asymptomatic pregnant women at high risk for prematurity. STUDY DESIGN: One hundred two pregnant women at high risk for premature delivery were followed up. Samples of the cervical secretion were taken every 2 weeks between the twenty fourth and the thirty-fourth weeks of pregnancy. The samples were obtained from the ectocervix with two swabs. One cervical sample was used for the immediate reading membrane test, and the other one for the immunoenzyme test. The correlation between the presence of fetal fibronectin in the cervical secretions and preterm birth was evaluated. In addition, a comparison between tests was made. RESULTS: The rate of preterm birth was 37.25% (38/102). Membrane tests revealed a sensitivity of 73.68% and a specificity of 92.18%; its positive predictive value was 84.84% and the negative predictive value was 85.50%. The enzyme-linked immunosorbent assays revealed a sensitivity of 78.94% and a specificity of 85.93%; its positive predictive value was 76.92%, and the negative predictive value was 87.30%. When compared with each other, the tests were found essentially concordant (p < 0.05). The elapsed time between the last sampling and the occurrence of preterm birth was 2.9 +/- 1.8 weeks. CONCLUSION: The rapid result membrane test is comparable to the standard fetal fibronectin enzyme linked immunosorbent assays for the detection of fetal fibronectin in cervical secretions between the twenty-fourth and thirty-fourth weeks of gestation. Moreover, both assays were found to be good tools for the prediction of premature delivery in asymptomatic pregnant women at high risk for prematurity. The availability of a rapid search for the presence of cervical fetal fibronectin should improve our ability to efficiently identify patients at risk for preterm delivery to discriminate between such patients and those with benign Braxton Hicks contractions. PMID- 8694049 TI - Employment, exertion, and pregnancy outcome: assessment by kilocalories expended each day. AB - OBJECTIVE: Our purpose was to evaluate the influence of employment and physical exertion on pregnancy outcome as quantified by kilocalories expended each day. STUDY DESIGN: This prospective study assessed 2743 pregnant women who received prenatal care and were delivered at the major perinatal center in Western Australia between May 1989 and November 1991. All women completed an extensive questionnaire on their social, medical, psychosocial, and economic circumstances. The women were allocated to five groups on the basis of kilocalorie expenditure per day. RESULTS: The characteristics of women in each energy expenditure group were different, with those in the least-expenditure group being younger and shorter, more likely to be living in worse socioeconomic conditions, smoke cigarettes, be nulliparous, and to be of an ethnic group other than white. After confounding effects were adjusted, women in the medium energy expenditure group were delivered of babies of higher birth weight than were women in other groups. However, the differences in birth weight between the energy expenditure categories were small, and mean birth weights within each group were within the normal range. Women in the medium energy expenditure group also had fewer incidences of prelabor rupture of membranes and women in the lower energy expenditure category had increased risks of antepartum admission to the hospital and preterm birth. A variety of other differences were observed in pregnancy outcomes for women in each of the categories of energy expenditure, but most of these differences were explained by the characteristics of the women in each expenditure level rather than the exercise pattern itself. CONCLUSION: These results indicate that the effects of daily energy expenditure on pregnancy outcome are not great. Enthusiasm for counseling pregnant women of the benefits or hazards of extremes in daily activity should be tempered by the relative lack of an effect and the fact that most apparent differences are due to confounding variables rather than the exercise itself. PMID- 8694050 TI - Pregnancy enhances cocaine-induced stimulation of uterine contractions in the chronically instrumented rat. AB - OBJECTIVE: Our purpose was to test whether cocaine stimulates uterine activity in nonpregnant and pregnant rats. STUDY DESIGN: The carotid artery and jugular vein were chronically catheterized, and a microballoon probe was inserted into the uterine cavity of 15 pregnant and 14 nonpregnant female rats. Conscious animals received a bolus dose of either cocaine or saline solution intravenously. Cardiovascular and uterine contractile responses were studied. RESULTS: Cocaine (2.5 mg/kg) induced a marked increase in uterine activity and arterial blood pressure in both pregnant and nonpregnant animals without producing systemic toxicity. The maximum change in uterine contractions was greater in the pregnant group than in the nonpregnant group, and blood pressure responses were transient in both. CONCLUSION: This study is the first demonstration that cocaine stimulates the rat uterus in vivo, with a greater increase in contractions in pregnant compared with nonpregnant animals. These differences are not related to the hemodynamic response or pharmacokinetic profile of cocaine. PMID- 8694051 TI - Vaginal birth after cesarean section in twin gestation. AB - OBJECTIVE: We report a 10-year experience with vaginal birth after cesarean section in women with twins. STUDY DESIGN: Data were gathered from labor and delivery records and maternal and neonatal hospital charts. Women with a vertical uterine scar, a previous uterine rupture, an unrepaired dehiscence, or obstetric contraindications to labor were excluded from a trial of labor. Full-thickness uterine defects requiring intervention were classified as ruptures; all others were classified as dehiscences. RESULTS: Between Jan. 1, 1985, and Dec. 31, 1994, at Los Angeles County/University of Southern California Women's Hospital, 210 women with previous cesarean births were delivered of twins. One hundred eighteen (56%) underwent repeat cesarean delivery without a trial of labor. Ninety-two (44%) undertook a trial of labor with no uterine ruptures and no increase in maternal or perinatal morbidity or mortality. CONCLUSIONS: In women with twins a trial of labor after a previous cesarean section is a safe and effective alternative to routine repeat cesarean delivery. PMID- 8694052 TI - Agonists increase the sensitivity of contractile elements for Ca++ in pregnant rat myometrium. AB - OBJECTIVE: The effects of agonists and guanosine 5'-triphosphate binding proteins (G proteins) on contractile properties were investigated in rat longitudinal myometrial tissues in late gestation and during delivery. STUDY DESIGN: The effect of carbachol was examined on the intracellular Ca++ concentration in intact thin muscle strips from pregnant rat myometrium. In addition, the action of carbachol with guanosine 5'-triphosphate was examined on the Ca(++)-induced contractions in beta-escin-treated skinned strips (membrane-permeable conditions and chemical clamping of intracellular Ca++ concentrations). The effects of guanosine 5'-0-(gamma-thiotriphosphate) (a nonhydrolyzable analog of guanosine 5' triphosphate), prostaglandin F2 alpha with guanosine 5'-triphosphate, prostaglandin E2 with guanosine 5'-triphosphate, and okadaic acid (a phosphatase inhibitor) were also examined in skinned strips. RESULTS: In intact longitudinal rat myometrium at late gestation the maximum contractions induced by carbachol were larger than the maximum contractions induced by high K+ (118 mmol/L), whereas increases in intracellular Ca++ concentration produced by both agents were similar. In beta-escin-treated skinned myometrial strips from late gestation, 0.3 mumol/L Ca++ evoked contractions. Carbachol (10 mumol/L) plus guanosine 5'-triphosphate (10 mumol/L) enhanced the 0.3 mumol/L Ca(++)-induced contractions of skinned strips; the increase was antagonized by 1 mmol/L guanosine 5'-0-(beta-thiodiphosphate). Guanosine 5'-0-(gamma-thiotriphosphate) (0.1 to 100 mumol/L), prostaglandin F2 alpha (10 mumol/L) plus guanosine 5' triphosphate (10 mumol/L), prostaglandin E2 (10 mumol/L) plus guanosine 5' triphosphate (10 mumol/L), and okadaic acid (1 nmol/L) also augmented 0.3 mumol/L Ca++ contractions in skinned strips. The increases of 0.3 mumol/L Ca(++)-induced contractility by the agonists with guanosine 5'-triphosphate or guanosine 5'-0 (gamma-thiotriphosphate) were similar between late gestation and delivery. CONCLUSION: These results suggest that agonists such as carbachol, prostaglandin F2 alpha, and prostaglandin E2 enhance the Ca(++)-induced contraction of myometrium at late gestation through G protein-mediated mechanisms. The agonist/G protein-mediated Ca(++)-sensitizing effects on contractile elements produce additional contractile force with the same amount of intracellular calcium, thus providing expelling forces for delivery of the fetuses. PMID- 8694054 TI - Fetal ionized magnesium levels parallel maternal levels during magnesium sulfate therapy for preeclampsia. AB - OBJECTIVE: Little is known about ion regulation in fetuses. Our aim was to determine the effects of magnesium sulfate therapy on ionized (bioactive) magnesium in the cord blood of pregnancies complicated by preeclampsia. STUDY DESIGN: Seventy-four pregnant women were studied (37 preeclamptic and 37 controls matched for maternal age, gravidity, and gestational age). The preeclamptic women received intravenous magnesium sulfate 6 gm load followed by 2 gm/hour for > or = 4 hours; controls were not preeclamptic and received no magnesium. Maternal venous and fetal cord blood samples were obtained from study and control patients and were analyzed for sodium, potassium, total magnesium, ionized magnesium, total calcium, and ionized calcium. Comparisons between the groups were made and analyzed by the Mann-Whitney U test. RESULTS: There were no significant differences between the treatment and control group cord samples with respect to sodium or potassium. However, total magnesium and ionized magnesium were significantly elevated (p < 0.001) in cord samples of the treated group. At the same time ionized calcium and total calcium were reduced. Interestingly, ionized calcium levels were lower in preeclamptic women before magnesium sulfate therapy was begun, whereas total calcium levels were not different. Importantly, there was no difference between maternal and fetal ionized magnesium levels in either treatment or control groups. CONCLUSIONS: In preeclamptic women undergoing magnesium sulfate therapy, ionized magnesium levels in cord blood parallel maternal levels. Before magnesium therapy ionized calcium levels were lower in preeclamptic women than in matched controls. In the presence of elevated magnesium levels ionized calcium appears to be tightly regulated. PMID- 8694053 TI - Preterm birth in rats produced by the synergistic action of a nitric oxide inhibitor (NG-nitro-L-arginine methyl ester) and an antiprogestin (onapristone). AB - OBJECTIVE: The aim of this study was to determine whether inhibition of nitric oxide synthesis would affect the action of an antiprogesterone to provoke preterm labor. STUDY DESIGN: Pregnant rats were continuously infused with NG-nitro-L arginine methyl ester starting on day 16 of gestation. On day 17 of gestation groups of animals were injected subcutaneously with a single dose of either 3 or 30 mg/kg onapristone; animals were monitored for preterm labor and delivery for up to 48 hours. RESULTS: Significant findings included the following results. (1) Combined treatment with NG-nitro-L-arginine methyl ester (50 mg per day) and low dose onapristone (3 mg/kg) produced preterm labor, > 70% of the fetuses were delivered within 27 hours of treatment, whereas < 5% of the fetuses were delivered in the animals receiving either of these compounds alone. (2) NG-nitro D-arginine methyl ester (50 mg per day) had no effect. (3) inhibition of nitric oxide by NG-nitro-L-arginine methyl ester also significantly increased the efficacy of high-dose onapristone (30 mg/kg) in preterm labor and delivery. CONCLUSION: Treatment of pregnant rats with a combination of a nitric oxide inhibitor with onapristone significantly potentiated the ability of the antiprogesterone to induce preterm labor. The interaction of nitric oxide and progesterone may be required to maintain pregnancy. PMID- 8694055 TI - Tumor necrosis factor-alpha in response to endotoxin administration in the pregnant guinea pig. AB - OBJECTIVE: Our purpose was to test the hypothesis that an intramuscular endotoxin challenge induces production of tumor necrosis factor-alpha in the pregnant guinea pig and to investigate some of the metabolic effects. STUDY DESIGN: Twelve randomly selected guinea pigs at 33 days' gestation with a sampling catheter in the carotid artery received an intramuscular injection of a solution of endotoxin isolated from Bacteroides fragilis (n = 6) or of solvent alone (n = 6). Plasma values of tumor necrosis factor-alpha, hematocrit, and 6-keto-prostaglandin F1 alpha were determined before and several hours after injection. RESULTS: Tumor necrosis factor-alpha was detected in five of six guinea pigs, but it could not be demonstrated in five of six placebo animals. The hematocrit was significantly decreased, and prostaglandin F1 alpha significantly increased 24 to 48 hours after endotoxin injection. CONCLUSION: In pregnant guinea pigs an intramuscular endotoxin challenge induces the release of tumor necrosis factor-alpha, followed by a reduced hematocrit and an increased prostacyclin concentration. These effects could be involved in the pathogenesis of endotoxin-induced fetal growth retardation. PMID- 8694056 TI - Lack of a critical cardiac output and critical systemic oxygen delivery during low cardiac output in the third trimester in the pregnant sheep. AB - OBJECTIVE: We sought to determine whether a critical cardiac output and oxygen delivery exist in normal pregnancy. We also sought to determine the role of fetoplacental oxygen demand on maternal oxygen transport variables in response to decreased maternal cardiac output. STUDY DESIGN: We studied 10 adult female sheep, 5 nonpregnant and 5 pregnant. We placed a flow-directed thermodilution catheter in the pulmonary artery and a balloon-tipped catheter in the right atrium of the sheep. We also placed a catheter for pressure monitoring and blood sampling in the descending thoracic aorta in both the mother and fetus. We decreased maternal cardiac output by incremental inflation of the right atrial balloon. We measured maternal cardiac output by intravenous bolus thermodilution technique. We also measured maternal and fetal acid-base status and serum lactate concentrations. We calculated a variety of maternal cardiorespiratory variables, including systemic oxygen delivery, systemic oxygen consumption, and fractional whole body tissue oxygen extraction. RESULT: The nonpregnant sheep displayed a critical cardiac output below which there was an abrupt decrease in oxygen consumption. In contrast, there was no critical level of cardiac output in the pregnant sheep. Maternal oxygen consumption was linearly dependent on cardiac output. Maximum fractional oxygen extraction was significantly lower in the pregnant sheep than in the nonpregnant sheep. CONCLUSION: States of low cardiac output in the pregnant sheep are associated with a lack of a critical cardiac output; the flow-dependent oxygen consumption observed is the result of either an impairment in tissue oxygen extraction or some degree of metabolic arrest or a combination of both. If this unique cardiac output-oxygen consumption relationship is seen in human pregnancy, it could have significant implications in the care of the critically ill obstetric patient. PMID- 8694057 TI - Umbilical artery pH measurement is superfluous! PMID- 8694058 TI - Measurement of fetal urinary sodium in obstructive uropathy: a question of units. PMID- 8694059 TI - How often should we perform nonstress tests in normal third-trimester pregnancies? Preferably, not as often as every 2 days! PMID- 8694060 TI - Evidence-based practice in obstetrics and gynecology: its time has come. PMID- 8694061 TI - Vitamin B1 and B6 substitution in pregnancy for leg cramps. PMID- 8694062 TI - Laparoscopic treatment of ovarian dermoid cysts. PMID- 8694063 TI - Misconceptions of sciatic nerve anatomy. PMID- 8694064 TI - Neurobiologic characteristics of umbilical artery lactate levels. PMID- 8694065 TI - Acute maternal hydration in third-trimester oligohydramnios. PMID- 8694066 TI - Beyond laparoscopic myomectomy. PMID- 8694067 TI - Maternal serum creatine kinase: a possible predictor of tubal pregnancy? PMID- 8694069 TI - High-dose oxytocin. PMID- 8694068 TI - Biochemical evidence of impaired trophoblastic invasion of decidual stroma in women destined to have preeclampsia. AB - OBJECTIVE: Reduced trophoblastic migration into the decidua during the first half of pregnancy is a fundamental abnormality in preeclampsia. CA 125 and insulin like growth factor binding protein-1 are major endometrial proteins whose primary sources are decidual epithelial and stromal cells, respectively. We hypothesized that reduced trophoblastic invasion in pregnancies destined for preeclampsia would affect the maternal vascular deportation of these decidual proteins. STUDY DESIGN: CA 125 and insulin-like growth factor binding protein-1 concentrations were analyzed by radioimmunoassays of plasma from preeclamptic and matched control patients in a longitudinal, nested case-control study. RESULTS: CA 125 concentrations did not differ with respect to pregnancy outcome or trimester. Midtrimester plasma insulin-like growth factor binding protein-1 concentrations were significantly lower in women who later had preeclampsia compared with normal pregnant controls. CONCLUSION: These findings provide biochemical evidence that abnormalities of trophoblastic invasion affect the maternal vascular deportation of a decidual stromal protein. Lower circulating concentrations of insulin-like growth factor binding protein-1 in women destined to have preeclampsia were observed 12 to 26 weeks before the onset of clinical signs of this syndrome. PMID- 8694070 TI - A "randomized" controlled trial without randomization. PMID- 8694071 TI - Attachment and differentiation in vitro of trophoblast from normal and preeclamptic human placentas. AB - OBJECTIVE: Trophoblast from preeclamptic patients shows impairment of various functions, including restricted invasive behavior of extravillous trophoblast. In this light the effect of different matrix components on attachment and differentiation of primary trophoblast cultures derived from normal and preeclamptic pregnancies was investigated. STUDY DESIGN: Trophoblast was isolated from placentas of normotensive (n = 5) and preeclamptic patients (n = 5) and cultured up to 7 days on LabTek slides precoated with fibronectin, laminin, or vitronectin. Attachment was evaluated 24 hours after plating, the degree of syncytialization was evaluated, and slides were immunocytochemically stained for cytokeratin, vimentin, human chorionic gonadotropin, and human placental lactogen. RESULTS: Trophoblast from placentas of preeclamptic patients showed a significantly lower attachment on fibronectin and vitronectin compared with controls. Diminished multinuclear cell formation was found on uncoated and laminin-coated slides in preeclamptic cases. No difference was found in the percentage of human chorionic gonadotropin- and human placental lactogen-positive cells between groups. CONCLUSIONS: Lower trophoblast attachment on fibronectin and vitronectin was observed in preeclamptic pregnancies, which may reflect differences in expression of matrix receptors. Lower syncytialization of trophoblast in this group indicates an intrinsic defect in differentiation, but otherwise no differences were found in differentiation between normotensive and preeclamptic patients. PMID- 8694072 TI - Maternal serum human chorionic gonadotropin level at fifteen weeks is a predictor for preeclampsia. AB - OBJECTIVE: Our purpose was to study the correlation between maternal serum human chorionic gonadotropin levels measured at 15 to 18 weeks of amenorrhea and pregnancy-induced hypertension, preeclampsia, and small-for-gestational-age neonates. STUDY DESIGN: Prospective trisomy 21 human chorionic gonadotropin screening data from 5776 patients were examined in a retrospective investigation of the relationship between human chorionic gonadotropin and pregnancy-induced hypertension (234 cases), preeclampsia (34 cases), and small-for-gestational-age neonates (238 cases). RESULTS: Maternal serum human chorionic gonadotropin (multiples of the median) was higher in the three populations with pathologic disorders. This difference was statistically significant in patients with small for-gestational-age neonates (p < 0.0163) and preeclampsia (p < 0.0001) but not in those with pregnancy-induced hypertension. In the preeclampsia subgroup, with a cutoff value of 2 multiples of the median, specificity was 32% and sensitivity was 10%; with a cutoff value of 1 multiples of the median, specificity was 100% and sensitivity was 50%. CONCLUSION: High maternal serum human chorionic gonadotropin levels at 15 weeks are related to a risk for preeclampsia. Depending on the human chorionic gonadotropin cutoff value, 32% or 100% of preeclampsia patients would be selected. The usefulness of preventive aspirin treatment from the fifteenth week needs more investigation in a larger multicenter study of preeclampsia. PMID- 8694073 TI - Transvaginal versus transabdominal Doppler auscultation of fetal heart activity: a comparative study. AB - OBJECTIVE: Our purpose was to determine whether transvaginal Doppler auscultation is more sensitive than transabdominal auscultation for the detection of fetal heart rate in the first trimester of pregnancy. STUDY DESIGN: In a prospective study 141 patients between 6 weeks and 11 weeks 6 days of gestation underwent both transvaginal and transabdominal Doppler evaluation by use of continuous-wave Doppler instruments for detection of fetal heart rate. Transvaginal ultrasonography was used as the gold standard to establish fetal cardiac activity and to help assign gestational age. The two methods of auscultation were compared for accuracy in different gestational age ranges. Sensitivities and specificities were calculated, and associations were investigated with chi 2 analysis. The direction of disagreement between modalities was tested with the McNemar chi 2 test. RESULTS: Transvaginal auscultation outperformed transabdominal auscultation in every gestational age range. Transvaginal Doppler auscultation performed significantly better than transabdominal Doppler auscultation at 8 weeks to 8 weeks 6 days (p < or = 0.004) and 9 weeks to 9 weeks 6 days (p < or = 0.006). In pregnancies with cardiac activity, fetal heart rate can be successfully detected transvaginally in 60.5% of pregnancies at 8 weeks to 8 weeks 6 days and in 87.5% of pregnancies at 9 weeks to 9 weeks 6 days of gestation. This compares with successful transabdominal detection rates of 22.9% and 56% at 8 and 9 weeks, respectively. As gestational age advances both methods became increasingly sensitive for the detection of fetal heart rate. The earliest fetal heart rate detected transvaginally was at 6 weeks 0 days of gestation compared with 7 weeks 0 days transabdominally. The transvaginal Doppler method was also more successful in detecting the fetal heart rate in women with a retroverted uterus (p < or = 0.01). CONCLUSION: By use of continuous-wave Doppler instrumentation, transvaginal auscultation is significantly better than transabdominal auscultation in detecting fetal heart rate between 8 weeks to 8 weeks 6 days and 9 weeks to 9 weeks 6 days of gestation. Use of transvaginal auscultation has potential in the evaluation of first-trimester fetal cardiac activity. PMID- 8694074 TI - Early midtrimester fetal nuchal thickness: effectiveness as a marker of Down syndrome. AB - OBJECTIVE: Our purpose was to assess the validity of nuchal thickness in the prediction of Down syndrome in early midtrimester fetuses. STUDY DESIGN: In 1543 consecutive pregnancies undergoing amniocentesis, primarily for advanced maternal age, nuchal thickness was prospectively measured between 13 and 18 weeks and then correlated with the karyotype obtained from amniotic fluid. RESULTS: With the cutoff value suggested in the literature (> or = 6 mm), 33.3% (6/18) of the cases of Down syndrome would be detected for a 0.1% (2/1424) false-positive rate, with a positive predictive value adjusted to a prevalence of Down syndrome in the general population of 1:3. To increase the sensitivity of the method, the threshold was lowered to 5 mm, achieving a sensitivity of 77.8% (14/18) for a 2.1% (30/1424) false-positive rate and an adjusted positive value of 1:19. CONCLUSIONS: In early midtrimester fetuses decreasing the nuchal thickness threshold to 5 mm substantially enhances the detection of Down syndrome with a reasonable false-positive rate. PMID- 8694075 TI - Pharmacokinetic and fetal cardiovascular effects of enalaprilat administration to maternal rhesus macaques. AB - OBJECTIVE: The purpose of this study was to determine the extent of placental transfer of the angiotensin-converting enzyme inhibitor enalaprilat and the effects on maternal and fetal cardiovascular parameters. STUDY DESIGN: Between gestational days 122 and 126 (term 167 days) five rhesus macaques underwent surgery for implantation of maternal and fetal vascular catheters. At least 4 days after surgery maternal and fetal blood pressures and heart rates were recorded for 1 hour. This was followed by a 5-minute maternal venous infusion of saline solution vehicle and recording for an additional hour. Enalaprilat was then infused over 5 minutes through the maternal femoral artery at doses of 0.05, 0.1, or 0.2 mg/kg. Maternal and fetal arterial blood samples were collected for determination of blood gas status and plasma enalaprilat concentrations. RESULTS: Enalaprilat rapidly crossed the placenta, and fetal values for areas under the concentration time curve were 50% to 65% of maternal values across dose groups. Drug was retained in the fetal plasma approximately threefold to fourfold longer than in maternal plasma. Maternal heart rate, blood pressure, arterial Po2 and pH were unchanged after enalaprilat infusion, as were fetal heart rate and blood gases. In contrast, fetal arterial pressure decreased significantly (19% to 23%, p < 0.01) after maternal treatment with 0.1 and 0.2 mg/kg and remained depressed throughout the 6-hour study interval. At 0.05 mg/kg fetal arterial pressure was decreased by 13% from baseline; differences were not significantly different (p > 0.05). CONCLUSIONS: Results from this study indicate that enalaprilat rapidly crosses the primate placenta with a single intravenous administration to the mother, resulting in significant and prolonged reduction of fetal arterial pressure. Because maternal cardiovascular parameters were unaffected, enalaprilat appears to have a direct effect on fetal arterial pressure. PMID- 8694077 TI - Fetal placental embolization in the late-gestation ovine fetus: alterations in umbilical blood flow and fetal heart rate patterns. AB - OBJECTIVE: Our goal was to determine the effect of chronic and acute umbilical placental embolization on placental hemodynamic and fetal heart rate patterns in relation to fetal oxygenation in the near-term ovine fetus. STUDY DESIGN: Daily fetal placental embolization was performed during 10 days in 9 sheep fetuses until fetal arterial oxygen content decreased by approximately 30%. Nine control fetuses received saline solution. Mean and pulsatile umbilical blood flow, perfusion pressure, placental vascular resistance, fundamental impedance, pressure pulsatility index, and umbilical artery resistance index corrected to a fetal heart rate of 160 beats/min were measured. On day 10 both groups were acutely embolized until fetal arterial pH decreased to approximately 7.00. Fetal heart rate was measured with the Sonicaid System 8000 (Oxford Sonicaid, Oxford, United Kingdom). RESULTS: Chronic fetal placental embolization was associated with a progressive reduction in umbilical blood flow (p < 0.00001) and fetal arterial oxygen content (p < 0.001) whereas fetal heart rate patterns remained unaltered. A chronic increase in umbilical artery resistance index corrected to a fetal heart rate of 160 beats/min could be entirely explained only if the changes in umbilical artery pressure pulsatility index and the fundamental impedance were taken into account, in addition to the changes observed in placental vascular resistance. During acute embolization leading to a 50% reduction in umbilical blood flow (p < 0.0002) and a three times increase in placental vascular resistance (p < 0.0001), the most consistent change in fetal heart rate patterns related to progressive metabolic acidosis was an 84% decrease in absolute acceleration frequency (p < 0.0001) whereas short-term fetal heart rate variability remained unaltered. CONCLUSION: Changes in umbilical artery resistance index induced by chronic umbilical-placental embolization resulting in fetal hypoxemia occurred before any changes in fetal heart rate patterns were detectable. A decrease in the absolute acceleration frequency was the only component of fetal heart rate patterns related to progressive metabolic acidosis in the near-term ovine fetus. PMID- 8694076 TI - Ketoacids attenuate glucose uptake in human trophoblasts isolated from first trimester chorionic villi. AB - OBJECTIVE: The objective of this study was to evaluate the hypothesis that ketoacids (acetoacetic acid and beta-hydroxybutyrate) diminish glucose transport in trophoblasts cultured from first-trimester chorionic villi. STUDY DESIGN: First-trimester trophoblasts were obtained by transabdominal chorionic villus sampling for subsequent cytogenetic analysis. The cells were established as a continuous line exhibiting trophoblast characteristics. Trophoblasts were cultured in Ham's F12/Dulbecco's modified Eagle's medium (1:1) supplemented with 15% fetal bovine serum. Experiments were initiated by a 24-hour preincubation in serum-free Ham's F12/Dulbecco's modified Eagle's medium followed by incubation with ketoacids (acetoacetic acid and beta-hydroxybutyrate, 0 to 10 mmol/L) in the presence or absence of insulin-like growth factor-I (100 ng/ml). The cells were challenged with 2-deoxy-[1,2-3H]D-glucose (0.1 mmol/L) for 5 minutes and then cell-associated radioactivity was measured. Total ribonucleic acid was extracted from cells incubated with ketoacids in the presence or absence of insulin-like growth factor-I, and Northern blots were probed with a phosphorus 32-labeled complementary deoxyribonucleic acid fragment encoding the rat GLUT 1. RESULTS: Ketoacids caused a dose-dependent inhibition of glucose transport. At 5 mmol/L acetoacetic acid there was a > 50% reduction in the rate of glucose transport in both control and insulin-like growth factor-I-treated cells. The diminution in glucose uptake by trophoblasts was not due to cellular toxicity of the ketoacids because there was no significant difference in trypan blue exclusion or lactate dehydrogenase release between control and ketoacid-treated cells. Northern analysis revealed that the steady-state expression of GLUT1 messenger ribonucleic acid was diminished in ketone-treated cells, but this effect was overcome by coincubation of cultures with insulin or insulin-like growth factor-I. CONCLUSIONS: These results indicate that ketoacids can suppress the uptake of glucose into first-trimester human trophoblasts. Because ketoacidosis in pregnant women with diabetes mellitus is a frequent clinical consequence of poor metabolic control, it is possible that elevated levels of acetoacetic acid and beta hydroxybutyrate may impair the transport of glucose across the placental trophoblast and into the fetal circulation. PMID- 8694078 TI - Racial differences in the predictive value of the TDx fetal lung maturity assay. AB - OBJECTIVE: Black newborns have lower rates of neonatal respiratory distress syndrome compared with nonblack newborns. This has been attributed to accelerated lung maturation. Previous studies have demonstrated a difference in the predictive value of the lecithin/sphingomyelin ratio, a test for lung maturity, between races. Our study examines the predictive value of the newer TDx Fetal Lung Maturity Surfactant-to-Albumin assay. STUDY DESIGN: We reviewed the records of 393 nonblack and 87 black infants delivered within 72 hours of the TDx FLM S/A assay testing. We compared the rates of neonatal respiratory distress syndrome by race, stratified by results. RESULTS: In our study population black newborns had less than one half the rate of respiratory distress syndrome compared with nonblack newborns (4.6% vs 10.4%). To adjust for possible differences in the timing of lung maturation, the results were stratified by the TDx FLM S/A assay result. Black race had a protective effect (Mantel-Haenszel weighted odds ratio 0.30, 95% confidence interval 0.06 to 0.93, p < 0.05). This significant racial difference remained when both TDx FLM S/A assay result and gestational age were controlled in a multiple logistic regression analysis. CONCLUSIONS: There are differences in the predictive value of the TDx FLM S/A assay among races. Black fetuses are less likely to have respiratory distress syndrome. The difference in rates of respiratory distress syndrome between races must be due to either a qualitative difference in the surfactant or to an anatomic difference in fetal lungs. Consideration should be given to a lower cutoff value for a mature test result in black women. PMID- 8694079 TI - A randomized comparison of Burch colposuspension and abdominal paravaginal defect repair for female stress urinary incontinence. AB - OBJECTIVE: Our aim was to compare Burch colposuspension and paravaginal repair for success rates, complications, and urodynamic effects when the procedures are used in the treatment of stress urinary incontinence. STUDY DESIGN: Thirty-six patients were enrolled. A full urodynamic evaluation was repeated 6 months postoperatively. RESULTS: Twelve (67%) and 17 (94%) subjects (Burch colposuspension vs paravaginal repair) voided spontaneously before discharge (p = 0.04). One patient receiving the Burch procedure underwent urethral dilation for urinary retention. Follow-up was for 1 to 3 years. Differences in subjective and objective cure rates favored the Burch colposuspension over the paravaginal repair: 100% versus 72% (p = 0.02) and 100% versus 61% (p = 0.004), respectively. The paravaginal repair did not produce significant modifications in profilometry. Postoperatively, cotton swab tests had negative results in all patients with the Burch operation and in 33% of those with the paravaginal repair (p = 0.01). CONCLUSION: Paravaginal repair is not recommended for the treatment of stress incontinence, although it was accompanied by a more immediate resumption of voiding. PMID- 8694080 TI - The obstetric outcome of in vitro fertilization and embryo transfer in women with congenital uterine malformation. AB - OBJECTIVE: Our purpose was to analyze 3 obstetric outcomes according to the various forms of congenital uterine malformation after in vitro fertilization and embryo transfer. STUDY DESIGN: We conducted a retrospective analysis of data from 24 patients with the following types of congenital uterine malformation: 6 unicomuate, 9 bicomuate, 5 septate, and 4 uterus didelphys. All patients underwent in vitro fertilization and embryo transfer at Boum Hall Clinic, a tertiary infertility referral center. RESULTS: Twenty-four patients conceived a total of 19 clinical pregnancies in 51 embryo transfer cycles. The clinical pregnancy rate was 19 of 51 (37.3%) per embryo transfer and 17 of 24 (70.8%) per patient. There were no significant differences in the clinical pregnancy rates when the various forms of uterine malformation were compared. There was a trend for the group with unicomuate uteri and uterus didelphys to have the highest rate of term delivery (6/9, 66.7%) and the lowest rate of first-trimester miscarriages (0/9, 0%) as compared with the group with septate and bicomuate uteri, in whom the term delivery rate was 1 of 10 (10%) and the spontaneous abortion rate was 3 of 10 (30%). The multiple pregnancy rate was 6 of 15 (40%) for women who had three embryos transferred, as compared with 0 in women who had two embryos or one embryo transferred. There was a high rate of preterm delivery (6/13, 46.2%) and cesarean section (10/13, 76.9%). CONCLUSION: In vitro fertilization and embryo transfer in women with congenital uterine malformation is associated with good pregnancy rates, and the patients should be counseled about the risks involved, in particular, the increased rate of preterm delivery and cesarean section. PMID- 8694081 TI - Operative management of ectopic pregnancy: a cost analysis. AB - OBJECTIVES: The purpose of this study was to analyze the cost for hospital-based services related to the operative management of ectopic pregnancies and determine the most cost-conscious approach by distinguishing the constituent components. STUDY DESIGN: This is a retrospective comparative review of every ectopic pregnancy that was surgically managed at the Memorial Medical Center of Long Beach. Unit cost estimates that are based on a cost accounting system were derived and compared between different procedures according to resources used among separate services. RESULTS: Hemodynamic instability significantly increases the cost of management by increasing the length of stay and laboratory costs. Among stable patients laparoscopic excision of ectopic pregnancies saves nearly 25% per case (p < 0.001) compared with laparotomy. However, when we compared all intended laparoscopic excisions (i.e., including the 21% of cases in which laparotomy was eventually done), the savings were markedly reduced. In addition, the cost savings was lost if patients undergoing laparotomy were discharged on or before postoperative day 2. Discharging patients after laparotomy on postoperative day 1 is the least costly management for operative treatment of ectopic pregnancy. CONCLUSIONS: Whereas laparoscopy may decrease recuperation time and incisional scarring, operative cost is not a significant reason to choose laparoscopy over laparotomy in a hemodynamically stable patient, especially as postoperative stays decrease. PMID- 8694082 TI - Transvaginal ultrasonography of pelvic masses: evaluation of B-mode technique and Doppler ultrasonography. AB - OBJECTIVE: The purpose of this study was to evaluate pelvic masses by B-mode and Doppler ultrasonography for identification of ovarian malignancies. STUDY DESIGN: A previously described scoring system for pelvic masses was applied in 310 women, and the lesions were classified into four groups according to the ultrasonographic structure. Pulsatility index values of vessels within the tumor and the contralateral ovary and of both uterine arteries were determined. RESULTS: A total of 259 masses were benign and 51 were malignant. The scoring system and classification into morphologic groups revealed similar sensitivity, specificity, and positive and negative predictive values. Intratumoral and opposite ovarian blood flow and ipsilateral and contralateral uterine blood flow did not differ in benign and malignant masses except in cases of benign lesions in postmenopausal women. In malignant lesions a lower pulsatility index (0.94 +/- 0.4) was measured than in benign lesions (1.06 +/- 0.4, p < 0.05), although a remarkable overlap was found. CONCLUSION: The results suggest that further refinement of assessment of pelvic masses with Doppler ultrasonography is needed. PMID- 8694083 TI - A prospective multicenter trial of excimer laser phototherapeutic keratectomy for corneal vision loss. The Summit Phototherapeutic Keratectomy Study Group. AB - PURPOSE: The 193-nm argon fluoride excimer laser can remove corneal scars and smooth corneal irregularities, obviating corneal transplantation. We conducted a prospective multicenter trial of excimer laser phototherapeutic keratectomy for corneal vision loss as a basis for Food and Drug Administration premarket approval. METHODS: We treated 232 eyes of 211 patients with corneal vision loss. All had corneal pathology in the anterior 100 microns of the stroma. Mean postoperative follow-up was 10 +/- 8 months. The primary outcome variable was change in best spectacle-corrected visual acuity. RESULTS: At postoperative month 12, best spectacle-corrected visual acuity improved in 46 (45%) of 103 eyes and worsened in nine (9%) of 103 eyes by 2 or more Snellen lines. Best spectacle corrected visual acuity improved by a mean of 1.6 +/- 2.8 Snellen lines (95% confidence interval, 1.1 to 2.1 lines). Every postoperative visit confirmed statistically significant improvement of mean best spectacle-corrected acuity. At month 12, treated eyes had a mean hyperopic shift in refraction of 0.87 diopter and a mean reduction in astigmatism of 0.36 diopter. Treatment appeared most effective in eyes with hereditary corneal dystrophies, Salzmann's nodular degeneration, and corneal scars, and least effective in eyes with calcific band keratopathy. Complications included recurrence of underlying pathology, corneal graft rejection, and bacterial keratitis. CONCLUSIONS: Argon fluoride excimer laser phototherapeutic keratectomy is effective, with relatively few complications, for treating vision loss from corneal opacification or irregularity. Efficacy, however, varies widely depending upon individual eyes and underlying diagnoses. PMID- 8694084 TI - Intraocular lens implantation in patients with juvenile rheumatoid arthritis. AB - PURPOSE: To study intraocular lens implantation in patients with cataracts associated with juvenile rheumatoid arthritis. METHODS: We reviewed the records of seven patients (eight eyes) with juvenile rheumatoid arthritis who had undergone cataract extraction by phacoemulsification with intraocular lens implantation. Initial and final visual acuities, preoperative and postoperative medications, and early and late complications were recorded. RESULTS: Posterior subcapsular cataracts and non-visually disabling peripheral band keratopathy were found in all eyes. The median postoperative follow-up was 17.5 months (mean, 16.6 months; range, nine to 36 months). Five patients were adults, and two patients were less than 10 years old. A best-corrected visual acuity of 20/40 or better was attained in all eyes, and the last recorded visual acuity was 20/40 or better in seven of eight eyes. Early complications included posterior synechiae formation in two eyes, one of which required reoperation. Late complications included visually disabling posterior capsular opacification in one eye and new glaucoma in two eyes. Preoperative corticosteroids were reduced postoperatively in five eyes, were the same in two eyes, and increased in one eye. Persistent postoperative inflammation, posterior synechiae, and a pupillary membrane occurred in one of the children in this study, suggesting that intraocular lens implantation in this age group may have more complications. CONCLUSIONS: Results of this study suggest that, in selected adults, cataracts caused by juvenile rheumatoid arthritis-associated uveitis can be treated by the standard phacoemulsification technique with intraocular lens implantation and can have excellent results. Intraocular lens implantation in children with juvenile rheumatoid arthritis merits further investigation. PMID- 8694085 TI - Efficacy and safety of rimexolone 1% ophthalmic suspension vs 1% prednisolone acetate in the treatment of uveitis. AB - PURPOSE: Two multicenter studies compared the efficacy and safety of rimexolone 1% ophthalmic suspension (Vexol 1%, Alcon) and 1% prednisolone acetate (Pred Forte, Allergan). METHODS: Patients with acute uveitis, recurrent iridocyclitis, or chronic uveitis treatable by topical corticosteroid were enrolled. Treatment regimen was one or two drops every hour during Week 1, every two hours during Week 2, four times a day during Week 3, and once a day for the last three days. Efficacy and safety were determined on Days 3, 4, 7 to 10, 14, 21, and 28. A poststudy evaluation was conducted 36 to 72 hours after treatment was stopped. RESULTS: When anterior chamber cell and flare were measured, rimexolone 1% was found to be as effective as 1% prednisolone. The largest difference observed between treatments was 0.5 score unit, not clinically significant. There were no statistically significant differences in cell scores in either study (P > .05). No statistically significant differences in flare scores were found except at Day 28 in Study One (P = .04). Also, prednisolone was found to be more likely than rimexolone to cause a clinically significant increase (10 mm Hg or more) in intraocular pressure (1.7 times more likely in Study One, eight times more likely in Study Two). CONCLUSION: Rimexolone 1% ophthalmic suspension is safe and effective for the treatment of uveitis. PMID- 8694086 TI - A six-week dose-response study of the ocular hypotensive effect of dorzolamide with a one-year extension. Dorzolamide Dose-Response Study Group. AB - PURPOSE: To investigate the efficacy and dose-response relationship of three concentrations (0.2%, 0.7%, and 2.0%) of dorzolamide hydrochloride in lowering elevated intraocular pressure (IOP) in patients during a six-week period and to evaluate the efficacy of 0.7% and 2.0% dorzolamide administered for an additional year. METHODS: This prospective, double-masked, randomized, placebo-controlled, multinational study enrolled 333 adults with open-angle glaucoma or ocular hypertension. During the six-week dose-response phase, patients were randomized to thrice-daily dosing of four treatments: 0.2%, 0.7%, or 2.0% dorzolamide or placebo (vehicle of dorzolamide). During a one-year extension, patients received 0.7% or 2.0% dorzolamide, and, if needed, 0.5% timolol twice daily for elevated IOP. RESULTS: In the dose-response phase, mean percent reduction of IOP (peak) was 16% to 18% for 2.0% and 0.7% dorzolamide and 4% to 7% for the placebo group, for a net reduction of IOP by dorzolamide of 11% to 14%. The 0.2% concentration of dorzolamide was not sufficiently active for further consideration. During the extension, dorzolamide maintained an adequate reduction of IOP in 55% (174 of 316) of patients. Throughout the study, the reduction in IOP was numerically greater for patients receiving 2.0% vs 0.7% dorzolamide. After 12 months of receiving dorzolamide, 20% to 28% of total carbonic anhydrase activity was observed. CONCLUSIONS: Topical dorzolamide used three times daily in concentrations of 0.7% or 2.0% lowered IOP and was generally well tolerated as monotherapy or in combination with 0.5% timolol. PMID- 8694087 TI - Needle elevation of the scleral flap for failing filtration blebs after trabeculectomy with mitomycin C. AB - PURPOSE: To report the incidence of failing filtration blebs after trabeculectomy with mitomycin C and to report the outcome of needling procedures for failing filtration blebs in these eyes. METHODS: We conducted a retrospective analysis of 537 eyes of 434 patients who had trabeculectomy with mitomycin C and reviewed the clinical course of 441 eyes of 338 patients with a minimum of three months of follow-up. RESULTS: In 441 eyes of 338 patients followed up for three months or more after trabeculectomy with mitomycin C, 88 (20.0%) eyes from 85 patients underwent needle elevation of the scleral flap. Forty-nine (22.4%) of 219 eyes required needle revision after trabeculectomy alone, and 39 (17.6%) of 222 eyes after trabeculectomy combined with cataract extraction and intraocular lens implantation. Mean intraocular pressure (IOP) after needle revision (17.9 +/- 11.6 mm Hg) was significantly less than the mean preneedling IOP (27.1 +/- 10.4 mm Hg, P < .00001, paired Student's t test). Sixty-three eyes of 60 patients had a minimum of three months of postneedling follow-up. Successful pressure control, defined as an IOP of 22 mm Hg or less with or without topical glaucoma control medications, was achieved in 46 (73.0%) of 63 eyes. Unsuccessful outcomes correlated significantly with higher preneedling IOP (R = 0.28, P = .03, df = 61) and prior surgery involving conjunctival incisions (R = 0.53, P < .00001, df = 61). CONCLUSIONS: Needle elevation of the scleral flap may provide significantly long-lasting pressure reduction in eyes with failing mitomycin C blebs. Higher success rates are achieved in eyes with fewer prior conjunctival incisions, eyes requiring a single needle revision, and eyes with lower preneedling IOP. PMID- 8694088 TI - Histopathologic and immunohistochemical analysis of the filtration bleb after unsuccessful glaucoma seton implantation. AB - PURPOSE: To analyze histopathologically and immunohistochemically the filtration bleb after unsuccessful glaucoma seton implantation. METHODS: A von Denffer implant and two Molteno implants that were nonfunctional at three months, at 11 months, and at five years after implantation, respectively, were compared by evaluating the adjacent bleb with light microscopy and a panel of 11 antibodies to epithelial, mesenchymal, and inflammatory cells. RESULTS: The wall of the filtration bleb three months after implantation consisted of loosely arranged collagenous connective tissue with relatively abundant fibroblasts labeled with monoclonal antibodies (MAbs) V9 and Vim 3B4 to vimentin. At 11 months and at five years, the collagenous layers had become increasingly thick and the fibroblasts scarce. All blebs showed metaplastic myofibroblasts surrounded by tenascin, as identified by MAb 1A4 to alpha-smooth muscle actin and TN2 to tenascin, respectively. One bleb was lined by a monolayer of cells that reacted with MAb CAM 5.2 and CY-90 to cytokeratin 8 and 18, respectively, and was apparently derived from the identically reacting proliferating corneal endothelial cells. Another bleb harbored many macrophages and foreign-body giant cells. Little evidence of chronic inflammation around the seton was detected. CONCLUSIONS: A glaucoma seton may induce several processes that potentially decrease filtration. In addition to formation of a collagenous cyst, presence of myofibroblasts suggests long-standing scar modulation that potentially leads to compaction of the filtration membrane. Furthermore, macrophages and corneal endothelial cells may invade the filtration bleb. PMID- 8694089 TI - Demographic factors in a population-based survey of hospitalized, work-related, ocular injury. AB - PURPOSE: To obtain population-based estimates of the incidence of severe work related ocular trauma and to identify demographic factors related to increased risk of this type of injury. METHODS: A statewide population-based survey of severe work-related ocular injury was performed using hospital discharge data. These data were derived from all inpatient admissions to nonfederal, acute-care hospital facilities in the state of California during 1988. Worker's compensation was used as the principal payor code to establish the work-relatedness of a given ocular injury. Census data for the state of California were used to obtain population denominators. RESULTS: Two hundred sixty-nine (approximately 14.3%) of all admissions for which ocular trauma was the principal diagnosis (1,876) were work related. Annual incidence for severe work-related ocular injury was 1.76 per 100,000 employed persons when ocular trauma was the principal diagnosis and 2.98 per 100,000 employed persons when ocular trauma was a principal or secondary diagnosis. Projected to the working-age United States population (128 million) these annual rates correspond to an estimated 2,165 acute hospitalizations for work-related ocular trauma as the principal diagnosis, and an estimated 3,745 acute hospitalizations for work-related ocular trauma as a principal or secondary diagnosis. Incidence of severe work-related ocular injury was highest among men, Hispanics, and individuals 20 to 24 years of age (5.02, 3.72, and 4.64 per 100,000 employed per year, respectively). CONCLUSIONS: The workplace accounts for a substantial proportion of severe ocular injury. Demographic groups at highest risk for this type of injury are men, Hispanics, and young adults. PMID- 8694090 TI - Measurement by nerve fiber analyzer of retinal nerve fiber layer thickness in normal subjects and patients with ocular hypertension. AB - PURPOSE: To measure retinal nerve fiber layer (NFL) thickness in normal subjects and patients with ocular hypertension and examine the relationship between age and normal NFL thickness. METHODS: Nerve fiber layer thickness was determined by scanning laser polarimetry in 210 normal subjects and 100 patients with ocular hypertension. Relative ratios for the superior and inferior NFLs were calculated by dividing the NFL values of the respective regions by the nasal value. RESULTS: Mean superior NFL in normal subjects measured 2.5 (95% confidence interval [CI], 1.3 to 3.7), and mean inferior NFL, 2.4 (95% CI, 1.2 to 3.6). Regression analysis showed a gradual decrease in NFL thickness with increasing age. In the patients with ocular hypertension, mean superior and inferior NFL were significantly lower compared with those of normal subjects: superior, 1.6 (95% CI, 0.4 to 2.8) and inferior, 1.6 (95% CI, 1.0 to 2.2). Of the patients with ocular hypertension, 58 of 100 (58%) had an abnormal NFL parameter. CONCLUSIONS: Normograms we obtained for NFL as determined by scanning laser polarimetry may serve as reference points for future studies. Patients with ocular hypertension had a significantly lower NFL thickness, although there was some overlap in resulting measurements with those of normal subjects. The Nerve Fiber Analyzer may be useful for individual follow-up of people at risk for glaucoma; however, its role as a screening instrument requires further study. PMID- 8694091 TI - Surgical treatment for chronic hypotony and anterior proliferative vitreoretinopathy. AB - PURPOSE: To determine whether vitreoretinal surgery to release anterior traction in eyes with chronic hypotony and attached posterior retinas increases the intraocular pressure and prevents atrophia bulbi. METHODS: In this prospective study, we operated on and followed-up postoperatively 17 eyes of 17 consecutive patients with previous vitreoretinal surgeries for retinal detachments and severe proliferative vitreoretinopathy. These eyes had developed chronic hypotony (intraocular pressure < or = 5 mm Hg for at least one month) and anterior proliferative vitreoretinopathy. RESULTS: After a minimum of six months of postoperative follow-up (mean, 10.6 months), mean intraocular pressure had increased significantly after surgery from 1.7 to 7.2 mm Hg (P < .001), and ten (59%) of the 17 eyes had a final intraocular pressure greater than 5 mm Hg. Visual acuity did not change significantly after surgery (P = .25). In 13 (76%) of the 17 eyes, visual acuity improved or remained the same. Factors associated with higher postoperative intraocular pressure included hypotony of less than three months' duration (P = .007), preoperative visual acuity of 2/200 or more (P = .02), extent of anterior proliferative vitreoretinopathy of less than 90 degrees (P = .003), absence of tissue over the pars plicata (P = .001), and no anterior reproliferation after surgery (P = .04). CONCLUSIONS: Early surgery to release traction over the anterior retina and uveal tissue in eyes with chronic hypotony and anterior proliferative vitreoretinopathy can increase intraocular pressure and stabilize visual acuity. PMID- 8694092 TI - Ocular findings in Down's syndrome. AB - PURPOSE: To identify the most common ocular findings in a pediatric group of patients with Down's syndrome. METHODS: A total of 152 children with Down's syndrome between two months and 18 years of age prospectively underwent ocular examination, including visual acuity assessment, slit-lamp biomicroscopy, ocular motility, cycloplegic retinoscopy, and ophthalmoscopy. RESULTS: Ocular findings in decreasing prevalence were the following: upward slanting of the palpebral fissure with the outer canthus 2 mm or higher than the inner canthus (82%), epicanthal folds (61%), astigmatism (60%), iris abnormalities (52%), strabismus (38%), lacrimal system obstruction (30%), blepharitis (30%), retinal abnormalities (28%), hyperopia (26%), amblyopia (26%), nystagmus (18%), cataract (13%), and myopia (13%). Visual acuity was assessed, and the Teller acuity cards were the most useful method of examination. The patients younger than five years old had a higher prevalence of hyperopia than did those in other age groups; patients between five and 12 years old had a higher prevalence of astigmatism; and patients older than 12 years of age had more iris abnormalities, strabismus, and cataract. Myopia and myopic astigmatism were more common in the patients with cardiac malformations. CONCLUSION: The early diagnosis of the ocular abnormalities in patients with Down's syndrome, by using Teller acuity cards in assessing visual acuity facilitates the treatment of refractive errors, strabismus, and amblyopia and may minimize handicaps. PMID- 8694093 TI - The effect of Staphylococcus aureus phage lysate vaccine on a rabbit model of staphylococcal blepharitis, phlyctenulosis, and catarrhal infiltrates. AB - PURPOSE: To evaluate the effect of Staphylococcus aureus phage lysate (SPL) vaccination on the development of blepharitis, corneal phlyctenules, and catarrhal infiltrates and on the development of antibodies and the delayed-type hypersensitivity response to S. aureus. METHODS: Eighty rabbits received an intradermal immunization of cell wall-complete Freund's adjuvant followed by a booster immunization. Rabbits were given topical applications of viable S. aureus in both eyes and 40 rabbits received subcutaneous SPL vaccinations. Clinical observations were made weekly. An enzyme-linked immunosorbent assay was used to measure IgG, IgA, and IgM antibody levels to ribitol teichoic acid in sera, corneas, and tears. The delayed-type hypersensitivity response was evaluated by skin testing after subcutaneous injection of staphylococcal antigens. RESULTS: In the SPL-vaccinated group, phlyctenules developed in eight of 40 rabbits while blepharitis developed in 13 of 40. In the nonvaccinated group, phlyctenules developed in three of 40 rabbits and blepharitis developed in five of 40. The number of rabbits with blepharitis was significantly higher in the SPL-vaccinated group than in the nonvaccinated group. In general, the antibody response to ribitol teichoic acid was enhanced, while the delayed-type hypersensitivity response to S. aureus was depressed. CONCLUSIONS: Vaccination with SPL was not found to have a beneficial effect on the development of blepharitis, phlyctenules, and catarrhal infiltrates in our rabbit model. PMID- 8694094 TI - Intraocular lens implantation in patients with juvenile rheumatoid arthritis associated uveitis: an unresolved management issue. PMID- 8694095 TI - Vitrectomy for diffuse macular edema in cases of diabetic retinopathy. AB - PURPOSE: To ascertain the effects of posterior vitreous detachment for diffuse diabetic macular edema. METHODS: We performed vitrectomy on 58 eyes of 41 consecutive patients with diabetic macular edema without posterior vitreous detachment. Follow-up was done at 12 months postoperatively. RESULTS: In 57 of 58 eyes after vitrectomy and posterior vitreous detachment, macular edema resolved, and diffuse fluorescein leakage disappeared in 35 of 36 eyes examined at the 12th month. Visual improvement was statistically significant (P < .0001, paired t test). CONCLUSION: In eyes with diffuse diabetic macular edema and without posterior vitreous detachment, vitrectomy with posterior vitreous detachment may be effective. PMID- 8694097 TI - Choroidal vascular abnormality in Purtscher's retinopathy shown by indocyanine green angiography. AB - PURPOSE: To report choroidal vascular abnormality in unilateral Purtscher's retinopathy. METHODS: Fluorescein angiography and indocyanine green angiography with a scanning laser ophthalmoscope were used to examine a 19-year-old man four days, three months, and five months after sustaining an injury in a car accident. RESULTS: Indocyanine green angiography showed an area of choroidal hypofluorescence that continued to be present up to five months after the accident. CONCLUSIONS: Choroidal vasculature may be affected in Purtscher's retinopathy. Disorder in the choroidal microcirculation could be an additional cause of the resulting poor vision observed in some patients with Purtscher's retinopathy. PMID- 8694096 TI - Retinal detachments by squash ball accidents. AB - PURPOSE: To evaluate the characteristics of retinal detachments caused by squash ball accidents. METHODS: Twenty-six patients had a retinal detachment after a squash ball hit their eyes. RESULTS: Characteristics of the 26 eyes with retinal detachment were large retinal tears parallel to the corneoscleral limbus located close to the ora serrata usually in the temporal superior fundus quadrant (in 14 [54%] of the 26 eyes) and in the temporal inferior quadrant (in seven eyes [27%]); primarily intact vitreous with a traumatic avulsion of the vitreous base in approximately one half the patients; relatively slow progression of the retinal detachment; and additional damage to the choroid and retinal pigment epithelium in the posterior fundus. The patients were young and did not have severe myopia. Reattachment of the retina was achieved in 22 (85%) of the 26 patients. In 11 patients (42%), visual acuity outcome was 20/40 or better with best correction. CONCLUSIONS: Retinal detachments after squash ball accidents show different characteristics with worse prognosis than do ordinary rhegmatogenous detachments. Protective eyewear should be worn when playing squash. PMID- 8694098 TI - Optic coherence tomography of optic disk pit maculopathy. AB - PURPOSE: To define the structure of optic disk pit maculopathy. METHODS: A patient was examined with optic coherence tomography before and after an intravitreal gas tamponade. RESULTS: Before intravitreal gas injection, optic coherence tomography defined a separation between the inner and outer layers of the retina that connected with the optic disk pit. An outer retinal layer detachment that centered on the fovea was also present. After pneumatic displacement of the intraretinal and subretinal fluid, optic coherence tomography disclosed that the two layers were opposed and in contact with the retinal pigment epithelium. CONCLUSIONS: Optic coherence tomography confirmed the two layer structure of optic disk pit maculopathy and demonstrated the positive effect of pneumatic displacement. PMID- 8694099 TI - Ocular lymphoma in a patient with chronic lymphocytic leukemia. AB - PURPOSE: To treat large-cell lymphoma in a patient with chronic lymphocytic leukemia and bilateral vitreous cells. METHODS: The patient underwent a diganostic vitrectomy. RESULTS: Biopsy of the vitreous specimen disclosed large B cell lymphoma. Large B-cell lymphoma occurring in patients with chronic lymphocytic leukemia is referred to as Richter's syndrome. CONCLUSIONS: Large cell lymphoma of Richter's syndrome can occur in the eye. This case expands the clinical spectrum of organ involvement in Richter's syndrome. PMID- 8694100 TI - Bone marrow transplantation retinopathy in the absence of radiation therapy. AB - PURPOSE: To describe a case of bone marrow transplantation retinopathy in a patient in the absence of prior radiation therapy. METHODS: Case report. RESULTS: Bilateral scotomata developed in a 26-year-old woman because of a retinal microvasculopathy two years after receiving an autologous bone marrow transplantation for acute promyelocytic leukemia. No prior radiation therapy had been given. CONCLUSIONS: Certain combinations of antimetabolites used during induction and transplantation may themselves be toxic to the retinal microvasculature. Patients who undergo bone marrow transplantation would benefit from regular and complete eye examinations, even in the absence of prior radiation therapy. PMID- 8694101 TI - Explantation of a foldable silicone intraocular lens. AB - PURPOSE: We used a novel technique for explanting an improperly oriented silicone intraocular lens. METHODS: The elastomeric property of silicone was used to deform the optic and remove the intraocular lens in one piece. RESULTS: We explanted a flexible intraocular lens without compromising the integrity of the original wound, posterior lens capsule, or corneal endothelium. CONCLUSIONS: The technique offers a superior means of intraocular lens explantation while retaining the benefits of small-incision cataract surgery. PMID- 8694103 TI - Detection of enterovirus 70 by polymerase chain reaction in acute hemorrhagic conjunctivitis. AB - PURPOSE: We have developed and applied reverse transcription-polymerase chain reaction for the detection of enterovirus 70 from conjunctival swabs of patients among the population of an acute hemorrhagic conjunctivitis epidemic on Okinawa, Japan, in 1994. METHODS: The primers used were selected from the VP1, VP2, and VP3 regions of the enterovirus 70 nucleotide sequence. RESULTS: Twelve of 27 culture-negative specimens were positive by reverse transcription-polymerase chain reaction. CONCLUSIONS: The reverse transcription-polymerase chain reaction test provides a reliable diagnostic method that readily allows specific detection of enterovirus 70 in patients with acute hemorrhagic conjunctivitis in whom low enterovirus 70 recovery rates have been obtained recently by cell culture. PMID- 8694102 TI - Ochrobactrum anthropi endophthalmitis after uncomplicated cataract surgery. AB - PURPOSE: To treat a case of Ochrobactrum anthropi endophthalmitis after uneventful cataract surgery. METHODS: A 66-year-old patient in good general health underwent uncomplicated cataract surgery in his right eye. Seven weeks later, pars plana vitrectomy with removal of the intraocular lens became necessary because of progressive low-grade endophthalmitis resistant to topical and systemic erythromycin, cephalosporins, aminoglycosides, and colistin. RESULTS: Microbiologic examination of the vitreous biopsy, capsule, and anterior chamber fluid disclosed O. anthropi, a nonfermentative gram-negative bacillus sensitive to imipenem, amikacin, ciprofloxacin, and vancomycin. CONCLUSION: Ochrobactrum anthropi and its natural resistance against many antibiotics should be considered in the treatment of low-grade endophthalmitis after uneventful cataract surgery. PMID- 8694104 TI - Treatment of persistent glaucoma secondary to periocular corticosteroids. AB - PURPOSE: To describe two patients with uveitis who developed increased intraocular pressure that was unresponsive to maximum medical therapy eight and 13 months after periocular injection of triamcinolone acetonide. METHODS: Excised periocular tissue was analyzed for corticosteroid activity by gas chromatography and mass spectrometry. RESULTS: Excision of the periocular tissue, which contained visible triamcinolone acetonide, resulted in a normal intraocular pressure within 14 days in both patients. Analysis of the excised tissue disclosed residual corticosteroid in one of the two patients. CONCLUSION: Removal of periocular tissue containing injected corticosteroids may facilitate the management of patients developing increased intraocular pressure unresponsive to maximum medical therapy. PMID- 8694105 TI - Migraine precipitated by head trauma in athletes. AB - PURPOSE: To present the clinical features of a case of migraine precipitated by head trauma. METHODS: Detailed history was obtained and ophthalmic and neurologic examinations were performed. RESULTS: This patient's history of transient loss of vision followed by severe headache precipitated by a direct blow to the top of the head is characteristic of this phenomenon. Normal neurologic and opthalmic examination findings, normal magnetic resonance imaging, and a history of similar episodes are all consistent with this diagnosis. CONCLUSION: Familiarity with this entity can obviate an expensive examination for patients with these classic symptoms. PMID- 8694106 TI - Progressive ophthalmoplegia with acute ischemic abducens nerve palsies. AB - PURPOSE: To determine the frequency of early progression of opthalmoplegia in patients with acute ischemic abducens nerve palsies. METHODS: Patients with ischemic abducens nerve palsy examined within one week from the onset of symptoms were identified using predetermined entry criteria and serially followed up using a standardized ophthalmoplegia grading scheme. RESULTS: Only two of the 35 patients initially had a complete abduction deficit. Of the 33 patients who initially had an incomplete abduction deficit, 18 (54%) showed progression of their ophthalmoplegia. CONCLUSIONS: Patients with acute incomplete ischemic abducens nerve palsies frequently demonstrate early progression of their ophthalmoplegia. PMID- 8694107 TI - Bilateral lateral geniculitis associated with severe diarrhea. AB - PURPOSE: We examined a 28-year-old woman who developed incongruous binasal and bitemporal visual field defects one week after having a febrile gastroenteritis characterized by severe diarrhea while traveling in Mexico. METHODS: The patient was treated with intravenous methylprednisolone sodium succinate, 1 g daily for three days, followed by an eight-week course of oral prednisone. RESULTS: Neuroradiologic examination demonstrated bilaterally increased signal intensity within the lateral geniculate bodies. Cerebrospinal fluid analysis disclosed isolated protein increase. CONCLUSION: Severe diarrhea may be associated with an aseptic bilateral lateral geniculitis resulting in hourglass-shaped visual fields. Corticosteroid therapy may provide mild improvement. PMID- 8694108 TI - A randomized, placebo-controlled, double-blind crossover study of the effect of pentoxifylline on ocular fundus pulsations. PMID- 8694109 TI - Incidence of acute angle-closure glaucoma after pharmacologic mydriasis. PMID- 8694110 TI - Excimer laser in situ keratomileusis under a corneal flap for myopia of 2 to 20 diopters. PMID- 8694111 TI - The habit of sniffing in nasal diseases as a cause of secretory otitis media. AB - To clarify the role of habitual sniffing caused by nasal diseases in the pathogenesis of middle ear diseases, 112 pediatric patients with secretory otitis media (183 ears) were examined for associated nasal diseases and habitual sniffing. Middle ear pressure and nasopharyngeal pressure were simultaneously measured during forceful sniffing. Fifty-four percent of the patients with secretory otitis media had allergic rhinitis and/or chronic sinusitis. Sixty percent of the patients with nasal diseases habitually sniffed, whereas only 30.8% of those without nasal diseases had this habit. In the patients with the habit of sniffing, a higher negative pressure tended to be created in the nasopharynx on forceful sniffing than in the patients who did not sniff. Thirty one of 112 patients (27.7%) were positive on the sniff test. Of these 31 patients, 20 were associated with the habit of sniffing, and in 14 of the 20 patients, nasal diseases were considered to be the primary cause of the habit of sniffing. That is, in 14 of the 112 patients (12.5%) with secretory otitis media, the patients with nasal diseases frequently sniffed and their middle ears were evacuated. This study suggests that in many patients, sniffing provoked by nasal diseases plays an important role in the pathogenesis of secretory otitis media through the creation of negative nasopharyngeal pressure. This mechanism is presumed to be present in approximately one-tenth of pediatric patients with secretory otitis media. PMID- 8694112 TI - Congenital stapedial fixation associated with Beckwith--Wiedemann syndrome: two cases of a woman and her brother. AB - Beckwith-Wiedemann syndrome (BWS) is characterized by the triad of exophthalmos, macroglossia, and gigantism (EMG syndrome) presented at birth. Two patients with BWS, a woman and her younger brother, who presented with conductive deafness caused by middle ear anomaly are reported. Stapedial fixations were confirmed by tympanotomy, and satisfactory hearing improvements were obtained by small fenestra stapedectomy. Hearing loss associated with BWS has not previously been reported. Characteristic sulci on the auricular lobe of BWS are thought to be caused by malposition of the antitragus, which originates from the second branchial arch. Stapedial fixation might be due to maldevelopment of the stapedial lamina, which also originates from the second branchial arch. There could be a causal relationship between stapedial fixation and BWS. PMID- 8694113 TI - Tympanoplasty for the anterior-superior perforation in children. AB - Anterior-superior perforations of the tympanic membrane have proven more difficult to repair than other perforations, and many investigators have found such repairs to be problematic. We report a technique in which the tympanic membrane is released from the malleus, and the graft is placed medical to the remnant, lateral to the malleus, and medial to the tympanomeatal flap. In a series of 42 cases the short-term surgical success rate (represented by an intact graft at 6 months) was 98%, with 95% of ears remaining free of reperforation to the end of follow-up. Postoperatively, 90% of children had an air-bone gap of 20 dB or less and 100% of children had an air-bone gap of 30 dB or less. Eighty seven percent of subjects demonstrated a speech reception threshold (SRT) of 20 dB or better, whereas 100% of subjects demonstrated an SRT of 30 dB or better. These results compare favorably with those reported at this institution for repair of perforations of any quadrant in children, and those of other investigators for anterior superior perforations in adults. PMID- 8694114 TI - Choroid plexus papilloma of the cerebellopontine angle. AB - Choroid plexus papillomas are rare tumors, representing less than 1% of all intracranial neoplasms in our review of the English literature. Derived from the neuroepithelial cells of the choroid plexus, these tumors recapitulate the structure of the normal choroid plexus, often demonstrating a well-developed papillary architecture. This tumor most commonly affects children and typically arises in the lateral ventricles. Before 1992, 26 cases have been reported arising in the cerebellopontine angle. We describe an example of choroid plexus papilloma of the cerebellopontine angle that was initially diagnosed as metastatic papillary carcinoma. A metastatic disease workup revealed a right thyroid lobe nodule. Fine needle aspiration biopsy of this nodule yielded a few atypical cells, but no evidence of papillary carcinoma. We performed additional laboratory investigations to rule out the possibility of a primary papillary carcinoma of the thyroid gland and to make a definitive diagnosis of a choroid plexus papilloma. This article reviews choroid plexus papilloma of the cerebellopontine angle and demonstrates the use of immunohistochemistry to differentiate this benign primary neoplasm from well-differentiated metastatic papillary carcinoma. PMID- 8694115 TI - Plasma cell granuloma of the temporal bone. AB - Plasma cell granulomas are uncommon, benign tumors comprised primarily of mature plasma cells and are a distinct entity, separate from plasmacytomas. They are rarely found in the head and neck, and have never been reported in the temporal bone. This case represents the first report of a plasma cell granuloma originating in the temporal bone. Treatment options include surgical removal and radiation therapy. PMID- 8694116 TI - Normal hearing in acoustic neuroma patients: a critical evaluation. AB - A series of 128 acoustic neuromas (ANs) managed in our center in the last 6 years were evaluated. Sixteen cases (12.5%) were found to have normal pure tone audiograms. A comparatively younger age was an important characteristic of these patients. Tinnitus, dysequilibrium, and subjective hearing loss or distortion were their most common complaints. Pure tone audiometry showed a mean pure tone average of 14.5 dB. Speech discrimination score and performance intensity phonetically balanced index were very insensitive and showed very high false negative results. Auditory brainstem responses proved to be a reliable test, being positive in 93.8% of cases. The mean tumor size did not show any significant difference when compared with acoustic neuroma cases with abnormal hearing. The combination of otologic and neurotologic symptoms in a young patient should prompt the clinician to investigation further even if hearing is within normal limits. A high index of suspicion is a prerequisite for the early diagnosis of such subtle lesions. PMID- 8694117 TI - Leiomyoma of the external auditory canal. AB - The differental diagnosis of aural polyps includes both benign and malignant processes, including carcinoma. We present the case of a polyp arising after trauma to the ear. The entire external auditory meatus was occluded, causing a maximal conductive hearing loss on the affected side. This did not appear to be a typical aural polyp and carcinoma was suspected. Biopsy revealed the mass to be a leiomyoma of the external auditory canal. This benign tumor was treated by complete excision. The clinical and pathological findings of this extremely rare tumor of the external auditory canal are described. To our knowledge, this is the first reported case of leiomyoma arising from the external auditory canal in the English literature. PMID- 8694118 TI - The use of the temporoparietal fascial flap in temporal bone reconstruction. AB - After routine canal wall down mastoidectomy, local muscle flaps with and without bone pate, cartilage and fascia are the standard techniques available to otologists wishing to obliterate the mastoid and reconstruct the external auditory canal. Reconstructive options for temporal bone defects after extirpative surgery for cancer, osteoradionecrosis, and revision surgery for chronic granulomatous otitis media, however, are few. Although the neighboring temporoparietal fascia flap (TPFF), based on the superficial temporal vessels, has been frequently employed for auricular reconstruction, its versatility in temporal bone reconstruction has not been widely explored. The TPFF has recently been employed at our institution in 11 patients who presented with a variety of reconstructive problems, including defects after temporal bone resection, surgery for malignant otitis externa, and revision mastoid surgery. Follow-up in these patients ranged from 1 to 43 months (average 18.4 months) and surgical objectives of achieving a dry mastoid bowl, fully epithelialized canal, and/or reduction of mastoid cavity volume was attained in 100% of cases. The TPFF offers many advantages to the otologic surgeon when faced with reconstruction dilemmas that center around a poorly vascularized mastoid cavity and temporal bone. The TPFF is a reliable source of local well-vascularized tissue that is extremely pliable and facilitates both hearing and nonhearing preservation temporal bone reconstruction. PMID- 8694119 TI - Unusual lesions of the internal auditory canal. AB - Tumor types other than acoustic neuromas are uncommonly encountered in the cerebellopontine angle, and unusual lesions limited to the internal auditory canal (IAC) are given more rare. We present five patients with unusual tumors of the IAC including two meningiomas, two arachnoid cysts, and a hemangioma. These unusual tumors, and lipomas, are discussed. Particular attention is paid to the pathophysiology of the lesions and treatment recommendations. The differential diagnosis of intracanalicular lesions using magnetic resonance imaging is also presented. PMID- 8694120 TI - Cochlear fistula in chronic otitis media with cholesteatoma. AB - Labyrinthine fistula in chronic otitis media with cholesteatoma most commonly involves the horizontal semicircular canal. We report three cases of cochlear fistula in chronic otitis media with cholesteatoma. All of them had a long history of otorrhea. One patient had total hearing loss of the affected side. The other two patients had conductive hearing loss. Radical mastoidectomy had been done in all cases. Cholesteatoma in the tympanic cavity destroyed the basal turn of the cochlea. These fistulas were sealed with muscle or Gelfoam with streptomycin. We found no fistula in the semicircular canal in any of the three cases. We report three cases of cochlear fistula in chronic otitis media with cholesteatoma, and review the literature. PMID- 8694121 TI - Far-field auditory brainstem response in neurotologic surgery. AB - This is a review of our experience using far-field auditory brainstem monitoring during acoustic neuroma removal. The observations are based on 144 consecutive cases beginning in 1986. The factors of importance are tumor size, preoperative auditory function, and the preoperative presence of a wave V on the auditory brainstem response. Our experience suggests that preservation of hearing in tumors > 2.5 cm is rare. It was observed that preserving wave V does not guarantee preservation of hearing. Conversely, loss of wave V does not preclude preservation of hearing. It has also been noted that the presence of only wave I preoperatively does offer some hope that hearing can be preserved postoperatively. Finally, postoperative hearing function is usually equal to or worse than the preoperative function. Only rarely does the postoperative function improve. PMID- 8694122 TI - Correlation of MRI, clinical, and electroneuronographic findings in acute facial nerve palsy. AB - Intratemporal enhancement of (Gd-DTPA) was investigated by an interleaved overlapping magnetic resonance imaging (MRI) technique in 35 cases of acute facial palsy. In a reference group (normal facial function), enhancement was localized from the ganglion geniculi to the stylomastoid foramen. In cases of acute palsy, the facial nerve enhanced in the meatal fundus independent of etiology (idiopathic, herpetic, or traumatic). In 70% of those with Ramsay-Hunt syndrome, the vestibular and cochlear nerves, the labyrinth, and the sheets of the internal and external auditory canal additionally enhanced. No correlation was found between intensity, extension, and duration of the enhancement and the clinical, intraoperative, or electroneuronographic degree of the facial palsy. The pathogenesis of the Gd-DTPA enhancement of the facial nerve appears to be closely connected with the vascular supply of the fallopian canal and the permeability of the neural sheets. PMID- 8694123 TI - Facial nerve monitoring: an EAR Foundation Alumni study. PMID- 8694124 TI - Auditory event-related potentials in multiple sclerosis. AB - The present study examined the effects of multiple sclerosis (MS) on the N1, P2, and P300 components of the late auditory evoked potential (LAEP). A group of 30 subjects with confirmed MS were compared with 30 control subjects who were pair matched to the MS subjects with respect to age and gender. A standard stimulus oddball procedure was used to elicit the LAEP, in which subjects had to selectively attend to rare tones randomly interspersed among more frequently occurring tones of a different frequency. LAEPs were recorded with and without the presence of simultaneous speech competition in the nontest ear. Although the presence of speech competition produced significant latency and amplitude changes with the different components of the LAEP, the magnitude of the changes were similar for both subject groups. However, in comparison to the control group, a significantly higher proportion of MS subjects exhibited absent P300 responses on all test runs. PMID- 8694125 TI - Rosenthal and the spiral canal of the modiolus. AB - Rosenthal's spiral canal of the modiolus of the cochlea is mentioned numerous times in the literature, but there are few references to both the man who discovered it and the article in which it was first described. Standard medical dictionaries attribute its discovery to the wrong Rosenthal. The correct Rosenthal is identified and his original description is referred to. The possibility of an even earlier description of the canal is discussed. This description links the origins of the electric telegraph and multiple-channel cochlear prostheses. PMID- 8694126 TI - Postural stability following mild head or whiplash injuries. PMID- 8694127 TI - Critical evaluation of the "jigsaw" assembly for ossiculoplasty. AB - A modification of an ossiculoplasty technique, in which a hole is drilled through an ossicular or cortical bone graft so that it can encircle the malleus handle, has been evaluated during a 4-year period. During this time, 26 operations have been carried out. The 1-year hearing results obtained have been compared with those for conventional operations in ears with the same ossicular defect by creating matched pairs whose preoperative air-bone gaps differed by no more than 5 dB. There is no difference between the hearing results for the two groups. Revision operations have been carried out in five cases. In two of these the cause of failure was iatrogenic cholesteatoma. This probably occurred because the technique demands the separation of the malleus handle from the tympanic membrane. This can be easily achieved except at the lower end, where the attachment is much firmer. The incidence of cholesteatoma in the study group is higher than that found in the author's patients who have undergone conventional ossiculoplasty operations. The "jigsaw" technique has no advantage over conventional ossiculoplasty techniques and, in view of the risk of cholesteatoma formation, cannot be recommended. PMID- 8694128 TI - Medial canal stenosis--chronic stenosing external otitis. AB - Chronic stenosing external otitis is an indolent condition that is difficult to treat. Twelve cases that were operated on during a 3-year period were reviewed. The results of treatment are presented and the surgical methods are discussed. This involves excision of all fibrous tissue and if necessary the drum, a wide canalplasty, a meatoplasty, and then reconstruction with a fascial graft if necessary followed by split skin grafts, with emphasis on maintaining the anterior tympanomeatal angle. PMID- 8694129 TI - The management of chronic suppurative otitis media with acid media solution. AB - An organism must maintain a fairly constant balance of pH to survive. Most bacteria grow the best in a narrow range of pH from 6.5 to 7.5. Ninety-six patients with chronic suppurative otitis media were selected. Two weeks before the treatment they were instructed to stop taking any antibiotics; then a sterile swab culture was taken from auditory canal secretions and at the same time the pH of the secretions were measured. Otomicroscopic examination of the ear with cleaning of purulent debris was done. All patients received ear irrigation with 2% acetic acid solution three times per week for the maximum of 3 weeks without antibiotic therapy. Any patients with cholesteatoma, polyp, granulation and otomycosis were excluded. Patients were followed for up to 3 years. Fifty-five patients (57%) had resolution of their original otorrhen, whereas 19 patients (20%) developed healed ear drum perforation. The remaining 14 patients (15%) showed recurrence and 8 of them (8%) had no response to the treatment. PMID- 8694130 TI - Hearing impairment in Engelmann disease. AB - There are several hyperostosis diseases of the skull that are accompanied by hearing impairment. In this article a case of Engelmann disease is presented. Currently > 130 cases of Engelmann disease are reported in literature. About 18% of these cases reported hearing impairment, but it is possible that this figure may be higher, because many of the authors concentrated on other aspects of the disease and made no reference to hearing loss in their reports. The etiology of deafness is the narrowing of the internal auditory canals cause by bony encroachment on nerves and vessels. This lends to progressive perceptive hearing loss and narrowing of the tympanic cavities. The result is fixation or adhesion of ossicle to tympanic walls, and narrowing of the bony part of auditory tubes, which causes serous otitis media. PMID- 8694131 TI - Early diagnosis of Usher syndrome in infants and children. AB - The electroretinogram (ERG) is the only test currently available that has the potential to identify patients with Usher syndrome before onset of fundoscopic and visual abnormalities. The ERG is a noninvasive technique that can diagnose retinitis pigmentosa via measurement of corneal-retinal potentials. Forty-seven children with bilateral severe to profound sensorineural hearing loss were evaluated. Usher syndrome was diagnosed in five children, all of whom subsequently underwent cochlear implantation. We have found that accurate diagnosis of Usher syndrome in infants and young children is possible via ERG. Benefits of early diagnosis include timely counseling regarding genetic issues, educational and vocational placement, and cochlear implantation. For this reason we recommend that all newly identified children with bilateral severe to profound sensorineural hearing loss undergo ERG testing. PMID- 8694132 TI - The ear in the acquired immunodeficiency syndrome: II. Clinical and audiologic investigation. AB - Patients with acquired immunodeficiency syndrome (AIDS) were investigated to determine the sites, nature, and severity of any otologic abnormalities. Tinnitus, "muffled" or "echoing" hearing, and vertigo were frequent complaints. Eight percent of the 155 patients studied showed evidence of chronic otitis media, usually with effusion. Mostly mild, but occasionally severe sensorineural hearing loss was found in many, affecting more severely the higher and lower frequencies than the middle range. Almost all patients showed diminished otoacoustic emissions, suggesting cochlear dysfunction resulting from infection or ototoxicity as the basis for the hearing loss. Impairment of the otoacoustic emissions by a subclinical otitis media with effusion cannot, however, be excluded. On the basis of this study it is suggested that the provision of otologic care to patients with AIDS may enhance their quality of life and, by the early detection and treatment of severe otitis media, may even prolong life. PMID- 8694133 TI - Preservation of cochlear function after extensive labyrinthine destruction. AB - We report a case of hearing preservation after removal of the semicircular canals and discuss the possible explanations for the mechanisms of preservation of hearing after removal of the labyrinth. We hope to promote the perspectives and possibilities of functional surgery of the inner ear and for tumors of the cerebellopontine angle. PMID- 8694134 TI - Nucleus 22-channel cochlear mini-system implantations in Mandarin-speaking patients. AB - This article evaluates the benefits of the Mini System of the Nucleus 22-Channel Cochlear Implant on the speech perception and auditory functions of Mandarin speaking patients. Tests adapted specifically for the assessment of a tonal language were administered in the best-aided condition preoperatively to four Mandarin-speakers. These scores were compared postoperatively with implant alone or with lipreading scores to quantify speech perception and auditory improvements resulting from the Nucleus 22 Mini-System cochlear implant. Four postlingually deafened adults underwent cochlear implant surgery using a Nucleus 22-Channel Mini-System Device via an inverted "U" postauricular incision and the posterior tympanotomy approach, without complications. After up to 2 years of rehabilitation, all four patients exhibited continuous improvement in both speech perception and auditory abilities over time. The improvements made by our Mandarin-speaking patients are comparable to studies on Western-language-speaking patients implanted with the same device, indicating that the Nucleus 22 Mini System enables profoundly and totally deaf patients to distinguish between the four separate tones present in Mandarin Chinese. PMID- 8694135 TI - Successful revision of failed cochlear implants in severe labyrinthitis ossificans. AB - Labyrinthitis ossificans may complicate the insertion of a multichannel cochlear implant in patients deafened after meningitis. Two children who initially underwent partial insertion of a 22-channel cochlear implant because of severe cochlear ossification required revision surgery after several months of unsuccessful device use. At the time of revision, resection of the car canal, tympanic membrane, malleus, and incus provided access to the lateral wall of the cochlea, permitting extensive drilling of the basal turn and a circumodiolar placement of the electrode. Functional integrity of the electronic components of the original device was documented intraoperatively, avoiding the expense of a new receiver-stimulator. Complete insertion of the active electrodes was accomplished in both cases, and electrophysiologic responsiveness to the implant was documented using intraoperative electrically evoked auditory brainstem response recordings. Postoperative performance has been similar to that of cochlear implant patients with nonossified ears. Experience with these two cases suggests that efforts to optimize electrode insertion at the original surgical procedure are appropriate and may help to avoid the disappointment of an unsuccessful cochlear implant. PMID- 8694136 TI - Speech recognition with a CIS strategy for the ineraid multichannel cochlear implant. AB - Wilson et al. proposed a new sound-processing strategy for multichannel cochlear implants, the Continuous Interleaved Sampling (CIS) strategy. Their study was performed on seven American patients, selected for their excellent performance with the Ineraid multichannel cochlear implant, and involved refined testing of several parameter modifications of the CIS strategy during a 1-week period. At the end of the week, the CIS strategy produced large improvements in speech recognition tests for all subjects. To evaluate the generality of this promising result, the goal of this study was to assess whether similar improvements of performance could be observed in a typical population of Ineraid users and implemented as a clinical protocol. Therefore we designed one unique, predetermined CIS processor that could be temporarily fitted to the patients in < 2 h, and we evaluated speech recognition with consonant-and vowel-identification tests in a group of patients with performances ranging from star to almost chance levels and speaking six different native languages. Scores of vowel and consonant identifications obtained with this predetermined CIS processor and with the standard processor of the Ineraid system were compared in 15 Ineraid users. Fourteen of 15 patients had significantly better scores of consonant identification with the new CIS strategy. The group mean scores of vowel identification with either strategy were not statistically different. In agreement with these observations, most patients immediately reported that the CIS strategy sounded subjectively "more clear" for real-time speech recognition. It is now possible to implement a CIS speech-coding strategy as a standard clinical procedure to improve speech-recognition performances of all Ineraid users. PMID- 8694137 TI - Type II collagen-induced autoimmune ear disease in mice: a preliminary report on an epitope of the type II collagen molecule that induced inner ear lesions. AB - To identify the epitope on the type II collagen molecule that induced autoimmune ear disease, electrophysiological and histological studies were carried out in DBA/1J mice immunized with native chick type II collagen (Clln) and cyanogen bromide (CNBr) peptide 1I (CB-I1 peptide) that was cleaved from chicken type II collagen with CNBr digestion. Four months after immunization, three of six Clln immunized mice and five of six CB-I1 peptide-immunized mice developed moderate hearing loss. No control animals showed hearing loss. The pattern of hearing loss was characteristic of progressive deafness. Furthermore, the immunized mice showed temporal lesions involving atrophy of the Corti organ and degeneration of the spiral ganglion, in proportion to the level of the hearing loss. Because similar inner ear lesions were induced by immunization with Clln and CB-I1 peptide, CB-I1 peptide contains at least one epitope that induces autoimmune inner ear disease in collagen II-induced disease on the chick type II collagen molecule involved in pathogenesis of autoimmune ear disease. CB-I1 peptides were concluded to contain the epitope that induces autoimmune inner ear disease in collagen IIn-induced disease. PMID- 8694138 TI - A surgical solution for the difficult chronic ear. AB - We all encounter them: difficult chronic ears that seem to confound management efforts and that constitute an unrelenting imposition to the patient. Typically these ears have undergone multiple surgeries and are chronically infected. Such cases are commonly associated with residual or recurrent cholesteatoma. Those rare ears that temporarily respond to therapy promptly recur once treatment is withdrawn. Even the most aggressive nonsurgical protocols fail these patients, who exhibit lifelong social and professional incapacity. They seem to ultimately defy resolution. The purpose of this article is to present a surgical solution to the difficult chronic ear dilemma that emphasizes disease control. Treatment outcome is reviewed in 541 cases. Management pitfalls are analyzed with follow up, in some cases 20 years. PMID- 8694139 TI - A subpopulation of Meniere's patients produce antibodies that bind to endolymphatic sac antigens. AB - The endolymphatic sac (ES) has been suggested to serve an important immunological role within the inner ear. Meanwhile, immunological mechanisms have been studied in connection with Meniere's disease. The aim of this study is to look for and recognize antibodies against the ES in the sera of patients with Meniere's disease, using the technique of indirect immunofluorescence. Sera from 50 patients with Meniere's disease, from an animal model of autoimmune inner ear disease, and from healthy controls were tested against ES tissue substrates obtained from guinea pigs. Immunoglobulin deposition in the ES was found in 20 patients (40%) compared with one control (10%). The difference was statistically significant when computing the odds ratios at 95% confidence level. Fluorescein labeling was demonstrated in the ES epithelium in 16% and in the surrounding perisaccular stroma in 24%. Identical immunoreactivity against the ES tissue was depicted in the sera of the experimental animal model. These findings support the possibility of humoral immunological involvement in the Meniere's disease process. Immunological derangement of the ES function could be the first step in a cascade of reactions leading to endolymphatic hydrops and presenting as Meniere's disease. PMID- 8694140 TI - CT imaging of radiopaque shunt catheter after endolymphatic duct surgery. AB - Until now, shunt catheters used in endolymphatic sac (ELS) and duct surgery have not been visible at computed tomography (CT) imaging. This report summarizes findings at postoperative CT in 50 patients who underwent endolymphatic system decompressive surgery with a new opaque shunt catheter placed at or into the endolymphatic duct (ELD). The catheter was visible in all 50 cases, and the best projection for visualization was the semicoronal view. The postoperative visualization of the opaque shunt catheter allows determination of the exact placement of the catheter (a) in the bony vestibular aqueduct (within the membranous ELD); (b) at the external aperture of the bony vestibular aqueduct (within or at the membranous ELD at its junction with the ELS); or (c) outside the bony vestibular aqueduct system or aperture but presumably within the membranous ELS. These objective findings may be used as a marker to help predict outcomes from this type of nondestructive inner ear surgery, as well as to determine exactly where the surgeon placed the shunt-tube catheter tip. PMID- 8694141 TI - Endolymphatic system shunting: a long-term profile of the Denver Inner Ear Shunt. AB - Endolymphatic system surgery for Meniere's disease, particularly endolymphatic shunting, remains controversial. In 1988, we presented our findings on the efficacy of the Denver Inner Ear Shunt in 100 patients. These data were accumulated in the short term. The purpose of this article is to review the long term results of our endolymphatic shunt procedure, highlighting the population of Denver Inner Ear Shunt recipients. Results were analyzed according to both 1972 and 1985 AAO-HNS criteria. We seek corroboration or refutation of our preliminary conclusion that (a) endolymphatic shunt surgery has little efficacy and that (b) the Denver valve does not appear to offer any advantage in this regard. PMID- 8694142 TI - Do Frenzel glasses have a place in the modern electronystagmography laboratory? AB - Electronystagmography (ENG) is generally performed with the patient's eyes closed to prevent visual fixation. In this way, direct observation of eye movements is impossible. By means of Frenzel glasses (FG), the direct observation of eye movements is possible, but the effectiveness of visual fixation suppression and the diagnostic contribution of FG must still be studied. One hundred seven patients with vertigo participated in this study. Each patient underwent a complete ENG test under two fixation modalities: (a) closed eyes and (b) open eyes with FG. The spontaneous nystagmus and the Hallpike test did not show any significant difference between the two fixation modalities. The slow-phase velocity of nystagmus with the caloric test was significantly greater with closed eyes, but the pattern of nystagmus with FG fixation was more tooth-shaped and regular than that with closed eyes. It is concluded that using FG when performing an ENG may improve its diagnostic value. PMID- 8694144 TI - Developmental anatomy of the supratubal recess in temporal bones from fetuses and children. AB - The supratubal recess (STR), located superior to the bony eustachian tube and anterior to the attic and often the site of disease, is clearly separated from the attic by the presence of a bony partition. Its anatomic development in childhood, however, remains nuclear. We reviewed serial horizontal sections of fetal and children's temporal bones from the collection of the Otopathology Laboratory, University of Minnesota. Apparently, upward expansion of the bony eustachian tube begins at a late fetal stage and continues throughout childhood, thus forming the STR. Our finding that the STR had already developed in temporal bones without pneumatization of petrous bone suggests that its formation is independent of the air-cell system. Absorption of mesenchymal tissue in the STR tends to be slower than elsewhere in the temporal bone. Surrounded solely by petrous bone, the STR seems, both developmentally and anatomically, a distinctive compartment of the middle ear. PMID- 8694143 TI - Surgical treatment of vertigo--the Karolinska Hospital policy. AB - Results are reported for 40 patients with disabling vestibular symptoms, treated with endolymphatic sac surgery (ELS), gentamicin injections in the middle ear, or vestibular neurectomy by the middle fossa approach. If ELS failed, an additional treatment with a second ELS procedure or gentamicin instillations was performed. If the gentamicin treatment failed, the patients were treated with a second series of gentamicin instillations or vestibular neurectomy or both. The results in relieving the patients of their vertigo were found to be almost the same with each of the treatment modalities: approximately 82% of the patients in each group reported total or substantial relief of vestibular symptoms, whereas the rate of complications differed between the groups. After ELS, one patient had a possible complication in that she became deaf 10 days after surgery. After gentamicin injections, 12 of the 14 patients with preoperatively measurable hearing had significantly decreased hearing, but no other complications were reported. After vestibular neurectomy, five of 11 patients had complications in the form of hearing loss, infections, or transient facial paralysis. No effect on tinnitus was seen after any of the methods. When evaluating the outcome after the final surgical treatment of the 40 patients, it was found that 38 patients (95%) reported total or substantial relief of vestibular symptoms. A future policy for surgical treatment of vertigo is discussed. PMID- 8694145 TI - Recent developments in our understanding of gastric lymphomas. AB - The histopathologic features of low-grade primary gastric lymphoma recapitulate the structure of Peyer's patches [mucosa-associated lymphoid tissue (MALT)] rather than that of lymph nodes. Transformation of low-grade MALT lymphoma to high-grade disease is well recognized, and it is likely that most high-grade primary gastric lymphomas evolve from low-grade lymphoma of the MALT type and are therefore derived from the same B-cell lineage. Molecular genetic studies of gastric MALT lymphomas have shown that these lymphomas do not share any of the features common to nodal lymphomas but, instead, exhibit a marked increase in the frequency of trisomy 3. Gastric MALT lymphomas also differ from their nodal counterparts with respect to their clinical behavior, which is remarkably favorable. The histologic features of gastric MALT lymphomas suggest that one explanation for their favorable behavior may be that their growth is influenced by antigen. That lymphoma should arise from gastric mucosa is paradoxical, because there is no lymphoid tissue in normal stomach. However, several studies have shown that lymphoid tissue accumulates in gastric mucosa almost exclusively as a consequence of Helicobacter pylori infection and that this lymphoid tissue has MALT characteristics. These findings suggested that H. pylori might provide the antigenic stimulus for the growth of gastric MALT lymphoma. Further evidence for this was the finding of H. pylori in more than 90% of cases of gastric MALT lymphoma. Subsequently, evidence supporting an etiologic role for the organism has steadily accumulated. The incidence of gastric lymphoma is greater in communities with a high prevalence of H. pylori, and a case control study has shown that gastric lymphoma is more common in patients infected with the organism; moreover, the infection precedes the onset of lymphoma. Laboratory studies have shown that the growth of tumor cells from low-grade gastric lymphomas can be stimulated by H. pylori and that the effect is strain-specific and is mediated by contact-dependent help from H. pylori-specific T cells. Parallel clinical studies have shown that cases of low-grade gastric lymphoma, when confined to the mucosa, may regress after eradication of H. pylori from the patient's stomach. It remains to be shown whether deeply penetrating or high grade tumors will respond in the same way. Other outstanding questions relate to the optimal interval between eradication of H. pylori and final evaluation of the response and to the expected duration of the response. On the basis of these laboratory experiments and clinical findings, it is possible to suggest a scheme for the pathogenesis of gastric MALT lymphoma. PMID- 8694146 TI - Recognizing atrophy: another step toward a classification of gastritis. AB - The Sydney System is a novel classification of gastritis that attempts to incorporate etiologic, topographic, and morphologic criteria into a clinically relevant scheme. In September of 1994, a group of 20 gastric pathologists from various parts of the world gathered in Houston, Texas, U.S.A., to reappraise the Sydney System 4 years after its introduction and to attempt to reach a broad consensus on gastritis. One of the most controversial issues at the Houston Workshop was the concept of atrophy. Several factors converge to foment confusion and disagreement. "Normal" is imprecisely defined; the loss of glands occurs with distinct patterns and has different functional significance in antrum and corpus; inflammatory infiltrate and lymphoid follicles in the lamina propria may alter the architecture of the gastric mucosa, particularly in the antrum, making loss especially arduous to discern from mere displacement; the relationship between atrophy and intestinal metaplasia remains incompletely understood; and finally, and perhaps most important, the topographic patterns of distribution and the genesis and evolution of atrophic gastritis have been among the most divisive predicaments in the tumultuous arena of gastritis. This article explores some of the difficulties surrounding the concept of atrophy, summarizes the resolutions made at the Houston Workshop, and presents a novel approach to the histopathologic evaluation of atrophic gastritis. PMID- 8694147 TI - The biopsy diagnosis of gastroesophageal reflux disease, "carditis," and Barrett's esophagus, and sequelae of therapy. AB - Histologic changes indicative of gastroesophageal reflux disease (GERD) are found on both sides of the squamocolumnar junction (Z-line). In the gastric cardia, inflammation is found as part of GERD in the absence of Helicobacter pylori or other causes of gastritis (carditis). The squamous mucosa is the location most likely to show inflammatory changes, such as neutrophils or eosinophils, close to the Z-line, whereas traditional reactive changes in the squamous mucosa are found only in biopsies taken at least 3 cm above the Z-line. Endoscopic criteria for GERD have a morphologic counterpart in capillary congestion and hemorrhage into the papillae, which have largely been ignored by pathologists as secondary to biopsy trauma. A biopsy protocol that maximizes the chances of detecting changes of GERD is suggested. The traditional definition of Barrett's esophagus as requiring 3 cm of glandular mucosa extending into the esophagus is no longer tenable. However, even the concept of short-segment Barrett's esophagus, in which less than 3 cm of intestinalized mucosa is present, often as tongues, is being challenged because random biopsies immediately distal to the Z-line may also show intestinal metaplasia when Barrett's esophagus is unsuspected endoscopically. Moreover, it is difficult or impossible to determine whether these changes indicate the earliest lesion of Barrett's esophagus or intestinal metaplasia in native cardiac mucosa. It is suggested that Barrett's esophagus be redefined as intestinal metaplasia in the lower esophagus. It is presently unclear whether patients with such minimal Barrett's epithelium are at increased risk for adenocarcinoma or require surveillance. Successful therapy for GERD results in healing of disease in squamous mucosa and may result in regression of Barrett's epithelium. In the stomach it may be associated with temporary regression of H. pylori and associated inflammation, migration of H. pylori into the oxyntic mucosa, hypertrophy and hyperplasia of parietal cells, and a variant of fundic gland polyps. Some patients may be at risk for accelerated atrophic gastritis if inflammation is present before therapy. PMID- 8694149 TI - The struggle for power in anaesthetic studies. PMID- 8694148 TI - Intestinal and diffuse gastric cancers arise in a different background of Helicobacter pylori gastritis through different gene involvement. AB - Investigation of extensively sampled nontumor gastric mucosa from 205 early gastric cancers showed Helicobacter pylori colonization in 85% of cases, including 100% of diffuse and 78% (83% in 97 cases with Swiss rolls) of glandular or mixed cancers. Intestinal metaplasia, including its type III variant, was prominent in the mucosa associated with glandular and mixed (but not diffuse) early cancers. Both glandular (usually called "intestinal") and diffuse-type cancers showed admixtures of intestinal and gastric tumor cell phenotypes. Both p53 gene mutations and p53 protein immunostaining were essentially restricted to glandular or mixed cancers and associated dysplastic lesions. Their appearance in the advanced stage of diffuse cancer was partly due to a change of the histologic pattern from glandular to diffuse during progression of some tumors. Loss of laminin, beta I integrin, or zonula adherens junctions was a common finding in both early and advanced diffuse cancer. It is concluded that two main pathways operate in gastric carcinogenesis, both starting from H. pylori gastritis and both leading to phenotypically variable, often mixed gastric/intestinal tumor growth. However, only one of the two pathways involves intestinal metaplasia, its type III variant, p53 gene alteration, and dysplasia to end in glandular cancer. In the other pathway, diffuse cancer apparently arises directly from hyperplastic, sometimes atypical necks of mostly nonmetaplastic gastric glands, through primary involvement of genes affecting cell-cell and cell-matrix junctional proteins. PMID- 8694150 TI - Acid aspiration prophylaxis for emergency Caesarean section. AB - Over a 3.5 year period, 384 patients requiring emergency Caesarean section under general anaesthesia received at random one of six acid aspiration prophylaxis regimens as soon as the decision was made for surgery. In the first phase of the study, sodium citrate administered orally 0.3 M, 30 ml (group C, n = 120) was compared with metoclopramide 10 mg administered intravenously and sodium citrate (group MC, n = 65). In the second phase, all patients received sodium citrate, and either intravenous administration of ranitidine 50 mg (group RC, n = 50), omeprazole 40 mg (group OC, n = 50), ranitidine 50 mg with metoclopramide 10 mg (group RMC, n = 50) or omeprazole 40 mg with metoclopramide 10 mg (group OMC, n = 49). Gastric contents were aspirated using a 16 FG Salem sump tube and acidity measured with a pH meter. Non-parametric tests were used for comparisons. There was no difference in gastric volume or pH between groups C and MC, or among OC, RC, OMC and RMC. After pooling the data, median (range) gastric volume in groups C and MC (55 (0-360) ml) was greater than in groups OMC and RMC (40 (3-270) ml, p < 0.05). Median (range) pH was lower in groups C and MC (4.97 (0.76-6.99)) than in groups OC, RC, OMC and RMC (5.76 (1.11-7.5), p < 0.001). The proportion of patients with pH < 3.5 and volume > 25 ml in the C and MC groups (43/185) was greater than that in the OC, RC, OMC and RMC groups (18/199, p < 0.001). Ranitidine and omeprazole administered intravenously were equally effective adjuncts to sodium citrate in reducing gastric acidity for emergency Caesarean section. Compared with sodium citrate alone, the addition of either ranitidine, omeprazole or metoclopramide alone did not reduce gastric volume while small reductions in gastric volume were seen with the addition of metoclopramide and either ranitidine or omeprazole. PMID- 8694151 TI - Endothelin-1 concentrations and optimisation of arterial oxygenation and venous admixture by selective pulmonary artery infusion of prostaglandin E1 during thoracotomy. AB - In order to improve arterial oxygenation and venous admixture during one lung ventilation, the effect of selective infusion of prostaglandin E1 into the pulmonary artery of the ventilated lung was investigated in 12 adult patients undergoing thoracotomy. Patients' bronchi were intubated with a Mallinckrodt bronchial tube and ventilated with 66% oxygen in air. Cardiopulmonary factors such as systemic and pulmonary arterial pressures, pulmonary vascular resistance, blood gas analyses, cardiac output and airway pressure were measured before and during one-lung ventilation; venous admixture (Qs/Qt) was calculated. Serial blood samples were taken from the pulmonary artery of the ventilated lung for endothelin-1 estimation. One lung ventilation reduced the mean PaO2 from 42.1 (2.3) kPa to 11.8 (1.4) kPa (p < 0.001) and increased Qs/Qt from 10.8 (3.2)% to 39.2 (4.7)% (p < 0.001). Pulmonary vascular resistance also increased from 167 (24) dyne.s.cm-5 to 262 (38) dyne.s.cm-5 (p < 0.05) with a corresponding increase of plasma endothelin-1 (p < 0.05). After 30 min of one lung ventilation, PGE1 was infused continuously into the pulmonary artery of the ventilated lung at a rate which increased incrementally from 0.04-0.10 micrograms.kg-1.min-1. PaO2 increased to 20.7 (2.6) kPa (p < 0.01) and Qs/Qt decreased to 30.6 (3.5)% (p < 0.05). During the infusion, pulmonary vascular resistance reduced to 173 (30) dyne.s.cm-5 (p < 0.01). The plasma endothelin-1 concentration reached a plateau between the end of one lung ventilation (before closing the thorax) and 6 h postoperatively. This correlated inversely with the pre-operative forced expiratory volume in one second (r = -0.68, p < 0.005), declining to normal values 72 h after operation. The selective infusion of PGE1 into the pulmonary artery of the ventilated lung corrected pulmonary vasoconstriction and improved both arterial oxygenation and venous admixture during one lung ventilation for thoracotomy. PMID- 8694152 TI - Patient-controlled alfentanil. Target-controlled infusion for postoperative analgesia. AB - We have compared the opioid effects of a patient-demand, target-controlled infusion of alfentanil (n = 10), with patient-controlled bolus administration of morphine (n = 10) following major spinal surgery in Chinese patients aged from 11 to 67 years. The same general anaesthesia regimen was used in all patients. One group of patients were given intra-operative morphine analgesia followed by postoperative intravenous morphine patient-controlled analgesia, while the other group received an intra-operative target-controlled infusion of alfentanil. Following surgery, the alfentanil group were given control of a handset and were able to increase the target alfentanil plasma level in 5 ng.ml-1 increments with a 2-min lockout interval. If analgesia was not demanded within a 15-min period, the computer reduced the target concentration by 5 ng.ml-1. All patients had continuous pulse oximetry monitoring and hourly recording of pain, sedation, nausea scores and respiratory rate. Patients receiving alfentanil had the target concentration noted hourly and four blood samples taken during the first 24 h for measurement of plasma alfentanil concentrations by high performance liquid chromatography. The alfentanil infusion system was equally effective as an analgesic technique when compared with morphine patient-controlled analgesia. There were no hypoxaemic episodes (oxygen saturation < 94%), no difference in sedation scores and the incidence of nausea (30%) was the same in both groups. There was a significantly (p < 0.001) lower respiratory rate in the alfentanil group compared with patients receiving morphine at, clinically assessed, equianalgesia. The predicted plasma alfentanil concentrations increased rapidly from about 30 ng.ml-1 during the first 4 h to around 100 ng.ml-1 at the end of the 24-h study period. The precision of the target-controlled infusion system was 75.4% and the mean prediction error (bias) 58.1%, suggesting an underestimation of the measured alfentanil concentrations by the alfentanil infusion system in these Chinese patients. PMID- 8694154 TI - Postoperative morbidity following cataract surgery. A comparison of local and general anaesthesia. AB - Two hundred and thirty-one patients were questioned the day following their cataract surgery to ascertain the incidence of postoperative morbidity. One hundred and nineteen patients received local anaesthesia (LA) and 112 received general anaesthesia (GA). There was a significant difference in the incidence of nausea (21% in GA group, 3% in LA group, p < 0.01), sore throat (41% GA group, 3% LA group, p < 0.01), and bruising of the eye (15% GA group, 39% LA group, p < 0.01). There was no significant difference in the incidence of vomiting, headache, double vision, the severity of postoperative pain, or the need for analgesia. The time before the patients drank and ate postoperatively was significantly shorter in the local anaesthetic group (1.3 h and 1.8 h LA group, 4.1 h and 6.7 h GA group respectively, p < 0.01). PMID- 8694153 TI - What changes drug metabolism in critically ill patients--III? Effect of pre existing disease on the metabolism of midazolam. AB - Liver samples were obtained at hepatectomy from patients with end stage alcoholic liver disease (n = 5), primary biliary cirrhosis (n = 5) and chronic rejection needing retransplantation (n = 5). Normal liver material was also obtained from five organ donors. From these samples microsomes were made containing cytochrome P450 3A. The amount of this enzyme was measured by Western immunoblotting and its function assessed by measuring the rate of production of two metabolites of midazolam, 1-hydroxy midazolam and 4-hydroxy midazolam. There was a wide range in all groups for both the expression and function of this enzyme. Liver tissue affected by cirrhotic disease showed greater preservation of enzyme function than that affected by hepatocellular disease. There was a good correlation between the expression of the enzyme and production of the 1-hydroxy metabolite, but a poor correlation between production of the 4-hydroxy metabolite and expression. This poor correlation may reflect the failure to measure the specific enzyme responsible for producing 4-hydroxy midazolam. PMID- 8694155 TI - Dose-response and minimum time to satisfactory intubation conditions after mivacurium in children. AB - We assessed neuromuscular blocking effects and tracheal intubation conditions following mivacurium in 121 anaesthetised children aged 1-10 years. The study was conducted in three parts. Parts 1 and 2 were undertaken during thiopentone alfentanil-nitrous oxide anaesthesia; neuromuscular blockade was evaluated by recording the force of contraction of the adductor pollicis in response to train of-four stimulation at 0.1 Hz. In part 1 the potency of mivacurium was determined in 15 children using a single dose-response technique; in part 2 onset and recovery times were determined in six children following a dose of mivacurium 0.2 mg.kg-1. In part 3 of the study, clinical intubation conditions were assessed in two groups of 50 children whose tracheas were intubated 60 or 90 s after injection of mivacurium 0.2 mg.kg-1 during thiopentone-nitrous oxide anaesthesia. The ED50 and ED95 of mivacurium were 54 and 105 micrograms.kg-1 respectively. The times to 90% and 100% depression of control twitch were 1.3 (0.3) and 1.9 (0.5) min; times to 5%, 25%, 75% and 90% recovery were 6.4 (1.0), 8.4 (1.1), 12.5 (1.1) and 14.4 (1.9) min, respectively. Intubation conditions were rated satisfactory in 33/50 children (0.66, 95% confidence interval 0.51-0.79) at 60 s and in 49/50 children (0.98, 95% confidence interval 0.89-1.0) at 90 s (p = 0.0001). Intubation conditions 90 s after mivacurium 0.2 mg.kg-1 were significantly better than those obtained in 10 patients given anaesthetic drugs alone (p = 0.002). PMID- 8694156 TI - Postanaesthetic shivering in children. AB - This study was designed to assess the incidence, severity and possible aetiological factors of postanaesthetic shivering in children. Three hundred and seventy-six children undergoing general anaesthesia were enrolled in the study. Tympanic membrane temperatures were recorded pre-operatively and every 15 min postoperatively in the recovery room until discharge to the ward. Also recorded were all anaesthetic data including fluid administration, methods of temperature preservation used, sedation scores and shivering (using a four-point scale). The overall incidence of shivering was 14.4%. Multiple regression analysis identified three factors that were significantly related to shivering: age, the administration of atropine and peri-operative temperature changes. Children who shivered rewarmed faster in the recovery room. PMID- 8694157 TI - The addition of tenoxicam to prilocaine for intravenous regional anaesthesia. AB - The analgesic effects of tenoxicam 20 mg added to prilocaine in a standard Bier's block (group 2) was studied in 45 patients who had their Colles' fractures reduced under intravenous regional anaesthesia, and compared both to a control group (group 1), and to a group who received a standard Bier's block combined with the same dose of tenoxicam given intravenously into the contralateral arm (group 3). Patients in group 2 obtained significantly better analgesia than group 1, as judged by a longer time before first additional analgesia was required (p < 0.05), less total analgesic consumption (p < 0.01), and lower pain scores (p < 0.01). These benefits were not obtained by patients in group 3. PMID- 8694158 TI - Gas kinetics during nitrous oxide analgesia for labour. AB - Hypoxaemia may occur after hyperventilation with nitrous oxide during labour. The purpose of this study was to assess whether diffusion hypoxia is a contributory factor. Twenty-four parturients were randomly allocated to receive 50 or 70% nitrous oxide in oxygen. The median nitrous oxide inhalation time per contraction was 58 s and 33 s, respectively. The end-tidal carbon dioxide and the minute ventilation remained unchanged. The end-tidal oxygen concentration was lowest at 120 s, reaching 15.4% in both groups. The oxygen saturation did not differ between the groups with a lowest median value of 96% before the start of nitrous oxide inhalation. Two parturients had episodes of desaturation. Both had low end tidal oxygen concentrations in association with the desaturation but, as the end tidal nitrous oxide concentrations were low, the desaturations could not be attributed to diffusion hypoxia. PMID- 8694159 TI - The importance of the expiratory pause. Comparison of the Mapleson A, C and D breathing systems using a lung model. AB - A physical lung model simulating spontaneous respiration was used to investigate the influence of the respiratory pattern on the efficiency of the Mapleson A, C and D breathing systems. It is shown that the Mapleson A system is always the most efficient breathing system and that its performance is relatively independent of the respiratory pattern. When the expiratory pause is minimal, the Mapleson C system is almost as efficient as the Mapleson A, but becomes ever less efficient as the expiratory pause increases. The Mapleson D system is very inefficient when the expiratory pause is short. With a longer expiratory pause, this system's efficiency approaches that of the Mapleson A. The experimental results are compared with predictions generated by a mathematical model. There is good agreement between the two, validating the mathematics used. PMID- 8694160 TI - Low pressure leakage in anaesthetic machines. Evaluation by positive and negative pressure tests. AB - Positive and negative pressure tests for checking the low pressure section of 36 anaesthetic machines in order to detect gas leaks were prospectively compared. The low pressure section was checked by the soap bubble test as a 'gold standard'. The leakage rate was 86.1%. The sensitivity and specificity of the positive pressure tests were 92% and 100% respectively, whilst the sensitivity and specificity of the negative pressure test were both 100%. However, seven machines revealed a leak which was only detected by the positive pressure test: this problem arose through defects in the emergency oxygen flush devices which allowed oxygen to leak around the valve even though it was in the 'off' position. This might reduce the specificity of the negative pressure test to 41.7%. For security, both tests should be carried out in series; the positive pressure test followed by the negative pressure test. The possibility of gaseous leakage around the oxygen flush device is not generally recognised. This study emphasises the need for skilled servicing of anaesthetic machines on a regular basis. PMID- 8694162 TI - Esmolol aids extubation in intensive care patient with ischaemic pulmonary oedema. AB - A 49-year-old man with a history of ischaemic heart disease failed successful tracheal extubation on four consecutive occasions following emergency surgery because of the development of acute pulmonary oedema. Attenuation of the cardiovascular responses to tracheal tube removal by pretreatment with an intravenous infusion of esmolol hydrochloride allowed successful extubation of the patient to be achieved. PMID- 8694161 TI - Immunomodulation: an important concept in modern anaesthesia. AB - This review summarises evidence for immunomodulatory effect of drugs administered peri-operatively. The clinical significance of the balance of pro- and anti inflammatory cytokines may be seen in certain disease states, for example, meningococcal meningitis and Lyme arthritis. This balance may be altered peri operatively. Traditionally, these changes are considered to be due to the stress response of surgery, the response to cardiopulmonary bypass, or endotoxaemia. This review presents in vitro evidence suggesting that drugs modulating this cytokine balance include non-steroidal anti-inflammatory agents, phosphodiesterase inhibitors and opioids, acting through effects on intracellular cyclic nucleotide messenger systems. An important consequence of the pro inflammatory cytokine activity is increased adhesion of neutrophils. Aspects of this process may be inhibited by avoiding low blood flow states, by reducing adhesion molecule expression (for example by use of pentoxifylline), or by use of negatively charged anions such as heparin. Neutrophil activity is generally depressed by intravenous anaesthetic induction agents, but is enhanced by opioids. Natural killer cell activity, which is involved in immunity against tumour cells and virally infected cells is transiently depressed by volatile anaesthetic agents and opioids. In contrast catecholamines enhance natural killer cell activity. Whereas decrease in immunoglobulin levels occur peri-operatively, this is not thought to be as a result of drugs at clinically used concentrations but rather due to haemodilution. PMID- 8694163 TI - Anaesthesia for Cockayne syndrome. Three case reports. AB - Cockayne syndrome is a rare autosomal recessive condition producing a dwarfed, mentally retarded infant or child. Problems with airway management and an increased risk of gastric aspiration are the main anaesthetic concerns. Anaesthetics given to three patients with Cockayne syndrome are described. In two of these, tracheal intubation was difficult and the use of a laryngeal mask airway proved invaluable. PMID- 8694164 TI - Flumazenil: an unreliable antagonist in baclofen overdose. AB - We report a case of inadvertent overdose of baclofen given intrathecally resulting in coma. This was unresponsive to flumazenil and required supportive intensive therapy. With the increasing use of baclofen intrathecally for spasticity and its wide interpatient dose variability, there is a need to find a safe antagonist to baclofen for routine medical use. PMID- 8694166 TI - Does post-laparoscopy pain relate to residual carbon dioxide? AB - We studied 20 day case gynaecological laparoscopy patients, who had an erect chest X ray taken before discharge. Patients were telephoned the next day for a semi-structured interview. Particular note was made of shoulder tip pain and pain relieved by changing posture. The X ray was analysed for measurements of the length of arc and height of the gas bubble under each hemi-diaphragm, from which an estimation of bubble volume was also made. We found statistically significant correlations between both the length of arc (p = 0.005) and volume of gas bubble (p = 0.008) on the right side, with the pain score. Residual gas can be a prominent cause of post-laparoscopy pain. PMID- 8694165 TI - The effect of syntocinon on blood loss during first trimester suction curettage. AB - We have studied 64 pregnant women (9 weeks gestation and greater undergoing elective vaginal termination of pregnancy). They were allocated randomly to one of two groups to receive either 1 ml (10 units) of syntocinon or 1 ml of saline (placebo) after cervical dilatation. Anaesthesia was standardised and surgery was performed by a single blinded gynaecologist, who assessed the size of the uterus and graded uterine contractility. All patients received a Cervagem vaginal suppository 70-270 min before surgery. The volume of blood loss was calculated colorimetrically and found to be less than 100 ml in all patients. The median blood loss in the syntocinon group (n = 30) was 17.6 ml, (range 6.1-72.7) and was significantly less than that in the placebo group (n = 34), median blood loss 24.5 ml, (range 6.7-94.3) (p = 0.02). Six patients in the saline group had unsatisfactory uterine contraction compared with none in the syntocinon group (p = 0.025). PMID- 8694167 TI - The haemodynamic effects of propofol in combination with ephedrine. AB - Forty ASA1 patients presenting for minor gynaecological surgery were randomly allocated into four study groups to compare the haemodynamic effects of adding different doses of ephedrine to an induction dose of propofol. Heart rate, oxygen saturation and non-invasive arterial blood pressure were monitored before and for 5 min after induction. In those patients who received propofol alone, there was a significant decrease in both systolic (p < 0.001) and diastolic (p = 0.003) blood pressure. The addition of ephedrine 15 mg or 20 mg to 1% propofol 20 ml was very effective in maintaining blood pressure at pre-induction values. There was a statistically significant increase from baseline in systolic (p = 0.004) and diastolic (p = 0.031) pressures, but this only occurred at 1 min postinduction. The addition of ephedrine 10 mg was insufficient to prevent hypotension. There was no significant effect on either heart rate or oxygen saturation in any group. We conclude that ephedrine may be safely employed to reduce the degree of hypotension during induction with propofol in this patient group. PMID- 8694168 TI - Akathisia following low-dose droperidol for antiemesis in day-case patients. AB - Akathisia has been described following the use of droperidol for antiemetic prophylaxis. In a double-blind, placebo-controlled study, we investigated both the incidence of akathisia and its relationship to the dose of droperidol (0.5 or 1 mg). One hundred and twenty healthy women undergoing day-case gynaecological surgery were anaesthetised with propofol, fentanyl, isoflurane and droperidol according to group. Patients were assessed by structured telephone interview at 24 h. There was an increasing incidence of both restlessness (p = 0.01) and unpleasant restlessness (p = 0.02) between the groups on Chi-squared testing. Compared to the control group, those women given droperidol 1 mg suffered more restlessness (p = 0.001) and unpleasant restlessness (p < 0.01). No statistical difference could be demonstrated between the two droperidol groups. We conclude that droperidol may commonly cause akathisia and may not, therefore, be an appropriate prophylactic antiemetic for day-case anaesthesia. PMID- 8694169 TI - Topical ibuprofen for skin analgesia prior to venepuncture. AB - The analgesic effect of topical ibuprofen was investigated in ten volunteers. There were no significant differences in visual analogue scale pain scores for pinprick after 15 and 60 min of application of ibuprofen, placebo and EMLA cream. Comparison of visual analogue scale scores for venous cannulation after similar durations of ibuprofen and EMLA creams found significantly (p < 0.014) lower scores for EMLA at 60 min. We do not consider ibuprofen cream to be clinically useful for venous cannulation. PMID- 8694170 TI - The effect of temperature upon pain during injection of propofol. AB - Propofol has been shown to cause pain on injection. This study investigated the effect of warming propofol to 37 degrees C on the pain of intravenous injection. One hundred and one women on outpatient gynaecology lists were allocated to receive propofol either at room temperature or at 37 degrees C. Warming propofol decreased the incidence of pain on injection by 37% (p < 0.001), and also decreased the severity of pain reported by patients (p < 0.001). We conclude that warming propofol to 37 degrees C provides a simple and safe method of reducing the incidence of pain on injection without the addition of other agents. PMID- 8694171 TI - Pre-operative hypertension; do we postpone surgery too readily? PMID- 8694172 TI - SCOTI device for detection of tracheal intubation. PMID- 8694173 TI - SCOTI device for detection of tracheal intubation. PMID- 8694174 TI - SCOTI device for detection of tracheal intubation. PMID- 8694175 TI - Peri-operative management of diabetic patients. PMID- 8694176 TI - McCoy levering laryngoscope. PMID- 8694177 TI - Erythromycin as a prokinetic agent in children. PMID- 8694178 TI - Is rectal administration of propofol effective? PMID- 8694179 TI - Re-establishment of paralysis after recovery from mivacurium block. PMID- 8694180 TI - Tetanus and rocuronium in the intensive care unit. PMID- 8694181 TI - Similarity of drug packaging. PMID- 8694182 TI - Bad backs and anaesthetists. PMID- 8694183 TI - Endotrol tube for blind nasotracheal intubation. PMID- 8694184 TI - Rotameter sequence. PMID- 8694185 TI - Thyroid function in the critically ill. PMID- 8694186 TI - Anaesthetic rooms--the debate continues. PMID- 8694187 TI - Adaptation of an intravenous cannula for paediatric regional anaesthesia. PMID- 8694188 TI - Compartment syndrome following prolonged positioning in the lithotomy position. PMID- 8694189 TI - Teaching fibreoptic nasotracheal intubation via the laryngeal mask airway. PMID- 8694190 TI - Risks of cross infection associated with anaesthesia; cleaning procedures for laryngoscopes--a need for Association guidelines? PMID- 8694191 TI - Through the needle approach for difficult epidurals. PMID- 8694192 TI - Is caudal anaesthesia a safe-choice for infant hernia repair? PMID- 8694193 TI - Nasal packing forceps as a part of anaesthesia armamentarium. PMID- 8694194 TI - Hidden sharps. PMID- 8694195 TI - The effect of hyaluronidase on peribulbar block. PMID- 8694196 TI - Untoward incident with PCA extension set. PMID- 8694197 TI - Hub disconnection and migration of a tunnelled central line. PMID- 8694198 TI - Is propofol infusion better than inhalational anaesthesia for paediatric MRI? PMID- 8694199 TI - The accuracy of references in journal articles. PMID- 8694200 TI - Stress. PMID- 8694201 TI - Patients' experiences of patient-controlled analgesia. AB - We examined patients' experiences of patient-controlled analgesia by the use of semistructured interviews in 26 patients shortly after discontinuation of the device. The options expressed by the patients were examined qualitatively to identify recurring themes in their experience of patient-controlled analgesia. The areas of interest were analgesia, factors influencing whether the patient pressed the button or not, whether they felt in control and side effects. Negative as well as the expected positive evaluations were found. The negative evaluations reflected problems with nausea and vomiting and inadequate analgesia. No clear strategy for pressing, or not pressing, the button emerged and the principle of control by the patient over their pain relief was not considered important. PMID- 8694202 TI - The influence of volume therapy and pentoxifylline infusion on circulating adhesion molecules in trauma patients. AB - Adhesion molecules appear to play a pivotal role in tissue damage secondary to the inflammatory process. Besides neutrophil- and endothelial-bound adhesion molecules, soluble forms have been detected in the circulating blood. They seem to be good markers of endothelial damage, but they may also have other biological functions. Plasma concentrations of soluble adhesion molecules (endothelial leucocyte adhesion molecules (sELAM-1), intercellular adhesion molecule-1 (sICAM 1), vascular cell adhesion molecule-1 (sVCAM-1), and granule membrane protein 140 (sGMP-140) were serially measured over 5 days by enzyme-linked immunosorbent assays (ELISA) in 45 consecutive trauma patients. These received, by random allocation, only either hydroxyethylstarch solution 10% (mean molecular weight 200,000 daltons) (n = 15) or human albumin 20% (n = 15) for volume therapy. Another 15 patients without defined volume therapy received pentoxifylline continuously (1.2 mg.kg-1.h-1). Measurements were carried out on the day of admission to the intensive care unit (baseline) and during the next 5 days. At baseline, plasma concentrations of all adhesion molecules were similar in all groups. In the hydroxyethyl starch group, sELAM-1 and sICAM-1 concentrations decreased significantly (p < 0.05) reaching normal values during the study period whereas the mean (SD) values increased in the pentoxifylline group (sELAM-1: 71.1 (16.7) to 91.6 (17.8) ng.ml-1) and the albumin group (sICAM-1: 400 (81) to 749 (101) ng.ml-1) (p < 0.05). sVCAM-1 increased outside the normal range only in the human albumin group (to 760 +/- 69 ng.ml-1) (p < 0.05). sGMP-140 plasma concentration increased only in those receiving albumin (432 (85) to 550 (93) ng.ml-1) and this was significantly different to the other groups (p < 0.05). None of the other haemodynamic or laboratory factors could be correlated with plasma concentrations of the adhesion molecules. We conclude that volume therapy with hydroxyethyl starch resulted in a decrease in circulating adhesion molecules in our trauma patients. In contrast, volume therapy with albumin did not exert this effect. Continuous infusion of pentoxifylline did not have a beneficial modulating action on circulating adhesion molecules. PMID- 8694203 TI - Induction of anaesthesia with midazolam and a target-controlled propofol infusion. AB - Eighty patients premedicated with temazepam were allocated randomly to receive an intravenous bolus of midazolam (either 0, 1, 2 or 4 mg) 4 min before a propofol infusion using a system designed to maintain a target blood concentration of 3 micrograms.ml-1. Anaesthesia was successfully induced within 3 min of starting the infusion in 45% of patients receiving no midazolam. This rose to 70%, 85% and 95% in the groups receiving 1, 2 and 4 mg midazolam boluses respectively (p < 0.005). There were reductions in arterial blood pressure 3 min after starting the infusion in all groups but there was no significant difference between the groups. Apnoea was rare. Small doses of midazolam usefully enhance the effect of a propofol infusion administered at a dose which by itself would not induce anaesthesia in a majority of patients. PMID- 8694204 TI - A comparison of the induction characteristics of sevoflurane and halothane in children. AB - The induction characteristics of sevoflurane and halothane were compared in 81 children aged 6 months to 6 years. The mean time taken to achieve loss of eyelash reflex was significantly shorter with sevoflurane than with halothane (sevoflurane, mean time (SD) 1 min 41 s (35 s), halothane, mean time (SD) 2 min 17 s (43 s), t = 4.11, p = < 0.01). The mean time taken to complete induction (to achieve steady spontaneous ventilation and small pupils with central gaze) was also shorter in children induced with sevoflurane (sevoflurane, mean time (SD) 3 min 58 s (1 min 8 s), halothane, mean time (SD) 4 min 50 s, (1 min 27 s), t = 2.29, p = 0.027). Effects on heart rate, blood pressure and oxygen saturation during induction were similar for both agents. There were no major complications during induction with either halothane or sevoflurane. PMID- 8694206 TI - A comparison of the effects of isoflurane and desflurane on the neuromuscular effects of mivacurium. AB - The effects of 1 MAC of desflurane and isoflurane (in 66% nitrous oxide) on the potency and duration of action of mivacurium were studied in 80 patients. The ED95 of mivacurium was 86 micrograms.kg-1 (74-100) and 88 micrograms.kg-1 (76 103) (mean and 95% confidence intervals) during anaesthesia with desflurane and isoflurane respectively. The onset and duration of recovery to 25, 75 and 90% of T1 (first response in the TOF) of 200 micrograms.kg-1 of mivacurium were 1.4 (0.3) and 1.5 (0.3) min (mean and SD), 22 (4.9) and 19 (4.0), 29 (6.6) and 26 (5.8), and 32 (7.3) and 29 (6.6) min respectively. There was no significant difference in any of the variables between desflurane and isoflurane. It is concluded that the neuromuscular effects of mivacurium are similar during anaesthesia with 1 MAC of desflurane and isoflurane. PMID- 8694205 TI - A comparison of the recovery characteristics of sevoflurane and halothane in children. AB - The recovery characteristics of sevoflurane and halothane anaesthesia were compared in 40 children aged 6 months to 6 years undergoing day case surgery. The mean time taken to open eyes after surgery had ended was appreciably and significantly shorter after sevoflurane than after halothane (sevoflurane, mean time (SD) 7 min 52 s (5 min 46 s), halothane, mean time (SD) 15 min 50 s (9 min 2 s), t = 3.32, p = 0.002). The time taken to be ready for discharge from the recovery unit to the ward was also significantly shorter after sevoflurane than after halothane (sevoflurane, mean time (SD) 12 min 46 s (4 min 11 s), halothane, mean time (SD) 19 min 13 s (9 min 48 s), t = 2.7, p < 0.01). However, more children were in pain and given analgesia after sevoflurane (p < 0.01) and the mean time to reach the criteria for discharge home was similar in both groups (sevoflurane, mean time (SD) 2 h 9 min (17 min), halothane, mean time (SD) 2 h 4 min (8 min)). There were no major complications in either group. PMID- 8694207 TI - Creatinine and urea clearance during continuous veno-venous haemofiltration in critically ill patients. AB - Urea and creatinine clearances achieved using continuous veno-venous haemofiltration were calculated in 16 critically ill patients, during 50 episodes of filtration. The effects of filter life and the volume of ultrafiltrate on these clearances were also evaluated. Clearances were calculated from urea and creatinine concentrations in blood and ultrafiltrate and the volume of ultrafiltrate produced. The overall mean (SD) urea clearance was 26.6 (6.0) ml.min-1 and the overall creatinine clearance was 30.1 (6.3) ml.min-1. The mean (SD) ultrafiltrate production was 29.6 (5.9) ml.min-1. Creatinine clearance was significantly lower in filters that failed within 24 h (filters < 24 h 27.5 (6.3) ml.min-1; filters > 24 h 32.2 (5.5) ml.min-1). The clearance of both solutes increased with increasing ultrafiltrate volume (p < 0.001). We conclude that satisfactory clearance of urea and creatinine can be achieved using continuous veno-venous haemofiltration. Increases in ultrafiltrate production lead to similar increases in urea and creatinine clearance. Prolongation of filter life may improve creatinine clearance. PMID- 8694208 TI - Infusions of subhypnotic doses of propofol for the prevention of postoperative nausea and vomiting. AB - We studied the antiemetic effects of a low dose infusion of propofol for 24 h after major gynaecological surgery in a double-blind, randomised, controlled trial. Fifty women of ASA physical status 1 or 2 undergoing major gynaecological surgery received an infusion of 1% propofol or intralipid at 0.1 ml.kg-1.h-1 for 24 h after surgery. Pain was managed using morphine delivered by a patient controlled analgesia pump. The degree of postoperative nausea and vomiting was assessed by the nurses using a four-point ordinal scale, by the patients using a visual analogue scale and by the amount of rescue antiemetic given by the nurses. There were no differences between the two groups in any of the measures of postoperative nausea and vomiting during the first 48 h after surgery. Postoperative nausea and vomiting in the control group was less on the second day compared with the first postoperative day, but not in the propofol group. There were no side effects from the propofol infusion. PMID- 8694209 TI - The delivery of oxygen by a venturi T piece. AB - We have evaluated the performance of the Intersurgical 40% Oxygen Recovery T-Kit in ten healthy volunteers. Inspired oxygen and end-tidal carbon dioxide concentrations were measured during normal respiration and with variations in respiratory rate and depth. The performance of the device was then studied after modifications to the inspiratory limb, the expiratory limb and the arrangement of the attachments to the T piece. The standard arrangement of the T piece was associated with inadequate inspired oxygen concentration (31.9 +/- 0.6%), independent of respiratory rate and depth. All three modifications increased the inspired oxygen concentration, the longer expiratory limb to 34.6% (p < 0.01) and the altered T piece arrangement to 37.3% (p < 0.01). The highest inspired oxygen concentration of 40.3% (p < 0.01) was obtained by increasing the length of the inspiratory limb. PMID- 8694210 TI - Evaluation of the Upsherscope. A new rigid fibrescope. AB - A new, rigid intubating fibrescope, the Upsherscope, was evaluated in clinical practice. Intubation was attempted in 200 adult patients and was successful in 191, with a median intubation time of 38 s, range 14-154 s. Intubation was straightforward in just under half of the patients. Difficulties were encountered in picking up the epiglottis, in passing the tracheal tube between the vocal cords and with secretions interfering with the view. In two patients known to be difficult to intubate, the Upsherscope was successful in one patient using an awake technique and failed in the other. PMID- 8694211 TI - Anaesthesia for cardioversion. AB - Cardioversion is a minor procedure requiring sedation and analgesia. However, it is often performed out-of-hours in remote sites by inexperienced anaesthetists. An understanding is required both of the pathophysiology underlying cardiac arrhythmias and of the technical side of defibrillation equipment, including electrical safety. Patients should have their coagulation status and electrolyte balance checked prior to the procedure to reduce the likelihood of complications. Almost all the available anaesthetic agents have been used for cardioversion in the past, with varying degrees of success. The anaesthetic agent chosen for patients undergoing cardioversion must provide analgesia and sedation, cause the least cardiovascular compromise possible and still enable rapid recovery. Propofol may be the closest anaesthetic agent to this ideal currently available, although careful titration of any agent chosen is also important. Cardioversion may be performed as an emergency, including in the pregnant patient, providing safe anaesthetic practice is followed. PMID- 8694212 TI - The practice of anaesthesia--a stressor for the middle-aged? AB - Surveys conducted in the United Kingdom over the last few years have revealed decreased job satisfaction and increased anxiety and depression in both hospital specialists and general practitioners. Anaesthesia is perceived to be a stressful specialty and there is evidence, albeit patchy, that certain stress-associated conditions are more common in anaesthetists. The 'middle years' seem to be a danger period. The analogy between the work of anaesthetists and airline pilots is often drawn and the principles underlying the assessment and maintenance of pilot competence could be adopted in anaesthesia. While outcome studies are numerous much less attention has been paid to the structure and process of anaesthetic practice. Models for studying these aspects have been developed for investigating stress in general practitioners and doctors in training. Even minor degrees of professional impairment may place patients at risk and an investigation into the effects of the specialty on those who practise it is justified. PMID- 8694213 TI - Anaesthetic management in maple syrup urine disease. AB - Two children with maple syrup urine disease undergoing emergency and elective surgery are reported. The administration of ketamine to a 12-month-old boy without neurological problems and propofol infusion to a 5-year-old girl with a history of convulsions, was uneventful. We believe that a full knowledge of the pathophysiology of maple syrup urine disease and potential peri-operative problems associated with the disease are essential, so that patients are not subjected to unnecessary risks. PMID- 8694214 TI - Use of liposome-associated bupivacaine in a cancer pain syndrome. AB - Bupivacaine 0.25% encapsulated by multilamellar liposomes was administered epidurally to a patient suffering pain associated with lung cancer and the effect compared with a plain bupivacaine solution of the same concentration. Complete analgesia was produced for 4 h with the plain solution and 11 h with the liposomal formulation. No motor blockade or haemodynamic instability was observed with the liposome-associated bupivacaine. PMID- 8694215 TI - Arnold-chiari malformation in pregnancy. AB - We report the case of a 30-year-old pregnant woman with an Arnold-Chiari malformation, who presented with severe pregnancy-induced hypertension at 30 weeks gestation. She was known to have had a difficult tracheal intubation during a previous general anaesthetic. Caesarean section was performed under an incremental epidural anaesthetic block. PMID- 8694216 TI - Anaesthesia for electroconvulsive therapy. Personnel and facilities. AB - In order to compare the anaesthetic staffing and facilities provided for patients undergoing electroconvulsive therapy with those provided for patients undergoing elective cystoscopy, a confidential telephone enquiry was conducted. An anaesthetist in each of the 40 hospitals where electroconvulsive therapy is performed in three Health Regions chosen at random was questioned. The results show that a high standard of care is provided for patients undergoing elective cystoscopy in terms of pre-operative assessment, anaesthetic assistance, intra operative monitoring and postoperative recovery facilities. The standards of care and of facilities for patients undergoing electroconvulsive therapy are substantially inferior and commonly fall short of accepted national guidelines. PMID- 8694217 TI - The effect of pre-incisional infiltration with lignocaine on postoperative pain after molar teeth extraction under general anaesthesia. AB - In a double-blind, placebo-controlled investigation, we studied the effects of pre-operative inferior alveolar nerve blockade and local anaesthetic intra-oral infiltration upon postoperative pain following third molar teeth extraction under general anaesthesia. Thirty six patients (12 male), mean (range) age 25.7 (18-40) years received an injection of 2% lignocaine 2 ml with 1:200,000 adrenaline around the inferior alveolar nerve and tissues adjacent to the third molar tooth on one side and of normal saline 2 ml in a similar fashion to the other side. We measured the pain on each side of the mandible on the 1st, 4th and 11th days after surgery using a visual analogue scale. The visual analogue pain score on the lignocaine and saline sides were 25/100 and 26/100 on day 1, 23/100 and 22/100 on day 4 and 0/100 and 1/100 on day 11. This study has a power of 80% to detect differences at the 5% level of significance of 11/100 on days 1 and 4 and 7/100 on day 11. We found no significant difference in the visual analogue scores between the lignocaine side and the saline side at any stage after the procedure. PMID- 8694218 TI - Postoperative pain in children. AB - An audit project was designed to assess and improve the provision of postoperative analgesia in a children's hospital. Pain assessment for all children and analgesia standards for our institution were introduced prior to data collection. Data were collected on consecutive samples of 316 and 325 children undergoing surgery as inpatients during 10-week periods. Change was initiated between the two periods in response to our findings; our action plan involved education, changes to documentation, the widespread use of diclofenac in children over 2 years of age and recommendations for the prescription of analgesia. The initial prescription of analgesia increased from 95% to 98% (p = 0.019), administration of analgesia to children experiencing bad or severe pain increased from 57% to 71% (p = 0.032) and the number of children experiencing severe pain reduced from 17% to 11% (p = 0.050). Application of audit, by a clinical nurse specialist, enabled us to achieve and demonstrate improvements in the prescription, administration and effectiveness of postoperative analgesia. PMID- 8694219 TI - Analgesia for day surgery. Evaluation of the effect of diclofenac given before or after surgery with or without bupivacaine infiltration. AB - One hundred patients undergoing breast lump excision using a standard anaesthetic technique in the Day Care Unit were randomly divided into five groups. Groups A and B received either saline or diclofenac in a double-blind fashion before and at the end of the procedure, with both groups receiving 10 ml of 0.5% bupivacaine infiltration at the end. Groups C and D also received saline or diclofenac before and after surgery but had no bupivacaine infiltration at the end. Group E did not receive any injections but had bupivacaine infiltration at the end of surgery. In the postoperative period, pain was assessed by a visual analogue scale at 30 min intervals until discharge. All patients were requested to complete a pain relief questionnaire over the 48 h following surgery. There were highly significant differences between those who received bupivacaine and those who did not in the visual analogue scale scores at 30 min (p < 0.001), 60 min (p < 0.001), 120 min postoperatively (p = 0.02) and at discharge (p = 0.03). Pain scores were lower in those who received bupivacaine and they were less likely to request rescue medication, although this did not reach significance (p = 0.07). There were significant differences between the groups who received bupivacaine and diclofenac injection and those who received bupivacaine alone for visual analogue scale scores at 60 min following surgery (p = 0.05) and at 48 h (p = 0.002). Pain relief was better in those patients who received both bupivacaine and diclofenac injection. Although not significant (p = 0.22), fewer patients required rescue medication when diclofenac was given before surgery (10%) rather than after surgery (22.5%). Fewer patients had a fair amount or a great deal of pain in the 48 h following surgery when diclofenac was injected before (7.5%) rather than after surgery (12.5%). The mean number of oral analgesics taken in the 48 h after surgery was also lower in those patients who had the diclofenac before the surgery rather than after. PMID- 8694220 TI - Insertion methods of the laryngeal mask airway. A survey of current practice in Wales. AB - The efficacy of the laryngeal mask is widely accepted, but there is a lack of consensus on the best insertion method and on the use of the mask for certain surgical procedures. We sent a questionnaire to all anaesthetists in Wales to discover the frequency of use of the laryngeal mask and the preferred insertion method. The questionnaire also enquired about the use of the laryngeal mask during anaesthesia for laparoscopic clip sterilisation. Replies were received from 125 consultants (89% of those circulated) and 122 non-consultants (69%). The insertion method described in the manufacturer's instruction manual was preferred by 30% of consultants and 34% of the others. The next most popular option was insertion of the mask with the cuff partially inflated. Twenty-three per cent of consultants and 34% of non-consultants were prepared to use the laryngeal mask during anaesthesia for laparoscopic clip sterilisation. Although the insertion technique described in the instruction manual is the most widely employed, a large number of alternative methods are frequently used. PMID- 8694221 TI - Drug labelling--a place for colour coding? PMID- 8694222 TI - Mistaken identity of syringe labels viewed through coloured eye protection glasses. PMID- 8694223 TI - Classic paper: a fibreoptic endoscope used for tracheal intubation. PMID- 8694224 TI - Airway protection with the new laryngeal mask prototype. PMID- 8694225 TI - Pressure in laryngeal mask airway cuffs. PMID- 8694226 TI - Potential hazard from incorrect cleaning of laryngeal mask airway. PMID- 8694227 TI - A means of stabilising laryngeal mask airways during dental procedures. PMID- 8694228 TI - The laryngeal mask airway--another trick. PMID- 8694229 TI - A complication of percutaneous dilatational tracheostomy: mediastinal emphysema. PMID- 8694230 TI - Filters and Ayre's T-piece. PMID- 8694231 TI - The Hayek Oscillator. PMID- 8694232 TI - Yet another aid to detect oesophageal intubation. PMID- 8694233 TI - Training, education, risk management and the trainee anaesthetist. PMID- 8694234 TI - Departmental database for training. PMID- 8694235 TI - Defective anti-reflux valve. PMID- 8694236 TI - Back pain--must be the anaesthetic! PMID- 8694237 TI - Anaesthetic assistance during electroconvulsive therapy. PMID- 8694238 TI - Standard error of the mean or standard deviation--does it matter? PMID- 8694239 TI - 'More than meets the eye'. PMID- 8694240 TI - The 'spaghetti' problem. PMID- 8694241 TI - Cerebral oximetry: a useful monitor during carotid artery surgery. PMID- 8694242 TI - Lignocaine metabolism as an assessment of liver dysfunction. PMID- 8694243 TI - Reliability of monitoring. PMID- 8694244 TI - High-resolution matrix-assisted laser desorption/ionization in a linear time-of flight mass spectrometer. AB - A time-lag focusing method is developed for the improvement of mass resolution in a linear time-of-flight mass spectrometer for matrix-assisted laser desorption/ionization (MALDI). In this technique, the ions generated by the MALDI process are extracted by a pulsed voltage. A short time delay (280 ns) is inserted in between the laser desorption/ionization event and the ion extraction. The region between the repeller and extraction grid is field-free during the delay. The time-lag extraction allows the ions generated in the region between the repeller and the extraction grid to separate according to their velocity (energy). Application, to the repeller, of the appropriate pulse voltage provides the energy correction necessary to simultaneously detect all ions of the same mass/charge regardless of their initial energy, resulting in improved mass resolution. It is demonstrated that mass resolution in the range of 3000-6000 fwhm can be obtained. With this mass resolution, isotopically resolved mass spectra are observed for peptides with masses up to 3000 Da. For proteins, such as bovine insulin, cytochrome c, and apomyoglobin, resolution in the range of 800 1000 fwhm is observed with a mass measurement accuracy better than 0.01%. PMID- 8694245 TI - Matrix-assisted laser desorption ionization of neutral clusters composed of matrix and analyte molecules. AB - A new version of the matrix-assisted laser desorption ionization experiment is described. Composed clusters created by laser desorption of a mixture of analyte and matrix material were injected into a supersonic jet and then analyzed by multiphoton ionization time-of-flight mass spectrometry. Selective two-photon ionization of matrix molecules of a cluster component caused their dissociation, followed by intercluster proton or cation transfer to an analyte that is transparent for the wavelength of ionizing radiation. The intercluster charge transfer reactions are the only pathway for analyte ion formation under these conditions, as can be concluded from analysis of the mass spectra of a variety of substances. PMID- 8694246 TI - Mass resolution improvement by incorporation of pulsed ion extraction in a matrix assisted laser desorption/ionization linear time-of-flight mass spectrometer. AB - A linear time-of-flight mass spectrometer has been modified to incorporate pulsed ion extraction of matrix-assisted laser desorption/ionization (MALDI) generated ions. A unique aspect of the experiments presented is the combination of pulsed extraction with very high source potentials (up to 25 kV) which allows improved mass resolution while maintaining excellent sensitivity for the large m/z ions generated by the MALDI technique. Mass resolution in excess of 1000 (fwhm) is demonstrated for cytochrome c (12,361.1 Da) with the pulsed ion extraction linear time-of-flight mass spectrometer described. The influence on obtainable mass resolution of experimental variables such as delay time between laser ionization and ion extraction, amplitude of the pulsed voltage employed, and the source bias voltage are presented. It is shown that, for any given source potential, the optimum pulsed extraction voltage is a linear function of the mass of the analyte. This is consistent with the observation that the initial ion velocity distribution for MALDI-generated ions is independent of mass. PMID- 8694247 TI - Chiral separation and detection of terbutaline and ephedrine by capillary electrophoresis coupled with ion spray mass spectrometry. AB - The enantiomers of both terbutaline and ephedrine were separated by capillary electrophoresis using electrolyte solutions of heptakis(2,6-di-O-methyl)-beta cyclodextrin in low pH buffers. The analytes were detected by ion spray mass spectrometry using selected ion monitoring or by selected reaction monitoring in the positive ion mode. Both the free drug enantiomers and the noncovalent enantiomer-cyclodextrin inclusion complexes for terbutaline can be detected simultaneously using this method. The feasibility of using CE/MS for chiral purity determination is demonstrated. In addition, a comparison of UV detection versus mass spectrometry detection for a spiked urine sample is included to demonstrate the selectivity and sensitivity advantages of the mass spectrometer as a CE detector. PMID- 8694248 TI - Effect of micelles and mixed micelles on efficiency and selectivity of antibiotic based capillary electrophoretic enantioseparations. AB - Vancomycin (an oligophenolic, glycopeptide, macrocyclic antibiotic) has been shown to be a superb chiral selector for anionic and neutral compounds. It was found that adding sodium dodecyl sulfate to the run buffer increased efficiency by over 1 order of magnitude, decreased analysis times, and reversed the elution order of the enantiomers. This allows for control of the retention order as well as the resolution of enantiomers in complex mixtures in a single run. A mechanism is proposed which explains all of the observed effects and is verified experimentally. Since vancomycin is present in both the micelle and in free solution, previously proposed micelle-selector models are, at best, limiting cases. A general equation is derived which can be used to describe all possible interactions, including those with the capillary wall, if needed. Also, it is shown that electrophoretic mobilities and not migration times must be used to calculate binding constants of a solute to the micelle, the chiral selector, or both. Furthermore, it is shown that a neutral marker molecule cannot be used to accurately correct mobilities that have been altered due to changes in solution viscosity. While this work utilizes the practical vancomycin-micelle system, the general conclusions and theory apply to most other analogous CE systems as well. PMID- 8694249 TI - Thermodynamics of solute partitioning into immobilized artificial membranes. AB - The solute retention mechanism on immobilized artificial membranes (IAMs) was studied using three different IAM.PC phases. IAMs were prepared by immobilizing either single-chain or double-chain phosphatidylcholine (PC) ligands. Solute affinity for the single-chain IAM.PC columns (with a ligand density of 127 mumol of PC/g of IAM) was 3-fold lower compared to solute affinity on the double-chain IAM.PC column (with a ligand density of 98 mumol of PC/g of IAM). This suggests that the solute retention on IAMs is dominated by a solute partitioning mechanism. Temperature-dependent studies indicated that the thermodynamics of solute partitioning is similar on both the single-chain and double-chain IAM.PC surfaces. For a set of phenol derivatives, the partitioning into IAM.PC surfaces is both enthalpy and entropy driven. For beta-blockers, the partitioning into IAM.PC surfaces is entropy driven. The free energy of solute partitioning into IAMs correlates very well with the free energy of solute partitioning into liposomes. PMID- 8694250 TI - High-performance collision-induced dissociation of peptide ions formed by matrix assisted laser desorption/ionization in a quadrupole ion trap mass spectrometer. AB - A modified ion trap detector has been utilized to obtain high-performance collision-induced dissociation (CID) mass spectra of peptide ions formed by matrix-assisted laser desorption/ionization (MALDI). MALDI ions are trapped while increasing the fundamental radio frequency field, obviating the need for elevated helium gas pressures. Molecular ion isotopic clusters are then isolated by a reverse-forward-reverse scan sequence. A single species within the isotopic cluster (generally the monoisotopic mass) is then selected for activation. Finally, modulation of the amplitude of the resonant excitation voltage on the end-cap electrodes, used previously to improve mass calibration in normal mass spectra, is now utilized to provide high mass accuracy for the product ions. The CID mass spectra of several protonated and sodium-cationized peptides are presented and are often characterized by a series of rearrangement ions that can be utilized in the determination of amino acid sequences. PMID- 8694251 TI - Spatial discrimination against background with different optical systems for collection of fluorescence in laser-excited atomic fluorescence spectrometry with a graphite tube electrothermal atomizer. AB - A single 90 degrees off-axis ellipsoidal mirror fragment was used in a dispersive detection system for electrothermal atomization laser-excited atomic fluorescence spectrometry. The performance of the new optical arrangement was compared with those of optical arrangements that employed a plane mirror in combination with biconvex or plano-convex lenses. All the optical arrangements collected fluorescence in a scheme called front surface illustration. BEAM-4, an optical ray tracing program, was used for calculations of spatial ray distributions and optical collection efficiency for the various optical configurations. Experimentally, the best collection efficiency was obtained by use of the ellipsoidal mirror, in qualitative agreement with simulations done by use of the BEAM-4 software. The best detection limit for cobalt with the new optical arrangement was 20 fg, which was a factor of 5 better than that obtained with conventional optical arrangements with otherwise the same instrumentation. The signal-to-background ratio and the fluorescence collection efficiency were also studied as a function of position of the optical components for the various optical arrangements. For both cobalt and phosphorus, the signal-to-background ratio with the new optical arrangement remained stable within 10-20% during +/- 8 mm shifts in the position of the detection system from the focal plane of the optics. Overall, the new optical arrangement offered high collection efficiency, excellent sensitivity, and facile optical alignment due to efficient spatial separation between the fluorescence signal and the background radiation. The advantages of the new optical arrangement were particularly important during measurements in the presence of high levels of blackbody radiation. PMID- 8694252 TI - Quantitative analysis of bandpass-filtered Fourier transform infrared interferograms. AB - The feasibility of performing quantitative analysis with short segments of bandpass-filtered Fourier transform infrared (FT-IR) interferograms is demonstrated. The protocol developed in this work addresses four limitations that hinder the use of FT-IR spectroscopy in nonlaboratory applications: (1) the need for a rugged, low-cost, and reliable spectrometer, (2) the lack of representative background spectra for use in acquiring absorbance spectra of the target analyte, (3) the presence of overlapping spectral bands that interfere with the analyte determination, and (4) the difficulty in obtaining useful information from data collected near the limit of detection. In this work, spectral information pertaining to a specific analyte band of interest is isolated directly from a short interferogram segment by the application of narrow-bandpass digital filters. When processed in this way, the filtered interferogram segments contain compound-specific information that can be utilized for quantitative analysis. Successful use of a univariate calibration procedure with filtered interferogram data of benzene and nitrobenzene of varying concentrations is demonstrated. Calibrations based on filtered interferogram segment magnitudes vs concentration yield models with values of R2 in excess of 99%. These results are obtained without the use of a separate background or reference interferogram. This interferogram-based analysis is shown to perform analogously to a conventional spectral-based analysis, with the interferogram method being more efficient in terms of data collection and computational requirements. PMID- 8694253 TI - Screening Pap smears with near-IR. PMID- 8694254 TI - Vanished into thin air. The search for children's fingerprints. PMID- 8694255 TI - Zeptomole-detecting biosensor for alkaline phosphatase in an electrochemical immunoassay for 2,4-dichlorophenoxyacetic acid. AB - A bienzyme substrate-recycling biosensor in a flow injection analysis system is described for the sensitive measurement of alkaline phosphatase (ALP) and applied to the fast readout of a competitive immunoassay for the widely used pesticide 2,4-dichlorophenoxyacetic acid (2,4-D). The phenol-indicating biosensor consists of a Clark-type electrode covered by a membrane with coentrapped tyrosinase and quinoprotein glucose dehydrogenase. ALP dephosphorylates phenyl phosphate to phenol (K(m) = 36 microM) outside the flow system. Phenol is oxidized in the sensor membrane by the oxygen-consuming tyrosinase via catechol to o-quinone. The quinone is reconverted to catechol by glucose dehydrogenase. This substrate cycling results in a 350-fold amplified sensor response to phenol. The oxygen consumption of the enzyme couple in the presence of phenol is monitored as a decrease in current. A total of 3.2 fM ALP (320 zmol/ 100 microL) has been detected after a 57.5 min incubation with phenyl phosphate. All involved reagents are stable over the time of measurement. The sensor does not produce any measurable blank signals. The immunoassay detects 0.1 microgram/L 2,4-D, the maximum concentration for pesticides allowed in drinking water by European Community regulations. The applicability of this biosensor for fast immunoassay readout is demonstrated by a 2 min incubation. By comparison, a standard photometric method (p-nitrophenyl phosphate) requires overnight incubation. PMID- 8694256 TI - Determination of parts per trillion levels of organophosphorus pesticides in groundwater by automated on-line liquid-solid extraction followed by liquid chromatography/atmospheric pressure chemical ionization mass spectrometry using positive and negative ion modes of operation. AB - Liquid chromatography/atmospheric pressure chemical ionization mass spectrometry with positive and negative ion modes of operations was used for the trace determination of several organophosphorus pesticides, (E)- and (Z)-mevinphos, dichlorvos, azinphos-methyl, azinphosethyl, parathion-methyl, parathion-ethyl, malathion, fenitrothion, fenthion, chlorfenvinphos, and diazinon, in groundwater. This method required only 100 mL of water, and it was combined with a prior automated online liquid-solid extraction step using an OSP-2 autosampler containing C18 cartridges. The limit of quantitation (LOQ) varied between 5 and 37 ng/L in positive ion (PI) mode. Under negative ion (NI) mode of operation, only the parathion group (both parathions and fenitrothion) had a better sensitivity as compared to that in PI mode, with a LOQ of 5-15 ng/L, whereas the rest of pesticides had 2-4 times higher LOQs as compared to those in PI mode. Selected ion monitoring of the group-specific fragment of the organophosphorus pesticides, e.g., [(CH3O)2PO2]- or the [M + H]+ ions, under NI or PI mode, respectively, was used. Sample cone voltage varied from 10 to 130 V. This parameter influenced the transmission and fragmentation of quasi-molecular ions, and it was optimized to achieve identification capabilities with the highest sensitivity. At 20 V, good fragmentation was obtained for most of the studied analytes. The system was used for the certification of a groundwater sample spiked at the nanograms per liter level with organophosphorus pesticides provided by Aquachek. PMID- 8694257 TI - Channel electrophoresis for kinetic assays. AB - A rectangular channel electrophoresis system and a cylindrical sampling capillary combination allows chemical changes in nanoliter-volume samples to be monitored as a function of time. The electrophoretic microseparation is carried out in a rectangular channel with a 7 -cm-long, 40-microm x 2.5-cm geometry and is coupled to a 50-microm-i.d. cylindrical sample introduction capillary. The channel width dimension is used as a time axis by moving the outlet of the sampling capillary across the entrance of the separation channel. Detection of the separated analyte bands is achieved with laser-induced fluorescence and spatially resolved detection based on a charge-coupled device. The system is characterized with a series of fluorescein thiocarbamyl amino acid derivatives; limits of detection are < 10(-8) M for amino acids and 10(-9)M (425 zmol) for fluorescein. The ability to achieve a time-based dynamic microseparation is demonstrated by monitoring fluorescent product formation during the enzyme-catalyzed hydrolysis of fluorescein di-beta-D-galactopyranoside (FDG), a commonly used fluorescent substrate for enzymological studies. PMID- 8694258 TI - Comparison and modeling study of vancomycin, ristocetin A, and teicoplanin for CE enantioseparations. AB - The structurally related glycopeptide antibiotics vancomycin, ristocetin A, and teicoplanin can all be used as chiral selectors in capillary electrophoresis (CE). Both experimental and modeling studies were done to elucidate their similarities and differences. There are identifiable morphological differences in the aglycon macrocyclic portions of these three compounds. In addition, there are other structural distinctions that can affect their CE enantioselectivity, migration times, and efficiency. Teicoplanin is the most distinct of the three and is the only one that is surface active. Its aggregational properties appear to affect its enantioselectivity among other things. The similar but not identical structures of the three glycopeptides produce similar but not identical enantioselectivities. This leads to the empirically useful "principle of complementary separations", in which a partial resolution with one chiral selector can be brought to baseline with one of the others. Overall, ristocetin A appears to have the greatest applicability for CE enantioseparations. PMID- 8694259 TI - Determinations of N-nitrosodimethylamine at part-per-trillion concentrations in contaminated groundwaters and drinking waters featuring carbon-based membrane extraction disks. AB - A new solid-phase extraction procedure extracts N-nitrosodimethylamine (NDMA) at part-per-trillion (ng/L) concentrations from aqueous samples using a C18 (reversed-phase) membrane extraction disk layered over a recently introduced carbon-based extraction disk. The reversed-phase disk removes nonpolar water insoluble neutrals and is set aside; the carbon-based disk is extracted with a small volume of dichloromethane. NDMA is quantified in the organic extract using a gas chromatograph equipped with both a short-path thermal desorber and a chemiluminescent nitrogen detector. The detection limit for the procedure, calculated using two statistically unbiased protocols, is 3 ng of NDMA/L; the analyte recovery is approximately 57%. A related procedure substitutes a standard automatic sampler for the short-path thermal desorber and is suitable for determining NDMA in heavily contaminated (> 300 ng of NDMA/L) aqueous samples. The detection limit for the procedure, calculated in the same manner as above, is 300 ng of NDMA/L, with an analyte recovery of approximately 64%. The detection limits and measured recovery values are comparable to those observed in earlier work, in which a conventional continuous overnight extraction with dichloromethane was used to remove NDMA from the aqueous samples. The newer procedures described herein offer a 50-fold savings in extraction time and a 100 fold reduction in dichloromethane consumed per sample while maintaining the wide range (3-4 orders of magnitude concentrations of NDMA) observed for the original procedures used in tandem. Authentic contaminated groundwaters are extracted using both the conventional and disk-based extraction procedures and analyzed; the observed NDMA concentrations are virtually identical over a target range spanning 100-10000 ng of NDMA/L. PMID- 8694260 TI - Bifunctional labeling reagent for oligosaccharides to incorporate both chromophore and biotin groups. AB - We have developed a convenient and effective method for biotinylation of oligosaccharides at their reducing ends. A novel biotin hydrazide having a phenyl group produced the biotin adduct of N-acetyllactosamine (LacNAc) by simple incubation at 90 degrees C for 1 h. Although the biotin adduct was obtained as a mixture of several stereoisomers, one of the isomers, cyclic beta-glycoside, became predominant upon letting the reaction mixture stand in a weakly acidic state (pH 3.5). This conversion may be very advantageous for functional analysis of oligosaccharides because natural N-linked oligosaccharides exist in the cyclic beta form. The limit of detection of labeled LacNAc in reversed-phase chromatography was 330 fmol and showed good linearity in the range from 330 fmol to 261 pmol. When this procedure was applied to complex type and high mannose type N-linked oligosaccharides, the labeled oligosaccharides were easily detected and separated by reversed-phase, gel filtration, and anion exchange chromatographies. Furthermore, these labeled oligosaccharides were able to be immobilized onto the solid phase using avidin-biotin technology and were stable enough to allow the binding assay to be performed repeatedly and under the conditions for in situ exoglycosidase digestion. These results suggest that this derivatization technique might be useful for both separation and functional analysis of oligosaccharides. PMID- 8694261 TI - o-Phenylenediamine-modified carbon fiber electrodes for the detection of nitric oxide. AB - Nitric oxide (NO.) sensors were prepared using o-phenylenediamine (o-PD) and Nafion to modify the surface of 30 microns diameter carbon fiber electrodes. These electrodes were compared with nickel porphyrin-type NO. sensors that have already been described. High-speed chronoamperometry, amperometry, and differential pulse voltammetry were used to compare the performance of sensors modified with various combinations of Nafion, o-PD, or nickel(II) meso-tetrakis(3 methoxy-4-hydroxyphenyl) porphyrin (Ni-TMPP), in order to determine which electrodes had the most sensitivity and selectivity for NO. Our findings showed that electrodes treated with Nafion first, followed by o-PD, were very sensitive to NO., with a detection limit of 35 +/- 7 nM. In addition, o-PD electrodes were also very selective against ascorbate (> 600:1), dopamine (> 300:1), and nitrite (> 900:1). Moreover, in the range of 0-6 microM NO., o-PD electrodes displayed excellent linearity (R2 > or = 0.997). In contrast, Ni-TMPP electrodes (with Nafion) had significantly poorer detection limits (76 +/- 12 nM) and were less selective against dopamine (< 5:1) and nitrite (< 200:1). Ni-TMPP electrodes were also less linear than o-PD electrodes (R2 > or = 0.911). Finally, we tested the in vitro and in vivo performance of the o-PD electrode in terms of its ability to detect NO. release from isolated rat renal arterioles and to measure NO. diffusion in the extracellular space of the rat brain. PMID- 8694262 TI - DNA electrochemical biosensor for the detection of short DNA sequences related to the human immunodeficiency virus. AB - An electrochemical biosensor for the detection of short DNA sequences related to the human immunodeficiency virus type 1 (HIV-1) is described. The sensor relies on the immobilization and hybridization of the 21- or 42-mer single-stranded oligonucleotide from the HIV-1 U5 long terminal repeat (LTR) sequence at carbon paste or strip electrodes. The extent of hybridization between the complementary sequences is determined by the enhancement of the chronopotentiometric peak of the Co(phen)3(3+) indicator. Numerous factors affecting the probe immobilization, target hybridization, and indicator binding reactions are optimized to maximize the sensitivity and speed the assay time. A detection limit of 4 x 10(-9) M HIV-1 U5 LTR segment is reported following a 30 min hybridization. The hybridization biosensor format obviates the use of radioisotopes common in radioactive methods for the detection of HIV-1 DNA. We also report on the direct adsorptive chronopotentiometric stripping measurements of trace levels of various HIV-1 DNAs. PMID- 8694263 TI - Miniature sodium-selective ion-exchange optode with fluorescent pH chromoionophores and tunable dynamic range. AB - An extension into the fluorescence mode of ion-exchange optodes is described, allowing miniaturization and its concomitant benefits. A micrometer-size, fluorescent fiber-optic sodium sensor is described, based on a highly sodium selective, crown ether-capped calix[4]arene ionophore, capable of ratiometric operation. Three sensor configurations are given, employing different lipophilic, fluorescent pH chromoionophores (Nile Blue derivatives), demonstrating the ability to improve the detection limit and tune the dynamic range to the desired region of interest. Two of the sensors are of special interest in that their working ranges lie within those desired for measuring intracellular cytosolic or blood levels of sodium at the respective physiological pH. These optodes have excellent sodium selectivity, with other physiologically relevant cations (e.g., potassium, calcium, and magnesium) being highly discriminated. Three simple mathematical relationships are given for the three experimentally used fluorescent signal mechanisms (intensity, intensity ratios, and inner-filter or energy transfer effects), permitting visualization on a single graph and enabling direct comparison of the different sensors' optical responses on a common platform. Finally, these optodes measure the sample's sodium activity, rather than the concentration, provided that the sample's pH is measured simultaneously by another sensor, such as a glass electrode. PMID- 8694264 TI - Genetic algorithm-based protocol for coupling digital filtering and partial least squares regression: application to the near-infrared analysis of glucose in biological matrices. AB - A multivariate calibration procedure is described that is based on the use of a genetic algorithm (GA) to guide the coupling of bandpass digital filtering and partial least-squares (PLS) regression. The measurement of glucose in three different biological matrices with near-infrared spectroscopy is employed to develop this protocol. The GA is employed to optimize the position and width of the bandpass digital filter, the spectral range for PLS regression, and the number of PLS factors used in building the calibration model. The optimization of these variables is difficult because the values of the variables employ different units, resulting in a tendency for local optima to occur on the response surface of the optimization. Two issues are found to be critical to the success of the optimization: the configuration of the GA and the development of an appropriate fitness function. An integer representation for the GA is employed to overcome the difficulty in optimizing variables that are dissimilar, and the optimal GA configuration is found through experimental design methods. Three fitness function calculations are compared for their ability to lead the GA to better calibration models. A fitness function based on the combination of the mean squared error in the calibration set data, the mean-squared error in the monitoring set data, and the number of PLS factors raised to a weighting factor is found to perform best. Multiple random drawings of the calibration and monitoring sets are also found to improve the optimization performance. Using this fitness function and three random drawings of the calibration and monitoring sets, the GA found calibration models that required fewer PLS factors yet had similar or better prediction abilities compared to calibration models found through an optimization protocol based on a grid search method. PMID- 8694265 TI - Dynamic on-column pH monitoring in capillary electrophoresis: application to volume-limited outlet vials. AB - With capillary electrophoresis, buffer pH must be constant to achieve consistent migration times. Irreproducible separations have been attributed to pH changes due to water hydrolysis in the inlet/outlet vials. A method of measuring the pH of the electrolyte on-column is described that uses wavelength-resolved fluorescence detection. C.SNARF-1 is a fluorescent pH indicator that has a large change in fluorescence emission profile depending on pH. When it is incorporated into the running buffer, monitoring the pH-dependent emission spectra of the C.SNARF-1 allows column pH to be calculated. With reduced-volume outlet buffer vials in the nanoliter to low microliter range, significant changes in pH and column conductivity are measured during a single electrophoretic run, with pH fronts greater than 3 units passing a fixed point on the capillary over a several second period. These changes appear to be caused by reverse-migrating OH- produced at the capillary outlet by the hydrolysis of water. PMID- 8694266 TI - Microwave distillation-solid phase adsorbent trapping device for the determination of off-flavors, geosmin and methylisoborneol, in catfish tissue below their rejection levels. AB - Described is a rapid microwave-mediated steam distillation device for determining two predominant off-flavor compounds, geosmin and methylisoborneol, in catfish tissue. A microwave on-time of 10 min is needed to efficiently remove these off flavor compounds from the sample matrix and trap them on a solid phase adsorbent. A minimal amount of organic solvent is used to elute the trapped compounds. The extract is then analyzed by gas chromatography with ion trap detection in the selective ion storage mode. Detection limits in the sub-parts-per-billion range are obtained with this method. PMID- 8694269 TI - An ultrastructural study of glomeruli associated with vomeronasal organs transplanted into the rat CNS. AB - Rat neonate vomeronasal organs were transplanted into the parietal cortex of littermates to examine their survival and the behavior of axon growth into the surrounding host brain parenchyma. After survival times of 10-100 days the brains were processed for ultrastructural examination. The transplanted vomeronasal organs (VNO) formed several vesicles lined with a sensory epithelium. From these sensory epithelia, VNO neurons leave the epithelium and enter the host brain. Transplant neurons grew axons that fasciculated into bundles surrounded by sheath cell processes and formed one or more fiber plexuses containing distinct globose or spherical-shaped glomerular-like structures. The glomeruli consisted of nerve terminals between which existed asymmetric synaptic contacts. Rarely did we observe clear reciprocal synapses. The glomeruli also contained terminals that showed signs of degeneration, such as increased density of the terminals, clumping of mitochondria and multivesicular bodies. The glomeruli were not partitioned or subdivided by glial septa; however, glial profiles were interspersed among the sensory terminals. Transplant glomeruli also lacked periglomerular cells and had no definitive glial envelope. These results suggest that glomerular formation is not dependent on dendrite contribution of second order neurons or glial support, but rather on a complementary population of receptor neurons. PMID- 8694268 TI - Axial structures control laterality in the distribution pattern of endothelial cells. AB - In the midline of the embryo an invisible barrier exists that keeps endothelial cells from migrating to the contralateral side. Interspecific grafting experiments between chick and quail were carried out in order to investigate the role of the axial structures in maintaining this barrier. The quail endothelial cells of the graft were therefore stained with QH1 antibody. In all experimental series quail paraxial mesoderm was used as a source of endothelial cells. First, a quail somite was transplanted either ipsilaterally or contralaterally. The results not only show the existence of laterality in the distribution pattern, but also demonstrate that the laterality does not depend on the origin of the graft but on the environment of the host embryo. Laterality in the distribution pattern of endothelial cells means that the endothelial cells of the two body halves migrate independently and do not change from one side to the other. Single cells do not know whether they are cells from the right or from the left half of the body. In the next series of experiments axial structures were removed in order to modify the barrier. In addition, paraxial mesoderm was exchanged with the corresponding quail tissue in order to determine the migration behaviour of the grafted endothelial cells. The removal of the neural tube does not influence the barrier. After notochordectomy, however, the endothelial cells exhibited a balanced distribution pattern over both halves of the embryo. We concluded that the notochord forms a barrier for endothelial cells that presumably operates on the basis of chemical substances. It is conceivable that our results can explain the lateralization of illnesses of the vascular system, as the Klippel-Trenaunay syndrome or the Sturge-Weber syndrome. PMID- 8694267 TI - Morphology of interstitial cells in the healthy kidney. AB - Renal interstitial cells play an important role in renal function and renal diseases. We describe the morphology of renal interstitial cells in the healthy kidney. We distinguish within the renal interstitium (1) renal fibroblasts and (2) cells of the immune system. Fibroblasts are in the majority and constitute the scaffold of the kidney; they are interconnected by junctions, and are attached to tubules and vessels. Although the phenotype of fibroblasts shows some variation depending on their location in the kidney and on their functional stage, their recognition as fibroblasts is possible on account of structural features. Among the cell types of the second group, antigen-presenting dendritic cells are the most abundant in in the peritubular interstitial spaces of healthy kidneys. Their incidence is highest in the inner stripe of the outer medulla. They share some morphological features with fibroblasts but lack others- junctional complexes, morphologically defined connections with tubules and vessels, and the prominent layer of actin filaments under the plasma membrane- that are characteristic for fibroblasts. Dendritic cells in healthy kidneys are morphologically different from macrophages, which are characterized by abundant primary and secondary lysosomes. In healthy kidneys macrophages are restricted to the connective tissue of the renal capsule and the pelvic wall, and to the periarterial connective tissue. Lymphocytes are rare in healthy kidneys. The distinction of cell types by morphology is supported by differences of membrane proteins. Among all interstitial cells in the renal cortex, fibroblasts alone exhibit ecto-5'-nucleotidase. Dendritic cells constitutively have a high abundance of MHC class II protein. Both proteins are mutually exclusive. Rat macrophages display the membrane antigen ED 2 and lymphocytes exhibit specific surface antigens, depending on their type and functional stage, e.g., CD4 or CD8. PMID- 8694270 TI - Ultrastructural characterization of the postnatal development of the thalamic ventrobasal and reticular nuclei in the rat. AB - Electron microscopy has been employed to analyze the normal maturational sequence that characterizes the postnatal development of synaptic circuits in the ventrobasal (VB) and reticular (Rt) thalamic nuclei of rats at different ages (from birth to the end of the third postnatal week). Throughout the first postnatal week, similar signs of immaturity are observed in both nuclei, mainly consisting in scarcity of cytoplasmic organelles, presence of wide extracellular spaces, and absence of myelinated fibers. Several synaptic terminals are however present from birth, thus indicating that some of the afferents have already reached and contacted their thalamic target during embryonic life. Most of the terminals are small and contain only a few round, clear vesicles, and therefore their cytological features do not allow the identification of their origin. In particular, in both nuclei, terminals with flat vesicles and symmetric specialization are only rarely observed, and in VB the ascending terminals are not distinguishable from terminals of other sources as they are in adults. During the second postnatal week, progressive maturational changes in VB and Rt lead to neurons having well-developed cytoplasmic organelles and to an elaborate neuropil containing myelinated fibers and synaptic terminals that are morphologically heterogeneous and resemble the adult ones. The permanence of growth cone-like profiles and of numerous somatic and dendritic protrusions, often contacted by synaptic terminals, indicates that a certain degree of reorganization is still taking place in both nuclei. By the end of the third postnatal week the synaptic organization of VB and Rt is indistinguishable from that observed in adults. This ultrastructural study shows that the appearance of the neuropil of VB and Rt and the morphological complexity of the synaptic arrangements characteristic of the adult rat are not present in neonates, but are gradually acquired during the first three postnatal weeks, and that they result from progressive modifications in circuit organization involving both pre- and postsynaptic elements. PMID- 8694271 TI - Extracellular matrix modifications in the interdigital spaces of the chick embryo leg bud during the formation of ectopic digits. AB - In previous studies we have observed that the interdigital mesenchyme of the chick leg bud, in the stages preceding the onset of cell death, retains a significant regulatory potential, forming ectopic extra digits under a variety of surgical manipulations. Most evidence suggests that interdigital extra digits are caused by the abolition of local antichondrogenic effects operating in the interdigital spaces under normal conditions rather than by modifications of the signalling mechanisms accounting for the normal patterning of the digits in early stages of development. The interdigital spaces exhibit a complex scaffold of extracellular matrix with well-defined domains of spatial distribution of type I and type VI collagens, tenascin, fibronectin, laminin and elastic matrix components that have been proposed to play a role in the establishment of the non chondrogenic fate of the interdigital tissue in situ. In an attempt to analyze this possible role of the interdigital extracellular matrix (ECM), in the present work we have studied changes in the pattern of ECM distribution associated with the formation of extra digits. Extra digits were induced by making a T-cut in the third interdigital space of the leg but of stage 29 HH chick embryos. Subsequent modifications of the ECM were detected immunohistochemically in whole-mount specimens using laser confocal microscopy. Our results reveal that in the first hours after the operation, changes in the ECM apparently related to the healing of the wound cause a significant reorganization of the normal ECM scaffold of the interdigit. In addition, chondrogenesis of the interdigital tissue is preceded by disappearance of elastin fibers in the interdigital mesenchyme subjacent to the wound and by an intense deposition of tenascin. Tenascin deposition and loss of the elastin fibrillar scaffold were also observed preceding chondrogenesis in fragments of interdigital tissue explanted to culture conditions. The significance of these observations in relation to the establishment of the skeletal elements of the autopodium is discussed. PMID- 8694273 TI - The effect of the ectoderm on the dorsoventral pattern of epidermis, muscles and joints in the developing chick leg: a new model. AB - In order to investigate the effect of the ectoderm on the pattern of mesodermal components in the chick leg, the ectoderm of the early limb bud was dorsoventrally reversed with respect to the mesoderm. The dorsoventral pattern was assessed by examination of the muscles, skeleton and epidermal differentiation. The earlier the stage at which the recombinants were made, the more complete was the reversal of the dorsoventral pattern of the limb mesoderm to conform with the ectoderm, and distal regions showed more complete reversals than proximal ones. Analysis of dorsoventral pattern along the leg shows that the dorsalization starts from the dorsal ectoderm and affects mesodermal structures in its progress to the midline and then to the ventral ectoderm. There was no strict congruence between the dorsoventral patterns of cartilage, muscle and epidermis. The results suggest that a signal from the dorsal ectoderm modifies ventral mesoderm before ventral ectoderm affects dorsal mesoderm. These observations about the way in which the mesoderm responds to ectoderm reversal suggest a new model. The model is based on two distinct signals, both initiated within the progress zone: (1) a factor made by dorsal ectoderm which specifies a dorsal state as distinct from a ventral state, and (2) a symmetrical positional signal from the apical ectodermal ridge which patterns the tissues along the dorsoventral axis. PMID- 8694272 TI - Characterization of Meibomian gland innervation in the cynomolgus monkey (Macaca fascicularis). AB - To characterize the innervation of the cynomolgus monkey (Macaca fascicularis) Meibomian (tarsal) glands, upper lids of six cynomolgus monkeys were investigated with electronmicroscopical and double-labeling immunocytochemical methods. Antibodies against calcitonin gene-related peptide (CGRP), dopamine-beta hydroxylase (DBH), neuropeptide Y (NPY), nitric oxide synthase (NOS), protein gene product 9.5 (PGP 9.5), substance P (SP), tyrosine hydroxylase (TH), and vasoactive intestinal peptide (VIP) were used. In addition, sections were processed for NADPH-diaphorase (NADPH-d) histochemistry. Staining for PGP 9.5 and electron microscopy showed that Meibomian gland acini were surrounded by a network of unmyelinated nerves and terminal varicose axons. The terminals contained small agranular (30-60 nm) and large granular vesicles (65-110 nm), and were observed in close contact with the basal lamina of the acini, but never internally to the basal lamina. Meibomian axons showed like-immunoreactivity (LI) for the neuropeptides SP, CGRP, NPY, and VIP. In addition, the axons stained for TH, DBH, NOS, and NADPH-d. VIP-LI, NOS- and NADPH-d-positive axons appeared to be more numerous, TH- and DBH-positive axons more rare than others. Most SP-LI axons were double-labelled for CGRP-LI, some for VIP-LI or NPY-LI. In addition, some VIP-LI axons were double-labeled for NPY-LI. NPY/VIP-LI and NPY/SP-LI axons were only observed close to the Meibomian acini. Conversely, NPY-LI colocalized with TH-IR or DBH-IR predominated in perivascular nerves of Meibomian gland vasculature. The close association of varicose axons with the acini of Meibomian glands indicates that nervous signals modulate meibomian secretion. Meibomian gland nerve fibers in the cynomolgus monkey appear to utilize various neuropeptides, catecholamines and nitric oxide as transmitter substances, and seem to derive from the pterygopalatine, superior cervical and trigeminal ganglion respectively. PMID- 8694274 TI - In situ hybridization for somatostatin mRNA in the adult rat: cingulate, insular, prepiriform, perirhinal, entorhinal, and retrosplenial cortical regions. AB - The expression of somatostatin mRNA within the allocortex of the rat was examined by in situ hybridization with an alkaline phosphatase labeled probe. We sought to determine whether parcellation of the allocortex could be based upon the number and laminar location of the hybridized cells and to contrast the allocortical features with those of the isocortical areas. The cingulate region was characterized by intense, moderate, and faint cells, small to medium in size throughout the laminae. The retrosplenial region demonstrated a somewhat stratified appearance with an abundance of cells expressing somatostatin mRNA in the upper portion of the composite layer II-IV and also in the upper portion of layer VI. The insular region displayed more heterogeneity. The distribution of the cells hybridized for somatostatin mRNA formed distinctive configurations within the insular region (dorsal and ventral agranular insular areas) with no obvious generality. The perirhinal area resembled the ventral agranular insular area, and the cell distribution of the entorhinal and prepiriform areas displayed a common characteristic in that the primary axis of the perikarya of somatostatin mRNA expressing cells within the lower layers were oriented at almost every possible angle. The conclusion of the investigation is that in situ hybridization for somatostatin mRNA provides a means by which the areal boundaries within the allocortex may be drawn. PMID- 8694275 TI - Structure of the amphibian mesonephric tubule during ontogenesis in Rana ridibunda L. tadpoles: early ontogenetic stages, renal corpuscle formation, neck segment and peritoneal funnels. AB - The morphological changes produced in the mesonephric tubule during ontogenesis, not previously reported in amphibians, are described in Rana ridibunda tadpoles using light and electron microscopic methods. The rudimentary nephron units do not develop synchronously along the subperitoneal nephrogenic ridged cord. The first signs of morphogenesis are the presence of round euchromatinic nuclei and mitotic figures. The subsequent developmental stages are characterized by detachment of the rudimentary nephrons from the nephrogenic cord. Renal corpuscle formation is characterized by glomerular expansion, differentiation of large fenestrated capillaries and the presence of a discrete mesangium and a small capsular space. Interstitial capillaries next to the renal corpuscle rudiments appear to induce invagination and differentiation of the capsular epithelium. Developing podocytes were cuboidal undifferentiated epithelial cells with scarce primary processes and with an extensive part of the cell surface lying flat on the glomerular basement membrane. These features reflect low or no glomerular filtration during nephron development. The ciliated neck segment and peritoneal funnels show similar structural features. The latter were not physically connected with the nephrons, but opened into renal blood vessels. Involutive peritoneal funnels were observed. PMID- 8694276 TI - Morphometry, scanning electron microscopy and X-ray spectral microanalysis of protostylid pits on human lower third molars. AB - Protostylid pits on 50 lower third molars were studied. The depth and width of the pits, the thickness of the enamel at the pit bottom and the concavity of the dentino-enamel junction under the pit were measured by light microscopy. The pit content was examined by scanning electron microscopy and X-ray spectral microanalysis. The results show that the morphometric variables of protostylid pits are similar to those of occlusal fissures and pits. The protostylid pits were seen to contain globular formations, belonging mainly to dental calculus; organic rod-shaped bodies, which could represent remnants of the enamel organ--or more probably--foreign bodies, were frequently observed. The study suggests that the development of the most common form of protostylid is basically similar to that of an occlusal cusp, with variations attributable to the low expression of the protostylid and particularities of cusp development in the lateral tooth wall. PMID- 8694277 TI - The organization of microtubules and filamentous actin in cytospin preparations of Sertoli cells from w/wwei mutant mice devoid of germ cells. AB - The microtubule (MT) cytoskeleton and the distribution of filamentous actin (F actin) were examined in the w/wwei mutant of the house mouse (Mus musculus), which is characterized by the absence of germ cells. Cytospin preparations of carefully minced testis tubules were stained with one of three different monoclonal antitubulin antibodies or with phalloidin conjugated with a fluorescent dye. The antibodies were directed to beta-tubulin, acetylated alpha tubulin, and tyrosinated alpha-tubulin. The antibody to beta-tubulin revealed prominent MT bundles oriented parallel to the long axes of the Sertoli cells. Acetylated alpha-tubulin was present only in a small subset of the MTs close to the nuclei, and tyrosinated alpha-tubulin was virtually missing in polymerized MTs. This pattern does not correspond to that reported for Sertoli cells in wild mammals. Thus, the absence of germ cells apparently affects the microtubular cytoskeleton. Our study showed that this also applies to F-actin. Bundles of F actin were found throughout about two thirds of the Sertoli cells cytoplasm lateral to the nucleus in w/wwei mice. In contrast, F-actin was reported to form sheets throughout the cytoplasm in wild-type mice. F-actin is part of the so called ectoplasmic specializations--elements that are involved in the contact between the spermatids and Sertoli cells. Thus, the absence of germ cells from testes appears to have far-reaching effects on the cytoskeleton of the Sertoli cells. PMID- 8694278 TI - Expression of tissue non-specific alkaline phosphatase stimulates differentiated behaviour in specific transformed cell populations. AB - BACKGROUND: Tissue non-specific alkaline phosphatase (TN-AP) is a membrane-bound glycoprotein enzyme which is characterized by its phosphohydrolytic activity. This enzyme is distributed virtually in all mammalian tissues during embryonic development (it can be demonstrated as early as the 2-cell stage) where its expression is stage specific. The expression of TN-AP is frequently associated with cell differentiation and as such it has been used as a marker for this process. By employing a stable gene transfer and forced gene expression technique, previous findings suggested that TN-AP expression might influence cellular proliferation and morphological differentiation. The focus of this study was to determine whether this was a cell-specific effect or not. METHODS: The effects of TN-AP on various aspects of cellular activity were assessed by transferring and expressing the gene for this enzyme into three target populations; 1) CHO, 2) R1610, and 3) Rat-2. The parameters of cellular activity studied included cellular proliferation, cell cycle, cell migration, and tumorigenic potential (in the nude mouse). Cell cycle and cell proliferation analyses were accomplished, in part, through the use of fluorescence activated cell sorting (FACS) as were determinations of cell-associated TN-AP activity and amount. Northern and southern blot analyses were used to estimate gene copy number and to evaluate gene expression respectively in transfected cell lines. RESULTS: Our data indicate that the TN-AP gene under control of various gene promoters was stably integrated into three fibroblast-like cell lines (CHO, R1610, and Rat-2). TN-AP activity and TN-AP protein levels were correlated to the strength of the various gene promoters, but not to inserted gene copy numbers. The expression of the TN-AP gene in these three cell types further suggests cell specific effects as demonstrated by the following findings. The expression of TN AP under control of a weak gene promoter in CHO and Rat-2 cells clearly decreased cell proliferation and cell migration. However, the expression of TN-AP under control of either a weak or even a strong gene promoter in R1610 cells did not induce any changes in that cell line's behaviour (apart from expression of TN AP). Such changes in CHO cells were also associated with a 2.2-fold increase in tubulin transcription as well as suppressed tumorigenic potential. CONCLUSION: Taken together, these findings suggest that the inhibitory effects of TN-AP expression on proliferation and cell migration are not non-specific and that high expression of TN-AP may induce changes in cell behaviour which may be consistent with or at least related to induction of terminal differentiation. PMID- 8694279 TI - Fine structure of the dorsal lingual epithelium of the juvenile hawksbill turtle, Eretmochelys imbricata bissa. AB - BACKGROUND: Various species of turtles are adapted to different environments, such as freshwater, seawater, and terrestrial habitats. Comparisons of histological and ultrastructural features of the tongue of the juvenile Hawksbill turtle, Eretmochelys imbricata bissa, with those of freshwater turtles should reveal some aspects of the relationship between the structure of the lingual epithelium and the environment. METHODS: The light microscope, scanning electron microscope and transmission electron microscope were used. RESULTS: Light microscopy revealed that the mucosal epithelium of the tongue was of the keratinized, stratified squamous type. Under the scanning electron microscope, no lingual papillae were visible on the dorsal surface of the tongue. Micropits and the thickening of cell margins were clearly seen on the surface of cells located on the outermost side. The transmission electron microscope revealed that the cells in the intermediate layer were gradually flattened from the basal side to the surface side, as were their nuclei. In the shallow intermediate layer, the cells were significantly flattened, and their nuclei were condensed or had disappeared. The cytoplasm contained keratohyalin granules, tonofibrils, free ribosomes, mitochondria, and rough endoplasmic reticulum. Numerous free ribosomes were attached to the surface of small keratohyalin granules. The cells of the keratinized layer were significantly flattened, and their nuclei had completely disappeared. Most of cytoplasm was filled with keratin fibers of high electron density. Keratin fibers of the shedding cells, which were located on the outermost side of the keratinized layer, appeared looser, and each fiber, which was somewhat thicker than the tonofibrils and tonofilaments, was clearly distinguishable. CONCLUSIONS: The lingual epithelium of the juvenile Hawksbill turtle differs significantly from that of the adult freshwater turtle, in spite of the similarity in gross morphology of the tongues of these species. PMID- 8694280 TI - Myosin isoforms and muscle fiber characteristics in equine gluteus medius muscle. AB - BACKGROUND: To date, four different myosin heavy chain (MyHC) isoforms have been identified in adult skeletal muscle of a number of species: types I, IIa, IIx or IId, and IIb. The aim of this study was to investigate the distribution of various MyHC isoforms in the equine gluteus medius and gluteus profundus muscles in relation with several morphometric variables of muscle fibers. METHODS: Samples from different depths of the gluteus medius muscle (2, 4, 6, and 8 cm) and gluteus profundus muscle of five sedentary horses were examined by MyHC gel electrophoresis, monoclonal antibodies staining against fast, slow and neonatal MyHC isoforms, myosin adenosine triphosphatase (m-ATPase) activity, nicotinamide adenine dinucleotide tetrazolium reductase, alpha-glycerophosphate dehydrogenase, and alpha-amylase-PAS. Data about relative frequencies, sizes, and capillaries of the various histochemical fiber types were collected by morphometry. RESULTS: Three MyHC isoforms were present in the gluteus medius muscle. Two of them comigrated with type I and IIa MyHC isoforms of rat diaphragm (used as a control). The third isoform showed an electrophoretic mobility closer to type IIx than to the IIb MyHC isoform of rat diaphragm. Only two MyHC isoforms (type I and IIa) were detected in the gluteus profundus muscle. In both muscles, type I fibers (high m-ATPase activity at pH 4.5) only reacted with the anti slow-MyHC antibody and both type IIA and IIB fibers (low and moderate m-ATPase activity at pH 4.5, respectively) only reacted with the anti fast-MyHC antibody. No cross reactivity of fibers positive for both antibodies was found except for the scarce type IIC fibers. Fiber types and capillaries were heterogeneously distributed across the gluteus medius muscle. The deeper regions of this muscle were found to contain a higher percentage of type I fibers, a large number of capillaries and a lower proportion of type IIB fibers compared to the superficial regions of the muscle. The gluteus profundus muscle had more abundant and larger type I fibers than the deepest sampling site of the gluteus medius muscle. CONCLUSIONS: These results show the existence of three different MyHC isoforms in the equine gluteus medius muscle and that fiber types and MyHC isoforms are heterogeneously distributed within this muscle. The distribution of slow-twitch and fast-twitch MyHCs among the fibers determined by immunohistochemistry was in agreement with histochemically identified type I and type II fibers, respectively. PMID- 8694281 TI - Penile bulb and its relationship with the pelvic urethra and the penile urethra in the rat: light and scanning electron microscopical observations. AB - BACKGROUND: In male rats the urethral tract consists of the following parts: the pelvic urethra, the transitional urethra, the urethral diverticle, and the penile urethra. Perusal of the literature results in only some more general descriptions and a very few which go more into detail. None of the latter deals with all the compartments nor with the relationships between each other. Aim of this study is to give a detailed morphological study of all the urethral compartments and their relationships to provide a platform for further experimental investigations. METHODS: From 40 adult male Wistar rats the urethral tract has been investigated by histology and scanning electron microscopy using intact tissue and casting techniques. RESULTS: Most striking is the existence of the sinusoids in the spongious tissues in the pelvic urethra into a system of two perpendicular layers of parallel sinusoids. In the spongious tissues of the penile corpus spongiosum the same organization can be found although less prominent. Smooth muscle cells are very unequally present along the urethral tract. In its pelvic part they do not form a continuous layer around the spongious tissue and compared to the distal part they appear proximally more abundant. In the bulbal part of the corpus spongiosum the smooth muscles form a massive sac around the spongious tissue. In the corpus spongiosum in the penile shaft they are absent. The smooth muscle cells are separated from the striated urethral muscle by a very thin layer of connective tissue, in the penile bulb a prominent tunica albuginea separates them from the striated penile muscles. In the spongious tissues of the pelvic urethra and the penile bulb large amounts of compound urethral glands are present. Their ducts open into the respective lumen. Helicine arteries are common in the pelvic urethra, especially in the glandular tissue. They are also normally present in the wing tips of the penile bulb. CONCLUSIONS: The transitional urethra, the urethral diverticle and surrounding spongious tissue are structurally closely related to the other parts, however their microscopical organization is intermediate between the pelvic part of the urethra and the corpus spongiosum. The highly ordered sinusoids in the spongious layers especially in the pelvic part together with a similar organization of the urethral muscle provide a possible basis for a peristaltic driving mechanism, suggesting these structures play a role in the high speed transport of sperms during ejaculation. PMID- 8694282 TI - Regional differences in the number of neurons in the myenteric plexus of the guinea pig small intestine and colon: an evaluation of markers used to count neurons. AB - BACKGROUND: Subsets of myenteric neurons have been identified. To determine the proportional representation of neurons in each, it is necessary to relate the number of neurons in the subset to that of the complete set. Prior estimates of total numbers of neurons, obtained with many different markers, have varied widely. METHODS: Markers were compared for counting myenteric neurons in dissected laminar preparations of guinea pig duodenum, jejunum-ileum, and colon; the effect of stretching preparations on these counts was also determined. Markers included the visualization of single-stranded nucleic acid with cuprolinic blue and the immunocytochemical demonstration of neuron specific enolase (NSE), PGP9.5, S-100, and the constitutive expression of a Fos related antigen (FRA). RESULTS: Neurons could not be counted accurately by demonstrating NSE, PGP9.5, or S-100. The number of neurons detected by demonstrating FRA was consistently less than that determined with cuprolinic blue (approximately 65%). Cuprolinic blue-derived estimates of neuron numbers were higher than most reported in the literature, but comparable to those recently obtained with "a nerve cell body" antiserum. Ganglionic area was found to be stretch independent. The rank order of neurons/cm2 and ganglionic area/ unit resting length was colon > duodenum >> jejunum-ileum; more neurons were found in the myenteric plexus of the colon (7.3 x 10(6)) than in that of the entire small intestine (6.5 x 10(6)). CONCLUSIONS: Prior studies that have obtained denominators for estimating the proportions of myenteric neuronal subsets with markers that do not reveal the entire population should be re-evaluated. The guinea pig colon contains a surprisingly large number of neurons, the physiological significance of which must be determined. PMID- 8694283 TI - Formation of interalveolar pores in the rat lung. AB - BACKGROUND: The aim of this morphological investigation was to obtain more information about the structural and cellular mechanisms of interalveolar pore formation in postnatal lung development. Assuming that alveolar pore formation is related to the general thinning of interalveolar walls observed in the postnatal period, we have focused our attention on the topographical relationship between epithelial cells and connective tissue in the septum. Thereby we tried to formulate a uniform concept of pore formation. METHODS: After fixation with glutaraldehyde and osmiumtetroxide, tissue blocks of rat lungs aged 44 days were embedded in Epon. Serial sections were obtained in order to analyse precisely pores and supposed sites of pore formation (type II cells and thin spots in transsections of interalveolar walls). RESULTS: We made the following observations: there are pores with or without type II cells in the neighbourhood, and "pre-pores" with either fully transseptal granular pneumocytes, or thin spots in the interalveolar wall consisting of one or two layers of type I cell epithelium or of type II and type I cells without intervening connective tissue. CONCLUSIONS: From these findings we deduce that there is a general principle of interalveolar pore formation which consists in the formation of transseptal interepithelial cell contacts (i.e., between cells of type II and type I or type I and type I), promoted by the thinning of interalveolar walls in the stage of microvascular maturation. Within the zone of contact the cells thin out and give way to form an interalveolar opening. PMID- 8694284 TI - Fusion of valve cushions as a key factor in the formation of congenital bicuspid aortic valves in Syrian hamsters. AB - BACKGROUND: Bicuspid aortic valve is the most frequent congenital cardiac malformation in humans. However, the morphogenesis of the defect is still unknown. Previous work showed that, in the Syrian hamster, congenital bicuspid aortic valves with the aortic sinuses arranged in ventrodorsal orientation are expressions of a trait the variation of which takes the form of a continuous phenotypic spectrum, ranging from a tricuspid aortic valve with no fusion of the ventral commissure to a bicuspid aortic valve devoid of any raphe. The present study was designed to elucidate the mechanism involved in the formation of bicuspid aortic valves in Syrian hamsters as a possible starting point for further investigation of this process in humans. METHODS: The sample examined consisted of 80 embryos, aged between 10 days, 16 hours and 13 days, 1 hour postcoitum. Most (n = 59) of the embryos belonged to a laboratory-inbred family of Syrian hamsters with a high incidence of bicuspid aortic valves. The study was carried out using scanning electron microscopy and histological techniques for light microscopy. RESULTS: Twenty-three embryos showed a still undivided conotruncus. In all of these cases there were six mesenchymal semilunar valve primordia protruding into the lumen of the conotruncus. In a further 29 embryos, the conotruncus had just divided into the aortic and pulmonary channels; the embryos were at the beginning of the valvulogenesis. In 13 of these 29 embryos there were three well-defined aortic valve cushions, right, left, and dorsal, whereas in the other 16, the right and left valve cushions were more or less fused toward the lumen of the aorta; when they were completely fused, only two aortic valve cushions, a ventral and a dorsal, could be identified. In the remaining 28 embryos, the aortic valve cushions showed a marked degree of excavation. In 23 of these cases, the valve exhibited a basically tricuspid architecture, whereas it was unequivocally bicuspid in the other five. CONCLUSIONS: All variants of the aortic valve morphologic spectrum occurring in the Syrian hamster develop from three mesenchymal valve cushions, right, left, and dorsal, after normal septation of the conotruncus. The bicuspid condition of the aortic valve is not the consequence of improper development of the conotruncal ridges, conotruncal malseptation, valve cushion agenesis, or lesions acquired after a normal valvulogenesis. Fusion of the right and left valve cushions at the beginning of the valvulogenesis appears to be a key factor in the formation of bicuspid aortic valves. Each aortic valve acquires its specific morphology prior to the end of the valvulogenetic process. PMID- 8694285 TI - Nonspecific cell-mediated cytotoxicity in the seawater teleosts (Sparus aurata and Dicentrarchus labrax): ultrastructural study of target cell death mechanisms. AB - BACKGROUND: In higher vertebrates, cytolytic lymphocytes lyse their targets by the mechanisms of cell death called necrosis and apoptosis. However, the mechanisms of target cell death mediated by fish cytotoxic cells have not been established. We report the ultrastructure of target cell death mediated by the seawater teleosts gilthead seabream (Sparus aurata) and sea bass (Dicentrarchus labrax). METHODS: Head-kidney, blood, and peritoneal exudate leukocytes were incubated with HeLa or B16 melanoma tumor cells, as targets, and processed for transmission electron microscopic studies. RESULTS: After incubation of tumor cells with leukocytes, substantial ultrastructural changes typically associated with both necrosis and apoptosis were observed in the plasmalemma, nucleus, and cytoplasm of the tumor cells. These morphological changes included loss of microvilli, the formation of long cytoplasmic processes and blebs, condensation and margination of the chromatin, swelling of the organelles, and vacuolation and condensation of the cytoplasm. CONCLUSIONS: Our results indicate that leukocytes from gilthead seabream and sea bass are able to kill their targets by the mechanisms of necrosis and apoptosis, in a similar way to mammalian cytotoxic cells. PMID- 8694286 TI - Histogenesis of the epithelial component of rat thymus: an ultrastructural and immunohistological analysis. AB - BACKGROUND: Despite the assumed importance of thymic cell microenvironments for governing T-cell maturation, little is known about the ontogeny of their cell components. A few studies have analyzed previously the ontogenetical development of rat thymic epithelium (Bogojevic et al. 1990. Period. Biol., 92:126; Kampinga and Aspinall 1990 Harwood Acad. Pub., London, pp. 149-186; Micic et al., 1991 Dev. Comp. Immunol., 15:443-450) and recently we have reported the development of both interdigitating/dendritic cells and macrophages (Vicente et al., 1994 Immunology, 82:75-81, 1995 Immunology, 85:99-105). METHODS: In the present work we analyze in situ ultrastructural, immunohistochemical, and histoenzymatically the appearance and development of the thymic epithelial cell component in both embryonic and neonatal Wistar rats with special emphasis on the origin of the different epithelial cell types, the occurrence or absence of a common precursor for these, and the expression of MHC molecules. RESULTS: The thymic primordium of 13-day-old embryos is formed by a homogeneous population of primitive epithelial cells differentiating gradually into various epithelial cell subtypes of both the cortex and the medulla. In the cortex, subcapsular and stroma-supporting epithelial cells appear at days 14-15 as two structurally different cell entities. At the same time, stroma-supporting, keratinized, and vacuolated epithelial cells occur in the thymic medulla. These last two cell types differentiate subsequently into Hassall's bodies and hypertrophied cells. Lympho epithelial cell complexes are identified in the deep cortex around birth, when the cortical parenchyma houses a transitional erythropoiesis. mAbs (His-39, RMC 20) which recognize medullary epithelial cells in the adult thymus stain positively cells of the thymic primordium as early as day 16 of embryonic life. Cortical epithelial cell markers (His-37, RMC-17) appear, however, slightly later and the subcapsulary region is not established until postnatal life. MHC class I and class II molecules can be identified on epithelial cells in the thymus of 15 day-old embryonic rats although they reach the highest expression around birth. CONCLUSIONS: Our results confirm the heterogeneity of the thymic epithelial component, the persistence of primitive, non-differentiated epithelial cells morphologically similar to those occurring in the early thymic primordium in adult thymus, and the mutual relevance of epithelial cells and thymocytes for an adequate development of rat thymus gland. PMID- 8694287 TI - Morphological changes in the masseter muscle and its motoneurons during postnatal development. AB - BACKGROUND: It has been suggested that the morphological properties of the masseter muscle are changed by the masticatory activity pattern. In the rat, the activity pattern of the muscle alters from sucking to biting around 3 weeks after birth. The working hypothesis in this study is that the unique alteration in masticatory activity has an important influence on the development of the masseter muscle and its motoneurons. METHODS: We examined the morphological changes in the muscle fibers of the superficial masseter muscle and its motoneurons from 2 days to 280 days after birth in the rat. The change in masseter muscle activity sucking and biting was confirmed by electromyography. To label motoneurons innervating the muscle, horseradish peroxidase was injected into the muscle. The muscle and lower brain stem were sliced and processed histochemically to measure the diameters of muscle fibers and its motoneurons in the trigeminal motor nucleus. In addition, composition of myosin heavy chain (MHC) isoforms of the muscles were analyzed using gradient sodium dodecyl sulphate-polyacrylamide gel electrophoresis. RESULTS: There was a rapid growth in both types of muscle fibers (fast-twitch oxidative glycolytic muscle fibers and fast-twitch glycolytic fibers) for 42 days after birth, and then a gradual growth lasting until 280 days after birth. Particularly, rapid growth of the muscle fibers was seen between 21 days and 42 days after birth. A large amount of neonatal type MHC disappeared between 21 days and 42 days after birth. In the motoneuron, there was a rapid growth of motoneurons by 42 days after birth but no significant growth was seen thereafter. CONCLUSIONS: These results suggest that the alteration of mastication activity from sucking to biting has a significant influence on morphological development of both types of muscle fibers, but not on that of motoneurons innervating the masseter muscle. PMID- 8694288 TI - Lymphatic stomata in the murine diaphragmatic peritoneum: the timing of their appearance and a map of their distribution. AB - BACKGROUND: Fluid and free cells in the peritoneal cavity enter the lymphatics through the lymphatic stomata which are channels connecting the lymphatics in the peritoneal side of the diaphragm with the peritoneal cavity. While the stomata thus play a very important in the physiology of the peritoneal cavity, it is unclear when they appear or how they are distributed on the diaphragm. We therefore conducted an embryological study of the process and timing of mouse lymphatic stomata development in the peritoneal surface of the diaphragm. METHODS: The mouse diaphragm, at stage ranging from embryonic day 18 (ED18) to postnatal week 10 (PW10), was observed by scanning electron microscopy, and the number of lymphatic stomata was counted on each observation day. A map of the data was constructed to illustrate the process of appearance of lymphatic stomata. RESULTS: Lymphatic stomata were not found on ED18. They were first found on PD0 and their number increased exponentially until PW10. Lymphatic stomata were usually located in cuboidal cell areas but not in the areas lined with flattened cells. The cuboidal cell area with several lymphatic stomata was first found in the retroparasternal region on PD0, followed by in the muscular portion, as "ridges" on PD4 and "bands" on PD6 or up to a few days later. The long axis of the ridges and bands was oriented from the center to periphery of the diaphragm. Subsequently, cuboidal cell areas with lymphatic stomata formed along the border between the central tendon and the muscular portion, most frequently on PD10. Another cuboidal cell area with lymphatic stomata appeared rather suddenly ventral to the inferior vena cava on PD10. This was the full complement of cuboidal cell areas seen in the adult of PW10. CONCLUSION: These results verified that the course of the change of the shape and distribution of cuboidal cell areas parallels that of the underlying lymphatic lacunae, suggesting the delivery of some stimuli from the lymphatic lacunae to the overlying mesothelial cells that results in alternation of their cell shape. PMID- 8694289 TI - Fibulin-1, vitronectin, and fibronectin expression during avian cardiac valve and septa development. AB - BACKGROUND: Extracellular matrix (ECM) proteins have been implicated as mediators of events important to valvuloseptal development (reviewed by Little and Rongish, Experentia, 51:873-882, 1995). The aim of this study was to identify connective tissue ECM proteins present at sites of valvuloseptal morphogenesis, and to determine how their patterns of expression change during the developmental process. METHODS: Immunofluorescence microscopy was used to examine the distribution of fibulin-1, vitronectin, and fibronectin in the embryonic chicken heart over a broad developmental time frame (Hamburger and Hamilton stages 14 to 44), emphasizing stages that illustrate endocardial cushion formation, growth, fusion, and development into valvuloseptal components. RESULTS AND CONCLUSIONS: Fibulin-1 immunolabeling was concentrated in endocardial cushions, notably at boundaries with the myocardium, during stages when the cushions are differentiating into valvular and septal components. Fibulin-1 was detected in the endocardial cushions prior to their seeding with cushion cells, but became undetectable by early midgestation. Vitronectin expression was similar to fibulin 1, but less restricted in its distribution. Vitronectin was observed before endocardial cushion cell migration commenced and persisted until the formation of prevalvular structures (early midgestation) in the atrioventricular cushions. Vitronectin remained detectable in the semilunar valves until late midgestation. Fibronectin was present in the endocardial cushion region and in portions of the endocardium and myocardium throughout the stages presented. Our data suggests that the ECM of the endocardial cushions undergoes remodelling in a regionally and temporally specific manner which corresponds with morphogenetic changes during valvuloseptal development. PMID- 8694291 TI - Distribution of mesencephalic trigeminal nucleus neurons in the reeler mutant mouse. AB - BACKGROUND: Reeler (gene symbol, rl) is an autosomal recessive mutation occurring in mice and characterized by the abnormal positioning of neurons in the central nervous system. In this mutant, however, the cytoarchitecture of the peripheral nervous system is normal, implying that the reeler genetic locus does not affect migration of neurons in the peripheral system. Mesencephalic trigeminal nucleus (Me5) neurons are unique in that they are derived from the neural crest like other neurons in the peripheral nervous system, but enter secondarily into the central nervous system. MATERIALS AND METHODS: Me5 neurons were labeled by injecting horseradish peroxidase or Fast Blue into the temporal muscle of normal and reeler mice to determine whether the migration of these neurons is affected by the reeler genetic locus. RESULTS AND CONCLUSIONS: Labeled Me5 neurons of the reeler mouse were more widely scattered in comparison with their normal counterparts, suggesting that the reeler genetic locus affects migration of neurons which originate in the neural crest and then migrate into the central nervous system. PMID- 8694290 TI - Suprachiasmatic nucleus of the human brain: an immunocytochemical and morphometric analysis. AB - BACKGROUND: The present paper describes the immunocytochemical and morphometric characteristics of two major cell groups of the suprachiasmatic nucleus (SCN) in the human hypothalamus: the vasopressin (VP) and vasoactive intestinal polypeptide (VIP) neuronal subdivisions. The dimensions (volume and length) and the number of neurons expressing each peptide in the two subdivisions were obtained, as well as the mean diameter of the cell nuclei. All morphometric parameters were studied in relation to sex and age. METHODS: Brains of 42 human subjects (22 males and 20 females) ranging in age from 10 to 92 years were obtained at autopsy. The hypothalamic area containing the SCN was dissected from each brain, dehydrated, and embedded in paraffin. Serial sections of 6 microns were cut in a coronal plane and stained with thionin for general orientation. To determine the architectonic boundaries of the VP- and VIP-expressing cell populations every 25th section was immunocytochemically stained by means of antibodies against arginine VP or VIP using the peroxidase-antiperoxidase method. The VP- and VIP-expressing cell numbers in the SCN of each subject were estimated by unilaterally counting the number of nuclear profiles with the aid of a Zeiss microscope under x 500 magnification, using a deconvolution procedure and a correction for section thickness. RESULTS: The main portion of the VP positive neurons is located in the dorsomedial part of the SCN and is rostrocaudally longer in females than in males (1.76 +/- 0.12 mm and 1.40 +/- 0.10 mm, respectively). The volume of the VP subdivision is 0.244 +/- 0.017 mm3 and contains 6,890 +/- 520 VP-immunoreactive neurons, with a mean density of about 29,000 neurons/mm3. No significant sexual dimorphism or age-related alterations in the population of VP neurons is found. The VIP positive neurons are mainly located in the ventral and central part of the SCN and extend rostrocaudally in a similar way in females and males (1.07 +/- 0.08 mm and 1.02 +/- 0.11 mm, respectively). The volume of the VIP subdivision is 0.034 +/- 0.004 mm3 and contains 1,700 +/- 140 VIP-immunoreactive neurons, with a mean density of about 63,000 neurons/mm3. An age-dependent sexual dimorphism is observed in the number of VIP-expressing neurons in the SCN: young males have about twice as many VIP neurons as females of the same age, whereas in middle-aged subjects this sexual difference is reversed, and less robust, with females now having about 1.7 times as many VIP neurons as males. In old subjects the difference in VIP cell number between men and women disappears. CONCLUSIONS: The present study clearly shows that the population of VP neurons in the human SCN is considerably larger than the population of VIP neurons. Furthermore, the age-related sexual differences in the VIP cell number reinforces the idea that the SCN is not only involved in the timing of circadian rhythms but also in the temporal organization of reproductive functions. PMID- 8694292 TI - Posterior "septum" of human spinal cord: normal developmental variations, composition, and terminology. AB - BACKGROUND: The boundary separating the posterior columns of the spinal cord is formed by the lateral margins of the neural groove approximating to form the neural canal. In anatomy texts this line is usually drawn as continuous, uniform, centered, and straight. It is universally termed posterior or dorsal, median "septum". METHODS: Sections from the cervical and lumbar enlargements and the mid thoracic region were examined from 35 human autopsy specimens from 20 weeks gestation to 70 years with no history of spinal cord disease or trauma. They were stained with Masson's trichrome, and by immunohistochemistry for collagen types 1 and 4, and for glial fibrillary acidic protein (GFAP). RESULTS: One or more variations were found in the position character, shape, or extent of the line at one or more levels in every case. There was no midline staining for collagen other than that associated with blood vessels. There is intense immunoreactivity for GFAP from 20 weeks gestation to 35 weeks diminishing thereafter. When the posterior columns are separated the "septum" divides. CONCLUSION: In the absence of any collagen this line of separation is more akin to a raphe than a septum. Inasmuch as there is an immediately adjacent subarachnoid posterior median septum it would be advantageous to re-name this intraspinal structure "dorsal" or "posterior" median raphe. PMID- 8694293 TI - Crystalloid versus colloid versus colloid: all colloids are not created equal. PMID- 8694294 TI - Signal extraction technology: a better mousetrap? PMID- 8694295 TI - Large-dose intrathecal morphine for coronary artery bypass grafting. AB - Aggressive control of pain during the immediate postoperative period after cardiac surgery, associated with decreased blood catecholamine levels, may decrease morbidity and mortality. This study investigated the use of large-dose intrathecal morphine for cardiac surgery and its effect on postoperative analgesic requirements and blood catecholamine levels. Patients were randomized to receive either 4.0 mg of intrathecal morphine (Group MS) or intrathecal saline placebo (Group NS). Perioperative care was standardized and included postoperative patient-controlled analgesia. Arterial blood samples were obtained perioperatively to ascertain catecholamine levels. Patients in Group MS required significantly less postoperative intravenous morphine than patients in Group NS. Although perioperative norepinephrine and epinephrine levels in Group MS patients tended to be lower than Group NS patients, the differences were not statistically significant. In conclusion, large-dose intrathecal morphine initiates reliable postoperative analgesia but does not reliably attenuate the stress response during and after cardiac surgery. PMID- 8694296 TI - Heparin neutralization with methylene blue, hexadimethrine, or vancomycin after cardiopulmonary bypass. AB - There are no clinically available alternatives for reversing heparin in protamine allergic patients. This study examined the ability of methylene blue, hexadimethrine, and vancomycin to reverse circulating heparin so that these compounds can be carefully examined in future placebo-controlled studies in humans. Heparin activity in blood obtained from extracorporeal circuits was reversed by adding protamine (13.5, 27.0, 81.1, 135.1, and 270.3 micrograms/mL), methylene blue (13.5, 27.0, 135.1, 202.7, 270.3, 337.8, 405.4, 473.0, 540.5, and 810.8 micrograms/mL), hexadimethrine (6.8, 13.5, 20.3, 27.0, 81.1, and 135.1 micrograms/mL), or vancomycin (13.5, 27.0, 135.1, 270.3, 540.5, and 810.8 micrograms/mL), and activated clotting times (ACTs) were measured with kaolin (n = 18). Heparinase-ACT was obtained to determine complete reversal. Heparin concentrations were 3.3 +/- 0.3 U/mL with ACT values of 485 +/- 97 s. The ACT at a protamine concentration of 81.1 micrograms/mL and at hexadimethrine concentrations of 81.1 and 135.1 micrograms/mL was not statistically different from heparinase-ACT; however, methylene blue or vancomycin did not reverse the anticoagulation at any concentrations. Hexadimethrine can reverse heparin-induced anticoagulation after cardiopulmonary bypass as well as protamine, although methylene blue or vancomycin did not neutralize heparin in vitro. PMID- 8694297 TI - Gastroesophageal reflux and tracheobronchial contamination after cardiac surgery: should a nasogastric tube be routine? AB - Nasogastric (NG) tubes are routinely used in patients undergoing cardiac surgery. This randomized study was designed to assess gastroesophageal reflux (GER) without a NG tube (control) compared with a NG tube managed either by gravity drainage (gravity) or continuous low-grade suction (suction). Antimony pH probes were placed in the lower esophagus and trachea after induction of anesthesia in 51 patients, and pH was recorded every 5 s until the time of tracheal extubation. GER was defined as reversible decrease in esophageal pH to less than 4.0. No significant difference was found between groups in age, weight, gender, duration of postoperative ventilation, morphine use, or antiemetic use. All indicators of GER were seen more frequently in the gravity group compared with the two other groups (P < 0.001). One episode of sudden decrease in tracheal pH was observed in a patient in the gravity group, indicating tracheal aspiration, which was associated with delayed extubation and postoperative pneumonia. The absence of a NG tube is not associated with reflux, probably since the gastroesophageal sphincter remains competent. NG tubes are not routinely necessary for cardiac surgery in patients without risk factors for GER, and increase reflux risk if managed without low-grade suction. PMID- 8694298 TI - Comparison of eltanolone and propofol on a pressure-volume analysis of the heart. AB - We designed a randomized study to compare the effect of eltanolone and propofol on cardiac contractility. Patients were anesthetized, tracheally intubated and ventilation controlled. Propofol, 1.25 or 2.5 mg/kg, or eltanolone, 0.5 or 1 mg/kg, or a lipid emulsion only was administered in an intravenous (i.v.) bolus dose. Pressure-volume analysis was used based on radial artery pressure and transesophageal left ventricular cross-sectional area. Both propofol and eltanolone have negative inotropic properties in humans. We conclude that equianesthetic doses of these drugs produce similar changes in myocardial contractility. PMID- 8694299 TI - Isoflurane anesthesia does not add to the bronchodilating effect of a beta 2 adrenergic agonist after tracheal intubation. AB - This double-blind study investigates whether isoflurane/N2O anesthesia adds to the bronchodilating effect of the beta 2-adrenergic agonist, fenoterol, after an endotracheal tube (ETT)-induced increase in airway resistance. Forty-five patients with ASA physical status I-II were randomly assigned to two groups: fenoterol-treated patients (n = 23) were given three metered-dose inhaler puffs (600 micrograms) of fenoterol 10 min before induction of anesthesia and placebo treated patients (n = 22) received three puffs of an aerosol containing no medication. Anesthesia was induced with thiopental and vecuronium intravenously. Respiratory system resistance (Rrs) was measured using a CP-100 pulmonary function monitor 5 min after endotracheal intubation. Inhalation anesthesia was then begun using 50% N2O in O2 with end-tidal 1.3% isoflurane. Rrs measurements were repeated at 5, 15, and 30 min after the initiation of inhalation anesthesia. Postintubation Rrs was significantly lower in the fenoterol-treated patients than in the placebo-treated patients. Rrs declined by a mean of 17.1% after 30 min of inhalation anesthesia in the placebo-treated patients but declined by only 1.4% in the fenoterol-treated patients (P < 0.05 for fenoterol provides protection versus placebo). Our results confirm that fenoterol provides protection against ETT-induced increase of airway resistance. However, isoflurane, while a potent bronchodilator, does not add to the effect of fenoterol. PMID- 8694300 TI - Plasma potentiates the priming effects of endotoxin on platelet activating factor induced pulmonary hypertension in the rabbit lung. AB - During Gram-negative sepsis, endotoxin lipopolysaccharide (LPS) may activate host inflammatory responses, resulting in the systemic inflammatory response syndrome and the adult respiratory distress syndrome. In cell culture systems, LPS activation of cellular responses may be potentiated by plasma proteins. In the isolated perfused rabbit lung, LPS administration markedly increases the pulmonary hypertensive response to subsequent administration of platelet activating factor (PAF). We examined whether plasma would potentiate the priming effects of LPS in this model. Male New Zealand White rabbits were used in a standard, isolated buffer-perfused rabbit lung preparation, and the pulmonary hypertensive response to 5 nM PAF was measured after 2 h of perfusion with different LPS doses (0, 1, and 10 ng/mL), with and without plasma (10% by volume). In the absence of plasma, 10 ng/mL LPS, but not 1 ng/mL LPS, increased the pulmonary hypertensive response to subsequent administration of 5 nM PAF. However, in the presence of plasma, 1 ng/mL LPS significantly increased the hypertensive response to subsequent administration of 5 nM PAF. We conclude that components of plasma--possibly LPS binding protein and soluble CD14--potentiate the priming effect of endotoxin, resulting in an augmented pulmonary hypertensive response to PAF. Thus, plasma proteins decrease the threshold at which endotoxin primes the lung and may have a critical role in the pathogenesis of endotoxin induced acute lung injury. PMID- 8694301 TI - Carbon dioxide elimination measures resolution of experimental pulmonary embolus in dogs. AB - Patients with severe pulmonary embolism can suffer progressive hypercapnia refractory to supramaximal mechanical ventilation, and may require open-thoracic or transvenous emergency embolectomy in addition to anticoagulation and/or thrombolysis. The functional recovery of gas exchange would be signaled by an increase in pulmonary CO2 elimination and decrease in CO2 retention; such data could guide the course of operative embolectomy. Accordingly, we studied five chloralose-urethane anesthetized, mechanically ventilated dogs with open thoraces in which the right pulmonary arteries (RPAs) were reversibly occluded with cloth snares. After waiting for steady state, we abruptly released the snare to restore RPA perfusion and experimentally simulate resolution of pulmonary embolism. For 70 min we serially measure the CO2 volume exhaled per breath (VCO2,br), arterial, mixed venous, and end-tidal PCO2 (PACO2, PVCO2, PETCO2), cardiac output (QT), and the alveolar dead space fraction (VDalv/VTalv = [PaCO2 - PETCO2/PaCO2). RPA reperfusion caused VCO2,br to significantly and abruptly increase from 8.9 +/- 2.7 to 11.6 +/- 3.6 mL; 70 min later VCO2,br had returned to baseline. PaCO2 and PVCO2 steadily decreased during 70 min of RPA reperfusion. PETCO2 increased from 25 +/- 5 to 33 +/- 5 mm Hg immediately after RPA reperfusion, as VDalv/VTalv decreased from 54% +/- 10% to 32% +/- 12%, but PETCO2 was still significantly greater than baseline at 70 min of RPA reperfusion. QT did not significantly change. We conclude that intraoperative measurement of VCO2,br should immediately detect and follow the resolution of CO2 retention in the lung and peripheral tissues after RPA reperfusion. PETCO2 could not detect the decrease of VCO2,br back to baseline because PETCO2 does not measure exhaled volume or the PCO2 waveform. PMID- 8694302 TI - The effects of albumin versus hydroxyethyl starch solution on cardiorespiratory and circulatory variables in critically ill patients. AB - Sufficient intravascular fluid therapy is of major importance in the treatment of the critically ill patient. The present study assessed whether the cardiorespiratory response of long-term volume replacement with low-molecular weight (LMW) hydroxyethyl starch solution (HES) differs from that of human albumin (HA). According to a randomized sequence, 30 trauma patients (injury severity score [ISS] between 15 and 30) and 30 sepsis patients (secondary to major general surgery) received either 10% HES (mean molecular weight 200,000 daltons; HES trauma [n = 15], HES sepsis [n = 15]) or human albumin 20% (HA trauma [n = 15], HA sepsis [n = 15]) over 5 days to keep pulmonary capillary wedge pressure (PCWP) between 12 and 18 mm Hg. Cardiorespiratory variables were measured by a pulmonary artery catheter on the day of inclusion into the study and daily during the next 5 days. Gastric intramucosal pH (pHi) was measured by tonometry. Central venous pressure and PCWP were comparable within the subgroups (trauma/sepsis) throughout the entire study period. In the trauma patients, cardiac index (CI), oxygen consumption index (VO2I), and oxygen delivery index (DO2I), significantly increased only in the HES-treated patients. In the sepsis patients, CI, VO2I, and DO2I increased and remained higher than baseline only in the HES group (P < 0.01). Right ventricular ejection fraction (RVEF) was reduced (< 40%) in the HA patients and increased only in the HES patients (from 34% +/- 4% to 42% +/- 3%; P < 0.05). pHi remained normal (> 7.35) in both trauma groups and in the HES-treated sepsis patients. In the HA sepsis group, pH, decreased (> 7.20) within the study period (7.15 +/- 0.12 on Day 4), indicating deteriorated splanchnic perfusion. We conclude that long-term intravascular fluid therapy with HA in traumatized and sepsis patients has no advantages in comparison to LMW-HES. In both groups, volume replacement with HES even resulted in improved systemic hemodynamics. Decrease in pHi in the sepsis patients was blunted by HES infusion indicating improved splanchnic perfusion by this regimen of volume therapy. PMID- 8694304 TI - Clinical evaluation of a prototype motion artifact resistant pulse oximeter in the recovery room. AB - The frequency and nature of spurious pulse oximetry readings were compared using both a conventional pulse oximeter (CPO) and a prototype Masimo signal extraction technology pulse oximeter (Masimo SET). At a university hospital, 50 ASA physical status I-IV adult patients who underwent general or spinal-epidural anesthesia were selected from a group of 250 patients on the basis of high-alarm generation with routine postoperative pulse oximetry. Pulse oximetry data were recorded simultaneously from both devices with a computer. Overall, the CPO alarm frequency (i.e., oxygen saturation < 90%, or complete signal loss) was once every 13 min, and 87% of these alarms were considered false. Alarms were considered false based on reference electrocardiographs (16 patients), arterial blood gases (7 patients), and clinical assessment. The prototype Masimo SET device alarm frequency was once every 30 min, and 59% of these were considered false. During arm motion with 15 patients, the CPO device produced spurious signals on 54 occasions compared with five for the prototype Masimo SET. The incidence of artifactual pulse oximetry events during patient motion appear to be substantially reduced with the prototype Masimo SET device, relative to a CPO device. PMID- 8694303 TI - Large-dose administration of 6% hydroxyethyl starch 200/0.5 total hip arthroplasty: plasma homeostasis, hemostasis, and renal function compared to use of 5% human albumin. AB - Within a daily dose of 20 mL/kg, medium-molecular hydroxyethyl starch (HES) is a safe and effective colloid for intravascular blood volume replacement. The effect of large doses on coagulation and renal function is unknown. We prospectively studied 41 patients undergoing total hip arthroplasty during the perioperative period. Inevitable blood loss was replaced with HES (HES group) or albumin (ALB group) in combination with packed red blood cells (PRBC), fresh frozen plasma (FFP), and platelets. Hemodynamic, oncotic, coagulation, and renal functions were compared initially, at the end of surgery, during the postoperative period (1, 3, and 6 h), and also with respect to the volume of colloid solution administered (1500, 2000, and 3000 mL). Total intake and output balances, as well as the costs of blood replacement therapy, were registered at the end of the study. We found differences in oncotic variables even at 6 h after surgery (total serum proteins [TSP]:HES 36.4 +/- 7.9 g/L versus ALB 55.6 +/- 6.1 g/L, P < 0.01; serum albumin:HES 25.5 +/- 5.3 g/L versus ALB 42.0 +/- 5.6 g/L, P < 0.01). Colloid osmotic pressure (COP) and hemodynamic, coagulation, and renal functions were comparable, as was total blood loss (HES 4247 +/- 2090 mL versus ALB 4051 +/- 2830 mL). Total requirements for colloid solutions (HES 35.9 +/- 7.4 mL/kg versus ALB 33.9 +/- 10.5 mL/kg), PRBC, FFP, or platelets were comparable, whereas total cost of blood replacement therapy was 33% less in the HES group. With respect to efficacy and side effects on coagulation and renal function, medium molecular HES is an appropriate and economic alternative to albumin at daily doses of up to at least 36 mL/kg. PMID- 8694305 TI - Percutaneous injuries in anesthesia personnel. AB - Anesthesia personnel are at risk for occupationally acquired blood-borne infections from human immunodeficiency virus, hepatitis viruses, and others after percutaneous exposures to infected blood or body fluids. The risk is greater after an infected, blood-contaminated, percutaneous injury, especially from a hollow-bore blood-filled needle, than from other types of exposures. Few data are available on the specific occupational hazards to anesthesia personnel from needles and other sharp devices. Fifty-eight percutaneous injuries (PIs) from anesthesia personnel in nine hospitals were analyzed. Thirty-nine of 58 PIs were from contaminated devices (all needles), and 19 were from uncontaminated devices or of unknown contamination status. Forty-three percent of contaminated percutaneous injuries (CPI) were classified as moderate (some bleeding) or severe (deep injury with profuse bleeding), and most were to health-care workers' hands. Fifty-nine percent of CPI were potentially preventable. Eighty-seven percent of CPI were from hollow-bore needles, and 68% of these were potentially preventable. The largest categories of devices causing CPI were needle on syringe, intravenous (i.v.) or arterial catheter needle-stylet, suture needle, and standard hollow bore needle for secondary i.v. infusion. Most CPI occurred between steps of a multistep procedure (8%), were recapping related (13%), or occurred at other times after use (41%). No CPI were reported from use of needlestick-prevention safety devices. The devices and mechanisms of injury identified in this study provide specific data that may lead to prevention strategies to reduce the risk of PI. PMID- 8694306 TI - A multicenter evaluation of total intravenous anesthesia with remifentanil and propofol for elective inpatient surgery. AB - Remifentanil is a mu-opioid receptor agonist with a context sensitive half-time of 3 min and an elimination half-life < or = 10 min. This study sought to evaluate the efficacy of remifentanil and propofol total intravenous anesthesia (TIVA) in 161 patients undergoing inpatient surgery. Remifentanil 1 microgram/kg was given intravenously (i.v.) followed by one of two randomized infusion rates: small dose (0.5 micrograms.kg-1.min-1) or large dose (1 microgram.kg-1.min-1). Propofol (0.5-1.0 mg/kg i.v. bolus and 75 micrograms.kg-1.min-1 infusion) and vecuronium were also given. Remifentanil infusions were decreased by 50% after tracheal intubation. End points included responses (hypertension, tachycardia, and somatic responses) to tracheal intubation and surgery. More patients in the small-dose than in the large-dose group responded to tracheal intubation with hypertension and/or tachycardia (25% vs 6%; P = 0.003) but there were no other differences between groups in intraoperative responses. Recovery from anesthesia was within 3-7 min in both groups. The most frequent adverse events were hypotension (systolic blood pressure [BP] < 80 mm Hg or mean BP < 60 mm Hg) during anesthesia induction (10% small-dose versus 15% large-dose group; P = not significant [NS]) and hypotension (27% small-dose versus 30% large-dose group; P = NS), and bradycardia (7% small-dose versus 19% large-dose group; P = NS) during maintenance. In conclusion, when combined with propofol 75 micrograms.kg-1.min-1, remifentanil 1 microgram/kg i.v. as a bolus followed by an infusion of 1.0 microgram.kg-1.min-1 effectively controls responses to tracheal intubation. After tracheal intubation, remifentanil 0.25-4.0 micrograms.kg-1.min-1 effectively controlled intraoperative responses while allowing for rapid emergence from anesthesia. PMID- 8694307 TI - Protein kinase C-induced contraction is inhibited by halothane but enhanced by isoflurane in rat coronary arteries. AB - Protein kinase C (PKC), important in signal transduction, may help generate and maintain vascular smooth muscle tone. We sought to examine the effect of the volatile anesthetics isoflurane and halothane on PKC agonist-induced vasoconstriction and PKC inhibitor-induced vasorelaxation. Subepicardial resistance arteries were dissected from rat hearts. Changes in vessel diameters were monitored in response to the membrane-bound PKC agonist 12-deoxyphorbol-13 isobutyric-20-acetate (PBE) 10(-8)-10(-7) M or the cytosolic PKC agonist oleic acid 10(-7)-10(-5.5) M either in the presence of isoflurane 1.15%, isoflurane 2.3%, halothane 0.77%, halothane 1.54%, or no volatile anesthetics (control). In addition, after preconstriction with the thromboxane analog U46619 1 microM, relaxation responses to the PKC inhibitor staurosporine 10(-8)-10(-7) M were examined in the presence or absence of the anesthetics as above. PBE-induced constriction was attenuated by either concentration of halothane (P < 0.05) but was unaltered by isoflurane (P > 0.5). Oleic acid-induced constriction was abolished by halothane (P < 0.001) but enhanced by isoflurane (P < 0.01). Staurosporine-induced relaxation of U46619-preconstricted vessels was attenuated by isoflurane (P < 0.05) but unaltered by halothane (P > 0.3). We conclude that isoflurane may enhance cytosolic PKC-mediated vasoconstriction, whereas halothane may attenuate both cytosolic and membrane-bound PKC-mediated vasoconstriction. PMID- 8694308 TI - In vivo imaging of human limbic responses to nitrous oxide inhalation. AB - Human behavioral studies have shown that nitrous oxide, in subanesthetic concentrations, impairs psychomotor function, cognitive performance, and learning and memory processes. However, the cerebral mechanisms of such effects remain unknown. Positron emission tomography (PET) was used to map the brain areas associated with nitrous oxide effects. Regional cerebral blood flow (rCBF) was measured in eight volunteers, during room air (control) or 20% nitrous oxide (nitrous oxide) inhalation using 15(O)-water, to reflect regional neuronal activity. To control for the possibility that 20% nitrous oxide uncoupled cerebral blood flow and metabolism, in four of the subjects, regional cerebral metabolic rate (rCMR) was also measured using 18F-deoxyglucose during the two experimental conditions. Results of rCBF and rCMR scans were compared between conditions using the statistical parametric mapping method, and areas of nitrous oxide-related activation or deactivation were identified at a significance level of 0.005. Percent changes in rCBF scan pixels from these activated or deactivated areas were then compared with those of stereotactically corresponding rCMR scan pixels with t statistics (P < 0.05 was defined as a significant difference). It was found that cerebral blood flow and metabolism were not uncoupled by 20% nitrous oxide, since percent changes in rCBF and rCMR, detected during nitrous oxide inhalation, did not differ significantly from each other (P < 0.05). Nitrous oxide inhalation was associated with significant activation in the anterior cingulate cortex, a limbic area known to mediate psychomotor and cognitive processes. Deactivation was found in the posterior cingulate, hippocampus, parahippocampal gyrus, and visual association cortices in both hemispheres; the former two regions are known to mediate learning and memory. These areas identified by PET in vivo may provide the neuroanatomical basis for the behavioral responses associated with subanesthetic nitrous oxide inhalation. PMID- 8694309 TI - The effects of varying volumes of crystalloid administration before cesarean delivery on maternal hemodynamics and colloid osmotic pressure. AB - The value of intravenous crystalloid administration in preventing spinal-induced hypotension in the parturient has recently been questioned. Also, the association between increasing crystalloid volume and decreasing postpartum colloid osmotic pressure (COP) raises concern regarding the risk of maternal and fetal pulmonary edema. To study the dose-response effect of varying amounts of crystalloid volume prior to spinal anesthesia, we measured maternal hemodynamic variables and maternal and fetal COP in three groups of healthy parturients receiving spinal anesthesia for elective cesarean delivery. Fifty-five parturients were randomized in a double-blind fashion to receive one of 10, 20, or 30 mL/kg of crystalloid volumes prior to induction of spinal anesthesia. Measurements included mean arterial blood pressure (MAP), cardiac index (CI), and systemic vascular resistance index (SVRI) recorded using noninvasive thoracic impedance monitoring until delivery. Maternal and neonatal COP were measured. All groups showed declines in MAP and SVRI from baseline at 5 min after spinal anesthesia, but the amount of decline did not differ among groups. Total ephedrine and additional intravenous (i.v.) fluid administered did not differ among groups. The 20- and 30 mL/kg groups showed a larger decline in maternal COP than the 10-mL/kg group; no differences in neonatal COP were seen with varying preload. We conclude that increasing the amount of i.v. crystalloid administered to 30 mL/kg in the healthy parturient does not significantly alter maternal hemodynamics or ephedrine requirements after spinal anesthesia and has no apparent benefit. PMID- 8694310 TI - A comparison of costs and efficacy of ondansetron and droperidol as prophylactic antiemetic therapy for elective outpatient gynecologic procedures. AB - Ondansetron and droperidol are both effective prophylactic antiemetics for gynecologic outpatient procedures. However, increased drowsiness, delayed discharge, and postdischarge restlessness may occur with droperidol, and ondansetron is costly. In this prospective, randomized, double-blind, placebo controlled study involving 161 women, we compared the efficacy, safety, and cost effectiveness of ondansetron (4 mg intravenously [i.v.] with droperidol (0.65 mg or 1.25 mg i.v.) in the prevention of postoperative nausea and vomiting (PONV) after outpatient gynecologic surgery. The incidence of PONV, times to achieving preset recovery criteria, and patient-evaluated visual analog scales for sedation, anxiety, pain, and nausea were recorded, along with postdischarge emetic episodes, medications, quality of sleep, and time to resumption of food intake, normal activity, and return to work. A decision analysis tree was used to divide each data set into nine mutually exclusive subgroups, and costs and probabilities were assigned to each subgroup. The cost-effectiveness ratio was determined by summing these weighted costs and dividing by the number of patients free from both PONV and side effects of antiemetic therapy. The incidence of PONV in the hospital and after discharge, the need for rescue antiemetic therapy, and recovery and discharge times were similar for the ondansetron and both droperidol groups but differed significantly from those for the placebo group. The cost effectiveness ratios for both droperidol 0.65 mg and 1.25 mg groups were significantly lower than those for the ondansetron and placebo groups. We conclude that droperidol 0.625 mg i.v. provides antiemetic prophylaxis comparable to that of ondansetron 4 mg i.v. without increasing side effects or delaying discharge and is most cost-effective. PMID- 8694311 TI - A multicenter comparison of maintenance and recovery with sevoflurane or isoflurane for adult ambulatory anesthesia. The Sevoflurane Multicenter Ambulatory Group. AB - Sevoflurane was compared with isoflurane in 246 adult ASA class I-III patients undergoing ambulatory surgery. After administration of midazolam 1-2 mg and fentanyl 1 microgram/kg, anesthesia was induced with propofol 2 mg/kg and maintained with either sevoflurane or isoflurane in 60% nitrous oxide to maintain arterial blood pressure at +/- 20% of baseline. Fresh gas flows were 10 L/min during induction and 5 L/min during maintenance. Times to eye opening, command response, orientation, and ability to sit without nausea and/or dizziness were significantly faster after sevoflurane. Significantly more sevoflurane patients met Phase 1 of postanesthesia care unit (PACU) Aldrete recovery criteria (> or = 8) at arrival, 95% vs 81%. Also, significantly more sevoflurane patients were able to complete psychomotor recovery tests during the first 60 min postanesthesia. Discharge times were not different. Sevoflurane patients had significantly lower incidences of postoperative somnolence (15% vs 26%) and of nausea both in the PACU (36% vs 51%) and in the 24-h postdischarge period (9% vs 24%). Patient satisfaction was high overall (sevoflurane 97%, isoflurane 93%). We conclude that sevoflurane is a useful inhaled anesthetic for maintenance of ambulatory anesthesia. PMID- 8694312 TI - Intubating conditions and onset of action after rocuronium, vecuronium, and atracurium in young children. AB - To evaluate muscle relaxant onset times and tracheal intubating conditions, 60 children (ASA physical status I or II) aged 18 to 72 mo were randomly assigned to receive a bolus of either rocuronium 0.6 mg/kg, vecuronium 0.1 mg/kg, or atracurium 0.5 mg/kg. After induction of anesthesia with etomidate 0.2-0.4 mg/kg and fentanyl 1-3 mg/kg, lungs were ventilated with 50% nitrous oxide in oxygen via a face mask. The evoked electromyogram of the adductor pollicis to a train-of four stimulation every 20 s was monitored. After administration of the muscle relaxant, endotracheal intubation was attempted every 30 s, beginning 30 s after drug administration, until intubation could be achieved with good or excellent conditions. Rocuronium produced acceptable intubating conditions significantly faster (all tracheas intubated within 60 s) compared with vecuronium (120 s) and atracurium (180 s). The quality of intubating conditions at the time of completed intubation was rated significantly better with rocuronium than with vecuronium or atracurium. However, onset to 95% block at the adductor pollicis muscle was not significantly different after rocuronium (92 +/- 46.9 s), vecuronium (112 +/- 33.3 s), or atracurium (134 +/- 57.1 s), and mean neuromuscular block achieved at the point of successful intubation was not complete in all groups. We conclude that clinically acceptable intubating conditions are produced more rapidly with rocuronium than with atracurium or vecuronium. PMID- 8694313 TI - Effects of ondansetron on emesis in the first 24 hours after craniotomy in children. AB - Children undergoing neurosurgical resection are at high risk for postoperative nausea and vomiting. Ondansetron, a selective serotonergic (5-HT3) antagonist, is effective in reducing postoperative vomiting in several high-risk populations. In a prospective, randomized study, we compared the prophylactic use of intravenous ondansetron, 0.15 mg/kg, versus placebo for the prevention of emesis in 60 children, aged 2-18 yr, undergoing craniotomies for resective procedures. Patients with preoperative emesis were excluded from the study. All patients were tracheally extubated at the conclusion of surgery, and each episode of emesis during the first 24 postoperative hours was recorded. For the entire 24-h interval, the incidence of emesis in children who received ondansetron (57%) was not significantly different from that in those who received placebo (66%); however, in the first 8 h, the incidence was 25% (ondansetron) vs 44% (placebo) (P = not significant). In those receiving placebo, there was no difference in emesis between patients undergoing operations above versus below the tentorium. Although our sample size was too small to completely exclude any beneficial effect, ondansetron appears ineffective in preventing postoperative emesis in this patient population. PMID- 8694314 TI - The effect of halothane on phrenic and chemoreceptor responses to hypoxia in anesthetized kittens. AB - We examined the effect of halothane on phrenic never and carotid sinus discharge during hypoxia in anesthetized kittens. In 12 animals, phrenic amplitude was measured during normoxia, during isocapnic hypoxia, and after a return to normoxia, both with and without halothane. Without halothane, all animals had an increase in phrenic amplitude during hypoxia. With halothane, half the animals showed an increase in phrenic amplitude followed by a decline. In a second group of animals, recordings were obtained from single or a few fiber strands of carotid sinus nerve. Without halothane, an increase in chemoreceptor discharge frequency during hypoxia was seen. With 1.0% halothane, frequency was decreased during normoxia and did not increase during hypoxia. Thus, halothane's effect on the ventilatory response to hypoxia, as measured by phrenic discharge, is at least partially explained by an effect on peripheral chemoreceptors. PMID- 8694315 TI - Hydroxyethyl starch solution attenuates blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats. AB - This study was performed to investigate whether a fraction of hydroxyethyl starch macromolecules, prepared from pentastarch and known as "Hes-Pz," with molecular weights of 100,000-1,000,000, protects against blood-brain barrier (BBB) disruption due to intracarotid injection of hyperosmolar mannitol. Rats were anesthetized with isoflurane, and retrograde catheterization of a unilateral eternal carotid artery was performed. Except for the Control group (n = 8), hemodilution was performed using lactated Ringer's solution LR group, n = 7), 6% hetastarch (HES group, n = 7), or 6% HES-Pz (HES-Pz group, n = 8) to reduce the hematocrit to about 23%. The BBB transfer coefficient (Ki) of 14C-alpha aminoisobutyric acid was determined after a unilateral intracarotid injection of 25% mannitol. Blood pressure and hematocrit were similar in all groups. In the control group, Ki was increased significantly in the ipsilateral cortex (IC) where mannitol was injected (16.3 +/- 6.1 vs 4.1 +/- 1.4 microL.min-1) when compared with the contralateral cortex (CC). Ki was similar in the CC in all four groups. The Ki in the IC was significantly lower in the HES-Pz(6.4 +/- 3.5 microL.g-1.min-1) than in the Control, HES, or LR group (16.3 +/- 6.1, 19.0 +/- 12.9, 17.9 +/- 10.8 microL.g-1.min-1, respectively). Our data suggest that HES-Pz significantly attenuates disruption of the BBB caused by an injection of hyperosmolar mannitol. PMID- 8694316 TI - Effect of oncotic pressure of diaspirin cross-linked hemoglobin (DCLHb) on brain injury after temporary focal cerebral ischemia in rats. AB - Previous studies have shown that diaspirin cross-linked hemoglobin (DCLHb, 10 g/dL) decreases cerebral ischemia and the resultant injury in a dose-dependent manner, requiring large volumes of DCLHb for maximum efficacy. We assessed the effect of a more concentrated (20 g/dL) and more hyperoncotic preparation of DCLHb on cerebral infarction volume. Immediately after middle cerebral artery occlusion, rats were randomized to one of the following groups: Control, hematocrit not manipulated; 10/Hb, hematocrit decreased to 30% with 10% DCLHb (oncotic pressure 43 mm Hg); 7.5/Alb, hematocrit decreased to 30% with 7.5% albumin (oncotic pressure 43 mm Hg); 20/Hb, the same dose of DCLHb (20%, oncotic pressure 129 mm Hg) as the 10/HB group (half the volume); or 15/Alb, the same dose of albumin (15%, oncotic pressure 130 mm Hg) as the 7.5/Alb group half the volume). After 90 min of ischemia, 72 h of reperfusion was allowed. Infarction volume (mm3, mean +/- sd) was less in the DCLHb groups (10/Hb = 79 +/- 17; 20/HB = 51 +/- 14) than the oncotically matched albumin groups (7.5/Alb = 124 +/- 21; 15/Alb = 85 +/- 18) and the Control group (135 +/- 17) (P < 0.05). These data indicate that in this model of cerebral ischemia, DCLHb decreases ischemic brain injury more effectively than albumin, and that a hyperoncotic preparation of DCLHb is preferable. PMID- 8694317 TI - Intracranial pressure and hemodynamic effects of remifentanil versus alfentanil in patients undergoing supratentorial craniotomy. AB - Remifentanil hydrochloride is an ultra-short-acting esterase metabolized mu opioid receptor agonist. The purpose of this study was to provide preliminary information regarding the effects of this drug on intracranial pressure (ICP) and mean arterial pressure (MAP) in patients scheduled for craniotomy. Twenty-six patients undergoing excision of supratentorial space-occupying lesions were anesthetized with 0.3-0.8 vol% isoflurane in a 2:1 mixture of nitrous oxide:oxygen. Ventilation was adjusted to provide a Paco2 of < 30 mm Hg. After the first burr hole was drilled, patients (n = 5-6 per group) were administered an intravenous infusion of study drug (placebo, remifentanil 0.5 micrograms/kg or 1.0 micrograms/kg, or alfentanil 10 micrograms/kg or 20 micrograms/kg) over 1 min. Epidural ICP and MAP values were recorded at baseline, at completion of infusion, and every minute for the next 10 min. Blood study drug concentrations were measured immediately after completion of infusion. Neither opioid caused a significant increase in ICP. Both drugs were associated with a dose-dependent decrease in MAP. Remifentanil was 31 times more potent than alfentanil for effects on MAP. We conclude that remifentanil produces similar cerebral perfusion pressure effects as does alfentanil. PMID- 8694318 TI - Monitoring the integrity of somatosensory pathways with evoked electroencephalographic bursts. AB - During isoflurane-induced electroencephalographic (EEG) suppression, external stimuli evoke high-amplitude cortical responses (bursts). We tested whether bursts evoked by somatosensory stimuli would reliably distinguish intact somatosensory pathways from pathways in which peripheral nerve conduction had been blocked by local anesthetic. Ten subjects were anesthetized with isoflurane until burst suppression was achieved. During EEG suppression, they were given somatosensory stimulation, consisting of 3-s episodes of 60 electric pulses (20 mA, 0.2 ms), to the tips of the left and right fifth fingers alternately for 10 min. One finger was then anesthetized at the base of the proximal phalanx with prilocaine and the other finger was injected with saline in a double-blind manner. The stimulation was continued for 20 min. In nine patients, the disappearance of bursts in response to stimuli applied to the anesthetized finger clearly indicated the side of the conduction block. After the injection of local anesthetic, there was a predominance of offset bursts over onset bursts in response to stimuli applied to the anesthetized finger (P < 0.05) before the responses disappeared. We conclude that evoked bursts merit further investigation for potential use in monitoring the integrity of neural pathways. PMID- 8694319 TI - Intensity of halothane- and hypercapnia-induced cerebral hyperemia is strain dependent in rats. AB - Cerebrovascular responses to physiologic and pharmacologic stimuli vary between laboratories using different strains of the same species. We tested whether the cerebral blood flow (CBF) response to 1% halothane or hypercapnia is strain dependent in rats. Age-matched adult male (n = 14 of each strain) Wistar, Wistar Kyoto (WKY), and spontaneously hypertensive rats (SHR) were anesthetized with pentobarbital and mechanically ventilated. Under baseline conditions blood flow to cerebrum (microspheres) in WKY (66 +/- 5 mL.min-1.100 g-1) was less than (P < 0.05) in Wistar (88 +/- 5 mL.min-1.100g-1) and SHR (83 +/- 5 mL.min-1.100 g-1). Blood flow to brainstem was greater (P < 0.05) in Wistar (106 +/- 8 mL. min-1.100 g-1) than in WKY (71 +/- 5 mL.min-1. 100 g-1) and SHR (84 +/- 4 mL.min-1.100 g 1). In the halothane protocol (n = 8 each strain), administration of 1% halothane, during normocapnia, increased blood flow to the cerebrum in WKY (64 +/ 6 to 120 +/- 12 mL.min-1.100 g-1, P < 0.05) and SHR (78 +/- 6 to 115 +/- 8 mL.min-1.100 g-1, P < 0.05) but not Wistar rats (88 +/- 8 to 102 +/- 5 mL.min 1.100 g-1, not significant). Discontinuing halothane caused blood flow to return to baseline values. In the hypercapnia protocol (n = 6 each strain), exposure to 3% CO2 (to achieve a PaCO2 of 50-55 mm Hg) and 6% CO2 (to achieve a PaCO2 of 60 70 mm Hg) caused blood flow to the cerebrum to increase in Wistar (87 +/- 11 to 112 +/- 15 to 162 +/- 23) to similar amount as observed in WKY (69 +/- 7 to 115 +/- 13 to 162 +/- 23 mL.min-1. 100 g-1) but less than that observed in SHR (89 +/ 7 to 174 +/- 24 to 237 +/- 28 mL.min-1.100 g-1). These data demonstrate that the cerebral hyperemic response to vasodilator stimuli is strain-dependent in rats. PMID- 8694320 TI - Digital pressure during interscalene block is clinically ineffective in preventing anesthetic spread to the cervical plexus. AB - The application of digital pressure above the injection site during interscalene block has been advocated to prevent cephalad spread of local anesthetic. In prior studies, radiographs taken immediately after interscalene injection of radiographic contrast have supported this concept. However, the clinical efficacy of digital pressure has not been previously tested. If digital pressure were effective in inhibiting cephalad spread of local anesthetic, attenuation of both hemidiaphragmatic paresis and the resulting compromise in pulmonary function would be expected. Sensory, motor, and pulmonary effects were prospectively evaluated in 20 patients presenting for elective shoulder surgery. Patients were randomly assigned to receive interscalene block with or without digital pressure. No clinical differences were seen between groups. All 20 patients had ipsilateral hemidiaphragmatic paresis by ultrasonographic evaluation and large mean decreases in forced vital capacity, 31.2% +/- 7.8% (with digital pressure), 33.7% +/- 12.8% (without digital pressure), and forced expiratory volume at one second, 27.9% +/- 9.3% (with digital pressure), 33.7 +/- 12.8% (without digital pressure). Peak sensory level of anesthesia to pinprick was not significantly different between groups, each group having mean levels of C-2 to C-3. Digital pressure was ineffective in limiting the flow of local anesthetic into the cervical plexus. Digital pressure influenced neither the incidence of diaphragmatic paresis nor the resulting large decreases in pulmonary function that result from interscalene block. PMID- 8694322 TI - Preoperative wound infiltration with bupivacaine reduces early and late opioid requirement after hysterectomy. AB - We conducted a randomized, double-blind trial to evaluate the early and late analgesic effect of preoperative wound infiltration with bupivacaine 0.25% (40 mL) compared to placebo (NaCl 0.9%, 40 mL) in patients undergoing major surgery. Forty-one patients scheduled for elective hysterectomy during general anesthesia were included. The pain management focused on pain prevention, including preoperative administration of nonsteroidal antiinflammatory drugs (NSAIDs), and peroperative administration of opioids. Postoperatively patients received buprenorphine and/or acetaminophen on demand. A significant difference between treatments was evident in the 3-day postoperative trial period. With identical pain scores in the two groups, the requested total amount of buprenorphine was greater in the placebo group (2.0 [0-5.1] mg) (median and [range]) than in the bupivacaine group (0.8 [0-2.8] mg) (P < 0.05). The demand for analgesics occurred earlier in those who received placebo (225 min) than in those who received bupivacaine (345 min), but did not reach the level of significance. In conclusion, preoperative wound infiltration with bupivacaine improved immediate and late postoperative pain management after hysterectomy compared to placebo. PMID- 8694321 TI - An evaluation of antidepressants in rheumatic pain conditions. AB - In a randomized, double-blind, parallel study, fluoxetine and amitriptyline were compared with placebo in the treatment of chronic rheumatic pain. A total of 59 patients were evaluated during 4 wk of treatment and received 20 mg fluoxetine, 25 mg amitriptyline, or placebo daily. Pain intensity, pain relief, vital variables, and global evaluation were used to assess efficacy. To evaluate safety variables, the incidence of side effects was noted. Both amitriptyline and fluoxetine significantly reduced pain intensity compared with placebo. Similarly, pain relief was greater with both amitriptyline and fluoxetine than with placebo. At the end of the fourth week, fluoxetine was superior in efficacy to amitriptyline. The incidence of adverse effects was significantly greater with amitriptyline; dryness of the mouth was the most predominant side effect. We conclude that fluoxetine is an effective analgesic with fewer side effects. PMID- 8694323 TI - Mechanism of action of an epidural top-up in combined spinal epidural anesthesia. AB - The purpose of this study was to elucidate the mechanism of action by which an epidural top-up reinforces anesthesia in combined spinal epidural anesthesia. Thirty patients scheduled to undergo lower limb orthopedic surgery were randomly allocated to three groups of 10 patients each. In all patients, a 16-gauge Tuohy needle was introduced into the epidural space. Using the needle through needle technique, each patient received a subarachnoid injection of 10 mg plain bupivacaine 0.5% through a long 27-gauge Whitacre spinal needle introduced into the subarachnoid space through the Tuohy needle. After withdrawal of the spinal needle, an epidural catheter was introduced into the epidural space. After the maximum level of sensory block after the subarachnoid injection had been established, an epidural top-up with 10 mL bupivacaine 0.5% (Group 1) or 10 mL saline (Group 2) was administered; patients in Group 3 received no epidural top up. The maximum level of sensory block was then assessed for an additional 30 min. After the epidural top-up the maximum level of sensory block increased significantly by 4.8 +/- 1.6 segments in Group 1 and 2.0 +/- 2.0 segments in Group 2. In Group 3 there was a nonsignificant increase of 0.3 +/- 0.5 segments. Intergroup comparisons showed that this increase in Group 1 was significant compared with those in Groups 2 and 3, and that the increase in Group 2 was significant compared with that in Group 3. We conclude that the mechanism of action by which an epidural top-up reinforces anesthesia in combined spinal epidural anesthesia can be explained partly by an epidural volume effect and partly by an effect of the local anesthetic itself. PMID- 8694324 TI - Alfentanil dose-response relationships for relief of postoperative pain. AB - The aim of this study was to characterize within-patient alfentanil dose-response curves for the relief of spontaneous postoperative pain and to test the closeness of relationships 1) between pain intensity and alfentanil analgesic requirements, and 2) between alfentanil requirements for analgesic and nonanalgesic (sedative and miotic) effects. The effects of alfentanil were studied in 23 patients after elective abdominal surgery. During a 40- to 60-min testing session, the patient received two intravenous (i.v.) injections of saline (placebo) and up to six 3 micrograms/kg increments of alfentanil at 5-min intervals. The patient rated the pain intensity with a visual analog scale, and in a subgroup of 15 patients the blinded observer rated patients' sedation and measured pupil diameter. Spontaneous postoperative pain was completely relieved in all patients with cumulative doses of alfentanil ranging from 6 to 8 micrograms/kg. The within patient alfentanil dose-analgesic response curves were primarily quantal in nature: a precipitous decrease in pain intensity (representing > or = 2/3 of the total effect) after the injection of only one of the increments of alfentanil was observed in 15 of 23 patients. When the analgesic effect of alfentanil was presented as the collective response of a group of individuals, the quantal nature of the response was concealed by the wide interindividual variability of the response. No statistically significant relationship was noted between predrug pain intensity and the cumulative dose of alfentanil necessary to produce pain relief. A strong correlation was found between interpatient variabilities in the analgesic and sedative effects of alfentanil (r = 0.75, P < 0.002). At the same time, the relationship between alfentanil requirements for pain relief and that for pupil constriction did not demonstrate any significant correlation. The results suggest that, in a population of patients with postoperative pain, the intensity of spontaneous pain cannot be the primary factor determining the dose of alfentanil necessary for its relief. PMID- 8694325 TI - The analgesic efficacy and adverse effects of continuous epidural sufentanil and bupivacaine infusion after thoracotomy. AB - We investigated analgesia and the adverse effects of epidural sufentanil infusion in a double-blind randomized study of 37 patients undergoing thoracic surgery. Sufentanil 1 microgram/mL was administered at a thoracic (Ts, n = 12) or lumbar level (Ls, n = 11), or combined with bupivacaine 1 mg/mL at a thoracic level (Tsb, n = 14). Postoperatively, the epidural infusion rate was titrated (4-20 mL/h) according to the visual analog pain scale when assessed during function (VAS-F) or the occurrence of side effects. When epidural analgesia failed, nonsteroidal antiinflammatory drugs (NSAIDs) were given. VAS-F was lowest in the Tsb group (Tsb < Ts = Ls) despite its having both the lowest rate of epidural infusion (Tsb < Ts < Ls) and need of additional NSAIDs (Tsb < Ts = Ls). Sedation (Tsb < Ts < Ls) and hypercapnia (Tsb = Ts < Ls) occurred most frequently in the Ls group. Vital capacity (VC) was reduced in all groups by 43%-58% (Ls > Ts) and had recovered only partially at 24 h after discontinuation of the epidural infusion. The slopes of the ventilatory response (minute ventilation [VE], inspiratory flow, and mouth occlusion pressure at 0.1 s [P0.1]) to 7% CO2 decreased during treatment in Ls, Ts, and Tsb groups at the most by 73%, 55%, and 52% (not significant [NS] between groups), 59%, 45%, and 38% (NS between groups), and 81%, 43%, and 18% (Ls > Tsb), respectively. Twenty-four hours after discontinuation of the epidural infusion, there was a complete recovery of the VE, inspiratory flow, and P0.1 response to CO2 in the Tsb group only. The study shows that, after thoracotomy, epidural sufentanil analgesia is optimal when tailored to the site of nociceptive input and combined with bupivacaine. PMID- 8694326 TI - The pharmacokinetics of continuous epidural sufentanil and bupivacaine infusion after thoracotomy. AB - In a double-blind, randomized study in patients undergoing thoracic surgery the plasma and cerebrospinal fluid (CSF) pharmacokinetics of the epidural sufentanil were studied by using radioimmunoassay analysis. Sufentanil was given as an infusion (1 microgram/mL) at the lumbar (Ls; n = 11), or thoracic (Ts; n = 12) level, or epidural sufentanil combined with bupivacaine (1 mg/ mL) at the thoracic level (Tsb; n = 14). Postoperatively, the infusion was adjusted to optimize analgesia. During the infusion, the sufentanil plasma concentrations were related to the rate of epidural infusion and unrelated both to the epidural infusion regimen and to the postoperative pain scores. The elimination half-life in plasma (mean +/- SEM) was 9.9 +/- 1.7 h (Ls), 8.6 +/- 0.7 h (Ts), and 11.7 +/- 2.2 h (Tsb). The distribution volume was 15.2 +/- 3.5 l/kg (Ls), 14.8 +/- 2.4 L/kg (Ts), and 12.9 +/- 1.2 L/kg (Tsb). Total sufentanil clearance was 17.8 +/- 1.4 and 16.9 +/- 2.0 mL.kg-1.min-1 (Ls), 22.9 +/- 3.5 and 20.0 +/- 2.6 mL.kg 1.min-1 (Ts), and 22.4 +/- 3.0 and 14.5 +/- 1.3 mL.kg-1.min-1 (Tsb). The terminal elimination half-life of sufentanil in CSF was 7.2 +/- 0.6 h. During steady state the CSF concentrations were not homogeneously distributed and they were higher than those in plasma. These pharmacokinetic findings support the concept that epidural sufentanil analgesia is optimal when administered segmentally and tailored to the surgical incision. PMID- 8694327 TI - Economic benefits attributed to opening a preoperative evaluation clinic for outpatients. PMID- 8694328 TI - Neurologic complications in critically ill patients. PMID- 8694329 TI - Propofol-induced dyskinesias in Parkinson's disease. PMID- 8694330 TI - Cephalic tetanus in a nontraumatized patient with left facial palsy. PMID- 8694331 TI - Obstruction due to retained carbon dioxide absorber canister wrapping. PMID- 8694332 TI - Tangier disease. PMID- 8694333 TI - The anesthetic management of patients with multiple pterygium syndrome. PMID- 8694334 TI - Aprotinin administration and disseminated intravascular coagulation. PMID- 8694335 TI - Extrinsic pathway--associated activated clotting time for anticoagulation monitoring during cardiopulmonary bypass. PMID- 8694336 TI - Spondyloepiphyseal dysplasia congenita syndrome: anesthetic implications. PMID- 8694337 TI - Facial nerve palsy after bat ear surgery. PMID- 8694338 TI - Transition from intrathecal analgesia to epidural anesthesia for emergency cesarean section using a combined spinal epidural technique. PMID- 8694339 TI - Critical care anesthesiology is not perioperative medicine. PMID- 8694340 TI - Myringotomy tube placement--another role for EMLA cream? PMID- 8694341 TI - Critical care anesthesiology--an alternative viewpoint. PMID- 8694342 TI - Preoperative pregnancy testing. PMID- 8694343 TI - Electromyographic comparison of obturator nerve block to 3-in-1 block. PMID- 8694344 TI - Transient neurologic symptoms after spinal anesthesia. PMID- 8694345 TI - Obtaining informed consent for anesthesia research. PMID- 8694346 TI - Preoperative pregnancy testing: "justice and testing for all". PMID- 8694347 TI - The cost of preoperative pregnancy testing. PMID- 8694348 TI - The cost of preoperative pregnancy testing. PMID- 8694349 TI - Preoperative pregnancy testing revisited. PMID- 8694350 TI - A new wrinkle. PMID- 8694351 TI - Laryngeal mask and aspiration of gastric contents. PMID- 8694352 TI - Sevoflurane-based anesthesia in a patient with myotonia dystrophica. PMID- 8694353 TI - Evolution of anesthesiology. PMID- 8694354 TI - Acetylcholine stimulates the release of nitric oxide from rat spinal cord. AB - BACKGROUND: Acetylcholine causes synthesis of nitric oxide in vascular endothelium, and presumptive evidence in vivo suggests spinally released acetylcholine causes antinociception and increased sympathetic nervous system activity via a nitric oxide mechanism. The purpose of this study was to determine, using a recently described bioassay system, whether acetylcholine stimulates nitric oxide release from spinal cord tissue in vitro. METHODS: Rat thoracolumbar spinal cord slices were incubated in a tissue chamber and perfused with Krebs-Henseleit solution. The perfusate was then passed through endotheliumdenuded rat aortic rings and their tension was measured. Vascular rings were preconstricted with phenylephrine, then were exposed to spinal cord perfusate with increasing concentrations (10(-12)-10(-4)M) of acetylcholine alone or with various antagonists. RESULTS: Acetylcholine perfusion of spinal tissue caused concentration-dependent relaxations of the aortic rings, an effect blocked by each of the muscarinic antagonists, atropine, pirenzepine, and AFDX-116. Acetylcholine-induced relaxation also was antagonized by an inhibitor of nitric oxide synthase (N-methyl-L-arginine), a nitric oxide scavenger (hemoglobin) and an inhibitor of guanylate cyclase (methylene blue). CONCLUSIONS: These results demonstrate release of a vasorelaxant from spinal cord tissue by acetylcholine, which results from an action on muscarinic receptors and exhibits a pharmacology consistent with nitric oxide. Although precise anatomic localization of acetylcholine's action is not possible with this system, these results add to evidence that acetylcholine causes nitric oxide synthesis in the spinal cord. PMID- 8694355 TI - Preemptive analgesia: intraperitoneal local anesthetic in laparoscopic cholecystectomy. A randomized, double-blind, placebo-controlled study. AB - BACKGROUND: A controversy exists over the effectiveness and clinical value of preemptive analgesia. Additional studies are needed to define the optimum intensity, duration, and timing of analgesia relative to incision and surgery. METHODS: One hundred twenty patients undergoing laparoscopic cholecystectomy under general anesthesia plus topical peritoneal local anesthetic or saline were studied. Local anesthetic (0.5% bupivacaine with epinephrine) or placebo solutions were given as follows: immediately after the creation of a pneumoperitoneum (blocking before surgery), and at the end of the operation (blocking after surgery). Patients were randomly assigned to one of four groups of 30 patients each. Group A (placebo) received 20 ml 0.9% saline both before and after surgery, group B received 20 ml 0.9% saline before surgery and 20 ml local anesthetic after surgery, group C received 20 ml local anesthetic both before and after surgery, group P received 20 ml local anesthetic before and 20 ml 0.9% saline after surgery. Pain was assessed using a visual analog scale and a verbal rating scale at 0, 4, 8, 12, and 24 h after surgery. Metabolic endocrine responses (blood glucose and cortisol concentrations) and analgesic requirements also were investigated. RESULTS: Pain intensity (visual analog and verbal rating scales) and analgesic requirements were significantly less in the group receiving bupivacaine after surgery compared to placebo. However, in the groups receiving bupivacaine before surgery, both pain intensity and analgesic consumption were less than in the group receiving bupivacaine only after surgery. Blood glucose and cortisol concentrations 3 h after surgery were significantly less in groups receiving bupivacaine before surgery. CONCLUSIONS: The results indicate that intraperitoneal local anesthetic blockade administered before or after surgery preempts postoperative pain relative to an untreated placebo-control condition. However, the timing of administration is also important in that postoperative pain intensity and analgesic consumption are both lower among patients treated with local anesthetic before versus after surgery. PMID- 8694356 TI - Influence of volatile anesthetics on left ventricular afterload in vivo. Differences between desflurane and sevoflurane. AB - BACKGROUND: This investigation examined the effects of desflurane and sevoflurane on quantitative indices of left ventricular afterload derived from aortic input impedance (Zin) interpreted using a three-element Windkessel model. METHODS: After Animal Care Committee approval, dogs (n = 8) were chronically instrumented for measurement of systemic hemodynamics including aortic blood pressure and flow. On separate days, aortic pressure and flow waveforms were recorded under steady-state conditions in the conscious state and after equilibration for 30 min at 1.1, 1.3, 1.5, and 1.7 minimum alveolar concentration of desflurane or sevoflurane. Aortic input impedance spectra were obtained via power spectral analysis of aortic pressure and flow waveforms. Characteristic aortic impedance (Zc) and total arterial resistance were calculated as the mean of the magnitude of Zin between 2 and 15 Hz and the difference between Zin at zero frequency and Zc, respectively. Total arterial compliance (C) was calculated from aortic pressure and flow waveforms using the Windkessel model. RESULTS: Desflurane and sevoflurane increased heart rate and decreased systolic, diastolic, and mean arterial pressure, left ventricular systolic pressure, left ventricular peak positive rate of increase in left ventricular pressure, percent segment shortening, and stroke volume. Sevoflurane, but not desflurane, decreased cardiac output. Desflurane, but not sevoflurane, decreased systemic vascular resistance. Desflurane decreased R (3,170 +/- 188 during control to 2441 +/- 220 dynes.second.centimeter-5 at 1.7 minimum alveolar concentration) and did not alter C and Zc. In contrast, sevoflurane increased C (0.57 +/- 0.05 during control to 0.79 +/- 0.05 ml/ mmHg at 1.7 minimum alveolar concentration) and Zc (139 +/- 10 during control to 194 +/- 14 dynes.second.centimeter-5 at 1.7 minimum alveolar concentration) but did not change R. CONCLUSIONS: The results indicate that desflurane and sevoflurane produce substantially different effects on left ventricular afterload in chronically instrumented dogs. Desflurane-induced decreases in systemic vascular resistance occur primarily because of effects on arteriolar resistance vessels. In contrast, sevoflurane increased C and Zc concomitant with pressure-dependent reductions in aortic diameter, suggesting that this anesthetic may alter left ventricular afterload by affecting the mechanical properties of the aorta. PMID- 8694357 TI - Effect of propofol on affective state as assessed by place conditioning paradigm in rats. AB - BACKGROUND: Whether propofol produces a pleasant affective state remains unclear from clinical studies. In the current study, the effect on affective state of subanesthetic and anesthetic doses of propofol was assessed at a preclinical level with rats in a place conditioning paradigm. Propofol was compared with methohexital. METHODS: In the place conditioning paradigm, propofol-induced effect was repeatedly paired with one of two distinguishable compartments of the apparatus, whereas the vehicle-induced effect was repeatedly paired with the other compartment. During a subsequent free-choice test, a preference for the drug-paired compartment over the vehicle-paired compartment would be indicative of pleasant state induced by the drug. For all experiments, the conditioning session lasted 8 days and consisted of four pairings of the drug with one compartment and four pairings of the equivalent volume of vehicle with the other compartment. In experiment 1A, four groups of rats were designated according to the dose of propofol that they received intraperitoneally: 0,30,60, or 90 mg/kg. In experiment 1B, the same procedure was used with subanesthetic doses of intraperitoneal methohexital: 0,10,20, or 30 mg/kg. In experiment 2, the rats were conditioned during the recovery period from short-term anesthesia. For one group, anesthesia was induced by propofol (100 mg/kg) whereas for the other group, anesthesia was induced by an equivalent anesthetic dose of methohexital (40 mg/kg). RESULTS: In experiment 1A, the 30-mg/kg, 60-mg/kg, and 90-mg/kg groups showed a place preference for the drug-paired compartment, but only the group conditioned with 60 mg/kg propofol significantly differed from the 0-mg/kg group. In experiment 1B, the groups conditioned with methohexital showed no place preference for the drug-paired compartment. In experiment 2, the rats showed a place preference for the compartment in which they recovered from propofol induced anesthesia but no place preference for the compartment in which they recovered from methohexital-induced anesthesia. CONCLUSIONS: Propofol, but not methohexital, induced a pleasant affective state in rats at subanesthetic doses as well as during recovery from an anesthetic dose. PMID- 8694358 TI - Volatile anesthetics depress spinal motor neurons. AB - BACKGROUND: Depression of spinal alpha-motor neurons apparently plays a role in the surgical immobility induced by isoflurane. Using the noninvasive technique of F-wave analysis, the authors tested the hypothesis that depressed motor neuron excitability is an effect common to other clinically relevant inhaled anesthetics. METHODS: The authors measured F-wave amplitude in rats anesthetized with desflurane, enflurane, halothane, or sevoflurane. Each animal received one anesthetic at five equipotent anesthetic concentrations (0.6, 0.8, 1.2, and 1.6 minimum alveolar concentration [MAC] and 0.8 MAC with 65% N2O). F waves were detected as late potentials in electromyographic responses evoked in the intrinsic muscles of the hind paw after monopolar stimulation of the ipsilateral posterior tibial nerve. RESULTS: All tested inhaled anesthetics depressed F-wave amplitude but not M-wave (orthodromic, early muscle activation) amplitude, and increased M-F latency in a dose-dependent manner. At 1.0 MAC, the estimated F/M ratio was 70 +/- 13% SD of that at baseline (0.6 MAC). Nitrous oxide added to 0.8 MAC of the potent vapors depressed F/M ratio by 63 +/- 17%. CONCLUSIONS: All anesthetics tested appeared to depress the excitability of spinal motor neurons. This effect may contribute to surgical immobility, and its magnitude is comparable at equipotent concentrations of agents. The authors hypothesize that this effect is due to hyperpolarization, although, currently, there is insufficient information to discriminate between pre- and postsynaptic mechanisms. PMID- 8694359 TI - Nitrous oxide depresses spinal F waves in rats. AB - BACKGROUND: Evoked, recurrent electromyographic activity (F waves) reflect alpha motor neuron excitability. Based on observations that other inhaled anesthetics do so, we hypothesized that nitrous oxide, alone or in combination with isoflurane, would depress F-wave activity and correlate with depression of movement response to tail clamp or electric stimulation. METHODS: In study 1, the authors examined the effect of nitrous oxide in combination with isoflurane in 13 normocapnic Sprague-Dawley rats anesthetized with 1.0% isoflurane (0.7 minimum alveolar concentration) in oxygen. The tibial nerve was stimulated at the popliteal fossa, and evoked electromyographic activity [M (direct neuromuscular junctional response) and F waves] were recorded from ipsilateral foot muscles. The effect of the addition of 30% or 70% nitrous oxide was measured. F-wave amplitude/M-wave amplitude ratio (F/M) was determined from each stimulus electromyographic response pair. F/M vs. movement response to 60-s tail clamp was assessed after each recording session. F-wave amplitude/M-wave amplitude ratio at adjacent doses that permitted and prevented movement were compared. In study 2, the authors examined the effect of (hyperbaric) nitrous oxide as the sole anesthetic agent on F waves. In 11 rats anesthetized with isoflurane, stimulation and recording electrodes were placed as described above, with additional electrodes for stimulation placed in the tail. Rats were placed in a pressure chamber pressurized with nitrous oxide/oxygen to 3.4 atm. Thirty m were allowed for isoflurane washout. Electromyographic activity was evoked and recorded at 1.0, 1.6, 2.2 and 2.7 atm N2O (random order). Movement in response to 60 s of 15 V, 50-Hz tail stimulation was evaluated after each recording session. RESULTS: Nitrous oxide with or without isoflurane produced a dose-dependent decrease in F/M. By interpolation of this data, the authors found that 2 atm N2O alone, or 44% N2O added to 1.0% isoflurane at 1.0 atm, produced 1.0 minimum alveolar concentration anesthesia. At the deepest level of isoflurane/ nitrous oxide that permitted movement, mean F/M was 20.6 +/- 17.5%; at the lowest concentration that blocked movement, rats had a mean F/M of 13.7 +/- 13.9% (P = 0.01). At the minimal hyperbaric nitrous oxide blocking movement, rats had a mean F/M of 3.7 +/ 2.9%, whereas the F/M at the highest nitrous oxide dose that permitted movement was 4.4 +/- 2.7% (P < 0.04). CONCLUSIONS: Because nitrous oxide depressed F-wave but not M-wave activity, the data suggest a central (spinal) rather than neuromuscular junctional site of action of this agent. The direct correlation between nitrous oxide dose, F-wave amplitude depression, and surgical immobility suggests the possibility of using F-wave activity to predict the likelihood of anesthetic-induced immobility. However, the mechanism of action of nitrous oxide may differ from that of the potent inhaled agents. PMID- 8694360 TI - Cardiac and regional hemodynamic interactions between halothane and nitric oxide synthase activity in dogs. AB - BACKGROUND: In vitro, halothane appears to affect the role played by nitric oxide in the regulation of vascular tone and cardiac function. In vivo, the results of the interactions between halothane and the nitric oxide pathway remain controversial. The authors investigated the effects of halothane on the cardiac and regional hemodynamic properties of N-methyl-L-arginine (NMA), a specific nitric oxide synthase inhibitor, in dogs. METHODS: Twenty-five dogs were chronically instrumented. Aortic pressure, the first derivative of left ventricular pressure, cardiac output, heart rate, and carotid, coronary, mesenteric, hepatic, portal and renal blood flows were continuously recorded. N methyl-L-arginine was infused intravenously at 20 mg/kg over 1 min in awake dogs (n = 11) and in 1.2% halothane-anesthetized dogs (n = 10). As a control group, the remaining four dogs were studied awake and during 1.2% halothane for 2 h in the absence of NMA. RESULTS: In awake dogs, NMA produced a sustained pressor response (34%) and systemic vasoconstriction (40%) associated with a decrease in cardiac output (16%). Regional circulation changes included an immediate and transient increase in carotid (43%) and coronary (237%) blood flows and a subsequent decrease in carotid blood flow (25%). Hepatic and mesenteric blood flows also decreased, by 43% and 16%, respectively. Except for the coronary circulation, regional vascular resistance increased significantly. Halothane did not affect the pressor response to NMA but did blunt the cardiac output changes. Consequently, the systemic vasoconstriction after nitric oxide synthase inhibition was of shorter duration and of lesser magnitude during halothane anesthesia. Halothane also blunted the carotid, mesenteric, and renal vasoconstriction induced by NMA. Finally, in 1.2% halothane-anesthetized dogs, NMA induced a coronary vasoconstriction. CONCLUSIONS: Halothane minimally interferes with the systemic and regional hemodynamic consequences of nitric oxide synthase blockade. The nature and magnitude of the interaction depend on the territory in which they occur. PMID- 8694361 TI - Concomitant administration of morphine and an N-methyl-D-aspartate receptor antagonist profoundly reduces inflammatory evoked spinal c-Fos expression. AB - BACKGROUND: After intraplantar injection of carrageenin, peripheral inflammation and spinal c-Fos expression are extensive, with the latter being sensitive to both large doses of morphine or N-methyl-D-aspartate receptor antagonism. The authors investigated the effects of coadministered morphine and (+)-HA966, a functional antagonist at the glycine site of the N-methyl-D-aspartate receptor, on the two parameters. METHODS: The effects of morphine, (+)-HA966 and coadministration of morphine and (+)-HA966 on spinal c-Fos expression in segments L4-L5 of the spinal cord and peripheral edema, induced at 1.5 h and 3 h after intraplantar carrageenin (6 mg/150 microliters) were studied. RESULTS: Previous coadministration of 0.3 mg/kg systemic morphine and 2.5 mg/kg subcutaneous (+) HA966 significantly reduced c-Fos expression induced 1.5 h, but not 3 h, after carrageenin administration. However, coadministration of a larger dose of morphine (3 mg/kg) with (+)-HA966 (2.5 mg/kg) reduced c-Fos expression at 3 h after carrageenin administration, in a partially naloxone-reversible manner. CONCLUSIONS: Concurrent mu-opioid receptor activation and N-methyl-D-aspartate receptor antagonism reduces nociceptive transmission at the level of the spinal cord, as shown by the reduction of carrageenin-evoked c-Fos expression. PMID- 8694362 TI - Effects of hypothermia, pentobarbital, and isoflurane on postdepolarization amino acid release during complete global cerebral ischemia. AB - BACKGROUND: Hypothermia and anesthetics may protect the brain during ischemia by blocking the release of excitatory amino acids. The effects of hypothermia (28 degrees C), pentobarbital, and isoflurane on postischemic excitatory amino acid concentrations were compared. METHODS: Rats were anesthetized with 0.8% halothane/50% N2O, vascular catheters were placed, and a glass microelectrode and microdialysis cannula were inserted into the cerebral cortex. Experimental groups were: (1) control, pericranial, t = 38 degrees C; (2) hypothermia, t = 28 degrees C; (3) pentobarbital, t = 38 degrees C; and (4) isoflurane, t = 38 degrees C. Halothane/N2O was continued in groups 1 and 2, whereas a deep burst-suppression or isoelectric electroencephalogram was achieved with the test drugs in groups 3 and 4. Cerebral metabolic rates were similar in groups 2, 3, and 4. After a baseline dialysis sample was collected, animals were killed with potassium chloride. The time to terminal depolarization was recorded, after which three consecutive 10-min dialysate samples were collected. Glutamate, aspartate, gamma aminobutyric acid, and glycine concentrations were measured using high performance liquid chromatography. RESULTS: Times to terminal depolarization were shorter in both pentobarbital and isoflurane groups than with hypothermia (103 +/ 15 and 127 +/- 10 vs. 195 +/- 20 s respectively, mean +/- SD). However, times to terminal depolarization in all three groups were longer than in control subjects (control = 70 +/- 9s). Postdepolarization concentrations of all compounds were lower in hypothermic animals (vs. normothermic control animals), but no reductions in glutamate, aspartate, or glycine concentrations were noted in pentobarbital or isoflurane groups. gamma-Aminobutyric acid concentrations were reduced by both anesthetics, but not to the same degree as with hypothermia. CONCLUSIONS: Pentobarbital and isoflurane prolonged the time to terminal depolarization, but did not influence the rate at which the extracellular concentrations of glutamate, aspartate, or glycine increased. By contrast, hypothermia reduced the release of all excitatory amino acids. These differences may explain the greater protective efficacy of hypothermia in the face of cerebral ischemia. PMID- 8694363 TI - Comparative pharmacology of cisatracurium (51W89), atracurium, and five isomers in cats. AB - BACKGROUND: Atracurium has four chiral centers and the marketed product is a mixture of ten optical and geometric isomers. Six of the isomers were prepared and evaluated for neuromuscular blocking activity and autonomic effects in anesthetized cats. This study reports the comparative pharmacology of the six isomers and atracurium that led to the selection of one isomer, cisatracurium (Nimbex, 51W89) for clinical development. METHODS: Purpose bred cats, anesthetized with alpha-chloralose (80 mg/kg) and pentobarbital sodium (7 mg/kg) administered intraperitoneally, were used in this study. Neuromuscular blocking effects were assessed from the effects on the tibialis anterior twitch evoked at 0.15 Hz. Inhibition of the autonomic nervous system was assessed from the effects on the nictitating membrane contraction, in response to preganglionic sympathetic nerve stimulation and the bradycardia/vasodepressor responses to vagal nerve stimulation. Cardiovascular effects and plasma histamine concentrations were determined after a bolus injection of cisatracurium or atracurium. RESULTS: Like atracurium, all six isomers produced dose-dependent neuromuscular block (NMB). The calculated ED95NMB values varied approximately tenfold (43 +/- 2 microgram/kg -488 +/- 56 microgram/kg. The "R-series" isomers were more potent than the corresponding "S-series" isomers. With the exception of the S,Trans-S', Trans isomers, the NMB effects, i.e., onset times (range 2.6 +/- 0.2 min to 4.7 +/- 0.3 min) and total durations (range 9.9 +/- 1.4 min to 14 +/- 0.9 min), of the other five isomers were very similar to that atracurium. The former isomers had relatively short duration of action. The 25-75% recovery times after cisatracurium at 1 x ED95 (4.4 +/- 0.4 min), 4 x ED95 (4.5 +/- 0.4 min), and continuous infusions lasting at least 60 min that maintained 95-99% NMB (4.8% +/- 0.4 min) indicated a noncumulative effect. The vagal ID50:NMB ED95 ratios for atracurium and the six isomers ranged from 2 to 27. The sympathetic ID25:NMB ED95 ranged from 2.7 to 60. Atracurium and all of the isomers, except cisatracurium, produced cardiovascular effects after intravenous bolus administration at large doses (700-4,800 micrograms/kg). In contrast to atracurium, there were no changes in plasma histamine concentrations associated with the administration of doses of cisatracurium equivalent to 60X the NMB ED95 (62 +/- 8 micrograms/kg). CONCLUSIONS: Cisatracurium has neuromuscular blocking effects identical to those of atracurium, is more potent, and does not produce cardiovascular effects or increase plasma histamine concentrations. PMID- 8694364 TI - Mitral valve prolapse. PMID- 8694365 TI - Development and effectiveness of an anesthesia preoperative evaluation clinic in a teaching hospital. PMID- 8694366 TI - Tolerance to propofol generally does not develop in pediatric patients undergoing radiation therapy. PMID- 8694367 TI - Cardiac trauma: an unusual cause of dysrhythmias and electrocardiographic changes during laparoscopic Nissen fundoplication. PMID- 8694368 TI - Exacerbation or unmasking of focal neurologic deficits by sedatives. AB - BACKGROUND: Transient focal neurologic deficits have been observed in patients emerging from brain tumor or carotid surgery, and a pharmacologic effect of anesthetic agents has been proposed as the cause of such neurologic dysfunction. Therefore, the effect of sedation with midazolam or fentanyl on motor neurologic function was studied prospectively and preoperatively in patients with carotid disease or mass lesions of the brain. METHODS: Fifty-four unpremedicated adult patients with carotid disease or a brain tumor were given small intravenous doses of either 2.8 +/- 1.3 mg midazolam or 170 +/- 60 micrograms fentanyl in the preoperative period. A thorough motor examination was performed at baseline and after sedation by an individual who was unaware of the details of the patient's disease or symptoms. A mental status examination also was performed to control for the effects of inattentiveness or lack of cooperation during the neurologic examination. RESULTS: Patients were sedated mildly but were fully cooperative. Focal motor deterioration occurred after sedation in 30% of patients, and the incidence was similar in patients in the fentanyl and midazolam groups. Among patients with a focal motor abnormality on baseline examination or a resolved prior motor deficit, 73% had exacerbation or unmasking of these signs by sedation, whereas no patient without a prior history of motor dysfunction had a sedative-induced change. Sedative-induced changes in neurologic function ranged from unilateral mild weakness to complete plegia, but appeared to be transient in nature. CONCLUSIONS: Sedation with midazolam or fentanyl can transiently exacerbate or unmask focal motor deficits in patients with prior motor dysfunction. PMID- 8694369 TI - New technique for the neurolytic celiac plexus block: the transintervertebral disc approach. PMID- 8694370 TI - Tracheal tube/laryngeal mask exchange for emergence. PMID- 8694371 TI - Difficult airway warning with automated anesthesia recording. PMID- 8694372 TI - A simple suction device to aid in transportation of the critically ill pediatric patient. PMID- 8694373 TI - New endotracheal tube cuff recalls past efforts: focuses on laryngeal placement. PMID- 8694374 TI - The Shaw Hemostatic Scalpel as an alternative to electrocautery in patients with pacemakers. PMID- 8694375 TI - General versus regional anesthesia for peripheral vascular surgery. PMID- 8694376 TI - New local anesthetic agents. PMID- 8694377 TI - A potential choking hazard. PMID- 8694378 TI - Cervical spine motion with direct laryngoscopy and orotracheal intubation. An in vivo cinefluoroscopic study of subjects without cervical abnormality. AB - BACKGROUND: Cervical spine kinetics during airway manipulation are poorly understood. This study was undertaken to quantify the extent and distribution of segmental cervical motion produced by direct laryngoscopy and orotracheal intubation in human subjects without cervical abnormality. METHODS: Ten patients without clinical or radiographic evidence of cervical spine abnormality underwent laryngoscopy using a #3 Macintosh blade while under general anesthesia and neuromuscular blockade. Cervical motion was recorded with continuous lateral fluoroscopy. The intubation sequence was divided into distinct stages and the corresponding fluoroscopic images were digitized. Segmental motion, occiput through C5, was calculated for each stage using the digitized data. RESULTS: During exposure and laryngoscope blade insertion, minimal displacement of the skull base and rostral cervical vertebral bodies was observed. Visualization of the larynx created superior rotation of the occiput and C1 in the sagittal plane, and mild inferior rotation of C3-C5. C2 maintained nearneutral posture. This pattern of displacement resulted in extension at each motion segment, with the most significant motion produced at the occipitoatlantal and atlantoaxial joints (mean = 6.8 degrees and 4.7 degrees, respectively). Intubation created slight additional superior rotation at the occiput and C1, without substantial alteration in the posture of C2-C5. After laryngoscope removal, position trended toward baseline at all levels, although exact neutral posture was not regained. CONCLUSIONS: This investigation quantifies the behavior of the normal cervical spine during direct laryngoscopy with a Macintosh blade. With this maneuver, the vast majority of cervical motion is produced at the occipitoatlantal and atlantoaxial joints. The subaxial cervical segments (C2-C5) are displaced only minimally. This study establishes a highly reliable and reproducible method for analyzing cervical motion in real time. PMID- 8694379 TI - Size of human lower thoracic and lumbosacral nerve roots. AB - BACKGROUND: Nerve root size may determine degree of blockade after epidural or spinal anesthesia, but good measures of this fundamental anatomic parameter have not been published. Models of subarachnoid anesthetic distribution have lacked valid cauda equina dimensions. In this study, the author sought to measure cross section areas of anterior and posterior roots at different levels for basic anthropomorphic analysis. METHODS: Samples from 12 adult autopsy subjects were obtained from roots at levels T6 through S5. Cross-section area was determined by dividing the root sample weight by length and correcting for tissue density. RESULTS: Roots were variably composed of as many as five easily separable independent strands. Areas of anterior roots are approximately half the area of posterior roots. On average, the largest anterior and posterior root is at S1, but this may occur at L3 through S2. There is a large degree of interindividual variability (e.g., range of posterior L5 root is 2.33-7.71 mm2). CONCLUSIONS: The large size of low lumbar and high sacral roots may cause resistance to anesthetic effects, whereas the smaller dimensions of the thoracic roots may facilitate neural blockade. The small size of the low sacral roots may, in part, explain selective neurotoxic damage of these fibers after subarachnoid injections. Interindividual variability in root sizes may contribute to lack of predictability in anesthetic response. PMID- 8694380 TI - Vomiting and recovery after outpatient tonsillectomy and adenoidectomy in children. Comparison of four anesthetic techniques using nitrous oxide with halothane or propofol. AB - BACKGROUND: The authors' purpose in this study was to compare prospectively four different anesthetic induction and maintenance techniques using nitrous oxide with halothane and/or propofol for vomiting and recovery after outpatient tonsillectomy and adenoidectomy procedures in children. METHODS: Eighty unpremedicated children, aged 3-10 yr, were assigned randomly to four groups: group H/H, 0.5-2% halothane induction/halothane maintenance; group P/P, 3-5 mg.kg 1 propofol induction and 0.1-0.3 mg.kg-1.min-1 propofol maintenance; group H/P, 0.1-0.3 mg.kg-1.min-1 halothane induction/propofol maintenance; and group P/H, 3 5 mg.kg-1 propofol induction and 0.5-2% halothane maintenance. Nitrous oxide (67%) and oxygen (33%) were administered in all the groups. Other treatments and procedures were standardized intra- and postoperatively. Results of postoperative vomiting and recovery were analyzed in the first 6 h and beyond 6 h. RESULTS: Logistic regression showed that vomiting occurred 3.5 times as often when halothane was used for maintenance of anesthesia (groups H/H and P/H) compared with the use of propofol (groups P/P and H/P; Odds Ratio 3.5; 95% confidence interval 1.3 and 9.4, respectively; P = 0.012). A significant association between vomiting ( < 6 h: yes/no) and discharge times ( > 6 h: yes/no) (Odd's Ratio = 3.6; 95% confidence interval: 1.02, 12.4, respectively) (P = 0.046) was shown. However, no significant differences among the groups in the incidence of vomiting beyond 6 h, recurrent vomiting, or hospital discharge times were shown. CONCLUSIONS: After tonsillectomy and adenoidectomy procedures, despite reduced postoperative vomiting with use of propofol rather than halothane, along with nitrous oxide for anesthetic maintenance, the authors found no differences in "true" endpoints such as unplanned admissions or discharge times. Among the groups, the main factor that delayed hospital discharge beyond 6 h was vomiting within the first 6 h. PMID- 8694381 TI - Internal jugular vein and carotid artery anatomic relation as determined by ultrasonography. AB - BACKGROUND: Cannulation of the internal jugular vein (IJV) is associated with a 95% success rate when external landmarks are used. Anatomic variability has been implicated as the cause for difficulty in cannulation without ultrasound. In contrast to an IJV located lateral to the carotid artery (CA), an IJV overlying the CA may result in CA puncture. The authors' purpose in this study was to examine, using ultrasound, the anatomic relation of the IJV and CA as viewed from the perspective of a cannulating needle. METHODS: Ultrasound imaging was used in 1,136 patients to examine the relation between the IJV and CA. A 7.5-MHz transducer was placed in the direction of a cannulating needle on the right neck at the apex of the angle formed by the division of the sternocleidomastoid muscle. A Polaroid photograph of the image was later scored by three blinded investigators according to the percentage of the CA overlaid by the IJV (0 to 4). RESULTS: Of the 1,136 Polaroid photographs of the ultrasound images, 1,009 were suitable for scoring. Fifty-four percent of all patients received a score of 4, which indicated that the IJV overlies more than 75% of the CA in an imaging plane positioned in the direction of a cannulating needle. Patients older than 60 yr were more likely to have this anatomy than patients younger than 60 yr (P < 0.05). None of the other patient characteristics recorded were predictive of this anatomic relation. CONCLUSIONS: In a majority of patients, the IJV is not lateral to the CA in an ultrasound imaging plane positioned in the direction of a cannulating needle. Instead, the IJV overlies the CA in 54% of patients overall, predisposing these patients to CA puncture if the cannulating needle traverses the IJV. PMID- 8694382 TI - Atelectasis and chest wall shape during halothane anesthesia. AB - BACKGROUND: Anesthesia produces atelectasis in the dependent areas of the lungs by mechanisms that remain unknown. It has been proposed that anesthesia produces a cephalad shift in the end-expiratory position of the diaphragm, which compresses the lungs and produces atelectasis. This study tested the hypothesis that the extent of atelectasis is correlated with the cephalad displacement of the dependent portion of the diaphragm produced by halothane anesthesia in healthy young human subjects. METHODS: Twelve volunteers (mean age 34 yr) were studied while awake and during approximately 1.2 minimum alveolar concentration halothane anesthesia. Chest wall configuration was determined using images of the thorax obtained by three-dimensional fast computed tomography. Functional residual capacity was measured by a nitrogen dilution technique. Measurements were performed during quiet breathing in all subjects and after paralysis with 0.1 mg/kg vecuronium and mechanical ventilation in six subjects. Atelectasis was assumed to be present in regions of the lung that showed radiographic attenuation values similar to solid organs such as the liver. RESULTS: Atelectasis in dependent lung regions was not apparent in scans performed while the subjects were awake. Anesthesia with spontaneous breathing increased the volume of atelectasis measured at end-expiration by more than 1 ml in 9 of 12 subjects. For all subjects, the volume of atelectasis was 29 +/- 10 ml (M +/- SE), representing 0.67 +/- 0.23% of the total thoracic volume. The distribution of atelectasis varied along the cephalocaudal axis, with less atelectasis in more cephalad transverse sections. Paralysis and mechanical ventilation significantly decreased the volume of atelectasis present at end-expiration. There was no correlation between the average amount of cephalad displacement of the most dependent region of the diaphragm and the amount of atelectasis, nor was there any correlation between the amount of atelectasis and anesthesia-induced changes in the end expiratory position of any chest wall structure. CONCLUSIONS: The dependent lung atelectasis produced by halothane anesthesia does not appear to be related to changes in the position of any single chest wall structure in these healthy young subjects, but rather to an interaction of several factors that remain to be identified. PMID- 8694383 TI - Ventilatory response to hypoxia in humans. Influences of subanesthetic desflurane. AB - BACKGROUND: At low dose, the halogenated anesthetic agents halothane, isoflurane, and enflurane depress the ventilatory response to isocapnic hypoxia in humans. In the current study, the influence of subanesthetic desflurane (0.1 minimum alveolar concentration [MAC]) on the isocapnic hypoxic ventilatory response was assessed in healthy volunteers during normocapnia and hypercapnia. METHODS: A single hypoxic ventilatory response was obtained at each of 4 target end-tidal partial pressure of oxygen concentrations: 75, 53, 44, and 38 mmHg, before and during 0.1 MAC desflurane administration. Fourteen subjects were tested at a normal end-tidal partial pressure of carbon dioxide (43 mmHg), with 9 subjects tested at an end-tidal carbon dioxide concentration of 49 mmHg (hypercapnia). The hypoxic sensitivity (S) was computed as the slope of the linear regression of inspired minute ventilation (V1) on (100-SPO2). Values are mean +/- SE. RESULTS: Sensitivity was unaffected by desflurane during normocapnia (control: S = 0.45 +/ 0.07 l.min-1.%-1 vs. 0.1 MAC desflurane: S = 0.43 +/- 0.09 l.min-1.%-1). With hypercapnia S decreased by 30% during desflurane inhalation (control: S = 0.74 +/ 0.09 l.min-1.%-1 vs. 0.1 MAC desflurane: S = 0.53 +/- 0.06 l.min-1.%-1; P < 0.05). CONCLUSIONS: On the basis of the data, subanesthetic desflurane has no detectable effect on the normocapnic hypoxic ventilatory response sensitivity. However, the carbon dioxideinduced augmentation of the hypoxic response was reduced. This indicates that subanesthetic desflurane effects the chemoreceptors at the carotid bodies. PMID- 8694384 TI - Transesophageal atrial pacing in anesthetized patients with coronary artery disease. Hemodynamic benefits versus risk of myocardial ischemia. AB - BACKGROUND: Transesophageal atrial pacing (TEAP) provides prompt and precise control of heart rate and improves hemodynamics in anesthetized patients with bradycardia and hypotension. The authors' purpose in this study was to examine the hemodynamic benefits of TEAP versus the risk of myocardial ischemia in patients about to undergo coronary artery bypass surgery. METHODS: Hemodynamics, ventricular filling pressures, mixed venous oxygen saturation, and end-diastolic, end-systolic, and fractional area change of the left ventricle, determined by transesophageal echocardiography (TEE), were measured after anesthesia induction with 30 micrograms/kg fentanyl and at incremental TEAP rates of 65, 70, 80, and 90 beats/min (bpm) in 40 adult patients. Monitoring for myocardial ischemia was accomplished with 12-lead electrocardiograms and biplane TEE assessment of left ventricular regional wall motion. Hemodynamics, electrocardiograms, and TEE measurements at each TEAP rate were compared with baseline awake measurements (except TEE) and with measurements obtained after anesthesia induction before TEAP. RESULTS: Sinus bradycardia occurred in 15 patients after anesthesia induction and was associated with a hypotensive response and a decrease in cardiac output in 10 patients. In these patients, TEAP restored diastolic blood pressure and cardiac output to baseline values at TEAP rates of 65 and 80 bpm, respectively. Stroke volume was similar to baseline measurements after anesthesia induction and at TEAP rates of 65, 70, and 80 bpm, but was significantly reduced from baseline at TEAP 90 bpm. Myocardial ischemia was detected in 7 and 5 patients at a TEAP rate of 80 and 90 bpm, respectively. CONCLUSIONS: Control of heart rate with TEAP restores intraoperative hemodynamics to baseline in patients in whom bradycardia and a hypotensive response develop before coronary artery bypass surgery. When using TEAP for patients with severe coronary artery disease, these results support using the lowest TEAP rate titrated to achieve optimal hemodynamics, while closely monitoring for myocardial ischemia, especially at TEAP rates > 80 bpm. PMID- 8694385 TI - Mivacurium neuromuscular block at the adductor muscles of the larynx and adductor pollicis in humans. AB - BACKGROUND: Laryngeal muscles must be paralyzed for tracheal intubation. Time to peak effect (onset time) is shorter and intensity of blockade is less at laryngeal muscles compared with the adductor pollicis. The authors' aim in this study was to determine the neuromuscular effects of mivacurium at the laryngeal adductor muscles and the adductor pollicis. METHODS: In 22 adults, anesthesia was induced and maintained with propofol and alfentanil. The force of contraction of the adductor pollicis was recorded, and the laryngeal response was evaluated by measuring the pressure change in the cuff of a tracheal tube positioned between the vocal cords after train-of-four stimulation. Mivacurium (0.07 mg.kg-1 or 0.14 mg.kg-1) was given intravenously (10s). RESULTS: With 0.07 mg.kg-1 mivacurium, onset time was 151 +/- 40 s(mean +/- SD) at the larynx and 241 +/- 79 s at the adductor pollicis, respectively (P < 0.005). Maximum block was 78 +/- 18% and 95 +/- 8%, respectively (P < 0.002), and time to 90% recovery was 11.1 +/- 2.9 min and 23.3 +/- 7.6 min, respectively (P < 0.001). With 0.14 mg.kg-1 mivacurium, onset time also was more rapid at the vocal cords (137 +/- 20 s) than at the adductor pollicis (201 +/- 59 s, P < 0.01). Maximum block was 90 +/- 7% and 99 +/ 1% (P < 0.005), and time to 90% recovery was 16.4 +/- 4.9 min and 27.4 +/- 7.8 min, respectively (P < 0.01). CONCLUSIONS: With mivacurium, onset and recovery are faster at the laryngeal muscles, but block is less intense than at the adductor pollicis. A dose greater than 0.14 mg.kg-1 mivacurium is necessary to ensure complete relaxation at the vocal cords. PMID- 8694386 TI - Stimulation of alpha 2 adrenoceptors dilates the rat middle cerebral artery. AB - BACKGROUND: Because alpha 2 adrenoceptor agonists are used as adjuncts to anesthetics, their effects on the cerebrovascular circulation are of prime importance. We studied changes in the diameter of rat middle cerebral arteries after stimulation of alpha 2 adrenoceptors with UK14,304. METHODS: Rat middle cerebral arteries were isolated, cannulated at each end with a glass micropipette, and pressurized to 85 mmHg. The middle cerebral arteries were immersed in a bath (37 degrees C) containing physiologic saline solution, and luminally perfused with physiologic saline solution (100 microliters/ min). Changes in vessel diameter were measured after magnification with a microscope. RESULTS: Resting diameter of the middle cerebral arteries was 239 +/- 13 microns (n = 8) for the first study. A dose-dependent dilation was produced by addition of UK14,304 to the extraluminal bath; a 10-15% increase in diameter occurred at a concentration of 10(-4)M. The dilations produced by UK14,304 were blocked with selective alpha 2-antagonists, idazoxan and rauwolscine, but not by the selective alpha 1-antagonist, prazosin. The dilations could be blocked by removal of the endothelium, or the nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester (10(-5) M). The inhibitory effects of N-nitro-L-arginine methyl ester were reversed with the addition of 10(-3) M L-arginine, but not 10(-3) M D-arginine. Furthermore the dilation produced by UK14,304 was completely abolished with pertussis toxin (100 ng/ml). CONCLUSIONS: It was concluded that the stimulation of alpha 2 adrenoceptors with UK14,304 produced a dilation in the rat middle cerebral artery that (1) was dependent on intact endothelium, (2) involved nitric oxide, and (3) acted via a pertussis toxin-sensitive G protein. PMID- 8694387 TI - Chronic cocaine administration reversibly increases isoflurane minimum alveolar concentration in sheep. AB - BACKGROUND: Significant numbers of patients are seen for surgery and anesthesia with a history of chronic cocaine use. However, little is known about how cocaine use influences anesthetic physiology and pharmacology. The purpose of this study was to investigate the effect of chronic cocaine exposure on the minimum alveolar concentration (MAC) of isoflurane in sheep. METHODS: Isoflurane MAC was determined at baseline in 12 sheep using a standard protocol. The animals were subsequently exposed to cocaine for 18 days. Cocaine exposure consisted of a continuous subcutaneous cocaine infusion at 0.2 mg.kg-1.h-1, twice daily 4-mg/kg intravenous boluses and repeated hourly 4 mg/kg cocaine boluses for 8 h on day 18. Minimum alveolar concentration determinations were repeated again on days 15, 18, and on day 28 after 10 days of cocaine abstinence. RESULTS: Compared to baseline MAC (1.53 +/- 0.12%) cocaine exposure significantly increased isoflurane MAC on days 15 (1.91 +/- 0.14%) and 18 (1.78 +/- 0.13%; P = .005). MAC decreased after discontinuation of cocaine and was not different from baseline on day 28 (1.67 +/- 0.11). CONCLUSIONS: In sheep, chronic cocaine exposure resulted in a reversible increase in isoflurane MAC. This finding contrasts with studies of other central nervous system stimulants, which have demonstrated a decrease in MAC after chronic drug exposure. PMID- 8694388 TI - Direct inhibitory mechanisms of halothane on human platelet aggregation. AB - BACKGROUND: Although halothane directly inhibits platelet aggregation, the mechanisms of this effect are still unknown. The current study aimed to clarify the inhibitory mechanisms of halothane on thrombin-induced human platelet aggregation by measuring (1) platelet-surface glycoprotein Ib expression, (2) the concentration of intracellular free Ca2+ ([Ca2+]i) measured simultaneously with aggregation, (3) the concentration of intracellular inositol 1,4,5-triphosphate, and (4) the concentration of intracellular cyclic 3',5'-adenosine monophosphate ([cAMP]i). METHODS: Washed platelet suspensions, obtained from healthy volunteers, were preincubated with halothane (0-2 mM) for 2 min and then exposed to 0.02 units/ml thrombin for 3 min. The glycoprotein Ib bound to fluorescein labeled antibody was measured by fluorescence flow cytometry. [Ca2+]i was measured, simultaneously with aggregation, in Fura-2 (Ca2+ indicator)-loaded platelets by use of a fluorometer. Inositol 1,4,5-triphosphate and [cAMP]i were measured by radioimmunoassay. RESULTS: Halothane had no effect on glycoprotein Ib expression with or without thrombin. Halothane decreased the thrombin stimulated [Ca2+]i transient and inhibited platelet aggregation in a dose-dependent manner, both in the presence and in the absence of external Ca2+. Isoflurane had no apparent effect on either platelet aggregation or [Ca2+]i in the absence of external Ca2+. Halothane inhibited the increase in inositol 1,4,5-triphosphate induced by thrombin. Halothane moderately but significantly increased [cAMP]i, but the adenylate cyclase activator forskolin (which has the same inhibitory ability on aggregation as halothane) increased [cAMP]i to a much greater extent than did halothane. CONCLUSIONS: Halothane inhibits thrombin-induced human platelet aggregation by decreasing [Ca2+]i without inhibiting agonist-receptor binding; the inhibitory effect of halothane on [Ca2+]i might be mediated by a decrease in inositol 1,4,5 triphosphate and in part by an increase in [cAMP]i. PMID- 8694389 TI - A continuum of care. More is not always better. AB - This article describes an $80-million project designed to test whether a continuum of mental health and substance abuse services for children and adolescents is more cost-effective than services delivered in the more typical fragmented system. The study showed that an integrated continuum was successfully implemented that had better access, greater continuity of care, more client satisfaction, and treated children in less restrictive environments. However, the cost was higher, and clinical outcomes were no better than those at the comparison site. The article concludes that reform of mental health systems alone is unlikely to affect clinical outcomes. Cooperation is needed between mental health providers and researchers to better understand how to improve services delivered in the community. PMID- 8694390 TI - A life span model of successful aging. AB - To lay the foundation for our model, we first describe existing conceptions of successful aging, underlying assumptions of development, and criteria for success. The model presented extends the discourse on this topic in three directions: (a) It frames the discussion of successful aging in the broader context of life course development; (b) it accounts for both normative and nonnormative (i.e., exceptional) success; and (c) it integrates motivational processes into a theory of successful aging. Successful aging is equated with the development and maintenance of primary control throughout the life course, which is achieved through control-related processes that optimize selection and failure compensation functions. Selection processes regulate the choice of action goals so that diversity is maintained and positive and negative trade-offs between performance domains and life stages are taken into account. Compensation mechanisms serve to maintain, enhance, and remediate competencies and motivational resources after failure experiences. Both compensation and selection processes are motivated by desires for primary control and can be characterized in terms of primary and secondary control processes. PMID- 8694391 TI - Basic behavioral science research for mental health. Sociocultural and environmental processes. Basic Behavioral Science Task Force of the National Advisory Mental Health Council. PMID- 8694392 TI - Revealing animal experiments in general psychology texts: opening Pandora's box. PMID- 8694393 TI - Right, but for the wrong reasons. PMID- 8694394 TI - Teaching about animal research in psychology. PMID- 8694395 TI - Applications for academic positions in psychology: recommendations for search committees. PMID- 8694397 TI - [Prognosis as a treatment frame. Considerations on schizophrenia]. AB - Prognosis holds an ambiguous position in today clinical practice, specially in psychiatry. It is either an impossible prediction or, worse, an oracle dangerous for its predetermined effects. Hippocratic tradition follows a different path: prognosis is what is being said publicly to the patient about his or her disease. It thus allows the doctor to get the patient's trust and to start the treatment. Those two meanings of the word prognosis have been used alternatively through the history of schizophrenia. Firstly, because of medical shortcomings, diagnosis and prognosis were mingled as they both were course criteria. Today, prognosis seems to be based more on actual therapeutic actions and then we are back to the hippocratic meaning of the word: prognosis as a therapeutic frame. PMID- 8694396 TI - [Psychological and psychiatric services provided to soldiers in the burial operation (Zaire, July-August 1994)]. AB - In July 1994, a small contingent of the French army had the physically and psychologically difficult task of burying 40,000 cadavers in Goma (Zaire). This was the only way to eradicate a cholera epidemic which decimated 1,200,000 Rwanda refugees fleeing from the war. The mission of the military psychiatrist posted in Goma consisted of promoting mental health actions and providing psychological support for the soldiers most "exposed" to the burial operations. He was unable to avoid a dozen sanitary evacuations (out of 200 soldiers), some of which were abusive, but discreetly helped the small proportion (25%) of soldiers determined to complete their mission despite the development of symptoms of anxiety, depression and personality disorders. The others assumed their task with no apparent difficulties. The solidarity of the military group (especially in the form of small units) and the hierarchical structure of the army enabled each member of the contingent to complete this dreadful task. PMID- 8694398 TI - [From Kandinsky to Clerambault. Value of eponyms]. AB - The Syndrome of Mental Automatism in delusional states has been described by the French psychiatrist G. de Clerambault in 1919. It consists mainly of involuntary production of impressions and ideas, ascribed by the patient to an external influence and still occurring within himself. Phenomena like thought echo, influence delusion, thought guess belong to M.A. Actually this syndrome is largely unknown in Anglo-Saxon countries. Somewhat similar description figures in DSM-III-R under the heading 295. A2-A3. Soviet psychiatrists claim that a quite similar clinical picture has been described by Kandinsky in his monograph posthumously published by his widow in 1890. The present writer shows that a great part of what Kandinsky described was actually based on self-observation. But it is true that Kandinsky described what he calls a "psychological chasm", where thought is either imposed upon the patient or stolen from him. The present writer considers that it is more a phenomenological approach than a semiological one and he is doubtful about the actual value of eponyms. PMID- 8694399 TI - [Structure of mental disorders and diagnostic criteria. On Clerambault syndrome]. AB - Observation of a patient followed during 25 years, which indicate Clerambault'syndrome of mental automatism, is reported. The systemal method makes it possible to confirm the structure of this complex pathological system and to set limits to the current diagnostic criteria. PMID- 8694400 TI - [Swindlers, swindling and expression of psychopathology]. AB - Earlier studies about swindlers and swindling don't show any perturbations about clinical disorders. For the authors, this analysis implies different levels of criminal act; they put emphasis on relation between victims and perpetrators, mainly seduction and falsification. Several personality traits are enduring patterns of relating to and thinking about the environment which is component of characteristic personality disorders. PMID- 8694401 TI - [Attempted suicide and menstrual cycle. An epidemiologic study]. AB - Relations between suicidal behaviours and menstrual cycle have been studied by various authors with different methodologies, from which miscellaneous and contradictory results. We have taken this relation again, about suicide attempts admitted in Dijon's emergency department. Were recorded for each suicidal woman aged 15 to 49 their sociodemographical and gynecological characteristics. The same data were collected among women admitted in such circumstances for various pathologies except suicidal disorders. Cases and witnesses were distributed in an ideal cycle of 28 days with the method called cycle adjusting. Statistic analysis reveals a significant difference between cases and witnesses for pre-ovulatory period but don't resist to the maximum bias hypothesis. Finally, our study emphasizes without our knowing, for the population concerned, cases and witnesses alike, an increase hospital-going during pre-ovulatory period. PMID- 8694402 TI - [Time factors and lack of motivation in the elderly]. AB - The time-being experienced by the elderly is analyzed through different nosologic frameworks. The older depressive person is haunted by the unpermanency of life whereas the unmotivated elder persons gives himself over to mortification. In dementia, the present time being, even unnatural seems to be the only working reference; but it is source of despair for it refers to an impossible imaginary, source of resignation for it is without pleasure and without any gratifying support for tomorrow. This insistence on the present focuses on a personal and familial will mechanism of time fixing in order to avoid the crisis and to refuse any risk in changing. PMID- 8694403 TI - [Adverse effects: priapism caused by paroxetine]. AB - The case of a young man with depressive illness who developed priapism while being treated with paroxetine is reported for the first time. Other sexual side effects are reported with paroxetine : delayed ejaculation, anorgasmy, erectile dysfunction and decreased libido. Other antidepressants are known to cause priapism : fluoxetine and especially trazodone. PMID- 8694404 TI - [German social psychiatry in 1934]. PMID- 8694405 TI - [Prediction of therapeutic response in depressive states]. AB - Predicting the clinical improvement of patients with antidepressant drugs, at an early stage and in a individualistic manner, allows to choose the product which is most adapted to each case and to avoid leaving patients under an inefficient medication for several weeks. Predictability studies have multiplied. A general review of these studies is made here by examining the clinical, biological, electrophysiological, and finally the pharmacokinetic predictors. Clinical predictors have a practical use as they define certain clinical types of depression which best respond to antidepressants specific to a monoaminergic axis. It has been shown that a complete absence of symptomatic improvement after two weeks of treatment predicts the inefficacy of the treatment. Inversely, to this day, none of the biological predictors lead to a practical application during the treatment of patients, but they allow a better understanding of the antidepressants' mode of action. Finally, the elaboration of pharmacokinetic equations define for each patient the doses that allow to determine the therapeutic zones when these have been recognized. PMID- 8694406 TI - Afferent calyces and type I hair cells during development. A new morphofunctional hypothesis. PMID- 8694407 TI - New Directions in Vestibular Research. Conference proceedings. New York, New York, June 25-27, 1995. PMID- 8694408 TI - Ionic conductances and hair cell tuning in the turtle cochlea. PMID- 8694409 TI - Routes of calcium entry and extrusion in turtle hair cells. PMID- 8694410 TI - Development of second-order vestibular projections in the chicken embryo. AB - The results reviewed here demonstrate that vestibulospinal and vestibulo-ocular interneurons in the chicken embryo are organized into coherent clusters, each of which occupies a unique spatial domain and has a characteristic axon trajectory. Moreover, the vestibulo-ocular clusters have specific termination patterns in the extraocular motoneuron pools and may to some extent have specific functions. The axon trajectories and termination patterns are established accurately during early development. This suggests the presence of selective mechanisms that ensure the generation of an appropriately specific connectivity pattern. The correlation of cluster domains with unique fields of regulatory gene expression at early stages suggests a mechanistic link between the position of a vestibular interneuron and the differentiation of its axon trajectory, termination pattern, and neurotransmitter phenotype. PMID- 8694411 TI - Filtering properties of vestibular hair cells: an update. PMID- 8694412 TI - Ionic current contribution to signal processing by toadfish semicircular canal hair cells. PMID- 8694413 TI - Synaptic organization of the crista ampullaris in vertebrates. PMID- 8694414 TI - Afferent and efferent responses from morphological fiber classes in the turtle posterior crista. PMID- 8694415 TI - Evidence of a sensory processing unit in the mammalian macula. AB - We cut serial sections through the medial part of the rat vestibular macula for transmission electron microscopic (TEM) examination, computer-assisted 3-D reconstruction, and compartmental modeling. The ultrastructural research showed that many primary vestibular neurons have an unmyelinated segment, often branched, that extends between the heminode (putative site of the spike initiation zone) and the expanded terminal(s) (calyx, calyces). These segments, termed the neuron branches, and the calyces frequently have spine-like processes of various dimensions with bouton endings that morphologically are afferent, efferent, or reciprocal to other macular neural elements. The major questions posed by this study were whether small details of morphology, such as the size and location of neuronal processes or synapses, could influence the output of a vestibular afferent, and whether a knowledge of morphological details could guide the selection of values for simulation parameters. The conclusions from our simulations are (1) values of 5.0 k omega cm2 for membrane resistivity and 1.0 nS for synaptic conductance yield simulations that best match published physiological results; (2) process morphology has little effect on orthodromic spread of depolarization from the head (bouton) to the spike initiation zone (SIZ); (3) process morphology has no effect on antidromic spread of depolarization to the process head; (4) synapses do not sum linearly; (5) synapses are electrically close to the SIZ; and (6) all whole-cell simulations should be run with an active SIZ. PMID- 8694416 TI - Development of the labyrinthine efferent system. AB - The data presented here show that labyrinthine and facial branchiomotor efferent cells in the chicken and the mouse become postmitotic overlappingly, both spatially and temporally. Differential migration of labyrinthine efferents and facial motoneurons leads to the already described distinct distribution of labyrinthine efferents and facial motoneurons in adult brains. Differences exist between the chicken and the mouse with respect to the origin of labyrinthine efferents (rhombomere 4 and 5 for the chicken; rhombomere 4 alone for the mouse) and the way contralateral labyrinthine efferents form (migration across the floor plate in the chicken; extension of an axon across the floor plate in the mouse). The different routes taken by migrating motoneurons may all be mediated by substances released from the floor plate, some of which were recently characterized. Labyrinthine efferent axons and facial motoneuron axons segregate at distinctly different areas in the chicken and mouse: outside the brain in the former and inside the brain in the latter. Examination of the possible basis for pathway selection tends to support the idea that efferents use intact afferent fibers as highways for their navigation to distinct sensory epithelia. PMID- 8694417 TI - Determinants of semicircular canal afferent response dynamics in fish. AB - Present results separate the relative contributions of semicircular canal biomechanics from hair cell/afferent biophysics in determining the amplitude and phase of afferent responses to sinusoidal motion of the head. Separation was achieved by combining electrical polarization of the endolymph with mechanical indentation of the canal limb to modulate the instantaneous firing rate of horizontal semicircular canal afferents. The electrical stimulus drives hair cell transduction currents via modulation of the Nernst-Planck potential, whereas the mechanical stimulus mimics head rotation and modulates the open probability of the transduction channels. Responses for electrical polarization therefore reflect post-transduction-current (PTC) mechanisms, and responses for mechanical stimulation include the additional influence of canal mechanics. Linear transfer functions defining individual afferent response dynamics were obtained for low levels of each stimuli and are reported in Bode form providing gain (spikes/s per micron or mV) and phase (deg re: peak stim) over the frequency range from 0.02 to 40 Hz. Combined results for electrical and mechanical stimuli distinguish the component of sensory signal processing carried out by canal mechanics from that carried out by the hair cell/afferent complexes. Individual afferents were categorized according to their response to the mechanical stimuli as low-gain velocity (LG), high-gain velocity (HG) or acceleration (A) sensitive, groups as originally defined by Boyle and Highstein to describe interafferent diversity present within the population. In contrast to the results for mechanical stimuli, all afferent groups exhibit nearly equal increases in gain and phase for increasing frequencies of electrical stimulation. Comparison of individual afferent responses for the two stimuli leads to the conclusion that the LG, HG, and A groups are distinguished primarily by diversity in the mechanical activation of associated hair cells and not by PTC mechanisms. Even though PTC processing does not contribute significantly to determining these groups, it is the primary determinant underlying high-frequency gain and phase enhancements observed in the population average. Comparison of mechanical and electrical responses also reveals the mechanical lower-corner responsible for phase enhancements and gain decreases in all afferents at low frequencies of mechanical stimulation (< 0.05 Hz). Results imply that LG afferents encode angular head velocity by canceling a phase lag and gain attenuation due to the mechanics with a phase lead and gain enhancement due to PTC mechanisms above approximately 0.2 Hz. In contrast, A group afferents encode angular head acceleration by combining high-frequency phase leads and gain enhancements present in both the mechanics and PTC mechanisms across the physiological frequency spectrum. HG afferents fall between these two extremes, and, other than the influence of the mechanical lower corner, their response primarily reflects PTC processing. PMID- 8694419 TI - Four convergent patterns of input from the six semicircular canals to motoneurons of different neck muscles in the upper cervical cord. AB - This study was performed to investigate the pattern of input and the pathways from the six semicircular canals to motoneurons of various neck muscles in anesthetized cats. Intracellular postsynaptic potentials from neck motoneurons were recorded in response to electrical stimulation of the six ampullary nerves. The results showed that motoneurons of a particular neck muscle have a homogeneous convergent pattern of input from the six semicircular canals; there are four patterns of input from the six semicircular canals to motoneurons of various neck muscles; and the trisynaptic connection between the semicircular canal nerves and neck motoneurons was identified in addition to the disynaptic connection. PMID- 8694418 TI - Responses of identified vestibulospinal neurons to voluntary eye and head movements in the squirrel monkey. PMID- 8694420 TI - Behavior of primate vestibulo-ocular reflex neurons and vestibular neurons during head-free gaze shifts. PMID- 8694421 TI - Behavior contingent processing of vestibular sensory signals in the vestibular nuclei. PMID- 8694422 TI - Vestibular signals in the fastigial nucleus of the alert monkey. PMID- 8694423 TI - Inverse-dynamics representation of eye movements by cerebellar Purkinje cell activity during short-latency ocular-following responses. PMID- 8694424 TI - Influence of sensorimotor context on the linear vestibulo-ocular reflex. PMID- 8694425 TI - Organizational principles of otolith- and semicircular canal-ocular reflexes in rhesus monkeys. PMID- 8694426 TI - Hair cell generation in vestibular sensory receptor epithelia. PMID- 8694427 TI - Modeling the organization of the linear and angular vestibulo-ocular reflexes. AB - A one-dimensional mathematical model of the compensatory linear vestibuloocular reflex (lVOR) was developed. The model was based on the concept that to effect oculomotor compensation, linear head acceleration sensed by the otoliths must be integrated twice to form the angular position-related signal required by the motoneurons. This contradicts the postulate that linear acceleration is differentiated to generate "jerk," which is then used to drive the compensatory lVOR. The transfer characteristics of different otolith afferent classes were modeled by a transfer function with a common modal structure and different degrees of compensation. Both the time and frequency domain behavior of regular and irregular otolith afferents were simulated. The outputs of the various afferent classes were superposed by a linear filter to generate the velocity command which drives the oculomotor velocity-position integrator. The model was used to simulate the dominant gain and phase characteristics of the compensatory lVOR in monkey and the dynamic characteristics of the compensatory human lVOR response for brief periods of linear acceleration on a sled. The model was then combined with the velocity storage-based model of the angular vestibulo-ocular reflex (aVOR) to simulate the eye velocity response to centrifugation in monkey and man. The model suggests that the orientation response that modifies the time constants of the velocity storage integrator is the dominant aspect of the response to linear acceleration in monkey. Human responses, on the other hand, are dominated by an effect of the beating field, which modifies the eye velocity command to the oculomotor system. PMID- 8694428 TI - Nodulo-uvular control of central vestibular dynamics determines spatial orientation of the angular vestibulo-ocular reflex. PMID- 8694429 TI - Whole-body rotations enhance hippocampal theta rhythmic slow activity in awake rats passively transported on a mobile robot. PMID- 8694430 TI - Vestibular and visual cues in navigation: a tale of two cities. PMID- 8694431 TI - Subjective sensation during interaction between horizontal vestibular and vertical pursuit stimulation. PMID- 8694432 TI - In vivo-in vitro correlations in the central vestibular system: a bridge too far? PMID- 8694433 TI - Activation of immediate early genes by vestibular stimulation. PMID- 8694434 TI - GABAergic neurons in the primate vestibular nuclei. PMID- 8694435 TI - Vestibular influences on the autonomic nervous system. AB - Considerable evidence exists to suggest that both sympathetic and respiratory outflow from the central nervous system are influenced by the vestibular system. Otolith organs that respond to pitch rotations seem to play a predominant role in producing vestibulo-sympathetic and vestibulo-respiratory responses in cats. Because postural changes involving nose-up pitch challenge the maintenance of stable blood pressure and blood oxygenation in this species, vestibular effects on the sympathetic and respiratory systems are appropriate to participate in maintaining homeostasis during movement. Vestibular influences on respiration and circulation are mediated by a relatively small portion of the vestibular nuclear complex comprising regions in the medial and inferior vestibular nuclei just caudal to Deiters' nucleus. Vestibular signals are transmitted to sympathetic preganglionic neurons in the spinal cord through pathways that typically regulate the cardiovascular system. In contrast, vestibular effects on respiratory motoneurons are mediated in part by neural circuits that are not typically involved in the generation of breathing. PMID- 8694436 TI - Hair cell regeneration and vestibulo-ocular reflex recovery. PMID- 8694437 TI - Transmission between the type I hair cell and its calyx ending. AB - The long, uninterrupted apposition between the type I hair cell and the calyx ending has implications for the intercellular communication between these structures. Conventional synaptic transmission will be compromised unless the impedance of the ending is made relatively high. The apposition also creates the possibility of ephaptic transmission between the hair cell and the ending. Ephaptic transmission from the hair cell to the outer face of the calyx ending is too weak to make more than a minor contribution to sensory coding. Basolateral currents associated with hair-cell transduction can result in a substantial accumulation of K+ ions in the intercellular space. The accumulation can alter conventional transmission by depolarizing the hair cell and can alter afferent firing by depolarizing the ending. Reasons were presented suggesting that K+ accumulation may play an essential role in transduction involving type I hair cells, including the linearization of input-output relations and an increase in the maximal rate of discharge. PMID- 8694438 TI - Candidate cellular mechanisms of vestibulo-ocular reflex plasticity. PMID- 8694439 TI - Potential mechanisms of plastic adaptive changes in the vestibulo-ocular reflex. PMID- 8694440 TI - Role of the Y group of the vestibular nuclei in motor learning or plasticity of the vestibulo-ocular reflex in the squirrel monkey. PMID- 8694441 TI - Motor learning and memory in the vestibulo-ocular reflex: the dark side. PMID- 8694442 TI - Pathways from cell groups of the paramedian tracts to the floccular region. AB - A group of cells lying along the midline of the mid-medulla, nucleus pararaphales, is shown to play a role in vertical eye movements. Its efferents project along the midline, then pass laterally to follow the ventral external arcuate fibers around the surface of the medulla into the restiform body. The fibers terminate in the flocculus and ventral paraflocculus. This nucleus is one of the "cell groups of the paramedian tracts," which, based on their connectivity, could provide a motor-feedback signal for eye-head position to the cerebellum. Lesions of these pathways could lead to gaze-evoked nystagmus. PMID- 8694443 TI - GABAergic pathways convey vestibular information to the beta nucleus and dorsomedial cell column of the inferior olive. PMID- 8694444 TI - Organization of the vestibulocerebellum. PMID- 8694445 TI - The interaction of the human linear otolith-ocular and angular horizontal vestibulo-ocular reflexes in darkness. PMID- 8694446 TI - Otolith directional sensitivity and ocular torsion. PMID- 8694447 TI - The physiological basis of imperfect compensation by the VOR at high frequencies of rotation. PMID- 8694448 TI - Properties of nucleus incertus neurons of the cat projecting to the cerebellar flocculus. PMID- 8694449 TI - Mitotic and nonmitotic hair cell regeneration in the bullfrog vestibular otolith organs. PMID- 8694450 TI - Improvements of the neural network simulation of the vestibulo- oculomotor integrator. PMID- 8694451 TI - Mild mal de debarquement after sailing. PMID- 8694452 TI - Inhibitory burst neuron activity encodes gaze, not eye, metrics and dynamics during passive head on body rotation. Evidence that vestibular signals supplement visual information in the control of gaze shifts. PMID- 8694453 TI - Individual Purkinje cell axons terminate on both inhibitory and excitatory neurons in the cerebellar and vestibular nuclei. PMID- 8694454 TI - Vestibular afferent projections to the brain stem in pigeons. PMID- 8694455 TI - Role of cerebellar uvula-nodulus in the control of head orientation-specific eye velocity in the rabbit. PMID- 8694456 TI - Three-dimensional human VOR in acute vestibular lesions. PMID- 8694457 TI - Rotational kinematics and eye position dependence during vestibular-optokinetic stimulation in the monkey. PMID- 8694458 TI - Exploring sites for short-term VOR modulation using a bilateral model. PMID- 8694459 TI - Eye position dependence of innervation on-directions of motoneurons in the monkey. PMID- 8694460 TI - Vestibular influences on the histaminergic and cholinergic systems in the rat brain. PMID- 8694461 TI - Altered gravitational conditions affect the early development of the static vestibulo-ocular reflex in lower vertebrates. PMID- 8694462 TI - Responses of rat primary afferent vestibular neurons to galvanic polarization of the labyrinth. PMID- 8694463 TI - Dynamics of visual cue control over head direction cells. PMID- 8694464 TI - Cell proliferation in the goldfish ear. A BrdU study. PMID- 8694465 TI - The mid-lateral region of the utricle generates the human transaural linear vestibulo-ocular reflex. PMID- 8694466 TI - Displacement sensitivity of mammalian vestibular transducers. PMID- 8694467 TI - Immunohistochemical study on the distributions of AMPA receptor subtypes in rat vestibular nuclear complex after unilateral deafferentation. PMID- 8694468 TI - A quantitative deoxyglucose study of the rat vestibular end organs. PMID- 8694469 TI - Nitric oxide synthase localized in a subpopulation of vestibular efferents with NADPH diaphorase histochemistry. PMID- 8694470 TI - Regional distribution of hair cell ionic currents in frog vestibular epithelium. PMID- 8694471 TI - Damage and recovery of otolithic function following streptomycin treatment in the rat. PMID- 8694472 TI - Human cortical activity during vestibular- and drug-induced nausea detected using MSI. PMID- 8694473 TI - Low-frequency stimulation abolishes the high-frequency induced long-term effects in rat medial vestibular nuclei. PMID- 8694474 TI - Dendritic growth and changes in electrophysiological properties during development of chick vestibular neurons. PMID- 8694475 TI - Regional distributions of efferent neurons in the semicircular canals in the gerbil. PMID- 8694476 TI - The effect of neomycin on organotypic cultures of the adult guinea-pig utricle. PMID- 8694477 TI - Error signals in horizontal gaze velocity Purkinje cells under stimulus conditions that cause learning in the VOR. PMID- 8694478 TI - A delayed rectifier conductance shapes the voltage response of type I hair cells. PMID- 8694479 TI - Perception and eye movement during low-frequency centripetal acceleration. PMID- 8694480 TI - NADPH-diaphorase histochemical staining in the rat vestibular nuclei during postnatal development. PMID- 8694482 TI - Acetylcholine enhances optokinetic modulation of floccular Purkinje cells. PMID- 8694481 TI - Brain-stem integrative sites for vestibulo-sympathetic reflexes. PMID- 8694483 TI - The vestibulo-ocular reflex during horizontal axis eccentric rotation and near target fixation. PMID- 8694484 TI - Changes in otolith VOR to off vertical axis rotation in infants learning to walk. Preliminary results of a longitudinal study. PMID- 8694485 TI - Voltage responses of mouse utricular hair cells to injected currents. PMID- 8694486 TI - Normalization effects of vision on the compensatory VOR after canal plugging. PMID- 8694487 TI - Effects of microinjection of muscimol in the vestibular nuclei on velocity storage and estimation of head velocity by the otolith organs. PMID- 8694488 TI - Ocular selectivity of units in oculomotor pathways. PMID- 8694489 TI - Structural variation in ciliary bundles of the posterior semicircular canal. Quantitative anatomy and computational analysis. PMID- 8694490 TI - Review: methods of monitoring for process micro-organisms in biotechnology. AB - Biotechnology encompasses the use of micro-organisms and other biological agents in a range of processes, including the production of pharmaceuticals, fine chemicals, enzymes, food and drink. This review looks at the sources of occupational exposure by describing the way in which process micro-organisms, some of which could be hazardous to health, can be released into the workplace or the environment. It also examines current practices, monitoring strategies and procedures used to monitor for release of micro-organisms during biotechnology processes and looks forward to methods that may be of use in the future. PMID- 8694491 TI - On-site monitoring of personal exposure to tetrachloroethylene at dry cleaning establishments. AB - Methods for monitoring personal exposure to tetrachloroethylene vapour in the dry cleaning industry have been investigated. A Draeger diffusive colorimetric gas detector tube and the Delta vapour detection system manufactured by Sabre Gas Detection were both shown to be suitable for preliminary on-site monitoring. A range of short-term pumped colorimetric tubes were also shown to perform well under a range of environmental conditions. Data on laboratory evaluations and field trials are presented. PMID- 8694492 TI - The use of a new static device based on the collection of the thoracic fraction for the assessment of the airborne concentration of asbestos fibres by transmission electron microscopy. AB - A new static device, the CATHIA sampling head, based on the collection of the thoracic fraction is proposed for the assessment of the airborne concentration of asbestos fibres by transmission electron microscopy. By comparison with a standard aerosol sampling head, it has been shown that this sampler reduces the total mass concentration, but does not introduce any change in the most common index used to characterize an asbestos aerosol fibre, that is the concentration of fibres with length greater than 5 microns, diameter less than 3 microns and length to diameter ratio greater than 3. The homogeneity of the deposited dust on the collection filter favours the use of this sampling head with both the indirect and direct preparation methods. PMID- 8694493 TI - The determination of silver in whole blood and its application to biological monitoring of occupationally exposed groups. AB - A sensitive and rapid technique for directly measuring silver in blood, using electrothermal atomization atomic absorption spectrophotometry (ETAAS) is described. The method can be used to analyse precisely up to 40 blood samples a day in duplicate. Well-mixed, whole blood samples, collected in EDTA, were diluted 1 + 4 with a diluent containing 40 g l.-1 ammonium dihydrogen orthophosphate and 0.5 ml l.-1 Triton X-100. Aliquots of diluted blood were then analysed by ETAAS using wall atomization with a pyrolytically coated tube. The coefficient of variation for within-run precision was 4.55% at 10 micrograms 1.-1 and 5% at 25 micrograms 1.-1 Between-run variation, it was 4.1% at 25 micrograms l.-1 The analytical recovery for the method was 98% +/- 3% at both 8 and 30 micrograms 1. -1 The detection limit of the method was 0.1 microgram 1. -1, which was sufficiently sensitive to distinguish exposed from non-exposed individuals. Blood silver levels in unexposed subjects were found to be between < 0.1 and 0.2 micrograms 1. -1. Blood silver levels were determined in 98 occupationally exposed workers involved in bullion production, cutlery manufacture, chemical manufacture, jewelery production and silver reclamation. Blood silver levels ranged from 0.1 to 23 micrograms 1.-1, with some of the highest levels found in silver reclaimers. PMID- 8694494 TI - Airborne exposure to polycyclic aromatic hydrocarbons (PAHs) and urinary excretion of 1-hydroxypyrene of carbon anode plant workers. AB - Workers in plants producing carbon anodes for aluminium electrolysis are exposed to PAHs containing coal tar pitch volatiles, pitch and coke. The aim of this study was to evaluate the suitability of urinary 1-hydroxypyrene to characterize respiratory exposure to PAH, which is most relevant for assessing individual health risks. Six workers in a carbon anode plant volunteered to take part in a personal air sampling and a biological monitoring programme lasting five consecutive 8-h shifts to determine occupational exposure to airborne PAHs and urinary excretion of 1-hydroxypyrene. Exposure to total PAH for all worksites varied from 3.99 to 120.6 micrograms PAH m-3 and for benzo(a)pyrene (BaP) from 0.17 to 4.88 micrograms BaP m-3. The concentration of 1-hydroxypyrene in post- and pre-shift urine samples was in the range (0.5- 61.8 mumol 1-OHP per mol creatinine) and depended on the worksite. The Spearman rank correlation test showed a low but significant (P<0.005) correlation of urinary 1-hydroxypyrene in the post-and pre-shift samples with respiratory pyrene exposure. The quantitative aspects of biological monitoring for the evaluation of respiratory PAH exposure were tested with a pharmacokinetic model. On the basis of individual pyrene exposure, excretion of urinary 1-hydroxypyrene during the working week was calculated for each worker. The results presented in this investigation indicate that biological monitoring of the pyrene metabolite 1-hydroxypyrene is a useful indicator of a general PAH exposure, but cannot replace personal air sampling for assessing the lung cancer risk of individuals. PMID- 8694495 TI - Magnetic resonance spectroscopy in cancer: phospholipid, neutral lipid and lipoprotein metabolism and function. AB - A Special Symposium on "Lipid Metabolism and Function in Cancer. Significance of Magnetic Resonance Spectroscopy (MRS) Measurements in Relation to Biochemical Processes and Cellular Control" was held by the EU BIOMED 1 Concerted Action for "Cancer and Brain Disease Characterization and Therapy Assessment by Quantitative MRS", within the 5th International Conference of Anticancer Research (Corfu, 18 20 October 1995). The aims of the Symposium were to discuss present knowledge and problems in the field of phospholipid, neutral lipid and lipoprotein metabolism in cancer, together with the new potential of these inter-linked areas of research arising from advanced in vitro and in vivo MRS methodologies. This guest editorial is intended to introduce the reader of the Proceedings published in this issue, into the stimulating atmosphere of the Symposium, by summarizing some of the exciting proposals, views, ideas and open questions which emerged from presentations and multi-disciplinary, plenary discussions. PMID- 8694496 TI - Lipid Metabolism and Function in Cancer. Significance of Magnetic Resonance Spectroscopy (MRS) Measurements in Relation to Biochemical Processes and Cellular Control. Proceedings. Corfu, Greece, 17-22 October 1995. PMID- 8694497 TI - An introduction to the potential of 1H-, 31P- and 13C-NMR-spectroscopy. AB - Multinuclear NMR spectroscopy (1H, 13C, 31P) of biological samples reflects their metabolic composition. The analysis of high field and high resolution spectra of body fluids, cell and biopsy extracts requires no separation of a complex mixture into individual metabolites. Pattern recognition methods can be used to classify normal and pathological samples. Stable isotope enriched precursors are used to follow-up biochemical pathways and metabolic trafficking demonstrated for the lipid biosynthesis. Finally, volume selective in vivo spectroscopy or spectroscopic imaging depicts acute and time dependent metabolic events noninvasively in intact tissue within a few minutes. PMID- 8694498 TI - High resolution nuclear magnetic resonance spectroscopy in clinical biology: application in oncology. AB - Nuclear Magnetic Resonance (NMR) technology is mainly known in medicine by the rapidly growing activity in proton imaging (MRI) and, to a lesser extent by the very promising in vivo spectroscopy (MRS). Though about forty years old, the idea of using high resolution MRS in clinical biology has been developed only recently. The in vitro high resolution MRS of body fluids, biopsy samples and surgery specimens has, however, demonstrated exciting potentialities as a multiparametric (full "biochemical profile" analysis), fast, and relatively inexpensive analytical method. Assisted by pattern recognition methods, MR spectra have already provided clinically relevant information in oncology, when the lack of highly specific and sensitive markers has to be deplored for some cancer types. PMID- 8694499 TI - Intracellular trafficking of phospholipids: import of phosphatidylserine into mitochondria. AB - Three mechanisms are commonly suggested for the movemerlt of lipids between intracellular organelles: transfer mediated by cytosolic lipid transfer proteins, vesicle-mediated transfer, and transfer via regions of membrane continuity between organelles. The mechanism of translocation of phosphatidylserine from its site of synthesis on the endoplasmic reticulum (and related membranes) to the site of phosphatidylserine decarboxylation in the mitochondria has been investigated. Several experiments indicate that a transfer mediated by soluble cytosolic phospholipid transfer proteins, or by vesicles, is unlikely. Rather, the most likely mode of import of newly-synthesized phosphatidylserine into mitochondria is contact between the endoplasmic reticulum and mitochondrial membranes. In support of this mechanism we have isolated an endoplasmic reticulum like."mitochondria-associated membrane" fraction and shown that it has some, but not all, properties of the endoplasmic reticulum. The mitochondria-associated membranes are enriched in lipid biosynthetic enzymes, especially phosphatidylserine synthase. When either phosphatidylserine translocation to mitochondria is blocked (by ATP depletion), or phosphatidylserine decarboxylation is blocked (with hydroxylamine), newly-synthesized phosphatidylserine accumulates in the mitochondria-associated membrane but not in microsomes, suggesting that phosphatidylserine traverses the mitochondria-associated membrane on its route from the endoplasmic reticulum to mitochondria. PMID- 8694500 TI - Glycerophosphoinositols as potential markers of ras-induced transformation and novel second messengers. AB - Glycerophosphoinositols are metabolites formed by the sequential action of a phospholipase A2 specific for membrane phosphoinositides, and a lysolipase. Increased levels of these compounds characterize cell lines of different origin transformed by ras and other oncogenes. Thus, glycerophosphoinositols have been proposed as markers of cell transformation. These compounds are also biologically active. In particular, glycerophosphoinositol-4-phosphate (GroPIns4P) is an inhibitor of adenylyl cyclase that acts on the Gs protein. Since GroPIns4P is formed physiologically upon hormone stimulation in several cell lines including fibroblasts, thyrocytes, neuronal and leukemia cells, we propose that GroPIns4P could act as a second messenger able to mediate a cross-talk between the ras cascade and adenylyl cyclase. PMID- 8694501 TI - Phosphatidylethanolamine synthesis in the normal and lymphomatous mouse liver; a 13C NMR study. AB - The lymphomatous liver contains high levels of phosphoethanolamine. This compound is a precursor of the phospholipid, phosphatidylethanolamine. The kinetics of phosphatidylethanolamine synthesis has been studied by 13C NMR spectroscopy of extracts of the lymphomatous mouse liver following the administration of (13C2)ethanolamine. The concentrations of (13C2)ethanolamine, (13C2)phosphoethanolamine, and (13C2)phosphatidylethanolamine were fitted to kinetic models and the maximal activities of the enzymes in the synthetic pathway were estimated. Phosphatidylethanolamine synthesis in the normal liver appears to be limited by the supply of ethanolamine. In the lymphomatous liver, both ethanolamine kinase and PE:CTP cytidylyltransferase had lower activities than in the normal liver, and there was evidence for a higher activity of ethanolamine base-exchange enzyme. PMID- 8694502 TI - Metabolism of phosphonium choline by rat-2 fibroblasts: effects of mitogenic stimulation studied using 31P NMR spectroscopy. AB - Phospholipid turnover increases with both mitogenic stimulation and oncogenic transformation (1-9). Recent 31P nuclear magnetic resonance (NMR) spectroscopy studies of human tumors, animal tumor models and cell systems have reported elevated phosphomonoesters with growth and oncogenic transformation, as well as changes in these levels associated with treatment (10). In order to gain insights into the mechanisms underlying these changes, we used a phosphonium analog of choline and 31P NMR spectroscopy to study choline metabolism in quiescent and mitogenically stimulated Rat-2 fibroblasts. Cell growth status of these cells has a significant effect on choline metabolism. While overall uptake of the analog was similar in both quiescent and growing cells, distribution among metabolite pools differed. Quiescent cells accumulate label in the phosphodiester pool, with little or none in the phosphomonoester pool. On the other hand, mitogenic stimulation resulted in a significant fraction of the label in the phosphomonoester pool. PMID- 8694503 TI - 31P MRS of human tumor cells: effects of culture media and conditions on phospholipid metabolite concentrations. AB - 31P magnetic resonance spectroscopy has been used to determine phosphate metabolite profiles in five human tumor cell lines in culture and as solid tumor xenografts in nude mice. Significant differences between cell lines, in particular in their phospholipid metabolite levels, were observed. The largest differences between metabolite profiles in vivo and in culture were observed for cell lines which exhibit low phosphoethanolamine levels in culture. One of these lines, the colon carcinoma CX-1, was studied in more detail in both incubated and perfused DMEM cultures with variation of the concentrations of glucose, choline and ethanolamine. Highly significant alterations of phospholipid metabolite concentrations and UDP-hexoses (primarily UDP-GlcNAc and UDP-GalNAc) were observed as a function of the precursor concentrations, culture time or perfusion time. A strong interaction between phospholipid metabolic pathways and UDP-hexose pathways could be demonstrated. PMID- 8694504 TI - Kinetics of choline transport and phosphorylation in human breast cancer cells; NMR application of the zero trans method. AB - The mechanism and kinetics of choline transport and phosphorylation in MCF7 human breast cancer cells was studied by 31P, 13C and 2H NMR, applying the zero trans method. Choline was transported by a Michaelis-Menten like mechanism with a maximum transport rate T(max) = 13.5 +/- 2.6 nmol/hour/mg protein (3.06 +/- 0.6 fmol/cell/hour) and choline concentration at half maximal transport rate of Kt = 46.5 +/- 2.8 microM. The rate of choline phosphorylation was more than two orders of magnitude faster than the rate of its transport (T(max)) maintaining the ratio [phosphocholine]/[choline] higher than 100. The results demonstrated enhanced choline transport and choline kinase activity in breast cancer cells. PMID- 8694505 TI - Variations in energy and phospholipid metabolism in normal and cancer human mammary epithelial cells. AB - By comparing the metabolism of human mammary epithelial cells and human breast cancer cells (MCF7 and T47D), proliferating at approximately the same rate, it was possible to isolate the effect of malignancy alone on the energetics and phospholipid metabolism of cancer cells. 31p NMR of perfused mammary cells and of water soluble extracts of these cells showed that the levels of phosphocholine, phosphoethanolamine, and glycerol derivatives of these metabolites were very low and significantly less than that in the cancer cells, suggesting an association of malignancy with induction of phospholipid biosynthesis and breakdown. The level of the high energy phosphates and the rates of glucose consumption and aerobic glycolysis did not reveal distinct differences between normal and cancer cells. The comparable energetic appear to be related to the similarity of proliferating capacity in culture of the normal and cancer cells. PMID- 8694506 TI - Phosphocholine and choline content of rat sarcoma cells grown in the presence and absence of serum. AB - Rat sarcoma cells were grown in vitro in tissue culture medium (DMEM) supplemented with 10% foetal calf serum for 5 to 8 days followed by serum withdrawal to produce populations of cells with a variety of cell cycle distributions. Phosphocholine (PCho) and choline content and S + G2 fraction were determined. The phosphocholine content of faster growing populations of serum supplemented cells was higher than the slower growing populations. Choline content was not consistently associated with S + G2 fraction. Serum deprivation was accompanied by a decrease in S + G2 fraction after 24 hours but even after 48 hours PCho content was only slightly decreased. PMID- 8694507 TI - Phosphomonoester metabolism as a function of cell proliferative status and exogenous precursors. AB - Elevations of phosphomonoesters (PMEs) correlate with increased cell growth or increased cell degradation, and have been shown to occur in human tumors as well as animal tumor models and cell lines. Furthermore, decreased PME levels have been observed in tumor patients who respond to therapy. Therefore, understanding the mechanisms underlying the interactions of intrinsic and extrinsic control of PMEs may assist diagnosis and treatment of tumors at the clinical level. In order to probe the underlying mechanisms controlling PME concentrations, we used cells grown in bioreactors and 31P nuclear magnetic resonance spectroscopy to study the effects of proliferative status and exogenous precursor amines on the PMEs phosphorylcholine (PCho) and phosphorylethanolamine (PEtn). In general, PEtn demonstrated an inverse correlation with cell growth, beginning to rise as the stationary growth phase was approached. PCho, on the other hand, generally decreased during log growth, an effect that was reversed by the addition of exogenous choline. The net effect of these changes was a consistent and dramatically lower PCho/PEtn ratio in stationary cultures compared to actively proliferating cultures. PMID- 8694508 TI - Detection of phosphatidylcholine-specific phospholipase C in NIH-3T3 fibroblasts and their H-ras transformants: NMR and immunochemical studies. AB - Although evidence supports constitutive activation of phosphatidylcholine specific phospholipase C (PC-plc) in rastransformed fibroblasts, no studies have been devoted to measure the basal activity levels of this enzyme, its molecular characteristics and subcellular localization. This paper reports for the first time measurements of the activity of different enzymes responsible for PC hydrolysis (PC-plc; phospholipases A2 (pla2) and A1 (pla1)) in homogenates of murine NIH-3T3 fibroblasts (3T3) and their transformants obtained by human H-ras transfection (3T3ras). To this end, 31P NMR analyses were carried out on total cell homogenates, incubated in the presence of mixed diheptanoylphosphatidylcholine: sphingomyelin (DHPC:SM) unilamellar vesicles (SLUV), in which DHPC acts as a suitable substrate for water-soluble lipolytic enzymes. The basal PC-plc activity levels (0.66 +/- 0.14 and 0.38 +/- 0.10 nmol/10(6) cells.hour in 3T3 and 3T3ras fibroblasts, respectively),were substantially higher (over 30-50x) than those reported in the literature for normal mammalian cells (dog heart myocytes). Moreover the PC-plc activity was about 15-30 times lower than the overall PC deacylation activity in both clones. The use of high titer polyclonal antibodies, raised in a rabbit against bacterial PC-plc, allowed identification of one cross-reactive mammalian PC-plc component (M(r) 66 kD) in cell lysates of both 3T3 and 3T3ras fibroblasts, and detection, by indirect immunofluorescence, of its subcellular localization. In control 3T3 fibroblasts (in the late log-phase of growth) the enzyme was exclusively located in the cytosol, while in H-ras transformed cells it was massively exposed on the external side of the membrane. This new finding strongly suggests that the oncogenic product p2Iras is able to induce (or mediate) translocation of PC-plc across the plasma membrane of ras transformed cells, with possible implications not only on cell biochemistry (enhancement of PC-plc activity, and consequent production of intra- and extracellular PCho and accumulation of neutral lipids) but also on cell-cell interaction mechanisms which facilitate tumour invasion and metastasis of oncogene-transformed cells. PMID- 8694509 TI - Phosphatidylethanolamine methylation and hepatoma cell growth. AB - Phosphatidylethanolamine is converted to phosphatidylcholine in hepatocytes via the enzyme phosphatidylethanolamine N-methyltransferase (PEMT). An isoform, PEMT2 has been cloned, expressed and localized to a mitochondria-associated membrane in rat liver. Expression of PEMT2 caused a decreased rate of cell division of cultured rat hepatoma cells. Mechanistic studies suggest that the slower growth of transfected hepatoma cells may be due to down regulation of CTP: phosphocholine cytidylyltransferase and the CDP-choline pathway for phosphatidylcholine biosynthesis. A role for PEMT2 in the regulation of hepatocyte cell division is also indicated by PEMT2 down-regulation in regenerating rat liver. PMID- 8694510 TI - Combined extraction techniques of tumour cells and lipid/phospholipid assignment by two dimensional NMR spectroscopy. AB - As the cell membranes are one of the targets of drug treatment in cancer cells, their membrane composition and variations in this composition need to be analyzed. Gradient selected 2D-NMR inverse heteronuclear chemical shift correlations are have described, which offer optimum sensitivity combined with a high reliability for unequivocal signal assignment in proton, carbon and phosphorous spectra, concerning neutral lipids and in particular phospholipids. Additionally, an extraction procedure is presented to extract subsequently the water soluble (PCA extract) and lipophilic metabolites (chloroform/methanol extract) from the same cell batch. PMID- 8694511 TI - Early stage monitoring of miltefosine induced apoptosis in KB cells by multinuclear NMR spectroscopy. AB - Synthetic ether lipids, like miltefosine (hexadecylphosphocholine), an alkylphosphocholine, are antineoplastic agents in vitro and in vivo. Their mode of action is mediated via the cell membrane, but the mechanism is still unclear. Miltefosine induces apoptosis in human epithelial KB cells, but slows down only proliferation in rat C6 glioma cells. NMR spectroscopy on lipid extracts reveals increased diacylglycerol and triacyglycerol biosynthesis in KB cells prior to DNA fragmentation indicating a CTP:phosphocholine-cytidylyl-transferase (CT) inhibition by the drug. Although C6 cells were morphologically affected by alterations in phospholipid composition and metabolism by a long term treatment (23 days) with the drug, no persistent diacylglycerol increase is observed. PMID- 8694512 TI - Neutral lipids production, transport, utilization. AB - Malignant tumors increase the levels of triacylglycerol carriers, i.e., very low density lipoproteins (VLDL), and lower the concentrations of cholesterol carriers, i.e., low-density and high-density lipoprotein fractions (LDL and HDL). The rise in VLDL levels may be caused by increased hepatic secretion of this lipoprotein fraction and reduced conversion of VLDL to LDL caused by cachexia inducing proteins. The hypocholesterolemia is probably related to lowered LDL and HDL cholesterol levels that depend on a greater utilization of cholesterol for the biogenesis of new membranes and the accumulation of cholesteryl ester in tumoral tissue. The involvement of neutral lipids in cancer development is further evidence by the occurrence of certain tumors following the intake of high fat diets. Furthermore, epidemiological and experimental studies showed that hypercaloric diets rich in n-6 polyunsaturated fatty acids (n-6, PUFA) stimulated tumorigenesis, while diets rich in marine fats (n-3, PUFA) inhibited it. In conclusion, changes ill neutral lipids production, transport and utilization play an importantly role in determining the alterations in energy storage and membrane properties observed in tumor cells. PMID- 8694513 TI - Proton nuclear magnetic resonance spectroscopy of plasma lipoprotein: technical problems and potential interest in cancer disease. AB - This paper reviews several methods presently available for analysing lipoprotein NMR spectra. Two main steps can be distinguished: NMR signal processing and data analysis. Time domain (wavelet transform) and frequency domain (curve fitting) signal processing methods are compared. Statistical methods of data analysis (Ascending Hierarchical Classification, Correspondence Analysis and Principal Component Analysis) have been tested on simulated NMR data of plasma lipoprotein with different numbers of sampling points and different noise levels. These few examples clearly attest that the NMR approach to complex "mixture" (such as body fluids) analysis is emerging from its infancy. New interest in plasma lipoprotein analysis in cancer biology is finally discussed in the light of previous clinical and experimental results and of understanding of lipid metabolism in cancer. PMID- 8694514 TI - Magnetic resonance spectroscopy of blood plasma lipoproteins in malignant disease: methodological aspects and clinical relevance. AB - NMR spectroscopy of blood plasma has been extensively investigated in the last decade, mainly motivated by a hope that the method would aid in the diagnosis of malignant disease. Although the 1H NMR indices have failed as a tumor marker suitable for cancer screening due to low specificity, the method has great potential in cancer research. Its use outside research laboratories, however, is still very limited. Several methodological problems require special attention. 1H NMR spectroscopy lipid line widths are composite signals that reflect a continuum of general responses to different stimuli. Few studies on the fatty acid distribution in blood plasma in malignancy have been done, using the saturated and unsaturated regions of the 13C NMR spectrum. NMR spectroscopy of blood plasma might be valuable in practical clinical use. We suggest that this method could estimate effects on blood lipid profile following endocrine therapies in cancer patients. PMID- 8694515 TI - Artificial neural network analysis of 1H nuclear magnetic resonance spectroscopic data from human plasma. AB - Nuclear magnetic resonance (NMR) spectroscopy is finding increasing use in studies of plasma and lipoproteins in health and disease, including cancer. Analysis of the NMR data is not straightforward due to complex systems and also partly unknown underlying biochemistry. Here we demonstrate how artificial neural networks can be utilised in biomedical NMR. Their quantification power is illustrated by establishing lipoprotein lipid quantification directly from plasma 1H NMR data. The biochemical rationale for this example is elucidated on the basis of the relative weights of the spectral inputs in a trained network. A novel application of a Kohonen-type network architecture to classify plasma 1H NMR spectra is also presented. PMID- 8694516 TI - C13 NMR spectroscopy of lipids: a simple method for absolute quantitation. AB - There is both epidemiological and experimental evidence of the effect of fatty acid molecular structure, particularly the degree of saturation in fatty acyl chains, on the growth and regulation of certain tumours. In vivo carbon nuclear magnetic resonance spectroscopy has previously been shown to offer a non invasive technique for the evaluation of proportions of monounsaturated, polyunsaturated and saturated fatty acids in human adipose tissue. We present a simple method, which uses both endogenous water and fat as reference, to quantify in molar terms these lipid sub-categories for tissues other than pure fat. This could provide additional information in the debate on the protective effect in cancer of high polyunsaturated fatty acid (PUFA) diet. The method was validated by characterization of a lipid emulsion of known composition in various experimental set-ups and was applied to measure the lipid composition of the calves of two volunteers. Limitations and perspectives of the method are discussed. PMID- 8694517 TI - Mobile lipid accumulation in necrotic tissue of high grade astrocytomas. AB - Multiple samples from 42 astrocytomas were investigated ex vivo by 1H MR spectroscopy followed by histological assessment. MR visible lipids were detected in 27 of 32 grade 4 astrocytomas. These lipids were heterogeneously distributed within the tumours. Their amount correlated positively with the amount of histologically detected necrosis. Mobile lipids were also observed in grade 4 astrocytoma samples without necrosis, as well as in one of three grade 3, two of three grade 2 and two of four grade 1 astrocytomas. The clinical significance of MR visible lipids, their cellular location, and their possible biological bases are discussed. PMID- 8694518 TI - Characterization of the metabolism of perinecrotic cells in solid tumors by enzyme histochemistry. AB - Hypoxic tumor cells resist most therapies and cause tumor regrowth when their environment improves. Identifying the adaptation strategies to hypoxia would help develop better tailored cancer therapies. Ehrlich carcinomas implanted on mice were analyzed histochemically for the following enzyme activities: lactate, succinate and glucose-6-phosphate dehydrogenases, dihydrofolate reductase, purine nucleoside phosphorylase, xanthine oxidoreductase, and acid phosphatase. With the exception of xanthine oxidoreductase, which was not active in tumor cells, and of succinate dehydrogenase the activity of which was not significatively altered, all other activities were much higher in perinecrotic cells with respect to cells close to blood vessels. These data suggest the integration of metabolic paths allowing purine and lipid biosyntheses. Degradation products from the necrosis are presumed to be employed as surrogates of blood-borne nutritive substances by cells distant from the vascularization. PMID- 8694519 TI - Introduction to in vivo MRS of cancer: new perspectives and open problems. AB - Measurements of tumour extracts and tumour cell lines using 1H and 31P MRS have demonstrated the potential of the technique to distinguish different types of tumour, and in a range of tumours to provide information on degree of malignancy, grade and prognosis. In vivo studies have shown that changes in the energetic status of tumours, and in the phospholipid metabolites, correlate with the response of tumours to treatment, providing the potential to monitor the effectiveness of cancer treatment. Routine application of these techniques in clinical measurements depends upon the development of robust equipment and measurement methods to aid clinical measurements. Considerable advances have been made. Imaging can now be performed very rapidly, and a range of localisation technique have been established. Equipment provides for automatic set up and shimming, and coils with increased sensitivity are available. Improvements in hardware provide more sensitive receive coils; and shielded gradients which provide for a more robust performance. 31P studies are being improved by the use of NOE enhancement and 1H decoupling, increasing the specificity and sensitivity of the techniques. These advances in instrumentation need to be complemented by advances in our understanding of the biochemical processes in tumours giving rise to the observed spectral changes. In this paper, recent reports of NMR spectroscopy in cancer are reviewed, together with the requirements for tumour measurements. PMID- 8694520 TI - Spatial resolution and spectral information content of proton NMR spectroscopic imaging of tumour metabolism. AB - The value of metabolic proton NMR spectroscopic imaging to detect and classify tumours increases with the spatial resolution and the information content of the spectra. Several factors influencing these quantities are discussed. PMID- 8694521 TI - Human cancers detected by proton MRS and chemical shift imaging ex vivo. AB - Proton magnetic resonance spectroscopy (1H MRS) has the potential to become a diagnostic adjunct for the detection and grading of human neoplastic disease. This paper describes the use of proton MRS to document changes arising in the lipid chemistry of biopsies arising from the human uterine cervix, thyroid and colon and demonstrates the diagnostic power of ex vivo spectroscopy. Proton chemical shift imaging (CSI) is further used to determine the spatial location of lipid changes in ex vivo human biopsy specimens and provides insight into the chemistry of neoplastic transformation. PMID- 8694522 TI - Intratumoral lipids in 1H MRS in vivo in brain tumors: experience of the Siemens cooperative clinical trial. AB - Fifteen institutions cooperated to examine the ability of 1H MRS to characterize metabolism in vivo in 102 primary brain tumors. Spectra were acquired from single 8 cc voxels in the tumor using a spin-echo method with an echo time of 135 ms. The most intense lipid signal was that of fatty acyl methylene protons at 1.3 ppm. Intratumoral lipid signals were not detected in oligodendrogliomas, ependymomas, or meningiomas and were evident in only 1 of 6 primitive neuroectodermal tumors. Among 75 astrocytic tumors, lipid signals occurred in 16% of low grade astrocytomas (AS), 36% of anaplastic astrocytomas (AA), and 44% of glioblastomas (GB). The amount of lipids, expressed as a ratio of the intensity of the methylene signal to that of choline, increased progressively with histopathological grade (p = 0.05). Greater amounts of mobile lipids in vivo in GB, which usually contain necrosis, is in accord with the recently discovered correlation between the fraction of microscopic necrosis and the intensity of the mobile lipid signal observed ex vivo using 1H MRS. The observation of lipid signals in AA, which do not contain necrosis, suggests that mobile fatty acids may appear at a stage of metabolic insult that precedes microscopic signs of cell death, and raises the possibility of an independent correlation between 1H MRS detectable lipids and prognosis in patients with astrocytic tumors. PMID- 8694523 TI - Phospholipid metabolites in 1H-decoupled 31P MRS in vivo in human cancer: implications for experimental models and clinical studies. AB - The use of 31P MRS in clinical cancer research has been hampered by both poor anatomic localization of spectra and poor resolution of overlapping signals. We found that accurate localization using 3D chemical shift imaging and improved resolution using 1H-decoupling and nuclear Overhauser-enhancement (NOE) increased signal-to-noise and permitted resolution of separate components within phosphomonoester (PME) and phosphodiester (PDE) regions. Fifty-three cancers of different types (lymphoma, sarcoma, adenocarcinoma) had the following common features: (1) phosphoethanolamine the dominant PME; (2) glycerophosphoethanolamine and -choline rarely detected; (3) a broad PDE signal probably from membrane phospholipids; and(4) prominent nucleoside triphosphates. 1H-decoupling with NOE-enhancement permitted us to obtain new information about in vivo metabolism in human cancers; generate new hypotheses and help guide development of experimental models appropriate to test them; and provide a firm basis with which to examine clinical uses of 31P MRS. PMID- 8694524 TI - Lipid selective MR imaging and localized 1H spectroscopy of bone marrow during therapy of leukemia. AB - In most patients with acute leukemia very low or absent lipid signals from central red bone marrow are detected using magnetic resonance (MR) techniques, in contrast to healthy persons with considerable signals from both, water and lipid protons. The proliferation of the malignant leukemic cells causes the displacement of fat cells in the marrow. This disorder is reversible during successful cytotoxic chemotherapy of acute leukemia: Lipid signals from vertebral bodies arise again due to the replacement of hypercellular leukemic marrow by fat. Different approaches for lipid selective MR imaging and spectroscopy are reported and results from typical examples are demonstrated and discussed. The report is based on examinations of 12 patients with leukemia in follow-up studies, 11 patients with other disorders of bone marrow, and 26 healthy volunteers. PMID- 8694525 TI - Diagnostic potential for cancer via 1H magnetic resonance spectroscopy of colon tissue. AB - Specimens of colon tissue were examined by 1H MRS (360 MHz) in order to determine the usefulness of rat colon (n = 44) as a model for human colon (n = 60), particularly for the characterization of preneoplastic lesions. Human tissue was characterized by 1H MRS as a precursor to in vivo studies. For both tissues, resonances from mobile lipids were not characteristic of pure mucosa, but correlated with the presence of submucosa. The mean intensities of the resonances at 3.2 and 3.4 ppm (assigned mainly to choline-containing compounds and taurine, respectively) of rat mucosa compared to those of human mucosa, and of rat tumours compared to human tumours, were not significantly different, while both resonances were significantly more intense in rat tumours compared to rat mucosa. The spectra of premalignant lesions in rat colon have features between those due to tumours and normal tissue. We conclude that rat colon is a useful model for human colon in 1H MR spectroscopic studies. MR spectra from human colon control tissue and tumours were classified with 100% accuracy using multivariate analysis. PMID- 8694526 TI - Differentiation of glioblastoma multiforme from astrocytomas by in vitro 1H MRS analysis of human brain tumors. AB - In vitro high resolution 1H NMR spectroscopy allows non-invasive metabolic evaluation of specimens derived from surgically biopsied or resected brain tumors, with the aim of identifying potential markers of different malignancy grading, and improving diagnostic and therapeutic strategies. In the present study we evaluated 36 patients affected by different brain gliomas (7 well differentiated astrocytomas, 7 anaplastic astrocytomas, 16 glioblastomas, 6 oligodendrogliomas). These analyses allowed discrimination between well differentiated and anaplastic astrocytomas (AII + AA) and glioblastoma multiforme (GM) samples on the basis of the ratio between the integrated choline-containing resonance (b"Cho") and the creatine peaks (creatine (Cr) + Phosphocreatine (PCr)). While no definite difference was found between AII and AA, significantly higher values were observed for this ratio in GM. Other signals, derived from different metabolites, such as Glycine (Gly) and N-acetyl-aspartate (NAA), may also assume relevance in differential tumor diagnosis. In this study an increased [Gly]/[Cr + PCr] ratio was observed in GM with respect to AII and AA. The NAA levels observed in our tumor specimens may be explained on the basis of tumor cell infiltration into brain adjacent tissue. Interesting, but inconclusive, are the data concerning oligodendrogliomas, which, also in well differentiated forms, exhibit increased levels of b"Cho"/(Cr + PCr) ratio. The present study confirms the role of MRS in the biochemical characterization of neoplastic brain tissue and its potential contribution to a better selection of multidisciplinary treatment strategies. PMID- 8694527 TI - In vivo proton MR spectroscopy: the diagnostic possibilities of lipid resonances in brain tumors. AB - The lipid resonances detected in proton MR spectra of brain tumors were evaluated from the diagnostic point of view. Seventy five non-radiated brain tumors were examined in vivo and lipids were detected in 29% of anaplastic astrocytomas grade III, 60% of glioblastomas multiforme and 50% of metastatic tumors. Lipids were also detected in all brain abscesses and an epidermoid cyst. No lipids were detected in benign tumors (low grade and pilocytic astrocytomas, oligodendrogliomas, meningiomas, pituitary adenomas etc.). Thus, the presence of lipids in the MR spectra is indicative of malignancy (with a few exceptions). PMID- 8694528 TI - Lipids in bone tumors assessed by magnetic resonance: chemical shift imaging and proton spectroscopy in vivo. AB - The methods of fat and water selective magnetic resonance (MR) imaging and localized 1H MR spectroscopy were evaluated in the course of 37 examinations on 27 primary bone tumors. These methods are capable of demonstrating small amounts of lipids inside the tumors and subtle edema in the adacent bone marrow, in contrast to the usually applied spin-echo and gradient-echo sequences providing signals dependent on the total proton density and on the relaxation times. The tumor masses of the malignant tumors were free of signals in the fat selective images, whereas in three out of six osteochondroma fat signals could be detected. Localized MR spectroscopy was more sensitive even to very low lipid content (lipid portion < 0.5%) in the tumors and revealed signals with J-coupling from seven out of 13 malignant tumors. PMID- 8694529 TI - Lipid metabolite peaks in pattern recognition analysis of tumour in vivo MR spectra. AB - The ability to classify spectra of tumours according to their stage and type will be essential if magnetic resonance spectroscopy (MRS) is to be used as an aid in the diagnosis of cancer. MRS data are normally classified on the basis of selected peak measurements but these may be difficult to extract automatically. We present two alternative methods of feature extraction which we used to discriminate between spectra from tumours and normal tissues. Discrimination could be achieved either using features from the whole spectrum, or from a selected region containing the peaks from the phospholipid precursors in the phosphomonoester region. PMID- 8694530 TI - Grading and therapy monitoring of astrocytomas with 1H-spectroscopy: preliminary study. AB - We examined 11 patients (9 male and 2 female, age 41 +/- 13) presenting astrocytomas of different malignancy grade (WHO) with single voxel (PRESS) and double voxel (STABLE) spectroscopy techniques. The content of choline in the tumors was determined as a function of their grade of malignity and a significant correlation was found. The measurements were repeated after interstitial radiosurgery. Observed spectra changes induced by this stereotactic treatment with 125I-seed demonstrated the possibility of therapy monitoring. PMID- 8694531 TI - Application of 31P NMR spectroscopy in clinical analysis of changes of serum phospholipids in leukemia, lymphoma and some other non-haematological cancers. AB - The sodium salt of cholic acid added to serum caused separation of three phospholipid peaks located upfield from inorganic phosphate (Pi) due to phosphatidylethanolamine with sphingomyelin (PE + SM), lysophosphatidylcholine (LPC), and phosphatidylcholine (PC). 31P NMR spectra were obtained from the sera of 15 healthy volunteers, 10 individuals suffering from acute leukemia, 4 persons with malignant lymphomas, 13 patients with digestive tract tumors and 5 with renal cell carcinoma. The present studies confirmed our previous observation that the 31P spectra of sera of patients with acute leukemia and malignant lymphomas revealed a significant decrease in the phospholipid level at the time of diagnosis and displayed a good correlation between spectral parameters and stage of disease in patients responding and non-responding to therapy. Contrary to the preliminary studies, peaks from PE + SM and PC, and also a peak from LPC were observed. Changes in phospholipids in the 31P NMR spectra observed in patients suffering from digestive tract tumors and renal cell carcinoma were primarily dependent on the advance of the disease. Most of our patients with these cancers were in the early stage of the disease, and the spectra showed statistically significant decrease only in the LPC peak area, and no statistically significant changes of peak areas of PC and PE+SM in comparison to the control group. In conclusion, we can state that the LPC peak area is the most sensitive indicator in the monitoring of treatment in acute leukemia and malignant lymphomas. Our results also showed that LPC peak areas were decreased in the early stages of digestive tract tumors and a renal cell carcinoma. PMID- 8694532 TI - Novel approaches to tumor detection and therapy using a combination of monoclonal antibody and cytokine. AB - Cytokine-based tumor antigen augmentation is one of the approaches researchers and clinicians are using to improve the effectiveness of MAb-directed tumor diagnosis and therapy. Other efforts encompass the use of dose-fractionation for multiple administrations of radioimmunoconjugates, exploitation of genetic engineering to construct antibody molecules with specific biological properties (i.e., altered pharmacokinetics, activation of cellular immune responses, etc.) and use of MAb-directed conjugates that can enhance tumor MAb uptake by altering tumor perfusion. The studies summarized here as well as those from other laboratories have served as the framework for clinical investigations designed to determine the effectiveness of the interferons and other differentiation-inducing agents to alter the tumor antigen phenotype in patients. In an earlier study, patients given IFN-alpha had improved tumor uptake of an antimelanoma MAb. Subsequently, we reported that i.p. IFN-gamma administration substantially upregulated TAG-72 and CEA on the surface of human tumor cells isolated from malignant ascites. A seminal investigation showed significant increase of TAG-72 and CEA levels in tumor biopsies from patients diagnosed with colorectal carcinoma and given systemic IFN-alpha. Those studies led to a clinical trial in which late stage breast cancer patients were administered interferon in combination with therapeutic doses of CC49. Some clinical responses were observed, however, the cytokine and MAb combination may have also enhanced marrow toxicity. Future studies will continue to evaluate the ability to enhance tumor antigen expression in the context of genetically engineered MAbs designed to minimize normal organ toxicity. PMID- 8694533 TI - Clinical applications of urinary gonadotropin peptides (UGP) in gynecologic oncology. AB - The past seven years has witnessed the development of research assays and now commercial assays for the measurement of a fragment of the beta subunit of human chorionic gonadotropin (beta-hCG). This fragment has been called the beta core fragment (beta-core), urinary gonadotropin fragment (UGF) and most recently urinary gonadotropin peptide (UGP). Clinical applications of UGP have been pursued most often but not exclusively in gynecologic oncology. This review presents evidence for a role for UGP in (1) the screening of women at high risk for ovarian cancer by virtue of their family history, (2) the differentiation of benign pelvic masses from malignant ones, particularly in premenopausal women and (3) monitoring women known to have previously been diagnosed with ovarian cancer and possibly cervical and advanced uterine cancer to determine efficacy of therapy. PMID- 8694534 TI - TAG-72 expression and its role in the biological evaluation of human colorectal cancer. AB - Immunohistochemical studies showed that TAG-72 is expressed in more than 80% of colorectal carcinomas, but is rarely expressed in normal epithelium and benign diseases. TAG-72 can also be found in the body fluids of patients with adenocarcinomas, and its direct measurement can be used in conjunction with immunocytochemical analysis to help in discriminating benign from malignant effusions. The evaluation of TAG-72 in serum of colorectal carcinoma patients showed a sensitivity of approximately 40%, comparable to that of the widely used CEA. TAG-72 serum levels correlate with the stage of disease, suggesting its utility in discriminating between early-stage versus late-stage colon carcinoma. Longitudinal studies demonstrated that TAG-72 serum levels may be used as a predictive marker of recurrences. Moreover, the simultaneous measurement of TAG 72 and CEA serum markers improves the monitoring of recurrent disease. Therefore, these data suggest that TAG-72 is a well suitable marker for colorectal cancer. PMID- 8694535 TI - Expression and function of squamous cell carcinoma antigen. AB - Squamous cell carcinoma antigen (SCCA) has been used as a promising aid for the management of squamous cell carcinoma of various sites. Recently, SCCA gene has been demonstrated at the 18q21.3 locus, and the exon sequence of SCCA gene shows a close homology with inhibitory-type serpins. Actually, SCCA inhibits human chymotrypsin, papain, calpain 1, or cathepsin L. Since serpins are involved in the intercellular adhesion events, it is likely that SCCA takes some part in the malignant behavious of squamous cancer, e.g. invasion or metastasis. SCCA is also present in the spinous and granular compartments of the mature squamous epithelium. Southern blot analysis of the SCCA gene in several vertebrates reveals that it is present in most of the eutherian species, but not in the metatheria, bird, reptile, amphibian or teleost. Thus, SCCA appears to play important roles in the stratification or differentiation of the integument. The present paper describes the expression and function of SCCA, and discusses its possible role in the biological behavious of malignant and nonmalignant squamous cells. PMID- 8694536 TI - Fibrinolysis components as prognostic markers in breast cancer and colorectal carcinoma. AB - The impact of prognostic markers on disease-free and overall survival reflects their relative role in tumour biology. Breast cancer and colon carcinoma can be taken as examples to demonstrate the clinical and biological relevance of 'new markers' of neoplastic disease. In breast cancer, receptor-bound urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 seem to play an important role in the dissolution of the surrounding tissue and the formation of tumour stroma. These processes are prerequisites for invasion and metastasis. The study of 'classical' and 'new' prognostic factors showed that uPA and PAI-1 content of breast cancer tissue are strong and independent prognostic factors. Also in colorectal cancer the prognostic relevance of plasminogen activators and inhibitors was analysed. In particular, low tissue plasminogen activator (tPA) levels, as antigen or as activity, high uPA: tPA antigen ratio in corresponding normal mucosa, high levels of uPA-related antigen and activity and of PAI-2 antigen in neoplastic tissue, and high uPA (neoplastic mucosa): tPA (normal mucosa) ratio, were all parameters associated with a poor overall survival. In conclusion, all these observations show the clinical importance of plasminogen activators and inhibitors at tissue levels with respect to cancer development and survival of patients affected by breast carcinoma or colorectal neoplasia. These new prognostic markers will also permit a better patient selection for a possible adjuvant treatment. PMID- 8694537 TI - Does the assessment of serum markers in patients with lung cancer aid in the clinical decision making process? AB - This survey describes potential clinical applications of the tumour markers CYFRA 21-1, SCC antigen, NSE, and CEA in patients with lung cancer. Due to the rather low prevalence of bronchogenic carcinoma in the general public and the limited diagnostic accuracy, currently available tumour markers are unsuitable for the screening of asymptomatic individuals. All studies performed so far in patients with histologically confirmed NSCLC, agree that the best performance characteristics, in terms of sensitivity and specificity, were obtained with the CYFRA 21-1 test (sensitivity: 40-66%, specificity: 95% versus patients with benign pulmonary disorders) while NSE was found to be the marker of first choice in patients with SCLC (sensitivity: 77-85%). For diagnostic purpose, the value of tumour markers must be compared with the efficiency of standard clinical methods including imaging techniques and cytopathological examinations (detection rates: sputum cytology: 40-70%, biopsy at bronchoscopy in central tumours: 95-98%, biopsy at bronchoscopy + bronchial washing + thin needle aspiration in peripheral tumours: 85%). These figures show that the diagnostic yield of cytopathological examinations by far exceeds that of tumour markers. In addition, these investigations supply with histology and give informations on the T-stage (bronchoscopy). Tumour markers, however, may be used for diagnosis in advanced stages in which patients are very often not eligible for extensive investigations due to their performance status. In the differential diagnosis between NSCLC and SCLC a combination of CYFRA 21-1 and NSE was claimed to be helpful. It was demonstrated that 97% of patients could be correctly classified. NSE was shown to be useful to distinguish SCLC from malignant lymphoma, both the Hodgkin's (rate of false-positive elevations: 6.5%) and the non-Hodgkin's (rate of false positive elevations: 22.4%) types. By applying a cut-off point of NSE assays of 21.9 ng/ml corresponding to a 95% specificity versus the lymphoma group, SCLC is still indicated by elevated NSE levels with a sensitivity of 57.7%. Although a positive correlation of marker concentrations with increasing anatomical tumour extent could be demonstrated, the markers cannot be used for staging purposes due to a considerable overlap of marker levels between the individual stages. CYFRA 21-1 was shown to be unable to differentiate between operable (TNM I-IIIa) and inoperable (TNM IIIb/IV) NSCLC patients. The latter were identified with a detection rate of only 17% by the CYFRA 21-1 test (specificity 95% versus operable patients, cut-off point 20 ng/ml). Pretreatment-measured tumour markers, in particular CYFRA 21-1, were shown to provide prognostic information for the overall survival. The negative prognostic effect of CYFRA-21-1 was independent of classical prognostic markers such as performance status and tumour extent. There are several potential applications of serially-assessed tumour markers for disease monitoring of patients under therapy. In SCLC, increasing NSE levels within the remission phase were demonstrated to be strongly suggestive of tumour recurrence. This finding should give rise to further diagnostic procedures. NSE, however, was not able to differentiate between partial and complete remission since, in both cases, NSE levels dropped to the normal range; thus, NSE cannot replace clinical response evaluations. In NSCLC, it was found that curative surgery resulted in a significant drop of preoperatively elevated CYFRA 21-1 or SCC antigen levels down to the normal range. Although rising SCC antigen levels in the postoperative surveillance of patients with squamous cell carcinoma indicated very early tumour relapse, these results are of minor clinical utility due to the absence of curative therapy. Serial measurement of CYFRA 21-1 during chemotherapy in patients with inoperable squamous cell carcinoma has shown that there is a concordance of 74% between the course of the m PMID- 8694538 TI - Determination of serum tumor markers TPS and CA 15-3 during monitoring of treatment in metastatic breast cancer patients. AB - Serum levels of tissue polypeptide specific antigen (TPS), a cytokeratin 18 marker, and CA 15-3 were determined in 42 patients with metastatic breast cancer during routine treatment follow-up. At the time of proved metastatic disease, 86% of the values for TPS were above the upper reference value as compared to 93% for CA 15-3. The combined use of TPS and CA 15-3 increased the overall sensitivity. The levels of the tumor markers followed the course of disease during a follow-up period of 6-10 months, even though the dynamics of the changes of tumor markers levels differed in some patients. An increase in the tumor marker level of 25% or more was seen in 60% (TPS) and 52% (CA 15-3), respectively of the studied patients. TPS appeared to indicate changes faster than CA 15-3. The overall results of this study suggest the combined use of TPS and CA 15-3 in the monitoring of breast cancer patients is preferable. PMID- 8694539 TI - TPA prognostic value in superficial bladder cancer. AB - We determined the levels of TPA in 133 patients with superficial bladder cancer. 79 cases were Ta stages, and 54 cases T1 stages. 53 of the tumors were well differentiated (I), 65 moderately differentiated (II) and 15 undifferentiated (III). The average follow-up time of these patients was 8.3 months; the standard deviation being 5.2 months (median value 7 months). In 43 cases a relapse of the tumor was observed. We detected high TPA levels in 25% of the patients, without observing meaningful differences in tumor invasion or in its differentiation degree. The usefulness of the TPA, the degree of tumor invasion, and the degree of cell differentiation were evaluated by means of single-variate and multivariate analysis in order to forecast tumor relapse. Only the TPA had a prognostic value, the relative risk of developing relapse being 2.03 times higher in patients with high TPA than patients with normal TPA. PMID- 8694540 TI - Metallopanstimulin as a novel tumor marker in sera of patients with various types of common cancers: implications for prevention and therapy. AB - Metallopanstimulin (MPS) is a 9.5-kDal subunit "zinc finger" protein which is expressed in a wide variety of actively proliferating cells and tumor tissues (J. Biol. Chem. 268:21198-21204, 1993; Cell Growth & Diff. 5:811-825, 1994). A sensitive and specific radioimmunoassay (RIA) has been developed to measure circulating levels of MPS and MPS-like proteins. The RIA was evaluated for its ability to detect accurately elevations of MPS-immunoreactive material in the blood of patients with various types of neoplastic diseases. MPS concentrations were determined in the blood of 147 healthy subjects having no evidence of neoplastic disease, in 260 patients with nonmalignant diseases, and in 225 patients diagnosed with various types of cancer such as prostate, colorectal, lung, head and neck (epithelial malignancies), neuroendocrine, central nervous system, etc. Elevated MPS levels identified patients with neoplasias with greater than 90% confidence. In patients, not having neoplastic disease the MPS levels were lower than 10 ng/mL (82% of the population). In untreated patients with cancer, the MPS level range was 20-50 ng/mL and in stage M1b (metastasis to the bones) the MPS levels were extremely high (100 to 1000 ng/mL). In M1b patients that did not respond to therapy, the MPS levels remained very high ( > 100 ng/mL). In M1b patients that went into remission after treatment, the MPS levels were reduced. The MPS test may be useful as an aid in: 1) the early detection of a wide variety of neoplastic conditions and 2) the prognosis and management of cancer patients by following the changes in the concentrations of MPS in sera. Moreover, the results suggest that the combined use of the MPS test with other currently available tumor maker tests may significantly improve the chances of identifying a large proportion of active oncogenic processes by serodiagnosis. PMID- 8694541 TI - Tumor markers as targets for selective diagnostic and therapeutic procedures. AB - Monoclonal antibodies (MAbs) that are reactive with tumor associated antigens (TAAs) have led to many of the recent advances made in tumor immunology. At the present time, many of these MAbs have already been used in various aspects of patient management and in better understanding the biology of carcinoma cell populations. Because of their diversity, specificity and biological activity, these MAbs are potentially ideal agents for a variety of applications in malignant disorders such as, clinical diagnosis using serum assays, immunocytopathological analyses of effusions or fine-needle aspiration specimens, immunoscintigraphy, radioimmunoguided surgery and, with additional development, site directed immunotherapy. Nevertheless, their clinical application shows advantages and limitations. Optimization of their clinical use is actually under evaluation in several Institutions, including our Department. Many innovations have been developed over the last decade which may enhance their clinical efficacy. In this view, an optimal tumor targeting for diagnostic or therapeutic applications may require a better choice of radiotracer, generation of new molecules and the characterization of TAAs at the target level. PMID- 8694542 TI - A simple mucus test for cancer screening. AB - Comparative and correlative studies of the pathology and pathogenesis of colon cancer in animal models and human disease have resulted in conceptualization of 'field effect" theory and identification of markers that are expressed early during carcinogenesis. This assimilated body of knowledge has resulted in development of a simple rectal mucus test for colon cancer screening. The marker galactose-N acetylgalactosamine (Gal-GalNAC) is expressed in the rectal mucus of patients with colonic cancer or precancerous lesions and is detected by enzymatic oxidation (10 minutes) followed by color reaction (1 minute). The high sensitivity, specificity, positive predictive value and negative predictive value, as well as the cost-effectiveness of this test makes it a great tool in our strategies for early detection, hence control of colon cancer. Because of its high accuracy (as opposed to the fecal occult blood tests), it would reduce the number of unnecessary colonoscopies, thereby decreasing the total national health care cost to the society. Similar expression of this marker in cancers of breast, lungs, prostate, pancreas, makes it a potentially useful general cancer screening test. PMID- 8694543 TI - Adenosine-N6-diethylthioether-N1-pyridoximine 5'-phosphate. A novel marker for human cancer detection. AB - The Schiff base conjugate of vitamin B6 with adenosine-N6-diethylthioether was originally reported as unknown compound B6X and considered to function as a storage form for vitamin B6 utilization by tumor cells. This novel compound is present in tumor cells in culture, the blood of normal and tumor-bearing animals, and the circulation of healthy individuals and patients with various ailments including malignancies. However, its level in the blood of cancer patients is significantly much greater -a desirable feature for cancer detection. Using HPLC pair-ion, reverse phase chromatography blood samples from patients with various malignancies and ailments were screened on a blind basis for the novel compound following its extraction at pH 4.2. The results show that the level of the vitamin B6 metabolite in the blood of cancer patients is up to 4x or higher than levels seen in the blood of normal volunteers, patients in remission or patients with other diseases. In addition, patients receiving treatment had lower levels than before treatment. Normal volunteers, cancer patients prior to treatment, cancer patients on therapy, cancer patients at remission and patients with other ailments had levels of 162.2; 601.7; 497.9; 216.5 and 179.3 (SEM range +/- 18.76 46.60), respectively. A comparison of the control, remission and other ailments groups with the cancer patient groups shows them to be significantly different (P < 0.00001) and strongly supports the use of the novel vitamin B6 conjugate metabolite for detection of human cancers. PMID- 8694544 TI - Serum tissue polypeptide antigen (TPA) as tumor marker for bladder cancer. AB - Tissue polypeptide antigen is a differentiation and proliferation marker of non squamous epithelium and derived neoplasms. No reliable tumor markers are available for bladder cancer. The value of tissue polypeptide antigen was therefore prospectively investigated. The serum tissue polypeptide antigen samples were obtained from 144 newly diagnosed transitional cell carcinoma patients and from 92 patients that were followed after treatment. The normal cut off value was defined at 95 units per liter. Nearly all TaT1 patients had normal TPA values, and 80% of the muscle invasive cancers had normal TPA levels. In those patients where TPA was elevated before treatment its monitoring proved to be a reliable predictor of tumor progression. Tissue polypeptide antigen is a useful marker not for the early detection of bladder cancer but for the monitoring of the efficacy of a treatment. PMID- 8694545 TI - Pattern of mucin gene expression in normal and neoplastic lung tissues. AB - This work evaluates the expression in lung cancer of the most well characterized mucin genes (MUC1, MUC2, MUC3) and of the recently described MUC4 in lung tissues, to check a correlation between the expression of any particular gene and this tumor. Hybridization with synthetic oligonucleotides obtained from a part of the sequences of MUC1, MUC2, MUC3 and MUC4, was performed on blotted RNA from 18 lung cancer tissue specimens and from 10 normal tissues samples taken, when possible, from the normal lung counterpart. By means of Northern blot analysis MUC1 revealed to be the most expressed mucin gene in lung cancer, followed by MUC4; by contrast, the expression of MUC2 and MUC3 was almost undetectable in all cancer specimens. The intensity of expression of MUC1 and MUC4 was always superior in cancer tissue than in the normal counterpart. As expected, the highest reactivity for MUC1 and MUC4 expression was observed mainly in the adenocarcinoma histotype which is mucin secreting. These findings represent a contribution to the study of mucin gene pattern in lung cancer, and, in particular, indicate that MUC4, in association with the MUC1 gene, seems to be strongly expressed in this neoplastic disease. PMID- 8694546 TI - Tumour markers: from laboratory to clinical use. PMID- 8694547 TI - Usefulness of pyridinium crosslinks and CA 15-3 as markers in metastatic bone breast carcinoma. AB - Numerous tumor markers such as CEA, MCA, CA 15-3 have been assayed in breast cancer patients to detect relapse at a preclinical stage and most of all to monitor the treatment of the advanced disease. Since they are not site-specific, pyridinium crosslink dosage has recently been reported as a specific bone resorption marker in several non neoplastic diseases. The aim of this study was to evaluate the urinary pyridinium crosslink levels in breast cancer with or without osseous involvement, and to correlate it with serial doses of CA 15-3. 285 breast cancer patients (226 free of disease and 59 with bone metastases) were measured for both pyridinoline and CA 15-3. In the metastatic patients the mean values of the two markers were significantly higher than in non evident disease patients (P = < 0.01 and p = < 0.001 respectively). Abnormal values over the normal were found in 22% for pyridinoline and 11% for CA 15-3 in patients free of disease while the normal values observed in patients with bone metastases were 22% for pyridinoline and 39% for CA 15-3. Tandem dosage of CA 15-3, was highly sensitive but site-aspecific, and pyridinoline, which is bone specific, may be useful chiefly in the monitoring of breast cancer treatment, since many physiological conditions such as age, menopausal status and variation over 24 hours, and cost effectiveness will influence the use of pyridinoline during follow-up. PMID- 8694548 TI - Immunocytochemistry of cytological specimens as a diagnostic and prognostic tool. AB - In the last two decades, immunocytochemistry has been increasingly used in diagnostic cytopathology and is now part of the routine work in a cytopathological laboratory. Immunostaining successfully complements morphological studies for the identification and classification of tumours, when performed with well-defined monoclonal antibodies (MoAbs). This article will briefly review the MoAbs most frequently utilized for diagnostic purposes and the field in which they may be applied. MoAbs against biological markers for malignant transformation and tumour progression, are now available and the feasibility of their application to clinical cytopathology will be discussed. PMID- 8694549 TI - Apoptosis and angiogenesis: two promising tumor markers in breast cancer (review). AB - Mammary epithelial homeostasis is dependent not only on the rate of cell proliferation, but also on apoptosis, a genetically programmed process of autonomous cell death. Cell death in tumours is commonly attributed to the induction of apoptosis. Angiogenesis is the process leading to the formation of new blood vessels, and it has been proposed that tumor growth is angiogenesis dependent. This review focuses on the biological role of apoptosis and angiogenesis in the development and progression of breast cancer; on the multiple genetic pathways regulating apoptosis and angiogenesis in breast cancer; and on clinical data demonstrating the prognostic significance of apoptosis and angiogenesis in breast cancer. Although evidence has suggested that decreased apoptosis and increased angiogenesis may play important roles in the biological aggressiveness of breast cancer, their precise molecular mechanisms in mammary tumorigenesis are unknown. There is accumulating evidence that apoptotic pathways and angiogenic status are controlled by a number of regulators, including inducers and inhibitors relevant to the pathogenesis of breast cancer. The inhibition of angiogenesis limits tumor growth by elevating the incidence of apoptosis. Several clinical studies have shown that apoptosis and angiogenesis are novel prognostic indicators in breast cancer, and they may have predictive value for the response to anticancer treatments. A recent study suggested that increased apoptosis plays a role in the response to hormonal treatment of breast cancer. Other studies have indicated that patients with breast cancer with high angiogenic activity have a worse prognosis. Overall, the evidence suggests that the progressive inhibition of apoptosis and induction of angiogenesis may contribute to tumor initiation, growth and metastasis in the pathogenesis of breast cancer. Apoptosis and angiogenesis may be valuable as markers for response in patients having primary or adjuvant chemotherapy for breast cancer. Furthermore, such tumor markers have the potential to develop a promising therapeutic strategy to regulate cell survival/death and neovascularization in breast cancer by the induction of apoptosis and/or the inhibition of angiogenesis. PMID- 8694550 TI - Clinical utility of CA 72-4 serum marker in the staging and immediate post surgical management of gastric cancer patients. AB - CA 72-4 is a high molecular weight, pancarcinoma human tumor mucin which may play an important role in the identification (i.e., staging) and clinical management of patients with gastric carcinoma. In the present study of 242 patients with primary or recurrent gastric cancer, a higher percentage of these patients had measurable serum CA 72-4 levels when compared with either CA 19.9 or CEA. Moreover, the presence of positive serum CA 72-4 levels correlated with the presence of lymph node involvement and with the identification of patients with a poor prognosis due to the presence of an advanced stage of gastric cancer. Post operative monitoring of serum CA 72-4 revealed that the disappearance of CA 72-4 often indicated curative surgery which correlated with a longer disease-free interval. Additional clinical studies are needed to better evaluate the role of CA 72-4 as a serum marker for human gastric carcinoma. Concomitant studies should also focus on what role CA 72-4 may play in the initiation and/or progression of the gastric carcinoma phenotype. PMID- 8694551 TI - Serum tumor markers in monitoring patients: interpretation of results using analytical and biological variation. AB - During cancer monitoring, data on biological and analytical variation are required in order to define the critical difference which provides an objective means to interpret serial values. We evaluated four tumor markers on serial samples collected from healthy subjects and patients. Analytical coefficients of variation (CV(A)), were obtained from "precision profiles" based on the differences between duplicates cumulated from assay runs in the laboratory. We defined the mean intrasubject biological variation (CV(I)) for CA 19-9 and TPA, separately for healthy people and patients; since the differences between the two groups were not statistically significant, we pooled the results and re-evaluated CV(I) in the combined groups (CA 19-9: CV(I) = 15.9%; TPA: CV(I) = 25.7%). In addition, we evaluated CV(I) for CEA (10.9%) and for TPS (25.9%) in patients. We then evaluated the inter-subject biological variations (CV(G)); the calculated indices of individuality for the four markers were less than 0.6 which shows conventional reference values to be of little utility for interpretation. We finally evaluated the critical differences (p < 0.05) for CA 19-9 (CD = 44.7%), for TPA (CD = 72.5%), CEA (CD = 32.7%) and TPS (CD = 72.5%); these are generally applicable since there was no heterogeneity in intra-subject biological variability. PMID- 8694552 TI - A new tumour associated antigen of non-small cell lung cancer: tumour liberated proteins (TLP)--a possible new tumor marker. AB - TLP (Tumour Liberated Proteins) is a 214 kDa protein, isolated from lung cancer tissue and synthetic nonapeptide CSH-275 is a major epitope identified on a 100 kDa TLP fragment and used to create antibodies in rabbit (antiserum termed CSH 419). CSH-419 antiserum, labelled or conjugated as necessary, was used to detect TLP on sera from NSCLC patients by a new ELISA test set up as a 1 step sandwich format test. This ELISA was performed on sera from 534 individuals. TLP was detected in 53.1% of NSCLC patients, with a 0% response in patients with cancers other than NSCLC, 7.6% response in unknown blood donors, and 17.4% response in patients with chronic lung diseases correlated with an elevated risk for lung cancer. TLP was particularly present in early stages of disease: 75% in stage I, 56% in stage II and III and 45% in stage IV. The presence of TLP antigen in sera from NSCLC patients indicates that TLP could represent an useful tumour marker. PMID- 8694553 TI - Biological characterization of laryngeal squamous-cell carcinoma. AB - The traditional prognostic factors, including stage of disease and tumour grade, have shown a limited prognostic significance and an inability to predict clinical response to specific treatment in patients with laryngeal squamous-cell carcinoma. More recent data suggest that cell kinetics indices, DNA-ploidy, lysosomal cysteine proteinase expression and genetic changes of both tumour suppressor genes and protooncogenes may be considered as reliable and reproducible indicators of biological aggressiveness in these patients. Moreover, the frequency of different genetic alterations suggests that several pathways are involved in the genesis of these neoplasias and, in particular, it is very probable that p-53 expression and PCNA indices (increased in normal mucosa and preinvasive lesions) may constitute more important biomarkers for the early steps of laryngeal carcinogenesis. PMID- 8694554 TI - Immunosuppressive acidic protein (IAP) level in serum and peritoneal washings, and its implication in determining multidisciplinary treatments. AB - In this study we examined the efficacy of the measurement of IAP (serum ancl peritoneal washings) during the treatment of colorectal cancers, and determined the possible benefits of using the IAP measurements from both serum and peritoneal washings. One hundred and six patients (peritoneal washings: 58, peritoneal fluid: 67) were investigated. Serum IAP levels were significantly higher in patients who underwent complicated surgical procedures which involved greater time and blood loss compared to those patients who underwent less involved surgical procedures with little loss of blood and time. In peritoneal washings, up to 66. 7% of cases with peritoneal dissemination showed elevated levels of IAP in the peritoneal cavity, while 37% of cases with no dissemination at surgery macroscopically had positive IAP levels (8 mg/g protein). The results suggest the value of IAP in determining the need for combined immunochemotherapy for patients in an immunosuppressive environment. PMID- 8694555 TI - Classification of tumor markers. AB - Since the discovery of the first tumor markers more than a century ago (Bence Jones proteins), a vast array of molecules have been described as being associated with cancer. These are generally naturally occurring biomolecules with the exception of neo-antigens expressed in certain tumors induced by viruses. Tumor markers can be broadly classified into tumor specific antigens and tumor associated markers. Most tumor markers were often heralded as highly tumor specific but subsequent studies demonstrated their presence in normal tissues of the adult or in various stages of ontogeny. As a result, very few tumor-specific antigens can be recognized. The idiotypes of immunoglobulins of B cell tumors and certain neo-antigens of virus induced tumors are two examples that are strictly tumor specific. The vast majority of tumor markers are in reality tumor associated antigens and can be classified into two types based on their size. The low-molecular weight tumor markers (approximately < 1000 Daltons) include some nucleosides, lipid associated sialic acid, polyamines, pseudouridine, pigment derivatives, and other metabolites. The macromolecular tumor antigens are the most important sub-type useful in the clinical management of cancer patients. The large cancer antigens are either enzymes, growth factors, hormones, receptors, biological response modifiers, oncogenes and their products, or glycoconjugates which include glycoproteins and glycolipids. Collectively all the commercial tumor marker assays available to the oncologist for cancer patient management amount to an annual sales of > $1 billion world wide. The demonstrated clinical usefulness and commercial success of tumor markers have continued to fuel exciting research into the discovery and novel uses of new analytes. PMID- 8694556 TI - Dynamic use of tumor markers, rationale-clinical applications and pitfalls. AB - The dynamic evaluation of tumor markers is a promising area of investigation which is expected to provide clinical information when serial samples are available from the same patient. This is feasible in the post-operatory evaluation, during the follow-up after the treatment for to the primary tumor and in the monitoring of the treatment for metastatic disease. Variations among serial samples may be assessed using both empirical and mathematical approaches. Empirical approaches rely on overcoming a given percentage usually chosen on the base of arbitrary decisions. Mathematical approaches include the actual half life, the doubling time, a dose/time regression analysis and the calculation of the critical difference. The two former are currently used in clinical practice whereas the two latter are still matter of investigation. As concerns the assessment of the radicality of the surgery for the primary tumor, the serum markers are used in germ cell tumors and in prostate cancer. The half-life of the markers is the decision criteria used in germ cell cancers, while in prostate cancer PSA is expected to be undetectable more than 30 days after the radical prostatectomy. Tumor markers are currently used during the follow-up of several malignancies after the treatment for primary tumor. Although several samples are available, decision criteria are still based on positive/negative cut-off values in several instances. Promising dynamic approaches are under investigation and are expected to lead to earlier and probably more accurate information concerning the disease progression. A critical point still under debate is the actual impact of tumor markers on patients' survival in malignancies incurable when metastatic, such as colorectal cancer and breast cancer. This matter urgently demands perspective clinical studies. Finally, the dynamic use of tumor markers is now commonly applied in the monitoring of the therapy for metastatic malignancies. In this clinical setting mathematical criteria are used for ovarian and and germ cell tumors with promising results. Nevertheless, the use of empirical criteria, namely the percentage of variation between two consecutive samples, is successfully used for the monitoring of the therapy of metastatic breast cancer. In conclusion, when several samples are available from an individual patient they may be evaluated according to dynamic criteria instead of referring to a conventional positive/negative cut-off point. Although mathematical decision criteria are expected to provide more reliable data, empirical approaches are used as well and provide useful information in decision making. PMID- 8694557 TI - Tumour serum markers: clinical and economical aspects. AB - Tumour serum markers represent one of the most interesting challenges in modern oncology. Although know for many years, tumour markers did not receive clinical attention until the '80s. Despite their widespread use, the identification of a tumour marker which is highly sensitive as well as specific for a certain type of cancer, and can be assayed by simple, reproducible and cheap methods, remains elusive. This review deals with the clinical use of the Prostate Specific Antigen (PSA). PSA is biochemically a glycoprotein, is the most valuable tool available for the diagnosis and staging of prostate cancer and one of the most widely used laboratory tests in oncology. Serum PSA can detect twice as many prostate cancers as digital rectal examination can and approximately 70% of these cancers are potentially curable. In assessing the role of PSA in the diagnosis and the monitoring of prostate cancer, new concepts have been developed and are in clinical use today: PSA velocity, free versus complexed PSA, PSA index or PSA density and age-specific reference ranges. By combining serum PSA concentration with histologic grade (Gleason grading system) and clinical stage (TNM staging system), we can predict metastasis to the pelvic lymph nodes. For instance, patients with clinical stage T1a-T2b, Gleason grade 1 or 2 and serum PSA level 17.1 ng/ml or less, have a probability of pelvic lymph nodes involvement approaching zero. So, surgical staging procedures can be avoided in these selected patients. Another group of patients with prostate cancer who can benefit from measuring serum PSA concentration, is the group of newly diagnosed patients, with no skeletal symptoms and a serum PSA concentration less than 10 ng/ml. In this group, the probability of a positive bone scan approaches zero and a staging bone scan is not necessary. From the standpoint of economic analysis, measurement of serum PSA can serve in two ways: Firstly, estimating the savings when PSA is used in a prevention programme in the general population and secondly, calculating the savings in patients with prostate cancer, when PSA is used to complement or substitute other diagnostic or staging procedures. PMID- 8694558 TI - Serum concentrations of type I collagen carboxyterminal telopeptide (ICTP) and type I procollagen carboxy-and aminoterminal propeptides (PICP, PINP) as markers of metastatic bone disease in breast cancer. AB - The most abundant protein in bone is type I collagen. During type I collagen formation two extension peptides from both ends of the procollagen molecule, carboxy- and aminoterminal propeptides (PICP and PINP), are liberated in equimolar concentrations into the circulation. Type I collagen carboxyterminal telopeptide (ICTP) is formed during bone collagen breakdown and is liberated into the circulation. Serum concentration of the propeptides reflect bone formation, and the concentration of the telopeptide, bone resorption. We evaluated the usefulness of these bone remodelling markers in diagnosing and monitoring metastatic bone disease in breast cancer patients. Serum concentrations of ICTP, PICP and PINP were measured and the PICP/PINP-ratio calculated in 25 patients with bone metastases, 12 patients without metastases and their age matched healthy controls. S-ICTP and S-PINP were significantly higher in metastatic patients (p = 0.0001 and 0.02 respectively), and the S-PICP/PINP-ratio lower (p = 0.002) than in controls. S-PICP in metastatic patients did not differ significantly from that of controls. ICTP values in patients without metastases also differed from those of controls (p = 0.01). The clinical sensitivity for diagnosing metastatic bone disease was 56% for ICTP, 24% for PICP, 30% for PINP and 52% for PICP/PINP ratio. The clinical specifities were 93%, 100%, 98% and 91% respectively. During follow-up the changes in the marker values were parallel to the behaviour of the disease. We conclude that these markers alone are not sensitive enough for diagnosis, but they seem to be of use in detecting bone metastases and monitoring the activity of bone disease. PMID- 8694559 TI - C-erbB-2 oncoprotein in the sera and tissue of patients with breast cancer. Utility in prognosis. AB - C-erbB-2 serum levels were studied in the sera of 50 healthy subjects, 56 patients with benign breast diseases and 412 patients with breast cancer. Using 15 U/ml as the cut-off, no healthy subjects, patients with benign disease and only 2.4% of patients with no-evidence of disease had serum levels higher than this cut-off point. Abnormal c-erbB-2 levels were found in 9.2% of the patients with locoregional breast carcinoma and in 45.4% of those with advanced disease. C erbB-2 serum levels in patients with locoregional breast cancer were not related to tumor size or nodal involvement. By contrast, significantly higher c-erbB-2 serum levels were found in ER- or PgR- tumors than in those ER+ or PgR+ tumors, in both locoregional or metastatic tumors. The correlation between serum and tissue levels of C-erbB-2 was studied in the tumors of 161 patients. Significantly higher c-erbB-2 serum levels were found in patients with overexpression in tissue by immunohistochemistry, in both locoregional and advanced disease (p = 0.0001). In patients with C-erbB-2 overexpression in tissue, c-erbB-2 serum levels were related to tumor size and nodes, with higher values in tumors greater than 5 cm or in those with more than 3 nodes involved. When the prognostic value of this oncoprotein was evaluated, patients with abnormally high presurgical c-erbB-2 had a worse prognosis than those patients with normal values, in both node-negative and node-positive patients. Serum concentrations in patients with advanced disease, were related to the site of recurrence with significantly higher values in patients with metastases (mainly in those with liver metastases) than in those with locoregional recurrence. In summary, c-erbB-2 serum level seem to be a useful tumor marker in the prognosis of patients with breast cancer. PMID- 8694560 TI - UGP in urogenital disorders: Egyptian experience. AB - UGP (Urinary gonadotropin peptide) also know as urinary gonadotropin fragment (UGF) or the beta-core of hCG (c beta hCG), was identified as a peptide with a molecular weight of 10.5 kD, having the same amino acid sequence as the core section of the beta-subunit of human chorionic gonadotropin. UGP has been found in normal pregnancy urine as well as in the urine of patients with gestational trophoblastic and non-trophoblastic malignancies. The aim of the present work was to investigate the clinical value of UGP in Egyptian patients with urogenital disorders. The study included 793 cases (462 males and 331 females) classified into 5 groups: 277 with bladder cancer, 121 with benign urinary tract disorders, 27 with different gynecological malignancies, 53 with benign gynecological disease and 315 apparently healthy individuals as a control group. The normal females included 88 premenopausal and 71 postmenopausal women. UGP was determined in 24- hour urine samples from all cases, and in morning urine samples from 151 subjects by ELISA technique using the reagents supplied by Ciba Corning Diagnostics, CA, USA (Triton UGP - EIA). The results of this study revealed significant elevation of UGP in cancer patients when compared to either normal controls or patients with benign diseases. Females in the control and benign diseases groups expressed higher UGP values than males and UGP in postmenopausal women was significantly elevated when compared to premenopausal control females. A a tumor marker, UGP was more sensitive and more specific in bladder than in gynecological cancer. A significant correlation (r = 0.934) was obtained between UGP levels in 24-hr and morning urine samples. PMID- 8694561 TI - Comparative study between sonography, pathology and UGP in women with perimenopausal bleeding. AB - Adenocarcinoma is the commonest primary malignancy encountered in the endometrium. Adenomatous hyperplasia represents an important precancerous endometrial lesion. In this study, different techniques have been applied in a trial to early detect endometrial carcinoma and to distinguish between hyperplasia with minimal and high risk of progression to endometrial adenocarcinoma. Eighty women were included in this study and classified into 4 groups: 10 with adenocarcinoma, 28 with simple hyperplasia, 12 with hyperplasia with atypia and 30 normal healthy women. All individuals were subjected to Doppler endovaginal ultrasonography (EVS) for endometrial thickness and uterine artery resistance index (RI). Endometrial biopsy was taken for histopathological examination and DNA analysis. 24-hr urine was collected for the estimation of UGP by ELISA using reagents supplied by Ciba Corning Diagnostica, Alameda, CA, USA (Triton UGP-EIA). On referring to histopathological findings, no single parameter was seen to be specific and sensitive enough to differentiate between benign and malignant endometrial lesions. Doppler endovaginal ultrasonography could detect 76% of endometrial abnormalities. DNA ploidy and UGP showed equal sensitivity rate (60%) in endometrial carcinoma but DNA ploidy was more specific than UGP (0% and 10% false positivity in benign endometrial diseases respectively. PMID- 8694562 TI - Cathepsin D, B and L circulating levels as prognostic markers of malignant progression. AB - Growing evidence indicates that lysosomal Cathepsins D (CD), B (CB) and L (CL) may promote carcinogenesis and tumor progression. Therefore, we evaluated their potential value as biochemical parameters of malignant progression in patients with benign diseases which may undergo malignant transformation, such as liver cirrhosis (LC) and chronic pancreatitis (CHP) as well as in hepatocellular carcinoma (HCC) and pancreatic cancer (DPC). CD, CB and CL serum levels were determined by immunoenzymatic assays in LC, CHP, HCC or DPC patients and correlated with a number of biochemical and clinical parameters of these diseases. CD serum levels were increased in LC, CHP and HCC, but not in the DPC group as compared to normal subjects (NS) (P < 0.01). Interestingly, higher levels of this enzyme were observed in LC patients compared to HCC patients ( P < 0.01). CB serum concentrations were increased in all patient groups (P < 0.01). However no difference was evidenced between benign and malignant diseases. CL serum levels were significantly increased only in DPC as compared to NS (P < 0.01) or CHP patients (P < 0.02) and in HCC as compared to NS (P < 0.01). The evaluation of CD, CB and CL serum pattern in LC, CHP, HCC and DPC patients may be useful as additional biochemical parameters in the differential diagnosis and therapeutic monitoring of these diseases. Prospective clinical investigations to assess the potential value of these enzymes as biochemical markers of malignant progression of LC or CHP are warranted by the present data. PMID- 8694563 TI - Beta 1 integrin expression: a marker of lymphatic metastases in cutaneous malignant melanoma. AB - BACKGROUND: Experimental evidence suggests that integrins are key regulators of the development of melanoma metastases, influencing both the likelihood and site of metastases. Whereas effective treatment of cutaneous melanoma remains surgical, elective lymph node dissection (ELND) is controversial. The present study was designed to investigate the relationship between integrin expression by a given primary melanoma and occult regional lymph node metastases. MATERIALS AND METHODS: We studied beta 1 integrin expression, by quantitative immunohistochemistry using an image analyzer, in the primary melanomas of 90 ELND patients. RESULTS: beta 1 integrin was expressed in > or = 10% of the primary tumor in 92% of cases eith lymph node involvement versus 9% of node negative cases (p < 0.001). CONCLUSIONS: Our data demonstrate that quantitative immunohistochemistry for beta 1 integrin expression in primary melanomas can identify patients likely to have occult lymph node metastases. This suggests that beta 1 integrins play a role in the lymphatic dissemination of cutaneous melanoma. PMID- 8694564 TI - Comparative evaluation of four tumor markers, CA 242, CA 19/9, TPA and CEA in carcinomas of the colon. AB - At present there is at least one optimal tumor marker and/or optimal marker combination available for the most frequent carcinomas. For colorectal carcinomas (CRC) the general consensus is that CEA is the best single marker, however, other markers, like CA 19/9, TPA and more recently CA 242 were reported to be just as useful. Since CA 242 is a relatively new marker we decided to assess comparatively the value of the four markers in CRCs. Although 308 sera from patients with CRCs, benign digestive diseases (n = 128) and healthy controls (n = 45) were analyzed using commercially available testkits. None of the mean values of the four markers were elevated above their respective cut-off levels in the controls. CEA was the most sensitive marker in early stage cancer, while CA 19/9 was the least sensitive marker, and hence should not be used for the study of this kind of malignancy. However, it remains usefull for carcinomas of the pancreas. As regards specificity, CA 242 was the most specific marker in hepatobiliary diseases. Used concomitantly, CEA and TPA and CEA plus CA 242 augmented the sensitivity markedly, hence these combinations can be recommended. CEA remains the most reliable marker for the follow-up of colon cancer patients, the novel marker CA 242 has a similar performance, the combination of the two markers ameliorates the specificity of CEA used as a single marker. PMID- 8694565 TI - Vitamin D receptor and cytokeratin expression may be progression indicators in human colon cancer. AB - Epidemiological data suggest the protective role of vitamin D against the development of colorectal carcinoma in man. This could be due to the anti mitogenic effect of the steroid hormone on human colon carcinoma cells which is mediated by a specific nuclear vitamin D receptor (VDR). Western blot analysis showed that VDR expression increases during the transition from normal mucosa to polyps and later to pT3 tumors. In later stages, however, VDR is dramatically reduced. Cytokeratin 20, which was monitored as a differentiation marker, decreases in parallel with advancing proliferation and disappears from "normal" mucosa adjacent to later stage carcinoma. Interestingly, VDR density was conspicuously higher in all tumors tested when compared to adjacent "normal" tissue. This suggest that, up to a certain degree of dedifferentiation, malignant colonocytes can upregulate the VDR, probably as a counteractive measure in response to tumor cell growth, but that this ability is finally lost in highly undifferentiated carcinoma cells. PMID- 8694566 TI - New markers for breast carcinoma-associated antigen in comparison with CA 15-3. AB - The objective of this study was the clinical comparison of newly developed antibodies used in commercially available test systems with CA 15-3 (CIS bio international). IMMULITE BR-MA is a sequential chemoluminescent assay using the Mab's Ma552 and Ma695. Truquant BR RIA is a competitive inhibition radioimmunoassay using the Mab B27.29. ELSA-CA 15-3 is a sequential immunoradiometric assay using the Mab's115D8 and DF3. In the study 32 breast cancer patients (206 serum samples) were included during therapy monitoring. Linear regression analysis was performed with the CA 15-3 test as the reference method. Clinical criteria of response were according to UICC). Regression analysis in the range 0-1000 kU/l revealed the equations: IMMULITE = 1.65CIS + 0.87 (r = 0.78) and Truquant = 1.16 CIS + 10.6 (r = 0.95). The upper reference level of normal controls were somewhat higher than using the CIS method (30 kU/l): IMMULITE and TRUQUANT 40 kU/l and 36 kU/l, respectively. In all patients (except in 1 serum sample) nearly complete parallel tumour marker changes were seen with only minimal discrepancies in a few patients. However, the average factor between different patients varied between 0.51-6.9 (IMMULITE) and 0.74-2.3 (Truquant). In comparison to UICC criteria no discrepancies were observed. Therefore, we concluded that the test systems from DPC and BIOMIRA for the CA 15 3 antigen can replace the CIS test. Patient results were not interchangable. All test systems followed the clinical course of the disease in the same way. PMID- 8694567 TI - Significance of cytokeratin markers TPA, TPA (cyk), TPS and CYFRA 21.1 in metastatic disease. AB - Tissue polypeptide antigen has been advocated over the past two decades as a serum tumour marker. It was a long time before it was proven that these proteins in the serum are related to cytokeratin fragments. In this study the different behaviour of the test systems TPA, TPS, TPA(cyk) and CYFRA 21.1 were investigated in serum samples, mainly of metastasized cancer patients. By selecting individual samples with a high and a low TPA/TPS ratio it could be proven that no correlation existed in these samples between TPS (determining fragments of cytokeratin 18) and CYFRA 21.1 (determining fragments of cytokeratin 19). On the contrary, a good correlation was established between the TPA test and the CYFRA 21.1 test, and intermediate correlations were present between these tests and TPA (cyk). The TPA (cyk) test determines cytokeratin 8 and 18 fragments. During therapy, monitoring of metastasized patients with these tests could show a different pattern of reactivity. It is concluded that the different test results during therapy monitoring are not always easy to interpretate. The release of cytokeratins from cancer cells needs further study. PMID- 8694568 TI - Estimation of serum level of pS2 protein in patients with lung adenocarcinoma. AB - We measured pS2 protein in the serum of patients with adenocarcinoma and non adenocarcinoma types of lung cancer, non-cancerous lung lesions, and the control sera. Although the serum pS2 protein level in patients with lung adenocarcinoma was significantly higher than that in patients with other diseases, as well in control samples, it had little clinical value as a screening tumor marker because the levels in control samples showed a wide range of variation. However, analysis according to the histological subtype of lung adenocarcinoma, ordinary and bronchioloalveolar, revealed a high serum level of pS2 protein in several patients with advanced stage disease in the former, and mucus-producing goblet cell subtypes in the latter, which showed strong pS2 protein expression in tissues, whose serum levels diminished to the control level after resection. Thus, the serum levels of pS2 protein may be a useful marker of tumor burden in selected patients with lung adenocarcinoma. PMID- 8694569 TI - Evolution of osteoporosis. PMID- 8694570 TI - Clinical usefulness of risk factors for osteoporosis. PMID- 8694572 TI - Multiple painful bone cysts in a young man. AB - To confirm the diagnosis of diffuse cystic angiomatosis, it is necessary to biopsy the bone: the walls of the cysts react to immunological markers of the endothelium (antigens related to factor VIII and CD31). Alternatively, lymphography can avoid the necessity for biopsy. Evolution of the condition is variable and depends on the extent of visceral involvement, and usually the extent of soft tissue and visceral involvement dictates the morbidity and mortality. There is no specific treatment, though osseous lesions can regress spontaneously. PMID- 8694571 TI - Psychological aspects of pain. PMID- 8694573 TI - One patient, two unusual conditions and three basic lessons. PMID- 8694574 TI - Radiological progression of hip osteoarthritis: definition, risk factors and correlations with clinical status. AB - OBJECTIVES: To determine a cut off value for changes in radiological joint space width that allowed definition of radiological progression of hip osteoarthritis not related to measurement method errors and, thereafter, to determine factors predictive of radiological progression of hip osteoarthritis and to evaluate the correlations between clinical and radiological parameters. METHODS: A prospective, longitudinal (one year duration), multicentre study was made of patients with osteoarthritis of the hip (American College of Rheumatology criteria). Data on clinical activity (pain, functional impairment), demographic data (age, gender, body mass index), and femoral head migration (superolateral, superomedial, concentric) were collected when the patient entered the study; radiological grade (joint space width in millimetres at the narrowest point using a 0.1 mm graduated magnifying glass, evaluated by a single observer unaware of the chronology of the films) was recorded at the patient's entry to the study and after one year. RESULTS: Analysis of the means of the differences between two analyses performed by a single observer of 30 pairs of radiographs (one performed after an interval of one year) (0.06 (SD 0.23)) suggested that a change of more than 0.56 mm (2 SD) after a one year follow up could define progression of osteoarthritis of the hip. Of the 508 patients recruited, 461 (91%) completed the one year follow up and radiological progression was observed in 102 (22%). The factors predictive of radiological progression that were identified in the multivariate analysis were: radiological joint space width at entry < or = 2 mm, superolateral migration of the femoral head, female gender, Lequesne's functional index > 10, age at entry > 65 years (odds ratios 2.11, 4.25, 2.51, 2.66, 1.90, respectively). The level of clinical parameters (pain, functional impairment) and the amount of symptomatic treatment required (non-steroidal anti-inflammatory drugs and analgesic intake) accounted for 20% (p < 0.0001) of the variability of the changes in radiological joint space width over the one year study period. CONCLUSION: These data suggest that radiological progression of hip osteoarthritis could be defined by a change in joint space width of at least 0.6 mm after a one year follow up period, is correlated with the changes in clinical status of the patients, and is related not only to demographic data (age, gender), but also to some specific characteristics of osteoarthritis (localisation, radiological severity, clinical activity). PMID- 8694575 TI - Role of enteric bacteria in the pathogenesis of rheumatoid arthritis: evidence for antibodies to enterobacterial common antigens in rheumatoid sera and synovial fluids. AB - OBJECTIVE: To study antibodies to Escherichia coli O:14, which expresses large amounts of enterobacterial common antigen (ECA), and their corresponding antigen molecules in serum and synovial fluid samples from patients with rheumatoid arthritis (RA). METHODS: Enzyme linked immunosorbent assay (ELISA) was used to measure antibodies to heat killed E coli O:14 in serum and synovial fluid samples from patients with RA and control subjects including healthy donors and patients with osteoarthritis. ELISA was also used to perform absorption analyses of antibodies to E coli O:14 with several enteric bacteria and their lipopolysaccharide (LPS). In addition, antigenic molecules reacting with E coli O:14 antibodies from patients with RA were examined using immunoblot analysis and N-terminal amino acid analysis. RESULTS: Compared with control subjects, patients with RA showed significantly increased titres of antibodies against heat killed E coli O:14 in 33 of 83 serum samples (39.8%) and 38 of 58 joint fluid samples (65.5%). Absorption analyses with enteric bacteria and their LPS resulted in the reduction of antibody titres to heat killed E coli O:14 in serum and synovial fluid samples from the RA patients. In addition, immunoblot analysis of the samples from RA patients revealed not only a ladder-like banding pattern equivalent to ECA associated with LPS, but also two clear bands of bacterial outer membrane proteins of 35 kDa (Omp A) and 38 kDa (Omp C), having amino acid sequence homology with those of other Enterobacteriaceae. CONCLUSION: These results suggest that some patients with RA are sensitised to antigens common to Enterobacteriaceae, and this may prove relevant to the future development of immunotherapy for RA. Furthermore, this sensitisation to antigens found commonly in Enterobacteriaceae may have a key role in the pathogenesis of human RA similar to that described previously in our animal model. PMID- 8694576 TI - Investigation of anal function in patients with systemic sclerosis. AB - OBJECTIVE: To investigate anorectal function in women patients with systemic sclerosis (SSc), with and without lower gastrointestinal symptoms. METHODS: Anorectal manometry was performed in 16 patients with SSc: six with no or minimal bowel symptoms, seven with constipation, and three with diarrhoea and faecal incontinence. Eleven healthy women acted as control subjects. Pressure data were recorded via an eight lumen polyvinylchloride water perfused catheter. Station and rapid pull through techniques were used. RESULTS: In the patients with SSc, mean resting pressure, maximal voluntary squeeze effort, and squeeze vector volume were lower, and squeeze asymmetry was greater, compared with the healthy controls. Differences were significant in the subgroup with constipation. CONCLUSION: Radial asymmetry and vector volume parameters provide detailed analysis of segmental anal canal function. Our findings suggest significant segmental deficits in those patients with SSc who have lower gastrointestinal symptoms. The trend towards smaller pressures and squeeze vector volumes in the asymptomatic SSc group suggests subclinical dysfunction in these patients. PMID- 8694577 TI - Interleukin-4 inhibits prostaglandin E2 production by freshly prepared adherent rheumatoid synovial cells via inhibition of biosynthesis and gene expression of cyclo-oxygenase II but not of cyclo-oxygenase I. AB - OBJECTIVE: To characterise the effect of interleukin-4 (IL-4) on the biosynthesis of cyclo-oxygenases I (COX I) and II (COX II), the rate limiting enzymes of the synthesis of prostaglandin E2 (PGE2), in freshly prepared rheumatoid synovial cells. METHODS: Adherent synovial cells were obtained from rheumatoid synovium by collagenase digestion. The concentrations of PGE2 in culture supernatants were determined by enzyme linked immunosorbent assay. The protein and mRNA concentrations of COX I and COX II were determined by Western blotting and reverse transcription polymerase chain reaction, respectively. RESULTS: Freshly prepared synovial cells produced large amounts of PGE2. They also showed increased gene expression of COX I and COX II, and synthesised these proteins. IL 4 had suppressive effects on the production of PGE2 by untreated or lipopolysaccharide (LPS) stimulated synovial cells. In addition, IL-4 inhibited the biosynthesis of COX II at the mRNA level. In contrast, it did not modify the protein concentration of COX I. In tests of cell specificity, IL-4 did not reduce the mRNA concentration of COX II in interleukin-1 alpha (IL-1 alpha) stimulated cultured synovial fibroblasts at passages 3-6, but it reduced considerably the mRNA concentrations of COX II in an LPS or IL-1 alpha stimulated U937 monocyte/macrophage cell line. CONCLUSIONS: These results suggest that IL-4 might inhibit overproduction of PGE2 in rheumatoid synovia via selective inhibition of the biosynthesis of COX II, and that this inhibition might be specific to macrophage-like synovial cells. PMID- 8694578 TI - Protection against peroxynitrite dependent tyrosine nitration and alpha 1 antiproteinase inactivation by some anti-inflammatory drugs and by the antibiotic tetracycline. AB - OBJECTIVE: To examine in vitro the ability of several drugs to protect against deleterious effects of peroxynitrite, a cytotoxic agent formed by reaction of nitric oxide with superoxide radical, that may be generated in the rheumatoid joint and could cause joint damage. METHODS: The ability of several drugs to protect against such possible toxic actions of peroxynitrite as inactivation of alpha 1-antiproteinase and nitration of tyrosine was evaluated. RESULTS: Most non steroidal anti-inflammatory drugs were moderately (indomethacin, diclofenac, naproxen, tolmetin) or only weakly (sulindac, ibuprofen, aurothioglucose, flurbiprofen, sulphasalazine, salicylate, penicillamine disulphide) effective in preventing tyrosine nitration and alpha 1-antiproteinase inactivation by peroxynitrite, but 5-aminosalicylate and penicillamine were much more effective, as was the antibiotic tetracycline (but not ampicillin). Phenylbutazone and flufenamic acid protected effectively against tyrosine nitration, but could not be tested in the alpha 1-antiproteinase system. The analgesic paracetamol was highly protective in both assay systems. CONCLUSION: Many drugs used in the treatment of rheumatoid arthritis are unlikely to act by scavenging peroxynitrite. The feasibility of peroxynitrite scavenging as a mechanism of penicillamine, 5-aminosalicylate, and paracetamol action in vivo is discussed. PMID- 8694579 TI - Arthroplasty implant biomaterial particle associated macrophages differentiate into lacunar bone resorbing cells. AB - OBJECTIVE: To study the pathogenesis of aseptic loosening: in particular, to determine whether macrophages responding to particles of biomaterials commonly used in arthroplasty surgery for arthritis are capable of differentiating into osteoclastic bone resorbing cells, and the cellular and hormonal conditions required for this to occur. METHODS: Biomaterial particles (polymethylmethacrylate, high density polyethylene, titanium, chromium-cobalt, stainless steel) were implanted subcutaneously into mice. Macrophages were isolated from the foreign body granulomas that resulted, cultured on bone slices and coverslips, and assessed for both cytochemical and functional evidence of osteoclast differentiation. RESULTS: Tartrate resistant acid phosphatase (TRAP) negative macrophages isolated from granulomas containing particles of all types of biomaterial composition were capable of differentiating into TRAP positive cells capable of extensive lacunar bone resorption (assessed by scanning electron microscopy). The presence of both UMR106 rat osteoblast-like cells and 1,25 dihydroxy vitamin D3 was necessary for this to occur. CONCLUSION: All implant materials produce wear particles that are the focus of a heavy foreign body macrophage response in the fibrous membrane between a loose implant component and the host bone undergoing resorption. These findings underline the importance of biomaterial wear particle generation and the macrophage response to different types of biomaterial wear particles in the pathogenesis of aseptic loosening. PMID- 8694580 TI - Carpal tunnel syndrome: evaluation of a new method of assessing median nerve conduction at the wrist. AB - OBJECTIVE: To compare median nerve conduction velocity measured using a new, portable electroneurometer with measurements made using conventional hospital nerve conduction apparatus. METHODS: Twenty five patients were studied who were consecutively referred to a hospital neurophysiology department with a clinical diagnosis of carpal tunnel syndrome. Sensory and motor latencies for the median nerve at the wrist were measured bilaterally using the portable electroneurometer and a Medilec MS 92 hospital apparatus operated by a trained technician. RESULTS: There was strong agreement between motor latency values obtained by the two techniques (r = 0.89, p < 0.001; mean difference -0.03 ms, limits of agreement 0.33 to 0.27 ms). Sensory latencies were less easy to detect with the electroneurometer, and correlated less well with the hospital apparatus (r = 0.78, p < 0.001; mean difference -0.16 ms, limits of agreement -0.50 to 0.18 ms). CONCLUSION: The portable electroneurometer provides a convenient, rapid, and inexpensive means of assessing median nerve conduction velocity at the wrist. Measurements of motor latency obtained with this new instrument agree more strongly with those made by conventional apparatus than do measurements of sensory latency. Although the utility of the instrument in clinical practice will be limited, it provides a helpful tool in epidemiological studies of carpal tunnel syndrome. PMID- 8694581 TI - Antiubiquitin antibody in localised and systemic scleroderma. AB - OBJECTIVE: To determine the presence of antiubiquitin antibody (AUbA) in localised scleroderma and systemic sclerosis, as it is frequently found in the sera of patients with systemic lupus erythematosus (SLE) and has also been shown to have a close relationship with antihistone antibodies that have an important role in scleroderma. METHODS: Serum samples from patients with localised scleroderma (n = 48) and systemic sclerosis (n = 52) were examined by enzyme linked immunosorbent assay. Twenty samples from patients with SLE, 20 from patients with dermatomyositis, and 30 samples from healthy individuals were used as controls. RESULTS: AUbA was demonstrated in 44% of patients with localised scleroderma and in 42% of those with systemic sclerosis. The presence of AUbA correlated with the presence of antihistone antibodies in both localised scleroderma and systemic sclerosis. CONCLUSIONS: AUbA is frequently present in patients with localised scleroderma and systemic sclerosis. Induction of AUbA is closely associated with that of antihistone antibodies, suggesting that ubiquitinated histone may be the target in autoimmune responses of these disorders. PMID- 8694582 TI - What is meant by 'rheumatoid'? PMID- 8694583 TI - Interleukin-6 in clinical relapses of polymyalgia rheumatica and giant cell arteritis. PMID- 8694584 TI - Role of androgens in the aetiology of rheumatoid arthritis. PMID- 8694585 TI - Results of myotomy and partial fundoplication after pneumatic dilation for achalasia. AB - BACKGROUND: We questioned whether results of myotomy for achalasia are influenced by previous pneumatic dilation and whether surgical outcome is influenced by a dilation-related perforation necessitating urgent operation. METHODS: We performed a retrospective analysis of 60 patients who underwent transthoracic myotomy and fundoplication from 1977 to 1995. Dysphagia, heartburn, pain, and regurgitation were scored on a scale of 0 to 3 and results were classified according to combined symptom score. RESULTS: Dilation was performed before myotomy once in 15 patients, twice in 25, 3 times or more in 9, and never in 11 patients. Operation was urgent due to perforation in 6 patients (10%). There was no postoperative leak or mortality. Overall symptom score at last follow-up (57 +/- 8 months; 90% of patients) was improved compared with preoperative score (2.1 +/- 0.3 months versus 5.1 +/- 0.2 months; p < 0.0001). Outcome was unrelated to whether or not a perforation occurred (excellent/good outcomes in 100% and 88%, respectively) or to whether or not preoperative dilations had been performed (excellent/good outcomes in 90% and 89%, respectively). CONCLUSIONS: Myotomy and partial fundoplication is an effective technique for management of achalasia. Results are unaffected by the need for urgent operation for perforation and are unrelated to whether pneumatic dilation is performed preoperatively. PMID- 8694586 TI - External cooling of warm ischemic rabbit lungs after death. AB - BACKGROUND: If lungs could be retrieved for transplantation after circulatory arrest, the shortage of donors might be significantly alleviated. However, in such non-heart-beating donors, there is great concern that even a short period of warm ischemia will be deleterious for lung tissue, jeopardizing the transplant recipient. It was the purpose of this study to look for the efficacy of different methods of lung cooling inside a cadaver after circulatory arrest. METHODS: New Zealand white rabbits were sacrificed with an intravenous overdose of pentobarbital and left at room temperature. Subcutaneous, rectal, lung core, lung surface, and endobronchial temperatures were measured at intervals after death. Cooling of the lung during ischemia differed between groups (n = 6 in each group): lungs left deflated at room temperature (24 degrees C) (group 1 = control non-heart-beating donors), lungs ventilated with cooled (4 degrees C) room air (group 2), lungs left deflated plus topical cooling (1 degree C) of both the cadaver and its lungs (group 3), and lungs flushed in situ immediately after circulatory arrest with a cold (4 degrees C) crystalloid solution followed by ex vivo deflated storage in cold (1 degree C) saline solution (group 4 = control heart-beating donors). RESULTS: There was a slow decline in lung core, lung surface, and endobronchial temperatures toward room temperature in group 1 (1.5 degrees +/- 0.0 degree C/h, 1.8 degrees +/- 0.2 degree C/h, and 1.9 degrees +/- 0.1 degree C/h, respectively). In contrast, all three lung temperatures immediately ( < 5 minutes) dropped to less than 10 degrees C in group 4. Hypothermic ventilation (group 2) decreased endobronchial temperature (p < 0.05 at 30 minutes) but not lung surface, rectal, or subcutaneous temperature when compared with group 1. Cooling rate for lung surface and endobronchial temperatures during the first 4 hours after death was faster (p < 0.01) in group 3 (6.6 degrees +/- 0.3 degree C/h and 6.1 degrees +/- 0.2 degree C/h, respectively) when compared with group 2 (2.5 degrees +/- 0.3 degree C/h and 3.9 degrees +/- 0.1 degree C/h, respectively), but slower (p < 0.001) when compared with group 4 (9.2 degrees +/- 0.1 degree C/h and 8.7 degrees +/- 0.1 degree C/h, respectively). CONCLUSIONS: These data demonstrate that in the non-heart-beating donor, (1) in situ cold flush will result in immediate cooling of the lung, (2) ventilation with cooled air will only accelerate the decline in endobronchial temperature but has no effect on lung surface temperature, and (3) topical cooling of the cadaver is more efficacious in decreasing lung temperature than hypothermic ventilation. PMID- 8694587 TI - Lung cancer staging: the value of ipsilateral scalene lymph node biopsy performed at mediastinoscopy. AB - BACKGROUND: The accurate preoperative staging of lung cancer remains an essential element in its proper treatment. In most centers, N3 disease contraindicates an operative approach, despite the advent of combined modality therapy. Although it is used to confirm palpable supraclavicular disease, routine scalene lymph node biopsy to stage nonpalpable disease has been abandoned. METHODS: From January 1991 to July 1995, 408 cervical mediastinoscopies were performed by a single surgeon for the staging of lung cancer. In those patients eligible for induction therapy, when N2 or N3 disease was strongly suspected or identified, ipsilateral scalene lymph node biopsy was performed through the same cervical incision using the mediastinoscope to reach the scalene fat pad. RESULTS: Eighty-one patients underwent this additional staging procedure. There was minimal morbidity and no deaths. Of these 81 fully staged patients, primary tumor histology was non-small cell in 95.1%. Thirty-nine patients were staged as N2 after standard mediastinoscopy. Of these, 6 (15.4%) harbored occult nonpalpable supraclavicular lymph node disease as well. Nineteen patients were staged as N3-contralateral after standard mediastinoscopy. Of these, 13 (68.4%) had occult supraclavicular disease as well. Of all 58 patients with superior mediastinal nodal involvement identified by standard mediastinoscopy, 19 (32.8%) also harbored occult scalene lymph node disease, rendering them ineligible for our induction therapy protocols. Scalene positive primary tumors were all centrally located (visualizable by flexible bronchoscopy) (19 of 19) and were uniformly of nonsquamous origin. CONCLUSIONS: We believe that this technique is a valuable extension to standard cervical mediastinoscopy and can be used in N2 or N3 staged patients with central, nonsquamous tumors before considering a combined modality therapeutic approach that includes operation. Through its use, more accurate staging before initiation of therapy and elimination of those patients who may derive no benefit from an aggressive surgical approach may be possible. PMID- 8694588 TI - Results of combined pulmonary resection and cardiac operation. AB - BACKGROUND: Concomitant lesions of the heart and lung are uncommon, but when present they pose a therapeutic challenge for thoracic surgeons. A combined procedure avoids the need for a second major thoracic procedure and may improve outcomes and provide economic benefit. However, cardiopulmonary bypass may adversely affect the natural history of pulmonary malignancies. METHODS: The clinical records of 30 patients were reviewed who underwent simultaneous lung resection and cardiac operations between January 1982 and July 1995. Follow-up was obtained on all 30 patients (mean follow-up, 22 months; range, 1 to 100 months). RESULTS: Twenty-four patients underwent coronary artery bypass grafting in conjunction with pulmonary resection. Six patients underwent aortic (n = 4) or mitral (n = 2) valve replacement. The pulmonary resections consisted of pneumonectomy (n = 3), lobectomy (n = 14), wedge excision (n = 12), and tracheal resection (n = 1). Twenty-one patients had pathologic findings that confirmed adenocarcinoma (n = 10), squamous cell carcinoma (n = 5), small cell carcinoma (n = 2), or other malignancy (n = 4). Tumor stage of primary lung cancers was stage I, n = 12; stage II, n = 3; and stage IIIa, n = 2. Pathologic examination revealed benign disease in 9 patients. There were two operative deaths, one due to aspiration and one due to stroke. There were three late deaths, two cardiac and one of metastatic disease. Overall late survival was 85% +/- 7% and 73% +/- 16% at 1 and 5 years, respectively. Actuarial survival for patients with malignant disease was 64% at 5 years. CONCLUSIONS: Simultaneous cardiac operation and lung resection was not associated with increased early or late morbidity or mortality. Cardiopulmonary bypass does not adversely affect survival in patients with malignant disease. Cardiac valve replacement can be performed safely in conjunction with pulmonary resection. PMID- 8694589 TI - Lung resection in patients with compromised pulmonary function. AB - BACKGROUND: Some patients are denied curative pulmonary resection for lung carcinoma because of pulmonary insufficiency. To identify factors that affect postoperative morbidity and mortality, we reviewed 85 consecutive patients (53 men and 32 women) with a preoperative forced expiratory volume in 1 second of less than 1.2 L who underwent pulmonary resection for lung cancer between January 1986 and December 1990. METHODS: Median age was 70 years (range, 49 to 82 years). Sixty patients (71%) had been previously denied operation because of pulmonary insufficiency. Preoperative pulmonary function demonstrated a median preoperative forced expiratory volume in 1 second of 1.0 L (44% of predicted normal; range, 0.5 to 1.2 L) and a diffusing capacity of the lung for carbon monoxide of 60% of predicted normal (range, 22% to 104%). RESULTS: Pneumonectomy was done in 6 patients (7.1%), bilobectomy in 6 (7.1%), lobectomy in 38 (44.7%), segmentectomy in 12 (14.1%), and wedge excision in 29 (27.1%). The median predicted postoperative forced expiratory volume in 1 second was 0.83 L (34% of predicted normal; range, 0.45 to 1.14 L), and the median predicted postoperative diffusing capacity of the lung for carbon monoxide was 48% of predicted normal (range, 19% to 87%). Seventy-two patients (85%) received postoperative epidural analgesia. Median hospitalization was 15 days (range, 5 to 66 days). Operative mortality was 2.4%, and complications occurred in 49%. We did not identify any factors that predicted postoperative morbidity and mortality. Median follow-up was 3.2 years (range, 0.2 to 9 years). Seven patients (8%) required supplemental home oxygen. A predicted postoperative percent forced expiratory volume in 1 second less than 43% correlated with the need for home oxygen (p < 0.05). Overall 5-year survival was 44.0%. Survival for stage I cancer was 54.2%; stage II, 33.1%; and stage IIIa, 21.3%. CONCLUSIONS: We conclude that some patients with lung cancer and compromised pulmonary function can safely undergo pulmonary resection if selected appropriately. PMID- 8694590 TI - Staging of primary lung cancer by computed tomography-guided percutaneous needle cytology of mediastinal lymph nodes. AB - BACKGROUND: The necessity of an easy and noninvasive technique to evaluate mediastinal node status cytopathologically is considered. METHODS: Eighteen cases of clinical N2 primary lung cancer were examined. Under local anesthesia, the lymph node was punctured with a 19-gauge needle using intermittent computed tomographic monitoring, and samples were studied cytologically. Subcarinal (no. 7) nodes and lower paratracheal (no. 4) nodes were sampled using the paraspinal posterior approach. Anterior mediastinal (no. 6) nodes were sampled using the parasternal anterior approach. Node status was diagnosed pathologically at operation. RESULTS: Number 7 nodes were examined in 11 cases, no. 4 nodes in 5 cases, and no. 6 nodes in 2 cases. Malignant cells were detected in 14 cases. Fourteen cases were diagnosed as true positive, 2 cases as true negative, and 2 cases as false negative. The sensitivity, specificity, and accuracy of this method were 88%, 100%, and 89%, respectively. Pneumothorax developed in 4 cases (22%). CONCLUSIONS: Computed tomography-guided percutaneous needle cytology of mediastinal lymph nodes is useful for staging primary lung cancer. Because this is a small series, additional studies are necessary. PMID- 8694591 TI - A systematic study of hypothermic lung preservation solutions: Euro-Collins solution. AB - BACKGROUND: Testing lung function after preservation is difficult because a suitable model is still lacking; thus, the effectiveness of different solutions for lung preservation has not been confirmed. This study tested the effectiveness of Euro-Collins solution alone for hypothermic preservation of rat lungs. METHODS: A living rat perfusion model was used, which allowed more than 5 hours of continuous perfusion for isolated lung function studies. Group 1 lungs (control, n = 8) were tested without preservation. In groups 2 through 6 (n = 8 lungs each), the lungs were flushed with 4 degrees C Euro-Collins solution and preserved for 4, 6, 8, 12, and 24 hours, respectively. Lung function studies were carried out after preservation. RESULTS: In groups 1 and 2, pulmonary arterial blood flow and pulmonary venous oxygen tension were higher and pulmonary resistance was lower than in the other groups. Airway pressure and resistance were lowest in group 1. Lungs in groups 5 and 6 demonstrated the worst function, but the lung tissue wet to dry ratio was higher only in group 6. CONCLUSIONS: At 4 degrees C, Euro-Collins solution can effectively preserve rat lungs for 4 hours. Six to 8 hours of preservation resulted in depressed lung function. More than 12 hours of preservation resulted in uniformly deficient lung function, rendering the lungs unsuitable for transplantation. PMID- 8694592 TI - Unilateral volume reduction after single-lung transplantation for emphysema. AB - BACKGROUND: Single-lung transplantation has become accepted therapy for patients with end-stage emphysema. Hyperinflation of the native lung can occur after single-lung transplantation with mediastinal shifting and compression of the transplanted lung. A volume reduction operation (pneumectomy) [corrected] may relieve symptoms of dyspnea and improve exercise tolerance. METHODS: Three of 66 patients who underwent single-lung transplantation for emphysema had development of native lung hyperexpansion and mediastinal shifting causing compression of the transplanted contralateral lung at 12, 17, and 42 months after transplantation. There were 2 men and 1 woman. Unilateral volume reduction was performed without complication in all 3 patients. RESULTS: All patients were noted to have marked improvement in chest radiographs after volume reduction, substantial relief of dyspnea, and improvement in exercise tolerance. An improvement in pulmonary function test results was noted in 1 patient, but tests were not done for the other 2 patients. CONCLUSIONS: Patients with chronic obstructive pulmonary disease who undergo single-lung transplantation may have symptomatic hyperexpansion of the native lung requiring volume reduction months to years after transplantation. Unilateral volume reduction can be safely performed in the posttransplantation period. PMID- 8694593 TI - Esophagectomy for benign disease: trends in surgical results and management. AB - BACKGROUND: Esophagectomy for benign disease is uncommon. METHODS: From July 1987 to April 1995, 45 consecutive patients (30 men, 15 women; mean age, 50 years) were evaluated in whom the senior author (R.F.H.) performed an esophagectomy, esophageal reconstruction, or both. The study period was divided into two time intervals, July 1987 to January 1992 (time 1) and February 1992 to April 1995 (time 2). RESULTS: Indications for operation included obstruction (23 patients, 51%), benign neoplasia (17.38%), and perforation (5 patients, 11%). A nonthoracotomy approach was used in 19 (42%) patients: 15 transhiatal and 4 substernal. Thoracotomies were performed in 26 (58%) patients through a left thoracoabdominal or multiincisional techniques. Morbidity occurred in 15 (33%) patients, and there was one operative death (2%). CONCLUSIONS: Despite an operative morbidity of 33%, esophagectomy for benign disease may be performed with acceptably low mortality. We observed the following trends: (1) an increase in patients with benign neoplasia and a decline in patients with obstruction, (2) an increased use of transhiatal esophagectomy, (3) a decreased use of colon, an increased use of stomach for esophageal replacement; and (4) a decreased length of hospital stay. PMID- 8694594 TI - Retrosternal bypass operation for unresectable squamous cell cancer of the esophagus. AB - BACKGROUND: A palliative bypass operation may be beneficial when severe dysphagia or tracheoesophageal fistula occurs after radiochemotherapy for unresectable tumor of the esophagus. METHODS: Thirty-two patients with an unresectable tumor of the esophagus underwent a palliative retrosternal gastric (29) or colonic (3) bypass operation with ligature of the lower esophagus (3) or drainage (27). Tracheoesophageal fistula was present at operation in 20 (62.5%), including 8 after radiochemotherapy. RESULTS: The overall operative mortality rate was 34.4%: 45% with tracheoesophageal fistula and 16.6% without (p < 0.01). Median intensive care and hospitalization times were 5 and 19 days, respectively. Median postoperative survival was 6 months (range, 53 to 492 days). Complications in 21 survivors were lung infections (seven), cervical fistulas (eight), and failure of the esophageal suture (two); 19 patients resumed oral nutrition, and quality of life was excellent in 6. All eight cervical fistulas regressed favorably. Postoperative radiotherapy or chemotherapy did not improve survival. CONCLUSIONS: Despite the high operative mortality rate, bypass operation can provide good palliation and allow subsequent radiochemotherapy in selected patients with an unresectable tumor of the esophagus. PMID- 8694595 TI - Inhibition of inducible nitric oxide synthase attenuates established acute cardiac allograft rejection. AB - BACKGROUND: We previously demonstrated that continuous treatment with aminoguanidine, a selective inhibitor of nitric oxide production by inducible nitric oxide synthase, attenuated acute cardiac allograft rejection. METHODS: A rat transplant model was used to determine (1) when inducible nitric oxide synthase was expressed in the allograft heart during unmodified acute rejection and (2) whether pulse therapy with aminoguanidine attenuated the histologic changes of established acute rejection, in comparison with the effects of pulse therapy with corticosteroids. RESULTS: Inducible nitric oxide synthase messenger RNA and protein were expressed during early and late acute rejection. Pulse therapy with aminoguanidine inhibited nitric oxide production and attenuated the histologic changes of acute rejection, but not as effectively as corticosteroid therapy (rejection scores of 4.1 +/- 0.4, 2.5 +/- 0.9, and 1.4 +/- 0.6 on postoperative day 8, for untreated, aminoguanidine-, and dexamethasone-treated allografts, respectively (scale, 0 to 5; p < 0.05). CONCLUSIONS: (1) Inducible nitric oxide synthase expression first occurs during early acute allograft rejection and persists throughout rejection and (2) nitric oxide is an important effector molecule in acute rejection. Inducible nitric oxide synthase inhibition may offer a therapeutic adjunct in the management of acute rejection. PMID- 8694596 TI - Cardiovascular-radical outcome method is effective in complex congenital cardiac lesions. AB - BACKGROUND: The cardiovascular-radical outcome method is a proactive process of patient care that uses standard critical pathway methodology to reduce negative variation while encouraging positive variation to accelerate recovery. Its effectiveness in patients with complex congenital heart disease is explored. METHODS: Two hundred fourteen consecutive patients with congenital heart disease were cared for using the cardiovascular radical outcome method. Age ranged from 2 days to 19 years (median age, 3 years). Cardiovascular radical outcome method data were compared with the pathway plan data for each patient. RESULTS: Survival was 99% (211 patients) with an overall reduction in stay of 156 days (0.74 day/patient) (p < 0.0001). Only 10 patients (5%) exceeded the pathway plan; 201 (95%) reached the planned length of stay (critical pathway method), and 127 patients (60%) had a shorter length of stay than expected by the critical pathway method. One hundred forty-eight patients (70%), including 95 (64%) with more complex conditions, had a length of stay of 3 days and 18% achieved a 2-day length of stay, the maximal response. The process was most effective in the most complex groups, although preoperative comorbidities influenced outcomes. Outcome assessment demonstrated minimal morbidity and excellent family satisfaction. CONCLUSIONS: The radical outcome method is effective in reducing the length of stay of patients with complex congenital heart disease. The power is in the process rather than the plan, and the method provides optimal patient care and family satisfaction. PMID- 8694597 TI - Fetal cardiac bypass using an in-line axial flow pump to minimize extracorporeal surface and avoid priming volume. AB - BACKGROUND: Progressive metabolic acidosis, hypoxia, and hypercarbia develop rapidly after fetal cardiac bypass mainly as a result of an increase in placental vascular resistance and a decrease in placental blood flow. A number of factors including fetal stress, priming substances, and extracorporeal surfaces have been identified as possible stimuli causing this placental dysfunction. The purpose of this study was to examine the effects of avoiding priming volume and minimizing extracorporeal surface area on placental hemodynamics and function. METHODS: Fetal sheep (n = 16) at 118 to 122 days of gestation were subjected to cardiac bypass for 30 minutes using either an in-line axial-flow pump (Hemopump group: n = 8, no prime) or a roller pump with a venous reservoir (control group: n = 8, priming volume = 150 mL). After bypass, the fetuses were observed for 90 minutes. Placental blood flow and combined ventricular output were continuously measured with ultrasonic flow probes, and fetal blood gases were measured at specific intervals. RESULTS: Three fetuses in the control group died during the study, whereas all 8 fetuses in the Hemopump group remained in stable condition throughout the study period. During and after bypass, placental blood flow was significantly higher (p < 0.0001) and placental vascular resistance was significantly lower (p < 0.0001) in the Hemopump group than in the control group. Arterial pH and partial pressure of arterial oxygen declined significantly less (p < 0.0001), and partial pressure of arterial carbon dioxide increased significantly less (p = 0.0002) in the Hemopump group than in the control group. CONCLUSIONS: Reducing the extracorporeal surface area and avoiding external priming substances preserves placental hemodynamics after fetal cardiac bypass. An in-line axial-flow pump is useful in miniaturizing the bypass circuits for potential use in fetal cardiac surgery. PMID- 8694598 TI - Efficacy and cost-effectiveness of preoperative IABP in patients with ejection fraction of 0.25 or less. AB - BACKGROUND: The purposes of this study are to determine whether patients with severe left ventricular dysfunction benefit from prophylactic insertion of an intraaortic balloon pump and to evaluate its cost-effectiveness. METHODS: Between January 1991 and December 1995, 163 consecutive patients with a left ventricular ejection fraction of 0.25 or less underwent isolated coronary artery bypass grafting. An intraaortic balloon pump was inserted before operation in 37 patients (group A). The remaining 126 patients underwent operation without preoperative insertion of the device (group B). Preoperatively, 91.9% (34/37) of group A patients and 54.8% (69/126) of group B patients were in New York Heart Association functional class III or IV (p < 0.001). RESULTS: The 30-day mortality rate was 2.7% (1/37) and 11.9% (15/126) for groups A and B, respectively (p < 0.005). All deaths occurred in patients in functional class III or IV. In group B, 28 patients (22.2%) required an intraaortic balloon pump after cardiotomy for low cardiac output, 42.9% (12/28) of whom died. Median postoperative hospital stay was 9.9 days and 12.0 days, and mean hospital charges were $50,627 and $54,818 for survivors in groups A and B; respectively (p = not significant). CONCLUSIONS: Our experience suggests that patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting may benefit from preoperative intraaortic balloon pump insertion, especially patients in functional class III or IV. This approach improved survival significantly, reduced hospital stay, and was more cost-effective. PMID- 8694599 TI - Heparin-bonded circuits with a reduced anticoagulation protocol in primary CABG: a prospective, randomized study. AB - BACKGROUND: A substantial proportion of patients undergoing primary coronary revascularization require homologous transfusions. To address this problem, a comprehensive strategy to diminish perioperative blood loss was developed. METHODS: A prospective randomized trial was undertaken to test the hypothesis that "tip-to-tip" heparin-bonded cardiopulmonary bypass circuits (HBC) can further enhance blood conservation and clinical outcomes in patients undergoing primary coronary artery bypass grafting. Two hundred thirty-four patients were treated with either HBC and lower anticoagulation therapy (activated clotting time > 280 seconds) or with conventional, nonheparin-bonded circuits and full anticoagulation therapy (activated clotting time > 480 seconds). RESULTS: Preoperative and intraoperative risk profiles and characteristics were similar in both groups, with 69.7% of the patients undergoing nonelective coronary artery bypass grafting. Compared with the group with nonheparin-bonded circuits, patients treated with HBC had a lower chest tube output in the first 24 hours (561 +/- 257 versus 651 +/- 403; p = 0.04), were less likely to receive blood products (31.6% versus 47.9%; p = 0.01), and required substantially fewer homologous donor units (1.98 +/- 4.8 versus 4.29 +/- 10.1; p = 0.029). Patients treated with HBC required a shorter duration of ventilatory support (13.2 +/- 16.9 versus 23.4 +/- 50.0 hours; p = 0.04), spent less time in the surgical intensive care unit (20.7 +/- 17.4 versus 35.5 +/- 61.7 hours; p = 0.01), spent fewer days in the hospital (6.0 +/- 2.5 versus 7.3 +/- 5.2 days; p = 0.02), and had fewer postoperative complications (25.6% versus 39.3%; p = 0.03). The use of HBC with a lower anticoagulation protocol was not associated with any adverse events. CONCLUSIONS: This study demonstrates that the use of HBC with a lower anticoagulation protocol in primary coronary artery bypass grafting safely and effectively reduces the incidence and magnitude of homologous transfusion, the duration of ventilation, and surgical intensive care unit and hospital stays. PMID- 8694600 TI - Twenty-year experience with repair of complete atrioventricular septal defects. AB - BACKGROUND: To determine factors predicting mortality and morbidity after repair of complete atrioventricular septal defect, we retrospectively analyzed preoperative, operative, and postrepair factors on the outcome of 115 consecutive complete atrioventricular septal defect repairs at The Children's Hospital of Wisconsin between January 1974 and December 1993. METHODS: For the entire experience the operative mortality was 13.9% (16 patients). During the most recent era, January 1988 to December 1993, operative mortality was 3.6% (2 of 55 patients). This was significantly improved from the two previous eras, January 1974 to December 1980, 28% (7 of 25) and January 1981 to December 1987, 20% (7 of 35 patients) (p = 0.02). There were seven late deaths; 10-year actuarial survival, including operative mortality was 81%. Age at complete repair decreased; before 1982 all patients were more than 12 months of age, whereas after 1982 64% (56 of 88 patients) were 12 months of age or less. RESULTS: Moderate or severe preoperative left atrioventricular valve regurgitation was not a risk factor for operative mortality. For operative survivors with moderate to severe preoperative left atrioventricular valve regurgitation (n = 17), late postoperative left atrioventricular valve regurgitation (follow-up data available on 15 patients) was significantly reduced (severe = 1, moderate = 5, mild = 9; p = 0.007). CONCLUSIONS: Early mortality was predicted by the era of surgical repair. Conversion to routine repair during infancy was achieved with a simultaneous decrease in operative mortality. For patients with moderate to severe preoperative left atrioventricular valve regurgitation, significant improvement in the degree of left atrioventricular valve regurgitation can be expected without an increase in operative or late mortality or morbidity. PMID- 8694601 TI - Direct in vivo gene transfer to canine myocardium using a replication-deficient adenovirus vector. AB - BACKGROUND: Direct myocardial gene transfer is a mordality that involves the introduction of genetic information into myocardial tissue to achieve a therapeutic effect. This study was designed to characterize the temporal and spatial limits of gene expression and to determine the safety of direct myocardial gene transfer in a large animal model using replication-deficient adenovirus vectors. METHODS: Mongrel dogs underwent left thoracotomy and direct myocardial injections (100 microL/injection) of adenovirus vectors (10(9) pfu) carrying the DNA for the reporter enzyme chloramphenicol acetyl transferase or the angiogenic protein vascular endothelial growth factor. Two to 14 days after vector administration, regional protein expression was evaluated in myocardium and distant organs. Left ventricular function, assessed by echocardiography, and routine hematologic and biochemical indices were evaluated before and after vector administration. RESULTS: Peak levels of chloramphenicol acetyl transferase activity were detected 2 days after vector administration, and levels above baseline persisted for at least 14 days. Local chloramphenicol acetyl transferase activity was detected at distances at least as far as 1.5 cm from the site of injection. Chloramphenicol acetyl transferase activity in distant organs was less than 0.1% of that in injected myocardium 7 days after vector administration. Localized expression of vascular endothelial growth factor was achieved for up to 7 days after a single vector administration. Cardiac function and laboratory values were unchanged during the study. CONCLUSIONS: Adenovirus-mediated direct myocardial gene transfer can be accomplished safely in a large animal model, providing high levels of protein expression in a greater spatial distribution than previously reported, with minimal transfection of distant organs. Sustained and localized expression of a potent angiogenic mediator has been accomplished, which may provide an innovative strategy to stimulate angiogenesis in ischemic myocardium. PMID- 8694602 TI - Port-access coronary artery bypass with cardioplegic arrest: acute and chronic canine studies. AB - BACKGROUND: Our goal is to perform minimally invasive coronary artery bypass grafting without sacrificing the benefits of myocardial protection with cardioplegia. METHODS: Twenty-three dogs underwent acute studies and 4 dogs underwent survival studies. The left internal mammary artery was taken down using a thoracoscope. Cardiopulmonary bypass was conducted via femoral cannulas and using an endovascular balloon catheter for ascending aortic occlusion, root venting, and delivery of antegrade blood cardioplegia. Pulmonary artery venting was achieved with a jugular vein catheter. An internal mammary artery-to-coronary artery anastomosis was performed using a microscope through a 10 mm port. RESULTS: All animals were weaned from cardiopulmonary bypass in sinus rhythm without inotropes. Cardiopulmonary bypass duration was 104 +/- 28 minutes and aortic clamp duration was 61 +/- 22 minutes. Cardiac output and pulmonary artery occlusion pressure were unchanged. The internal mammary artery was anastomosed to the left anterior descending artery (25) or the first diagonal (2) with patency shown in 25 of 27. One dog in the survival study had a very short internal mammary artery pedicle under tension and was euthanized for excessive postoperative hemorrhage. Three weeks postoperatively the remaining dogs had angiographically patent anastomoses, normal transthoracic echocardiograms, and histologically normal healing and patent grafts. CONCLUSIONS: Endovascular cardiopulmonary bypass using a balloon catheter is effective in arresting and protecting the heart to allow thoracoscopic internal mammary artery-to-coronary artery anastomosis. PMID- 8694604 TI - Pulmonary autograft reoperation: incidence and management. AB - BACKGROUND: Pulmonary autograft replacement of the aortic valve is accepted in the young, those with an active life style, and those who are not candidates for anticoagulation. However, concern remains about autograft or homograft valve failure. METHODS: One hundred ninety-five operative survivors of the Ross operation (August 1986 through December 1995) were reviewed for operative pathology and factors associated with reoperation or valve dysfunction. RESULTS: Actuarial freedom from reoperation (autograft or homograft) is 89% +/- 3% at 5 years, 92% +/- 3% for the autograft alone. Early autograft valve failures (< 6 months) were due to technical error in 2 patients and persistent endocarditis in 1. Late autograft valve failure (1 to 6.2 years) was due to aortic annulus dilatation in 5 patients, bacterial endocarditis in 1, and valve degeneration in 2. Six autograft valves were replaced and five were repaired. Five patients required reoperation for pulmonary homograft stenosis (1 to 5.4 years) involving obstruction of the conduit distal to the pulmonary valve. CONCLUSIONS: Pulmonary autograft replacement of the aortic valve has a low incidence of reoperation for autograft dysfunction or homograft obstruction. Autograft dysfunction can be corrected by autograft repair in patients with central insufficiency and aortic annular dilatation. PMID- 8694603 TI - Aortic root replacement with the pulmonary autograft in children with complex left heart obstruction. AB - BACKGROUND: The optimal surgical treatment of complex (multiple level or recurrent) left ventricular outflow tract obstruction (LVOTO) in infancy is controversial. Staged procedures expose the children to the need for reoperation, and currently available techniques of aortoventriculoplasty are associated with the morbidities of biological and mechanical prostheses. METHODS: Between July 1992 and January 1996, we have performed 24 aortic root replacements with the pulmonary autograft in pediatric patients (< 18 years). Of this group, 8 were infants and children with complex LVOTO aged 9 days to 22 months (mean, 8.6 +/- 8 months) and weighing 3.3 to 10.2 kg (mean, 6.3 +/- 2.6 kg). The diagnoses were interrupted aortic arch/ventricular septal defect/subaortic stenosis in 3, recurrent aortic stenosis in 2, aortic stenosis and subaortic stenosis in 1, and aortic stenosis/subaortic stenosis/mitral stenosis/regurgitation in 2. All patients had undergone one to three previous operative procedures (mean, 1.5 +/- 0.8 procedures/patient). Preoperative echocardiographic peak LVOT gradient was 71.7 +/- 25 mm Hg (range, 40 to 110 mm Hg) and aortic annulus size was 7.2 +/- 2.3 mm (range, 4 to 10.6 mm). The surgical technique included replacement of the aortic root with the pulmonary autograft combined with incision of the conal septum to relieve subaortic stenosis or accommodate for size discrepancy between the aortic and pulmonary autograft root and a pulmonary homograft placed in the right ventricular outflow tract. RESULTS: There were no perioperative or late deaths at follow-up (range, 2 to 25 months; mean, 13.5 +/- 8 months). Mean hospital stay was 15 +/- 17 days (range, 4 to 53 days). Three children had the following complications: diaphragmatic paresis (1), delayed pericardial effusion (1), and atrioventricular block requiring a pacemaker (1). In follow-up, echocardiographic findings showed absent aortic regurgitation in 3 and trivial aortic regurgitation in 5, and no significant LVOTO (mean peak gradient, 6.2 +/- 7.6 mm Hg; range, 0 to 16 mm Hg). Pulmonary homograft regurgitation was absent in 5, trivial in 2, and moderate in 1. Peak right ventricular outflow tract gradient by echocardiogram was trivial in 7, and a significant gradient of 55 mm Hg has developed in 1 infant. There were no infective or embolic complications during follow-up. CONCLUSIONS: Our experience shows that aortic root replacement with the pulmonary autograft can be performed in children with excellent clinical results. The technique of root replacement combined with ventriculoplasty allows definitive and simultaneous relief of complex and multiple-level obstructive lesions. Considering the growth potential of the pulmonary autograft, this should be regarded as the optimal treatment modality in infants with complex LVOTO: PMID- 8694605 TI - Early reduction of the volume work of the single ventricle: the hemi-Fontan operation. AB - BACKGROUND: In hearts with a functional single ventricle, cavity volume and myocardial muscle mass increase as a consequence of the excessive volume work associated with parallel pulmonary and systemic circulations. The hemi-Fontan operation was conceived as a means of accomplishing early reduction of the volume work of the single ventricle. METHODS: All patients presenting in infancy with single-ventricle physiology were managed by early hemi-Fontan operation in anticipation of a subsequent completion Fontan operation. Between May 1989 and August 1995, 400 patients less than 2 years of age underwent hemi-Fontan operations. Mean age at operation was 8.5 months (range, 2 months to 24 months). The hemi-Fontan operation included association of superior vena(e) cava(e) with the branch pulmonary arteries, augmentation of the central pulmonary arteries, occlusion of the inflow of the superior vena cava into the right atrium, and elimination of other sources of pulmonary blood flow. RESULTS: Operative mortality ( < 30 days) was 31 of 400 patients (7.8%). For the last 200 patients, operative mortality was 8 of 200 (4.0%). Younger age at operation was not an independent risk factor for operative mortality. Urgent operation in the presence of a hemodynamic burden requiring concomitant procedures was associated with increased mortality. CONCLUSIONS: The hemi-Fontan operation can be accomplished with low operative mortality in young patients, achieving early reduction of the volume work of the single-ventricle heart. PMID- 8694606 TI - Reduced mortality and morbidity for ascending aortic aneurysm resection regardless of cause. AB - BACKGROUND: This study was done to answer the question, "What is the current risk of resection of ascending aortic aneurysms regardless of acuity or cause?" METHODS: One hundred fifteen consecutive patients who underwent ascending aortic aneurysm repair from January 1, 1990, to July 1, 1995, were retrospectively reviewed, excluding those with acute ascending aortic dissection. The mean age was 59 years; 55% were male. Concomitant procedures included coronary artery bypass in 23 (20%) and arch repair in 12 (10%). In group 1, 54 patients had replacement of the aortic valve, root, and ascending aorta with a valve-graft conduit using the "Bentall" technique, and of these 19 (35%) had Marfan's syndrome. In group II, 44 patients had separate aortic valve repair or replacement and supracoronary ascending aortic replacement. In group III, 17 patients had supracoronary ascending aortic replacement, without aortic valve operation. Operative techniques included frequent use of (1) intraoperative transesophageal echocardiography or epiaortic ultrasound scanning of the ascending and descending thoracic aorta to help guide arterial cannulation, avoid atherosclerotic embolization, and assess the repair; (2) antegrade and retrograde multidose cold blood cardioplegia for myocardial protection; (3) exclusion and button anastomotic techniques to ensure secure suture lines; (4) antifibrinolytic agents and collagen-impregnated aortic grafts to reduce bleeding; and (5) deep hypothermic circulatory arrest and the open distal anastomotic technique in patients with distal ascending and arch aortic disease. RESULTS: Operative mortality overall was 2/115 (1.7%). Mortality was 1/54 (1.8) in group I and 1/44 (2%) in group II, and there was no mortality in group III. The overall postoperative morbidity was 3% due to bleeding, 2% due to stroke, and 1% due to myocardial infarction. The length of stay in the past year has decreased to less than 7 days. CONCLUSIONS: The current risk for ascending aortic aneurysm repair is low (< 2%) whether or not the aortic root or valve also needs repair, regardless of the cause of the aneurysm. PMID- 8694607 TI - Influence of preconditioning on rat heart subjected to prolonged cardioplegic arrest. AB - BACKGROUND: Ischemic preconditioning (IP) can reduce lethal injury to the myocardium induced by prolonged ischemia. However, little is known about the effect of preconditioning on the heart subjected to cardioplegic arrest and hypothermic preservation. We evaluated the effect of IP on myocardial metabolism, mechanical performance, and coronary endothelial function after cardioplegic arrest and prolonged hypothermic preservation. METHODS: An isovolumic Langendorff perfused rat heart model was used, and hearts were divided into two groups. The first group (IP, n = 14) was preconditioned by 5 minutes of global normothermic (37 degrees C) ischemia followed by 10 minutes of normothermic reperfusion before 6 hours of cold (4 degrees C) preservation, followed by 60 minutes of reperfusion. The second group (control, n = 15) was subjected to 6 hours of cold preservation followed by 60 minutes of reperfusion without preconditioning. Mechanical function was assessed using left ventricular balloon by constructing pressure-volume curves in two ways: at defined left ventricular volumes or at defined left ventricular end-diastolic pressures. Initially, the volume of the balloon was increased incrementally from 0 to 150 microL in 25-microL steps. Measurements were then repeated with loading balloon to achieve left ventricular end-diastolic pressure of 5, 10, 15, or 20 mm Hg. Myocardial function was assessed before ischemia and at 15 or 60 minutes of reperfusion. Metabolic status of the heart was evaluated by measuring the release of purine catabolites during the initial 15 minutes of reperfusion and concentrations of myocardial nucleotides at the end of reperfusion. Endothelium-mediated vasodilatation was evaluated using 10 mumol/L 5-hydroxytryptamine before and after ischemia. RESULTS: Left ventricular end-diastolic pressure values were significantly lower in the IP group, by 20% to 40%, during the reperfusion phase at each volume of the balloon compared with the control group. The rate-pressure product was more favorable during reperfusion in the IP than in the control group because of a 15% increased heart rate in the IP group. The release of purine catabolites from the heart during the reperfusion phase was reduced (p < 0.01) in the IP group (0.66 +/- 0.04 mumol) relative to the control group (0.92 +/- 0.06 mumol). No difference in the recovery of systolic function, myocardial adenosine triphosphate concentration, or endothelial function was observed between the groups. CONCLUSIONS: Under conditions of cardioplegic arrest and hypothermic preservation, IP can offer additional protection for the heart by preventing an increase in diastolic stiffness. However, metabolic improvement or better preservation of the systolic or endothelial function was not observed in this model. PMID- 8694608 TI - Myocardial revascularization with the radial artery: a clinical and angiographic study. AB - BACKGROUND: It has been well documented that the use of the internal thoracic artery yields better long-term patency rates than saphenous vein grafts for coronary artery bypass grafting. This knowledge has prompted surgeons to use other arterial conduits such as the radial artery. METHODS: Between April 1994 and January 1996, radial artery grafts were used in 83 patients (mean age, 54.6 years) undergoing myocardial revascularization. All patients received diltiazem, 80 mg orally three times daily. Angiographic studies were performed in the early post-operative period in 61 patients, and 6 to 19 months later in 12 patients. RESULTS: There were four hospital deaths (4.8%), none of them due to cardiac causes. Perioperative myocardial infarction was observed in 3 patients, 1 related to a radial artery graft occlusion. Of 61 grafts studied early, 59 were patent (96.7%), but two grafts showed diffuse spasm. Twelve patients had a second angiogram after a mean interval of 8.7 months, and all grafts were patent. One patient who had a diffuse spasm at the early study had recurrent symptoms, and repeat angiogram showed further narrowing of the graft (string sign). CONCLUSIONS: Our results suggest that with proper care, the radial artery may be used for coronary artery bypass grafting with good early results. Long-term follow-up and angiography studies will be needed to establish the merit of the radial artery as a graft for coronary artery operations. PMID- 8694609 TI - Crystalloid cardioplegia route of delivery and cardiac troponin I release. AB - BACKGROUND: Cardiac troponin I (CTn I) has been shown to be a marker of myocardial injury. Incomplete distribution of cardioplegic solution may be responsible for injury in jeopardized myocardial areas. The aim of this study was to compare CTn I release with respect to the route of delivery of crystalloid cardioplegia, either antegrade only or initially antegrade followed by retrograde cardioplegia for the remainder of the operation, in patients undergoing elective coronary artery bypass grafting. METHODS: Sixty patients were randomly assigned to one of two cardioplegia groups. Cardiac troponin I concentrations were measured in serial venous blood samples drawn just before cardiopulmonary bypass and after aortic unclamping at 6, 9, 12, and 24 hours and daily thereafter for 5 days. Analysis of variance with repeated measures was performed to test the effect of route of delivery, coronary disease, collateral circulation, risk of cardioplegia maldistribution, and number of grafts on release of CTn I. RESULTS: Compared with the antegrade route, the combined route offered no advantage in an unselected group of patients undergoing an elective first cardiac operation and having preserved left ventricular function. The CTn I concentration did not differ between groups for any of the samples considered. In patients with major left main coronary artery stenosis, CTn I release was significantly higher at hour 9 in the antegrade group than in the group with combined delivery. CONCLUSIONS: A combined route of delivery of crystalloid cardioplegia is beneficial in patients with major stenosis of the left main coronary artery. Cardiac troponin I sensitivity is relevant in this study. Release of CTn I should be useful in determining the best form of myocardial protection for each patient. PMID- 8694610 TI - Early repair of postinfarction ventricular septal defect with gelatin-resorcin formol biological glue. AB - BACKGROUND: Early surgical repair of postinfarction ventricular septal defect has improved early mortality rate. Mortality remains high in patients presenting within 1 week of infarction, or when rupture has occurred in the inferior part of the septum. METHODS: We describe a surgical technique for repair of postinfarction ventricular septal defect that involves no infarctectomy: continuous suturing of a bovine pericardial patch to healthy myocardium around the infarcted area and use of gelatin-resorcin-formol biological glue as a sealant between the patch and the interventricular septum. RESULTS: We have used this technique successfully in 3 consecutive patients in whom repair was performed within 1 week of myocardial infarction. The rupture of the interventricular septum was located anteriorly in 2 patients and inferiorly in the other. They all made an uneventful recovery, and at follow-up there was no evidence of residual shunt. CONCLUSIONS: This technique can be a useful adjunct to the surgical management of this difficult group of patients. PMID- 8694611 TI - Direct and interactive effects of cardioplegic arrest and protamine on myocyte contractility. AB - BACKGROUND: Cardioplegic arrest with rewarming and protamine administration have been implicated in causing transient left ventricular dysfunction perioperatively. However, whether interactive effects between cardioplegic arrest and rewarming with protamine occur with respect to myocyte contractile processes remains unclear. Accordingly, using an isolated myocyte model, the present study tested the hypothesis that simulated cardioplegic arrest with rewarming and protamine would have direct and interactive effects on myocyte contractile function. METHODS: Left ventricular isolated myocyte contractile function was examined using computer-aided videomicroscopy under normothermic conditions (37 degrees C, cell medium; n = 183) and after simulated hypothermic, hyperkalemic cardioplegic arrest with rewarming (4 degrees C, 24 mEq/L K+, 2 hours; then 37 degrees C, cell medium, 5 minutes; n = 268). Myocyte function was then examined in the presence of protamine (10 to 40 micrograms/mL) under normothermic conditions (n = 102) and after cardioplegic arrest with rewarming (n = 175). RESULTS: Myocyte contractile function decreased by 43% from baseline after simulated cardioplegic arrest with rewarming. Under normothermic conditions, protamine (20 micrograms/mL) reduced myocyte contractile function by 43.9% +/- 4.3%, whereas myocyte contractile function decreased by only 31.1% +/- 2.7% with protamine (20 micrograms/mL) after cardioplegic arrest with rewarming. Thus, the negative effects of protamine on myocyte contractility were attenuated after cardioplegic arrest when compared with normothermic conditions. CONCLUSIONS: The present study demonstrated that simulated cardioplegic arrest with rewarming and protamine have direct and interactive effects on myocyte contractile function, which are not additive or synergistic. PMID- 8694612 TI - Postoperative management of patients with Hemopump support after coronary artery bypass grafting. AB - BACKGROUND: In this study, we describe postoperative monitoring, pharmacologic therapy, and hemodynamic responses in patients receiving Hemopump support after postcardiotomy heart failure. METHODS: The Hemopump was used in 24 patients with severe left ventricular dysfunction after coronary artery bypass grafting. RESULTS: Fourteen patients (58%) were weaned from the Hemopump. Low to moderate doses of a combination of catecholamines, phosphodiesterase inhibitors, vasodilators, and vasoconstrictors were required to optimize Hemopump function and left ventricular unloading. Mean arterial blood pressure, mixed venous oxygen saturation, and urinary output were the most important therapy guidelines. CONCLUSIONS: Together with our clinical protocol, the Hemopump effectively unloaded the failing ventricle while maintaining vital-organ perfusion. Doses of vasoactive drugs could be kept low. This approach to treatment provides good conditions for recovery of the stunned myocardium. PMID- 8694613 TI - Angiographic 5-year follow-up study of right gastroepiploic artery grafts. AB - BACKGROUND: The right gastroepiploic artery (RGEA) has been used from 1987 in coronary artery bypass grafting in several clinical studies. However, the published 1- to 5-year patency rates have been dependent on the selection of patients for angiography. METHODS: In our study, the RGEA was used from March 1987 to May 1990 for coronary artery bypass grafting in 31 consecutive patients, 25 male and 6 female. All but 1 patient had triple-vessel disease, and the mean number of distal anastomoses was 3.9 (range, 2 to 5). Internal thoracic artery grafts were used concomitantly in all patients. RESULTS: One early and two late deaths occurred. All but 1 of the 28 surviving patients underwent clinical and angiographic follow-up examinations 3 months and 5 years after the operation. The 5-year patency of RGEA grafts was 82.1%, with a 95% confidence interval of 63.1% to 93.9%. In 4 of the 5 nonvisualized cases, the recipient coronary artery showed proximal stenosis of up to 70%, allowing substantial competitive flow. The 5-year patency of the RGEA graft was near that of the left internal thoracic artery, at 90.3%, and the right internal thoracic artery, at 94.4%; and superior to the 66.7% patency of venous grafts. CONCLUSIONS: At 5-year follow-up, angiography of RGEA grafts showed good function and a smooth lumen, especially if the proximal stenosis was more than 70%. PMID- 8694614 TI - Efficacy of aprotinin with various anticoagulant agents in cardiopulmonary bypass. AB - BACKGROUND: Aprotinin has recently been approved for clinical use in cardiopulmonary bypass. Although unfractionated heparin has been the only anticoagulant widely used for cardiopulmonary bypass, disadvantages involving heparin have led to ongoing investigations of alternative anticoagulant agents. METHODS: The objective of this study was to evaluate the efficacy of aprotinin in combination with other anticoagulant agents, specifically low molecular weight heparin and recombinant hirudin, using a dog model of cardiopulmonary bypass. RESULTS: The blood conservation resulting from the use of aprotinin was observed only with unfractionated heparin. Efficacy of anticoagulation as measured by protein deposits in the bypass circuit filter revealed an unexpected reduction in the quantity of deposits when aprotinin was used in combination with low molecular weight heparin. CONCLUSIONS: As alternative anticoagulant agents are sought, the potential benefits of aprotinin in the reduction of operative blood loss must be evaluated independently for each anticoagulant agent. PMID- 8694615 TI - Sternal plating for the treatment of sternal nonunion. AB - BACKGROUND: Sternal nonunion, defined as sternal pain with clicking, instability, or both for more than 6 months in the absence of infection, is an uncommon complication of median sternotomy. Nonunion is frequently complicated by the presence of multiple transverse fractures, which make simple rewiring inadequate. METHODS: Six patients with debilitating pain secondary to sternal nonunion were treated with the technique of sternal plating between 1989 and 1995. RESULTS: Sternal plating corrected sternal instability and provided excellent pain relief in all 6 patients. All patients reported an improved quality of life and were able to resume recreational activities. Two patients have had plate removal for late bursa formation. Sternal healing was complete in both instances. CONCLUSIONS: Sternal plating, which is based on the tension-band principle, is an effective treatment of sternal nonunion. The technique is applicable to both simple and complex nonunions. The stainless steel plates resist bending stresses, and the cortical bone resists compressive forces. The technique requires minimal dissection of the posterior sternal border, is not circumferential, and provides secure sternal approximation. PMID- 8694617 TI - Assessment of endothelial preservation in human cell cultures. AB - BACKGROUND: Impairment of microcirculation due to endothelial cell damage must be considered a limiting factor in organ preservation. The present study aims at a quantitative assessment of preservation-induced injury in cultured human endothelial cells. METHODS: Monolayer cultures of human umbilical vein endothelial cells were exposed to cold (40 degrees C) hypoxic storage in University of Wisconsin solution, histidine-tryptophane-ketoglutarate solution, Euro-Collins solution, and saline solution. Cellular integrity was evaluated by viable cell count, ultrastructural analysis, and prostacyclin release after 24, 48, and 72 hours of storage and subsequent 6 hours of reincubation in culture medium at 37 degrees C. Expression of intercellular adhesion molecule-1 was investigated after 6, 12, and 24 hours of cold preservation and after 6 hours of rewarming. RESULTS: Cellular viability was best maintained with University of Wisconsin and histidine-tryptophane-ketoglutarate solutions with no significant reduction of cell count up to 72 hours; Euro-Collins solution and saline solution caused a significant decline in cell numbers after 24 hours (p < 0.05). Morphology was best preserved by University of Wisconsin solution. Prostacyclin values were elevated after 24 hours in Euro-Collins solution and saline solution, after 48 hours in histidine-tryptophane-ketoglutarate, Euro-Collins, and saline solutions, and after 72 hours in Euro-Collins solution (p < 0.05, compared with University of Wisconsin solution). ICAM expression was weak after cold storage (24 hours) in University of Wisconsin solution, moderate after incubation in histidine-tryptophane-ketoglutarate and Euro-Collins solutions and intensive after storage in saline solution. In contrast, rewarming caused intensive expression of intercellular adhesion molecule-1 in all experimental groups as compared with controls, which showed baseline expression at any time. CONCLUSIONS: From our results we conclude that in this model cellular integrity is best protected by University of Wisconsin solution, increased prostacyclin release is consistent with morphologic alterations and intercellular adhesion molecule-1 expression is clearly up-regulated in endothelial cells under reperfusion conditions after cold hypoxic storage. PMID- 8694618 TI - In vitro effect of hemodilution on activated clotting time and high-dose thrombin time during cardiopulmonary bypass. AB - BACKGROUND: Extreme dilution of clotting factors, as may occur during pediatric or neonatal cardiopulmonary bypass, often leads to inadequate monitoring of anticoagulation with activated clotting time (ACT). In this study we postulate that the high-dose thrombin time (HiTT) is less influenced by extreme dilution of clotting factors because it stimulates clotting through the common pathway. METHODS: Heparinized prebypass blood was obtained from 30 adult cardiac surgical patients and was diluted in a laboratory setting with saline solution to mimic the clinical clear prime solution (group I; n = 10), with saline solution containing similar heparin as in the prebypass blood (group II; n = 10), and with fresh frozen plasma to substitute clotting factors in the diluted blood (group III; n = 10). Blood was diluted to four different degrees: a control without dilution, 25%, 50%, and 75% dilution. The ACT and HiTT were measured and compared. RESULTS: In group I, significant prolongation of ACT was observed in blood diluted to 75% as compared with the nondiluted blood (p < 0.01). In contrast, HiTT was not prolonged at any degree of dilution but reduced proportionally to dilution up to 75%, reflecting the concomitant reduction of heparin. In group II, ACT increased at 25% dilution (p < 0.01) whereas HiTT increased at 50% dilution (p < 0.01). In group III, no prolongation of ACT or HiTT was found in any degree of dilution. Furthermore, adding fibrinogen to the diluted blood (n = 4) did not cause ACT to recover at 75% dilution, suggesting that dilution of other factors in the early clotting cascade rather than fibrinogen alone increases ACT. CONCLUSIONS: These results imply that when blood is extremely diluted during cardiopulmonary bypass with a clear prime without substituted clotting factors, HiTT is a better test than ACT for anticoagulation monitoring. PMID- 8694616 TI - Correction of complete atrioventricular septal defects with the double-patch technique and cleft closure. AB - BACKGROUND: Controversy continues to surround determining which is the most beneficial method of complete atrioventricular septal defect repair, eg, one- versus two-patch repair, closure of mitral cleft, and the necessity of annuloplasty. METHODS: Between January 1988 and November 1995, 120 patients with complete atrioventricular septal defect underwent total correction at the German Heart Institute Berlin. Sixty-nine of the patients were infants and 51 were children or adolescents. Eleven patients had previously undergone pulmonary artery banding. One hundred three patients had Down's syndrome. In all 120 patients complete atrioventricular septal defect repair was performed using the two-patch technique. The mitral cleft was closed with interrupted sutures in 119 cases. RESULTS: Thirty-four patients required aggressive treatment of postoperative pulmonary hypertensive crises (including nitric oxide inhalation). There were 12 hospital deaths (10%). Mortality was highest in patients with persistently high postoperative pulmonary arterial pressure (pulmonary artery pressure/systemic artery pressure > 0.6) (7 of 17 patients died; 41%). Associated atrioventricular valve anomalies, especially dysplastic valve tissue and severe preoperative cardiopulmonary instability necessitating catecholamine support and artificial ventilation, represented other risk factors. There were six late deaths (5%); cumulative mortality was 15%. Four patients suffered a complete heart block and sick sinus node syndrome necessitating pacemaker implantation 1 to 6 months after operation. During the follow-up period (3 to 80 months after operation), 7 patients (6.8% of survivors) were successfully reoperated on after significant mitral valve incompetence due to an open "cleft" (suture failure) developed. CONCLUSIONS: Correcting complete atrioventricular septal defect using the two-patch technique, routine cleft closure, and atrial septal incision led to a low incidence of residual mitral valve incompetence. Mortality was primarily influenced by severe cardiopulmonary instability and additional atrioventricular valve anomalies preoperatively and the persistence of high pulmonary arterial hypertension postoperatively. PMID- 8694620 TI - Transient ischemia cannot precondition the rabbit heart against postischemic contractile dysfunction. AB - BACKGROUND: The rat heart is preconditioned against postischemic contractile dysfunction by a brief period of transient ischemia before a prolonged ischemic period. However, the rabbit heart does not receive such cardio-protection from pretreatment with a single transient ischemia periods. We hypothesized that in the rabbit heart, a multiple cycle of transient ischemia is required to reach a threshold necessary to precondition against postischemic contractile dysfunction. METHODS: To test this hypothesis, we subjected isolated, perfused rabbit hearts to either one 5-minute transient ischemic period or three 5-minute transient ischemic periods followed by a 40-minute period of warm ischemia and 30 minutes of reperfusion. Control hearts (no pretreatment with transient ischemia) were examined simultaneously. Left ventricular developed pressure was measured with an intraventricular balloon. RESULTS: Postischemic recoveries (expressed as percent of preischemic values) of left ventricular developed pressure for the group with one ischemic period and the group with three ischemic periods were 43% +/- 5% (n = 5) and 38% +/- 6% (n = 6), respectively. These values were not significantly different from control values. CONCLUSIONS: Neither one nor three periods of transient ischemia protect the isolated, perfused rabbit heart from postischemic contractile dysfunction. Therefore, the rabbit heart may not have the capacity to be ischemically preconditioned against postischemic contractile dysfunction. PMID- 8694619 TI - Acute-phase responses to cardiopulmonary bypass in children weighing less than 10 kilograms. AB - BACKGROUND: Cardiopulmonary bypass induces a systemic inflammatory response. This study investigated, in a pediatric population, cytokine-induced responses and their potential modification by intraoperative steroid administration. METHODS: Markers of the acute-phase response were measured perioperatively in 24 children weighing less than 10 kg undergoing cardiac operations. Those having operations with cardiopulmonary bypass were randomized to receive either no steroid (group I, n = 8) or 10 mg/kg methylprednisolone in the pump prime (group II, n = 10); patients undergoing nonbypass procedures were controls (group III, n = 6). RESULTS: In all groups, plasma interleukin-6 level was elevated (p < 0.01) above baseline throughout the post-operative period, peaking earlier in group I. Levels of C-reactive protein peaked at 48 hours, and postoperative core temperature was raised in all groups. Levels of interleukin-6 from 2 to 6 hours and C-reactive protein at 24 hours postoperatively were greater (p < 0.05) in group I than in group II. Maximum interleukin-6 level, C-reactive protein level, and temperature were all significantly greater in group I than in group III. Maximum interleukin 6 level correlated with maximum C-reactive protein level in group I only (rs = 0.76; p < 0.05) and showed no association with temperature. Duration of bypass did not correlate with levels of interleukin-6. CONCLUSIONS: This study demonstrated a marked acute-phase response to operation; the greater response to procedures with cardiopulmonary bypass was abrogated by intraoperative steroid administration. The importance of interleukin-6 as an inducer of acute phase proteins after bypass is supported by its association with C-reactive protein levels, but other factors must be important in the induction of pyrexia. PMID- 8694621 TI - Surgical angioplasty of the left main coronary artery: follow-up with magnetic resonance imaging. AB - BACKGROUND: Ostial stenosis of the left main coronary artery is a serious condition with a dismal prognosis. The treatment is surgical, with the two viable options being coronary artery bypass grafting and surgical angioplasty of the left main coronary artery. METHODS: We describe the use of surgical angioplasty to treat 3 patients (2 women and 1 man) with left main ostial stenosis using the posterior approach. Patency of the angioplasty was demonstrated subsequently with magnetic resonance imaging. RESULTS: All 3 patients were free of angina 12, 18, and 24 months after operation. Magnetic resonance imaging scans in all 3 patients demonstrated the widely patent left main coronary artery. CONCLUSIONS: Surgical angioplasty is an effective alternative to coronary artery bypass grafting in patients with left main ostial stenosis. Magnetic resonance imaging is an excellent noninvasive method for monitoring the patency of the left main coronary artery. PMID- 8694622 TI - Thrombomodulin and angiotensin-converting enzyme activity during pediatric open heart operations. AB - BACKGROUND: Thrombomodulin and angiotensin-converting enzyme are endothelial glycoproteins. The metabolism of these substances is altered when endothelial cells are damaged. METHODS: Serum thrombomodulin level was assayed in 56 children and angiotensin-converting enzyme activity determined in 27 children with congenital heart disease before, during, and after open heart operations. RESULTS: The thrombomodulin level was significantly higher in children with a high pulmonary blood flow who had pulmonary hypertension than in those with a normal pressure (p < 0.01), and although all patients showed an increase in serum thrombomodulin after coming off cardiopulmonary bypass, the increase was greater in those with preoperative pulmonary hypertension (p < 0.05). Serum angiotensin converting enzyme activity was normal preoperatively in all children, irrespective of pulmonary arterial pressure, and decreased in all after coming off cardiopulmonary bypass but decreased to a significantly greater extent in those who had pulmonary hypertension preoperatively (p < 0.05). CONCLUSIONS: These findings are compatible with the presence of pulmonary endothelial cell injury and dysfunction before intracardiac repair, which is exacerbated by cardiopulmonary bypass. PMID- 8694623 TI - Primary cardiac tumors in infants and children: immediate and long-term operative results. AB - BACKGROUND: The literature contains few large or long-term series involving infants and children with primary cardiac tumors. This article summarizes our 35 year experience with such lesions. METHODS: Between January 1961 and January 1996, 40 infants and children (mean age, 3.3 years; range, 2 days to 17 years; 65% female) were diagnosed at our institution with primary cardiac tumors. Of these tumors, 37 (92%) were benign and 3 (8%) were malignant. Tumors were resected in 38 patients (95%). In 2 patients (5%), biopsy confirmed rhabdomyoma; however, presenting symptoms spontaneously resolved, so these patients did not undergo tumor resection. Follow-up echocardiographic studies showed a diminishing tumor mass in each of these patients. RESULTS: Immediate, symptom-free status was achieved in all patients. There were two early deaths, for an operative mortality of 5%. Three late postoperative deaths (7.5%) occurred as follows: 1 patient with a myocardial hamartoma died at 3 months of congestive heart failure. Another patient with a recurrent rhabdomyosarcoma died at 6 months, and a third patient with a recurrent fibrosarcoma died at 28 months. Long-term follow-up was available for 34 survivors (97% complete) and totaled 240.2 patient-years (mean, 7.1 years/patient). All remaining survivors were without evidence of presenting symptoms and tumor recurrence or progression. CONCLUSIONS: The data suggest that an aggressive operative approach is warranted for benign symptomatic and malignant tumors. This aggressive approach has resulted in extended symptom-free status in patients with benign lesions, and significant palliation and longer survival in patients with malignant lesions, with acceptably low operative risk. PMID- 8694624 TI - Blalock-Taussig operation with an assist of venovenous extracorporeal membrane oxygenation. AB - Three infants with congenital cyanotic heart disease encountered severe hypoxemia during a Blalock-Taussig shunt procedure using a right thoracotomy approach. Pericardiotomy was performed and venovenous extracorporeal membrane oxygenation was instituted using right atrial canulation. The shunt procedure was completed with good oxygenation and hemodynamic stability in all cases. Venovenous extracorporeal membrane oxygenation can be easily established in the right thorax, and is an effective support technique for unexpected hypoxemia encountered during systemic-to-pulmonary artery shunt operations. PMID- 8694625 TI - Absent right superior vena cava with hypoplastic proximal inferior vena cava. AB - We describe the precise preoperative diagnosis of a very rare anomaly that comprises absence of the right superior vena cava, persistence of the left superior vena cava, and proximal hypoplasia of the inferior vena cava draining into the left superior vena cava via the hemiazygos vein associated with a large atrial septal defect and tricuspid regurgitation. PMID- 8694626 TI - Revascularization of the ischemic gastric tube using the left internal thoracic artery. AB - Ischemia of the gastric tube during use as an esophageal substitute may have serious consequences. We describe a method to correct substernal gastric tube ischemia using the left internal thoracic artery as a source of arterial inflow to a short gastric artery. This permitted successful reconstruction of the upper alimentary tract in this patient. PMID- 8694627 TI - A technique of positive-pressure single-lung ventilation via a silicone T-Y stent. AB - Airway control and protection, in any operation, is the first priority. The presence of a T-Y stent in the proximal airway can complicate this fundamental principle. Here we describe an effective and safe technique for positive-pressure single-lung ventilation via a T-Y stent for a lung lobectomy. PMID- 8694628 TI - Tetralogy of Fallot with total anomalous pulmonary venous drainage and esophageal atresia: complete correction in infancy. PMID- 8694629 TI - Complete congenital sternal cleft in an adult: repair by autogenous tissues. AB - We are reporting here a rare case of congenital complete sternal cleft in an adult of 25 years of age, with absent anterior pericardium and "diastasis recti." Successful surgical repair was achieved along with the preservation of the already existing anatomic and mechanical sanctity of thoracic cage, sternal reconstruction, and protection of the underlying heart and great vessels with a good cosmetic result using autogenous tissue i.e., iliac bone and "V-Y" myoplasty of pectoralis major muscles with their functional preservation and correction of associated anomalies. PMID- 8694630 TI - Cardiac tamponade due to spontaneous rupture of right coronary artery aneurysm. AB - A case of acute cardiac tamponade caused by spontaneous rupture of a right coronary artery aneurysm is reported. The aneurysm, which was present distally, was ligated during operation. Postoperative angiography suggested the aneurysm was congenital. The patient is doing well 5 months after operation. PMID- 8694631 TI - Occult ascending aortic rupture in the presence of an air bag. AB - A patient presented to the emergency department after a high-speed decelerating type motor vehicle accident. Due to activation of his air bag device, the patient was without significant obvious injury. Upon evaluation in the emergency department he was also without any radiographic or physical signs of serious injury. In the ensuing 24 hours, severe chest pain developed, and subsequent aortography demonstrated a tear of his ascending aorta just distal to the root. Although occult injury to the aorta and great vessels does occur in a small percentage of patients, it is quite rare. However, with the advent of air bags, in the absence of associated injuries, signs, and symptoms, a high index of suspicion must be entertained in decelerating-type accidents to diagnose occult injury to the aorta and great vessels. PMID- 8694632 TI - Biventricular assist device as a bridge to transplantation in a pediatric patient. AB - A 5 1/2-year-old boy with idiopathic cardiomyopathy and rapidly worsening hemodynamic parameters underwent placement of a biventricular assist device as a bridge to transplantation. Direct anastomoses to both the aorta and pulmonary artery with Dacron grafts attached to Carmeda-coated tubing facilitated the support period. Inflow was provided by right atrial appendage and left ventricular apex cannulas. A centrifugal pump provided support for 2 days until a suitable donor was identified. The technique is simple, reproducible, and effective for patients with small body surface areas. PMID- 8694633 TI - Complicated right subclavian artery pseudoaneurysm after central venipuncture. AB - Life-threatening complications of central venipuncture are rare. We report an unusual case of a patient in whom a large right subclavian pseudoaneurysm developed, causing pressure necrosis of the membranous trachea and esophagus, after right internal jugular vein cannulation. The patient underwent oversewing of the proximal and distal ends of the subclavian artery and primary tracheal repair. An esophageal leak that presented on the sixth postoperative day was treated by primary suture repair with proximal and distal diversion. PMID- 8694634 TI - Intermittent hypoxia due to right atrial compression by an ascending aortic aneurysm. AB - Two cases are described wherein right atrial compression from a dilated and elongated ascending aorta caused intermittent positional hypoxia. Extrinsic compression of the right atrium caused shunting though a patent foramen ovale. PMID- 8694635 TI - Successful management of junctional tachycardia by hypothermia after a Fontan operation. AB - We report herein the findings of a 2-year-old boy in whom junctional tachycardia developed 2 days after he underwent a modified Fontan operation and thereafter was successfully treated by hypothermia without paralyzing and artificially ventilating the patient. Chlorpromazine was useful in achieving moderate hypothermia by surface cooling without producing any unfavorable effects associated with topical cooling. PMID- 8694636 TI - Catamenial pneumothorax caused by thoracic endometriosis. AB - A 28-year-old woman presented with monthly returning thoracic pain and cough. Catamenial pneumothorax was diagnosed. Thoracoscopy showed multiple nodules on the diaphragm, parietal pleura and lung itself, which proved to be thoracic endometriosis. Thoracoscopy is a useful procedure for diagnosis and treatment of this rare condition. PMID- 8694637 TI - Arterial switch operation: myocardial ischemia reversed by internal mammary artery graft. AB - We report a case in which an internal mammary artery graft to the left anterior descending coronary artery was successfully used in a newborn boy to reverse life threatening myocardial ischemia 24 hours after arterial switch operation. One year later, angiography showed patency of both the graft and the transposed coronary ostium with normal left ventricular function. A brief review of the literature shows encouraging results of internal mammary artery grafts in pediatric patients. PMID- 8694638 TI - Aortoesophageal fistula after repair of descending aortic dissection. AB - The development of aortoesophageal fistula after aortic repair is rare. We describe a patient who presented with hematemesis 4 months after emergent repair of a descending thoracic aortic dissection using a prosthetic graft. Diagnosis was supported by computed tomographic, angiographic, and endoscopic findings. Resection of the involved graft was performed through a left thoracotomy after placement of an ascending aorta-to-abdominal aorta conduit through an anterior approach. The patient died of uncontrollable bleeding a few hours after the procedure. Surgical intervention offers the potential for cure in this otherwise uniformly fatal condition. But like medical therapy, operative management has thus far been associated with 100% mortality. PMID- 8694639 TI - Successful conduit repair using aortic homograft in a Jehovah's Witness child. AB - A 10-year-old female child of the Jehovah's Witness faith presented with congenitally corrected transposition of the great arteries (S,L,L), pulmonary atresia, and a ventricular septal defect. A successful surgical correction was performed using an aortic homograft as a valved extracardiac conduit without the use of homologous blood or blood products. We used permanent splinting of the sternum with a methyl methacrylate resin plate to prevent compression of the conduit. PMID- 8694640 TI - Revascularization using angioplasty and minimally invasive techniques documented by thermal imaging. AB - Minimally invasive direct coronary artery bypass grafting offers mortality and morbidity advantages to selected patients. To broaden indications for such, an appropriate and combined disciplinary approach using angioplasty and minimally invasive direct coronary artery bypass grafting is described in a patient requiring reoperative grafting. Documentation of patency of new left internal mammary artery-to-left anterior descending artery anastomoses performed without the use of cardiopulmonary bypass was obtained intraoperatively using a Thermal Imaging Camera. PMID- 8694641 TI - Pacemaker lead placement via a small cephalic vein. AB - The development of implantable defibrillators with single lead systems has necessitated the need for larger transvenous electrodes. This article describes a modified Seldinger technique that can be used when the cephalic vein is too small to allow passage of these larger leads. When successful, the procedure eliminates the need for direct needle cannulation of the subclavian vein and the accompanying risk of pneumothorax. PMID- 8694642 TI - Minimally invasive approach for aortic valve operations. PMID- 8694643 TI - Mismatch of aortotomy and saphenous vein graft size: a simple solution. AB - Bleeding may occur at the proximal anastomosis of an aortocoronary bypass graft due to the aortotomy being larger than the vein graft diameter. This results in the wall of the vein being under tension, so that the anastomotic suture or further stitches may cut through. A partial thickness suture placed as a pursestring around the aortotomy may alleviate this situation, resulting in a smaller aortotomy with reduced vein wall tension, improved hemostasis, and a more satisfactory anastomotic vein contour. PMID- 8694644 TI - Memories of a scrub nurse. PMID- 8694646 TI - Strategic directions plan--1996. Ad Hoc Committee on Strategic Directions, The Society of Thoracic Surgeons. PMID- 8694645 TI - The current status of lung volume reduction operations for emphysema. AB - In the 1990s, the concept of surgical therapy was introduced once again for the treatment of end-stage emphysema. The earliest reports touted laser ablation of emphysematous lung as definitive therapy. Although some discernable benefit was reported, this was associated with significant operative morbidity. In 1993, the concept of parenchymal resection or "lung volume reduction" was reintroduced as treatment for end-stage lung disease. Over the ensuing 3 years, different techniques and approaches have evolved at different institutions. Lung volume reduction has been performed bilaterally and unilaterally through multiple approaches including sternotomy, thoracotomy, and thoracoscopy. The results of these various approaches are reviewed and compared. Lung volume reduction appears to be a beneficial procedure when performed in carefully selected patients by personnel and at institutions that are experienced in the care of patients with end-stage emphysema. PMID- 8694647 TI - Female sex: a strong marker of increased cardiac risk. PMID- 8694648 TI - Potassium conversion of ventricular fibrillation. PMID- 8694649 TI - Omniscience valve evolution and literature. PMID- 8694650 TI - Unidirectional valve patch. PMID- 8694651 TI - Coronary artery bypass grafting without cardiopulmonary bypass. PMID- 8694652 TI - Improved sternal osteosynthesis using any sternal retractor. PMID- 8694653 TI - The origins of successful closed valvular surgery. PMID- 8694654 TI - Internal mammary artery atherosclerosis fifteen years after correction of aortic coarctation. PMID- 8694655 TI - Right ventricular failure. PMID- 8694656 TI - Intercostal pedicle flap in tracheobronchial surgery. PMID- 8694657 TI - VATS is not thoracoscopy. PMID- 8694658 TI - The revolution and evolution of prehospital cardiac care. AB - Prehospital cardiac care, first established in Belfast, Northern Ireland, in 1966, may be called revolutionary in that it was a radical break from existing practices. The Belfast program "moved" the coronary care unit into the community by treating the early complications of acute myocardial infarcation. The program staffed a mobile coronary care unit with a physician and nurse and demonstrated that patients with out-of-hospital sudden cardiac arrest could be resuscitated. The idea of prehospital cardiac care spread to other countries after publication of the Belfast experience in the Lancet. The first program in the United States, stationed at St Vincent's Hospital in New York, NY, began in 1968 and was modeled after the Belfast program. The physician-staffed model, however, was not widely imitated in the United States. Rather, beginning in 1969, programs using specially trained personnel, know as paramedics, began in Miami, Fla, Seattle, Wash, Columbus, Ohio, Los Angeles, Calif, Portland, Ore, and Nassau County, New York. Paramedic-staffed programs were designed not only to treat early complications of acute myocardial infarction, but also to attempt resuscitation for primary cardiac arrest. Most of the early paramedic programs were based in fire departments. Other programs used private ambulance or police personnel. Prehospital cardiac care has evolved significantly in the past 3 decades. Some notable developments include the tiered response system, training of the general public in cardiopulmonary resuscitation, low-energy defibrillators, automatic external defibrillators, and 12-lead electrocardiographic telemetry. The basic lesson of prehospital cardiac care is that the timely provision of cardiopulmonary resuscitation and defibrillation saves lives. PMID- 8694659 TI - NSAID gastropathy. A new understanding. AB - Nonsteroidal anti-inflammatory drug (NSAID) gastropathy is associated with substantial morbidity and mortality, which result in high costs to both the patient and society. The subset of patients who are at greatest risk for developing NSAID gastropathy continues to be better defined, but various risk factors, such as age and previous gastrointestinal tract disease, have been identified. In patients receiving older NSAIDs, the choice of NSAID should be based on differences in formulations at the lowest effective dose. Gastroprotective cotherapy should be instituted if treatment with older NSAIDs is continued in at-risk patients; misoprostol is currently the only agent approved for this indication. The impact of misoprostol on clinical gastrointestinal tract end points has recently been documented. Newer NSAIDs may have an improved safety profile over older NSAIDs; some have a clinically documented reduction in the incidence of adverse gastrointestinal tract effects. An understanding of these issues should enable the informed clinician to choose an NSAID on the basis of risk-benefit and cost-benefit considerations. PMID- 8694660 TI - Renal tubular acidosis. Pathophysiology and diagnosis. AB - The pathophysiology of renal tubular acidosis is slowly being unraveled, which has implications for the traditional classification of the condition. Nonetheless, the diagnosis of renal tubular acidosis is still easy to establish, and identification of the specific pathophysiological subtype is relatively straightforward. The diagnostic information required usually includes only urinary pH and sodium, potassium, and chloride concentrations and serum potassium level. The urinary pH is not a diagnostic test for renal tubular acidosis, but it serves to distinguish between the various subtypes. PMID- 8694661 TI - How safe are folic acid supplements? AB - Periconceptual use of folic acid supplements by women is effective in preventing neural tube defects in the fetus. Folic acid supplements also may prevent atherosclerosis and some malignant neoplasms. Nevertheless, safety concerns have delayed recommendations to increase folic acid consumption by the general population. Among the potential safety issues of folic acid supplementation are (1) difficulty identifying cobalamin deficiency, precipitation of neurologic complications of cobalamin deficiency, and lowering of cobalamin levels; (2) folate neurotoxicity; (3) antagonism of drugs that inhibit folate metabolism; (4) reduced zinc absorption; (5) association with malignant neoplasms; (6) hypersensitivity reactions; and (7) increased susceptibility to malaria. The data that suggest that folic acid supplements are unsafe are weak and consist predominantly of case series and reports. Nevertheless, greater difficulty diagnosing cobalamin deficiency due to "masking" of hematologic abnormalities by folic acid is a potential risk. Strict vegetarians need to be informed that they are at risk of cobalamin deficiency. Physicians need to be aware that routine hematologic indexes have a low sensitivity for cobalamin deficiency, especially in patients who are receiving folic acid supplements. Because no high-quality data exclude specific adverse effects, physicians should be vigilant in identifying detrimental effects when patients increase their consumption of folic acid. PMID- 8694662 TI - The effectiveness of implementing the weight-based heparin nomogram as a practice guideline. AB - OBJECTIVE: To determine the effectiveness of the nomogram in a community hospital that implemented it as a practice guideline. DESIGN: A nonexperimental, retrospective time series. SETTING: A 600-bed community teaching hospital and regional referral center in Phoenix, Ariz. PATIENTS: The study population included 591 consecutive patients with venous thromboembolism, treated over a 5 year study period. METHODS: During this period, the weight-based heparin nomogram was adapted into a preprinted order sheet and distributed to the hospital wards. The main outcome variables were the time to achieve a therapeutic activated partial thromboplastin time and the rate of bleeding complications. RESULTS: Voluntary implementation of the nomogram steadily increased, reaching 94%. Comparison of the periods before and after 50% implementation demonstrated an increase in initial heparin dose (1185 vs 1420 U/h, P < .001), a decrease in time to achieve therapeutic activated partial thromboplastin time (19.6 vs 11.8 hours), a decrease in the variance of this parameter (25 vs 4 hours, P < .001), and no change in bleeding rates. The proportion of patients achieving a therapeutic activated partial thromboplastin time within 24 hours decreased from 97% to 86% when the results from our previous randomized controlled trial (efficacy) are compared with the present results (effectiveness). CONCLUSIONS: The weight-based heparin nomogram was well accepted by clinicians at our institution and led to more aggressive heparin dosing and improvements in intermediate outcomes, without increasing bleeding. Mitigation of benefit is likely to occur when practice guidelines are moved from the realm of efficacy research into clinical practice. Therefore, the effectiveness of such measures requires monitoring. PMID- 8694663 TI - Prevalence of hypercholesterolemia among siblings of persons with premature coronary heart disease. Application of the Second Adult Treatment Panel guidelines. AB - BACKGROUND: Increased blood cholesterol, specifically high low-density lipoprotein cholesterol, increases risk for coronary heart disease (CHD). Persons with a positive family history of premature CHD also are at markedly increased risk. OBJECTIVE: To examine the prevalence of hypercholesterolemia based on the second report of the National Cholesterol Educational Program Adult Treatment Panel (ATP II) guidelines in the asymptomatic healthy siblings of people with premature CHD. METHODS: A total of 668 asymptomatic healthy siblings (354 men and 314 women) underwent screening for risk factors for CHD. Siblings were categorized into treatment categories for primary prevention defined by ATP II. The percentage who were candidates for intervention were compared with the published national estimates for those without CHD from the third National Health and Nutrition Examination Survey (NHANES III). RESULTS: Based on ATP II guidelines, 65% of the asymptomatic adult siblings required fasting lipoprotein analysis compared with 33% of adults without CHD in the national reference population. Of the siblings who met the criteria for fasting lipoprotein analysis, most (56%) were candidates for dietary therapy, more than twice the proportion of adults from NHANES III. The percentage of the siblings who qualified for drug intervention and dietary therapy was 3 times greater than the national sample, 33% vs 11%, respectively. Assuming a 10% hypothetical reduction in low-density lipoprotein cholesterol levels as the result of dietary modification, the proportion of the sibling sample who were possible candidates for drug therapy was 20%, still 4 times that predicted for the national sample. CONCLUSIONS: These results underscore the need for aggressive detection and treatment of hypercholesterolemia in this easily identifiable high-risk population of siblings of people with premature CHD. PMID- 8694664 TI - Antithrombotic strategy after total hip replacement. A cost-effectiveness analysis comparing prolonged oral anticoagulants with screening for deep vein thrombosis. AB - BACKGROUND: Deep vein thrombosis (DVT) in the lower limbs is a major postoperative complication in patients undergoing total hip replacement. However, even with the most effective perioperative antithrombotic prophylactic methods, its incidence at the time of hospital discharge remains as high as 15 to 25. METHODS: We used a decision analysis model to determine the clinical and economic effects of the following interventions: (1) stopping prophylactic antithrombotic therapy after the in-hospital perioperative period (7-14 days), (2) extending prophylactic antithrombotic therapy with oral anticoagulants up to 6 weeks or 3 months, and (3) screening for DVT at the time of hospital discharge by compression ultrasonography or venography. We measured for a hypothetical cohort of 10 000 patients the risk of developing recurrent DVT and symptomatic pulmonary embolism, the risk of major bleeding complications, and the costs associated with each strategy. Data were drawn from the published literature (MEDLINE search) and from our hospital cost manager. RESULTS: Compared with stopping prophylaxis at the time of hospital discharge, a 6-week course of prophylactic oral anticoagulant therapy would reduce the number of cases of recurrent DVT from 1172 to 493 and the number of symptomatic pulmonary embolisms from 234 to 99, and would be less costly. This gain would be achieved at the cost of 29 major bleeding complications if the bleeding risk is low (0.2 per month) and 71 if the bleeding risk is moderate (0.5 per month). Compared with stopping prophylaxis at discharge, ultrasound screening would reduce symptomatic pulmonary embolisms from 234 to 142, induce only 13 major bleeding episodes, and be cost-effective, with marginal costs per additional pulmonary embolism averted ranging from $3000 to $7000, depending on ultrasound sensitivity. Venography screening would be the most effective strategy; however, compared with ultrasound, its marginal costs per additional pulmonary embolism averted would exceed $80 000. CONCLUSIONS: After hip replacement with conventional perioperative antithrombotic prophylaxis, oral anticoagulation administered for 6 weeks is effective in preventing recurrent DVT and symptomatic pulmonary embolism, unless the bleeding risk is very high. Moreover, this strategy is less costly compared with stopping antithrombotic prophylaxis at the time of hospital discharge. Alternatively, ultrasound screening is also effective, minimizes the risks of bleeding, and has a low marginal cost-effectiveness ratio. PMID- 8694665 TI - Mortality risk and patterns of practice in 4606 acute care patients with congestive heart failure. The relative importance of age, sex, and medical therapy. Clinical Quality Improvement Network Investigators. AB - OBJECTIVE: To define contemporary patterns of risk and management among patients with congestive heart failure (CHF). METHODS: Cross-sectional records audit of 4606 hospitalized patients with CHF in 1992 and 1993. RESULTS: Overall medication use was diuretics, 82%; angiotensin-converting enzyme inhibitors, 53%; nitrates, 49%; digoxin, 46%; potassium, 40%; acetylsalicylic acid, 36%; calcium antagonists, 20%; warfarin, 17%; beta-blockers, 15%; and magnesium, 10%. Angiotensin-converting enzyme inhibitors were used less frequently in women and patients 70 years or older (P < .01). Total in-hospital mortality was 19%. The most common single cause of death was CHF progression, but noncardiac causes accounted for 30% of all deaths. Logistic regression analysis revealed age 70 years or older and the use of magnesium and nitrates to be associated with increased relative risk of in-hospital mortality; angiotensin-converting enzyme inhibitors, acetylsalicylic acid, calcium antagonists, beta-blockers, and warfarin were associated with decreased risk. CONCLUSIONS: Hospitalized patients with CHF have high all-cause mortality risk and less than optimal use of proven efficacious therapy, particularly among women and the elderly. Increased use of proven CHF therapy would likely decrease the risk of cardiac events, but the competing non-cardiac risks in this patient population are high and may not be affected by improved use of efficacious cardiac therapies. PMID- 8694666 TI - The relation between the activated partial thromboplastin time response and recurrence in patients with venous thrombosis treated with continuous intravenous heparin. AB - BACKGROUND: It is unknown whether the true risk of recurrent venous thromboembolism (VTE) is increased in patients with proximal deep vein thrombosis who are treated with continuous intravenous heparin and fail to reach a therapeutic activated partial thromboplastin time (APTT) within 24 to 48 hours of initiation of treatment. METHODS: To compare the risk of recurrent VTE in patients with early subtherapeutic APTT results and those with APTT results above the lower limit of the therapeutic range, we performed a formal review of the literature. We examined all available studies that provided information on the relation between the risk of recurrent VTE and the APTT response to heparin when initiated as a bolus followed by a continuous intravenous infusion of at least 30 000 U/24 h. RESULTS: Five studies were included in the final analysis. The overall recurrence rate was 6.3% in patients whose APTT results were subtherapeutic for the first 24 to 48 hours and 7% in patients whose APTT results were above the lower limit of the therapeutic range, providing a pooled odds ratio of 0.89 with a 95% confidence interval of 0.2 to 4.0. CONCLUSIONS: In patients with VTE who are treated with a bolus of heparin followed by a continuous intravenous infusion of at least 30 000 U/24 h, no convincing evidence shows that the risk of recurrent VTE is critically dependent on achieving a therapeutic APTT result at 24 to 48 hours. PMID- 8694667 TI - Risk factors for domestic acquisition of legionnaires disease. Ohio legionnaires Disease Group. AB - BACKGROUND: Legionnaires disease is a common cause of adult pneumonia. Outbreaks of legionnaires disease have been well described, but little is known about sporadically occurring legionnaires disease, which accounts for most infections. Exposure to contaminated residential water sources is I plausible means of disease acquisition. METHODS: Employing a matched case-control study design in 15 hospitals in 2 Ohio counties, we prospectively enrolled 146 adults diagnosed as having nonepidemic, community-acquired legionnaires disease and compared each with 2 hospital-based control patients, matched for age, sex, and underlying illness category. An interview regarding potential exposures was followed by a home survey that included sampling residential sources for Legionella. Interview and home survey data were analyzed to estimate the risk of acquiring legionnaires disease associated with various exposures. RESULTS: Multivariate analysis showed that a nonmunicipal water supply (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.17-4.37), recent residential plumbing repair (OR, 2.39; 95% CI, 1.10 5.18), and smoking (OR, 3.48; 95% CI, 2.09-5.79) were independent risk factors for legionnaires disease. Univariate analysis suggested that electric (vs gas) water heaters (OR, 1.97; 95% CI, 1.10-3.52), working more than 40 hours weekly (OR, 2.13; 95% CI, 1.12-4.07), and spending nights away from home before illness (OR, 1.68; 95% CI, 1.03-2.74) were additional possible risk factors. Lower chlorine concentrations in potable water and lower water heater temperatures were associated with residential Legionella colonization. CONCLUSIONS: A proportion of sporadic cases of legionnaires disease may be residentially acquired and are associated with domestic potable water and disruptions in residential plumbing systems. Potential strategies to reduce legionnaires disease risk include consistent chlorination of potable water, increasing water heater temperatures, and limiting exposure to aerosols after domestic plumbing repairs. PMID- 8694668 TI - Effect of hormone replacement therapy on lipoprotein(a) and lipid levels in postmenopausal women. Influence of various progestogens and duration of therapy. AB - BACKGROUND: Estrogen replacement therapy in postmenopausal women reduces the risk of coronary artery disease. One of the possible mechanisms of this effect is the modification of lipid profiles. However, there is controversy concerning the effects on lipoprotein(a) [Lp (a)] and lipid levels of progestogens administered with estrogen. METHODS: Five hundred fifty-one postmenopausal women were divided into 5 groups: group 1, 0.625 mg of conjugated equine estrogen (CEE) (n = 140); group 2, 0.625 mg of CEE plus 5 mg of medroxyprogesterone acetate (MPA) (n = 97); group 3, 0.625 mg of CEE plus 10 mg of MPA (n = 109); group 4, 2 mg of estradiol valerate plus 0.5 mg of norgestrel (n = 134); and group 5, control (n = 71). The Lp(a) and lipid levels were measured before and 2, 6, and 12 months after hormone replacement therapy. RESULTS: Estrogen replacement therapy for 12 months lowered the Lp(a) level by 37.1%. The addition of progestogen attenuated the Lp(a) lowering effect of estrogen. The high-density lipoprotein cholesterol (HDL-C) level was markedly increased in group 1 (16.5%), was moderately increased in groups 2 (10.8%) and 3 (11.3%), and was not changed in group 4. The low-density lipoprotein cholesterol level was decreased by 10.9% to 17.6% in all the treatment groups. Estrogen replacement therapy for 2, 6, and 12 months raised the HDL-C level by 7.2%, 17.4%, and 17.8%, respectively. In the group with combined estradiol plus norgestrel therapy, the HDL-C level was decreased after 2 months and was not changed after 6 and 12 months. The groups that received CEE plus MPA showed intermediate effects between the group that received CEE only and the group that received estradiol plus norgestrel. CONCLUSIONS: Combined estrogen and progestogen therapy may have effects on the heart different from those of estrogen therapy alone because of adverse impact of progestogens on Lp(a) and HDL C levels. The effects of progesterones were dependent on the androgenic potency of progestogen and the duration of therapy. PMID- 8694669 TI - Admission serum magnesium level does not predict the hospital outcome of patients with acute myocardial infarction. AB - OBJECTIVE: To establish whether hypomagnesemia at admission predicts excessive morbidity, particularly cardiac arrhythmias, and mortality in patients with acute myocardial infarction. METHODS: We compared hypomagnesemic and normomagnesemic patients with acute myocardial infarction in 517 patients admitted to the coronary care unit. The serum magnesium concentration, along with a large array of other parameters, was measured on admission to the emergency department. Other baseline attributes and variables related to the patients' hospital course were used to compare the 2 groups. RESULTS: The 132 patients (25.9%) with low serum magnesium concentrations at admission (mean +/- SD, 0.61 +/- 0.06 mmol/L [1.48 +/ 0.15 mg/dL]) were comparable to the patients with normal serum magnesium concentrations (0.81 +/- 0.11 mmol/L [1.96 +/- 0.26 mg/dL]) except for a higher rate of prehospital use of diuretic agents (32.6% vs 22.5%, P = .02) and earlier presentation after onset of symptoms (mean +/- SD, 3.2 +/- 4.1 vs 4.8 +/- 6.6 hours, P = .003). There was no correlation between serum magnesium and potassium concentrations in the emergency department (r = 0.14). No difference was detected between the hypomagnesemic and normomagnesemic cohorts in rates of total mortality (18.9% vs 18.5%, P = .91), cardiac mortality (15.2% vs 15.3%, P = .99), atrial fibrillation (13.6% vs 13.8%, P = .97), ventricular tachycardia (18.2% vs 15.3%, P = .44), or ventricular fibrillation (15.2% vs 13.5%, P = .63). Management of the 2 cohorts was not different, except for higher rates of use of magnesium (17.4% vs 1.3%, P < .001) and potassium (59.8% vs 42.1%, P < .001) supplements and antiarrhythmic drugs (62.9% vs 48.7%, P = .005) in the hypomagnesemic patients. An endogenous rise in serum magnesium level was documented in a subgroup of 161 patients who had a repeated measurement (0.74 +/- 0.12 mmol/L [1.79 +/- 0.29 mg/dL] in the emergency department vs 0.77 +/- 0.09 mmol/L [1.88 +/- 0.23 mg/dL] in the coronary care unit, P < .001). CONCLUSIONS: We conclude that hypomagnesemia is seen in approximately one fourth of patients with myocardial infarction, is not linked to hypokalemia, has some relationship to preadmission use of diuretic agents, is associated with early presentation to the hospital, and is not a predictor of increased morbidity or mortality. PMID- 8694670 TI - Tuberculous meningitis among adults with and without HIV infection. Experience in an urban public hospital. AB - BACKGROUND: Tuberculous meningitis remains a frequently diagnosed entity in urban US hospitals, with the incidence increasing as a consequence of infection with the human immunodeficiency virus (HIV). OBJECTIVE: To describe the occurrence, characteristics, and therapeutic responses of tuberculous meningitis among adult patients of an urban public hospital, with special attention to the effects of HIV infection. DESIGN: Retrospective clinical review of all cases identified among adults over a 12-year interval, collecting demographic and clinical variables. SETTING: A 550-bed urban teaching hospital. MAIN OUTCOME MEASURE: Nine month outcome stratified by survival. RESULTS: Among 31 adult patients identified as having definite or probable tuberculous meningitis, a majority (n = 20 [65%]) were infected with HIV. Cumulative rates of occurrence per 100 000 persons over the 12 years of the study were estimated at 1.72 for those without HIV infection and 400 for those with HIV infection. The most common symptoms at presentation were fever (83% [24/ 29]) and abnormal mental status (71% [20/28]). One or more abnormalities were present in the cerebrospinal fluid of 97% (30/31) of subjects, and 74% (23/31) had cerebrospinal fluid cultures positive for Mycobacterium tuberculosis. Neuroimaging of 28 patients revealed 1 or more abnormalities in 82% (n = 23). Among 30 patients with available outcome data at 9 months, 43% (n = 13) had died, 40% (n = 12) had survived without sequelae, and 17% (n = 5) had survived with morbidity. HIV infection had no discernible effect on findings. CONCLUSIONS: Tuberculous meningitis remains relatively common among indigent urban nonwhite populations. While HIV infection has contributed to the increased incidence of tuberculous meningitis, it has not significantly altered the presenting clinical, laboratory, or radiographic findings or the response to therapy of this disease. Parameters associated in a multivariate regression analysis with mortality at 9 months were black race and the absence of corticosteroid use. PMID- 8694671 TI - Routine transesophageal echocardiography for cerebral ischemia. Is it really necessary? AB - BACKGROUND: Patients presenting with stroke or transient cerebral ischemic episodes often undergo transesophageal echocardiography (TEE) as part of their initial evaluation. Previous studies have demonstrated that TEE is superior to transthoracic echocardiography for the detection of potential cardiac sources of embolism. In our institution, this scenario now represents the most frequent reason for requesting TEE. For the most part, these TEE examinations are ordered by a neurologist, and transthoracic echocardiography is not performed beforehand. PATIENTS: Over a 2-year period, TEE was requested for 137 patients at our institution for the evaluation of a cerebral ischemic event. The complete hospital chart was available for review in 106 of these patients, and they form the study group. METHODS: All patients underwent TEE using either a biplane or omniplane transducer, with Doppler color flow imaging and saline contrast administration performed in every case. Studies were reviewed for the presence of possible cardiac or aortic sources of cerebral emboli, and hospital charts were reviewed to collect clinical information. RESULTS: A potential cardiovascular embolic source was detected in 35% of patients. Abnormalities were discovered in 53% (16/30) of patients with atrial fibrillation vs 28% (21/76) of patients in sinus rhythm (P < .001). Both patients who had left atrial thrombus and 12 of 13 with left atrial spontaneous contrast had atrial fibrillation (P < .001). Protruding aortic atherosclerotic debris was the most frequent abnormality among patients in sinus rhythm. CONCLUSIONS: It may not be cost-effective to perform TEE as a routine diagnostic procedure in patients presenting with cerebral ischemic events. Most patients with atrial fibrillation are candidates for empiric warfarin sodium therapy, and patients in sinus rhythm usually have findings for which there is no recommended therapy or for which only aspirin is indicated. PMID- 8694672 TI - Ketorolac vs chlorpromazine in the treatment of acute migraine without aura. A prospective, randomized, double-blind trial. AB - BACKGROUND: Many treatments for acute migraine exist. Chlorpromazine is effective but has serious side effects. Ketorolac has only rare side effects. OBJECTIVE: To compare intramuscular ketorolac troinethamine with intravenous chlorpromazine hydrochloride in treating acute migraine. METHODS: We performed a prospective, randomized, double-blind trial comparing the clinical effectiveness of 60 mg of intramuscular ketorolac tromethamine with 25 mg of intravenous chlorpromazine hydrochloride in patients with acute migraine headache seen in the emergency department. Pain intensity, quantitated using the Wong-Baker Faces Rating Scale, was measured every 30 minutes for 2 hours in the emergency department. Patients returned pain scores at 6, 12, 24, and 48 hours by mail. RESULTS: Fifteen patients were entered into each treatment arm. No differences were seen between the mean pain scores or the mean change in pain scores. The ketorolac group mean (+/- SEM) pain score decreased from 4.07 +/- 0.18 to 0.73 +/- 0.3 in 2 hours. The chlorpromazine group pain score decreased from 4.47 +/- 0.17 to 0.87 +/- 0.4. Two of the 3 nonresponders responded to the alternate group's treatment. No side effects were seen. CONCLUSIONS: Using 60 mg of intramuscular ketorolac tromethamine is as effective as 25 mg of intravenous chlorpromazine hydrochloride in the treatment of acute migraine headache. Patients who do not respond to one of these medications may respond to the other. PMID- 8694673 TI - A large-scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Valaciclovir HSV Study Group. AB - BACKGROUND: Valaciclovir, the 1-valyl ester of acyclovir, has provided a peroral acyclovir bioavailability 3 to 5 times that of acyclovir itself and is rapidly and completely converted to acyclovir by the liver. Accordingly, valaciclovir has the same antiviral activity as acyclovir, but the potential for enhanced clinical activity and/or less frequent administration because of its superior pharmacokinetics. METHODS: We conducted a double-blind, placebocontrolled, patient-initiated clinical trial of peroral valaciclovir, 500 or 1000 mg, or matching placebo tablets twice daily for 5 days for the acute treatment of 1 episode of recurrent herpes genitalis among 987 otherwise healthy volunteers. RESULTS: Both doses of valaciclovir were equally effective. Patients receiving the lower dose of valaciclovir experienced a median episode length of 4.0 days compared with 5.9 days for those receiving placebo treatment (hazard ratio, 1.9; 95% confidence interval [Cl], 1.6-2.3). Valaciclovir therapy increased the proportion of patients in whom the development of vesicular and ulcerative lesions was prevented in comparison with placebo treatment: 31% vs 21% (relative risk, 1.5; 95% CI, 1.1-1.9). Valaciclovir therapy accelerated the resolution of pain (hazard ratio, 1.8; 95% CI, 1.5-2.1) and the time to cessation of viral shedding (hazard ratio, 2.9; 95% CI, 2.1-3.9). Adverse reactions among the valaciclovir groups were comparable with those of the placebo group. CONCLUSIONS: Valaciclovir therapy provided a clinically significant benefit to patients that included shortening of the duration of lesions, the duration of pain or discomfort, and the duration of virus shedding. In addition, this study, to our knowledge, provides the first convincing demonstration that antiviral therapy can prevent lesion development. These results should prompt a reconsideration of the role that episodic treatment plays in the management of recurrent herpes genitalis. PMID- 8694674 TI - Is economic hardship on the families of the seriously ill associated with patient and surrogate care preferences? SUPPORT Investigators. AB - BACKGROUND: Serious illness often causes economic hardship for patients' families. However, it is not known whether this hardship is associated with a preference for the goal of care to focus on maximizing comfort instead of maximizing life expectancy or whether economic hardship might give rise to disagreement between patients and surrogates over the goal of care. METHODS: We performed a cross-sectional study of 3158 seriously ill patients (median age, 63 years; 44% women) at 5 tertiary medical centers with 1 of 9 diagnoses associated with a high risk of mortality. Two months after their index hospitalization, patients and surrogates were surveyed about patients' preferences for the primary goal of care: either care focused on extending life or care focused on maximizing comfort. Patients and surrogates were also surveyed about the financial impact of the illness on the patient's family. RESULTS: A report of economic hardship on the family as a result of the illness was associated with a preference for comfort care over life-extending care (odds ratio, 1.26; 95% confidence interval, 1.07-1.48) in an age-stratified bivariate analysis. Similarly, in a multivariable analysis controlling for patient demographics, illness severity, functional dependency, depression, anxiety, and pain, economic hardship on the family remained associated with a preference for comfort care over life-extending care (odds ratio, 1.31; 95% confidence interval, 1.10-1.57). Economic hardship on the family did not affect either the frequency or direction of patient-surrogate disagreements about the goal of care. CONCLUSIONS: In patients with serious illness, economic hardship on the family is associated with preferences for comfort care over life-extending care. However, economic hardship on the family does not appear to be a factor in patient-surrogate disagreements about the goal of care. PMID- 8694676 TI - Ipodate therapy in patients with severe destruction-induced thyrotoxicosis. AB - We describe 4 patients with severe destruction-induced thyrotoxicosis who had a rapid clinical response to oral sodium ipodate (500 mg daily). The underlying thyroid disorders in the patients were postpartum thyroiditis, subacute thyroiditis, silent thyroiditis, and radiation-induced thyroiditis. Ipodate therapy was given for 6 to 10 weeks until restoration of thyroid function to normal. In all patients, an almost complete resolution of symptoms occurred by the third day of ipodate treatment. In the patient with radiation thyroiditis, a daily clinical score of thyrotoxicosis declined within 2 to 3 days. The score remained low as long as the patient was receiving ipodate, but 2 attempts to discontinue ipodate therapy while thyroxine levels were elevated resulted in a rise of the thyrotoxicosis clinical score. This suggests that ipodate therapy, by rapidly reducing triiodothyronine levels through inhibition of the 5' monodeiodination and blockage of the peripheral effects of thyroid hormone, controls severe thyrotoxicosis mediated by destruction and should be considered in this setting in conjunction with beta-adrenergic blockade. PMID- 8694675 TI - Involvement of cardiovascular rehabilitation programs in advance directive education. AB - BACKGROUND: Cardiac rehabilitation programs represent opportunities to educate patients with cardiac disease about living wills and durable powers of attorney for health care. The extent of advance directive education that is currently provided in cardiac rehabilitation programs, however, is unknown. METHODS: A questionnaire was mailed to nonphysician directors of cardiac rehabilitation programs to determine the programs' involvement in educating enrollees about end of-life issues and the directors' opinions regarding the appropriateness of such education in cardiac rehabilitation curricula. Data were presented as proportions with 95% confidence intervals (Cls). RESULTS: Of the 1013 cardiac rehabilitation program directors, 845 (83%) responded to the questionnaire, of which 48 stated they were no longer enrolling patients. Of the remaining 797 program directors (83%), 71% (95% CI, 67%-74%) informed patients of their prognosis, but only 18% (95% CI, 15%-20%) and 12% (95% CI, 9%-14%) asked patients if they had a living will or a durable power of attorney for health care, respectively. Only 9% (95% CI, 7%-11%) offered educational sessions on advance directives and 17% distributed advance directive informational material. Education about cardiopulmonary resuscitation was provided by 27% (95% CI, 23%-30%), but only 3% (95% CI, 2%-4%) provided information on do-not-resuscitate topics. Fifty percent (95% CI, 46%-53%) were in favor of including advance directive education and 49% (95% CI, 45%-52%) favored inclusion of do-not-resuscitate topics into curricula. CONCLUSIONS: Cardiac rehabilitation programs are potentially valuable but not widely used sites for educating patients with cardiac disease about advance directives. PMID- 8694677 TI - Cost-effective approaches to the diagnosis of pulmonary embolism. PMID- 8694678 TI - Neisseria subflava bacteremia in a neutropenic patient. PMID- 8694679 TI - The contribution of psychotherapy and pharmacotherapy research to national mental health care. Introduction to the special series. PMID- 8694680 TI - Relapse prevention by acamprosate. Results from a placebo-controlled study on alcohol dependence. AB - BACKGROUND: The effectiveness of acamprosate (calcium bisacetylhomotaurinate) as a treatment to maintain abstinence in alcohol-dependent patients was assessed for 1 year. METHODS: After short-term detoxification, 272 patients participated in a randomized, double-blind, placebo-controlled study. Patients received routine counseling and either the study medication or placebo for 48 weeks; they were followed up for another 48 weeks without medication. Statistical analysis was performed according to the intention-to-treat principle. RESULTS: Patients who were receiving acamprosate showed a significantly higher continuous abstinence rate within the first 60 days of treatment compared with patients who were assigned to placebo treatment (67% vs 50%) until completion of the treatment period (43% vs 21%, log rank P = .005), and they had a significantly longer mean abstinence duration of 224 vs 163 days, or 62% vs 45% days abstinent (P < .001); however, there was no difference in psychiatric symptoms. Of the patients who were receiving acamprosate, 41% had dropped out, whereas 60% of the placebo treated patients dropped out of the study. Few side effects (mainly diarrhea and headache) were recorded. At the end of a further 48 weeks without receiving study medication, 39% and 17% of the acamprosate- and placebo-treated patients, respectively, had remained abstinent (P = .003). CONCLUSION: Acamprosate proved to be a safe and effective aid in treating alcohol-dependent patients and in maintaining the abstinence of patients during 2 years. PMID- 8694681 TI - Replication of the Stockholm Adoption Study of alcoholism. Confirmatory cross fostering analysis. AB - BACKGROUND: Two forms of alcoholism with distinct clinical features and mode of inheritance were first distinguished in the Stockholm Adoption Study. This involved a large sample of children born in Stockholm, Sweden, who were adopted at an early age and reared by nonrelatives. Type 1 alcoholism had adult onset and rapid progression of dependence without criminality, whereas type 2 had teenage onset of recurrent social and legal problems from alcohol abuse. METHODS: A replication study was carried out with 577 men and 660 women born in Gothenburg, Sweden, and adopted at an early age/by nonrelatives. The genetic and environmental backgrounds of the adoptees were classified by the exact procedures calibrated by discriminant analysis in the original study. RESULTS: Both type 2 and severe type 1 alcoholism were confirmed as independently heritable forms of alcoholism in male adoptees. The lifetime risk of severe alcoholism was increased 4-fold in adopted men with both genetic and environmental risk factors characteristic of type 1 alcoholism compared with the others (11.4% vs 3.0%). Neither genetic nor environmental risk factors for type 1 alcoholism by themselves were sufficient to cause alcoholism. In contrast, the risk of type 2 alcoholism was increased 6-fold in adopted sons with a type 2 genetic background compared with others; regardless of their postnatal environment (10.7% vs 2.0%). The sons with a type 2 genetic background in the replication sample had no excess of type 1 alcoholism, and vice versa. There was no increased risk of mild abuse in adopted men regardless of their genetic or environmental background. CONCLUSION: Type 1 and type 2 alcoholism are clinically distinct forms of alcoholism with causes that are independent but not mutually exclusive. PMID- 8694682 TI - Does brief dynamic psychotherapy reduce the relapse rate of panic disorder? AB - BACKGROUND: Although panic disorder can be effectively alleviated by drug treatment, the relapse rate is high. By adding brief dynamic psychotherapy focused on the psychosocial vulnerability of patients with panic disorder to an established drug treatment regimen, we hypothesized that this would result in a lower relapse rate after pharmacotherapy. METHODS: Patients with panic disorder (defined by DSM-III-R) were randomized to treatment with either clomipramine for 9 months (n = 20), or clomipramine for 9 months combined with 15 weekly sessions of brief dynamic psychotherapy (n = 20). Measures of anxiety and depression were collected at intake and at regular intervals. The patients had blind follow-up interviews at 6, 12, and 18 months after beginning treatment. RESULTS: All patients in both groups became free of panic attacks within 26 weeks of the start of treatment. On termination of pharmacotherapy, the relapse rate was significantly higher in the clomipramine-only group during the follow-up period. There were significantly lower scores for most anxiety measures in the clomipramine plus psychotherapy group at the 9-month follow-up. CONCLUSION: The addition of brief dynamic psychotherapy to treatment with clomipramine significantly reduces the relapse rate of panic disorder compared with clomipramine treatment alone. PMID- 8694683 TI - Patterns of mental health service utilization. AB - How many and which individuals, with which psychiatric disorders, receive (and do not receive) mental health services from which professionals in what settings? This question falls within the purview of mental health services research, which is a multidisciplinary field that brings together the methodologies of epidemiology, econometrics, and clinical research. First, in this article, we present an explication of what is known about those individuals in need of psychotherapy and how they access services. Next, we describe the numbers, professional affiliations, and service sites of professionals who are engaged in the practice of psychotherapy. We summarize our current knowledge about the actual utilization of psychotherapy services relative to the needs of patients and the professional background of therapists. Finally, we identify aspects of psychotherapy service utilization that are, as yet, unaddressed. PMID- 8694684 TI - Psychotherapy research in historical perspective. Implications for mental health care policy. AB - This article is a sketch of the historical development of the field of behavioral and non-behavioral therapy research. Four phases are characterized: (1) establishing scientific research (1927-1954), (2) searching for scientific rigor (1955-1969), (3) expansion and organization (1970-1983), and (4) consolidation and reformulation (1984-present). Continuities between and key developments within successive phases are outlined, with emphasis given to methodological innovations. The corroboration of select findings about process and outcome and the development of several critical discourses within the third and fourth phases have implications for the provision of mental health care and for policy discussions. PMID- 8694685 TI - Psychotherapy of depression. Implications for reform of the health care system. AB - This article reviews the empirical evidence supporting the role of psychotherapy and psychosocial interventions in the treatment of patients with depression. Treatment models and the evidence for their effectiveness in the acute-and maintenance-treatment phases are reviewed. Whereas the sophistication of research designs and data analysis for the study of psychotherapy have substantially improved, the review highlights current gaps in our knowledge. Most important for reform of the health care system is the need for studies of efficacy to lead to large-scale investigations of effectiveness. PMID- 8694686 TI - Advances in the psychosocial treatment of anxiety disorders. Implications for national health care. AB - Recent developments in the psychosocial treatments for anxiety disorders suggest that we have reached an early plateau. Evidence now exists on the effectiveness of psychosocial treatment approaches for every anxiety disorder when compared with no treatment or credible psychosocial placebos. In many cases these procedures have limited clinical effectiveness and much remains to be learned about the disseminability and clinical utility of these approaches in the context of emerging national health care plans. We are just beginning the first generation of multisite studies examining the potentially synergistic effects of proven psychosocial treatments and proven drug treatments. These studies that have substantial significance for national health care are reviewed and some preliminary results are reported. PMID- 8694687 TI - Alcohol treatment and health care system reform. AB - After reviewing the empirical literature, we suggest that advances in the assessment and treatment of alcohol problems have the following important implications for health care system reform: (1) alcohol use disorders and problems associated with alcohol use are prevalent and are complicated by various comorbid conditions, and they result in large costs to the health care system and to society; (2) alcohol treatment generally results in reduced drinking and more efficient use of health care resources; (3) specific treatments have demonstrated effectiveness; (4) screening and assessment instruments with excellent sensitivity to the heterogeneity of alcohol problems have been developed; (5) evidence that specific treatments have differential effectiveness with different patients groups is accumulating; and (6) good evidence exists for the effectiveness of brief interventions, particularly with less severe and chronic alcohol problems. These findings suggest that alcohol treatment services in a reformed health care system should include (1) universal coverage for alcohol treatment, including full benefits for outpatient care; (2) a rational system of assessment and triage for treatment, including an increased emphasis on screening and brief interventions in primary medical care settings; (3) a full range of treatment services that vary in intensity; and (4) addictions treatment provider incentives and contingencies to provide treatments of proven effectiveness. When fully implemented, an efficient approach to the treatment of alcohol-related problems will result in one of the largest pools of cost savings in a reformed American health care system. PMID- 8694688 TI - Psychosocial treatment for drug abuse. Selected review and recommendations for national health care. AB - Substance abuse and dependence remains an important public health concern because of health-related and other costs to our society. We review selected articles that address questions about the psychosocial treatment of substance abuse disorders; these articles could aid in setting the parameters of a national health care insurance. Data from major program evaluation studies of existing substance abuse treatment programs are presented, followed by reviews of controlled studies of opiate, cocaine, and marijuana abuse and dependence; particular attention is given to studies that have standardized treatment through the use of treatment manuals. Articles about the treatment of substance abuse in adolescents are also reviewed. The existing data suggest that substance abuse treatment should be intensive and should probably involve multiple modalities targeted to various problems encountered in patients with substance use disorders, including comorbid psychiatric problems. However, only a few well controlled studies have been performed to date; therefore, substantial research is needed before a system truly informed by research can be designed. Suggestions for future research directions are provided. PMID- 8694689 TI - Can we treat dilated cardiomyopathy using a left ventricular assist device? PMID- 8694690 TI - Bacterial and fungal infection in neonates undergoing venoarterial extracorporeal membrane oxygenation: an analysis of the registry data of the extracorporeal life support organization. AB - A review and analysis of 5,001 neonatal venoarterial (VA) extracorporeal membrane oxygenation (ECMO) cases showed that bacterial and fungal infection occurred in 147 (2.9%) and 26 (0.6%) patients, respectively, with an overall incidence of 3.5%. Bivariate analysis was used to compare infected infants with controls, bacterial versus fungal groups, and bacterial subgroups with respect to patient demographics, primary diagnosis, mechanical complications, patient complications, duration of the ECMO course, and hospital mortality. Logistic regression models were constructed using variables that were statistically significant from the bivariate comparisons. Variables that remained significant after multivariate analysis included primary diagnosis of pneumonia/sepsis, mechanical complications of oxygenator failure, rupture of raceway or tubing, clots, and patient complications of hypertension and hyperbilirubinemia. The infection group had significantly longer mean total hours on bypass and higher hospital mortality. Infants with fungal infection had a significantly higher hospital mortality rate compared with those with bacterial infection. We conclude that infection during ECMO, especially fungal infection, carries an increased risk of hospital mortality and that mechanical complications are associated with an increased risk of infection, Key Words: Extracorporeal membrane oxygenation-Nosocomial-Bacterial infection-Fungal infection-Extracorporeal membrane oxygenation outcome. PMID- 8694691 TI - Cytokine generation in rabbits during extracorporeal lung assist with a mini hollow fiber lung. AB - To examine host responses to extracorporeal lung assist (ECLA) in small animals, we developed a mini hollow fiber lung of nonmicroporous polyolefin and an extracorporeal bypass circuit with a priming volume of 25 ml. This circuit allowed ECLA of up to 72 h without blood transfusion in 20 rabbits. The ECLA procedure induced the appearance of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) receptor antagonist (IL-1Ra) in plasma, but not IL-1 beta. However, these changes were observed only at the initial stage of ECLA, and the levels returned to pre-ECLA levels within 24 h. Although leukocytes adhering to the hollow fibers were immunohisto-chemically positive for IL-1 beta and IL-Ra, the plasma levels of these cytokines in response to ECLA were not different from those observed in rabbits given anesthesia and subjected to minor surgery but without ECLA. Thus, ECLA itself is a minor factor in the production of these cytokines. PMID- 8694692 TI - Effect of simulated valvular stenoticity on predicted flow area for a bileaflet valve using the Gorlin equation. AB - The possibility that the discharge coefficient (Cd) for a mechanical heart valve (MHV) is affected by valvular stenosis is addressed. A 29 mm bileaflet (Si. Jude Medical) mitral valve is tested on a cardiovascular duplicator (CVD) in its normal state and under two degrees of simulated stenosis. Stenoticity is simulated by bracing the occluders such that full opening is impossible. The pressure drop through the valve is described by a two-term second-order polynomial in flow, from which it is shown that the Cd should be a nonlinear function of the flow rate through the valve. The average difference between measured and calculated areas decreased from 74%, when a constant value of 0.7 was used for the Cd, to 3.7%, when the Cd was a nonlinear function of the flow rate. PMID- 8694693 TI - A physical analog of the failing left ventricle for in vitro studies of mechanical wall actuation. AB - Mechanical repowering of a failing heart with devices or skeletal muscle could circumvent blood-pump lining problems. Requirements are complex: indefinite support with preservation of valve competence and coronary flow, avoidance of wall coaptation, and allowance of both rapid low impedance refilling and independent left and right pressures. An accurate in vitro physical failing-heart analog could facilitate the choice and screening of surgical and engineering approaches in mock circulation experiments. Prosthetic models, transplant recipient hearts, normal animal hearts, existing in vivo animal failure models, and failing cadaver hearts all have serious limitations. One hundred and four excised porcine hearts were dilated and fixed by three iterative protocols. Geometric and passive mechanical parameters were assessed and compared with targets expected for an end-stage failing heart. For Protocol 3, Subgroup 2 (reinforcing valve support, dilatation by compliant ventricular balloon, and ethyl alcohol fixation), the left ventricular shape and capacity (ellipsoid, 201 377 ml/500 g of heart weight), passive valve function, wall flexural rigidity (Et3 range 0.101-0.331 Nm), and refilling mechanics (99 +/- 17.46 ml during 200 400 ms at < or = 10 mm Hg transmural gradient) were all within goal criteria. PMID- 8694694 TI - Effects of right ventricular failure on renal function during pneumatic left ventricular assist. AB - In an experiment dog model of acute biventricular failure, the effects of left ventricular (LV) assist on renal hemodynamics and function were evaluated. After the induction of severe cardiac failure by multiple ligation of the coronary arteries, LV assist with a 40 ml pneumatic pulsatile pump was initiated, and the aortic flow was maintained at control values. The right atrial pressure (RAP) rose to 21.3 mm Hg with the appearance of profound right ventricular (RV) failure. Renal arterial blood flow (RAF) decreased to about 60% of the control value after 2 h of LV assist. The urine volume decreased and renal function deteriorated progressively. RV assist decreased the RAP to 4.8 mm Hg, and the reduced RAF recovered. After 3 h of RV assist, the RAF returned to initial values and the urine volume increased, but renal function did not recover. Advanced biventricular failure with elevated RAP during LV assist reduced renal perfusion and impaired renal function and may be an indication for early RV assist. PMID- 8694695 TI - Monitoring the native cardiac output during femoral venoarterial cardiopulmonary bypass support. AB - To manage postcardiotomy patients with cardiopulmonary bypass support (CPS), it is very important to evaluate the native cardiac function. In 5 postcardiotomy cases without CPS, the alternative thermodilution outputs by right ventricular (RV) injection were compared with simultaneous thermodilution outputs by standard right atrial (RA) injection. Cardiac output determined by RV injections, ranging from 3.4 to 10.1 L/min, showed close agreement with the values by RA injections (r = 0.993). Four cases with postcardiotomy profound heart failure were placed on femoral venoarterial CPS and managed with monitoring native cardiac output determined by an RV injection thermodilution method. It was very easy and reasonable to decide the pump flow relative to native cardiac output. The cardiac output determined by RV injection provides a means of accurate evaluation for the failing heart in postcardiotomy cases with venoarterial CPS and optimizes the staged weaning off CPS or the change to a pneumatic pulsatile ventricular assist device for long-term assist. PMID- 8694696 TI - The effect of the impeller-driver magnetic coupling distance on hemolysis in a compact centrifugal pump. AB - Blood trauma is one of the important performance parameters of centrifugal pumps. To investigate the blood trauma induced by these pumps, in vitro hemolysis tests have become an important procedure and are increasingly used for pump development and comparisons. The Baylor compact eccentric inlet port (CIE) centrifugal blood pump was developed as a long-term centrifugal ventricular assist device (VAD) as well as a cardiopulmonary bypass pump (CPB). The Baylor CIE pump incorporates a seal-less design with a blood stagnation-free structure. This pump can provide flows of 5 L/min against 350 mm Hg of total pressure head at 2,600 revolutions per minute. The pump impeller is magnetically coupled to the driver magnet in a seal-less manner. The latest hemolysis study revealed that hemolysis may be affected by the gap distance between the driver and the impeller magnet. The purpose of this study was to verify the effect of the magnetic coupling distance on the normalized index of hemolysis (NIH) with the CIE model and to obtain an optimal gap distance. The NIH value was clearly decreased by alteration of the magnetic coupling distance from 7.7 to 9.7 mm in CPB and left ventricular assist device (LVAD) conditions. The NIH, when using the pump as an LVAD condition, was reduced to a level of 0.0056 from 0.095 when the magnetic coupling distance was extended. The same results were also obtained when the pumps were used in a CPB condition. The magnetic coupling distance is an important factor for the CIE model in terms of hemolysis. Different coupling forces effect the bearings and impeller stability. These results suggest that an optimal driving condition with a proper magnetic coupling and an optimal force between the impeller and driver is necessary to develop an atraumatic centrifugal pump. PMID- 8694697 TI - Modification of a pivot bearing system on a compact centrifugal pump. AB - The pivot bearing centrifugal blood pump was developed as a long-term centrifugal ventricular assist device (VAD) as well as a cardiopulmonary bypass pump. This pivot bearing supported centrifugal pump with an eccentric port (CIE) incorporates a seal-less design with a blood stagnation-free structure. This pump can provide flows of 12 L/min against 650 mm Hg total pressure head at 3,600 rpm, and in a CPB condition 5 L/min against 350 mm Hg total pressure head at 2,600 rpm. Very recently, the pivot bearing system was modified to obtain a stable and smooth spinning movement. The material of the female pivot was changed from ceramic to polyethylene. Three kinds of bearings were tested simultaneously with bovine blood in two types of in vitro circuits to determine the blood damage from the bearings. Pressure differences across the pump (total head pressure, delta P) of 140 mm Hg (n = 12) and 330 mm Hg (n = 12) were examined. The normalized index of hemolysis (NIH) was slightly higher in a ball bearing (BB) pump than in a polyethylene bearing (PB) pump and statistically higher than the BioMedicus Pump (BP-80) on delta P of 140 mm Hg. When the delta P was at 330 mm Hg, a comparison between the three types of pumps revealed no difference in NIH. In addition, the primary vane of the impeller was redesigned to obtain an atraumatic structure. In the second study (n = 14), there was no difference in the NIH between BP-80 and the current model when the delta P was 300 mm Hg (0.019 +/- 0.002 vs. 0.027 +/- 0.006, p = 0.3) and/or when the delta P was 100 mm Hg (0.0008 +/- 0.0001 vs. 0.0014 +/- 0.0002, p = 0.07). The modified pivot bearing had an improved spinning condition and no change in hemolysis. A proper selection of pivot bearing materials is important to develop an atraumatic centrifugal pump. The modification of the bearing system and redesign of the vane enabled a compact centrifugal pump to become a reality. PMID- 8694698 TI - Effect of an pyruvate-based peritoneal dialysis solution on the pH of a residual peritoneal dialysis fluid. AB - An acidic (pH 5.2) pyruvate-based peritoneal dialysis solution or an equally acidic lactate-based counterpart was added to a residual fluid (i.e., peritoneal effluent) obtained from each of 6 continuous ambulatory peritoneal dialysis patients. It was found that the residual fluids were able to raise the pH of the resultant residual fluid/peritoneal dialysis solution mixture to a higher level in the case of the pyruvate-based solution than in the case of the lactate-based one. PMID- 8694699 TI - Modulation of idiotypic and antiidiotypic immunoglobulin G responses in an alloimmune thrombocytopenic patient associated with extracorporeal protein A immunoadsorption. AB - In the present case study, a patient with Non-Hodgkin. Lymphoma underwent combination chemotherapy resulting in severe pancytopenia requiring transfusion support with blood products. The patient became refractory to random donor platelet transfusions and subsequently received five immunoadsorption treatments. The patient's clinical response to immunoadsorption therapy was assessed by monitoring platelet transfusion recovery and survival. In addition, changes in antibody responses were assessed. Early during the course of immunoadsorption therapy, antiplatelet immunoglobulin G (IgG) alloantibody was detected. There was a decline in antiplatelet IgG alloantibody levels by the last immunoadsorption treatment associated with increases to platelet correct count increments after completion of immunoadsorption therapy. In addition, elevated levels of antiidiotypic IgG antibody detected early during the course of therapy were significantly reduced by the last immunoadsorption treatment. This case study suggests that specific alloimmune idiotypic IgG antibody and corresponding antiidiotypic IgG antibody responses may be modulated in association with extracorporeal immunoadsorption employing protein A/silica columns. PMID- 8694700 TI - Physiologic control of cardiac assist devices. AB - Total artificial hearts (TAHs) and biventricular assist devices (BVADs) have varying levels of acceptance and reliability, and the research on both focuses on their control mechanisms. Efforts generally aim to achieve a response to physiologic demand and left/right output balance, and beneficial cardiac output (CO) and effective control mechanisms have been achieved by eliciting a Starting like response to preload and afterload. Such control mechanisms, however, generally base device output on a single parameter, such as the preload on the heart. Current TAHs and BVADs provide relatively fixed oxygen delivery to patients with large physiologically induced variations in oxygen consumption. This paper aims to document fluctuations in oxygen consumption that are normal in BVAD and TAH patients, identify a number of patient-generated signals that reflect these fluctuations, and describe a multitiered control algorithm based upon these signals. Such a control system may offer better response times and more physiologic cardiac outputs. There currently exists a microprocessor-based control mechanism that can be adapted to control TAHs and BVADs using input from a variety of sensors, and it can be found in modern implantable pulse generators (IPGs). Today's pacemakers are capable of rate control and can run diagnostic programs and store data that could be valuable in the evaluation of the patient's condition. PMID- 8694701 TI - Changes of intraaortic balloon volume during pumping in a mock circulation system. AB - The effects of hemodynamic changes on intraaortic balloon (IAB) volumes were studied experimentally using a helium tachometer in a mock circulatory system. The IAB volume decreased with increases in the heart rate and mean aortic pressure, but the degree of reduction in the IAB volume was different among 4 commercially available IAB drivers. Improvements in IAB consoles are needed to compliment the progress made in percutaneous techniques for IAB insertion resulting in smaller balloons. PMID- 8694702 TI - Advantage of monitoring skin vibration as an index of arteriovenous fistular blood flow. AB - Monitoring of the skin vibration is disturbed little by environmental noise. Therefore, the skin vibration is more relevant than bruit on the skin by means of monitoring the fistular blood flow. Frequency analysis of the skin vibration generated by an internal arteriovenous fistula indicated two peaks of power spectral density (PSD), one in the frequency range of 4-10 Hz and the other from 100-300 Hz. The analysis of the skin vibration generated by an external fistula, however, showed only one peak in the range of 4-10 Hz and a moderate flat PSD level in the range of 100-300 Hz. The PSD level in the range of 100-300 Hz decreased dramatically or disappeared when the fistular blood flow diminshed or ceased. Therefore, the optimal frequency for monitoring skin vibration may be the range of 100-300 Hz. PMID- 8694703 TI - Is the choice of membrane important for patients with acute renal failure requiring hemodialysis? PMID- 8694704 TI - Corticosteroid therapy of eye disease. Fifty years later. PMID- 8694705 TI - The Residency Review Committee for Ophthalmology. PMID- 8694706 TI - The utility of the x rays in detecting and locating metallic particles in the eye. 1897. PMID- 8694707 TI - Botryomycosis of limbal conjunctiva with Splendore-Hoeppli phenomenon. AB - An 84-year-old man complained of irritation of the left eye of several months' duration. He had had several previous surgical procedures including removal of bilateral pterygia and bilateral cataract extraction. Examination of the bulbar conjunctiva on the left eye disclosed a collection of cilia (eyelashes) located adjacent to the limbus at the 11:30-o'clock position. This aggregate of cilia was associated with irregular yellowish deposits 1.5 mm in diameter. The cilia and redundant conjunctival tissues were surgically excised. Histopathologic examination showed a botryomycotic granule surrounded by a prominent acidophilic ring (Splendore-Hoeppli phenomenon). Gram stains demonstrated the presence of microcolonies of gram-positive cocci and gram-negative rods within the granule. We postulate that the entrapment of displaced cilia provided a nidus for the bacterial colonization forming the botryomycotic granule. To our knowledge, botryomycosis of the conjunctiva has not been reported previously. PMID- 8694708 TI - Identification of glycosaminoglycans in age-related macular deposits. AB - We investigated the presence and localization of glycosaminoglycans in basal laminar deposit and drusen in age-related maculopathy. Conventional histological staining techniques and monoclonal antibodies specific for several glycosaminoglycans were used on paraffin-embedded human maculae. Furthermore, macular homogenates were analyzed with two-dimensional electrophoresis. Quantitative analysis of glycosaminoglycans was done spectrophotometrically using dimethylmethylene blue. Immunohistochemically, all basal laminar deposit stained positive for chondroitin 4-sulfate and focally positive for heparan sulfate proteoglycan. Drusen were not stained with any of the monoclonal antibodies. With two-dimensional electrophoresis, it was demonstrated that macular extracts with and without age-related maculopathy contained chondroitin sulfate. Heparan sulfate was only expressed in maculae with age-related maculopathy. The total amount of glycosaminoglycans was significantly higher in maculae with basal laminar deposit than in maculae without basal laminar deposit (P = .001). There were significant differences in the amount and composition of glycosaminoglycans between maculae with and without age-related maculopathy. PMID- 8694709 TI - Anterior nodular scleritis secondary to syphilis. PMID- 8694710 TI - Bilateral optic disc edema and multifocal retinal lesions without loss of vision in cat scratch disease. PMID- 8694711 TI - Choroidal melanomas in American Indians. COMS Group. Collaborative Ocular Melanoma Study. PMID- 8694712 TI - Disordered meibomian gland function in pseudohypoaldosteronism. PMID- 8694713 TI - Conjunctival cyst. PMID- 8694714 TI - Electric cataracts. PMID- 8694715 TI - The Endophthalmitis Vitrectomy Study. PMID- 8694716 TI - The Endophthalmitis Vitrectomy Study. PMID- 8694717 TI - The Endophthalmitis Vitrectomy Study. PMID- 8694718 TI - The Endophthalmitis Vitrectomy Study. PMID- 8694719 TI - The Endophthalmitis Vitrectomy Study. PMID- 8694720 TI - Comparison of the Baerveldt implant with the double-plate Molteno implant. PMID- 8694721 TI - Primary corneal graft failure. PMID- 8694722 TI - Topical dorzolamide-induced hypotony and ciliochoroidal detachment in patients with previous filtration surgery. PMID- 8694723 TI - Iris-sutured posterior chamber lens dislocation late after penetrating keratoplasty. PMID- 8694724 TI - Corneal sensitivity and burning sensation. Comparing topical ketorolac and diclofenac. AB - OBJECTIVES: To compare the effect of topical 0.5% ketorolac tromethamine and 0.1% diclofenac sodium on human corneal sensitivity and to assess the intensity of burning sensation at specific intervals after drop instillation. DESIGN AND SETTING: Double-masked parallel clinical study. PATIENTS: Eleven women and 4 men (8 white, 4 Hispanic, 3 Asian), 22 to 60 years of age (mean [ +/- SD], 34 +/- 10 years). INTERVENTIONS: Repeated instillation of either ketorolac and placebo or diclofenac and placebo at 5-minute intervals. MAIN OUTCOME MEASURES: Assessment of corneal sensitivity before instillation, immediately after instillation, and after termination of drop application; and subjective evaluation of burning sensation by asking participants to rate burning on a scale ranging from 0 (none) to 3 (severe) after each drop application. RESULTS: Both diclofenac (P < .01) and ketorolac (P < .01) decreased corneal sensitivity significantly, while the placebo had no measurable effect. After administration of additional drops over time, the effect of diclofenac and ketorolac increased. After termination of the drug instillation, corneal sensitivity returned to baseline significantly slower (P < .01) in participants receiving diclofenac than in those receiving ketorolac. Ketorolac (P = .01) and diclofenac (P < .05) were significantly more effective in whites than in nonwhites. Mean burning sensation was mild, and there was no statistically significant difference between the 2 drugs on this measure (P = .12). CONCLUSIONS: The decrease in corneal sensitivity in normal human corneas is more pronounced and longer lasting with diclofenac than with ketorolac. Both drugs are well tolerated topically and may be useful for pain reduction after refractive corneal surgery. PMID- 8694725 TI - Central and peripheral endothelial cell changes after excimer laser photorefractive keratectomy for myopia. AB - OBJECTIVE: To investigate changes in the human corneal endothelium after photorefractive keratectomy for treatment of myopia. DESIGN: Specular microscopy of the central, paracentral, and peripheral zones of the corneas of 14 patients (12 of whom were previous contact lens wearers) was performed preoperatively and at 1, 2, 3, 6, and 12 months after photorefractive keratectomy. The corneal endothelial cell density, coefficient of variation (CV) of the endothelial cell area, and percentage of hexagonal cells were assessed at each examination. RESULTS: The central endothelial cell density was increased by 7% during the first 3 postoperative months (P < .05). In contrast, the peripheral cell density declined steadily by 6.9% during the first year (P < .01). The CV of the cell area was decreased in all 3 zones, whereas the percentage of hexagonal cells was increased in the central and paracentral zones (P < .05). CONCLUSIONS: We observed statistically significant changes in the central and peripheral endothelial cell densities and morphological features that could have resulted from photorefractive keratectomy; however, these changes also may have been explained by the discontinuation of contact lens wear. If such changes are contact lens-related, they could mask the effects of laser-induced damage to the central zone of the endothelium. PMID- 8694726 TI - A comparison of latanoprost and timolol in primary open-angle glaucoma and ocular hypertension. A 12-week study. AB - OBJECTIVE: To evaluate the intraocular pressure (IOP)-reducing effect and the side effects of latanoprost (PhXA41), a new phenyl-substituted prostaglandin F2 alpha-isopropyl ester analogue, in patients with elevated IOP, using timolol maleate as the reference drug. METHODS: A total of 184 patients with primary open angle glaucoma or ocular hypertension at 35 medical centers participated in this randomized double-masked study. The patients were randomized to receive either 0.005% latanoprost once daily or 0.5% timolol maleate twice daily, for a period of 12 weeks. Intraocular pressure was measured 24 hours after the administration of timolol, at 2, 4, 8, and 12 weeks of treatment. RESULTS: Latanoprost reduced IOP at the end of 12 weeks by 6.2 +/- 2.7 mm Hg (mean +/- SD) (26.8%), while timolol reduced IOP by 4.4 +/- 2.3 mm Hg (19.9%). At all visits latanoprost reduced IOP significantly more than timolol did. The main ocular side effects observed in both groups were conjunctival hyperemia and smarting. The main systemic side effect was a reduced pulse rate, which occurred in patients treated with timolol. CONCLUSIONS: The results of this study demonstrated that 0.005% latanoprost taken once daily is well tolerated and more effective in reducing IOP than 0.5% timolol taken twice daily. Thus, latanoprost may become an important choice for the medical treatment of glaucoma. PMID- 8694727 TI - Intraocular pressure-raising potential of 1.0% rimexolone in patients responding to corticosteroids. AB - OBJECTIVE: To compare the intraocular pressure (IOP) elevating potential of 1.0% rimexolone and 0.1% fluorometholone alcohol ophthalmic suspensions in patients known to have responded to corticosteroids. DESIGN: In a double-masked, randomized, single-eye, crossover protocol, corticosteroid responsiveness initially was verified in 40 asymptomatic known steroid responders by challenge with either 0.1% dexamethasone sodium phosphate or 1.0% prednisolone acetate for up to 6 weeks. After a 1-month medication washout, subjects randomly received either rimexolone or fluorometholone for 6 weeks. Medications were again discontinued for 1 month, and subjects then received the alternate drug for 6 weeks. RESULTS: There was no significant difference between rimexolone and fluorometholone in the number of subjects demonstrating a 10-mm Hg increase in IOP or in the mean number of weeks required to achieve a 10-mm Hg response. Responses occurred in significantly more subjects receiving dexamethasone sodium phosphate (P = .001) or prednisolone acetate (P < .001) and in a significantly shorter interval than in subjects receiving rimexolone. CONCLUSIONS: Rimexolone has a low IOP-elevating potential, comparable to that of fluorometholone and less than that of dexamethasone sodium phosphate and prednisolone acetate. PMID- 8694728 TI - A 90-day study of the efficacy and side effects of 0.25% and 0.5% apraclonidine vs 0.5% timolol. Apraclonidine Primary Therapy Study Group. AB - OBJECTIVE: To compare long-term intraocular pressure (IOP)-lowering efficacy of 0.25% and 0.5% apraclonidine hydrochloride with 0.5% timolol maleate. DESIGN: Multicenter, randomized, double-masked trial. Adult patients of either sex diagnosed as having open-angle glaucoma or ocular hypertension were enrolled following appropriate washout from all ocular hypotensive medications. Morning IOPs of 22 to 35 mm Hg were required for entry. Patients received 0.25% or 0.5% apraclonidine 3 times a day or 0.5% timolol twice a day for 90 days. Intraocular pressure was measured at 8 AM (before morning dosing) and at 4 PM (8 hours after dosing) on days 1, 30, and 90, and only at 8 AM on day 14. RESULTS: All 3 medications significantly reduced IOP from baseline at all observation times (P < .001): 0.5% apraclonidine reduced IOP more than 0.25% apraclonidine; no significant difference was observed between 0.5% apraclonidine and 0.5% timolol 8 hours after dosing on days 1, 30, and 90; and a significant difference (P < .05) in favour of 0.5% timolol over 0.25% apraclonidine was observed 8 hours after dosing on day 30. At all morning visits following evening dosing, 0.5% timolol significantly reduced IOP more than both concentrations of apraclonidine. CONCLUSIONS: Both 0.25% and 0.5% apraclonidine significantly reduce IOP when used as primary ocular hypotensive medication. Although 0.25% and 0.5% apraclonidine reduce IOP to a similar degree as 0.5% timolol 8 hours after morning dosing, neither concentration is as effective for reducing morning IOP after evening dosing. PMID- 8694729 TI - Endophthalmitis after filtering surgery with mitomycin. AB - OBJECTIVE: To identify the incidence, causative organisms, and clinical outcomes of eyes with bleb-associated endophthalmitis after glaucoma filtering procedures with adjunctive mitomycin. METHODS: Retrospective analysis of 773 consecutive eyes that underwent glaucoma filtering surgery at the Bascom Palmer Eye Institute, Miami, Fla. The course of 609 eyes from 485 patients with a minimum of 3 months of follow-up were reviewed. RESULTS: Mean follow-up was 16.0 +/- 11.5 months (range, 3-48 months). Of the 609 eyes, 13 (2.1%) developed bleb-associated endophthalmitis an average of 18.5 +/- 13.2 months after surgery (range, 1-45 months). The incidence of bleb-associated endophthalmitis was significantly greater after inferior trabeculectomy (7.8% per patient-year) than after superior trabeculectomy (1.3% per patient-year) by Kaplan-Meier estimates (P = .02, log rank test). The cumulative incidence was 13% for inferior limbal blebs and 1.6% for superior limbal blebs. Nine (69.2%) of the 13 eyes were culture positive. Streptococcus sanguis and Haemophilus influenzae (6/13 [46.2%]) were the most frequent causative organisms. The mean increase in intraocular pressure after endophthalmitis treatment was 1.2 mm Hg, with a mean decrease in visual acuity of 1.42 logMAR units. Eight (61.5%) of the 13 eyes had a final acuity of 20/400 or better. CONCLUSIONS: The incidence of bleb-associated endophthalmitis after guarded filtering surgery performed with adjunctive mitomycin is higher than the reported rate in eyes undergoing filtering surgery without the use of antifibrotic agents (0.2%-1.5%). Inferior limbal trabeculectomy carries the highest risk of infection. Eyes with mitomycin blebs maintained excellent filtration capacity. However, after treatment of the infection, the visual outcomes were generally poor. PMID- 8694730 TI - Clinical and histopathologic findings in clumped pigmentary retinal degeneration. AB - OBJECTIVE: To describe the clinical and histopathologic features of clumped pigmentary retinal degeneration (CPRD). DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS: Twenty-four patients, aged 7 to 83 years, were identified from the medical record filed of the Berman-Gund Laboratory, Boston, Mass, as having the clinical features of CPRD. The autopsy eye from a 56-year-old man with CPRD was studied with light and electron microscopy. MAIN OUTCOME MEASURES: Visual acuities, visual fields, dark adaptation thresholds, and results of electroretinograms; histopathologic study of an autopsy eye. RESULTS: The functional deficit of patients with CPRD seems to be similar to that of patients with typical retinitis pigmentosa. Different degrees of severity were observed among patients of similar age. The histopathologic data showed that the clinically distinct areas of clumped pigment are due to excessive accumulation of melanin granules in retinal pigment epithelial cells. CONCLUSION: Based on the distinct clinical and histopathologic appearance, CPRD should be considered as a separate form of retinal degeneration. PMID- 8694731 TI - Diffuse choroidal melanoma. Clinical features predictive of metastasis. AB - OBJECTIVE: To assess the clinical features that predict metastasis of diffuse choroidal melanoma. DESIGN: A review of patients who had been diagnosed clinically as having diffuse choroidal melanoma evaluated on the Oncology Service at Wills Eye Hospital, Philadelphia, Pa. MAIN OUTCOME MEASURE: Effect on metastasis of clinical features of the tumor. RESULTS: Of 3500 consecutive patients with choroidal melanoma, 111 (3%) had diffuse choroidal melanoma. Of these 111 tumors, the mean tumor base was 14.7 mm and the mean overall tumor thickness was 2.1 mm. The thickness-to-base percentage averaged 14.8%. The tumor had poorly defined margins in 39 patients (35%), orange pigment on its surface in 49 (44%), and a secondary serous retinal detachment in 76 (68%). Optic nerve invasion was clinically suspected in 2 patients (2%) and transcleral extension in 3 (3%). Initial management was enucleation in 36 patients (32%), plaque radiotherapy in 60 (54%), laser photocoagulation in 3 (3%), and observation in 12 (11%). During a mean follow-up of 5.3 years (median, 3.9 years), metastasis developed in 29 patients (26%). Using Kaplan-Meier survival estimates, the probability of metastasis developing was 16% at 3 years, 24% at 5 years, and 36% at 10 years. The clinical factors predictive of metastasis by univariate analysis included tumor basal dimension 18 mm or more (P = .002), poorly defined tumor margins (P = .03), transcleral extension (P = .003), and optic nerve invasion (P = .03). The clinical factors predictive of metastasis by multivariate analysis included basal dimension of 18 mm or more (P = .01), optic nerve invasion (P = .03), and poorly defined tumor margins (P = .05). CONCLUSIONS: Despite its relative flatness, diffuse choroidal melanoma carries a metastatic potential of 24% at 5 years. The risks for metastasis are greatest with increasing tumor base and poorly defined margins. Recognition of the clinical features of this tumor in the earliest stage and prompt treatment are encouraged. PMID- 8694732 TI - Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. AB - OBJECTIVE: To determine whether the angiogenic peptide vascular endothelial growth factor (VEGF) is sufficient to produce iris neovascularization in a nonhuman primate (Macaca fascicularis). METHODS: Eight eyes of 4 animals were studied. The 165-amino acid isoform of human recombinant VEGF (VEGF165) was injected into the vitreous of 5 cynomolgus monkey eyes (doses ranging from 0.25 2.5 micrograms per injection). Equal amounts of inactivated human recombinant VEGF (2 eyes) or vehicle (1 eye) were injected into contralateral control eyes. Eyes were assessed by slitlamp biomicroscopy, tonometry, iris color photography, fluorescein angiography, histopathologic examination, and immunostaining with antibodies against proliferating cell nuclear antigen. RESULTS: All 5 bioactive VEGF-injected eyes developed neovascularization with dilated and tortuous iris vessels that leaked fluorescein. None of the 3 control eyes exhibited any iris vascular changes. Inflammation was absent in both treatment groups. A dose response to VEGF was observed in the single animal that received 2.5 micrograms and 0.25 microgram in the right and left eyes, respectively. Iris vessel endothelial cells were positive for proliferating cell nuclear antigen in the bioactive VEGF-injected eyes only. Injections of 1.25 micrograms of VEGF every 3 days during a 30-day period produced advanced iris neovascularization, ectropion uvea, and neovascular glaucoma. CONCLUSIONS: Intravitreal injections of recombinant human VEGF165 in amounts comparable with those measured in eyes with active neovascularization are sufficient to produce noninflammatory iris neovascularization in a nonhuman primate. Prolonged exposure to VEGF165 can produce ectropion uveae and neovascular glaucoma. PMID- 8694733 TI - Localization of vascular endothelial growth factor in human retina and choroid. AB - OBJECTIVE: To examine the distribution and relative levels of vascular endothelial growth factor (VEGF) in the nondiabetic and preproliferative diabetic human retina and choroid. METHODS: Immunohistochemical localization was performed on frozen sections from cryopreserved postmortem human tissue using a polyclonal antibody against VEGF and a streptavidin peroxidase system. Eyes from 5 subjects without diabetes and 8 subjects with diabetes were examined and analyzed using a 7-point immunohistochemical grading system. RESULTS: In subjects without diabetes, weak or no VEGF immunoreactivity was associated with retinal blood vessels. In subjects with diabetes, we found significantly increased immunoreactivity in the retinal vascular endothelium and blood vessel walls. Vascular endothelial growth factor immunoreactivity was also associated with intravascular leukocytes in subjects with and without diabetes. In the choroid of subjects without diabetes, immunoreactivity was almost exclusively associated with intravascular leukocytes, whereas in diabetic subjects, immunoreactivity was localized within choriocapillaris endothelium, choroidal neovascular endothelium, and migrating retinal pigment epithelium cells. CONCLUSIONS: The observed increase in VEGF immunoreactivity in the diabetic retina and choroid suggests that VEGF may contribute to 2 well-documented events during retinopathy: increased vascular permeability and angiogenesis. PMID- 8694734 TI - Intravenous infusion of liposomal benzoporphyrin derivative for photodynamic therapy of experimental choroidal neovascularization. AB - OBJECTIVE: To compare the effectiveness of photodynamic therapy to close experimental choroidal neovascularization using an intravenous infusion of liposomal benzoporphyrin derivative (verteporfin) with previous work using a rapid intravenous injection, before initiating clinical trials. METHODS: Choroidal neovascularization was induced in cynomolgus monkey eyes using argon laser. Liposomal benzoporphyrin derivative was delivered by an intravenous infusion pump for 10 or 32 minutes at a dose of 0.375 mg/kg. Irradiation was performed with 689- or 692-nm laser light (600-mW/cm2 irradiance and 150-J/cm2 fluence) in 7 normal eyes and 11 eyes with choroidal neovascularization between 30 and 105 minutes after the start of dye infusion. Findings were documented by fundus photography, fluorescein angiography, and light and electron microscopy. RESULTS: Irradiation within 32 to 50 minutes of the start of the fast (10 minutes) or slow (32 minutes) dye infusion resulted in closure of choroidal neovascularization. In normal eyes, this technique caused choriocapillaris closure and retinal pigment epithelium damage with minimal damage to surrounding tissues. CONCLUSION: Photodynamic therapy using intravenous infusion of liposomal benzoporphyrin derivative selectively closed experimental choroidal neovascularization. This may be a suitable modality for clinical use. PMID- 8694735 TI - A mouse model of diabetic retinopathy. AB - OBJECTIVE: To obtain a model of diabetic retinopathy to which modern methods of genetic engineering may be applied, by determining the response of 2 strains of mice to long-term galactose feeding. METHODS: Both C57BL/6 mice BALB/c mice were fed each of 2 galactose-rich diets (30% and 50% galactose), and trypsin digests of their retinas were compared with those of controls at durations of up to 26 months. RESULTS: The mortality rate in galactose-fed animals was lower in C57BL/6 mice than in BALB/c mice, and both strains tolerated the 30% galactose diet significantly better than the 50% galactose diet. In C57BL/6 mice fed 30% galactose for 21 to 26 months, saccular microaneurysms were observed in the retina, together with significant increases in the thickness of capillary basement membrane and the prevalence of acellular capillaries and pericyte ghosts. The 50% galactose diet caused significantly more acellular capillaries than normal by 15 months, but excessive mortality precluded study at longer durations. The frequency of acellular capillaries also was greater than normal in BALB/c mice fed 30% galactose for 21 months. Retinal polyol levels in galactose fed mice were found to be lower than those in galactosemic rats. CONCLUSION: The mouse may provide an inexpensive model suitable for in vivo study of the pathogenesis of diabetic retinopathy using molecular biological techniques. PMID- 8694736 TI - Association of zinc and antioxidant nutrients with age-related maculopathy. AB - OBJECTIVE: To quantify relationships between dietary intake of zinc and antioxidant nutrients and early and late age-related maculopathy (ARM). DESIGN: A retrospective longitudinal cohort design using data pertaining to diets in the past (1978-1980), which were assessed retrospectively using a food frequency questionnaire. SETTING: Beaver Dam, Wis. PATIENTS: A 50% random sample of free living Beaver Dam Eye Study participants, 43 to 86 years of age (N = 1968). MAIN OUTCOME MEASURE: The presence of early and late ARM determined from fundus photography. RESULTS: People in the highest vs lowest quintiles for intake of zinc from foods had lower risk for early ARM (odds ratio = 0.6, 95% confidence interval, 0.4-1.0, P for trend < .05). This relationship appeared to be stronger for some types of early ARM (increased retinal pigment) than for others. Zinc intake was unrelated to late ARM. However, small numbers (n = 30) of people with this condition limit the ability to draw conclusions about this later stage. Levels of carotenoids were unrelated to early or late ARM. Odds for early ARM were lower in people in the highest vs lowest quintiles for the intake of vitamins C or E. However, these associations were not statistically significant. CONCLUSIONS: The data are weakly supportive of a protective effect of zinc on the development of some forms of early ARM. Prospective studies are needed to further evaluate the potential influence of these and other nutritional factors on different types and stages of age-related macular degeneration. PMID- 8694737 TI - Will latanoprost be the 'wonder' drug of the '90s for the treatment of glaucoma? PMID- 8694738 TI - [The present and the future of alcohol study in the field of Pharmacology]. PMID- 8694739 TI - [A case of volatile solvent psychosis accompanied with multiple neurological and psychological symptoms]. AB - A case of psychosis accompanied with variable symptoms induced by chronic volatile solvent inhalation is reported in this study. The patient was a 27-year old male who had abused volatile solvents for 15 years, and was sent to the hospital because of a tonic-clonic seizure. Severe psychomotor excitement was observed on the first day and the 7th day after admission. After 10 days of admission, we observed visual transformation and hyperthermia, which suggested acute toxic symptoms due to a volatile solvent. Furthermore, symptoms such as incoherence, delusions of persecution, and catalepsy were also observed in this case. There have been few reports of multiple neurological and mental symptoms appearing in cases of volatile solvent psychosis. Although we sometimes experience cases of solvent abuse with acute mental symptoms and recurrent excitement after sedation, such symptoms are not always observed because of flashback in the strict sense. Therefore, careful early treatment should be employed to prevent 'secondary excitement'. PMID- 8694740 TI - [A clinicopathological study of primary liver cancer associated with alcoholic liver injury]. AB - We described a clinicopathological study of primary hepatoma associated with alcoholic liver diseases without viral liver diseases. In 150 patients with primary hepatoma, 6 patients (4%) have hepatoma associated with pure alcoholic liver disease, although 143 hepatoma were associated with chronic viral liver diseases and one was with primary biliary cirrhosis. All patients were male. The diagnosis of hepatoma was obtained at the age of 54 to 67 years old, and the duration of ethanol intake was 33 to 40 years. Three cases had a history of temperance. As an underlying liver disease, liver fibrosis was found in 3 cases and liver cirrhosis was in 3 cases. Chronic infections of hepatitis B and C viruses were ruled out by assaying serum virus markers. Autoimmune hepatitis and primary biliary cirrhosis were neglected by serum autoantibody. Hemochromatosis and Wilson's disease were also excluded. Hepatocellular carcinoma was diagnosed histologically in all the cases. Serum alpha-fetoprotein and PIVKA-II were positive in patients with advanced hepatocellular carcinoma. In cases with small hepatoma, the tumor was resected surgically in two cases and percutaneous ethanol injection against hepatoma was performed in one case. In these cases with small hepatoma, the patients were alive without tumor recurrence during observation period. In advanced hepatoma, transcatheter arterial infusion of anticancer agent was performed in two cases and no therapy was performed due to poor general condition in one case. One case was alive with recurrent hepatoma for 27 months, during which a therapy was repeated five times. Other 2 cases were died. The clinicopathological features of hepatoma associated with alcoholic liver disease were essentially same as those associated with chronic viral infection, although the incidence of hepatoma in alcoholic liver disease was lower than in viral liver disease. The mechanism of hepatocarcinogenesis in alcoholic liver disease was unclear and, therefore, further study of molecular biology and biochemistry was necessary. PMID- 8694741 TI - [Changes in platelet adenylyl cyclase system in alcoholics]. AB - Platelet GTP binding protein (G protein) in 25 alcoholics with a first-degree alcoholic relative (family history positive alcoholic; FHP), in 25 alcoholics without alcoholic relatives (family history negative alcoholic; FHN) and in 25 controls without alcoholic relatives was investigated to determine whether this protein is a trait marker for alcoholism. The alcoholic subjects met DSM III-R criteria for alcohol dependence and had been abstinent from alcohol for at least one year. Lowered platelet guanine nucleotide (GppNHp)-stimulated adenylyl cyclase (AC) activity and reduced sensitivity of AC to ethanol were recognized in FHP but not in FHN. Remarkable reduction in ethanol enhancement of functional photoaffinity GTP (azidoanilido GTP; AAGTP) binding to Gs alpha and Gi alpha in platelet membrane was observed in FHP but not in FHN. A quantitative reduction in Gs alpha and GsH alpha (high molecular weight Gs alpha) levels as assessed by immunoblotting was seen in platelet membrane from FHP but not from FHN. These results indicate that the characteristic of platelet G protein may be used as a trait marker for alcoholism. PMID- 8694742 TI - [Effect of vitamin E and vitamin C deficiency on the development of alcoholic liver diseases]. AB - Effects of vitamin E (V.E) and vitamin C (V.C) deficiency on the progress of alcoholic liver disorder in 72 Osteogenic Disorder Shionogi (ODS) male rats were studied. Animals were divided into two groups which received 5% ethanol liquid diet (A group) or pair-fed an isocalorical liquid diet with carbohydrate replacing ethanol (C group). All animals were pair-fed with these diets free of V.E during experiment period. In first experiment, after pair-feeding with the diets free of V.C for 2 or 5 weeks, the animals were killed. In another experiment, after pair-feeding with the diets free of V.C for 4 weeks, and then with the diets addition of 0.1 or 1.0 mg/ml V.C. for 2 weeks, the animals were killed. In first experiment, hepatic V.E concentrations in rats fed with V.E. and V.C deficient diets decreased more severely than those fed with only V.E deficient diets. After 2 weeks hepatic lipid peroxide content was increased, while at 5 weeks, it's decreased both in A and C group. In another experiment, hepatic aniline hydroxylase activity increased both by ethanol administration and by addition of V.C. Total P450 and P450 2E1 contents also increased by addition of V.C. And then hepatic lipid peroxide contents increased by addition of V.C. in A groups. These results suggested that V.E and V.C deficiency disturbed alcohol metabolic enzyme activity on the progress of alcoholic liver disorder. PMID- 8694743 TI - [Helminth burden of slaughter sheep in Upper Bavaria. 1: Species spectrum, infestation extent and infestation intensity]. AB - The helminth fauna of 136 slaughtered sheep (99 lambs < 1 year, and 37 sheep > or = 1 year) from Upper Bavaria, Germany, was examined. In all 2 species of trematodes, 3 species of cestodes and 24 species of nematodes were found. All the animals harboured gastrointestinal nematodes, 9 of them liver flukes, 33 Moniezia spp., 19 Cysticercus tenuicollis, and one sheep Setaria sp. Lungworms were not seen. The most prevalent species were Cooperia curticei (74.3%), Trichuris ovis (69.1%), Ostertagia circumcincta (68.4%), Oesophagostomum venulosum (63.2%) and Chabertia ovina (61.8%). The highest mean wormburden was seen in Cooperia curticei (12471) followed by Trichostrongylus axei (1856), Trichostrongylus colubriformis (1752), Nematodirus filicollis (1551) and Nematodirus battus (1238). In both lambs and older sheep the small intestine harboured the highest wormburden followed by abomasum and large intestine. The total nematode counts were much higher in lambs than in older sheep. The lambs harboured more intestinal nematodes than older sheep but fewer abomasal worms. PMID- 8694744 TI - [Resistance pattern of bovine Pasteurella]. AB - The sensibility of 375 pasteurellae of bovine origin (215 pasteurella multocida- and 160 pasteurella haemolytica--strains) was examined against 16 antibiotics or chemotherapeutics by agar diffusion technique. A great part of the strains was resistant to oxacillin (41,18%), tylosin (79,14%), streptomycin (53,21%), sulfonamides (57,33%) and tetracycline (47,20%). Only a few resistant strains were found for cephalothin (5,07%), polymyxin B (0,27%) and enrofloxacin (0,53%). While 16,27% of all isolates were resistant to chloramphenicol, 100% of the pasteurella strains proved to be sensible to its structural analogon florfenicol. This is affirmed by the low minimal inhibitory concentrations (0,25-1,0 micrograms/ml) of this antibiotic. PMID- 8694745 TI - [Some hematologic values of Peking ducks]. AB - This work has been done to investigate physiological values of some hematological parameters of peking ducks. For this purpose 20 healthy peking ducks have been studied. Total red (R.B.C.) and white (W.B.C.) blood cell counts by routine methods in Thoma hemocytometers after diluting with Natt-Herrick solution, packed cell volume (P.C.V. = Htc) by the microhematocrit centrifuge method, hemoglobin (Hb) by the cyanmethaemoglobin method were carried out. Blood films were stained by Pappenheim's method and the percentage of neutrophils, lymphocytes, eosinophils, basophils, and monocytes was estimated on a differential count of 200 cells. The mean values have been found as follows: R.B.C. = 3,835 x 10(6)/mm3, W.B.C. = 15.950/mm3, Hb = 12 g%, P.C.V. = 36,15%, neutrophils = 62,10%, lymphocytes = 30,95%, basophils = 5,8%, eosinophils = 0,6% [corrected], monocytes = 0,6%. PMID- 8694746 TI - [Case report: dental fistula of the mandible in a rabbit]. AB - Report on a purulent fistulation of the mandibula in a rabbit, caused by displaced molar teeth. Diagnosis, surgery and recovery are being described. PMID- 8694747 TI - [Distribution of Borna disease virus in naturally infected animals with clinical disease]. AB - Borna disease (BD) is a naturally occurring enzootic encephalomyelitis of horses and sheep. The aetiological agent, Borna disease virus (BDV) is an unclassified, neurotropic, negative stranded RNA virus. The study aimed at providing further information on BD of naturally infected animals. Samples obtained from 20 animals (18 horses, 1 donkey, 1 sheep) were investigated by a series of virological and molecular biological tests. The highly sensitive reverse transcription-polymerase chain reaction (RT-PCR) method was used to analyze the tissue distribution of BDV specific RNA. BDV-specific RNA was detected in bulbus olfactorius, nucleus caudatus, hippocampus and cerebral cortex of all infected animals. BDV-RNA was also present in the spinal cord, eye, nasal mucosa, parotide gland, lung, heart, liver, kidney, bladder and ovaries. In addition, BV-specific RNA was also detected in conjunctival fluid, nasal secretions and saliva of two infected animals. By Western Blot assays the highest amounts of BDV antigens were demonstrated in bulbus olfactorius, nucleus caudatus, hippocampus and cerebral cortex. PMID- 8694748 TI - ["Spoils of war"--losses of the Berlin Veterinary Medicine Library in 1945]. AB - All the German veterinary libraries suffered heavy losses during World War II and its aftermath, but the Berlin Veterinary Faculty, whose library was known until 1945 as the biggest veterinary book collection of the world, was exceedingly affected. The reports on the damage during these years note losses of up to 35,000 or 43,000 of nearly 60,000 books. Actually, diverse papers did mention this fact but they concealed the underlying causes of the losses or simply referred to effects of war. However, new evidence allows to claim, that most of the losses have been caused by a very different measure: the confiscation of parts of the library by units of the Soviet Army in May and June 1945 as spoils of war. Eye witnesses and unpublished official as well as unofficial reports show that the choice as to what books should be seized was purposefully made according to special criteria: the most modern specialists' literature (journals and books) and the rare books of bibliophilic value. The library lost important parts of its stock: medical books, parts of the irreplaceable historical collection in veterinary medicine, the foreign language books, the biggest part of the natural science literature (physics, chemistry, biology with botany and zoology) and books on adjacent fields of interest (geography and travel literature, belles lettres, history, philosophy and so on). This contribution deals with the events during the weeks before and after VE day and the course of measures taken in selecting and expropriating the books mentioned above. It is intended to invite additional contemporary witnesses who might bei knowledgeable about these events to help in specifying them more precisely and clearing open questions, which still remain. PMID- 8694749 TI - The denaturation and degradation of stable enzymes at high temperatures. AB - Now that enzymes are available that are stable above 100 degrees C it is possible to investigate conformational stability at this temperature, and also the effect of high-temperature degradative reactions in functioning enzymes and the inter relationship between degradation and denaturation. The conformational stability of proteins depends upon stabilizing forces arising from a large number of weak interactions, which are opposed by an almost equally large destabilizing force due mostly to conformational entropy. The difference between these, the net free energy of stabilization, is relatively small, equivalent to a few interactions. The enhanced stability of very stable proteins can be achieved by an additional stabilizing force which is again equivalent to only a few stabilizing interactions. There is currently no strong evidence that any particular interaction (e.g. hydrogen bonds, hydrophobic interactions) plays a more important role in proteins that are stable at 100 degrees C than in those stable at 50 degrees C, or that the structures of very stable proteins are systematically different from those of less stable proteins. The major degradative mechanisms are deamidation of asparagine and glutamine, and succinamide formation at aspartate and glutamate leading to peptide bond hydrolysis. In addition to being temperature-dependent, these reactions are strongly dependent upon the conformational freedom of the susceptible amino acid residues. Evidence is accumulating which suggests that even at 100 degrees C deamidation and succinamide formation proceed slowly or not at all in conformationally intact (native) enzymes. Whether this is the case at higher temperatures is not yet clear, so it is not known whether denaturation of degradation will set the upper limit of stability for enzymes. PMID- 8694750 TI - Flavodoxin 1 of Azotobacter vinelandii: characterization and role in electron donation to purified assimilatory nitrate reductase. AB - Flavodoxins synthesized by Azotobacter vinelandii strain UW 36 during growth on nitrate as nitrogen source were separated by FPLC on a Mono Q column into two species, flavodoxin 1 (AvFld 1) and flavodoxin 2 (AvFld 2). Both proteins migrated as single bands on SDS/PAGE. AvFld 1 was approx. 5-fold more abundant than AvFld 2 in the unresolved flavodoxin mixture. N-terminal amino acid analysis showed the sequence of AvFld 2 to correspond to the nif F gene product, an electron donor to nitrogenase. The sequences also show that these species corresponded to the flavodoxins Fld A and Fld B isolated from N2-grown cultures of the closely related organism Azotobacter throococcum [Bagby, Barker, Hill, Eady and Thorneley (1991) Biochem.J.277, 313-319]. Electrospray mass spectrometry gave M, values for the polypeptides of 19430 +/- 3 and 19533 +/- 5 respectively. 31P-NMR measurements showed that in addition to the phosphate associated with the FMN (delta = -136.3 p.p.m. and -135.48 p.p.m.), AvFld 1 had a signal at delta = 142.1 p.p.m. and AvFld 2 at delta = -138.59 p.p.m. present in substoichiometric amounts with FMN. These appeared to arise from unstable species since they were readily lost on further manipulation of the proteins. The mid-point potentials of the semiquinone hydroquinone redox couples were -330 mV and -493 mV for AvFld 1 and AvFld 2 respectively, but only AvFld 1 was competent in donating electrons to the purified assimilatory nitrate reductase of A. vinelandii to catalyse the reduction of nitrate to nitrite. Flavodoxin isolated from NH4(+)-grown cells (Fld 3) also functioned as electron donor at half the rate of AvFld 1, but ferredoxin 1 from A. chroococcum did not. PMID- 8694751 TI - Stimulation of phosphatidylinositol hydrolysis, protein kinase C translocation, and mitogen-activated protein kinase activity by bradykinin in rat ventricular myocytes: dissociation from the hypertrophic response. AB - In ventricular myocytes cultured from neonatal rat hearts, bradykinin (BK), kallidin or BK(1-8) [(Des-Arg9)BK] stimulated PtdinsP2 hydrolysis by 3-4-fold. EC50 values were 6 nM (BK), 2 nM (kallidin), and 14 microM [BK(1-8)]. BK or kallidin stimulated the rapid (less than 30 s) translocation of more than 80% of the novel protein kinase C (PKC) isoforms nPKC-delta and nPKC-epsilon from the soluble to the particulate fraction. EC50 values for nPKC-delta translocation by BK or kallidin were 10 and 2 nM respectively. EC50 values for nPKC-epsilon translocation by BK or kallidin were 2 and 0.6 nM respectively. EC50 values for the translocation of nPKC-delta and nPKC-epsilon by BK(1-8) were more than 5 microM. The classical PKC, cPKC-alpha, and the atypical PKC, nPKC-zeta, did not translocate. BK caused activation and phosphorylation of p42-mitogen-activated protein kinase (MAPK) (maximal at 3-5 min, 30-35% of p42-MAPK phosphorylated). p44-MAPK was similarly activated. EC50 values for p42/p44-MAPK activation by BK were less than 1 nM whereas values for BK(1-8) were more than 10 microM. The order of potency [BK approximately equal to kallidin >> BK (1-8)] for the stimulation of PtdInsP2 hydrolysis, nPKC-delta and nPKC-epsilon translocation, and p42/p44-MAPK activities suggests involvement of the B2 BK receptor subtype. In addition, stimulation of all three processes by BK was inhibited by the B2BK receptor-selective antagonist HOE140 but not by the B1-selective antagonist Leu8BK(1-8). Exposure of cells to phorbol 12-myristate 13-acetate for 24 h inhibited subsequent activation of p42/p44-MAPK by BK suggesting participation of nPKC (and possibly cPKC) isoforms in the activation process. Thus, like hypertrophic agents such as endothelin-1 (ET-1) and phenylephrine (PE), BK activates PtdInsP2 hydrolysis, translocates nPKC-delta, and nPKC-epsilon, and activates p42/p44-MAPK. However, in comparison with ET-1 and PE, BK was only weakly hypertrophic as assessed by cell morphology and patterns of gene expression. This difference could not be attributed to dissimilarities between the duration of activation of p42/p44-MAPK by BK or ET-1. Thus activation of these signalling pathways alone may be insufficient to induce a powerful hypertrophic response. PMID- 8694752 TI - Chemical cross-linking of pleckstrin in human platelets: evidence for oligomerization of the protein and its dissociation by protein kinase C. AB - The major substrate of protein kinase C(PKC) in platelets is the 40 kDa protein, pleckstrin. Addition of the homobifunctional reagent, bis(sulphosuccinimidyl)suberate (BS3), to platelet lysate, cytosol fraction or to electropermeabilized platelets resulted in cross-linking of pleckstrin to give higher-molecular-mass complexes of 68 kDa, 90 kDa and 100-120 kDa respectively, which were visualized by immunoblotting with an anti-pleckstrin antibody. Higher levels of cross-linking were observed in permeabilized platelets than in platelet lysates. The yields of the cross-linked complexes were much reduced after dilution of platelet lysate or lysis of electropermeabilized platelets and, in the case of the 90 kDa and 100-120 kDa species, after activation of PKC by phorbol 12-myristate 13-acetate. Similar experiments with purified pleckstrin indicated that the 90 kDa and 100-120 kDa species consist, at least in part, of pleckstrin dimers and higher oligomers. After incubation of purified pleckstrin (0.45 mg/ml) for 1 h with 2 mM BS3, about 25% of the protein was present in cross linked species. The results indicate that pleckstrin undergoes a reversible self association that can be prevented by phosphorylation of the protein, and also interacts with an unidentified platelet protein of about 28 kDa. PMID- 8694753 TI - Brefeldin A enables synthesis of active lipoprotein lipase in cld/cld and castanospermine-treated mouse brown adipocytes via translocation of Golgi components to endoplasmic reticulum. AB - Brown adipocytes cultured from newborn combined-lipase-deficient (cld/cld) mice and castanospermine (CST)-treated 3T3-L1 adipocytes synthesize lipoprotein lipase (LPL) which is inactive and retained in the endoplasmic reticulum (ER) [Masuno, Blanchette-Mackie, Chernick and Scow (1990) J.Biol. Chem. 265, 1628-1638; Masuno, Blanchette-Mackie, Schultz, Spaeth, Scow and Okuda (1992) J. Lipid Res.33, 1343 1349]. Brefeldin A (BFA), which is known to block protein transport from ER and translocate Golgi components to ER, was used here to study the effect of translocated Golgi enzymes on LPL retained in ER of cld/cld and CST-treated mouse brown adipocytes. Brown adipocytes cultured from newborn normal mice contained 3000-5000 m-units of LPL activity/mg of DNA and secreted 35 m-units of LPL activity/mg of DNA per h. BFA at 10 micrograms/ml doubled LPL activity in normal cells within 2 h as it stopped completely secretion of active LPL. LPL in mouse cells has two N-oligosaccharide chains per subunit. Analyses with SDS/PAGE and immunoblotting showed that about one-third of LPL subunits in untreated normal cells were totally endo-beta-N-acetylglucosaminidase (endo H)-resistant, one third were partially endo H-resistant, and one-third were totally endo H sensitive. BFA decreased to zero the proportion of subunits which were totally endo H-resistant, while it increased the proportion which were partially endo H resistant. Thus, BFA blocked processing of one oligosaccharide chain per subunit to endo H-resistance. Sucrose-gradient centrifugation studies showed that BFA increased the proportion of LPL subunits in normal cells which were present as active dimers. LPL activity in cld/cld adipocytes was 120 m-units/mg of DNA and that in normal adipocytes treated with CST was 430 m-units/mg of DNA. Most LPL subunits in such cells were totally endo H-sensitive and some were partially endo H-resistant, but none were totally endo H-resistant. Some of the subunits, in both cld/cld and CST-treated cells, were present as inactive LPL dimers. BFA increased LPL activity in cld/cld cells to 2100 m-units/mg of DNA and that in CST treated cells to 2600 m-units/mg of DNA within 2 h. BFA increased in both groups the proportion of LPL subunits which were partially endo H-resistant. BFA also increased the proportion which were present as active dimers. Immunofluorescence studies in normal and cld/cld adipocytes showed that BFA caused retention of LPL in large tubular and spherical structures and in ER, but not in Golgi. When BFA was withdrawn and protein synthesis was blocked with cycloheximide, LPL in normal cells was transferred to Golgi within 30 min and disappeared within 60 min, whereas LPL in cld/cld cells was retained in large vesicles and ER. The findings indicate that BFA enabled synthesis of active LPL in cld/cld and CST-treated cells via translocation of Golgi components to ER. Also, cld/cld cells synthesized LPL which could be processed to active lipase and the enzymes needed for activation of the lipase were present in Golgi of such cells. Production of inactive LPL in cld/cld adipocytes probably results from their inability to transport LPL from ER to Golgi. PMID- 8694754 TI - Research communication copper-1,10-phenanthroline induces internucleosomal DNA fragmentation in HepG2 cells, resulting from direct oxidation by the hydroxyl radical. AB - In view of the current speculation regarding the possible role of reactive oxygen species (ROS) in apoptosis, both under physiological conditions and in response to chemicals that promote their intracellular formation, the present investigation was undertaken to examine whether DNA fragmentation during oxidative stress results from endonuclease activity (apoptosis) or from direct attack by ROS. We report that the incubation of HepG2 cells (a human-derived hepatoma cell line) with the copper(II) complex of 1,10-phenanthroline, CuII(OP)2, results in internucleosomal DNA fragmentation, which is widely recognized as being a hallmark of apoptosis. DNA fragmentation did not occur at low temperature, but activity was restored by the addition of ascorbic acid. It is proposed that DNA fragmentation results from the direct attack of hydroxyl radicals upon DNA. Hydroxyl radicals are produced from oxygen by the redox cycling of CuII(OP)2, which is supported by metabolic processes at normal temperature. At low temperature ascorbic acid provides an artificial cellular reducing environment, thereby restoring hydroxyl radical formation. These findings were confirmed by the detection of internucleosomal DNA fragmentation following the exposure of isolated chromatin to a biomimetic CuII(OP)2 redox cycling system. We conclude that DNA laddering, the widely employed hallmark of apoptosis, is not unique to endonuclease activity and may also result from direct attack upon DNA by the hydroxyl radical. PMID- 8694755 TI - Panagrellus redivivus ornithine decarboxylase: structure of the gene, expression in Escherichia coli and characterization of the recombinant protein. AB - A southern blot analysis of the Panagrellus redivivus ornithine decarboxylase (ODC) gene suggests that it is a single-copy gene that resides on a genomic 3.2 kb EcoRI fragment. Phage clones possessing ODC gene sequences were isolated from a genomic EMBL-4 library and purified. The phage DNA inserts were analysed and a 3.2 kb EcoRI fragment containing the entire ODC gene was isolated. The nucleotide sequence analysis of this fragment reveals that the gene is interrupted by two introns of 47 and 49 bp. In the 5' non-translated region of the gene, putative AP1, VPE2 and c-Myc binding sites were identified. The ODC cDNA was expressed in a bacterial system as a His-fusion protein and the enzyme was purified by Ni(2+) chelating affinity chromatography. The subunit molecular mass, as deduced from the cDNA and shown by SDS/PAGE, is 47.1 kDa. On the basis of gel filtration analyses it is shown that the active enzyme is a dimer. The specific enzyme activity was determined to be 4.2 mumol CO2/min/mg protein. The enzyme is dependent on pyridoxal 5-phosphate as a cofactor, and the presence of dithioerythritol or other thiol-reducing agents is essential for maximal activity. The Km value for L-ornithine was determined as 44 microM. The Ki values for putrescine, alpha-diffluoromethylornithine, alpha-hydrazino-ornithine and alpha-methylornithine were calculated as 51, 34, 0.34 and 42 microM respectively. PMID- 8694756 TI - Probing the S-adenosylmethionine-binding site of rat guanidinoacetate methyltransferase. Effect of site-directed mutagenesis of residues that are conserved across mammalian non-nucleic acid methyltransferases. AB - Most mammalian non-nucleic acid methyltransferases share three sequence motifs. To gain insight into the S-adenosyl-methionine (AdoMet)-binding site of guanidinoacetate methyltransferase, we mutated several conserved residues that are found in or near motifs I and II. Conversion of either of two glycine residues of motif I (Gly67 and Gly69) to an alanine resulted in an inactive enzyme. These enzymes, although having UV absorption, fluorescence and far-UV CD spectra virtually identical with those of the wild-type enzyme, seem to be conformationally different from the wild-type enzyme as judged by near-UV CD spectra and the extent of urea denaturation, and are apparently not capable of binding AdoMet. Mutation of Tyr136 of motif II to a valine resulted in a decrease in Kcat/Km values for substrates. Changing this residue to a phenylalanine caused only a minor change in Kcat/Km for AdoMet. This suggests that the aromatic side chain stabilizes the binding of AdoMet. Mutagenic changes of Glu89, which is the residue corresponding to the conserved acidic residue on the C-terminal side of motif I, indicated its contribution to AdoMet binding. These results are consistent with the idea that both motifs I and II are crucial in forming the AdoMet binding site of guanidinoacetate methyltransferase. PMID- 8694757 TI - Purification and characterization of assimilatory nitrite reductase from Candida utilis. AB - Nitrate assimilation in many plants, algae, yeasts and bacteria is mediated by two enzymes, nitrate reductase (EC 1.6.6.2) and nitrite reductase (EC 1.7.7.1). They catalyse the stepwise reduction of nitrate to nitrite and nitrite to ammonia respectively. The nitrite reductase from an industrially important yeast, Candida utilis, has been purified to homogeneity. Purified nitrite reductase is a heterodimer and the molecular masses of the two subunits are 58 and 66 kDa. The native enzyme exhibits a molecular mass of 126 kDa as analysed by gel filtration. The identify of the two subunits of nitrite reductase was confirmed by immunoblotting using antibody for Cucurbita pepo leaf nitrite reductase. The presence of two different sized transcripts coding for the two subunits was confirmed by (a) in vitro translation of mRNA from nitrate-induced C. utilis followed by immunoprecipitation of the in vitro translated products with heterologous nitrite reductase antibody and (b) Northern-blot analysis. The 66 kDa subunit is acidic in nature which is probably due to its phosphorylated status. The enzyme is stable over a range of temperatures. Both subunits can catalyse nitrite reduction, and the reconstituted enzyme, at a higher protein concentration, shows an activity similar to that of the purified enzyme. Each of these subunits has been shown to contain a few unique peptides in addition to a large number of common peptides. Reduced Methyl Viologen has been found to be as effective an electron donor as NADPH in the catalytic process, a phenomenon not commonly seen for nitrite reductases from other systems. PMID- 8694758 TI - N-acetyl-D-neuraminic acid lyase generates the sialic acid for colominic acid biosynthesis in Escherichia coli K1. AB - Colominic acid is a capsular homopolymer from Escherichia coli K1 composed of alpha (2-8)-linked N-acetyl-D-neuraminic acid (NeuAc) residues. Recently, we have described that NeuAc synthesis in this bacterium occurs through the action of NeuAc lyase (EC 4.1.3.3) [ Rodriguez-Aparicio, Ferrero and Reglero (1995) Biochem. J.308, 501-505]. In the present work we analysed and characterized this enzyme. E. coli K1 NeuAc lyase is detected from the early logarithmic phase of growth, is induced by NeuAc and is not repressed by glucose. The enzyme was purified to apparent homogeneity (312-fold) using two types of hydrophobic chromatographies (butyl-agarose and phenyl-Sepharose CL-4B), gel filtration on Sephacryl S-200, and anion-exchange chromatography on DEAE-FPLC. The pure enzyme, whose amino acid composition and N-terminal amino acid sequence are also established, has a native molecular mass, estimated by gel filtration, of 135 +/- 3 kDa, whereas its molecular mass in SDS/PAGE was 33 +/- 1 kDa. The enzyme was able to synthesize and cleave NeuAc in a reversible reaction. The maximal rate of catalysis was achieved in 125 mM Tris/HCl buffer, pH 7.8, at 37 degrees C. Under these conditions, the K(m) values calculated for N-acetyl-D-mannosamine and pyruvate (condensation direction), and NeuAc (hydrolysis direction) were 7.7, 8.3 and 4.8 mM respectively. NeuAc synthesis by the pure enzyme was activated by Ca2+ and inhibited by Mn2+ and NeuAc, whereas the enzyme cleavage direction was inhibited by Ca2+, Mn2+ and pyruvate. The reaction products, NeuAc and pyruvate, and Ca2+ are able to regulate the direction of this enzyme (synthesis or cleavage of sialic acid) and, accordingly, to modulate colominic acid biosynthesis. PMID- 8694759 TI - Muscarinic activation of Ca2+/calmodulin-dependent protein kinase II in pancreatic islets. Temporal dissociation of kinase activation and insulin secretion. AB - We have demonstrated previously that glucose activates the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) in isolated rat pancreatic islets in a manner consistent with a role of this enzyme in the regulation of insulin secretion [Wenham, Landt and Easom (1994) J. Biol. Chem. 269, 4947-4952]. In the current study, the muscarinic agonist, carbachol, has been shown to induce the conversion of CaM kinase II into a Ca(2+)-independent, autonomous form indicative of its activation. Maximal activation (2-fold) was achieved by 15 s, followed by a rapid return to basal levels by 1 min. This response was primarily the result of the mobilization of Ca2+ from intracellular stores since it was not affected by a concentration (20 microM) of verapamil that completely prevented the activation of CaM kinase II by glucose. Surprisingly, carbachol added prior to, or simultaneously with, glucose attenuated nutrient activation of CaM kinase II. This effect was mimicked by cholecystokinin-8 (CCK 8) and thapsigargin, suggesting its mediation by phospholipase C and the mobilization of intracellular Ca2+. In contrast, carbachol, CCK-8 and thapsigargin markedly potentiated glucose (12 mM)-induced insulin secretion. These results suggest that CaM kinase II activation can be temporally dissociated from insulin secretion but do not exclude the potential dependence of insulin exocytosis on CaM kinase II-mediated protein phosphorylation. PMID- 8694760 TI - Oxidative denitrification of N omega-hydroxy-L-arginine by the superoxide radical anion. AB - The superoxide radical anion (O2-.) produced during the catalytic activity of nitric oxide synthase (NOS) and cytochrome P-450 has been implicated in the oxidative denitrification of hydroxyguanidines ( > C = NOH). The reactivity of the radiolytically generated O2-. radical with N omega-hydroxy-L-arginine (NHA) is pH dependent and appears to parallel the prototropic equilibrium of the hydroxyguanidino group ( > C = NOH reversible > C = NO(-)+H+; pK = 8). The N omega-hydroxyguanidino group is more reactive towards O2-. when deprotonated but exhibits negligible reactivity when protonated. Based on a model, the rate constant for the reaction of the O2-. with NHA was estimated as kappa (O2-.+ > C = NO-) approximately 200-500 M-1.s-1, which is probably too low to compete with O2-. reactions with NO- or superoxide dismutase, which occur many orders of magnitude faster. The oxidative elimination of NO from NHA by O2-. was not accompanied by the formation of L-citrulline. Since only 21% of NHA will exist in the deprotonated > C = NO- form at physiological pH, it is unlikely that oxidative denitrification of NHA by cytochrome P-450 or NOS-derived O2-. radicals will prove a major free-radical pathway to NO. and L-citrulline. PMID- 8694761 TI - Evidence that filaggrin is a component of cornified cell envelopes in human plantar epidermis. AB - Cornified cell envelope (CE) is generated during the late stages of epidermal differentiation and is made up of proteins covalently linked together by transglutaminases. To determine whether filaggrin is a component of this structure in humans, we analysed highly purified CE from plantar stratum corneum. An immunoelectron microscopy analysis showed specific binding of four different anti-(pro)filaggrin monoclonal antibodies to the surface of the CE, proved previously to be free of non-covalently linked proteins. Moreover, the anti filaggrin activity of one of the antibodies was absorbed by preincubation with the plantar CE, as determined by ELISA. Convincingly, fragments of CE produced by proteolytic digestion of the structures were stained by this antibody on immunoblots. These data provide direct evidence that filaggrin is a component of CE purified from human plantar stratum corneum. Cross-linking between CE and the filaggrin-containing fibrous matrix may enhance the structural cohesion of the corneocytes and thus the resistance of the stratum corneum. PMID- 8694762 TI - Cloning and biochemical characterization of the cyclophilin homologues from the free-living nematode Caenorhabditis elegans. AB - Cyclosporin A (CsA) is the most widely used immunosuppressive agent, whose properties are exerted via an interaction with cyclophilin, resulting in down regulation of signal-transduction events in the T-cell. Cyclophilin is identical with peptidylprolyl cis-trans isomerase (PPI; EC 5.2.1.8), an enzyme which catalyses the isomerization between the two proline conformations in proteins, thereby acting as a catalyst in protein-folding events. Several reports indicate that CsA has potent anti-parasitic activity, effective against both protozoan and helminth species. In order to understand the various biological roles that cyclophilins play we have initiated a study of these proteins in the genetically tractable nematode Caenorhabditis elegans. Here we describe the cloning and characterization of 11 cyclophilin genes (cyp-1 to -11) derived from this nematode; this is currently the greatest number of isoforms described in a single species. Southern blotting and physical mapping indicated that these genes are dispersed throughout the nematode genome. A high degree of conservation exists between several isoforms, which also share characteristics with the ubiquitous isoforms previously described. The remaining isoforms are divergent, having altered CsA-binding domains and additional non-cyclophilin domains, which may impart compartmental specificity. Ten of these isoforms have been expressed in Escherichia coli, and the resultant fusion proteins have been examined biochemically for PPI activity, which they all possess. Isomerase activity is highest in the conserved and lowest in divergent isoforms, perhaps indicating a more specific substrate for the latter. Analysis of the C. elegans cyp genes will provide answers as to the roles played by cyclophilins in protein folding and signal transduction. PMID- 8694763 TI - The variable subunit associated with protein phosphatase 2A0 defines a novel multimember family of regulatory subunits. AB - Two protein phosphatase 2A (PP2A) holoenzymes were isolated from rabbit skeletal muscle containing, in addition to the catalytic and PR65 regulatory subunits, proteins of apparent molecular masses of 61 and 56 kDa respectively. Both holoenzymes displayed low basal phosphorylase phosphatase activity, which could be stimulated by protamine to an extent similar to that of previously characterized PP2A holoenzymes. Protein micro-sequencing of tryptic peptides derived from the 61 kDa protein, termed PR61, yielded 117 residues of amino acid sequence. Molecular cloning by enrichment of specific mRNAs, followed by reverse transcription-PCR and cDNA library screening, revealed that this protein exists in multiple isoforms encoded by at least three genes, one of which gives rise to several splicing variants. Comparisons of these sequences with the available databases identified one more human gene and predicted another based on a rabbit cDNA-derived sequence, thus bringing the number of genes encoding PR61 family members to five. Peptide sequences derived from PR61 corresponded to the deduced amino acid sequences of either alpha or beta isoforms, indicating that the purified PP2A preparation was a mixture of at least two trimers. In contrast, the 56 kDa subunit (termed PR56) seems to correspond to the epsilon isoform of PR61. Several regulatory subunits of PP2A belonging to the PR61 family contain consensus sequences for nuclear localization and might therefore target PP2A to nuclear substrates. PMID- 8694764 TI - Type-III procollagen assembly in semi-intact cells: chain association, nucleation and triple-helix folding do not require formation of inter-chain disulphide bonds but triple-helix nucleation does require hydroxylation. AB - Procollagen assembly is initiated within the endoplasmic reticulum by three alpha chains associating via their C-propeptides (C-terminal propeptides). To study the requirements for the association of procollagen monomers at synthesis we have reconstituted the initial stages in the folding, assembly and modification of procollagen using semi-permeabilized cells. By translating a type-III procollagen "mini-gene' which lacks part of the triple-helical domain, we demonstrate that these cells efficiently carry out the assembly of hydroxylated, triple-helical, procollagen trimers and allow the identification of specific disulphide-bonded intermediates in the folding pathway. Mutant chains, which lack the ability to form inter-chain disulphide bonds within the C-propeptide, were still able to assemble within this system. Furthermore, characterization of the trimeric molecules formed suggested that inter-chain disulphide bonds had formed within the C-telopeptide (C-terminal telopeptide). However, when hydroxylation of prolyl and lysyl residues was inhibited no inter-chain disulphide bonds were formed in the C-telopeptide, indicating that hydroxylation is required for the initial nucleation of the triple-helical domain. Mutant chains which lacked the ability to form inter-chain disulphide bonds within the C-propeptide or the C-telopeptide could still assemble to form trimeric triple-helical molecules linked by inter chain disulphide bonds within the N-propeptide (N-terminal propeptide). These results indicate that inter-chain disulphide bond formation within the C propeptide or the C-telopeptide is not required for chain association and triple helix formation. PMID- 8694765 TI - Proteoglycan synthesis in human and murine haematopoietic progenitor cell lines: isolation and characterization of a heparan sulphate proteoglycan as a major proteoglycan from the human haematopoietic cell line TF-1. AB - Proteoglycans of bone-marrow stromal cells and their extracellular matrix are important components of the microenvironment of haematopoietic tissues. Proteoglycans might also be involved in the interaction of haematopoietic stem and stromal cells. Recently, several studies have been reported on the proteoglycan synthesis of stromal cells, but little is known about the proteoglycan synthesis of haematopoietic stem or progenitor cells. Here we report on the isolation and characterization of proteoglycans from two haematopoietic progenitor cell lines, the murine FDCP-Mix A4 and the human TF-1 cell line. Proteoglycans were isolated from metabolically labelled cells and purified by several chromatographic steps, including anion-exchange and size-exclusion chromatography. Biochemical characterization was performed by electrophoresis or gel-filtration chromatography before and after digestion with glycosaminoglycan specific enzymes or HNO2 treatment. Whereas FDCP-Mix A4 cells synthesize a homogeneous chondroitin 4-sulphate proteoglycan, isolation and characterization of proteoglycans from the human cell line TF-1 revealed, that TF-1 cells synthesize, in addition to a chondroitin sulphate proteoglycan, a heparan sulphate proteoglycan as major proteoglycan. For this heparan sulphate proteoglycan a core protein size of approx. 59 kDa was determined. Immunochemical analysis of this heparan sulphate proteoglycan revealed that it is not related to the syndecan family nor to glypican. PMID- 8694766 TI - Purification and characterization of cysteine-S-conjugate N-acetyltransferase from pig kidney. AB - Microsomal cysteine-S-conjugate N-acetyltransferase catalyses the N-acetylation of various S-substituted cysteines in liver and kidney. We describe here the purification and more detailed characterization of this enzyme catalysing the final reaction of mercapturic acid biosynthesis, and thus playing a crucial role in the detoxicating metabolism of many xenobiotics. The solubilization of cysteine-S-conjugate N-acetyltransferase by deoxy-BIGCHAP [N,N'-bis-(3-D gluconamidopropyl)deoxycholamide] was the prerequisite for partial purification by means of anion-exchange chromatography. The molecular mass of the enzyme was determined by gel filtration. A polyclonal antiserum was raised against the excised protein band from SDS/PAGE and purified antibodies were used for the complete purification of native cysteine-S-conjugate N-acetyltransferase by immuno-affinity chromatography. A dimeric form of the enzyme was sometimes detected on SDS/PAGE, depending on the degree of purification. For further characterization of cysteine-S-conjugate N-acetyltransferase, the stability of catalytic activity, the pH optimum and K(m) values were determined. The inhibitory effects of various agents were tested, revealing a substantial, yet not complete, loss of cysteine-S-conjugate N-acetyltransferase activity after treatment with cysteine proteinase inhibitors or probenecid under various conditions. PMID- 8694767 TI - Phosphorylation of GAP-43 (growth-associated protein of 43 kDa) by conventional, novel and atypical isotypes of the protein kinase C gene family: differences between oligopeptide and polypeptide phosphorylation. AB - GAP-43 (growth-associated protein of 43 kDa; also known as neuromodulin, P-57, B 50 and F-1) is a neuronal calmodulin binding protein and a major protein kinase C (PKC) substrate in mammalian brain. Here we describe the phosphorylation by and the site specificity of different PKC isotypes. The conventional PKC beta 1 and the novel PKCs delta and epsilon effectively phosphorylated recombinant GAP-43 in vitro; atypical PKC zeta did not. The K(m) values (between 0.6 and 2.3 microM) were very low, demonstrating a high-affinity interaction between kinase and substrate. All PKC isotypes were shown to phosphorylate serine-41 in GAP-43. When using a 19-amino-acid oligopeptide based on the GAP-43 phosphorylation site as substrate, there was a significant difference compared with polypeptide phosphorylation. The V(max) values of PKC beta 1 and PKC epsilon were much higher for this oligopeptide than for the complete protein (up to 10-fold); in contrast, their apparent affinities for the peptide were much lower (up to 100-fold) than for the intact GAP-43 polypeptide. Furthermore, phosphorylation of the GAP-43 oligopeptide by PKC beta 1 was more sensitive to a catalytic-site inhibitor than was phosphorylation of intact GAP-43. These results suggest that there are multiple sites of interaction between GAP-43 and PKC. PMID- 8694768 TI - Identification of two cDNA clones encoding small proline-rich proteins expressed in sheep ruminal epithelium. AB - Small proline-rich (SPRR) proteins are markers frequently associated with squamous cell differentiation. They have been proposed to be a novel group of precursor polypeptides for the cornified envelope in epidermal keratinocytes. A plus/minus screening procedure was used to identify cDNA clones expressed in mature but not in neonatal sheep ruminal epithelium. Two clones encoding SPRR proteins were identified and are reported here. Clone 27 encodes an ovine SPRR protein corresponding to the human type-II SPRR protein. Clone 26 encodes an ovine SPRR protein similar to human type-II SPRR protein, but which also contains an N-terminal His-Pro repeat similar to the paired repeats found in the Drosophila paired proteins. The unique combination of a paired domain and an SPRR protein has not been reported prior to this study. The tissue distribution indicates that specific expression of the genes corresponding to these two clones occurs in the epithelium of the ruminant forestomach, and to a lesser extent in skin epithelium. In situ hybridization demonstrated that the SPRR mRNA for both clones were localized in the stratum granulosum, in support of their putative physiological function, i.e. formation of the cornified envelope. Based on Northern blot analysis, mRNA complementary to the two clones appears in the ruminal epithelium by 1 week of age, corresponding to the formation of the stratum granulosum during ruminal epithelial development. The different patterns of changes in amount of mRNA corresponding to these clones during rumen epithelial development indicate that they play different roles in rumen epithelial development. PMID- 8694769 TI - Membrane receptor for odour-binding proteins. AB - Specific binding of 125I-labelled bovine odour-binding protein (OBP) to isolated membranes from nasal mucosa was demonstrated. The interaction reached equilibrium within 30 min at 37 degrees C and was reversible. A Scatchard analysis of the equilibrium binding revealed a single population of binding sites, with the calculated equilibrium dissociation constant and maximum number of binding sites being 2.25 +/- 0.5 microM and 18.5 +/- 2 pmol/mg of membrane protein respectively (n = 2). Receptor activity was decreased on digestion by trypsin, proteinase K or endoglycosidase H, was heat labile and was sensitive to thiol-group-specific reagents. With the exception of rat and mouse major urinary proteins, which exhibit a high degree of structural similarity with OBP and bind similar ligands, other members of the lipocalin family, such as retinol-binding protein and beta lactoglobulin, failed to inhibit the binding of 125I-labelled OBP to its receptor. The receptor seems not to be restricted to olfactory tissues, as it was detected in a variety of other tissues. This suggests that OBP is unlikely to play a role only in olfactory signal transduction. It might have a much broader role within the body; possibilities include a role in detoxification or signalling. PMID- 8694770 TI - Tetrameric malate dehydrogenase from a thermophilic Bacillus: cloning, sequence and overexpression of the gene encoding the enzyme and isolation and characterization of the recombinant enzyme. AB - The gene encoding the tetrameric malate dehydrogenase (MDH) in a thermophilic Bacillus species (BI) has been cloned in an Escherichia coli plasmid. The nucleotide sequence of the gene, the first to be elucidated for a tetrameric MDH, shows the MDH subunit to contain 312 amino acids and have a molecular mass of 33648 Da, which confirms the experimentally determined value of about 35 kDa. Like the genomic DNA of BI, the MDH gene is relatively AT-rich; this contrasts with the generally GC-rich nature of the DNA of thermophilic Bacillus species. Comparison of amino acid sequences reveals that BI MDH bears greater structural similarity to lactate dehydrogenases (LDHs) than to other (dimeric) MDHs. MDHs and LDHs resemble each other in catalytic mechanism and several other respects. However, whereas MDHs in the majority of organisms are dimers, the tetrameric structure is favoured among LDHs. The stronger structural resemblance that BI MDH has to LDHs than to the dimeric MDHs provides some explanation as to why Bacillus MDH, unlike most other MDHs, is tetrameric. A 1 kb fragment containing the BI MDH gene, produced in a PCR, has been cloned into a high-expression E. coli plasmid vector. BI MDH synthesized from this clone constitutes about 47% of the total protein in cell extracts of the E. coli strain carrying the clone. MDH purified from BI and that purified from the E. coli strain carrying the MDH gene clone appear to be identical proteins by several criteria. A number of characteristics of the MDH have been elucidated, including the molecular masses of the native enzyme and the subunit, N-terminal amino acid sequence, isoelectric point, pH optimum for activity, thermostability, stability to pH, urea and guanidinium chloride and several kinetic parameters. Whereas the MDH is a stable tetramer in the pH range 5-7, it appears to be converted into a stable dimer at pH 3.5. This suggests that the dimer is a stable intermediate in the dissociation of the tetramer to monomers at low pH. PMID- 8694771 TI - Biosynthesis of lipophosphoglycan from Leishmania major: solubilization and characterization of a (beta 1-3)-galactosyltransferase. AB - Lipophosphoglycan (LPG), is the major cell surface molecule of promastigotes of all Leishmania species. It is comprised of three domains: a conserved glycosylphosphatidylinositol anchor linked to a repeating phosphorylated disaccharide (P2; PO4-6Gal beta 1-4Man alpha 1-) backbone and capped with a neutral oligosaccharide. In Leishmania major the backbone is substituted at the C(O)3 of the Galp residue with side chains containing Galp, Glcp and Arap residues whereas in Leishmania donovani the backbone is unsubstituted. We report the solubilization of a (beta 1-3) galactosyltransferase [(beta 1-3)GalT] from a L. major microsomal preparation using Triton X-100. Solubilization occurs with a 10-fold stimulation of enzyme activity. This (beta 1-3)GalT specifically transfers Gal residues from UDP-Gal to exogenously added L. donovani LPG acceptor. Depolymerization of the [14C]Gal-labelled LPG product with mild acid and analysis by high-performance anion-exchange chromatography detected only the phosphotrisaccharide. (P3; PO4-6([14C]Gal beta 1-3-4Man alpha 1-) found in L. major LPG. This contrasts with the activity of the membrane-bound enzyme which also synthesizes the larger phosphosaccharide units[Ng, Handman and Bacic (1994) Glycobiology 4, 845-853]. This suggests that more than one (beta 1-3)GalT is involved in the addition of these Gal units and that the solubilized activity is the (beta 1-3)GalT that adds the first beta Gal residue to the acceptor. The (beta 1-3)GalT was partially purified by lectin-affinity chromatography and used to establish the K(m) values for UDP-Gal (445 microM) and L. donovani acceptor (280 microM as P2 molar equivalent) in kinetic assays. Inhibition studies with various glycosides and mono- and di-saccharides established the P2 repeating unit as the minimum acceptor structure recognized by (beta 1-3)GalT. The detergent solubilized (beta 1-3)GalT was reversibly inactivated by millimolar concentrations of univalent anionic salts. The (beta 1-3)GalT had an absolute requirement for Mn2+ and also required Mg2+ for optimum activity; Mg2+ cannot substitute for Mn2+, which is loosely bound to beta (1-3)GalT and is probably involved in the correct folding of the enzyme. The (beta 1-3)GalT was unaffected by Ca2+ ions, but were irreversibly inactivated by micromolar levels of transition metal ions (Cu2+ > Zn2+ > Ni2 > Co2+). The (beta 1-3)GalT activity was also inhibited by diethyl pyrocarbonate, but not by N-ethylmaleimide or iodoacetamide, suggesting that active-site histidine residues, rather than cysteine residue(s), are important for enzyme activity. PMID- 8694772 TI - Transcriptional regulation of the rat fatty acid synthase gene: identification and functional analysis of positive and negative effectors of basal transcription. AB - The gene for fatty acid synthase (FAS), which contains both GC-rich sequences and a TATA box in its promoter region, is expressed in a tissue-specific manner in response to developmental, nutritional and hormonal signals. Here we report the identification of sequence elements in the 5'-flanking region responsible for modulation of basal promoter activity. Transient transfection of H4IIE hepatoma cells and 3T3-30A5 preadipocytes with plasmids containing the chloroamphenicol acetyltransferase gene driven by FAS promoter sequences of different lengths revealed that two regions between nucleotides -249 and -30 contain elements capable of enhancing transcription. One of these positive regulatory elements was localized to nucleotides -241/-236 using DNase I footprinting, electrophoretic mobility-shift assays and mutagenesis. The sequence element is a typical GC box and the nuclear protein binding to this region appears immunochemically indistinguishable from Sp1. The second positive regulatory element, an inverted CCAAT box, was localized to nucleotides -98/-92 by electrophoretic mobility-shift assays and mutagenesis. A putative negative regulatory element, initially identified by reporter gene transfection experiments, was localized between nucleotides -319 and -301 by DNase I footprinting, electrophoretic mobility-shift assays and deletion mutagenesis; this region consists of 78% G residues. In conclusion, initiation of FAS transcription from a single start site is enhanced by the presence of an adjacent TATA motif, an inverted CCAAT box and an upstream binding site for the transcription factor Sp1; further modulation of transcription is achieved through complex interactions between these promoter elements and an upstream negative regulatory element. PMID- 8694773 TI - Flavinylation in wild-type trimethylamine dehydrogenase and differentially charged mutant enzymes: a study of the protein environment around the N1 of the flavin isoalloxazine. AB - In wild-type trimethylamine dehydrogenase, residue Arg-222 is positioned close to the isoalloxazine N1/C2 positions of the 6S-cysteinyl FMN. The positively charged guanidino group of Arg-222 is thought to stabilize negative charge as it develops at the N1 position of the flavin during flavinylation of the enzyme. Three mutant trimethylamine dehydrogenases were constructed to alter the nature of the charge at residue 222. The amount of active flavinylated enzyme produced in Escherichia coli is reduced when Arg-222 is replaced by lysine (mutant R222K). Removal or reversal of the charge at residue 222 (mutants R222V and R222E, respectively) leads to the production of inactive enzymes that are totally devoid of flavin. A comparison of the CD spectra for the wild-type and mutant enzymes revealed no major structural change following mutagenesis. Like the wild-type protein, each mutant enzyme contained stoichiometric amounts of the 4Fe-4S cluster and ADP. Electrospray MS also indicated that the native and recombinant wild-type enzymes were isolated as a mixture of deflavo and holo enzyme, but that each of the mutant enzymes have masses expected for deflavo trimethylamine dehydrogenase. The MS data indicate that the lack of assembly of the mutant proteins with FMN is not due to detectable levels of post-translational modification of significant mass. The experiments reported here indicate that simple mutagenic changes in the FMN binding site can reduce the proportion of flavinylated enzyme isolated from Escherichia coli and that positive charge is required at residue 222 if flavinylation is to proceed. PMID- 8694774 TI - Firefly luciferase can use L-luciferin to produce light. AB - L-Luciferin is a competitive inhibitor of firefly luciferase with a K1 between 3 and 4 microM. Furthermore L-luciferin can serve as an alternative substrate for light production. Catalysis of L-luciferin can be observed in the absence of, or at low concentrations of, D-luciferin. The light production from L-luciferin increases slowly (maximal half-time 8 min) to a stable plateau. At low concentrations of enzyme and L-luciferin, maximal light production is about half of that observed at corresponding D-luciferin concentrations. Increasing the concentration of enzyme or L-luciferin reduces the light production relative to that obtained by D-luciferin catalysis. In contrast to the catalysis of D luciferin the light production from L-luciferin can be effectively stimulated by the addition of PP1 provided that luciferase is premixed with inorganic pyrophosphatase (PP1-ase). A flash is emitted if PP1 is injected into a mixture of luciferase, L-luciferin, ATP and PP1-ase. The system maintains its responsiveness and emits further flashes of about equal duration and intensity upon repeated additions of PP1. It is proposed that PP1 induces a racemization of enzyme-bound L-luciferyl adenylate. The potential usefulness of PP1-dependent intracellular ATP monitoring is discussed. The proposed activation of firefly luciferase by PP1 may be part of the regulation of in vivo flashing. PMID- 8694775 TI - Intestinal HT-29 cells with dysfunction of E-cadherin show increased pp60src activity and tyrosine phosphorylation of p120-catenin. AB - 1. HT-29 M6 cells are a subpopulation of HT-29 cells that, contrarily to the parental cells, establish tight cell contacts and differentiate. Cell-to-cell contacts in HT-29 M6 cells are also regulated by protein kinase C; addition of the phorbol ester phorbol 12-myristate 13-acetate (PMA) decreases the homotypic contacts of these cells. We show here that HT-29 cells or HT-29 M6 cells treated with PMA contain lower levels of functional E-cadherin, determined by analysing the association of this protein with the cytoskeleton. No significant differences in the localization of alpha-, beta-, or p120-catenins were detected under the three different conditions. 2. Dysfunction of E-cadherin can be reversed by incubation of HT-29 cells with the tyrosine kinase inhibitor herbimycin A. On the other hand an augmentation of c-src activity in HT-29 cells or HT-29 M6 cells treated with PMA was observed with respect to control HT-29 M6 cells. The phosphorylation status of catenins was also investigated; in HT-29 or in HT-29 M6 cells treated with PMA, dysfunction of E-cadherin was accompanied by an increased phosphorylation of p120-catenin and by an elevated association of this protein to E-cadherin. These results suggest a role for pp60src and the pp60src substrate p120-catenin in the control of E-cadherin function in HT-29 cells. PMID- 8694776 TI - Affinity purification of 5-methylthioribose kinase and 5-methylthioadenosine/S adenosylhomocysteine nucleosidase from Klebsiella pneumoniae [corrected]. AB - Two enzymes in the methionine salvage pathway, 5-methylthioribose kinase (MTR kinase) and 5'-methylthioadenosine/ S-adenosylhomocysteine nucleosidase (MTA/SAH nucleosidase) were purified from Klebsiella pneumoniae. Chromatography using a novel 5'-(p-aminophenyl)thioadenosine/5-(p-aminophenyl)thioribose affinity matrix allowed the binding and selective elution of each of the enzymes in pure form. The molecular mass, substrate kinetics and N-terminal amino acid sequences were characterized for each of the enzymes. Purified MTR kinase exhibits an apparent molecular mass of 46-50 kDa by SDS/PAGE and S200HR chromatography, and has a Km for MTR of 12.2 microM. Homogeneous MTA/SAH nucleosidase displays a molecular mass of 26.5 kDa by SDS/PAGE, and a Km for MTA of 8.7 microM. Comparisons of the N-terminal sequences obtained for each of the enzymes with protein-sequence databases failed to reveal any significant sequence similarities to known proteins. However, the amino acid sequence obtained for the nucleosidase did share a high degree of sequence similarity with the putative translation product of an open reading frame in Escherichia coli, thus providing a tentative identification of this gene as encoding an MTA/SAH nucleosidase. PMID- 8694777 TI - Molecular cloning of delta 9 fatty acid desaturase from the protozoan Tetrahymena thermophila and its mRNA expression during thermal membrane adaptation. AB - In response to a decrease in its growth temperature, the protozoan Tetrahymena is known to increase the level of unsaturated fatty acids in its membrane phospholipids so as to maintain the correct physical state (fluidity) of the membranes. In this organism, synthesis of unsaturated fatty acids is initiated by delta 9 acyl-CoA desaturase. Our previous studies have shown that, during cold adaptation, the activity of microsomal palmitoyl- and stearoyl-CoA desaturase increases, reaching a maximal level at 2 h after a temperature down-shift to 15 degrees C. Two hypotheses have been proposed to explain this increase in desaturase activity: (1) self-regulation via a direct effect of reduced membrane fluidity, and (2) induction of desaturase mRNA. However, the precise mechanism is not clearly understood. In order to obtain further insight into the mechanism of regulation of the desaturase, we have isolated a gene that encodes delta 9 fatty acid desaturase from T. thermophila and examined its expression during cold adaptation. The nucleotide sequence indicates that the 1.4 kbp gene encodes a polypeptide of 292 amino acid residues which shows marked sequence similarity to delta 9 acyl-CoA desaturases from other sources, e.g. rat, mouse, Amblyomma americanum and Saccharomyces cerevisiae. This protein has three histidine-cluster motifs (one HXXXXH and two HXXHH), and two hydrophobic regions which are conserved among delta 9 acyl-CoA desaturases. The level of desaturase mRNA was sensitive to decreasing the temperature of the culture media, and was close to maximal immediately after the temperature was shifted down from 35 degrees C to 15 degrees C (0.8 degrees C/min). Thereafter, the amount of mRNA gradually decreased with time, but remained above the control level for at least 5 h. Furthermore, during the course of the cooling process to 15 degrees C, the increased expression of desaturase mRNA became evident at 27 degrees C. Nuclear run-on analysis and actinomycin D chase experiments revealed that the elevation of the mRNA level was due to increases in both transcription and mRNA stability. These results suggest that the enhanced desaturase activity is controlled, at least in part, at the transcriptional level. PMID- 8694778 TI - Protein kinase C in rod outer segments: effects of phosphorylation of the phosphodiesterase inhibitory subunit. AB - The inhibitory subunit (PDE gamma) of the cGMP phosphodiesterase (PDE alpha beta gamma 2) in rod outer segments (ROS) realizes its regulatory role in phototransduction by inhibition of PDE alpha beta catalytic activity. The photoreceptor G-protein, transducin, serves as a transducer from the receptor (rhodopsin) to the effector (PDE) and eliminates the inhibitory effect of PDE gamma by direct interaction with PDE gamma. Our previous study [Udovichenko, Cunnick, Gonzalez and Takemoto (1994) J: Biol. Chem. 269, 9850-9856] has shown that PDE gamma is a substrate for protein kinase C (PKC) from ROS and that phosphorylation by PKC increases the ability of PDE gamma to inhibit PDE alpha beta catalytic activity. Here we report that transducin is less effective in activation of PDE alpha beta (gamma p)2 (a complex of PDE alpha beta with phosphorylated PDE gamma, PDE gamma p) than PDE alpha beta gamma 2. PDE gamma p also increases the rate constant of GTP hydrolysis of transducin (from 0.16 S-1 for non-phosphorylated PDE gamma to 0.21 s-1 for PDE gamma p). These data suggest that phosphorylation of the inhibitory subunit of PDE by PKC may regulate the visual transduction cascade by decreasing the photoresponse. PMID- 8694779 TI - Ligand selectivity of 105 kDa and 130 kDa lipoprotein-binding proteins in vascular-smooth-muscle-cell membranes is unique. AB - Using ligand blotting techniques, with low-density lipoprotein (LDL) as ligand, we have previously described the existence of atypical lipoprotein-binding proteins (105 kDa and 130 kDa) in membranes from human aortic medical tissue. The present study demonstrates that these proteins are also present in membranes from cultured human (aortic and mesenteric) and rat (aortic) vascular smooth-muscle cells (VSMCs). To assess the relationship of 105 and 130 kDa lipoprotein-binding proteins to known lipoprotein receptors, ligand binding specificity was studied. We tested effects of substances known to antagonize ligand binding to either the LDL [apolipoprotein B,E (apo B,E)] receptor (dextran sulphate, heparin, pentosan polysulphate, protamine, spermine, histone), the scavenger receptor (dextran sulphate, fucoidin), the very-low-density-lipoprotein (VLDL) receptor [receptor associated protein (RAP)], or LDL receptor-related protein (RAP, alpha 2 macroglobulin, lipoprotein lipase, exotoxin-A). None of these substances, with the exception of dextran sulphate, influenced binding of LDL to either 105 or 130 kDa proteins. Sodium oleate or oleic acid, known stimuli for the lipoprotein binding activity of the lipolysis-stimulated receptor, were also without effect. LDL binding to 105 and 130 kDa proteins was inhibited by anti-LDL (apo B) antibodies. LDL and VLDL bound to 105 and 130 kDa proteins with similar affinities (approximately 50 micrograms/ml). The unique ligand selectivity of 105 and 130 kDa proteins supports the existence of a novel lipoprotein-binding protein that is distinct from all other currently identified LDL receptor family members. The similar ligand selectivity of 105 and 130 kDa proteins suggests that they may represent variant forms of an atypical lipoprotein-binding protein. PMID- 8694780 TI - Temperature-dependence of open-complex formation at two Escherichia coli promoters with extended -10 sequences. AB - We have studied the formation of open complexes between purified RNA polymerase from Escherichia coli and DNA fragments carrying the galP1 promoter, a promoter with an extended -10 region. Unusually, these complexes are formed readily at low temperatures. This low-temperature opening is unaffected by deletions of either upstream or downstream promoter sequences. We conclude that low-temperature open complex formation is due to specific base sequences in and just upstream of the extended -10 region. In contrast, open complexes are not formed at low temperatures with DNA fragments carrying the E. coli cysG promoter, which also has an extended -10 region. This demonstrates that an extended -10 sequence alone is not sufficient for low-temperature opening. Additionally, we report the temperature dependence of a hybrid galP1-cysG promoter, the related galP2 and galP3 promoters and a derivative of galP1 with an improved -10 hexamer sequence. PMID- 8694781 TI - Kinetic analysis of the mitochondrial quinol-oxidizing enzymes during development of thermogenesis in Arum maculatum L. AB - The dependence of the rate of oxygen uptake upon the ubiquinone (Q)-pool reduction level in mitochondria isolated during the development of thermogenesis of Arum maculatum spadices has been investigated. At the alpha-stage of development, the respiratory rate was linearly dependent upon the reduction level of the Q-pool (Qr) both under state-3 and -4 conditions. Progression through the beta/gamma to the delta-stage resulted in a non-linear dependence of the state-4 rate on Qr. In the delta-stage of development, both state-3 and -4 respiratory rates were linearly dependent upon Qr due to a shift in the engagement of the alternative oxidase to lower levels of Qr. Western blot analysis revealed that increased alternative oxidase activity could be correlated with expression of a 35 kDa protein. Respiratory control was only observed with mitochondria in the alpha-stage of development. At the beta/gamma-stage of development, the addition of ADP resulted in a significant oxidation of the Q-pool which was accompanied by a decrease in the respiratory rate. This was due either to decreased contribution of the alternative pathway to the overall respiratory rate under state 3 or by deactivation of succinate dehydrogenase activity by ADP. Cold-storage of the spadices at the beta-stage of development led to increased activity of both the cytochrome pathway and succinate dehydrogenase, without any change in alternative oxidase activity. Results are discussed in terms of how changes in the activation level of the alternative oxidase and succinate dehydrogenase influence the activity and engagement of the quinol-oxidizing pathways during the development of thermogenesis in A. maculatum. PMID- 8694782 TI - Decreased accumulation and dephosphorylation of the mitosis-specific form of nucleophosmin/B23 in staurosporine-induced chromosome decondensation. AB - Nucleophosmin/B23 is highly phosphorylated by cdc2 kinase during mitosis, and this phosphorylation most probably has a role in initiating and controlling the entry of cells into mitosis [Peter, Nakagawa, Doree, Labbe and Nigg (1990) Cell 60, 791-801]. In the present study, the protein kinase inhibitor staurosporine has been used to examine possible changes in nucleophosmin/B23 at mitosis in HeLa cells. Addition of staurosporine to HeLa cells already arrested at mitosis by nocodazole causes: (i) decreased accumulation of the mitosis-specific form of nucleophosmin/B23, (ii) dephosphorylation of nucleophosmin/ B23, (iii) redistribution of nucleophosmin/B23 to the cytosol, and (iv) concomitant decondensation of chromosomes. These results suggest that the mitosis-specific phosphorylated form of nucleophosmin/B23 may play a role in maintaining mitotic chromosomes in their condensed state. PMID- 8694783 TI - Determination of the ionization state of the active-site histidine in a subtilisin-(chloromethane inhibitor) derivative by 13C-NMR. AB - Subtilisin BPN' has been alkylated using benzyloxycarbonyl-glycylglycyl[1 13C]phenylalanylchloromethane+ ++. Using difference 13C-NMR spectroscopy a single signal due to the 13C-enriched alpha-methylene carbon of the subtilisin (chloromethane inhibitor) derivative was detected. No evidence for the denaturation/ autolysis of this derivative was obtained from pH 3.5 to 11.5. However, incubating at pH 12.75 or heating in the presence of SDS at pH 6.9 did denature this derivative. The negative titration shift of the alpha-methylene carbon of the denatured derivatives confirmed that the inhibitor had alkylated N 3 of the imidazole ring of the active-site histidine. The positive titration shift of 3.96 p.p.m. and the pKa of 7.04 obtained from studying the native subtilisin-(chloromethane inhibitor) derivative are assigned to oxyanion formation. We conclude that the pKa of the alkylated histidine residue in the native subtilisin-(chloromethane inhibitor) derivative must be > 12 and that subtilisin preferentially stabilizes the zwitterionic tetrahedral adduct consisting of the oxyanion and the imidazolium ion of the active-site histidine residue. We show that even before the oxyanion is formed the pKa of the active site histidine must be much greater than that of the oxyanion in the zwitterionic tetrahedral adduct. We discuss the significance of our results for the catalytic mechanism of the serine proteinases. PMID- 8694784 TI - The plasma membrane Ca2+ pump mutant lysine591 --> arginine retains some activity, but is still inactivated by fluorescein isothiocyanate. AB - Inactivation of the wild-type human plasma membrane Ca2+ pump (isoform 4b) by fluorescein isothiocyanate is accompanied by covalent modification of Lys591. The mutation of Lys591 to arginine reduced the Ca2+ transport activity to 35% of the wild-type, and diminished the amount of acylphosphate formed from ATP by a corresponding amount. When this mutant was treated with fluorescein isothiocyanate; the enzyme was still irreversibly inactivated, even though no reactive residue was available at position 591. The results show that, although Ca2+ pump function is sensitive to the residue at position 591, Lys591 is not essential for enzyme activity. They also demonstrate that irreversible inhibition of the plasma membrane Ca2+ pump by fluorescein isothiocyanate does not require the covalent modification of Lys591. This indicates that fluorescein isothiocyanate reacts with lysine residues at other positions in addition to Lys591. PMID- 8694785 TI - Molecular cloning of MADM: a catalytically active mammalian disintegrin metalloprotease expressed in various cell types. AB - A peptide sequence of a metalloprotease purified from bovine brain [Chantry, Gregson and Glynn (1989) J. Biol. Chem. 264, 21603-21607] was used to design an oligonucleotide probe for screening a bovine brain cDNA library. A contig of the two overlapping cDNA clones that were isolated encoded a 748-amino-acid polypeptide with similarity to the disintegrin-metalloprotease precursor proteins of haemorrhagic snake venom. The bovine protein has been named MADM, for mammalian disintegrin-metalloprotease. The predicted mature protein has 534 amino acids arrayed as extracellular metallo-protease and disintegrin (potential integrin-binding) domains, a transmembrane helix and a basic/proline-rich cytoplasmic C-terminus. Highly conserved homologues of bovine MADM were found in cDNA libraries of rat brain and a human U937 histiocytic lymphoma cell line. A wide variety of mammalian cell lines expressed low levels of MADM mRNA (4.5 and 3.2 kb transcripts) and mature polypeptide (M(r) 62000), as assessed by Northern analysis and Western blotting with an antiserum raised to a peptide within the disintegrin domain. MADM appears to be a rather distantly related member of the reprolysin protein family, which includes both the snake venom disintegrin metalloproteases and a number of predicted cell-surface disintegrin-containing mammalian proteins. PMID- 8694786 TI - Human extracellular superoxide dismutase is a tetramer composed of two disulphide linked dimers: a simplified, high-yield purification of extracellular superoxide dismutase. AB - Studies examining the biochemical characteristics and pharmacological properties of extracellular superoxide dismutase (EC SOD) have been severely limited because of difficulties in purifying the enzyme. Recently EC SOD was found to exist in high concentrations in the arteries of most mammals examined and it is the predominant form of SOD activity in many arteries. We now describe a three-step, high-yield protocol for the purification of EC SOD from human aorta. In the first step, the high affinity of EC SOD for heparin is utilized to obtain a fraction in which EC SOD constitutes roughly 13% of the total protein compared with only 0.3% of that of the starting material. In addition, over 80% of the original EC SOD activity present in the aortic homogenate was retained after the first step of purification. EC SOD was further purified using a combination of cation- and anion-exchange chromatography. The overall yield of EC SOD from this purification procedure was 46%, with over 4 mg of EC SOD obtained from 230 g of aorta. Purified EC SOD was found to exist predominantly as a homotetramer composed of two disulphide-linked dimers. However, EC SOD was also found to form larger multimers when analysed by native PAGE. It was shown by urea denaturation that the formation of multimers increased the thermodynamic stability of the protein. Limited proteolysis of EC SOD suggested that there is one interchain disulphide bond covalently linking two subunits. This disulphide bond involves cysteine-219 and appears to link the heparin-binding domains of the two subunits. PMID- 8694787 TI - Nucleation and inhibition of hydroxyapatite formation by mineralized tissue proteins. AB - Many proteins found in mineralized tissues have been proposed to function as regulators of the mineralization process, either as nucleators or inhibitors of hydroxyapatite (HA) formation. We have studied the HA-nucleating and HA inhibiting properties of proteins from bone [osteocalcin (OC), osteopontin (OPN), osteonectin (ON) and bone sialoprotein (BSP)], dentine [phosphophoryn (DPP)] and calcified cartilage [chondrocalcin (CC)] over a wide range of concentrations. Nucleation of HA was studied with a steady-state agarose gel system at sub threshold [Ca] x [PO4] product. BSP and DPP exhibited nucleation activity at minimum concentrations of 0.3 microgram/ml (9 nM) and 10 micrograms/ml (67 nM) respectively. OC, OPN, ON and CC all lacked nucleation activity at concentrations up to 100 micrograms/ml. Inhibition of HA formation de novo was studied with calcium phosphate solutions buffered by autotitration. OPN was found to be a potent inhibitor of HA formation [IC50 = 0.32 microgram/ml (0.01 microM)] whereas OC was of lower potency [IC50 = 6.1 micrograms/ml (1.1 microM)]; BSP, ON and CC all lacked inhibitory activity at concentrations up to 10 micrograms/ml. The effect of OPN on HA formation de novo is mainly to inhibit crystal growth, whereas OC delays nucleation. These findings are consistent with the view that BSP and DPP may play roles in the initiation of mineralization in bone and dentine respectively. OPN seems to be the mineralized tissue protein most likely to function in the inhibition of HA formation, possibly by preventing phase separation in tissue fluids of high supersaturation. PMID- 8694788 TI - Protein phosphatase and kinase activities possibly involved in exocytosis regulation in Paramecium tetraurelia. AB - In Paramecium tetraurelia cells synchronous exocytosis induced by aminoethyldextran (AED) is accompanied by an equally rapid dephosphorylation of a 63 kDa phosphoprotein (PP63) within 80 ms. In vivo, rephosphorylation occurs within a few seconds after AED triggering. In homogenates (P)P63 can be solubilized in all three phosphorylation states (phosphorylated, dephosphorylated and rephosphorylated) and thus tested in vitro. By using chelators of different divalent cations, de- and rephosphorylation of PP63 and P63 respectively can be achieved by an endogenous protein phosphatase/kinase system. Dephosphorylation occurs in the presence of EDTA, whereas in the presence of EGTA this was concealed by phosphorylation by endogenous kinase(s), thus indicating that phosphorylation of P63 is calcium-independent. Results obtained with protein phosphatase inhibitors (okadaic acid, calyculin A) allowed us to exclude a protein serine/threonine phosphatase of type I (with selective sensitivity in Paramecium). Protein phosphatase 2C is also less likely to be a candidate because of its requirement for high Mg2+ concentrations. According to previous evidence a protein serine/threonine phosphatase of type 2B (calcineurin; CaN) is possibly involved. We have now found that bovine brain CaN dephosphorylates PP63 in vitro. Taking into account the specific requirements of this phosphatase in vitro, with p-nitrophenyl phosphate as a substrate, we have isolated a cytosolic phosphatase of similar characteristics by combined preparative gel electrophoresis and affinity-column chromatography. In Paramecium this phosphatase also dephosphorylates PP63 in vitro (after 32P labelling in vivo). Using various combinations of ion exchange, affinity and hydrophobic interaction chromatography we have also isolated three different protein kinases from the soluble fraction, i.e. a cAMP-dependent protein kinase (PKA), a cGMP-dependent protein kinase (PKG) and a casein kinase. Among the kinases tested, PKA cannot phosphorylate P63, whereas either PKG or the casein kinase phosphorylate P63 in vitro. On the basis of these findings we propose that a protein phosphatase/kinase system is involved in the regulation of exocytosis in P. tetraurelia cells. PMID- 8694789 TI - Proteasome pathway operates for the degradation of ornithine decarboxylase in intact cells. AB - Ornithine decarboxylase (ODC) is degraded in an ATP-dependent manner in vitro by the 26 S proteasome in the presence of antizyme, an ODC destabilizing protein induced by polyamines. In the present study we examined whether the proteasome catalyses ODC degradation in living mammalian cells. Lactacystin, the most selective proteasome inhibitor, strongly inhibited the degradation of ODC that had been induced in hepatoma tissue-culture (HTC) cells by refeeding with fresh medium. Furthermore the inhibitor inhibited the rapid degradation of ODC that had been induced by hypotonic shock. Interestingly, hypertonic shock was found to increase the proportion of OD present as a complex with antizyme (the ratio of ODC-antizyme complex to total ODC). Cycloheximide, which partly inhibited rapid ODC degradation caused by hypertonic shock, also part inhibited the increase in the ratio of ODC-antizyme complex total ODC. These results suggest that a common ODC degradation pathway, namely the antizyme-dependent and 26 proteasome catalysed ODC degradation pathway, is also operating in intact cells for osmoregulated ODC degradation. PMID- 8694790 TI - Overexpression of human glucocerebrosidase containing different-sized leaders. AB - Gaucher disease results from impaired activity of the lysosomal enzyme glucocerebrosidase. Aiming at overexpressing the human glucocerebrosidase and testing the efficiency of the two in-frame ATGs of its gene in directing synthesis of an active enzyme, it was coupled to the T7 RNA polymerase promoter in a vaccinia virus-derived expression vector (pTM-1). cDNAs containing either one or both ATGs of the glucocerebrosidase mRNA were linked to the T7 polymerase promoter. Recombinant viruses were produced and used for infecting human cells in tissue culture. The results demonstrated that both ATGs directed translation of active glucocerebrosidase, resulting in a 10-fold increase in enzymic activity. Most of the protein remained sensitive to endoglycosidase H. The active enzyme represented a small fraction of the expressed glucocerebrosidase. The recombinant enzyme had the same Km and optimal pH towards the artificial substrate 4 methylumbelliferyl glucopyranoside as the authentic endogenous human enzyme. Measurements of intracellular enzymic activity directed by the cDNAs with either one or both ATGs in cells loaded with a fluorescent glucosylceramide demonstrated a 30% increase in activity directed by the cDNAs containing the first ATG over that containing the second ATG. This indicates that the protein synthesized from the first ATG, with a 38 amino acid leader, is translocated through the endoplasmic reticulum more readily than its counterpart directed by the second ATG, with a 19 amino acid leader. The elevation in glucocerebrosidase activity and the reproducibility of the data leads us to propose the use of the vaccinia virus-derived expression system as a tool for studying glucocerebrosidase mutants in Gaucher disease. PMID- 8694791 TI - The genes YNI1 and YNR1, encoding nitrite reductase and nitrate reductase respectively in the yeast Hansenula polymorpha, are clustered and co-ordinately regulated. AB - The nitrite reductase-encoding gene (YNI1) from the yeast Hansenula polymorpha was isolated from a lambda EMBL3 H. polymorpha genomic DNA library, using as a probe a 481 bp DNA fragment from the gene of Aspergillus nidulans encoding nitrite reductase (niiA). An open reading frame of 3132 bp, encoding a putative protein of 1044 amino acids with high similarity with nitrite reductases from fungi, was located by DNA sequencing in the phages lambdaNB5 and lambdaJA13. Genes YNI1 and YNR1 (encoding nitrate reductase) are clustered, separated by 1700 bp. Northern blot analysis showed that expression of YNI1 and YNR1 is co ordinately regulated; induced by nitrate and nitrite and repressed by sources of reduced nitrogen, even in the presence of nitrate. A mutant lacking nitrite reductase activity was obtained by deletion of the chromosomal copy of YNI1. The mutant does not grow in nitrate or in nitrite; it exhibits a similar level of transcription of YNR1 to the wild type, but the nitrate reductase enzymic activity is only about 50% of the wild type. In the presence of nitrate the delta ynil::URA3 mutant extrudes approx. 24 nmol of nitrite/h per mg of yeast (wet weight), about five times more than the wild type. PMID- 8694792 TI - Testosterone-dependent induction of metallothionein in genital organs of male rats. AB - Metallothioneins (MTs) are a group of cysteine-rich heavy-metal-binding proteins. We have investigated MT gene expression in the ventral and dorsolateral lobes of the prostate and coagulating gland of male Wistar rats. In intact rats, both MT mRNA and MT were present in the dorsolateral lobe and coagulating gland but not in the ventral lobe. Orchidectomy caused involution of the above organs, and both MT mRNA and MT were considerably decreased or become undetectable. An injection of testosterone propionate into orchidectomized rats restored not only the size of these organs, but also MT mRNA and MT concentrations, particularly in the dorsolateral lobe and coagulating gland. In the dorsolateral lobe, no selective uptake of Zn2+ preceding the increase in MT was observed, suggesting that Zn2+ ions are not associated with the increased expression of the MT gene. The present result suggests that of the male auxiliary genital organs, the dorsolateral lobe and coagulating gland, but not the ventral lobe, contain MT, the biosynthesis of which is regulated by testosterone. PMID- 8694793 TI - Expression and characterization of lacrimal gland water channels in Xenopus oocytes. AB - Lacrimal glands transport fluid for secretion as tears. To examine whether the expression of the aquaporin family of water channels is essential for water transport in lacrimal glands, we determined the water permeability in Xenopus oocytes injected with rat lacrimal gland poly(A)+ RNA. In oocytes injected with poly(A)+ RNA, osmotic water permeability was 4-fold higher than that observed in vehicle-injected controls. The enhanced water permeability was inhibited by 65% by coinjection of poly(A)+ RNA with antisense aquaporin-5 but not antisense aquaporin-1 oligonucleotide. To detect aquaporin mRNA in rat lacrimal glands, we performed reverse transcription-polymerase chain reaction analysis. PCR products were detected using specific aquaporin-5 primers. Our results strongly suggest that rat lacrimal glands express aquaporin-5 water channels for lacrimation. PMID- 8694794 TI - Cyclic AMP inhibits expression of D-type cyclins and cdk4 and induces p27Kip1 in G-CSF-treated NFS-60 cells. AB - The addition of cAMP inhibits G-CSF-mediated proliferation and suppresses pRB phosphorylation in NFS-60 cells. We show that the latter could be attributed to different effects of cAMP in these cells: (i) down-regulation of the levels of cyclins D2 and D3, and cdk4, and (ii) induction of the p27Kip1 inhibitor of cdk4. PMID- 8694795 TI - Association of a 14-3-3 protein with CMP-NeuAc:GM1 alpha 2,3-sialyltransferase. AB - CMP-NeuAc:GM1 alpha 2,3-sialyltransferase (ST-IV) was purified to homogeneity from rat brain. Microsequencing of the tryptic peptides derived from the purified enzyme revealed two amino acid sequences homologous to the 14-3-3 proteins. A polyclonal antibody was raised against purified ST-IV. A 33 kDa protein was co immunoprecipitated from rat brain extracts with the anti-(ST-IV) antibody as detected by Western blot analysis. This protein was identified as a subtype of 14 3-3 family by an anti-(14-3-3) antibody. Screening of a rat brain lambda gt11 library using the anti-(ST-IV) antibody resulted in the identification of a cDNA clone coding for the subtype of 14-3-3 protein. These results indicate an association of the 14-3-3 protein with the sialyltransferase. Since the 14-3-3 protein has PKC inhibitor activities and the activity of sialyltransferases is, at least in part, regulated by PKC, the association of the 14-3-3 protein with ST IV may indicate a role for this protein in the post-translational regulation of the sialyltransferase activity through the processes of phosphorylation and dephosphorylation. PMID- 8694796 TI - Human erythrocyte band 7.2b is preferentially labeled by a photoreactive phospholipid. AB - A head-group modified, photoreactive analog of phosphatidylethanolamine, N ([125I]iodo-4-azidosalicy- lamidyl)-1,2-dilauryl-sn-glycero-3 phosphatidylethanolamine ([125I]-N-ASA-DLPE), has been used in photoaffinity labeling studies of proteins of the human erythrocyte membrane. [125I]-N-ASA-DLPE was shown to be preferentially incorporated into a protein with an apparent molecular weight of 31 kDa. Protein sequencing and immunoprecipitation were used to identify this protein as the erythrocyte membrane protein, band 7.2b or stomatin. A sulphydryl-reactive ligand, 4-hydroxy-3-(iodo-[125I])-N-[2-(2 pyridinyldithio)ethyl]- benzenepropanamide ([125I]-PDA), was also shown to preferentially label band 7.2b. We propose that band 7.2b may act as a site of transbilayer reorientation of membrane phospholipids. PMID- 8694797 TI - One electron reduction of vanadate(V) to oxovanadium(IV) by low-molecular-weight biocomponents like saccharides and ascorbic acid: effect of oxovanadium(IV) complexes on pUC18 DNA and on lipid peroxidation in isolated rat hepatocytes. AB - One electron reduction of vanadate(V) to vanadyl(IV) occurs in the presence of biocomponents, such as, saccharide s and L-ascorbic acid under physiological conditions. The vanadyl(IV) complexes thus generated have been demonstrated to introduce nicks in pUC18 DNA in the absence or in the presence of hydrogen peroxide and also exhibit lipid peroxidation in isolated rat hepatocytes. Thus the reducing and complexing abilities of these molecules may help in understanding the in vivo reduction and the resultant toxicity to cells incubated with vanadate(V). PMID- 8694798 TI - Hormonal influences on beta-lactoglobulin transgene expression inferred from chromatin structure. AB - The major milk whey protein of ruminants is beta-lactoglobulin. Transgenic mice which carry genomic fragments of ovine beta-lactoglobulin express the transgene at high levels in the mammary gland. Using DNaseI as a probe for transcription complex formation in chromatin, the temporal induction pattern of beta lactoglobulin in transgenic mice has been addressed and compared to the known hormonal profiles during pregnancy. Prior to the 9th day of pregnancy no obvious hypersensitivity to DNaseI digestion at the beta-lactoglobulin promoter was evident. From the 9th day of pregnancy through to lactation, the beta lactoglobulin promoter displays DNaseI hypersensitivity. These results support the hypothesis that placental lactogens are the major lactogenic influence from mid-pregnancy to parturition. PMID- 8694799 TI - The putative membrane anchor protein for yeast Sec7p recruitment. AB - Proteins required for yeast secretory pathway function have been identified by genetic selection and characterization of the temperature-sensitive secretory (sec) mutants. The use of genetic and biochemical approaches has expanded the catalog of components of the secretory pathway, yet many proteins, especially membrane and lumenal proteins, remain to be identified. Sec7p, one of the original SEC gene products to be described, is required at multiple stages of the yeast secretory pathway in the coating of transport vesicles. A chemical cross linking approach was used to identify proteins associated with Sec7p protein complexes from yeast cell lysates. A 90 kDa integral membrane protein (p90) was isolated whose interactions with Sec7p were reproduced in the absence of chemical cross-linking. Further biochemical analysis indicated that p90 may act as the anchor protein for Sec7p membrane recruitment in transport vesicle assembly. PMID- 8694800 TI - Identification of the snake venom substance that induces apoptosis. AB - Hemorrhagic snake venom induces apoptosis of vascular endothelial cells [S. Araki, T. Ishida, T. Yamamoto, K. Kaji, and H. Hayashi (1993) Biochem. Biophys. Res. Comm. 190 , 148-153]. We have identified that a cytotoxic substance of Korean snake venom which is responsible for the apoptosis is L-amino acid oxidase (LAO). The purified enzyme is a homodimeric glycoprotein of 110,000 and is capable of generating H2O2 by catalyzing oxidation of L-amino acid. In the presence of the enzyme, cultured L1210 cell nuclei were splitted and showed the characteristic ladder-like pattern of DNA fragmentation. The enzyme binds directly to the cell surface, thereby increasing local concentration of H2O2. However, experimental evidence suggests that the LAO-induced apoptotic mechanism is distinguished from the one caused by exogenous H2O2. PMID- 8694801 TI - Localization of prothymosin alpha in the nucleus. AB - Prothymosin alpha is a widely distributed acidic protein to which an immunological function that involved its secretion was initially assigned. However, recent experiments suggest that it is a nuclear protein related to cell proliferation. To study the subcellular distribution of prothymosin alpha we have used a polyclonal antibody raised against its C-terminus. Using indirect immunofluorescence prothymosin alpha was located in the nucleus of HeLa, L929, IT 45R1, and NIH3T3 cells, mouse thymocytes, and human thymic stromal cells. The levels of prothymosin alpha mRNA were increased when the proliferation of IT-45R1 cells was induced, as has been described by others in thymocytes and NIH3T3 cells. These results show that prothymosin alpha is a nuclear protein related to cell proliferation. PMID- 8694802 TI - Transglutaminase forms midkine homodimers in cerebellar neurons and modulates the neurite-outgrowth response. AB - Midkine is a prominent acyl donor substrate for the protein cross-linking enzyme transglutaminase type 2 in rat brain neurons. Transglutaminase type 2 and midkine immunoreactivity are regionally colocalized in developing cerebellar cortex. Monomeric midkine is present in the embryonic dorsal rhombic lip which gives rise to the cerebellar cortex. A high-molecular weight (29-30 kDa) midkine appears during postnatal cerebellar development. The presence of the high-molecular weight midkine in cultured cerebellar cortical interneurons is dependent upon culture conditions. Transglutaminase catalyzes the calcium-dependent cross linking of midkine predominantly into 29-30 kDa dimers. Dimer-formation of midkine in vitro and in cultured neurons is reduced in the presence of a transglutaminase inactivator. Neurons plated onto previously cross-linked midkine exhibit larger growth cones and enhanced neurite outgrowth compared to those plated onto monomeric midkine alone. PMID- 8694803 TI - Expression of heme oxygenase and inducible nitric oxide synthase mRNA in human brain tumors. AB - Heme oxygenase-1, a key enzyme in heme catabolism, and inducible nitric oxide synthase (iNOS) are responsible for production of carbon monoxide and nitric oxide (NO), respectively. Expression of each enzyme has been shown to be modulated by heme and NO, raising a possibility for the coordinated regulation of the two enzymes. We therefore analyzed the expression levels of both mRNA in humans using brain tumors. Either heme oxygenase-1 or iNOS mRNA was expressed at higher levels in brain tumors compared to the brain tissue, but their expression levels were not apparently correlated. In the brain tumor cell lines, treatment with cytokines increased the expression of iNOS mRNA but not heme oxygenase-1 mRNA, whereas treatment with an NO donor increased the expression of heme oxygenase-1 mRNA but not iNOS mRNA. These results suggest the separate regulation of expression of both enzyme mRNA in humans. PMID- 8694804 TI - Interleukin-12 gene-expression of macrophages is regulated by nitric oxide. AB - Interleukin-12 is a heterodimeric cytokine, mainly produced by macrophages. In our present study we demonstrate that interleukin-12 expression is regulated by nitric oxide. Incubation of the macrophage cell line IC 21 with interferon-gamma gave rise to both interleukin-12 p40 mRNA and nitric oxide production. The concurrent addition of the nitric oxide synthase inhibitor N(G)-monomethyl-L arginine inhibited nitrite production and in parallel completely suppressed interleukin-12 p40 mRNA formation. This indicated that endogenous nitric oxide synthase activity was required for IL-12 p40 gene expression. Exposure of the cells towards the nitric oxide generating compounds nitroprusside or S-nitroso-N acetyl-penicillamine induced interleukin-12 p40 mRNA. Maximal mRNA levels were induced with nitric oxide donors at 1 microM concentration. We conclude that nitric oxide may exert an autoregulatory and paracrine control of interleukin-12 gene expression. PMID- 8694805 TI - Iron metabolism-related genes and mitochondrial genes are induced during involution of mouse mammary gland. AB - To understand molecular mechanisms of mammary gland involution, several clones were isolated after the primary differential screening of a total 40,000 pfu of involution-specific cDNA library, and further characterized. The partial sequences and Northern analysis revealed that iron metabolism-related genes and mitochondrial genes were induced during mammary gland involution. The expression of the lactoferrin gene was induced at involution days 1, 2, and 3. The expression of ferritin heavy chain gene was induced at involution days 1, 2, 3 and 4. Cytochrome oxidase subunit 1 and cytochrome oxidase subunit 2 genes were induced at involution days 4 and 7. The expression of cytochrome b gene was induced at involution day 7. These results imply that iron metabolism and mitochondrial function may be altered during mammary gland involution. PMID- 8694806 TI - Et-1 and Et-3 actions mediated by cloned ETA endothelin receptors exhibit different sensitivities to BQ-123. AB - Et-1 and Et-3 activate phospholipase C in fibroblasts expressing cloned ETA receptors of bovine, rat and human origins. BQ-123 competitively antagonizes both responses but Et-3 actions are 10 times more sensitive to BQ-123 than Et-1 actions. It is suggested that differential sensitivity to BQ-123 is an intrinsic property of Et-1 and Et-3 activated ETA receptors and that there is no need to postulate the existence of new ETA receptor isoforms to account for singular actions of BQ-123. PMID- 8694807 TI - Oxidative DNA damage in human respiratory tract epithelial cells. Time course in relation to DNA strand breakage. AB - When human respiratory tract epithelial cells were exposed to 100 microM H2O2, there was rapid induction of DNA strand breakage and chemical modifications to all 4 DNA bases suggestive of attack by OH.. The major products were FAPy adenine, FAPy-guanine, and 8-OH-guanine. Some of the base modifications were removed very quickly from the DNA (e.g., 8-OH-guanine), whereas others persisted for longer (e.g., thymine glycol), probably due to differential activity of different repair enzymes. By contrast, strand breaks continued to increase over the time course of the experiment, perhaps because strand breakage is also implicated in the repair process. One should therefore be cautious in using strand breakage as a sole measure of oxidative DNA damage, and when drawing conclusions about the pattern and biological significance of oxidative DNA damage in cells the relative persistence of different lesions must be considered. PMID- 8694808 TI - Analysis of CSK homologous kinase (CHK/HYL) in hematopoiesis by utilizing gene knockout mice. AB - CHK/HYL is a non-receptor tyrosine kinase that belongs to CSK (C-terminal Src kinase) family. Northern blotting and RT-PCR analyses showed that CHK/HYL was expressed in large spectrum of hematopoietic cells except for erythroid cells and brain. To explore the function of CHK/HYL in hematopoietic cells, we generated CHK/HYL deficient mice. The mutant mice were apparently normal and fertile, while CSK knockout mice died until E11.5 from a defect in the neural tube formation. Hematological observations including blood counts and FACS analysis showed no significant abnormalities in CHK/HYL mutant mice. CHK/HYL did not affect the activity of Src, Hck, and Fgr in cultured bone marrow cells, although CSK negatively regulates Src family kinases. These results suggest that CHK/HYL might not have the same function as CSK. PMID- 8694809 TI - K252a inhibits the phosphorylation of pRb without changing the levels of G1 cyclins and Cdk2 protein in human hepatoma cells. AB - A protein kinase inhibitor K252a suppressed the growth of HuH7 hepatoma cells and the hyperphosphorylation of retinoblastoma protein (pRb) at late G1 phase of cell cycle. However, K252a treatment did not alter the levels of cyclin D1, cyclin E, cyclin A and Cdk2 protein bound to cyclin E or cyclin A. Therefore, the K252a inhibition of pRb phosphorylation is considered to be brought about probably by inhibiting the action of Cdk-cyclin complex rather than by changing its cellular level. These results also suggest that K252a is a useful tool for investigating the mechanism of phosphorylation of pRb mediated by Cdk-cyclin. PMID- 8694811 TI - Chemically synthesised human immunodeficiency virus P7 nucleocapsid protein can self-assemble into particles and binds to a specific site on the tRNA(Lys,3) primer. AB - The zinc-bound form of the human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein, p7, aggregates into particles visible by electron microscopy. The HIV primer tRNA(Lys,3) forms similar high molecular weight complexes with p7 that are also detected by gel mobility shift assays. RNA oligonucleotides of the three stem-loop structures in tRNA(Lys,3) were assayed for the competitive inhibition of p7-tRNA(Lys,3) binding by the intensities of free tRNA(Lys,3) bands on native gels. This reveals that the p7 binds specifically to the central domain of tRNA(Lys,3) where the D and T psi C loops come together, but not the anticodon stem-loop. PMID- 8694810 TI - Abnormal activation of K+ channels underlies relaxation to bacterial lipopolysaccharide in rat aorta. AB - We have examined the role of K+ channels in mediating vasorelaxation produced by bacterial lipopolysaccharide (LPS) in endothelial-denuded strips of rat aorta precontracted with phenylephrine (1 microM). Salmonella typhosa LPS (0.1 microgram/ml) caused significant relaxation of tension which peaked at approximately 4hr. The K+ channel blocker, tetraethylammonium chloride (TEA; 10 mM), fully reversed these relaxations whether applied before or after long term exposure to LPS. L-arginine, the substrate for nitric oxide synthase, caused large relaxations in tissues incubated with LPS that were markedly inhibited by TEA. In contrast, TEA or L-arginine had little effect on phenylephrine contractions in control tissues. Furthermore, the inducible nitric oxide synthase inhibitor, aminoguanidine (0.4 mM), reversed the effects of LPS and blocked responses to TEA. These results suggest that activation of K+ channels, possibly Ca-activated K+ channels, through induction of the nitric oxide synthase pathway, may well be responsible for endotoxin-mediated hyporeactivity to vasoconstrictor agents in vascular smooth muscle. PMID- 8694812 TI - Effects of the nitric oxide synthase inhibitor N omega nitro-L-arginine methyl ester on electrical activity and ion channels of mouse pancreatic B cells. AB - The effects of the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) were studied on electrical activity, K+ATP currents and voltage-dependent K+ and Ca2+ channel currents in mouse pancreatic B cells. In the presence of 15 mM glucose, L-NAME (> 5 mM) depolarized the B cell membrane and electrical activity became continuous. The depolarization caused by L-NAME was not reversed by the addition of a membrane permeant cyclic GMP analogue. L NAME inhibited the whole-cell K+ATP current reversibly by reducing the single channel current conductance and open probability. The results are consistent with the assumption that L-NAME depolarizes the B cell membrane by a direct action on the K+ATP channel. L-NAME also influenced the whole-cell current through voltage dependent K+ and Ca2+ channels. PMID- 8694813 TI - Expressed sequence tags identify human isologs of the ARF-dependent phospholipase D. AB - By searching into Expressed Sequence Tags databases (dbEST) using Blast X algorithm software and a plant phospholipase D as template, we have identified a cDNA from human brain (Z45777) which encodes for a protein similar to the amino acid region 743-929 of the human phospholipase D1 (PLD1), and a cDNA from human liver (R93485) which encodes for a protein similar to region 815-932 of PLD1. Sequence comparison between cloned phospholipases showed the presence of 3 conserved amino acid sequences: AFVGGIDLAYGRWD (box A), IIGSANINDRS (box B), and YIYIENQFFI (box C). Phylogenic analysis indicated that the cDNA from brain and liver encoded for human isologs of PLD1. PMID- 8694814 TI - Receptor pattern formation as a signal for the capture of lipoproteins. AB - A critical step in the uptake of dietary cholesterol by the liver is the binding of remnant lipoprotein particles to receptors in the space of Disse. We have found that increases in the cholesterol content of hepactocyte membranes reduces the binding of beta-very low density lipoproteins (beta-VLDL) and decreases internalization. This increase in membrane cholesterol of human hepatoma cells (HepG2) produces a similar effect on binding to primary human fibroblasts. However, receptor-negative familial hypercholesterolemic (FH) fibroblasts lack the ability to respond to membrane cholesterol modification. A polyclonal antibody directed against the C-terminus region of the apo-B,E-(LDL) receptor importantly affects the internalization process, suggesting that protein-protein interactions consolidate the pattern formation of receptors, a process that triggers lipoprotein internalization. We propose that cholesterol interferes with this pattern formation by affecting the lateral movement and organization of the receptors. PMID- 8694816 TI - The effect of cysteine-43 mutation on thermostability and kinetic properties of citrate synthase from Thermoplasma acidophilum. AB - In this study, we have substituted serine-43 by cysteine in the recombinant citrate synthase from a moderately thermophilic Archaeon Thermoplasma acidophilum, for site-specific attachment of labels and have investigated the effects of this mutation on the biochemical properties and thermal stability of the enzyme. Both wild-type and the mutant enzymes were purified to homogenity using affinity chromatography on Matrex Gel Red A. The mutant Thermoplasma citrate synthase is very similar to wild-type citrate synthase in its substrate and co-factor specificities, pH profile and thermal stability. The mutation, however, has decreased the enzyme activity. The newly introduced reactive sulphydryl group could be easily modified by DTNB and labelled with 4-chloro-7 sulphobenzofuran, without loss of any activity. PMID- 8694815 TI - A single amino acid determines the specificity for the target sequence of two zinc-finger proteins in plants. AB - The EPF family is a group of DNA-binding proteins with two canonical Cys2/His2 zinc-finger motifs in Petunia. These proteins are unique in terms of structure in that (i) the two zinc fingers are separated by spacers of various lengths and (ii) the sequence QALGGH is strongly conserved in the zinc-finger motifs of members of the family. In this study, domain-swapping and site-directed mutagenesis experiments with two members of the protein family, EPF2-5 and EPF2 7, which have different target sequences, revealed that only a single amino acid in the second zinc finger is responsible for the difference in target specificity. The position of this amino acid is different from those of determinants of target-sequence specificity in other zinc-finger proteins. Thus, the EPF family recognizes target sequences in a unique manner, together with the recognition of spacings in the target sequence that we demonstrated recently. PMID- 8694817 TI - cDNA cloning and deduced amino acid sequence of fibrinolytic enzyme (lebetase) from Vipera lebetina snake venom. AB - The complete amino acid sequence of lebetase is deduced from the nucleotide sequence of a cDNA clone isolated by screening a venomous gland c DNA library of Central Asian Vipera lebetina snake. The cDNA sequence with 2011 basepairs encodes an open reading frame of 478 amino acids which includes an 18 amino acid signal peptide, plus an 175 amino acid segment of zymogen-like propeptide, a mature protein of 204 amino acids, a spacer of 18 amino acids and a disintegrin like peptide of 63 amino acids. The mature protein lebetase as isolated from the crude venom has the molecular weight of approximately 23.7 kD and, thus, lebetase as well as several other snake venom metalloproteinases is translated as a precursor protein, which may be processed posttranslationally. The lebetase proprotein has a "cysteine switch" motif (PKMCGV) similar to that involved in the activation of matrix metalloproteinase zymogens. The mature protein (residues 223 427) shows the strongest similarity with fibrolase (63% identity), fibrinolytic enzyme from Agkistrodon contortrix contortrix venom. The metalloproteinase domain has a typical zinc-chelating sequence (HEXXHXXGXXH). In the disintegrin-like domain of protein, the RGD sequence is replaced by VGD. PMID- 8694818 TI - Phosphatidylinositol 3-kinase activity is required for the activation process of focal adhesion kinase by platelet-derived growth factor. AB - Platelet-derived growth factor (PDGF) is one of the agents which stimulate increase in phosphotyrosine content of focal adhesion kinase (FAK) in cultured cells. In the present study we report that wortmannin, a highly specific and potent inhibitor of the catalytic subunit of mammalian phosphatidylinositol (PI) 3-kinase, completely abolishes PDGF-BB-mediated increase in tyrosine phosphorylation of FAK in human umbilical vein smooth muscle cells. Furthermore, analysis of the wild-type and mutant human PDGF beta-receptors stably expressed in porcine aortic endothelial cells also demonstrates that the Y740/751F mutant receptor, which cannot interact with PI 3-kinase due to the mutational alteration of its binding sites for PI 3-kinase, fails to increase FAK phosphorylation after PDGF-BB stimulation. These data suggest the requirement for PI 3-kinase activity in the activation process of FAK downstream of the PDGF receptor. PMID- 8694819 TI - First evidence for accumulation of protein-bound and protein-free pyrraline in human uremic plasma by mass spectrometry. AB - Glucose-derived advanced glycation end products (AGEs) cross-link proteins and cause various biological tissue damage. One of them, pyrraline [epsilon-2-(formyl 5-hydroxymethyl-pyrrol-1-yl) -L-norleucine], has been demonstrated by utilizing antibody to accumulate in plasma and sclerosed matrix of diabetic individuals, suggesting responsibility for diabetic complications. To elucidate the involvement of pyrraline in uremia, we examined the pyrraline levels in patients with chronic renal failure by a mass spectrometric approach. Here we show that protein-free pyrraline as well as pyrraline with binding protein are significantly increased in non-diabetic uremic plasma compared to healthy subjects. Our results suggest that circulating pyrraline could be a substance contributing to complications in uremia. PMID- 8694820 TI - Interaction of RGD liposomes with platelets. AB - The interactions of platelets and liposomes with the tripeptide arginine-glycine aspartic acid (RGD) as a surface ligand (RGD liposomes) were studied. The results suggest that the presence of the RGD ligand on the liposomes results in receptor mediated mixing of lipid and aqueous contents of the liposomes and platelets. Mixing of the lipid and aqueous contents of RGD liposomes with platelets is approximately 4-9 times and 3-4 times greater than that for unlabeled liposomes, respectively. Measurements of the cytoplasmic free Ca2+ concentration in platelets, [Ca2+]i, show that the RGD liposomes have little effect on [Ca2+]i. PMID- 8694821 TI - Transcriptional inhibition of the beta-amyloid precursor protein by interferon gamma. AB - Attenuating beta-amyloid precursor protein (beta-APP) gene expression may have relevance in diseases such as Alzheimer's disease, where beta-APP has been implicated in neuropathological processes. We report here on the transcriptional down-regulation of beta-APP by interferon-gamma (IFN-gamma) in SKNMC human neuroblastoma cells. Treatment of the cells with IFN-gamma resulted in a 85% dose dependent inhibition of beta-APP promoter activity after 24 h of exposure, with no changes observed at 5 h. For comparison, additional cytokines and signaling agents were also investigated for effects on beta-APP promoter activity. Elevated levels of activity were observed after treatment with phorbol 12-myristate 13 acetate and basic fibroblast growth factor whereas no significant effects were seen after treatment with lipopolysaccharide or interleukin-1 beta. Thus, IFN gamma was shown here to be a suppressor of beta-APP promoter activity and is the first cytokine reported to possess such down-regulating effects. PMID- 8694822 TI - Urokinase-type plasminogen-activator receptor associates to a cell surface molecule in monocytic cells. AB - The monocyte-like THP-1 cells express on their surface the urokinase-type plasminogen activator receptor (uPA-R). This receptor, chemically cross-linked to its possible ligands, migrates, in SDS PAGE, slower than the uPA-R expressed on the epithelial thyroid cell line TAD-2, cross-linked to the same ligands. The different migration corresponds to a difference in molecular weight of 15 kDa. Similar results were obtained with peripheral monocytes and primary cultures of thyroid cells. The molecular weight of the native receptor is about 50 kDa and appears to be identical in these two cell types. Such results suggest that, in monocytic cells, uPA-R associates to a 15 kDa molecule. This molecule is probably linked to the cell surface by a glyco-phospho-inositol anchor since, by phospholipase-C treatment, it is co-eluted with the urokinase-type plasminogen activator receptor from THP-1 cells. PMID- 8694823 TI - Constitutively enhanced nbl expression is associated with the induction of internucleosomal DNA cleavage by actinomycin D. AB - Previous studies have found nbl expression to transiently rise and fall during glucocorticoid-induced thymic apoptosis. This induction of apoptosis is blocked by the transcriptional inhibitor actinomycin D. However, actinomycin D can trigger apoptosis in other cell types, e.g., HL-60 cells. This study found that internucleosomal DNA cleavage typical of apoptosis is induced by actinomycin D in cell lines such as HL-60 which constitutively express high levels of nbl above a certain "threshold." In contrast, "DNA ladder" formation was not induced by actinomycin D in cell lines with low constitutive nbl expression. Enhanced nbl expression therefore appears to be associated with apoptosis which is either blocked or induced by actinomycin D. PMID- 8694824 TI - Pseudogenes for the human uracil-DNA glycosylase on chromosomes 14 and 16. AB - Two clones containing nonfunctional pseudogenes for the human uracil-DNA glycosylase gene have been isolated. The sequences of the two clones that are homologous to the UNG cDNA span 670 and 580 bp, respectively. In the longest of these, a full length Sx type Alu sequence interrupts the homologous sequence. Chromosomal mapping locates the clones to chromosomes 16 and 14. Comparison of the pseudogene sequences to the cDNA sequence indicates that the pseudogenes diverged from the functional gene approximately 31 and 22 million years ago, which is before the point in evolution when great apes and hominides separated. PMID- 8694825 TI - NF-kappa B is induced in the nuclei of cultured rat aortic smooth muscle cells by stimulation of various growth factors. AB - We investigated whether induction of transcription factor NF-kappa B is involved in the proliferation of cultured rat aortic smooth muscle cell using electrophoretic mobility shift assay and immunocytochemistry. NF-kappa B was induced in the nucleus in a dose-dependent manner when the smooth muscle cells were stimulated by various growth factors such as PDGF-BB, bFGF, EGF and IGF-1, but not growth inhibitors such as TGF-beta and IFN-gamma. Among growth factors, PDGF-BB and bFGF, more potent growth stimulators, induced higher kappa B binding activity than EGF or IGF-1. These evidences were also supported by the results obtained with immunocytochemistry. Immunocytochemistry also showed that the induced NF-kappa B contained p50 and p65. These results suggest that NF-kappa B induction may be involved in the proliferation of vascular smooth muscle cell. PMID- 8694826 TI - Modulation by polycationic Ca(2+)-sensing receptor agonists of nonselective cation channels in rat hippocampal neurons. AB - We recently cloned an extracellular calcium (Ca2+0)-sensing receptor (CaR) from bovine parathyroid. The CaR is also expressed in various regions of brain, suggesting that it could potentially mediate some of the well-known but poorly understood effects of Ca2+0 on neuronal function. We have now examined the effects of polycationic CaR agonists on the activity of nonselective cation channels (NCC) in cultured rat hippocampal neurons, using the cell-attached configuration of the patch clamp technique and applying CaR active agents to the external bath solution. The polycationic CaR agonist, neomycin (100 microM), as well as an elevated concentration of Ca2+0 (3 mM), which is known to activate the cloned CaR, significantly increased the probability of channel opening (Po). The polyamine, spermine (300 microM), which also mimics the actions of Ca2+0 on the cloned CaR, produced similar changes in Po in rat hippocampal neurons. Elevation of Ca2+0 also increased Po for a similar NCC in HEK293 cells transfected with the cloned human CaR but not in nontransfected HEK cells. Thus the CaR can regulate the activity of Ca(2+)-permeable NCC in hippocampal neurons and could potentially modulate key functions of these cells, including neurotransmission and neuronal excitability. PMID- 8694827 TI - Molecular cloning & functional characterization of a mouse bradykinin B1 receptor gene. PMID- 8694828 TI - Organization of the human prostacyclin synthase gene. PMID- 8694829 TI - Roles of basigin, a member of the immunoglobulin superfamily, in behavior as to an irritating odor, lymphocyte response, and blood-brain barrier. AB - Basigin is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. Using the knockout mouse lacking the basigin gene (Bsg), we analyzed the function of basigin in adult mice lacking the gene [Bsg (-1-)]. Although histochemical studies on the localization of basigin (also called HT7 and neurothelin) strongly indicated that it is involved in the function of the blood brain barrier, basigin knockout mice showed only a little difference, if any, to wild-type mice in the function of the blood brain-barrier. The mitogenic response of lymphocytes upon mixed lymphocyte reaction was greater in Bsg (-1-) mice. Finally, Bsg (-1-) mice repeatedly visited filter paper impregnated with acetic acid or isozine, indicating an abnormality in either reception of the odor or behavior as to it. PMID- 8694830 TI - Substrate stereospecificity in oxidation of (25S)-3 alpha, 7 alpha, 12 alpha trihydroxy-5 beta-cholestanoyl-CoA by peroxisomal trihydroxy-5 beta-cholestanoyl CoA oxidase. AB - Partly purified 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestanoyl-CoA oxidase from rabbit liver peroxisomes was found to convert the 25S- but not the 25R diastereoisomer of 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestan-27 oyl-CoA into (24E)-3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholest-24-en-27 oic acid. In the presence of a peroxisomal THCA-CoA racemase, however, also the 25R isomer was oxidized. Since the mitochondrial steroid-27-hydroxylase, responsible for formation of THCA, is 25R specific a racemase seems to be obligatory for formation of cholic acid by the normal peroxisomal-dependent pathway. PMID- 8694831 TI - Sustained transgene expression by transfection of renin gene into liver of neonates. AB - Although transfection of renin gene into adult liver resulted in increased blood pressure (BP) for 1 week, sustained transgene expression must be considered to produce a continuous hypertensive animal. We hypothesized that gene transfer into neonatal rats would result in long-term transgene expression, given with highly replicating hepatocytes in neonates. Initially, chloramphenicol acetyltransferase (CAT) vector was transfected into the liver of 1-day-old rats. Immunohistochemical staining showed positive staining of CAT throughout the liver. Therefore, we transfected renin vector to study biological effects. At 2, but not 4 and 8, weeks, a significant increase in plasma angiotensin II concentration was observed in rats transfected with renin vector. Expression of renin mRNA in the liver transfected with renin vector could be detected at least up to 6 weeks, while no significant changes in BP were observed. These results demonstrated that in vivo gene transfer into the neonatal liver resulted in sustained transgene expression, suggesting the potential use of in vivo gene transfer as a tool to produce a novel model. PMID- 8694832 TI - Conformation of an antigenic determinant for experimental autoimmune neuritis. AB - The conformation of SP-26, the synthetic peptide (residues 53-78) of myelin P2 protein that causes experimental autoimmune neuritis (EAN) in the peripheral nervous system, has been investigated in D2O using Fourier transform infra-red spectroscopy. Turns were found in 26% of the residues in the peptide, with rest of the residues in random coil (72%). The presence of 26% turns agrees well with the number of residues forming three turns in the antigenic region of the intact protein and the number of turns correlates well with the severity of EAN. Since turns also exist in peptides inducing experimental autoimmune encephalomyelitis, the central nervous system counterpart of EAN, turn structure may be a common structural motif for these closely related autoimmune neurological disorders. PMID- 8694833 TI - Effects of 1,25-dihydroxy vitamin D3 on all-trans retinoic acid sensitive and resistant acute promyelocytic leukemia cells. AB - Following challenge of the acute promyelocytic leukemia (APL) cell line, NB4, with 1, 25 dihydroxy vitamin D3 (1, 25 D3), no increase in the expression of the monocytic surface markers, CD11c, CD14 and HLA-DR is observed. By contrast, 1, 25 D3 increases the expression of CD11b, an early myeloid marker and enhances adherence to plastic following priming of the cells with phorbol 12-myristate 13 acetate (PMA). NB4.306 and NB4.007/6, two all-trans retinoic acid-resistant cell lines originated from NB4 promyelocytes and lacking expression of a complete form of PML-RAR, are totally resistant to 1, 25 D3-dependent induction of CD11b. In addition, NB4.306 cells do not show enhanced plastic adherence following treatment with the vitamin D metabolite and PMA. NB4 and NB4.306 express similar amounts of the transcripts coding for the vitamin D3 receptor and the retinoid accessory receptors, RXR alpha and RXR beta, both in basal conditions and upon treatment with 1, 25 D3. PMID- 8694835 TI - Muscarinic stimulation increases Na+ entry in pancreatic B-cells by a mechanism other than the emptying of intracellular Ca2+ pools. AB - Stimulation of muscarinic (M3) receptors depolarizes pancreatic B-cells by increasing Na+ influx. Here, we measured [Na+]i and [Ca2+]i in B-cell clusters to investigate whether depletion of intracellular Ca2+ pools triggers this unusual transduction pathway for muscarinic receptors. Acetylcholine emptied Ca2+ pools less completely than did the SERCA pump inhibitors, thapsigargin, and cyclopiazonic acid. However, the rise in [Na+]i produced by acetylcholine was not mimicked by thapsigargin or cyclopiazonic acid and was not prevented by previous depletion of Ca2+ pools. Depolarization of B-cells by acetylcholine stimulates Ca2+ influx and steadily increases [Ca2+]i. In the presence of glucose and extracellular Ca2+, B-cells treated with thapsigargin or cyclopiazonic acid displayed large [Ca2+]i oscillations. Subsequent application of acetylcholine was followed by a sustained rise in [Ca2+]i as in untreated cells. In conclusion, intracellular Ca2+ pool depletion does not mediate acetylcholine stimulation of Na+ entry and of subsequent events. We propose that the muscarinic receptors are coupled to Na+ channels in B-cells. PMID- 8694834 TI - Mechanisms of transcriptional activation of the promoter of the rainbow trout prolactin gene by GHF1/Pit1 and glucocorticoid. AB - The transcription factor GHF1/Pit1, required for the expression of the prolactin (PRL) and other pituitary-specific genes, is highly conserved from fish to mammals but the mechanisms by which it activates transcription are poorly understood. The activity of the promoter (-627/+15 region) of the rainbow trout PRL (tPRL) gene fused to the luciferase reporter gene was studied using GHF1 expressing rat pituitary GC cells. Nuclear extracts of GC cells produced five GHF1-specific footprints in the tPRL promoter, with the position of the two most proximal ones being highly conserved in trout and mammalian GHF1-regulated genes. Deletional and mutational analyses of the tPRL promoter showed that the most proximal GHF1 site alone is sufficient to confer sub-maximal GHF1-dependent transcriptional activity and that a glucocorticoid response element-like motif mediates dexamethasone stimulation. It is suggested that GHF1 molecules bound to different sites of the tPRL promoter cannot interact simultaneously with the transcriptional apparatus. Moreover, GHF1 and the ligand-bound glucocorticoid receptor tethered to their cognate elements in the promoter could cooperate to enhance transcription by interacting simultaneously with different members of the basal transcriptional complex. PMID- 8694837 TI - Alpha 1b-adrenoceptor-mediated calcium oscillation is specific for the S phase in cell cycle and dependent on the extracellular calcium. AB - Using Chinese hamster ovary cells stably expressing alpha 1b-adrenoceptor (alpha 1bAR) as a model, we examined the effect of the cell cycle on the agonist promoted intracellular [Ca2+]i oscillation. In cells synchronized into either the G1 state or the M phase, no oscillatory behavior was observed under any extracellular Ca2+ concentrations ([Ca2+]o < or = 3 mM), whereas in cells synchronized into the S phase, norepinephrine caused [Ca2+]i oscillation in a [Ca2+]o-dependent manner, indicating that alpha 1AR-mediated [Ca2+]i oscillation is specific for the S phase in cell cycle and dependent on [Ca2+]o. The S phase specific occurrence of alpha 1AR-mediated [Ca2+]i oscillation is not associated with changes in alpha 1AR density. As the cells consistently developed [Ca2+]i oscillation in the S phase, the cells would provide a valuable system to study further the biochemical mechanism for agonist-induced [Ca2+]i oscillation phenomenon. PMID- 8694836 TI - Enhancement of CPP32-like activity in the TNF-treated U937 cells by the proteasome inhibitors. AB - CPP32, which is most closely related to CED-3 in the apoptotic protease in C. elegance, is activated during apoptosis induced by anti-Fas and TNF. Since processing of CPP32 is important for the activation, we examined the effects of protease inhibitors on CPP32-like activity in the TNF-treated U937 cells. Unexpectedly, proteasome inhibitors (at 5 microM) such as Z-LLnV, Z-LLL, and lactacystin enhanced CPP32-like activity, Ac-DEVD-MCA degrading activity, in the TNF-treated U937 cells in 3 hr, but E64d, cysteine protease inhibitor, did not. These proteasome inhibitors alone did not enhance CPP32-like activity in the untreated U937 cells under the condition used. The proteasome seems to protect the cells from apoptosis by degrading CPP32-like protease or its processing enzyme. PMID- 8694838 TI - Activation of mitogen activated protein kinase in dolichyl phosphate-induced apoptosis in U937 cells. AB - Exogenous dolichyl phosphate (Dol-P) induced apoptosis in the human monoblastic leukemia cell line U937 within 4 hours. Phosphorylation of p42 mitogen-activated protein kinase (MAP kinase) increased prior to DNA fragmentation. MAP kinase activation occurred within 5 min, and the maximum response was observed at 30 min. Inhibition of tyrosine phosphorylation of MAP kinase by herbimycin A resulted in complete inhibition of DNA fragmentation and partial inhibition of cell death. These results suggested that Dol-P-induced apoptosis is mediated by the MAP kinase cascade. PMID- 8694839 TI - Autoantibody against Na+/I- symporter in the sera of patients with autoimmune thyroid disease. AB - Using recombinant rat Na+/I- symporter (NaIS) protein, we have immunochemically searched for the autoantibody in the sera from patients with autoimmune thyroid disease. We found that 22 out of 26 sera (84%) from patients with Graves' disease and 3 out of 20 sera (15%) from patients with Hashimoto's thyroiditis recognized it. By Western blot, these IgGs reacted with 80 kDa protein in FRTL-5 cell membrane, which co-migrated with the band stained by rabbit antibody toward NaIS. These results indicate that autoantibody against NaIS, newly identified antibody, frequently exists in patients with autoimmune thyroid disease, especially in Graves' disease. PMID- 8694840 TI - ADP-ribosylation of wild-type p53 in vitro: binding of p53 protein to specific p53 consensus sequence prevents its modification. AB - We have recently reported that mutant but not wild-type (wt) p53 protein was ADP ribosylated in primary rat cells overexpressing the temperature-sensitive murine p53val135 gene. To examine whether the lack of susceptibility to modification is a specific feature of p53val135 adopting wt conformation or rather a general property of this tumor suppressor protein, we have studied ADP-ribosylation of wt p53 of different origin in vitro using semi-purified poly(ADP-ribose) transferase (pADPRT). In vitro pADPRT modified human and mouse wt p53 and p53val135. Under limiting substrate concentration, the molar mass of ADP-ribosylated p53 was only slightly altered. Chase experiments with high NAD concentration resulted in the formation of poly(ADP-ribosyl)ated p53 protein shifted to 64 kD. However, preincubation of wt p53 proteins with a p53 consensus sequence resulting in complex formation abolished the modification of wt p53. This indicates that in the cellular environment the specific DNA binding of wt p53 prevents its covalent modification by poly(ADP-ribose). PMID- 8694841 TI - Engineered biosynthesis of peptide antibiotics. AB - In certain bacteria and filamentous fungi, a wide variety of bioactive peptides are produced non-ribosomally on large protein templates, called peptide synthetases. Recently, significant progress has been made towards understanding the modular arrangement of these complex multifunctional enzymes and the mechanisms by which they generate their corresponding peptide products. It has now been established that the synthesis of bioactive peptides and the specification of their sequence are brought about by a protein template that contains the appropriate number and the correct order of activating units (domains). These advances have enabled the development of a technique that permits the construction of hybrid genes encoding peptide synthetases with specifically altered substrate specificities. A programmed alteration within the primary structure of a peptide antibiotic is achieved by the substitution of an amino acid-activating domain in the corresponding protein template at the genetic level by a two-step recombination method. It utilizes successive gene disruption and reconstitution and demonstrates, for the first time, the potential of genetic engineering in the biosynthesis of novel peptide antibiotics. Many organisms, for instance those that cause diseases like tuberculosis and pneumonia, have evolved potent mechanisms of drug resistance. Therefore, the targeted engineering of peptide antibiotics could be one potential strategy for the development of novel drugs that overcome this resistance. PMID- 8694842 TI - Inhibition of bovine lung semicarbazide-sensitive amine oxidase (SSAO) by some hydrazine derivatives. AB - Microsomal semicarbazide-sensitive amine oxidase (SSAO) from bovine lung was shown to be inhibited by a number of hydrazine derivatives, but the mechanisms of inhibition were found to differ. Hydralazine behaved as an irreversible and partially time-dependent inhibitor with an IC50 value of 1 microM under the conditions used. Phenylhydrazine was found to be a potent irreversible inhibitor of SSAO (IC50 30 nM). Semicarbazide behaved as a specific irreversible inhibitor (active-site-directed irreversible inhibitor) in first forming a non-covalent enzyme-semicarbazide complex (with a Ki value of 85 microM), which then reacted to give an irreversibly inhibited enzyme species in a reaction defined by the first-order rate constant k2 = 0.065 min-1. Phenelzine behaved as a reversible inhibitor, but dialysis at 37 degrees C was found to be necessary to obtain full recovery of enzyme activity. The dependence of inhibition on phenelzine concentration was complex and consistent with multiple binding sites for this inhibitor. This diversity in the action of a family of compounds with the same functional group must be taken into account in attempts to design more specific inhibitors of this enzyme. PMID- 8694844 TI - Protection by glutathione against the antiproliferative effects of nitric oxide. Dependence on kinetics of no release. AB - Pretreatment by L-buthionine sulfoximine (BSO), which inactivates gamma glutamylcysteine synthetase and, therefore, inhibits glutathione (GSH) synthesis, greatly increased the sensitivity of tumor cells to the antiproliferative effects of several NO-donating compounds. The sensitization that resulted from depletion of cellular GSH pools was observed in tumor cells exhibiting different degrees of resistance to NO. In contrast, GSH depletion of tumor target cells did not affect their sensitivity to the cytostatic activity of activated macrophages and other NO-producing cells (EMT6 cells treated by interferon gamma and LPS). The kinetics for NO generation is a parameter that may differentiate NO-producing cells and short-lived NO donors. To study the relationship between the magnitude of NO fluxes and the increased toxicity on BSO-pretreated cells, two NO-releasing zwitterions derived from polyamines (NONOates) with different half-lives were selected. NO fluxes as a function of time were simulated, according to the donor half-life and initial concentration, and antiproliferative effects on control and BSO-treated cells were compared. GSH depletion increased the sensitivity of tumor cells in the case of the less stable NO donor only. We, thus, propose that intracellular GSH is specifically protective against high fluxes of NO. PMID- 8694845 TI - Study of P-glycoprotein functionality in living resistant K562 cells after photolabeling with a verapamil analogue. AB - To our knowledge, this is the first study to investigate the modification of P glycoprotein functionality in living resistant cells after photolabeling. For this purpose, four new photoactive verapamil analogues were synthesized. These compounds have the same efficacy as verapamil to increase pirarubicin (pira) incorporation into living multidrug resistant (MDR) K562 cells and to sensitize them to the cytotoxic effect of this anthracycline derivative, indicating that they act as typical MDR modifiers in MDR cells. These compounds were used to photolabel P-glycoprotein (P-gp) in living resistant cells. Irradiation did not result in photodamage to cells, and P-gp functionality was verified by the ability of living cells to incorporate pira. The irradiation of resistant cells, 10(6)/mL, in the presence of a verapamil analogue at concentrations equal to or higher than 3 microM yielded 70% inhibition of P-gp functionality. Our data provide the first evidence that the binding of a verapamil analogue to P-gp is not sufficient to completely inhibit the efflux of this anthracycline. The cells were, subsequently, cultured for several days. Resistance was progressively recovered with time, with the treated cells being just as resistant as before photolabeling after 6 days. PMID- 8694846 TI - Effects of metyrapone on expression of CYPs 2C11, 3A2, and other 3A genes in rat hepatocytes cultured on matrigel. AB - Hepatocytes cultured on matrigel express many liver-specific functions, but the levels and activities of the predominant male-specific rat hepatic CYPs, 3A2 and 2C11, decline rapidly in culture. Metyrapone maintains the level of total cytochrome P450 of rat hepatocytes in primary culture, but the mechanism underlying this effect has not been completely elucidated. The present study sought to determine whether metyrapone acts solely to stabilise CYP proteins in rat hepatocytes cultured on matrigel, or whether it also influences mRNA levels of the encoding genes. Metyrapone maintained the level of total cytochrome P450 in cultured hepatocytes so that values were > 200% of those found in untreated control cells 24 hr after isolation. At this time, CYP3A2-mediated testosterone 6 beta-hydroxylation was approximately 7-fold higher in hepatocytes cultured in the presence of metyrapone than in control cells, and CYP2C11-dependent testosterone 2 alpha- and 16 alpha-hydroxylation activities were between 2 and 3-fold greater. The results inferred from catalytic activities were supported by immunoquantitation of CYP3A and 2C11 proteins. The trend of increased CYP protein levels in metyrapone-treated cells continued throughout the 48-hr culture period. In control cells, CYP3A2 and 2C11 mRNA levels fell abruptly in culture to reach values at 24 hr that were < 30% of those in freshly isolated cells; addition of metyrapone failed to arrest this fall. However, treatment of cells with metyrapone considerably elevated levels of one or more CYP3A subfamily mRNA species, as detected by a riboprobe based on the cDNA for CYP3A1 ("CYP3A1-like mRNA') that were demonstrated, by another riboprobe, not to be CYP3A2 or RNCYP3AM. RT-PCR of mRNA prepared from cultured hepatocytes, followed by restriction mapping of the cloned cDNAs was used to characterise the CYP3A induced by metyrapone. This revealed that elevated levels of the CYP3A1-like mRNA were attributable to induction of RL33/cDEX mRNA; there were no CYP3A1 cDNAs isolated from these cells. These data are interpreted as indicating that metyrapone stabilises the expression of cytochrome P450 in culture by both pre- and posttranslational mechanisms. The particular mechanism employed is gene specific, whereby even the highly homologous genes CYP3A2, RL33/cDEX and, possibly, RNCYP3AM are subject to different types of regulation in the presence of metyrapone. PMID- 8694847 TI - Inhibition and metal ion activation of pig kidney aminopeptidase P. Dependence on nature of substrate. AB - Pig kidney aminopeptidase P (AP-P; EC 3.4.11.9) has been purified to homogeneity after its solubilisation from brush border membranes by phosphatidylinositol specific phospholipase C. The effects of various activators and inhibitors of AP P activity have been examined with a number of different substrates for the enzyme. The hydrolysis of bradykinin and ArgProPro is inhibited at Mn2+ concentrations above 10(-5) M, whereas the hydrolysis of other substrates (GlyProHyp, beta-casomorphin, substance P) is substantially activated, with 4-10 mM Mn2+ being optimal. The thiol reagent, p-chloromercuriphenylsulphonic acid, inhibits the hydrolysis of GlyProHyp but markedly activates the hydrolysis of bradykinin. A number of inhibitors of angiotensin converting enzyme (ACE; EC 3.4.15.1), previously reported to inhibit the hydrolysis of GlyProHyp, have no effect on the hydrolysis of bradykinin except in the presence of Mn2+. Differences were also observed in the degree of inhibition of GlyProHyp and bradykinin hydrolysis by EDTA and their reactivation by divalent cations. The hydrolysis of GlyProHyp follows Michaelis-Menten kinetics with a Km value of 2.7 mM. Bradykinin inhibits GlyProHyp hydrolysis with an I50 of 1.4 microM. The hydrolysis of bradykinin by AP-P reveals anomalous nonlinear kinetics indicative of negative cooperativity or the presence of more than one active site for this substrate. These results indicate that substrates for AP-P can be divided into 2 groups based on their responses to inhibitors and cation activators. PMID- 8694848 TI - Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the incidence of and mortality from colon cancer. We observed that NSAIDs inhibit the proliferation rate, alter the cell cycle distribution, and induce apoptosis in colon cancer cell lines. We evaluated whether the inhibition by NSAIDs of prostaglandin (PG) synthesis is required for their effects on colon cancer cells by studying two human colon cancer cell lines: HCT-15 and HT-29. HCT-15, which lacks cyclooxygenase transcripts, does not produce PGs even when exogenously stimulated, whereas HT-29 produces PGE2, PGF2 alpha, and PGI2. HCT-15 and HT-29 cells, when treated for up to 72 hr with 200 microM sulindac sulfide (an active metabolite of sulindac) or 900 microM piroxicam, showed changes in proliferation, cell cycle phase distribution, and apoptosis. Treatment with PGE2, PGF2 alpha, and PGI2, following a variety of protocols, and at concentrations between 10(-6) and 10(-11) M, failed to reverse the effects of NSAIDs on these three parameters of cell growth. We concluded that NSAIDs inhibit the proliferation rate of the two colon cancer cell lines independent of their ability to inhibit PG synthesis. Thus, alternative mechanisms for their activity on tumor cell growth must be entertained. These observations may be relevant to the mechanism of colon tumor inhibition by NSAIDs. PMID- 8694849 TI - NAD+ biosynthesis and metabolic fluxes of tryptophan in hepatocytes isolated from rats fed a clofibrate-containing diet. AB - Hepatocytes were isolated from rats fed a diet with or without 0.25% clofibrate, and NAD+ synthesis by the hepatocytes was determined using either [carboxyl 14C]nicotinic acid or [5-3H]tryptophan. NAD+ and total pyridine nucleotides synthesized from [14C]nicotinic acid by the clofibrate-treated cells were not significantly different from those synthesized by the control cells when expressed on the basis of nanomoles per hour per milligram of DNA. On the contrary, NAD+ synthesized from [3H]tryptophan was significantly higher in the clofibrate-treated cells (158% of the control cells) on the basis of nanomoles per hour per milligram of DNA. Clofibrate was inhibitory to tryptophan metabolism as a whole, affecting the glutarate pathway more (decreased to 37% of control) than the kynureninase flux (decreased to 64% of control). As a result, the quinolinate-NAD flux, estimated as the difference in the amounts of tryptophan metabolized by the two metabolic pathways, increased in the clofibrate-treated hepatocytes. The increase in quinolinate during the incubation was 8 times more in the clofibrate-treated cells than in the control cells, which confirmed alteration in the metabolic fluxes of tryptophan in the clofibrate-treated cells. Hepatic quinolinate phosphoribosyltransferase (EC 2.4.2.19) activity increased with dietary clofibrate and returned to the control level 1 week after removing clofibrate from the diet. Nicotinate phosphoribosyltransferase (EC 2.4.2.11) and NAD+ glycohydrolase (EC 3.2.2.5) activities remained unchanged with dietary clofibrate. PMID- 8694843 TI - In vitro inhibition of rat and human glutathione S-transferase isoenzymes by disulfiram and diethyldithiocarbamate. AB - The drug disulfiram (DSF, Antabuse) has been used in the therapy of alcohol abuse. It is a potent inhibitor of aldehyde dehydrogenase. Its reduced form, diethyldithiocarbamate (DDTC), and further metabolites show similar activities. DSF and DDTC have also been widely used to inhibit mixed-function oxidases. In this study, the reversible inhibition and time-dependent inactivation of the major rat and human glutathione S-transferase (GST) isoenzymes by DSF and DDTC was investigated. Reversible inhibition, using 1-chloro-2,4-dinitrobenzene as substrate for the GST alpha-, mu-, and pi-class, expressed as I50 (in microM), ranged from 5-18 (human A1-1), 43-57 (rat 4-4) and 66-83 (rat 1-1), for both DSF and DDTC. The I50 for rat GST theta, using 1,2-epoxy-3-(p-nitrophenoxy)-propane as substrate, was 350 microM for DDTC. The other GSTs were significantly less sensitive to inhibition. The major part of reversible inhibition by DSF was shown to be due to DDTC, formed rapidly upon reduction of DSF by the glutathione (GSH) present in the assay to measure GST activity. The oxidized GSH formed upon reduction of DSF might also have made a minor contribution to reversible inhibition. The rat and human pi-class was, by far, the most sensitive class for time-dependent inactivation by DSF, but no such inactivation was observed for any of the GSTs by DDTC. Moderate susceptibility to inactivation by DSF of all the other GSTs was observed, except for human A2-2, which does not possess a cysteine residue. Consistent with the assumption that a thiol residue is involved in this inactivation, a significant part of the activity could be restored by treatment of the inactivated GST with GSH or dithiotreitol. PMID- 8694850 TI - Stimulation by chelerythrine of the phosphorylation of the amino acid serine in an approximately 20 kDa protein present in the mitochondrial fraction of the rat retina. AB - It has been reported that chelerythrine chloride, a benzophenanthridine alkaloid, with a wide variety of biologic effects stimulates the phosphorylation of an approximately 20 kDa protein present in the mitochondrial fraction of the rat retina. It has also been shown previously that both the serine and threonine resides in this phosphoprotein are phosphorylated when the retinal preparation is incubated in the presence of [gamma-32P]ATP. Phosphorylation of the serine residue(s) was determined to predominate over phosphorylation of the threonine residue(s). In the present investigation, it was demonstrated that chelerythrine stimulates the incorporation of radioactive phosphate into the serine residue(s), increasing the radioactivity in the phosphoserine/ phosphothreonine ratio by 80%. This observation represents a novel and apparently contradictory effect for chelerythrine, which is used normally as a selective protein kinase C inhibitor. In addition to testing chelerythrine for its effects on the phosphorylation of the approximately 20 kDa protein, a number of other protein kinase inhibitors and activators were investigated. The results suggest that the enzyme responsible for the phosphorylation of the approximately 20 kDa protein is not a well characterized or documented kinase. PMID- 8694851 TI - Pathways of glutathione metabolism and transport in isolated proximal tubular cells from rat kidney. AB - Cellular uptake and metabolism of exogenous glutathione (GSH) in freshly isolated proximal tubular (PT) cells from rat kidney were examined in the absence and presence of inhibitors of GSH turnover [acivicin, L-buthionine-S,R-sulfoximine (BSO)] to quantify and assess the role of different pathways in the handling of GSH in this renal cell population. Incubation of PT cells with 2 or 5 mM GSH in the presence of acivicin/BSO produced 3- to 4-fold increases in intracellular GSH within 10-15 min. These significantly higher intracellular concentrations were maintained for up to 60 min. At lower concentrations of extracellular GSH, an initial increase in intracellular GSH concentrations was observed, but this was not maintained for the 60-min time course. In the absence of inhibitors, intracellular concentrations of GSH increased to levels that were 2- to 3-fold higher than initial values in the first 10-15 min, but these dropped below initial levels thereafter. In both the absence and presence of acivicin/BSO, PT cells catalyzed oxidation of GSH to glutathione disulfide (GSSG) and degradation of GSH to glutamate and cyst(e)ine. Exogenous tert-butyl hydroperoxide oxidized intracellular GSH to GSSG in a concentration-dependent manner and extracellular GSSG was transported into PT cells, but limited intracellular reduction of GSSG to GSH occurred. Furthermore, incubation of cells with precursor amino acids produced little intracellular synthesis of GSH, suggesting that PT cells have limited biosynthetic capacity for GSH under these conditions. Hence, direct uptake of GSH, rather than reduction of GSSG or resynthesis from precursors, may be the primary mechanism to maintain intracellular thiol redox status under toxicological conditions. Since PT cells are a primary target for toxicants, the ability of these cells to rapidly take up and metabolize GSH may serve as a defensive mechanism to protect against chemical injury. PMID- 8694853 TI - Structural studies of a human pi class glutathione S-transferase. Photoaffinity labeling of the active site and target size analysis. AB - The glutathione S-transferases (GSTs; EC 2.5.1.18) are a family of dimeric proteins that catalyze reactions between glutathione (GSH) and various electrophiles. A partial cDNA for human GST pi was obtained and the open reading frame completed. The completed cDNA was cloned, and GST pi protein was expressed in bacteria. Cloned enzyme was purified and had the same kinetic constants, molecular mass, pI value, and N-terminal sequence as placental GST pi except that some of the polypeptides had N-terminal methionines. A radiolabeled azido derivative of GSH, S-(p-azidophenacyl)-[3H]glutathione, was used to photoaffinity label the active site of the cloned enzyme. Labeled enzyme did not bind to a GSH agarose affinity column. Labeling was prevented in the presence of S hexylglutathione, and noncovalently-bound azido affinity label was a competitive inhibitor towards 1-chloro-2,4-dinitrobenzene and GSH. These results suggest that the azido label was binding at the active site of the enzyme. Photoaffinity labeled enzyme was trypsinized, and two labeled peptides were purified and sequenced. One peptide corresponded to residues 183-188, whereas the other corresponded to residues 183-186. These residues appear to form part of the hydrophobic (H-site) binding region of human GST pi that has not been shown previously. Cloned enzyme was subjected to radiation inactivation to assess the importance of subunit interactions in the maintenance of catalytic activity. The target size of enzymatic activity (23 kDa) was not significantly different from that of the protein monomer (24 kDa). Therefore, each subunit of human GST pi appears to be capable of independent catalytic activity. PMID- 8694852 TI - Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone. AB - The mechanism of the anti-anginal effect of perhexiline is unclear but appears to involve a shift in cardiac metabolism from utilization of fatty acid to that of carbohydrate. We tested the hypothesis that perhexiline inhibits the enzyme carnitine palmitoyltransferase-1 (CPT-1), which controls access of long chain fatty acids to the mitochondrial site of beta-oxidation. Perhexiline produced a concentration-dependent inhibition of CPT-1 in rat cardiac and hepatic mitochondria in vitro, with half-maximal inhibition (IC50) at 77 and 148 mumol/L, respectively. Amiodarone, another drug with anti-anginal properties, also inhibited cardiac CPT-1 (IC50 = 228 mumol/L). The rank order of potency for inhibition was malonyl-CoA > 4-hydroxyphenylglyoxylate (HPG) = perhexiline > amiodarone = monohydroxy-perhexiline. Kinetic analysis revealed competitive inhibition of cardiac and hepatic CPT-1 by perhexiline with respect to palmitoyl CoA but non-competitive inhibition with respect to carnitine. Curvilinear Dixon plots generated "apparent inhibitory constant (Ki)" values for perhexiline, which indicated a greater sensitivity of the cardiac than the hepatic enzyme to inhibition by perhexiline. Perhexiline inhibition of CPT-1, unlike that of malonyl-CoA and HPG, was unaffected by pretreatment with the protease nagarse. These data establish for the first time that two agents with proven anti-anginal effects inhibit cardiac CPT-1. This action is likely to contribute to the anti ischaemic effects of both perhexiline and amiodarone. PMID- 8694854 TI - Effects of mebendazole on protein biosynthesis and secretion in human-derived fibroblast cultures. AB - Previous results of our group revealed that mebendazole, a broad spectrum anthelmintic drug with antimicrotubular properties, used for the treatment of liver cirrhosis, decreased total collagen content and biosynthesis in liver upon treatment. In the present study, we have evaluated the effects of mebendazole (5 50 micrograms/mL) on protein synthesis, secretion, and deposition in human derived fibroblast cultures. The results showed a decrease in cell viability (18.5 +/- 0.9%) at 50 micrograms/mL. [3H]Thymidine incorporation diminished gradually with increasing mebendazole concentrations, reaching a plateau (53.67%) between 30 and 50 micrograms/mL. In late logarithmic phase cultures, the drug caused a decrease of [3H]proline incorporation (43.10%) and collagen biosynthesis (58.61%) in the extracellular matrix. This correlated with an increase in radioactivity in total proteins (51.28%) of the intracellular fraction. Similar results were obtained when mebendazole was assayed in post-confluent fibroblast cultures. The electrophoretic patterns of the extracellular matrix showed a decrease of radioactive collagenous components (alpha chains and beta dimers). By contrast, in the intracellular fraction an increase of radioactive collagen precursors (pro alpha chains) was observed. Immunofluorescence studies and immunotransfer analysis, using polyclonal anti-type I collagen antibodies, revealed an accumulation of intracellular collagen which included: collagen pro alpha chains, alpha chains, and low molecular weight peptides. The results obtained suggest that mebendazole interferes with the transcellular mobilization of proteins, resulting in a decrease of secretion and deposition of extracellular matrix proteins, and an accumulation of intracellular collagenous components. The intracellular accumulation of newly synthesized proteins could cause a feedback regulation in fibroblast cultures. PMID- 8694855 TI - Requirements for cytochrome b5 in the oxidation of 7-ethoxycoumarin, chlorzoxazone, aniline, and N-nitrosodimethylamine by recombinant cytochrome P450 2E1 and by human liver microsomes. AB - NADH-dependent 7-ethoxycoumarin O-deethylation activities could be reconstituted in systems containing cytochrome b5 (b5), NADH-b5 reductase, and bacterial recombinant P450 2E1 in 100 mM potassium phosphate buffer (pH 7.4) containing a synthetic phospholipid mixture and cholate. Replacement of NADH-b5 reductase with NADPH-P450 reductase yielded a 4-fold increase in 7-ethoxycoumarin O-deethylation activity, and further stimulation (approximately 1.5-fold) could be obtained when NADPH was used as an electron donor. Removal of b5 from the NADH- and NADPH supported systems caused a 90% loss of 7-ethoxycoumarin O-deethylation activities in the presence of NADPH-P450 reductase, but resulted in complete loss of the activities in the absence of NADPH-P450 reductase. Km values were increased and Vmax values were decreased for 7-ethoxycoumarin O-deethylation when b5 was omitted from the NADPH-supported P450 2E1-reconstituted systems. Requirements for b5 in P450 2E1 systems were also observed in chlorzoxazone 6-hydroxylation, aniline p-hydroxylation, and N-nitrosodimethylamine N-demethylation. In human liver microsomes, NADH-dependent 7-ethoxycoumarin O-deethylation, chlorzoxazone 6 hydroxylation, aniline p-hydroxylation, and N-nitrosodimethylamine N demethylation activities were found to be about 55, 41, 33, and 50%, respectively, of those catalyzed by NADPH-supported systems. Anti-rat NADPH-P450 reductase immunoglobulin G inhibited 7-ethoxycoumarin O-deethylation activity catalyzed by human liver microsomes more strongly in NADPH- than NADH-supported reactions, while anti-human b5 immunoglobulin G inhibited microsomal activities in both NADH- and NADPH-supported systems to similar extents. These results suggest that b5 is an essential component in P450 2E1-catalyzed oxidations of several substrates used, that about 10% of the activities occur via P450 2E1 reduction by NADPH-P450 reductase in the absence of b5, and that the NADH supported system contributes, in part, to some reactions catalyzed by P450 2E1 in human liver microsomes. PMID- 8694856 TI - Dual effect of 1 alpha,25-dihydroxyvitamin D3 on hsp28 and PKC beta gene expression in phorbol ester-resistant human myeloid HL-525 leukemic cells. AB - We investigated the effect of 1 alpha-25-dihydroxyvitamin D3 [1,25-(OH)2D3] on the expression of the 28-kDa heat shock protein gene (hsp28) and the protein kinase C beta gene (PKC beta) in the human myeloid HL-60 leukemic cell variant HL 525, which is resistant to phorbol ester-induced macrophage differentiation. Northern and western blot analysis showed little or no hsp28 gene expression in the HL-60 cell variant, HL-205, which is susceptible to such differentiation, while a relatively high basal level of hsp28 gene expression was observed in the HL-525 cells. However, both cell lines demonstrated heat shock-induced expression of this gene. During treatment with 50-300 nM 1,25-(OH)2D3, a marked reduction of hsp28 gene expression along with an induction of PKC beta gene expression was observed in HL-525 cells. A gel mobility-shift assay demonstrated that the 1,25 (OH)2D3-induced alteration of hsp28 gene expression was associated with decreased binding activity to the vitamin D3 receptor-vitamin D3 response element (VDR VDRE), whereas binding to the heat shock transcription factor-heat shock element (HSF-HSE) was not altered. Our results suggest that the dual effect of 1,25 (OH)2D3 on hsp28 and PKC beta gene expression is due to the different sequence composition of the vitamin D response element in the promoter region as well as an accessory factor for each gene or that 1,25-(OH)2D3 increases PKC beta gene expression, which, in turn, negatively regulates the expression of the hsp28 gene or vice versa. PMID- 8694857 TI - A cardiotonic steroid bufalin-induced differentiation of THP-1 cells. Involvement of Na+, K(+)-ATPase inhibition in the early changes in proto-oncogene expression. AB - Human monocytic leukemia THP-1 cells were induced to differentiate into macrophage-like cells by treatment with cardiotonic steroid bufalin, which was previously shown to interact with the Na+, K+-ATPase with similar kinetics to ouabain, a specific inhibitor of the enzyme. This induction of differentiation was characterized by loss of proliferation, cell adherence, increased ability to reduce Nitro Blue tetrazolium (NBT), and increased expression of interleukin 1 beta (IL-1 beta). During this process, bufalin downregulated c-myb and c-myc expressions and induced c-fos and Egr-1 transcripts. Ouabain also caused similar changes in proto- oncogene expression and induced phenotypic markers of differentiated cells at concentrations comparable to bufalin. The 12-O tetradecanoyl phorbol-13-acetate resistant THP-1 cell variant, which was unresponsive to this agent as to growth inhibition and proto-oncogene expression, responded to bufalin. The finding that protein kinase inhibitor H7 failed to bufalin-mediated c-fos induction further supports the theory that the signal transduction machinery caused by bufalin is separable from the phorbol ester. The cytotoxic effect of high doses of bufalin apparently disappeared in the medium where Na+ was replaced with choline ions. Furthermore, bufalin failed to induce c fos expression and to downregulate c-myb transcripts in the low-Na+ medium. These findings indicate that an increased intracellular Na+ concentration resulting from the Na+, K(+)-ATPase inhibition possibly triggers the change in proto oncogene expression evoked by bufalin. PMID- 8694859 TI - Membrane stabilizing, anti-oxidative interactions of propranolol and dexpropranolol with neutrophils. AB - We have investigated the effects of the beta-adrenoreceptor-blocking agent, propranolol (9-300 microM) on several pro-inflammatory activities of human neutrophils in vitro. Superoxide production by calcium ionophore (A23187) activated neutrophils was particularly sensitive to inhibition by low concentrations (9-18.7 microM) of this drug. However, inhibition of superoxide generation by neutrophils activated with phorbol myristate acetate (PMA), opsonized zymosan (OZ), and arachidonate (AA) only occurred with higher concentrations of propranolol, and coincided with decreased intracellular calcium fluxes, phospholipase A2 (PLA2) activity and synthesis of platelet-activating factor (PAF). Propranolol possessed neither cytotoxic nor superoxide-scavenging properties but, using a haemolytic assay of membrane-stabilizing activity, this agent neutralized the membrane-disruptive effects of the bioactive phospholipids, lysophosphatidylcholine (LPC), PAF, and lysoPAF(LPAF). A mechanistic relationship between the anti-oxidative and membrane-stabilizing properties of propranolol was suggested by the observation that pretreatment of neutrophils with LPC or PAF eliminated the inhibitory effects of the drug on superoxide generation by PMA activated neutrophils. Dexpropranolol, a stereoisomer with minimal beta-blocking activity, and propranolol were equally effective with respect to their membrane stabilizing and anti-oxidative interactions with neutrophils, but several other beta-blocking agents (atenolol, metoprolol, sotalol, and timolol) did not possess these activities. Inhibition of oxidant generation is, therefore, not a common property of beta-blocking agents and, in the case of propranolol, appears to occur as a consequence of membrane-stabilization rather than by beta-receptor directed effects. PMID- 8694860 TI - Lipocortin 1 and the control of cPLA2 activity in A549 cells. Glucocorticoids block EGF stimulation of cPLA2 phosphorylation. AB - Epidermal growth factor (EGF) rapidly stimulates the release of arachidonic acid in A549 cells by a mechanism that is sensitive to pertussis toxin [1]. We show that EGF treatment of A549 cells stimulates phosphorylation of cytosolic phospholipase A2 (cPLA2) through a mechanism that is similarly inhibited by pertussis toxin. The level of cPLA2 expression is, apparently, not changed during this period. Pretreatment of cells with dexamethasone (10-100 nM) for 3 hr prevents this activation of cPLA2 by EFG, without changing the level of cPLA21 expression. The effect of dexamethasone is reversed in the presence of the neutralizing antilipocortin Mab 1A but not by the nonneutralizing antilipocortin 1 control Mab 1B. This strongly suggests that lipocortin 1 mediates the effect of dexamethasone by inhibiting activation of cPLA2. This concept is supported by the fact that a peptide Lc13-25 (10-200 micrograms/mL), derived from the N-terminus of lipocortin 1, also inhibits activation of cPLA2 by EGF in these cells. PMID- 8694863 TI - Use of inhibitors of ion transport to differentiate iron transporters in erythroid cells. AB - Iron uptake by rabbit reticulocytes and mature erythrocytes was investigated using 4 incubation systems: 1. Fe-transferrin in NaCl at pH 7.4, 2. Fe transferrin in sucrose at pH 5.9, 3. Fe(II)-sucrose in sucrose at pH 6.5, and 4.Fe(II)-sucrose in KCl at pH 7.0. These systems were compared with respect to their magnitude and response to many membrane transport inhibitors and modifying agents. Iron uptake via the first 3 systems had many similar features that were quite distinct from those of iron uptake in the fourth system. On the basis of these results, it is concluded that erythroid cells contain two iron transport mechanisms, one with high affinity and relatively low capacity for iron transport, which can be studied using incubation systems 1-3, and the other of low affinity but high capacity (incubation system 4). High-affinity transport is present only in immature erythroid cells, is relatively sensitive to inhibition by N-ethylmaleimide (NEM), N,N1- dicyclohexylcarbodiimide (DCCD), and 7-chloro-4 nitrobenz-2-oxa-1,3 diazole (NBD), and is probably the mechanism by which iron, released from transferrin within endosomes, is transported across the endosomal membrane into the cytosol. DCCD and NBD are also inhibitors of the endosomal H(+) ATPase, which is in keeping with the hypothesis that this ATPase functions as the iron transporter in endosomal membranes. However, the more-specific inhibitor of this enzyme, bafilomycin A1, inhibited iron uptake only in incubation system 1, where its action can be attributed to inhibition of endosomal acidification. Hence, it is unlikely that the ATPase also functions as the iron transporter. The low-affinity uptake mechanism is sensitive to inhibition by amiloride, valinomycin, quinidine, imipramine, quercetin, and diethylstilbestrol (to all of which high-affinity transport is relatively resistant), and is present in mature erythrocytes as well as reticulocytes. PMID- 8694862 TI - Identification and isolation of two rat serum proteins with A-esterase activity toward paraoxon and chlorpyrifos-oxon. AB - The active metabolites (oxons) of phosphorothionate insecticides can be detoxified via A-esterase hydrolysis. Two enzymes with A-esterase activity have been isolated from rat serum. Whole serum was applied to anion exchange gel (DEAE Sepharose Fast Flow) and incubated (1 hr). Tris-HCl buffer (0.05 M; pH 7.7, at 5 degrees) containing 0.25 M NaCl was added to the slurry and incubated. The decant, containing low A-esterase activity but a high protein concentration, was discarded. Further displacement of A-esterase from DEAE gel was achieved with 1.0 M NaCl in 0.05 M Tris-HCl buffer (Ph 7.7 at 5 degrees). Following desalting and concentration, further separation was achieved by gel filtration (Sephacryl S-100 HR) and two sequential preparative scale isoelectric focusings. Final fractions contained two proteins of high molecular mass (one about 200 kDa and one between 137 and 200 kDa). The apparent range of isoelectric points for the two enzymes was 4.5 to 5.6. Following native-PAGE analysis, activity stains with beta naphthyl acetate and Fast Garnet GBC in the presence of paraoxon (10-5 M) verified that A-esterase activity was associated with both proteins. Spectropho tometric assay detected A-esterase activity toward paraoxon, chlorpyrifos-oxon, and phenyl acetate in the final preparation. PMID- 8694861 TI - Diisopropylphosphorofluoridate-induced muscle hyperactivity associated with enhanced lipid peroxidation in vivo. AB - Acute exposure to acetylcholinesterase (AChE) inhibitors such as organophosphates and carbamates induces functional changes at the neuromuscular junctions, leading to fasciculations that ultimately cause muscle fiber necrosis. There is recent evidence that oxygen free radical formation may be a factor in the toxicity of these insecticides. One of the targets of free radical-induced injury is lipid peroxidation. The role of lipid peroxidation in diisopropylphosphorofluoridate (DFP)-induced muscle necrosis was investigated by quantifying two products resulting from the oxidation of lipids in muscle tissue-the thiobarbituric acid malondialdehyde complex (TBA-MDA) and F2-isoprostanes, the latter being a novel and extremely accurate marker of lipid peroxidation in vivo. When compared with control animals, significant increases in MDA of 96% and in F2-isoprostanes of 56% were found in the diaphragms of rats treated with 2.0 mg/kg DFP after 60 min (P < 0.01). In rats pretreated with the neuromuscular blocking agent d tubocurarine or the lazaroid U-78517F, an antioxidant, no DFP-induced increases in either MDA or F2-isoprostanes were observed. It is suggested that the AChE inhibitor-induced cholinergic hyperactivity initiates that accumulation of free radicals leading to lipid peroxidation, which may be the initiator of the AChE inhibitor-induced cell injury. PMID- 8694865 TI - Sequential multielement analysis of Cd, Cr, Ni, and Pb in human tissues by inductively coupled plasma spectrometry. PMID- 8694864 TI - Detection of cytochrome P450 gene expression in human placenta in first trimester of pregnancy. AB - Human first-trimester placentas were screened for the expression of xenobiotic metabolizing cytochrome P450 (CYP) genes. mRNAs of CYP1A1, CYP1A2, CYP2C, CYP2D6, CYP2E1, CYP2F1, CYP3A4, CYP3A5, CYP3A7, and CYP4B1 were identified by reverse transcriptase-polymearse chain reaction (RT-PCR) in at least some of the six placental samples studied. CYP2A and CYP2B message were absent in all samples. The level of all of these CYP mRNAs was lower compared to the corresponding levels in liver or lung. the catalytic activity marker (7-ethoxyresorufin O deethylase) was inducible in the placentas by maternal cigarette smoking. Thus, the regulatory system of placental CYP1A1, mediated by the Ah-receptor, appears to be developed as early as the first trimester of pregnancy. Three immunoreactive bands from placental microsomes were detected by an antihuman CYP3A4 antibody, but no functional activity of CYP3A enzymes could be detected. These results show that placental tissue during the first trimester of pregnancy has the potential of expressing several CYP genes, and forms a basis for subsequent analysis of these forms at the protein and functional level. PMID- 8694866 TI - Magnesium deficiency and cerium promote fibrogenesis in rat heart. PMID- 8694867 TI - Solid phase extraction and GC-MS techniques for the confirmation of chlorpyrifos contamination of surface water supplies. PMID- 8694868 TI - Organochlorine residue levels and bioconcentration factors in otters (Lutra lutra L.) from northeast Spain. PMID- 8694869 TI - Runoff losses of surface-applied metribuzin as influenced by yard waste compost amendments, no-tillage, and conventional-tillage. PMID- 8694858 TI - Guinea pig lung tryptase. Localisation to mast cells and characterisation of the partially purified enzyme. AB - Tryptase (EC 3.4.21.59), the major secretory product of human mast cells, has become widely used as a biochemical marker for mast cells and mast cell activation, and is attracting attention as a mediator of allergic disease. However, there is little information available on the properties, or even the presence, of this protease in commonly used species of laboratory animals. We, here, report the demonstration and characterisation of this enzyme in the guinea pig lung. Tryptic activity resistant to alpha 1-proteinase inhibitor and soybean trypsin inhibitor was detected in sections of guinea pig lung tissue with the histochemical substrate Z-Gly-Pro-Arg-MNA. It was localised to mast cells and appeared to be present in all mast cells staining with Alcian Blue. A tryptic protease was purified 2400-fold from whole lung tissue by high salt extraction, cetylpyridinium chloride precipitation, heparin agarose chromatography, and gel filtration. This enzyme was found to be multimeric with a subunit of 38 kDa and a native molecular mass of 860 +/- 100 kDa. Inhibitor studies identified it as a serine protease. Like human tryptase, it was inhibited by leupeptin, benzamidine, and APC 366 (N-(1-hydroxy-2- naphthoyl)-L-arginyl(-L-prolinamide hydrochloride), but not by alpha 1-proteinase inhibitor, soybean trypsin inhibitor, or antithrombin III. Its response to changes in pH and ionic strength was similar to that of human tryptase. Differences between the guinea pig and human enzymes were seen in activity toward a panel fo 10 tryptic p_nitroanilide peptide substrates. Kinetic constants were determined for two of these: with L-Pyr-Pro-Arg-pNA the guinea pig tryptase had a similar Km but a 5-fold lower kcat than human tryptase, and with L-Pyr-Gly-Arg-pNA the guinea pig enzyme had a 10-fold lower Km and a 30% greater kcat than human counterpart. Heparin stabilised guinea pig tryptase, but did not alter its kinetic parameters as it did with human tryptase, decreasing the Km towards both substrates. The presence of a protease with similarities to human tryptase in the mast cells of guinea pigs suggests that this species may be an appropriate model to investigate the actions to tryptase in vivo, provided cognizance is taken of the differences that do exist. PMID- 8694870 TI - Residues of malathion in stored grains. PMID- 8694871 TI - Toxic metals in food products originating from locally reared animals in Kuwait. PMID- 8694872 TI - Formaldehyde levels in rain water from Kobe City in Japan. PMID- 8694873 TI - Role of a laccase in the degradation of pentachlorophenol. PMID- 8694874 TI - HCH and DDT contamination of rural ponds of India. PMID- 8694875 TI - Sodium, calcium, and resin acid levels in ground water and sediments from two sites adjacent to the Tarawera River, New Zealand. PMID- 8694877 TI - Heavy metals in blue mussels (Mytilus edulis) in the Bergen Harbor area, Western Norway. PMID- 8694878 TI - Mercury concentrations in three species of freshwater fishes from the lower Gallego and Cinca Rivers, Spain. PMID- 8694879 TI - Replacement of the medium for a natural phytoplankton community by tangential flow filtration, with special emphasis on toxicity tests. PMID- 8694880 TI - Design of an electronically operated flow-through respirometer and its use to investigate the effects of copper on the respiration rate of the amphipod Gammarus pulex (L.). PMID- 8694883 TI - Effects of agrochemicals on the immune systems of earthworms. PMID- 8694882 TI - Effect of an acute exposure to sublethal concentrations of cadmium on liver carbohydrate metabolism of Atlantic salmon (Salmo salar). PMID- 8694876 TI - Toxicity of copper to Porcellio scaber Latr. (Isopoda) under different nutritional status. PMID- 8694881 TI - Copper transfer and influence on a marine food chain. PMID- 8694884 TI - Adverse effects of polluted continental water bodies in Chile on frog adrenergic synapse. PMID- 8694885 TI - Histopathological changes induced by specific pesticides on some tissues of the fresh water snail, Bellamya dissimilis Muller. PMID- 8694886 TI - Chronic toxicity of acrylonitrile and acetonitrile to Daphnia magna in 14-d and 21-d toxicity tests. PMID- 8694887 TI - Inter- and intra-laboratory testing of the Daphnia magna IQ toxicity test. PMID- 8694889 TI - Acute toxicity of methanol to Mytilus edulis. PMID- 8694888 TI - Activation of in vivo metabolism of malathion in male Tilapia nilotica. PMID- 8694890 TI - Characterization and identification of a human dentin phosphophoryn. AB - The present study further characterizes an extract from immature, human tooth apicies from which an intact dentin phosphoprotein has been identified. Third molar apicies from developing roots were decalcified in 10% EDTA until Ca2+ was undetectable in the decalcifying solution. The crude extract was run on 7.5% SDS PAGE and stained with "Stains-All." Four distinct bands were found and the molecular weights were 140, 60, 50, and 34 k. When run on a SDS-PAGE under nonreducing conditions the 60, 50, and 34 k bands were absent. These results suggest that the lower molecular weight bands may be subunits of the larger protein. The extract was then further purified by adding CaCl2 and MgCl2 to precipitate the phosphoprotein. The precipitate was subjected to a DEAE-Sepharose CL6B column and eluted by 0-0.7 M NaCl gradient solution. The amino acid composition of the purified phosphoprotein was determined and the extract was found to be rich in serine and aspartic acid residues. The N-terminal peptide Asp Asp-Pro was identified. The sequence of the three amino acids is identical to rat incisor phosphoprotein. PMID- 8694891 TI - The role of glucocorticoids and prostaglandin E2 in the recruitment of bone marrow mesenchymal cells to the osteoblastic lineage: positive and negative effects. AB - The role of glucocorticoids in bone formation presents a problem because although pharmacological doses in vivo give rise to osteoporosis, physiological concentrations are required for osteoblast (OB) differentiation in vitro. To try and rationalize this dichotomy, we investigated the effect of dexamethasone on the recruitment of OB precursors present in bone marrow. Using the CFU-f assay, we can measure (1) total colony formation; (2) the osteoblastic differentiation of the colonies defined as their ability to express alkaline phosphatase, synthesize collagen, and to calcify; and (3) colony expansion as either average colony surface area or average colony number. In control cultures and in the presence of 10(-10)-10(-9) M dexamethasone, colony formation and total cell number was maximal, but the addition of PGE2 had no effect on colony number and very few colonies expressed the OB phenotype. In the presence of 10(-8)-10(-7) M dexamethasone, colony numbers and total cell numbers were reduced but were increased by the addition of PGE2, the average colony cell number and surface area were relatively unchanged and a proportion of the colonies expressed APase, calcified and synthesized collagen. In cultures containing 10(-6)-10(-5) M dexamethasone, colony numbers were further reduced but were stimulated by the addition of PGE2 and some colonies differentiated; however, colony expansion was dramatically reduced by up to 80%. These results suggest that physiological levels of glucocorticoids are necessary for OB differentiation and allow the control of OB recruitment by PGE2. High levels of glucocorticoids drastically reduce proliferation of the OB precursors leading to glucocorticoid-induced osteoporosis. PMID- 8694892 TI - Bone chondroadherin promotes attachment of osteoblastic cells to solid-state substrates and shows affinity to collagen. AB - Chondroadherin, which is reported to be synthesized by chondrocytes and to promote their attachment, was purified from bovine bone. It was a minor component of bone organic matrix, and was present in the 4 M guanidine extract of demineralized bone. Chondroadherin promoted attachment of osteoblastic cells to solid-state substrates, and bound to collagen. Binding of chondroadherin to collagen was significantly higher than that of osteonectin or decorin. These findings imply that chondroadherin may play a role in maintaining bone cells on the collagen matrices of bone. PMID- 8694893 TI - Effect of 17beta-estradiol-bisphosphonate conjugates, potential bone-seeking estrogen pro-drugs, on 17beta-estradiol serum kinetics and bone mass in rats. AB - In order to target 17beta-estradiol directly at bone we synthesized three 17beta estradiol-bisphosphonate conjugates (E2-BPs) with different esterase-sensitive linkers between both molecular moieties. The systemic administration of these compounds should result primarily in local estrogenic effects on bone with no or negligible systemic hormonal effects. Only if a considerable margin exists between the doses required for inhibition of bone loss and those for systemic hormonal effects can such a pro-drug be considered acceptable for patients refusing systemic estrogen replacement therapy for several reasons. The conjugates were tested in vitro for their 17beta-estradiol release in rat serum and in vivo for their local and systemic effects in rats: in vitro, the conjugates expressed cleavage resistance, low cleavage (4.8%), or high cleavage (33.1%) within 48 hours of incubation. The conjugate with the low-cleavage doubled 17beta-estradiol serum half-life (3.78 hours) whereas the high-cleavage conjugate resulted in approximately four times higher serum half-life (8.36 hours) when compared with free 17beta-estradiol. In ovariectomized rats, bone loss was optimally prevented by 50 nmol/kg/day of 17beta-estradiol when administered S. C. over a period of 5 weeks, and protection against uterine atrophy was achieved at doses as low as 5 nmol/kg/day. The cleavage-resistant conjugate was ineffective in preserving bone and uterus in doses ranging from 5 to 150 nmol/kg/day. The other two E2-BPs revealed a dose-dependent inhibition of bone loss which was paralleled by the respective uterus weight with a dose range of 1.5-150 nmol/kg/day being fully effective in a range similar to 17beta estradiol alone. The higher sensitivity of the uterus versus bone to protective estrogenic effects (1:10) was abolished by the conjugates. We conclude that E2 BPs containing esterase-sensitive linkers failed to act as bone-seeking pro-drugs expressing primarily local effects on bone without systemic effects. PMID- 8694894 TI - The effect of estrogen deficiency on bone mineral density, renal calcium and phosphorus handling and calcitropic hormones in the rat. AB - The oophorectomized (OOX) rat has been proposed as a good model of postmenopausal osteoporosis in women. The aim of this study was to compare the effect of OOX in 6-month-old rats to the effects of menopause in women with respect to bone mass, the renal handling of calcium and phosphorus, and calcitropic hormones. To more closely replicate the human situation the rats were pair fed a 0.1% calcium diet. Thirty four, 6-month-old rats were randomized to sham operation or OOX. Whole body and regional bone density was performed at baseline and 6 weeks postoperation. Blood and 24-hour urine samples were obtained at baseline, 1, 3, and 6 weeks and assayed for various biochemical variables, parathyroid hormone (PTH), and calcitriol. The OOX rats lost significantly more bone than the sham operated rats (change in global bone mineral density, sham -1.7 +/- 2.0%, OOX 3.9 +/- 2.6%, P < 0.001). In the OOX animals, an increase in the 24-hour urine calcium was observed at 1 and 3 weeks, which had returned to sham-operated levels by 6 weeks. In the whole group, the increase in urine calcium at 1 week was negatively correlated with the change in bone mass at 6 weeks (r = -0.39, P = 0. 029). OOX resulted in an increased filtered load of calcium and phosphorus. There was an increase in the maximal renal tubular reabsorption of phosphorus (TmP-GFR) but no clear change in renal calcium handling. Neither calcitriol nor parathyroid hormone showed a significant change as a result of OOX. As in postmenopausal women, following oophorectomy in the rat, there was significant generalized bone loss and a negative calcium balance. This was associated with an initial rise in urine calcium due to a rise in the filtered calcium load; plasma phosphorus and TmP-GFR also rose. The rat model may differ from postmenopausal bone loss in that the initial rise in urine calcium was not present at later time points as occurs in natural menopause in women. Calcitropic hormone levels did not change. This study has shown that the 6-month-old OOX rat fed a 0.1% calcium diet has many similarities of calcium and phosphorus homeostasis to that seen at menopause in women. PMID- 8694895 TI - Aromatization of androgens is important for skeletal maintenance of aged male rats. AB - A nonsteroidal aromatase inhibitor vorozole (VOR) was administered to aged (12 months old) male Wistar rats and its effect was compared with the effect of androgen deficiency. The rats were either sham-operated (SHAM) or orchidectomized (ORCH) and treated with or without VOR. Thus, four experimental groups were created (SHAM, ORCH, SHAM + VOR, ORCH + VOR). The follow-up period was 4 months. At the end of the experimental period, bone mineral density (BMD) of the first four lumbar vertebrae and right femur was measured ex vivo with dual-energy X-ray absorptiometry, bone formation was evaluated by serum osteocalcin, and bone resorption by urinary excretion of (deoxy)pyridinoline. Orchidectomy increased bone resorption 2- to 3-fold whereas bone formation was only slightly increased. Treatment of intact male rats with VOR also increased bone resorption (+30% increase) whereas bone formation was not increased in this SHAM + VOR group. Their BMD was 7% lower in the femur (P < 0.01) and 6% lower in the lumbar vertebrae (P < 0.01) compared with the SHAM group that had not received VOR. Moreover, this decrease of bone mineral density was not significantly different from the expected decrease of bone density observed in the ORCH groups (6-10%). This was also reflected by a decrease of calcium content of the first four lumbar vertebrae of 15% (P < 0.001) in the SHAM + VOR group and 9-14% (P < 0.05) in the ORCH groups compared with the SHAM group, respectively. These data therefore suggest that inhibition of aromatization of androgens into estrogens increases bone resorption and bone loss similar to that observed after complete removal of androgens. Aromatization of androgens into estrogens may therefore, at least partly, explain the effects of androgens on skeletal maintenance. PMID- 8694896 TI - Effects of continuous glucocorticoid infusion on bone metabolism in the rat. AB - The effects of continuous administration of supraphysiologic doses of dexamethasone (DEX) on bone metabolism were examined in rats. Adult, male, Sprague Dawley rats were infused with DEX at a constant rate of 16.25 microg/day for 19 days. Despite soft tissue catabolism, DEX treatment led to a significant increase in bone volume in all experiments. This was accompanied by a significant gain in femoral weight and calcium content. These findings were also observed in DEX-treated parathyroidectomized animals indicating that intact parathyroid function was not required for this effect. DEX treatment did not affect mean levels of serum calcium or phosphorus but led to significant declines in circulating levels of PTH and 1,25(OH)2D and in the urinary calcium/creatinine ratio. This latter finding was also observed in PTX animals in which 1,25(OH)2D levels did not change. Serum concentrations of osteocalcin and tartrate-resistant acid phosphatase both declined in a time-dependent manner with DEX treatment suggesting a slowing of bone turnover with the net effect favoring formation. However, histomorphometric findings were variable. Two of three experiments demonstrated a decrease in cellular parameters of formation and resorption and in one experiment, these indices increased. Mineralized surface increased with DEX treatment. We conclude that, in marked contrast to the findings in man and certain other species, DEX treatment increases bone mass in rats. This may in part relate to a relatively greater suppression of resorption vis a vis formation. PMID- 8694897 TI - Immunolocalization of the cation-independent mannose 6-phosphate receptor and cathepsin B in the enamel organ and alveolar bone of the rat incisor. AB - In order to examine our hypothesis that maturation ameloblasts could degrade the enamel matrix in a manner analogous to bone resorption mediated by osteoclasts, we have assessed the distribution of lysosomal enzymes in the enamel organ by immunolocalizing the cation-in-independent mannose 6-phosphate receptor (MPR) and the lysosomal enzyme cathepsin B at all stages of amelogenesis. Secretory ameloblasts showed strong immunoreactivity for MPR in the supranuclear Golgi region and in the cytoplasm between the Golgi region and the distal junctional complexes. However, cathepsin B immunoreactivity was mainly seen in the distal portion of Tomes' process, which was unreactive for MPR immunogenicity. In maturation ameloblasts, the MPR was observed on the ruffled border of the ruffle ended ameloblast (RA) but not on the distal cell membrane of the smooth-ended ameloblast (SA), although both cell types demonstrated strong immunoreactivity for MPR in the Golgi region. Immunoreactive cathepsin B was seen at the distal ends of both RA and SA. It is postulated that the nascent lysosomal enzymes bind to the mannose 6-phosphate receptors which target them not only to intracellular lysosomes, but also to the ruffled border of maturation ameloblasts where these enzymes are secreted into the enamel. Since MPR and lysosomal enzymes were also detected on the ruffled border of osteoclasts (Ocl) adjacent to alveolar bone, our immunocytochemical approach provides strong evidence for a similarity between the maturation process in enamel, as mediated by the ruffle-ended maturation ameloblasts, and bone resorption mediated by osteoclasts. This study has established that a common mechanism, based on MPR-targeted lysosomal secretion and matrix degradation, is basic to the maturation process involved in calcified tissues as different as bone and enamel. PMID- 8694898 TI - Enhanced osteonectin expression in the chondroid matrix of the unloaded mandibular condyle. AB - Osteonectin provided a spatial and temporal marker for proliferating and differentiating chondrocytes, and during the chondroid matrix formation. The goal of this investigation was to examine early cellular and molecular regulation of mandibular growth. Unloading was induced by anterior functional mastication. The proliferative activity measured by tritiated thymidine incorporation increased 8. 3-fold at 24 hours compared with the corresponding control group. Mandibular unloading for 24 hours increased osteonectin mRNA expression 60% in the condyle over the corresponding control group. Microscopic inspection of the condyle demonstrated osteonectin immunostaining of proliferating, early hypertrophic chondrocytes, and the chondroid matrix across the sagittal section in an anterior posterior direction. An increasing gradient intensity from a medial-superior to posterior direction was produced with treatment in direct contrast to the control group. The posterior chondroid matrix immunostaining increased 11.7-fold (P = 0.038) after 24 hours treatment over a corresponding control group. Unloading of the mouse mandible caused an increased cellular proliferation, a coincident increase of osteonectin mRNA, and a subsequent increased secretion of the osteonectin protein in the chondroid matrix formation. PMID- 8694900 TI - Effect of a hypergravity environment on cortical bone elasticity in rats. AB - There is considerable interest in determining whether hypergravity can be used as a countermeasure for microgravity-induced bone loss. This study was conducted on 20 immature male rats in order to investigate possible elastic adaptations of cortical bone in rapidly growing rats exposed to chronic hypergravity. Ten rats were continuously centrifuged for 14 days at twice gravitational acceleration (2G) on a 12.75 foot radius centrifuge and 10 rats concurrently acted as stationary controls. The effect of hypergravity on the elastic characteristics of cortical bone was quantified via ultrasonic wave propagation. Propagation velocities of longitudinal and shear waves were measured through cubic cortical specimens from the posterior femoral diaphyses. Density was measured with an Archimedes' technique. The orthotropic elastic properties were calculated and used to compare the difference between groups. Results showed an average increase in both the Young's moduli (Eii, + 2.2%) and shear moduli (Gij, + 4.3%) with a statistically significant increase only in G12 (+15.7%, P = 0.046). The ratio of transverse to axial strain (Poisson's ratio, nuij) demonstrated statistically significant changes in nu12, nu21, nu13, and nu31 (P < 0.05). These findings suggest that although slight elastic changes were incurred via a hypergravity environment, the treatment level or duration in this study do not dramatically perturb the normal elastic behavior of cortical bone and that dramatic biomechanical differences noted in previous studies were due more to structural changes than material elasticity changes. Hypergravity applied post facto to a microgravity environment would offer further illucidation of this method as treatment for a degenerative spaceflight experience. PMID- 8694899 TI - Inhibition of prostaglandin synthesis leads to a change in adherence of mouse osteoclasts from bone to periosteum. AB - When mouse parietal bones were incubated for 1 day in medium containing indomethacin (Ind), the number of tartrate-resistant acid phosphatase-positive osteoclasts (TRAP+OC) counted on the bone surface was drastically reduced. This reduction did not occur with calcitonin or if the endocranial membrane (periosteum) was removed prior to incubation with Ind. The aim of this work was to determine the mechanism involved. TRAP+OC were found to be increased on the endocranial membrane adjacent to the resorbing surface after Ind treatment, compared with cultures supplemented with parathyroid hormone (PTH) or prostaglandin E2 (PGE2). However, this increase accounted for only half of those lost from the bone surface. TRAP negative osteoclasts were also seen on the membrane and, to a lesser extent, on the bone. Increased TRAP specific activity could be extracted from the endocranial membranes of bones incubated with Ind compared with PGE2 controls. When bones that had been exposed to Ind were then cultured for 1 day in PGE2, an increase in TRAP+OC occurred. This increase was blocked by the removal of the endocranial membrane prior to incubation with PGE2. We conclude that when prostaglandin production ceases, TRAP+OC become less adherent to bone and more adherent to the endocranial membrane. Stimulators of bone resorption appear to reverse this process. PMID- 8694902 TI - Hydraulic properties of MDCK cell epithelium. AB - The water permeability of the apical and basolateral cell membranes and the compliance of the lateral intercellular spaces (LIS) of MDCK monolayers were measured on confluent cultures grown on permeable supports. Cell membrane water permeabilities were determined, using quantitative differential interference light microscopy, from the rate of cell volume decrease after exposure to a hyperosmotic bathing solution. Both membranes exhibited osmotic water permeabilities (POSM) of approximately 10 microm/sec, comparable to that of unmodified lipid bilayers. The compliance of the cell membranes forming the lateral intercellular space (LIS) between cells was determined from the pressure volume relation. Confocal microscopy of fluorescent labeling of the basolateral cell membranes was used to delineate the LIS geometry as transepithelial hydrostatic pressure was varied. The LIS were poorly deformable as a function of transepithelial hydrostatic pressure until a pressure of >/=8 cm H2O (basolateral > apical) was reached where catastrophic failure of intercellular connections occurred. The compliance of the LIS was calculated from the geometry changes at pressures <8 cm H2O and ranged from 0.05-0.11 cm H2O-1, comparable to that previously predicted in mathematical models of the rat proximal tubule. PMID- 8694903 TI - G protein-mediated activation of a nonspecific cation current in cultured rat retinal pigment epithelial cells. AB - We used whole-cell patch-clamp recording techniques to investigate G protein activated currents in cultured rat retinal pigment epithelial (RPE) cells. Using 140 mM KCl intracellular and 130 mM NaCl extracellular solutions, rat RPE cells possessed both inward and outward K+ currents. Upon addition of the nonhydrolyzable guanine triphosphate analogue, guanosine-5'-O-(3-thiophosphate) (GTPgammaS, 0.1 mM), to the recording electrode, a nonspecific cation (NSC) current was elicited. The NSC current had a mean reversal potential of +5.7 mV in 130 mm extracellular NaCl with Cs+-aspartate in the pipette, and was not affected by alterations in the extracellular Ca2+ or Cl- concentration. The GTPgammaS activated current was found to be permeable to several monovalent cations (K+, Na+, choline, TRIS, and NMDG). Addition of fluoroaluminate, an activator of large molecular weight heterotrimeric GTP-binding proteins (G proteins), to the intracellular recording solution activated the NSC current. The G protein involved was pertussis toxin (PTX)-sensitive, since GTPgammaS failed to activate the NSC current in cells pretreated with PTX. Further investigation of second messenger molecules suggested that activation of the NSC current was not affected by alterations in intracellular Ca2+ or ATP. From these results, we conclude that a G protein-regulated NSC current is present in rat RPE cells. Activation of the NSC current may sufficiently depolarize RPE cells to activate outward K+ currents. This would provide a mechanism by which these cells could rid themselves of accumulated K+. PMID- 8694904 TI - Calcium and magnesium: low passive permeability and tubular secretion in the mouse medullary thick ascending limb of Henle's loop (MTAL). AB - Recent studies from our laboratory have shown that in the mouse and rat nephron Ca2+ and Mg2+ are not reabsorbed in the medullary part of the thick ascending limb (mTAL) of Henle's loop. The aim of the present study was to investigate whether the absence of transepithelial Ca2+ and Mg2+ transport in the mouse mTAL is due to its relative low permeability to divalent cations. For this purpose, transepithelial ion net fluxes were measured by electron probe analysis in isolated perfused mouse mTAL segments, when the transepithelial potential difference (PDte.) was varied by chemical voltage clamp, during active NaCl transport inhibition by luminal furosemide. The results show that transepithelial Ca2+ and Mg2+ net fluxes in the mTAL are not driven by the transepithelial PDte. At zero voltage, a small but significant net secretion of Ca2+ into the tubular lumen was observed. With a high lumen-positive PDte generated by creating a transepithelial bath-to-lumen NaCl concentration gradient, no Ca2+ and Mg2+ reabsorption was noted; instead significant and sustained Ca2+ and Mg2+ net secretion occurred. When a lumen-positive PDte was generated in the absence of apical furosemide, but in the presence of a transepithelial bath-to-lumen NaCl concentration gradient, a huge Ca2+ net secretion and a lesser Mg2+ net secretion, not modified by ADH, were observed. Replacement of Na+ by K+ in the lumen perfusate induced, in the absence of PDte changes, important but reversible net secretions of Ca2+ and Mg2+. In conclusion, our results indicate that the passive permeability of the mouse mTAL to divalent cations is very low and not influenced by ADH. This nephron segment can secrete Ca2+ and Mg2+ into the luminal fluid under conditions which elicit large lumen-positive transepithelial potential differences. Given the impermeability of this epithelium to Ca2+ and Mg2+, the secretory processes would appear to be of cellular origin. PMID- 8694906 TI - Differences in hydration state of nucleus and cytoplasm of the amphibian oocyte. AB - Nuclear magnetic resonance (NMR) microimaging and proton relaxation times were used to monitor differences between the hydration state of the nucleus and cytoplasm in the Rana pipiens oocyte. Individual isolated ovarian oocytes were imaged in a drop of Ringer's solution with an in-plane resolution of 80 microm. Proton spin echo images of oocytes arrested in prophase I indicated a marked difference in contrast between nucleoplasm and cytoplasm with additional intensity gradations between the yolk platelet-rich region of the cytoplasm and regions with little yolk. Neither shortening taue (spin echo time) to 9 msec (from 18 msec) nor lengthening taur (spin recovery time) to 2 sec (from 0.5 sec) reduced the observed contrast between nucleus and cytoplasm. Water proton T1 (spin-lattice) relaxation times of oocyte suspensions indicated three water compartments that corresponded to extracellular medium (T1 = 3.0 sec), cytoplasm (T1 = 0.8 sec) and nucleoplasm (T1 = 1.6 sec). The 1.6 sec compartment disappeared at the time of nuclear breakdown. Measurements of plasma and nuclear membrane potentials with KCl-filled glass microelectrodes demonstrated that the prophase I oocyte nucleus was about 25 mV inside positive relative to the extracellular medium. A model for the prophase-arrested oocyte is proposed in which a high concentration of large impermeant ions together with small counter ions set up a Donnan-type equilibrium that results in an increased distribution of water within the nucleus in comparison with the cytosol. This study indicates: (i) a slow exchange between two or more intracellular water compartments on the NMR time-scale, (ii) an increased rotational correlation time for water molecules in both the cytoplasmic and nuclear compartments compared to bulk water, and (iii) a higher water content (per unit dry mass) of the nucleus compared to the cytoplasm, and (iv) the existence of a large (about 75 mV positive) electropotential difference between the nuclear and cytoplasmic compartments. PMID- 8694905 TI - The binding specificity of amino acid transport system y+L in human erythrocytes is altered by monovalent cations. AB - System y+L is a broad-scope amino acid transporter which binds and translocates cationic and neutral amino acids. Na+ replacement with K+ does not affect lysine transport, but markedly decreases the affinity of the transporter for L-leucine and L-glutamine. This observation suggests that the specificity of system y+L varies depending on the ionic composition of the medium. Here we have studied the interaction of the carrier with various amino acids in the presence of Na+, K+, Li+ and guanidinium ion. In agreement with the prediction, the specificity of system y+L was altered by the monovalent cations. In the presence of Na+, L leucine was the neutral amino acid that interacted more powerfully. Elongation of the side chain (glycine - L-norleucine) strengthened binding. In contrast, bulkiness at the level of the beta carbon was detrimental. In K+, the carrier behaved as a cationic amino acid specific carrier, interacting weakly with neutral amino acids. Li+ was found to potentiate neutral amino acid binding and in general the apparent affinities were higher than in Na+; elongation of the nonpolar side chain made a more important contribution to binding and the carrier was more tolerant towards beta carbon substitution. Guanidinium stimulated the interaction of the carrier with neutral amino acids, but the effect was restricted to certain analogues (e.g., L-leucine, L-glutamine, L-methionine). Thus, in the presence of guanidinium, the carrier discriminates sharply among different neutral amino acids. The results suggest that the monovalent cations stabilize different carrier conformations. PMID- 8694907 TI - Nerve growth factor increases sodium current in pancreatic beta cells. AB - Nerve growth factor (NGF) induces neuritelike process outgrowth in cultured adult pancreatic beta cells. DbcAMP partially mimics this effect on cell morphology, and both compounds act synergistically to promote neuritelike process outgrowth. To determine if NGF- and dbcAMP-induced differentiation was accompanied by changes in beta cell electrical activity, we studied the macroscopic Na current of adult rat beta cells identified with the reverse hemolytic plaque assay and cultured for one week with these factors. After 5-7 days, beta cells cultured in the presence of 2.5S NGF exhibited a 48% increase on the macroscopic Na current, which was due to an increase on Na current density. We did not observe changes on voltage dependence of current activation, nor on steady-state inactivation. Although dbcAMP also promotes changes on beta cell morphology, it did not affect the Na current density. PMID- 8694908 TI - Isolation of heavy endosomes from dog proximal tubules in suspension. AB - During the preparation of a suspension of dog kidney proximal tubules by collagenase treatment, an uptake of FITC-albumin was demonstrated. This process is attributed to the activation of receptor-mediated endocytosis leading to the appearance of FITC-albumin into intracellular vesicular structures. The isolation of brush border membrane vesicles (BBMV) from the dog kidney proximal tubules in suspension by the magnesium precipitation technique leads to the copurification of a large population of endosomes. These endosomes were separated from BBM vesicles by a technique involving wheat-germ agglutinin. The enrichment in BBM markers and in bafilomycin-sensitive ATPase activity was comparable in endosomes and BBM vesicles. However, the acridine orange acidification assay showed a V type ATPase-dependent acidification in endosomes but not in BBMV, demonstrating a different orientation of the proton pumps in these structures. SDS-PAGE analysis also showed significant differences in protein pattern of vesicles and endosomes. The most notable difference was the presence of 42-44 kDa and 20-24 kDa proteins in BBMV and their complete absence in endosomes. Western blot analysis identified these proteins as actin and RhoA, among other small proteins, respectively. Western blot experiments also demonstrated a different distribution of beta-COP, beta-adaptin, and RhoGDI in vesicles and endosomes. The morphological aspect (electron microscopy) and sedimentation of endosomes in a 50% Percoll gradient identified these structures as "heavy endosomes" (buoyant density D = 1.036 g/ml). Flow cytometry analysis of heavy endosomes purified from tubules isolated in presence of FITC-albumin showed the presence of FITC-albumin in up to 92% of these intracellular organelles. Western blot analysis using anti-FITC and anti collagenase antibodies allowed quantification of the FITC-albumin and collagenase A in the purified endosomes. Our results indicate that heavy endosomes are formed during the preparation of the proximal tubules following activation of receptor mediated endocytosis, probably by soluble proteins. The suspension of tubules thus offers a experimental tool to study the protein reabsorption and traffic of endosomal vesicles in the proximal tubules. PMID- 8694909 TI - Reversible binding of long-chain fatty acids to purified FAT, the adipose CD36 homolog. AB - Transport of long-chain fatty acids into rat adipocytes was previously shown to be inhibited by the reactive derivative sulfosuccinimidyl oleate consequent to its binding to a membrane protein FAT, which is homologous to CD36. In this report, the ability of the purified protein to bind native fatty acids was investigated. CD36 was isolated from rat adipocytes by phase partitioning into Triton X-114 followed by chromatography on DEAE and then on wheat germ agglutinin. Fatty acid binding was determined by incubating CD36, solubilized in buffer containing 0.1 Triton X-100, with fatty acids at 37 degrees C, and then by adsorbing the unbound ligand with Lipidex 1,000 at 0 degrees C. Bovine serum albumin was used as a positive control and gelatin, a protein that does not bind fatty acids, as a negative control. Measurements with albumin yielded reproducible binding values which were not altered by the presence of 0.1% Triton X-100. Under the same conditions, gelatin yielded reproducibly negative measurements that did not differ significantly from zero. CD36 bound various long chain fatty acids at low ligand to protein ratios. Warming the protein-FA-Lipidex mixture to 37 degrees C removed the FA off the protein. Thus, binding was reversible and distinct from the palmitoylation of the protein known to occur on an extracellular domain. Comparison of the predicted secondary sequence of CD36 with that of human muscle fatty acid binding protein suggested that a potential binding site for the fatty acid on CD36 may exist in its extracellular segment between residues 127 and 279. PMID- 8694937 TI - The common bile duct: quo vadimus. PMID- 8694938 TI - The role of preoperative investigations in predicting difficult laparoscopic cholecystectomies. Results in 200 consecutive cases. AB - BACKGROUND: When we began laparoscopic cholecystectomy (LC) we set up a strict preoperative workup in order to assess whether currently available investigations could help predict difficult laparoscopic procedures. METHODS: Reported here are the results of a prospective trial carried out in our first 200 consecutive patients, who underwent routine intravenous cholangiography (IVC), abdominal ultrasound scan (US), blood tests-namely, markers of biliary stasis (MBS)-and preoperative endoscopic retrograde cholangiopancreatography (ERCP) in case of clinically suspected common bile duct stones (CBDS). RESULTS: On the basis of our experience we think that the US findings relate to the difficulty of the laparoscopic procedure more closely than the other preoperative investigations, and the association of US and liver chemistry provides an accurate evaluation of biliary stones. CONCLUSIONS: In agreement with data emerging from the literature, the preoperative investigations do not seem to be useful in predicting biliary and vascular complications, whose prevention lies in the adoption of correct surgical technique and a low threshold for conversion. PMID- 8694939 TI - Recognition of laparoscopic bile duct injuries by intraoperative ultrasonography. AB - BACKGROUND: The purpose of this study was to investigate the possibility of detecting bile duct injuries using laparoscopic intraoperative ultrasound (LIOU). METHODS: Fifty bile duct injuries were created using laparoscopic techniques in ten farmer pigs. The lesions created were: (1) partial occlusion, (2) complete occlusion (1 clip), (3) complete occlusion (2 clips), (4) transection between clips, (5) excision between clips. RESULTS: All injuries were easily visualized using LIOU. The relation of clips impinging upon or occluding the bile duct was readily visualized on LIOU in all cases. In some cases it was difficult to distinguish between partial and complete occlusion. It was also difficult to distinguish between transection and excision due to retraction of the severed bile duct. CONCLUSIONS: In cases of iatrogenic occlusion of the bile duct involving hemoclips (including transection or excision between clips), LIOU is a potentially useful modality that may allow earlier recognition and repair. Further studies are needed to evaluate the efficacy of LIOU in detection of bile duct injuries that do not involve hemoclips. PMID- 8694941 TI - Stratification for elective laparoscopic cholecystectomy. AB - BACKGROUND: In a former retrospective study in our clinic, an improvement in patient care was observed after the introduction of laparoscopic cholecystectomy. The aim of this study was to verify whether this improvement could be maintained or even be further improved. METHODS: Retrospective evaluation of all patients who underwent an elective cholecystectomy due to symptomatic cholelithiasis. We compared the results of 1992, the year of the introduction of laparoscopic cholecystectomy with 1993, the year that laparoscopic cholecystectomy became standard procedure. Also we compared specialized with general surgeons. RESULTS: In comparison with 1992 more elective cholecystectomies were performed in 1993 (162 vs 211). In 1993 there were more primary laparoscopic procedures (86 vs 93%) but due to an increase in conversion rate in 1993 (2.5 vs 10%) the overall number of open procedures remained comparable (17 vs 16%). In 1993 there was an increase in cholecystectomies by general surgeons (56 vs 72%). The general surgeons almost doubled their conversion rate in 1993 (6 vs 13%) while that of the specialized surgeons remained comparable (0 vs 2%). Morbidity and mortality remained comparable between 1992 and 1993 and between specialized and general surgeons. CONCLUSIONS: The quality of patient care has not significantly been altered. An improvement could be made if more laparoscopic operations were performed by specialized surgeons, but this would negatively interfere with the working methods of a general hospital. Therefore we suggest stratification: Certain patients, as high-risk patients, preferably should be operated on by specialized surgeons, while routine operations could be performed by general surgeons. PMID- 8694940 TI - Confirmation of a "safety zone" by intraoperative cholangiography during laparoscopic cholecystectomy. AB - BACKGROUND: Creating a "safety zone" during laparoscopic cholecystectomy is defined as dissection of the cystic duct as close as possible to the gallbladder. METHODS: In 29 out of 802 cases in which laparoscopic cholecystectomy was difficult to perform due to uncertainty about the orientation of Calot's triangle, intraoperative cholangiography was performed, using a titanium clip as a marker that designated the safety zone. The distance between the clip and the common hepatic duct or the common bile duct could be determined by evaluation of two intraoperative cholangiograms taken in different orientation. RESULTS: If the clip was located in the safety zone, and was distant from the common hepatic duct or common bile duct, the safety of preparation around the clip was ensured. No complication was encountered in these cases with this method. Eventually, no biliary tract injury was experienced, and the overall conversion rate to open cholecystectomy was only 0.4% (3 of 802 consecutive cases). CONCLUSIONS: This method of confirming the safety zone by intraoperative cholangiography is a useful procedure for avoiding inadvertent injury to the biliary tract. PMID- 8694942 TI - Theoretical basis for camera control in teleoperating. AB - BACKGROUND: The triangle paralaxis method for camera control in teleoperating is presented. METHODS: For orientation in the 3D space of the corporic cavity there are three points necessary for the creation of the paralaxis triangle. This triangle is then imagined and compared with topography during surgery. The first and second points are created in one's mind at the locus of the entry of the instruments into the viewing field of the camera. The third apex of the triangle is the area of dissection-the point in which the instruments converge. The fourth point to be viewed determines the course of dissection. Triangle paralaxis may be applied in dissection with only one instrument as well as in the zooming technique, closely viewing a part of the dissecting instrument. RESULTS: Using this technique a 7.78% rate of conversion and 2.15% rate of reoperation could be achieved in 334 evaluated laparoscopic cholecystectomies performed in a small public hospital. CONCLUSIONS: Triangle paralaxis seems to be a simple method for ensuring an optimal camera view during laparoscopic surgery. PMID- 8694943 TI - The influence of a pneumoperitoneum on the peritoneal implantation of free intraperitoneal colon cancer cells. AB - BACKGROUND: In order to test the influence of a pneumoperitoneum on the peritoneal implantation of free intraperitoneal colon cancer cells, 40 male syngeneic WAG rats were at random divided into four groups. METHODS: Group 1 (n = 10) animals underwent a midline laparotomy and 10(4) CC531 colon cancer cells were injected intraperitoneally (IP); in group 2 (n = 10) 10(4) CC531 cells were injected IP without further manipulation; in group 3 (n = 10) a pneumoperitoneum up to 10 mmHg was created after the IP injection of the same amount of CC531 cells. The pneumoperitoneum was maintained for 15 min. Finally in group 4 (n = 10) after the IP injection of 10(4) CC531 cells and after the creation of a pneumoperitoneum, two 14-G IV catheters simulating trocars were introduced in each flank. A follow-up period of 8 weeks was used. Tumor implantation was scored according to the peritoneal cancer index of Eggermont and the index of Chauffert. RESULTS: Tumor nodules were found varying from 60% in groups 1-3 to 50% in group 4. There was no statistical difference between the implantation rate in the four groups. A port-site recurrence was seen in group 4; all the other tumor implants were located in the mesenterium, omentum, internal genitals, or parietal peritoneum. CONCLUSIONS: The presence of a pneumoperitoneum does not enhance the implantation of free intraperitoneal malignant colon cancer cells in the rat, but the presence of a "port" may lead to abdominal-wall metastases. PMID- 8694944 TI - Laparoscopic unroofing of symptomatic congenital liver cysts. AB - BACKGROUND: Unroofing is the therapy of choice in patients with symptomatic, nonparasitic benign liver cysts-either solitary or diffuse. Techniques which require laparotomy, such as cystojejunostomy or pericystectomy, generally do not justify surgical morbidity in benign conditions. METHODS: We report the outcome of eight fenestration operations in seven patients with hepatic cysts in laparoscopic performance. Patients were reexamined after a mean follow-up period of 30 months. RESULTS: All operations were finished without conversion. There were no perioperative complications. Only one patient had a recurrence and was successfully reoperated via laparoscopy including cholecystectomy without refilling of the cyst until reexamination. CONCLUSIONS: Adoption of minimal access surgery in these patients occurred without loss of quality and offered the well-known benefits of laparoscopic surgery. PMID- 8694945 TI - The use of a modular skills center for the maintenance of laparoscopic skills. AB - BACKGROUND: A reliable method supplying graduated experience and practice is needed to develop and refine laparoscopic skills. The laparoscopic surgeon, like the microvascular surgeon, must have ongoing training to refine and maintain his or her skills. METHODS: The authors describe a new modular training unit. The unit consists of a box with a built-in television camera, a light source, and a rotating platform. A videotape recorder with a timing device documents the actual "operating time" required for the various exercises. The first phase of training consists of a basic skills board. This initial phase enhances the use of dominant and nondominant hand motor activity. RESULTS: The surgeon then progresses to lifelike models (biliary, suturing, hernia, gynecologic) to simulate the human operative setting. Ten surgeons spent 5 h each working with the module. The specific exercises were recorded and timed. Their progress is described. CONCLUSIONS: The modular laparoscopic skills center is an integral part of any laparoscopic educational program. It facilitates the acquisition and maintenance of laparoscopic skills. PMID- 8694946 TI - Transesophageal echocardiography in fetal sheep. A monitoring tool for open and fetoscopic cardiac procedures. AB - BACKGROUND: Cardiac procedures in exteriorized fetuses or assisted by fetoscopy require monitoring capabilities not attended by conventional maternal transabdominal echocardiography. METHODS: We, therefore, assessed the potential of fetal transesophageal echocardiography (TEE) utilizing an intravascular ultrasound catheter (IVUC) for fetal cardiac monitoring. We inserted a 10-F-10 MHz IVUC into the esophagus in 12 exteriorized fetal sheep and by a fetoscopic approach in 4 fetal sheep. Cardiac events were observed. Heart rate, cardiac rhythm, patency of the foramen ovale and ductus arteriosus, and the width of the branch pulmonary arteries could be assessed in all fetuses. Ventricular contractility could be assessed only in fetuses weighing less than 2.5 kg. Larger fetuses did not allow adequate imaging of the apical portion of the ventricles because of limited tissue penetration of the IVUC. Fetal TEE permitted placing small guide wires in the cardiac atria and left ventricle. Short-lived premature beats following intracardiac manipulations of these wires could be observed by fetal TEE in all cases. RESULTS: At autopsy, no complications from IVUC insertion were observed in the exteriorized fetuses. Fetoscopic placement of the IVUC resulted in minor perioral skin erosion in two nonexteriorized fetuses. CONCLUSIONS: In conclusion, fetal TEE can be achieved with minor fetal injury and may provide useful information during open and fetoscopic cardiac procedures. Further improvements in IVUC design will permit the application of this technique to monitor human fetal cardiac procedures. PMID- 8694947 TI - Upper gastrointestinal endoscopic and histologic findings before and after vertical banded gastroplasty. AB - BACKGROUND: A total of 30 consecutive morbidly obese patients, six males and 24 females, who underwent vertical banded gastroplasty (VBG) between January 1992 and December 1994 and were followed up by endoscopy and biopsy were included in this study with the aim to determine the short- and mid-term complications and to investigate alterations in esophageal, gastric, and duodenal mucosa after surgery. METHODS: All patients underwent endoscopy before operation. Postoperatively, 28 patients were reendoscoped at 6 months, 26 at 12 months, and 22 at 18 months. Biopsies were taken from the lower part of esophagus, just below the esophagogastric junction (vertical part of the partitioned stomach), corpus, antrum, and duodenal bulb. RESULTS: Before operation 5 patients (16.6%) had a hiatus hernia and four of them (13.3%) had esophagitis. Endoscopic gastritis was diagnosed in nine patients (30%) and endoscopic duodenitis in two (6. 6%). Histologically, in 15 patients (50%) esophagitis was recognized; in 24 patients (80%) corpus gastritis; in 27 patients (90%) antral gastritis; and in 23 (76.6%) duodenitis. Helicobacter pylori was found in 20 (66.6%) patients. Postoperatively, three patients developed a mild stoma stenosis and were treated only by passing the endoscope 6 months after operation; one patient, with a severe stoma stenosis, was treated by Eder-Puestow dilatations and surgery. Gastric ulcer was found in two patients 6 and 12 months after surgery. One patient developed an endostomach channel because of staple line dehiscence 18 months after VBG. An increasing incidence of esophagitis and gastritis of the vertical part of the stomach was found at 6 and 12 months. Endoscopic and histologic gastritis of the corpus and antrum, as well as endoscopic and histologic duodenitis decreased gradually after surgery. CONCLUSIONS: Our findings suggest that postoperative complications of VBG can be diagnosed by endoscopy, and some of them can easily be managed. Vertical banded gastroplasty causes not only no harm to the esophageal, gastric, and duodenal mucosa but also influences them favorably. PMID- 8694948 TI - Laparoscopic and conventional closure of perforated peptic ulcer. A comparison. AB - BACKGROUND: After the first successful laparoscopic closure of a perforated peptic ulcer in 1990, 18 patients with laparoscopic closure were compared to 16 patients with conventional surgery. METHODS: The endpoint adverse events (complications), pain intensity, operation time, fever, leucocytosis, and duration of hospital stay showed no clinically relevant differences. RESULTS: Consumption of analgesics was lower in the laparoscopic group. CONCLUSIONS: Laparoscopic closure of perforated peptic ulcer is technically feasible. The safety of the method and the benefit for the patient need proof by means of a randomized controlled trial. PMID- 8694949 TI - Laparoscopic nissen fundoplication with simultaneous percutaneous endoscopic gastrostomy in children. AB - BACKGROUND: The aim of the study was to evaluate the results of laparoscopic Nissen fundoplication (LNF) with simultaneous percutaneous endoscopic gastrostomy (PEG) in children with gastroesophageal reflux (GER) disease documented by upper gastrointestinal contrast and/or pH monitoring and/or esophageal endoscopy. METHODS: Fifteen LNF + PEGs were performed in children with pathologic antecedents: ten neurologically impaired children, two ORL (otorhinolaryngeal) pathologies. Two cases of AIDS, and one neuroblastoma. In one case, disruption of the fundoplication occurred during insufflation of the stomach. The child was reoperated on the 3rd day using an open procedure, so she was excluded from the results of the LNF. RESULTS: Two children had postoperative complications: one with cardiac insufficiency, one case of dehydration. Fourteen LNFs were controlled at 3 months by gastroesophageal X-ray and pH-metry. The 14 gastroesophageal X-rays were normal in 12 cases; gastroesophageal reflux was present in two cases. Twelve pH monitorings were analyzed (two technical failures), the median time pH <4 was 0.2% (0-20). Only one pH monitoring was pathologic (pH <4: 20%). This recurrent reflux to led to a second LNF with a good clinical result. CONCLUSIONS: In conclusion, it is possible to perform LNF and PEG during the same operative procedure. Short-term results are satisfactory with 14% recurrent GER. Long-term results need to be evaluated. PMID- 8694950 TI - Retrospective failure analysis in laparoscopic hernia repair possible because of routine videodocumentation. AB - BACKGROUND: Studies performed to date show that laparoscopic hernia repair is superior to conventional procedures with regard to postoperative pain, complications, and duration of inability to work. METHODS: From August 1, 1992, to February 16, 1995, we performed 245 laparoscopic hernia procedures on 224 patients utilizing a transabdominal preperitoneal polypropylene mesh-plasty (TAPP). RESULTS: We observed in the first 100 patients a total of 21 postoperative complications in 20 patients (21%). We observed 3 hernia occurrences (3%) in this group. Due to careful video documentation of all procedures, retrospective analysis of operative failure was possible. Working on the complications occurring resulted in a modification of the procedure, leading to a standardization of the operative technique and to a rigorous reduction in the number of complications and recurrences. CONCLUSIONS: Video-assisted retrospective failure analysis is consequently an effective method to use to optimize the results of minimal invasive hernia repair. PMID- 8694951 TI - Controlled multicenter trial of laparoscopic transabdominal preperitoneal hernioplasty vs Shouldice herniorrhaphy. Early results. AB - BACKGROUND: In February 1993 a prospective randomized multicenter trial was initiated to compare laparoscopic transabdominal preperitoneal hernioplasty to Shouldice herniorrhaphy as performed by surgeons of nonspecialized clinics. METHODS: Until January 1994, 87 patients with 108 hernias took part in the trial (43 Shouldice and 44 laparoscopic repairs). RESULTS: The laparoscopic procedure took significantly longer than did the open operation but caused less pain as measured by pain analogue score and consumption of paracetamol and narcotics. The postoperative complication rate was 26% in the open and 16% in the laparoscopic group. The patients in the laparoscopic group were discharged earlier and their convalescence was shorter than after open hernia repair. There has been one early recurrence in the laparoscopic and two in the open group to date with a mean follow-up of 201 days. CONCLUSIONS: Laparoscopic hernia repair causes less pain than the conventional operation and enables the patient to return to full work and usual activities earlier. The recurrence rate will not be known for 5 years. PMID- 8694953 TI - Thoracoscopic repair of traumatic diaphragmatic rupture. A case report. AB - A 51-year-old man with a traumatic diaphragmatic rupture is presented. Preoperatively, diaphragmatic rupture and herniation of the stomach into the left thoracic cavity were suspected. Under thoracoscopic guidance, the stomach and omentum were repositioned in the abdominal cavity using Babcock forceps, and then the rupture site was closed using an endoscopic hernia stapler. The postoperative course was uneventful and the patient was discharged from our hospital with no symptoms. PMID- 8694952 TI - Herpes zoster mistaken for biliary colic and treated by laparoscopic cholecystectomy: a cautionary case report. AB - Herpes zoster must be included in the differential diagnosis of acute right upper quadrant pain. The presence of a dermatomal vesicular rash should be considered a contraindication to surgical intervention. PMID- 8694954 TI - Videotunneler for minimal and direct access aortoiliac reconstructive surgery. AB - Despite improvements in surgical practice and postoperative care, the large vertical midline or transverse transperitoneal approaches used in abdominal aortic surgery are still associated with a relatively high perioperative morbidity and mortality rate even in patients who are considered good risks for undergoing aortic surgery. This significant perioperative morbidity is partly caused by the major surgical trauma. To decrease the surgical stress on these patients we have developed a less-extensive procedure for this type of vascular reconstruction. TECHNIQUE: The abdominal aorta is explored using a special retractor through a short upper median minilaparotomy utilizing modified conventional surgical hand instruments. For an aortobifemoral graft implantation, a retroperitoneal tunnel is necessary. During the creation of this tunnel special care should be exercised to avoid troublesome hemorrhage with iliac and other vein lacerations. To overcome these difficulties, we have developed a new tunneling device, which allows us to have visual control of the tunneling procedure. This prototype device contains a semiflexible tube with an inflatable balloon and a flexible videoendoscope. It is introduced along the external iliac artery into the retroperitoneal space and creates a tunnel through step-by-step inflation of the balloon. After this, the graft is implanted in the usual manner. To date, 19 abdominal vascular reconstructions have been performed with this method. PMID- 8694955 TI - A case of bronchial obstruction by metastatic renal cell carcinoma. AB - A 68-year-old Chinese male with a history of renal cell carcinoma presenting with increasing shortness of breath and hemoptysis was found to have subtotal left main bronchial obstruction secondary to a metastatic endobronchial tumor. The mass was completely resected through a rigid ventilating bronchoscope, and a silicone stent was placed over the tumor bed in the left main bronchus. He remained asymptomatic with no evidence of bronchoscopic recurrence 4 months after the procedure. Obstructive endobronchial metastases from nonpulmonary primaries are rare. Endoluminal resection with stent placement can provide good palliation in this group of patients with limited survival. PMID- 8694956 TI - Laparoscopic cholecystectomy utilizing two ports. AB - Laparoscopic cholecystectomy is usually performed via four to five cannulas; a few surgeons employing only three. A technique utilizing two entry ports, an infraumbilical Hasson 10 mm and a medial subcostal 5 mm, is described. The operation was feasible in six of seven patients. In the seventh, a third cannula was placed to allow traction on a floppy gallbladder. No complications ensued and all patients went home the day following operation. While cosmesis was impressive, the patients appeared to experience pain similar to that of patients in whom more cannulas were employed. PMID- 8694957 TI - Pediatric laparoscopic splenectomy using the lateral approach. AB - Laparoscopic splenectomy in children has been shown to be safe, to reduce postoperative pain and hospital stay, and to accelerate return to full activities. We describe our experience with a four-port "lateral" approach in 18 patients. Patients were placed in the lateral decubitus position and the table was flexed to separate the left subcostal margin and iliac crest. The camera port was inserted at the umbilicus and additional ports were placed in the epigastrium and left lower quadrant. After mobilization of the splenic flexure a port was inserted in the left flank below the 12th rib for elevation of the spleen. A 30 degrees laparoscope was used and the splenic vessels were controlled with an endo GIA and/or clips. The spleens were placed in a bag, morcellated, and extracted through a port site. Eight females and 10 males with a median age of 12.5 years (5-17 years) and weight of 55.5 kg (17-124 kg) underwent splenectomy of idiopathic thrombocytopenia purpora (10), spherocytosis (6), elliptocytosis (1), and Hodgkin's disease (1). The median operating time was 160 min (90-300 min) and median blood loss was 105 ml (5-350 ml). Accessory spleens were removed in four cases. Three patients required extensions of a port site to remove large spleens which could not be placed in a bag. The sole complication was a transient pancreatitis with associated pleural effusion. The median postoperative hospital stay was 2 days (1-11 days) and time to full activities was 8 days (3-25 days). The lateral approach affords excellent visualization of the splenic vessels, pancreas, and accessory spleens. This approach is safe and reliable and is our preferred approach for laparoscopic splenectomy in children. PMID- 8694958 TI - Laparoscopically-induced Littre's hernia. PMID- 8694959 TI - Thoracoscopic guided percutaneous cannulation of the azygos vein in children. PMID- 8694960 TI - Laparoscopically induced hernia. PMID- 8694961 TI - Division of short gastric vessels during laparoscopic fundoplication. PMID- 8694963 TI - Assessing body composition: the skinfold method. AB - 1. Excess body fat contributes to many chronic diseases. Using a case scenario, an initial screening assessment is performed on two clients. The occupational health nurse provides feedback on current lifestyle behaviors and educates the clients about relevant lifestyle changes. 2. Tables illustrate the step by step procedures for measuring body fat using the skinfold thickness method. Photographs show the multiple body sites used in the skinfold analysis. 3. Commonly asked client questions related to body fat are discussed in detail, and the use of body fat assessment as a screening method for the health promotion professional is described. PMID- 8694964 TI - Reproductive hazards: an overview of exposures to health care workers. AB - 1. Anesthetic gases, particularly nitrous oxide, have been investigated for potential reproductive, mutagenic, and carcinogenic effects. Waste gases have been found in high concentrations, even with work settings with scavenger systems in place. 2. Antineoplastic drugs, commonly used to treat persons with cancer, are virtually all considered to be embryo-fetal toxic. OSHA has issued comprehensive guidelines covering staff training, handling practices, and use of protective equipment. 3. The toxic effect of non-ionizing radiation has been a frequent topic of public and scientific debate. At this time no evidence exists of a reproductive hazard to health care workers. 4. Biologic agents such as rubella, hepatitis, cytomegalovirus, varicella, and human immunodeficiency virus frequently have the potential for adverse effects on the fetus. Administration of a vaccine or care of patients with active infection may be contraindicated in pregnancy. PMID- 8694965 TI - Childhood immunizations: an update for occupational health nurses. AB - 1. Nationally, toddlers and preschool children are under-immunized against vaccine preventable diseases. 2. Personal health care providers should comply with the Standards for Pediatric Immunization Practices, and should eliminate all barriers to immunizations. 3. Occupational health nurses are in a position to inform employees of the need to get their children immunized and to teach employees what to expect from private sector health care provider immunization services. PMID- 8694967 TI - Smoking: issues and interventions for occupational health nurses. PMID- 8694966 TI - The status of tetanus in the United States: implications for occupational health nurses. AB - 1. Tetanus is a potentially lethal, preventable illness. Tetanus spores exist in all environments. 2. Tetanus occurs in individuals over the age of 50 years who have not maintained decade boosters. 3. Occupational health nurses should assess clients for primary series booster tetanus status during routine health promotion and in association with all wound treatment. 4. Tetanus-diptheria immunization should be used for more complete prophylaxis unless diptheria is contraindicated. PMID- 8694968 TI - Do occupational health nurses have an informatics future? PMID- 8694969 TI - Preventing lead poisoning. PMID- 8694970 TI - Managed rehabilitative care: overview for occupational health nurses. AB - Managed rehabilitative care (MRC) is a comprehensive approach to return ill or injured employees to the workplace as soon as they are medically fit to function. A MRC program is designed to maintain the health of employees and the integrity of corporate short term disability, long term disability, and workers' compensation programs. MRC can be an effective method of returning employees to health and work while contributing to cost containment. Ideally, one person is responsible for the overall program management and the daily operations of a MRC program. In many companies, this role is assumed by the occupational health nurse. To measure the productivity and effectiveness of a MRC program, data must be collected and documented. PMID- 8694971 TI - Preventing burnout: increasing professional self efficacy in primary care nurses in a Balint Group. AB - Nursing is reported to be a stressful occupation, and chronic stress is often associated with burnout. Many ways of reducing stress have been proposed. Of these, the Balint group method provides a forum in which health professionals can present and attempt to resolve stressful situations with clients, coworkers, or other professionals. Balint groups help health professionals improve coping with psychosocial stressors in a supporting and accepting group atmosphere. This article reports changes in professional self efficacy associated with reduced burnout in a group of 13 nurses working in community based primary care clinics. Results showed significant increases in awareness and ability cognitions after the Balint group and reduced emotional exhaustion and cognitive weariness. The ramifications of these findings are discussed. PMID- 8694973 TI - Low back pain: prevention and management. PMID- 8694972 TI - Musculoskeletal symptoms related to video display terminal use: an analysis of objective and subjective exposure estimates. AB - The occupational use of video display terminals (VDTs) has been associated with the increasing incidence of upper extremity musculoskeletal disorders, often called cumulative trauma disorders. To guide clinical and policy decisions about the prevention and treatment of these VDT related disorders, valid and economic measures of total daily VDT use and VDT related job tasks such as data entry or editing will be important. In this study of newspaper reporters and copy editors (n = 83), VDT use was measured with employee self reports and by sampling the work behaviors of a subsample of employees. Behavioral sampling estimated VDT use as a characteristic of the job as opposed to a characteristic of individual employee performance. Overall, the two techniques of measuring occupational VDT use compared favorably, with the exception that self reported hours of VDT use tended to exceed the hours of use estimated by behavioral observation for employees who were younger and those who reported greater job demands. The findings suggest that behavioral sampling is a valid technique for estimating VDT use as a job characteristic. PMID- 8694974 TI - AAOHN advisory: cost benefit and cost effectiveness analyses. PMID- 8694976 TI - Collaboration: the right ingredient for success. PMID- 8694977 TI - Fostering expertise in occupational health nursing: levels of skill development. AB - 1. Levels of nursing expertise described by Benner--novice, advanced beginner, competent, proficient, and expert--hold potential for fostering improved practice among occupational health nurses. 2. Lacking a clear understanding of the full potential of the role of the occupational health nurse, employers may not reward the development of clinical expertise that incorporates employee advocacy within the context of written standards and guidelines. 3. Expertise in occupational health nursing can be fostered by job descriptions that incorporate a broader view of nursing (one that stresses judgment and advocacy), retention and longevity, innovative strategies for consultation and collegial interaction to foster mentoring, and distance learning strategies. PMID- 8694978 TI - Violence and sexual harassment: impact on registered nurses in the workplace. AB - This study sought to determine the prevalence and impact of violence and sexual harassment experienced by registered nurses (RNs) in their workplaces in Illinois. A random sample of 1,130 RNs were selected to participate in the mail survey. The instrument used was the Nurse Assault Survey originally developed by the Nurse Assault Project Team in Ontario, Canada, and modified by the author. Three hundred forty-five subjects completed the survey (response rate: 30%). Fifty-seven percent of those responding reported personal experience with some aspect of sexual harassment, and 26% reported being victimized by physical assault while on the job. About one third of those who indicated they had been sexually harassed also had been physically assaulted. Patients/clients were the most frequent perpetrators of sexual harassment and physical assault, while physicians committed over half of the sexual assaults. Bivariate analysis showed a significant relationship between physical assault and levels of job satisfaction. A significant relationship also was found between sexual harassment and levels of job satisfaction. Results demonstrate that nurses need to take and active role in fostering a work environment free from violence and sexual harassment. They should be knowledgeable about institutional policies and, where none exist, they should work with administrators to develop them. Prevention and intervention programs should be developed for both student and registered nurses. PMID- 8694975 TI - Nursing staff back injuries: prevalence and cost in long term care facilities. AB - This report describes the period prevalence and cost of back injuries to nursing staff of long term care facilities in comparison to nurses employed industry wide and to other occupations industry wide. The period prevalence of back injuries to nursing staff in long term care facilities was highest for nurse aides, followed by LPNs and then RNs. Nurses (combined) had a period prevalence of back injuries nearly 1.5 times higher than all employees of long term care facilities and 6 times higher than all occupations combined industry wide. Within long term care facilities, nurses sustaining back injuries were younger and had been employed for a shorter period of time than the average for all nurses employed in long term care facilities. Back injuries accounted for more than half of the indemnity and medical costs for all injuries incurred in nursing homes and industry wide. The findings highlight the need for better prevention and rehabilitation PMID- 8694981 TI - The diagnosis and management of asthma: an update. PMID- 8694980 TI - Management of chronic fatigue syndrome: case study. AB - 1. Chronic fatigue syndrome (CFS) is a complex disorder marked by incapacitating fatigue of uncertain etiology which has resulted in a least a 50% reduction in activity and is of at least 6 months' duration. 2. Definitive diagnosis can be very challenging. Because no markers objectively identify the presence of CFS, diagnosis depends heavily on the presence of subjective complaints. 3. The current philosophy of CFS management is to use a multidisciplinary approach incorporating these rehabilitation goals: restore a sense of self efficacy and control; gradually increase physical activity; and decrease the restrictions imposed by CFS. PMID- 8694982 TI - A clinical comparison of the efficacy of an electromechanical flossing device or manual flossing in affecting interproximal gingival bleeding and plaque accumulation. AB - This one-month clinical trial was designed to compare the effect of an electromechanical flossing device and manual flossing on reducing interproximal gingival bleeding and plaque accumulation in a cohort of 60 healthy adults. After baseline evaluation of interproximal gingival bleeding, soft tissue trauma and plaque, patients were randomly assigned to one of the two experimental groups, given flossing instructions, and had their teeth cleaned. At 30 days all three clinical parameters were again evaluated. The results showed a reduction in GI from baseline to follow-up in each group. This effect is significant (p<0.0001) in the analysis of variance. There was no overall difference in the groups (p=0.93). There was no difference in the reduction in GI from baseline to follow up between the two groups (p=0.91); interaction). As with the GI, there was a significant reduction in PI from baseline to follow-up in each group (p<0.0001). There was no overall difference between the groups (p=0.24). There was no difference in the reduction in PI from baseline to follow-up between the two groups (p=0.59; interaction). No soft tissue trauma was noted at the baseline examination or at the follow-up examination after 30 days. PMID- 8694979 TI - Diagnosis and management of asthma: occupational health nurses' awareness and use of national consensus practice guidelines. AB - A regional sample of members of the American Association of Occupational Health Nurses (AAOHN) from Maryland, Delaware, Virginia, and the District of Columbia was surveyed prior to the publication of the Expert Panel Report on Guidelines for the Diagnosis and Management of Asthma (time 1). The guidelines were disseminated directly to AAOHN members through an article in AAOHN Journal and an annual convention plenary session presentation at which copies of the Report were distributed. They were disseminated indirectly through medical journals and government documents. A follow up survey of AAOHN members' familiarity with and use of the Expert Panel Report was conducted 1 year later (time 2). Of the total eligible sample of 570 persons, 325 (57.0%) responded at time 1. Of these, 232 (71.4%) responded at time 2. One year after publication, 31 (13.4%) of the nurses participating in the time 2 survey were aware of the Report, 16 (6.9%) reported having an available copy of the Report, 31 (13.4%) were familiar with the recommendations in the Report, 17 (7.3%) referred to the guidelines and 34 (14.7%) based care on the guidelines. Multiple direct dissemination strategies of consensus guidelines to improve practice will be necessary if nurses' awareness and use are to be enhanced. PMID- 8694984 TI - Clinical evaluation of the plaque removal efficacy of three toothbrushes. AB - A single-blind, randomized triple crossover study was conducted to compare the plaque removal effectiveness of three toothbrushes: Sunstar Do New Type, Reach Compact Head, and New Dental-H. Thirty-three female students were recruited from a dental school and a dental hygiene school. All subjects brushed with a control toothbrush for the first week and with each one of the three test toothbrushes in each subsequent one-week period. Plaque removal efficacy was determined by subtracting the plaque score for the test toothbrush from that of the control toothbrush. The Sunstar Do New Type toothbrush had a significantly (p<0.05) higher plaque removal efficacy than the other two toothbrushes. The differences were prominent on the distal line angle of the second molars. Differences in plaque removal efficacy between the Reach Compact Head and the New Dental-H toothbrushes were not statistically significant (p<0.05) in this study. PMID- 8694983 TI - A comparative clinical investigation of the safety and efficacy of an oscillating/rotating electric toothbrush and a sonic toothbrush. AB - This clinical study compared the ability of a sonic toothbrush to remove plaque and control gingivitis with that of an oscillating/rotating electric toothbrush. One-hundred and sixteen subjects from a general population were randomly allocated to either a sonic toothbrush group (Sonicare) or an electric toothbrush group (Braun Oral-B Plaque Remover). After 8 weeks use, there was found to be no statistically significant difference in either plaque removal or gingival index between the two groups. Both devices were found to be safe, but whereas 100% of volunteers in the Braun Oral-B Plaque Remover group expressed a wish to continue using the toothbrush, approximately 25% of the Sonicare group did not like the device and said that they would not continue to use it. The Sonicare device was found to offer no advantages in clinical terms over an established oscillating/rotating electric toothbrush (Braun Oral-B Plaque Remover) with respect to removal of supragingival plaque or improvement in gingival health. PMID- 8694985 TI - Serendipitous results of a pilot study: precaution indicated. AB - A pilot study was conducted to estimate sample size for a clinical trial in a F area. In 1992, 98 children 14 years of age living in Fall River, MA were examined for dental caries: Fall River was fluoridated in 1973. Residence histories showed that 74% lived there from birth (B), 12% were residents from kindergarten or 1st grade (K1) and 14% moved into the community at a later time (LT). Findings on caries prevalence showed an inverse relation between DMFS and initial age of residence; mean DMFS was 3.00 for Group B, 5.33 for Group K1 and 6.93 for Group LT. A one-way ANOVA indicated significant differences among the groups (p=0.05). Because residence from birth or from early life can be considered a proxy for systemic fluoride exposure, and because controversy currently surrounds the issue of topical versus systemic benefits in explaining the mechanism of action of fluoride, the results appeared to have importance. However, internal analyses of the data comparing surface-specific (pit and fissure) results among the groups for early erupting teeth with varying systemic exposure to fluoridated water and for late erupting teeth, all with appreciable systemic exposure, showed comparable relative differences in DMFS scores. Lack of internal validity, therefore, discounted a conclusion from overall results of the role of systemic fluorides in providing decay preventive benefits. If there is any conclusion that can be drawn it is that serendipitous escapades with data from a pilot study, if not rigorously analyzed and cautiously interpreted, tend to further muddy the waters (fluoridated in this case) on controversial issues and should best be avoided. PMID- 8694986 TI - One month evaluation of the manually rotating "Bio-Bright" toothbrush for clinical safety and efficiency. AB - A clinical trial, based on the guidelines of the American Dental Association, was conducted to evaluate the efficacy and safety of Bio-Bright, a new manually rotating toothbrush. The brush was used by 28 adults and compared to a group of 26 adults who used an ADA-accepted toothbrush (Oral-B 35). Examinations were recorded for safety, plaque level, gingival inflammation and gingival bleeding at baseline, 15 days and one month. Analysis of the data revealed no statistically significant differences between the two groups at any of the measurement periods. When calculating the cumulative longitudinal effect on plaque increase or decrease, a consistent and statically significant advantage was revealed for the Bio-Bright group, as compared to the control. No significant differences were demonstrated when comparing safety, gingival, and bleeding indices between the two groups. PMID- 8694987 TI - New approaches to delivery of fluorides. PMID- 8694988 TI - [Frequency of pregnant HBsAg carriers in a Brazilian community]. AB - In view of the benefits of immunoprophylaxis among newborns of mothers who are seropositive for hepatitis B virus (HBV) surface antigen (HBsAG), these women must be correctly identified so that this measure can be instituted in Brazil. The research reported here studied 7992 women who gave birth in the Hospital das Clinicas of the Ribeirao Preto School of Medicine, University of Sao Paulo (HCFMRP-USP), Brazil, in order to determine the rate of serum reactivity of HBsAg and other markers of HBV infection among these women, and also to evaluate the risk factors for this infection. Serum reactivity for HBsAg was determined by means of an immunoenzymatic test (ELISA) carried out in two stages: the first with an incubation period of 2 hours (screening), and the second with an incubation period of 18 hours (confirmation) for those samples that were positive in the screening test. The markers anti-HBsAg, HBeAg, anti-HBcAg, and anti-HBeAG were tested in the samples that were confirmed positive. The screening test found 1.05% (95% CI: 0.84 - 1.30) of the samples to be positive for HBsAg. However, only 0.95% (95% CI: 0.75 - 1.19) were confirmed positive, the percentage being significantly higher among patients whose pregnancies had ended in abortion (1.84%) than among those who had given birth (0.84%) (X2, Yates correction = 7.76; P < 0.005). Risk factors for HBV infection could be identified for only 27.6% of the study subjects, based on their recall and reporting. Of the women with confirmed positive samples, 21.3% also were positive for HBeAG, indicating that these patients ran a greater risk of transmitting the virus vertically. These results underline the need for specific serologic studies in the final stage of pregnancy in order to offer the maximum benefit of neonatal immunoprophylaxis. PMID- 8694990 TI - [Defense of the nil hypothesis: a comment on statistical significance and acceptance of the nil hypothesis]. PMID- 8694989 TI - [Contamination of fish ceviche by Salmonella in Guadalajara++, Jalisco, Mexico]. AB - This study was done to find out the incidence of Salmonella contamination of fish prepared and sold in 89 fixed and mobile food-vending establishments in the city of Guadalajara, Jalisco, Mexico. The pH of the samples analyzed varied between 3.8 and 5.2 (median = 4.55), and their temperature ranged from 9 to 29 degree C. Of the 221 samples studied (20 g each), 16% were positive for Salmonella. The proportions positive in fixed and mobile establishments were, respectively, 12% and 20%. The positive percentages were higher during mild and hot periods than during cold weather. The preenrichment technique proved less efficient for isolating Salmonella than direct enrichment. Salmonella was isolated from two of eight samples with pH below 4.0. The results indicate that eating ceviche may pose a health risk, especially for persons whose resistance to food-transmitted enteropathogens is low. Therefore, it should be emphasized that lime juice does not guarantee the safety of ceviche. PMID- 8694991 TI - [Physical punishment in children: endemic or epidemic?]. PMID- 8694992 TI - [Iberoamerican conference on teaching for quality in health services. Iberoamerican Panel of Teaching and Quality in Health Services]. PMID- 8694994 TI - The SAS maximal principle: a new approach to the phase problem. AB - The phase problem, when single-wavelength anomalous scattering (SAS) diffraction data are available, is formulated as a problem in global optimization. Although the objective function has a myriad of local maxima, its global maxima, never more than two, are readily accessible and easily identified by virtue of their isolation. The ability to determine the global maxima of the objective function represents the latest and most successful attempt to go directly from the known probabilistic estimates of the three-phase structure invariants to the values of the individual phases. The relationship between the maxima of the objective function and the solutions of the newly formulated system of SAS tangent equations plays a key role in this development. PMID- 8694993 TI - Direct phasing in protein electron crystallography--phase extension and the prospects for ab initio determinations. AB - Zonal diffraction amplitudes and crystallographic phases, derived from an averaged electron micrograph of two-dimensionally crystalline E. coli Omp F outer membrane porin (plane group p31m, a = 72 A), embedded in glucose, were used as a model data set to test the feasibility of direct phase extension and ab initio direct phase determination. If 17 phase terms derived from e.g. a 10 A (diffraction) resolution image are expanded to 6 A by the Sayre-Hughes equation, the unknown phases are found with reasonable accuracy (mean error 43 degrees for 25 reflections). This, however, is not the most optimal starting point. As a function of initial image resolution, the accuracy of the phase extension to 6 A is approximately a parabolic function. That is, an optimal basis resolution, found at 11 A (i.e. 14 defined reflections), produces a least mean error of 18 degrees for 28 new reflections. In addition, ab initio phase determination is possible via a multisolution technique, using a test for density flatness as a figure of merit. The success of the determination, again is sensitive to the size of the starting basis set generated from the permuted unknown reflections. If an annealing step is used to improve the basis set, the test for flatness will identify which reflections should be changed in phase. However, this figure of merit is not absolutely reliable for finding the exact value of the unknown phases. PMID- 8694995 TI - Clinical decision-making in critical care. AB - A survey of 230 practising critical care nurses was conducted to examine the frequencies with which the nurses made decisions to perform 10 critical care tasks drawn from cardiac, respiratory and gastrointestinal management. The relationship between the nurses' levels of appointment and the frequencies with which they made their decisions was also studied. Substantial intra-respondent and inter-respondent variations were found in the frequencies with which nurses reported that they made the decisions. Chi-square analysis showed that there was a positive association (p < 0.05) between nurses' appointment levels and the frequency with which decisions were made to perform five of the tasks. Notwithstanding these associations, it is of concern that the professional preparation of some nurses had not been at a level that equipped them to routinely make these decisions. The findings of the study have implications for the development of standards of practice guidelines and critical care education. PMID- 8694998 TI - Emancipation--is it just a dream? PMID- 8694996 TI - Dementia assessment: to do or not to do? AB - In this article, the authors summarise the diagnostic investigations that may be used to assess the health status of people with dementia. They express their concern with opposition to the use of the investigations on the grounds of expense and the incapacity of the tests to definitively diagnose Alzheimer's disease. The argument of the paper is that thorough investigation of people with dementia is warranted. Without such assessment, reversible or arrestable conditions that produce symptoms of dementia are not detected or treated. When dementia is diagnosed early, people with the condition and their carers are better prepared to plan and cope and expenses associated with mismanagement of people with some forms of dementia are minimised. The authors conclude that withholding diagnostic investigation of dementia deprives a group of people of the health care to which they are entitled. PMID- 8694997 TI - The Difficult Patient Stress Scale: a new instrument to measure interpersonal stress in nursing. AB - This study describes the development of the Difficult Patient Stress Scale, an instrument designed to investigate the stress that nurses experience when they are involved in interpersonal conflict with patients. The DPSS is based on the theoretical conceptualization of stress proposed by DeLongis, Lazarus and Folkman and on the personality theory of Individual Psychology. The DPSS utilises visual analog scales to measure nurses' responses to hypothetical scenarios that present typical, difficult nurse-patient situations. The DPSS has been tested over a period of two years with 228 nurses and the results to date indicate that it is valid, reliable and suitable for use in the clinical environment. It is proposed that it may provide a useful instrument for exploring the impact and frequency of interpersonal stressors in nursing and may assist in the development of educational programs to better equip nurses to deal with interpersonal nurse patient conflict. PMID- 8694999 TI - Children's experience of a parent's chronic illness and death. AB - Five dependent young people who had experienced the chronic illness and death of a parent were asked to reflect on the meanings of their loss. The most important of the eight themes revealed by analysis of the data were the interviewees' emotional upheavals and the shock of being forced to face the realities of illness and death. During the illness phase, the participants had felt powerless and isolated. Through appropriate goodbyes and acceptance of their situation, the participants had identified the meaning and ongoing nature of loss and had resolved their feelings. They also acknowledged that a positive outcome of loss was that their self-esteem had increased as they identified and drew on their inner strengths. PMID- 8695000 TI - Telephone triage: protocols for an unacknowledged practice. AB - A survey was conducted of the telephone callers who sought advice from the accident and emergency department of a 250 bed public hospital. The aim of the one month long survey was to determine the extent of the department's telephone triage and whether there was a need for formal protocols that reflected the medical and legal responsibilities attached to giving health-related advice by telephone. The study found that 206 calls seeking advice were received; 79% of calls were of less than five minutes' duration and 40% were made between 6pm and 12mn. Callers were advised by the registered nurses or doctors who happened to answer the telephone and there were no guidelines and no documentation of calls. As a result of the study, the Riverina Health Service instituted telephone triage protocols for all hospitals in its area and nurses now receive inservice education about their telephone triage role and responsibilities. PMID- 8695001 TI - Caries diagnosis with dye-staining at amalgam restoration margins. AB - PURPOSE: To determine the strength of agreement between detection of caries at the margin of amalgam restorations with a caries detector dye, and detection of caries histologically utilizing light/polarizing light microscopy. MATERIALS AND METHODS: 17 permanent molars with intact amalgam restorations, determined to be caries-free by visual inspection and explorer probing, cleansed with an air/water/abrasive slurry system, and with evidence of amalgam enamel marginal staining from application of a 1% solution of sulforhodamine B caries detector dye were utilized. Longitudinal, undecalcified sections, 80-100 micrometers thick, were prepared including stained and unstained regions of the amalgam/enamel margin of each tooth, providing 34 margins for study. The sections were examined in the light/polarizing light microscope for evidence of marginal caries. The Kappa Index was calculated to determine the strength of agreement between the caries dye method and the light/polarizing light microscopic method of caries diagnosis. RESULTS: Microscopically, caries was detected in 14 of 34 margins (41%). Agreement for presence of caries was 5 of 34, and for absence of caries 8 of 34 (total agreement 38%). 12 of 17 dye-stained margins were microscopically caries-free, and 9 of 17 unstained margins had caries microscopically. Kappa Index for these findings was 0.23, indicating poor strength of agreement. PMID- 8695002 TI - Effect of Amalgambond on cervical sensitivity. AB - PURPOSE: To evaluate in vivo the feasibility of utilizing Amalgambond adhesive agent alone for the treatment of cervical sensitivity on teeth that did not require a restoration. MATERIALS AND METHODS: Nineteen subjects were selected from a group of patients reporting sensitivity at the cervical region of anterior or posterior teeth. The degree of sensitivity was determined by tactile sense (scraping an explorer over the surface area) or "fluid-shift" sensitivity determined by an air-blast from a syringe for 5 seconds. Patient reactions to stimuli were qualified as : (1) none; (2) slight; (3) moderate; and (4) severe. Only patients with at least two teeth experiencing moderate or severe sensitivity were used. Each of the patients had at least one sensitive tooth treated with Amalgambond and at least one untreated sensitive tooth to act as control. Results were recorded at 24 hours, 7 days, 1 and 6 months. RESULTS: At 6 months, 18 of 19 treated teeth recalled showed decreased sensitivity with 15 showing no sensitivity, and only one remained as sensitive as at baseline. All control teeth remained unchanged from original sensitivity ratings. The teeth with cervical sensitivity treated with Amalgambond adhesive alone had a high probability of decrease or complete loss of sensitivity immediately and the decrease was sustained for at least 6 months (P<0.001). PMID- 8695003 TI - Shear bond strengths of four resin cements to cobalt-chromium alloy. AB - PURPOSE: To evaluate the shear bond strengths of four resin cements to cobalt chromium (Co-Cr) alloy using two adhesive primers. MATERIALS AND METHODS: The adhesive luting agents Imperva Dual (ID), Panavia 21 (P21), Super-Bond C&B (SB) and Bistite Resin Cement (BR), and the adhesive primers Metal Primer (MP) and Cesead Opaque Primer (COP) were used. Two sizes of dental casting alloy disks were nonprimed or primed and cemented with each adhesive luting agent. The specimens were stored in water at 37 degrees C for 1 day, and then immersed alternately in water baths at 4 degrees C and 60 degrees C for 1 minute each for up to 100,000 thermocycles before shear mode testing at a cross-head speed of 0.5 mm/minute. RESULTS: The application of COP was effective for improving the shear bond strengths of ID, SB or BR to Co-Cr alloy compared with nonprimed specimens and those primed with MP. However, when Co-Cr alloy was cemented with P21, there were no significant differences in bond strengths between the three groups at all thermocycles. PMID- 8695005 TI - Influence of protecting agents on the solubility of glass ionomers. AB - PURPOSE: To evaluate the influence of protective agents (varnish and glaze-resin resin) on water solubility of two glass ionomer restorative cements (Chelon-Fil and Vidrion-R), with the graviometrical test (A.D.A Specification No 9). MATERIALS AND METHODS: Fifteen samples of each restorative cement were obtained and divided in one control and two experimental groups: (a) control, no protection; (b) protected with varnish; (c) protected with glaze-resin. On the two experimental groups, after the initial gelification reaction, the specimens were protected and immersed in distilled water for the period of 1 and 24 hours. RESULTS: The two glass ionomer restorative cements tested required surface protection to avoid the early solubility. Among the protective materials evaluated, the varnish was the most effective agent. PMID- 8695004 TI - Bond strengths and SEM evaluation of Clearfil Liner Bond 2. AB - PURPOSE: To evaluate a dental adhesive system that uses a single conditioning/primer agent. MATERIALS AND METHODS: Twenty-five flat enamel and dentin bonding sites were prepared to 600 grit on human molar teeth. The Clearfil Liner Bond 2 adhesive system was used to bond Clearfil AP-X composite to both enamel and dentin. After 24 hours of water storage, shear bond strengths were determined using an Instron testing machine. Fifty V-shaped cavity preparations were prepared in human molar teeth with an enamel and cementum margin. Composite restorations were placed using the new adhesive system. The teeth were stored for 24 hours, thermocycled, stained with AgNO3 , sectioned and examined for microleakage. SEM examinations were also completed to evaluate the effects of the treatment steps on enamel and dentin surfaces. RESULTS: Mean shear bond strengths for the experimental adhesive to enamel and dentin were 28.2 +/- 4.9 and 19.4 +/- 3.1 MPa. A t-test revealed that the enamel bond strength was significantly greater (P<0.05) than the dentin strength. No marginal leakage was observed from the enamel margins of the restorations. Three restorations showed minimal leakage from the cementum margins. SEM examinations showed resin penetration into both the conditioned enamel and dentin surfaces. The adhesive system produced high bond strengths to both enamel and dentin, exhibited very minimal microleakage and was easy to use. PMID- 8695007 TI - Contraction gaps in Class II restorations with self-cured and light-cured resin composites. AB - PURPOSE: To evaluate in vitro the cervical gap formation in composite restorations in which an increment of autopolymerizing composite was interposed between the light-cured filling material and the dentin bonding system. Two different self-cured materials and two different adhesives were used and compared. MATERIALS AND METHODS: In 40 Class II cavity preparations with the gingival margins in dentin or cementum, an increment of either of two different autopolymerizing composites, Palfique or Bisfil 2B, was interposed between the light-cured filling material (Palfique Estelite) and either of two different dentin bonding systems, All-Bond and Superbond D (20 restorations each). The specimens were immersed in toluidine blue dye. A section was taken from each specimen and examined under an optical microscope. The extent of dye penetration was measured. The specimens were then stored in water for 1-4 months and replicas of the sections were examined by SEM. RESULTS: Good marginal adaptation was observed for All-Bond/Bisfil 2B in all the restorations. All-Bond/Palfique showed good adaptation in 7 out of 10 cases, the failures occurring between bonding agent and composite. Superbond D/Palfique and Superbond D/Bisfil 2B showed marginal gap formation in 8 out of 10 and in all the restorations respectively. In the latter, four gaps occurred between bonding agent and dentin. As a consequence, a very significant difference (P<0.001) was found between All-Bond and Superbond treatments; no significant difference was found between Bisfil 2B and Palfique in each group treated with either All-Bond or Superbond. After 1-4 months storage in water, hygroscopic expansion of the restorative materials reduced the total number of gaps and the efficacy of the treatments was no more significantly different. PMID- 8695006 TI - Interfacial morphology and strength of bonds made to superficial versus deep dentin. AB - PURPOSE: To evaluate the interfacial morphology (SEM) of two bonding systems to superficial and deep dentin using a reverse-sandwich technique, coupled with measurement of micro-tensile bond strengths (MTBS). MATERIALS AND METHODDS: Superficial and deep dentin disks were prepared from the same tooth in freshly extracted human third molars. All-Bond 2 (total etch versus no etch) or Imperva Bond (total etch versus no etch) were applied to superficial versus deep dentin surfaces and the two disks were bonded together into a reverse-sandwich configuration. RESULTS: SEM revealed that All-Bond 2 and Imperva Bond applied under total etch conditions formed thicker resin-infiltrated layers (4-8 micrometers) on deep dentin than on superficial dentin (2-4 micrometers), and that All-Bond 2 and Imperva Bond applied to unetched dentin formed very thin resin-infiltrated layers (less than 0.5 micrometers) on both dentin substrates. MTBS of All-Bond 2 and Imperva Bond were more than 20 MPa irrespective of dentin depth and were not significantly different. Without acid etching, the MTBS of both systems to deep dentin was significantly lower than to superficial dentin. These results suggested that for the total-etch systems, dentin depth affected the thickness of the resin-infiltrated layer, but the thickness of the resin infiltrated layer had no significant relationship with MBTS. The present data also indicated that the acid-etch technique could prevent the decrease of bond strength seen in deep dentin in the absence of etching. PMID- 8695008 TI - Enhanced bactericidal activity of Arm and Hammer Dental Care. AB - PURPOSE: To compare and contrast antibacterial activities of a baking soda containing dentifrice, Arm and Hammer Dental Care (AHDC) with two fluoride dentifrices without baking soda (Crest and Colgate). MATERIALS AND METHODS: A biphasic approach was taken, utilizing newly-developed laboratory model systems to: (1) assess the activity of brief exposure to dentifrices on single and mixed cultures; and (2) determine the effect of multiple, short-term exposure of sucrose-colonized Streptococcus mutans to simulate cumulative activity against cariogenic plaque. RESULTS: The short-term exposure assays revealed that S. mutans was significantly more susceptible to AHDC than either Crest of Colgate (P<0.05). Moreover, exposure of mixed suspensions of bacteria by AHDC resulted in complete killing of Actinomyces viscosus and significantly greater decreases in S. mutans (P<0.05). This enhanced bactericidal effect was not due to an alkaline pH as pH-adjusted AHDC solutions exhibited similar activity. The comprehensive in vitro plaque studies showed that exposure of colonized S. mutans to AHDC resulted in significantly greater decreases in numbers of viable cells than Crest (P<0.05). Under the conditions employed, the baking soda-containing AHDC exhibited greater antibacterial efficacy overall than the standard Crest or Colgate pastes. These studies suggest that the use of AHDC may provide additional clinical benefit as a result of the enhanced bactericidal activity. PMID- 8695010 TI - Symposium: Clinical Management of Root Surface Caries. San Antonio, Texas, August 5, 1995. Proceedings. PMID- 8695009 TI - Guided tissue regeneration. A status report for the American Journal of Dentistry. AB - This report reviews clinical results which have been obtained with guided tissue regeneration (GTR) using non-resorbable and resorbable materials. The report highlights the clinical factors that affect and that should be considered in order to improve the predictability of the results obtained after GTR. The indications for GTR procedures are reviewed and the surgical technique is described. The importance of periodontal maintenance, and the significance of adjunctive therapies in GTR procedures are also discussed. Based upon the vast scientific information and clinical experience with GTR, it can be stated that with the use of either resorbable or non-resorbable materials a new attachment, determined both clinically and histologically, will be promoted providing that the principles of GTR are properly implemented. PMID- 8695012 TI - Epidemiology of root caries. AB - This paper discusses the influence of changes in population characteristics on root caries and re-examines the epidemiology of the disease. The difficulties in interpreting the available data on the prevalence and incidence are high-lighted and the last decade of studies are summarized in table form. The effect on clinical data of dentists' treatment decisions are addressed and demonstrated using data from a longitudinal study involving 24 dental practitioners in Manchester, UK. These dentists recruited and collected clinical information on a group of their regularly attending dentate adult patients. For the over 55 year olds, the results indicate that a conventional epidemiological study would have underestimated the number of surfaces filled for caries by 50%. The paper concludes by suggesting that consideration should be given to novel ways of collecting data so that more information is available on the etiology, prediction and management of the disease. PMID- 8695011 TI - The microbiology and histopathology of human root caries. AB - Based on numerous microbiological studies performed over the past several decades, it is clear that mutans streptococci can cause human root caries. S. mutans fulfills the criteria for implicating bacteria in the etiology of a mixed infection. For example, S. mutans is found in high numbers in lesion sites, higher than on sound root surfaces in the same subject. Subjects make elevated antibody levels to S. mutans antigens. The organism produces a number of virulence factors including metabolic acid from dietary sucrose and extracellular polysaccharides which facilitate bacterial colonization of tooth surfaces. Eliminating or reducing the number of S. mutans reduces the number of root caries lesions and can even result in "healing" of incipient lesions. There is also data demonstrating the cariogenic potential of S. mutans in animal models. Clearly, S. mutans fulfills the aforementioned requirements. Further, there is also evidence to implicate Lactobacillus as being important in the pathogenesis of root caries by virtue of its association with S. mutans in these lesions. There is less recent evidence regarding the importance of Actinomyces in this disease. While this microorganism is present in root caries and while animal studies clearly point to their cariogenic potential, more recent studies with few exceptions fail to find much association between Actinomyces and root caries. There is an important caveat, however. The Actinomyces may have subspecies groups which are more highly virulent and more closely involved in the etiology of root caries than other groups. For example, A. viscosus serovar 2 is associated with root caries. This and other subspecies groups may produce certain virulence factors not found within Actinomyces species as a whole. For this group of microorganisms and for other potential pathogens, techniques in molecular biology such as 16S ribosomal RNA sequencing offers the hope of more precisely defining species and unraveling what may be largely problems in bacterial taxonomy. Ribosomal RNA sequencing may reveal taxonomic relationships not apparent with classical phenotypic or serologic analyses. Other molecular methods, such as DNA or RNA probes to specific virulence factors may also reveal relationships between clinical lesions and microorganisms possessing these virulence factors. Finally, there are clearly a number of additional species which may have importance in root surface caries as shown in some studies. These techniques can be used to identify the distribution of novel, even uncultivable bacteria in root caries lesions and in this way establish their role in this important disease. PMID- 8695013 TI - The clinical diagnosis of root caries: issues for the clinician and the researcher. AB - This paper, after presenting a brief case for the relevance of root caries to today's practitioner, describes the differing diagnostic needs of clinical practitioners and clinical researchers. The goal is to inform the clinician of the state-of-the-art that exists today for the diagnosis of root caries in both clinical and research settings. Differing definitions for the diagnosis of root caries are presented that are useful, respectively, for the clinician and for the clinical researcher. Reasons for why there are differing definitions for clinicians and researchers are presented. Finally, eight critical issues are presented that will have to be resolved if clinical research on root caries is to improve its rigor: (1) active vs. inactive lesions, (2) supra- vs. sub-gingival lesions, (3) lesions crossing the CEJ, (4) prior clinical treatment: a visibility issue, (5) oral debris: a visibility issue, (6) instruments for tactile clues, (7) radiographs, and (8) diagnostic conventions. PMID- 8695014 TI - Dental materials for the restoration of root surface caries. AB - Specific material recommendations for the restoration of root surface caries are difficult because of a lack of data on the clinical performance of restorative materials in these situations. Although silver amalgam has been successfully used to restore carious roots, resin composite, glass ionomer, and resin-modified glass ionomers are also used to restore root surfaces since they are esthetic and bond to tooth structure. Fluoride releasing materials may inhibit recurrent caries in restored surfaces; however, clinical documentation of this phenomenon is sparse. This paper describes the efficacy of restorative materials used to restore root surfaces, the dynamic movement of fluoride into and out of restorative materials, and the role that fluoride releasing materials may play in the inhibition of recurrent caries in vitro and in vivo. In addition, classifications are given for low, medium, and high caries risk patients and material recommendations are made for each category of patient. PMID- 8695015 TI - Root caries: prevention and chemotherapy. AB - PURPOSE: Root caries is a problem of importance among dentate elderly. Greater life expectancies at both birth and age 65, combined with improvements in tooth retention across all age groups, have resulted in an increasing number of Americans who have retained their teeth into old age. This increase in numbers of teeth combined with the increase in the percent of teeth with recession has in turn resulted in older persons with more root surfaces at risk for caries than ever before. The purpose of this article is to review the literature on the prevention and chemotherapeutic approach to root caries. METHODS: A review of the literature and synthesis of this information resulted in recommendations for the improved root caries risk assessment and the development of clinical examination protocols and strategies for prevention and treatment. RESULTS: Clinicians can better identify persons at risk for root caries in their practice. People who are older, have moderate to severe periodontal bone loss and gingival recession, are impaired, have poor oral hygiene, take multiple medications, have partials, have retained root tips and the recently unemployed or retired are all at increased risk for root caries. Examination strategies should include the use of at least annual bite-wing radiographs (vertical bite-wings in persons with significant attachment loss) and careful examination of the proximal tooth surfaces. Once identified as low, moderate or high risk, daily and professionally applied fluoride therapies should be combined with dietary modifications, and in high risk individuals, antimicrobial agents for both the remineralization of early lesions and prevention of further root caries. PMID- 8695016 TI - Insulin and blood pressure among healthy children. Cardiovascular risk in young Finns. AB - We evaluated the role of insulin in regulating and predicting blood pressure among 3596 to 2799 Finnish children and adolescents aged 3 to 18 years who were followed from 1980 to 1986. Blood pressure, weight, and height were measured in three surveys 3 years apart. Fasting blood samples were drawn and serum insulin was analyzed. The effect of insulin on blood pressure was evaluated in each of the 3 study years, together with the effect of fasting insulin on future blood pressure and the effect of insulin on the change in blood pressure. We also analyzed the correlation between insulin and blood pressure in different age groups and the correlation between change in insulin and change in blood pressure. A constant positive correlation was found between insulin and both systolic and diastolic (Korotkoff's fifth phase) blood pressures measured in the respective years (correlation coefficients 0.10 to 0.41 and partial correlation coefficients 0.02 to 0.15), except between insulin and diastolic blood pressure in the first two surveys in terms of partial correlation and multiple regression analysis. Similarly insulin and blood pressure correlated positively in every age group. Insulin measured in 1980 or 1983 predicted systolic blood pressure as measured 3 and 6 years later (correlation coefficients 0.30 to 0.47 and partial correlation coefficients 0.06 to 0.13), and likewise diastolic blood pressure as measured 3 and 6 years later (correlation coefficients 0.17 to 0.35 and partial correlation coefficients 0.05 to 0.08), except among the males in 1983. Correlation between insulin and the change in blood pressure was not significant or remained marginal. Similarly, the correlation between change in insulin and change in blood pressure was not significant or remained marginal. We suggest that insulin seems to regulate actual blood pressure within the normal range and to predict future blood pressure among children and adolescents, independently of age and weight. However, insulin does not enhance the rise in blood pressure. PMID- 8695021 TI - Cardiac hypertrophy in the Dahl rat is associated with increased tyrosine phosphorylation of several cytosolic proteins, including a 120 kDa protein. AB - Because of the well established role that tyrosine phosphorylation (tyr phos) plays in growth factor signalling and regulating cell growth, we hypothesized that cardiac hypertrophy might be associated with altered tyr phos of certain cellular proteins in the heart. Furthermore, we hypothesized that angiotensin II (ang II), a putative growth factor for cardiac cells, might be useful as a probe to highlight any differences in intracellular signalling between normal and hypertrophied hearts. The heart and, for comparison, skeletal muscle, from Dahl S rats, which are predisposed to cardiac hypertrophy, and Dahl R rats, which are not, were examined. Antiphosphotyrosine immunoprecipitation and immunoblotting of heart cell extracts revealed the presence of a constitutively tyr phos 120 kDa cytosolic protein. Hearts from Dahl R rats on a high salt diet displayed a smaller amount of constitutive tyr phos of this protein. In the hearts of both Dahl R and S rats maintained on low salt diets there was little evidence of constitutive tyr phos of this protein. Ang II induced tyr phos of this protein in Dahl S rats on a low salt diet and Dahl R rats on a high salt diet, both of which show mild cardiac hypertrophy. In contrast, the markedly hypertrophied ventricle showed a minimal response to Ang II. Thus the severity of cardiac hypertrophy correlated directly with the tyr phos level of this protein. In an attempt to identify this protein, immunoblotting was carried out with antibodies to the signal transducing proteins rasGAP, JAK2 iNOS, p125FAK, and the Src substrate, pp120, but all proved negative. Ang II also stimulated an increase in tyr phos of proteins with apparent molecular masses of 42, 55, and 69 to 85 kDa in hearts from Dahl S rats on high salt diet. By comparison, there was no 120 kDa tyr phos protein in skeletal muscle even in response to Ang II. Silver stained sodium dodecyl sulfate gels demonstrated that this 120 kDa tyr phos protein is present in substantial amounts in the ventricles of rats fed high salt diets. Thus cardiac hypertrophy is characterized by an abundant 120 kDa cytosolic tyr phos protein, which is apparent with Ang II stimulation in milder degrees of cardiac hypertrophy, and is most likely an as yet uncharacterized protein. PMID- 8695017 TI - Acute aerobic exercise reduces ambulatory blood pressure in borderline hypertensive men and women. AB - Ambulatory blood pressure (BP) monitoring was undertaken on two days in 31 men and women (11 with elevated resting and ambulatory BP and 20 who were normotensive), once following each of these treatment conditions: 20 min of moderate aerobic bicycle ergometry, and an equivalent control rest period. The two monitoring days were conducted within a 72 h period with the order of treatments counterbalanced across subjects. Mean BP and heart rate (HR) levels were calculated for each individual on an hourly basis and for work, home, and sleep periods, In the elevated BP group, the exercise day compared to the control day was associated with lower BP at work. Hour-by-hour analyses confirmed that the BP-lowering effect of exercise was significant for 5 h and diminished in magnitude between hours 6 and 9. These effects were not attributable to any marked differences in mood, total daily stress, posture, or activities between test days. Exercise was not associated with any appreciable differences in sleep BP or in the 24-h HR profile No differences in BP or HR as a function of exercise were seen in the normotensive group; however, the exercise-induced reduction in mean arterial BP (MAP) for hours 2 through 5 was significantly positively correlated with control day MAP levels at work in the total sample. Thus, moderate aerobic exercise, when engaged in prior to the stresses of daily living, seems to confer a protective reduction in ambulatory BP, particularly in individuals with elevated BP. PMID- 8695020 TI - Interactions between dietary calcium and caffeine consumption on calcium metabolism in hypertensive humans. AB - Abnormal calcium metabolism has been implicated in human hypertension. Caffeine consumption may contribute to hypertension since it increases urinary calcium excretion. Nineteen hypertensive subjects (HTN) and nineteen age and gender matched normotensive controls (NTC) who habitually consumed at least 175 mg caffeine daily were studied before and after abstinence from all caffeine (CAF) consumption for 2 weeks. Caffeine abstinence (CAF-) increased fasting serum ultrafiltrable calcium in HTN and NTC, but not serum total calcium. Parathyroid hormone (PTH) levels decreased after CAF abstinence in 14 of 18 HTN subjects, including all seven subjects consuming less than 700 mg calcium daily. Three day dietary calcium intakes and 72 h urinary excretion of calcium were not different between CAF+ and CAF- or between HTN and NTC. A morning caffeine dose of 6 mg/kg lean body mass increased urinary Ca/creatinine ratios similarly for 2 h after beverage consumption in both HTN and NTC. Caffeine consumption stresses calcium metabolism in hypertensive individuals, especially those consuming less than 700 mg calcium daily. PMID- 8695022 TI - Central depressor action of nitric oxide is deficient in genetic hypertension. AB - Inhibition of NO synthase (NOS) in the central nervous system (CNS) causes a pressor response. This observation indicates that NO is normally produced at CNS site(s) where it has a tonic blood pressure lowering effect. The current study tests the hypothesis that a deficient NOS activity in the CNS may contribute to the pressure elevation in genetically hypertensive rats. NO administered intracerebroventricularly (ICV) caused a greater fall in mean arterial pressure (MAP; femoral artery) in hypertensive (SHRSP) than in normotensive (WKY) rats, 66.1 +/- 3.4 mm Hg v -23.7 +/- 3.9 mm Hg, respectively. Yet when endogenous NO was increased by stimulating NOS with ICV calcium, the depressor response was less in SHRSP than in WKY, 13.7 +/- 1.1 mm Hg v 26.7 +/- 1.9 mm Hg. Likewise, when NOS was blocked with N omega- nitro-L-arginine methyl ester (L-NAME), the resultant pressor response was less in SHRSP than in WKY, 13.8 +/- 1.1 mm Hg v 22.2 +/- 1.1 mm Hg. Blockade of the action of cGMP, a mediator of the action of NO, caused a pressor response of 6.0 +/- 2.8 mm Hg and 22.6 +/- 8.7 mm Hg (P < .01) in the hypertensive and normotensive rats, respectively. Electrolytic ablation of the anteroventral third cerebral ventricle (AV3V) did not alter blood pressure responses to NO or to agents that alter NOS activity. We conclude that a deficit in NOS activity in some other central cardiovascular regulatory area may contribute to the elevated arterial pressure of these genetically hypertensive rats. PMID- 8695019 TI - Reduction of development of left ventricular hypertrophy in salt-loaded Dahl salt sensitive rats by angiotensin II receptor inhibition. AB - To determine the effect of the angiotensin II AT1 receptor antagonist losartan (DuP753) on echocardiographic left ventricular (LV) anatomy in Dahl rats on high sodium diet, 27 Dahl salt-sensitive (Dahl-S, 13 on drug and 14 receiving tap water) and 27 Dahl salt-resistant rats (Dahl-R, 13 on drug and 14 receiving tap water) were studied by M-mode echocardiography during 8 weeks of 8% NaCl diet. At the endpoint (after 8 weeks or the last echocardiogram for animals who died earlier), Dahl-S receiving losartan had lower LV mass (1.6 +/- 0.4 g/kg 0.59) than Dahl-S receiving tap water (2.2 +/- 0.7 g/kg 0.59; P < .005), although blood pressure was only partially reduced (167 +/- 29 v 195 +/- 52; P = .05). This difference was mainly due to lower LV wall thickness (P < .02), with a less consistent decrease in LV chamber size in Dahl-S receiving losartan. Blood pressure was normal in Dahl-R (tap water group = 116 +/- 11 mm Hg; losartan group = 115 +/- 13 mm Hg) and losartan had no effect on LV mass (1.6 +/- 0.4 g/kg 0.59) in both groups). In the majority of rats, echocardiographic measurements were compared between the end of second or third week and the last available study: LV mass increased in salt-loaded Dahl-S receiving tap water (1.6+/- 0.6 to 2.1 +/- 0.7 g/kg 0.59, P < .04) and was stable in Dahl-S receiving losartan (1.5 +/- 0.1 to 1.5 +/- 0.3 g/kg 0.59), paralleling changes in LV chamber dimension. Thus, a high salt diet leads to hypertension and eccentric LV hypertrophy in Dahl-S but not in Dahl-R. Inhibition of angiotensin II AT1 receptors reduces the development of LV hypertrophy in Dahl-S rats despite lack of efficient control of blood pressure. PMID- 8695023 TI - Differential classification of blood pressure by fourth and fifth Korotkoff phases in school-aged girls. The National Heart, Lung, and Blood Institute Growth and Health Study. AB - The use of the onset of the fourth (K4) or fifth (K5) Korotkoff phase to determine diastolic blood pressure in children has been controversial; most recently, the Second Task Force recommended the use of K4 for children up to age 13 years and K5 for children age 13 and above. We performed a cross-sectional analysis of 1,155 nine-year old (53% white and 47% black) and 1,224 ten-year old girls (45% white and 55% black) in the National Heart, Lung, and Blood Institute Growth and Health Study (NGHS). The mean blood pressures for the first, fourth, and fifth Korotkoff phases were 100.1 (+/- 8.9) mm Hg, 66.6 (+/- 9.8) mm Hg, and 56.8 (+/- 11.8) mm Hg for nine-year-olds and 102.8 (+/- 9.0) mm Hg, 68.1 (+/- 10.1) mm Hg, and 58.1 (+/- 11.9) mm Hg for ten-year-olds. The mean difference between K4 and K5 was 9.9 (+/- 6.4) mm Hg. The correlation between K1 and K4 was 0.45, between K1 and K5 was 0.34, and between K4 and K5 was 0.84. Elevation of blood pressure was defined at or above the 95th percentile based on the NGHS distribution for K1, K4, or K5; the relative risk of having an elevated K1 was 10.1 if K4 was elevated and 5.9 if K5 was elevated. Of the 159 subjects potentially classified with elevated diastolic pressure, 95 subjects (60%) would be classified differently depending on whether K4 or K5 was used to define elevated diastolic blood pressure. The choice of the onset of the fourth or fifth Korotkoff phase for determining diastolic blood pressure in children may have important implications for which individuals are classified as having hypertension. PMID- 8695024 TI - Absence of enhanced sympathoadrenal activity and behaviorally evoked cardiovascular reactivity among offspring of hypertensives. AB - To determine whether offspring of hypertensives show enhanced sympathetic nervous system activity, we evaluated several indices of sympathoadrenal activation and cardiovascular responsiveness to behavioral stimuli among 90 normotensive, young adult men having either one or two hypertensive parents (PH+(-), PH++) or normotensive parents only (PH--) (n = 30/group). Measurements included heart rate (HR) and blood pressure (BP) reactions to three mental stressors (the Stroop test, mental arithmetic, mirror tracing), a cold pressor test, postural adjustment (60 degrees upright tilt), isometric exercise and bicycle ergometry, as well as the 24-h excretion of catecholamines (epinephrine [E], norepinephrine [NE]) and venous plasma catecholamine concentrations, both at rest (seated and supine) and in response to the Stroop test and upright tilt. The three groups did not differ in age, education, body mass index (BMI), estimated aerobic fitness, resting HR, cardiac preejection period (PEP) and PEP:LVET (left ventricular ejection time) ratio, 24-h Na or K excretion, or fasting lipids, insulin or plasma renin activity. Resting systolic and diastolic BP varied as a function of parental hypertension, and were significantly higher in PH++ than among PH-- subjects (P < .05). No significant group difference was observed on any measure of plasma or urinary catecholamines, nor did offspring of hypertensives (PH++ or PH+-) showed greater HR or BP reactions than PH-- subjects to any of the several laboratory challenges. In sum, we find no evidence of enhanced sympathetic activity or heightened cardiovascular responsiveness among normotensive young adults who are familially predisposed to essential hypertension. PMID- 8695018 TI - Influence of humoral and neurohormonal factors on cardiovascular hypertrophy in untreated essential hypertensives. AB - In essential hypertension, cardiovascular structure is believed to be influenced by hormonal and by hemodynamic factors. The objective of the present study was, in essential hypertensives, to investigate the relationship between blood pressure (BP) level as well as circulating hormones on the one hand and cardiovascular structure on the other. Seventy-nine untreated essential hypertensives were examined by 24-h ambulatory BP monitoring, echocardiography, microscopy of subcutaneous resistance vessels and analyzes of plasma for angiotensin II (P-Ang II), aldosterone, atrial natriuretic factor and 24-h urinary excretion of catecholamines. Multiple regression analysis showed a statistically significant correlation between P-Ang II and the end diastolic interventricular septal diameter (IVSDd) (R = 0.32, P = .005) and a weak correlation between P-Ang II and the left ventricular posterior wall diameter (R = 0.22, P = .049). These correlations were closer in the subgroup of patients (N = 54) who had never received antihypertensive treatment (R = 0.42/0.32, respectively). A weak, though statistically significant, correlation was found between the catecholamine excretion and systolic BP (R = 0.26, P = .03). A statistically negative correlation existed between catecholamines and end diastolic left ventricular internal diameter index (R = -0.36, P = .001). No significant relationship was found between hormonal levels and the tunica media structure of the resistance arteries. In conclusion, P-Ang II was in this study significantly correlated to IVSDd, but not to resistance artery structure. In essential hypertension a complex relationship exists between humoral and hemodynamic factors and cardiovascular remodeling. PMID- 8695026 TI - Changes in frequency of orthostatic hypotension in elderly hypertensive patients under medications. AB - To evaluate changes in frequency of orthostatic blood pressure (BP) reduction (orthostatic hypotension; OH) in elderly hypertensive patients (HT) before and after treatment for hypertension, we measured BP after supine for 10 min and standing position for 2 min, before and after treatment for 2 years by five kinds of antihypertensive drugs in 50 elderly normotensive subjects (NT) and each of 50 HT in double-blind study. Orthostatic hypotension was defined as 10% or more decline of supine mean BP, and the frequency of OH was in 27% of HT following BP reduction by any kinds of antihypertensive drugs. In conclusion, the reducing or normalized BP by treatment for hypertension in elderly HT decreases the prevalence of orthostatic hypotension. PMID- 8695028 TI - The blood pressure response to antihypertensive treatment with lisinopril or bendrofluazide is related to the calcium and magnesium contents in skeletal muscle. AB - To evaluate the association between skeletal muscle mineral balance and effect of antihypertensive treatment, 37 patients with essential hypertension, randomly treated with either lisinopril or bendrofluazide, were investigated with skeletal muscle biopsies before and after 6 months of treatment. The ratio between calcium and magnesium concentrations in skeletal muscle prior to treatment predicted the blood pressure response during active treatment (r = -0.38, P < .02). During treatment the change in blood pressure was related to the change in muscle Ca/Mg ratio (r = 0.35, P < .05), especially in the patients treated with lisinopril. Thus, an association between the calcium and magnesium balance in skeletal muscle and the blood pressure response to antihypertensive treatment was found in the present study. PMID- 8695025 TI - Utility of an automatic instrument for blood pressure measurement in children. The Bogalusa Heart Study. AB - The Dinamap 845XT automatic blood pressure monitor, Dinamap 8100 (an update model), and two mercury sphygmomanometers were compared in 417 school-aged children examined in the spring of 1992 as part of the Bogalusa Heart Study. This study was conducted in the nearby community of Franklinton, Louisiana, to verify data obtained as part of a cross-sectional survey (1987 to 1988) of school-aged children in Bogalusa. Systolic blood pressure levels were on the average 3 mm Hg higher on the Dinamap instruments than on the sphygmomanometers. Mean levels of diastolic blood pressure using either Dinamap instrument were slightly higher until eight years of age and then were considerably lower than mercury sphygmomanometer fourth phase readings. Diastolic blood pressure levels on the Dinamap 8100 were 4 mm Hg lower than on the Dinamap 845XT. Height was identified as the predominant predictor variable of differences in diastolic blood pressure between the mercury sphygmomanometer and either Dinamap instrument. A 10% random sample of children was reexamined each screening day in the cross-sectional survey to estimate measurement errors. The diastolic readings of the Dinamap 845XT had a lower intraclass correlation (0.68) compared to the mercury sphygmomanometers (0.83 fourth phase and 0.76 fifth phase). The Dinamap offers the ease of measuring systolic blood pressure although the diastolic blood pressure appears to be biased and especially low, particularly on the new 8100 model. PMID- 8695033 TI - Sleep promotion. AB - The aging process introduces many changes that affect the whole person, including sleep. Age-related changes in the nervous system, acute and chronic illnesses, medications, primary sleep disorders, and factors associated with hospitalization in the critical care unit are elements identified with sleep disturbance in the elderly patient hospitalized in the critical care unit. One of the most important challenges for critical care nurses is to promote a healing environment for elderly patients where they can obtain the sleep necessary for recovery. Potentially effective nursing interventions for sleep promotion are those caring interventions that focus on the body-mind connection, such as back massage, relaxing music, imagery, and muscle relaxation. Investigations of the effectiveness of nursing interventions for sleep promotion are needed. PMID- 8695029 TI - Chymase-dependent angiotensin II forming systems in humans. AB - Recent studies have provided evidence that human cardiovascular tissues contain components of the renin angiotensin system: angiotensinogen, renin, angiotensin I converting enzyme (ACE), chymase, and angiotensin (Ang) II receptors. It is likely that locally produced Ang II plays an important role in cardiovascular homeostasis in autocrine and paracrine fashions and may also be involved in remodeling of the heart and vasculature in pathological conditions. In addition to ACE, a cardiac Ang II-forming serine proteinase (human heart chymase) has been identified in the left ventricle of the human heart. The different cellular and regional distribution of ACE and heart chymase in the heart as well as in blood vessels implies distinct pathophysiological roles of these two Ang II-forming enzymes. Several reports indicate that both ACE dependent and ACE independent Ang II formation appears to take place in hypoxic or ischemic heart or blood vessel in vivo and seems to be involved in their pathological changes. However, chymase dependent Ang II formation, chymostatin sensitive but aprotinin insensitive, does not explain all of ACE independent Ang II formation. Therefore, it has become quite important to clarify the detailed mechanisms of the tissue Ang II formation in humans and their contribution to the pathophysiological changes in cardiovascular diseases. PMID- 8695027 TI - Daytime and nighttime ambulatory blood pressures should be calculated over the true sleep/waking cycle and not over arbitrary periods. AB - The present study was done to compare the values of mean daytime and nighttime blood pressure (BP) calculated over arbitrary periods to those calculated over the true retiring and rising times of the individual patients. A total of 88 individuals, including 55 untreated hypertensives (office BP > 140/90 mm Hg) and 33 normotensives, were recruited. Ambulatory BP was monitored over 24 h during the normal routine of the patient. The patient was requested to trigger a recording on going to bed and on rising in the morning to clearly identify these periods. The mean daytime and nighttime values were calculated over arbitrarily defined periods (6 AM to 10PM daytime and 10 PM to 6 AM nighttime) and as a function of the true retiring and rising times of the individual patients. The true daytime BP was significantly higher than the value calculated over the arbitrary period and the true nighttime BP was significantly lower than the value calculated between 10 PM and 6 AM (paired t test, P < .05). Employing a cutoff value of 135/85 mm Hg for daytime BP, a significant proportion of patients classified as normotensive when daytime BP was calculated over arbitrary periods were in fact classified as hypertensive from the values calculated over true retiring and rising times. PMID- 8695032 TI - Continence management. AB - The elderly, critically ill patient is particularly prone to transient and established fecal or urinary incontinence. With proper management, these devastating problems can be managed, alleviated, or prevented promptly. Care of incontinence is not simply a hygienic consideration. Elderly persons who experience loss of bladder or bowel control frequently are depressed, isolated, and fearful of discovery. Left untreated, these individuals are prone to mental and social deterioration that may lead to social isolation or institutionalization. With adequate awareness and prompt management, however, the critical care nurse can prevent transient incontinence from becoming an established pattern, and he or she can serve as a resource for the elderly patient who seeks care and understanding for this significant condition. PMID- 8695030 TI - Sepsis in the elderly. AB - Sepsis in the elderly occurs frequently and carries a high rate of mortality. With increasing numbers of elderly patients being cared for in critical care units, the critical care nurse must have a thorough understanding of the unique aspects of this patient population. Nurses must be prepared to deliver expert nursing care that is knowledge-based and incorporates current research findings. Unit protocols that encompass the preventive measures needed by these special patients will assist in reducing the incidence of sepsis. When sepsis occurs, careful trending of data will signal the need for timely and precise interventions that may result in a good outcome for the elderly patient with sepsis. PMID- 8695031 TI - Protecting the skin of the elderly patient in the intensive care unit. AB - This article summarizes the ways in which factors in the ICU setting can affect skin breakdown in the elderly patient. The effects of aging, the presence of underlying chronic factors, and the imposition of critical illness may affect the skin of the elderly patient in ways not experienced in a younger patient population. It is important that ICU nurses recognize the unique differences and challenges in maintaining the skin integrity of the elderly, critically ill patient. Even though not all pressure ulcers in this population will be preventable in the ICU setting, an awareness of special risk factors in the geriatric patient will enable the ICU nurse to maintain the highest level of skin care for the geriatric patient. PMID- 8695034 TI - Delirium in hospitalized elderly patients: off track. AB - Delirium in the hospitalized elderly patient is highly prevalent and has severe consequences. Critically ill elderly individuals are at particular risk for delirium because of impaired physical and mental defense mechanisms. More research in terms of etiology, detection, treatment, and especially prevention, needs to be done. Although nursing care and nursing research have contributed much to our current knowledge of this complex condition, more will be contributed toward its understanding and management during the next decade. It is imperative that nurses attempt to keep abreast of this progress to provide the quality and cost-effective care that can keep older patients "on track." PMID- 8695035 TI - Physical restraint of elderly patients in critical care: historical perspectives and new directions. AB - The use of physical restraints in health care settings is being examined carefully at all levels. Experience with the elderly in long-term care settings teaches us that in many instances physical restraints are not only unnecessary, they are also not the best available therapy. There can be little doubt that careful evaluation of the use of restraints in the critical care unit is likely to reveal alternatives to their use in many situations. In the American health care system, nurses primarily determine restraint use. Professional nurses are leading the movement to find alternatives to restraints, and critical care nurses can contribute much to the effort. Nurses must recognize restraint application as a serious treatment decision, and must apply risk-to-benefit analysis to each decision. Continuing nursing education and nursing research on restraint reduction will lead to improved care for our elderly patients. PMID- 8695036 TI - Failure to wean: exploring the influence of age-related pulmonary changes. AB - Half of the patients admitted to intensive care units are elderly and may require mechanical ventilation for respiratory failure. Although age is not an independent factor for determining weaning outcomes, it may play a role. Elderly patients are predisposed to hypoxic-hypercapnia failure caused by age-related pulmonary changes and coexisting diseases. These age-related changes limit the respiratory reserve, which affects the body's ability to provide an adequate oxygen supply to meet the demand. The consequence is that during weaning there may be an imbalance between supply and demand and weaning failure may result. More research is needed regarding the weaning of elderly patients. Some specific areas that require further investigation are the relationship between age and dyspnea, the influence of age on weaning, and the relationship between age and the work of breathing. PMID- 8695038 TI - Pharmacokinetic and pharmacodynamic monitoring of the elderly in critical care. AB - The cases presented illustrate the clinical application of several of the common pharmacokinetic and pharmacodynamic changes in the elderly. The number of drugs that must be used with caution in the aging person is potentially quite large. In addition, there are numerous other diseases that can result in additional changes in drug absorption, distribution, metabolism, excretion, and target-organ effect. These conditions are particularly prevalent in the elderly patient in the critical care setting, and include the systemic inflammatory response syndrome, sepsis, acute renal failure, diabetic ketoacidosis, and the postoperative state. It must be emphasized, however, that the elderly are not a homogeneous group. The rate of decline of many physiologic functions varies widely. Chronic diseases and lifestyle alterations are additional variables that affect the function of many body systems. Furthermore, it is likely that the different pharmacokinetic and pharmacodynamic parameters discussed in this article do not all change to the same degree in a given individual. Pharmacologic therapy, therefore, always will be quite empiric in elderly patients. There is no substitute for meticulous monitoring of the patient using every available modality. This is particularly crucial in the critical care setting, where drugs can be lifesaving and life threatening at the same time. PMID- 8695039 TI - Interventions for aged family members. AB - Is Mrs. B's family unusual? Is this a hypothetical situation made too dramatic? The answer is no, to both questions. This situation is real, the family is real, and a typical, elderly spouse was driven to feel helpless and out of control, experiencing what no person should ever go through, and needing to reevaluate and rethink her whole future. Hospitalization for a critical injury can disrupt even the most highly organized and functional family. Family-focused care may mitigate family stress by providing support based on the unique needs of each family. As Mrs. B's family illustrates, the family members may have suffered as much pain as the patient. They, too, deserve special attention and consideration. Their reactions are typical and manageable, and professionals who are interested in the welfare and functioning of the family must ensure that the family of the patient receives adequate and appropriate care, no matter what their age. PMID- 8695040 TI - Effect of pergolide on endogenous and exogenous L-DOPA metabolism in the rat striatum: a microdialysis study. AB - We used a model of intrastriatal microdialysis in freely moving rats to study the effect of pergolide, a mixed D1/D2 dopamine (DA) receptor agonist with predominant D2 action in vivo, on the biotransformation of endogenous and exogenous L-DOPA. Levels of L-DOPA, DA, DOPAC, HVA and 5-HIAA were measured by high performance liquid chromatography. Pergolide (50 micrograms/kg, i.p.) caused a 47%, 65% and 70% decrease in basal striatal extracellular (EC) levels of DOPAC, HVA and DA, respectively. L-DOPA (100 mg/kg, i.p.), injected 2 hours after carbidopa, produced significant increase in EC levels of L-DOPA, DOPAC, HVA and DA in rats with and without local perfusion of 10(-4) M pergolide. The DOPAC peak value was lower and was reached 60 minutes later in the group with pergolide. This study demonstrated inhibitory effects of pergolide on endogenous DA release and influence of pergolide on exogenous L-DOPA biotransformation. PMID- 8695041 TI - MK801 induces late regional increases in NMDA and kainate receptor binding in rat brain. AB - We have previously shown that a single dose of PCP produces a dose-related increase in NMDA-sensitive 3H-glutamate binding in CA1 of hippocampus 24 hours later, and some regional changes in kainate binding. Here we report that dizocilpine (MK 801) (0.1 mg/kg and 1 mg/kg), a selective agonist at the PCP receptor and a noncompetitive antagonist of NMDA, produces a similar increase in NMDA-sensitive glutamate and kainate receptor binding in hippocampus 24 hours after a dose. These observations support the conclusion that blockade of glutamate-mediated transmission at the NMDA receptor selectively increases NMDA sensitive glutamate receptor binding in CA1 of hippocampus and kainate binding in CA3 and dentate gyrus at putatively delayed time points. Several additional areas outside of hippocampus also showed receptor changes at 24 hours after MK801. PMID- 8695037 TI - Seizures and the elderly. AB - The care of elderly patients with seizure disorders in the critical care unit is an important nursing challenge. The potential that a seizure is an isolated event or one that will require lifelong treatment must be expected. The critical care nurse is in a unique position to help the patient and his or her family as they begin to grapple with the important changes the seizure may bring. The critical care nurse also can assist in the transition from the acute setting to the less acute setting in which the patient and the family will be assisted in developing plans for long-term management of this serious situation. PMID- 8695044 TI - Differential regional and kinetics effects of piribedil and bromocriptine on dopamine metabolites: a brain microdialysis study in freely moving rats. AB - Brain microdialysis coupled to HPLC was applied to freely moving rats to investigate the regional kinetics of piribedil and bromocriptine on the extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in striatum, nucleus accumbens, and frontal cortex. Both D2 agonists (20 mg/kg i.p.) decreased DOPAC and HVA in the three brain regions. The responsiveness of frontal cortex to both compounds was greater than those previously reported with other dopaminergic drugs. Regional and temporal differences were observed under piribedil: DOPAC and HVA levels decreased more in the nucleus accumbens than in striatum or frontal cortex but increased over basal values from the 5th hour in the frontal cortex suggesting a late stimulatory effect of piribedil on dopamine synthesis in this area. Such regional effects differentiate piribedil from most other D2 agonists and could explain some behavioural and therapeutic actions possibly related to involvement of nucleus accumbens or/and frontal cortex. PMID- 8695042 TI - Behavioural and neurochemical interactions of the AMPA antagonist GYKI 52466 and the non-competitive NMDA antagonist dizocilpine in rats. AB - The behavioural and neurochemical effects of the N-methyl-D-aspartate (NMDA) antagonist dizocilpine and the alpha-amino-3-hydroxy-5-methylisoxazole- 4 propionic acid (AMPA) antagonist GYKI 52466, given alone or in combination, were investigated in rats. Locomotor activity was increased by dizocilpine (0.2 mg/kg), but not by GYKI 52466 (2.4 mg/kg). Dizocilpine-induced hyperlocomotion was reduced by co-administration of GYKI 52466. In dizocilpine-treated rats dopamine (DA) metabolism (measured as DOPAC [dihydroxyphenylacetic acid] or DOPAC/DA in post mortem brain tissue) was increased in the prefrontal cortex and nucleus accumbens. In GYKI 52466-treated rats serotonin was reduced in the prefrontal cortex and nucleus accumbens while DA metabolism was not affected. In rats treated with dizocilpine plus GYKI 52466, DA metabolism was increased only in the prefrontal cortex, but not in the nucleus accumbens, when compared with vehicle-treated animals. These data confirm that AMPA and NMDA antagonists do not have synergistic effects on locomotor activity. A differential role of NMDA and AMPA antagonists in the control of mesolimbic DA neurons will be discussed here. PMID- 8695045 TI - The muscarine antagonist methscopolamine and the NMDA antagonist AP-5 injected unilaterally into the nucleus accumbens cause mice to rotate in opposite directions. AB - Previously, we have reported that the NMDA antagonist AP-5, injected unilaterally into the nucleus accumbens of mice, induces ipsilateral rotation in monoaminergically intact mice, but contralateral rotation in monoamine-depleted animals. In this paper we report that the muscarine antagonist methscopolamine, injected unilaterally into the nucleus accumbens, induced predominantly contralateral rotation in monoaminergically intact mice. In monoamine-depleted animals intra-accumbens methscopolamine induced only a weak stimulation of rotational behaviour (not significant), but the direction of the rotation was exclusively contralateral, and the animals showed contralateral body deviation. Moreover, when these animals received additional treatment with the alpha adrenergic agonist clonidine, which potentiates the motor effects of cholinergic antagonists in monoamine-depleted mice (Carlsson et al., 1991), a clear-cut contralateral rotation was induced. The observed behavioural effects are discussed in relation to the positive and negative feedback circuits, which link the nucleus accumbens with the cerebral cortex and thalamus. In previous papers, we have suggested that the ipsilateral rotation induced by AP-5 is mediated primarily by the positive feedback circuit, whereas the AP-5-induced contralateral rotation is due to interference with primarily the negative feedback circuit. Applying this reasoning to the rotational effects of methscopolamine, it seems that methscopolamine interferes primarily with the negative feedback circuit. PMID- 8695043 TI - Crucial role of the accumbens nucleus in the neurotransmitter interactions regulating motor control in mice. AB - Previous work, based on systemic drug administration, has shown that neurotransmitter interactions between dopaminergic, adrenergic, glutamatergic and cholinergic systems are involved in locomotor control in mice. In an attempt to identify the target sites in the brain of these interactions, we have started a series of experiments, where the drugs are administered intracerebrally in mice. The locomotor threshold doses of the competitive NMDA antagonist AP-5 and the noncompetitive NMDA antagonist MK-801 were investigated by means of local application in the accumbens nucleus of monoamine-depleted and monoaminergically intact mice, respectively. The threshold dose of AP-5 was lower in depleted than in intact animals, whereas the threshold dose of MK-801 was lower in monoaminergically intact than monoamine-depleted mice. The locomotor effects of AP-5 and the AMPA-kainate receptor antagonist CNQX were registered in monamine depleted mice after local application in the accumbens or entopeduncular nucleus (= medial pallidum). Both AP-5 and CNQX stimulated locomotor activity in the accumbens, but had no effects in the entopeduncular nucleus. We have previously shown synergistic interactions with regard to locomotor stimulation in monoamine depleted mice, between an NMDA antagonist and an alpha 2-adrenoceptor agonist or a dopamine D1 agonist (all drugs given systemically). In the present study the alpha 2-adrenoceptor agonist alpha-methylnoradrenaline was applied intracerebrally in combination with a subthreshold dose of MK-801 given intraperitoneally: Locomotor stimulation was produced after alpha-methyl noradrenaline injection into the accumbens nucleus, but not after injection into the dorsal striatum, prefrontal cortex or thalamus. Likewise, local application of the D1 agonist SKF 38393, in combination with a subthreshold dose of MK-801 given intraperitoneally, point to an important role of the accumbens nucleus in motor control. Previous experiments based on systemic drug administration have also shown a synergistic interaction between a muscarine antagonist and an alpha 2-adrenoceptor agonist in monoamine-depleted mice. Local application of the muscarine antagonist methscopolamine, in combination with the alpha 2 adrenoceptor agonist clonidine given intraperitoneally, showed that the striatum, in this case both the ventral and dorsal parts of the striatum, is an important target for the muscarine antagonist. Unilateral injection of AP-5 into the accumbens nucleus of mice induces rotational behaviour: Previous findings have shown that the rotation is ipsilateral in monoaminergically intact animals, whereas monoamine-depleted animals rotate contralaterally. In addition, these findings have shown that dopamine D2 receptor stimulation seems to determine whether AP-5 will induce ipsilateral or contralateral rotation. In the present study we report further evidence for a crucial role of the D2 receptor in this respect. Finally, the rotational effects of AP-5 injected into the dorsal striatum or hippocampus were investigated: As after AP-5 application into the accumbens nucleus, monoaminergically intact mice rotated ipsilaterally, whereas monoamine-depleted animals rotated contralaterally, following AP-5 application in the dorsal striatum or the hippocampus. The present data show that the accumbens nucleus has an important role in motor control. Both glutamatergic, muscarine cholinergic, dopaminergic and alpha-adrenergic systems are involved in the control of motor functions in the accumbens nucleus. PMID- 8695046 TI - Cortical stimulation and reflex excitability of spinal cord neurones in man. AB - The H reflex technique was used to evaluate the influence exerted by cortical conditioning on the excitability of the alpha-motoneurone pool and on IA interneuronal activity (reciprocal inhibition). In ten subjects at absolute rest electrical and magnetic stimulation of the motor cortex was transcranially applied during flexor carpi radialis H reflex eliciting and in conditions of reciprocal inhibition induced by radial nerve stimulation. The time courses showed that at intensities below motor threshold, electrical brain conditioning induced an increase in the amplitude of the test reflex when the cortical shock was given 4 ms after the test H reflex. On the contrary, reciprocal inhibition was reduced by electrical cortical conditioning when the scalp stimulation was applied 2-3 ms after the test stimulus. Magnetic transcranial stimulation induced an increase of H reflex amplitude when the test shock was administered 5 and 2 ms prior to the scalp shock; it did not modify the degree of reciprocal inhibition. The experimental findings could be considered the electrophysiological manifestation of a differential cortico-spinal control on the pathway alpha motoneurone/IA interneurone. Considerations on the delay allow the hypothesis of a further synapse between the cortico-spinal ending and the IA interneurone. Discrepancies with magnetic conditioning might be ascribed to a preferential transsynaptic action of magnetic mode of neural activation. PMID- 8695047 TI - In vivo formation of diazepam-like 1,4-benzodiazepines by Penicillium verrucosum var. verrucosum after administration of 2-aminobenzophenones and glycine. AB - The in vivo formation of the diazepam-like 1,4-benzodiazepine deschloronordiazepam from its assumed biogenetic precursors, 2-amino-benzophenone and glycine, by the mould strain Penicillium verrucosum var. verrucosum, is described. Deschloronordiazepam formation was established by GC/MSD analysis monitoring characteristic fragment patterns of the benzodiazepine moiety. The identification of deschloronordiazepam was confirmed by feeding experiments of D5 2-aminobenzophenone, as well as its brominated and chlorinated derivatives to the mould. The formation of the 1,4-benzodiazepine was observed to depend on various factors, e.g. the time of application of the precursors, duration of the incubation and kind of cultivation. The results represent the first actual de novo synthesis of such diazepam-like 1,4-benzodiazepines from plausible biosynthetic precursors in a living organism, in agreement with a biosynthetic concept recently established in our group. Such pharmacologically active 1,4 benzodiazepines had been detected in trace amounts in mammalian and plant tissues. Because of their unusual molecular framework, they had previously been considered not to fit into any conventional biosynthetic route. PMID- 8695048 TI - Urethane reduces contraction to 5-hydroxytryptamine (5-HT) and enhances the action of the 5-HT antagonist ketanserin on the rat thoracic aortic ring. AB - The general anesthetic urethane (ethyl carbamate) is widely used in electrophysiological in vivo experiments. However, its pharmacological effects are poorly understood. Here, the effects of urethane on in vitro contractile responses of the rat thoracic aortic ring preparation were investigated. Bath application of 5-HT produced a concentration-dependent contractile response (EC50 = 4.3 x 10(-6) M). Urethane (11.2 mM = 1 mg/ml) shifted the concentration response curve (CRC) for 5-HT to the right (EC50 = 1.7 x 10(-5) M) and decreased the maximal contraction by 30.8%. The CRC for NA (EC50 = 7.2 X 10(-9)M) was also shifted to the right by urethane (EC50 = 1.4 X 10(-8)M), but the shift of the 5 HT-CRC was twice that of the NA-CRC (3.95 vs. 1.95). The CRC to KCl was shifted rightwards only slightly by urethane (ratio 1.27) and the maximal contraction to KCl was not affected. The CRC to replacement of CaCl2 (0.1-10 mM) to KCl depolarized vessels in a Ca(2+)-free Krebs solution was unaffected by urethane. Ketanserin (10(-9)M) antagonized the contraction to 5-HT, and a combination of ketanserin and urethane was markedly more effective than either drug alone, decreasing the maximal contraction by 58%. Antagonism of NA contraction by prazosin (5 X 10(-8)M) was not increased by addition of urethane. The urethane dose used here approximates blood and brain concentrations required to produce anesthetic effects in mammals. It is possible that reductions in 5-HT transmission and, to a lesser extent, in NA transmission, but not blockade of Ca2+ or K+ channels, may contribute to the anesthetic effect of urethane. In addition, the action of the selective 5-HT2 antagonist ketanserin is clearly altered by urethane. These findings are important to consider when urethane is used for in vivo neurophysiological investigations, particularly when 5-HT mechanisms are involved. PMID- 8695049 TI - Influence of age on the GH response to sumatriptan administration in man. AB - The present study was undertaken in order to assess the influence of aging on the serotonergic control of GH secretion in humans. For this purpose, 6 mg 5-HT1D serotonergic receptor agonist sumatriptan (or placebo during control tests) was injected subcutaneously in a group of 9 young (26-40 yr old) and a group of 9 elderly male subjects (64-80 yr old). Sumatriptan-induced plasma GH rise was recorded during the next 2 hours. Plasma ACTH levels were also measured. The administration of the placebo was without effects in all subjects. Sumatriptan induced a striking increase in plasma GH levels in the younger group, whereas it slightly increased GH secretion in the older group (f = 9.59, p < 0.02). Plasma ACTH levels showed a similar physiological decline in all subjects during tests, regardless of sumatriptan treatment. These data show impaired serotonergic stimulatory regulation of GH secretion in elderly subjects. PMID- 8695050 TI - Effects of localized histamine microinjections into the hippocampal formation on the retrieval of a one-way active avoidance response in rats. AB - The possible role of histamine (HA) locally applied into the hippocampus on memory mechanisms of the rats was studied. The acquisition of a one-way active avoidance response to an ultrasonic 40 kHz sinus-wave tone anticipating an electric shock was used as experimental model. Learning sessions consisted in placing animals into a two compartment cage were they learnt to escape to the safe compartment after an ultrasonic tone anticipating an electric feet shock. After acquiring the conditioned avoidance response, animals were implanted with microinjection cannulae and injected with 1 microliter of saline, or increasing doses of histamine (9, 22.5, 45, and 90 nmol) into the hippocampus. In the experimental sessions, 4 trials before (PRE) and 4 trials afterward treatment (POST), the percentage of conditioned avoidance responses (% CAR) and the latency time to escape (LT) were measured. Results showed that HA increased significantly the LT and this effect was grossly dose-dependent. % CAR was also affected and the score was significantly inhibited by the imidazolamine administration. Results suggest that HA may be involved in memory retrieval processes in the hippocampus. PMID- 8695051 TI - Sex differences in conflict behaviour and in plasma corticosterone levels. AB - The levels of plasma corticosterone and conflict behaviour were followed in male and female water deprived Wistar rats exposed to the punished (0.2 or 0.8 mA) drinking test. The unpunished drinking, performed under familiar or unfamiliar conditions, and plasma corticosterone levels of these male and female rats were determined. Plasma corticosterone was elevated in water-deprived rats compared to rats under normal conditions. In all cases plasma corticosterone levels were considerably higher in water deprived females than in males. The highest levels in both sexes were obtained following drinking punished with 0.8 mA shocks. While the unpunished drinking did not differ between the two sexes, the punished drinking was significantly lower in females than in males. Although female rats displayed less punished licks and had higher plasma corticosterone levels than males, there was no correlation between the two parameters. PMID- 8695052 TI - Effects of ACTH and ACTH 4-10 on aversive memory retrieval in rats. AB - The aim of the study was to examine whether ACTH and ACTH-fragment 4-10, given before the test would produce a selectively enhanced retrieval of aversive memories, in the same way as preexposure to inescapable footshocks, in rats. For this purpose animals conditioned in a T-maze with appetitive (10% sucrose) and aversive (2.0 mA footshock) events were administered (s.c.) a single dose of 10, 20 or 40 ug/rat of ACTH or 5, 10 or 20 ug/rat of ACTH-fragment 4-10, 20-min before testing. The retention test conducted in the same training apparatus 72 hrs after conditioning showed a dose-dependent increase in latencies to enter the previously shocked goalarm with the absence of such a difference in responding to the nonshocked goalarm, in ACTH and ACTH 4-10 treated groups. This differential response was not observed in saline treated rats. This effect of peptides on memory retrieval was similar to that seen following inescapable footshock in rats. The results suggest the possible involvement of ACTH in the differential enhancement of memory of helplessness condition. PMID- 8695053 TI - Long-term treatment with haloperidol or clozapine does not affect dopamine D4 receptors in rat frontal cortex. AB - We examined the effects of long-term treatment with haloperidol and clozapine on dopamine D4 receptors in rat frontal cortex. Dopamine D4 receptor binding sites were indirectly determined from the displacement experiments of [3H]clozapine binding using nemonapride. Three-weeks administration of haloperidol (0.5 mg/kg) or clozapine (10 mg/kg) did not significantly affect the D4 receptors in the frontal cortex. The density of D2 receptors, determined by [3H]spiperone binding to striatum, was increased by long-term treatment with haloperidol, but it was not significantly changed by that with clozapine. PMID- 8695055 TI - Effects of dopamine D3 preferring compounds on conditioned place preference and intracranial self-stimulation in the rat. AB - Compounds showing an in vitro binding preference for the dopamine D3 receptor were tested in two models designed to assess positive reinforcement in the rat: intracranial self-stimulation (ICSS) and conditioned place preference (CPP). R (+)-7-OH-DPAT, a D3 preferring agonist, inhibited ICSS behaviour over a wide dose range. At higher doses, a facilitation of ICSS was seen. In the CPP model, 7-OH DPAT was inactive except at the highest dose where a significant change in preference was seen. A dose of R-(+)-7-OH-DPAT, that significantly inhibited ICSS behaviour, was combined with a dose of d-amphetamine, that significantly facilitated ICSS behaviour. Surprisingly, this resulted in a significant synergistic facilitation of the amphetamine response. The putative D3 antagonist, U99194A was inactive in the ICSS model but induced significant place preference. The present results suggest that the dopamine D3 receptor, in contrast to the D2 receptor, has an inhibitory influence on reward mechanisms. PMID- 8695057 TI - Characterization of [3H]clozapine binding sites in rat brain. AB - We examined the characteristics of [3H]clozapine binding sites in four rat brain regions (frontal cortex, limbic area, hippocampus and striatum) in order to elucidate the pharmacological profile of this unique atypical antipsychotic drug. The specific [3H]clozapine binding was found to be saturable and reversible in all these brain regions. Scatchard analysis of the saturation data indicated that the specific binding consisted of high- and low-affinity components. Displacement experiments showed that the muscarinic cholinergic receptor represented about 50% of [3H]clozapine binding in each brain area. Serotonin 5-HT2 and dopamine D4 receptor binding sites could also be detected by displacement experiments using ketanserin and nemonapride, respectively, in frontal cortex and limbic area, but not in hippocampus or striatum. Alpha-1, alpha-2, histamine H1, dopamine D1, D2, or D3 receptor components could not be determined within the high-affinity [3H]clozapine binding sites in any brain region. It is possible that the atypical property of clozapine may depend on the modulatory effect on dopaminergic function via 5-HT2 receptor blockade and/or may be mediated via D4 receptor blockade in the mesocortical and mesolimbic area. PMID- 8695056 TI - Drug-induced oral dyskinesias in rats after traditional and new neuroleptics. AB - Tardive dyskinesia (TD) is a serious human side effect of neuroleptic treatment in psychotic disorders. Although the etiology is clear (i.e. chronic neuroleptic drugs), its pathophysiology has not yet been satisfactorily explained. This is important not only theoretically but also to inform drug development, allowing the introduction of antipsychotic compounds without TD liability. The development of an animal condition which putatively models these delayed onset dyskinesias, has provided a technique to differentiate between neuroleptic drug effect and dyskinesia correlates. We report here the development of oral dyskinesias in rats in response to a number of different neuroleptics, which have a range of neurochemical and clinical characteristics. Traditional neuroleptics (e.g. haloperidol) produced rat oral dyskinesias, in an open-cage environment. Clozapine, while it produced an increased rate of oral movements, showed a significantly decreased potency in this model. SCH23390 (D1 antagonist) neither produced the oral movements nor modified their onset by coadministration with raclopride. These data replicate and extend other similar studies in the literature. They suggest that clozapine differs from traditional neuroleptics with respect to motor side effects. PMID- 8695054 TI - Isolation of a full-length cDNA clone for human GTP cyclohydrolase I type 1 from pheochromocytoma. AB - Although the existence of three different cDNA forms of human GTP cyclohydrolase I (GCH I) have been reported (Togari et al., 1992), the full-length sequence of any human GCH I cDNA involving poly (A) tail has not yet been documented. In the present study, we first isolated a full-length cDNA clone encoding human GCH I type 1 from human pheochromocytoma cDNA library. The length of the cDNA insert was 2,921 base pairs including poly (A) tail. RNA blot analysis showed a single mRNA species of 4.0 kb in human pheochromocytoma tissue. PMID- 8695060 TI - SPECT imaging of dopamine receptors with [123I]epidepride: characterization of uptake in the human brain. AB - [123I]Epidepride is a new ligand for single photon emission computerized tomography (SPECT) that specifically labels D2-like dopamine receptors with very high affinity. Here, we report on the regional kinetic uptake of [123I]epidepride in the brain of 4 normal volunteers and 3 patients with choreatic movement disorders. In healthy subjects striatal activity peaked at 2.5 hours after injection of the tracer and decreased slowly thereafter. There were no significant differences between left and right brain hemispheres. Activity above background was also measurable in areas corresponding to the thalamus, temporal cortex and frontal cortex. The striatal to cerebellar ratio was about 14 after 2.5 hours and this ratio steadily increased with time. The striatal to cerebellar ratio was clearly reduced in all 3 patients with choreatic movement disorders (from about 14 in control subjects after 2.5 hours to about 7 in choreatic patients). [123I]Epidepride may be a useful SPECT ligand for studying D2 receptors in the living human brain because of its high target to background ratio, its high affinity and the possibility to investigate extrastriatal D2 receptors. PMID- 8695059 TI - Effect of aging on lazabemide binding, monoamine oxidase activity and monoamine metabolites in human frontal cortex. AB - Age-related modifications of monoamine oxidase-A and -B (MAO-A and MAO-B) and amine metabolite concentrations were studied in human frontal cortex taken postmortem from 22 subjects of various ages (21-75 years). Qualitative and quantitative analysis for MAO-B was provided by kinetic studies with a specific radioligand, [3H]lazabemide. The data demonstrated a significant (P < 0.05) positive correlation between the density of [3H]lazabemide binding sites (Bmax) and age of the subject, without showing an apparent modification in the dissociation constant (KD) of the radioligand. In parallel experiments, MAO-B but not MAO-A activity was shown to correlate with age (P < 0.05). The concentrations of the amine metabolites 4-hydroxy-3-methoxyphenylacetic acid (HVA), 5 hydroxyindole-3-acetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), 4 hydroxy-3-methoxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG) were all devoid of a correlation with age. Neither did the concentrations of these metabolites relate to the respective subject's MAO-B enzymatic activity nor to [3H]lazabemide Bmax. A correlation, though rather weak, was obtained between MAO A activity and MHPG concentration (P = 0.045). The MAO-A and -B enzyme characteristics in subjects who had committed suicide (n = 9) did not differ from those of subjects deceased for other causes (n = 13). Among the measured monoamine metabolites the concentrations of DOPAC and HVA were higher in the suicide versus control group (P < 0.05). The present data confirm in a direct manner that the increase in MAO-B activity in aging brain is due to an enhancement of the number of active sites of the enzyme and not through modifications of its kinetic characteristics. Furthermore, that neither the characteristics nor the activity of the enzyme are changed in the frontal cortex of suicide victims compared to control subjects. PMID- 8695062 TI - Transfructosylating enzyme activity of Penicillium roquefortii. AB - The blue cheese mold, Penicillium roquefortii NRRL 844, was found to produce a transfructosylating enzyme that exhibited optimal activity at 50 degrees C in the pH range of 5.0-6.0. The enzyme rapidly catalysed the conversion of sucrose to a syrup containing nearly 60% fructo-oligosaccharides of the total sugars present. PMID- 8695061 TI - The survival benefit of short-chain organic acids and the inducible arginine and lysine decarboxylase genes for Escherichia coli. AB - The short-chain organic acids (SCOAs), acetic and propionic acids, are used widely as food preservatives. The production of these two acids plus butyric acid in the colon by anaerobes serves as a mechanism for controlling the numbers of enterobacteria (which can be pathogens) in this organ. It has been found in this study that the acid tolerance of cells initially grown at near neutral pH (6.5) to a lethal pH of 3.5 is enhanced by their exposure to 0.1% propionate or butyrate. The data also indicate that the inducible arginine and lysine decarboxylases are important for the survival of Escherichia coli exposed to a combination of mildly acidic pH (5.5) and 0.5% butyrate. This study suggests that the presence of SCOAs could trigger an adaptive survival response which may be important in the survival of food-borne pathogens. PMID- 8695063 TI - Presence of STA gene sequences in brewer's yeast genome. AB - STA genes are responsible for producing extracellular glucoamylase enzymes in Saccharomyces cerevisiae var. diastaticus. These genes exist in three forms, which are located on three different chromosomes. The nucleotide sequences of the STA genes are highly homologous. A sporulation-specific glucoamylase gene called SGA1 exists in every Saccharomyces cerevisiae strain, this also having a partly homologous DNA sequence with the STA genes. In this study S. cerevisiae var. diastaticus and brewer's yeast strains were characterized by pulsed-field gel electrophoresis. In many cases chromosome length polymorphism (CLP) was found. The chromosomes were hybridized with a DNA probe which was homologous with STA genes and the SGA1 gene. Presence of the SGA1 gene was detected in each strain used. Four brewing yeasts were found to have homologous sequences with the STA3 gene on chromosome XIV despite the fact that these strains were not able to produce extracellular glucoamylase enzyme. PMID- 8695064 TI - Effect of short-chain fatty acids on the size of enteric bacteria. AB - The size of Escherichia coli and Salmonella enteritidis PT4 cells was measured using both transmission electron micrographs and image analysis. Incubation in the presence of formic and propionic acids resulted in larger cells, possibly as a result of DNA inhibition, with no apparent damage to the cell membranes. Bacteria incubated with propionic acid were more resistant to shrinkage after fixation, possibly as a result of altered phospholipid and fatty acid composition. PMID- 8695065 TI - Purification and N-terminal amino acid sequence of Enterocin CRL 35, a 'pediocin like' bacteriocin produced by Enterococcus faecium CRL 35. AB - Enterocin CRL 35, a bacteriocin produced by Enterococcus faecium CRL 35 that inhibits food-borne pathogens, was purified by precipitation with (NH4)2SO4, gel filtration, ion exchange and reverse phase chromatography. The partial N-terminal amino acid sequence indicated a strong homology with other 'pediocin-like bacteriocins' previously described. PMID- 8695058 TI - Short and long-term changes in cerebral [14C]-2-deoxyglucose uptake in the MPTP treated marmoset: relationship to locomotor activity. AB - The "short-term" (0.7 +/- 0.1 months post-MPTP) and "long-term" effects (36.7 +/- 4.4 months) of MPTP treatment on motor behaviour and [14C]-2DG uptake were investigated in the common marmoset. The subcutaneous administration of MPTP greatly reduced locomotor activity (-94% with respect to controls) and induced motor disability in the "short-term" MPTP-treated marmoset group. In the "long term" MPTP group, MPTP treatment did not significantly affect locomotor activity (-27% with respect to controls) and there was partial recovery of motor disability. In the "short-term" MPTP group, there were increases in [14C]-2DG uptake in the GPl (+31 to +37%), SNc (+34 to +42%), VTA (+35%), LC (+23%), PPN (+19%) and in the VA (+19%), VL (+20%) and AM (+17%) thalamic nuclei. [14C]-2DG uptake was decreased in the STN (-15%). In the "long-term" MPTP group, [14C]-2DG uptake was increased in the GPl (+18%), SNc (+27%), VTA (+25%), PPN (+19%), ventral caudate nucleus (+18 to +23%), NAc (+22%), F.Ctx (+18%) and in the VA (+34%), VL (+28%), AV (+33%) and AM (+24%) thalamic nuclei. [14C]-2DG uptake was unchanged in the STN. The increase in metabolic activity of the surviving DA neurones and/or the reactive gliosis may account for the initial increase in [14C]-2DG uptake in the SNc and VTA. On the other hand, in the "long-term" MPTP treated animals the increase in [14C]-2DG uptake in the SNc (though less than in the "short-term" MPTP group), ventral caudate and NAc may reflect the regenerative changes in the dopaminergic system in these areas. Despite the behavioural recovery, [14C]-2DG uptake remained elevated in the target areas for medial pallidal output (the thalamic nuclei and PPN). However, the attenuation of the changes in [14C]-2DG uptake in the GPl and STN of "long-term" MPTP-treated marmosets suggest that the striato-GPl and GPl-STN outputs closely reflect motor function in this primate model of Parkinson's disease. PMID- 8695067 TI - Thermal inactivation of Listeria monocytogenes during rapid and slow heating in sous vide cooked beef. AB - Heating at slowly rising temperatures is suspected to enhance thermotolerance in Listeria monocytogenes and, since anaerobic environments have been shown to facilitate resuscitation of heat-injured cells of this micro-organism, concern may arise about the possibility of L. monocytogenes surviving in minimally preserved products. The effect of rapid ( > 10 degrees C min-1) and slow (0.3 and 0.6 degrees C min-1) heating on survival of L. monocytogenes in sous vide cooked beef was therefore examined at mild processing temperatures of 56 degrees, 60 degrees and 64 degrees C. No statistically significant difference (P = 0.70) was observed between the tested heating regimes. Since the average pH of beef was low (5.6), and little or no effect was observed, a pH-dependency of heat shock induced thermotolerance in L. monocytogenes is suggested to account for this result. PMID- 8695069 TI - The effect of nisin on Listeria monocytogenes in culture medium and long-life cottage cheese. AB - The sensitivity to nisin of 27 strains of Listeria monocytogenes, four of L. innocua and one of L. ivanovii was estimated at pH 6.8 and pH 5.5. Strains of L. monocytogenes showed differences in sensitivity which were not correlated with serotype. Strains of L. innocua were as resistant as the most resistant strains of L. monocytogenes, whereas the strain of L. ivanovii was relatively sensitive. Two of the most resistant strains of L. monocytogenes multiplied in aerated liquid medium adjusted to pH 5.0 with HCl, incubated at 20 degrees C; nisin, 500 IU ml-1, prevented multiplication and caused death. Following inoculation of a resistant strain into long-life cottage cheese, pH 4.6-4.7, the number of viable L. monocytogenes decreased approximately 10-fold during storage at 20 degrees C for 7 d; addition of nisin, 2000 IU g-1, to the cottage cheese increased the rate of inactivation to approximately a 1000-fold decrease in 3 d. PMID- 8695066 TI - Salivacin 140, a novel bacteriocin from Lactobacillus salivarius subsp. salicinius T140 active against pathogenic bacteria. AB - Fifteen of 353 environmental isolates of lactic acid bacteria consistently showed activity against Listeria monocytogenes, Streptococcus mutans, Actinomyces viscosus, and/or Propionibacterium acnes. Strain T140, isolated from the surface of Japanese pampas grass leaves and identified as Lactobacillus salivarius subsp. salicinius, also had activity against several Lactobacillus species, Staphylococcus aureus and Yersinia enterocolitica. Since the antagonistic factor(s) produced by T140 was sensitive to a proteolytic enzyme, it was concluded that a bacteriocin (named salivacin 140) was involved in the inhibition activity. Strain T140 required a high initial pH (7.5-8.5) in agar plates for bacteriocin production. PMID- 8695070 TI - Comparison of the adherence of three Lactobacillus strains to Caco-2 and Int-407 human intestinal cell lines. AB - Adhesion of three Lactobacillus strains onto human epithelial intestinal Caco-2 and Int-407 cell lines was compared. More adhesion occurred onto Int-407. The trypsin and sodium periodate pretreatment of bacteria revealed different mechanisms of adhesion depending on the Caco-2 and Int-407, involving carbohydrates and proteins. The absence of adherence for one Lactobacillus strain onto both cell lines indicated the specificity of the adhesion. Electron microscopic observations showed that bacteria adhered by underlying the brush border microvilli of the Caco-2 surface contrasting onto the Int-407 which entrapped and surrounded them by fimbrial extracellular cell matrix material. PMID- 8695071 TI - Confirmation and identification of Listeria spp. AB - All confirmation and identification methods used in this study can be used for the screening of suspected colonies on isolation media for Listeria spp. In traditional enrichment procedures the Microscreen Listeria latex test gives fast results. The DNA probes (Accuprobe and Gene-Trak) are very specific in detecting Listeria monocytogenes. For identification of Listeria spp. both tests (API and Micro-ID) performed equally well. Preference may be given to the API test, since differentiation of L. monocytogenes from L. innocua is based on the absence of arylamidase, through which tests for haemolytic activity and/or CAMP reactions can be omitted. However, the use of Enhanced Haemolysis Agar as isolation medium makes further testing essentially superfluous, since L. monocytogenes strains can be differentiated from L. innocua. PMID- 8695068 TI - Regulatory aspects of alkali tolerance induction in Escherichia coli. AB - Escherichia coli shifted from external pH (pH(O)) 7.0 to pH(O) 8.5-9.5 rapidly becomes tolerant to pH(O) 10.0-11.5, induction of tolerance (alkali habituation) being dependent on periplasmic or external alkalinization with either NaOH or KOH. Induction needs protein synthesis and makes organisms resistant to DNA damage by alkali and better able to repair any damage that occurs. Induction of tolerance was reduced by glucose (not reversed by cAMP) and by amiloride, was dependent on DNA gyrase and was abolished by fur and himA lesions (the latter suggests IHF involvement). Tolerance induction was not prevented by L-leucine, FeCl3 or FeSO4 nor by hns or relA mutations. Habituation probably involves attachment of IHF upstream of the promoter leading to DNA bending which switches on transcription. Habituation is aberrant in nhaA mutants, so ability to resist alkali damage may only arise if NhaA is induced, with extrusion of Na+ by this antiporter during alkali challenge. In accord with one tolerance component involving NhaA induction, beta-galactosidase formation from nhaA-lacZ fusions at pH(O) 9.0 was inhibited by glucose and amiloride. PMID- 8695072 TI - The name of the game. PMID- 8695074 TI - An electrocardiographic lead system for coronary artery bypass surgery. AB - STUDY OBJECTIVES: To identify the optimal subset of two electrocardiographic (ECG) leads for monitoring of ischemic ST depression and elevation during coronary artery bypass grafting (CABG) surgery. DESIGN: Prospective observational clinical study. SETTING: University hospital cardiac surgery operating room. PATIENTS: 120 patients undergoing primary surgery or reoperation for CABG. INTERVENTIONS: All six ECG limb leads and a precordial matrix of four leads were recorded intraoperatively approximately every 3 minutes. The limb leads were placed on the torso in modified Mason-Likar positions. The precordial leads were placed at V4, V5, and one interspace below them. MEASUREMENTS AND MAIN RESULTS: New ischemic 1 mm ST depression and elevation episodes were determined. New ST deviation episodes attributed to nonischemic causes such as cooling at the onset of cardiopulmonary bypass (CPB), defibrillation at the end of CPB, new cardiac conduction changes after CPB, and postoperative pericarditis were excluded. Fixed ST deviation that did not change by 1 mm in the perioperative period was also excluded. Leads V5 and III constituted the best two-lead set. These leads recorded 15 of the 16 ischemic ST elevation episodes and all 8 ischemic ST depression episodes. One ST elevation episode was not recorded intraoperatively but was recorded in lead V1 in the immediate postoperative ECG. Leads V5 and II recorded 13 of the 16 ischemic ST elevation episodes and all 8 ischemic ST depression episodes. Lead V5 alone missed 8 episodes of ischemic ST elevation and one episode of ischemic ST depression. CONCLUSIONS: For monitoring of ischemia during CABG, leads V5 and III are preferable to other two-lead sets, including the commonly used V5 and II. No single lead is adequate. Lead V5 alone missed approximately one half the episodes of ST elevation that were recorded by lead III or another inferior lead. PMID- 8695073 TI - The pharmacokinetics of oxycodone in uremic patients undergoing renal transplantation. AB - STUDY OBJECTIVE: To determine the pharmacokinetics of oxycodone and the excretion of oxycodone and its metabolites noroxycodone and oxymorphone in uremic patients undergoing renal transplantation. DESIGN: Open study of the pharmacokinetics and excretion of oxycodone. SETTING: IV Department of Surgery, Helsinki University Central Hospital. PATIENTS: 10 uremic patients undergoing renal transplantation and 10 ASA status I patients undergoing general surgery. INTERVENTIONS: Intravenous (IV) oxycodone chloride 0.07 mg/kg was administered 30 minutes before induction of standardized anesthesia. Sampling of blood and urine was conducted for 24 hours. MEASUREMENTS AND MAIN RESULTS: The concentrations of oxycodone and noroxycodone in plasma and the 24 hour urine recoveries of the conjugated and unconjugated forms of oxycodone, noroxycodone, and oxymorphone were measured. Mean elimination half-life was prolonged in uremic patients due to increased volume of distribution and reduced clearance. Interindividual variation was very great. Plasma concentrations of noroxycodone were higher in uremic patients. Significantly smaller quantities of free oxycodone and noroxycodone and both free and conjugated oxymorphone were excreted in the urine in the uremic than in the control patients. CONCLUSIONS: Elimination of oxycodone is impaired in end-stage renal failure. PMID- 8695076 TI - A comparison of alfentanil, esmolol, lidocaine, and thiopental sodium on the hemodynamic response to insertion of headrest skull pins. AB - STUDY OBJECTIVES: To compare the effects of four techniques for preventing or blunting the hypertensive response to the insertion of Mayfield headrest skull pins: intravenous (IV) alfentanil (ALF), esmolol (ESM), thiopental sodium (TPL), and local anesthesia using plain lidocaine (Xylocaine; XYL). DESIGN: Randomized open study. PATIENTS: 40 adult patients undergoing intracranial or spinal surgery requiring the use of Mayfield headrest skull pins for head positioning and immobilization. INTERVENTIONS: 20 minutes after anesthetic induction, and 2 to 3 minutes prior to the insertion of headrest skull pins, one of three drugs was administered IV: ALF 10 mcg/kg, ESM 1 mg/kg, or TPL 1.5 mg/kg. The fourth drug, XYL, was administered by injection into the scalp. MEASUREMENTS AND MAIN RESULTS: Blood pressure and heart rate (HR) were recorded immediately prior to and after pin insertion with balanced general anesthesia, and at 30, 60, 120, and 180 second intervals after pin insertion. The measurements were compared with the immediate preinsertion values. In the ALF and XYL groups, there was no significant increase in mean arterial pressure (MAP) or HR for any of the measurement periods. MAP was elevated immediately on pin insertion and for up to 2 minutes in the TPL group, and for up to 3 minutes in the ESM group (p < 0.05). HR changes were seen in the TPL group for up to one minute (p < 0.05). Increases in systolic blood pressure were seen in the TPL and ESM groups for up to 3 minutes, and in diastolic blood pressure for up to 2 minutes (p < 0.05). No other significant changes were observed. CONCLUSIONS: IV ALF and local injection of XYL in the scalp prevent the hemodynamic response to the insertion of skull pins in anesthetized patients. Neither ESM nor TPL prevented the hypertensive response. Local anesthetic injection into the scalp requires coordination between the anesthesiologist and surgeon, it carries the risk of needle stick injury, and it must be repeated if the surgeon repositions the headrest. The rapid onset and short half-life of ALF, coupled with the absence of hemodynamic effects at the dose used, makes this drug an alternative to the use of XYL injection. PMID- 8695077 TI - Intraoperative EEG changes in relation to the surgical procedure during isoflurane-nitrous oxide anesthesia: hysterectomy versus mastectomy. AB - STUDY OBJECTIVES: To investigate topographical changes in electroencephalographic (EEG) frequencies and spectral power density in relation to different surgical procedures (abdominal hysterectomy versus mastectomy) during steady-state isoflurane-nitrous oxide (N2O) anesthesia. DESIGN: Prospective, nonrandomized, open study. SETTING: University hospital. PATIENTS: 34 ASA status I and II patients scheduled for elective abdominal hysterectomy or mastectomy. INTERVENTIONS: 12 patients were studied without surgery (Group I, control). 22 patients were studied for the first 14 minutes following skin incision during hysterectomy (Group 2, n = 11) or mastectomy (Group 3, n = 11). MEASUREMENTS AND MAIN RESULTS: Anesthesia was maintained with 0.6% isoflurane in 66% N2O in oxygen (O2). EEG was recorded via 17 channels followed by calculation of spectral power densities in selected frequency bands for each recording site. In addition, heart rate, mean arterial pressure (MAP), end-tidal carbon dioxide tensions, and isoflurane concentration were recorded. Total observation time was 20 minutes in all groups. At baseline, EEG variables were comparable in all groups. The EEG demonstrated slow wave activity superimposed with alpha waves. Start of surgery resulted in increases of slower waves and decreases in alpha activity. In both surgical groups, these EEG changes were most pronounced at frontal recording sites (p < 0.05) with differences in the frequency content. In Group 2 (hysterectomy), delta-activity became dominant, whereas in Group 3 (mastectomy), a shift to theta waves was observed. During surgery MAP was increased by 40% (Group 2; p < 0.05) and 21% (Group 3; p < 0.05), respectively. CONCLUSIONS: These results show that specific surgical procedures may induce EEG slow wave activity to a different degree. The EEG response varied in relation to the surgical procedure and/or the intensity of noxious stimulation. Mastectomy resulted in the appearance of theta activity whereas, during laparotomy, the EEG frequency content was shifted to delta waves. The topographical analysis indicates spatial inhomogeneities in the EEG responses with a dominance at frontal areas. From this findings, it may be concluded that the electrode montage used for intraoperative EEG recordings has to be carefully selected. PMID- 8695078 TI - Patient-controlled intranasal analgesia (PCINA) for the management of postoperative pain: a pilot study. AB - STUDY OBJECTIVE: To compare patient-controlled intranasal analgesia (PCINA) for post-operative pain management with ward-provided pain therapy. DESIGN: Randomized, prospective pilot study. SETTING: University medical center. PATIENTS: 20 ASA status I and II orthopedic patients. INTERVENTIONS: On the first postoperative day, 20 patients were randomized to receive either PCINA for 4 hours followed by 5 hours of ward-provided pain therapy (Group 1; n = 10) or ward provided pain therapy for 5 hours followed by 4 hours of PCINA (Group 2; n = 10). The PCINA device used permits self-administration up to a maximum 0.025 mg dose of fentanyl every 6 minutes. Pain intensity (101-point numerical rating scale) and vital signs, as well as possible side effects, were registered at 30-minute intervals. MEASUREMENTS AND MAIN RESULTS: Within 30 minutes after the start of PCINA, pain intensity had decreased significantly in both groups. At the 60, 150, 210, 240, 270, 390, 420, and 480 minute measuring points, there was a significant intergroup difference in pain intensity, the level being significantly lower in the PCINA period. The handling of the PCINA device presented no problem to any patient. The PCINA fentanyl requirement was 0.415 +/- 0.083 mg (Group 1) and 0.408 +/- 0.06 mg (Group 2), respectively (NS). The ward-provided pain therapy included pethidine, tramadol, metamizole, acetaminophen, codeine, and diclofenac alone or in combination. Patient satisfaction was greater with PCINA than with ward-provided pain therapy (p < 0.0005). CONCLUSIONS: PCINA provides an adequate, noninvasive mode of postoperative pain management. The PCINA device is easy to handle and offers new perspectives in the management of postoperative pain. PMID- 8695081 TI - Use of EMLA cream in the treatment of post-herpetic neuralgia. AB - EMLA cream is an acronym for eutectic mixture of local anesthetics. It contains lidocaine and prilocaine creams. A eutectic preparation, applied topically, penetrates into the dermis after an application period of 1 to 2 hours. This case report describes the successful treatment with EMLA cream of post-herpetic neuralgia, which was resistant to other modes of therapy, and briefly discusses the pharmacology of EMLA cream. PMID- 8695082 TI - Failed emergency transtracheal ventilation through a 14-gauge intravenous catheter. AB - We encountered two patients who could be neither ventilated nor intubated after induction of anesthesia. In both cases, transtracheal ventilation failed after emergent cricothyroid membrane puncture with a 14-gauge intravenous (i.v.) catheter. In the first case, two catheters placed in rapid succession kinked, preventing gas exchange. In the second case, absence of a plunger on the needle over-catheter assembly prevented confirmation of intratracheal placement. Both patients required emergent tracheal access by the surgeon. We suggest that transtracheal ventilation via standard i.v. catheters as a primary emergent rescue technique be reassessed. PMID- 8695083 TI - Controlling the hemodynamic response to laryngoscopy and endotracheal intubation. AB - The hemodynamic response to the stress of laryngoscopy and endotracheal intubation does not present a problem for most patients. However, patients with cardiovascular or cerebral disease may be at increased risk of morbidity and mortality from the tachycardia and hypertension resulting from this stress. These hemodynamic effects gained notice after the introduction and use of muscle relaxants, such as curare and succinylcholine, for endotracheal intubation at the time of anesthesia induction. A variety of anesthetic techniques and drugs are available to control the hemodynamic response to laryngoscopy and intubation. The method or drug of choice depends on many factors, including the urgency and length of surgery, choice of anesthetic technique, route of administration, medical condition of the patient, and individual preference. The possible solutions number as many as the medications and techniques available and depend on the individual patient and anesthesia care provider. This paper reviews these medications and techniques to guide the clinician in choosing the best methods. PMID- 8695085 TI - Potential for air embolism using Hotline Model HL90 fluid warmer. PMID- 8695087 TI - A pressurized rapid infusion system at no added cost. PMID- 8695086 TI - A more successful method for laryngeal mask airway insertion? PMID- 8695088 TI - Precise identification of the epidural space depth. PMID- 8695080 TI - Anesthesia with antiphospholipid antibodies: anesthetic management of a parturient with lupus anticoagulant and anticardiolipin antibody. AB - The anesthetic management of a parturient with a circulating lupus anticoagulant and an anticardiolipin antibody presenting to the obstetric suite taking heparin and aspirin is discussed. Issues concerning placement of a regional anesthetic with recent aspirin ingestion and heparin therapy are discussed. Documentation of heparin dissipation via a whole blood heparin concentration assay before induction of regional anesthesia, including several laboratory tests that could be used in monitoring coagulation status in this patient population, is discussed in detail. PMID- 8695075 TI - Effect of ketorolac on bleeding time and postoperative pain in children: a double blind, placebo-controlled comparison with meperidine. AB - STUDY OBJECTIVE: To determine whether ketorolac 0.75 mg/kg would provide a comparable degree of analgesia to that of meperidine 1 mg/kg in terms of postoperative opioid requirements and pain scores in children undergoing surgeries associated with mild to moderate postsurgical discomfort. DESIGN: Randomized, prospective, placebo-controlled, double-blinded study of the initial 6 postsurgical hours. SETTING: University affiliated teaching hospital. PATIENTS: 90 healthy ASA status I and II children scheduled for elective general, orthopedic, or genitourinary procedures associated with mild to moderate postsurgical pain. Extensive surgical procedures associated with a significant risk of bleeding were excluded. INTERVENTIONS: Ketorolac 0.75 mg/kg, meperidine 1 mg/kg, or placebo (normal saline) was administered intramuscularly (IM) at the beginning of surgery. MEASUREMENTS AND MAIN RESULTS: Bleeding times were measured prior to and 180 minutes after study drug administration. Time to first rescue medication, total opioid requirement, pain scores, incidence of vomiting and length of stay were evaluated. Placebo-treated patients were rescued earlier (p < 0.0001) and required twice the rescue dosage (p = 0.013) when compared with either the ketorolac or meperidine groups. The ketorolac and meperidine groups did not differ with regard to time until first rescue, cumulative proportion requiring rescue, or the number of rescue doses required. A single dose of IM ketorolac prolonged bleeding time by 53 +/- 75 seconds (p = 0.006). CONCLUSIONS: Ketorolac provided analgesia comparable to that of meperidine and significantly reduced opioid requirements. Since ketorolac was not associated with a reduction in postoperative vomiting or length of stay, and in view of the uncertain risk of bleeding, it offers no advantage over meperidine in the management of mild to moderate acute postsurgical pain. PMID- 8695084 TI - The Bullard laryngoscope and a "directional tip" RAE tube. PMID- 8695089 TI - Pressure support improves efficiency of spontaneous breathing during inhalation anesthesia. AB - STUDY OBJECTIVE: To determine if reducing respiratory muscle load or increasing tidal volume (VT) with pressure support (PS) would improve ventilatory efficiency by reducing respiratory rate (RR) and resting PaCO2. DESIGN: Prospective, and patient-controlled, with randomized treatment crossover. SETTING: University cancer center and research institute. PATIENTS: ASA status I and II patients scheduled to undergo inhalation anesthesia for operations in which neuromuscular relaxation is undesirable. INTERVENTIONS: Propofol and succinylcholine were used to induce anesthesia and facilitate tracheal intubation. General anesthesia was maintained with desflurane, nitrous oxide, and oxygen. Patients breathed spontaneously at atmospheric pressure for 15 minutes and then randomly received alternate 15-minute trials of PS adjusted to provide either 5 cmH2O or a level titrated to produce VT of 8 ml/kg body weight. Then patients breathed spontaneously at atmospheric pressure for 15 minutes. MEASUREMENTS AND MAIN RESULTS: In 20 patients aged 52 +/- 11 years and weighing 72 +/- 18 kg, airway gas flow and pressure, esophageal pressure, arterial blood gas tensions and pH, and mean arterial pressure (MAP) were measured. Heart rate (HR), VT, RR, minute ventilation (VE), carbon dioxide production (VCO2), ratio of dead space to VT (VD/VT), and inspiratory work of breathing (WI) were calculated. End-tidal desflurane (6.7 +/- 0.4%), VCO2 (142 +/- 39 ml/min), HR, and MAP were unchanged throughout the study. WI, RR, VE, VD/VT, and PaCO2 were reduced significantly when PS was titrated to produce a VT of 8 ml/kg and spontaneous breathing before and after PS trials (p < 0.05). CONCLUSIONS: PS titrated to produce a near normal VT improves the efficiency of spontaneous breathing by lowering RR and PaCO2 while preserving hemodynamic homeostasis in patients undergoing inhalation anesthesia. Lesser PS levels will unload the respiratory muscles, but have no effect on RR or PaCO2. PMID- 8695091 TI - Can nitrous oxide be administered effectively by nasal cannula? A preliminary report. AB - STUDY OBJECTIVE: To predict the inspired concentrations achieved when nitrous oxide (N2O)/oxygen mixtures are administered to patients by way of a nasal cannula. DESIGN: The method used for estimating the FiN2O is based on one employed to calculate the FiO2 obtained with a nasal cannula. We assume a tidal volume of 500 ml, a respiratory rate of 20 breaths per minute, an inspiratory time of 1 second, an expiratory time of 2 seconds, and an anatomic reservoir volume of 50 ml. The reservoir consists of the nose, the nasopharynx, and the oropharynx. Its volume is assumed to be one-third of the anatomic dead space. It is also assumed that during the last 0.5 second of expiration, there is negligible flow of expired respiratory gases. A 6 L/min flow from the cannula will completely fill the reservoir. The FiO2 or FiN2O is then calculated by assuming that during the 1 second inspiratory time period, the gases in the anatomic reservoir that are provided by the nasal cannula and a volume of air such that the sum of the components of the tidal volume equals 500 ml are inspired. SETTING: Research laboratory of a university-affiliated metropolitan medical center. MEASUREMENTS AND MAIN RESULTS: The calculated FiO2 values for 100% oxygen delivered by nasal cannula agree with those determined by others. The FiN2Os estimated were directly proportional to the cannula flow rate and the fraction of N2O delivered. At the maximum total flow rate considered, 6L/min flow, with 70% N2O (remainder O2) delivered to the nasal cannula, an FiN2O of only 0.21 was estimated due to the large volume of air inspired. The FiO2 under these conditions would only be 0.23. CONCLUSIONS: Our analysis shows that the maximum FiN2O achievable by using a nasal cannula is limited to 0.21 even with a 6 L/min flow of 70% N2O for the defined respiratory parameters. PMID- 8695093 TI - The effect of laparoscopic cholecystectomy on respiratory compliance as determined by continuous spirometry. AB - STUDY OBJECTIVE: To evaluate the effect of pneumoperitoneum on dynamic compliance during laparoscopic cholecystectomy with continuous spirometry. DESIGN: Prospective, open clinical study with the patients serving as their own controls. SETTING: Operating room at a university hospital. PATIENTS: 11 ASA status I and II patients scheduled for elective laparoscopic cholecystectomy. INTERVENTIONS: Pneumoperitoneum up to an intraabdominal pressure of 12 mmHg was created with carbon dioxide (CO2) insufflation. Thereafter, the patients were placed in a position combining a head-up tilt with a left side down lateral tilt, for dissection of the gallbladder. Steady levels of anesthesia and neuromuscular block, as well as a constant tidal volume of ventilation, were maintained throughout the procedure. MEASUREMENTS AND MAIN RESULTS: Airway pressures and respiratory volumes were continuously measured. Compliance was calculated by dividing expiratory tidal volume by end inspiratory pressure, and was displayed as a pressure-volume loop. After the creation of pneumoperitoneum, end inspiratory airway pressure increased by 40%, and compliance decreased by 30%. These levels remained unchanged during surgery with the patient in a head-up and left side down lateral tilt position. After release of intraabdominal pressure, inspiratory airway pressure and compliance returned to control levels. The pressure-volume loop sloped to the right and its horizontal diameter was elongated during pneumoperitoneum. The new configuration was maintained until the loop returned to the control shape after evacuation of the pneumoperitoneum. CONCLUSIONS: Increased intraabdominal pressure during laparoscopic cholecystectomy causes a significant, but fully reversible, decrease in dynamic compliance. On-line spirometry with a graphic display of the pressure-volume loop facilitates the immediate discovery of these alterations. PMID- 8695097 TI - Head turning in brain death. AB - Criteria for determination of brain death in adults have been defined. Spinal cord reflexes may persist after brain death. We present the case of a brain dead patient who had a complex spinal automatism resulting in head shaking and arm extension. The report reviews guidelines for the diagnosis of brain death and discusses complex spinal cord reflexes in brain dead patients. PMID- 8695096 TI - Quantitative improvement in laryngoscopic view by optimal external laryngeal manipulation. AB - STUDY OBJECTIVE: To determine the improvement in laryngoscopic view obtained using both the Macintosh and Miller blades by applying optimal external laryngeal manipulation (OELM). DESIGN: Prospective, with each patient serving as his or her own control. SETTING: Inpatient operating rooms of a University Medical Center. PATIENTS: 181 informed and consenting adult nonpregnant patients requiring general anesthesia and tracheal intubation. The only exclusion criteria was the need to apply cricoid pressure to prevent aspiration of gastric contents. INTERVENTIONS: Anesthetized, paralyzed patients underwent laryngoscopy without external laryngeal manipulation and the laryngoscopic view was graded ("A") according to visualized structures [1.0-1.9 = all (1.0) or part of the vocal cords (90% = 1.1 and 10% = 1.9); 2 = just the arytenoids; 3 = just the epiglottis; 4 = just the soft palate]. The larynx was then quickly manipulated by the thumb and index and middle fingers of the laryngoscopist's right hand in both cephalad and posterior directions over the hyoid, thyroid, and cricoid cartilages until it was determined which vector and spot produced the optimal laryngoscopic view ("B"). MEASUREMENTS AND MAIN RESULTS: It was found that in every patient with a "A" greater than 1.0, OELM improved the view; i.e., "B" decreased relative to "A." For both the Macintosh blade patients and Miller blade patients with an "A" equal to 2, "B" decreased by one whole laryngoscopic grade in all patients. For both the Macintosh and Miller blade patients with an "A" equal to 3, "B" decreased by at least one whole laryngoscopic grade in all patients and by two laryngoscopic grades in most patients. No patient had an "A" equal to 4. The distribution of optimal-external-laryngeal-manipulation (OELM) spots for all patients was 1%, 40%, 48%, and 11% for the hyoid, high thyroid, low thyroid, and cricoid cartilages, respectively, and the distribution was not significantly different for either the Macintosh and Miller blade groups or for the "A" and "B" subgroups (i.e., "A" < 1.9, = 2 or = 3). CONCLUSIONS: We conclude that OELM can improve the laryngoscopic view by at least one whole grade, that the best way to determine OELM for an individual patient is on an empirical basis by manipulation of the larynx with the laryngoscopist's right hand, and that OELM should be an instinctive and reflex response to any "A" of 2, 3, or 4. PMID- 8695079 TI - Cumulative reduction in serum cholinesterase following repeated therapeutic plasma exchange. AB - STUDY OBJECTIVE: To investigate the magnitude of serum cholinesterase reduction following repeated therapeutic plasma exchange in patients with neuromuscular disease. DESIGN: Serum cholinesterase activity was measured immediately before and after each plasma exchange in open-label fashion and then analyzed using an analysis of variance model. SETTING: Inpatient neurology and allergy and immunology clinics at a university-affiliated hospital. PATIENTS: 50 consecutive patients with neuromuscular disease. INTERVENTIONS: All patients underwent repeated therapeutic plasma exchange, with each subject receiving up to a maximum of six plasma exchanges. MEASUREMENTS AND MAIN RESULTS: Serum cholinesterase activity was determined spectrophotometrically. Analysis of variance revealed a significant reduction in serum cholinesterase following each therapeutic plasma exchange (p < 0.0001), a significant and consistent reduction across the six treatments (p < 0.0001), and a significant interaction between (before versus after exchange) and treatment number (p < 0.0001). Mean serum cholinesterase before repeated therapeutic plasma exchange was 4817 U/L, but it decreased to a mean of 929 U/L following six plasma exchanges. CONCLUSIONS: There is a significant reduction in serum cholinesterase following repeated therapeutic plasma exchange. It is suggested that drugs metabolized by serum cholinesterase (e.g., succinylcholine, mivacurium) be used with caution in the period immediately following repeated therapeutic plasma exchange. PMID- 8695098 TI - High-dose oral morphine in cancer pain management: a report of twelve cases. AB - We present 12 case reports from patients treated with more than 600 mg of morphine per day. We found no "opioid-nonresponsive pain" under treatment with a combination of morphine and nonopioids, supplemented with coanalgesics where appropriate. Side effects of morphine therapy were controlled with adjuvant drugs. Serious adverse effects were not observed. Episodes of break-through pain, dysphagia, and dyspnea caused by far advanced cancer disease were seen frequently. PMID- 8695095 TI - Desflurane is not associated with faster operating room exit times in outpatients. AB - STUDY OBJECTIVE: To determine the influence of anesthetic technique and primary drug on operating room (OR) exit time (time between end of surgery until time patient exists the OR) after addition of desflurane to the hospital formulary. DESIGN: Prospective study. SETTING: Ambulatory surgery unit of a university hospital. PATIENTS: 1,568 outpatients requiring anesthesia. INTERVENTIONS: Addition of desflurane to the hospital formulary, and substitution of desflurane vaporizers for enflurane vaporizers in the ambulatory surgery unit. MEASUREMENTS AND MAIN RESULTS: The following information was recorded for all anesthetic encounters over a six-month time interval: demographics, duration of surgery, primary anesthetic technique, primary anesthetic drug, and exit times. General anesthesia was used in 907 patients [desflurane: 209 patients, isoflurane: 429 patients, halothane: 192 patients, propofol: 72 patients, other intravenous (i.v.): 5 patients], major conduction anesthesia (spinal and epidural) in 43 patients, peripheral nerve blocks in 90 patients, and i.v. sedation in 528 patients. The exit time was significantly greater ( < 0.05) in patients who received general anesthesia (mean +/- SEM 14 +/- 0.2 min) compared with spinal/epidural (8 +/- 0.7 min), nerve blocks (8 +/- 0.4 min) and i.v. sedation (7 +/- 0.2 min). Exit times were longer in older patients receiving general anesthesia (exit time = 12.3 + 0.04 x age, SE = 6.7 min, p < 0.0009), whereas exit times were shorter in older individuals receiving i.v. sedation (exit time = 8.97 - 0.038 x age, SE = 3.6 min, p < 0.0001). For patients receiving i.v. sedation, exit times were shorter as duration of surgery increased (exit time = 7.86 - 0.015 x duration of surgery, SE = 3.6 min, p < 0.0002). Primary anesthetic drug did not affect exit times. CONCLUSION: Regional anesthesia and i.v. sedation were associated with faster OR exit times compared with general anesthesia. Despite desflurane's shorter elimination kinetics and recovery characteristics, use of this drug did not result in shorter exit times. PMID- 8695099 TI - Respiratory depression: an adverse outcome during patient controlled analgesia therapy. AB - Patient-controlled analgesia (PCA) is one of the more popular means of controlling postoperative pain. However, there is very little in the literature concerning the adverse outcome of respiratory depression in PCA. This report is a prospective study of 4,000 patients on PCA postoperatively. Nine of these patients experienced respiratory problems while on PCA. The respiratory depressions were associated with drug interactions, continuous narcotic infusion, nurse- or physician-controlled analgesia and inappropriate use of PCA by patients. This report identified the common precipitating factors in PCA associated respiratory depression and its prevention. PMID- 8695092 TI - Comparison of neuromuscular, cardiovascular, and histamine-releasing properties of doxacurium and pipecuronium. AB - STUDY OBJECTIVES: To determine the neuromuscular, cardiovascular, and histamine releasing properties of doxacurium and pipecuronium at three times effective ED95 doses (3XFD95). DESIGN: Prospective, randomized clinical trial of adult patients. SETTING: University teaching hospital. PATIENTS: 20 ASA status I and II adult patients. INTERVENTIONS: Subjects were anesthetized with thiopental sodium, fentanyl, and nitrous oxide and oxygen (N2O:O2). Plasma samples were taken preoperatively, after thiopental, and 2 and 5 minutes after doxacurium 75 micrograms/kg or pipecuronium 123 micrograms/kg were given for the determination of histamine levels. The ulnar nerve was stimulated via surface electrodes using train-of-four stimulation at 0.1 Hz. The force of contraction of adductor pollicis was recorded using a mechanomyograph. Recovery of the twitch response was followed and, if necessary, neuromuscular block was antagonized with neostigmine and glycopyrrolate. MEASUREMENTS AND MAIN RESULTS: Three patients in the doxacurrium group and one patient in the pipecuronium group exhibited a marked increase in plasma histamine levels. In both groups statistically significant changes were seen in heart rate (HR) measurements (p < 0.02). Doxacurium had a slower onset than pipecuronium [3.1 +/- 0.2 min vs. 1.8 +/- 0.1 min (p < 0.0003)] and a more rapid recovery [72 +/- 8 min vs. 123 +/- 9 min (p < 0.01)]. CONCLUSION: Neither drug caused a clinically significant change in HR or histamine release. In the doses chosen for this study, the rate of onset of block is slower with doxacurium while recovery is more rapid. Histamine release in three patients was caused by thiopental, while in a fourth patient it may have been due to doxacurium. PMID- 8695090 TI - Trimethaphan (Arfonad) control of hypertension and tachycardia during electroconvulsive therapy: a double-blind study. AB - STUDY OBJECTIVE: To ascertain the optimal dose of trimethaphan camsylate administered by intravenous (i.v.) bolus injection for the control of hypertension and tachycardia during electroconvulsive therapy (ECT). DESIGN: Prospective, double blind, within-subject study. SETTING: Treating room of the psychiatric unit of the University Hospital at Stony Brook, NY. SUBJECTS: Patients undergoing ECT for major psychiatric illnesses. MEASUREMENTS AND MAIN RESULTS: Fifteen ASA status I or II patients received in a random sequence placebo, or 5, 10, or 15 mg boluses of trimethaphan during their second to fifth treatments. Blood pressure (BP) and heart rate (HR) were recorded every 30 seconds by automated oscillometric recorder. Recordings taken before administration, during seizure, 5, and 20 minutes after seizure were examined. All doses ameliorated BP (systolic, diastolic, and mean), HR, and rate pressure product (RPP) increases during the seizure, compared with placebo. The group that received 15 mg exhibited smaller increases in RPP, i.e., 67.7% increase compared with 155.4%, 110.9%, and 98.7% increases for the placebo, 5, and 10 mg, respectively. The 10 mg and 15 mg doses caused a faster return to baseline than did the 5 mg dose or placebo. No rebound hypertension, prolonged hypotension, arrhythmias, or other side effects were noted. Trimethaphan did not alter seizure duration. CONCLUSIONS: Trimethaphan is safe, practical, and effective in the management of the hyperdynamic response to ECT. An i.v. bolus injection of 15 mg is more effective than 10 mg or 5 mg. PMID- 8695094 TI - Patient-controlled analgesia with sufentanil: a comparison of two different methods of administration. AB - STUDY OBJECTIVE: To examine the safety and analgesic efficacy of sufentanil administered via either epidural or intravenous (i.v.) patient-controlled analgesia (PCA) in patients recovering from gynecologic surgery. DESIGN: Randomized, double-blind comparison. SETTING: Patient care unit at a university medical center. PATIENTS: 29 healthy women presenting for major intraabdominal gynecologic surgery with epidural anesthesia who requested postoperative PCA. INTERVENTIONS: Following completion of surgery performed using epidural anesthesia with 2% lidocaine and i.v sedation, patients were assigned to one of three treatment groups: Group 1-epidural PCA (EPCA) with sufentanil: 0.3 microgram/kg bolus followed by 8 micrograms/hr infusion plus epidural PCA boluses of 4 micrograms every 6 min as needed; Group 2-i.v. PCA with sufentanil: 0.3 microgram/kg bolus followed by 8 micrograms/hr infusion plus IV PCA boluses of 4 micrograms every 6 min as needed; or Group 3-i.v. PCA with morphine: 0.1 mg/kg bolus followed by 0.5 mg/hr infusion plus i.v. PCA boluses of 1 mg every 6 min as needed. MEASUREMENTS AND MAIN RESULTS: Patients were observed at regular intervals during a 24-hour evaluation period. Visual analog scale (VAS) scores were used to assess analgesia and satisfaction with therapy. Pulmonary function was assessed by monitoring respiratory rate, oxygen (O2) saturation, and forced expiratory flow. Total opioid dose delivered and the presence/severity of side effects was also collected. Sufentanil plasma levels were measured in a subset of eight patients. Patients receiving either EPCA or i.v. PCA sufentanil experienced equivalent analgesia that was more rapid in onset than i.v. PCA morphine. Total dose administered and plasma concentration of drug were similar in both sufentanil groups; however, a greater number of patients in the i.v. delivery group experienced clinically significant O2 desaturation. CONCLUSIONS: The main advantage of EPCA sufentanil in this postsurgical setting was its ability to provide a more rapid onset of analgesia than traditional i.v. PCA with morphine while offering greater safety than i.v. sufentanil. PMID- 8695100 TI - Malignant hyperthermia during epidural anesthesia. AB - We anesthesized a patient susceptible to malignant hyperthermia (MH) three different times by epidural anesthesia with different types of local anesthetics. His skinned fiber test showed a marked acceleration of calcium (Ca2+)-induced Ca2+ release (CICR). When ester type local anesthetic was used for ankle contracture repair, MH signs appeared following the release of the tourniquet. CICR test is reliable for diagnosing different types of MH. PMID- 8695101 TI - Latex allergy in the operating room: case report and a brief review of the literature. AB - A patient with a history of spina bifida and cerebral palsy was anesthetized for an ileal conduit. The procedure was uneventful until penetration of the abdominal cavity, immediately after which the patient suffered severe hypotension and her peak inspiratory pressure doubled. The patient's skin became flushed and the capnogram tracing was consistent with bronchospasm. The patient was treated with phenylephrine hydrochloride (Neo-Synephrine), and then epinephrine. This was followed with an epinephrine infusion, intravenous (i.v.) methylprednisolone sodium succinate (Solu-Medrol), inhaled albuterol sulfate, and diphenhydramine hydrochloride (Benadryl) i.v.. The patient responded to these interventions and the procedure was completed without further incident. A diagnosis of latex allergy was made based on the patient's clinical status, underlying diseases, and positive postoperative radioallergosorbent test (RAST). Anesthesiologists must be able to diagnose the signs and symptoms of allergic reactions in patients under anesthesia. This article will review the types of hypersensitivity reactions involved, define the risk groups, and examine the treatment protocols available for latex allergy. PMID- 8695102 TI - Sudden postoperative death of a "recreational" drug user. PMID- 8695103 TI - Desflurane advantage? Lower solubility or improved vaporizer? PMID- 8695104 TI - A method to avoid accidental arterial placement of an introducer sheath. PMID- 8695106 TI - Airway sealing pressures of the laryngeal mask airway in pediatric patients. AB - STUDY OBJECTIVES: To determine if the laryngeal mask airway (LMA) seal is maintained during surgery, to evaluate the safety of an LMA leak test, and to determine the time course of the increase in LMA cuff pressure in vivo in the presence of nitrous oxide (N2O). STUDY DESIGN: Descriptive clinical study. SETTING: University teaching hospital. PATIENTS: 78 ASA Physical Status I and II pediatric patients, aged 3 months to 17 years, undergoing general anesthesia with an LMA; 14 patients were studied on two occasions approximately 2 months apart. INTERVENTIONS: The airway pressure at which the LMA seal was broken (leak pressure) was determined immediately following insertion of the LMA and at the end of surgery. In 17 patients, the LMA cuff pressure was continuously measured during surgery, during which 67% N2O was administered. The mean duration of surgery was 29.5 minutes. MEASUREMENTS AND MAIN RESULTS: The LMA leak pressure was determined by closing the circuit popoff valve and recording the pressure at which gas was first heard to escape around the LMA at the mouth. The LMA cuff pressure was determined by connecting the check valve of the LMA pilot balloon to a sphygmomanometer. The elastance of the LMA was determined from the slopes of the regression lines of pressure versus volume for the various sized LMAs in vitro (Sizes 1-4) and in vivo (sizes 2 and 2 1/2). The initial LMA leak pressure was 25.9 cm H2O, and it increased to 31.2 cm H2O during surgery (p < 0.001). 146 leak tests were performed without causing gastric dilatation or LMA dislodgement. The mean LMA cuff pressure increased during surgery from 106.2 mmHg to 132.8 mmHg (p < 0.001), a pressure increase that corresponds to a volume increase of 1.4 ml. CONCLUSIONS: The LMA leak test can be safely performed. The airway seal provided by the LMA is well maintained during surgery. The increase in LMA cuff pressure during surgery in the presence of N2O is small and probably is not a cause for clinical concern. If positive pressure is to applied in the presence of an LMA, one should limit this pressure to below the LMA leak pressure so as to lower the risk of inflating the stomach with gas that may than leak around the LMA. PMID- 8695105 TI - Bowel function recovery after radical hysterectomies: thoracic epidural bupivacaine-morphine versus intravenous patient-controlled analgesia with morphine: a pilot study. AB - STUDY OBJECTIVE: To determine if the use of continuous epidural bupivacaine morphine in the perioperative period is associated with a significant decrease in the recovery time of postoperative ileus when compared with parenteral morphine administration. DESIGN: Prospective (quality of analgesia) and retrospective (bowel function recovery), nonrandomized study. SETTING: Inpatient gynecology oncology patients at a university-affiliated tertiary cancer center hospital. PATIENTS: 68 women who experienced uncomplicated radical hysterectomies for cancer. INTERVENTIONS: Intraoperative epidural-general anesthesia or general anesthesia only was administered. Postoperative continuous epidural analgesia with bupivacaine-morphine and intravenous (IV) morphine via patient-controlled analgesia (PCA). Both forms of therapy were titrated to provide patients with a dynamic visual analog pain score of 5 or less on a 10-point scale throughout the study period. Patients were weaned from infusions when pain scores remained at less than 5 for 12 hours and no breakthrough medication was used. MEASUREMENTS AND MAIN RESULTS: Rest and dynamic pain scores, time of first flatus, length of nasogastric therapy, time to solid food intake, daily and total morphine requirements and length of hospitalization were recorded. The epidural group required fewer days of nasogastric therapy (4 +/- 3 versus 8 +/- 2 days, p = 0,0001), tolerated solid foods sooner (6 +/- 2 versus 11 +/- 3 days, p < 0.0001), and had a shorter hospitalization time (10 +/- 3 versus 14 +/- 4 days, p = 0.0001) when compared with the PCA group. CONCLUSIONS: The use of thoracic epidural bupivacaine-morphine results in a decrease in the duration of postoperative ileus, which was associated with earlier hospital discharge. PMID- 8695107 TI - Hemodynamic effects of intrathecal fentanyl in nonlaboring term parturients. AB - STUDY OBJECTIVE: To determine the effect of intrathecal fentanyl on maternal hemodynamics. DESIGN: Prospective. SETTING: Labor and delivery suite of a university medical center. PATIENTS: 23 ASA status I nonlaboring term parturients presenting for elective cesarean section. INTERVENTIONS: Patients were given either 1,200 ml lactated Ringer's Solution (Group 1, n = 12) or no intravenous (i.v.) fluid (Group 2, n = 11). A combined spinal-epidural technique was then performed. Fentanyl 25 micrograms was administered intrathecally through a 24 gauge Sprotte or 25-gauge Whitacre spinal needle. After completion of the hemodynamic study, a catheter was threaded into the epidural space for local anesthetic administration. MEASUREMENTS AND MAIN RESULTS: Baseline hemodynamic data [systolic (SBP), diastolic, and mean arterial pressure, heart rate, stroke volume, cardiac output, end-diastolic volume, and ejection fraction] were obtained in triplicate using noninvasive blood pressure monitoring and impedance cardiography. After administration of intrathecal fentanyl, hemodynamic measurements were recorded at 3-minute intervals for 30 minutes. These values were compared with baseline for both groups. Ten patients in each group completed the study. Intrathecal fentanyl administration did not result in any maternal hemodynamic changes in Group 1, and a few small statistically significant changes in Group 2. Measured SBP was always greater than 100 mmHg in all patients during the study. CONCLUSION: Intrathecal administration of fentanyl 25 micrograms in nonlaboring term parturients does not produce clinically important maternal hemodynamic changes. PMID- 8695108 TI - Target-controlled infusions: stress free anesthesia? PMID- 8695110 TI - Intravenous anesthesia and analgesia: what is the role of target-controlled infusion? PMID- 8695109 TI - Target-controlled infusion delivery systems: application outside the operating room. PMID- 8695111 TI - Implications of automation surprises in aviation for the future of total intravenous anesthesia (TIVA). PMID- 8695113 TI - Inhalation versus intravenous anesthesia: a fictitious debate between E.I. Eger II and P.F. White. PMID- 8695112 TI - An anesthetic-sensitive superfamily of neurotransmitter-gated ion channels. PMID- 8695114 TI - Receptor regulation: why should an anesthesiologist care? PMID- 8695115 TI - Pharmacodynamics as a research tool. PMID- 8695116 TI - Cardiopulmonary bypass and the central nervous system: potential for cerebral protection. PMID- 8695117 TI - Perioperative use of propofol for cardiac surgery. PMID- 8695118 TI - New advances in the pharmacologic approach to circulatory shock. PMID- 8695119 TI - Fast track in the postanesthesia care unit: unlimited possibilities? PMID- 8695120 TI - Patient-controlled intraoperative sedation. PMID- 8695121 TI - Monitored anesthesia care: how much sedation, how much analgesia? PMID- 8695122 TI - Intravenous drug delivery systems: toward an intravenous "vaporizer". PMID- 8695123 TI - The EEG as a monitor of sedation: encouraging progress. PMID- 8695124 TI - The pharmacokinetics and pharmacodynamics of remifentanil in volunteers with severe hepatic or renal dysfunction. PMID- 8695125 TI - Steroid anesthetics: old compounds, new drugs. PMID- 8695126 TI - Evolving role of the pharmacist in the critical care environment. PMID- 8695128 TI - The laryngeal mask airway: a new technique for fiberoptic guided vocal cord biopsy. AB - STUDY OBJECTIVE: To describe a new technique for vocal cord biopsy involving placement of a laryngeal mask airway (LMA) during general anesthesia and fiberoptic guided biopsy. To report our early experience with this technique. DESIGN: Descriptive study. SETTING: Teaching hospital. PATIENTS: 10 patients undergoing vocal cord biopsy for minor laryngeal pathology and with no evidence of infraglottic airway obstruction. INTERVENTIONS: Patients were premedicated 1 hour preoperatively with pethidine 1 mg/kg and atropine 0.01 mg/kg. Following preoxygenation, anesthesia was induced with propofol 2.5 mg/kg and fentanyl 1 mg/kg. Once airway control was established with a facemask, vecuronium 0.1 mg was given and anesthesia established with oxygen (O2) and nitrous oxide mixture and isoflurane 1% to 2%. Gentle direct laryngoscopy was then performed to inspect the pharyngeal structures and the LMA was then inserted in the standard manner by highly experienced LMA users. A fiberoptic scope was passed via a self-sealing mount down the shaft of the LMA to the level of the vocal cords. The vocal cords were then sprayed with local anesthetic and the biopsy taken. MEASUREMENTS AND MAIN RESULTS: The age and weight range were 29 to 57 years and 65 to 85 kg, respectively. All patients were smokers or recent ex-smokers. LMA insertion was readily achieved in all patients, and an excellent view of the vocal cords was obtained. There were no problems with ventilation or obtaining tissue samples, and O2 saturation remained greater than 95% throughout the perioperative period. Tissue samples were adequate in all patients. Hypertension and other adverse cardiac events did not occur during the procedure, which lasted 10 to 20 minutes. There were no problems during emergence from anesthesia, and all patients were discharged home on the same day. CONCLUSIONS: The technique has potential advantages over suspension microlaryngoscopy in that it is relatively noninvasive, it allows good airway control with adequate views of the vocal cords, and it facilitates a smooth recovery. PMID- 8695127 TI - Effect of oral clonidine premedication on anesthetic requirement, hormonal response, hemodynamics, and recovery in coronary artery bypass graft surgery patients. AB - STUDY OBJECTIVE: To examine how premedication with clonidine affects opioid use, hemodynamic effects, hormonal responses, and recovery effects. DESIGN: Double blind, placebo-controlled study. SETTING: Operating room and surgical intensive care unit of a university medical center. PATIENTS: 54 patients undergoing elective coronary artery bypass graft (CABG) surgery. INTERVENTIONS: Patients received approximately 5 micrograms/kg of oral clonidine or a placebo together with 40 micrograms/kg lorazepam 90 minutes prior to titrated sufentanil induction of anesthesia. Thirty minutes prior to cardiopulmonary bypass, a second dose of either approximately 5 micrograms/kg clonidine or placebo was given as a slurry via a nasogastric tube. MEASUREMENTS AND MAIN RESULTS: Opioid use, hemodynamic effects, hormonal responses, and recovery effects were recorded. Values for ten hemodynamic variables were compiled on the evening prior to surgery, prior to induction, and during seven additional events and compared. Catecholamines and beta-endorphins were measured prior to induction, after intubation, and after sternotomy. The amount of sufentanil used for induction, maintenance, and total opioid were compared. The times to awakening and response to verbal commands were compared. The two groups exhibited similar patient demographics, cardiopulmonary bypass time, and duration of surgery. Patients receiving clonidine required significantly (p < 0.04) less sufentanil for induction (clonidine: 2.19 +/- 0.95 micrograms/kg vs. placebo: 2.93 +/- 1.07 micrograms/kg) and total amount of sufentanil (clonidine: 9.1 +/- 3.9 micrograms/kg vs. placebo: 11.7 +/- 4.6 micrograms/kg). Patients receiving clonidine required significantly (p < 0.01) less isoflurane (9.7 +/- 6.8 MAC min vs. 19.7 +/- 9.9 MAC min) to maintain heart rate (HR) and mean arterial pressure (MAP) to within 15% of baseline without significant differences in other vasoactive drugs. Catecholamine concentrations were significantly (p < 0.02) lower in patients receiving clonidine without any difference in beta-endorphin concentrations. Patients receiving clonidine had significantly (p < 0.02) lower HR, systolic arterial pressure, MAP, and systemic vascular resistance prior to induction than patients receiving placebo without differences in other hemodynamic variables. CONCLUSION: Clonidine decreases opioid use and lowers hormonal response while maintaining stable hemodynamics in patients undergoing CABG with sufentanil anesthesia. PMID- 8695129 TI - Efficacy and safety of divided dose administration of mivacurium for a 90-second tracheal intubation. AB - STUDY OBJECTIVE: To compare the safety and effectiveness of 0.25 mg divided doses of mivacurium chloride to succinylcholine for a 90-second tracheal intubation. DESIGN: Randomized, double-blind, multicenter study in two groups. SETTING: Operating rooms at four university medical centers. PATIENTS: 200 healthy ASA status I and II adult patients scheduled for elective surgery with general anesthesia and endotracheal intubation. INTERVENTIONS: Patients were premedicated with 1 to 2 mg midazolam and 2 micrograms/kg fentanyl. Anesthesia was induced with 2 mg/kg propofol. Group A received 0.25 mg/kg mivacurium given as a divided dose (0.15 mg/kg followed in 30 seconds with 0.1 mg/kg). Group B (control) received 1.5 mg/kg succinylcholine (SCh) preceded two minutes earlier by 50 micrograms/kg d-tubocurarine (dtc). MEASUREMENTS AND MAIN RESULTS: Tracheal intubation grading, train-of-four response of the adductor pollicis, heart rate (HR), and mean arterial blood pressure (MAP) were measured and evaluated. Chi square analysis was performed for comparison between Group A and Group B with respect to the frequency distribution of intubation using the scores excellent, good, and poor and not possible (combined). Group B had a significantly higher excellent score of intubation than Group A, 84% versus 56% (p < 0.0001). No significant difference was found between the two groups when the scores excellent and good were combined (Fisher's Exact test, p = 0.28). The changes in MAP and HR were similar for the two groups. CONCLUSIONS: When Sch is not desirable, mivacurium 0.25 mg/kg given as a divided dose provides good to excellent intubation conditions 90 seconds after the initial dose without significant changes in MAP or HR. It can be an appropriate alternative for short surgical procedures. It must be emphasized that this conclusion does not apply to rapid sequence induction-intubation. PMID- 8695130 TI - Use of alfentanil for in vitro fertilization oocyte retrieval. AB - STUDY OBJECTIVES: To determine alfentanil levels with a specific radioimmunoassay in serum and ovarian follicular fluid. DESIGN: Observational study. SETTING: University hospital. PATIENTS: 14 ASA status I women undergoing oocyte retrieval for in vitro fertilization. INTERVENTIONS: General anesthesia was induced with alfentanil 15 micrograms/kg and midazolam 2 mg and maintained with alfentanil 0.5 mg, 60% nitrous oxide (N2O) in oxygen (O2) and midazolam up to a total of 4 mg. Oocyte retrieval was performed using a transvaginal ultrasound guided technique, 34 to 36 hours after human chorionic gonadotrophin administration. MEASUREMENTS AND MAIN RESULTS: Mean procedure time for oocyte retrieval was 18 +/- 2.4 (SEM) minutes. All patients were fully awake within 5 minutes and all patients except one were able to move from the operating table to the stretcher with minimal help. Mean total protein concentration in the follicular fluid was 3.8 +/- 0.4 mg%. Maximal serum alfentanil concentrations (Cmax) were attained 5 minutes after start of the procedure (tmax) and were 92 +/- 20 ng/ml. In contrast, alfentanil concentrations in the follicular fluid increased constantly throughout the procedure up to 8.9 +/- 0.8 ng/ml at 15 minutes. Clinical pregnancy rate was 3 of 14 patients. CONCLUSION: It is evident that during the oocyte retrieval procedure, the alfentanil concentrations in the follicular fluid are about ten fold smaller than the serum alfentanil concentrations at the same time points. Similar pharmacokinetics have been shown when propofol was used as anesthetic. The low accumulation of alfentanil in the follicular fluid increases the attractiveness of alfentanil for anesthesia during oocyte retrieval for in vitro fertilization. PMID- 8695131 TI - Application of cost-utility and quality-adjusted life years analyses to monitored anesthesia care for sedation only. AB - STUDY OBJECTIVE: To determine how much society should spend to decrease anxiety lasting for the duration of a surgical case. DESIGN: Indications for monitored anesthesia care (MAC) include: (1) management of an unstable patient, (2) possible induction of general anesthesia, (3) need for the patient to be unconscious for part of the case, and (4) provision of sedation and/or analgesia. The first three indications facilitate quality surgical care. However, MAC solely to decrease anxiety has been criticized on economic grounds. Although MAC for these cases may improve the patient's experience during surgery, it does not facilitate safer surgery. I limited my theoretical analysis to (1) MAC for sedation only and (2) procedures that have an equal outcome with or without an anesthesiologist. Cost-utility analyses compare costs and benefits of technologies by using a common measure of health outcomes. The quality adjusted life year (QALY) gives the expected life years gained from a procedure, with each year weighted to reflect quality of life in that year. Quality of life generally ranges from zero (dead) to one (healthy without distress). Technologies costing more than $75,000 per QALY are usually considered too expensive to justify. I used a deliberately absurd, one unit change in quality of life to calculate the maximum hourly cost of MAC, which lets the cost per QALY be less than $75,000. MEASUREMENTS AND MAIN RESULTS: Hourly cost must be less than $8.56 per hour. Current Medicare reimbursement corresponds to $876,000 per QALY. CONCLUSION: MAC for sedation only is a very expensive technology compared with other medical interventions. PMID- 8695132 TI - Unplanned endotracheal extubation in the intensive care unit. AB - STUDY OBJECTIVE: To identify the frequency, outcome, and factors associated with unplanned endotracheal extubation (UE) in the intensive care unit (ICU). DESIGN: Prospective study. SETTING: An urban, university trauma-surgical ICU. PATIENTS: 96 intubated ICU patients who underwent 101 episodes of UE. INTERVENTIONS: Patient, nursing, respiratory, and demographic factors associated with UE and patient outcome were determined for one year. Results were presented to nursing staff. The incidence of UE as a function of the total number of ventilator days was determined for one year post nursing education. ENDPOINTS: Patients with UE were identified. Patients with reintubation were followed until final extubation. MEASUREMENTS AND MAIN RESULTS: 85% of UE were self-extubations and 15% were accidental. Self-extubations occurred with equal frequency during all three nursing shifts in alert or agitated patients who were not being weaned. Accidental extubations occurred during the day shift in less alert patients and were associated with transport procedures and the use of rotary beds. Overall, 57% of patients were reintubated and most reintubations were in the first hour. Difficulty with reintubation was common, and one patient who could not be reintubated died. There were significantly fewer UE per ventilator day after nursing education. CONCLUSIONS: Patients should be observed closely after unplanned extubation, although many may not require reintubation. Reintubation can be quite difficult, necessitating highly skilled airway management. Attention to associated risk factors may decrease the incidence of both accidental and self extubation. PMID- 8695133 TI - Oxygen administration during transport and recovery after outpatient surgery does not prevent episodic arterial desaturation. AB - STUDY OBJECTIVE: To compare the efficacy of two different oxygen (O2) delivery systems in preventing episodic arterial desaturation in the immediate postoperative period. STUDY DESIGN: Randomized, prospective, nonblinded comparison in patients. SETTING: Operating room and postanesthesia care unit (PACU) of a university outpatient surgery center. PATIENTS: 100 ASA status I and II adults, male and female, age greater than 18 years, undergoing outpatient surgical procedures not involving the upper airway. INTERVENTIONS: Group I received supplemental O2 administered by bag-valve-mask during transport, followed by 40% face shield in the PACU. Group 2 received supplemental O2 by nasal cannula at 4 L/min both during transport and during PACU stay. MEASUREMENTS AND MAIN RESULTS: Arterial O2 saturation (SpO2) was collected by computer from a recording pulse oximeter at 15-second intervals beginning before extubation and continuing until O2 administration was discontinued in PACU. Neither mode of therapy was successful in completely eliminating arterial desaturation defined as SpO2 less than 90%, nor was there any difference in efficacy between the two treatment groups. Group 1 had 8 patients desaturate on 9 different occasions (5 times during transport, 4 times in PACU). Group 2 had 5 patients desaturate on 9 different occasions (4 times during transport, 5 times in PACU). CONCLUSION: Routine O2 administration during transport and PACU stay did not abolish episodic desaturation, even in healthy patients undergoing minor surgical procedures. Given the marked difference in acquisition cost, it would appear that O2 administration by nasal cannula is a more cost-effective alternative for routine postoperative O2 administration in certain groups of patients undergoing general anesthesia for outpatient surgery. PMID- 8695134 TI - A comparison of mivacurium dosage requirements during isoflurane and desflurane anesthesia. AB - STUDY OBJECTIVE: To evaluate the dose requirement and recovery characteristics of mivacurium infusions during anesthesia with equipotent concentrations of either desflurane or isoflurane. DESIGN: Randomized, open-study comparing the effects of desflurane and isoflurane on mivacurium-induced neuromuscular blockade. SETTING: Operating suite of a university-affiliated medical center. PATIENTS: 41 ASA status I, II, and III adult patients, requiring more than 45 minutes of neuromuscular blockade for surgery. INTERVENTIONS: Following a standardized induction sequence and established steady desflurane-nitrous oxide (DES group) or isoflurane-nitrous oxide (ISO group) anesthesia at 1 minimum alveolar concentration (MAC), an intubating dose of 0.2 mg/kg of mivacurium chloride was administered. Ventilation was maintained with a face mask until the first twitch (T1) of the evoked train-of-four (TOF) reached 10% or less of control when tracheal intubation was performed. T1 was allowed to return to 10% of its control value. An infusion of mivacurium at the initial rate of 5 micrograms/kg/min was then started and adjusted to maintain T1 at 10% +/- 2% of control. Within 20 minutes of completion of surgery, the mivacurium infusion was stopped, and the time for the evoked electromyograph (EMG) to return to 25% and 75% of the original baseline was noted. MEASUREMENTS AND MAIN RESULTS: Neuromuscular function was monitored continuously by an evoked EMG. The average infusion rate was 5.7 +/- 2.4 micrograms/kg/min (mean +/- SD) for DES group (n = 20) and 6.6 +/ 2.7 micrograms/kg/min for ISO group (n = 21) (p = NS). There was no change in the infusion rate of mivacurium over time for both groups. However, there was an inverse relationship in both groups between the time to recovery following a bolus dose and the subsequent mean infusion rate of mivacurium (correlation coefficient = -5.0; p < 0.005). The spontaneous recovery index (T25-75) for the two groups was identical, 11.5 +/- 4.9 min (mean +/- SD) for DES group and 11.5 +/- 7.9 min for ISO group (p = NS). CONCLUSION: There were no differences in the dose requirement and recovery indices of mivacurium during either desflurane or isoflurane-based anesthesia. Patients who took longer to recover from the bolus dose in both groups showed a subsequent reduction in dose requirements of mivacurium. PMID- 8695135 TI - Prospective, randomized comparison of the Flotem Iie and Hotline fluid warmers in anesthetized adults. AB - STUDY OBJECTIVE: To compare the fluid warming capabilities of the Hotline and Flotem IIe devices in surgical patients, and whether warming intravenous (i.v.) fluids with the Hotline device resulted in less hypothermia and less need for other warming methods compared with the Flotem IIe device. STUDY DESIGN: Part 1. Prospective, nonrandomized. Part 2. Prospective, randomized. SETTING: Teaching hospital, tertiary care center. PATIENTS: Part 1. 24 adult patients undergoing elective surgery. Part 2. 49 adult patients scheduled for major elective orthopedic or gynecologic surgery of greater than 2 hours' duration with general anesthesia. INTERVENTIONS: Part 1. Insertion of sterile in-line thermistors along the path of fluids delivered using the Hotline or Flotem device. Part 2. Patients were randomly assigned to receive i.v. fluids via the Hotline (n = 21) or Flotem IIe (n = 18) warmers. Intervention for core hypothermia [lower esophageal temperature (Teso) less than 35.5 degrees C], was with forced air warming. Intervention for postoperative shivering was with meperidine by a nurse who was blinded to the treatment group. MEASUREMENTS: Part 1. Temperature of infused fluids before and after the warmer (T in and T out) and before the fluid entered the patient after insertion of a standard 84 cm extension set having a stopcock for injection of medications (T distal). Part 2. Tympanic (Ttym) was recorded before induction of anesthesia (baseline) and at 15-minute intervals after induction. Teso was recorded at 15-minute intervals after induction. The maximum intraoperative Ttym decline from baseline (delta Ttym max) was calculated. MAIN RESULTS: Part 1. Flow rates were between 1 and 33 ml/min. T out and T distal (mean +/- SEM) of fluids infused through the Hotline device were warmer compared with those infused via the Flotem IIe device (Hotline T out: 35.7 +/- 0.1 degrees C and Hotline T distal: 33.4 +/- 0.2 degrees C vs. Flotem IIe T out: 28.9 +/- 0.2 degrees C and Flotem IIe T distal: 28.3 +/- 0.2 degrees C; p < 0.001 between warmers). Part 2. Maximal decrease in Ttym from preoperative baseline (before intervention) was greater in the Flotem IIe compared with the Hotline group (delta Ttym max = -1.4 +/- 0.1 vs. -0.9 +/- 0.1 degree C, p = 0.01). Five patients in the Flotem IIe group required forced air warming for treatment of hypothermia versus none in the Hotline group (p < 0.01). Postoperatively, five patients in the Flotem IIe group required treatment with meperidine for severe shivering versus one patient in the Hotline group (p < 0.05). CONCLUSIONS: The Hotline device delivered fluids to the patient at consistently warmer temperatures compared with the Flotem IIe device during actual clinical conditions. This was associated with maintenance of near normal core temperatures throughout the procedure in the Hotline group, and a decreased need for interventions such as forced-air warming and treatment for severe shivering. PMID- 8695136 TI - Propofol infusion for induction and maintenance of anesthesia in elderly patients: recovery and hemodynamic profiles. AB - STUDY OBJECTIVE: To evaluate the effect of propofol infusion for both induction and maintenance of anesthesia on hemodynamics and recovery in elderly patients compared with conventional thiopental-isoflurane anesthesia. DESIGN: Randomized, prospective, study. SETTING: Teaching hospital. PATIENTS: 60 nonpremedicated ASA physical status I, II, and III adult elderly patients scheduled to undergo total hip replacement surgery. INTERVENTIONS: Patients received either intravenous propofol infusion at 0.75 mg/kg/min or thiopental bolus 2 to 4 mg/kg for induction, followed by variable-rate propofol infusion up to 0.15 mg/kg/min or isoflurane 0.5% to 1.5% for maintenance of anesthesia. Nitrous oxide and fentanyl supplements were given in all patients. MEASUREMENTS AND MAIN RESULTS: Perioperative hemodynamic changes, patient recovery profile, and myocardial ischemia incidents were assessed in both anesthetic groups. Induction of anesthesia by propofol infusion (1.6 mg/kg) did not produce significant hypotension (-8.3% +/- 5.5%) or bradycardia; these changes were similar to induction by thiopental bolus injection (3.3 mg/kg). Furthermore, increases in blood pressure and heart rate (HR) during endotracheal intubation were limited to 6% following propofol induction compared with 22% for thiopental induction. During maintenance of anesthesia, the decrease in MAP and HR was comparable in both anesthetic groups. Postanesthetic recovery times for patient to achieve wakefulness, mental orientation, and a maximum Aldrete score (10) were significantly faster in the propofol group, by 4 minutes, 6 minutes, and 20 minutes, respectively; however, the time to discharge from the postanesthesia care unit was not different. Holter-monitored perioperative myocardial ischemic events detected in 23% of the patients occurred independent of hemodynamic changes or the type of anesthetic administered. CONCLUSION: Induction of anesthesia by propofol infusion in elderly patients produces greater attenuation of cardiovascular sympathetic response than thiopental bolus induction. Induction and maintenance of anesthesia by propofol infusion results in more rapid recovery in our elderly patients than thiopental isoflurane anesthesia. PMID- 8695137 TI - Incidence of nausea and vomiting in outpatients undergoing general anesthesia in relation to selection of intraoperative opioid. AB - STUDY OBJECTIVE: To measure the incidence of nausea and vomiting in outpatients in relation to selection of, or withholding of, intraoperative opioid. DESIGN: Prospective, randomized, double-blind control trial. SETTING: University general hospital. PATIENTS: 200 unpremedicated ASA status 1 and 11 patients, 8 to 80 years old, undergoing general anesthesia for ambulatory surgery. INTERVENTION: Patients were randomized to four groups, three of which received equipotent doses of different opioids intravenously (i.v.) during induction of anesthesia. Group 1 received nalbuphine 0.25 mg/kg, Group 2, alfentanil 20 ug/kg; Group 3, fentanyl 2 ug/kg; and Group 4, normal saline. MEASUREMENTS AND MAIN RESULTS: We evaluated (1) incidence and severity of nausea and vomiting in the postanesthesia care unit (PACU) and over the next 24 hours; (2) time to PACU discharge; (3) need for antiemetic therapy; and (4) need for analgesic rescue in the PACU. The incidences of nausea and vomiting were similar in all groups, as were time to discharge, antiemetic, and nonsteroidal antiinflammatory drug requirements. The highest incidences of nausea and vomiting occurred at 6 hours in all groups (23% and 9.5%, respectively). Group 1 required lower rescue doses of morphine in the PACU but this result may have been an artifact due to employing the mixed agonist antagonist opioid, nalbuphine, in this group. CONCLUSIONS: Opioid administration at the doses employed during induction of anesthesia does not promote postoperative nausea or vomiting, nor increase length of stay in the PACU. PMID- 8695138 TI - Compatibility of propofol, fentanyl, and vecuronium mixtures designed for potential use in anesthesia and patient transport. AB - STUDY OBJECTIVE: To determine whether propofol emulsion, fentanyl, and vecuronium remain compatible and stable when mixed in clinically appropriate concentrations. DESIGN: Seven separate in vitro experiments. Two different propofol-fentanyl vecuronium mixtures were formulated. Regular assays of propofol, fentanyl, and vecuronium were performed during a 90-minute infusion period and also during storage of one of the mixtures for 30 days at 4 degrees C, 22 degrees C, and 30 degrees C. Initial and storage pH were determined, and assays of the three drugs were performed when pH of the mixtures was varied between 1.4 and 12.7. Emulsion stability was assessed by measuring immediate and delayed alterations in droplet charge (zeta potential) and size. Finally, samples of the stored mixtures were incubated in culture medium for one week. SETTING: Teaching hospital and university laboratories. MEASUREMENTS AND MAIN RESULTS: Concentrations of the three drugs remained unchanged during infusion. During storage, concentrations of all three drugs were stable for two weeks at 4 degrees C or 22 degrees C, and for several days at 30 degrees C. Initial pH of the two mixtures was 5.1 and 5.3, and pH of the stored mixture increased slowly after 8 days. When the pH of mixtures was greater than or equal to 5.6, concentrations of fentanyl and vecuronium were unstable, but the concentration of propofol remained unchanged. Despite a reduction in zeta potential, immediate droplet size was essentially unchanged. No microbial growth was detected in stored mixtures. CONCLUSION: The propofol, fentanyl, and vecuronium mixtures studied were compatible and stable immediately after mixing. Appropriate in vitro compatibility testing is recommended before clinical evaluation of propofol-opioid or propofol-opioid-muscle relaxant mixtures. PMID- 8695139 TI - Elective tracheostomy in an obstetric patient. PMID- 8695140 TI - Re: Cardiac output measurement: lack of agreement between two methods of clinical measurement. PMID- 8695141 TI - Re: Spinal phobia: survey results of patient attitudes and preferences regarding anesthesia. PMID- 8695142 TI - [Drug treatment of frequent disorders in patients with Parkinson's disease]. AB - The patient with Parkinson's disease often needs concomitant treatment for disorders that accompany the disease, such as depression, insomnia or constipation, or for frequent concomitant alterations such as dizziness, high blood pressure or heart disease. The many drugs that can worsen motor symptoms in Parkinson's disease must be avoided, especially if use will be prolonged. Not all drugs that induce or aggravate parkinsonism have the same potency. We describe 3 groups: 1) drugs that invariably induce or aggravate parkinsonism if taken long enough or at high enough doses; 2) drugs that only provoke parkinsonism in some individuals, and 3) drugs that interfere with the action of levodopa. Knowledge of these drugs is essential for all doctors who treat patients with Parkinson's disease. PMID- 8695144 TI - [Primary dural lymphoma]. AB - We describe a 48-year-old woman with an intracranial tumor located in the meninges. Radiologic images were consistent with meningioma. Pathology showed that it was well differentiated and diffuse lymphocytic lymphoma. No evidence of systemic disease was found. Primary meningeal lymphomas generally infiltrate the subarachnoid space in a diffuse way and their presentation as focal and localized masses in unusual. PMID- 8695143 TI - [Image of the month: familial multiple cavernous angiomas]. PMID- 8695145 TI - [Neuropsychological disorders due to left fronto-striatal lesions: a longitudinal study of an adolescent]. AB - Relatively little is known of the neuropsychological consequences of isolated frontal-striatal lesions in children. We study the case of an adolescent boy who suffered a stroke in the left hemisphere at the age of 11. In addition to the expected frontal dysfunctions, the patient at first suffered lowered IQ and attention disorder with hyperactivity. Four years after the stroke, only frontal lobe dysfunctions (difficulties in planning, anticipating, responding, generating words, attending, and sequencing with loss of mental flexibility) persisted. The functional recovery might have come about because the right hemisphere striate assumed functions of the left hemisphere. The persistence of frontal dysfunctions favors specialization of the left frontal lobe and the relatively early maturity of this cortical structure. PMID- 8695146 TI - [Paramedian thalamo-mesencephalic infarct con triphasic waves]. AB - Triphasic waves are usually associated with metabolic encephalopathies but have been reported in patients with other etiologies. The pathophysiology of this EEG pattern remains poorly understood, although they have been attributed to lesion in the connections between the thalamus and cortex. We report a case of top-of the-basilar artery occlusion with selective paramedian thalamic-mesencephalic infarct in which triphasic waves were evident on the EEG during clinical hypersomnia. To our knowledge this is the first reported case of triphasic waves with selective paramedian thalamomesencephalic infarct. We conclude that triphasic waves are a nonspecific manifestation of diencephalic dysfunction, probably of the paramedian thalamomesencephalic reticular system. PMID- 8695147 TI - [The use of FD-6 monoclonal antibody in diagnosing and detecting the carriers of familial amyloidotic polyneuropathy type I]. AB - Familial amyloidotic polyneuropathy type I (FAF-I) is caused by a specific genetic mutation that gives rise to a transthyretin anomaly whose presence in serum constitutes the biochemical marker for this disease. We studied the serum of 7 patients and 16 asymptomatic members of their immediate families using ELISA with FD-6 monoclonal antibody to detect the transthyretin anomaly. Positive results were found for the 7 patients, including the 2 patients whose disease was apparently sporadic, and 12 carriers were detected among the family members. This technique makes sural nerve biopsy unnecessary for establishing a diagnosis in patients whose clinical signs are consistent with FAP-I. Asymptomatic carriers are also detected, facilitating appropriate genetic counseling. PMID- 8695148 TI - [Amyotrophic lateral sclerosis]. AB - Several aspects of amyotrophic lateral sclerosis are reviewed, with special emphasis on arguments based on etiological and pathogenic theories currently in vogue: free radicals, glutamate-induced toxic excitation, trophic factors, autoimmunity and axon transport. Each of these theories has inspired therapeutic trials, some of which are already completed and others are still in progress. More than one neurodegenerative mechanism may be involved in amyotrophic lateral sclerosis, meaning that it might be necessary to combine several drugs in future trials. PMID- 8695149 TI - Lung cancer in Swedish males on the decline. PMID- 8695150 TI - A decline in the lung cancer incidence amongst men in Swedish cities. AB - A statistically-significant (p < 0.01) decrease in the incidence of lung cancer has been observed amongst men in larger Swedish cities, but not in the country as a whole. The decrease is foremostly attributable to changes within the group of older men (i.e., > 65 years). The investigation is based on the Swedish Cancer Registry and covers the period 1975-1989. PMID- 8695151 TI - Full chemotherapy in elderly patients with small cell bronchial carcinoma. AB - Data on small cell lung cancer (SCLC) in elderly patients with full chemotherapy are sparse. We present material of 345 patients treated with chemotherapy (CT) with no age limits. CT was given with 2 different types of 4-drug combinations, including cyclophosphamide, doxorubicin, vincristine, methotrexate, lomustine and etoposide. Radiotherapy 40 Gy was given to 85% of the limited disease (LD) and 15% of the extensive disease (ED) patients. In 345 consecutive SCLC patients (50% LD and 50% ED) with a median survival time (MST) of 10 months and a disease-free 5-year survival 3.8%. Multivariate analysis showed clear correlation between stage of disease and survival as well as between age and survival though less pronounced. One hundred and ten patients were > 70 years of age with a median survival time of 7.4 months (LD 12.3 and ED 4.6) and 235 patients < 70 years of age had a median survival time of 10.9 months (LD 14.4 and ED 7.5) and a disease free 5-year survival of 5.1%. The survival differences were statistically significant. Treatment toxicity was higher in patients > 70 years of age. Seventy seven patients 70-75 years of age had an MST of 9.5 months (LD 13.2 and ED 6.2) and a disease-free 5-year survival of 1.3%. The survival differences between patients 70-75 years old and those < 70 years of age were small but statistically significant in LD at 5% level but not in ED. There were more septicemias per courses CT given in all patients 70-75 years of age and also more lethal septicemias in ED patients. Patients with LD SCLC 70-75 years of age might benefit from full treatment in terms of median and long-term survival. PMID- 8695153 TI - Anxiety, depression and worry in gastrointestinal cancer patients attending medical follow-up control visits. AB - Anxiety, depression and worry were assessed in 141 consecutive gastrointestinal cancer patients scheduled for follow-up control visits. Participants completed two questionnaires, one including the Hospital Anxiety and Depression Scale (HAD) in conjunction with the visit and one completed after. The overall levels of anxiety before, during and after the visit were low. There were no differences between those who were considered cured and those who were not. Anxiety levels after the visit were higher for those patients for whom less than one year had passed since diagnosis. Mean HAD scores for anxiety and depression were 4.2 and 4.3 respectively. Women reported a higher degree of anxiety than men. Using a score of 8 or more for 'borderline-possible cases', 15% fell into these categories on the anxiety scale and 12% on the depression scale. About 30% of the patients worried about seeing a new physician and 25% about what the examination or tests would show. It is concluded that regular, scheduled control visits pose a significant threat to the psychological well-being of only a minority of gastrointestinal cancer patients. PMID- 8695152 TI - Genetic heterogeneity in breast cancer susceptibility. AB - Approximately 20% of breast cancer patients have a family history of the disease, and in one-fourth of these cases breast cancer appears to be inherited as an autosomally dominant trait. Five genes and gene regions involved in breast cancer susceptibility have been uncovered. Germ-line mutations in the recently cloned BRCA1 gene at 17q21 is considered to be responsible for the disease in a majority of the breast-ovarian cancer families and in 40-45% of the site-specific breast cancer families, but appears not to be involved in families with both male and female breast cancer cases. The BRCA2 locus at 13q12-q13 appears to be involved in 40-45% of the site-specific breast cancer families, and in most of the families with affected males. The gene located in this region, however, does not seem to confer susceptibility to ovarian cancer. The TP53 gene is involved in breast cancer development in the Li-Fraumeni syndrome and Li-Fraumeni syndrom like families, whereas germ-line mutations in the androgen receptor (AR) gene is present in a subset of male breast cancers. Furthermore, females who are obligate carriers of ataxia telangiectasia (AT) have a 4-12 times relative risk of developing breast cancer as compared with the general female population, indicating that germ-line mutations in AT also confer susceptibility to breast cancer. PMID- 8695154 TI - Quantitative immunocytochemical assays of topoisomerase II in lung adenocarcinoma cell lines. Correlation to topoisomerase II alpha content and topoisomerase II catalytic activity. AB - The examination of topoisomerase II alpha content by Western blot analysis or topoisomerase II catalytic activity by decatenation of kDNA requires a large number of cells, but it is difficult to collect sufficient cells for these biochemical analyses from lung cancer patients by transbronchial brushing or aspiration. In this study, we explored the relationship between these biochemical analyses and topoisomerase II immunostaining in cytospin preparations of three lung adenocarcinoma cell lines. The levels of topoisomerase II alpha content were about 8.4 for A549, 2.9 for PC-3 and 1 for RERF-LC-MS, and the levels of topoisomerase II catalytic activity were about 4, 2, and 1, respectively. The percentages of strongly positive cells for topoisomerase II immunostaining were 60.9% for A549, 33.3% for PC-3, and 14.3% for RERF-LC-MS, and these were compatible with the levels of topoisomerase II alpha content or topoisomerase II catalytic activity. Our results indicate that topoisomerase II immunostaining can be utilized in place of biochemical analysis. PMID- 8695155 TI - Immunohistochemical evaluation of lymph node micrometastases from breast cancer. AB - The lymph node micrometastasis was retrospectively immunohistochemically investigated in 185 patients with node-negative breast cancer and compared with the routine conventional findings. The monoclonal antibodies to epithelial membrane antigen (EMA) and mucinous-like carcinoma antigen (MCA) were used. Of 19 EMA-positive cases, 16 were false positive. Therefore only 3 cases were found to show staining with both EMA and MCA. The patients are all living and well and free of recurrence. No micrometastasis was immunhistochemically demonstrated in 11 node-negative breast cancer patients with subsequent metastases. The results of the present study indicate that the detection rate containing occult cells afforded by conventional routine evaluation is sufficient, at least in Japanese. PMID- 8695156 TI - The p53-MDM2 interaction in a cancer-prone family, and the identification of a novel therapeutic target. AB - One approach to developing novel anti-cancer agents is to identify and characterise targets that directly regulate cell growth and are dysfunctional in the disease state. One such target is the interaction between the p53 tumour suppressor and the oncogene product of the murine double minute gene, MDM2. MDM2 is known to bind wild-type p53 and block the transcriptional activation of p53 dependent genes. We have previously described a cancer-prone family with elevated levels of wild-type p53, and now show that MDM2 is also over-expressed in the proband from this family. Interestingly, the overexpression of MDM2 is independent of other p53-regulated genes such as p21WAF1. The present work and a review of recent insights into the p53-MDM2 interaction, and p53 transcriptional activity, identify a new target site for the rational development of novel anti cancer agents. PMID- 8695157 TI - Is the MVP regimen less active than previously described? Results of a phase II study in advanced non-small cell lung cancer. AB - Combination chemotherapy with anti-proliferative agents is often used in patients with advanced non-small cell lung cancer (NSCLC) in good performance status. The mitomycin C, vinblastine and cisplatin (MVP) regimen has been the Eastern Cooperative Oncology Group (ECOG) standard for several years because of high response rates in spite of significant toxicity. In a phase II study, we observed 55 consecutive patients treated with MVP chemotherapy using the same dosage, schedule, and precautions as used by the ECOG group. The dose intensity reached for each drug was 85% of the projected dose. Fifty-one patients were assessable for response and toxicity, while all subjects were evaluable for survival. There was no complete remissions, 8 partial (15%), 34 stable (66%) and 9 progressive (17%) in patients. The median survival rate was 34 weeks (95% confidence interval 28-37 weeks). There were no treatment-related deaths and no grade 4 toxicity. Alopecia and emesis were the most significant adverse effects. Haematological toxicity was minimal. Other side-effects, such as neuropathy and nephrotoxicity, were also rare. Hence, response rates and toxic complications were lower than previously reported. We conclude that the MVP regimen has to be re-evaluated. PMID- 8695158 TI - A prospective evaluation of the treatment of primary or metastatic liver carcinoma with hepatic arterial infusion chemotherapy. AB - The efficacy of hepatic arterial infusion chemotherapy (HAICT) in the treatment of primary or metastatic liver carcinoma was evaluated in 37 patients. The infusions were administered through a catheter that was placed in the hepatic artery, either surgically or by percutaneous puncture of the femoral artery. A complete response was observed in four patients. A partial response was observed in six patients and a minor response in another six. In nine patients the disease had stabilized, while a progression of the disease had developed in 12 patients. After a mean of 4.7 cycles per patient, the response rate (complete, partial and minor responses) was 43.2% and median survival 12.0 months. Seventeen Grade III toxicities were observed in a total of 174 cycles, but none of them were fatal. HAICT has demonstrated a successful palliation with minimal toxicity in patients with unresectable liver carcinoma. PMID- 8695159 TI - Adverse effects after radical external beam radiotherapy of localized prostatic adenocarcinoma using two-dimensional dose-planning and a limited field technique. AB - Adverse effects were assessed after definitive limited field, 2-dimensional CT planned radiation treatment of localized prostatic adenocarcinoma. In 66 surviving patients, out of a total of 176 treated patients, personal interviews were performed and self-administered questionnaires distributed. The average follow-up was 6.6 years. Adverse effects with regard to bowel function and micturition were investigated, and graded 0-4 with increasing severity and impact on performance status, essentially according to the RTOG toxicity scoring system. Sexual functions were registered on visual analogue scales. The majority of adverse effects were considered minor (grade 1) and did not require any treatment. Late adverse effects on bowel and bladder or urethra that required treatment (grade 2-4) were reported in up to 8% (n = 5) of cases respectively. Late bowel side-effects that interfered with life style (grade 3-4) occurred in up to 3% (n = 2) of patients; the majority were rectal complications. Corresponding urinary side-effects were registered in up to 6% (n = 4) of the patients. Major surgical interventions were not required. Sexual functions were substantially affected in 60% of cases not administered endocrine treatment. Multivariate analyses could not identify patient or treatment risk factors related to complications. PMID- 8695160 TI - Radiosensitivity of mesothelioma cell lines. AB - The present study was carried out in order to examine the radiosensitivity of malignant pleural mesothelioma cell lines. Cell kinetics, radiation-induced delay of the cell cycle and DNA ploidy of the cell lines were also determined. For comparison an HeLa and a human foetal fibroblast cell line were simultaneously explored. Six previously cytogenetically and histologically characterized mesothelioma tumor cell lines were applied. A rapid tiazolyl blue microtiter (MTT) assay was used to analyze radiosensitivity and cell kinetics and DNA ploidy of the cultured cells were determined by flow cytometry. The survival fraction after a dose of 2 Gy (SF2), parameters alpha and beta of the linear quadratic model (LQ-model) and mean inactivation dose (D(MID)) were also estimated. The DNA index of four cell lines equaled 1.0 and two cell lines equaled 1.5 and 1.6. Different mesothelioma cell lines showed a great variation in radiosensitivity. Mean survival fraction after a radiation dose of 2 Gy (SF2) was 0.60 and ranged from 0.36 to 0.81 and mean alpha value was 0.26 (range 0.48 - 0.083). The SF2 of the most sensitive diploid mesothelioma cell line was 0.36: less than that of the foetal fibroblast cell line (0.49). The survival fractions (0.81 and 0.74) of the two most resistant cell lines, which also were aneuploid, were equal to that of the HeLa cell line (0.78). The alpha/beta ratios of the most sensitive cell lines were almost an order of magnitude greater than those of the two most resistant cell lines. Radiation-induced delay of the most resistant aneuploid cell line was similar to that of HeLa cells but in the most sensitive (diploid cells) there was practically no entry into the G1 phase following the 2 Gy radiation dose during 36 h. PMID- 8695161 TI - Non-Hodgkin's lymphoma of the thyroid. A clinical study of twenty-two cases. AB - Non-Hodgkin's lymphoma (NHL) of the thyroid gland is a rare disease. In the present study, the survival rate and characteristics were retrospectively analyzed in 22 patients with stage IE and IIE thyroid NHL treated with radiotherapy with or without combination chemotherapy. Seventeen NHL had histological evidence of lymphoma of mucosa-associated lymphoid tissue (MALT) type. The 5-year survival rate was 85% in all patients, with 100% and 63% respectively, for stage IE and stage IIE patients. The highly significant factor correlated with decreased determinate survival was concomitant stridor. PMID- 8695162 TI - The efficacy of gold-198 grain mold therapy for mucosal carcinomas of the oral cavity. AB - Gold-198 grain mold therapy was given to 27 patients with 29 oral cancers and the results were analysed. Single plane mold alone was chosen for treatment when the maximum thickness of the tumor was below 2 mm. For thicker tumors, external irradiation prior to mold therapy was added. The 5-year survival following these principles was 82%. Initial tumor control was obtained in all 27 lesions followed for more than 2 years but recurrence took place in 7 (26%). Of 20 patients whose primary lesion did not recur within 2 years, 6 subsequently required surgery (2 cases) or non-surgical treatment (4 cases) for bone complications. The results obtained by single plane mold therapy are encouraging, particularly with regard to gum cancers showing a minimum bone invasion, and should therefore be advocated for selected patients with oral carcinoma. PMID- 8695163 TI - Thymidylate synthase in advanced gastrointestinal and breast cancers. AB - Knowledge of population thymidylate synthase (TS) levels in malignant tumors and normal tissues is essential for the use of TS as a predictor for 5-fluorouracil treatment. Tumor tissue TS levels in fresh frozen surgical biopsies from 136 patients with gastrointestinal or breast cancer, not previously subjected to chemotherapy, were analysed by [3H]FdUMP radioligand binding assay. TS levels were 2.4 +/- 0.31 pmol/g in liver metastases of colorectal cancer (n = 87), 4.2 +/- 1.0 pmol/g in primary colorectal cancer (n = 13), 2.7 +/- 0.93 pmol/g in gastric cancer (n = 13), 3.1 +/- 1.7 pmol/g in pancreatic cancer (n = 10), 3.4 +/ 1.4 pmol/g in breast cancer (n = 13) and 0.58 +/- 0.075 pmol/g in normal liver parenchyma (n = 24). TS levels were significantly higher in malignant tumor tissues compared to normal liver parenchyma. PMID- 8695165 TI - Serum beta 2-microglobulin and prognosis of patients with renal cell carcinoma. AB - Beta 2-Microglobulin (beta 2-M) was analysed in serum of 145 patients with renal cell carcinoma, and serum creatinine < 125 mumol/1 by a radioimmunometric method. Forty-nine (34%) patients had serum beta 2-M level > or = 3.0 mg/l. Of the patients with distal metastases 46% had elevated levels, compared with 19% with stage I disease. Serum beta 2-M correlated with histopathologic grade; 58% of the patients with poorly differentiated (grade 4) tumours had elevated levels compared with 18% in grade 1-2 tumours. Also tumour cell type was associated with serum beta 2-M; 52% of the patients with plasmic tumours had elevated levels compared with 6% in the clear cell type. In a univariate prognostic analysis elevated serum beta 2-M level was inversely correlated with survival time. Using a multivariate analysis the strong prognostic factors were clinical stage and tumour diameter. Weaker factors were age and cell type, whereas the prognostic value of serum beta 2-M disappeared. However, if tumour cell type was excluded from the analysis, serum beta 2-M was identified as a prognostic factor. PMID- 8695164 TI - Effects of interferons and tumour necrosis factor-alpha on human lung cancer cell lines and the development of an interferon-resistant lung cancer cell line. AB - Thirteen human lung cancer cell lines, 7 representing small cell lung cancer (SCLC) and 6 different types of non-SCLC, were tested for sensitivity to tumour necrosis factor alpha (TNF-alpha) and interferon alpha and gamma (IFN-alpha and gamma) using an automated fluorometric microculture cytotoxicity assay (FMCA). One SCLC line (H-82) was found to be sensitive to IFN-alpha in short-term (72 h) culture, whereas after prolonged (5 days) culture two additional SCLC cell lines responded to IFN-gamma. TNF-alpha inhibited the growth of one large cell carcinoma cell line (H-157), whereas all SCLC lines were found to be insensitive. The combination of IFN-gamma and TNF-alpha produced no further response compared with the single agents used alone. By continuous cultivation of the IFN-alpha sensitive cell line H-82 in the presence of increasing concentrations of IFN alpha, an IFN-alpha-resistant subline (H-82) was established. This line displayed a high degree of resistance ( > 100 fold) to IFN-alpha and cross-resistance to IFN-gamma. There was no alteration in the number of IFN binding sites, in the growth rate, the expression of selected surface markers for SCLC or the expression of multidrug resistance markers in the H-82R subline compared with the parental H-82 cell line. The results demonstrate a heterogeneous response of SCLC cell lines to IFN-alpha and gamma and TNF-alpha with only a minority of the cell lines responding to these agents by growth inhibition. The IFN-alpha and gamma H 82R subline may serve as a valuable tool in future studies on the mechanisms of IFN antitumour activity. PMID- 8695166 TI - Estramustine-binding protein (EMBP) in renal cell carcinoma immunohistochemistry, immunoscintigraphy and in vitro estramustine effects. AB - The present report shows that the human renal cell carcinoma (RCC) cell lines, A498 and CAKI-2, express the estramustine-binding protein (EMBP). The RCC cell lines investigated were highly sensitive for estramustine, with cell arrest in atypical metaphase. In vitro experiments using a fluorimetric cytotoxicity assay (FMCA) showed a pronounced cytotoxic effect mediated by estramustine. Immunohistochemical analysis of tumour specimens from patients with RCC showed positive staining for EMBP in 12/16 cases. Immunoscintigraphy was performed in an experimental system in nude mice, heterotransplanted with the CAKI-2 cell line. A radiolabelled monoclonal anti-EMBP antibody was used. The results show a specific uptake of the antibody in the RCC tumour, expressed as a percentage of the injected dose per gram tissue, which ranged from 4.03 to 6.9. The results obtained form the basis for clinical studies on the feasibility of utilizing estramustine in the management of RCC. Immunoscintigraphy using the monoclonal anti-EMBP antibody is of potential use for in vivo characterization of the malignancy and in the selection patients suitable for treatment with estramustine. PMID- 8695167 TI - 99mTc-dextran-antibody conjugates. Labelling procedures. AB - Dextran forms stable chelates with 99mTc, a radionuclide with ideal properties for planar scintigraphic and tomographic imaging. This study investigates some of the factors of importance to the formation of 99mTc-dextran. The complex was used for the technetium labelling of a monoclonal antibody. Two radiolabelling methods were studied: direct dextran labelling with the reductant dissolved in HCI and labelling via a weak 'transfer' chelator (tartaric acid) with the reductant dissolved in ethanol. Different conditions during the labelling reaction were studied. Finally, dextran was coupled to a monoclonal anticytokeratin antibody and the conjugate was subsequently radiolabelled with 99mTc. Gel filtration (GFR) and thin layer chromatography (TLC) were compared as methods for estimation of the labelling efficiency. When using 10-500 microM of ligand, 5-100 microM SnCl2 with 10-500 MBq of technetium at pH 7 incubated for 10-15 min, the radiolabelling seemed optimal (70-75% labelling efficiency). It was found that 100 microM tartaric acid used as a weak intermediate chelator with SnCl2 dissolved in ethanol improved the reproducibility of the labelling. The labelling efficiency was not affected by either the presence of oxygen or the addition of an oxygen scavenger during the labelling incubation. In general, TLC showed higher labelling efficiencies than GFR, indicating inadequate separation of the different moieties. PMID- 8695168 TI - Breast cancer tissue preparation for routinary steroid receptors and epidermal growth factor receptor determination. PMID- 8695169 TI - Primary cutaneous rhabdomyosarcoma in adults--description of an uncommon aggressive disease. PMID- 8695170 TI - Lack of N-myc-amplification and normal karyotype in stage IV-N neuroblastoma. PMID- 8695171 TI - Long-term response to radiotherapy of vertebral hemangioma resulting in paraplegia. PMID- 8695172 TI - Severe hepatobiliary complication in a patient with acute promyelocytic leukemia treated with all-trans retinoic acid. PMID- 8695173 TI - Tumour-induced hypercalcaemia, resistant to systemic anti-hypercalcaemic and chemo-endocrine treatments, but responding to radiotherapy in a breast cancer patient. PMID- 8695174 TI - [Investigation on VNTR in intron 40 of vWF gene in Chinese Han population]. AB - The VNTR in the intron 40 of vWF gene was investigated with a method of combination of Amp-FLP and RFLP. Two amplified fragments from a heterozygous person were separated by a non-hydratable polyacrylamide electrolyte gradient electrophoresis. After elution from gel, the preliminary products were amplified again, the amplified fragments were digested with AluI, then the genotype could be directly determined through electrophoresis. For the first time SSCP was used to detect the subtypes of microsatellite DNA. 136 alleles were found from 156 unrelated Hans in Changsha area. There were 153 genotypes in this sample and all of them were heterozygous. The calculated heterozygosity was 0.9884. The distribution of genotypes was in according with the Hardy-Weinberg equilibrium. The polymorphic information content (PIC) was 0.9883. The polymorphism of this VNTR was the highest one in the Amp-FLPs that had been found before. Our data did not show any recombination even in 2 generations of 66 families and 3 generations of 5 families. Aco-dominant segregation was demonstrated. PMID- 8695175 TI - [Studies on the multiple gene system and gene linkage of lactate dehydrogenase in Rana chensinensis]. AB - (1) With polyacrylamide gel electrophoresis, the LDH isozymes of 333 individuals of Rana chensinensis were analyzed, the frogs were sampled from four geographic population in Shanxi province, P.R. China. The results indicated that the LDH isozymes of Rana chensinensis are determined by three genes, they are LDH-A, LDH B, LDH-C, LDH-A is a monomorphic locus, both LDH-B and LDH-C are polymorphic loci and each locus has two alleles, respectively. LDH-B links with LDH-C closely, it is assumed that LDH-C was produced by duplication of LDH-B. (2) Studies on the thermalstability, urea sensitivity and specific distribution in tissues showed that the order of LDH isozymes stability for heat and urea treatment is A4 > B4 > C4. A4 is abundant in skeleton muscle and B4 predominant in heart muscle and ovary. LDH-C expresses specifically in eye and ovary. (3) Ldh-b and Ldh-b' distribute differently in different geographic populations, with the increase of latitude, the frequence of Ldh-b becomes greater in population. PMID- 8695176 TI - [RAPD markers for wheat chromosomes in Langdon disomic substitution lines]. AB - Optimal conditions were developed for a random amplified polymorphio DNA (RAPD) assay of hexaploid bread wheat and tetraploid durum wheat. AmpliTaq Stoffcl fragment was found to be better than Taq DNA polymerase in generating RAPDs. Studies on chromosome specific RAPD markers of the A- and B- and D-genome were performed using the complete set of Langdon disomic substitution lines and the parental lines (Langdon and Chinese Spring) as templete. Seven out of twelve arbitrary primers (all Operon 10-mer sequences) yielded 13 products that could be assigned to 1.0 chromosomes of A- and B- and D-genome, five of 13 markers for A genome (2A: J6a and J11b; 3A: D11b; 6A: J17; 7A: J15a), seven for B-genome (1B: J11c; 2B: D5, D11c and J18) and one for D-genome (1D: J11a). Using Chinese Spring ditelosomic lines, four RAPD markers were further mapped to a specific chromosome arm (i.e., J11b-2AL, J17-6AL, D11c-2BL, and J11a-1DL). This study demonstrates that reproduoible RAPID markers can be generated and assigned to wheat chromosomes except 4AL, using Langdon disomic substitution lines and Chinese Spring euploid and aneuploids as malerids. PMID- 8695177 TI - [Analytic methods for seed models with genotype x environment interactions]. AB - Genetic models with genotype effect (G) and genotype x environment interaction effect (GE) are proposed for analyzing generation means of seed quantitative traits in crops. The total genetic effect (G) is partitioned into seed direct genetic effect (G0), cytoplasm genetic of effect (C), and maternal plant genetic effect (Gm). Seed direct genetic effect (G0) can be further partitioned into direct additive (A) and direct dominance (D) genetic components. Maternal genetic effect (Gm) can also be partitioned into maternal additive (Am) and maternal dominance (Dm) genetic components. The total genotype x environment interaction effect (GE) can also be partitioned into direct genetic by environment interaction effect (G0E), cytoplasm genetic by environment interaction effect (CE), and maternal genetic by environment interaction effect (GmE). G0E can be partitioned into direct additive by environment interaction (AE) and direct dominance by environment interaction (DE) genetic components. GmE can also be partitioned into maternal additive by environment interaction (AmE) and maternal dominance by environment interaction (DmE) genetic components. Partitions of genetic components are listed for parent, F1, F2 and backcrosses. A set of parents, their reciprocal F1 and F2 seeds is applicable for efficient analysis of seed quantitative traits. MINQUE(0/1) method can be used for estimating variance and covariance components. Unbiased estimation for covariance components between two traits can also be obtained by the MINQUE(0/1) method. Random genetic effects in seed models are predictable by the Adjusted Unbiased Prediction (AUP) approach with MINQUE(0/1) method. The jackknife procedure is suggested for estimation of sampling variances of estimated variance and covariance components and of predicted genetic effects, which can be further used in a t-test for parameter. Unbiasedness and efficiency for estimating variance components and predicting genetic effects are tested by Monte Carlo simulations. PMID- 8695178 TI - [Transgenic Brassica napus resistant to turnip mosaic virus]. AB - A system for obtaining regenerated plantlets of "double low" Brassica napus by using cotyledonary petioles as material was established. The turnip mosaic virus coat protein (TuMV-CP) gene inserted in the binary vector pBTu in the Agrobacterium tumefaciens LBA 4404 was integrated into Brassica napus through co culture of cotyledonary petioles with LBA4404, and the material in co-culture was selected under the stress of Kanamycin. Regenerated plantlets were obtained, and the specific TuMV-CP gene was proved to be integrated into the genomic DNA of the regenerated plants by the specific PCR amplification, dot hybridization and Southern blot. All these transgenic plants were proved to be resistant to virulent TuMV by virus challenge in different degree. PMID- 8695179 TI - [Linkage analysis between milk protein loci and lactation trait loci]. AB - The linkage relationship between milk protein loci and lactation trait loci, such as milk yield, fat percent, protein percent and dry matter percent, were fully investigated by the methods of heterozygosity analysis and linkage group analysis. The results showed that each single protein locus showed a higher homozygosity while the three easein loci showed a lower homozygosity when they were investigated simultaneously. There was no significant regression of deviations in lactation traits on overall marker heterozygosity. Significant linkage between kappa-CN locus and milk fat percent and protein percent, and that between alpha sl-CN locus and 305-d milk yield were found. PMID- 8695180 TI - [A PCR marker-based selection for resistance to bacterial blight in rice]. AB - Molecular marker-based selection in plant breeding requires not only suitable molecular markers closely linked to the known genes, but a simple, economic and reliable analyzing technique. We report here a useful PCR marker for genetic diagnostics in breeding for resistance to rice bacterial blight. Xa21 is a newly found gene of rice which confers resistance to bacterial blight caused by Xanthomonas oryzae pv. oryzae. We produced two F2 populations between one resistant line IRBB21 containing Xa21 and two susceptible varieties, respectively. One PCR marker, PB78, detected polymorphism between the susceptible varieties and the resistant line. Cosegregation between Xa21 and PB78 was studied in the two F2 populations. The results showed that Xa21 was closely linked to the molecular marker, the crossing over value was 2.48%. Marker-based selection revealed that 100% of the plants with homozygous resistant genotype of PB78 showed resistance to bacterial blight. The available approaches detecting molecular markers in plant breeding are also discussed. PMID- 8695181 TI - [Studies on the cloning, expression and function of the yeast PHO 80 gene]. AB - Through in situ hybridization, a 4.2 kb Pst I-BamH I fragment was obtained from S. cerevisiae gene library. The cloned fragment contained 1100 bp upstream sequence and 879 bp coding sequence of the PHO80 gene. Coding region of PHO80 gene was substituted with URA3 gene and used as donor to transform YPH499 to URA3. A pho80 mutant resulted from deletion of the chromosomal counterpart in PHO80 was obtained. In vivo functional study of the PHO80 gene indicated that PHO80 was a negative regulator in the Pi-repressible acid phosphatase system including the structural genes PHO5 and PHO11 and the regulatory gene PHO81, whereas the expression of PHO4 or PHO85 was independent of PHO80. The coding region of PHO80 was fused in frame with LacZ and beta-galactosidase activities in various cells was determined. The results Showed that the PHO80 gene was expressed at a low level and suppressed by itself and PHO85. PMID- 8695182 TI - [The study of insertion sequence IS2. II. Polarity effect of the mutant and DNA sequence analysis]. AB - Insertion Sequence IS2 brought about polarity effect when it was inserted into a transcription. In study I, we found that the into polarity effects were different whether IS2 was inserted into the left side or into the right side. In this study, further research also showed that the polarity effects were very different when different IS2 was inserted into the left side. The analysis on IS2 DNA sequence showed that when the direction of IS2 ORF was the same as the transcription direction of the inserted transcription, known as a left insertion, the polarity effect was weaker. When the direction of IS2 ORF was opposite to the transcription direction of the inserted transcription, known as a right insertion, the polarity effect was stronger. When a stop codon was produced in IS2 due to base mutation, the polarity effect of a left insertion was increased. PMID- 8695183 TI - [Molecular mechanism of suppressing lambda N gene's expression in E. coli ribosomal protein S12 streptomycin-dependent mutant]. AB - Using the polymerase chain reaction (PCR) method, the rpsLd gene was amplified and cloned, which encodes the streptomycin-dependent (Smd) mutant of ribosomal protein S12 in E.coli T83. The result of DNA sequencing showed an AAA to CAA mutation at codon 42, leading to the substitution of glutamine (Gln, Q) for lysine (Lys, K). According to the principle of Garnier, we predicted that there might be alterations in the secondary structural propensity of protein S12 due to the mutation. The outcome indicated that the beta-turn propensity at position 42 and its nearby region was increased evidently and the relative position of relevant subdomains were changed. As a result, the special conformation of the whole protein S12 was influenced. In view of that ribosomal proteins and ribosomal RNAs (rRNA) mutually adapted in structures and functions, the probable molecular mechanism. That how protein S12 Smd mutant in E.coli T83 suppressed lambda N gene's expression is discussed. PMID- 8695184 TI - [Site-directed mutagenesis of the gene of Echistatin Leu14-Lys15-Glu16]. AB - In order to probe relationship of inhibition activity of platelet aggregation and RGD conformation beneficial to binding in Echistatin, we used the site-directed mutation technique to install another RGD sequence into one of irregular loops retaining a degree of conformational flexibility and substituting Leu-14, Lys-15, Glu-16 of (Leu-28) Echistatin. The mutant (Arg-14, Gly-15, Asp-16, Leu-28) Echistatin did not lose its inhibition activity of platelet aggregation; however, it showed at least as high activity as (Leu-28) Echistatin, or even a little higher than (Leu-28) Echistatin. This suggested that both RGD sequences inserted in one loop with a degree of conformational flexibility. The original RGD (Arg 24, Gly-25, Asp-26) motif projecting significantly from the surface of the scaffold or core might contribute synergistically to the function of inhibiting platelet aggregation induced by 10 mumol/ L ADP (final concentration). These results are useful in the elucidation of the relationship of structure and function of Echistatin-like disintegrins and GPIIb/IIIa-like integrins. PMID- 8695185 TI - [Calculation of specific evolution rate of proteins based on phylogenetic]. AB - A method of calculating specific protein evolution distance and evolution rate is presented. This is based on the reconstruction of the phylogenetic tree and on the deduction of ancestral sequences according to temporally homologous protein sequences. The evolution distance and evolution rate are calculated from the difference percentage of the sequence between the temporal and deduced ancestral sequences. A comparison with Dayoff simulation method and an example of using it to calculate the specific evolution rates of mammalian erythropoietin. The method presented here would be specially useful under certain circumstances. PMID- 8695186 TI - [Cloning and sequencing of VH and VL genes of an anti-human lung adenocarcinoma monoclonal antibody]. AB - By comparing the conserved regions at each end of the nucleotide sequences of murine germ-line genes encoding FR1 and FR4 regions of immunoglobulin heavy and light chain variable regions, we designed two sets of primer for amplification of VH and VL genes. Hybridoma cell WLA-2C4, secreting an antihuman lung adenocarcinoma McAb, was cultured and the genome DNA was extracted and used as template for PCR. After PCR the desired VH and VL fragments were amplified. The PCR products were then cloned into pUC19 vector. By screening and identification, several recombinants that had been inserted with the target fragments were obtained. Then they were sequenced with Sanger's method. It was confirmed by computer-assisted comparative sequence analysis that clones of full-length and potentially functional VH and VL genes from the hybridoma cell line WLA-2C4 were ob-tained. PMID- 8695188 TI - Teaching complete dentures. AB - Success in wearing complete denture depends, in order of importance, on motivation, neuromuscular control and technical considerations. To address the two aspects of motivation and neuromuscular control, fourth year students at Sydney University are taught a protocol which encompasses duplication of the patient's existing denture and modification of this duplicate to satisfy the patient's needs and wants. This modified duplicate denture acts as a diagnostic prototype which is used as a guide during construction of the new denture. PMID- 8695187 TI - Magnet overdentures. AB - Magnets were first used for overdenture retention in 1977. A novelty then, they are now an accepted alternative to conventional attachments, and available commercially from a number of manufacturers. Nearly all of them use a "closed field" magnet configuration, which provides optimum retention and eliminates any possibility of magnetic field effects on tissues. Initial corrosion problems are now being eliminated by improved designs. Clinical experience has shown that overdentures preserve alveolar bone and that magnetic retention can be used effectively on tooth roots which would have a poor prognosis with conventional attachments. Magnets can also be used to retain overdentures against implants as an inexpensive alternative to conventional implant dentures. PMID- 8695189 TI - The prevalence and aetiology of craniomandibular disorders among completely edentulous patients. AB - Two hundred and one patients awaiting complete denture treatment with the Victorian Denture Scheme participated in the study. One hundred and fifty three of these were females and 48 were male. The majority of the participants were above 65 years of age and had been wearing their present complete dentures for more than 15 years. Most of these patients were seeking prosthodontic treatment in order to replace their dentures which they said had become "loose" over the years. The information obtained from the interview-questionnaire and the clinical examination showed that parafunctional habits were common among 70% of the participants. In addition to this, pain and tenderness to palpation of the lateral pterygoid muscles was the only symptom which had a significant percentage distribution among the patients. Statistical analysis showed that there were some signs and symptoms of craniomandibular disorders which were correlated with these patients' complaint of loose dentures. It was also shown that signs and symptoms of craniomandibular disorders may be related to the patients' age and the number of sets of complete dentures worn in the past. PMID- 8695190 TI - Titanium. A review of investments for high temperature casting. AB - Conventional silica (SiO2) based dental casting investments are used for the casting of pure titanium using casting machines specifically developed for this metal. Highly reactive molten titanium reduces SiO2 and titanium is in turn oxidised. For this reason possible alternatives to SiO2 have been studied in the past decade and MgO and Al2O3 are the most common in current commercial investments released for titanium casting. The surface of titanium castings presents a layered structure and its evaluation in relation to clinical performance requires further study. It is also urgently required to know setting and thermal behaviour of the newly developed investments for successful compensation of metal shrinkage. PMID- 8695191 TI - Impact testing of denture base polymers. AB - Acrylic resin has been the denture base material of choice since its initial production in 1936, due to its aesthetic properties and ease of processing. It would be desirable, however, to have a material which is also unbreakable under clinical conditions. A wide range of materials has been suggested for use as denture base materials. The impact resistance of a polysulphone denture base polymer has been compared with that of a linear poly(methyl methacrylate) and four rubber-methacrylate denture base polymers. When tested under oral conditions, the polysulphone material had an impact resistance about twice as high as the best rubber-methacrylate and about four times as high as ordinary poly(methyl methacrylate). PMID- 8695192 TI - The dimensional accuracy and stability of composite inlays. AB - The dimensional accuracy and stability of two composite inlay materials was studied by assessing polymerisation shrinkage, thermal expansion and water sorption. Impression taking, die accuracy and stability and wear of the material were also considered. The mean coefficients of thermal expansion (20 to 65 degrees C) determined using a differential dilatometer were: Clearfil 21 X 10-6 and Isosit 31 X 10-6. A metal die similar to that used by Taylor in 1931 to assess casting shrinkage of gold inlays was used to assess polymerisation shrinkage. Isosit had a mean protrusion value of 0.321 mm providing a value for linear polymerisation shrinkage of 0.9%. In contrast Clearfil specimens had a mean protrusion of 0.108 mm providing a value for linear polymerisation shrinkage of 0.3%. The expansion due to water sorption at seven days was very small and did not offset the polymerisation shrinkage. However, these must be interpreted in light of the results of long term immersion studies. The total dimensional change of an Isosit specimen is -1.06%. For an inlay of 5 mm in diameter the linear dimensional change would be 54 micrometers, providing a cement space of 27 micrometers. The total dimensional change of a Clearfil specimen is -0.53%. For an inlay of 5 mm in diameter the linear dimensional change would be 27 micrometers, providing a cement space of 13.5 micrometers. PMID- 8695193 TI - Resilient lining materials for dentures. AB - Modern resilient liners may be broadly classed as plasticized resins, silicone rubbers and fluoropolymers. Desirable properties would be pronounced softness and resiliency, or visco elasticity. Compression tests of Molloplast B (a silicone rubber), Kurepeet (a fluoropolymer), Visco-gel (a tissue conditioner) and Xantopren ( a silicon impression material) (as control) showed a displacement of 4% and recovery to 0.4% permanent deformation after 15s of loading for Molloplast and Xantopren, and up to 32% and 13% displacement respectively for Visco-gel and Kurepeet followed by considerable permanent deformation. Recovery of the latter showed a typical curve for visco-elasticity. The small amount of initial deformation of the elastic materials on the other hand indicated unyielding and consequently unsatisfactory properties. The deformation of Kurepeet was not as great as Visco-gel but the fact that it was visco-elastic meant that it was likely to be a suitable long-term lining material. It therefore complied with requirements that a resilient denture liner should be soft and visco-elastic. PMID- 8695194 TI - Denture-induced fibrous inflammatory hyperplasia (epulis fissuratum): research aspects. AB - Denture-induced fibrous inflammatory hyperplasia (FIH) is a common lesion of the oral mucosa which can be treated by either surgical excision, conservative methods or both combined. Clinical aspects are briefly reviewed and a newer conservative approach to treatment is suggested. This is based on the observation that light pressure using soft lining materials may facilitate shrinkage of the fibrous mass. The histopathogenesis is discussed from the view point of the modern technologies of immunocytochemistry, and digital image analysis. The recent development of a microwave instrument with sophisticated control of power and temperature is discussed and its use in the field of histotechnology outlined. PMID- 8695195 TI - The In-Ceram metal free ceramic system for fixed prosthodontics. AB - The recent return of interest to Porcelain Jacket Crowns has been accompanied by the development of improved ceramic systems for their fabrication. One such system, In-Ceram, uses an interesting variation of the aluminous porcelain (Vitadur Alpha). It is important to realise the requirements for tooth preparation so that long lasting restorations may be produced. This article endeavours to present a method for preparation which is both efficient clinically and satisfies the physical requirements for this type of metal-free ceramic procedure. PMID- 8695196 TI - Awareness and needs of dental implants by patients in New South Wales. AB - An exploratory cross-sectional analytical study of patients presenting for prosthodontic treatment to private general dental practices and public hospitals in New South Wales was completed. Significantly more patients attending private dentists had 'heard' of dental implants compared with the hospital group (G2=79.404; df=1; p<0.001) and significantly more of the former patients were aware that dental implant treatment is available in New South Wales (G2=32.823; df=1; p<0.001). Of the patients attending private practice 19.2% felt that it is likely that they may require dental implant treatment in the future and 14.1% of their current treatment requests involved implants. These figures may be considered moderately high whereas the corresponding figures for the patients attending public hospitals were low. PMID- 8695197 TI - [Basal and non-hair cells in the regenerated mucosa of the maxillary sinus]. AB - In 10 albino New Zealand rabbits, a study was made of the regeneration of the hair cells in the maxillary sinus mucosa three months after removing the sinus mucosa. Using optical microscopy and transmission and scanning electron microscopy, basal and non-hair cells were studied as the probable origin of hair cells. The regenerated sinus mucosa showed areas of epithelium consisting only of a basement membrane and a layer of basal cells. Ultrastructurally, two types of basal cell were visible in the regenerated mucosa. The proportion of non-hair cells was greater than in normal mucosa. PMID- 8695198 TI - [Acoustic distortion product recording in patients with sensorineural hearing loss]. AB - Distortion products are a subtype of otoacoustic emission. The normality of distortion products reflects correct outer hair cell function. Test results obtained from patients with neurosensorial, cochlear and retrocochlear hearing loss were analyzed, focusing on four points: correlation with audiometric results, reliability for the follow-up of dynamic cochlear disorders, frequency specificity, and topographic diagnosis. PMID- 8695199 TI - [Cytogenetic study in otosclerosis]. AB - In 50 patients (32 females and 18 males) with otosclerosis who underwent stapedectomy, a cytogenetic study of chromosomal abnormalities was made. No description of G banding in patients with otosclerosis was found in the literature. No chromosomal abnormalities were found in the karyotype using this technique. PMID- 8695200 TI - [Acoustic rhinometry in a normal population]. AB - Acoustic rhinometry is a new method for objectively studying the geometry of the nasal cavity which is based on sound-wave reflection. One hundred normal subjects were studied by acoustic rhinometry under baseline conditions and after decongestion of the nasal mucosa. The minimum cross-section, area distance from this point to the nostril, nasal cavity volumen, and variations in these parameters after decongestion gave useful information about the state of the nasal cavity under normal conditions. PMID- 8695201 TI - [Conservation surgery for supraglottic carcinoma. Oncological and functional results]. AB - Conservative surgical treatment of carcinomas limited to the supraglottic larynx has been shown to be an oncologically and functionally effective therapeutic approach. A retrospective study was made of the medical records of 792 patients who underwent conservative surgery for supraglottic laryngeal carcinoma at the Gregorio Maranon University Hospital of Madrid, Spain, in 1962-1991. Our theoretical protocol for treating supraglottic tumors is presented. The oncological results (survival, local control, recurrences) and functional results (breathing, swallowing, voice quality) were analyzed. PMID- 8695202 TI - [The study of the evolution of laryngeal premalignant lesions]. AB - Hyperkeratosis of the laryngeal epithelium is considered a clinically premalignant lesion that develops into invasive carcinoma in about 7-20% of cases. We reviewed 125 cases of patients with laryngeal keratosis in biopsy obtained by direct laryngocopy over a 10-year period. The evolution of these lesions to malignancy was conditioned by age, the presence of atypias in the initial lesions, and smoking; smoking is a modifiable factor. Surgery is the treatment of choice, with periodic follow-up for three to five years. The literature was reviewed. PMID- 8695203 TI - ["Near-total" laryngectomy: functional results]. AB - "Near total" laryngectomy is an alternative to total laryngectomy in some advanced laryngeal tumors. A prospective study was made of the results obtained in 40 patients treated with near total laryngectomy. Speech was achieved in 74.3% of patients within a mean time interval of 63 days. Of the subjects who had more than 5 months of follow-up, 84.6% could speak. Half of the patients who achieved speech used the Barton-Mayo button and did not need to use their hand for phonation. Major swallowing problems were found in 13.9%. The most common complication was pharyngo-cutaneous fistula (58.9%). PMID- 8695204 TI - [Epidemiology and clinical manifestation of laryngeal tumors treated at the Hospital Virgen de la Salud of Toledo, Spain]. AB - A descriptive, retrospective study was made of 110 cases of laryngeal neoplasm diagnosed at the Hospital Virgen de la Salud of Toledo, Spain, between 1988 and 1991. Cases were studied by sex, age, alcohol use, smoking, first symptom, and time to treatment. PMID- 8695205 TI - [Review of epiglottitis]. AB - Seven cases of acute epiglottitis in children (mean age 38 months) are reported. The major clinical features are described. The review of the literature on current diagnosis and treatment underlined the value of early orotracheal or nasotracheal intubation when this serious condition is suspected. PMID- 8695206 TI - [Hemangiosarcoma of the nasal cavity]. AB - Hemangiosarcoma is a rarely diagnosed in the nasal cavity and there are few reports in the ENT literature. The most interesting aspect of our 82-year-old male's case was that he presented all the findings characteristic of angiosarcoma, but the final post-mortem diagnosis was unexpected because of the poor information available until that moment. PMID- 8695207 TI - [Juvenile giant nasopharyngeal fibroma: the hinge maxillotomy approach]. AB - A giant juvenile nasopharyngeal fibroma in a 29-year-old male was removed by hinge maxillotomy. The diagnosis and treatment of these tumors is discussed. PMID- 8695208 TI - [Bilateral Warthin tumors. Case report and review of literature]. AB - Tumors of the salivary glands are fairly frequent among the tumors of the head and neck. Cystoadenolymphoma is a benign salivary tumor. A case of bilateral Warthin tumor was diagnosed eight years after the appearance of the first homolateral lesion. The diagnosis, literature review, and treatment are discussed. PMID- 8695209 TI - [Benign lymphoepithelial cervical cyst: a case report]. PMID- 8695210 TI - [Skin flaps with subcutaneous pedicle in the reconstruction of facial defects]. PMID- 8695212 TI - [Systematization of otorhinolaryngology training]. AB - Resident training in otorhinolaryngology is a continuous learning process which includes academic, clinical, and research activities, the purpose of which is to develop skilled specialists. To achieve this goal, systematic planning of the educational process is needed. Planning should contemplate establishing the aims of training, defining the instruments to be used to achieve these aims, and determining how results will be evaluated. We described our philosophy as regards planning the educational process in otorhinolaryngology training, and define and develop the content of the stages involved. In our opinion, systematic application of these principles would facilitate educational efforts, improve specialist training, and enhance the performance of future specialists. PMID- 8695211 TI - [Induction of oral aphthae after anesthesia in a patient with Behcet's disease]. PMID- 8695213 TI - [Simultaneous screening of HPV-6b and 16 in pharyngolaryngeal cancer]. AB - It has been suggested that some human papilloma viruses (HPV) may play a causal role in cancer of the pharynx, larynx, and oral cavity, together with factors such as smoking, alcohol, toxins, and heredity. Using the polymerase chain reaction (PCR), we detected the two most common genotypes in pharyngolaryngeal cancer, HPV-6b and 16, in 15 patients from a series of 57 cases. One patient had both genotypes. The fact that this was the only positive case in which no other risk factors were present, particularly alcohol and smoking, suggests that the synergetic oncogenic action of both viruses could have played an important role in carcinogenesis. PMID- 8695214 TI - [Amplification of oncogene c-erb-B1 and cellular DNA content in squamous cell carcinoma of the head and neck]. AB - Tumoral DNA content was studied by flow cytometry and PCR amplification of c erbB1 in tissue samples from 31 patients with squamous cell carcinoma of the head and neck. Eighteen cases (58%) were aneuploid and 13 (42%) were diploid. Aneuploidy correlated with pharyngeal site and poorly differentiated tumors, but not with clinical stage or metastases. Six (19.3%) cases had c-erbB1 amplification, which correlated with tumor size, nodal metastasis, poor differentiation, and hypopharyngeal site. Only 20% of patients with amplification survived 30 months, compared with 64% of patients without amplification. None of the patients with aneuploidy and c-erbB1 amplification survived more than 15 months. To conclude, the measurement of cellular DNA content and c-erbB1 amplification seem to have prognostic value in squamous cell carcinoma of the head and neck. PMID- 8695215 TI - Quality of prostate cancer data in the cancer registry of Norway. AB - Completeness of reporting and internal validity of the coding of prostate cancer in the Cancer Registry (CR) in Norway were examined. Data were matched and evaluated against diagnostic indices at eight selected hospitals in the country and against death certificates from Statistics Norway. Validity control was based on detailed re-analysis of an approximately 1% sample of the registered data during the period 1957-1986. The deficiency in reporting of prostate cancer was less than 1%. The grave deficiencies in hospital patient registers were considered to be of non-systematic nature and should, therefore, not impair the reliability of our investigation of incompleteness. The validity control revealed errors in 0.5% of the data elements, or, illustrated differently, 6% of the patient files had an error, of importance or not, in one of the data elements. One false positive registration was found among 298 controlled patient files (0.3%). PMID- 8695216 TI - Cancer of the prostate in Norway 1957-1991--a descriptive study. AB - The incidence and mortality of prostate cancer from 1957 to 1991 were studied in the Cancer Registry of Norway. The age-adjusted incidence rate increased from 26.3 to 46.6 per 100,000 person-years during the period, and more than 2000 cases are now registered yearly. The increase tends to be higher in the younger age groups, 50-59 years, and among the oldest, 90+ years. An increase was also found in cause-specific mortality, signifying a real increase in incidence over time. There is a slight urban dominance in incidence of prostate cancer. Autopsy findings account for less than 1.7% of the total. The histo- and cytological verification rate reached 94% in 1987-1991 and the percentage of localised cases was 68.4%. The median age at diagnosis in 1987-1991 was 75.1 years. Data on stage at time of diagnosis, histological differentiation and survival, reflect a small influence of earlier diagnosis. Model analysis revealed no particular birth cohort effect, either on incidence or on mortality. PMID- 8695218 TI - What do we know on variables influencing clinical decision-making in elderly cancer patients? PMID- 8695217 TI - Does age at the last birth affect breast cancer risk? AB - We studied the relative importance of age at first and age at last full-term pregnancy (FTP) in a large data set of 3950 cases and 11,510 controls, of whom 2263 cases and 7359 controls had two or more FTPs. We found that a 5-year delay in age at first FTP is associated with an odds ratio of 1.17 (95% confidence interval of 1.05-1.29), whereas a 5-year delay in the age of last FTP is associated with an odds ratio of 1.05 (95% confidence interval 0.96-1.14). Misleading results concerning the relative importance of age at first and last FTP may be obtained when parity is only adjusted in broad categories, uniparous women whose FTP is, simultaneously, both the first and the last are not excluded from the analysis, and age at any FTP between the first and last is not controlled for. PMID- 8695219 TI - Ectopic vasopressin expression in MMTV-v-Ha-ras transgenic mice delays the onset of mammary tumorigenesis. AB - Neuropeptides are often ectopically expressed by non-endocrine tumours. We used transgenic mice to assess the effect of ectopic expression of the neuropeptide, vasopressin, in mammary tumours induced by the transgenetic expression of an activated ras oncogene. Mice bearing a mouse mammary tumour virus-vasopressin (MMTV-VP) fusion transgene synthesise authentic VP in mammary ducts and alveoli. Bitransgenic mice bearing both MMTV-VP and MMTV-v-Ha-ras transgenes developed tumours that were histologically indistinguishable from those of single MMTV-v-Ha ras animals. However, tumour onset was significantly delayed in the bitransgenic animals. These data provide evidence that an ectopic neuropeptide can slow the development of ras tumours in vivo. PMID- 8695220 TI - Multiple drug resistance-related messenger RNA expression in archival formalin fixed paraffin-embedded human breast tumour tissue. AB - A method is described by which RNA, suitable for reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, can be extracted from formalin-fixed paraffin embedded (FFPE) tissues and subsequently used for detecting the expression of several genes. Using this technique, RNA can be extracted from specimens, quantified, reverse transcribed and regions of interest amplified and analysed within 36 h. The tissue specimens included in this study were from human breast carcinoma, investigating a range of genes associated with the development and/or maintenance of multiple drug resistance (MDR). This technique, applied to archival tissues, offers great potential for increasing our understanding of alterations in expression levels of genes associated with MDR. The method developed is also applicable to studies on expression of other genes in paraffin embedded tissues. PMID- 8695221 TI - Anti-oestrogen stimulation of ERBB2 ectodomain shedding from BT-474 human breast cancer cells with ERBB2 gene amplification. AB - Oestrogen has previously been shown to downregulate the expression of ERBB2 oncogene in human breast cancer cells, which contain a normal non-amplified ERBB2 gene. However, amplified ERBB2 seems to escape from hormonal regulation. We studied shedding of the extracellular domain (ectodomain, ECD) of the ERBB2 encoded protein in BT-474 human breast cancer cells treated with oestrogen or anti-oestrogen. Oestrogen-responsiveness of these cells has been previously demonstrated by stimulation of cell growth and expression of pS2, a marker gene known to be regulated by oestrogen receptor at transcriptional level. The concentration of the soluble ECD in the culture medium was increased by the anti oestrogen toremifene as a function of time. In contrast, the level of ERBB2 mRNA and protein in cell lysates was not stimulated, but was transiently suppressed by toremifene. In the presence of oestrogen, the level of ECD remained low. The increased shedding of ECD in the presence of toremifene, without parallel change in ERBB2 transcripts (4.8 and 2.3 kb) and in cellular ERBB2 protein level, suggests that toremifene specifically contributes to the shedding of the ERBB2 ectodomain. These results show that shedding of ECD is an additional level of regulation of ERBB2 by the anti-oestrogen toremifene. This may contribute to resistance to growth inhibition by anti-oestrogens of breast cancers which overexpress ERBB2. PMID- 8695222 TI - Expression of MHC molecules and ICAM-1 on non-small cell lung carcinomas: association with early lymphatic spread of tumour cells. AB - Early microdissemination of tumour cells determines the prognosis of patients with apparently localised non-small cell lung cancer (NSCLC). Monoclonal antibodies to epithelial antigens can now be used to detect single carcinoma cells present in mesenchymal secondary organs such as bone marrow or lymph nodes. The present study was designed to obtain insights into the potential role of the immune system in lymphatic and haematogenous microdissemination of NSCLC cells. Using immunohistochemical staining of primary NSCLC, we assessed the expression pattern of molecules mediating an efficient cellular immune response, that is, MHC class I and class II antigens and the intercellular adhesion molecule-1 (ICAM 1). All 58 patients evaluated were staged as free of overt metastases by conventional clinico-pathological screening. Isolated tumour cells in bone marrow or lymph nodes were identified with mAb CK2 to cytokeratin component No. 18 and mAb BerEp-4 to glycoproteins of 34 and 39 kd present on epithelial cells, respectively. MHC class I expression on primary tumours was reduced or absent in 6/10 (60.0%) patients with isolated cancer cells in lymph nodes as compared to 6/33 tumours (18.1%) without such tumour cell dissemination (P = 0.01). MHC class II molecules on primary tumours were detected in 1/10 (10.0%) patients with micrometastases to regional lymph nodes and in 10/33 (30.3%) patients without such a tumour cell spread. None of the 10 patients with nodal microdissemination expressed ICAM-1 on their primary NSCLC, while such expression was detectable in 12/33 (36.4%) patients without this dissemination (P = 0.01). In contrast, the detection of tumour cells in bone marrow was not correlated to the expression of any of these immunoregulatory molecules. Our data suggest that escape caused by deficient expression of MHC class I antigens and ICAM-1 on tumour cells may support homing or survival of disseminated tumour cells in lymphoid tissue. PMID- 8695224 TI - Cathepsin D and breast cancer. PMID- 8695223 TI - Inhibitions of protein kinase C and proto-oncogene expressions in NIH 3T3 cells by apigenin. AB - Apigenin, a low-toxic and non-mutagenic plant flavonoid, suppresses 12-O tetradecanoyl-phorbol-13-acetate (TPA)-mediated tumour promotion of mouse skin. TPA has the ability to activate protein kinase C (PKC) and induce proto-oncogene expression. Our study shows that apigenin inhibits PKC by competing with ATP, and exhibits an IC50 value of 10 +/- 0.5 microM. Apigenin also reduces the level of TPA-stimulated phosphorylation of cellular proteins. Of the protein tyrosine kinases tested, the fibroblast growth factor (FGF) receptor was most strongly affected by apigenin (IC50 20 microM), and pp60v-src most weakly affected (IC50 > 200 microM). Treatment of NIH 3T3 cells with 100 ng/ml TPA and 10, 50 and 100 microM apigenin resulted in 50, 80 and 100% suppression of TPA-induced C-JUN expression, respectively. Treatment of TPA with 10 microM apigenin inhibited TPA induced C-FOS expression. TPA-stimulated cell growth was suppressed by 25 microM apigenin. Our results provide some evidence for understanding apigenin's inhibitory effects of TPA-mediated tumour promotion. PMID- 8695225 TI - The antimetabolite Tiazofurin (TR) inhibits glycoconjugate biosynthesis and invasiveness of tumour cells. AB - We investigated the effect of Tiazofurin (TR-2-beta-D-furanosylthiazole-4 carbamide) on tumour cell invasion using metastatic 3LL-HH murine lung carcinoma and HT168-M1 human melanoma as experimental models. TR pretreatment of 3LL-HH cells, in a dose range of 15-60 microM, caused inhibition of cell proliferation, adhesion to plastic and extracellular matrix proteins. The TR-induced altered matrix interactions of 3LL-HH cells were reflected in decreased migration through matrix-covered filters. Analysis of the expression of certain invasion markers indicated that TR suppressed the expression of alpha v beta 3 integrin and MMP2 metalloproteinase. Biochemical studies indicated that 24 h 60 microM TR treatment of 3LL-HH cells inhibited glycosylation of a wide range of glycoproteins with the most pronounced effect on proteoglycans. TR pretreatment of 3LL-HH tumour cells resulted in the loss of lung colonisation potential in vivo. Furthermore, in vivo TR treatment inhibited the formation of liver metastases of 3LL-HH murine carcinoma. TR treatment also induced inhibition of integrin and MMP2 expression, migration and liver colonisation of the human melanoma HT168-M1 cell line. Since the TR concentration which inhibited various cellular functions was much lower for cell adhesion and lung colonisation than for cell proliferation, we suggest that the predominant effect of TR is the inhibition of metastasis in these model systems. We also suggest that both the effect of TR on tumour cell proliferation and on extracellular matrix interaction contribute to its remarkable antimetastatic potential in vivo. PMID- 8695226 TI - SR8--the establishment and characterisation of a new ovarian carcinoma cell line and xenograft model. AB - A new cell line, SR8, and xenograft model of ovarian carcinoma has been established in this laboratory over the past 20 months from a patient with advanced ovarian cancer. Electron microscopic examination of SR8 cells demonstrated the presence of desmosomes and tonofilaments; SR8 cells expressed epithelial membrane antigen (EMA) and glandular associated cytokeratin, all of these confirmed the epithelial origin of this cell line. In addition, SR8 cells expressed CA125, as did the original ovarian tumour. EGF-R and TP53 expression was identified by immunocytochemistry (ICC) in this line. Nearly all the SR8 cells (93%) expressed HLA-class I antigen while 13.5% expressed HLA-DR. SR8 cells showed near-diploid and -triploid chromosome populations with several clonal and non-clonal rearrangements. Subcutaneous and intraperitoneal xenografting of SR8 cells resulted in invasive tumour production at both sites in 3/4 and 4/4 female nude mice, respectively. These xenografts exhibited similar morphology as that of original tumour and were found to express EMA, cytokeratin, CA125 and TP53. The potential research applications of this cell line are discussed. PMID- 8695227 TI - Immunostaining of human melanomas by a monoclonal antibody to B700 mouse melanoma antigen. AB - Previous studies have shown that B700, an albumin-like murine melanoma antigen, has a human homologue termed H700. Polyclonal antibodies to B700 also bind to all cultured human, swine and hamster melanoma cells, suggesting that B700 is a "pan melanoma" antigen. The objects of this investigation were: (a) to determine if 2 3-3, a monoclonal antibody to B700, can be used to identify human melanomas in formalin-fixed, paraffin-embedded tissues, and (b) to determine the specificity and potential diagnostic value of 2-3-3. Forty-eight of the 49 human melanomas, including spindle melanoma cells, stained positively, as did five of the eight pigmented naevi including cellular spindle naevi. Twenty-six of the 32 human non melanomatous lesions were negative for 2-3-3 staining (weakly positive on one breast carcinoma and positive on five neural tumours). These results indicate that 2-3-3, a monoclonal antibody to the mouse melanoma antigen B700, can be used to identify H700 in archival specimens. 2-3-3 may have an advantage over HMB45, which is the most commonly used antibody for melanoma diagnosis, because of its immunoreactivity with spindle melanocytic lesions. Antibodies to B700 may prove to be a useful adjunct in the diagnosis of human melanoma and related lesions. PMID- 8695228 TI - Adjuvant tamoxifen: 5 year control of dormant disease? PMID- 8695229 TI - High frequency of urothelial cancers in patients with kidney transplantations for end-stage analgesic nephropathy. PMID- 8695230 TI - Lonidamine plus epirubicin and cyclophosphamide in advanced breast cancer. A phase II study. PMID- 8695232 TI - Chemotherapy with doxorubicin, etoposide and cyclophosphamide (DEC) in ovarian cancer persistent after platinum-based treatment. PMID- 8695231 TI - MSH2 sequence variations and inherited colorectal cancer susceptibility. PMID- 8695234 TI - Upper age limit for cervical cancer screening. PMID- 8695233 TI - Dacarbazine, vincristine, bleomycin and lomustine plus natural interferon-alpha for metastatic melanoma. PMID- 8695235 TI - Results of a phase II trial with cystemustine in advanced malignant melanoma. A trial of the EORTC Clinical Screening Group. PMID- 8695236 TI - Octreotide treatment of chemotherapy-induced diarrhoea. PMID- 8695237 TI - Palliative endoscopic therapy of rectal carcinoma. AB - Curative surgery is not feasible in a considerable proportion of patients with rectal cancer because of extensive local spread or metastatic disease. However, most of these patients require palliative treatment to improve the symptoms of the disease, e.g. obstruction, pain and haemorrhage. Palliative surgery may be associated with a morbidity of 20-40% and a mortality of more than 10%. Endoscopic procedures can provide effective palliation with less complications. Before the development of lasers, endoscopic electrocoagulation and cryosurgery were used with some success. Currently, endoscopic Nd:YAG photocoagulation must be considered the treatment of choice in non-resectable rectal cancer. Laser therapy allows effective palliation in 85-95% of the patients, and generally, treatment-related complications occur in less than 10% of the patients and mortality is negligible. Transanal endoscopic resection may be effective in selected patients. New approaches to endoscopic palliation include photodynamic therapy (PDT) and implantation of self-expanding metal stents. PMID- 8695238 TI - Role of oxygen free radicals in cancer development. AB - In aerobic life, oxidative stress arises from both endogenous and exogenous sources. Despite antioxidant defence mechanisms, cell damage from oxygen free radicals (OFR) is ubiquitous. OFR-related lesions that do not cause cell death can stimulate the development of cancer. This review discusses the effects of oxidative stress at the different stages of carcinogenesis. Mutagenesis through oxidative DNA damage is widely hypothesised to be a frequent event in the normal human cell. A large body of evidence suggests important roles of OFR in the expansion of tumour clones and the acquisition of malignant properties. In view of these facts, OFR may be considered as an important class of carcinogens. Therefore, the ineffectiveness of preventive antioxidant treatments, as documented in several recent clinical trials, is surprising. However, the difficulties of antioxidant intervention are explained by the complexity of both free radical chemistry and cancer development. Thus, reducing the avoidable endogenous and exogenous causes of oxidative stress is, for the present, the safest option. In the near future, new insights in the action of tumour suppressor genes and the DNA repair mechanisms may lead the way to additional tools against carcinogenesis from OFR. PMID- 8695239 TI - Selecting high-risk early breast cancer patients: what to add to the number of metastatic nodes? AB - High-risk early breast cancer patients are usually identified by the number of metastatic axillary nodes. To study whether other easily and inexpensively detectable morphological factors are able to detect high-risk patients, we performed a retrospective analysis of tumor size, and skin/fascia and nipple invasion. The data consisted of 941 node-positive cases registered between 1978 and 1991. Tumour size, and skin/fascia and nipple invasion were closely associated with the number of metastatic nodes (chi 2 test). The number of metastatic nodes, tumour size, skin/fascia and nipple invasion significantly affected disease free survival (DFS) and overall survival (OS) at univariate analysis. These results were confirmed by multivariate analysis with a model containing the number of metastatic nodes, tumour diameter categories, skin/fascia invasion, nipple invasion and adjuvant therapy as covariates: all variables significantly and independently affected risk of relapse and of death. All the variables studied were prognostic, within individual nodal categories, for both DFS and OS. In conclusion, the number of metastatic nodes is not the only prognostic tool with which to select high-risk patients for new intensive adjuvant programmes. Tumour size, and skin/fascia invasion or nipple invasion, taken singly or combined, are valuable prognostic factors that can identify patients with few metastatic nodes and poor outcome. On the basis of our data, we believe that a reconsideration of the pT4 category within the pTNM classification is in order, that is, chest wall invasion should be substituted by fascia invasion, and combined skin/fascia invasion could be a subcategory of each class defined by tumour size. PMID- 8695240 TI - A phase II study of paclitaxel in advanced breast cancer resistant to anthracyclines. AB - 33 women with advanced breast cancer resistant to anthracyclines were treated with paclitaxel 175 mg/m2 in a 3 h infusion every 3 weeks. The median age was 53 years (range 30-72) and the median performance status was 1 (range 0-2). 24 (73%) patients had visceral metastases while 22 (67%) had > or = two involved sites. 23 (70%) patients received anthracycline or mitoxantrone in an adjuvant setting and 21 (64%) for advanced disease. There were two (6%, 95% confidence interval (CI) 1 20%) complete responses (CRs) and 12 (36%, 95% CI 20-55%) partial responses (PRs). Median dose intensity of paclitaxel delivered was 58 mg/m2/week. Median time to progression was 24 weeks (range 4-61) and median survival was 41 weeks (range 8-66). Grade 3-4 toxicities included leucopenia (9%), stomatitis (3%), alopecia (91%), neurotoxicity (9%), infection (3%) and diarrhoea (3%). In conclusion, paclitaxel at a dose of 175 mg/m2 exhibits significant activity in advanced breast cancer resistant to anthracyclines. PMID- 8695241 TI - A randomised study comparing granulocyte-colony stimulating factor (G-CSF) with G CSF plus thymostimulin in the treatment of haematological toxicity in patients with advanced breast cancer after high dose mitoxantrone therapy. AB - 54 patients with advanced breast cancer were randomised into a prospective, non blinded, controlled trial to receive: mitoxantrone 28 mg/m2 intravenous day 1 and granulocyte-colony stimulating factor (G-CSF) 5 micrograms/kg/day subcutaneously days 2 to 16 (n = 27) or the same regimen plus thymostimulin (TS) 50 mg/day intramuscular at days 2 to 16 (n = 27). The median time to reach a neutrophil count greater than 0.5 x 10(9)/l was lower in the G-CSF+TS treated group (9.13 versus 3.24 days; P < 0.0005). More patients experienced neutropenic fever in the G-CSF group than in the G-CSF+TS group (59.3% versus 22.2%, P = 0.0119). The incidence, duration and severity of clinically or bacteriologically documented infection were lower in patients who received TS. 16 patients (59.3%) in the G CSF group contracted infection, and 4 patients (14.8%) receiving G-CSF+TS (P = 0.0016). These data indicate that the combination of G-CSF and TS is well tolerated and may enhance haematological recovery following myelosuppressive chemotherapy in patients with advanced breast cancer. PMID- 8695242 TI - An economic model to assess the savings from a clinical application of haematopoietic growth factors. AB - Patients receiving chemotherapy frequently develop fever and neutropenia. Haematopoietic growth factors (HGFs) may decrease the duration of such episodes or may prevent a febrile neutropenic episode. In this study we introduce a Markov type economic model for the hospital which calculates all relevant direct costs and savings of HGF therapy and may support decisions on HGF administration. A distinction is made between patients receiving intensive and standard chemotherapy schedules. Our results indicate that HGFs can induce savings in intensive chemotherapy and standard chemotherapy following neutropenic fever. Prophylactic administration of HGF is cost-effective if the risk of infection is considerable. The risk of infection depends on underlying malignancy, corresponding treatment modalities and the health condition of the patient. The model is meant as an analytical framework and should be used carefully, as not all benefits (e.g. benefits to the patients) are considered. These benefits may be balanced against the additional costs or savings resulting from the economic model. PMID- 8695243 TI - The prognostic value of serum and immunohistochemical tumour markers in advanced gastric cancer. AB - Using a prospectively acquired database of 290 patients with advanced gastric adenocarcinoma, the prognostic significance of serum levels of carcinoembryonic antigen (CEA) (237 patients), alphafeto protein (AFP) (164 patients), beta-human chorionic gonadotrophin (beta HCG) (165 patients), CA19-9 (64 patients) and CA125 (104 patients) and tissue staining for C-erb B-2 (160 patients) and beta HCG (160 patients) was investigated. Serum was taken prior to 5-fluorouracil (5FU)-based chemotherapy and immunohistochemistry was performed on diagnostic specimens. In the univariate analysis, tumour markers of poor prognosis were CEA > or = 5 micrograms/l (P = 0.01; median survival (MS) 42 versus 35 weeks), serum beta HCG > or = 4 U/l (P = 0.02; MS 42 versus 25 weeks), CA125 > or = 35 U/ml (P = 0.03; MS 43 versus 31 weeks) and CA125 > or = 350 U/ml (P = 0.001; MS 42 versus 17 weeks). Other significant factors were poor performance status, the presence of metastases and poorly differentiated tumour histology. Tumours markers of poor prognosis in the multivariate analysis were serum beta HCG > or = 4 IU/l [hazard ratio (HR) 1.7; 95% confidence interval (CI) 2.8-1.1] and CA125 > or = 350 U/ml (HR 2.2; CI 4.2-1.2). There was a degree of subgroup variability in this model but, in general, other factors correlating with a poor survival were poor performance status, metastases and poorly differentiated tumour histology. This is the largest prognostic study of each tumour marker in advanced disease and demonstrates that serum beta HCG and CA125 in gastric cancer prior to chemotherapy do convey an independent poor prognosis which may reflect not just tumour burden but aggressive biology. PMID- 8695244 TI - A phase II trial of fotemustine and cisplatin in central nervous system metastases from non-small cell lung cancer. AB - A phase II study was conducted in order to determine the feasibility and toxicity of cisplatin combined with the nitrosourea fotemustine in central nervous system metastases from non-small cell lung cancer. 31 chemotherapy-naive patients were included between November 1990 and April 1993. Computed tomography scan documented tumour regression in brain metastases was observed in 7 of the 25 evaluable patients, but only 4 of these (16%) lasted more than 4 weeks. In 2 of these 4 patients, the response on central nervous system metastases was considered as complete. The median duration of response was 20.5 weeks and the median survival was 16 weeks overall and 28.5 weeks for responding patients. The limiting toxicity of this regimen was haematological. 2 patients died from infectious pneumonitis while in neutropenia. Treatment delays due to haematological toxicity occurred in 57% of patients. Despite the rather encouraging response rate, such toxicity appears too high when compared to the overall bad prognosis of this population of patients. Cranial radiotherapy remains the standard treatment in this setting and should only be compared in the future to less aggressive schedules. PMID- 8695245 TI - The prognostic value of cathepsin D in breast cancer. A long road to the clinic. PMID- 8695246 TI - The quality of life of patients with newly diagnosed M1 prostate cancer: experience with EORTC clinical trial 30853. AB - This study was undertaken to evaluate the quality of life (QoL) of previously untreated patients with M1 prostate cancer before and during androgen-suppressive treatment. Assessment of QoL was included as an optimal component of EORTC protocol 30853, a phase III trial comparing LH-RH (luteinising hormone-releasing hormone) analogue combined with a non-steroidal anti-androgen versus orchiectomy in patients with M1 prostate cancer. At pretreatment and during the follow-up period, patients were asked to complete a questionnaire assessing their physical and psychosocial functioning, and their symptom levels. Physicians rated the patients' performance status, pain, urological symptoms and erectile function. Due to its optional nature, only a minority of the patients in the trial were recruited for the QoL investigation. 63 patients completed a pretreatment questionnaire, of whom 49 completed a second questionnaire at least once during the initial 15 month follow-up period. While statistically significant correlations were observed between patients' and physicians' ratings of physical functioning and pain, these were of only a moderate magnitude (r = 0.43 and 0.30, respectively). No significant association was observed between physicians' and patients' ratings of micturation problems or of erectile function. Before treatment, fatigue, pain and decreased social role and sexual functioning were the problems most frequently reported by patients. With an average of approximately 1 year follow-up, statistically significant improvements were observed in patients' self-reported urological symptoms and metastatic pain. No significant changes were noted for the other QoL domains assessed. The results of this study confirm earlier findings that physicians' ratings may not reflect accurately the functional health and symptom experience of their patients. Patient-based QoL questionnaires offer the most direct means of evaluating the subjective morbidity associated with prostate cancer and its treatment. To increase participation and compliance rates in future studies, it is recommended that QoL assessment be made mandatory in those clinical trials in which QoL is considered to be an important study endpoint. PMID- 8695247 TI - Helping cancer patients disclose their concerns. AB - Health professionals are reluctant to enquire actively about cancer patients' concerns and feelings. They fear that probing will damage patients psychologically and believe they have had insufficient training in the relevant interviewing skills. In considering how their interviewing skills might be improved, the key question is which interviewing behaviours promote patient disclosure and which inhibit it. To test our predictions about the utility of specific interviewing behaviours, we asked 206 health professionals, who were attending workshops on communication and counselling skills, to interview a simulated patient before and after the workshop to establish the patient's current problems. They were given 20 min to do this and the interviews were tape recorded and transcribed to permit detailed assessment by trained raters using an utterance by utterance analysis. This permitted the form, function, content and emotional level of each utterance to be rated. Correlation coefficients were calculated between specific interviewing behaviours and patient disclosure of significant information. Significant information was defined as any information disclosed by patients about their perceptions of their illness or prognosis or any adverse physical, psychological or social sequelae of their cancer and treatment. Spearman correlation coefficients were calculated between specific interviewing behaviours and patient disclosure. The use of these behaviours by those 41 (20%) of interviewers who achieved most disclosure was compared with those 41 (20%) who obtained least disclosure. Patient disclosure of significant information was promoted by the use of open directive questions, focusing on and clarifying psychological aspects, empathic statements, summarising and making educated guesses. The use of leading questions, focusing on and clarifying physical aspects, moving into advice and reassurance mode inhibited patient disclosure. Inhibitory behaviours were used 2-3 times more frequently before training than facilitative ones. Training of health professionals involved in cancer care should, therefore, ensure they acquire these positive skills and relinquish the inhibitory behaviours. PMID- 8695248 TI - An open randomised cross-over study on granisetron versus ondansetron in the prevention of acute emesis induced by moderate dose cisplatin-containing regimens. AB - The aim of the study was to compare granisetron (GRA) with ondansetron (OND) in the prevention of acute emesis in consecutive chemotherapy-naive patients admitted to our department to receive a cytotoxic treatment containing cisplatinum (CP) at a dose > or = 50 mg/m2. Eligible patients were randomised at their first cycle to receive either OND or GRA with cross-over of the anti-emetic treatment on the second cycle. The cytotoxic treatments included five different multidrug regimens containing CP (median dose 60 mg/m2, range 50-70 mg/m2) administered on day 1 and repeated every 21-28 days. OND was administered at the dose of 8 mg x 3 i.v. on day 1 and 8 mg x 2 orally on day 2. GRA was always administered at the dose of 3 mg i.v. on day 1. 124 patients entered the study. 58 patients received OND at their first cycle and 66 received GRA. Complete protection of acute emesis with OND and GRA was observed, with the first and second cycles combined as follows: nausea 53 and 60%, vomiting 68 and 71%, respectively (no statistically significant difference). The cross-over analysis comprising 101 patients confirmed no difference between the two anti-emetic treatments. 21 patients (19%) on OND and 14 patients (12%) on GRA suffered headaches (P = 0.15). 25 (25%) patients preferred OND, 45 (45%) preferred GRA, while 31 (30%) expressed no preference (P = 0.003). However, these differences also depended on the sequence of anti-emetics in the cross-over. In conclusion, in this study, a single dose of GRA is demonstrated to be as effective as multiple doses of OND in the prevention of acute emesis. PMID- 8695249 TI - MDR1 gene expression: evaluation of its use as a molecular marker for prognosis and chemotherapy of bone and soft tissue sarcomas. AB - Successful chemotherapeutic treatment of malignant tumours is often limited by the intrinsic or acquired multidrug resistance (MDR). The classical MDR phenotype is characterised by reduced drug accumulation within the cell, caused by overexpression of the MDR1 gene encoded P-glycoprotein. Some reports have been published evaluating MDR1 expression as a molecular marker for response to chemotherapy in human bone and soft tissue sarcomas. In this review, an attempt is made to summarise the accuracy of the measurement of MDR1 expression for use in prognosis, as well as in decisions on chemotherapeutic treatment of sarcomas. In addition, general problems for the performance of such studies is discussed. PMID- 8695250 TI - The breast screening controversy. PMID- 8695251 TI - Radiolabelled mIBG in the treatment of neuroblastoma. PMID- 8695252 TI - Myocardial function in children and adolescents after therapy with anthracyclines and chest irradiation. AB - Cardiotoxicity is a potential adverse effect of anthracycline (A) therapy. Radiotherapy (XRT) may also cause a variety of cardiac complications. The purpose of the present study was to evaluate these cardiac side-effects in children and adolescents treated for cancer. We assessed the cardiac status of 91 patients, divided into three groups: Group A (n = 53) had anthracyclines at a mean cumulative dose of 410 mg/m2, group A+XRT (n = 26) had both chest irradiation (XRT) and A (mean 360 mg/m2), and group XRT (n = 12) had XRT alone. The patients differed from the controls in both systolic and diastolic indices of myocardial function. In echocardiography, the left ventricular (LV) contractility was abnormal in 32% in group A, in 50% in group A+XRT, and in 8% in group XRT. In radionuclide cineangiography, the LV ejection fraction was subnormal in 19% in group A, in 24% in group A+XRT, and in 1 patient in group XRT. A higher cumulative dose of A predicted decreased contractility. Treatment with A and/or XRT often leads to cardiotoxicity. Although in most cases this cardiotoxicity seems to be mild and subclinical, the long-term clinical sequelae merit further evaluation. PMID- 8695253 TI - Significant trends in cancer in the elderly. PMID- 8695254 TI - Chemotherapy for ovarian germ cell tumours. PMID- 8695255 TI - Drug evaluation and approval in the European Community. PMID- 8695256 TI - New endocrine therapies for breast cancer. AB - How do the new endocrine therapies stand up to the aims of modern endocrine therapy outlined in Table 1? We wish to see increased efficacy, decreased toxicity and improved general health in women taking a new agent. None of the new non-steroidal anti-oestrogens have shown unequivocal evidence of improved efficacy in the clinic to mirror their improved profiles over tamoxifen in preclinical studies. We know that toremifene is equivalent to tamoxifen, but we do not have any phase III data from the other four compounds in development. The specific steroidal antioestrogen, ICI 182,780, looks very promising, but is early in its developmental programme. The new aromatase inhibitors are likely to prove equal to tamoxifen or progestagens, but it is disappointing that improved oestrogen suppression has not led, to date, to improved efficacy. No comment can be made about adjuvant or preventative therapy for any of the new agents, although trials are planned for the new aromatase inhibitors in this clinical situation. Currently, the antiprogestins are disappointing and we will need to wait a considerable time for new agents in preclinical testing to reach the clinic. Many of the new agents are associated with decreased toxicity. It is likely that the NSAEs will be equitoxic with tamoxifen. The steroidal antioestrogen looks particularly non-toxic as do the new aromatase inhibitors, and thus we have an advance in terms of reduced toxicity. The effects of the new agents on the uterus, lipids and bone are in the early stages of testing. Raloxifene, ICI 182,780 and the new aromatase inhibitors are expected to have no proliferative effects on the endometrium, but only the new NSAEs are expected to have beneficial cardiovascular and skeletal effects. If the steroidal anti oestrogens and new aromatase inhibitors become adjuvant therapies of choice, other agents to prevent osteoporosis and cardiovascular events may also have to be administered. PMID- 8695257 TI - Magnetic resonance imaging: present position and future prospects. PMID- 8695259 TI - Mutant p53 protein as a predictor of survival in endometrial carcinoma. AB - The expression of mutated p53 protein was studied in paraffin-embedded, formalin fixed tumour specimens from 183 women with endometrial carcinoma. Fifty-five per cent of the specimens were negative, whereas the staining intensity was weak, moderate or strong in 15, 2 and 28% of cases, respectively. Strong p53 expression (> 75% of the cells stained) was more common in uterine papillary serous cancers and clear cell cancers than in other tumour subtypes (P < 0.001), as well as in poorly differentiated tumours (P < 0.01) and in tumours with nuclear grade 3 (P < 0.0001). Strong p53 expression was also more frequently found in aneuploid tumours (P < 0.0001) and in tumours with a high S-phase fraction (P < 0.001). Strong p53 expression was highly predictive of poor survival in the univariate analysis (P = 0.006) and in the Cox multivariate analysis which included age, stage and grade. However, it lost most of its impact when the strongly prognostic nuclear grade and ploidy were added to the multivariate models. PMID- 8695258 TI - Chemotherapy for ovarian germ cell tumours. AB - 59 patients were treated for newly diagnosed metastatic ovarian germ cell tumours with POMB/ACE chemotherapy (which contains cisplatinum, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide and etoposide). The median follow-up was 7.7 years. The 3 year survival is 87.8% (95% confidence interval 76.9-93.9%) and no relapses occurred more than 3 years after treatment. 4 (7%) patients had primary drug resistance to POMB/ACE and 4 (7%) have relapsed. One patient in complete remission developed secondary acute myeloid leukaemia after receiving a total of 1.3 g/m2 etoposide. 6 of 12 (50%) patients referred at relapse were salvaged by POMB/ACE. 14 of 33 (42%) women (> 18 years old) have had successful pregnancies after fertility conserving surgery and chemotherapy with no congenital abnormalities reported. The POMB/ACE regimen is as efficacious as other published regimens for ovarian germ cell tumours (OGCT) and balances a low incidence of life-threatening toxicity with a high success rate. PMID- 8695260 TI - Reproducibility of histological diagnosis of breast lesions: results of a panel in Italy. AB - Sixteen pathologists independently examined and classified a series of 81 breast lesions selected from the files of several Italian Pathology Departments in the context of a national task force on breast cancer (FONCAM). A four category classification system was used for analysis; according to the majority diagnosis (MD), simply defined as the most frequently reported in the panel, the series included 37 benign lesions without atypia (45.7%), nine atypical hyperplasias (11.1%), 18 in situ (22.2%) and 17 invasive carcinomas (21.0%). Concordance, estimated for all possible pair-wise comparisons between pathologists, was good (mean kappa value: 0.59). A comparison between the diagnoses of each pathologist and the panel majority diagnosis was also made. Overall, a global kappa value of 0.72 was found (range 0.57-0.85), with category-specific values being excellent for invasive carcinoma (0.89) and benign lesions without atypia (0.77), relatively good for in situ carcinoma (0.69) but poor for atypical hyperplasia (0.38). These results confirm that quality assurance procedures are particularly indicated for large screening programmes for breast cancer, and suggest that for atypical lesions strict diagnostic criteria should be adopted. PMID- 8695261 TI - Inadequacy of iridium implant as sole radiation treatment for operable breast cancer. AB - In order to avoid a prolonged course of external irradiation as part of breast conservation therapy, 27 patients received an iridium implant to the primary tumour bed as sole radiation treatment. Surgery was standardised comprising tumourectomy and axillary clearance. Using a rigid implant afterloading with iridium192 wires, 55 Gy was delivered on a continuous basis over 5 days. After 6 years median follow-up, relapse of cancer within the treated breast has occurred in 10 of the 27 patients (37%). Compared with historical controls treated by similar surgery and iridium192 implant (20 Gy) with external radiotherapy (46 Gy), there was a significantly increased breast relapse rate in those treated by iridium implant alone. However, the incidence of distant metastases and overall survival was similar. Thus, a continuous iridium192 implant delivering 55 Gy in 5 days is not an effective means of achieving local control in patients with operable breast cancer. PMID- 8695262 TI - An image analysis study of DNA content in early colorectal cancer. AB - The DNA content of 168 consecutive T3,N0,M0 (Dukes' B, Astler-Coller B2) colorectal cancers was studied using image analysis on formalin-fixed paraffin embedded tissues. 72 cases (43%) were classified as diploid and the remaining 96 (57%) as non-diploid. After a median follow-up period of 6.7 years, a significant survival advantage was found for diploid compared with non-diploid cases (logrank test; P = 0.008). The long-term (8 year) survival rate was 70% for diploid and 46% for non-diploid tumours. Subgroup analysis showed that the survival advantage conferred by tumour diploidy was greatest in large (> or = 5 cm) cancers and was found both in colonic and rectal cancer cases. These data indicate that tumour ploidy status measured by image analysis might be useful in determining risk of colorectal cancer recurrence and death in patients following resection of early colorectal cancer. PMID- 8695263 TI - Isolated axillary recurrences after conservative treatment of breast cancer. AB - This retrospective study presents the diagnostic, prognostic and therapeutic problems raised by axillary recurrences (AR). 1589 cases of breast cancer measuring less than 3 cm, treated at the Institut Curie between 1981 and 1987, were studied by a combination of surgery and radiotherapy. Treatment of the breast always included wide local excision associated with irradiation. The axilla was treated either by dissection (865 cases) or by irradiation (724 cases) and 159 patients received chemotherapy. 26 patients (2%) developed AR, confirmed by fine needle aspiration cytology in 92% of cases. None of these 26 patients had initially received chemotherapy. The treatment of the AR was variable, adapted to the initial treatment. 22 patients retained their breast during treatment of the AR and none subsequently developed a local recurrence. 4 mastectomies were performed and histological examination revealed a subclinical local recurrence in 2 cases. The TNM classification, menopausal status, size of the tumour and hormonal receptor status were not risk factors for AR. Young age (P = 0.01) and high histological grade (P = 0.03) were significant risk factors for AR. The AR rate was similar whether axillary dissection or axillary irradiation had been performed. The overall 5-year survival after initial treatment was 85% for AR and 95% for the reference population. The overall 4-year survival after recurrence was 69% and the incidence of metastasis was markedly increased (P = 0.002). 2 of the 26 patients developed lymphoedema of the arm after treatment of AR. We confirm that AR worsens the prognosis, but not significantly more than local recurrence. Young age and the modified histological grading of Scarff Bloom and Richardson were risk factors for AR. Although excision of the AR is necessary to ensure local control, mastectomy is unnecessary when clinical examination and mammography are normal. PMID- 8695264 TI - The management of retroperitoneal soft tissue sarcomas. AB - Over a 5-year period, all retroperitoneal soft tissue sarcomas (119) referred to the Royal Marsden Hospital, London, U.K., were recorded prospectively on a database and managed with a consistent treatment policy. On multivariate analysis, the significant factors responsible for determining prognosis were grade and completeness of excision. Despite improvements in surgical clearance rates (nearly 50% completely excised in this series), the prognosis was poor with 2- and 5-year survival rates of 53 and 20%, respectively. Further improvements in survival rates will depend on better adjuvant treatment. PMID- 8695265 TI - Soluble CD44 molecules in serum of patients with prostate cancer and benign prostatic hyperplasia. AB - Recent studies suggest that expression of CD44 splice variants are of prognostic significance for a variety of neoplasias. It was the aim of this study to investigate whether any correlation exists between the concentration of soluble CD44 molecules in serum (CD44 standard form and CD44 splice variants v5 and v6) and the prostate cancer stage. Serum levels of these soluble CD44 isoforms were measured by ELISA tests specific for these proteins in controls (n = 30), patients with benign prostatic hyperplasia (BPH; n = 30), with prostate cancer without metastasis (T1,2,3pN0M0; n = 30) and with locally advanced prostate cancer and/or metastatic disease (T3,4pN1,2M1; n = 19). sCD44std and sCD44v6 concentrations were not significantly different among the four groups studied, with few patients' levels outside the central 95% reference intervals. The mean sCD44v5 concentrations of both prostate cancer and BPH patients were significantly lower than those of the controls. There was no significant difference between the soluble CD44 concentrations of the two groups of prostate cancer patients studied. In contrast to results observed in other carcinomas, the determination of soluble CD44 proteins in serum is not suitable for providing additional prognostic information on patients with prostate cancer. PMID- 8695266 TI - Phase I trial of etoposide, doxorubicin and cisplatin (EAP) in combination with GM-CSF. AB - The aim of this study was to ameliorate the toxicity of the etoposide, doxorubicin and cisplatin (EAP) regimen and to investigate the feasibility of dose escalation, using the molgramostim form of granulocyte macrophage-colony stimulating factor (GM-CSF) 10 micrograms/kg/day s.c. into the regimen. The design of the trial allowed for amended scheduling of the agents in the event of suboptimal results. Initially the regimen comprised etoposide 120 mg/m2, days 1 3, doxorubicin 40 mg/m2, day 1, and cisplatin 40 mg/m2, days 2 and 8. GM-CSF was begun on day 4 and continued until recovery of granulocyte counts. Courses were repeated every 21 days. 3 patients were treated at these doses. 5 patients received escalated doses (etoposide 180 mg/m2; doxorubicin 60 mg/m2; cisplatin 60 mg/m2) on this schedule; 4 out of 5 had intolerable myelosuppression (grade IV neutropenia or thrombocytopenia lasting > or = 7 days). These results prompted the administration of the day 8 cisplatin dose on day 3, with GM-CSF beginning on day 4. At the lowest doses of each agent (etoposide 120-doxorubicin 40-cisplatin 40), 3 of 6 patients had intolerable myelosuppression, and 3 patients had febrile neutropenia. Dose escalation of all of the drugs to etoposide 180 mg/m2, doxorubicin 60 mg/m2, cisplatin 60 mg/m2 resulted in documented infections in 4 out of 4 patients. GM-CSF toxicity included rash, dyspnoea, arrhythmias and pericardial effusions. The conclusion was that the use of GM-CSF does not permit escalation of drug doses on either schedule of EAP administration, and that these results do not support the combined use of GM-CSF and EAP. PMID- 8695267 TI - Multiple infusions of anti-epidermal growth factor receptor (EGFR) monoclonal antibody (EMD 55,900) in patients with recurrent malignant gliomas. AB - In a prospective phase I/II trial, EMD 55,900, a murine monoclonal antibody (MAb) directed against EGF receptor, was administered at tumour recurrence to 16 patients previously treated with surgery, radiotherapy and chemotherapy for high grade supratentorial gliomas (11 glioblastomas, five anaplastic astrocytomas). Duration of treatment was planned for at least 4 weeks. The first 10 patients received 40 mg of MAb three times per week (median cumulative dose, 760 mg) and the last 6 patients received 200 mg three times per week (median cumulative dose, 2400 mg). Serum levels of EMD 55,900 were proportional to the injected dose. Repeated infusions of EMD 55,900 were well tolerated. In 13/16 patients, there were no adverse events. Among the 3 others, one had a grade IV neutropenia, one had a clinically asymptomatic hepatitis, and one had a skin rash. This last patient was the only one who had increased human antimouse antibodies (HAMA). After 4 weeks of therapy, 13 patients were evaluable for response. No measurable tumour regression was obtained with either schedule. 6 of the 13 patients (46%) showed evidence of progressive disease, while 7/13 (54%) had stable disease. All patients had progressive disease by 3 months. In this study, repeated infusions of EMD 55,900 were well tolerated but no therapeutic benefit was demonstrated. PMID- 8695268 TI - Multidrug resistance reversal in childhood malignancies--potential for a real step forward? PMID- 8695269 TI - N-MYC amplification, loss of heterozygosity on the short arm of chromosome 1 and DNA ploidy in retinoblastoma. AB - Recurrent genetic alterations different from the alteration of the RB1 gene on chromosome 13q14 have been described in retinoblastoma, including structural alterations on the short arm of chromosome 1 and amplification of the N-MYC oncogene. These two genetic alterations are major prognostic factors in neuroblastoma, another embryonic neuro-ectodermal tumour. In order to assess the frequency of these alterations and their possible association with clinical parameters in retinoblastoma, we studied a series of 46 retinoblastoma tumour samples. Ploidy was assessed by flow cytometry, N-MYC copy number was evaluated by a spot-blot procedure using the pNb-1 probe and loss of heterozygosity was investigated by PCR analysis at mini- and microsatellites located on the short arm of chromosome 1. Most tumours were in the diploid or near diploid range; only one case exhibited tetraploidy. N-MYC amplification was observed in only one of the 45 tumours. Loss of heterozygosity on the short arm of chromosome 1 was observed in 9/43 tumours (21%); in particular, its incidence was higher in metastatic than in localised disease (P < 0.05). We suggest that alterations of one or several genes on chromosome 1p might play a role in the oncogenesis or progression of retinoblastoma. Analysis of the long term follow-up of these and additional patients should determine the prognostic value of this parameter. PMID- 8695270 TI - Kaposi's sarcoma in children with AIDS in Europe and the United States. PMID- 8695271 TI - Worldwide trends in cancer mortality in the elderly, 1955-1992. AB - Trends in age-standardised mortality for all cancers and 21 cancers or groups of cancers over the period 1955-1992 were analysed for 33 countries from four continents in a population aged 65-84 years. Mortality from all neoplasms in the elderly showed heterogeneous patterns in various countries and in the two sexes. Trends were generally more favourable for females than for males, reflecting essentially the earlier and more extensive impact of the lung cancer (and other tobacco-related neoplasms) epidemic in elderly males, in addition to the earlier decline of gastric cancer and a widespread decline of cervical cancer rates in females. In several countries, particularly from western Europe, but also Japan, cancer mortality trends were more favourable over the last two decades than in earlier calendar periods. Some countries of northern and central Europe (including Finland, Germany, Austria and Switzerland) showed stable or even downward trends over time for total cancer mortality in both sexes, particularly in males. This reflects the different patterns of the tobacco-related (lung) cancer epidemic in various countries, and the impact of a few other major neoplasms, including in particular the systematic downward trends in stomach cancer. In contrast, rates were moderately upwards in males in North America, and several countries of southern and eastern Europe, where cancer mortality in the elderly was comparatively low in the 1950s, showed appreciable upward trends, mostly in males. Thus, there was a generalised tendency towards a levelling of the differences in certified cancer mortality in the elderly population in various areas of the world. Although there are substantial limits and uncertainties in the reliability and validity of cancer death certification and their trends in the elderly, there is no widespread and generalised upward trend in cancer mortality, with a major exception of lung and other tobacco-related neoplasms. Furthermore, in several countries, cancer mortality trends over the last four decades have been favourable for elderly women. PMID- 8695272 TI - Dietary risk factors for renal cell carcinoma in Denmark. AB - The role of diet in the aetiology of renal cell carcinoma was investigated in a population-based case-control study in Denmark. Cases were 20-79 years old, with a histologically verified diagnosis of renal cell carcinoma. Controls were sampled from the general population and were frequency-matched on age and sex. A total of 351 cases (73% of the eligible) and 340 controls (68% of the eligible) were included in the study. Dietary information was obtained in a self administered food frequency questionnaire and the information was confirmed in a subsequent interview performed by trained interviewers who also elicited information on other suspected risk factors such as smoking, occupation, medical history, education and reproductive history. Logistic regression models were used to calculate the odds ratios, and, both frequency of consumption of various food stuffs and computed nutrients were examined. A positive association was observed between risk of renal cell carcinoma and total energy intake (odds ratio, OR, for highest quartile compared to lowest: 1.7 (95% confidence interval, CI, 1.0-3.0) for men, and 3.5 (95% CI 1.6-6.5) for women), fat intake (OR for highest quartile compared to lowest: 1.9 (95% CI 1.1-3.5) for men, and 3.3 (95% CI 1.6-6.9) for women). For women, an effect was also seen for intake of carbohydrates (OR for highest quartile compared to lowest: 3.2 (95% CI 1.5-6.8), while no protective effect was seen for vegetables or fruit. Dairy products may be associated with risk of renal cell cancer (OR for women using thickly spread butter compared to thinly spread: 11.4 (95% CI 2.8-45), OR for women who drank more than one glass of milk with 3.5% fat content compared to never drink milk: 3.7 (95% CI 1.2-11). As expected, total energy intake, intake of fat, protein and carbohydrates were closely correlated making it difficult to identify one of the energy sources as more closely associated with risk of renal cell cancer than the other. Several energy sources have been identified as possible risk factors for renal cell carcinoma. It is possible that a high energy intake as such rather than the individual sources are responsible for the increased risk. Furthermore, dairy fats may be associated with renal cell carcinoma risk. The observed associations appeared stronger in women, and did not explain the association with obesity and low socio-economic status previously found in Denmark. PMID- 8695273 TI - Multiple primary cancers and estimation of the incidence rates and trends. AB - The use of different registration rules from one registry to another, both generally and also for paired organs, leads to variations in the proportion of multiple primary cancers: in men, from 0.4 to 4.9% for the colon, 0.1 to 2.7% for the lung, and 4.1 to 8.6% for the mouth and pharynx. Subjective factors, often impossible to verify, contribute to these variations. The impact on the estimation of incidence rates and trends is not negligible for cancers of the mouth and the pharynx and for all the cancers taken together. The trend towards an increase of cancers of the mouth and pharynx in the Bas-Rhin disappeared when the incidence was expressed taking only the first cancer (incidence by individual) into consideration, and the differences in incidence between the Calvados and the Bas-Rhin registries for the same site also disappeared. In the absence of harmonisation of the rules and methods followed for registration, incidence by individual is the only approach which makes it possible to compare incidence rates and trends between registries. PMID- 8695274 TI - Direct gene transfer of a plasmid carrying the herpes simplex virus-thymidine kinase gene (HSV-TK) in transplanted murine melanoma: in vivo study. AB - The aim of the study was to use a virus-free system to transfer the Herpes Simplex Virus-thymidine kinase (HSV-TK) gene in mice bearing melanoma tumours. B16 F1 murine melanoma cells were injected subcutaneously. On days 11 and 14, an intratumoral injection of either naked plasmid containing the HSV-TK gene (pAG0) or pAG0-lipofectamine complexes was given. Ganciclovir (120 mg/kg/day) was given for 5 days starting on day 14. Tumour weight reduction (40-50%) was observed in treated animals versus different control groups. Moreover, histopathological analysis on tumours showed large areas of cavitary necrosis (85%) in treated groups compared to controls (10%). Using a simple and safe method, the results presented here demonstrated that virus-free mediated delivery of the HSV-TK gene is efficient in vivo in murine malignant melanoma. PMID- 8695275 TI - Androgen-like and anti-androgen-like effects of antiprogestins in human mammary cancer cells. AB - In addition to their antiprogestational activity, the antiprogestins RU486, ZK98.299 and ZK98.734 possess varying antiglucocorticoid as well as androgen-like or antiandrogen-like properties in human mammary cancer cells. The human mammary cancer cell line MFM-223, which contains only androgen receptors, was used as a model to investigate androgen receptor mediated effects of these antiprogestins. Proliferation of MFM-223 cells is inhibited by androgens and does not respond to oestrogens, progestins and glucocorticoids. As shown in proliferation assays, ZK98.734 was a strong inhibitor of cell proliferation. This effect was antagonised by the antiandrogen hydroxyflutamide. ZK98.734 was found to displace [3H]R1881 from the androgen receptor in MFM-223 cells, substantiating the involvement of the androgen receptor. The antiprogestin ZK98.299 failed to influence the proliferation of MFM-223 cells. ZK98.299 did not bind to the androgen receptor and was devoid of androgenic or antiandrogenic activity. RU486 bound to the androgen receptor. It was a weak inhibitor of MFM-223 cell proliferation, but the inhibition of proliferation by RU486 was not antagonised by hydroxyflutamide. This effect was probably not mediated by the androgen receptor. RU486 had antiandrogenic activity in this cell line, as it antagonised the inhibitory effect of dihydrotestosterone at a 100-molar excess. These results were confirmed by transfection experiments with an MMTV-CAT construct in the same cell line, demonstrating the biological function of the ZK98.734-androgen receptor complex. ZK98.299 and RU486 were not able to induce CAT activity. The different androgenic or antiandrogenic properties of the antiprogestins investigated should be considered when selecting antiprogestational properties of the antiprogestins investigated should be considered when selecting antiprogestational compounds for clinical applications, as a partial androgenic activity may be of benefit in breast cancer but can have undesired side-effects in other diseases. PMID- 8695276 TI - In vitro anti-proliferative and anti-invasive role of aminoterminal fragment of urokinase-type plasminogen activator on 8701-BC breast cancer cells. AB - 8701-BC cells, derived from a primary carcinoma of the breast, constitutively express mRNA for urokinase-type plasminogen activator (uPA). In this paper, we demonstrated the presence of uPA in the conditioned medium, and of uPA-receptor (uPAR) on the cell surface of 8701-BC cells, which therefore have the potential for an autocrine mechanism of uPA-mediated stimulation. We examined whether exogenous addition of either intact uPA, or its amino-terminal fragment (uPA ATF), which lacks catalytic activity but retains the uPAR binding site and a growth factor-like domain, or immunoneutralisation of endogenous uPA-uPAR interactions could exert any effect on the proliferative and invasive behaviour of 8701-BC cells. The data demonstrate that, while uPA promotes growth and invasion of 8701-BC cells, its effect reversed by blocking uPA-uPAR interactions, uPA-ATF not only fails to impart growth factor-like signals, but also restrains cell invasion in vitro. In the light of these and other data, an active participation of ATF in the complex cell-ECM network of interactions underlying cancer progression can be postulated. In addition, it appears worth considering the possibility of testing the effect of this uPA fragment in vivo for the therapy of breast (and possibly other) human invasive carcinomas. PMID- 8695277 TI - From amsacrine to DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide): selectivity for topoisomerases I and II among acridine derivatives. AB - A number of acridine derivatives, including the clinical antileukaemia agent amsacrine and the experimental agent DACA (N-[2-(dimethylamino)ethyl]acridine-4 carboxamide), target the enzyme topoisomerase II. We demonstrate here that DACA induces DNA cleavage in the presence of topoisomerase I as well as of topoisomerase II. We also investigate a series of acridine derivatives which link amsacrine to DACA in terms of DNA binding, topoisomerase poisoning and biological activity. The presence of an acridine 4-linked N-2-(dimethylamino)ethyl group provides both a pronounced G-C preference for DNA binding and activity towards topoisomerase I. The removal of the anilino side chain of amsacrine, in combination with the presence of the N-2-(dimethylamino)ethyl group, provides in vitro biological activity against "atypical" multidrug resistant leukaemia lines with low topoisomerase II activity. Among these compounds, suppression of the ionisation of the acridine nitrogen to produce the compound DACA is associated with experimental activity against solid tumours. The addition of an acridine 2 chloro substituent to DACA suppresses the stimulation of topoisomerase II dependent DNA cleavage but increases stimulation of topoisomerase I cleavage. 2 Substitution also increases activity against the "atypical" multidrug resistant cell lines. Overall, the results suggest that augmentation of topoisomerase I dependent activity in this series by appropriate chemical substitution in this series leads to circumvention of topoisomerase II-mediated multidrug resistance. PMID- 8695279 TI - Application of competition theory to tumour growth: implications for tumour biology and treatment. AB - To assess critical parameters controlling tumour growth and response to therapy, competition theory models the tumour-host interface as a network of interacting normal and malignant cell populations using coupled, non-linear differential equations. When the equations are analysed under conditions which simulate tumour development, three phases of tumour growth, each with different critical parameters, can be predicted. Transitions between these phases correspond to the initiation, promotion and invasion stages demonstrated in experimental models of carcinogenesis. Critical cellular properties for each transition are predicted including phenomena already demonstrated experimentally such as the linkage of invasive tumour growth with acquisition of angiogenesis. The model also predicts the previously unknown phenomenon of "functional equivalence" in which disparate tumour traits can play identical roles in tumour growth and invasion. This approach allows the diverse but inconsistent properties of transformed cells to be understood according to their specific contribution to tumorigenesis. The models have significant implications for treatment strategies. PMID- 8695278 TI - Characterisation of platelet aggregation induced by PC-3 human prostate adenocarcinoma cells and inhibited by venom peptides, trigramin and rhodostomin. AB - PC-3 cells, a metastatic human prostate adenocarcinoma line, caused dose dependent platelet aggregation in heparinised human platelet-rich plasma (PRP). PC-3 tumour cell-induced platelet aggregation (TCIPA) was completely inhibited by hirudin (5 U/ml) and limited by increasing concentrations of apyrase. This TCIPA was unaffected by cysteine proteinase inhibition with E-64 (10 microM), but was limited by cell pretreatment with phospholipase A2. PC-3 cell suspension caused marked, dose-dependent decreases in plasma recalcification times using normal, Factor VIII-deficient and Factor IX-deficient, but not Factor VII-deficient, human plasma. This effect was potentiated in cell lysates, but was inhibited in intact cells preincubated with sphingosine. Overall, these data suggest that PC-3 TCIPA arises from PC-3 tissue factor activity expression. Trigramin and rhodostomin, RGD-containing snake venom peptides which antagonise the binding of fibrinogen to platelet membrane glycoprotein IIb-IIIa, prevented PC-3 TCIPA. Similarly, synthetic peptide GRGDS as well as monoclonal antibodies against platelet membrane glycoproteins IIb-IIIa and Ib prevented PC-3 TCIPA, which was unaffected by control peptide GRGDS. On a molar basis, trigramin (IC50, 0.11 microM) and rhodostomin (IC50, 0.03 microM) were approximately 5000 and 18000 times, respectively, more potent than GRGDS (IC50, 0.56 mM). PMID- 8695280 TI - The invisible colours of melanoma. A telespectrophotometric diagnostic approach on pigmented skin lesions. AB - Reflectance images of 43 pigmented lesions of the skin (18 melanomas, 17 common melanocytic naevi and eight dysplastic naevi) were acquired by a telespectrophotometric system and were analysed in the spectral range from 420 to 1040 nm, to discriminate melanoma from benign melanocytic entities. Different evaluations were carried out considering the whole spectrum, the visible and the near infra-red. A total of 33 (76.7%) lesions were correctly diagnosed by the telespectrophotometric system, compared with 35 (81.4%) correct clinical diagnoses. Reflectance in the infra-red band appears diagnostically relevant. A larger study is needed to prove the validity of this diagnostic method. PMID- 8695282 TI - Increased risk of malignancy for patients with chronic granulomatous disease and its possible link to the pathogenesis of cancer. PMID- 8695281 TI - Subcutaneous recombinant interleukin-2 plus chemotherapy with cisplatin and dacarbazine in metastatic melanoma. AB - The aim of our study was to verify the efficacy and tolerability of subcutaneous low doses of interleukin-2 with cisplatin and dacarbazine for malignant melanoma. 24 patients were included. The following schedule was used: cisplatin (CDDP) 100 mg/m2 day 1; darcarbazine (DTIC) 375 mg/m2 days 1-5; recombinant interleukin-2 (rIL-2) 4.5 million IU x 2/day days 13-17 and 20-24. The therapy was recycled every 28 days. 10 patients obtained clinical remission (42%), with 2 complete responses (8%) persisting for 12 and 15+ months, and 8 partial responses (35.5%) with a median duration of 5 months. Median survival of all 24 patients was 8 months, 13 months for responders and 6 months for non-responders. Responses were seen predominantly in lymph nodes (48%) and skin-soft tissue (38%), but were also seen in the liver (29%) and lung (14%). Treatment was relatively well tolerated and toxicity was mainly related to chemotherapy. PMID- 8695283 TI - Home therapy with autologous tumour-infiltrating lymphocytes and subcutaneous interleukin-2 in metastatic melanoma. PMID- 8695284 TI - Beneficial effects of octreotide in a patient with a metastatic paraganglioma. PMID- 8695285 TI - Rapid tumour lysis syndrome in a metastatic colorectal cancer increased by treatment (CPT-11) PMID- 8695286 TI - Major interactions between radiation therapy and systemic sclerosis: is there an optimal treatment? PMID- 8695287 TI - 2nd Educational Convention of the European School of Oncology. Vienna, Austria, 27-29 June 1996. Abstracts. PMID- 8695288 TI - Factors influencing post-menopausal African-American women's participation in a clinical trial. PMID- 8695289 TI - Assessment and approach to treatment in post-stroke depression. AB - Recent research indicates that post-stroke depression results from neurobiological changes associated with focal cerebral injury. Family or medical personnel may identify potential depression. An accurate assessment process will determine the extent of depression and indicate treatment options. Treatment approaches using both medication and cognitive therapy can help the individual replace negative thinking patterns with positive patterns. Depression has been accepted as a normal accompaniment of stroke. The area of injury may correlate with the degree of mood disorder. Interventions to reverse depression will serve to improve rehabilitation potential and increase chances of recovering pre-stroke capabilities. PMID- 8695290 TI - Distance education for nurse practitioners: a partial solution. AB - Health professionals who live and practice in rural areas have limited opportunities to further their education. In order to pursue advanced nursing degrees, nurses have to leave their communities. A collaborative distance education project involving the University of New Mexico College of Nursing, the Area Health Education Center, and Western New Mexico University has provided a partial solution to this problem. Six registered nurses living and practicing in a rural site are now receiving their Family Nurse Practitioner degrees via two way audio/video teleconferencing equipment. Distance education can improve the numbers of primary care providers in rural areas; however, projects will require extensive planning and resources. PMID- 8695291 TI - Emergency post-coital contraceptive therapies. PMID- 8695292 TI - Adult epiglottitis. PMID- 8695293 TI - Update on human papillomavirus. PMID- 8695294 TI - Getting started in clinical research. PMID- 8695295 TI - Diabetes management. PMID- 8695296 TI - PERC: a nursing syndrome for AIDS. AB - Perc is an acronym and represents a proposed nursing syndrome for people with AIDS. It incorporates the NANDA human response patterns of perceiving, exchanging, relating and choosing. These patterns were identified through a review of literature on AIDS, especially that which addressed NANDA nursing diagnoses. The analysis showed that the most frequently used nursing diagnoses across various clinical areas were concentrated in the four human response patterns. Following an analysis of the concept, syndrome, PERC was seen as an appropriate way of consolidating those nursing diagnoses, signs and symptoms that the nurses will generally encounter in working with people with aids. PMID- 8695297 TI - You make the diagnosis: case study. A battered woman. PMID- 8695298 TI - Barriers to the use of nursing diagnosis language in clinical settings. AB - Ongoing evaluation of the use of nursing diagnoses at the clinical level is critical to the facilitation of further development and refinement of the language of nursing. Therefore, the purpose of this study was to identify the status of utilization of nursing diagnosis in Illinois. A survey instrument was mailed to 239 Illinois hospitals 139 (58%) responded. Results included: 78% of the responding hospitals had implemented nursing diagnosis, with almost all (95%) utilizing NANDA terminology. Components of continuing education efforts related to nursing diagnosis were identified by 75% of the hospitals. Ongoing monitoring of quality improvement methods was reported by 45% of the respondents. The barriers to implementation cited most frequently included: limited ongoing education, lack of motivation to learn, or nurses' difficulties in adjusting to its use. PMID- 8695299 TI - Do clinicians use diagnostic labels to direct intervention selection? AB - The authors report a descriptive, correlational study that evaluated the relationship between accuracy in selecting diagnostic labels and nursing interventions, and the relationship between accuracy in selecting outcome statements and nursing interventions. An instrument developed by the authors was used, based on previously published case studies. For two case studies, respondents (N = 17) were asked to indicate how important the nursing problem, the intervention, and the outcome statement would be in patient care. No relationship between accuracy in diagnostic label selection and accuracy in intervention selection was found. A positive correlation between accuracy in outcome selection and accuracy in intervention selection was found for one of the cases. PMID- 8695300 TI - Nursing diagnosis research: forging ahead. PMID- 8695301 TI - Nursing diagnoses for hospitalized patients with AIDS. AB - This study examined the reliability of nursing diagnoses identified from the medical records of 100 patients hospitalized for HIV disease on a 22-bed designated unit at a large metropolitan teaching hospital in Los Angeles. The diagnoses were identified in two ways: (a) staff nurses identified 16 different nursing diagnoses using preprinted care plans found in the medical records, with 2 to 9 problems per patient (M = 4.8, SD = 1.6) and (b) the nurse researcher identified 45 different nursing diagnoses derived from defining characteristics documented in the medical records, with 1 to 9 identified problems per patient (M = 3.3, SD = 1.8). The most frequent problems identified were the same as those addressed in the clinical literature: pain, respiratory problems, nutritional deficits, and psychosocial concerns. The results of this study raise concerns about the limitations of nursing diagnosis research using existent data bases and the use of preprinted care plans. PMID- 8695302 TI - Developing a patient-focused care system. PMID- 8695303 TI - Physician outcome data dissemination: how nurse executives can impact methodology design. PMID- 8695304 TI - Why re-engineering flounders or succeeds. PMID- 8695305 TI - The top 10 complaints of angry ex-employees. PMID- 8695306 TI - Reducing surgical supply expenses: one hospital's experience. PMID- 8695307 TI - Between a rock and a hard place: problem management skills set for unsolvable problems. PMID- 8695308 TI - 21st century leadership for nurse administrators. PMID- 8695310 TI - Four tips for managing conflict in work teams. PMID- 8695309 TI - Finding spirituality at work. PMID- 8695311 TI - Nurse-physician relationships--Part II. Grasping the new business realities and what they mean to you. PMID- 8695312 TI - The aftermath of mergers. What have we learned? PMID- 8695313 TI - Downsizing experiences. First-person reports. PMID- 8695314 TI - Understanding managed care law. Key issues for nurse executives. PMID- 8695315 TI - The new employee contract. From entitlement to achievement. PMID- 8695316 TI - Hourly professionals. Is it time to change? PMID- 8695317 TI - Laughter really is the best medicine. PMID- 8695318 TI - Glove-associated reactions: addressing an increasing concern. AB - Increasingly, the dermatology professional will be called upon to assist in establishing protocols for recognizing, differentiating, and managing glove related reactions. Addressing preventative measures upfront will decrease possible morale problems, long-term treatment and compensation expenses, as well as potential career-limiting situations. PMID- 8695319 TI - Hydrocolloid dressings clarified. PMID- 8695320 TI - Topical silastic gel sheeting for treating and controlling hypertrophic and keloid scars: case study. AB - Hypertrophic and keloid scars form in a healed skin wound by the overgrowth of fibrous tissue after injury or surgery. In this case study the treatment and control of hypertrophic and keloid scars in an adult Chinese male with third degree burns is presented, emphasizing the use of topical silastic gel for scar treatment and control. PMID- 8695322 TI - What's your assessment? Secondary syphilis. PMID- 8695321 TI - Teamwork and leadership: the development of the National Psoriasis Tissue Bank. AB - The National Psoriasis Tissue Bank is the first tissue bank of its kind for psoriasis, providing cell lines and DNA samples to researchers worldwide who are actively seeking to locate the genes that cause psoriasis. Developed by a multidisciplinary, multi-institutional team, the tissue bank is also an interesting study in teamwork and leadership, as well as an excellent example of the expanding roles and opportunities for nurses. PMID- 8695323 TI - Health effects and regulation of tanning salons. AB - The use of artificial tanning devices to achieve year-round tanned skin has become big business. Clear and overwhelming evidence proves that skin exposure to natural or artificial ultraviolet radiation is harmful. Skin which has been exposed to ultraviolet light ages prematurely and has an increased risk of developing skin cancer. Education may be the best tool in preventing problems related to ultraviolet exposure. PMID- 8695324 TI - The healing of burn wounds. AB - Burn injuries can be the most devastating wounds of all. Knowledge of burn wound healing can be valuable not only for the care of small, minor burns but improved wound coverage of major burns can also lead to improved survival. Differentiating between types of burns and how these wounds heal will be discussed. Strategies for treating patients with extensive burns will also be presented. Finally, an evaluation of the newer technologies that are available for these injuries will be covered. Understanding the processes of burn wound healing will help optimize care of these often overwhelming injuries. PMID- 8695325 TI - Educating children and parents about sun protection. AB - The incidence of skin cancer in the United States is rising at an alarming rate. Sun exposure in childhood is a risk factor for the development of skin cancer. The important role of the dermatology nurse in educating children about protecting themselves from the sun is reviewed. PMID- 8695326 TI - What's your assessment? Skin tags (acrochordons). PMID- 8695327 TI - Pressure ulcer research: etiology, assessment, and early intervention. AB - Pressure ulcers are a significant health care problem in the United States. Cost effective provision of health care requires that basic and applied research serve as the basis for clinical care. Only then can the benefits and risks of therapeutic interventions be documented, understood, and used to improve health care delivery. This document describes the research priorities regarding the etiology, assessment, and early prevention of pressure ulcers that the National Pressure Ulcer Advisory Panel deems important. PMID- 8695328 TI - Determining efficacy of electroepilation treatments. AB - Evaluating the efficacy of electroepilation treatments must begin by establishing a baseline for each proposed treatment site. However, the need for identifying a baseline for epilation patients is often overlooked. The Electroepilation Charting System is a simple, systematic, standardized evaluation method which enables evaluation of treatment methods as well as new products as they are introduced into the marketplace. PMID- 8695329 TI - Leaders needed, apply within. PMID- 8695330 TI - Specializing in nursing: nephrology certification and recertification: benefits and barriers. AB - The diversity and complexity of nephrology is increasing and specialized knowledge and skills are required to practise this subspeciality. As a result, specialization and certification by the Canadian Nurses' Association (CNA) in nephrology nursing has become a reality. Specialization benefits patients, nurses and employers by ensuring high professional standards, providing an increased sense of professional achievement and innovative ways of providing quality care. Maintaining these high standards requires continuing education and recertification. A number of educational opportunities meet these needs. Recognition of speciality services would motivate more nurses to commit to nephrology certification. Specialization demands a greater commitment from the health care system, but provides significant dividends to both the health care system and the patient. PMID- 8695331 TI - Care and management of the pre-dialysis/pre-transplant population: a decade of growth. PMID- 8695332 TI - Epidemic diarrhoea due to Vibrio cholerae non-O1. PMID- 8695333 TI - Expanded programme on immunization. High measles case-fatality rates during an outbreak in a rural area. Niger. PMID- 8695334 TI - Nutrition. Making hospitals "baby-friendly": an example from China. PMID- 8695335 TI - Injury prevention. Bicycle helmet promotion programmes, Canada, Australia, and United States of America. PMID- 8695336 TI - Human plague in 1994. PMID- 8695337 TI - Expanded programme on immunization. National immunization days. India. PMID- 8695338 TI - Expanded programme on immunization (EPI). Immunization schedules in the WHO eastern Mediterranean region, 1995. AB - There are 23 countries/areas in this Region (Tables 1-3). BCG is used in all but 3 countries (Cyprus, Jordan and Lebanon). Most countries/areas give BCG vaccine at birth, 2 countries (Bahrain and Tunisia) schedule additional doses at school age and Kuwait uses 1 dose at the age of 3 1/2-4 years. Diphtheria-pertussis tetanus (DPT) vaccine is used as a primary series of 3 doses in all countries/areas. Fifteen countries/areas use a fourth dose of DPT vaccine in the second year of age or later (Bahrain, Cyprus, Egypt, Iran [Islamic Republic of], Jordan, Kuwait, Lebanon, Libyan Arab Jamahiriya, Oman, Qatar, Saudi Arabia, Syrian Arab Republic, Tunisia, and the United Arab Emirates, the United Nations Relief and Works Agency for Palestine Refugees in the Near East [UNRWA]). Six countries use 5 doses of DPT vaccine, the fifth dose being given at the age of 4 6 years (Bahrain, Cyprus, Iran [Islamic Republic of], Kuwait, Qatar, and Saudi Arabia). One or 2 booster doses of diphtheria-tetanus (DT) vaccine are used in 9 countries/areas from the age of 6-12 years. Td vaccine is used as a booster in Bahrain and Cyprus. Oral poliovirus vaccine (OPV) is used in a primary series of 3 doses simultaneously with DPT vaccine in all countries/areas. Ten countries/areas use an additional dose of OPV at birth (Djibouti, Iran [Islamic Republic of], Iraq, Kuwait, Libyan Arab Jamahiriya, Morocco, Oman, Pakistan, Syrian Arab Republic, and UNRWA). An additional dose of OPV in the second year of life is used in 15 countries, and additional doses of OPV are recommended in some countries. In UNRWA, the first 2 doses of OPV 2 and 3 months of age are given simultaneously with the inactivated poliovirus vaccine (IPV). Measles vaccine is given in most countries/areas at 9-12 months of age, usually in the form of monovalent measles vaccine. The 2-dose policy is implemented in 12 countries. In 8 countries, the second dose is given as measles-mumps-rubella (MMR) vaccine, and in 3 countries as monovalent measles vaccine. The age for the second dose varies. In 10 countries, it is given at 12-15 months of age, and in the Libyan Arab Jamahiriya at 18 months of age. The United Arab Emirates uses 3 doses. Rubella vaccine is scheduled for girls of 12-13 years of age in Bahrain, the United Arab Emirates and UNRWA and for boys and girls in Kuwait at 12 years of age. Hepatitis B vaccine is used in 15 countries/areas. All these countries use 3 primary doses of vaccine in infancy. The immunization time varies from birth (12 countries/areas) to 9 months of age. In Cyprus, hepatitis B vaccine is used in a 4-dose schedule, including a booster dose given to 5 to 6-year-old children. Tetanus toxoid is used for pregnant or non-pregnant women of childbearing age. It is also given to school-children in the Islamic Republic of Iran. The schedule includes 2-5 doses. PMID- 8695339 TI - Expanded programme on immunization (EPI). Inclusion of yellow fever vaccine in the EPI. PMID- 8695340 TI - The WHO network on antimicrobial resistance monitoring. PMID- 8695341 TI - Expanded programme on immunization. Progress towards the global eradication of poliomyelitis, 1995. PMID- 8695342 TI - Lassa fever. Update. PMID- 8695343 TI - Dengue and dengue haemorrhagic fever. PMID- 8695344 TI - Influenza vaccine formula for 1996-1997. PMID- 8695346 TI - Mutation analysis of the c-mos proto-oncogene and the endothelin-B receptor gene in medullary thyroid carcinoma and phaeochromocytoma. AB - The characteristic tumours of MEN 2 are medullary thyroid carcinoma (MTC) and phaeochromocytoma. Somatic RET mutations have been found in only 23-40% of sporadic MTC and 10% of sporadic phaeochromocytomas. Thus, we sought other genes which may play a role in the pathogenesis of these tumours. We carried out direct sequence analysis of human c-mos and human ENRB in a series of sporadic MTC and phaeochromocytomas to determine if somatic mutations in these two genes could account for some of the sporadic MEN 2-related tumours in which no RET mutations are detected. No somatic mutations were found. PMID- 8695345 TI - Current perspectives on camptothecins in cancer treatment. AB - The camptothecins are a new class of chemotherapeutic agents which have a novel mechanism of action targeting the nuclear enzyme topoisomerase I. Knowledge of the structure-activity relationships of the parent compound camptothecin has led to the development of effective soluble analogues with manageable toxicities. Broad anti-tumour activity shown in preclinical studies has been confirmed in phase I/II studies for irinotecan and topotecan. Two other derivatives, 9 aminocamptothecin and GI 147211C, are undergoing phase I and early phase II evaluation. Although camptothecin is a plant extract, it and most of its derivatives are not affected by the classic P-gpMDR1 mechanism of resistance which may allow the development of novel combination chemotherapeutic regimens. Important areas of future endeavour will include the development of rational combination regimens and the pursuit of randomised trials. Based on single agent data, colorectal cancer and non-small-cell lung cancer should be the focus for future irinotecan studies. Small-cell lung cancer and ovarian carcinoma are logical tumour types to pursue with topotecan. Both 9-aminocamptothecin and GI 147211C are too early in their clinical evaluation to make recommendations about their future roles. Finally, the unfolding story of camptothecin analogue development will give important insights into the predictive value of preclinical observations on relative efficacy, schedule dependency, combination strategies and resistance mechanisms which have helped determine the strategies for clinical evaluation of these agents. PMID- 8695348 TI - Synthesis and secretion of transforming growth factor beta isoforms by primary cultures of human breast tumour fibroblasts in vitro and their modulation by tamoxifen. AB - Tamoxifen may mediate its effect in early breast cancer in part via an oestrogen receptor (ER)-independent pathway by directly stimulating fibroblasts to produce the negative paracrine growth factor transforming growth factor (TGF)-beta. We have previously shown that secretion of this factor is induced 3-to 30-fold in human fetal fibroblasts in vitro, and by stromal fibroblasts in vivo following tamoxifen treatment of ER-positive and ER-negative breast cancer patients. Primary cultures of breast tumour fibroblasts have been exposed to tamoxifen for 48 h, and rates of secretion of TGF-beta 1 and TGF-beta 2 measured using a quantitative immunoassay. Fibroblast strains derived from malignant and benign tumours produced and secreted similar amounts of TGF-beta 1, but benign breast tumour fibroblasts secreted significantly higher levels of TGF-beta 2 compared with fibroblasts of malignant origin. Tamoxifen did not induce any consistent increase in TGF-beta secretion into the conditioned medium, but immunofluorescence analysis for the intracellular form of TGF-beta 1 revealed evidence of increased immunoreactive protein in tamoxifen-treated fibroblasts, which is localised to the nucleus. Therefore synthesis of TGF-beta 1 appears to be stimulated by tamoxifen, but increased secretion may be abrogated in vitro. Furthermore, using immunocytochemistry and transient transfection with an ER responsive reporter construct, no ER was demonstrable in these fibroblasts supporting the proposed ER-independent paracrine pathway. PMID- 8695347 TI - Alternatively spliced variants of the cell adhesion molecule CD44 and tumour progression in colorectal cancer. AB - Increased expression of alternatively spliced variants of the CD44 family of cell adhesion molecules has been associated with tumour metastasis. In the present study, expression of alternatively spliced variants of CD44 and their cellular distribution have been investigated in human colonic tumours and in the corresponding normal mucosa, in addition to benign adenomatous polyps. The expression of CD44 alternatively spliced variants has been correlated with tumour progression according to Dukes' histological stage. CD44 variant expression was determined by immunohistochemisty using monoclonal antibodies directed against specific CD44 variant domains together with RT-PCR analysis of CD44 variant mRNA expression in the same tissue specimens. We demonstrate that as well as being expressed in colonic tumour cells, the full range of CD44 variants, CD44v2-v10, are widely expressed in normal colonic crypt epithelium, predominantly in the crypt base. CD44v6, the epitope which is most commonly associated with tumour progression and metastasis, was not only expressed by many benign colonic tumours, but was expressed as frequently in normal basal crypt epithelium as in malignant colonic tumour cells, and surprisingly, was even absent from some metastatic colorectal tumours. Expression of none of the CD44 variant epitopes was found to be positively correlated with tumour progression or with colorectal tumour metastasis to the liver, results which are inconsistent with a role for CD44 variants as indicators of colonic cancer progression. PMID- 8695349 TI - Generation of human monoclonal antibodies recognising membranous antigens of the lung adenocarcinoma cell line A549 using an AMeX immunohistostaining method. AB - Four monoclonal antibodies (MAbs) from hybridoma obtained by in vitro stimulation of regional lymph node lymphocytes from lung cancer patients and electrofusion of the stimulated cells with murine or human-mouse myeloma cells were reactive to lung cancer cells in enzyme-linked immunoabsorbent assay, and to lung cancer tissue in immunohistochemical analysis using acetone-methyl benzoate-xylene (AMeX) fixed tissue and in immunofluorescence analysis. Three of the MAbs (designated ZLG40, 27D57 and 28K29) recognised cell-surface antigens of the lung adenocarcinoma cell line A549 and the remaining one (designated 29D38) recognised nuclear membrane antigens of the same cell line. The three surface-binding MAbs showed a significant complement-dependent cytotoxicity (CDC) to the A549 cells, but the membrane-binding 29D38 showed no CDC to the A549 cells. Western blotting of the extracts of the A549 or PC6 (small-cell lung cancer) cell lines by the four MAbs showed a 28K29 antigen band at M(r) of approximately 600,000 (+/- 2 ME), a ZLG40 antigen band at M(r) 50,000 (+/- 2-ME), and one 29D38 antigen band at M(r) of more than 1,000,000 (-2-ME) and M(r) between 20,000 and 80,000 (+2 ME), but no detectable band for 27D57 antigen. PMID- 8695350 TI - DNA damage and repair in tumour and non-tumour tissues of mice induced by nicotinamide. AB - In vivo DNA damage and repair was induced by nicotinamide (NAM) in adenotype 12 virus-induced mouse sarcoma A12B3 and sarcoma F inoculated into CBA mice. DNA damage, NAM and NAD concentrations were measured after in vivo exposure to NAM, in tumours and spleens by alkaline elution and by HPLC analysis. Our results indicate that NAM between 100-1000 mg kg-1 causes a high level of in vivo DNA strand breaks in tumours and normal tissues in mice bearing the immunogenic sarcoma A12B3 but not in the non-immunogenic sarcoma F. The repair process was also delayed by the NAM treatment probably owing to inhibition of the DNA repair enzyme, poly(ADP-ribose)polymerase, as evidenced by accumulation of NAM and NAD. These data are consistent with NAM having a mechanism of action as a radiosensitiser at least in part by DNA repair inhibition. In addition, it should also be considered that high doses of NAM might cause considerable complications to normal tissue in tumour-bearing individuals. PMID- 8695351 TI - Induction of apoptosis in human cancer cell lines by the novel anthracenyl-amino acid topoisomerase I inhibitor NU/ICRF 505. AB - Anthracenyl-amino acid conjugates represent a novel chemical class of topoisomerase (topo) inhibitor. NU/ICRF 505 is a lead compound that stabilises topo I cleavable complexes and is actively cytotoxic at low microM concentrations. In this study, endonucleolytic DNA cleavage was used as a marker of apoptosis to investigate mechanisms of cell death produced by this compound. NU/ICRF 505 (5 microM) induced a substantial increase in the level of DNA fragmentation in HL60 cells (up to 30% of total extracted DNA) but only after a 48 and 72 h drug exposure (compared with 6 h after treatment with camptothecin), as determined qualitatively by conventional gel electrophoresis and quantitatively by spectrofluorimetry. This effect was substantially reversed by co-treatment with zinc (1 mM). Subsequent studies with the human lung (NX002), ovarian (A2780) and colon (HT29) cancer cell lines yielded evidence of formation of higher molecular weight DNA fragments in NX002 and A2780 cells in response to NU/ICRF 505 (5 microM). Co-treatment with zinc (1 mM) caused a small decrease in DNA fragmentation. These data suggest that the induction of apoptosis may play an important role in the mechanism of cytotoxicity of NU/ICRF 505 in HL60 cells and that other pathways of cell death may also be operative in NX002 and A2780 in conjunction with apoptosis. PMID- 8695352 TI - Intracellular metabolism of the orally active platinum drug JM216: influence of glutathione levels. AB - JM216 (bis-acetato ammine dichloro cyclohexylamine Pt IV) is an oral platinum complex presently undergoing phase II clinical trials. Previous studies have identified some of its biotransformation products in clinical materials. This study evaluated the nature of JM216 biotransformation products intracellularly in two different human ovarian carcinoma cell lines, one relatively sensitive to platinum agents (CH1: JM216 4 h IC50 of 5.8 microM) and the other relatively resistant (SKOV3: JM216 4 h IC50 of 60.7 microM). Metabolic profiles were also evaluated at different growth status and in cells pretreated with buthionine sulphoximine (BSO), an agent known to decrease intracellular glutathione levels. Results showed that JM216 enters the cells and that the nature and percentage of biotransformation products was dependent upon glutathione levels. Furthermore, results support the view that the previously reported peak A biotransformation product contains a glutathione adduct. In exponentially growing SKOV3 cells which contain higher glutathione levels than CH1, (82.5 vs 37.8 nmol mg-1 protein), peak A represented 89% of total platinum 4 h after JM216 exposure compared with only 24% in CH1. Moreover, 60-70% depletion of glutathione achieved by 24 h pretreatment of cells with BSO resulted in a significant decrease in peak A in both cell lines and increased the cytotoxicity of JM216 in both CH1 and SKOV3 by approximately 2-fold. Following a 4 h exposure of exponentially growing SKOV3 cells to JM216, only peak A (89%) and JM216 (11%) could be detected whereas in CH1 cells, peak A (24%), JM216 (73%) and JM118 [cis-ammine dichloro (cyclohexylamine) platinum II] (3%) were detected. However, in CH1 cells at confluence, where glutathione is lower (8 nmol mg-1 protein) four metabolites (plus JM216 itself) were detected following exposure to 50 microM JM216; peak A, JM118, JM383 (bis-acetato ammine (cyclohexylamine) dihydroxy platinum IV) and an unidentified metabolite (D), also observed in patient's plasma ultrafiltrate. In confluent SKOV3 cells exposed to 50 microM JM216, peak A, JM216 and JM118 were detected. A further unidentified metabolite observed in patients receiving JM216 (metabolite F) was not formed inside these tumour cells. Overall, these data suggest that glutathione conjugation represents a major deactivation pathway for JM216. PMID- 8695353 TI - Effect of cisplatin and c-myb antisense phosphorothioate oligodeoxynucleotides combination on a human colon carcinoma cell line in vitro and in vivo. AB - We investigated the effect of c-myb antisense phosphorothioate oligodeoxynucleotides [(S)ODNs] and cisplatin (CDDP) combination on the human colon carcinoma cell line LoVo Dx both in vitro and in nude mice bearing LoVo Dx solid tumour. We show that antisense (S)ODN treatment decreases c-myb mRNA and protein expression, induces growth arrest in the G1 phase of the cell cycle, and inhibits cell proliferation. In vivo treatment with c-myb antisense (S)ODNs results in a reduction in tumour growth. A greater inhibition of cell proliferation in vitro and a higher increase of tumour growth inhibition and growth delay in vivo were obtained with the combination of (S)ODNs and CDDP than when the two agents were administered separately. This comparative study, using the same tumour cell line in vitro and in vivo, suggests that c-myb antisense (S)ODNs might be useful in the therapy of colon cancer in combination with antineoplastic drugs. PMID- 8695355 TI - Detection of circulating prostate-specific antigen-positive cells in patients with prostate cancer by flow cytometry and reverse transcription polymerase chain reaction. AB - The presence of prostate-specific antigen (PSA)-positive cells has previously been demonstrated in the peripheral blood of prostate cancer patients by flow cytometry (FC), but the identity of these cells has not been established. In this study, the reverse transcriptase polymerase chain reaction (RT-PCR) was compared with analytical FC in an attempt to detect and characterise these cells. Peripheral blood was obtained from 12 patients with newly diagnosed and untreated prostate cancer and five controls. Nine of the 12 patients with prostate cancer (75%) had circulating PSA-positive cells as shown by FC. Only one of those patients (11.1%) was found to express PSA mRNA by RT-PCR. The absence of PSA mRNA in the majority of samples showing PSA-positive cells suggests that they do not represent haematogenous micrometastases. PSA-positive cells in the blood could represent monocytes that express PSA, either following binding/phagocytosis of free serum PSA or phagocytosis of tumour cells. PMID- 8695354 TI - Antiproliferative effects of the arotinoid Ro 40-8757 in human gastrointestinal and pancreatic cancer cell lines: combinations with 5-fluorouracil and interferon alpha. AB - The arotinoid Ro 40-8757 was previously shown to inhibit the growth of a variety of human cancer cell lines derived from breast, lung and uterus. In view of the high incidence of human digestive cancers, and the slow progress in the development of new therapy, we examined in this paper several combinations between the new arotinoid Ro 40-8757, 5-fluorouracil (5FU) and interferon alpha 2a on the growth of nine human cancer cell lines derived from the gastrointestinal and pancreatic system. Half-maximal inhibition of cell proliferation by Ro 40-8757 was observed at concentrations ranging between 0.18 and 0.57 microM, and increased up to 4.7 microM in retinoid-resistant CAPAN 620 pancreatic cells. All-trans-retinoic acid was 70 times less potent. The sensitivity of HT29-5FU-resistant colonic cells was similar to that observed in the parental cells, suggesting an action independent of pyrimidine metabolism. Ro 40-8757 did not induce any differentiation on HT29 cells, as suggested by ultrastructural analysis. The arotinoid did not interact with receptor signal transduction pathways under the control of serum components, such as growth factors as half-maximal inhibiton of growth was similar in HT29-S-B6 cells cultured in the absence or presence of serum. Cell cycle analysis showed that Ro 40-8757 was not acting at a phase-specific transition in HT29 cells and, accordingly, did not induce overexpression of the protein kinase C (PKC)alpha isoform, or conversion of hyperphosphorylated p105 Rb into hypophosphorylated forms. However, the arotinoid induced significant accumulation of the dephosphorylated, active form of the tumour-suppressor protein. Combinations of Ro 40-8757 with 5FU and interferon alpha 2a resulted in an additive but not synergistic antiproliferative action in HT29 cells. Our data support the interest in Ro 40-8757 as a potent anti-cancer drug, especially in combination therapy with 5FU and interferon, in gastrointestinal and pancreatic cancers, where new active therapeutic modalities are urgently needed. PMID- 8695356 TI - Comparative alterations in p53 expression and apoptosis in the irradiated rat small and large intestine. AB - Temporal and spatial relationships between radiation-induced apoptosis and expression of p53 mRNA and protein were compared in rat small and large intestine. Apoptosis was quantified using morphological criteria, and p53 expression determined by immunohistochemistry or whole-tissue Northern analysis. In the small intestine, peak levels of apoptosis appeared earlier (4 h) than in the large intestine (6 h). p53 mRNA transcript levels in small and large intestine were not significantly altered from control levels at any time after treatment. However, in treated small and large intestine, cells showed increased positivity for p53 protein, increasing 10-fold over control levels 4-5 h after irradiation. A strong spatial relationship was found between high incidence apoptosis and p53 protein positivity. We compared published data of stem cell population positions for small and large intestine with our results. Target cells for apoptosis and p53 expression occurred at approximately fifth position from the crypt base of the small intestine, a zone coincident with stem cell population. Target cell position for apoptosis and p53 expression in the large intestine was again at fifth or sixth position from the base, but this zone is not the reported stem cell position (first or second position) for large intestine. Results from our model of radiation-induced intestinal apoptosis indicate that p53 protein is closely associated both temporally and spatially with the induction of apoptosis, and support the work of others in suggesting that p53 expression is modulated post-transcriptionally. Furthermore, our results support a hypothesis that apoptotic targeting of damaged stem cell populations, early response for apoptotic removal of DNA-damaged cells and/or early repair of these damage cells are all important parameters that determine differences in levels of tumorigenesis in the small and large intestine. PMID- 8695357 TI - Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma. AB - Proteinases are involved in tumour invasion and metastasis. Several matrix metalloproteinases (MMPs) have been shown to be increased in various human carcinomas. We assessed the levels of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) in 50 gastric carcinomas and corresponding mucosa using quantitative gelatin zymography. Both MMP levels were significantly enhanced in gastric carcinomas compared with adjacent mucosal tissue, showed a relatively poor intercorrelation and no relation was found with histopathological carcinoma classifications according to Lauren, WHO and tumour-node-metastasis (TNM). Cox's multivariate proportional hazards analyses revealed that high carcinomatous MMP values are of prognostic significance for a poor overall survival of the patients, independent of the major clinicopathological parameters. PMID- 8695358 TI - Soluble factors produced by PC-3 prostate cells decrease collagen content and mineralisation rate in fetal rat osteoblasts in culture. AB - Approximately 70% of patients with prostate cancer develop bone metastases in the advanced state of the disease. In the present study, we sought to test the hypothesis that prostatic cancer cells produce factors that inhibit the mineralisation process in vitro, decreasing the content of type I collagen in rat fetal calvaria osteoblasts. We investigated the capacity of conditioned media (CM) from the human prostatic tumour cell line PC-3 to inhibit the expression of the differentiation programme on osteoblasts in culture, with a primary focus on type I collagen synthesis and degradation. Our results show that PC-3 CM inhibits collagen synthesis and stimulates the production of interstitial collagenase from osteoblasts. A consequential decrease in the content of immunoreactive type I collagen was observed. We have previously demonstrated that PC-3 CM blocks osteoblast differentiation in culture. We propose that under the effect of factors present in PC-3 CM, osteoblastic cells retain the undifferentiated phenotype. PMID- 8695359 TI - Syndecan-1 alterations during the tumorigenic progression of human colonic Caco-2 cells induced by human Ha-ras or polyoma middle T oncogenes. AB - The products of ras and src proto-oncogenes are frequently activated in a constitutive state in human colorectal cancer. In this study we attempted to establish whether the tumorigenic progression induced by oncogenic activation of p21ras and pp60c-src in human colonic Caco-2 cells is associated with specific alterations of syndecan-1, a membrane-anchored proteoglycan playing a role in cell-matrix interaction and neoplastic growth control. To this end, we used Caco 2 cells made highly tumorigenic by transfection with an activated (Val 12) human Ha-ras gene or with the polyoma middle T (Py-MT) oncogene, a constitutive activator of pp60c-src tyrosine kinase activity. Compared with control vector transfected Caco-2 cells, both oncogene-transfected cell lines (1) contained smaller amounts of membrane-anchored PGs; (2) exhibited decreased syndecan-1 expression at the protein but not the mRNA level; (3) synthesized 35S-labelled syndecan-1 with decreased specific activity; (4) produced a syndecan-1 ectodomain with a lower molecular mass and reduced GAG chain size and sulphation; and (5) expressed heparanase degradative activity. These results show that the dramatic activation of the tumorigenic potential induced by oncogenic p21ras or Py MT/pp60c-src in Caco-2 cells is associated with marked alterations of syndecan-1 expression at the translational and post-translational levels. PMID- 8695360 TI - Beta-adrenergic signalling in neoplastic lung type 2 cells: glucocorticoid dependent and -independent defects. AB - Tumorigenic mouse lung-derived type 2 cell lines have large reductions in both beta-adrenergic-stimulated cAMP production and ligand binding to beta-adrenergic receptors. These tumorigenic cells are also relatively insensitive to glucocorticoids. Because glucocorticoids regulate both beta-adrenergic receptor expression and receptor coupling to the stimulatory guanine nucleotide binding protein Gs interactions between the glucocorticoid and beta-adrenergic signalling systems were examined. This study demonstrates that beta-adrenergic ligand binding and agonist sensitivity are increased in a tumorigenic cell line stably expressing a normal glucocorticoid receptor transgene. However, although the transfected tumour cells and non-tumorigenic cells have similar amounts and affinities of beta-adrenergic agonist and antagonist binding, similar amounts of Gs subunits and similar forskolin-stimulated adenylyl cyclase activities, the former remain much less isoproterenol responsive. Competition binding studies demonstrate that tumour cell beta-adrenergic receptors have both high- and low affinity agonist binding but are functionally uncoupled from Gs. This uncoupling may involve an alteration in Gs, as guanine nucleotides exhibit a reduced ability to stimulate adenylyl cyclase. Thus, some aspects of tumorigenic cell dysfunction in beta-adrenergic signalling can be ameliorated by interactions with the glucocorticoid pathway, but additional defects are also involved. PMID- 8695361 TI - Enhanced paracellular barrier function of rat mesothelial cells partially protects against cancer cell penetration. AB - To study pathophysiological roles of mesothelial barrier functions in protection against cancer cell invasion, we isolated mesothelial cells from the rat abdominal cavity and then cultured them with 10(-6)M all-trans-retinoic acid (RA) for 10 days. Mesothelial barrier function assessed by measuring transcellular electrical resistance (TER) and the expression of 7H6 tight junction-associated antigen at the cell border were induced by the treatment (10.01 +/- 0.8 vs 6.05 +/- 0.7 omega cm2, without RA; mean +/- s.e.m., n = 10). Then we quantified the attachment and penetration of rat mammary cancer cells (SST-2 cells) into the mesothelial cell monolayer by prelabelling of the cancer cells with fluorescent dye and by observing optical sections at different heights using a laser confocal scanning microscope. When SST-2 cells were overlaid onto the mesothelial cell monolayer treated with RA, the number of cancer cells found at the basal level of the monolayer was significantly reduced. These results showed that enhanced mesothelial barrier function at least partially prevents the penetration of cancer cells into mesothelial cells and suggested that 7H6 antigen serves as a reliable immunocytochemical marker for monitoring mesothelial barrier function. PMID- 8695362 TI - Absence of constitutive EGF receptor activation in ovarian cancer cell lines. AB - Previous investigators have noted that certain ovarian cancer cell lines secrete and respond to transforming growth factor-alpha (TGF-alpha), suggesting that endogenous activation of the epidermal growth factor (EGF) receptor through autocrine or paracrine mechanisms might contribute to the proliferative response. In order to determine whether autocrine stimulation was partly responsible for the proliferative response in ovarian cancer, we investigated whether the EGF receptor expressed by ovarian cancer cell lines was constitutively activated as assessed by the presence of tyrosine phosphorylation. A specific anti phosphotyrosine antibody was used in conjunction with an immunoblotting technique in order to detect EGF receptor phosphorylation in ovarian cancer cell lines in the absence and presence of exogenous EGF. The effects of neutralising anti-EGF receptor antibody on the proliferation of ovarian cancer cell lines was also examined. We found no evidence for constitutive tyrosine phosphorylation of the p170 EGF receptor in eight epithelial ovarian cancer cell lines tested, although each line demonstrated inducible phosphorylation in response to exogenous EGF. The absence of constitutive EGF receptor activation was also noted when cells were grown under high density conditions, thus excluding a role for membrane bound EGF or TGF-alpha in this process. Media conditioned by five ovarian cancer cell lines, as well as malignant ascites obtained from 12 different ovarian cancer patients, were not capable of stimulating EGF receptor phosphorylation. Finally, the proliferation of ovarian cancer cell lines was not significantly inhibited in the presence of neutralising anti-EGF receptor antibody. These data suggest that EGF receptor activation through autocrine pathways is not a major mechanism for the growth of many ovarian cancer cell lines. Other pathways of signal transduction which bypass the requirement for EGF receptor activation may be important in the proliferation for ovarian cancer cells. Such EGF receptor independent pathways may limit the effectiveness of strategies designed to inhibit ovarian cancer cell growth through disruption of EGF receptor function. PMID- 8695363 TI - No evidence of microsatellite instability in bone tumours. AB - Microsatellite instability has recently been reported in sporadic and familial colorectal tumours and can be due to defects in DNA mismatch repair genes. Such instability has subsequently been detected in several other types of sporadic tumours. We studied 29 specimens of bone tumours with different histopathological diagnoses and found no evidence of microsatellite instability. Our results suggest that mismatch repair defects are unlikely to play a significant part in the tumorigenesis of bone neoplasms. Loss of heterozygosity with at least one marker was detected in 11, i.e. in 38% of the tumour samples, most frequently with markers D2S136 at 2p (eight of 28 informative specimens, 29%) and D11S904 at 11p (four of 21 informative specimens, 19%). PMID- 8695364 TI - 'Tumour volume' as a predictor of survival after resection of non-small-cell lung cancer (NSCLC) AB - Many factors have been individually related to outcome in populations of non small-cell lung cancer (NSCLC) patients. Factors responsible for the outcome of an individual after surgical resection are poorly understood. We have examined the importance of 'tumour volume' in determining prognosis of patients following resection of NSCLC in a multivariate model. Cox's proportional hazard analysis was used to determine the relative prognostic significance of stage, patient age, gender, tumour cell-type, nodal score and estimated 'tumour volume' in 669 cases with NSCLC treated with surgical resection, of which 280 had died. All factors (except tumour cell-type, P = 0.33) were individually related to survival (P < 0.05). When examined together, survival time was significantly and independently related to 'tumour volume' and stage (P < 0.001), and other factors ceased to be significant. In cases with stage I or II tumours, risk of death was found to increase significantly with increasing estimated 'tumour volume' (23.8% relative increase in hazard to death per doubling of 'tumour volume', 95% confidence interval 13.2-35.2%, P < 0.001 stage I; P < 0.006 stage II). In cases with stage IIIa tumours this factor alone was the significant prognostic variable. In conclusion, an estimate of 'tumour volume' significantly improves prediction of prognosis for individual NSCLC patients with UICC stage I or II tumours. PMID- 8695365 TI - A phase I study of a 24 hour infusion of gemcitabine in previously untreated patients with inoperable non-small-cell lung cancer. AB - A phase I study to determine the maximum tolerated dose and toxicity of gemcitabine when given as a 24 h infusion to patients with inoperable non-small cell lung cancer (NSCLC). A total of 24 patients with unresectable stage IIIa-IV NSCLC were entered into the study. Gemcitabine was administered as a 24 h infusion on days 0, 7 and 14. Courses of therapy were repeated every 28 days. There were 16 males and 8 females with a median age of 51 years (range 40-73 years). The WHO performance score was 1 (21 patients) or 2 (3 patients). The TNM stage was IIIa (6), IIIb (10) and IV (8). Three patients were entered at each dose level with six at the maximum tolerated dose (MTD). Dose levels were 10, 20, 40, 80, 120, 180 and 210 mg m-2. The MTD was 180 mg m-2 and dose-limiting toxicity was neutropenia and lethargy. Partial response was observed in five (21%) patients (95% CI 7-42%) lasting 10, 14, 18, 47 and 51 + weeks. The maximum tolerated dose of gemcitabine given as a 24 h infusion was 180 mg m-2. PMID- 8695366 TI - Serum neuron-specific enolase (S-NSE) and the prognosis in small-cell lung cancer (SCLC): a combined multivariable analysis on data from nine centres. AB - The influence of pretreatment serum neuron-specific enolase (S-NSE) in addition to more conventional prognostic factors on survival duration in small-cell lung cancer (SCLC) was investigated in 770 patients from nine centres in six countries. The other variables included stage of disease, performance status (PS), age, sex, serum lactate dehydrogenase (S-LDH), serum alkaline phosphatase (S-AP), and serum carcinoembryonic antigen (S-CEA). Increased values of S-NSE (> 12.5 micrograms-1 l) were observed in 81% of the patients, whereas S-LDH, S-AP and S-CEA were elevated in only half of the patients or less. Multivariable analysis by Cox's proportional hazard model disclosed S-NSE as the most powerful prognostic factor followed by poor PS and extensive stage disease. If PS was ignored, S-LDH came up as a significant prognostic factor. S-AP, S-CEA, age and sex had no significant influence on the prognosis. The three prognostic factors, S-NSE, PS and stage of disease, enabled establishment of a prognostic index (PI) based on a simple algorithm PI = zNSE + z(stage) + 2zPS. This segregated the patients into four groups with clearly different prognosis. The median survival and 95% confidence intervals of the four groups were: 468 days (540-408), 362 days (405-328), 256 days (270-241) and 125 days (179-58). Based on the present results we recommend S-NSE and PS, in addition to stage, for prognostic stratification in treatment trials on SCLC. PMID- 8695367 TI - The relationship between tumour glutathione concentration, glutathione S transferase isoenzyme expression and response to single agent carboplatin in epithelial ovarian cancer patients. AB - There is evidence to suggest that glutathione (GSH) and glutathione-S transferases (GST) are important factors in determining sensitivity to cytotoxic drugs in vitro and in preclinical in vivo model systems. To define the relationship between tumour GSH concentration, GST isoenzyme expression and response to carboplatin in epithelial ovarian cancer (EOC), tumour samples from 39 patients with assessable disease after primary surgery were analyzed for GSH content and GST expression. Response was assessed after completing six courses of single agent carboplatin therapy. GSH was measured by high performance liquid chromatography (HPLC) in fresh tumour samples taken at primary laparatomy. GST isoenzyme expression was assessed by immunohistochemistry of fixed tumour material using antibodies specific for pi, alpha and mu classes. GST isoenzyme expression was defined as positive if the staining intensity was strong and more than 10% of tumour cells were involved. The mean GSH concentrations were: 8351 +/ 4496, 7211 +/- 5026, 6559 +/- 4573 and 3758 +/- 1885 (nmol g-1 tissue dry weight mean +/- s.d.) for tumours from patients who subsequently achieved a complete response (CR, n = 18), partial response (PR, n = 10) or who had static disease (SD, n = 7) or progressive disease (PD, n = 4) respectively. There was no relationship between GSH concentration and response (ANOVA, P = 0.32). There were also no relationship between GST isoenzyme expression and response (P Fisher's exact test 0.51-0.55 and chi-squared test 0.98-0.99). In conclusion, there was no association between the concentration of GSH or expression of GST isoenzymes and response to single agent carboplatin in primary previously untreated EOC. PMID- 8695368 TI - Changes in expression of transforming growth factor beta mRNA isoforms in patients undergoing tamoxifen therapy. AB - Tumour was obtained from 37 patients with oestrogen receptor-positive breast cancer, before and during treatment with tamoxifen, and examined qualitatively and semi-qualitatively for mRNA of the three mammalian TGF-beta isoforms. Levels of TGF-beta isoforms were then correlated with tumour response to tamoxifen, as assessed by monthly ultrasound. A high incidence of expression by each isoform was found in tumour material taken both before and during treatment. Semiquantitative assessment of mRNA showed that in the majority of tumours, expression of TGF-beta s did not change markedly with treatment, i.e. beyond that which might have been caused by method reproducibility and tumour heterogeneity (variations of < 100% between pre- and post-treatment samples). In those displaying significant variation with treatment, expression of TGF-beta 1 and beta 3 increased or decreased in equal numbers, whereas TGF-beta 2 expression tended to increase with treatment. Subdividing tumours by clinical response revealed no significant association between changes in expression of TGF-beta 1 and TGF-beta 3. There was, however, a significant correlation between changes in expression of TGF-beta 2 and response (P = 0.018). Thus, of 15 responding tumours displaying substantial changes, 11 showed an increase in TGF-beta 2 expression with treatment, whereas none of the non-responding tumours were associated with increased expression. While not providing evidence for a generalised increase in TGF-beta expression with tamoxifen treatment, the present study suggests that response to tamoxifen therapy may be associated with an increase in expression of specific TGF-beta isoforms in some, but not all, tumours. PMID- 8695369 TI - A phase II study in advanced breast cancer: ZD1694 ('Tomudex') a novel direct and specific thymidylate synthase inhibitor. AB - ZD1694 ('Tomudex'), a novel, direct and specific thymidylate synthase (TS) inhibitor, was developed in a collaborative research programme between Zeneca Pharmaceuticals and the Institute of Cancer Research (UK) and entered clinical trials in 1991; phase II studies began in 1992, using 3.0 mg m-2 every 3 weeks as a short 15 min infusion. Forty-six patients entered a phase II study of ZD1694 in advanced breast cancer. A total of 74% of patients had received prior systemic therapy (either as adjuvant cytotoxic or hormonal therapy or hormone therapy for advanced disease); 39% had received prior adjuvant cytotoxic chemotherapy. All patients had measurable disease and 50% had liver metastases. In all 43 patients were evaluable for response. Of these patients 26% achieved complete (CR) or partial response (PR) (95% Cl 14-42%). A response rate of 44% was seen in liver metastases. Two patients achieved CR of 265 and 301 days' duration respectively, one in locoregional disease, and one in liver metastases. The most common grade 3/4 adverse events were nausea and vomiting (11%), diarrhoea (11%) and leucopenia (20%). Grade 3/4, self-limited and reversible increases in transaminases were seen in 22% of patients. ZD1694 has useful single agent activity in patients with hormone-refractory advanced breast cancer, comparable with that reported for other anti-metabolites, with acceptable tolerability. PMID- 8695370 TI - Familial breast cancer: a controlled study of risk perception, psychological morbidity and health beliefs in women attending for genetic counselling. AB - The present study set out to evaluate perceptions of risk, psychological morbidity and health behaviours in women with a family history of breast cancer who have attended genetic counselling and determine how these differ from general population risk women. Data were collected from 62 genetic counselees (cases) attending the Royal Marsden and Mayday University Hospital genetic counselling services and 62 matched GP attenders (controls). Levels of general psychological morbidity were found to be similar between cases and controls; however, cases reported significantly higher breast cancer-specific distress despite clinic attendance [mean (s.d.) total Impact of Event Scale score, 14.1 (14.3) cases; 2.4 (6.7) controls, P < 0.001]. Although cases perceived themselves to be more susceptible to breast cancer, many women failed correctly to recall risk figures provided by the clinic; 66% could not accurately recall their own lifetime chance. Clinics appeared to have a positive impact on preventive behaviours and cases tended to engage more regularly in breast self-examination (monthly, 66% of cases vs 47% of controls), although few differences were found between groups in terms of health beliefs. We conclude that counselees and GP controls showed considerable similarities on many of the outcome measures, and risk of breast cancer was not predictive of greater psychological morbidity; although cases were more vulnerable to cancer-specific distress. Despite genetic counselling, many cases continued to perceive their risk of breast cancer inaccurately. PMID- 8695371 TI - Transformation zone location and intraepithelial neoplasia of the cervix uteri. AB - We examined the relationship between the frequency of premalignant lesions of the cervix and location of the transformation zone on the cervix among 8758 women as assessed using cervicography. An endo- and exocervical smear test was performed at the same time. Women with smear test classified CIN I or more were recalled and any abnormal area was biopsied under colposcopy. The transformation zone was located on the exocervix in 94% of women younger than 25 years old; as age increased, the proportion of women with a transformation zone located on the exocervix steadily decreased to reach less than 2% after 64 years old. As compared with women having a transformation zone in the endocervical canal, the age-adjusted likelihood of discovering a histologically proven dysplastic lesion was 1.8 times more frequent among women with a transformation zone located on the exocervix (95% confidence interval 1.1-2.9). This higher frequency seemed not attributable to a lower sensitivity of the smear test when the transformation zone was hidden. The results also showed that deliveries tended significantly to maintain the transformation zone on the exocervix. Parity is a known risk factor for cervix cancer, but the mechanism by which it favours malignant lesions remain unknown. Our results suggest that with increasing numbers of livebirths, the transformation zone is directly exposed for longer periods to external agents involved in dysplastic lesions. PMID- 8695372 TI - Low prevalence of hepatitis C infection in hepatocellular carcinoma (HCC) cases and population controls in Guangxi, a hyperendemic region for HCC in the People's Republic of China. AB - Southern Guangxi, China has one of the highest incidences of hepatocellular carcinoma (HCC) in the world. Serum samples collected from subjects of an earlier case-control study (39 cases, 41 controls) and from a random sampling of a residential male cohort (n = 100) were tested for antibodies for the hepatitis C virus (anti-HCV) using ELISA version 2.0 with confirmation by RIBA version 2.0. Only one of 141 (0.7%, upper 95% confidence limit, 3.2%) control subjects and none of 39 (upper 95% confidence limit, 6.07%) HCC cases tested positive for anti HCV. Our results indicate that hepatitis C infection is not an important environmental determinant of HCC risk in this hyperendemic region. PMID- 8695373 TI - Neurofibromatosis and childhood leukaemia. PMID- 8695376 TI - Employment. Recruitment crisis. PMID- 8695375 TI - People are more likely to have unprotected sex after negative HIV tests, survey finds. PMID- 8695374 TI - Joint meeting of the British Oncological Association in association with Royal College of Radiologists, British Institute of Radiology, British Society for Cell Biology. Cardiff, 7-9 July 1996. Abstract. PMID- 8695377 TI - Do they mean us? PMID- 8695378 TI - Is the grass greener? PMID- 8695379 TI - Transcultural nursing. Using reflection in a critical care unit. PMID- 8695380 TI - Tissue viability. Pressure relief in the community. AB - The prevention of pressure sore development can make a major contribution to allowing at risk patients to remain in their own homes. This article describes a cooperative initiative between district nurses and medical engineers to provide appropriate pressure relieving devices quickly to patients in the community. PMID- 8695382 TI - Developing nursing (continuing education credit). PMID- 8695381 TI - Improving chances for working abroad. AB - There appears to have been a decline in mobility since the start of the decade partly because of a lack of recognition of overseas experience, and partly due to a lack of willingness to support temporary work abroad. The NHS Executive, however, is now encouraging NHS trusts to consider work abroad more favourably. PMID- 8695383 TI - Essential evidence. PMID- 8695384 TI - Pregnancy counselling: finding out for themselves. PMID- 8695385 TI - Medical records: off the record. PMID- 8695386 TI - Occupational health: a new kind of health service. PMID- 8695387 TI - No limits. AIDS and community nursing. PMID- 8695388 TI - No limits. Strengths in diversity. Interview by Christina Potrykus. PMID- 8695389 TI - No limits. Poverty: survival of the fittest. PMID- 8695390 TI - No limits. From slaughterhouse to staff nurses via P2000. PMID- 8695391 TI - No limits. Why is our maturity not valued? PMID- 8695404 TI - Career structure in danger. PMID- 8695392 TI - No limits. Electives: mass appeal needed. PMID- 8695405 TI - Prescribing in all but name. PMID- 8695406 TI - Counting beds. PMID- 8695407 TI - Replacing doctors. PMID- 8695408 TI - Nursing shortages: a virtual reality? PMID- 8695409 TI - Risk factors for occupational HIV. PMID- 8695410 TI - Systematic reviews: keeping up with research evidence. PMID- 8695411 TI - Using nursing initiatives to encourage the use of research. AB - This year the International Council of Nurses has decided to make nursing research the theme for its Nurses' Day. To coincide with the launch of the ICN's pack to help nurses get involved with the theme, this article outlines the development of nursing research and discusses what progress has been made. The author also discusses the difficulties involved in getting research into practice and what can be done to rectify the problem. PMID- 8695413 TI - Bionursing: the management of migraine and vomiting. PMID- 8695412 TI - Clinical guidelines: improving practice at local level. PMID- 8695414 TI - Budgeting skills (continuing education credit). PMID- 8695415 TI - Tissue viability. Clinical guidelines: a pilot study of pressure sore care. AB - Guidelines on the prevention and management of pressure sores resulting from a pilot study commissioned by the NHS Executive are expected to be published soon, as discussed on pages 37-39 of this issue. This article looks at the experience of the nurses involved in the pilot study and identifies how other nurses caring for patients with pressure sores can use guidelines to improve their practice. PMID- 8695416 TI - The case for pressure sore and leg ulcer management. PMID- 8695418 TI - NHS chiefs were given pay rises of up to 30 percent last year. PMID- 8695417 TI - Ways of seeing: promoting development in children with a visual impairment (continuing education credit). PMID- 8695419 TI - Ethical arguments. PMID- 8695420 TI - Unions fear privatisation. PMID- 8695421 TI - Crisis in emergency. PMID- 8695422 TI - Hacked off. PMID- 8695423 TI - Meeting the skills crisis in nursing homes. PMID- 8695424 TI - Unequal opportunities. PMID- 8695425 TI - Something to shout about. PMID- 8695426 TI - On-line. PMID- 8695427 TI - Systematic reviews: how to use the information. PMID- 8695428 TI - Promoting compliance with tuberculosis drug therapy. AB - The recent increase in the notifications of tuberculosis infections has focused the attention of healthcare professionals on reasons for the disease's resurgence. This article describes how directly observed therapy and an enlightened approach to health promotion for groups of people perceived as being at risk, could prevent further increases in incidence. PMID- 8695429 TI - The nurse's role as patient advocate for mentally ill people. AB - The recent report of the Confidential Inquiry into Homicides and Suicides by Mentally Ill People (the Boyd report) compiled for the government, and the imminent publication of the Mental Health Patient's Charter, highlight national concern over the provision of care for this group of people. This article examines some of the dilemmas facing mental health nurses when caring for patients under detention orders and evaluates guidelines and recommendations which can aid the nurse in providing appropriate care. PMID- 8695430 TI - Assessing the impact of delayed discharge on acute care. AB - This study examined the incidence of delayed discharge in three acute treatment wards. Of 118 admissions during the eight-week study period, 13.5 per cent (n = 16) were categorised as 'inappropriately located' by the study tool. The staff cited lack of rehabilitative facilities or care of the elderly facilities as reasons for patients' inappropriate stay in the acute ward. The authors recommend that healthcare professionals and social services departments liaise more closely to reduce the incidence of delayed discharge and allow these patients to return to the community whenever feasible. PMID- 8695431 TI - Developing standards of care to meet older patients' needs. AB - This article describes an assessment of the needs of older people in order to develop standards of care and a competencies matrix. The nurses involved in the initiative attempted to define the knowledge, skills and attitudes required to deliver a quality service, and identify which of these could be used to enhance their own professional development. PMID- 8695432 TI - Marketing nursing. PMID- 8695433 TI - Road to local pay. PMID- 8695435 TI - Amazed and angry. PMID- 8695434 TI - Ignoring evidence. PMID- 8695436 TI - Continuous cycles. PMID- 8695437 TI - Bottling up. PMID- 8695439 TI - It could be you. PMID- 8695438 TI - Creating a monster. Interview by Charlotte Alderman. PMID- 8695440 TI - Assessing need for district nursing: study findings. AB - To determine whether an appropriate level of nursing care is being provided in the community, this study aimed to explore whether patients' needs are being identified through the referral system and whether those needs are being met. PMID- 8695441 TI - Evaluating the workload of practice nurses: a study. AB - In 1990 and 1991, 67 practice nurses with a total of 12,725 consultations took part in a before and after study of health board attached and practice-employed nurse workload. The intervention of the New General Practitioner Contract (DoH 1989) and other primary care changes in April 1990 provided an opportunity to examine the process of care, and identify and changes in workload or differences in working patterns of attached and practice-employed nurses, as a result of these modifications. Practice-employed nurses initiated more of their own appointments following implementation of the New Contract and saw fewer GP referrals. Routing treatment room work had decreased for both groups of nurses in the second year. Both groups of nurses had also increased their level of therapeutic listening in the second year, but practice-employed nurses reported higher levels of therapeutic listening than their attached colleagues during both recording periods. PMID- 8695443 TI - The health and social care divide: bridging the gap. AB - It is nearly three years since the full introduction of the reforms advocated in the Caring for People White Paper (DoH 1989) and reports and articles are now being published which comment on the initial effects of these changes, particularly those which have arisen from the health and social care divide created by the reforms. This article examines the nature of this division of responsibility, its implications for patients and for nursing practice. Some positive developments and possible courses of action are also considered. PMID- 8695442 TI - Designing a nurse training programme for venepuncture. AB - This article describes how one trust developed a training programme specifically for nurses to learn how to perform venepuncture and cannulation. Problems encountered and the lessons learnt from the programme are also discussed. PMID- 8695444 TI - Blood transfusion (continuing education credit). PMID- 8695446 TI - Time for answers. PMID- 8695445 TI - Determined to replace a central pay system. Interview by Dina Leifer. PMID- 8695447 TI - Falling morale. PMID- 8695448 TI - Top of the class. PMID- 8695449 TI - Funding research and development in Scotland. PMID- 8695450 TI - Nurses' views of the decision not to resuscitate a patient. AB - The decision not to resuscitate a patient is a complex issue and there is little guidance for nurses on how such a decision is made. The aim of this study was, therefore, to explore the views and working practices of staff in relation to current guidelines and theories, using a situational analysis. Overall, the staff seemed to meet the criteria outlined in the guidelines, although there was little awareness of the guidelines. Nurses in the clinical area should be both educated in the recommendations for practice and should be consulted and involved in developing such recommendations. PMID- 8695451 TI - Head and neck cancer: oral care during radiotherapy. AB - For patients with head and neck cancer who are compromised by the side-effects of radiotherapy, effective mouth care is essential. This article describes the detrimental effects of radiotherapy to the oral cavity and provides a practical guide to oral cleansing. PMID- 8695452 TI - The nurse's role as change agent in the audit cycle. AB - This article describes the role of an audit nurse in relation to the theory and practice of processes of change. The author describes the theoretical background to the audit cycle and how this was used in one NHS trust to assess standards of care and implement change where necessary. PMID- 8695453 TI - Bionursing: how drugs can cause weight gain. PMID- 8695454 TI - Hormone replacement therapy (continuing education credit). PMID- 8695455 TI - New homes but old money? PMID- 8695456 TI - Computers and confidence. PMID- 8695457 TI - We must change too. PMID- 8695458 TI - Unfolding crisis. PMID- 8695459 TI - Convinced of the cause. Interview by Kate Williams. PMID- 8695460 TI - Monday's child. Interview by Kate Williams. PMID- 8695461 TI - Networking ideas worldwide on ethical issues. PMID- 8695462 TI - Pre-operative visits to reduce patient anxiety: a study. AB - The aim of this study was to evaluate the effect of pre-operative visits by theatre nurses on pre- and post-operative levels of anxiety in two groups of general surgical patients, and to see if the outcome was reflected in the level of post-operative pain, nausea, mobility or length of hospitalisation. One group received pre-operative visits while the other group did not. Results of the study showed a significant decrease in anxiety 24 to 72 hours post-operatively for the visited group. A positive relationship between pre-operative anxiety levels and the level of pain, nausea and lack of independence experienced by both groups was also found. Length of hospitalisation was unaffected by the level of anxiety experienced in both groups. The author recommends that all surgical patients should receive a visit from theatre nurses before their operation. PMID- 8695463 TI - Evaluating primary care interventions for incontinence. AB - Regular urinary incontinence affects one in six adult women. However, for the majority, good continence services are difficult to access and few primary care based assessment and treatment facilities are available. A large randomised trial of assessment and treatment in primary care using a trained nurse was conducted in Somerset in 1990. This report summarises the methods and results of the initial study and reports the four-year follow-up results. The results show that 70 percent of women will gain long lasting benefit. This model of service provision will also benefit secondary care specialist services by ensuring that patients are appropriately managed in primary care before any possible referral. PMID- 8695464 TI - Quality assurance and the palliative care team. AB - Part of the nurse manager's role is to understand the complexities of running a specialist unit and to be aware of the increased focus on quality assurance programmes. This article describes how one model can be applied to involve all members of a palliative care team in the process of assessing and improving the quality of service provided. PMID- 8695465 TI - Rehabilitation after myocardial infarction: the role of the community nurse. AB - This article explores how the education and training of community nurses and the part they play in the provision of primary health care equips them to undertake home or health centre-based myocardial infarction rehabilitation programmes. PMID- 8695467 TI - Cardiology. Exercise: a review. AB - There is now little doubt that a lifestyle lacking in exercise can contribute to the development of heart disease. There have been many local and national initiatives to promote exercise and its relation to health and well-being, many linked to the targets set out in The Health of the Nation (DoH 1992). PMID- 8695466 TI - Hypertension and heart disease. AB - Peripheral blood pressure and heart disease are closely linked. Hypertension is not only associated with, but also a cause of, heart disease and evidence is mounting that treating hypertension reduces cardiac events. The knowledge and management of blood pressure is a key element of cardiac care. PMID- 8695468 TI - Cardiology. Maudsley Hospital Smokers' Clinic: a progress report. AB - Tobacco causes more deaths each year than alcohol, heroin, cocaine, AIDS, fires, homicide, suicide and road traffic accidents combined. Despite this staggering statistic, persuading smokers to stop and reducing the number of young people who take up the habit have proved very difficult. This article looks at the Smokers' Clinic at the Maudsley Hospital, London, which is undertaking research to develop more effective approaches. PMID- 8695469 TI - Cardiology. Diet, fat and diabetes. AB - Cardiovascular and cerebrovascular disease are the principle causes of death in people with non-insulin dependent diabetes. This is thought to be due to insulin resistance, which is particularly associated with obesity where the fat is deposited in the abdomen, commonly in men and post-menopausal women. High fat diets, usually also high in saturated fatty acids in the UK, are associated with higher blood cholesterol concentrations, a major risk for cerebrovascular disease. PMID- 8695470 TI - A new lease of life: caring for people with renal impairment. AB - There are currently 5,000 people in the UK receiving dialysis treatment while they are waiting for a kidney transplant. It is conceivable, therefore, that nurses working in general practice, the community and on general wards will meet such patients. This Unit aims to enable those nurses to gain the skills required to be able to participate in the care of patients with renal impairment. This Unit is relevant to the UKCC professional development categories of Practice Development and Educational Development. PMID- 8695472 TI - Creating demand. PMID- 8695471 TI - Old diseases return. PMID- 8695473 TI - Supporting the survivors. PMID- 8695474 TI - Under pressure. PMID- 8695475 TI - What's new for children? PMID- 8695476 TI - Thirty years on. PMID- 8695477 TI - Airing your views. PMID- 8695478 TI - The prevention and treatment of pressure sores. PMID- 8695480 TI - Shared record keeping in the multidisciplinary team. AB - This article describes an attempt to improve discharge planning procedures by introducing multidisciplinary patient records and a joint approach to patient care. The one-year project involved collecting information about the record keeping system in use, before introducing a comprehensive shared package of documents kept at the patient's bedside. Evaluation showed dramatic overall changes in record keeping, although some duplication of documents still occurred. Positive benefits were also noted in team communication and discharge planning. PMID- 8695479 TI - Women's knowledge of HRT and the prevention of osteoporosis. AB - This article reports the findings of a study into the information given to women about hormone replacement therapy (HRT) and the prevention of osteoporosis. The author examines the reasons for prescription of HRT and why some women discontinue the treatment before a preventive effect is likely to have taken place. The study found a lack of appropriate information being given by health professionals to enable women to consider their overall postmenopausal health and recommends a review of the content of information given on the subject. PMID- 8695481 TI - Using a stent to treat patients with portal hypertension. AB - This article is based on work undertaken in the radiology department at the Royal Infirmary of Edinburgh, the first centre in the UK to practise transjugular intrahepatic portosystemic stent shunt (TIPSS) insertion. This is an effective treatment for patients with the signs and symptoms of portal hypertension. The author describes the indications for the procedure and details the nursing care of the patient before, during and after the intervention. PMID- 8695482 TI - Introducing nurse-initiated management of cardiac arrest. AB - Extending practice has been a matter of debate for nurses. This article describes an initiative to extend nursing practice safely at a local level, in response to changes in service provision. The author describes the benefits that training in life support techniques has had for nurses involved in the management of cardiac arrest. PMID- 8695483 TI - Arterial leg ulcer (continuing education credit). PMID- 8695484 TI - E-mail the nurse. PMID- 8695485 TI - Each decision is different. PMID- 8695486 TI - Sacred cows or rogue elephants. PMID- 8695487 TI - Deciding who gets care. PMID- 8695488 TI - Towards equality. PMID- 8695489 TI - Lining up. PMID- 8695490 TI - The virtual university. PMID- 8695491 TI - A convert to the net. PMID- 8695493 TI - Research links in Newcastle. PMID- 8695492 TI - Time on her side. Interview by Charlotte Alderman. PMID- 8695494 TI - Extending the role of the stoma care nurse. AB - Recently, there has been a great deal of interest, argument and debate regarding the extension of nursing roles and the development of nurse practitioner roles in particular. Much of this argument has centred around whether nurses are seeking to gain professional standing by taking on doctors' tasks, but little is heard about the potential benefits to patients and the possibility of developing new patient support services. In this article, the author looks specifically at the area of stoma care and outlines potential advantages and disadvantages to role extension. PMID- 8695495 TI - Perceived carer attitudes to alcohol dependent patients. AB - Negative attitudes among carers towards people with alcohol-related problems have been reported in many studies. However, few studies have examined whether these attitudes are perceived by patients during face to face contact with healthcare professionals when receiving inpatient treatment. A sample of 26 discharged patients completed a 37-item questionnaire following treatment for alcohol problems. The Likert scale was used to measure whether patients felt that the attitude under investigation existed in the caring environment. The findings indicated that negative attitudes reported in other studies were not perceived by patients during inpatient treatment. Some barriers to treatment effectiveness such as prognostic pessimism were detected by the patients. Many upheld the view that the only goal of treatment adopted by staff was that of total abstinence. There is an increasing need to obtain feedback from patients who have received inpatient care. Greater flexibility and creativity in the care of the alcohol dependent person needs to be explored rather than the maintenance of a prescriptive approach. PMID- 8695496 TI - Forging links between academe and practice through research. PMID- 8695497 TI - No limits. As good as the supervisor. PMID- 8695500 TI - No limits. An open letter. PMID- 8695499 TI - No limits. Degree status. PMID- 8695498 TI - No limits. Desperate measures. PMID- 8695501 TI - Giving false hope? PMID- 8695502 TI - Law governing practice nurses to be clarified. PMID- 8695503 TI - Unanswered questions. PMID- 8695504 TI - From policy to practice. PMID- 8695505 TI - Giving advice on sex... and safety. PMID- 8695506 TI - What the papers say. PMID- 8695507 TI - Working in harmony. PMID- 8695508 TI - Handle with care. PMID- 8695509 TI - Handle with care: case study. PMID- 8695511 TI - Networking research in mental health nursing. PMID- 8695510 TI - AIDS epidemic. PMID- 8695512 TI - An overview of policies guiding health care for children. AB - Following the recent publication of the Children's Charter, this article examines existing legislation and guidance surrounding child health services. The author stresses that an understanding of the development of policies in this area is a prerequisite for informed nursing and health visiting practice. PMID- 8695513 TI - What nurses think of library services: a research study. AB - The need for more research in nursing has been highlighted by many organisations and official bodies. However, there is evidence to suggest that many nurses involved in research are reluctant to use libraries. This study aimed to ascertain the attitudes of nursing researchers towards libraries by means of questionnaires and interviews. A five-page questionnaire was sent to 289 nursing researchers throughout the UK in July 1994. Common problems found by the researchers were lack of time to get to the library (67 per cent), the library not having the information required (60 per cent) and the library being too far away (40 per cent). The author suggests that nurses and researchers should work more in co-operation with the librarian. PMID- 8695514 TI - Implementing 'A Vision for the Future' targets in a hospice. AB - This article outlines the response of a palliative care unit to the targets set out in A Vision for the Future (DoH/NHSME 1992). The authors explain how the unit has evaluated the existing service, using audit and quality assurance techniques, and how changes have been implemented to the benefit of staff and patients alike. PMID- 8695515 TI - Teaching technical skills to Project 2000 students. AB - Nurses are increasingly having to take on more technical tasks in response to changing healthcare delivery, new technologies and rising demands from patients. Meanwhile, students are expected to have acquired more and more technical nursing skills by the time they are qualified. In this article, the author looks at why technical care is becoming increasingly important to nurses and asks who should prepare students to provide such care. Some suggestions of how students can be better prepared to provide technical care will also be presented. PMID- 8695516 TI - Oral care (continuing education credit). PMID- 8695517 TI - Project 2000 students are definitely worth employing. PMID- 8695518 TI - The toughest battle yet. PMID- 8695519 TI - Should rapists ever be allowed to nurse again? PMID- 8695520 TI - Risky business. PMID- 8695521 TI - An uphill task. PMID- 8695522 TI - Different ways to make a difference. PMID- 8695523 TI - Theory and practice. PMID- 8695524 TI - Equality matters. PMID- 8695525 TI - Turning fiction into fact. PMID- 8695526 TI - An idea becomes reality. PMID- 8695527 TI - Industrial relations. PMID- 8695528 TI - The use of neuroleptic drugs. PMID- 8695529 TI - A study of prescribing patterns in the community. AB - Qualified nurse practitioners working in the community prescribe from a wide formulary. Despite degree level education, their prescriptions still have to be signed by a GP. This study describes the prescribing patterns of 41 nurse practitioners over one month. The medications prescribed were categorised and their frequency of prescription noted. The author notes the amount of time wasted by nurses waiting for a doctor's signature due to legal restrictions and states the case for autonomy in prescribing for nurse practitioners. The types of medication and situations where they are being prescribed are also discussed. PMID- 8695530 TI - Guidelines on how to prepare and present a seminar. AB - The seminar is a popular teaching method in pre- and post-registration nursing courses. This article explores the values and limitations of this approach and offers guidelines to optimise its usefulness as both a teaching and learning strategy. PMID- 8695531 TI - How to use models of clinical supervision in practice. AB - It is important when considering how to implement clinical supervision to tailor the system adopted to the needs of the staff and the unit or ward. In this article, the author describes five scenarios where clinical supervision could be introduced and the best approach for each situation, using a list of six key areas. PMID- 8695532 TI - Psoriasis. AB - This article looks at psoriasis and describes the psychological support and physical care nurses can offer. The article relates to UKCC professional development categories: Care enhancement and Patient, client, family and colleague support. PMID- 8695533 TI - Annual scientific meeting of the British Society for Haematology. Birmingham, UK, 22-25 April 1996. Abstracts. PMID- 8695534 TI - 2nd meeting of the European Haematology Association. Paris, France, 29 May-1 June 1996. Abstracts. PMID- 8695535 TI - Arterio-venous malformations (AVM) hemorrhage in children: the importance of nursing neurological assessment during the acute phase and early recovery. AB - Arterio-venous malformation (AVM) is a rare phenomenon in children. However, when this event does occur, the outcome can be devastating. This paper outlines the underlying pathogenesis of AVM and the early clinical features associated with an AVM bleed. Clinical manifestations include hemorrhage, seizures, headaches, bruit and congestive heart failure in neonates. Common diagnostic studies include cranial ultrasound, cerebral angiography, CT scan, MRI, brain scan, EEG, skull films, lumber puncture and blood flow studies. Treatment for AVM bleeds includes conservative management, surgical intervention, flow-directed embolization and laser beam/proton beam radiation. The components of a nursing neurological assessment are illustrated best in a case study. Steps in the press include: pre bleed/pre-operature control, fluid and electrolytes, nutrition, musculoskeletal and emotional support. PMID- 8695536 TI - Clinical indicators contributing to I.C.U. length of stay in elective craniotomy patients with brain tumour. AB - The immediate purposes of this study are (a) to indicate the I.C.U. and hospital length of stay in elective craniotomy patients with brain tumour, and (b) to identify the clinical indicators that contribute to the I.C.U. length of stay. The ultimate purpose is to contribute to a growing body of knowledge in providing quality and cost effective patient outcomes by creating appropriate vehicles for further research in the field of neuroscience. The following clinical indicators are identified: pre-op patient admission to ward or same day admit unit, O.R. cancellations, type of tumour, nursing staff availability, intubation on admission, I.C.U. length of stay, and post-op complications. The results of this pilot study, with sample size of 55 patients, could assist us in the nursing profession to develop an appropriate Care Map for craniotomy patients with brain tumour. PMID- 8695537 TI - Participative decision making: multidisciplinary team involvement in unit design. AB - This article describes the multidisciplinary team's input into the design and construction of an Epilepsy Monitoring Unit. The unit construction was a collaborative effort of a multidisciplinary team based in part on patient input as well as economic and efficiency factors. The Unit has resulted in long term rewards for both patients and staff. Patients benefit from the friendly environment created and staff benefits are due to the increased efficiency of the unit--working smarter not harder and the knowledge that staff nurses were an integral part of the planning process of this highly successful project. PMID- 8695538 TI - High-dose chemotherapy of solid tumours. AB - The use of high-dose chemotherapy (HDC) in the range requiring autologous haematopoietic stem cell support can produce very high rates of response in patients with a variety of solid tumours but it remains controversial. The solid tumour in which HDC has been most extensively studied is breast cancer, and this disease is used as a model for the current discussion. Comparisons are made with ovarian, testicular and small-cell lung cancers and random assignment trials are suggested to demonstrate and to quantitate any survival advantages associated with therapy. Further development work is indicated. PMID- 8695539 TI - Current options in the management of gastrointestinal cancer. AB - Surgery is the standard approach for localized gastrointestinal malignancy both in the upper GI tract and for cancer of the large bowel. Adjuvant chemotherapy following curatively resected colorectal cancer, results in a definite survival advantage. The use of chemotherapy in an attempt to downstage inoperable gastric cancer to allow for subsequent radical resection has yielded promising results. Likewise improved survival rate in patients treated with adjuvant chemotherapy after resection, justify further exploration of perioperative chemotherapy in operable gastric cancer. In squamous oesophageal cancer, modem chemo-radiation regimens are superior to radiotherapy alone in localized disease. Some series demonstrate impressive survival rates in the absence of surgical intervention raising the question as to the precise role of surgery in a combined modality approach. Ongoing randomized trials will clarify the relative contributions of these treatment modalities in the management of this disease. In metastatic disease of both upper GI and colonic tumours maintenance of good quality of life should be the primary endpoint. Randomised trials of chemotherapy against best supportive care have provided strong justification for the use of chemotherapy in the management of advanced gastric, pancreatic and colorectal cancer. PMID- 8695540 TI - Somatic genetic changes in lung cancer and precancerous lesions. AB - BACKGROUND: Morphological abnormalities of the bronchial epithelium are associated with lung cancer development and are considered likely to represent the preneoplastic stage of the disease. The association of these lesions with different histological types of lung cancer was reviewed in a series of 97 samples. Lesions associated with squamous cell carcinomas provided the best samples for further study. The objective of this study was to describe the somatic genetic changes which occur in these preinvasive lesions. Among the various candidate somatic genetic changes, loss of heterozygosity on chromosome 3 and changes to the p53 gene were selected as being the most informative. It was demonstrated that these genetic changes, characteristic of fully invasive lung tumours, also occur at the premalignant stage of the disease. In an attempt to take a less directed approach to the comparison of invasive and preinvasive lesions, karyotype analysis was performed on short-term cultures of bronchial cells adjacent to the bronchial margin obtained from patients undergoing lung tumour resection. One such karyotype had a deletion to chromosome 3 (del 3p13-14) as the single abnormality. CONCLUSION: It was concluded that genetic damage to p53 and chromosome 3 is involved in the preinvasive stage of lung cancer, and that damage to chromosome 3 is a particularly early event. PMID- 8695541 TI - Neoplasia in childhood--25 years of progress. AB - BACKGROUND: Several factors have contributed to the improved prognosis for the survival and quality of life of children with cancer. Childhood tumours tend to have their origin in intrinsic genetic abnormalities, and are usually disseminated by the time of diagnosis. As a result, conventional treatments, such as ablative surgery and/or radiotherapy (the effects of which are detrimental to the growth and development of normal tissues), are rarely successful. The advent of effective combination chemotherapy, given as an adjuvant to eradicate micrometastases, has led also to the dramatic regression of inoperable primary tumours. Subsequent surgery often enables complete resection without the need for radiotherapy. Primary surgery is now used to obtain sufficient tissue to make a precise diagnosis, and recently developed molecular techniques make this possible with great precision from needle biopsies in many instances. The development of an effective treatment regimen is the single most important prognostic factor. This also permits analysis of the differences between successfully treated groups and those not cured by standard treatment. These prognostic factors usually have a biological basis that is identifiable at diagnosis, allowing stratification of treatments and further development. Some of the worst prognosis cases on past standard therapy, such as B-cell acute lymphoblastic leukaemia, have an excellent prognosis when specific treatment regimens are designed to fit their particular characteristics. The finding of specific genetic mutations underlying many childhood tumours may now provide an 'Achilles heel' to enable the development of highly specific therapies that are relatively non-toxic to the normal tissues undergoing rapid growth and development during childhood. The rarity of childhood cancer and the need for multidisciplinary management make it impossible for the ordinary district hospital to deliver optimal treatment, though 'maintenance' treatment and follow-up can be delivered locally as part of 'shared care' with a regional centre. These centres are members of the U.K. Children's Cancer Study Group which was formed in 1977 and now treats 75%. of all cases of childhood malignancy, with sufficient numbers to run randomized clinical trials for most tumour types, often in collaboration with other national paediatric oncology groups in Europe and the U.S.A. CONCLUSION: Children with cancer are likely to be major beneficiaries from the recent advances in the understanding of neoplasia, many of which stem from work on paediatric malignancies. It is therefore important and mutually advantageous to foster and maintain close links with mainstream 'adult' oncology and with the cancer research institutions. PMID- 8695542 TI - The surgery of lung cancer. AB - Surgery remains the best chance of cure in lung cancer, and should be offered to between 10% and 20% of patients. The success of surgery depends on accurate assessment of patient fitness and tumour stage. Surgery has an established role in stages I and II and some subtypes of stage III non-small cell carcinoma of the lung. The combination of surgery with radiotherapy and/or chemotherapy may have survival benefit. A multidisciplinary approach is essential for optimum patient care and the promotion of further research into this terrible disease. PMID- 8695543 TI - Radiotherapy of lung cancer. AB - Radiotherapy is the most common nonsurgical treatment for patients with lung cancer. Its value in controlling specific cancer related symptoms is undisputed and can be achieved with unsophisticated and undemanding schedules. However, these treatment regimens cannot be expected to produce durable local control or significant impact on survival. Their use cannot be generally accepted for all inoperable patients. The use of high-dose radiotherapy with curative intent has been brought into disrepute by often inappropriate patient selection and subsequently poor results. In a number of small pilot studies, survival comparable to surgical series can be achieved in operable patients. Safe delivery of high-dose radiotherapy to intrathoracic tumours represents a formidable technical challenge. The sophisticated treatment planning which is necessary and consistent diagnostic evaluation is often lacking in practice when the value of local therapy is perceived as minimal. Recent developments in radiation technology, tumour biology and understanding of normal tissue responses bring an opportunity to design new and more effective treatment schedules. New developments in systemic therapy far from making thoracic irradiation obsolete, demand higher rates of durable local control. The interrelationships between toxicities to normal tissues and potential advantage in antitumour activity bring further challenges in design of optimal combined modality schedules. The challenge facing the Radiation Oncologist interested in thoracic malignancies is how to balance the multiple and often conflicting possibilities and formulate novel schedules that can be evaluated in practice. A further challenge is how to facilitate the introduction of these resource-intensive strategies into the real world of shrinking resources and increasing waiting lists. The potential gains may be individually small but with the numerical importance of lung cancer may have a global impact. PMID- 8695544 TI - Adjuvant and neo-adjuvant chemotherapy in non-small cell carcinoma. AB - BACKGROUND: There have been many trials investigating the influence of chemotherapy on survival following surgery or radiotherapy in non-small cell lung cancer. Few have been large enough to detect the sort of differences likely to emerge, given the limited efficacy of chemotherapy. The technique of meta analysis using individual patient data can allow worthwhile conclusions to be derived from the contradictory data generated by multiple small trials. This paper summarizes published data from randomized trials testing: (1) adjuvant chemotherapy following 'curative' surgery; (2) neoadjuvant chemotherapy prior to surgery in cases of borderline operability; (3) chemotherapy in inoperable, but still localized, disease where standard therapy would be radical radiotherapy. CONCLUSION: All the indications are that combinations including cisplatin confer a small, but real, prolongation of survival. However, meta-analysis is not a substitute for individual trials large enough to detect clinically important differences in survival. Other worthwhile endpoints like symptom control, quality of life and cost cannot be addressed in a meta-analysis. Large, well designed and executed randomized trials are still urgently needed if more time and money is not going to be wasted in the search for better treatments in lung cancer. PMID- 8695545 TI - New drugs in the treatment of non-small cell lung cancer. AB - Non-small cell lung cancer accounts for 75% of all lung tumours, and only about 10% of patients will remain alive 5 years after diagnosis. Few cytotoxic drugs currently registered produce more than a 15% response rate as a single agent or 30%-35% in combination, with only modest survival benefits. New cytotoxic drugs entering phase II and III studies, however, appear to have more than 20% activity against this disease. They include the taxanes (taxol and taxotere), camptothecin analogues (CPT-11 and topotecan), antimetabolites (edatrexate and gemcitabine) and the vinca alkaloid, navelbine. Taxol produces response rates of about 25% in previously untreated patients and is currently undergoing trials at higher doses in combination with cisplatin and granulocyte colony-stimulating factor. Taxotere produces response rates of 33% in previously untreated patients and 21% in patients previously refractory to platinum-containing regimens. The camptothecin analogues, which are inhibitors of topoisomerase I, may produce response rates of up to 41% in previously untreated patients, but these results have varied considerably between different trials (response rates as low as 13.5% have been reported for topotecan). A phase II study with edatrexate produced a response rate of 32% but subsequent trials using combination chemotherapy including this agent have been disappointing. The activity of gemcitabine as a single agent is 20%-25%. Three ongoing phase II studies combining cisplatin and gemcitabine have shown response rates of up to 50%. Gemcitabine has minimal subjective toxicity. Navelbine produces response rates of 22%-33% as a single agent and up to 65% in combination. These new cytotoxic agents with significant activity in non-small cell lung cancer provide exciting potential for developing novel combination regimens in the advanced setting and as neoadjuvant and adjuvant therapy. PMID- 8695546 TI - Anticancer drug development at Lilly Research Laboratories. AB - BACKGROUND: The discovery and clinical development of new drugs to treat cancer at Lilly Research Laboratories has undergone significant change during the past 15 years. During the early 1980s drug discovery relied heavily on a panel of syngeneic murine solid tumour models to identify new agents for clinical trial. New classes of oncolytic agents identified by this methodology include the difluoronucleoside antimetabolites, diarylsulfonylureas, and a series of folate based enzyme inhibitors. Within the folate-based discovery programme at Lilly, a broad understanding of the structure activity relationships of folate antimetabolites and the biochemical basis of folate transport, processing, and enzyme inhibition has enabled a more rational approach for drug discovery. CURRENT STUDIES: Folate receptor binding properties are being studied to predict tumour sensitivities and tissue toxicities. This information, together with knowledge of a compound's ability to undergo polyglutamation via the enzyme folylpolyglutamate synthase, assist in the more rational selection of agents with designed cellular selectivities. Ultimately, the complex metabolic pathways involving folate metabolism provide numerous targets for enzyme inhibition. Inhibitors of purine biosynthesis and thymidylate synthesis have demonstrated broad activity in preclinical models of disease including several human tumour xenografts, and are undergoing clinical testing. The folate-based drug discovery programme serves as a model for other biochemically based drug discovery programs including those based in drug resistance, signal transduction and cell cycle control. PMID- 8695547 TI - Opportunities for pharmacological intervention in the ras pathway. AB - The delineation of a ras-dependent signalling pathway from tyrosine kinases to mitogen-activated protein kinases, which is common to a variety of effectors of cell proliferation, suggests that this pathway may provide targets for agents to inhibit cell proliferation. Considerable investigation is needed to determine which points of the pathway are the most suitable for inhibition in terms of effectiveness and selectivity. The use of interfering mutants derived from each component in the pathway is one approach to determining at which point it is best to inhibit. PMID- 8695550 TI - Is there a role for chemotherapy of non-small cell lung cancer? AB - This paper reviews the results of individual studies and meta-analyses of chemotherapy of non-small cell lung cancer. The published results from studies of chemotherapy as part of a combined modality therapy which have been carried out in the last decade are conflicting. Some show a statistically superior survival for the group receiving chemotherapy compared with a best supportive care group, while the others show no advantage. The differences, however, are small. Meta analysis of data from published randomized trials has been used by some authors to assess combination chemotherapy compared to supportive or palliative treatment of patients of non-resectable non-small cell lung cancer. In some of the randomized trials and meta-analyses results, a statistically significant effect on survival parameters following chemotherapy against non-small cell lung cancer is shown. The clinical significance of these observations is questionable and the results from larger ongoing trials must be awaited before chemotherapy is used routinely in the treatment of advanced NSCLC. PMID- 8695549 TI - Gene therapy for lung cancer. AB - BACKGROUND: The techniques of molecular genetics are being applied in many areas of oncology and have been spectacularly successful in elucidating the pathogenesis of cancer. Attempts are now being made to harness this knowledge for therapeutic use. Lung cancers are common solid tumours of complex aetiology and represent a major challenge for gene therapy. CURRENT INVESTIGATIONS: The approaches presently under investigation include the correction of acquired genetic abnormalities, such as mutation of p53 and activation of the ras oncogene, immunotherapy, enhancement of host resistance to cytotoxic insult, and genetic activation of prodrugs by tissue-specific promoters. A variety of vector systems arc available, including liposomes, replication-defective retroviruses and adenoviruses. Local, regional and systemic routes of administration are being studied, and it seems likely that a combination of these approaches will be needed if such treatments are to become generally available. PMID- 8695548 TI - Immune intervention against virus-associated human cancers. AB - BACKGROUND: A number of viruses have been shown to be carcinogenic in humans, including Epstein-Barr virus (EBV), hepatitis B virus (HBV), human papillomavirus (HPV) types 16 and 18, and human T-lymphotrophic virus (HTLV) 1. Cancer results from viral transformation of a single progenitor cell; the pathogenesis is complex, and viral infection is only one of many factors involved. Taking EBV associated tumours as an example, a number of potential immune interventions, aimed at preventing viral infection or targeting virus-positive tumour cells, have been investigated. ENVELOPE GLYCOPROTEIN-BASED VACCINES: The gp340 glycoprotein is the principal target of the neutralizing antibody response to EBV. A vaccine based on purified gp340 has been shown to protect against EBV associated lymphoproliferative disease (B-cell lymphoma) in an animal model. Phase I clinical trials are being established. CYTOTOXIC T-LYMPHOCYTE(CTL) EPITOPE-BASED VACCINES: EBV infection provokes a powerful CTL-mediated immune response that is directed primarily against the EBNA 3A, 3B, 3C subset of lal viral antigens. Clinical trials are investigating the effect of immunization with synthetic peptides representing EBNA3-derived CTL epitopes. CTL-BASED IMMUNOTHERAPY: Administration of activated T-cells has been shown to reverse lymphoproliferative disease in patients undergoing bone marrow transplantation. This approach may also be useful in other forms of cancer. PMID- 8695551 TI - Chemotherapy in non-small cell lung cancer. AB - BACKGROUND: Non-small cell lung cancer can no longer be regarded as resistant to chemotherapy, and there have recently been considerable improvements in the use of the older agents and advances in the identification of new drugs. Recent meta analysis has also confirmed the view that chemotherapy can have small but modest survival benefits. Although in the treatment of stage IV disease the criteria of efficacy have concentrated on tumour response rates, more recently it has become obvious that these patients can also benefit in terms of improved symptom control. RECENT ADVANCES: For patients with locally advanced stage III disease there have been important developments indicating the benefit of combined modality treatment with chemotherapy and thoracic irradiation. Furthermore, the use of neoadjuvant chemotherapy indicates that resection is possible in about half the patients, and on pathological examination of 15%-20% of the resected specimens there is no evidence of residual tumour. These results justify an increase in the use of systemic chemotherapy in this disease. PMID- 8695552 TI - Seven million too many. PMID- 8695553 TI - Oxygen free radicals and retinopathy of prematurity. PMID- 8695554 TI - Ophthalmic services for children. PMID- 8695555 TI - Number of people with glaucoma worldwide. AB - AIM: To estimate the prevalence of glaucoma among people worldwide. METHODS: Available published data on glaucoma prevalence were reviewed to determine the relation of open angle and angle closure glaucoma with age in people of European, African, and Asian origin. A comparison was made with estimated world population data for the year 2000. RESULTS: The number of people with primary glaucoma in the world by the year 2000 is estimated at nearly 66.8 million, with 6.7 million suffering from bilateral blindness. In developed countries, fewer than 50% of those with glaucoma are aware of their disease. In the developing world, the rate of known disease is even lower. CONCLUSIONS: Glaucoma is the second leading cause of vision loss in the world. Improved methods of screening and therapy for glaucoma are urgently needed. PMID- 8695556 TI - Intraocular pressure changes after peribulbar injections with and without ocular compression. AB - AIM: Two prospective studies were carried out in order to investigate (1) the rise in intraocular pressure (IOP) following peribulbar anaesthesia with a fixed volume of anaesthetic agent administered by a single surgeon, and (2) the efficacy of ocular compression with the Honan balloon for lowering IOP. Glaucomatous eyes were excluded from both studies. METHODS: In study group 1, 36 eyes of 36 patients undergoing cataract and/or implant surgery each received peribulbar injections consisting of 5 ml of anaesthetic from an inferotemporal site through the conjunctiva and a further 5 ml from a medial injection through the caruncle. IOP values were measured immediately before and after the injections and then after a variable period of external ocular compression. In study group 2, 20 eyes of 20 patients undergoing cataract surgery received peribulbar injections of local anaesthetic as above. IOP values were measured immediately before and after the injections and after 20 minutes without ocular compression. After a further 20 minute period with ocular compression the IOP was again measured. RESULTS: In study group 1, the mean immediate rise in IOP induced by the injections was 11.44 (95% confidence interval 8.97-13.90) mm Hg. The mean change in IOP after ocular compression was an overall fall of 2.42 (0.49-4.34) mm Hg from the pre-injection value. In study group 2, the mean injection induced rise in IOP was 9.45 (6.90-12.00) mm Hg. The mean fall in IOP during the first 20 minutes without ocular compression was 2.85 (1.20-4.50) mm Hg. During the second 20 minutes with ocular compression the mean fall in intraocular pressure was 11.05 (8.14-14.96) mm Hg. CONCLUSIONS: There is a large and individually variable rise in IOP following peribulbar anaesthesia. Ocular compression with the Honan balloon is effective in reversing this rise even when the initial rise is large. PMID- 8695557 TI - Glaucoma laser suture lysis. AB - AIM: Suture lysis is commonly performed after trabeculectomy to improve bleb function. It is often thought to be an innocuous procedure. This is the first large study to determine the safety of the procedure and compare results with a control group. METHODS: Two hundred successive trabeculectomies performed between January 1992 and October 1993 were analysed. RESULTS: Ninety nine eyes underwent trabeculectomy and suture lysis; 101 eyes underwent trabeculectomy and did not require postoperative suture lysis. The following complications were noted with suture lysis: flat chambers (13.1%), external aqueous leaks (9%), malignant glaucoma (2%), iris incarceration (2%), and large blebs (2%). All resolved with appropriate management. There was no significant difference in the final postoperative mean pressures between the lysis and the non-lysis groups. CONCLUSION: Suture lysis is not an innocuous procedure. However if managed appropriately, complications do not affect the intraocular pressure outcome. PMID- 8695558 TI - Association of HLA type with pseudoexfoliation of the lens capsule. AB - AIMS/BACKGROUND: To identify an HLA association with pseudoexfoliation of the lens capsule to support the hypothesis that there is a genetic predisposition to pseudoexfoliation. A randomised trial would be ideal for establishing a relation but is more costly and time consuming to conduct. Case-control studies provide an alternative method of establishing a relation. METHODS: The study group comprised 128 subjects who presented to a major eye centre with pseudoexfoliation. Data from blood donors representative of the population of Ireland were used to form a control group. RESULTS: An HLA association with pseudoexfoliation is identified for 14 antigens. Eleven antigens (HLA A1, A33, B8, B47, B51, B53, B57, B62, DR3, DR12, and DR13) are significantly more common in the pseudoexfoliation group while three antigens (HLA B12, B17, and DR2) are significantly less common. Four HLA antigens are strongly associated, with odds ratios of over 7.5. CONCLUSION: The strength of this HLA association is supportive evidence for a genetic component to the development of pseudoexfoliation of the lens capsule. PMID- 8695559 TI - Lens thickness and insulin dependent diabetes mellitus: a population based twin study. AB - AIM: To investigate the relation between lens thickness and duration of insulin dependent diabetes mellitus (IDDM). METHODS: From the new population based Danish twin register, containing 20,888 twin pairs born between 1953 and 1982 (inclusive), all twin pairs having one or both partners affected with IDDM were searched. Among the 45 twin pairs available for clinical eye examination there were 15 monozygotic pairs, 14 dizygotic pairs of same sex, and 16 dizygotic pairs of opposite sex. Lens thickness was measured by ultrasonography. Using a twin control design, the relation between lens thickness and duration of IDDM was assessed by estimating the correlation between the intrapair difference in lens thickness and the intrapair difference in diabetes duration. RESULTS: In monozygotic twin pairs a statistically highly significant correlation between duration of diabetes and lens thickness was found (right eye: r = 0.88, p < 0.0001; left eye: r = 0.90, p < 0.0001). In dizygotic twin pairs of the same sex the correlations were r = 0.58 (p = 0.029) and r = 0.53 (p = 0.053) for right eye and left eye, respectively. For dizygotic twin pairs of opposite sex the correlations were r = 0.58 (p = 0.018) and r = 0.69 (p = 0.005) for right eye and left eye, respectively. The slope in regression analysis were similar for monozygotic twin pairs (0.025, common for both eyes) and dizygotic twin pairs grouped (0.024, common for both eyes). CONCLUSIONS: There is a statistically significant positive correlation between duration of IDDM and lens thickness, as assessed by the twin control method. The higher correlation in monozygotic twins compared with dizygotic twins suggests that genetic factors play an additional role in the determination of lens thickness. The similar slopes in regression analysis indicate that the effect of diabetes duration on lens thickness is independent of zygosity. PMID- 8695560 TI - Infectious keratitis with corneal perforation associated with corneal hydrops and contact lens wear in keratoconus. AB - BACKGROUND: Corneal perforation is an uncommon complication associated with keratoconus. The first cases of infectious keratitis and corneal perforation associated with corneal hydrops and contact lens wear are reported in two keratoconus patients. METHODS: A retrospective chart review and histopathological examination were carried out. RESULTS: Both patients progressed to corneal perforation and emergency penetrating keratoplasty. One patient cultured Fusarium and the second patient Serratia marcesens. Both patients wore contact lenses against medical advice. CONCLUSIONS: The tear in Descement's membrane, stromal oedema, and epithelial bedewing associated with corneal hydrops results in loss of the epithelial-endothelial barrier of the cornea, creating a conduit for infectious organisms through the cornea. Acute hydrops associated with epithelial keratitis, stromal swelling, and a Descement's membrane tear may be a significant risk factor for infectious keratitis and corneal perforation. Contact lenses should not be worn during an active corneal hydrops owing to the increased risk for severe infectious keratitis and corneal perforation. PMID- 8695561 TI - Clinical evaluation of carbocyclic oxetanocin G eyedrops in the treatment of herpes simplex corneal ulcers. AB - BACKGROUND: Acyclovir (ACV) ophthalmic ointment is effective in the treatment of herpetic keratitis. However, when applied, the ointment has an unpleasant feeling and some cases are resistant to ACV. A new antiviral compound, carbocyclic oxetanocin G (C.OXT-G) has potent anti-herpes simplex virus activity and high water solubility, so the clinical effect of C.OXT-G eyedrops on ulcerative herpetic keratitis was evaluated. METHODS: Studies were conducted on the corneal ulcers in 37 eyes of 27 patients. Patients with typical dendritic or geographic corneal ulcers were treated with 0.1% C.OXT-G eyedrops, applied five times a day, together with eyedrops of an antibiotic applied four times a day. The eyes were examined at least twice a week until the ulcers healed, and thereafter at intervals for up to 3 months. RESULTS: All of the ulcers healed, their average healing time being 4.9 (SD 2.2) (range 2 to 9) days. The ulcers in 20 of the 37 eyes were induced by the use of corticosteroid or immunosuppressive drugs, and their average healing time was 4.8 (2.3) days. No adverse drug reactions were seen during the observation period in this trial. CONCLUSION: Eyedrops containing 0.1% C.OXT-G are excellent and safe for treatment of herpes simplex corneal ulcers in humans. PMID- 8695562 TI - Iris indocyanine green videoangiography in diabetic iridopathy. AB - AIMS/BACKGROUND: Iris fluorescein angiography (IFA) is not commonly used in clinical practice, although its value has been demonstrated especially in cases of diabetic disease. IFA is able to show neovascular tufts in order to guide the laser treatment, and it is highly recommended in diabetic patients who need cataract surgery or vitrectomy. Nevertheless, IFA fails to demonstrate the iris vascular pattern in heavily pigmented iris and conspicuous leakage cases. The aim of the study was to evaluate the feasibility of iris indocyanine green videoangiography (IICGV) and to correlate its findings with those of IFA in diabetic iridopathy. METHODS: Thirty six patients affected in varying degrees by diabetic retinopathy underwent an ophthalmic examination including retinal fluorescein angiography, IFA, and IICGV. IICGV was performed using IMAGEnet System H1024. RESULTS: The results demonstrated that IICGV allows precise visualisation of the iris vascular pattern, also in cases of heavily pigmented iris. CONCLUSIONS: Three main findings seemed to be evident: firstly, iris neovascularisations are detected with IFA far more easily than IICGV; secondly, capillary dilatations and iris hypoperfusion are identified far more clearly using IICGV; thirdly, there is no evident relation between capillary dilatation or iris hypoperfusion, and degree of diabetic retinopathy. PMID- 8695563 TI - Retinopathy of prematurity in a controlled trial of prophylactic surfactant treatment. AB - AIMS: To investigate the incidence of acute and cicatricial retinopathy of prematurity (ROP) in a cohort of premature neonates entered into a randomised, multicentre trial of prophylactic exogenous surfactant for respiratory distress syndrome (RDS) compared with controls receiving surfactant only if severe RDS developed. METHODS: The incidence of acute and cicatricial ROP was assessed in 304 neonates born at less than 30 weeks' gestation in a geographically defined population of approximately three million. RESULTS: There was a trend towards improved survival in the group receiving prophylactic surfactant with 102/151 (67.5%) surviving compared with 82/141 controls (58.2%, p = 0.12). The prophylactic surfactant group would be expected to have an increased risk of ROP due to improved survival, particularly of the most premature infants. However, there was no statistically significant difference in the incidence of acute ROP between the two groups and the incidence of cicatricial ROP was lower in the group receiving prophylactic surfactant (4/100 survivors, 4.0%) compared with neonates receiving rescue surfactant as required (6/81, 7.4%). This difference did not reach statistical significance (p = 0.35). CONCLUSION: The trend for a lower incidence of cicatricial ROP in those neonates treated with prophylactic surfactant compared with the rescue surfactant group, despite improved survival, suggests that the use of prophylactic surfactant also had a beneficial effect on the development of cicatricial ROP. PMID- 8695564 TI - Systemic effects of screening for retinopathy of prematurity. AB - AIMS: To detect systemic complications of screening for retinopathy of prematurity (ROP), paying particular attention to the physical examination. METHODS: Oxygen saturation, pulse rate, and blood pressure were monitored before, during, and after 110 ROP screening examinations. RESULTS: Following topical mydriatics diastolic blood pressure was elevated by a mean of 6 (SD 7.2) mm Hg. Immediately after the examination there was a further rise in both systolic and diastolic pressure of 4.3 (14.5) mm Hg and 3.3 (11.6) mm Hg, respectively. Oxygen saturation and pulse rate remained stable during the control period and administration of eyedrops. Saturation fell by a median of 3% (95% confidence interval plus or minus 1.2%) after the examination while there was rise in pulse rate of 7 (SD 23.1) beats per minute. This change in pulse rate was not observed in infants on concurrent methylxanthine therapy. No infant had clinically significant changes at the end of the study. CONCLUSION: The initial changes in blood pressure may represent side effects of topical mydriatics but the later changes following the physical examination may be an additional response to the stress of ROP screening. PMID- 8695565 TI - An elevated level of copper zinc superoxide dismutase fails to prevent oxygen induced retinopathy in mice. AB - BACKGROUND: To determine whether a higher level of copper zinc superoxide dismutase (CuZnSOD) can reduce the severity of oxygen induced retinopathy (OIR) in a mouse model. METHODS: CuZnSOD transgenic mice with a threefold increase in CuZnSOD activity and control non-transgenic mice were exposed to 90% oxygen for 12 hours a day during the first 5 days of life. After oxygen treatment, all mice were reared in room air for 10 days. Another group of transgenic and non transgenic mice were kept in room air for 15 days and served as control groups for the oxygen effect. At day 15, all mice were killed and perfused with India ink. The retinas were flat mounted on slides and examined with a light microscope. RESULTS: There was a statistically significant increase in the incidence of OIR in mice exposed to high levels of oxygen, whether or not they were transgenic. However, there was no statistically significant difference in the severity of OIR between oxygen treated transgenic and non-transgenic mice. CONCLUSION: A threefold higher CuZnSOD activity does not protect against OIR in mice. This is an unexpected finding, since oxygen radicals are considered a major factor causing OIR, and increased CuZnSOD activity has reduced oxygen radical induced damage in several neuronal and non-neuronal systems. The possibility of a damaging role for other radicals not affected by CuZnSOD cannot be excluded. PMID- 8695567 TI - Red blood cell antioxidant enzymes in age-related macular degeneration. AB - AIMS/BACKGROUND: Oxidative damage has been proposed to be involved in the pathogenesis of age-related macular degeneration (ARMD). The purpose of this study was to evaluate whether red blood cell antioxidant enzyme activity correlates with severity of aging maculopathy in affected individuals. METHODS: Blood samples were obtained from 54 patients with varying severity of aging maculopathy and 12 similarly aged individuals with normal ophthalmoscopic examination. Macular findings were graded according to a modification of the method described for the Age-Related Eye Disease Study. (AREDS). The activities of superoxide dismutase, catalase, glucose-6-phosphate dehydrogenase, glutathione peroxidase, and glutathione reductase were measured in red blood cells. Haemoglobin content of whole blood was measured, and enzyme activity was determined per mg haemoglobin. RESULTS: Multiple regression analysis and ordinal logistic regression analysis were performed to determine whether antioxidant enzyme activity was associated with severity of ARMD. No significant association between disease severity of ARMD and antioxidant enzyme activity was identified for any of the enzymes. CONCLUSION: These results do not provide evidence for a relation between oxidative stress, as measured by antioxidant enzyme activity in red blood cells, and disease severity in ARMD. PMID- 8695566 TI - Glycans of the trabecular meshwork in primary open angle glaucoma. AB - AIMS: Glycan expression was compared in glaucomatous trabecular meshwork (TM) and normal TM in order to determine any differences which may reflect pathological changes underlying primary open angle glaucoma (POAG). METHODS: Resin embedded TM from trabeculectomy specimens from 15 eyes with POAG and from 12 eyes with normal anterior segments were probed with a panel of biotinylated lectins and an avidin peroxidase revealing system at the light microscope level. Statistical analyses were performed on the comparative staining results. RESULTS: The lectins ConA and ePHA showed strong staining in all areas of both glaucomatous and normal TM; ePHA staining of Schlemm's canal (SC) from POAG TM was significantly less than that from normal TM (ePHA-SC p = 0.04). The lectins PSA, LCA, and SNA bound moderately strongly to SC endothelium and weakly to the endothelium of the corneoscleral meshwork (CSM); glaucomatous SC endothelial binding was significantly less than that of normal SC endothelium for PSA and LCA (PSA-SC p = 0.002, LCA-SC p = 0.002). STA and DSA showed moderately strong binding while WGA, ECA, AHA, and MPA bound weakly throughout the TM; for DSA and MPA this staining was significantly greater in POAG than in normal TM (DSA-SC p = 0.001, DSA-CSM p = 0.002, MPA-SC p = 0.01, MPA-CSM p = 0.02). Jac stained strongly throughout the TM and showed no significant difference in POAG compared with normal TM (Jac-SC p = 0.6, Jac-CSM p = 1). 1PHA, SBA, DBA, CTA, UEA-1 and LTA did not bind to glaucomatous TM or normal TM. There were no age-related changes seen. CONCLUSIONS: The expression of some complex and hybrid, bisected and non-bisected N-linked glycans is significantly diminished in glaucomatous TM compared with normal TM. Some glycans with multiple N-acetylglucosamine residues and O-linked glycans with terminal and subterminal galactosyl groups are significantly increased in POAG TM. Glycan expression does not change significantly with age in POAG or normal TM. PMID- 8695568 TI - Effects of allopurinol and steroids on inflammation and oxidative tissue damage in experimental lens induced uveitis: a biochemical and morphological study. AB - AIMS: To evaluate the effects of allopurinol in lens induced uveitis (LIU) by morphological methods and to compare these effects with those of steroids and a combination of both drugs biochemically and morphologically. METHODS: Lipid peroxides (LPO) of the retinal tissue were determined by two different methods (thiobarbituric acid assay (TBA) and high performance liquid chromatography expressed as malondialdehyde-like substances). Myeloperoxidase (MPO) activity in the iris/ciliary body complex was analysed spectrophotometrically. Histological changes on three morphological levels of LIU eyes were evaluated. RESULTS: Both allopurinol and the combination of allopurinol/prednisolone led to a significant reduction in the increaed retinal LPO values. Prednisolone only revealed significant effects on retinal LPO when being measured with the TBA method. MPO activity in iris and ciliary body was significantly reduced in all therapy groups. The morphological evaluation of the sections by two masked investigators revealed a significant reduction (p < 0.05) in the inflammation score in all therapy groups. Morphometric studies using the QUANTIMED system (Leica, Cambridge) showed significantly reduced values (p < 0.05) in the allopurinol group and in the group receiving prednisolone and allopurinol. Prednisolone alone did not lead to a significant reduction in the values. CONCLUSIONS: The findings show that both allopurinol and steroids exert positive effects on the variables determined in LIU. The effects of steroids are believed to be mostly due to their direct action on inflammatory cells. The recently reported scavenging effects of methylprednisolone should play a minor role in this disease model. Allopurinol and oxypurinol act as direct scavengers of free radicals and hypochlorous acid, which is produced via MPO catalysis, thus leading to a reduction in tissue inflammation and tissue damage. PMID- 8695569 TI - Development and role of retinal glia in regeneration of ganglion cells following retinal injury. AB - AIMS/BACKGROUND: Recent observations have shown that the glial scar resulting from a surgical lesion of the immature retina differs from elsewhere in the central nervous system, in that it permits the through growth and reconnection of regenerating axons. This study in the opossum examines in detail the development and reaction to injury of retinal glia at different developmental stages, and specifically examines the distribution of the gliosis related inhibitory molecule, chondroitin sulphate proteoglycan (CSPG), making comparisons with a control site of gliosis in the cerebral cortex. METHODS: A linear slit was cut into the retina or cortex with a fine tungsten probe. After a variable time delay, immunocytochemistry of the resulting gliosis was employed to detect astrocytes with glial fibrillary acidic protein (GFAP), Muller cells with vimentin, and CSPG with CS-56 antibodies. GFAP was also used at different ages to examine the normal development of astrocytes in the retina of this species. RESULTS: Astrocytes entered the retina 12 days after birth (P12), closely associated with blood vessels in the nerve fibre layer. In experiments at all ages studied, cellular continuity was re-established across the lesioned retina, which did not result in a significant astrocyte proliferation or CSPG expression. In contrast, cortical injury led to the development of a cystic cavity surrounded by astrocytes and CSPG. Muller cells expressed GFAP but not CSPG in the lesioned retina. CONCLUSION: Successful regrowth of ganglion cells through a retinal lesion may be partly the result of the scarcity of astrocytes in the retina, which results in minimal gliosis, or of their apparent inability to express inhibitory molecules. PMID- 8695571 TI - In vivo human lens epithelial cell proliferation on the anterior surface of PMMA intraocular lenses. AB - AIMS: To study in vivo human lens epithelial cell proliferation on the anterior surface of PMMA implants and its interaction with postoperative blood-aqueous barrier breakdown in eyes undergoing cataract surgery. METHODS: A prospective study was carried out on three consecutive patient cohorts undergoing cataract surgery with intraocular lens implantation using three different surgical techniques which produce different anatomical relations between the implant and lens capsule. Specular microscopy of the anterior implant surface was used to document the natural history, topography, and density of lens epithelial cells and the laser flare and cell meter were used to measure postoperative blood aqueous barrier breakdown. RESULTS: All groups showed lens epithelial cell proliferation onto the anterior surface of PMMA implants. This was initiated by and restricted to the region of anterior capsule-implant contact and decreased with the onset of anterior capsular opacification. Significant correlation was found in all groups between lens epithelial cell proliferation and postoperative blood-aqueous barrier breakdown. CONCLUSIONS: Human lens epithelial cell behaviour on PMMA surfaces in vivo differs from that seen in culture studies. Humoral factors in the aqueous, biomaterial properties of the implant, and its anatomical relations with the anterior and posterior lens capsule influence lens epithelial cell behaviour in vivo. PMID- 8695570 TI - Detecting herpesvirus DNA in uveitis using the polymerase chain reaction. AB - BACKGROUND: Herpesviruses are involved in the pathogenesis of many ocular diseases including keratitis, iridocyclitis, and acute retinal necrosis syndrome. The rapid and accurate diagnosis of herpetic infections has become increasingly important with the rising incidence of immunosuppressive diseases. The purpose of this study was to evaluate the use of the polymerase chain reaction (PCR) to detect herpesvirus DNA in uveitis patients. METHODS: Aqueous samples were aspirated from 11 patients with active uveitis of suspected viral origin. Using PCR, masked samples were assayed for herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV) to assist in supporting the clinical diagnosis of viral aetiology. Masked controls included 10 aqueous humour specimens from normal patients undergoing cataract surgery and specimens from seven patients diagnosed with active non-viral uveitis--Behcet's disease, sarcoidosis, Fuchs' heterochromic iridocyclitis, or Harada's disease. RESULTS: Ten of 11 cases clinically diagnosed as being of possible viral aetiology yielded aqueous PCR positive for a herpesvirus. Eight patients were PCR positive for amplified HSV DNA, of whom two had acute retinal necrosis, one had corneal endotheliitis, and five had recurrent iridocyclitis. VZV DNA was detected in one case of iridocyclitis, and CMV DNA in one case of chorioretinitis. Successful therapy was based on the PCR results. Ten normal aqueous specimens and the seven uveitis samples from cases not suspected of a viral aetiology were PCR negative for HSV, VZV, and CMV. CONCLUSION: These results demonstrate that detecting herpesvirus DNA in the aqueous humour is useful to support a clinical diagnosis of viral uveitis. PMID- 8695572 TI - Measurement of retinal blood flow with fluorescein leucocyte angiography using a scanning laser ophthalmoscope in rabbits. AB - AIMS: To measure blood flow in the rabbit retinal circulation with fluorescein leucocyte angiography using a scanning laser ophthalmoscope. METHODS: Blood was withdrawn from the ear vein of a rabbit (New Zealand White), mixed with fluorescent dye in a test tube and centrifuged. The yellow-brown layer containing fluorescein stained leucocytes was collected and injected into the ear vein of the same rabbit while performing fluorescein angiography with a scanning laser ophthalmoscope. The image of retinal angiography displaying circulating fluorescent leucocytes was recorded on video tape. From each frame of the video tape, the consecutive positions of fluorescein stained leucocytes were digitised using an image analysis system and the velocity of blood flow was calculated. RESULTS: Fluorescent leucocytes were clearly visualised in the retinal arteries, capillaries, and veins which allowed measurement of blood flow. The mean capillary velocity was 0.69 (SD 0.21) mm/s. The mean velocities of leucocytes measured in different sized vessels were as follows: 5.83 (2.42) mm/s in arteries over 50 microns, 3.33 (0.62) mm/s in those 35-50 microns, and 2.42 (1.08) mm/s in arteries under 35 microns, 3.08 (1.56) mm/s in veins over 50 microns, 2.79 (1.49) mm/s in those 35-50 microns, and 1.21 (0.50) mm/s in veins under 35 microns. Blood flow pulsation occurs in arteries, arterioles, veins, and venules but not capillaries. CONCLUSION: Fluorescein leucocyte angiography can be used for simultaneous measurement of the blood flow in retinal arteries, veins, and capillaries. PMID- 8695574 TI - Aspirin is a hazard for vitreoretinal surgery. PMID- 8695573 TI - The emerging roles of topical non-steroidal anti-inflammatory agents in ophthalmology. PMID- 8695575 TI - The 'pupil snap' sign of posterior capsule rupture with hydrodissection in phacoemulsification. PMID- 8695576 TI - Bilateral corneal contusion and angle recession caused by an airbag. PMID- 8695577 TI - Airbag injury during low impact collision. PMID- 8695578 TI - Unilateral Malassezia furfur blepharitis after perforating keratoplasty. PMID- 8695579 TI - Combined granular lattice dystrophy (Avellino corneal dystrophy) PMID- 8695580 TI - A new oculorenal syndrome: retinal dystrophy and tubulointerstitial nephropathy in cranioectodermal dysplasia. PMID- 8695581 TI - Circannually herpetic eye attacks: questionable significant rhythmicities. PMID- 8695582 TI - Modulation of amblyopia therapy. PMID- 8695583 TI - Half a century of fluoridation. PMID- 8695584 TI - A study of the sedative effect of home-administered oral diazepam for the dental treatment of children. AB - This study investigated the effects of oral diazepam administered at home to fearful child patients prior to dental treatment. Twenty-five healthy, uncooperative children, mean age 3 years 8 months (+/- 1 year 3 months), requiring at least three visits for the treatment of dental caries, were studied. Each child's behaviour was assessed during three treatment sessions: (i) control, with no diazepam or placebo; (ii) with diazepam; and (iii) with a placebo. Each child acted as his/her own control, being initially assigned to the control session. Subsequently each was randomly assigned to receive either diazepam or placebo for the second session and the other for the third session. The diazepam and placebo were administered by the parents at home approximately 60 minutes before treatment. Each patient's behaviour was assessed on a scale of 1 (definitely positive) to 4 (definitely negative) by two calibrated examiners who were blind to the medications given and independent of the treatment. Vital signs were monitored at 5-minute intervals. Behaviour was significantly better with diazepam than with the placebo or with neither. No significant differences were observed between the placebo and control sessions. At no time were any adverse effects noted, such as vomiting or respiratory depression. It was concluded that oral administration of 0.3 mg/kg diazepam at home by the parent is an effective and safe technique for preoperative sedation of fearful child patients. PMID- 8695585 TI - Effect of glucose polymers in water, milk and a milk substitute on plaque pH in vitro. AB - Glucose polymers are widely used as an energy supplement in dietetic practice and are increasingly being used in commercially available products, such as some infant formulae and dried baby foods. Information on the effect of glucose polymers on dental health does not exist, yet is essential in order to advise how these carbohydrates should be incorporated into the diet with least risk to dental health. This study aimed to investigate whether glucose polymers taken as 10% solutions in water, in cow's milk, or in a solution of a milk substitute (Calogen) are acidogenic and, if so, whether these solutions decrease plaque pH to levels associated with enamel demineralization. The solutions alone and with 10% sucrose served as negative and positive controls, respectively. Plaque was collected from the teeth of 14 adult subjects before and at 3, 7, 11, 15, 23 and 27 minutes after rinsing the mouth with one of the solutions. pH curves were compiled and acidogenicity expressed as: pH area, minimum pH reached, maximum pH decrease and length of time below pH 6.0. Glucose polymers caused a decrease in plaque pH but, for some of the measures of acidogenicity, to a significantly lesser extent than sucrose. Glucose polymers showed equal acidogenicity when given in water, milk or Calogen. In view of their potential cariogenicity, advice for mode of consumption of glucose polymers and products containing glucose polymers should be the same as that for non-milk extrinsic sugars. PMID- 8695587 TI - Caries prevalence of 5-year-old children in Athens and in South London. AB - This study compared the dental health of 5-year-old children in the London boroughs of Lambeth, Lewisham and Southwark with that in the municipality of Athens, Greece. Three hundred and eighty-four children were examined in London, and 318 in Athens; both samples had a mean age of 5 years 6 months. The proportion of London children who were caries free was 56%, and of Athens children 57.5%, and the mean dmft was 1.63 and 1.48, respectively; these differences were not statistically significant. However, excluding caries-free children from the analysis, the London children had significantly fewer decayed teeth (mean 2.35 compared with 2.93 in Athens) and significantly more missing teeth (mean 0.63 compared with 0.02), indicating marked differences in treatment patterns. PMID- 8695586 TI - Dentists' perceptions and management of pain experienced by children during treatment: a survey of groups of dentists in the USA and Finland. AB - Dentists' perceptions and management of the pain experienced by children during treatment were examined in surveys of 198 American and 230 Finnish dentists. Two pain management areas were studied: communication and the use of anaesthetics and sedation. Neither group of dentists routinely questioned children about pain, but encouraging the child to report pain during treatment was more common; the USA dentists asked about pain more often than the Finnish dentists, whereas the Finnish dentists more often encouraged children to report pain. Finnish dentists were much less likely to use local anaesthetics during restorative treatment of either primary or permanent teeth than USA dentists. Neither group of dentists routinely prescribed nitrous oxide sedation, or premedication, or post-operative pain medications. Regarding the dentists' perceptions of pain experienced by children during dental treatment, neither group rated dental treatment procedures as particularly painful or unpleasant. Most dentists found the pain reports of children credible, yet a sizeable minority (up to 67% of the USA dentists and 21% of the Finnish dentists) did not find them strongly credible. There was little relationship between the dentists' pain management behaviour and their perceptions of the pain experienced by their patients. PMID- 8695588 TI - Problems of root resorption in relation to orthodontic treatment planning: a report of three cases. AB - Three cases are described illustrating problems of root resorption related to orthodontic treatment. In the first case the short roots of many of the teeth made it inappropriate to carry out orthodontic treatment. In the second case there were no signs of root resorption initially, but, following retraction of maxillary incisors with a removable appliance, root resorption was noted affecting molar and premolar teeth, but not the maxillary incisors. In the third case several teeth had short roots, and further shortening of roots occurred during fixed appliance therapy. These cases illustrate the unpredictable nature of root resorption. PMID- 8695589 TI - Juvenile systemic hyalinosis--a rare cause of gingival hypertrophy: a case report. AB - A 5-year-old boy was referred because of gross gingival hypertrophy which caused severe feeding difficulties in addition to obvious aesthetic concern. The patient also suffered from frequent upper respiratory tract infections and diarrhoea. In addition, he had pigmentation on bony prominences of his hands, elbows, knees and ankles, cutaneous nodules behind his ear and granulomatous tissue adjacent to his nose. Excess gingival tissue was removed under general anaesthesia. Histological features suggested a diagnosis of juvenile hyaline fibromatosis, which is considered to represent the same underlying pathological condition as infantile systemic hyalinosis. It is suggested that systemic hyalinosis should be preceded by 'infantile' or 'juvenile' depending on the clinical presentation. PMID- 8695590 TI - A computer software package to facilitate clinical audit of outpatient paediatric dentistry. AB - This paper reports the development and function of a computer program for clinical audit of outpatients in hospital paediatric dentistry in the United Kingdom. The project was one of several national audit projects supported by the Faculty of Dental Surgery, Royal College of Surgeons of England, and funded by the Department of Health. The software is designed to record data utilizing a nationally-agreed minimum set of codes for dental diagnosis, treatment and medical complications, together with patient demographic details pertaining to source of referral, age and sex of patient, and area of residence. A significant component of the software is a flexible report generator which allows data to be analysed using any combination of the above criteria. Audit of activity in hospital dentistry is desirable to enable comparisons to be made between groups of patients and treatments related to diagnosis. This provides the information necessary to enable improvements in clinical practice whilst also assisting the development of both local and national clinical guidelines. Use of this software package will enable such comparisons to be made not only within one hospital but also between different hospital and regions in the United Kingdom. PMID- 8695591 TI - An audit of anterior periapical radiographs taken in a paediatric dentistry unit. AB - The aim of this study was to audit the use of periapical radiographs taken during the endodontic treatment of traumatized incisor teeth in a Paediatric Dentistry Unit. Fifty consecutive radiographs and their accompanying written records were evaluated, using methods which were developed and applied by ten staff and postgraduate students working in the Unit. Less than half of the films and their accompanying records were considered to be completely satisfactory and the performance of permanent staff was no better than that of junior staff and postgraduate students. The audit suggested methods for improving the quality of this service, which were subsequently implemented. PMID- 8695592 TI - The use of inhalation sedation and local anaesthesia instead of general anaesthesia for extractions and minor oral surgery in children: a prospective study. AB - One hundred and thirty-three children aged 4-17 years were treated to assess the viability of operating a regular inhalation sedation service for extractions and minor oral surgery in children. The study evaluated treatment success, assessed parents' and children's satisfaction, and compared the cost of inhalation sedation with that of existing general anaesthesia services. Eighty-four per cent of the children had been referred for orthodontic extractions. Treatment was successfully completed for 120 of the patients; 201 permanent and 130 primary teeth were extracted and six minor surgical procedures were performed. Postal questionnaire assessment of the parents' and children's views showed that 97% were satisfied with the treatment provided. Of those parents who had previous experience of general anaesthesia, 79% stated that inhalation sedation was 'better' or 'much better' than general anaesthesia. It was estimated that the cost of providing treatment under inhalation sedation was considerable less than under general anaesthesia. It was concluded that it is viable to offer a regular inhalation sedation service for orthodontic extractions in children because it is clinically successful, acceptable to children and their parents, and cost effective. PMID- 8695593 TI - Measurement of body fat in young and elderly women: comparison between a four compartment model and widely used reference methods. AB - Body composition was measured in twenty young females aged 19-27 years and eighteen elderly females, aged 65-78 years by densitometry (underwater weighing), deuterium oxide dilution and dual-energy X-ray absorptiometry (DXA). From body weight, bone-mineral content, total body water and body density, percentage body fat (BF%) was calculated using a four-compartment model. BF% obtained by this four-compartment model was regarded as a reference method and BF% obtained by the single methods were compared with this value. Differences in BF% from the four compartment model minus the single methods were 2.1 (SD 1.2) for densitometry, 3.1 (SD 1.8) for DXA and -0.6 (SD 0.9) BF% for deuterium oxide dilution in the young women. In the elderly women these values were -0.6 (SD 2.3), 5.3 (SD 3.8) and 0.7 (SD 2.2) BF%. When a three-compartment model (calculated from body density and total body water) was compared with the four-compartment model, the bias was 0.4 (SD 0.3) BF% in the young and 0.0 (SD 0.3) BF% in the elderly women. From the mineral and water fractions in the fat-free mass the true density of the fat-free mass was calculated as 1.1070 (SD 0.0047) kg/l in the young females and 1.0970 (SD 0.0088) kg/l in the elderly women (P < 0.001). This study shows that the single methods have considerable mean and individual biases compared with the four-compartment model, but that a three-compartment model calculated from density and total body water offers an acceptable alternative. The difference in calculated density of the fat-free mass between the young and the elderly women shows the need to adapt Siri's formula for specific groups. PMID- 8695594 TI - Unexpected relationship between fat mass and basal metabolic rate in pregnant women. AB - We investigated the relationships between BMR, fat-free mass (FFM) and fat mass in pregnancy. BMR was measured by indirect calorimetry and body composition was assessed by densitometry in seventeen non-pregnant women (79.9 (SD 26.3, range 50.5-151.4) kg) and sixteen pregnant women (75.7 (SD 20.6, range 54.5-115.9) kg). The pregnant women were evaluated during weeks 31-35 of gestation. Multiple regression analysis of BMR with FFM and fat mass in the non-pregnant women showed that FFM was a highly significant predictor of BMR (P < 0.0001), but fat mass was not (P = 0.09). In contrast, in the pregnant women, multiple regression analysis revealed that fat mass was a highly significant predictor (P < 0.001), while FFM was not (P = 0.69). Evaluation of the interaction terms in the combined data set confirmed that the relationships of BMR with FFM and fat mass differ significantly in non-pregnant and pregnant women. It is proposed that pregnancy represents a unique condition during which BMR is regulated by maternal adipose reserves. An augmented BMR in overweight pregnant women may be protective, given that excessive weight gain may be detrimental to neonatal and maternal health. PMID- 8695595 TI - Rebalancing essential amino acids intake by self-selection in the rat. AB - The purpose of the present study was to assess whether rats are capable of selecting the right proportions of two diets that are individually inappropriate in terms of essential amino acid composition to satisfy their amino acid requirements. Rats were offered a choice of one protein-free regimen and another devoid of only one essential amino acid (either threonine or isoleucine) set up in such a way as to provide amino acid balance if they were consumed in 1/3 and 2/3 proportions respectively. Preliminary experiments had established that all our diets were aversive by themselves except for the 60 g casein/kg diet. Rats did reach almost the necessary proportion with, according to published standards (National Research Council, 1978), some excess in isoleucine intake. In addition, given access to two aversive diets that were each nutritionally inadequate, rats showed no aversion and gained body weight when they had the opportunity to consume both of them. Beyond the capacity that rats have of rebalancing their micronutrient intake, the present experiment brings out the idea that the imbalance-induced aversion:preference ratio may be completely upset when this omnivore has access to more than one feed. PMID- 8695596 TI - The effect of cottonseed condensed tannins on the ileal digestibility of amino acids in casein and cottonseed kernel. AB - The effect of adding cottonseed hulls to casein- and cottonseed-kernel-based diets on the apparent and true ileal digestibility of N and amino acids, and the proportion of this effect accounted for by condensed tannin (CT), were determined using the growing rat. Sixty rats were allocated randomly to ten semipurified diets, containing either casein (four diets) or purified unheated solvent extracted cottonseed kernel (six diets) as the sole protein source, with Cr2O3 added as an indigestible marker. Two of the casein diets contained no hulls whilst the remaining two diets contained 70 g cottonseed hulls/kg. Two of the cottonseed-kernel-based diets contained no hulls, with two containing 23 g hulls/kg and the remaining two containing 46 g hulls/kg. For each pair of diets, PEG was either included or excluded. The effect of CT was quantified by comparing control rats (-PEG; CT acting) with PEG-supplemented rats (+PEG; CT inactivated) at each level of dietary hulls. The rats were given their respective experimental diets for 14 d. Each rat was given the food ad libitum for 10 min hourly from 08.00 to 18.00 hours. On day 14, samples of digesta were collected at death from the terminal 150 mm of ileum at 7 h from the first meal. Apparent and true ileal digestibilities were calculated for DM, N and the individual amino acids. The principal finding was that the inclusion of hulls depressed the apparent and true ileal digestibilities of N and amino acids, but with the response differing between diets. With the casein-based diet the mean apparent and true ileal amino acid digestibilities were significantly depressed from 0.89 and 0.96 to 0.85 and 0.92 respectively, by the inclusion of 70 g hulls/kg in the diet, and addition of PEG then restored these to 0.89 and 0.95. All of the depression could be explained by the CT content of the hulls. However, with the cottonseed-kernel based diet the responses fell into three categories. The apparent and true ileal digestibilities of the essential amino acids cystine and methionine were not affected by hull addition, ileal digestibilities of leucine, isoleucine, lysine, threonine and valine were markedly depressed by hull addition with approximately 50% of the depression being explained by CT, whilst the ileal digestibilities of histidine, arginine and phenylalanine were depressed by hull addition but little or none of this effect could be explained by CT. Thus the effect of hulls on protein digestion clearly differed with source of protein. With the cottonseed kernel-based diet it seems that components of the hulls other than CT also depressed the apparent and true ileal digestibilities of N and amino acids. The identity of these components is unknown. PMID- 8695597 TI - Determination of rumen microbial-nitrogen production in sheep: a comparison of urinary purine excretion with methods using 15N and purine bases as markers of microbial-nitrogen entering the duodenum. AB - The present study compares estimates of rumen microbial-N production derived from duodenal flow measurements (15N and purine bases) with those from measurements of the urinary excretion of purine derivatives. Four Rasa Aragonesa ewes fitted with simple cannulas in the rumen and proximal duodenum were used. Four diets consisting of 550 g lucerne (Medicago sativa) hay/d as sole feed or supplemented with 220, 400 and 550 g rolled barley grain/d were given in a 4 x 4 random factorial arrangement. Duodenal digesta flows were determined by the dual-phase marker technique during continuous intraruminal infusions of Co-EDTA and Yb acetate. Microbial contribution to the non-NH3 N (NAN) flow was estimated from 15N enrichment and purines: N ratio in duodenal digesta and bacterial fractions isolated from the rumen content. Whole tract organic matter (OM) digestibility and duodenal flow of OM and NAN increased (P < 0.001) with the level of barley supplementation. Digestible OM intake ranged from 19.0 to 42.7 g/kg metabolic weight (W0.75) and the duodenal flow of purine bases and the urinary excretion of allantoin increased linearly (P < 0.001) from minimum values of 7.47 (SD 1.524) and 4.65 (SD 0.705) mmol/d respectively on the basal diet to 18.20 (SD 1.751) and 11.62 (SD 0.214) mmol/d on the 400 g barley diet; a further increase in barley supplementation decreased both variables (13.50 (SD 2.334) and 8.77 (SD 0.617) mmol/d respectively). Urinary excretion of uric acid and hypoxanthine showed a slight but significant increase (P < 0.05) over all levels of barley. Molar recoveries of duodenal purine bases as purine derivatives or allantoin in the urine were 0.78 (SD 0.156) and 0.65 (SD 0.130) respectively. The increase on barley supplementation significantly augmented microbial-N, but large differences between microbial markers employed were observed. Mean values of microbial-N estimated from the duodenal purine bases or urinary allantoin excretion were on average 18 and 29% lower than those measured by 15N. PMID- 8695598 TI - Dietary fat influences Ia antigen expression, cytokines and prostaglandin E2 production of immune cells in autoimmune-prone NZB x NZW F1 mice. AB - To elucidate further the influences of dietary fat on autoimmune diseases, two groups of NZB/W F1 mice were fed with diets containing 200 g dietary fat/kg and 50 g dietary fat/kg (control) respectively. The difference in energy intake between these two groups was compensated with carbohydrate. Mice were bled regularly every month and some of them were killed for in vitro experiments after 5 months experimental diets. Higher immunoglobulin (Ig)M and IgG anti-double stranded DNA antibody levels, shortened life span and worsened proteinuria were noted in mice fed on the high-fat diet compared with those fed on 50 g dietary fat/kg. Phenotypic analyses of spleen cells and peritoneal exudate cells showed that the percentage of CD5+ B cells and the mean fluorescent intensity of major histocompatibility molecules on the surface of both types of cells were higher in mice fed on the high-fat diet. In general, higher type 2 T-helper cell activity was noted in mice fed on the high-fat diet. In addition, cytokines such as interleukin-6, tumour necrosis factor-alpha and prostaglandin E2 (PGE2) produced by lipopolysaccharide-stimulated peritoneal exudate cells were also higher in the high-dietary-fat group. These studies suggest that high dietary fat and its related PGE2 level might have a critical effect on the frequency of CD5+ B cells, cytokine production, macrophage function and subsequent autoimmune regulation in autoimmune mice. PMID- 8695599 TI - Effects of long-term low-glycaemic index starchy food on plasma glucose and lipid concentrations and adipose tissue cellularity in normal and diabetic rats. AB - The present study aimed to assess the metabolic consequences of the chronic ingestion of two starches giving different postprandial glycaemic responses in normal and diabetic rats. The two starches chosen were mung-bean (Phaseolus aureus) starch (97% pure starch) and wheat starch presented as ground French toast. First, we studied the characteristics of these two starches. In vitro the alpha-amylase (EC 3.2.1.1) digestibilities of these starches were 40 (SE 3) and 62 (SE 4)% respectively at 30 min, whereas the contents of resistant starch were 77 (SE 4) and 22 (SE 4) g/kg respectively. In vivo the mung-bean starch produced lower postprandial glycaemic responses than the wheat starch (areas under the curve were: 91 (SE 28) and 208 (SE 33) mmol.min/l, P < 0.05) in normal rats (n 8). We then submitted twenty-eight normal and twenty-eight diabetic (neonatal streptozotocin on second day of birth) male Sprague-Dawley rats (6 weeks old) to a diet containing 570 g starch/kg as either mung-bean starch or wheat starch (n 14 rats/group). After 5 weeks on the diets food intakes and body weights were identical in each group. Liver and kidney weights were comparable when expressed as relative weight. The mung-bean-starch diet slightly decreased epididymal fat pad weight (P < 0.14, ANOVA) and led to a marked decrease in adipocyte volume (P < 0.05). Plasma triacylglycerol and phospholipid concentrations were lower after the mung-bean-starch diet than after the wheat-starch diet in both normal and diabetic rats, whereas free fatty acid concentrations were lower only in normal rats. Similarly, non-fasting plasma glucose concentrations decreased (P < 0.05) in normal rats fed on mung-bean starch but not in diabetic ones (P < 0.14). Insulin levels tended to be lower, but not significantly, after mung-bean-starch feeding than after wheat starch. We conclude that the replacement of 570 g wheat starch/kg diet with mung-bean starch for 5 weeks resulted in (1) lowered non fasting plasma glucose and free fatty acid levels in normal but not in diabetic rats, (2) a reduction in plasma triacylglycerol concentration and adipocyte volume in both normal and diabetic rats. Thus, the type of starch mixed into the diet may have important metabolic consequences in normal and diabetic rats. PMID- 8695600 TI - Digestion and physiological properties of resistant starch in the human large bowel. AB - The digestion of four sources of resistant starch (RS) has been studied in twelve healthy volunteers who ate controlled diets for 15 d periods. RS from potato, banana, wheat and maize (17-30 g/d) was compared with a starch-free diet, a diet containing wheat starch that was fully digested in the small intestine, and with 18.4 g NSP from brand/d. RS increased stool wet weight by 1.6 g/d per g RS fed for potato, 1.7 for banana, 2.5 for wheat and 2.7 for maize, but this was significantly less than bran NSP at 4.9 g/g. RS was extensively digested in twenty-seven of thirty-four diet periods but five subjects were unable to break down one or two of the RS sources. Faecal N and energy excretion were increased. RS decreased NSP breakdown and RS2 (resistant starch granules) tended to prolong transit time. All forms of RS increased faecal total short-chain fatty acid excretion. RS2 (from potato and banana) gave greater proportions of acetate in faeces, and RS3 (retrograded starch from wheat and maize) more propionate. We have concluded that RS2 and RS3 are broken down in the human gut, probably in the colon although in 26% of cases this breakdown was impaired. RS exerts mild laxative properties, predominantly through stimulation of biomass excretion but also through some sparing of NSP breakdown. PMID- 8695601 TI - Measurement of resistant starch in vitro and in vivo. AB - The digestibility of the starch in plant foods is highly variable, and is dependent on a number of factors, including the physical structure of both the starch and the food matrix. An in vitro technique has been developed to categorize starch in plant foods according to its likely rate and extent of digestion in the human small intestine. The in vitro method provides values for rapidly digestible starch, slowly digestible starch and resistant starch (RS). In the present study values for the RS content of foods, as measured by the analytical technique, were compared with the recovery of starch from these foods when fed to healthy ileostomates. Nine ileostomy subjects were given a polysaccharide-free diet with a breakfast supplement, on eac of 2 d (two subjects) or 3 d (seven subjects), of biscuits made from wheat, potato or banana flours or from moist-heat-processed wheat or maize flours. RS intakes measured in vitro ranged from 8.5 to 15.0 g/d for the test biscuits, and mean starch recoveries in ileostomy effluent were 100.4 (n5, range 91-106)% of those values, but there was substantial variation between individuals. It is proposed that RS is defined as 'the sum of starch and starch-degradation products that, on average, reach the human large intestine'. The analytical method for the measurement of RS in vitro based on this definition is shown to provide an accurate prediction of the average amount of starch that is likely to escape complete digestion and absorption in the human small intestine. PMID- 8695602 TI - Fermentable carbohydrate modulates postprandial enteroglucagon and gastrin release in rats. AB - We studied the effects of a fermentable sugar-alcohol (lactitol) on the concentrations of enteroglucagon and gastrin in the blood of rats for 7.5 h after feeding. The control and treatment groups were fed on semi-purified diets containing either non-fermentable cellulose or lactitol respectively, at 100 g/kg. Compared with the cellulose-fed group, the animals fed with lactitol had higher levels of enteroglucagon (5-10 times higher than control; P < 0.05) and lower serum gastrin (70-80% of control; P < 0.05) for several hours after the withdrawal of feed. In contrast, varying the level of dietary lipid (maize oil) over a range of 8-120 g/kg had no effect on the release of either peptide. These results suggest that poorly absorbed fermentable dietary carbohydrate stimulates postprandial plasma enteroglucagon and inhibits serum gastrin release in the rat. The mechanism is uncertain but an endocrine response by the colon to fermentation products seems probable. PMID- 8695603 TI - Lipid fluidity of triacylglycerol-rich lipoproteins isolated from copper deficient rats. AB - Triacylglycerol-rich lipoproteins (TGRLP) were isolated from Cu-deficient and control rats. TGRLP from Cu-deficient rats appeared more fluid than those from controls as sensed by the fluorescence anisotropy of 1,6-diphenyl-1,3,5 hexatriene (DPH). This high fluidity was related to a low cholesterol:phospholipid ratio and high triacylglycerol content in these lipoproteins. TGRLP from Cu-deficient rats were more susceptible to in vitro peroxidation than lipoproteins from control rats as shown by the rate of diene conjugation. The damage induced by the peroxidation resulted in a more ordered state of the lipid fraction especially in lipoproteins from Cu-deficient rats. Thus, after in vitro peroxidation, TGRLP from Cu-deficient rats were more rigid than those from controls. These results suggest that Cu deficiency induces modifications in physicochemical properties of TGRLP which could affect their metabolism. PMID- 8695604 TI - Prevention of coprophagy modifies magnesium absorption in rats fed with fructo oligosaccharides. AB - We developed a new type of anal cup for prevention of coprophagy and determined whether the absorption of Ca and Mg and the stimulatory effects of feeding fructo oligosaccharides (FO) on the absorption of Ca and Mg were altered by prevention of coprophagy in rats. Rats were fed on a FO-free diet or a diet containing 50 g FO/kg for 2 weeks with or without prevention of coprophagy. FO-feeding increased the apparent absorptive ratio of Ca and Mg in rats with or without prevention of coprophagy. However, in the FO-fed groups the absorptive ratio of Mg in rats with prevention of coprophagy was higher than in rats without prevention of coprophagy. The Ca content of the femur was higher in rats fed on the FO-diet than in rats fed on the FO-free diet both with and without coprophagy. In conclusion, FO-feeding increased the absorption of Ca and Mg in rats both with and without coprophagy. Moreover, prevention of coprophagy enhanced the absorption of Mg in rats fed with FO. Coprophagy has to be considered when the effects of luminal fermentation or mineral absorption are examined in rats. PMID- 8695605 TI - Conjunctival impression cytology with transfer (CICT) to detect pre-clinical vitamin A deficiency among slum children in India. AB - In order to establish a method usable in the field for diagnosis of pre-clinical vitamin A deficiency, conjunctival impression cytology with transfer (CICT) was used in 200 normal slum children aged 6-120 months in Chandigarh, India. Conjunctival impressions taken on cellulose acetate paper were transferred to glass slides which were fixed in ethanol and stained with alcian blue and carbol fuchsin. Sixty samples of cellulose acetate paper were preserved after transfer of impression and were stained later. Transfer was complete in forty-eight samples and in the other twelve it was incomplete. Conjunctival impressions on paper and slide of these twelve cases were comparable. At a plasma retinol concentration of < 0.70 mumol/l measured by HPLC the sensitivity, specificity and positive predictive values of CICT were 90.59%, 100% and 100% respectively. Compared with conventional conjunctival impression cytology, CICT is less time consuming, cheaper and comparable in validity. It is thus more suitable than the conventional method for mass screening. PMID- 8695606 TI - The clinical nurse specialist, clinical nurse specialist/nurse practitioner and other titled nurse in Ontario. AB - This study examines the preparation, employment and functions of nurses with titles of clinical nurse specialist, nurse practitioner, and others whose scope of practice exceeds that of the staff nurse. Two established categories of nurses were identified, the Clinical Nurse Specialist (CNS) and the Clinical Nurse Specialist/Nurse Practitioner (CNS/NP). A third category was called Other Titled Nurse (OTN) because of the lack of uniformity in the position descriptions. Surveys were distributed to 379 health service agencies, 33 educational institutions and 204 members of the RNAO Clinical Nurse Specialist Interest Group. This article is based on the responses from the health service agencies and discusses issues pertaining to advanced practice nursing from an administrative perspective. PMID- 8695607 TI - Making policy and procedure systems work effectively. AB - Policy and procedure manuals can be cumbersome to keep current and updated. One approach to meet this challenge is by implementing a decentralized system to develop, review, revise and approve policies and procedures. Mechanisms to operationalize such a system involve sharing of responsibility and accountability of specified policies and procedures by various existing committees and development of coordinating systems and support mechanisms. Other key attributes of a decentralized system included collaboration and extensive communication strategies. PMID- 8695608 TI - Applying the Stetler-Marram model to a nursing administration problem: a graduate student learning experience. AB - Research utilization models have not commonly been used in attempts to solve workplace problems using the results of nursing administration research. This paper describes a graduate learning experience in which the Stetler-Marram Research Utilization Model was applied to a fictitious case in nursing administration. In this case, the model was used to develop a research-based intervention to improve job satisfaction in a hospital setting. PMID- 8695609 TI - The chief of nursing practice: a model for nursing leadership. AB - The role and structure of the Canadian Health Care System and its facilities are changing rapidly. Regionalization, decentralization, and flattening of hierarchical structures have occurred in governments and institutions. Traditional management roles, including the Vice President/Director of Nursing have been eliminated. There is a need to create a new model of nursing leadership if nurses are to continue to provide quality patient care. This article describes the initiative at Women's College Hospital to meet the expressed needs of nurses by developing a unique nursing role. The development of the chief of nursing practice role is defined within the context of the changing environment and Kanter's theory of empowerment. The position of the chief of nursing practice is a role model for nursing leadership and one that is pivotal for the professional identity of nursing, and for the provision of high quality patient care. PMID- 8695610 TI - A framework for planned change: achieving a funded PhD program in nursing. AB - This paper describes a process of planned change undertaken by a group of graduate nursing students of the University of Alberta. Their goal, a funded PhD program in Nursing, was realized fourteen months after their initial meeting. The message of their story is a simple yet significant one for all nurses who wish to influence their environment: Using a framework of planned change, a group of people who organize and commit themselves to a clear goal can become impossible to ignore. In the complexities and uncertainties of today's health care system, many nursing leaders wonder how to effectively insert themselves into the changes occurring in their environments. In this paper, the process of planned change is described through the story of one group of nurses who deliberately set out to reach a desired goal: a funded PhD Program in Nursing at the University of Alberta. Fourteen months later on December 21, 1990, a funded PhD Program in Nursing became a reality. In the early 1980's, several nurses attempted to establish doctoral education for nurses in Canada. The need was for nurse researchers and leaders with doctoral qualifications within the Canadian context. By 1986, the collaboration of nursing faculties at the University of Alberta in Edmonton and the University of Calgary was well under way. The work of Dr. Shirley Stinson, Dr. Janetta McPhail, and Dr. Margaret Scott-Wright with their colleagues resulted in academic approval for the first PhD Program in Nursing in Canada, at the University of Alberta in Edmonton. The starting date of the program, however, was subject to the availability of funding. Funding remained elusive for the next three years, and in the fall of 1989, the Nursing Graduate Student Association decided to form a committee to obtain funding for the doctoral nursing program. Nineteen graduate nursing students from the University of Alberta and the University of Calgary banded together to create the "Nursing PhD Program a Reality" group (NPPR). The group used a framework of planned change based on concepts found in the literature on power, politics, and political action. PMID- 8695612 TI - Home health care in the nineties. PMID- 8695611 TI - Effective consultation in nursing. AB - Given the fiscal challenges within health care today, nurse administrators, whether acting in the role of client or consultant, must determine the most effective and efficient way to solve problems and achieve goals. The consultation process can be viewed from both the client's and the consultant's perspective. This article is intended to provide a practical approach to addressing the issues within the consultation process. The steps of the consultation process are reviewed. The evolution from solving problems to achieving goals is described. The importance of the use of a screening tool when interviewing prospective consultants is emphasized and an example of a generic screening tool is provided. During the interview, consultants are advised to clearly determine the problem or goal, the outcomes which the client expects, possible barriers and risks, and the philosophical fit between both parties. Nurses practise consultation skills daily and, therefore, consultation is a viable opportunity for self-employment. PMID- 8695613 TI - Going home: transition strategies for professional practice in home care and hospice. PMID- 8695614 TI - A salute to hospice nurses. PMID- 8695615 TI - A letter to my children. PMID- 8695616 TI - Craniofacial surgery: the experiment on the experiment of nature. PMID- 8695617 TI - Early palatal changes after initial palatal surgery in children with cleft lip and palate. AB - Early palatal growth and development after primary palatal closure was studied in children with different types of cleft lip and palate (CLP). Palatal dimensions were measured on dental casts taken at fixed ages, from 9 months to 4 years of age. The results showed that soft and hard palatal closure in one stage had a significant impeding influence on posterior sagittal palatal growth compared to closure of the soft palate only. Timing of surgery possibly had a small temporary restrictive effect on posterior transverse palatal growth and development. Type and severity of the oral cleft had a significant effect on transverse palatal development and anterior sagittal dimensions. Anterior arch width was reduced in children with a complete unilateral (U) CLP or bilateral (B) CLP. The palates of the latter children had consistently larger anterior arch depths. Compared to normal children, palates of cleft children changed anteriorly from wider at 9 months of age to narrower at 4 years of age. Arch depths were smaller in cleft children except for anterior arch depths in children with complete BCLP. PMID- 8695618 TI - Prediction of early palatal growth and development in children with cleft lip and palate. AB - With the use of multilevel modeling of longitudinal data, the relationship between the developmental status of the palate at 4 years of age and early palatal growth and development from birth to 1.5 years of age was studied. A model to predict palatal depths and widths at 4 years of age was developed and tested. The sample consisted of 130 children with cleft lip and/or palate. They were divided into three groups according to surgical treatment; (1) no palatal surgery, (2) soft palatal surgery, and (3) soft and hard palatal surgery. Results showed that in groups 1 and 2, the total arch depth at 4 years of age is strongly related to the initial arch depth at birth. No or low correlations were found between palatal depth at 4 years of age and the growth velocity at birth. The anterior arch width in groups 2 and 3 at 4 years of age appeared to be strongly related to the early growth velocity. In group 1, a moderate correlation with the palatal width and growth velocity at birth was observed. The results of the individual predictions of arch depths and arch widths were reasonable to fair. It was concluded that prediction of individual arch variables at 4 years of age is possible, although within limits. Clinically this means that extreme development can be discriminated from more average development. PMID- 8695619 TI - Respiratory and laryngeal function associated with experimental coupling of the oral and nasal cavities. AB - Three experimental openings (10 mm2, 20 mm2, 30 mm2) were placed one at a time in a man's palatal obturator at a location approximating the junction of the prepalate and the palatal shelves. The man's laryngeal and respiratory function were examined during his production of a series of CV syllables [pa] repeated at a comfortable and loud vocal intensity for each of the three experimental conditions. Two more conditions, in which the subject's obturator was not altered (no hole) and in which no obturator was worn, were also included for study. Laryngeal and respiratory function adjustments were most apparent during the 30 mm2 hole size and no obturator conditions. Laryngeal adjustment, as measured by fundamental frequency, was the most identifiable. A respiratory adjustment, which involved the expenditure of more lung volume as nasal airflow leakage increased, was also observed. These observations imply an active physiologic adjustment rather than a passive response to aberrant oronasal coupling. PMID- 8695620 TI - Comparison of the hearing histories of children with and without cleft palate. AB - Aggressive otologic management has been recommended for children with cleft palate because of the almost universal occurrence of otitis media with effusion (OME) in these children and the association of OME with hearing loss and possible language, cognitive, and academic delays. In this study, 28 children with cleft palate and 29 noncleft children were seen at 3-month intervals from 9 to 30 months to compare otologic treatment and management. Hearing and middle ear function were tested at each session; information on ventilation tube placement was obtained from medical records. Ventilation tubes were placed earlier and more often in children with cleft palate, but children with cleft palates failed the hearing screening more often. The correlation between age at first tube placement and frequency of hearing screening failures was significant for the children with cleft palate, indicating that the later tubes were first placed, the poorer the child's hearing. PMID- 8695621 TI - Use of standardized video recordings to assess cleft surgery outcome. AB - A standardized method of video recording the nasolabial area of children with complete unilateral clefts of the lip and nose is described. Assessment of the outcome of cleft surgery using a scoring system to evaluate the video recordings was carried out by a panel of plastic surgeons familiar with the problems of secondary deformity in cleft patients. Nine features of the appearance and function of the lip and 10 features of the nose appearance were assessed in 30 children, aged 11 to 14 years, from two cleft treatment centers. The reliability of the panel ranged from poor to excellent for different features of the lip and nose. With further development this technique may be useful in quality assurance, intercenter comparisons, or outcome studies of surgical techniques. PMID- 8695622 TI - Nasalance and nasal area values: cross-racial study. AB - Nasometry and nasal cross-sectional area data were obtained from 80 normal male and female speakers (40 African-Americans and 40 white Americans) all of whom were over the age of 18 and spoke the Mid-Atlantic dialect of American English. The nasalance scores for readings of the Zoo Passage did not differ significantly between the groups. However, nasalance scores for readings of the Nasal Sentences were found to be significantly higher among the white speakers. The pressure-flow method was used to obtain nasal cross-sectional area values. There were no racial differences in nasal cross-sectional area. The Nasal Sentences scores were not highly correlated with nasal cross-sectional area. The clinical significance of these findings is discussed. PMID- 8695623 TI - Studies in cranial suture biology: in vitro cranial suture fusion. AB - The biology underlying craniosynostosis remains unknown. Previous studies have shown that the underlying dura mater, not the suture itself, signals a suture to fuse. The purpose of this study was to develop an in vitro model for cranial suture fusion that would still allow for suture-dura interaction, but without the influence of tensional forces transmitted from the cranial base. This was accomplished by demonstrating that the posterior frontal mouse cranial suture, known to be the only cranial suture that fuses in vivo, fuses when plated with its dura in an organ-culture system. In such an organ-culture system, the sutures are free from both the influence of dural forces transmitted from the cranial base and from hormonal influences only available in a perfused system. For the cranial-suture fusion in vitro model study, the sagittal sutures (controls that remain patent in vivo) and posterior frontal sutures (that fuse in vivo) with the underlying dura were excised from 24-day-old euthanized mice, cut into 5 x 4 x 2 mm specimens, and cultured in a chemically defined, serum-free media. One hundred sutures were harvested at the day of sacrifice, then every 2 days thereafter until 30 days in culture, stained with H & E, and analyzed. A subsequent cranial suture without dura in vitro study was performed in a similar fashion to the first study, but only the calvariae with the posterior frontal or sagittal sutures (without the underlying dura) were cultured. Results from the cranial suture fusion in vitro model study showed that all sagittal sutures placed in organ culture with the underlying dura remained patent. More importantly, the posterior frontal sutures with the underlying dura, which were plated-down as patent at 24 days of age, demonstrated fusion after various growth periods in organ culture. In vitro posterior frontal mouse-suture fusion occurred in an anterior-to-posterior direction but in a delayed fashion, 4 to 7 days later than in vivo posterior frontal mouse-suture fusion. In contrast, the subsequent cranial-suture without dura in vitro study showed patency of all sutures, including the posterior frontal suture. These data from in vitro experiments indicate that: (1) mouse calvariae, sutures, and the underlying dura survive and grow in organ-culture systems for 30 days; (2) the local dura, free from external influences transmitted from the cranial base and hormones from distant sites, influences the cells of its overlying suture to cause fusion; and (3) without dura influence, all in vitro cranial sutures remained patent. By first identifying the factors involved in dural-suture signaling and then regulating these factors and their receptors, the biologic basis of suture fusion and craniosynostosis may be unraveled and used in the future to manipulate pathologic (premature) suture fusion. PMID- 8695624 TI - Intranasal tooth in a patient with a cleft lip and alveolus. AB - Ectopic dental eruption into the nasal cavity is a rare phenomenon with an obscure cause. A case of an early erupted intranasal tooth in a patient with a repaired cleft lip, an unrepaired cleft alveolus, and fusion of lower incisor teeth is reported. Only three similar cases of intranasal teeth in cleft patients have been reported in the literature. The unusual features in the present case are highlighted. PMID- 8695626 TI - Three-layer corrections of secondary cleft-lip/nasal deformities. PMID- 8695625 TI - Electropalatography treatment in an adult with late repair of cleft palate. AB - This paper describes the use of electropalatography (EPG) in the treatment of a speech disorder in a Cantonese-speaking woman who had primary repair of the palate at age 13. A multiple-baseline approach was used to document treatment efficacy using electropalatography. The client showed rapid improvement in articulatory placement, with generalization to nontarget phonemes. In addition, improvement was noted in her manner of articulation, with a reduction of nasal emission. The relationship between articulatory placement errors and nasal emission in late repair cleft is discussed. Explanations for the effectiveness of EPG with this client are offered. PMID- 8695628 TI - Craniofacial morphology in twins with cleft lip and palate. AB - The craniofacial morphology of 11 pairs of monozygotic (MZ) and 28 pairs of dizygotic (DZ) Finnish twins, discordant or concordant for cleft of the lip (CL), unilateral cleft lip and palate (UCLP), or cleft palate only (CP) were investigated by means of lateral cephalometric radiographs. The results were compared to those of age-, sex-, and cleft-type matched single-birth cleft subjects, and also with normative data from the Nordic population. The co-twins with no cleft lip or palate (NONC) showed only slightly more obtuse gonial and steeper mandibular angles compared to normative data. Twins with CL, UCLP or CP had a more retrusive mandible, a wider cranial base and mandibular angle, and a wider angle between the maxilla and mandible than did the single-birth cleft subjects. Comparison of the noncleft twin group with the CL, UCLP, and CP twin groups for the CL twins showed no significant differences. For the UCLP twins, a more retrusive and down- and backward rotation of both jaws, a wider gonial angle, and a wider cranial base angle was seen. The CP twins had their maxillae slightly retrusive, the down- and backward rotation of both jaws was apparent, and the gonial angle was more obtuse. A comparison between the noncleft MZ and noncleft CDZ twins showed no significant differences. The MZ CP twins had a more retrusive mandible and more down- and backward rotation of both jaws than did DZ CP twins. It thus can be suggested that twinning itself does not seem to have an effect on maxillofacial morphology, but the features of the mandibular structure, the cranial base angulation, and the inclination of the jaws are at least partly genetically induced. PMID- 8695627 TI - Comparison of facial form in primary alveolar bone-grafted and nongrafted unilateral cleft lip and palate patients: intercenter retrospective study. AB - The purpose of this study was to describe and compare posttreatment craniofacial morphology in samples of complete unilateral cleft lip and palate (CUCLP) patients treated at two leading clinics: The Children's Memorial Hospital Cleft Palate Clinic, Chicago, Illinois, and the Lancaster Cleft Palate Clinic, Lancaster, Pennsylvania. These centers have well-defined treatment protocols that allow the long-term effects on craniofacial form of the following treatment regimes to be contrasted: (1) Chicago--primary alveolar bone grafting, with definitive lip repair at age 4 to 6 months and hard and soft palate repair at 6 to 12 months; and (2) Lancaster--definitive triangular-flap lip repair at 3 months of age, followed by staged surgeries of the hard and soft palates, both completed by 18 months of age, but without primary alveolar bone grafting. Although the Lancaster center now performs secondary alveolar bone grafting, the majority of the patients studied here were treated before this procedure became part of their protocol. Patients were eligible for inclusion if they had no other congenital anomalies and no previous orthodontic treatment. A sample of 43 (24 male, 19 female) CUCLP patients was obtained from the Chicago Center, each of which was then matched to a nongrafted Lancaster CUCLP patient. The matching criteria were age, sex, and sella-nasion distance (to control, at least in part, for size differences). Lateral cephalometric radiographs of these 86 CUCLP patients were traced, digitized, and analyzed. Additionally, all linear data were adjusted to a standard magnification of 8% because the cephalograms from each center featured different enlargements. The Chicago and Lancaster samples had mean posttreatment ages of 10.32 years (SD = 1.96) and 10.40 years (SD = 2.18), respectively. The grafted Chicago group had faces that were on average less maxillary protrusive compared with the nongrafted Lancaster sample; it appeared, however, that the mandible compensated for the maxillary position by downward and backward rotation. As a result, a similar maxillomandibular relationship was noted in both groups, although, in the Chicago group, the lower anterior facial height increased. PMID- 8695629 TI - Blocking one non-catalytic ADP binding site results in complete inhibition of the F-type ATPase from the thermophilic Bacillus PS3. AB - The F-type ATPase, TF0F1, from the thermophilic Bacillus PS3, which is free of nucleotides after isolation, was specifically loaded with one 2-azido ADP on a non-catalytic site. The enzyme was covalently modified to various extents and the rate of ATP synthesis and ATP hydrolysis was measured. Both ATP synthesis and ATP hydrolysis extrapolated to zero for covalently binding one nucleotide per enzyme. This was interpreted such that the non-catalytic sites are involved in the coupled catalytic process. PMID- 8695630 TI - Molecular cloning, DNA sequence and transcriptional analysis of the Rhodospirillum molischianum B800/850 light-harvesting genes. AB - The amino acid sequences of the B800/850 light-harvesting proteins from Rhodospirillum molischianum were determined by Edman degradation. On the basis of these amino acid sequences, two degenerated oligonucleotides were synthesized and used for PCR of genomic DNA. The resulting 150 bp DNA fragment was cloned, sequenced and used for subsequent Southern blot analysis of digested genomic DNA. A 2.3 kbp EcoRI fragment strongly hybridized to the probe and a size selected genomic library from genomic DNA was constructed. One clone scored positive during screening of the library with the PCR-fragment and subsequent DNA sequence analysis of the clone revealed the presence of three A-genes (A1A2A3) encoding alpha-polypeptides and of two B-genes (B1B2) encoding beta-polypeptides of the B800/850 complex. The arrangement of the different genes are B1A1, B2A2 and A3 where only B1 and B2 are preceded by typical Shine-Dalgarno sequences. In addition, typical nucleotide sequences for a rho-independent termination of transcription are located downstream of the genes A1 and A2. The deduced amino acid sequences revealed that the alpha-genes encoded for identical polypeptides, whereas the deduced beta-polypeptides differed in their amino acid sequence at four positions. Transcriptional operon analysis revealed that the genes A1B1 and A2B2 are both dicistronically transcribed, whereas the gene A3 is not. PMID- 8695631 TI - Primary structure of a ferredoxin-like iron-sulfur subunit of complex I from Neurospora crassa. AB - We have isolated cDNA clones encoding an iron-sulfur polypeptide subunit of the mitochondrial complex I of Neurospora crassa. The fungal cDNA library was screened by hybridisation with an heterologous probe from Paracoccus denitrificans. The DNA sequence of relevant isolates was determined and revealed an open reading frame encoding a precursor protein of 219 amino acid residues. The gene product is a ferredoxin-like protein that contains two cysteine-rich motives that may each bind a tetranuclear iron-sulfur cluster. The primary structure of the protein is highly homologous to the 23 kDa iron-sulfur subunit of complex I from bovine and P. denitrificans. Interestingly, an alanine residue within the second cluster-binding motif, which is conserved in complex I but replaced by tyrosine in similar chloroplast genes, is substituted for serine in N. crassa. PMID- 8695632 TI - Structure of chromosomal DNA coding for Pseudomonas putida S-1 salicylate hydroxylase. AB - A gene coding for the salicylate hydroxylase has been isolated from chromosomal DNA of Pseudomonas putida S-1 and sequenced. The DNA fragment contained an open reading frame of 1266 bp encoding a polypeptide of 421 amino acid residues. The predicted amino acid sequence of the protein gave a good agreement with the sequences determined with the peptides isolated from the enzyme but methionine residue in the amino terminal was deleted in the N-terminal sequence of the enzyme protein. The nucleotide and amino acid sequences of the salicylate hydroxylase shared several common characteristics with those of the enzyme encoded on the plasmid DNA of P. putida PpG7; homology of nucleotide sequence is 58% and that of amino acid sequence is 56%. We could find two large conserved regions of the amino acid sequence at or near FAD- and NADH-binding regions. The FAD-binding site locates on the amino terminal and a lysine residue, functioning as an NADH-binding site (K. Suzuki, M. Mizuguchi, T. Gomi, and E. Itagaki, 1995, J. Biochem. 117,579-585), locates as Lys163. PMID- 8695633 TI - Cloning and sequencing of nhaB gene encoding an Na+/H+ antiporter from Vibrio alginolyticus. AB - A gene has been cloned from the marine bacterium Vibrio alginolyticus that functionally complements a mutant strain of Escherichia coli, TO114, defective in three Na+/H+ antiport genes (nhaA, nhaB, chaA). The nucleotide sequence of the cloned fragment revealed an open reading frame, which encodes a protein with a predicted 528 amino acid sequence and molecular mass of 57212 Da. This gene has 62% identity to nhaB gene at the DNA level from Escherichia coli and the deduced amino acid sequence is 67% identical with E. coli NhaB. This gene is presumably the V. alginolyticus nhaB gene and will be named nhaBv. PMID- 8695634 TI - The ferritins: molecular properties, iron storage function and cellular regulation. AB - The iron storage protein, ferritin, plays a key role in iron metabolism. Its ability to sequester the element gives ferritin the dual functions of iron detoxification and iron reserve. The importance of these functions is emphasised by ferritin's ubiquitous distribution among living species. Ferritin's three dimensional structure is highly conserved. All ferritins have 24 protein subunits arranged in 432 symmetry to give a hollow shell with an 80 A diameter cavity capable of storing up to 4500 Fe(III) atoms as an inorganic complex. Subunits are folded as 4-helix bundles each having a fifth short helix at roughly 60 degrees to the bundle axis. Structural features of ferritins from humans, horse, bullfrog and bacteria are described: all have essentially the same architecture in spite of large variations in primary structure (amino acid sequence identities can be as low as 14%) and the presence in some bacterial ferritins of haem groups. Ferritin molecules isolated from vertebrates are composed of two types of subunit (H and L), whereas those from plants and bacteria contain only H-type chains, where 'H-type' is associated with the presence of centres catalysing the oxidation of two Fe(II) atoms. The similarity between the dinuclear iron centres of ferritin H-chains and those of ribonucleotide reductase and other proteins suggests a possible wider evolutionary linkage. A great deal of research effort is now concentrated on two aspects of ferritin: its functional mechanisms and its regulation. These form the major part of the review. Steps in iron storage within ferritin molecules consist of Fe(II) oxidation, Fe(III) migration and the nucleation and growth of the iron core mineral. H-chains are important for Fe(II) oxidation and L-chains assist in core formation. Iron mobilisation, relevant to ferritin's role as iron reserve, is also discussed. Translational regulation of mammalian ferritin synthesis in response to iron and the apparent links between iron and citrate metabolism through a single molecule with dual function are described. The molecule, when binding a [4Fe-4S] cluster, is a functioning (cytoplasmic) aconitase. When cellular iron is low, loss of the [4Fe-4S] cluster allows the molecule to bind to the 5'-untranslated region (5'-UTR) of the ferritin m-RNA and thus to repress translation. In this form it is known as the iron regulatory protein (IRP) and the stem-loop RNA structure to which it binds is the iron regulatory element (IRE). IREs are found in the 3'-UTR of the transferrin receptor and in the 5'-UTR of erythroid aminolaevulinic acid synthase, enabling tight co-ordination between cellular iron uptake and the synthesis of ferritin and haem. Degradation of ferritin could potentially lead to an increase in toxicity due to uncontrolled release of iron. Degradation within membrane-encapsulated "secondary lysosomes' may avoid this problem and this seems to be the origin of another form of storage iron known as haemosiderin. However, in certain pathological states, massive deposits of "haemosiderin' are found which do not arise directly from ferritin breakdown. Understanding the numerous inter-relationships between the various intracellular iron complexes presents a major challenge. PMID- 8695635 TI - Control of frequency and amplitudes is shared by all enzymes in three models for yeast glycolytic oscillations. AB - The three main existing models for glycolytic oscillations in yeast were re examined to investigate how these oscillations are controlled. We implemented the operational definitions provided by metabolic control analysis to quantify the control properties of enzymes with regard to glycolytic oscillations. In all three models, the control of the frequency and that of the amplitudes of the metabolites were distributed among the enzymes. There was no obvious correlation between the control of the average flax and the control of the frequency. Most importantly, the so-called 'oscillophore' of the system, traditionally the enzyme primarily held responsible for the generation of the oscillation, was not the only controlling step. We conclude that just like steady-state flux control is not necessarily limited to a rate-limiting step, oscillations are not dictated by a single 'oscillophore'. PMID- 8695636 TI - Photodynamic inactivation of gramicidin channels:a flash-photolysis study. AB - Photosensitized inactivation of ionic channels formed by gramicidin in the planar bilayer lipid membrane (BLM) has been studied upon exposure of the BLM to single flashes of visible light in the presence of tetrasulphonated aluminium phthalocyanine. The gramicidin photoinactivation is inhibited by the addition of unsaturated phospholipids to the membrane-forming solution as well as by the addition of azide to the bathing solution, consistent with involvement of singlet oxygen. The characteristic time of the photoinactivation (tau) does not change markedly under these conditions. Moreover, tau remains nearly constant upon alteration of the flash energy and the photosensitizer concentration. The value of tau appears to be sensitive to the gramicidin concentration and to the factors affecting the open time of the gramicidin channels, namely the temperature and the solvent used in the membrane-forming solution. The photoinactivation is not observed with covalent gramicidin dimers. The equations derived from the model of Bamberg and Laeuger (J. Membrane Biol. (1973) 11, 177-194), describing the relaxation of the gramicidin-induced conductance after a sudden distortion of the dimer-monomer equilibrium, are shown to explain consistently the time course of the photoinactivation provided that the damage of the gramicidin molecules leads to deviation from the equilibrium. PMID- 8695637 TI - A cDNA clone from Arabidopsis thaliana encoding plastidic ferredoxin:sulfite reductase. AB - A cDNA with an open reading frame of 1929 bp (termed sir) was isolated from a lambda ZapII library of Arabidopsis thaliana leaf tissue. The polypeptide sequence deduced from the cDNA is homologous to the ferredoxin-dependent sulfite reductase (EC 1.8.7.1) from Synechococcus PCC7942 and distantly related to the hemoprotein subunit of Escherichia coli NADPH-dependent sulfite reductase (EC 1.8.1.2). A molecular mass of 71.98 kDa can be predicted for a ferredoxin sulfite reductase from A. thaliana. The polypeptide consists of 642 amino acids including a transit peptide of 66 residues (6.72 kDa) that is assumed to direct the protein into the plastid. For expression and enzymatic characterization of a putative A. thaliana ferredoxin sulfite reductase, the DNA of the transit peptide was deleted by a PCR method. The truncated cDNA clone was expressed as his-tag fusion protein. The modified gene product was enzymatically inactive but specific cross reaction with polyclonal antibodies against ferredoxin sulfite reductase from Synechococcus is seen as confirmation of its identity as higher plant ferredoxin sulfite reductase. PMID- 8695638 TI - Kinetic and modelling studies of NAD+ and poly(ethylene glycol)-bound NAD+ in horse liver alcohol dehydrogenase. AB - Poly(ethylene glycol)-bound nicotinamide adenine dinucleotide (PEG-NAD+) has been successfully employed in the continuous production of L-amino acids from the corresponding alpha-keto acids by stereospecific reductive amination. Like many other dehydrogenases also horse liver alcohol dehydrogenase (HLADH) appears to be active with PEG-NAD+ as coenzyme, although the turnover number is three to four times lower. The possibilities were considered that the PEG-tail of a PEG-NAD+ bound to one active site of the HLADH dimer prevents the binding of another PEG NAD+ to the second site, or that the PEG-tail causes destabilization of the active dimer. Both could be ruled out by kinetic studies. Neither can the observed lower intrinsic reactivity of PEG-NAD+ account for the diminished activity of the enzyme. Molecular dynamics studies, on the other hand, show that the pulling action of the polymer chain shifts the NAD position in the active site in the outside direction, causing small but significant changes in the enzyme/coenzyme interactions of a sufficient extent to explain the experimental results. PMID- 8695639 TI - Calcium-induced conformational change in cardiac troponin C studied by fluorescence probes attached to Cys-84. AB - Residue Cys-84 of bovine cardiac troponin C (cTnC) located at the C-terminal end of helix D was selectively labeled in the presence of Ca2+ with two fluorescent probes: IAANS (2-(4-(iodoacetamido)anilino)naphthalene-6-sulfonic acid) and acrylodan (6-acrylol-2-(dimethylamino)naphthalene). The fluorescence of the attached probes was studied by the steady-state and time-resolved methods to gain an insight about the nature of Ca(2+)-induced conformational changes in the N domain regulatory region of cTnC. Changes in the experimental emission spectra, quantum yields, and excited-state lifetimes suggested that bound Ca2+ at the single regulatory site induced a less polar microenvironment for both probes attached to Cys-84. However, a twofold increase in the bimolecular collisional quenching constant was observed for both probes in the presence of activator Ca2+, indicating an increased exposure of the probes to solvent. These data were interpreted with reference to the origins of the observed Stokes' shifts. In the apo and 2Mg states of cTnC, the attached probes were partially shielded by helices B and C, and their excited-states were highly quenched in the tertiary structure through strong interactions of a dipolar nature with neighboring amino acid side chains. In the 3Ca state, these interactions were disrupted so that nonradiative decay processes were suppressed and radiative processes were enhanced, leading to the observed increases in quantum yields and lifetimes and blue-shifts of the emission spectra. As the disruption of internal quenching resulted from separation of helices B and C from helix D, the attached probes became more accessible to solvent and experienced increases in the rate of collisions with external molecules in the solvent. Although this increased exposure to solvent would lead to suppression of radiative decay processes, this effect apparently was overcompensated by the effect of elimination of internal quenching. The present results are consistent with a Ca(2+)-induced open conformation of the N-domain in cTnC. PMID- 8695641 TI - Characterization and enzyme activity of argininosuccinate lyase/delta-crystallin of the embryonic duck lens. AB - Argininosuccinate lyase (ASL)/delta-crystallin, a major soluble protein of the transparent eye lens of birds and reptiles, is a mixture of tetramers comprising all possible combinations of two similar polypeptides (delta 1 and delta 2). Only the delta 2 polypeptide has ASL activity. In the present investigation we have purified each of the 5 major isoforms (delta A to delta E, pI 5.2 to 5.8) of delta-crystallin tetramers from the embryonic duck lens by isoelectric focussing and established by peptide sequencing that the delta 1 and delta 2 polypeptides are encoded in the previously identified, linked delta 1 and delta 2 genes, respectively. The relative amounts of the different tetramers in the 14-day-old embryonic lens were consistent with equal expression of the 2 delta-crystallin genes and no preference for assembly of the 2 delta polypeptides. The relative amount of ASL activity of the tetramers was a linear function of the relative amount of their delta 2 polypeptides, with delta A (only delta 1) lacking enzymatic activity altogether. delta B (3 delta 1:1 delta 2), delta C (2 delta 1:2 delta 2), delta D (1 delta 1:3 delta 2) and delta E (4 delta 2) all gave normal Michaelis-Menten kinetics for fumarate production from argininosuccinate at 40 degrees C and had a similar Km (average Km for mixture was 0.15 mM). delta E had a Km of 0.187 mM and a Vmax of 9 mumol/min per mg protein. Unlike bovine and like human ASL, both reported previously, embryonic duck ASL/delta-crystallin showed no evidence of cooperativity or activation by GTP. Each isoform had a similar far ultraviolet circular dichroism spectrum and thermal stability between 20 degrees C and 60 degrees C, with denaturation occurring at 65 degrees C. Our data suggest that gene duplication, structural modifications leading to greater thermal stability of the delta 1 and delta 2 polypeptides, and selective loss of ASL activity in the delta 1 polypeptide all occurred during the recruitment of ASL for a refractive role in the duck lens, resulting in the generation of ASL isoenzymes. PMID- 8695640 TI - Characterization of site I on human serum albumin: concept about the structure of a drug binding site. AB - Human serum albumin (HSA) possesses at least three sites or areas for high affinity binding of drugs. Of these sites, site I was investigated by series of ultrafiltration and equilibrium dialysis experiments. Three ligands, acenocoumarol, dansyl-L-asparagine (DNSA) and n-butyl p-aminobenzoate (n-butyl p ABE) were employed as marker ligands. Each ligand binds to a single high-affinity site on HSA, and binding studies with different pairs of the ligands revealed independent high-affinity binding. Preliminary displacement studies performed with the typical site I binding drugs warfarin, phenylbutazone and iodipamide showed different displacement patterns of the three marker ligands. These studies were followed by stringent competition experiments involving all possible combinations of the three test ligands themselves and of these and the three marker ligands. On the basis of the results obtained it seems that the acenocoumarol and DNSA binding regions correspond to the warfarin and azapropazone binding regions, respectively, of site I reported by others (Fehske, Schlafer, Wollert and Muller (1982) Mol. Pharmacol. 21, 387-393). The new binding region, represented by n-butyl p-ABE, is probably located adjacent to the acenocoumarol binding region but apart from that of DNSA. We have elaborated a model for binding site I in which we propose novel nomenclatures, region Ia, Ib, and Ic for the acenocoumarol, DNSA and n-butyl p-ABE binding regions, respectively. Furthermore, the relation between these regions and the high affinity binding sites for other drugs have been discussed. PMID- 8695642 TI - Ligation of the iron in the heme-heme oxygenase complex: X-ray absorption, electronic absorption and magnetic circular dichroism studies. AB - Heme oxygenase (HO) catalyzes the first steps in the breakdown of heme to biliverdin and carbon monoxide. It is a membrane-bound protein that has been shown to exist in two isoforms, HO-1 and HO-2. Recently, a soluble, truncated form of rat HO-1 (rHO) lacking the 23 amino-acid membrane anchor has been expressed in E. coli. Extended X-ray absorption fine structure (EXAFS) data on ferric rHO and its fluoride derivative support assignment of the axial iron ligands as oxygen and/or nitrogen donors having distances similar to ferric myoglobin. The electronic absorption and magnetic circular dichroism (MCD) spectra of the ferric and ferrous protoheme complexes of rHO as well as various ligand adducts are very similar to the corresponding spectra of myoglobin. The present study is the first investigation of the heme-heme oxygenase complex with EXAFS and MCD spectroscopy and establishes that the proximal ligand to the heme in rHO is histidine. Furthermore, the close similarity between the electronic absorption and MCD spectra of ferric rHO and myoglobin over the pH range 6 to 10 is consistent with distal heme ligation of ferric rHO as a water molecule or hydroxide ion, depending on pH. Taken together and in conjunction with the results of earlier studies, EXAFS, electronic absorption, and MCD spectroscopy solidly establish that the ligands to the heme in rHO are identical to those in myoglobin, namely, histidine/H2O at low pH and histidine/OH at high pH. PMID- 8695643 TI - Factor J, an inhibitor of the classical and alternative complement pathway, does not inhibit esterolysis by factor D. AB - Factor J (FJ) is an inhibitor of the classical and alternative complement pathways. On the classical pathway factor J disrupts the C1 component, and on the alternative pathway, factor J disrupts the C3 convertase (C3b,Bb) by a direct interaction of FJ with the components C3b and Bb. The aim of this work was to verify whether FJ could have any effect on factor D proteolytic activity since previous experiments could not rule out an eventual inhibition by factor J on factor D enzymatic activity. For this purpose, the reactivity of serine proteinase factor D was determined by using two peptide thioester substrates, Z Lys-SBzl.HCl and Z-Lys-Arg-SBzl.2HCl, in the presence and in the absence of factor J. Kinetic studies evidenced that FJ did not affect the enzymatic activity of factor D in any case. PMID- 8695644 TI - N-peptidyl, O-acyl hydroxamates: comparison of the selective inhibition of serine and cysteine proteinases. AB - Two series of N-aminoacyl, O-benzoyl hydroxamates were designed to investigate the influence of the substituted benzoyl residue on the hydrolytic stability and the reactivity of these potential inhibitors towards selected cysteine and serine proteinases. The inactivators react more rapidly with cysteine proteinases than with the serine enzymes tested. While Z-Phe-Gly-NHO-Nbz is the most reactive inhibitor of cathepsin L, inhibiting the target protein by a second order rate constant of 932.000 M-1 s-1, the bacterial serine proteinase thermitase is inhibited best by Z-Gly-Phe-NHO-Nbz, exhibiting a second-order rate constant of 1.170 M-1 s-1. Thiolsubtilisin, having the thiol-group as the reactive nucleophile instead of serine, exhibits specificity constants of the inactivation two orders of magnitude smaller than subtilisin. The degree of selectivity of the inhibitors relative to cathepsin B, cathepsin L, cathepsin S and papain varies up to two orders of magnitude with respect to their second order rate constant of inactivation. The inhibitory reactivity of these compounds varies only up to sixfold depending on the benzoyl substituent. Similarly, the rate constants for the hydrolytic decomposition of the compounds vary by a factor of about 6, suggesting that the structural and mechanistic features of the compounds which are responsible for decomposition as well as for the enzyme inhibition are the same. Comparing both reactions, the data allow the calculation of an acceleration factor of 2.4 x 10(10) for the inhibition of cathepsin L by its most effective inhibitor, clearly characterizing this enzyme inhibition reaction as enzyme activated. PMID- 8695645 TI - Phosphoserine aminotransferase from Bacillus circulans subsp. alkalophilus: purification, gene cloning and sequencing. AB - Two peaks of aspartate aminotransferase (AspAT) catalytic activity were observed during DEAE chromatography of a protein extract from alkalophilic B. circulans. The enzyme purified from the major peak appeared to be not aspartate but phosphoserine aminotransferase (PSAT) with a considerably high AspAT side activity. The sequence of the enzyme N-terminus was determined, and the PSAT gene was cloned as two separate fragments. DNA sequencing revealed the open reading frame for the PSAT starting from TTG, putative ribosomal binding site and terminator of transcription. The PSAT gene encodes a protein of 361 amino acids (M(r) 39793) which shows moderate homology to other known phosphoserine aminotransferases (36-46% of identity, 60-64% of similarity). The PSAT from the alkalophile shares with all of them the consensus sequence pattern around the pyridoxal 5'-phosphate attachment site. PMID- 8695646 TI - Structural consequences of neopullulanase mutations. AB - Bacillus stearothermophilus neopullulanase (NPL) structure was modeled based on Aspergillus oryzae alpha-amylase (TAA) to understand the structure-function relationships of this pullulan hydrolyzing enzyme. The NPL structure seems to consist of a central (alpha/beta)8 barrel to which the other domains are attached. The immediate surroundings of the NPL catalytic site were found to have very similar structure to TAA. The more distant sites are different due to the stereochemical requirements of accommodating in the substrate alpha-1,6-linkages at every third position instead of alpha-1,4-linkages. The substrate binding cleft is wider than in alpha-amylases. The NPL structure, function, substrate binding and the consequences of mutations were discussed based on the modeled structure. PMID- 8695647 TI - The influence of conserved aromatic residues on the electron transfer reactivity of 2[4Fe-4S] ferredoxins. AB - The detailed mechanism used by [4Fe-4S] ferredoxins to exchange electrons is not known. The importance of two highly conserved aromatic residues, each located close to one cluster of 2[4Fe-4S] ferredoxins has been probed by site-directed mutagenesis of Clostridium pasteurianum ferredoxin. All generated variants are less stable than the native protein and only hydrophobic residues can replace one of the two conserved aromatic residues. With leucine substituting both aromatics, Clostridium pasteurianum ferredoxin cannot even be completely purified because of its deleterious instability. The reduction potentials of Clostridium pasteurianum ferredoxin variants do not depend on the presence of aromatic residues near the clusters. However, the ferredoxin from Entamoeba histolytica which is naturally devoid of aromatic residues displays a reduction potential nearly 60 mV less negative than that of Clostridium pasteurianum ferredoxin. The rate constants for the oxidation of the reduced ferredoxins by the inorganic complexes hexaamine cobalt(III) chloride and sodium ethylenediaminetetra-acetatecobaltate(III) are similar. This implies that electron transfer from the clusters of these molecules is not mediated by the conserved aromatic residues. These residues rather appear to be involved in maintaining the overall stability of ferredoxins. PMID- 8695648 TI - Iron ligand recognition by monomeric hemoglobins. AB - Binding affinities of monomeric Glycera dibranchiata hemoglobin for some anions and heterocyclic amines, including imidazoles, pyrazole, triazole and tetrazole have been evaluated and compared with those of sperm whale and horse heart myoglobin. The proteins' affinities for substituted heterocyclic amines are strongly influenced by the steric bulk and flexibility of the aromatic ring. The ligand coordination mode depends on the heme oxidation state, iron(III) amine adducts being more stable than the iron(II) adducts, the higher affinities of stronger Bronsted-Lowry bases reflecting their essentially sigma-donor character. The bifunctional molecule morpholinoethylisocyanide acts as a redox-state dependent ambidentate ligand, binding as an N-donor to iron(III), but as a C donor to iron(II). pH-Dependences of the ESR and optical spectra of the azole adducts reveal iron-linked ionisations and spin-equilibria in the heme pocket. Enthalpy and entropy changes for the binding process were estimated for several ligands, and mutually compensatory behaviour is observed globally for delta H degree and delta S degree. At the compensation temperature theta, the binding affinities of monomeric Glycera dibranchiata hemoglobin and sperm whale myoglobin are similar and associated with free energy changes delta G degree (theta) approximately -9 +/- 1 kJ mol-1 for the heterocyclic and anionic ligands. PMID- 8695649 TI - Reversible inhibition and irreversible inactivation of catalase in presence of hydrogen peroxide. AB - Spectroscopic and kinetic investigations have been carried out on catalase from bovine liver and from Aspergillus niger to address the mechanism of activity loss at high hydrogen peroxide concentrations (0.01 to 2 M). The mammalian enzyme was both reversibly inhibited and irreversibly inactivated in the presence of hydrogen peroxide, whereas the fungal enzyme did not show any reversible inhibition. A comparison of reaction rates with catalase preparations containing different proportions of Compound III indicated that the formation of Compound III is responsible for the reversible inhibition of bovine liver catalase at high H2O2 concentrations. Superoxide radical did not appear to be the inactivating species in this mechanism. Kinetic modelling emphasises the role of Compound III in both types of activity loss. It shows that the higher activity of A. niger catalase at high substrate concentration, compared to bovine liver catalase, the lack of reversible inhibition of the former and its lower rate of irreversible inactivation may be attributed both to a high rate of conversion of Compound III into native form and to a low rate of conversion of Compound I to Compound II. PMID- 8695650 TI - Sequential unfolding of adenylate kinase during denaturation by guanidine hydrochloride. AB - The unfolding of adenylate kinase in GuHCl of increasing concentrations has been followed by a combination of different methods. Molecular packing was measured by size-exclusion chromatography (SEC), exposure of buried Tyr residues by second- derivative spectra, loss of secondary structure by circular dichroism in the far ultraviolet and the decrease in surface hydrophobicity by ANS binding. The conformational changes of adenylate kinase as followed by the above methods depend differently on GuHCl concentration. The concentrations of GuHCl at which 50% changes as measured by the above four methods occur are 0.3, 0.46, 0.64 and 0.64 M, respectively. SEC measurements show that with increasing GuHCl concentrations, the process of unfolding of adenylate kinase involves two slowly interconvertible intermediate stages, I1, and I2, the last is in a more advanced state of unfolding but is still more compact than the fully unfolded state, U, as indicated by their elution volumes in the SEC profile. There is also evidence to suggest that both the intermediates I1 and I2 may contain additional intermediary components in rapid equilibrium as indicated by the gradual shift of both peaks in the SEC elution profile. A sequential mechanism is suggested for the unfolding of adenylate kinase with increasing guanidine hydrochloride concentrations. PMID- 8695651 TI - Redox reactivity of the type 1 copper protein amicyanin from Thiobacillus versutus with its physiological partner cytochrome C550 and inter-protein cross reaction studies. AB - Reduction potentials Eo' for the T. versutus amicyanin couple, AmCuII/I, were determined at pH values in the range 4.4-9.0 by direct measurement using cyclic voltammetry, and from rate constants for the reactions AmCu1 + [Co(terpy)2]3+ and [Co(terpy)2]2+ + AmCuII, using an Eo' for the [Co(terpy)2]2+/3+ couple of 260 mV. At pH > 7.5 the value obtained is 236 mV, which increases with decreasing pH in keeping with proton inactivation of AmCuI. Together with previously determined Eo' values for the T. versutus cytochrome C550 FeIII/FeII couple, it is concluded that the physiologically relevant reaction AmCuI + cyt C550FeIII (kf) is thermodynamically favourable at pH > 6.25, but that the back reaction cyt C550FeII + AmCuII (kb) is favourable at pH < 6.25. Values of kf (25 degrees C) at pH > 6.25 were determined directly by the stopped-flow method, I = 0.100 M (NaCl). At pH < 6.25 kf values were obtained indirectly from the measured kb and equilibrium constants from delta Eo'. The combined kf variations with pH give an acid dissociation pKa for AmCuIH+ of 6.6. In further studies (25 degrees C) rate constants/M-1 S-1 (pH 6.0-8.6) were determined for the cross-reactions of AmCuI with P. aeruginosa azurin AzCuII, and AmCuI with P. aeruginosa cyt C550FeIII, and are 11.0 x 10(5) and 6.4 x 10(5) M-1 S-1 respectively at pH 8.6. Using the Marcus equations corresponding electron self-exchange rate constants (kese/M-1 S-1) of 1.3 x 10(5) and 0.6 x 10(5) M-1 S-1 were calculated for the exchange of AmCuII with unprotonated AmCuI, in good agreement with the value 1.2 x 10(5) M-1 S-1 determined by NMR at pH 8.6. Information was also obtained as to the effect of pH on these kese values. PMID- 8695652 TI - Escherichia coli as a model for the regulation of dissociable (type II) fatty acid biosynthesis. PMID- 8695653 TI - Lipids and membrane function in green algae. PMID- 8695654 TI - Cholesterol esterification is not essential for secretion of lipoprotein components by HepG2 cells. AB - Hepatic acyl CoA:cholesterol acyltransferase (ACAT) activity may determine storage of cholesterol and supply of cholesteryl esters for the neutral lipid core of very low density lipoprotein. Inhibition of cholesterol esterification in HepG2 cells, by the ACAT inhibitor 447C88, partially reduced the secretion of labelled total cholesterol, but the secretion of apoprotein B mass, and of radiolabelled triacylglycerol and phosphatidylcholine were unaffected. Furthermore, this compound was shown to substantially deplete the intracellular cholesteryl ester mass without affecting secretion of lipoprotein components. In contrast, the less potent ACAT inhibitor, CL277,082, significantly decreased secretion of labelled triacylglycerol, phosphatidylcholine and total cholesterol, in a manner which mirrored the decreases in secretion of apoB. This study clearly illustrates that ACAT inhibitors can exert differential effects on secretion of apoB-containing lipoproteins, which do not correlate with their efficacy in inhibiting ACAT, arguing that cholesterol esterification is not essential for lipoprotein secretion from these cells. PMID- 8695655 TI - Irreversible inhibition of Ca(2+)-independent phospholipase A2 by methyl arachidonyl fluorophosphonate. AB - Methyl arachidonyl fluorophosphonate (MAFP) has been recently reported to be a selective, active-site directed, irreversible inhibitor of the Group IV 85 kDa cytosolic phospholipase A2 (cPLA2). We have now shown that this compound also potently inhibits the Ca(2+)-independent cytosolic phospholipase A2 (iPLA2). MAFP inhibited iPLA2 in a concentration-dependent manner with half-maximal inhibition observed at 0.5 microM after a 5 min preincubation at 40 degrees C. This inhibition was not reversed upon extensive dilution of the enzyme into the assay mixture. Preincubation of iPLA2 with MAFP resulted in a linear, time-dependent inactivation of enzyme activity, and the enzyme was protected from inactivation by the reversible inhibitor PACOCF3. The ability of MAFP to inhibit the iPLA2 suggests that this enzyme proceeds through an acyl-enzyme intermediate as has been proposed for the cPLA2. Further testing indicated that MAFP did not inhibit the arachidonoyl-CoA synthetase, CoA-dependent acyltransferase, or CoA independent transacylase activities from P388D1 cells. Thus, MAFP is not a general inhibitor for enzymes which act on arachidonoyl substrates. Instead, the inhibitor appears to show some selectivity for PLA2, although it does not discriminate between cPLA2 and iPLA2. Particular caution must be exercised to distinguish these activities if this inhibitor is used in intact cells. PMID- 8695656 TI - The acylation of lysophosphatidylglycerol in rat heart: evidence for both in vitro and in vivo activities. AB - The reacylation of lysophospholipids back to their parent molecules is important for attaining the appropriate fatty acyl composition in many phospholipids and for preventing the accumulation of arrhythmia generating lysophospholipids in the heart. In this study, we report the presence of an active acyltransferase activity for lysophosphatidylglycerol reacylation to phosphatidylglycerol in rat heart membrane preparations. The activity of acyl-Coenzyme A:1 acylglycerophosphorylglycerol acyltransferase in rat heart subcellular fractions was in the order of microsomal > mitochondrial > cytosol. The activity in the membrane fractions were characterized and found to have a pH optimum in the alkaline range. However, significant enzyme activity was observed at physiological pH. With oleoyl-Coenzyme A as substrate, the microsomal activity had a preference for lysophosphatidylglycerol substrates in the order of myristoyl > palmitoyl > oleoyl > stearoyl. The apparent K(m) values for 1 palmitoylglycerophosphorylglycerol and oleoyl-Coenzyme A were 9.4 and 7.1 microM, respectively. In contrast, the mitochondrial activity had a preference for lysophosphatidylglycerol substrates in the order of oleoyl > myristoyl = stearoyl = palmitoyl. The apparent K(m) values for 1-oleoylglycerophosphorylglycerol and oleoyl-Coenzyme A were 17.8 and 18.0 microM, respectively. Both membrane activities were heat labile as pre-incubation at 55 degrees C for 1 min completely abolished the activity. However, pre-incubation at 50 degrees C resulted in different profiles of inactivation in both microsomal and mitochondrial fractions. Both membrane activities were inhibited by high concentrations of lysophosphatidylglycerol and affected to a similar extent by various detergents. To demonstrate whether reacylation of lysophosphatidylglycerol to phosphatidylglycerol occurred in vivo, isolated rat hearts were perfused for 60 min in the Langendorff mode with 0.1 microM 1 palmitoylglycerophosphoryl[14C]glycerol bound to albumin. 1 Palmitoylglycerophosphoryl[14C]glycerol was readily taken up by the isolated perfused rat heart and significant synthesis of phosphatidyl[14C]glycerol was observed. The findings indicate the presence of an acyl-Coenzyme A:1 acylglycerophosphorylglycerol acyltransferase activity in the rat heart subcellular membranes which is capable of catalyzing lysophosphatidylglycerol acylation to phosphatidylglycerol in vitro and in vivo. PMID- 8695657 TI - Arbutin inhibits PLA2 in partially hydrated model systems. AB - Arbutin is a glycosylated hydroquinone found at high concentrations in certain plants capable of surviving extreme and sustained dehydration. In this paper, we examine a potential role of this molecule in anhydrobiosis. We have studied its effects on the physical properties of phospholipids and on preservation of liposomes during drying. Arbutin depresses the gel to liquid crystalline phase transition temperature of dry phospholipids, as measured by differential scanning calorimetry, with a pattern similar to that seen in phospholipids dried with the disaccharide trehalose. Unlike trehalose, however, arbutin does not protect dry liposomes from leaking their contents. Also, using Fourier transform infrared spectroscopy, we found an increase in the vibrational frequency of the phosphate asymmetric stretch in partially hydrated phospholipids in the presence of arbutin. Trehalose, by contrast, depresses the frequency of the phosphate in dry phospholipids, indicating that the modes of interaction of trehalose and arbutin with the bilayer are different. Previously, we have shown that phospholipases can be active in liposomes with surprisingly low water contents. Based on the structural similarity of arbutin to a known inhibitor of phospholipase A2 (PLA2), it appeared possible that arbutin might serve as an inhibitor of phospholipases. Liposomes of varying composition were lyophilized in the presence and absence of phospholipases. When the liposomes were partially rehydrated at 76% relative humidity, arbutin inhibited PLA2, but did not inhibit phospholipases B or C. Accumulation of enzyme product in the liposome membranes was measured by analytical thin layer chromatography, and was taken as a measure of enzyme activity. Arbutin did not inhibit any of the enzymes in the presence of excess water. Based on these data, hypotheses are presented concerning the mechanism of PLA2 inhibition by arbutin in the mostly dehydrated state. PMID- 8695658 TI - Identification of cryptic peanut agglutinin-reactive sites in human lipoprotein(a). AB - After treatment of human lipoprotein(a) (Lp(a)) with neuraminidase, formerly cryptic sites became available for binding to peanut agglutinin (PNA) lectin and a Thomsen-Friedenreich antigen (T-antigen)-specific monoclonal antibody. The PNA reactive sites were localized to the apo(a) moiety of Lp(a) and O-specific carbohydrate side chains. Lp(a) with larger isoforms of apo(a) contained more potential PNA reactivity per molecule of Lp(a) apoB than did smaller isoforms. Very low density lipoproteins (VLDL), low density lipoproteins (LDL), and high density lipoproteins (HDL) did not contain comparable amounts of the cryptic PNA reactive sites. PMID- 8695659 TI - Elevation of cyclic AMP in human skin fibroblasts results in increased capacity for HDL binding. AB - Pre-incubation of cultured human skin fibroblasts, lung fibroblasts and vascular smooth muscle cells, for 24 h with cAMP-elevating agents resulted in a significant increase (40-60%) of the cells' capacity to bind HDL. The increase was due to enhancement of the maximal binding capacity of a high affinity saturable site which binds HDL in preference to LDL. The effect was dependent upon the concentration of the cAMP-elevating agents and required more than 4 h to become evident. Cyclic AMP-mediated elevation of HDL binding occurred in cells with access to an exogenous source of cholesterol, which could be the physiological donor LDL or non-lipoprotein in origin. The observed effects were not subsequent to changes in cellular balance of cholesterol to cholesterol ester and were not due to inhibition of cellular proliferation. PMID- 8695660 TI - Sterol carrier protein-2 expression in mouse L-cell fibroblasts alters cholesterol uptake. AB - Despite the progress made on the possible functions of sterol carrier protein (SCP-2) using assays in vitro, very little is known regarding the role of SCP-2 in intact cells. To further elucidate this role, mouse L-cell fibroblasts were transfected with cDNA encoding for mouse 15 kDa or 13.2 kDa SCP-2. The data show for the first time, that SCP-2 expression increases cholesterol uptake into transfected L-cell fibroblasts. Untransfected L-cells expressed SCP-2 at levels near or below the lower limit of detectability. SCP-2 immunoreactive protein levels were 0.030 +/- 0.004% and 0.036 +/- 0.002% of total cytosolic proteins in the 15 and 13.2 kDa stable transfectants, respectively. Both the 15 and 13.2 kDa SCP-2 expressions products were found as 13.2 kDa proteins, consistent with rapid post-translational cleavage of the putative amino terminal mitochondrial targeting sequence from the 15 kDa SCP-2. The effect of expressing either form of SCP-2 on [3H]cholesterol uptake was determined. Expression of the 15 kDa form, but not the 13.2 kDa form of SCP-2, enhanced the rate and extent of [3H]cholesterol uptake compared to control or mock-transfected L-cells. The [3H]cholesterol uptake rate in 15 kDa SCP-2 expressing cells was increased 1.3 fold, while the extent of [3H]cholesterol uptake was increased 1.4-fold after 12 h of uptake compared to control L-cells. The differences in cholesterol uptake between the cells expressing the 13.2 versus the 15 kDa protein, suggest that the 15 kDa form of SCP-2 is functionally localized within the cell, while the 13.2 kDa product is not. PMID- 8695662 TI - Lipid composition of the phosphatidylcholine-producing bacterium Hyphomicrobium vulgare NP-160. AB - The extractable lipids of the PC-producing, methylotrophic, budding bacterium Hyphomicrobium vulgare NP-160 grown in a mineral-salts medium containing methanol as the carbon source, were studied by chromatographic and spectrometric methods. They were found to be comprised of PC (35% of the total lipids), PDME (33%), PMME (1%), PE (9%), PG (10%), DPG (6%), and a non-phosphorus, ornithine-containing lipoamino acid, OL (6%). No low-polarity lipids, such as fatty acid esters of glycerol or of other alcohols, were detected. The sole fatty-acyl constituents of PDME and PMME were cis-octadec-11-enoic (cis-vaccenic) acid residues, whereas the other phospholipids contained, in addition, 1 to 5 mol % of MOA (lactobacillic acid) residues located predominantly at the sn-1 position of their glycerol residues. OL consisted of two molecular species, 2-N-[3'-(cis-octadec-11" enoyloxy)octadecanoyl]-L- ornithine and 2-N-[3'-(cis-11", 12" methyleneoctadecanoyloxy)octadecanoyl]-L-ornithine in the molar ratio 94:6. When the culture medium was devoid of phosphate, a threefold increase in OL together with a three-fold decrease in PE were observed, no significant changes in proportions of the remaining lipids occurring. The most striking feature of the lipid composition in this case was the presence of considerable amounts of fatty acid methyl esters, mainly methyl cis-vaccenate, along with minute amounts of wax esters. PMID- 8695661 TI - Effects of human polymorphonuclear leukocyte elastase upon surfactant proteins in vitro. AB - Recent evidence has suggested that elastase is released by polymorphonuclear leukocytes (PMN) recruited from the pulmonary microcirculation into the alveoli during acute lung injury. This study was undertaken to test the hypothesis that elastase from PMN (PMN elastase) damages or degrades one or more of the surfactant proteins (SP-A, SP-B and SP-C) of the lung, and thereby alters its function. We attempted to use amounts of PMN elastase and quantities of surfactant that would be plausible in the lungs of patients with ARDS. Surfactant from normal dog lungs (2 mg phospholipid, 200 micrograms protein), and purified SP-A (20 micrograms), SP-B (10 micrograms) and SP-C (10 micrograms) from the surfactant (identified by SDS-PAGE and N-terminal amino acid sequences) were incubated for 4-8 h at 37 degrees C with various amounts (0.25-1.0 U) of human PMN elastase purified by affinity chromatography. SDS-PAGE and amino acid composition analysis of the surfactant as well as of the purified SP-A, SP-B, and SP-C showed that degradation of these proteins progressed with incubation time and with the amount of PMN elastase, and was accompanied by decreases in isopycnic density (g/cm3) and surface adsorption, and increase of surface tension of the surfactant. No effects were observed with heat inactivated PMN elastase (95 degrees C, 30 min) or with PMN elastase in the presence of human alpha-1 protease inhibitor (2 micrograms/microgram elastase). Phospholipid compositions of the surfactant after exposure to PMN elastase were not significantly different from those of the controls, suggesting that SP-A, SP-B, and SP-C play a major role in altering the surfactant properties. SP-A was also degraded by elastase and trypsin from pancreas whereas SP-B and SP-C remained intact, providing a natural surfactant without SP-A. Surface adsorption rate of the SP-A deficient surfactant was lower than that of the control, but was much higher than that of the surfactant with completely degraded SP-A, SP-B, and SP-C, suggesting that hydrophobic SP-B and SP-C are the essential components in enhancing adsorption. We conclude that proteolytic degradation of SP-A, SP-B, and SP-C causes the decrease of surfactant isopycnic density, and is responsible for retarding adsorption resulting in surfactant dysfunction. PMID- 8695663 TI - Pretransition-ripples in bilayers of dipalmitoylphosphatidylcholine: undulation or periodic segments? A freeze-fracture study. AB - Freeze-fracture analysis of ripple structures of 1,2 dipalmitoylphosphatidylcholine bilayers leads to the conclusion that the asymmetric ripple is the basic structure formed by periodic segments with different tilt direction. The molecules are tilted by about 30 degrees from the bilayer normal but arranged in two positions. Symmetric ripples are also formed by an alternation in tilt direction of the segments but the succession is more complex. A ridge in their valleys or a cleft at their crests may indicate structures formed or deformed during preparation (replication, etching). The freeze-fracture method reveals transition structures in ripple formation which are helpful in interpretation, but does not support a model consisting of an undulation of the bilayer by periodic fluid-like and gel-like domains. PMID- 8695664 TI - The oxysterols cholest-5-ene-3 beta,4 alpha-diol, cholest-5-ene-3 beta,4 beta diol and cholestane-3 beta,5 alpha,6 alpha-triol are formed during in vitro oxidation of low density lipoprotein, and are present in human atherosclerotic plaques. AB - Isolated human low density lipoprotein (LDL) was oxidized with either cupric ions or soybean lipoxygenase and linoleic acid. Cholesterol oxidation products (oxysterols) were determined by isotope dilution gas chromatography-mass spectrometry. A new cholestane-3,5,6-triol isomer, cholestane-3 beta,5 alpha,6 alpha-triol, which has not previously been recognized as a cholesterol autoxidation product, was found at similar concentrations as the well-known cytotoxic cholestane-3 beta,5 alpha,6 beta-triol during both copper- and lipoxygenase-mediated LDL oxidation. Furthermore, two epimeric cholest-5-ene-3 beta,4-diols were identified in the oxidized LDL at similar concentrations. These two isomers were also identified in human atherosclerotic tissue in a ratio of 1:1 at a concentration more than 10-times higher than in non-atherosclerotic vessels. In vitro oxidation of LDL under an 18O2 atmosphere revealed that molecular oxygen was the only source of the oxygen functions at C-4 in the cholest-5-ene-3 beta,4-diols. Taken together, these findings suggest that the cholest-5-ene-3 beta,4-diols in atherosclerotic plaques are formed by autoxidation. PMID- 8695665 TI - Age-related changes in mRNA, protein and catalytic activity of hepatic neutral cholesterol ester hydrolase in male rats: evidence for transcriptional regulation. AB - Messenger RNA, protein mass and catalytic activity of hepatic neutral cholesteryl ester hydrolase (CEH) were measured in male Sprague-Dawley rats, aged 6, 8, 9.5, 12 and 24 weeks (wks). CEH mRNA increased 101% from 6 to 9.5 wks, corresponding to onset of puberty, and declined by 52% from 12 to 24 wks. CEH mass was highly correlated with mRNA levels at all ages, increasing 170% from 6 to 9.5 wks and declining 61% from 12 to 24 wks. CEH activity was highly correlated with mass and mRNA from 8-24 wks, but was greater at 6 wks than the activity predicted by the measured mass. In all age groups, activity was consistently increased by activation of endogenous protein kinase A and consistently inhibited by alkaline phosphatase, suggesting that age-related differences in catalytic activity were not due to differences in the level of enzyme phosphorylation. These data suggest transcriptional regulation and indicate an important role for CEH in cholesterol homeostasis in the developing rat. PMID- 8695666 TI - Common sequence variants of lipoprotein lipase: standardized studies of in vitro expression and catalytic function. AB - We have assessed the functional activity of three common sequence variants of human lipoprotein lipase (LPL). Two of these, Asn291Ser and Asp9Asn arise from missense mutations while the third, Ser447Ter, derives from a nonsense mutation, truncating LPL by two residues. As previous in vitro studies have produced conflicting results, we have re-analyzed the catalytic function of these variants using the COS cell transfection system, under optimized and standardized experimental protocols. We found the Asn291Ser variant to manifest with a decrease in catalytic activity (57% of normal) due to a reduction in secretion and stability of the active homodimeric form. The Asp9Asn variant also showed a significant decrease in catalytic activity (85% of normal), but this was found to be due to a decreased rate of secretion only, as the homodimeric form was stable. The findings for these mutants contrasted with those of the Ser447Ter truncation variant which proved to be catalytically normal; this variant also manifested normal homodimer stability. The truncated variant did however, present with a higher total secreted mass level (131%) than control LPL. This was most likely due to enhanced secretion of the monomeric form. None of these mutations exhibited defects in binding affinity to cell surface proteoglycans. Each of these variants deviated significantly from normal as regards to their secreted activity or mass levels in the COS cell transfection system. PMID- 8695667 TI - A novel glycolipid, 1,2-diacyl-3-alpha-D-glucuronopyranosyl-sn-glycerol taurineamide, from the budding seawater bacterium Hyphomonas jannaschiana. AB - A previously unknown glycolipid has been isolated from the budding seawater bacterium Hyphomonas jannaschiana VP-2T devoid of phospholipids. Using a combination of chromatographic, spectrometric, enzymic- and chemical-degradation methods, the structure of the lipid has been determined to be 1,2-diacyl-3-alpha D-glucuronopyranosyl-sn-glycerol taurineamide. Its main fatty acyls are n-16:0, cis-16:1 omega 7, n-18:0, cis-18:1 omega 7, and n-19:0. The hydroxyl at the sn-1 position of the glycerol residue is acylated predominantly with unsaturated fatty acids, and the secondary hydroxyl at the sn-2 carbon is acylated mainly with saturated ones. PMID- 8695668 TI - Mutation of the catalytic site Asp177 to Glu177 in human pancreatic lipase produces an active lipase with increased sensitivity to proteases. AB - The catalytic mechanism for members of the lipase gene family incorporates a serine-histidine-acidic group triad. In general, the acidic group is an aspartate, Asp177 in human pancreatic lipase, but glutamate is found in some lipases. Previously, we demonstrated that site-specific mutagenesis of Asp177 to Glu177 produced a mutant human pancreatic lipase with near normal activity against triolein, thereby, raising questions about the role of Asp177 in the catalytic triad and about the evolutionary pressure which selected Asp over Glu in the catalytic mechanism. To address these questions, we constructed and expressed mutants of Asp177 and Asp206, another acidic residue that could participate in the catalytic triad. The Glu177 mutant had a substrate specificity, specific activity, pH profile, colipase dependance, and interfacial activation comparable to the native lipase, Asp177. Several mutants of Asp206 were normally active, thus, confirming the important role of Asp177 in pancreatic lipase function. Additionally, we found that the Glu177 mutant had increased susceptibility to proteases and to urea denaturation. These findings demonstrated decreased conformational stability of the mutant lipase and provided an explanation for the preference of aspartate in the catalytic triad of human pancreatic lipase. PMID- 8695669 TI - The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. AB - The three types of peroxisome proliferator activated receptor (PPAR), alpha, beta (or delta), and gamma, each with a specific tissue distribution, compose a subfamily of the nuclear hormone receptor gene family. Although peroxisome proliferators, including fibrates and fatty acids, activate the transcriptional activity of these receptors, only prostaglandin J2 derivatives have been identified as natural ligands of the PPAR gamma subtype, which also binds thiazolidinedione antidiabetic agents with high affinity. Activated PPARs heterodimerize with RXR and alter the transcription of target genes after binding to specific response elements or PPREs, consisting of a direct repeat of the nuclear receptor hexameric DNA core recognition motif spaced by one nucleotide. The different PPARs can be considered key messengers responsible for the translation of nutritional, pharmacological and metabolic stimuli into changes in the expression of genes, more specifically those genes involved in lipid metabolism. PPAR alpha is involved in stimulating beta-oxidation of fatty acids. In rodents, a PPAR alpha-mediated change in the expression of genes involved in fatty acid metabolism lies at the basis of the phenomenon of peroxisome proliferation, a pleiotropic cellular response, mainly limited to liver and kidney and which can lead to hepatocarcinogenesis. In addition to their role in peroxisome proliferation in rodents, PPAR is also involved in the control of HDL cholesterol levels by fibrates and fatty acids in rodents and humans. This effect is, at least partially, based on a PPAR-mediated transcriptional regulation of the major HDL apolipoproteins, apo A-I and apo A-II. The hypotriglyceridemic action of fibrates and fatty acids also involves PPARs and can be summarized as follows: (1) an increased lipolysis and clearance of remnant particles, due to changes in LPL and apo C-III levels, (2) a stimulation of cellular fatty acid uptake and their conversion to acyl-CoA derivatives by the induction of FAT, FATP and ACS activity, (3) an induction of fatty acid beta-oxidation pathways, (4) a reduction in fatty acid and triglyceride synthesis, and finally (5) a decrease in VLDL production. Hence, both enhanced catabolism of triglyceride-rich particles as well as reduced secretion of VLDL particles are mechanisms that contribute to the hypolipidemic effect of fibrates and FFAs. Whereas for PPAR beta no function so far has been identified, PPAR gamma triggers adipocyte differentiation by inducing the expression of several genes critical for adipogenesis. PMID- 8695670 TI - The effect of age on hemopoiesis. AB - Although several workers have described numerous changes affecting the hemopoietic system during senescence, the existence of univocal "hematological disease" closely related to the elderly is controversial. Many of the hematological changes described, such as sideropenic or megaloblastic anemia, are frequently the consequence of the different pathological conditions which often affect elderly patients. This review will consider the most important alterations of hemopoiesis and coagulation in the elderly, the causes capable of influencing hematological changes in old people, and their pathogenesis. Some of the major diagnostic problems encountered in the management of elderly subjects with hematological changes are also addressed. In the presence of an elderly patient with hematological alteration, it is necessary to follow a precise diagnostic schedule, which should first of all exclude the presence of a primary hematological disorder, and consider the different extrahematological conditions which frequently occur in elderly subjects (malignancies, malnutrition, chronic infections from immunological abnormalities, hormonal changes, deficiencies of various organs and systems etc.) and are responsible for many different hematological changes. These must be tackled rationally so that treatment may not only be symptomatic, but may also directly intervene on the cause of the disorder. PMID- 8695671 TI - Insulin response during the oral glucose tolerance test: the role of age, sex, body fat and the pattern of fat distribution. AB - To clarify their primary roles on insulin response to oral glucose, age and sex differences in body composition should be taken into account. Oral glucose tolerance tests were performed on 472 men and 299 women of the Baltimore Longitudinal Study of Aging, ranging in age from 20 to 96 years. Subjects who were taking medications or had any diseases which could affect glucose tolerance were excluded. In addition to insulin and glucose values for the glucose tolerance test, we calculated body mass index (BMI), percentage body fat from skinfolds (% Body Fat), waist hip ratio (WHR), mean glucose level over the 2-hour test (GM), the basal insulin (IO), and the mean insulin response over the 2-hour test (IM). There was no significant sex difference in mean age, but men had significantly higher BMI (25.6 vs 24.0 kg/m2), WHR (0.93 vs 0.76), and GM (8.5 vs 7.7 mM), while % Body Fat was lower (25% vs 33%). Unadjusted IO and IM levels were significantly higher in men than in women (51 vs 44 and 303 vs 231 pM- antilogs of log-normalized values). Insulin levels, adjusted for differences in age, % Body Fat, WHR, and GM by analysis of covariance, however, showed no sex differences (49 vs 46 and 282 vs 257 pM). Adjusted insulin levels declined significantly with age; IM fell progressively from 323 pM in 20 to 39-year olds, 267 pM in 40 to 59-year, 253 pM in 60 to 79-year, and 228 pM in 80 to 96-year olds (p < 0.01). We conclude that the sex differences in insulin levels are explained by differences in body habitus and post-load glucose levels, but that insulin levels decline with age per se. PMID- 8695672 TI - Determinants of survival: an analysis of the effects of age at observation and length of the predictive period. AB - The main objective of this study was to analyze how the identification of determinants of survival is dependent on age at the time of data collection and on the length of the predictive period. The study is part of a gerontological and geriatric population investigation in Goteborg (Gothenburg), Sweden, called H70, which is a longitudinal study based on a large random sample of men and women born in 1901/1902 in Goteborg. They were first examined at the age of 70, and have then been re-examined at the ages of 75 and 79. Twelve variables from different areas were selected for use in the present study. As physical health has proven to be highly correlated to survival, the sample was split into two subgroups, one consisting of elderly with few health problems and the other of less healthy elderly. All analyses were performed on each gender separately, and on the whole samples of men and women, respectively, as well as on each health subgroup. The results show that the statistically significant determinants of survival differ substantially between the two subgroups. In addition, age at examination and length of predictive period proved to be very important in identifying determinants of survival. Lung capacity, measured be peak flow, was the only variable, among those selected for this study, that had predictive power for both genders, in both health groups and at each of the three observation ages. PMID- 8695674 TI - Aging effects on the perception of noxious and non-noxious thermal stimuli applied to the face. AB - While age-related sensory deficits have been demonstrated for the senses of vision, audition, and the chemical senses, reports have differed with regard to changes in painful and non-painful thermal sensation. One hundred and seventy nine healthy, community-dwelling individuals aged 20-89 years rated threshold and suprathreshold warming, cooling, and painful stimuli delivered to glabrous (upper lip) and hairy (chin) sites of the face in three separate testing sessions. Threshold measures were determined by the Method of Limits. Suprathreshold stimuli were assessed by a cross-modality matching procedure and a Pooled Adjacent Violators Algorithm-based analysis. The analyses of the effect of age on the threshold and suprathreshold measures of sensory performance yielded disparate findings. There are modest changes in warming and cooling perception with increased age, but pain perception is relatively unaffected. There is a slight diminution in threshold and suprathreshold thermal performance with increasing aging. PMID- 8695673 TI - Correlation of paroxysmal supraventricular tachycardia, atrial fibrillation, and sinus rhythm with incidences of new thromboembolic stroke in 1476 old-old patients. AB - The relationship between supraventricular tachycardia and the incidence of thromboembolic stroke has not been previously reported. We investigated in a prospective study the incidence of new thromboembolic stroke in 1476 patients, mean age 81 years, with atrial fibrillation, paroxysmal supraventricular tachycardia, or sinus rhythm detected by 24-hour ambulatory electrocardiograms. New thromboembolic stroke developed at 31-month follow-up in 87 of 201 patients (43%) with atrial fibrillation, at 43-month follow-up in 84 of 493 patients (17%) with paroxysmal supraventricular tachycardia, and at 45-month follow-up in 143 of 782 patients (18%) with sinus rhythm (p < 0.0001 comparing atrial fibrillation with paroxysmal supraventricular tachycardia or sinus rhythm). Kaplan-Meier survival curves showed a higher significance of thromboembolic stroke in patients with atrial fibrillation, compared to patients with paroxysmal supraventricular tachycardia or sinus rhythm (log-rank: p < 0.0001). Multivariate Cox regression model showed that independent significant predictors of thromboembolic stroke were: a) atrial fibrillation (relative risk = 3.31); b) prior thromboembolic stroke (relative risk = 2.85); c) sex (relative risk for women = 0.75); and d) age (relative risk = 1.02). These data show that atrial fibrillation is an independent predictor of thromboembolic stroke in elderly patients, and that paroxysmal supraventricular tachycardia is not associated with thromboembolic stroke. PMID- 8695675 TI - Influences of intentionality at encoding and retrieval on memory in adulthood and old age. AB - This research investigated whether different memory functions are differentially affected by the adult aging process. Four groups of normal adults (18-35, 60-68, 69-78, and 79-91 years of age) were presented with a set of pictures of faces with first names and surnames. Subjects were instructed to memorize the faces and the surnames for subsequent memory tests. Memory performance was assessed in four ways: stem completion of surnames; recognition of faces; recognition of surnames and recognition of first names. These memory tests varied in terms of intentionality at encoding and retrieval. The stem completion task involved intention at encoding, but not at retrieval, and thus served as a measure of implicit memory. With respect to the three explicit memory tasks, recognition of faces and surnames involved intention at both encoding and retrieval, whereas recognition of first names involved intention at retrieval, but not at encoding. Results indicated no age-related differences in implicit memory, as assessed by the stem completion test. In addition, there was an age-related deficit in recognition of faces and surnames, although there were no age-related differences in recognition of first names. The overall pattern of results suggests that age related deficits in memory may be most likely to occur when there are demands of conscious mental activity at encoding and retrieval. PMID- 8695676 TI - Urinary incontinence in elderly inpatients in Japan: a comparison between general and geriatric hospitals. AB - This is the first multi-hospital epidemiological study to elucidate the prevalence and characteristics of urinary incontinence in elderly inpatients throughout Japan. Of the 2586 subjects to whom questionnaires were issued, 1563 (60.4%) (65 to 102 years old, 598 men, 965 women) were suitable for the study. A total of 817 patients were hospitalized in geriatric hospitals; that is, geriatric facilities under the regulation of the Department of Health and Welfare. All patients were evaluated by medical doctors for the following items: age, sex, duration of hospitalization, activities of daily living, medical diagnosis, presence or absence of urinary incontinence, type of urinary incontinence, and therapy for urinary incontinence. The prevalence of urinary incontinence in patients under 70, 70-79, 80-89, and over 90 years old was 59.3%, 67.7%, 79.8%, and 82.2%, respectively. Overall, 1142 patients (72.0%) suffered from urinary incontinence. Cerebrovascular disease was the major cause of admission to hospital in patients with urinary incontinence (37.0%). The most frequent type of urinary incontinence was functional urinary incontinence in patients who were mentally and/or physically unable to go to the bathroom without aid (21.5%). Specifically, 38.1% of patients in geriatric hospitals were diagnosed as having functional urinary incontinence, in contrast to only 3.9% of patients in non-geriatric units. In patients with dementia, 88.7% were incontinent, whereas in patients without dementia, the prevalence of urinary incontinence was much lower (51.5%, p < 0.001). Another predisposing factor for urinary incontinence was urinary tract infection. The prevalence of urinary incontinence in patients with and without urinary tract infection was 87.8% and 59.5%, respectively (p < 0.001). Almost all patients with poor activities of daily living (who were bedridden) suffered from urinary incontinence (98.5%). On the other hand, urinary incontinence was not so frequent in patients who could walk (26.9%). Pad (42.8%) and indwelling bladder catheter (18.3%) were the major means of management of incontinence, whereas behavioral therapy (4.9%) and surgery (0.5%) were not common. These results suggest that elderly patients with treatable urinary incontinence do not receive adequate therapy in Japan. PMID- 8695677 TI - Pupillometric evaluation and analysis of light reflex in healthy subjects as a tool to study autonomic nervous system changes with aging. AB - To assess the relationships between aging and autonomic control of pupillary functions, TV-pupillometry and light reflex evaluation were performed in 52 healthy volunteers in the age range 15-75 years, grouped into four age classes (group 1: 15-29 years, Group 2: 30-44 years, Group 3: 45-59 years, Group 4: 60-75 years). Baseline light pupil diameter was found to be age-dependent, together with light reflex contraction velocity, which presented a linear correlation with age. Light reflex amplitude and half-redilatation velocity were reduced in older subjects, but presented only a weak linear correlation with age, while latency, contraction time and half-redilatation time percent of secondary dilatation and redilatation at 5 seconds did not show significant changes with age. These results confirm that there are important age-dependent changes in the mechanisms involved in pupillary autonomic functions, regarding both sympathetic and parasympathetic components. These changes appear to be easily detectable by making use of a sensitive and non-invasive technique such as TV-pupillometry. PMID- 8695678 TI - The relationship between Piaget and cognitive levels in persons with Alzheimer's disease and related disorders. AB - Clinical observations and research studies have documented that people with Alzheimer's disease and related disorders (ADRD) appear to regress developmentally during the course of the disease. The purpose of this study was to prospectively determine the association between changes in Piaget levels of cognitive development and cognitive decline in nursing home residents in various stages of ADRD. Fifty-seven people were tested three times at yearly intervals, using the Folstein Mini-Mental State Exam to determine cognitive levels and a set of 14 Piaget tasks to determine cognitive developmental levels: 1) Formal Operations; 2) Concrete Operations; 3) Preoperational; and 4) Sensorimotor. Mean MMSE scores declined from 12.7 to 9.4, and there was a downward trend in Piaget levels over the study period. ANOVA showed significant differences (p < 0.0005, Years 1, 2, 3) in MMSE scores among all Piaget levels, and Spearman rho analysis showed significant correlations between Piaget levels and MMSE for each year (p < 0.0005, Years 1, 2, 3). The results suggest that there is a concurrent decline in cognitive developmental levels and cognition in people in various stages of Alzheimer's disease and related disorders. PMID- 8695679 TI - Estrogen replacement therapy and the risk of hip fracture in old age. PMID- 8695680 TI - [Current status of the management of cytomegalovirus retinitis in patients with AIDS]. PMID- 8695681 TI - [Microbiological study of the respiratory tract in children with cystic fibrosis]. AB - PURPOSE: Pulmonary infections is a main cause of morbimortality in patients suffering from cystic fibrosis. The objective of this study was to know the flora implicated in respiratory pathology of all mucoviscidotic children attending Hospital Sant Joan de Deu of Barcelona. METHODS: Quantitative cultures from respiratory samples (most of them: sputum) of 26 patients were performed from January 91 to June 93. There were 13 girls and 13 boys, aged 1 to 13 years (mean: 7 years). RESULTS: 282 microorganisms were isolated from 203 positive samples. Cultures of 88.4% of patients yielded in some moment Haemophilus influenzae, 82.6% of them Haemophilus parainfluenzae, 65.3% Pseudomonas aeruginosa, 50% Streptococcus pneumoniae, 38.4% Staphylococcus aureus. The most prevalent microorganism was P. aeruginosa (66%) followed by H. influenzae (29%) and S. aureus (26.6%). 59% of P. aeruginosa strains showed a mucoid phenotype. CONCLUSIONS: Haemophilus sp. causes short term infections that affect children of all ages, whereas infections due to P. aeruginosa persist in spite of correct antimicrobial therapy. PMID- 8695682 TI - [Toxoplasmosis in pregnancy: new diagnostic techniques]. AB - BACKGROUND: The diagnosis of primoinfection by Toxoplasma gondii in immunocompetent patients is not always easy because detectable levels of IgM are found in serum for months or even years. METHODS: We studied the prevalence of T. gondii antibodies in pregnant women and the usefulness of several commercial IgM and IgA detection systems as well as IgG avidity for the diagnosis of primoinfection by T. gondii. We also developed an IgA detection system in our laboratory and studied antigenic determiners recognized by various immunoglobulins by means of Western blot patterns. RESULTS: The prevalence of antibodies in our environment is 56.70% and the incidence of primoinfection in pregnant women is 0.056%. In cases of primoinfection by T. gondii demonstrated by antibody seroconversion, we obtain positive results with all the systems tested. However, when seroconversion does not occur, we continue to get positive results in many cases with some of the technique tested. Nevertheless, there is a higher degree of correlation between the study of IgG avidity and IgA detection and seroconversion. With the Western blot technique, we can see that each type of immunoglobulin recognizes a different antigenic pattern, with antigen 31 kD being recognized by three types of immunoglobulins. CONCLUSION: In spite of the high incidence of antibodies for Toxoplasma gondii in our medium, the incidence of primoinfection during pregnancy is low. As regards the evaluation of the different serological tests, except for seroconversion, none of the serological methods that we tested can independently diagnose primoinfection by T. gondii, even though IgG avidity studies and IgA produce the best results. PMID- 8695683 TI - [Comparison of 2 ELFA methods for the automatized diagnosis of HIV infection]. AB - BACKGROUND: Evaluate two recent tests for HIV infection diagnosis using the Enzyme-Linked Fluorescent Assay (ELFA) technique for rapid diagnosis in microbiology or virology laboratories. METHODS: A panel of 429 sera with different Ab prevalencies and different sources was prepared: 50 blood bank samples from habitual donors; 8 with positive results from other blood banks; 50 from individuals infected with HIV at various stages; 164 from subjects having practices of risk, with a prevalence of 24.4%; and 157 hospital samples selected at random, with a prevalence of 12.2%. All the samples were analyzed using IMX HIV-1/HIV-2 (ELFA A) and VIDAS HIV-1+2 (ELFA B) tests. Samples yielding positive results from either of the two tests were confirmed by WB. In the cases of indeterminate WB, p24 antigenemia was detected, the positive cases being confirmed by neutralization. RESULTS: From the panel of sera studied, 112 samples were reactive by ELFA A and 109 by ELFA B. The concordance between both assays was 97.3% for reactive samples and 99.1% for non-reactive. WB confirmation showed a global sensitivity of 100% in both tests, with a specificity of 98.4% for ELFA A and 99.3% for ELFA B. Three samples positive for both tests but indeterminate for WB corresponded to sera in the seroconversion window period, one with positive p24 antigenemia. CONCLUSIONS: The new ELFA technology is shown to be an adequate rapid, automatized diagnosis method which decreases risks from laboratory manipulation, with good sensitivity and specificity characteristics for the diagnosis of Ab HIV in health care settings. PMID- 8695684 TI - [Outbreak of Shigella boydii dysentery in the county of El Bierzo]. AB - BACKGROUND: Investigation of an outbreak of bacillar dysentery of possible transmission by water produced by Shigella boydii. METHODS: The strains were isolated in the stools and studies of identification, serotyping, susceptibility to antibiotics and plasmid profile were carried out according to standard methods. The epidemiological investigation was carried out retrospectively. RESULTS: 51 strains were isolated from 48 patients. All were identified as S. boydii serotype 4. The pattern of susceptibility was variable, all of them showed resistance to ampicillin, tetracycline and chloramphenicol. The plasmid profile was homogeneous. Of the 41 patients who completed the questionnaire all were living in the same town or nearby localities. CONCLUSIONS: The serotype 4 of S. boydii, infrequent in Spain, the homogeneous plasmid profile and the relationship between time and place of the cases, suggest that we find ourselves faced with an outbreak epidemiologically relationed. The localisation of the cases and the network of the drinking water supply represented on the plan of the town, support the hypothesis of the origin of hte outbreak as being in the lack of chlorination of one of the tanks of the network of supply. PMID- 8695685 TI - [Usefulness of DR, PGRS, and spoligotyping in the typing of Mycobacterium tuberculosis. Comparison with IS6110]. AB - BACKGROUND: To evaluate 4 markers (IS6110, DR, PGRS and spoligotyping) to differentiate the strains of Mycobacterium tuberculosis isolated in our surroundings, most specially in those which contain a reduced number of IS6110 copies. In addition, to confirm the identity of the strains that share the same IS6110 restriction-hybridization pattern. METHODS: We selected 37 strains from a previous study: 25 had a unique IS6110 pattern and 12 grouped in 3 clusters (8 strains with 11 bands, 2 with 17 bands and 2 which shared the same six-band pattern). The PGRS and DR-RFLPs were obtained by AluI restriction and synthetic oligonucleotides specific to these sequences. The polymorphism of the DR region spacers was analyzed by spoloigotyping. For the amplification of the spacers we used the DRa and DRb primers. Detection was done hybridizing the PCR products on a membrane in which 43 specific spacers had been previously immobilized. RESULTS: Twenty-three different PGRS patterns and 18 spolygotyping patterns were obtained from 25 strains with unique IS6110 pattern. Eight patterns resulted from the 10 strains studied by DR. The 8 strains which shared an 11-band pattern, as well as the 2 strains which shared a 17-band pattern, resulted identical by the other markers. However, 2 strains which shared a 6-band pattern were different by both PGRS and DR or spoligotyping. CONCLUSIONS: 1) IS6110 resulted the most discriminative marker of all. 2) The clonality of clusters with a low number of bands has to be confirmed with alternative markers. PMID- 8695686 TI - [Intracellular penetration of 5 quinolones into non-phagocytic cells]. AB - BACKGROUND: The intracellular penetration and activity of antimicrobial agents can be an important factor in the treatment of infections caused by intracellular pathogens. The new quinolones are able to penetrate into phagocytes, but only a few studies have evaluated other types of cells. The purpose of this study is to evaluate the intracellular penetration of ofloxacin, levofloxacin, lomefloxacin, sparfloxacin and BAY Y 3118 into human polymorphonuclear leukocytes and tissue cultured epithelial cells. METHODS: Intracellular penetration was evaluated by a fluorometric assay for all the quinolones evaluated except for sparfloxacin, which was evaluated by a radiometric assay. RESULTS: All the quinolones evaluated reached intracellular concentrations higher than extracellular ones. The penetration of sparfloxacin and BAY Y 3118 into the epithelial cells was similar to those observed for PMNs (cellular to extracellular concentration ratio; C/E > or = 4). The C/E values of ofloxacin, levofloxacin and lomefloxacin for epithelial cells were lower than those observed in PMN, but still yielding C/E values > or = 2. PMID- 8695687 TI - [Clinical relevance of gram-negative bacteria having inducible chromosomic beta lactamase at an intensive care unit]. AB - BACKGROUND: The aim of the study was to determine the frequency of third generation cephalosporins and aztreonam resistance in gram-negative bacteria with inducible chromosomal beta-lactamase (beta Lac-ind) after beta-lactam therapy in the medical-surgical intensive care unit (ICU) at a university-affiliated hospital. PATIENTS AND METHODS: We studied 34 infections in 29 patients admitted to the ICU. All were infected by strains with beta Lac-ind and all were treated with beta-lactam antibiotics. Susceptibility was determined by disc-diffusion. The beta-lactamase activity of those strains showing constitutive beta-lactamase overproduction were characterized by isoelectrofocusing. When this derepression occurred during the therapy, the strains were compared by genomic macrorestriction (PGFE). RESULTS: In 29 out of 34 infections the initial strains was susceptible. In 11 cases, the culture were not negativized in spite of their susceptible pattern. In 4 cases there was derepression during therapy. In 5 cases the initial strains were derepressed. The microorganisms isolated more frequently were Pseudomonas aeruginosa (22 cases) and Enterobacter cloacae (5 cases). The beta-lactamase activity detected correspond well with a betaLac-ind. In those cases with derepression during therapy, the initial susceptible strain and the resistant strain were identical by PGFE. PMID- 8695688 TI - [Rhodococcus equi pneumonia in patients with HIV infection: report of 2 cases and review of the literature]. AB - BACKGROUND: Pneumonia by Rhodococcus equi is infrequent and is associated with patients with important immunosuppression. To date 66 cases of pneumonia by Rhodococcus equi in patients with HIV infection have been published. The diagnosis, problems in determining diagnosis and treatment are discussed. MATERIALS AND METHODS: Two new cases of pneumonia by Rhodococus equi in C3 stage patients with HIV infection are reported. Diagnosis was achieved by study of bronchoalveolar lavage samples with the Apy-Coryne method and gas chromatography. RESULTS: The two patients presented pneumonia, one of which was necrotizing pneumonia with localization in the upper left lung and in the lower right lung, respectively. The clinical manifestations were characterized by respiratory involvement of a subacute course with pleural involvement in both cases and hemoptisis in one. Prolonged, combined antibiotic treatment was administered with good response in both cases. One patient died at one year of diagnosis from consumptive syndrome while the other remains asymptomatic. CONCLUSIONS: Infection by Rhodococcus equi should be suspected in HIV patients with slow evolution pneumonia, especially in the pneumonia is necrotizing. Combined i.v. antibiotic treatment is recommended and followed from 3 to 5 months with an association including clarithromycin. PMID- 8695689 TI - [Isolation of Haemophilus influenzae and Haemophilus parainfluenzae in genitourinary infections: a 4-year review]. AB - BACKGROUND: Haemophilus spp. had been previously suggested as a potential pathogen in genitourinary infections that could be sexually transmitted. In order to check that suggestions we have determined the incidence, pathogenic role, possible sexual transmission and susceptibility to antibiotics in isolates of Haemophilus parainfluenzae and Haemophilus influenzae from genital tract infections. The microbiological samples were taken during a period of four years from patients attended in a Service of Sexual Transmission Diseases and the data were further reviewed. METHODS: The study included 5,572 genital specimens from 2,182 women prostitutes with different genitourinary infections and from 825 men with urethritis. Microbiological samples were cultured in a non-specific media for genital pathogens and species of Haemophilus spp. and clinical circumstances of isolation were evaluated. Susceptibility tests were performed by using a standard microdilution test. RESULTS: Haemophilus spp. was isolated in 155 samples (2.8%) using a non-selective culture method. H. parainfluenzae was isolated in 100 cases (64.5%), Haemophilus influenzae in 45 cases (29%) and Haemophilus spp. in 10 strains (6.4%). Haemophilus spp. was isolated as a sole pathogen in men with urethritis (8 cases), epididymo-orchitis (2 cases), cervicitis and/or vaginitis (9 cases) and Bartholin's Abscess (2 cases). The most frequent biotypes were H. parainfluenzae biotype II (43%) and III (19%), and H. influenzae biotype IV (35.5%). Beta lactamase activity and ampicillin resistance were present in 29% of the H. parainfluenzae strains and in the 26.7% of clinical isolates of H. influenzae. CONCLUSIONS: 1) Haemophilus spp. was isolated from genitourinary infections at a low frequency in the studied group. 2) The pathogenic role of Haemophilus spp. was suggested when was isolated as a sole pathogen present from some infections of the genitourinary tract such as urethritis in men and Bartholin's abscess in women. 3) The susceptibility to antibiotics in the clinical isolates of Haemophilus spp. from genitourinary infections was similar previously reported studies performed in Spain. PMID- 8695690 TI - [Treatment of endocarditis and other severe infections caused by enterococci]. PMID- 8695691 TI - [Intermittent diarrhea in a traveller]. PMID- 8695692 TI - [Alcoholic patient with dyspnea and dental phlegmon]. PMID- 8695693 TI - [Abscessed skin lesions caused by Mycobacterium marinum]. PMID- 8695694 TI - [Streptococcus pneumoniae spondylodiscitis]. PMID- 8695695 TI - [Gardnerella vaginalis skenitis]. PMID- 8695696 TI - [Fatal anaphylactic shock caused by rifampicin in a patient with HIV infection]. PMID- 8695697 TI - [Blood cultures and contaminations]. PMID- 8695698 TI - [Puncture of adrenal cyst and anaphylaxis]. PMID- 8695699 TI - Creating our future. AB - The evolving health-care system in the United States increasingly rewards successful efforts to keep people healthier and more productive. This is exactly what applied psychophysiology and biofeedback have to offer. However, if we wait to be included in the system, we will wait forever. Inclusion can only come as a result of our efforts to educate decision-makers about the value of our research and services. That education won't take place unless we have an instructional plan and materials. Detailing that plan and producing those materials is the immediate challenge to this Association. PMID- 8695700 TI - A time series analysis of the relationship between ambulatory EMG, pain, and stress in chronic low back pain. AB - Twenty-one subjects with chronic back pain (CBP) participated in an ambulatory electromyography (EMG) monitoring study to ascertain the relationships between muscle activity, physical activity, psychosocial stress, and pain. A time-series analysis approach was adopted to investigate both immediate and lagged associations between these variables in an attempt to determine potential causal relationships. Results for group relationships showed a significant relationship between physical activity and pain, self-report of stress and pain, but no relationship between EMG activity and pain. A lagged relationship between physical activity and pain was found, suggesting a causal relationship between physical activity and pain. However, no time lag was observed between stress and pain, hence no causal relationship can be elucidated. Analysis at the individual level indicated stronger relationships between several combinations of these variables, highlighting the need to consider the heterogeneity of the CBP population and etiology of CBP. The use of ambulatory monitoring of pain, stress, and EMG is suggested as one avenue to further explore the population's heterogeneity. PMID- 8695701 TI - Spectral characteristics of skin temperature indicate peripheral stress-response. AB - High-resolution measurement of skin temperature in 11 normal subjects revealed low-amplitude temperature oscillations (40 x 10(-3) degrees C). The temperature signal measured on two hands during baseline, stress, and recovery periods, was filtered to separate the low-amplitude oscillations from the temperature signal. Spectral analysis of the filtered signal showed that most of the energy of the signal is in a range of 0.01 to 0.03 Hz. Frequency shifts and amplitude changes of the largest component were observed in response to mental stress. In subjects with high baseline values of either of these two variables, a decrease was observed in response to stress. An opposite response was observed in subjects with significantly lower baseline levels. Stress-related changes in peak frequency ranged from -25% to +18.2%; changes in peak amplitude ranged from 74.6% to +280%. Changes in the mean temperature were limited to 2.4%. Thus, the oscillatory component showed higher sensitivity to psychological stress than mean temperature. The spectrum of this component was compared to the spectrum of the blood pressure waves measured noninvasively. Both exhibited similar dynamics of energy, peak amplitude, and peak frequency in response to psychological stress. This similarity suggests that the oscillatory temperature component reflects stress-related changes of peripheral vasomotor activity. PMID- 8695702 TI - Highlights of the 13th International Symposium on Respiratory Psychophysiology held at the inaugural meeting of the International Society for the Advancement of Respiratory Psychophysiology. AB - This article presents a summary of selected events that highlighted the 13th International Symposium on Respiratory Psychophysiology held at the inaugural meeting of the International Society for the Advancement of Respiratory Psychophysiology, Saint Flour, France, 1994. The topic of basic and applied research includes summaries of presentations of research on (a) the control of breathing, (b) dyspnea, (c) dyspneic-fear, (d) hyperventilation (panic disorder, somatic changes, pain, fatigue, occupational stress, and strain), and (e) asthma. The topic of evaluation of treatment includes (a) a review of breathing retraining outcome studies and (b) a discussion of recent advances and continuing controversies regarding breathing patterns and breathing retraining. The topic of technical advances is provided by a description of a visual feedback device for pulmonary rehabilitation. The symposium banquet celebration was highlighted by an award ceremony in which L. C. Lum was recognized for his distinguished contributions to respiratory psychophysiology. PMID- 8695703 TI - The analysis of a blood pressure diary for a patient report. AB - In order to make a more valid assessment of blood pressure (BP), self-monitoring of BP by the patient is generally advised. Self-monitoring usually results in a lower BP level. We are currently investigating whether the BP lowering effect of self-monitoring may be enhanced by not only monitoring BP but also monitoring physical and emotional status at the moment of and activity prior to the BP measurement in a diary. In this article we focus on the individual feedback that the participating patients received. Various methods that can be used for this purpose are described. For our individual reports we first assessed linear trends in the variables. When a trend was present, residuals were calculated. Then a principal-components analysis on BP measurements, BP estimates, symptoms, moods, and activities was performed. Results are presented for two hypertensive patients. PMID- 8695704 TI - Assessment of lumbar EMG during static and dynamic activity in pain- free normals: implications for muscle scanning protocols. PMID- 8695705 TI - [Enteral nutrition: reduction in the contamination risk]. AB - Enteral nutrition is used as a routine therapy in patients with caloric-protein malnutrition, severe dysphagia, major burns, intestinal resection, and enterocutaneous fistulae, as long as a portion of the digestive tract still has an active absorptive function. The administration takes place by means of surgical (ostomies) or non-surgical (nasogastric) tubes. In our country, a significant number of hospitalized patients with various diseases receive this type of nutrition. Given that the colonization of the digestive tract by hospital flora is the first step towards developing intra-hospital infections, the contamination implies serious risks. The objective of this study was to study the most appropriate conditions for the manufacturing, storage and administration of the mixture of nutrients of enteral nutrition, to guarantee nutrition with a lower contamination risk. This study was conducted by the Unit of Nutritional Assistance of the Mater Dei Clinic, by means of bacteriological controls, from January 1991 to December 1992, and in 1993 in which the work systematics were reviewed. The study was prospective, and those solutions whose bacteriological counts were lower than 100.000 colony forming units (CFU), and which showed an absence of enteropathological micro-organisms, were considered acceptable, and those solutions which had a bacteriological count greater than or equal to 100.000 CFU and or the presence of enteropathological micro-organisms, were considered unacceptable. During the first period, "usual working conditions", we analyzed the infra-structure, the personnel, the constituents, and the apparatus used in the manufacturing, for which 36 samples were studied at t0 (moment of preparation). Afterwards, in the second period "special working conditions", we analyzed the manufacturing procedures, the storage and the administration of 103 solutions, corresponding to 36 patients, taking samples at t0 and t24 (after 24 hours of preparing). In the first phase, we found a 53% contamination. In the second phase, 99.03% of the solutions were within the limits of acceptability, and only 0.07% were unacceptable. We conclude that it is necessary to have access to a working area which meets the biosecurity norms, to use sterile technique in the preparation, to prefer pharmacologically sterile products for the preparation, to store the prepared mixture between 4 and 8 degrees C, and to keep it cooled during the administration. Lastly, we saw the need to continuously capacitate the nursing, dietary (ABSTRACT TRUNCATED) PMID- 8695706 TI - [CO2 production and thermogenesis induced by enteral and parenteral nutrition]. AB - The objectives of this study were to quantify, in critically ill patients, the thermogenesis induced by artificial nutrition (AN), when the caloric supply restores the energetic losses, and to evaluate the effects of the AN suppression on the production of CO2 (VCO2). MATERIAL AND METHODS: 20 patients were studied, 14 with mechanical ventilation and 6 with spontaneous respiration, divided into two groups, depending on whether the AN was enteral (EN) or parenteral (PN). The VCO2 and the consumption of oxygen (VO2) were measured by means of the Douglas bag. The resting energy expenditure during the AN (REET) and 2 hours after discontinuing the AN (REE) were measured. The thermogenesis induced by the nutrition (TIN) was defined as the difference between REET and REE, expressed as a percentage of the caloric supply. RESULTS: After discontinuing the AN, there were no statistically significant differences between EN and PN patients in the VCO2 decreases (p = 0.60) and the VO2 decreases (p = 0.78), and in the TIN percentage referred to the caloric supply (p = 0.82). After discontinuing the caloric supply, which was 1.12 times the REET, the VCO2 decreased 5 +/- 4.9% (Confidence interval (CI) of 95%, from 3% to 7%), the VO2 decreased 2 +/- 6.1% (CI of -0.36% to 5.32%), and the TIN represented 3 +/- 4.5% of the caloric supply (CI of 0.72% to 4.95%). CONCLUSIONS: The results of this study indicate that the thermogenesis induced by artificial nutrition, when restores the energetic losses, is equivalent to 3% of the caloric supply. The discontinuation of the artificial nutrition induced a VCO2 decrease of 5% and thus this measure would probably not be useful for decreasing the ventilatory demand. PMID- 8695707 TI - [The epidemiology of central venous catheterization (CVC) in parenteral nutrition. The clinical implications and factors that determine the selection of germs]. AB - The objective of the study is, on one hand, to determine the etiology and the clinical implications as a function of the isolated germ, of central venous catheterization in patients with parenteral nutrition in our hospital, and on the other hand, to determine which factors are associated with the selection of germs of central venous catheterization in parenteral nutrition. For this we included venous catheters, colonized for 5 years, and with a study of the different segments (connection, insertion point, and tip). As a function of the appearance of associated clinical symptoms, of the results of the blood culture, and of the clinical evolution of the patient, the variables which determine the level of pathogenicity of the different groups of germs in the central venous catheterization, are defined; for the study of the factors associated with the selection of the different groups of germs, 8 variables were chosen. The data obtained are statistically treated, and the results are considered to be significant if p < 0.05. The understanding of the different factors associated with the selection of germs, and the level of clinical pathogenesis of the different groups, allows a better level of the clinical action in the prevention of the infection associated with the catheter. PMID- 8695708 TI - [The utilization of parenteral nutrition at Hospital de Jerez (Cadiz): a description and comparison with other hospital centers]. AB - This retrospective study aims to analyze, and compare with other Spanish hospitals, the use of parenteral nutrition, its characteristics and complications, in a general hospital with 610 beds, during 1992. To conduct this study, we have used clinical histories and follow up sheets made up by the Department of Pharmacy for each patient, as well as the results of the sample processing in the microbiology laboratory. Between 1992 and 1993 we have seen an increase in the use of parenteral nutrition, with the number of bags increasing from 2134 to 2575. The departments which have used parenteral nutrition most, were Surgery (57.3%), and ICU (24.8%), with the mean duration being 10.4 days 8SD = +/- 9.3 days). The most frequently used access route in the hospital was the drum, but there are significant differences between the departments. Gastroenterological pathology was, with 71.4% the most frequent indication for its use, and within this, the neoplasias stand out with 26.3% of the total of parenteral nutrition. The complications which affected most patients are: increases of the liver enzymes, hypokalemias, hyponatremias, and hyperglycemias. PMID- 8695709 TI - [Endocrine metabolic and arterial pressure changes in morbidly obese patients treated with vertical gastroplasty]. AB - When overweight surpasses 100% of the ideal weight, morbid obesity, the obese patients is condemned to a complete inability to work, social and sexual inability, and shall suffer from an increase in its morbidity and mortality. This depends to a large degree on the additions to the obesity of insulin resistance, carbohydrates intolerance, hypertriglyceridemia, hypercholesterolemia, and arterial hypertension, all of which is enveloped in a atmosphere of neuroendocrine alterations. An efficient method of treating this syndrome is weigh loss. Medical treatments have not achieved prolonged weight losses during long periods in morbid obese patients, which is a reason for surgery to try and propose new lines of treatment for these patients. The purpose of our study is to examine the effect of weight loss in 100 patients treated with vertical gastroplasty, on the metabolic disorders (triglycerides, cholesterol, glucose) and the arterial hypertension, which are considered to be risk factors in the mortality associated with morbid obesity. Our results indicate that the weight loss modified the metabolic conditions of the patients, with there being a decrease of the levels of triglycerides, cholesterol, glucose, and arterial pressure, after 6 to 12 months after the weigh loss. PMID- 8695710 TI - [Enteral nutrition in maxillofacial surgery patients (1989-1995)]. AB - One of the clearest indications for enteral nutrition is made up by patients who underwent treatment for orofacial pathology. In this way, we have reviewed retrospectively, 321 clinical histories of patients who underwent treatment (orofacial surgery), dividing these according to the pathology; neoplasia or non neoplasia (173/148), with enteral nutrition 24 hours after the intervention. Data are collected with regard to the tolerance (vomiting, diarrhea), time needed to reach 1.500 kcal/day, need of parenteral nutritional support, transferrin, prealbumin, and albumin quantification at the start of the nutritional therapy, as well as the total duration there of. Globally, the good enteric tolerance of both groups of patients is noted, despite the fact that the oncological group showed a greater degree of protein malnutrition (statistically significant). As for the total duration of the nutrition, this is greater in the neoplasias, probably due to a more aggressive surgery. The results obtained permit modification of the basic enteral nutrition protocol (reduction of the time used to reach the maximum volume), as well as stressing the preoperative and postoperative regulated nutritional evaluation. PMID- 8695711 TI - [An infection study of total parenteral nutrition catheters for Y-site drug administration]. AB - When faced with the frequent use of parenteral nutrition (TPN) and the multiple problems which the maintenance of venous pathways presents, we initiated this study to try and show that the use of TPN catheters for the perfusion of drugs in "Y", does ot increase the incidence of infection. 70 patients subjected to TPN were studied, divided into 3 groups: I: TPN with exclusive use catheter (23 patients). II: TPN with a catheter through which antibiotic medication is administered in "Y" (22 patients). III: TPN with a catheter through which non antibiotic medication is administered in "Y" (25 patients). Despite there being no extra manipulation in group I, when applying Cramer's "Y" we did not find any significant differences between the three groups as to incidence of infection. When relating the variables of infection and number of manipulations by means of chi-squared, we did not find significant differences either. There is no increase in the incidence of infection with the increase of manipulation. When we relate the variables of infection and number of days of treatment with TPN by chi squared, we did not find significant differences either. There were no more infections of the catheters with more days of treatment. Neither did we find significant differences with respect to the number of manipulations, according to the calculation done by the Student T-rest, between groups II and III. Therefore, we have reached the conclusion that although the use of TPN for the administration of other drugs should not be used indiscriminately, it is absolutely valid for concrete cases, with a difficulty of multiple venolysis, as long as the drugs that shall be administered are stable with TPN and as a long as the norms form the correct administration and the aseptic techniques are observed. PMID- 8695712 TI - [A possible hypersensitivity reaction to total parenteral nutrition]. AB - We present a possible case of a hypersensitivity reaction to parenteral nutrition in a surgical patient of 61 years, weighing 49 kg, who presented facial, thoracic, and underarm erythema, proximal to the peripheral line, accompanied by pruritus: the symptoms disappeared after discontinuing the nutrition and after administration of dexchlorpheniramine. Analysis of the possible causes of this manifestation takes place, as well as of the components of the parenteral nutrition, route of administration, and concomitant medication. PMID- 8695713 TI - [Lipid vehicles for the parenteral administration of drugs (2): liposomes]. AB - The studies conducted in the past decades of the different medication carriers, have made different active substances available to the therapeutic arsenal, by using liposomes as a vehicle. Since Bangham discovered their preparation in the sixties, important technological advances have taken place on this formulation, with there being great expectations for its potential application as a vehicle for medication or other active molecules. The presently available knowledge in preclinical and clinical studies with different liposomal formulations of narrow range active substances with a high toxicity, have allowed them to be objectively seem as a good administration system for these drugs, since their more selective action improves their tolerance. Nevertheless, there are problems with regard to the implementation of their use, which in general we could summarize as its chemical instability, difficulty in manufacturing, and high cost of technology. In the present study, the physical and chemical characteristics, the properties and the formulations of the liposomes are reviewed, as well as the results of studies published with reference to the efficacy and the therapeutic applications, mainly in the area of chemotherapy and anti-infectious therapy. PMID- 8695714 TI - [New prospects in the treatment of acute kidney failure]. AB - In the last 25 years, the mortality of renal failure, far from decreasing, has shown a slight tendency towards increasing, despite continuously more sophisticated and expensive therapeutic measures. As an explanation, the greater frequency of intrahospital renal failures, as past of the systemic inflammatory response syndrome which covers dysfunction of various organs and systems, is brought into this. This relative treatment inefficiency leads to the need of investigating new lines of treatment. After reviewing the conservative treatment of acute renal failure, the main alternatives which exist at present, are reviewed, some of which are in the experimental phase. As prognostically poor renal failure appears in relation to the inflammatory response syndrome, the possibility of eliminating mediators there of by means of continuous hemofiltration systems, is being considered. Despite some positive effects, the majority of authors have not managed to achieve a significant reduction of acute renal failure. The theoretical possibility of improving renal function by administration of certain amino acids (Arginine and Glycine), is not confirmed in practice, possibly due to the incidence of oxidative stress. This stress may be a determining factor in the evolution of renal failure, as it induces many risk factors in these patients. However, carefully, the bases for the anti-oxidant therapy are being established. Finally, the treatment with hormones and growth factors, with the aim of stimulating the rapid regeneration of the renal tubule, represents a very attractive therapeutic alternative, though still in the experimental phase. PMID- 8695715 TI - [The mechanisms of satiation]. AB - There are many published experimental studies which attempt to explain certain aspects of satiety, but only very few treat this problem as a whole, synthesizing concepts. At present, the understanding of the mechanisms of satiety is extremely interesting for the study and application of medical or surgical anti-obesity treatments. PMID- 8695716 TI - [The incidence of the refeeding syndrome in cancer patients who receive artificial nutritional treatment]. AB - We determine the incidence of the malnutrition syndrome and its relation with probable risk factors, in 106 patients, with a mean age of 53.3 +/- 15.4 years, with a diagnosis of cancer confirmed histologically, and who received artificial nutrition either enterally or endovenously, during an average of 16.8 +/- 2 days, which included a supply of 60 to 100 mmol/day of phosphorus. We considered there to be a renutrition syndrome when there as hypophosphatemia; < 2.5 mmol/l, which took place during the nutritional treatment phase, and previous to which, the patients had normal serum levels of phosphorus. The serum electrolyte concentrations were measured prior to the start of the treatment, and daily during the first week, and later every 3 days until the end. The study variables were: age, sex, type of cancer, degree of malnutrition, degree of hypophosphatemia, day on which in occurred, and clinical manifestations associated to this. The relative risk was calculated for the variables of age, sex, malnutrition and cancer. The incidence of the renutrition syndrome was 24.5%; it was more frequent in the enteral group than in the endovenous group (37.5% vs. 18.9%, p < 0.005); and it took place 72 hours after starting the nutritional support, in 61.5% of the cases, with a mean phosphorus concentrations of 1.9 mmol/l; the most frequent clinical manifestations were the neuromuscular ones (30%), and the most frequent type of cancer was lymphoma (15.4%). The risk factors were age greater than 60 years (RR = 1.7), and moderate or severe malnutrition 8RR = 2.0). We conclude that the prevalence of the renutrition syndrome is high in the cancer patients, despite an intense preventive treatment with phosphorus. PMID- 8695718 TI - Therapy of childhood acute myelogenous leukemias. AB - Acute myelogenous leukemia (AML) accounts for approximately 20% of acute leukemias in children. Although AML is more resistant to chemotherapy than acute lymphoblastic leukemia (ALL), significant progress in improving outcome for AML patients has been achieved over the past 15 years. This can be attributed to intensification of chemotherapy, increased use of bone marrow transplantation, and improved supportive care. Thus 30-50% of children with AML achieve long-term event-free survival with current treatment strategies [61, 66, 85, 96]. This review gives an overview about the evolution of and rationale for current pediatric treatment protocols, with special emphasis on the German Berlin Frankfurt-Munster (BFM) studies, and discusses new directions for the future. PMID- 8695717 TI - Macrophage-stimulating protein, a ligand for the RON receptor protein tyrosine kinase, suppresses myeloid progenitor cell proliferation and synergizes with vascular endothelial cell growth factor and members of the chemokine family. AB - Macrophage-stimulating protein (MSP), originally identified as an inducer of murine resident macrophage responsiveness to chemoattractants, is a ligand for human RON/murine STK receptor protein tyrosine kinases. Since STK was cloned from populations enriched for hematopoietic stem cells, we initiated studies on the effects of MSP on colony formation by granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) myeloid progenitor cells. MSP alone had no colony stimulating activity. However, MSP caused about a 50% suppression of CFU GM colony formation induced by synergistic combinations of SLF or Flt-L plus GM CSF, G-CSF, or IL-3 and of BFU-E and CFU-GEMM colonies induced by SLF or Flt3-L plus Epo or Epo and IL-3. In contrast, MSP had no effect on progenitors stimulated by one growth factor. MSP also suppressed colony formation by stimulated cord blood progenitors, but only after preinduction to a rapidly cycling state. It was previously reported that several members of the chemokine family synergistically suppress myeloid progenitor proliferation. Likewise, synergistic suppression was observed when MSP was paired with VEGF, MIP-1 alpha, IL-8, PF4, MCP-1, IP-10, or ENA-78, or when VEGF was paired with the chemokines; and the required MSP concentration was more than 100-fold less than for MSP alone. Additionally, MSP or VEGF inhibited proliferation of the human myeloid growth factor-dependent cell line, M07e, but a sustained effect required multiple additions over time. At the least, some of the MSP suppressive effects on myeloid progenitors, as assessed on single isolated CD34 marrow cells, appeared to be directly on the progenitors; sustained additions of MSP were required to see this effect. The suppressive action of MSP and its synergism with proteins of the chemokine family may be of relevance to regulation of blood cell production. PMID- 8695719 TI - Evaluation of procollagen-III peptide as a marker for veno-occlusive disease after bone marrow transplantation. AB - Procollagen-III peptide (PIIIP) has been suggested as a marker for hepatic veno occlusive disease (VOD) after bone marrow transplantation (BMT). Using the RIA gnost PIIIP assay, we examined frozen plasma samples from three groups of patients. The groups included (A) four patients with clinically proven VOD, (B) nine patients with remarkably uneventful post-BMT courses, and (C) patients with either early complications other than VOD or pulmonary fibrosis in their later course. In group A, PIIIP levels increased parallel to the clinical course, with maximum values of 2.7-5.5 units/ml. In group B, values did not exceed 1.4 units/ml. In group C, higher values were occasionally observed. In one patient with early relapse of a lymphoma PIIIP peaks correlated with episodes of fever and graft versus host disease (GVHD). In another patient mild VOD seems possible retrospectively. The highest levels ( > 15 units/ml) occurred in one patient with ileus. Several patients with interstitial pneumonia (IP), adult respiratory distress syndrome (ARDS), or lung fibrosis showed increases in PIIIP levels corresponding to the clinical course; most of these events occurred later than day 30 after BMT. One patient with severe GVHD of the liver showed a maximum of only 1.4 units/ml. PIIIP elevation correlated with clinical VOD and may help to differentiate it from hepatic GVHD. In the presence of other complications (pulmonary, gastrointestinal), some caution in interpreting the results may be advisable. PMID- 8695720 TI - Color Doppler ultrasound investigation of the therapeutic effect of plasmapheresis on a lymphoplasmocytoid lymphoma (immunocytoma): a case of central retinal artery occlusion. AB - The lymphoplasmocytoid immunocytoma (Waldenstrom's disease) is a non-Hodgkin's lymphoma of low malignancy. The disease is defined by the production of monoclonal IgM-globulins in the bone marrow. These macroglobulins affect the aggregation of thrombocytes and bind the coagulation factors, which leads not only to hemorrhagical diathesis, but also to hyperviscosity syndrome. We present the rare case of a 79-year-old woman suffering from an immunocytoma with sudden painless loss of vision in her right eye. Ophthalmoscopic examination revealed an occlusion of the central retinal artery. The immediately performed blood examination showed the following results: IgM serum level was 6610 mg/dl (normal range: 60-370 mg/ dl), kappa-paraproteinemia showed values of 702 mg/dl (normal range: 200-440 mg/dl), and the plasma viscosity was 3.4 mPa/s (normal range: 1.5 1.72 mPa/s). Plasmapheresis was promptly initiated. Subsequently, the highly pathological serum levels were markedly lower and sight improved from complete amaurosis to qualitative vision. Blood-flow velocity and vascular resistance parameters (resistive index) in all nutritious vessels [ophthalmic artery (OA), posterior ciliar arteries (PCA) and central retinal artery (CRA)] were recorded before and after each of the six cycles of plasmapheresis, using color Doppler velocity (CDV). It was proven that even after the first plasmapheresis, circulation in the central retinal artery was restored. After each further cycle of plasmapheresis, an improvement in blood-flow velocity in OA, PCA, and CRA was recorded by CDV. CDV verifies variations in circulation of the eye vessels and gives an objective assessment of the influence of therapy. PMID- 8695722 TI - Progression of a myelodysplastic syndrome to pre-B acute lymphoblastic leukemia: a case report and cell lineage study. AB - The evolution of acute lymphoblastic leukemia from a myelodysplastic syndrome is a very uncommon event. We describe a 46-year-old man in whom refractory anemia with excess blasts (RAEB) evolved to a pre-B acute lymphocytic leukemia. Trisomy 8 was one of the cytogenetic abnormalities in the dysplastic clone and was detected in both peripheral blood and bone marrow smears of interphase cells by the fluorescence in situ hybridization (FISH) technique. Using a chromosome 8 centromeric specific DNA probe we identified the trisomy 8 to be present in lymphoblasts, erythroid precursors, myeloblasts, promyelocytes, myelocytes, metamyelocytes, granulocytes, and monocytes. Our case supports the hypothesis that in MDS the pluripotent precursor cell is affected, and we examine the potential role of FISH for the study and follow-up of some hematological diseases. PMID- 8695721 TI - Adjuvant therapy with rhGM-CSF for the treatment of Blastoschizomyces capitatus systemic infection in a patient with acute myeloid leukemia. AB - We report a patient with acute myeloid leukemia and Blastoschizomyces capitatus sepsis who developed multiple abscesses when neutrophils recovered. The patient did not respond to antifungal therapy and her clinical condition showed an improvement only after rhGM-CSF was added to the treatment. PMID- 8695723 TI - Unusual bone marrow relapse of Hodgkin's disease with typical Pel-Ebstein fever. AB - We report the unusual case of a 43-year-old man with a diagnosis of clinical stage I A mixed cellularity Hodgkin's disease (HD), who relapsed 4 years after diagnosis with exclusive bone marrow involvement and a cyclic variation in body temperature typical of Pel-Ebstein fever. In the absence of clinical and laboratory signs of infection, a restaging of the lymphoma was performed. Total body CT scan revealed no parenchymal or lymph node involvement, while a bone marrow biopsy was positive for the presence of Reed-Sternberg cells. Therefore, the patient was started on combination chemotherapy, which promptly induced a normalization of the temperature curve. The presence of typical Pel-Ebstein fever, which is reported to be very rare, in association with bone marrow localization as the only site of relapse, suggests a relationship between these two rare manifestations of the disease. PMID- 8695724 TI - Non-Hodgkin's lymphoma presenting with amegakaryocytic thrombocytopenic purpura. AB - A 91-year-old patient was diagnosed with amegakaryocytic thrombocytopenic purpura (AATP) as a presenting symptom for CD5-positive B cell non-Hodgkin's lymphoma. Lymphoma is another condition that should be considered in the differential diagnosis of AATP. PMID- 8695725 TI - Multilobated B cell lymphoma (Pinkus variant) with isolated muscular localization in a patient with systemic sclerosis: a case report. AB - The association of systemic sclerosis (SSc) and non-Hodgkin's lymphoma (NHL) is a rare event whose pathogenesis remains to be clarified. We describe a case of NHL in a patient with SSc, in whom the NHL was particular in terms of clinical presentation (primitive muscle and bone involvement) and histologic type (large multilobated B-cell variant). The lymphoma was clinically aggressive but responded well to therapy. Surveillance for the development of "atypical" NHL is suggested in SSc cases. PMID- 8695726 TI - A case of localized Castleman's disease with systemic involvement: treatment and pathogenetic aspects. AB - A patient is presented who had Castleman's disease with constitutional symptoms, a palpable supraclavicular/ axillar mass, and a microcytic anemia, among other laboratory abnormalities, including elevated levels of interleukin-6. Treatment consisted of irradiation of the involved area, with subsequent disappearance of all symptoms and normalization of the laboratory abnormalities. Iron kinetic studies demonstrated a hypoproliferative erythropoiesis, which normalized after radiotherapy. Hypoproliferative erythopoiesis could not be ascribed to serum inhibitors, since normal burst-forming units were observed in the absence or presence of autologous serum. The role of interleukin-6 in relation to Castleman's disease is highlighted. PMID- 8695727 TI - Pentosan polysulfate-induced thrombocytopenia: a case diagnosed with an ELISA test used for heparin-induced thrombocytopenia. AB - We report a patient who developed severe thrombocytopenia and ischemic stroke following pentosan polysulfate treatment. An ELISA test employed in type-II heparin-induced thrombocytopenia was highly positive. To our knowledge, this is the first case in which this test has been performed in a pentosan polysulfate induced thrombocytopenia (PIT). Our data suggest that the antibody against pentosan polysulfate-platelet complex also cross-reacts with heparin-platelet factor 4 complex. Due to its greater sensitivity and wider availability, this ELISA test should be used in cases where PIT is suspected. PMID- 8695728 TI - Ehlers-Danlos type IV syndrome. A review from a vascular surgical point of view. PMID- 8695729 TI - Cardiac function in primary hyperparathyroidism before and after operation. An echocardiographic study. AB - OBJECTIVE: To identify possible causes for the increased cardiovascular morbidity and mortality seen in patients with primary hyperparathyroidism. DESIGN: Prospective, blind study. SETTING: University hospital, Sweden. SUBJECTS: 44 Patients with primary hyperparathyroidism and 23 (sex and age matched) control patients with atoxic nodular goitres. INTERVENTIONS: Exploration of the neck with removal of pathological parathyroid glands or thyroid resection. Echocardiography before, and one year after, the operation. MAIN OUTCOME MEASURES: Blood pressure and echocardiographic findings. RESULTS: Hyperparathyroid patients had higher blood pressure and greater left atrial diameter than control patients preoperatively. They also had a significantly lower E:A ratio (mitral flow velocity pattern) than the controls (p = 0.02) indicating a disturbance in early diastolic filling of the left ventricle. The E:A ratio correlated negatively with the systolic blood pressure. 19 of the hyperparathyroid patients (43%) had cardiac calcifications as did 14 (61%) of the controls. Most of calcifications were located in the aortic and mitral valves; only a few patients had calcifications in the myocardium. No significant changes had occurred one year after parathyroidectomy, except for a reduction in systolic blood pressure, in the hyperparathyroid patients. CONCLUSION: Echocardiographic investigation of patients with primary hyperparathyroidism shows early signs of left ventricular dysfunction that may be of clinical importance. PMID- 8695730 TI - Encapsulated papillary neoplasm of the thyroid: retrospective clinicopathological study with long term follow up. AB - OBJECTIVE: To study the clinical course of patients with the encapsulated variant of papillary thyroid carcinoma, in which there is a well-defined fibrous wall completely separating the tumour cells from the adjacent tissue. DESIGN: Retrospective review. SETTING: University hospital, Spain. SUBJECTS: Of a total of 163 patients whose papillary thyroid carcinomas were treated surgically between 1975 and 1985, there were 25 encapsulated tumours. MAIN OUTCOME MEASURES: Clinicopathological features and survival rate compared with those of non encapsulated papillary thyroid carcinomas. RESULTS: Mean follow up was 9 years (range 7-17), and 42 were excluded because follow up was incomplete. Encapsulated tumours differed from the earlier age of other types in that they presented earlier (mean age 36 years compared with 45), they were significantly less likely to have symptoms of compression (1/25 compared with 24/96, p = 0.024), or nodal metastases (3/25 compared with 43/96, p = 0.002), or to recur (0/25 compared with 33/96, p = 0.002). No patients died in the encapsulated group compared with 11/96 in the other group. CONCLUSIONS: Encapsulated papillary carcinomas have an excellent prognosis, and can be cured by operation. PMID- 8695731 TI - Influence of abdominal incision on the formation of postoperative peritoneal adhesions: an experimental study in rats. AB - OBJECTIVE: To see if the three most commonly used abdominal incisions were associated with the development of postoperative peritoneal adhesions. DESIGN: Prospective experimental study. SETTING: University hospital, Spain. SUBJECTS: 30 Wistar rats. INTERVENTIONS: Three groups each of 10 rats underwent suprainfraumbilical midline laparotomy, right subcostal laparotomy or infraumbilical right transrectal laparotomy. MAIN OUTCOME MEASURES: The animals were killed after 30 days and adhesions quantified according to a special designed score which assessed the number of adhesions, their site, vascularisation, thickness, and strength. RESULTS: The transrectal incision was associated with most adhesions (median: 9.3, interquartile 7-10), followed by subcostal laparotomy (5.5, 4-6.7), and midline laparotomy (2.0, 0-7). CONCLUSIONS: Infraumbilical incisions away from the midline are more traumatic, damage more of the peritoneum, and are more likely to come into contact with the omentum, peritoneal fat, bowel loops, and pelvic contents, thereby predisposing to the formation of peritoneal adhesions. PMID- 8695732 TI - The metabolic response to cholecystectomy: insulin resistance after open compared with laparoscopic operation. AB - OBJECTIVE: To study the changes in insulin sensitivity and plasma concentrations of interleukin-6 (IL-6) after open compared with laparoscopic cholecystectomy. DESIGN: Prospective open study. SETTING: University hospital, Sweden. SUBJECTS: 12 otherwise healthy patients undergoing either open (n = 6) or laparoscopic (n = 6) cholecystectomy. MAIN OUTCOME MEASURE: Relative insulin sensitivity (compared with preoperative) on the day after operation. Changes in IL-6 concentrations postoperatively. RESULTS: The mean (SEM) relative reduction in insulin sensitivity was significantly smaller after laparoscopic (18 (5)%) compared with the open operation, (58 (4)%) (p < 0.01). There was a significant increase in plasma concentrations of IL-6 postoperatively, but there was no difference between the groups. CONCLUSION: Insulin sensitivity is less affected 24 hours after laparoscopic than after open cholecystectomy, which in this study was not accompanied by a simultaneous difference in the IL-6 response. The small postoperative reduction of insulin sensitivity may be a contributing factor to the clinical benefit of improved wellbeing observed after laparoscopic surgery. PMID- 8695733 TI - Laparoscopic cholecystectomy in a surgical training programme. AB - OBJECTIVE: To assess the impact of the introduction of the laparoscopic cholecystectomy on surgical training, and the outcome of laparoscopic cholecystectomies performed by residents compared with those of surgeons. DESIGN: Retrospective analysis. SETTING: University hospital, The Netherlands. SUBJECTS: 943 Patients who underwent cholecystectomies from January 1987-December 1993 by residents and surgeons. In 527 patients the cholecystectomy was open and in 416 laparoscopic. MAIN OUTCOME MEASURES: The percentage of cholecystectomies done by residents in the period 1987-1993. The outcome of laparoscopic cholecystectomies done by surgeons and residents in terms of duration of operation, conversion rate, postoperative complications, and hospital stay. RESULTS: Before the laparoscopic era about 70% of all cholecystectomies were done by residents. After its introduction in 1990, the residents did 38% of the laparoscopic cholecystectomies in 1991, 39% in 1992, and 64% in 1993. There were no differences in outcome of laparoscopic cholecystectomy in terms of duration of operation, conversion rate, postoperative complications and hospital stay between surgeons and residents. CONCLUSIONS: The introduction of laparoscopic cholecystectomy caused a temporary decline in the number of cholecystectomies done by residents. Laparoscopic cholecystectomy was integrated as a standard surgical procedure in the residents' training programme within two years of its introduction. The outcome of laparoscopic cholecystectomies done by supervised residents and surgeons was similar, and so laparoscopic cholecystectomy should be part of residents' training. PMID- 8695734 TI - Rise and fall in the number of cholecystectomies: Stockholm 1932-1993. AB - OBJECTIVE: To assess the annual rates of cholecystectomy 1932-1993 in Stockholm and compare them with the rates for other common surgical procedures. DESIGN: Retrospective collection of data from annual hospital records. SETTING: Teaching hospital, Sweden. SUBJECTS: All subjects in Stockholm county who underwent cholecystectomy, herniorrhaphy, appendicectomy, colonic resection for cancer and mastectomy for cancer or who were admitted to hospital with acute cholecystitis and not operated on. MAIN OUTCOME MEASURES: Annual rates from 1932-1993. RESULTS: The rate of cholecystectomies/100000 inhabitants increased slowly from 1932 and peaked in 1957 at 315. It then decreased to 67 in 1990 after which the introduction of laparoscopic technique caused an increase to the present rate of 90. CONCLUSION: There has been a rise and a fall of the cholecystectomy rate during the last 60 years in Stockholm county which are probably explained by changes in the indications for the operation. There was no association with health care facilities or with changes in the rates of other operations. PMID- 8695735 TI - Preoperative ERCP in the management of common bile duct stones before laparoscopic cholecystectomy. AB - OBJECTIVE: To evaluate the effectiveness of a policy of preoperative endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincterotomy (ES) before laparoscopic cholecystectomy. DESIGN: Retrospective review. SETTING: University hospital, Singapore. SUBJECTS. From January 1991 to December 1992, 303 patients underwent elective laparoscopic cholecystectomy, of which 46 (15%) were selected to have ERCP preoperatively because they had clinical, biochemical, and ultrasound signs of the presence of stones in the common bile duct (CBD). MAIN OUTCOME MEASURES: Effectiveness and efficiency of ERCP. RESULTS: Successful cannulation of the CBD was achieved in 45/46 cases (98%). In 19 patients (42%) stones were found, of which 18 (95%) were removed endoscopically. There were no major complications from the ERCP or the sphincterotomy. One patient developed symptoms from an unsuspected common duct stone two weeks after cholecystectomy and it was removed endoscopically. CONCLUSION: Selective preoperative ERCP is an effective and safe way of clearing the CBD before laparoscopic cholecystectomy, but its efficiency can be improved further by widening the criteria for preoperative ERCP and by doing operative cholangiography for patients with a low risk of stones in the CBD. PMID- 8695736 TI - Indications for and limitations of extended cholecystectomy in the treatment of carcinoma of the gall bladder. AB - OBJECTIVE: To assess the indications for, and limitations of, extended cholecystectomy in the treatment of carcinoma of the gall bladder. DESIGN. Retrospective study. SETTING: University hospital, Japan. SUBJECTS: 23 Patients who were operated on for carcinoma of the gall bladder, 1982-92 out of the total of 73 who presented to our department with the disease. INTERVENTIONS: Extended cholecystectomy with en bloc lymph node dissection with or without resection of the extrahepatic bile duct, or hepatic resection, or pancreaticoduodenectomy, or a combination. MAIN OUTCOME MEASURES: Outcome related to TNM classification. RESULTS: 7 Patients had stage I or II disease, and their cumulative five year survival rates (including one censored death) were 67% and 100%, respectively; 9 patients had stage III disease and of these 2/4 patients with T3N1 tumours died of their cancer, but the remaining 7 were alive a mean of 58 months later (though there was one censored death). Of the 7 with stage IV disease all but one were dead within 16 months despite more extensive surgery. The cumulative five year survival was 92% in patients with stage I, II and III (except T3N1 tumours). CONCLUSION: Extended cholecystectomy with or without resection of the extrahepatic bile duct is indicated for patients with stage I, II, or III (except T3N1) tumours of the gall bladder. PMID- 8695737 TI - Effects of vitamin A on immunological deficiencies in rats with obstructive jaundice. AB - OBJECTIVE: To investigate the ability of an immunostimulant, vitamin A, to reverse dysfunction of the mononuclear phagocyte system and impaired peritoneal neutrophil chemotaxis in rats with obstructive jaundice. DESIGN: Open laboratory study. SETTING: Medical School, Turkey. MATERIAL: 60 male Wistar-Albino rats. INTERVENTIONS: Two different experimental studies with 30 rats each were performed. Ten of the 20 rats in which the common bile duct was ligated and divided, were given vitamin A (vitamin A group) and the other 10 were given saline (saline group). Ten rats which underwent laparotomy with mobilisation of the common bile duct (sham group) were given saline. Rats in the vitamin A group were given 200 IU/g/day vitamin A and other groups of rats had an equal volume of saline intraperitoneally for 20 days. MAIN OUTCOME MEASURES: Function of the mononuclear phagocytic system was studied by the use of 99mTc sulphur colloid uptake, peritoneal neutrophil chemotaxis was measured by the Boyden chamber method, and liver function tests were studied 21 days after operation. RESULTS: Hepatic uptake of 99mTc sulphur colloid decreased, and lung uptake increased in the saline group compared with the sham and vitamin A groups (p < 0.05). Neutrophil chemotaxis was reduced in the saline and vitamin A groups compared with the sham group (p < 0.05). Serum aspartate aminotransferase and alanine aminotransferase activities and unconjugated bilirubin concentrations in the saline group were higher than in the vitamin A and sham groups (p < 0.05). CONCLUSION: Vitamin A stimulates mononuclear phagocytic function in jaundiced rats. It also improves liver function and may enhance peritoneal neutrophil chemotaxis. PMID- 8695738 TI - Effect of octreotide on pancreatic regeneration in rats measured by bromodeoxyuridine uptake. AB - OBJECTIVE: To study the effects of up to 60 days intermittent octreotide on regeneration of rat pancreas stimulated by cholecystokinin after 70% distal resection. DESIGN. Random controlled experimental study. SETTING: University hospital, Italy. MATERIALS: 60 Male Wistar rats. INTERVENTIONS: Distal resection of splenic and gastric lobes of pancreas (70% of whole gland). Rats were allocated to three groups (n = 20 in each): group A (control) were given saline solution 0.5 ml; group B were given cholecystokinin 300 ng/kg; and group C were given cholecystokinin 300 ng/kg and octreotide 2.5 micrograms/kg. All substances were injected subcutaneously twice a day until death. Four rats were killed weekly for four weeks, and the remainder at 60 days. MAIN OUTCOME MEASURES: Increase in weight of the gland as a percentage of the weight of the whole gland, and DNA synthesis measured by bromodeoxyuridine (BrdU) nuclear labelling index. RESULTS: In the cholecystokinin alone group pancreatic weight had increased significantly on days 21 and 28 (95% confidence intervals (CI) - 13.8 to 12.2 and -44.1 to 19.7, respectively) and the BrdU index had increased significantly at 21 (0.56 to 0.80), 28 (0.26 to 1.3), and 60 (0.09 to 0.51) days compared with the control group. In the group given both cholecystokinin and octreotide the weight was significantly lower than in the cholecystokinin alone group at 21 and 28 days (95% CI - 1.02 to 66.7 and 3.5 to 34.7, respectively) and the BrdU index was significantly lower at 28 days (0.40 to 1.19). CONCLUSIONS: Octreotide seems to reduce the pancreatic regeneration induced by cholecystokinin in rats after 70% distal resection. To our knowledge this has not previously been shown, and the mechanism must be elucidated further. PMID- 8695739 TI - Prognostic model for patients treated for colorectal adenomas with regard to development of recurrent adenomas and carcinoma. AB - OBJECTIVE: To quantify the risk of developing recurrent adenomas or colorectal cancer for patients who had already had colorectal adenomas removed. DESIGN: Retrospective study. SETTING: University hospital, Denmark. SUBJECTS: 479 patients who had colorectal adenomas removed between 1958-80. INTERVENTIONS: All patients were followed up by rectoscopy and double contrast barium enema. The survival data were analysed by Cox's proportional hazards model. MAIN OUTCOME MEASURES: Variables of significant prognostic importance for recurrence of adenomas and the development of cancer were identified. Results. For the long term risk of recurrence of the adenoma (more than 1.5 years after removal of the first adenoma), two variables were of prognostic significance: The occurrence of synchronous adenomas or recurrent adenomas, and the sex of the patient. The model for development of colorectal cancer identified two variables of prognostic significance: the grade of dysplasia and the size of the first adenoma. CONCLUSION: We suggest that these variables can be used in the management of patients with adenomas, particularly in developing individual follow-up regimens. PMID- 8695740 TI - Recurrent pilonidal sinus after excision with closed or open treatment: final result of a randomised trial. AB - OBJECTIVE: To find out the recurrence rate of chronic pilonidal sinus after excision and primary suture compared with open excision and healing by second intention. DESIGN: Randomised trial. SETTING: Teaching hospital, Norway. SUBJECTS: 120 Patients treated between 1987 and 1989. INTERVENTIONS: 60 Patients were treated by excision and primary suture and 60 by open excision. The median follow-up period was 4.2 years. RESULTS: Recurrent pilonidal sinus was seen in six patients (10%) after primary suture compared with three patients (5%) after open treatment (p = 0.49); 57 (95%) and 55 (92%), respectively, were satisfied with the outcome of treatment at follow-up (p = 0.72). CONCLUSION: Excision and primary suture compares favourably with open excision and healing by second intention in the treatment of chronic pilonidal sinus. PMID- 8695741 TI - Thoracic duct drainage. PMID- 8695742 TI - Cholesterol embolisation causing chronic acalculous cholecystitis. PMID- 8695743 TI - Mesh infection after laparoscopic herniorrhaphy. PMID- 8695744 TI - Iliopsoas bursa: a rare type of swelling in the groin. PMID- 8695745 TI - Squamous cell carcinomas of the anus and infection with human papillomavirus in patients with AIDS. PMID- 8695746 TI - Effects of calcitonin gene-related peptide and interleukin 6 on myoblast differentiation. AB - Effects of calcitonin gene-related peptide (CGRP) and interleukin 6 (IL-6) on muscle cell differentiation were studied using cultured rat myoblasts (L6 cells). Cell morphology and the amounts of the messenger RNAs (mRNAs) of myogenin and Myf 5, DNA content, creatine kinase (CK) activity, and myoglobin (Mb) content in the cultured cells were examined serially over 10 days of culture. In the presence of CGRP or IL-6, the mRNAs of myogenin and Myf-5 were expressed earlier and at a higher concentration in the treated cells than in the control cells. The ratios of CK activity to DNA content (CK/DNA) and of Mb content to DNA content (Mb/DNA) on day 10 of culture also were greater than in the control cells. Furthermore, the mRNAs of myogenin and Myf-5 in cultured cells incubated with both CGRP and IL 6 increased more rapidly than in cells cultured with CGRP or IL-6 alone, and the ratios of CK/DNA and Mb/DNA on day 10 were more than twice those in the presence of CGRP or IL-6. These findings indicate that both CGRP and IL-6 facilitate the differentiation of myoblasts and may have an additive effect. PMID- 8695747 TI - Expression of proliferation-associated nuclear autoantigens, p330d/CENP-F and PCNA, in differentiation and in drug-induced growth inhibition using two parameter flow cytometry. AB - p330d/CENP-F is a recently described nuclear autoantigen that was detected in PHA stimulated but not in resting peripheral lymphocytes. This protein accumulates in the nucleus during S-phase and reaches maximum levels during the G2 and M phases of the cell cycles. We compared the expression of p330d/CENP-F and proliferating cell nuclear antigen (PCNA) during the induction of terminal myeloid differentiation of HL-60 tumour cells. HL-60 cells were induced to differentiate with retinoic acid (RA), dimethyl sulfoxide (DMSO), and 3-nitrobenzothiazolo [3,2 ]quinolinium (NBQ), and collected at different intervals. Control and treated cells were analyzed by two-parameter flow cytometry using propidium iodide and antibodies to p330d/CENP-F and PCNA. The percentage of p330d/CENP-F and PCNA positive cells was found to be proportional to the percentage of proliferating cells. After two cell cycles (65 h), the percentage of p330d/CENP-F and PCNA positive cells was reduced proportionately to the number of cells that had differentiated. Reduction in the expression of both antigens was completed after 120 h when 80% to 85% of the cells were arrested in G1 and displayed the mature phenotype. The expression of p330d/CENP-F and PCNA was also assessed in the growth inhibition of HT-29 cells induced by various concentrations of camptothecin (CPT), etoposide (VP-16), and aphidicolin (APH). There was a dose dependent displacement of cells to late S-phase by CPT while VP-16 induced cells to accumulate in G2+M, and as expected these effects caused a strong increase in the cellular levels of both antigens. The arrest of cells in G1 by APH led to a significant decrease in their expression. The dramatic reduction in p330d/CENP-F levels during differentiation, and the correlation of its expression with the cell cycle effects of the cytotoxic drugs are consistent with the behaviour expected for a proliferation marker. PMID- 8695749 TI - Reducing punitive damages punishes only victims. PMID- 8695748 TI - Protecting yourself from breach of contract. PMID- 8695750 TI - Gerontological nursing standards. PMID- 8695751 TI - Workers' compensation: a productive field for LNCs. PMID- 8695752 TI - Postnatal growth of the heart and its blood vessels. AB - Although rapid growth of the heart during early postnatal development ceases with maturation of the organism, the potential for cardiomyocyte growth is not lost and may be observed even in senescent hearts. Rapid developmental heart growth is accompanied by a proportional growth of capillaries but not always of larger vessels, and thus coronary vascular resistance gradually increases. Growth of adult hearts can be enhanced by thyroid hormones, catecholamines and the renin angiotensin system hormones, but these do not always stimulate growth of coronary vessels. Likewise, chronic exposure to hypoxia leads to growth, mainly of the right ventricle and its vessels but without vascular growth elsewhere in the heart. On the other hand, ischaemia is a potent stimulus for the release of various growth factors involved in the development of collateral circulation. Heart hypertrophy develops in response to training, pressure or volume overload. Training usually leads to growth of larger coronary vessels but little growth of capillaries, except in young animals. However, growth of the capillary bed, but not the resistance vasculature capacity, can be induced by either increased coronary blood flow, bradycardia (electrically or pharmacologically induced) or increased inotropism, all of which are involved in the training stimulus. Thus, what actually promotes growth of larger vessels as opposed to capillaries in training is unclear. Pressure overload hypertrophy is mediated by both the renin angiotensin system and the response of cardiomyocytes to stretch; both lead to activation of early oncogenes (c-fos, c-jun, c-myc) and angiotensin II activates several protein kinases involved in cell growth. In this condition, growth of larger vessels is inadequate, although some capillary growth may occur. Volume overload leads to cardiomyocyte hypertrophy and hyperplasia and some increase in vascular supply. Deficits in capillary supply in pressure or volume overload hypertrophy can be reversed by chronic administration of ACE inhibitors, dipyridamole, the bradycardic drug alinidine or pacing-induced bradycardia respectively, but in neither case is training effective. Mechanical and humoral factors are involved in growth of cardiomyocytes and vessels. For cardiomyocytes, stretch is most important, activating oncogenes, protein kinases and possibly the inositol phosphate pathway, but not ion channels, with regulation by the balance of angiotensin II, TGF-beta 1 and IGF-1, but not FGFs. For vessels, growth is stimulated by stretch and shear stress, possibly with involvement of VEGF. Increased shear stress disrupts the glycocalyx on the luminal side of vessels and releases plasminogen activator and metalloproteinases which disrupt the basement membrane and enable endothelial cell migration and proliferation. It also causes rearrangement of the endothelial cytoskeleton and transmission of mechanical signals to the abluminal side disturbing extracellular matrix and causing distortion of capillary basement membrane. Stretch acting from the abluminal side has a similar effect resulting also in basement membrane disruption and endothelial cell proliferation. PMID- 8695753 TI - Serotonin stimulates protein tyrosyl phosphorylation and vascular contraction via tyrosine kinase. AB - Serotonin (5-HT, 5-hydroxytryptamine) is a mitogen in vascular smooth muscle and vascular reactivity to 5-HT is significantly enhanced in hypertension and atherosclerosis. We have tested the hypothesis that tyrosine kinases, enzymes important for mitogenesis, may play a role in 5-HT-induced vascular smooth muscle contractility. Helical strips of rat carotid artery and aorta denuded of endothelium were mounted in tissue baths for measurement of contractile force. The tyrosine kinase inhibitor genistein (5 x 10(-6) M) decreased the potency of 5 HT approximately 4-fold and reduced maximal contraction to 5-HT in carotid arterial strips denuded of endothelium (58% control). Genistein's inactive congener daidzein (5 x 10(-6) M) did not reduce maximal contraction to 5-HT in carotid arteries but did shift the 5-HT concentration response curve 3-fold to the right. Tyrphostin 23 (5 x 10(-5) M), another tyrosine kinase inhibitor, decreased the potency of 5-HT 4-fold and reduced the maximal contraction to 5-HT in the carotid artery (10% control). Contractions induced by phorbol-12,13 dibutyrate (10(-9) to 10(-5) M) were not reduced or shifted by either tyrosine kinase inhibitor, indicating that phorbolester-sensitive protein kinase C isoforms were not affected. KCl-induced contraction was shifted 2-fold and the maximum significantly inhibited by tyrphostin 23 (38.6% control) but not genistein or daidzein, indicating that tyrphostin 23 but not genistein may inhibit voltage-gated calcium channels to reduce contractility. Western blot analysis using antiphosphotyrosine antibody confirmed that 5-HT produced a time- and concentration-dependent increase in the phosphotyrosine immunoreactivity of a 42-kD protein in cultured aortic smooth muscle cells. Lysate immunoprecipitation with an antimitogen-activated-protein (MAP)-kinase antibody indicated that the 42 kD protein was most likely a MAP kinase. 5-HT (10(-5) M) stimulated contraction and increased antiphosphotyrosine immunoreactivity in whole aorta mounted in tissue baths. Importantly, aortic contraction to 5-HT was shifted (5-fold rightward) and reduced (69% control) by genistein but not daidzein. These findings demonstrate that (1) tyrosine kinase activation may partially mediate contractility to 5-HT in arterial smooth muscle, (2) tyrphostin 23 is somewhat nonselective and (3) 5-HT stimulates tyrosine kinase as documented by increased tyrosyl phosphorylation of proteins in cultured aortic smooth muscle cells and aortic tissue in active contraction of 5-HT. These findings have significant implications not only in understanding a novel pathway of 5-HT signal transduction but also in vascular diseases in which growth and/or contractility to 5-HT is increased (e.g. hypertension, atherosclerosis). PMID- 8695754 TI - Photorelaxation is not attenuated by inhibition of the nitric oxide-cGMP pathway. AB - Photorelaxation of arteries by ultraviolet (UV) light is hypothesized to result from nitric oxide (NO) released from photoactivable stores. Recently, a study reported enhanced photorelaxation of aortic tissue from rats administered the NO synthase (NOS) inhibitor N omega-nitro-L-arginine (L-NNA). Presumably, the potentiated photorelaxation was due to NO generated from UV-light-induced decomposition of the NO2 moiety of L-NNA. However, we hypothesized that photorelaxation is: (1) not the result of NO synthesis and subsequent activation of guanylate cyclase and (2) not due to hyperpolarization induced by NO or any other factor. Endothelium-denuded rat aortic rings were suspended in isolated baths for isometric force measurement. Rings were exposed to UV light (366 nm) before addition of phenylephrine or KCI, and then at each agonist concentration during a cumulative concentration response curve. NOS inhibition by L-NNA and L thiocitrulline, which lacks an NO2 group, enhanced photorelaxation of basal myogenic tone and contraction to phenylephrine (EC70). Furthermore, relaxation of a maximum phenylephrine-induced contraction to the NO donor S-nitroso-N-acetyl D,L-penicillamine during UV light exposure was not altered by incubation of rings with L-NNA or tissues from animals fed L-NNA. These data demonstrate that NO is not produced endogenously or from the breakdown of L-NNA to result in photo relaxation. Methylene blue (MB) did not alter photorelaxation, suggesting that cGMP is not essential to the response. MB and L-NNA together potentiated photorelaxation of basal myogenic tone and phenylephrine-induced contraction. Photorelaxation of KCl-induced contraction was unaltered, indicating that hyperpolarization does not contribute to the relaxation. Photorelaxation of basal myogenic tone and KCl-induced contraction excludes the possibility that UV light is interfering with agonist-receptor binding. Collectively, these results refute the hypotheses that photorelaxation results from activation of the NO-cGMP pathway, release of a hyperpolarization factor, or inhibition of drug-receptor interaction. Interestingly, photorelaxation may be inhibited by NO-cGMP pathway activation, uncovering a novel effect of this messenger system on vascular reactivity. PMID- 8695755 TI - Effectiveness of hirulog in reducing restenosis after balloon angioplasty of atherosclerotic femoral arteries in rabbits. AB - BACKGROUND: Thrombin may play an important role in restenosis after balloon angioplasty (BA). Angiographic and pathologic restenosis have been shown to be reduced after BA in an atherosclerotic rabbit model using recombinant desulfatohirudin, a selective and direct thrombin inhibitor. We hypothesized that potent and specific thrombin inhibition with the synthetic peptide hirulog given intravenously at the time of angioplasty would reduce restenosis in rabbits, confirming a specific role of thrombin in restenosis. METHODS AND RESULTS: Focal femoral atherosclerosis was induced in 27 rabbits by air desiccation endothelial injury followed by a 2% cholesterol diet for 1 month. Rabbits received either heparin (150 units/kg bolus, n = 14) or hirulog (5 mg/kg bolus followed by 5 mg/kg/h for 2 h, n = 13) at the time of BA (2.5-mm balloon with three 60-second, 10-atm inflations 60 s apart). Angiograms performed before and after BA and before sacrifice were analyzed quantitatively. Rabbits were sacrificed 28 days after BA for quantitative histopathologic analysis. Minimum luminal diameter (mm) did not differ between treatment groups before (1.1 +/- 0.2 vs. 1.2 +/- 0.1 mm) or after (1.5 +/- 0.2 vs. 1.6 +/- 0.1) BA in arteries from heparin-versus hirulog treated rabbits, respectively. At 28 days, however, minimum luminal diameter was significantly less (1.0 +/- 0.4 vs. 1.5 +/- 0.2, p = 0.0001) and percent stenosis was greater (0.46 +/- 0.25 vs. 0.22 +/- 0.08, p = 0.0002) in arteries from heparin- versus hirulog-treated rabbits, respectively. Similarly, quantitative histopathology showed less cross-sectional area narrowing by plaque in the hirulog group (56 +/- 24 vs. 42 +/- 21%, p = 0.04). CONCLUSION: A 2-hour infusion of hirulog at the time of angioplasty improved late angiographic luminal dimensions and reduced cross-sectional area narrowing by plaque in rabbits compared with heparin controls. Together with previous studies, this confirms a specific role for thrombin in restenosis after angioplasty. PMID- 8695756 TI - Does aldosterone-induced cardiac fibrosis involve direct effects on cardiac fibroblasts? AB - To investigate the hypothesis that aldosterone plays a role in the development of fibrosis, cultured fibroblasts from adult rat heart have been examined for their expression of aldosterone receptors and the effects of aldosterone on collagen synthesis. Binding assays with both 3H-aldosterone and 3H-RU26752 in intact cardiac fibroblasts and cytosolic extracts from cardiac fibroblasts failed to reveal expression of aldosterone receptors. However, using the method of reverse transcription-polymerase chain reaction, we could demonstrate the expression of mRNA for the mineralocorticoid receptor in both cardiac fibroblasts and neonatal rat cardiomyocytes. Functional studies investigating the effect of aldosterone on collagen synthesis (3H-proline incorporation into collagenous protein) revealed that aldosterone does not stimulate collagen synthesis in cardiac fibroblasts at concentrations (10(-8) to 10(-9) M) observed in primary or secondary hyperaldosteronism. At higher concentrations (10(-6) to 10(-7) M) aldosterone inhibited collagen synthesis. Expression of collagen genes I alpha 1, III alpha 1, IV alpha 1 and of the collagenase gene was not affected by aldosterone. The collagen gene VI alpha 2 was also found to be expressed in cultured cardiac fibroblasts, and its expression was also independent of aldosterone. The data indicate that fibrosis is not due to a direct effect of aldosterone on fibroblast collagen synthesis. PMID- 8695757 TI - Induction of cell-rich and lipid-rich plaques in a transfilter coculture system with human vascular cells. AB - Cell-to-cell interactions are mainly involved in the control of the proliferation, migration, differentiation and function of different cell types in a wide range of tissues. In the arterial vessel wall, human arterial endothelial cells (haEC) and smooth muscle cells (haSMC) coexist in close contact with each other. In atherogenesis, haSMC can migrate from the media to the subintimal space to form fibromuscular and atheromatous plaques. In the present study, a transfilter coculture system is described, in which the interface between haSMC and confluent or proliferative haEC can be studied in detail. Cells were cocultured on the opposite sides of a porous filter which separates both cell types like the internal elastic lamina in vivo. In cocultures containing proliferative haEC, haSMC growth was significantly stimulated (33.4 +/- 5.7 cells/section, p < 0.05) compared to haSMC monocultures (22.9 +/- 2.5 cells/section) and cocultures containing confluent haEC (15.6 +/- 2.9 cells/section). If confluent haEC were injured mechanically, haSMC growth increased highly significantly (71.3 +/- 16.8 cells/section, p < 0.001). Thus, cell-rich proliferates containing 5-7 layers of haSMC embedded in extracellular matrix were formed after 14 days. On the other hand, after haSMC migration to the endothelial side had occurred, the addition of LDL and monocytes to cocultures with arterial media explants and haEC resulted in the formation of lipid-rich, low-cellular structures. After 28 days, characteristic in vitro plaque growth was induced; the plaque contained a lipid core with predominantly necrotic cells, extracellular lipid accumulations, atypically shaped lipid-loaded haSMC and macrophages, similar to in vivo foam cells, as well as an increased amount of extracellular matrix (collagen I, III and IV). These areas were surrounded by typical fibromuscular caps consisting of smooth muscle alpha-actin-positive haSMC. Finally, the formation of capillaries by haEC could also be observed within these structures. PMID- 8695759 TI - IX International Vascular Biology Meeting. Seattle, Washington, USA, September 4 8, 1996. Abstracts. PMID- 8695758 TI - Methylene blue restores vasodilation to bradykinin after inhibition of nitric oxide production in the isolated dog lung. AB - Methylene blue (MB) is a widely used putative inhibitor of nitric oxide (NO) dependent responses, particularly in cell culture and vascular ring studies. MB is postulated to diminish vasodilation to NO either by preventing activation of guanylate cyclase by NO or by oxidizing NO formed by NO synthase. In the present study we examined whether MB inhibited vasodilation to bradykinin (BK) in the cyclooxygenase-inhibited, isolated canine lung lobe perfused with blood at constant flow. One group of lobes (n = 5) was challenged with BK at baseline vascular tone, after tone was doubled by infusion of serotonin (5-HT), and again after MB treatment. Bradykinin challenge failed to evoke a depressor response at baseline vascular tone but induced marked vasodilation after vascular tone was increased by 5-HT. Subsequent treatment with MB, however, failed to significantly diminish vasodilation to BK (p > 0.05). A second group of lobes (n = 4) was challenged with BK after cyclooxygenase inhibition and the doubling of vascular tone with serotonin infusion. The dose-dependent vasodilation to BK was diminished (p < 0.01) after treatment with 1.8 mM N omega-nitro-L-arginine (L NA), a potent inhibitor of nitric oxide synthase. However, subsequent treatment with MB restored the vasodilator response to bradykinin to pre-L-NA values (p < 0.01). While our results suggest that vasodilation to bradykinin is mediated in part by NO formation, MB treatment does not appear to alter BK-induced vasodilation, and even enhanced vasodilation to bradykinin after L-NA. MB appears to have some nonspecific effects on vascular tone and reactivity that are unrelated to NO formation. PMID- 8695760 TI - Mass spectrometry, high performance liquid chromatography, and brain peptides. AB - This paper is a personal recollection of some of the events and research that surrounded the amino acid sequence determination of the hypothalamic releasing factor, TRF (now known as TRH), by mass spectrometry (MS), and the development of reverse phase high performance liquid chromatography (RP-HPLC) MS and tandem MS (MS/MS) methods for the qualitative and quantitative analysis of native opioid neuropeptides in human pituitary tissue extracts. PMID- 8695761 TI - Peptide chemistry: development of high performance liquid chromatography and capillary zone electrophoresis. AB - The development of relatively non-compressible supporting media of small particle size as well as pumps that deliver constant flow rates at high pressures has enabled investigators to perform rapid, high resolution liquid chromatography for more than two decades. Studies initiated in this laboratory in 1975, evaluating the compatibility of unprotected peptides with commercially available chromatographic supports and development of solvent systems ultimately led to separations not previously observed with both synthetic peptides and native peptides from tissue extracts. It was rapidly realized however, that recovery of certain molecules could be problematic. To meet the challenges presented by the isolation of natural hormones (such as corticotropin releasing factor and growth hormone releasing hormone) and proteins (such as inhibin and activin) and the need for large quantities of highly purified peptides for clinical investigations, our group invested heavily in identifying new supports (high carbon loading and 300 A pore sizes) and solvent systems (triethylammonium phosphate and trifluoroacetic acid) compatible with reverse phase, size exclusion and ion exchange chromatographies from a practical and economical perspective. More recently, we have contributed to the identification of unusual buffer systems (inclusive of organic modifiers) compatible with capillary zone electrophoresis that will both modulate the capillaries' selectivity, increase resolution and serve as an orthogonal approach to determining peptide purity. From a pragmatic point of view, in this paper we highlight the original and timely contributions (technical and strategical) of this laboratory in the field of analytical and preparative high performance liquid chromatography and capillary zone electrophoresis of synthetic and native biologically active peptides and proteins over the past twenty years. PMID- 8695762 TI - Microsatellite instability and DNA mismatch repair in human cancer. AB - A form of genome instability in human tumours is associated with defects in a DNA mismatch repair pathway that normally corrects replication errors. The instability is observed as highly polymorphic mono- and dinucleotide microsatellites. Alterations in microsatellite length are due to accumulated frameshift mutations that arise because of uncorrected misalignments between template and daughter DNA strands during replication. Loss of mismatch repair is associated with some familial cancers, occurs at an early stage in tumour development and confers a general mutator phenotype. The latter may accelerate the accumulation of mutations in critical target genes during progression to malignancy. Biochemical analysis is providing insights into the mechanisms of mismatch repair. PMID- 8695763 TI - Clinical applications of genetic rearrangements in cancer. AB - Genetic aberrations in cancer cells can be of immediate relevance to the patient. They enable definitive diagnoses to be reached and sub-classification of certain tumour types into good or bad prognostic groups, information which can influence therapy. These aberrations can also be used as tumour markers for monitoring the response to therapy. Major technological advances in the last few years have facilitated these applications in the routine clinical setting and encouraged searches for new genetic markers. As the genes directly affected are identified and their roles in tumorigenesis elucidated, they are likely to provide novel targets for therapeutic intervention. PMID- 8695764 TI - Gene fusions encoding chimaeric transcription factors in solid tumours. AB - Analysis of chromosomal alterations in human malignancies has revealed recurring genetic changes that are often closely associated with specific subtypes of tumours. Among solid tumours, cytogenetic analysis of a group of primitive sarcomas occurring principally in children and young adults has identified specific non-random chromosomal translocations associated with these malignancies. A number of the translocation breakpoints have now been cloned, revealing the in frame fusion of genes located at each partner breakpoint. The common theme is the expression by these hybrid genes of chimaeric proteins containing functional domains from each fusion partner. These domains confer transcriptional activation or repression, DNA binding specificity, or other novel protein-protein interactions. The net result appears to be the expression of chimaeric oncoproteins that function in transformation by dysregulating gene transcription. PMID- 8695765 TI - Mutations of the BRCA1 gene in human cancer. AB - BRCA1 is a putative tumour suppressor gene located on chromosome 17q21. It spans 100kb of genomic DNA and encodes a protein of 200kD consisting of 1863 amino acids. Sixty-three distinct germline mutations of BRCA1 have now been identified in more than 100 patients with breast and/or ovarian cancer. These mutations are distributed across the entire coding region of the BRCA1 gene, and the majority (87%) are predicted to result in truncated proteins or loss of a BRCA1 transcript. No somatic mutations of the BRCA1 gene have been identified in sporadic breast cancers, though five mutations have been found in sporadic ovarian tumours. This suggests that mutations in the BRCA1 gene may play a significant role in the tumorigenesis of familial breast cancer but not of sporadic breast cancer. PMID- 8695766 TI - Genomic imprinting in tumours. AB - In recent years it has become apparent that genomic imprinting may have a role in the development of certain types of cancer. Preferential loss or retention of one parental genotype in chromosomal regions known to be subject to imprinting have been found in specific cancers. This finding raises the possibility that an epigenetic mechanism such as imprinting may alter gene expression and lead to inactivation of tumour suppressor genes or activation or dominant oncogenes. Rearrangements within imprinted chromosomal domains have the potential to influence the stage- and tissue-specific expression of both tumour suppressor and growth promoting genes that cluster to such regions, thus influencing the initiation and progression of cancer. PMID- 8695767 TI - Genetic predisposition to cancer--issues to consider. AB - The importance of molecular genetic events in the development of inherited cancers has evolved from the clinical study, molecular and genetic epidemiology and molecular biology of affected families. As our understanding of the mechanisms of carcinogenesis improves, numerous concerns revolving around the potential impact of laboratory-based predictive genetic testing arise. Through mult-disciplinary approaches supported in part by the Human Genome Project and other research efforts, information is being gathered that may lay the foundation for legislative, scientific and clinical guidelines and recommendations throughout the international community. PMID- 8695768 TI - [77th German Congress of Radiology. Wiesbaden, 15-18 May 1996. Abstracts]. PMID- 8695769 TI - Hypertonic saline challenge in an adult epidemiological survey. AB - Bronchial provocation tests using pharmacological agents such as methacholine or histamine are used in epidemiological studies to identify asthma despite recognition of limitations in specificity, positive predictive value and availability of reagents. Hypertonic saline (4.5%) bronchial challenge (HSBC), although less sensitive than pharmacological challenges, is reportedly highly specific in diagnosing current asthma. Added advantages are that reagents are cheap, stable and recognized by participants. Thus, HSBC may offer benefits over pharmacological tests in epidemiological surveys. This paper reports on the second field survey using the test, a study of 99 adults from the timber industry in Western Australia. The test is described and critically appraised as a practical epidemiological tool for assessing asthma prevalence. At a cutoff point of 20% FEV, fall, HSBC was positive in 8% of subjects, appeared specific for asthma, was safe, well-accepted and easy to use in the field. PMID- 8695770 TI - Physician-based case-control study of non-melanoma skin cancer in Baytown, Texas. AB - A physician-based case-control study of non-melanoma skin cancer was conducted to test the hypothesis that employment in the petroleum industry increased the risk of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), or both (BCC+SCC). Other potential risk factors were also investigated. There were 174 cases of BCC, 59 cases of SCC, 72 cases of both and 229 controls completing a self-administered questionnaire. The most important risk factors common to all skin cancer categories were a family history of skin cancer and time spent outdoors. Employment in the petroleum industry showed a slight association with BCC+SCC, but only in the multivariate model. Further study is needed to evaluate whether this association is causal, or due to chance, bias or confounding. PMID- 8695771 TI - Feasibility study of respiratory questionnaire and peak flow recordings in autobody shop workers exposed to isocyanate-containing spray paint: observations and limitations. AB - Diisocyanates, highly reactive monomers which cross-link polyurethane, are the most widely recognized causes of occupational asthma. Many exposed workers are end-users, including autobody spray painters who form a large population at risk. Neither the factors which determine incidence rate nor strategies for control have been adequately studied in this setting. We have conducted a cross-sectional survey of 23 (about one in five) autobody shops in the New Haven area to determine the feasibility of clinical epidemiological studies in this population. Among 102 workers, there was a high rate of airway symptoms consistent with occupational asthma (19.6%). Symptoms were most prevalent among those with the greatest opportunity for exposure (dedicated spray painters) and least among office workers; part-time painters had intermediate rates. Atopy was not associated with risk while smoking seemed to correlate with symptoms. Regular use of air-supplied respirators appeared to be associated with lower risk among workers who painted part- or full-time. We were unable to validate the questionnaire responses with peak expiratory flow record data attempted on a 1/3 sample of the workers. Despite intensive training and effort, subject compliance was limited. Among those who provided adequate data (24 of 38), only two demonstrated unequivocal evidence of labile airways; two others demonstrated lesser changes consistent with an occupational effect on flow rates. There was no clear association between these findings and either questionnaire responses or exposure classification. Overall, the survey suggests that there is a high prevalence of airway symptoms among workers in autobody shops, at least in part due to work-related asthma. However, there is need for both methodological and substantive research in this setting to document rates of occupational asthma and to develop a scientific basis for its effective control. PMID- 8695772 TI - Occupational allergic contact dermatitis in Lodz: 1990-1994. AB - Occupational skin diseases in Poland constitute about 9% of all occupational diseases. Occupational allergic contact dermatitis (OACD) account for 95% of diagnosed occupational skin diseases. During 1990-1994 we have diagnosed 332 OACD cases (159 men, 173 women). OACD was most frequent in health care workers (25.6%), the metal-working and machine-building industry (19.6%), and the house building industry (13.9%). Occupational allergy was most frequently due to exposure to chromates (38.8%), cobalt (38.8%), nickel (30.7%), and also formaldehyde (18.1%) and epoxy resins (9.1%). When comparing our present results with those obtained in 1972-1987, we note an increased overall number of OACD cases (the number of diagnosed OACD cases at that time was 34 per annum, compared with 66 cases per annum at present) and increased OACD cases in women. There was an increase of OACD among health care workers. Recently, there has been an increase in the number of patients with allergies to nickel and formaldehyde, and a decrease of the patients hypersensitive to turpentine. PMID- 8695773 TI - Minor psychiatric morbidity, its prevalence and outcome in a cohort of civil servants--a seven-year follow-up study. AB - During the years 1979-1986, a cohort of direct entrant executive officers in the Civil Service were followed up to examine the prevalence and outcome of minor psychiatric morbidity in an occupational setting. All studies using epidemiological standardized research methods agree that prevalence rates are high in occupational settings. As in primary care settings, half of the illness episodes followed a chronic course, which emphasizes the need for early detection and prompt management of these conditions, and for evaluative studies of intervention strategies. PMID- 8695774 TI - AIDS programmes at the workplace: a scoresheet for assessing the quality of services. AB - Little data is available on the extent or comprehensiveness of AIDS prevention activities at South African workplaces. A cross-sectional postal survey was performed of all members of the local occupational health nursing association in the area of greater Cape Town in 1994 to assess the quality of such programmes. Use was made of an index to score services based on their comprehensiveness, using criteria based on recommendations previously identified in the South Africa literature on AIDS control. The presence of a workplace policy on AIDS was the strongest predictor of high quality AIDS prevention activities. Substantial numbers of companies reported sending staff for HIV-related training, and the presence of training was non-significantly associated with higher quality services with regard to HIV prevention. Treatment of sexually-transmitted diseases (STDs) was reported in slightly over half of the sample. Given the central importance of STD treatment for the prevention and control of AIDS, improvements in STD management at the workplace may significantly assist attempts at the public health control of the HIV epidemic. In addition, worker involvement in the planning, management and implementation of AIDS prevention activities is also limited at present and needs attention. Recommendations for the use of a scoring system to promote evaluation of AIDS programmes in the workplace are made. PMID- 8695775 TI - A study of the impact of occupational and domestic factors on insomnia among industrial workers of a manufacturing company in Japan. AB - Insomnia is one of the most common health problems and has recently been re termed 'Disorders of initiating and Maintaining Sleep', or DIMS. The main purpose of the present study was to investigate the relationship between daily psychosocial stressors, to which workers are exposed in occupational and/or private life, and insomnia among male industrial workers in a medium-sized company located in Nagasaki City, Japan. All of the workers in the company (n = 368, male = 319) were asked to answer six sleep related questions and 24 questions about working and private conditions. Two hundred and seventy-one (85.0%) of them completed the questionnaire (average age was 40.9 years old). Twenty seven point seven per cent of the subjects complained of insomnia in the last month prior to the survey and the prevalence was in general accord with previous surveys. On the other hand, the proportion of hypnotic use (1.1%), especially in insomniac group (2.7%) was lower than previous reports. The results of multiple logistic regression analysis demonstrated that four psychosocial factors were significantly associated with insomnia: i.e. VDT work overload (odds ratio [OR] 5.058; 95% confidence intervals [95% CI] 2.381-10.745), limited space of bedroom (OR 2.612; 95% CI 1.283-5.683), over-involvement in job (OR 2.78; 95% CI 1.188-6.540), frequent alcohol beverages consumption (OR 2.595; CI 1.77 5.719). PMID- 8695776 TI - Blood pressure variability at annual periodic health examination for employees and cardiovascular risk factors. AB - The employees with hypertension at the annual periodic health examination (HE) for employees in Japan usually receive a re-examination of blood pressure (BP) on another day and are often found to be normotensive. In this study, we analyzed data from the HE at the workplace to determine whether or not such employees should receive medical care. Two groups of subjects were selected. One group (group 1) was composed of 50 subjects with normotension at the HE (controls). Another group (group 2) was composed of 33 subjects with hypertension at the annual HE but with normotension in re-examinations. Cardiovascular risk factors were significantly higher in group 2 than in group 1: mean values of the body mass index (group 1, 22 +/- 2.7 vs. group 2, 24.3 +/- 3.1 kg/m2, p < 0.01), total cholesterol (group 1, 197 +/- 36 vs. group 2, 222 +/- 42 mg/dl, p < 0.01), and low density lipoprotein (group 1, 118 +/ 32 vs. group 2, 137 +/- 38 mg/dl, p < 0.05). The proportion of the employees with high-normal BP in group 2 (42.5%) was significantly higher than that in group 1 (28.0%) (p < 0.01). These indicate that the employees with hypertension at the annual HE but with normotension in the re examination require further medical attention and should receive medical supervision. The occupational physician should supervise these employees. PMID- 8695777 TI - Post-splenectomy sepsis--the role of occupational health. AB - Persons who have had their spleens removed (asplenics) have a high risk of infection. The risks from infection are life-long and the illness can be a quick, overwhelming, septicaemia, that can lead to death within 48 hours, without appropriate treatment. Many persons who have had elective splenectomy, especially before 1977, may not have had prophylactic vaccinations, antibiotics or advice. This paper describes the risks of serious infection, the prophylaxis available and the role of the occupational health department in protecting asplenic employees. PMID- 8695778 TI - Superficial copper staining of the teeth in a brass foundry worker. AB - A 21 year-old man developed green surface staining of the cervical margins of his teeth 10 months after starting work in a brass foundry. During this time he was exposed intermittently to brass fumes which contained approximately 75% copper and 2-5% lead. The staining of his teeth was attributed to the absence of respiratory protection in the knock-out process and was accompanied by a rising blood lead concentration. Staining of the teeth by copper was described early this century but seems to have been neglected in the recent literature and texts on occupational medicine. We suggest that in brass foundry workers it is a warning of failure to control fume or dust exposure with the attendant risk of lead toxicity. PMID- 8695779 TI - An outbreak of pruritic skin lesions in a group of laboratory workers--a case report. AB - In May 1993, an outbreak of pruritic skin lesions occurred among a group of employees located in four laboratories in the basement of an office building. Medical interviews with the affected workers were performed and an industrial hygiene survey of the site was conducted. Workers commonly reported a pricking sensation on exposed skin. Four of the workers had small (< 5mm) erythematous papules on their forearms. Just prior to the outbreak, the installation of fibrous glass insulation had commenced in the mechanical rooms which provided air to the basement of the building. Because of the nature of the symptoms and the temporal relationship with the nearby insulation work, direct skin contact with fibrous glass fibres was thought to be the cause of the outbreak. The poorly maintained air handling unit supplying air to the laboratories probably contributed to this outbreak by inefficient filtering of the circulating air. PMID- 8695780 TI - Potential problems in peak expiratory flow data used to diagnose occupational asthma. PMID- 8695781 TI - Walkfree. PMID- 8695782 TI - A systematic approach to health surveillance in the workplace. PMID- 8695783 TI - Innovations in undergraduate occupational medicine teaching. PMID- 8695784 TI - Solvents degreasing and the Montreal protocol. PMID- 8695785 TI - Molecular thanatopsis: a discourse on the BCL2 family and cell death. PMID- 8695786 TI - A model of myelofibrosis and osteosclerosis in mice induced by overexpressing thrombopoietin (mpl ligand): reversal of disease by bone marrow transplantation. AB - We have previously shown that mice induced to overexpress thrombopoietin (TPO) by retroviral-mediated gene transfer into bone marrow (BM) cells develop myelofibrosis and osteosclerosis. It was speculated that these effects were secondary to TPO, resulting from high levels of megakaryocytes and platelets. Also, it was proposed that these mice represent a model for myelofibrosis and osteosclerosis. In this report, we show that levels of both transforming growth factor-beta 1 and platelet-derived growth factor are increased twofold to fivefold in the platelet-poor plasma of TPO overexpressing mice compared with control mice. These data suggest that the increased megakaryocytes produce elevated levels of these cytokines that lead to the pathogenesis of disease. Further, we retransplanted TPO overexpressing mice, at 40 to 42 weeks after primary transplantation, with normal BM cells. After the secondary transplantation, megakaryocytes and platelets returned to normal levels and the myelofibrosis and osteosclerosis were completely corrected. These data extend our initial studies of the effects of overexpression of TPO and show the potential use of this model to explore the underlying cause of myelofibrosis and osteosclerosis and potential treatments for these diseases. PMID- 8695787 TI - Presence of autoantibodies to interleukin-8 or neutrophil-activating peptide-2 in patients with heparin-associated thrombocytopenia. AB - Eighty-seven patients with heparin-associated thrombocytopenia (HAT) showed either a positive heparin platelet aggregometry test result and/or the presence of antibodies to heparin-platelet factor 4 (H-PF4) complexes by enzyme-linked immunosorbent assay (ELISA). Fifteen of these patients lacked antibodies to H PF4, and plasma from these patients was analyzed for the presence of antibodies to PF4-related chemokines, Neutrophil-activating peptide-2 (NAP-2) and interleukin-8 (IL-8). Of these 15 patients, 6 showed antibodies to IL-8 and 3 to the platelet basic protein (PBP)-derived protein, NAP-2. Antibodies to IL-8 and NAP-2 were not observed in control patients (n = 38), patients with HAT and H-PF4 autoantibodies (n = 72), patients with autoimmune diseases (n = 21), or patients with non-HAT thrombocytopenia (n = 30). Five of these nine patients with anti-IL 8 or anti-NAP-2 developed thrombosis during heparin treatment, which is not statistically different from the patients with H-PF4 antibodies. The existence of autoantibodies to IL-8 and NAP-2 in HAT patients highlights the significance of chemokines in the pathogenesis of HAT. The contribution of heparin in vitro was minimal in patients with anti-IL-8 and anti-NAP-2 antibodies, suggesting a biologic difference from the majority of patients with HAT and anti-PF4 antibodies. It may be that antibodies to IL-8 and NAP-2 have weaker affinity for heparin and that the ELISA system may not reflect in vivo heparin-chemokine complex formation. Alternatively, antichemokine autoantibodies may predate heparin exposure, and the role of heparin in initiating HAT may be to mobilize the chemokines and to target them to platelets, neutrophils, or endothelial cells. Subsequent chemokine-binding autoantibodies then lead to cell activation resulting in thrombocytopenia and thrombosis. PMID- 8695788 TI - Characterization of RAFTK, a novel focal adhesion kinase, and its integrin dependent phosphorylation and activation in megakaryocytes. AB - We have recently isolated a cDNA encoding a novel human intracellular tyrosine kinase, termed RAFTK (for a related adhesion focal tyrosine kinase). The RAFTK cDNA, which encodes a polypeptide of 1,009 amino acids, shares 65% homology to the focal adhesion kinase (FAK), including several consensus motifs. In this report, we describe the biochemical characterization and functional analysis of the RAFTK protein. Coexpression of RAFTK and FAK proteins in megakaryocytic cells and blood platelets was observed. Using a specific antibody to RAFTK and the monoclonal antibody 2A7 to FAK, FAK and RAFTK could be distinguished antigenically. RAFTK had intrinsic tyrosine kinase and autokinase activities. It was phosphorylated on tyrosine in growing cultures of COS cells transfected with the pCDNAIII/flag-RAFTK expression vector containing the RAFTK cDNA ligated with the 8 amino acid flag peptide sequence. Similar to FAK, dephosphorylation of RAFTK was observed when adherent transfected COS cells were detached. Phosphorylation was regained upon replating of these cells on the fibronectincoated dishes. Analysis of tyrosine-phosphorylated RAFTK from adherent transfected COS cells showed that the Src homology 2 (SH2) domains of the Src and Fyn protein kinases as well as the Grb2 adaptor protein were able to specifically associate with RAFTK. Tyrosine phosphorylation of endogenous RAFTK was observed upon fibronectin-induced activation of human megakaryocytic cells. Furthermore, colocalization of RAFTK protein with vinculin, a focal adhesion protein, was observed by confocal microscopy in focal adhesion-like structures in adherent CMK cells and in transfected pCDNAIII/flag-RAFTK COS cells upon fibronectin activation. These data suggest that RAFTK is a novel member of the FAK family, that it localizes to focal adhesion-like structures in CMK megakaryocytic cells, that it participates in integrinmediated signaling pathways in megakaryocytes, and that it is able to associate with the tyrosine kinases Src and Fyn as well as the adaptor protein Grb2 via SH2-phosphotyrosine interactions. PMID- 8695789 TI - Thrombopoietin supports proliferation of human primitive hematopoietic cells in synergy with steel factor and/or interleukin-3. AB - We have studied the effects of recombinant human thrombopoietin (TPO; mpl ligand) on the proliferation of human primitive hematopoietic progenitors in vitro. CD34+ cells were enriched for cell-cycle-dormant primitive progenitors by separation on the basis of expression of c-kit and CD38. In the presence of varying combinations of TPO, Steel factor (SF), and interleukin-3 (IL-3), CD34+/c kit(low)/CD38neg/low cells produced fewer colonies than CD34+/c-kit(low)/CD38high cells. However, when cultured in suspension for 7 days and replated in methylcellulose culture for measurement of colony-forming cells, the former population generated more colony-forming cells than the latter. In suspension culture of CD34+/c-kit(low)/CD38neg/low cells, TPO acted synergistically with SF and/or IL-3 in support of the production of colony-forming cells for granulocyte/macrophage colonies, erythroid colonies, and mixed colonies. Culture studies of individual CD34+/c-kit(low)/CD38neg/low cells provided the evidence for the direct nature of the effects of TPO. When combined with SF, TPO showed stronger stimulation of production of progenitors in suspension culture than other early-acting factors, such as IL-6, IL-11, and granulocyte colony stimulating factor (G-CSF). TPO may be an important cytokine for in vitro manipulation of human hematopoietic stem cells. PMID- 8695790 TI - Structure-function relationships of stem cell factor: an analysis based on a series of human-murine stem cell factor chimera and the mapping of a neutralizing monoclonal antibody. AB - Although much is now known about the biological properties of the c-kit receptor and its ligand, stem cell factor (SCF), little is known of the structural basis for the binding and function of this hematopoietic cytokine. By analyzing the activities of chimeric interspecies and homologue muteins and epitope mapping of a monoclonal antibody (MoAb) to the human protein, we have found that three distinct regions of SCF are essential for full biological function. Homologue and interspecies swapping of polypeptide sequences between the amino terminus and G35, between L79 and N97, and between R121 and D128 reduced or eliminated the ability of the chimera to act in synergy with murine granulocyte-macrophage colony-stimulating factor (GM-CSF) to promote hematopoietic colony formation. Moreover, a nonconformation-dependent MoAb that neutralizes human, but not murine SCF, was found to bind to residues within the L79-N97 segment of the human homologue. As these three regions localize to the putative first, third, and fourth helices of the protein, findings remarkably similar to previous studies of cytokines as diverse as growth hormone, GM-CSF, and interleukin (IL)-4, our results suggest that cytokines of multiple classes share a common functional organization. PMID- 8695791 TI - Characterization of peripheral blood stem cells in mice. AB - Peripheral blood stem cells (PBSCs) were mobilized in mice by treatment with cytosine-arabinoside on day 0, followed by the administration by injection of granulocyte colony-stimulating factor for 4 days. There were remarkable increases in the numbers of cells with lineage-negative (Lin-) c-kit+ markers, cells with colony-forming unit-cell (CFU-C) and colony-forming unit-spleen (CFU-S) activities, and cells with marrow-repopulating ability (MRA) in the extramedullary sites (the spleen, peripheral blood, and liver) on day 5, whereas the number of these immature hematopoietic cells decreased in the bone marrow (BM) on day 5. This finding suggests the mobilization of immature hematopoietic cells from the BM to the extramedullary sites. Three-color flow cytometric analyses showed that CD4 antigen was not expressed on the Lin-Sca-1+ cells in the mobilized PB cells (PBCs), although CD4lo cells were found in those of normal BM cells. Lin-c-kit+ cells in the mobilized PBCs contained more cells with immature phenotypes (Sca-1+, Thy1.2lo, CD71-, and Rh123dull) than in normal BMCs, indicating an alteration of the hierarchical composition of the Lin-c-kit+ cells. The Lin-c-kit+Sca-1+ cells in the mobilized PBCs had similar CFU-C and CFU-S activities to those in normal BMCs. Electron microscopic studies of these cells in the mobilized PBCs showed that only 10% to 20% of these cells had a thin rim of cytoplasm with poorly developed organelles. Allogeneic transplantation [B6 --> C3H] of PBSCs showed long-term reconstituting activity across the major histocompatibility complex barrier 24 weeks after transplantation, although longer observation is necessary. PMID- 8695792 TI - A constitutively activated chimeric cytokine receptor confers factor-independent growth in hematopoietic cell lines. AB - The high-affinity receptor for granulocyte-macrophage colony-stimulating factor (GMR) comprises at least 2 distinct subunits, alpha and beta common (beta c), whereas the normal erythropoietin receptor (nEpoR) comprises only one known subunit. An arginine to cysteine (R129C) mutation of the extracytoplasmic domain of the murine EpoR leads to Epo-independent growth in transduced cells (cEpoR). To investigate the proliferative functions of the cytoplasmic regions of each GMR subunit separately and the potential of the R129C EpoR mutation to induce factor independent growth through heterologous receptor regions, we constructed four hybrid receptors: the extracellular region of either murine nEpoR or cEpoR linked to the transmembrane and cytoplasmic regions of either the human GMR alpha or beta c subunit (nE alpha, nE beta, cE alpha, and cE beta). We then expressed them in an interleukin-3-dependent murine cell line, Ba/F3. Expression of nE beta led to Epo-dependent growth, whereas expression of cE beta conferred factor independent growth. Surprisingly, expression of cE alpha also resulted in factor independent cell growth, whereas nE alpha did not respond to Epo. Furthermore, the functional hybrid receptors showed Epo-dependent (nE beta) or constitutive (cE alpha and cE beta) tyrosine phosphorylation of the cytoplasmic kinases JAK1 and JAK2. We reasoned that the proliferative signal of cE alpha was transduced either through the alpha tail itself or through an accessory protein such as the endogenous murine beta common subunit (mu beta c). To distinguish these possibilities, the chimeric receptor cE alpha was expressed in the interleukin-2 dependent murine cell line, CTLL-2, that does not express mu beta c. cE alpha did not induce cell growth in CTLL-2; however, when mu beta c was coexpressed with cE alpha in CTLL-2, factor-independent growth was reconstituted. In conclusion, the cytoplasmic domain of the GMR alpha subunit requires a beta chain for transduction of a proliferative signal. Furthermore, the R129C EpoR mutation can constitutively activate heterologous receptors to mediate factor-independent proliferation. PMID- 8695793 TI - Anti-erythropoietin receptor monoclonal antibody: epitope mapping, quantification of the soluble receptor, and detection of the solubilized transmembrane receptor and the receptor-expressing cells. AB - A hybridoma cell line producing the monoclonal antibody against erythropoietin receptor (EpoR) was established using the soluble ectodomain of mouse erythropoietin receptor (sEpoR) as an antigen. The monoclonal antibody termed 1G3 bound to the denatured sEpoR. Epitope mapping with peptide library revealed that 1G3 recognized the amino terminal region including the hexapeptide (positions 6 to 11; LeuProAspProLysPhe). The amino acid sequence in this hexapeptide was identical in mice, rats, and humans, and therefore 1G3 bound to EpoR from all of these sources. Using 1G3, we evaluated sEpoR by a sandwich enzyme-linked immunoassay, and EpoR in the solubilized membrane preparation was detected by Western blotting. The cells expressing EpoR were identified with immunochemical staining. We confirmed the presence of EpoR in a neuronal cell line and PC12 cells, and EpoR was expressed in primary cultured hippocampal neurons. PMID- 8695794 TI - In situ radiation sensitivity of recombinant human granulocyte colony-stimulating factor-recruited murine circulating blood and bone marrow progenitors (colony forming unit [CFU]-granulocyte-macrophage and CFU-megakaryocyte): evidence for possible biologic differences between mobilized blood and bone marrow. AB - Increasing evidence especially stemming from peripheral blood progenitor transplantation studies points to a possible biologic difference between mobilized blood and bone marrow progenitor cells. The objective of this study was to compare the in situ radiation sensitivity of recombinant human granulocyte colony-stimulating factor (rhG-CSF)-recruited circulating granulopoietic (blood colony-forming unit-granulocyte-macrophage [CFU-GM(blood)]) and megakaryocytopoietic (blood CFU-megakaryocyte [CFU-Meg(blood)]) progenitors, with the nonmobilized fraction remaining in the bone marrow (CFU-GM(femur) and CFU Meg(femur)). Splenectomized male B6D2F1 mice received 50 micrograms/kg/d rhG-CSF daily for 8 days to induce high levels of circulating progenitors, followed by either total body X-irradiation (TBI) or X-irradiation of the chest (CI) with 62.5, 125, 250, or 500 cGy. Progenitor cells were assayed 24 hours after irradiation. Circulating CFU-GM and CFU-Meg in the blood were decreased in a dose dependent fashion by both TBI and CI, with TBI causing greater damage than CI. Average D0 values for TBI were 53 cGy for CFU-GM(blood) and 40 cGy for CFU Meg(blood) D0 values for CI were 90 cGy for CFU-GM(blood) and 140 cGy for CFU Meg(blood). As seen for blood progenitor cells, TBI caused a dose-dependent decrease of both CFU-GM(femur) (D0, 136 cGy) and CFU-Meg(femur) (D0, 148 cGy). However, radiation-induced bone marrow progenitor cell kill was significantly lower when compared with blood progenitors. Despite the fact that circulating blood elements only received a fraction of the total dose administered as Cl, the extent of blood progenitor kill caused by Cl was higher than the effects of identical TBI doses on bone marrow CFU. The results of this study showed that rhG CSF-recruited CFU-Meg(blood) and CFU-GM(blood) were considerably more radiosensitive than femoral progenitors, thereby providing novel evidence for a biologic difference between rhG-CSF-recruited peripheral blood progenitors and the nonrecruited bone marrow CFU. PMID- 8695795 TI - Granulocyte-macrophage colony-stimulating factor receptor: stage-specific expression and function on late B cells. AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors (GMR) are expressed on myeloid cells throughout their maturational sequence. During myelopoiesis, GM-CSF induces the proliferation of precursors and has multiple effects on more mature cells; such effects include induction of maturation and priming for subsequent stimulation. GMR is expressed on a range of other cell types including acute leukemic blasts of myeloid and lymphoid lineage, but has been little studied on more mature lymphoid cells. Using sensitive triple-layer immunophenotypic techniques, we show here that both the alpha and beta c chains of the GMR are expressed on hairy cells (HCs) and myelomatous plasma cells (PCs), but not on chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL) lymphocytes. The receptor was demonstrable on normal PCs in tonsil, but not on either activated or resting tonsillar B cells or on circulating normal B lymphocytes. The expression of the receptor is therefore stage specific, rather than a feature of activation. Perhaps, surprisingly, in view of its effects on myeloid cells, GM-CSF did not stimulate the proliferation or differentiation of HCs and did not protect them from apoptosis. However, the cytokine had a profound effect on the interaction of the HC with its environment. Thus, the cytokine caused a major cytoskeletal reorganization resulting in the inhibition of motility and loss of adhesion to cellular and matrix ligands. These studies indicate the importance of GM-CSF outside myelopoiesis and demonstrate a previously unrecognized stage specific role for the cytokine in B-cell biology. Taken together with our previous report that M-CSF enhances B-cell motility, the present findings indicate that myeloid growth factors act in concert to facilitate the controlled migration of certain B cells into and within tissues. PMID- 8695796 TI - Characterization of mouse lymphohematopoietic stem cells lacking spleen colony forming activity. AB - The classical definition of lymphohematopoietic stem cells (LHSC), the most primitive progenitors of all blood cells, requires that they have the capacity for self-renewal and for the long-term production of all blood cell lineages. However, other characteristics of LHSC have been debated. Our previous data suggested that mouse LHSC are very slowly proliferating cells that generate delayed multilineage engraftment, while "radioprotection" (rapid engraftment that will prevent early death from radiation-induced marrow aplasia) results from more committed progenitors. Alternatively, some groups have reported that mouse LHSC are responsible for both radioprotection and long-term repopulation of all blood cell lineages. A possible explanation for this difference is that cells with the capacity for long-term production of all blood cell lineages are biologically heterogeneous. We now show that 10 LHSC can generate all blood cell lineages for the lifetime of the animal. However, these cells lacked radioprotection and spleen colony-forming activity. LHSC were identified and isolated by their small size, their lack of expression of antigens characteristic of mature blood cell lineages, and their high expression of aldehyde dehydrogenase. In addition, these cells were found to express undetectable or low levels of many antigens presumed to mark LHSC, including Thy-1, Ly-6A/E (Sca-1), c-kit, and CD34. There appears to be at least two classes of LHSC with the capacity for long-term production of all blood cell lineages: one that generates both radioprotection and long-term engraftment and one that produces delayed but durable engraftment. Our data suggest that this latter class may represent a very primitive class of LHSC. PMID- 8695797 TI - Integration of adeno-associated virus vectors in CD34+ human hematopoietic progenitor cells after transduction. AB - Gene transfer vectors based on adeno-associated virus (AAV) appear promising because of their high transduction frequencies regardless of cell cycle status and ability to integrate into chromosomal DNA. We tested AAV-mediated gene transfer into a panel of human bone marrow or umbilical cord-derived CD34+ hematopoietic progenitor cells, using vectors encoding several transgenes under the control of viral and cellular promoters. Gene transfer was evaluated by (1) chromosomal integration of vector sequences and (2) analysis of transgene expression. Southern hybridization and fluorescence in situ hybridization analysis of transduced CD34 genomic DNA showed the presence of integrated vector sequences in chromosomal DNA in a portion of transduced cells and showed that integrated vector sequences were replicated along with cellular DNA during mitosis. Transgene expression in transduced CD34 cells in suspension cultures and in myeloid colonies differentiating in vitro from transduced CD34 cells approximated that predicted by the multiplicity of transduction. This was true in CD34 cells from different donors, regardless of the transgene or selective pressure. Comparisons of CD34 cell transduction either before or after cytokine stimulation showed similar gene transfer frequencies. Our findings suggest that AAV transduction of CD34+ hematopoietic progenitor cells is efficient, can lead to stable integration in a population of transduced cells, and may therefore provide the basis for safe and efficient ex vivo gene therapy of the hematopoietic system. PMID- 8695798 TI - The supportive effects of erythropoietin and mast cell growth factor on CD34+/CD36- sorted bone marrow cells of myelodysplasia patients. AB - In the present study, we analyzed the capacity of CD34+/CD36- sorted bone marrow cells of myelodysplasia patients (n = 4) to differentiate along the erythroid lineage in the presence of erythropoietin (Epo) and mast cell growth factor (MGF). Two subgroups could be identified. In 6 patients, a normal number of burst forming units-erythroid (BFU-Es) were cultured from CD34+/CD36- sorted cells. Cells from these patients did have the capacity to differentiate to colony forming units-erythroid (CFU-Es) progenitors in cell suspension cultures with Epo plus MGF followed by Epo in the culture assay. Moreover, the cells became CD34 /CD36+/gly-cophorin A (GpA)+ after 7 days of culture with Epo plus MGF, a pattern comparable to that of normal progenitors. In contrast, in 8 patients, a different pattern was observed. No BFU-Es or a low number of BFU-Es were cultured from the CD34+/CD36- sorted cell fraction that was, in most of the cases, incapable of differentiating to CFU-E progenitors. Flow cytometry of the sorted population showed that, after 7 days of culture with Epo plus MGF, a high proportion of CD34+/CD36- cells persisted, whereas a low proportion of cells became CD34 /CD36+/GpA+. The unresponsiveness is not caused by the used growth factor combination, because the addition of interleukin-3 did not correct the defect. Evi-1 expression was studied in 9 cases to show whether an aberrant Evi-1 expression correlates with a disturbed erythroid development. Evi-1 expression was shown in 4 of 9 cases, whereas 3 of 9 cases did have a disturbed erythroid differentiation. In summary, the results show that the defects in the erythroid development in a subpopulation of patients with myelodysplasia is localized at an early stage of the erythroid differentiation and is associated with the persistent expression of the CD34 antigen and, in some cases, with the expression of Evi-1. PMID- 8695799 TI - Dose-response effects of pegylated human megakaryocyte growth and development factor on platelet production and function in nonhuman primates. AB - Thrombopoietin (TPO) is the physiologic Mpl-ligand regulating platelet production. Pegylated human recombinant megakaryocyte growth and development factor (PEG-rHuMGDF), a truncated polypeptide Mpl-ligand derivitized with poly (ethylene glycol), induces megakaryocyte endoreduplication and proliferation in vitro and in vivo. In the present study, the dose-response effects of PEG-rHuMGDF on pharmacokinetics, megakaryocytopoiesis, platelet production, and platelet function were characterized for dosing 0.05, 0.10, 0.50, or 2.5 micrograms/kg/d in 22 baboons for 28 days. Daily subcutaneous injections of PEG-rHuMGDF produced linear log-dose responses in (1) steady-state trough plasma levels of PEG-HuMGDF (P < 10(-3)); (2) marrow megakaryocyte volume (P < 10(-3)), ploidy (P < 10(-4)), and number (P < .01); and (3) peripheral platelet concentrations (P < 10(-4)) and platelet mass turnover (P < 10(-3)). Platelet morphology, life span, and recovery were normal, and peripheral leukocyte, neutrophil, and erythrocyte counts were not significantly affected by PEG-rHuMGDF (P > .1 in all cases). PEG-rHuMGDF at 0.5 micrograms/kg/d produced similar blood concentrations of Mpl-ligand and platelets as 10 times the dose of rHu-MGDF (5.0 micrograms/kg/d), reflecting the extended plasma half-life achieved through pegylation. Whereas PEG-rHuMGDF did not induce platelet aggregation in vitro, platelet aggregatory responsiveness induced by thrombin receptor agonist peptide (TRAP1-6) and collagen was transiently enhanced ex vivo during the initial few days of PEG-rHuMGDF administration. However, adenosine diphosphate (ADP)-induced platelet aggregation was not enhanced ex vivo by PEG-rHuMGDF therapy. 111In-platelet deposition on segments of homologous endarterectomized aorta (EA) and vascular graft (VG) interposed in arteriovenous femoral shunts increased in direct proportion to the circulating platelet concentration (P < 10(-4) for both EA and VG); 125l-fibrin accumulation was not affected by PEG-rHuMGDF-induced increases in peripheral platelet counts. Changes in platelet production and function produced by PEG rHuMGDF returned to baseline within 2 weeks after discontinuing treatment. Thus, in nonhuman primates, PEG-rHuMGDF increases platelet production in a linear log dose-dependent manner by stimulating megakaryocyte endoreduplication and new megakaryocyte formation from marrow hematopoietic progenitors. These findings suggest that appropriate dosing of PEG-rHuMGDF therapy during periods of chemotherapy-induced marrow suppression may maintain hemostatic concentrations of peripheral platelets without increasing the risk of thrombosis. PMID- 8695800 TI - Characterization of Grb2-binding proteins in human platelets activated by Fc gamma RIIA cross-linking. AB - Glutathione-S-transferase (GST)-Grb2 fusion proteins have been used to identify the potential role of Grb2-binding proteins in platelet activation by the platelet low-affinity IgG receptor, Fc gamma RIIA. Two tyrosine phosphoproteins of 38 and 63 kD bind to the SH2 domain of Grb2 following Fc gamma RIIA stimulation of platelets. Both are located in the particulate fraction following platelet activation and are also able to bind to a GST-construct containing the SH2 and SH3 domains of phospholipase C gamma 1. p38 also forms a complex with the tyrosine kinase csk in stimulated cells and is a substrate for the kinase. The SH3 domains of Grb2 form a stable complex with SOS1 and two proteins of 75 kD and 120 kD, which undergo tyrosine phosphorylation in Fc gamma RIIA stimulated cells. The 75-kD protein is recognized by antibodies to SLP-76, which has recently been isolated from T cells and sequenced. Tyrosine phosphorylation of p38 and p63 is also observed in platelets stimulated by the tyrosine kinase-linked receptor agonist collagen and by the G protein-coupled receptor agonist thrombin, although phosphorylation of SLP-76 is only observed in collagen-stimulated platelets. p38 and p63 may provide a docking site for Grb2, thereby linking Grb2 SH3-binding proteins SOS1, SLP-76, and p120 to downstream signalling events. PMID- 8695801 TI - Stimulation of tissue-type plasminogen activator expression by retinoic acid in human endothelial cells requires retinoic acid receptor beta 2 induction. AB - We previously showed the involvement of retinoic acid receptor alpha (RAR alpha) in the induction of tissue-type plasminogen activator (t-PA) synthesis by RA in human umbilical vein endothelial cells (HUVECs). However, the rather slow onset of this induction of t-PA synthesis suggested an indirect role of RAR alpha. Here, we show that the protein synthesis inhibitor, cycloheximide completely blocks the induction of t-PA by RA, which points to the need of an intermediary protein in t-PA stimulation. This intermediary protein is likely to be RAR beta 2 on the basis of the following findings: (1) the induction of RAR beta by RA exactly precedes that of t-PA; (2) HUVECs with elevated RAR beta mRNA levels show an undelayed t-PA induction on stimulation with RA, and this response can be almost completely inhibited with an RAR antagonist; and (3) an antisense oligodeoxynucleotide against the translation initiation site of RAR beta 2 mRNA greatly reduces the t-PA induction by RA. Thus, induction of t-PA by RA in HUVECs involves a 2-step mechanism requiring induction of RAR beta 2 via RAR alpha, followed by induction of t-PA synthesis via RAR beta 2. Each of these steps is shown to have a different activation profile with RA and 9 cis RA. PMID- 8695802 TI - Interaction of single-chain urokinase with its receptor induces the appearance and disappearance of binding epitopes within the resultant complex for other cell surface proteins. AB - Binding of urokinase-type plasminogen activator (uPA) to its glycosylphosphatidylinositol-anchored receptor (uPAR) initiates signal transduction, adhesion, and migration in certain cell types. To determine whether some of these activities may be mediated by associations between the uPA/uPAR complex and other cell surface proteins, we studied the binding of complexes composed of recombinant, soluble uPA receptor (suPAR) and single chain uPA (scuPA) to a cell line (LM-TK- fibroblasts) that does not express glycosylphosphatidylinositol (GPI)-anchored proteins to eliminate potential competition by endogenous uPA receptors. scuPA induced the binding of suPAR to LM TK- cells. Binding of labeled suPAR/scuPA was inhibited by unlabeled complex, but not by scuPA or suPAR added separately, indicating cellular binding sites had been formed that are not present in either component. Binding of the complex was inhibited by low molecular weight uPA (LMW-uPA) indicating exposure of an epitope found normally in the isolated B chain of two chain uPA (tcuPA), but hidden in soluble scuPA. Binding of LMW-uPA was independent of its catalytic site and was associated with retention of its enzymatic activity. Additional cell binding epitopes were generated within suPAR itself by the aminoterminal fragment of scuPA, which itself does not bind to LM-TK- cells. When scuPA bound to suPAR, a binding site for alpha 2-macroglobulin receptor/LDL receptor-related protein (alpha 2 MR/LRP) was lost, while binding sites for cell-associated vitronectin and thrombospondin were induced. In accord with this, the internalization and degradation of cell-associated tcuPA and tcuPA-PAI-1 complexes proceeded less efficiently in the presence of suPAR. Further, little degradation of suPAR was detected, suggesting that cell-bound complex dissociated during the initial stages of endocytosis. Thus, the interaction of scuPA with its receptor causes multiple functional changes within the complex including the dis-appearance of an epitope in scuPA involved in its clearance from the cell surface and the generation of novel epitopes that promote its binding to proteins involved in cell adhesion and signal transduction. PMID- 8695803 TI - Two functionally distinct pools of vitronectin (Vn) in the blood circulation: identification of a heparin-binding competent population of Vn within platelet alpha-granules. AB - The biological functions of vitronectin (Vn) are dependent on its conformation. Whereas plasma Vn is present in a conformation that does not bind to heparin, platelet Vn has been recognized to be in a multimeric, conformationally altered form. To further understand the characteristics of platelet Vn, the molecules present in plasma and total and size-fractionated platelet releasates were compared (1) immunologically using three conformationally sensitive epitope defined monoclonal antibodies, (2) functionally for their ability to interact with heparin, and (3) structurally using denaturing and nondenaturing polyacrylamide gel electrophoresis (PAGE). Our data indicate that Vn is present in platelet releasates in two molecular weight (M(r) forms. The high M(r) fractions contain conformationally and structurally altered Vn capable of interacting with heparin, and this form is distinct from plasma Vn and purified denatured Vn. In contrast, the lower M(r) forms of Vn are similar to plasma Vn. To determine if the presence of multimeric Vn requires platelet activation, platelets were disintegrated by sonication and fractionated by density gradients. Combined sodium dodecyl sulfate-PAGE (SDS-PAGE) and immunoblotting analysis showed a codistribution of multimeric Vn and type 1 plasminogen activator inhibitor in alpha-granule-rich fractions. Thus, platelet Vn is stored in a structurally and functionally distinct form from the molecule in plasma, raising the possibility that platelet-derived heparin-binding competent Vn will accumulate in areas of vascular injury. PMID- 8695804 TI - Identification of Bruton's tyrosine kinase (Btk) gene mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families: a nationwide study of Btk deficiency in Japan. AB - Deficiencies of Bruton's tyrosine kinase (Btk) have been implicated in the pathogenesis of human X-linked agammaglobulinemia (XLA). The distinctive phenotype observed in B-cell deficiency indicates the crucial role of Btk in B cell development. This report describes a nationwide study of Btk deficiency in Japan, covering 51 XLA patients (35 independent families). Along with the identification of mutations, the resulting protein products were characterized by an in vitro kinase assay and a Western blot analysis. Thirty-one of the families were found to have mutations in the coding region of Btk. Although mutations were not found in the cDNA of 4 families, the Btk transcripts of these patients were greatly reduced. The identification of several novel missense mutations, in combination with the result of other studies, clarified the presence of two (missense) mutation hot spots, one in the SH1 and the other in the PH domain. The absence of kinase activity seen in 32 of the families underscored the importance of Btk protein analysis as a diagnostic indicator of XLA. The protein analysis also clarified the different effects of missense mutations on kinase activity and protein stability. PMID- 8695805 TI - Human immunodeficiency virus (HIV) phenotype and interleukin-2/ interleukin-10 ratio are associated markers of protection and progression in HIV infection. AB - Human immunodeficiency virus (HIV) isolability, rate of viral replication, HIV phenotype, type 1 and type 2 cytokine production, and CD4 counts were cross sectionally analyzed in 63 HIV seropositive (HIV+) individuals to establish possible correlations between virologic and immunologic markers of protection and progression. We observed that these markers are tightly correlated. Thus, lack or low prevalence of HIV isolability and the presence of nonsyncitium inducing strains are associated with the strongest type 1 cytokine production, the weakest type 2 cytokine production, and highest CD4 counts. Conversely, the isolation of highly replicating, syncitium-inducing HIV strains is associated with the weakest type 1 cytokine production, the strongest type 2 cytokine production, and lowest CD4 counts. Additionally, it was determined that the interleukin (IL)-10/IL-2 ratio best discriminates among different virologic scenarios. These data suggest that the virologic and immunologic correlates of disease protection and progression might be associated variables that define two different subsets of HIV+ individuals and lend support to a viro-immunologic hypothesis of HIV infection. PMID- 8695806 TI - Tumor-specific, cytotoxic T-lymphocyte response after idiotype vaccination for B cell, non-Hodgkin's lymphoma. AB - Patients with non-Hodgkin's B-cell lymphoma who received an antitumor vaccine of idiotypic ig protein showed humoral and proliferative immune responses. Because immunity to some antigens, including tumor antigens and human pathogenic viruses, may be better correlated with the cytolytic cellular immune response, we evaluated 16 non-Hodgkin's lymphoma patients immunized with autologous idiotypic ig molecules for changes in tumor-specific cytotoxic T-lymphocyte precursor (CTLp) frequency using limiting dilution analysis. Eleven patients had a significant increase in tumor-specific CTLp. Eight of these 11 patients remain without evidence of disease or with stable minimal disease. In contrast, all five patients who did not have a significant change in tumor-specific CTLp have developed progressive disease. Patient vaccination with tumor associated protein antigens can increase tumor-specific CTLp frequencies. The correlation of increased tumor specific CTLp with freedom from progression is significant at P = .002. This study indicates that measurement of CTLp frequencies are relevant to the clinical evaluation of human tumor vaccines and suggests that cell-mediated cytolytic immune responses may be an important determinant of vaccine efficacy. PMID- 8695807 TI - CD38-mediated growth suppression of B-cell progenitors requires activation of phosphatidylinositol 3-kinase and involves its association with the protein product of the c-cbl proto-oncogene. AB - The signalling pathways that arrest the cell cycle and trigger cell death are only partially known. Dimerization of CD38, a 45-kD transmembrane type II glycoprotein highly expressed in immature B cells, inhibits cell growth and causes apoptosis in normal and leukemic B-cell progenitors, but the molecular mechanisms underlying these cellular responses are unknown. In the present study, we found that CD38 ligation in the immature B-cell lines 380, REH, and RS4;11 caused rapid tyrosine phosphorylation of the protein product of the proto oncogene c-cbl. Dimerization of CD38 was accompanied by the association of cbl with the p85 subunit of phosphatidylinositol 3-kinase (Pl 3-K), resulting in markedly increased Pl 3-K activity in antiphosphotyrosine and anti-cbl immunoprecipitates. Wortmannin and LY294002, two potent inhibitors of Pl 3-K, rescued immature B cells from CD38-mediated growth suppression. This effect was observed not only in model B-cell lines, but also in cultures of leukemic lymphoblasts from patients, and in normal bone marrow B-cell progenitors as well. Concentrations of inhibitors that reversed cellular responses to CD38 significantly decreased Pl 3-K activity. By contrast, rapamycin, a p70 S6-kinase inhibitor, did not rescue immature B cells from CD38-mediated suppression. These results suggest that Pl 3-K activity is essential for CD38-mediated inhibition of lymphopoiesis and that cbl and Pl 3-K are regulatory molecules whose activation can result in suppression of cell proliferation and apoptosis in immature lymphoid cells. PMID- 8695808 TI - Apoptosis of Burkitt's lymphoma cells induced by specific interaction of surface IgM with a self-antigen: implications for lymphomagenesis in acquired immunodeficiency syndrome. AB - In a previous study, we described a cell line (BRG-P) derived from a woman with Burkitt's lymphoma (BL) and acquired immunodeficiency syndrome that shared the same characteristic cytogenetic abnormalities as the patient's malignant cells. This cell line contained subclones that displayed an isotype switch from IgM to IgA1 and an accumulation of point mutations in the Vh region genes. Because these two features suggested an antigen-driven process, we began a search for the antigen responsible for the stimulation of the malignant B cells. Specifically, we hypothesized that because the patient's tumor had presented as a lymphomatous infiltration of the breast, the malignant B cells were recruited to this site because of the reactivity of their surface lg with breast tissue. A hybridoma (BRG-H) was obtained by fusing BRG-M cells (an IgM producing subclone of the BRG P cell) with an appropriate cellular partner. The monoclonal antibody (BRG MoAb) produced by this hybridoma reacted strongly with two of five breast cancer cell lines and stained normal and malignant ductal epithelial cells on breast tissue sections. The antigen recognized by the BRG MoAb consisted of a single, minimally glycosylated polypeptide chain of 45 kD (p45). The BRG MoAb failed to react with a panel of human cell lines from different tissues, except for one cell line from a uterine cervical carcinoma. No reactivity was detected for a panel of exogenous antigens from various pathogens, including human immunodeficiency virus and self antigens frequently recognized by polyspecific antibodies. Experiments were performed to investigate the functional consequences of the interaction of surface IgM with its specific ligand. Coculture of BRG-M cells with p45+, but not with p45-, breast cells caused apoptosis of BRG-M cells. The specificity of the interaction was shown by the observation that apoptosis was prevented by pretreatment of BRG-M cells with a monovalent F(ab') fragment of rabbit IgG antibody to human mu chains. Moreover, only BRG-M cells, but not other BL cells, underwent apoptosis after exposure to p45+ breast cells. The interaction between the CD40 molecule expressed by BRG-M cells and its specific ligand (CD40L) prevented p45-induced cell apoptosis. Because this interaction mimics that occurring in vivo between T and B cells during immune responses, our data suggest that various events contributed to the emergence of the BL, in this particular patient, including antigenic stimulation possibly assisted by T-cell help. PMID- 8695809 TI - Lymphocytic progenitor cell origin and clonal evolution of human B-lineage acute lymphoblastic leukemia. AB - At presentation, bone marrow specimens from over 25% of B-lineage acute lymphoblastic leukemias (ALL) display more than two clonal rearrangements of immunoglobulin heavy chain (IgH) genes in Southern blot analyses. Nucleotide sequence analysis has shown predominantly different V(H)DJ(H) junctions among these genes, leading to the frequent description of such cases as oligoclonal leukemias. In the present study, we have analyzed the lgH genes from four patients whose leukemic cells contained different patterns of lgH gene rearrangements between presentation and relapse. Nucleotide sequence analysis of the lgH genes showed that three mechanisms could account for these differences: de novo V(H)DJ(H) rearrangement, V(H) to DJ(H) recombination, and V(H) replacement. In all cases, more than two totally different V(H)DJ(H) rearrangements appeared during evolution of the disease, formally consistent with the conclusion that these tumors were composed of apparently unrelated clones. However, the retention of some of the antigen receptor gene rearrangements, as well as the persistence of a chromosomal marker in two cases, indicated that these leukemias had a monoclonal origin. These findings support the hypothesis that some ALLs arise from a lymphoid progenitor cell at a stage of lymphocyte development before the onset of IgH gene rearrangement. These leukemic lymphocyte progenitors generate malignant daughter cells capable of an in vivo maturation that involves the completion of multiple different lgH rearrangements as well as the modification of preexisting rearrangements by V(H) to DJ(H) recombination or by a V(H) replacement. PMID- 8695810 TI - Tumor-specific aneuploidy not detected in CD19+ B-lymphoid cells from myeloma patients in a multidimensional flow cytometric analysis. AB - Aneuploidy and lg light chain restriction were used as separate, independent tumor specific markers to study 26 patients with multiple myeloma to determine whether bone marrow B cells, as defined by CD19 expression, are clonally related to myeloma plasma cells. Specimens were characterized using multidimensional flow cytometry to identify the presence of clonality in both the B lymphoid and plasma cell populations using both surface and cytoplasmic staining with antibodies specific for kappa or lambda lg light chain In none of the patients with multiple myeloma were CD19+ cells found to be clonally restricted to kappa or lambda. The monoclonal plasma cells (MPC) were found to be uniformly negative for CD10, CD19, and CD34, while the CD19+ B lymphoid cells present within the samples expressed normal intensities and relationships of these antigens, which allowed them to serve as internal positive controls. Combined analysis of call surface antigen expression and DNA content allowed plasma cell populations to be characterized for aneuploidy without interference from normal bone marrow cells. The MPC, detected on the basis of bright CD38 expression (CD38+2), demonstrated DNA aneuploidy in 65% of cases (DNA index range of 0.9 to 1.3). These aneuploid DNA distributions had typical cell cycle profiles (including G1,S and G2+M) expected of a proliferating population. In all cases, DNA aneuploidy was confined almost entirely to the CD38+2, CD19- malignant plasma cells, while cells expressing CD19 were diploid. These results support the concept that myeloma is a disease process mediated by self-replicating, late compartments of B-cell ontogeny. PMID- 8695811 TI - The novel anthracycline annamycin is not affected by P-glycoprotein-related multidrug resistance: comparison with idarubicin and doxorubicin in HL-60 leukemia cell lines. AB - A major factor in limiting the efficacy of anthracyclines is overexpression of the MDR1-encoded p-glycoprotein (p-gp). A new analogue less affected by p-gp is annamycin (ANN), an anthracycline antibiotic with high affinity for lipid membranes and significantly more activity than doxorubicin (DOX). We investigated whether ANN was affected by p-gp-mediated multidrug resistance (MDR) by comparing the cellular accumulation and retention of ANN, idarubicin (IDR), and DOX in the p-gp-negative human leukemia cell lines (HL-60S) and its DOX-selected p-gp positive subline (HL-60/DOX) with and without verapamil (VER). As expected, HL 60/DOX cells showed lower DOX uptake than HL-60S cells; coincubation with VER (10 mmol/L) increased uptake 2.6-fold restoring it to 100% of uptake in HL-60S cells. IDR uptake increased 1.5-fold in the presence of VER, but ANN was not affected. Coincubation with VER increased DOX retention in HL-60/DOX cells 2.8-fold and IDR retention 1.4-fold; unchanged ANN retention indicated that ANN may overcome p-gp. In the cytotoxicity assay to correlate intracellular anthracycline content with antitumor activity, we found ANN to be less potent than DOX and IDR In sensitive cells, ID 50 being the drug concentration that inhibits cell growth by 50% but its resistance index (RI; ID50 resistant cells divided by ID50 sensitive cells) was lower than that of IDR and DOX (2.6 v 40 and 117.5). Coincubation in the presence of VER resulted in 4.5-fold and 2-fold RI decreases of DOX and IDR, respectively, whereas ANN did not change, further confirming ANN's ability to circumvent p-gp-mediated MDR. Confocal microscopy studies of IDR, ANN, and DOX showed higher intracellular drug compartmentalization for DOX in HL-60/DOX cells incubated in the presence of VER. This study provided evidence that, unlike DOX and IDR, ANN is not affected by p-gp-mediated MDR. PMID- 8695812 TI - Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. AB - We recently discovered the Kaposi's sarcoma-associated herpes virus (KSHV/HHV-8) in an uncommon and unusual subset of AIDS-related lymphomas that grow mainly in the body cavities as lymphomatous effusions without an identifiable contiguous tumor mass. The consistent presence of KSHV and certain other distinctive features of these body cavity-based lymphomas suggest that they represent a distinct entity. We tested this hypothesis by investigating 19 malignant lymphomatous effusions occurring in the absence of a contiguous tumor mass for their clinical, morphologic, immunophenotypic, viral, and molecular characteristics, KSHV was present in 15 of 19 lymphomas. All four KSHV-negative lymphomatous effusions exhibited Burkitt or Burkitt-like morphology and c-myc gene rearrangements and, therefore, appeared to be Burkitt-type lymphomas occurring in the body cavities. In contrast, all 15 KSHV-positive lymphomatous effusions exhibited a distinctive morphology bridging large-cell immunoblastic lymphoma and anaplastic large-cell lymphoma, and all 12 cases studied lacked c myc gene rearrangements. In addition, these lymphomas occurred in men (15/15), frequently but not exclusively in association with HIV infection (13/15), in which homosexuality was a risk factor (13/13), presented initially as a lymphomatous effusion (14/15), remained localized to the body cavity of origin (13/15), expressed CD45 (15/15) and one or more activation-associated antigens (9/10) in the frequent absence of B-cell-associated antigens (11/15), exhibited clonal immunoglobulin gene rearrangements (13/13), contained Epstein-Barr virus (14/15), and lacked bcl-2, bcl-6, ras and p53 gene alterations (13/15). These findings strongly suggest that the KSHV-positive malignant lymphomatous effusions represent a distinct clinicopathologic and biologic entity and should be distinguished from other malignant lymphomas occurring in the body cavities. Therefore, we recommend that these malignant lymphomas be designated primary effusion lymphomas (PEL), rather than body cavity-based lymphomas, since this term describes them more accurately and avoids their confusion with other malignant lymphomas that occur in the body cavities. We further recommend that these PEL be considered for inclusion as a new entity in the Revised European American Lymphoma Classification. PMID- 8695813 TI - Nodular lymphocyte-predominant Hodgkin's disease associated with large-cell lymphoma: analysis of Ig gene rearrangements by V-J polymerase chain reaction. AB - The clonality of nodular lymphocyte-predominant Hodgkin's disease (NLPHD) and the relationship to composite or sequential large-cell lymphomas (LCLs) is poorly understood. Clonal Ig heavy-chain gene rearrangements (lgHGR) have infrequently been observed in NLPHD by Southern hybridization. The goals of this study were (1) to determine if IgHGR could be identified by polymerase chain reaction (PCR) techniques in the LCL associated with NLPHD; (2) to determine if the lgHGR identified in the LCL could also be found in the associated NLPHD; and (3) to determine if Epstein-Barr virus (EBV) played a role a role in histologic progression to LCL. Using consensus primers to conserved regions in the lgH variable (V) and joining (J) region genes, we analyzed formalin-fixed paraffin embedded sections from the biopsies of 25 patients referred to the National Cancer Institute (NCI) registry for NLPHD and LCL using both single-step and seminested V-J PCR. The histologically aggressive component was further subclassified as frank LCL or as L&H-cell-rich, but not fulfilling criteria for LCL. Matched samples representing both NLPHD and aggressive components were available in 13 cases. In 12 cases, only one component was available (aggressive, n = 8; NLPHD, n = 4). In addition, we also amplified, with 32P labeling, 12 cases of NLPHD without associated LCL. Two clonal IgHGR were identified in 29 cases (7%) of typical NLPHD, both of which were associated with LCL containing a similar sized band by PCR. The clonal identity of the bands in the NLPHD and associated LCL was confirmed by sequencing the products in these two cases. Eight of 10 cases (80%) of LCL associated with NLPHD contained a clonal band by this technique. By contrast, none of the cases classified as L&H-cell-rich contained an IgHGR. The single-step and seminested PCR methods produced identical results. All clonal LCLs were studied for EBV sequences by in situ hybridization using the EBER1 probe, and were negative. We conclude that the LCLs associated with NLPHD are clonal B-cell malignancies. However, by these methods, the same clone can be identified in only a minority of cases of NLPHD and LCL. EBV does not appear to play a role in histologic progression. Moreover, our results suggest that many cases suspected of being LCL may actually represent NLPHD with increased numbers of L&H cells. In histologically equivocal cases, the diagnosis of LCL should be reserved for those cases in which a clonal B-cell neoplasm can be demonstrated. PMID- 8695814 TI - Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor associated endothelium. AB - We previously showed that endothelial cells (EC) from the vasculature of human solid tumors have a decreased expression of intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 as compared with normal tissue EC. This effect is explained by EC exposure to angiogenic factors. It is known that upregulation of endothelial adhesion molecules (EAM) is a sign of EC activation in inflammatory responses. We therefore tested the effect of angiogenic factors on upregulation of EAM on tumor EC and human umbilical vein EC (HUVEC) by proinflammatory cytokines. Incubation of tumor-derived EC in tumor necrosis factor alpha (TNF alpha) did result in expression levels of only 20% of the level of similarly treated normal tissue-derived EC. Pretreatment of HUVEC with 10 ng/ml basic fibroblast growth factor (bFGF) for 3 days, before TNF alpha- or interleukin-1 alpha (IL-1 alpha) stimulation, resulted in ICAM-1 levels of only 30% to 60% of cells without pretreatment. Also, the induction of vascular EC adhesion molecule 1 (VCAM-1) and E-selectin by TNF alpha was significantly inhibited by prior exposure to bFGF. Vascular endothelial growth factor had similar but less prominent effects. The effect of transforming growth factor-beta and IL-8 was studied as well. The functional relevance of the finding of a decreased EC inflammatory response was confirmed by adhesion assays. Our results show that tumor angiogenesis induces EC anergy. This may serve as a tumor-protecting mechanism by impairing the development of an efficient leukocyte infiltrate in tumors. PMID- 8695815 TI - Dysregulation of cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines. AB - Translocations involving the IgH locus at chromosomal locus 14q32.3 are a common event in many B-cell malignancies. The translocations, which generally occur into JH and switch regions, are mediated by errors in the two developmentally regulated, lymphocyte-specific pathways: VDJ-and switch-mediated recombination. Dysregulation of cyclin D1 by a t(11;14)(q13;q32) translocation occurs in most cases of mantle-cell lymphoma and in approximately 30% of multiple myeloma (MM) tumors in which a 14q32 translocation can be detected. We show here that in two of three myeloma lines that overexpress cyclin D1, there is an 11;14 translocation into a gamma switch region, suggesting an error in switch recombination. By contrast, 11;14 translocations in mantlecell lymphoma are invariably into or near a JH segment, suggesting an error in VDJ recombination. This is consistent with the fact that myeloma cells have undergone lgH switch recombination, whereas mantle-cell lymphoma cells generally have not. PMID- 8695816 TI - Fluorescence in situ hybridization analysis of t(3; 12)(q26; p13): a recurring chromosomal abnormality involving the TEL gene (ETV6) in myelodysplastic syndromes. AB - We have identified a new recurrent reciprocal translocation between chromosome 3 and 12 with breakpoints at bands 3q26 and 12p13, t(3;12)(q26;p13) in the malignant cells from five patients with acute transformation of myelodysplastic syndrome or blast crisis of chronic myelogenous leukemia. t(3;12)(q26;p13) appears as a rare but nonrandom event present in various myeloid leukemia subtypes, which is frequently associated with dysplasia of megakaryocytes, multilineage involvement, short duration of any blastic phase, and a very poor prognosis. Here, we report the molecular cytogenetic analysis of the t(3;12). Fluorescence in situ hybridization results indicate that the 3q26 breakpoints are quite heterogeneous and occur 5' of MDS1, 3' of EVI1, or between MDS1 and EVI1. Our results are very similar to those observed in other 3q26 rearrangements in which breakpoints were shown to occur over considerable distances 5' and 3' of EVI1. Fluorescence in situ hybridization investigations proved that, in three myelodysplastic syndrome cases with t(3;12)(q26;p13), the 12p 13 breakpoint occurred within the TEL gene. PMID- 8695817 TI - Tumor necrosis factor-alpha and FMLP receptors are functionally linked during FMLP-stimulated activation of adherent human neutrophils. AB - Human peripheral blood neutrophils (PMN) plated onto fibrinogen and activated with FMLP release H2O2 and lactoferrin, a specific granule component, with parallel kinetics. Although tumor necrosis factor-alpha (TNF alpha) only primes PMN in suspension, it is a potent agonist of adherent PMN. Activation of adherent PMN by FMLP (10(-7) mol/L) stimulated detectable release of TNF alpha within 45 minutes of stimulation, with maximal release (45.5 pg/10(6) cells) detected by 90 minutes. TNF alpha release paralleled the release of both lactoferrin and H2O2. To determine if TNF alpha plays a role in H2O2 and lactoferrin release, we investigated the effect of anti-TNF alpha antibodies on FMLP-stimulated activation of adherent PMN. A neutralizing rabbit anti-TNF alpha antibody inhibited both H2O2 and lactoferrin release stimulated by FMLP, whereas rabbit lgG, anti-HLA-A,B,C, anti-CD 14, and anti-interleukin-8 antibodies were without effect. The simultaneous addition of TNF alpha (1,000 U/mL) with anti-TNF alpha antibody reversed the inhibition seen with anti-TNF alpha alone. Furthermore, treatment of PMN with either actinomycin D or cylcoheximide resulted in partial (33%) inhibition of H2O2 and lactoferrin release, suggesting that protein synthesis is required for FMLP-mediated activation of adherent PMN. The addition of TNF alpha to either cycloheximide or of actinomycin D-treated PMN overcame the inhibition, indicating that the effect was specific for TNF alpha. The addition of antibodies against either the 55-or 75-kD TNF alpha receptors (referred to as p55 and p75, respectively) resulted in partial (32%) inhibition of FMLP-mediated activation of H2O2 and lactoferrin release, whereas a combination of both antibodies reduced their release to control levels. These data indicate that both p55 and p75 are involved in FMLP activation of adherent PMN. Taken together, these findings indicate that the production of TNF alpha and ligation of TNF alpha receptors are central to FMLP activation of PMN adherent to fibrinogen. PMID- 8695818 TI - Glutamine- and phosphate-containing hypotonic storage media better maintain erythrocyte membrane physical properties. AB - We have shown that red blood cell (RBC) adenosine-5'-triphosphate (ATP) is better maintained and that there is less hemolysis and K+ leakage in hypotonic experimental additive solutions (EASs) containing glutamine and glutamine plus phosphate (Pi) than in the conventional additive solution Adsol during blood bank storage. The objective of this study was to determine if the beneficial effect produced in these media correlates with better preservation of RBC membrane properties including lipid content, phospholipid organization, aminophospholipid transport (flippase), and prothrombin converting activity. Aliquots of packed RBCs were stored in EASs containing adenine, glucose, sodium chloride, and mannitol, with 10 mmol/L glutamine (EAS 44) or with 10 mmol/L glutamine and 20 mmol/L Pi(EAS 45), or in Adsol. RBC membranes were studied after 0, 28, 42, and 84 days of storage, and vesicle membranes were studied after 84 days. RBC cholesterol and phospholipid content remained significantly greater (P < .01) in EASs than in Adsol. The degree of membrane vesiculation was more than 50% lower in EASs than in Adsol (P < .01). After 42 days of storage, the accessibility of phosphatidylethanolamine to phospholipases was approximately 1.5 times greater for Adsol and EAS 44 samples than for EAS 45 samples (43.5% v 28%). The rates of phosphatidylserine transport were 43% to 70% lower for stored cells but were not dependent on storage media. The amounts of bands 3 and 4.1 in the microvesicle membranes were not statistically different in any of the preparations. These results suggest that storage of RBCs in glutamine and Pi-medium better maintains ATP, lipid content, and phospholipid asymmetry and results in decreased vesiculation. PMID- 8695819 TI - Kinetics of removal and reappearance of non-transferrin-bound plasma iron with deferoxamine therapy. AB - The rapidity and duration of the response of non-transferrin-bound iron (NTBPI) to chelation therapy are largely unknown and have important implications for the design of optimal chelation regimens. Methodology was developed to measure simultaneously NTBPI, deferoxamine (DFO), and its major metabolite. NTBPI was present in all but 2 of 28 thalassaemia major (TM) patients who had received conventional subcutaneous DFO the previous night, suggesting a short duration of NTBPI clearance by DFO. The detailed kinetics of NTBPI were therefore studied in response to intravenous DFO at 50 mg/kg/27 h for 48 hours and compared in 17 regularly transfused TM and 8 untransfused thalassaemia intermedia (TI) patients to determine the influence of hypertransfusion and iron overload on NTBPI response. Before DFO infusion, NTBPI was present in all patients and was significantly higher in TI (4.52 +/- 0.53 mumol/L) than TM (2.92 +/- 0.03 mumol/L; P = .03). NTBPI values in TM correlated with transferrin saturation (r = .6, P = .03) but not with serum ferritin. Removal of NTBPI by intravenous DFO is in a biphasic manner. The initial rapid rate constant (alpha) was similar in TI (1.5 hour-1) and TM (1.6 hour-1), but the subsequent beta phase was slower (0.04 hour-1) in TI when compared with TM (0.4 hour-1, P = .002). Detectable NTBPI persisted during the beta phase, particularly in TI, despite an excess of plasma DFO also being present (steady state 8 mumol/L). On cessation of DFO infusion, NTBPI reappearance was rapid; the kinetics also being biphasic. The rapid initial rate constant (alpha = 2.5 hour-1) lasted less than 30 minutes and was approximately equal to the summation of the initial rate constant for removal of DFO (1.8 hour-1) and its major metabolite (0.6 hour-1). This was followed by a slower return to pretreatment levels, usually between 6 and 12 hours, which was faster in TI than in TM. This marked NTBPI lability supports the use of continuous rather than intermittent DFO in high risk patients. PMID- 8695820 TI - Relapse after non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: early transplantation, use of an unrelated donor, and chronic graft-versus-host disease are protective. AB - We analyzed the incidence of posttransplant chronic myelogenous leukemia (CML) relapse in 283 consecutive related-donor (n = 177) and unrelated-donor (n = 106) allogeneic transplant recipients. Twenty-two of 165 related-donor recipients with stable or advanced disease at the time of transplant had hematologic relapse of CML following transplant (5-year Kaplan-Meier estimate of relapse, 20%; 95% confidence interval [CI], 11 to 30%). One of 12 patients transplanted in second stable phase following blast crisis also relapsed. Fifteen related-donor transplant recipients relapsed within 5 years of transplant; however, seven relapsed between 5 and 9 years after transplant. Factors independently associated with an increased risk of posttransplant relapse for related-donor recipients included prolonged interval between diagnosis and transplant (relative risk, [RR], 3.81; P = .009) and bone marrow basophilia (RR, 5.62; P = .01). Related donor recipients with posttransplant chronic graft-versus-host disease (CGVHD) had a decreased risk of relapse (RR, 0.24; P = .005). Only two of 106 unrelated donor transplant recipients relapsed following transplant (5-year Kaplan-Meier estimate of relapse, 3%; 95% CI, 0% to 7%). When both related- and unrelated donor recipients were considered, the use of an unrelated donor was independently associated with a decreased risk of relapse (RR, 0.24; P = .07). Twelve of 16 relapsing patients who received further therapy (nine of 13 who underwent second transplant and three of three who received donor leukocyte infusions) remain alive. This analysis shows that relapse, sometimes occurring long after transplant, is an important adverse outcome in allogeneic transplantation for CML. Early transplant, posttransplant CGVHD, and use of an unrelated donor are associated with a reduced incidence of relapse, perhaps due to allogeneic disparities enhancing the graft-versus-leukemia effect. PMID- 8695821 TI - Generation of primary antigen-specific human cytotoxic T lymphocytes in human/mouse radiation chimera. AB - Severe combined immunodeficient (SCID) mice are increasingly used as hosts for the adoptive transfer of human lymphocytes. Human antibody responses can be obtained in these xenogeneic chimeras, but information about the functionality of the human T cells in SCID mice is limited and controversial. Studies using human peripheral blood lymphocytes (PBL) injected intraperitoneally (IP) into SCID mice (hu-PBL-SCID mice) have shown that human T cells from these chimeras are anergic and have a defective signaling via the T-cell receptor. In addition, their antigenic repertoire is limited to xenoreactive clones. In the present study, we tested the functionality of human T cell in a recently described chimeric model. In this system, BALB/c mice are conditioned by irradiation and then transplanted with SCID bone marrow, followed by IP injection of human PBL. Our experiments demonstrated that human T cells, recovered from these hu-PBL-BALB mice within 1 month posttransplant, proliferated and expressed activation markers upon stimulation with anti-CD3 monoclonal antibody. A vigorous antiallogeneic human cytotoxic T-lymphocyte (CTL) response could be generated in these mice by immunizing them with irradiated allogeneic cells. Moreover, anti-human immunodeficiency virus type 1 (HIV-1) Net-specific human CTLs could be generated in vivo from naive lymphocytes by immunization of mouse-human chimeras with a recombinant vaccinia-nef virus. This model may be used to evaluate potential immunomodulatory drugs or cytokines, and could provide a relevant model for testing HIV vaccines, for production of antiviral T-cell clones for adoptive therapy, and for studying human T-cell responses in vivo. PMID- 8695822 TI - Electroporation of synthetic oligodeoxynucleotides: a novel technique for ex vivo bone marrow purging. AB - Recent data suggest that tumor cells contaminating reinfused bone marrow may contribute to relapse in patients undergoing autologous bone marrow transplantation. Purging strategies that are able to remove these contaminating tumor cells need to be developed. This study describes how electroporation (EP) can be used to improve intracellular delivery of synthetic antisense oligodeoxynucleotides (ODNs), thereby enhancing their ability to suppress a target protein. Antisense ODNs that were introduced into cells by EP led to immediate suppression of targeted c-myc protein; this was associated with rapid cell death in the diffuse histiocytic lymphoma, U937; Burkitt's lymphoma, ST486; breast carcinoma, MCF-7; and Ewing's sarcoma, CHP-100, cell lines. Electroporation was found to have little or no detrimental effect on cells responsible for murine hematopoietic long-term reconstitution as determined from in vivo competitive repopulation studies. Using human c-myc-directed antisense ODNs as a model for the application of this approach to bone marrow purging, selective killing of human lymphoma U937 cells relative to normal human bone marrow cells was shown in cell mixing studies. In vivo studies were performed in which a survival advantage was shown for athymic mice that were inoculated with antisense-treated U937 cells as opposed to control cells. These studies suggest that EP of bone marrow may be of use in enhancing intracellular delivery of a variety of molecular/pharmaceutical agents. Taken together, these data suggest that the use of electroporation to enhance delivery of antisense ODNs is a promising new approach towards ex vivo bone marrow purging. PMID- 8695823 TI - Syngeneic bone marrow transplantation without conditioning in a patient with paroxysmal nocturnal hemoglobinuria: in vivo evidence that the mutant stem cells have a survival advantage. AB - A 10-year-old girl with paroxysmal nocturnal hemoglobinuria (PNH) received an infusion of syngeneic bone marrow without preparative marrow ablation or immunosuppression. Following transplant, the patient became asymptomatic in concordance with an increase in the percentage of peripheral blood cells with normal expression of glycosyl phosphatidylinositol-anchored proteins (GPI-AP). However, molecular analysis suggested engraftment of a relatively small number of donor stem cells and persistence of an abnormal stem cell with mutant PIG-A. During 17 months of observation, the percentage of cells with normal GPI-AP expression gradually decreased, while intravascular hemolysis progressively increased. Approximately 16.5 months post-transplant, the patient once again became symptomatic. Together, these results indicate that syngeneic marrow infusion provided a clinical benefit by increasing the proportion of erythrocytes with normal expression of GPI-anchored complement regulatory proteins without supplanting the abnormal stem cells. However, evidence of insidious disease progression following the marrow infusion implies that the abnormal stem cells have a survival advantage relative to the transplanted stem cells. Thus, these studies contribute in vivo data in support of the hypothesis that PNH arises as a consequence of a pathological process that selects for hematopoietic stem cells that are GPI-AP-deficient. PMID- 8695824 TI - Splenic marginal zone lymphoma. PMID- 8695826 TI - High-dose cytarabine induction for acute myeloid leukemia. PMID- 8695825 TI - Hepatitis C virus infection: a new bridge between hematologists and gastroenterologists? PMID- 8695827 TI - Autologuous marrow recovery in a multitransfused beta-thalassemia major patient after umbilical cord blood transplantation. PMID- 8695828 TI - A stratification system for evaluating and selecting therapies in patients with relapsed or primary refractory acute myelogenous leukemia. PMID- 8695829 TI - Interferon gamma and tumor necrosis factor alpha mRNA expression in mycosis fungoides progression. PMID- 8695830 TI - Severe combined immunodeficient mouse models of human leukemia. PMID- 8695831 TI - Transduction of primitive human hematopoietic cells with recombinant adenovirus vectors. AB - We have examined the ability of recombinant adenoviral vectors to transduce human hematopoietic cells. Our findings indicate that adenovirus readily infects a large proportion of CD34+ cells. Using adenovirus vectors that transduce either a lacZ or an alkaline phosphatase reporter gene, we observed up to 45% of total CD34+ cells infected. Upon more detailed analysis, we observed comparable levels of transduction for CD34+/CD38- cells and for CD34+ cells in G(zero) phase of the cell cycle. Importantly, exposure to adenovirus resulted in negligible levels of toxicity as assayed by propidium iodide staining and colony-forming ability. Using adenovirus vectors, we also describe a model system for regulated gene expression in early hematopoietic tissues. CD34+ cells were simultaneously infected with two viruses, one carrying a TetR/VP16 transactivator (tTA) and the second carrying a tTA-dependent lacZ reporter gene. Using this approach, beta-gal expression was only observed upon coinfection with the transactivator vector. In addition, as shown previously (Gossen and Bujard, Proc Natl Acad Sci USA 89:5547, 1992), tetracycline was able to inhibit tTA mediated induction, thereby providing an effective means to regulate expression of the reporter gene. We conclude that recombinant adenovirus is an effective vehicle for transiently expressing genes in primitive human hematopoietic cells. PMID- 8695832 TI - A novel protein tyrosine phosphatase expressed in lin(lo)CD34(hi)Sca(hi) hematopoietic progenitor cells. AB - Stem cells are capable of extensive self-renewal in the absence of differentiation. The maintenance of this undifferentiated state occurs despite the fact that this cell is exposed to a milieu that is rich in a variety of growth and differentiation factors. A unifying feature of such hematopoietic factors is that they mediate their effects through the phosphorylation of tyrosine residues by various cellular kinases. Therefore, one mechanism that might inhibit such differentiation signals in the self-renewing stem cell is the dephosphorylation of tyrosine residues by protein tyrosine phosphatases (PTPs). We have thus investigated the types of tyrosine phosphatases expressed by murine embryonic lin(lo)CD34hiSca(hi) hematopoietic progenitor cells by using a consensus polymerase chain reaction (PCR) approach. Although many known tyrosine phosphatases were detected using this method, a novel PTP related to the previously described PTP PEST type enzymes, murine PTP PEP and murine/human PTP PEST, was also observed. Cloning of the full-length cDNA encoding this enzyme showed that it was indeed a novel new member of this family, with an amino terminal tyrosine phosphatase domain followed by a region rich in serine, threonine, and proline. The carboxy terminus of this novel PTP contained a short sequence that was homologous to a region of the murine PTP PEP that was involved with nuclear localization. Bacterial expression of the phosphatase domain showed that this enzyme could efficiently dephosphorylate tyrosines in vitro. Analysis of the expression of the novel nuclear PTP by quantitative PCR showed that the transcript disappeared as the lin(lo)CD34hiSca(hi) cells differentiated in the presence of interleukin-1, interleukin-3, erythropoietin, and granulocyte macrophage colony-stimulating factor. In agreement with its potential role in the hematopoietic progenitor cell, this novel PTP was expressed at a barely detectable level in a very limited subset of adult tissues. However, analysis of several murine hematopoietic progenitor cell lines, but not of a differentiated T cell line, showed a high level of expression of the novel PTP. These data suggest that this novel phosphatase may play a critical role in the maintenance of the undifferentiated state of the hematopoietic stem cell. PMID- 8695833 TI - Cytokine regulation of proliferation and cell adhesion are correlated events in human CD34+ hemopoietic progenitors. AB - Adhesive interactions with the extracellular matrix of the bone marrow (BM) stroma are of critical importance in the regulation of hematopoiesis. In part, these interactions are presumed to play an important role in retaining CD34+ hematopoietic progenitor cells (HPCs) within the BM environment, in close proximity with BM stromal cells and the cytokines they produce. Evidence of a more direct role for cell adhesion in the regulation of hematopoiesis is provided by recent data showing that adhesive interactions can also provide important costimulatory signals. We have previously shown that normal CD34+ HPCs express high levels of fibronectin (Fn) receptors very late antigen-4 (VLA-4) and VLA-5 in a low-affinity state, which do not allow HPCs to strongly adhere on immobilized Fn, and that cytokines such as interleukin-3, granulocyte-monocyte colony-stimulating factor, and stem cell factor transiently activate these receptors, providing HPCs with an adhesive phenotype on Fn. Thus, knowledge of the functional states of adhesion receptors is critical to our understanding of the physiological mechanisms responsible for the regulation of normal hematopoiesis. Herein, we show that combinations of cytokines that synergize to stimulate the proliferation of CD34+ HPCs result in additive stimulation of the adhesion of these cells to Fn. Thus, the activation level of Fn receptors expressed by normal CD34+ HPCs is highly correlated with their proliferative state, suggesting a functional link between these two events. Therefore, we propose a 2-step model with an initial activation of VLA-4 and VLA-5 generated by cytokine receptors that is followed by a secondary signal resulting from Fn binding to VLA-4 and VLA-5, which may cooperate with those generated by cytokine receptors. PMID- 8695834 TI - Direct visualization of dispersed 11q13 chromosomal translocations in mantle cell lymphoma by multicolor DNA fiber fluorescence in situ hybridization. AB - Several hematologic malignancies are associated with specific chromosomal translocations. Because of the dispersed distribution, chromosomal breakpoints may be difficult to detect using molecular techniques. We present a new application of a recently developed method, DNA fiber fluorescence in situ hybridization (fiber FISH), which allows direct visualization and mapping of chromosomal breakpoints. We tested this method for detection of the t(11;14)(q13;q32) translocation in mantle cell lymphoma. In DNA fiber FISH, a series of fluorochrome-labeled DNA probes covering several hundreds of kilobasepairs is hybridized to linear DNA molecules (or fibers) prepared from frozen tissue or intact cells. By using alternate fluorescent colors, a potential breakpoint region is stained in a color barcode pattern. Breaks in this region will split the barcode in two complementary parts, from which the breakpoint position can be derived. We used a 250-kb barcode covering the BCL-1 locus to detect 11q13 breakpoints in 20 well-characterized mantle cell lymphomas. A t(11;14) was shown by cohybridization of these probes with probes for the Ig heavy chain locus at 14q32. In 18 of 20 mantle cell lymphomas, a breakpoint within the 11q13/BCL-1 barcode was shown by the presence of multiple, complementary translocation products. Fusion of 11q13 and 14q32 sequences on single fibers indicating t(11;14)(q13;q32) was found in all 18 breakpoint positive mantle cell lymphomas. In one additional case, fusion of an intact 11q13 barcode with 14q32 sequences indicated a breakpoint 100 kb centromeric of the major translocation cluster of BCL-1. Within the 120-kb region of BCL-1, breakpoints were widely scattered. This explains why, so far, a BCL-1 breakpoint had been detected by Southern blot analysis in only 10 of 19 cases. DNA fiber FISH analysis showed a t(11;14) in 95% of mantle cell lymphoma. The results indicate that DNA fiber FISH is a rapid, simple, and equally powerful method for detection of clustered and dispersed translocation breakpoints. PMID- 8695835 TI - Moderation of hemophilia A phenotype by the factor V R506Q mutation. AB - Although many examples of unrelated hemophilia A patients carrying identical point mutations in the factor VIII (FVIII) gene have been reported, the clinical phenotype is not always the same among patients sharing the same molecular defect. Possible explanations for this discrepancy include undetected additional mutations in the FVIII gene or coinheritance of mutations at other genetic loci that modulate FVIII function. We report molecular genetic analysis of potential modifying genes in two sets of unrelated patients carrying common FVIII missense mutations but exhibiting different levels of clinical severity. Both mutations (FVIII R1689C and R2209Q) are associated with severe hemophilia A in some patients and mild/moderate disease in others. The common von Willebrand disease type 2N mutation (R91Q) was excluded as a modifying factor in these groups of patients. However, analysis of the recently described factor V (FV) R506Q mutation (leading to activated protein C resistance) identified a correlation of inheritance of this defect with reduced hemophilia A severity. Two moderately affected hemophilia A patients, each with either of two FVIII gene mutations, were heterozygous for FV R506Q, whereas two severely affected patients and two moderately affected patients were homozygous normal at the FV locus. Our results suggest that coinheritance of the FV R506Q mutation may be an important determinant of clinical phenotype in hemophilia A and that modification of the protein C pathway may offer a new strategy for the treatment of FVIII deficiency. PMID- 8695836 TI - A phase I study of bolus versus continuous infusion of the anti-CD19 immunotoxin, IgG-HD37-dgA, in patients with B-cell lymphoma. AB - IgG-HD37-SMPT-dgA is a deglycosylated ricin A chain (dgA)-containing immunotoxin (IT) prepared by conjugating the monoclonal murine (MoAb) anti-CD19 antibody, HD37, to dgA using the heterobifunctional hindered disulfide linker, N succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyldithio) toluene (SMPT). In this report, we have used two regimens for the administration of IgG-HD37-SMPT dgA to patients with non-Hodgkin's lymphoma (NHL) in two concomitant phase I trials. One trial examined four intermittent bolus infusions administered at 48 hour intervals. The other studied a continuous infusion (CI) administered over the same 8-day period. In the intermittent bolus regimen, the maximum tolerated dose (MTD) was 16 mg/m2/8 d and the dose-limiting toxicity (DLT) consisted of vascular leak syndrome (VLS), aphasia, and evidence of rhabdomyolysis encountered at 24 mg/m2/8 d. Using the CI regimen, the MTD was defined by VLS at 19.2 mg/m2/8 d. At the MTD of both regimens, a novel toxicity, consisting of acrocyanosis with reversible superficial distal digital skin necrosis in the absence of overt evidence of systemic vasculitis, occurred in 3 patients. Of 23 evaluable patients on the bolus schedule, there was 1 persisting complete response (CR; > 40 months) and 1 partial response (PR). Of 9 evaluable patients on the continuous infusion regimen, there was 1 PR. Pharmacokinetic parameters for the bolus regimen at the MTD showed a mean maximum serum concentration (Cmax) of 1,209 +/- 430 ng/mL, with a median T1/2 beta for all courses of 18.2 hours (range, 10.0 to 80.0 hours), a volume of distribution (Vd) of 10.9 L (range, 3.1 to 34.5 L), and a clearance (CL) of 0.45 L/h (range, 0.13 to 2.3 L/h). For the CI regimen at MTD, the mean Cmax was 963 +/- 473 ng/mL, with a median T1/2 beta for all courses of 22.8 hours (range, 24.1 to 30.6 hours), a Vd of 9.4 L (range, 4.4 to 19.5 L), and a CL of 0.32 L/h (range, 0.12 to 0.55 L/h). Twenty-five percent of the patients on the bolus infusion regimen and 30% on the CI regimen made antibody against mouse Ig (HAMA) and/or ricin A chain antibody (HARA). We conclude that this IT can be administered safely and that both regimens achieve comparable peak serum concentrations at the MTD; these concentrations are similar to those achieved previously using other regimens with IgG-dgA ITs at their respective MTDs. Thus, toxicity is related to the serum level of the IT and does not differ with different targeting MoAbs. PMID- 8695837 TI - Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study. AB - A phase III prospective randomized multicenter study was performed to determine whether quinine could improve the response rate of poor-risk acute leukemias (ALs) to standard chemotherapy including a multidrug resistance (MDR)-related cytotoxic agent. The rationale of the study was based on the negative prognostic value of MDR phenotype in ALs and the ability of quinine to reverse this phenotype both in vitro and ex vivo. Three hundred fifteen patients (median age, 49 years; range, 16 to 65) with relapsed (n = 108) or refractory (n = 32) acute myeloblastic leukemia (AML), relapsed (n = 27) or refractory (n = 9) acute lymphoblastic leukemia (ALL), secondary AL (n = 22) or blastic transformation of myelodysplastic syndrome ([MDS] n = 74) or myeloproliferative syndrome ([MPS] n = 43) were randomly assigned to receive mitoxantrone ([MXN] 12 mg/m2/d, days 2 to 5) and cytarabine ([Ara-C] 1 g/m2/12 h, days 1 to 5) alone or in combination with quinine (30 mg/kg/d, days 1 to 5; continuous intravenous infusion beginning 24 hours before MXN infusion). Side effects of quinine were observed in 56 of 161 quinine-treated patients and disappeared in all but four cases after one or two 20% dose decreases. Sera from quinine-treated patients showed increased MXN uptake in an MDR-positive cell line compared with matched sera obtained before quinine infusion. Quinine induced a significant increase in the incidence of nausea, vomiting, mucositis, and cardiac toxicity. A complete response (CR) was observed in 85 of 161 patients (52.8%) from the quinine-treated group versus 70 of 154 patients (45.5%) in the control group (P = .19). The most important differences between quinine and control group CR rates were observed in patients with refractory AMLs and blastic transformation of MDS and MPS. The CR rate was higher in P-glycoprotein-positive cases, although the difference was not significant. Failure of the regimen due to blastic persistence or blast number increase was higher in the control group (61 of 154 patients) than in the quinine group (45 of 161, P = .04). Early death was observed in eight cases (four in each arm) and death in aplasia in 27 cases (20 in quinine group v seven in control group, P = .01). The significant increase of toxicity in the quinine arm could have masked the clinical benefit of MDR reversion in poor-risk ALs. PMID- 8695838 TI - Granulocyte-macrophage colony-stimulating factor preferentially activates the 94 kD STAT5A and an 80-kD STAT5A isoform in human peripheral blood monocytes. AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces immediate effects in monocytes by activation of the Janus kinase (JAK2) and STAT transcription factor (STAT5) pathway. Recent studies have identified homologues of STAT5, STAT5A, and STAT5B, as well as lower molecular weight variants of STAT5. To define the activation of the STAT5 homologues and lower molecular weight variant in human monocytes and monocytes differentiated into macrophages by culture in macrophage-CSF (M-CSF), we measured the GM-CSF induced tyrosine phosphorylation of STAT5A, STAT5B, and any lower molecular weight STAT5 isoforms. Freshly isolated monocytes expressed 94-kD STAT5A, 92-kD STAT5B, and an 80-kD STAT5A molecule. Whereas 94-kD STAT5A was clearly tyrosine phosphorylated and bound to the enhancer element, the gamma response region (GRR), of the Fc gamma RI gene, substantially less tyrosine phosphorylated STAT5B bound to the immobilized GRR element. Macrophages lost their ability to express the 80-kD STAT5A protein, but retained their ability to activate STAT5A. STAT5A-STAT5A homodimers and STAT5A-STAT5B heterodimers formed in response to GM-CSF. Therefore, activation of STAT5A predominates compared to STAT5B when assayed by direct immunoprecipitation and by evaluation of bound STATs to immobilized GRR. Selective activation of STAT5 homologues in addition to generation of lower molecular isoforms may provide specificity and control to genes expressed in response to cytokines such as GM-CSF. PMID- 8695839 TI - Recombinant human macrophage colony-stimulating factor in nonhuman primates: selective expansion of a CD16+ monocyte subset with phenotypic similarity to primate natural killer cells. AB - The CD16 receptor (Fc gamma R-III) is found on many tissue macrophages (M phi s), but its expression on circulating monocytes is restricted to a small, phenotypically distinct subset. The number of these CD16+ monocytes may be markedly increased in response to sepsis, human immunodeficiency virus infection, or metastatic malignancy. We have recently shown that the CD16+ monocyte population is selectively expanded by administration of recombinant human macrophage colony-stimulating factor (rhM-CSF). In the current study, we used the highly rhM-CSF-responsive cynomolgus primate model to further characterize this novel monocyte population. Animals treated with rhM-CSF underwent a progressive and essentially complete conversion to the CD16+ monocyte phenotype, with up to a 50-fold increase in the number of CD16+ cells. This increase was paralleled by the emergence of a population of circulating cells that morphologically resembled large granular lymphocytes (LGLs). However, quantitatively, this population corresponded closely to the number of CD16+ monocytes, and fluorescence-activated cell sorting (FACS) confirmed that they were the same. In addition to their LGL like morphology, many rhM-CSF-induced CD16+ monocytes showed a pattern of size, granularity, and quantitative cell surface marker expression that closely resembled the pretreatment LGL/natural killer (NK) cell population but that did not resemble the pretreatment monocyte population. However, rhM-CSF-induced CD16+ monocytes could be distinguished from LGL/ NK cells by fact that they all expressed cell surface receptors for rhM-CSF, and many of them showed reduced but detectable phagocytic and respiratory burst activity. Studies of human subjects treated with rhM-CSF also showed an analogous population of "LGL-appearing" CD16+ mononuclear cells. Thus, our studies reveal a previously unsuspected ability of cells in the monocyte lineage to adopt a phenotype similar to that of LGL/NK cells. The extent of this phenotypic convergence suggests that the two lineages retain access to elements of a similar developmental pathway. PMID- 8695840 TI - Involvement of transcription factor encoded by the mi locus in the expression of c-kit receptor tyrosine kinase in cultured mast cells of mice. AB - The mi locus of mice encodes a member of the basic-helix-loop-helix-leucine zipper (bHLH-Zip) protein family of transcription factors (hereafter called MITF). Cultured mast cells of mi/mi genotype (mi/mi CMCs) did not normally respond to stem cell factor (SCF), a ligand for the c-kit receptor tyrosine kinase. The poor response of mi/mi CMCs to SCF was attributed to the deficient expression of c-kit both the mRNA and protein levels. The purpose of the present study is to investigate the effect of MITF on the transcription of the c-kit gene. First, we introduced cDNA encoding normal (+) MITF or mutant (mi) MITF into mi/mi CMCs using the retroviral vector. Overexpression of (+)-MITF but not mi MITF normalized the expression of the c-kit and the poor response of mi/mi CMCs to SCF, indicating the involvement of (+)-MITF in the c-kit gene transactivation. Second, we analyzed the promoter of the c-kit gene. Three CANNTG motifs recognized by bHLH-Zip-type transcription factors were conserved between the mouse and human c-kit promoters. Among these three CANNTG motifs, only the CACCTG motif (nt -356 to -351) was specifically bound by (+)-MITF. When the luciferase gene under the control of the c-kit promoter was contransfected into NIH/3T3 fibroblasts with cDNA encoding (+)-MITF or mi-MITF, the luciferase activity significantly increased only when (+)-MITF cDNA was cotransfected. The deletion of the promoter region containing the CACCTG motif or the mutation of the CACCTG to CTCCAG abolished the transactivation effect of (+)-MITF, indicating that (+) MITF transactivated the c-kit gene through the CACCTG motif. When the luciferase gene under the control of the c-kit promoter was introduced into the FMA3 mastocytoma and FEC-P1 myeloid cell lines, remarkable luciferase activity was observed only in FMA3 cells. Thus, the involvement of (+)-MITF in the c-kit transactivation appeared to be specific to the mast cell lineage. PMID- 8695841 TI - PU.1 (Spi-1) and C/EBP alpha regulate the granulocyte colony-stimulating factor receptor promoter in myeloid cells. AB - Cytokines, important for lineage commitment and differentiation during hematopoiesis, exert their influence by binding specific receptors. Receptor expression is tightly regulated and examining the factors that govern their expression will allow better understanding of the events that determine lineage commitment. The granulocyte colony-stimulating factor (G-CSF) receptor is expressed exclusively in myeloid cells and the placenta. We show here that the G CSF receptor transcription start site is identical in each of these tissues. A 1,391-bp fragment of the G-CSF receptor promoter is both active in myeloid cell lines and tissue specific. We have also found two regions that are important for G-CSF receptor promoter activity. One region, located at bp -49, contains a GCAAT site that specifically binds the C/EBP alpha transcription factor in myeloid nuclear extracts. Mutation of this site prevents C/EBP alpha binding and reduces promoter activity by 60%. The other functionally important region of the G-CSF receptor promoter is in the 5' untranslated region, at bp +36 and +43, where there are two sites for the ets family member PU.1. Mutation of these sites prevents PU.1 binding and reduces promoter activity by 75%. These results reinforce the importance of both PU.1 and C/EBP alpha in the expression of myeloid-specific genes and neutrophil development. PMID- 8695842 TI - The proto-oncogene c-myc blocks myeloid differentiation independently of its target gene ornithine decarboxylase. AB - Ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis, has been shown to be required for entry into and progression through the cell cycle and to be a transcriptional target of the proto-oncogene, c-myc. We show that ODC transcripts and enzyme activity are down-regulated following induction of myeloid differentiation, using M1 myeloblastic leukemic cells and normal cells from bone marrow (BM), and fail to be suppressed when c-myc expression is deregulated. In M1mycer cells, when endogenous c-myc expression has been suppressed following stimulation by interleukin-6 (IL-60), treatment with estrogen and cycloheximide results in induction of ODC transcripts. These data demonstrate that ODC is a c-myc target gene in M1 cells. It was of interest to determine whether deregulated ODC expression would alter the myeloid differentiation program. To answer this question, M1-ODC cell lines constitutively expressing ODC were established. These cells can undergo terminal differentiation and growth arrest following IL-6 stimulation, exactly like parental M1 cells, demonstrating that deregulated ODC expression is not sufficient to block myeloid differentiation. Another question to be answered was whether ODC expression is necessary for the c-myc-mediated block in differentiation. The use of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC enzyme activity, indicates that ODC is not necessary for the c myc-mediated differentiation block. PMID- 8695844 TI - A limited temporal window for the derivation of multilineage repopulating hematopoietic progenitors during embryonal stem cell differentiation in vitro. AB - Embryonal stem cells have been shown to differentiate in vitro into all hematopoietic lineages. This has been used successfully as one approach to the study of genetic events occurring during haematopoiesis. However, studies on the commitment of mesodermal precursors to the hematopoietic lineage have been limited due to the inability to define a system in which embryonal stem (ES) cells will give rise to primitive hematopoietic stem cells in vitro. Using a colony forming assay (CFU-A), we determined that the earliest time point at which primitive multilineage hematopoietic precursors can be detected during ES cell differentiation in vitro in the absence of exogenous conditioned medium or stromal cell culture is 4 days. Lethally irradiated adult recipient mice that received differentiated ES cells from this time point survived for more than 3 weeks; and in two out three experiments, peripheral blood from these animals contained ES-derived progeny. Fluorescence activated cell sorting (FACS) found ES derived CD45+ hematopoietic cells in both lymphoid and myeloid compartments at 12 weeks posttransplantation, suggesting that the population of day 4 differentiated ES cells contains primitive hematopoietic precursors. A preliminary RT-PCR analysis of gene expression around this time point suggests that there are very few hematopoietic cells present. This approach should prove useful in studies of genetic control of commitment to and maintenance of hematopoietic lineages in vitro and in vivo. PMID- 8695843 TI - Combined signaling through interleukin-7 receptors and flt3 but not c-kit potently and selectively promotes B-cell commitment and differentiation from uncommitted murine bone marrow progenitor cells. AB - Multiple cytokines can synergize to stimulate the in vitro proliferation and exclusive myeloid differentiation of multipotent bone marrow progenitor cells. The ligand for c-kit (stem cell factor [SCF]) plays a key role in stimulating myeloid and erythroid cell production of primitive hematopoietic progenitors. SCF in combination with interleukin-7 (IL-7) can also stimulate the combined myeloid and B-cell differentiation of uncommitted hematopoietic progenitor cells as well as the growth of early B-cell progenitor cells, although the involvement of c-kit in early B lymphopoiesis remains controversial. In the present study, the flt3 ligand (FL), which, in combination with other cytokines, has overlapping activities with SCF on myeloid cell production from uncommitted progenitors, was investigated for its ability to induce selective stroma-independent B-cell commitment from uncommitted Lin-Sca-1+ bone marrow progenitor cells. IL-7 alone did not induce any clonal growth and FL alone gave rise to a few clusters (< 50 cells) but no colonies (> 50 cells), whereas the combined stimulation with FL and IL-7 resulted in clonal growth of 10% of Lin-Sca-1+ bone marrow cells. After 12 days of incubation of Lin-Sca-1+ cells in FL + IL-7, an almost 400-fold increase in cell production was observed. Phenotyping showed that greater than 99% of the cells produced were of the B-cell lineage, in that they expressed B220, but not cell surface markers specific for myeloid, erythroid, or T-cell lineages. Furthermore, the cells did not express cytoplasmic mu-heavy chain (cmu) or surface IgM, but were positive for CD24 (heat stable antigen [HSA]) and CD43 (leukosialin), suggesting that the cells produced were blocked at a late pro-B cell stage. Interestingly, although all FL + IL-7-responsive Lin-Sca-1+ progenitor cells and the resulting pro-B cells expressed c-kit, FL + IL-7 was much more potent (62-fold) than SCF + IL-7 in stimulating production of cells of the B-cell lineage. In addition, whereas FL + IL-7 selectively stimulated the production of pro-B cells, SCF + IL-7 predominantly stimulated the production of mature granulocytes. Replating studies showed that FL + IL-7-responsive Lin-Sca 1+ progenitors were not committed to the B-cell lineage, because after 2 days of incubation in FL + IL-7, 80% of the progenitors retained a myeloid potential. As much as 27% of the FL + IL-7-responsive progenitors remained uncommitted after 7 days of incubation, but all had committed to the B-cell lineage after 10 days of incubation in FL + IL-7. These results show that FL much more potently and selectively than SCF synergizes with IL-7 to enhance B-cell commitment and development from uncommitted progenitor cells. PMID- 8695845 TI - Direct infection of CD34+ progenitor cells by human cytomegalovirus: evidence for inhibition of hematopoiesis and viral replication. AB - We successfully infected fluorescence-activated cell-sorted CD34+ cells from normal cord blood by the human cytomegalovirus (HCMV) laboratory strain Towne. An inhibitory effect of HCMV on clonogenic myeloid progenitors was observed in primary methylcellulose cultures. After an initial 7-day liquid culture of CD34(+)-infected cells, this inhibition was further amplified in secondary methylcellulose cultures, then involving both the myeloid and erythroid lineages. Under these conditions, viral DNA was detected both in erythroid and myeloid colonies using the polymerase chain reaction (PCR), but reverse transcription PCR (RT-PCR) failed to detect viral RNA. In contrast, when CD34(+)-infected cells were maintained in liquid suspension, both immediate, early, and late transcripts were detected as soon as day 3. In addition, viral production was demonstrated in the culture supernatants, thus confirming that a complete viral cycle occurred under liquid conditions. Furthermore, by resorting cells into CD34+ and CD34- fractions, we showed by RT-PCR that viral replication took place in cells still expressing CD34 antigen, whereas no RNA was found in more differentiated cells that had subsequently lost their CD34 antigen. These findings suggest that HCMV replication can occur at the early steps of progenitor differentiation and may be involved in the viral-induced myelosuppression. PMID- 8695846 TI - Characterization of a bipotent erythro-megakaryocytic progenitor in human bone marrow. AB - The aim of the present study was to determine if the human erythroid (E) and megakaryocytic (MK) lineages were closely linked to the existence of a bipotent burst-forming unit (BFU) E/MK progenitor. In methylcellulose cultures, BFU-E/MK colonies were observed at day 12 and closely resembled mature BFU-E with the exception that the erythroid component was surrounded by MK. These colonies were quite different from the colony forming unit (CFU)-GEMM-derived colonies, which were composed of a larger number of erythroblasts and which developed later in culture. The existence of these bilineage colonies composed of 100 to 1,000 erythroblasts intermingled with a few MK and without granulocytic cells was confirmed by the plasma clot technique and immunoalkaline phosphatase labeling of the MK. To investigate if this bipotent progenitor belonged to the compartment of primitive progenitors, CD34+ marrow cells were subfractionated according to expression of the CD38 antigen. The bipotent BFU-E/MK progenitor as well as a large fraction of MK progenitors were found in the CD34+ CD38+/- or in the CD34+ CD38- cell fractions. Growth of this bipotent BFU-E/MK progenitor required the combination of stem cell factor (SCF), Interleukin-3 (IL-3), and Epo in serum free conditions. Addition of IL-6 had only a marginal effect, whereas megakaryocyte growth and development factor (MGDF) was not an absolute requirement, but slightly increased the plating efficiency of CFU-MK and of BFU E/MK progenitors when combined with SCF, IL-3, and Epo. In contrast, when these cultures were performed in the presence of 30% fetal calf serum, no BFU-E/MK colonies were observed irrespective of the combination of growth factors used, including the presence of MGDF; however, inclusion of the MS-5 cell line restored the growth of this bipotent progenitor. In contrast, in cultures performed in the presence of human normal or aplastic plasma, MS-5 had only a slight effect on the cloning efficiency but improved MK cytoplasmic maturation and MK size, suggesting that the main effect of MS-5 is to diminish the inhibitory effect of the fetal calf serum on the MK differentiation. The clonal origin of bipotent BFU-E/MK colonies was demonstrated in liquid culture of single CD34+ CD38low cells by immunophenotyping individual clones. At day 12, 30% of the clones contained erythroblasts (glycophorin A+) and some MK (CD41+) without granulocytes (G) or macrophages (M) (CD14+ and CD15+). At day 20, clones containing erythroblasts and MK were rare (5%). In contrast multilineage clones could be frequently detected at this time without passage from BFU-E/MK clones at day 12 to GEMM at day 20. These results suggest that a bipotent BFU-E/MK progenitor may be a nonrandom step in the hierarchical development of stem cells. PMID- 8695847 TI - Primitive human hematopoietic cells displaying differential efflux of the rhodamine 123 dye have distinct biological activities. AB - Human bone marrow (BM) CD34+ cells were stained with the vital dye, rhodamine 123 (Rh123), and analyzed for their biological properties based on the level of dye retention. Heterogeneous rhodamine staining is seen within the CD34+ population, and the staining patterns differ dramatically between fetal BM (FBM), adult BM (ABM) and mobilized peripheral blood (MPB). Kinetic analysis of the efflux of Rh123 from ABM CD34+ cells showed that efflux of Rh123 was most rapid from the most primitive Thy-1+ subset. The efflux of Rh123 could be inhibited by verapamil, suggesting that rhodamine efflux from primitive hematopoietic cells is primarily due to the P-glycoprotein (P-gp) pump or another intracellular transport system affected by verapamil. When four CD34+ subpopulations were plated onto SyS1 BM stromal cell cocultures after 1 to 2 weeks, only wells plated with CD34+ Thy-1+Rh123lo (low-level Rh123 retention) or CD34+Thy-1+Rh123mid (mid level Rh123 retention) cells maintained greater than 50% of cells in an uncommitted CD34+33- stage. CD34+Lin- (lineage-negative) cells were fractionated based on Rh123 dye staining into Rh123hi (high-level Rh123 retention), Rh123mid, and Rh123lo and deposited as single cells into long-term SyS1 BM stromal cell cultures. The Rh123mid fraction had immense early proliferative activity in vitro, but lost the ability to form cobblestone areas after 5 to 6 weeks in culture. In contrast, the Rh123lo fraction proliferated more slowly but sustained long-term in vitro hematopoiesis as evidenced by continued cobblestone area forming cells (CAFC) activity for at least 6 weeks. The Rh123hi fraction showed a plating efficiency similar to that of the Rh123lo or Rh1123mid fractions but did not extensively proliferative in vitro and did not show evidence of CAFC activity. We predicted from these in vitro results that the Rh123lo subsets possesses long-term engrafting potential. Indeed, on transplantation into the SCID-hu bone assay, all long-term engrafting potential and multilineage differentiation potential resided within the Rh123lo-mid but not Rh123hi subset. Furthermore, human marrow subpopulations derived from chimeric sheep after in utero transplantation with CD34+Thy-1+Lin- cells were reisolated based on Rh123 staining. Again, CD34+Lin- subsets showing Rh123lo-mid had long-term growth in culture, whereas Rh123hiCD34+Lin- cells did not. These results show that, after injection of CD34+Thy-1+Lin- cells into an in utero microenvironment, primitive CD34+ cells maintain a Rh123 phenotype that correlates with their in vitro CAFC activity. Thus, Rh123 staining is an effective way to define functional subsets of primitive hematopoietic cell populations. PMID- 8695848 TI - Association of smooth muscle cell tissue factor with caveolae. AB - There is still no satisfactory explanation for the low catalytic activity of tissue factor (TF)/factor VII(a) complexes towards coagulation factor X, as found on the apical surface side of cell layers. It has been hypothesized that TF exists in a latent form. Layers of cultured human smooth muscle cells, constitutively expressing TF, were immunogold-labeled for TF in situ and processed for electron microscopy. We showed that, besides internalization and accumulation in lysosomal-like structures, TF remained associated with noncoated, flask-shaped microinvaginations of the plasma membrane. These invaginations were identified as caveolae. In regions in which intercellular contacts were interrupted, more TF-positive caveolae were observed. Enzymatically detached smooth muscle cells exhibited a similar enlargement of caveolar structures. Concomitantly, an increase of catalytic activity of apically formed TF/VIIa complexes towards factor X was found on the suspended cells. We speculate that caveolae-associated TF may function as a latent pool of procoagulant activity, which can rapidly be activated at sites in which vessel wall integrity is lost. PMID- 8695849 TI - Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo. AB - Long-term heparin treatment causes osteoporosis through an as yet undefined mechanism. To investigate this phenomenon, we treated rats with once daily subcutaneous injections of heparin (in doses ranging from 0.25 to 1.0 U/g) or saline for 8 to 32 days and monitored the effects on bone both histomorphometrically and by serial measurements of urinary type 1 collagen cross linked-pyridinoline (PYD) and serum alkaline phosphatase, markers of bone resorption and formation, respectively. Histomorphometric analysis of the distal third of the right femur in the region proximal to the epiphyseal growth plate showed that heparin induces both a time- and dose-dependent decreased in trabecular bone volume, with the majority of trabecular bone loss occurring within the first 8 days of treatment. Thus, heparin doses of 1.0 U/g/d resulted in a 32% loss of trabecular bone. Heparin-treated rats also showed a 37% decrease in osteoblast surface as well as a 75% decrease in osteoid surface. In contrast, heparin treatment had the opposite effect on osteoclast surface, which was 43% higher in heparin-treated rats, as compared with that in control rats. Biochemical markers of bone turnover showed that heparin treatment produced a dose-dependent decrease in serum alkaline phosphatase and a transient increase in urinary PYD, thus confirming the histomorphometric data. Based on these observations, we conclude that heparin decreases trabecular bone volume both by decreasing the rate of bone formation and increasing the rate of bone resorption. PMID- 8695850 TI - Human platelet cGI-PDE: expression in yeast and localization of the catalytic domain by deletion mutagenesis. AB - Cyclic adenosine monophosphate (cAMP) is an important modulator of platelet responses to agonists. Cyclic nucleotide phosphodiesterase (PDE) controls intracellular cAMP concentrations by hydrolyzing it to AMP. The major PDE activity in platelets is PDE3A (cyclic guanosine monophosphate [cGMP]-inhibited PDE). To obtain structural information on platelet PDE3A, we cloned the enzyme cDNA from a human erythroleukemia cell (HEL) library since the cell line expresses many platelet proteins. This clone consists of 87% of the full-length human myocardial PDE3A cDNA, spanning from nucleotides 456 to 4606, and is identical in sequence. The nucleotide coding for the N terminal 179 amino acid sequence (nt 1-536) as well as four other cDNAs (nt 1459-1632, nt 1765-1986, nt 2152-2538, and nt 2978-3375) obtained by RT-PCR of platelet RNA are also identical to the myocardial sequences, indicating that the HEL, myocardial, and platelet PDE3As are the same. Northern blot analysis of HEL cell RNA detected two mRNAs of 7.5 and 4.4 kb. Four new deletion mutants are reported. PDE 3A delta 1 and PDE 3A delta 2, encoding amino acids 665 to 1141 and amino acids 679 to 1141, respectively, were expressed in a PDE-deficient yeast. They displayed PDE activities of 172 and 79 pmol/mg/min, respectively. PDE 3A delta 3 and PDE 3A delta 4, encoding amino acids 686 to 1141 and 700 to 1141, had no detectable PDE activity. All mutant proteins were expressed as determined by Western blot analysis. These findings localize the PDE3A catalytic domain to within amino acid residues 679 to 1141. PMID- 8695851 TI - p120c-cbl is present in human blood platelets and is differentially involved in signaling by thrombopoietin and thrombin. AB - To investigate the signaling processes induced by recombinant thrombopoietin, we used human platelets to recently show that thrombopoietin induces rapid tyrosine phosphorylation of Jak2, Tyk2, Shc, Stat3, Stat5, and other proteins in human platelets. Because the apparent molecular weight of a major tyrosine phosphorylated protein in platelets stimulated by thrombopoietin is approximately 120 kD, we examined the possibility that this could be p120c-cbl, a protein known to be involved in signaling by many growth factors. Specific antisera against p120c-cbl recognized the same 120-kD protein in lysates of Jurkat cells, which are known to express p120c-cbl, and platelets, indicating that platelets have p120c-cbl. Thrombopoietin induced rapid tyrosine phosphorylation of p120c-cbl in platelets. Thrombopoietin also induced tyrosine phosphorylation of p120c-cbl in FDCP cells genetically engineered to express the thrombopoietin receptor, c-Mpl. Interestingly, FDCP cells, expressing a truncated c-Mpl devoid of the box-2 domain, proliferate in response to thrombopoietin. However, no increase in tyrosine phosphorylation of p120c-cbl was observed upon treatment of these cells with thrombopoietin, indicating that in this system tyrosine phosphorylation of p120c-cbl may not be essential for cell proliferation. This suggests that tyrosine phosphorylation of p120c-cbl may be required for nonmitogenic responses induced by thrombopoietin in postmitotic cells such as platelets. On the other hand, p120c-cbl was not significantly tyrosine-phosphorylated upon treatment of platelets with thrombin. However, it became incorporated into the Triton X-100 insoluble, 10,000g-sedimentable residue in an aggregation-dependent manner, suggesting that it may have a regulatory role in platelet cytoskeletal processes. p120c-cbl was constitutively associated with a 28-kD adapter protein, Grb2, that was also incorporated into the Triton X-100-insoluble, sedimentable residue dependent on aggregation. Further, we found that p120c-cbl is an endogenous substrate for calpain, a protease that may play a role in postaggregation signaling processes. Our data suggest that p120c-cbl may be involved in signal transduction following ligand binding to c-Mpl through its inducible tyrosine phosphorylation, and it may also be involved in signaling during platelet aggregation by its redistribution to the cytoskeleton. PMID- 8695853 TI - Molecular characterization of antigenic polymorphisms (Ond(a) and Mart(a)) of the beta 2 family recognized by human leukocyte alloantisera. AB - We show that the previously described alloantisera Ond and Mart, which recognize the alloantigens Ond(a) and Mart(a), react with polymorphic variants of alpha L and alpha M subunits of the beta 2 integrin family (CD11a and CD11b molecules). This was shown by testing the alloantisera in a monoclonal antibody-specific immobilization of leukocyte antigens, immunoprecipitation, and immunofluorescence assay against cells from normal donors and from patients with leukocyte adhesion deficiency (beta 2 intergrin deficient). To elucidate the molecular basis of the Ond(a) and Mart(a) alloantigens, RNA was isolated from mononuclear leukocytes derived from individuals of known serologic phenotype. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to amplify the entire coding region of the alpha L and alpha M mRNAs. The Ond(a) antigen was found to be due to a G2466C substitution in the DNA coding for the alpha L subunit, which predicts an Arg766Thr amino-acid polymorphism. The Mart(a) antigen was also found to be due to a single nucleotide substitution (G302A) in the DNA coding for the alpha M subunit, which predicts an Arg61His amino acid polymorphism. Using allele specific restriction enzyme analysis, the association between point mutations and phenotypes was confirmed. The localization of these alloantigens on integrin molecules further illustrates the polymorphic nature of this class of proteins. Whether the polymorphisms influence the adhesive capacity of the leukocyte integrins remains to be investigated. PMID- 8695852 TI - Opposite sorting of tissue factor in human umbilical vein endothelial cells and Madin-Darby canine kidney epithelial cells. AB - Tissue factor (TF) is a 48-kD transmembrane glycoprotein that triggers the extrinsic pathway of blood coagulation by interacting with the plasma coagulation factor VII (FVII). TF is also a true receptor in that a cellular signal is generated when activated FVII (FVIIa) binds to TF. For both of these functions, the cellular surface distribution of TF is important, since FVII is primarily available on the apical side of vascular endothelial cells and on the basolateral side of epithelial cells lining the internal and external surfaces. We show that in endothelial cells, TF (both antigen and procoagulant activity) is sorted to the apical surface, whereas in wild-type and stably transfected Madin-Darby canine kidney epithelial cells (MDCK), which form tight junctions and express TF constitutively, TF antigen is on the basolateral surface. No significant clotting activity is detectable on this surface. Truncated TF (cytoplasmic tail residues 246 to 263 deleted) is sorted as wild-type in MDCK cells. PMID- 8695854 TI - Bcl-x rather than Bcl-2 mediates CD40-dependent centrocyte survival in the germinal center. AB - Both rapid B-cell proliferation and programmed cell death (PCD) occur during the differentiation and selection of B cells within the germinal center. To help elucidate the role of Bcl-x in B-cell antigen selection and PCD within the germinal center, we examined its expression in defined B-cell populations and by immunochemistry of tonsil tissue. Purified B-cell fractions enriched for centrocytes express high amounts of Bcl-x and relatively low amounts of Bcl-2, whereas fractions enriched for centroblasts lack significant levels of both proteins. Consistent with this observation, immunocytochemistry localized Bcl-x within cells scattered throughout the germinal center. Stimulation of tonsil B cells with either CD40 or Staphylococcus aureus Cowan increase bcl-x mRNA and protein levels. Treatment of a cell line with a germinal center phenotype (RAMOS) or the tonsillar B-cell centroblast fraction with CD40 rapidly increased Bcl-x levels and partially rescued B cells from PCD. These data suggest that Bcl-x rather than Bcl-2 may rescue centrocytes during selection in the germinal center. PMID- 8695855 TI - CD38 expression distinguishes two groups of B-cell chronic lymphocytic leukemias with different responses to anti-IgM antibodies and propensity to apoptosis. AB - The expression of CD38 by B cells chronic lymphocytic leukemia (B-CLL) was studied in 20 untreated patients. The cells expressed abundant CD38 (relative fluorescence intensity range, 6 to 15) in 6 cases (group I patients), whereas CD38 expression was low to absent (relative fluorescence intensity range, 0 to 3) in the remaining cases (group II patients). Exposure of the cells from group I patients to goat antihuman mu chain antibodies (Ga mu-ab) resulted in the elevation of intracellular free Ca2+ concentration([Ca2+]i) followed by apoptosis. In contrast, exposure of group II cells to Ga mu-ab was not followed by increased levels of [Ca2+]i, programmed cell death or cell proliferation. No differences in the expression of surface IgM were noted in the two groups of B CLL cells. Normal peripheral blood B cells, which expressed low to absent CD38, were capable of mobilizing [Ca2+]i and of proliferating after exposure to Ga mu ab. The collected data suggest that, although group I B-CLL cells were able to transduce the signals delivered by IgM crosslinking, this pathway was severely impaired in group II B-CLL cells. However, unlike that observed in normal circulating B cells, stimulation of group I cells with Ga mu-ab resulted in apoptosis rather than proliferation. CD38 did not appear to be directly involved in [Ca2+]i mobilization induced by Ga mu-ab in group I B-CLL cells because their exposure to anti-CD38 monoclonal antibodies failed to cause [Ca2+]i mobilization or to block the [Ca2+]i response induced by Ga mu-ab. These data indicate that CD38 expression identified a particular subset of B-CLL cells with defined functional properties, including the propensity to undergo apoptosis. PMID- 8695856 TI - CD4+ T-cell induction of Fas-mediated apoptosis in Burkitt's lymphoma B cells. AB - Cytotoxic function of CD4+ Th1 cells is mediated by Fas (CD95, APO-1) and its ligand (Fas ligand). Recent studies using nontransformed B cells and the Ramos Burkitt's lymphoma (BL) B-cell line cells show that CD40 ligation at the B-cell surface by activated, CD40 ligand (CD40L)-bearing, CD4+ T cells upregulates Fas expression on B cells and primes B cells for Fas-mediated death signals. In this work, we examine whether this CD4+ T-cell-dependent molecular pathway for Fas upregulation and B-cell apoptosis reflects a peculiarity of the Ramos B-cell line or is applicable to other Burkitt's tumors as well. In 5 of the 6 Epstein-Barr virus-negative BL cell lines examined, the cells constitutively express undetectable or low levels of Fas and are resistant to Fas-mediated signals induced by monoclonal anti-Fas antibody. All 6 of the BL cell line B cells upregulate Fas in response to CD40 ligation, and in 4 of the cases they become sensitive to Fas-mediated death signals. In one BL cell line, the cells are constitutively sensitive to Fas-mediated cytolysis and are unaffected by CD40 signals. Next, we applied these immunologic manipulations to cells from a refractory clinical sample and observed that the tumor cells could be induced to express Fas and undergo apoptosis in our system. These results establish CD4+ T cells and the Fas-Fas ligand system as important immune regulators of Burkitt's lymphoma B cells and indicate that the susceptibility of tumor cells to Fas mediated death signals can be modulated by specific activation events at the cell surface. PMID- 8695857 TI - Sezary syndrome T-cell clones display T-helper 2 cytokines and express the accessory factor-1 (interferon-gamma receptor beta-chain). AB - Sezary syndrome (SS) is a leukemic variant of low-grade cutaneous T-cell lymphomas (CTCLs). The clonal T cells in this lymphoproliferative disorder are poorly characterized. Using antibodies against the variable region of the T-cell receptor (TCR V alpha/beta), we identified four predominant T-cell clones (two V beta 8+ clones, one V beta 5.1+, and one V alpha 2(a)+) in peripheral blood mononuclear cells (PBMC) of SS patients. Their phenotype was CD3+, CD4+, CD5+, CD45RO+. Clonal T cells were purified, and cytokine transcription and secretion was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) followed by hybridization with biotinylated probes and enzyme-linked immunosorbent assays (ELISAs). The interleukin-10 (IL-10) PCR product was cloned and sequenced and found to be identical to the published cDNA sequence. The presence of accessory factor-1 (AF-1, or interferon-gamma [IFN-gamma] receptor beta-chain) encoding mRNA was assessed by RT-PCR and immunostaining using serum of rabbits immunized with the extracellular domain of a recombinant human AF-1 protein followed by APAAP staining. Clonal T cells transcribe and secrete mainly T-helper 2 cytokines (IL-10, -5, and -13). mRNA from purified SS clones but not mRNA from SS total PBMC was positive for AF-1 in an agarose gel and/or after hybridization. AF-1 transcription was associated with membrane-bound immunoreactivity for AF-1 in SS clones. SS-derived T-cell clones display T-helper 2 cytokines. This weakens cell mediated immunosurveillance, and explains the clinical and immunologic abnormalities in SS patients. The T-helper 2 cytokine spectrum of all clones investigated is associated with overexpression of AF-1. This suggests that AF-1 is a potential marker for these clones (and eventually other T-helper 2 lymphocytes) and might represent a target for treatment of the disease. PMID- 8695858 TI - AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study. AB - From March 1993 to October 1993, 20 consecutive, newly diagnosed acute promyelocytic leukemia (APL) patients from 13 Italian institutions entered in a pilot study named AIDA, combining all-trans retinoic acid (ATRA) with idarubicin (IDA). ATRA was administered orally beginning on the first day of induction at the dosage of 45 mg/m2/d until complete remission (CR), whereas IDA was administered intravenously at the dosage of 12 mg/m2/d on days 2, 4, 6, and 8 of the induction. Patients who achieved CR were consolidated with 3 courses of chemotherapy without ATRA; thereafter, they were followed up for molecular and hematologic CR. The median age was 35.3 years (range, 6.5 to 67.6 years); 8 patients were males and 12 females; 4 had the hypogranular variant of APL (M3v), and 4 (2 with M3v) presented with leukocyte counts > or = 10,000/microL. Molecular analysis for the promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) hybrid gene at diagnosis was performed in 16 patients by means of reverse transcription-polymerase chain reaction (RT-PCR) analysis, and all were RT-PCR+ for the hybrid gene. In the remaining 4 patients, the cytogenetic study showed the presence of the t(15;17). After a median time of 36 days (range, 28 to 52 days) 18 (90%) patients achieved CR; the remaining 2 patients died 12 and 34 days after diagnosis from myocardial infarction caused by fungal myocarditis and from massive hemoptysis, respectively. ATRA syndrome was observed in only 2 patients, and, after the prompt discontinuation of ATRA and initiation of dexamethasone, both recovered from the syndrome. However, after recovering, 1 patient achieved CR, whereas the other died at day 34 because of massive hemoptysis; other side effects were very limited. At recovery from the third consolidation course, only 3 of 14 (21.4%) tested patients were RT-PCR+ for the PML-RAR alpha hybrid gene. Of these, 2 relapsed shortly afterwards; however, in the last patient, the PML-RAR alpha disappeared at successive testing performed 2 months later. As of September 30, 1995, after a median follow-up period from diagnosis of 27 months (range, 24 to 31 months), the overall survival and event free survival durations are 85% and 69%, respectively; moreover, 14 of 18 (78%) patients who achieved CR are still alive and in first molecular and hematologic CR. Of the 4 relapsed patients, 3 achieved a second CR with ATRA and, after further treatment, are now in molecular and hematologic CR after 4+, 16+, and 17+ months from the second CR. These results indicate that (1) the AIDA protocol is highly effective in treating APL; (2) after 3 consolidation courses, the majority of patients who achieved CR are RT-PCR- for the hybrid gene PML-RAR alpha; (3) the persistence of an RT-PCR positivity for the PML-RAR alpha hybrid gene after 3 consolidation courses is indicative of early relapse, thus these patients still require additional treatment. These results have prompted the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) to initiate, in cooperation with the Associazione Italiana di Ematologia ed Oncologia Pediatrica and some European Organization for Research and Treatment of Cancer (EORTC) centers, a new multicentric clinical trial named AIDA LAP 0493 for the treatment of adult and pediatric APL patients. All patients are considered eligible if APL diagnosis is confirmed with molecular or cytogenetic studies for PML-RAR alpha hybrid gene or t(15;17) and are enrolled to receive the same induction and consolidation therapy of this pilot study. After consolidation, patients who are RT-PCR- for PML-RAR alpha hybrid gene are randomized to four arms, whereas patients who are RT-PCR+ after consolidation undergo, if eligible, an allogenic transplantation procedure. PMID- 8695859 TI - Identification of an oncogenic form of the thrombopoietin receptor MPL using retrovirus-mediated gene transfer. AB - Thrombopoietin and its receptor (MPL) are important regulators of megakaryopoiesis. We have identified an activating mutation of MPL using a combination of a retrovirus-mediated gene transfer and polymerase chain reaction driven random mutagenesis. This point mutation causes a single amino acid substitution from Ser498 to Asn498 in the transmembrane region and abrogates factor-dependency of all interleukin-3-dependent cell lines tested. Murine interleukin-3-dependent Ba/F3 cells expressing the mutated but not the normal form of MPL were tumorigenic when transduced into syngeneic mice. Analysis of intracellular signaling pathways indicated that the mutant MPL protein constitutively activated two distinct signaling pathways, SHC-Raf-MAPK and JAK2 STAT3/STAT5. PMID- 8695860 TI - A clonally distinct recurrence of Burkitt's lymphoma at 15 years. AB - A human immunodeficiency virus-negative male was successfully treated for two occurrences of Burkitt's lymphoma, 15 years apart. As consolidation of his second remission, he underwent high-dose chemotherapy with peripheral blood stem cell transplantation. In an effort to prove whether the second lymphoma was a relapse of the first or a second primary lymphoma, we obtained paraffin-embedded material from both lymphomas. DNA was extracted from this material and amplified by polymerase chain reaction (PCR) using consensus JH and VH region primers. Analysis of the PCR products, which mostly reflects VDJ joints, showed two sharp bands of different molecular size, proving the monoclonal nature of the lymphomas and suggesting that each had different Ig gene rearrangements. Sequencing of both PCR products showed a marked dissimilarity in nucleotide sequence in the clonally unique VDJ joint region, providing strong evidence for the separate cellular genesis of each lymphoma. These results suggest that late relapses of Burkitt's lymphoma should be examined for clonal distinctiveness. If the second lymphoma is distinct from the primary one, it might be treated as a primary lymphoma rather than as recurrent disease. PMID- 8695861 TI - In vitro transcription and translation inhibition by anti-promyelocytic leukemia (PML)/retinoic acid receptor alpha and anti-PML peptide nucleic acid. AB - Peptide nucleic acids (PNAs) complementary to the 15 bases around the fusion point of both genomic DNA and cDNA of the promyelocytic leukemia/retinoic acid receptor alpha (PML/ RAR alpha; P/R) hybrid gene present in acute promyelocytic leukemia cells were synthesized and shown by gel retardation experiments to specifically bind oligonucleotides corresponding to the fusion region of the P/R molecule. PNA was also able to successfully compete with anti-P/R DNA for duplex formation with P/R DNA and to displace the anti-P/R DNA from dsDNA. In vitro transcribed P/R RNA from two inserts of approximately 350 to approximately 700 bp were tested in gel acceleration experiments with fluorescein-conjugated PNA and showed stable binding (resistant to denaturing conditions) of PNA to the newly transcribed RNA. Control RNA or transcripts from the noncoding strand did not bind PNA. However, this PNA, although able to specifically clamp polymerase chain reaction, was incapable of inhibiting in vitro translation of the PML/RAR alpha mRNA, even when a bis-PNA was used. Therefore, a PNA was targeted against the start region of the P/R cDNA and against poly-purine regions of the gene. Specific inhibition of in vitro translation and transcription was shown, starting at concentrations as low as 100 nmol/L. When oligonucleotides presenting the same sequence were compared, PNA proved to be approximately 40 times more active. In conclusion, in vitro inhibition of translation and transcription of the P/R gene can be obtained with PNA; however, it is still necessary to target the ATG start region or poly-purine regions of the gene. PMID- 8695862 TI - Localization by chromosome microdissection of a recurrent breakpoint region on chromosome 6 in human B-cell lymphoma. AB - Deletion of the long arm of chromosome 6 (6q) is one of the most common chromosomal alterations in human B-cell lymphomas. Conventional cytogenetic banding analysis and loss-of-heterozygosity (LOH) studies have detected several common regions of deletion ranging across the entire long arm (6q), with no defined recurrent breakpoint yet identified. We describe here a strategy combining chromosome microdissection and fluorescence in situ hybridization (Micro-FISH) to determine a minimal region of deletion along chromosome 6. Seven clinical cases and one cell line of follicular lymphoma containing a t(14;18) and one case of diffuse lymphoma, also with a t(14;18), were used for this study. All nine cases had previously defined abnormalities of chromosome 6 determined by cytogenetic analysis. The results of chromosome dissection were unexpected and in contrast to the suggestion of disparate breakpoints by conventional chromosome banding. Specifically, Micro-FISH analysis provided evidence for a common breakpoint at 6q11 in seven of nine cases. After Micro-FISH analysis, all of the presumed simple deletions of chromosome 6 were carefully reanalyzed and shown to actually represent either nonreciprocal translocations (three cases), interstitial deletions (five cases), or isochromosome (one case). The recurrent proximal breakpoint (6q11) was detected in seven of nine cases, with the minimal region of deletion encompassing 6q11 to 6q21. By analogy to other tumor systems, the identification of recurring breakpoints within 6q11 may suggest that a gene(s) important to the genesis or progression of follicular lymphoma can be localized to this band region. PMID- 8695863 TI - LYSP100-associated nuclear domains (LANDs): description of a new class of subnuclear structures and their relationship to PML nuclear bodies. AB - The PML gene is fused to the retinoic acid receptor alpha (RAR alpha) gene in t(15;17) acute promyelocytic leukemia (APL), creating a PML-RAR alpha fusion oncoprotein. The PML gene product has been localized to subnuclear dot-like structures variously termed PODs, ND10s, Kr bodies, or PML nuclear bodies (PML NBs). The present study describes the cloning of a lymphoid-restricted gene, LYSP100, that is homologous to another protein that localizes to PML NBs, SP100. In addition to SP100 homology regions, one LYSP100 cDNA isoform contains a bromodomain and a PHD/TTC domain, which are present in a variety of transcriptional regulatory proteins. By immunofluorescence, LYSP100 was localized to nuclear dots that were surprisingly largely nonoverlapping with PML NBs. However, a minority of LYSP100 nuclear dots exactly colocalized with PML and SP100. We term the LYSP100 structures "LANDs," for LYSP100-associated nuclear domains. Although LYSP100 is expressed only in lymphoid cells, LANDs could be visualized in HeLa cells by transfection of a LYSP100 cDNA. Immunoelectron microscopy revealed LANDs to be globular, electron-dense structures morphologically distinct from the annular structures characteristic of PML NBs. LANDs were most often found in the nucleoplasm, but were also found at the nuclear membrane and in the cytoplasm, suggesting that these structures may traffic between the cytoplasm and the nucleus. By double-immunogold labeling of PML and LYSP100, some LANDs were shown to contain both PML and LYSP100. Thus, PML is localized to a second subnuclear domain that is morphologically and biochemically distinct from PML NBs. PMID- 8695864 TI - High incidence of chromosomal imbalances and gene amplifications in the classical follicular variant of follicle center lymphoma. AB - The classical follicular variant of follicle center lymphoma (FCL-fo) is associated with the chromosomal translocation t(14;18)(q32;q21). However, the sole presence of this translocation is not sufficient for malignant transformation, as demonstrated by experiments in a transgenic mouse model. Most of the secondary changes, which play a central role in tumor development and progression and which are presumed to be of prognostic value, are gains and losses of chromosomal material. We analyzed 28 FCL-fo patients using comparative genomic hybridization (CGH). The most frequent imbalances were gains on chromosomes X, 7, 8, 12, and 18 as well as losses of material on chromosome arm 6q. For chromosomes X, 8, 12, and 18, the CGH data allowed further narrowing of the relevant subregions. In addition, novel high-level DNA amplifications were identified in five instances mapping to chromosome bands 1p36, 6p21, 8q24 (2 patients), and 12q13-14. Previously, such amplifications have been identified very rarely in lymphomas. In the 2 patients with amplifications mapping to chromosomal band 8q24, involvement of the MYC proto-oncogene in the amplification unit was demonstrated by Southern blot analysis. These data provide further entry points for studies to identify genes relevant for tumor progression in FCL-fo. PMID- 8695865 TI - Reactivity of murine cytokine fusion toxin, diphtheria toxin390-murine interleukin-3 (DT390-mIL-3), with bone marrow progenitor cells. AB - Myeloid leukemias can express interleukin-3 receptors (IL-3R). Therefore, as an antileukemia drug, a fusion immunotoxin was synthesized consisting of the murine IL-3 (mIL-3) gene spliced to a truncated form of the diphtheria toxin (DT390) gene coding for a molecule that retained full enzymatic activity, but excluded the native binding domain. The DT390-mIL-3 hybrid gene was cloned into a vector under the control of an inducible promote. The fusion protein was expressed in Escherichia coli and then purified from inclusion bodies. The fusion toxin was potent because it inhibited FDC-P1, an IL-3R-expressing murine myelomonocytic tumor line (IC50 = 0.025 nmol/L or 1.5 ng/mL). Kinetics were rapid and cell-free studies showed that DT390-mIL-3 was as toxic as native DT. DT390-mIL-3 was selective because anti-mIL-3 monoclonal antibody, but not irrelevant antibody, inhibited its ability to kill. Cell lines not expressing IL-3R were not inhibited by the fusion protein. Because the use of DT390-mIL-3 as an antileukemia agent could be restricted by its reactivity with committed and/or primitive progenitor cells, bone marrow (BM) progenitor assays were performed. DT390-mIL-3 selectively inhibited committed BM progenitor cells as measured by in vitro colony-forming unit-granulocyte-macrophage and in vivo colony-forming unit-spleen colony assays. To determine if this fusion protein was reactive against BM progenitor cells required to rescue lethally irradiated recipients, adoptive transfer experiments were performed. Eight million DT390-mIL-3-treated C57BL/6 Ly5.2 BM cells, but not 4 million, were able to rescue lethally irradiated congenic C57BL/6 Ly5.1 recipients, suggesting that progenitor cells might be heterogenous in their expression of IL-3R. This idea was supported in competitive repopulation experiments in which DT390-mIL-3 treated C57BL/6 Ly5.2 BM cells were mixed with nontreated C57BL/6 Ly5.1 BM cells and used to reconstitute C57BL/6 Ly5.1 mice. A significant reduction, but not elimination, of Ly5.2-expressing cells 95 days post-BM transplantation and secondary transfer experiments indicated that IL-3R is not uniformly expressed on all primitive progenitor cells. The fact that some early progenitor cells survived DT390-mIL-3 treatment indicates that this fusion toxin may be useful in the treatment of myeloid leukemias that express the IL-3R. PMID- 8695866 TI - Protease receptors in Hodgkin's disease: expression of the factor Xa receptor, effector cell protease receptor-1, in Reed-Sternberg cells. AB - The expression of a cellular receptor for the blood-clotting protease factor Xa, designated effector cell protease receptor-1 (EPR-1), was investigated in lymphoma. Immunohistochemical analysis demonstrated prominent reactivity of monoclonal antibodies to EPR-1 with Reed-Sternberg cells in 30 of 35 cases of nodular-sclerosis, lymphocyte-depletion, and mixed-cellularity Hodgkin's disease (HD). In contrast, several non-Hodgkin's lymphomas, or the nonneoplastic cellular components of HD, did not react with anti-EPR-1 monoclonal antibodies. A single molecular species of approximately 62 kD, consistent with the size and structural organization of EPR-1, was immunoblotted by an anti-EPR-1 monoclonal antibody from tissue samples of HD, but not from normal lymph nodes. Expression of EPR-1 transcripts in Reed-Sternberg cells was demonstrated by in situ hybridization with an antisense EPR-1 riboprobe, and by amplification of reverse-transcribed HD RNA with EPR-1-specific primers. These findings identify the factor Xa receptor, EPR-1, as a novel marker of Reed-Sternberg cells, and suggest its potential role in the histopathogenesis of HD. PMID- 8695867 TI - Opposite effects of tumor necrosis factor alpha on the sphingomyelin-ceramide pathway in two myeloid leukemia cell lines: role of transverse sphingomyelin distribution in the plasma membrane. AB - Tumor necrosis factor alpha (TNF alpha) mediates proliferation, functional activation, and apoptotic cell death depending on the target cell type. Although sphingomyelin (SPM) hydrolysis and ceramide generation may function as an important mediator in TNF alpha signaling, the molecular mechanisms of the signaling pathway(s) are still not well understood. The aim of the present study is to compare the effect of TNF alpha on SPM metabolism and cell growth in two myeloid leukemic cell lines (U937 and KG1a) that differ in their sensitivity to TNF alpha. Our results show that TNF alpha induced apoptosis in U937 but not in KG1a cells. TNF alpha triggered in KG1a cells neither SPM hydrolysis nor ceramide generation, but induced SPM synthesis and ceramide breakdown as well as dose dependent cell proliferation. In contrast, TNF alpha induced in U937 SPM hydrolysis and ceramide generation as well as dose-dependent cell death. Synthetic cell permeant ceramide, as well as natural ceramide, generated by treatment with bacterial sphingomyelinase (SPMase), all induced apoptosis in both U937 and KG1a cells. These findings indicate that the SPM-ceramide pathway is altered in KG1a cells upstream of the ceramide generation. Analysis of the transverse distribution of SPM in the plasma membrane showed that the SPM pool involved in cell signaling (inner leaflet) was markedly reduced in KG1a cells; it is 7-fold lower than that found in the inner leaflet of U937 cells. Therefore, our study strongly suggests that the different responses induced by TNF alpha in myeloid cells are dependent on the SPM plasma membrane transverse asymmetry. PMID- 8695868 TI - Defective lymphocyte glycosidases in the macrophage activation cascade of juvenile osteopetrosis. AB - Generation of macrophage-activating factor requires a precursor protein, Gc protein (serum vitamin D3-binding protein), as well as participation of beta galactosidase of inflammation-primed B lymphocytes and sialidase of T lymphocytes. The treatment of human peripheral blood mononuclear cells with an inflammatory lysophospholipid induced beta-galactosidase and sialidase activity of lymphocytes, leading to the generation of macrophage-activating factor and activation of monocytes/macrophages. However, lysophospholipid treatment of peripheral blood mononuclear cells from three infantile patients with osteopetrosis resulted in no significant activation of monocytes/macrophages. The lysophospholipid-inducible beta-galactosidase activity of B lymphocytes as well as that of the sialidase of T lymphocytes was found to be defective in these patients. PMID- 8695869 TI - Specific loss of protein kinase activities in senescent erythrocytes. AB - Rabbit erythrocytes of progressively increasing age were isolated using an avidin biotin affinity technique and the activity of protein kinases and other enzymes was analyzed in cytosols and membranes from the isolated cells. The activities of cytosolic protein kinase C (PKC), cAMP-dependent kinase (PKA), and casein kinase type I and II (CKI and II) were all found to undergo an age-dependent decrease of twofold to fourfold over the 8-week lifespan of the cells. Membrane-associated tyrosine kinase showed little or no decrease, but membrane-associated CKI showed a dramatic eightfold decrease over the 8-week period. By contrast, various cytosolic enzymes, including lactate dehydrogenase, phosphoglycerate kinase, pyruvate kinase, and acid phosphatase, showed no change in activity over the same time period. Density-separated human erythrocytes showed qualitatively similar decreases in cytosolic protein kinase activities in the densest fractions, which contain the oldest cells. Our results show that aging erythrocytes undergo progressive loss of protein kinases that may adversely affect various cellular processes. The age-dependent loss of kinase activity reported here is one of the most striking manifestations of erythrocyte senescence yet to be reported. PMID- 8695870 TI - Nucleotide sequence diversity of hypervariable region 1 of hepatitis C virus in Japanese hemophiliacs with chronic hepatitis C and patients with chronic posttransfusion hepatitis C. AB - Hemophiliac patients with chronic hepatitis C might be exposed to and become infected with multiple hepatitis C virus (HCV) strains by means of frequent use of blood products, even if they are infected with a single subtype of HCV. To test this hypothesis, we analyzed the genetic diversity of hypervariable region 1 (HVR1) of HCV in chronically infected hemophiliacs and in patients with chronic posttransfusion hepatitis with a single HCV inoculation. The diversity of nucleotide sequences in HVR1 of serum HCV RNA was compared between 21 hemophiliacs infected with a single HCV subtype and 16 patients with posttransfusion HCV infection. The number of HCV quasispecies was determined by fluorescence single-strand conformation polymorphism (SSCP) analysis. Direct sequencing was performed to determine the diversity in HVR1. The number of HCV quasispecies in the blood was 5.2 +/- 2.0 clones in hemophiliacs and 4.0 +/- 2.3 clones in posttransfusion patients, a nonsignificant difference (P = .0943). The number of sites at which the nucleotide was not homogenous in all quasispecies was significantly higher in hemophiliacs (13.0% +/- 7.4%) than in posttransfusion hepatitis patients (2.7% +/- 2.8%; P < .0001). In conclusion, there was a high degree of genetic variation in HVR1 of HCV specimens isolated from hemophiliacs compared with posttransfusion patients. These findings indicate the possibility that multiple infections of a single HCV subtype may occur among patients frequently exposed to blood products; single HCV subtypes may therefore derive from multiple origins. PMID- 8695871 TI - Detection of maternal DNA in placental/umbilical cord blood by locus-specific amplification of the noninherited maternal HLA gene. AB - A critical issue regarding the broader utilization of placental/ umbilical cord blood (PCB) in unrelated bone marrow restoration is the possibility of contamination with maternal lymphocytes capable of immunological reactivity against the eventual recipient. On transplantation, such maternal cells might lead to graft-versus-host disease (GVHD) even if the intended donor's neonatal lymphocytes were unresponsive. We measured the proportion of PCB samples that were contaminated with maternal cells. Placental-maternal sample pairs were selected so that the mother was heterozygous for the DR53 haplotype, whereas the placental sample was DR53-negative. The PCB samples were investigated for the presence of the noninherited maternal gene DRB4, exclusive to the DR53 haplotypes. Locus-specific polymerase chain reaction amplification with DRB4 sequence-specific primers was followed by either gel electrophoresis or blotting and hybridization to an internal sequence DRB4 probe. Polymerase chain reaction products from DNA mixtures containing as low as 0.5 ng of a DRB4-positive DNA control in 1.0 microgram of a DRB4-negative DNA sample (1:2 x 10(3) dilution) showed a visible DRB4 band in agarose gels stained with ethidium bromide. Locus specific hybridization increased the detection sensitivity to 1:10(5) (0.01 ng of the DRB4-positive DNA control). Control mixtures of known amounts of DRB4 positive and -negative DNA were included in all experiments. Comparison of the thickness of DRB4 bands after electrophoresis and the intensity of the DRB4 specific hybridization signals to the concentration controls allowed a rough estimation of the amount of maternal DNA in the placental blood specimens. A total of 213 PCB samples were tested. By gel electrophoresis, DRB4-specific bands were observed to be as strong or stronger in 23 (10.8%) samples as those in the 1:2 x 10(3) control, and 153 (17.8%) samples were negative in this test. The remaining 37 (17.3%) samples disclosed weaker DRB4 bands, suggesting the presence of maternal genetic material. By hybridization, 81 (38%) samples were positive and 132 were negative for the noninherited maternal gene. Review of the clinical characteristics of the mothers (demographics and labor and delivery information), the newborns (birth weight, sex, and gestational age), and PCB collections (placental weight, white blood cell count, and collected volume) failed to show any significant differences between the units testing positive or negative for the noninherited maternal gene. Thus, transplantable PCB units carry a high probability of having maternal DNA in detectable amounts. Whether this DNA comes from potentially graft-versus-host disease-inducing maternal lymphocytes or whether the putatively transplacentally-acquired maternal cells are immunologically dysfunctional, as in most infants with severe combined immunodeficiency disease, remains to be shown. PMID- 8695872 TI - Evidence for a graft-versus-tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer. AB - Graft-versus-leukemia (GvL) has been shown to be an important immune-mediated antitumor effect in hematologic malignancies. It is still unknown whether such an immunemediated antitumor effect has clinical implications in patients with solid tumors. A 32-year-old woman with inflammatory breast cancer received a bone marrow transplant (BMT) from her HLA-identical sibling. During graft-versus-host disease (GvHD) cytotoxic T lymphocytes were grown and tested in a chromium release assay against B and T lymphocytes of the patient and donor and against a panel of breast cancer cell lines. Resolution of liver metastases was observed simultaneously with clinical GvHD in the first weeks after transplant. In addition, minor histocompatibility antigen (MiHA)-specific and major histocompatibility complex (MHC) class I antigen-restricted cytotoxic T lymphocytes recognizing breast carcinoma target cells were isolated from the blood of the patient. Pretreatment of such target cells with tumor necrosis factor (TNF)-alpha but not with interferon (IFN)-alpha or IFN-gamma increased susceptibility of these cells to lysis by cytotoxic T lymphocytes. Clinical course and in vitro results suggest that a graft-versus-tumor (GvT) effect might exist after allogeneic BMT for breast cancer. However, clinical experience on a larger scale would be required to determine the clinical efficacy of GvT effects in patients with solid tumors. PMID- 8695873 TI - Megakaryocyte growth and development factor stimulates enhanced platelet recovery in mice after bone marrow transplantation. AB - Megakaryocyte growth and development factor (MGDF) is a recently characterized ligand for the cell surface receptor mpl. We have evaluated the effects of polyethylene glycollated recombinant human MGDF (PEG-rHuMGDF) on recovery of hematopoietic cells in mice following bone marrow transplantation (BMT) to support lethal irradiation. Mice treated with PEG-rHuMGDF (50 micrograms/kg/d) had accelerated recovery of platelet numbers compared with BMT mice treated with carrier or recombinant human granulocyte colony-stimulating factor (rHuG-CSF, 72 or 200 micrograms/kg/d). In contrast, PEG-rHuMGDF had no effect on white blood cell (WBC) or red blood cell (RBC) recovery. As previously reported, animals treated with rHuG-CSF had an enhanced recovery of WBC but not platelet or RBC levels. Interestingly, BMT receipient mice treated with the combination of PEG rHuMGDF and rHuG-CSF showed simultaneous enhanced recovery of both leukocytes and platelets. PEGylated rHuMGDF was found to be considerably more potent than non PEGylated rHuMGDF in this setting. PEG-rHuMGDF is an effective growth factor for enhancing platelet recovery in mice following BMT either alone or in combination with rHuG-CSF. It will be of interest to evaluate in a clinical setting the ratios of PEG-rHuMGDF and rHuG-CSF for simultaneous administration of these factors and accelerated recovery of both leukocytes and platelets. PMID- 8695874 TI - Prevention of transfusion-associated cytomegalovirus infection: defining the method of preparation for leukocyte-reduced blood products. PMID- 8695875 TI - Engraftment failure associated with peripheral blood stem cell transplantation after B19 parvovirus infection. PMID- 8695876 TI - Bone marrow purging with oligodeoxynucleotides. PMID- 8695877 TI - Highly effective CD34+ selection of granulocyte colony-stimulating factor mobilized allogeneic peripheral blood progenitor cells. PMID- 8695878 TI - Lack of RHCE-encoded proteins in the D--phenotype may result from homologous recombination between the two RH genes. PMID- 8695879 TI - Use of calcitonin in sickle cell bone crisis. PMID- 8695881 TI - Ergonomics in rehabilitation. PMID- 8695880 TI - Detection of maternal progenitor cells in human umbilical cord blood by single colony karyotyping. PMID- 8695882 TI - Energy expenditure and fatiguability in paraplegic ambulation using reciprocating gait orthosis and electric stimulation. AB - To clarify the relationship between metabolic energy expenditure and fatiguability in paraplegic persons fitted with orthoses, we measured energy consumption in six thoracic paraplegic patients ambulating by means of reciprocating gait orthosis (RGO) used with and without functional electrical stimulation (FES). The data obtained from persons using both RGO and FES were adjusted to allow for the effects of fatiguability so as to obtain an approximate value for upper-body consumption. The data obtained from persons using RGO only were not adjusted, because no energy consumption occurred in the lower portion of the body. The data, expressed in kcal/kg-min and kcal/kg-m, were plotted against walking speed attained using RGO, and RGO with FES. The results were compared with those from persons fitted with long leg braces (LLB), hip guidance orthoses (HGO) and an FES walking aid (data obtained from available literature). We found that the lowest energy expenditure in kcal/kg-m across the full range of walking speeds occurred when both RGO and FES were used together, followed by RGO only, HGO, LLB, and FES only, respectively. The lowest energy expenditure in kcal/kg min, for walking speeds, below 0-28 m/s, also occurred when both RGO and FES were used together, followed by RGO only, HGO, LLB, and FES only. The results suggest that, although the use of FES with RGO may increase oxygen uptake, it decreases energy expenditure in the upper extremities, thereby reducing patient fatigue. They also suggest that mechanical orthosis giving passive support to the hip, knee and ankle in combination with FES may provide the most efficient walking aid for paraplegic persons. PMID- 8695883 TI - A force feedback joystick and control algorithm for wheelchair obstacle avoidance. AB - Many powered wheelchair users have difficulty manoeuvring in confined spaces. Common tasks such as traversing through doorways, turning around in halls or travelling on a straight path are complicated by an inability to accurately and reliably control the wheelchair with a joystick or other common input device, or by a sensory impairment that prevents the user from receiving feedback from the environment. An active joystick with force feedback to indicate obstacles in the environment has been developed. Two force feedback schemes designed to assist a powered wheelchair user have been developed and implemented using the active joystick. The development of the joystick and associated control algorithms are described. PMID- 8695884 TI - Testing and evaluation of a hip extensor tricycle for children with cerebral palsy. AB - The design and testing of a modified tricycle (hip extensor tricycle) designed to isolate and exercise the hip extensor muscles in children with cerebral palsy is presented. Initial laboratory tests involved stability evaluation and EMG studies of two normal children. Field evaluation involved five children diagnosed with cerebral palsy who were given hip extensor tricycles for home use during an 8 week test period. The hip extensor strength and gait pattern of the subjects were recorded at 2-week intervals. The clinical tests indicated that the hip extensor tricycle was more stable, and resulted in more hip extensor muscle activity, than the traditional therapeutic/exercise tricycle. A panel of experts judged that the gait patterns of four of the five subjects improved during the course of the study. Parent evaluations indicated that the use of the hip extensor tricycle improved the subjects' physical condition, coordination, sense of accomplishment, and self-esteem. PMID- 8695885 TI - Application of biomechanical growth models of the quantitative evaluation of the motor system in children. AB - To evaluate the effectiveness of rehabilitation methods, and to assess the progress of the rehabilitation process in an individual patient, quantitative methods are necessary. The large number of motor system parameters makes the problem of data collection time-consuming and expensive. A quantitative evaluation of the child's motor system is an assessment of a combination of the growth and rehabilitation processes. The aim of the study was to establish methods of differentiation between these two processes. The chosen anthropometric measures, biomechanical parameters of the lower leg segment, maximal voluntary extension and flexion torques of lower leg and chosen gait parameters, were measured in various groups of healthy children 6-18 years old. Mathematical functions were calculated describing these parameters against developmental parameters (body mass, body stature, age). Using the maximal correlation criterion the best growth parameters were established. Normalized databases for these parameters were developed. It is suggested that, using their approach, differentiation between the influences of growth and rehabilitation processes can be achieved, thus eliminating the need for tedious data collection. PMID- 8695886 TI - Outcome of rehabilitation programmes for employees with lowered working capacity. AB - Outcome of rehabilitation programmes emphasizing intensive cooperation between workplace and rehabilitation specialists was evaluated. Outcome of rehabilitation was assessed 6 months after the beginning of the rehabilitation process. Outcome measures presented here were based on questionnaires. Benefits of changes in work related factors (e.g. ergonomics) carried out after the programme at the workplace were also assessed. The results showed significant improvement in the subjects' working capacity, as well as a decrease in symptom severity and disability caused by individual and work-related factors. Improvements in working methods and work tasks during the follow-up period were connected to better outcome. PMID- 8695887 TI - Cardiac rehabilitation: potential for ergonomic interventions with special reference to return to work and the Americans with Disabilities Act. AB - This paper briefly reviews the contemporary cardiac rehabilitation process and highlights its limitations. It argues that, in order to improve return-to-work chances, cardiac rehabilitation should focus on simulating actual work conditions. The role of ergonomics in the cardiac rehabilitation process is also outlined. Finally, the current impediments to early return to work are identified and corrective actions are suggested. PMID- 8695888 TI - The effects of anterior hypothalamic lesions on short-day responses in Siberian hamsters given timed melatonin infusions. AB - The suprachiasmatic nucleus (SCN) of the hypothalamus is an area of dense 2 [125I]Iodomelatonin binding in Siberian hamsters (Phodopus sungorus sungorus) that is suggestive of a possible role in the reception and/or relaying of melatonin (MEL) signals. Indeed, in pinealectomized male Siberian hamsters given short day (SD) MEL signals (long-duration MEL infusions), lesions of the SCN (SCNx) block testicular regression and decreases in body and fat pad masses seen in identically treated hamsters with sham lesions (SCNs). In similar studies using Syrian hamsters (Mesocricetus auratus), anterior hypothalamic lesions (AHx), but not SCNx, blocked SD MEL signal-induced gonadal regression despite the similarity in the 2-[125I]Iodomelatonin binding pattern between the two species. The discrepancy between the ability of SCNx to block the reception of SD MEL signals between the two species is puzzling, given the similarity in the reproductive status of the Syrian and Siberian hamsters to systemically administered and timed MEL infusions. One possible way of reconciling the differences between these studies was that ancillary damage to areas neighboring the SCN, including the AH, may have occurred in our attempt to achieve complete SCNx in Siberian hamsters. Therefore, the purpose of the present study was to challenge AHx Siberian hamsters with SD MEL signals. Adult male hamsters were pinealectomized, fitted with subcutaneous catheters, and given daily timed infusions of MEL for 5 or 10 h (long day-like and short day-like, respectively) or the saline vehicle for 6 wk following bilateral electrolytic, or sham (AHs) lesions of the AH. Hamsters receiving 10 h MEL infusions that lacked evidence of anatomical or functional damage to the SCN showed SD-like gonadal regression, decreases in body and fat pad mass, and food intake similar to that observed in AHs animals. In contrast, 10 h MEL-infused SCNx hamsters did not exhibit SD-like responses, a finding confirming our previous report. These data suggest that interspecies differences exist between Syrian and Siberian hamsters in central nervous system sites and pathways involved in the reception/transmission of SD MEL signals. PMID- 8695889 TI - Phase response curves to neuropeptide Y in wildtype and tau mutant hamsters. AB - Neuropeptide Y (NPY)-containing fibers project from the intergeniculate leaflet to the suprachiasmatic nucleus. NPY has been shown to phase shift the circadian locomotor activity rhythm of wildtype hamsters, producing large phase advances in the subjective day and small delays in the subjective night. Previous studies have implicated this pathway in the mediation of activity-induced resetting of the circadian clock. Homozygous tau mutant and wildtype hamsters respond very differently to pulses of activity. Not only is the amplitude of the phase response curve exaggerated in the mutants with shifts of up to 7 h, but the stimuli are effective at different times during the cycle. Homozygous tau mutant hamsters and wildtype controls were implanted with guide cannulas aimed at the suprachiasmatic nucleus and injected with NPY at various times during the circadian cycle. The responses of homozygous tau mutant hamsters to NPY resembled their responses to nonphotic stimuli in both timing and direction of phase shift. This finding provides correlational evidence that NPY is involved in the effects of nonphotic behavioral events on the circadian system. PMID- 8695891 TI - Daily melatonin treatments regulate the circadian melatonin rhythm in the adult Djungarian hamster. AB - The present study tested the hypothesis that daily melatonin treatments influence the biological clock mechanism controlling the circadian melatonin rhythm. Adult male and female Djungarian hamsters in light:dark = 16L:8D (lights on 0300-1900 h) were administered melatonin subcutaneously (s.c.) each day (5 micrograms/0.2 ml saline) in the morning at 1000 h (AM) or late afternoon at 1700 h (PM); controls received a vehicle injection (CON). After 14 days, pineal and serum melatonin concentrations were determined at various times on the last day of treatment and the next day in constant darkness (no treatment). The rhythm in pineal gland melatonin content was similar in each of the three groups on the last day of treatment (about 6 h duration). On the next day in constant dark, the rising phase was advanced and duration extended by 2 h or more in melatonin treated hamsters compared to that in CONs (ANOVA). In circulation, the melatonin rhythm in AM and PM groups was phase advanced (onset and peak) on both days of the study. Thus duration was extended by up to 4.5 h compared to that in saline treated controls. Moreover, amplitude of the nighttime serum melatonin rise was elevated up to fivefold relative to that in the CON group (ANOVA and Accumulated Sums analysis). The effects of repeated melatonin treatments on amplitude and phase of the serum melatonin rhythm raise the possibility that the circadian clock that controls pineal gland production of melatonin may also regulate melatonin secretion. From this and another study, the apparent half-life of melatonin in circulation was estimated to be 7.5 min; the melatonin injection initially produced pharmacological concentrations that were followed by low serum melatonin levels within 2 h. Thus, in both melatonin treatment groups, the data suggest that two distinct periods of elevated serum melatonin were present each day. The cellular mechanism for melatonin action must take into consideration how a brief interruption in elevated melatonin in circulation (about 1 h in the PM group) is recognized as a continuous duration (short daylength), whereas a more extended baseline period is transduced as an abbreviated or long daylength (about 7 h in the AM group). These data further suggest that the biological clock mechanism that generates the circadian melatonin rhythm is responsive to the influence of daily melatonin treatments and presumably to the feedback action of endogenous melatonin on its own rhythm in the Djungarian hamster in long days. PMID- 8695890 TI - Unexpected c-fos gene expression in the suprachiasmatic nucleus of mice entrained to a skeleton photoperiod. AB - Several authors have suggested that the transcriptional regulatory protein c-Fos might be part of the mechanism for photic entrainment of the circadian pacemaker in the suprachiasmatic nucleus (SCN) to environmental light:dark cycles. This hypothesis has been based on evidence gathered using single light pulses administered acutely to animals free-running in constant darkness. In order to begin to analyze SCN c-fos gene expression in animals during steady-state entrainment to photic cycles, we exposed male BALB/c mice to a skeleton photoperiod consisting of two 1-h light pulses separating a long (14 h) and a short (8 h) dark interval. The cycle was designed so that stable entrainment could be achieved in either one of two patterns (with rhythmic locomotor activity occurring during either the long or the short dark interval); SCN c-fos mRNA levels could then be measured during entrainment to light pulses at different phases of the circadian cycle, while controlling for the duration of preceding darkness. We found that c-fos was induced equally well by a light pulse that represented ZT 12 or ZT 3. The ZT 12 pulse functioned as an entraining pulse, because animals free-ran after it was removed from the lighting regimen, whereas removing the ZT 3 pulse caused little or no phase shift of activity onset. The data confirm that the expression of SCN c-Fos is not itself sufficient to reset rhythm phase, and they indicate that the role of this gene in the mechanism of photic entrainment is not yet fully understood. PMID- 8695893 TI - Phased protein synthesis at several circadian times does not change protein levels in Gonyaulax. AB - The synthesis rates of 13 individual proteins in Gonyaulax polyedra, resolved by two-dimensional gel electrophoresis, were estimated from the amount of 35S methionine incorporated during in vivo pulse labeling at 2-h intervals over one circadian period. The synthesis rates of three proteins, taken as controls, varied 2-3 fold, and no systematic pattern to these variations was apparent. In contrast, the synthesis rates of 10 other proteins varied at least tenfold and in a smooth and systematic pattern. The patterns of protein synthesis were placed into three different groups, the first occurring during the late day/early night phase, the second during the middle of the night phase, and the third during the late night/early day phase. The length of time that individual proteins within each group could incorporate radiolabel was variable, raising the possibility that additional groups might be present. However, both a replicate experiment in continuous light and a light:dark experiment confirmed the presence of at least three different groups of protein synthesis patterns. Unlike the circadian changes in the synthesis rate of the luciferin binding protein, which produces variations in protein levels that correlate with the bioluminescence rhythm, no substantial changes were found in the levels of any other rhythmically synthesized proteins examined. PMID- 8695892 TI - The use of a reversible transcription inhibitor, DRB, to investigate the involvement of specific proteins in the ocular circadian system of Aplysia. AB - Previously, the effects of 2-h treatments with the reversible transcription inhibitor 5,6-dichloro-1-beta-D-ribobenzimidazole (DRB) on the phase of the circadian rhythm in the eye of Aplysia californica were studied. Here we report a study of the effects of DRB on protein synthesis and a more detailed investigation of the effects of DRB on the phase of the circadian rhythm. Treatments of DRB for 30 min reduced the rate of transcription to about 30% of control values, and this inhibition reversed completely within 2 h after the end of the treatment. A phase-response curve was obtained for 30-min treatments of DRB. Shorter (30 min) treatments with DRB produced phase shifts comparable to those produced by treatments with DRB for 2 h. The phase-response curve obtained using 30-min treatments of DRB was similar to one obtained using 2-h treatments with respect to the phase at which DRB exerts its maximum effect on the rhythm (around circadian time [CT] 6). However, some aspects of the two phase-response curves were different. The effect of DRB on the phase of the rhythm appeared rapidly after removal of DRB treatments given during CT 22-6, but the effects of DRB on the phase of the rhythm appeared more slowly (approximately 10 h) after the treatments given during CT 6-12. Because the effects of DRB on the phase of the overt rhythm appear to be rapid at a particular phase, it is very likely that DRB affects the phase of the rhythm by altering the synthesis of proteins during or shortly after the treatment. Thus we searched for proteins whose synthesis was altered by DRB. Incorporation of labeled amino acids into 2 proteins was found to be altered during the DRB treatment, whereas 15 proteins were affected after the DRB treatment. Among the proteins affected during or shortly after the DRB treatment were four previously identified proteins affected by other treatments that can shift the phase of the eye circadian rhythm. These four proteins are worthy of further study as possible candidates for components of the circadian oscillator. PMID- 8695894 TI - S-antigen antibody partially blocks entrainment and the effects of constant light on the circadian rhythm of locomotor activity in the adult blow fly, Calliphora vicina. AB - Injection of S-antigen (arrestin) antibody into the brain of the blow fly, Calliphora vicina, appeared to reduce sensitivity to the photic effects of a light:dark cycle (LD; entrainment) or continuous "bright" light (LL; arrhythmicity). In LD, a proportion of the injected flies evaded entrainment or showed delayed entrainment. In bright LL, flies continued with a free-running rhythm, which remained unchanged (as in continuous darkness) or lengthened (as in "dim" LL). These results focus attention on four groups of arrestin-positive neurons in the fly's brain as potential components of the photoreceptive system. PMID- 8695895 TI - Developmental state and the circadian clock interact to influence the timing of eclosion in Drosophila melanogaster. AB - In Drosophila melanogaster, the emergence of adults from their pupal cases (eclosion) is gated by the circadian clock such that it occurs during a window of approximately 8-10 h starting 1-2 h before lights-on in 12-h light:12-h dark cycles (LD). This gate is shifted several hours earlier by the clock mutant per(s), indicating that the clock controls the phase of eclosion under these conditions. Both the day and the time of eclosion are determined by the interplay between developmental state and the circadian clock. At a certain phase of the circadian cycle, the circadian clock, either directly or through some circadian clock-controlled mechanism, measures development state, and those pharate adults that have reached a certain developmental state by this phase eclose during the first available gate, while those that have not wait until a subsequent gate. Using wing pigmentation as a late developmental state marker, an early boundary for when the circadian clock assesses developmental state occurs roughly at the time when lights go out during LD cycles. This event is shifted several hours earlier in per(s), showing that it is under circadian control. A fly's developmental state at the time of developmental assessment also influences when eclosion will occur (during the gate) in that flies whose wings have become pigmented early (12-24 h before assessment) will eclose earlier in the gate than those whose wings become pigmented late (0-12 h before assessment). These data suggest that the circadian clock (or some clock-controlled mechanism) measures developmental state (wing pigmentation) in wild-type flies between lights-off and expression of the first clock-regulated marker approximately 4-5 h before eclosion and that the developmental state of the fly determines both which gate is chosen for eclosion and when eclosion occurs during that gate. PMID- 8695896 TI - Ultrastructure of the iris. PMID- 8695897 TI - Ciliary body. PMID- 8695898 TI - Effectiveness of green tea tannin on rats with chronic renal failure. AB - The effects of green tea tannin on nephrectomized rats were examined. There were increases in blood urea nitrogen, serum creatinine, and urinary protein, and a decrease in creatinine clearance in the nephrectomized control rats, whereas better results for these parameters were obtained in rats given green tea tannin after nephrectomy, demonstrating a suppressed progression of the renal failure. When the renal parenchyma was partially resected, the remnant kidney showed a decrease in the activity of radical scavenger enzymes. Green tea tannin, however, was found to lighten the kidney under such oxidative stress. Mesangial proliferation and glomerular sclerotic lesions, which were conspicuous in the rats that were not given green tea tannin after nephrectomy, were also relieved. PMID- 8695899 TI - Specific binding of allergenic soybean protein Gly m Bd 30K with alpha'- and alpha-subunits of conglycinin in soy milk. AB - When defatted soy milk was ultracentrifuged, 34kDa allergenic soyabean protein Gly m Bd 30 K was more abundant in the precipitate than in the supernatant by an SDS-PAGE analysis. The addition of more than 10 mM of 2-mercaptoethanol (2-ME) to the soy milk resulted not only in further removal of the 34kDa allergenic protein to the precipitate, but also in better recovery of conglycinin in the supernatant. After a two-dimensional SDS-PAGE analysis (the first dimension, minus 2-ME; the second, plus 2-ME) of the precipitates, superimposition between the CBB-stained gel and the eletroblotted membrane stained with a monoclonal antibody specific to Gly m Bd 30 K indicated that part of Gly m Bd 30 K was preferentially bound to the alpha'- and alpha-subunits of conglycinin, and that part of them had formed the dimer through a disulfide bond. PMID- 8695902 TI - Effects of n-3 polyunsaturated fatty acids and lectins on immunoglobulin production by spleen lymphocytes of Sprague-Dawley rats. AB - We examined the effects of n-3 polyunsaturated fatty acid (PUFA), such as alpha linolenic (alpha-LA), eicosapentaenoic (EPA), and docosahexaenoic acid (DHA) on immunoglobulin (Ig) production by spleen lymphocytes of Sprague-Dawley rats. n-3 polyunsaturated fatty acid (PUFA) strongly inhibited the production of IgA and IgM and that of IgG weakly at 100 microM. When the lymphocytes were treated with n-3 PUFA in the presence of other inhibitory biomaterials such as lectins, some PUFA attenuated their inhibitory effect on Ig production. In the presence of concanavalin A (ConA), all n-3 PUFA attenuated the inhibitory effect of ConA on the production of IgM or IgG but increased its inhibition of IgA synthesis. Thus, the interaction of n-3 polyunsaturated fatty acid and lectins in spleen interfere with each other or the expression of Ig production regulating activity. PMID- 8695901 TI - Suppression of interleukin-2 receptor expression on mouse CD4+ T cells by bovine kappa-caseinoglycopeptide. AB - Bovine kappa-caseinoglycopeptide (residues 106-169, CGP) completely inhibited the PHA-induced proliferation of mouse splenocytes when CGP was added simultaneously with PHA. The inhibitory effect, however, was reduced to about one-half when CGP was added after 24 h of cultivating the splenocytes with PHA or when anti-IL-1ra antibody was added simultaneously with PHA and CGP. On the other hand, CGP bound to mouse CD4+ T cells but not to CD8+ T cells. CGP suppressed IL-2 receptor expression of the PHA-stimulated mouse CD4+ T cells. PMID- 8695900 TI - Application of long-distance PCR to restriction site mapping of a cloned DNA fragment on the lambda EMBL3 phage vector. AB - Long-distance PCR was applied to rapidly map the restriction sites of long inserts cloned on lambda EMBL3 phage vector. The restriction sites of 9 of 15 enzymes were completely assigned in a model experiment within 14 h, including 8h for the PCR amplification. This method was found particularly useful for genomic DNA cloning when the partial sequence of the corresponding cDNA is known. PMID- 8695903 TI - Identification of pheophorbide a and its related compounds as possible anti-tumor promoters in the leaves of Neptunia oleracea. AB - Six chlorophyll-related compounds isolated from leaves of Neptunia oleracea (Leguminosae) inhibited the activation of tumor promoter-induced Epstein-Barr virus (EBV). Photo-irradiation of pheophorbide a, the major active constituent, did not enhance this inhibitory activity, and thus ruled out any photosensitizing effect playing the major role. PMID- 8695904 TI - Immunochemical and biochemical identification of the rice seed protein encoded by cDNA clone A3-12. AB - Previously isolated cDNA clone A3-12 that was expressed in E. coli as the fusion protein with Trp E showed immunoreactivity with the mouse antibody raised against isolated alpha-globulin from rice seed. The N-terminal amino acid sequences determined for the purified alpha-globulin and its tryptic peptides were identical with the deduced amino acid sequence reported, except for two residues at the protein N terminus. An error in the reported sequence was confirmed by re sequencing the cDNA, the nucleotide sequence for the two N-terminal residues being shown to be CAGCTG and not CACGTG. Thus, the protein encoded by cDNA clone A3-12 was identified to be the major rice seed globulin, alpha-globulin, with an apparent molecular mass of 26kDa. PMID- 8695905 TI - Boromycin, an anti-HIV antibiotic. AB - The polyether-macrolide antibiotic, boromycin, was isolated as a potent anti human immunodeficiency virus (HIV) antibiotic from a fermentation broth of Streptomyces sp. A-3376. Boromycin was found to strongly inhibit the replication of the clinically isolated HIV-1 strain as well as the cultured strain in in vitro laboratory experiments. The mechanism for the anti-HIV activity of boromycin is suggested to involve blocking the later stage of HIV infection, and probably the maturity step for replication of the HIV molecule. PMID- 8695906 TI - Isolation and structure of staph-cAM373 produced by Staphylococcus aureus that induces conjugal transfer of Enterococcus faecalis plasmid pAM373. AB - Enterococus faecalis plasmid pAM373 encodes a mating response to the sex pheromone, cAM373, which is secreted from pAM373-free E. faecalis. cAM373-like activity was detected in a culture filtrate of Staphylococcus aureus. The major active substance, termed staph-cAM373, was isolated, and its structure was identified as a H-Ala-IIe-Phe-IIe-Leu-Ala-Ala-OH heptapeptide. PMID- 8695907 TI - Antioxidant behaviors of vitamin E analogues in unilamellar vesicles. AB - The antioxidant behaviors of vitamin E and its analogues, 2,2,5,7,8-pentamethyl-6 hydroxychroman and 1,2-diacyl-sn-glycero3-phospho-2'-(hydroxyethyl)-2'- 5',7',8' tetramethyl-6'-hydroxychroman, were studied in unilamellar vesicles. The two analogues scavenged aqueous radicals generated from azo compounds more efficiently than vitamin E. On the other hand, vitamin E scavenged the lipid peroxyl radicals preferentially. It is concluded that the superior antioxidant activity of vitamin E is attributed to its location suitable for breaking the chain propagation reaction. PMID- 8695908 TI - A new cytotoxic cholestane bisdesmoside from Ornithogalum saundersiae bulbs. AB - Bioassay-guided fractionation of the MeOH extract of Ornithogalum saundersiae bulbs led to the isolation of a new cholestane bisdesmoside with potent cytotoxic activities toward leukemia HL-60 and MOLT-4 cells. The structure was deduced mainly from spectroscopic information. PMID- 8695909 TI - The monoamine regulon including syntheses of arylsulfatase and monoamine oxidase in bacteria. AB - Bacterial cells respond to monoamine compounds, such as tyramine, dopamine, octopamine, or norepinephrine, and induce the syntheses of tyramine oxidase encoded by tynA and monoamine oxidase encoded by maoA. These monoamine compounds also derepress the synthesis of atsA-specified arylsulfatase that is repressed by sulfur compounds. These complex mechanisms of regulons regulated by monoamine and sulfur compounds has been analyzed by cloning and characterization of genes that are involved in the repression and derepression of the synthesis of arylsulfatase. The atsA gene forms an operon with the atsB gene, which encodes an activator of the expression of atsA. The negative regulator gene for arylsulfatase was found to code for dihydrofolate reductase (folA). The maoA gene forms an operon with the maoC gene, which has similarity to a dehydrogenase involved in the tyramine metabolism. The moaF gene encoding a 30-kDa protein, which is induced by tyramine, also forms an operon with the moaE gene. Finally, the moaR gene, which is induced by monoamine, was found to play a central role in the positive regulation of the expression of the monoamine regulon (moa) including the atsBA, maoCA, moaEF, and tyn operons. The moaR expression is subject to autogenous regulation and to cAMP-CRP control. The MoaR protein has a helix-turn-helix motif in its C terminus. Thus, the MoaR protein probably regulates the operons by binding to the regulatory region of the moa regulon. PMID- 8695910 TI - Protection against oxidative damage by dihydroflavonols in Engelhardtia chrysolepis. AB - Dihydroflavonol taxifolin and its glycoside, astilbin, from Engelhardtia chrysolepis were evaluated as antioxidants and radical scavengers. These dihydroflavonols inhibited superoxide anion production in the xanthine/xanthine oxidase system. Microsomal lipid peroxidation induced by NADPH-cytochrome P-450 reductase was also inhibited by these flavonoids. Mitochondrial lipid peroxidation was inhibited only by the aglycon. Taxifolin protected peroxy radical-damaged mitochondria with no effect on enzyme activity. Furthermore, taxifolin and astilbin protected red cells against oxidative hemolysis. These dihydroflavonols were found to be effective for protecting subcellular systems and red blood cells against oxidative stress in vitro. PMID- 8695911 TI - Cloning of catBCIJFD genes for catechol degradation into chromosomal pobA and genetic stability of the recombinant Acinetobacter calcoaceticus. AB - A possible obstacle in the development of hybrid strains of Acinetobacter calcoaceticus by the introduction of a metabolic pathway into the chromosome is genetic instability of the resulting recombinant strains. Therefore, the possibility that the pobA gene can be used as a chromosomal cloning site where the transposed genes can be maintained and expressed, was explored in this study. For this purpose, two model hybrid strains of A. calcoaceticus were created, in which a DNA fragment carrying catBCIJFD genes for catabolic degradation of catechol was inserted into pobA in opposite directions of each other, and their genetic stabilities were experimentally examined. Our data demonstrated that the stability of the genes neighboring the insertions depends on the orientations of the insertions. Also, the data further indicated that the functional metabolic pathways introduced into pobA can be expressed successfully as far as the insertion is engineered in an appropriate way. Concurrently, it was proposed that the pobA can be used as a chromosomal cloning site, and that introduction of an useful metabolic pathway into pobA may offer considerable promise to the construction of a hybrid strain with improved metabolic capabilities. PMID- 8695912 TI - Degradation of beta 1-->6 galactofuranoside linkages in the polysaccharide of Fusarium sp. M7-1 by endo-beta-galactofuranosidase from Bacillus sp. AB - A polysaccharide, in which the main part of the side chains were depleted, was prepared from the acidic polysaccharides of Fusarium sp. M7-1 by digestion with lyase of Cellulomonas sp. and mild acid treatment. This polysaccharide was degraded into several fragments, neutral oligosaccharides, neutral polysaccharide, and acidic polysaccharide, by an enzyme, endo-beta galactofuranosidase, produced by Bacillus sp. The main components of the oligosaccharides were isolated and identified as Gal[sequence: see text] The molecular mass of the neutral polysaccharide fragment was estimated to be about 6000 Da by gel filtration chromatography. The polysaccharide fragment consisted of an alpha 1-->6 linked mannan main chain to which various sugars, namely Glc, Man, and Rha were attached through alpha 1-->3 (or 2) linkages. The molecular mass of the acidic polysaccharide fragment was estimated to be about 6000 Da from the amounts of the reducing terminal galactose. The chemical structures of the oligosaccharides derived from the acidic polysaccharide fragment by mild acid hydrolysis were identified as reported structural units [Iwahara et al., J. Biochem., 112, 355-359 (1992)]. The structure of the mild-acid-resistant part of the acidic polysaccharide fragment was assumed to be a polyuronide to which various sugars such as Glc, Man, and GlcNac are attached as the side chains. The linkage modes of each sugar are not clear. PMID- 8695913 TI - Biological activity of brain-derived neurotrophic factor with mismatched disulfide linkages produced by Escherichia coli. AB - E. coli cells harboring an expression plasmid with a brain-derived neurotrophic factor (BDNF) gene obtained from rat BDNF cDNA were sonicated and centrifuged to obtain a precipitate containing BDNF. Ten different proteins of BDNF were purified from the precipitate and the three disulfide linkages of six proteins were identified. Those disulfide structures were different from that of authentic BDNF and the biological activities of BDNF with mismatched disulfide linkages (EC50 of 2 to 15 ng/ml) were much lower than that of authentic BDNF (EC50 of 30 pg/ml). The BDNF with mismatched disulfide linkages inhibited the biological activity of authentic BDNF. PMID- 8695914 TI - Nutritional regulation of insulin-like growth factor-I receptor mRNA levels in growing chickens. AB - Insulin-like growth factor-I (IGF-I) exerts its effect through the IGF-I receptor. To investigate the effects of nutritional status on chicken IGF-I receptor gene expression, a solution hybridization/RNase protection assay for IGF I receptor mRNA was developed. A cDNA clone corresponding to the carboxyl terminal region of the IGF-I receptor was obtained by reverse transcription-PCR (RT-PCR). Sequence analysis of the clone showed that this region of the chicken IGF-I receptor is highly divergent from the human IGF-I receptor. IGF-I receptor mRNA was detected in all tissues examined from newly hatched chickens. The rank order of the IGF-I receptor mRNA levels was liver < thigh muscle < stomach < heart < lung < kidney < brain. In 1-week-old chickens, 5 days of starvation caused a 2.5- to 3-fold increase in the mRNA in muscle and kidney. Starvation of 4-week-old chickens for 5 days caused a 1.7 to 2.2-fold increase in IGF-I receptor mRNA levels in kidney, liver, and muscle. In contrast, IGF-I receptor mRNA levels in brain failed to change. The mRNA levels were reduced to the control level by refeeding of the starved chickens for 24h. These data suggest a tissue- and development-specific response of chicken IGF-I receptor gene expression to nutritional status. PMID- 8695915 TI - A simple assay for xylanase using o-nitrophenyl-beta-D-xylobioside. AB - We measured xylanase activities upon eight chromogenic substrates, o- or p nitrophenyl-beta-D-xylopyranoside (oNP-X or pNP-X) and o- or p-nitrophenyl-beta-D xylooligosaccharides (oNP-Xn or pNP-Xn, n = 2-4), and studied for their uses as substrates in a kinetic study. The Kcat and K(m) of Bacillus pumilus xylanase (EC 3.2.1.8) activities for pNP-X2 were 0.24s-1 and 0.5 mM, respectively. The relative xylanase activities with the other substrates to that with pNP-X2, pNP X3, pNP-X4, oNP-X, oNP-X2, oNP-X3, and oNP-X4 were < 0.001, 9.4, 9.7, < 0.001, 19, 190, and 200, respectively. HPLC analysis of the digestion products of oNP-X2 or pNP-X2 showed that the xylanase hydrolyzed each of the substrates only at the ether bond between nitrophenol and xylobiose. All ether bonds of pNP-X3, oNP-X3, pNP-X4, or oNP-X4 were hydrolyzed by the xylanase and further hydrolyses proceeded in the digestion products, e.g., oNP-X2 and oNP-X3 from oNP-X4. Therefore, oNP-X2 was screened as a useful substrate in a kinetic study of the xylanase. The K(m) and Kcat of the xylanase for oNP-X2 were 0.38 mM 2.29s-1, respectively. Thermodynamic studies showed that the higher reaction rate obtained with oNP-X2 than that with pNP-X2 was due to a significant decrease in the activation energy change, despite a decrease in the activation entropy change. PMID- 8695916 TI - Synthetic studies on polysaccharide HS-142-1, a novel nonpeptide antagonist for the atrial natriuretic peptide receptor: syntheses of the gentiobiosyl fragments. AB - Possible disaccharide fragments of the major component of HS-142-1, a novel polysaccharide antagonist for functional atrial natriuretic peptide (ANP) receptors, O-(4-O-caproyl-beta-D-glucopyranosyl)-(1 --> 6)-4-O-caproyl-D glucopyranose (1) and O-(3-O-caproyl-beta-D-glucopyranosyl)-(1 --> 6)-3-O-caproyl D-glucopyranose (2), were respectively synthesized in a stereo- and regio controlled manner. Deprotection of 2,2'-di-O-caproyl derivative 35 gave a complex mixture due to undesired acyl migration. In contrast, 2,4'-di-O-caproyl analog 39 was successfully deprotected to give O-(4-O-caproyl-beta-D-glucopyranosyl)-(1 --> 6)-2-O-caproyl-D-glucopyranose (40). PMID- 8695917 TI - Genetic analysis of the sam mutations, which induce sexual development with no requirement for nutritional starvation in fission yeast. AB - The cAMP pathway and the Ras pathway are the two major pathways to sexual development in the fission yeast Schizosaccharomyces pombe. To understand the cAMP pathway or the related pathway, we analyzed mutants that display a phenotype similar to cyr1-, that is, hyper-sporulation. Nine mutants termed sam (sporulation abnormal mutant), which are highly inclined to sexual development despite the presence of nitrogen sources, were partially characterized. Cyclic AMP was detected in all nine sam mutant cells, and over-expression of the adenylyl cyclase gene (cyr1) failed to suppress the hyper-sporulation phenotype of these sam mutants, suggesting that none of the sam mutants were likely to be allelic to cyr1. Epistatic tests of sam mutants showed that they were divided into two dominant and seven recessive mutants. Dominants were able to make spores in sam/sam+ heterodiploid cells upon abundant nutrients. Both two dominant mutants bypassed the inability to make spores in ras1 deficient diploid cells, suppressed the deficiency to execute sporulation in byr2 deficient diploid cells, but failed to suppress the byr1 deficiency. Two dominant mutations seem not to occur within the byr2 gene. PMID- 8695918 TI - [Ataxia telangiectasia and genetic predisposition to cancer]. AB - Ataxia telangiectasia (AT) is a genetic disorder with an autosomic recessive transmission. Occurring during childhood, it affects different organs and/or systems. Physiopathology is still unclear. The first clinical signs are evident early in childhood and evolution always leads to death. The secondary cause of mortality in 10 to 15% of the affected is the development of cancers. Genetic predisposition to cancer for homozygotes, as well as for heterozygotes, is one of the most remarkable aspects of this disease. For heterozygotes the risk of cancer is three times that of the norm. The gene responsible for the disease has been cloned. Its function may resolve some questions, and provide the link between degenerative process, cancer susceptibility and immunodeficiency evident in AT patients. PMID- 8695919 TI - [Pharmacology of Catharanthus alkaloids]. AB - Catharanthus alkaloids are antitumoral drugs widely used in the treatment of malignant diseases. This review summarizes different aspects of their pharmacology (mechanism of action, resistance, clinical pharmacokinetics) as well as information on their uses in the clinical setting. PMID- 8695920 TI - [Low rectal cancer: conservative approach integrating radiotherapy]. AB - During the past two decades, the general acceptance of the surgical conservative treatments in tumors such as breast cancer, bone and soft tissue sarcoma, represents one of the significant steps achieved in the treatment of solid tumors. For low rectal cancer, abdominoperineal resection is considered the standard treatment. However, conservative treatments (mono- or multimodality) seem to be as effective, provided that the selection of patients and the choice of the treatment are adequate. This opens a real perspective in favour of conservative treatments resulting already in a restriction in the indications of abdominoperineal resection. In those conservative strategies, radiotherapy has often been used, and some authors consider it essential in several clinical situations. PMID- 8695921 TI - [Induction of apoptosis, in vitro and in vivo, on colonic tumor cells of the rat after sodium butyrate treatment]. AB - Sodium butyrate (NaB) is known to induce the process of cell differentiation, particularly for epithelial colonic cells. We previously observed that treatment with NaB in association with interleukin 2 (IL2), cures 60% of peritoneal carcinomatosis induced by injection of DHDK12/TRb cells in syngenic rats [15]. In the present work, we evidenced in vitro metabolic alterations of the DHDK12/TRb cell line treated with NaB, followed by an apoptotic process. Flow cytometric analysis evidenced that the tumour cells were arrested in the G1 and G2 phases of the cell cycle for the adherent cells to the plastic. Biological analysis of cells and debris released in the culture medium were essentially apoptotic cells. Complementary, the NaB-induced apoptotic process was confirmed by the staining of the nucleus from releasing cells by Hoechst 33258 and the DNA fragmentation revealed by DNA electrophoresis. Mitochondrial activity and glucose consumption were significantly stimulated after NaB treatment, which reveal an alteration of the metabolic activity of the treated tumour cells. As a consequence, we measured a significant increase of the active TGF beta 1 production, a cytokine previously described to participate to the epithelial cell differentiation. These in vitro data were confirmed in vivo showing a significant expression of apoptotic tumour cells in NaB- or NaB/IL2-treated tumours. Thus, the present results in the rat peritoneal carcinomatosis treatment show that combination of apoptotic process induced by NaB with immunostimulation by IL2 has powerful therapeutic properties. PMID- 8695922 TI - [Apoptosis of human leukemic cells induced by topoisomerase I and II inhibitors]. AB - Comparison between five human leukemic lines (BV173, HL60, U937, K562, KCL22) suggest that the main determinant of their sensitivity to topoisomerase I (camptothecin) and II (VP-16) inhibitors is their ability to regulate cell cycle progression in response to specific DNA damage, then to die through apoptosis: the more the cells inhibit cell cycle progression, the less sensitive they are. The final pathway of apoptosis induction involves a cytoplasmic signal, active at neutral pH, needing magnesium, sensitive to various protease inhibitors and activated directly by staurosporine. Modulators of intracellular signaling (calcium chelators, calmodulin inhibitors, PKC modulators, kinase and phosphatase inhibitors) have no significant influence upon apoptosis induction. Conversely, apoptosis induction pathway is modified during monocytic differentiation of HL60 cells induced by phorbol esters. Lastly, poly(ADP-ribosyl)ation and chromatine structure should regulate apoptotic DNA fragmentation that is prevented by 3 aminobenzamide and spermine, respectively. PMID- 8695923 TI - [Bcl-2 proto-oncogene expression in neoplastic and non neoplastic thyroid tissue]. AB - bcl-2 protein which protects cells from apoptosis is found to be expressed in several neoplastic and non neoplastic tissues. bcl-2 is consistently expressed in normal thyroid tissue but the regulation of its expression in thyroid tumors derived from the follicular cells remains to be discovered. In this study, we have assessed bcl-2 expression in different samples of non neoplastic and neoplastic thyroid tissues. Sixteen papillary carcinomas (including four papillary carcinomas of follicular variant), eight follicular carcinomas and five undifferentiated carcinomas were selected for this study. The tissues were routinely fixed and paraffin embedded. Four cases of normal thyroid tissue, four cases of Hashimoto's thyroiditis and five cases of thyroid tissue with Graves' disease were also investigated. Immunohistochemistry was performed with an anti bcl-2 monoclonal antibody on paraffin sections. bcl-2 was highly expressed in normal follicular cells but also in follicles of Hashimoto's thyroiditis and Graves' disease while its expression appeared to be downregulated in papillary (14 cases on 16), in follicular (five cases on eight) and undifferentiated (five cases on five) carcinomas. However, in five carcinoma cases (one papillary, one papillary follicular variant, three of follicular type), bcl-2 expression was similar or higher than in normal tissue. The highest expression of bcl-2 was observed in one case of follicular carcinoma with large amounts of atypical cells. bcl-2 protein seems to play a more important role in non-neoplastic thyroid cells rather than in carcinoma cells. The heterogeneity of its expression in thyroid neoplasms opens the question as to whether bcl-2 detection could serve as a prognostic factor in such tumors. This question could be answered on large series of cases with concomitant analysis of clinical data. PMID- 8695924 TI - [Vaccination with genetically modified IL-2 secreting cells in a rat model of colonic carcinoma]. AB - Genetically engineered tumor cells secreting immunostimulatory molecules could facilitate the obtention of a vaccination against tumor antigens. To test this approach, we transfected genes encoding for rat and mouse IL-2 into PROb cells. These cells originate from a dimethylhydrazine induced colon carcinoma of BD IX rats. We observed an inhibition of the in vivo tumor growth directly proportional to the IL-2 secretion. An immunohistochemical analysis revealed that the tumors were infiltrated by leucocytes expressing the IL-2 receptor, suggesting their activation within the tumor. A strong delay of tumor growth was observed in rats challenged with PROb cells after a previous rejection of IL-2 secreting cells. Yet two rats out of six were completely protected. This protection is specific since rejection of PROb-IL-2 does not confer protection towards the syngeneic glioma A15A5. In addition, we could show by depletion experiments that NK/LAK, CD8, and CD4 lymphocytes were involved in the rejection of cells secreting large amounts of IL-2. Macrophages appear to be involved in the rejection process too, but also in the induction of an immune memory. Vaccination experiments using irradiated PROb IL-2 cells were performed. Only a partial protection towards a challenge with parental PROb cells could be obtained, also depending on the amount of secreted IL-2: the best protection being obtained after vaccination with cells synthesizing a small amount of IL-2. However, this protection was not superior to that obtained by coinjection of irradiated PROb cells and BCG. PMID- 8695925 TI - [High incidence of p53 mutations in primary and metastatic head and neck tumors. Frequent protein overexpression in normal epithelium]. AB - Mutation of the p53 tumor suppressor gene is the most commonly observed gene alteration in human cancers. In order to identify new prognostic factors and tumor aggressiveness in squamous cell head and neck carcinomas, we analyzed 50 node metastases and 28 primary tumors including 13 matched specimens for p53 alterations. Mutations were found in 54 (69%) tumors, 76% of which were missense, 9% were nonsense and 15% were microdeletions or microinsertions. Twenty-five mutations were transitions mostly G-->A (40%) and 20 were transversions mostly G- >T (25%) thus confirming the role of tobacco carcinogens in the induction of these mutations. For eight patients mutations were observed in matched primary tumors and metastases, indicating clonal dissemination of tumor cells in most of these carcinomas. Furthermore the incidence of mutations was not different in primary tumors and node metastases indicating that this gene alteration was not related to the metastatic dissemination. No correlation was found between mutation and clinical parameters, the 8-year survival rates were not different (log rank test: P = 0.49) in patients with and without mutation. There was a good correlation between p53 mutation and protein overexpression (Fisher's exact test: P < 10(-4). Interestingly, immunostaining was also observed in basal cells from normal mucosa and in early lesions adjacent to the primary tumor in 11/15 specimens irrespective of the presence of mutation in the corresponding tumors. p53 protein overexpression may therefore constitute a biomarker for early stages of carcinogenesis of the head and neck epithelium. PMID- 8695926 TI - [Survival results after 10 years of 39 patients with inflammatory breast cancer treated by two different neoadjuvant chemotherapy protocols]. AB - The aim of this study was to compare the survival results at ten years of two groups of respectively 19 and 20 females who had an inflammatory breast cancer, treated with two different neoadjuvant chemotherapy protocols of six days for the first one, and of one day for the second one. Among these 39 patients, 16 are alive, 15 without any symptoms of disease since the end of the treatment. There is no statistically significant difference between the two groups for the disease free survival interval and for the survival population. PMID- 8695928 TI - [French Society of Cancer, 16th Cancer Forum. Paris, France, 17-19 June 1996. Abstracts]. PMID- 8695927 TI - [Unusual relapse for neuroblastoma. Case of an intracranial relapse]. AB - The usual sites of initial metastatic deposits in neuroblastoma are osteo medullary. With modern therapies including megatherapy and hematopoietic rescue, prolonged survival is obtained. However, unusual metastatic sites are more and more often described during the prolonged evolution of these patients such as brain metastases. A case of isolated intracerebral metastatic relapse is reported here in a patient who had received 4 months before a megatherapy in first complete remission. Pathogeny and therapeutical implications are discussed. PMID- 8695929 TI - Audit of ward to theatre communication. December 1994-March 1995. AB - Since practising anaesthetic nursing the author discovered much time and energy can be wasted if the patient checklist and handover from the ward is not completed correctly. Her colleagues expressed similar frustrations at various problems faced daily, that could be easily avoided by actions earlier on in the patients' management. PMID- 8695930 TI - Training for anaesthetic nurses in France. PMID- 8695932 TI - African diary. PMID- 8695931 TI - Changing roles--changing titles. A report of the NATN national seminar. PMID- 8695933 TI - Laparoscopic surgery--a patient's experience. PMID- 8695934 TI - Thoracic anaesthesia. AB - The uniqueness of thoracic anaesthesia is that it is conducted concurrently with operative surgery on, or in the vicinity of, those very organs which are receiving the anaesthetic gases. Although some procedures do not directly involve the lungs, e.g. oesophageal surgery, all consist of breaches in the integrity of one or both pleural cavities, whether in open thoracotomies or thoracoscopic procedures. Thus, hypoxia and hypercarbia are a constant threat. This is compounded by the fact that the patients are frequently elderly with chronic health problems and, consequently, poor anaesthetic risks. In view of this, an overview of respiratory anatomy and physiology will be given, followed by consideration of some of the anaesthetic strategies applied to meet the particular challenges of this surgical specialty. PMID- 8695936 TI - First of all--do no harm! PMID- 8695935 TI - Managing in difficult situations. PMID- 8695937 TI - Can music therapy reduce anxiety in theatre? PMID- 8695938 TI - Opportunities for a specialist practitioner and advanced nursing practice. NATN Education Committee. National Association of Theatre Nurses. PMID- 8695940 TI - The role of the nurse in theatre. A reply. PMID- 8695939 TI - Attitudes of nurses to donor organ retrieval and visiting surgical teams. The Papworth experience. AB - Donor organ retrieval can be a stressful procedure for theatre nurses. These experiences may be influenced by the relationship between visiting surgical teams and nurses at donor hospitals. When donor organs are referred to Papworth Hospital and a suitable recipient identified on the waiting list, a visit to the referring hospital is organised in order to retrieve the organs. The multidisciplinary donor team is comprised of a surgeon, anaesthetist, theatre nurse and technician who may find themselves called, often at short notice, to travel anywhere in the United Kingdom. Most donors are multi-organ donors which means that surgical teams, visiting or local, will be working together retrieving the heart and/or lungs, liver, kidneys, pancreas, cornea, long bones and skin. This multi faceted procedure on the donor and the number of visiting medical staff in theatre, may have an impact on local theatre nurses of which the visitors should be aware. The retrieval of thoracic organs takes 3-4 hours and the team needs to leave as soon as the excised organs have been packed so that preservation is not compromised. PMID- 8695941 TI - Stress in the operating theatre--a literature review. PMID- 8695942 TI - Operating department practitioners NVQ level 3 the new updated standards. A statement from NATN. National Association of Theatre Nurses. PMID- 8695943 TI - Pre-operative visiting--making it work. AB - Several key features are emerging about the management situation in the NHS which has an effect, in part, on the way a pre-operative visiting scheme must be introduced. Fewer nurses are being employed Technicians (ODP's) are being trained in ever greater numbers to take over the non-nursing duties of theatre nurses. Managers, even at theatre manager level, are increasingly coming from non nursing, non-medical or non-healthcare backgrounds. Budgets are being devolved down to theatre sister level. Theatre sisters are being downgraded to what was once a senior staff nurse grade. Two of the more significant concerns of managers are 'value for money' and 'quality at a given price'. It is very likely that clinical based nurses will be the ones who are trying to implement a pre operative visiting system. If so, then they must take these factors into account in order to be successful. This requires an understanding of the management process and how to 'speak the same language' as a manager. The following paper is based on my experiences both in this country and abroad, and upon my perception of how the role of a clinical nurse interacts with the role of manager. PMID- 8695944 TI - A review of glutaraldehyde alternatives. PMID- 8695945 TI - Four hugs a day using therapeutic touch. AB - Imagine a prescription which prescribed four hugs per day to a patient suffering from depression. Hanning described findings that four hugs per day was an antidote for depression, eight hugs per day would achieve mental stability and twelve hugs per day would achieve real psychological growth. If this is the case, touch has a greater significance than most of us would realise. The following assignment was written whilst I was undertaking ENB 176 using reflective practice to explain the benefits or problems in using certain techniques. PMID- 8695946 TI - The development of a post-operative pain service (1): An overview. AB - Slapping the patient on the face and saying: "It's all over" is a complete inversion of the truth. As far as the patient is concerned, it is just the beginning. This patient's view is supported by the report of a Working Party on Pain after Surgery which concluded that "the treatment of pain after surgery in British hospitals is inadequate and has not advanced significantly for many years". Yet failure to relieve pain is unacceptable not only for humanitarian reasons but also because unrelieved pain may inhibit optimal recovery. In their recommendations the Working Party placed a high priority on the establishment of an acute pain team in all acute general hospitals. This team would be responsible for education, research, audit, promoting pain assessment and ensuring adequate resources and safe practice. PMID- 8695947 TI - Duty of care--(3). AB - It will be recalled, from Part 1 of this series of articles, that a nurse is under a mandatory, absolute duty to speak out where a patient's care is, or may be, compromised. Section 10 of the UKCC Code is explicit: Each registered nurse...shall...make known to appropriate persons or authorities any circumstances which could place patients/clients in jeopardy or which militate against safe standards of practice. UKCC Code pp2 and 3. PMID- 8695948 TI - INANE. International Academy of Nursing Editors. PMID- 8695949 TI - Interview with Anne Jarvie, Chief Nursing Officer for Scotland. Interview by Paul Wicker. PMID- 8695950 TI - An invitation to Russia. PMID- 8695951 TI - African diary. PMID- 8695952 TI - Buzz words in the NHS--skill mix. AB - Buzz words have become commonplace in the new NHS and they provide a rich source of interest as to their real meaning. One of those frequently heard in this brave new world is that of Skill Mix. It is interesting to consider what it is intended to mean and what it may in fact mean in practice. PMID- 8695953 TI - An interview with Sheila Broome. PMID- 8695954 TI - Daisy Ayris Lecture--theatre nursing in a competitive environment. PMID- 8695955 TI - A monkey could do your job! AB - The present ethos in the health service of cost effectiveness and quality assurance requires nurses to identify the value of nursing practice in a way previously unheard of. Questions arise from this in relation to nursing and the nature of nursing. Some managers I have discussed these issues with believe that nurses are not required in theatre. It is not really surprising that such beliefs abound. Nurses have traditionally been more preoccupied with getting the work done than analysing the value of the nursing role. Much of this role is practical and there has, in the past, been little written about the nature of practical nursing let alone specifically about the practice of theatre nurses. Benner's work, with its emphasis on practice and recognition of nursing expertise, has brought about a reconceptualisation of the value of practice and of the knowledge found in that practice. In addition, the whole area of practical knowledge and expertise is now benefiting from further exploration. PMID- 8695956 TI - Where have all the student nurses gone? AB - Since the mid-eighties the elective allocation of student nurses to the operating department during their nurse education programme, has steadily diminished. Nursing programmes prior to 1988 usually incorporated a period of supervised learning of four to six weeks in theatres. During this time the student was expected to observe and participate in the care of the peri-operative surgical patient. The student was generally on rostered service and would be supervised by an experience Operating Department nurse. PMID- 8695957 TI - Uncovering the knowledge to care. AB - Quality of care requires knowledge of care. This article addresses the concept of 'care'. Leininger describes caring as the 'central and unifying domain for the body of knowledge and practices in nursing'. Much has been written on this concept and yet still there is much more to the concept than meets the eye. Attributes to the concept are identified using Walker and Avants framework of concept analysis. The attributes identified (forty) are utilised in determining their occurrence in forty-two articles submitted the the British Journal of Theatre Nurses (BJTN) from June 1993 to May 1994. The results show that not all forty attributes identified in the analysis are present. Recommendations are put forward for theatre nurses to critically examine caring situations that occur in looking after patients undergoing surgical procedures if we truly believe that ours is a caring environment. PMID- 8695959 TI - Building bridges. An interview with Libby Campbell. Interview by Paul Wicker. PMID- 8695958 TI - The development of a post-operative pain service (2): Audit of clinical practice. PMID- 8695960 TI - Challenging nursing myths and traditions. AB - This paper was presented to the World Conference of Operating Room Nurses XI held in Hamburg. Steeped in tradition as nursing is, some observably comical traditions, myths and behaviours have been dragged into a century where they clearly don't belong. Rather like the Flintstones, an exploration of some of these aberrations provides nurses with an opportunity to laugh at themselves and benefit from it. To carry the Flintstones analogy a little further, Fred and Wilma, Barney and Betty, seem to have all the modern luxuries of life - TV, microwave and hi-fi; however these are made of stone and have very implausible operating mechanisms. What have we got in nursing and what implausible mechanisms are we perpetuating in carrying out day-to-day activities? PMID- 8695961 TI - Diagnostic value of ultrasound analysis and bone densitometry as predictors of vertebral deformity in postmenopausal women. AB - Bone fractures depend not only on bone density, but also on bone quality. Ultrasound (US) has been proposed as a technique for evaluating skeletal status. Speed of sound (SOS) and broadband ultrasound attenuation (BUA) are the US properties currently used to assess bone strength and fragility. In 304 postmenopausal women (age 58.8 +/- 5.5 years) we measured: bone mineral density (BMD) of the lumbar spine (by dual-energy X-ray absorptiometry), SOS, BUA and Stiffness in the os calcis (using an Achilles machine). In all subjects we performed lateral lumbar and thoracic radiographs. Morphometric parameters were derived by measuring the anterior, middle and posterior height of each vertebral body, to obtain a semiquantitative grading of vertebral fractures as follows: 0, no vertebral deformity; 1, any vertebral height reduced between 20% and 25%; 2, any vertebral height reduced between 25% and 40%; 3, any vertebral height reduced more than 40%. On the basis of the number and severity of vertebral deformities the women were divided into: group 1 (n = 79), normal; group 2 (n = 80), mild; group 3 (n = 85), moderate; and group 4 (n = 60), severe. Mean values of SOS, BUA, Stiffness and BMD were significantly lower (p < 0.001) in women with vertebral deformity than in normals. In the whole population SOS, BUA and Stiffness values were significantly correlated with BMD. SOS, BUA and Stiffness values were significantly decreased (p < 0.001) with vertebral deformity, as was BMD. Receiver operating characteristic (ROC) curve analysis showed BMD to be slightly better than Stiffness in discriminating among groups. Logistic regression analysis showed that BMD, BUA, SOS and Stiffness were independent predictors of vertebral fracture risk. Ultrasound parameters were still significant independent predictors of vertebral fracture even after adjusting for BMD. PMID- 8695962 TI - Age-related hip fractures in men: clinical spectrum and short-term outcomes. AB - Clinical spectrum, treatment and short-term outcomes were assessed among the 131 Rochester, Minnesota, men who contracted an initial hip fracture due to moderate trauma during 1978-89. Three-fourths of falls leading to hip fracture occurred indoors with little seasonality, and 91% of fractures were in men 65 years of age or older. The ratio of cervical to intertrochanteric femur fractures was 1.4:1, and there was a tendency toward more neurological conditions among the patients with cervical fractures. Hemiarthroplasty and total hip replacement were mostly performed for cervical fractures, while internal fixation was preferred for intertrochanteric fractures. In-hospital mortality was 11.5%, and the 30-day case fatality rate was 16.0%. Age and postoperative deterioration of mental status significantly increased the risk of early death, the latter even after adjustment in a multivariate model, while comorbidity had a suggestive but not statistically significant influence on mortality. More than half the men were discharged to nursing homes, and 79% of the patients who survived at 1 year resided in nursing homes or intermediate care facilities or were attended by home care. Only 41% of survivors recovered their prefracture level of functioning and nearly 60% of patients limped and required a cane or walker. After implementation of the prospective payment system in 1984, the length of hospital stay was reduced, but there was no change in early mortality rates, in the duration of physical therapy following fracture or in attendance at nursing homes. The results of this population-based study demonstrate the strong impact of hip fractures on short term outcomes in men. PMID- 8695963 TI - Direct clinical and welfare costs of osteoporotic fractures in elderly men and women. AB - Osteoporosis is an increasing health care problem in all aging populations, but overall direct costs associated with the total fracture burden of osteoporosis remain uncertain. We have examined direct costs associated with 151 osteoporotic fractures occurring between 1989 and 1992 in a large cohort of elderly men and women followed prospectively as part of the Dubbo Osteoporosis Epidemiology Study. The median cost of hospital treated fractures was $A10,511 per fracture and for fractures treated on an outpatient basis $A455 in 1992 Australian dollars. Femoral neck fractures were the most expensive fractures ($15,984 median cost). There was no significant difference in costs between men and women for either hospital- or outpatient-treated fractures. Rehabilitation hospital costs comprised the largest proportion of costs (49%) for hospital-treated fractures. Community services comprised the major cost (40%) of outpatient-treated fractures. Univariate predictors of costs were quadriceps strength and bone density, although multivariate analysis showed quadriceps strength to be the best overall predictor of costs. The predicted annual treatment costs in Australia for atraumatic fractures occurring in subjects > or = 60 years was $A779 million or approximately $A44 million per million of population per annum. Estimated total osteoporotic fracture-related costs for the Australian population were much higher than previously reported. The majority of direct costs (95%) were incurred by hospitalized patients and related to hospital and rehabilitation costs. Extrapolation of these data suggests that the direct costs for hip fracture alone will increase approximately twofold in most Western countries by 2025. Improving the cost-effectiveness of treating osteoporotic fractures should involve reduced hospitalization and/or greater efficiency in community rehabilitation services. The costs of various approaches to osteoporosis prevention must be placed into the context of these direct costs and prevention should target men as well as women. PMID- 8695965 TI - Hologic QDR 2000 whole-body scans: a comparison of three combinations of scan modes and analysis software. AB - This study reports on the short-term in vivo precision and absolute measurements of three combinations of whole-body scan modes and analysis software using a Hologic QDR 2000 dual-energy X-ray densitometer. A group of 21 normal, healthy volunteers (11 male and 10 female) were scanned six times, receiving one pencil beam and one array whole-body scan on three occasions approximately 1 week apart. The following combinations of scan modes and analysis software were used: pencil beam scans analyzed with Hologic's standard whole-body software (PB scans); the same pencil-beam analyzed with Hologic's newer "enhanced" software (EPB scans); and array scans analyzed with the enhanced software (EA scans). Precision values (% coefficient of variation, %CV) were calculated for whole-body and regional bone mineral content (BMC), bone mineral density (BMD), fat mass, lean mass, %fat and total mass. In general, there was no significant difference among the three scan types with respect to short-term precision of BMD and only slight differences in the precision of BMC. Precision of BMC and BMD for all three scan types was excellent: < 1% CV for whole-body values, with most regional values in the 1%-2% range. Pencil-beam scans demonstrated significantly better soft tissue precision than did array scans. Precision errors for whole-body lean mass were: 0.9% (PB), 1.1% (EPB) and 1.9% (EA). Precision errors for whole-body fat mass were: 1.7% (PB), 2.4% (EPB) and 5.6% (EA). EPB precision errors were slightly higher than PB precision errors for lean, fat and %fat measurements of all regions except the head, although these differences were significant only for the fat and % fat of the arms and legs. In addition EPB precision values exhibited greater individual variability than PB precision values. Finally, absolute values of bone and soft tissue were compared among the three combinations of scan and analysis modes. BMC, BMD, fat mass, %fat and lean mass were significantly different between PB scans and either of the EPB or EA scans. Differences were as large as 20%-25% for certain regional fat and BMD measurements. Additional work may be needed to examine the relative accuracy of the scan mode/software combinations and to identify reasons for the differences in soft tissue precision with the array whole-body scan mode. PMID- 8695964 TI - Spinal bone mineral assessment in postmenopausal women: a comparison between dual X-ray absorptiometry and quantitative computed tomography. AB - We compared quantitative computed tomography (QCT) and dual X-ray absorptiometry (DXA) with respect to their ability to discriminate subjects with and without prevalent vertebral fractures. In 240 post-menopausal women (mean age 63.7 +/- 6.9 years) lateral spine radiographs (T4-L4) were reviewed for the presence of vertebral fracture. Using a semiquantitative technique to grade the severity of vertebral deformities, we classified fractures as mild, moderate or severe (grade 1 to 3, respectively). Postero-anterior DXA (PA-DXA) and lateral DXA (L-DXA) measurements (L2-4) as well as QCT measurements of the lumbar spine (T12-L3 or L1 14) were obtained in all women. Seventy-two women were diagnosed with at least one fracture, and of these 40 were graded as mild. Comparing normal women with fractured women, we found the area under the receiver operating characteristics (ROC) curves to be greatest for QCT (0.81), followed by L-DXA (0.72) and PA-DXA (0.65). The differences among all three techniques were significant. Comparing the normal women with women having only mild fractures, the areas under the ROC curves were 0.79, 0.73 and 0.63 for QCT, L-DXA and PA-DXA, respectively. Significant differences existed between QCT and PA-DXA as well as between L-DXA and PA-DXA. Logistic regression analysis also revealed the highest age-adjusted odds ratios for QCT (3.67; 2.25-5.97) while L-DXA and PA-DXA showed substantially lower odds ratios (2.00; 1.39-2.87, and 1.54; 1.11-2.15, respectively). We conclude that low bone density as measured by QCT, PA-DXA or L-DXA is significantly associated with the prevalence of vertebral fractures. Of the methods studied, QCT of trabecular bone offered the best discriminatory capability. L-DXA proved to be superior to PA-DXA in its diagnostic sensitivity, particularly in women with mild fracture. Mild vertebral fractures are associated with decreased spinal bone density and may be regarded as osteoporotic deformities. PMID- 8695966 TI - Cortical thickness assessed by peripheral quantitative computed tomography: accuracy evaluated on radius specimens. AB - The purpose of the present study was to evaluate the accuracy of peripheral quantitative computed tomography (pQCT) in measuring the thickness of the radial cortex. Thirty left forearm specimens were scanned on an XCT 960 Stratec pQCT device using a 2.5 mm thick slice at the junction of the middle and the distal third of the radius. Cortical and trabecular areas were assessed using a threshold procedure; cortical thickness was subsequently calculated assuming a circular ring model for the radius. Cortical thickness was also measured on the true shape of bone using an iterative contour detection procedure. Subsequently 2.5 mm thick resin-embedded cylindrical radial specimens, matched with the site of pQCT examination, were obtained and contact radiographs were performed. After tenfold magnification, the cortical and trabecular areas of the specimens were measured using computerized planimetry and cortical thickness was calculated assuming a circular ring model. The cortical thickness could be assessed by pQCT in all cases using the threshold algorithm (mean (SD) 2.51 (0.58) mm) and in 21 cases could be directly measured on the true shape of bone (2.62 (0.32) mm). The cortical thickness of the specimens showed good correlation and high proportionality with that measured using pQCT with either the threshold algorithm (r = 0.941, slope = 0.976) or the iterative contour detection procedure (r = 0.883, slope = 0.987). In conclusion, pQCT is able to assess the thickness of the radial cortex, at the junction of the middle and the distal third, with high accuracy. PMID- 8695967 TI - Influence of age and body mass on the effects of vitamin D on hip fracture risk. AB - The role of vitamin D in the prevention of hip fracture is controversial and protective effects appear to be confined to the institutionalized and elderly population. The aim of this study was to assess the interaction of age and body mass index (BMI) on the effects of vitamin D on the risk of hip fracture in the community. We studied 1634 women with low-energy fractures of the hip aged 50 years or older, and 3532 age-matched controls from 14 centres in six Mediterranean countries (the MEDOS study), with a structured retrospective questionnaire. The use of vitamin D supplements was associated with a modest and non-significant decrease in the risk of hip fracture (RR = 0.74; 95% confidence interval (CI) 0.53-1.03; p = 0.07). The risk reduction was influenced by age and body mass. Women aged above 80 years had a significant decrease in the relative risk of hip fracture (RR = 0.63; 95% CI 0.40-0.98) as did women with a BMI below 20 kg/m2 (RR = 0.45; 95% CI 0.24-0.84). Elderly women were more likely to have a low BMI but the elderly did not appear to benefit from vitamin D where their BMI was 20 kg/m2 or higher. The findings could not be explained by differences in sun exposure or in physical exercise. We conclude that the use of vitamin D for the prevention of hip fracture might usefully be targeted to the frail and elderly. PMID- 8695968 TI - Bone mass and mineral metabolism in Klinefelter's syndrome. AB - A reduced bone mineral density (BMD) is frequently observed in hypogonadal males; however, very little is known on bone and mineral metabolism in Klinefelter's syndrome (KS). In this study 32 XXY KS patients and 24 healthy age-matched male controls were examined. Serum total and free testosterone (TT and FT) were significantly lower in patients than in controls (TT in KS, 15.1 +/- 7.8 nmol/l; controls, 30.4 +/- 9.1; p < 0.001. FT in KS, 81.8 +/- 24.9 pmol/l; controls, 135.7 +/- 16.4; p < 0.001). 17 beta-Estradiol was slightly higher in KS patients (KS, 49.0 +/- 27.1 pg/ml; controls, 39.3 +/- 16.4 pg/ml), but the difference was not significant. BMD, measured at the spine (L2-4) and at the proximal epiphysis of the left femur, was similar in patients and in the control group (spine: KS, 1.016 +/- 0.142; controls, 1.085 +/- 0.144 g/cm2; p = not significant. Femoral neck: KS, 0.926 +/- 0.149; controls, 0.926 +/- 0.122 g/cm2; p = not significant). Bone GLA protein (BGP) was significantly higher in the KS group (12.7 +/- 4.8 vs 8.9 +/- 5.2 ng/ml; p < 0.02), while serum calcium, serum phosphate, calciotrophic hormones and the fasting urinary hydroxyproline/creatinine ratio (OHP/Creat) were similar in the two groups. A positive relationship between FT and both spine and femoral BMD was found in KS patients. Furthermore, OHP/Creat ratio was inversely related to BMD at the femur, and positively related to BGP in KS patients, but not in normal subjects. These findings suggest that (1) KS patients have normal bone mass, most probably because the hypogonadism is moderate; and (2) patients with lower bone mass appear to have higher bone turnover. PMID- 8695969 TI - Prevention of early postmenopausal bone loss using low doses of conjugated estrogens and the non-hormonal, bone-active drug ipriflavone. AB - Hormone replacement therapy is the optimal therapeutic choice for postmenopausal syndrome. While low doses of estrogens (0.3 mg/day of conjugated estrogens) can counteract neurovegetative menopausal symptoms, higher doses (0.625 mg/day of conjugated estrogens) are required to prevent bone loss in postmenopausal women. Experimental and clinical studies have shown that ipriflavone, a non-hormonal isoflavone derivative, is effective in the prevention and treatment of postmenopausal osteoporosis. The aim of the present investigation was to evaluate the efficacy and tolerability of ipriflavone and very low doses of equine conjugated estrogens on bone loss in early postmenopausal women. Eighty-three healthy postmenopausal women (50.3 +/- 0.7 years) were enrolled for this 1-year multicenter study. All subjects were randomly allocated to receive: double placebo (n = 24; group A), placebo plus conjugated equine estrogens 0.30 mg/day (n = 31; group B) or conjugated equine estrogens 0.30 mg/day plus oral ipriflavone 200 mg tris in die at meals (n = 28; group C), according to a double masked design. Among women who completed the treatment period (valid completers), those of group A showed a progressive decrease in forearm bone density (FBD; measured by dual photon absorptiometry) that reached 1.7% after 12 months. The women in group B maintained their FBD in the first 6 months of treatment but, at the end of the study, showed a bone loss of 1.4% compared with basal values. By contrast, women in group C showed a significant increase in FBD after 1 year of treatment (+5.6%; p < 0.01). Both valid completers and intention to treat analyses revealed a significant difference (p < 0.05) between group A and group C over the study period. None of the treatments produced significant changes of biochemical markers of bone turnover, while hot flushes and other climacteric symptoms were significantly reduced after the sixth month of treatment in women receiving estrogens. Adverse events were generally mild, and did not differ among the groups. The results of this study suggest that low doses of estrogens combined with ipriflavone could represent a new therapeutic approach to the treatment of the postmenopausal syndrome. PMID- 8695970 TI - Treatment of postmenopausal vertebral osteopenia with monofluorophospate: a long term calcium-controlled study. AB - The aim of the present study was to assess the effects of the new fluorine pro drug monofluorophosphate (MFP) in postmenopausal women with vertebral osteopenia and high bone turnover. We enrolled postmenopausal women (PMW, 43-59 years) who had had a natural menopause 2-5 years before the study, had vertebral bone mineral density (BMD) < 1 SD from the premenopausal mean, and had at least one of the biochemical markers of bone remodeling > 1 SD over the mean for premenopausal women. Patients were randomly divided into two treatment groups (group 1, 500 mg/day of oral calcium; group 2, MFP at the dose of 20 mg F-equivalents + 600 mg calcium/day) for 2 years (n = 21 in each group). The lumbar vertebral (L2-4) BMD and total body bone mineral (TBBM) were measured by dual-energy X-ray absorptiometry (Lunar DPX, Lunar Corporation, USA). Urinary hydroxyproline excretion (OH-P/Cr), plasma bone Gla protein (BGP) and serum alkaline phosphatase (AP) were assayed. In group 1 the markers of bone turnover and vertebral BMD did not show any significant modification, while TBBM showed a significant (p < 0.05) decrease after 24 months. In group 2 a significant (p < 0.05) decrease in OH-P/Cr (-23.9 +/- 2.0%), and an increase in both BGP (+19.4 +/- 2.6%) and AP (+10.3 +/- 2.6%) levels were observed after 24 months of MFP administration. In this group, both vertebral BMD (+5.01 +/- 0.9%, p < 0.01) and TBBM (+4.0 +/- 0.6%, p < 0.05) showed a significant increase after 24 months. Present results suggest that, in osteopenic PMW, MFP administration induces a significant increase in vertebral BMD without impairment of cortical bone, with a reduction in bone resorption and an increase in bone formation rate. PMID- 8695971 TI - Circadian rhythm in type I collagen formation in postmenopausal women with and without osteopenia. AB - A circadian rhythm in the serum concentration of the procollagen type I carboxyl terminal propeptide (sPICP) has previously been demonstrated in premenopausal women. This study was performed to investigate the circadian rhythm in sPICP in healthy and osteopenic postmenopausal women. Blood samples were taken every third hour for 27 h from three groups of women: 12 early postmenopausal women (aged 55 +/- 2 years; mean +/- SD); 12 late postmenopausal women (aged 73 +/- 1 years); and 12 osteopenic but otherwise healthy late postmenopausal women (aged 73 +/- 1 years). A circadian rhythm in sPICP was found in all three groups, as shown by cosinor analysis (p = 0.000003-0.03). The circadian rhythm in sPICP was significantly different between the osteopenic group and the age-matched healthy group (p < 0.008). The amplitude of the circadian rhythm in sPICP was about twice as high in the osteopenic group, and the time of the maximum tended to be about 3 h later, as compared with the age-matched healthy group. The plasma concentration of osteocalcin, as measured by a recently developed two-site enzyme-linked immunosorbent assay, also showed a circadian rhythm in all three groups (p = 0.0001-0.05), with no significant differences between groups. In conclusion, we have found a significant circadian rhythm in sPICP in both early and late postmenopausal women. In osteopenic women the nightly peak in sPICP is larger and persists later into the night as compared with non-osteopenic women. PMID- 8695972 TI - Age-related changes in Os calcis ultrasonic indices: a 2-year prospective study. AB - We performed repeated ultrasound measurements approximately 2 years apart (average 23 months +/- 3 months) on the os calcis of 113 healthy postmenopausal women recruited from two large prospective cohort studies named OFELY and EPIDOS. Group A (from OFELY) consisted of 88 women aged 52-72 (63 +/- 5) years, randomly selected from a large insurance company, and group B (from EPIDOS) consisted of 25 women aged 75-88 (80 +/- 4) years, randomly selected from the voting lists. We obtained broadband ultrasonic attenuation (BUA) and speed of sound (SOS) measurements, as well as the Stiffness index, with a Lunar Achilles ultrasound machine. We performed dual energy X-ray absorptiometry (DXA) measurements of femoral neck bone mineral density (neck BMD) with a Hologic QDR 2000 for group A and with a Lunar DPX Plus for group B. The decrease that we observed over 2 years was on average +/- 1 SD: -1.01 +/- 4.6 dB/MHz (p = 0.02) for BUA (which is approximately equal to the long-term precision error in vitro), -11.3 +/- 9.2 m/s (p = 0.0001) for SOS (approximately 5 times the precision error), -3.8 +/- 4.2% YA (p = 0.0001) for Stiffness (2.5 times the precision error) and -0.01 +/- 0.03 g/cm2 (p = 0.0001) for neck BMD (approximately equal to the precision error). In terms of percentage change this represents: -1.0% +/- 4.3% for BUA, -0.8% +/- 0.6% for SOS and -1.85% +/- 4.4% for neck BMD. At the individual level, most SOS and Stiffness values were consistent with a decrease, whereas BUA and neck BMD values were spread out above and below the zero line of no change. The decreases in SOS and Stiffness were significantly larger in the early postmenopause (< or = 20 years since menopause [YSM]) than in the late postmenopause (> 20 YSM). We observed a similar trend for BUA and BMD but this did not reach statistical significance. We found a weak but significant correlation between changes in ultrasound variables and changes in neck BMD. However, the 2-year changes observed in SOS were not significantly correlated with changes in BUA. This study suggests that the heel ultrasound measurements of SOS and Stiffness are valuable indices of postmenopausal bone loss, and could be used for follow-up in therapeutic trials. PMID- 8695973 TI - Trends in submitting abstracts to the Italian society of osteoporosis: do they reflect a changing attitude of medical doctors? PMID- 8695974 TI - Certificate program in holistic nursing. Healing touch workshops 1996. 1996 aromatherapy schedule. PMID- 8695975 TI - Slow learner. PMID- 8695976 TI - Energy-based healing arts and Christian teaching. PMID- 8695977 TI - Clinical implications of unstable DNA repeat sequences. AB - In this article we review the clinical and genetic features characteristic of a number of diseases recently explained by a novel genetic mechanism: unstable segments of the genome containing trinucleotide repeat sequences. Disorders identified to date are mostly progressive, and display unusual inheritance patterns such as anticipation. Anticipation is manifested as an earlier age at onset or a more severe phenotype in later generations of a family, and can be correlated to an increased repeat expansion size. Thus in later generations the disease onset can take place in childhood whereas affected individuals in earlier generations had only adult symptoms. Paediatric cases of typically adult disorders have been shown to be caused by exceptionally long repeat sequences. Anticipation has been observed in a number of disorders not yet identified at the molecular level. Such disorders could be caused by repeat expansions, and are presently subject to intense research efforts. If repeat sequence expansions are related to these disorders, the longest expansions should be seen in the childhood cases, making these the optimal cases to study. Various DNA-based methods have been developed for the detection of these mutations, making possible preclinical and prenatal diagnostics as well as detection of novel expansions. PMID- 8695978 TI - The impact of phototherapy in the management of neonatal hyperbilirubinemia: comparison of historical cohorts. AB - To quantitatively assess the impact of phototherapy (PT) in the prevention of kernicterus we calculated the rate of exchange transfusion (ET) in two large historical cohorts of Greek neonates (birthweight > or = 2.5 kg), one before (period I: 1957-61) and one after (period II: 1980-92) the introduction of PT. Overall, the introduction of PT was associated with a reduction of the rate of ET from 0.43% in period I to 0.05% in period II. The reduction was observed in all etiological categories but was more marked in the ABO-incompatible group. With an estimated rate of kernicterus without treatment of 0.085% (excluding rhesus hemolytic disease of the newborn and prematurity) we estimated that 4.2 and 0.36 infants were treated by ET for each spared kernicterus in periods I and II, respectively. Finally, in period II 185 infants were treated with PT or PT and ET for each spared kernicterus. PMID- 8695979 TI - Phototherapy for neonatal jaundice. AB - Exchange transfusion for severe neonatal jaundice is a tedious and expensive procedure with high morbidity and mortality rates, and is followed by a prompt and marked bilirubin rebound. It has largely been replaced by phototherapy, which though more gradual in its effect results in a prolonged reduction of the bilirubin concentration. Its efficacy is influenced by the gestational age, birthweight and postnatal age of the infant, the aetiology of the jaundice, and the spectral emission and intensity (dose) of the light; its dose-response relationship enables it, at the optimal dose, to control very severe jaundice or a rapidly rising bilirubin concentration, including severe haemolysis. Its relative freedom from complications together with its non-invasive nature, ease of usage and convenience has resulted in widespread acceptance in virtually all neonatal units. PMID- 8695980 TI - Prevention of HIV infection. PMID- 8695981 TI - A potential danger of bedclothes covering the face. AB - Investigations of infants dying unexpectedly have reported up to 28% being found completely under bedding. No detailed physiological studies looking at the possibilities of asphyxia in this situation are available. The aim was to determine the potential for asphyxia under different types and thicknesses of bedding. A mechanical model of a 3-month-old infant's respiratory system was used. Bedding was positioned over the head in a supine position, and inspired carbon dioxide recorded. With a fixed respiratory rate and tidal volume, carbon dioxide accumulation increased with increasing layers of blankets. Up to 8.3% inspired carbon dioxide was recorded with more than four layers of blankets. A cotton sheet between the face and blankets reduced the accumulation by half. An infant found dead under bedding may have been exposed to an asphyxial stress. Suffocation from rebreathing trapped, expired gases can be a cause of death in this situation. PMID- 8695982 TI - Accidents in childhood: relation to psychosocial conditions and mental development. AB - In a longitudinal cohort study we investigated if children experiencing psychosocial stress and exhibiting certain psychopathological symptoms run a higher risk of having accidents than other children. In 366 children the number of hospital-treated casualties during the first 10 years of their lives was related to the physical and mental characteristics of the children and to the social conditions in their families. Boys had a higher number of accidents when one or both of the parents were known to have alcohol problems. Girls exhibiting symptoms of depression, anxiety and problems in social relationships at 4-5 years of age had more accidents than girls without such symptoms. However, the differences in accident rates were small, perhaps due to the physical environment in the housing areas and the general attitude, both aiming towards reducing childhood accidents. PMID- 8695984 TI - Congenital chloride diarrhoea: a prenatal differential diagnosis of small bowel atresia. AB - We compared ultrasound findings and pre- and postnatal clinical signs in 8 patients with congenital chloride diarrhoea and 14 with small bowel atresia diagnosed in 1977-1991 in order to evaluate the possibility of a prenatal distinguishing diagnostic sign. In the patients with congenital chloride diarrhoea the pregnancy was complicated by marked polyhydramnios, the symphysis fundus distance exceeded + 2 SD before gestational week 31 and the fetus displayed normal peristalsis in extensively dilated intestines and the "frog position". In the patients with small bowel atresia the symphysis-fundus distance was normal before gestational week 31 and the fetus displayed increased peristalsis in a few dilated intestinal loops. PMID- 8695983 TI - Serum lipids and apolipoproteins in Spanish children and adolescents: a 5 year follow-up. AB - This study was designed to assess "tracking" of serum lipids and apolipoproteins in three age groups of Spanish children over a 5 year period. A total of 84 6 year-old, 89 10-year-old and 64 14-year-old children were evaluated in 1989 (with measurement of serum total cholesterol, triglycerides, lipoproteins and apolipoproteins A1 and B), and re-evaluated in 1994. Correlation coefficients between initial and final lipid and apolipoprotein values were as follows: total cholesterol, 0.66; low-density lipoprotein (LDL) cholesterol, 0.65; high-density lipoprotein (HDL) cholesterol, 0.61; triglycerides, 0.61; apolipoprotein A1, 0.60; apolipoprotein B, 0.66. When age groups were analysed separately, children who were 14 years old at the beginning of the study showed higher correlation coefficients, particularly for total cholesterol and LDL cholesterol ( > 0.7 in both cases). More than 70% of children who were in the top quintile of total, LDL or HDL cholesterol as well as apolipoprotein A1 or B in 1989 remained in the top quintile 5 years later. PMID- 8695985 TI - Parvovirus B19 infection and Diamond-Blackfan anaemia. AB - It is the purpose of the study to report the frequency of parvovirus in children with a diagnosis of Diamond-Blackfan anaemia and to discuss the possible aetiological role of parvovirus in Diamond-Blackfan anaemia. We found parvovirus DNA in 3 of 11 bone marrow smears. Giant pronormoblasts showed low sensitivity (33%) and poor specificity (75%). The presence of giant pronormoblasts was associated with a very high myeloid:erythroid ratio, and may not be specific for parvovirus infection, but a feature of severely suppressed erythropoiesis. The three parvovirus-positive patients were the only children who experienced a remission, and who are free of medication. The seven surviving parvovirus negative patients are all currently on steroid treatment. PMID- 8695986 TI - Relationship of interleukin-8 and colony-stimulating factors to neutrophil migration in aseptic meningitis. AB - Polymorphonuclear neutrophilic leucocyte (PMNL) migration into the subarachnoid space in aseptic meningitis of probable enteroviral aetiology was evaluated in relation to cerebrospinal fluid and serum levels of interleukin-8 (IL-8), macrophage colony-stimulating factor (M-CSF) and granulocyte colony-stimulating factor (G-CSF). IL-8 levels reached a plateau within 12h of onset, while M-CSF and G-CSF levels reached a peak between 12 and 24 h after onset, corresponding to the peak increase in PMNL count. G-CSF levels had the closest correlation with PMNL count. M-CSF levels were weakly correlated with PMNL count. IL-8 levels were not correlated with PMNL count except within 12 h of onset. IL-8 and G-CSF were detected predominantly in cerebrospinal fluid, while the M-CSF levels in the two compartments were not different except between 12 and 24 h after onset. It is considered that IL-8 triggers rapid and transient migration of PMNL, and that G CSF then promotes gradual and consistent infiltration of PMNL. PMID- 8695987 TI - Outcome of idiopathic membranoproliferative glomerulonephritis in children. Arbeitsgemeinschaft Padiatrische Nephrologie. AB - The aim of this multicentre study was to analyse the long-term outcome of idiopathic membranoproliferative glomerulonephritis (MPGN) according to histological type and to the presence of C3 nephritic factor. Fifty patients aged 2-14 years at the onset of the study were followed over 2-20 years; 26 patients had MPGN type I, 17 had type II and 7 had type III. Treatment was variable. At the last observation, 30 patients had reached terminal and four pre-terminal renal failure. The median survival probability until renal death was 15.3, 8.7 and 15.9 years for disease types I, II and III respectively (difference between MPGN types I + III versus type II: p = 0.013). The presence of an initial nephrotic syndrome was associated with a more rapid progression (p = 0.018). C3 nephritic factor was of no prognostic value. We conclude that the outcome of MPGN mainly depends on the histological type observed. PMID- 8695988 TI - A prospective, longitudinal study examining the development of retinopathy in children with diabetes. AB - A prospective longitudinal study of 182 children and adolescents with diabetes revealed that during a follow-up of 2.5 +/- 0.5 years the prevalence of retinopathy increased from 10.8% to 28.0%, corresponding to an annual increase of 7%. Retinopathy was diagnosed at a mean age of 15.3 years (95% CI, 14.8-15.8 years) after a mean duration of diabetes of 8.9 years (95% CI, 8.0-9.7 years). Prepubertal years of diabetes contributed to the risk of developing retinopathy. The initial signs of retinopathy were microaneurysm(s) in 56%, microaneurysm(s) and haemorrhage(s) in 30%, and haemorrhage(s) in 10%. A combination of microaneurysm, haemorrhage and cotton-wool spot was observed in 2%, and microaneurysms, haemorrhage and an IRMA lesion were seen in 2%. Most of the initial lesions disappeared during the follow-up period, but at the same time new lesions developed elsewhere in the retina in all but 2 cases. In 8 patients (15% of patients with retinopathy) aged 13.7-19.8 years and having had diabetes for 3.7-14.8 years, retinal changes progressed from mild to a more advanced background retinopathy. A higher glycated haemoglobin level during puberty was the only factor which differentiated these patients from control patients matched for sex, age, puberty and duration of diabetes. PMID- 8695989 TI - No fine motor deficits in patients with untreated non-phenylketonuria hyperphenylalaninaemia. AB - Twenty-four untreated adolescent and adult patients with non-phenylketonuria (PKU) hyperphenylalaninaemia (HPA) (serum phenylalanine levels < 600 mumol l-1) and 24 healthy controls matched for age, sex and IQ were investigated for their neurological outcome, especially for fine motor abilities by the Motor Performance Task. No pathological findings could be revealed by clinical neurological examination. Patients with HPA and healthy controls did not significantly differ in their fine motor performances. These performances were not significantly influenced by serum phenylalanine concentrations. Our results indicate that untreated patients with non-PKU HPA are not at clinically significant risk for developing fine motor deficits and severe neurological impairment. From this point of view a dietary treatment is not necessary in patients with HPA, as recommended most recently. PMID- 8695990 TI - Long-term pulmonary function in children with Hodgkin's disease. AB - We studied the long-term pulmonary function of 25 patients who were at least 5 years post-treatment for Hodgkin's disease. The mean age of the patients was 17 years (range 9.5-25 years) at the time of study. Twenty-one of the patients were male. All patients received six courses of COPP chemotherapy and, in addition, 8 of the 25 patients received radiotherapy to the mediastinum in low or moderate doses (20-30 Gy). One patient had symptoms of bronchiectasia. The chest radiographs of nine patients (36%) showed minimal abnormalities. We divided patients into two groups while evaluating their pulmonary function tests according to whether they received mantle irradiation or not. In patients who received mantle irradiation, pulmonary function tests showed a minimal decrease in FEV1. The decrease in FEV1 indicated an obstructive ventilatory defect. We concluded that our treatment protocols for paediatric Hodgkin's disease were curative, well tolerable and might minimize pulmonary functional changes. PMID- 8695991 TI - Bone marrow transplantation in children using unrelated donors at Huddinge Hospital. AB - Twenty-eight out of 31 children that underwent bone marrow transplantation (BMT) from unrelated donors between 1984 and 1995 received HLA-A, HLA-B and HLA-DR matched unrelated donor (MUD) marrows as defined by serologic HLA class I and genomic HLA class II typing. Compared with 28 case-matched controls transplanted with HLA identical sibling donors, MUD patients received a more intensive conditioning. Twenty-six patients (93%) engrafted while two died of septicaemia during the aplastic phase. Two patients rejected their grafts and four developed Evans syndrome. All controls engrafted without incidents of rejection or Evans syndrome. The probability of acute graft-versus-host disease (GVHD) of grade II or above was 27% after MUD-BMT and 7% in the controls. The 5-year probability of survival was 60% in MUD patients and 89% after sibling BMT (p = 0.03). Leukaemia free survival was 60% with one relapse in the MUD patients, and 59% with five relapses in the sibling group. Three children who received a mismatched donor marrow died, two of severe GVHD and one after graft rejection. In conclusion, today, a matched unrelated donor BMT is an acceptable alternative for many children who need a BMT but lack a suitable related donor. PMID- 8695992 TI - A comparison of pulmonary and femoral artery thermodilution cardiac indices in paediatric intensive care patients. AB - We have assessed the agreement between pulmonary artery and femoral artery (COLD) thermodilution measurements of the cardiac index (Cl) in a group of paediatric intensive care patients. The COLD method gave consistently higher cardiac index values than the pulmonary artery catheter (PAC); however, the difference was small, with a mean value of 0.19 l/min-1 m-2 or 4.4% of the mean cardiac index. This difference is not clinically important and suggests that, under these circumstances, the COLD system provides an acceptable alternative to the pulmonary artery catheter for measurement of the cardiac index at the bedside. PMID- 8695993 TI - Grief following the loss of a newborn twin compared to a singleton. AB - This study, involving five level III neonatal intensive care units, investigated whether there are any differences between parental grief following the death of a newborn twin and parental grief following the death of a newborn singleton. A total of 142 parents were examined using the Perinatal Grief Scale (PGS): 72 who had lost a newborn twin and 70 matched controls who had lost a newborn singleton 0.5-3.5 years previously. We found that bereaved twin parents did not differ in grief reactions from bereaved singleton parents (PGS: F = 0.00, p = 0.962). This held true both for the short and the long term (F = 0.13, p = 0.721). Mothers showed more grief than fathers (F = 8.16, p = 0.005). In conclusion, grief in bereaved twin parents should be taken as seriously as grief in bereaved singleton parents. The present guidelines regarding care for the latter ought to be adapted to meet the needs of the former. PMID- 8695994 TI - Generation of hydroxytrimethyllysine from trimethyllysine limits the carnitine biosynthesis in premature infants. AB - epsilon-N-Trimethyl-L-lysine (TML) was given orally for 1 day to two groups of premature infants. There was no change in the output or plasma levels of carnitine at a dose of 100 mumol/day; however, the urinary TML increased 17-fold. In the second group, administration of 1 mmol TML increased the plasma levels and urinary output of carnitine; the output of TML increased 62-fold. During a search of the metabolites of carnitine biosynthesis by 1H NMR analysis of urine, only one new resonance (corresponding to the TML) could be identified in both groups. Fast atom bombardment mass spectrometry (FAB-MS) analysis of urine samples indicated an increase in TML in the treated patients; no changes were found in the relative abundance of any other precursors. These data show that a significant limitation of the conversion of hydroxy-TML to carnitine is not likely; rather, the conversion of TML to hydroxy-TML is regulatory in neonatal carnitine biosynthesis. PMID- 8695996 TI - Measurement of transepidermal water loss in Tanzanian cot-nursed neonates and its relation to postnatal weight loss. AB - In healthy cot-nursed Tanzanian neonates (n = 92, gestation 26-42 weeks) measurements of trans-epidermal water loss (TEWL) and weight change were performed during the first 24 h after birth at an average ambient humidity of 70% and an environmental temperature of 32 degrees C. Urine production on day 1 (ml/kg per 24 h) was documented for a subgroup of 13 preterm and 8 term infants. In a limited group of preterm infants (n = 5) TEWL measurements, weight and 24 h urine volume measurements were repeated daily for 7 days. Maximum weight loss was determined in 7 preterm (gestational age 30-36 weeks) and 6 term infants. TEWL was estimated by measuring the evaporation rate at three sites of the body using the water vapour pressure gradient method. On day 1, TEWL was highest in the most preterm infants, whereas TEWL and urine production were higher in large for gestational age infants as compared to appropriate for gestational age (AGA) infants of the same gestational age (31-36 weeks). For the whole group, weight loss on day 1 was correlated with TEWL (r = 0.49, p < 0.05). At follow-up TEWL in preterm infants remained almost constant during the first 4 days and decreased after the fourth day, at which time weight gain commenced. Preterm AGA infants (gestational age 24-37 weeks) showed a mean postnatal weight loss of 4.4% of the birth weight, while in term infants this loss was only 2.6%. A reduced postnatal weight loss as compared to Caucasian infants may be explained by a lower water loss during the first days after birth, through both skin evaporation and urine excretion. PMID- 8695995 TI - Plasma concentration of granulocyte-colony-stimulating factor in neonates. AB - We determined the plasma concentration of granulocyte-colony-stimulating factor (GCSF) and the neutrophil count in 108 infants (gestational age 23-41 weeks; birthweight 478-4935g). The GCSF levels in the very low birthweight infants without infection were comparable to those in the full-term infants. Infants as premature as 23 weeks of gestation showed similar GCSF levels to mature neonates. GCSF levels decreased significantly by day 7 after birth. The levels were not significantly correlated with the neutrophil count. The mean plasma level of GCSF increased significantly when infection developed and was significantly higher in the infants with sepsis than in those with non-septic infections (p < 0.01). The results suggest that GCSF may be the major determinant of neutrophil kinetics both during fetal life and after birth. PMID- 8695998 TI - Fibreoptic phototherapy in the management of jaundice in low birthweight neonates. AB - A fibreoptic phototherapy device has been compared with conventional white and special blue fluorescent phototherapy lamps to evaluate its efficacy in lowering serum bilirubin levels in low-birthweight neonates. Fibreoptic phototherapy was found to be as effective as white light and less effective than blue light, as assessed by (i) the bilirubin concentration after 24 h of phototherapy and at the end of phototherapy, (ii) the duration of phototherapy, (iii) the percentage daily decline rate and (iv) the overall percentage decline rate (p < 0.05). There were no failures of phototherapy and the need for re-exposure was low (4.7% of the total sample), with no difference between groups. The fibreoptic approach represents a promising way to aggregate synergically the most recent optical technologies and develop a modern, efficient and caring phototherapy system for low-birthweight infants. PMID- 8695997 TI - Effects of fentanyl administration on general and cerebral haemodynamics in sick newborn infants. AB - Despite the wide use of fentanyl for analgesia in newborns, concerns have been raised about potential haemodynamic side-effects. Since sick newborns may lose their cerebral blood flow autoregulation, a drug-induced haemodynamic instability could lead to brain injury. We assessed the effects of a 15-min infusion of fentanyl (3 micrograms/kg) on the general and cerebral haemodynamics in 15 newborns (median gestational age 29 weeks, 25th-75th percentile, range 28-31 weeks; birthweight 1170 g, range 955-1790 g). The heart rate and mean arterial blood pressure were continuously recorded. Mean cerebral blood flow velocity and pulsatility index were measured using pulsed Doppler ultrasound before, during and up to 60 min after the onset fentanyl administration. No significant modification of general or cerebral haemodynamics was observed. In conclusion, the infusion of 3 micrograms/kg of fentanyl did not lead to any deleterious effect on the general or cerebral haemodynamics in sick normovolaemic newborns. PMID- 8695999 TI - Serum interleukin-1 beta in neonatal sepsis. AB - Serum levels of interleukin-1 beta (IL-1 beta) in newborn infants with septicaemia were measured and possible relationships between the clinical course of the infants, causative micro-organisms and IL-1 beta levels were investigated in a prospective study. The study groups comprised 49 newborn infants (25 mature, 24 premature) with proven sepsis and 40 healthy newborn infants (20 mature, 20 premature). Serum IL-1 beta levels were measured using the IL-1 beta immunoradiometric assay. The levels were found to be lower in neonates with sepsis (median 0.1 pg/ml) than in healthy controls (median 27.9 pg/ml) (p < 0.001). Non-significant trends towards lower levels were observed in children with shock and in non-survivors. No correlation was found between IL-1 beta and postnatal age, gestational age or the study weight of the patients. There was no significant difference in the serum IL-1 beta level in septic patients infected with Gram-positive bacteria and those infected with Gram-negative bacteria. The results show that the concentration of IL-1 beta is significantly decreased in preterm and term neonates with sepsis. PMID- 8696000 TI - Short subsequent-birth interval does not affect previous child's nutritional status in the fifth year of life. PMID- 8696001 TI - Extracorporeal shock wave lithotripsy in children. AB - An experience with 103 children treated with extracorporeal shock wave lithotripsy (ESWL) is reviewed in this report. The success rate was 63%. The stone volume was of major importance for the result. There was a continuous decrease in success rate with increasing stone size. It was also shown that stone free rates decreased with an increasing number of stones. Short-term complications were minor and hospitalization times were short. It is concluded that ESWL is a first-choice treatment in children with urinary calculi smaller than 200 mm2 in size. PMID- 8696002 TI - Mitral and aortic insufficiency in polyarticular juvenile rheumatoid arthritis. PMID- 8696003 TI - The bronze baby syndrome: evidence of increased tissue concentration of copper porphyrins. AB - A case regarding a newborn infant with severe Rh haemolytic disease, who presented with the bronze baby syndrome and eventually died, is reported. The postmortem examination showed marked extramedullary haematopoiesis in the liver and spleen, heavy hepatic haemosiderosis and mild intralobular cholestasis. The porphyrin content, which was assayed in different tissues, was very high in the liver, suggesting that the increased erythropoiesis seen in Rh haemolytic disease leads to an increased synthesis of porphyrins as by-products of haem synthesis. Phototherapy causes photodestruction, sensitized by bilirubin, of porphyrins (mainly copper porphyrins), yielding brown photoproducts. PMID- 8696004 TI - Peripheral intravenous infusion--another cause of air embolism. AB - We report an unusual complication of intravenous infusion. A 4-week-old baby developed acute cardiopulmonary distress because of air embolism caused by improper preparation of peripheral intravenous set. The estimated amount of infused air was 12 ml (approximately 3.5 ml/kg). The infant recovered promptly after short supportive treatment. PMID- 8696005 TI - Treatment of pituitary resistance to thyroid hormone (PRTH) in an 8-year-old boy. AB - We report on an 8-year-old boy with pituitary resistance to thyroid hormone (PRTH) having a cysteine for arginine substitution at codon 320 in the TR-beta gene who was presented because of thyrotoxicosis. Due to its suppressive effect on the pituitary thyrotropin secretion, treatment with D-thyroxine (D-T4) was started. After a few days, clinical euthyroidism was achieved but thyroid stimulating hormone secretion was not suppressed. Symptoms of thyrotoxicosis relapsed when therapy was interrupted so that therapy with D-T4 was reinstituted and continued to date. Symptoms did not recur, and the psychomotor development proceeded normally. D-T4 should therefore be considered in the treatment of thyrotoxicosis in PRTH. PMID- 8696006 TI - Evidence for possible Mendelian inheritance of septo-optic dysplasia. AB - We describe two siblings from a highly consanguineous pedigree with absent mid line brain structures and hypopituitarism. This raises the possibility of a heritable basis for at least some forms of the septo-optic dysplasia sequence. PMID- 8696007 TI - Extrathymic T cells stand at an intermediate phylogenetic position between natural killer cells and thymus-derived T cells. AB - A series of recent studies have revealed that extrathymic pathways of T cell differentiation exist at multiple sites in mice and humans. In terms of their properties, extrathymic T cells may stand at an intermediate position between natural killer (NK) cells and thymus-derived T cells in phylogenetic development. It is speculated that primitive lymphocytes such as NK cells and extrathymic T cells develop from primordial macrophages in intraepithelial regions of e.g., the intestine, skin and liver. In this regard, the immune system of the bone marrow and thymus is relatively recent, developing after the emergence of living beings onto the land (i.e., amphibia). A complete elimination of self-reactive T cell clones occurs in mainstream intrathymic T cell differentiation and a consistent generation of such clones occurs through the extrathymic pathways. Therefore, thymus-derived T cells are efficient for processing foreign antigens, whereas extrathymic T cells recognize abnormal self-cells. Although thymus-derived T cells play the major role in youth, extrathymic T cells may play rather a pivotal role with aging and under conditions of malignancy, intracellular infections, pregnancy, and autoimmune diseases. PMID- 8696008 TI - Human intestinal V delta 1+ T cells obtained from patients with colon cancer respond exclusively to SEB but not to SEA. AB - The function and activation requirements for gamma delta T cells residing in the human intestine are still poorly defined. We have established two gamma delta + T cell tumor-infiltrating lymphocyte (TIL) lines derived from a primary colorectal cancer (gamma delta TIL No. 3481), and from a colorectal cancer lesion metastatic to the liver (gamma delta TIL No. 7279). Both gamma delta TIL lines used exclusively the V delta 1 segment and predominantly the V gamma 2 segments of the T cell receptor (TCR) variable regions and lysed allogeneic colorectal cancer cell lines, e.g. HCT 116, but not natural killer/lymphokine-activated-killer sensitive target cell lines, e.g. K562 or Daudi. gamma delta T cell effector functions were evaluated on the basis of their recognition and cytolysis of colorectal cancer cell lines, T cell proliferation, and interferon (IFN)-gamma release. Both gamma delta T cell lines exhibited similar responses to the staphylococcal superantigens (SE) A and B. SEA and SEB did not influence target cell cytolysis of colon cancer targets. Neither gamma delta + T cell line responded to SEA as measured by IFN-gamma release of T cell proliferation. In marked contrast, SEB induced T cell proliferation and IFN-gamma release in the absence of stimulator cells. SEB induced secretion of IFN-gamma by gamma delta T cells which could be augmented if stimulator cells (HCT116) were also added to gamma delta T cells. On the basis of these data, we suggest that intestine derived V delta 1/V gamma 2+ T cells respond preferentially to SEB and not to SEA. This disparity may reflect the inherently higher affinity of individual gamma delta TCR subsets for SEB but not to SEA and/or indicate that a subset of gamma delta + TILs in patients with colon cancer may be preferentially expanded with a TCR rearrangement favoring the interaction with SEB. The induction of IFN gamma release and proliferative gamma delta + T cell responses by SEB suggests a pivotal role for intestinal gamma delta T cells in mediating immune responses against bacteria and bacterial products, or potentially in anti-tumor-directed immunity. Such immune responses mediated by gamma delta + T cells may take place prior to the maturation of antigen-specific MHC-restricted alpha beta + T cell responses. PMID- 8696009 TI - Inhibition by dexamethasone of human neutrophil apoptosis in vitro. AB - We investigated in this study the effect of a synthetic glucocorticoid hormone, dexamethasone (Dex), on apoptosis of human peripheral blood neutrophils. Dex inhibited spontaneous and tumor necrosis factor-alpha (TNF-alpha)-induced neutrophil apoptosis in a concentration- and time-dependent manner. This effect of Dex on neutrophil apoptosis was completely reversed by a glucocorticoid receptor antagonist, RU38486, and by cycloheximide. The decrease in sensitivity to TNF-alpha-induced apoptosis cannot be ascribed to a down-modulation of TNF receptors on these cells. These observations suggest that a glucocorticoid hormone participates in the regulation of neutrophil apoptosis and that inhibition of human neutrophil apoptosis by Dex is mediated through glucocorticoid-receptor-induced de novo synthesis of macromolecules. Possible mechanisms and implications of this phenomenon are discussed. PMID- 8696010 TI - Strong cytolytic activity of natural killer cells is neither necessary nor sufficient for preimmune resistance to Toxoplasma gondii infection. AB - That strong cytolytic activity of natural killer (NK) cells is neither necessary nor sufficient for defense against acute Toxoplasma gondii infection is demonstrated. T. gondii-infected anti-interferon (IFN)-gamma-treated mice and IFN gamma gene knockout mice died despite good induction of NK activity, while infected beige mice, deficient in NK cytolytic activity, survived. PMID- 8696011 TI - Increased natural killer cell activity in uterine cervix cancer patients undergoing radiation therapy. AB - Natural killer (NK) cell activity in peripheral blood mononuclear cells (PBMCs) from women with carcinoma of the uterine cervix was studied using a 4-hour 51Cr release assay and K562 cells as the sensitive target. PBMCs were obtained from 21 previously untreated patients at different stages of disease according to the International Federation of Gynecology and Obstetrics classification. PBMCs were also obtained from 36 patients treated with radiation therapy at different disease stages. Seventeen healthy age-matched volunteer women were used as controls. Mean cytotoxicity for the normal donors was 25.1 +/- 6.56% at a 100:1 effector-target cell ratio, 33.8 +/- 7.96% for the previously untreated cancer patients and 52 +/- 18.4% for the treated cancer patients. Most of the treated patients (86%) showed a complete response to radiation therapy and the mean cytotoxicity of the whole group (36 treated patients) was significantly increased compared to controls (p < 0.05). It is suggested that radiation therapy may produce cell alterations leading to an increase in NK cell activity in patients treated for uterine cervical cancer. The significance of this increase is discussed. PMID- 8696012 TI - Injury flow sheets: tools for school nurse documentation. AB - School nurses see students with injuries in the midst of large numbers of student encounters. Because of distractions, they are at risk of missing critical aspects of assessment, intervention, and documentation. Flow sheets can be used as a time efficient, thorough system for dealing with injuries in the school. PMID- 8696013 TI - Unsafe practices in the treatment of pediculosis capitis. AB - The purpose of this descriptive study was to identify unsafe uses of prescription, over-the-counter and home remedies used in the treatment of pediculosis. Twenty-seven families with 119 children were visited at home and interviewed about their use of remedies for head lice. In addition to prescription and over-the-counter products home remedies were commonly used. Kerosene, alcohol, insecticides, and head shaving were some of the home remedies reported. PMID- 8696014 TI - School-based aftercare for adolescents recovering from substance abuse: a secondary school needs assessment. AB - Adolescent substance abuse is a critical problem facing an increasing number of families. Abuse and subsequent treatment and recovery often have negative effects on students' educational experience. The purpose of this study was to assess the need for school-based aftercare for recovering adolescents in a secondary school setting. A purposive sample of 37 secondary students responded to a Likert-type survey as well as two open-ended questions. The data indicated generally negative attitudes of where the students perceived themselves to be in their recovery process, but also revealed the respondents' desire for aftercare support at school. PMID- 8696015 TI - Talking with elementary school-age children about AIDS and death: principles and guidelines for school nurses. AB - Teaching school children about sensitive or controversial issues presents difficulties for classroom teachers as well as school nurses. At each developmental stage, there is appropriate information that can be absorbed by children that will help them in dealing with such things as death and AIDS. However, many children will have been involved at home with these events before they have come to understand them. Nurses and teachers have the task of imparting to young students what they know, while being sensitive to the probing and questioning that must precede a child's comprehension of unfortunate facts that still trouble adults. PMID- 8696017 TI - Learning for life. PMID- 8696016 TI - Methylphenidate. PMID- 8696018 TI - Paediatric admissions to general adult intensive care units: BACCN survey report. PMID- 8696020 TI - Critical care nurses' perception of a bereavement follow-up service. AB - Over the last decade, care of patients' relatives has increasingly been seen to be of growing importance in the holistic approach to nursing care. Care of recently bereaved people has been encompassed within this and is now being seen as part of the nurses' role. Although there has been little empirical research, there is an increasing school of thought with the belief that much improvement can be achieved in the care of bereaved people in acute settings. The aim of this report is to give an insight into benefits and failings of a bereavement follow up service within a critical care setting, as perceived by nurses. PMID- 8696019 TI - The efficacy of eye care for ventilated patients: outline of an experimental comparative research pilot study. AB - The aim in this study was to investigate the efficacy of eye care given to mechanically ventilated and unconscious patients in an intensive care unit; and to answer the research question: "Is eye surface integrity maintained after the application of a "Geliperm" dressing to the closed eye of a ventilated patient?' Six patients formed the sample group. In each patient one eye received standard eye care, forming the control group, and the other eye received a 'geliperm' dressing, forming the treatment group. Tear production, using the Schirmer test, and the degree of eye surface staining by rose bengal were used as the measurement indicators. As a pilot study this project was primarily concerned with establishing a sound methodology for further enquiry. There were some difficulties in validating the degree of rose bengal staining; no statistically significant difference could be demonstrated between outcomes of the two forms of eye care after a 24-hour test period, with a P = 0.05 significance level, using the Mann-Whitney-U test. It should be noted, however, that the sample size was too small to measure a statistically significant change or its absence, in either the treatment or control eye between pre- and post-test results, with the same significance level, and using the Wilcoxon signed rank test. This study does provide evidence to support the need for eye care for critically ill patients. The methodology may offer a way forward for future investigation in the search for optimal eye surface preservation. PMID- 8696021 TI - Humidification in the upper respiratory tract: a physiological overview. AB - Over the last 30 years, there has been a wealth of literature investigating the principles of humidification in the upper respiratory tract. Most of the nursing literature provides subjective information, whilst the medical profession presents concrete objective data based on sound clinical research. A great deal of information does not date; the physiological principles of humidification remain unchanged. As a clinical nurse adviser with previous experience of humidification trials (Jackson & Webb 1992), I was invited by the Trust Clinical Practice Group, which is responsible for practice development issues, to design humidification guidelines for use in the Trust. Such work is necessarily based on sound knowledge of normal physiology and hazards of artificial humidification. This article contains an outline of the concept of humidity, examination of the normal mechanism of humidification, and details of consequences of over- and under-humidification. Finally, the concept of optimal humidification is discussed, and the main mechanisms of viral and bacterial contamination of the upper airways are briefly detailed. PMID- 8696022 TI - Knowledge of resuscitation. AB - This paper describes an exploration of nurses' levels of knowledge over 6 months following a resuscitation workshop. Two concurrent but separate studies were run in the acute specialties of cardiac services and intensive care. The tools used were three identical questionnaires distributed at 3-monthly intervals, using the United Kingdom and European Resuscitation Council's guidelines (BLS Working Part of the ERC 1992) as the standard. The results of the questionnaire were supported by a semi-structured interview and workshop evaluation. The results show that initially knowledge levels were poor but that an increase in knowledge was observed over the 6 months. The results prompt recommendations in the form of education, clinical practice and further research. PMID- 8696023 TI - Persistent vegetative state: what decides the cut-off point? AB - Advances in medicine and technology have allowed us early and effective diagnosis and treatment of many disease processes, with new and developing interventions ensuring this progression. However, in some illnesses and conditions, despite appropriate treatment, deterioration in the person's condition ensues. This may occur following a cardiopulmonary arrest, where resuscitation may have been 'successful' at the time, but the brain has suffered irreversible anoxic damage. It has been seen that only 10-25% of patients survive to discharge following a cardiac arrest (Broadway 1993), and the consequences of cardiopulmonary resuscitation can not only be costly but can leave the patient in a persistent vegetative state (PVS). PVS, however, does not confine itself to these patients alone, and can present following other cerebral traumas, including head injuries. This is therefore especially pertinent to intensive care nurses, who may find themselves caring for such patients in a critical care setting. Growing public awareness of this altered health state due, for instance, to the Tony Bland case in the UK in 1993, has highlighted a need for greater knowledge of the consequences of the condition and the proposed management of patients in PVS. This paper attempts to describe the course of this syndrome, and considers some of the ethical and moral issues surrounding the care and treatment of patients with PVS. The issues surrounding euthanasia are briefly explored together with the attitudes of those caring for these patients. PMID- 8696024 TI - A study of clinical nursing research priorities of renal specialist nurses caring for critically ill people. AB - The aim of this pilot research project was to identify priority areas for clinical nursing research for renal specialist nurses practising in general critical care. Research participants in the study included Clinical Nurse Specialists (CNSs) and Clinical Nurse Consultants (CNCs), n = 12. The study sample was national with representation from a number of major metropolitan teaching hospitals in Australia. The Delphi technique was used to obtain the most reliable consensus of the specialist nurses. Research priorities emerged in four areas: 1) clinical research which is of highest value to patients; 2) clinical research which is of highest value to CNSs/CNCs; 3) clinical research which would provide improved community care and 4) research that would be of value for CNSs/CNCs professional needs. In the final phase of the study nine high priorities were identified. The findings of the study suggest directions for clinical nursing research which would benefit renal specialist nurses and their patients. PMID- 8696025 TI - Temperature measurement: why and how in intensive care. AB - In this paper the importance of temperature regulation for nurses is discussed with review of the methods most frequently used for recording core temperature in intensive care. Use of a tympanic thermometer is considered as an alternative method and is viewed favourably. PMID- 8696026 TI - Septic shock: a case study. AB - Septic shock is a pathological process that is common to most intensive care units; however, despite major developments in intensive care and medicine, it continues to be one of the commonest causes of morbidity and mortality. This article describes the management of a patient admitted to intensive care with septic shock. Some of the principles regarding septic shock, including the pathophysiology, management and nursing care, are explored. Also included are some of the current theories and research into the sepsis syndrome. PMID- 8696027 TI - Clarithromycin (klaricid, Abbott). AB - During the 1990s newer antibiotics of the erythromycin group have been introduced. One of these, clarithromycin, may offer advantages over erythromycin in the treatment of difficult respiratory tract infections. PMID- 8696028 TI - Nursing as healing work. AB - This paper describes the therapeutic potential of nursing practice as healing work, by addressing the growing trend in nursing to consider how the work of nursing and the nurse-client relationship are potentially of a healing nature. The work of nursing, presencing, concern and authenticity are discussed, before a redefinition of healing is offered. To exemplify nursing as healing work, some stories are shared from nurses working in different work settings. These stories are of human interest, especially in terms of their healing outcomes. PMID- 8696029 TI - Nursing diagnosis: language antithetical to nursing's ontology. AB - The term nursing diagnosis is constructed in male, medical language. As such, it is proposed that it has no legitimacy in nursing discourse as it is antithetical to notions claimed foremost in nursing's ontology. It is also posited that the term 'nursing diagnosis', whilst reinforcing biomedicine, has little or no meaning to many nurses, is not understood by patients and has no justifiable place in health care discourse. PMID- 8696030 TI - Health assessment: a study of registered nurses' knowledge and skill level. AB - In Australia, there is a paucity of published studies which investigate the role of health assessment in nursing practice. The purpose of the following study was to establish whether registered nurses perceived health assessment to be a central component of their nursing practice. A pre- and post-test design was used to evaluate if any changes were evident in perceived nursing knowledge and skill level following an educational program. The target population was all registered nurses enrolled in a health assessment subject offered in a post-registration Bachelor of Nursing course. A paired, two-tailed t-test showed statistically significant changes in the registered nurses' attitudes towards health assessment. In addition, statistically significant changes were demonstrated in the group's perceived comfortableness with health assessment knowledge and skill level. The results of this project have been used to guide and shape nursing curricula in the area of teaching health assessment. PMID- 8696031 TI - Significant relationships: nurses caring for adolescents with cystic fibrosis. AB - Nurses in this study manage the challenges of meeting the unique needs of adolescents with cystic fibrosis (CF) by fostering 'significant relationships' with them. These relationships are characterised by friendship, reciprocity, choice, involvement and 'being there'; while shared histories, dealing with a protracted illness trajectory, and nursing within a chronic/terminal dichotomy emerge as the contextual aspects. The relationships are perceived as beneficial and mutually rewarding. However, such implications as the line between professional and personal involvement, the adolescents' vulnerability and the resources and support needs of nurses must be considered. PMID- 8696032 TI - Caring in a multicultural society. PMID- 8696033 TI - Reflection on care. PMID- 8696034 TI - Nine steps to better nursing management of incontinence. AB - This paper describes the development of a new framework for nursing assessment and management of incontinence using action research (Gibb, O'Brien, Bradford and Curtis 1993). The authors worked with nurses and residents in a large extended care setting--clarifying their current understandings of continence issues and looking at ways of improving incontinence management. This process led to the development of a model for assessment and management of incontinence. PMID- 8696035 TI - The politics of pap smears. PMID- 8696036 TI - A failing health care system. PMID- 8696037 TI - Research, language, politics, complacency and AIDS. PMID- 8696038 TI - Physical assessment skills--use them. PMID- 8696039 TI - The scandalous neglect of mental health care ethics. PMID- 8696040 TI - The case for critical research. PMID- 8696041 TI - Continuity of care: discharge planning and community nurses. AB - Continuity of patient care between hospital and community is becoming increasingly important with a trend to shorter hospital stays and more care in the community. This paper describes how community nurses determine patient care provision after hospital discharge. The research presented is a component of a larger study exploring the interface of hospital and community nursing services. Semi-focused interviews were conducted with twelve community nurses to elicit their perceptions and experiences of discharge planning. The findings revealed that although discharge planning influenced continuity of care, community nurses make autonomous decisions about the provision of care to patients in the community setting. PMID- 8696042 TI - Nursing, narrativity and research: toward a poetics and politics of orality. AB - 'Telling' our lives as they happen to us is an extremely pervasive activity in our social world. Through the stories which suture together the multiple ways we can make sense of a life as a nurse, is woven the fabric of a culture. Clinical nursing culture is, as yet, poorly understood and little theorised. By appropriating narrative as a research technology I suggest that we might be better placed to first articulate, and then critique, the complexity and diversity of clinical practice through a postmodern poetics and politics of orality. PMID- 8696043 TI - 'You're more your own boss': nurses' experiences of agency work. AB - Agency nurses and their work has received little attention in research in Australia. The study seeks to expand on the current literature from the United Kingdom and the United States that is predominantly personal accounts of individual nurses' experiences of agency work. The descriptive study explores four registered nurses' experiences of working through a nursing agency. Findings identified that agency work met the needs of the four women at that particular time in their lives. The concept of control over work scheduling, as described in much of the literature, was experienced by all four women. However, they indicated a lack of professional autonomy and isolation in their practice. Issues such as accessing continuing education and maintaining skills were identified as problems associated with agency work. PMID- 8696044 TI - Assisted reproductive technology: a dilemma for the nursing profession. AB - Assisted Reproductive Technology, despite poor outcomes in the treatment of infertility, is poised to take on a new supplementary role to genetic engineering. As an extreme example of medical/reductionist philosophy it is diametrically opposed to the emerging commitment to holism within the nursing profession. Nurses in Australia have been noticeably absent from the debate, research and decision making that has occurred about this technology, yet the implications for professional practice are far-reaching. PMID- 8696045 TI - Changing attitudes. PMID- 8696046 TI - Feminist research: strengths and challenges. AB - In the process of carrying out feminist research some method and methodological issues have surfaced. These issues are discussed within the context of work in progress exploring the embodied experience of large body size for nine New Zealand women who are medically deemed to be obese. The applicability of feminist research in this and other settings is argued and the specific issues considered. These included aspects of objectivity in feminist research and insertion of myself into the research process and presentation of findings. Mutuality, thematic analysis and the beneficial effects of the research are also discussed. PMID- 8696047 TI - Do RNs preceptor new medical graduates? PMID- 8696048 TI - Care for the carers. PMID- 8696049 TI - Authorship. A matter of concern. PMID- 8696050 TI - Network between main protagonists and events leading to AIDS. AB - A definitive single hypothesis about HIV pathogenesis is still lacking in specialized literature. Rather, a picture of the extreme complexity in AIDS causality ensues from the extensive information available. This article contains an outline of the most relevant data on the subject of AIDS pathogenesis, organized into genetic, molecular, cellular, immunological and physiological levels. This scheme shows how events triggered by HIV, together with virus and host factors, compose a network whose interacting components define the heterogeneity of disease manifestations and which redefine the necessity of considering multiple approaches to therapy and vaccine design. PMID- 8696051 TI - Bacterial translocation and wasting in stressed mice. AB - The effects of stress on immunity and on the bacterial translocation from intestine to mesenteric lymph nodes, liver, and spleen were studied in a group of newborn CD1 mice. Animals were separated into three experimental groups. Mice from group I were stressed by intraperitoneal (i.p.) injections of heat-killed staphylococci for 4 weeks. Mice from group II were i.p. injected with saline solution only. The remaining mice, group III, were not injected. The clinical condition, presence of bacteria in abdominal organs, mitochondrial activity in splenic cells, lymphocyte proliferative response to Concanavalin-A and in vitro antibody production were evaluated in each mouse. Results showed that prolonged i.p. stressor challenge causes severe weight loss and immunodeficiency. The splenic lymphocytes from stressed mice exhibited a significant depression of both proliferative response to Concanavalin-A stimulation and anti-erythrocytes antibody synthesis. Instead, cultured in basal conditions, the splenic cells from stressed mice have an increased capacity to reduce the tetrazolium salts. Bacterial dissemination from intestine to mesenteric lymphoid nodes was also confirmed in the same group of mice. In contrast, mice in groups II and III presented no weight loss and no immunodeficiency. Results suggest that chronic biological stress induced in newborn mice could facilitate the translocation of Gram-negative bacteria. Probable pathogenic mechanisms are commented upon and a correlation is proposed between the bacterial dissemination and the wasting development. PMID- 8696052 TI - Cell to stroma contacts in the tunica media of the hypertensive rat thoracic aorta. AB - The variation in mechanical stress to which the aortic wall is subjected requires that forces be transmitted between its components by means of relatively strong but compliant attachments. We have used transmission electron microscopy in order to study the cell to stroma contacts (smooth muscle cell-elastic fiber contact) in the tunica media of normotensive and hypertensive aortas of Sprague-Dawley rats. Hypertension was produced with a silver clip positioned around the left renal artery and the vessels were fixed by intravital perfusion at normal and elevated pressure. In ultrathin sections, the density of cell to stroma contacts per 100 microns cell perimeter and per 100 cell profiles were determined using an image analysis computer. In the hypertensive group the density of cell to stroma contacts fell considerably when compared with the control group. This research provides insights into the conditions under which high blood pressure may produce medial injuries and, perhaps, be a factor in the precipitation of dissections. PMID- 8696053 TI - Electrochemical fixation techniques. II. Electrochemical dog body fixation. Histological study. AB - This is the first attempt to harden all organs of a body together without excising them. This process was accomplished in bottom-belted, gastrointestinal (GI) or intravenously (i.v.) catheterized dog cadavers so as to influx an electrolytic solution containing formaldehyde (ESF). The i.v. influx of ESF was found to be the best perfusion pathway. After 48 h of immersion in ESF, 24 h current time of 17.5 A of current intensity, 24 degrees to 56 degrees C, we ended up with thoroughly fixed dog cadavers that were wrapped with ethyl alcohol:glycerol gauzes and stored in plastic bags at room temperature. Optical microscopy of every sliced tissue showed normal blood vessels, neurons, glial and Purkinje cells and their nuclei of brain and cerebellum, respectively. Cardiac muscle fibers were of normal appearance. Kidney Bowman's capsule and space were found to be normal except for vacuolarly degenerated tubules. Small intestine showed normal epithelial cells and crypts of Lieberkuhn. In liver, sinusoids were normally arrayed but showed vacuolar cell degeneration. Herein a method to attain an electrochemical whole body fixation is described. PMID- 8696054 TI - Experimental infection by Haemophilus influenzae type b in inbred mice. AB - The epidemiological situation of bacterial meningitis is increasing dramatically. There is no doubt that the lack of proper animal models has hampered the achievement of effective prophylactic and therapeutic means. We report the characterization of the experimental disease caused by Haemophilus influenzae type b (Hib) in mice, taking into account its importance as an etiological agent of such a type of meningitis. The high resistance of C57BL/6, CBA/ J and BALB/cJ mice to Hib infection was proven. LD50 of Hib using trypsin or iron dextran as virulence enhancement factors (VEF), both being similar and more than 1000 times lower than that without any VEF, were determined. Lesions of CNS compatible with meningitis were found in about one third of specimens. Hair bristling, conjunctivitis, diarrhea, depression and prostration were the most characteristic symptoms. The proportion of animals which die is highest on the first day, lower on the second and almost zero after 48 h of infection. Water and food intake was higher in control than in infected animals; nevertheless, there were no differences in body weight increase among the mice after 5 days post-infection. Microorganisms were isolated from CSF and blood after 6 h of infection and positive results remained according to the size of the inoculum. Despite the acuteness of the experimental disease, antibiotic treatment with internationally recommended drugs was shown to be effective. Similar results were achieved when hyperimmune serum vs. Hib was applied. PMID- 8696055 TI - Pharmacological analysis of acute morphine dependence in infant rats: close molecular relationship of head-shaking precipitated by opiate antagonists and cholinergic neurotransmission. AB - The influence of drugs affecting different neurotransmitter systems on an acute abstinence head-shaking (AHS) model induced by nalorphine or naloxone was studied in 9-day-old rat pups pretreated (3 h before) with morphine (10 mg/kg, i.p.). One hour after the injection of nalorphine (10 mg/ kg, i.p.) AHS was stopped by a second dose of morphine (10 mg/kg, i.p.) and reinitiated 1 h later by a higher dose of nalorphine (20 mg/kg, i.p.). In other groups AHS was blocked by spiroperidol (0.1 mg/kg, i.p.), clonidine (0.01 mg/kg, i.p.) or scopolamine (50 mg/kg, i.p.). In these groups a second injection of nalorphine did not reinitiate AHS. In dose-effect curve experiments the AHS induced by naloxone or nalorphine was significantly reduced by previous injections of scopolamine, spiroperidol, metergoline or phentolamine in the corresponding groups. Scopolamine was the only antagonist which displaced the AHS dose-effect curves to the right without affecting the maximal response. Since no common receptors exist for a direct competitive interaction between opiate antagonists and scopolamine, these experiments suggest that a direct molecular relationship exists between the tissue concentration of nalorphine (or naloxone) and the endogenous ACh release during abstinence. Thus, the AHS model in 9-day-old rats clearly differentiates specific from non-specific blockade of the abstinence syndrome, and confirms a distinct or primary role of cholinergic neurotransmission in morphine abstinence. PMID- 8696056 TI - Possible effect of air pollutants (Mexico City) on superoxide dismutase activity and serum lipoperoxides in the human adult. AB - The action of air pollutants, through their constituents, (O3, NO2, tobacco smoke) are capable of causing damage due to their lipoperoxidative properties or, indirectly, by inducing production of free radicals. As a consequence of photochemical processes, the ozone levels in the atmosphere of Mexico City are generally higher (mean of 0.325 ppm; period between 1987-1992) and may be harmful to health. Sixty two volunteers (medical doctors), aged 27-32 years, were divided into three groups. Group A was composed of those persons (17) who had never lived in Mexico City; a second group (B) (21) had recently arrived in Mexico City (1-8 days); and a third group (C) (24) who had permanently resided in Mexico City. Serum was obtained from fresh whole blood. Superoxide dismutase (SOD) activity and thiobarbituric acid-reactive materials were higher in group B while chromolipids and the serum inhibitory capacity (for lipoperoxidation) was higher in group C. The acute exposure to pollutants in group B apparently may have induced SOD as an antioxidant defense and was responsible for the increased level of TBA reactive material. In group C, the significant finding is better antioxidative defenses and slightly higher chromolipids. PMID- 8696057 TI - Carrier detection in Duchenne and Becker muscular dystrophy using dinucleotide repeat polymorphisms. A study in Mexican families. AB - In order to improve carrier detection of Duchenne and Becker muscular dystrophy, dinucleotide sequences repeats (CA) of introns 44, 45, 49 and 50 were used as well as two markers located at the 5' and 3' ends of the dystrophin gene. Haplotypes of the unaffected and affected persons of ten DMD/ BMD Mexican families were determined. Fifty eight females were studied, 30 of whom were at risk STR haplotypes. Furthermore, it was possible to identify a recombination event in the dystrophin gene in one family, and a gonadal mosaicism was found in another family. PMID- 8696058 TI - Circadian variation of human acute phase response. AB - Circadian variation of temperature, both normal and febrile, is a well known fact. Mediators of fever are also regulators of acute phase response and are associated with stimulation of pituitary hormone production related with defervescence and with a circadian pattern of secretion. Acute phase response may consequently have circadian variations in its components. Measurements of temperature, erythrocyte sedimentation rate, complete blood cell count, serum cortisol and fibrinogen were made at 7:00, 15:00, and 23:00 h during two consecutive days in 35 patients with fever and acute infection, 15 patients with clinically active ankylosing spondylitis without fever and 10 healthy volunteers. Temperature curves showed statistically significant circadian rhythms, with higher values at night and lower ones during early morning. Erythrocyte sedimentation rate, leukocyte count and fibrinogen also showed statistically significant circadian rhythms, but with higher values at 15:00 h. Serum cortisol also showed statistically significant circadian rhythmicity but with a higher rhythm adjusted mean (MESOR), and a 100 degrees (6 h) phase shift in patients with fever, as compared to patients with ankylosing spondylitis and healthy controls. In conclusion, components of acute phase response, including fever, have circadian rhythmicity, but asynchronically. Differences between fever and ankylosing spondylitis can be due to the intensity of acute phase response stimulation. PMID- 8696059 TI - Clinical stage, age and treatment in tropical pyomyositis: a retrospective study including forty cases. AB - A comparative and retrospective trial of 40 patients with tropical pyomyositis covering studies done between January 1, 1987 and November 31, 1990, at the General Hospital at Cosamaloapan, Veracruz, IMSS, was undertaken. The objectives were to compare predisposing factors, clinical data, morbidity, mortaity and hospital stay among 1) medical (group I) and surgical treatment (II), 2) adult and pediatric populations and 3) the clinical stage of the disease (invasive, suppurative and late). In group I, the family history of diabetes (56%), fever (66%) and hospital stay (6.5 +/- 1.8 days) were significantly different from group II (19%, 100% and 12.8 +/- 5.5 days), respectively. The mean age in adult and pediatric populations was 38 and 8 years, respectively. Pediatric patients had lowest hemoglobin levels (9.7 +/- 1.3). Upper respiratory antecedent was highest in suppurative stage (65%). In the late stage eosinophilia (5.9 +/- 6.9), fluctuance muscles (100%), complication rate of 57%, surgical drainage (100%) and mortality of 29% were found. Cultures were performed in 20 cases with negative results in 55% and the remaining 45% were positive to Staphylococcus aureus. Pyomyositis appears to be multifactorial in origin, the antecedents of trauma and upper respiratory infection were the major predisposing factors. Septicemia caused high morbidity and mortality in the late stage. Surgical treatment was frequently needed, increasing costs. PMID- 8696060 TI - Correlation between dobutamine stress transesophageal echocardiography, thallium 201-dipyridamole scintigraphy and coronary angiography in the early detection of myocardial ischemia. AB - In order to establish the sensitivity and specificity of transesophageal stress echocardiography with dobutamine (TEE-dobutamine) in the early detection of myocardial ischemia we studied 30 consecutive patients from the Coronary Care Unit (CCU) of the Hospital de Cardiologia, Centro Medico Nacional Siglo XXI. The results were correlated with thallium-201-dipyridamole scintigraphy (TDS), and coronary angiography. Two groups were formed: Group I-20 patients, 18 females/2 males, aged 37-73 years (mean 55 years) within the first week of myocardial infarction and/or unstable angina; Group II-10 patients, five males/five females, aged 35-65 years (mean 48 years) with atypical chest pain but with high suspicion of CHD. All group I patients, and none of group II, had significant stenoses on coronary angiography. Twenty patients had a positive TDS (18 patients from group I and two from group II). Twenty one patients had a positive test with TEE dobutamine, 20 from group I and one from group II, which yields a sensitivity of 100%, a specificity of 90%, positive predictive value of 95% and negative predictive value of 100%. PMID- 8696061 TI - Diabetic ketoacidosis in adults: clinical and laboratory features. AB - In this retrospective study, we report the clinical and biochemical features of diabetic ketoacidosis (DKA) in adult patients who were managed at the Instituto Nacional de la Nutricion during a 6.5 year period. There were 98 episodes in 46 patients: 22 females (48%) and 24 males (52%). Six patients (13%) had four or more episodes of DKA. Thirty five percent of the events occurred in patients with IDDM; 48% in "late onset" NIDDM: 9% in "early onset" and 9% in classical NIDDM. Infections as the precipitating factor in 41% of episodes of DKA were the initial manifestation of diabetes. We compared our results with those from other reported series, finding no differences among them. The mean anion gap in our series was 30.4. Main complications identified were hypokalemia in five cases, hypoglycemia in four cases, hypernatremia in four cases, and acute pulmonary edema, ventricular fibrillation, neurological deficit and coma in one case each. There were three deaths (6.5%) in the whole group. To our knowledge, this is the largest series on adult patients with DKA reported in our country in the last decade. The obtained results may help evaluate prospectively the impact of different diagnostic and therapeutic strategies in the management of DKA. PMID- 8696062 TI - Kinetic effects of trimethoprim-sulfamethoxazole in children with biliary atresia: a new dosing regimen. AB - Pharmacokinetics for combination trimethoprim/ sulfamethoxazole (TMP/SMX) was studied in only four patients with biliary atresia (BA): three girls, 6.2,8.0 and 8.2 years of age and one boy 8.4 years of age, as this is an uncommon obstructive anomaly of the extrahepatic biliary system and has been described as having a poor prognosis. These four patients are the survivors of 27 initial children who were operated on previously. They have been receiving 2.3 +/- 0.5 mg/kg TMP, and 11.5 +/- 2.6 mg/kg SMX every 12 h since 2 weeks after surgical treatment for biliary atresia performed at 2-2.5 months of age. The patients have suffered some episodes of cholangitis during their short lives, most of them after interrupting temporally the chemotherapy. Nevertheless, they have achieved a favorable quality of life. TMP/SMX disposition was well characterized by a one compartment open pharmacokinetic model. Wide interpatient variability was observed for all pharmacokinetic parameters with coefficients of variation for t1/2 el, ClT, and Vd of 33.2, 49.6, and 26.3%, respectively, for SMX and 108.9, 52.1, and 71.0%, respectively, for TMP. A marked difference in the pharmacokinetics of TMP and SMX was observed, for example; (ClT: mean +/- SD; 90.3 +/- 47.0 ml/kg/g for TMP and 13.7 +/- 6.8 ml/kg/h for SMX), (t1/2 el with 7.93 +/- 8.64 h for TMP and 10.51 +/ 3.49 h for SMX). In order to develop dosage schedules that would reliably achieve peak serum concentrations of TMP/SMX in the therapeutic range, we found that established dose leads to high fluctuations at steady state between C(max), ss and C(min), ss, without maintaining therapeutic levels. Recommended maintenance dose varied from 8 to 30 mg/kg for SMX with a mean of 21.9 +/- 10.89 mg/kg/12 h, and from 0.8 to 4.5 mg/kg/12 h with a mean of 3.2 +/- 1.7 mg/kg/12 h. The present study illustrates the need for pharmacokinetic studies for the individualization of drug dosing in patients with BA. PMID- 8696063 TI - Methods of nutritional assessment for determining nutritional care at the pre school level. AB - Prevalence of malnutrition in pre-school children may be used to determine the need for nutrition surveillance or nutritional care. That prevalence depends on the nutritional classification used. The authors consider that one of the most recommended classifications used for identifying Protein Energy Malnutrition (PEM) was developed by Waterlow. The criteria includes weight-for-height and height-for-age. Frisancho suggested that Arm Muscle Area (AMA), related to height, could provide useful measurements for assessing mass reserve, thus, in beginning stages of PEM it is worth while to determine those who could benefit from nutritional services. The aim of this study was to determine the percentages of pre-school children considered well nourished by Waterlow indicators, but wasted or below average using the AMA for height criteria. Children (881) of either sex, from 48 to 79 months of age, were studied from the Tijuana, Baja California, Mexico pre-school system. Standard anthropometric measurements were taken including weight, height, upper-arm circumference, and triceps skinfold. Arm muscle area was created from those measurements. Using Waterlow indicators, results showed deficit of height-for-age alone was seen in 25.6%; deficit of weight-for-height alone was observed in 1%; deficit of AMC-for-height, but well nourished by Waterlow indicators was seen in 14.9%. If one speculates that children with deficits of AMC-for-height could have different risks of acquiring a disease compared to those apparently normal, then 14.9% of the studied sample would also need nutritional care. Thus, using these criteria, the need for nutritional surveillance and nutritional education is greater for PEM than that established exclusively using Waterlow criteria. PMID- 8696064 TI - Riboflavin and pyridoxine status in a group of pregnant Mexican women. AB - In order to assess the nutritional status of riboflavin and pyridoxine during pregnancy, 24 Mexican women were studied during the second trimester and 17 during the third trimester of gestation. The biochemical evaluation of the riboflavin and pyridoxine status was performed by measuring the activation coefficients (AC) of the erythrocyte glutathione reductase (eGR) and aspartate aminotransferase (eAAT), respectively. Dietary protein, riboflavin, thiamin, and calcium intake decreased significantly in the last trimester of gestation. The women presented biochemical deficiency of pyridoxine in the second and third trimester of pregnancy, but they developed biochemical deficiency of riboflavin and pyridoxine deficiency. None showed clinical signs of vitamin deficiency. No significant correlation was found between individual serum concentrations of estradiol or progesterone and eGR-AC or eAAT-AC in both trimesters of pregnancy. Six newborns studied showed normal eGR-AC and eAAT-AC. PMID- 8696065 TI - The spectrum of HIV infection in patients seen at a private hospital in Mexico City: 115 patients seen from 1984 to 1990. AB - The objective of this study was to describe the epidemiology and clinical presentation of HIV infection among upper middle class patients in Mexico City. A retrospective review of outpatient and hospital records of all HIV-infected patients was accomplished by one of the authors between 1984 and 1990. A total of 115 patients were seen during the study period, 109 men and 6 women. One hundred and seven patients acquired HIV infection through sexual contact, six patients had HIV infection associated with blood transfusion and two were homosexual men who also had a history of intravenous drug use. The mean age of the patients was 36.2 years (range 13 - 65 years). CDC classification at presentation was predominantly stage IV (65%) with the most common AIDS associated diseases at presentation being wasting syndrome in 30 (42.2%), P. carinii pneumonia in 22 (30.9%), cytomegalovirus infection in 11 (15.5%), Cryptosporidium parvum diarrhea in 7 (9.8%), and Kaposi's sarcoma in 6 (8.4%). CD4+ T-lymphocyte cell counts at the time of HIV diagnosis were available in 87 patients (median = 150 cells/microliters; mean = 224 cells/microliters, SD +/- 219). Zidovudine was used in 37 patients after 1988 when it first became available in Mexico, in six patients the drug had to be discontinued because of serious hematologic toxicity. The average follow-up on zidovudine was 8.5 months. Similar age, gender, age distribution, risk categories and CDC classification at presentation was seen compared to other series reported from Mexico. However, the spectrum of opportunistic infections found were similar to that seen in the United States. PMID- 8696066 TI - Concordance between retina specialists and a preferred practice pattern in treatment and follow-up criteria for diabetic retinopathy. The Mexico City Diabetes Study Retinopathy Group. AB - Proper detection, adequate laser therapy and follow-up of diabetic retinopathy (DR), using guidelines established by landmark studies, are important to prevent blindness. In this report we analyze the agreement between 11 retina specialists and the Preferred Practice Pattern of the American Academy of Ophthalmology in the therapeutic and follow-up criteria for DR. Color fundus stereophotographs of seven standard fields of each eye of 15 diabetics were sent to 11 retina specialists. Their treatment and follow-up criteria were surveyed. For treatment of DR mean percent agreement was 65%. Kappa statistic, which corrects for chance agreement, was between -0.23 and 0.63 with a mean of 0.26. The therapeutic recommendations for macular edema were analyzed separately and the mean kappa was between -0.10 and 0.71 with a mean of 0.32. With respect to recommendations for interval until follow up, following initial visit, mean percent agreement was 73% with a kappa statistic between -0.22 and 0.33 and a mean of 0.07. Based on conventional interpretation of kappa statistic these mean values are in the range of poor agreement. Since there is a significant discrepancy in the concordance level in both therapeutic and follow-up recommendations for the management of DR, there is a need to improve agreement in these criteria, since these are key elements in the decision making process of the specialist caring for diabetic patients. PMID- 8696067 TI - High blood pressure and cardiovascular risk factors in an adult population of Mexico City. Characteristics of the studied population. AB - The present report is a description of the characteristics of a studied population and of the methodology used in a study performed to investigate high blood pressure prevalence and cardiovascular risk factors among the adult population of Mexico City. A cross-sectional study was conducted from January 1991 to March 1992. Random samplings of multiple stages was used and 825 adult subjects were studied in Mexico City. The following measurements were registered: blood pressure, body mass index (BMI), waist-hip ratio (WHR), total cholesterol (TC), triglycerides (TG), high density lipoproteins (HDL-C) and low density lipoproteins (LDL-C), lipoprotein (a) (Lp(a)), glucose and insulin. Personal and family history of cardiovascular illness were investigated, as well as exposure to some risk factors such as smoking, alcohol consumption and sedentarism. The response rate was 86.6%. The prevalence of high blood pressure was 21.1%, and of non-insulin dependent diabetes mellitus was 8.7%. Frequency of dyslipidemia in the studied sample was 24.4% for high TG, 23.6% for low HDL-C, 23.6% for high LDL C, 14.9% for Lp(a) excess (Lp(a) > or = 30 mg/dl; overweight and obesity were more prevalent among women. The diversity of living conditions among the population of Mexico City was included in the sampling strategy design, not only to register the high blood pressure (HBP) frequency in each stratum but to identify other cardiovascular risk factors which could be decisive in the development of HBP. Regarding the features of the studied population, BMI did not reveal differences among men, but their TG levels were higher and HDL levels lower than those of other populations. In women, the results obtained for BMI, WHR, lipids and lipoproteins were also higher compared with the mean reported for other populations. PMID- 8696068 TI - Incidence trends of acute leukemia among the children of Mexico City: 1982-1991. AB - The objective of this study was to identify the tendency of acute leukemia among children in Mexico City from 1982 to 1991. A hospital survey was performed. Medical records of children under 15 years of age with a diagnosis of acute leukemia were reviewed. The cases were chosen from hospitals which provide medical attention to children with cancer in Mexico City. The annual incidence rate (AIR) was calculated in general, by sex, age groups (under 1 year of age, from 1 to 4 years, 5 to 9 years and 10 to 14 years) and standardized with the world population. The trend was evaluated with Spearman's correlation method. Acute lymphoblastic leukemia showed a significantly increasing trend during the study period. The AIR was 7.75 (per million) in 1982 and 22.19 (per million) in 1991. For age groups a tendency to increase was observed in females of age group 1 to 4 years and in males of age group 10 to 14 years. Acute non-lymphoblastic leukemia did not display a specific trend. In conclusion, acute lymphoblastic leukemia shows a tendency to increase in the children of Mexico City. PMID- 8696069 TI - Parasite search in strawberries from Irapuato, Guanajuato and Zamora, Michoacan (Mexico). AB - A seasonal research was carried out in Irapuato, Guanajuato and Zamora, Michoacan, Mexico, the location of the most important producers of strawberries, in order to assess fecal contamination through the finding of protozoan cysts and helminth eggs, specifically of Taenia sp eggs. Three techniques were used: direct observation, flotation and sedimentation. Low numbers of protozoan cysts and only one Ascaris egg were found. What is most interesting is that no Taenia eggs were identified. Results indicate that although strawberries are contaminated with human feces, contamination is minimal. PMID- 8696070 TI - Prevalence of antibodies to the repeat epitope of the circumsporozoite protein of Plasmodium vivax in San Luis Potosi, Mexico. AB - The prevalence of antibodies against the repeat epitope of the circumsporozoite protein (cs) of the standard (PV210) and variant (PVK247) strain of Plasmodium vivax was determined by ELISA in 1170 sera from individual residents of seven localities of the Region Huasteca of San Luis Potosi, Mexico. The capture antigens were the synthetic peptides DDAAD and (ANGAGNQPG) that correspond to the repeats of the PV210 and PVK247 cs proteins, respectively. Of the analyzed serum samples, 34.1% (400/1170) were positive with one or both of these antigens. Of the sera, 18.2% (214/1170) reacted with the DDAAD peptide and 6.6% (78/1170) were positive with the variant synthetic peptide. Additionally, 9.2% (108/1170) of the samples reacted with both peptides. A sample of 10% of positive sera for the variant cs repeat (18/78) was tested with the cs repeat peptide of P. malariae/P. brasilianum (NAAG); almost all of them (16/18, 89%) being positive. These results confirm that the transmission of the variant strain of P. vivax is a common phenomenon in endemic regions in Latin America, as well as in other tropical regions of the world. These findings may have implications for the development of aP. vivax vaccine since that based on the standard cs repeat only would not be universally protective. PMID- 8696071 TI - Prevalence of gallbladder disease and associated clinical variables in a low income population of Mexico City. AB - We present the results of a population-based survey carried out in a low income area of Mexico City. The aim of this study is to characterize the prevalence of clinically significant gallbladder disease (CSGD) using the self-reported history of cholecystectomy (CG) or cholelithiasis (CL) demonstrated by cholecystography and/or ultrasonography. The population of the studied area was 15,532 inhabitants, of whom 3505 (22.6%) were age eligible (35-64 year-old men and non pregnant women). Home interviews were obtained in 2810 (80.2%). A physical and laboratory examination was performed in 2282 individuals (65.1%; 941 men and 1341 women). The prevalence of CSGD in men was 2.0% (95% confidence intervals 1.1 2.9%) and 9.2% in women (95% confidence intervals 7.7-10.7%). Patients with CSGD were older, men (p < 0.003) and women (p < 0.001). Women with CSGD had higher waist to hip circumference ratio (p < 0.06), higher fasting glucose (p < 0.03) as well as 2 h post challenge glycemia (p < 0.04) and insulinemia (p < 0.03). In the multiple logistic regression model only age (p < 0.001) and sex (p < 0.001) remained significantly associated. We conclude that CSGD is quite prevalent in this population. It is associated with age in both genders and in women, higher glucose and insulin levels. The prospective follow-up of this cohort is important since it could generate the information needed to implement a preventive program to diminish the impact of this condition. PMID- 8696072 TI - Risk estimation of ABO and Rho(D) incompatibility in persons with mono- and polyphyletic surnames in Monterrey, Mexico. Comparison with other Mexican populations. AB - ABO and Rh(o)(D) blood groups were determined in 3813 males and females affiliated with the Instituto Mexicano del Seguro Social (IMSS) who are residents of the Monterrey Metropolitan Area (MMA) in northeastern Mexico. They were selected by their monophyletic or polyphyletic surnames. The ABO and Rh(o)(D) blood group phenotypes and gene frequencies were determined and based upon these, the risk of incompatibilities was estimated for both marriages (MI) and maternal fetal incompatibility (MFI). These were compared with those estimated for other populations of residents in the MMA, and in other locations in Mexico, as well as with the two most important ancestral populations, Spanish and Tlaxcaltecan Mexican Indians, with the hypothesis that the percent of risk of ABO and Rh(o)(D) MI and MFI are greater in the population with monophyletic surnames than those with polyphyletic surnames. It was found that for persons with monophyletic and polyphyletic surnames, as well as for the other populations in the MMA and other places in Mexico, their ABO and Rho(D) MI and MFI percent of risk are intermediate to the ones estimated for their ancestry. The percentages of MI and MFI are higher for the persons with monophyletic than for the ones with polyphyletic surnames, other populations from the MMA and those from other locations in Mexico. The risks are higher when the similarity with Spanish increases and are lower when their similarities with the Mexican Indians increase. PMID- 8696074 TI - The bioavailability of 26Al-labelled aluminium citrate and aluminium hydroxide in volunteers. AB - A study was undertaken to determine the fraction of ingested aluminium taken up by two male volunteers, following their ingestion of either aluminium citrate or aluminium hydroxide. In addition, the effects of simultaneous citrate ingestion on the gastrointestinal absorption of aluminium from its hydroxide was studied. Volunteers received three oral doses of 26Al-labelled aluminium compound in water. The doses were administered directly into the stomach using a paediatric feeding tube. Blood samples were collected from the volunteers at 1, 4 and 24 h after administration, and their daily output of urine and faeces was collected for 6 days. These samples were analysed for their 26Al content using either coincidence gamma-counting or accelerator mass spectrometry. The uptake of aluminium was greatest following its administration in the citrate form and was least following intake as the aluminium hydroxide suspension. The co administration of citrate, with the aluminium hydroxide suspension, was found to enhance the levels of 26Al uptake in both volunteers. Using a urinary excretion factor based on the results of previous studies, the fractional aluminium uptake from each of the species was calculated: aluminium citrate, 5.23 x 10(-3); aluminium hydroxide, 1.04 x 10(-4); aluminium hydroxide with citrate, 1.36 x 10( 3). PMID- 8696073 TI - Mercury distribution and renal metallothionein induction after subchronic oral exposure in rats. AB - The effects of long-term daily intake of low and high levels of mercury on its organ distribution and binding to renal metallothionein (MT) in male rats were studied. The animals were exposed to mercuric chloride labelled with 203Hg via drinking water for 8 weeks (5, 50 and 500 microM Hg). The greatest concentration of mercury was found in the kidneys. Similar levels of radioactivity in the buccal cavity and oesophagus were also observed by whole-body autoradiography. In the kidneys, the mercury was accumulated in the outer stripe of the outer zone of the medulla and, to a minor degree, in the renal cortex. Almost 50% the total renal mercury was associated to MT. The binding capacity of the renal MT for mercury tends to saturate with increasing doses, thus this means that the capacity of the kidneys to accumulate mercury is limited. PMID- 8696075 TI - Cytotoxic properties of iron-hydroxynaphthoquinone complexes in rat hepatocytes. AB - The mechanisms of toxicity to isolated rat hepatocytes of Fe(II) and Fe(III) complexes of two structurally related naphthoquinones have been studied. All complexes were found to show a dose-dependent toxicity which precedes cell death. Within the naphthoquinone series the order of toxicity is Fe(II) > parent naphthoquinone > Fe(III). The iron complexes of 5-OH-1,4 naphthoquinone (5-OH-1,4 NQ; Juglone) are more toxic than the iron complexes of 2-OH-1,4 naphthoquinone (2 OH-1,4 NQ; Lawsone) indicating that the mechanisms of toxicity are different. Electrochemical studies on these complexes shows that 5-OH-1,4 NQ facilitates formation of stable semiquinone species while 2-OH-1,4 NQ does not. The low redox potential of 2-OH-1,4 NQ makes it a poor substrate for metabolism by reductases. PMID- 8696077 TI - Antitumor activity of titanocene amino acid complexes. AB - Seven ionic titanocene alpha-amino acid (aa) complexes [(C5H5)2Ti(aa)2]2+[X]2- with aa = glycine, L-alanine, 2-methylalanine, D-L-phenylalanine, D,L-4 fluorophenylalanine and X = Cl or AsF6, were investigated for antitumor activity against fluid Ehrlich ascites tumor growing in CF1 mice. These complexes are the first stable model compounds of titanocene units with protein components, synthesized from a water-like, methanolic medium. All titanocene amino acid complexes induced antitumor activity which was manifested by maximum cure rates ranging from 30 to 70% and increases in life span from 78 to 276% in comparison with untreated control animals. The complexes containing chloride as anion X were more effective than the hexafluoroarsenate derivatives, which surprisingly showed a low substance toxicity. In all cases, the antitumor activity of the ionic titanocene amino acid complexes tested was less pronounced than that of the neutral parent compound [(C5H5)2TiCl2]. PMID- 8696076 TI - Cation effects on the conformations of muscle and non-muscle alpha-actinins. AB - We examined the effects of changing KCl concentration on the secondary structures of alpha-actinins using circular dichroism (CD), 1,1'-bis(4-anilino) naphthalene 5,5'-disulfonic acid (bisANS) fluorescence and proteolysis experiments. Under near-physiological conditions, divalent cations also were added and changes in conformation were investigated. In 25 mM KH2PO4, pH 7.5, increasing KCl from 0 to 120 mM led to decreases in alpha-helix conformation for brain, platelet and heart alpha-actinins (40.5-30.2%, 65.5-37.8% and 37.5-27.8%, respectively). In buffered 120 mM KCl, 0.65 mM calcium produced small changes in the CD spectra of both brain and platelet alpha-actinin, but had no effect on heart alpha-actinin. bisANS fluorescence of all three alpha-actinins also showed significant changes in conformation with increasing KCl. However, in buffered 120 mM KCl increasing concentrations of Ca2+ or Mg2+ did not have significant effects on the bisANS fluorescence of any alpha-actinin. Digestion of brain, platelet and heart alpha actinins with alpha-chymotrypsin showed an increase of proteolytic susceptibility in 120 mM KCl. These experiments also showed that increasing the concentration of Ca2+ or Mg2+ led to greater changes in digestion fragment patterns in the absence of KCl than in the presence of 120 mM KCl. The results suggest that alpha actinins exist in different conformations depending on the ionic strength of the medium, which could explain the differences in calcium and F-actin binding results obtained from different alpha-actinins. PMID- 8696078 TI - On the mechanism of citrate inhibition of ceruloplasmin ferroxidase activity. AB - Ceruloplasmin is a plasma protein, which oxidizes ferrous ions in a catalytic manner. It is considered to function as a ferroxidase in vivo. Citrate was found to inhibit the reaction. The ceruloplasmin catalyzed oxidation of p phenylenediamines, however, was not affected by citrate. The inhibitory effect is proposed to be due to formation of Fe(2+)-citrate, which does not react with ceruloplasmin. The stability constant for the Fe(2+)-citrate complex estimated from the present inhibition study is in good agreement with previously published data. PMID- 8696079 TI - Impact of aluminium, fluoride and fluoroaluminate complex on ATPase activity of Nostoc linckia and Chlorella vulgaris. AB - This study demonstrates a pH-dependent inhibition of Mg(2+)- and Ca(2+)-ATPase activities of Nostoc linckia and Chlorella vulgaris exposed to AlCl3, AlF3, NaF and AlCl3+NaF together. AlF3 and the combination of AlCl3+NaF were more inhibitory to both the enzymes as compared with AlCl3 and NaF. Toxicity of the test compounds increased with increasing acidity. Interaction of AlCl3+NaF was additive on N. linckia and C. vulgaris, respectively, at pH 7.5 and 6.8, and synergistic at pH 6.0 and 4.5. In the presence of 60 and 100 microM PO4(3-) an increased NaF concentration (in the AlCl3+NaF combination) was required to produce the same degree of inhibition in ATP synthesis and ATPase activity. Toxicity of fluoroaluminate was reduced in the presence of EDTA and citrate. Except for beryllium to some extent, combinations of cadmium, cobalt, iron, manganese, tin and zinc with fluoride were not as effective as aluminium in inhibiting the ATPase activity. The presence of a 100 kDa protein band in SDS PAGE of both control as well as AlCl3+NaF-treated samples suggested that AlF4- inhibits the ATPase activity by acting as a functional barrier without affecting the structure of the enzyme. PMID- 8696080 TI - Dynamic equilibria in iron uptake and release by ferritin. AB - The function of ferritins is to store and release ferrous iron. During oxidative iron uptake, ferritin tends to lower Fe2+ concentration, thus competing with Fenton reactions and limiting hydroxy radical generation. When ferritin functions as a releasing iron agent, the oxidative damage is stimulated. The antioxidant versus pro-oxidant functions of ferritin are studied here in the presence of Fe2+, oxygen and reducing agents. The Fe(2+)-dependent radical damage is measured using supercoiled DNA as a target molecule. The relaxation of supercoiled DNA is quantitatively correlated to the concentration of exogenous Fe2+, providing an indirect assay for free Fe2+. After addition of ferrous iron to ferritin, Fe2+ is actively taken up and asymptotically reaches a stable concentration of 1-5 microM. Comparable equilibrium concentrations are found with plant or horse spleen ferritins, or their apoferritins. After addition of ascorbate, iron release is observed using ferrozine as an iron scavenger. Rates of iron release are dependent on ascorbate concentration. They are about 10 times larger with pea ferritin than with horse ferritin. In the absence of ferrozine, the reaction of ascorbate with ferritins produces a wave of radical damage; its amplitude increases with increased ascorbate concentrations with plant ferritin; the damage is weaker with horse ferritin and less dependent on ascorbate concentrations. PMID- 8696081 TI - Microbial interactions with aluminium. AB - Although aluminium is the most abundant metal in the Earth's crust, it lacks biological functions and shows a low bioavailability. Acid rain, however, solubilizes aluminium to toxic levels. Most research on the biological effects of aluminium has been centred on the analysis of aluminium-tolerant plants as well as its possible relationship with neurological disorders in humans. Also, several studies have been reported concerning aluminium effects on microorganisms, with more interest directed to cyanobacteria, soil bacteria and mycorrhizal fungi. Competition with iron and magnesium, and binding to DNA, membranes or cell walls are considered the main toxic effects of aluminium in microbes. PMID- 8696082 TI - Practice nursing: will it survive? PMID- 8696083 TI - Oral contraception scare has reduced confidence in medical services. PMID- 8696084 TI - Minor injuries clinics: dealing with trauma. AB - This article examines the emerging development of nurse-led minor injuries units. It considers the impact of this on doctor-nurse relationships and the factors that need to be assessed and planned when initiating such a service. PMID- 8696085 TI - 'Last-resort' dressings for intractable pressures sores. AB - Twenty-five years of recommending dressing techniques for the most intractable pressure sores has taught the author some interesting lessons about the practical problems of wound healing when all else has failed. It is hoped that these personal experiences and opinions will be of some help to the many nurses who are involved in the management of pressure sores and chronic wounds. PMID- 8696086 TI - Nursing and health education: victim blaming. AB - Health education may contribute to creating victims. In this article, the concept of victim blaming, and how the victim role is created, is explored using transactional analysis. Specifically, the Drama Triangle is used as a tool for analysis rather than a model for practice. PMID- 8696087 TI - A basic guide to the principles of drug therapy. AB - Why must glyceryl trinitrate tablets be given sublingually? Why can you crush some tablets but not others? Can drug therapy cause red urine? How can suppositories stop vomiting? This article discusses why certain drugs are given by specific routes of administration and examines issues related to drug therapy, giving examples of drugs used in practice. Clinical tutors may wish to use this and subsequent articles for teaching purposes. PMID- 8696088 TI - Pain assessment in the elderly. AB - A major increase in the elderly population presumes a proportionate increase in chronic brain syndrome sufferers, who may have chronic pain. This article discusses the difficulties in assessing pain in this care group, with specific reference to those who are confused and non-verbal. Areas for further research are highlighted. PMID- 8696089 TI - Oral health in elderly patients. AB - A study of the oral health of elderly institutionalised patients and their oral care has revealed significant deficiencies, illustrating the need for a multi disciplinary approach to oral health care centred on the development of mouth care regimens for nursing staff. PMID- 8696090 TI - Treating post-traumatic stress disorder using Riehl's Interaction Model. AB - Following a succinct overview of post-traumatic stress disorder (PTSD), this article highlights the benefit of using Riehl's conceptual model, in conjunction with a cognitive behavioural approach, to help a serviceman suffering from PTSD. The case history and treatment are presented. PMID- 8696091 TI - Common problems with wound care: infection with HIV. AB - The issue of the care required by wounded patients infected with human immunodeficiency virus should be addressed by all nursing personnel. The virus can be transmitted through blood, blood products or wound exudate. Promotion of universal precautions should greatly minimise the risk. The patient's infection status is not always known and the problem may not be a major wound but an associated condition. PMID- 8696092 TI - UKCC's review should make the organization more open. PMID- 8696093 TI - Parameters of clinical supervision. PMID- 8696094 TI - Hip fracture and elderly patients. PMID- 8696095 TI - Care of the elderly with hip fractures: legal and clinical risk management implications. PMID- 8696096 TI - Is the new Disability Bill radical enough? PMID- 8696097 TI - The development of postgraduate surgical courses. AB - Postgraduate education opportunities for registered nurses working in surgical areas are increasing. Sound course programmes are an essential prerequisite for specialist practice but require effective collaboration between education and clinical managers. This article describes the successful validation and implementation of three postgraduate surgical nursing courses in 1994. PMID- 8696098 TI - Twenty-four hour pressure area management: study report. AB - The aim of the pilot study presented in this article was to evaluate the effectiveness of an alternating-pressure mattress overlay (AlphaXcell) used in combination with a pressure-reducing cushion (Multitec) in providing 24-hour pressure area care in a wide range of patients within a district general hospital. PMID- 8696099 TI - Alcohol home detoxification: a way forward. AB - Alcohol detoxification within the home environment is a safe, cost-effective alternative to inpatient care and the problem drinker is more likely to complete the treatment. Yet health trusts continue to ignore this community approach for those individuals with alcohol-related problems. PMID- 8696100 TI - Are specialist nurses cost-effective? PMID- 8696101 TI - Impact of The Patient's Charter on A&E departments. 2: The emergency nurse practitioner. AB - This article is the second of a two-part study based upon the results of a national survey of senior nurses in accident and emergency (A&E) departments. It explores the development of the nurse practitioner role in A&E. In particular, the extent to which this expanded role has become a means by which patients with minor injuries can be 'fast-tracked', to the possible detriment of more holistic goals for care delivery. PMID- 8696102 TI - Nurse practitioners: the American experience. AB - Nurse practitioners have been used in the USA for 30 years and have been shown to provide better and more cost-effective care than doctors in primary care settings. Consequently, they are a powerful vehicle for professional change in the current cost-cutting health-care reforms. This article examines the American experience. PMID- 8696103 TI - Marketing specialist practice to managers and purchasers. AB - Specialist nurses need to find a way of describing their practice that leaves managers and purchasers in no doubt about the level of service they offer and the contribution they make to the provision of high-quality care. This article suggests how they might market their expertise. PMID- 8696104 TI - FADE: a strategy for action in the mild stage of dementia. AB - This article introduces the Framework for Action in Dementia (FADE), a new strategy aimed at the mild stage of dementia. It suggests that empowering people with dementia from the onset of their illness is a crucial role for nurse practitioners. PMID- 8696105 TI - HNE Diagnostics Dopplex ultrasound machines. AB - Doppler ultrasound is a technique that has a variety of uses. These include venous and arterial circulation assessment, pre- and postoperative arterial assessment, digital pulse assessment, carotid stenosis screening, penile blood flow measurement and fetal heart rate assessment. PMID- 8696107 TI - Is nursing the Cinderella of academic disciplines? PMID- 8696106 TI - Methicillin-resistant Staphylococcus aureus and wound management. AB - The incidence of methicillin-resistant Staphylococcus aureus (MRSA) infection is increasing in the UK. MRSA is mainly transmitted via the hands of health-care workers. MRSA can cause colonization or infections. MRSA infections can be fatal. PMID- 8696108 TI - Nutritional assessment. AB - Undernutrition and obesity have serious implications for both health and recovery from illness or surgery. These nutritional problems are common in hospital patients but often go unnoticed. This article reviews the means of carrying out nutritional assessment and recommends simple techniques for routine use at ward level to identify patients who need nutritional intervention. Nursing staff are in an ideal position to undertake nutritional screening and simple nutritional assessment should be routinely included as part of patient assessment. PMID- 8696109 TI - The challenge of the Children's Charter: rhetoric vs reality. AB - The rights of children are not enshrined in statute. However, over recent years, a number of organizations such as Action for Sick Children and The Children's Trust, Tadworth, have produced guidelines related to the rights of children and their families in hospital. The voluntary sector has led the way in influencing policy makers. This is exemplified in the publication of the Department of Health's draft Children's Charter. This article explores the strengths, weaknesses, opportunities and threats of this recent innovation. PMID- 8696110 TI - Service provision for sickle-cell disease: school-based education. AB - Screening and genetic counselling for individuals at risk of having children affected by sickle-cell disease are often limited to the antenatal period. Only in rare situations of innovation are school children informed of the potential risk that this disorder can pose for them in the future. School children should receive instruction about the possible risks and effects of sickle-cell disorders as part of a health education programme, to enable them to make informed decisions about their future. PMID- 8696111 TI - Parent participation. 1: Literature review and methodology. AB - A qualitative exploratory study was undertaken to examine parents' views and experiences of participation in the care of their child in hospital and to identify factors that inhibit or facilitate participation. Parents of children aged 2-5 years of age were interviewed within 2 months of discharge, using tape recorded, semi-structured interviews. The findings demonstrate that parents clearly wish to participate in their children's care at a level of their own choosing. However, they preferred professionals to be responsible for their children's clinical care, while they continue to be responsible for the children's normal day-to-day care. Problems were identified in the area of relationships between parents and professionals, centred on communication and the continuing paternalistic nature of these relationships. Parents of children who experienced single, short hospital admissions found involvement in their children's care particularly difficult. Guidelines were developed from the results, to facilitate parent participation in the care of children in this age group. PMID- 8696112 TI - IV hydration in the terminally ill: ritual or therapy? AB - The management of dehydration is both a clinical and an ethical problem. Artificial hydration may increase pharyngeal and pulmonary secretions, which causes a choking sensation, nausea and vomiting. Food and fluid have a strong social, cultural, religious and psychological significance. Competent nursing requires expert knowledge and moral skill. The interests of the patient must always be paramount. An ethical decision-making framework provides a systematic approach to ethical problems. PMID- 8696113 TI - Towards care in the community: a carer's tale. AB - It is not easy to write about the recent death of a parent. While carrying out action research on community care planning in the Midlands, the author was compelled to gain first-hand experience of the impact of care in the community at the sharp end by his mother's terminal illness. The learning curve was steep. Care workers have to take a lot of knocks in the current political environment. It is a relief--and no little personal therapy--to be able to report a success story. Writing up the experience provided an opportunity to express gratitude to all members of the care team involved and at the same time to vaunt the concept of the 'live-in carer' scheme, an innovation deserving replication elsewhere. PMID- 8696114 TI - Nursing should be an all-graduate profession. PMID- 8696115 TI - Are British nurses lethargic? PMID- 8696116 TI - The background to the national clinical guidelines for the prevention and management of pressure sores. AB - Clinical guidelines are systematically developed statements to assist health-care professionals in decision-making and should be viewed as a means of improving clinical effectiveness. The NHS Executive wishes to encourage their development and use. To this end it has commissioned a number of clinical guidelines. As these will be used in a number of health-care settings, the need for multiagency and multiprofessional care is recognized. The main themes of the guidelines are that care should be patient focused, clinically useful and multidisciplinary. This article introduces a monthly series in the British Journal of Nursing examining the national clinical guidelines for pressure sore prevention and management. PMID- 8696118 TI - Developing a research culture for nursing in higher education. PMID- 8696117 TI - From methodology to method: the building blocks of research literacy. AB - Last year, the British Journal of Nursing published a series of articles outlining some of the major concepts underpinning the research process. This article is the first in a second series which will develop further a number of themes. This series begins with a description of broad methodological approaches before moving on to consider specific methods. The main aim is to assist nurses to improve their research literacy so that they may become more informed and critical readers of research. Before beginning the series proper this article identifies some of the main barriers to research utilization and argues that, in order to overcome these barriers, both decision-driven and knowledge-driven approaches are required. PMID- 8696119 TI - Nursing must first become a profession of graduates. PMID- 8696120 TI - Central venous cannulation. AB - This article addresses a learning experience involving the insertion of central venous cannulae, for both the assessment of a patient's internal environment in relation to the need for medical intervention and the administration of medical treatment. The issues explored highlight the important uses of such cannulae and stress the potential problems which may be encountered during insertion of the cannulae or when they are used for the administration of drug therapy. PMID- 8696121 TI - Nurses will be affected by NHS management cuts. PMID- 8696122 TI - Choosing a home: the discharge of elderly people from hospital. PMID- 8696124 TI - Paracetamol overdose: pathophysiology and nursing management. AB - Paracetamol overdose now represents one third of all self-poisoning cases. In contrast to other drugs, the use of paracetamol as a self-poisoning agent is increasing. As very large doses of the drug cause severe liver injury, which can result in fulminant hepatic failure when left untreated, it is essential that nurses have a complete understanding of the mechanisms of normal paracetamol metabolism, effects of overdosage and treatment strategies to guide the nursing management of clients. This review therefore critically examines the pathophysiology and nursing management of clients with acute paracetamol overdosage. PMID- 8696125 TI - Voluntarism and health education in nursing. AB - The concept of voluntarism, as it applies to models of health education, underpins the nursing care of people who are chronically confused and their relatives. This article argues that voluntarism needs to be balanced by the notion of collectivism which takes full account of the contribution made by sociopolitical determinants of health. The central concepts of voluntarism and health education are defined and then the article proceeds to examine the extent to which voluntarism has underpinned various models of health education which can be used to support nursing practice. A critique of the concept of voluntarism, as used in health education, is provided. It is argued that models of health education which are polarized towards either voluntarism or collectivism are based on an inadequate understanding of human social action and that this polarization undermines the usefulness of these models of health education. PMID- 8696123 TI - A new model for Project 2000 students in theatres. AB - Changes in nurse education have brought into focus the status of the student nurse in the operating department. This article outlines some of the historical perspectives of the role of student nurses undertaking their operating department experience and describes a new model for preparing students for this part of their preregistration education as piloted by one college of health studies after the implementation of Project 2000. PMID- 8696126 TI - How much should patients be told about their medication? AB - Much has been written on the education of patients about their medication, and yet what patients need to know has not been identified and agreed upon by professionals. This study sought to design a tool for this purpose using a series of interviews with experts to identify categories of information. Many core categories were identified and ambiguous sections such as 'side-effects' were clarified. A test-re-test strategy was used to identify the reliability of the resulting questionnaire. A high level of inconsistencies and a low response rate were, in part, attributable to poor design and distribution of the questionnaire. Other contributory factors and the reluctance/inability of respondents to identify what they felt patients should know about their medication are discussed. Some deficits are identified, in addition to an agreement that current systems for educating patients are inadequate. Areas for future research are also identified. PMID- 8696127 TI - The biology of Alzheimer's disease: 1. AB - This article, the first of two parts, attempts to take dementia care back to its foundations by informing nursing practice of the biology and degenerative effects on the brain of Alzheimer's disease, the most prevalent form of dementia. This biological understanding will then be used to illustrate the effect on the emotional, perceptual, behavioural and social world of the individual sufferer and will be selectively applied to inform nursing practice. Studying the biological process of AD is not easy, but an understanding is essential if a comprehensive and holistic stance is to be adopted by clinical nurse practitioners. These articles will also address the medical definitions of dementia, the onset and spread of neuritic plaques and neurofibrillary tangles, and the genetic and aluminium components, and will compare the impact of AD on brain structure and function with that of the normal ageing brain. At the conclusion of the second article, future prospects and the nursing response will be considered. PMID- 8696128 TI - Testicular cancer. PMID- 8696129 TI - Genital warts: a study of patient anxiety and information needs. AB - Infection with genital warts is one of the most commonly seen infections in genitourinary medicine (GUM) clinics. A study of 50 women with a first-time diagnosis of genital warts was undertaken to determine the patients' levels of knowledge and anxiety in relation to their diagnosis. The findings revealed that 42 (84%) of these women were aware of their possible diagnosis before attending the clinic. Just over a half of them received this information from their GPs. Eight (35%) patients lacked and fundamental knowledge about the mode of transmission of genital warts and the need for prophylactic use of condoms. Seventeen (74%) of the women did not know or were unsure about the methods of treatment. High levels of anxiety were reported by the patients on their first clinic attendance. To increase knowledge and lessen anxiety in this client group, the author recommends reciprocal liaison between GPs, their practice nurses and GUM clinics. PMID- 8696130 TI - Pressure sore guidelines: patient/carer involvement and education. AB - The important issue of patient/carer involvement in relation to pressure sore prevention and management is referred to in the NHS Executive's (1994) draft document on the prevention and management of pressure sores, commonly known as the 'Pressure sore consensus guidelines'. It states that: 'A multidisciplinary plan of care should be negotiated with individual patients and/or carers taking into consideration their knowledge and experience.' This article explores some of the specific aspects of patient/carer involvement in various settings. Key factors identified during the course of the consensus guidelines development in relation to patient/carer involvement are the assessment of risk, the educational strategy adopted, what information should be included and individual freedom of choice to accept or refuse advice or care. PMID- 8696131 TI - Granugel: hydrocolloid gel. AB - Hydrogels have been used for some time in wound management to maintain a moist wound interface and to aid the debridement of slough and necrotic tissue. Granugel (ConvaTec) is a combination of both hydrogel and hydrocolloid, which has been shown to be a safe and effective dressing that is also cost-effective. PMID- 8696132 TI - Nursing elderly people with dignity and respect. PMID- 8696133 TI - Dental offices designed specifically for pediatric dentistry. PMID- 8696134 TI - Dentistry in the Bible, Talmud and writings of Moses Maimonides. PMID- 8696135 TI - The history of the Working Group on Dental History of the F.D.I. PMID- 8696136 TI - Did you know--a dentist embalmed President Lincoln? PMID- 8696138 TI - Dentistry on stamps. Malta. PMID- 8696137 TI - Gleanings about dentistry from the world of literature. No. 11. "Disaster in Paris.". PMID- 8696139 TI - The Marburg Dioscorides. PMID- 8696140 TI - Surprise! The leaders of dentistry were not that pleased with Morton's discovery. PMID- 8696142 TI - Brazilian artists select dental themes to show their art. PMID- 8696141 TI - Gold fillings. PMID- 8696143 TI - Dentistry enters the opera repertoire with the premiere performance of "McTeague". PMID- 8696144 TI - Tongue and taste in the past. PMID- 8696145 TI - Papa moves his office... PMID- 8696146 TI - Dentistry on stamps. PMID- 8696147 TI - Mutilation of the dentition: an initiation rite observed in aboriginal Australians. PMID- 8696148 TI - Gleanings about dentistry from the world of literature (12th in a series). John Updike. "Self-Consciousness". PMID- 8696149 TI - Found: first dental school's first DDS diploma--or so the date said. PMID- 8696150 TI - Kurt and Wilhelm Sprengel and the historiography of dentistry. PMID- 8696151 TI - Facial neuralgia cured by acupuncture a century and a half ago. PMID- 8696152 TI - The mixing and placement of amalgam. PMID- 8696153 TI - Swedish military dentistry: a historical background. PMID- 8696154 TI - The Tooth Fairy Museum: an historically important collection. PMID- 8696155 TI - An 1836 career guide to dentistry. AB - In a guide to careers published in 1836 one chapter is dedicated to dentistry. It gives a basic account of teeth and of the work of the dentist. PMID- 8696156 TI - Nursing Education Coalition: NEC December update. PMID- 8696157 TI - Independent practice: legal considerations. PMID- 8696158 TI - SaskHealth system captures world-wide interest. PMID- 8696159 TI - Nursing on a global scale: the Trilateral Initiative. PMID- 8696160 TI - London conference on professional regulation impacts nursing. PMID- 8696161 TI - The CNA goes global in Eastern Europe: strengthening nursing in Ukraine. PMID- 8696162 TI - NAFTA, AIT, GATS, WTA and the RN. PMID- 8696163 TI - Nursing in Poland: journaling the issues. PMID- 8696164 TI - Life after job loss: one nurse's journey of self-discovery. PMID- 8696165 TI - Acute exacerbation and superinfection in patients with chronic viral hepatitis. AB - Recent studies, particularly those in Orientals, have shown that both acute exacerbation from the reactivation of the original virus and acute superinfection with other viruses occur frequently in patients with chronic viral hepatitis. The clinicopathologic features of acute exacerbation and acute superinfection are similar to those of acute hepatitis caused by a single virus, but acute exacerbation is usually less severe than acute superinfection. Recurrent acute exacerbations result from the host's intermittent but persistant efforts to eliminate the replicating virus by immune-mediated mechanisms, thus killing hepatocytes with viral replication. Severe acute exacerbation or acute superinfection may result in immediate hepatic decompensation, or even mortality, and late disease progression, including liver cirrhosis and hepatocellular carcinoma. Further studies are needed to elucidate the basic mechanisms and provide more effective ways to avoid acute exacerbation and acute superinfection in patients with chronic viral hepatitis. PMID- 8696166 TI - Detection of Y-chromosome sequences in patients with X-chromosome abnormalities. AB - The polymerase chain reaction was used to test 18 adults and eight fetuses with numerical or structural X-chromosome abnormalities for the presence of nine Y specific loci. Y-chromosomal DNA was detectable in one adult patient with X chromosome mosaicism. This study and previous reports provide evidence to support further screening of patients with X-chromosome abnormalities for the presence of Y-chromosomal DNA sequences. Long-term follow-up of patients with Y-chromosomal sequences is required to determine the risk of gonadal neoplasms and other abnormal phenotypes. PMID- 8696167 TI - Adenocarcinoma of the gastric cardia: prognostic significance of pathologic and treatment factors. AB - The records of 146 patients who had surgery for adenocarcinoma of the gastric cardia between 1977 and 1992 at National Taiwan University Hospital were retrospectively analyzed. The prognostic significance of pathologic and surgical treatment factors was examined by log rank test and stepwise regression procedures. The overall 2-year and 5-year survival rates were 40.2% and 23.7%, respectively. The pathologic factors analyzed included: age, sex, tumor diameter, esophageal invasion, pathologic grading, vascular invasion, perineural invasion, depth of invasion, node-status, distant metastasis and number of positive lymph nodes. The surgical treatment factors analyzed included:surgical procedure, region of lymphadenectomy, resection margin and resection status. Resection status was classified into three categories: absolute curative, relative curative and palliative. Univariate analyses showed that esophageal invasion, vascular invasion, depth of invasion, node status, node number, resection margin and resection status were significant prognostic factors. The selected stepwise regression model identified three significant independent factors: node status, resection status and esophageal invasion. Aggressive surgical management, including combined resection and extended lymphadenectomy, may be helpful for patients with adenocarcinoma of the gastric cardia. PMID- 8696168 TI - Changes in coagulatory profile after orthopedic surgery. AB - Platelet count, prothrombin time (PT), partial thromboplastin time (PTT) and fibrinogen concentrations were prospectively evaluated in 65 patients undergoing orthopedic surgery at the National Cheng-Kung University Hospital between June 1990 and February 1991. All patients were hospitalized for at least 7 days after surgery. Coagulation data were collected preoperatively and on the first, third and seventh postoperative days (POD 1, 3, 7). The average estimated blood loss was 374 mL (range, 25-2.350 mL). Stored whole blood transfusion of 2 to 5 units (1 unit = 250 mL) was required by 12 patients. A further 12 patients received a transfusion of two to six units of packed red cells. Platelet count decreased to the lowest level on POD 1, recovered to normal on POD 3 and was even greater by POD 7. PT was prolonged on POD 1, recovered by POD 3 and remained stable on POD 7. PTT was prolonged on POD 1, became more prolonged on POD 3 and returned to normal by POD 7. Fibrinogen concentrations were not significantly altered on POD 1, but increased above the preoperative level on POD 3 and returned gradually to normal by POD 7. Variables such as age, sex, type of operation and duration of tourniquet did not affect these patterns. There was a positive correlation between duration of surgery, net blood loss and decrease in platelet count. This study examined some of the physiologic coagulatory variations after orthopedic surgery. Recognition of these patterns might lead to better clinical judgment when perioperative coagulatory disorders are suspected. PMID- 8696169 TI - Antimicrobial susceptibility and beta-lactamase production of Moraxella catarrhalis isolates in Taiwan. AB - Between 1 August 1993 and 31 July 1994, 135 clinical isolates of Moraxella catarrhalis were collected from 12 large medical laboratories in Taiwan. The majority of specimens came from sputum (124 isolates). Other specimens included four isolates from throats, three isolates from wounds or pus, two isolates from eyes, one isolate from blood and one from cerebrospinal fluid. Epidemiologically, M. catarrhalis isolates were found frequently in winter and spring with a peak in February, and only sporadically from April to September. The overall rate of beta lactamase producing isolates was 98.5% (132/135). All isolates were considered to be ampicillin-resistant, none were found to be resistant to other beta-lactam agents. Among other antimicrobial agents, all isolates were susceptible to chloramphenicol, erythromycin, roxithromycin, ofloxacin and ciprofloxacin, but uniformly resistant to trimethoprim (minimum inhibitory concentration (MIC) > or = 4 micrograms/mL, zone diameter < or = 19 mm). There were 12 isolates (8.8%) resistant to sulfamethoxazole (MIC > or = 32 micrograms/mL, zone diameter < or = 19 mm) and 19 isolates (14.4%) resistant to tetracycline (MIC > or = 16 micrograms/mL, zone diameter < or = 19 mm). The high level of resistance to ampicillin due to beta-lactamase production indicates that this is no longer a reliable agent for the treatment of M. catarrhalis infections. Among the beta lactam agents tested, amoxicillin + clavulanate and the cephalosporins were active. These agents appear to be reliable first-line therapies when infection with M. catarrhalis is suspected. Misidentification of the species and difficulties in determining susceptibility to ampicillin are still widespread in Taiwanese laboratories. The application of the butyrate hydrolysis test and an appropriate test for beta-lactamase production is necessary for the resolution of these problems. PMID- 8696170 TI - Effects of mild bladder outlet obstruction on rabbit bladder structure and function. AB - Mild bladder outlet obstruction was created in 42 New Zealand white rabbits by placing a 5-mm inner diameter polyethylene tube around the urethra. Periods of obstruction lasted for 1 day (7 rabbits), 3 days (7 rabbits), 1 week (7 rabbits), 2 weeks (6 rabbits), 4 weeks (7 rabbits), 6 weeks (4 rabbits) and 8 weeks (4 rabbits). Whole bladder functional study was performed in control (5 rabbits) and the obstructed bladders. The obstructed bladders increased in weight two-to threefold. There was no significant difference in bladder weight after different periods of obstruction. Electric stimulation showed a diminished response after 3 days of obstruction. Pharmacologic stimulation with 500 microM carbachol revealed a decreased response after obstruction, but intravesical pressure returned to the control level at 6 and 8 weeks of obstruction. However, the bladder weight and the expelling function of the obstructed bladders remained the same as on day 1 of obstruction. Histologic study of control and obstructed bladders revealed that: 1) dense submucosal fibrous tissue developed after 3 days of obstruction, 2) detrusor muscle hypertrophy and hyperplasia were noted with intermuscular collagenous fiber deposition after 2 weeks of obstruction, 3) trabeculation of the bladder wall with hyperplasia of muscular bundles was noted after 2 weeks of obstruction, 4) acute edematous and inflammatory reaction were apparent after 3 days and 1 week of obstruction, but resolved later and 5) degenerative changes of muscular cells were noted at 8 weeks of obstruction. The results show that despite apparent morphologic changes after outlet obstruction, no significant difference was observed in bladder expelling between short-term and long-term infravesical mild outlet obstruction. The bladder contractile apparatus appears to have a compensatory ability after mild outlet obstruction. PMID- 8696171 TI - Sinusoidal fetal heart rate pattern during chemotherapy in a pregnant woman with acute myelogenous leukemia. AB - A 22-year-old woman was referred to our hospital because of severe anemia in the 20th week of gestation. Acute myelogenous leukemia was diagnosed and she was treated with multiple-agent chemotherapy in the second and third trimesters. Although the patient tolerated the intensive treatment, an intermittent sinusoidal fetal heart rate pattern was detected during chemotherapy. Complete remission was achieved at the 35th week of gestation. An underweight baby boy, suffering from pancytopenia, was delivered by cesarean section at 36 weeks' gestation. The baby recovered well and had adequate growth. No abnormalities where found at examination two months after birth. The fetal sinusoidal heart rate pattern may have been induced by severe anemia due to myelosuppression caused by the transplacental receipt of chemotherapeutic agents. PMID- 8696172 TI - In vitro fertilization pregnancy achieved with epididymal caput sperm of a patient with obstructive azoospermia. AB - A successful epididymal sperm aspiration, in vitro fertilization and embryo transfer in a woman whose husband had previously undergone extensive attempts at recanalization of the spermatic ducts is reported. A twin pregnancy was achieved using sperm obtained from the husband's epididymal caput. This case demonstrates that pregnancy can be achieved by this reproductive technique in cases of obstructive azoospermia, even after extensive surgery. PMID- 8696173 TI - Gonadoblastoma and chroiocarcinoma in dysgenic gonads: report of a case. AB - Dysgenetic gonads are well known to be associated with gonadoblastoma and various germ cell tumors, but very rarely with choriocarcinoma. We describe a 16-year old, phenotypic female patient with a 46XY karyotype who developed gonadoblastoma on the right gonad and choriocarcinoma on the left. There was no co-existence of the two tumor cell types in the same gonad. This case emphasizes the importance of bilateral gonadectomy for "46XY female" patients, as soon as the cytogenetic evidence is known. PMID- 8696174 TI - Disseminated Penicillium marneffei infection in a patient with acquired immunodeficiency syndrome. AB - Penicillium marneffei is a rare human pathogen in Southeast Asia and Southern China. A 26-year-old heterosexual male had intermittent fever, diarrhea and weight loss for 3 months. He was severely immune deficient (CD4+ count, 4/microL) and serologic tests for antibodies against human immunodeficiency virus type-1 were positive. P. marneffei infection was disseminated with involvement of the liver, spleen and bone marrow. The diagnosis was established by histologic examination and confirmed by isolation of the fungus. This infection responded well to amphotericin B. He was discharged with maintenance therapy of itraconazole and continued to be stable during his 2-month follow-up. PMID- 8696175 TI - Primary small cell carcinoma of the urinary bladder: report of a case. AB - A 66-year-old male presented with diffuse abdominal pain and microscopic hematuria characteristic of perirenal urinoma formation. After a biopsy, he was diagnosed with small cell carcinoma of the urinary bladder. The patient was treated by radical cystoprostatectomy with orthotopic bladder replacement using the Camey II procedure. Daytime urinary continence was achieved 6 months after surgery. The patient died of carcinomatosis 15 months after diagnosis. PMID- 8696176 TI - Hepatic portal vein gas following blunt colon injury: report of a case. AB - Blunt colon injuries sometimes result in signs of peritoneal irritation requiring exploratory laparotomy. More frequently there are no specific symptoms, and this leads to a delay in diagnosis and management. Some imaging studies point to blunt colon injury, but gas in both the hepatic portal and mesenteric veins has rarely been reported. Hepatic portal venous gas (HPVG) is a rare roentgenographic picture, and its presence usually represents a serious intra-abdominal catastrophe. Computed tomography and plain abdominal X ray in a 52-year-old man with blunt abdominal injury showed significant gas in the portal venous system and pneumatosis intestinales of the ascending colon. Exploratory laparotomy revealed segmental necrosis of the transverse colon in front of the vertebrae. The presence of HPVG may have been due to mucosal disruption, vascular compromise or prolonged increased intra-abdominal pressure. Its presence in patients with blunt abdominal trauma suggests the possibility of bowel injury. Surgical exploration should be considered when HPVG is noted on roentgenographic studies. PMID- 8696177 TI - Vitamin K at birth. PMID- 8696179 TI - Inappropriate treatment for dysentery. PMID- 8696178 TI - Sudden infant death syndrome: after the "back to sleep" campaign. PMID- 8696180 TI - Preventing sports and leisure injuries. PMID- 8696181 TI - Health impact assessment. PMID- 8696182 TI - Climate change: not a threat but a promise. PMID- 8696183 TI - Court action over smoking report. PMID- 8696184 TI - Growth hormone deaths blamed on MRC and DoH. PMID- 8696186 TI - Fast track scheme for medical negligence starts. PMID- 8696185 TI - Medical community is outraged at tobacco funded chair. PMID- 8696187 TI - Four die in food poisoning outbreak in Japan. PMID- 8696188 TI - Antiabortionists hijack fetal pain argument. PMID- 8696189 TI - Storage period ends for 4000 embryos. PMID- 8696190 TI - BSE agent: there may be even more trouble ahead. PMID- 8696191 TI - Irish determination on drugs. PMID- 8696192 TI - Safeguards for surgery by non-doctors produced. PMID- 8696193 TI - Environment of infants during sleep and risk of the sudden infant death syndrome: results of 1993-5 case-control study for confidential inquiry into stillbirths and deaths in infancy. Confidential Enquiry into Stillbirths and Deaths Regional Coordinators and Researchers. AB - OBJECTIVE: To investigate the role of sleeping arrangements as risk factors for the sudden infant death syndrome after a national risk reduction campaign. DESIGN: Two year population based case-control study. Parental interviews were conducted for each infant who died and for four controls matched for age and date of interview. SETTING: Three regions in England with a total population of 17 million people. SUBJECTS: 195 babies who died and 780 matched controls. RESULTS: Prone and side sleeping positions both carried increased risks of death compared with supine when adjusted for maternal age, parity, gestation, birth weight, exposure to smoke, and other relevant factors in the sleeping environment (multivariate odds ratio = 9.00 (95% confidence interval 2.84 to 28.47) and 1.84 (1.02 to 3.31), respectively). The higher incidence of side rather than prone sleeping led to a higher population attributable risk (side 18.4%, prone 14.2%). More of the infants who died were found with bed covers over their heads (21.58; 6.21 to 74.99). The use of a dummy had an apparent protective effect (0.38; 0.21 to 0.70). Bed sharing for the whole night was a significant risk factor for infants whose mothers smoked (9.25; 2.31 to 34.02). No protective effect of breast feeding could be identified on multivariate analysis. CONCLUSIONS: This study confirms the importance of certain risk factors for the sudden infant death syndrome and identifies others-for example, covers over the head, side sleeping position-which may be amenable to change by educating and informing parents and health care professionals. PMID- 8696194 TI - Smoking and the sudden infant death syndrome: results from 1993-5 case-control study for confidential inquiry into stillbirths and deaths in infancy. Confidential Enquiry into Stillbirths and Deaths Regional Coordinators and Researchers. AB - OBJECTIVE: To investigate the effects of exposure to tobacco smoke and of parental consumption of alcohol and illegal drugs as risk factors for the sudden infant death syndrome after a national risk reduction campaign which included advice on prenatal and postnatal avoidance of tobacco smoke. DESIGN: Two year population based case-control study. Parental interviews were conducted for each infant who died and four controls matched for age and date of interview. SETTING: Three regions in England with a total population of 17 million people. SUBJECTS: 195 babies who died and 780 matched controls. RESULTS: More index than control mothers (62.6% v 25.1%) smoked during pregnancy (multivariate odds ratio = 2.10; 95% confidence interval 1.24 to 3.54). Paternal smoking had an additional independent effect when other factors were controlled for (2.50; 1.48 to 4.22). The risk of death rose with increasing postnatal exposure to tobacco smoke, which had an additive effect among those also exposed to maternal smoking during pregnancy (2.93; 1.56 to 5.48). The population attributable risk was over 61%, which implies that the numbers of deaths from the syndrome could be reduced by almost two third if parents did not smoke. Alcohol use was higher among index than control mothers but was strongly correlated with smoking and on multivariate analysis was not found to have any additional independent effect. Illegal drug use was more common among the index parents, and paternal use of illegal drugs remained significant in the multivariate model (4.68; 1.56 to 14.05). CONCLUSIONS: This study confirms the increased risk of the sudden infant death syndrome associated with maternal smoking during pregnancy and shows evidence that household exposure to tobacco smoke has an independent additive effect. Parental drug misuse has an additional small but significant effect. PMID- 8696196 TI - Characteristics of orf in a farming community in mid-Wales. PMID- 8696195 TI - Vitamin K and childhood cancer: a population based case-control study in Lower Saxony, Germany. AB - OBJECTIVE: To confirm or refute a possible association of parenteral vitamin K prophylaxis and childhood cancer. DESIGN: Population based case-control study. Comparison of vitamin K exposure in children with leukaemia or other common tumours with two control groups. SETTING: State of Lower Saxony (north western part of Germany); case recruitment from the German childhood cancer registry. SUBJECTS: 272 children with leukaemia, nephroblastoma, neuroblastoma, rhabdomyosarcoma, and tumours of the central nervous system diagnosed between 1 July 1988 and 30 June 1993; children were aged between 30 days and 15 years at diagnosis. 334 population based controls without diagnoses of cancer matched to the leukaemia cases for age and sex. MAIN EXPOSURE MEASURES: Parenteral vitamin K prophylaxis (intramuscular and subcutaneous) versus oral and no vitamin K prophylaxis. RESULTS: An association between parenteral vitamin K exposure and childhood cancer (leukaemias and other tumours combined) could not be confirmed (odds ratio 1.04, 95% confidence interval 0.74 to 1.48). For leukaemias the observed odds ratio was only 0.98 (0.64 to 1.50) (comparison of leukaemia cases with local controls 1.24 (0.68 to 2.25); state controls 0.82 (0.50 to 1.36)). These odds ratios remained almost unchanged when several potential confounders were considered in the logistic regression model. CONCLUSIONS: This population based study adds substantial evidence that there is no association between parenteral vitamin K and childhood cancer. PMID- 8696197 TI - Childhood leukaemia and intramuscular vitamin K: findings from a case-control study. PMID- 8696198 TI - Medical practitioners' knowledge of dysentery treatment in Bangladesh. PMID- 8696199 TI - Home visiting by general practitioners in England and Wales. AB - OBJECTIVE: To use data from the fourth national survey of morbidity in general practice to investigate the association between home visiting rates and patients' characteristics. DESIGN: Survey of diagnostic data on all home visits by general practitioners. SETTING: 60 general practices in England and Wales. SUBJECTS: 502 493 patients visited at home between September 1991 and August 1992. MAIN OUTCOME MEASURES: Home visiting rates per 1000 patient years and home visiting ratios standardised for age and sex. RESULTS: 10.1% (139 801/1 378 510) of contacts with general practitioners took place in patients' homes. The average annual home visiting rate was 299/1000 patient years. Rates showed a J shaped relation with age and were lowest in people aged 16-24 years (103/1000) and highest in people aged > or = 85 years (3009/1000). 1.3% of patients were visited five or more times and received 39% of visits. Age and sex standardised home visiting ratios increased from 69 (95% confidence interval 68 to 70) in social class I to 129 (128 to 130) in social class V. The commonest diagnostic group was diseases of the respiratory system. In older age groups, diseases of the circulatory system was also a common diagnostic group. Standardised home visiting ratios for the 60 practices in the study varied nearly eightfold, from 28 to 218 (interquartile range 67 to 126). CONCLUSIONS: Home visits remain an important component of general practitioners' workload. As well as the strong associations between home visiting rates and patient characteristics, there were also large differences between practices in home visiting rates. A small number of patients received a disproportionately high number of home visits. Further investigation of patients with high home visiting rates may help to explain the large differences in workload between general practices and help in allocation of resources to practices. PMID- 8696200 TI - Drugs in sport. PMID- 8696201 TI - Tuberculous enteritis. PMID- 8696202 TI - Homes and housing for elderly people. AB - Most elderly people in Britain live independently in their own homes. Moving to alternative accommodation may be necessary for some people but requires careful consideration. A multidisciplinary assessment should be performed when a person plans to move into residential care; this should include the input of a doctor trained in geriatric medicine. A range of housing options is open to elderly people and these options are discussed here. PMID- 8696203 TI - Pitfalls in contact tracing and early diagnosis of childhood tuberculosis. PMID- 8696204 TI - ABC of work related disorders. Occupational hearing loss and vibration induced disorders. PMID- 8696205 TI - Jack Kevorkian: a medical hero? Better palliative care is the answer. PMID- 8696206 TI - Jack Kevorkian: a medical hero? Pope should be doctors' hero. PMID- 8696207 TI - Jack Kevorkian: a medical hero? Possibly a hero, but not a medical one. PMID- 8696208 TI - Jack Kevorkian: a medical hero? Law has a protective function for both patients and doctors. PMID- 8696209 TI - Jack Kevorkian: a medical hero? Doctors should indeed cry, "enough". PMID- 8696210 TI - Jack Kevorkian: a medical hero? Editorial's objectivity is in doubt. PMID- 8696211 TI - Jack Kevorkian: a medical hero? His actions are the antithesis of heroism. PMID- 8696212 TI - Haem iron intake in young children. Other health promotion activities would have higher priority in Africa. PMID- 8696213 TI - Tea flavonoids have little short term impact on serum antioxidant activity. PMID- 8696214 TI - Immediate enteral feeding after gastrointestinal resection. Tests of intestinal permeability were inadequate. PMID- 8696215 TI - Immediate enteral feeding after gastro-intestinal resection. Fluid regimen given to control group is increasingly being abandoned. PMID- 8696216 TI - Immediate enteral feeding after gastro-intestinal resection. Serum albumin concentration is not a marker of nutritional status. PMID- 8696217 TI - Immediate enteral feeding after gastro-intestinal resection. Study was not sufficiently rigorous. PMID- 8696218 TI - Psychiatric and psychological aspects of hysterectomy. Authors did not specify type of hysterectomy carried out. PMID- 8696219 TI - Psychiatric and psychological aspects of hysterectomy. Study did not reliably exclude possibility of psychological damage. PMID- 8696220 TI - Serum IgM testing is needed in all cases of suspected measles. PMID- 8696221 TI - Psychiatric and psychological aspects of hysterectomy. Results will depend on whether hysterectomy was essential or not. PMID- 8696222 TI - Genetic liability to osteoarthritis may be greater in women than men. PMID- 8696223 TI - Hospital at home. Research is needed into organisation and development as well as cost effectiveness. PMID- 8696224 TI - Hospital at home. Scheme in Peterborough is expanding. PMID- 8696225 TI - Efficacy of colchicine in familial Mediterranean fever is well established. PMID- 8696226 TI - Proposed academy of medicine. Proposal is a fudge between academy of medicine and of health. PMID- 8696227 TI - Use of placebo in studies of postoperative vomiting is unethical. PMID- 8696228 TI - Proposed academy of medicine. Academy of Medical Royal Colleges has its own, independent secretariat. PMID- 8696229 TI - New confidential inquiry established into homicides and suicides by mentally ill people. PMID- 8696230 TI - Proposed academy of medicine. Editorial did not acknowledge BMA's work. PMID- 8696231 TI - Proposed medical academy. Junior Doctors Committee proposed an academy in 1994. PMID- 8696233 TI - Health, society and alcohol. PMID- 8696232 TI - Proposed medical academy. Profession should resist further fragmentation. PMID- 8696234 TI - Culture, drugs and unsafe sex: confusion about causation. PMID- 8696235 TI - Comments on Hall et al.'s Australian National Drug Strategy Monograph no. 25 "The health and psychological consequences of cannabis use". PMID- 8696236 TI - Good report but scanty research. PMID- 8696237 TI - When too much caution can be harmful. PMID- 8696239 TI - Cannabis's hidden harm. PMID- 8696238 TI - Cannabis: a note from Bengal. PMID- 8696240 TI - Cannabis: weighing up the odds. PMID- 8696241 TI - A view of alcohol policy and the public good from Turkmenistan. PMID- 8696242 TI - How to have a high success rate in treatment: advice for evaluators of alcoholism programs. AB - Two seasoned alcohol treatment researchers offer tongue-in-cheek advice to novice program evaluators faced with increasing pressure to show high success rates. Based on published examples, they advise: (1) choose only good prognosis cases to evaluate; (2) keep follow-up periods as short as possible; (3) avoid control and comparison groups; (4) choose measures carefully; (5) focus only on alcohol outcomes; (6) use liberal definitions of success; (7) rely solely upon self report and (8) always declare victory regardless of findings. PMID- 8696243 TI - Explaining abstinence rates following treatment for alcohol abuse: a quantitative synthesis of patient, research design and treatment effects. AB - We examined the relationships of treatment, patient and research design characteristics to treatment outcome (i.e. abstinence rates) in a sample of 150 treatment conditions drawn from 100 alcohol treatment outcome studies published between 1980 and 1992. Treatment characteristics were related to abstinence rates: more intensive treatments had higher abstinence rates than less intensive treatments, whereas treatments with an expressed goal other than abstinence had lower abstinence rates than treatments with an abstinence goal. When the public vs. private ownership status of the treatment facility was taken into account, the presence of behavioral elements in the treatment condition also was related to higher abstinence rates. Because of inconsistent reporting in primary studies, we assessed the effects of only one patient pre-treatment characteristic; treatment conditions with a higher proportion of socially stable patients had better outcomes. Research design characteristics were also related to abstinence rates. Treatment conditions with shorter follow-ups and treatments drawn from studies that did not use criteria to exclude more impaired subjects had better outcomes. We discuss possible reasons why our findings regarding the effects of treatment intensity and the use of exclusionary criteria differ from those in previous reviews. PMID- 8696244 TI - Cultural orientation and adolescents' alcohol use in Zimbabwe. AB - A classroom survey was conducted in June 1994 among 3061 secondary school students in four provinces in Zimbabwe, with the main objective of measuring health behaviours, school performance and environmental and cultural factors as predictors for drug use. This paper presents an analysis of the relationship between cultural orientation and alcohol use. The survey instrument was based on previous studies undertaken in Zimbabwe and in Europe and adapted to the local situation. A two-staged stratified random sampling strategy distinguished between four different socio-cultural groups. Standardized instructions were given in classrooms by a trained research team. Respondents' mean ages were 14.9 years for boys and 15.1 years for girls, and 51.4% were boys. For a number of core questions, test-retest reliability was shown to be satisfactory. A 14-item scale focusing on language, mass media and music preferences was constructed to measure cultural orientation. Principal component analysis revealed two distinct factors with low interfactor correlation and acceptable scale reliability (alpha), one representing Western orientation and the other Zimbabwean or traditional cultural orientation. Zimbabwean orientation was found to be associated with lower alcohol use, whereas western orientation was associated with higher probability for alcohol use. PMID- 8696245 TI - The effect of a moderate dose of alcohol on the traffic hazard perception profile of young drink-drivers. AB - Hazard perception latency has been identified as one source of individual differences in road accidents, but alcohol's effects on hazard perception has not been addressed thoroughly. Furthermore, individuals convicted of driving while impaired (DWI), in comparison with other drink-drivers, have been found to possess a poor driving record, suggesting that they may also respond poorly to hazards. Therefore, this research studied young drivers across the spectrum of drink-driving practices, from non drink-drivers to DWI offenders. It examined alcohol's effects on their hazard perception profile, including aspects of both driving skill (hazard perception latency) and driving style (the perceived level of risk in hazards). Thirty-two subjects aged 18-25 years underwent two experimental conditions in a counterbalanced design: no alcohol and moderate alcohol. Alcohol was found to affect both driving skill and driving style. With a 0.05% BAC subjects took longer to detect hazards and responded to them in a more abrupt manner and these effects were particularly pronounced for DWI offenders. The results also supported a distinction between active hazards (hazards arising from the driver's own actions) and passive hazards (hazards arising from the actions of other road users). Irrespective of their drink-driving practices, subjects perceived active hazards as less dangerous than passive hazards. Furthermore, compared with other drink-drivers, DWI offenders perceived less risk during passive hazards (with a 0.05% BAC) and active hazards (when sober). It is suggested that these effects may underlie, at least in part, the increase in accident risk associated with impaired driving. PMID- 8696246 TI - Combining methods to identify new measures of women's drinking problems. Part I: The ethnographic stage. AB - In recent years, some researchers in the alcohol survey field have raised concerns about the shortcomings in severity/frequency scales for drinking and drinking problems used for both clinical and household survey purposes, especially with regard to women. This article reports on Part I of a two-part study that used ethnographic and survey methods to assess indicators of drinking problems among women across various US subcultures. Methodology for the ethnographic component consisted of three steps: analysis of findings in literature on indicators of women's drinking problems, and analysis of indicators addressed in the most commonly used standard instruments for alcohol assessment; semi-structured interviews with 12 specialists in treatment and/or research who focused on alcohol problems of women; and semi-structured interviews with 65 women from four ethnic populations who were clients in alcohol treatment centers. Analysis of these data from the ethnographic component produced a taxonomy of indicators of women's drinking problems and fourteen novel indicators that are not included or are inadequately examined in the most commonly used alcohol assessment instruments. The novel indicators were then incorporated into a questionnaire used for a county-wide survey of men and women that assessed indicators of drinking problems. Report of findings from the survey are presented in the second paper of this series. PMID- 8696247 TI - Black identity and drinking in the US: a national study. AB - The relationship between ethnic identity and drinking patterns was explored in 1947 black adults from a nation-wide study of drinking behavior. Factor analysis revealed that a multi-dimensional construct which included four factors-media preferences, socio-political awareness, endogamy and social networks-was necessary to operationalize and measure the concept of ethnic identity. Using structural equation modeling, a model was tested which analyzed the impact of ethnic identification on religiosity and drinking norms, which in turn were predictors of drinking and heavier drinking latent variables. The results showed that ethnic identity influenced drinking behavior indirectly through its effects on drinking norms and religiosity as well as directly. Most aspects of ethnic identity decreased drinking levels. Respondents who scored higher on involvement with black social networks and black social and political awareness drank at lower levels than other respondents. These results were attributed to the prevalence of norms for abstinence and high levels of social control regarding drinking in black communities. However, high scores on using black media increased drinking rates. It was suggested that the promotion of alcohol use in black orientated media as well as the social settings attended by those who prefer black media might increase alcohol consumption. PMID- 8696248 TI - Validity of the SCID in substance abuse patients. AB - Structured or semi-structured interviews, including the Structured Clinical Interview for DSM-III-R (SCID), are used widely to maximize the reliability and validity of psychiatric diagnoses. Although the reliability of such interviews appears adequate, there has been little effort to evaluate their validity. In a sample of 100 substance abuse patients, we evaluated the concurrent, discriminant and predictive validity of SCID substance use diagnoses, as well as co-morbid disorders that occur commonly among these patients. The validity of current and life-time substance use diagnoses obtained by a research technician using the SCID was good; it was moderate for antisocial personality disorder and major depression and poor for anxiety disorders. Although accurate diagnosis of substance use disorders in substance abuse patients can be accomplished by a research technician, the diagnosis of co-morbid psychiatric disorders requires either additional expertise or the use of a diagnostic instrument specially designed for that purpose. PMID- 8696249 TI - Cannabis use correlates with schizotypy in healthy people. AB - Cannabis use or high scores on self-report schizotypy questionnaires predict an increased risk of developing clinical psychosis. We tested whether cannabis use correlated with schizotypal and other personality traits in 211 healthy adults. Subjects who had used cannabis showed higher scores on schizotypy, borderline and psychoticism scales than never-users. Multivariate analysis, covarying lie scale scores, age and educational level indicated that high schizotypal traits best discriminated subjects who had used cannabis from never-users, whether or not they reported having used other recreational drugs. These results indicate that cannabis use is related to a personality dimension of psychosis-proneness in healthy people. PMID- 8696250 TI - Smoking a cigarette has no effect on visual temporal order discrimination in regular smokers. AB - A temporal order discrimination task was performed by 20 regular smokers who were tested with and without a pre-test cigarette in a repeated measures design following overnight abstinence. Subjects were asked to discriminate the temporal order of the rapid sequential illumination of two lights positioned equidistant from a central fixation point. None of the measures of performance in this task were significantly affected by smoking. PMID- 8696251 TI - Sensitivity of ribosomes from Agrobacterium tumefaciens to the ribosome inactivating protein crotin 2 depending on the translocational state. AB - The GTP analog guanylylmethylene diphosphonate (GppCH2p) strongly inhibited polyuridylic acid-directed polypeptide synthesis in a cell-free translation system prepared from Agrobacterium tumefaciens. Fusidic acid increased even further the inhibitory action. The pre-translocational ribosomal complexes formed with the GppCH2p and the elongation factor G protected the ribosome against the depurinating action of crotin 2 assayed as the acid-dependent release of the RNA fragment whose terminal sequence is 5'-GAGGACCGGGAUGGAC-3'. The results allowed to conclude that the interaction of both crotin 2 and the elongation factor G with the A. tumefaciens ribosomes in the pre-translocational state must take place at overlapping, either sterically or allosterically, ribosomal sites which are equally accessible to the RIP. PMID- 8696252 TI - The distribution of Ag-NORs proteins and ribosomal RNA genes in human spermatogonia: an original procedure associating silver-staining, fish and confocal microscopy. AB - It is generally accepted that Ag-NORs proteins are associated with nucleolar components engaged in rRNA synthesis. Since conflicting results have been reported concerning the intranucleolar sites of active ribosomal genes, the relationships between the silver-stained areas and the distribution of rDNA were analyzed in human spermatogonia using confocal microscopy of fluorescent in situ hybridized preparations previously stained with silver. The fluorescent signal strictly corresponded to the silver-stained area, identified at the ultrastructural level as the fibrillar center and the surrounding dense fibrillar component. A quantitative evaluation of nucleolar activity solely based on silver staining may be misleading, taking into account that only Ag-positive proteins located in the dense fibrillar component can be associated with transcriptional activity, while those stored in the fibrillar center are associated with non transcribed rRNA genes. PMID- 8696253 TI - Distribution of hepatic glycosaminoglycans during acute schistosomiasis: modulation by IFN gamma treatment. AB - An important pathological outcome of schistosomiasis is hepatic fibrosis, with a significant deposit of collagens and proteoglycans. In this study, hepatic and granuloma-associated glycosaminoglycans (GAGs) were analyzed both quantitatively and qualitatively at the acute stage of murine infection with Schistosoma mansoni. The effects of IFN gamma, which has been successfully used for reducing collagen deposition in the liver during schistosomiasis, were also analyzed in granulomas and the surrounding liver parenchyma. Acute schistosomiasis resulted in a 4.4-fold increase in total hepatic GAG content, from which granulomatous GAGs--mainly chondroitin sulfates A/C and B--represented only one sixth of total GAGs amount. Therefore, the increase was found predominantly in the parenchyma. In this compartment, qualitative changes were also induced with a marked increase in the proportion of chondroitin sulfates A/C balanced by a decrease in the proportion of heparan sulfate and dermatan sulfate. IFN gamma reduced parenchymal GAG content by 47%. Qualitatively, the cytokine increased the proportion of heparan sulfate and reduced the quantity of chondroitin sulfates A/C by half in this compartment. By contrast, IFN gamma had neither quantitative nor qualitative effect on fibroinflammatory granulomas. In these structures, the absence of heparan sulfate--which is suspected to mediate IFN gamma activity--might explain these observations. PMID- 8696254 TI - Short-term effects of secretagogues on the mouse parotid and sublingual gland tissular water. AB - The effects of isoproterenol and pilocarpine on the tissular water of mouse parotid and sublingual glands were studied by thermogravimetry (TG) coupled with Fourier transform infrared spectroscopy (FTIR). Results demonstrated that the short-term effects partly resemble the long-term action of these substances on the above-mentioned organs. Due to the different stages examined, it is difficult to speculate on the comparison between previous and the present findings. The original data resulting from the present research corresponded to the dimorphism expressed in the thermoanalytical profile of the parotid glands treated with secretagogues. PMID- 8696255 TI - Evidence of true protein kinase CKII activity in mitochondria and its spermine mediated translocation to inner membrane. AB - A true protein kinase CKII (CKII) activity was characterized in liver mitochondria by its phosphorylating activity on the specific peptide substrate of CKII, the binding and elution profile of the enzyme on a phosphocellulose column and immunostaining of a 36 kDa polypeptide with antibodies against the alpha subunit of human CKII. This CKII activity was located predominantly in the intermembrane space of quiescent mitochondria. A translocation of the enzyme to inner membrane of energized mitochondria occurred in the presence of spermine. Translocated CKII activity was tightly bound to inner membrane, and high salt concentrations were necessary to release the activity. The inner face of the inner membrane could constitute the in vivo localization of mitochondrial CKII since the potential substrates of the enzyme are 4 matrix proteins. PMID- 8696256 TI - Thymocyte proliferation-inducing activity of high molecular weight fraction from the culture supernatant of thymic epithelial cell line established from normal rat thymus. AB - Precursor T cells originated from bone marrow proliferate, differentiate and maturate (thymic education process) to relatively mature T cells under the influence of thymic epithelial cells (TECs). Thymic hormonal factors (THFs) released from TECs presumably play a pivotal role in the thymic education. The THFs related to the thymocyte differentiation and maturation were carefully examined and some of them identified. However, the relation of THFs with thymocyte proliferation (TPIFs) are poorly understood. Consequently we attempted to study the activities of TPIFs under physiological conditions. In this investigation, we employed a TEC line derived from normal rat thymus, disposable reversed-phase column cartridge for concentrating the culture supernatant of TEC (TECS) and high-performance liquid chromatography. By separating TECS sample with ion exchange chromatography, the thymocyte proliferation-inducing activity (TPIA) was efficiently separated from the thymocyte proliferation-suppressing activity. The TPIA was detected in the fraction with high molecular weight (198 to 310 kDa) by gel filtration chromatography. The TPIA was completely reduced by trypsin digestion, while heat-treatment affected only slightly the TPIA. PMID- 8696257 TI - Regional differences in the distribution of catalase in the epithelium of the ocular lens. AB - Oxidative stress is thought to play a major role in cataract formation. The present experiments are aimed at gaining a better understanding of the systems that protect the lens from damage by reactive oxygen species. The aqueous humor normally contains hydrogen peroxide (H2O2), a compound capable of generating reactive oxygen species. The systems protecting the ocular lens from oxidative damage are primarily confined to the epithelium, a single layer of cells on the anterior side of the organ directly beneath the lens capsule. When cultured rabbit lenses were challenged with a single dose of 0.2 mM H2O2, cells in the peripheral region of the epithelium survived; those in the central region died. Here we investigate the histochemical and immunoperoxidase distributions of catalase, an enzyme which detoxifies H2O2, in cells from the peripheral and central regions of the epithelium on flat mount preparations of the epithelium. In a flat mount, the entire population of lens epithelial cells can be viewed on one preparation. The reaction product for catalase activity and its immunoperoxidase localization were more intense in peripheral epithelial cells than in cells throughout the central epithelium. Treatment of cultured lens epithelial cells or rabbit lenses with 3-aminotriazole or potassium cyanide, inhibitors of catalase, reduced or abolished the histochemical reaction product. Ultrastructural cytochemistry confirmed the presence of catalase in microperoxisomes of the epithelial cells from whole lenses. The decreased level of catalase throughout the central epithelium may account for the increased susceptibility of these cells to H2O2-induced cell death. PMID- 8696258 TI - Carbachol stimulates inositol phosphate formation transiently in Trypanosoma cruzi. AB - The effect of carbachol on Trypanosoma cruzi epimastigote forms was studied. Suspension of epimastigote cells prelabelled with myo[3H]-inositol were incubated at 28 degrees C in the presence of carbachol. The levels of inositol phosphate after the challenge of carbachol were determined to see if the accumulation of inositol phosphate was time-dependent. In the presence of Li+ the levels of IP3 and IP4 were significantly increased during the 3 min. with a peak at 1 min. after the carbachol challenge. This effect was suppressed by atropine. The results show that carbachol influences rapid changes in phosphoinositide metabolism and they are time-dependent involving second-messenger systems associated with the generation of IP3. In addition they would suggest that this IP3 generation is through a receptor-mediated process linked to phospholipase C by a G-protein. PMID- 8696259 TI - Suppression of glucocorticoid-induced thymocyte apoptosis by co-culture with thymic epithelial cells. AB - There are many reports concerning glucocorticoid-induced thymocyte apoptosis, but little is known about the participation of thymic stromal cells, especially the thymic epithelial (TE) cells, in the apoptosis. In this study, we investigated the in vitro effect of TE cells on dexamethasone-induced DNA fragmentation of thymocytes as a parameter for apoptosis. By co-culture of thymocytes with TE cell line, at the condition without cell-cell contact, the DNA fragmentation of thymocytes caused by physiological level of glucocorticoid was significantly suppressed. Same effect was detected when treated the thymocytes with the supernatant from the cultures of TE cell line. These results suggest that the humoral factors released from TE cells rescue the thymocytes from the glucocorticoid-induced apoptosis. Chemical and physico-chemical nature of the factors are discussed. PMID- 8696260 TI - Transformation of Aspergillus nidulans by RNA from rat macrophages stimulated with lipopolysaccharide. AB - Exogenous RNA molecules can be incorporated into eukaryotic cells and can exert a variety of biological effects. We have previously described a model system for correcting genetic alterations of an Aspergillus nidulans mutant using homologous RNA and this phenomenon was named retrotransformation. In the present study, the retrotransformation of A. nidulans was performed with heterologous RNA which was extracted from rat macrophages stimulated with lipopolysaccharide (LPS). Protoplasts of A. nidulans were treated with this mammalian RNA and retrotransformants were detected by their ability to secrete the neutrophil recruitment inhibitory factor (NRIF) which is released by LPS-stimulated macrophages. Twenty two retrotransformant colonies were analyzed and only two retrotransformants, named RT1 and RT2, were able to secrete NRIF. The occurrence of sectors (RT1.1, RT2.1 and RT2.2) in retrotransformants RT1 and RT2 is due to mitotic instability which can be accompanied by loss of genomic extra-segments. The three sectors detected did not exhibit NRIF activity possibly due to loss of the NRIF gene present in the genome of retrotransformants RT1 and RT2. The NRIF like material secreted by RT2 shows the same lectin property and biological activity of NRIF released by LPS-stimulated macrophages. To date, this work is the first example of retrotransformation described in lower eukaryotes with heterologous RNA. PMID- 8696261 TI - Demonstration of NADPH-diaphorase (NO-synthase) in sebaceous glands of the mammalian integument, with remarks on the glandular capillary net. AB - The study demonstrates weakly to strongly positive reaction staining for NADPH diaphorase/NO- synthase in the peripheral cells of sebaceous glands in the hairy skin of domesticated mammals. Additionally, the structure of the blood capillary system surrounding these glands is better elucidated. The results obtained are discussed in view of a modulatory action of NO generated by these enzyme activities, implying a direct influence of this substance on the contractile elements of gland-associated blood capillaries. In this way, a simple and self regulatory mechanism to couple blood flow and glandular metabolism can be proposed. PMID- 8696262 TI - Anti-tumor effect of splenocytes treated with RNA from animals immunized with bovine myelin basic protein. AB - Chemically and immunologically, myelin basic protein (MBP) is very similar with the basic protein extracted from animal and human tumors. The results of this study demonstrated that splenocytes from C57BL/6 mice bearing B16 melanoma cells are sensitized to MBP, suggesting that this protein may share common antigenic determinants with antigens from B16 melanoma cells. The RNA preparations isolated from lymphoid tissues of normal or immunized guinea pigs with bovine MBP are referred to as N-RNA or MBP-RNA, respectively. It was also found that MBP-RNA is active in transferring MBP reactivity to normal splenocytes whereas N-RNA had no effect. To investigate whether this transfer to MBP immunoreactivity could result in a protective immunity, C57BL/6 mice transplanted with B16 melanoma received normal splenocytes treated with N-RNA or MBP-RNA. Two weeks after injection of B16-F10 cells, the mice were sacrificed and the tumor of each animal was removed and weighed. A significant inhibition of B16 melanoma growth was only achieved in C57BL/6 mice treated by splenocytes incubated with MBP-RNA which acts as an anti tumor RNA. In this context, MBP could be considered as a tumor antigen. PMID- 8696263 TI - Study on DNA synthesis of aging mouse colon by light and electron microscopic radioautography. AB - Aging changes of DNA synthesis and of ultrastructure in mouse colon were analyzed by light and electron microscopic radioautography. The sites of 3H-thymidine uptake were identified in each layer of the colon. The highest labeling index (LI) of the epithelial cells was found at embryonic day 19; it decreased from neonatal day to 1 week and then remained on a constant value until 1 year. The LI's of the other layer cells were high at prenatal day 19, followed by a decrease with the development of the colon disappearing between 2 and 6 months after birth. The LI of the inner circular muscle layer was in every experimental age group higher than that of the outer longitudinal layer. The LI of vacuolated cells, high in the late embryonic and neonatal periods, decreased significantly between 3rd and 8th day and then remained unchanged until the old stage. The LI of the goblet cells showed a peak at prenatal day 19, decreased afterwards with time and disappeared 2 months after birth. The ultrastructural aspects showed that many silver grains located over the nuclei of the labelled cells which contained less cell organelles, in their cytoplasm as compared to unlabelled cells. PMID- 8696264 TI - In vivo uptake of Cu, Zn superoxide dismutase. Morphological evidence for preferential endocytosis and accumulation by sinusoidal liver cells. AB - Bovine Cu, Zn superoxide dismutase (SOD), conjugated to colloidal gold, was intravenously administered to rats and its distribution studied by electron microscopy. Liver was the preferential site of accumulation of gold-labelled SOD. Among liver cells types, Kupffer and endothelial cells showed the presence of the protein earlier than hepatocytes. Uptake by kidney showed slower kinetics than liver. No uptake by heart could be detected. The gold-labelled SOD was localized inside coated pits, coated vesicles and other non-coated endocytic compartments. Absence of binding by BSA-gold complexes and competition between free SOD and the gold-labelled one demonstrated the specificity of the uptake process. Our morphological evidences suggest that in vivo internalization of SOD occurs most likely through receptor-mediated endocytosis. PMID- 8696265 TI - Radioautographic studies on aging change of DNA synthesis and the ultrastructural development of mouse adrenal gland. AB - In this paper the DNA synthesis changes as well as ultrastructural aspects of the endocrine cells of the mouse adrenal gland from the 19th prenatal day until 2 years of life have been examined. The percentage of the labelled cells after injection of tritiated thymidine was maximal in the zona glomerulosa and in the medullaris at the 19th embryonic day whereas it was at the first postnatal day in the zonae fasciculata and reticularis, decreasing thereafter, reaching a low level on the 14th postnatal day. From the first month of life onwards, the labeling indices in both cortex and medullaris remained low, without significant differences in the different groups of age, but some regional differences. The number of labelled cells in the zona glomerulosa was higher than in both other cortex zones from the 19th embryonic day to the first day postpartum, whereas the labeling index (LI) was higher in the medullaris during the early postnatal period. At these embryonic and early postnatal periods the ultrastructural aspects appeared undeveloped, but abundant cell organelles like smooth endoplasmic reticulum, mitochondria with tubular or vesicular cristae and lipid inclusions could be observed in all three cortical zones, from two weeks onwards. A comparison has been attempted between the DNA synthesis and EM: the ultrastructural development. PMID- 8696266 TI - [Cherubism and surgery]. AB - Cherubism is a hereditary bone disease, increasing the volume of both cheeks (whence the name, alluding to Renaissance paintings cherubs), during childhood. Usually cure or at least stabilisation is expected around the puberty. Some cases monstruously extensive impose a surgical management, sometimes difficult but with impressive results. PMID- 8696267 TI - [Role of kinins in local and systemic inflammatory reactions]. AB - The development of highly sensitive and specific immunoassays allowed the characterization of bradykinin and desArg9-BK metabolism in vitro. The same methods were used to study the time course evolution of the tissue content of both kinins in an carragenan inflammatory model. Quantification of T-kininogen in the same animal model allowed to show an influence of BK on the neosynthesis of this acute phase protein. PMID- 8696268 TI - [Commission "Organ Donation"]. PMID- 8696269 TI - [Biology of bovine pestivirus infection responsible for mucosal disease]. AB - The virus BVD/MD belongs to the genus pestivirus from the family Flaviviridae, as well as viruses responsible for hog cholera and border disease. BVD/MD virus is responsible for two distinct disease entities in cattle: bovine virus diarrhoea (BVD), which is characterized by high morbidity and low mortality, and mucosal disease (MD) which is sporadic but highly fatal. BFV/MD virus exists under two biotypes among which antigenic pairs: a non cytopathic and a cytopathic biotypes. These biological characters are purely cultural and do not correspond to the in vivo pathogenic behaviour. Recent experiments from our group show that the two biotypes of a same antigenic pair differ by their biological properties in the target animal. The cytopathic strain, contrary to the non cytopathic one, induces belated both humoral and cellular immune responses. Only non-cytopathic strain produces viraemia and nasal excretion. These results confirm the fact that non cytopathic strains represent an epidemiological dead end. These results also permit to envisage a logical modelisation of the infection at a population level. PMID- 8696270 TI - [Polyamines and cell growth: specific aspects in Amoeba proteus and in certain cancer cell lines]. AB - The differences between the metabolic schemes of polyamines can be the starting point to investigate the discovery of new antiparasitic or anticancer drugs which would be cell type specific. The studies, which were undertaken with the P388 cancer cells and Amoeba proteus, have shown that the pool of polyamine was very different in both cell types. Moreover, the cytotoxicity of putrescine, spermidine, spermine and 1-3 diaminopropane was found to be dependent of the activity of cell enzymes which could play a role to control cell proliferation by producing toxic metabolites. PMID- 8696271 TI - The Committee to Advise on Tropical Medicine and Travel (CATMAT) and the National Advisory Committee on Immunization (NACI). Preliminary conjoint statement on oral cholera vaccination. PMID- 8696272 TI - Cholera in British Columbia. PMID- 8696273 TI - Cholera in Africa. PMID- 8696274 TI - New variant of Creutzfeldt-Jakob disease (V-CJD)--France. PMID- 8696275 TI - The lottery of long-term care. PMID- 8696276 TI - 'It's a lifeline'. PMID- 8696277 TI - Psychological factors of rehabilitation. PMID- 8696278 TI - Promoting a personal plan of care. PMID- 8696279 TI - Health assessment of people over 75. PMID- 8696280 TI - Call for early diagnosis in continence care. PMID- 8696281 TI - Room for improvement. PMID- 8696282 TI - ENs: qualification in question. PMID- 8696283 TI - 'Flaunt a noisy pride' in your work. PMID- 8696284 TI - Fast Track recovery after aortocoronary bypass surgery: early extubation and intensive care unit transfer. AB - Fast Track is a practical method of delivering care to aortocoronary bypass (ACB) patients with minimal risks to the patients or their care providers. A prospective study designed by an interdisciplinary practice team will evaluate the effects of an accelerated recovery program on clinical and financial outcomes of ACB patients. Essential components of the accelerated recovery program include early extubation, accelerated activity, and appropriate patient selection. Preliminary results on early extubation are discussed. PMID- 8696285 TI - Evaluating financial outcomes in perioperative services. AB - Analyzing and managing key budget outcomes such as operating room use (routine and emergency), room turnover, labor costs per hour, supply costs per hour, and cost per case by specific surgeon is critical to improving productivity and efficiency in the perioperative service. PMID- 8696286 TI - Outcomes management: driving enhancement of interdisciplinary practice with outcomes research. PMID- 8696287 TI - Staffing outcomes: skill mix changes. AB - Skill mix changes can have a severe impact on patient outcomes. In recent years, changes in staffing patterns have been necessitated by an effort to reduce the cost of health care. The increased use of Unlicensed Assistive Personnel has raised the question of what is a safe-cost-effective skill mix. PMID- 8696288 TI - An outcomes approach to designing an orthopedics prosthetics inventory management process. PMID- 8696289 TI - Team building for continuous quality improvement. AB - The effective use of teams is becoming critical to problem solving and cost effective management of complex processes. This report suggests a set of critical success factors to guide the nursing manager from team design through team maintenance. These factors should be considered a framework from which to develop an organizationally appropriate approach to the management of teams. PMID- 8696290 TI - Interdepartmental collaboration: focus on outcomes. AB - Building effective interdisciplinary teams depends on interventions to create a shared vision of the future, to clarify roles and relationships, and to establish a culture of positive change. PMID- 8696291 TI - Physiology of the Hypothalamus: Feeding, Drinking, Learning, Autonomic and Immune Regulation. Symposium proceedings. Santiago de Compostela, Spain, 17 May 1995. PMID- 8696292 TI - Role of forebrain glucose-monitoring neurons in the central control of feeding: I. Behavioral properties and neurotransmitter sensitivities. AB - Extracellular single neuron recording experiments were performed in the lateral hypothalamic area (LHA), amygdaloid body (AMY) and globus pallidus (GP) of anesthetized rats and anesthetized or alert rhesus monkeys during microelectrophoretic administration of different neurochemicals including glucose. Neuron activity in the behaving primate was also investigated during a conditioned bar press alimentary task, as well as during presentation of food and non-food objects. In the LHA, AMY and GP specific glucose-sensitive (GS) neurons were found, as their activity were suppressed by glucose. The proportion of GS neurons was approximately 29%, 11% and 14%, respectively. The GS neurons in the monkey were especially likely to respond to phase of the conditioned alimentary task, and these same neurons appeared to be particularly influenced by sensorimotor and motivational factors. LHA, AMY and GP GS neurons displayed distinct sensitivities to various neurotransmitters applied microelectrophoretically. The present results, along with previous data, indicate that a hirearchically organized network of the brainstem and forebrain glucose monitoring neurons exit and this system is involved in the regulation of feeding. PMID- 8696293 TI - Role of forebrain glucose-monitoring neurons in the central control of feeding: II. Complex functional attributes. AB - Our parallel investigations in the lateral hypothalamic are (LHA), amygdaloid body (AMY) and globus pallidus (GP) provided evidence for the existence of glucose-sensitive (GS) neurons in these forebrain regions. To examine exogenous chemosensory responsiveness of these cells, extracellular single neuron activity was recorded in anesthetized or alert rhesus monkeys and in anesthetized rats during 1) microelectrophoretic administration of chemicals and 2) gustatory and 3) olfactory stimulations. The GS cells in all three forebrain structures were more likely than the glucose-insensitive (GIS) neurons to change in firing rate in response to tastes and smells. The gustatory (and olfactory) GS neurons, compared to the non-gustatory GS or both types of GIS cells, displayed significantly higher sensitivities to catecholamines. Neurons with both "endogenous" and "exogenous" chemosensitivity were found to be topographically organized in the LHA, AMY and GP as well. While receiving further evidence for the substantial morphological and functional overlapping of the brain's glucose monitoring neural network and the central gustatory representations, on the basis of the present and previous findings, it is suggested that constituents of this complex system accomplish a simultaneous monitoring, integration and control of a broad variety of feeding-associated signals of the internal and external milieux for the biological welfare of the organism. PMID- 8696294 TI - Hypothalamic neurons are resistant to the intoxication with 3-nitropropionic acid that induces lesions in the striatum and hippocampus via the damage in the blood brain barrier. AB - Modulation of the function of the blood-brain barrier (BBB) in the hypothalamus was investigated after the intoxication with 3-nitropropionic acid (3-NPA) that inhibits the succinate dehydrogenase. 3-NPA was administered to rats for three days. Following transcardial perfusion, brain sections were studied by immunohistochemistry. On the 2nd or 3rd day after 3-NPA, strong immunoreactions for blood-borne macromolecules, IgG, appeared in the striatum and hippocampus. Glial fibrillary acidic protein (GFAP) positive astroglias distributed heterogeneously, and induced nitric oxide synthase (iNOS) positive cells appeared around the vessels. A week later, bilateral lesions were detected in these areas. In the hypothalamus, there appeared a moderate immunoreaction for IgG, but no expression of iNOS. GFAP positive astroglias were rich especially around the vessels, and no loss in microtubule-associated protein 2 (MAP2) immunoreaction was detected, suggesting an intact BBB structure and no neuronal loss following 3 NPA intoxication. Data indicate that hypothalamic neurons are resistant to 3-NPA that induces specific lesions in the striatum and hippocampus via the damage in the BBB. PMID- 8696295 TI - Central enhancement of taste pleasure by intraventricular morphine. AB - Do centrally-administered opioid agonists stimulate feeding by enhancing the palatability of foods? This hypothesis has been supported by several lines of evidence, including previous 'taste reactivity' studies of the influence of systemic morphine on affective (hedonic and aversive) behavioral reactions to taste palatability. The presents study examined whether opioid agonists enhance palatability by acting centrally on brain palatability systems. Here we report the effect of intraventricular microinjections of morphine (0, 12, 25, 50 nmols) on hedonic taste reactions to a 0.12 M sucrose solution. The effect on feeding was also assessed in order to determine whether feeding and palatability enhancement are linked, as would be required by the hypothesis that feeding is due to enhanced palatability. Both hedonic taste reactivity patterns and feeding were significantly increased together by morphine administration into the lateral ventricle. We conclude that opioid-induced enhancement of the hedonic palatability of food is a centrally mediated effect. Enhancement of food palatability may be an important psychological route by which intracranial administration of opioid agonists induce feeding. PMID- 8696296 TI - Brain mechanisms of satiety and taste in macaques. AB - Flavor is the primary reinforcer of eating. As satiety is induced, the reinforcement of flavor is lost. Since flavor derives largely from taste, one might expect gustatory responsiveness to decline with increasing satiety. However, no such loss of sensitivity occurs in humans, even as the reinforcing value of taste declines with satiety. Thus, we explored the effect of satiety on taste responses at several levels of the macaque's nervous system to determine where is influence began. Taste-evoked activity in the NTS and primary taste cortex was unaffected by the induction of satiety through or administration of glucose. Taste cortex projects to amygdala and orbitofrontal cortex (OFC). In amygdala, satiety reduced responsiveness by 58%; in OFC, neurons were fully suppressed. Both amygdala and OFC project to the hypothalamus, where taste responsiveness was also suppressed. Thus, the neural impact of food is reduced not in area devoted to quality analysis, but in those concerned with motivation and reinforcement. PMID- 8696297 TI - Heterogeneous development of voltage dependency of NMDA receptor-mediated response in central nervous system. AB - Developmental changes of voltage dependency of NMDA response were investigated on nucleus solitarii (NTS) ventromedial hypothalamic (VMH) and visual cortical neurons acutely dissociated from rats aged between 19 days in gestation (E19) and 21 days after birth (P21) using a whole cell patch clamp recording. Sensitivity of NMDA response to extracellular Mg2+ developed by P3 in the NTS, by P6 in the VMH and by P6 in the VMH and by P12 in the VMH and by P12 in the cortex, Protein kinase C modulators could not modulate the voltage dependency of NMDA response in immature neurons. These finding suggest that a regional heterogeneity of developmental change of the sensitivity of NMDA response to extracellular Mg2+ exists. This regional difference in development of NMDA response might be related to the order of vital necessities after birth. PMID- 8696298 TI - Effects of arginine-lysine mixture, glucose and ATP on the autonomic outflows to the thymus and spleen. AB - Effect of arginine-lysine mixture, glucose and ATP on the efferent activities of the vagal thymic branch and splenic nerve were studied in urethane anesthetized rat. In male Wistar rats jugular vein was cannulated for drug administration. In one group the thymus was exposed and a nerve filament of the central cut end of vagal thymus was isolated. In another group a filament was isolated from that of the splenic nerve. The nerve filament was placed on electrodes to record efferent activity before and after administration of argininelysine mixture solution, glucose or ATP solution. Enhancement of efferent activity of vagal thymic nerve was observed after i.v. administration of arginine-lysine mixture, glucose and ATP solution. Suppression in efferent activity of splenic nerve was investigated following i.v. administration of arginine-lysine mixture, glucose and ATP solution. These results suggest that i.v. arginine-lysine, glucose and ATP increase thymic lymphocyte release, and that i.v. arginine-lysine, glucose and ATP enhance NK cell activity. PMID- 8696299 TI - The hypothalamo-sympathetic nervous system modulates peripheral cellular immunity. AB - Our findings reviewed in this article have revealed that the stimulation of opioid receptors of the hypothalamic neurons by interferon alpha and beta endorphin synthesized in the brain or by stress causing the opioid-dependent analgesia suppresses the natural killer cytotoxicity, an important component of immunosurveillance, through an activation of the hypothalamic CRF-sympathetic nervous system. PMID- 8696300 TI - Roles of cytokines in the neural-immune interactions: modulation of NMDA responses by IFN-alpha. AB - Several lines of evidence have indicated that interferon-alpha (IFN-alpha) induces a variety of central actions; e.g., fever anorexia, slow wave sleep and depression. However, little is known about the cellular mechanisms by which IFN alpha affects neuronal activity. In the present article, the effects of recombinant human IFN-alpha on N-methyl-D-aspartate (NMDA)-induced responses of rat medial preoptic (MPO) neurons were examined by means of slice patch method as an in vitro model of neural-immune interactions. The results suggest that IFN alpha suppresses the NMDA responses through its action on opioid receptors and the production of free radicals such as hydroxyl radicals and nitric oxide (NO) due to the neuron-glial cell interactions. PMID- 8696301 TI - Effects of acidic fibroblast growth factor on neuronal activity of the parvocellular part in rat paraventricular nucleus. AB - The effects of acidic fibroblast growth factor (aFGF) and its amino-terminal and carboxyl-terminal fragments (aFGF(1-15) and aFGF(114-140), respectively were examined on the neuronal activity in the parvocellular part of the paraventricular nucleus. As well known, this part contains a lot of corticotropin releasing factor (CRF)-immunoreactive neurons. Application of 1 pg/ml and 2 pg/ml aFGF produced responses in 29.7% and 46.7% of neurons tested, respectively. Half or more than half of the responding neurons increased their discharge rate. Application of 0.2 ng/ml and 0.4 ng/ml aFGF(1-15) (1-15) also elicited response in 46.2% and 68.8% of neurons tested, respectively. Of these responding neurons, more than two third increased their firing rate. However, most of neurons tested for 0.67 ng/ml and 1.33 ng/ml aFGF(114-140) did not respond. Results suggest that aFGF and aFGF(1-15) promote the release of CRF through the activation of CRF containing neurons. PMID- 8696302 TI - Hypothalamus regulates calcium metabolism in rats. AB - Hypothalamic mechanisms of blood calcium homeostasis and their functional heterogeneity were investigated in rats. Electrical and chemical stimulation of the lateral hypothalamic area (LHA), the paraventricular nucleus (PVN) and the ventromedial nucleus of the hypothalamus (VMH) induced hypocalcemia. The hypocalcemic effect of PVN stimulation was suppressed by vagotomy of the thyroid/parathyroid branches, while that of LHA and VMH stimulation was eliminated by gastric vagotomy. Immobilization (IMB) stress elicited hypocalcemia through VMH-gastric vagal activation. Both IMB- and LHA stimulation-induced hypocalcemia was antagonized by muscarinic antagonist and histamine H2 blocker. The former was also blocked by alpha-blocker and gastrin release inhibitor, while the latter was antagonized by an beta-blocker. The results suggest that hypothalamic nuclei are involved in regulation of blood calcium homeostasis via the gastric or thyroid/parathyroid vagus. Muscarinic, histamine H2, adrenergic and gastrin receptors mediate the hypocalcemic effect of the hypothalamo-vagal activation depending on behavioral conditions and receptor subtypes. PMID- 8696303 TI - Osmoresponsiveness of the rat supraoptic nucleus in vivo depends on glutamatergic inputs. AB - Intracellular recording from supraoptic nucleus (SON) neurones in hypothalamic slices revealed that a 40 mOsm change in osmolality had little effect on membrane conductance. However, intracellular recordings in vivo revealed a significant increase in EPSP frequency after the plasma osmolality had been raised by approximately 10 mOsM. We recorded extracellularly in vivo from 18 antidromically identified SON neurones in urethane-anaesthetised male Wistar rats, while hypertonic saline was infused intravenously (1.05M NaCl, 50 microliters/min for 35 minutes). In 9 experiments an intracerebroventricular (ICV) injection of 5 microliters 10mM kynurenic acid was given 5 minutes prior to start of the infusion. Kynurenate significantly reduced the osmotic response (P < 0.001, Student's t-test); the rat of increase in spike frequency was reduced from 0.089 +/- 0.004 Hz/min (n = 9) to 0.035 +/- 0.003 Hz/min (n = 9). Kynurenic acid did not reduce the basal firing rate of SON neurones, but in osmotically stimulated neurones, it reduced the firing rate to basal levels. Hence the osmoresponsiveness of SON neurones depends on a glutamatergic input that is independent of mechanisms that maintain basal electrical activity. PMID- 8696304 TI - Inhibition of nitric oxide synthase attenuates osmotic thirst in the rat. AB - Changes in water intake after intraperitoneal injection of a nitric oxide synthase (NOS) inhibitor was studied in the rat. Administration of NW-nitro-L arginine methyl ester (L-NAME) at a dose of 50 mg/kg attenuated osmotic thirst induced by intraperitoneal injection of hypertonic saline, but did not affect spontaneous intake of water and thirst induced by subcutaneous injection of angiotension II. Pretreatment with L-arginine significantly attenuated the inhibition of osmotic thirst evoked with subsequent L-NAME. Administration of NW nitro-D-arginine methyl ester (D-NAME) altered neither the spontaneous nor the osmotic drinking behavior. These findings suggest that NO may affect the osmotically induced drinking. PMID- 8696305 TI - Acidic fibroblast growth factor protects memory and immunoreactivity impairment in senescence accelerated mice. AB - Subcutaneous injection of aFGF once per a week into senescence accelerated mice (SAM)P8 was begun at 3 weeks after birth and continued for 10 months. Saline was injected as a control. Learning and memory and cellular immunological functions in the aFGF (F) group were enhanced significantly and while those of the saline (S) group deteriorated. The number of cholinergic neurons was decreased slightly and choline acetyltransferase activity in individual neurons in the medial septum which send monosynaptic terminals to the hippocampus was significantly decreased in the S group, but were more spared in the F group. The MAO-B activity was significantly lower in the F group than in the S group. The respective densities of muscarinic and NMDA receptors and the aFGF receptor, i.e. FGFR-1 in the hippocampus were also significantly higher in the F group than in the S group. The delayed type hypersensitivity reactions (DTH) in the footpad caused by challenge with trinitrophenyl or sheep red blood cells as measured at the end of the 2nd and 7th months, indicated the T cell immune response. Both types of DTHs were reduced in the 7th month as compared with the 2nd month in the S group. However, aFGF administration protected against this reduction in response with age. These results show that aFGF provides protection against impairment of not only learning and memory but also the DTH immunoreactivity in SAMP8, indicating thereby a close relationship between learning-memory and T cell immune function. PMID- 8696306 TI - Reflections of a "senior physiologist": bridge over the Pacific ocean. PMID- 8696307 TI - Effects of hypothalamic paraventricular nucleus: electrical stimulation produce marked analgesia in rats. AB - The effect of the electrical simulation induced analgesia (ESIA) on the hypothalamic paraventricular nucleus (PVN) was investigated by the paw pressure test, which was used to avoid any tissue damage to the paw of Wistar-SPF/VAF male rats. A stimulating electrode was chronically implanted in the parvocellular (PVN prv) or magnocellular (PVN-mgn) divisions of the PVN. The ESIA was examined at least 10 days after surgery. The electrical stimulation of the PVN markedly showed analgesia (ESIA), but stimulation of most locations outside the PVN did not produce ESIA. Stimulation threshold for the ESIA was lower from PVN-prv than from PVN-mgn, but neither region was affected by naloxone administration (10 mg/kg, i.p.). These results indicate that the PVN is a part of the pain inhibitory system in the CNS, and show that PVN-ESIA might not be mediated either by opioids or by neuropeptides such as vasopressin. PMID- 8696308 TI - Predatory aggression induced by hypothalamic stimulation: modulation by midbrain periaqueductal gray (PAG). AB - Adequate electrical stimulation of extreme lateral hypothalamic regions of healthy, non-aggressive male cats was employed to produce aggression on live but anaesthetized rats. Stimulus response (S-R) curves based on scoring systems for both somatic and affective display components of behaviour were used to assess how manipulation of midbrain PAG by electrocoagulative lesions or drug microinjections affected the sensitivity of attack producing hypothalamic loci. Anodal lesions of dorsal PAG and adjoining tectum increased the excitability of hypothalamic loci producing predatory attack. Microinjection of 250 ng of delta alanine-methionine enkephalin (DAME) in dPAG completely suppressed the somatomotor components of attack behaviour and markedly inhibited the affective display components. Administration of naloxone, an opioid antagonist (1 microgram) at the same sites facilitated the hypothalamically induced attack behaviour and annulled the inhibitory effect of DAME. These findings indicate the involvement of midbrain enkephalinergic mechanisms in the modulation of predatory attack behaviour elaborated by hypothalamic stimulation. PMID- 8696309 TI - Cardiovascular system related peptides and hypothalamic neurons. AB - The hypothalamus is known to be an integrative site of cardiovascular, endocrine and autonomic functions. Our previous studies, using extracellular, intracellular and/or whole cell patch-clamp recordings in rat hypothalamic slice preparations, revealed that cardiovascular related peptides such as atrial natriuretic polypeptides (ANP), B-type polypeptides (BNP), endothelin (ET), angiotensin II (AII) and interleukin-1 beta (IL-1 beta) influence the hypothalamic neurons. ANP modulated the firing rates in the supraoptic nucleus (SON). BNP inhibited the SON neurons and these effects were mediated through cGMP and cGMP-dependent protein kinase. ET also inhibited approximately 60% of SON neurons. By using slice patch clamp techniques, AII inhibited the transient outward potassium current in the SON neurons. IL-1 beta increased the firing rate and depolarized the membrane of the most SON neurons. A new type of transmitter, nitric oxide (NO), identified as an endothelial-derived relaxing factor (EDRF), modulated the glutaminergic inputs of the SON neurons. The results suggest that cardiovascular related peptides and NO modulate the neuronal activity of neurosecretory cells in the SON. PMID- 8696310 TI - Constructing arousal profiles for vegetative state patients--a preliminary report. AB - Arousal profiles are a method that we have developed for using data derived from time sampling to examine how behaviours such as the frequency with which the eyes are observed open, and the frequency of spontaneous movements, vary in the periods immediately before and immediately after sensory stimulation treatment. We believe changes in such behaviours reflect changes in arousal. The use of this new technique is illustrated with examples from a pilot study using data from 15 day treatment blocks, gathered for 10-minute periods immediately before and after sensory stimulation treatment from three patients using single-case research methods. The patients were diagnosed as being in vegetative state following traumatic brain injury. The possible significance of the differing characteristics of the profiles is discussed. PMID- 8696311 TI - Late rehabilitation for closed head injury: a follow-up study of patients 1 year from time of discharge. AB - Subsequent to the setting up of an outpatient psychological service for head injured patients, 50 patients were interviewed a year from the time of their discharge from our neurorehabilitation unit. The problems which persisted at this stage are presented and discussed. Some of the difficulties encountered in the evaluation of rehabilitation effects are identified. We conclude that: (1) there is a desperate need in the UK for more long-term support and rehabilitation services for this group of patients and (2) it is essential that such services are carefully monitored and evaluated despite the difficulties involved. PMID- 8696312 TI - Clients' view of neuropsychological rehabilitation. AB - Postacute neuropsychological rehabilitation cannot be done successfully without the personal engagement of the brain-injured client. However, systematically collected data referring to clients' satisfaction with rehabilitation programmes are rare. In this study a structured interview was developed to assess various aspects of treatment evaluation by clients. In addition, handicap was judged by primary therapists. An aetiologically mixed sample of 130 mildly to moderately brain-injured clients undergoing a comprehensive neuropsychological rehabilitation programme was investigated. About two-thirds of the sample seemed content with the training programmes whereas a minority (13%) of mostly highly handicapped persons reported being largely discontented. In this respect no differences between cognitive, speech/language, and physical therapies were found. Even though many subjects were satisfied with the programme, a majority of clients desired a substantial amelioration in the future (80%), judged their life quality as reduced in comparison to the time preceding brain injury (77%), reported difficulties in accepting 'deficits' (52%), and were frightened of becoming dependent on others (52%). PMID- 8696313 TI - Staff stress in head injury rehabilitation. AB - Recent research has suggested that staff working with head-injured (HI) patients experience higher levels of psychopathology than those working with non-HI patients, mirroring findings obtained with relatives of HI subjects. The present study examined this issue further while controlling for the influence of a range of occupational and extraneous, non-occupational factors which moderate the experience of staff stress. The results indicated that nurses involved in the rehabilitation of HI patients did not differ significantly from those working with non-HI patients on measures of overall stress, job satisfaction or psychopathology. The implications of these findings are discussed, with particular relevance to the potentially important protective effect of staff patient ratios. PMID- 8696314 TI - Trends in incidence of hospitalization for traumatic brain injury in Wisconsin from 1989 through 1992. AB - To aid in determining health care service needs, Wisconsin Department of Health and Social Services (DHSS) data on Wisconsin hospital discharges for traumatic brain injury (TBI), using ICD-9-CM codes for intracranial injury with and without skull fracture, and Wisconsin Department of Transportation data on incapacitating non-fatal head injuries (INHI) from traffic accidents from 1989 through 1992 were reviewed. Yearly TBI hospital discharges in Wisconsin declined 15.0%, and by 23.9% for Milwaukee County residents, over 1989 through 1992, correlating closely with changes in yearly INHI in Wisconsin (r = 0.999; p < 0.01) and in Milwaukee County (r = 0.989; p < 0.05). Using 1990 census data the yearly TBI risk ratio for Milwaukee County residents compared to the rest of Wisconsin increased from 1989 (1.76) to 1990 (1.92) and then decreased in 1991 (1.83) and 1992 (1.51). The results of this pilot study suggest there was a decrease in the incidence of hospitalization of patients with TBI in Wisconsin from 1989 through 1992, paralleling a decline in INHI from motor vehicle accidents. There appeared to be a relatively greater decline in these patients in Milwaukee County from 1991 to 1992 as compared to the rest of the state. The techniques employed in this study may be used to help assess rehabilitation service needs in other areas. PMID- 8696315 TI - Amphetamine in recovery from brain injury. AB - A chart review of dextroamphetamine treatment in 27 traumatic brain injury patients during rehabilitation therapy suggests that amphetamine treatment enhanced the recovery and functional status of 15 patients. PMID- 8696316 TI - Late cognitive and behavioural improvement following treatment of disabling orthopaedic complications of a severe closed head injury. AB - Interactions of physical, emotional, cognitive and behavioural impairments after severe closed head injury (CHI) remain poorly understood. A 47-year-old man was referred to our department 13 months after a severe CHI. He demonstrated severe left hemiplegia and disabling orthopaedic complications (left hip infectious arthritis, after surgical treatment for heterotopic ossification). His hip was blocked and extremely painful. He was totally dependent for daily-life activities (Functional Independence Measure (FIM) score = 18). Moreover he exhibited severe cognitive and behavioural troubles, which had been stable for many months beforehand, e.g. complete disorientation for time and place, major memory disorders, agitation, anxiety, depression, irritability, disinhibition, aggressiveness and lack of initiative. Pain disappeared within a few weeks after treatment. Progressively, functional improvement occurred (sitting position, transfers, walking between parallel bars). The FIM score increased to 63. Aggressiveness, irritability and agitation disappeared. Surprisingly, neuropsychological assessment demonstrated parallel improvement of cognitive functions, especially in regard to orientation, and to a lesser degree attention and memory. Such an observation should encourage use of active treatment of physical disabilities, even in patients presenting with an apparently poor cognitive prognosis at a late stage of severe CHI. PMID- 8696317 TI - Hemiballismus following closed head injury. AB - Movement disorders are relatively rare after closed head injury (CHI), but when present they can go unrecognized if clinicians are not aware of their occurrence. We are presenting a case of hemiballismus which was not recognized over 3 years and was labelled as malingering or as psychosomatic. The symptoms have responded significantly to pharmacological interventions. The SPECT scan of the brain showed the lesions in the subthalamic areas while MRI, CT scans of brain and EEGs were reported normal. It is concluded that one should be aware of the existence of movement disorders after mild to moderate CHI, and that SPECT scan of the brain should be considered if a patient is symptomatic and other neuroimaging studies prove 'normal'. PMID- 8696318 TI - Attention deficits and dual task demands after mild traumatic brain injury. AB - Attention deficits are a prominent aspect of cognitive dysfunction after mild traumatic brain injury (MTBI). Patients frequently complain of distractibility and difficulty attending to more than one thing at a time, and several neuropsychological studies have found evidence for a specific attention deficit without general neuropsychological impairment. The present study examined the nature of attentional disturbance after MTBI using an extended version of the 2 and 7 Test, which introduced two conditions reflecting patients' subjective complaints: the ability to perform with background 'noise', and while simultaneously attending to a secondary task. The dual task demands produced a significant slowing in processing speed for both the MTBI patients and control subjects. However, the relative decline in processing speed appeared much greater for the patients with MTBI, and they differed from control subjects only in this condition. The results are consistent with findings that patients with MTBI exhibit relatively subtle cognitive deficits which are apparent primarily under conditions which require effortful or controlled cognitive processing and exceed their available cognitive resources. Thus, the attentional deficits apparent during dual task demands may represent decreased cognitive, and perhaps neural, efficiency which reflects MTBI patients' subjective complaints and functional impairments. PMID- 8696319 TI - Language performance of severely closed head injured children. AB - The language functioning of a group of children who had sustained a severe closed head injury (CHI) was evaluated. The subjects were administered a battery of language assessments including measures of syntax, semantics and pragmatics. Performance of the experimental group was compared with that of a control group matched for age and sex. Results indicated that all areas of language competence assessed (syntax, semantics, pragmatics) appeared to be compromised by the childhood CHI. The findings of this study are considered in light of the implications for the existence of different language components (syntax, semantics, pragmatics) as opposed to a unified concept of language. Also considered is the evidence of a specific linguistic impairment in the childhood CHI population as opposed to a more generalized cognitive decline expressed as an overall decrease in performance across all domains of language skill. PMID- 8696320 TI - Neuropsychological deficits following concussion. AB - The term 'concussion' has been applied to head injuries of varying severity. Most studies have examined subjects suffering concussion of a severity requiring hospital observation, usually as a consequence of motor vehicle accidents. Milder concussive injuries such as those resulting from contact sport are often not reported in hospital-based studies. In this study, subjects with mild concussive injuries were studied with the aim of determining if neuropsychological sequelae are detectable. The subjects received their injuries while playing Australian Rules Football. Baseline (pre-injury) measures on the Paced Auditory Serial Addition Test (PASAT), Digit Symbol Substitution Test (DSST) and Four-Choice Reaction time, involving measures of decision time (DT) and movement time (MT), were obtained in a sample of 130 players. Ten players subsequently concussed were re-tested at 5 days post-injury. A control group of age-matched umpires were assessed on two corresponding occasions. Analyses of covariance showed poorer performances following concussion on the DSST and DT measures. The results suggested that neuropsychological deficits are detectable after resolution of neurological symptoms in the early stages following mild concussive injury. PMID- 8696321 TI - Haemochromatosis... definite maybe! PMID- 8696322 TI - Multiple loci for multiple sclerosis. PMID- 8696323 TI - Two genes for missing teeth. PMID- 8696324 TI - Huntingtin: new marker along the road to death? PMID- 8696325 TI - No pain, some gain. PMID- 8696326 TI - Counting strokes. PMID- 8696327 TI - Haemochromatosis: strike while the iron is hot. PMID- 8696328 TI - Microsatellites show mutational bias and heterozygote instability. PMID- 8696330 TI - Non-mendelian inheritance of X chromosome markers in interspecific backcrosses. PMID- 8696329 TI - Directional evolution in germline microsatellite mutations. PMID- 8696331 TI - Endothelin-3 frameshift mutation in congenital central hypoventilation syndrome. PMID- 8696332 TI - Alternative mechanism for pathogenesis of an inherited epilepsy by a nicotinic AChR mutation. PMID- 8696334 TI - X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. AB - Ectodermal dysplasias comprise over 150 syndromes of unknown pathogenesis. X linked anhidrotic ectodermal dysplasia (EDA) is characterized by abnormal hair, teeth and sweat glands. We now describe the positional cloning of the gene mutated in EDA. Two exons, separated by a 200-kilobase intron, encode a predicted 135-residue transmembrane protein. The gene is disrupted in six patients with X;autosome translocations or submicroscopic deletions; nine patients had point mutations. The gene is expressed in keratinocytes, hair follicles, and sweat glands, and in other adult and fetal tissues. The predicted EDA protein may belong to a novel class with a role in epithelial-mesenchymal signalling. PMID- 8696333 TI - A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. AB - Hereditary haemochromatosis (HH), which affects some 1 in 400 and has an estimated carrier frequency of 1 in 10 individuals of Northern European descent, results in multi-organ dysfunction caused by increased iron deposition, and is treatable if detected early. Using linkage-disequilibrium and full haplotype analysis, we have identified a 250-kilobase region more than 3 megabases telomeric of the major histocompatibility complex (MHC) that is identical-by descent in 85% of patient chromosomes. Within this region, we have identified a gene related to the MHC class I family, termed HLA-H, containing two missense alterations. One of these is predicted to inactivate this class of proteins and was found homozygous in 83% of 178 patients. A role of this gene in haemochromatosis is supported by the frequency and nature of the major mutation and prior studies implicating MHC class I-like proteins in iron metabolism. PMID- 8696335 TI - A human MSX1 homeodomain missense mutation causes selective tooth agenesis. AB - We demonstrate that a mutation in the homeobox gene, MSX1, causes a common developmental anomaly, familial tooth agenesis. Genetic linkage analyses in a family with autosomal dominant agenesis of second premolars and third molars identified a locus on chromosome 4p, where the MSX1 gene resides. Sequence analyses demonstrated an Arg31Pro missense mutation in the homeodomain of MSX1 in all affected family members. Arg 31 is a highly conserved homeodomain residue that interacts with the ribose phosphate backbone of target DNA. We propose that the Arg31 Pro mutatrion comprises MSX1 interactions, and suggest that MSX1 functions are critical for normal development of specific human teeth. PMID- 8696336 TI - A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease. AB - Pelizaeus-Merzbacher disease (PMD) is a leukodystrophy linked to the proteolipid protein gene (PLP). We report a cellular basis for the distinction between two disease subtypes, classical and connatal, based on protein trafficking of the two PLP gene products (PLP and DM20). Classical PMD mutations correlate with accumulation of PLP in the ER of transfected COS-7 cells while the cognate DM20 traverses the secretory pathway to the cell surface. On the other hand, connatal PMD mutations lead to the accumulation of both mutant PLP and DM20 proteins in the ER of COS-7 cells with little of either isoform transported to the cell surface. Moreover, we show that transport-competent mutant DM20s facilitate trafficking of cognate PLPs and hence may influence disease severity. PMID- 8696337 TI - Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease. AB - Stroke is a complex disorder with a poorly understood multifactorial and polygenic aetiology. We used the stroke-prone spontaneously hypertensive rat (SHRSP) as a model organism, mated it with the stroke-resistant spontaneously hypertensive rat (SHR) and performed a genome-wide screen in the resultant F2 cohort where latency until stroke, but not hypertension (a major confounder) segregated. We identified three major quantitative trait loci, STR1-3, with lod scores of 7.4, 4.7 and 3.0, respectively, that account for 28% of the overall phenotypic variance. STR2 colocalizes with the genes encoding atrial and brain natriuretic factor, peptides with important vasoactive properties. Our results demonstrate the existence of primary, blood pressure-independent genetic factors predisposing to a complex form of stroke. PMID- 8696338 TI - A role for nuclear NF-kappaB in B-cell-specific demethylation of the Igkappa locus. AB - The immunoglobulin kappa gene is specifically demethylated during B-cell maturation in a process which utilizes discrete cis-acting modules such as the intronic kappa enhancer element and the matrix attachment region (MAR). While any MAR sequence is sufficient for this reaction, mutation analysis indicates that tissue specificity is mediated by kappaB binding sequences within the kappa intronic enhancer. The plasmacytoma cell line S107 lacks kappaB binding activity and fails to demethylate the kappa locus. However, B-cell specific demethylation is restored by the introduction of an active kappaB binding protein gene relB. This represents the first demonstration of a trans-acting factor involved in cell type-specific demethylation, and suggests that the same protein-DNA recognition system used for transcription may also contribute to the earlier developmental events that bring about activation of the kappa locus. PMID- 8696339 TI - Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. AB - Apoptosis has recently been recognized as a mode of cell death in Huntington disease (HD). Apopain, a human counterpart of the nematode cysteine protease death-gene product, CED-3, has a key role in proteolytic events leading to apoptosis. Here we show that apoptotic extracts and apopain itself specifically cleave the HD gene product, huntingtin. The rate of cleavage increases with the length of the huntingtin polyglutamine tract, providing an explanation for the gain-of-function associated with CAG expansion. Our results show that huntingtin is cleaved by cysteine proteases and suggest that HD might be a disorder of inappropriate apoptosis. PMID- 8696341 TI - A common region of 10p deleted in DiGeorge and velocardiofacial syndromes. AB - DiGeorge (DGS, MIM 188400) and velocardiofacial (VCFS, MIM 192430) syndromes may present many clinical problems including cardiac defects, hypoparathyroidism, T cell immunodeficiency and facial dysmorphism. They are frequently associated with deletions within 22q11.2, but a number of cases have no detectable molecular defect of this region. A number of single case reports with deletions of 10p suggest genetic heterogeneity of DGS. Here we compare the regions of hemizygosity in four patients with terminal deletions of 10p (one patient diagnosed as having hypoparathyroidism and three as DGS) and one patient with a large interstitial deletion (diagnosed as VCFS). Fluorescence in situ hybridization (FISH) analysis demonstrates that these patients have overlapping deletions at the 10p13/10p14 boundary. A YAC contig spanning the shortest region of deletion overlap (SRO) has been assembled, and allows the size of SRO to be approximated to 2 Mb. As with deletions of 22q11, phenotypes vary considerably between affected patients. These results strongly support the hypothesis that haploinsufficiency of a gene or genes within 10p (the DGSII locus) can cause the DGS/VCFS spectrum of malformation. PMID- 8696340 TI - Plectin deficiency results in muscular dystrophy with epidermolysis bullosa. AB - We report that mutation in the gene for plectin, a cytoskeleton-membrane anchorage protein, is a cause of autosomal recessive muscular dystrophy associated with skin blistering (epidermolysis bullosa simplex). The evidence comes from absence of plectin by antibody staining in affected individuals from four families, supportive genetic analysis (localization of the human plectin gene to chromosome 8q24.13-qter and evidence for disease segregation with markers in this region) and finally the identification of a homozygous frameshift mutation detected in plectin cDNA. Absence of the large multifunctional cytoskeleton protein plectin can simultaneously account for structural failure in both muscle and skin. PMID- 8696342 TI - Evidence for a familial Wilms' tumour gene (FWT1) on chromosome 17q12-q21. AB - Wilms' tumour (WT) is one of the most common solid tumours of childhood, occurring in 1 in 10,000 children and accounting for 8% of childhood cancers. It is believed to result from malignant transformation of abnormally persistent renal stem cells (nephrogenic rests) which retain embryonic differentiation potential. Although WT is usually sporadic, approximately one percent occur in families in which susceptibility appears to be inherited as an autosomal dominant trait with incomplete penetrance. Predisposition to other cancers or to the developmental abnormalities associated with sporadic WT is not usually apparent in WT families. The WT1 gene at 11p13 (ref.2), and additional genes on chromosomes 11p15 (ref. 3) and 16q (ref. 4) have been implicated in the development of WT but are not responsible for familial WT. We have carried out a genome linkage search in a large Canadian family with seven confirmed cases of WT. Our results provide strong evidence for the localisation of a familial WT predisposition gene, FWT1, to an 18-centimorgan (cM) interval on chromosome 17q12 q21. PMID- 8696343 TI - A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. AB - The population prevalence of multiple sclerosis is 0.1%; however, the risk of the disease in the siblings of affected individuals is very much higher at 3-5%. The importance of genetic factors in accounting for this increased risk is confirmed by the results of twin and adoption studies. Despite the evidence for a strong genetic effect, a weak major histocompatibility complex (MHC) association is the only consistently observed feature in the genetics of multiple sclerosis. Other candidates have been proposed, including genes encoding the immunoglobulin heavy chain, T cell receptor beta chain and APOC2, but none has yet been confirmed. Evidence for linkage and association to the myelin basic protein gene has been reported in a genetically isolated Finnish population, but it has not been possible to reproduce these results in other populations. We used a two-stage approach to search the human genome for the genes causing susceptibility to multiple sclerosis. Two principal regions of linkage are identified, chromosomes 17q22 and 6p21 (MHC). Our results are compatible with genetic models involving epistatic interaction between these and several additional genes. PMID- 8696344 TI - A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex. The Multiple Sclerosis Genetics Group. AB - Multiple sclerosis (MS), an inflammatory autoimmune demyelinating disorder of the central nervous system, is the most common cause of acquired neurological dysfunction arising in the second to fourth decades of life. A genetic component to MS is indicated by an increased relative risk of 20-40 to siblings compared to the general population (lambda s), and an increased concordance rate in monozygotic compared to dizygotic twins. Association and/or linkage studies to candidate genes have produced many reports of significant genetic effects including those for the major histocompatability complex (MHC; particularly the HLA-DR2 allele), immunoglobulin heavy chain (IgH), T-cell receptor (TCR) and myelin basic protein (MBP) loci. With the exception of the MHC, however, these results have been difficult to replicate and/or apply beyond isolated populations. We have therefore conducted a two-stage, multi-analytical genomic screen to identify genomic regions potentially harbouring MS susceptibility genes. We genotyped 443 markers and 19 such regions were identified. These included the MHC region on 6p, the only region with a consistently reported genetic effect. However, no single locus generated overwhelming evidence of linkage. Our results suggest that a multifactorial aetiology, including both environmental and multiple genetic factors of moderate effect, is more likely than an aetiology consisting of simple mendelian disease gene(s). PMID- 8696345 TI - A full genome search in multiple sclerosis. AB - The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility. PMID- 8696346 TI - A putative vulnerability locus to multiple sclerosis maps to 5p14-p12 in a region syntenic to the murine locus Eae2. AB - Multiple sclerosis (MS) is a chronic inflammatory disorder characterized by multifocal damage of myelin in the central nervous system (CNS). The prevalence of this putative autoimmune disease is 0.1% in individuals of northern European origin. Family, adoption and twin studies implicate genetic factors in the aetiology. MS is widely speculated to be a multifactorial disorder with a complex mode of inheritance. Despite many studies of candidate genes, only an association with HLA-DR2-DQ6 has been generally detected, and the number of susceptibility genes remains unknown. The chronic variant of experimental allergic encephalomyelitis (EAE), a T-cell mediated autoimmune disease in rodents, represents a relevant animal model for MS given the chronic relapsing disease course and inflammatory changes of CNS observed in these demyelinating disorders. Susceptibility to EAE is also influenced by the major histocompatibility complex (MHC). Human syntenic regions to murine loci predisposing to EAE were tested as candidate regions for genetic susceptibility of MS. Three chromosomal regions (1p22-q23, 5p14-p12 and Xq13.2-q22) were screened in 21 Finnish multiplex MS families most originating from a high risk region in western Finland. Several markers yielded positive lod scores on 5p14-p12, syntenic to the murine locus Eae2. Our data provide evidence for a predisposing locus for MS on 5p14-p12. PMID- 8696347 TI - Double-strand breaks on YACs during yeast meiosis may reflect meiotic recombination in the human genome. AB - Meiotic recombination in the yeast Saccharomyces cerevisiae is initiated at double-strand breaks (DSBs), which occur preferentially at specific locations. Genetically mapped regions of elevated meiotic recombination ('hotspots') coincide with meiotic DSB sites, which can be identified on chromosome blots of meiotic DNA (refs 4,5; S.K. et al., manuscript submitted). The morphology of yeast artificial chromosomes (YACs) containing human DNA during the pachytene stage of meiosis resembles that of native yeast chromosomes. Homologous YAC pairs segregate faithfully and recombine at the high rates characteristic of S. cerevisiae (vs. approximately 0.4 cM/kb in S. cerevisiae versus approximately 10 3 cM/kb in humans). We have examined a variety of YACs carrying human DNA inserts for double-strand breakage during yeast meiosis. Each YAC has a characteristic set of meiotic DSB sites, as do yeast chromosomes (S.K. et al., manuscript submitted). We show that the positions of the DSB sites in the YACs depend on the human-derived DNA in the clones. The degree of double-strand breakage in yeast meiosis of the YACs in our study appears to reflect the degree of meiotic recombination in humans. PMID- 8696348 TI - Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. AB - Congenital insensitivity to pain with anhidrosis (CIPA; MIM 256800) is an autosomal-recessive disorder characterized by recurrent episodes of unexplained fever, anhidrosis (absence of sweating) and absence of reaction to noxious stimuli, self-mutilating behaviour and mental retardation. The genetic basis for CIPA is unknown. Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. Mice lacking the gene for TrkA, a receptor tyrosine kinase for NGF, share dramatic phenotypic features of CIPA, including loss of responses to painful stimuli, although anhidrosis is not apparent in these animals. We therefore considered the human TRKA homologue as a candidate for the CIPA gene. The mRNA and genomic DNA encoding TRKA were analysed in three unrelated CIPA patients who had consanguineous parents. We detected a deletion-, splice- and missense-mutation in the tyrosine kinase domain in these three patients. Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF-TRKA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermoregulation via sweating in humans. These results also implicate genes encoding other TRK and neurotrophin family members as candidates for developmental defect(s) of the nervous system. PMID- 8696349 TI - DNA ligase I is required for fetal liver erythropoiesis but is not essential for mammalian cell viability. AB - Four distinct DNA ligase activities (I-IV) have been identified within mammalian cells. Evidence has indicated that DNA ligase I is central to DNA replication, as well as being involved in DNA repair processes. A patient with altered DNA ligase I displayed a phenotype similar to Bloom's syndrome, being immunodeficient, growth retarded and predisposed to cancer. Fibroblasts isolated from this patient (46BR) exhibited abnormal lagging strand synthesis and repair deficiency. It has been reported that DNA ligase I is essential for cell viability, but here we show that cells lacking DNA ligase I are in fact viable. Using gene targeting in embryonic stem (ES) cells, we have produced DNA ligase I-deficient mice. Embryos develop normally to mid-term when haematopoiesis usually switches to the fetal liver. Thereupon acute anaemia develops, despite the presence of erythroid committed progenitor cells in the liver. Thus DNA ligase I is required for normal development, but is not essential for replication. Hence a previously unsuspected redundancy must exist between mammalian DNA ligases. PMID- 8696350 TI - Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome. AB - Beare-Stevenson cutis gyrata syndrome (MIM 123790) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death. Many of these features are characteristic of some of the autosomal dominant craniosynostotic syndromes. Mutations in Crouzon, Jackson-Weiss, Pfeiffer and Apert syndromes have been reported in the FGFR2 extracellular domain. In Crouzon syndrome patients with acanthosis nigricans, a recurrent mutation occurs in the transmembrane domain of FGFR3. We now describe the detection of FGFR2 mutations in the Beare-Stevenson cutis gyrata syndrome. In three sporatic cases, a novel missense mutation was found causing an amino acid to be replaced by a cysteine; two had the identical Ty375Cys mutation in the transmembrane domain and one had a Ser372Cys mutation in the carboxyl-terminal end of the linker region between the immunoglobulin III like (Iglll) and transmembrane domains. In two patients, neither of these mutations were found suggesting further genetic heterogeneity. PMID- 8696351 TI - Comparison of passive urethral resistance relation and urethral resistance factor in analysis of bladder outlet obstruction in patients with benign prostatic enlargement. AB - Analysis of the pressure/flow relation renders objective and detailed information on bladder outlet obstruction. The benefit of pressure/flow analysis for clinical and fundamental research questions, however, cannot be acknowledged without comparison of the different methods that exist. We compared one parameter analysis (URA) with two parameter (PURR) analysis in 99 consecutive patients with benign prostatic enlargement. The normal (instantaneous intrapatient) variability of both the PURR parameter Pvoidmin (minimal pressure during voiding) and the URA is approximately 10-15 cm H2O. Within these limits agreement between the two methods of analysis in the quantification of (minimal) outlet obstruction was observed in about 50% of the cases. However, when Qmax is less than 6 ml/s (in 49.5% of the patients) the URA number exceeds the value Pvoidmin in 96% of the cases. Predominantly this is caused by the fact that in the majority of these cases the type of bladder outlet obstruction is more constrictive than the URA curve, based on Pdet at Qmax indicated. In patients with a low flow rate and/or a constrictive type of obstruction, the Pvoidmin resulting from PURR analysis indicates a lower minimal pressure during voiding compared to URA. PMID- 8696352 TI - Regarding "Significance of rectal contractions noted on multichannel urodynamics", Combs AJ, Nitti VW (1995): Neurourology and Urodynamics 14:73-80. PMID- 8696353 TI - Levator ani muscle in women with genitourinary prolapse: indirect assessment by muscle histopathology. AB - The objective of this study was to assess the state of innervation in levator ani muscle sites using muscle histopathology. Asymptomatic women and patients with genitourinary prolapse were included. Histopathologic analysis allows indirect assessment of a muscle's innervation. Therefore, levator ani muscle was collected in a standardized fashion during abdominal surgery and frozen in the operating room using isopentane slush cooled by liquid nitrogen. Serial sections of levator ani muscle in cross-section were studied with standard histochemical and immunohistochemical techniques. The staining patterns from these histochemical techniques allowed quantitative determination of the ratios of fiber types I, IIA, and IIB and their fiber diameters. Objective assessment of fiber type grouping was performed. The distribution of both fiber type percentage and diameter were non-parametric. Therefore, the Mann-Whitney U-test was used to analyze the data for statistical differences between the means for these variables. There was no statistical difference in levator ani muscle fiber type percentage and diameter in patients with prolapse and/or urinary incontinence when compared to asymptomatic women. Levator ani muscles have a higher proportion of slow fibers (66%) than found in other human female muscle (48%). There was no evidence for denervation/reinnervation in any of the biopsy specimens. In this study, levator ani muscle biopsies from incontinent and/or prolapse patients were neither denervated nor reinnervated. PMID- 8696355 TI - Efficacy of biofeedback, when included with pelvic floor muscle exercise treatment, for genuine stress incontinence. AB - We performed a randomized clinical trial on the efficacy of physical therapy on genuine stress incontinence. STUDY OBJECTIVE: "Is a physical therapeutical training program (pelvic floor muscle training) combined with biofeedback, more effective than the same program without biofeedback in patients with mild or moderate stress incontinence?" Forty-four patients were referred by a general practitioner or a urologist. After informed consent, 40 patients were randomized in an exercises and biofeedback group (BF), or treated with exercises exclusively (pelvic floor muscle training = PFMT). After a diagnostic phase of 1 week every patient received twelve treatment sessions, three times weekly. The primary measure of effect, the quantity of involuntary urine loss, was measured with the 48 hours PAD test (Inco-test Molnlycke). Before every treatment session the Symptoms questionnaire was filed out by the patient and the Patient dairy was controlled. The data of the trial were analysed according to the principal of intention to treat. During the trial there was 100% compliance. There were no drop-outs. Both treatment modalities appeared to be effective. After twelve treatment sessions there was a mean improvement of +/- 55% (P = 0.00) in both treatment groups, measured by the primary measure of effect. In the group with BF this improvement was already realized after six treatment sessions (P = 0.01). Yet, the difference between BF and PFMT faded to reach significance at six treatment sessions (P = 0.08). Although differences in treatment effects between both groups were not significant, our findings suggest that adding biofeedback to pelvic floor muscle exercises might be more effective than pelvic floor muscle exercises alone after six treatments. PMID- 8696354 TI - Influence of pudendal nerve blockade on stress relaxation in the female urethra. AB - The urethral pressure decay following a sudden and sustained dilatation corresponds to stress relaxation. Urethral stress relaxation can be described by the equation Pt = Pequ + P alpha e-t/tau alpha + P beta e-t/tau beta, where Pt is the pressure at time t, Pequ is the equilibrium pressure after dilatation, P alpha and P beta are pressure decay, and tau alpha and tau beta are time constants. The time constants have previously proved independent of the way the dilatation is performed. The urethral stress relaxation obtained in 10 healthy women before and after pudendal nerve blockade was analysed by the mathematical model and the pressure parameters and time constants determined. The fast time constant, tau beta, was reduced by the nerve blockade, whereas tau alpha was unaffected, however, both P alpha and P beta were reduced. No single stress relaxation parameter can therefore be related to the muscle or the connective tissue components. The method may prove useful in the further evaluation of the closure function of the urethra with special reference to the pathophysiology of stress urinary incontinence. PMID- 8696356 TI - Urge incontinence in elderly people: factors predicting the severity of urine loss before and after pharmacological treatment. AB - Geriatric patients with urge incontinence lose different amounts of urine and respond differently to treatment. Identification of factors predicting the amount of urine loss before or after treatment might help to select therapy. We have sought such factors in 41 elderly patients (23 women and 18 men), mean age 79 years with established urge incontinence that was urodynamically proven to be associated with detrusor hyperreflexia, who were treated with oxybutynin chloride. Urine loss was measured by 24-hour monitoring (mean 378 g/24 hour). Demographic, psychosocial, behavioral, cortical, circulatory, urodynamic, and urological factors were studied before and after treatment. Multiple regression analysis showed that, before intervention, factors predicting the amount of urine loss were fluid intake, voiding frequency, and impaired orientation on cognitive testing. After intervention, urine loss was significantly smaller (mean 259 g/24 hour). Different factors predicted the amount of this persistent incontinence: underperfusion of the cerebral cortex, reduced bladder sensation, and (again) impaired orientation. The analysis confirms that the severity of geriatric urge incontinence associated with detrusor hyperreflexia, particularly incontinence that is resistant to anticholinergic therapy, depends on cortical factors, that bladder sensation plays an important role, and that therapeutic manipulation of fluid intake and voiding frequency may offer a modest reduction in urine loss (e.g., about 40 g/day). PMID- 8696357 TI - Effects of various phosphodiesterase-inhibitors, forskolin, and sodium nitroprusside on porcine detrusor smooth muscle tonic responses to muscarinergic stimulation and cyclic nucleotide levels in vitro. AB - The cyclic nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are second messengers involved in the regulation of contractility in various smooth muscle organs including detrusor smooth muscle. They are synthesized by activation of adenylate and guanylate cyclases, respectively, and inactivated by phosphodiesterases (PDEs). In order to delineate the intracellular regulation of porcine detrusor contractility by cyclic nucleotides and phosphodiesterases, functional organ bath studies and determinations of intracellular cyclic nucleotide contents were performed after incubation of porcine detrusor strips with forskolin (adenylate cyclase activator), sodium nitroprusside (guanylate cyclase activator), and various phosphodiesterase-inhibitors. Significant relaxant responses were achieved only by forskolin, the nonspecific phosphodiesterase-inhibitor papaverine, and the phosphodiesterase 1-inhibitor vinpocetine (62.4 +/- 5.6%, 73 +/- 4.3%, and 53 +/- 7.9%, respectively). Sodium nitroprusside and the selective PDE-inhibitors milrinone, rolipram, zaprinast, and dipyridamole were significantly less efficacious (26.9 +/- 3.9%, 15.5 +/- 3.8%, 15.3 +/- 3.0%, 13 +/- 4.0%, and 13.2 +/- 2.1%, respectively). Forskolin, papaverine, and vinpocetine elevated intracellular cAMP concentrations (7.3-, 1.9-, and 1.7-fold increase at 100 microM, respectively), whereas the other substances failed to enhance cAMP levels. cGMP levels were only increased by sodium nitroprusside (7.8-fold). The adenylate cyclase-cAMP system seems to be the more important signal transduction system involved in the relaxation of carbachol induced smooth muscle tone of the porcine detrusor. The role of the guanylate cyclase-cGMP system is less clear. In addition, the calcium/calmodulin-stimulated PDE I seems to be of major functional importance in regulating cAMP hydrolysis in the porcine detrusor smooth muscle in vitro. PMID- 8696358 TI - Effects of glucose deprivation on the contractile response of the rabbit bladder to repetitive stimulation. AB - The urinary bladder requires an adequate energy supply to maintain contractile function. The primary metabolic fuel is glucose. Through glycolysis and oxidative phosphorylation, high energy phosphates are generated, which in turn supply the metabolic energy for the contractile activities of the urinary bladder. The aim of this study was to determine the effects of glucose deprivation and recovery from glucose deprivation on the phasic and tonic components of the contractile responses of rabbit bladder strips to field stimulation, bethanechol, and KCl. The results can be summarized as follow: In response to glucose deprivation, (1) the tonic responses to field stimulation, bethanechol, and KCl all decreased at a significantly greater rate than the phasic responses; (2) the phasic and tonic responses to field stimulation were both reduced to less than 10% of control within 70 minutes of initiating glucose deprivation; (3) the tonic responses to bethanechol and KCI were reduced to approximately 10% of control within 180 minutes whereas the phasic responses remained stable at 40 and 30%, respectively; and (4) glucose replacement stimulated a rapid and nearly complete recovery of the phasic and tonic components of the responses to field stimulation, bethanechol, and KCI. These results indicate that the tonic responses to all forms of stimulation are more sensitive to glucose deprivation than the phasic responses. PMID- 8696359 TI - Comparative response of rabbit bladder smooth muscle and mucosa to anoxia. AB - Recent studies indicate that the mucosa of the urinary bladder plays a major role in the maintenance of normal bladder function. Previous studies have demonstrated that rabbit bladder mucosa has higher rates of basal glycolysis and oxidative phosphorylation than that of bladder smooth muscle. The current study compares the response of rabbit bladder mucosa and smooth muscle compartments to anoxia. The results demonstrate that the rate of high energy phosphate degradation of the mucosa is significantly greater than the rate of high energy phosphate degradation of the smooth muscle. The implication is that the mucosa would be significantly more sensitive to ischemia than the smooth muscle of the bladder. This hypothesis may be extremely relevant to conditions such as interstitial cystitis and recurrent urinary bladder infections, in which ischemia has been implicated in their etiology. PMID- 8696360 TI - Analysis of the relative biomechanical effects of alpha 1 and alpha 2 antagonists in modifying the compliance of the prostate and micturition parameters of the hormonally manipulated male rat. AB - The potential of the alpha 1 and alpha 2 antagonists to modify prostate compliance, and micturition characteristics of rats with hormonally enlarged prostates was studied. Prostate growth was induced in Sprague-Dawley rats using dihydrotestosterone (DHT) and estradiol (E) by daily subcutaneous injections of DHT 1.25 mg/kg and E 0.25 mg/kg together with 0.1ml of sesame oil, as a vehicle, for a period of 3 weeks. A control group of six rats was used wherein the vehicle alone was administered. Dose levels of 3, 10, 30, and 300 micrograms/kg of alpha 1 or alpha 2 antagonist were given at weekly intervals to each of the groups defined above. Voiding characteristics, in terms of micturition frequency and volume per micturition, were measured and correlated with the pharmacological and hormonal stimulus. Prostate compliance and weight was evaluated in each of the groups after rats were terminated and the ventral prostate was dissected and removed in in toto. Compliance measurements were made using a new biosensor system which is based on the principle of detecting the shift in the resonance frequency of the biosensor produced by the hormones on the acoustic impedance of prostate. The results show that DHT and [DHT+E] significantly increased prostate weight and decreased prostate compliance. The alpha 2 antagonist atipamezole significantly increased the compliance of all prostates, including controls, while the alpha 1 antagonist did not alter the compliance. It is concluded that this alpha 2 antagonist is more effective than the prazosin in reversing the hardening effect of hormones on the prostate. PMID- 8696361 TI - A novel tetrasaccharide, with a structure similar to the terminal sequence of an arabinogalactan-protein, accumulates in rice anthers in a stage-specific manner. AB - Analysis of free sugars in developing rice anthers by high-performance anion exchange chromatography (HPAEC) showed that a very high concentration of a novel oligosaccharide accumulated specifically during microsporogenesis. Structural analysis of the purified oligosaccharide by methylation analysis, mass spectrometry/mass spectrometry (MS/MS), and nuclear magnetic resonance (NMR) spectroscopy revealed its structure to be beta-L- Ara(f)-(1-->3)-alpha-L-Ara(f) (1-->3)-beta-D-Gal(p)-(1-->6)-D-Gal, which is closely related to a tetrasaccharide unit found in the glycan chain of a plant cell surface proteoglycan, the arabinogalactan-protein (AGP). Chilling treatment (12 degrees C, 4 days), which injures rice anthers during microsporogenesis, decreased the concentration of the tetrasaccharide, but the sucrose level increased. This effect was especially evident in a chilling-sensitive mutant line, YM56-1. These results suggest that this unique tetrasaccharide may play an important role in both the development of the rice anther and its response to chilling. PMID- 8696362 TI - Male sterility in transgenic tobacco plants induced by tapetum-specific deacetylation of the externally applied non-toxic compound N-acetyl-L phosphinothricin. AB - A system for the inducible destruction of plant tissues based on the deacetylation of the non-toxic compound N-acetyl-L-phosphinothricin (N-ac-Pt) has been developed. The argE gene product of Escherichia coli, representing a N acetyl-L-ornithine deacetylase was identified to remove the acetyl-group from N ac-Pt giving the cytotoxic compound L-phosphinothricin (Pt, glufosinate). Transgenic Nicotiana tabacum plants constitutively expressing the argE gene were constructed. No effect of the bacterial N-acetyl-L-ornithine deacetylase on plant growth and reproduction could be traced. However, application of N-ac-Pt on leaves of the transgenic plants led to the formation of necrotic areas due to the release of Pt. Additionally, due to the uptake of the N-ac-Pt by roots, transgenic shoots grown on medium containing N-ac-Pt bleached within 6-7 days and finally died. Untransformed controls showed no reaction to high amounts of N-ac Pt applied, either under sterile or under unsterile conditions. In order to construct inducible male-sterile plants, the argE coding region was fused to a DNA fragment carrying sequences homologous to the tobacco TA29 promoter, known to function exclusively in the tapetum. Owing to the tapetum-specific expression of the chimeric gene the application of N-ac-Pt led to empty anthers resulting in male-sterile plants. The sanity of the female reproductive part of the male sterile flowers could be demonstrated by cross-pollination. Without N-ac-Pt treatment the plants turned out to be completely fertile making fertility restoration in the F1 generation superfluous. The system presented is easy to handle and might be applicable to a wide range of crop plants. PMID- 8696363 TI - A receptor for protein import into potato mitochondria. AB - Five potential surface receptors for protein import into plant mitochondria were identified by gentle trypsin treatment of intact mitochondria from potato tubers and subsequent preparation of outer mitochondrial membranes. One of them, a 23 kDa protein, was purified to homogeneity and analysed by direct protein sequencing. Copy DNA clones encoding the corresponding polypeptide were isolated with labelled oligonucleotides derived from the amino acid data. The 23 kDa protein shares significant sequence similarity with protein import receptors from fungal mitochondria and contains one of their typical tetratricopeptide motifs. Its integration into the outer membrane is independent of protease accessible surface receptors and not accompanied by proteolytic processing. Monospecific antibodies against the 23 kDa protein significantly reduce import capacity of isolated mitochondria indicating that this component is indeed involved in the recognition or import of precursor proteins. As in fungi, immunological inhibition of protein import with IgGs against a single receptor is incomplete suggesting the existence of other receptors in the outer mitochondrial membrane of plant mitochondria. PMID- 8696364 TI - Sucrose metabolism during cotyledon development of Vicia faba L. is controlled by the concerted action of both sucrose-phosphate synthase and sucrose synthase: expression patterns, metabolic regulation and implications for seed development. AB - The roles of sucrose-phosphate synthase (Sps) and sucrose synthase (Sus) in developing embryos of Vicia faba have been characterized. In the cotyledons the expression of both Sps and Sus is initiated in cells differentiating into storage tissue. This stage is characterized by a switch in the carbohydrate state from a high to a low hexoses to sucrose ratio. The carbohydrate state was found earlier to be controlled by seed coat-associated invertase. During cotyledon development the Sps-enzyme undergoes a cycle of deactivation and reactivation: the activated state is associated with the prestorage phase, desiccation and germination and the deactivated state with the storage phase. Sus activity is associated with the storage phase. Sps and Sus are differentially influenced by free sugars. Feeding hexoses to storage phase cotyledons increases levels of Sps-mRNA but not Sus mRNA, Sps activity and Sps activation state and impairs storage functions evidenced by an increased sucrose to starch ratio and a downregulation of storage protein legumin B-mRNA. Sus enzyme activity is inhibited by free hexoses in vitro. It is proposed that the changing carbohydrate state during cotyledon development controls the ratio of Sps to Sus. Sps may have some significance for the initiation of the storage process possibly decreasing hexoses and/or increasing sucrose. The relevance of the changing carbohydrate state with respect to development and storage processes is discussed. PMID- 8696365 TI - Members of a low-copy number gene family encoding glutamyl-tRNA reductase are differentially expressed in barley. AB - In plants tetrapyrrole synthesis is initially light regulated on the level of 5 aminolevulinate (ALA) synthesis. ALA is formed from glutamate in three enzymatic steps. Glutamyl tRNA reductase (GluTR) catalyses the NADPH-dependent reduction of glutamyl tRNA to glutamate 1-semialdehyde. GluTR is encoded by a low-copy gene family consisting of three to four genes. Three different cDNA clones are presented. Full-length clones BHA1 and 87 differ in the length of the 3' untranslated region and code for a 58.5 kDa protein. The sequence of the partial clone, BHA13, contains at least 87 base mismatches in the coding region for the mature GluTR resulting in 11 amino acid substitutions. Synthesis of a recombinant mature and a truncated GluTR lacking the first 19 amino terminal amino acids in Escherichia coli lead only in the latter case to complementation of an E. coli hemA mutant. Steady-state level of BHA1- and BHA13-specific mRNA encoding GluTR were analysed by Northern blot hybridization using cDNA-specific oligo nucleotides and quantitative reverse transcriptase-polymerase chain reaction. Accumulation of the two RNA species is light induced in greening barley and controlled during cellular development. In contrast to BHA13, BHA1 transcripts are present in roots and are elevated after cytokinin treatment of dark-grown seedlings. Furthermore, BHA1 mRNA shows oscillation under circadian growth conditions. GluTR transcript levels correlate with the capacity for ALA synthesis indicating that the rate-limiting substrate flux through the ALA synthesizing pathway can be at least partially attributed to GluTR expression. Consequences of the initial control of the chlorophyll metabolic pathway on the level of ALA formation are discussed. PMID- 8696366 TI - The Arabidopsis XET-related gene family: environmental and hormonal regulation of expression. AB - Enzymes that modify cell wall components most likely play critical roles in altering size, shape, and physical properties of plant cells. Regulation of such modifying activity is expected to be important during morphogenesis and in eliciting developmental and physiological alterations that arise in response to environmental conditions. Previous work has shown that the Arabidopsis TCH4 gene encodes a xyloglucan endotransglycosylase (XET) which acts on the major hemicellulose of the plant cell wall. The expression of TCH4 is dramatically upregulated in response to several environmental stimuli (including touch, wind, darkness, heat shock, and cold shock) as well as the growth-enhancing hormones, auxin and brassinosteroids. This paper reports the presence of an extensive XET related (XTR) gene family in Arabidopsis. In addition to TCH4, this family includes two previously identified genes, EXT and Meri-5, and at least five additional genes. The cDNAs of the XTR family share between 46 and 79% sequence identity and the predicted XTR proteins share from 37 to 84% identity. All eight proteins include potential N-terminal signal sequences and most have a conserved motif (DEIDFEFLG) that is also found in Bacillus beta-glucanase and may be important for enzyme activity. The members of the XTR gene family are differentially sensitive to environmental and hormonal stimuli. Magnitude and kinetics of regulation are distinct for the different genes. Differential regulation of expression of this complex gene family suggests a recruitment of related, yet distinct, cell wall-modifying enzymes that may control the properties of cell walls and tissues during development and in response to environmental cues. PMID- 8696367 TI - A second form of adenine phosphoribosyltransferase in Arabidopsis thaliana with relative specificity towards cytokinins. AB - Adenine phosphoribosyltransferase (APRTase) is an important enzyme for its ability to convert adenine, a byproduct of many biochemical reactions, into AMP. By functional complementation of an Escherichia coli mutant, cDNAs encoding two APRTases have been cloned from Arabidopsis thaliana. One of the cDNAs (ATapt1) has been previously identified while the second (ATapt2) is of a previously unknown type. Kinetic analysis of the two enzymes purified from E. coli expressing the two cDNAs indicates that ATapt2 has a higher affinity for cytokinin than the ATapt1. RNase protection studies indicate that the ATapt2, is not expressed in leaves. Analysis of the gene structure indicates that ATapt2 has identical intron positions to ATapt1, but neither the intron sequence nor intron size are conserved between the two genes. The implications of a second, differentially expressed APRTase with affinity for both adenine and cytokinin are discussed. PMID- 8696368 TI - A role for arabinogalactan-proteins in plant cell expansion: evidence from studies on the interaction of beta-glucosyl Yariv reagent with seedlings of Arabidopsis thaliana. AB - Seedlings of Arabidopsis thaliana were germinated and grown in medium containing beta-glucosyl Yariv reagent (beta GlcY), a synthetic phenyl glycoside that interacts specifically with arabinogalactan-proteins (AGPs), a class of plant cell surface proteoglycans. The effect of beta GlcY on the seedlings was to reduce the overall growth of both the root and the shoot. beta GlcY only accumulated in the root tissues and the reduced growth of the shoot appeared to be an indirect effect of impaired root growth. Reduced root growth was a consequence of a reduction in cell elongation during the postproliferation phase of elongation at the root apex and this was associated with extensive radial expansion of root epidermal cells. beta GlcY penetrated roots as far as the endodermis and it is suggested that the interaction of beta GlcY with AGPs in the load-bearing cell layers inhibited root elongation. When beta GlcY was added to carrot suspension-cultured cells that had been induced to elongate rather than proliferate, cell elongation was inhibited. The AGP-unreactive alpha-galactosyl Yariv reagent (alpha GalY) had no biological activity in either of these systems. PMID- 8696370 TI - Design in Arabidopsis thaliana of a synchronous system of floral induction by one long day. AB - A system of one-shot induction of flowering in Arabidopsis thaliana, ecotype Columbia, is described. Plants from vernalized seeds are grown for 2 months in 8 h short days at an irradiance of 48 mumol m-2 sec-1 (fluorescent light only). At that age they can be induced to flower by exposure to either a single long day or a single displaced short day. Non-induced plants stay vegetative for at least a further month. Synchrony of induction among the individuals of the population exposed to one long day is of the same order as in the best classical model plants, that is, the fastest individuals are only 6 h ahead of the slowest ones. A further advantage of this system is the large size of plants at the time of induction, allowing easy analysis of changes in leaves, leaf exudate and shoot meristem. The design of such a synchronous system will allow the timings of gene activations and deactivations to be established in the different plant parts, before flowers are initiated. PMID- 8696369 TI - Use of Ac as an insertional mutagen in Arabidopsis. AB - A pilot-scale transposon mutagenesis experiment using a modified autonomous Activator (Ac) element, Ac delta Nael, was carried out in Arabidopsis thaliana. Four different transformants carrying Ac elements in different and defined genomic locations were used to generate 1000 plants carrying approximately 500 independent germinal transposition events. These plants were then selfed and the 1000 families screened in tissue culture and soil for phenotypic mutants. Fifty different families segregated mutations in their progeny. Preliminary Southern blot analysis of 29 families which segregated mutant progeny, showed that 28 had a transposed Ac. Six of the families were further tested for linkage between the transposed Ac and the mutant phenotype, and instability of the putatively tagged locus. Two of the mutants were shown to be tagged as they were tightly linked to a transposed Ac, and somatic and germinal reversion was associated with loss of Ac. One other mutant locus was shown to be closely linked to a transposed Ac, and therefore was likely to be tagged. The remaining three mutations were not tagged as they were not linked to a transposed Ac. In two of the tagged mutants Ac had transposed to closely linked sites, while in a third mutant the co-segregating Ac had transposed to a site which was not tightly linked to the donor T-DNA. Multiple insertions into the DIF1 locus were found, due to the preferential transposition of Ac to a linked site. PMID- 8696371 TI - Building blocks for life. PMID- 8696372 TI - With scars in my uterus and heart. PMID- 8696374 TI - Vaginal ultrasound: diagnostic aid or tool of abuse? PMID- 8696375 TI - A blending of two worlds. PMID- 8696373 TI - Knitting needles, cameras and electronic fetal monitors. PMID- 8696376 TI - The pain of labour. PMID- 8696377 TI - Urban guerrilla midwives. "The true stories are endless". PMID- 8696378 TI - Midwifery symbols. PMID- 8696379 TI - The belly of the beast. PMID- 8696380 TI - No heroics, just love. PMID- 8696381 TI - Send us a birth story that illustrates appropriate or inappropriate use of technology. PMID- 8696382 TI - A grand triumph. PMID- 8696383 TI - First, do no harm. PMID- 8696384 TI - This man loves midwives. Interview by Poppy Shell. PMID- 8696385 TI - Pursuing the birth machine. PMID- 8696386 TI - What's wrong with an early discharge? PMID- 8696387 TI - Birth plan. PMID- 8696388 TI - Chaos! It can be positive. PMID- 8696389 TI - Improving the safety and effectiveness of medication administration and teaching. PMID- 8696390 TI - Inflammatory bowel disease: implications for the medical-surgical nurse. AB - Inflammatory bowel disease (IBD) is a relatively common but frequently misunderstood condition. In this review, Crohn's disease and ulcerative colitis, the two major forms of IBD, are explored and treatment options are discussed. As a result, the medical-surgical nurse will be better able to discriminate between and manage these two conditions. PMID- 8696391 TI - Developing and implementing a self-learning packet on epidural analgesia. AB - Epidural analgesia offers a highly effective route of providing acute pain relief. As this mode of medication delivery is used more frequently in the acute care setting, nurses must acquire theoretical knowledge, apply monitoring parameters, and demonstrate technical competency. Implementing a self-learning packet to educate nursing staff caring for patients receiving epidural analgesia is an effective teaching medium and can help improve clinical performance. PMID- 8696392 TI - Needs of family members of critically ill adults. AB - The hospitalization of a person for a critical illness is a crisis situation for the patient and family. Although family members can easily identify their needs, assessment of these needs differs. A descriptive survey was conducted with a sample of 60 family members representing 35 critically ill patients. Family members reported many needs, most importantly the need for assurance, information, and proximity. Several implications for medical-surgical nurses are discussed. PMID- 8696393 TI - Ethics in nursing practice: confidentiality for women and their children with HIV/AIDS. AB - HIV-positive women and their children experience substantial problems brought about by the illness itself and service-delivery issues. Significant ethical concerns are raised when providing care to this patient population, and the ramifications of compromises in patient confidentiality are extremely serious. All practicing nurses should be familiar with the issues and potential solutions. PMID- 8696394 TI - Nurses' perceptions of harmful outcomes from medication errors. AB - To determine if factors associated with medication errors explained perceived harmful outcome from such errors, perceptions of vividly recollected medication errors were reported by a convenience sample of 206 hospital-employed RNs and LPNs who completed the Medication Error Risk Profile (MERP). Symptoms related to the error, radiology studies performed, the toxicity of the medication given, adverse drug reaction unrecognized at first, and transfer of the patient to another unit explained 38% of the variance in perceived harmful outcome. The implications of the this study for medical-surgical nurses are explored. PMID- 8696395 TI - Managing ascites via the Tenckhoff catheter. AB - Ascites is a serious and uncomfortable symptom experienced by a significant percentage of cancer patients. The use of the Tenckhoff catheter provides rapid relief of the mechanical effects of ascites. When this technology is used in the hospital or in the home, nurses act to prevent complications and inform patients and families about safety and other issues. PMID- 8696396 TI - Prevention: what is the cost? PMID- 8696397 TI - Hopelessness: the key to suicidal risk. PMID- 8696398 TI - Consent to treat: a risk for the medical professional. PMID- 8696399 TI - Adverse reactions to metoclopramide (Reglan) presenting as depression in a bone marrow transplant patient. PMID- 8696401 TI - Venous leg ulcers. PMID- 8696400 TI - Optimizing ethical decision making: the decision analysis model. PMID- 8696402 TI - Lubricating American health care: better, faster, cheaper. PMID- 8696403 TI - Behavioral management of altered patterns of urinary elimination in women. AB - Urinary incontinence is a serious problem for many women. Nurses in a variety of settings can help women by thorough assessment, behavioral and environmental interventions, and appropriate referrals to urologic specialists. PMID- 8696404 TI - Case management: integrating roles in the subacute setting. AB - Nurses have great potential to advance the professional practice of nurse case management in the subacute care industry. This health care setting has created a new arena in which nursing may adapt and redefine the role of the case manager to meet the needs of an integrated system of outcomes based health care. Through cooperation and collaboration with a multidisciplinary team, the nurse case manager increases the cost effectiveness of care and enhances patient outcomes. PMID- 8696405 TI - Pain management in sickle cell disease. AB - Sickle cell disease is a chronic disorder characterized by painful crises, debilitating complications, and a shortened life span. The pain associated with sickle cell crises is often severe, but poorly managed in many health care settings. The disease process and recommendations for effective pain management in this population of patients are discussed. PMID- 8696406 TI - Quality of life in COPD patients using transtracheal oxygen. AB - Transtracheal oxygen offers patients with chronic obstructive pulmonary disease many benefits. A qualitative study was conducted to examine patients' perceptions of how the technology affects quality of life. This study has several implications for nurses working in hospital and home settings. PMID- 8696407 TI - Sickle cell leg ulcers. PMID- 8696408 TI - An elusive weakness: myasthenia gravis. AB - Individuals with myasthenia gravis often enter the health care system in crisis without a "working diagnosis". Since this disorder is potentially life threatening, especially if undiagnosed, it is essential that the front-line care provider be sensitive to the symptom patterns and complex needs of these special patients. PMID- 8696409 TI - Understanding fluoxetine (Prozac). PMID- 8696410 TI - Feminism and bioethics. PMID- 8696411 TI - Decision-support interventions for patients. PMID- 8696412 TI - Professional organizations: a valuable entity. PMID- 8696413 TI - One in nine: risks and prevention strategies for breast cancer. PMID- 8696414 TI - Visual records augment BSE. PMID- 8696415 TI - To our health. PMID- 8696416 TI - Obesity and breast cancer. AB - The high incidence of breast cancer in Western women has been linked to nutritional factors such as high-fat/low-fibre diet, obesity and timing of weight gain. A mechanism is postulated through which the Western diet could act in conjunction with inadequate exercise and excessive weight gain at the time of a major change in hormonal balance. All these factors favour the manifestation of insulin resistance, and the concomitants of hyperinsulinaemia might then synergise with oestrogen in promoting the development of breast cancer. The mechanism is compatible with the 'breast tissue age' model of mammary carcinogenesis. The concomitants of hyperinsulinaemia could also influence the growth of established disease subsequent to its promotion, and it is suggested that the hypothesis be tested by an adjuvant randomised trial of a high-fibre/low fat diet in patients following primary surgery for early breast cancer. It has been suggested that the development of insulin resistance may link the Western lifestyle not only to an increased risk of hypertension and arteriosclerosis, but also to increased breast cancer risk. Large abdominal fat deposits in women are frequently a marker of the presence of insulin resistance and are generally associated with an increased level of bio-available oestrogen. There is evidence that predominantly abdominal distribution of fat in women may be a marker of increased breast cancer risk from puberty onwards. Abdominal obesity may however be hidden, and it is more reliably demonstrated by imaging techniques such as CAT or MRI scans, than by anthropometric measurements such as increased waist-to-hip ratio. PMID- 8696417 TI - Autoregulation of body composition during weight recovery in human: the Minnesota Experiment revisited. AB - OBJECTIVES: To gain insights into the control systems underlying human variability in the regulation of body composition during weight recovery, as well as the disproportionate recovery of fat relative to lean tissue, the classical Minnesota Experiment conducted on 32 men subjected to long-term semi-starvation and refeeding was revisited with the following objectives: (1) to determine whether the control of energy-partitioning between lean and fat tissues during weight loss and weight recovery is an individual characteristic, and if a predictor can be statistically identified, (2) to determine whether the reduction in thermogenesis during weight loss persists during weight recovery, and underlies the disproportionate recovery of fat tissue and (3) to integrate the control of energy-partitioning and that of thermogenesis in order to explain the pattern of lean and fat tissue mobilisation and deposition during weight loss and weight recovery. METHODS: Individual data on body weight, body fat, fat-free-mass (FFM), and basal metabolic rate (BMR), assessed during the control baseline period (i.e. prior to weight loss), at the end of 24 weeks of semi-starvation, and at the end of a 12 week period of restricted refeeding, were used to calculate the following parameters: (i) a quantitative index of energy partitioning, the P-ratio, defined as the proportion of body energy mobilised as protein during weight loss, or as the proportion of body energy deposited as protein during weight recovery, (ii) a quantitative index of changes in thermogenesis, defined as the change in BMR adjusted for FFM (or for both FFM and fat mass) and (iii) the degree of replenishment of fat and FFM compartments, defined as the recovery of body fat and FFM (during refeeding) as a percentage of that lost during semi-starvation. RESULTS: This re-analysis indicates the following: (i) a large inter-individual variability in P-ratio during both weight loss and weight recovery, but for a given individual, the P-ratio during refeeding is strongly correlated with the P-ratio during semi-starvation, (ii) body composition during the control period is the most important predictor of variability in P-ratio, such that the higher the initial % body fat, the lower the proportion of energy mobilised as protein, and hence the greater the propensity to mobilise fat during semi-starvation and to subsequently deposit fat during refeeding and (iii) at week 12 of refeeding, the change in adjusted BMR is found to be reduced by a magnitude which is inversely proportional to the degree of fat recovery, but is unrelated to the degree of FFM recovery. A quantitative relationship is derived between the P-ratio during refeeding, the % fat recovery, and the P-ratio during semi-starvation. CONCLUSIONS: Evidence is presented here suggesting that (i) human variability in the pattern of lean and fat tissue deposition during weight recovery is to a large extent determined by individual variations in the control of energy-partitioning, for which the initial % body fat is the most important predictor and (ii) the disproportionate gain in fat relative to lean tissue during weight recovery is contributed by a reduction in thermogenesis (i.e. increased efficiency of food utilization) for accelerating specifically the replenishment of the fat stores. These control systems, operating via energy-partitioning and thermogenesis, have been integrated into a compartmental model for the regulation of body composition during underfeeding/refeeding, and can be used to explain the individual pattern of lean and fat tissue deposition during weight recovery in situations ranging from the rehabilitation after malnutrition to the relapse of obesity. PMID- 8696418 TI - Adiposity and body mass indices in children: Benn's index and other weight for height indices as measures of relative adiposity. AB - OBJECTIVES: Several forms of weight for height or body mass index (BMI) are in widespread epidemiological and clinical use as measures of relative adiposity. The form derived by Benn for adults has been advocated for use in children and practical aspects of this proposition are considered. METHODS: Height and weight data from 8492 Australian schoolchildren aged 7 to 15 were studied. A subsample of 2753 children aged 9, 12 and 15 years had skinfold thicknesses measured. The sum of four skinfolds and percentage body fat predicted from skinfolds were used as measures of adiposity. RESULTS: Of the various forms of power type BMI examined, weight/(height)2 was most closely associated with adiposity in this sample. Benn's assumption of low correlation between height and adiposity (which holds in adults) was not satisfied in children. CONCLUSIONS: Benn's index is not recommended for general use as a body mass index in children. However, Benn's relative weight has advantages as an indirect measure of adiposity which may be of value in epidemiological studies among children. PMID- 8696419 TI - A shared care approach in obesity management: the general practitioner and a hospital based service. AB - OBJECTIVE: To describe the process of establishing a Shared Care obesity management programme between general practitioners and a hospital based specialist obesity service and to compare outcomes of the Shared Care programme (SC) to an established hospital based programme (MOS). DESIGN: A comparative study of two obesity management programmes. Patients were matched on gender, age and BMI (kg/m2). SUBJECTS: 29 female and eight male (age: 47.0 +/- 2 years, BMI 35.9 +/- 0.8 kg/m2) patients enrolled in the Shared Care programme (SC) were matched to 81 female and 20 male (age: 45.8 +/- 1.1 years, BMI 35.7 +/- 0.4 kg/m2) patients enrolled in a hospital based programme (MOS). MAIN OUTCOME MEASURES: Relative and absolute weight loss and retention rate were compared between the programmes at 10 and 26 weeks. Food habits were assessed at enrolment and week 10 of the programme in the SC group by a Food Habits Questionnaire and cognitive restraint, disinhibition and hunger were assessed by the Eating Inventory Questionnaire. RESULTS: Shared Care patients (n = 28) lost significantly more weight than the MOS patients (n = 60) (SC 4.8 +/- 0.6 kg and MOS 2.6 +/- 0.4 kg; p = 0.0016) over the 10 weeks of the programme. At 26 weeks both groups demonstrated a 5 kg weight loss. There was a significant improvement in food habits, and cognitive restraint, disinhibition and hunger over the 10 weeks of the programme in the SC group. Patient satisfaction was reflected in a better retention rate at 26 weeks by the Shared Care group. CONCLUSION: The study demonstrated that the obese patient managed in a shared care setting achieved better weight loss in the short term and attrition was lower in the longer term than a similar patient attending a specialist service based in a hospital. PMID- 8696420 TI - Major gene for abdominal visceral fat area in the Quebec Family Study. AB - OBJECTIVES: The abdominal visceral fat depot is considered to be the most atherogenic, diabetogenic and hypertensiogenic fat depot of the human body. Although the amount of abdominal visceral fat is correlated with total body fat, there remain considerable inter-individual differences in visceral fat at any level of body fat content. No study has been reported to date on the contribution of genetic factors to the variability in abdominal visceral fat level. DESIGN: Abdominal visceral fat area was assessed by computerized tomography in 382 adult men and women from 100 families of the Quebec Family Study. After adjustment for the effects of age and age plus total fat mass (assessed by underwater weighing), a major gene hypothesis for abdominal visceral fat area was investigated using segregation (POINTER) analyses. RESULTS: Segregation analysis of the age-adjusted variable indicated that variability in visceral fat area was accounted for by a major gene transmitted according to Mendelian expectations. Data support an autosomal recessive locus, associated with high levels of abdominal visceral fat, accounting for 51% of the phenotypic variance and affecting 10% of the sample. An additional 21% of the variance was due to multifactorial (polygenic and/or familial environment) sources. However, after adjusting for total fat mass, support for a major gene for abdominal visceral fat was less strong. CONCLUSIONS: These results suggest that the familial etiology of abdominal visceral fat level involves a major autosomal recessive locus. Given the critical role of abdominal visceral fat in the metabolic complications of obesity, it will now be important to identify the gene responsible for the high levels of abdominal visceral fat observed in some adults and to investigate whether this gene is the same as that which influences total body fat content. PMID- 8696421 TI - Effects of several putative beta 3-adrenoceptor agonists on lipolysis in human omental adipocytes. AB - BACKGROUND: Atypical beta 3-adrenoceptor agonists have attained an increasing interest as potential drugs against obesity and diabetes. However, their pharmacological actions on the native, human beta 3-adrenoceptor are not well defined. DESIGN: In the present study, the lipolytic effects of several putative beta 3-adrenoceptor agonists were investigated in human omental adipocytes. RESULTS: CL 316 243 and CGP 12177 had selective partial beta 3-agonist effects (pD2 about 4 and 8, respectively); the latter drug is a beta 1-/beta 2 adrenoceptor blocker in addition to its beta 3-adrenoceptor agonist activity. BRL 37344 and SM 11044 were also partial agonists, but with significant beta 1- and/or beta 2-adrenoceptor agonist properties. Bucindolol, ZD 2079, ICI D7114 and SR 58611A were ineffective as lipolytic drugs. In addition, ICI D7114 was a non selective beta 1-/beta 2-/beta 3-adrenoceptor antagonist in human adipocytes. CONCLUSION: None of the beta 3-adrenoceptor agonists tested is an ideal drug for therapeutic use in man (i.e. regarded as a selective and full agonist with high receptor potency). Only CL 316 243 may have a potential therapeutic role, although the potency is very low. CGP 12177 is useful as a reference substance for human in vitro studies. PMID- 8696422 TI - Covert manipulation of the ratio of medium- to long-chain triglycerides in isoenergetically dense diets: effect on food intake in ad libitum feeding men. AB - OBJECTIVE: This study examined whether isoenergetic substitution of MCT for LCT in HF, HE diets (639 kJ/100 g) limits the excess energy intakes frequently observed on high-fat diets of high energy density (HF, HE). SUBJECTS: Six healthy male volunteers [mean age (SD) = 27.17 (4.17 y) mean weight = 63.33 (7.33 kg), mean height = 1.72 (0.05 m)]. DESIGN: The subjects were each studied three times during 14 d throughout which they had ad libitum access to one of three covertly manipulated diets, which were randomly assigned in a counter-balanced design. The fat, carbohydrate (CHO) and protein in each diet (as percent energy) were identical at 62:28:10, with 2 day maintenance (1.5 x BMR, MF) beforehand. The ratio of MCT to LCT was 1:2, 1:1 and 2:1 on the low-, (LMCT) medium- (MMCT) and high-MCT (HMCT) diets, respectively. Within each diet every item was of the same composition and offered as a 3 day rotating menu. RESULTS: Energy intakes were significantly lower on the HMCT diet [F (2,240) = 7.52; p < 0.001] giving mean values of 13.50, 13.67, and 12.43 MJ/d on the LMCT, MMCT and HMCT diets, respectively. Food intake followed a parallel trend. By day 14 body weight changes amounted to +0.45, +0.41 and -0.03 kg, respectively. CONCLUSION: These data suggest that substitution of a readily metabolised fat for a less readily metabolised fat, in very high fat diets can limit the excess energy intakes and weight gain that is usually produced by HF, energy-dense diets. PMID- 8696423 TI - Neonatal outcome and obstetric complications in women with gestational diabetes: effects of maternal body mass index. AB - OBJECTIVE: To evaluate in a selected population the clinical characteristics (time of diagnosis, different treatment, metabolic parameters, etc.) of gestational diabetes in relation to prepregnancy body mass index (BMI) and the influence of BMI on neonatal outcome. DESIGN: This study was retrospectively led using a computerized data system for all deliveries that occurred at the Departments of Obstetrics and Gynecology of the University of Pisa (Italy) from 1 January 1987 to 31 December 1992. SUBJECTS: 93 women with GDM and 110 control subjects divided into three groups according to their pre-pregnancy BMI: normal weight (Nw), overweight (Ow) and obese (Ob). MEASUREMENTS: Time of diagnosis, mode of treatment and metabolic control of GDM; time and mode of delivery, neonatal outcome (macrosomia, respiratory distress syndrome, hyperbilirubinemia, hypoglycemia, polycythemia, hypocalcemia). RESULTS: GDM was diagnosed earlier in Ow and Ob than in Nw (p < 0.01) and insulin treatment was used in 86% of Ob-GDM, 91% of Ow-GDM and in 77% of Nw-GDM women (p < 0.001). Preterm deliveries and cesarean sections resulted significantly increased in all BMI categories of GDM patients with respect to matched normal controls. Prevalence of neonatal macrosomia was higher in GDM patients (44.6%) compared with normal controls (15.4%) and correlated (p > 0.01) with prepregnancy BMI in both groups. The body weight increase during pregnancy was not associated with neonatal macrosomia. CONCLUSIONS: The degree of overweight is associated with an earlier diagnosis of GDM; prepregnancy BMI is more predictive of macrosomia than weight gain, both in control and GDM women; GDM seems to play the most important role in increasing the possibility of the occurrence of macrosomia. PMID- 8696424 TI - Obesity and risk of gallstone development on a 1200 kcal/d (5025 Kj/d) regular food diet. AB - OBJECTIVE: Previous studies report a greatly increased risk of gallstone formation in obese persons during periods of caloric restriction on very low calorie formula diets. The aim of the present study was to assess the risk of gallstone development in moderately obese patients losing weight on a prescribed 1200 kcal/d (5025 Kj/d) regular food diet. DESIGN AND SUBJECTS: A consecutive sample of 70 men and women (body mass index > 25 kg/m2) (mean +/- SD, 28.9 +/- 2.8 kg/m2) responding to an announcement of an outpatient weight loss program in a major metropolitan research and teaching hospital were enrolled in a meal replacement program which prescribed 1200 kcal/d (5025 Kj/d) consisting of regular foods with approximately 20 g/d fat (15% of kcal) for 16 weeks. RESULTS: Participants who completed the study (n = 34) lost a mean of 5.1 +/- 3.6 kg (p < 0.001) (range, +2.7 kg to -12.5 kg; 6.7 +/- 5.0% of body weight, range +/-3.1% to -17.0%; 0.36 +/- 0.25 kg/week) with no clinically significant adverse effects. There were no discernible new gallstones as measured by ultrasonography during the study period. Liver enzyme blood concentrations did not change significantly after 16 weeks except for alkaline phosphatase, which decreased by 4.5 mu/l from a mean initial level of 72.7 mu/l (p < 0.05). CONCLUSION: Weight loss over 16 weeks on a 1200 kcal/d (5025 Kj/d) regular food/approx 20 g/d fat (15% of kcal) diet was not accompanied by a high rate of gallstone formation in moderately obese persons. PMID- 8696425 TI - Metabolic propensity toward obesity in black vs white females: responses during rest, exercise and recovery. AB - OBJECTIVE: To examine the existence of a metabolic propensity toward the development of obesity in black vs white females. DESIGN: Cross-sectional comparison of responses during 30 min of rest, 30 min of treadmill exercise at 65% VO2max, and 30 min of recovery. SUBJECTS: 22 (11 black, 11 white) healthy, normal weight, sedentary females with a family history of obesity. MEASUREMENTS: Biometric measures (body mass index, waist-to-hip ratio, and body composition by hydrodensiometry) to insure inter-group homogeneity. Oxygen consumption (VO2), respiratory exchange ratio (RER), insulin, glucose and free fatty acids (FFA) during rest, exercise and recovery were measured to test for metabolic differences between the groups. RESULTS: Black females displayed lower VO2 during rest (p = 0.04) and recovery (p = 0.04), higher RER during rest, exercise and recovery (p = 0.003), and higher levels of insulin (p = 0.03). No significant differences were observed for levels of blood glucose (p = 0.29) or serum FFA (p = 0.73). CONCLUSION: Normal weight black and white females with comparable family histories of obesity exhibit dissimilar metabolic responses during rest, exercise and recovery. Lower rates of oxygen consumption, higher metabolic reliance on carbohydrate, and higher levels of insulin may slowly impact energy balance predisposing these black females toward the eventual onset of obesity. PMID- 8696426 TI - Weight fluctuation, mortality and vascular disease in Pima Indians. AB - OBJECTIVE: To examine the relationship of weight fluctuation to mortality rates and incidence of vascular disease. SUBJECTS: A cohort of Pima Indians, 572 of whom had non-insulin-dependent diabetes mellitus and 766 without diabetes. DESIGN: Individuals were invited biennially to research examinations. The root mean square error (RMSE) of the linear trend of weight with time for the first four examinations after age 20 years was used as an index of weight fluctuation. Subjects were followed from the fourth examination until death or until 31 December 1991. The mortality rate ratio (MRR) and its 95% confidence interval (CI) for those with a high weight fluctuation index relative to those with a lower value were determined. The median duration of follow up was 9.3 (range 0.1 22.6) years. MEASUREMENTS: All cause mortality (n = 356); incidence of diabetic retinopathy (n = 145), diabetic nephropathy (n = 132) and electrocardiographic abnormalities (n = 82). RESULTS: There was no significant relationship between weight fluctuation and mortality for diabetic subjects (MRR = 1.0, 95% CI 0.8 1.3, p = 0.91). Nondiabetic subjects with a high weight fluctuation index had a higher mortality rate than those with a lower index (MRR = 1.5, 95% CI 1.0-2.1, p = 0.03); the association was stronger among men than among women. The excess mortality in the high weight fluctuation group was not due to cardiovascular diseases, but to noncardiovascular causes and the risk for alcohol-related death was particularly increased. Weight fluctuation was not associated with the incidence of diabetic retinopathy, nephropathy or electrocardiographic abnormalities. CONCLUSIONS: A high weight fluctuation index was associated with higher mortality rates in nondiabetic, but not in diabetic, Pima Indians. The excess mortality is largely due to noncardiovascular causes of death and may reflect lifestyle factors associated with weight fluctuation, rather than its metabolic effects. PMID- 8696428 TI - Determinants of weight loss following ileogastrostomy. AB - To examine the factors associated with weight loss following ileogastrostomy, (i) energy expenditure, (ii) body composition and (iii) urinary and fecal energy losses were examined in 11 morbidly obese subjects (36 +/- 3 y, 43.7 +/- 0.9 kg/m2 BMI, 47.0 +/- 1.3% body fat (BF) (mean +/- SEM) prior to and after this surgical procedure. Respiratory gas exchange analysis was used to measure changes in basal energy expenditure (BEE) and thermic effect of food (TEF). Total energy expenditure (TEE) was determined by doubly labeled water (DLW) method over 14 d during 6-8 weeks after surgery. Body composition was assessed using isotope dilution space (IDS) method. Illegastrostomy did not significantly influence BEE levels but TEF declined following surgery (p = 0.001). There was a significant decline (p < 0.0001) in fat-free mass (FFM) and fat mass (FM). Weight loss was closely associated with TEE (r = 0.719, p = 0.019, n = 10), and fecal energy content (r = 0.808, p = 0.052, n = 6) but not with urinary energy loss (r = 0.011, p = 0.983, n = 6). The results indicate that ileogastrostomy blunts TEF levels and both FFM and FM declined following surgery. Total energy expenditure and fecal energy losses appear to be important determinants in the extent of weight loss following ileogastrostomy. PMID- 8696427 TI - Defining obesity in children by biological endpoint rather than population distribution. AB - OBJECTIVE: To investigate the association of fatness in children with dyslipoproteinemia and high blood pressure, with the purpose of proposing standards for childhood obesity which are directly related to intermediate biological parameters that predict future disease. DESIGN: A cross-sectional study of a large, nationally representative sample of Australian schoolchildren. SUBJECTS: 1834 children aged 9 or 15 years, with skinfolds blood lipid measurements on 1144 and with skinfolds and blood pressure measurements on 1757. MEASUREMENTS: Skinfolds thicknesses measured at four locations (triceps, biceps, subscapular and suprailiac) using holtain calipers, percent body fat calculated from the sum of four skinfolds, Quetelet's index calculated from weight and height, waist and hip circumferences, plasma total cholesterol and triglycerides determined using a Technicon Autoanalyser II, high density lipoprotein cholesterol (HDLC) analysed following precipitation with heparin manganese, and systolic blood pressure (SBP) measured using a standard mercury sphygmomanometer. RESULTS: For 9 years old girls, 15 year old girls and 9 years old boys, dichotomising their HDLC and SBP measurements by percent body fat defined the two groups most homogeneous in terms of a measure of within-group variation. The cut points in percent body fat were in the ranges 29-35% (girls) and 17-20% (boys). CONCLUSION: It is feasible to use the current biomedical status of individual children to define criteria for obesity. A cut-off point of 30% body mass as fat for girls and 20% for boys appears to be an appropriate standard. PMID- 8696429 TI - Prevalence of obesity in Greece. AB - The purpose of the present study is the presentation of the available literature on obesity in Greece. The heterogeneity of design, small sample size and limited number of studies conducted, complicates the delineation of definite trends. Nevertheless, the existing literature appears to point at a high prevalence of obesity among Greek children. Childhood obesity, may partly be accounted for by the over-protection and forced feeding by Greek parents. With regard to the incidence of obesity among Greek adolescents, studies have yielded controversial results. On the other hand, the existing evidence appears to indicate a high prevalence of obesity among Greek adults and the elderly, particularly those above 30 years of age. In contrast to the females, males appear to be characterised by central obesity. These observations highlight a need for primary prevention measures. PMID- 8696430 TI - A case study on energy balance during an expedition through Greenland. AB - A 59-year-old man who had always been lean was submitted to overfeeding for two months in preparation for a 3-week expedition through Greenland, during which a considerable negative energy balance was expected. The overfeeding protocol consisted of an estimated energy surplus of 2000 kJ per day and this induced body weight and fat gains of 4.7 and 3.6 kg, respectively. Whole-body indirect calorimetry measurements following 4 and 8 weeks of overfeeding showed that there was no change in the subject's daily energy expenditure. Ad libitum energy intake measured during a buffet-type meal was substantially increased during overfeeding. As expected, the expedition induced a negative energy balance which reduced body weight below the pre-overfeeding level. Daily energy expenditure measured 12 days after the expedition, when the subject had recovered his initial body weight, was decreased by 1.4 MJ/day. The increase in ad libitum energy intake observed during the pre-expedition overfeeding persisted after the expedition. These adaptations tended to persist three weeks and four months after the end of the expedition. These results suggest that both energy expenditure and intake were modified after the expedition to prevent a subsequent body energy deficit. PMID- 8696432 TI - A unified standard of obesity. PMID- 8696431 TI - On estimating the minima of BMI-mortality curves. AB - OBJECTIVE: To identify the 'optimal' BMI, that is, the BMI associated with minimal mortality, researchers frequently fit a quadratic function to data and identify the nadir of the BMI-mortality curve. However, Waaler (1984)8 has argued that this approach systematically overestimates the optimal BMI because the true curve might not be quadratic. The purpose of this study was to test this proposition. DESIGN: We simulated 25 decidedly nonquadratic curves in which the true minimum corresponded to a BMI of 24. RESULTS: When fitting a quadratic model to this data and solving for the nadir of the curve, the estimated optimal BMI was 21.14 (SD = 0.586). CONCLUSIONS: It is concluded that there is no way of knowing a priori whether the BMI associated with minimum mortality will systematically overestimate, underestimate, or estimate in an unbiased manner the true optimal BMI when the true model underlying the data is not known. PMID- 8696433 TI - The American society of hand therapists: a part of the solution. PMID- 8696434 TI - Specialization: the past, the present, and the future. PMID- 8696435 TI - Early versus late range of motion following cubital tunnel surgery. AB - The purpose of this study was to evaluate the effects of early versus late range of motion exercises following cubital tunnel release and medial epicondylectomy. Fifty-seven consecutive cases were studied and divided into two groups. Physical therapy consisting of active and passive range of motion exercises was started 14 days postoperatively for the first group and 3 days postoperatively for the second group. Fifty-two percent of the patients in group 1 sustained flexion contractures of more than 5 degrees compared with only 4% of the patients in group 2. Early initiation of therapy did not adversely affect the grip strength and/or other functions of the upper extremity, and the patients in group 2 returned to work sooner than the patients in group 1 (in fact, in half the time). Institution of range of motion exercises immediately postoperatively is more effective in preventing flexion contractures of the elbow than is delayed treatment. PMID- 8696437 TI - Silicone rubber splinting for athletic hand and wrist injuries. AB - The use of a silicone rubber protective playing splint facilitates an athlete's continued or earlier return to sport participation following injury. The purposes of this paper are to review the literature and to describe the properties, fabrication procedures, and indications for use of the silicone rubber compound materials used to splint athletic hand and wrist injuries. In general, the use of silicone rubber protective splints for stable orthopedic hand and wrist injuries has been shown to be effective. PMID- 8696436 TI - The effect of ice application versus controlled cold therapy on skin temperature when used with postoperative bulky hand and wrist dressings: a preliminary study. AB - Skin temperature of the hands of 12 volunteers was monitored. The hands were placed in bulky dressings and treated with a standard ice bag (group I) or a new cooling blanket (group II). The contralateral hands served as controls. The mean difference in skin temperatures between group I and controls was 1.5 degrees F, while the difference between group II and controls was 13 degrees F. Temperatures of the controls did not decrease with time. Newer cooling devices appear to be more efficacious than standard ice bags in accurately and significantly lowering skin temperature when used with traditional bulky hand dressings. PMID- 8696438 TI - Characteristics in addition to size of the contralateral hand predict hand volume but are not clinically useful. AB - Traditionally, therapists who treat hand edema have used the volume of the contralateral hand to estimate normal or pre-injury hand volume. This presupposes that for the average person the difference in volumes between the two hands is so small that it is clinically insignificant. Left and right hand volumes, as well as a number of other hand characteristics, and health history were collected for a sample of 512 persons. Over 15% of the subjects had a measured volume difference of 30 ml or more. The difference in absolute and relative volumes between hands was minimally affected by gender, age, lifestyle, hand dominance, size of the largest hand, health problems, or previous hand injuries. Regression analysis uncovered a number of characteristics, including gender, handedness, and age, that predicted hand volume over and above the contralateral hand, but they boosted the proportion of variance explained only from 0.968 to 0.973, a clinically insignificant increase. It was concluded that the traditional methods of estimating pre-injury volume are still useful. PMID- 8696439 TI - Determining sample size. PMID- 8696440 TI - The proximal interphalangeal joint swing traction splint. AB - Conventional PIP joint flexion splints exhibit several shortcomings regarding kinematic and kinetic behavior. A new PIP joint swing traction splint (STS) has been developed to overcome these shortcomings while maintaining the advantage of the ease of use of conventional simple rubber band traction devices. This article defines the advantages of the STS system in terms of physics and also describes the fabrication technique involved. PMID- 8696441 TI - Combination splint for distal interphalangeal joint stability and protected proximal interphalangeal joint mobility. PMID- 8696442 TI - Reducing risks in blood transfusion: process and outcome. AB - The last decade has seen substantial improvements in the provision of safe "infection-free' blood for patients in many countries. This has resulted from the combined effects of better donor education, selection, testing and exclusion processes. The residual risk of infection with HBsAg attributable to laboratory error is less than 0.1/ 100,000 (1/750,000). The risk for HIV remains to be quantified but may approach this figure. With such low risks it will be difficult to provide statistical evidence that further improvements in the process of selection, testing or exclusion will have an impact on reducing risk from either agent. Over the same time, less progress has been made reducing risk to the recipient attributable to problems in the clinical supply process, i.e. getting the right blood, to the right person, at the right place, at the right time. Uniform definitions of terminology defining blood donation characteristics, together with the sharing of performance data are essential if we are to make national and international comparison of the risks that patients face when they receive a transfusion. Equally, the use of agreed definitions, and the sharing of data on the clinical outcomes of transfusion can provide the key to better prescribing based on evidence of actual risks and benefits. PMID- 8696443 TI - Quality assurance of clinical transfusion practice by implementation of the privilege of blood prescription and computerized prospective audit of blood requests. AB - Guidelines, algorithms and recommendations have been issued in the attempt to ensure appropriateness of transfusion practice, but the results are less than satisfactory, mainly due to the difficulty to turn paper procedures into actual practice. In our hospital we have tried to overcome this difficulty through the implementation of a quality assurance programme which includes giving the privilege of nonurgent blood prescription to a limited number of physicians and a computerized prospective audit of blood requests. The latter is performed through verification of the compliance of blood requests, which are designed to include a patient's laboratory and clinical data, with hospital guidelines for the proper use of blood. In the 12 months since implementation of the computerized prospective audit the transfusion service has evaluated 7884 requests. Of these, 63.4% (n = 4998) were for red blood cells, 21.1% (n = 1664) for platelets and 15.5% (n = 1222) for fresh frozen plasma. The prospective audit showed that 96.8% and 98.1% of requests for red units and platelets were appropriate, respectively. Conversely, approximately 27% of plasma requests did not comply with guidelines, mainly because the evidence of coagulopathy was missing. However, inappropriateness of plasma requests for elective general surgery decreased from 39% at the onset of the programme to 14% in the last trimester considered. Moreover, the evaluation by retrospective audit of the proportion of patients transfused with both red blood cells and plasma in the perioperative period out of those transfused with red blood cells only, as an indicator of unwanted reconstitution of whole blood, showed that this proportion decreased from 47.6% (320/672) in the 12 months before implementation of computerized audit to 37.8% (244/646) in the following 12 months (difference = -9.8%, 95% confidence interval of the difference from -4.5% to -15.1%; P < 0.005 by chi 2 test). Our initial experience, together with the present system, shows that (1) the restriction of nonurgent blood prescription to a group of clinicians more educated in transfusion medicine than average clinicians practicing in a large multispecialty hospital is feasible; (2) prospective audit is a useful tool for assuring the quality of blood requesting. PMID- 8696444 TI - Analysis of blood donor return behaviour using survival regression methods. AB - The acquisition of a sufficient and safe supply of blood products is required to support modern medical care; in most countries this has meant a reliance on voluntary, nonremunerated blood donors. Recent reported shortages in the United States and elsewhere have highlighted the need for a method to measure and evaluate blood donor return behaviour. This paper describes a framework within which standard time-to-outcome methods can be used to analyse blood donor return behaviour. Survival curves and relative risk estimates derived from a proportional hazards analysis of a large administrative dataset are reported. In addition to assessing the effect of sex, age and other key donor demographic factors on the probability of a subsequent donation attempt, the analysis reveals that the relative risks are time-dependent. This suggests that the likelihood of attempting a subsequent donation may also depend on the time since the index donation attempt. The implications for blood collection agencies and transfusion researchers of this new perspective on donor behaviour are discussed. PMID- 8696445 TI - Behavioural risk factors for HIV infection amongst blood donors in London. AB - This paper compares the prevalence of risk factors for sexual acquisition of human immunodeficiency virus infection (HIV-1) among blood donors with the risk in the general population. Sexual behaviour data collected as part of a cross sectional survey of central London blood donors were compared, after indirect standardization for age and sex, with those collected among Greater London participants of the National Survey of Sexual Attitudes and Lifestyles (NATSSAL). Overall, male blood donors had lower risk sexual lifestyles than age-matched NATSSAL participants in that they had had fewer lifetime female sexual partners, were more likely to have had first sexual intercourse after 16 years and were less likely to have had a homosexual partner. Men who have had sex with men since 1977 were asked not to donate blood. Despite this, 3.6% of male donors had had some sexual experience with another man and 1.9% had had sexual intercourse with at least one male partner. In contrast, female donors had had more sexual partners, were more likely to have had first sexual intercourse before 16 years and had probable higher rates of sexually transmitted disease (STD) clinic attendance than NATSSAL participants, explained by the much higher proportion of single rather than married female blood donors at each age. In conclusion, male donors had lower risk sexual lifestyles than age-matched NATSSAL participants, although even low levels of homosexual contact give some cause for concern. Female donors appeared to have higher risk sexual lifestyles than the general population because a much higher proportion of the female blood donors were single. The results provide important insights for those defining blood donor referral criteria. PMID- 8696446 TI - Study on medical donor deferrals at sessions. AB - A 10-month audit of reasons for donor medical deferral at sessions was carried out in two Scottish regions of the SNBTS. Six thousand deferred donors were assessed. Although the deferred donor population mirrored the attending donor population in both regions, significantly more donors, both new and regular, were deferred in the Edinburgh and South East region, compared with the North East. The main differences in deferral were attributable to three clinical conditions (cervical carcinoma in situ, other gynaecological conditions and hypertension) and to donors admitting to high-risk behaviour. Although the staff in the deferral process - doctors, nurses and clerks - were involved in roughly equal proportions in both regions, the spectrum of medical conditions seen by each staff grouping appeared to be different in each region. The staff in the South East appeared to have made more correct decisions. Further analysis and audits are being undertaken in areas highlighted by this study. PMID- 8696447 TI - The plasma turnover of transfused antithrombin concentrate in patients with acquired antithrombin deficiency. AB - Antithrombin concentrate, prepared from human plasma, has been used as replacement therapy in 35 patients with acquired antithrombin deficiency. The inhibitory activity of the concentrate, measured by chromogenic assay, correlates well with the manufacturer's quoted activity. The mean in vivo recovery of the product was 0.0124 iu mL-1 per iu of antithrombin (AT) concentrate administered by kilogram body weight. The recovery was similar in all diagnostic groups studied and did not vary during the course of treatment. Consumption of the antithrombin concentrate was monitored by measuring the production of thrombin antithrombin complexes and the loss of plasma antithrombin activity. The mean concentration of thrombin-antithrombin complexes was elevated (23 ng mL-1) at the time of admission to the intensive care unit and fell progressively over the next 4 days. The mean time for the decay of half the antithrombin activity was 23 h during the first 24 h of therapy and rose to 42.1 h after day 1. The recovery and half-life measurements are necessary to plan an appropriate dosage regimen for the administration of this antithrombin concentrate in acquired deficiency states. PMID- 8696448 TI - Blood group A antigen expression in platelets is prominently associated with glycoprotein Ib and IIb. Evidence for an A1/A2 difference. AB - Blood group ABH antigens are associated with platelets as intrinsic determinants and extrinsically adsorbed antigens, and exist both on glycosphingolipids and on glycoproteins (GPs). We now provide direct evidence that the blood group ABH antigens are prominently associated with platelet GPIb and GPIIb. By immunoprecipitation, a murine monoclonal anti-A antibody precipitated surface biotin-labelled blood group A1 platelet membrane proteins with electrophoretic characteristics identical to those of GPIb/IX and GPIIb/IIIa. By immunoblotting of SDS-PAGE separated blood group A1 platelet proteins the monoclonal anti-A antibody bound to proteins with electrophoretic characteristics identical to those of GPIb and GPIIb. When immunoaffinity purified GPIb/IX and GPIIb/IIIa, derived from blood group O, A1 and A2 platelets, were employed for immunoblotting, GPIb and GPIIb only from A1 platelets bound the monoclonal anti-A antibody. By ELISA, wherein monoclonal antibodies specific for GPIb (APl) and the GPIIb/IIIa complex (AP2) were used to capture and hold antigens from platelet lysate, human anti-A antibodies reacted with these proteins derived from blood group A1 platelets; proteins from blood group A2, O and B platelets showed no reactivity. These results indicate that blood group A antigen is associated with GPIb and GPIIb derived from blood group A1 but not A2 platelets. PMID- 8696449 TI - Yersinia enterocolitica transmission from a red cell unit 34 days old. AB - In 1993 the North London Blood Transfusion Centre received its first report of Yersinia enterocolitica transmission from a unit of red cells supplied to a local hospital. The recipient was a 23-year-old male who was neutropenic following a third cycle of chemotherapy for treatment of acute myeloblastic leukaemia (FAB type M6) and received a 34-day-old red cell unit. During transfusion the patient developed septicaemia and endotoxin-mediated shock. The transfusion was stopped immediately and broad spectrum antibiotics administered immediately on suspicion of bacteraemia from the transfused unit. This prompt action undoubtedly prevented a fatal outcome. Y. enterocolitica was isolated from the blood bag. Antibody was also detected in the bag and in a sample taken from the donor 39 days post donation. Antibody to serotype 03 was identified, the commonest serotype reported in transfusion-transmitted Y. enterocolitica. The donor reported no gastrointestinal upset or illness prior to donation. This transfusion reaction might not have occurred had the red cells been transfused earlier in their storage period, but would not have been prevented by the exclusion of donors with a history of gastrointestinal illness as the donor was asymptomatic. Nor would it have been prevented by inspecting the blood for a change in colour, as no such change was observed. Y. enterocolitica is a significant problem in transfusion medicine and transmission is generally associated with a high mortality rate. Hospitals should be urged to investigate bacteriologically all appropriate transfusion reactions so that the true extent of the problem in the United Kingdom can be assessed. PMID- 8696450 TI - Comparison of plasma and serum for antibody detection using DiaMed microtubes. AB - Atypical antibody detection in DiaMed microtubes using a low-ionic-strength saline (LISS) indirect antiglobulin technique (IAT) was assessed using both serum and plasma. During the first period of the study all atypical antibodies originally detected in serum were also detected in EDTA plasma with comparable reaction strengths. Two of 73 antibodies were not detected in citrated plasma. During the second period of the study all routine antibody screens were performed in both serum and EDTA plasma. More clinically significant antibodies were detected in EDTA plasma than in serum. More false positives and non-specific antibodies were also detected in EDTA plasma. It is concluded that EDTA plasma is a suitable medium for antibody detection using LISS IAT in DiaMed gel microtubes. PMID- 8696451 TI - Consensus statement on autologous transfusion. Royal College of Physicians of Edinburgh. PMID- 8696452 TI - Guidelines for blood grouping and red cell antibody testing during pregnancy. British Committee for Standards in Haematology, Blood Transfusion Task Force. PMID- 8696453 TI - [The art of caring. Between hope and fear]. PMID- 8696454 TI - [Apology for change. Interview by Andre Lachance]. PMID- 8696455 TI - [Ethics and the fragility of certainty ]. PMID- 8696456 TI - [Nurses and reform. Giving the imagination free range]. PMID- 8696457 TI - [To be a nurse... Interview by Suzanne Blanchet]. PMID- 8696458 TI - [Intravenous antibiotics therapy at home. Quality, efficiency, economy]. PMID- 8696459 TI - [Assisted ventilation at home. A complex management of specialized care]. PMID- 8696460 TI - [The nurse as a first assistant in the operating room. An innovative project]. PMID- 8696461 TI - [Sound use of drugs for the aged. A step towards autonomy]. PMID- 8696462 TI - [Conquering pain. Knowing, know how, acting right]. PMID- 8696463 TI - [Birth of a disabled child. Partnership between nurse and family]. PMID- 8696464 TI - [Management of stress. A solution to the rehabilitation of patients with schizophrenia]. PMID- 8696465 TI - [Head injuries. Educational measurement for intensive care nurses]. PMID- 8696466 TI - [Maximizing the abilities of hemiplegics]. PMID- 8696467 TI - [Parents of anorexic adolescents. First support]. PMID- 8696468 TI - [Heart surgery. Peer support]. PMID- 8696470 TI - [The "milieu" approach. A proactive intervention in community health]. PMID- 8696471 TI - [An enlarged center for education about asthma. The nurses adapt their intervention strategies]. PMID- 8696472 TI - [Professional ethics. A daily challenge]. PMID- 8696469 TI - [The elderly with irreversible cognitive deficits. A model of quality of life and quality of nursing care]. PMID- 8696474 TI - [Ethno-cultural care in geriatrics. A different approach]. PMID- 8696473 TI - Health system reform: second wave or tidal wave? PMID- 8696475 TI - [Health education. Time to act]. PMID- 8696476 TI - [Evaluation of the effects of biological and clinical factors on plutonium excretion in man]. AB - The values of the natural urine excretion coefficient in 84 workers have been received. The observations were ranging from 1970 to 1984. To analyse this data the references about radiobiological, medical, anthropometrical and other factors which potentially influence osteotropic radionuclide excretion in man and animals have been studied. By means of linear regression (program KWAZAR) it was confirmed that 6 factors including liver and heart diseases were important. Mathematical description of this results is suggested. PMID- 8696477 TI - [Schematic model of genesis of osteosarcoma induced by Sr-90]. AB - The development of radiation osteosarcoma genesis scheme induced by 90Sr was the subject of the present study. The production of cancer cells after exposure to a specific dose-rate of emitting 90Sr incorporated in the skeleton are typical for the initiation period. However not all the cells remain in the mutant DNA. In some of them DNA reparation occurs, other cells are killed in the process of the subsequent divisions, and only a few of them containing mutant DNA are preserved in the state of repression up to the end of life time. Disorders of homeostasis due to exhausted of physiological reserves - (natural or early aging) are manifested as a promoter. In that period the derepression of mutant DNA occurs and malignant growth of tumor starts. PMID- 8696478 TI - [State of the lymphoid tissue of tracheobronchial lymph nodes in rats after incorporation in respiratory organs of low-transportable Pu-239]. AB - After single inhalation exposure of rats to low transportable 239Pu the alpha irradiation doses in tracheo-bronchial lymph nodes (TBLN) were one order of magnitude lower than those in lung. The reduction of cell population in TBLN was observed in late (12-18 month after) post-inhalation period. Dose-response curve for the reduction (as a whole for 12 month) were presented as a line function. Functional abilities of these cells were less damaged and observed in different periods after inhalation. As one of the probable mechanisms of different radiation damage to cells in TBLN population, a variety in their spatial distribution is discussed. PMID- 8696479 TI - [State of the urea-producing function of the liver in gamma-irradiated rats]. AB - The investigations of some metabolites and enzymes of ornithine cycle in irradiated rats were performed. It was shown that ionizing radiation furthered the intensification of liver ammonium-connecting function. It took place without visible enzyme activation during the first period of defeat. It was shown also the increasing of enzyme activity at the top of pathological process development. The definite dose-dependence was observed in this period. The month after irradiation the liver function wasn't normal. PMID- 8696480 TI - [Structural and biochemical parameters of blood components of mice after gamma irradiation with small doses of different intensity]. AB - The complex study on the low gamma-irradiation on the structural feature of lymphocyte DNA and lipid peroxidation (LPO) regulatory system parameters in mice blood was carried out depending on irradiation intensity. It was found that DNA alkaline elution rate constants, viscosity of the different regions of erythrocyte membranes and LPO products content in mice blood plasma varied nonlinearly depending on dose or dose rate. The proportion of the damage types and the range of the DNA structural changes substantially differ depending on the gamma-irradiation dose and its intensity. It is considered that the proportion of the DNA and membrane damage and repair can change depending on radiation dose and dose rate. PMID- 8696481 TI - [Study of reproductive behavior in Russian and Byelarus populations exposed to ionizing radiation as a consequence of the Chernobyl AES accident]. AB - As a result of the Chernobyl accident the population in Gomel and Mogilev districts of Belorussia as well as in Bryansk district in Russia were exposed to ionizing radiation. The changes in pregnancy outcomes (spontaneous abortions, stillbirths, etc) are the integral indices reflecting the state of the population under post-accident conditions. The data obtained don't allow us to isolate reliably the radiation-induced component in post-accident behavior of the studied populations. PMID- 8696482 TI - [Significance of cyclic AMP system activation in restoration of colony forming capacity of hematopoietic stem cells and prolongation of life of lethally irradiated animals]. PMID- 8696483 TI - [Mechanism of the radiation-protective effect of indralin]. AB - Pharmacological test demonstrated that radioprotective activity of indralin occurs by interaction with alpha-adrenoreceptor. Radioprotective effect of indralin decreased by alpha-adrenoblocker, aminazine and theophylline. Normobaric hyperoxia during irradiation reduced radioprotective effect of indralin in doses about ED50. In experiment with mice and rats it was shown that indralin induced acute hypoxia, impaired oxygen consumption and heat production by 30-46%, spleen bloodflow to 26.3% of control level, rectal temperature by 1.5-2 degrees C (mouse). After 30-min indralin raised resistance of mice to hypoxic hypoxia that is believed due to rapid development of biochemical adaptive process in hypoxic cells. PMID- 8696484 TI - [Changes in heat production in experimental animals during irradiation and administration of radiation-protective agents]. AB - Due to the improvement of field method of oxygen consumption measuring, the instrument to realize simultaneous determination of micromammals heat production has been elaborated. These investigations estimated that the irradiation of mice at the dose of 3 mGy/hour caused the increase of heat production for 11.4%. Injection of radioprotectors increases the animals' heat production with the simultaneous decrease of oxygen consumption. PMID- 8696486 TI - [Determination of radioresistance of microbes of different species irradiated separately and jointly]. AB - Radioresistance of lactose positive and lactose negative Esch. coli, lactose positive Esch. coli and proteus, yellow sarcina and white staphylococcus, white and pink yeasts, white and yellow staphylococcus was studied after irradiation and seeding on hard media using separate and combined methods. In most cases radioresistance of the microbes did not depend of exposure conditions. However, lactose positive Esch. coli irradiated with proteus increased proteus radioresistance to its own standard. Yellow staphylococcus cannot form yellow pigment after irradiation with a dose of 1000 Gy. PMID- 8696485 TI - [Microecology of nuclear reactor pool water]. AB - In the course of research it was found that the circulation of pool water through the nuclear reactor core produces a bactericidal effect of microflora due to the influence of radiation of various types. The amount of microbes returns to initial level after 2-4 months after circulation was stopped. Microflora of pool water comprises large amounts of coccus, Gram-positive rods, fungi and a lower content of Gram-negative rods if compared to water which had been used to fill reactor pool. No difference in radioresistance was noticed for unitype microbes isolated from initial water and from reactor pool water. Quality of microflora reflects a unique phenomenon called "selection" which results in vanishing of all the radiosensitive types of microbes and survival of the radioresistant types. Radioresistance grows with increasing of catalase and nuclease activity. PMID- 8696487 TI - [Effects of single and fractionated irradiation on Bacillus subtilis spores under different incubation conditions]. AB - Effect of 60Co gamma-rays on inactivation of Bac. subtilis spores was studied. In the course of investigation, the dose of gamma-rays was divided in to two parts with an interval of 4 or 24 hours between irradiation. Fractional irradiation was found to be more effective for decontamination of Bac. subtilis spores than single irradiation. PMID- 8696488 TI - [Immunoendocrine homeostasis in mice after local irradiation of immune and endocrine system organs]. AB - Immunoendocrinological studies were carried out in mice during a year after local X-ray irradiation of thymus, hypothalamus-hypophysis, gonads, spleen and thigh muscles. Irradiation of the organs caused the stress regardless of the dose and localisation. No stable immunoendocrinological changes was observed in exposed spleen and thigh muscles. Post-irradiation disfunction of the central and peripheral endocrine gland (hypothalamus-hypophysis, gonads, thymus) induced alterations in function of other endocrine glands and depressive state of the endocrine system. Functional deviations in immune and endocrine systems has a phase character with some dose dependence. The effect of combined irradiation of thymus and hypothalamus-hypophysis is similar to those under separate irradiation. PMID- 8696490 TI - [Chemiluminescence and triboluminescence of the endothelium of the thoracic aorta in gamma-irradiated rabbits with experimental hypercholesterolemia]. AB - A comparative study of chemiluminescence and triboluminescence of endothelium of the thoracic aorta in the intact rabbits and in ones with experimental hypercholesterolemia 3, 6, 24 hours after single total influence of low doses of ionizing radiation allowed us to conclude that higher fluctuation of the examined parameters is characteristic feature of the rabbits with hypercholesterolemia. At the same time it was found that the changes in chemiluminescence and triboluminescence of endothelium of the thoracic aorta three hours after irradiation with a dose of 0.25 Gy were different in the experiments in vitro and in vivo. PMID- 8696489 TI - [Mast cells of the inflammatory focus in irradiated body]. PMID- 8696492 TI - [Soil-plant linkage and expected doses in humans from incorporated long-lived radionuclides]. AB - The algorithm for calculation of the expected received dose resulted from intake of long-lived 137Cs and 90Sr radionuclides accepted with food has been proposed. The contamination rate and agrochemical type of soils which were involved into trophical chain formation were considered in evaluation of radionuclide level in diet. The calculation of dose loading was made for seven main types of soil in Ukrainian wooded district. PMID- 8696491 TI - [Long-term consequences of the effects of single inhalation of Pu-239 in association with tributyl phosphate and hexachlorobutadiene in rats]. PMID- 8696493 TI - [Comparative study of hazards of energy plutonium and standard Pu-239 using non stochastic effects]. AB - In experiment with rats it was found that the "energy" Pu is more toxic than standard 239Pu when entered endotracheally. The comparison was made by the non stochastic effects. The toxicity in respiratory system and blood system was 1.8 and 1.6 times higher when calculated per 1sGy of absorbed dose and 1.6 and 1.1 times higher when calculated per 1kBg/kg of the amount taken, respectively. PMID- 8696494 TI - Acute midtarsal sprains: frequency and course of recovery. AB - In a prospective consecutive registration of 711 ankle inversion sprains, the dorsal ligaments and capsule of the midtarsal joints were involved in 237 of the cases (33%), and in 172 cases (24%) only these joints seemed to be injured. A total of 162 isolated midtarsal injuries and 161 cases of isolated lateral talocrural lesions selected at random were followed using questionnaires 1, 3, 6, 9, and 12 months after injury. The frequencies of pain after 1 month and swelling after 1 and 3 months were significantly lower in isolated dorsal midtarsal sprains compared with isolated lateral talocrural sprains. At the following controls, frequencies of both pain and swelling were the same for both groups. Functional instability appeared with the same frequency in both groups during the 12 months of follow-up. Regarding the social impact of the sprains, absence from work and sports did not differ between groups. When avulsions were present in midtarsal injuries recovery was slow, with two thirds of the patients experiencing pain after 6 months. We conclude that the dorsal midtarsal sprain is a common entity with a course of recovery and a frequency of residual symptoms very like the lateral talocrural lesions. PMID- 8696495 TI - Fractures of the central metatarsal. AB - We reviewed the evolution and final results of 57 patients with central metatarsal fractures treated in Hospital "La Fe" in Valencia between 1982 and 1993. The treatments were nonsurgical in 36 cases and surgical in 21 cases. The most frequent etiologies were traffic accidents, followed by work-related accidents. The fractures were classified according to their anatomic localization and whether they were closed (44 cases) or open (13 cases). Poor functional results manifested by metatarsalgia were present most often when one or two of the following were present: comminution, sagittal plane displacement, open fracture, or severe soft tissue injury. The mean follow-up was 5 years. PMID- 8696496 TI - Reliability of an in-shoe pressure measurement system during treadmill walking. AB - We examined the reliability of in-shoe foot pressure measurement using the Pedar in-shoe pressure measurement system for 25 participants walking at treadmill speeds of 0.89, 1.12, and 1.34 meters/sec. The measurement system uses EMED insoles, which consist of 99 capacitive sensors, sampled at 50 Hz. Data were collected for 20 seconds at two separate times while participants walked at each gait speed. Differences in some of the loading variables across speed relative to the total foot and across the different anatomical regions were detected. Different anatomical regions of the foot were loaded differently with variations in walking speed. The results indicated the need to control speed when evaluating loading parameters using in-shoe pressure measurement techniques. Coefficients of reliability were calculated. Variables such as peak force for the total foot required two steps to achieve a coefficient of reliability of 0.98. To achieve excellent reliability (> 0.90) in the peak force, force time integral, peak pressure, and pressure time integral across the total foot and the seven regions, a maximum of eight steps was needed. In general, timing variables, such as the instant of peak force and the instant of peak pressure, tended to be the least reliable measures. PMID- 8696497 TI - Two case reports of a technique of medial external fixation in calcaneal fractures: indirect control of the sustentacular fragment. AB - In attempted open reduction and internal fixation of displaced calcaneal fractures, comminution of the sustentacular fragment can pose major problems. Two cases of a form of external fixation are presented. The method takes advantage of the strong superomedial and plantar calcaneonavicular ligaments, which link the sustentaculum to the navicular. Traction along these structures (by pins placed in the first metatarsal) indirectly controls the sustentacular fragment, while countertraction from medially placed pins in the tuberosity allows derotation of the fragment and correct repositioning in relation to the sustentaculum. The essential deformities of a calcaneal fracture are corrected by this technique. In addition, distortion of the middle facet appears to correct as well. PMID- 8696498 TI - A method for combined percutaneous and open surgical repair of Achilles tendon ruptures: a report of three cases. AB - Surgical treatment of Achilles tendon ruptures provides excellent functional results in active individuals, although it carries an incidence of wound complications. After experiencing a 25% wound complication rate with the traditional techniques in Achilles tendon ruptures, we modified the Bosworth technique by passing the gastrocsoleus flap percutaneously through the distal stump. This modification eliminated one third of the distal incision, which appears to be the most vulnerable part. We performed the operation in three consecutive cases. At 2-year follow-up there were no wound complications and no reruptures. PMID- 8696499 TI - Recurring desmoid tumor of the foot: a case study. AB - The desmoid tumor is benign, uncommon, and frequently recurs after excision. It can be confusing in terms of diagnosis and treatment due to its ability to achieve large size, causing functional limitation and/or pain. Its overall clinical characteristics can mimic those of its malignant counterparts. Because of its high rate of recurrence, surgical treatment should include a wide excision around the margins. PMID- 8696500 TI - Fracture of the entire posterior process of talus associated with subtalar dislocation: a case report. AB - This is a case report of a 52-year-old woman who sustained a medial subtalar dislocation with fracture of the posterior process of the talus in a traffic accident. After closed reduction of the subtalar dislocation, tomography demonstrated that the talus fracture involved the entire posterior process and the posterior portion of the talar body. The fracture of the talus was treated with an open reduction and miniscrew fixation. At follow-up examination 32 months later, the functional and radiographic results were graded as good. The proposed mechanism of this case was a forced plantarflexion and inversion acting simultaneously on the subtalar joint. This was different from an isolated medial subtalar dislocation, which was caused by an inversion. PMID- 8696501 TI - Fractures of the calcaneus. Part I: Anatomy, injury mechanism, and classification. AB - Calcaneal fractures have been treated by closed methods since the time of Hippocrates. The understanding of the anatomy, injury mechanism, and classification of these fractures has advanced since surgical treatment was introduced in 1850. Despite 145 years of different treatment techniques, no consensus has been reached. Investigation into the injury patterns, anatomy, and outcomes has lead to the advances reviewed in this article. PMID- 8696502 TI - The first metatarsal rise sign: a simple, sensitive sign of tibialis posterior tendon dysfunction. AB - Although foot deformation starts in the early stage of tibialis posterior (TP) tendon dysfunction, this condition is often overlooked or misdiagnosed. We observed consistently a clinical sign of TP tendon dysfunction that, to our knowledge, has not yet been described. Patients were tested while they were standing and fully weight-bearing with both feet. When the shank of the affected foot was taken with one hand and externally rotated, or when the heel of the affected foot was taken with one hand and brought passively into a varus position, the head of the first metatarsal raised in the case of TP dysfunction and remained on the ground in normal TP function. The purpose of this prospective study was to validate this clinical finding by surgical exploration, and to compare its sensitivity with other common clinical signs. Our series included 21 consecutive feet with TP tendon dysfunction (19 patients). The deformity was supple in 12 feet and fixed in 9 feet. Radiographs and magnetic resonance imaging were found to be unreliable in diagnosing dysfunction of the TP tendon. While other clinical signs (too many toes, the single-heel rise, and the double-heel rise) were noted to be negative in 20% to 35%, we found our first metatarsal rise sign to be positive in all cases of TP tendon dysfunction. This simple clinical test enables us to recognize and treat a dysfunction of the TP tendon at an early stage, when the foot is still supple. As the foot deformation progresses, early treatment may be the most effective measure in preventing long-term functional impairment. PMID- 8696503 TI - Bone grafting in foot surgery. PMID- 8696504 TI - Gas chromatographic-mass spectrometric study of photodegradation of carbamate pesticides. AB - The photodegradation of seven carbamate pesticides (bendiocarb, isoprocarb, promecarb, ethiofencarb, furathiocarb, fenoxycarb and pirimicarb), in aqueous solution, has been examined by GC-MS. The most general result was formation of the corresponding phenols. Irradiation of isoprocarb and promecarb also resulted in photo-Fries rearrangement to ortho- and para-hydroxybenzamides. In the case of ethiofencarb photocleavage of the carbon-sulfur bond gave 2-methylphenyl methylcarbamate as main product. Likewise, N-S bond cleavage occurred upon irradiation of furathiocarb, to allow the formation of the carbamate insecticide carbofuran, butyl methylcarbamate and carbofuranphenol. Under similar conditions, fenoxycarb gave p-phenylphenol and 2-hydroxydibenzofuran, through primary homolysis of the aryloxy-methylene bond. Finally, pirimicarb gave rise to 2 formylamino-5,6-dimethylpyrimidin-4-yl dimethylcarbamate. PMID- 8696505 TI - Comparison of four homologous retention index standard series for qualitative gas chromatography of nitrogenous acidic and neutral drugs. AB - Four homologous retention index standard series, the alkylmethylhydantoins, alkylhydantoins, alkylmaleimides and alkylbis(trifluoromethyl)phosphine sulphides, were evaluated for the screening of blood samples for acidic and neutral drugs on Ultra 2 and HP-1701 capillary columns over a six-month period. An index series consisting of actual drug substances was used as a standard of comparison. All the series produced high precision, and the precision differences between the series were rather small. Considering the limitations of the other series, the alkylmethylhydantoins and alkylhydantoins turned out to be the most feasible internal retention index standard series in the present dual column setting. PMID- 8696506 TI - Chemical selectivity in micellar electrokinetic chromatography. II. Rationalization of elution patterns in different surfactant systems. AB - Retention behavior in micellar electrokinetic chromatography (MEKC) is investigated using linear solvation energy relationships (LSERs) for two pseudo stationary phases, one consisting of cationic micelles of tetradecyltrimethylammonium bromide (C14TAB) and the other of an anionic triblock copolymer, poly(methyl methacrylate-ethyl acrylate-methacrylic acid) (Elvacite 2669). It was found that solutes' migration behaviors in these two MEKC systems are mainly influenced by their size (V/100) and hydrogen bonding acceptor (HBA) strength (beta). However, solutes' hydrogen bonding donor (HBD) strength (alpha) has minor effects on their migration in MEKC. The characteristics of these two systems were compared to three other previously reported anionic micellar systems of sodium dodecyl sulfate (SDS) (anionic hydrocarbon), sodium cholate (SC) (anionic bile salt) and lithium perfluorooctane sulfonate (LiPFOS) (anionic fluorocarbon). It was concluded that hydrogen bonding interactions play a major role in providing different chemical selectivity among these five MEKC systems. Both C14TAB micelles and the ionic polymer of Elvacite 2669 provide hydrogen bonding acceptor (HBA) sites for solutes, which is similar to SC micelles. In fact, C14TAB is the strongest HBA, while Elvacite 2669 has HBA strength similar to that of SC micelles. On the other hand, the fluorocarbon micelles of LiPFOS are the strongest hydrogen bond donor (HBD) micelles, followed by the weak HBD SDS micelles. In general, cavity formation has little or no effect on chemical selectivity among hydrocarbon surfactant MEKC systems (i.e., SDS, SC and C14TAB). Information obtained from the LSER analysis is used to rationalize the elution patterns in MEKC with different types of pseudo-stationary phases. PMID- 8696507 TI - Mixed micelles of short chain alkyl surfactants and bile salts in electrokinetic chromatography: enhanced separation of corticosteroids. AB - The separation of a complex mixture of 17 corticosteroids was investigated by mixed micellar electrokinetic chromatography (MMEKC) employing various bile salts and/or alkylsulfonates. In this study, influence of individual surfactants and mixed micelles of hydrocarbon-bile salt surfactants on retention behavior, selectivity and the size of the elution window is investigated. Retention behavior of corticosteroids in SDS and bile salt micelles is examined using linear solvation energy relationships (LSER). In addition, the effects of type of bile salt surfactant on elution patterns were investigated. It was found that separation patterns are mostly influenced by the number of hydroxyl functional groups on the steroidal backbone of the bile salts, while the type of ionic head group has little, if any, effect on the steroids separation. Comparisons between mixed micellar techniques and the inclusion of conventional modifiers to various single and binary surfactant systems were made. The addition of modifiers such as acetonitrile, urea and beta-cyclodextrin to SDS surfactant systems, as well as mixed bile salt systems of sodium taurocholate and sodium glycodeoxycholate, did not improve the separation of the steroids. On the other hand, the addition of the short-chain alkylsulfonate sodium butanesulfonate to the mixture of taurocholate and glycodeoxycholate greatly improved the separation of the 17 corticosteroids and provided a baseline separation of all solutes. The effects of carbon chain length and concentration of alkylsulfonate on capacity factor, selectivity, efficiency and the size of the elution window were investigated. PMID- 8696508 TI - High-performance liquid chromatographic separation of an HIV-1 reverse transcriptase inhibitor and its enantiomer. AB - This article describes the direct separation of an HIV-1 reverse transcriptase inhibitor and its enantiomer by HPLC on a silica-bonded polyacrylamide (ChiraSpher) column. The column selection was based on specific interactions between the individual enantiomers and the chiral stationary phase. The influence of some chromatographic conditions, such as concentration of the polar modifier in the mobile phase, column flow-rate and column temperature, on column performance was investigated. The separation was applied to the determination of the minor enantiomer in the bulk drug and as low as 0.3% of minor enantiomer was detectable. PMID- 8696510 TI - Phone-in tells of aged care neglect. PMID- 8696509 TI - Method development for trace analysis of heteroaromatic compounds in contaminated groundwater. AB - An analytical method providing high sensitivity (limit of quantitation of 50 ng/l) with acceptable reproducibility (mean R.S.D. 19%) has been developed for determining heteroaromatic compounds in creosote-contaminated groundwater. The best technique (highest recovery and reproducibility) found between liquid-liquid extraction using either dichloromethane, diethyl ether or pentane and solid-phase extraction with reversed-phase bonded columns, was the classical liquid extraction with dichloromethane from weak basic solutions and GC-MS (selective ion monitoring) analysis of concentrated extracts. PMID- 8696511 TI - Is the Accord important to nurses? PMID- 8696513 TI - Charting in badly charted waters. PMID- 8696512 TI - We will protect you. PMID- 8696514 TI - Senator Cheryl Kernot: federal leader of the Australian Democrats. Interview by Andrea Baker. PMID- 8696515 TI - Dr Bob Brown: spokesperson for the Green Party of Australia. Interview by Sam Prenesti. PMID- 8696516 TI - Older people deserve better: who cares, who cares? PMID- 8696517 TI - Ethical and legal dilemmas: the daily grind. PMID- 8696518 TI - Drugs, drips and & check-out tricks. PMID- 8696519 TI - Cytological factors relating to posterior capsule opacification following cataract surgery. AB - This paper discusses tissue culture experiments with human lens epithelial cells that demonstrate that cells from all parts of the anterior capsule have regenerative capacity, that the cells from younger patients proliferate more than those from older patients and that cells from cataractous lens retain their growth potential. Epithelial cells may be removed from the anterior capsule by EDTA in an infusion fluid and epithelial cells adhere more to PMMA than HEMA intraocular lenses. The clinical implications of these studies are discussed. PMID- 8696520 TI - An essay on cataract in Latin by Polycarpus Schacher (1701 Dresden). AB - An essay about cataract published in 1701. Although much was known on physiology of vision, this did not yet result in fundamental change on the understanding and treatment of the disease. PMID- 8696521 TI - Prospective HLA-DR matching in penetrating keratoplasty. AB - This prospective study examines whether HLA-DR matching has a beneficial effect on corneal graft survival of high risk patients. Until now, 196 donors have been typed in order to provide 20 patients with a matching graft. The results, though preliminary, are very encouraging. PMID- 8696522 TI - Management of psoteriorly dislocated crystalline lenses or lens fragments. AB - The authors conducted a retrospective study during a 4-year period (jan. 91-dec. 94) of the charts of 26 patients (27 eyes) treated by pars plana vitrectomy for posteriorly dislocated crystalline lenses or lens fragments. One patient had a spontaneous lens luxation on both eyes and 3 patients presented with a posttraumatic dislocation of their lens. Twenty one eyes had retained intravitreal lens material after cataract surgery and 1 after perforating injury. Six eyes received an intraocular lens (IOL) at the end of the vitrectomy procedure; in 11 eyes an IOL had already been inserted at the time of primary cataract surgery. Ten eyes were left aphakic. Surgical details and visual outcome are discussed. PMID- 8696523 TI - Diplopia as an uncommon complication of cataract surgery. AB - Two patients are presented with diplopia after cataract extraction performed under local anesthesia. Since there was no spontaneous recuperation after several months, strabismus surgery was performed. The first patient presented a restriction of the inferior rectus muscle probably caused by the retrobulbar injection of anesthetics. The second patient had a decompensation of a congenital superior oblique palsy. A survey of the different etiologies of diplopia after cataract surgery is given. PMID- 8696524 TI - Congenital intranasal cyst in dacryocystocele. AB - The authors present a case of a newborn with bilateral dacryocystocele in whom repeated probing was unsuccessful. An associated intranasal cyst was diagnosed. Using fiberoptic nasal endoscopy, treatment consisted of probing, irrigation and marsupialization of the cyst. This rarely reported anomaly is a more common finding in dacryocystocele than previously recognized. Careful nasal examination in all infants with congenital dacryocystocele is recommended. PMID- 8696525 TI - Metipranolol associated granulomatous anterior uveitis: not so uncommon as thought. AB - Two case reports of bilateral granulomatous anterior uveitis are described in patients with open angle glaucoma treated with metripranolol 0.6% eye drops. Several cases have been described in the United Kingdom and recently in the United States. In my opinion this reaction is not so uncommon as thought. Possible causes of this phenomenon are proposed keeping in mind that a hypotensive drug can cause intra ocular pressure rise. The incidence of similar cases seems to increase. PMID- 8696526 TI - Indocyanine green angiography in cases of inflammatory chorioretinopathy. AB - We studied 13 patients with various chorioretinal inflammatory diseases, comparing fluorescein angiography and indocyanine green angiography. The study included cases of presumed ocular histoplasmosis syndrome, Birdshot chorioretinopathy, serpiginous choroiditis and acute posterior multifocal placoid pigment epitheliopathy. Based on our findings and comparing them to the few previous reports, we try to better understand the pathogenesis of these inflammatory chorioretinopathies. PMID- 8696527 TI - Bilateral endogenous Staphylococcus aureus endophthalmitis: a case report. AB - In this article the authors present a case of bilateral endophthalmitis caused by Staphylococcus aureus. The characteristics, the treatment and the prognosis of endogenous bacterial endophthalmitis are discussed. The patient was diabetic and treated for a septicaemia caused by Staphylococcus aureus. After a few days we diagnosed a bilateral endophthalmitis. Despite treatment with antibiotics and a bilateral vitrectomy, the final visual outcome was limited. PMID- 8696528 TI - Relationship between carotid wall thickness and forearm blood flow reserve in hypertension. AB - BACKGROUND: The development of a reduced forearm blood flow reserve and an increased carotid intima media thickness is a well known consequence of the structural adaptation of arterioles and large arteries in response to hypertension. It is unknown, however, how those two processes relate to each other in the individual hypertensive patient. METHODS: Minimal forearm vascular resistances (Rmin, the ratio of mean blood pressure to postischemic plethysmographic peak forearm blood flow), common carotid intima media thickness (IMT, high-resolution ultrasonography), blood pressure (indirect method), left ventricular mass, posterior wall and septum thickness (by echocardiography) and lipids were measured in 15 men with mild-to-moderate essential hypertension without evidence of atherosclerotic involvement of the carotid arteries, and in 14 normotensive controls with a similar age range. RESULTS: Rmin and IMT were greater in hypertensives, and a statistically significant positive correlation existed between the two variables. Both Rmin and IMT correlated with left ventricular structure indices and blood pressure. Age showed a positive correlation with IMT, while lipids were unrelated to either parameter. CONCLUSIONS: The micro- and macrovascular segments of the hypertensive circulation readapt in parallel in response to elevated blood pressure, possibly through the commensurate development of medial hypertrophy. PMID- 8696529 TI - Homocysteinaemia after methionine overload as a coronary artery disease risk factor: importance of age and homocysteine levels. AB - BACKGROUND: Homocysteinaemia is now accepted as an independent risk factor for coronary artery disease (CAD). Our goal was to study the influence of age plasma homocysteine level on the CAD risk attributable to homocysteinaemia. METHODS: We studied a group of 98 patients under 55 years of age who had suffered a myocardial infarction 3-12 months before the study. The patients were matched by sex and age with a group of 98 controls without vascular disease. We measured the plasma homocysteine levels 6h after a methionine overload of 0.1 g/kg body weight in patients and controls. Afterwards, the odds ratio for homocysteinaemia was determined by homocysteine level, and that for hyperhomocysteinaemia (homocysteine level > 34 mumol/l) by age group. RESULTS: After methionine loading, the homocysteine odds ratio varied from 0.47 (homocysteine level < 23 mumol/l) to 2.88 (homocysteine level > 34 mumol/l). In patients under the age of 46 the odds ratio for hyperhomocysteinaemia was 18.6. In patients between 46 and 55 years of age the odds ratio for hyperhomocysteinaemia was 1.2. CONCLUSIONS: Low homocysteine levels are protective against CAD, and the higher the homocysteine level the higher the coronary risk appears to be. This clearly means that heterozygosity for cystathionine beta synthase deficiency alone is not enough to explain the vascular risk associated with homocysteinaemia. Hyperhomocysteinemia was shown to be a significant risk factor only in patients under the age of 46 years old. PMID- 8696530 TI - Thrombocytopenia: a risk factor for acute myocardial infarction during the acute phase of Kawasaki disease. AB - BACKGROUND: We report on 10 patients with Kawasaki disease and thrombocytopenia who were found to have a high incidence of coronary artery aneurysm and acute myocardial infarction. The clinical features of these patients, the cause of their thrombocytopenia and the relationship between cardiovascular pathology and thrombocytopenia were analyzed. METHODS: The clinical features of 10 patients with Kawasaki disease found to have thrombocytopenia (group A: mean age 8.0 +/- 7.0 months) and those of 293 patients with Kawasaki disease (group B, controls: mean age 13 +/- 20 months) were analyzed. Coagulation studies and bone marrow aspiration were performed to ascertain the cause of the thrombocytopenia in nine out of 10 subjects in group A. RESULTS: The minimum platelet count was 4-12 x 10(4)/mm3 (average day of illness, 10.3) and platelet counts were elevated to the baseline value within 1-2 weeks of onset of the illness. Low fibrinogen concentrations, high levels of fibrin degradation products, and low erythrocyte sedimentation rates with high C-reactive protein levels were observed in seven patients. In two other patients, immature megakaryocytes with normal coagulation values were observed. The differences in the incidence of coronary artery aneurysm and acute myocardial infarction between groups A and B were highly significant (coronary artery aneurysm: 60% in group A, 8.9% in group B; acute myocardial infarction: 40% in group A, 0.3% in group B). CONCLUSIONS: In many patients with Kawasaki disease and thrombocytopenia, the thrombocytopenia appears to be a result of intravascular coagulation, and to be one of the risk factors for acute myocardial infarction. PMID- 8696531 TI - Prognostic value of exercise stress testing versus ambulatory electrocardiography after acute myocardial infarction: a 3 year follow-up study. AB - BACKGROUND: The aim of this study was to evaluate the prognostic significance of myocardial ischemia detected by ambulatory ECG monitoring (AEM) and exercise stress testing (ExT) following acute myocardial infarction. METHODS: The prognostic value of AEM versus ExT was studied prospectively in 74 patients with a recent acute myocardial infarction. Myocardial ischemia was diagnosed by the presence of ST-segment depression occurring during AEM or ExT 4 +/- 2 and 7 +/- 4 days after hospital admission respectively. ST-segment depression during AEM was defined as a horizontal/downsloping depression of > or = 0.1 mV from the reference baseline, measured 80 ms after the J point, elapsing > or = 1 min. ST segment depression at ExT was determined as > or = 1mm horizontal or downsloping ST-segment depression in at least two consecutive ECG leads. RESULTS: Twenty-two patients (30%) showed ST-segment depression during AEM and 34 (49%) on ExT. During a mean follow-up period of 3 years (36 +/- 15 months), 10 patients (45%) with ST-segment depression on AEM died compared with eight (15%) without; 12 patients (35%) with ST-segment depression on ExT died versus three (8%) without. Death or reinfarction occurred in 13 patients (59%) with ST-segment depression on AEM versus nine (17%) without, and in 13 patients (38%) with ST-segment depression on ExT compared with six (17%) without. Revascularization procedures were similar in patients with or without ST-segment depression during AEM and ExT. Cardiac events defined as death, nonfatal reinfarction or revascularization, occurred in 18 patients (82%) with ST-segment depression on AEM versus 20 (38%) without, and in 23 patients (68%) with ST-segment depression on ExT versus 11 (31%) without. Survival analysis using Kaplan-Meier curves showed that patients showing no ST-segment depression with either technique had longer survival times than did patients showing ST-segment depression on either AEM or ExT, or showing ST-segment depression with both techniques. This was also true when analyzing the cumulative survival rate until the occurrence of any endpoint. With multivariate regression analysis, ST-segment depression on AEM was the variable most strongly predictive of mortality, followed by ST-segment depression on ExT, hypertension, and diabetes. CONCLUSIONS: These findings illustrate the ability AEM and Ext independently to predict long-term cardiac mortality and morbidity rates in patients recovering from acute myocardial infarction. The combined use of these techniques is useful for detecting patients at high risk after acute myocardial infarction. PMID- 8696532 TI - Inferior wall acute myocardial infarction with one-lead ST-segment elevation: electrocardiographic distinction between a benign and a malignant clinical course. AB - BACKGROUND: In most clinical trials, ST-segment elevation in two contiguous leads is required for diagnosis of acute myocardial infarction (AMI). This study describes the clinical course of patients with inferior wall AMI with one-lead ST segment elevation in lead L3 in the initial ECG. METHODS: Of 394 consecutive patients with inferior wall AMI, 31 (7.8%) had an initial ECG showing ST-segment elevation (+/- 1 mm) only in lead L3 (ST < 1 mm in leads L2 and aVF) and upright T waves in inferior leads. Patients were categorized into three groups: (I) no precordial ST-segment depression (n = 6), (II) maximal precordial ST-segment depression in leads V1-V3 (n = 4), and (III) maximal precordial ST-segment depression in leads V4-V6 (n = 21). RESULTS: Patients in group III developed severe heart failure (pulmonary edema or cardiogenic shock) six times more frequently than those in groups I-II (62 versus 10%). Among patients who underwent coronary angiography, three-vessel coronary artery disease (> 50% stenosis) was more common in group III. Five of six patients in group III who underwent emergency angioplasty of the right coronary artery because of cardiogenic shock survived. CONCLUSION: Patients with inferior wall AMI and an initial ECG with ST-segment elevation only in lead L3, and maximal precordial ST segment depression in leads V4-V6, are at risk of severe complications, especially heart failure, but their clinical course may be ameliorated by employing an aggressive interventional strategy. PMID- 8696533 TI - Prevention of restenosis by bezafibrate after successful coronary angioplasty. AB - BACKGROUND: To study the role of bezafibrate in prevention of restenosis after successful percutaneous transluminal coronary angioplasty (PTCA), we evaluated the incidence of restenosis and its correlation with serum lipid levels and effects on the coagulation-fibrinolytic system. METHODS: Subjects who had undergone successful elective PTCA were classified into three groups based on their triglyceride level and whether or not bezafibrate was administered. Fifty two patients who had a triglyceride level < 150 mg/dl were classified as group A. Those with a triglyceride level +/- 150 mg/dl were randomly and prospectively allocated to receive either bezafibrate (group B, n = 21), or no lipid-lowering treatment (group C, n = 22). The restenosis rates in all three groups were subsequently monitored and correlated with serum levels of lipids and coagulation fibrinolytic system markers. RESULTS: In the bezafibrate group, three of 21 patients (14%) had restenosis compared with 12 of 22 (55%) in group C and 18 of 52 (35%) in group A. In groups A and C, fibrinogen and triglyceride levels were significantly higher in the patients with restenosis. At the time of re evaluation, serum triglyceride, fibrinogen, and plasminogen activator inhibitor type 1 (PAI-1) levels were lower and high-density lipoprotein (HDL) cholesterol levels were higher in the bezafibrate group than in group C. By logistic regression analysis, triglyceride and PAI-1 were found to be significant risk factors for postangioplasty restenosis. CONCLUSIONS: Triglyceride is a risk factor for post-PTCA restenosis, and bezafibrate reduces the post-PTCA restenosis rate in patients with a high triglyceride level. In the bezafibrate group, a significant decrease in PAI-1 was observed in association with a decrease in triglyceride level and an elevation of HDL cholesterol level. This suggests that improvement in fibrinolytic capacity is involved in the mechanism of decrease in the rate of restenosis. PMID- 8696534 TI - Management of unstable angina in patients over 75 years old. AB - BACKGROUND: Although there have been reports of successful percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG) in elderly patients, few data are available on the optimal management of unstable angina in such patients. This study was therefore designed to identify the preferred revascularization strategy in patients with unstable angina over 75 years of age. METHODS: Early and late results were evaluated for patients over 75 years with unstable angina undergoing PTCA (n = 51) or CABG (n = 53). The two groups were comparable with respect to age, sex distribution, clinical manifestation of symptoms, left ventricular ejection fraction and accompanying non-cardiac diseases. In the CABG group, significantly more patients had left main coronary artery stenosis (13 and 2%, respectively). RESULTS: Both PTCA and CABG treatment showed similar procedural success rates (91 and 94% respectively) and hospital mortality rates (4 and 6% respectively). Procedural complications were comparable regarding Q-wave myocardial infarction, stroke, renal failure and vascular complications. Patients undergoing CABG received significantly more blood transfusions than those undergoing PTCA (17 and 2% respectively). During follow-up, the mortality rate was comparable in both groups (4% with CABG and 8% with PTCA), but significantly fewer patients in the CABG group developed unstable angina (8 versus 21% in the PTCA group), fewer patients were readmitted to hospital for cardiac reasons (CABG group 17%, PTCA group 31%) and fewer patients needed repeat coronary interventions (CABG group 4%, PTCA group 18%). CONCLUSION: Both PTCA and CABG were comparable with regard to short- and long-term mortality, but CABG treatment was favourable with regard to clinical symptoms, readmission to hospital and repeat coronary interventions. PMID- 8696535 TI - Myocardial necrosis and QRS complex changes in the ischemia-reperfusion setting in a baboon model. AB - BACKGROUND: This study was performed in attempt to draw a correlation between the percentage of myocardial infarction across the left ventricular wall and changes in the QRS complex in the epicardial ECG in a primate model of ischemia reperfusion injury. METHODS: Myocardial infarction was induced in six baboons by ligating the left anterior descending coronary artery for 2h. Using ECG leads, the presence of Q and R waves was recorded along with their associated left ventricular wall thickness. RESULTS AND CONCLUSIONS: The results indicate that Q wave development and R-wave loss can be correlated with depth of infarct. PMID- 8696537 TI - Newspeak in the managed care era. PMID- 8696536 TI - The atherogenic potential of endothelin. PMID- 8696538 TI - Bibliography of the current world literature. PMID- 8696539 TI - The prognostic significance of previous benign breast disease for women with carcinoma of the breast. AB - BACKGROUND: Risk factors for carcinoma of the breast may also have prognostic influence. Because benign breast disease is a risk factor for carcinoma of the breast, we compared the outcomes of patients with carcinoma of the breast with a history of benign breast disease to patients with carcinoma of the breast without a history of benign breast disease. STUDY DESIGN: Patients with benign breast disease and subsequent carcinoma of the breast were matched by age and ethnicity to patients with carcinoma of the breast with no prior history of benign breast disease. Risk factors, pathologic findings, and disease-free survival rates were compared. RESULTS: Patients with previous benign breast disease had a significantly greater family history of carcinoma of the breast (35 percent compared with 22 percent, p = 0.015) and used postmenopausal hormones significantly more frequently (16 percent compared with 5 percent; p < 0.001) than women without benign breast disease. In patients with benign breast disease, their subsequent carcinomas were smaller (T1, 53 percent compared with 43 percent), with significantly fewer nodes involved (1.8 compared with 2.7, p = 0.031), and were significantly more likely to contain an infiltrating lobular component (9 percent compared with 3 percent, p = 0.023). Significantly fewer patients with previous benign breast disease had metastatic disease (18 percent compared with 31 percent; p = 0.001). The ten-year cumulative disease-free survival rate for patients with benign breast disease was 68 percent compared with 59 percent for women without a history of benign breast disease. CONCLUSIONS: This study indicates that women with benign breast disease who have carcinoma of the breast develop may have a better outcome than women without a history of benign breast disease. PMID- 8696540 TI - Survival factors in 186 patients younger than 40 years old with colorectal adenocarcinoma. AB - BACKGROUND: We sought to determine the clinical factors and tumor characteristics associated with the reported poor prognosis in young patients with carcinoma of the colon and rectum. STUDY DESIGN: A retrospective review was performed of 186 patients younger than 40 years of age who were treated for primary colorectal adenocarcinoma. The median age was 34.3 years, and the median follow-up period was 9.4 years. Clinical and tumor histopathologic parameters were analyzed. RESULTS: Regional lymph node metastases, distant metastases, or both, were seen at first examination in 65.6 percent of young patients. Histopathologic indicators of more aggressive tumor biology were present at a significantly higher frequency in young patients compared with patients older than 40 years (p < 0.001). Poorly differentiated tumor grade was present in 41.0 percent, signet ring cell tumors were found in 11.1 percent, and infiltrating tumor leading edges were present in 69.0 percent of young patients. Among young patients with stage II disease, vascular invasion was a significant negative prognostic variable (p < 0.05). CONCLUSIONS: We have demonstrated an increased incidence of three biological indicators of aggressive and potentially metastatic tumor biology in 186 young patients with carcinoma of the colon and rectum: signet-ring cell carcinoma, infiltrating tumor edges, and aggressive histologic grade in the primary adenocarcinoma. The increased incidence of these three histologic measures of more aggressive carcinoma of the colon and rectum in part accounts for the higher rate of advanced disease at presentation in patients younger than 40. PMID- 8696541 TI - Resection of benign hepatic lesions with selective use of total vascular isolation. AB - BACKGROUND: The main morbidity associated with hepatic resection is related to excessive blood loss. Total vascular isolation (TVI) may be used to minimize blood loss in difficult hepatic resection cases. STUDY DESIGN: We reviewed our criteria for use of TVI and our experience in 43 patients who underwent hepatic resection for benign lesions between January 1990 and January 1995. Total vascular isolation was used in 23 patients; 20 resections were performed without TVI. RESULTS: We found TVI particularly useful for resection of highly vascular lesions, and lesions located centrally or adjacent to major vessels. The use of TVI reduced blood loss in difficult hepatic resections; transfusion requirements for these patients were similar to requirements for the resection of peripheral lesions. Fewer complications directly related to hepatic resection were encountered in the TVI group. CONCLUSIONS: Appropriate use of TVI will improve results after difficult hepatic resections and allow maximal sparing of normal hepatic tissue when operating on benign lesions. PMID- 8696543 TI - Laparoscopic aortic replacement in the porcine model: a feasibility study in preparation for laparoscopically assisted abdominal aortic aneurysm repair in humans. AB - BACKGROUND: Current laparoscopic vascular techniques have centered around aortofemoral bypass for the treatment of patients with aortic occlusive disease. However, the majority of aortic surgeries are performed for the treatment of aortic aneurysmal disease. With this mind, we undertook this study to assess the feasibility of laparoscopic aortic replacement in the porcine model in preparation for laparoscopically assisted abdominal aortic aneurysm (AAA) repair in humans. STUDY DESIGN: Twenty-three female pigs weighing between 35 and 40 kg underwent laparoscopic aortic dissection by either a transabdominal or retroperitoneal approach. The infrarenal aorta was laparoscopically dissected, isolated, and cross clamped. Then a custom designed cuffed polytetrafluoroethylene graft was inserted. After reestablishing and confirming distal flow, the animals were sacrificed. RESULTS: Fifteen functioning aortic grafts were placed in 21 animals who had the transabdominal approach. One functioning graft was placed in the retroperitoneal group. Complications included bladder, ureteral, inferior vena cava, renal vein, and aortic injuries. By the end of the study, the operative time was reduced from six to less than two hours; blood loss was reduced from 1,000 to 150 mL; and cross-clamping time was reduced from 60 to 15 minutes. CONCLUSIONS: In the porcine model, laparoscopic abdominal aortic replacement is associated with a significant learning curve. However, this method of repair is technically feasible and warrants further investigation in the treatment of AAA in humans. PMID- 8696542 TI - The Pittsburgh randomized trial of tacrolimus compared to cyclosporine for hepatic transplantation. AB - BACKGROUND: Tacrolimus (formerly FK506) was first used clinically in 1989 to successfully replace cyclosporine in hepatic transplant recipients who were experiencing intractable rejection or as the baseline drug from the time of operation. After extensive pilot experience, an institutional review board mandated clinical trial comparing cyclosporine with tacrolimus was performed. STUDY DESIGN: From February 16, 1990 to December 26, 1991, 154 patients were recruited. The competing drugs were combined with equal induction doses of prednisone in both arms of the study for the first 81 patients and with subsequently higher doses of prednisone in the remaining 35 patients who received cyclosporine and were entered into the trial. Drug crossover was permitted for lack of efficacy or adverse events. End points were rejection confirmed by biopsy and treatment failure leading to retransplantation or death. RESULTS: Seventy nine patients were randomized to the tacrolimus arm and 75 to the cyclosporine arm during 1990 and 1991. All patients were available for follow-up throughout the trial, which terminated on May 30, 1995. The mean duration of follow-up was four years. Patients randomized to the tacrolimus arm were less likely to experience acute rejection than were those receiving cyclosporine, with 36.2 percent of the patients receiving tacrolimus and 16.8 percent of the patients receiving cyclosporine showing freedom from rejection at one year (p = 0.003, likelihood ratio test). Survival of patients over the course of the study was virtually the same in the two groups. PMID- 8696544 TI - Nonoperative management of blunt splenic injury in adults: age over 55 years as a powerful indicator for failure. AB - BACKGROUND: Selective nonoperative management of adults with blunt splenic injury continues to evolve. Predictive factors associated with successful nonoperative management have primarily been clinical criteria such as hemodynamic stability and the degree of associated injuries. This study evaluates the role of patient selection in the safety and success of nonoperative management of adults with blunt splenic injury. STUDY DESIGN: Herein, we present a retrospective analysis of the management and outcome of 135 adult (16 years of age or older) patients with blunt splenic injury at a large urban Level 1 trauma center during a six year period. RESULT: A total of 46 adult patients were treated nonoperatively after blunt splenic injury during the study period. Patient ages ranged from 16 to 93 years (mean, 36.9 years) with 11 patients 55 years of age or older. Nonoperative management was successful in 24 (52 percent) patients. Patients failing nonoperative management were significantly older than patients successfully observed (mean age, 48.1 and 26.7 years, respectively). There were ten (91 percent) failures among the 11 patients 55 years of age or older compared to 12 (34 percent) failures among younger adults despite similar mean computed tomography splenic injury grading and Injury Severity Scores (p < 0.01). Complications were significantly more prevalent in older patients than in younger patients who failed observation (p < 0.01). CONCLUSIONS: Nonoperative management of adults with blunt splenic injury commonly fails in older patients independent of other clinical and radiographic variables. We conclude that age over 55 years is a contraindication to nonoperative management of patients with blunt splenic injury. PMID- 8696545 TI - A randomized, prospective trial of standard Hickman compared with Groshong central venous catheters in pediatric oncology patients. AB - BACKGROUND: Safe and reliable central venous access is critical in the management of children with cancer. A recently described valved catheter (Groshong) requires less frequent flushing to preserve catheter patency, theoretically reducing daily care costs for the catheter as well as lessening the risk of mechanical or infectious complications. This study compared standard Hickman to Groshong catheters in a group of pediatric oncology patients. STUDY DESIGN: From December 1992 to May 5, 1994, 20 consecutive pediatric oncology patients were randomized by medical record number to receive either a standard dual lumen Hickman (7F) or Groshong (9.5F) catheter. All patients were prospectively followed on a weekly basis and a log was maintained regarding complications and cost of maintenance of the catheter until it was removed. RESULTS: Ten patients received Groshong catheters and ten received Hickman catheters. Total catheter days for each group were similar (Hickman, 2,599 compared with Groshong, 2,389 days). Five Groshong catheters required removal because of mechanical complications and several required daily flushes because of blood backing up into the catheter lumen. When taking into account the cost of associated complications, no differences were noted in daily cost for maintenance between the two catheters. CONCLUSIONS: When considering the cost of complications, Groshong catheters were no less expensive to maintain compared with standard Hickman catheters. Furthermore, Groshong catheters malfunctioned more frequently and required a greater number of urokinase instillations for withdrawal occlusion. The use of the Groshong catheter in pediatric oncology patients cannot be supported by the present study. PMID- 8696547 TI - Primary duodenal adenocarcinoma: role for aggressive resection. PMID- 8696546 TI - A prospective randomized study of end points of resuscitation after major trauma: global oxygen transport indices versus organ-specific gastric mucosal pH. AB - BACKGROUND: Gastric tonometry, as a method of organ-specific monitoring of the status of the splanchnic circulation, has demonstrated prognostic and therapeutic implications in critically ill patients. The experience with this method in patients with trauma has been limited. STUDY DESIGN: Fifty-seven patients were prospectively randomized into two groups: group 1, n = 30, normalization and maintenance of gastric mucosal pH (pHi) at or above 7.3 and group 2, n = 27, maintenance of oxygen delivery index of 600 or an oxygen consumption index of greater than 150. The groups had statistically similar injury severity scores, lactate levels, and base deficits. RESULTS: Of the 44 patients with pHi greater than 7.3 at 24 hours, three (6.8 percent) died of multiple organ dysfunction syndrome as compared with seven (53.9 percent) of 13 in whom pHi was not optimized, p = 0.006. Optimization times for oxygen delivery index, oxygen consumption index, lactate levels, and base excess were similar between survivors and nonsurvivors. The time for pHi optimization was significantly longer in nonsurvivors. Multiple organ dysfunction syndrome points were significantly higher in patients who did not have pHi optimized within 24 hours (6.08 compared with 2.5, p = 0.03). Optimization time for pHi was predictive of mortality on multiple regression. Persistently low pHi was frequently associated with systemic or intra-abdominal complications. It was the first finding in all the nonsurvivors at least 48 to 72 hours before death. CONCLUSIONS: Gastric mucosal pH may be an important marker to assess the adequacy of resuscitation. Monitoring of pHi may provide early warning for systemic complications in the postresuscitation period. PMID- 8696548 TI - Cervical esophagogastric anastomosis by the cuff technique using a stapler. PMID- 8696549 TI - "Protected" double needle biopsy technique for hepatic tumors. PMID- 8696550 TI - Pancreatic adenocarcinoma: an update. PMID- 8696551 TI - Primary duodenal adenocarcinoma: a ten-year experience with 79 patients. AB - BACKGROUND: Duodenal adenocarcinoma is a rare malignancy with a poorly defined natural history and outcome. The factors that affect management and survival of patients with this disease remain controversial. This study analyzed the ten-year experience at one institution with primary duodenal adenocarcinoma to define factors that have an impact on patient survival. In addition, the outcome of patients with resected duodenal adenocarcinoma was compared with that of patients with gastric and pancreatic adenocarcinoma. STUDY DESIGN: A retrospective review of the prospective database for patients with peripancreatic lesions treated at Memorial Sloan-Kettering Cancer Center between 1983 and 1994 identified 79 patients with a primary duodenal adenocarcinoma. Demographics, presenting symptoms, operative variables, pathologic findings, and survival data were analyzed. Multivariate comparisons and actuarial survival were calculated using these variables. RESULTS: A curative resection was performed in 42 (53 percent) of the 79 patients, including 38 pancreaticoduodenectomies and four duodenal resections. The overall projected five-year survival rate was 31 percent, with resected and nonresected patient survival rates of 60 and zero percent, respectively (p < 0.0001). Nodal metastases, regardless of location, did not have an impact on survival. While stage was a significant factor in survival on univariate analysis, no survival difference was noted between stages I, II, and III. Only resectability and presence of non-nodal metastases predicted outcome on multivariate analysis. CONCLUSIONS: Resectability and presence of distant metastatic disease are the strongest determinants of outcome for patients with duodenal adenocarcinoma. Staging and nodal status offer little prognostic information and nodal positivity should not preclude resection. As patients have symptoms similar to those of pancreatic adenocarcinoma but have an outlook more comparable to gastric adenocarcinoma, a vigorous approach to resection is justified. PMID- 8696552 TI - Surgical management of internal fistulas in Crohn's disease. AB - BACKGROUND: Internal fistulas in Crohn's disease join a diseased intestinal segment to a "victim organ" (VO) that is affected by proximity. While the diseased segment is resected, the other can be sutured in selected cases. STUDY DESIGN: Seventy-four patients with 100 internal fistulas were retrospectively reviewed to assess the results of this conservative operative approach. RESULTS: Closure of the fistulous defect of the VO was achieved by resection (n = 41) or suture (n = 59). The VO was histologically unaffected by Crohn's disease in 86 cases. One patient died postoperatively. Three patients had postoperative fistulas after suture of the VO. There was no long-term recurrence of an internal fistula. CONCLUSIONS: Surgical treatment of internal fistulas can be achieved safely by resection of the source of the fistula and suture repair of the VO when the latter is not affected by active Crohn's disease and when local conditions make it feasible. PMID- 8696554 TI - [The hospital and all its dangers]. PMID- 8696553 TI - [Danger, violence and nursing diagnosis]. PMID- 8696555 TI - [The nurse-patient relation]. PMID- 8696556 TI - [The notion of danger in nursing students]. PMID- 8696557 TI - [Fear in nursing students and dangers during training]. PMID- 8696558 TI - [Stress without distress in baccalaureate nursing education if that were possible?]. PMID- 8696559 TI - [Handling antimitotic drugs. Danger or security]. PMID- 8696560 TI - [Mental management: a teaching tool]. PMID- 8696561 TI - [Admission to nursing school]. PMID- 8696562 TI - [Care and dangers]. PMID- 8696563 TI - [Creativity in the service of education]. PMID- 8696564 TI - [Preparation for the competition for admission to the schools for health managers. Nurses options]. PMID- 8696566 TI - [Letters from ... to...]. PMID- 8696565 TI - [A propos of nursing apprenticeship]. PMID- 8696567 TI - [Software for the teaching of anatomy and physiology]. PMID- 8696568 TI - Counseling parents and prospective parents with epilepsy. PMID- 8696569 TI - Assessing children's concerns about epilepsy. PMID- 8696570 TI - Myths and misperceptions about epilepsy: national survey results. PMID- 8696571 TI - Adolescent psychosocial issues in epilepsy. AB - Adolescence is a period of profound biological, emotional, intellectual, and social transformation unmatched, perhaps, by any other period of life. Ideally, the individual emerges from this period with a positive self-image, a strong sense of identity, and the capacity for intimacy with peers and independence from the family (McAnarney, 1985). The adolescent with epilepsy is confronted with the additional task of adjusting to a chronic seizure condition. Epilepsy leads to problems when it interferes with the completion of developmental tasks at the proper time. PMID- 8696572 TI - Sexual assessment & intervention for people with epilepsy. PMID- 8696574 TI - Comparison of tape products on skin integrity. AB - A two-group, nonconcurrent design was used in this comparative study to assess the incidence of skin breakdown accompanying Durapore silk tape and Medipore soft cloth tape (both manufactured by 3M Health Care). A significantly higher number of skin tears were found with silk tape use (mean 2 = 7.69, p < 0.01). This type of skin damage caused patient discomfort and incurred additional treatment costs. Soft cloth tape is recommended to decrease skin tears in surgical patients. PMID- 8696573 TI - Pressure ulcers: the Minimum Data Set and the Resident Assessment Protocol. AB - As Americans age and live longer with chronic disabilities, more elderly citizens will reside in nursing homes. The nationally mandated Minimum Data Set (MDS) and Resident Assessment Protocol (RAP) were designed to help plan for the care of the frail elderly residing in nursing homes. One of the areas specifically targeted was pressure ulcers. This study was designed to describe the prevalence, incidence, and current management practices relating to pressure ulcers in nursing homes based on MDS data. In addition, a cross-sectional investigation was performed to examine the MDS items found in the pressure ulcer RAP. The MDS data for 2,011 nursing home residents, aged 60 or older, who lived in 270 facilities from 10 states were evaluated. The results found a prevalence of 11.2% for Stage II-IV lesions and a 6-month incidence of 6.2%. Logistic regression analysis determined that dependence in transfer or mobility, being bedfast, having diabetes mellitus, and having had a pressure ulcer in the past were significantly associated with a Stage II-IV pressure ulcer. The MDS and its associated RAP for pressure ulcers provide the data to begin devising a care plan for patients with pressure ulcers. PMID- 8696575 TI - Report of the task force on the implications for darkly pigmented intact skin in the prediction and prevention of pressure ulcers. PMID- 8696576 TI - Compartment syndrome in the diabetic foot. AB - The compartment syndrome is a well-described clinical entity that results from increased pressure within a myofascial compartment. The infection in a diabetic foot usually presents in the whole compartment and can spread to a neighboring compartment. The association of infection and increased compartment pressure in the diabetic foot makes its treatment a formidable challenge. Fasciotomies of the feet when indicated may accelerate infection control and wound healing in the diabetic foot. The presence of a compartment syndrome in the diabetic foot is seldom recognized. Awareness of this problem is mandatory for physicians dealing with diabetic feet. PMID- 8696577 TI - The Minimum Data Set-2 and skin ulcers. PMID- 8696578 TI - The emergence of survivor syndrome. PMID- 8696579 TI - Nurse absence--the causes and the consequences. AB - This paper addresses nurse absence as it occurs in health care organizations and as a form of withdrawal behaviour from work. Absence represents a traditional domain of conflict between nursing management and their employees in day-to-day practice. The aim of the following discussion is to extend nursing management's understanding of the topic as a precondition for well-balanced schedules and effective human resource planning. A discussion of planned and unplanned absence thus arises and appropriate types of measurement, taking employee absence behaviour into account, are outlined. The implications of the arguments, developed in detail in the first part of the paper, are applied in the second part using a hypothetical account. In order to illustrate the importance of managing absence by nursing management, a method for calculating schedules is described which investigates the organizational control of planned and unplanned absence. This method proposes a seven stage calculation and highlights the processes that are essential for taking absence into account. PMID- 8696580 TI - Quality and quality assurance in the health care setting: an equitable life? AB - Research studies alluding to quality and quality assurance within the health care arena are increasingly utilized to justify management initiatives, particularly in relation to the provision and resourcing of patient services, both within the institutional and community setting. The following paper considers the role and utility of quality indicators and presents a critical analysis of the literature pertaining to the concept of quality as it applies to the provision and organization of health care and the relationship between quality assurance and patient satisfaction per se. The paper concludes with a dual challenge not only to nurses to better understand and articulate the specific contribution of the discipline, particularly in relation to positive patient outcomes, but also to current, narrow focused interpretations of quality assurance and calls for definitions of quality to reflect an appreciation of the particular involvement and role of the patient in determining policy affecting care provision. PMID- 8696581 TI - The implementation and evaluation of a quality improvement initiative at Oaklands. AB - Striving for high quality care is one of the cornerstones in the management of nursing practice and implementing quality improvement initiatives contributes to this goal. In this paper an account is given of how the implementation of a quality initiative, a redesigned needs and strengths nursing assessment, contributed to an improvement in quality of life for a group of children who have learning disabilities. It is also postulated that the initiative may improve staff morale and lessen the likelihood of burn-out-- a phenomenon which can adversely effect the quality of care provided by nurses. A small pilot evaluation study using questionnaires and observation was undertaken to evaluate the initiative. Findings suggest that nursing assessment is one of the factors which has contributed to an improvement in the quality of interpersonal aspects of nursing care for the children at Oaklands. PMID- 8696582 TI - Organizational culture: a useful concept for nurse managers? AB - The use of the term culture, in the context of health care organizations, has become commonplace in a wide range of literature, however, the exact meaning intended when this word is used is not always clear. This paper questions the current widespread recourse to the concept of organizational culture as a way of explaining all 'soft' organizational issues and suggest a greater degree of clarity is necessary if the concept is to retain its explanatory utility. Using three components of the concept as an organizing framework to guide the analysis, its application to health care organizations, and nursing in particular, is examined. This demonstrates how the concept can be effectively utilized without losing an appreciation of its inherent complexity. The dimensions of the concept identified for this purpose are: instrumental; cognitive; and interpretive. It is argued that, when clearly defined and appropriately applied, culture can be a useful concept for nurse managers in that it increases understanding of, and thereby contributes to, the effective management of complex health care organizations. PMID- 8696583 TI - Key strategic challenges facing purchasers of health care--a Scottish perspective. AB - This paper describes the key strategic challenges facing a purchaser of health care services in central Scotland. The paper describes a number of key issues including influencing the health of the local population, the financial constraints, the development of alliances and the involvement of service users in planning. It highlights the importance of organizational development and the management of the external environment. Long-term challenges associated with the purchase of health care are suggested and the paper concludes that achieving health status targets and the desires of the local population could well conflict. It suggests that health boards/authorities will need to enhance their planning and developmental work for the future. PMID- 8696584 TI - Between the trapezes--making the most of change. AB - This paper recounts the author's own experience of mismanaging change and describes the unfortunate outcome. Two theories are introduced and applied retrospectively to the case cited in order to identify how it could have been handled more sensitively and successfully. The first theory relates to the stages involved in the process of change as described by William Bridges. The second refers to the specific relationship between the psychometric instrument, Myers Briggs Type Indicator (MBTI) and the different ways in which individuals are likely, and to a certain extent can be predicted to behave in a time of change. PMID- 8696585 TI - Mergers and acquisitions: some implications of cultural change. AB - A result of recent National Health Service reforms is the need to investigate, and possibly change, the culture of the professional working relationship between members of staff and their employer. This is particularly the case in situations of mergers and acquisitions where staff working from different cultural environments must work together. Mergers are becoming a feature of health service provision, perhaps this becomes most obvious with the recent moves by colleges of nursing and midwifery into the higher education sector and amalgamations of some purchasing authorities. Mergers highlight the practical issues of bringing together different organizational and work cultures to deliver a high quality service. This article discusses some aspects of the nature of organizational culture, the human impact of mergers and acquisitions and offers strategies for managing these events. PMID- 8696586 TI - Client and patient needs in community practice: whose work is it anyway? PMID- 8696588 TI - Eating despite severe difficulties: assessment of poststroke eating. AB - A programme for the assessment and nursing diagnoses of eating difficulties among stroke patients was tested. The patients' experiences regarding eating were expressed in interviews and dialogues. Eating was observed during both a test meal and regular meals. The assessments included the prerequisites for eating as well as oral, pharyngeal and oesophageal functions. General and specific nursing diagnoses as well as life consequences (handicap) were established, based on assessment of disabilities and impairments, and interviewing the patients and their families, respectively. The general nursing diagnoses were formulated on admission after the test meal and these were reformulated to form specific nursing diagnoses after assessments of the functions. The programme presented proved to be useful in clinical practice. It is emphasized that many assessments must be co-ordinated for each individual. PMID- 8696589 TI - Intravenous filters, panacea or placebo? AB - Proponents of intravenous filters claim that they remove bacterial contaminants, particulate matter, air emboli and reduce the incidence of phlebitis. From unstructured observation by the author at a large general hospital not using filters it was concluded that the incidence of complications was no greater than at a hospital having a policy for using these filters. Despite the introduction of a filter that claims to retain endotoxin for up to 96 h, filters are still misused, over used or unused in different departments of the same hospital. This paper examines the literature that supports and criticizes the advantages and disadvantages of using such filters. The research is reviewed to ascertain whether the widespread use of filters is justified and whether they effectively reduce or prevent the complications of intravenous therapy. The paper reviews the causes and incidence of complications of intravenous therapy and alternative methods used for reducing these complications. The evidence shows conflicting results and argues that complications are inevitable despite the use of filters or careful medical action. The manufacturer's claims are supported by a plethora of literature but discrepancies are evident and the author remains unconvinced of their widespread use in today's fragile economic climate when the cost of treating the adverse effects of intravenous therapy is considered. PMID- 8696587 TI - An action research investigation into the feasibility of experienced registered sick children's nurses (RSCNs) becoming children's emergency nurse practitioners (ENPs). AB - Emergency nurse practitioners (ENPs) formally developed in accident and emergency (A & E) departments as a direct response to waiting times for the walking wounded, the need to reduce junior doctor hours and changes in nursing practice. ENPs existed informally for many years in minor injuries units and specialist ophthalmic departments. This study aimed to examine whether or not the role of ENP could be applied to the specialist service of a paediatric casualty department. The results showed that 3% of patients could be seen and treated to conclusion by a children's ENP, and some patients could have their care accelerated by a children's ENP. The introduction of children's ENPs would have an impact on waiting times, junior doctors work-load and the quality of patient care. PMID- 8696590 TI - Assessing patient satisfaction. Part 2. Findings: nursing, the hospital and patients' concerns. AB - Part 1 of this article discussed the process of evaluating patient satisfaction by means of unstructured, in-depth interviews. In this part, the content of interviews will be presented and the analytic domains derived from the research will be described. These are 'nursing', 'the hospital' and 'patients' concerns', and the categories which make up these domains will be discussed. PMID- 8696591 TI - Clinical practice development and research activities in four district health authorities. AB - This review is based on findings from a postal survey undertaken between March and September 1993 to elicit information from nurses in four district health authorities regarding development and research activity in which they were involved. The objectives of the review were to obtain baseline information on the extent, variety and scope of work being carried out, to provide staff with a mechanism for networking good practice and to identify any areas of replication. A snowball sampling technique was used to obtain information from nursing personnel. A total of 141 responses were received out of which 4% (n = 5) reported no activity. Response rates varied between organizations and specialist groups but were similar in terms of the number of small-scale clinical practice developments undertaken without identified support or supervision. Fifty-five per cent (n = 75) of the reported developments related to the organization and management of services while 11% (n = 15) focused on consumer-related issues. Few studies identified dissemination strategies and there was generally a lack of clarity over expected benefits of the study in terms of measurable outcomes to the organization, nursing staff or patients. Funding for clinical practice development and research in nursing was found to be very sparse; the reasons for this were not identified. Overall the review confirmed statements from other sources (DoH, 1993 a,b) that nursing development and research tends to be small scale and unsupported with nursing staff trying hard to implement research findings or be innovative in their practice without the necessary expertise and support. Such findings have implications for the current drive to implement research into practice. PMID- 8696592 TI - Establishing a framework for research: the example of needs assessment. AB - This paper explains the early planning stage of a study commissioned by the English National Board which will investigate the changing educational needs of community nurses with regard to needs assessment and quality of care in the context of the NHS and Community Care Act 1990. Two focus groups, comprising 22 participants altogether, generated data which were used to augment and clarify issues explored in an initial literature review. Some of the methodological issues are explained. Traditional community nursing approaches to needs assessment appeared to value process and integration, while the new legislation emphasizes the separateness of assessment; there is a danger that it may be seen as a single event. The consumer views were both supportive and critical about each of the approaches; some important insights were gained, and a confident basis from which to launch the study identified. The approach offers one possible way to clarify the starting point of a project when carrying out a standard literature review seems insufficient. This may occur with under-researched or rapidly changing phenomena, or if a field of interest is the subject of multiple interpretations or lack of consensus. PMID- 8696593 TI - Issues of reliability and validity in the measurement of challenging behaviour (behavioural difficulties) in learning disability: a discussion of implications for nursing research and practice. AB - The purpose of this paper is to contribute to the debate on issues related to the reliability and validity of measurement of challenging behaviour (behavioural difficulties) in learning disability. A number of practical, theoretical and methodological issues are discussed that have significance for the nurse both as practitioner and/or researcher in learning disability. These issues are equally important to both provider and purchaser of health care in order that resources can be most effectively targeted. The term 'challenging behaviour' would appear to be used both in literature and research synonymously with behavioural difficulties, this has implications for nurses in both their clinical practice and/or research. The author concludes by identifying a need to replace the term challenging behaviour, with 'behavioural difficulties'. It is argued that such a term is much more explicit in meaning and amenable to operational definition, thus enabling empirical study. Such a proposal will not be accepted by all as justifiable; this is because some might argue that adopting the term behavioural difficulties may be a retrograde step that perpetuates negative imagery and inappropriate labelling of people with a learning disability. PMID- 8696594 TI - Staff perspectives on the role of the nurse in rehabilitation wards for elderly people. AB - The increasing demand for cost-effective and efficient health care may create a demand for more demonstrably effective hospital-based rehabilitation services, with the explicit goal of enabling patients to return home after short admissions; thus rehabilitation is centre stage. This paper reports the findings from a study of the rehabilitation of elderly people in hospital; in particular it focuses on an aspect of the process of care: namely staff perceptions of rehabilitation work, with particular emphasis on the role of the nurse. A conversational style of interviewing was used with 56 staff respondents from two rehabilitation wards for elderly people. Findings suggest that therapists are often seen as experts, and nursing is viewed as separate from rehabilitation, and hence nurses are an under-utilized resource in this field. It is suggested that there is a need to examine further the reality of multidisciplinary teamwork in rehabilitation, particularly with respect to maximizing the potential contribution of nurses, with the end goal of improving patient outcomes. PMID- 8696595 TI - The effects of patient suicide on nursing staff. AB - Attitudes towards patient suicide, and the effects that this has on nursing staff are rather complex, and should not be viewed on a simple negative/positive continuum. Suicide is a difficult but inevitable incident that affects psychiatric units, and the limited literature on nurses' attitudes to suicide, and the effects that patient suicide has on them has highlighted the need for emotional and professional support from their colleagues, including senior nurses, psychiatrists and managers, to cope better after a patient has committed suicide. Furthermore, the importance of regular meetings and reviews of assessment and prevention policies has also been emphasized. The present study looked at the effects that suicide has on nursing staff, their attitudes, and ways of improving their coping skills. Major findings include the lack of emotional support, the need for training, formal assessment of patients at risk, regular multidisciplinary meetings following a suicide and nursing staff's acceptance of suicide as the patient's personal choice. Recommendations for helping nursing staff during the post-suicide period are suggested. PMID- 8696596 TI - Nursing the physically disabled in a general hospital ward. AB - Progress in medical treatment over the last three decades has meant that many more people survive either traumatic birth situations or diseases/injuries which would have previously resulted in death, and are leading normal lives with some form of physical disability. Until quite recently, little attention has been given to their longer-term health needs. The following article looks at the attitudes of nurses towards physically disabled patients, the experiences and attitudes of these patients, the interaction between nurse and patient, practical outcomes and future directions. Literature on this subject is not extensive. More empirical research is required focusing on the impact of admission of such people on general hospital ward functioning, the experiences/insights of nursing staff caring for them and the reaction and comments of physically disabled patients. PMID- 8696597 TI - First steps towards evaluating clinical supervision in nursing and health visiting. I. Theory, policy and practice development. A review. AB - The subject of clinical supervision for nurses and health visitors in the UK is considered in this paper. The paper highlights recent debates in thinking and rapid developments in practice. The original concept of clinical supervision, its theoretical propositions and development, recent policy influences and current strategies for evaluation are debated. PMID- 8696598 TI - Do larger caseloads cause greater stress in community mental health nurses. PMID- 8696599 TI - 'The practice of caring is central to nursing' (Watson, 1979) PMID- 8696600 TI - Caring research and concepts: a selected review of the literature. AB - A selected review of the literature on caring in nursing is presented. The review relies on the work of the major theorists in this area. The major conceptualizations of caring are compared and contrasted, along with some of the research approaches which have been applied to investigate the phenomenon of caring in nursing. The outcome of quantitative and qualitative research on caring is described and the justification for an extension of the quantitative work, through the development of an appropriate inventory and the application of multivariate statistical analysis, is discussed. PMID- 8696601 TI - Preoperative hair removal: a case report with implications for nursing. AB - Preoperative hair removal has been a practice since the beginning of this century. Research in the 1970s and 1980s provide support for the contention that the procedure is unnecessary for wound asepsis and may increase the rate of surgical site infections (Seropian & Reynolds, 1971; Hamilton et al., 1977; Cruse & Foord, 1980; Court-Brown, 1981; Alexander et al., 1983; Winfield, 1986; Fairclough et al., 1987). However, some hospitals have continued routine preoperative hair removal long after dissemination of recommendations against it. This begs the question, 'Why is it that so often research findings are not applied in practice'. In Stroud v. General Hospital Corp. and Pollett (1993), a man died of sepsis resulting from cuts he gave himself after he was asked by a nurse, in complete violation of the hospital's preoperative skin preparation protocol, to clip hair from his abdomen. The court held the hospital liable for the nurse's negligent breach of its protocol. The case clearly supports findings in the literature that preoperative hair removal is potentially dangerous. It reinforces the importance of strict adherence to hospital protocols which have been put in place to protect patients' safety. PMID- 8696602 TI - Self-care: the application of a ward philosophy. AB - The purposes of this study were twofold. The first was to determine the rationale behind the adoption of a self-care approach to nursing. The second, to determine how a self-care philosophy is applied in practice. The study was carried out from a phenomenological perspective, as it facilitated an understanding of nursing practice from the practitioners' perspective. The adoption of a self-care philosophy and approach to caring, appears to have evolved through patients need. This finding has implications for all practitioners. PMID- 8696603 TI - Paediatric nursing and research ethics: is there a conflict? AB - This paper briefly outlines the major ethical issues which need to be considered when conducting paediatric research. An overview of ethical theories and principles will highlight the difficulties which may be experienced when making decisions about children's competency to consent to participate in research. The congruency of the paediatric nurse as 'researcher' and 'practitioner' will be examined. Does the nurse involved in paediatric research experience a conflict between a commitment to research and safeguarding the interests and well-being of the child. PMID- 8696604 TI - Can elderly residents with memory problems be prepared for relocation? AB - Relocation of elderly clients between residential establishments can be unsettling, although good preparation can help reduce negative effects and contribute to successful transfer. However, it is less clear whether preparation is feasible for residents with cognitive deficits and clarification of this issue was the objective of the study. Results indicated that with the exception of those with severe cognitive deterioration, residents generally retained awareness of impending relocation and reported feelings appropriate to the situation. Implications for the types of preparation are discussed. PMID- 8696606 TI - [1500 nurses demand the retention of the nursing personnel regulation but: politics is ignoring the protest]. PMID- 8696605 TI - [The introduction of nursing documentation, supported by electronic data processing in an old age home]. PMID- 8696607 TI - [The paperless hospital is approaching]. PMID- 8696608 TI - [Meeting "the Old Age Home facing new Requirements. The need for care is rising- but fewer people are nursing]. PMID- 8696609 TI - [Burns and scalds in children. A special hospital in Poland is using new ways of therapy]. PMID- 8696610 TI - [Observation of patients. Much of the time children can not express their condition verbally]. PMID- 8696611 TI - [Administration of enteral feeding. Much empathy is needed]. PMID- 8696612 TI - [The provision of an electronic data processing duty book. A leadership task in the hospital]. PMID- 8696613 TI - [Use of alternative medical methods: foot reflex zones are of importance in nursing]. PMID- 8696614 TI - [Indemnity payment: secret HIV test is the basis for claim]. PMID- 8696615 TI - [Depression in old age. The contact should be sober and dependable]. PMID- 8696616 TI - [European symposium in Lubeck. Sold out, but many empty chairs]. PMID- 8696618 TI - [New fields in continuing education. Nurses need supervision by nurses]. PMID- 8696617 TI - [Occupational diseases of nursing personnel. 1. Working conditions: there is a cleft between the law and reality]. PMID- 8696619 TI - [Naomi Feil will demonstrate "Validation" on February 15 and 16]. PMID- 8696620 TI - [A Leipzig Forum for Natural Medicine. A new way of thinking is breaking through]. PMID- 8696622 TI - Psychiatric consultations in the general hospital. PMID- 8696621 TI - The management of endometrial carcinoma. PMID- 8696623 TI - Glaucoma: current thinking. AB - This article reviews primary open-angle glaucoma as a cause of blindness. New thoughts on causation, identification and case finding, progression and treatments are discussed. PMID- 8696625 TI - Current management of fractures of distal radius and ulna. AB - Distal radial and ulnar fractures are very common and their morbidity is greatly underestimated. This article reviews the current management of these injuries and that of their associated complications. PMID- 8696624 TI - Priapism associated with psychotropic drugs. AB - Priapism, a rare, potentially dangerous but largely preventable condition, remains associated with the use of drugs, many of which are of the psychotropic variety. This article reviews various aspects of this condition, with a view to increasing awareness and understanding of the condition among clinicians. PMID- 8696626 TI - Chronic renal failure in childhood. AB - Chronic renal failure in childhood is associated with diverse renal conditions, and the progression to end-stage renal failure requiring dialysis and transplantation may be ameliorated by close attention to blood pressure control, correction of metabolic abnormalities and expert dietetic advice. The morbidity has been improved by the availability of vitamin D analogues, erythropoietin and growth hormone. Dialysis and renal transplantation are possible at any age in specialist centres. PMID- 8696627 TI - The Royal College examinations: preparation and practice. AB - Membership examinations are complex and difficult. Important practical issues must be considered at an early stage, and you can improve upon your chance of success by addressing your learning style, revision strategy and examination technique. PMID- 8696630 TI - The specialist registrar grade and its implementation. PMID- 8696629 TI - From the deans' postbag... PMID- 8696628 TI - The severed airway. PMID- 8696631 TI - Transforming the apprenticeship model of training. PMID- 8696632 TI - The outpatient setting as a teaching environment. PMID- 8696633 TI - The place of basic skills workshops in surgical training. PMID- 8696634 TI - Allergy to bee and wasp venom. AB - Insects make up 80% of the animal kingdom with over 800,000 species worldwide. Allergic reactions to bee or wasp stings are common and they may rarely be fatal. Patients who experience systemic sting reactions must receive effective treatment and assessment. PMID- 8696635 TI - Sleep disorders. AB - Sleep disorders carry a high risk of morbidity and mortality, yet they receive little medical attention. This article outlines the clinical features, aetiology, diagnosis and management of some common sleep disorders. PMID- 8696636 TI - Compliance with hormonal treatment for prostate cancer. AB - Compliance is an important factor when choosing drug therapy for chronic illnesses such as prostate cancer. Antiandrogens can be used, either in combination with medical castration or as monotherapy, to treat prostate cancer. In selecting appropriate therapy, drug-related factors which might influence compliance need to be considered. PMID- 8696637 TI - Prostate-specific antigen (PSA) immunohistochemistry in the presence of a normal serum PSA as an aid to diagnosis of adenocarcinoma of unknown primary site. PMID- 8696638 TI - A case of facial erysipelas? PMID- 8696640 TI - A future for British postgraduate medicine? PMID- 8696639 TI - League tables. AB - Each year a new set of hospital league tables features briefly in the press, and on TV and radio stations. Local newspapers carry articles praising or berating their local hospitals to a bemused and mystified public. How seriously should we take this annual ritual? Where do the figures come from and what do they mean? PMID- 8696641 TI - Salivary gland stone management. PMID- 8696642 TI - Telemedicine and new technology. PMID- 8696643 TI - [Lung transplantation in primary pulmonary hypertension]. PMID- 8696644 TI - [The utility of the flow-volume curve in detecting fixed extrathoracic stenoses in patients with chronic obstructive pulmonary disease]. AB - The flow-volume curve is the usual noninvasive diagnostic test for upper airways obstruction. In order to assess its usefulness for the detection of fixed upper airways obstruction in chronic obstructive pulmonary disease (COPD), we plotted flow-volume curves using maximum inspiratory and expiratory maneuvers in 60 COPD patients and in 15 healthy controls. Baseline readings were taken, followed by readings after random application of fixed external resistances with diameters of 4, 6, 8 and 10 mm in all cases. Although PEF and FIF50 decreased significantly with resistance of 10 mm, even in the group with the most severe ventilatory limitation it was necessary to reduce the internal diameter to 6 mm to detect changes in FEV1. In patients with baseline values under 50% of theoretical values, 4 mm stenosis was required to provoke changes in FEV1. The fall in FEV1 and PEF was less evident as the severity of COPD increased, with both parameters correlating with percent baseline FEV1 only at diameters of 6 mm (p < 0.01) and 4 mm (p < 0.001). The sensitivities of the usual indices for detecting upper airways obstruction, such as FEV1/PEF and FEV1/FEV0-5, were low (below 50%) in all groups at diameters over 6 mm, and in the most severe cases of COPD, even with stenosis of 4 mm. Nor did other indices, such as FEF50/FIF50 and FEV1/FIV1,, give better diagnostic yield. We conclude that the flow-volume curve may not detect the existence of upper airways obstruction in COPD, and that in the most severely affected patients alternative diagnostic methods should therefore be considered. PMID- 8696645 TI - [The treatment of tracheobronchial ruptures: a review of 6 cases]. AB - Tracheobronchial ruptures represent a serious pathology difficult to diagnose at the first examination. The authors review 6 cases: four as acute types with pneumomediastinum, pneumothorax and subcutaneous emphysema with a delay in diagnosis of 3.25 days, meanwhile 2 cases were chronic forms with a delay in diagnosis of 124.5 days. Diagnosis should be performed as soon as possible based in the presence of uni or bilateral pneumothorax with pneumomediastinum being confirmed by fiber bronchoscopy. The treatment is based in the resection of the fractured fragments, followed by bronchoplasty always with reabsorbable sutures the most frequent surgical technique, meanwhile in the atelectatic forms it is not possible to perform sometimes and we must practise lung resections. PMID- 8696647 TI - [Pleurodesis with the patient's own blood: the initial results in 14 cases]. AB - Fourteen adults with spontaneous pneumothorax (SP), 9 of whom had primary SP (PSP) and 5 of whom had secondary forms (SSP), were given intrapleural infusions of self-donated blood for pleurodesis. Instillations of 50 ml were given to all except 1, who required a total volume of 120 ml. The procedure was performed in each patient's bed in all cases. With apical chest tube placement in most cases and the lung expanded, the outer tip of the tube was elevated and the patient's own blood was taken from a superficial forearm vein and instilled. Them, with the tube occluded, the patient's were rotated un bed for a period of 2 hours to distribute the blood evenly throughout the pleural cavity. Tolerance was excellent, with no pain reported by any patient. The only noteworthy complication was 1 case of infectious pleural effusion of unknown etiology which was treated by evacuation and antibiotics. In 13 (92%) patients closure of the fistula was achieved, in under 12 h in 7 (53%), in under 24 h in 3 (23%), in under 48 h in 2 (15%), and in under 72 h in the remaining 2 (15%). In 4 (28.5%) there was recurrence (2 SSP and 2 PSP patients). Over a 10 to 32 month follow-up period (mean 16 months), 10 (71.4%) patients experienced no recurrences or complications. These results allow us to speculate that blood instilled in the pleural cavity may act in 2 ways: in the short term as a blood patch that adheres to and closes the fistula in the visceral pleura, and over the longer term by creating pleural symphysis by adhesions and fibrous tissue. Our limited experience indicates that pleurodesis with self-donated blood is an easy-to perform, painless, convenient, rapid and inexpensive procedure that is moderately effective in the short and medium term. Its main drawbacks are the lack of consensus on certain technical considerations, such as the optimum amount of blood to be instilled, the number of instillations to perform and, if multiple instillations are carried out, what the interval between them should be. Further study is needed to confirm or discount our results and to determine the place this technique may have in the clinical management of pneumothorax. PMID- 8696646 TI - [Ambulatory oxygen therapy via a transtracheal catheter]. AB - Oxygen therapy by transtracheal catheter (TTC), as described by Heimlich in 1982, was originally conceived to conserve oxygen but later proved to be truly useful as a treatment for chronic respiratory insufficiency, although the technique is little used in Spain. We conducted a one-year long prospective study of 10 patients with chronic respiratory insufficiency in whom a TTC was placed for ambulatory oxygen therapy. Complications appearing were bloody expectoration (100%), granulomas at the site of incision (20%) and accidental extubation (10%). The index of acceptance among our patients was 9%. The oxygen savings achieved amounted to 46%. The number of hospitalized days before and after insertion of the catheter amounted to 28 and 3, respectively (p < 0.001). PCO2 levels were 62 +/- 14 at baseline, 51.9 +/- 8.8 (p < 0.1) after one week, and 52.9 +/- 10 (NS) after one year. The hematocrit was 45.6 +/- 10.22 before TTC placement and 43.4 +/- 3.02 (NS) after one year. Changes in PO2, FVC and FEV1 were not statistically significant. No problems derived from TTC or liquid oxygen management. PMID- 8696648 TI - [Legislative bases for the prevention of smoking in school]. AB - For the last years we have witnessed and increasing awareness of the part of doctors and teachers who by means of the education for the health (EpS) promote the acquisition of healthy habits among students at schools. One of those educational contents is the smoking prevention. The participation of pneumologists in those activities is still rather limited. Doctors and teachers should reach a better understanding and doctors should get more involved helping the school boards and the teaching staff to outline these aspects regarding health in the educational project of each school. Their collaboration is essential in the training on health topics made by the teaching staff and their later development. Smoking prevention among young people can't be viewed from a detached perspective and comprehensive health policies, with a legislative development including all aspects, become absolutely necessary. In order to provide such activities, western governments have developed a various non-smoking legislation for the last years. Knowing the legislation which holds the achievement proves to be interesting for the teachers responsible of the carrying out as well as for the doctors willing to participate in their project. The most important Spanish legislation about smoking is the Royal Order 192/1988 of the Ministry of Health. The legislation of the Ministry of Education concerning the educational contents for compulsory education in nursery, primary and secondary schools includes the EpS and shapes a legislative framework which enables to develop those preventing activities at schools. PMID- 8696649 TI - [Tobacco and women]. PMID- 8696650 TI - [Chlamydia pneumoniae infection associated with autoimmune hemolytic anemia due to warm antibodies]. AB - Chlamydia pneumoniae has often been implicated in respiratory tract infections concomitant with other pathogens. Although this agent has also been associated with other nonrespiratory diseases, to our knowledge it has never been described with autoimmune hemolytic anemia. We present a case of pneumonia in which C. pneumoniae was found in association with another important respiratory pathogen, Legionella, and with hemolytic autoimmune IgG to warm antibodies, an entity that has not been reported previously with this or any other germ of the genus Chlamydia. PMID- 8696651 TI - [Large-cell lung carcinoma producing chorionic gonadotropin hormone: the difficulty in its differential diagnosis from choriocarcinoma]. AB - We describe a patient with giant cell carcinoma with ectopic production of chorionic gonadotrophin hormone (CGH). This entity is compared with choriocarcinoma, given that the immunologic, histologic and chemical similarities between the two neoplasms can make their anatomic and pathologic differential diagnosis difficult. Clinical examination, response to treatment and CGH blood levels are the criteria for differentiation. PMID- 8696652 TI - [Metastatic pulmonary fibrosarcoma: apropos a case and a review of the literature]. AB - Fibrosarcoma is a rare entity that affects soft tissues in a variety of locations, although it is most commonly found on the extremities. Local recurrence is frequent and metastasis usually takes place in pulmonary tissues early on, within a mean interval of 12 months. We present a case of pulmonary metastasis after fibrosarcoma of the leg that had been diagnosed and treated 14 years earlier. PMID- 8696653 TI - [Interstitial lung disease and ulcerative colitis: a case report]. PMID- 8696654 TI - [Hospital pneumonia due to Xanthomonas maltophilia and AIDS]. PMID- 8696655 TI - [Idiopathic pulmonary hemosiderosis]. PMID- 8696656 TI - Current approaches to the psychopharmacologic treatment of depression in children and adolescents. AB - TOPIC: A review of major depressive disorder and antidepressant drug treatment in children and adolescents. PURPOSE: This paper provides a synthesis of current information regarding diagnosis, psychobiology, psychopharmacology, and practice guidelines for psychiatric nurses involved in the treatment of depression in children and adolescents. SOURCES: Recent journal and book publications regarding the psychopharmacological treatment of depression in children and adolescents. CONCLUSION: Although there is far less research to guide the psychopharmacological treatment of depression in children and adolescents than there is for adults, these treatments can be safely administered and effective for some individuals in this age group. PMID- 8696657 TI - Contemporary approaches to pharmacotherapy in Tourette's syndrome and obsessive compulsive disorder. AB - TOPIC: Contemporary approaches used in the pharmacological treatment of children and adolescents with Tourette's syndrome or obsessive-compulsive disorder. BACKGROUND: Tourette's syndrome (TS) and obsessive-compulsive disorder (OCD) now are recognized as more common than previously believed. Moreover, there is accumulating evidence that these two disorders may share common neurobiological underpinnings. Nonetheless, pharmacologic approaches to treatment may be quite different. SOURCES: Using recently published information, this paper reviews current treatment for TS and OCD. CONCLUSION: There have been major advances in the understanding of the pathophysiology of OCD and TS. These advances provides guidance for the treatment of children and adolescents with these disorders. However, additional research is needed to refine current treatment approaches. PMID- 8696658 TI - Special edition on psychopharmacology. PMID- 8696659 TI - Neuroanatomy and physiology in modern child psychiatric nursing. AB - TOPIC: Brain anatomy and brain function pertinent to clinical practice in child and adolescent psychiatric nursing. PURPOSE: Over the past two decades psychiatry has increasingly turned to biological explanations for the etiology of mental disorders. In addition, public awareness of neurobiology has been kindled by a steady flow of articles in the media about the brain. Finally, there has been a tremendous proliferation of psychopharmacological agents used in the treatment of mental disorders in both adult and pediatric populations. Hence, nurses are increasingly expected to employ a knowledge base that embraces the fundamentals of neuroscience. SOURCES: This article briefly reviews current information about brain anatomy and function in order to provide a foundation for current practice. CONCLUSION: Contemporary psychiatric nursing practice all but requires nurses to acquire a basic understanding of neuroanatomy and physiology. PMID- 8696660 TI - Sisters under the stress. PMID- 8696661 TI - Can they understand you? PMID- 8696662 TI - Second place in primary-led care? PMID- 8696663 TI - Right plan for elderly care? PMID- 8696664 TI - What is confidential? PMID- 8696665 TI - Private healthcare on the march. PMID- 8696666 TI - Leadership development? PMID- 8696667 TI - Patient-focus pocus? PMID- 8696668 TI - Are some people born dissatisfied? PMID- 8696670 TI - The scope comes into clearer focus. PMID- 8696669 TI - King's Fund ignites the leading lights. PMID- 8696671 TI - A look up the scope. PMID- 8696672 TI - CPNs in court trap. PMID- 8696673 TI - Managed care scare. PMID- 8696674 TI - PFC: stuck at stage one. PMID- 8696675 TI - Career wise. People skills that work. PMID- 8696676 TI - Fair shares in practice? PMID- 8696677 TI - Take cover from the take-overs. PMID- 8696679 TI - Just for the record. PMID- 8696678 TI - Developing managers for the future. PMID- 8696680 TI - Fix the skill mix. PMID- 8696681 TI - Mental health care--gone astray? PMID- 8696682 TI - The team's the thing. PMID- 8696684 TI - Focus on the benefits. PMID- 8696683 TI - A world of difference--but for how long? PMID- 8696686 TI - Leadership as a notion is forever on the lips of senior managers. PMID- 8696685 TI - Dependent on change. PMID- 8696687 TI - Managing a health and safety policy. PMID- 8696688 TI - So you'd like an award for quality.... PMID- 8696689 TI - Gypsy-class retrotransposon sequences in organisms related to the leaf mould fungus, Cladosporium fulvum. AB - Gypsy retrotransposons are a major branch of retroid elements and have been found in a wide diversity of eukaryotic organisms including CfT-1 in the tomato leaf mould pathogen, the fungus Cladosporium fulvum (syn. Fulvia fulva). We have examined organisms that are either ecologically or phylogenetically related to C. fulvum, for elements related to CfT-1. Using PCR and Southern hybridisation, similar sequences were found only in the co-genic fungus Cladosporium cladosporioides. This finding confirms the apparent ubiquity of retroelements, suggests that the phylogeny of retrotransposons is consistent with the phylogeny of their hosts and argues against frequent horizontal gene transfer. PMID- 8696690 TI - [The strategy for pharmaceutical research and development. I. Original drugs]. AB - Pharmaceutical research and development are characterized by high costs, which in the countries with developed pharmaceutical industry range from 12 to 16% of the total turnover. Purposeful use of considerable financial resources requires rational management of research and development. The principal criteria of rational research can be stated as follows: (a) profitable measure of risk, (b) strategy of research and development, (c) use of financial resources, (d) organization and methods of research. These aspects of rational management are discussed and the prospects and limits of this research in the Czech Republic in relation to general regularities are formulated. Attention is paid to the Research Institute for Pharmacy and Biochemistry which has obtained the position of the only institute for comprehensive research and development of human medicaments in the country. The hitherto results are summed up and the contemporary strategy of research and development in the Institute is discussed. PMID- 8696691 TI - [Acetylsalicylic acid matrices for use in stomatology]. AB - In stomatological practice acetylsalicylic acid in the form of preparations suitable for insertion into the created wound is used to alleviated pain after extraction of teeth with good results. Such a preparation are also tablets containing 85 mg of the above-mentioned drug with retarded release. They possess the character of a hydrophilic matrix, which after administration softens and is adapted to the shape of the wound. Tentative use in patients gave positive experience. PMID- 8696692 TI - [Comparison of the effect of HI-6 oxime and its derivatives in combination with benactyzine on cholinergic and stress effects of soman in rats]. AB - In male rat experiments, the therapeutic effect of oxime HI-6 and its derivatives (HI-6 ester and amide) in combination with benactyzine on the cholinergic and stressogenic effects of a sublethal dose of soman was compared. Cholinergic effects were investigated by monitoring the changes in the activity of cholinesterases in the whole blood, brain and diaphragm, stressogenic effects by monitoring the changes in the level of corticosterone in the plasma and the activity of tyrosine aminotransferase in the liver. The monitoring of the changes in the selected parameters of cholinergic and stressogenic effects of soman has demonstrated that neither of the derivatives of oxime HI-6 under study achieves its therapeutic effect and thus seems to be a suitable substitute of oxime HI-6 for the therapy of acute intoxications with the organophosphate soman, which are difficult to treat. PMID- 8696693 TI - Review article: imaging in bronchiectasis. AB - Bronchiectasis remains an important and relatively common cause of pulmonary disability. High resolution computed tomography has revolutionized imaging of the bronchi and has superseded the chest radiograph and bronchogram in the diagnosis of bronchiectasis. It has enabled a better understanding of the association between clinical features of the disease and structural abnormalities in the airways and has an important role to play in understanding the pathogenesis and natural history of bronchiectasis. PMID- 8696694 TI - Dynamic magnetic resonance mammography of both breasts following local excision and radiotherapy for breast carcinoma. AB - The purpose of this study was to evaluate a dynamic gadolinium-diethylene triaminepentacetate (Gd-DTPA) enhanced magnetic resonance mammography (MRM) protocol, incorporating image subtraction and using a dedicated double breast coil, in patients with treated breast cancer. 36 patients who had undergone breast conserving surgery and radiotherapy, with clinical or mammographic suspicion of locally recurrent breast carcinoma, were examined. 3D rapid volume imaging of both breasts was performed before and repeated three times, at 1, 2 and 3 min, following Gd-DTPA enhancement. Image subtraction allowed identification of enhancing lesions and quantitative analysis of these was performed. Five patients had six lesions demonstrating rapid enhancement in the first minute, all of which were histologically confirmed recurrent or second primary tumours. Slower enhancement was seen in six benign lesions and diffuse enhancement was seen in one patient within 6 months of treatment. The dynamic protocol used allowed sufficient temporal resolution for distinguishing malignant from benign lesions at the site of previous surgery and ensured that both breasts were imaged in their entirety, thus enabling the diagnosis of multifocal and second primary tumours. PMID- 8696695 TI - Acute subarachnoid haemorrhage: detection with magnetic resonance imaging. AB - The purpose of this study was the evaluation of fluid attenuated turbo inversion recovery (FLAT TIRE) MR pulse sequence for detecting acute subarachnoid hemorrhage (SAH). Seven patients with SAH were studied within 6 days of ictus. Six of them underwent both CT and MRI and one MRI only. Pulse sequences included T1 spin echo (SE), PD and T2 turbo spin echo (TSE) and FLAT TIRE (TR/TI/TE = 6500/1800/140-180). All studies were performed on a 0.5 T system (Gyroscan T5, Philips Medical Systems). Simulated acute SAH was also studied with MRI. The FLAT TIRE sequence was better than the SE and TSE in all seven cases and better than CT in two cases. In two cases MRI was equivalent to CT, and in another two MRI underestimated the extent of SAH. The simulated acute SAH could be detected easily with the FLAT TIRE sequence, with difficulty on the T1 weighted images and not at all on the PD/T2 weighted images. The specific FLAT TIRE sequence used seems promising for the detection of acute SAH. PMID- 8696696 TI - Transrectal ultrasound in the evaluation of cervical carcinoma and comparison with spiral computed tomography and magnetic resonance imaging. AB - 38 women with biopsy proven untreated cervical carcinoma were prospectively studied with transrectal ultrasound (TRUS), spiral computed tomography (SCT) and magnetic resonance imaging (MRI). 20 women had radical hysterectomy and pelvic lymphadenectomy with detailed histological evaluation of the parametra. The echographic features of cervical carcinoma on TRUS are a hypoechoic (60%) or isoechoic (40%) (relative to normal uterine muscle/cervical stroma), poorly defined mass lesion with indistinct margins in an enlarged cervix. This relatively high percentage of isoechoic tumours and relative lack of contrast resolution may pose a problem in the identification of some tumours, and to our knowledge has not been previously reported. Further limitations of TRUS are in the evaluation of advanced cervical cancer, due to bulky tumours rendering poor access to the parametrium and pelvic sidewall. The overall accuracy in staging of early cervical cancer (less than stage 2b) was 85% for examination under anaesthesia (EUA), 75% for TRUS, 65% for MRI and 50% for SCT. The positive predictive value in evaluating the parametra in this group of patients was also lower for SCT (14%) and MRI (33%) compared with TRUS (100%). In the evaluation of advanced cervical cancer (stage 2b or higher), there was poor correlation between TRUS and EUA, with MRI showing the best correlation with EUA. We conclude that SCT is inferior to both TRUS and MRI in the staging of early stage cervical cancer. PMID- 8696697 TI - Sonographic abnormalities of the thyroid gland following radiotherapy in survivors of childhood Hodgkin's disease. AB - The aims of this study were as follows. (1) To demonstrate the spectrum, frequency and changes on follow-up of sonographic abnormalities in the thyroid gland of survivors of Hodgkin's disease who had received radiotherapy to the neck in childhood. (2) To compare the sonographic findings with clinical examination and radionuclide imaging. (3) To investigate the association between the presence or absence of focal sonographic abnormalities with age at radiotherapy, the interval from radiotherapy, the presence of a raised thyroid stimulating hormone (TSH) and the length of time the TSH had been raised. 46 patients were scanned prospectively and rescanned at 6-18 months. The mean age at first sonography was 22.7 years, the median age at radiotherapy was 12.5 years, and the median interval post-radiation was 10.3 years. Sonographic abnormalities were seen in all 46 patients. 45 had diffuse atrophy and 30 had focal sonographic abnormalities. 18 patients developed new focal sonographic abnormalities on follow-up. Focal sonographic abnormalities were more commonly associated with longer duration of a raised TSH. Two patients had thyroid carcinoma. Sonographic abnormalities of the thyroid are common in patients following neck radiotherapy in childhood. Focal abnormalities are usually associated with a longer duration of raised TSH. PMID- 8696698 TI - Pregnancy after uterine artery embolization to control haemorrhage from gestational trophoblastic tumour. AB - Gestational trophoblastic tumour (GTT) of the uterus can cause severe and even life threatening haemorrhage in patients who may be contemplating future pregnancy. Three cases of successful pregnancy after uterine artery embolization to control severe haemorrhage from uterine GTT are reported. Both uterine arteries had been selectively catheterized and embolized in these patients. The areas of pathological circulation measured on the pre- and post-embolization films had been reduced by over 80%. Embolization failed to control haemorrhage in another four patients in whom the uterine arteries had not been selectively catheterized and embolized and where the embolization procedures had reduced the areas of pathological circulation by less than 65%. The conclusions are that control of severe haemorrhage from uterine GTT is likely if both uterine arteries are selectively catheterized and embolized. Patients thus treated can become pregnant. PMID- 8696699 TI - Nasolacrimal duct opacity on CT. AB - A retrospective analysis of 100 coronal sinus CT scans was performed to investigate the frequency of opacity of the nasolacrimal duct and determine if there was any correlation between the pattern of duct opacity and the presence of inflammatory sinus disease. The study showed that the nasolacrimal ducts are opaque in the majority of normal people and that there is no relationship to inflammatory sinus disease. PMID- 8696700 TI - Bipedal lymphography in the management of carcinoma of the anal canal. AB - The purpose of this study was to determine the extent of metastatic pelvic lymph nodes evident on bipedal lymphography in a group of patients under consideration for combined radiation therapy and chemotherapy as definitive treatment for carcinoma of the anal canal. Lymphography was attempted in 32 patients and successful bilateral cannulation and opacification of nodes was achieved in 28 (88%). Seven patients had lymphographic evidence of external iliac node metastases (25%). When patients were categorized according to the extent of clinically evident disease at presentation, 0/15 patients with T1/T2 tumours had positive lymphograms whereas 7/13 patients with T3/T4 tumours and/or positive inguinal or peri-rectal nodes had positive lymphograms (Fisher's exact test p = 0.0015). All patients with a positive lymphogram had undergone CT scanning of the pelvis and in only one patient was external iliac node involvement detected. In none of these patients was visceral or more extensive nodal metastases discovered. Subsequently, the external iliac nodes with radiological evidence of metastases on lymphography were included in the treatment volume taken to radical dosage. The projected cause specific actuarial 5 year survival for this cohort of patients is 86% (median follow-up 4 years). Since the prognosis for patients who relapse in pelvic nodes is poor, bipedal lymphography is advocated as a staging procedure in patients with advanced primary tumours and in all patients with clinically positive inguinal or peri-rectal lymph nodes who are being considered for curative therapy. PMID- 8696701 TI - Flat and curved crystal spectrography for mammographic X-ray sources. AB - The demand for improved spectral understanding of mammographic X-ray sources and non-invasive voltage calibration of such sources has led to research into applications using curved crystal spectroscopy. Recent developments and the promise of improved precision and control are described. Analytical equations are presented to indicate effects of errors and alignment problems in the flat and curved crystal systems. These are appropriate for all detection systems. Application to and testing of spectrographic detection (using standard X-ray film) is presented. Suitable arrangements exist which can be used to measure X ray tube voltages well below 1 kV precision in the operating range of 20-35 kV. PMID- 8696702 TI - Clinical evaluation of manual and automatic exposure control techniques in film based chest radiography. AB - Chest radiographs obtained with either automatic exposure control (AEC) technique, or manual exposure control (MEC) technique, were compared in a sample of 329 cardiological and cardiosurgery patients. Parameters evaluated, were various anatomical regions, according to their appearance in both posteroanterior (PA) and lateral radiographs. Lateral radiographs obtained with the AEC technique demonstrated better image quality than those obtained with the manual technique. There was no definite advantage of the AEC technique in PA radiographs. The AEC technique has the potential to improve the quality of lateral chest radiographs of cardiological and cardiosurgery patients. It is considered to be a useful tool in chest radiography. PMID- 8696704 TI - Short communication: detection of early scirrhous carcinoma of the stomach by endoscopic ultrasonography. AB - The endoscopic ultrasonography (US) characteristics of early scirrhous carcinoma of the stomach (ESS) were evaluated in four patients. ESS was defined as the presence of poorly differentiated carcinoma cells spreading through the submucosa and muscularis propria in association with a marked desmoplastic reaction without serosal invasion. ESS was characterized by localized irregular hypoechoic enlargement of the third (submucosal) and the fourth (muscularis propria) layers. The fifth (serosal) layer was normal. The third and fourth layers showed a threefold increase in thickness compared with the thickness of these layers in healthy subjects. Our results suggest that endoscopic US is useful for diagnosis of ESS. PMID- 8696703 TI - Reference ranges of bone mineral density for women in southern England: the impact of local data on the diagnosis of osteoporosis. AB - The construction of reference ranges that accurately represent the population at large is essential for the correct identification of osteoporosis from bone mineral density (BMD) measurements. In this study, reference data supplied by the manufacturer of the Lunar DPX+ bone densitometer were compared with data obtained locally. Lumbar spine, proximal femur and total body BMD measurements were made in an age-stratified random sample of 702 Southampton women aged 20 to 89 years. Relevant demographic and medical data were recorded for each subject using a questionnaire. Reference curves of BMD (mean +/- SD) were plotted against age for each measurement site and were found to be higher than the manufacturer's reference values at all ages and sites. Exclusion of women with factors known to affect bone mass only served to increase this discrepancy. According to World Health Organisation definitions, osteoporosis may be identified from BMD values alone. Based upon neck of femur BMD values, 100 (14.8%) of the women in this study group were categorized as osteoporotic using local young normal reference data, compared with only 39 (5.8%) using the manufacturer's data. By normalizing for age distribution, these findings were extrapolated to the local population where it was predicted that 26.0% and 10.1% of females over 50 years of age would be classified as osteoporotic using the respective reference ranges. This study clearly illustrates how the numbers of women diagnosed as osteoporotic vary with the use of different reference populations. PMID- 8696705 TI - Short communication: endoanal ultrasound during contraction of the anal sphincter -improved definition and diagnostic accuracy. AB - Endoanal ultrasound was used in the investigation of 26 patients with faecal incontinence. In each case images of the anal sphincter were taken at rest and during contraction or squeezing (dynamic). Better definition of the normal anal sphincter or anal sphincter defects was obtained in 16 (62%) of the patients with imaging during contraction. In eight of the 13 patients with a sphincter defect there was better definition of the defect and increased separation of the ends of the sphincter during contraction. Imaging during contraction improves diagnostic accuracy and is a useful adjunct with endoanal ultrasound. PMID- 8696706 TI - Short communication: MR imaging of fetal brain abnormalities using a HASTE sequence. AB - HASTE (half-Fourier acquisition single-shot turbo spin echo) is a sequence that enables T2 weighted magnetic resonance (MR) images to be obtained in a few seconds. The purpose of this study was to evaluate the usefulness of this sequence in the diagnosis of fetal cerebral abnormalities. Five fetuses suspected of having cerebral abnormalities on ultrasound examination were studied by MR imaging using the HASTE sequence in utero. We compared the images with post-natal MR images or computed tomography (CT) scans. In four fetuses, the abnormality was diagnosed correctly, and the diagnosis was almost correct in the remaining fetus. This sequence is useful because it provides images of diagnostic quality in a very short scanning time. PMID- 8696707 TI - Case report: fracture of central intrauterine tube following insertion of high dose rate intracavitary applicator. AB - We present a unique complication of high dose rate afterloading intrauterine brachytherapy occurring in a patient requiring treatment for carcinoma of the uterus. A high dose rate afterloading intrauterine insertion was performed under general anaesthetic, following which routine check films revealed that the central uterine tube had fractured at the level of the cervical os. PMID- 8696708 TI - Case report: radiation prevention of heterotopic ossification after bone and joint surgery in sites other than hips. AB - Five patients were given single dose irradiation in an attempt to prevent heterotopic ossification after bone and joint surgery in sites other than hips. All patients were at risk for the development of post-operative heterotopic ossification. Two patients were treated with 6 Gy and three patients were treated with 7 Gy the day after operation. No complications were encountered. Post operative heterotopic ossification did not develop in patients who received 7 Gy, whereas treatment failed in the two patients who received 6 Gy. Because this is a case report study, no conclusion could be made. Further investigation is needed to assess the efficacy of post-operative single dose irradiation in heterotopic ossification prophylaxis in sites other than hips in high risk patients. PMID- 8696709 TI - Case report: squamous cell carcinoma of the skin metastasizing to the breast- imaging findings. AB - An extremely rare case of metastatic squamous cell skin carcinoma to the breast is reported with imaging features. Ultrasonography and magnetic resonance imaging revealed well circumscribed, complex solid masses with papillary fronds projecting into cystic centres. PMID- 8696710 TI - Case of the month: "air-in a view". PMID- 8696711 TI - Latent image fading in mammography. PMID- 8696712 TI - Radiology UK 1996. 20-22 May 1996. Abstracts. PMID- 8696713 TI - A proposed new international TNM staging system for malignant pleural mesothelioma from the International Mesothelioma Interest Group. AB - STUDY OBJECTIVE: investigation of the behavior and treatment of diffuse malignant pleural mesothelioma (MPM) is hindered by the lack of an accurate universally accepted staging system. To address this problem, the International Mesothelioma Interest Group (IMIG) has developed a new TNM based staging system. METHODS: the staging system was developed at a consensus meeting of IMIG members involved in clinical research in MPM, including the originators of previously proposed staging systems. The new staging system is based on the analysis of emerging information about the impact of T and N status on survival. RESULTS: in contrast to five previous staging systems, the T descriptors designated as T1, T2, T3 and T4, provide precise anatomic definitions of the local extent of the primary tumour. The N descriptors, designated as N0, N1, N2 and N3, are virtually identical to those used in the International Lung Cancer Staging System. The stage groupings recognize new data about the better prognosis of T1 and N0 tumours and classify those tumours into stages I and II. The adverse impact of nodal metastases on survival noted in some recent surgical series warrants placing node positive tumours in stage III. Locally advanced unresectable (T4) tumours and extrathoracic disease (N3 or M1) are classified as stage IV. CONCLUSION: this proposed staging system reconciles and updates several earlier systems, and can provide the framework for analyzing the results of prospective clinical trials aimed at improving the currently dismal prognosis of MPM. PMID- 8696714 TI - Efficacy and toxicity of mitomycin, ifosfamide, and cisplatin (MIP) in patients with inoperable non-small cell lung cancer. AB - Seventy-two patients with advanced stage IIIB (42%) or stage IV (58%) non-small cell lung cancer (median age 57 years, Karnofsky PS 60-100) were treated with mitomycin C (6 mg/m2, day 1), ifosfamide (1500 mg/m2, days 1-3), and cisplatin (30 mg/m2, days 1-3) every 4 weeks. The objective response rate was 37% in the overall population; 50% in stage IIIB patients and 29% in stage IV patients. Twenty four patients achieved partial response (33%) and three patients achieved complete response. Despite this relatively high objective response rate, the overall median survival time was 32 weeks. The median survival was significantly better in stage IIIB patients (55 weeks) than in stage IV patients (25 weeks) (P = 0.003). MIP regimen was permanently suspended in 14 patients because of toxic events. Seventeen patients developed grade III or IV febrile neutropenia and two patients died from sepsis. Two patients experienced acute mitomycin peumonitis. Despite increased doses of cisplatin and ifosfamide, compared with the original description for MIC chemotherapy, with probably higher toxicity, no apparent increased response rate or median survival was observed in this study. The MIP regimen could be tested in a randomized trial in comparison with other administration plans in a comparable population. PMID- 8696715 TI - Multicenter randomized trial comparing cisplatin-mitomycin-vinorelbine versus cisplatin-mitomycin-vindesine in advanced non-small cell lung cancer. 'Groupe Francais de Pneumo-Cancerologie'. AB - The study was designed to evaluate the value of vinorelbine in a cisplatin mitomycin-vinca alkaloid regimen for treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). A group of 227 patients with inoperable NSCLC in stage III (58%) or stage IV (42%) were included in this randomized multicenter trial comparing a reference regimen (VDS group, n = 113) cisplatin (120 mg/m2 on day 1, day 29 and day 71), mitomycin (8 mg/m2 on day 1, day 29 and day 71) and vindesine (3 mg/m2/week for 5 weeks and then every 2 weeks up to the 15th week) to a cisplatin-mitomycin-vinorelbine combination (VNB group, n = 114), with cisplatin and mitomycin at the same doses, and vinorelbine 25 mg/m2/week for 16 weeks. The objective response rate (evaluated at 17th week) was 17% in the VDS group and 25% in the VNB group (P = 0.15). Median survival was 33.4 weeks and 34.5 weeks in the VDS and VNB arms, respectively. Overall survival duration was not significantly different between the two arms (logrank test, P = 0.20) despite a trend to an increased survival in the VNB group. This essentially benefited the patients with stage III disease with a clear-cut lengthening of median (45.9 vs. 33.4 weeks) and 1 year survival (44.6% vs. 26.2%, P < 0.05) in favor of the VNB group. Nevertheless, there was no significant difference in overall survival (logrank, P = 0.13). Survival duration of the patients with stage IV disease was comparable in the two arms (logrank test, P = 0.90). Grade 3 or 4 neutropenia was found in 61% and 87% of the VDS and VNB groups, respectively (P < 0.01). Grade 2 4 peripheral neuropathy was observed in 23% of the patients in the VDS group and in 6% of the patients in the VNB group (P < 0.01). Replacement of vindesine by vinorelbine in a cisplatin-mitomycin-vinca alkaloid chemotherapeutic regimen did not lead to a significant improvement in objective response rate or in duration of survival. There was a reduction in neurotoxicity at the expense of an increased hematologic toxicity. However, for patients with stage III disease there was an increase in 1 year survival with the vinorelbine combination. PMID- 8696716 TI - The economics of lung cancer. PMID- 8696717 TI - Phase I trial of gemcitabine and cisplatin in advanced non-small cell lung cancer: a preliminary report. AB - A phase I trial was performed to investigate the tolerability and efficacy of the novel nucleoside analogue gemcitabine in combination with cisplatin in the treatment of advanced non-small cell lung cancer. Both cisplatin and gemcitabine were administered as 30 min infusions weekly x 3 with a week of rest. There was one dose escalation of cisplatin from 25 mg/m2 (dose level 1) to 30 mg/m2 (in subsequent dose levels 2-5), such that the mean dose intensity for the weekly x 3 q 4 week cycle was 22.5 mg/m2/week which is close to that achieved with 100 mg/m2 bolus monthly. Gemcitabine was initiated at 1000 mg/m2 (dose levels 1 and 2) then escalated by 250 mg/m2/week to 1750 mg/m2 (dose level 5). Of 32 chemotherapy naive patients entered (22 males, 10 females; median age 61 years, range 29-74 years), 11 had localized tumours (2 stage IIIa, 9 IIIb) and 21 had stage IV tumours with haematogenous metastases and a poor prognosis. Twenty-one patients had adenocarcinoma, 4 squamous cell carcinoma, 6 large cell undifferentiated tumors, and one had mixed squamous and adenocarcinoma. Dose-limiting toxicity was not seen in more than one patient in cycle 1 at any dose level. Grade 4 granulocytopenia and thrombocytopenia occurred more frequently with repeated dosing, necessitating dose reductions except at the lowest dose level (cisplatin 25 mg/m2, gemcitabine 1000 mg/m2). Non-haematological toxicity was mild and rapidly reversible. Cisplatin administration led to a higher frequency of nausea and vomiting than that seen with gemcitabine alone, but this was easily controlled with antiemetics. In the 28 patients evaluable, to date responses have been seen at most dose levels, with an overall response rate 35.7%. This phase I trial is ongoing and further dose escalation is intended to determine the MTD of gemcitabine. PMID- 8696718 TI - The economics of lung cancer management in Canada. AB - Because lung cancer is a major health care problem in Canada, it is imperative to understand how resources are used to diagnose and treat this disease. This paper describes a method of modelling the direct patient care costs for lung cancer from the perspective of the government as payer in a universal health care system. Clinical algorithms were developed to describe the management of non small cell (NSCLC) and small cell (SCLC) lung cancer. Patients were allocated to the treatment algorithms in the model based on a knowledge of their distribution by cell type and stage in Canadian cases. A microsimulation model developed by Statistics Canada was used to integrate the data on type of lung cancer, extent of disease, clinical management, survival and health care resource utilization. The direct care costs for diagnosis and treatment of NSCLC ranged from $Cdn 17 889 for the surgery/post-operative radiotherapy treatment of Stages I and II to $Cdn 6333 for supportive care for patients with Stage IV disease. The costs of determining relapse for NSCLC were estimated to be $Cdn 1528 and terminal care costs, made up largely of hospitalization charges and some palliative radiotherapy, were $Cdn 10 331. Direct care costs for the diagnosis and initial treatment of SCLC ranged from $Cdn 18 691 for management of limited stage disease to $Cdn 4739 for the supportive care of patients with extensive disease. The cost of determining relapse for SCLC was estimated to be $Cdn 1590 and terminal care costs averaged $Cdn 9966. For all 15 624 cases of lung cancer diagnosed in Canada in 1988, it was estimated that the total cost of providing treatment and follow up, and managing relapse over 5 years was $Cdn 328 million. Despite the large total cost of lung cancer management, estimates of cost effectiveness of therapy showed that the cost per life year gained was approximately $Cdn 11 000 for NSCLC and $Cdn 19 560 for SCLC. These estimates of the direct health care costs assume that all patients have access to care, treatment is uncomplicated and practice is standard, and must be viewed as an idealized assessment of the cost of lung cancer management. The microsimulation model, however, does provide a useful framework for evaluating the costs of new diagnostic procedures, treatment strategies and new drugs. PMID- 8696719 TI - Cost analysis of hospital treatment--two chemotherapic regimens for non-surgical non-small cell lung cancer. GFPC (Groupe Francais Pneumo Cancerologie) AB - STUDY OBJECTIVES: compare the costs of two regimens of chemotherapy. Apply weighted costs to an economic model in a hospital perspective. DESIGN: prospective randomized study of two groups of patients receiving: branch B, mitomycin-navelbine-cisplatin (MNP); branch A, mitomycin-vindesine-cisplatin (MVP). SETTING: pneumologic units of University and non-University hospitals. METHODS: clinical evaluation during chemotherapy incorporated events enabling construction of an event tree. Direct hospital costs included those of: cytostatic agents, materials used and nursing time; costs of side-effects (medical and paramedical time, diagnostic and therapeutic examinations). Effectiveness was measured in terms of response rates. PATIENTS: 209 patients were included, 100 in arm B, 109 in arm A. RESULTS: the response rates were 25% in branch B, 17% in branch A. In the hypothesis of equivalence of the two strategies, we compared only overall mean cost per patient. Despite the fact arm B needed more hospital injections, the difference was low (+4.6%). For a difference in effectiveness, the opposite was observed for the average cost effectiveness ratio: arm B was less costly (-12 339.40 FF for a responder). CONCLUSION: incorporation of economic parameters was found to have a bearing on the choice of chemotherapeutic regimen for the treatment of non-small cell lung cancer. Economic analyses of this kind can provide useful extra information for rational therapeutic decisions. PMID- 8696720 TI - Economic value of gemcitabine compared to cisplatin and etoposide in non-small cell lung cancer. AB - Although chemotherapy costs have not been highlighted traditionally, there is increasing pressure to demonstrate the value of new treatments within the health care budget. Pharmaceutical companies are assessing the economic value of their products before launch. Gemcitabine is a nucleoside analogue developed for use in solid tumours. The purpose of this model was to investigate the clinical outcomes and potential cost savings for gemcitabine used as monotherapy compared to cisplatin and etoposide combination therapy in late stage non-small cell lung cancer (NSCLC), in a palliative (as opposed to aggressive) chemotherapy setting. Gemcitabine treatment data were taken from a large NSCLC study and data from retrospective chart reviews identified through the National Oncology Data Base. The model population and effectiveness of the two regimens were judged to be similar, except for baseline performance status. If drug costs were not included, the probability distribution resulting from the simulation showed median cost savings per cycle ranging from $US 1504 to $US 7425, with a medium value of $US 2154. The model suggested that gemcitabine would result in cost savings per cycle more than 90% of the time. Outpatient versus inpatient drug administrations accounted for the majority of potential cost savings. Most of the remaining cost savings were attributable to the difference in febrile neutropenia and antiemetic use. This economic model showed susbstantial savings if gemcitabine was used instead of cisplatin and etoposide combination therapy in the United States' community care setting. Some savings would be realized even if the location of treatment for both regimens was mostly outpatient. Assessment of the product's economic value before launch has assisted in our understanding of the potential areas of cost savings for gemcitabine and has guided us in the design of prospective randomized studies which included pharmacoeconomic endpoints. PMID- 8696722 TI - Binding capacities of two immunomodulatory lectins, carrier-immobilized glycoligands and steroid hormones in lung cancer and the concentration of nitrite/nitrate in pleural effusions. AB - Combined analysis of the binding properties of inflammatory and tumor cells in pleural effusion, and tumor imprints for various carrier-immobilized types of ligands and lectins, and of a biochemical feature of the effusions is performed to extend the characterization of these cells and their activity. In detail, the binding of Viscum album agglutinin (VAA), Urtica dioica agglutinin (UDA), and of carrier-immobilized N-acetyl-D-glucosamine (GlcNAc), lysoganglioside GM1, estradiol, progesterone, testosterone, and hydrocortisone to native specimens consisting of 46 tumor imprints from surgically treated patients with lung cancer and 74 smears of pleural effusion (PE) cells from cancer or non-cancer patients was studied using fluorescence microscopy with Texas red-labeled streptavidin. Among the tested ligands, VAA was found to provide the most effective staining of cells (60-78.1% of positive cases). When compared with inflammatory cells from PE, cancer cells were seen to bind more frequently only two ligands, namely UDA and estradiol. Significant (P < 0.001) difference between patients with bronchial carcinoma and non-cancer patients were found, when the content of NO2-/NO3- in PE fluids was measured. Whereas the level of NO2-/NO3- in PE of non-cancer patients was 12.6 +/- 10.7 microM (n = 12), it was 37.7 +/- 19.4 microM (n = 14) in cancer patients without pleural metastases and 37.5 +/- 16.0 microM (n = 26) in patients with pleural metastases. The level of NO2-/NO3- in PE appeared to correlate with extent of staining with GM1 and GlcNAc: in non-cancer patient groups it was significantly higher (P = 0.032) for negative subjects than those binding the ligand GlcNAc, whereas in the patient group with adenocarcinoma it was significantly lower (P = 0.032) for patients without binding capacities for GlcNAc and GM1. The results obtained suggest that the combined analysis of increased levels of NO2-/NO3- in PE and of glycohistochemical properties of cancer and inflammatory cells may be useful in exploring the interrelationship of functionally important cellular characteristics. PMID- 8696721 TI - Acquired TGF beta 1 sensitivity and TGF beta 1 expression in cell lines established from a single small cell lung cancer patient during clinical progression. AB - Three small cell lung cancer cell lines established from a single patient during longitudinal follow-up were examined for in vitro expression of TGF beta and TGF beta receptors, i.e. the components of an autocrine loop. GLC 14 was established prior to treatment, GLC 16 on relapse after chemotherapy and GLC 19 on recurrence after radiotherapy. TGF beta was detected by ELISA and TGF beta receptors by chemical crosslinking to radiolabelled TGF beta 1. Furthermore, TGF beta and TGF beta receptor mRNAs were detected by northern blot analysis. Expression of type II TGF beta receptor mRNA and protein was found in GLC 16 and GLC 19. These cell lines were also growth inhibited by exogenously administrated TGF beta 1. TGF beta 1 mRNA and protein in its latent form was only expressed in the radiotherapy resistant cell line, GLC 19. The results indicate that disease progression in this patient was paralleled by a gain in sensitivity to the growth inhibition by TGF beta 1 due to type II TGF beta receptor, and a gain of latent TGF beta 1 protein. Lack of type II receptor expression in GLC 14, which was also resistant to growth inhibition by exogenous TGF beta 1, was not due to gross structural changes in the type II receptor gene, as examined by Southern blotting. Also, the type I receptor could not be detected by ligand binding assay in this cell line, despite expression of mRNA for this receptor. This agrees with previous findings that type I receptor cannot bind TGF beta 1 without co-expression of the type II receptor. PMID- 8696723 TI - Expression of early lung cancer detection marker p31 in neoplastic and non neoplastic respiratory epithelium. AB - In an immunocytochemical study of sputum, two antibodies, including a mouse monoclonal antibody (703D4) to a 31 kDa protein (p31) antigen, have been previously shown to detect lung cancer earlier than routine cytomorphology or chest X-ray. To understand the basis of p31 expression, the distribution of this antigen in the respiratory epithelium of individuals known to have lung cancer was mapped. These individuals are likely to demonstrate extensive changes throughout the epithelium due to field cancerization. p31 immunoreactivity was examined in primary tumors and surrounding non-neoplastic lungs containing both histologically normal and abnormal areas obtained from 28 Stage I non-small cell lung cancer (NSCLC) patients. Distribution and intensity of p31 expression was scored in three lung compartments (bronchi, bronchioli, alveoli). While p31 was present in histologically unremarkable bronchial and bronchiolar epithelium, no expression was detected in bronchi or bronchioli containing histologic abnormalities. Furthermore, in the peripheral lung p31 staining was frequently observed in alveolar type II cells and was most commonly detected in reactive, hyperplastic type II cells. When p31 immunoreactivity was correlated with clinicopathological features, a statistically significant increase in p31 expression was found both in bronchioli and alveoli of older individuals a well as in bronchioli of patients with most extensive smoking exposure. We conclude that p31 expression occurs in both non-neoplastic and neoplastic epithelium of the human respiratory tract. The increased expression of p31 in the peripheral lung may be potentially informative as to what critical cell populations are involved in the development of invasive cancers. Moreover, this study provides a model approach for analysis of the nature of early epithelial changes leading to the development of lung cancer. PMID- 8696724 TI - Postoperative radiotherapy for radically resected N2 non-small-cell lung cancer (NSCLC): randomised clinical study 1988-1992. AB - In the period 1988-1992, 74 consecutive radically resected patients with NSCLC were randomised to postoperative radiotherapy or surgery alone in order to evaluate the influence of postoperative radiotherapy on survival. There were 61 males and 13 females, aged 35-80 years, median 59 years. Their distribution by stage was as follows: pT1N2 = 19, pT2N2 = 54, pT3N2 = one patient; histology: 32 squamous, 32 adeno and 10 large cell carcinomas; surgery: atypical resection in six, lobectomy in 27, bilobectomy in ten, and pneumonectomy in 31 patients. In 27 patients, only one lymph node in a single mediastinal lymph node site was affected; in 31 patients more than one lymph node in one site; in 16 patients more sites were affected. In 35/74 patients radiotherapy of hilar and mediastinal sites with 3000 cGy in 2 weeks was performed. On December 31, 1994, 19 patients (26%) were still alive; 39/55 patients died of the following causes: locoregional failure-10(26%), distant metastases- 25 (64%), other tumor-unrelated causes-four patients (10%). Five-year survival rates did not show statistically significant differences between the irradiated and surgically treated patients only with respect to sex, pTNM stage, histology and frequency of locoregional failure. The number of metastatic mediastinal lymph nodes was the only significant prognostic factor (P < 0.005) in both randomised groups. PMID- 8696725 TI - Laparoscopic adrenal surgery. PMID- 8696726 TI - Cholangiography and laparoscopic cholecystectomy. PMID- 8696727 TI - Strategies to decrease the incidence of intra-abdominal recurrence in resectable gastric cancer. AB - Two main approaches are suggested to improve treatment results in resectable gastric cancer: extended lymphadenectomy and adjuvant antitumour therapy. Progress is to some extent stalled by the perception of gastric cancer as a pathophysiologically uniform disease; it has been demonstrated, however, that there are variants of gastric cancer associated with predominantly intra abdominal spread or with haematogenous metastases. Recent clinicopathological studies have provided information about the mechanisms of this metastatic diversity. A review of clinical trials suggests that no single method of treatment can efficiently address all variants of gastric cancer spread, but new treatment strategies may be based on defining the pathophysiological variant of gastric cancer and selecting adjuvant therapy according to the most probable mode of tumour spread. Treatment should start with surgery which includes a 'reasonably' extended lymphadenectomy aimed at achieving an increased rate of curative resection and more accurate staging. Risk factors for peritoneal spread of tumour require the perioperative use of intraperitoneal chemotherapy. Subsequent adjuvant therapy may be indicated in patients at high risk of further cancer spread or occult metastases, as determined by pathological examination of the resected specimen. PMID- 8696728 TI - Role of the Shouldice technique in inguinal hernia repair: a systematic review of controlled trials and a meta-analysis. AB - The Shouldice technique for inguinal hernia repair has been suggested by some authors as the best conventional method against which other methods using prostheses should be compared. The paper which follows is a systematic review involving a comprehensive search of the medical literature to identify all clinical trials (article or abstract) evaluating the Shouldice repair. After assessment of certain quality criteria, the best studies were pooled in a meta analysis. Nine publications were found with 11 study arms. In ten studies the results of the Shouldice technique were better than the results of the control arm. Six studies could be pooled in a meta-analysis of 2500 patients; Shouldice was significantly better than control methods (relative risk 0.62 (95 per cent confidence interval 0.45-0.85)). In spite of possible bias caused by different variables (modifications in operative technique, suture material, level of surgeon, follow-up methods and outcome measurement), the results of this systematic review suggest that the Shouldice method is the best current conventional technique for inguinal hernia repair. PMID- 8696729 TI - Colorectal cell kinetics. AB - The assessment of cell proliferation in colorectal tissue may provide information with both prognostic and therapeutic implications. A variety of methods are available, including flow cytometric estimations of S phase fraction, immunohistochemical and autoradiographic visualization of exogenous and endogenous proliferation proteins, and morphological and stathmokinetic techniques. There is some correlation between Dukes stage and proliferation state features, and there is increased proliferative activity throughout the adenoma carcinoma sequence. Data on cell proliferation rates are difficult to obtain. When correctly applied, the metaphase arrest technique remains the 'gold standard' of measuring proliferation, but its usefulness in clinical practice is limited. Recent studies have employed dual measurement flow cytometry and double labelling techniques to produce rate data. PMID- 8696730 TI - Routine preoperative infusion cholangiography at elective cholecystectomy: a prospective study in 694 patients. AB - The role of preoperative infusion cholangiography (PIC) before elective cholecystectomy has yet to be defined. Between 1985 and 1991 PIC was performed routinely in 694 patients with median (range) age of 52 (17-85) years with biliary calculus disease 1 or 4 days before elective cholecystectomy. Satisfactory opacification of the biliary system was achieved in 90.1 per cent and mild to moderate adverse reactions to the infusion of contrast medium occurred in 0.9 per cent of patients. Peroperative cholangiography (POC) in 43 of 499 patients with a normal PIC was normal. The presence of common bile duct stones was confirmed in 34 of 36 patients with prominent stones at bile duct exploration and in 8 of 26 with suspected stones at PIC. Bile duct dilatation (median diameter 10 mm) without concomitant stones was seen at PIC and confirmed at POC in 20 patients. Bile duct anomalies were found or suspected in 35 patients at PIC and were confirmed in six by POC (n = 5), or during the cholecystectomy making the anomaly incidence 0.9 per cent. Information provided by the PIC was not of crucial importance for safe execution of cholecystectomy in any patient, while a single (minor) bile duct lesion (1 of 694; 0.1 per cent) could be ascribed to severe pericholecystitis. The results of this study suggest that routine PIC is not warranted. However, PIC is an alternative to selective preoperative endoscopic retrograde cholangiography or selective POC. PIC needs to be supported by POC in approximately 20 per cent of patients (in case of absent or poor opacification of the bile ducts or suspicion of stones or anomalies at PIC). PMID- 8696731 TI - Intravenous infusion cholangiography for investigation of the bile duct: a direct comparison with endoscopic retrograde cholangiopancreatography. AB - Laparoscopic cholecystectomy has led to an increase in preoperative endoscopic retrograde cholangiopancreatography (ERCP) for the investigation of bile duct stones. ERCP and intravenous infusion cholangiography (IIC) were compared in 111 consecutive patients without jaundice considered to be at high risk for bile duct stones. Both investigations were successfully completed in 100 patients. IIC and ERCP demonstrated a normal bile duct in 81 patients and bile duct stones in 16 patients. IIC failed to identify bile duct stones in two patients (1.8 per cent). IIC was 89 per cent sensitive and 99 per cent specific for detecting bile duct stones in patients without jaundice. It is suggested that IIC is a cost-effective preoperative investigation for bile duct calculi. PMID- 8696732 TI - Resection of hepatocellular carcinoma in patients with cirrhosis. AB - Between 1987 and 1993, 53 hepatic resections for hepatocellular carcinoma (HCC) were performed in 51 patients with cirrhosis. Limited hepatic resection was performed in 66 per cent of patients. The postoperative mortality rate was 13 per cent. The tumours recurred in 27 patients (53 per cent), and the cumulative recurrence rate at 1 and 4 years was 41 and 89 per cent, respectively. Mean time to recurrence was 11.7 months and the most frequent site was the liver (21 patients). The only significant risk factor for recurrence was symptomatic tumours. The recurrence rate of HCC in patients with cirrhosis with surgical resection alone is high and actuarial survival at 4 years is very low. Other approaches to the treatment of HCC in patients with cirrhosis require consideration. PMID- 8696733 TI - Re-reconstruction of a single remnant hepatic vein. PMID- 8696734 TI - Long-term results of endoscopic stenting and surgical drainage for biliary stricture due to chronic pancreatitis. AB - A retrospective evaluation was made of the long-term results of endoscopic stenting in 58 patients with benign biliary stricture due to chronic pancreatitis. Immediate relief of jaundice and cholestasis was achieved in all patients after endoscopic stent insertion. Median follow-up was 49 months. Five (9 per cent) of the 58 patients had complications following therapeutic endoscopic retrograde cholangiopancreatography. Late stent-related complications occurred in 37 (64 per cent) of 58 patients. There were no deaths. Sixteen (28 per cent) of the 58 patients had regression of the biliary stricture and permanent removal of the stent. Forty-two patients had persistent biliary stricture: 26 had continued stenting and 16 underwent surgical procedures. Early morbidity after surgery was found in six of 16 patients, with no deaths. Postoperative relief of jaundice was achieved in 15 of the 16 patients. In conclusion, endoscopic stenting and surgery are both effective treatments for biliary stricture in patients with chronic pancreatitis. Endoscopic stenting is associated with fewer early complications. However, late stent-related complications remain a major limitation. Endoscopic stenting offers definitive treatment in more than one-quarter of patients (28 per cent). PMID- 8696735 TI - Can we safely delay or avoid prophylactic colectomy in familial adenomatous polyposis? PMID- 8696736 TI - Topical glyceryl trinitrate in the treatment of chronic anal fissure. AB - The aetiology of anal fissure is unclear, but there is an association with high maximum resting pressure (MRP). Internal sphincterotomy reduces MRP and heals fissure through an increase in local blood supply. Glyceryl trinitrate (GTN) is a nitric oxide donor which contributes to internal anal sphincter relaxation via a non-adrenergic non-cholinergic pathway. GTN ointment was applied topically in different concentration to the anal margin in patients with chronic anal fissure to monitor its effect primarily on MRP and secondarily on fissure healing. Nineteen patients with chronic anal fissure were treated with ointment containing increasing concentrations of GTN (0.2-0.8 per cent) to produce a reduction in MRP of greater than 25 per cent. The actual dose of GTN varied as no standard delivery system has been developed, but a 'typical amount' of GTN ointment weighed about 200 mg. In 15 of 19 patients, a concentration greater than 0.2 per cent was required to lower the MRP by at least 25 per cent. The minimum concentration of GTN that reduced the resting pressure by at least 25 per cent was prescribed and local application was carried out by the patient twice daily for 6 weeks. At 6 weeks, nine patients had healed, six required sphincterotomy and four were lost to follow-up. Eight of the nine patients with healed fistula required a GTN concentration of 0.3 per cent or more. Sixteen patients were resistant to the usually effective does of 0.2 per cent GTN. In three there was tachyphylaxis and the duration of action of GTN was less than the 12 h described previously in control patients. Two patients did not fulfil the study because of headache. PMID- 8696737 TI - Use of glyceryl trinitrate ointment in the treatment of anal fissure. AB - Anal fissure is often treated surgically by sphincterotomy. There is growing concern over the effects of this procedure on continence. Nitric oxide donors such as glyceryl trinitrate are thought to cause a reversible 'chemical sphincterotomy', capable of healing the fissure. Twenty-one consecutive patients with chronic anal fissure (13 women, mean age 36 years) were treated for 4-6 weeks with 0.2 per cent glyceryl trinitrate ointment applied to the fissure twice daily. Maximum anal resting pressure (MARP) was measured before and after application of the ointment at the first visit. There were 16 posterior and five anterior fissures. Mean(s.d.) MARP fell from 118.7(45.0) to 70.3(34.1) cmH2O over 20 min after application of the ointment (P < 0.001). Healing was complete in 11 patients at 4 weeks and in 18 at 6 weeks. The fissure recurred in four patients after cessation of treatment; three were successfully treated by further glyceryl trinitrate. Mild headache occurred in four patients. Anal fissure can be successfully treated with 0.2 per cent glyceryl trinitrate ointment applied topically. PMID- 8696738 TI - Severe complications of perianal sepsis in patients with human immunodeficiency virus. AB - Fifty human immunodeficiency virus (HIV)-infected patients with perianal sepsis were studied. Seven (14 per cent) had serious septic complications, four patients with severe necrotizing gangrene, and three with abscesses in the mediastinum, liver and brain respectively. CD4+ lymphocyte counts were significantly lower in patients with severe septic complications as compared with those with uncomplicated perianal sepsis (P < 0.05). In patients with HIV presenting with rare (metastatic) abscesses, perianal sepsis must always be kept in mind as a possible focus. Although HIV-infected patients have a limited life expectancy perianal fistulas and abscesses should be aggressively treated, because of the high risk of severe complications. PMID- 8696740 TI - Colonic decompression without on-table irrigation for obstructing left-sided colorectal tumours. PMID- 8696739 TI - Prognostic significance of radial margins of clearance in rectal cancer. AB - A retrospective review of 325 patients was undertaken to analyse whether involvement of the radial resection margin (RRM) could predict locally recurrent disease or distant metastases in patients who had curative surgery for rectal or rectosigmoid cancer. Information on the RRM was available in 253 patients. The RRM was involved in 31 (12 per cent). Nine of these 31 patients developed local recurrence (29 per cent), while only 17 local recurrences were diagnosed in 217 patients (8 per cent) without involvement of the RRM (P < 0.01). At 2 years the overall local recurrence rate was 10 per cent. Distant metastases were diagnosed in 46 patients (18 per cent) and RRM involvement was identified as a prognostic factor depending on lymph node involvement (N stage) (P = 0.02). Local recurrence and some distant metastases result from microscopically incomplete resection. Assessment of the radial depth of tumour invasion by careful histological examination of x791p4ecimen may be used for selection of patients for adjuvant radiotherapy and/or chemotherapy. PMID- 8696741 TI - Prospective audit of discharge summary errors. AB - During an 8-month interval of prospective audit, 63 of 637 (10 per cent) vascular discharge summaries were found to contain 94 errors. These comprised 11 (12 per cent) general errors, 21 (22 per cent) diagnostic errors, 19 (20 per cent) operative data errors, 19 (20 per cent) cases of incorrect clinical text information, 14 (15 per cent) missed complications and 10 (11 per cent) concerning follow-up arrangements. Overall, 2 per cent of consultant discharge summaries contained errors compared with 7 per cent for the senior registrar, 10 per cent for registrars and 17 per cent for senior house officers. Given that the majority of discharge summaries are currently prepared by junior staff, this study suggests that verification of the accuracy of clinical and management data should be an essential component of departmental audit meetings. PMID- 8696742 TI - Blood flow in the lower limb after balloon angioplasty of the superficial femoral artery. AB - Using duplex ultrasonography lower-limb blood flow measurements were obtained in 20 patients with intermittent claudication. Assessments of flow were made in the common femoral artery, profunda femoris artery (PFA) and superficial femoral artery (SFA) before and after angioplasty for stenoses of short segments of the SFA. Blood flow was measured at rest and after exercise on a cycle ergometer. Collateral flow was calculated using an established mathematical model. Results were compared with the ankle:brachial systolic pressure index (ABPI) after exercise. Although there was no overall increase in resting limb blood flow, an increase in mean(s.d.) SFA flow from 148(79) to 312(94) ml min-1, with a concomitant decrease in PFA flow from 224(84) to 98(43) ml min-1 was noted 1 week after angioplasty (P < 0.05). At rest there was an increase in mean(s.d.) ABPI from 0.62(0.12) to 0.89(0.23) (P < 0.05). Collateral flow was estimated to have decreased from 186(34) to 18(8) ml min-1; the pattern of change in flow was similar after exercise. Angioplasty of the SFA remains controversial because of the risk of restenosis. The above methodology allows assessment of whether patients can re-establish collateral flow or whether limb blood flow will be significantly compromised if restenosis occurs. PMID- 8696743 TI - Iliac arteriovenous fistula following lumbar disc surgery treated by percutaneous endoluminal stent grafting. PMID- 8696744 TI - Skin from the amputated limb should not be wasted. PMID- 8696745 TI - Xanthine oxidase in critically ischaemic and claudicant limbs: profile of activity during early reperfusion. AB - Xanthine oxidase activity in blood from the ipsilateral femoral vein, and the relationship between xanthine oxidase production and the products of lipid peroxidation, were studied before operation and for 60 min following release of clamps after successful revascularization in two groups of patients with claudication or critical ischaemia. Before revascularization, detectable levels of xanthine oxidase were found only in patients with critical ischaemia. Clamping during bypass surgery led to release of xanthine oxidase in claudicants, but this activity reduced after 60 min. There was no evidence of lipid peroxidation during this time. Xanthine oxidase activity in brachial vein blood was higher than in femoral vein blood in patients with critical ischaemia before revascularization. PMID- 8696747 TI - Late failure of endoluminal abdominal aortic aneurysm repair due to continued aneurysm expansion. PMID- 8696746 TI - Experimental application of controlled limb reperfusion after incomplete ischaemia. AB - Severe local and systemic complications may occur after revascularization of extremities exposed to prolonged complete or incomplete ischaemia. These complications may be reduced by controlling the reperfusate and the circumstances of the reperfusion period. Ten adult German domestic pigs were exposed to 6 h of incomplete limb ischaemia by occlusion of the left iliac artery. To simulate the clinical situation of embolectomy, the occlusive snares were released after the ischaemic period in five pigs and normal blood flow developed with systemic pressure (uncontrolled reperfusion). In the other five pigs, a controlled reperfusate was delivered at controlled pressure before establishing normal blood reperfusion (controlled reperfusion). At the end of the observation period (90 min after start of reperfusion), the group with controlled reperfusion had a lower mean(s.e.m.) tissue water content (81.8(0.7) versus 84.3(0.7) per cent, P < 0.05, a greater increase in tissue adenosine 5'-triphosphate compared with values at the end of ischaemia (6.2(1.5) versus -2.5(1.8) mumol per g protein, P < 0.03), a higher tissue pH (7.2(0.1) versus 6.8(0.1), P < 0.03), a smaller temperature decrease (0.3(0.2) versus 1.2(0.3) degrees C, P < 0.05), lower concentrations of creatine kinase (355.0(87.5) versus 624.4(73.4) units/l, P < 0.05) and lactate dehydrogenase (LDH) (369.5(42.5) versus 538.4(39.2 units/l, P < 0.03) in the femoral vein blood and lower LDH concentrations (356.5(48.9) versus 546.0(37.8 units/l, P < 0.03) in central venous blood. These data indicate that severe local and systemic damage occurs with uncontrolled (normal blood) reperfusion even after incomplete limb ischaemia, and that these changes can be reduced by delivering a controlled reperfusate under controlled conditions. PMID- 8696748 TI - Loop end colostomy: a new technique. PMID- 8696749 TI - An evaluation of the POSSUM surgical scoring system. AB - POSSUM (Physiological and Operative Severity Score for the enUmeration of Morbidity and mortality) has been studied as a possible surgical audit system for a 9-month interval using a sample of 28 per cent of the general surgical workload. Mortality or survival was analysed as an endpoint. In this sample the published POSSUM predictor equation for mortality overpredicted deaths by a factor of more than two. The bulk of the overprediction occurred in the group at lowest risk (predicted mortality 10 per cent or less), in which death was overpredicted by a factor of six. This is the most important group for audit purposes since it contains the majority of surgical patients and is composed of fit patients undergoing minor surgery. The published predictor equation for mortality returns a minimum predicted mortality of 1.08 per cent, clearly far higher than that expected for a fit patient having minor surgery. Logistic regression was done on a set of 1485 surgical episodes to generate a local predictor equation for mortality. This process gave a predictor equation that fitted well with the observed mortality rate and gave a minimum predicted risk of mortality of 0.20 per cent. The previously published POSSUM predictor equation for mortality performed badly when tested using a standard test of goodness of fit for logistic regression and must be modified. PMID- 8696750 TI - Diagnostic role of cytology in screen-detected breast cancer. AB - Fine-needle aspiration cytology (FNAC) of the breast was performed in 491 patients over a 3-year period. Some 365 examinations (74.3 percent) were performed by palpation and the remaining 126 (25.7 percent) by stereotaxis. Ninety-six patients were excluded because of inadequate follow-up. Using a standard method of reporting the results 247 smears were classified as C1 and C2, but based on clinical and radiological criteria excision biopsy was recommended and performed in 122 patients with these lesions. Twenty-two per cent of C2 lesions were found to be malignant after histological examination. Forty-two patients with C3 or C4 cytology were advised to have excision biopsy and 41 had surgery. In all but one case the lesion was found to be malignant histologically. Definitive surgery was performed on 106 patients with C5 cytology and the diagnosis of malignancy was confirmed histologically in 105 of them. FNAC is a useful diagnostic tool in breast screening but in view of the number of false negative results, cytology alone is unreliable and, therefore, full triple assessment is recommended. PMID- 8696751 TI - Periductal mastitis and duct ectasia: different conditions with different aetiologies. AB - A prospective study of 14,225 patients has been undertaken to determine the inter relationship between periductal mastitis and duct ectasia and to establish whether there is an association between smoking and either of these two conditions. Periductal mastitis affected women at a younger age than did duct ectasia. Of 139 patients with the clinical syndrome of periductal mastitis, 97 (70 per cent) had a past history of previous periductal mastitis, compared with only one (1 per cent) of 186 patients with the clinical syndrome of duct ectasia (P < 0.0001). There was a significant excess of smokers in patients with clinically (124 (89 per cent) of 139) and pathologically (71 (91 per cent) of 78) diagnosed periductal mastitis compared with age-matched controls (both P < 0.001), but there was no such excess in those with clinically (52 (28 per cent) of 186) or pathologically (15 (23 per cent) of 64) diagnosed duct ectasia. These data suggest that periductal mastitis and duct ectasia are separate conditions which affect different age groups, have different aetiologies, and should now be considered as separate entities. PMID- 8696752 TI - Parathyroidectomy in the west Midlands. AB - A retrospective audit was made of 101 patients undergoing parathyroidectomy, performed by 20 general surgeons in the West Midlands region during 1992. The mean number of cases per surgeon was five; nine surgeons performed fewer than three parathyroidectomies. Some 57 patients had primary hyperparathyroidism. Only seven were diagnosed by general practitioners and referral was invariably to a non-endocrine physician. Delay between diagnosis and surgical referral exceeded 2 years in 12 patients. Four patients (7 per cent) with primary hyperparathyroidism remained hypercalcaemic after first exploration; all were operated on by surgeons who performed fewer than four parathyroidectomies per year. Minor complications occurred in 32 per cent of patients. All 44 patients with renal hyperparathyroidism were treated in specialist units where diagnosis and treatment were expeditious; parathyroidectomy was successful in 41. Hyperparathyroidism should be managed in specialized units and by surgeons who perform parathyroidectomy frequently. A heightened awareness of primary hyperparathyroidism is required at primary care level. PMID- 8696753 TI - Magnetic resonance imaging of thyroid swellings. AB - The preoperative diagnosis of some thyroid neoplasms remains difficult even with the routine use of fine-needle aspiration cytology. The potential of nuclear magnetic resonance imaging (MRI) to discriminate between different thyroid pathologies was explored prospectively and compared with the final pathology in a series of 37 patients. MRI yielded high-quality images of the thyroid swelling but did not provide additional information to differentiate benign from neoplastic lesions. MRI does not contribute to the routine management of thyroid swellings. PMID- 8696754 TI - Long-term results of a prospective randomized comparison of total fundic wrap (Nissen-Rossetti) or semifundoplication (Toupet) for gastro-oesophageal reflux. AB - The importance of the extent of the fundic wrap that encircles the distal oesophagus for the establishment of long-term control of gastro-oesophageal reflux disease (GORD) and for the risk of symptoms after fundoplication was evaluated in a prospective, randomized clinical trial. Of 137 consecutive patients with GORD, 72 were allocated to a semifundoplication (180-200 degrees, Toupet) and 65 to a total fundoplication (360 degrees, Nissen-Rossetti). Dysphagia was more common in the early postoperative period after a total fundic wrap, a difference which disappeared with time. This corresponded to a higher resting tone in the lower oesophageal sphincter area. Seven patients (5 per cent) experienced relapse of GORD during follow-up of more than 3 years. Although no difference in the cumulative relapse rate (5 per cent for Nissen-Rossetti versus 6 per cent for Toupet) was found between the two study groups, the total failure rate was higher (P < 0.05) among patients who had a Nissen-Rossetti procedure because of a procedure-specific complication: intrathoracic herniation of the fundoplication in five patients caused obstructive symptoms without reflux (four had no posterior crural repair). In addition, symptoms in the form of flatulence were more frequently seen after Nissen-Rossetti fundoplication (P < 0.05 at 2 years and P < 0.01 at 3 years). Both Nissen-Rossetti and Toupet fundoplication equally well and durably controlled GORD. Fewer symptoms occurred in those having a semifundoplication, both in the early and late postoperative period. PMID- 8696755 TI - Limited operation for gastric cancer in the elderly. AB - The relationship between operative procedures for treatment of patients with gastric carcinoma and complications was studied with special reference to the age of patients, who were divided into four groups: 50-59 years; 60-69 years; 70-79 years; and over 80 years. Preoperative risk factors that were common in patients over 70 years of age were hypertension and cardiac disease. The selected operative procedures were similar for each age group. However, neither proximal gastrectomy nor reconstruction by jejunal interposition was selected for patients of 80 years and over. In these patients, resection of the neighbouring organs was seldom performed and lymph node dissection was usually limited to the primary and secondary nodes. There was no significant difference in the rate of postoperative complications between groups. Although only limited surgery was performed for patients of 80 years and over, there was no significant difference in age corrected cumulative survival rate between groups. Therefore, limited resection and/or lymph node dissection may allow safe surgical treatment for patients of 80 years and over with gastric carcinoma, without any negative effect on prognosis. PMID- 8696756 TI - Risk of further ulcer complications after an episode of peptic ulcer bleeding. AB - To identify the risk factors for developing recurrent ulcer complications after recovery from an episode of peptic ulcer bleeding 611 patients admitted with peptic ulcer bleeding were studied. Some 557 (91 per cent) were discharged without operation. A total of 22 patients were lost to follow-up and five were excluded as maintenance H2 blockers were required. Of the remaining 530 patients at risk, 169 (32 per cent) developed another complication (166 bleeding, three perforations) over a median follow-up period of 36 months. Patients with duodenal ulcers at the time of bleeding, previous history of peptic ulcer, previous bleeding, history of dyspepsia longer than 3 months, and a short interval between previous ulcer complications and the index bleed were more likely to develop further complications. Sex, age, smoking, coexisting illness, non-steroidal anti inflammatory drugs intake and time taken to achieve ulcer healing had no predictive value. PMID- 8696757 TI - Endoscopic perforation in unsedated patients undergoing endoscopy. PMID- 8696758 TI - Renal transplantation from non-heart-beating donors. PMID- 8696759 TI - Long-term results of giant prosthetic reinforcement of the visceral sac for complex recurrent inguinal hernia. PMID- 8696760 TI - Balloon tamponade for control of massive presacral haemorrhage. PMID- 8696761 TI - Diagnosis of arterial disease of the lower extremities with duplex ultrasonography. PMID- 8696762 TI - The retrocaecal appendix appears to be less prone to infection. PMID- 8696763 TI - Open diagnostic peritoneal lavage. PMID- 8696764 TI - Importance of human immunodeficiency virus-associated lymphadenopathy and tuberculous lymphadenitis in patients undergoing lymph node biopsy in Zambia. PMID- 8696765 TI - Residual appendicitis following incomplete laparoscopic appendectomy. PMID- 8696766 TI - Surgical management of rectal cancer. PMID- 8696767 TI - Cell proliferation kinetics are abnormal in transitional mucosa adjacent to colorectal carcinoma. PMID- 8696768 TI - Management of intestinal obstruction after gastrectomy for carcinoma. PMID- 8696769 TI - Mammary duct ectasia-periductal mastitis complex. PMID- 8696770 TI - Treatment and survival in 13,560 patients with pancreatic cancer, and incidence of the disease, in the west Midlands: an epidemiological study. PMID- 8696771 TI - Polyposis: the Peutz-Jeghers syndrome. PMID- 8696772 TI - Endoscopic subtotal parathyroidectomy in patients with primary hyperparathyroidism. PMID- 8696773 TI - Effects of ryegrass on biodegradation of hydrocarbons in soil. AB - The effects of growing ryegrass (Lolium perenne L.) on the biodegradation of hydrocarbons was studied in laboratory scale soil columns. Degradation of hydrocarbons as well as bacterial numbers, soil respiration rates and soil dehydrogenase activities were determined. In the rhizosphere soil system, aliphatic hydrocarbons disappeared faster than in unvegetated columns. Abiotic loss by evaporation was of minor significance. Elimination of pollutants was accompanied by an increase in microbial numbers and activities. The microbial plate counts and soil respiration rates were substantially higher in the rhizosphere than in the bulk soil. The results indicate that biodegradation of hydrocarbons in the rhizosphere is stimulated by plant roots. PMID- 8696775 TI - PDA comments on "EU guide to good manufacturing practice; annex on the manufacture of sterile medicinal products". Parenteral Drug Association. PMID- 8696776 TI - FDA crisis management and the media. PMID- 8696774 TI - Interaction of 2,4,4'-trichloro-2'-hydroxydiphenyl ether with microsomal cytochrome P450-dependent monooxygenases in rat liver. AB - We studied the effects of 2,4,4'-trichloro-2'-hydroxydiphenyl ether (Irgasan DP300) on the kinetics of the cytochrome P450 (P450)-dependent monooxygenases in rat liver microsomes. The activities of 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depentylase (PROD) in rat liver microsomes exposed to 3 methylcholanthrene (MC) and phenobarbital (PB) respectively, were substantially inhibited by Irgasan DP300. The inhibition profile of EROD was competitive, whereas that of PROD was noncompetitive; the Ki values from Hanes plots were 0.24 and 1.48 microM for EROD and PROD, respectively. Phenacetin O-deethylase (PCOD) and 4-nitrophenol hydroxylase (4NPH) activities in rats exposed to PB were also inhibited by Irgasan DP300, at Ki values lower than those for other microsomes. Irgasan DP300 slightly inhibited testosterone 6 beta-hydroxylase (TS6BH) activities in some microsomes. No effect of Irgasan DP300 on lauric acid omega hydroxylase (LAOH) activity was evident in any microsomal preparations. These results indicated that Irgasan DP300 inhibits MC- and PB-inducible P450-dependent monoxygenase in vitro competitively or noncompetitively, and that the P450 enzymes of the CYP1A or CYP2B subfamily may contribute to Irgasan DP300 toxicity. PMID- 8696777 TI - Evaluation of recovery filters for use in bacterial retention testing of sterilizing-grade filters. AB - Membrane filters with pore-size ratings of 0.22 microns and 0.45 microns were tested for their ability to recover Pseudomonas diminuta ATCC 19146 (P. diminuta), the organism typically used in bacterial retention testing of sterilizing-grade membrane filters. For each of the two pore-size ratings, filters of two membrane filter polymer materials, hydrophilic PVDF (Millipore Durapore) and mixed esters of cellulose, were tested, resulting in an evaluation of four potential recovery filters. The 0.45 microns mixed esters of cellulose filter is the currently accepted membrane for this purpose. The data show no difference in the ability of the four filters to recover freshly cultured P. diminuta. Moreover, the membrane-filter method was shown to provide a very high bacterial-recovery efficiency, equivalent to that of the spread-plate method. Thus, 0.22 micron filters, despite their ability to retain higher levels of bacteria, proved not to have an advantage over 0.45 micron membranes in terms of bacterial recovery. This result, combined with (1) the knowledge that more open membranes have been shown experimentally to more efficiently recover stressed organisms; (2) the potential to produce stressed cells in an actual bacterial retention test; and (3) the long history of the successful use of 0.45 microns mixed esters of cellulose for bacterial recovery, support the continued use of the 0.45 micron filter in this application. PMID- 8696778 TI - Endotoxin removal using 6,000 molecular weight cut-off polyacrylonitrile (PAN) and polysulfone (PS) hollow fiber ultrafilters. AB - The removal of pyrogenic and microbial contaminants from high purity water and parental solutions during production is a concern to pharmaceutical manufacturers. In a previous study, 6000 molecular weight cut-off (MWCO) polyacrylonitrile (PAN) and polysulfone (PS) ultrafilters were shown to remove poliovirus (Titer reduction [Tr], > 6 logs) and phages T1 and PP7 (Tr, 7 logs) from ultrapure water, 0.85% saline with 1% trypicase soy broth, and Dulbecco's Eagle minimal essential medium with 10% fetal bovine serum (15). In this study, we evaluated the ability of the 6,000 MWCO PAN and PS ultrafilters to remove purified endotoxin (Escherichia coli lipopolysaccharide) which was added to commercial Water for Irrigation. An endotoxin concentration reduction of > 6 logs was achieved with both PAN and PS ultrafilters (detection sensitivity, 0.0031 EU/ml) when a minimum of 3.92 x 10(3) EU/ml of endotoxin was added to Water for Irrigation. These results indicate that the 6,000 MWCO PAN and PS ultrafilters are very effective in removing endotoxin from fluids such as Water for Irrigation. PMID- 8696779 TI - Photodegradation of furosemide solutions. AB - Photodegradation of furosemide was studied under the influence of fluorescent and UV lights. Photodecomposition of furosemide solutions appeared to follow first order kinetics. The compound was found to be most stable at an optimum pH of 7. Long-wave UV light caused the fastest rate of degradation of furosemide. Glutathione, thiourea, EDTA, sodium thiosulfate, sodium metabisulfite, glycine, sodium benzoate and uric acid were found to be ineffective as photoprotective agents. Increase in ionic strength did not cause any change in the degradation rate constant. Amber glass vials and transparent glass vials covered with aluminum foil offered complete protection against fluorescent light. A vehicle consisting of a mixture of 50% (v/v) propylene glycol in phosphate buffer offered slight photoprotection. PMID- 8696780 TI - Identification of antioxidants for prevention of peroxide-mediated oxidation of recombinant human ciliary neurotrophic factor and recombinant human nerve growth factor. AB - Peroxides present in non-ionic surfactants used to stabilize certain recombinant protein formulations (e.g. polysorbate 80) can result in the oxidative degradation of proteins. In this study, the ability of various pharmaceutically acceptable antioxidants to prevent the oxidative degradation of two therapeutic proteins, recombinant human Ciliary Neurotrophic Factor (rhCNTF) and recombinant human Nerve Growth Factor (rhNGF), caused by alkyl hydroperoxides and hydrogen peroxide was studied. For rhCNTF, the rank order of effectiveness of the antioxidants tested was: thiols (cysteine, glutathione, thioglycerol) >> thioethers (methionine). Other parenterally acceptable antioxidants (ascorbic acid, propyl gallate and sodium bisulfite) destabilized the protein. The thiol antioxidants (cysteine and glutathione) were also the most effective antioxidants for rhNGF; however, in contrast to rhCNTF, ascorbic acid did not destabilize rhNGF. The rank order of effective antioxidants for rhNGF was: thiols (cysteine, glutathione) > > thioethers (methionine) > ascorbic acid. PMID- 8696781 TI - Microwave continuous sterilization of injection ampoules. AB - A new microwave continuous sterilizer (MWS) for applying microwave dielectric heating as an alternative to an autoclave was developed. The developmental objectives of the MWS were: 1. Achieving sufficient sterilization for the drugs containing heat-sensitive ingredients. 2. Measuring and recording sterilization temperature of each ampoule. 3. Ensuring automatic continuous operation and linkage with the preceding and following machines in an injection ampoule production process. The temperature of the drug solution in an ampoule was heated to 140 degrees C within about 30 seconds by the MWS. Target F0 value is achieved through the maintaining heater to maintain the target temperature for 12 seconds. Ampoules are cooled with air and water after completion of heating. The MWS is capable of processing 150 ampoules per minute. The newly developed techniques which minimized temperature distribution of heated ampoule solution were: 1. Microwave irradiation in a direction opposite to the direction of ampoules transportation. 2. Microwave irradiation in the lower part of ampoule solution (i.e., heating up the drug solution by thermal convection.) 3. Microwave power control by feedback of measured temperatures. 4. Heating rate control corresponding to the dielectric property of ampoule solution. The drug stability test was performed using 3% pyridoxamine phosphate solution, and the inactivation of spores in 3% pyridoxamine phosphate solution was examined using Bacillus stearothermophilus ATCC 7953 spores. The MWS was proved to have an adequate efficiency of sterilization with less chemical degradation of the contents than an autoclave. PMID- 8696782 TI - Inspection qualification (IQ) and operational qualification (OQ) for a vacuum freeze-dryer--Part I. General discussion. AB - The principle objectives of this paper are (a), to develop the rationale for conducting an inspection qualification (IQ) and operational qualification (OQ) of a vacuum freeze-dryer; (b), to identify the key elements that require verification for completion of the IQ; and (c), to establish the necessary environmental and operational parameters necessary for the OQ of the vacuum freeze-dryer. PMID- 8696783 TI - The ISO draft international standard--aseptic processing of health care products. PMID- 8696784 TI - Mental disorder among a homeless population in Belfast: an exploratory survey. AB - This study aimed to identify the prevalence of mental disorder in hostels for the homeless in Belfast, Northern Ireland. In addition, it attempted to assess the facilities and support offered from both the hostels and the Health Service to homeless people who have a mental disorder. Lastly it sought to determine whether or not psychiatric hospital bed closure had any influence on the prevalence of homelessness among these persons in Belfast. An exploratory approach was adopted, using semi-structured interviews as the method of data collection. The sample consisted of 12 hostels for the homeless with a total occupancy of 250 residents. Officers in charge were surveyed. The results obtained indicated that approximately 25% of the homeless in Belfast hostels have a diagnosed mental disorder and that hospital closure has had a direct effect on the size of this percentage. In addition, it was found that the hostels generally are not able to offer the levels of therapy and support given in hospital or in designated hostels for people with mental health problems. Responses also suggest that support from Health Service personnel is less than satisfactory. While the findings in this study do not look at the entire homeless population in Northern Ireland, interesting and useful information emerged that has implications for policy and further areas of study elsewhere. PMID- 8696785 TI - Staff perception of illicit drug use within a special hospital. AB - This paper presents the results of a survey of staff perceptions of issues related to illicit drug use amongst patients within a UK Special (forensic) Hospital. The issues examined were: the nature and extent of drug-related problems; current management strategies and their perceived efficacy; suggestions for improved management strategy; and identification of staff training needs. Data were collected utilizing a questionnaire distributed all patient-care team members and representatives of disciplines working in off-ward areas (n = 311). The response rate was approximately 40%. Analysis of the returns suggests that staff concerns are largely focused on issues around the supply of drugs. A significant level of ignorance regarding illicit drugs and their usage was revealed, indicating a need for coordinated training. A review of literature suggests that future management strategies should not be solely directed towards supply restriction. A discussion of the results highlights parallels between Ashworth Hospital staff perceptions of illicit drug problems, media coverage of the same, and the findings of earlier sociological studies of deviance, subculture and moral panic. PMID- 8696786 TI - Attitude to treatment and direction of interest of forensic mental health nurses: a comparison with nurses working in other specialties. AB - The attitudes of nurses working within forensic psychiatry are often perceived as being custodially oriented. Working on this commonly held assumption the authors hypothesized that nurses working within a physically controlled environment such as a Regional Secure Unit would hold more conservative/biological attitudes toward treatment, and would be more 'object'-oriented (as opposed to 'psychologically' oriented) than those working in less physically controlled clinical areas. [For the purpose of this paper the term 'Regional Secure Unit' is used to describe the medium secure facilities that were included in this study, although one of the units did not serve a wholly regional function.] This paper outlines a study that attempted to examine this hypothesis. A total of 84 nurses from three clinical specialties (Regional Secure Units, Acute Admission Wards and Drug Dependence Units) completed the Attitude to Treatment Questionnaire (ATQ) and the Direction of Interest Questionnaire (DIQ) (Caine et al. 1981). Each nurse also completed a demographic information questionnaire, supplying details of age, professional experience and educational attainment. The results indicate no significant differences on measures used between specialty groups. Significant positive correlations were found between age and conservatism on the ATQ, and between ATQ conservatism and DIQ object centredness. Implications of these results are discussed and suggestions for future research are made. PMID- 8696788 TI - The effect of staffing levels on the use of seclusion. PMID- 8696787 TI - The report of the clinical standard advisory group: standards of care for people with schizophrenia in the UK and implications for mental health nursing. AB - The Clinical Standards Advisory Group Schizophrenia Committee has spent two years (1993-1995) developing a standards protocol to assist all Purchasers and Providers with the task of producing optimum services for people with schizophrenia and other serious and enduring mental illnesses. This work has been underpinned by research that included visits to a representative sample of services throughout the UK. The report of this initiative, which was published in the summer of 1995, has many implications for mental health nursing. These include the continuing necessity to focus on serious mental illness; more effort to develop multidisciplinary working and the use of the Care Programme Approach; an increased focus on relevant training in case management and psychosocial interventions; the need to recognize physical health problems; the importance of medication management; and, as the Review of Mental Health Nursing emphasized, the issue of leadership should be targeted as a priority for action. PMID- 8696789 TI - Trivia-psychotica: the development and evaluation of an educational game for the revision of psychiatric disorders in a nurse training programme. PMID- 8696790 TI - A response to Rolfe. PMID- 8696791 TI - The future of psychiatric and mental health nursing in the Australian region. PMID- 8696792 TI - Suicide in Northern Ireland: a comparison of two quinquennia (1982-1986 and 1987 1991). AB - This study compares government records of death by suicide, in Northern Ireland, during two quinquennia in the decade 1982-1991. Specifically these quinquennia are 1982-1986 and 1987-1991. During the latter quinquennium there was an increase in rate for males in most age groups, except the 45-54 and the over 65 years age groups. However, females had an increase rate in the 15-24 and 35-54 years age groups, but have a decreased rate in the other age groups. There has been a decrease in the rate of suicides by poisoning with solids and liquids for both sexes. However, male suicide rates by more violent methods have increased substantially during the latter quinquennium. Three cohorts of males, those in the 15-24, 25-34, and 55-64 age groups, have shown substantial increases during the latter quinquennium. Suggestions for psychiatric intervention strategies are made. PMID- 8696793 TI - The Strategy for Action on Farmers' Emotions (SAFE): working to address the mental health needs of the farming community. AB - Within the United Kingdom farmers are considered to be the fourth highest occupation group at risk of committing suicide. However, the mental health needs of the farming community are currently poorly understood or addressed by mental health nurses and community mental health teams. This is unacceptable both in terms of the presented level of risk, and in the direction of the most recent mental health review, which suggests that mental health nurses have unique skills in identifying and responding to suicidal behaviour. By building upon the practice of the first author, this paper outlines the Strategy for Action on Farmers' Emotions (SAFE), which develops a comprehensive strategy to respond to the mental health needs of the farming community. Where it is applicable, it is vital that these needs are brought from the margins to the mainstream of policy and service provision. This paper suggests that this position will only be achieved once an increased understanding of farming life and culture is gained. PMID- 8696795 TI - Discourse, social exclusion and empowerment. PMID- 8696794 TI - An exploration of nurses' attitudes to the nursing care of the suicidal patient in an acute psychiatric ward. AB - Suicidal patients admitted to hospital following a suicidal attempt or expressing suicidal ideation present a real challenge to health professionals with regard to their therapeutic care. This study was undertaken to explore the attitudes of psychiatric nurses caring for such patients. Results reveal that psychiatric nurses do hold positive views on caring for potentially suicidal patients, contradicting previous studies where more negative feeling were expressed by nurses, especially those with initial contact. Findings also show that some nurses experience an element of distress, and the length of experience within such a working environment does not affect the nurses' level of satisfaction gained on caring for the suicidal patient. This study also identifies an expression of need for further education and practice in interpersonal skills and therapeutic modalities to enhance and develop a more effective delivery of care for this group of patients. PMID- 8696796 TI - Evaluating services for women with serious and ongoing mental health problems: developing an appropriate research method. AB - Despite an increase in the literature on women with less disabling or transitory mental health problems, there is little relating to women with serious and ongoing difficulties. In considering the means by which the needs of this population might be studied, tension arises over methodology. Research comparing the clinical, functional and service use characteristics of women and men might demonstrate their different mental health problems but would neither elucidate women's particular needs nor examine the social reasons for this difference. A feminist methodology would, however, offer a means of exploring the experiences of women, a framework for understanding sex differences, and generate findings that would be beneficial to women. The present study gives an insight into ways in which the exploration of sex differences can be combined with a study of women for women without compromising the relevance and impact of the findings. PMID- 8696797 TI - Verbal and non-verbal behavior immediately prior to aggression by mentally disordered people: enhancing the assessment of risk. AB - In this study we seek to enhance the assessment of imminent violence risk by providing empirical data on the types of verbal and non-verbal behaviour exhibited by 31 psychiatric inpatients immediately prior to assaulting a staff member, and 31 non-aggressive controls. Verbal abuse, high overall activity level and standing uncomfortably close to the intended victim were the most common behaviours immediately prior to the assault, but most preassault behaviours were also exhibited when patients were not assaulting staff. In the 3 days prior to the assault, aggressive patients differed from non-aggressors in terms of verbal abuse, abnormal activity level (P < 0.05), threatening gestures and threatening stance (P < 0.01). Only one patient was aggressive in the absence of any predictive behaviours. We conclude that most patients exhibit easily identifiable signs of imminent aggression, but that many of these signs occur in the absence of aggression. PMID- 8696798 TI - Genogram: a useful tool for nurse practitioners. AB - This paper presents the genogram, originated by family therapists and utilized in the psychosocial field, as a valuable tool to be used by the nurse practitioner. The nurse practitioner from any area of practice, primary care, women's health, paediatrics, geriatrics, psychiatry, in any setting (hospital, clinic, school, industry, community and home), requires a tool that provides a comprehensive assessment of the client and the factors that affect their health. The theoretical background of Bowen's family system theory and of systems theory is reviewed as the genogram evolved from the theories. Two hypothetical case illustrations utilizing the genogram are presented, one presenting only medical problems, the other presenting medical, psychiatric and family relationships. The usefulness of the genogram is not new, but it is reviewed here for its value to the nurse practitioner. Evidence leads to the conclusion that the genogram is an assessment tool that enhances intervention strategy and communication in the client's record. It augments treatment planning, care provision, health promotion and prevention, as well as cost management. PMID- 8696800 TI - Staff and patient satisfaction in a forensic unit. PMID- 8696799 TI - Reasons for non-attendance at a day hospital for people with enduring mental illness: the clients' perspective. AB - This paper describes a research project which aimed to discover the reasons clients give for failing to attend a mental health day hospital. There was concern that this service provision, for people with enduring mental illness, had a high level of non-attendance and therefore might not be meeting the needs of the people for whom it is targeted. Over a period of 6 months 36 people failed to attend, despite assessment and apparent agreement to attend. Of the 36, 14 agreed to talk about their reasons for not attending. An open interview format was used which enabled the clients to talk in depth about their experiences, which they felt led to the decision to stop attending. Content analysis of the interview data resulted in the identification of common themes. Main findings suggest a lack of partnership in decisions on choice of therapy, particularly the emphasis on groupwork, which 86% found unhelpful. Other main factors for non-attendance were a lack of an individual approach to care, not being listened to, and a lack of warmth from the staff. Recommendations for future practice are given, with particular attention to the need to develop a partnership with clients aimed at meeting individual needs. PMID- 8696801 TI - The determinants of user satisfaction with community psychiatric nursing care. PMID- 8696802 TI - Schizophrenia: a review of the contemporary literature and implications for mental health nursing theory, practice and education. AB - Contemporary research in the aetiology, neuropsychology and epidemiology of schizophrenia is reviewed. The picture coming from this work is a group of brain diseases of neurodevelopmental origin which manifest themselves in a variety of ways. In turn, there are a range of cognitive deficits associated with the schizophrenias which may, in the extreme, produce major functional handicap. This new knowledge has obvious implications for nurse education and a priority is to place this in undergraduate programmes. However, more importantly, it is argued that we need to alter conceptual frameworks. for example, in some cases we should care for people with schizophrenia in the same way as one would care for an individual suffering the after-effects of a head injury. In the more severe forms of the illness we should take into account the probability that our patients may have significant problems of memory and attention, and thus modify interventions accordingly. It seems clear that our current nursing theories are not underpinned by relevant knowledge of the nature of schizophrenia and this problem warrants urgent attention. PMID- 8696803 TI - Psychological aspects of trauma: raising awareness in nurses and other professionals. PMID- 8696804 TI - Exploring factor analysis. PMID- 8696805 TI - Rediscovering the proper focus of nursing:- a critique of Gournay's position on nursing theory and models. PMID- 8696806 TI - Domestic violence in pregnancy. PMID- 8696807 TI - Bacterial vaginosis. AB - Bacterial vaginosis is the most common cause of vaginal infectious morbidity, including vaginal discharge. The condition is easily diagnosed and treated. If undiagnosed or left untreated, the condition is associated with serious adverse sequelae in both obstetrics and gynaecology. If bacterial vaginosis is detected in early pregnancy, the woman has a five-fold increased risk of late miscarriage or preterm delivery compared with women without the condition. Further research is necessary to establish whether adverse sequelae such as premature labour, preterm prelabour rupture of the membranes, late miscarriage or postpartum endometritis can be reduced by treating the condition in early pregnancy. PMID- 8696808 TI - Complementary therapies for nausea in pregnancy. PMID- 8696809 TI - Managing pain in labour. Part 1: Perceptions of pain. PMID- 8696810 TI - One-to-one midwifery. PMID- 8696811 TI - Hazards to pregnant women at work. PMID- 8696812 TI - Advertising: an ethical dilemma for midwives. PMID- 8696813 TI - Communications and the midwife. PMID- 8696815 TI - 'Midwifery supervision is alive and well'. PMID- 8696814 TI - Equal opportunities for midwives--too much to ask? PMID- 8696816 TI - Delegation: more art than science. PMID- 8696818 TI - Product-line analysis. PMID- 8696817 TI - Delegation: a developmental practice or ritualized activity? PMID- 8696819 TI - Three things the leader can't delegate. PMID- 8696820 TI - Delegation: a change for the better? PMID- 8696821 TI - Nursing's new frontier: reinventing our practice in a restructured health care system. AB - Nurse managers who are faced with the challenge of maintaining productivity in today's turbulent health care environment need new strategies for managing a redesigned workforce. Registered nurses have assumed leadership responsibilities in work teams that include other nurses, licensed personnel from other disciplines, and unlicensed assistive personnel (UAP). Myths, rumors, and questions deserve thoughtful consideration and response if managers want full cooperation from team leaders. Legal and professional issues relating to assignment, delegation, and supervision of a multidisciplinary team must be understood by everyone. Team leaders must have clearly defined boundaries of authority and an understanding of the competencies of each team member to be effective. PMID- 8696822 TI - Teaching the process of delegation. AB - Registered nurses can no longer expect to perform all patient care activities in this age of decentralization, shared governance, and redefining of work duties to include nurse extenders. Delegation is a much needed skill for hospital nurses, because it can free them to deal with professional activities of care, if it is learned and practiced over time. Practitioners of delegation must learn how to assess readiness for delegation in the extender and must recognize that delegation should be a planned process, not an act of desperation. Clear communication is critical at all stages of the process, and evaluation is necessary to be sure that the delegated tasks were completed accurately and promptly. The benefits of delegating far outweigh the loss of control and potential as a result of inconsistency. PMID- 8696823 TI - The psychology of delegation. AB - There are many issues and fears surrounding the concept of delegation, both by the delegator and the delegatee. The factors that affect these issues and fears include individuals' achievement motivation, fear motivation, worry about the consequences of delegation, concern about power, and worry about loss of control. This article suggests several practical techniques to select a staff that will function well in delegation, to help staff work through delegation fears, to assist different genders to understand and work with each other, and to manage power and control issues when they emerge. PMID- 8696824 TI - Practical strategies for delegation and team building in a redesigned environment. AB - Many hospitals, health systems, and agencies are undertaking work on redesign projects, many of whom contain the use of unlicensed assistive personnel (UAP). This is not a new concept in health care, but it does require strong delegation skills on the part of all parties to be successful. One must consider the delegatee's level of training and experience, state laws and regulations, and the presence of appropriate competency processes. The decision to delegate should be based on potential for harm to patients, complexity of nursing activity in question, need for problem solving and intervention, predictability of outcomes, and extent of patient interaction. There are numerous barriers to delegation, which must be addressed, including agency policies, experience and training of all staff, levels of confidence and trust, and unclear role expectations. The challenge for all is to learn to work together better as a team. PMID- 8696825 TI - Delegation: the new driving forces in the home care delivery system. AB - The new driving forces in the home care delivery system are a reflection of the larger health care changes across our nation. This article will explore what these forces are and how they impact home care, as well as the communities we serve. Delegation issues are part of these forces and will have a major impact on the integrated model. We have the opportunity to move our health care system towards improving the health of our communities and expanding our medical focus to a true continuum of care. PMID- 8696826 TI - The politics of delegation. AB - The American Nurses Association has stated that every patient needs a nurse, and they are right. But what do patients need a nurse to do? Politics has arisen around this issue in two ways: the development of new patient care delivery system models that use unlicensed assistive personnel to help professional staff, and a decrease in inpatient census has been seen throughout the country, resulting in changes in jobs and job locations. We argue that the best way to deal with these two factors is for nurses to redefine their functions, to focus on the professional aspects of care that only they can deliver and to keep open minds about where the delivery of services may take place. In the long run, this approach will take the profession much farther than blind adherence to outdated tradition. PMID- 8696827 TI - Just another look at delegation. AB - Twenty-first century health care is a given. Delegation to and by the professional nurse may well be one empowering tool that will strengthen the scope of 21st century professional practice. Nurses as leaders can make it happen. PMID- 8696828 TI - From a regulatory lens: a perspective on the delegation of nursing activities to unlicensed assistive personnel. AB - Along with the reforming of health care, nursing services and related regulatory approaches are concurrently adapting. As the health care environment changes, the number and preparation of individuals who perform health-related activities has increased dramatically. Heightened interest is expressed at both ends of the nursing care delivery spectrum, unlicensed and advanced nursing practice. Boards of nursing, the States' regulatory arm over the profession, pay particular attention to public health and safety issues attached to the delegation of nursing tasks to unlicensed assistive personnel (UAPs). Equally important to the appropriate use of delegation is the provision of adequate supervision of those who are serving in the role of "delegatee." Mechanisms exist in a number of states whereby professional nurses can ascertain the level of competence of a UAP and feel assured that safe and appropriate care can be delegated. It is the role of the professional nurse to provide the required supervision, once a nursing activity is delegated. Nurse practice acts should not be used as barriers to escape required and prudent alterations to the traditional delivery of nursing care. Conversely, these same acts should not be manipulatively circumvented solely in the name of cost containment and as a needed response to "health care reform." As health care reforms, humanity would be best served with public or patient safety and protection as a guiding principle. PMID- 8696829 TI - Patient-focused redesign revisited. PMID- 8696830 TI - Organizational and operational redesign: if we should, then how? AB - Health care leaders and clinical professionals are reconfiguring their environments. However, restructuring of management, reengineering of work, and redesigning process work flows and care delivery modalities contribute to demands that are inherent in an industry that deals with multiple variables of the human condition. After approximately 7 years of health care reengineering and redesign, fundamental tenets are being validated regarding leadership attributes, employee preparation and involvement, and commitment to the process of ongoing redesign and improvement. PMID- 8696831 TI - Breaking the unbroken: women's leadership dilemma. PMID- 8696832 TI - Why empowerment does not empower: the bankruptcy of current paradigms. AB - As a result of the rapid changes taking place in health care, nurse leaders are more challenged than ever to assume a new and different kind of leadership. Under the current paradigm, leaders are responsible for the performance of their people. Leaders do things TO the organization and the people in it. That paradigm of leader responsibility for other people's performance, given today's circumstances, guarantees organizational failure. A radical transformation in leadership thinking must take place. The leader's job is to get the people to be responsible for their own performance. PMID- 8696833 TI - Sharing patient care among disciplines: mandates and pitfalls. AB - Patient-focused care has been used to help cut health care costs. This model changes the way work is done, with a focus on processes rather than individual functions of distinct professions, and it implies shared responsibility for patient outcomes. It also requires that different disciplines share patient care. The goal of sharing patient care among disciplines can be quite challenging to accomplish and sustain. This article describes the difficulties encountered when multiple disciplines share patient care, explores in some depth the causes of these difficulties, and gives suggestions on how this aspect of redesign can be proactively managed. PMID- 8696834 TI - The role of the professional nurse in a reformed health care system. AB - Radical reforms in the dynamic health care arena are calling all professionals to examine their role function and its relationship to emerging new structures and processes. This article places the essence of nursing as the foundation for care delivery redesign, strategically positioning differing RN roles to match the differing needs of clients across the care continuum. PMID- 8696835 TI - Another issue to keep nurses divided or they are dead ... we are they. AB - Ready or not ... health care delivery and all of its components and providers are going to redefine their work and practice. Nurse leaders and nurses at the practice level are fearful of what this means for quality and service to customers, and what it means dynamically to their own careers. Establishing strategic connections, and trusting relationships will be critical to movement in the right direction, and to the creation of a web of inclusion that makes all nurses full partners in creating nursing's future. PMID- 8696836 TI - Multidisciplinary shared governance: the next step. AB - There is a new paradigm for organizations and the way people work within them. It is not possible to manage and structure these organizations in the same way as older industrial organizational designs. More empowerment and the need to build around the knowledge of the worker calls for a different approach to constructing and managing the health care organization. Shared governance has been an innovative approach for building a professional and empowered nursing organization within any health care system. As health care becomes more integrated, it becomes necessary to extend the parameters of shared governance for the next stage of organizational development. Whole-systems shared governance is an approach to implementing the principles of partnership, equity, accountability, and ownership, thus engaging and empowering the whole health care system. PMID- 8696837 TI - The influence of organizational culture on patient care restructuring. AB - University Medical Center in Tucson, Arizona, embarked on a 3-year patient care restructuring project that altered all the patient care delivery systems throughout the organization. In the patient care services areas, patient care managers faced many new challenges in dealing with changes in professional practice and the introduction of multiskilled workers. The influence of the existing organizational culture on patient care restructuring was identified as an important factor to assess early into the project to ensure successful change. The Cultural Assessment Survey (CAS) was used to evaluate unit culture on the four pilot units (two Adult Health and two Pediatric). The results of the survey, implications for managers, and organizational culture are discussed. PMID- 8696838 TI - The continuous quality improvement process in dynamic and rapid change. AB - Patient-focused care is a unique and highly adaptable method of delivering quality patient care. A cornerstone to its success is the use of Continuous Quality Improvement (CQI). CQI is a cultural change. It requires nurse managers to ask good, solid questions, to collect and analyze patient care data, and to reduce redundant or overly complex steps in caring for patients. Nurse managers are ideally suited to the use of CQI. They see the patient's environment in its larger context. They see the flow of health care professionals, equipment, supplies, and procedures 24 hours a day, 7 days a week. Through CQI, the nurse manager can appropriately ask "...what is the best process for the care of this patient?" The old way of doing business is to manage people and focus on quantity. CQI offers a better way: manage processes and focus on quality. PMID- 8696839 TI - Management of working capital. PMID- 8696840 TI - Training/learning/accountability ... never ending. AB - Patient-focused redesign exemplifies a radical change in the patient care delivery system. The focus shifts from fragmented, centralized departmental functions to a point of service, collaborative orientation. The profundity of this shift evokes a myriad of seemingly endless learning opportunities that permeates the organization. This article offers an overview of some of these learning opportunities from global training, functional unit, and specific procedural perspectives. PMID- 8696841 TI - Is computerization keeping up with patient-focused care? AB - It is essential to improve patient care in both quality and efficiency. Lessons gleaned from implementing bedside computing in a patient-focused care environment are presented. Although selective application of computer-based solutions can be effective, such efforts can also be risky and expensive. PMID- 8696842 TI - Old financial systems do not match the new world process or need. AB - Patient-focused care delivery system restructuring has significant implications for changes in "old world" financial and productivity systems. Patient care units in effect become "mini hospitals" as services are moved closer to the patient, thus creating a need for supporting systems to adapt to the "new world" environment of patient-focused care. This article describes the experiences of an organization in monitoring operations and impacts of redesign, and the ongoing challenges to create financial and productivity systems that support patient focused care restructuring. PMID- 8696843 TI - The union movement: legislative and regulatory issues in California. AB - In the late 1980s, hospitals began to identify that patient care services needed to be restructured to deliver services in a more cost-effective and efficient way. As more and more hospitals adopted this philosophy, unions began to take an increasingly aggressive role advocating against the strategies that hospitals employed, which often put unlicensed assistive personnel in a role that more appropriately used the professional training of a registered nurse. The strategies taken by the unions took several forms: regulatory and legislative, which sought to preserve nurses' jobs through mandatory staffing ratios; a public relations campaign aimed at discrediting hospitals that have restructured and informing the public that the changes jeopardize patient welfare; and targeted organizing. This article addresses the impact the union strategies have had on hospitals and the changing health care market. PMID- 8696845 TI - The challenges and evolution of patient-focused redesign. PMID- 8696844 TI - Reengineer the process first. PMID- 8696846 TI - Reporting drug errors. PMID- 8696847 TI - Introducing children to the accident and emergency department: the 999 club. PMID- 8696848 TI - The nasopharyngeal airway: a useful adjunct for the accident and emergency patient. AB - The use of an airway adjunct, usually an oropharyngeal airway, e.g. Guedel, is common in the Accident and Emergency department. In some patients, the oropharyngeal airway may be difficult to insert. This article considers the short term use of a nasopharyngeal airway. PMID- 8696849 TI - Clinical supervision: from rhetoric to accident and emergency practice. AB - Clinical supervision is firmly on the nursing agenda and, when implemented, will affect every practising nurse. However, current literature offers little in the way of advice on the practical application in a setting like the Accident and Emergency department (A & E). The aim of this article is to encourage A & E nurses to consider how clinical supervision can best be implemented into their current practice. A framework is presented to show how one A & E department has embraced the concept of clinical supervision and incorporated in into their A & E nursing practice. The evaluation, to date, has been positive and A & E nurses have reported that they enjoy the sessions and consider clinical supervision to be a useful learning experience. PMID- 8696850 TI - A study of the contribution of effective pressure care on elderly female patients attending accident and emergency who have a suspected fractured neck of femur. AB - This study describes the benefit of pressure relief and the use of pressure reducing mattresses on elderly female patients with a suspected fractured neck of femur, attending an Accident and Emergency department. The main aim of the study was to determine if pressure care, appropriate to each individual patient, reduced red pressure areas and if so, in what way? The results demonstrated that pressure relief given at regular intervals was most effective at reducing red pressure areas. The pressure reducing mattresses also showed to be beneficial in reducing these areas. The study highlighted the importance of giving regular pressure relief in all patients at risk of development of pressure sores. PMID- 8696851 TI - The Children Act. PMID- 8696852 TI - Reflective practice in the accident and emergency setting. AB - The object of this paper is critically to analyse the issue of reflective practice within the writer's own professional arena. The writer is a senior nurse within an Accident and Emergency (A & E) department. It has long been recognised that a gap exists between theory and practice in nursing. There has been much discussion in the nursing literature about the development of the reflective practitioner and how reflection in practice can assist in closing the theory practice gap. Nurses have always experienced great difficulty in identifying a theory of practice. Jarvis (1992) states that reflective medicine is a frequently used but infrequently defined concept in nursing at the present time. For both qualified nurses and students alike, reflection can be utilised as a learning process to help them expand and develop their clinical knowledge and skills to directly benefit client care (Dewing 1990). Schon (1987) has identified reflection as a process of knowledge acquisition originating in practice and best suited to solving complex practice based problems. Reflection is an active process of exploration and discovery which often leads to unexpected outcomes (Boud et al 1985). Reflection that occurs in the process of an experience is referred to as reflection-in-action (Schon 1987). Nurses have the ability to think about their actions while they are carrying them out and change the actions should the professional's assessment of the situation change (Schon 1983). Reflection can lead to new understanding and appreciation which can be put to use in future experiences (Dewing 1990). This paper will commence with a brief explanation of how nurse education is developing reflection and experience to assist the student nurse to close the theory-practice gap. PMID- 8696853 TI - Safety within the community: legislation, change and education. AB - Accidents are commonplace within society and hence have been identified as one of the key areas of the Government's Health of the Nation document (Department of Health 1992). This places a significant emphasis upon the nature of work undertaken in the Accident and Emergency setting. It is intended that this paper addresses issues related to clinical practice and highlights ways in which this practice may serve to enhance safety within the community as a whole. PMID- 8696854 TI - Cycle helmets: promotion or legislation? AB - Health promotion has been put forward by the Government as the way to achieve a healthy lifestyle. However, this has had mixed success in relation to the reduction of injuries and fatalities amongst pedal cyclists. Many cyclists still do not wear protective headgear, for whatever reason, particularly in the under 15 age group, who are most at risk. Various strategies have been tried to encourage the wearing of head protection, yet this is not 'normal' practice. Should the Government step up the campaign and hope it works or should it legislate in favour of proactive head gear for pedal cyclists as it has for motor cyclists? PMID- 8696855 TI - Stress debriefing: reality or myth? PMID- 8696856 TI - Reading Rock Festival: a nursing perspective. AB - Working in the Accident and Emergency (A & E) department at the Royal Berkshire Hospital, Reading, is in itself fairly unremarkable - the unit functions in much the same way as any other Trust Hospital department. It does, however, provide a rather unique opportunity - the option to participate in the running of an on site medical facility, at the internationally acclaimed Reading Rock Festival. This article explores the impact of the festival on the local A & E department, and highlights the experience of a staff nurse working at the Festival site. PMID- 8696857 TI - The nurse practitioner: management of minor trauma. AB - OBJECTIVE: to identify patient groups within Accident and Emergency (A & E) practice where the nurse practitioner, following agreed protocols and treatment regimes, might make a contribution to patient care; and to describe a possible process of preparation required to introduce nurse practitioners into an A & E department. DESIGN: A 14-day study (6-12 January and 24-30 July 1994) in which the case notes of all patients attending the A & E department were analysed. SETTING: The A & E department of Aberdeen Royal Infirmary, UK. PARTICIPANTS: A census of the case notes of 1785 patients. MAIN OUTCOME MEASURES: Demographic and clinical characteristics of new patients, diagnosis, investigations, treatment ordered, numbers of return visits, source of referrals and disposal destinations. RESULTS: On analyses of the workload profile it became apparent that a small number of injury categories, investigations and treatments, accounted for a significant percentage of patient throughput and that 75% of cases attended between 09:00 and 21:00 h. Many cases were of a minor nature, discharged home after minimal treatment and no follow-up. It was thought possible that the assessment and treatment of a significant percentage of patients (30%) could be carried out by suitably trained and experienced nurses working to an agreed protocol. CONCLUSIONS: The paper discusses the concept of the nurse practitioner and seeks to demonstrate a possible role for such a clinical worker using previously agreed protocols devised from a clinical database of patient requirements. Their employment could possibly bring a considerable routine saving in waiting time for patients with minor injuries. PMID- 8696858 TI - The organ donation process through a review of the literature. Part I. AB - This paper considers organ donation from a US perspective, including US statistics and legislation. In Part I, aspects discussed are 'required request', determining brain death, donor criteria and the roles and attitudes of nurses and organ recovery co-ordinators. Literature on the delicate issue of approaching families, and caring for them after the decision is made, is reviewed. Part II of the paper, to be published in the next issue, examines cultural, religious and ethical aspects of organ donation, and communicating with donor families, their misconceptions and their experiences. Finally, there is a discussion of the effects on the bereaved and their grieving process, and on nurses and their attitudes to their work. PMID- 8696859 TI - The ethics of the health care market. AB - The free market theory has as its basis the assumption of equity. This equity is ascribed to both purchasers and providers in a perfectly balanced system so that there are seen to be no 'winners' or 'losers' in the market-place. The health system that is developing in the UK is structured as a managed market, but agency relationships between GPs and health authorities buffer the costing process of goods and therefore may be described as distorting the price. This could also be distorting the ability of the users, who are the real purchasers, from exercising their economic freedom. They may also lose the autonomy to choose goods that suit their particular needs, and equally not to choose those services that they do not want or wish to pay for vicariously (i.e. that the common good is respected by both providers and purchasers). This assumes that users of the service know the level of choice that they have and that not only are providers protected at present by the practices of the purchasers but also entry into the market for new providers is severely curtailed. The exercise of true freedom of the market in economic terms is one of moral obligation to provide services that not only have a market value that is affordable and a requirement of the 'common good' but also are historically acceptable for social requirements (i.e. that the services are valued as fundamental tenets of the rights of individuals in society). The expression of this need will therefore be utilitarian (i.e. the users of the services should benefit from them rather than the providers). PMID- 8696860 TI - Ethical decision-making by staff nurses. AB - Ethical decision-making is inherent in nursing practice. Although a definite portion of the nursing literature is devoted to ethics and ethical decision making, the profession is just beginning to ground its ethics research in the actual experience of nurses. Therefore, the purpose of this phenomenological study was to examine the experience of staff nurses as they engage in ethical decision-making. Interview data were collected from 19 staff nurses in a large, midwestern American metropolitan hospital. Interviews were subsequently transcribed and Giorgi's method of data analysis applied. The emerging description revealed four common aspects of ethical decision-making among staff nurses: context, trigger, ethical decision-making process (i.e. deliberation and integration), and outcomes. This description provides a foundation for future research regarding a descriptive theory of ethical decision-making in nursing. PMID- 8696862 TI - Educating nurses for their future role in bioethics. AB - The emerging new multidisciplinary and crosscultural field of bioethics will require sensitive, open-minded professionals to take the lead in hospital ethics, in genetic counselling, and in the teaching of bioethics to students in nursing, medicine and the basic sciences. Nurses with ward experience who return to university to gain an MA or PhD in bioethics are eminently suited for this leadership role, for they may be more likely than physicians to study for a liberal education to supplement their professional knowledge; their first-hand experience in nursing is an antidote to the pointless subtleties into which philosophical ethics so often degenerates. When teaching ethics to nurses one must remember that, while some will simply use this knowledge in their own clinical work, others will go on to be teachers and researchers in bioethics. Their training must therefore be broad and interdisciplinary, including real substantive philosophy (as opposed to philosophical ethics), as well as mystical bioethics, religious law, ethics of genetic counselling, clinical approaches to ethical pseudo problems, research skills, etc. PMID- 8696861 TI - The attitudes of nurses and third and fourth year nursing students who deal with ethical issues. AB - Ethical attitudes towards pregnant women were examined by using a questionnaire among 50 nurses, 50 midwives and 100 nursing students (third and fourth years). The main findings show that nurses and students differ in: (1) their knowledge of the Code of Ethics; (2) their protection of patients' rights with regard to secrecy and privacy; and (3) their reporting of mistakes. These findings highlight the need for more serious study of ethics among senior professional nurses. PMID- 8696863 TI - Ethics education and nursing practice. AB - This paper suggests that a consideration of health care practice is a necessary step in gaining insight into the appropriate composition of an ethics course for students in the health care professional. Health care practice, if it responds to the needs of society, is dynamic in nature. In the current climate of change in the health service, the author suggests that the nursing profession needs to become more proactive in analysing and attempting to determine the future shape of nursing. To protect patient care the nursing profession needs to have its eyes open to the ethical dimensions of changes in role and practice. The author argues that, in attempting to ensure that the education to which nursing students are exposed is of relevance, it is necessary to introduce an element of the ideal into the ethics component of their professional education. From early on in their professional development students should be aware of the scope and standards of practice, and the type of role enactment to which the profession requires them to aspire. PMID- 8696864 TI - Giving information to sick children. AB - This article describes a study carried out among 14-18-year-old nursing students in Hungary. The students were asked to consider an ethical problem. The parents of a sick child ask that she should not be told of a forthcoming operation. Are the nurses to agree to this demand or not? The author concluded from this study that nurses need more training in ethical decision-making, that they need to know about the rights of children in hospital, and that nursing training should start when students are older. PMID- 8696865 TI - Nursing ethics: what lies ahead? The case of Bulgaria. AB - In Bulgaria, we are sharing a transition to a civic society and a market economy, which means transferring to new parameters of our culture. Many old customs based on coercion, obedience and unacceptable interference are gradually dying out, and new principles tend to shape the way we live our collective lives. These include the ethics of partnership, which tend to create an assertion of individual rights and an affirmation of free will and autonomy, and within which the individual is protected in the pursuit of personal judgements. It is remarkable, however, that we have so much difficulty in talking about and identifying the most beneficial approaches for the achievement of the new design of our society. In this paper, I propose to illustrate the current crisis in nursing ethics with information mainly from Bulgaria. However, I think that the problems and trends in the other Eastern European countries are similar. PMID- 8696866 TI - The immorality of pre-registration nurse education: a personal perspective. AB - Since the introduction of the new nursing curriculum in the United Kingdom, nurse education has undergone a series of fundamental changes, including the introduction of student status, closer links (and in many cases full integration) with higher education, and, for the majority of preregistration courses, the award of a higher education diploma. It is this author's opinion that, given the duration, nature and location of such courses, the award of a diploma amounts to a grave injustice and is representative of a situation that is immoral and corrupt. This opinion is presented from the perspective of educational awards as goods or rewards to be distributed fairly, in recognition of the efforts and abilities of students. PMID- 8696867 TI - Values and Canadian health care: an Alberta exploration. AB - In March 1994, a health care conference was held in Edmonton, Alberta, at which the values of conference participants towards health care were systematically recorded and analysed. This exploration is significant because the values that underpin the structure of the current publicly-funded and administered Canadian health care system rarely enter current discussions regarding health care system reform. Rather, economic and other sociopolitical forces now seem to be having a major impact on plans and actual changes within the health care system. Thus, the underlying attitudes and beliefs of Canadians towards health care have not been articulated or given due credence. The conference participants identified three dominant values: (1) the dignity of the human person as an individual and social being; (2) respect for pluralism and difference; and (3) accountability. These values were found to be robust, in that they sustain a focus on the 'common good'. The common good is the core of the Canadian health care system, and is enshrined in the 1984 Canada Health Act. Conceptually, these values could also lead to significant changes in health care, in keeping with the common good, particularly those changes focusing on the current deficiencies of the Canadian health care system. PMID- 8696868 TI - [From X-rays to radioactivity and radium. The discovery and works of Henri Becquerel (1851-1908)]. AB - The discovery of radioactivity was the outcome of a methodical experimental study achieved by Becquerel. He continued his discovery with studies which give evidence of his scientific and experimentative mind. These studies explored the nature and properties of the emitted radiation and brought basic data to the disintegration theory. The twin discoveries of Rontgen and Becquerel opened new scientific areas, and their practical applications were unprecedented. They gave a new dimension to basic and applied research. PMID- 8696869 TI - [Bertha Rontgen or the transparency of the hand]. AB - It is to Wilhelm Conrad Rontgen, the first elected "radiologist" of our Academy and the first Nobel Prize winner in physics, that we owe the transparency of the hand. We celebrate today the centenary of the great scientific discovery which was to revolutionize the diagnosis, and thereby the treatment, of a large number of illnesses the discovery of X-rays. It would be unjust not to link the name of this scientist with that of his wife, Bertha, who, ignorant of the dangers of all "novel medical inventions" volunteered her own hand for his research experiments: the hand which was to bring to the world tangible proof of this remarkable discovery. To a lesser degree, but nonetheless essential, we acknowledge, albeit not in exhaustive detail, all the progress made by the work of pioneers using this new investigative technique. So let us now return to the hand:--a body part which it was easy to immobilize, remembering that in those days a single radiographic exposure took up to an hour to obtain,--we will consider the immortalised hand of Bertha Rontgen,---to whom this address is dedicated,---and its radiographic exposures which allow us to appreciate the advances and to perceive the limitations of this technique. They also enable us better to envisage future investigative approaches whereby a deeper knowledge of the human body may be acquired. We note that compared with the histopathological sciences, imaging is not specific. Numerous microscopic structures, in particular neurological and vascular ones, are still insufficiently well visualised and the transmission pathways between the hand and the central nervous system deserve better characterisation. Current, research programmes are attempting to overcome these limitation of modern imaging. All the experience gained in studying the transparency of the hand, as we have discussed, is applicable to every part of the human anatomy. To credit: Rontgen's discovery with all its originality, we could say that the hand was to radiology what the brain was to CT and MRI scanning: an exceptional victory is rendering the human body transparent. PMID- 8696870 TI - [French contribution to the progress of new surgical disciplines]. PMID- 8696871 TI - [Nuclear medicine in vivo and functional imaging. Historical perspective]. AB - Nuclear Medicine is the application of radioactive materials to the diagnosis and treatment of patients and the study of human disease. The field had its beginning with the discovery of radioactivity by H. Becquerel in 1896 and the tracer principle proposed in 1913 by G. de Hevesy who used a naturally occurring radioactive isotope of lead to obtain information regarding certain aspects of calcium metabolism in plants. The actual development is more recent. F. and I. Joliot-Curie just after the discovery of the artificial radioactivity predicted in their visionary Nobel conference in 1935 the future applications of radioisotopes in biology and medicine. The development of Nuclear Medicine was made possible by the possibility of producing routinely the radioisotopes after World War II and by the development of suitable detectors: moving detector devices (scanners) then gamma cameras after 1957. Nuclear Imaging is today a unique tool for the in vivo investigation of the biochemical functioning of an organ. Two techniques are in rapid development, SPECT (single photon emission computed tomography) and PET (positron emission tomography). PMID- 8696873 TI - [Prospects for the use in medicine of new detectors of ionizing radiation]. AB - The evolution in particle physics requires new detectors at the emergence of new accelerators, requiring higher rates and better position accuracy. The wire chambers have found applications in the imaging of beta rays and low dose radiography. The new detectors foreseen for the end of this century will have position accuracy of the order of 10 microns and high rate capabilities passing by one or two orders of magnitude the wire chambers. They are promised to wide applications in all fields of radiation imaging. PMID- 8696872 TI - [The first century of radiotherapy in France]. AB - The first X-ray treatment ever given to a patient was done by Victor Despeignes of Lyon, five months after Roentgen's discovery. The first brachytherapies with radium emanation (radon) were performed a few years after the discovery (March 1st, 1896) of natural radioactivity by Becquerel and that of radium by the Curies (December 28, 1898). Marie Curie organised the Radium Institute and personally calibrated more than five thousand sources of radium disseminated in various French cancer departments. Bergonie and Tribondeau discovered (1906) the basic laws of tissular radiosensitivity. Since the work of Regaud and Coutard, published in 1925, fractionation has become the widely accepted mode of external radiation therapy. Mallet discovered the Cerenkov effect in 1926 and the Joliot Curies artificial radioactivity in 1934. After the golden age of 200 kV X-rays and radium applications, the megavoltage era with imported telecobaltherapy units and betatrons began in 1954. Then the first french linear accelerator was manufactured. Recently the national manufacturer of linear accelerators (CGR-MeV) became a branch of General Electric Medical Systems. The French Atomic Energy Commission produces radioactive cobalt, cesium and iridium sources. In France, one century after the discovery of X rays, 326 megavoltage units are operating in 185 cancer centers, 18 university hospital radiotherapy departments, 20 comprehensive cancer centers including the Curie and the Gustave Roussy Institutes, 51 general public hospitals and 96 private clinics for a population of 58 millions inhabitants. PMID- 8696874 TI - [Allocution]. PMID- 8696875 TI - [Evolution of blood glucose control and retinopathy during long-term treatment of insulin-dependent diabetes mellitus with intraperitoneal infusion of insulin]. AB - To evaluate the efficacy on blood glucose control of long-term peritoneal insulin infusion and its consequences on the evolution of diabetic retinopathy, we analyzed retrospectively the values of glycosylated haemoglobin measured quarterly and the retinal angiograms obtained after 1, 5 and 9 years from seventeen insulin-dependent diabetic patients treated by this technique during 9.0 +/- 2.2 years. Blood glucose control was significantly improved from the first year of treatment (p < 0.01). Seventy-one per cent of patients had a level of glycosylated hemoglobin below one standard deviation of normal values after five years and ninety-two per cent of 12 patients treated up to nine years remained in the same near-normal range. Glycaemic excursions below 0.5 g/l and over 2 g/l were limited to 5-7% and 15-17% of four times-daily capillary glucose measurements respectively, along the whole IP insulin infusion period. Among 7 patients with no retinopathy (n = 1) or with mild to moderate nonproliferative retinopathy, requiring no specific ophthalmological treatment, (levels 20 to 40 on worse eye according to a simplified version of ETDRS classification, n = 6), 3 remained stable, 2 improved and 2 impaired although remaining under level 50 of the classification, after 5 to 9 years. Nine patients with severe nonproliferative (level 50, n = 1) or proliferative (level 65, n = 8) retinopathy, all treated by panretinal photocoagulation before initiation of IP treatment, improved and one patient with severe nonproliferative retinopathy, incompletely treated by laser photocoagulation, remained stable, after 5 to 9 years. No macular edematous reaction or impairment of existing macular edema occurred after panretinal photocoagulation under IP treatment. These data indicate that a sustained near-normal blood glucose control can be achieved under long-term peritoneal insulin infusion, without significant impairment of diabetic retinopathy when an initial ophthalmological evaluation, and a specific treatment if necessary, are performed. PMID- 8696876 TI - [Reconstruction of amputated thumb: 20 years of development of techniques and indications]. AB - The loss of a thumb is traumatic on the functional, cosmetic and psychological level. If immediate replantation cannot be successfully accomplished, the surgeon must plan to treat the patient within the first days or, at the latest, within the first weeks following the injury. If the patient is left to "mourn" his lost thumb, he will find it difficult to incorporate his new thumb into his body image and this will compromise the results of a late reconstruction. There is a vast range of therapeutic options, even for cases of severe injury. The most classic treatments include lengthening the first metacarpal, osteoplasty, pollicization of long fingers or stump. These techniques were very common up until the late 1970's at which time microsurgical techniques of partial or total toe transfer became popular. For a short time, there was some opposition between proponents of classic techniques and microsurgeons. In fact, there was a role for each method and classic and microsurgical techniques became complementary. Since 1976, we have performed 196 thumb reconstructions in our department; it is interesting to note that classic techniques were used in 14.1% of cases and microsurgical techniques in 85.7% of cases. Very early on, we decided against the use of the big toe because of the resulting plantar sequelae and preferred use of the second toe (50% of cases). Our experience with the reliability of dissection of big toes has led us to prefer partial toe transfer especially the wrap-around technique of Morrison. The failure rate for microsurgical transfer is 3.6%. PMID- 8696877 TI - [Value of calcium channel blockers in the prevention of ventricular fibrillation of ischemic etiology: experimental arguments]. AB - The prevention of ventricular fibrillation raises a special problem when related to myocardial ischaemia, since class I antiarrhythmic drugs are then ineffective and may even behave as profibrillatory agents: the usual antifibrillatory properties of these drugs which are inhibitors of sodium channel, activated at high potentials, disappear with the disappearance of the role of sodium channel caused by ischaemic depolarization. Calcium channel then replacing sodium channel, calcium channel inhibitors should tend to prevent ischaemic ventricular fibrillation. Therefore, vulnerability to ventricular fibrillation was assessed in open-chest pigs by the threshold for fibrillation electrically induced with impulses of 100 ms duration at the rate of 180 beats/min. Ischaemia was produced by total occlusion of the left anterior descending coronary artery near its origin. Electrical fibrillation threshold was measured at the end of ischaemic period of increasing duration (30, 60, 120, 180, 240, 360 s) under control conditions and after i.v. administration of verapamil (50 micrograms/kg loading dose and 2 micrograms/kg/min infusion). Unaffected by verapamil when coronary circulation was normal, fibrillation threshold was raised by the drug when lowered by ischaemia, increasingly with the prolongation of ischaemia responsible for depolarization of the fibres, up to 500%. The rise of fibrillation threshold resulted in a delay in the triggering of fibrillation which occurs when the fibrillation threshold (6-8 mA) falls down to the pacing threshold (0.3-0.4 mA). These experiments tend to confirm the positive results recently obtained in man with verapamil in the prevention of postinfarction sudden death, provided that myocardial contractility is not too much adversely affected. But, in these experiments, left ventricular dP/dt max was not reduced by more than 15%, even just after the loading dose and returned to its control values within a few minutes. PMID- 8696878 TI - [The new patient]. PMID- 8696879 TI - [Eulogy of Emile Hervet (1913-1994)]. PMID- 8696880 TI - [Electrocardiographic changes due to halofantrine in the treatment of malaria: therapeutic implications]. AB - Electrocardiographic changes and their relationship with profiles of halofantrine (H) and desbutylhalofantrine (DBH) were assessed in a prospective study of 34 male patients with an uncomplicated falciparum malaria. H. was delivered in a one day in three intakes, 24 mg/kg/day. Seven days later the same regimen was administered. This study included a twelve-lead-electrocardiogram (to measure QTc interval), an ambulatory ECG monitoring a signal-averaged-electrocardiogram (to detect late ventricular potentials), and a kinetic-time profile of H. and DBH with high performance liquid chromatography. Data were obtained as follows: day 1 just prior to drug intake, 6 hours (H6), 12 hours (H12) after to drug delivery on day 1 and 8. There after on days 2, 3, 4, 9, 10, 11. Ambulatory ECG monitoring was recorded on day 1 and 8. QTc lengthening was noted in 10 patients with a mean QTc interval of 451 msec (range: 440-469 msec). Maximum QTc interval was obtained at H12 on day 1 (p < 0.0002) and 8 (p < 0.03). Signal-averaged electrocardiogram performed in 8 cases disclosed late potential in 4 cases (day 4: one case, day 9: 3 cases). No ventricular arrhythmia was observed on day 1 and 8. Plasma concentration time profile of H. showed a significant increase at day 8 H12 with a time effect (p < 0.0008) and a significant time-intake interaction (p < 0.02). QTc interval was significantly correlated with H. plasma level (p < 0.01) but not with D.B.H.. Late potentials were associated in 3 cases with a maximum plasma concentration level of H. These data showed that H. is potentially deleterious with a cardiac toxicity which appears dose-related, particularly during the second cure. Following this study, new prescription rules has been proposed before H. therapy. PMID- 8696881 TI - [Cryopreservation of human embryos after in vitro fertilization: immediate and long-term results]. AB - Between 1990 and 1994, a clinical retrospective study has been carried out at Tenon Hospital on 1200 patients: during this periods. 4845 embryos have been cryopreserved and 31% of the patients had this procedure for their supranumerary embryos. The rate of implantation by embryo was 8% per transfer, comparable to those fresh embryos. Less than 1% of the embryos were abandoned. The contribution of cryopreservation to the IVF program is substantial, increasing pregnancy rate by 10%. Moreover, the rate of multiples pregnancies is significantly lower when implanting frozen thawed embryos (9.6%) vs fresh embryos (p < 0.001). There was no difference between frozen-thawed and fresh embryos, in the implantation rate by embryo, the mean gestational age, and birth weight of singleton, twin and triplet births. From a biological point de vue, a series of 3693 embryos, carried on the same period, in our center has showed that for the success of this procedure, the quality of the embryos was more important, than the duration of the storage. The incidence of major and minor congenital malformations was not different in the two groups of babies (less than 3%). But a retrospective analysis carried out on 84 children, showed 4 major abnormalities, after a follow up of 1 to 9 years. However these anomalies do not seem to have some evident correlation with the cryopreservation procedure; a larger series and a prospective study are needed to get significant results concerning the health of the children born after the procedure of cryopreserved embryos. PMID- 8696882 TI - [Wilhelm Conrad Rontgen and the discovery of X-rays]. AB - W.C. Rontgen reported the discovery of X-rays in December 1895 after seven weeks of assiduous work during which he had studied the properties of this new type of radiation able to go through screens of notable thickness. He named them X-rays to underline the fact that their nature was unknown. The news of this discovery immediately aroused an immense interest in the public and also initiated intense research in several directions. Physicians and physicists began as early as January 1896 to use X-rays on patients to investigate the skeleton and subsequently the lung and other organs. This was the birth or radiology. Rapidly they observed skin erythema, which led to the idea of using X-rays against a variety of lesions. In June 1896 the first patient was treated by radiotherapy. J.J. Thomson (Cambridge, U.K.) showed that X-rays were able to ionize gaz and the study of this phenomenon led to the discovery of electrons in 1897. In order to understand the emission of X-rays, H. Becquerel (Paris) investigated the role of the phosphorescence of the glass of the tube and while doing so discovered radioactivity in March 1896. X-rays and radioactivity were at the origin of the scientific revolution at the end of the 19th and the beginning of the 20th centuries. Research on radioactive materials demonstrated the existence of atoms which had been till then only a convenient hypothesis for explaining chemical reactions, but whose reality was considered as dubious by most physicists. Moreover, interaction of particles emitted by radionuclides and atoms enabled first the study of the structure of the atom and subsequently its nucleus. Matter, elements which were thought to be immutable were found to be transmutable, and eventually to disintegrate. The origin of the energy transferred to the radiation which was emitted appeared as a mystery and in order to explain it the physicist had to accept that matter could convert energy. In 1903 Einstein established the equivalence between matter and energy. Matter, energy, electricity, light which were formerly considered as continuous quantities were found to be discrete: there are particles of matter (elementary particles), energy (quanta, Planck 1905), electricity (electron), light (photons). Radioactive decay, particle interactions imposed a probabilistic physics which progressively replaced classic deterministic physics. Radioactivity can be used as a clock to measure time in the universe. Datations were made for fossils, art masterpieces and also for the earth, the solar system and universe. X-rays diffraction proved to be a powerful tool for studying crystals and molecules, in particular protein, and in 1953 enabled to demonstrate the DNA double helix. Hence X-rays and radioactivity originated a revolution in physics and science and in the vision of nature. The imperceptible and yet so powerful rays demonstrated the deficiencies of our senses. Mathematical entities and instrumentation must complement our sensations. The huge increment in our knowledge is accompanied by a divorce between the scientist and the layman who now often has great difficulties understanding new concepts not only in physics but also in biology. PMID- 8696883 TI - Transcranial Doppler for carotid endarterectomy. PMID- 8696884 TI - Endovascular remote endarterectomy in femoropopliteal occlusive disease: one-year clinical experience with the ring strip cutter device. AB - OBJECTIVES: One-year clinical outcome of a new endovascular treatment for long segmental arterial occlusive disease using a ring strip cutter (RSC) to minimise surgical exposure. DESIGN: Prospective, open study. MATERIALS: Thirty-eight consecutive RSC procedures in 36 consecutive patients with lengthy occlusive (34) or multiple stenotic (4) femoropopliteal lesions were performed. Indications for operation were disabling claudication in 25 (66%), rest pain in 3 (8%), and gangrene in 10 (26%) patients. METHODS: A newly developed endovascular ring strip cutter device was used to perform a remote endarterectomy through a single groin incision. Clinical data were analysed based on intention-to-treat. RESULTS: Initial angiographic, clinical and haemodynamic success was achieved in all 38 (100%) limbs. Mean ankle-brachial index increased significantly from 0.62 +/- 0.14 to 1.02 +/- 0.14 postoperatively (p = 0.01). Four failures have occurred during follow-up. After one-year experience the cumulative (assisted) primary and secondary patency rates are 80% and 85% respectively. Duplex surveillance has detected progressive recurrent stenoses in 10 cases. CONCLUSIONS: Remote endarterectomy of long segmental femoropopliteal occlusive disease through a single groin incision with the Ring Strip Cutter device is a safe and effective procedure. The early patency rates are good. Further long-term results are needed to evaluate this technique. PMID- 8696885 TI - A prospective study of anatomico-pathological changes in abdominal aortic aneurysms following endoluminal repair: is the aneurysmal process reversed? AB - AIM: The aim of this prospective study was to analyse early anatomico pathological changes in abdominal aortic aneurysms (AAA) following endoluminal repair to determine if the natural history of continued expansion of AAA is reversed. MATERIALS AND METHODS: Sixty-seven of 85 patients undergoing endoluminal AAA repair between May 1992 and August 1995 had their operations prior to the end of February 1995 and were potentially available for follow up at 6 months or longer after operation. Excluded were: patients with failed endoluminal repairs (n = 14), patients who died within 6 months of operation (n = 5), patients with anastomotic AAA (n = 1), leaving 47 patients in the study group. Based on contrast enhanced CT performed preoperatively, within 10 days of operation and 6, 12 and 18 months after operation patients were divided into two groups: those in whom the AAA maximum transverse diameter (MTD) decreased Group I (n = 39) and those in which it increased Group II (n = 8). The following parameters were analysed: diameter of the supra coeliac aorta, MTD and the dimensions of the proximal and distal necks of the AAA plus extravasation ("leak") of contrast into the aneurysmal sac. RESULTS: Leak of contrast was seen in 0 of 39 patients in Gp I and 5 of 8 patients in Gp II. Patients in Group I experienced a progressive diminution in AAA mean MTD. The diameters of the proximal and distal necks increased but there was no shortening of the length of the necks in this group. In Group II the AAA MTD was dependent on whether or not the aneurysmal sac was isolated from the circulation. The diameter of the proximal and distal necks increased irrespective of this fact. CONCLUSION: We conclude that in early follow up AAA which diminish in diameter following endoluminal repair remain isolated from the general circulation. Co-incident with this decrease in AAA diameter, the proximal and distal necks increase in diameter but do not undergo any shortening in length. This paradoxical increase in neck diameter, was not progressive in the period of follow-up. PMID- 8696886 TI - The varicid: a new device for saphenous sclerotherapy. PMID- 8696887 TI - Endovascular exclusion of juxtarenal anastomotic pseudoaneurysm. PMID- 8696888 TI - Hydrostatic systolic toe pressure for diagnosis of peripheral ischaemic vessel disease in diabetes mellitus. PMID- 8696889 TI - Pulse spray thrombolysis. PMID- 8696890 TI - Quality of life. PMID- 8696891 TI - Biological responses differ considerably between endovascular and conventional aortic aneurysm surgery. AB - OBJECTIVES: To determine the inflammatory responses in endovascular abdominal aortic aneurysm (AAA) repair and their relation to clinical findings. DESIGN: Prospective non-randomised study. SETTING: University Hospital, Department of Surgery. PATIENTS AND METHODS: Seven patients treated with an endoluminal procedure (AAA-E) and seven patients undergoing conventional surgery (AAA-C) were included. Inflammatory parameters were assessed by measurements of the cytokines interleukin (IL)-1 beta, IL-6, IL-8 and Tumour Necrosis Factor-alpha (TNF-alpha); analyses of complement proteins C1q, C4, C3, C5a and Terminal Complement Complexes (TCC); haematologic parameters and determination of C-reactive protein (CRP). RESULTS: In six of seven patients in the AAA-E group blood pressure decreases were recorded during introduction of the device. IL-6 and CRP levels were found to be significantly higher in AAA-C patients compared to the AAA-E group. On the other hand, high TNF-alpha levels were recorded in the AAA-E group. Less consumption of the complement proteins C1q, C4 and C3 was observed in AAA-E compared to AAA-C patients. Increased C5a levels were recorded in the AAA-C group, whereas only slight fluctuations were noticed in the AAA-E group. TCC levels were unchanged in both groups. CONCLUSION: Endovascular aortic aneurysm repair induced a significant inflammatory response, mainly involving TNF-alpha and differing from the findings during open AAA repair. These inflammatory responses were probably related to blood pressure decreases during the procedures. On the other hand, conventional repair induced responses related to the more extensive surgical trauma and reperfusion injury. PMID- 8696892 TI - Saphenous vein bypass: an alternative to internal carotid reconstruction. AB - OBJECTIVE: Venous grafting is rarely employed for carotid reconstruction; the aim of this retrospective study was to assess its value as an alternative to endarterectomy. MATERIAL: Between January 1980 and June 1990, we performed 212 carotid artery venous bypasses (CVB) on 208 patients. Twenty-nine patients were asymptomatic, 60 had non-hemispheric symptoms and 119 focal symptoms. The indication for surgery was stenosis in 185 cases, kinking in 18 and aneurysms in nine. The main criteria to use CVB were length of the lesion in 86 cases, extent of atherosclerosis in 75, dysplasia in 12, intraoperative failure of endarterectomy in 21, aneurysms in seven and long-term restenosis or occlusion in 12. RESULTS: There were 11 deaths, three strokes and nine transient ischaemic attacks. Angiographic control showed one occlusion giving an immediate patency rate of 99.5%. Mean follow-up was 104.3 +/- 46.1 months with 15 patients lost to follow-up. Eighty patients died; life expectancy was 52.4 +/- 7.5 at 10 years. Including occlusions and restenosis as failures, the secondary patency rate was 96.4 +/- 3.7 at 10 years. The annual stroke rate was 1.3% and the neurologic event-free-population 87 +/- 2.4% at 10 years. CONCLUSION: CVB is a valuable alternative to endarterectomy for reconstruction of the carotid artery. The indications are extensive atherosclerosis involving the common carotid artery, intraoperative anatomic failure of endarterectomy, and long-term restenosis. PMID- 8696893 TI - Regulatory requirements for medical devices in the European Union. PMID- 8696894 TI - The long-term outcome of proximal vein thrombosis during pregnancy is not improved by the addition of surgical thrombectomy to anticoagulant treatment. AB - OBJECTIVES: To compare the long-term outcome for pregnant/puerperal women with iliofemoral venous thrombosis treated either with thrombectomy and additional anticoagulants or with anticoagulants alone. DESIGN: Retrospective study of two treatment methods. MATERIALS: Thirty women with iliofemoral venous thrombosis during pregnancy or puerperium were treated with thrombectomy and additional anticoagulants. Twenty-five women, with the same condition, treated with anticoagulants only were obtained from a registry. The mean follow-up time for both groups was 9 years. The patients of the two groups were well matched, had the same risk factor score and were comparable except for duration of symptoms before treatment. METHODS: The follow-up comprised history and clinical examination, colour Duplex ultrasound and venous strain-gauge plethysmography. RESULTS: Patency of iliac veins, symptoms of chronic venous disease, venous emptying and venous reflux did not differ between the groups. A significant reduction of outflow was found in 20% of the surgically treated patients and 16% of the controls. Impaired muscle pump function was seen in less than half of the patients in both groups. CONCLUSIONS: Surgical thrombectomy does not offer any advantage over anticoagulation treatment alone in the long-term outcome for patients with iliofemoral venous thrombosis during pregnancy or puerperium. PMID- 8696895 TI - Computerised tomography findings as a risk factor in carotid endarterectomy: early and late results. AB - OBJECTIVES: To evaluate whether preoperative CT evidence of brain infarction is associated with an increased risk of early and late stroke and death in patients undergoing CEA. DESIGN: Retrospective clinical study. MATERIALS AND METHODS: We evaluated 844 CT scanning records from 893 patients undergoing CEA from 1986 1994: 43% (367) CT positive for cerebral infarction and 57% (477) negative. Univariate and multivariate analysis was performed for risk factors and preoperative symptoms in patients with positive and negative CT scans, and Kaplan Meier survival curves for late events. RESULTS: A positive CT was significantly more frequent in males vs. females (p < 0.0001; O.R. 2.52; C.I. 1.73-3.73), diabetics vs. non-diabetics (p = 0.03; O.R. 1.52; C.I. 1.03-2.26), symptomatics vs. asymptomatics (p < 0.001; O.R. 2; C.I. 1.93-3.53) and contralateral occlusion vs. patency (p < 0.001; O.R. 2; C.I. 1.30-3.10). The perioperative disabling stroke/ death rate was higher in patients with a positive CT (p = 0.002; O.R. 6.27; C.I. 1.73-34.20); in asymptomatic patients this difference was striking (5 patients vs. O, p = 0.0002). Multiple logistic regression analysis for risk factors, CT findings, symptoms preceding surgery, and congruity of brain infarction confirmed a significantly higher incidence of perioperative stroke/death rate (p = 0.003; O.R. 6.37; C.I. 5.12-7.63) and early and late stroke (p = 0.02; O.R. 1.95; C.I. 1.38-2.53) and death (p = 0.0005; O.R. 2.38; C.I. 1.89-2.88) in patients with brain lesions. After 7 years, the survival rate (p = 0.0009) and stroke-free interval (p = 0.003) were lower in patients with a positive CT. After 5 years, in asymptomatic patients the survival rate (p = 0.003) and stroke-free interval (p = 0.01) were lower in the positive CT group. CONCLUSIONS: A positive CT finding, regardless of congruity of the lesion, should be regarded as an indicator of an increased risk of stroke and death in patients scheduled for carotid surgery, especially in those with asymptomatic stenosis. PMID- 8696896 TI - Endothelial cell seeding of de-endothelialised human arteries: improvement by adhesion molecule induction and flow-seeding technology. AB - OBJECTIVES: To assess re-endothelialisation of denuded human arteries by two different seeding techniques using adhesion molecule induction and a dynamic flow seeding. DESIGN: Prospective, open study. SETTING: University Department of Cardiovascular Surgery. MATERIALS AND METHODS: In the first group (I) segments of human common carotid arteries (n = 4) were balloon-denuded, short-time seeded with cultured adult human venous endothelial cells (EC) and exposed to a mock circulation. In the second group (II) (n = 4), EC were incubated with a synthetic RGD peptide (arginine-glycine-aspartate) prior to seeding with the aim of upregulating the cellular adhesion molecules and increasing EC attachment. In the third group (III) (n = 4), EC were seeded not using the common technique of instillating cells and sequentially rotating the graft but by a dynamic flow application. The percentage of EC-covered luminal surface was assessed by image analysis of scanning electron micrographs. RESULTS: EC attachment was significantly increased in groups II (73%) and III (94%) compared with group I (34%). In group III, a preconfluent monolayer could be established immediately after seeding. One hour of artificial perfusion resulted in no significant EC loss in any of the study groups. CONCLUSIONS: RGD-peptide preincubation improves EC seeding of biological surfaces. Because of accelerated seeding times it may have good potential for clinical applications. The flow-seeding technology may be indispensable if EC seeding of the vascular surface of complete organ systems is required. PMID- 8696897 TI - Primary aortoenteric fistula: two new case reports and a review of 44 previously reported cases. PMID- 8696898 TI - Recovery of endothelial cells and prostanoid production in endothelial cell seeded grafts. AB - OBJECTIVE: To investigate the function and morphology of endothelial cell (EC) seeded grafts. DESIGN: Experimental, open study. CHIEF OUTCOME MEASURES: Endoluminal release of prostacyclin (6-Keto-PGF1 alpha) and thromboxane B2 (TxB2), patency, EC coverage and cell identity. MATERIALS: In 12 sheep, segments of both carotid arteries were excised. On one side a seeded and on the other an unseeded dacron graft were inserted. After 3 months the grafts were excised. In grafts and arteries, the endoluminal release of 6-keto-PGF1 alpha and TxB2 was determined in a perfusion system. Scanning electron microscopy (SEM) and light microscopy were used to determine the EC coverage and cell identity. RESULTS: Eight animals survived. Three seeded and two unseeded grafts were occluded. Prostacyclin release did not differ significantly between seeded and unseeded grafts and arteries, when the arteries were looked upon as one group. When the graft was compared with its corresponding artery, i.e. the artery it replaced, a significantly lower release was found in the unseeded group. Thromboxane release was undetectable in arteries but significantly higher in both graft groups. SEM revealed a cellular coverage of 75% in the seeded grafts and 50% in the unseeded (not significant). Light microscopy showed a patchy staining for Factor VIII related antigen in some grafts in both groups. CONCLUSION: Prostacyclin release in unseeded and seeded dacron grafts did not differ 3 months after implantation in sheep, except when the graft was compared with its corresponding artery. The significance of this remains to be settled. Seeded grafts did not have a higher proportion of endothelial coverage than unseeded grafts. PMID- 8696899 TI - Natural history of infrainguinal vein bypass stenoses: early lesions increase the risk of thrombosis. AB - OBJECTIVES: To describe the natural history of stenoses in infrainguinal vein bypasses and to identify factors predicting outcome. METHODS: Forty-two patients with non-revised vein bypass stenoses were followed prospectively by ultrasound Duplex scanning and ankle blood pressure measurements. RESULTS: During a median follow-up of 8 (range 0-22) months 18 (43%) (95% confidence limits 28-59%) bypasses thrombosed and 6 (14%) (95% confidence limits 5-29%) patients were amputated. Bypass patency was lower in 12 patients with stenoses associated with reduction in ankle brachial index (ABI) exceeding 0.15 than in 30 patients with no or only marginal reduction in ABI (12 month patency 33% vs. 68%, p = 0.005). Among the 30 patients without distal pressure reduction, stenoses identified within 3 months from surgery were associated with an increased risk of thrombosis as compared to stenoses identified at a later stage (12 month patency 51% vs. 92%, p = 0.03). CONCLUSION: Time interval from surgery to stenosis detection seems to be an independent parameter influencing outcome in patients with vein bypass stenoses. PMID- 8696900 TI - Combined vascular reconstruction and microvascular muscle flap transfer for salvage of ischaemic legs with major tissue loss and wound complications. AB - OBJECTIVE: To assess the safety and short-term efficacy of combined vascular revascularisation and free microvascular muscle flap transfer in patients with advanced lower limb ischaemia caused by occlusive arterial disease. DESIGN: A prospective follow-up study of 2-72 months. SETTING: Academic referral centre. MATERIALS: Consecutive first 15 patients with extensive tissue loss due to advanced leg ischaemia or wound complications after bypass surgery. CHIEF OUTCOME MEASURES: Graft patency, free tissue transfer viability, amputation rate. MAIN RESULTS: There was no perioperative mortality. The cumulative rates for secondary vascular patency, microvascular graft viability and limb salvage were 80%, 87% and 76% at one year provided that vessels and grafts that were functioning at the time of amputation were considered lost to follow-up rather than failed at that point. If, however, amputation was also regarded as vessel and graft failure the corresponding rates were 68%, 62% and 76%, respectively. CONCLUSIONS: Combining microvascular muscle flap transfer with vascular reconstruction for salvage of legs with extended ischaemic tissue loss or wound complications after bypass surgery gave acceptable preliminary results and deserves an attempt in selected patients. PMID- 8696901 TI - Oxygen free radical and cytokine generation during endovascular and conventional aneurysm repair. AB - OBJECTIVES: Endovascular aneurysm repair has been proposed as a "minimally invasive" alternative to conventional aneurysm resection. One of the most important potential benefits of endoluminal surgery is the avoidance of aortic cross clamping, which may attenuate the ischaemia-reperfusion injury that complicates open aneurysm repair. This study aimed to quantify the metabolic response to both conventional and endovascular aortic surgery. DESIGN: Prospective clinical study. SETTING: University hospital. METHODS: Femoral vein blood samples (pre-clamp, during aneurysm repair and 5 and 30 min post reperfusion) were obtained from 12 patients undergoing aortoaortic aneurysm repair, six by conventional transperitoneal inlay replacement (median age 71 years, median aneurysm diameter 5.8 cm), and six by endoluminal deployment of a straight endograft (median age 73 years, median aneurysm diameter 5.5 cm). All endovascular procedures were completed satisfactorily with no conversions to conventional surgery. OUTCOME MEASURES: Venous blood samples were analysed for oxygen free radical (OFR) production using the quantifiable oxidation of IgG in plasma, and cytokine (IL-1 beta and TNF-alpha) generation by radioimmunoassay. [table: see text] RESULTS: The results are given as median values with interquartile ranges: CONCLUSIONS: These results suggest that the ischaemia reperfusion response associated with conventional aneurysm surgery may be largely negated by endovascular techniques. This may have significant consequences as the generation of oxygen free radicals and cytokines have been implicated in the development of systemic organ failure following aortic surgery. PMID- 8696902 TI - Aspirin increases tissue oedema after skeletal muscle ischaemia and reperfusion. AB - PURPOSE: Skeletal muscle ischaemia reperfusion syndrome affects patients following lower limb revascularisation. Aspirin has the potential to attenuate these effects. METHODS: Using an established model of hind limb tourniquet ischaemia, the effects of oral and intravenous aspirin administration were observed after 6 h of ischaemia and 18 h reperfusion. Samples were obtained and analysed for muscle viability and oedema, and lung neutrophil infiltration. RESULTS: Aspirin, when compared to placebo and controls, significantly increased muscle interstitial oedema when given orally and intravenously. It had no effect on tissue viability or lung neutrophil infiltration. CONCLUSION: Aspirin increases tissue oedema after ischaemia and reperfusion but has no effect on tissue viability. Although its mechanism of action has not been clarified, aspirin may influence the no-reflow component of ischaemia-reperfusion syndrome. PMID- 8696903 TI - Cerebral haemodynamics during thoracic- and thoracoabdominal aortic aneurysm repair. AB - OBJECTIVE: To investigate cerebral haemodynamics during operations for thoracic and thoracoabdominal aortic aneurysms. DESIGN: Prospective clinical study. MATERIAL: 10 patients operated on consecutively with resection for thoracic (5) or thoracoabdominal aortic (5) aneurysms. METHODS: Blood flow velocity of the middle cerebral artery was measured through a temporal approach using a TC Doppler with a 2 MHz probe. Recordings were made during induction of anaesthesia and performed continuously before, during and after cross-clamping of the aorta. RESULTS: Following 10 min. of aortic cross-clamping blood flow velocity of the middle cerebral artery increased from 44 to 55 cm/s (p < 0.01). A further increase to 69 cm/s (p < 0.01) was observed 5 min after declamping. The pulsatility index averaged 0.74 increasing to 1.21 (p < 0.05) at clamping and 0.87 (p < 0.05) after declamping. CONCLUSION: There was an increased blood flow velocity of the middle cerebral artery during cross-clamping of the descending thoracic aorta in patients operated on for thoracic and thoracoabdominal aortic aneurysms. This increase in cerebral blood flow and blood volume could explain the acute increase in cerebrospinal fluid pressure observed during cross-clamping of the thoracic aorta. PMID- 8696904 TI - Intraoperative heparinisation, blood loss and myocardial infarction during aortic aneurysm surgery: a Joint Vascular Research Group study. AB - OBJECTIVES: The primary aim of this prospective multi-centre study involving patients undergoing elective abdominal aortic aneurysm (AAA) surgery was to investigate the relationship between intraoperative intravenous heparinisation, blood loss during surgery and thrombotic complications. METHODS: Two hundred and eighty-four patients were randomised to receive intravenous heparin (n = 145) or no heparin (n = 139). Groups were evenly matched for age, sex, weight, aneurysm size, haemoglobin concentration, platelet counts and distal occlusive disease measured by ankle/brachial systolic pressure. RESULTS: There were no statistically significant differences in blood loss (median 1400 ml vs. 1500 ml; z = 0.02, p = 0.98, 95% C.I. = -200 to 200), blood transfused (4.0 units vs. 4.0 units; z = 1.09, p = 0.28, 95% C.I. = -1 to 0) or distal thrombosis between the two groups. However, analysis of the clinical outcome revealed that 5.7% of the non-heparin group but only 1.4% of the heparinised patients suffered a fatal perioperative myocardial infarction (MI); p < 0.05. All MI, including non fatal events, affected 8.5% and 2% respectively (p = 0.02). CONCLUSIONS: Heparin does not increase blood loss or the need for blood transfusion during surgery. Heparin is not necessary to prevent distal thrombosis when the aorta is cross clamped. The results of the study are consistent with the known mechanisms leading to intraoperative MI and strategies for its prevention. Intravenous heparin, given before aortic cross clamping, is an important prophylaxic against perioperative MI in relation to AAA surgery. PMID- 8696905 TI - Validation of a new transit time ultrasound flowmeter in man. AB - OBJECTIVES: To validate the new CardioMed CM 4000 transit time ultrasound apparatus for intraoperative measurement of volume blood flow in vivo in man. DESIGN: Open, prospective series. MATERIALS: Thirteen patients undergoing in situ saphenous vein grafting for chronic critical leg ischaemia and 12 patients subjected to myocardial revascularisation with the internal thoracic artery as coronary bypass. METHODS: During operations, volume blood flows were measured simultaneously by exsanguination from the cut distal end of the in situ saphenous vein graft or the internal thoracic artery and by the transit time flowmeter equipment. In addition, the feasibility to detect arteriovenous fistula during in situ saphenous vein grafting was examined. RESULTS: Within the examined blood flow range, the volume blood flow determined by the transit time method corresponded to the directly measured blood flow. For in situ saphenous vein grafts: y = -2.4 + 0.95.x (r = 0.99; 35 measurements in 13 patients), and for internal thoracic artery grafts: y = -9.6 + 1.1.x (r = 0.99; 21 measurements in 12 patients), where y is blood flow determined by transit time, and x is directly measured blood flow by exsanguination (r = correlation coefficient) as calculated by the least squares regression method. Fistula detection was easy and swift. CONCLUSIONS: The transit time apparatus was simple to use during intraoperative settings and gave fast, precise measurements of volume blood flow. PMID- 8696906 TI - Peripheral arterial occlusions: local low-dose thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA). AB - OBJECTIVE: To study the efficacy and risks of local thrombolytic therapy of peripheral arterial occlusions using rt-PA. DESIGN: This open study was performed in one clinic in Munich, Germany. METHODS: 288 patients suffering from occlusions of the lower limb arteries were subjected to 336 treatments performed with a permanently controlled technique. In a short pilot study 10mg rt-PA/h were administered for 5 h but in the majority of the cases only 2.5mg/h were administered for a maximum of 5 h. The average total dose of rt-PA was 2.97mg and the average time for lysis was 78 min. RESULTS: 43 (84.3%) out of 51 embolic occlusions and 168 (71.5%) out of 235 thrombotic occlusions were recanalised with a cumulative patency of 95% and 79.7% respectively after 2 years. One systemic bleeding occurred in the pilot study with 10mg rt-PA/h whereas with the 2.5mg/h dosage no systemic bleeding or embolism occurred in the 315 treatments. There were no deaths during hospitalisation. Six major and two forefoot amputations were necessary. Thirteen patients required a bypass operation and one an embolectomy. The advantages of our controlled technique are: short duration of treatment, small doses of activating agent, an accurately directed pathway with the possibility of dilating stenoses during the same session, no danger of systemic bleeding or embolism and, therefore, good prospects of success with minimal risk. CONCLUSION: The use of rt-PA for local lysis substitutes the inadequate tissue activator available for effective spontaneous lysis and is, therefore, almost physiological. The effect of a very low dose of rt-PA was as good as that of higher doses. PMID- 8696907 TI - Further characterisation of substance P induced histamine release from human bronchoalveolar lavage mast cells. PMID- 8696908 TI - Effect of chloroquine on arachidonic acid pathway in isolated mast cells. PMID- 8696909 TI - Rapid non-genomic effects of hydrocortisone on rat mast cells. PMID- 8696910 TI - Characteristics of the inhibitory effect of tricyclic antidepressants on histamine release from rat peritoneal mast cells. PMID- 8696911 TI - The effect of adenosine on histamine release from rat peritoneal mast cells induced by the calcium ionophore in buffers containing different calcium concentrations. PMID- 8696912 TI - On the effect of the antihistaminic drug bromadryl on human platelets in vitro. PMID- 8696913 TI - Microfungi in indoor air are able to trigger histamine release by non-IgE mediated mechanisms. PMID- 8696914 TI - Free radical mediated release of histamine from rat mast cells induced by drugs of abuse. PMID- 8696915 TI - The effect of relaxin on myocardial ischaemia-reperfusion injury and histamine release in vitro and in vivo. PMID- 8696916 TI - The H1-histamine antagonist Dithiaden inhibits human platelets in vitro. PMID- 8696917 TI - 24th Meeting of the European Histamine Research Society. Moscow, Russia, May 20 25, 1995. PMID- 8696918 TI - Changes in mast cell reactivity in the course of allergic inflammation. PMID- 8696919 TI - Analysis of immunosuppressive activity of serial dilutions of histamine on human basophil activation by flow cytometry. PMID- 8696921 TI - Histamine concentrations in gastric mucosa of patients with Schonlein-Henoch purpura. PMID- 8696920 TI - Diagnosis of latex allergy: comparison of histamine release and flow cytometric analysis of basophil activation. PMID- 8696922 TI - Correlation of blood histamine levels with immunological indices in patients with Schonlein-Henoch purpura. PMID- 8696923 TI - Histamine metabolism in mastocytosis patients treated with interferon alpha-2b. PMID- 8696924 TI - Models with clinically-relevant and life-threatening histamine-related cardiovascular disturbances: evaluation of the clinical effectiveness of H1/H2 histamine receptor antagonists in perioperative histamine release. PMID- 8696925 TI - The effect of some gastrointestinal peptides on pentagastrin-stimulated acid secretion and oxyntic mucosal histamine in rats. PMID- 8696926 TI - Histamine-induced skin reactions using iontophoresis and H1-blockade. PMID- 8696927 TI - Histamine release from mast cells and monocytes: the effects of azelastine, reproterol and vitamin A-analogues. PMID- 8696929 TI - Intestinal mucosal microdialysis: histamine release in splanchnic ischemia/reperfusion injury in piglets. PMID- 8696928 TI - Purification of human intestinal diamine oxidase. PMID- 8696930 TI - Histamine H3 receptor inhibition of K(+)-evoked release of acetylcholine from rat cortex in vivo. PMID- 8696931 TI - The effect of an ICV H3-agonist on plasma prolactin in portocaval shunted and sham operated rats. PMID- 8696932 TI - Histamine and NMDA-receptors in the hippocampus: polyamines and intracellular binding site. PMID- 8696933 TI - Receptor-mediated regulation by histamine of the acid phosphatase activity in cultured cerebral endothelial cells. PMID- 8696934 TI - Histamine receptors in neoplastic transformation: studies in human cell lines. PMID- 8696935 TI - Histamine regulates the expression of histidine decarboxylase in N-nitroso-N methylurea (NMU)-induced mammary tumors in rats. PMID- 8696936 TI - Effect of cyclosporin-A on histamine release from tracheal strips of sensitized guinea pigs. PMID- 8696937 TI - Histamine release from rat peritoneal mast cells and human basophils induced by the free radical generator 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH). PMID- 8696938 TI - Interleukin-1 beta in coronary arteries of patients with ischemic heart disease. AB - Interleukin-1 beta (IL-1 beta) is known to have a number of effects on the different cell types present within coronary arteries. In this study we identified the location and phenotype of cells containing IL-1 beta in human coronary artery specimens from patients suffering from either coronary atherosclerosis or cardiomyopathy and correlated the presence of IL-1 beta with disease severity. Luminal endothelial cells, adventitial vessel wall cells, and macrophages were double labeled immunohistochemically for IL-1 beta protein and a cell type-specific monoclonal antibody for either endothelial cells or macrophages. In situ hybridization was performed to locate the presence of IL-1 beta mRNA within the coronary artery wall. In this study IL-1 beta protein was found to be increased in the adventitial vessel walls of atherosclerotic coronary arteries compared with coronary arteries from nonischemic cardiomyopathic hearts. This increase was directly proportional to the severity of coronary atherosclerosis. IL-1 beta protein was also detected in luminal endothelium and macrophages of atherosclerotic coronary arteries and coronary arteries from nonischemic cardiomyopathic hearts. IL-1 beta mRNA was found in luminal endothelial cells, adventitial vessel endothelial cells, and macrophages. We conclude that IL-1 beta is produced by endothelial cells and macrophages in coronary arteries from ischemic hearts and to a lesser extent from nonischemic cardiomyopathic hearts. PMID- 8696939 TI - Interleukin-8 production by macrophages from atheromatous plaques. AB - Interleukin-8 (IL-8) is a chemotactic peptide produced by macrophages that may be involved in the recruitment of inflammatory cells into atherosclerotic plaques. In vitro, IL-8 production by macrophages isolated from carotid plaques (1240 +/- 510 pg.10(5) cells-1.24h-1, mean +/- SEM, n = 6) and noncarotid plaques (4312 +/- 1588 pg.10(5) cells-1.24 h-1, n = 9) was significantly greater than IL-8 production by blood monocytes isolated from the same patients (526 +/- 278 pg.10(5) cells-1.24 h-1, n = 6, P < .05 and 726 +/- 384 pg.10(5) cells-1.24 h-1, n = 9, P < .01, respectively). IL-8 produced by atherosclerotic macrophages was demonstrated to be biologically active in a neutrophil chemotaxis assay. IL-8 mRNA was detectable in plaque macrophages and blood monocytes from these patients, but blood monocytes from normal donors did not exhibit detectable IL-8 mRNA. IL-8 mRNA was localized in macrophage-rich areas of atherosclerotic plaques by in situ hybridization. These studies demonstrate that macrophages from atherosclerotic plaques show an enhanced capacity to produce IL-8 compared with normal and patient blood monocytes and that macrophages are a major site of IL-8 mRNA production in atherosclerotic plaques. These results provide further evidence for a proinflammatory role for macrophages in atherosclerosis. PMID- 8696940 TI - Lymphocyte populations in atherosclerotic lesions of apoE -/- and LDL receptor -/ mice. Decreasing density with disease progression. AB - Lymphocytes are prominent components of human atherosclerotic lesions, but their presence in murine models of disease has not been confirmed. Lymphocyte subpopulations have been identified in apoE -/- and LDL receptor -/- mice fed a cholesterol-enriched diet for up to 3 months. ApoE -/- mice had higher serum cholesterol concentrations than did LDL receptor -/- mice during most of the feeding period, primarily due to large increases in VLDL concentrations. Total area of atherosclerotic lesions was greater at all times in apoE -/- than LDL receptor -/- mice (lesion area after 3 months on cholesterol-enriched diet: apoE /-, 993 +/- 193 and LDL receptor -/-, 560 +/- 131 microns2 x 10(3), mean +/- SEM, n = 6 in each group). Lesions in apoE -/- mice contained larger macrophage-rich necrotic cores and more calcification than did those in LDL receptor -/- mice. Immunocytochemical analyses of tissue sections of ascending aortas performed with monoclonal antibodies to T and B lymphocytes and macrophages revealed that T lymphocytes immunoreactive for Thy 1.2, CD5, CD4, and CD8 were observed in lesions from both strains, but no B lymphocytes were detected. The density of Thy 1.2+ T lymphocytes in lesions was greatest at 1 month (apoE -/-, 98 +/- 23 and LDL receptor -/-, 201 +/- 40 lymphocytes/mm2, n = 6 in each group), decreasing in apoE -/- mice to 12 +/- 3 and in LDL receptor -/- mice to 51 +/- 20 lymphocytes/mm2 at 3 months. The presence of T lymphocytes in murine atherosclerotic lesions makes these animals potentially useful for studying the involvement of the immune system in atherogenesis. PMID- 8696941 TI - Regulation of monocyte CD36 and thrombospondin-1 expression by soluble mediators. AB - CD36 is an 88-kD integral membrane protein expressed on platelets, monocytes, macrophages, certain microvascular endothelia, and retinal pigment epithelium. It functions as an adhesive receptor for thrombospondin-1 (TSP-1), collagen, and malaria-infected erythrocytes and as a scavenger receptor for oxidized LDL and photoreceptor outer segments. The CD36-TSP-1 interaction plays a role in cell adhesion and the phagocytosis of apoptotic cells by macrophages. Because of the potential importance of the CD36-TSP-1 interaction in mediating atherogenic and inflammatory processes, we studied their expression in human peripheral blood monocytes exposed to soluble mediators known to regulate inflammation and atherogenesis. RNase protection assays showed 6- to 12-fold increases in CD36 mRNA in response to interleukin-4, monocyte colony-stimulating factor, and phorbol myristate acetate, while lipopolysaccharide and dexamethasone strongly downregulated CD36 mRNA. The downregulation of CD36 mRNA was associated with the disappearance of surface expression of CD36 antigen and loss of TSP-1 surface binding capacity. Upregulation of CD36 mRNA was associated with a modest increase in surface antigen expression and a larger expansion of an intracellular pool of CD36. As with CD36, monocytes treated with monocyte colony-stimulating factor showed a rapid increase in TSP-1 mRNA expression. Moreover, while dexamethasone treatment decreased CD36 expression, it resulted in a rapid increase in TSP-1 mRNA, and while PMA increased CD36 mRNA, it rapidly decreased TSP-1 expression. Interferon gamma, which had no effect on CD36 mRNA, rapidly increased steady state TSP-1 mRNA. Thus, expression of both CD36 and its ligand TSP-1 is regulated by soluble mediators, although certain mediators induce concordant changes and others discordant changes. PMID- 8696942 TI - A single nucleotide insertion in codon 317 of the CD36 gene leads to CD36 deficiency. AB - CD36 is a multifunctional integral-membrane glycoprotein that acts as a receptor for thrombospondin, collagen, long-chain fatty acids, and oxidized LDL. Platelet CD36 deficiency can be divided into two groups. In type I, neither platelets nor monocytes/macrophages express CD36; in type II, monocytes/macrophages express CD36 but platelets do not. Two known mutations cause CD36 deficiency, ie, a 478C- >T substitution in codon 90 (proline90-->serine) and a dinucleotide deletion at nucleotide 539 in codon 110. In this study we investigated a type I Japanese subject (A.T.) and identified a new mutation, a single nucleotide insertion at nucleotide 1159 in codon 317. This mutation leads to a frameshift and the appearance of a premature stop codon. CD36 gene analysis indicated that A.T. was a compound heterozygote for a dinucleotide deletion at nucleotide 539 and the single nucleotide insertion at nucleotide 1159. RNase protection studies suggested that the new mutation as well as the dinucleotide deletion led to a marked reduction in the level of CD36 mRNA in her macrophages. However, the new mutation could be detected in macrophage but not platelet CD36 mRNA. These data suggest that the allele having the single nucleotide insertion in this subject has an additional abnormality that results in the absence of the mutated CD36 mRNA in platelets. PMID- 8696943 TI - Identification on human CD36 of a domain (155-183) implicated in binding oxidized low-density lipoproteins (Ox-LDL). AB - Uptake of oxidized LDL (oxLDL) by macrophages is one of the key events implicated in the initiation and perpetuation of atherosclerotic lesions. One of the major scavenging receptors, which binds modified LDL, on macrophages is CD36. The domain on CD36 implicated in the binding of oxLDL remains to be elucidated. In this study, COS cells transfected with human CD36 cDNA bound FITC-oxidized human LDL in a dose-dependent, saturable manner. This binding was inhibited by an excess of oxLDL but not by native LDL. Anti-CD36 monoclonal antibodies (mAbs) 10/5, FA6-152, and 8A6 (directed against domain 155-183), but not mAb 13/10 (directed against domain 30-76), completely inhibited oxLDL binding to human CD36 transfected COS cells. Cells transfected with a chimeric human CD36 construct (hmh 155-183), resulting from the swapping of human domain 155-183 with its murine counterpart, resulted in low binding of oxLDL. In contrast, cells transfected with a chimeric murine CD36 construct (mhm 155-183), resulting from the swapping of murine domain 155-183 with its human counterpart, resulted in high binding of oxidized human LDL. Binding of oxLDL to cells transfected by chimeric construct mhm 155-183 were only partially blocked by mAbs 10/5, FA6-152, and 8A6. In the present study we have identified, for the first time, an important functional domain (encompassing amino acids 155-183) on CD36 involved in the binding of oxLDL. In addition, the binding site for oxidized human LDL on murine CD36 seems to differ from its human counterpart. PMID- 8696944 TI - Compositional differences of LDL particles in normal subjects with LDL subclass phenotype A and LDL subclass phenotype B. AB - A predominance of small LDL particles (subclass phenotype B), as determined by gradient-gel electrophoresis is found among patients with myocardial infarction. Despite physical differences in phenotype A and B particles, differences in lipid composition of particles in these phenotypes have yet to be reported in an unselected population of males and females. The present study used lipid/apoB ratios to analyze the amount of lipid per LDL particle, isolated by density gradient ultracentrifugation, in 70 healthy subjects. Relative to apoB, the LDL particles from phenotype B subjects were found to contain less free cholesterol (0.391 +/- 0.05 versus 0.465 +/- 0.05; mean +/- SD; P < .001), phospholipid (1.26 +/- 0.2 versus 1.43 +/- 0.2; P < .001), and cholesteryl ester (1.97 +/- 0.1 versus 2.11 +/- 0.2; P < .001) than particles from phenotype A subjects. The amount of triglyceride per LDL particle did not differ between the two phenotypes (0.410 +/- 0.1 versus 0.406 +/- 0.1; P = NS) despite higher plasma triglyceride levels in the phenotype B subjects. LDL size and buoyancy were positively correlated with particle free cholesterol, phospholipid, and cholesteryl ester but not with particle triglyceride. These data suggest that the physical properties of LDL from subjects with phenotype A and B reflect their lipid composition. The compositional differences between LDL particles of the two phenotypes may provide new insight into the increased risk of myocardial infarction in subjects with small, dense LDL. PMID- 8696945 TI - Probucol downregulates E-selectin expression on cultured human vascular endothelial cells. AB - Probucol, which inhibits monocyte adhesion, is a potent antioxidant to vascular endothelium in the cholesterol-fed rabbit. The accumulation of macrophages in the lesion is influenced by increased expression of specific adhesion molecules on vascular endothelial cells. We investigated the effect of probucol on the expression of cell adhesion molecules in cultured human umbilical vein endothelial cells (HUVECs). HUVECs were treated with lipopolysaccharide in the presence or absence of probucol (0 to 5 mumol/L) and assayed for the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and E selectin by cell-enzyme-linked immunosorbent assay. Probucol significantly downregulated the expression of E-selectin on HUVECs in a dose-dependent manner. In contrast, the expression of ICAM-1 was not affected. E-selectin but not ICAM-1 mRNA expression on HUVECs was also significantly inhibited by probucol in a dose dependent manner. We also examined whether probucol affects cellular binding between the human monocytic cell line U937 and lipopolysaccharide-stimulated HUVECs by using an in vitro binding assay and found that probucol significantly suppressed their mutual binding in a dose-dependent manner. These data indicate a novel mechanism of action for probucol to reduce the development of atherosclerotic lesions in hyperlipidemic states. PMID- 8696946 TI - Gemfibrozil stimulates apolipoprotein A-I synthesis and secretion by stabilization of mRNA transcripts in human hepatoblastoma cell line (Hep G2). AB - Gemfibrozil is a widely used drug that elevates plasma HDL and lowers triglycerides and LDL. The mechanism of action of this pharmacological agent on HDL metabolism is not established. Since the liver is the major organ involved in HDL production and removal, we assessed the effect of gemfibrozil on the modulation of apoA-I (a major protein of HDL)-containing particles by a human hepatoblastoma cell line (Hep G2). Incubation of Hep G2 cells with gemfibrozil resulted in the following statistically significant findings: (1) increased accumulation of apoA-I in the medium without affecting uptake of radiolabeled HDL protein or HDL-apoA-I; (2) accelerated incorporation of [3H]leucine and [35S]methionine into apoA-I; (3) equivalent increases in [3H]leucine incorporation into HDL particles without and with apoA-II (LpA-I and LpA-I+A-II, respectively); (4) equal efflux of fibroblast cholesterol by harvested LpA-I and LpA-I+A-II particles; (5) increased steady state apoA-I mRNA without affecting apoA-I transcription; and (6) increased apoA-I mRNA half-life (2.2-fold). These data indicate that gemfibrozil stabilizes apoA-I mRNA transcripts, resulting in increased translation of functional apoA-I-containing particles capable of effluxing cellular cholesterol, thus defining a major mechanism by which gemfibrozil increases HDL. PMID- 8696947 TI - Heparin-induced overexpression of basic fibroblast growth factor, basic fibroblast growth factor receptor, and cell-associated proteoheparan sulfate in cultured coronary smooth muscle cells. AB - Basic fibroblast growth factor (bFGF), a potent mitogen for arterial smooth muscle cells (SMCs), plays a pivotal role in the pathogenesis of arteriosclerosis and restenosis. Heparin in nanogram quantities may promote or even be required for binding of bFGF to its cognate receptor. Conversely, heparin in microgram doses is a strong inhibitor of arterial SMC replication in vitro and in vivo. Bovine coronary SMCs (cSMCs) express bFGF, bFGF receptor (FGF-R1), and cell membrane-integrated proteoheparan sulfate (HSPG). These three molecules are known to form a trimolecular complex that promotes signal transduction and mitogenesis. The bFGF synthesized by cSMCs is distributed to an intracellular and a pericellular compartment. Resting cultured cells retain about 80% of their bFGF intracellularly; 20% is found in the pericellular region. During proliferation, 70% to 80% of total bFGF is expressed in the pericellular compartment. Trypsinization generates soluble forms of the complex of bFGF with the ectodomains of the bFGF receptor and cell membrane-integrated HSPG in the pericellular compartment, thus allowing quantification of pericellular bFGF by a highly specific enzyme immunoassay. Standard heparin inhibits the proliferation of cSMCs by up to 80% in a concentration range between 10 and 100 micrograms/mL medium in a dose-dependent manner but increases the protein content of cSMCs compared with proliferating control cells. The heparin-induced increase in cellular protein content includes a 60% to 100% increase in the expression of pericellular bFGF, FGF-R1, and cell membrane-integrated HSPG. Thus, under heparin treatment, the heparan sulfate side chains of cell membrane-integrated HSPG incorporate more [35S]sulfate, and the proportion of [35S]heparan sulfate among total glycosaminoglycans increases from 36% to 52%. Fluorescence-activated cell sorting analysis and [3H]thymidine incorporation experiments provide evidence for multiple effects of heparin, including blocks at early and late checkpoints of the cell cycle in heparin-treated cells. These results indicate that heparin, despite its anti-proliferative potency, stimulates the expression of all components of the bFGF system even in coronary SMCs in which growth is inhibited. PMID- 8696948 TI - Circumferential stress and matrix metalloproteinase 1 in human coronary atherosclerosis. Implications for plaque rupture. AB - Atherosclerotic plaque rupture may occur when regions of weakened extracellular matrix are subjected to increased mechanical stresses. Since collagen is a major determinant of extracellular matrix strength, enzymes that degrade collagen may play an important role in destabilizing the atherosclerotic lesion. To test the hypothesis that matrix metalloproteinase 1 (interstitial collagenase, or MMP-1), which initiates degradation of fibrillar collagens, colocalizes with increased stress in the fibrous cap of the atherosclerotic lesion, 12 unruptured human coronary lesions were studied. Finite-element analysis was used to determine the distribution of stress in the lesion, with estimates of material properties from previous measurements of human tissues. A computerized image analysis system was used to determine the distribution of immunoreactive MMP-1 within the fibrous tissue of the lesion. There was a significant correlation between immunoreactive MMP-1 and circumferential tensile stress in the fibrous cap within a given lesion (median Spearman rank correlation coefficient, .36; interquartile range, -.02 to .81; P < .02). Within a given lesion, the highest-stress region had twofold greater MMP-1 expression than the lowest-stress regions. In unruptured human atherosclerotic coronary lesions, overexpression of MMP-1 is associated with increased circumferential stress in the fibrous plaque. Degradation and weakening of the collagenous extracellular matrix at these critical high-stress regions may play a role in the pathogenesis of plaque rupture and acute ischemic syndromes. PMID- 8696949 TI - Effect of immunization with homologous LDL and oxidized LDL on early atherosclerosis in hypercholesterolemic rabbits. AB - Although the existence of an immune response against modified lipoproteins in atherosclerosis has been observed in experimental animals as well as in humans, the precise pathophysiological relevance of these findings remains unclear. In this study we determined the effect of an immunization with homologous LDL and copper-oxidized LDL on the formation of atherosclerotic plaque in hypercholesterolemic rabbits. Immunizations were performed at the start of a cholesterol-rich diet and 3 weeks later. After 16 weeks, antibodies against oxidized LDL had developed in rabbits given hypercholesterolemic diet alone, but the titers were increased by twofold in rabbits immunized with oxidized LDL as well as in rabbits immunized with LDL, suggesting that the LDL had also become oxidized during the preparation and/or immunization procedure. Immunization with LDL and oxidized LDL reduced atherosclerotic lesions in the proximal aorta by 74% (P < .05) and 48% (P = NS), respectively. The cellular composition of the lesions was not affected by the immunizations. These results support the hypothesis that an immune response against modified LDL has a protective effect against the development of early atherosclerotic lesions. PMID- 8696950 TI - Suppression of atherosclerotic changes in cholesterol-fed rabbits treated with an oral inhibitor of neutral endopeptidase 24.11 (EC 3.4.24.11). AB - Neutral endopeptidase 24.11 (NEP), widely distributed in the body, hydrolyzes and inactivates a number of endogenous vasoactive peptides, some of which could alter various functions of cells present in the arterial wall. Recently NEP has been found to exist in the vascular endothelium. The aim of this study was to assess the influence of chronic NEP inhibition by daily administration of UK79300 (candoxatril), an orally active NEP inhibitor (NEPI), on the development of atherosclerotic changes in high-cholesterol-fed rabbits. Male New Zealand White rabbits were fed for 8 weeks as follows: normal rabbit diet (Normal, n = 15), 1.5% cholesterol diet (Cholesterol, n = 15), or 1.5% cholesterol diet containing NEPI (20 mg.kg-1.d-1) (Cholesterol+NEPI, n = 15). At the end of the dietary period, NEPI treatment was found to suppress the surface area of the aorta covered by plaques (% surface area: Cholesterol, 59 +/- 6 versus Cholesterol+NEPI, 36 +/- 7, P < .01) and decreased contents of cholesterol and cholesterol esters in the aortas. NEPI also reduced plasma total cholesterol by 27% of Cholesterol rabbits (1781 +/- 130 mg/dL). The endothelial function, estimated by the endothelium-dependent relaxation of the isolated aortas in response to acetylcholine, was preserved in Cholesterol+NEPI rabbits compared with that in Cholesterol rabbits. NEP enzymatic activities in plasma and the particulate fraction of the homogenates from the aortas in Cholesterol rabbits were both increased, 3.1- and 3.9-fold, respectively, above those in Normal rabbits, but the activities in Cholesterol+NEPI rabbits were significantly lower than those in Cholesterol rabbits. UK73967, an active form of UK79300, or phosphoramidon partly reversed the atherosclerotic impairment of relaxation of the isolated thoracic aortic rings from Cholesterol rabbits in response to exogenous additions of C-type natriuretic peptide (CNP) and substance P, which are NEP substrates known to exist endogenously in the vascular endothelium. The results suggest that the increased NEP activity plays a significant role in atherogenesis, and NEPIs might be therapeutically useful in the prevention of atherosclerosis. Reduction of plasma cholesterol and suppression of degradations in the arteries of endogenously released CNP, substance P, or possibly other kinins known to have anti-atherosclerotic actions may at least partially contribute to the inhibitory effects of NEPIs on atherosclerotic changes. PMID- 8696951 TI - Effect of estrogen and progesterone on the expression of hepatic and extrahepatic sterol 27-hydroxylase in baboons (Papio sp). AB - Sterol 27-hydroxylase plays an important role in cholesterol metabolism in hepatic and extrahepatic tissues. To determine whether female sex steroid hormones influence its expression, we measured plasma and hepatic 27 hydroxycholesterol, hepatic mRNA levels, activity of sterol 27-hydroxylase, and adrenal mRNA levels of this enzyme in baboons (n = 6 per group) treated with placebo, estrogen, estrogen + progesterone, and progesterone. We also measured hepatic cholesterol concentration and hepatic acyl coenzyme A:cholesterol acyltransferase (ACAT) activity to determine their relationship with hepatic sterol 27-hydroxylase activity. Plasma 27-hydroxycholesterol concentration was increased by estrogen and estrogen + progesterone and was negatively correlated with plasma (P = .090) and LDL (P = .026) cholesterol concentrations. Similarly, hepatic sterol 27-hydroxylase activity was increased by estrogen and estrogen + progesterone and was negatively correlated with plasma (P = .056) and LDL (P = .052) cholesterol concentrations but was positively correlated with hepatic and plasma 27-hydroxycholesterol concentrations (P < .001). Hepatic ACAT activity was increased by progesterone (P < .004) and was positively correlated with plasma (P = .002) and LDL (P = .009) cholesterol concentrations but was negatively correlated with hepatic sterol 27-hydroxylase activity (P = .035). Hepatic and adrenal gland mRNA levels for sterol 27-hydroxylase were increased by estrogen alone or in combination with progesterone (P < .05). Hepatic sterol 27 hydroxylase activity was positively correlated with hepatic mRNA levels (P < .001), an observation suggesting that estrogen increases the activity of sterol 27-hydroxylase by increasing its synthesis. Hepatic cholesterol concentration was not influenced by the hormone treatment. These observations suggest that estrogen alone or in combination with progesterone increases the synthesis of sterol 27 hydroxylase in hepatic and extrahepatic tissues, and the increased activity of hepatic sterol 27-hydroxylase resulting from the increased synthesis is associated with a hypolipidemic effect on plasma LDL levels. Furthermore, progesterone alone increases the hepatic ACAT activity, but given in combination with estrogen progesterone does not have the same effect on hepatic ACAT activity. The effect of estrogen on hepatic ACAT activity may be mediated by sterol 27-hydroxylase and its effect on cholesterol metabolism (decreased cholesterol synthesis and increased output of cholesterol in the bile) in liver. PMID- 8696952 TI - Urinary excretion of apo(a) fragments. Role in apo(a) catabolism. AB - The biosynthesis and assembly of lipoprotein(a) [Lp(a)], a marker for atherosclerotic disease, appears to be well understood. However, information is lacking concerning the mode and site of Lp(a) catabolism. Apo(a) is reported to be excreted into the urine. To study the effect of this pathway on the overall catabolism of Lp(a), urinary apo(a) was characterized by immunoblotting. More than 10 distinct apo(a) bands with molecular masses between 30 and 160 kD were observed. Apo(a) fragments were not complexed to apoB. In more than 30 individuals the size of apo(a) bands was comparable irrespective of their apo(a) phenotype, although marked differences in the relative intensities of the bands were observed. Eight batches of 24-hour urine collections collected from one proband at 2-week intervals exhibited a significant correlation between creatinine and apo(a) concentrations as measured by DELFIA (r = .93; P < .01). In 193 healthy volunteers a highly significant correlation was found between urinary apo(a) concentrations normalized to creatinine levels and plasma Lp(a) values (p = 0.659; P < .0001). Of the total plasma apo(a), 0.073%, i.e., 121 micrograms apo(a), was excreted in the form of apo(a) fragments in 24-hour urine samples from 12 healthy volunteers. We conclude that the catabolism of Lp(a) via excretion of apo(a) fragments accounts for < 1% of the daily Lp(a) catabolism. PMID- 8696953 TI - Evidence for a major gene elevating serum bilirubin concentration in Utah pedigrees. AB - In case-control studies, lower serum bilirubin levels have been associated with increased risk of developing coronary heart disease (CHD). We have also previously shown that serum bilirubin has a significant polygenic component. The purpose of the present investigation was to determine whether there was statistical evidence for a major gene explaining a significant portion of individual variation in serum total bilirubin levels and whether this gene might alter the risk of CHD. Serum bilirubin measurements were obtained from 1240 adults in 84 Utah pedigrees screened twice: from 1980 to 1983 and again from 1983 to 1986. Bivariate maximum-likelihood segregation analysis of serum bilirubin levels obtained from the two clinic visits indicated that a major gene was responsible for elevated levels in 11.5% of the persons in these pedigrees. Phenotypic variations in visit 1 bilirubin arising from polygenes were highly correlated with the phenotypic variation due to polygenes in visit 2 bilirubin, indicating a stable genetic contribution to bilirubin over 2.5 years of follow up. The major gene explained 27% and 28% of the variance in bilirubin levels at visit 1 and visit 2, respectively. There were no correlations of unmeasured environmental factors influencing bilirubin between the two clinic visits. At both visits, persons with early CHD had lower levels of bilirubin than unaffected persons (P < .01). The odds ratio for the risk of CHD in the high-homozygote group was 0.31, P = .09. We conclude that there is a major gene modestly raising serum bilirubin levels. Since cross-sectional data indicate that low serum bilirubin levels increase the risk of CHD, this major gene may be protective against CHD for about 12% of the persons in this study. PMID- 8696954 TI - Apolipoprotein E polymorphism in American Indians and its relation to plasma lipoproteins and diabetes. The Strong Heart Study. AB - Apo E is an important genetic factor in the development of cardiovascular disease, which is the leading cause of death among American Indians. We investigated the occurrence of the apo E alleles and the relation between apo E polymorphism and blood lipoproteins and apoproteins in members of 13 American Indian communities in three geographic areas. The frequencies of the epsilon 2 alleles in American Indians are significantly lower than those in white Americans, with the lowest frequencies of epsilon 2 in American Indians who reside in Arizona. Levels of LDL cholesterol and apo B were highest in those with epsilon 4 and lowest in those with epsilon 2. Concentrations of HDL cholesterol and apo A-I, however, tended to be lowest in epsilon 4 and highest in epsilon 2. Concentrations of total and VLDL triglycerides were lowest in the epsilon 3 group and higher in groups epsilon 2 and epsilon 4. Differences in concentrations of LDL cholesterol, HDL cholesterol, apo B, and apo A-I with apo E polymorphism were greater in women than in men, and differences in total and VLDL triglyceride concentrations by apo E phenotype were greater in men. Relations of total and VLDL triglycerides with apo E phenotype were stronger in women after menopause. In addition, differences in nearly all lipid and apoprotein concentrations between postmenopausal women and premenopausal women were greater if they had epsilon 2. Relations between apo E phenotype and lipoproteins were seen in individuals with diabetes mellitus as well as in nondiabetics. Apo E was significantly related to glucose control in diabetic women; those with epsilon 3 had higher glucose and hemoglobin A1C concentrations. Our findings show that (1) American Indians have low frequencies of apo epsilon 2; (2) apo E phenotype can influence levels of VLDL, LDL, HDL, apo B, and apo A-I; (3) the associations of apo E polymorphisms with lipid parameters differ between men and women; and (4) the associations in women of apo E polymorphisms with lipid parameters are modified by menopausal status. PMID- 8696955 TI - Quantitative assessment of aortic atherosclerosis in APOE*3 Leiden transgenic mice and its relationship to serum cholesterol exposure. AB - Transgenic mice overexpressing the human dysfunctional apolipoprotein E variant, APOE*3 Leiden, develop hyperlipidemia and are highly susceptible to diet-induced atherosclerosis. In the present study, we investigated the effects of diet composition and feeding period on serum cholesterol exposure and the amount of atherosclerosis in the aortic sinus in these mice, using quantitative image analysis. On each of the three diets tested--a low-fat diet, a high-saturated fat/cholesterol diet, and a high saturated-fat/high-cholesterol/0.5%-cholate diet -transgenic animals showed a marked hyperlipidemia compared with nontransgenic littermates. Measurement of the atherosclerotic lesion areas in cross sections of the aortic sinus in animals exposed to these three diets for up to 6 months showed a 5 to 10 times greater lesion area in transgenic mice compared with nontransgenic controls. Highly significant positive correlations were found between the log-transformed data on lesion area and serum cholesterol exposure (r = .82 to .85 for the 1-, 2-, and 3-month treatment groups), indicating that the hyperlipidemia is likely to be a major determinant in lesion formation. On the basis of these findings, we suggest that the APOE*3 Leiden mouse represents a promising model for intervention studies with hypolipidemic and antiatherosclerotic drugs. PMID- 8696956 TI - Both lipolysis and hepatic uptake of VLDL are impaired in transgenic mice coexpressing human apolipoprotein E*3Leiden and human apolipoprotein C1. AB - Transgenic mice overexpressing human APOE*3Leiden are highly susceptible to diet induced hyperlipoproteinemia and atherosclerosis due to a defect in hepatic uptake of remnant lipoproteins. In addition to the human APOE*3Leiden gene, these mice carry the human APOC1 gene (APOE*3Leiden-C1). To investigate the possible effect of simultaneous expression of the human APOC1 gene, we examined the phenotypic expression in these APOE*3Leiden-C1 mice in relation to transgenic mice expressing the APOE*3Leiden gene without the APOC1 gene (APOE*3Leiden-HCR). APOE*3Leiden-C1 and APOE*3Leiden-HCR mice had comparable liver expression for the APOE*3Leiden transgene and high total cholesterol levels on a sucrose-based diet compared with control mice (4.3 and 4.3 versus 2.1 mmol/L). In addition, on this diet APOE*3Leiden-C1 mice displayed significantly higher serum triglyceride levels than APOE*3Leiden-HCR mice and control mice (4.4 versus 0.6 and 0.2 mmol/L). Elevated triglyceride and cholesterol levels were mainly in the VLDL sized lipoproteins. In vivo turnover studies with endogenously triglyceride labeled VLDL showed a reduced VLDL triglyceride fractional catabolic rate for APOE*3Leiden-C1 and APOE*3Leiden-HCR mice compared with control mice (3.5 and 11.0 versus 20.4 pools per hour). To study whether the difference in fractional catabolic rates between the two transgenic strains was due to an inhibiting effect of apoC1 on the extrahepatic lipolysis or hepatic-mediated uptake of VLDL, turnover experiments were performed in functionally hepatectomized mice. Strikingly, both APOE*3Leiden-C1 and APOE*3Leiden-HCR mice showed a decreased lipolytic rate of VLDL triglyceride in the extrahepatic circulation compared with control mice (1.5 and 1.8 versus 6.3 pools per hour). We conclude that next to an impaired hepatic uptake, overexpression of the APOE*3Leiden gene influences the extrahepatic lipolysis of VLDL triglycerides, whereas simultaneous overexpression of the APOC1 gene leads to a further decrease in hepatic clearance of VLDL. PMID- 8696957 TI - Polymorphic markers in apolipoprotein C-III gene flanking regions and hypertriglyceridemia. AB - Hypertriglyceridemia and hyperlipidemia are common disorders associated with coronary artery disease and premature death. The proteins encoded by the apolipoprotein (apo) A-I/C-III/A-IV gene cluster are involved in the metabolism of both triglycerides and cholesterol. In a large sample of individuals from the ARIC study, six polymorphic markers were typed and plasma lipid values were measured to determine whether the well-established association between the Sst I S2 allele in the 3'-untranslated region of the apo C-III gene and hypertriglyceridemia was due to disequilibrium with variation in the 5' regulatory region of the apo C-III gene. The Sst I polymorphism was significantly associated with hypertriglyceridemia (P = .006) but not with carotid artery wall thickness, plasma apo C-III levels, or elevated cholesterol. The frequency of the S2 allele was 0.14 in those with high triglyceride levels and 0.05 in those with low triglyceride levels. None of the 5' flanking polymorphisms were significantly associated with any of the plasma lipids studied. There was substantial linkage disequilibrium between the Sst I polymorphism and each of the 5' apo C-III polymorphisms; however, the significant association between the apo C-III haplotypes and hypertriglyceridemia (odds ratio, 4.0; P < .0001) was solely attributable to the effects of the Sst I polymorphism (odds ratio, 3.96). As a part of these analyses, we also defined a unique haplotype that is inversely associated with the occurrence of hypertriglyceridemia, suggesting further molecular analyses of this important gene region. PMID- 8696958 TI - Inhibition of thrombin generation by aspirin is blunted in hypercholesterolemia. AB - Recent evidence indicates that aspirin inhibits thrombin generation in clotting blood. We noticed that this effect was less pronounced in patients with hypercholesterolemia. The aim of the study was to prove this observation. The effects of aspirin on thrombin generation were evaluated in (1) 46 healthy volunteers, 2 hours after ingestion of a single, 500-mg dose and (2) 28 survivors of myocardial infarction who took 300 mg aspirin/d for 2 weeks. In both populations, two well-matched subgroups were distinguished, using a serum cholesterol level of 6.2 mmol/L (240 mg/dL) and an LDL cholesterol level of 4.0 mmol/L (155 mg/dL) as borderline. Thrombin generation was monitored ex vivo in blood emerging from a skin microvasculature injury and additionally, in a single dose study in vitro in recalcified plasma. Aspirin depressed thrombin generation in the group of subjects with serum cholesterol < 6.2 mmol/L and LDL cholesterol < 4.0 mmol/L but not in the group with high blood cholesterol levels. Inhibitory effects of aspirin were more pronounced after the 2-week treatment than after a single dose. There was a significant correlation between total serum cholesterol or LDL cholesterol and total amount of thrombin generated after aspirin treatment. In subjects with high blood cholesterol levels, thrombin generation was not affected by aspirin. Blunting of aspirin action in hypercholesterolemia might be explained by (1) alterations in platelet lipid-protein matrix that render their membrane proteins less accessible for acetylation by aspirin and (2) changes in composition and structure of plasma lipoproteins that diminish the chance of aspirin to interact with prothrombin. PMID- 8696959 TI - Improvement of atherosclerosis and stiffness of the thoracic descending aorta with cholesterol-lowering therapies in familial hypercholesterolemia. AB - The thoracic aorta is frequently involved in atherosclerotic lesions associated with familial hypercholesterolemia (FH). Transesophageal echocardiography (TEE) allows quantitative evaluation of the wall properties of the thoracic aorta. Using TEE, we tested whether atherosclerosis of the thoracic aorta in FH could be improved by cholesterol-lowering therapies. The subjects investigated were 22 FH patients and 22 age-matched normal subjects. The descending aorta (DA) was divided into four longitudinal portions of equal length. Atheromatous lesions of each portion of the DA were scored by character and extension of lesions by biplane two-dimensional TEE. The scores of atheromatous lesions from all four portions of the DA were added together to give the total atheromatous score (TAS). We also measured instantaneous dimensional changes of the DA in a cardiac cycle by M-mode TEE and blood pressure by a cuff method and calculated the stiffness parameter beta (In[SBP/DBP]/[Dmax-Dmin]/Dmin), where SBP is the systolic arterial blood pressure, DBP is the diastolic arterial blood pressure, Dmax is the maximum aortic dimension during the ejection period, and Dmin is the minimum aortic dimension during the preejection period. TAS was higher in FH (3.70 +/- 1.32) than normal (0.62 +/- 0.54, P < .0001) subjects. Beta in FH (10.35 +/- 4.87) was greater than in normal (5.10 +/- 1.25, P < .0001) subjects, but there were no significant differences of DA dimensions between the groups. In both normal subjects and FH patients, beta correlated with age (r = .52, P < .02 and r = .59, P < .005, respectively). In FH patients, beta and TAS correlated well with pretreatment total cholesterol levels (r = .43, P < .05 and r = .60, P < .005, respectively). In 12 of 22 FH patients, strict cholesterol-lowering therapies with diet and cholesterol-lowering drugs (pravastatin and probucol) were undertaken for 13 months. Cholesterol levels were significantly decreased from 333 +/- 45 to 219 +/- 39 mg/dL (P < .0001); this was associated with significant decreases in beta and TAS (from 9.88 +/- 5.03 to 7.88 +/- 3.92, P < .005, and from 3.61 +/- 1.50 to 2.94 +/- 1.22, P < .0005, respectively). In FH patients, the incidence and severity of morphological and physiological atherosclerosis of the DA were significantly higher than in age-matched normal subjects. A significant regression of atherosclerosis was achieved by strict cholesterol-lowering therapies in relatively young FH patients. PMID- 8696960 TI - Risk factors for abdominal aortic aneurysms in older adults enrolled in The Cardiovascular Health Study. AB - B-mode ultrasound examinations of the abdominal aorta were performed from 1990 to 1992 to evaluate the prevalence of abdominal aortic aneurysm (AAA) in a subgroup of the Pittsburgh cohort (656 participants, aged 65 to 90 years) of the Cardiovascular Health Study (CHS). In this pilot study, we evaluated various definitions of aneurysm and the reproducibility of the measurements. In year 5 (1992 to 1993) of the CHS, the entire cohort (4741 participants) was examined. AAA was defined as an infrarenal aortic diameter of > or= 3.0 cm, or a ratio of infrarenal to suprarenal diameter of > or= 1.2, or a history of AAA repair. For the entire CHS cohort, prevalence of aneurysms was 9.5% (451/4741) overall, with a prevalence among men of 14.2% (278/1956) and prevalence among women of 6.2% (173/2785). Variables significantly related to AAA were older age; male sex; history of angina, coronary heart disease, and myocardial infarction; lower ankle arm blood pressure ratio; higher maximum carotid stenosis; greater intima-media thickness of the internal carotid artery; higher creatinine; lower HDL levels and higher LDL levels; and cigarette smoking. The study has documented the strong association of cardiovascular risk factors and measures of clinical and subclinical atherosclerosis and cardiovascular disease and prevalence of aneurysms. We used a definition that is more sensitive than previously reported (diameter or ratio), which allowed the detection of smaller aneurysms and possibly those at an earlier stage of development. Follow-up of this cohort may lead to new criteria for determining the risk factors for progression of aneurysms. PMID- 8696961 TI - Atherosclerotic disease in the femoral artery in hypertensive patients at high cardiovascular risk. The value of ultrasonographic assessment of intima-media thickness and plaque occurrence. Risk Intervention Study (RIS) Group. AB - The aim of the present investigation was to examine the occurrence of ultrasound assessed morphological changes in the right common femoral artery and relate these findings to the ankle-arm index and to symptoms of lower-extremity arterial disease in hypertensive men at high cardiovascular risk (n = 143). Comparisons were made with a healthy reference group consisting of age-matched men at low risk (n = 46). The results showed that it was possible to obtain high-quality measurements of intima-media thickness in about 80% of all men and that the intraobserver variability was satisfactory (14%). A normal mean intima-media thickness was defined, using data from the low-risk group. Plaque occurrence and mean intima-media thickness in the right common femoral artery were significantly associated with ankle-arm index both in the right and left leg. There were more and larger plaques, as well as thicker mean and maximum intima-media complexes, in the high-risk group than in the low-risk group. In the high-risk group, 11% suffered from symptoms of right lower-extremity artery disease, 20% had an ankle arm index < or= 0.9, 62% had moderate or large plaques (compared with 28% in the low-risk group, P < .001), and 77% had an enlarged intima-media complex. The cumulative frequency of signs of atherosclerosis in the right leg was 81% among the 110 patients in whom complete results from all examinations were available. Our conclusion is that ultrasound measurement of the intima-media thickness of the common femoral artery is a valuable method to evaluate morphological changes related to atherosclerotic disease in the lower extremity. PMID- 8696962 TI - Medial artery calcification. A neglected harbinger of cardiovascular complications in non-insulin-dependent diabetes mellitus. AB - Medial artery calcification (MAC) is a nonobstructive condition leading to reduced arterial compliance that is commonly considered as a nonsignificant finding. The aim of our study was to investigate the predictive value of MAC in relation to 7-year cardiovascular mortality, coronary heart disease (CHD) events, stroke, and lower extremity amputation in 1059 patients (581 men and 478 women) with non-insulin-dependent diabetes mellitus (NIDDM). At baseline radiologically detectable MAC in femoral arteries was found in 439 patients (41.5%) and intimal type calcification in 310 diabetic patients (29.3%). The mean fasting plasma glucose at baseline was somewhat higher in women and the duration of diabetes somewhat longer in patients with MAC than in those without, but otherwise the presence of MAC was unrelated to conventional cardiovascular risk factors. During the follow-up 305 diabetic patients died: 208 from cardiovascular disease, 158 from CHD, and 34 from stroke. Furthermore, 58 NIDDM patients underwent their first lower extremity amputation. MAC was a strong independent predictor of total (risk factor-adjusted odds ratio and 95% confidence interval: 1.6; 1.2, 2.2), cardiovascular (1.6; 1.1, 2.2), and CHD (1.5; 1.0, 2.2) mortality, and it was also a significant predictor of future CHD events (fatal or nonfatal myocardial infarction), stroke, and amputation. This relationship was observed regardless of glycemic control and known duration of NIDDM. MAC is a strong marker of future cardiovascular events in NIDDM unrelated to cardiovascular risk factors, supporting the hypothesis that reduced arterial elasticity could lead to clinical manifestations of diabetic macroangiopathy. PMID- 8696963 TI - Risk factors related to carotid intima-media thickness and plaque in children with familial hypercholesterolemia and control subjects. AB - To assess the relationship between risk factors for cardiovascular disease and early atherosclerotic changes in the carotid artery, we measured carotid intima media thickness by B-mode ultrasonography in 61 boys and 29 girls 10 to 19 years old with familial hypercholesterolemia (FH) and 30 control subjects matched for age and sex. All were nonsmokers, and all the FH adolescents had a known mutation in the LDL receptor gene. Mean intima-media thickness in the far wall of the carotid bulb was greater (P = .03) in the FH group than in the control subjects: 0.54 mm (95% confidence interval [CI], 0.52 to 0.56) versus 0.50 mm (95% CI, 0.47 to 0.52). In the entire group, mean and maximum intima-media thicknesses in the carotid bulb were positively associated with levels of apolipoprotein B and fibrinogen after control for pubertal stage (r = .19 to .24; P < .05), as was male sex. Plasma total homocysteine was similar in the FH and control groups and was associated with mean and maximum intima-media thicknesses in the far wall of the common carotid artery and carotid bulb after control for pubertal stage (r = .22 to .28; P < .05). With the exception of the relation between plasma fibrinogen level and mean carotid bulb intima-media thickness, these associations were essentially unchanged in stepwise multiple linear regression analyses, allowing for the entry of BMI and level of HDL cholesterol into the analysis. Carotid artery plaque was present in 10% of the children with FH versus none of the control subjects. Children with plaque had a higher mean cholesterol-years score than children without plaque. These findings suggest that the classic lipid and hemostatic risk factors as well as plasma total homocysteine are associated with markers of early carotid atherosclerosis from the second decade of life. B mode ultrasonography may prove to be a useful tool in risk stratification of children with FH. PMID- 8696964 TI - Accumulation of HDL apolipoproteins accompanies abnormal cholesterol accumulation in Schnyder's corneal dystrophy. AB - Schnyder's corneal dystrophy is an autosomal dominant disorder that results in clouding of the central cornea and premature development of peripheral arcus in the cornea. Previous studies showed that abnormal lipid accumulation is the basis for the corneal clouding. We examined whether apolipoproteins are involved in this disorder and characterized the lipid accumulation in the central portion of corneas removed from patients with Schnyder's dystrophy. Our findings show that cholesterol and phospholipid contents increased greater than 10-fold and 5-fold, respectively, in affected compared with normal corneas. In addition, the percentage of cholesterol that was unesterified (63% versus 50%) and the molar ratio of unesterified cholesterol to phospholipid (1.5 versus 0.5) were higher in affected compared with normal corneas. Large multilamellar vesicles and electron dense granules (100 to 300 nm in diameter) as well as cholesterol crystals accumulated in the extracellular matrix of affected corneas. Immunohistochemical analysis showed that apolipoprotein constituents of HDL (apoA-I, apoA-II, and apoE), but not apoB, a marker of LDL, accumulated in the affected cornea. Western blot analysis confirmed the increased amounts of these HDL apolipoproteins in affected corneas and showed that the apparent molecular weights of the apolipoproteins were normal. Our findings show for the first time that HDL apolipoproteins accumulate in the corneas of patients with Schnyder's corneal dystrophy. Thus, this disorder influences the metabolism of HDL in the corneas of these patients. PMID- 8696965 TI - Folding and binding. PMID- 8696966 TI - Alternative conformations of amyloidogenic proteins govern their behavior. AB - Recent publications strongly support the hypothesis that conformational changes in amyloidogenic proteins lead to amyloid fibril formation and cause disease. Biophysical studies on several amyloidogenic proteins provide insights into the conformational changes required for fibrilogenesis. In addition, newly available moderate to high resolution structural studies are bringing us closer to understanding the structure of amyloid. PMID- 8696967 TI - Protein-nucleic acid interactions. PMID- 8696968 TI - Mechanisms and uses of hydrogen exchange. AB - Recent work has largely completed our understanding of the hydrogen-exchange chemistry of unstructured proteins and nucleic acids. Some of the high-energy structural fluctuations that determine the hydrogen-exchange behavior of native macromolecules have been explained; others remain elusive. A growing number of applications are exploiting hydrogen-exchange behavior to study difficult molecular systems and elicit otherwise inaccessible information on protein structure, dynamics and energetics. PMID- 8696969 TI - Structural analysis of non-native states of proteins by NMR methods. AB - Established NMR methods are increasingly being applied to the non-native states of proteins. For small denatured proteins, full assignment of proton, 15N and 13C resonances is often straightforward. Sensitive methods exist for detecting fractionally populated alpha helices and beta strands, but defining transient interactions among side chains is proving more problematic. The non-native states of several small proteins are being intensively investigated to address a number of questions about protein folding. PMID- 8696970 TI - Sequence space, folding and protein design. AB - Protein design efforts are beginning to yield molecules with many of the properties of natural proteins. Such experiments are informed by and contribute to our understanding of the sequence determinants of protein folding and stability. The most important design elements seem to be the proper placement of hydrophobic residues along the polypeptide chain and the ability of these residues to form a well packed core. Buried polar interactions, turn and capping motifs and secondary structural propensities also contribute, although probably to a lesser extent. PMID- 8696971 TI - Collapse and cooperativity in protein folding. AB - The folding of a polypeptide chain is associated both with compactness and cooperativity within local and global regions of the protein structure, and with the formation of the native-like molecular architecture. Recent experiments shed light on these issues and their relationships to the pathways of protein folding. PMID- 8696972 TI - Molecular chaperones in protein folding and translocation. AB - Chaperonin cpn60 and heat shock protein hsp70 couple their ATPase cycles to the binding and dissociation of non-native proteins. cpn60 is a cylindrical tetradecamer that uses a co-protein (cpn10) and both positive and negative cooperativity to alter the properties of its two voluminous protein-binding chambers in an alternating, asymmetric cycle. In the hsp70 reaction cycle, short segments of polypeptide bind rapidly and weakly to the ATP state, so triggering hydrolysis and consequent stabilization of the complex. Co-proteins of the hsp40 family enhance this partial reaction, whereas nucleotide exchange factors destabilize the product. The individual steps in the two energy transducing mechanisms have only recently been elucidated and provide us with a more detailed picture of the way in which these chaperones can influence the folding, assembly and translocation of protein structures in the cell. PMID- 8696973 TI - RNA-protein complexes. AB - The three commonly found RNA-binding domains, the ribonucleoprotein (RNP) domain, the double stranded RNA binding domain (dsRBD) and the K homology (KH) domain, have now been shown to have an alpha/beta fold similar to that found in many ribosomal proteins. Crystal structures of two hairpin RNA-protein complexes have been determined recently: the U1A spliceosomal protein bound to hairpin II of U1 small nuclear RNA, and MS2 bacteriophage capsid protein bound to a hairpin present at the ribosomal binding site of MS2 replicase mRNA. The crystal structure of the tryptophan operon RNA binding attenuation protein from Bacillus subtilis shows a novel structure with 11 monomers arranged in a doughnut-shaped ring that binds 11 copies of (U/G)AG triplets presented in the leader sequence of the tryptophan operon polycistronic message. PMID- 8696974 TI - Homeodomain interactions. AB - Homeodomain proteins play key roles in development and gene regulation in eukaryotes. Past structural studies have focused on the binding of monomeric homeodomains to DNA, but two recent structures have revealed how homeodomains bind DNA as multimers. The structures of the Drosophila Paired homodimer and the yeast a1/alpha2 heterodimer bound to DNA, along with a high-resolution study of a Drosophila eve-DNA complex, have deepened our understanding of how homeodomains locate their DNA targets. PMID- 8696975 TI - The TATA box binding protein. AB - The TATA box binding protein is required by all three eukaryotic RNA polymerases to correctly initiate the transcription of ribosomal, messenger, small nuclear and transfer RNAs. Since the first gene encoding a TATA box binding protein was cloned from Saccharomyces cerevisiae, it has been the object of considerable biochemical and genetic study. Substantial progress has recently been made on structural and mechanistic studies of the protein. Three-dimensional structures newly elucidated include two TATA box binding proteins alone and bound to distinct TATA elements, and the ternary complex of transcription factor IIB recognizing a TATA box binding protein bound to a TATA element. PMID- 8696976 TI - Retroviral integrases and their cousins. AB - The recently determined structures of the catalytic domains of HIV integrase, avian sarcoma virus integrase and the Mu transposase are strikingly similar to each other and also exhibit significant similarity to several nucleases. All these enzymes of cut polynucleotides, leaving 3'OH and 5'PO4 groups. The integrase and transposase also possess a strand-transfer activity that splices DNA. The structural similarities among members of this superfamily of polynucleotidyl transferases suggest that they share a similar mechanism of catalysis. PMID- 8696977 TI - Recent developments in DNA topoisomerase II structure and mechanism. AB - Type II DNA topoisomerases are enzymes that are capable of transporting one duplex DNA through another. Recent experimental results, including the structure of a fragment of yeast topoisomerase II, have provided new insights into the mechanism of the strand passage reaction. Other results have begun to define the role of ATP in the catalytic cycle and illuminate how DNA breaks mediated by topoisomerase II can occur. PMID- 8696978 TI - The Rel family of eukaryotic transcription factors. AB - Members of the Rel transcription factor family mediate the response of eukaryotic cells to a broad range of environmental threats, in addition to serving an essential role in the development of certain vertebrate and insect cells. It is now apparent that there are two classes of Rel proteins, which differ in whether they bind DNA as monomers or dimers and which use markedly different mechanisms to transduce intracellular signals. Recent progress has been made towards understanding the structural basis for the fascinating biology of these proteins. PMID- 8696979 TI - Alterations in cell signaling and related effector functions in T lymphocytes in burn/trauma/septic injuries. AB - Suppressions in T-cell responses in burn, trauma, and septic injuries could result from alterations in the T-cell signaling pathway linked to the stimulation of the T-cell antigen receptor complex. Recent studies have correlated T-cell IL 2 expression and proliferation with those in the signaling pathways. T-cells from injured hosts were stimulated with a calcium ionophore (to upregulate Ca2+ mobilization) and a phorbol ester (to activate protein kinase C); these T-cells were found to be unresponsive. These studies suggested that the defect in the pathway is located downstream of the Ca2+ mobilization and protein kinase C activation steps. In contrast, the exposure of T-cells from injured hosts to a phorbol ester along with a mitogen (PHA) was found to abrogate the burn/trauma injury-induced suppression in IL-2 expression; these studies remain to be clarified further. Studies from the author's laboratory have shown decreased Ca2+ mobilization and tyrosine phosphorylation correlated with suppressed T-cell IL-2 production and proliferation. These studies support the view that the T-cell signaling defect in the injury condition occurs at the Ca2+ signal step and/or in the upstream signaling component effecting protein tyrosine phosphorylation. PMID- 8696980 TI - Potential roles for endothelins in systemic inflammatory response syndrome with a particular relationship to cytokines. AB - Endothelins (ETs) are multifunctional isopeptides and their role in several pathophysiologies is slowly emerging. They are possible therapeutic targets in sepsis and other systemic inflammatory response syndromes (SIRS). In such conditions, elevated concentrations of ETs have been reported, together with other proinflammatory markers such as several cytokines. Some of the cytokines even modulate the expression, production, and release of ETs from cells and also the biological responsiveness of ETs into the circulation. Here, we systematically review the literature and discuss the role of these peptides in affecting vascular and inflammatory responses in SIRS. This review also intends to provide a better understanding of the mechanisms of ETs and their interrelationships to other mediators, mainly cytokines, in SIRS. There is no doubt that ETs are useful markers of vascular injury in SIRS. From experimental evidence in animals, endothelins, as potent vasoconstrictors, play a beneficial central compensatory role against the loss of vascular tone associated with SIRS. Conversely, endothelins compromise the circulation in several vascular beds and exacerbate conditions in which inadequate perfusion already exists during the early stages of SIRS. Since no single magic solution has been found for complex diseases related to SIRS, we should look toward a group of mediators, such as cytokines and endothelins, acting as team players. PMID- 8696981 TI - Alveolar macrophages of patients with adult respiratory distress syndrome express high levels of heat shock protein 72 mRNA. AB - Adult respiratory distress syndrome (ARDS), a multifactorial disease with poor prognosis, is characterized by an accumulation of inflammatory cells within the airspaces of the lungs. There is evidence that alveolar macrophages (AM) are involved in the pathogenesis of this pulmonary disease. It has been demonstrated that AM synthesize heat shock proteins (HSPs) after exposure to certain stress factors. Increasing evidence suggests that HSPs could confer protection against oxidative injury, noxious molecules, and bacterial toxins. In stressed cells HSP 72 appears to be essential for survival during and after exposure to cellular injury. The aim of this study was to evaluate the magnitude of HSP 72 expression by human AM of patients with ARDS and correlate that with respiratory burst activity. Bronchoalveolar lavage was performed in six ARDS patients, 10 patients with high risk for developing ARDS, and two patients who underwent bronchoscopy for other reasons. Spontaneous ex vivo expression of HSP 72 in AM could be demonstrated by immunocytochemistry. Total RNA as well as poly(A)-rich mRNA were extracted from recovered AM and analyzed by Northern blot and slot blot using a human HSP 72-specific probe. Signals of slot blot were analyzed by densitometry and expressed as relative levels of HSP 72 mRNA of stressed (42 degrees C) HT 1080 control cells. Significantly (p < .001) higher levels of HSP 72 mRNA were measured in patients with ARDS (96.2 +/- 9.5 relative levels) in comparison to those not developing this syndrome (46.0 +/- 4.2). With regard to respiratory burst activity of AM in patients with ARDS, there was a negative correlation between HSP 72 expression and reactive oxygen species production. The AM of patients with ARDS with high relative levels of HSP 72 expression showed low respiratory burst activity. A predictive value for disease severity of high level of HSP 72 mRNA in AM in patients at risk for ARDS has to be evaluated by future studies. This demonstration of HSP 72 expression ex vivo suggests a protective role of HSP response against endo/exogenously generated stress factors in AM. PMID- 8696982 TI - Effect of transfusion on oxygen transport in critically ill patients. AB - The role of isolated blood transfusion as a means toward improving oxygen transport was evaluated in 19 critically ill patients having sepsis syndrome as defined by standard criteria. ICU therapies were unchanged during transfusion and hemodynamic profiles with serum lactate levels were obtained before and after packed red blood cells were given. Blood transfusions in these patients did not cause a change in hemodynamic status. Arterial lactate determination was normal before and after transfusion was administered. Oxygen uptake failed to increase with transfusion, corresponding to increased arterial and mixed venous oxygen content. In the presence of sepsis, patients having oxygen delivery and uptake above normal without evidence of ischemia (normal lactate) will not increase oxygen consumption by raising the hemoglobin. PMID- 8696983 TI - Endotoxin tolerance is induced in Chinese hamster ovary cell lines expressing human CD14. AB - Changes in patterns of gene induction by myeloid lineage cells following multiple exposures to endotoxin (lipopolysaccharide; LPS) is a feature of LPS tolerance. To further understand the mechanism of this phenomenon we describe studies using stably transfected Chinese hamster ovary cell lines that express human CD14 (CHO hCD14). Using NF-kappa B activation as a measure of LPS-induced cell activation we show that a single treatment with LPS renders CHO-hCD14 cells tolerant to subsequent challenge with LPS, but not with other stimuli such as tumor necrosis factor. Tolerance may result from the induction of gene(s) that control LPS induced signaling pathways and here we suggest that such genes may be found in the group of immediate, early response genes characterized by the protein phosphatase 3CH134. The CHO-hCD14 cell lines provide a novel model system to further explore the mechanism of endotoxin tolerance. PMID- 8696984 TI - The impact of femur fracture with associated soft tissue injury on immune function and intestinal permeability. AB - Alterations in intestinal permeability and immune function were investigated in a murine femur fracture (FFx) model. We postulated that soft tissue injury associated with closed FFx (crush injury) would result in greater immunosuppression that open FFx (surgical division). AKR mice were randomized to four groups (Normal, Sham, Open FFx, Closed FFx) and studied at 24 and 96 h post injury. Immune function was assessed by splenocyte blastogenic response and class specific immunoglobulin production. Intestinal permeability was assessed by measurement of whole blood fluorometry after gavage administration of fluorescein dextran (FITC-dextran). Closed FFx is associated with increased splenocyte blastogenesis and increased immunoglobulin production at 24 h post-injury. This immunostimulatory response was associated with altered intestinal permeability early after injury (FITC-dextran:.185 +/- .070 Closed FFx vs. .069 +/- .011 Normal, p = .06). Immunosuppression was evident at 96 h post-injury in the closed FFx group, documented by significant reductions in splenocyte blastogenesis to all mitogens studied. The Open FFx group did not demonstrate any reduction in splenocyte blastogenesis at 96 h post-injury. These data suggest that the soft tissue injury associated with Closed FFx is associated with significant immunosuppression and altered gastrointestinal permeability, which may adversely affect the host by increasing the relative risk of post-trauma infection. PMID- 8696985 TI - Release site of TNF alpha after intravenous and intraperitoneal injection of LPS from Escherichia coli in rats. AB - Lipopolysaccharide (LPS) concentrations in the portal vein after intraperitoneal (i.p.) injection were slightly higher than those in the arteries. The tumor necrosis factor (TNF alpha) levels in arterial serum were higher after i.p. injection than after i.v. injection and rose to a peak at 90 min after some delay. Infusion of LPS into the portal vein increased the TNF alpha levels in the arterial serum. Pretreatment with indomethacin further increased the arterial levels of TNF alpha after portal infusion, but did not after them after i.p. injection, because of the reduction by indomethacin of LPS absorption after i.p. Injection of LPS. TNF alpha was also generated in the peritoneal cavity after i.p. injection of LPS. The TNF alpha concentrations in the arterial serum and in the peritoneal cavity were accelerated by mast cell degradation. In conclusion, TNF alpha was generated mainly in the liver, but also in the peritoneal cavity, after i.p. injection of LPS, and was negatively regulated by prostaglandins. PMID- 8696986 TI - H1-antagonism improves intestinal mucosal pH and heart function in porcine hypodynamic endotoxic shock. AB - Porcine hypodynamic shock was induced by continuous infusion of 5 micrograms lipopolysaccharide/kg per hour. This resulted in a decrease of cardiac output from baseline values of 3.5 +/- .9 L/min to 1.5 +/- .8 L/min and a reduced left ventricular stroke work index in the endotoxin-group (n = 6 animals). Pretreatment with the H1-antagonist dimethindene (2 mg/kg) in a second group (n = 6) significantly prevented these effects. Furthermore animals pretreated with the H1-antagonist showed a stable mean arterial blood pressure, whereas the control endotoxin-treated group revealed a drastic reduction in mean arterial blood pressure (99 +/- 4.7 mmHg versus 65.8 +/- 10 mmHg after 240 min, respectively). Pulmonary function and systemic vascular resistance were not ameliorated by the H1-antagonist in hypodynamic shock. Gastrointestinal mucosal pH (pHi), which indicates oxygenation of the mucosa, was decreased by endotoxin-infusion (7.45 +/ .32 baseline value to 6.92 +/- .24 after 120 min). This parameter as well as base excess values and lactate levels were significantly improved by dimethindene pretreatment (p < .05). These results may indicate a beneficial effect of H1 antagonist-pretreatment on endotoxin-induced deterioration of the microcirculation. Furthermore our results clearly demonstrated that only pretreatment before endotoxemia with H1-antagonism is effective, since infusion of H1-antagonist in hypodynamic shock 45 min after addition of endotoxin (n = 6 animals) did not improve the cardiovascular system or the microcirculation. PMID- 8696987 TI - Endotoxin-induced oxidative stress in the rat small intestine: role of nitric oxide. AB - Reactive oxygen species have been implicated in the gastrointestinal pathogenesis of septic and endotoxic shock. The objective of this study was to investigate the role of inducible nitric oxide synthase during endotoxin-induced formation of oxidants by cells of the small intestine. After intravenous Escherichia coli lipopolysaccharide (LPS) (1 mg/kg) injection, nitric oxide production was measured as nitrosyl complex formation in the ileum using electron paramagnetic resonance spectroscopy. Oxidative stress biomarkers were determined as duodenal mucosal-reduced thiols, the ileal lipid peroxidation and luminal free radical production using spin trapping methodology. Demonstration of nitrosyl complex formation commenced at 3 h and diminished 24 h post-LPS. Mucosal thiol levels were decreased at 3, 6, 12, and 18 h post-LPS treatment. At these time point, the ileal lipid peroxidation also increased as did luminal formation of hydroxyl radical adduct. Nitric oxide synthase inhibitors reversed the elevation of hydroxyl radical formation and reversed the decrease in mucosal-reduced thiol levels in the LPS-treated rats. Our data indicate that nitric oxide or its oxidant product(s), such as peroxynitrite, contribute to oxidative injury in the small intestine of rats treated with endotoxin. PMID- 8696988 TI - Alterations in coagulation and fibrinolysis during sepsis. AB - Circulating levels of thrombin-antithrombin III complex (TAT) and plasmin-alpha 2 plasmin inhibitor complex (PIC) in 49 septic patients (23 patients with organ dysfunction (OD), 26 without OD) and 11 postgastrectomy patients were measured to determine the significance of the coagulation-fibrinolytic systems in the development of OD. Tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), and thrombomodulin were also measured. The mean level of TAT on the day when OD occurred was significantly higher compared with the maximum level of TAT in septic patients without OD (P < .01) or postoperative patients (P < .01). There was no difference in PIC levels between the three groups. The TAT/PIC ratio was significantly higher in septic patients with OD compared with the other groups (P < .001). Septic patients with OD showed higher levels of PAI 1 (P < .001) but not of t-PA. Thrombomodulin levels were significantly higher in the septic patients with OD compared with the others (P < .001). We conclude that suppression of the fibrinolytic system contributes to the imbalance between coagulation and fibrinolysis, and that this hypercoagulable millieu on the endothelial surface leads to the onset of OD. PMID- 8696989 TI - Amrinone prevents the inhibition of muscle pyruvate dehydrogenase complex activity during sepsis. AB - A decreased proportion of active pyruvate dehydrogenase complex (PDH) in skeletal muscle has been implicated as an important factor in elevating plasma lactate concentrations in hypermetabolic sepsis. The mediators of the septic process responsible for the inhibition of PDH complex in muscle are unknown. To assess the role of tumor necrosis factor in mediating the effects of sepsis, the effect of daily injections of amrinone (5 mg/kg/day), which inhibits the release of tumor necrosis factor during sepsis, on the proportion of PDH in the active form (PDHa) was investigated in a model of chronic hypermetabolic sepsis. In skeletal muscle from untreated septic rats, PDHa was decreased 50%. Treatment of septic rats with amrinone for 5 days prevented the sepsis-induced decrease in PDHa. Sepsis caused a 2.5-fold elevation in plasma lactate concentrations. The maintenance of the PDH complex activity at control values following injection of amrinone in septic rats was associated with reduced lactate concentrations in plasma. Thus, amrinone prevented the sepsis-induced abnormalities in skeletal muscle PDH activity and plasma lactate concentrations. PMID- 8696990 TI - Hereditary deficiency of protein C, protein S and antithrombin III. AB - It is estimated that 5% of patients with deep vein thrombosis and 50% of those with recurrent thrombosis have an inherited abnormality of coagulation, most commonly deficiency of protein C, protein S or antithrombin III. These disorders should be suspected when venous thrombosis occurs in a young person, if there is a family history of thrombosis, if thrombosis occurs at an unusual site or if there is recurrent thrombosis with no predisposing factors. Affected patients are treated with lifelong anticoagulation therapy. Thromboembolism and its sequelae often produce abnormal findings on radiologic examinations, and therefore the radiologist who is familiar with these abnormalities is in a position to be the first to suggest the diagnosis. PMID- 8696991 TI - The relative diagnostic impact of screening mammography and physical examination. AB - OBJECTIVE: To determine the relative diagnostic impact of screening mammography and physical examination. METHODS: Data from the first 3.5 years of operation of the Ontario Breast Screening Program's regional facility in London were analyzed. A total of 14,646 women underwent screening, which involved both mammography and physical examination. The authors examined the relative contribution of the two types of examination according to detection rate, as well as size, stage and histologic type of the identified breast cancers. RESULTS: In total, 135 cancers were detected. Mammography revealed 131 (97.0%) of all cancers, whereas physical examination revealed only 66 (48.9%). Furthermore, the lesions detected by mammography were generally smaller and found at an earlier stage. CONCLUSION: Although most other screening programs involve mammography only, physical examination did make a contribution to the detection rate at the authors' facility. However, in an era of declining resources and cost containment, critical analysis of the value added by physical examination is necessary. PMID- 8696992 TI - [Diagnosis using x-ray computed angiotomography of an iliac artery aneurysm in an infant]. AB - The authors describe an infant with an aneurysm of the right iliac artery, associated with three sites involving the inferior mesenteric artery and its first two branches, most likely related to an episode of chicken pox. Helical angiography with computed tomography, performed with a continuous-rotation scanner, allowed precise assessment of the lesions, in particular those affecting the inferior mesenteric artery. PMID- 8696993 TI - Value of three-dimensional gradient-echo magnetic resonance cholangiography in diagnosing choledocholithiasis. AB - OBJECTIVE: To evaluate the role of magnetic resonance cholangiography (MRC) in patients with suspected choledocholithiasis. PATIENTS AND METHODS: Twenty-six consecutive patients with suspected choledocholithiasis (11 men and 15 women ranging in age from 25 to 81 years) underwent three-dimensional gradient-echo MRC; each patient also underwent endoscopic retrograde cholangiography or operative cholangiography. Each set of images for each patient was reviewed independently by a radiologist who was unaware of the results of the other type of imaging. RESULTS: Diagnostic-quality MRC images were obtained for 17 of the patients. Of these, 13 had stones in the common bile duct, as confirmed by another imaging method, and MRC indicated the presence of these stones in all 13 patients. In the other four patients bile duct obstruction was due to either acute pancreatitis (in three) or cholangiocarcinoma (in one). For seven of the nine nondiagnostic-quality MRC studies, the bile duct was not obstructed, so there was no bile stasis and the MRC images could not be obtained. Motion artifacts due to inability to hold the breath were the limiting factors in the other two patients. CONCLUSION: Although MRC has some limitations, this new noninvasive technique may be used as a screening test in selected patients with suspected choledocholithiasis. PMID- 8696994 TI - Duodenocolostomy: a surgical complication of duodenal atresia repair. AB - A variety of complications after repair of congenital duodenal obstruction have been reported. The authors describe a case in which the duodenum was mistakenly anastomosed to the transverse colon, which resulted in intractable diarrhea. PMID- 8696995 TI - Oversized inferior vena cava: use of a single Vena Tech--LGM filter. AB - The authors describe placement of the LG-Medical filter (B. Braun/Vena Tech, Evanston, Ill.) in four patients with an oversized inferior vena cava. The corrected caval diameter at the level of the most inferior renal vein was greater than 28 mm in each patient. However, in each case the vena cava tapered inferiorly to a segment with a diameter less than 28 mm, and the filter was placed at this site. Filter placement was accomplished without difficulty or complication in all cases. One patient died of underlying disease. The three surviving patients were followed for 119 to 374 (mean 276) days. There was no evidence of filter migration, recurrent pulmonary embolism, occlusion of the venacava, access-site thrombosis or other complication. The authors concluded that placement of bi-iliac filters can be avoided by this technique. PMID- 8696996 TI - Magnetic resonance imaging of primary osteosarcoma of the lumbar vertebra with metastasis to the perirenal fat. AB - Primary osteosarcoma of the spine not associated with any predisposing factor is rare. The authors describe a case of osteosarcoma of the lumbar spine in a 44 year-old woman with biopsy-proven ulcerative colitis. The patient underwent bone scanning, computed tomography (CT) and magnetic resonance imaging (MRI), and the authors present the first record of the MRI appearance of this disease in a vertebral body. Relative to classical osteosarcoma of long bone, this case involved a higher degree of soft-tissue ossification, which was readily visible with both CT and MRI. The patient had extensive metastasis, including metastasis to the perirenal fat, and died 10 months after presentation. PMID- 8696997 TI - [X-ray computed tomographic aspects of malignant meningioma and meningeal hemangiopericytoma]. AB - OBJECTIVE: To correlate the computed tomography (CT) features with the histologic findings of meningiomas. PATIENTS AND METHODS: The authors reviewed 184 intracranial meningiomas (161 primary and 23 recurrent lesions in 172 patients) and classified the lesions on the basis of six histologic characteristics as benign (82), atypical (64), anaplastic (26) or sarcomatous (12). Among the last two groups, the characteristics of 12 tumours were histologically compatible with hemangiopericytoma. The authors also reviewed the available CT scans for 86 meningiomas: 51 benign lesions, 23 anaplastic or sarcomatous (13 primary and 10 recurrent), and 12 hemangiopericytomas (8 primary and 4 recurrent). RESULTS: Of the 12 radiologic characteristics studied, 8 were associated significantly more often with malignant than with benign meningiomas: presence of necrosis (in 54% of primary malignant meningiomas and 8% of benign cases), cysts (15% and 2%), poorly defined margins (38% and 6%), fringes (23% and 4%), "mushrooming" (8% and 0%) and substantial edema (31% and 8%); large size (62% and 25%); and absence of calcifications (100% and 58%). Despite the fact that the risk of malignancy of meningioma was higher for men, patients with benign and malignant meningiomas did not differ by age or sex. In contrast, more of the patients with hemangiopericytoma were men (5 [56%] of 9 patients), and these patients were younger (average age 45 years, compared with 57 years for those with all other types of meningioma). From a radiologic point of view, the presence of necrosis (in 38% of hemangiopericytomas and 8% of benign meningiomas) and large size (in 75% and 25%) distinguished hemangiopericytoma from benign meningioma. CONCLUSION: None of these CT findings is an absolute sign of malignancy, but the association of two or more of them should suggest the aggressive nature of a meningioma. PMID- 8696998 TI - Computed tomography appearance of idiopathic aneurysm of the azygos vein. AB - True idiopathic aneurysm of the azygos vein is a rarely described abnormality. The authors present a case of this anomaly in a 70-year-old woman with a history of rectal carcinoma. The aneurysm was found incidentally on computed tomography, performed to characterize the appearance of a lung nodule. The aneurysm decompressed when the patient was upright. The effects of respiratory and postural manoeuvres on the lesion are discussed and the computed tomography appearance is described. PMID- 8696999 TI - Residents' corner. Answer to case of the month #38. Pneumatosis intestinalis after bone marrow transplantation. PMID- 8697000 TI - Residents' corner. Answer to case of the month #39. Radiation-induced fibrosarcoma. PMID- 8697001 TI - Localization of osteoid osteoma. PMID- 8697002 TI - [Physical exercise and the skeleton]. AB - The skeleton provides more than only a framework for the body. Bone is a calcified conjunctive tissue sensitive to various mechanical stimuli, mainly to those resulting from gravity and muscular contractions. Numerous animal and human studies demonstrate the importance of weight-bearing physical activity as well as mechanical loading for maintaining skeletal integrity. Lack of weight-bearing activity is dangerous for the skeleton: a decrease in bone mineral density (BMD) has been demonstrated in animals and humans under conditions of weightlessness or immobilization. Other studies have also reported a lower vertebral BMD among young amenorrheic athletes than among athletes with regular cycles and/or non athletes. The main factor responsible for this lower BMD in the amenorrheic athletes is the persistent low level of endogenous estrogen observed among these women. However this does not represent a premature and irreversible loss of bone mass since the resumption of menses following a decrease in training is the primary factor for a significant increase in vertebral BMD in these formerly amenorrheic athletes. A weight-bearing exercise is likely to be more beneficial at weight-bearing than at non weight-bearing sites, and hypogonadism resulting from very intensive training and exercise is more detrimental to trabecular than cortical bone. Bone deficit at non weight-bearing sites may be attenuated by maintenance of body weight. Nevertheless the etiology of "stress fractures" among athletes remains poorly understood, and the exact relationship between soft tissue mass and BMD is not clear. Osteoporosis, the most common bone disorder in France, is a pathological condition associated with increased loss of bone mass, resulting in a greater risk of fracture. Although symptoms of osteoporosis do not generally occur until after menopause, recent evidence suggests that bone loss starts much earlier in life. Therefore osteoporosis might be prevented by increasing peak bone mass and/or by slowering bone loss after menopause. Exercise such as resistance training or weight-bearing activities like running or walking have an osteogenic effect on increasing BMD in young people, and the decrease in BMD is slower in exercised than in non-exercised post-menopausal women. Nevertheless the influence of the length and of the intensity of such physical activities remain to be determined. PMID- 8697003 TI - Experimental research on the morphofunctional differentiation of the rat ventral prostate: roles of the gonads at birth. AB - In the male rat, a dramatic increase in serum testosterone (T) of testicular origin occurs during the first few hours of postnatal life. This experiment sought to determine whether this increase affects the physiology of the adult rat ventral prostate. Male rats were castrated at the time of caesarean delivery performed at different precise stages between 21 days and 22 days of gestation (0h males). Newborn male rats were castrated after spontaneous delivery at 22 days of gestation at 6, 12, 24 or 48 h after birth. Some male rats were castrated at fetal stage 21 days 13-15 h and injected at the time of surgery with 1, 2.5 or 5 micrograms of testosterone propionate (TP). Control males were sham operated at fetal stage 21 days 13-15 h and castrated at 23 days postnatal. At 30 days of age, each male was given T replacement therapy through a T filled silastic capsule until the time of sacrifice at 100 days of age. Before T implantation at 30 days of age, castration at 0 h or 48 h after birth does not impair neither branching morphogenesis nor the organization of the prostatic acinus. In contrast, the histological structure of the ventral prostate of the 0 h males implanted with T from puberty on is greatly disturbed. Cribriform and severe atypic hyperplastic acini with various epithelial cell arrangements are common. The alveolar sheath of the prostatic glands and the interacinar stroma are enlarged. In acini with severe intraepithelial hyperplasia, the disorganized epithelium rests over a thick basement membrane that stains strongly for laminin. In some 0 h males, epithelial cells break through the periacinar fibromuscular sheath and invade the interacinar stroma. It is as though all the categories of cells comprising the ventral prostate were not programmed in the absence of neonatal androgens. The secretory activity and the expression of Prostate Binding Protein (PBP) are impaired in the ventral prostate of the 0 h males. Castration performed after 12 h after birth has no deleterious effect on either secretory activity or PBP expression. The critical period during which perinatal T affects the histological structure and the functional differentiation of the ventral prostate extends from fetal stage 21 days up to 1 or 2 days postnatal. A single injection of 2.5 micrograms TP, a dose which mimicks the postpartum T surge is sufficient for programming the histological structure and the functional differentiation of the adult ventral prostate. PMID- 8697004 TI - Effects of growth factors on the enzymes of purine metabolism in culture of regenerating rat liver cells. AB - Hepatocytes are affected by many cytokines and growth factors during liver regeneration. In regenerating rat liver cells cultures, liver cell growth factor (LCGF), hepatic stimulator substance (HSS), interleukin-1 beta (IL-1 beta), as well as their combination, were tested for their ability to activate the enzymes involved in purine metabolism. The enzymes tested were 5' nucleotidase, AMP deaminase, adenosine deaminase and xanthine oxidase. The cytokines alone or in combination, activated 5' nucleotidase and adenosine deaminase. Activity of AMP deaminase was stimulated by IL-1 beta associated with LCGF, HSS and IL-1 beta. Xanthine oxidase was stimulated by IL-1 beta but not with HSS and LCGF. Associated with IL-1 beta these two substances decreased its activity. A novel approach to the understanding of the mechanisms involved in the regulation of purine metabolism during liver regeneration, is proposed. PMID- 8697005 TI - FDA points to decline in drug review times in 1995. PMID- 8697006 TI - Study affirms primacy of paclitaxel-cisplatin in advanced ovarian cancer. PMID- 8697007 TI - Panelists describe collaborative drug therapy management efforts. PMID- 8697008 TI - Liability insurance coverage for nontraditional services. PMID- 8697009 TI - Creating patient care opportunities. PMID- 8697011 TI - Lessons from the other literature. PMID- 8697010 TI - Coping with the layoff of coworkers. PMID- 8697012 TI - High-dose chemotherapy with stem-cell rescue for the treatment of breast cancer. AB - The use of high-dose chemotherapy with stem-cell rescue (HDC-SCR) in the treatment of breast cancer is reviewed. The rationale for HDC-SCR in breast cancer is based on the principles of dose response and dose intensity. After conventional-dose chemotherapy, hematopoietic progenitor cells are harvested from the bone marrow or peripheral blood. The patient then undergoes HDC-SCR. Peripheral-blood progenitor cells are becoming the preferred cells for hematopoietic rescue. Most clinical trails of HDC-SCR in metastatic breast cancer have resulted in high overall objective response rates (57-100%), with the highest rates occurring in patients with minimal residual disease or chemotherapy sensitive disease at the time of high-dose treatment. Most protocols now include induction therapy before HDC-SCR; only patients who show sensitive disease proceed to high-dose therapy. In most studies published to date, the median duration of remission was less than one year from the time of high-dose therapy; however, 10-15% of patients achieved complete remissions lasting two or more years. Most patients relapse, however. Some studies have suggested value of HDC SCR as consolidation therapy in the adjuvant setting for women at high risk of relapse. Short-term toxicities of HDC-SCR are manageable in experienced hands. Notable long-term adverse effects include leukemia, sterility, pulmonary toxicity, and hemolytic uremic syndrome. Unresolved issues include the utility of purging occult cancer cells from stem-cell-bearing specimens, the best preparative regimen, the implications of autologous graft-versus-host disease, the use of sequential cycles of high-dose chemotherapy, cost-effectiveness, and effectiveness compared with standard therapy. HDC-SCR appears to be a valid option for selected patients with metastatic breast cancer, and in the adjuvant setting for patients at high risk of recurrence. The cost-benefit profile remains to be defined in randomized trials. PMID- 8697013 TI - Disease management program for asthma: baseline assessment of resource use. AB - Resource use by asthma patients was assessed as a step in the development of a disease management program by a university teaching hospital, a health maintenance organization (HMO), and a national pharmacy benefit management company (PBM). Medication profiles and medical records were reviewed for all HMO patients who had a diagnosis of asthma and a pharmacy claim for an asthma-related drug in 1993; patients with chronic obstructive pulmonary disease were excluded. These 656 patients' use of health care resources (outpatient clinic visits, emergency room and urgent care visits, hospital admissions, and, the associated costs were determined, as were variances from the PBM's clinical guidelines for asthma. Members 0-4 years of age had the most outpatient and emergency/urgent care visits and the most hospital admissions. Forty-four of the patients received high-dose beta-agonist therapy, and 20 of these patients did not receive either an inhaled anti-inflammatory drug or a short course of corticosteroids. The 44 patients had more outpatient clinic and emergency room/urgent care visits, more admissions, and greater total health care costs than the other patients with asthma. The asthma patients' mean health care cost in 1993 was $203, compared with $110 for all enrollees in the HMO. For patients with high use of beta agonists, the mean cost was nearly three times that for the other asthma patients. The baseline review of resource use identified aspects of medication use that were at variance with treatment guidelines for asthma patients. PMID- 8697014 TI - Implementing comprehensive pharmaceutical services at an academic tertiary care hospital. AB - The implementation and impact of comprehensive pharmaceutical services at a hospital are described. Before 1992, pharmaceutical services at Detroit Receiving Hospital and University Health Center were comparable to those of many departments serving similar academic tertiary care institutions. A major conflict with the principles of pharmaceutical care existed in that specific tasks were assigned to pharmacists, so that up to four pharmacists may have been involved in one patient's drug therapy while other patients were ignored. Several steps were taken to solve this problem. The department's mission and vision statements were modified to embrace pharmaceutical care. The support of administration and department leaders was secured, pharmacist evaluations were adjusted to make pharmaceutical care skills baseline competencies, and staffing was reconfigured. A voluntary pharmaceutical care committee was formed to transform pharmaceutical services at the hospital. It was decided that all staff pharmacists would provide clinical and distributive services on a rotating basis. The drug distribution system was altered to free more pharmacist time for patient care, and two technician positions were added. The clinical program was made more patient focused. The program was implemented in a stepwise manner beginning in September 1992. Computerized systems for tracking workload and documenting clinical interventions and drug cost savings were established. Later changes included making pharmacists responsible for all patients on a medical service rather than for specific problems in a particular location and changing scheduling to enhance the continuity of care. The number of clinical interventions by pharmacists increased from 3,563 in 1993 to 15,476 (projected) in 1995, and drug cost savings and avoidance increased from $239,248 in 1992 to $562,402 (projected) in 1995. Major change was necessary to implement comprehensive pharmaceutical services at an academic tertiary care hospital. PMID- 8697015 TI - Work activities before and after implementation of an automated dispensing system. AB - The impact of an automated dispensing system (ADS) on medication-related work activities by nurses and pharmacists was studied. A point-of-care ADS (Baxter Sure-Med) was installed on two nursing units (the surgical intensive care unit [SICU] and a medicine unit [4NMU]) of a 400-bed university hospital as part of a pilot project. A self-reported work-sampling study was used to collect observations of medication-related work activities by nurses, health unit coordinators (nursing support staff), and pharmacists for a seven-day period before ADS implementation and a seven-day period after implementation. There were 7797 observations of nurse work activities, 1408 observations of health unit coordinator work activities, and 4236 observations of pharmacist work activities. The percentage of nurse work activities that were medication related decreased from 20.7% before ADS implementation to 18.4% afterward on 4NMU and increased slightly from 10.8% to 11.0% on the SICU. Medication-related health unit coordinator work activities increased from 17.5% to 25.3% of total activities on 4NMU and decreased from 16.6% to 10.7% on the SICU. None of these changes was significant. For decentralized pharmacists supporting 4NMU, the percentage of work activities classified as clinical increased significantly from 36.5% to 49.1%. For decentralized pharmacists supporting the SICU, clinical activities increased from 27.9% to 35.1%. There were no significant changes on either unit in pharmacist activities classified as technical. An overall measure of the efficiency with which pharmacists used their time for patient care-related activities increased. A point-of-care ADS did not affect the proportion of time spent by nurses on medication-related activities and seemed to give pharmacists more time for clinical work. PMID- 8697017 TI - Academia's role in managed care education. PMID- 8697016 TI - Making decisions about drug repackaging. PMID- 8697018 TI - A journal club. PMID- 8697019 TI - Pharmacy degrees the second time around. PMID- 8697020 TI - Opinions on useful patient drug information aired at FDA workshop. Opposition to MedGuide proposal runs strong. PMID- 8697021 TI - Meeting Joint Commission requirements for competence assessment. PMID- 8697022 TI - Deciding between once- and twice-daily dosing. PMID- 8697023 TI - Preventing chemotherapy errors. PMID- 8697024 TI - Oncology pharmacy as a specialty. PMID- 8697025 TI - Preventing medication errors in cancer chemotherapy. AB - Recommendations for preventing medication errors in cancer chemotherapy are made. Before a health care provider is granted privileges to prescribe, dispense, or administer antineoplastic agents, he or she should undergo a tailored educational program and possibly testing or certification. Appropriate reference materials should be developed. Each institution should develop a dose-verification process with as many independent checks as possible. A detailed checklist covering prescribing, transcribing, dispensing, and administration should be used. Oral orders are not acceptable. All doses should be calculated independently by the physician, the pharmacist, and the nurse. Dosage limits should be established and a review process set up for doses that exceed the limits. These limits should be entered into pharmacy computer systems, listed on preprinted order forms, stated on the product packaging, placed in strategic locations in the institution, and communicated to employees. The prescribing vocabulary must be standardized. Acronyms, abbreviations, and brand names must be avoided and steps taken to avoid other sources of confusion in the written orders, such as trailing zeros. Preprinted antineoplastic drug order forms containing checklists can help avoid errors. Manufacturers should be encouraged to avoid or eliminate ambiguities in drug names and dosing information. Patients must be educated about all aspects of their cancer chemotherapy, as patients represent a last line of defense against errors. An interdisciplinary team at each practice site should review every medication error reported. Pharmacists should be involved at all sites where antineoplastic agents are dispensed. Although it may not be possible to eliminate all medication errors in cancer chemotherapy, the risk can be minimized through specific steps. Because of their training and experience, pharmacists should take the lead in this effort. PMID- 8697026 TI - Top-priority actions for preventing adverse drug events in hospitals. Recommendations of an expert panel. PMID- 8697027 TI - Computer software for pharmacy oncology services. AB - A computer program designed to manage the informational, clinical, and data requirements for a pharmacy oncology service is described. Specialized pharmacy oncology software was developed at Rhode Island Hospital and implemented in a multihospital, integrated health system. The software performs various safety functions, supplies on-screen access to pertinent drug and patient information, manages data, and assists in the product formulation process. The programmed safeguards can be modified to meet changing requirements. The system has been in use for more than seven years and has helped detect prescribing errors and prevent preparation and administration errors. A pharmacy oncology computer program streamlines pharmacists' work and helps prevent errors in antineoplastic drug therapy. PMID- 8697028 TI - Quality-improvement processes in an oncology pharmacy service. PMID- 8697029 TI - Asking a pharmacist to resign for making an error. PMID- 8697030 TI - Stability of dextrose and sodium chloride in injectable solutions stored in an elastomeric infusion device. PMID- 8697031 TI - Enforcing antimicrobial restrictions. PMID- 8697032 TI - Structuring the acquisition and retrieval environment to facilitate learning in individuals with dementia of the Alzheimer type. AB - Three experiments using variations of the Subject Performed Task (SPT) paradigm examined whether structuring the learning and retrieval environment would improve learning in individuals with mild to moderate dementia of the Alzheimer type (DAT). Experiment 1 examined the role of enactment at encoding and retrieval, and found that with appropriate retrieval support DAT volunteers do benefit from enactment at encoding. Experiment 2 showed that recall was further enhanced when the list of SPTs formed a cohesive, goal-directed sequence of actions. In Experiment 3, DAT subjects acquired a more complex action-based sequence and maintained it accurately over a short period of time. It is concluded that the provision of contextual support at encoding and at retrieval can enhance residual memory in individuals with DAT. PMID- 8697033 TI - Association as a cause of dating bias. AB - Two experiments investigated a dating bias in which people tend to estimate recent dates too remotely and remote dates too recently. Experiment 1 examined and upheld a prediction of the hypothesis that bias arises because events whose time of occurrence is unknown are dated through associated events for which some time information is available. Experiment 2 required some subjects to date prototype events while others dated specific events. Prototype events were dated more recently, and the errors in dating specific events were related to differences in the way the prototype events were dated. Both sets of results were predicted by the association hypothesis, according to which events whose dates are well known are dated with reference either to specific associated events or to prototype events. PMID- 8697034 TI - In my era: evidence for the perception of a special period of the past. AB - Do individuals perceive a time of their lives that is special with regard to their identity as part of a generation or era? In an interview study, 89 subjects were asked to list favourite films (and the ages at which they saw them) and to list films that defined their era (and the ages at which they saw them). Subjects also stated the years that they felt began and ended their eras. Additional age information questions about ages of schooling and co-workers and friends were asked. Results suggest that subjects perceive their era to be between ages 14 and 24; the mean age at which subjects viewed era films was 21.85 (inside the era), whereas the mean age at which subjects viewed favourite films was 27.59 (outside the era). Although most subjects perceived their eras to begin at approximately the same age (14), those subjects who attended college perceived extended era periods (by 2.5 years). Relationships between an era and social identity are discussed, as well as the relationship between the era and the autobiographical memory phenomenon of the reminiscence peak. PMID- 8697035 TI - Single and multiple test repetition priming in implicit memory. AB - Using a picture naming task, we compared the magnitude of repetition priming after one prior study episode (single test priming) versus multiple prior study presentations (multiple test priming). Pictures were repeated either one, two, or three times, and the interval between tests was either several minutes (blocked test) or one week (spaced test). Priming increased with additional prior presentations (beyond one) in the multiple test format. In addition, single test priming decreased within one hour after initial exposure, with little change from one hour to two weeks. Priming was unaffected by a simultaneous recognition task, suggesting that picture naming is an implicit task relatively immune from explicit memory contamination. PMID- 8697036 TI - The effect of experimental design on memory for typical and distinctive faces. AB - The effect of experimental design on memory for typical and distinctive faces was investigated in three experiments. In Experiments 1 and 2, a between-subjects, between-lists (distinctive-only faces, or typical-only faces) manipulation of distinctiveness was compared with a within-subjects mixed-list design. The results demonstrated an interaction between design type and distinctiveness, indicating an increase in the rate of misidentifications and a decrease in the response criterion to distinctive faces in the distinctive-only set relative to distinctive faces in the mixed-list condition. Experiment 3 addressed the locus of this effect by comparing the standard mixed-list within-subjects design with two sets of faces in which the target images were different in type from the distractor images, i.e. a typical target-distinctive distractor set and a distinctive target-typical distractor set. The results of this experiment demonstrated that distinctive distractor faces were more readily rejected as new faces when typical target faces were included in the same set. The relative sensitivity of memory for typical and distinctive faces to manipulations of experimental design are discussed with reference to current models of facial distinctiveness. PMID- 8697037 TI - Explaining impossible phenomena: object permanence beliefs and memory failures in adults. AB - In three experiments, adult subjects' explanations of the observed nonpermanence of a physical object and their recollections of the order of the events during the experiment were obtained and analysed. The data showed that in order to conserve their strong beliefs in object permanence subjects systematically distorted the real temporal succession of events preceding the phenomenon. The frequency of the distortions depended on the salience of the nonpermanence phenomenon ("disappearance" versus "appearance" of the physical object) and on the time interval between the events whose temporal order was reversed, but not on subjects' nationality (English versus German), gender, type of reproduction (immediate versus delayed), role in the experiment (subject versus observer), and degree of prompting in questioning. PMID- 8697038 TI - Proceedings of a satellite symposium on Pharmacologic Treatment of Obesity. 7th International Congress on Obesity. Sainte-Adele, Quebec, August 18-20, 1994. PMID- 8697039 TI - Opinions of obesity experts on the causes and treatment of obesity--a new survey. AB - A survey of opinions on the causes of and effectiveness for treatment of obesity was carried out on data provided by questionnaires from 57 physicians and scientists involved in obesity research. Responses were grouped by region (Europe, North America, and South America), gender, age (30-50 and over 50 years), and professional training (MD or PhD). Metabolic factors were considered the most important cause of obesity overall with physical inactivity only slightly behind. There were no gender differences, but the older group thought physical inactivity was a more important cause than the younger group. Weight cycling overall was not considered very important, although it was significantly more important among the Ph.D. group. Low-fat diets were considered the most effective treatment, with the older group of respondents rating low-fat diet more highly than their younger colleagues. Exercise was viewed as a more important treatment among North Americans, and medications as less in the treatment of obesity. All groups viewed serotonergic and thermogenic drugs as the most effective treatments whose usefulness would increase during the next 10 years. PMID- 8697040 TI - Evaluation of drugs for treating obesity. AB - Criteria for the evaluation of new drugs to treat obesity are important as guides for designing clinical trials to test these agents. These criteria must be developed in relation to the realities of obesity, which is a chronic disease associated with morbidity and mortality that is increased by visceral fat deposits. The observation that patients regain weight after stopping drug treatment for obesity argues for the proposition that drugs work only when taken and NOT that the drugs are ineffective. The analogy between the development of treatments for obesity to those for the treatment of hypertension is used to highlight potential areas for new developments. Several features of an ideal drug for the treatment of obesity are suggested. Criteria for evaluating new drugs include both primary and secondary endpoints. The primary endpoint for an anti obesity drug should be weight loss, possibly by category of success. Losses of total body fat or visceral fat might be alternative primary endpoints. Secondary endpoints include reduction in risk factors for associated diseases and improvement in the quality of life. In trials where vigorous placebo designs including highly aggressive behavior modification or very-low-calorie diets were used, it may be difficult or impossible to detect a response to a drug. PMID- 8697041 TI - Drugs that cause weight gain. AB - Among drugs which cause weight gain, the tricyclic antidepressant medications are a drug class producing persistent and problematic body weight gain in many treated patients. Major depressive illness is often associated with reductions in appetite and body weight, and treatment with antidepressants effectively restores mood, appetite and weight. However, a frequent complaint of patients treated with tricyclic drugs is of excessive and unwanted weight gain, often times resulting in medication noncompliance. The incidence of weight gain during acute and chronic treatment with different, frequently prescribed antidepressant drugs will be reviewed, as will the possible mechanisms by which such drugs alter caloric intake and expenditure, contributing to drug-induced weight gain. PMID- 8697042 TI - Molecular biology of serotonin receptors. AB - Over the last several years the use of molecular cloning technology has revealed a vast diversity among serotonin (5-HT) receptors, whereby what was previously thought to be a family of three pharmacologically defined classes of 5-HT receptors is actually composed of seven distinct subfamilies designated 5-HT1-7. The 5-HT1, 5-HT2, and 5-HT5 subfamilies currently consist of five, three and two subtypes respectively while the 5-HT3, 5-HT4, 5-HT6, and 5-HT7 "subfamilies" have at present one subtype each. Fourteen separate genes encode 13 receptors which fall in the superfamily of G protein-coupled receptors and one ligand-gated ion channel receptor. Our lab has contributed to the elucidation of this subtype diversity by cloning the cDNAs from both rat and human encoding the 5-HT2B receptor. This receptor subtype is equally homologous (approximately 70%) to the 5-HT2A and 5-HT2C receptors when amino acids comprising the transmembrane domains are compared and is clearly the third member of the 5-HT2 subfamily. The 5-HT2B receptor has been shown to couple to phosphoinositide hydrolysis as do the other two members of this subfamily when expressed in AV12-664 cells. Limited pharmacological analyses indicated that both rat and human 5-HT2B receptors are similar but distinguishable. With one tantalizing exception, the mRNAs for these receptors appear to be similarly distributed within rat and human. The 5-HT2B receptor mRNA is not found in rat brain, whereas in human brain it has been identified in multiple regions. This later finding suggests that the 5-HT2B receptor may be serving a unique CNS function in man that is absent in rat. PMID- 8697043 TI - Multiple serotonin receptors: opportunities for new treatments for obesity? AB - Recent progress in the molecular pharmacology of 5-HT receptors and the development of selective ligands for various 5-HT receptor subtypes has advanced our understanding of the role of 5-HT mechanisms in the control of food intake and bodyweight. The most intensively investigated 5-HT receptor subtypes have been the 5-HT1A receptor, the 5-HT1B receptor and the 5-HT2C receptor. The overall pattern of results to date suggests that selective 5-HT2C agonists may be novel anorectic drugs and prove useful in the treatment of obesity. However, a number of issues remain unresolved, particularly regarding potential side effects, as the 5-HT2C receptor agonist mCPP has been reported to induce anxiety and nausea in humans, actions that would clearly limit its therapeutic utility. In addition, the possible role of recently cloned 5-HT receptor subtypes such as 5-ht5, 5-ht6 and 5-ht7, remains unexplored and the development of selective ligands for these sites has the potential to lead to new treatments for obesity. PMID- 8697044 TI - Biological actions of drugs affecting serotonin and eating. AB - The present status of knowledge on drugs affecting food intake and presumably acting via a serotoninergic mechanism is reviewed. The mechanism of action of these drugs is analyzed at the neurochemical level. All the drugs, to various extents, inhibit the uptake of serotonin (5HT), increase the release of 5HT and decrease brain levels of 5HT and 5HIAA. However, the underlying mechanisms are not identical as exemplified by comparisons made with d-fenfluramine, d norfenfluramine, fluoxetine, sertraline and paroxetine. An analysis of the role of 5HT in the inhibition of food intake reveals that only d-fenfluramine is inhibited by antiserotonin agents. The role of the different 5HT receptor subtypes in this antagonism is discussed. More selective 5HT antagonists are needed to establish which 5HT receptor(s) controls food intake. PMID- 8697045 TI - Serotonin, eating behavior, and fat intake. AB - There is an intimate relationship between nutritional intake (eating) and serotonin activity. Experimental manipulations (mainly neuropharmacological) of serotonin influence the pattern of eating behavior, subjective feelings of appetite motivation, and the response to nutritional challenges. Similarly, nutritional manipulations (food restriction, dieting, or altered nutrient supply) change the sensitivity of the serotonin network. Traditionally, serotonin has been linked to the macronutrient carbohydrate via the intermediary step of plasma amino acid ratios. However, it has also been demonstrated that 5-HT drugs will reduce energy intake and reverse body weight gain in rats exposed to weight increasing high fat diets. 5-HT drugs can also reduce food intake and block weight gain of rats on a high fat cafeteria diet. Some diet selection studies in rats indicate that the most prominent reduction of macronutrient intake is for fat. These data indicate that 5-HT activity can bring about a reduction in fat consumption. In turn, different types of dietary fat can alter brain 5-HT activity. In human studies the methodology of food choice experiments has often precluded the detection of an effect of 5-HT manipulation on fat intake. However, there is evidence that in obese and lean subjects some 5-HT drugs can readily reduce the intake of high fat foods. Data also suggest that 5-HT activation can lead to a selective avoidance of fat in the diet. These effects of 5-HT on the intake of dietary fat may involve a pre-absorptive mechanism and there is evidence that 5-HT is linked to cholecystokinin and enterostatin. These proposals have theoretical and practical implications and suggest possible strategies to intensify or advance fat-induced satiety signals. PMID- 8697046 TI - Brain serotonin, carbohydrate-craving, obesity and depression. AB - Serotonin-releasing brain neurons are unique in that the amount of neurotransmitter they release is normally controlled by food intake: Carbohydrate consumption--acting via insulin secretion and the "plasma tryptophan ratio"- increases serotonin release; protein intake lacks this effect. This ability of neurons to couple neuronal signaling properties to food consumption is a link in the feedback mechanism that normally keeps carbohydrate and protein intakes more or less constant. However, serotonin release is also involved in such functions as sleep onset, pain sensitivity, blood pressure regulation, and control of the mood. Hence many patients learn to overeat carbohydrates (particularly snack foods, like potato chips or pastries, which are rich in carbohydrates and fats) to make themselves feel better. This tendency to use certain foods as though they were drugs is a frequent cause of weight gain, and can also be seen in patients who become fat when exposed to stress, or in women with premenstrual syndrome, or in patients with "winter depression," or in people who are attempting to give up smoking. (Nicotine, like dietary carbohydrates, increases brain serotonin secretion; nicotine withdrawal has the opposite effect.) It also occurs in patients with normal-weight bulimia. Dexfenfluramine constitutes a highly effective treatment for such patients. In addition to producing its general satiety-promoting effect, it specifically reduces their overconsumption of carbohydrate-rich (or carbohydrate-and fat-rich) foods. PMID- 8697047 TI - Efficacy and safety of long-term fluoxetine treatment of obesity--maximizing success. AB - Obesity is a major health care concern because of its associated medical complications and increased mortality. Despite a myriad of short-term weight loss strategies and the motivation of improving health, patients have difficulty maintaining reduced weight. Pharmacologic agents, such as fluoxetine, a selective serotonin uptake inhibitor, have been investigated as adjunctive therapy to standard weight management programs. Extended therapy with fluoxetine has demonstrated clinically meaningful benefits on weight loss and obesity-associated medical conditions in double-blind placebo-controlled studies. However, the magnitude of these benefits for individuals vary. Such findings are consistent with the belief that the obesity syndrome has differing etiologies. Accordingly not all patients are likely to benefit from a particular therapy. Studies should identify patient subgroups that are more likely to respond to a specific therapy. In this study of 719 fluoxetine-treated and 722 placebo treated patients in four multicenter, randomized, double-blind, long-term clinical trials, we investigated possible predictors of a beneficial long-term outcome from fluoxetine therapy. Patients' age, current smoking activity, and baseline uric acid concentration were predictors of a meaningful long-term treatment effect. Further review of the weight loss patterns of patients achieving long-term success provided the basis for a treatment monitor. Use of the predictors and the treatment monitor are strategies to maximize the benefits of therapy through improved patient selection and monitoring during a therapeutic program. PMID- 8697048 TI - Clinical studies with dexfenfluramine: from past to future. AB - d Fenfluramine (dF) (15 mg twice daily) has been studied in controlled trials in human obesity. It has been shown to increase adherence to weight lowering programs, to double the number of patients losing 10 kg or more when compared with a fairly efficient placebo plus dietary counselling, and to prevent weight regain when continued over a 1 year period. Weight loss after 1 month and 4 months is likely to predict subsequent outcome. Also, significant improvement in metabolic risk factors and blood pressure were clearly demonstrated, even more markedly in some obesity-associated diseases, when body weight is maintained at a lower level. Even moderate but sustained weight loss of some 10% of starting weight or less has been confirmed to be of medical value. Tolerance and safety of dF can be considered acceptable, even if longer term follow-up is clearly needed. These studies support the concept that long-term pharmacotherapy with this serotoninergic drug might help achieve better outcome in the management of many obese patients, particularly in preventing relapse. The long-term managerial strategies to be developed for each patient might thus include dF together with dietary advice, behavioral modification and physical exercise, either simultaneously or sequentially. PMID- 8697049 TI - Combined drug treatment of obesity. AB - Pharmacological treatment of obesity has been neglected as a viable therapeutic option for many years. Recent long term studies with combinations of obesity drugs gives promise that drugs may play a role in weight maintenance, which classically has been the most difficult aspect of treating obesity. Currently available obesity drugs include centrally acting adrenergic agents and serotonin agonists. Drugs still in development include a lipase inhibitor that produces fat malabsorption, a combined adrenergic-serotonergic reuptake inhibitor, various gut central nervous system peptides, and a number of beta-3 agonists. Any of these obesity drugs given alone produces modest weight loss, and for most, weight loss continues for as long as medication is given. The most successful drug regimens to date are combinations of phentermine and fenfluramine or of ephedrine, caffeine, and/or aspirin. The former combination produces reduction in body weight and complications of obesity for 2 to almost 4 years in clinical trials to date. More research is needed to document long term efficacy and particularly the long term safety of these and other combinations. PMID- 8697050 TI - Structure, function, and regulation of the three beta-adrenergic receptors. AB - Three beta-adrenergic receptor subtypes are now known to be functionally expressed in mammals. All three belong to the R7G family of receptors coupled to G-proteins, and characterized by an extracellular glycosylated N-terminal and an intracellular C-terminal region and seven transmembrane domains, linked by three extra- and three intracellular loops. The catecholamine ligand binding domain, studied using affinity-labeling and site-directed mutagenesis, is a pocket lined by residues belonging to the transmembrane domains. The region responsible for the interaction with the Gs protein which, when activated, stimulates adenylyl cyclase, is composed of residues belonging to the parts most proximal to the membrane of intracellular loop i3 and the C-terminal region. The pharmacology of the three subtypes is quite distinct: in fact most of the potent beta 1/beta 2 antagonists (the well known beta blockers) act as agonists on beta 3. The subtype is resistant to short-term desensitization mediated by phosphorylation through PKA or beta ARK, in stark contrast to the beta 1 or beta 2 subtypes. Various compounds (dexamethasone, butyrate, insulin) upregulate beta 1 or beta 2 subtypes while down-regulating beta 3 whose expression strictly correlates with differentiation of 3T3-F442A fibroblasts into adipocytes, thus confirming that the expression of the three subtypes may each be regulated independently to exert a specific physiologic role in different tissues or at different stages of development. PMID- 8697051 TI - Adrenergic receptors and fat cells: differential recruitment by physiological amines and homologous regulation. AB - The control of fat cell lipolysis by the catecholamines involves at least four different adrenoceptor subtypes; three beta (beta 1-, beta 2-, and beta 3-ARs) and one alpha 2-adrenoceptor (alpha 2-AR). The physiological importance of the beta- and alpha 2A-ARs varies according to the species, the sex, the age, the anatomical location of fat deposits and the degree of obesity in humans and animals. The physiological amines operate through differential recruitment of these sites on the basis of their relative affinities. This point has been assessed by in vitro studies and has partly been confirmed in in vivo experiments using selected alpha/beta-AR antagonists and in situ microdialysis. The affinity of the beta 3-AR for catecholamines is less than that of the classical beta 1- and beta 2-ARs in the various species investigated. Conversely, it is the alpha 2 AR which exhibit the highest affinity for the physiological amines in all fat cells. The relative order of affinity of the various fat cell ARs for the physiological amines defined in binding studies and in vitro assays is alpha 2 > beta 1 > or = beta 2 > beta 3 for norepinephrine and alpha 2 > beta 2 > beta 1 > beta 3 for epinephrine. When considering differential beta-AR recruitment by catecholamines, it is the beta 1-AR which is always activated at the lowest norepinephrine levels, whatever the species, while the activation of the beta 3 AR requires higher norepinephrine levels. In addition to the differential recruitment, differential regulation by hormones could also occur for each fat cell AR subtype. The alpha 2-and beta 3-ARs are less prone to desensitization and down-regulation by comparison with the beta 1- and beta 2-AR. PMID- 8697052 TI - Dopamine receptor subtype agonists and feeding behavior. AB - Stimulation or blockade of various dopamine receptor subtypes is associated with reduced feeding. For example, D2 receptor agonists suppress feeding in food deprived and free-feeding rats, and in rats given access to a highly palatable diet. Similarly, reduced food intake is associated with the actions of diverse D1 receptor agonists, and these compounds can interact synergistically with D2 receptor agonists to potentiate reductions in feeding. Using microstructural analysis to compare D1 and D2 agonist effects, specific differences emerge in their modes of action. D1 agonists reduce the duration of feeding, primarily by decreasing the frequency of feeding bouts, whereas D2 agonists reduce the local rate of eating. However, since D1 agonists uniquely reduce feeding in the absence of other behavioral impairments and are less disruptive of the pattern of feeding behavior, it has been suggested that D1 agonists are more likely than D2 agonists to act on central mechanisms regulating food intake. Moreover, only D1 agonists are effective in suppressing sucrose sham-feeding, suggesting that D1 receptor stimulation may promote satiety. Nevertheless, many questions remain. For example, antagonist studies have implicated 5-HT receptor stimulation in the anorectic effects of D1 agonists, suggesting that further pharmacological and behavioral analyses of receptor-subtype agonist effects are required. Above all, recent developments in the classification of dopamine receptor subtypes reveal the need for new studies examining the involvement of D3, D4 and D5 receptors in feeding. PMID- 8697053 TI - Chronic food deprivation decreases extracellular dopamine in the nucleus accumbens: implications for a possible neurochemical link between weight loss and drug abuse. AB - In rats reduced to 80% of normal body weight (n = 9), the basal levels of extracellular dopamine (DA) in the nucleus accumbens (NAC), as determined by microdialysis, decreased significantly to 33% (mean +/- SEM) of their normal baseline (p < 01). Basal extracellular DA did not change significantly over a matching 3-week period in controls (n = 7). No changes were observed in NAC serotonin after weight reduction. These results indicate that parts of the mesolimbic DA system are depressed in underweight rats. The observed decrease in basal DA may be responsible for a variety of behavioral changes observed in undernourished humans and animals including the tendency to eat and gain weight when food becomes available. Given that DA can be released in the NAC when rats self-inject drugs of abuse, the present findings may help explain why animals increase drug intake when they are underweight. PMID- 8697054 TI - Beta-agonists as antiobesity, antidiabetic and nutrient partitioning agents. AB - In the past decade, the antiobesity, antidiabetic and nutrient partitioning activities of beta-agonists have been extensively studied. The data generated from these compounds in experimental and farm animals have convincingly proved that body fat content and body weight can be modified to some degree by a metabolic agent without decreasing food consumption. Marginal antiobesity and antidiabetic activities in humans have been demonstrated with a few mixed beta agonists under certain conditions, but their utility is limited by side effects. The concept of a beta 3-receptor rose from the study of these compounds and has been verified by the cloning and expression of this receptor from several species. Rat beta 3-selective agonists have so far shown no antiobesity efficacy in humans. The resolution of several issues is critical for the discovery and development of efficacious antiobesity and antidiabetic agents with minimum side effects. Ultimately, the further investigation of these beta-agonists and beta receptors should lead to a better understanding of the relationship between energy metabolism and feeding behavior. PMID- 8697055 TI - Pharmacological and clinical studies of ephedrine and other thermogenic agonists. AB - When given as a supplement to an energy restricted diet the sympathomimetic agent ephedrine, in combination with methylxanthines such as caffeine, improves fat loss by dual actions: a central suppression of appetite and peripheral stimulation of energy expenditure covered by fat oxidation. Mean weight loss was found to be 16.6 kg after 6 months when E+C was given as an adjuvant to an efficient hypoenergetic diet, which was 3.4 kg higher than in the placebo group. An additional 24 weeks treatment with E+C prevented relapse. In the first weeks of treatment E+C offset the hypotensive effect of energy restriction and weight loss, but the effect was transient, and after 8 weeks blood pressures were indistinguishable from those of the placebo group. E+C has no adverse effect on glucose and lipid metabolism, but has been shown to prevent the decline in HDL cholesterol caused by weight loss. In a comparative trial the weight loss produced by E+C was similar to that of dexfenfluramine. More research on sympathomimetics and methylxanthines should be carried out to identify combinations with improved efficiency and safety. Moreover, more long-term trials and studies in males are required. PMID- 8697056 TI - Histamine receptor and its regulation of energy metabolism. AB - In a series of studies on brain functions of histamine, probes to manipulate activities of histaminergic neuronal systems were applied to assess histaminergic function in non-obese normal, and lean and obese Zucker rats. Food intake was suppressed by both activation of H1-receptors and inhibition of H3-receptors in the ventromedial hypothalamic nucleus (VMH) and the paraventricular nucleus, each of which is a satiety center. Feeding circadian rhythm was decreased in its amplitude through histaminergic modulation in the hypothalamus. Histamine neurons in the mesencephalic trigeminal nucleus (Me5) were involved in regulation of masticatory functions, particularly eating speed, while histamine-containing neurons in the VMH controlled intake volume of meals. Energy deficiency in the brain enhanced satiation through histaminergic activation of VMH neurons, which in turn produced glycogenolysis in the hypothalamus to maintain homoestatic control of glucose supply. A very-low-calorie conventional Japanese diet, which is a fiber rich and low energy food source, enhanced satiation by increased mastication and because of the low energy supply of the diet. Hypothalamic histamine neurons were activated by high ambient temperature and also by interleukin-1 beta, an endogenous pyrogen, to maintain homeostatic thermoregulation. Behavioral and metabolic abnormalities of Zucker obese rats were mediated by a deficit in hypothalamic neuronal histamine, and the Zucker rat was evaluated as an animal model of histamine deficiency. Transplantation of the lean fetal hypothalamus into the third cerebroventricle of host obese Zuckers attenuated the abnormalities. PMID- 8697057 TI - Clinical studies with mazindol. AB - An anoerxiant, mazindol suppresses food intake by 1) stimulating beta-adrenergic receptors, 2) inhibiting the feeding center and, 3) stimulating the satiety center in the hypothalamus. In Japan, mazindol is available for clinical use. We examined the effects of mazindol on 1) body weight, appetite, and abnormalities of obesity-related diseases in long-term use 2) maintenance of the reduced body weight after very-low-calorie diet (VLCD) therapy 3) combined use with VLCD therapy and, 4) inhibition of body weight gain in Prader-Willi syndrome. In long term effects of mazindol, the average reduction of individual body weight was around 6.8 kg. The appetite of 59% of obese subjects was moderately suppressed. Systolic blood pressure, serum GOT, serum triglyceride, serum cholesterol, and glucose tolerance were also improved. With mazindol, 53.3% of obese subjects kept the reduced body weight after VLCD, in contrast, 20.0% of them kept it without mazindol. Combined use of mazindol with VLCD made the VLCD therapy more effective in outpatients. Two of 3 patients with Prader-Willi syndrome inhibited their body weight gain with mazindol. Thus, mazindol produced positive effects in these studies, although the effects were limited. PMID- 8697058 TI - Sibutramine: a novel new agent for obesity treatment. AB - Sibutramine is a novel new pharmacologic agent which is a specific reuptake inhibitor for norepinephrine and serotonin. Preclinical data show that sibutramine and its two metabolites reduce food intake of animals eating either high or low carbohydrate diets and of obese Zucker rats. An 8-week clinical trial showed a dose-dependent decrease on body weight. Sibutramine, 5 and 20 mg/day, produced a dose-related weight loss in obese subjects compared to placebo in an 8 week trial. In doses varying from 1 to 30 mg, sibutramine also produced a dose dependent decrease in weight in the healthy obese population when used in 6-,8 ,12-24- and 52-week trials. Although the majority of the weight loss occurred during the first 12 weeks of treatment, weight loss had not plateaued in by 24 weeks in the higher doses. Side effects were mild. This drug shows promise as an antiobesity drug. PMID- 8697059 TI - Topical fat reduction. AB - The fat on women's thighs is more difficult to mobilize due to increased alpha-2 adrenergic receptor activity induced by estrogen. Lipolysis can be initiated through adipocyte receptor stimulation (beta adrenergic) or inhibition (adenosine or alpha-2 adrenergic) or by inhibition of phosphodiesterase. Since many women desire regional thigh fat loss, a series of clinical trials were initiated using one thigh as a double-blinded control. Trial #1: Five overweight women had injections of isoproterenol at intervals around the thigh three times a week for 4 weeks with diet and walking. Trial #2: Five overweight woman had ointment containing forskolin, yohimbine and aminophylline applied to the thigh five times a week for 4 weeks after hypertonic warm soaks with a diet and walking. Trial #3: Eighteen overweight women were divided into three groups of six and trial #2 was repeated with each agent alone vs. placebo using forskolin, yohimbine or aminophylline in separate ointments. Trial #4: Thirty overweight women had 10% aminophylline ointment applied to the thigh five times a week for 6 weeks with diet and walking. Chemistry panel, theophylline level and patch testing were performed. Trial #5: Twelve women had trial #4 repeated with 2% aminophylline cream without a diet or walking. Trial #6: Trial #5 was repeated with 0.5% aminophylline cream. All trials except yohimbine ointment gave significantly more girth loss from the treated thigh (p < 0.05 to p < 0.001). Chemistry panel showed no toxicity. Theophylline was undetectable and patch testing was negative. We conclude that topical fat reduction for women's thighs can be achieved without diet or exercise. PMID- 8697060 TI - Nutrient intake is modulated by peripheral peptide administration. AB - Many peptides have been shown to modulate nutrient intake. In most cases, these peptides decrease food intake, but in a few cases they have been demonstrated to stimulate feeding. Infusion of insulin peripherally will decrease food intake unless hypoglycemia occurs where the reduced glucose is a stimulus to feeding. Other pancreatic hormones including glucagon, amylin, pancreatic polypeptide, and enterostatin reduce food intake. Of the gastrointestinal hormones, cholecystokinin has been the most widely studied and reduces food intake in a number of species, including human beings. Gastrin-releasing peptide and its relative bombesin have been shown to decrease food intake in experimental animals and man. Somatostatin reduces food intake in experimental animals, but no clinical studies are available. Four pituitary peptides also modify food intake. Vasopressin decreases feeding. In contrast, injections of desacetyl melanocyte stimulating hormone (dMSH), growth hormone, and prolactin are associated with increased food intake. Finally, there are a group of miscellaneous peptides which modulate feeding. beta-casomorphin, a hepta peptide produced during the hydrolysis of casein, stimulates food intake in experimental animals. In contrast, the other peptides in this group including calcitonin, apolipoprotein A IV, the cyclized form of histidyl-proline, several cytokines, and thyrotropin releasing hormone decrease food intake. Many of these peptides act on gastrointestinal or hepatic receptors which relay messages to the brain via the afferent vagus nerve. As a group they provide a number of leads for potential drug development. PMID- 8697061 TI - Brain peptides and obesity: pharmacologic treatment. AB - Obesity results from an imbalance between nutrient ingestion and metabolism, with more calories being ingested than utilized. The brain plays an important role in coordinating these complex behavioral and physiological functions, operating through multiple neurochemical systems with distinct properties. This review focuses on two hypothalamic peptide systems, neuropeptide Y (NPY) and galanin (GAL), that illustrate how the brain operates through different mechanisms to control the body's nutrient stores, in different states or conditions. These peptides have different behavioral and physiological effects and are, themselves, differentially responsive to feedback signals from circulating steroids, peptides, and nutrients. They can be distinguished by their relation to natural feeding patterns and endogenous hormones and by their specificity of action in relation to natural biological rhythms. The neuroanatomical substrates involved in these actions of NPY and GAL are also distinct. The neurocircuit mediating NPY's actions originates in the arcuate nucleus and terminates in the medial portion of the paraventricular nucleus; the GAL-containing neurons, in contrast, are concentrated in the lateral portion of the paraventricular nucleus, in addition to the medial preoptic area, which contribute to local GAL innervation as well as projections to the median eminence. Regarding their distinct functions, the evidence suggests that the NPY system is more closely related to patterns of carbohydrate ingestion and carbohydrate utilization, channeling nutrients towards the synthesis of fat. It is most strongly activated at the start of the active feeding cycle or after weaning, in close association with the adrenal steroid, corticosterone. The GAL system, in contrast, is more closely associated with patterns of fat consumption and signals related to fat oxidation. This peptide system is most active during the middle of the feeding cycle or immediately after puberty, in close association with the gonadal steroids. The gene expression and synthesis of these peptides in their respective neuronal cell groups is inhibited by circulating insulin and altered by dietary nutrients. Disturbances in sensitivity to insulin and steroid feedback regulation in the brain are believed to be involved in producing abnormal patterns of peptide function that result in overeating and body weight gain. PMID- 8697062 TI - Insulin normalization as an approach to the pharmacological treatment of obesity. AB - Hyperinsulinemia and exaggerated insulin response to glucose are among the hallmarks of obesity. However, the role of hyperinsulinemia in the etiology and maintenance of obesity has been controversial. If hyperinsulinemia plays a critical role as proposed, then its reversal may have therapeutic potential. To test this hypothesis, the activity of Ro 23-7637, (4-(2,2-diphenylethenyl)-1-[1 oxo-9-(3-pyridinyl) nonyl]piperidine), which partially normalizes plasma insulin by an action on pancreatic islets from obese rats, was assessed. When islets were cultured for 2 days with 10 microM Ro 23-7637, a significant reduction in the exaggerated glucose-induced insulin secretion was observed. When islets from lean rats were exposed to Ro 23-7637, no reduction in insulin secretion was observed. The effects of oral administration of Ro 23-7637 were assessed in Zucker and diet induced obese rats in doses ranging from 5 to 90 mg/kg/day. Dose-related reductions were observed in: 1) glucose-induced insulin secretion; 2) basal insulin concentration; 3) daily food intake; and 4) bodyweight gain. In diet induced obese rats, selective mobilization of fat, maintenance of body protein, and decreased energetic efficiency were also observed. An association between the partial normalization of glucose-induced insulin responses and reductions of basal insulin, reduced rates of body weight gain or body weight loss and decreased food intake was observed in obese rats. Therefore, these studies indicate that Ro 23-7637 is an orally active, efficacious antiobesity agent. PMID- 8697063 TI - Effects of D-chiroinositol added to a meal on plasma glucose and insulin in hyperinsulinemic rhesus monkeys. AB - We have previously demonstrated that D-chiroinositol, administered intravenously to insulin-resistant monkeys, increases the rate of disappearance of plasma glucose and insulin. The purpose of the present study was to determine whether orally administered D-chiroinositol might also similarly improve the postprandial plasma glucose profile of hyperinsulinemic insulin-resistant monkeys. A complete liquid diet meal (15 ml/kg body weight) was ingested by each of six monkeys on two occasions separated by 10 days, with conditions identical except D chiroinositol (500 mg/kg body weight) was added to the second meal. At 110 minutes following each meal, the monkeys were anesthetized and blood samples obtained at 120, 150, 180, 210, 240, 270 and 300 minutes. Plasma glucose and insulin concentrations were determined. The mean plasma glucose concentration (120-300 minutes) was significantly lower after the meal containing D chiroinositol compared to the control meal (7.1 +/- 1.2 vs. 7.8 +/- 1.2 mM) (p < 0.05). Plasma insulin concentrations tended to be lower after the meal containing D-chiroinositol compared to the control meal (3930 +/- 1068 vs. 4518 +/- 1200 pM) (p < 0.15, ns). We conclude that in hyperinsulinemic monkeys, D-chiroinositol added to a meal lowers postprandial plasma glucose without an increase in plasma insulin, and therefore may be a useful agent for reducing meal-induced hyperglycemia without inducing hyperinsulinemia. PMID- 8697064 TI - Testosterone and regional fat distribution. AB - The effects of testosterone treatment of abdominally obese men have been assessed by evaluating the following parameters: The metabolic activity of different adipose tissue regions in vivo (using lipid label as a tracer) and in vitro (measuring lipoprotein lipase (LPL) activity), the total and visceral adipose tissue mass, insulin sensitivity, fasting blood glucose, blood lipids, and blood pressure as well as prostate volume. Middle-aged men with abdominal obesity were treated with transdermal administration of testosterone (T), dihydrotestosterone (DHT) or placebo (P) during 9 months. The study was double-blind. Treatment with T was followed by an inhibited uptake of lipid label in adipose tissue triglycerides, a decreased LPL-activity and an increased turn-over rate of lipid label in the abdominal adipose tissue region in comparisons with the DHT and P groups. These effects on adipose tissue metabolism were not detected in the femoral adipose tissue region in any of the groups. T treatment was also followed by a specific decrease of visceral fat mass (measured by CT-scan), by increased insulin sensitivity (measured with the euglycemic glucose clamp), by a decrease in fasting blood glucose, plasma cholesterol and triglycerides as well as a decrease in diastolic blood pressure. In the DHT group an increased visceral mass was detected. No other changes in these variables were found in the DHT and P groups. There were no detectable changes in prostate volume (measured by ultra sound), prostate specific antigen concentration, genito-urinary history or urinary flow measurements in any of the groups. It is suggested that T substitution to a selected group of men results in general metabolic and circulatory improvements. The prostate area needs further careful attention. PMID- 8697065 TI - Dehydroepiandrosterone and body fat. AB - Dehydroepiandrosterone sulfate (DHEA-S) is the most abundant circulating adrenal steroid in man, yet its physiologic role and that of its parent compound DHEA are unknown. Age-related decreases in DHEA in association with increases in obesity, insulin resistance, and atherosclerosis are well known. Recent investigations in lower mammals (which do not secrete DHEA) have suggested that DHEA (or its metabolites) may function as an antiobesity agent in these models of obesity independent of food intake. Proposed mechanisms for the decrease in fat mass and lower weight gain when DHEA is given orally include increases in futile cycling and peroxisomal beta-oxidation and decreases in de novo lipogenesis. Alterations in the availability of reducing equivalents for lipid synthesis do not appear to explain this decrease. Changes in pancreatic insulin secretion or insulin sensitivity may also be responsible for some of these effects. Studies in humans have failed to demonstrate a beneficial effect of DHEA on body composition or energy expenditure at either pharmacologic or physiologic replacement doses for 1 3 months. Administration of DHEA to men or women has also not been shown to alter insulin sensitivity as measured by the minimal model or the euglycemic clamp technique. The effect of DHEA on peroxisomal beta-oxidation and de novo lipogenesis is not known. We conclude that a significant role for DHEA in the pharmacologic treatment of human obesity is unlikely. PMID- 8697066 TI - AO-128, alpha-glucosidase inhibitor: antiobesity and antidiabetic actions in genetically obese-diabetic rats, Wistar fatty. AB - Antiobesity and antidiabetic actions of the alpha-glucosidase inhibitor AO-128 were examined using genetically obese-diabetic rats, Wistar fatty. Ten-week-old, male fatty rats were kept on CE-2 diet containing 10 or 25 ppm of AO-128 for 4 weeks. The average drug intake was calculated to be 0.74 or 1.78 mg/kg/day from the average food intake, respectively. The intestinal maltase and sucrase activities were decreased by AO-128 in a dose-related fashion. Food intake of fatty rats treated with AO-128 was decreased throughout the experiment. This decrease in food intake could hardly be explained only by diarrhea which occurred for the first 5 days of the administration of AO-128. AO-128 normalized hyperglycemia and markedly reduced hypertriglyceridemia and hyperinsulinemia in fatty rats. In addition, AO-128 decreased body weight gain, food efficiency, epididymal adipose tissue weight, carcass weight, and body fat deposition. These findings indicate that AO-128 may be useful for treating human obesity and diabetes. PMID- 8697067 TI - First clinical studies with orlistat: a short review. AB - Lipase inhibition, leading to decreased intestinal fat adsorption can be used in the treatment of obesity. Orlistat, a lipase inhibitor, in a dose of 50 mg three times a day leads to a significant increase in weight loss compared to placebo in moderately obese people. These results are confirmed in a multiple-dose study using 10 mg, 60 mg and 120 mg Orlistat three times a day vs. placebo. The use of lipase inhibition has no significant influence on fasting levels of several hormonal systems, including thyroid hormones, catecholamines and IGF-I. The same is true for the responses of several gastrointestinal and pancreatic hormones after a liquid high-fat mixed meal. In general, Orlistat is tolerated very well, although a higher occurrence of gastrointestinal side effects is seen. PMID- 8697068 TI - [Molecular biology and biochemical study of hyperlipemia and atherosclerosis]. PMID- 8697069 TI - [The relationship between 4-hydroxynonenal-derived epitopes on apolipoprotein B and coronary heart disease]. AB - When lipid peroxidation takes place in plasma low density lipoprotein (LDL), a lot of aldehydes-derived epitopes are generated. To explore the relationship between these aldehydes-derived epitopes on apolipoprotein B (apo B) and coronary heart disease (CHD), we used both antibody against 4-hydroxynonenal (HNE)-derived epitopes and antibody against apo B to establish a sandwich enzyme-linked immunoassay (ELISA). The sera from 160 normal controls as well as from 103 patients with CHD were tested by ELISA for the expression of HNE-derived epitopes on apo B. The measurements showed that the mean expression of HNE-epitopes in the patients with CHD (183.5 +/- 63.6 mg/L, n = 103) was higher than that of normal controls (133.3 +/- 47.5 mg/L, n = 160). The difference of the expression of HNE epitopes on serum apo B between the patients and normal controls was statistically significant. The results analysed by a multiple regression demonstrated that the expression of HNE-epitopes, levels of LDL-cholesterol and age were positively related to CHD, while the levels of HDL-cholesterol and female were negatively related to CHD. Thus, it was proven for the first time that the enhanced expression of HNE-epitopes on apo B might be an independent risk factor of CHD. PMID- 8697070 TI - [DNA polymorphisms of the apolipoprotein AI-CIII-AIV gene cluster in coronary artery disease]. AB - Two polymorphic sites of the apolipoprotein AI (ApoAI) gene, PstI and SstI, were examined in a sample of 43 unrelated Chinese patients with coronary artery disease (CAD) and 60 unrelated healthy individuals. Allele frequencies were compared between patients and controls and their impact on lipid and oxygen free radicals metabolism were also studied. The frequencies of the uncommon P2 and S2 alleles in CAD cases were found as 0.14 and 0.22 respectively, which were significantly higher than 0.05 and 0.13 in controls. The more the number of vessel disease in CAD cases, the higher the frequencies of S2 alleles which were the highest in the group of 3 vessel diseases. Some serum lipid and oxygen free radicals levels differed between CAD cases of different genotypes. These data suggest that genetic variation in P2 and S2 alleles of APOAI gene may contribute to the development and extent of CAD in Chinese subjects. PMID- 8697071 TI - [Apolipoprotein (a) polymorphism in relation to coronary heart disease in Chinese Han nationality]. AB - We investigated the association of apolipoprotein (a) [apo(a)]polymorphism with coronary heart disease in Chinese Han nationality. The effects of the apo(a) phenotypes on lipoprotein [Lp (a)], total cholesterol (TC), high density lipoprotein cholesterol (HDL), and triglyceride (TG) levels were also investigated. The CHD group consisted of 105 patients (85 were survivors from previous myocardial infarction and 20 had > or = 75% narrowing in at least one of the major coronary arteries found by coronary angiography). The control group included 102 healthy individuals who had no symptoms and clinical signs of cardiovascular diseases. Apo(a) phenotype was performed by SDS-polyacrylamide gel electrophoresis (PAGE) under reducing conditions followed by immunoblotting. Determination of (a) Lp(a) and other lipoproteins were also performed. The apo(a) low molecular weight phenotypes (B, S1, S2) were more frequent in the CHD patients than in the healthy individuals (30.5% vs 15.7%, P < 0.05). Lp(a) concentrations were significantly higher in the patients than in the controls (257 +/- 225 mg/L vs 145 +/- 157 mg/L, P < 0.001). The results from stepwise logistic regression analysis indicated that apo(a) phenotype was a significant predictor of CHD, independent of TC, LDL-C and HDL-C. But apo(a) molecular weight was inversely related to Lp(a) levels. The apo(a) low molecular weight phenotypes associated with elevated Lp(a) levels was a primary genetic risk factor for CHD in Han Chinese. PMID- 8697073 TI - [The mechanism for splenic promoting effects on liver cirrhosis]. AB - The model of liver cirrhosis was induced by CCl4 and alcohol in rats, which were subjected to splenectomy or given Tuftsin. The isolated and purified liver parenchymal, Kupffer and Ito cells were cultured with CCl4 and splenic conditional fluid or Tuftsin. The RNA isolated from the liver tissues of cirrhosis animals were hybridized with five kinds of cDNA probes. In this study we explored the mechanism of spleen's promoting effects on the liver cirrhosis formation at the whole body, cellular and molecular levels. The result showed that in cirrhosis model, the levels of IL1, IL6 and TNF alpha in serum of rats in imitative splenectomy or Tuftsin group were significantly increased compared to those in splenectomy group (P < 0.05). Cell culture showed that if medium contained CCl4 and splenic conditional fluid or Tuftsin, its cells can secrete more fibronectin, laminin and collagen I than those cultured in medium only contained CCl4 (P < 0.05). Slot blot hybridization showed that the RNA isolated from liver of rats in imitative splenectomy or Tuftsin group hybridized with probes of TNF alpha, IL1 beta, TGF beta and Collagen I had a more high density picture of X-ray than that isolated from liver of rats in the splenectomy group. Should be it a complex process for spleen to promote liver cirrhosis formation, in which the TGF beta gene expression enhancement may be the key of splenic effects on liver fibrosis. PMID- 8697072 TI - [Detection of human cytomegalovirus DNA in vascular plaques of atherosclerosis by in situ hybridization]. AB - To examine the possible role of HCMV in the etiology of atherosclerosis, we searched for the presence of HCMV DNA in arterial vascular tissues by in situ hybridization. Biotin labelled HCMV DNA probe was used on specimens of arterial wall taken from patients with clinically significant atherosclerosis. Evidence for the presence of HCMV DNA was obtained in 13 specimens out of 32 atherosclerosis specimens. In contrast, only 1 specimen was positive in the control group (Total 15 specimens of normal arterial and venous wall), suggesting that there is a close relationship between human cytomegalovirus infection and atherosclerosis development. The results also showed that the positive hybridization signals were mainly observed in the nuclei of smooth muscular cells, rarely found in outer layer of arterial walls, cell membrane and cytoplasm. It was indicating that HCMV infection might be an etiological agent in the development of atherosclerosis. PMID- 8697074 TI - [Gene diagnosis and carrier detection of hemophilia B by using genomic amplification with transcripts sequencing]. AB - Using GAWTS technique (genomic amplification with transcripts sequencing), we studied germline mutation patterns of 36 hemophilia B patients from the mainland of China. Some distinctions between Chinese and USA caucasians were found. The GAWTS was strongly recommanded to be used in the direct genomic sequencing as a good technique. Seventeen carriers were identified. PMID- 8697075 TI - [Antitumor effect of interleukin-2 gene-transfected tumor vaccine in combination with interleukin-6 gene-transfected tumor vaccine]. AB - It has been shown that IL-2 and IL-6 can cooperate to induce immune responses more effectively. In order to increase the therapeutic efficacy of cytokine gene transfected tumor vaccines, we treated the experimental pulmonary metastatic melanoma-bearing mice with IL-2 gene-transfected tumor vaccine and IL-6 gene transfected tumor vaccine. After the combined treatment, the pulmonary metastases were reduced more significantly and the survival time of tumor-bearing mice was also prolonged more significantly. The CTL activity, NK activity and IL-2-induced LAK activity, IL-2 and TNF secretion from the splenocytes of the above tumor bearing mice increased more significantly than that of tumor-bearing mice treated with IL-2 gene-transfected vaccine or IL-6 gene-transfected vaccine alone. These results demonstrated that the combined use of IL-2 gene-transfected tumor vaccine and IL-6 gene-transfected tumor vaccine could achieve more potent antitumor effect via more efficient activation of immune functions. The experiment outlines a novel approach to the cytokine gene therapy of cancer. PMID- 8697076 TI - [cDNA clones of differential expression between human normal liver tissue and hepatocarcinoma]. AB - Using mRNA differential display technique, we studied the interesting cDNA clones of differential expression between human normal liver and hepatocarcinoma. mRNA extracted from normal liver tissue and hepatocarcinoma cell line Hep3B were subjected to RT-PCR reaction with ten combinations of two 3' primers and five 5' primers. After subjecting these PCR products to labelling with 35S(a)-dATP, PAGE and autoradiography, we obtained a lot of cDNA clones of differential expression. Thirty-one of these clones were partially sequenced. It was shown that 30 clones had no sequences matched with GenBank except one. Dot hybridization showed that 2 cDNA clones were overexpressed in liver cancer tissue and 1 cDNA clone was overexpressed in normal liver tissue. The further characterization of these cDNA clones is in progress. PMID- 8697077 TI - [Cultured human retinal pigment epithelial cell produced and secreted epidermal growth factor: its bioactivity and clinical significance]. AB - The epidermal growth factor bioactivity from cultured primary human and monkey retinal pigment epithelial (RPE) cell systems was detected by using the radioreceptor assay. We report that the cultured human and monkey RPE cells produce and secrete the EGF bioactively to the media as demonstrated by radioreceptor binding assay. The EGF bioactivities secreted by human and monkey RPE cells were at peak of 48 hours (human RPE cells secreted 2.11 +/- 0.46 ng/ml vs monkey RPE was 1.56 +/- 0.12 ng/ml) in the serum-free media. The results indicate that the RPE is one of important sources for EGF in the eye. The RPE cells may play much important roles in the development of proliferative retinal diseases through the autocrine or paracrine mechanism. This new discovery will be helpful to elucidate the pathogenesis of proliferative retinal diseases and also provide an important basis for the treatment of such diseases. PMID- 8697078 TI - [The infection of hepatitis D virus in adult tupaia]. AB - A new animal model of HDV/HBV infection in adult tupaia (tree shrews) was established to study its pathogenesis and treatment of hepatitis D. In 20 artificially fed adult tupaiae, the positive rate of serum HBsAg was 75% (15/20) after inoculation of human HBV DNA positive serum. After inoculation with positive human serum HBV DNA and positive HDV RNA by way of coinfection and superinfection, serum HBsAg, HDAg and anti-HD were positive one after another in 8 out of 13 tupaiae of the coinfection group and in 6 out of 9 tupaiae of the superinfection group. In some of them HDV RNA was positive in serum or in liver tissue. Transmission of HDV/HBV infection among tupaiae was successful. In group I, animals were inoculated with human HDV/HBV positive serum. In Group II and III, animals were inoculated with tupaia HDV/HBV positive serum of the Group I and II respectively. Serum HBsAg, HDAg and anti-HD became positive one after another in 3 out of 4 tupaiae of the Group II and 4 out 5 tupaiae of the group III. In 2 animals of the Group III, serum HDV RNA was positive and HBsAg and HDAg were detected in the liver tissue. Serum HBsAg was persistantly positive for 16 19 months in the superinfection group. In 2 of them, serum HDAg and anti-HD were alternatively positive and in one of them serum anti-HD was positive persistantly indicating that HDV infection may persist and transform into chronic HDV infection. In the HDV infected tupaiae, there were elevated serum ALT and hepatitis-like pathological changes in the liver tissue which were similar to those in the chimpanzee. We conclude that tupaia may be used as an experimental model of hepatitis D. PMID- 8697079 TI - [Preparation and characterization of liposomal adriamycin]. AB - We established a more suitable methodology for preparing liposomal adriamycin (Lipo-ADM) by a remote loading technique. This procedure is convenient, simple with an entrapment efficiency of 95%. The mean diameter of liposome is about 100nm showing unilamellar spherical shape. The leakage ratio is about 10% within 24hr. Those characteristics fit for clinical demand. PMID- 8697080 TI - [Survival rates in patients with systemic lupus erythematosus]. AB - To assess the impact of demographic and clinical factors on prognosis in patients with systemic lupus erythematosus (SLE), we examined the survival rate by lifetable analysis in 566 patients. All patients were Shanghai citizens who were diagnosed as having SLE in Huashan Hospital between 1959 and 1992. According to American Rheumatism Association's preliminary criteria. The survival rate from the time of SLE onset was 93% at 1 year, 73% at 5 years and 60% at 10 years. On univariate analysis, we found that the following factors worsened the probability of survival; male, neuropsychiatric manifestation, pleurisy-pericarditis, anemia, thrombocytopenia, lymphocytopenia, proteinuria, hematuria, urinary cast, azotemia, decreased endogenous creatinine clearance, increased cholesterol in serum, hypocomplementemia, abnormal electrocardiograph and high corticosteroid dose of treatment. On multivariate analysis, we found the four independent risk factors were male, azotemia, hypocomplementemia and high corticosteroid dose of treatment. PMID- 8697082 TI - [The application of hepatic surgery to bile duct diseases]. PMID- 8697081 TI - [Heredity and medicine]. PMID- 8697083 TI - [The relationship between serum lipids, apolipoproteins level and bile lipids level, chemical type of stone]. AB - To pick up serum high risk lithogenic factors predisposing one to gallstone formation and protective factors against gallstone formation in gallbladder. We compared serum lipid and apolipoprotein level of patients with gallbladder stone (stone group) with that of patients without gallbladder stone (control group). The correlation between serum lipid, apolipoprotein level and bile lipid level, cholesterol saturated index (CSI), characteristics of lipidemia in different kinds of gallbladder stones were studied. The results showed that the increase of serum Apo A1, C2 and E level in the stone group was more significant than in the control group. But there was no statistical significance in TC, TG, LDL-C, HDL-C, Apo A2, B, C3 level between the stone and control groups. These results suggested that serum apolipoproteins perhaps are more sensitive parameters than serum lipids in distinguishing patients with stones from those without stones. There were different profiles of serum lipid and apolipoproteins in different chemical types of gallbladder stones. Increased level in serum LDL-C, Apo B and ratio of LDL-C/HDL-C were characterized by an index for cholesterol stone, otherwise that in serum TG and Apo C2 an index for pigment stones. There was a positive correlation between serum total cholesterol (TC) or Apo B, C2, C3 and cholesterol amount or CSI in gallbladder bile. Therefore, TC, Apo B, C2, C3 could be considered as high risk lithogenic factors. A positive correlation existed between serum HDL-C and lecithin in gallbladder or common bile duct (CBD) bile as well as between HDL-C and bile acids in CBD bile. Thus, HDL-C might be a protective factor against gallstone formation in gallbladder. PMID- 8697084 TI - [Role of type IV collagenase in tumor cell invasion and effect of laminin on invasive potential in bile duct carcinoma]. AB - In the present experiment, the secretion of type IV collagenase, the invasive potential of tumor cell in vitro, and the effects of exogenous laminiu and anti laminin antibody on the invasive potential of tumor cells in a newly established cell line of bile duct carcinoma, QBC939, were observed by using an amnion invasion culture system and a substrate capture immunoassay. The biological mechanism of tumor invasion, especially the role of the type IV collagenase in the invasive process, was discussed. QBC939 cells secreted type IV collagenase with high invasive potential. Different doses of laminin (1 micrograms, 5 microgram, 10 microgram/ml) stimulated the release of type IV collagenase and increased the invasive potential of the tumor cells in varying degrees. The effect of laminin could be antagonized by the anti-laminin antibody. The results demonstrate that the type IV collagenase is one of the important enzymes involved in the tumor invasion. The effects of laminin on the release of type IV collagenase and the invasive potential suggest that laminin play an important role in mediation of tumor invasion. The results also suggest that inhibiting type IV collagenase or blocking the effect of laminin on tumor cells may be a prospective therapy for tumor treatment in future. PMID- 8697085 TI - [Morphological transformation of BHK-21 cells by nickel titanium shape memory alloy particles encapsulated by titanium oxide]. AB - The special treatment process formed a compact titanium oxide thin film on the surface of medical nickel titanium shape memory alloy (NiTiSMA) particles (< or = 5 microns). The BHK-21 cells were cultivated in 10% infant calf serum containing NiTiSMA particles and NiTiSMA particles encapsulated by titanium oxide respectively, and morphological transformation clones were observed. The results showed that NiTiSMA particles induced obviously morphological transformation clones, and that NiTiSMA particles induced obviously morphorogical transformation of BHK-21 cells (the rate of morphological transformation clones was 13.46%), especially in TPA medium. The rate of morphological transformation in the group containing NiTiSMA particles was not more significantly different than that in the positive control group. The rate of morphological transformation in the group containing NiTiSMA particles encapsulated by titanium oxide was not more significantly different than that in the negative control group, but significantly different than that in the NiTiSMA particles group. Therefore, it is possible that NiTiSMA particles are directly carcinogenic and that NiTiSMA particles encapsulated by titanium oxide are not potentially carcinogenic. PMID- 8697086 TI - [The interstitial response and postoperation recurrent mechanism in liver cancer]. AB - Immunoactive cell group markers and glycoproteins of extracellular matrix and basement membrane (fibronectin, laminin, type IV collage) in 156 human hepatocellular carcinomas and their surrounding tissues were localized with immunoperoxidase technique. T lymphocytes were the major immunoactive cells in the regions of local invasion in liver cancer. The distributing patterns of the glycoproteins were similar to the results of previous reports, mainly localized in the surrounding cancer cells, interstitium and vessel walls or sinusoids in tumor, and tumor capsule. The patients, whose hepatocarcinomas showed stronger cell immunoactivity (T and help T cells were in the majority) and higher expression of glycoproteins of extracellular matrix and basement membrane had a longer tumor-free survival (63.2 to 12.8 months) and lower recurrences (P < 0.01). Of the 156 patients 92.9%, 82.6%, 65.4%, 44.2% and 30.8% and 1, 2, 3, 4 and 5 postoperative tumor-free years respectively with a total currence rate of 53.2% (83 patients). In the 83 recurrences, 65 were intrahepatic subclinical, which were promptly reresected 78.3%, recurrence related factors included tumor number and size, capsule infiltration, and portal veins involvement. Being different from those with single node, capsulated hepatocellular carcinomas and multiple/daughter ones had invisible tumor cells disseminated to the remnant liver. Those without capsule infiltration had a low recurrence rate, which agrees to the hypothesis that capsules can bar the dissemination of tumor cells. Additional results show that postoperative tumor recurrence is mainly pertinent to histopathological characteristics of the primary focus. According to the phenomenon that nearly 63.1% of recurrent liver carcinomas are located at the ipsilateral segment of the primary ones, we emphasize that the occurrence and recurrence of liver carcinoma are mainly unicentral. PMID- 8697087 TI - [Detections of hepatitis C virus RNA and NS3 antigen and their relation to liver histopathology]. AB - To detect the distribution of hepatitis C virus and investigate the pathogenesis mechanisms of the viral infection in the liver tissues of the patients with acute or chronic hepatitis C, we examined HCV antigen expression by using the murine monoclonal antibody against HCV C33c peptide in the paraffin-embedded liver tissues from 28 patients with acute or chronic hepatitis C. The NS3 antigen was detected in 85.7% (24/28) of all the biopsy specimens. The distribution and staining density of the antigen immunoreactive signal varied according to different types of patients and the regions in the liver sections, but they obviously had a topographical relationship with the inflammatory-necrosis areas such as fatty and ballooning degeneration and focal necrosis in the liver tissues of nearly all the patients. In addition, the localization of HCV RNA investigated by in situ hybridization assay in 20 liver tissues the above 28 biopsy HD in the Chinese. They also provide valuable data for HD molecular diagnosis, genetic counselling and genetic health. PMID- 8697088 TI - [Growth pattern and metastatic behaviour of orthotopically metastatic model of human hepatocellular carcinoma in nude mice]. AB - Growth pattern, metastatic behaviour and serial alph-a-fetoprotein (AFP) level of highly metastatic model of human hepatocellular carcinoma in nude mice (LCI-D20), which constructed by using orthotopic implantation of histologically intact patient specimens, were studied by implanting into the liver, subcutis and peritoneum of nude mice. Pathologic (by light and electronmicroscopic examination) and biologic (chromosome karyotype and DNA contents by flow cytometry) characteristics of LCI-D20 were also observed. The results showed that transplantability of LCI-D20 was 100% in 12 generations (passage time: 20 days) and all of these mice implanted tumors died within 40 days after transplantation due to serious metastasis. After LCI-D20 implanted into the liver of nude mice, growing implant-tumors in progress were negatively related to their double time during animal survival. LCI-D20 maintained 100% (70/70) metastatic rate in nude mice that showed early intrahepatic metastasis and late lymphatic and pulmonary metastasis. The high metastatic potentials of LCI-D20 tumor cells were kept in subcutis and peritoneum (70%, 100% respectively). The increase of the serial AFP secreting from the tumor cells was correlated with the implantation tumor growth rate (797.5 micrograms/L/5th week). The data from histological and electronmicroscopic findings, chromosome karyotype and DNA content analysis of the tumor cells revealed characteristics of human hepatocellular carcinoma. The results indicated that LCI-D20 exhibited the variety of clinical behaviours seen in hepatoma patients and it could be a useful model for investigating the metastasis mechanism of human hepatoma and anti-metastasis therapy. PMID- 8697089 TI - [Reversing effect of dimethyl-4,4'-dimethoxy-5,6,5'6'-dimethylenedioxybiphenyl 2,2'- dicarboxylate(DDB) on the phenotypes of human hepatocarcinoma cell line]. AB - When human Bel-7402 hepatocarcinoma cell line grew in a medium containing 10(-4)M DDB, the secretion of alpha-fetoprotein (AFP) and the activity of gamma-glutamyl transpeptidase (gamma-GT) were significantly lower than the control cells, whereas the albumin (ALB) secretion and the activity of tyrosine-alpha ketoglutarate transaminase (TAT) were markedly increased. DDB at the concentration of 10(-4)M could significantly increase the content of cAMP in Bel 7402 cells, and also suppressed the expressions of oncogene c-myc and hepatocarcinoma marker AFP gene and enhanced the anti-oncogene p53 expression. The results of this paper suggest that DDB has some reversing effects on the phenotypes of human Bel-7402 hepatocarcinoma cell line. PMID- 8697090 TI - [Multiple gene alterations involved in the processor of human gastric carcinogenesis]. AB - The investigation of molecular evidence of gastric carcinoma will be contributable to the prevention, gene diagnosis and therapy of human gastric neoplasms. To determine the specific genetic change in human gastric cancer (HGC) and precancerous lesions, we analysized FISH, PCR/SSCP, IHC and DNA sequencing by using multiple probes to detect the gene abnormalities (mutation, deletion, amplification or overexpression of genes) of 67 fresh tumors, 63 endoscopic biopsies including 30 dysplasia (DYS) and 33 intestinal metaplasia (IM, and 4 tumor cell lines from HGC patients. Multiple genetic abnormalities including hypomethylation of H-ras gene, amplification and overexpression of met and erbB2, deletion of APC, mts1/p16, p53 and nm23 gene and point mutation of p53 gene were noted in HGC and precancerous lesion of human gastric mucosa. Among these changes, p53 gene was the highest frequence genetic alteration in 39/67 (54-58%) of gastric carcinoma. These results indicate that overexpression of met and H-ras occurs at early stage in progression of neoplasia, amplification of met, erbB2 and akt2 gene occurs at progressing stage of tumorigenesis, deletion of p53, APC, mts1/p16 and nm23 occurs at advanced stage in the progression of cancer. The abnormalities should be associated with malignant phenotypes: poor differentiation, vascular invasion, lymph nodes metastasis, and low survival time. We detected p53 gene mutation in both cancer and precancerous lesions of IM and DYS. These results suggest that p53 may be a susceptible gene and alteration of p53 gene plays an important role in the development of HGC. PMID- 8697091 TI - [Induction of differentiation by all-trans-retinoic acid in a human lung adenocarcinoma cell line]. AB - All-trans-retinoic acid (RA) is a powerful differentiation-inducing reagent. We examined the effect of RA on malignant phenotype of human lung adenocarcinoma cell line GLC-82 in vitro. Treatment of GLC-82 cell with 10(-5)mol/L. RA for 1-7 days resulted in suppression of cell proliferation (33-55%), inhibition of colony formation in soft agar (97.5%), and a decrease of 3H-TdR incorporation (30-60%). Cytokinetic studies demonstrated that the cells arrested in G1/G0 phase increased from 36.0% to 72.4%, which is typical for cell differentiation. Human endothelial cell transglytaminase (TGase) was expressed persistently during RA treatment. Treatment of GLC-82 cell with RA gave rise to senescence and apoptosis gradually. The results indicated that induction of differentiation and modulation of gene expression can be achieved by RA treatment in human lung adenocarcinoma cell line GLC-82. PMID- 8697092 TI - [Expression of MDM2 gene in acute leukemia]. AB - In order to study expression of MDM2 gene, antagonist of tumor suppressor gene p53 in acute leukemia, forty acute leukemia patients were tested using RT-PCT to evaluate expression level of MDM2 gene. Over-expression of MDM2 gene was found in 52.5% patients (21/40). No significant relations were found between the level of MDM2 gene expression and FAB subtypes of acute leukemia. It is suggested that the over-expression of MDM2 gene may play a role in acute leukemia. PMID- 8697093 TI - [Molecular diagnosis of Huntington's disease: an analysis of two large families]. AB - At present molecular techniques comprise a main resource in the early accurate diagnosis for Huntington's disease. We describe the molecular diagnosis for 8 HD patients and 39 risky family members in two large HD pedigrees by using G8 RFLP linkage analysis as well as direct detection of the expanded (CAG) repeat in IT15 gene with the nested PCR denaturing polyacrylamide gel electrophoretic autoradiography and direct DNA sequencing. The results showed that the normal IT15 alleles contained 13 to 26 CAG repeat but major in 16, while all the HD alleles had over 40 copies of (CAG)n. There was no overlap between the normal and affected alleles. The presymptomatic diagnosis of 39 family members at risk for HD disclosed that 11 subjects carried the affected alleles. All these results indicated that the unstable mutations in IT15 gene were responsible for HD in the Chinese. They also provide valuable data for HD molecular diagnosis, genetic counselling and genetic health. PMID- 8697094 TI - [Effect of erythroid enhancer on the expression of beta-globin gene in mice erythroleukemia (MEL) cells]. AB - Our previous works have verified that the beta-globin gene carrying large fragments of erythroid enhancer transferred by retrovirus vector caused the unstable provirus integration and low virus titer in infected cells, but the 36bp enhancer had not this negative effect. In order to circumvent this problem, we inserted the intact beta-globin gene (beta) or partially IVS II deleted beta globin gene (delta beta) and truncated erythroid enhancer (36bp, 292bp and 341bp) into the N2A retrovirus vector. Recombinants were transfected into psi-2 ecotropic pachaging cells first, then the produced virus were used to infect PA317 amphotropic packaging cells. Virus supernatent from PA317 clonies with high virus titer and intact provirus integration was used to infect MEL cells. RNase protection assay was used to detect the expression of beta-globin gene. Results showed that not only the stable provirus integration and high virus titer of the transferred genes, but also the high levels expression of beta-globin gene carrying 292bp or 341bp erythroid enhancer were got. PMID- 8697095 TI - IGF-I: a mitogen also involved in differentiation processes in mammalian cells. AB - The main source of insulin-like growth factor I (IGF-I) postnatally is the liver, under growth hormone stimulation, although IGF-I is already present in embryonic tissues and in fetal serum, when its expression is independent of growth hormone. The extracellular alpha-subunit of the IGF-I receptor (IGF-IR) contains an IGF-I binding domain, and the beta-subunit possesses tyrosine kinase activity, which is greatly enhanced when IGF-I binds to the alpha-subunit and leads to its autophosphorylation. Insulin receptor substrate 1 (IRS-1) is the most well characterized cellular substrate for IGF-I, containing at least 20 potential tyrosine phosphorylation sites. The tyrosine phosphorylated form of IRS-1 acts as a docking protein by associating SH2-containing proteins including the p85 regulatory subunit of phosphatidylinositol-3-kinase (P13-kinase), the protein tyrosine phosphatase SH-PTP2, the SH2- and SH3-containing adaptor protein Nck and the growth factor receptor-bound protein-2 (Grb2/Sem5) protein. Grb2 is found associated with mSOS, a GTP/GDP exchange factor involved in converting the inactive Ras-GDP to the active Ras-GTP. The p85 regulatory subunit of PI3-kinase can be also a direct in vitro substrate of the IGF-IR. Although IRS-1 is the major substrate of the IGF-IR, there is another early phosphotyrosine substrate termed SHC, which also activates Ras via Grb2-mSos complex. Activation of p21-Ras induces a serine/threonine kinase cascade leading to the activation of MAP kinases. The importance of IGF-I as a mitogen throughout development has been clearly demonstrated in IGF-I and IGF-IR knockout mouse studies and also in transgenic mice over-expressing IGF-I. IGF-I is a mitogen in many cell types in culture such as T lymphocytes, chondrocytes or osteoblasts and it is considered to be a progression factor in mouse fibroblasts. IGF-I is also involved in muscle, neurons and adipogenic differentiation of mesenchymal cells. However, IGF I induces proliferation and differentiation in fetal brown adipocytes, suggesting that both cellular processes are not necessarily mutually exclusive in fetal cells. PMID- 8697096 TI - The effect of endotoxin on skeletal muscle protein gene expression in the rat. AB - Sepsis is associated with net breakdown of skeletal muscle protein, mediated partly by reduced rates of muscle protein synthesis. This study investigated the role of altered gene expression for specific muscle proteins in mediating reduced protein synthesis in a rat model of acute severe sepsis. Adult rats were given a single sublethal intraperitoneal dose of endotoxin (bacterial lipopolysaccharide). Protein, RNA and DNA contents of muscle were measured and changes in expression of mRNA in tibialis anterior and extensor digitorum longus muscles were detected by quantification of Northern blots at 6, 24, 48 and 72 hr after endotoxin and in animals starved for 24 hr. Results showed that at 24 hr after endotoxin there was a loss of about 14% of muscle protein content. No reduction in mRNA was found at any time point for beta-myosin heavy chain (MHC), fast-MHC, alpha-actin, skeletal muscle troponin or carbonic anhydrase III (CA III); rather, at 48 hr there was increased expression of beta-MHC (224 +/- 123% control) and CA III (202 +/- 56%). Blocking TNF-alpha by pre-treatment with a monoclonal antibody did not appear to influence this. Total RNA content of muscle was reduced to 67% of the control values 24 hr after LPS, although this was no different to pair-fed animals starved for 24 hr. It is concluded that reduced protein synthesis in skeletal muscle in early acute sepsis is not primarily associated with reduced muscle protein gene expression. PMID- 8697097 TI - Ostrich (Struthio camelus) carboxypeptidase B: purification, kinetic properties and characterization of the pancreatic enzyme. AB - Carboxypeptidase B has been isolated from numerous mammalian and invertebrate species. In contrast, very little is known about carboxypeptidases of avian origin. To provide information for a comparative study, we have undertaken an investigation of the kinetic and physical properties of ostrich carboxypeptidase B. Carboxypeptidase B from the pancreas of the ostrich was purified by water extraction of acetone powder and aminobenzylsuccinic acid affinity and hydroxylapatite chromatography. The effects of pH and temperature on CPB activity were examined. K(i)-values for numerous inhibitors (PCI, ABSA, hipp-D-lys, epsilon-aminocaproic acid, D-arg and 3-phenylproprionic acid) and kinetic parameters (K(m), k(cat) and k(cat)/K(m)) for several substrates (hipp-arg, hipp lys, FAAA, FAAL and hipp-AA) were determined. N-terminal sequencing and amino acid analysis were also performed. Purified ostrich carboxypeptidase B was assessed to be homogeneous by SDS-PAGE with a M(r) value of approx. 35,000. For ostrich carboxypeptidase B the K(m) values for the different substrates were of the same order as those reported for other species, whereas the k(cat) values were 8- to 21-fold lower than the reported values. FAAA and hipp-AA were the preferred substrates. PCI was the most effective inhibitor, with a K(i) in the nM region, and no inhibition was shown with 3-phenylpropionic acid. The N-terminal sequence showed a high degree of homology when aligned with CPB from other species. Amino acid analysis showed significantly lower levels of Asx and Cyh and higher levels of Trp and Leu when compared with other species. Ostrich carboxypeptidase B would appear to show many physical, chemical and kinetic properties similar to those of other known carboxypeptidases. PMID- 8697098 TI - Analysis of the human gene encoding latent transforming growth factor-beta binding protein-2. AB - Transforming growth factor (TGF)-beta is secreted as an inactive complex, which frequently contains a large molecular weight binding protein designated latent TGF-beta-binding protein (LTBP). Recently, the LTBPs have been shown to be a gene family that contains three known members and exhibits a multidomain structure containing cysteine-rich motifs that are also found in the fibrillin gene family. The present work seeks to characterize the gene encoding LTBP-2 and to compare its features to that of the other LTBPs and to the fibrillins. Human fibroblast libraries were used to isolate cDNA encoding LTBP-2 which was then used to identify LTBP-2 transcripts and to isolate the corresponding LTBP-2 gene. The cloned cDNA encodes a 195 kDa protein containing 20 epidermal growth factor (EGF) like repeats, three repeats containing eight cysteines, and one segment that appears to be a hybrid of the two. Single exons encode EGF repeats while the eight-cysteine repeats are encoded in two exons. Northern analysis identified two transcripts of 7.5 and 9.0 kb, with the presently analyzed cDNA probably corresponding to the 7.5 transcript. Phylogenetic sequence comparisons demonstrated that LTBP-3 is more similar to LTBP-1 than LTBP-2, while LTBP-2 shows the most similarity to the fibrillins. These analyses suggest that LTBP-1 diverged from LTBP-3, and that LTBP-2 diverged from LTBP-1. Within the fibrillin family, fibrillin-1 is nearest to the LTBPs. While the domain structure of LTBP-2 is similar to that of the other LTBPs, LTBP-2 possesses unique regions that make it the largest member of the LTBP family. LTBP-2 may have dual functions as a member of the TGF-beta latent complex and as a structural component of microfibrils. PMID- 8697099 TI - A novel cystathionine beta-synthase from Panagrellus redivivus (Nematoda). AB - The free-living nematode Panagrellus redivivus can be used as a biochemical model for parasitic nematodes in the search for new chemotherapeutic agents. A novel cystathionine beta-synthase has been purified 3600-fold from the cytosol of P. redivivus. The enzyme catalyses the synthesis of cystathionine from homocysteine plus serine or cysteine. The enzyme, native M(r) 71.7 kDa, pI 4.7, is a dimer and also catalyses the replacement of the beta-SH group of cysteine with 2 mercaptoethanol to yield a thioether, S-(2-hydroxyethyl) cysteine and H2S. This reaction proceeds much faster than cystathionine synthesis and L-cysteine cannot be replaced by D-cysteine, L-cystine, N-acetyl L-cysteine, cysteamine of D,L homocysteine. 2-Mercaptoethanol in the assay can be replaced by monothiolglycerol and to a lesser extent by cysteamine. The absolute K(m) values for L-cysteine and 2-mercaptoethanol were 0.13 +/- 0.05 mM and 1.72 +/- 0.24 mM, respectively, the absolute V(max) was 55 +/- 4.9 mumol.min(-1).mg protein(-1). The enzyme had a pH optimum of approx. 8.5 and did not require metal ions for activity. The enzyme was inhibited by a series of substrate analogues, anthelmintics and plant phenols. The P. redivivus enzyme differs markedly from its mammalian equivalent and suggests distinctive differences in sulphur amino acid metabolism in nematodes. PMID- 8697100 TI - Molecular cloning and sequencing of trypsin cDNAs from Penaeus vannamei (Crustacea, Decapoda): use in assessing gene expression during the moult cycle. AB - Trypsin is the most abundant protease in Crustacea. This enzyme was purified from the digestive gland of Penaeus vannamei, revealing three major isoforms (molecular weights 31-32 kDa) and several minor components. Five cDNAs encoding five isoforms of trypsin were detected by two successive screenings of an amplified cDNA library from the digestive gland of P. vannamei. The longest isolated and sequenced cDNA encoded a preproenzyme of 255 amino acids containing a putative precursor peptide of 14 residues and a highly hydrophobic signal sequence of 14 amino acids. Amino acid sequence alignments revealed a high degree of identity between the trypsin from P. vannamei and that from crayfish (74%) and an equal level of sequence similarity to that from mammals and insects (approximately 40). Dot blot hybridization and subsequent analysis of the variation in trypsin-specific activities revealed that mRNA expression is at a maximum during early premoult (D1), declining sharply in late premoult (D2-D3). The specific activity of trypsin also followed this pattern, suggesting the regulation of trypsin biosynthesis is, at least in part, transcriptional. The characterization of trypsin cDNA from P. vannamei provides the first description of a putative zymogen sequence in a crustacean species, enabling us to elucidate the regulatory mechanism of trypsin synthesis in these important marine organisms. PMID- 8697101 TI - cDNA cloning and expression of a new form of human aryl sulfotransferase. AB - To date, four human cytosolic sulfotransferases have been cloned and characterised. The aim of the present study was to identify new forms of these enzymes using molecular cloning techniques. Two full length human aryl sulfotransferase (HAST) cDNAs were cloned from a lambda gt10 liver cDNA library. The COS cell expression system was used to express the cDNAs and to determine the ability of the encoded proteins to metabolise the model substrates p-nitrophenol and dopamine. The two cDNAs were 1036 bp (HAST4) and 1060 bp (HAST4v) in length, and encoded proteins that differed by two amino acids (Thr-7 to Ile and Thr-235 to Asn). The coding domains of HAST4 and HAST4v were 97 and 94% homologous to previously reported phenol (HAST1) and monoamine (HAST3) sulfonating forms of sulfotransferase, respectively. On expression of these cDNAs in COS cells the encoded proteins were capable of sulfonating p-nitrophenol with markedly different affinities: the K(m)s for HAST4 and HAST4v being 73.7 and 7.75 microM, respectively. For the same reaction HAST1 and HAST3 have K(m)s of 0.7 and 2200 microM, respectively. Unlike HAST1 and HAST3, the expressed HAST4/4v proteins could not sulfonate dopamine. In addition to having markedly different K(m)s for p-nitrophenol as a substrate, the expressed HAST4/4 proteins also differed significantly in their affinity for the cofactor 3'-phosphoadenosine-5' phosphosulfate. This report on the functional dissimilarity between two allelic variants of HAST4 highlights that substitution at two residues, Thr-7 and -235, markedly alters their substrate specificities and provides insight into the domains that determine these characteristics. PMID- 8697102 TI - Ginsenosides stimulate endogenous production of nitric oxide in rat kidney. AB - Ginsenosides (GS), saponins purified from Panax ginseng, increase renal blood flow in rats. Nitric oxide (NO) is thought to be the substance endogenously released by GS in preconstricted lungs and cultured endothelial cells. The present study aims to determine whether GS could stimulate endogenous release of NO in rat kidney and whether GS affected the activity of NO synthase in kidney tissues. The serum and urine levels of the stable NO metabolites, nitrite (NO2) and nitrate (NO3) and urinary cGMP levels were measured 8 hr after a single intraperitoneal injection of GS (200 mg/kg) into rats. The effects of the NO synthesis inhibitor, N omega-nitro-L-arginine methyl ester and the NO precursor, L-arginine, on the GS-induced changes were also determined. The activity of NO synthase, as determined by conversion of [14C]-L-arginine to [14C]-L-citrulline, in whole kidney, glomeruli and cortical tubules was also investigated. A single injection of GS resulted in endogenous production of NO as reflected by increase in serum and urine levels of NO2/NO3 and urinary cGMP levels, which were inhibited by the addition of N omega-nitro-L-arginine methyl ester and restored by L-arginine. GS also stimulated the activity of NO synthase in whole kidney as well as glomeruli and cortical tubules, and this increase was significantly prevented by N omega-nitro-L-arginine methyl ester. It was concluded that stimulation in endogenous production of NO by GS may contribute to its antinephritic action and may play a protective role in the kidney. PMID- 8697103 TI - Electrostatic interactions of the butyrylcholinesterase dimer of mucosal cells of rat intestine with glycosaminoglycans. AB - The G2 form of butyrylcholinesterase (BChE) of mucosal cells of rat intestine is a rare amphiphilic species, which is related to class II of acetylcholinesterase. Preliminary work indicated that the enzyme can bind heparin and suggested particular properties as compared to other BChEs. Ionic properties of the G2 form BChE were studied with different ionic exchangers. Heparin-Sepharose chromatography, nondenaturing electrophoresis and sucrose gradient centrifugation were used to study heparin interaction with the G2 form BChE. The enzyme structure was modified with reagents that react specifically with amino groups (p hydroxyphenylglyoxal and 2,4,6-trinitrobenzene sulfonic acid). The G2 form was not retained by DEAE-cellulose which was generally used to isolate BChE from human serum, but was completely bound by strong cation exchanger (Dowex 50). Heparin-Sepharose quantitatively retained the enzyme which was partially eluted only by charged compounds. Nondenaturing gel electrophoresis showed a reduction in enzyme migration with increasing concentrations of heparin and chondroitin sulfate, but not with heparan sulfate. Triton X-100 dissociated the G2 form into monomers but failed to reverse the association between the enzyme and heparin. Reagents specific to amino groups indicated that arginine and lysine residues were involved in this association. In summary, these studies demonstrate that the ionic properties of the G2 form BChE are involved in the binding with heparin. Our results rule out the possibility of amphiphilic interactions in the formation of heparin-enzyme complex and indicate that amino groups are predominately involved in this association. PMID- 8697104 TI - ATP-diphosphohydrolase activity in rat renal microvillar membranes and vascular tissue. AB - Ecto-nucleotidases may have a role in the regulation of purinoceptor-mediated responses. ATP-diphosphohydrolase or apyrase has been described as an ecto nucleotidase, which is characterized by a low specificity for its substrates and bivalent cations. The aim of this work was to demonstrate the presence of apyrase as an ecto-enzyme in the rat kidney. ATPase-ADPase activities of the renal microvillar membrane preparation, which correspond to "right side out' membranes, were characterized. The detection of ATP-diphosphohydrolase in the renal vasculature was done through perfusion of isolated rat kidney. ATPase-ADPase activities of the microvillar membrane preparation and apyrase share similar kinetic properties. These include: low substrate and bivalent metal specificities and insensitivity towards inhibitors like: oligomycin, ouabain, verapamil, levamisole and Ap5A. The M(r) or native ATPase and ADPase activities was determined by the 60Co irradiation-inactivation technique being around 65 kDa for both hydrolytic activities. Immunowestern blot analysis also supports the presence of apyrase in microvilli. Perfusion of isolated rat kidney with ATP and ADP, in the presence or absence of different inhibitors or apyrase antibodies indicated the existence of this enzyme in the vascular endothelium. The identification of ATP-diphosphohydrolase as an ecto-enzyme both in microvilli and vasculature support the proposal that the enzyme may have an important role in the extracellular metabolism of nucleotides. PMID- 8697106 TI - Critical care of the pediatric oncology patient. AB - The survival rate of children with neoplastic disease has increased significantly because of advances in the diagnosis and treatment of malignancy. The consequences of these scientific advances have led to increased malignancy related critical complications requiring the expertise of intensive care practitioners. In this article, the authors review common complication associated with malignancies that require admission to the pediatric intensive care unit. Disorders are grouped according to the pathophysiologic mechanism: mechanical effects, systemic effects, related to brain tumors, and complications of intensive chemotherapy or chemo-radiotherapy regimens. Superior vena cava syndrome and brain tumors are described in detail. In conclusion, there is a discussion of outcome data for children with neoplastic disease who are admitted to the pediatric intensive care unit and the role of the advanced practice nurse in influencing patient and family perceptions of the experience. PMID- 8697105 TI - Polysaccharide-peptide complexes from the cultured mycelia of the mushroom Coriolus versicolor and their culture medium activate mouse lymphocytes and macrophages. AB - The aim of this study was to investigate the effects of the mushroom Coriolus versicolor on cells of the immune system. The cultured mycelia of the mushroom Coriolus versicolor and their culture medium were separately extracted with boiling water. The resulting polysaccharopeptide preparations were designated intramycelial (IM) and extramycelial materials (EM), and were separated by gel filtration before determining their effects on lymphocytes and macrophages in vitro and in vivo. After gel filtration on Sepharose 6B, only a single peak with a molecular weight of 13-19 KDa was obtained. Gel filtration of IM and EM on Sephadex G-50 revealed the presence of a larger peak of 28 KDa (from IM) and 15 KDa (from EM) and a smaller peak of 3.5 KDa. IM, EM and their large molecular peaks enhanced the mitogenic response of T-cells from BALB/c mice in vitro. Splenocytes from C57BL/6 mice pre-treated by force-feeding with IM and EM demonstrated an augmented mitogenic response to Con A. The macrophages of C57BL/6 mice that had been pre-treated with IM or EM showed an enhanced production of nitrite ions. The results indicate that both mouse lymphocytes and macrophages were activated by preparations of polysaccharopeptide from cultured mycelia and culture medium of C. versicolor. However, no direct cytotoxic activity against fibroblasts, hepatoma cells and choriocarcinoma cells could be demonstrated. PMID- 8697107 TI - The role of the advanced practice nurse in the care of patients critically ill with cancer. AB - Although the proliferation of potent standard and experimental protocols to combat cancer has resulted in life-threatening complications, growth and changes in the field of oncology and critical care have increased the life expectancy of patients with cancer. Several authors have describe the multifaceted role of the advanced practice nurse in critical care and oncology settings. How the critical care oncology advanced practice nurse translate these roles into practice is not known. In this article, the author describes the challenges of the critical care oncology advanced practice nurse to improve patient care, improve outcomes, and advance the nursing profession. PMID- 8697108 TI - Outcomes management: an interdisciplinary search for best practice. AB - Rising U.S. health-care costs have resulted in mandates to reform the health system. Payors are closely scrutinizing care delivery and have empowered themselves as gatekeepers for consumer health-care access. In the late 1980s, outcomes management emerged as an interdisciplinary process advocating the measurement of health outcomes among populations undergoing medical care. Outcomes management provides a mechanism to foster development of patient-driven health services aimed to impact clinical quality through intermediate and long term outcome analysis. Outcomes measurement facilitates ongoing enhancement of interdisciplinary health-care delivery, enabling determination of "best" practice and identification of opportunities for practice improvement. The advanced practice nurse's unique educational preparation provides a framework for development of the prerequisite leadership qualities necessary to cultivate an outcomes management program. PMID- 8697109 TI - Getting started in outcomes research. AB - Outcomes research is being advocated as a means for providing information needed to support decision making in health care. In this article, the author defines terminology related to outcomes assessment, describes the process of outcomes measurement, and reviews suitable study designs for use in outcomes research. PMID- 8697110 TI - Collaborative practice teams: the infrastructure of outcomes management. AB - Collaborative practice teams consist of interdisciplinary providers who are charged with the process of implementing and refining an outcomes management program within a targeted population. Collaborative practice teams work under the assumption that clinical quality enhancement through practice standardization decreases care fragmentation, resulting in improved physiologic, psychosocial, and financial outcomes. Collaborative practice team members identify best practice through the implementation and testing of interdisciplinary interventions. Represented on a critical pathway, these practices are evaluated toward achievement of defined population outcomes. In this article, the authors review the process of collaborative practice team formation, expected pitfalls and barriers to effective collaboration, and the work accomplished by a collaborative practice team. PMID- 8697111 TI - Program assessment through outcomes analysis: efficacy of a comprehensive supportive care team for end-of-life care. AB - Addressing end-of-life care issues is difficult in our death-denying society, particularly in the hospital environment, which is characterized by a proliferation of life-sustaining therapy. A hospital model for end-of-life care has been in practice at an urban university hospital since late 1985. Outcomes analysis at the micro-level permitted a demonstration of the practice's effectiveness over time. PMID- 8697113 TI - Selected critical care complications of cancer therapy. AB - In this article of critical care complications of radiation therapy, chemotherapy, and biological therapy, the authors focus on the pathophysiology of the toxicities, causative agents, and patient presentation. They provide an overview of the types of toxicities that advances practice and expert critical care nurses may encounter in the care of the critically ill patient who has received cancer therapy. The purpose of providing this information is to increase the awareness of potential causes for admission to the intensive care unit and to described the toxic effects that have an impact on the critical care nursing the patient receives. The nursing management of these problems follows the standard guidelines for patients with any of the particular organ system dysfunctions. PMID- 8697112 TI - Predicting resource use for patients with traumatic brain injury. AB - Approximately 2 million traumatic brain injuries (TBIs) occur each year in the United States. Outcomes of TBI include catastrophic disability that affects mobility, self-sufficiency, cognition, language and communication, sensory and perceptual function, neurobehavior, marital relationships, and vocational status. Few programs exist that address all of these needs comprehensively, and resource allocation for care across the continuum for patients after TBI remains limited. In this article, the author describes outcomes of TBI, barriers to outcome achievement, and alternative care delivery approaches to achieve these outcomes. PMID- 8697114 TI - Transfusion therapy for patients critically Ill with cancer. AB - Patients with cancer receive antineoplastic therapy that affect their ability to produce and maintain circulating levels of blood cells at any given time. Frequent and varied transfusion requirements necessitate a highly developed and specialized practice of blood component therapy in cancer care. In this article, the author discusses factors affecting the selection of blood components and the influence that expert critical care nurses can contribute to safe and effective transfusion therapy. Administration of leukocyte-poor or cytomegalovirus-negative erythrocytes, pheresed platelets, and granulocyte transfusions are described. PMID- 8697115 TI - Oncologic pharmacology: selected topics for critical care nurses. AB - Administration of multiple and complex medications is common in the intensive care setting, but the response of a patient with cancer to medications and the specific types of medications is a unique specialty practice. In this article, the author provides the experienced critical care nurse with a condensed overview of the most important nursing issues in pharmacologic therapy for patients with cancer. There is a discussion of physiologic variables that influence how patients with cancer respond to pharmaceutical agents. This is followed with detailed information about cancer chemotherapy, biotherapy, and antiemetic practices. PMID- 8697116 TI - Critical care of the patient with hematologic malignancy. AB - Patients with leukemia, lymphoma, or multiple myeloma are prone to critical illness because of the diffuse nature of their disease and the disruption of protective mechanisms. Despite high morbidity rates, a number of these patients have an excellent probability of long-term remission if supported through a crisis. Complications that cause critical illness can be categorized as related to disease or those caused by therapy. Those with unique features or management strategies for the hematologic malignancy patient and are included in this discussion include: leukostasis, disseminated intravascular coagulation, tumor lysis syndrome, respiratory failure, and typhlitis. A case study of an acutely ill, newly diagnosed patient with several of these oncologic emergencies is used to exemplify typical clinical finds and management strategies. PMID- 8697117 TI - Critical care of the patient with lung cancer. AB - Critical care of patients with lung cancer requires a knowledge of the behavior of this malignancy and the implications of several prognostic variables. Lung cancer's location, cellular characteristics, and metastatic patterns predispose patients to many emergencies that may require critical care intervention. In this article, the author presents important background on the behavior of this malignancy, its treatment, and predicted critical care problems. Included is a discussion of complications such as spinal cord compression, superior vena cava syndrome, airway obstruction, pleural effusions, and neoplastic cardiac tamponade, with an overview of common paraneoplastic syndromes. A case study exemplifies a possible presentation and management of a patient with lung cancer and some of these complications. PMID- 8697118 TI - Issues and trends in critical care of patients with cancer. AB - The specialty of critical care oncology has emerged as a result of changes in treatment of malignancies and technologic critical care developments. In this article, the author provides the experienced critical care nurse with an overview of the practice of critical care oncology and the unique needs of these patients. Methods for predicting critical illnesses in specialized cancer populations are provided. Also included is a summary of universal cancer care issues such as bone marrow suppression, venous access, chronic pain, and nutrition disorders that cross all specialty areas. This article serves as a basis and resource for practicing critical care nurses and includes background information for the other articles included in this journal issue. PMID- 8697119 TI - Bone marrow transplantation: issues for critical care nurses. AB - Bone marrow transplantation (BMT) is becoming a wide used therapeutic modality in the field of cancer care. Offering long-term disease-free survival in more than half of some patients with previously fatal diseases, this therapy has challenged clinicians to reevaluate critical care management strategies for such patients. Critical illness occurs in approximately one third of allogeneic transplants, necessitating that critical care nurses be familiar with this therapy and its reported complications. Critical care nurses are an integral part of producing the reported cure and remission rates, despite significant complications. In this article, the authors outline the common critical care problems of this patient population. The chronologic format enables the practitioner to correlate and differentiate key characteristics of potential complications. A case study, with clinical symptoms representing several potential etiologies, demonstrates the application of these concepts. Through the use of nursing knowledge of the unique needs of these patients, there is the potential to continue to improve patient outcomes. PMID- 8697120 TI - Grant application information for 1996 NNSA research award. PMID- 8697122 TI - Guidelines for poster presentations. PMID- 8697121 TI - Position paper: access to therapeutic cannabis. National Nurses Society on Addictions. PMID- 8697124 TI - Pressure damage associated with prolonged unconsciousness. PMID- 8697123 TI - Dressings for treating cavity wounds. AB - Two treatment protocols for the management of patients with non-infected cavity wounds were studied, using data obtained from both the community and the outpatients clinic. Patients were treated with either a polyurethane foam hydrophilic dressing (Allevyn) or a calcium sodium alginate dressing (Kaltostat). Although alginate fibres were found to be incorporated in tissue, both dressing regimes were found to be easy to use, effective and acceptable to patients and clinicians. PMID- 8697125 TI - Peripheral arterial disease. PMID- 8697126 TI - Methicillin-resistant Staphylococcus aureus. PMID- 8697127 TI - Management of pressure sores in a spinal injuries unit. PMID- 8697128 TI - High-compression bandages. AB - This report describes the results of a programme of tests carried out on a new high-compression bandage, with two application aids designed to produce specific pressures on normal-size and oedematous limbs. The product was tested to examine its performance in relation to the specified criteria of a Type 3c compression bandage and other pre-defined features. The results show that, with the use of both application aids, the bandage can provide the target pressure of 40 mmHg +/- 10% on ankles ranging from 21-26 cm and 27-33 cm in circumference. Ankles with circumferences between 26 and 27 cm will fall marginally outside the design criteria (40 +/- 6 mmHg). PMID- 8697129 TI - The use of antiseptics in wound care. Critique. PMID- 8697130 TI - Evaluation of treatments for wounds in clinical trials. PMID- 8697131 TI - Biosurgery in wound healing. PMID- 8697132 TI - Towards consensus. PMID- 8697133 TI - Management of neuropathic ulceration. AB - Patients with diabetes who develop neuropathic foot ulcers are often managed with prolonged bed-rest or given a total contact cast. As these methods are not ideal for many patients, we examined a boot cast as an alternative approach to treating intractable neuropathic ulcers. Fourteen diabetic patients with a total of 16 neuropathic ulcers have been treated. The boot cast is a fibreglass, removable cast, tailor-made for individual patients. For treatment of neuropathic ulcers, a window is cut over the area of the ulcer site to reduce weight-bearing pressure. Despite the long pre-existing duration of the ulcers studied (mean 912 days), ulcers that reached 100% healing did so by 130 days. The mean period in which there has been no recurrence to date is 218 days. The boot cast was found to be an effective treatment in the management of diabetic foot problems. It allows patients to remain ambulant and reduces risk factors for amputation. PMID- 8697134 TI - Recommendations for additions to the Drug Tariff. PMID- 8697135 TI - Using larvae in modern wound management. AB - Initial clinical experience in the UK with maggot therapy for the treatment of necrotic or infected wounds has proved very encouraging. Sterile larvae have been reared in the Surgical Materials Testing Laboratory for this purpose. This paper reports the use of larvae in six patients and discusses some of the advantages and disadvantages of this form of therapy. PMID- 8697136 TI - The management of leg ulcers. PMID- 8697137 TI - Hydroactive dressings and serum proteins: an in vitro study. AB - An in vitro approach was used to obtain information about the compatibility of hydroactive dressing materials with the serum proteins which are thought to be relevant to wound healing. Artificial wound fluid was incubated with different hydroactive dressings (Cutinova hydro, Varihesive E, Comfeel Ulcer Dressing and Allevyn), and concentrations of total protein, albumin, immunoglobulin and growth factors were measured after one day of incubation. Cutinova hydro and Allevyn absorbed considerable amounts of fluid. Fluid uptake was lower for the hydrocolloid dressings. An unexpected finding was that Cutinova hydro showed an approximately two-fold increase over control values in the concentration of all proteins tested, indicating a selective absorption of water by this dressing. For the other dressings tested, zero or very low absorption of proteins was found, indicating a basically satisfactory protein compatibility. PMID- 8697138 TI - Arterial disease: reversible and irreversible risk factors. PMID- 8697139 TI - The Norton score and pressure sore prevention. Critique. PMID- 8697140 TI - Enhanced platelet recovery in myelosuppressed mice treated with interleukin-1 and macrophage colony-stimulating factor: potential interactions with cytokines having megakaryocyte colony-stimulating activity. AB - Studies were carried out to determine whether the combination of IL-1 + M-CSF, similar to the effect of these cytokines on neutropenia, was able to reduce the duration of thrombocytopenia in the 5-fluorouracil (5-FU)-myelosuppressed mouse. In addition, comparisons were made between the in vivo effects of IL-1 + M-CSF and other "thrombopoietic" cytokines (e.g., IL-3, IL-6, and GM-CSF) that demonstrate some form of megakaryocytopoietic activity in vitro. Of the five cytokines studied, only IL-1 and IL-6, by themselves, were able to effect thrombopoietic recovery in the myelosuppressed mouse. IL-1, either when acting alone or interacting synergistically with M-CSF, was able to reduce significantly the period of thrombocytopenia, but the effects of IL-6 were restricted to enhancing platelet production during the period of rebound thrombocytopenia without altering the kinetics of thrombopoietic recovery. Moreover, none of the cytokine combinations studied were found to interact to reduce further the duration of thrombocytopenia beyond that observed with IL-1 + M-CSF. Nonetheless, IL-3, IL-6, and, to a lesser extent, GM-CSF were each able to interact with IL-1 + M-CSF to extend further the period of enhanced platelet production in the animal. However, scheduling studies suggested that these thrombopoietic cytokines interacted in sequence, rather than in concert, with IL-1 + M-CSF to enhance platelet production during thrombopoietic recovery. Furthermore, the data presented are consistent with the hypothesis that IL-1 + M-CSF initially acts on a multilineage, 5-FU-resistant target cell and that IL-6 (and possibly IL-3 and GM-CSF) serves as a secondary cytokine further to enhance platelet production during rebound thrombopoiesis in the 5-FU-treated mouse. PMID- 8697141 TI - Comparative effects of interferon-consensus 1, interferon-alpha 2a, and interferon-beta 1b on HLA expression and lymphoproliferation: a preclinical model for treatment of multiple sclerosis. AB - Interferon-consensus 1 (IFN-Con 1) is a novel synthetic protein generated from codons for the most frequent amino acids in different type 1 IFNs. Compared with natural IFNs, IFN-Con 1 has been shown to have higher specific activity and antiproliferative activity and a higher ability to induce natural killer cells. In this study, the effects of IFN-Con 1 were compared with those of IFN-beta 1b and IFN-alpha 2a on HLA expression and lymphoproliferation. Human umbilical vein endothelial cells (HUVEC) express HLA class I but not class II molecules; however, both class I and class II molecules can be upregulated by IFN-gamma. IFN Con-1 shared with IFN-beta 1b and IFN-alpha 2a the capacity to enhance HLA class I expression on HUVEC, alone and in combination with IFN-gamma. Although IFN-Con 1 had no effect on the basal expression of HLA class II molecules, it inhibited the IFN-gamma-induced class II expression on the HUVEC in a dose-dependent fashion. When this effect was compared among the three IFNs on mass basis, IFN Con 1 activity was intermediate between that of IFN-beta 1b and IFN-alpha 2a. IFN Con 1 also demonstrated an inhibitory effect on mitogen-driven lymphoproliferation similar to that of IFN-alpha 2a and exceeded that of IFN-beta 1b. The results indicate that IFN-Con 1 has immunomodulatory effects similar to those of IFN-beta 1b and IFN-alpha 2a, which could be relevant to the treatment of autoimmune and virus-mediated diseases. PMID- 8697142 TI - Interferon-gamma and tumor necrosis factor-alpha treatment of ex vivo human carcinoma cells potentiates their interaction with allogeneic lymphocytes. AB - Short-term exposure of ex vivo carcinoma and sarcoma cells to IFN-gamma and TNF alpha induced or elevated to detectable levels the surface expression of MHC class I, class II, and ICAM-1 (CD54), but only rarely the B7 (CD80) molecules. The cytokine-treated tumor cells interacted more efficiently with allogeneic blood lymphocytes collected from healthy donors compared with untreated cells. This was demonstrated (1) by the induction of DNA synthesis and generation of cytotoxic activity in mixed cultures and (2) by the elevated susceptibility to the cytotoxic effectors. Although the cytokine-induced increase in MHC and ICAM-1 on the low-expressor tumors were probably important to the interaction with lymphocytes, it is likely that other properties were also induced that contributed to the phenomenon. This was indicated by the results obtained with several tumors that expressed indigenously high levels of these molecules but reacted with the allogeneic lymphocytes only or more efficiently after treatment with IFN-gamma and TNF-alpha. In these experiments B7 expression did not influence the efficiency of interactions between lymphocyte and tumor cells. The results also showed that, under the conditions used, the untreated tumor cells that did not activate allogeneic lymphocytes were sensitive to appropriately activated effectors. Thus the afferent and efferent arms of lymphocyte-tumor cell interactions appeared to have different requirements. PMID- 8697143 TI - Autocrine induction of macrophage synthesis of complement subcomponent C1q by endogenous interferon-alpha/beta. AB - Peritoneal macrophages (M phi) constitutively synthesize and secrete interferon alpha (IFN-alpha) and IFN-beta, as well as complement subcomponent C1q. Because exogenous interferon-gamma (IFN-gamma) stimulates Mo synthesis of C1q, our purpose was to determine if endogenous secretion of IFN-alpha/beta regulated the constitutive level of endogenous C1q mRNA synthesis in an autocrine fashion. Both exogenous IFN-alpha and IFN-beta effectively substituted for IFN-gamma in stimulating M phi C1q mRNA expression in a dose-dependent fashion by northern blot analysis. Neutralizing anti-INF-alpha/beta antibodies inhibited M phi constitutive C1q mRNA synthesis by approximately twofold and abrogated the feedback stimulatory effects of exogenous C1q on C1q mRNA expression. Paraffin oil-elicited inflammatory M phi displayed distinctively different constitutive levels of C1q mRNA expression from thioglycollate brothelicited M phi, which was correlated with their relative levels of secretory IFN-alpha/beta by ELISA. Exogenous IFN-alpha/beta also restored C1q mRNA synthesis of AKR mouse M phi with low constitutive C1q mRNA expression. The cumulative results support the concept that constitutive synthesis of C1q by M phi is regulated by the endogenous synthesis and secretion of IFN-alpha/beta, which appears to act in an autocrine fashion. PMID- 8697144 TI - Effect of interferon therapy on bone marrow morphology in chronic myeloid leukemia: a cytochemical and immunohistochemical study of trephine biopsies. AB - The effect of interferon (IFN) therapy on bone marrow features in chronic myeloid leukemia (CML) has been studied on successive trephine biopsies (mean interval 13 +/- 8 months) by cytochemical and immunohistochemical methods in combination with morphometry and in comparison with a control group of patients who received monotherapy by busulfan (BU). Following IFN administration (IFN-alpha frequently in combination with IFN-gamma), there was a decrease in neutrophil granulopoiesis accompanied by a significant expansion of erythroid precursors and increased numbers of hemosiderin-laden macrophages. These changes corresponded with the hematologic response in 21 of the 25 patients investigated. Numbers of megakaryocytes and reticulin/collagen fiber density increased during treatment. Most conspicuously, in responding patients atypical micromegakaryocytes, usually characterizing CML, were partially replaced by normal-sized cells of this lineage. These features are in keeping with the assumption of a reappearance of the normal hematopoietic cell clone as the result of IFN therapy, which was not found in the BU-treated control group. On the other hand, a relevant subpopulation of micromegakaryocytes (about 30%) was still maintained. This result probably relates to the failure to improve myelofibrosis more effectively. Analysis of cell proliferation (proliferating cell nuclear antigen-PCNA) and apoptosis (in situ end labeling) revealed a reduction in PCNA labeling and increased numbers of cells undergoing programmed death. Identification of the activated subset of macrophages (alpha-D-galactosyl residues expression) by appropriate lectin histochemistry disclosed an increase in the number of GSA-I binding cells. These findings were exclusively limited to IFN administration and reflect an inhibitory effect of IFN on cell proliferation and stimulation of programmed cell death. The latter phenomenon probably results in increased phagocytosis of clonally transformed myeloid cells by GSA-I-positive (activated) macrophages. PMID- 8697145 TI - Effect of staphylococcal enterotoxin B-induced anergy on cytokine gene expression: anergy-sensitive and resistant mRNA expression. AB - We examined the effect of staphylococccal enterotoxin B (SEB)-induced anergy on expression of six different cytokine genes in T cells restimulated with SEB in vitro. We found that although IL-2, IL-3, and IL-4 mRNA levels are substantially reduced in anergic T cells, mRNAs for IL-6, IL-10, IFN-gamma, and TNF-alpha are expressed normally. Thus, there appeared both anergy-sensitive and resistant cytokine mRNA expression in restimulated anergic T cells. The same pattern of cytokine mRNA responses was observed in anergic CD4+ T cells, indicating that the preferential induction of anergy in Th1-like cells is not evident in this in vivo model. Employing TCR V beta 8.2 transgenic mice in which almost all T cells become anergic, we found that the TCR/CD3 complex can transduce both anergy sensitive and resistant signals. Furthermore, a series of experiments using FK506, A23187, and PMA suggests that signals between TCR and activation of calcineurin and protein kinase C may be blocked in anergic T cells. This is supported by our gel mobility shift assays indicating that calcineurin and/or PMA inducible NF-ATp, OAP40, and AP-1, but not calcineurin-independent Oct-2, are repressed in anergic spleen T cells upon restimulation with SEB. Taken together, these results suggest that, among signals elicited by stimulation of TCR with SEB, a Ca2+/calcineurin-NF-ATp pathway and other signals, including protein kinase C, are repressed in anergic T cells upstream of their activation, which are essential for the cytokine mRNA expression of the anergy-sensitive type but are dispensible for those of the anergy-resistant type. PMID- 8697146 TI - Phenotypic change and proliferation of murine Kupffer cells by colony-stimulating factors. AB - Kupffer cells were isolated from C57BL/6 mice by collagenase perfusion and assessed for response to colony-stimulating factors (CSFs) in terms of their phenotypic change and proliferation. Kupffer cells expressed F4/80, but not Mac 1, CD71, or asialo-GM1 initially. This phenotype pattern was different from that of alveolar and peritoneal macrophages. After stimulation with recombinant human macrophage CSF (M-CSF) or mouse granulocyte-macrophage CSF (GM-CSF), Kupffer cells expressed Mac-1 and a low level of CD71 in addition to F4/80 and increased in phagocytotic activity in association with the expression of CR3. Both M-CSF and GM-CSF, but not human IL-3, induced the proliferation of Kupffer cells in a dose-dependent manner, and after 7 days, the number of the cells increased to about four to six times the initial number. The relatively high dose of GM-CSF downmodulated the M-CSF receptor on Kupffer cells and inhibited the cell proliferation induced by the optimal dose of M-CSF. These data indicated that murine Kupffer cells have a different phenotype from other macrophages and that they respond to M-CSF and GM-CSF, leading to functional maturation and proliferation. PMID- 8697147 TI - Stimulation of macrophage synthesis of complement C1q by interferon-gamma mediated by endogenous interferon-alpha/beta. AB - Both exogenous interferon-gamma (IFN-gamma) and interferon-alpha/beta (IFN alpha/beta) stimulate C1q mRNA synthesis in murine macrophages. Previous studies suggested that IFN-gamma induced endogenous synthesis of IFN-alpha/beta by murine macrophages. In the present study, we determined the indirect effect of IFN-gamma on macrophage synthesis of C1q mRNA mediated by endogenous IFN-alpha/beta production. Upregulation of macrophage synthesis of C1q mRNA by both IFN-gamma and IFN-alpha/beta was reversed by neutralizing antibody to IFN-alpha/beta but not by nonimmune control serum. IFN-gamma was confirmed by ELISA to stimulate a six- to eightfold increase in macrophage secretion of IFN-alpha/beta compared with untreated control cells. We tentatively conclude that IFN-gamma stimulates macrophage synthesis and secretion of IFN-alpha/beta, which in turn promotes C1q mRNA synthesis in an autocrine or paracrine manner. Thus, exogenous IFN-gamma, derived from activated T lymphocytes, may act primarily on the macrophage to stimulate the endogenous synthesis of IFN-alpha/beta for autocrine modulation of a variety of biologic functions, including C1q synthesis. PMID- 8697148 TI - Involvement of interleukin-6 and interferon-alpha in the poly(A).Poly(U)-induced 2',5'-oligoadenylate synthetase activity in the mouse monocyte-macrophage cell line, J774A1. AB - The synthetic polyribonucleotide poly(A).poly(U) induces 2',5'-oligoadenylate synthetase activity in the murine macrophage cell line J774A1. The possible role of several cytokines involved in macrophage activation (i.e., IL-1, IL-6, TNF, and IFN) was examined in the present study. It was first demonstrated that among the anticytokine antibodies, only monoclonal antibodies directed against IL-6 inhibited the induction of 2',5'-oligoadenylate synthetase by poly(A).poly(U) in a dose-dependent manner. Moreover, it was established that poly(A).poly(U) elicited IL-6 production in J774A1 cells in a time-and dose-dependent manner. Consequently, the effect of IL-6 on 2',5'-oligoadenylate synthetase activity was studied. IL-6 either alone or in combination with IL-1 and TNF did not induce 2',5'-oligoadenylate synthetase activity. IL-6 did not potentiate IFN-gamma induced 2'-5'-oligoadenylate synthetase activity. In contrast, addition of IL-6 to the incubation medium potentiated the stimulation of 2'-5'-oligoadenylate synthetase activity by IFN-alpha. These results suggest that IL-6 is a necessary but not sufficient factor in the induction of 2'-5'-oligoadenylate synthetase activity in the J774A1 cell line by poly(A).poly(U). PMID- 8697149 TI - Qualitative and quantitative differences in the cellular responses mediated through Fas antigen and tumor necrosis factor receptor. AB - Like tumor necrosis factor (TNF), antibodies against the Fas antigen (anti-Fas) are cytotoxic to some and induce proliferation of other Fas-expressing cells. In this study, we compared cellular responses mediated through TNF with anti-Fas using a T cell line (Jurkat) and a macrophage cell line (U-937). These two cell types differed in that the Jurkat cells expressed higher levels of Fas antigen than U-937 cells, whereas the latter expressed higher levels of the p80 form of the TNF receptor than Jurkat cells. Treatment for 72 h with anti-Fas inhibited the growth of both Jurkat and U-937 cells, the 50% inhibitory concentrations (IC50) being 10 and 100 ng/ml, respectively. Under similar conditions, the IC50 for TNF was > 100 and 0.8 ng/ml for Jurkat and U-937 cells, respectively. Like TNF, the cytotoxic effects of anti-Fas were potentiated by cycloheximide, showing they did not require protein synthesis. Interestingly, in the presence of cycloheximide, the kinetics of cell killing was more rapid for TNF than anti-Fas (50% inhibition occurred at 3 versus 6h). Treatment of both cell types with anti Fas led to time-dependent DNA fragmentation, but TNF-induced DNA fragmentation occurred only in the presence of cycloheximide. Pretreatment of cells with TNF led to resistance to TNF but not to anti-Fas, suggesting that the receptors for the two are not cross-modulated. Furthermore, TNF activated the nuclear transcriptional factor NF-kappa B in both cell types, whereas anti-Fas had no effect. Overall, our results demonstrate that anti-Fas and TNF transduce over lapping and nonoverlapping signals in macrophage-like and T cell lines through distinct pathways. PMID- 8697150 TI - Adventitia as a target for intravascular local drug delivery. PMID- 8697151 TI - Extraction of permanent pacing leads: there are still controversies. PMID- 8697152 TI - Are there any useful investigations that predict which patients with bifascicular block will develop third degree atrioventricular block? PMID- 8697153 TI - Coronary artery bypass surgery in smokers. PMID- 8697154 TI - Some thoughts on the present and future of coronary artery stenting. PMID- 8697155 TI - Expression of platelet derived growth factor B chain and beta receptor in human coronary arteries after percutaneous transluminal coronary angioplasty: an immunohistochemical study. AB - OBJECTIVE: To evaluate whether expression of platelet derived growth factor B (PDGF-B) protein is associated with expression of its receptor protein in human coronary arteries after angioplasty and to identify cells involved. BACKGROUND: PDGF is considered an important growth factor in the repair process of the vessel wall after angioplasty. In situ hybridisation has revealed expression of PDGF-A and -B chain messenger ribonucleic acid (mRNA) in human coronary arteries at sites of postangioplasty injury. METHODS: Target and non-target sites of eight coronary arteries were studied immunohistochemically for PDGF-B and PDGF-beta receptor proteins in relation to macrophages, T lymphocytes, smooth muscle cells, and HLA-DR positive cells. RESULTS: The PDGF-B and PDGF-beta receptor proteins were expressed in areas with distinct repair, containing alpha actin negative spindle cells, macrophages and, at later stages, alpha actin positive smooth muscle cells as well. When the neointima was composed mainly of alpha actin smooth muscle cells, PDGF-B expression was rare and PDGF-beta receptor expression was negative. CONCLUSIONS: There is expression of PDGF-B and PDGF-beta receptor proteins at sites of postangioplasty repair in human coronary arteries. The associated cells are mainly macrophages and alpha actin negative spindle cells; the latter may be dedifferentiated smooth muscle cells. A link between PDGF expression and the postangioplasty time interval suggests a relation with cell differentiation as part of the maturation of the repair tissue. Mutual expression of both the growth factor and its receptor protein strongly suggests that in humans a PDGF mediated repair process occurs, with involvement of smooth muscle cells and macrophages. PMID- 8697156 TI - Cigarette smoking in British men and selection for coronary artery bypass surgery. AB - OBJECTIVE: To examine the relation between smoking status, clinical need, and likelihood of coronary artery bypass grafting in middle aged men. DESIGN: A prospective study of cardiovascular disease in British men aged 40 to 59 years, screened in 1978-80 and followed until December 1991. SUBJECTS AND SETTING: 7735 men drawn from one general practice in each of 24 British towns. MAIN OUTCOME MEASURE: Coronary artery bypass graft surgery. RESULTS: Of the 3185 current smokers, 38 (1.03/1000/year) underwent coronary artery bypass surgery compared with 47 of 2715 (1.45/1000/year) ex-smokers, and 19 of 1817 (0.85/1000/year) never-smokers. Ex-smokers had a lower incidence of major ischaemic heart disease during follow up than current smokers. After adjustment for incidence of ischaemic heart disease during follow up, the hazard ratio of coronary artery bypass surgery for ex-smokers compared with smokers was 1.52 (95% confidence interval 0.99 to 2.34). Ex-smokers were more likely at screening to recall a doctor diagnosis of ischaemic heart disease than smokers (7.1% v 5.3%), but among those who recalled a doctor diagnosis, smokers were less likely to undergo coronary artery bypass surgery than ex-smokers (9.4% v 3.5%, P = 0.026). By 1992, men defined as smokers at screening were no less likely than ex-smokers to have been referred to a cardiologist (18.5% v 18.8%), nor to report having undergone coronary angiography less frequently than ex-smokers (12.7% v 11.4%). CONCLUSION: Even allowing for the strong relation between coronary artery bypass surgery and clinical need, continuing smokers were less likely to undergo coronary artery bypass surgery than ex-smokers. A complex interplay exists between the men's experience of heart disease, the decision to stop smoking, and the willingness of doctors to consider coronary artery bypass surgery. PMID- 8697157 TI - Acute heavy alcohol intake increases silent myocardial ischaemia in patients with stable angina pectoris. AB - OBJECTIVE: To evaluate the effect of acute alcohol ingestion on myocardial ischaemia in patients with coronary heart disease and stable angina. DESIGN: Randomised crossover study using fruit juice with and without ethanol. SETTING: Division of cardiology in a university hospital. PATIENTS: 20 patients with stable exertional angina and > or = 50% luminal diameter narrowing of at least one major coronary artery. INTERVENTIONS: Each patient was studied on two separate days, once after administration of 1.25 g of ethanol per kilogram of body weight diluted to 15% in juice, and once after an equivalent volume of juice; both tests were in the evening and lasted 90 minutes. The patients were scheduled to have 8 periods of walking for 10 min according to a time table. An ambulatory electrocardiogram and the occurrence of anginal attacks were recorded and blood pressure and blood ethanol concentration were measured until the next morning. RESULTS: The blood ethanol concentration (mean (SD)) rose to 28.8 mmol/l (1.3 (0.4)/1000). Alcohol raised the systolic blood pressure from 132 (16) to 141 (14) mm Hg (P < 0.05 compared with juice). The mean heart rate increased from 57 (7) to 64 (8) beats/min (P < 0.05) for 13 hours after ethanol ingestion compared with juice. The total duration of ischaemia during the ethanol test was 3.5 (median, range 0-80) min, compared with 0 (range 0-67) min for the juice test (P < 0.05). The difference resulted mainly from more silent ischaemia after ethanol ingestion (2.3 (0-80) v 0 (0-67) min; P < 0.05). The ST segment depression time integral increased during the ethanol test (4.4 (0-170) mm x min) relative to that during the juice test (0 (0-103) mm x min; P < 0.01) and especially during the following 13 hours after alcohol (3.5 (0-123) mm x min) compared with juice (0 (0-67) mm x min; P < 0.005). There were no changes in the number, duration, or ST segment depression time integral of the episodes of symptomatic angina, indicating that ethanol augmented the appearance of silent ischaemia. CONCLUSIONS: Acute heavy ethanol drinking aggravates myocardial ischaemia in patients with stable angina pectoris. PMID- 8697158 TI - Prospective relations between Helicobacter pylori infection, coronary heart disease, and stroke in middle aged men. AB - OBJECTIVE: To determine whether Helicobacter pylori, a chronic bacterial infection often acquired in childhood, is associated with increased risk of coronary heart disease and stroke later in life. DESIGN: Nested case-control study. SETTING: Prospective study of cardiovascular disease in men aged 40-59 years at entry (1978-1980) in 24 British towns. SUBJECTS: 135 cases of myocardial infarction and 137 cases of stroke occurring before December 1991; 136 controls were identified, frequency matched to cases by town and age group. METHODS: Serum samples stored at entry were analysed by an enzyme linked immunosorbent assay for the presence of H pylori specific IgG antibodies. RESULTS: 95 of the myocardial infarction cases (70%) and 93 (68%) of the stroke cases were seropositive for H pylori compared with 78 (57%) of the controls (odds ratio for myocardial infarction 1.77, 95% confidence interval (CI) 1.06 to 2.95, P = 0.03; odds ratio for stroke 1.57, 95% CI 0.95 to 2.60, P = 0.07). Helicobacter pylori infection was associated with manual social class, residence in Northern England or Scotland, cigarette smoking, higher systolic pressure and blood glucose, and a lower height-standardised forced expiratory volume in one second. Adjustment for these factors attenuated the relation between H pylori and myocardial infarction (odds ratio = 1.31, 95% CI 0.70 to 2.43, P = 0.40) and effectively abolished the relation with stroke (odds ratio = 0.96, 0.46 to 2.02, P = 0.92). The relation between helicobacter infection and fatal myocardial infarction was slightly stronger (odds ratio 2.41, 95% CI 1.13 to 5.12) but was also markedly attenuated after adjustment (1.56, 95% CI 0.68 to 3.61). CONCLUSION: In this prospective study the association between Helicobacter pylori infection and increased risk of myocardial infarction and stroke was substantially confounded by the relation between this infection, adult social class, and major cardiovascular risk factors. PMID- 8697159 TI - Could Helicobacter pylori infection increase the risk of coronary heart disease by modifying serum lipid concentrations? AB - OBJECTIVE: To investigate the relation between Helicobacter pylori infection and coronary heart disease (CHD). DESIGN: A case-control study. SETTING: Northern Finland (about 650,000 inhabitants). PATIENTS: 116 patients with angiographically documented CHD and 116 controls matched for age and gender randomly recruited from the register of the Finnish Social Insurance Institute. MAIN OUTCOME MEASURES: The odds ratio (OR) estimates for the association of H pylori infection with CHD. RESULTS: 64% of the CHD patients and 53% of the controls were seropositive for H pylori; the OR adjusted for age and gender was 1.5 (95% confidence interval (CI) 0.9 to 2.5). An additional adjustment for the common risk factors of CHD, including lipid concentrations, in a logistic regression analysis produced an OR estimate of 1.1 (95% CI 0.6 to 2.1). Among the controls, those who were H pylori positive had significantly (P = 0.03) higher concentrations of serum triglycerides than those who were H pylori negative: the trend among the cases was similar, but non-significant. The concentrations of HDL cholesterol tended to be lower in those who were H pylori positive than in those who were H pylori negative, among both the cases and the controls. CONCLUSIONS: The impact of H pylori infection as an independent risk factor for CHD seems to be minor. On the other hand the results are consistent with the hypothesis that H pylori infection might modify the serum lipid concentrations in a way that could increase the risk of CHD. PMID- 8697160 TI - Hormonal and renal differences between low dose and high dose angiotensin converting enzyme inhibitor treatment in patients with chronic heart failure. AB - OBJECTIVE: To assess the differential effects of low dose (5 mg) and high dose (20 mg) lisinopril treatment on cardiovascular hormones, renal function, and blood pressure over 24 hours in patients with heart failure. DESIGN: Double-blind crossover study. SETTING: Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee. PATIENTS: 19 patients with chronic heart failure and left ventricular ejection fraction < or = 45%. RESULTS: Plasma concentrations of aldosterone and endothelin were lower on the 20 mg dose (plasma aldosterone mean at peak drug effect: 90.7 v 152.0 pg/ml, P < 0.001; mean at trough effect: 124.7 v 174.4 pg/ml, P < 0.01; plasma endothelin at trough effect 4.70 v 6.04 pmol/l, P = 0.03). Creatinine clearance was lower on 20 mg lisinopril (68.7 v 82.1 ml/min, P < 0.05). The area under the curve for diastolic blood pressure over 24 hours was significantly lower on 20 mg (mean difference 3.0 mm Hg, P = 0.04); for systolic blood pressure there was a similar trend (mean difference 5.7 mmHg, P = 0.05). Plasma concentrations of atrial natriuretic peptide (ANP) and B-type natriuretic peptide were similar for both doses; urinary excretion of ANP was lower on 20 mg (12.2 v 13.6 pmol, P < 0.05). CONCLUSIONS: These results indicate that within the usual therapeutic range, high doses of lisinopril cause greater suppression of selected cardiovascular hormones than low doses in heart failure, but are associated with lower creatinine clearance in some patients. PMID- 8697161 TI - Prognostic significance of ST-T segment alterations in patients with non-Q wave myocardial infarction. AB - OBJECTIVE: To determine whether, among patients with non-Q wave myocardial infarction, the characteristics of the segment ST-T shifts at presentation in the diagnostic electrocardiogram can identify those with more severe coronary artery disease and predict a poor clinical outcome. DESIGN: Prospective controlled clinical trial. SETTING: Primary referral medical centre. PATIENTS: 93 patients (mean (SD) 62.0 (7.5) years) were studied: 41 with non-Q wave myocardial infarction and T wave inversion and 52 with ST segment depression. Cardiac events and mortality rates were assessed over 42 months. Age, sex, risk factors, creatinine kinase MB isoenzyme peak, and left ventricular function were comparable. RESULTS: 31 patients with T wave inversion myocardial infarction (94.6%) had total occlusion of the infarct related artery, compared with 12 patients with ST segment depression myocardial infarction (26.7%) (P < 0.05). When compared with patients with T wave inversion, patients with ST segment depression had a higher incidence of cardiac events during the first month and in the 41 subsequent months: 9.6% and 30.8% v 0% (P < 0.01) and 9.8% (P < 0.02), respectively. For the same observation periods, the mortality rates in patients with T wave inversion were 4.9% and 7.3%, and in patients with ST segment depression they were 5.8% and 9.6%, respectively. CONCLUSION: These data suggest that during a non-Q wave myocardial infarction the presence of ST segment depression is related to higher rates of short and long term cardiac events when compared with T wave inversion--possibly because of a higher incidence of residual stenosis of the infarct related artery. PMID- 8697162 TI - Post-stent management with a pneumatic groin compression device and self injected low molecular weight heparin. AB - BACKGROUND: The benefits of intracoronary stent implantation are offset by an increased risk of complications at the arterial puncture site and a prolonged hospital stay. Much of this morbidity can be attributed to the generally perceived need to achieve systemic anticoagulation after stent implantation. AIM: To test a simplified protocol for post-stent management using the Femostop pneumatic groin compression device and low molecular weight (fractionated) heparin (LMWH) administered by subcutaneous injection. PATIENTS: A case series of 100 consecutive patients, with stable angina pectoris, undergoing coronary stenting for a suboptimal result after conventional balloon angioplasty. METHODS: All patients were managed with a new post-stent protocol using the Femostop pneumatic groin compression device and LMWH. The incidence of complications and the length of hospital stay were recorded. RESULTS: The clinical course was uncomplicated in 92 patients and their discharge from hospital was achieved on the first post-procedural day for 44 patients and on the second for the remaining 48. The rate of vascular or bleeding complications was 6%. CONCLUSIONS: LMWH administered by subcutaneous injection may provide a practical and effective alternative to the use of intravenous heparin when systemic anticoagulation is used after stent implantation. PMID- 8697163 TI - Increased risk of heart valve regurgitation after mediastinal radiation for Hodgkin's disease: an echocardiographic study. AB - OBJECTIVE: To assess by echocardiography the occurrence and degree of late cardiac sequelae after treatment for Hodgkin's disease by radiation and chemotherapy. PATIENTS AND METHODS: In Norway from 1980 to 1988, 129 patients < 50 years old with Hodgkin's disease had curative treatment with mediastinal radiation, with or without chemotherapy. 116 (90%) of these patients (mean (SD) age 37 (7) years, 67 males) were examined by echocardiography 5-13 years after treatment. 40 healthy individuals (mean (SD) age 40 (11), 20 males) were examined as controls. All those examined were in regular sinus rhythm. RESULTS: Grade > 1 (scale 0-3) aortic and/or mitral valvar regurgitation was found in 24% of the patients (15% aortic, 7% mitral, and 2% aortic+mitral), affecting 46% of the females v 16% of the males (P < 0.001). Female gender was a significant risk factor for aortic and mitral regurgitation (odds ratio 4.7, 95% confidence interval 2.0 to 11.2), whereas age, period of follow up, radiation dose, and chemotherapy were not. Thickened pericardium was diagnosed in 15% of the patients. No risk factors were identified. No cases of pericardial thickening or valvar regurgitation grade > 1 were recorded in the control group. Mean values for measured and calculated indices of systolic and diastolic function were within the normal range for patients and controls. The patients had reduced E/A ratio compared with the healthy controls (E/A 1.1 v 2.0, P < 0.001). CONCLUSIONS: Abnormal left sided valvar regurgitation was detected in one fourth of the patients, affecting the aortic valve in more than half of the cases. Females had an increased risk of valvar regurgitation. Echocardiographic screening after high dose mediastinal radiation is recommended. PMID- 8697164 TI - Long-term follow up of patients with dilated heart muscle disease treated with human leucocytic interferon alpha or thymic hormones initial results. AB - OBJECTIVE: To determine whether giving interferon-alpha or thymomodulin in addition to conventional treatment improves cardiac function in patients with idiopathic myocarditis and idiopathic dilated cardiomyopathy. DESIGN: Single centre, randomised, open label, parallel group comparison of conventional treatment plus interferon-alpha, conventional treatment plus thymomodulin, and conventional treatment alone. PATIENTS: 38 patients aged 19-54 years (23 men) with biopsy-proven myocarditis or dilated cardiomyopathy. 12 were treated with conventional treatment alone, 13 were treated with interferon-alpha and conventional treatment, and 13 with thymomodulin and conventional treatment. SETTING: Tertiary cardiac referral centre. MAIN OUTCOME MEASURES: Clinical evaluation, echocardiography, and Holter monitoring at baseline, 6 months, and 1 and 2 years. Radionuclide ventriculography at rest and during exercise after 2 years. Endomyocardial biopsy at baseline and after a year if the initial diagnosis was myocarditis. RESULTS: Left ventricular ejection fraction was improved in 21 (81%) of 26 patients after interferon-alpha or thymomodulin administration and in 8 (66%) of 12 conventionally treated patients (P < 0.05) at 2 year follow up. The maximum exercise time was significantly longer at 2-year follow up in patients treated with immunomodulators (mean (SEM) 5.1 (0.6) minutes for interferon-alpha and 5.0 (0.4) minutes for thymomodulin) than in conventionally treated patients (3.3 (0.4) minutes). Left ventricular ejection fraction during exercise (assessed by radionuclide ventriculography) improved in 9 of 12 patients treated with interferon-alpha, 10 of 12 patients treated with thymomodulin, and 3 of 9 conventionally treated patients at 2 year follow up. The electrocardiogram was normal in 21 (88%) of 24 patients after interferon-alpha or thymomodulin treatment and 2 (22%) of 9 conventionally treated patients. At 2 year follow up, 19 (73%) of 26 patients treated with immunomodulators and 4 (25%) of 12 conventionally treated patients had improved their functional class. CONCLUSIONS: The results suggest that treatment of idiopathic myocarditis and/or idiopathic dilated cardiomyopathy with interferon-alpha or thymomodulin induces an earlier and significantly superior clinical improvement than conventional treatment alone. PMID- 8697166 TI - Additional diagnostic value of multiplane echocardiography over biplane imaging in assessment of mitral prosthetic valves. AB - OBJECTIVE: To evaluate how often multiplane transoesophageal echocardiography yields new or complementary data in mitral prostheses in comparison with the exclusive use of biplane imaging. PATIENTS: 73 consecutive patients with mitral prostheses who underwent multiplane transoesophageal echocardiograpy between January 1993 and December 1994. METHODS: Biplane images (transverse and longitudinal planes) and multiplane images (transverse, longitudinal, and intermediate planes) were recorded on two separate videotapes. The data provided by multiplane transoesophageal echocardiography were evaluated as (a) new data (abnormalities missed by biplane imaging); (b) complementary data (better delineating lesions already visualised by biplane imaging); or (c) redundant data (data already provided by biplane imaging). RESULTS: Multiplane transoesophageal echocardiography revealed new abnormalities in seven patients (9.5%) (thrombi in three and paraprosthetic leaks in the remaining four) and complementary data in nine (12.3%). In patients with paraprosthetic regurgitation, the possibility of continuously visualising the sewing ring by means of sequential angulations allowed the circumferential extension of the leak to be measured. In seven patients with paravalvar regurgitation who underwent surgery, the extension of the leak as measured by the multiplane approach closely corresponded with the surgical data. CONCLUSIONS: In comparison with the exclusive use of biplane imaging, the multiplane approach added new or complementary data in a significant proportion of patients with mitral prostheses. The ability to obtain the sequential adjacent planes allowed a more reliable appraisal of the extension of the leak and other abnormalities. PMID- 8697165 TI - After-effects of exercise on haemodynamics and muscle sympathetic nerve activity in young patients with dilated cardiomyopathy. AB - OBJECTIVE: To determine the after-effects on sympathetic nerve activity and calf and systemic haemodynamics of symptom-limited exercise in young patients with dilated cardiomyopathy. PATIENTS: 14 young patients with dilated cardiomyopathy (mean (SEM) age 35 (2) yr) and 17 healthy controls (age 29 (2) yr). METHODS: Blood pressure, muscle sympathetic nerve activity, calf blood flow, plasma noradrenaline, and stroke volume were recorded during baseline rest and an hour after symptom-limited treadmill exercise (up to 45 min) at 70% of resting heart rate reserve. RESULTS: Before exercise, sympathetic nerve activity (45 (6) v 21 (2) bursts.min-1; P = 0.001) and calf vascular resistance (55 (5) v 31 (3) units; P < 0.0005) were higher in the dilated cardiomyopathy group, and there was a significant correlation between these two variables (r = +0.64; P < 0.001). Patients with ventricular dysfunction exercised for 31 (3) min. In both groups there were significant and similar reductions in diastolic blood pressure, total peripheral resistance, and calf vascular resistance after exercise. Sympathetic nerve activity and plasma noradrenaline were unchanged and there was no longer any relation between muscle sympathetic nerve activity and calf vascular resistance. Cardiac output increased in both groups but, in contrast to healthy controls, mean values for systolic blood pressure and stroke volume (P < 0.005) did not decrease in the cardiomyopathy group. For similar reductions in total peripheral resistance, there were two to three fold greater increases in stroke volume after exercise in patients with left ventricular dysfunction (P < 0.03). There was no relation between exercise duration and the magnitude of these after effects of exercise in these patients. CONCLUSIONS: In young patients with dilated cardiomyopathy the haemodynamic after-effects of submaximal symptom limited exercise resemble responses to pharmacological afterload reduction but are not accompanied by reflex sympathetic activation. Sustained calf and systemic vasodilation after exercise were not attenuated, as compared with healthy controls. These cardiac, peripheral, and sympathoneural after-effects provide further support for exercise training as a non-pharmacological adjunct to the management of chronic stable heart failure. PMID- 8697167 TI - Magnetic resonance spectroscopy in congenital heart disease. AB - OBJECTIVE: To determine the feasibility of studying myocardial and skeletal muscle bioenergetics using 31P magnetic resonance spectroscopy (MRS) in babies and young children with congenital heart disease. SUBJECTS: 16 control subjects aged 5 months to 24 years and 18 patients with CHD, aged 7 months to 23 years, of whom 11 had cyanotic CHD, five had cardiac failure, and two had had a Senning procedure. DESIGN: 31P MRS was carried out using a 1.9 Tesla horizontal 65 cm bore whole body magnet to study the myocardium in 10 patients and skeletal muscle (gastrocnemius) in 14 patients, eight of whom were exercised, together with appropriate controls. RESULTS: In hypoxaemic patients, in skeletal muscle at rest intracellular pH (pHi) was abnormally high [7.06 (SEM 0.04) v 7.04 (0.05), P < 0.01] and showed a positive correlation with haemoglobin (P < 0.03). On exercise, hypoxaemic patients fatigued more quickly but end-exercise pHi and phosphocreatine recovery were normal, implying that an equivalent but smaller amount of work had been performed. End-exercise ADP concentration was lower. On recovery, the initial rate of phosphocreatine resynthesis was low. Skeletal muscle bioenergetics were within normal limits in those in heart failure. In the myocardium, the phosphocreatine/ATP ratio was similar in controls and hypoxaemic subjects, but low in those in heart failure. CONCLUSIONS: In heart failure, the myocardial phosphocreatine/ATP ratio was reduced, as in adults, while resting skeletal muscle studies were normal. By contrast, hypoxaemic children had normal myocardial bioenergetics, but showed skeletal muscle alkalinity, and energy reserves were more readily depleted on exercise. On recovery, the initially slow phosphocreatine resynthesis rate reflects a low rate of mitochondrial ATP synthesis, probably due to an inadequate oxygen supply. 31P MRS offers a safe, non-invasive method of studying myocardial and skeletal muscle bioenergetics in children as young as 5 months. PMID- 8697168 TI - Twenty four hour variation in plasma atrial natriuretic factor during VVI and DDD pacing. AB - OBJECTIVE: To investigate whether plasma atrial natriuretic factor (ANF) follows a pattern of circadian variation similar to that of other hormones in patients paced under VVI and DDD pacing modes and to determine if the known effect of pacing mode on ANF secretion is maintained throughout the 24 hour period. PATIENTS AND DESIGN: 20 patients were studied. They had complete atrioventricular block and had been paced for 17 (SD 3.5) months with a dual chamber multiprogrammable pacemaker. They were divided into two groups according to the duration of pacing in either VVI or DDD mode before the measurements: group A, n = 11 (8 men, 3 women, aged 65 (7) years), each paced for 24 h under each of VVI and DDD modes in random order; group B, n = 9 (7 men, 2 women, aged 63 (8) years), each paced for 60 d under each pacing mode before the measurements. Blood samples were taken and ANF concentrations measured every 4 h over a 24 h period, starting at 09.00. Measurements were also made of plasma cortisol, which has a known circadian pattern, so that the 24 h curve could be compared with that of ANF. RESULTS: In contrast to cortisol, ANF values indicated a pulsatile pattern of secretion throughout the 24 h period, with no clear circadian variation. In group B, ANF concentrations were significantly higher during VVI than during DDD pacing throughout the 24 h period, whereas in group A this difference was statistically significant only at certain times of day. CONCLUSIONS: ANF does not show the circadian pattern of variation shown by cortisol and other hormones. Dual chamber pacing contributes to an improvement not only in cardiac haemodynamics but also in the neuroendocrine system, especially in the long term. PMID- 8697169 TI - Normal coronary angiograms: financial victory from the brink of clinical defeat? AB - OBJECTIVE: To examine the hypothesis that, in patients undergoing coronary angiography for suspected ischaemic heart disease, a normal angiographic result is associated with a fall in consumption of health care resources following the angiogram. DESIGN: Retrospective cost-benefit analysis comparing the 12 month periods before and after coronary angiography. SETTING: Tertiary cardiac referral centre. SUBJECTS: 69 consecutive patients investigated in the financial year 1991 92 whose angiograms were normal. MAIN OUTCOME MEASURES: Drug and hospital admission costs in the 12 month periods before and after angiography; urgent and elective consultations with general practitioner in that time. RESULTS: The mean cost of care per patient in the year before investigation was 656.89 pounds. A highly significant fall in all indices of resource consumption was observed in the year following investigation, the mean resulting difference in the cost of care being 35.15 pounds per month. The cost of coronary angiography would, if this fall were maintained, be recouped in a mean time of 18 months. CONCLUSIONS: Patients suspected on clinical grounds to have coronary atherosclerosis who are found at angiography to have normal coronary arteries are heavy consumers of health care resources. Early investigation for these patients is safe and has beneficial resource consequences in the medium term. PMID- 8697170 TI - Value and impact of necropsy in paediatric cardiology. AB - OBJECTIVE: To assess the current value of necropsy in paediatric cardiology and cardiothoracic surgery and determine its potential impact on clinical practice. DESIGN AND SETTING: Descriptive study of all paediatric cardiac deaths occurring over four years in a tertiary referral centre. Data were obtained from reviewing the hospital files, available necropsy records and specimens, and audit reports. PATIENTS: Paediatric patients with congenital or acquired heart disease, who died of a cardiac cause between January 1992 and July 1995. Inclusion criteria were that the diagnosis of heart disease was made before death, and that patients were managed thereafter medically and/or surgically at the referral centre. The value of necropsy was assessed according to its contribution in establishing the cause of death (confirmed, clarified, precise cause of death uncertain) and the anatomy (simple confirmation or additional information provided). For cases not submitted to necropsy the clinical information relating to the cause of death was assessed and the case assigned as cause of death firm, uncertain, or unknown. RESULTS: One hundred and six deaths were identified (61 males, age at death: one day to 20 years). Seventy occurred early (a month or less) after surgery and were graded as postoperative deaths. The rest were considered to be either medical or late surgical deaths. Necropsy was performed in 59 (55.6%). The precise cause of death was confirmed in 33 (55.9%), clarified in 22 (37.3%), and remained uncertain in four (7.8%). Additional information regarding the anatomy was found in eight (13.6%) cases. In five cases (8.5%) the necropsy detected findings which, if known before death, would probably have improved outcome. For the patients dying without a necropsy, the cause of death remained uncertain in 10 (21.3%) and unknown in seven (14.9%). In 36% of cases, therefore, a firm cause of death that might have been provided by a necropsy was missing. CONCLUSION: In paediatric cardiology necropsy continues to provide clinically relevant information at a high level. It remains vital for ensuring quality of medical care, in instigating improvements in future management, and increasing understanding of congenital heart disease. The procedure should therefore be sought actively in all cases. PMID- 8697171 TI - Open-access paediatric echocardiography: changing role and referral patterns to a consultant-led service in a tertiary referral centre. AB - OBJECTIVES: To evaluate the changing role of an open-access consultant-led paediatric echocardiography service for the detection and assessment of cardiac disease in children. DESIGN: A retrospective analysis comparing two patient groups undergoing echocardiography over two corresponding six month periods in 1989 and 1994. SETTING: A tertiary referral centre. MAIN OUTCOME MEASURES: Patient demographics, indication for echocardiogram, source of referral and findings on scan in new referrals, subsequent follow up arrangements. RESULTS: The total workload increased by 51% over 5 years but in 1994 fewer neonates were scanned. Patients were referred by hospital paediatricians, community paediatricians, and general practitioners and the number of "new referrals" as a percentage of the total number of patients scanned remained constant. The number of children referred with asymptomatic murmurs who had "normal" echocardiograms increased. Fewer patients were referred directly for surgery in 1994, but the number of children referred for interventional catheterisation rose. CONCLUSIONS: Open-access echocardiography has an expanding role in the tertiary referral centre despite increasing availability of echocardiography facilities in local hospitals and increased demand in local outreach clinics with paediatricians. Asymptomatic murmurs continue to be the single most common reason for referral of "new patients" and many scans are used to confirm the clinical suspicion of a "normal" heart. The appropriateness of using echocardiography as a screening procedure must be questioned where it would be more logical to refer only the children who present diagnostic difficulty. None the less these data confirm the impression of increasing demands on the paediatric cardiologist, and thus may be useful in planning consultant services within the specialty. PMID- 8697172 TI - Low energy internal cardioversion of atrial fibrillation resistant to transthoracic shocks. AB - OBJECTIVE: To investigate the efficacy of internal cardioversion using low energy shocks delivered with a biatrial electrode configuration in chronic atrial fibrillation resistant to transthoracic shocks. METHODS: Low energy internal cardioversion was attempted in 11 patients who had been in atrial fibrillation for 233 (SD 193) days and had failed to cardiovert with transthoracic shocks of 360 J in both apex-base and anterior-posterior positions. Synchronised biphasic shocks of up to 400 V (approximately 6 J) were delivered, usually with intravenous sedation only, between high surface area electrodes in the right atrium and the left atrium (coronary sinus in nine, left pulmonary artery in one, left atrium via patent foramen ovale in one). RESULTS: Sinus rhythm was restored in 8/11 patients. The mean leading edge voltage of successful shocks was 363 (46) V [4.9 (1.2) J]. Higher energy shocks induced transient bradycardia [time to first R wave 1955 (218) ms]. No proarrhythmia or other acute complications were observed. CONCLUSIONS: Low energy internal cardioversion of atrial fibrillation can restore sinus rhythm in patients in whom conventional transthoracic shocks have failed. PMID- 8697173 TI - Bronchogenic cyst mimicking an intracardiac mass: diagnosis by magnetic resonance imaging and treatment by needle aspiration. PMID- 8697174 TI - Exertional atrioventricular block presenting with recurrent syncope: successful treatment by coronary angioplasty. PMID- 8697175 TI - Investigation in general practice of patients with suspected heart failure. PMID- 8697176 TI - Investigation in general practice of patients with suspected heart failure. PMID- 8697177 TI - Investigation in general practice of patients with suspected heart failure. PMID- 8697178 TI - Investigation in general practice of patients with suspected heart failure. PMID- 8697179 TI - Investigation in general practice of patients with suspected heart failure. PMID- 8697180 TI - 5-HT4 receptors are not involved in the control of small intestinal transit in the fasted conscious rat. AB - Cisapride and metoclopramide are used clinically in the treatment of gastro oesophageal reflux disease and also in a variety of motility disorders of the gastrointestinal tract. Their prokinetic effect is thought to be due to the augmentation of acetylcholine release from the myenteric plexus, an effect likely to be mediated through the stimulation of 5-HT4 receptors. The role of 5-HT4 receptors in the control of intestinal motility in man and animals is not clear, therefore we have investigated their role in the control of small intestinal transit in the rat. Radioactive microspheres were administered into the proximal duodenum of fasted conscious rats through an indwelling cannula. The extent of small intestinal transit was examined by determining the distribution of the microspheres within the intestine. Following i.p. injection small intestinal transit was inhibited (78%) by atropine (3 mg/kg), suggesting the presence of a basal cholinergic influence. Furthermore, in the presence of p-amino clonidine intestinal transit was stimulated (126%) by bethanechol (3 mg/kg). The 5-HT4 receptor agonists cisapride (1.0 mg/kg) and zacopride (1.0 mg/kg) failed to increase small intestinal transit. The 5-HT4 receptor selective antagonist GR125487 (1 mg/kg) was also without effect. These data suggest that 5-HT4 receptors are not involved in the control of small intestinal transit in the fasted conscious rat. PMID- 8697181 TI - Methods for studying intestinal sensitivity and compliance: in vitro studies of balloons and a barostat. AB - The aim of this study was to compare in vitro various methods for recording intestinal sensitivity and compliance. Relationships between volume and pressure were determined in segments of penrose tubing and pig gut ("artificial intestine') using pressure increments of 2 mmHg (0-24 mmHg). We tested two direct methods of distension of the entire segments (by syringe inflation and the Mayo barostat); we also used three different balloon devices for indirect distension (a 10 cm polyethylene barostat bag, a 10 cm latex condom balloon and a 6 cm latex condom balloon). Maximal distending diameters of the recording systems were measured by injecting from 0 to 160 mL of air. The elastic properties of the balloons were also tested by distensions in air and in rigid tubes. All recording systems accurately detected a lesser compliance of the penrose drain as compared to pig gut. In absolute terms, only the compliance measured with a polyethylene barostat bag distended with a syringe was not different from the compliance of the segment as measured directly. The bellows of our barostat and the latex balloons had significant intrinsic compliances which interfered with the recorded pressure-volume curves. On the other hand, highly compliant plastic bags recorded most faithfully the compliance of artificial gut and that of non-compliant rigid tubes. For comparable volumes of distension, external diameters were larger with the 6 cm latex balloon than with the 10 cm latex balloon or the 10 cm polyethylene barostat balloon. A polyethylene bag distended with a non-compliant air injector (syringe) reflected most accurately the pressure-volume relationships of tubular structures. The different maximal diameters assumed by the three distending devices may explain, in part, why lower volumes of distension are required to elicit symptoms with smaller distending balloons in vivo. PMID- 8697182 TI - Gallbladder motility in vitro in men with gallstones following Billroth II gastric resection. AB - Gastric surgery induces an increased incidence of gallstones. To investigate the changes in gallbladder kinetics after gastric resection, 20 male patients were studied: ten patients undergoing cholecystectomy for gallstones developed after Billroth II gastric resection and ten patients undergoing cholecystectomy for cholelithiasis without previous abdominal surgery. Longitudinal strips from the gallbladder wall were suspended in an organ bath and the isometric tension recorded. Dose-response curves to cholecystokinin-octapeptide and carbachol were obtained. Half the maximal response to cholecysto-kinin-octapeptide was 0.50 +/- 0.11 x 10(-7) M in the first group and 1.36 +/- 0.37 x 10(-7) M in the second group (P < 0.05). The ED50 to carbachol was 24.33 +/- 2.69 x 10(-7) M in the gastrectomy group and 40.39 +/- 5.01 x 10(-7) M in the control group (P < 0.01). There was no significant difference in the maximal contractile response either to cholecystokinin-octa-peptide or carbachol in the two groups. Our study shows an increased gallbladder sensitivity to cholecystokinin-octapeptide and carbachol in patients with gallstones developed after Billroth II gastric resection. PMID- 8697184 TI - Comparison between intraluminal multiple electric impedance measurement and manometry in the human oesophagus. AB - Conventional oesophageal manometry and intraluminal electrical impedance measurement were simultaneously applied in eight healthy volunteers to study the effect of wet and semisolid bolus viscosities on oesophageal motility and bolus transit. Contraction front velocity measured by electrical impedance and manometry were identical for wet and semisolid swallows and highly associated. Bolus front velocity as measured by electrical impedance was significantly faster than contraction front velocity in both wet and semisolid swallows. Bolus front velocity during semisolid swallows was significantly slower compared to wet swallows. It is concluded that intraluminal electrical impedance measurement is a reliable technique to detect oesophageal motility as well as to differentiate between transit of wet and semisolid bolus consistencies. PMID- 8697183 TI - Manometric responses of human duodenum during infusion of HCl, hyperosmolar saline, bile and oleic acid. AB - Duodenal motor activity is incompletely understood. The purpose of this study was to define the contractile patterns of the duodenum that occur in response to rate controlled injection of various solutions. In nine healthy volunteers we placed a six channel perfused catheter, and recorded pressure activity in the antrum, pylorus and duodenum. Volumes of 10 and 20 mL of 0.9% NaCl, 100 mM HCl (pH 1), 5% NaCl (1711 mOsm/kg), human bile and iso-osmolar sodium oleate were randomly injected into the duodenum at 20 ml/min, starting 15 min after phase III migratory motor complex (MMC). A 20 mL bolus of each solution caused more activity (P < 0.05) than a 10 mL bolus, but the motor pattern was similar. The control, 0.9% NaCl, produced occasional pressure waves, whereas bile and sodium oleate induced more (P < 0.05) activity which consisted of low amplitude, isolated or clusters (2-4 cycle/min) of non-propagating pressure waves that occurred at random sites. In three subjects, oleate produced isolated pyloric phasic contractions. In contrast, HCl and 5% NaCl induced high amplitude pressure waves that were seen either at a single channel or at multiple channels, occurring simultaneously. The motility index was also greater (P < 0.05) than that induced by other solutions. Additionally, within 2 min of infusion, a phase III MMC like pattern was observed in five of the nine subjects who received HCl and three of the nine who received 5% NaCl. A non-nutrient iso-osmolar solution induced occasional motor activity. HCl and hyperosmolar solutions induced more frequent and large amplitude, segmental contractions whereas lipid and bile induced fewer and smaller amplitude contractions. The volume, the pH, the osmolar and the nutrient make up of the infusate may each influence the duodenal motor responses. PMID- 8697185 TI - Coordination of biliary and upper gastrointestinal motility in the fasted conscious pig. AB - A chronic pig model was developed which permits the simultaneous measurement of integrated biliary motility as resistance to flow (CBD inflow), gallbladder, duodenal and gastric motility in addition to collection of venous blood samples for gut hormones estimations. Animals displayed a duodenal interdigestive cycle of 55.4 +/- 3.4 min (mean +/- SEM, n = 6), consisting of phase I, II and III (21.2 +/- 2.1, 70.5 +/- 2.0, 8.7 +/- 0.5% of the cycle, respectively). A gastric interdigestive cycle of 60.2 +/- 6.5 min (n = 4) was similarly demonstrated consisting of three phases which corresponded to the three duodenal phases. The gastric phases I, II and III comprised 26.3 +/- 3.0, 71.2 +/- 2.7 and 2.5 +/- 0.8% of the cycle, respectively. The gastric phase III immediately preceded the onset of the duodenal phase III. The gallbladder likewise displayed an interdigestive cycle of 54.5 +/- 7.2 min (n = 6) consisting of a quiescent period (37.2 +/- 3.7% of the cycle) corresponding temporally to duodenal phase III and phase I. This quiescent phase was followed by a period of rhythmic contractions (64.5 +/- 4.1% of the cycle) which corresponded temporally to duodenal phase II. The onset of the gallbladder quiescent period coincided with the onset of duodenal phase III. The CBD inflow similarly demonstrated an interdigestive cycle of 53.4 +/- 9.6 min (n = 4) duration, consisting of three phases. The initial phase was evident as a period of rapid inflow, the onset of which coincided with the onset of duodenal phase III and the gallbladder quiescent period, and occupied 12.0 +/- 0.8% of the cycle. The second phase which occupied 18.0 +/- 7.4% of the cycle, was typified as a period of declining inflow which reached a relatively stable level at a time corresponding to the end of duodenal phase I. The third phase consisted of the maintenance of the inflow rate achieved at the end of the previous phase (60% of maximum inflow), corresponding in onset and duration with duodenal phase II and occupied 70.0 +/- 8.6% of the cycle. Plasma motilin levels fluctuated in relation to the duodenal interdigestive cycle, peaking during phase III relative to phase I (36.9 +/- 8.5 vs 25.4 +/- 7.7 pg mL 1, respectively, n = 5, P < 0.05). Cholecystokinin levels did not fluctuate, remaining low (2.3 +/- 2.1 pM cholecystokinin octapeptide equivalents, n = 5) throughout the duodenal interdigestive cycle, but increased about two fold after ingestion of solid food. Feeding disrupted the gastric, duodenal, gallbladder and CBD inflow cycles. PMID- 8697186 TI - In vitro contractility of stimulated and non-stimulated human gallbladder muscle. AB - In an attempt to define, more clearly, the nature of gallbladder contraction we obtained muscle strips from human gallbladder wall, removed at cholecystectomy. Samples were taken from various areas of the gallbladder to seek evidence of a dominant axis of contraction. The strips were stimulated with increasing concentrations of cholecystokinin-8 (CCK-8) and carbachol, and, to determine maximal contractile force, 0.25 M potassium chloride. No differences were seen between samples taken from the long-itudinal, circular and oblique axes. In a second series of experiments, samples were taken from the body and neck regions of the gallbladder. In these, it was seen that the samples from the body contracted more forcefully than those of the neck tissue and that they were more sensitive to carbachol stimulation. The difference in response to CCK-8 measured in the strips from the body and cystic duct/neck of the gallbladder cannot be explained by a difference in sensitivity to CCK-8, but is mainly due to the difference in the amount of muscle tissue present. Strips from the body are more sensitive to muscarinic stimulation that those from the neck. Overall, there is a functional difference in sensitivity between the body and neck which would serve to facilitate bile flow into the common bile duct during gallbladder contraction. PMID- 8697188 TI - Trauma case management of the multiply injured patient: a case study. AB - The role of the trauma case manager is multifaceted: coordinator, facilitator and educator. It requires an expert knowledge of trauma care and the consequences of injury to the human body. This paper discusses the role of the trauma case manager in the care of a multiply injured trauma patient. The case manager's knowledge and activation of resources, ongoing evaluation, and ability to reset priorities allowed the patient, his family, and the healthcare team to achieve the highest level of function and personal satisfaction. PMID- 8697187 TI - Effects of the corticotropin-releasing factor (CRF) on rectal afferent nerves in humans. AB - Corticotropin-releasing factor (CRF) released in the gastrointestinal mucosa from immune cells or enterochromaffin cells may play a role in the modulation of rectal afferent function. In the current study we evaluated the effects of peripherally administered CRF on afferent mechanisms in the human rectum. We used rectal balloon distention in seven healthy volunteers to evaluate the effect of CRF (1 microgram/kg) on visceral afferents originating in the rectum which are involved in the following functions: thresholds and intensity of conscious perception, receptive relaxation, reflex inhibition of internal anal sphincter and a viscerosomatic reflex. Rectal mechanoreceptors were stimulated either by distending the rectum using a volume ramp (40 and 400 mL/min), or by intermittent phasic distention. CRF decreased the thresholds and increased the intensity for the sensation of discomfort in response to both ramp and phasic distention. During slow ramp distention, CRF also lowered the stool threshold. CRF increased rectal compliance during slow ramp distention without affecting the rate of receptive relaxation or the inflection point of the compliance curve. CRF had no effect on viscerosomatic referral patterns, or on the rectoanal inhibitory reflex. These findings are consistent with a dual effect of CRF on afferent pathways mediating perception of aversive rectal sensations, and on rectal smooth muscle. PMID- 8697189 TI - Fluid and blood warming systems. PMID- 8697190 TI - Top 10 ways to balance trauma patient care with attention to price tag. PMID- 8697191 TI - Change: will it ever stop? PMID- 8697192 TI - A framework of trauma and trauma recidivism in adolescents and young adults. AB - Trauma resulting from violence and unintentional causes has reached epidemic proportions in the United States, particularly among urban adolescents and young adults. Many of these injuries can be predicted because of participation of adolescents and young adults in risky behaviors. In addition, subsequent injuries to survivors can be predicted because of their return to risk taking behavior. This paper presents a model that addresses risk-taking behaviors, antecedents to risk taking, and the possible outcomes, including trauma and trauma recidivism. It focuses attention on the growing problem of trauma and trauma recidivism among adolescents and young adults and identifies implications for research and practice for trauma nurses. PMID- 8697193 TI - Protective effect of diethyldithiocarbamate on mercury-induced toxicity in kidney mitochondria. AB - The protective effect of diethyldithiocarbamate on several functions of kidney mitochondria, isolated from rats poisoned with mercury, was analyzed. The drug, administered at a concentration of 10 mg/ kg body weight to rats treated with a sublethal dose of Hg2+, for example, 2 mg/kg body weight, prevented the mercury induced damage on: a) transmembrane potential, b) ATP synthesis, and c) Ca2+ accumulation. It is demonstrated that such a protective effect of diethyldithiocarbamate is due to its ionophoretic properties on mercury. PMID- 8697196 TI - Comparative teratological studies on TCDD, endrin and lindane in C57BL/6J and DBA/2J mice. AB - The teratogenic effects of endrin and lindane have been determined and compared to those induced by TCDD in the fetuses of C57BL/6J and DBA/2J mice after the administration of single oral doses to pregnant mice on day 12 of gestation. TCDD produced dose-dependent decreases in fetal weight, fetal thymic weight and placental weight, and dose-dependent increases in fetolethality, cleft palate formation and hydronephrosis at doses of 10-30 and 30-60 micrograms/kg body weight in C57BL/6J and DBA/2J mice, respectively. No maternal death was observed at the given doses in both strains of mice. Endrin (4.5 and 6 mg/kg body weight) and lindane (30 and 45 mg/kg body weight) produced significant decreases in fetal weight and placental weight in C57BL/6J and DBA/2J mice, and dose-dependent decreases in fetal thymic weight in C57BL/6J mice but not DBA/2J mice. Endrin and lindane caused 0-25 and 14-25% maternal deaths, respectively, at the above mentioned doses. Neither cleft plate nor hydronephrosis were induced by endrin or lindane in the two strains of mice. The results support the hypothesis that TCDD induced cleft plate and hydronephrosis involve mechanisms that are Ah (aryl hydrocarbon) receptor mediated. However, other fetotoxic effects induced by TCDD, and the fetotoxic effects induced by endrin and lindane may involve additional unknown mechanisms that are not related to the Ah-receptor. PMID- 8697197 TI - Effects of an acute dose of ethanol on dopaminergic and serotonergic systems from rat cerebral cortex and striatum. AB - Intraperitoneal injection 10 min before sacrifice of 1.5 g ethanol/kg weight produced an increase in rat striatal levels of homovanillic acid (HVA) (p < 0.05) but did not affect the striatal concentrations of dopamine (DA), 3,4 dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). A similar ethanol treatment led to decreases in 5-HT (p < 0.05) and 5-HIAA (p < 0.05) from cerebral cortex (prefrontal and anterior cingulate areas). The results point to several ethanol-linked alterations in central serotonergic and dopaminergic systems. PMID- 8697195 TI - Regional differences of endogenous ATP release in rabbit arteries. AB - The releases of endogenous ATP from ear, femoral, renal and pulmonary arteries of rabbit were compared. Adenyl purines, such as ATP, ADP, AMP and adenosine, and norepinephrine (NE) were quantified by HPLC-fluorescence detection and HPLC electrochemical detection, respectively. In all four blood vessels, electrical stimulation (ES) at 16 Hz significantly increased overflow of adenyl purine and NE. ATP was the main largest among adenyl purine released; release of adenosine was very small. The rank order of amounts of total purine released by ES was ear artery > renal artery = femoral artery >> pulmonary artery. There was no significant difference among the amounts of NE release induced by ES from these four arteries. ES-induced purine release was notably reduced by denudation of endothelium and prazosin at 1 muM. Methoxamine, alpha 1-adrenoceptor agonist, also produced release of adenyl purines in the four arteries. The rank order of amount of total purine released was ear artery > renal artery = femoral artery >> pulmonary artery. These suggest that the sources of ATP released by sympathetic nerve stimulation, which seems to be alpha 1-adrenoceptors on endothelial cells, not distributed homogeneously in the vasculature. PMID- 8697194 TI - The presence of the mu3 opiate receptor in invertebrate neural tissues. AB - A previous report demonstrated the presence of the newly discovered opiate alkaloid selective and opioid peptide insensitive mu3 receptor in ganglia of several invertebrate- and one vertebrate species as well as in microglial cells that had egressed from these ganglia after their maintenance in culture medium for several days. In the present study carried out in two representatives of invertebrates, the binding densities of this receptor determined in intact ganglia were compared with those in ganglia depleted of microglial cells. The aim was to ascertain whether the differences in binding capacity recorded in those two groups of ganglia might give an indication of the possible presence of this opiate receptor in nonmicroglial components of the nervous tissue, i.e., neurons. Within a period of 72 h of incubation, the gradual reduction in binding density had reached a plateau, in accordance with the termination of the egress of microglia. The fact that at least two thirds of the binding capacity of mu3 receptors were retained by the ganglia strongly suggests that part of this capacity may be attributed to neurons. This view is supported by additional data, in particular the demonstration of endogenous morphine in nervous tissue and its localization within distinct neurons. PMID- 8697198 TI - Stimulation of arachidonic acid mobilization by adherence of resident peritoneal macrophages to plastic substrate. AB - To interpret results of studies on arachidonic acid (AA) mobilization and metabolism in vitro, it is essential that the influence of culture and conditions should be well defined. Thus, we investigated the effects of murine resident peritoneal macrophage adherence and the presence of foetal calf serum in culture medium on arachidonic acid mobilization. The present data demonstrate that [3H] AA mobilization was triggered simply by contact between cell and substrate. The presence of serum can modulate cell-substrate interactions but not AA mobilization. Protein kinase C, and calmodulin inhibitors failed to inhibit [3H] AA release induced by cell adherence. Finally, low molecular weight PLA2 inhibitors were not able to inhibit [3H] AA mobilization stimulated by cell adherence. PMID- 8697199 TI - The stimulatory effect of L-glutamate and related agents on inositol 1,4,5 trisphosphate production in the cestode Hymenolepis diminuta. AB - The effects of L-glutamate, acetylcholine, and serotonin (5HT) were examined on generation of inositol 1,4,5-triphosphate [Ins(1,4,5)P3], in membrane preparations of the cestode Hymenolepis diminuta. Only L-glutamate and acetylcholine stimulated a significant elevation in Ins(1,4,5)P3. The response to L-glutamate was stereospecific; D-glutamate or L-aspartate were not as potent. A role for G-protein(s) was supported by the observations that sodium fluoride stimulated Ins(1,4,5)P3 generation, and the L-glutamate response was potentiated by GTP and GTP-S and was suppressed by GDPS. However, studies with pertussis and cholera toxins indicated that the putative G-protein(s) was not pertussis or cholera toxin sensitive. The pharmacological profile of the L-glutamate response was examined partially. Trans-ACPD was a very effective agonist at 10(-5)M. While 10(-3)M L-glutamate, NMDA, and AMPA significantly elevated Ins(1,4,5)P3 levels, quisqualate and kainate did not. The elevation of Ins(1,4,5)P3 levels by L glutamate and NMDA was antagonized by the specific glutamatergic antagonists AP 5, AP-7, CNQX, and CPP. While the response to ACPD was antagonized by AP5, CPP and CPG, CNQX was without effect. Collectively, the data support the hypothesis that in the cestode H. diminuta, L-glutamate activation of a metabotropic (ACPD) and/or ionotropic-like AMPA/NMDA receptor subtypes proceeds via a G protein(s) to enhance phospholipase C activity, ultimately resulting in the elevation of Ins(1,4,5)P3 levels in the tissues. PMID- 8697200 TI - [The choice of the method for surgical intervention in patients with a hemorrhaging pyloroduodenal ulcer taking into account gastric helicobacteriosis]. PMID- 8697201 TI - [The action of oxygen on Campylobacter pylori]. PMID- 8697202 TI - [Gastric and duodenal motor function before and after performing gastric resection for ulcerative pyloric stenosis]. PMID- 8697203 TI - [Closure of the duodenal stump in a penetrating low-lying ulcer]. PMID- 8697204 TI - [Decompression of the digestive tract and enteral feeding after performing an operation on the esophagus and stomach]. PMID- 8697205 TI - [A clinical evaluation of the efficacy of using Zanocin (ofloxacin) in surgery]. PMID- 8697206 TI - [The prevention of surgical wound suppuration in abdominal surgery]. PMID- 8697207 TI - [The functional activity of primed neutrophilic granulocytes in patients with suppurative-septic complications]. PMID- 8697209 TI - [The indications for the combined surgical treatment of patients with complicated insulin-dependent diabetes mellitus]. PMID- 8697208 TI - [Changes in the immune status of patients with rectal cancer while using specific immunotherapy]. PMID- 8697211 TI - [Deportalization of the pancreatic venous outflow in the combined treatment of diabetics]. PMID- 8697212 TI - [The experience of the first year of operations of a regional transplantation center]. PMID- 8697210 TI - [Iridological indices in cancerous and precancerous stomach diseases]. PMID- 8697213 TI - [Orthotopic liver transplantation in an experiment using suture-free methods for joining vessels]. PMID- 8697214 TI - [Intramural hemodynamics in the large intestine during measured blood loss in combination with occlusion of the inferior mesenteric artery in an experiment]. PMID- 8697216 TI - [Regional adjuvant chemotherapy in colorectal cancer]. PMID- 8697215 TI - [Emergency surgical care for the rural population]. PMID- 8697218 TI - [Catheterization of the umbilical vein in liver diseases]. PMID- 8697217 TI - [The use of laparostomy in treating peritonitis]. PMID- 8697219 TI - [Gastric resection for peptic ulcer in patients with obesity]. PMID- 8697220 TI - [The clinical manifestations of injury to the duodenum]. PMID- 8697221 TI - [The use of splenic artery embolization in treating complicated liver cirrhosis]. PMID- 8697222 TI - [Profuse hemorrhage from an ulcerating leiomyosarcoma of the stomach]. PMID- 8697224 TI - [A repeat reconstructive intervention after performing an extensive Garlock operation for neoplasm of the cardia]. PMID- 8697223 TI - [The observation over the course of 28 years of a female patient operated on three times for recurrent insulinoma]. PMID- 8697225 TI - [A case of profuse intestinal hemorrhage in typhoid fever]. PMID- 8697226 TI - [The surgical treatment of a biliary cyst combined with calculous cholelithiasis at a district hospital]. PMID- 8697227 TI - Effect of binocular cortical misalignment on ocular dominance and orientation selectivity. AB - We model a two-eye visual environment composed of natural images and study its effect on single cell synaptic modification. In particular, we study the effect of binocular cortical misalignment on receptive field formation after eye opening. We show that binocular misalignment affects principal component analysis (PCA) and Bienenstock, Cooper, and Munro (BCM) learning in different ways. For the BCM learning rule this misalignment is sufficient to produce varying degrees of ocular dominance, whereas for PCA learning binocular neurons emerge in every case. PMID- 8697228 TI - A numerical study on learning curves in stochastic multilayer feedforward networks. AB - The universal asymptotic scaling laws proposed by Amari et al. are studied in large scale simulations using a CM5. Small stochastic multilayer feedforward networks trained with backpropagation are investigated. In the range of a large number of training patterns t, the asymptotic generalization error scales as 1/t as predicted. For a medium range t a faster 1/t2 scaling is observed. This effect is explained by using higher order corrections of the likelihood expansion. It is shown for small t that the scaling law changes drastically, when the network undergoes a transition from strong overfitting to effective learning. PMID- 8697229 TI - Effects of nonlinear synapses on the performance of multilayer neural networks. AB - The problems arising from the use of nonlinear multipliers in multilayer neural network synapse structures are discussed. The errors arising from the neglect of nonlinearities are shown and the effect of training in eliminating these errors is discussed. A method for predicting the final errors resulting from nonlinearities is described. Our approximate results are compared with the results from circuit simulations of an actual multiplier circuit. PMID- 8697230 TI - Modeling slowly bursting neurons via calcium store and voltage-independent calcium current. AB - Recent experiments indicate that the calcium store (e.g., endoplasmic reticulum) is involved in electrical bursting and [Ca2+]i oscillation in bursting neuronal cells. In this paper, we formulate a mathematical model for bursting neurons, which includes Ca2+ in the intracellular Ca2+ stores and a voltage-independent calcium channel (VICC). This VICC is activated by a depletion of Ca2+ concentration in the store, [Ca2+]cs. In this model, [Ca2+]cs oscillates slowly, and this slow dynamic in turn gives rise to electrical bursting. The newly formulated model thus is radically different from existing models of bursting excitable cells, whose mechanism owes its origin to the ion channels in the plasma membrane and the [Ca2+]i dynamics. In addition, this model is capable of providing answers to some puzzling phenomena, which the previous models could not (e.g., why cAMP, glucagon, and caffeine have ability to change the burst periodicity). Using mag-fura-2 fluorescent dyes, it would be interesting to verify the prediction of the model that (1) [Ca2+]cs oscillates in bursting neurons such as Aplysia neuron and (2) the neurotransmitters and hormones that affect the adenylate cyclase pathway can influence this oscillation. PMID- 8697231 TI - Type I membranes, phase resetting curves, and synchrony. AB - Type I membrane oscillators such as the Connor model (Connor et al. 1977) and the Morris-Lecar model (Morris and Lecar 1981) admit very low frequency oscillations near the critical applied current. Hansel et al. (1995) have numerically shown that synchrony is difficult to achieve with these models and that the phase resetting curve is strictly positive. We use singular perturbation methods and averaging to show that this is a general property of Type I membrane models. We show in a limited sense that so called Type II resetting occurs with models that obtain rhythmicity via a Hopf bifurcation. We also show the differences between synapses that act rapidly and those that act slowly and derive a canonical form for the phase interactions. PMID- 8697232 TI - A Bayesian evolutionary distance for parametrically aligned sequences. AB - There is an inherent relationship between the process of pairwise sequence alignment and the estimation of evolutionary distance. This relationship is explored and made explicit. Assuming an evolutionary model and given a specific pattern of observed base mismatches, the relative probabilities of evolution at each evolutionary distance are computed using a Bayesian framework. The mean or the median of this probability distribution provides a robust estimate of the central value. The evolutionary distance has traditionally been computed as zero for an observed homology of 20 bases with no mismatches; we prove that it is highly probable that the distance is greater than 0.01. The mean of the distribution is 0.047, which is a better estimate of the evolutionary distance. Bayesian estimates of the evolutionary distance incorporate arbitrary prior information about variable mutation rates both over time and along sequence position, thus requiring only a weak form of the molecular-clock hypothesis. The endpoints of the similarity between genomic DNA sequences are often ambiguous. The probability of evolution at each evolutionary distance can be estimated over the entire set of alignments by choosing the best alignment at each distance and the corresponding probability of duplication at that evolutionary distance. A central value of this distribution provides a robust evolutionary distance estimate. We provide an efficient algorithm for computing the parametric alignment, considering evolutionary distance as the only parameter. These techniques and estimates are used to infer the duplication history of the genomic sequence in C. elegans and in S. cerevisiae. Our results indicate that repeats discovered using a single scoring matrix show a considerable bias in subsequent evolutionary distance estimates. PMID- 8697233 TI - Probabilistic learning in immune network: weighted tree matching model. AB - Adaptive learning properties (of clonal selection and affinity maturation) in the immune network model are investigated in this paper under a nonlinear data structural representation of the involved molecules. Weighted trees are constructed to model the multiple paratopes/epitopes on the antibodies/antigens. Parallel computing experiments are carried out for the canonical coding of these trees and the corresponding multiple matching interactions. Our experiments on real data have shown significant results on the cognitive properties of the immune network. These and other computational results are presented along with a discussion of future applications. PMID- 8697234 TI - Improving prediction of protein secondary structure using structured neural networks and multiple sequence alignments. AB - The prediction of protein secondary structure by use of carefully structured neural networks and multiple sequence alignments has been investigated. Separate networks are used for predicting the three secondary structures alpha-helix, beta strand, and coil. The networks are designed using a priori knowledge of amino acid properties with respect to the secondary structure and the characteristic periodicity in alpha-helices. Since these single-structure networks all have less than 600 adjustable weights, overfitting is avoided. To obtain a three-state prediction of alpha-helix, beta-strand, or coil, ensembles of single-structure networks are combined with another neural network. This method gives an overall prediction accuracy of 66.3% when using 7-fold cross-validation on a database of 126 nonhomologous globular proteins. Applying the method to multiple sequence alignments of homologous proteins increases the prediction accuracy significantly to 71.3% with corresponding Matthew's correlation coefficients C alpha = 0.59, C beta = 0.52, and Cc = 0.50. More than 72% of the residues in the database are predicted with an accuracy of 80%. It is shown that the network outputs can be interpreted as estimated probabilities of correct prediction, and, therefore, these numbers indicate which residues are predicted with high confidence. PMID- 8697235 TI - A simple flexible program for the computational analysis of amino acyl residue distribution in proteins: application to the distribution of aromatic versus aliphatic hydrophobic amino acids in transmembrane alpha-helical spanners of integral membrane transport proteins. AB - We describe a simple, flexible program (AAD) with a primary function of depicting the distribution of aliphatic and aromatic amino acid residues along the linear aligned sequence of a family of homologous proteins and a secondary function of depicting the distribution of all amino acids along the same linear sequence. The program is used to examine the distribution of aromatic versus aliphatic residues in representative well-characterized families of polytopic membrane proteins. Many but not all such protein families are shown to exhibit a predominance of aliphatic residues in the central regions of their transmembrane spanners but a predominance of aromatic residues at the peripheries of their spanners. We propose that this distribution stabilizes the hydrophobic-hydrophilic interface and renders the centers of these integral membrane proteins more fluid than their peripheries. PMID- 8697236 TI - Complete families of linear invariants for some stochastic models of sequence evolution, with and without the molecular clock assumption. AB - For various models of sequence evolution, the set of linear functions of the frequencies of the nucleotide patterns forms a vector space, the invariant space. Here we distinguish between the model of nucleotide substitution, and the phylogenetic tree T describing the paths on which these changes occur. We describe a procedure to construct a basis of the invariant space for those models that are extensions of models incorporating Kimura's three substitution model of nucleotide change, including both the Jukes-Cantor and Cavender-Farris models. The dimension of the invariant space is determined, for those models where it is independent of the tree topology, as a function of the number of sequences. These are calculated where the nucleotide distribution at the root is unspecified, and both with, and without, the assumption of the molecular clock hypothesis. The invariants have a number of potential applications, including tree identification, and testing the fit of models (which could include the molecular clock) to sequence data. PMID- 8697237 TI - Integrated access to metabolic and genomic data. AB - The EcoCyc system consists of a knowledge base (KB) that describes the genes and intermediary metabolism of Escherichia coli, and a graphical user interface (GUI) for accessing that knowledge. This paper addresses two problems: How can we create a GUI that provides integrated access to metabolic and genomic data? We describe the design and implementation of visual presentations that closely mimic those found in the biology literature, and that offer hypertext navigation among related entities, and multiple views of the same entity. We employ a frame knowledge representation system (FRS) called HyperTHEO to manage the EcoCyc knowledge base. Among the advantages of FRSs are an expressive data model for capturing the complexities of biological information, and schema-evolution capabilities that facilitate the constant schema changes that biological databases tend to undergo. HyperTHEO also includes rule-based inference facilities that are the foundation of expert systems, a constraint language for maintaining data integrity, and a declarative query language. A graphic KB editor and browser allow the EcoCyc developers to interactively inspect and modify this evolving KB. PMID- 8697238 TI - Approximate matching of network expressions with spacers. AB - Two algorithmic results are presented that are pertinent to the matching of patterns typically used by biologists to describe regions of macromolecular sequences that encode a given function. The first result is a threshold-sensitive algorithm for approximately matching both network and regular expressions. Network expressions are regular expressions that can be composed only from union and concatenation operators. Kleene closure (i.e., unbounded repetition) is not permitted. The algorithm is threshold-sensitive in that its performance depends on the threshold, k, of the number of differences allowed in an approximate match. This result generalizes the O(kn) expected-time algorithm of Ukkonen for approximately matching keywords. The second result concerns the problem of matching a pattern that is a network expression whose elements are approximate matches to network or regular expressions interspersed with specifiable distance ranges. For this class of patterns, it is shown how to determine a backtracking procedure whose order of evaluation is optimal in the sense that its expected time is minimal over all such procedures. PMID- 8697239 TI - Fast protein folding in the hydrophobic-hydrophilic model within three-eighths of optimal. AB - We present performance-guaranteed approximation algorithms for the protein folding problem in the hydrophobic-hydrophilic model (Dill, 1985). Our algorithms are the first approximation algorithms in the literature with guaranteed performance for this model (Dill, 1994). The hydrophobic-hydrophilic model abstracts the dominant force of protein folding: the hydrophobic interaction. The protein is modeled as a chain of amino acids of length n that are of two types; H (hydrophobic, i.e., nonpolar) and P (hydrophilic, i.e., polar). Although this model is a simplification of more complex protein folding models, the protein folding structure prediction problem is notoriously difficult for this model. Our algorithms have linear (3n) or quadratic time and achieve a three-dimensional protein conformation that has a guaranteed free energy no worse than three eighths of optimal. This result answers the open problem of Ngo et al. (1994) about the possible existence of an efficient approximation algorithm with guaranteed performance for protein structure prediction in any well-studied model of protein folding. By achieving speed and near-optimality simultaneously, our algorithms rigorously capture salient features of the recently proposed framework of protein folding by Sali et al. (1994). Equally important, the final conformations of our algorithms have significant secondary structure (antiparallel sheets, beta-sheets, compact hydrophobic core). Furthermore, hypothetical folding pathways can be described for our algorithms that fit within the framework of diffusion-collision protein folding proposed by Karplus and Weaver (1979). Computational limitations of algorithms that compute the optimal conformation have restricted their applicability to short sequences (length < or = 90). Because our algorithms trade computational accuracy for speed, they can construct near-optimal conformations in linear time for sequences of any size. PMID- 8697240 TI - A mathematical solution to a network designing problem. AB - One of the major open issues in neural network research includes a Network Designing Problem (NDP): find a polynomial-time procedure that produces minimal structures (the minimum intermediate size, thresholds and synapse weights) of multilayer threshold feed-forward networks so that they can yield outputs consistent with given sample sets of input-output data. The NDP includes as a subproblem a Network Training Problem (NTP) where the intermediate size is given. The NTP has been studied mainly by use of iterative algorithms of network training. This paper, making use of both rate distortion theory in information theory and linear algebra, solves the NDP mathematically rigorously. On the basis of this mathematical solution, it furthermore develops a mathematical solution procedure to the NDP that computes the minimal structure straightforwardly from the sample set. The procedure precisely attains the minimum intermediate size, although its computational time complexity can be of nonpolynomial order at worst cases. The paper also refers to a polynomial-time shortcut of the procedure for practical use that can reach an approximate minimum intermediate size with its error measurable. The shortcut, when the intermediate size is prespecified, reduces to a promising alternative as well to current network training algorithms to the NTP. PMID- 8697241 TI - [Experimental study and clinical application of rapid diagnosis of systemic candida albicans infection in burns by polymerase chain reaction]. AB - For rapid diagnosis of systemic candidiasis, the polymerase chain reaction (PCR) was used to amplify a segment of Candida albican DNA coding for the cytochrome P450 L1 A1 in vitro. The technique provided unambiguous evidence of the presence of Candida albicans in as short as 8 hours with a detection threshold of 20 organisms. 200 blood and 120 urine specimens were collected from thirty rabbits with burn and candidiasis. Specimens of blood (n = 6), urine (n = 6), sputum (n = 7) and wound exudate (n = 7) were also collected from eight serious burn patients. PCR technique was used in all the specimens, and the result was compared with conventional fungus culture. It was shown that: (1) The positive detection rate of Candida by PCR was significantly higher than by culture for blood specimens (P < 0.01) and serial specimens of urine (P < 0.05) in infected burn animals. The clinical specimens showed the same results; (2) In evaluating diagnostic value of PCR for systemic Candida albicans infection, it was found that sensitivity, accuracy and negative prediction rate were superior to the conventional culture method. These results suggest that PCR technic may provide a rapid sensitive and specific means for the diagnosis of systemic Candida albicans infection. In addition, it may be helpful in the evaluation of therapeutic response or recurrence of infection. PMID- 8697242 TI - [An investigation into antibiotic resistance and plasmid pattern of Enterobacter cloacae in burn infection]. AB - In view of a high positive isolation rate and resistance to antibiotics of Enterobacter cloacae in our department, 32 strains of E. cloacae, which were isolated from blood and infected wounds of burned patients from June through November 1990, were randomly selected to determine their susceptibility to 21 antibiotics and their plasmid patterns. It was found that 29 of 32 strains were resistant to at least nine antibiotics, while the other three strains were relatively sensitive. 27 of 32 strains of E. cloacae were tested for plasmid, and among them, three strains (relatively sensitive to antibiotics) contained no plasmid. The plasmid patterns of the other 24 isolates varied with strains, but all of them had a 80 kb plasmid. The 80 kb plasmid was obviously related to the high isolation rate and high resistance to antibiotics of E. cloacae isolated in our department. PMID- 8697243 TI - [Preliminary study on multi-resistant gene location of 20 strains of Pseudomonas aeruginosa]. AB - 20 strains of Pseudomonas aeruginosa were isolated from burn patients of Xijing Hospital in Xi'an. These 20 strains which showed resistance to multiple antibiotics were selected to be studied regarding the location of multi-resistant gene. According to the sensitivity tests before and after plasmid removal, we found that in 70% of the bacteria resistance to multiple antibiotics was mediated by the plasmid. In 30% the bacteria remained resistant to antibiotics after plasmids were removed. Two explanations were postulated. (1) plasmids were not removed completely; (2) resistance gene was encoded by the chromosomes. PMID- 8697244 TI - [Assessment of effectiveness of AgSD-ZnSD-Azone cream, negative ion irradiation and "moisture burn ointment" in prevention of burn wound infection as judged by changes in LPS, TNF and ET levels]. AB - 40 Wistar rats were scalded resulting in 15% TBSA full-thickness burn. Pseudomonas aeruginosa (10(9)/ml) was seeded on the wounds. The animals were divided into 4 groups. AgSD and ZnSD (with Azone) cream was applied to the wounds in the group I. The wounds were irradiated with negative ion current in the group II. The "moisture burn ointment" was applied to the wounds in the group III. Group IV consisted of controls without any treatment. Judging by changes in levels of LPS, TNF and ET, it was shown that the best result was obtained in the group I and II. The "moisture burn ointment" group yielded the poorest results. PMID- 8697245 TI - [Statistical analysis of 4,547 burn patients and the mortality in different periods]. AB - 4,547 burn patients from 1983-1993 were reviewed by analysing the general data, mortality, and the causes of the death, and the mortality of 606 burn patients in different periods from 1958 to 1993. The purpose was to present some statistical and epidemiological data. The results showed: The incidence of burn injury in children, whose ages were less than 5 years, reached 36.2%, and the causes of burn was mainly thermal injury. The total mortality was 3.2%, and the main cause of the death was burn wound sepsis. No significant difference in the relationship between the mortality and the burn wound area was observed in these burn patients. In different age groups, the size of III degree burn, which accounted for higher mortality, was much different. The incidence of burn wound sepsis, which was the main cause of mortality, was on the increase, as the analysis of 606 burn patients in four different periods from 1958-1963 showed. In regard to the cure rate, the improvement had not been obvious since 1983. PMID- 8697246 TI - [Effect of hyaluronic acid-stimulating factor on scar formation in wound healing process of deep partial thickness burns]. AB - Hyaluronic acid-stimulating factor (HASF) was purified from the amniotic fluid and fetal serum of the gestational rabbit by means of affinity chromatography. After topical application of HASF on the deep partial thickness burn wounds, the level of hyaluronic acid (HA) in wound exudate was determined daily during the early period of healing. One month after wound healing, the local skin was harvested for collagen analysis. Histologic study was made to check the outline of collagen fibrils. The HASF was also used in rabbit fibroblast culture. The HA level contained in the supernatant was assayed. Result showed that HASF could elevate and maintain the HA level in the extracellular matrix of burn wound. In vitro, HASF was able to stimulate the fibroblast to produce hualuronic acid. The presence of HA in extracellular matrix then modulated collagen synthesis in the process of wound repair resulting in a higher content of type III collagen, thus bringing about a scarless healing of the deep patrial thickness burns. PMID- 8697247 TI - [A study on the factors influencing bFGF to improve wound healing in severe burn]. AB - The factors influencing basic fibroblast growth factor (bFGF) to improve wound healing in severe burn were studied. Rats were subjected to 15% III degrees burn. The results showed that high activity of bFGF was maintained after escharectomy in early period. In treated group 84.0% of rats wound healing was observed on the 40th day, while it was 9.0% in control group. Heparin could enhance activity of bFGF to stimulate formation of granulation tissue, regeneration of capillary, proliferation of fibroblast and DNA synthesis. Control of infection was beneficial to preserve activity of bFGF. The authors believe that the proper time to use bFGF is one week after injury. PMID- 8697248 TI - [The change in tissue oxygenation after severe steam inhalation injury]. AB - Tissue oxygenation was observed in dogs inflicted with steam inhalation injury in this study. Main findings were as follows: there was significant decrease in cardiac output (CO), oxygen delivery (DO2), alveolar oxygen partial pressure (PAO2), arterial oxygen partial pressure (PaO2), mixed venous oxygen partial pressure (PVO2), arterial oxygen saturation (SaO2), mixed venous oxygen saturation (SVO2), and pH (P < 0.01), and marked increase in P(A-a)O2, oxygen extraction ratio (ERO2), and arterial carbon dioxide partial pressure (PaCO2) (P < 0.01 and P < 0.05). However there was no obvious change in oxygen consumption rate (VO2) within four hours after inhalation injury. The results indicated that the tissue hypoxia was caused directly by insufficient blood perfusion and oxygen supply as well. PMID- 8697249 TI - [Maintenance of the auriculocephalic sulcus in total auricle reconstruction]. AB - The auriculocephalic sulcus is important for the position and shape of a reconstructed ear. With an additional cartilage graft, the sulcus has been created in 31 cases since 1985 and the results have been satisfactory. In the first stage of auricle reconstruction while assembling and implanting cartilage framework, a piece of cartilage was buried in the subcutis of the donor site. Three months later in the second stage, after the framework was elevated, the stored cartilage was taken out, carved and fixed between the auricular framework and the periosteum of the skull, which then was covered with a retroauricular fascial flap. The raw surface was covered with skin graft. PMID- 8697250 TI - [Simultaneous nasal reconstruction and facial defect repair using expanded forehead flap]. AB - The expanded forehead flap has been used to reconstruct the nose and repair facial defects simultaneously since Sept. 1991. During operation, the expanded flap was divided into two parts: one based on the supratrochlear vessels for nasal reconstruction, the other based on the frontal branch of the superficial temporal vessel for the facial defects, e.g. periorbital or zygomatic area, upper or lower lip. Four patients were treated with this method and satisfactory results obtained. PMID- 8697251 TI - [Copper needle puncturing for the treatment of cavernous hemangioma]. AB - From the beginning of 1990 to Oct. 1993, we have treated 31 patients with cavernous hemangioma using copper needle puncturing. Three months' to one and half years' follow-up showed positive effects in all cases. The paper describes general and local reaction of the treatment, the changes in blood copper concentration and echocardiography and complications. PMID- 8697252 TI - [Effects of copper needling therapy on cavernous hemangioma assessed by echogram]. AB - Thirty-one patients with subcutaneous cavernous hemangioma were observed by echogram before and after treatment with copper needling. Different characteristics of echogram were found in hemangioma before and after treatment. Color Doppler imaging gave great help in the diagnosis and treatment of this disease and follow-up. PMID- 8697253 TI - [Correction of the secondary nasal deformity in bilateral cleft lip with a new technique]. AB - Bilateral cleft lip often has nasal deformities of various degrees. It is not enough to elongate the nasal columella for such deformities. Based on the thoughts that secondary deformities of the nose and lip should be treated as a whole, the authors introduced a new technique, in which five aspects of the deformities were considered and treated at the same time. Thirteen patients have undergone surgical correction with satisfactory results. PMID- 8697254 TI - [Second nose contouring with two kinds of alloplastic implants]. PMID- 8697255 TI - [Histomorphology research of keloid in different regions]. AB - In order to explore the mechanism of keloid and provide scientific basis for clinical treatment, we carried out a study on histomorphologic comparison of keloids of different tissues. Based on the histomorphologic features, a keloid was divided into three different parts: invasive, proliferative and aged parts. Its pathologic process was described as invasive period, proliferative period, stable period and aging period, to provide scientific basis for treatment. PMID- 8697256 TI - [Observations of blood circulation disturbance in random skin flap]. AB - Thirty-nine rats were used to study the mechanism of random flap necrosis. A random flap (3 cm x 9 cm) created on the back of each rat was observed with naked eye, microscope, skin thermometer and laser Doppler flowmeter. The average surviving length of the flap was 4.69 +/- 0.47 cm. We found that the following observations indicated circulation disturbance in the "shock flap": After surgery, the color of the flap became dark; skin temperature kept falling; when the room temperature was about 20 degrees C, the flap temperature was below 28.5 29.0 degrees C; at one hour postoperation, LDF value decreased more than 50%; microcirculation of the flap stagnated without recovery. We conclude that necrosis of the flap can be fully predicted. PMID- 8697257 TI - [Experimental study on rapid expansion of soft tissue]. AB - Nine white pigs weighing about 15 kg were divided into three groups: rapid expansion group (REG), conventional expansion group (CEG) and control group (CON). Expansion was carried out under monitoring of interal pressure of the expander and blood flow of the skin over the expander. After completion of expansion, hemodynamic, physical, histologic and ultrastructure changes of the expanded skin were measured and recorded. The study showed: (1) The immediate retraction ratios of skin of three groups were 41.37%, 20.82% and 10.01%, respectively (P < 0.01). (2) The thickness of the epidermis of the three groups was not statistically different, though the dermis of the expanded skin was thinner than that of the control (P < 0.01). (3) The density of collagen in the dermis of the three groups was 80.57 +/- 5.47, 79.49 +/- 6.31 and 82.72 +/- 2.69, respectively; the density of elastin of the three groups was 2.88 +/- 1.24, 2.77 +/- 0.74 and 2.56 +/- 0.63, respectively (P < 0.05). We concluded that the delay phenomenon of the expanded flap depends mainly on the intensity of expansion. The immediate retraction ratio of the rapidly expanded skin was greater than that of conventionally expanded skin. Rapid expansion also results in tissue hypertrophy but does not cause destruction of collagen. With proper calculating the size of the defect and estimating immediate skin retraction, rapid expansion is feasible in clinical applications. PMID- 8697258 TI - [Using temporal bone artificial implantation for the fixation of external ear prosthesis]. PMID- 8697259 TI - Interactions with terfenadine. PMID- 8697260 TI - New hope for treatment of Lou Gehrig's disease. PMID- 8697261 TI - Cardiovascular diseases in women: an equal opportunity killer. AB - Despite the public perception that heart disease primarily affects men, as women age, their risk equals and eventually outpaces that of men. Gender-specific differences in cardiovascular diseases have been reported related to onset, diagnosis, therapy, pharmacokinetics, adverse drug reactions, and mortality rates, but most of these differences are unexplained. Research in coronary heart disease has been performed almost exclusively in men, but the findings have been used to set standards for both sexes. Studies suggest a 50% reduction in heart disease risk among women receiving postmenopausal hormone replacement therapy. PMID- 8697262 TI - Screening for peripheral arterial disease. AB - Peripheral arterial disease (PAD) is an age-dependent condition that limits ambulation and compromises quality of life in an estimated two million Americans. Early detection and treatment is essential for minimizing the signs and symptoms of PAD. Using a methodology developed by the National Council on the Aging, a noninvasive screening program was conducted for this disease in a population of 1,092 elderly ambulatory Rhode Island residents. Possible PAD was detected in 17.7% of the subjects, while 42% were identified as being at high risk for the disease. PMID- 8697263 TI - Understanding capitation and pharmaceutical care. AB - Although capitation has not yet emerged as the predominant mode of payment for health care, many experts believe that this will happen within a few years, and that capitation will predominate among methods to pay for pharmaceutical care services as well. Capitation is confusing because it exists in many forms. This article: Explains alternative forms of capitation for pharmaceutical care services. Offers some thoughts on what might be acceptable and not-so-acceptable forms from the perspective of the pharmacy manager. PMID- 8697264 TI - Advertising health risk products: ethics vs. economics. PMID- 8697265 TI - Getting the most from your employee benefits: retirement plans. PMID- 8697267 TI - Clinical monitoring plans for the delivery of pharmaceutical care. PMID- 8697266 TI - APhA House of Delegates adopts 13 new policies. PMID- 8697268 TI - [Adoption of health promotion behaviors in first-year baccalaureate nursing students: pilot study]. AB - The goal of this pilot study was to test the usefulness of Pender's (1987) theoretical model in predicting the adoption of health-promotion behaviours in 176 first-year undergraduate nursing students. Hierarchical regression analysis indicated that the perception of self-efficacy, perception of one's state of health, the influence of professors, and place of birth are predictive variables of health-promoting behaviours in this group. The results of this study suggest, among other things, that it is important for professors to use strategies that foster and support students' confidence in their ability to commit to health promoting behaviours. A longitudinal study currently in progress will examine whether a health-oriented program significantly influences the adoption of health promotion behaviours in nursing students during their university education. PMID- 8697269 TI - Hospital nurses and health promotion. AB - This study examined the role of acute-care nurses in health promotion (HP), using a survey designed to measure the knowledge, attitudes, and practices of nurses in relation to HP. Staff nurses in eight British Columbia hospitals surveyed in 1992 responded that HP is an integral part of nursing care, yet several barriers in the hospital environment inhibit their efforts in this domain. The perceived barriers are lack of time, insufficient resources for patient teaching, and lack of continuity of care. Respondents identified positive features as the attitudes of patients and families, supportive colleagues, and hospital support for HP activities. The study concludes that acute-care nurses are an underutilized resource for HP. The challenge is to make more effective use of nurses' knowledge, attitudes, and skills in promoting health in the hospital setting. PMID- 8697270 TI - Evaluation of a home-based traction program for children with congenital dislocated hips and Legg Perthes disease. PMID- 8697271 TI - Changes in the school-to-work transition for Canadian nursing program graduates. AB - This paper investigates changes in the school-to-work transition for graduates of Canadian community college and university nursing programs between 1978 and 1992, using data from four different National Graduates Surveys conducted by Statistics Canada. By examining four distinct cohorts of nursing program graduates (1976 graduates in 1978, 1982 graduates in 1984, 1986 graduates in 1988, and 1990 graduates in 1992), we can identify salient trends over time. These observed employment trends include a marked increase in part-time employment approximately two years after graduation (with a corresponding decline in full-time employment), and an associated increase in temporary positions (with declining permanent employment). These data suggest that the school-to-work transition for graduates of nursing programs has become more difficult over time. Implications from these empirical findings on the school-to-work transition for this segment of post-secondary graduates are discussed. The impact of significant labour market changes (transition from an acute shortage of nurses in hospital settings in the late 1980s to nursing layoffs, bed closures, and ward and hospital shutdowns in the early 1990s) is also addressed. PMID- 8697272 TI - Valuing research in clinical practice: a basis for developing a strategic plan for nursing research. AB - With a view to developing a strategic plan for nursing research in a clinical practice setting, a survey was conducted to examine nurses' attitudes towards research as a part of their work. The 348 nurse respondents represented various nursing roles: staff nurses, head nurses, clinical nurse specialists, nurse educators, hospice nurses, expanded-role nurses, and an enterostomal therapist. They were classified into two groups, staff nurses and leadership nurses. The subjects reported that they valued research highly and that they believed the nursing division was supportive of research activities. Few were actually involved in conducting research; the nurses reported a lack of confidence in their ability to participate in designing and conducting studies. Most staff nurses were not using research in their work, while the majority of leadership nurses were. Factors that explain both research use by nurses and their participation in designing and conducting research differed for the two groups. PMID- 8697273 TI - Changes in acute care: questions in need of answers. PMID- 8697274 TI - Factors affecting acute-care nurses' use of research findings. AB - This study describes staff nurses' perceptions of hospital support for research and their expectations for research; and relationships between organizational factors, individual factors, and staff nurses' use of research. These factors were compared for groups of nurses by education level and hospital size. Stratified random sampling of 450 nurses was obtained from a provincial nurses' association. The mailed survey was completed by 183 nurses. Use of specific research findings was related to organizational factors and was congruent with earlier studies. Nurses' perceptions of their general use of research were related to individual characteristics such as interest in research and expectations to use research, which scored high regardless of educational level. Nurses' perceptions of organizational support and expectations differed significantly according to hospital size. This study suggests that the organizational context is influential, but nurses' value of, interest in, and expectations to use research may mediate this influence. Enhancing research-based practice will require attention to the organizational context of practice. PMID- 8697275 TI - Methodological considerations in acute-care research: issues in securing self report data. PMID- 8697276 TI - The meaning of critical illness to families. AB - Critical illness creates stress in patients and their families. However, families' reactions vary and suggest that having a loved one in an intensive care unit (ICU) may not be a crisis for all families. The purpose of this study was to explore and describe the meanings that families ascribe to an ICU experience. In depth unstructured interviews took place with 18 family members from eight families of ICU patients. Interviews were analyzed qualitatively and revealed five categories of meanings that the ICU experience had for families: "it could go either way," "everything is good," "going upstairs," "like living on a roller coaster," and "there is no hope." All eight families described an initial period of uncertainty during which they were unsure whether the patient would survive. The subsequent trajectory of critical illness followed one of two paths: positive or negative. The results of this study are of interest to nurses who seek to broaden their understanding of the impact of critical illness on the family. PMID- 8697277 TI - Nursing and the body. PMID- 8697278 TI - The meaning of respect: a First Nations perspective. AB - A qualitative study was conducted to explore the meaning of respect from the perspective of five Cree-Ojibway key informants. Data were obtained from in-depth interviews conducted in a First Nations community in northern Manitoba. Interviews focused on key informants' understanding of the meaning of respect, and their experiences of being treated with or without respect during clinical interactions. The qualitative analysis identified characteristics of respect and lack of respect that reflected the informants' experiences as First Nations persons interacting with Western health-care providers. The features of respect reflected ethical values related to equality, inherent worth, and the uniqueness and dignity of the individual. Findings highlighted the need for nurses to be cognizant of the sociopolitical context of interactions with First Nations patients. The preliminary descriptions of respect identified in this study provide a foundation for further analysis of the concept. PMID- 8697279 TI - What are the odds? PMID- 8697280 TI - Operating rooms don't have to be so scary! PMID- 8697281 TI - Risk management. PMID- 8697282 TI - Parse's nursing theory and the practice of perioperative nursing. AB - Many nurse theorists have emerged in the midst of the Nursing Profession's struggle for recognition as a science. To gain autonomy we as nurses must first examine our personal philosophies of nursing. Then we can examine why so many nursing professionals experience "burn out" so early in their careers. I propose that we must change how we define our practice from the use of the medical model to our own model. Although we work closely with medicine, we are not physicians or medical aids; we are nurses. PMID- 8697283 TI - BCAM sterile. "A lesson in asepsis". AB - This article presents the principles and rationale for aseptic practice in the operating room. The mnemonic "BCAM STERILE: has been chosen as the framework in which the principles are presented. The principles apply to all personnel who care for the patient during the intraoperative experience. PMID- 8697285 TI - Potential hazards from electrosurgery plume--recommendations for surgical smoke evacuation. PMID- 8697284 TI - Negative pressure pulmonary edema. AB - Pulmonary Edema associated with negative airway pressure caused by upper airway obstruction is a most serious complications in anaesthetic practice (Tami et al, 1986). Laryngospasm associated with intubation and general anaesthesia is the most common cause of upper airway obstruction leading to negative pressure pulmonary edema (NPPE) in the anaesthetic adult (Tami et al, 1986). Other risk factors for the development of upper airway obstruction are identified, and individuals at risk should be observed closely while they remain at risk during the post anaesthetic period. NPPE appears to be related to markedly negative intrathoracic pressure due to forced inspiration against a closed upper airway resulting in transudation of fluid from pulmonary capillaries to the interstitium. The following is a presentation of a case of a healthy young male who developed NPPE secondary to airway obstruction caused by biting down on the endotracheal tube while awakening from general anaesthesia. PMID- 8697286 TI - Survey of physicians attitudes toward surgical smoke. PMID- 8697287 TI - Perioperative team building through decentralization and empowerment. PMID- 8697288 TI - Continuous quality improvement: a perioperative nursing approach. AB - This article describes in detail the steps taken in the Operating Room at the Toronto Hospital in implementing a Continuous Quality Management framework. Focusing on active participation, all levels of the O.R. staff worked through a process of identifying, developing, measuring and evaluating standards of practice. A step by step framework was followed in order to monitor current standards and develop new ones, thereby complying with the institution's mandate of supporting Continuous Quality Improvement. PMID- 8697289 TI - President's message: ORNAC's standards under review. PMID- 8697290 TI - Visual laser ablation of the prostate (VLAP). AB - Benign Prostatic Hyperplasia is a condition which occurs commonly in men as they age. The degree of impedence of the flow of urine from the bladder due to prostate gland enlargement varies from a slight slowing of the stream to complete urinary retention. Transurethral Resection of the Prostate (TURP) has historically been the most common treatment of this condition. While other alternative treatments are available, the use of lasers to perform Visual Laser Ablation of the Prostate (VLAP) is moving to the forefront as a treatment of choice for many Urologists. PMID- 8697291 TI - Changes in autonomic nervous system activity and consecutive hyperinsulinaemia: respective roles in the development of obesity in rodents. AB - The autonomic nervous system plays a major role in metabolism regulation by modulating metabolic pathways directly or indirectly via control of hormone (particularly insulin) secretion in various organs and tissues. In addition, the system modulates the proliferation and differentiation of some cell types. This activity is directly controlled by certain brain areas, particularly those located in the hypothalamus. A feedback loop signals metabolic changes at the periphery to these brain areas. This review focuses on the role of the autonomic nervous system in the activity and plasticity of pancreas and adipose tissues under normal conditions or in obesity, with special attention to the importance of alterations in these functions. PMID- 8697292 TI - Minimally oxidised LDL as estimated by a new method increase in plasma of type 2 diabetic patients with atherosclerosis or nephropathy. AB - A new sensitive and reproducible method was used to assess LDL oxidative status in Type 2 diabetic patients and control subjects, and the relationships between LDL oxidation and atherosclerosis or nephropathy were determined. LDL oxidation was measured in 35 patients with Type 2 diabetes and 15 control subjects 40 to 60 years of age. Atherosclerosis was assessed by clinical examination, vascular ultrasound, and measurement of intima-media thickness (IMT). Twenty-four hour urinary albumin excretion measurements were performed. Although no differences in lipid values were found between the 22 diabetic patients with atherosclerosis (ATS+) and the 13 without (ATS-), LDL oxidation was significantly higher in ATS+ than ATS- patients (p = 0.009) or control subjects (p = 0.007). LDL oxidation was also increased in the 15 patients with nephropathy (p = 0.003). Oxidation was correlated with IMT in patients with normal to moderately increased IMT ( < or = 1.05 mm). Determination of LDL oxidative status could thus be very helpful in assessing cardiovascular risk, especially in high-risk subjects such as patients with diabetes mellitus. PMID- 8697293 TI - Acute effects of the alpha 2-adrenoreceptor antagonist idazoxan on hormonal responses and symptoms of hypoglycaemia in patients with type 1 diabetes mellitus. AB - The aim of the present study was to evaluate the effect of the alpha 2 adrenoceptor antagonist idazoxan on hormonal responses and hypoglycaemia symptoms in patients with insulin-dependent (Type 1) diabetes mellitus. Six male Type 1 diabetic patients were studied with and without intravenous infusion of idazoxan. Hypoglycaemia was induced by an intravenous infusion of insulin (100 mU.kg-1.h 1), together with a glucose clamp, to obtain an arterialised venous blood glucose level of 2.3 mmol/l. Idazoxan was given at a dose of 295 micrograms/kg. Venous blood samples were obtained for analyses of free insulin, growth hormone (GH), glucagon and catecholamines. Symptoms were scored on a visual-analogue rating scale. Areas under the curves with and without idazoxan were respectively 22.4 +/ 7.0 vs 33.0 +/- 9.6 micrograms.l-1.h (p = 0.17) for GH, 4.1 +/- 1.1 vs 2.4 +/- 0.9 nmol.l-1h (p < 0.05) for adrenaline, 5.6 +/- 0.9 vs 1.3 +/- 0.5 nmol.l-1.h (p < 0.05) for noradrenaline and 51 +/- 38 vs -40 +/- 11 ng.l-1.h (p < 0.05) for glucagon. Sweating and palpitations were more pronounced during idazoxan infusion than during the control test. It is concluded that idazoxan increases catecholamine and glucagon responses as well as some of the warning signals of hypoglycaemia in Type 1 diabetic patients, whereas the GH response seems less affected by idazoxan. PMID- 8697294 TI - Impaired glucose tolerance in patients with chronic hypoxic pulmonary disease. AB - This study investigated glucose metabolism and glucose-mediated hormone responses in patients with chronic respiratory hypoxaemia. Glucose as well as insulin, glucagon, adrenaline, cortisol and growth hormone (GH) were measured before and at 30, 60 and 120 min during an oral glucose-tolerance test. The following chronic obstructive pulmonary disease (COPD) patients were studied: 10 normoxaemic (mean paO2 10.9 +/- 0.4 kPa), 10 hypoxaemic (mean paO2 7.6 +/- 0.2 kPa before, and 10.6 +/- 0.4 after 24-h oxygentherapy, and 6 hypoxaemic patients on long-term oxygen therapy (LTOT) (mean paO2 10.9 +/- 0.7 kPa before, and 7.1 +/ 0.3 after 4 h with less than 0.5 litre oxygen per minute). The hypoxaemic patients were tested both with and without (or reduced) oxygen therapy. Twenty healthy sex- and age-matched subjects served as controls. Plasma glucose at 120 min was significantly higher in LTOT patients than in controls (p < 0.01), normoxaemic patients (p < 0.01) or hypoxaemic patients (p < 0.01). The areas under the curve for plasma glucose and insulin were significantly higher in both the LTOT and hypoxaemic groups compared to controls (p < 0.01 and 0.05, respectively). Glucose values for normoxaemic COPD patients were similar to those for controls. Glucagon, adrenaline, cortisol and GH levels did not differ significantly between the groups. A 4-h low-dose or oxygen-free interval in the LTOT group or 24 h of oxygen supplementation in the hypoxaemic group did not affect glucose and hormone levels significantly. It is concluded that severely hypoxaemic COPD patients have altered glucose metabolism which cannot be readily explained by changes in gluco-regulatory hormones or short-term alterations in oxygenation. PMID- 8697295 TI - Is metformin safe enough for ageing type 2 diabetic patients? AB - We assessed the effect of adding low doses of metformin to sulfonylurea therapy in 76 elderly Type 2 diabetic patients by monitoring glycaemic control and blood lactate for one year. Metformin markedly improved glycaemic control. Fasting lactate concentrations were not affected and post-meal lactate peaks were minimally increased. Additional benefits included an improvement in some lipid parameters, a reduction in serum uric acid and a significant weight loss in overweight patients. Metformin was clinically well-tolerated. Instead of advanced age alone, renal function and/or any other age-related factor likely to contribute to lactate overproduction should be the basis for deciding on metformin therapy. No evidence indicated that metformin should be denied "a priori" to ageing Type 2 diabetic patients. PMID- 8697296 TI - Effects of tryptophan load on amino acid metabolism in type 1 diabetic patients. AB - Tolerance to an oral tryptophan load (50 mg/kg body weight) was evaluated in a group of 15 insulin-dependent diabetic patients of both sexes in poor metabolic control. Tryptophan was measured fluorometrically, and the plasma levels of the other physiological amino acids were determined by HPLC. The ratio of the plasma concentration of each large neutral amino acid (LNAA) to the sum of the others was calculated to serve as an index for the competitive transport of these amino acids into the brain. The results show that post-loading plasma tryptophan levels in diabetic patients increased less than in healthy controls, suggesting enhanced liver catabolism of this amino acid (as reported for diabetic animals). Small changes were observed in the post-loading plasma concentrations of other amino acids. Therefore, the increment in the tryptophan/LNAA ratio in controls (basal, 0.12 +/- 0.01; 120 min after the load, 0.89 +/- 0.04; 240 min, 0.51 +/- 0.03) was greatly attenuated in diabetic patients (basal, 0.11 +/- 0.01, NS; 120 min, 0.46 +/- 0.04, p < 0.01; 240 min, 0.31 +/- 0.04, p < 0.01). Post-loading excursions in some other ratios were slightly larger in control than diabetic subjects. These differences, which may occur to a lesser extent after a protein-rich meal, could modify the availability of precursor amino acids to the brain for synthesis of neurotransmitters. Thus, as happens in certain animal species, an impairment of the post-absorptive accumulation of tryptophan and serotonin in the brain may occur in diabetic patients as a result of altered metabolic disposal of tryptophan. PMID- 8697297 TI - A minimal model using stable isotopes to study the metabolism of apolipoprotein B containing lipoproteins in humans. AB - A protocol using stable isotopes, developed to measure apolipoprotein B turnover in humans, was tested by intravenous infusion of [2H3]-leucine into 5 normolipidemic volunteers during a 14-h fast. Tracer-to-tracee ratio curves were analyzed by four different approaches: linear regression, monoexponential regression, a minimal compartmental model (3 compartments) and a complex model (4 compartments and two shunt pathways). The three-compartment model was validated by qualitative analysis of data obtained after injection of a [2H3]-leucine bolus. This simple model gave an FCR of 0.48 +/- 0.05 h-1 for VLDL, 0.62 +/- 0.08 h-1 for IDL and 0.022 +/- 0.002 h-1 for LDL. The total production rate of apolipoprotein B in plasma was 24.8 +/- 6.5 mg.kg-1.day-1. Kinetic parameters were similar for the complex model which showed no improvement in fit. Lower estimates were observed with the non-compartmental approaches. PMID- 8697298 TI - [Arterial hypertension and diabetes. Members of the Board of Directors and Scientific Directors of ALFEDIAM]. PMID- 8697299 TI - Insulin-secreting cell lines: classification, characteristics and potential applications. AB - The use of primary beta-cells in biochemical and molecular research is limited by the availability of pancreatic endocrine tissue. Numerous investigators have attempted to establish an insulin-secreting cell line that retains normal regulation of insulin secretion. Different approaches have been used, including induction of pancreatic tumors by irradiation or viral infection, immortalization of beta-cells in vitro, and development of transgenic mice with targeted expression of a recombinant oncogene in the beta-cell. Few of these attempts have proven successful, because cell differentiation and proliferation capacities are mutually exclusive. The most widely used insulin-secreting cell lines are RIN, HIT, beta TC, MIN6 and INS-1 cells. These cells contain mainly insulin and small amounts of glucagon and somatostatin. RIN cells, except for the subclone RIN-38, are not glucose-responsive. HIT cells and beta TC cells secrete insulin in response to glucose, but their dose-response curve is markedly shifted to the left MIN6, INS-1 and a newly available subclone of beta TC cells (beta TC-6 F7) are reported to retain normal regulation of glucose-induced insulin secretion. Although the behaviour of none of these cell lines perfectly mimics primary beta cell physiology, they are extremely valuable tools for the study of molecular events underlying beta-cell function and dysfunction. In addition, insulin secreting cell lines represent a potential source of transplantable tissue to overcome the limited availability of primary islets for this procedure. PMID- 8697300 TI - [Genes and obesity: the ob gene product and the beta3-adrenergic receptor]. PMID- 8697301 TI - [Role of conservative orthopedic surgery in the treatment of the diabetic foot]. PMID- 8697302 TI - Pancreas and islet transplantation in humans. AB - Pancreas transplantation is the only treatment presently available for patients with Type 1 diabetes that establishes both insulin independence and sustained normoglycaemia. This normoglycaemia is associated with potential beneficial effects on the secondary microvascular complications of diabetes. Pancreas transplantation also improves the quality of life for diabetic patients. Islet transplantation has had only limited success to date, but when successful restores regulated insulin secretion and establishes insulin independence. However, despite the benefits of both pancreas and islet transplant for carbohydrate metabolism and diabetic complications, neither is considered standard therapy for patients with IDDM. Both types of transplantation require life-long immunosuppressive therapy. Pancreas transplant is further limited by the significant risks of the surgical procedure. In order for either pancreas or islet transplantation to achieve the clinical acceptability of other forms of transplantation, clear advantages over exogenous insulin therapy must be demonstrated. PMID- 8697303 TI - Insulin gene: organisation, expression and regulation. AB - Insulin, a major hormone of the endocrine pancreas, plays a key role in the control of glucose homeostasis. This review discusses the mechanisms of cell specific expression and regulation of the insulin gene. Whereas expression is restricted to islet beta-cells in adults, the insulin gene is more widely expressed at several embryonic stages, although the role of extrapancreatic expression is still unclear. beta-cell-specific expression relies on the interactions of 5'-flanking sequence motifs of the promoter with a number of ubiquitous and islet-specific transcription factors. IEF1 and IPF-1, by their binding to the E and A boxes, respectively, of the insulin gene promoter, appear to be the major determinants of beta-cell-specific expression. IEF1 is a heterodimer of the basic helix-loop-helix family of transcription factors, whereas IPF-1 belongs to the homeodomain-containing family. beta-cell specific determinants are conserved throughout evolution, although the human insulin gene 5'-flanking sequence also contains a polymorphic minisatellite which is unique to primates and may play a role in insulin gene regulation. Glucose modulates insulin gene transcription, with multiple elements of the promoter involved in glucose responsiveness. Remarkably, IPF-1 and IEF1 are involved in both beta-cell specific expression and glucose regulation of the insulin gene. cAMP also regulates insulin gene transcription through a CRE, in response to various hormonal stimuli. On the whole, recent studies have provided a better understanding of beta-cell differentiation and function. PMID- 8697304 TI - Modification of the sensitivity of glucose sensor implanted into subcutaneous tissue. AB - The mechanism of reducing the glucose sensitivity of sensors implanted into the subcutaneous tissue of the normal rat was evaluated (n = 10) by comparing sensitivities observed in vitro and in vivo. In vivo sensitivity was significantly lower than that observed in vitro before implantation (p < 0.005). Most interestingly, in vitro sensitivity immediately after explanation did not differ from that in vivo and increased progressively during rinsing (p < 0.02 after 30 min). These results demonstrate that the reduction of in vivo sensitivity was not due to a local factor or factors but to a reversible alteration of the glucose sensor characteristics induced in vivo by some local factor(s). This suggests that modifications of the outer sensor membrane, the nature of which remains to be determined, may prevent this effect and resolve the problem. PMID- 8697305 TI - Accessibility of human apolipoprotein B-100 epitopes in insulin-dependent diabetes: relation with the surface lipid environment of atherogenic particles. AB - The physicochemical modifications (composition and conformation) of lipoproteins containing apolipoprotein B-100 (apo B-100) were studied in normocholesterolaemic adequately controlled Type 1 insulin-dependent diabetic patients. Thirty-one normocholesterolaemic (serum cholesterol < 6.50 mmol/l) diabetic male patients and 31 age-and body mass index-adjusted healthy normolipaemic male controls were studied. Cholesterol and choline-containing phospholipids were measured in total serum and in two lipoprotein subfractions containing or not apo B (LpB and LpnoB respectively). These subfractions were separated by precipitation with concanavalin A. Total apo B-100 and two lipoprotein particles defined according to their apo B-100 epitope accessibility were determined using respectively anti apo B polyclonal and two monoclonal antibodies that reacted with specific epitopes on the apo B molecule. Despite a classical lipid profile (cholesterol and triglyceride levels), which was quite normal in plasma from patients as compared to controls, a depletion of choline-containing phospholipid content in serum and more specifically in LpB particles was observed in diabetic patients. Decreased cholesterol content was also observed in LpB particles. Immunological analysis demonstrated an increased number of lipoprotein particles (a condition previously related to coronary artery disease) and decreased immunoaccessibility of a conformationally expressed apo B-100 epitope. These conformational changes were correlated with modifications of the surface phospholipid environment of LpB particles. It is concluded that subtle abnormalities in the composition and conformation of atherogenic apo-B-containing lipoproteins occur in Type 1 diabetes mellitus. These structural modifications may be one factor accounting for the increased rate of atherosclerosis in diabetes, despite the existence of a normal classical lipid profile. PMID- 8697306 TI - Progressive deterioration of beta-cell function in nonobese type 2 diabetic subjects. Postprandial plasma C-peptide level is an indication of insulin dependency. AB - The purpose of the present study was to characterize secondary failure (SF) to oral hypoglycaemic agents by assessment of threshold insulin-secretion values in relation to diabetes duration. One hundred and forty-seven nonobese diabetic patients, 35 to 80 years of age, with disease duration ranging from 1 to 36 years, were studied. Beta-cell function was assessed by meal-stimulated (delta CP) and glucagon-stimulated (delta aCP) C-peptide concentrations. The quality of glycaemic control was considered good if mean daily blood glucose was less than 8.5 mmol/l. One group with good (NOb-GC) and another with poor control (NOb-SF) were established. Mean daily glycaemia was negatively correlated with delta CP or delta aCP (r = -0.703 vs r = -0.696; p < 0.001) more than with basal C-peptide (r = -0.453; p < 0.001). A close positive correlation between meal-stimulated (delta CP) and glucagon-stimulated (delta aCP) C-peptide concentrations was observed (r = 0.869; p < 0.001). Residual beta-cell function (delta CP and delta aCP) was significantly correlated with known disease duration in both groups (GC: r = 0.693 and SF: r = -0.680; p < 0.001). Nonobese patients with SF showed early impaired secretion during the first years of disease, meal-stimulated delta CP being below 0.350 mmol/l. The most useful result in this study was the incremental value of C-peptide (delta CP), which showed minimal overlapping between the two groups. Basal, postprandial or postglucagon absolute values were less discriminating. The daily profile allowed measurement of both glycaemic control and insulin production after a regular meal. The validity of this measurement was confirmed by the strong correlation between meal-stimulated and glucagon-stimulated delta C-peptide concentrations. This parameter is a useful physiological marker of secondary failure. PMID- 8697307 TI - Case report: insulin-dependent diabetes mellitus in childhood associated with scleroderma. AB - A 14-year-old boy presented with Type I diabetes mellitus and subsequently developed pancreatic exocrine insufficiency and systemic sclerosis (SSc). His diabetes had been diagnosed when he was about 5 years old, after the onset of ketoacidosis. Insulin treatment was provided from then until the time he was treated in our department. Exocrine pancreatic insufficiency, which occurred at age 9, was treated with pancreatic extracts. Cystic fibrosis was excluded after a chloride sweat test. The diagnosis of SSc was confirmed at age 14 on the basis of skin sclerosis, sclerodactyly and oesophageal and pulmonary involvement and then at age 18 by the occurrence of Raynaud's disease. Thus, this patient demonstrated a rare and previously unreported association of Type I diabetes mellitus and systemic scleroderma. Limited joint mobility and skin abnormalities are frequent in childhood diabetes mellitus but should not be misdiagnosed as systemic scleroderma. PMID- 8697308 TI - Effect of ramipril on insulin sensitivity in obese patients. Time-course study of glucose infusion rate during euglycaemic hyperinsulinaemic clamp. AB - To assess the effects of angiotensin converting enzyme (ACE) inhibitor on insulin action in obesity, five normotensive non-diabetic obese women were examined on two occasions as part of a double-blind, randomized, cross-over study involving ten days of treatment with either 1.25 mg ramipril or placebo. The study consisted of a euglycaemic hyperinsulinaemic clamp (two periods of insulin infusion at rates of 0.4 and 1 mU/kg/min, 2 h for each step) combined with indirect calorimetry. The most notable results involved a significantly faster time-course of glucose infusion rates during the first 30 min of each insulin infusion period [analysed by calculating slopes (S1 and S2)] after ramipril than placebo administration. The mean glucose infusion rates reached during the last 30 min of each insulin infusion period (G1 and G2), as well as the increases in carbohydrate oxidation rates during the clamp (C1-C0 and C2-C0) and the decreases in plasma nonesterified fatty acids (A0-A1 and A0-A2), were not significantly different after ramipril and placebo. According to robust principal component analysis of S1, S2, G1, G2, C1, C2, A1 and A2 (orthogonally to C0 and A0), insulin sensitivity was improved with ramipril as compared to placebo (p = 0.013). This study strongly suggests that a low dose of an ACE inhibitor increases the activation phase of insulin action in normotensive nondiabetic obese patients and may accelerate insulin action. PMID- 8697309 TI - Influence of 16-week monotherapy with acarbose on cardiovascular risk factors in obese subjects with non-insulin-dependent diabetes mellitus: a controlled, double blind comparison study with placebo. PMID- 8697311 TI - [How to detect diabetics with risk of foot complications]. PMID- 8697310 TI - [Detection, monitoring and treatment of diabetic retinopathy. Recommendations of ALFEDIAM. Committee of above-mentioned experts and validated by the board of directors and scientific board of ALFEDIAM]. PMID- 8697312 TI - Surgical management of thyroglossal duct carcinoma: is an aggressive approach justified? PMID- 8697313 TI - Adenocarcinoma of the head of the pancreas. PMID- 8697314 TI - Acetabular fractures and seat belts. PMID- 8697315 TI - Radiology for the surgeon. Case 10. Traumatic abdominal wall disruption with hernia. PMID- 8697316 TI - Biliary-tract diagnosis by magnetic resonance imaging. PMID- 8697317 TI - 1995 Roussel Lecture. Management of adenocarcinoma of the head of the pancreas: 10 questions for the 1990s. AB - Carcinoma of the head of the pancreas is a lethal condition because it presents clinically late in the disease and because of its unfavourable biologic course. Surgical approaches have become progressively more aggressive in recent years, without a significant increase in long-term survival. Controversy persists as to the appropriate surgical procedure for this disease, nonoperative or operative palliation, and and future prospects for management. This review considers questions often posed by clinicians and offers answers based on a literature reivew and the experience of the hepatobiliary service at the Toronto Hospital, Toronto General Division. PMID- 8697318 TI - Endoscopic management of biliary hydatid disease. AB - OBJECTIVE: To determine the effect of endoscopic sphincterotomy in the management of biliary hydatid disease. DESIGN: A case study between January 1992 and December 1994. SETTING: A university-affiliated hospital in Adana, Turkey. PATIENTS: Five patients with biliary hydatid disease, in which the cyst had ruptured into the biliary tree. The follow-up ranged from 3 to 12 months. INTERVENTIONS: Endoscopic sphincterotomy. MAIN OUTCOME MEASURES: Morbidity, morality and recurrence of the disease. RESULTS: All patients underwent successful endoscopic sphincterotomy, including removal of daughter cysts. During the follow-up period, ultrasonography and laboratory investigations showed complete cure in all patients. There were no complications due to endoscopic sphincterotomy. CONCLUSION: Endoscopic sphincterotomy is the treatment of choice for the management of hydatid cysts that have ruptured into the biliary tract causing obstructive jaundice. PMID- 8697319 TI - Traumatic rupture of hydatid cysts. AB - OBJECTIVE: To stress the relation between rupture of hydatid cysts and trauma. DESIGN: A case series. SETTING: A university-affiliated hospital for emergency medicine. PATIENTS: Four college students who suffered traumatic rupture of hydatid cysts. All injuries were sustained during sporting activities. INTERVENTIONS: Resection or unroofing of the cysts with careful removal of all hydatid elements, and suture-plication of the residual liver cavities. RESULTS: The ruptured cysts were located in the liver, spleen and splenic flexure of the colon. At exploration, additional hydatid cysts were found, usually in the liver. Treatment resulted in complete recovery in all patients. CONCLUSIONS: Traumatic rupture of hydatid cysts related to sporting activities may be commoner than indicated by the rarity of reports. Increased awareness of this possibility in areas where hydatid disease is endemic is encouraged. PMID- 8697320 TI - Sternotomy infections: sternal salvage and the importance of sternal stability. AB - OBJECTIVE: To review the management of sternal wound infection after cardiovascular surgery. DESIGN: Retrospective case study. SETTING: All management took place in a single tertiary-care university hospital. PATIENTS: Twenty-one consecutive patients seen over a 3-year period who had infected median sternotomy incisions after cardiovascular surgery. INTERVENTIONS: Surgical eradication of infection, including sternal debridement and rewiring or placement of vascularized muscle flaps, or both. MAIN OUTCOME MEASURES: Resolution of infection and restoration of sternal stability. RESULTS: The development of sternal wound infection was found to be associated with sternal instability. In 12 of 17 patients treated initially with sternal debridement and rewiring the infection was cured. Vascularized muscle flap transfers were required to eradicate the infection in the remaining patients. CONCLUSIONS: Sternal debridement and rewiring is an effective initial treatment for sternal wound infections in selected patients. Some patients may require placement of muscle flaps for definitive treatment. PMID- 8697321 TI - Combined fine-needle aspiration, physical examination and mammography in the diagnosis of palpable breast masses: their relation to outcome for women with primary breast cancer. AB - OBJECTIVE: To examine the combined and individual predictive values of fine needle aspiration (FNA), physical examination (PE) of the breast and mammography (the "triple test") in diagnosing breast cancer in relation to the results of open surgical biopsy. DESIGN: A study of the records of patients who received both FNA and open surgical biopsy for the same palpable breast lump. The results of diagnostic assessment and open surgical biopsy were categorized as positive or negative. Concordance (percentage of tests found to be correct at biopsy), sensitivity, specificity (percentage of patients without breast cancer for whom the diagnostic test was negative) and positive predictive value (percentage of patients with a positive test found to have breast cancer) were determined for the triple test for each diagnostic modality. In addition, prognostic variables (tumour size, node positivity, estrogen and progesterone receptor status) and outcomes were assessed in patients with a diagnosis of breast cancer. SETTING: A university-affiliated general hospital with a special focus on women's health. PATIENTS: Of 290 patients who had both FNA and open surgical biopsy, 191 underwent all three diagnostic procedures. MAIN OUTCOME MEASURES: The diagnostic accuracy of FNA, PE and mammography to permit preoperative definitive therapy or to allow observation without mandating open surgical biopsy. RESULTS: In 81 patients all three diagnostic modalities were in agreement for a diagnosis of either benign or malignant disease; the concordance for the triple test was 98.8% specificity was 100% and sensitivity was 95.5%. Nodal status, tumour size and outcome were similar whether or not the triple test was positive, but, interestingly, when the triple-test results were positive, estrogen (p < 0.05) and progesterone (p < 0.03) receptor values were more likely to be negative. CONCLUSIONS: When all three diagnostic modalities were in agreement for a diagnosis of malignant disease, the combination of FNA, PE and mammography had excellent concordance with the results of open surgical biopsy, and in this situation definitive treatment may be carried out. If all three modalities are in agreement for a diagnosis of benign disease, a period of close observation with repetition of FNA may be safely entertained. Lack of concordance of the three diagnostic modalities mandates biopsy. Triple-test positively does not predict a worse outcome. PMID- 8697322 TI - Alterations in respiratory mechanics after laparoscopic and open surgical procedures. AB - OBJECTIVE: To compare the effects of laparoscopic and open surgical procedures on postoperative strength and respiratory mechanics. DESIGN: Prospective cohort study. SETTING: Adult university hospital. PARTICIPANTS: Fifty-one women aged 21 to 62 years scheduled to undergo elective cholecystectomy or hysterectomy (or related procedures), otherwise in good health. INTERVENTIONS: Open or laparoscopic cholecystectomy or hysterectomy (or related procedures). MAIN OUTCOME MEASURES: Maximum voluntary handgrip strength (HGS), forced vital (VC), forced expiratory volume in 1 second (FEV1), and maximal inspiratory pressure (MIP) were each measured preoperatively and on the first postoperative morning. A visual analogue pain scale score was evaluated in relation to performance of the postoperative strength and respiratory measurements. RESULTS: VC, FEV1, and MIP, but not HGS, were decreased after surgery. Postoperative VC, FEV1, and MIP were lower after open procedures than after laparoscopic procedures and after cholecystectomy than after hysterectomy (all p < 0.001). Pain scores were lower after laparoscopic than after open procedures (p < 0.005) and could account in part for differences in postoperative respiratory mechanics. CONCLUSIONS: Cholecystectomy and hysterectomy do not result in generalized muscle weakness, unlike more major abdominal procedures. Postoperative alterations in respiratory mechanics are related to the site of the surgery, the use of an open versus a laparoscopic approach and postoperative pain. PMID- 8697323 TI - Acetabular fractures before and after the introduction of seatbelt legislation. AB - OBJECTIVES: To compare the incidence and severity of acetabular fractures and associated injuries before and after seatbelt legislation. DESIGN: A retrospective study. SETTING: Two major trauma centres, which are teaching hospitals. PATIENTS: Three hundred and ninety-three patients who sustained acetabular fractures during the 5 years before and 5 years after seatbelt legislation was enacted. Of these, the fractures in 198 patients (50.4%) resulted from a motor vehicle accident. MAIN OUTCOME MEASURES: The number and severity of acetabular fractures and associated injuries. RESULTS: There has been a significant reduction in the number of acetabular fractures (p = 0.005) since seatbelt use became mandatory, and the complexity of the fractures has decreased. There has also been a marked reduction in associated injuries, such as fractures of other bones, and head, chest and abdominal injuries (p < 0.001). CONCLUSION: The seatbelt law has been a useful preventive measure, resulting in a reduction in the incidence of acetabular fractures and associated injuries. PMID- 8697324 TI - Thoracic outlet syndrome: fact or fancy? A review of 409 consecutive patients who underwent operation. AB - OBJECTIVES: From an analysis of patients operated on by a single surgeon between 1973 and 1994 for thoracic outlet syndrome (TOS), to determine what findings are helpful in substantiating this diagnosis and what are the results of decompressive thoracic outlet surgery in the management of TOS. DESIGN: A chart review with emphasis on signs, symptoms and results. A preoperative questionnaire was presented to all patients operated on since 1989. Postoperative follow-up was by interview or telephone. SETTING: A 560-bed university-affiliated tertiary-care teaching hospital. PATIENTS: There were 409 adults; 83% were women and the average age was 36 years. In 95% of patients physiotherapy had been unsuccessful. Patients presented with neurologic type (368 [(90%]), arterial impingement (29 [7%]) and venous obstructive symptoms (12 [3%]). The series included 44 patients with bilateral symptoms and 26 patients with cervical ribs. Some form of litigation or compensation was associated with 177 patients. INTERVENTIONS: Transaxillary first rib resection in 380 (93%) patients and supraclavicular thoracic outlet decompression in 29 (7%). In 244 patients there was a follow-up of at least 2 years. These patients constituted the follow-up group. RESULTS: Preoperatively, in the 368 patients who had neurologic TOS, 99% displayed supraclavicular brachial plexus tenderness and 98% exacerbation of symptoms with arms in the abduction external rotated position. There were eight complications of surgical intervention (1.9%). In the follow-up group, there were no deaths, no subclavian/axillary artery or vein damage and no brachial plexus injury. Seventy eight percent of the patients with neurologic TOS in this group improved postoperatively; 21% had complete relief, 32% had good relief and 25% had fair relief. Twenty-two percent showed no improvement. CONCLUSIONS: Signs and symptoms helpful in making the diagnosis of neurologic TOS are supraclavicular tenderness on palpation and exacerbation of symptoms with the arms in the abducted external rotated position. The surgical procedures are safe. Patients with TOS refractory to medical management can benefit from thoracic outlet decompression. PMID- 8697326 TI - Bilateral primary breast lymphoma in pregnancy: a case report and literature review. AB - Primary lymphoma of the breast is an uncommon malignant breast tumour, which is seldom distinguished preoperatively from other more common forms of breast cancer. The management differs from the more typical adenocarcinoma of breast in that the emphasis is on systemic chemotherapy. A young white woman presented during the 3rd trimester with bilateral breast enlargement, which failed to involute post partum. Subsequent biopsy revealed primary breast lymphoma of the large cell immunoblastic type. She received systemic chemotherapy and was alive and well with no evidence of recurrence 28 months later. PMID- 8697327 TI - Iatrogenic perforation of perivaterian duodenal diverticulum: report of a case. AB - The author reports a case of iatrogenic perforation of a duodenal diverticulum, an extremely rare occurrence, during percutaneous radiologic extraction of a retained common-bile-duct-stone. Perforation was related to the perivaterian location of the duodenal diverticulum. Because an inflammatory reactions was present, tube duodenostomy was chosen over excision, closure and drainage to prevent the complication of lateral duodenal fistula and sepsis. Whenever iatrogenic duodenal perforation is suspected, prompt radiologic documentation and early surgical consultation should be sought. PMID- 8697325 TI - Concurrent papillary and squamous carcinoma in a thyroglossal duct cyst: a case report. AB - Carcinomas of thyroglossal duct cysts are rare. Most are papillary carcinomas; only about 5% are squamous cell carcinomas. Only one case of mixed papillary and squamous cell carcinoma of a thyroglossal duct cyst has been reported so far. The authors present a second case, that of a 38-year-old man who was first seen with a midline neck lump. It was diagnosed clinically as a thyroglossal duct cyst and was locally excised. Pathological examination showed both a concurrent papillary carcinoma and a squamous cell carcinoma. Treatment consisted of a near-total thyroidectomy, ablative radioactive iodine and adjuvant external radiation therapy. The authors review the literature and explain the rationale behind their choice of treatment. PMID- 8697328 TI - Lateral tibial plateau fractures. PMID- 8697329 TI - Retroareolar leiomyoma. PMID- 8697330 TI - Papillary and squamous carcinoma of thyroglossal duct cyst. PMID- 8697331 TI - [Present status and future of alcohol studies in the field of public health]. PMID- 8697332 TI - [30-year progress of Japanese Medical Society of Alcohol and Drug Studies- present status and future of alcohol studies]. PMID- 8697333 TI - Effects of bezafibrate on erythrocyte membrane phospholipids in alcohol-treated rats. AB - Male rats of the Wistar strain were divided 4 groups, and give a liquid diet of control feed, bezafibrate (150 mg/kg), ethanol, and ethanol plus bezafibrate for 5 week. The effect of bezafibrate supplementation on rats fed ethanol was examined in terms of the fatty acid composition of the phospholipids in the erythrocyte membrane. In the phospholipids profiles of erythrocyte membranes, PI was significantly decreased. The decrease in PI caused by bezafibrate appeared to substantially affect the membrane and consequently lead to changes in the membrane anchor. In the fatty acid composition of the PC, C20: 4 was significantly decreased in the group receiving alcohol (p < 0.05) but increased in the groups receiving bezafibrate (p < 0.05). In the fatty acid composition of the PE, C16: 0 was significantly increased in the three groups when compared with the control, and C20: 4 was decreased in the alcohol group (p < 0.05). In the fatty acid of SM and PI, C20: 4 was decreased and C18: 0 increased in the alcohol group. In the PS, C14: 0 was increased in the alcohol group, and decreased in the alcohol plus bezafibrate group (p < 0.01). The levels of arachidonic acid in the total fatty acids that constituted the membrane phospholipids were decreased in the rats given ethanol (p < 0.05). However, arachidonic acid in the group of bezafibrate supplementation on rats fed ethanol were elevated in comparison with the alcohol group (p < 0.05). With decreasing arachidonic acid as a marker of alcohol tissue injury following chronic alcohol intake, the effects of bezafibrate supplementation appear to contribute to membrane fluidity by altering the biochemical flexibility of the membrane. PMID- 8697334 TI - [The effect of work-related stress with change of working conditions for workers with alcohol drinking habit and liver disorder]. AB - To evaluate the relationship between working conditions and workers' health, particularly the effect of work-related stress with change of working conditions for those with alcohol drinking habit and liver disorder, we analyzed physiological examination data and a questionnaire survey including the Japanese version of Karasek's Job Content Questionnaires (JCQ) on work-related stress, working hours, sleeping hours, alcohol consumption and cigarette smoking among male workers of a car manufacturing plant, who engaged in car sales work temporarily and then returned to manufacturing work. In the physiological examination data, the values of body mass index (BMI), GOT, GPT, gamma-GTP, TG and T-CHO rose and the prevalence of obesity and liver disorder increased during the term of car sales work. Comparing the term of car sales work with the term of car manufacturing work, the number of habitual drinkers and heavy smokers increased during the former and decreased during the latter. Increased alcohol consumption and cigarette smoking were also noted during the term of car sales work. Logistic regression analysis showed that the odds ratio of decreasing 'decision latitude (DL)' as work-related stress was statistically significant for increased alcohol consumption. The increased alcohol consumption probably contributing to the prevalence of liver disorder was assumed to be associated with work-related stress due to change of work conditions. Workers who showed liver disorder strongly complained of work-related stress, and it was assumed that the work-related stress was related to liver disorder. Longitudinal observations which take into account work-related stress, alcohol drinking habit and liver disorder must be well planned and personal traits of work-related stress always be taken into consideration. PMID- 8697335 TI - Role of brain cocaethylene levels in combined cocaine-ethanol lethality in mice. AB - The purpose of this study was to examine the lethal effects of combining cocaine with ethanol in mice by assaying for cocaethylene at the time of death. After the voluntary oral ingestion of ethanol in the form of a liquid diet containing 35% ethanol-derived calories for 5 days, intraperitoneal cocaine (60 mg/kg) was administered daily for up to 5 days while the ethanol diet continued (ethanol diet group). The mice in the ethanol diet group were paired with control mice that received a control liquid diet containing equivalent carbohydrate calories in the form of sucrose instead of ethanol (control diet group). In order to analyze the drugs, samples (blood, liver and brain) were collected for both groups from the dead animals that could not tolerate the 5 days of cocaine administration. A higher rate of lethality was observed in the ethanol diet group as compared to the control diet group. Furthermore, various patterns of cocaine lethality were revealed under different conditions of ethanol intake. According to the survival times after the last cocaine administration, observed respiratory and locomotive disorders, and drug concentrations, a total of 5 subgroups in the ethanol diet group (Groups E1-E5) and a total of 3 subgroups in the control diet group (Groups C1-C3) were differentiated. The ratio of the mean cocaethylene concentration relative to the mean cocaine concentration was over 30% in the livers of animals in an earliest lethal subgroup (Group E1). In addition, examination of all of the dead animals in the ethanol diet group revealed the prolonged presence of cocaethylene in the brain of the mice that died within 2 hours. Thus, it was suggested that cocaethylene has strong effects on the brain receptors and influences cocaine lethality. PMID- 8697337 TI - Case report: torsion of a gravid horn of a didelphic uterus. AB - Acute abdominal pain during pregnancy presents a dilemma as signs and symptoms are often modified. Abdominal massage by traditional birth attendants (TBAs') during early labour is a common practice in the rural population, as it is perceived to give a soothening effect to the labouring mother. Many instances of abruptio placentae were reported in the past by this procedure, and in this case, the clinical picture presented as an abruptio placenta. Malpresentation and failure to progress were the indications for caesarean section despite the fetal demise. Severe post partum haemorrhage and failure to contract despite massive oxytocics resulted in the hysterectomy of the gravid horn, leaving the other horn intact. PMID- 8697336 TI - A prospective study on the relationship between intrapartum maternal group-B streptococcal concentration and signs of infection in neonates. AB - OBJECTIVE: Our purpose was to examine the effects of intrapartum vaginal Group-B streptococcal (GBS) colonization on neonatal signs of infection. STUDY DESIGN: We performed a quantitative GBS culture of vaginal specimens in 1,280 pregnancies within 24 hours before delivery and examined signs of neonatal infection within 48 hours after birth. Among them, 287 pregnant women had premature ruptures of membranes. RESULTS: The rate of vaginal GBS colonization in groups with and without ruptured membranes was 22.0% and 11.3%, respectively. The incidence of neonates with signs of infection born to GBS-carrier women in each group was 28.6% and 8.8%, respectively. There were significant differences between the groups with regard to both the rate of colonization and the incidence of infection. Signs of neonatal infection increased in proportion to the maternal GBS concentration only in women with ruptured membranes. CONCLUSION: This study suggests that there is an important association between maternal GBS concentration and mild neonatal infections after birth, especially in women with premature ruptures of membranes. PMID- 8697338 TI - Successful pregnancy after intracytoplasmic injection of a single testicular spermatozoon into a human oocyte: a case report. AB - Testicular sperm was retrieved from a man with an epididymal obstruction, and an intracytoplasmic sperm injection was made into his wife's oocytes. In 4 mature oocytes treated, 2 fertilized eggs were obtained, and a clinical pregnancy was established with embryo transfers. Our experience demonstrated the possibility of fertilization and conception with testicular sperm. PMID- 8697339 TI - Preinduction cervical ripening with intravaginal prostaglandin E1 methyl analogue misoprostol: a randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy of intravaginal prostaglandin E1 methyl analogue misoprostol in cervical ripening in patients with unfavorable cervix (Bishop score < 4) requiring labor induction. METHOD: A randomized controlled clinical trial of 62 women in the third trimester with various indications for induction of labor were randomly allocated to receive either 100 micrograms misoprostol inserted vaginally (32) or placebo similarly applied (30). Transvaginal sonography was performed to measure the cervical length before and 12 hrs after insertion. RESULTS: The mean change in cervical length and Bishop score was significantly greater in the misoprostol group (24 mm and score 8) compared with in the placebo group (2.2 mm and score 1) (p = 0.001). All but one patients receiving misoprostol went into labor while only one in the placebo group did so. The interval from insertion to vaginal delivery was significantly shorter in the misoprostol group (12.0 vs 25.5 hrs, p < 0.001). Delivery occurred within 24 hrs in 75% and 30% of patients in the misoprostol and placebo groups respectively. Uterine tachsystole occurred more frequently in the misoprostol group (38%) than in the placebo group (0%) (p < 0.001). All could be rapidly reversed by tocolytics without apparent untoward intrapartum effects. No significant differences were noted in the 2 groups in terms of perinatal outcomes and mode of delivery. CONCLUSION: Intravaginal misoprostol is an effective, cheap and safe method for cervical ripening. The higher frequency of uterine tachysystole in the misoprostol group did not increase the risk of adverse intrapartum and neonatal outcomes. PMID- 8697340 TI - Spontaneous rupture of the uterus due to placenta percreta at 25-weeks' gestation: a case report. AB - Placenta percreta is a rare but serious complication of pregnancy, and is rarely diagnosed in the second trimester of pregnancy. We report a very rare case of placenta percreta accompanied by spontaneous uterine rupture at 25-weeks of gestation. A 30-year-old woman with severe abdominal pain was admitted to our hospital at 25 weeks of gestation. A laparotomy was immediately performed because of intraabdominal bleeding. The uterus revealed a perforation of the fundus. A supra-vaginal hysterectomy was performed. A pathological investigation of the uterus revealed placenta percreta. The patient had neither gravity nor any prior uterine operation. It is very rare for placenta percreta to be recognized in a primigravida woman or in the second trimester of pregnancy. PMID- 8697341 TI - Multilocular peritoneal inclusion cysts (benign cystic mesothelioma): a case report. AB - We report a case of a rare lesion, a multilocular peritoneal inclusion cyst (MPIC), and describe in detail its appearance on MRI. A young woman with pain of the lower abdomen underwent surgical removal of a mass that was histologically diagnosed as an MPIC. The characteristic MRI features were a multilocular cystic mass with thin septa in the pelvic cavity, located both anterior and posterior to the uterus and the adnexa, showing hypointensity of the cyst contents on T1 images and variable hyperintense signals on T2 images. PMID- 8697342 TI - The evaluation of a new 7-day gonadotropin-releasing hormone agonist protocol in the controlled ovarian hyperstimulation for in vitro fertilization. AB - OBJECTIVE: Gonadotropin-releasing hormone agonist (GnRHa) was used in the controlled ovarian hyperstimulation (COH) for the in vitro fertilization program. However, the traditional long protocol demanded more human menopause gonadotropin (hMG) and sometimes causes unnecessary delay in the procedure. A new 7-day GnRHa/hMG protocol required to conserve cost and time is thus evaluated for better outcome. METHODS: Sixty consecutive IVF candidates less than 40 years of age were recruited for the study. Cases with severe male factor or polycystic ovarian disease were excluded. The perspective candidates were divided into two groups, one received the traditional, GnRHa2hMG protocol and the other received the new 7-day regimen. RESULTS: When comparing the results in pregnancy rate (33.3% vs 30%), cleavage rate (75.7% vs 75.5%), and the number of oocyte obtained (5.96 +/- 0.91 vs 6.63 +/- 0.90), the 7-day GnRHa/hMG protocol is as good as those of the traditional regimen. The amount of hMG used nevertheless was significantly less (21.48 +/- 0.78 vs 50.59 +/- 2.07). CONCLUSIONS: The new regimen will surely reduce the cost to relieve patient's financial burden and to increase patient's comfort. PMID- 8697343 TI - Mother-to-infant transmission of hepatitis C virus in human immunodeficiency virus-coinfected mother: a case report. AB - We report a case of vertical transmission of HCV in a mother infected with both HCV and HIV. Our case suggests that coinfection with HIV, by causing an immune dysfunction, might be one of the risk factors for the transmission of HCV. PMID- 8697344 TI - Chorionic villus sampling: clinical experience of the initial 750 cases. AB - OBJECTIVE: To assess the factors that might influence the success rate, safety and reliability of chorionic villus sampling (CVS) and to evaluate the relationship between CVS and other congenital anomalies. DESIGN: Analysis of the outcome of 750 cases of CVS (730 cases with transcervical and 20 cases with transabdominal). SETTING: The outpatient prenatal genetic clinic of a university tertiary care center. SUBJECT: Seven hundred and fifty pregnant women that underwent CVS for prenatal genetic diagnosis from 7 to 12 weeks of gestation. RESULTS: Advanced maternal age was the most common indication for CVS (32.8%). The overall sampling success rate was 98.0% (735/750), representing 93.9% at 7 to 8 weeks, 98.1% at 9 to 10 weeks, and 98.3% at 11 to 12 weeks of gestation. The majority of cases (93.1%) required one or two aspirations. Cytogenetic analysis routinely included direct overnight and long-term culture methods which revealed 16 abnormalities (2.2%). Of 735 cases in which CVS was successful, 700 advanced to normal offspring, 17 had therapeutic termination, and 18 resulted in spontaneous abortions; there was an overall fetal loss rate of 2.4% (18/750). CONCLUSION: CVS in early pregnancy is a relatively safe and reliable method of prenatal genetic diagnosis capable of replacing genetic amniocentesis. However, it must be done by experienced personnel. No congenital anomalies were found to be related to CVS in this series. PMID- 8697345 TI - Abdomino perineal repair of pulsion enterocele. AB - OBJECTIVES: To review the techniques, results and complications of the combined abdomino perineal repair and mersilene mesh sacrocolpopexy. METHODS: From March 1988 to December 1993; 45 cases of pulsion enterocele were treated by a combination of the Zacharin type abdomino perineal repair and mersilene mesh sacrocolpopexy. Forty cases were followed from between 1 month and 18 months (mean 5.95 months). The notes were reviewed retrospectively. RESULTS: There were 3 recurrences (7.5%). Complications were not insignificant: wound infection in 3, urinary tract infection in 6, bowel dysfunction in 8, ventral hernia, vaginal stricture necessitating surgical release, and brachial nerve plexus injury occurred once. In one patient a peritoneal cyst developed necessitating laparoscopic aspiration. CONCLUSIONS: The combined abdomino perineal and sacrocolpopexy procedure offers the restoration of normal anatomy and the relief of the symptoms of prolapse in 92.5% of patients. The complication rate is significant and it should be undertaken as a secondary procedure. PMID- 8697346 TI - Bone mineral density of the spine using dual energy X-ray absorptiometry in patients with non-insulin-dependent diabetes mellitus. AB - To evaluate the influence of non-insulin-dependent diabetes mellitus (NIDDM) on bone mineral density (BMD), we measured BMD in 185 female patients with NIDDM using dual energy X-ray absorptiometry (DEXA). BMD was measured in lumbar vertebrae (L2-4). BMD is slightly higher in the diabetic patients compared with control subjects and bone loss related to menopause starts before the onset of menopause. The BMD of postmenopausal women showed a definite decrease with aging and there was abrupt bone loss after 55 years of age (p < 0.05). In relation to the duration of diabetes, the decrease of BMD for 15 years was 10.0%. BMD was negatively correlated with age, years since menopause (YSM), and disease duration (r = -0.584, r = -0.470, r = -0.186). These results suggest that age, YSM, and the duration of disease appear to be the risk factors for decreased BMD in the diabetic patients. PMID- 8697347 TI - Cervical cytology by means of fluorescence in situ hybridization with a set of chromosome-specific DNA probes. AB - OBJECTIVE: To reveal the numerical aberration of chromosome 1 and chromosome 17 in cervical neoplasia. METHODS: Fluorescence in situ hybridization (FISH) with chromosome-specific repetitive DNA probes was applied on cervical smears of cervical intraepithelial neoplasia (CIN) I, CIN II, and CIN III, and of invasive carcinoma cases, to detect numerical aberrations of chromosome 1 (#1) and chromosome 17 (#17). The cases were histologically classified as CIN I (n = 9), CIN II (n = 12), CIN III [severe dysplasia (n = 14), carcinoma in situ (CIS) (n = 14)], and invasive carcinoma (IC) squamous-cell carcinoma, large-cell nonkeratinizing type (n = 12). FISH was applied on the same cervical smears of these cases after Papanicolaou's staining, and copies in marked atypical cells were counted using a fluorescence microscope. RESULTS: The 9.49 +/- 2.59%/9.72 +/ 1.40% (#1/#17) cells showed an aneuploid pattern in CIN I, 22.5 +/- 3.98%/15.5 +/- 3.02% (#1/#17) in CIN II, 44.3 +/- 7.18%/ 45.01 +/- 5.61% (#1/#17) in severe dysplasia, 52.66 +/- 6.32/48.9 +/- 7.55% (#1/#17) in CIS, and 66.22 +/- 3.20%/57.38 +/- 5.35% in IC. The loss of a chromosome in CIN III cases and the gain of a chromosome in CIS and IC cases should be noted (p < 0.01). CONCLUSION: Because FISH has revealed the numerical aberrations of chromosome 1 and 17 in cervical neoplasia, this is an especially useful method for biological dosimetry and cancer biology. PMID- 8697348 TI - HER-2/neu gene amplification in cervical cancer in Chinese women of Hong Kong and China. AB - OBJECTIVE: To determine the amplification of proto-oncogene HER-2/neu in invasive cervical cancer and its relationship with the stage of disease, grade of tumor and prognosis of patients. METHODS: In this retrospective study 70 women with invasive cervical squamous cell carcinoma were included. DNA was extracted from the paraffin-embedded tumor tissue. The amplification of HER-2/neu was studied using a differential polymerase reaction (PCR) technique. Assessment of significance was performed using Peason's Chi-square test and Fisher's exact test. RESULTS: Eleven of the 70 cases (16%) showed an amplification of HER-2/neu but there was no relation between amplification and tumor histologic grading (p = 0.408) or clinical staging (p = 0.180). Follow-up information in 67 patients was available. The incidence of amplification in the patients who were alive with disease was not statistically different from that in the patients who were alive with no evidence of disease (p = 0.315). The incidence of amplification in the patients who died of disease was higher than that in the patients who were still alive, but statistical significance did not reached (p = 0.062). CONCLUSION: The results suggest that HER-2/neu amplification does exist in a subgroup of invasive cervical cancer and may play a role in cervical carcinogenesis. The role as independent prognostic factor has to be evaluated by further prospective studies. PMID- 8697349 TI - HLA sharing, anti-paternal cytotoxic antibodies and MLR blocking factors in women with recurrent spontaneous abortion. AB - OBJECTIVE: To study the prevalence of HLA sharing between spouses and its correlation with presence of antipaternal cytotoxic antibody (APCA) and mixed lymphocyte reaction (MLR) blocking factors in recurrent spontaneous aborters (RSA). DESIGN: Study was carried out at Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGI), Lucknow, from 1988-1992. Hundred couples with 3 or more consecutive recurrent spontaneous abortions and equal number of age, parity and ethinically matched normal controls were selected for studying HLA, APCA and MLR blocking factors. Meta-analysis was performed using standard formula and significance was tested by Chi-square analysis. RESULTS: Significant HLA sharing was observed in couples with RSA at A and DR loci compared to normal controls (p < 0.001). Twenty-seven point eight percent of couples with RSA were positive for APCA compared to 49% of controls (p < 0.01). MLR blocking factors were detected in 26% couples with RSA compared to 78% in controls (p < 0.001). An inverse correlation between HLA sharing and APCA and MLR positivity was demonstrated. CONCLUSION: The study supports that greater HLA sharing between spouses, associated with lack of an appropriate immune response to them could be responsible for RSA. PMID- 8697350 TI - Maternal congenital heart disease and pregnancy outcome. AB - OBJECTIVE: To study the obstetrics and neonatal outcome of women with congenital heart disease. METHOD: This is a retrospective study of 85 women with congenital cardiac disease. Data collected include maternal characteristics, New York Heart Association Class, cardiac complications and obstetric and neonatal outcome. RESULTS: The maternal and neonatal outcomes were excellent with no maternal and perinatal mortality. The main cardiac lesions were mitral valve prolapse (60.8%), atrial septal defect (8.6%), ventricle septal defect (6.5%) and aortic regurgitation (4.3%) and 2.1% each of tricuspid regurgitation, pulmonary regurgitation, Ebstein's anomaly, coarctation of aorta, patent ductus arteriosus, and Eisenmenger's syndrome. Six deliveries were associated with New York Heart Association deterioration. Compared to the general obstetric population, more women in the study group were primigravida, had pregnancy induced hypertension, underwent instrumental vaginal deliveries and caesarean sections and had more babies with lower birth weights. CONCLUSION: Despite potential difficulties and complications associated with congenital heart disease, careful cardiac and obstetric management in a tertiary referal centre resulted in good maternal and fetal outcomes. PMID- 8697351 TI - Differentiating advanced practice interventions and outcomes. PMID- 8697352 TI - The CNS and staff empowerment: a case of shifting paradigms. AB - The essence of nursing practice occurs at the bedside. In the midst of shifting health care dynamics, the need for excellence and stability at the bedside remains paramount. Past bureaucratic paradigms, focused on power hoarding and competitiveness, create dysfunctional work conditions in nursing units. Successful nursing administrations are turning to newer paradigms of staff empowerment where values focus on initiative, creativity and perpetual learning in the work place. The CNS has a unique opportunity to contribute to staff empowerment by enhancing staff impact in clinical practice, building staff competence in dynamic situations, revitalizing the meaningfulness of patient care and facilitating intelligent choice alternatives in complex situations. PMID- 8697353 TI - Demonstrating CNS impact on patient outcomes. PMID- 8697354 TI - An overview of urinary incontinence in adults: assessments and behavioral interventions. AB - Urinary incontinence affects millions of Americans. Often the goal of treatment is to improve the condition, prevent complications and provide comfort. Behavioral interventions can improve the condition in 54-75% of patients with urge and/or stress incontinence and can cure 12-16% of patients. Advanced practice nurses (APNs) are in a unique position of both providing direct care to patients who experience these problems and educating other nurses about signs, symptoms and appropriate nursing interventions for urinary incontinence. The scope of the problem, costs of urinary incontinence and potential cost savings with treatment are discussed in this article. Acute and chronic urinary incontinence and the necessary assessments to be performed by the APN are reviewed. Bladder training, habit training, prompted voiding and pelvic muscle exercises are the behavioral interventions used with urinary incontinence. Adjunct therapy, including biofeedback, vaginal cones and electrical stimulation, also is discussed. PMID- 8697355 TI - Use of quality management to provide nutrition to intubated patients. AB - CLINICAL NURSE SPECIALISTS are in a pivotal position to impact patient outcomes. Quality management is one method CNSs can use to measure and validate the effect they are having on patient outcomes. An example of such a quality management program was implemented by the CNS to monitor initiation of feeding for intubated patients. Because it was determined that many patients were not being fed for over 7 days after intubation, nutritional guidelines were developed and implemented for physicians and nurses to follow. One year after implementation of the guidelines, 51 patients were identified as needing nutritional support. The average number of days to institute feeding was reduced by a mean 6.4 days across all types of feeding, including oral feeding, enteral bolus feeding, continuous postpyloric feeding and parenteral nutrition. The early nutrition quality management program initiated by the CNS had a positive outcome for patients. PMID- 8697357 TI - Research role component revisited. PMID- 8697356 TI - Constraints and perspectives of advanced practice nursing in Taiwan, Republic of China. AB - Although master's-prepared advanced practice nurses (APNs) are used intensively in the United States, they are uncommon in most other countries. Statistics about APNs across the world are difficult to interpret because the term "specialist" does not necessarily equate with graduate preparation. This article focuses on the difficulties of implementing advanced practice nursing in Taiwan. Suggestions for future actions that may decrease these problems are presented. Based on discussions with nurses from other Asian countries, these suggestions may apply to increasing the use of APNs in these countries as well as in Taiwan. PMID- 8697358 TI - Labeling revisited: diagnoses in disguise? AB - The study examines 125 labels central to nursology used by practicing nurses to describe patients. Each nurse described the response pattern identified by each label, organizing and prioritizing its characteristics to produce a diagnostic algorithm. After work-peer affirmation of the chart's accuracy, the response pattern was renamed as a "syndrome." Predominant characteristics of each syndrome were analyzed. Nurses developed treatment protocols that they believed would reduce, control or "cure" defining characteristics. Field testing of these protocols demonstrated that conditions identified by labels (which normally lead to nurse avoidance) could be effectively treated when approached proactively. Some syndromes involved response patterns related to medical diagnosis or treatment, specific units in the hospital or the health care system itself. Nursology also includes less-than-ideal responses to circumstances that threaten personal well-being. PMID- 8697360 TI - Thinking critically ... and publicly. PMID- 8697359 TI - Validating the CNS role in acute care through research. AB - Research is widely accepted as an integral component of the CNS role. However, nursing literature reveals controversy over the ideal form and extent of CNS involvement in research. Acute care CNSs are in an ideal position to conduct clinical research. A model for support of CNS involvement in research in acute care and three examples of CNS-led research that impacted nursing practice are described in this article. PMID- 8697361 TI - Clinical journal: a tool to foster critical thinking for advanced levels of competence. AB - Rapid changes in the health care system and the challenge of meeting complex patient care needs require that nurses function at the competent, or higher, levels of expertise. Advanced levels of competence are facilitated through development and application of critical thinking abilities. Journal writing is a tool that can be used by CNSs and other nurses to improve basic thinking abilities and application of critical thinking for clinical decision making. Guidelines are presented for writing this type of clinical journal and for providing feedback to others. PMID- 8697362 TI - The elusiveness of the human will: Melville's Bartleby the Scrivener. PMID- 8697363 TI - Something old, something new. PMID- 8697364 TI - Specialty nursing council: a coalition of advanced practice nurses. AB - Advanced practice nurses (APNs) are often isolated within their specialty area, placing unnecessary limits on their range of influence and making professional networking more difficult. Networking and sharing of information are critical to developing a broadened perspective. As APNs become more systems and program oriented, a strong affiliation base must be maintained. How a group of APNs in one hospital developed a coalition to decrease the isolation gap, promote sharing of information and encourage cohesiveness is discussed in this article. The process of moving from the rather narrowed perspective of individual practice to the concept of group unity and collaboration is explored. PMID- 8697365 TI - Self-in-relation theory and the role of the clinical nurse specialist. Part I: Theory and role development. AB - Concepts and assumptions of the self-in-relation theory of women's development are discussed in this article. Proposed by feminist scholars at the Stone Center in Wellesley. Massachusetts, the theory is used to explore staff development and mentorship roles of the CNS. How the theory provides a new way to view these roles and applies concepts from the theory to advanced practice is examined. PMID- 8697366 TI - Making the connections to patient outcomes. PMID- 8697367 TI - Self-care reform. PMID- 8697368 TI - Severe psychiatric disorder and physical health risks. AB - IN THIS ARTICLE, research findings are discussed that indicate a high rate of general physical health problems in persons with persistent, long-term psychiatric disorders. The self-regulation theory of health behaviors is proposed as a method to examine the complexity of interpreting physical complaints and discomforts. Attribution of meaning to vague physical symptoms is confounded by mood states, especially negative moods. Little is known about how persons with persistent mental disorders assess physical symptoms, which is relevant to self care behavior. Research evidence suggests that persons with chronic health problems use different patterns of symptom interpretation and management than do healthy persons with similar symptoms. PMID- 8697369 TI - The rehabilitation CNS in the home health care setting. AB - THE REHABILITATION CNS is a rarity in the home health care setting. Rehabilitation nursing theory is consistent with home care practice. Both emphasize independence and self-care. In this article, experiences of one rehabilitation CNS in a home care agency during development of the role are described, and potential for the rehabilitation CNS role in home care under ideal conditions is explored. PMID- 8697370 TI - Science and nursing practice. PMID- 8697371 TI - Triangulation reveals theoretical linkages and outcomes in a nursing intervention study. AB - CNSs ROUTINELY GIVE psychosocial support to patients dealing with life threatening illnesses. Yet few studies discuss theoretical aspects of psychosocial support. The purpose of this paper is to report results of a study using an efficacy-enhancing intervention given to 49 patients receiving chemotherapy for cancer. Analysis of qualitative data revealed (1) linkages of a supportive psychosocial intervention with the theoretical basis of the study and (2) outcomes not apparent in statistical analysis of the hypothesis-testing study. Interventions were based on Orem's self-care framework and Bandura's description of sources of efficacy expectations. Data triangulation to identify areas where previous findings had not revealed interpretations provided a different perspective on the same phenomena and led to revisions in further study. Implications for CNS practice and research are discussed. PMID- 8697372 TI - Quantitative methods for clinical validation of nursing diagnoses. AB - CLINICAL VALIDATION STUDIES of nursing diagnoses are necessary to support use of diagnostic concepts and their defining characteristics in clinical settings. Diagnostic concepts approved by the North American Nursing Diagnosis Association, i.e., human responses to health problems and life processes, need to be tested through clinical research. Because validation studies have some unique procedures, we explain methods to be used by CNSs to conduct clinical studies. PMID- 8697373 TI - Advanced or specialty knowledge ... or both? PMID- 8697374 TI - Diabetes care concentration: a program of study for advanced practice nurses. AB - THE DIABETES RESEARCH and Training Center at the Albert Einstein College of Medicine, in collaboration with Yale University School of Nursing, initiated a project to develop and implement a concentration of study at the Master's level within the field of diabetes. The concentration has resulted in involvement of advanced practice nurses in management and care of individuals with diabetes. In the article, an epidemiological perspective in diabetes care is given, along with information on how the program developed and evolved over the past 5 years. Program graduates have become certified diabetes educators and completed a Master's thesis in the area of diabetes care, resulting in practice-oriented publications. PMID- 8697375 TI - Setting the stage for the 21st century. PMID- 8697376 TI - CNS and expanded role in hospitals. AB - THE CNS ROLE in teaching hospitals is expanding. How does this CNS function? What is the prevalence of the expanded role? In this article, the current status of the CNS working in an expanded role with house staff is described, the literature is reviewed, and results of an informal survey completed by the author are reported. Implications for advanced practice in this CNS role are addressed. PMID- 8697377 TI - Self-in-relation theory and the role of the clinical nurse specialist. Part II: Application to advanced nursing roles in a professional practice model. AB - CONCEPTS AND ASSUMPTIONS of self-in-relation theory of women's development, as proposed by feminist scholars at the Stone Center in Wellesley, Massachusetts, are applied in this article. This theory was used as a framework to guide staff development and mentorship roles of advanced practice nurses. How the theory served to direct these roles and assisted in development of a professional practice model is discussed. Exemplars from the authors' practices and professional practice outcomes after 2 years of theory implementation are presented. PMID- 8697378 TI - Should CNSs manage rumor? PMID- 8697379 TI - Rumor management in nursing systems: role of the psychiatric CNS. AB - RUMOR MANAGEMENT AND control is particularly important in nursing systems during times of change. In this article, a brief history of the study of rumor and the rumor process is given and applied to nursing, systems thinking and the CNS, and three types of rumor are described. Examples are given and strategies and approaches for managing rumor are prescribed. The first approach, used when a final decision about a planned change has not been made, helps avoid "trickle down" and builds trust and empowerment by soliciting and using input from those who will be affected by the proposed change. The intent of the second approach, used when a decision has been finalized or an event has occurred and rumor has preceded an official announcement, is to debrief from the occurrence or transform the decision. The last approach is used to interrupt a pattern of misinformation and to clarify or inform. The nurse leader or manager must stay in the communication loop and refrain from blaming a speculated source in order to correct information. PMID- 8697380 TI - Desmoplastic malignant melanoma of the oral mucosa. An underrecognized diagnostic pitfall. AB - BACKGROUND: Although cutaneous desmoplastic malignant melanoma (DMM) has been well characterized, those arising from the oral mucosa have been less well defined. METHODS: We evaluated the clinical and pathologic features of three patients with biopsy-proven DMM examined at the North Carolina Baptist Hospital. Routine hematoxylin and eosin-stained slides were reviewed in all three cases. Sections from all cases were examined immunohistochemically using the avidin biotin-peroxidase (ABC) technique and employing commercially available antibodies to the following antigens: S-100 protein, HMB-45, NK1C3, and cytokeratin (AE1/AE3). Appropriate positive and negative controls were utilized throughout these procedures. Clinical data were obtained from the patients' medical records. RESULTS: Age at diagnosis for the three male patients were 42, 64, and 75 years. Anatomically, these neoplasms arose from the left maxillary oral mucosa (two patients) and the vermilion border of the lower lip (one patient). Initial incisional biopsies of all three patients were misinterpreted as desmoid tumor (one patient) and squamous cell carcinoma (two patients), respectively. Histologically, all tumors were poorly circumscribed and composed of fascicles and bundles of spindle-shaped cells with hyperchromatic nuclei and associated with extensive stromal collagenization. Perineural invasion was noted in two tumors. An overlying atypical, intraepidermal melanocytic proliferation was observed in two tumors. Immunohistochemically, all three tumors showed positive immunoreactivity with S-100 protein and vimentin. One tumor also expressed HMB 45. Wide surgical incision was the primary mode of therapy in all patients. One patient also received multiple courses of radiation therapy and chemotherapy. One patient died of widespread metastatic disease. CONCLUSIONS: DMM of the oral mucosa is a rare, often unrecognized, form of malignant melanoma associated with a fibrosarcoma-like morphologic appearance and abundant collagenization. Meticulous attention to histomorphology and judicious use of immunohistochemical stains will help prevent misdiagnosis. PMID- 8697381 TI - Cyclin D1 overexpression in primary hypopharyngeal carcinomas. AB - BACKGROUND: Hypopharyngeal squamous cell carcinomas (HPCS) are associated with an extremely poor prognosis. Generally, conventional clinicopathologic factors have only limited value as prognostic factors for this malignancy. It is therefore clinically important to identify new prognostic factors that accurately reflect the biologic aggressiveness of this malignancy. The amplification and overexpression of the cyclin D1 protooncogene have been reported in a variety of malignancies, and are thought to be related to tumor progression. Based on this phenomenon, the authors immunohistochemically evaluated overexpression of the cyclin D1 gene in 42 cases of primary HPCS. In addition, the immunohistochemical staining of the proliferation marker MIB-1 (Ki-67 antibody) was also performed. METHODS: Formalin fixed, paraffin embedded biopsy specimens obtained prior to treatment were examined. Cyclin D1 and Ki-67 were detected using monoclonal antibodies by means of the streptavidin-biotin method. The relationship between cyclin D1 overexpression and the stage, histologic grade, presence of lymph node metastases, proliferation index, and survival was then statistically analyzed. The correlation between the proliferation index, other clinicopathologic factors, and survival was also evaluated. RESULTS: Twenty-three (54.8%) HPCS specimens showed a 20% or greater immunoreactivity for cyclin D1. Cyclin D1 overexpression was related to cervical lymph node metastases (P = 0.037) but not to clinical stage, histologic grade, or the proliferation index. Cyclin D1 negative tumors were associated with a significantly better prognosis (P = 0.023), particularly in patients who underwent multimodality treatment. Finally, the MIB-1 labeling index showed no correlation with either the clinicopathologic parameters or overall survival. CONCLUSIONS: Based on these findings, cyclin D1 immunohistochemical staining is considered to be useful, not only as a prognostic factor for HPCS, but also as a means of determining the optimum treatment for each individual patient. Conversely, the MIB-1 labeling index appears to have no clinical significance in HPCS. PMID- 8697382 TI - Gastric lesions in 76 patients with adult T-cell leukemia/lymphoma. Endoscopic evaluation. AB - BACKGROUND: Adult T-cell leukemia/lymphoma (ATLL) is caused by human T lymphotropic virus type I. Gastric lesions in ATLL have not been described precisely, whereas the clinical features of ATLL have been well documented. The goal of the present study was to review gastric lesions, including gastric involvement, of patients with ATLL who were admitted to our hospital. METHODS: Endoscopic examination of the upper gastrointestinal tract was performed on 76 of 110 patients who were admitted to our hospital between 1981 and 1994. Gastric involvement was diagnosed by histologic examination of biopsy specimens of gastric lesions. Types of gastric lesions, histologic features, and survival periods in patients with ATLL were summarized. RESULTS: Of the 76 patients with ATLL who underwent an endoscopic examination, 23 had gastric involvement (30.3%). Twenty-seven patients had other gastric lesions: 10 with peptic ulcers (13.2%), 8 with gastric erosions (10.5%), 3 with submucosal tumors (3.9%), 2 with hyperplastic polyps (2.6%), 1 with gastric adenoma (1.3%), and 3 with gastric carcinomas (3.9%). The most frequent endoscopic configuration of gastric involvement with ATLL was the diffuse type with ulceration, and the most common histology was large cell type. Among those with the acute type ATLL, the survival period of those patients with gastric involvement was less than that of the patients without gastric involvement. In contrast, the survival period for lymphoma type ATLL did not differ among the groups regardless of gastric involvement. CONCLUSIONS: This study demonstrated that 30.3% of patients with ATLL had gastric involvement and 13.2% had peptic ulcers. Gastric involvement of ATLL was one of the prognostic factors in acute type ATLL, whereas it had no influence on the prognosis of lymphoma type ATLL. PMID- 8697383 TI - Prognostic factors for patients with colon or rectal carcinoma treated with resection only. Five-year follow-up report. AB - BACKGROUND: The prognostic factors and natural history of recurrence in patients with colorectal carcinoma who underwent curative resection and no other therapy were analyzed. METHODS: The object of analysis was the potentially curative resection only subgroup in the randomized clinical trial (RCT) that we performed. Cox's proportional hazards model was used mainly to analyze recurrence rates during the first 5 years after surgery. RESULTS: The analysis was performed on a subgroup of the RCT (279 patients with colon carcinoma and 293 patients with rectal carcinoma). Five-year disease free survival rates were 76.3% and 56.5% for colon and rectal carcinomas, respectively. The prognostic factors for recurrence for colon carcinoma patients were different from those with rectal carcinoma. For colon carcinoma, only Dukes stage was significant, whereas for rectal carcinoma, Dukes stage, age, location of the tumor, and serosal and venous invasion by cancer cells were prognostic factors. Log-transformed disease free survival rates were linear in Dukes Stage B and biphasic in Dukes Stage C for both colon and rectal carcinoma. The two phases in Dukes Stage C intersected at 2.85 and 3.04 years, respectively. The annual hazard value was high for the first 3 years in both colon and rectal carcinoma. CONCLUSIONS: We conclude that follow-up of patients with colorectal carcinoma who undergo potentially curative resection is of particular importance in the first 3 years after surgery. Furthermore, the usefulness of adjuvant chemotherapy can be adequately evaluated from data yielded during this postoperative period. PMID- 8697384 TI - Prognostic significance of tumoral angiogenesis in completely resected late stage lung carcinoma (stage IIIA-N2). Impact of adjuvant therapies in a subset of patients at high risk of recurrence. AB - BACKGROUND: Angiogenesis plays a critical role in human tumor growth and metastasis. Microvessel count (MC), as a measure of tumor angiogenesis, has been significantly correlated with metastatic disease in cutaneous, mammary, prostatic, head and neck, and early stage lung carcinoma. METHODS: Ninety-six consecutive patients affected by T1-3N2MO nonsmall cell lung carcinoma (NSCLC), who underwent radical surgery between March 1991 and March 1995 (in many cases followed by adjuvant therapies) were prospectively investigated to assess the prognostic significance of both traditional and new biologic parameters like proliferative activity, blood vessel invasion by tumoral cells, and neovascularization (estimated by the MC). RESULTS: With a median follow-up of 24 months, the projected 3-year survival was 42.1%. Forty-eight of the patients (50%) had already experienced a local (n=14) or systemic (n=34) relapse. The extent of resection (lobectomy vs. pneumonectomy; P=0.0045), the number of mediastinal lymph node levels (single vs. multiple; P=0.014), and the MC (on a X200 field; P=0.015) correlated significantly with metastatic disease. By univariate analysis, significant predictors of survival were: the extent of surgery (P=0.03), adjuvant therapy (P=0.05), and MC (< or = vs. > cut-off; P=0.00076). On multivariate analysis, however, only the MC (P=0.02) retained its level of prognostic significance. CONCLUSIONS: Our results provide evidence that neovascularization, estimated by the MC, can predict metastatic disease and survival in patients with completely resected T1-3N2M0 NSCLC, and may also be useful in patient selection for effective adjuvant treatment. PMID- 8697385 TI - Immunohistochemical expression of glutathione S-transferase-Pi can predict chemotherapy response in patients with nonsmall cell lung carcinoma. AB - BACKGROUND: Resistance to chemotherapy agents is a major problem in the treatment of patients with nonsmall cell lung carcinoma (NSCLC). Recent studies have indicated that glutathione S-transferase-Pi (GST-Pi) may play an important role in the resistance of cancer cells to alkylating agents, including cisplatin compounds. METHODS: The expression of GST-Pi in tissues obtained by bronchoscopic biopsy from 38 NSCLC patients was investigated immunohistochemically. These patients were treated with a combination of cisplatin-based chemotherapy and were evaluated to determine the relationship between GST-Pi expression and chemotherapy response. RESULTS: Of the 38 patients, 25 (66%) were GST-Pi-positive and 13 (34%) were negative. There was no significant correlation between GST-Pi expression and the clinicopathologic factors examined (age, sex, performance status, histology, differentiation grade, and stage). Of the 38 patients treated with cisplatin-based chemotherapy, 12 patients responded to chemotherapy (overall response rate, 32%). For the patients with negative GST-Pi expression, the response rate was 69% (9 of 13 patients). In the patients with positive GST-Pi expression, the response rate was 12% (3 of 25 patients). This difference was statistically significant (P=0.0012). CONCLUSIONS: The expression of GST-Pi in NSCLC patients was significantly related to response to cisplatin-based chemotherapy, and may be a useful predictor of chemotherapy response. PMID- 8697386 TI - A combination chemotherapy with low doses of cytarabine and etoposide for high risk myelodysplastic syndromes and their leukemic stage. A pilot study. AB - BACKGROUND: Even now, no definitely effective therapy is inducted to high risk myelodysplastic syndromes (MDS) and their leukemic stage (MDS-AML) except bone marrow transplantation. METHODS: Ten patients with high risk MDS and 6 with MDS AML were treated with daily low doses of cytarabine (10 mg/m2/12h, infused over 2h) etoposide (50 mg/m2/day, infused over 2h). RESULTS: Fourteen of these patients were finally evaluated among whom 6 with high risk MDS and 3 with MDS AML (64.3%) had complete remission, and 2 with high risk MDS (14.3%) achieved partial remission after this chemotherapy for 9 to 21 days. Three of 11 responders were resistant to the prior chemotherapies with single and low dose cytotoxic agents including cytarabine, etoposide, or aclarubicin. Although all of the patients who could be assessed developed severe marrow hypoplasia after chemotherapy, the nonhematologic side effects were mild enough to be tolerated. CONCLUSIONS: This combination chemotherapy must be effective and useful in high risk MDS and MDS-AML not only without prior chemotherapy but in cases which have been resistant to single and low dose oncostatic agent. PMID- 8697387 TI - Predicting five-year outcome for patients with cutaneous melanoma in a population based study. AB - BACKGROUND: In numerous studies tumor thickness has been shown to be the most important prognostic factor for patients with localized cutaneous melanoma. However, to our knowledge there are no population-based studies analyzing the prognosis of patients living in the United States with cutaneous melanoma. METHODS: A prognostic model was developed with death as an outcome for 548 patients from Connecticut with localized cutaneous melanoma. Only patients with invasive melanoma who either died of the disease or were followed-up at least five years were studied. Fourteen pathologic parameters (histologic type of melanoma, Clark level, microscopic satellites, histologic regression, tumor thickness [Breslow], ulceration, vascular invasion, mitotic rate per mm2, tumor infiltrating lymphocytes, radial vs. vertical growth phase, solar elastosis, co existing nevus, lymphocytic response, and pigmentation) and three clinical variables (age, sex, and anatomic site) were analyzed using logistic regression. RESULTS: After univariate analysis, 10 pathologic variables showed prognostic significance: histologic type (nodular and "other" types only), Clark level, microscopic satellites, regression (protective), tumor thickness, ulceration, vascular invasion, mitotic rate, vertical growth phase, and solar elastosis (protective). In the final model employing multivariate analysis, only tumor thickness and mitotic rate continued to have independent predictive value. CONCLUSIONS: In this population-based study of 548 patients in Connecticut, tumor thickness was the most significant prognostic factor for survival of patients with localized cutaneous melanoma. Other prognostic factors studied to date have not been conclusively verified as providing any additional information beyond that of tumor thickness. PMID- 8697388 TI - Evaluation of the prognostic significance of cathepsin D, epidermal growth factor receptor, and c-erbB-2 in early cervical squamous cell carcinoma. An immunohistochemical study. AB - BACKGROUND: This study evaluated the prognostic significance of immunohistochemical staining for cathepsin D, epidermal growth factor receptor (EGFR), and c-erbB-2 in patients with early cervical squamous cell carcinoma. METHODS: This retrospective analysis comprised 132 patients, all subjected to radical hysterectomy with bilateral pelvic lymphadenectomy for International Federation of Gynecology and Obstetrics (FIGO) Stage IB cervical squamous cell carcinoma. Immunohistochemical staining was correlated with various histopathologic and morphologic characteristics (i.e., tumor size, grade of differentiation, vessel invasion, invasion into parametria, and lymph node metastasis) and relapse free survival. RESULTS: Positive staining for cathepsin D was observed in 47% of tumors, more frequent in tumors giving rise to lymph node metastases. The relapse free survival was lower for patients with cathepsin D positive tumors. Overexpression of EGFR was observed in 25.8% of the tumors. There was no correlation with any of the histopathologic variables investigated. Relapse free survival was lower for patients with tumors overexpressing EGFR. Immunohistochemical staining for c-erbB-2 was observed in 12.1% of tumors with no correlation with relapse free survival. In multivariate analysis, immunostaining of cathepsin D and EGFR obtained independent prognostic significance, and considered together (both negative, one positive, or both positive) was the strongest prognostic factor after tumor size. CONCLUSIONS: Immunohistochemical staining for cathepsin D and EGFR is useful as a tool for evaluation of tumor aggressiveness in patients with early cervical squamous cell carcinoma. PMID- 8697389 TI - Natural history of patients with pulmonary metastases from uterine cancer. AB - BACKGROUND: Endometrial cancer is the most common female genital cancer and approximately 90% of the cases are diagnosed while they are still confined to the uterus. However, the natural history and treated course after the development of pulmonary metastasis (PM) have not been studied systematically in a large series of patients. METHODS: Between 1962 and 1992, 100 patients (6%) with PM were identified by computerized search of the medical records from 1.665 patients admitted to our hospitals with the diagnosis of uterine cancer. The median age of the patients was 65.5 years (range: 42-87 yrs). The usual histologic types of the uterine neoplasms were 59 adenocarcinomas (59%), 21 sarcomas, and 14 adenosquamous carcinomas. Of the 83 patients with reported tumor grade, 11 had Grade 1 tumor, 12 Grade II, and 60 Grade III. RESULTS: Lung metastases were found at the time of diagnosis of the primary tumor in 22 patients. Hemoptysis was the first symptom of 3 of the 22; the majority had no respiratory symptoms. In the remaining 78 patients with PM appearing after primary therapy, the mean interval time between primary diagnosis and PM was 29.4 months, whereas between PM and death was 15.7 months. Of all patients with lung metastases, 75% did not survive 1 year; however 6% survived more than 5 years after diagnosis of metastatic disease. Patients with isolated PM had prolonged survival (36.1 mos, P=0.001), whether treated medically or with pulmonary resection. Progestin therapy was given to 39 patients, with complete response consisting of radiographic resolution of all disease in 6 patients (15%) and prolonged stabilization in an additional 5 (13%). The histologic grade of the primary tumor was predictive of clinical response to progestine therapy. CONCLUSIONS: Asymptomatic pulmonary metastases represent a common site of extra pelvic spread of disease. The majority of patients with PM (75%) do not survive 1 year. Low grade uterine tumors are more likely to respond to progestin therapy and do so for extended periods of time. PMID- 8697390 TI - Interferon-beta can induce progesterone receptors in human endometrial adenocarcinoma. AB - BACKGROUND: The induction of estrogen and progesterone receptors (ER and PGR) has been reported in breast and endometrial cancer cells exposed to human fibroblast interferon-beta (hIFN-beta). Clinical verification of this finding might provide the rationale for new therapeutic approaches. This study was designed to evaluate whether clinical treatment with high doses of hIFN-beta induced ER and PGR in patients with endometrial adenocarcinoma. METHODS: Two biopsies were obtained, 1 before and 1 after hIFN-beta treatment (3 x 10(6) i.m. every other day for 3 weeks) from 36 patients with endometrial adenocarcinoma. ER and PGR were determined with standard procedures using radiolabeled ligands. RESULTS: hIFN beta treatment did not affect the proportion of ER-positive (i.e., >15 fmol/mg protein) or PGR-positive (i.e., >20 fmol/mg protein) cases. However, in patients with detectable ER and PGR at baseline, hIFN-beta raised the levels. Using a 35% difference before and after therapy as a cut-off, 72 and 79% of cases had increases in ER and PGR, respectively. The difference was highly significant for PGR. CONCLUSIONS: In patients with endometrial adenocarcinoma with undetectable ER or PGR, hIFN-beta did not induce the expression of these receptors. When the receptors were present they were upregulated by hIFN-beta. Whether this increase in receptor levels, particularly PGR, has therapeutic applications remains to be established. PMID- 8697391 TI - Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in endometrial carcinoma. AB - BACKGROUND: Solid tumors, including endometrial carcinomas, must induce a vascular stroma to grow beyond a minimal size. The mechanisms responsible for angiogenesis in endometrial carcinoma, however, are not well defined. Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a multifunctional cytokine that is an important regulator of tumor angiogenesis. We evaluated VPF/VEGF mRNA and protein expression, as well as VPF/VEGF receptor mRNA expression, in endometrial carcinoma. METHODS: Fourteen examples of endometrial carcinoma were evaluated by in situ hybridization; in 7 cases, benign atrophic endometrium from the same patient was also examined. Histologic sections were subjected to in situ hybridization using 35S-labeled riboprobes specific for VPF/VEGF and, in a subset of cases, riboprobes specific for the VPF/VEGF receptors flt-1 and KDR. In addition, ten examples of endometrial carcinoma were evaluated for VPE/VEGF protein expression by immunohistochemistry. RESULTS: All 14 examples of endometrial carcinoma studied by in situ hybridization exhibited focal strong VPF/VEGF mRNA expression by tumor cells. In addition, the endothelial cells of surrounding microvessels strongly expressed flt-1 and KDR mRNAs in all ten cases examined. In contrast, no strong expression of VPF/VEGF, flt-1, or KDR mRNA was observed in the seven examples of benign atrophic endometrium studied. All ten cases of endometrial carcinoma studied by immunohistochemistry exhibited strong VPF/VEGF protein expression by tumor cells. CONCLUSIONS: These observations suggest that VPF/VEGF is an important angiogenic factor in endometrial carcinoma. PMID- 8697392 TI - Expression of component desmosomal proteins in uterine endometrial carcinoma and their relation to cellular differentiation. AB - BACKGROUND: While the assessment of the malignancy of neoplasms is based on morphologic studies of cells and tissues, use of objective molecular markers is leading to a better understanding and more biologically meaningful classification of neoplasms. In recent years, changes in the expression of cell adhesion molecules, especially E-cadherin, catenin, and adenomatous polyposis coli (APC), in carcinomas have attracted the attention of researchers. However, little is known about desmosomes in the uterine endometrium or in endometrial carcinomas. In this study, we semiquantified the desmosomal components desmoplakin I and II and desmoglein, in tissue sections using confocal laser scanning microscopy (LSM), and examined their relationship to the pathological type, the occurrence of lymph node metastases, and the extent of myometrial invasion. METHOD: Frozen sections of 31 specimens of normal endometrium, 5 specimens of atypical hyperplasia, and 41 specimens of endometrial carcinoma were stained by the immunofluorescence method using antidesmoplakin I and II and antidesmoglein, and these markers were then semiquantified in tissue sections by LSM. RESULTS: The expression and location of desmoplakin I and II and desmoglein were similar, and their expression decreased with loss of differentiation. The expression was lower in cases of lymph node metastasis than in negative cases and was lower in the cases with > one-half myometrial invasion than in cases with < one-half myometrial invasion. CONCLUSIONS: Reduction of desmoplakin I and II and desmoglein expression may play an important role in the invasiveness and metastatic activity of human endometrial carcinoma. They can therefore be used as differentiation markers for endometrial carcinoma. PMID- 8697393 TI - Factors associated with intention to undergo annual prostate cancer screening among African American men in Philadelphia. AB - BACKGROUND: This study assesses whether African American men in Philadelphia are receptive to annual prostate cancer screening. Factors associated with intention to undergo prostate cancer screening are also identified. METHODS: The authors randomly selected 218 African American men from the patient population of a large primary care practice in Philadelphia. The men were 40 to 70 years of age and were available for a telephone survey. Responses to survey items defined by the Preventive Health Model were collected from 154 respondents (71%). Univariate and multivariate analyses of screening intention were performed using survey data on sociodemographic background and medical history; knowledge, attitudes, and beliefs about prostate cancer and screening; social support and influence; and, intention to undergo a screening examination. RESULTS: Overall, 69% of subjects reported that they intended to have annual prostate cancer screening. Logistic regression analyses showed that subject belief in screening efficacy (P=0.0002) were positively and significantly associated with intention to screen. CONCLUSIONS: Findings reported here show that African American men in an urban primary care practice setting are receptive to annual prostate cancer screening and that psychologic and social influence factors are associated with screening intention. The data highlight the need for health care professionals to provide education and advice regarding prostate cancer care to men in this population. PMID- 8697394 TI - Teratoma in primary testis tumor reduces complete response rates in the retroperitoneum after primary chemotherapy. The case for primary retroperitoneal lymph node dissection of stage IIb germ cell tumors with teratomatous elements. AB - BACKGROUND: Recent advances in the therapy of advanced testicular nonseminomatous germ cell tumors (NSGCT) have resulted in increased attention to avoiding double therapy in cases where single modality therapy will suffice. METHODS: Over an 8 year period, 104 patients with Stage II and III testicular NSGCT received primary chemotherapy. Seventy-nine patients had retroperitoneal lymph nodal metastases, 33 of whom had a radiologic complete response, 43 a radiologic incomplete response, and 3 were not re-evaluated after induction chemotherapy. Thirty-nine patients underwent retroperitoneal lymph node dissection (RPLND). The radiologic and pathologic response of the nodes to primary chemotherapy was correlated with tumor burden (lymph node metastasis size < or = 2 cm, 2.1-5 cm, 5.1-10 cm, and >10 cm), primary tumor pathology, and prechemotherapy marker levels. RESULTS: Larger initial lymph node size, metastases size, the presence of teratoma in the primary tumor, and prechemotherapy alpha-fetoprotein (alpha-FP) > 80 mg/L and beta-HCG (bHCG) 10000 IU/L were found to correlate significantly with an incomplete radiologic response. Lymph node metastases size was the only independent prognostic factor on multivariable logistic regression analysis. Prechemotherapy alpha-FP > 80 mg/L and beta-HCG > 10000 IU/L were associated with the presence of teratoma or carcinoma in the retroperitoneal nodes. The presence of teratoma in the primary tumor is associated with a higher incomplete response rate and residual teratoma in the retroperitoneal lymph nodes after primary chemotherapy. CONCLUSIONS: Predictors of need for postchemotherapy RPLND include large lymph node metastasis size and presence of teratomatous elements in the primary tumor. To reduce the need for and morbidity of double therapy, patients with low volume clinical Stage II, NSGCT and teratomatous elements in the primary tumor are arguably better served by primary RPLND. PMID- 8697395 TI - Clinical relevance of urokinase plasminogen activator, its receptor, and its inhibitor in patients with renal cell carcinoma. AB - BACKGROUND: Urokinase plasminogen activator (u-PA) plays a key role in the metastatic process by promoting plasmin mediated tissue degradation. Metastatic cell invasion requires localized proteolysis, which may be directed by u-PA receptor. The binding of u-PA and PAI-1 to the u-PA-receptor may cause internalization of the trimeric complex into the cell and activate a tyrosine kinase. In a prospective study the u-PA, u-PA-R, and PAI-1 content in patients with renal cell carcinoma (RCC) and benign renal tissue were correlated with traditional prognostic factors such as the TNM staging, histologic grading, ploidy, and the clinical outcome of the patients. METHODS: One hundred fifty-two patients who underwent transperitoneal tumor nephrectomy for RCC were followed up for a mean of 23.9 months. u-PA, u-PA-R, and PAI-1 from the tumor tissue and corresponding benign renal tissue were quantified from detergent extracted tissue samples (1% Trinton-X-100 in triethanolamine-buffered saline) and measured with an enzyme-linked immunoadsorbent assay. RESULTS: PAI-1 significantly correlated with the prevalence of distant metastasis (M0: 10.04 vs. M1 23.79, P=0.02) and the development of new metastasis postoperatively (M0: 10.85 vs. M1 27.36, P=0.001). A cut-off level of 12 ng/mg protein for PAI-1 selected a group of patients at high risk for relapse. Forty-one patients had PAI-1 > 12 ng/mg with 6 relapses compared with 55 patients with PAI-1 < 12 ng/mg with 1 relapse during the follow-up. Content of mu-PA correlated with the development of distant metastases (log rank 4.32, P=0.037). A cut-off value of 0.84 ng/mg selected 2 groups: a group at high risk for metastasizing (u-PA > 0.84, n=11 with 9 events and a group at low risk (u-PA < 0.84 with 94 patients and 5 events). Applying a cut-off value of 0.85 for u-PA-R 2 groups could be discriminated: 31 patients had no relapse with u-PA-R < 0.85 and 18 had 3 recurrences with u-PA-R > 0.85 g/ml. CONCLUSIONS: u-PA, u-PA-R, and PAI-1 are strong and independent prognostic factors for predicting early relapse for RCC. Especially with PAI-1, a high and low risk group for disease free survival can be discriminated. PMID- 8697396 TI - Clinical outcome of patients with papillary thyroid carcinoma who have recurrence after initial radioactive iodine therapy. AB - BACKGROUND: Among patients with well differentiated papillary thyroid carcinoma who generally have an excellent prognosis and a near-normal lifespan, there exist subsets of patients who have significant risk for morbidity and mortality from this disease. It is important to define the patterns of disease progression and the clinical outcome of such patients to develop effective surveillance and treatment strategies. Patients with recurrence after surgery and therapeutic administration of radioactive iodine (RAI) for papillary thyroid carcinoma represent one such subset of high-risk patients. METHODS: At the University of Texas M. D. Anderson Cancer Center, 65 patients with papillary thyroid carcinoma were diagnosed between 1970 and 1990. Their medical records were reviewed with particular attention to disease recurrence and outcome as well as RAI imaging and treatment. RESULTS: Following diagnosis and initial therapy, 19 patients died from thyroid carcinoma after a median of 64 months; 34 had no evidence of disease for a median of 112 months of available follow-up; and 7 are alive with disease 61 to 153 months after diagnosis. Cervical lymph node metastases were present in 41 patients and extrathyroidal or extranodal tumor invasion was seen in 25 patients at the time of initial surgery; distant metastases (lung, bone, brain, liver, and adrenal) developed later in 18 patients. RAI uptake by recurrent tumor deposits in the neck was seen most frequently in patients with no direct invasion of adjacent tissues but with recurrence limited to cervical lymphadenopathy; this group of patients was the most likely to become clinically and radiologically disease free. RAI generally did not concertrate in invasive cancers with extrathyroidal or extranodal extension in the neck; patients with this type of invasive carcinoma were also more likely to die from the disease. CONCLUSIONS: We suggest that among patients with recurrent papillary thyroid carcinoma, invasive cancers are less likely to concertrate RAI, whereas patients with disease confined to lymph nodes are more likely to have RAI-avid tumors and to benefit from RAI therapy. PMID- 8697397 TI - The World Health Organization classification of adenohypophysial neoplasms. A proposed five-tier scheme. AB - BACKGROUND: Although numerous attempts have been made, the classification of pituitary neoplasms remains controversial. METHODS: The present proposal is based on correlative clinical and pathologic (histologic, immunocytochemical, and electron microscopic) studies of more than 8000 surgically removed human pituitary tumors. RESULTS: Anterior pituitary tumors have been variously classified on the basis of their clinical presentation, biochemical findings, histology (growth pattern, tinctorial characteristics), proliferation indices, immunocytochemical profile, and ultrastructural features. Herein we propose a five-tier classification, clinicopathologic in nature, which focuses on endocrine activity, imaging, operative findings, histology, immunocytochemistry, and ultrastructure. The integration of these five complementary approaches into what is fundamentally a pathologic classification is as practical as it is novel. Its importance lies in the fact that the collected data provide valuable information to the clinical endocrinologist, neurosurgeon, and oncologist involved in the assessment of a tumor's biologic behavior, growth potential, therapeutic responsiveness, and prognosis. Due to financial restraints, lack of facilities, and unavailability of well trained personnel, we realize that at present the five approaches cannot be fully implemented in all institutions. Nonetheless, clinical and biochemical data, imaging, and operative findings, as well as basic histologic parameters are generally readily available. Collectively they are indispensable in establishing the correct diagnosis and in directing patient management. Conversely, the cost-effectiveness of immunocytochemistry and electron microscopy is debatable in that their performance and interpretation requires time, financial resources, and expertise. Nonetheless, it should be clear that any correlation between endocrine activity, growth potential, morphologic features, immunocytochemical profile, and ultrastructural features provides greater insight into the pathobiology of adenohypophysial tumors than is gained by routine histology alone. Thus we feel justified in including immunocytochemical and ultrastructural investigation of pituitary tumors in a modern classification. At present, more sophisticated molecular biologic methods represent investigative tools that play no significant role in the classification. CONCLUSIONS: A five-tier classification of adenohypophysial neoplasms based on clinical and biochemical results, imaging, operative findings, histology, immunocytochemistry, and electron microscopy is proposed. It is recommended to the World Health Organization for acceptance. PMID- 8697398 TI - Selective decrease in serum immunoglobulin G1. A tissue nonspecific tumor marker detecting early stages of gynecologic malignant disease with high efficiency. AB - BACKGROUND: Malignant diseases of various tissue origin have previously been found to be associated with a characteristic shift in the serum pattern of IgG subclasses, i.e., a highly significant reduction of the percent of IgG1 and an increase of the percentage of IgG2 relative to the total IgG. In the present study we examined the diagnostic performance of this indirect tumor marker in patients with carcinomas of various sites within the female reproductive tract. METHODS: Using quantitative affinity chromatography, the percents of IgG1 and IgG2 in the total IgG were determined for 207 patients with carcinoma of the ovary, cervix, or corpus uteri, prior to any treatment. The data were compared with those of 135 age matched healthy females and 52 patients with benign gynecologic diseases. RESULTS: It was found that (1) mean values for the percents of IgG1 and IgG2 of all of the cancer patients differed significantly from those of the patients with benign disease and healthy controls; (2) no differences were noted between carcinomas of the ovary, corpus or cervix uteri; (3) early stages of carcinoma exhibited the effect to the same extent as late stages; (4) the specificity of the percent of IgG1 to discriminate between controls and cancer patients ranged between 90 and 100%, regardless of localization and stage of tumor; and (5) whereas with ovarian cancer CA 125 showed a slightly greater sensitivity, the percent of IgG1 was by far more sensitive than the conventional markers CA 125, TPA, CEA, Ferritin, and SCC to diagnose carcinoma of the cervix and corpus uteri, notably at early stages. Combined analysis of the percent of IgG1 and CA 125 and/or TPA led to an increase in sensitivity with tumors of all three sites. CONCLUSIONS: Thus, the determination of the percent of IgG1 by itself and/or in combination with conventional markers may provide relevant information regarding the noninvasive detection of early stages of gynecologic carcinoma. PMID- 8697399 TI - Low dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone with zalcitabine in patients with acquired immunodeficiency syndrome-related lymphoma. Effect on human immunodeficiency virus and serum interleukin-6 levels over time. AB - BACKGROUND: Use of multiagent chemotherapy has been associated with complete remission (CR) in approximately 50% of patients with newly diagnosed acquired immunodeficiency syndrome (AIDS)-lymphoma, although additional AIDS-related complications may occur. Both chemotherapy and antiretroviral therapy were employed in an attempt to ascertain if the combination was safe, and associated with changes in human immunodeficiency virus (HIV) p24 antigen levels during the course of treatment. METHODS: Low dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone(M-BACOD) chemotherapy and zalcitabine (ddC) were employed in 28 patients. Since both vincristine and zalcitabine may cause peripheral neuropathy, a Phase I/II study design was employed. Serum was analyzed for immune complex dissociated (ICD) HIV p24 antigen and interleukin (IL)-6 levels during therapy. RESULTS: CR was achieved in 14 of 25 patients (56%), with partial response (PR) in 5 (20%). CRs were equivalent in patients with good or poor prognostic indicators, including a history of AIDS prior to lymphoma (CR = 60%); and/or CD4 lymphocytes < 200/mm3 (CR = 53%). Five patients with a CR subsequently relapsed (36%); median survival of CR patients was 29.2 months (4.1-61+), whereas that of all of the treated patients was 8.1 months. No significant peripheral neuropathy or other toxicity was observed. Serum ICD p24 antigen levels either fell (7/14) or remained consistently negative (2/14) in 9 of 14 patients (64%), whereas 36% experienced an increase. Elevated serum IL-6 levels at diagnosis were associated with systemic "B" symptoms (P = 0.023), whereas changes in IL-6 correlated with response to therapy over time (P = 0.006). CONCLUSIONS: Combination antineoplastic and zalcitabine antiretroviral therapy may be safely administered to patients with AIDS-related lymphoma, resulting in CR in 56%, lack of significant neurotoxicity, and favorable effect on HIV p24 antigen in 50%. Elevation of serum IL-6 is associated with systemic "B" symptoms, whereas changes in serum IL-6 may correlate with response. PMID- 8697400 TI - Phase II evaluation of topotecan for pediatric central nervous system tumors. AB - BACKGROUND: Topotecan is a topoisomerase I inhibitor that has good penetration across the blood-brain barrier and significant antitumor activity against human brain tumor xenografts. In a Phase I trial in children with refractory cancer, topotecan was well tolerated when administered as a 24-hour infusion. The maximum tolerated dose was 5.5 mg/m2 and the dose-limiting toxicity was myelosuppression. This Phase II study of topotecan was performed to assess the activity of topotecan against childhood brain tumors. METHODS: Forty-five children with either a previously treated primary brain tumor that was refractory to standard therapy, or an untreated brain stem glioma or glioblastoma multiforme, received topotecan administered as a 24-hour intravenous infusion every 21 days. The initial dose was 5.5 mg/m2 with escalation to 7.5 mg/m2 on the second and subsequent doses in patients who did not experience dose-limiting toxicity. RESULTS: There were no complete or partial responses in the patients with high grade glioma (n=9), medulloblastoma (n=9), or brain stem glioma (n=14). One of 2 patients with a low grade glioma had a partial response lasting more than 17 months; 3 patients with a brain stem glioma had stable disease for 12 to 28 weeks; and 1 patient with a malignant neuroepithelial tumor and 1 patient with an optic glioma had stable disease for 41 weeks and 22 weeks, respectively. Dose escalation from 5.5 mg/m2 to 7.5 mg/m2 was well tolerated in the first 11 patients enrolled on this study who had not received prior craniospinal radiation therapy. The starting dose was subsequently increased to 7.5 mg/m2 for patients without prior craniospinal radiation. CONCLUSIONS: Topotecan administered as a 24 hour infusion every 21 days is inactive in high grade gliomas, medulloblastomas, and brain stem tumors. PMID- 8697401 TI - Trends in cancer incidence among children in the U.S. AB - BACKGROUND: This report provides results of an analysis of temporal trends in childhood cancer incidence in the U.S. stratfied by age, sex, and to a lessor extent, race, within common histologic subtypes. METHODS: Population-based data from nine registries of the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute were analyzed. The analysis was limited to children age < or = 14 years. Cancer cases were restricted to those patients with a malignant neoplasm diagnosed between 1974 and 1991; more than 12,000 children were included. Average annual percentage change in incidence rates and corresponding 95% confidence intervals were estimated from the maximum likelihood method of Poisson regression. RESULTS: Among children age < or = 14 years there was a 1% average yearly increase (95% CI 0.6, 1.3) in the incidence rates of all malignant neoplasms combined. The average annual percentage change was similar for males and females, and slightly higher for black children compared with white children. Rates increased an average of 2% or more per year for astroglial tumors, rhabdomyosarcomas, germ cell tumors, and osteosarcomas. The average annual percentage change for acute lymphoid leukemia was 1.6% and trends were somewhat stronger for blacks than whites. Cancer trends, in general, were strongest in young children. In particular, increases in astroglial tumors and rhabdomyosarcomas were most apparent among children age < 3 years, and for retinoblastoma and neuroblastoma among children in their first year of life. The average annual percentage change for acute lymphoid leukemia did not vary dramatically with age, however children age < 2 years had stronger trends compared with older children. We found little evidence for increasing trends in Wilms' tumor, primitive neuroectodermal tumors, or hematopoietic neoplasms other than acute lymphoid leukemia. CONCLUSIONS: These results suggest that cancer occurrence among children within specific histologies increased modestly in the U.S. between 1974 and 1991, and that the increases were most apparent among young children. PMID- 8697402 TI - The history of the oxazaphosphorine cytostatics. PMID- 8697403 TI - An interdisciplinary approach to populations at high risk of cancer. PMID- 8697404 TI - Hereditary cancer susceptibility. PMID- 8697405 TI - A research shortcut from a common cold virus to human cancer. PMID- 8697406 TI - Elimination of dose limiting toxicities of cisplatin, 5-fluorouracil, and leucovorin using a weekly 24-hour infusion schedule for the treatment of patients with nasopharyngeal carcinoma. PMID- 8697407 TI - Incidence and treatment of periampullary duodenal cancer in the U.S. veteran patient population. PMID- 8697408 TI - Resection and adjuvant chemotherapy of pulmonary blastoma. A case report. PMID- 8697409 TI - Resection and adjuvant chemotherapy of pulmonary blastoma. A case report. PMID- 8697410 TI - Complete remission seven years after treatment for metastatic malignant melanoma. PMID- 8697411 TI - Benefit of mammography screening in women ages 40-49 years. Current evidence from randomized controlled trials. PMID- 8697412 TI - Significance of lymphocytic sister chromatid exchange frequencies in ovarian cancer patients. AB - Very few studies report the analysis of sister chromatid exchanges in ovarian cancer patients. We tested the null hypothesis that SCE frequency increases with the advancing stages of ovarian cancer and follows a Poisson distribution. As controls we examined age- and sex-matched healthy volunteers who had no such past history. An increased average SCE frequency was observed in ovarian cancer patients (6.34 +/- 0.09) vis-a-vis controls (4.47 +/- 0.12). Further, the data also suggested a stage-wise increase in the SCE frequency. PMID- 8697413 TI - ider(9)(q10)t(9;22)(q34;q11) is a recurrent chromosomal abnormality in acute lymphoblastic leukemia and lymphatic blastic phase of chronic myelogenous leukemia. AB - We report on two cases, one with acute lymphoblastic leukemia and a second with lymphatic blastic phase of Philadelphia chromosome-positive chronic myelogenous leukemia, cytogenetically characterized by ider(9)(q10)t(9;22)(q34;q11). Our findings and the data of the 4 cases previously published indicate that ider(9)(q10)t(9;22)(q34;q11) represents a rare but recurrent chromosomal abnormality occurring in hematological malignancies with lymphoid differentiation, namely acute lymphoblastic leukemia and lymphatic blastic phase of chronic myelogenous leukemia, and most likely evolves from a preexistent der(9) involved in the standard t(9;22). PMID- 8697414 TI - Trisomy 10 in acute myeloid leukemia. AB - We observed two patients with acute myeloid leukemia (AML) exhibiting trisomy 10 as the sole chromosome abnormality at the time of diagnosis. One patient was diagnosed with AML-MO, and the other with AML-M2. Both cases were CD7-antigen positive. However, we could not find any distinct clinico-hematologic characteristics of AML with trisomy 10 in these two patients. Trisomy 10 might be a rare recurring numerical chromosome abnormality and the incidence may be about 0.5% in de novo AML. PMID- 8697417 TI - Partial deletion of the long arm of chromosome 5: a fluorescence in situ hybridization study using band-specific painting probes generated by chromosome microdissection. AB - A series of 17 patients with myeloid disorders and partial deletions of the long arm of chromosome 5 were investigated using fluorescence in situ hybridization with 5q34-q35 region-specific painting probes generated by chromosome microdissection. This approach confirmed that partial 5q deletions are interstitial in all the cases studied. In addition no translocation involving chromosome 5 was detected. PMID- 8697416 TI - Detection of aneuploidy in interphase nuclei from non-small cell lung carcinomas by fluorescence in situ hybridization using chromosome-specific repetitive DNA probes. AB - Interphase fluorescence in situ hybridization (FISH) is particularly useful for detecting chromosome changes in tumors exhibiting a low mitotic index, as is the case in many human non-small cell lung carcinomas (NSCLCs). A panel of centromeric DNA probes specific for the autosomes 6, 7, 8, 9, 12, 17, and 18 was used to analyze 17 primary NSCLCs. Evidence for aneuploidy was obtained in all specimens. Gain of part or all of chromosome 7 was especially prominent, occurring in a large population of cells in each of 14 tumors (82%). Extra centromeric copies of chromosomes 6, 12, and 17 were also common, being observed in 9 to 11 cases each. Gain of chromosome 9 was infrequent (three tumors). In two cases, most of the nuclei had only a single chromosome 9 fluorescent signal. Karyotypic findings were available for six cases and were generally consistent with the FISH data. Both methods revealed considerable heterogeneity within individual tumors. NSCLC specimens from 26 males were assayed with a Y-specific centromeric sequence; loss of the Y was observed in 13 cases (50%). These investigations demonstrate the feasibility of interphase FISH for the successful analysis of numerical chromosome changes in NSCLCs. PMID- 8697415 TI - t(12;20)(q13;p11.2)--a new translocation involving the 12q13 breakpoint in acute nonlymphoblastic leukemia. PMID- 8697418 TI - Evidence for somatic pairing of chromosome 7 and 10 homologs in a follicular lymphoma. AB - Fluorescence in situ hybridization using centromeric probes for chromosomes 7 and 10 in a follicular lymphoma revealed only one signal in about 40% of interphases, whereas two copies of each chromosome were consistently seen in metaphases. In four out of 18 metaphases both copies of chromosome 7 were situated close to one another. In contrast, two signals for chromosome 1 were seen in 94% of interphases, consistent with observations on metaphases. The findings suggest chromosome-specific somatic pairing, the functional significance of which is at present unknown, and reinforce previous evidence suggesting that care should be taken in the interpretation of interphase signal numbers using centromeric probes in neoplastic as well as normal material. PMID- 8697419 TI - A case of isodicentric 7p as sole abnormality in a patient with acute myeloid leukemia. AB - The detection of isochromosomes in the leukemias and in solid tumors has been well described in the literature, the most common being the i(17q), which is found in the blast crisis of CML and terminal stages of acute myeloid leukemia. Reports of isochromosome 7 have, however, been less well represented, particularly isochromosomes of the short arm of chromosome 7, which represent approximately 1% of all reported isochromosomes in neoplasia. We present here a case report of an elderly female patient with AML-M2 who manifested an idic(7p) in the majority of her bone marrow cells. Fluorescence in situ hybridization (FISH) studies with both centromere-7--and chromosome-7--specific DNA probes verified the diagnosis of idic(7p). To the best of our knowledge, this is the first report of this type of leukemia with an acquired idic(7p) as the sole cytogenetic abnormality. PMID- 8697420 TI - A subtle deletion of 12p by routine cytogenetics is found to be a translocation to 21q by fluorescence in situ hybridization: t(12;21)(p13;q22). AB - A 4-year-old boy with acute lymphoblastic leukemia (ALL) whose leukemic cells contained at diagnosis a del(6q) had a different clone at relapse, characterized by an abnormal short arm of chromosome 12 (12p). Fluorescence in situ hybridization (FISH) analysis using a cosmid probe from the 12p12-13 region indicated a translocation of the 12p to another unknown chromosome of "G-group" size. Further analysis by dual chromosome painting confirmed the presence of a translocation, identified as t(12;21)(p13;q22). Previously reported cases showed this translocation at diagnosis of ALL, whereas this is the first case showing the specific t(12;21)(p13;q22) at relapse. This case study illustrates the value of FISH in resolving subtle recurrent chromosomal rearrangements that escape detection by routine cytogenetic analysis. Subsequent molecular evaluation of the patient's leukemic cells with the t(12;21) demonstrated a TEL/AML1 fusion protein. PMID- 8697421 TI - Restriction endonuclease in situ digestion (REISD) and fluorescence in situ hybridization (FISH) as complementary methods to analyze chimerism and residual disease after bone marrow transplantation. AB - The efficiency of restriction endonuclease in situ digestion (REISD) with Sau3A to analyze chimerism and residual disease (RD) has been tested before and after an allogenic bone marrow transplant (BMT) in an acute lymphoblastic leukemia (ALL) patient. The combined results obtained with REISD and FISH using the appropriate probes for detecting chromosome rearrangements have proven to be useful for the identification and quantification of both the hemopoietic chimerism achieved after BMT and the RD persistent in the patient. The sensitivity of REISD has been determined to be around 95%, i.e., similar to that obtained by FISH. REISD with Sau3A was particularly useful in the analysis of chimerism since this enzyme revealed the polymorphic status of constitutive heterochromatin in human chromosome 3 and thus allowed discrimination of cells derived from donor and recipient. The method itself seems promising since neither a donor/recipient sex mismatch nor a cytogenetic disease marker are needed for its application. PMID- 8697422 TI - Comparative genomic hybridization of germ cell tumors of the adult testis: confirmation of karyotypic findings and identification of a 12p-amplicon. AB - Comparative genomic hybridization (CGH) was carried out on 15 primary testicular germ cell tumors (TGCT) of adolescents and adults and two metastatic residual tumors after chemotherapeutic treatment. The results were compared with karyotypic data obtained form the same tumor specimens after direct harvesting of metaphases or short-term in vitro culture. Both techniques revealed that the most consistent abnormality in primary TGCT is gain of 12p-sequences. Although in most cases over-representation of the complete short arm was observed, CGH revealed a specific amplification of 12p11.1-p12.1 region in two independent primary tumors. In addition, loss of (parts of) chromosome 13 (always involving q31-qter), and gain of (parts of) chromosome 7 (mostly involving q11), (parts of) chromosome 8, and the X chromosome were detected in more than 25% of the tumors by this latter technique. Loss of 6q15-q21 in both residual tumors analyzed may suggest a role for this anomaly in acquired resistance to chemotherapeutic treatment. Overall, the CGH analyses confirmed gains and losses of certain chromosomal regions in TGCT as observed by karyotyping, and thus support their role in the development of these neoplasms. The amplification of a restricted region of 12p in primary TGCT confirms and extends our previous observations and, as such, represents an important step forward in the identification of gene(s) on 12p relevant for the pathogenesis of these tumors. PMID- 8697423 TI - Detection of the breakpoint cluster region-ABL fusion in chronic myeloid leukemia with variant Philadelphia chromosome translocations by in situ hybridization. AB - Fluorescence in situ hybridization (FISH) technique has been successfully used to detect the BCR-ABL gene fusion in chronic myeloid leukemia (CML) with the classic form of the Philadelphia chromosome (Ph). We applied FISH to study three CML patients showing variant Ph chromosome (either complex or simple type). The results demonstrate that the use of a yeast artificial chromosome (YAC)-derived probe (D107F9) and a cosmid probe (cos-abl 8), specific for BCR and ABL genes respectively, allows also the detection of the BCR-ABL fusion in CML patients with variant Ph. PMID- 8697424 TI - A Philadelphia chromosome positive CML patient with a unique translocation studied via GTG-banding and fluorescence in situ hybridization. AB - The Philadelphia (Ph) chromosome was the first consistently occurring chromosome abnormality associated with a single cancer type, chronic myelogenous leukemia (CML). This translocation has since been reported with other chromosome abnormalities. The present report describes a case of Ph chromosome positive CML with a unique complex translocation identified using molecular cytogenetics in addition to routine techniques. GTG-banding revealed abnormalities in at least chromosomes 9, 13, 17, and 22. Fluorescence in situ hybridization (FISH) studies were performed as an adjunct to conventional cytogenetic analyses. Using FISH with the Oncor bcr/abl probe, the Ph translocation previously hypothesized was confirmed. Applying FISH with paired painting probes in various combinations, a complex translocation involving chromosomes 9, 13, 15, 17, and 22 was observed. The results of the GTG-banding and FISH studies were compared with each other and correlated with those of the hematological findings. In an extensive search of the medical literature database (Medline, Health, Cancerlit, Ovid, and CINAHL) spanning nearly three decades (1965-1994), we found no previous report of this specific translocation. Therefore, to the best of our knowledge, this is a unique translocation associated with Ph chromosome positive CML. PMID- 8697425 TI - t(5;12)(q31;q24) in childhood acute lymphoblastic leukemia. PMID- 8697426 TI - Duplication of chromosome 9 carrying a BCR/ABL chimeric gene in Philadelphia chromosome negative chronic myeloid leukemia. AB - We investigated a patient with Philadelphia chromosome (Ph) negative but BCR positive chronic myeloid leukemia (CML) by fluorescence in situ hybridization (FISH). In the chronic phase one chromosome 9 contained a BCR/ABL fusion gene instead of chromosome 22. Although in blast crisis, both chromosomes 9 had BCR/ABL fusion genes. This could be caused by duplication of the rearranged chromosome 9, which may have a significance similar to a double Ph chromosome. This may suggest that the critical event in CML is the formation of a BCR/ABL chimeric gene regardless of its locus in the genome. PMID- 8697427 TI - Familial supernumerary chromosome and malignancy. AB - No familial marker chromosome associated with a malignancy has been reported to date. We used fluorescence in situ hybridization (FISH) to characterize a supernumerary marker chromosome 15 ascertained during prenatal diagnosis. This supernumerary chromosome 15 was found to span three generations of a family. Three family members carrying the supernumerary chromosome 15 have also had malignancies, namely, a cystic glioma, leukemia, and thyroid cancer. PMID- 8697428 TI - Trisomy 10: age and leukemic lineage associations. AB - We observed three cases of acute leukemia with trisomy 10 (+10) as the sole abnormality, two were adult patients with ANLL (subtype M0 and M1 respectively), and the third that of a child with ALL. The literature describes nine additional cases, four with ALL (all of whom were children) and five with ANLL (all of whom were adults). Cell marker studies on the ANLL cases showed a common positivity for CD7 and CD33 in our two cases, as well as in four of the previously reported cases, whereas in ALL the only two informative cases were classified as early pre B ALL. There appears to be an age-related pattern in the specificity of the leukemic lineage. Trisomy 10 appears to be associated exclusively with ALL in children and with ANLL (usually M0-M1) in adults. The prognosis appears to be also divided between the two groups, being good in the pediatric group and moderate in the adult group. PMID- 8697429 TI - Another case of t(17;22)(q22;q13) in an infantile dermatofibrosarcoma protuberans. AB - We have identified a new dermatofibrosarcoma protuberans (DP) case with a t(17;22) (q22;q13) occurring in a child. The translocation was substantiated by the presence of one or two copies of the sole der(22)t(17;22). This rearrangement added to two normal chromosomes 17 and one or two chromosomes 22, resulted in trisomy 22cen-q13 and trisomy (or tetrasomy) 17q22-25. This observation confirms the specificity of the association of DP with the t(17;22) found together with extra copies of the der(22)t(17;22). It also points out a possible prevalence of translocation rather than rings in DP of the childhood disease. PMID- 8697430 TI - Monozygotic twins with congenital acute lymphoblastic leukemia (ALL) and t(4;11)(q21;q23). AB - Congenital acute lymphoblastic leukemia (CALL) is a rare disorder and is frequently associated with t(4;11)(q21;q23). To our knowledge this is the first case report of monozygous twins with CALL and t(4;11)(q21;q23). PMID- 8697431 TI - Thymoma with a t(15;22)(p11;q11). AB - Cytogenetic analysis of a thymoma revealed the presence of a t(15;22)(p11;q11) as the only chromosome abnormality. From the few thymomas so far analyzed, no characteristic chromosome change seems to be emerging. PMID- 8697432 TI - No evidence for the amplifications of MDM2 and C-myc genes involved in the genetic susceptibility to esophageal cancer in a high-risk area of north China. PMID- 8697433 TI - Monosomy 22 in two ovarian granulosa cell tumors. AB - Cytogenetic studies of ovarian sex cord stromal cell tumors, although limited in number, have found trisomy 12 to be a recurring abnormality, especially in fibromas and granulosa cell tumors (GCTs). However, recent fluorescence in situ hybridization (FISH) studies have failed to confirm a high prevalence of trisomy 12 in GCTs. We describe the karyotypic findings in one adult and one juvenile GCT. Only the juvenile GCT had an extra, abnormal chromosome 12, but both the adult and juvenile GCT had monosomy 22. In light of these findings and the data in the literature, we suggest that monosomy 22 may be important in the genesis of these relatively rare tumors. PMID- 8697434 TI - Detection of chromosomal abnormalities in uterine leiomyoma using conventional cytogenetic method and interphase fluorescence in situ hybridization. AB - Seventy-nine uterine leiomyomas were examined using a conventional cytogenetic method and fluorescence in situ hybridization (FISH) for detection of chromosomal abnormalities of chromosome 12. Nine (17.6%) of 51 tumor samples examined showed chromosomal abnormalities by conventional cytogenetic analysis. Rearrangements of chromosome 12 were detected in two tumors. Other tumors showed abnormalities affecting chromosomes 1, 4, 6, 7, 10, 13, 14, and 22. For FISH, the whole chromosome painting probe and the D12Z3 probe specific for the centromeric region were used to detect structural and numerical abnormalities of chromosome 12. Of forty-one tumor samples, six showed structural aberrations and four showed numerical aberrations of chromosome 12 by FISH analysis. Of the tumors with structural aberrations identified by FISH, two had normal karyotypes, two showed structural rearrangements of chromosome 12 cytogenetically, and two could not be analyzed because of an insufficient number of metaphases. There were no correlations between the cytogenetic data and clinical parameters. The results indicate that chromosomal abnormalities are important in the biology of at least some types of uterine leiomyomas, and that FISH is a useful complement to conventional cytogenetic analysis in the study of solid tumors. PMID- 8697435 TI - Molecular and genetic events in schistosomiasis-associated human bladder cancer: role of oncogenes and tumor suppressor genes. AB - Carcinoma of the urinary bladder is the most common malignancy in many tropical and subtropical countries and is mainly due to endemic schistosomal infection. Schistosomiasis-associated bladder cancer defines a characteristic pathology and cellular and molecular biology that differs from urothelial carcinoma of non schistosomal origin. N-Nitroso compounds are suspected etiologic agents in the process of bladder cancer induction during schistosomiasis. Elevated levels of DNA alkylation damage have been detected in schistosome-infected bladders and are accompanied by an inefficient capacity of DNA repair mechanisms. Consequently, high frequency of G --> A transition mutations were observed in the H-ras gene and at the CpG sequences of the p53 tumor suppressor gene. Genetic changes have also been detected in the c-erbB-1 and c-erbB-2 oncogenes and in the cdkn2 and Rb tumor suppressor genes. The potential application of these mutational patterns in providing a biological marker suitable for the biomonitoring and early detection of this neoplasm could indicate new avenues of approach that might alleviate the problem in the future. It can also assist in elucidating the mechanisms by which schistosomiasis augments human bladder cancers. PMID- 8697436 TI - Expression of programmed cell death regulatory p53 and bcl-2 proteins in oral lesions. AB - With the ultimate goal of characterizing the molecular pathogenesis of oral cancer, the most predominant malignancy in India, immunocytochemical evaluation of p53 and bcl-2 proteins was carried out in hypeplastic oral mucosa, dysplastic oral mucosa and invasive oral cancer. All subjects gave a similar and almost uniform history of prolonged use of betal quid and tobacco. Expression of p53 was insignificant while bcl-2 was absent in hyperplastic leukoplakia lesions. Both proteins were however expressed in leukoplakia with apparent dysplasia. Almost all invasive cancer lesions showed high levels of both p53 and bcl-2. Good correlation was therefore evident between expression of these two proteins and increasing histologic abnormality. Moreover relative risk evaluation revealed that lesions expressing p53 and bcl-2 had a high probability of having a histology of dysplasia or worse. Since it has been previously shown that wild type p53 regulates the expression of bcl-2, it may be presumed that the protein detected in the dysplastic and malignant oral tissue is of the mutant type. It is also known that p53 is a positive regulator of programmed cell death or apoptosis while bcl-2 is an anti-apoptotic protein. This suggests the possibility that alterations in p53 followed by over-expression of bcl-2 occur early in oral carcinogenesis resulting in defective apoptosis and subsequent tumor progression. PMID- 8697437 TI - Refined carbohydrate enhancement of aberrant crypt foci (ACF) in rat colon induced by the food-borne carcinogen 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ). AB - The aberrant crypt foci (ACF) bioassay has been used extensively to study the early effects of different dietary components on the colonic mucosa of laboratory rodents. ACF are proposed to represent preneoplastic lesions of colon cancer. Compared to the normally used initiators 1,2-dimethylhydrazine dihydrochloride (DMH) and azoxymethane (AOM), the use of a diet-related colon cancer initiator, such as the heterocyclic amine 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) formed during meat cooking, would probably give a more relevant insight into diet related colon carcinogenesis. In the present study it is shown that a feeding regimen with continuous low IQ doses (0.03% in the diet) throughout a study period of 10 weeks has a significant effect on the induction of ACF in the colon of male F344 rats. In addition, the study illustrates that the incidence of the IQ-induced ACF can be modulated by the amount of refined carbohydrates in the diet. Rats given a high sucrose/dextrin diet showed a significantly higher number of ACF compared to rats given a diet high in starches. The effect on tumor outcome will await the termination of a ongoing parallel study. PMID- 8697438 TI - DNA damage induced by etoposide; a comparison of two different methods for determination of strand breaks in DNA. AB - Etoposide induces DNA damage to cells by interacting with the nuclear enzyme topoisomerase II. In this investigation the human lymphoblastic leukemia cell line (CEM) was used to study induction of DNA-strand breaks and cellular drug uptake after treatment with etoposide at a concentration of 0.5-2 micrograms/ml. High performance liquid chromatography was used for determination of etoposide concentrations. The alkaline elution assay and the DNA unwinding technique were compared for quantifying strand breaks in DNA induced by etoposide. The concentrations required to increase the level of DNA damage significantly was as follows: the DNA unwinding technique, 0.20 microgram/ml; the alkaline elution assay with proteinase K, 0.45 microgram/ml; the alkaline elution assay without proteinase K, 0.60 microgram/ml. When the half-life was adjusted, considering the efflux time of etoposide from cells, it was found to be only a few minutes. The present data show that the DNA unwinding technique is to be preferred for the screening of DNA damage. This technique is easier and quicker to perform than the alkaline elution technique. PMID- 8697439 TI - Anti-tumor promoting activity of Dryopteris phlorophenone derivatives. AB - As a part of screening studies for cancer chemopreventive agents (anti-tumor promoters) 33 Dryopteris phlorophenone derivatives have been evaluated. The compounds tested comprised of monomeric acylphloroglucinols (e.g. desaspidinol, aspidinol) as well as dimeric (e.g. aspidin, desaspidin), trimeric (e.g. filixic acids), and tetrameric (e.g. dryocrassin) phlorophenone, wherein hexacyclic rings are bound together by a methylene bridge. These compounds were examined for their in vitro anti-tumor promoting effect on Epstein-Barr virus antigen activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). The two dimeric compounds aspidin and desaspidin, which were found to be the most active among the tested phlorophenones, were also examined in vivo on two stage mouse skin carcinogenesis, and found to show significant inhibitory effect on 7,12 dimethylbenz[alpha]anthracene (DMBA)-TPA tumor promotion. PMID- 8697440 TI - Mitochondrial DNA copy number changes in human gliomas. AB - Gene amplification has been found to be biologically important in cancer. We report a complementary DNA sequence obtained using a subtractive hybridization approach which is frequently and highly amplified in human gliomas. 39/45 (87%) glial tumor specimens (of pathologically low and high grade) revealed increases in copy number of this clone from 5- to 25- fold; erb-b amplification was found in 8/45 (18%). This clone revealed homology to non-continuous mitochondrial DNA positions 1679-1948 and 2017-2057, with the interspersed sequences deleted. A non mitochondrial genomic addition of 15 bases at the 5' end of the clone and a 7 base insertion adjacent to position 1948 were also present. Evaluation of the entire mitochondrial genome in a subset of 11 tumors showed maximal amplification between mitochondrial positions 748 and 5882, and a lower degree of amplification elsewhere, with a recurrent deletion of a 1.2 kb EcoRI fragment noted in 5/11 (46%) tumors. The mitochondrial genome is frequently affected in human gliomas, and warrants further study to determine its role in glial malignancy. PMID- 8697441 TI - Effect of metallothioneins on transformation of gelatinase A from human fibroblast WI-38 cells. AB - The effect of metallothioneins (MTs) on gelatinase A activity was investigated. The collagenolytic activity of gelatinase A from human fibroblast WI-38 cells was enhanced by the addition of MTs. This enhancement may be caused by the transformation of the inactive 62 kDa intermediate species of gelatinase A to the 59 kDa active enzyme. This enhancement was also observed in the conditioned medium of WI-38 cells exposed to heavy metals, but intracellular 72 kDa pro gelatinase A did not change. Furthermore, degradation of gelatinase A occurred in the reaction between gelatinase A with substrate and MTs. Our results suggest that MTs may be an endogenous activator of gelatinase A, and may provide a host factor in cancer metastasis. PMID- 8697442 TI - In vivo studies on genotoxicity and cogenotoxicity of ingested UICC anthophyllite asbestos. AB - Early cytogenetic action of oral exposure to UICC anthophyllite, an amphibole type of asbestos, was studied in Fischer-344 rats. The animals were gavaged with a suspension of untreated fibres (50 mg/kg) and fibres which had been allowed to adsorb benzo[alpha]pyrene molecules from aqueous solutions of 0.25-2.5 micrograms/ml. HPLC measurements indicated effective adsorption of the benzo[alpha]pyrene molecules on the fibres. The authors consider this system a suitable model for the drinking of water containing asbestos fibres and organic micropollutants. The formation of micronuclei and sister chromatid exchanges was studied in bone marrow samples taken from animals 24 h after oral administration of suspensions. Whereas anthophyllite fibres failed to induce cytogenetic alterations, fibres pretreated with the polycyclic aromatic solutions caused dose dependent increase in the sister chromatid exchange frequencies. The observed cytogenetic impact can be explained by a local action of carcinogen molecules accumulated and subsequently transported. The results support the hypothesis that epidemiological evidence of carcinogenicity of asbestos in potable water may rather be explained by cogenotoxic action of the asbestos fibres and biologically active organic micropollutants adsorbed on their surface. PMID- 8697443 TI - Novel asymmetric photosensitizers: an in vitro study. AB - A series of compounds based on an asymmetrical protoporphyrin molecule have been examined. The paired groups of sensitizers differed in terms of the presence or absence of a permanent positive charge, in the alkyl side chain length and in having either a primary or secondary amine substituent. The effects of these variables on drug uptake, partition coefficient and photodynamic cell kill were tested. Drug uptake and partition coefficient were shown to be correlated. Differences in gross uptake were found within paired groups of sensitizers although cell-associated uptake alone did not correlate with clonogenic cell survival. Of the compounds tested it was the sensitizers with alkyl side chains, rather than the permanently positively charged compounds, which resulted in the greatest degree of clonogenic cell kill. PMID- 8697445 TI - The effects of theanine, as a novel biochemical modulator, on the antitumor activity of adriamycin. AB - We studied the effects of theanine, a component of green tea leaves, on the antitumor activity of adriamycin (ADR) from the biochemical modulation view point. In vitro, theanine inhibited the ADR efflux from Ehrlich ascites carcinoma cells and maintained the ADR concentration in tumor cells. Theanine enhanced the inhibitory effect of ADR on tumor growth by 2.1-fold in vivo, and increased 2.9 fold the ADR concentration in the tumor, compared to the ADR alone group. An increase in ADR concentration was not observed in normal tissues, such as the heart and liver. Theanine did not enhance, rather tended to normalize the increase of lipid peroxide level and reduction of glutathione peroxidase activity as indicators of the ADR-induced side toxicity. PMID- 8697444 TI - Lack of tumor promoting effects of KCB-1, a recombinant human basic fibroblast growth factor, on two-stage skin carcinogenesis in female CD-1 (ICR) mice. AB - Skin tumor promoting and co-promoting potentials of KCB-1, a recombinant human basic fibroblast growth factor, were investigated in a two-stage skin carcinogenesis model using female ICR mice. Animals were allocated to either normal (non-injured) or injured skin groups, and given a single topical application of dimethylbenz[alpha]anthracene (DMBA) at 100 micrograms/mouse to fur-clipped back skin. One week after the DMBA initiation step, mice were injected with KCB-1 (0.4, 4.0 and 40 micrograms/mouse, s.c.) and/or 12-O tetradecanoylphorbol-13-acetate (TPA) at 4.0 micrograms/mouse twice a week until the termination at week 20. The treatment with KCB-1 was not associated with any increases of papillomas and hyperplasias in either the normal or the wounded skin cases. High incidences and multiplicities of skin papillomas and hyperplasias developed in TPA-treated groups. The positive control TPA promotion was not influenced by the KCB-1 treatment in the present initiation/promotion protocol. Thus, KCB-1 exerted no tumor promoting effects on mouse skin two-stage carcinogenesis, and also no amplification activity for the established skin tumor promoter TPA. PMID- 8697446 TI - The altered activity of membrane-bound protein kinase C in human liver cancer. AB - The activity of protein kinase C (PKC) in human liver cancer and adjacent normal liver tissue was determined. It was found that the activity of the membrane-bound PKC was significantly decreased in cancer tissue compared with that of the adjacent normal tissues (245.3 +/- 49.3 versus 396.9 +/- 82.4 pmol 32P/min per mg, P < 0.05); while the PKC activity in the cytosolic fraction was not significantly different (50.6 +/- 11.3 versus 40.0 +/- 6.6 pmol 32P/min per mg) concerning protein concentration. The reduced expression of membrane-bound PKC activity was observed at least in 8 of 9 patients. Moreover, the cancer tissue showed a significant decrease in total membranous PKC activity compared with the adjacent normal tissue of each patient (163.1 +/- 38.8 versus 433.8 +/- 92.4 pmol 32P/min per g tissue; P < 0.005) and no difference in total cytosolic PKC activity (285.9 +/- 58.8 versus 311.6 +/- 44.0 pmol 32P/min per g tissue). These results indicate that the progression of the human liver cancer might be associated with the decrease of membrane-bound PKC activity. PMID- 8697447 TI - The effects of 5-fluorouracil and doxorubicin on expression of human immunodeficiency virus type 1 long terminal repeat. AB - Previous work by many groups has documented induction of the human immunodeficiency virus (HIV) long terminal repeat (LTR) following exposure of cells to ultraviolet light and other DNA damaging agents. Our experiments set out to determine the relative activation or repression of the HIV-LTR in response to two classes of chemotherapeutic agents: Doxorubicin is a DNA damage-inducing agent, and 5-fluorouracil has an antimetabolic mode of action. Using HeLa cells stably transfected with a construct in which HIV-LTR drives expression of the chloramphenicol acetyl transferase reporter gene, we demonstrated an up to ten fold induction following doxorubicin treatment at 24 h post-treatment. This induction was repressed by treatment with salicylic acid, suggesting a role for prostaglandin/cyclo-oxygenase pathways and/or NF-kappa B in the inductive response. Induction by 5-fluorouracil, in contrast, was more modest (two-fold at most) though it was consistently elevated over controls. PMID- 8697448 TI - A novel profile of expressed sequence tags for zinc finger encoding genes from the poorly differentiated exocrine pancreatic cell line AR4IP. AB - Genes encoding for C2H2 zinc finger proteins are known to regulate normal cell proliferation and differentiation and have often been found to be mutated in different forms of cancer. We are interested in understanding the role of these genes as regulators of cell proliferation and differentiation in the exocrine pancreas. Therefore, we have generated expressed sequence tags (ESTs) encoding pancreas-enriched zinc finger peptides using the polymerase chain reaction and hybridization techniques [Adams, M.D. et al. (1991) Science, 252, 1651-1656]. Here we report the primary structure and expression pattern of 18 different zinc finger-encoding cDNAs (DZF-1-18) from the azaserine-derived tumoral cell line AR4IP which displays a poorly differentiated phenotype. Sequence analysis shows that all of these clones encode peptides which share the consensus DNA-binding motif with the Drosophila zinc finger transcription factor kruppel. High stringency Northern blot analysis shows that eight different zinc finger transcripts are expressed at high levels in normal adult rat pancreas and therefore constitute good candidates to play a role as transcription factors in exocrine pancreatic cells. PMID- 8697450 TI - Quantitative analysis of changes in cell proliferation and apoptosis during preneoplastic and neoplastic stages of hepatocarcinogenesis in rat. AB - In situ markers for quantitative analysis of cell proliferation and apoptotic cell death have been used to evaluate both the proliferation level and net growth potential of preneoplastic nodules and malignant tumor tissues from rats experimentally induced for hepatocarcinogenesis by the dietary administration of 2-acetylaminofluorene. The findings show that although tumors have a much higher level of cell proliferation than preneoplastic liver nodules, the nodules have a higher potential for net growth when apoptosis is taken into account. These results support a role for a decrease in apoptosis during the promotion stage of carcinogenesis. PMID- 8697449 TI - Effects of inhibitors of deoxyhypusine synthase on the differentiation of mouse neuroblastoma and erythroleukemia cells. AB - Deoxyhpusine synthase catalyzes the conversion of lysine to deoxyhypusine residue on the eukaryotic initiation factor 5A (eIF-5A) precursor using spermidine as the substrate. Subsequent hydroxylation of the deoxyhypusine residue completes hypusine formation on eIF-5A. Polyamines (putrescine, spermidine, and spermine) have been implicated in tumor growth and differentiation. Because deoxyhypusine/hypusine formation is one of the most specific polyamine-dependent biochemical events, we decided to use N1-guanyl-1,7-diaminoheptane (GC7), a potent inhibitor for deoxyhypusine synthase, to assess the role of hypusine formation on tumor growth and differentiation. GC7 suppressed the growth of N2a mouse neuroblastoma cells and DS19 murine erythroleukemia cells at micromolar concentrations. However, within a narrow concentration range, GC7 could promote the differentiation of mouse neuroblastoma cells in the presence of suboptimal amount of dibutyryl cAMP. In contrast, GC7 blocked the differentiation of DS19 cells induced with hexamethylene bisacetamide. Polyamine depletion by difluoromethyl ornithine (DFMO) has previously been shown to promote differentiation of neuroblastoma cells but inhibits erythrodifferentiation. Since our studies demonstrated that GC7 mimics the action of DFMO on tumor differentiation, it is likely that the effect of DFMO on tumor differentiation is mediated by hypusine formation and that GC7 represents a more specific inhibitor that can alter the differentiation program in certain tumor cells. PMID- 8697451 TI - Tirapazamine (SR 4233) interrupts cell cycle progression and induces apoptosis. AB - Tirapazamine (Tira), a bioreductive agent, is highly toxic to cells under low oxygen conditions. Since active investigations of this agent are focusing on its potential as an adjunct of radiotherapy to improve overall effects on radioresistant hypoxic tumor cells, understanding its toxic mechanisms under aerobic conditions is important to the clinical application of this agent. Tira treated V79 Chinese hamster cells were tested for cytotoxicity by colony assay and growth inhibition by the MTT assay. The survival of V79 cells after being exposed to 100 microM of Tira for 2 h was about 78% of untreated controls. The mitotic cell counts of V79 cells approached zero after 4 h treatment of Tira at 100 microM or 3 h at 300 microM. The fragmentation pattern of DNA isolated from cells 2 h after 300 microM Tira treatment showed characteristics of apoptotic cells. The induction of apoptosis by Tira was also detected by flow cytometric analysis and microscopic observation. These effects of Tira may be part of underlying toxic mechanisms to cells (including normal cells) under aerobic conditions. PMID- 8697452 TI - Lymphoma induced in mice chronically exposed to very strong low-frequency electromagnetic field. AB - Three successive generations of CFW mice were exposed to a 25-mT (250,000 mG), 60 Hz electromagnetic field for prolonged periods. At the end of the exposure period, animals from both the exposed and control groups were sacrificed for tests. A complete autopsy was performed and tissue sections were taken from the main organs for histopathological examination. The results from the pathological findings in the various animals were classified under the following categories: (1) normal; (2) lymphoid hyperplasia; (3) premalignant changes; (4) early lymphoma; (5) advanced lymphoma. The three first-generation animals developed generalized lymphoid hyperplasia. In the second-generation animals, 5% developed premalignant changes, and 15.8% had lymphoid hyperplasia. In addition, 4 female mice left in the field for 418 days developed malignant lymphoma. In the third generation animals, 58% developed premalignant changes or malignant lymphoma. An additional 30% had lymphoid hyperplasia. Statistical analysis of the data using the Mantel-Haenszel test for the difference in the prevalence of lymphoma between the exposed and control groups shows a very significant difference for the male groups (P < 0.001), the female groups (P < 0.001), and all animals combined (P < 0.001). The results suggest a cause-effect relationship between chronic exposure to very strong 60-Hz magnetic field for prolonged period and the development of malignant lymphoma in CFW mice. PMID- 8697454 TI - Proton magnetic resonance spectroscopic imaging of pediatric low-grade astrocytomas. AB - Despite their uniform histologic appearance, pediatric low-grade astrocytomas (LGA) often exhibit a rather unpredictable clinical course. It is presently unclear whether certain specific genetic, immunologic and/or metabolic features underlie these observed variations. In order to address this question we examined the tumor distribution of choline compounds (Cho), creatine (Cr) and N-acetyl aspartate (NAA) in seven children with midline LGA by means of proton magnetic resonance spectroscopy imaging (H-MRSI). Studies were performed with a 1.5 T GE Signa Scanner equipped with the standard head coil; nominal voxel size was 7.5 x 7.5 x 15 mm. This spatial resolution allowed us to select and independently evaluate multiple regions of interest (ROI) in the tumor as well as in areas of normal brain from the same individual. Normalized values of the observed signal intensities demonstrated a lower NAA and Cr content in the tumors than in the surrounding normal brain. Intratumoral Cho signals were also below normal values in all but one patient. The average Cho:NAA ratio was consistently higher in the tumor than in the normal brain. However, there was a wide variation (up to fourfold) in the Cho:NAA ratios of different ROIs, even within the same tumor. Our results clearly indicate that pediatric LGAs are metabolically heterogeneous, a feature that may be relevant to the understanding of their variable biologic behavior. Inasmuch as unique metabolic patterns were observed in some LGAs, we believe that systematic HMRSI studies of these patients may help define subsets within the group with specific therapeutic requirements. PMID- 8697453 TI - Intra-axial endophytic primitive neuroectodermal tumors in the pons: clinical, radiological, and immunohistochemical aspects in four children. AB - We present the clinical findings, radiological aspects, operative results, and histopathological features of four typical primitive neuroectodermal tumors (PNET) located in the pontine region in children. All the tumors had an endophytic intra-axial growth pattern. All the children had a short history of severe neurological deficits with involvement of the cranial nerves and pyramidal tract. MRI did not reveal any common feature of malignancy. Compared to our successful experience in operations of intra-axial endophytic brainstem tumors in a total of 32 children, the outcome was poor: all 4 children died within 13 months. We conclude that PNET occurring in the pons is not as rare as was believed, and, compared to PNET in other areas the prognosis is worse. PMID- 8697455 TI - Allogeneic cartilage used for skull base plasty in children with primary intranasal encephalomeningocele associated with cerebrospinal fluid rhinorrhea. AB - Three children with primary intranasal encephalomeningocele associated with cerebrospinal fluid rhinorrhea were operated on at the Department of Neurosurgery, Hradec Kralove. In two children, aged 4 and 9.5 years, freeze-dried allogeneic costal cartilage was glued into the skull base defect. This plugging was covered up with deep frozen allogeneic fascia lata. In the third child, an only 1-year-old boy, after transection of the neck of the encephalomeningocele freeze-dried allogeneic dura mater was glued on extradurally and deep-frozen allogeneic fascia lata applied intradurally. The cerebrospinal fluid rhinorrhea ceased immediately after surgery. Spontaneous atrophy of the intranasal portion of the encephalomeningocele was demonstrated respectively 11, 1, and 7 years postoperatively on computed tomography. To evaluate cartilage healing histologically, the extracted allogeneic cartilage used for orbital roof plasty after 4 months was examined. The extent of spotty regressions represented about 7% of the tissue volume. It is stressed that, once diagnosed, intranasal encephalomeningocele associated with cerebrospinal fluid rhinorrhea should be operated on for prevention of meningitis as soon as possible. PMID- 8697456 TI - Cerebrospinal fluid shunt valve fracture with separation: report of three cases. AB - Three cases of shunt valve fracture with separation are reported. Fracture with separation of the shunt valve of a cerebrospinal fluid shunt is an infrequent occurrence. Because a portion of the shunt valve is radiolucent on a shunt survey radiograph, this problem is easily overlooked if it occurs. The diagnosis can be made by comparing old and new shunt survey radiographs and noting the increased distance between radiopaque portions of the shunt on the new x-ray films. PMID- 8697457 TI - Traumatic extradural hematomas of the posterior fossa in children. AB - The most favorable type of traumatic intracranial bleeding in childhood is the extradural hemorrage (EDH). The posterior fossa location is less frequent than the supratentorial site. In the period from January 1989 to January 1994 we treated 2,372 patients with craniocerebral trauma; 31 had extradural hematomas (1.3%); 3 of them were located in the posterior fossa (9.7%): 1 boy and 2 girls aged from 6 to 16 years. The traumatic mechanism was an occipital fall in all cases. Diagnosis was made by computed tomography scan (CT). Two of them had a rapidly deteriorating course. The three patients were operated on without mortality and there was no morbidity. The role of CT in the early detection of lesions and prompt surgical evacuation may reduce the mortality and morbidity from this lesion. The interaction between these factors is discussed. PMID- 8697458 TI - Primary CNS demyelinating diseases in childhood: multiple sclerosis. AB - We report on five children (three female and two male, age span 11-16 years) with laboratory-supported definite multiple sclerosis or clinically definite multiple sclerosis, diagnosed on the basis of Poser and Paty criteria. All patients were subjected to serial clinical examinations, magnetic resonance investigations, CSF biochemical and immunological studies, and neurophysiological and neuropsychological assessments. Four of the five examined subjects underwent steroid treatment. Over a period of 3 years relapses have been observed in three of them. The first symptoms and signs of multiple sclerosis may be subtle and misleading; careful assessment of them may be crucial for an early diagnosis of the disease. PMID- 8697459 TI - Clinicopathological study of familial late infantile Hallervorden-Spatz disease: a particular form of neuroacanthocytosis. AB - The cases of two sisters with late infantile Hallervorden-Spatz disease are reported, one of whom has died. Autopsy of the deceased patient showed typical pallidal lesions, such as axonal spheroids and iron deposits, without involvement of the substantia nigra. Ultrastructural examination revealed that pallidal axonal enlargements consisted of collection of mitochondria, dense bodies, vesicles and amorphous material. In the living patient, brain MRI showed the classical "tiger's eye" appearance of the globus pallidus. Retinitis pigmentosa, acanthocytosis and slight neuromuscular involvement with an increase in serum creatine kinase were observed in both subjects. The appearance of the globus pallidus on MRI was in line with the pathological abnormalities. Ultrastructural differences between the principal disorders characterized by neuroaxonal dystrophy are compared and the clinical spectrum and similarities of the different forms of neuroacanthocytosis analysed. PMID- 8697460 TI - Regional cerebral hemodynamics during re-build-up phenomenon in childhood moyamoya disease. An analysis using 99mTc-HMPAO SPECT. AB - We investigated the role of ischemic hypoxia in the appearance of re-build-up phenomenon on electroencephalography in childhood moyamoya disease using 99mTc hexamethyl propyleneamine oxime and single photon emission computed tomography (99mTc-HMPAO SPECT). In the case reported on, critical reduction of regional cerebral blood flow (rCBF) was observed during re-build-up phenomenon in the bilateral parieto-occipital area where acetazolamide testing revealed severe impairment of the perfusion reserve. On electroencephalography, the re-build-up phenomenon originated in these areas. In addition, re-build-up phenomenon developed into the entire hemisphere 30 s later, even where the severe ischemia was not observed. These results suggest that rCBF reduction induced by hyperventilation plays a critical role in the appearance of the re-build-up phenomenon, but other factors such as ischemic hypoxia after hyperventilation are also important in the development of this phenomenon. PMID- 8697461 TI - Heterotopic spinal cord? A curiosity. AB - Unusual morphological findings were encountered in a high cervical meningomyelocele sac of a neonate. Magnetic resonance imaging revealed a massive liquid-filled sac traversed by a linear structure. The spinal cord was seen to be located normally within the spinal canal. At operation, a spinal cord-like structure was identified within the sac. This cord terminated posteriorly at the neural tissue lining the meningomyelocele sac. There were fibrous strands connecting the cord to the sac like the rigging of a ship. The anterior end of this cord terminated in a fibrous band. It extended upwards into the spinal canal through the narrow neck of the meningomyelocele sac above the arch of the atlas. The whole of this cord, along with the meningomyelocele sac, was excised. Histological analysis confirmed that this spinal cord-like structure consisted of glial tissue with an ependymal-lined cavity. The excised sac was lined by neural tissue. PMID- 8697463 TI - Cerebral venous malformation complicated by spontaneous thrombosis. AB - A case of spontaneous thrombosis and infarction leading to death as complications of a cerebral venous malformation in a 13-year-old boy is reported. This is the first published report of this type of complication occurring in a case of venous angioma. While the biologic behavior of cerebral venous malformations has suggested that they are benign in nature, and the results of surgical management have encouraged a conservative approach, the present case illustrates a potential complication and argues against the assumption that these malformations are completely benign in nature. PMID- 8697462 TI - Multilevel lumbar disc herniation in 12-year-old twins. AB - Herniation of a lumbar disc in the pediatric age group is rare. A 12-year-old female twin developed backache and left sciatica after a mild lifting injury. Magnetic resonance imaging of the spine showed multilevel lumbar disc herniation. The patient was managed conservatively and her symptoms subsided within 6 weeks. Magnetic resonance imaging of her asymptomatic twin sister revealed a similar pattern of disc degeneration and multilevel herniation. This report emphasizes the hereditary nature of juvenile lumbar disc degeneration. PMID- 8697465 TI - [The role of coronary vasomotoricity in ischemic cardiopathy: fluctuating preconceptions]. PMID- 8697467 TI - Three-dimensional echocardiography: methods and clinical application. PMID- 8697466 TI - Closure of atrial septal defect in adult life. PMID- 8697464 TI - Unusual proximal migration of ventriculoperitoneal shunt into the heart. AB - Quite a number of cases of upward shunt migration have already been reported in the literature. In this paper, the intracardiac migration of a peritoneal shunt tube of a ventriculoperitoneal shunt system is reported. This is a rare complication of ventriculoperitoneal shunting and was diagnosed by a plain radiograph of the chest and a direct open heart surgery. To the author's knowledge this is the first reported case of migration of a peritoneal shunt tube into the heart. The authors postulate possible mechanisms and a physioanatomical explanation on the basis of the surgical findings. PMID- 8697468 TI - [Percutaneous mitral valvuloplasty in patients who have undergone surgical commissurotomy]. AB - Percutaneous mitral valvuloplasty (PMV) was performed with Inoue's catheter, by anterograde approach, in 19 patients (2 males and 17 females, mean age of 56 +/- 13 years) with restenosis after surgical commissurotomy. Mean valvular area increased from 1.2 +/- 0.2 to 1.9 +/- 0.2 cm2 while mean transvalvular gradient decreased from 13 +/- 6 to 7 +/- 4 mmHg. All but 2 patients reached optimal results; one had a suboptimal result (final valvular area > 1.5 cm2, percentage of increase less than 25%), and 1 was sent to the surgeon for a significant increase in mitral regurgitation ( ). At 1 year follow-up, (available for 11 patients), mean valvular area was 1.7 +/- 0.3 cm2 and transmitral gradient was of 5.4 +/- 2 mmHg. Four patients showed a restenosis; 1 of them underwent surgical mitral valve replacement after a second unsuccessful PMV; 2 showed good clinical conditions, while the fourth patient was sent to the surgeon for the high echocardiographic score. At 2-year follow-up, available for 4 patients, the mean gradient was of 5.5 +/- 2.5 mmHg and the mitral valve area was 1.8 +/- 0.2 cm2. NYHA functional class progressively improved after the procedure in all patients but those undergoing mitral valve replacement. In conclusion, despite the occurrence of restenosis, PMV seems to be feasible in patients who already underwent surgical commissurotomy; this procedure can avoid the risks of a second surgery, and should be considered the first choice treatment in these patients. PMID- 8697469 TI - [Radiologic practice and radioprotection in Italian hemodynamic laboratories]. AB - Increasing numbers of diagnostic and therapeutic cardiac catheterization procedures are performed in Italy each year. Radiation exposure of the cardiac catheterization laboratory staff is a known hazard, and there is growing public and professional concern over the risks of low-energy medical ionizing radiation for the patients. The aim of this study was to outline the range of current radiological and radiation protection practice in large-volume cardiac catheterization laboratories in Italy. In August 1994 a questionnaire was submitted to the chief invasive cardiologist of the 32 cardiac catheterization laboratories nation-wide having performed at least 1000 procedures in 1993. All laboratories responded. There were variations in both the radiologic technique (cine framing speed, mean film lengths and fluoroscopy times) and the radiation protection practice (use of shields, leaded collars and glasses, and sites where dosimeters are worn). In 22 of 32 laboratories the cardiologists were not aware of radiation exposure data, and only 6 laboratories could quote the exposure provided by their X-ray system or estimates of the dose absorbed by patients during diagnostic or therapeutic procedures. The results of this survey indicate that radiological practice, and techniques for measuring and reducing exposure of the personnel vary widely in cardiac catheterization laboratories in Italy. These data suggest also that reducing patients' radiation exposure is not, in general, considered to be a quality assurance priority by interventional cardiologists. PMID- 8697470 TI - [Inactivated factor VII exercises a powerful antithrombotic activity in an experimental model of recurrent arterial thrombosis]. AB - The extrinsic coagulation pathway is activated when tissue factor (TF) is exposed as a consequence of arterial damage. TF binds to factor VII (FVII) or activated FVII (FVIIa), generating a complex that activates both FX and FIX, ultimately leading to thrombin formation. To determine whether inhibition of FVII binding to TF would result in antithrombotic effects, active site-blocked FVIIa (FVIIai) was used in a rabbit model of intravascular thrombus formation. In addition, to study the interaction between extrinsic coagulation pathway activation and platelet aggregation, in the same model of intravascular thrombus formation, recombinant human FVIIa was administered in antiplatelet-treated rabbits. Cyclic flow variations (CFVs), due to recurrent thrombus formation, were initiated by placing an external constrictor around the endothelially-injured rabbit carotid arteries (Folt's model). Carotid blood flow was measured continuously by a Doppler flow probe placed proximally to the constrictor. CFVs were induced in 29 New Zealand White rabbits. After CFVs were observed for 30 min, the animals were randomly divided in four groups: 5 animals received via a small catheter (26G) placed proximally to the stenosis, an intra-arterial infusion of human recombinant FVIIai (0.1 mg/kg/min for 10 min); 9 animals received AP-1, a monoclonal antibody against rabbit TF (0.1 mg/kg i.v. bolus); 7 animals received ridogrel, a dual thromboxane A2 synthetase inhibitor and thromboxane A2 receptor antagonist (10 mg/kg i.v. bolus); finally, 8 rabbits received aurintrycarboxilic acid (ATA), an inhibitor of platelet glycoprotein Ib/von Willebrand factor interaction (10 mg/kg i.v. bolus). FVIIai abolished CFVs in 5 of 5 animals (CFV frequency minutes 0 cycles/hour; p < 0.05; carotid blood flow velocity minutes 106 +/- 9% of the baseline values; NS vs baseline). AP-1 abolished CFVs in 7 of 9 animals (CFV frequency minutes 0 cycles/hour; p < 0.05; carotid blood flow velocity minutes 58 +/- 35% of the baseline values; NS vs baseline). Finally, in all the animals receiving ridogrel or ATA CFVs were abolished (CFV frequency 0 cycles/hour; p < 0.05 in both groups; carotid blood flow velocity, respectively 62 +/- 32 and 66 +/- 40% of the baseline values; NS vs baseline in both groups). Thirty minutes following inhibition of CFVs, in the FVIIai treated rabbits, human recombinant FVIIa was infused, via the small catheter placed proximally to the stenosis, at the dose of 0.1 mg/kg/min for 10 min. In the other three groups, FVIIa, at the same dose, was infused i.v. Infusion of FVIIa restored CFVs in all FVIIai treated animals and in 6 of 7 AP-1 treated animals, thus indicating that AP-1 and FVIIai bindings to TF was competitive and was replaced by FVIIa. Infusion of FVIIa failed to restore CFVs in ridogrel e ATA treated rabbits (1 of 7 and 0 of 8 rabbits, respectively), showing that activation of extrinsic coagulation by FVIIa was overcome by inhibition of platelet function. Activated partial thromboplastin time, and ex vivo platelet aggregation in response to ADP and thrombin, were not different after FVIIai infusion, while prothrombin time was slightly but significantly prolonged as compared to baseline values. Thus, FVII-VIIa plays an important role in initiating thrombus formation in vivo. Administration of FVIIai exerts a potent antithrombotic effects in this model without affecting systemic coagulation. In addition, in this model platelets exert an important role in arterial thrombosis, since in the presence of inhibition of platelet function, activation of the extrinsic coagulation pathway failed to restore thrombus formation. PMID- 8697471 TI - [Protocol for the diagnosis of ischemic cardiopathy in the diabetic patient. The Diabetes, Lipoproteins and Atherosclerosis Study Group of the Italian Society of Diabetology]. PMID- 8697472 TI - [Heart rupture at the right atrial level as the first manifestation of malignant lymphoma]. AB - Primary heart lymphoma is an extremely rare condition and metastatic lymphomas constitute 9% of the total heart metastases. In most cases the lymphomatous involvement of the heart and/or pericardium is seen only at autopsy. It is unlikely that cardiac manifestations are the initial presentation of malignant lymphoma. We report a case of malignant lymphoma presenting with cardiac tamponade secondary to right atrial rupture. PMID- 8697474 TI - [The lymphatics and lung fluid resorption]. PMID- 8697473 TI - [Alcoholic cardiomyopathy in the initial phase: the earliness of an arrhythmic substrate in relation to Doppler echocardiographic changes]. PMID- 8697475 TI - [Directional coronary atherectomy]. PMID- 8697476 TI - [Nervous mechanisms and ischemic cardiopathy]. PMID- 8697477 TI - [Calcium antagonists and hypertension: a slice of real life]. PMID- 8697478 TI - Anti-ischemic properties of ACE-inhibitors. PMID- 8697479 TI - Angiotensin II as a modulator of cardiovascular autonomic control. PMID- 8697480 TI - [How to regulate the heart rate in a wearer of a cardiac pacemaker]. PMID- 8697481 TI - [Cardiovascular response to physical exercise]. PMID- 8697482 TI - [Left ventricular volumetric and contractility behavior during stress echocardiography with dobutamine]. AB - Aim of this study was to assess the behaviour of left ventricular volumes during dobutamine echocardiography in patients with coronary artery disease (CAD) compared to subjects with normal coronary angiograms. We have measured the end diastolic and end-systolic volumes and a non invasive index of myocardial contractility (the ratio between systolic blood pressure and end-systolic volume index, SBP/ESVI) in 67 patients undergoing dobutamine echocardiography and quantitative coronary angiography. Patients were divided into 3 groups: Control group (n = 10) without CAD; Group I (n = 30) with CAD but normal resting wall motion; Group II (n = 27) with CAD and resting wall motion abnormalities. Volumetric response to dobutamine was deemed abnormal when percent changes of left ventricular volumes from baseline to peak infusion were below 2 standard deviations of the mean values obtained in the control group. The normal or pathological volumetric response was compared with the extent of significant ( > 70% lumen stenosis) coronary artery disease. In the control group, dobutamine produced a significant decrease in both end-diastolic and end-systolic volumes, with percent changes from rest to peak of 24 +/- 5% and 29 +/- 5% respectively, and an average increase of 70 +/- 20% in the SBP/ESVI ratio. Among the 22 Group I patients who showed dobutamine-induced asynergies, volumetric response in those with multivessel disease was normal in 5/14 (36%) and abnormal in 7/8 (87%, p < 0.05), whereas among the remaining 8 patients who had no dobutamine-induced asynergies, an abnormal volumetric response was always associated with multivessel disease (n = 3/3, 100%). In Group II, the prevalence of abnormal volumetric responses in the presence (n = 15) or absence (n = 12) of dobutamine induced new or worsening asynergies was respectively 92% and 87% in patients with multivessel disease, whereas in those with single vessel disease the prevalence was lower, although not significantly (8 and 13%, p = 0.08 vs multivessel CAD). Predictive accuracy of an abnormal volumetric response for identifying multi vessel coronary artery disease in Groups I and II was not significantly different (77 and 85%, respectively, NS). Our preliminary data indicate that the evaluation of left ventricular volumes during dobutamine echocardiography yields additional information on myocardial intropic reserve, useful for diagnostic and functional assessment of patients with coronary artery disease. Moreover, this study emphasizes the importance of defining the "normal" left ventricular performance during DE to be able to regard an abnormal volumetric behaviour as a reliable marker of impaired inotropic reserve. PMID- 8697483 TI - [The immediate and midterm results of percutaneous mitral valvuloplasty in subjects over 60]. AB - We have analyzed the immediate and mid-term (1 and 2 years) results of percutaneous mitral valvuloplasty (PMV) by Inoue's catheter in 97 patients < 60 years (Group A) compared with 34 patients > 60 years (Group B). In 61% Group A the patients were in NYHA functional class II, 36% in III, and 3% in I; in Group B, 56% of the patients were in NYHA functional class III, 38% in II, and 6% in IV. Mean mitral valve area was 1.1 cm2 before dilatation in both groups, and a significant (p < 0.0001) increase was obtained in both Group A (0.9 +/- 0.3 cm2) and Group B (0.8 +/- 0.3 cm2). No significant differences were observed between the two groups. Mean transvalvular gradient decreased significantly (p < 0.0001) from 13.6 +/- 5.7 to 7.2 +/- 3.1 mmHg in Group A, and from 9.9 +/- 4 to 6.5 +/- 2.3 mmHg in Group B (A vs B: p < 0.02). Optimal result was obtained in 94% and 88% of Group A and Group B patients, respectively. Suboptimal result was obtained in 2% and 6% of Group A and Group B patients, respectively. These differences were not significant. Failure of PMV occurred in 4% and 6%, respectively. At 1 year follow-up Group A 7 patients and 5 Group B patients showed restenosis; at 2 year follow-up one more restenosis was present in Group A (A vs B at 1 and 2 years: NS). We conclude that PMV is a safe and effective technique in young patients and in patients > 60 years. PMID- 8697485 TI - [Myocardial lipofuscinosis of unknown etiology in a young asymptomatic woman]. AB - An asymptomatic 32-year-old woman was examined because of a family history of unexplained sudden deaths and a left ventricular strain pattern of the ECG during a routine examination. No abnormal finding of the cardiovascular system was present but an endomyocardial biopsy showed focal interstitial fibrosis, myocyte hypertrophy with heavy perinuclear accumulation of lipofuscin. The cause of these abnormalities remains unknown. PMID- 8697484 TI - [The methods of using the echocardiogram in outpatients. The role of the cardiologist for more appropriate use of the procedure. The Ligurian Group of the Italian Society of Cardiovascular Echocardiography]. AB - Concerns about the increasing medical care costs are causing the medical community to focus its attention on the appropriate of diagnostic tests such as echocardiography. Prerequisite to a better utilization of the limited economic resources assigned to our health care system is an analysis of how, why, and with which results diagnostic tests with a widespread use and relevant cost, like echocardiography, are requested. During the last 2 weeks of September 1994, a transversal, observational study was carried out at 13 hospital echocardiographic laboratories. Ordering physician characteristics, reasons for ordering the test, cardiological diagnostic tests previously performed and their relationship with the test results, were evaluated with a questionnaire completed by the physician who performed the test, in all the out-patients undergoing echocardiogram in that fortnight. Five hundred and sixteen consecutive questionnaires were successfully completed. Fourty-five percent of the echocardiograms were ordered by cardiologists, 35% by general practitioners, 10% by internists, and 10% by other specialists. Hypertension (16.4%) and ischemic heart disease (14.8%) were the most common indications for the test, followed by palpitations or arrhythmias (7.5%), mitral valve prolapse or mitral valve disease (7.3%), chest pain or angina pectoris (6.3%), cardiac murmur (5.5%), dyspnea or heart failure (5.2%), aortic valve disease (5%), prosthetic heart valve evaluation (4.6%), others (27%). Before undergoing the echocardiogram, 433 (84%) patients underwent an electrocardiogram, 242 (47%) a cardiological clinical evaluation, 196 (38%) a chest X-ray, and 191 (37%) had had a previous echocardiogram. The most common echocardiographic diagnosis was normal (29.2%) followed by hypertensive heart disease (16.2%), mitral valve disease (12.3%), aortic valve disease (10.5%), ischemic heart disease (9.3%), cardiomyopathy (4.9%) normal prosthetic heart valve function (4.5%), pericardial effusion (3.8%), others (11.3%). Among the echocardiograms ordered by cardiologists, 21.8% were normal in comparison with 35.4% of those ordered by general practitioners (p < 0.004), 35.3% of those ordered by internists (p = 0.04), 35.3% of those ordered by other specialists (p = 0.04). Among the 284 patients whose echocardiograms were not requested by a cardiologist, only 215 (76%) had undergone an electrocardiogram and only 68 (24%) a clinical evaluation by a cardiologist. In these patients, the frequency of normal echocardiograms was not influenced by having undergone a previous electrocardiogram or a chest X-ray. Conversely, patients in whom the echocardiogram was ordered after a cardiology consult showed a significant lower frequency of normal results compared to patients not evaluated by a cardiologist (23% vs 39%; p < 0.05). More than 50% of the echocardiograms performed in out patients are ordered by physicians who are not cardiologists. Among these echocardiograms, about 1 out of 3 results normal. This finding suggests an improper use of echocardiogram as a screening tool by non-cardiologists in out patients. A preceding clinical evaluation by a cardiologist, but not an electrocardiogram or a chest X-ray alone, may determine a more appropriate use of the test being associated with a reduced frequency of normal results. PMID- 8697486 TI - [The angiographic application of spiral computed tomography]. PMID- 8697487 TI - Factors related to the recovery of women following coronary artery bypass surgery. PMID- 8697489 TI - Endothelial function and coronary risk reduction: mechanisms and influences of nitric oxide. AB - The biological mechanisms related to progression and regression of CAD are indeed complex. While endothelial injury and lipid accumulation play an important role in the progression/regression of CAD, mechanisms of vascular function, particularly that of the endothelial modulation of vasodilation, cannot be ignored. Much is yet to be learned about the influences of endothelial function on the progression/regression and stabilization of CAD. Initial evidence suggesting that risk reduction interventions favorably influence vascular function argues for further investigation of this role. To date, much of the research on risk reduction has focused on lipid lowering and regression of artery plaque, a focus on artery structure. A focus on both function and structure is likely to expand our understanding of the effect of risk reduction interventions beyond lipid lowering. Given the multifactorial causes associated with development of CAD, such an approach is necessary. PMID- 8697488 TI - Relation of sociodemographic, clinical, and quality-of-life variables to adherence in the cardiac arrhythmia suppression trial. AB - Clearly, age and education are important factors for predicting adherence in CAST, given that they appear in all three regressions. Moreover, the 4-month and 1-year results indicate that mental health and presence of a spouse are important predictors. Physical function, stress, angina, and history of MI may also provide additional information regarding adherence levels. It is interesting to note that although adherence was higher for patients who have "good" social characteristics, such as having a spouse, support, integration, perceived good health, good mental health, low stress, and education, it was also better for those patients who had "poor" physical characteristics such as a history of angina, a history of MI, and low physical function. In the multivariate analysis, older age was also associated with good adherence. These observations are not necessarily intuitive and support the need for further research in this area. If patients at risk for poor adherence can be identified prospectively, strategies may be developed to improve their subsequent medical care in such a way to favorably affect and improve their outcomes. PMID- 8697490 TI - Liver dysfunction in the early post-bone marrow transplant period. AB - In the paper hepatic dysfunctions occurring in more than 80% recipients of HLA matched bone marrow transplants (BMT) in the early post-transplant period (< 100 days) is described. They involve veno-occlusive disease (VOD) and acute graft versus-host disease (aGVHD). Liver dysfunctions can be also caused by unfavourable effects of drugs and by infections. Etiopathogenesis, clinical and laboratory findings, diagnosis, therapy and prophylaxis of the dysfunctions in question is being described in detail. PMID- 8697491 TI - [Ischemic cerebrovascular strokes in childhood]. AB - BACKGROUND. Cerebrovascular attacks are a very frequent disease in adults and in particular in the elderly. In postneonatal child age they are very rare. In all age groups ischaemic attacks predominate over haemorrhagic ones. The objective of the present work was to evaluate the clinical picture and severity of residual affection in children, to attempt to find risk factors for the development of these attacks and to compare them with risks in the adult population. Diagnostic methods, incl. their advantages and disadvantages, are described. METHODS AND RESULTS. Twelve attacks in 10 children hospitalized in the course of 10 years were analyzed retrospectively. A more frequent incidence in boys, a predominance of attacks in the carotid region, more frequent affection of the left hemisphere, clinical picture and etiology-all is consistent with data in the literature. PMID- 8697492 TI - [Comparison of the effects of a low protein diet and angiotensin converting enzyme inhibitors on renal insufficiency in hypertensive rats]. AB - BACKGROUND: It is known that hypertension to aggravate the course of chronic renal insufficiency (CRI). It is too know the beneficial effect of the angiotensin-converting enzyme inhibitors (ACEI) and the low-protein diet. In this study, the effect of a low protein diet on the course of CRI was compared with that of administration of enalapril (ENA), an ACEI. METHODS AND RESULTS: A new model of genetic hypertension, the Prague Hypertensive Rat (PHR) was used. In rats just after weaning, 5/6 of renal parenchyma were removed surgically (5/6NX). The rats were observed for 8 weeks after 5/6NX. The animals were fed either a normal rat chow containing 23% of protein, or a low-protein diet containing only 6% protein. Control groups drank tap water, experimental groups received water containing ENA at a dose of 5 mg/kg BW. The rats on normal diet drinking water had the highest levels of blood pressure (200 +/- 4.3 mm Hg), proteinuria (56.2 +/- 14.6 mg/24 hours) and heaviest kidney remnants i.e. highest compensatory hypertrophy (2352 +/- 239.4 mg). Both ENA and low-protein diet significantly improved these functions to the same extent. However, a combination of low protein diet with ENA had no further beneficial effect as against any of these manoeuvres alone. CONCLUSIONS: We assume every manoeuvre (low-protein diet and enalapril) exerts a maximal beneficial effect per se: the mechanism of this effect is highly speculative: inhibition of growth factors seems to be the most logical explanation. ACEIs are known to inhibit the production of angiotensin II, low-protein diet should inhibit transforming growth factor beta. PMID- 8697493 TI - [Prognostic significance of impaired intra-and infra-bundle of His conduction in the heart]. AB - BACKGROUND: So far no final solution was found as regards the relationship of impaired conduction in the His-Purkyne system and the incidence of cardiac and in particular sudden deaths. The objective of the present work was to assess by long term prospective follow-up of subjects with a normal and pathological prolongation of the intra- and infrahisian conduction in the heart, based on the electrogram of the bundle of His, the importance of these findings for assessment of the patient's prognosis. METHODS AND RESULTS: After elimination of subjects with ventricular preexcitation the authors included in the group 340 patients (243 men, 97 women, aged 16-81 years, mean 49 +/- 16), where they recorded the electrogram of the bundle of His (without cardiac stimulation, during graded and programmed stimulation of the atria, after i.v. administration of ajmaline). In 206 cases they implemented at the same time programmed stimulation of the ventricles. The HV interval or the length of the H wave were in 286 patients normal and in 54 patients protracted. All patients were followed up by the authors for 6 to 144 months (mean follow up period 56.1 months). In the group of subjects with normal intra- and infrahisian conduction, as compared with the group with protracted conduction in the same area, the number of cardiac deaths was lower, i.e. 10.1 %, as compared with 22.2 %, sudden "cardiac" deaths (death within one hour after the onset of symptoms), i.e., 6.6 % as compared with 11.1 %, and sudden bradyarrhythmic" deaths (sudden "cardiac" death except subjects with diagnostic programmed ventricular stimulation), i.e. 2.8 % as compared with 11.1 %. CONCLUSIONS: The results support significantly the prognostic impact of pathological conduction in the His-Purkyne system as regards the occurrence of cardiac deaths and sudden "brady arrhythmic" deaths (p < 0.05). Conversely, the differences as regards the occurrence of sudden "cardiac" deaths were not significant. PMID- 8697494 TI - [Antioxidant enzyme activity in erythrocytes in children with kidney diseases]. AB - BACKGROUND: An important place is ascribed to the formation and action of free oxygen radicals in the pathogenesis of some kidney diseases. The objective of the present work was to examine the antioxidant enzyme defence mechanism in children with different nephropathies. METHODS AND RESULTS: In a group of 58 children (32 boys and 26 girls, mean age 13.9 years) with different renal diseases (35 children with chronic glomerulonephritis-GN, 8 children with a relapse of the nephrotic syndrome and 15 patients with chronic renal insufficiency-CHRI) the concentration of superoxide dismutase and catalase (KAT) was examined. The SOD and KAT activity in erythrocytes was assessed spectrophotometrically at 240 nm. In the whole group of patients the mean SOD values (632 +/- 102 U/g Hb) and KAT values (3.29 +/- 0.54 mukat/g Hb) were within the reference range. The highest mean SOD and KAT values were recorded in children with a relapse of nephrotic syndrome. In the group with chronic GN the SOD concentration in erythrocytes correlated significantly with total protein levels and serum creatinine resp. (r = 0.350, p < 0.05 and r = -0.458, p < 0.01 resp.). In the CHRI stage the authors revealed a significant relationship between the SOD activity and total protein levels (r = 0.550, p < 0.05). CONCLUSIONS: The activity of basic antioxidant enzymes SOD and KAT in erythrocytes of children with nephropathies is not significantly reduced. In patients with chronic GN there is a significant correlation between renal functions and SOD. PMID- 8697495 TI - [The danger of neurosyphilis is again a reality]. AB - The contemporary epidemiological position as regards syphilis, worldwide and in the Czech Republic, is deteriorating in a dangerous way. New cases are not adequately detected, their treatment is frequently implemented by non professionals and the symptoms of the 1st and 2nd stage remain unnoticed and may be even lacking. In the near future we must foresee an increasing incidence of late complications of syphilis. The authors present four catamnestically followed up cases of progressive paralysis which were detected during the past five years at the Psychiatric Clinic of ther First Medical Faculty, Charles University, Prague. The observation confirms the old view that patients who contracted neurosyphilis must remain throughout life on the records of VD clinics despite excellent remission of the clinical condition as in none of their patients complete normalization of the finding in the cerebrospinal fluid was found. PMID- 8697496 TI - Treatment of myofascial pain dysfunction syndrome with occlusal therapy to reduce lengthy disclusion time--a recall evaluation. AB - A recall study of 102 myofascial pain dysfunction syndrome-temporomandibular disorder (MPDS-TMD) patients, treated with disclusion time reduction therapy from 1983 to 1991, was undertaken to determine the long-term results of this treatment on symptom reductions. The patients were asked to fill out a symptom questionnaire which used ordinal number scales to determine their disease status (frequency and intensity of muscular, joint and dysfunctional symptoms; frequency of medication and appliance use) before and after they were treated with disclusion time reduction. The statistical results indicate that discluson time reduction therapy is a highly effective treatment regimen for MPDS and that it has lasting effects on symptom reduction. In addition, the results of this recall study indicate that occlusion, and more specifically, lengthy pretreatment disclusion time, does play a primary role in the symptomatology, and most probably, in the etiology of MPDS and TMD. PMID- 8697497 TI - Clinical comparative study of microcurrent electrical stimulation to mid-laser and placebo treatment in degenerative joint disease of the temporomandibular joint. AB - Mid-laser and microcurrent stimulation (MENS) have been found to be effective in the reduction of painful temporomandibular joints (TMJ) with internal derangement. There was significant improvement in mobility with the reduction of pain. Mid-laser was superior to MENS in its application and effect, and both were significantly better than the placebo treatment. PMID- 8697498 TI - Simplified approach in interpretation of the temporomandibular joint tomography. AB - This article presents a simple systematic methodology in interpretation of parasagittal and coronal tomography views of the temporomandibular joint (TMJ). A step-by-step approach for screening the condyle, articulating eminence and fossa, and the joint as a whole is discussed. PMID- 8697500 TI - Chairside fabrication of occlusal biteplane splints using visible light cured material. PMID- 8697499 TI - Comparison of two patients with similar facial pain complaints of dental and non dental etiologies. AB - The medical and lay communities have become more aware of the role of dentistry in the diagnosis and management of facial pain disorders. In some cases, the patient or physician may presume that a facial pain complaint is of odontogenic origin and seek the opinion of a dental practitioner. While the majority of facial pain complaints may be due to dental pathologies, some may also be due to non-dental causes. The diagnostic acumen of the dentist must include a basic understanding of non-dental causes for facial pain as well as those related to dentistry. The following case reports may serve to underscore this observation. PMID- 8697502 TI - Biologic vs. psychologic dentistry. PMID- 8697501 TI - Modified functional distraction appliance. An appliance for chronic lock and ankylosis. PMID- 8697503 TI - Tinnitus in patients with temporomandibular joint internal derangement. AB - Tinnitus has commonly been reported in patients with temporomandibular joint (TMJ) disorders. The aim of this study was to determine if there was any correlation between arthographically verified disk displacement of the TMJ and ear symptoms related to tinnitus. Fifty-three patients with unilateral tinnitus and disk displacement and 82 individuals with disk displacement, but no tinnitus, were analyzed. Disk displacement was found to be present in the ipsilateral joint in all 53 patients with unilateral tinnitus, while the contralateral joint was asymptomatic in 50 (94.3%) of them. Patients with tinnitus suffered more extensive and intense pain in the oro-facial area compared to patients without tinnitus. The results of this study revealed a significant correlation between internal derangement of the TMJ and tinnitus. PMID- 8697504 TI - Symptoms of temporomandibular joint osteoarthrosis and internal derangement 30 years after non-surgical treatment. AB - To evaluate the long-term condition of temporomandibular joints (TMJs) affected by osteoarthrosis and internal derangement, 99 patients treated non-surgically between 1958 and 1962 were recalled for follow-up. The patients, 16 men and 83 women (mean age 58.2 years) with either reducing or permanent disk displacement, were submitted to a structured interview concerning previous treatment, masticatory function, and the presence of symptoms of osteoarthrosis and internal derangement of the masticatory system, and of complaints of the musculoskeletal system in general. A control group, consisting of eight men and 27 women (mean age 58.9 years) without complaints of the masticatory system, matching the patient group for sex, age and state of dentition, was included in the study to avoid simply documenting age-related joint conditions. Satisfaction with the treatment outcome was high. Chewing ability of the the patients did not differ from that of the controls, although patients more often expected pain and difficulty with opening the mouth wide. The main TMJ symptoms of the patients had decreased significantly; patients reported joint noises more often than controls. It is concluded that, despite some persisting symptoms, the non-surgical treatment approach of TMJ osteoarthrosis and internal derangement provides long lasting satisfactory subjective results and is well-accepted by the patients. PMID- 8697506 TI - Chewing pattern analysis in TMD patients with and without internal derangement: Part II. AB - In order to investigate the chewing movement of temporomandibular disorders (TMD) patients with and without internal derangement of the temporomandibular joint (TMJ), the velocity of chewing movement was analyzed in 103 TMD patients with unilateral internal derangement (D group), 94 TMD patients without internal derangement (NID group) and 10 normal subjects (normal group). The ID group showed a significantly reduced maximum opening velocity, a significantly smaller standard deviation for the velocity and a significantly frequent opening velocity pattern with a deceleration in the middle of opening compared to the NID or the normal groups. The NID group demonstrated significantly frequent opening velocity patterns without any velocity peak compared to the ID or normal groups. PMID- 8697505 TI - Craniomandibular disorders and skeletal mineral status. AB - Values for bone mineral density of the femoral neck and lumbar spine were determined by dual-energy x-ray absorptiometry for 355 postmenopausal women 48 to 56 years of age. The bone mineral density in three regions of the mandible was measured by quantitative computed tomography for 77 of the 355 women. Existing symptoms of craniomandibular dysfunction were recorded in both an anamnestic inquiry and a clinical examination. The purpose of this study was to determine whether the bone mineral density of the skeleton and mandible is associated with symptoms of craniomandibular dysfunctions. The results suggest that the habits and conditions that provoke development of general bone loss in the skeleton may disturb the functional harmony of the masticatory system and, thus, increase the possibility for craniomandibular disorders (CMD). PMID- 8697507 TI - Clinical and MRI findings of the temporomandibular joint in relation to occlusion in young adults. AB - Magnetic resonance imaging (MRI) is excellent for visualizing soft tissues of the temporomandibular joint (TMJ) . Because it has no harmful effects, it can be used in asymptomatic subjects. MRI and clinical findings relating to TMJs were correlated with findings relating to occlusion in 20 medical and dental students (13 women, 7 men) who volunteered to participate in our study. Subjects with clinically evident joint signs such as clicking, crepitation or tenderness on palpation also exhibited pathologic MRI findings, especially in regards to configuration, position and function of the disk, and, often, disturbances of occlusal relationships between the upper and lower teeth. PMID- 8697508 TI - [Uses of polymerase chain reaction in the diagnosis of tuberculosis and its problems]. PMID- 8697509 TI - [Increased expression of platelet-derived growth factor beta receptor gene in hypoxic rat lungs]. AB - The changes of platelet-derived growth factor (PDGF) beta receptor gene expression in hypoxic rats lungs was examined. Northern blots analysis revealed that normal lungs expression PDGF-beta receptor mRNA, with the longer of hypoxia the level of the mRNA increased rapidly. It reached a maximum at day 4, and was 1.34 fold as compared with the control (P < 0.05). Immunohistochemistry investigation showed that PDGF-beta receptor mainly distributed on smooth muscle cells and endothelial cells of middle and small arterial trees in rat lung. With hypoxia, the distribution of PDGF-beta receptors did not change, but it was more intense and reached a maximum at day 7, and was 2.40 fold as compared with the control (P < 0.05). The results suggested that increased expression of PDGF receptor gene may play a role in hypoxic pulmonary vascular remodeling. PMID- 8697510 TI - [Immunohistochemical analysis of nm23 gene product/nucleoside-diphosphate kinase expression in human lung carcinoma]. AB - It was proposed that nm23 gene may function as a suppressor gene for tumor metastasis. Using an antibody to NDPK, levels of NDPK/nm23 expression in lung carcinomas were examined immunohistochemically, 45 of 58 squamous carcinomas and 26 of 36 adenocarcinomas showed strong immunoreactivity for NDPK/nm23 in most of cancer cells within tumor tissues. On some normal bronchial epithelium and serous glands, there also show weak expression. No relationship was found between NDPK/nm23 expression and clinicopathological parameters including tumor grade, size, nodal involvement and stage but the increases in NDPK/nm23 expression were stronger in advanced stages of squamous cell carcinomas. In conclusion, our results indicate that the increased NDPK/nm23 expression in the analysed carcinomas is not consistent with the proposed metastasis-suppressor function, but the nm23 gene may be implicated in the mechanism of carcinogenic process and tumor progression. PMID- 8697511 TI - [The detection and significance of HBV-DNA in serum of pulmonary tuberculous patients]. AB - Hepatitis B virus deoxyribonucleic acid (HBV-DNA) in the serum and the liver function from 268 patients with pulmonary tuberculosis were investigated. The patients have been followed up for 3.5 years. In the course of antituberculous chemotherapy, the abnormal liver function rate turned to be 95% in the positive HBV-DNA group but only 10% and 5.1% in the negatives, HBV-DNA group and pulmonary tuberculosis group respectively (P < 0.01, P < 0.01, P > 0.05). The abnormal liver function rate turned to be 49% in the positive HBV-M group but only 5.1% and 10% in the negative control group and pulmonary tuberculosis group (P < 0.01, P < 0.01, P > 0.05) respectively. The presence of HBV-DNA in patients with pulmonary tuberculosis was associated with high mortality rate and the cause of death was related to hepatic failure. The results suggest that to detect serum HBV-DNA is important in pulmonary tuberculous patients. Antiviral therapy for patients with pulmonary tuberculosis who had detectable HBV-DNA may improve prognosis. PMID- 8697512 TI - [Detection of serum procollagen III peptide in tuberculous patients]. AB - The serum procollagen peptide (PIIIP) levels of 132 cases of tuberculosis and 37 healthy persons have been detected with RIA. The results showed that the serum PIIIP level in tuberculous patients is significantly higher than that of healthy persons (P < 0.001) and strongly related to the severe degree of activity and the size of pathological change of tuberculosis and patient condition. It suggests that there might be some significance in assessing serum PIIIP in tuberculous patients for evaluating the severity and prognosis of the illness. PMID- 8697513 TI - [The value of CT and MRI in differentiating malignant nodule from tuberculoma]. AB - Correlative study of CT, MRI and pathology was done on 121 cases with solitary pulmonary nodule less than 3 cm in diameter, including 97 malignant nodules and 24 tuberculoma. On CT, the main morphological characteristics of the malignant nodules is lobucation, spiculation, vessele involvement, heterogeneous density, and vacuole sign and air bronchogram, and that of the tuberculoma, the smooth margin, homogeneous density, calcification. On the other hand, the relative signal intensity of these pulmonary nodules were evaluated on T1, T2 weighted image. Our prelminary results indicated that though MRI is inferior to CT in the assessment of the margin and internal feature of the nodule, it can provide further information in differentiating between malignant nodule and tuberculoma. PMID- 8697514 TI - [The relationship between H2 receptor and the pathogenesis of bronchial asthma in guinea-pigs]. AB - H2 receptor (H2R) is one of the three histamine receptor subtypes. In order to explore the relationship between H2R and the pathogenesis of bronchial asthma, we investigated the effects of H2R agonist impromidine on guinea-pig isolated tracheal smooth muscle and the effects of dimaprit on the lung function of guinea pigs provoked by antigen. RESULTS: (1) Impromidine (10(6) mol/L) relaxed partly the guinea-pig isolated tracheal spirals contricted by histamine challenge. After pretreating the spirals with impromidine, the maximum response to histamine was reduced in a dose-dependent manner and the cumulative dose-response curve to histamine was shifted to right. (2) Dimaprit (3mg/kg) given by intravenous injection protected the lung function from damage caused by antigen. These results suggest that H2R agonist produces relaxation of guinea-pig tracheal smooth muscle and inhibits the release of inflammatory mediators in anaphylactic reaction. We concluded that H2R plays some protective roles in the pathogenesis of bronchial asthma. PMID- 8697515 TI - [A clinicopathological analysis of 11 patients with pulmonary sclerosing hemangioma]. AB - Eleven cases of pulmonary sclerosing hemangioma proved by operation and pathological examination were reported. All patients showed at least 3 different typical pathological features and infiltration of the histocytes and dilated blood vessels with papillary projections were the commonest manifestations. The clinical manifestations, pathology and histogenesis were discussed and related literature reviewed. PMID- 8697516 TI - [Analysis of the results of fibrobronchoscopy relevant to x-ray examination in 138 cases with hemoptysis]. AB - Only 90 abnormal cases of the chest X-ray examination were found among 138 patients with hemoptysis. However the main results of the fibrobronchoscopy for 138 cases were: chronic bronchitis and pulmonary inflammation 59 cases (42.8%), bronchogenic carcinoma 41 cases (29.7%), tuberculosis 10 cases (7.2%) and others 28 cases (20.3%). Authors conclude that fibrobronchoscopy can clarify the nature of lesions and the cause of hemoptysis on the basis of chest X-ray examination. PMID- 8697517 TI - [The change of serum alpha 1-antitrypsin level in patients with spontaneous pneumothorax]. AB - The serum level of alpha 1-antitrypsin (alpha 1-AT) were observed in 32 cases with spontaneous pneumothorax. The results showed the level of alpha 1-AT in patients of spontaneous pneumothorax is higher than normal control. The degree and duration of elevated alpha 1-AT level was related with the recovery of spontaneous pneumothorax and its reoccurrence. PMID- 8697518 TI - [Diagnosis and surgical treatment of tuberculous lymphadenopathy of hilar and mediastinal lymph nodes]. AB - Fifty-eight patients with hilar and mediastinal tuberculous lymphadenopathy treated with surgical operation were reported. The authors presented their preliminary experience in diagnosis, surgical technique and satisfactory outcome. The concluded that in certain situation, thoractomy is indicated for both acquiring objective, accurate diagnosis and definitive, effective treatment. PMID- 8697519 TI - Research on teaching nursing: where is it? PMID- 8697520 TI - The South African Nursing Council: 50 years of professional self-regulation. PMID- 8697522 TI - [Psychiatric nursing support for the families of patients in an oncology unit: Part I]. AB - The family of a patient in an oncology unit or at home, experiences mental discomfort as a result of additional pressure placed on the family system due to long-term implications of cancer. Families are often uncertain about ways of effective coping in their stressful situation. As a result of this uncertainty, they tend to withdraw from one another, thereby worsening their mental discomfort and impeding their pursuit of wholeness. An exploratory, descriptive and contextual study was carried out during the course of which the design for case studies was used. The purpose of the study was to determine the contribution made by a psychiatric nursing specialist offering psychiatric nursing accompaniment to the family of a patient in an oncology unit or at home, regarding the lessening of their mental discomfort. A further goal was to set guidelines as to the manner in which this accompaniment should be presented by the registered nurse in order to lessen the mental discomfort of the family of such a patient. PMID- 8697521 TI - Blood donation behaviour and beliefs among a sample of high school students in Mmabatho. AB - This study was aimed at establishing the extent of blood donation and beliefs about donating blood among high school students in Mmabatho. A random sample of 40 Standard 10 students (20 males, 20 females; mean age = 20.8 years) was selected to participate in the study. A structured questionnaire was used to determined blood donation behaviour and accompanying beliefs. The results showed that although 80 percent of the participants believed that donating blood was important only 17.5 percent had actually ever donated blood. The data also showed that donating blood was a health risk or were uncertain if donating blood was safe. It is recommended that public appeals for blood donors should include information to dispel myths about dangers of donating blood. PMID- 8697523 TI - [Instructions for nurses for the support of families of patients in oncology home care: Part II]. AB - Whenever cancer is diagnosed in a member of a family, additional pressure and demands are placed on the family system. Certain issues occur in the family to the extent that they experience their situation and cope with it in their own way. The family's main concern is their experience of mental discomfort. One way of coping with this is by submitting to psychiatric nursing accompaniment tendered by a psychiatric nursing specialist. As the family proceeds to acceptance, specific needs occur, which should be addressed by means of a long term approach of support. This support rests mainly with the registered nurse who works with the family, since the number of trained psychiatric nursing specialist available is small. PMID- 8697524 TI - Breastfeeding in crisis: survey results of the Baby-Friendly Hospital Initiative. AB - OBJECTIVE: To assess current breastfeeding practices in hospital in South Africa. DESIGN: Survey conducted by means of a postal questionnaire for hospitals and a questionnaire based on the baby-friendly initiative action folder for mothers. SETTING: All private and provincial hospitals according to the 1992 address list supplied by the Department of National Health: Readers of "Living and Loving" and breastfeeding liaison groups. MAIN OUTCOME MEASURE: The level of implementation of the "Ten Steps to Successful Breastfeeding" RESULTS: Less than half of the responding hospitals reported having a written breastfeeding policy. Most hospitals have a shortage of specialized training in the support of breastfeeding. This is consistent with the outcome of the maternal questionnaire indicating that the average hospital is not baby friendly. CONCLUSIONS: A concerted effort should be made by hospitals to implement the "Ten Steps to Successful Breastfeeding" and attention should be given to building breastfeeding skills into the curriculum for medical students, nurses and allied disciplines as well as in-service training for current health care workers. PMID- 8697525 TI - [Nursing assessment of the needs of mothers with premature babies]. AB - Premature labour is and remains an actual problem. There will always be mothers that undergo the crisis of having a premature baby. The unique needs of these mothers remains unfulfilled. Possible reasons for this are that the nurse, working in the neonatal intensive care, special care units or in the post natal ward, does not do a complete assessment of the mother. Nurses are set on the physical needs of the mother and baby during hospitalization and pay more attention to these needs than to others. Those needs which are in fact neglected, are those which are so crucial and important, concerning the mother. In this study, it is needs, other than physical needs, which are emphasized. PMID- 8697526 TI - Neonatal nursing workload--can it be measured? AB - Continuing pressure on tertiary hospitals to reduce expenses has inevitably meant a demand to reduce nursing staff. This has intensified the need to ensure that staffing allocation is appropriate. A method to calculate staffing needs based measurement of neonatal workload is explored. PMID- 8697527 TI - Teenagers' knowledge of human sexuality and their views on teenage pregnancies. AB - There is concern about poor knowledge of human sexuality and a high rate of teenage pregnancies among Blacks. The primary aim of the study was to measure the knowledge that teenagers have on human sexuality and to identify the sources from which they obtain such knowledge. The secondary aim was to detect how teenagers perceive the teenage pregnancy problem and its consequences. A descriptive study was undertaken. Questionnaires were handed out and collected from 210 teenagers in two Senior Secondary Schools at a Black township near Empangeni. The study revealed that teenagers have reasonable knowledge about the anatomy and development of the reproductive organs at puberty but lacked sex counselling which resulted in their failure to understand the implications of sexual behaviour. The levels of knowledge an utilisation of the Youth Health Services was found to be low. The study also revealed a high level of awareness of the negative consequences of teenage pregnancies. The teenagers had numerous suggestions to make for the prevention of teenage pregnancies. PMID- 8697529 TI - Nurses are people too. PMID- 8697528 TI - A marketing strategy for a nursing college. AB - The objective of this study is to explore and describe a marketing strategy for a nursing college. An explorative and descriptive research design, within the context of a nursing college and affiliated hospitals, was followed. A literature study of marketing models was undertaken and the Delphi-method was utilised to determine the contribution of marketing staff and the possible content of a marketing strategy for a nursing college. The results were utilised to describe guidelines for such a strategy, consisting of marketers/marketing agents, target market, product, price, promotional activities, place and market research. Recommendations include the planning, implementation and evaluation of strategy, inservice training for potential marketing agents, inclusion of marketing as part of the formal education of tutors and nurse managers, as well as an impact study of the scholar as the main consumer. PMID- 8697530 TI - An investigation of compliance in type II diabetic patients attending clinic at Church of Scotland hospital. AB - Thirty Type II diabetic patients attending a clinic at a rural hospital were interviewed, using structured interviews and clinic records. The patients' clinic cards were also used to obtain the required information. The study was conducted to identify the factors that lead to non compliance with the recommended treatment regimen, to establish whether diabetic patients are able to keep appointments and to identify factors that influence patients from keeping appointments. Factors that led to non compliance were financial problems and forgetfulness. Most clients were unemployed while others were pensioners and could not afford the expensive means of transport to the clinic. Additional issues were rough terrain and roads which depended on good weather. The most common complication found in the study was hypertension, which when combined with minor ailments, led to clients taking multiple medications. PMID- 8697531 TI - Psychiatric nurses' communication with psychiatric patients. AB - The psychiatric nurses, as a member of the multi-professional mental health team, utilises a goal-directed approach to assist the psychiatric patient in mobilising resources to promote, restore and maintain his mental health as an integral part of his quest for wholeness. This goal-direct approach is the nursing process which comprises assessment, planning, implementing and evaluation. All four steps of the nursing process and the nurse's interaction with the patient are dependent upon therapeutic communication. Therapeutic communication remains important as the core of all nurse-patient interactions. The aim of this research was to explore and describe the viewpoints of psychiatric nurses on their communication with psychiatric patients and to formulate guidelines for psychiatric nurses. Such guidelines should assist nurses with their communication with psychiatric patients, helping in the restoration and maintenance phases of the patients' mental health. Exploratory, descriptive and contextual research was done with the purpose of gaining insight into the viewpoints of psychiatric nurses on their communication with psychiatric patients. PMID- 8697532 TI - Determination of needs of black aged persons in Port Elizabeth: direction for future interventions. AB - Social, economic and health care needs of elderly black persons in Port Elizabeth and areas in its immediate vicinity are investigated. Conclusions are drawn from a sample study of 301 elderly people. The investigation reveals that the majority of pensioners are women, their educational standard is below standard 10, and they have little vocational or specialized training. A high proportion (86%) of them are breadwinners and therefore they are unwilling to reside in institution. Recreational facilities are inadequate. Pension payout points are overcrowded and disorganized. Also health care services are inaccessible to most elderly people. In view of these findings, a community-based approach to care for the elderly is recommended. The approach should promote social interaction among elderly through establishment of luncheon clubs and service centres and well-being of all elderly through geriatric clinics as well as home care services for the infirm. This entails an intersectorial collaboration, with the elderly being fully involved and participating. Considering the exponential growth of the elderly population in South Africa, it is imperative that the government and other organizations should take cognizance of studies of this nature when making future decisions as regards the care of this group. PMID- 8697533 TI - Midwifery care standards for the first stage of labour. PMID- 8697534 TI - [Distance education retraining program: general nursing]. AB - Distance- or distance contact education provides registered nurses with an ideal opportunity for professional growth. This method also fulfils a need to study without the problem of being absent from family, occupational and social responsibilities. It seemed that students are enthusiastic about their studies despite personal, financial and other difficulties. At the end of the course students claimed that their self-confidence improved and that they were better equipped to give high quality nursing care. Using the Spearman Correlation Coefficient there was substantial correlation between the metric results and the final course symbol for this group of students [alpha .05 (p.002)]. No correlation existed between the selection average of 1-9 and the different subjects as for example General Nursing and Ethos. If the decision is taken to present courses according to the distance contact education method, careful planning is essential. Some of the recommendations to assure the success include: * sound structuring of infrastructure and subject material * improvement of selecting procedures; and * the orientation of lectures to cope with the role of facilitator. The professional growth of students during their period of study proves to be worth the effort to present such a course. PMID- 8697535 TI - [Patient activity level plans for personnel scheduling in nursing in-patient units]. AB - This study of patient activity level plans (PALP) to determine nursing levels for in-patients units was carried out by means of an exploratory, descriptive instrumental study within the context of a nursing situation. With the literature study serving as background, a patient activity level plan (PALP) was designed, according to accepted criteria, to find data on which to base post determination of nursing staff. This study was done at a private research hospital in Johannesburg where all the patients and nursing staff (first- as well as second in-charge) were involved. The PALP-instrument was designed by the researcher, and under supervision of the researcher it was implemented in seven nursing units in the hospital. (The instrument proved to be highly reliable p = 0.999). The difference between nursing post determination as recommended and determined by PALP, and nursing post determination as determined by means of a pragmatic subjective approach by the nursing service manager of the hospital, proved to be statistically insignificant. The PALP instrument showed, however, that more nursing staff were needed in four of the seven units. The quality of the nursing care was not investigated nor was a productivity study carried out. The total difference between the recommended and actual nursing hours needed for all the nursing units shows a statistically significant difference (p = 0.0001) on a 1% significance level. The instrument proved to be easily comprehended, easily implemented and relevant to its purpose. It also shows a high inter-rator reliability (a chronbach alpha value of 0.999). Thus a reliable PALP-instrument was developed and successfully implemented at a research hospital for the determination of nursing posts. The most significant recommendations include national standardization of the PALP-instrument in hospitals and refining and testing of the PALP-instrument in other clinical areas e.g. out-patients and critical care units. This instrument could also contribute towards a more cost effective post determination in nursing. PMID- 8697536 TI - Developing nurses' moral reasoning skills. AB - Analysis of data from a Nursing Dilemma Test administered to 69 registered nurses employed at the Groote Schuur Hospital in Cape Town revealed a pattern of principled thinking in the groups with 5 to 9, 20 to 24, 25 to 29 and 30 to 34 years of clinical experience, whereas the group with the least clinical experience (0 to 4 years) showed no distinguishable pattern of thinking stages in moral judgement development. PMID- 8697537 TI - [Post-registration nursing students' perceptions on the subject of nursing ethics]. AB - The registered nurse's pursuit of professionalism is of prime importance in the execution of her task. This research attempts to assess the perceptions concerning the subject Ethos of Nursing held by post-registration nursing students--after they had written the examination on the subject. The purpose was to determine the extent of the student's pursuit of professionalism, as her perception of Ethos is synonymous with her attitude towards professionalism. During the student's basic education in Nursing Science she was taught the fundamental principles of Ethos. This research revealed that this basic teaching failed to meet the requirements of the nurse subsequent to registration. It appeared that the students' perceptions changed from negative to positive during their studies at Unisa. This finding supported the assumption that the subject Ethos, and its impact on the nurse practitioner's pursuit of professionalism, might only reach its full potential at the post-basic level. PMID- 8697538 TI - The experiences of parents where pregnancy ended in an unplanned caesarean section. AB - The purpose of this study was to determine the experiences of parents prior to, during and following an unplanned caesarean section. Parents who experienced this event had mixed emotions. The related occurrences may have influenced their behavior and consequently their relationships with their spouses, themselves and their environment. These continually interacted with each other and thus needed to be looked at in context. "The Nursing of the Whole Person Theory" ensured a holistic approach to the parents. Unstructured, in-depth interviews held with five mothers and five fathers, respectively, on day three post-delivery, were transcribed and analysed. At six weeks a follow-up semi-structured questionnaire was answered by these same respondents and analysed. The experiences of the parents were then compared. A literature survey was undertaken in order to determine the conclusion of other researchers in this field, the results of which were compared with those of the present study and conclusions were reached. Recommendations concerning nursing practice, education and further study were made at the end of the study. A list of limitations affecting the study is included. PMID- 8697539 TI - [A study on the personal experience and competence of student nurse midwives in the performance of episiotomy repairs]. AB - A non-experimental, descriptive study was conducted to determine the knowledge and efficiency of student midwives in the performing of episiotomy repairs. A questionnaire was administered to 50 students from the two universities and affiliated colleges in the Western Cape. Sixty percent (N = 30) of the respondents regarded themselves as efficient. However, only one of these respondents had all the necessary knowledge concerning perineal repairs with 15 (50%) of these respondents' knowledge that could be considered as insufficient. Fifty-four percent of the respondents (N = 27) considered it necessary to repair more than 3 episiotomies in order to feel confident. PMID- 8697540 TI - Putting Leininger's nursing theory "culture care diversity and universality" into operation in the curriculum--Part 1. AB - The culturally diverse South African society necessitates inclusion of transcultural nursing in the curriculum. This article focuses on research regarding the putting of Leininger's nursing theory into operation in the curriculum to provide a scientific base for the inclusion of such nursing. The research process and results are discussed. PMID- 8697541 TI - Including transcultural nursing content in the curriculum--Part 2. AB - Transcultural nursing should be included in the curricula of the basic nursing courses. In this article, the transcultural nursing curriculum content that could be included, is discussed. To ensure a comprehensive approach to this field, a basic course in socio-cultural anthropology should be followed by transcultural nursing study units at strategic points in the curriculum. PMID- 8697542 TI - [A study of the use of simulation in clinical instruction at the Ann Latsky Nursing College]. AB - Simulation gives the student the opportunity for creativity while experimenting under simulated circumstances. Simulation provides an area where complex objectives can be achieved and potentially dangerous procedures can be practised in a risk-free area. Students can also repeat aspects of a complicated procedure until they reach the required competency level and gain the necessary self confidence of function in the work situation. Where learning experiences are lacking in the practical area, simulation could be used. An effective simulation facility should present the practical situation of the ward. PMID- 8697543 TI - Companionship in labour: do the personality characteristics of labour supporters influence their effectiveness. AB - Recent research has revealed beneficial post-partum, psychosocial effects on the mother following labour which was accompanied by supportive companions. Whether these effects are obtained as a result of having companionship during labour or because of specific personality characteristics of the companions provided is important and is explored in this paper. Although findings revealed few differences in adjustment between women who were supported by different companions, some variability in the postpartum state anxiety and depression scores were noted which suggest that selection of an appropriate supporter is an important aspect of such programmes. PMID- 8697544 TI - Anaesthetic care and audit: 150 years on. PMID- 8697545 TI - Optimal labour analgesia 1996. PMID- 8697546 TI - Planned and unplanned postoperative admissions to critical care for mechanical ventilation. AB - PURPOSE: To determine which factors influence the clinician in choosing critical care admission and postoperative ventilation, we prospectively examined the incidence, timing, causes, and risk factors for admission to critical care for postoperative ventilation within 48 hr of a surgical procedure (excluding cardiac and neurosurgical). METHODS: Patients were categorized as: admission planned preoperatively; admission unplanned and identified in the OR (Operating Room) or PACU (Post Anaesthetic Care Unit); and admission unplanned, identified after PACU discharge. Rates of admission by category for those with specific preoperative and intraoperative characteristics were compared to those without the characteristics to determine risk factors for admission (P < 0.01). RESULTS: Only 329 of 15,059 cases (2.2%) had a critical care admission. Of these, 288 were planned, 31 identified in the OR or PACU, and 10 after PACU discharge. A respiratory aetiology was the reason for admission in 75% of unplanned cases. Preoperatively, age > or = 60 yr and common systemic illnesses (cardiac, renal, pulmonary) were markers for planned admission, but only positive HIV status was a risk factor for unplanned admission. The two main physiological features which identified all critical care admissions were haemoglobin oxygen saturation < 90% (preoperatively breathing room air and intraoperatively) and tachycardia during the operative period. Six of ten of the unplanned after PACU discharge patients underwent bronchoscopy with a neurolept analgesic technique. CONCLUSION: Postoperative admissions to a critical care unit, both planned and unplanned, are uncommon. This study has identified haemoglobin oxygen desaturation during the perioperative period and intraoperative tachycardia as important markers for all admissions to critical care. PMID- 8697547 TI - Epidural analgesia for labour and delivery: fentanyl or sufentanil? AB - PURPOSE: The highly lipid soluble opioids, fentanyl and sufentanil, are used in combination with local anaesthetics with/without epinephrine to provide epidural analgesia during labour and delivery. Our aim was to determine whether wither opioid was superior when used with low dose local anaesthetic. METHODS: In a double-blind study patients were randomized to two epidural infusion groups: Group I (n = 50) fentanyl 2 micrograms.ml-1 with bupivacaine 0.015% and epinephrine 2 micrograms.ml-1, Group II(n = 50) sufentanil 1 microgram.ml-1 with bupivacaine 0.015% and epinephrine 2 micrograms.ml-1. Following a 20 ml bolus of the study solution an infusion was started at 10 ml.h-1. To achieve analgesia patients could receive two boluses of 5 ml of the study solution and if analgesia was still inadequate, a further 5 ml bupivacaine 0.25% was used. Pain and overall satisfaction were assessed with a 10-point visual scale. Plasma samples obtained from the mother at the time the infusion was discontinued and from the umbilical cord vein at delivery were assayed to determine opioid concentration. RESULTS: Pain scores were greater for Group I than for Group II patients throughout the first and second stages of labour (P = 0.002). More patients in Group I (42%) requested a dose of bupivacaine 0.25% than in Group II (6%) (P < 0.001) and the total dose of bupivacaine given to Group I patients was greater than that of Group II, 26.0 +/- 22.0 mg vs. 13.4 +/- 12.6 mg, P = 0.005. There were no differences with respect to first or second stage duration, incidence of side effects, infusion duration, outcome of labour or neonatal Apgar scores. There was no opioid accumulation in either maternal or foetal blood. CONCLUSION: Epidural opioid infusion with very low dose bupivacaine (0.015%) achieved an overall high level of patient satisfaction in both groups without serious maternal or neonatal side effects. At the fentanyl-to-sufentanil ratio used here patients receiving sufentanil had lower pain scores and substantially fewer patients required bupivacaine rescue. PMID- 8697548 TI - Haemodynamic consequences and uterine contractions following 0.5 or 1.0 litre crystalloid infusion before obstetric epidural analgesia. AB - PURPOSE: The efficacy of infusion of 0.5 L and 1.0 L Ringer's lactate (LR) to prevent hypotension during induction of obstetric analgesia was studied. The effect of the different fluid boluses on fetal heart rate (FHR) and frequency of uterine contractions were also determined. METHODS: Ninety-two ASA 1-2 parturients were randomized to receive 0.5 L (Group 1) and 1.0 L (Group 2) LR immediately before incremental epidural injections with lidocaine to achieve T10 sensory block. Systolic blood pressure (SBP) was measured with an automated BP cuff every two minutes for 30 min after infusion of fluid bolus. Fetal heart rate monitoring and tocometry were used continuously. The number of uterine contractions were recorded 30 min before and 60 min after i.v. bolus. RESULTS: The SBP decreased in both groups, but there was no difference between groups in mean SBP or maternal heart rate. The incidence of hypotension (SBP < 90 mmHg or decrease of 20%) was 4% in both groups. The FHR record of a patient in Group 1 showed a single late deceleration, and a decrease in beat-to-beat variability occurred in one patient in Group 2. A decrease in the frequency of uterine contractions of two or more contractions per 30 min was noted more frequently in Group 2 (P < 0.05). The duration of iv bolus was longer in Group 2 than Group 1 (18.8 +/- 4.3 min vs 12.3 +/- 4.5 min, P < 0.01). CONCLUSION: Administration of 1.0 L LR i.v. does not provide added protection against maternal hypotension, and is associated with delay in providing pain relief and a risk of decreasing uterine contraction frequency. PMID- 8697549 TI - Continuous infusion of rocuronium in a paediatric intensive care unit. AB - PURPOSE: To evaluate prospectively the efficacy and dose requirements of rocuronium administered by continuous infusion for neuromuscular blockade in a paediatric ICU population. METHODS: Neuromuscular function was monitored by train of-four (TOF) stimulation of the ulnar or peroneal nerve. Rocuronium was administered as a bolus dose (0.6 mg.kg-1) followed by a continuous infusion starting at 0.6 mg.kg-1.hr-1. The infusion was increased or decreased by 0.1 mg.kg-1.hr-1 to maintain one visible twitch of the TOF. All patients also received a benzodiazepine or a barbiturate infusion. RESULTS: The study population included 20 patients (12 boys, eight girls) ranging in age from two months to 16 yr and in weight from 3.6 to 64 kg. The duration of the rocuronium infusion varied from 26 to 172 hr for a total of 1492 hr in the 20 patients. The rocuronium infusion requirements for day 1 varied from 0.3 to 0.8 mg.kg-1.hr-1 (0.76 +/- 0.3 mg.kg-1.hr-1). When considering all patients and all patient days, the rocuronium infusion rate required to maintain one twitch of the TOF varied from 0.3 to 2.2 mg.kg-1.hr-1 (mean for all patient days = 0.95 +/- 0.4 mg.kg-1.hr 1). The infusion requirements were 0.5 to 0.8 mg.kg-1.hr-1 in 45 of the 64 patient days (70%) and 0.3 to 1.0 mg.kg-1.hr-1 in 58 of the 64 patient days (90%). No problems with the infusion were noted. CONCLUSIONS: Continuous infusion of rocuronium can be used to provide neuromuscular blockade in the paediatric ICU patient. Due to the variability in infusion requirements, monitoring of neuromuscular function is suggested. PMID- 8697550 TI - Early neuromuscular recovery characteristics following administration of mivacurium plus vecuronium. AB - PURPOSE: This study was designed to describe the early recovery characteristics, as well as the speed of onset of neuromuscular block, after a combination of mivacurium and vecuronium. METHODS: In this controlled, randomized study, 30 consenting ASA I-III patients were assigned to three treatment groups. The "2M2V" group received twice the dose necessary to cause 95% depression of the evoked twitch response (2 x ED95) of mivacurium (0.15 mg.kg-1) plus 2 x ED95 of vecuronium (0.1 mg.kg-1); the "2V" group received 2 x ED95 of vecuronium; and the "4V" group received 4 x ED95 of vecuronium. Evoked neuromuscular responses of the adductor pollicis were assessed with an adductor pollicis force transducer. The time until maximum block and times to 10% and 25% recovery (T10 and T25) in each group were expressed as mean +/- standard deviation and compared using ANOVA. RESULTS: Onset of block in the 2M2V group was 27% faster than in the 2V group (2.0 +/- 0.6 vs. 2.7 +/- 0.8 min respectively, P < 0.05) and was similar to the 4V group (1.95 +/- 0.3 min, P = NS). The times until 10% recovery were similar in the 2M2V and 4V groups (59.9 +/- 12 vs 68.2 +/- 25 min, P = NS) and were slower than in the 2V groups (37.2 +/- 9 min, P < 0.05). Between T10 and T25 recovery after 2M2V resembled that after 2V (6.7 +/- 3 vs 5.7 +/- 1 min, P = NS) and was faster than after 4V (10.9 +/- 7 min, P < 0.05). CONCLUSIONS: When 2 x ED95 of mivacurium is added to 2 x ED95 of an intermediate or long-acting relaxant, recovery after T10 will proceed as if one had administered the longer-acting agent alone. PMID- 8697551 TI - Recovery of post-tetanic and train-of-four responses at the first dorsal interosseous and adductor pollicis muscles in patients receiving vecuronium. AB - PURPOSE: To compare recovery of accelographical responses to post-tetanic twitch (PTT) and train-of-four (TOF) stimuli obtained at the first dorsal interosseous muscle (DI) with those at the adductor pollicis muscle (AP) after administration of vecuronium 70 micrograms.kg-1. METHODS: Sixty adult patients were randomly assigned to one of four groups: PTT-DI (n = 15), PTT-AP (n = 15), TOF-DI (n = 15), or TOF-AP (n = 15) group. In PTT-DI and PTT-AP groups, responses to PTT were measured accelographically at the DI and at the AP, respectively. In TOF-DI and TOF-AP groups, responses to TOF were measured at the DI and at the AP, respectively. RESULTS: The T1/T0 (T0 = control) was greater in the TOF-DI than in TOF-AP group throughout recovery (P < 0.05), and the T4/T1 was greater in the TOF DI than in TOF-AP group during the 30-40 min after vecuronium injection (P < 0.05). Time to the return of the first response to PTT (post-tetanic count(1), PTC1) was less in the PTT-DI than in the PTT-AP group (17.7 +/- 4.2 vs 21.7 +/- 5.6 min, mean +/- SD, P = 0.0341). The post-tetanic count PTC (number of single twitch stimuli in response to PTT) was greater in the PTT-DI than in the PTT-AP group during the 10-30 min after vecuronium (P < 0.05). Time to the return of T1 was less in the TOF-DI than in the TOF-AP group (23.1 +/- 6.0 vs 27.6 +/- 4.9 min, P = 0.0334). CONCLUSION: Recovery of responses to PTT and TOF stimuli occurred earlier at the DI than at the AP. PMID- 8697552 TI - [Effects of different doses of edrophonium antagonism of mivacurium-induced neuromuscular block in the presence of nitrous oxide, propofol, and alfentanil anesthesia]. AB - PURPOSE: The purpose of this study was to determine the dose-response relationships for edrophonium antagonism of mivacurium-induced neuromuscular block. METHOD: Seventy-five ASA physical status I or II adults were given mivacurium 0.15 mg.kg-1 followed by an infusion (7 micrograms.kg-1.min-1) during alfentanil-propofol-N2O anaesthesia. Train-of-four stimulation (TOF) was applied to the ulnar nerve every 20 sec and the response of the adductor digiti minimi was recorded (Relaxograph NMT-100, DATEX, Helsinki, Finland). Mivacurium infusion was adjusted at five minutes intervals in order to keep the height of the first twitch in TOF (T1) at 5% of its control value. At the end of surgery, the mivacurium infusion was stopped and edrophonium 0.0, 0.05, 0.1, 0.5 or 1.0 mg.kg 1 combined respectively with glycopyrrolate 0.0, 0.0005, 0.001, 0.005 or 0.01 mg.kg-1 were administered by random allocation. RESULTS: All four edrophonium doses tested were statistically different from placebo with regard to time to attain a TOF ratio (fourth twitch in TOF/T1) = 0.7 (0.05:780 +/- 179, 0.1:727 +/- 216, 0.5:547 +/- 287 and 1.0:640 +/- 236 vs 0.0 mg.kg-1:1089 +/- 323 sec P < 0.05). Does of 0.1, 0.5 and 1.0 mg.kg-1 permitted faster recovery time of T1 from 10 to 95% (T10-95) (567 +/- 236, 419 +/- 166, 555 +/- 288 vs 861 +/- 224 sec P < 0.05) and from 25 to 75% (T25-75) (253 +/- 121, 147 +/- 92, 217 +/- 175 vs 429 +/ 154 sec P < 0.05) than did placebo. However, data showed considerable variability for all neuromuscular indices, no matter the dose of edrophonium used. CONCLUSION: Edrophonium in doses of 0.1 mg.kg-1 and higher permitted faster recovery of all indices from a mivacurium-induced block during alfentanil propofol-N2O anaesthesia than did placebo. PMID- 8697553 TI - Neostigmine decreases heart rate in heart transplant patients. AB - PURPOSE: This study evaluated the effect of neostigmine on heart rate in cardiac transplant patients. METHODS: Neostigmine (2.5-50 micrograms.kg-1) was administered to ASA 1 or 2 patients with normally innervated hearts (controls), and to patients who had undergone recent (< six months before study) or remote (> six months before study) cardiac transplantation. RESULTS: Baseline heart rate was 66 +/- 3 beats.min-1 in controls (n = 10, mean +/- SEM), which was slower than that observed in recently (95 +/- 4 beats.min-1, n = 15, P < 0.001) and in remotely (88 +/- 3 beats.min-1, n = 16, P < 0.001) transplanted patients. Neostigmine produced a dose-dependent decrease in heart rate in all patients. Controls were the most sensitive to neostigmine, with a 10% decrease in heart rate produced by an estimated dose of 5.0 +/- 1.0 micrograms.kg-1. The recently transplanted group was the least sensitive, with the maximum dose producing only an 8.3 +/- 0.9% reduction. The response to neostigmine of the remotely transplanted patients was variable. The estimated dose to produce a 10% decrease in heart rate in this group was 24 +/- 6 micrograms.kg-1 which was greater than that for controls (P = 0.008). Administration of atropine (1.2 mg) reversed the neostigmine-induced bradycardia in all three groups. Reversal of the bradycardia consisted of a transient peak increase in heart rate in controls to 145 +/- 6% of baseline, a value which was greater than that observed in recent (103 +/- 1%, P < 0.001) and in remote (109 +/- 3%, P < 0.001) transplants. CONCLUSIONS: Neostigmine produces a dose-dependent bradycardia in heart transplant patients. Some remotely transplanted patients may be particularly sensitive to the bradycardic effects of neostigmine. PMID- 8697554 TI - Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain. AB - PURPOSE: Ketamine has been administered epidurally and intrathecally for operative and post-operative pain control. Animal studies showed potentiation of analgesia induced by ketamine and morphine. We hypothesized that intrathecal ketamine would potentiate the effects of intrathecal morphine in the treatment of cancer pain. METHODS: A double blind, cross over study was designed to evaluate the effect of ketamine on spinal morphine analgesia in terminal cancer pain patients. A two-phase protocol was used; phase M, intrathecal morphine alone twice daily; phase M + K, co-administration of ketamine (1.0 mg) with morphine intrathecally twice daily. The dose of morphine was titrated upwards until acceptable pain relief was achieved, defined by numeric rating scales (0-10) < or = 3, and the rescue dose of morphine was less than 5 mg after each intrathecal administration for two days. The dose of intrathecal morphine was defined as the effective dose. RESULTS: The effective dose of intrathecal morphine in phase M of 0.38 +/- 0.04 mg.day-1 was higher than that in phase M + K (0.17 +/- 0.02 mg.day 1) (P < 0.05). The average pain scales were 7.95 +/- 0.25 before intrathecal drug administration. Pain scales were decreased to 2.2 +/- 0.17 (P < 0.05) in phase M and 1.95 +/- 0.20 (P < 0.05) in phase M + K after the effective dose of morphine had been reached. No serious side effects were observed in this study. CONCLUSION: The present study demonstrates that ketamine enhances the analgesic effect of morphine, thus reducing the dose of intrathecal morphine. PMID- 8697555 TI - [Alkalinization of local anesthetics: theoretically justified but clinically useless]. AB - PURPOSE: In vitro studies have demonstrated the potential advantages of alkalinization on anaesthetic activity, by decreasing the ratio of ionized to nonionized molecules, there by permitting more rapid penetration of local anaesthetic through biological membranes, thus decreasing the onset time. The proportion of each form depends on the pKa of the agent and the ultimate pH of the solution. When NaHCO3 is mixed with local anaesthetics, CO2 is produced. Carbon dioxide has been reported to enhance local anaesthetic action by diffusion trapping of the cationic form in pH gradient combined with a direct depressant action of CO2. The purpose of this study was to examine if clinical studies confirmed the in vitro action of alkalinisation. SOURCE: The literature pertinent to alkalinization of local anaesthetics published in the major anaesthesia and pharmacology journals of North America and Europe. PRINCIPAL FINDINGS: While in vitro studies have demonstrated potential advantages for alkalinization on anaesthetic activity, clinical studies have shown that alkalinization of local anaesthetics produces inconsistent results. For bupivacaine and etidocaine, alkalinization of local anaesthetic solution can produce precipitation, thus limiting the feasibility of increasing the pH. CONCLUSIONS: On the basis of this review, routine alkalinization of local anaesthetics is not recommended. PMID- 8697556 TI - Neostigmine-induced bradycardia following recent vs remote cardiac transplantation in the same patient. AB - PURPOSE: This report describes the effects of neostigmine on heart rate in the same patient following recent and remote cardiac transplantation. CLINICAL FEATURES: Eighty-six months following the first transplant, neostigmine 5.0 micrograms.kg-1 i.v. produced a 10% reduction in heart rate which was reversed by atropine 1.2 mg. For 24 months prior to this initial study, the patient experienced angina, suggesting cardiac afferent reinnervation. Three months after the second heart transplant, a second study showed that a six-fold increase in the dose of neostigmine, 30.0 micrograms.kg-1, only produced a 3.5% reduction in heart rate which was reversed by atropine 1.2 mg. CONCLUSIONS: These observations indicate that neostigmine produces bradycardia following cardiac transplantation, and suggest that a greater response may be observed in remotely than in recently transplanted patients. PMID- 8697557 TI - Meningitis following a combined spinal-epidural technique in a labouring term parturient. AB - PURPOSE: To report a case of probable bacterial meningitis in a parturient who received a combined spinal-epidural (CSE) technique for labour analgesia. CLINICAL FEATURES: A 28-yr-old GIPO at 40 wk gestational age presented in labour and requested analgesia. A CSE technique was used to inject a mixture of fentanyl 25 micrograms and bupivacaine 2.5 mg into the subarachnoid space following which a catheter was inserted into the epidural space. Sixteen hours after delivery her body temperature increased to 38.7 degrees C and she complained of a non positional frontal headache. This was associated with chills, photophobia, and mild nuchal rigidity. Diagnostic lumbar puncture revealed cloudy cerebrospinal fluid (CSF) with increased polymorphonuclear (PMN) white cell count and increased protein and decreased glucose concentrations. Peripheral blood cytology also showed an increased leukocyte count with a shift to the left. Immediate treatment with antibiotics was instituted and the patient rapidly recovered without sequelae. CONCLUSIONS: Meningitis may occur, albeit rarely, with any neuraxial blocks including CSE techniques. Early diagnosis and appropriate antibiotic therapy are important in preventing serious neurological sequelae. PMID- 8697558 TI - Anaesthetic management of labour and delivery in the parturient with mitochondrial myopathy. AB - PURPOSE: We describe the anaesthetic management for Caesarean section in a parturient with a defect in complex III of the respiratory chain who had increased lactate concentrations at rest and with exercise. CLINICAL FEATURES: We administered effective epidural anaesthesia with lidocaine for Caesarean delivery. The serum lactate concentration was less than the preoperative value both during and after surgery. Shivering during the perioperative period was avoided by administering warm i.v. fluids, warm local anaesthetic solution and epidural meperidine. Pain relief after surgery was provided with i.v. PCA morphine augmented by local infiltration with bupivacaine to fascia and skin edges and epidural injection with meperidine. CONCLUSION: Mitochondrial myopathies are an uncommon group of disorders in which mitochondrial dysfunction leads to clinical disease of muscle and sometimes of other organs with high energy requirements. The management of labour and delivery in women with mitochondrial myopathies should be individualized according to severity of disease and formulated by consultation between attending physicians and the anaesthetist. Epidural analgesia reduces stress and work associated with labour and reduces oxygen demand during labour. However, parturients with defects of the respiratory chain with documented increased lactate concentrations at rest and with exercise are best managed with elective Caesarean delivery with regional anaesthesia to prevent life-threatening lactic acidosis during labour. The association between malignant hyperthermia and these disorders has not been proved, but it appears prudent to consider these women as MH susceptible until definitive data regarding this possible relationship are available. PMID- 8697560 TI - Cricoid pressure decreases lower oesophageal sphincter tone in anaesthetized pigs. AB - PURPOSE: Previous studies have shown a decrease of lower oesophageal sphincter (LOS) tone during stimulation of the upper oesophageal sphincter. Therefore, we hypothesized that during anaesthesia, cricoid pressure could result in a decrease in LOS pressure. METHODS: The LOS and oesophageal barrier pressures (BrP = LOSP minus gastric pressure) were obtained in 11 anaesthetized pigs with intraabdominal pressure of 15 mmHg using a manometric method (perfused catheters) before and during firm application of cricoid pressure. Reflux was assessed with concomitant recording of the lower oesophageal pH. RESULTS: Cricoid pressure decreased LOSP from 31.0 +/- 14.5 mmHg to 26.1 +/- 12.7 mmHg (P < 0.001) leading to a 35% reduction of oesophageal barrier pressure (9 +/- 10.3 mmHg vs 13.7 +/- 12.4 mmHg; P < 0.001). No episodes of reflux were recorded. CONCLUSIONS: This study shows that cricoid pressure decreases LOS tone in anaesthetized pigs. Although no gastrooesophageal reflux was recorded, this study suggests that, if cricoid pressure does not completely occlude the oesophagus, the decrease of oesophageal barrier pressure induced could favour the appearance of pulmonary aspiration. PMID- 8697559 TI - Antinociceptive effects of epidural and intravenous ketamine to somatic and visceral stimuli in rats. AB - PURPOSE: To evaluate the antinociceptive effect of epidural and intravenous ketamine on somatic and visceral stimuli and to address the emergency reaction. METHODS: Rats were randomly allocated into nine groups (n = 6); five groups with chronically implanted epidural catheters received saline or 0.5, 1, 2 and 4 mg. kg-1 ketamine epidurally, four groups received saline, or 1, 5 and 10 mg. kg-1 ketamine i.v. To assess somatic and visceral antinociceptive effects, tail flick (TF) test and colorectal distension (CD) test were carried out, respectively. Emergence reactions were graded. Maximal possible effects (% MPE) were calculated. RESULTS: Epidural ketamine increased % MPE in both tests in a dose dependent fashion for 30 min (vs saline group, P < 0.05). Epidural ketamine 0.5 mg. kg-1 produced an increase in % MPE in the CD test (P < 0.05) but failed in the TF test. Intravenous ketamine, 10 mg. kg-1, produced 100 +/- 0 (mean +/- SE) % MPE in the CD test but 36 +/- 15% MPE in the TF test. Dose response curves indicated greater visceral antinociception than somatic. All rats showed emergence reactions following intravenous ketamine 10 and 5 mg. kg-1. CONCLUSION: Both epidural and intravenous ketamine produce greater antinociceptive effects to visceral than to somatic stimulation, and that epidural ketamine has a low incidence of emergence reactions. PMID- 8697561 TI - Reuse of syringes in anaesthesia practice. PMID- 8697562 TI - Postoperative pain in children. PMID- 8697563 TI - Brevibloc drug errors. PMID- 8697564 TI - Pneumothorax complicating hypertrophic cardiomyopathy. PMID- 8697565 TI - An unusual foreign body. PMID- 8697566 TI - American Association for Clinical Chemistry 48th annual meeting. Chicago, Illinois, July 28-August 1, 1996. Abstracts. PMID- 8697567 TI - Improving immunoassay performance and convenience. PMID- 8697568 TI - High sensitivity of the single-strand conformation polymorphism method for detecting sequence variations in the low-density lipoprotein receptor gene validated by DNA sequencing. AB - We designed oligonucleotide primer pairs to amplify the promoter region, the translated exon sequences, and the flanking intron sequences of all 18 exons of the LDL receptor gene to compare the ability of the PCR single-strand conformation polymorphism (PCR-SSCP) method with semiautomated solid-phase genomic DNA sequencing to detect sequence variations. In 20 apparently unrelated Danish patients with a clinical diagnosis of heterozygous familial hypercholesterolemia (FH), we identified 13 different mutations in the LDL receptor gene: two silent (C331C, N494 N); five missense (W66G, E119K, T383P, W556S, T7051); one nonsense (W23X); three splice-site (313 + 1G-->A, 1061-8T-->C, 1846-1G-->A); and two frameshift (335del10, 1650delG) mutations. Four of these mutations, N494 N, T383P, 1061-8T-->C, and W556S, have not been reported earlier. The pathogenicity of the T383P, 1061-8T-->C, and W556S mutations remains to be established by in vitro mutagenesis and transfection studies. One patient had three mutations (335del10, 1061-8T-->C, and T705I) on the same allele. Further, nine well-known polymorphisms were detectable with this methodological setup. Direct DNA sequencing of the PCR products used for the SSCP analysis did not reveal any sequence variations not detected by the PCR-SSCP method. In two patients we did not detect any mutation by either method. We conclude that the PCR-SSCP analysis, performed as described here, is as sensitive and efficient as DNA sequencing in the ability to identify the sequence variations in the LDL receptor gene of the patients with heterozygous FH of this study. PMID- 8697569 TI - Noncompetitive ELISA for human serum insulin-like growth factor-I. AB - Measurement of serum insulin-like growth factor I (IGF-I) is important in assessing the growth hormone/IGF axis. Competitive immunoassay methods for IGF-I are complicated by substantial interference from IGF-binding proteins (IGFBPs) due to the relatively low ratio of specific antibody to IGFBPs in the sample, even after standard acid-ethanol sample extraction. We report of development of a noncompetitive ELISA for human IGF-I that avoids this problem by utilizing excess amounts of capture and detection antibodies. Serum samples were prepared by using an abbreviated acid-ethanol extraction method. Neutralized supernatant was added to microwells coated with IGF-I capture antibody; horseradish peroxidase-labeled detection antibody was then added, incubated for 2 h, and then developed. Compared with the "gold standard" method of acid-column chromatography, the simplified acid-ethanol extraction yields a mean +/- SD recovery of 103% +/- 5.5% despite the presence of residual IGFBPs in the extracted sample. Comparisons with a centrifugal filtration sample extraction method are also shown. The ELISA is specific for IGF-I with an absolute sensitivity of 0.03 microgram/L and inter- and intraassay CVs of 3.9-8.8% and 2.6-6.7%, respectively. The availability of a rapid IGF-I ELISA combined with a simple and reliable sample preparation procedure should facilitate clinical and research studies of this important growth factor. PMID- 8697570 TI - Direct determination of plasma endothelin-I by chemiluminescence enzyme immunoassay. AB - A highly sensitive sandwich-type chemiluminescence enzyme immunoassay for plasma endothelin-I (ET-1), involving no extraction steps, has been developed. Two populations of polyclonal antibodies were used in the present study: One is specific to the C-terminus of the endothelin family of peptides; the other, a Fab' fragment against the N-terminal core region of ET-1, is coupled with horseradish peroxidase (HRP). Labeled HRP activity was measured by using an enhanced chemiluminescence reaction of luminol/hydrogen peroxide. The assay was sensitive enough to detect 0.5 ng/L (0.05 pg/well) of plasma ET-1 and had no significant cross-reactivities with other related peptides, including endothelin 3 and the endothelin precursor peptide, big ET-1. Reliability of the assay was confirmed by comparison with an extraction-based procedure and a commercial kit. PMID- 8697571 TI - Development of a two-site solid-phase immunochemiluminescent assay for measurement of dimeric inhibin-A in human serum and other biological fluids. AB - Inhibin is a heterodimeric glycoprotein that inhibits the secretion of follitropin from the pituitary and has been isolated in two distinct forms composed of a common alpha subunit and either a beta A or beta B subunit. Utilizing paired monoclonal antibodies specific to the alpha and beta A subunit, we have developed an immunochemiluminescent assay for dimeric inhibin-A. The assay is capable of quantifying free and bound inhibin-A in human serum and follicular fluid. The limit of detection is 10 ng/L. Related proteins exhibit little cross-reactivity or interference. Recovery is excellent. Whereas samples from men and postmenopausal women are near the detection limit of the assay, inhibin-A is higher in the luteal than the follicular phase of normally cycling women, 20-fold higher during in vitro fertilization treatment, and approximately 200-fold greater in pregnancy. The assay measures inhibin-A in follicular fluid from a variety of other species. PMID- 8697572 TI - Monoclonal antibody assay for free urinary pyridinium cross-links. AB - The pyridinium cross-links of collagen, pyridinoline (Pyd) and deoxypyridinoline (Dpd), provide structural integrity and rigidity to collagen fibrils in bone. During bone degradation (resorption), the cross-links are released into the circulation and eventually excreted in urine. Pyridinium cross-link measurements in urine have been shown to be sensitive and specific indicators of resorption by both established HPLC and newer enzyme immunoassay (EIA) techniques. We have developed a monoclonal antibody that preferentially binds to the non-peptide bound free forms of Pyd & Dpd. We have incorporated the antibody conjugated to alkaline phosphatase in a competitive EIA by using Pyd-coated microtiter strip wells. After a 3-h incubation of sample and antibody-enzyme conjugate, color is developed for 1 h with p-nitrophenyl phosphate as the substrate. The intraassay (n = 52) CVs were 3.0-7.6%, and interassay (n = 8) CVs were 6.1-7.4%. Comparisons of the assay (y) with HPLC (x) and a polyclonal antibody-based EIA (x') gave regression equations of y = 0.46x + 4, r = 0.96, and y = 0.56x' + 8, r = 0.96. The EIA detected increased Pyd & Dpd concentrations in urine from postmenopausal women and patients with osteoporosis, hyperthyroidism, hyperparathyroidism, and Paget disease of bone. EIA concentrations also reflected the reduction in Pyd&Dpd excretion resulting from estrogen replacement in surgically menopausal women. Measurement of pyridinium cross-links with this simple EIA appears to provide an accurate index of the rate of resorption and may be useful for metabolic bone disease assessment and monitoring the effects of antiresorptive therapy. PMID- 8697573 TI - Effects of androgen suppression by gonadotropin-releasing hormone agonist and flutamide on lipid metabolism in men with prostate cancer: focus on lipoprotein(a). AB - No clear relation between lipoprotein(a) [Lp(a)] and endogenous gonadal hormones has been demonstrated. In this study, we compared the effects on Lp(a) of pharmacological castration in 50 patients with prostate cancer who were undergoing therapy with a gonadotropin-releasing hormone agonist (goserelin), with effects on 58 age-matched controls. We also studied 16 untreated patients under baseline conditions and after 3 months of therapy with goserelin alone or combined with an antiandrogen (flutamide). Neither cross-sectional nor prospective studies showed any significant effects of therapy on Lp(a). However, cluster analysis identified a subgroup of patients showing slight but significant increases in Lp(a) concentrations, as well as greater declines of testosterone and estradiol, suggesting that androgen, like estrogen, can exert some slight, though not easily detectable, influence on Lp(a). PMID- 8697574 TI - Analytical performance and clinical utility of a direct LDL-cholesterol assay in a hyperlipidemic pediatric population. AB - This study compares a new latex immunoseparation method for the direct determination of plasma low-density lipoprotein cholesterol (LDL-C) with the reference procedure for LDL-C (beta-quantification) in a pediatric hyperlipidemic population. The direct LDL-C assay has a mean bias of -98 mg/L in a fasting group (n = 96) of patients (mean triglycerides 1057 +/- 720 mg/L) and a bias of +177 mg/L in a nonfasting group (n = 42, mean triglycerides 4854 +/- 5457 mg/L). The mean total analytical error calculated from our data is 13.8%. The direct LDL-C assay and the commonly used Friedewald calculation respectively classified 81% and 84% of fasting patients correctly, according to the cutoffs of 1100 and 1300 mg/L for LDL-C set by the National Cholesterol Education Program for pediatric patients. Of combined fasting and nonfasting patients, 80% were correctly classified by the direct LDL-C assay. Therefore, despite several analytical shortcomings, the direct LDL-C assay may be useful in managing hyperlipidemic children without the need for a fasting specimen. PMID- 8697575 TI - Distribution of blood viscosity values and biochemical correlates in healthy adults. AB - Increases in the viscosity of blood and plasma predict clinical manifestations of atherothrombotic vascular disease. The clinical utility of viscosity measurements in cardiovascular risk factor analysis requires reference values established from a healthy disease-free population. A cohort of 126 (71 men, 55 women) healthy nonsmoking adults had fasting blood analysis after a 12-14-h fast. Viscosity measurements were made on samples of whole blood, plasma, and serum at 37 degrees C with a coaxial cylinder microviscometer. The mean blood viscosity at shear rates of 100, 50, and 1 s-1 were 3.26 +/- 0.43, 4.37 +/- 0.60, and 5.46 +/- 0.84 mPa.s, respectively. Men had significantly higher blood viscosity values than women at each shear rate. The differences in blood viscosity did not remain significant after blood viscosity values were normalized to a hematocrit of 45%, except at 100 s-1. For the entire group, normalized blood viscosity values at each measured rate correlated inversely with HDL cholesterol and positively with fibrinogen. The mean plasma viscosity was 1.39 +/- 0.08 mPa.s and the mean serum viscosity was 1.27 +/- 0.06 mPa.s. Plasma viscosity correlated with fibrinogen (r = 0.51, P < 0.0001), total serum protein (r = 0.33, P < 0.0001), and triglyceride concentrations (r = 0.33, P < 0.0015). Serum viscosity correlated with total serum protein (r = 0.50, P < 0.0001) and LDL cholesterol (r = 0.24, P = 0.0065). This study provides reference values for the viscosity of blood, plasma, and serum that may assist in evaluating hemorheological profiles. PMID- 8697576 TI - One-step all-in-one dry reagent immunoassays with fluorescent europium chelate label and time-resolved fluorometry. AB - The availability of an intrinsically fluorescent, inert, and stable Eu chelate label made it feasible to design one-step all-in-one immunoassays with time resolved fluorometry for detection. Both competitive and noncompetitive immunoassays are performed in microtitration wells containing all assay-specific components in a stable dry form. Only the sample and one assay buffer common for all analytes need to be added. Model assays for human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), and progesterone all reached equilibrium in 15 min or less without compromising the performance characteristics of the measurements, all of which perform at least equivalent to state-of-the-art assays. The detection limits for hCG, AFP, and progesterone were 0.3 IU/L, 0.1 microgram/L, and 0.5 nmol/L, respectively. The assay ranges for hCG and AFP were linear to 5000 IU/L and 1200 micrograms/L, respectively. The immunoassay format can be readily implemented in a fully automated random-access immunoassay system with optimal performance characteristics and no handling of analyte-specific assay components. PMID- 8697577 TI - New enzymatic assay for calcium in serum. AB - We established a simple and rapid kinetic assay for measurement of calcium in serum by using urea amidolyase (EC 3.5.1.45) from yeast species. The method is based on inhibition of the enzyme by calcium. In the assay, we eliminated endogenous ammonium ion by use of glutamate dehydrogenase (GLDH; EC 1.4.1.4); then in the presence of urea amidolyase, urea, ATP, bicarbonate, magnesium, and potassium ions, ammonium ion production was inversely proportional to calcium ion concentration in serum. The concentration of ammonium ion formed was determined by adding GLDH to produce NADP+ in the presence of 2-oxoglutarate and NADPH; we then monitored the change of absorbance at 340 nm. The within-run CVs of this method were 1.7-3.2% (n = 10) at 1.53-3.08 mmol/L, respectively. Day-to-day (total) CVs were 2.8-4.1%. Analytical recovery was 92-112%. The presence of other ions, ascorbic acid, reduced glutathione, bilirubin, hemoglobin, citrate, lipemic material, or human serum albumin did not affect this assay system. The correlation between values obtained with our method (y) and o-cresolphthalein complexone method (CPC) (x) was: y = 1.001x + 0.077 mmol/L (r = 0.949, Sy[symbol: see text]x = 0.079, n = 100); with the other enzymatic method (x) it was: y = 0.952x + 0.021 mmol/L (r = 0.955, Sy[symbol: see text]x = 0.074, n = 100). The SEs for each method were: 0.025 mmol/L, our method; 0.023 mmol/L, CPC method; and 0.025 mmol/L, the other enzymatic method. PMID- 8697578 TI - Rapid method for visual identification of specific DNA sequences based on DNA tagged liposomes. AB - We describe a rapid method for visually determining specific DNA sequences at femtomole concentrations. Liposomes, encapsulating a red dye and labeled with oligonucleotide, were used in a capillary migration-sandwich hybridization assay. Capture probe was immobilized on nitrocellulose strips, and liposomes, migrating along each strip, formed a visually discernible band in the presence of target DNA. One femtomole of synthetic target sequence could be detected in < 10 min. Sufficiently stringent hybridization conditions can be used to allow the discrimination of a 10% mismatch sequence from perfectly complementary DNA. A 366 base PCR product was detected at 200 fmol. PMID- 8697579 TI - Automated assay of plasma bromide after a single deproteinization step. AB - This study aimed to simplify the spectrophotometric fluorescein method for measuring plasma bromide, improve its reproducibility, and automate it. After major modifications of the method, we obtained an essentially linear calibration curve for plasma concentrations of bromide between 0 and 5.0 mmol/L. The intraassay CV for measuring bromide in the supernatants of deproteinized plasma samples (initial plasma concentrations 2.5-5.0 mmol/L) was as low as 0.5-1.0% (n = 9). When all the procedures were incorporated, including deproteinization and dilution of plasma, the intraassay CV was 2% at 2.5 mmol/L (n = 5) and 1% at 5.0 mmol/L (n = 5). The interassay CV for measuring bromide in plasma supernatants (initial plasma bromide concentration > 2.5 mmol/L) was 1%. Analytical recovery of bromide added to plasma was 99.1% +/- 2.5%. The new method is simpler and more reproducible than other spectrophotometric methods. Conditions for its automation are described. PMID- 8697580 TI - Development and evaluation of a urine protein expert system. AB - Based on the quantitative determination of creatinine, total protein, albumin, alpha 1-microglobulin, IgG, alpha 2-macroglobulin, and N-acetyl-beta, D glucosaminidase in urine in combination with a test strip screening, the findings of hematuria, leukocyturia, and proteinuria can be assigned to prerenal, renal, or postrenal causes. Using this graded diagnostic strategy as a knowledge base, we developed a computerbased expert system for urine protein differentiation ("UPES") as a decision-supporting tool. The knowledge base was implemented as a combination of "if/then" rules and two-step bivariate distance classification of marker proteins. The knowledge for this form of pattern recognition was derived from the results for a set of 267 patients with clinically and histologically documented nephropathies. To determine the diagnostic value of UPES, we tested another set of data: results for 129 urine analyses from 94 patients. Using these data, the system reached 98% concordance with the clinical diagnoses for the patients and was superior to the diagnostic interpretations of four human experts. UPES has been successfully integrated into the laboratory routine process, including automated data import. PMID- 8697581 TI - Validation protocol of analytical hemostasis systems: measurement of anti-Xa activity of low-molecular-weight heparins. AB - A standard validation protocol adapted to the chromogenic assay of anti-Xa activity of low-molecular-weight heparins was used in a multicenter study to assess its suitability for comparing and evaluating analytical hemostasis systems. The protocol included: familiarization with the system (repeatability); assessment of limits of linearity, detection limits, and cross-contamination; and validation (reproducibility and accuracy of measurements of treated patients' plasmas). We calibrated the systems with the same range of lyophilized plasmas daily and evaluated repeatability and reproducibility by using a single batch of lyophilized plasmas at three anti-Xa activities. The two automated systems tested [SB 300 (Gilford) and ACL (IL)] and the two semiautomated systems [ST 888 (D. Stago) and Chromotimer (Behring)] gave similar mean values. Dispersion of results was lower with the automated systems than with the semiautomated ones, especially at low anti-Xa activities, a tendency that also was observed for reproducibility. Because each analytical system gave linear results for activities as great as 1000 IU/L, suitable sample dilution is advisable for higher anti-Xa activities. Accuracy was greater in the automated systems. We conclude that this protocol is feasible and is applicable to validation of other analytical hemostasis instruments, in particular the latest generation of fully automated instruments. PMID- 8697582 TI - Accumulation of arsenic species in serum of patients with chronic renal disease. AB - Speciation of arsenic was determined in serum of 19 non-hemodialysis (non-HD) and 18 HD patients. The respective mean values of serum creatinine in these groups were 410 +/- 250 and 914 +/- 173 mumol/L (reference range for healthy subjects: females 50-80; males 57-93 mumol/L). The mean total arsenic concentrations were 5.12 +/-5.58 and 6.47 +/- 4.28 micrograms/L, respectively (reference value: 0.958 +/-1.52 micrograms/L). Dimethylarsinic acid (DMA) and arsenobetaine (AsB) were the major As species in serum of the non-HD and HD patients, with mean values of 0.82 +/- 1.05 and 1.93 +/- 1.51 micrograms/L for DMA and 3.55 +/- 4.58 and 3.47 +/- 2.89 micrograms/L for AsB, respectively. Serum concentrations of inorganic As and monomethylarsonic acid in both groups were below the detection limits for these compounds. Measurement of As concentration before vs after 4 h of HD treatment indicated that 68% of total As in serum was removed, as was 16% of the total As in packed cells. The efficiency of DMA and AsB removal during dialysis corresponded to that of total As. PMID- 8697583 TI - Determination of dexamethasone in saliva. AB - We conducted experiments to demonstrate that the determination of dexamethasone in saliva is a valuable tool to assess dexamethasone concentrations in the body after administration of this synthetic corticosteroid. After extraction of saliva, a RIA involving highly specific commercially available antibodies was established and evaluated. This RIA was easy to conduct, reliable, and sensitive enough to measure dexamethasone until approximately 24 h after oral administration of 1 mg per 70 kg of body weight. On the morning after the administration, the mean concentration in saliva was 540 pmol/L. Over a large range (10(3)-10(6) pmol/L), plasma concentrations correlated very well with salivary concentrations; plasma contained six times more dexamethasone than saliva. PMID- 8697584 TI - Evaluation of a two-site immunoradiometric assay for measuring noncomplexed (free) prostate-specific antigen. AB - Serum prostate-specific antigen (PSA) in men is present as two different molecular forms separable by gel-filtration chromatography (GFC). We have evaluated a two-site IRMA that measures only the noncomplexed (free) form of PSA (F-PSA). Verification that the F-PSA assay measures solely F-PSA was obtained by assaying GFC-fractionated serum samples with both the F-PSA IRMA and a commercial PSA assay that measures total PSA (T-PSA: F-PSA plus alpha 1-antichymotrypsin complexed PSA). The F-PSA assay detected only the 30-kDa peak corresponding to the free form of PSA, whereas the T-PSA assay detected two peaks: complexed PSA at approximately 90 kDa and F-PSA at approximately 30 kDa. The F-PSA assay had an analytical detection limit of 0.03 microgram/L and a measuring range up to 50 micrograms/L. The intraassay CV was 1.7-10% in the concentration range of 0.2-30 micrograms/L. The interassay CV was 3.4-12.5% in the same concentration range. Dilution and recovery studies showed no significant deviation from linearity across the assay range. The assay was insensitive to interference from hemoglobin, bilirubin, and total lipids up to concentrations of 5, 0.2, and 10 g/L, respectively. No significant loss of immunological activity (analyte stability) was seen day-to-day ( < or = 5) or after repeated freeze/thaw ( < or = 5) cycles. We conclude that the F-PSA IRMA is an accurate, precise, and reliable tool for measuring F-PSA in human serum. PMID- 8697585 TI - Calpastatin autoantibodies: detection, epitope mapping, and development of a specific peptide ELISA. AB - Autoantibodies against calpastatin (CAST) were detected in a 53-year-old female patient with a history of arthritis and thrombosis. The specificity of the autoantibodies was determined by screening expression cDNA libraries, sequence analysis of positive clones, and subsequent Western blotting against recombinant antigen. Because the Western blot lacked satisfactory reproducibility, an ELISA for anti-CAST antibodies was established. The major epitope recognized by 24 Western blot-positive sera was located within the C-terminal 27 amino acids. The ELISA was therefore based on a synthetic peptide representing these amino acids. The assay was calibrated with serial dilutions of a positive reference serum. Intraassay precision is high with a CV of approximately 4% for low- and high titer samples. Interassay precision (CV) was 5.6-8.2% for sera with low and intermediate titers [10-60 arbitrary units (AU), where 1:100 dilution of the positive reference serum = 100 AU, 1:1000 dilution = 10 AU, etc.], which increases with higher titers ( > 60 AU). Among 205 healthy blood donors, the mean + 3 SD (after logarithmic transformation) was 30 AU; higher values were seen in 2.9% of 138 hospitalized patients. The newly developed ELISA will be a useful tool for further clinical studies on the association of anti-CAST antibodies to disease, because it permits rapid and reproducible analysis of patient sera. PMID- 8697586 TI - Measurement of ascorbic acid in human plasma and serum: stability, intralaboratory repeatability, and interlaboratory reproducibility. AB - We demonstrate that total ascorbic acid (TAA, the sum of ascorbic acid and dehydroascorbic acid) in properly prepared human plasma is stable at -70 degrees C for at least 6 years when preserved with dithiothreitol. TAA in human plasma or serum preserved with metaphosphoric acid degrades slowly, at the rate of no more than 1% per year. As assessed from our stability data and from data obtained from 23 laboratories over a period of > 2 years, the intralaboratory repeatability of TAA measurement is approximately 2 mumol/L, irrespective of TAA concentration. Nonchromatographic analytical methods involving dinitrophenylhydrazine and 0 phenylenediamine yield biased results relative to chromatographic methods. Within groups of laboratories that use roughly similar analytical methods, the interlaboratory measurement reproducibility CV for TAA is 15%. PMID- 8697587 TI - Differential diagnosis between hepatocellular carcinoma and cirrhosis through a discriminant function based on results for serum analytes. AB - We applied a multivariate analysis to a large series of serum biochemical tests in an attempt to identify a function that could efficiently discriminate cirrhosis from hepatocellular carcinoma (HC). We analyzed two successive temporal cohorts (1987-90; 1991-94) of HC and cirrhotic patients, all histologically classified (first cohort: 69 cirrhosis and 39 HC; second cohort: 66 cirrhosis and 38 HC). Using data from the first temporal cohort of patients, we obtained a discriminant function based on seven serum analytes: alpha-fetoprotein, the hepatic isoenzyme of alkaline phosphatase, lactate dehydrogenase isoenzyme 5, total gamma-glutamyltransferase (GGT), GGT isoforms complexed with low-density lipoprotein, aspartate aminotransferase, and copper. The same panel of analytes emerged when the second cohort was tested and also when both cohorts were tested together. In the two successive cohorts (total, 212 patients) with a prevalence of cirrhosis vs HC of approximately 2:1, the discriminant function correctly classified 93% of cases, the highest percentage of correct classification of the two diseases obtained so far by laboratory approaches. Validation with the jackknife reallocation statistical algorithm confirmed these results. In addition, of six patients with liver cirrhosis for whom we had the opportunity of following up and observing the evolution to HC, five were classified as HC at diagnosis by the multivariate discriminant analysis; i.e., discriminant analysis provided a diagnostic lead time of 6-12 months over histology. This discriminant function, based on easy-to-perform serum biochemical tests, may help solve a fundamental problem of differential diagnosis in the evolution of chronic liver diseases from cirrhosis to HC. PMID- 8697588 TI - Hair iron content: possible marker to complement monitoring therapy of iron deficiency in patients with chronic inflammatory bowel diseases? AB - Measurements of the concentration of iron in hair from 10 patients with chronic inflammatory bowel diseases and from 10 healthy controls showed that the iron concentrations were significantly (P < 0.05) lower in patients before iron intake than in controls. Three weeks after beginning iron treatment, the hair iron concentrations were found to be significantly correlated (r = 0.68; P < 0.05) to reticulocyte counts. Changes in the hair iron concentrations were accompanied by similar changes in the concentrations of the markers most commonly used to diagnose and monitor iron deficiency. The results suggest that quantification of hair iron may be useful to complement evaluations of the body iron status. PMID- 8697589 TI - Quantification of vanadium in serum by electrothermal atomic absorption spectrometry. AB - We describe an ultrasensitive and reliable method for determining vanadium in human serum by electrothermal atomic absorption spectrometry. After lyophilization, the serum is digested in acid at high pressure, and the digests are evaporated to a small volume. Vanadium in the digests is complexed with cupferron, extracted, and dried. The residue is redissolved in formic acid, where it is 15-fold more concentrated than in the original serum sample. To enhance the furnace sensitivity, we injected six 40-microL aliquots (total, 240 microL) of the concentrated extract. The median concentration of vanadium in 108 persons was 50 ng/L, in good agreement with previously reported results by neutron activation analysis. The characteristic mass obtained (the mass required to give a signal of 0.0044A. s) was 28 pg, the limit of detection 11 ng/L, the limit of quantification 17 ng/L, and the total imprecision (CV) 5.5% at 1.54 micrograms/L. In two assays of Standard Reference Material 1577a (certified vanadium content 99 +/- 8 ng/g), we obtained values of 94.1 and 97 ng/g. PMID- 8697590 TI - Adding albumin normalizes electrophoretic mobility of lipoproteins in sera with high concentrations of free fatty acids. PMID- 8697591 TI - Completely automated extraction of DNA from whole blood. PMID- 8697593 TI - A case of immunoglobulin A-lambda conjugated with lactate dehydrogenase-5 isoenzyme, causing an extremely high enzyme activity in serum. PMID- 8697592 TI - Traces of cadmium in human scalp hair measured by electrothermal atomic absorption spectrometry with the slurry sampling technique. PMID- 8697594 TI - 6 beta-hydroxycortisol interferes with immunoassay of urinary free cortisol. PMID- 8697595 TI - Characterization of a rapid immunochromatographic assay for simultaneous detection of high concentrations of myoglobin and CK-MB in whole blood. PMID- 8697596 TI - Simple gold overstaining enhances sensitivity of automated electrophoresis of unconcentrated urine. PMID- 8697597 TI - Abbreviated area-under-the-curve strategy for monitoring cyclosporine microemulsion therapy in immediate posttransplant period. PMID- 8697598 TI - Lyophilized PSA-ACT complex is stable. PMID- 8697599 TI - Monoclonal immunoglobulin interferences in measurement of serum inorganic phosphate with a new modified reagent. PMID- 8697600 TI - Variation in plasma potassium when using collection tubes containing gel separators. PMID- 8697601 TI - Discrimination among dyshemoglobins: analytical approach to a toxicological query. PMID- 8697602 TI - Detection of false lithium readings in whole-blood specimens from cadavers by flame photometry. PMID- 8697603 TI - Clinical studies of drug effects in humans. AB - Many important drug properties cannot be predicted from in vitro or animal studies but must be quantified from studies of clinically relevant endpoints in humans. Clinical study designs include the randomized controlled trial (RCT) and a variety of observational designs. In RCTs, randomization usually ensures treatment group comparability with respect to other factors, so outcome differences reflect treatment differences per se. Properly conducted RCTs thus are the strongest study design, the mainstay of mandatory premarketing studies, and essential for evaluation of therapeutic efficacy. RCT limitations include frequent use of surrogate endpoints, limited power, short-term follow-up, and cross-contamination of study groups. For ethical reasons, some questions cannot be studied with RCTs. The simplest observational design, the case series, has limited value because it lacks a denominator. Limitations of cohort and case control studies include misclassification, selection bias, and confounding. Despite their limitations, properly conducted experimental and observational clinical studies provide essential data for clinical practice. PMID- 8697604 TI - Titrating cardiovascular drugs. AB - Titrating cardiovascular drugs is important to ensure efficacy and to minimize the risk of toxicity. A serum assay is extremely useful to guide digoxin therapy. Assessment of the effect of warfarin on blood clotting should be used to adjust dose. Serum cholesterol and lipid measurements guide therapy with antilipemic agents. The antihypertensive drugs, beta blockers, calcium channel blockers, and vasodilators can be assessed by their clinical effects. There is no strict relation between serum concentration of antiarrhythmic drugs and their effects, nor is it clear that the long-term efficacy of these drugs can be assessed by surrogate end points. PMID- 8697606 TI - Concepts in use of high-dose methotrexate therapy. AB - In cancer chemotherapy, routine monitoring of drug concentrations has been practical only for methotrexate (MTX). The primary setting for pharmacokinetic monitoring of MTX is its use in high doses (HDMTX) for adjuvant therapy of osteosarcoma, for single-agent treatment of intracranial lymphomas, and in combination therapy of childhood leukemia as well as adult and pediatric non Hodgkin lymphomas. Typically, HDMTX is infused in doses of 3-15 g/m2 over a period of 6-24 h. Precautions must be taken to ensure a high urine flow and an alkaline urine pH, so as to prevent precipitation of MTX in urine. Patients with decreased renal function, advanced in age, and taking nonsteroidal anti inflammatory drugs or nephrotoxic agents are at increased risk of developing renal dysfunction during MTX infusion, thus being placed at high risk for toxicity. At the end of HDMTX infusion, and periodically thereafter for 24-48 h, drug concentrations are measured to assure that the disappearance rate of MTX from plasma is occurring at a normal rate. Also, at the end of HDMTX infusion, the patient is given leucovorin (5-formyl-tetrahydrofolic acid; LV), which replenishes intracellular stores of reduced folate and attenuates the toxicity secondary to HDMTX. In the presence of inappropriately high concentrations of MTX, routine doses of LV will be ineffective; the dose of LV required must be increased in proportion to the MTX concentration it faces in plasma. In practice, routine monitoring of plasma MTX concentrations allows early detection of abnormal clearance, as well as institution of early and effective countermeasures, including the use of increased and prolonged LV rescue. PMID- 8697605 TI - Toxic effects of immunosuppressive drugs: mechanisms and strategies for controlling them. AB - Since cyclosporine (CsA) was introduced into clinical practice in late 1983 to prevent rejection in transplant patients, there has been an almost explosive growth in the number and types of transplants and the number of transplant centers, an increase in the life expectancy of the transplanted organ, and substantial decreases in rates of acute rejection and life-threatening infections. Despite these successes, major improvements in immunosuppressive therapy are needed, especially a reduction in toxic side effects and a rigorous definition of the relation between drug concentration and clinical effects. Such improvements may be achievable with the incorporation of new drugs such as tacrolimus and mycophenolate mofetil into immunosuppression protocols and the development of rigorously defined therapeutic drug-monitoring programs. PMID- 8697608 TI - Role of the clinical toxicologist in court. AB - The clinical toxicologist may play a role in court when issues arise concerning therapeutic drug monitoring, drug abuse, environmental chemicals, or toxic torts, where the traditional forensic toxicologist may not have expertise. Beyond being credible in court, the toxicologist's testimony must be based on good scientific evidence. The ruler for measuring good scientific evidence had previously been the Frye Test, or the general acceptance test. In 1993, however, the US Supreme Court established four balancing tests that should be used for the admissibility of scientific evidence. Although the ruling is binding only in federal courts, state courts are expected to follow. When testifying, the clinical toxicologist should be aware of other court rules and expectations. As with all testimony, objections from opposing counsel can be raised to disallow the presentation of evidence by a toxicologist. The toxicologist is usually used to establish causation of injury, whether from negligence, prenatal injury, or environmental chemicals. Several examples are presented. PMID- 8697607 TI - Epidemiology of illicit and abused drugs in the general population, emergency department drug-related episodes, and arrestees. AB - National trends in substance abuse are presented: the civilian noninstitutionalized general population; drug-related emergency department episodes; and booked arrestees. Major metropolitan differences are also noted. This study was based on the primary national data systems for these groups: The Substance Abuse and Mental Health Services Administration (SAMHSA) National Household Survey on Drug Abuse, SAMHSA's Drug Abuse Warning Network (DAWN), and the National Institute of Justice Drug Use Forecasting (DUF) system. While the most prevalent drug differed in the three data sources, all three showed recent increases in marijuana. Despite the general decline in drug use seen in the general population, both the number of drug-related cases in the DAWN system and the drug use detected in the DUF arrestees showed recent increases. PMID- 8697609 TI - Health consequences of short- and long-term postmenopausal hormone therapy. AB - Some women take an estrogen preparation for as long as several years to ease symptoms of the menopause. Such women appear to have little or no alteration in their risk of endometrial cancer, especially if they are also taking a progestogen, and no alteration in their risk of breast cancer. Similarly, the incidence of fractures is unaffected by relatively short-term hormone use. The risk of ischemic heart disease also is reduced among women who currently take estrogens (with or without a progestogen), but the influence of duration of use on this association is uncertain. Postmenopausal women who take estrogens for an extended period of time (e.g., a decade or more) incur a sharply increased risk of cancer of the endometrium. This is largely abated by use of a progestogen for at least 10 days per month. Such long-term estrogen use, whether accompanied by a progestogen or not, may increase the risk of breast cancer slightly, but this is an area of great controversy, at present unresolved. The incidence of both myocardial infarction and fracture is substantially reduced in long-term users of menopausal hormones. PMID- 8697610 TI - Evaluating the impact of exposure to environmental contaminants on human health. AB - Humans are exposed daily to low concentrations of many different chemical substances, natural and some man-made. Although many of these substances can be toxic at high levels, typical exposures are far below the effect levels. The responses produced by man-made aromatic hydrocarbon receptor agonists, such as dioxins, polychlorinated dibenzofurans, coplanar polychlorinated biphenyls, and polycyclic aromatic hydrocarbons, are also produced, often to greater extents [corrected], by naturally occurring constituents of fried meat, cabbage, broccoli, cauliflower, cocoa, and curry. Our society seems to be concerned about the health risks associated only with the synthetic chemicals, regardless of their proportional contribution to the total agonist activity, and regulates on the basis of such concerns. It would be more protective of the public health to determine acceptable concentrations for each type of response, regardless of the origin of the inducing agent, and issue advisories or regulations accordingly. PMID- 8697611 TI - Clinical evaluation of the poisoned patient and toxic syndromes. AB - Poisonings and toxic exposures are prominent causes of morbidity and mortality in patients that present to the emergency department. The American Association of Poison Control Centers, in its 1994 annual report, cites a 10% increase in the number of reported cases of poison exposure. The clinical evaluation and management of such patients remain challenging. Few specific antidotes are available for the many potential poisonings that occur annually. Rapid stabilization, resuscitation, and recognition of major toxic syndromes, along with appropriate utilization of laboratory testing, guide the clinician in the treatment of such patients. PMID- 8697612 TI - Pediatric poisonings. AB - In a general exposition of clinical and laboratory issues in the emergency management of poisoning in the pediatric patient I briefly discuss the epidemiology of poisonings in the child population, the categories of poisons to which children are exposed most frequently, and clinical and laboratory considerations, focusing on the importance of understanding the pharmacological properties of the compound involved. I review diagnostic and therapeutic decision making in light of the characteristics of the known or suspected chemical involved. Finally, the information presented is integrated in a discussion of two cases of poisoned patients in a hospital emergency department. PMID- 8697613 TI - Advances in poison management. AB - This article advances the most current concepts in the management of poisoned patients including the use of ipecac, lavage, activated charcoal, whole-bowel irrigation, and specific antidotes. The benefits vs the risks of each of these procedures are reviewed. PMID- 8697614 TI - The mononuclear phagocyte-dendritic cell dichotomy: myths, facts, and a revised concept. AB - Since Aschoff's reticuloendothelial system was abandoned a few decades ago, classification and characterization of the mononuclear phagocyte and dendritic cell systems have evolved separately or even in competition with one another. New information has now become available indicating that monocytes/macrophages and dendritic cells have a common origin in the bone marrow, and may even transdifferentiate. Morphological and functional distinctions-although valid under certain conditions-have been blurred by revelation of the versatility of monocytes/macrophages and dendritic cells in response to different contextual needs in inflammation and immunity. Monocytes/macrophages and dendritic cells share a sentinel, receptor/effector, and presentation mode, and may either activate or silence specific immune reactions. In keeping with the view of monocytes/macrophages and dendritic cells as interactive sentinels, we suggest that the mono-nuclear phagocyte and dendritic cell systems be replaced by the custocyte system (custos, Lat = sentinel, guard) as a unifying concept. Within the custocyte system, we recognize type I, type II, and type III custocytes. Type I and II custocytes exhibit predominance of presentation or effector/presenter interdependency, respectively, while type III custocytes are bipolar, passing through type I- and type II-like phases during their development and in inflammatory responses. The custocyte system brings into view monocytes/macrophages and dendritic cells as dynamic players in immunity and inflammation with a high degree of derivational, phenotypic, functional, and molecular plasticity. PMID- 8697615 TI - Are polysaccharide antibody responses independent: the T cell enigma? PMID- 8697616 TI - Transforming growth factor-beta (TGF-beta) expression and interaction with proteinase 3 (PR3) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. AB - TGF-beta is a multifunctional cytokine modulating the onset and course of autoimmune diseases as shown in experimental models. The aim of this study was to investigate TGF-beta expression in ANCA-associated vasculitis (AAV), and the possible interactions of this cytokine with lysosomal enzymes identified as ANCA autoantigens (e.g. PR3). This included TGF-beta effects on the translocation of the lysosomal enzymes to the cell surface of polymorphonuclear neutrophils (PMN), and the presumed activation of non-bioactive, latent TGF-beta by these enzymes. Patients with various types of systemic vasculitis (SV) were studied, including three different types of AAV (Wegener's granulomatosis (WG), Churg-Strauss syndrome (CSS) and microscopic polyangiitis (MPA)). Regardless of the type of assay applied, the TGF-beta 1 isoform was found to be over-expressed in SV, including AAV, and to correlate with disease activity as shown for WG. Mean TGF beta 1 plasma levels in AAV patients ranged from 8.9 ng/ml (WG) to 13.3 ng/ml (CSS) (control 4.2 ng/ml; P < 0.01), while TGF-beta 2 levels were not elevated. Flow cytometry analysis showed TGF-beta 1 to be a potent translocation factor for PR3 comparable to other neutrophil-activating factors such as IL-8. PR3 membrane expression on primed PMN increased by up to 51% after incubation with TGF-beta 1. PR3 itself was revealed as a potent activator of latent TGF-beta, thus mediating bioeffects of this cytokine. These findings, together with other features of TGF beta such as induction of angiogenesis and its strong chemotactic capacity, indicate that TGF-beta might serve as a proinflammatory factor in SV, especially in AAV. PMID- 8697617 TI - IL-6 acts on endothelial cells to preferentially increase their adherence for lymphocytes. AB - Using a quantitative monolayer adhesion assay, the current report shows that treatment of human umbilical vein endothelial cells (HUVEC) with IL-6 increases their adhesiveness for blood lymphocytes, particularly CD4+ cells, but not for polymorphonuclear cells and monocytes. This effect, which was most pronounced when using low concentrations of the cytokine (0.1-1.0 U/ml) and a short incubation period (4h), was also apparent with microvascular endothelial cells and a hybrid endothelial cell line. Skin lesions from patients with mycosis fungoides contain high levels of IL-6, and blood lymphocytes from patients with this disorder also exhibited an enhanced adhesion to IL-6-treated HUVEC. The cytokine enhanced intercellular adhesion molecule-1 (ICAM-1) expression and induced the expression of vascular cell adhesion molecule-1 (VCAM-1) and E selectin on endothelial cells. Antibody blocking studies demonstrated that the vascular adhesion molecules ICAM-1, VCAM-1 and E-selectin and the leucocyte integrin LFA-1 all contributed to lymphocyte binding to endothelium activated by IL-6. It is proposed that IL-6 may be involved in the recruitment of lymphocytes into non-lymphoid tissue. PMID- 8697618 TI - Human antibody response to a pneumococcal vaccine in SCID-PBL-hu mice and simultaneously vaccinated human cell donors. AB - Severe combined immunodeficient (SCID) mice were transplanted intraperitoneally with human peripheral blood lymphocytes (PBL) from nine healthy human donors (SCID-PBL-hu mice). None of the donors had ever received pneumococcal vaccine. Ten days after transplantation, 62 out of 111 transplanted mice and six of the nine donors were vaccinated with a 23-valent pneumococcal polysaccharide vaccine. For each donor, human IgG was detected in 91.7-100% of the SCID-PBL-hu mice, whereas specific human IgG antipneumococcal antibodies were demonstrated in 16.7 100% of the vaccinated SCID-PBL-hu mice. Most of the mice transplanted with cells from the same donor showed similar antibody response patterns in terms of kinetics and antibody levels. A significant antibody response was only obtained in mice that received cells from donors with relatively high antipneumococcal antibody levels at the time of transplantation, or donors that showed a substantial increase in antibody levels after vaccination. The immune response in the SCID-PBL-hu mice did not always reflect the ability of the respective donor to produce antipneumococcal antibodies. The donor dependency of the antipneumococcal antibody response has great practical importance for the use of the SCID-PBL-hu model. Donors should not be chosen randomly. By selecting donors whose cells have been found to result in successful engraftment, functional SCID PBL-hu mice can be obtained for the study of human immune responses and function in an in vivo experimental model. PMID- 8697619 TI - Anti-neutrophil cytoplasmic antibodies (ANCA) in ulcerative colitis: anti cathepsin G and a novel antibody correlate with a refractory type. AB - We analysed the clinical significance of ANCA in patients with ulcerative colitis. On either an indirect immunofluorescence assay or an ELISA with fixed neutrophils, 71% (25/35) of the patients were positive for ANCA. However, only half of them reacted with either cathepsin G or lactoferrin. Western blot assays revealed positive bands in 40% (10/25) of the antibody-positive patients. The sizes of the bands detected were approximately 58, 47, 44, 40, and 28 kD. No significant correlation was found between the ANCA positivity and various variables, i.e. disease activity, extent of lesion, or treatment of the disease. The anti-cathepsin G and 28-kD positivity, however, significantly correlated with a refractory type of ulcerative colitis. PMID- 8697620 TI - Frequency of anti-bactericidal/permeability-increasing protein (BPI) and anti azurocidin in patients with renal disease. AB - The major subtypes of anti-neutrophil cytoplasmic antibodies (ANCA) detected by indirect immunofluorescence assay (IFA) are P-ANCA and C-ANCA. In patients with vasculitis, myeloperoxidase (MPO) is the major P-ANCA antigen and proteinase 3 (PR3) is the major C-ANCA antigen. BPI and azurocidin, which are also called 57 kD cationic antimicrobial protein (CAP 57) and 37-kD cationic antimicrobial protein (CAP 37), respectively, have been proposed as less frequent target antigens for C-ANCA and P-ANCA. In patients with renal disease, we determined the frequency of antibodies against BPI and azurocidin. By IFA on alcohol-fixed neutrophils, monoclonal and polyclonal anti-BPI antibodies produced a C-ANCA pattern, whereas rabbit anti-azurocidin antibody produced a P-ANCA pattern. By ELISA, sera from 229 P-ANCA-positive patients, 99 C-ANCA-positive patients and 48 ANCA-negative (by IFA) patients with renal biopsies were tested for reactivity with recombinant human BPI and purified human azurocidin. Of these sera, 17.5% of P-ANCA, 30.3% of C-ANCA and 20.8% of IFA-ANCA-negative sera were positive for anti-BPI; and 8.3% of P-ANCA, 3.0% of C-ANCA and 8.3% of IFA-ANCA-negative sera were positive for anti-azurocidin. There was no statistical difference in frequency of anti-BPI between pauci-immune necrotizing and crescentic glomerulonephritis (NCGN) and other glomerular disease (OGD), and there was a lower frequency of anti-azurocidin in NCGN samples than in OGD samples. By Western blot, anti-BPI-positive sera reacted with a 57-kD BPI band and anti azurocidin-positive sera with a 29-kD azurocidin band. In conclusion, there is a low frequency of anti-BPI and anti-azurocidin antibodies in ANCA-positive patient sera; however, this does not correlate with NCGN, which is a marker for ANCA associated small vessel vasculitis, and a similar positivity is found in IFA-ANCA negative patients with renal disease. Therefore, serologic detection of anti-BPI and anti-azurocidin is not diagnostically specific in patients with renal disease. PMID- 8697621 TI - Significance of anti-nuclear and anti-extracellular matrix autoantibodies for albuminuria in murine lupus nephritis; a longitudinal study on plasma and glomerular eluates in MRL/l mice. AB - The relationship between autoantibody reactivities and nephritis in systemic lupus erythematosus (SLE) is unclear. We studied MRL/l mice which developed a considerable albuminuria (either mice with short ( < 1 week) or heavy and prolonged (3 weeks) albuminuria) and compared them with non-albuminuric age matched controls, with young (12 weeks old) non-albuminuric mice and with mice which were followed for 36 weeks and did not develop albuminuria. In a longitudinal prospective study on plasma samples we correlated a variety of anti nuclear reactivities and reactivities against extracellular matrix (ECM) components, with the onset of albuminuria. We found that at the onset of albuminuria, anti-DNA was higher while anti-nucleosome and anti-H2A/H2B-DNA subnucleosome reactivities were lower compared with age-matched non-albuminuric mice. We also studied glomerular eluates of these mice in ELISA and in indirect immunofluorescence (IF). In the eluates we found with IF that anti-glomerular basement membrane (GBM)-tubular basement membrane (TBM) antibodies were already present in 12-week-old non-albuminuric mice. These eluates showed no anti-nuclear antibodies. In eluates of albuminuric mice more immunoglobulin was deposited, and anti-ECM, anti-DNA and anti-nucleosome reactivities were higher than in eluates of age-matched non-albuminuric mice. The deposition of anti-nucleosome antibodies preceded the deposition of anti-DNA antibodies since they were deposited to a greater extent in mice with a short albuminuria. We conclude that anti-GBM-TBM antibodies are the first autoantibodies that deposit in glomeruli of MRL/l mice at an early age. The onset of albuminuria is associated with additional deposition of both anti-ECM and anti-nuclear (anti-nucleosome and anti-DNA) antibodies, but the difference with non-albuminuric mice seems to be more quantitative than qualitative. PMID- 8697622 TI - Autoantibodies to thyroid hormones: the role of thyroglobulin. AB - Autoantibodies against thyroid hormones (THAA) are frequently detected in the sera of patients with thyroid disorders together with autoantibodies against thyroglobulin (TGAA). THAA are considered to be a subset of TGAA, but alternative possibilities have not been excluded. We hypothesize that if THAA arise through an immune response to iodothyronines carried by circulating thyroglobulin (hTg), THAA should be found together with autoantibodies against the peptide backbone of hTg (TPAA) close to the hormone-forming sites. We measured TPAA in 178 serum samples, obtained from healthy subjects and patients with thyroid disorders, using two hormone-forming peptides isolated from hTg. The occurrence of TPAA was much lower than that of TGAA. Autoantibodies to the hormone-rich peptide, P3, were significantly more common than autoantibodies to the hormone-poor peptide, P1 (111/178 = 62.3% for TGAA versus 21/178 = 11.8% for anti-P3 TPAA and 7/178 = 3.9% for anti-P1 TPAA). The presence of autoantibodies to thyroid hormones was investigated in 25 TPAA+ and 26 TPAA- sera. THAA were found more frequently in TPAA+ sera (10/25 = 40% for TPAA+ and 4/26 = 15.3% for TPAA-). Correlation analysis shows that the anti-P3, but not the anti-P1 binding activity, correlates positively with the THAA-binding activity (P < 0.001 for anti-T4 THAA; P < 0.01 for anti-T3 THAA). Specificity of anti-P3 TPAA indicates that a subset of the anti-P3 antibodies is directed against the thyroid hormone moiety and another subset is directed against the peptide backbone near the hormone-forming peptide, according to our hypothesis. These results indicate that the THAA response is an anti-hTg response directed, in a significant number of cases, against the hormone forming site included in the P3 peptide. This response seems to be elicited by either native hormone-rich hTg or by hTg fragments. PMID- 8697623 TI - Expression of tumour necrosis factor-alpha (TNF-alpha) mRNA and protein in pathological thyroid tissue and carcinoma cell lines. AB - There has been much controversy about the presence of TNF-alpha within thyroid tissue. We therefore conducted a study to determine if TNF-alpha mRNA is present in thyroid tissue and thyroid-derived cells. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was employed with a heterologous competitor fragment. Significantly lower levels of TNF-alpha mRNA were found in the autonomous nodules from patients with thyroid autonomy (TA; n = 4; 5.7 +/- 1.3 arbitrary units (AU) (mean +/- s.e.m.); P < 0.03) and in normal thyroid tissue (n = 2, 7.0 +/- 3.1 AU) compared with tissue from patients with Graves' disease (GD; n = 13; 27.9 +/- 10.3 AU), non-toxic multinodular goitre (NTG; n = 5; 20.9 +/- 5.8 AU) and perinodular tissue from TA patients (20.3 +/- 4.0 AU). Higher levels were detected in tissues from patients with Hashimoto's thyroiditis (HT; n = 2; 51.3 +/- 10.3 AU). Cultures of pure thyroid-derived fibroblasts (46 +/- 18 AU thyrocytes (33 +/- 8 AU), and the anaplastic thyroid carcinoma cell lines 8505 C (39 +/- 11 AU), SW 1736 (214 +/- 16 AU) and C643 (3 +/- 1 AU) showed significantly lower TNF-alpha mRNA levels than thyroid-derived lymphocytes (1650 +/- 32 AU). TNF-alpha was detected in the supernatants of unstimulated lymphocytes (22.1 +/- 1.1 pg/ml) and SW 1736 cells (3.5 +/- 0.9 pg/ml), but not in unstimulated fibroblasts and thyrocytes. Using an intracellular labelling technique in flow cytometry, the immunophenotype of stimulated TNF-alpha-positive lymphocytes was determined as predominantly CD3+CD45RO+. Our results suggest that TNF-alpha is present in the thyroid tissue of different thyroid disorders. Thyroid-derived lymphocytes are potential TNF-alpha producers and may thus locally influence thyroid function. PMID- 8697624 TI - Enhanced binding of lymphocytes from patients with multiple sclerosis to tumour necrosis factor-alpha (TNF-alpha)-treated endothelial monolayers: associations with clinical relapse and adhesion molecule expression. AB - This study investigated the adherent properties and adhesion molecule expression of blood mononuclear cells (MNC) from a total of 84 patients with multiple sclerosis (MS). The MNC from MS patients were significantly more adherent than cells from normal healthy subjects to endothelial monolayers pretreated with 0.01 U/ml TNF-alpha (103% increase; P = 0.002), 0.1 U/ml TNF-alpha (80% increase; P < 0.01) and 1.0 U/ml TNF-alpha (41% increase; P < 0.02), and to endothelium pretreated with 10 U/ml IL-1 beta (44% increase; P < 0.05) and 100 U/ml interferon-gamma (IFN-gamma) (100% increase; P < 0.05). This augmented adhesion was a property of the lymphocytes, in particular CD4+ cells, and was inversely related to the time of onset of clinical relapse. The percentage of lymphocytes bearing the adhesion molecules CD49d, CD29 and CD62L was increased in MS blood, but the level of CD29 and CD62L expression was reduced. We infer that circulating lymphocytes in MS are predisposed to cross endothelial barriers at sites where inflammation has already commenced. PMID- 8697626 TI - Experimental hypersensitivity pneumonitis: cellular requirements. AB - We previously demonstrated that Thy1.2+, CD4+, Ia-T cells are responsible for transfer of murine adoptive experimental hypersensitivity pneumonitis (adoptive EHP). To characterize the culture conditions necessary for development of these cells, we depleted cell cultures of Thy1.2+, CD4+, CD8+, or Ia+ cells using MoAbs and complement or magnetic beads, prior to culture of sensitized C3H/HeJ murine spleen cells (SC) with Micropolyspora faeni. After culture, cells were transferred to recipients which were later challenged intratracheally with M. faeni. The extent of pulmonary inflammatory changes in these animals was determined 4 days after intratracheal (i.t.) challenge with M. faeni. Cultured M. faeni-sensitized SC which had been treated before culture with media, complement only, anti-CD8 plus complement or magnetic beads alone could transfer EHP to naive animals. SC treated with anti-Thy1.2 or anti-CD4 plus complement could not transfer EHP. Treatment of SC with anti-Iak plus magnetic beads diminished the ability of cultured cells to transfer EHP. We conclude that the ability to produce cells able to adoptively transfer EPH is dependent on the presence of Thy1.2+, CD4+, and Ia+ cells, but not CD8+ cells, at the onset of culture. PMID- 8697625 TI - A vascular smooth muscle-specific CD4+ T cell line that induces pulmonary vasculitis in MRL-+/+ mice. AB - We established a T cell line, MV1, specific for rat vascular smooth muscle antigen from the regional lymph nodes of immunized MRL/Mp-+/+ mice. Adoptive transfer of MV1 T cells induced vasculitis lesions in the lungs of the syngeneic recipient mice pre-treated with cyclophosphamide. Flow cytometric analysis showed that MV1 was a CD4+ T cell line. The T cells proliferated in the presence of the vascular smooth muscle antigen and mitomycin C-treated syngeneic spleen cells. The cross experiments using an ovalbumin-specific T cell line demonstrated that MV1 was specific for vascular smooth muscle antigen. The antigen-specific proliferation of MV1 was CD4-dependent, which was consistent with the flow cytometric analysis. In addition, MV1 T cells, upon activation with anti-CD3 antibody or antigen-specific activation, killed A20.2J mouse B lymphoma cells. MV1 T cells also killed a CD95 (Fas)-transfected T lymphoma line, but not its parental Fas-negative cell line. These findings indicate that MV1 T cells killed target cells via a Fas ligand (FasL)/Fas pathway. The cytotoxicity of MV1 T cells may play an important role in the development of vasculitis in this model. Although the antigenic epitopes of MV1 and the lung specificity of vasculitis remain to be clarified, MV1-induced vasculitis should serve as an experimental model of human pulmonary vasculitis. PMID- 8697627 TI - Activation antigen expression on human T cells. I. Analysis by two-colour flow cytometry of umbilical cord blood, adult blood and lymphoid tissue. AB - Activation antigens (actags) were detected on T cells at low levels of intensity by carefully defining negative cells with a panel of control antibodies. The mean percentage of blood T cells from healthy volunteers that expressed actags were 22% (CD25), 54% (CD26), 38% (CD38), 12% (CD54), 6% (CD69) and 21% (HLA-DR). The variability of actag expression detected by this sensitive method was determined on healthy volunteers by repeated estimation over a year. The percentage of T cells expressing CD25 and CD26 varied no more than repeated estimation of the CD4 T cell subset, whereas other actags showed greater variability. The antigen density of these actags on T cells was determined in relation to CD4 antigen density, and for most actags ranged from 10% to 75% of the level of CD4 antigen density except for CD7 and HLA-DR, which could exceed that of CD4. Different degrees of actag expression characterized T cells from different blood and lymphoid tissues. CD26, CD38 and CD45RA were universally expressed in cord blood at higher antigen density than adult blood. This immature pattern was consistent with recent thymic emigration. CD25, CD45RO, CD54 and HLA-DR progressively increased from cord blood through adult blood to lymphoid tissues, consistent with antigen-driven activation, whereas CD26 and CD45RA decreased. CD69, a very early activation antigen, abruptly increased in lymphoid tissue, exceeding CD25 by two-to-three-fold and suggesting a pre-activation state that may not involve commitment to antigen-driven proliferation. CD7 and CD38 expression was higher in cord blood and lymphoid tissue than in adult blood, indicating both an antigen independent and -dependent up-regulation. PMID- 8697628 TI - Peptide immunization in humans: a combined CD8+/CD4+ T cell-targeted vaccine restimulates the memory CD4 T cell response but fails to induce cytotoxic T lymphocytes (CTL). AB - Immunization with short antigenic peptides represents a potential strategy to induce peptide-specific CTL in vivo. In this study, a synthetic vaccine consisting of an HIV-derived, HLA-A2.1-binding CTL epitope and a tetanus toxin derived T helper epitope was evaluated for its capacity to induce peptide specific CTL in humans. Thirteen volunteers were immunized and boosted twice with 100 micrograms of the CTL epitope plus 300 micrograms of the T helper peptide (p30). Peripheral blood mononuclear cells (PBMC) were regularly analysed for cytotoxic and proliferative responses before, between and after the immunizations, and the serum was tested for anti-peptide antibodies. No unequivocal induction of HIV peptide-specific CTL in any of the volunteers was observed. However, a wide pattern of mild and transient side reactions was observed, ranging from local redness at the injection site to generalized exanthema, myalgias, arthralgias and fever. The side-effects were related to the T helper epitope, as they were similar to the side-effects experienced after tetanus immunization, correlated to the magnitude of the p30-specific in vitro proliferative response, and occurred only if p30 was co-injected. No antibodies against the HIV-derived peptides nor against p30 were detectable in the serum after repeated immunizations. The data suggest that the CTL peptide, at the concentration used in this study, failed to induce a cytotoxic immune response in vivo, although the T helper peptide seems to be capable of restimulating the specific memory T cells. PMID- 8697629 TI - Rapid cytotoxicity of human B lymphocytes induced by VH4-34 (VH4.21) gene-encoded monoclonal antibodies. AB - We have previously described two human cold agglutinin MoAbs 216 and A6(H4C5), that are derived from the VH4-34 (VH4.21) gene that bind specifically to a cell surface ligand on human B lymphocytes. In this study, we report that binding of 216 and A6(H4C5) leads to rapid killing of target B cells. This complement independent cytotoxicity was measured by three independent assays, cell viability dye uptake on FACS, 3H-thymidine uptake, and the 3(4,5)-dimethylthiazol-2,5 diphenyl tetrazolium bromide (MTT) assay. Cytotoxicity was specific for CD20+ mononuclear cells in human spleen and peripheral blood. The MoAbs were also cytotoxic to human B cell lines Nalm-6, OCI-LY8, Arent and SUP-B8, but not to T cell lines HuT 78 and PEER. As observed by scanning electron microscopy, membrane pores were formed within 15 min of exposure to the MoAbs. Cytotoxic activity was dependent on MoAb concentration and temperature of exposure. Killing with greater at 4 degrees C than 37 degrees C. Sodium azide and EDTA did not block the cytotoxic activity. No DNA fragmentation typical of apoptosis was observed. This rapid cytotoxic activity, independent of physiologic cellular process and independent of complement, suggests a novel mechanism of all death via membrane perturbations. PMID- 8697630 TI - The catabolism of intact, reactive centre-cleaved and proteinase-complexed C1 inhibitor in the guinea pig. AB - Clearance rates in the guinea pig were determined for intact guinea pig and human C1 inhibitor, the complexes of both inhibitors with human Cls, beta factor XIIa and kallikrein, and for each inhibitor cleaved at its reactive centre with trypsin. Intact human and guinea pig C1 inhibitor were cleared from the circulation more slowly (t1/2s of 9-7 h and 12.1 h and fractional catabolic rates (FCRs) of 0.09 and 0.117) than any of their cleaved or complexed forms. The reactive centre-cleaved inhibitors were cleared with half-lives of 6.75 h for humans and 10.1 h for the guinea pig. The complexes with target proteases were catabolized much more rapidly, with half-lives ranging from 3-08 h to 4.3 h. The complexes with kallikrein were cleared more slowly than those with Cls and beta factor XIIa. Complexes prepared with the guinea pig and human inhibitors were cleared at equivalent rates. The free inactivated proteases were cleared at rates similar to the equivalent complexes, except for kallikrein, which was cleared more rapidly than its complex. The fact that the complexes with different target proteases differed in their catabolism and that protease and complex catabolism were similar suggests that protease may play a direct role in clearance. PMID- 8697631 TI - In vitro activation of antigen-presenting cells (APC) by defined composition of Quillaja saponaria Molina triterpenoids. AB - The capacity of adjuvants to stimulate cytokine production by APC is important for the initiation of the immune response. Novel adjuvant formulations based on the iscom technology have been developed using selected triterpenoid components from Quillaja saponaria Molina. Five of these new Quillaja formulations were used to prepare matrix (an antigen-free particle) and tested for their capacity to stimulate IL-1 secretion by murine peritoneal cells in vitro. The formulation denominated QH 7.0.3 was superior to the other matrix formulations, including the original spikoside matrix. The QH 7.0.3 formulation in iscoms containing influenza virus envelope antigens induced IL-1 secretion more efficiently than the antigen-free matrix, or a mixture of matrix and viral antigens, or the free Quillaja components of similar composition. Compared with adjuvants known as IL-1 inducers, QH 7.0.3 flu-iscoms were as efficient as the most prominent IL-1 inducer, i.e. lipopolysaccharide (LPS) and superior to cholera toxin (CT) and muramyl dipeptide (MDP). These results indicate that the composition per se of triterpenoids included in iscoms or matrix has a prominent influence on the level of APC activation which may result in qualitatively different immune responses in vivo. PMID- 8697632 TI - Selective CD4+ T cell deletion after specific activation in HIV-infected individuals; protection by anti-CD28 monoclonal antibodies. AB - AIDS is characterized by a progressive decline in the number of CD4+ T cells. This is preceded by an early selective defect in the proliferation of these cells to recall antigens [1-3], pokeweed mitogen (PWM) [4-6] and to superantigens (SAg) [4,7]. In contrast, the proliferative response to phytohaemagglutinin (PHA) remains intact [1,2,5]. We and others have shown that the proliferative defect in response to some stimuli was in fact due to the induction of cell death [4,7]. The activation-induced cell death mechanism that explains the proliferative defects observed in vitro might also account for the progressive in vivo deletion of CD4+ T cells. Indeed, studies performed on different models of primates have shown that induction of cell death in CD4+ T cells was detected only when T cells were isolated from animals infected with a type of retrovirus that induces an AIDS-like disease [8]. This correlation prompted us to analyse further the mechanism of HIV-induced activation cell death to determine the specificity and rate of induction of cell death. T cells from HIV-infected individuals were activated with superantigens and the V beta T cell receptor (TCR) expression analysed. Data presented here show that cell death is restricted to activated CD4+ T cells, and does not affect bystander cells. More importantly, addition of anti-CD28 MoAb specifically inhibited the induction of apoptosis, raising possibilities for therapy. PMID- 8697633 TI - Complement-dependent cytotoxic antibodies to human T lymphotropic virus type I (HTLV-I)-infected cells in the sera of HTLV-I-infected individuals. AB - To investigate whether HTLV-I induces the development of complement-dependent cytotoxic antibodies in humans, sera of asymptomatic HTLV-I carriers and of patients suffering from tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) or adult T cell leukaemia (ATL) were used in a cytotoxicity assay against a panel of target cells. This panel included uninfected cell lines (CEM, Jurkat, Molt and H9), cell lines chronically infected with HTLV-I (MT2, MT4, C9IPL and HUT102), as well as lines H36 (H9 infected with HTLV-I), H9-IIIB (H9 infected with HIVms) and H9-MN (H9 infected with HIMVMN). HTLV-I+ sera induced lysis of H36 and of lines expressing HTLV-I antigens in the presence of rabbit complement, but did not lyse cells in presence of human complement. The HTLV-I+ sera also failed to lyse the HTLV-I- lines and H9 cells, suggesting that lysis was specific for HTLV-I. H36 cell lysis was prevented by IgG depletion of the sera and by dialysis of rabbit complement against EGTA or EDTA. Rabbit complement dependent cytotoxic antibodies were present in the sera of 14/14 HTLV-I-infected individuals; the highest titres were predominantly found in the sera of the TSP/HAM patients. Such antibodies were also detected in 5/5 individuals coinfected with HIV-1 and HTLV-I, although no cytotoxic antibody could be found against HIV-infected cells. Vice versa, sera of HIV-1-infected individuals did not exert a lytic effect in the presence of complement (of human or rabbit origin) against HIV-1- or HTLV-I-infected cells. Incubation of the sera of four HTLV-I-infected patients with HTLV-I env-specific synthetic peptides demonstrated that some of the complement-dependent cytotoxic antibodies recognized epitopes located on gp46 between amino acids 190 and 209. There is no correlation of rabbit complement-dependent cytotoxic HTLV-I antibodies with the development of disease. PMID- 8697634 TI - Natural killer (NK) lymphocytosis induced by Epstein-Barr virus (EBV) reactivation in monoclonal gammopathy of undetermined significance (MGUS). AB - We investigated the relationship between NK lymphocytosis and EBV infection in MGUS. We found that two out of 10 patients showed an increase of NK cells compared with normal controls In addition, these two patients had far higher levels of CD5LOW+ NK cells (activated NK cells) than controls. EBV DNA was detected by polymerase chain reaction in peripheral blood mononuclear cells from the two patients, although the other eight patients with MGUS and all 20 normal controls had no detectable EBV DNA. Furthermore, EBV DNA was detected in sorted CD5LOW+ NK cells. These results suggest that reactivation of EBV might be related to the increase of NK cells, particularly CD5LOW+ NK cells in some patients with MGUS. PMID- 8697635 TI - Regulation of the neutralizing anti-hepatitis B surface (HBs) antibody response in vitro in HBs vaccine recipients and patients with acute or chronic hepatitis B virus (HBV) infection. AB - Antibodies directed to the HBs antigen indicate viral clearance and the development of life-long immunity in patients that recovered from HBV infection. In HBs antigen vaccine recipients anti-HBs antibodies provide protective immunity. However, little is known about the regulation of this HBs-specific antibody response. The existence of anti-HBs-secreting B cells was demonstrated using the highly sensitive ELISPOT technique compared with conventional ELISA in serum and cell culture supernatants. In the peripheral blood of patients with acute self-limited hepatitis B, HBs-specific B cells were demonstrated with a high frequency despite undetectable anti-HBs serum antibodies. HBV-immunized patients that had recovered from infection and vaccine recipients had significantly lower frequencies, whereas chronic HBV carriers and negative controls showed no anti-HBs-secreting B cells. Coculture experiments of isolated B and T cells revealed that the anti-HBs antibody response was restricted to the presence of T helper cells, but not to identical HLA class II molecules. Allogeneic T cells derived from vaccine recipients or chronic HBV carriers stimulated the HBs-specific B cell response in HBs vaccine recipients. Otherwise, isolated T helper cells could never provide sufficient help to induce the HBs specific B cell responses in chronic HBV carriers. Furthermore, peripheral blood mononuclear cells (PBMC) of six out of 10 vaccine recipients, one out of five HBV immunized patients, but of no chronic HBV carrier showed a proliferative response to different HBs antigen preparations. This study demonstrated a high frequency of circulating anti-HBs-producing B cells in the early phase of acute HBV infection, but a lower frequency of HBs-specific B cells years after resolution of HBV infection. In chronic HBV carriers. However, deficient HBs-specific T and B cell responses were observed. PMID- 8697636 TI - Differential humoral immune response against hepatitis C virus antigenic synthetic peptides in infected patients with and without mixed cryoglobulinaemia. AB - In this study we have evaluated the prevalence of antibodies against core region peptides (residues 1-28, 21-38 and 51-68), the envelope 1, the non-structural (NS) 4 and 5 proteins of hepatitis C virus (HCV) in sera from 65 chronically HCV infected patients, 47 with mixed cryoglobulinaemia (MC+) and 18 without (MC-). The major binding sites were located within the core region. Regions 1-28 and 51 68 were recognized by a similar proportion of MC+ and MC- patients, while peptide 21-38 was less frequently detected by samples from MC+ patients (65.5% versus 100%, P = 0.011). The patterns of the reactions showed a minimum of three binding sites: one, located within region 51-68, was shared by both groups; a second determinant was identified at residues 1-21 for MC+ patients and at residues 28 38 for MC- patients; a third, not exactly localized, lay between residues 1 and 38. Recognition of NS5 peptides was not significantly different between MC+ and MC- patients, but while the former mostly reacted either with peptide 1 (residues 2294-2309) (five of 15 sera) or with peptide 2 (residues 2304-2319) (nine of 15 sera), the latter group showed a more scattered reaction. Antibodies to HCV peptides prevalently belonged to IgGl subclass. However, whereas IgGl antibodies against peptide 21-38 and peptide 1 of NS5 were more frequently found in MC- rather than in MC+ patients (100% versus 63.8%, P = 0.003, and 22.2% versus 4.2%, P = 0.025, respectively), IgG3 antibodies against region 1-28 were more frequent in MC+ patients (53.19% versus 16.6%, P = 0.0078). Overall, the data suggest that a differential humoral immune response to HCV antigens occurs in patients with and without cryoglobulinaemia. PMID- 8697637 TI - Soluble adhesion molecules in sera of patients with leprosy: levels of soluble intercellular adhesion molecule-1 (sICAM-1) rapidly decrease during multi-drug therapy. AB - The clinicopathological spectrum of leprosy is associated with an altered immunological reaction. The expression of adhesion molecules on endothelial cells directs the cellular traffic to sites of local skin and nerve inflammation. Soluble forms of adhesion molecules, which are released upon cytokine activation, can be detected in the circulation and may reflect ongoing tissue inflammation. We determined the serum levels of sICAM-1, sE-selectin and sL-selectin in 74 patients with leprosy (tuberculoid form, n = 23; lepromatous form, n = 36; acute leprous reaction, n = 16) and 15 healthy age- and sex-matched control donors. Patients with lepromatous leprosy had significantly higher levels of sICAM-1 (564 +/- 174 versus 450 +/- 92 versus 334 +/- 57 ng/ml) and E-selectin (90 +/- 31 versus 74 +/- 29 versus 50 +/- 10 ng/ml) than patients with tuberculoid leprosy and normal donors (P < 0.01). No differences between groups were detected for L selectin. Patients with leprous reactions had similar high levels to lepromatous patients. Twenty lepromatous patients were re-examined after 4 weeks of therapy. A significant decrease in sICAM-1 serum levels was observed after 1 month of anti mycobacterial treatment, which was accompanied by a reduction of mycobacteria in skin biopsies (P < 0.01). Patients with leprous reactions (n = 13) also demonstrated a drop in sICAM-1 after anti-inflammatory therapy. sE-selectin and sL-selectin serum values decreased only in lepromatous patients after therapy. It can be concluded that soluble adhesion molecules like sICAM-1 and sE-selectin are promising activity markers in patients with leprosy, which may be useful for treatment monitoring. PMID- 8697638 TI - Soluble products of inflammatory reactions are not induced in children with asymptomatic Plasmodium falciparum infections. AB - A proportion of children with Plasmodium falciparum infection have a high parasitaemia without accompanying fever, indicative of different clinical thresholds of parasitaemia. Higher levels of IL-10, IL-1Ra and sIL-4R but not sIL 2R were found in children with P. falciparum malaria, compared with levels in children with asymptomatic P. falciparum infections and in healthy children. Concentrations of IL-10 and IL-1Ra were correlated with levels of parasitaemia, but the association of cytokine levels with disease was independent of the association with parasitaemia. Children may tolerate a high parasitaemia by neutralizing the parasite-derived toxins. When studying potential anti-toxic molecules we found that children with symptomatic infections had lower concentrations of a phospholipid-binding molecule, beta 2-glycoprotein I (beta 2 GPI), compared with children with asymptomatic infections or healthy children. In conclusion, cytokines were found in much higher concentrations in children with symptomatic P. falciparum malaria than in children with asymptomatic infections, whilst the former had lower concentrations of beta 2-GPI. PMID- 8697639 TI - Elevated levels of soluble CD14 in serum of patients with acute Plasmodium falciparum malaria. AB - Serum sCD14, tumour necrosis factor-alpha (TNF-alpha), IL-6, and endotoxin were analysed in 45 patients with complicated malaria, in 14 patients with Gram negative septicaemia and in 24 healthy subjects by ELISA. Malaria patients with renal failure (n = 16) had higher levels than patients without renal failure (n = 29) (8116 + 1440 micrograms/l versus 9453 + 1017 micrograms/l; P < 0.05) and both had higher levels than patients with septicaemia (6155 + 1635 micrograms/l) and normal subjects (2776 + 747 micrograms/l). A significant correlation between sCD14 and IL-6 (r = 0.756) and TNF (r = 0.822) existed. However, no relation between sCD14 and serum endotoxin or indices of clinical disease severity (parasitaemia, fever, parasite or fever clearance time) was seen. Although the role of sCD14 in malaria remains to be determined, elevated levels may participate in the inflammatory response in complicated malaria. PMID- 8697640 TI - Antibodies from patients with psoriasis recognize N-acetylglucosamine terminals in glycoproteins from Pityrosporum ovale. AB - We have previously reported the finding of circulating antibodies recognizing two proteins of 100 and 120 kD (PO100 and PO120) from Pityrosporum ovale in patients with psoriasis. These antibodies were specific, since they were not detected in normal sera nor in other diseases linked to P. ovale such as seborrhoeic dermatitis or pityriasis versicolor. The present study aimed at further characterizing the specificity of these antibodies. Enzyme-labelled lectins were used to determine the carbohydrate composition of PO120 and PO100. BSII, a lectin that recognizes terminal N-acetylglucosamine (GlcNAc), showed the same banding pattern as sera from patients. Reactivity against these proteins was inhibited after mild oxidation of the carbohydrate moieties of the extract. Treatment of the extracts with lyticase altered the immune reactivity against the PO120 band as seen in Western blot assays. PO100 was not detected after lyticase digestion. Digestion with lysozyme did not alter the immune reactivity of the PO100 and PO120 bands, although the protein pattern in SDS-PAGE was modified. To examine the relevance of anti-GlcNAc antibodies in the immune response to P. ovale in psoriasis, we performed a binding inhibition ELISA. Psoriatic sera that were positive in the ELISA against a heat-denatured extract of P. ovale were rendered negative only by pre-incubation with GlcNAc in a concentration-dependent manner. Our results are indicative that the antibody response to PO100 and PO120 in patients with psoriasis is directed towards terminal GlcNAc residues. PMID- 8697641 TI - Tyrosinase as an autoantigen in patients with vitiligo. AB - Vitiligo is considered an autoimmune disorder due to the generation and presence of autoantibodies directed against melanocyte antigens in the patients' sera. In the present study we point towards a newly defined autoantigen in vitiligo, the enzyme tyrosinase, which participates in the process of melanogenesis. Anti tyrosinase antibodies were detected in the sera of seven patients with diffuse and 11 patients with localized vitiligo. Employing solid-phase ELISA to mushroom tyrosinase, we found that patients with diffuse vitiligo had significantly higher titres of IgG anti-tyrosinase autoantibodies than patients with localized disease or healthy subjects. These anti-tyrosinase autoantibodies have relatively high functional affinity to tyrosinase and can be recovered from vitiligo patients' sera by affinity purification. The anti-tyrosinase antibodies do not cross-react with other enzymes recognized as autoantigens in different autoimmune disorders and the autoantibodies do not block the enzymatic activity of tyrosinase, indicating that they are not reacting with the catalytic site of the enzyme. These data point to tyrosinase as an autoantigen in vitiligo and suggest that anti-tyrosinase titres can serve as a marker for disease activity. PMID- 8697642 TI - Analysis of V kappa genes in rheumatoid arthritis (RA) synovial B lymphocytes provides evidence for both polyclonal activation and antigen-driven selection. AB - To define mechanisms of sustained activation of synovial B lymphocytes in RA, we studied hybridomas established from the local synovial B cell repertoire of two RA patients for V kappa gene expression and for antigen-binding specificity. The analyses revealed that members of the main V kappa families (I, II and III) were utilized at frequencies consistent with random V kappa gene family use. Furthermore, although the hybridomas expressed genes frequently seen in response to other self- and exogenous antigens, only one V kappa I- and two of three V kappa III-expressing hybridomas exhibited reactivity with self-antigens. Nucleotide sequence analysis revealed that all hybridomas, with the exception of rheumatoid factor (RF)-producing hybridomas, expressed V kappa genes highly related to known germ-line genes (99.3-100% homology) and that diversity was generated by deletions and random nucleotide insertions at the V kappa-J kappa junction. Examination of the few nucleotide changes seen with the V kappa genes revealed a predominance of silent to replacement changes. Moreover, most of these changes can be attributable either to allotypic variations or to limited random nucleotide replacements independent of antigen selection. In contrast, one IgG-RF (B4D8) exhibited predominantly replacement nucleotide changes in the complementarity-determining regions, suggestive of antigen-driven selection. The random expression of immunoglobulin variable region genes with no, or little, evidence of mutation in the synovial B lymphocyte repertoire, including natural polyreactive antibodies, alongside mutated IgG-RF, suggest that both polyclonal activation and antigen-driven responses occur in RA synovia. PMID- 8697643 TI - The relationship between exposed galactose and N-acetylglucosamine residues on IgG in rheumatoid arthritis (RA), juvenile chronic arthritis (JCA) and Sjogren's syndrome (SS). AB - The relationship between exposed galactose and N-acetylglucosamine on IgG in RA, JCA and SS was investigated. This was achieved using IgG isolated from serum where the levels of galactose and N-acetylglucosamine (GlcNAc) were detected using biotinylated lectins. Galactose and GlcNAc on IgG from patients with RA and JCA are inversely related, but in contrast, in SS, galactose expression on IgG decreased while GlcNAc expression remained similar to normal levels. Alterations in IgG glycosylation are closely associated with the development of adult and juvenile chronic arthritis and SS, but the changes involved are different in RA compared with SS, suggesting that the precise pattern of exposed sugars is associated with different rheumatological diseases. PMID- 8697644 TI - Treatment of Wegener's granulomatosis: new horizons? PMID- 8697645 TI - Parvovirus infection mimicking a systematic onset of juvenile chronic arthritis (Still's disease) PMID- 8697646 TI - Comment on the treatment of early rheumatoid arthritis. PMID- 8697647 TI - High levels of bcl-2 protein in the T lymphocytes of patients with Behcet's disease. PMID- 8697648 TI - Dual-energy X-ray absorptiometry in patients with multiple myeloma and benign gammopathies. PMID- 8697649 TI - Bilateral Baker's cyst in a patient with psoriatic arthritis of pediatric onset. PMID- 8697650 TI - Polymyalgia rheumatica with temporal arteritis following intravesical Calmette Guerin bacillus immunotherapy for bladder cancer. PMID- 8697651 TI - Hepatocellular carcinoma in mixed cryoglobulinemia patients. PMID- 8697652 TI - Positive and negative association of HLA-DR genotypes with Japanese rheumatoid arthritis. AB - OBJECTIVE: To clarify the relationship between the HLA-DR genotype and susceptibility to rheumatoid arthritis (RA) in Japanese patients. METHODS: HLA-DR typing and DRB1* genotyping were carried out by PCR and PCR-SSCP (single stranded DNA conformation polymorphism), respectively. RESULTS: In RA, the prevalence of HLA-DR4 was significantly higher (57.3%, p < 0.05). In particular, DRB1*0405 was predominantly higher (46.9%, p < 0.05) and DRB1*0401 was also increased although not significantly. HLA-DR8, especially DRB1*0802, was significantly lower (1.0%, p < 0.01). RA patients homozygous for DRB1*0405 showed slightly higher values for the erythrocyte sedimentation rate, gamma-globulin, and IgG, as well as positivity for rheumatoid factor and high titers for the Waalar-Rose test, and a decrease in the albumin/globulin ratio, albumin, and hemoglobin in comparison to patients without RA susceptibility genes, although the difference for each of these parameters was not significant. CONCLUSION: DRB1*0405 and DRB1*0802, which are both rare alleles in Caucasians, are positively and negatively correlated, respectively, with the pathogenesis of RA in Japan. PMID- 8697653 TI - Decreased levels of a soluble form of the human adhesion receptor CD58 (LFA-3) in sera and synovial fluids of patients with rheumatoid arthritis. AB - OBJECTIVE: Soluble forms of adhesion molecules (sAM) can block cellular interactions and potentially prevent the adhesion of mononuclear cells to inflammatory tissue. We therefore wondered whether levels of a soluble form of the CD2-ligand CD58 (sCD58) are decreased in patients with different types of joint disease. METHODS: SCD58 concentrations were measured by an enzyme-linked immunosorbent assay (ELISA) of sera from 60 patients with rheumatoid arthritis (RA), 13 patients with osteoarthritis (OA), 16 patients with psoriatic arthropathy (PsA), 15 patients with spondylarthropathy (SpA), and 61 age-matched normal controls (NC). SCD58 was also determined in synovial fluid samples (SF) from 42 patients with RA, 12 with PsA, and 12 with SpA. Concentrations of sCD58 were correlated with clinical and laboratory measures of disease activity. Binding of biotinylated human albumin to recombinant CD58 or casein was assessed by a modified ELISA: RESULTS: SCD58 levels were significantly reduced in sera from RA patients compared to NC (p < 0.0001), OA (p = 0.019), and SpA (p < 0.0001). Normal concentrations were found in sera from patients with OA, PsA, or SpA. SF sCD58 concentrations were generally lower than serum concentrations (between 18 and 28%). RA SF had significantly lower sCD58 levels than SpA SF (p = 0.01). Reduction of serum sCD58 levels correlated significantly with the ESR (r = 0.56; p < 0.0001), CRP (r = 0.4; p = 0.003), and TJS (r = 0.47; p = 0.0001). In addition, sCD58 serum levels correlated significantly with the reticulocyte count (r = 0.47; p = 0.02) and serum albumin (r = 0.42; p = 0.002). Accordingly, biotinylated human albumin bound to recombinant CD58 in a dose dependent fashion, but not to casein. CONCLUSION: This study indicates that serum and SF sCD58 levels in patients with RA are reduced compared to the levels in normal controls and patients with OA or SpA. Decreased albumin concentrations due to systemic inflammation may lead to reduced sCD58 levels. Since sCD58 may normally mediate de-adhesion, such a reduction could result in increased T cell adhesiveness. PMID- 8697654 TI - Quantitation and distribution of vitronectin in synovial fluid and tissue of patients with rheumatic disease. AB - OBJECTIVE: Our study was undertaken to determine the quantity and pattern of distribution of vitronectin (Vn) in the synovial fluid and tissue of patients with rheumatic disease. METHODS: We quantitated synovial fluid Vn levels in 37 patients (17 with rheumatoid arthritis (RA), 12 with crystal induced arthritis (CIA), and 8 with osteoarthritis (OA)) using a competitive-binding ELISA: Immunofluorescence studies were performed on synovial pannus tissue specimens from 3 RA patients. SDS-PAGE analysis of the synovial fluids was performed to demonstrate the molecular forms of Vn present in inflammatory and noninflammatory synovial fluids. Albumin levels of synovial fluids were determined using an automated chemistry analyzer. RESULTS: Immunoreactive Vn was detected in 36 of 37 synovial fluid specimens examined, over a wide range of dilutions. Concentrations of Vn in inflammatory synovial fluid were significantly elevated compared to non inflammatory synovial fluid and normal human plasma (NHP). Immunofluorescence studies revealed immunoreactive Vn most heavily concentrated in the lining layers of RA pannus tissue. Similar to NHP, molecular forms of Vn were heterogeneous in the synovial fluid; however, the inflammatory milieu appears to predispose Vn to cleavage at its protease-sensitive site. Overall there was a positive correlation of synovial fluid Vn to albumin. CIA and OA revealed a very strong relationship, whereas RA synovial fluid Vn levels correlated poorly to the levels of albumin. CONCLUSION: Vitronectin is present in synovial fluid. Levels are significantly enhanced in the inflamed joint and in the RA synovial lining, where it may influence cell adhesion and modulate tissue repair. PMID- 8697655 TI - Extremely active murine amyloid enhancing factor. AB - OBJECTIVE: To generate and characterize a highly active amyloid enhancing factor (AEF). METHODS: AEF was obtained from amyloidotic and pre-amyloidotic mice spleens that were homogenized in 50% acetone in H2O. The grade of AEF enhancing activity was studied in relation to the procedure used to generate the AEF, the amount of AEF administered, the duration of amyloid induction and the effect of solvent and denaturing agents. RESULTS: Both priming of the splenic source of the AEF with an amyloidogen and acetone processing were essential for the AEF activity. AEF in a single intravenous dose as low as 1 nanogram per mouse induced amyloidosis in mice within 2-6 days. Polyacrylamide gel electrophoresis of the AEF showed two protein bands of molecular weight (MW) 9-11 KD not present in normal spleen homogenates. Dialysis of the AEF showed that the active components can pass through a dialysis bag with an MW cutoff of 12 KD. CONCLUSIONS: These findings suggest that ours is the most active AEF currently available and that it has active constituents of low MW ( < or = 12 KD) which appear in the spleen during amyloidogenesis. PMID- 8697656 TI - Reinnervation of post-arthritic joints in the rat. AB - OBJECTIVE: To clarify the role of articular innervation during the acute and post arthritic phases, we investigated the changes taking place over time in the nerve fibers from joint tissues of adjuvant arthritic rats. METHODS: Nerve densities (i.e., the number of nerve fibers observed per unit area of tissue section) were estimated in periarticular tissues, synovium and epiphysis from ankle joints. Nerves were identified by immunofluorescence microscopy using antibodies against general neuronal markers (Protein Gene Product 9.5, synaptophysin, neurofilaments and Schwann cells), and markers specific for either sensory or sympathetic nerves (Substance P, calcitonin gene related peptide, neuropeptide tyrosine and its C terminal flanking peptide, and the catecholamine synthesising enzyme tyrosine hydroxilase). RESULTS: In arthritic rats, the density of nerve fibers in the periarticular tissues, epiphysis and synovium was significantly reduced when compared to control animals. This decrease was observed using antibodies for both non releasable neuronal products (Protein Gene Product 9.5, synaptophysin, neurofilaments and Schwann cells) and neuropeptides (Substance P, calcitonin gene related peptide, neuropeptide tyrosine and its C-terminal flanking peptide), thus suggesting the existence of a structural nervous lesion with the parallel depletion of peptides. As the clinical arthritis subsided, there was a progressive reinnervation of all the articular structures analysed, which often exceeded the density of nerves in the control animals. CONCLUSION: This work supports a close relationship between the nervous system and arthritis. We propose that cycles of nerve destruction and regeneration may be related to the characteristic periods of remission and activity of some forms of chronic arthritis. PMID- 8697657 TI - Association between ankylosing spondylitis and diffuse idiopathic skeletal hyperostosis: reality or fiction? PMID- 8697658 TI - Assessment of sulphasalazine as a treatment modality in Sjogren's disease in NZB/NZW F1 hybrid mice. AB - OBJECTIVE: Sulphasalazine is a recognised second-line agent in the treatment of rheumatoid arthritis. The aim of this study was to determine if it might prove useful in the treatment of Sjogren's syndrome. METHODS: The trial was performed in NZB/NZW F1 hybrid mice and efficacy was assessed on the basis of a reduction in the lymphocytic infiltration of the submandibular salivary and lacrimal glands. The animals were divided into three groups; the control group remained untreated, the second group received the drug from 14-42 weeks and the third group received sulphasalazine from 26-42 weeks. At four-weekly intervals throughout the study, five animals in each group were killed using ether and the glands assessed for lymphocytic infiltration using a modified focus scoring technique with light microscopy. RESULTS: No significant reduction in the lymphocytic infiltration occurred consistently throughout the trials with sulphasalazine. CONCLUSION: Sulphasalazine did not significantly alter the development of Sjogren's disease in NZB/NZW F1 mice. PMID- 8697659 TI - Dupuytren's disease in type 1 diabetic patients: a five-year prospective study. AB - OBJECTIVE: To clarify which are the underlying factors in the development of Dupuytren's disease (DD) in diabetic patients and to evaluate if the presence of DD can predict the development of diabetic complications. METHODS: A total of 207 type 1 diabetic patients [age (mean +/- SD): 29.9 +/- 9.5 years] was studied at baseline. A follow-up study was performed five years later in 166 patients. The presence of DD was examined and the patients were assessed in terms of the following diabetic complications: background and proliferative retinopathy, peripheral symmetrical polyneuropathy, and clinical nephropathy. RESULTS: The prevalence of DD was 4% at the baseline study. DD was significantly associated with the age of the patient and the duration of diabetes, but not with the age at the onset of diabetes, BMI or the control of diabetes. DD was associated with somatic peripheral symmetrical polyneuropathy (p < 0.01), a history of myocardial infarction (p < 0.01) and limited joint mobility (LJM) (p < 0.05), but all of these associations could be exclusively explained by the age of the diabetic patients and the duration of diabetes. DD developed in 17 new subjects (2% per year) during the five years of the study. The subjects' age and the duration of diabetes were associated with the development of DD. There was a predominance of the development of DD in women (p < 0.05), and in subjects with retinopathy (p < 0.05), nephropathy (p < 0.05), neuropathy (p < 0.05) or hypertension (p < 0.01), but these associations could also be exclusively explained by the time-related variables. The presence of DD at the baseline study did not predict the development of diabetic complications or hypertension when the confounding effects of age and the duration of diabetes were controlled by logistic regression analysis. CONCLUSION: This study shows that the patient's age and the duration of diabetes are the most important factors predicting the development of DD in diabetic patients. The associations between DD and diabetic complications were exclusively explained by the age and the duration of diabetes. The presence of DD did not predict the development of diabetic complications. PMID- 8697660 TI - TAP2D is associated with HLA-B44 and DR4 and may contribute to rheumatoid arthritis and Felty's syndrome susceptibility. AB - OBJECTIVES: TAP2 transporter gene polymorphisms have been ascertained in patients with rheumatoid arthritis (RA) and Felty's syndrome (FS) to determine whether particular alleles of this gene are disease associated. METHODS: TAP2 dimorphisms at amino acid positions 379, 565 and 665 were detected using ARMS-PCR in 89 RA patients, 24 FS patients and 64 control subjects. TAP 2 alleles were assigned from these results. RESULTS: The frequency of one particular allele, TAP2D, was increased in both RA (OR 2.6, 95% CI 1.2 - 5.8) and FS (OR 3.9, 95% CI 1.4 - 10.7). When individual amino acid polymorphisms were compared between patients and controls, isoleucine at position 379 (present in TAP2D and TAP2C) was significantly increased, indicating that this dimorphism itself may be associated with RA (OR 5.0, 95% CI 2.4 - 10.2) and FS (OR 5.0, 95% CI 1.91 - 3.2). DISCUSSION: The presence of TAP2D was greatly increased in HLA-B44/DR4 positive RA (83%) and FS (67%) patients. These frequencies were appreciably higher than in the HLA-B44/DR4 controls (11%), suggesting that linkage disequilibrium alone may not explain the increase in TAP2D frequency in patients and that this allele may represent an additional risk factor in these conditions. PMID- 8697661 TI - Parvovirus B19 infection in Behcet's disease. AB - OBJECTIVE: To investigate whether parvovirus B19 infection is associated with Behcet's disease (BD). METHODS: Serum samples from 41 patients with BD and from 40 age- and sex-matched controls were studied. An ELISA assay was used to detect antibodies against parvovirus B19. RESULTS: Six patients with BD (15.7%) had anti B19 IgM antibodies in their serum samples indicating a recent infection, while no positivity for IgM antibodies was detected in the control group (p = 0.03). CONCLUSION: Although there have been several reports of B19 infection associated with vasculitis, our findings do not strongly support the involvement of B19 in the pathogenesis of BD. The serological evidence of acute infection in 6 BD patients may be purely coincidental. There was also no positive correlation with the articular and vascular manifestations of BD. PMID- 8697662 TI - Communicating hydrocephalus in a patient with mixed cryoglobulinemia and chronic hepatitis C. AB - This report describes a case of communicating hydrocephalus (CH), associated with mixed cryoglobulinemia (MC), which complicated chronic hepatitis C. The possible role of MC vasculitis and plasma hyperviscosity in the pathogenesis of CH is also discussed. Furthermore, we suggest screening MC patients for CH and to search for cryoglobulins in CH patients whose etiology is unknown. PMID- 8697663 TI - Severe necroziting vasculitis in a patient with hepatitis C virus infection treated by interferon. AB - We report a case of polyarteritis nodosa occurring in a patient with hepatitis C, ten days after the beginning of alpha-IFN therapy. There was no cryoglobulinemia. Serum HCV-RNA was detectable before INF therapy and disappeared during the vasculites. The patient received boli of methylprednisolone and the neurological and skin lesions regressed after 5 months. This observation could suggest a precocious response to alpha-INF and a relationship between INF and the occurrence of vasculites. PMID- 8697664 TI - Rapidly progressive seronegative spondylarthropathy with atlantodental subluxation in a patient with moderately advanced HIV infection. AB - It has been suggested that the immunosuppressed state associated with HIV infection may influence the clinical course of rheumatic diseases. We describe the case of a patient with moderately advanced HIV infection who developed a psoriatic rash and a rapidly progressive spondylarthropathy of the cervical spine with atlantodental subluxation requiring spondylodesis. This case supports the hypothesis that HIV infection may be associated with uncommon manifestations and a rapidly progressive course refractory to medical therapy in patients with spondylarthropathy. PMID- 8697665 TI - Sex hormones, proto-oncogene expression and apoptosis: their effects on rheumatoid synovial tissue. AB - Programmed cell death (apoptosis), is a non-random physiological process characterized by cell fragmentation without leakage of the cellular contents into the extracellular space. Apoptosis is especially important in the immune system. On the other hand the capacity of cells to proliferate and to show local invasiveness, as in cancer cells or the "tumor-like" synoviocytes in rheumatoid arthritis (RA), seems to be controlled by a group of genes called "proto oncogenes". The early metabolic events in cell apoptosis and proliferation are remarkably similar. The primary location of apoptotic cells in RA synovial tissue is at the level of the synovial lining, varying from rare positive cells to > 50% positive cells. C-jun, c-fos and c-myc oncoproteins seem to be largely restricted to the synovial cells attached to the sites of cartilage and bone destruction. Ovarian follicle atresia could serve as a useful model to study the hormonal regulation of apoptosis in different endocrine tissues. Based on ovarian studies it seems that estrogens generally prevent apoptosis whereas androgens induce apoptosis. The binding of steroids to their receptors forms a complex wherein the receptors are transformed, so that they can then pass through the nuclear membrane and associate with specific recognition sites on DNA. In the majority of cases, the steroid receptors mediate the rapid regulation of the nuclear proto oncogene transcription. Therefore, they may serve as important "early" regulatory genes and as excellent universal markers in all tissues in steroid hormone action. Since the macrophages are considered to be target cells for sex hormones, we recently evaluated c-myc expression in cytocentrifuge preparations obtained from primary cultures of RA synovial macrophages treated with estrogens, and observed a marked upregulation. Further studies of the influence of sex hormones on synoviocyte apoptosis and proto-oncogene expression should offer new perspectives on the pathogenesis and therapy of synovitis in RA and other rheumatic diseases. PMID- 8697666 TI - Monthly intravenous pulse cyclophosphamide therapy in Wegener's granulomatosis. AB - OBJECTIVE: To study the long term effects of monthly intravenous cyclophosphamide therapy in Wegener's granulomatosis. METHODS: Fourteen consecutive patients with active Wegener's granulomatos treated with a first-line combination of high-dose prednisone and monthly intravenous pulse cyclophosphamide were retrospectively studied. RESULTS: One patient died from septicemia complicating severe leukopenia after the first pulse. At 8 months after instituting intravenous pulse cyclophosphamide therapy, failure was observed in 6 other patients. Between month 16 and 18, 2 other patients relapsed when the time between 2 pulses was lengthened. Five patients developed cyclophosphamide-related side-effects: infection (n = 2), amenorrhea (n = 1), alopecia (n = 2) and vomiting (n = 2). Except for one fatal infection, no major side-effect of intravenous cyclophosphamide therapy was observed. At the end of the study, all patients were off intravenous cyclophosphamide therapy with more than 6 months of followup. The 6 responders were in remission on low-dose prednisone or without treatment. CONCLUSION: A combination of high-dose prednisone and intravenous cyclophosphamide may achieve long-term remission in 42% of patients with Wegener's granulomatosis. Responders to intravenous cyclophosphamide therapy had less extensive disease than non-responders. PMID- 8697667 TI - Leukocyte adhesion deficiency: report of a case and review of the literature. AB - Leukocyte adhesion deficiency (LAD) is a rare inherited immunodeficiency that is characterized by deficiency of the beta 2 integrin leukocyte adhesion molecules Mac-1, LFA-1, and p150,95. We describe a case of the severe form of LAD in an infant with recurrent infections and with a complete deficiency of beta 2 integrin molecules, and review the clinical aspects of the syndrome. PMID- 8697668 TI - Incidence of anti Hsp 90 and 70 antibodies in children with SLE, juvenile dermatomyositis and juvenile chronic arthritis. AB - OBJECTIVE: To determine the incidence of anti-hsp90 and 70 antibodies in children with SLE, juvenile dermatomyositis and juvenile chronic arthritis. METHODS: We utilized a previously described ELISA to detect the presence of antibodies to mammalian hsp90 and 70 in 33 children with SLE, 55 with juvenile chronic arthritis (JCA) and 11 with dermatomyositis. Sera from 19 children with non autoimmune conditions served as controls. RESULTS: Antibodies reactive with hsp90 and/or 70 were detected in 35% of the children with SLE, and the numbers of children with SLE who have raised IgG anti-hsp90 antibodies (24%) is very similar to our adult onset cases, although the prevalence of IgM antibodies is much smaller. However, serum antibodies to hsp70 were as infrequent in children with SLE or JCA as in adults with SLE or RA, although IgG antibodies to hsp70 were detected in 50% of the synovial fluid of JCA patients. CONCLUSION: The incidence of antibodies to hsp90 in childhood-onset SLE resembles that described in adult onset disease suggesting that, despite clinical differences between the two, a subset of each may share a similar pathological mechanism of disease. PMID- 8697669 TI - Contractility of longitudinal smooth muscle after massive intestinal resection in rat. AB - To determine whether functional changes in contractility of jejunal longitudinal smooth muscle in vitro accompany the adaptive structural changes after massive intestinal resection, the investigators subjected rats either to surgical resection of 75% of the mid-jejuno-ileum or to a sham operation. The development of isometric tension in strips of jejunal tissue was measured 10, 20, 30 or 40 days after surgery. Basal stress in response to stretch was similar for both groups at all of the post-operative times. The optimal length (Lo) needed for the generation of maximal stress (130% of initial resting length) did not differ between the group that had undergone a sham operation and the group that had undergone resection. Concentration-response curves to the muscarinic agonist bethanechol had similar values for the estimated concentration at which the response is half-maximal (EC50) and maximal active stress in both groups. However, significant increases were observed in the frequency and amplitude of spontaneous and bethanechol-stimulated phasic contractions of jejunal tissues obtained from resected rats. The presence of tetrodotoxin (10(-6) mol/L) did not alter the active contractile response (tonic stress, phasic frequency and amplitude) of resected tissues. Thus, after massive intestinal resection, longitudinal smooth muscle shows no adaptive change with respect to basal or active stress but does exhibit an increase in phasic contractile activity. This altered response is non-neural; it may reflect changes in the smooth muscle itself or, alternatively, modulation of myogenic activity by prejunctional effects or by the activity of the interstitial cells of Cajal. PMID- 8697670 TI - A decade of research on the natural history of HIV infection: Part 1. Markers. AB - Within the context of HIV disease, a marker may be described as a consequence of disease that varies over time but does not necessarily predict future disease course. To date, the most powerful marker of HIV disease progression is the CD4 cell count. Other immunologic markers include neopterin, beta 2-microglobulin, and total and HIV-specific immunoglobulin levels. Further research, which focuses on cell-mediated factors such as interleukins, tumour necrosis factor, natural killer cell activity and apoptosis, is required. Measures of viral burden, such as p24 antigenemia and proviral DNA or RNA, may also offer additional prognostic information. As methods involving quantitative polymerase chain reaction become more refined, it is hoped that they may soon be applied to the clinical setting. Clinical markers of interest include the appearance of minor opportunistic infections and the occurrence of acute retroviral syndrome, which may indicate a faster disease course. Although population-based studies have identified a number of HIV disease markers, further research is required to generalize these findings to the individual level. PMID- 8697671 TI - A decade of research on the natural history of HIV infection: Part 2. Cofactors. AB - Cofactors of HIV disease may be considered risk modifiers that are causally related to future disease course. The search for potential cofactors, of viral, host or environmental origin, may provide avenues for altering the natural history of HIV infection. Potential viral cofactors include viral strains, such as syncytium-inducing and nonsyncytium-inducing variants, and strains that are resistant to specific antiretroviral therapies. Although there is strong evidence that sexually transmitted diseases that lead to genital ulcers or abrasions are important cofactors of HIV transmission, their role as cofactors in HIV disease progression is less clear. Further study of agents such as human herpesviruses 6 and 8 and hepatitis C may shed light on the role of other infectious agents in progressive HIV disease. Far less research has been conducted on behavioural, genetic and sociodemographic factors that may influence HIV disease progression rates. Since current anti-HIV therapies do not offer a cure, but only a means of prolonging life, the identification of possible cofactors is critical. PMID- 8697672 TI - Intestinal morphology and transport after ileal resection in rat is modified by dietary fatty acids. AB - The authors tested the hypothesis that the intestinal morphology and uptake of nutrients after resection of the distal half of the small intestine of rats responds to alterations in the dietary content of saturated (SFA) and polyunsaturated (PUFA) fatty acids. Adult female Sprague-Dawley rats were subjected to a sham operation or to the surgical resection of the distal half of the small intestine, leaving the ileocecal valve intact. The animals were fed chow for 3 weeks, then either chow or isocaloric semisynthetic SFA or PUFA diets for a further 2 weeks. Food consumption, weight gain and jejunal mucosal surface area were unchanged after ileal resection. A microdensitometric autoradiographic technique was used to examine the distribution of 3H-leucine and 3H-lysine along the villus: approximately 70% of uptake occurred in the upper 30% of the enterocytes of the villus in chow-fed rats, and this portion was unchanged by ileal resection. The jejunal uptake of 40 mM of glucose, observed in vitro, was twice as high in animals that had undergone resection and were fed SFA than in those fed PUFA. In summary, (1) there is a separation between the adaptation of intestinal transport function and dynamic/static morphology after ileal resection, and (2) glucose uptake after ileal resection is enhanced by SFA in the diet and is not explained by any changes in the animals' food intake, weight gain or intestinal morphology. PMID- 8697673 TI - Improved counter-regulatory hormonal and symptomatic responses to hypoglycemia in patients with insulin-dependent diabetes mellitus after 3 months of less strict glycemic control. AB - This study of patients with insulin-dependent diabetes mellitus (IDDM) and hypoglycemia unawareness examines the effect of a period of less strict glycemic control on the defective counter-regulatory hormonal responses to and impaired awareness of hypoglycemia. In seven patients with IDDM with strict glycemic control and hypoglycemia unawareness, responses were studied with the use of a hyperinsulinemic hypoglycemic clamp test before and after 3 months of test treatment, which aimed at increasing daily mean blood glucose levels to 8 to 10 mmol/L, based on self-monitoring four times per day. The 3 months of test treatment elevated the patients' levels of glycosylated hemoglobin HbAlc from a mean of 6.9% (standard error [SE] 0.3%) at baseline to 8.0% (SE 0.3%, p < 0.05) and decreased the number of episodes of hypoglycemia (blood glucose level less than 3.0 mmol/L) per patient from a mean of 4.7 (SE 1.3) per week to 1.9 (SE 0.5) per week (p < 0.05). Although the same nadir (2.2 mmol/L) and duration of hypoglycemia were reached during each of the two clamp tests, the scores for sweating and lack of concentration were improved (p < 0.05) at the second test. The release of growth hormone and epinephrine during hypoglycemia were significantly improved (p < 0.05) at the second test, whereas the glucagon, cortisol and norepinephrine responses were unchanged. There were no significant differences in the results of the autonomic and cognitive function tests between the two tests. The results suggest that impaired hormonal and symptomatic responses to hypoglycemia in IDDM can be partially reversed by a modest rise in glucose levels for 3 months. PMID- 8697674 TI - Theoretical modelling of the release rate of low-density lipoproteins and their breakdown products at arterial stenoses. AB - Arterial stenoses and luminal-surface irregularities at anastomoses cause blood flow disturbances with slow recirculation. The authors created a computer simulation to study the rates of the release into blood of atherogenic substances such as low-density lipoproteins and their breakdown products from within the arterial walls at stenoses. Finite-difference methods were used to solve the Navier-Stokes equations (in the form of stream function and vorticity function) and the steady-state mass transfer equation for bell-shaped stenoses with two different degrees of constriction. This simulation indicated that the efflux rates of lipids and their breakdown products from the vessel walls were suppressed in the region of disturbed flow, with slow circulation distal to stenoses. The lowest efflux rate was found at the point of flow separation, and this rate was much lower than rates in regions of undisturbed flow. Therefore, this mathematical model predicts that locally disturbed blood flow at arterial stenoses and arterial anastomoses is responsible for two distinct phenomena: first, it provides favourable conditions for lipid infiltration into vessel walls; and, second, it impairs the release into the blood of atherogenic substances accumulated in the vessel wall. Such mass transfer abnormalities may account for atherogenesis and the late failures of arterial reconstructions at these sites. PMID- 8697675 TI - Surface properties of Helicobacter mustelae and ferret gastrointestinal mucosa. AB - Helicobacter mustelae is a gastric pathogen in ferrets that adheres to epithelial cells both in vitro and in vivo. In this study, the authors examine the role of surface hydrophobic properties in the adhesion of these organisms to eukaryotic cell surfaces. The surface properties of six H. mustelae strains were characterized by hydrophobic interaction chromatography (HIC), salt aggregation testing (SAT) and contact-angle measurement by axisymmetric drop-shape analysis (ADSA). Contact angles in multiple regions of the gastrointestinal tract, obtained from infected and uninfected ferrets, were also measured. The cell surface of H. mustelae was found to be hydrophilic by SAT but relatively hydrophobic by HIC. Contact-angle measurements for H.mustelae (mean 22.5 degrees, 95% confidence interval [CI] 9.3 degrees to 35.7 degrees) were higher than values previously reported for Helicobacter pylori (mean 12.1 degrees, 95% CI 2.0 degrees to 22.2 degrees, p < 0.05). The body of the stomach was more hydrophilic in infected ferrets (mean contact angle 59.9 degrees, 95% CI 52.5 degrees to 67.3 degrees) than in uninfected animals (mean contact angle 94.2 degrees, 95% CI 84.4 degrees to 104.0 degrees, p < 0.05). Reductions in the surface hydrophobicity of the ferrets' stomachs were correlated with the degree of mucosal inflammation (p < 0.01). These findings demonstrate that H. mustelae has surface properties comparable to those of H. pylori strains. Like the human stomach infected by H. pylori, there is a reduction in surface hydrophobicity of the ferret antrum associated with H. mustelae infection and the resulting mucosal inflammatory cell response. PMID- 8697676 TI - Therapy dose calculation in Graves' disease using early I-123 uptake measurements. AB - A retrospective study was performed to assess the feasibility of using the 4-hour I-123 early uptake value in the calculation of the treatment dose of radioactive iodine in Graves' disease patients. The Graves' disease patients were randomly divided into two groups. Data from the first group of 35 patients were used to obtain a regression relationship between the early 4-hour uptake (EUp) and 24 hour late uptake values (LUp). This equation, LUp = -38.618 + 65.216 Log (EUp) was used to estimate the predicted late uptake (PUp) from (EUp) in the second group of 34 patients. LUp was used to calculate the I-131 therapy dose for treatment in these patients. In 28 clinically euthyroid patients, the 4-hour uptake I-123 radioactive iodine uptake (RAIU) ranged from 7% to 20% (mean, 12 +/- 3.5%). In 60 Graves' disease patients, the 4-hour RAIU ranged from 15% to 100% (mean, 57 +/- 24.8%). Of these, there were five patients with a normal 4-hour uptake, but elevated 24-hour uptake. LUp correlated well with PUp (r = 0.81162), as did the dose calculation based on predicted and observed 24-hour uptake values (r = 0.82204). Thus, same day measurement of uptake and treatment of Graves' disease is feasible. PMID- 8697677 TI - The clinical utility of visual evaluation of scintigraphic perfusion patterns for Alzheimer's disease using I-123 IMP SPECT. AB - The authors examined the role of SPECT perfusion pattern in the diagnosis of Alzheimer's disease (AD) using I-123 IMP. They studied 93 patients who had memory and cognitive disorders, including 42 patients with a diagnosis of probable AD, classifying SPECT images into determined perfusion patterns. The probability of AD was 54% with bilateral temporal and/or parietal defects, 69% with bilateral temporoparietal defects with additional defects, 17% with no defects, and 11% with frontal defects only. The sensitivity of bilateral temporoparietal perfusion defects for AD was 95.2%, whereas the specificity was 56.9%. In the absence of bilateral temporal and/or parietal defects on visual evaluation of SPECT, the diagnosis of AD was unlikely, although it is not pathognomonic for AD, because this sign would be seen in various neuropsychiatric diseases causing memory and cognitive impairments. Visual evaluation of SPECT is of value in the diagnosis of AD among patients with dementia. PMID- 8697678 TI - A "changing stripe sign" in serial pulmonary perfusion imaging. AB - A stripe sign in pulmonary perfusion imaging is reported to be predictive of the absence of pulmonary embolism in the specific area of the stripe sign, and generally does not change on serial pulmonary perfusion imaging. The authors present the case of a patient with a stripe sign that disappeared on serial perfusion imaging without a ventilation abnormality. A "changing stripe sign" may raise suspicion for the possible existence of acute pulmonary embolism. PMID- 8697679 TI - Bilateral signet-ring cell carcinoma of the breast: scintigraphic findings. AB - Signet-ring cell carcinoma of the breast, first recognized in 1976, behaves aggressively and is associated with a poor prognosis. The tumor is a rare type of breast cancer and often metastasizes to the gastrointestinal tract and female genital tract. The authors report a case of a 48-year-old woman with bilateral signet-ring cell carcinoma of the breasts with multiple skeletal metastases and gastric metastasis. The breast cancer was depicted on a Tc-99m MIBI scintimammogram. PMID- 8697680 TI - Comparison of Tc-99m MIBI and Tl-201 uptake in musculoskeletal lesions. AB - The aim of this study was to make a comparison between the uptake of Tc-99m MIBI and Tl-201 in evaluation of musculoskeletal lesions. Fourteen cases were studied. Each study consisted of a Tl-201 study followed by a Tc-99m MIBI scan. In addition, a whole-body bone scan was performed in each patient to visualize bone metastases. Tl-201 and Tc-99m MIBI uptakes were evaluated by visual assessment and by using lesion-to-background (L/B) ratio. The authors found increased Tl-201 uptake with a mean L/B ratio of 2.81 and less Tc-99m MIBI uptake with a mean L/B ratio of 2.18 in malignant lesions. Both agents showed lower uptake with mean L/B ratios of 1.6 and 1.2 in benign lesions, but there was no statistical difference between the uptakes of either Tl-201 or Tc-99m MIBI in those with malignant and those with benign lesions. In addition, false-positive imaging was observed with both Tl-201 and Tc-99m MIBI. The results demonstrated that Tl-201 and Tc-99m MIBI accumulations in musculoskeletal lesions are not specific for malignancy. PMID- 8697681 TI - Preliminary evaluation of the usefulness of Tc-99m (V) DMSA in pancreatic neuroendocrine tumors. AB - The authors describe the possible application of Tc-99m (V) DMSA scintigraphy in pancreatic neuroendocrine tumors. In consideration of the common embryonic origin of these tumors and other neoplastic diseases (medullary thyroid carcinoma, pheocromocytoma, neuroblastoma) that have been well studied with radionuclide imaging, five cases of pancreatic neuroendocrine tumors (two insulinomas, one vipoma, and two unclassified neuroendocrine tumors) were successfully visualized with Tc-99m (V) DMSA scintigraphy, thus giving an overall "imaging confirmation" of the histologic and/or cytologic results in terms of primary and metastatic localization. The authors point out the importance of their results, obtained in a simple and repeatable manner, and suggest a real comparison in this setting between this approach and octreotide scintigraphy. PMID- 8697682 TI - Tl-201 SPECT in Kimura's disease involving the parotid glands and cervical nodes. AB - Kimura's disease is a chronic inflammatory condition producing subcutaneous tumor like nodules, mainly in the head and neck region. Most patients have involvement of regional lymph nodes and major salivary glands. The authors present two cases of Kimura's disease with parotid gland and postauricular lymph node involvement. With Tl-201 SPECT, elevated uptake was noted on early and delayed images. Kimura's disease should be included in the differential diagnosis when increased Tl-201 uptake in head and neck mass lesions is noted. PMID- 8697683 TI - Imaging of olfactory neuroblastoma by In-111 bleomycin complex. AB - No other successful nuclear method, besides bone scanning, has been reported in the literature for in vivo imaging of olfactory neuroblastoma. In this article, excellent uptake is reported by an In-111 labeled bleomycin complex (BLMC) in the ethmoid region of a histologically confirmed olfactory neuroblastoma. The uptake of BLMC was 0.7 x 10(-3)% ID/g at 48 hours after injection, and tumor-to-muscle and tumor-to-fat ratios were 6:1 and 11:1, respectively. The authors conclude that BLMC should be considered as a useful imaging agent, and the BLMC has potential as a radiochemotherapeutic agent against an olfactory neuroblastoma. PMID- 8697684 TI - Hepatic perfusion scintigraphy. Relationship of liver perfusion and ascites in patients with liver cirrhosis. AB - Radionuclide studies were performed on 38 patients with biopsy proven liver cirrhosis in an attempt to evaluate the interrelationship between liver perfusion and ascites in cirrhotic patients. Quantitative hepatic scintigraphy was used to evaluate the relative contribution of hepatic arterial and portal venous blood flow to the hepatic circulation. Using a gamma camera and on-line computer system, a bolus of 370 MBq Tc-99m pertechnetate was injected intravenously. Time activity curves of the abdominal aorta and right lobe of the liver were obtained using a region of interest analysis where arterial and portal components were calculated. Ascites was determined by clinical examination and by ultrasonography. Of 38 patients, 10 patients (26.3%) showed normal liver perfusion (group A), 22 patients (58%) showed reduced portal venous perfusion (group B), and 6 patients (15.7%) showed pure arterial hepatic perfusion (group C). The incidence, as well as the advancement, of ascites were significant (P < 0.05) and were most frequent in group C, frequent in group B, and less frequent in group A. The results of this study suggest that the development of ascites in patients with liver cirrhosis is closely correlated with the reduction in portal blood perfusion. PMID- 8697685 TI - Atlas of iodocholesterol scintigraphy (NP-59) in Cushing's syndrome with CT and MR correlation. AB - An atlas of I-131 iodocholesterol scintigraphy, each with correlative CT or MRI illustrates the findings in 12 patients with biochemically proven Cushing's syndrome and ultimate surgical cure. Included are patients with both ACTH dependent and independent disease, as well as patients with postoperative functional adrenal remnants. Emphasis will be on the concordance or discordance of the anatomical and functional imaging modalities. PMID- 8697686 TI - Tc-99m MIBI in a patient with parathyroid carcinoma. What to expect from it. PMID- 8697687 TI - Tc-99m DMSA imaging in kidney contusion. PMID- 8697688 TI - Incidental finding of paraesophageal hernia on hepatobiliary imaging. PMID- 8697689 TI - Isolated liver metastases from follicular thyroid cancer. PMID- 8697690 TI - Visualized renal pelves with Tc-99m-N-pyridoxyl-5-methyltryptophan. PMID- 8697691 TI - Misinterpretation of I-131 scintigraphy because of diaphragmatic hernia. PMID- 8697693 TI - In-111 pentetreotide accumulation in a teratoma. A case report. PMID- 8697692 TI - Abdominal wall uptake of Tc-99m MDP secondary to subcutaneous heparin injection. PMID- 8697694 TI - Marked lung uptake of Tc-99m HMPAO in a polysubstance-abusing marijuana and tobacco smoker. PMID- 8697695 TI - Incidental finding of Tl-201 accumulation in an empyema. PMID- 8697696 TI - Current readings in nuclear medicine. PMID- 8697697 TI - The three-phase bone scan and exercise induced lower-leg pain. The tibial stress test. AB - The three-phase bone scan is finding increasing utility in acute and chronic pain syndromes in sports medicine settings. This useful technique may have significant clinical application in assessing the increasing numbers of patients with exercise induced lower leg or medial tibial pain. The authors present a case of exertional lower leg pain or medial tibial pain in which three-phase bone imaging exhibited a dramatic increase in early flow after a simple derived exercise stress. The three-phase bone scan should play a key role in the assessment of exercise pain, and may be enhanced by the addition of simple exercise intervention. PMID- 8697698 TI - "Cold" reflex sympathetic dystrophy in an adult. AB - The classical presentation of acute reflex sympathetic dystrophy (RSD) or triple phase bone scintigraphy usually consists of increased periarticular uptake in each phase. The authors present a rare case of acute adult RSD characterized by bone hypofixation of Tc-99m MDP. Reflex sympathetic dystrophy in adults and children is reviewed. PMID- 8697699 TI - Alagille's syndrome. New manifestations. AB - The authors present the case of an infant with Alagille's syndrome who had cholestatic jaundice. The findings on IDA scintigraphy differed in several significant respects from previously reported cases. The hepatobiliary scintigraphic manifestations of Alagille's syndrome are more varied than previously thought. PMID- 8697700 TI - Characteristics of the sodium/hydrogen exchange in non-insulin-dependent diabetic patients with microalbuminuria and hypertension. AB - 1. An association has been described between increased sodium/hydrogen (Na+/H+) exchange rates in various cells and microalbuminuria in type 1 diabetic patients. However, no data are available on the Na+/H+ exchange rate in type 2 diabetes and its association with urinary albumin excretion rates. 2. We have estimated platelet sodium-activated proton efflux (Na+/H+ exchange rate), based on a fluorimetric method, in 43 type 2 diabetic patients, of whom 29 were normoalbuminuric and 14 microalbuminuric, and in 10 non-diabetic control subjects. The factors measured were: buffering power, Km for external Na+ and Vmax. of the exchange rate. 3. There were no differences in Km and Vmax. for the Na+/H+ exchange between the subject groups. However, the 14 patients with microalbuminuria showed a significantly lower buffering capacity [17.2 (4.6) mmol l-1 pH unit-1] [mean (SD)] compared with non-diabetic control subjects [21.1 (1.9) mmol l-1 pH unit-1] (P = 0.020). 4. Among the 43 diabetic patients, 16 were hypertensive. These patients had similar characteristics of Na+/H+ exchange to the 27 normotensive diabetic patients and the control subjects. 5. There was no correlation between exchange rate variables of type 2 diabetic patients and fasting concentrations of insulin or albumin excretion rate. 6. We conclude that the platelets of microalbuminuric diabetic patients manifest a significantly lower buffering capacity. This lower buffering capacity may be due to abnormalities of other ion transport systems or to abnormalities in intermediary metabolism. PMID- 8697701 TI - Effect of angiotensin-converting enzyme inhibitors on resistance artery structure and endothelium-dependent relaxation in two-kidney, one-clip Goldblatt hypertensive and sham-operated rats. AB - 1. This study was designed to examine the effect of angiotensin-converting enzyme inhibitors on resistance artery structure and endothelium-dependent relaxation in Goldblatt two-kidney, one-clip hypertensive rats. Four weeks after clipping, hypertensive and sham rats were treated with either perindopril (1 mg day-1 kg-1) or quinapril (3 or 30 mg day-1 kg-1). After 6 weeks mesenteric resistance arteries were mounted in a myograph for measurements of vascular structure. The endothelium-dependent relaxation response to acetylcholine and bradykinin and the response to the nitric oxide donor sodium nitroprusside were recorded. 2. All treatment regimes lowered the blood pressure and reversed both cardiac and resistance artery hypertrophy. Two-kidney, one-clip rats treated with quinapril showed a dose-dependent reduction in media cross-sectional area and media to lumen ratio. 3. Hypertension of 10 weeks' duration was associated with an impaired endothelium-dependent relaxation response to acetylcholine and bradykinin. Treatment with perindopril and either dose of quinapril prevented the development of impaired endothelium-dependent relaxation but had no effect on the response to sodium nitroprusside. Treatment had no effect on endothelium dependent relaxation in sham rats. 4. Angiotensin-converting enzyme inhibitor treatment is effective in normalizing blood pressure and cardiovascular structural changes. Angiotensin-converting enzyme inhibitor treatment prevented the development of impaired endothelium-dependent relaxation to both acetylcholine and bradykinin. The ability of angiotensin-converting enzyme inhibitors to reverse cardiovascular structural changes and prevent the development of abnormal endothelium-dependent relaxation may contribute to the overall effect of this type of antihypertensive drug. PMID- 8697702 TI - Increased inward passive permeability in vitro to sodium in uraemic erythrocytes. AB - 1. We have reported a normal sodium (Na) pump, but decreased loop-diuretic sensitive Na efflux in erythrocytes from patients with chronic renal failure on haemodialysis, suggesting a different mode of co-transport in uraemia. 2. The present work extends these findings and examines in vitro simultaneous unidirectional and radiolabelled Na and K fluxes through the Na/K/Cl co-transport and the Na/K pump in washed erythrocytes from seven subjects with chronic renal failure and seven controls. Erythrocyte cytosolic calcium was also examined. 3. Ouabain-sensitive 86Rb influx was similar in patients and controls (1.76 +/- 0.19 versus 1.72 +/- 0.13 mmol h-1 litre-1 of erythrocytes) as was ouabain-sensitive 22Na efflux (3.62 +/- 0.36 versus 4.04 +/- 0.39 mmol h-1 litre-1 of erythrocytes). 4. Bumetanide-sensitive 86Rb and 22Na influx and 22Na efflux were measured at three concentrations (4, 8 and 12 mmol/l) of external K. In chronic renal failure, mean bumetanide-sensitive 22Na efflux was decreased at all external K concentrations compared with controls, and at physiological concentrations (4 mmol/l) external K was lower than controls (0.14 +/- 0.01 versus 0.38 +/- 0.05 mmol h-1 litre-1 of erythrocytes, P < 0.01). Mean bumetanide sensitive 86Rb influx was also reduced in chronic renal failure at all external K concentrations, and at 4 mmol/l external K was lower than controls (0.13 +/- 0.04 versus 0.34 +/- 0.04 mmol h-1 litre-1 of erythrocytes, P < 0.01). Conversely, bumetanide-sensitive 22Na influx was markedly increased at all external K levels in chronic renal failure, and at 4 mmol/l external K values were elevated compared with controls (0.64 +/- 0.18 versus 0.34 +/- 0.04 mmol h-1 litre-1 of erythrocytes, P < 0.001). The mean cytosolic calcium concentration was higher in erythrocytes in chronic renal failure than controls (134.4 +/- 8.6 versus 63.7 +/ 5.8 nmol/l, P < 0.001). 5. Thus, in washed erythrocytes incubated in artificial media there is a markedly increased ouabain-insensitive Na influx in subjects with chronic renal failure which might be explained in part by the higher levels of cytosolic calcium. In vivo, this cell defect combined with suppression of the Na/K pump could lead to intracellular Na accumulation and play a role in uraemic complications. PMID- 8697703 TI - Cardiomegaly and vasoactive hormones in rats with chronic myocardial infarction: long-term effects of chlorothiazide. AB - 1. The effects of prolonged chlorothiazide treatment of left ventricular failure on cardiac hypertrophy, circulating vasoactive hormones and exchangeable body sodium were examined in rats with chronic myocardial infarction induced by left coronary artery ligation. Chlorothiazide therapy commenced either immediately or 2 weeks after infarction. For 4 weeks, the rats were given either chlorothiazide (50 mg day-1 kg-1) in their drinking water or drinking water alone. 2. Cardiac weight increased in untreated rats with infarction in comparison with sham operated controls, indicating the presence of chronic left ventricular dysfunction, although exchangeable body sodium, plasma renin activity, plasma vasopressin and plasma osmolality remained unchanged. 3. Chlorothiazide raised haematocrit and plasma renin activity equally in rats with and without infarction, although exchangeable body sodium, plasma vasopressin and plasma osmolality were not changed by the treatment. Plasma atrial natriuretic peptide was 2-fold higher in rats with infarction and this response was not affected by chlorothiazide treatment. Chlorothiazide therapy did not prevent or reverse cardiac hypertrophy. 4. Chronic diuretic therapy in this experimental model of heart failure did not reduce extracellular sodium, plasma vasopressin or the extent of ventricular hypertrophy, possibly because the condition was associated with activation of the renin-angiotensin system. PMID- 8697704 TI - Expression of endothelin peptides and mRNA in the human heart. AB - 1. We have examined the expression of endothelin isoforms and their precursors in the human heart using RIA, HPLC, immunocytochemistry and reverse transcriptase polymerase chain reaction assays. 2. Highly specific RIAs were used to measure the levels of mature endothelin and big endothelin-1 immunoreactivity in extracts of human right ventricle. There was no significant difference between samples from patients with ischaemic heart disease and idiopathic dilated cardiomyopathy. 3. HPLC coupled with RIAs allowed the separation and identification of the three mature isoforms of endothelin, big endothelin-1 and the C-terminal fragment of big endothelin-1. In extracts of human endocardial endothelial cells, peaks of immunoreactivity that co-eluted with authentic endothelin-1, big endothelin-1 and C-terminal fragment were found. 4. Intense immunocytochemical staining of mature endothelin immunoreactivity was detected in the cytoplasm of endothelial cells of all regions of the heart tested. Big endothelin-1 immunoreactivity mirrored that of the mature peptide and, in two of three individuals tested, big endothelin-2 immunoreactivity was also detected. No big endothelin-3 immunoreactivity was detected in any of the tissues examined. 5. Reverse transcriptase-polymerase chain reaction assays demonstrated endothelin-1 and endothelin-2 mRNA in all three samples of human left ventricle tested. In two of the individuals, additional bands were also detected with the endothelin-2 primers which corresponded to splice variants. There was no evidence for the expression of endothelin-3 mRNA. 6. These data suggest that endothelin-1 is the predominant isoform of endothelin in the human heart and is probably largely synthesized by the endothelial cells within the heart. If released from the endothelial cells in vivo, this potent cardiotonic peptide may play an important paracrine role in human cardiovascular function. PMID- 8697705 TI - Ischaemia--reperfusion injury in the rat is modulated by superoxide generation and leads to an augmentation of the hypoxic pulmonary vascular response. AB - 1. The effects of the scavengers of reactive oxygen species superoxide dismutase and catalase, the iron chelator desferrioxamine and the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester and saline (control vehicle) on hypoxic pulmonary vasoconstriction, a measure of albumin flux and an index of lipid peroxidation (palmitic:linoleic acid ratio) were investigated after ischaemia-reperfusion in an isolated, blood-perfused rat lung model. 2. Lungs treated immediately before reperfusion with catalase (5,000 units), desferrioxamine (2 mg/kg), NG-nitro-L-arginine methyl ester (5 mmol/l) or saline showed a significant augmentation in pre-ischaemia-reperfusion hypoxic pulmonary vasoconstriction (57.7 +/- 6.0%, 82.7 +/- 28.8%, 95.2 +/- 36.6% and 45.95 +/- 10.53% respectively), an increase in albumin flux (0.35 +/- 0.04, 0.31 +/- 0.06, 0.29 +/- 0.04 and 0.33 +/- 0.02) and an increase in pre-ischaemia-reperfusion palmitic:linoleic acid ratio (0.64 +/- 0.08, 0.51 +/- 0.19, 0.5 +/- 0.04 and 0.17 +/- 0.07). Superoxide dismutase (2,750 i.u.) administered immediately before reperfusion prevented completely the changes in hypoxic pulmonary vasoconstriction (-0.3 +/- 5.4%), albumin flux (0.09 +/- 0.11) and palmitic:linoleic acid ratio (-0.06 +/- 0.12). In control lungs (2h of continuous perfusion), superoxide dismutase, catalase, desferrioxamine and saline did not affect hypoxic pulmonary vasoconstriction (5.5 +/- 4.9%, 1.0 +/- 3.1%, -5.1 +/- 1.8% and 3.0 +/- 6.6%). However, NG-nitro-L-arginine methyl ester significantly augmented hypoxic pulmonary vasoconstriction (275.1 +/- 39.3%). There was no effect of superoxide dismutase, catalase, desferrioxamine, NG-nitro-L-arginine methyl ester or saline in control lungs on albumin flux (0.10 +/- 0.04, 0.11 +/- 0.01, 0.1 +/- 0.01, 0.12 +/- 0.01 and 0.11 +/- 0.01 respectively) or palmitic:linoleic acid ratio (-0.08 +/- 0.08, 0.73 +/- 0.76, -0.03 +/- 0.12, 0.01 +/- 0.17 and 0.00 +/- 0.0 respectively). 3. We conclude that superoxide dismutase attenuates ischaemia-reperfusion-induced increases in albumin flux and hypoxic pulmonary vasoconstriction, and prevents consumption of linoleic acid in the isolated, blood-perfused rat lung. PMID- 8697707 TI - Effects of intermittent pressure-induced strain on the electrophysiology of cultured human chondrocytes: evidence for the presence of stretch-activated membrane ion channels. AB - 1. Cyclical pressurization of cultured chondrocytes results in increases in cyclic AMP and in the rate of proteoglycan synthesis. Intermittent increases in hydrostatic pressure are also associated with hyperpolarization of chondrocyte cell membranes and activation of Ca(2+)-dependent K(+)-ion channels but the physiological basis for this response to mechanical stimulation is unclear. 2. Experiments have been undertaken to better define the types of ion channels involved and to explore the possibility that the hyperpolarization response associated with cyclical pressurization of chondrocytes follows activation of stretch-activated ion channels. 3. The mean membrane potential of chondrocytes in non-confluent monolayer cell culture rose from -15.3 +/- 0.24 mV to -21.1 +/- 0.28 mV (n = 60, P < 0.0001) after intermittent pressurization (0.33 Hz, 16 kPa, 20 min). 4. Strain gauge measurements showed that cyclical pressurization was associated with strain on the base of the culture plate. The amplitude of the hyperpolarization response was proportional to the microstrain to which cells were subjected. 5. Membrane hyperpolarization did not occur when chondrocytes were subjected to cyclical pressurization in rigid glass culture dishes or plastic dishes positioned in the pressurization chamber so as to avoid bending of the base of the culture dish. 6. Indirect evidence that the hyperpolarization response after intermittent pressure-induced strain was associated with stimulation of stretch-activated ion channels was obtained from experiments with gadolinium, amiloride and hexamethylene amiloride, each of which abolished hyperpolarization. 7. Experiments with apamin, charybdotoxin and iberiotoxin showed that the Ca(2+)-activated K+ channels involved in the hyperpolarization response are apamin-sensitive, charybdotoxin- and iberiotoxin-resistant, low conductance channels. 8. Somatostatin and cadmium chloride, which block L-type calcium channels, abolished strain-induced chondrocyte hyperpolarization. EGTA, which chelates extracellular Ca2+, reduced the response to 48% of control values, and thapsigargin, which raises intracellular Ca2+ by inhibition of Ca(2+)-ATPase in endoplasmic reticulum, caused hyperpolarization independently with further hyperpolarization after pressure-induced strain. These data indicate that chondrocyte hyperpolarization was dependent on intracellular Ca2+ concentrations. 9. Further work is required to determine whether stretch-activated ion channels shown to be associated with chondrocyte hyperpolarization after cyclical pressure induced strain are also involved in the signal transduction process that leads to increases in proteoglycan synthesis. PMID- 8697706 TI - Seasonal variation in blood pressure in normotensive women studied by home measurements. AB - 1. The factors influencing the seasonal variation in blood pressure measured at home in normotensive women were examined. 2. Sixteen female subjects (56.3 +/- 7.9 years old, mean +/- SD) measured their blood pressure and pulse rate at home each morning for more than 20 times per month for at least 1.5 years. Blood pressure and body weight were also determined in the office once or twice a month in that period. Monthly means of outdoor and indoor temperatures and daytime length were obtained from the Meteorological Observatory. The single cosinor method was used to evaluate circannual rhythm. 3. We observed a biphasic seasonal variation in self-recorded blood pressure measured at home, environmental temperature and daytime length but found no apparent seasonal variation in body weight and blood pressure measured in the office. The lowest levels of systolic and diastolic blood pressure measured at home were observed in July. The longest daytime length was recorded in June, while the highest outdoor temperature and indoor temperature were recorded in August, indicating that the longest daytime length preceded and the highest environmental temperature lagged behind the lowest level of blood pressure. The shortest daytime length is in December. The lowest outdoor and indoor temperature were observed in January, while the highest levels of self-recorded systolic blood pressure and diastolic blood pressure were in January and December, respectively. Half-amplitudes of self-recorded systolic and diastolic blood pressure were 2.6 +/- 1.0 mmHg and 2.0 +/- 0.8 mmHg, respectively. 4. These findings indicate the importance of a seasonal effect, i.e. daytime length and the environmental temperature, on the blood pressure of individuals. PMID- 8697708 TI - Bed rest decreases whole-body protein turnover in post-absorptive man. AB - 1. Whole-body protein turnover was measured using the [15N]glycine tracer technique in 10 post-absorptive healthy volunteers during normal daily activities and a period of bed rest. 2. Bed rest reduced whole-body protein turnover (25%), synthesis (26%) and breakdown (25%), but short-term urinary nitrogen excretion remained unchanged. PMID- 8697709 TI - Plasma inhibitory activity against tumour necrosis factor in fulminant hepatic failure. AB - 1. Soluble tumour necrosis factor receptors released into the circulation inhibit the effects of excess tumour necrosis factor-alpha and represent an important protective response. 2. In this study we have measured the levels of tumour necrosis factor and soluble tumour necrosis factor receptors p55 and p75 in the plasma of 10 patients with fulminant hepatic failure and 10 healthy control subjects. The capacity of the plasmas at varying dilutions to inhibit the biological activity of 1000 pg/ml of recombinant tumour necrosis factor in a tumour necrosis factor cytotoxicity assay in vitro was also determined. 3. The mean plasma levels of tumour necrosis factor in patients with fulminant hepatic failure (48.4 +/- 10.9 pg/ml) were significantly increased compared with normal control subjects (6.1 +/- 1.04 pg/ml, P < 0.01). Plasma soluble tumour necrosis factor receptors p55 and p75 were also significantly elevated in patients with fulminant hepatic failure (18.16 +/- 9.94 ng/ml and 16.06 +/- 9.93 ng/ml respectively) when compared with normal control subjects (1.28 +/- 0.24 ng/ml and 1.62 +/- 0.91 ng/ml, P < 0.001). 4. Fulminant hepatic failure plasma had a much lower capacity to inhibit tumour necrosis factor bioactivity in vitro, with a statistically significant difference between the inhibitory capacity of the fulminant hepatic failure and normal plasma seen at plasma dilutions of 1:5 and 1:20 (P < 0.05). 5. The reduced tumour necrosis factor neutralization capacity observed in fulminant hepatic failure, despite the increased levels of soluble tumour necrosis factor receptors, suggests enhanced susceptibility to the potential deleterious effects of tumour necrosis factor in fulminant hepatic failure. PMID- 8697710 TI - Are Himalayan Sherpas better protected against brain damage associated with extreme altitude climbs? AB - 1. The potential risk of brain damage when low-landers attempt to climb the highest summits is a well-known fact. However, very little is known about what occurs to Himalayan natives, perfectly adapted to high altitude, when performing the same type of activity. 2. Taking into account their long-life climbing experience at extreme altitudes, we examined seven of the most recognized Sherpas with the aim of performing a comprehensive neurological evaluation based on medical history, physical examination and magnetic resonance brain imaging. We compared them with one group of 21 lowland elite climbers who had ascended to altitudes of over 8000 m, and another control group of 21 healthy individuals who had never been exposed to high altitude. 3. While all of the lowland climbers presented psychoneurological symptoms during or after the expeditions, and 13 of them (61%) showed magnetic resonance abnormalities (signs of mild cortical atrophy and/or periventricular high-intensity signal areas in the white matter), only one Sherpa (14%) showed similar changes in the scans, presenting neurological symptoms at extreme altitude. The neurological examination was normal in all three groups, and no neuroimaging abnormalities were detected in the control group. 4. The significant differences, in both clinical and neuroimaging terms, suggest that Sherpa highlanders have better brain protection when exposed to extreme altitude. Although the key to protection against cerebral hypoxia cannot be established, it is possible that an increase in the usually short period of acclimatization could minimize brain damage in those low-landers who attempt the highest summits without supplementary oxygen. PMID- 8697711 TI - Low concentrations of ouabain increase cytosolic free calcium concentration in rat vascular smooth muscle cells. AB - 1. Low ouabain concentrations in the nanomolar range significantly increased cytosolic free calcium concentration. 2. The ouabain-induced cytosolic free calcium concentration increase was due to transplasmamembrane calcium influx, which could be prevented in the absence of extracellular calcium or by addition of the calcium channel blocker nifedipine. 3. The amount of stored cellular Ca2+, as determined by the thapsigargin-induced cytosolic free calcium concentration increase, was also enhanced by 1 nmol/l ouabain. 4. It is concluded that low ouabain concentrations affect intracellular cytosolic free calcium concentration homoeostasis. PMID- 8697712 TI - Gene targeting and its application to basic hypertension research. PMID- 8697713 TI - New insights into myocardial arrhythmogenesis: distribution of gap-junctional coupling in normal, ischaemic and hypertrophied human hearts. AB - 1. Ischaemic and hypertrophic heart diseases are associated with ventricular arrhythmias, in which abnormal cellular coupling is implicated as having a causative role. The aim of this series of studies was to characterize gap junctional organization in normal human ventricular myocardium, and to investigate the hypothesis that alterations in the quantity and patterns of expression of myocardial gap junctions occur in ischaemic and hypertrophic myocardial disease. 2. An antibody raised against connexin43 was used for immunohistochemical labelling of myocardium examined by confocal laser scanning microscopy, permitting highly sensitive and quantifiable immunofluorescent imaging of gap junctions through volumes of intact cardiac tissue. 3. Connexin43 gap junctions in normal adult human ventricular myocardium are highly organized into clusters of fluorescent label confined to the intercalated disks as a peripheral ring of larger junctions, with smaller junctions centrally, and occupy a surface area of 0.005 micron2/micron3 myocyte volume. 4. Neonatal human myocardium has a punctate distribution of connexin43 over the entire surface of the ventricular myocytes, with a progressive polarization of the gap junctions towards the positions of the mature intercalated disks, reaching the adult pattern at about 6 years. 5. At the myocardial interface with the scar of a healed infarct, connexin43 gap junction distribution is grossly disturbed, being strewn in longitudinally orientated arrays along the lateral interfaces between degenerated but viable myocytes, which may be due to a redistribution of the pre existing population of junctions. This altered distribution is present as early as 4 days after coronary occlusion in a canine model, in which it defines the location of circuits causing ventricular tachycardia. 6. Myocardium distant from infarction in patients with ischaemic heart disease has a normal pattern of connexin43 gap junction distribution, but has a 47% reduction in gap junction surface area per unit cell volume, and a 30% reduction per cell. 7. In hypertrophied myocardium from chronically pressure-loaded human left ventricles, connexin43 gap junction expression per myocyte is not significantly different from normal, but is reduced by 40% per unit volume of myocyte. 8. The early phases of the hypertrophic response of myocardium to renovascular hypertension in guinea pigs revealed a substantially increased connexin43 gap junction expression compared with controls, both when measured per cell (increased by 45%) and per unit volume of myocyte (increased by 30%), and therefore showed an alteration apparently contrary to that observed in chronically hypertrophied human ventricular myocardium. 9. In this series of studies, normal adult human ventricular myocardium and the post-natal developmental changes have been characterized with respect to connexin43 gap junction content, and the observed alterations of both distribution and quantity in ischaemic and hypertrophied hearts would be expected to influence myocardial conduction and the arrhythmogenic substrate. PMID- 8697714 TI - Interstitial glycerol concentration in human skeletal muscle and adipose tissue is close to the concentration in blood. AB - 1. The suggestion that the interstitial glycerol concentration in both adipose tissue and skeletal muscle is around 3 mmol/I (Maggs DG, Jacob R, Rife F, et al. J Clin Invest 1995; 96: 370-7), rather than close to the blood concentration as previously supposed, was tested by independent methods. 2. Free glycerol was infused, as part of a triacylglycerol emulsion, into six normal subjects and the arteriovenous difference for glycerol across the forearm was measured. In addition the relative interstitial glycerol concentration in subcutaneous adipose tissue was assessed simultaneously in four of the subjects by microdialysis. 3. During glycerol infusion the arterialized glycerol concentration rose from 52 +/- 5 mumol/I to 250-300 mumol/I (P < 0.001) in a square wave fashion. The net arteriovenous difference for glycerol across the forearm changed from negative (output) to positive (uptake) (P < 0.01). In subcutaneous adipose tissue the interstitial glycerol concentration rose during glycerol infusion (P < 0.001). 4. These observations are most easily explained by the movement of glycerol from plasma to interstitial fluid down a concentration gradient. We conclude that the interstitial glycerol concentration in skeletal muscle and adipose tissue is closer to the arterial concentration than to 3 mmol/I. PMID- 8697715 TI - Muscle protein and amino acid turnover in rats in vivo: effects of short-term and prolonged starvation. AB - 1. Protein loss in muscle can be caused by decreased protein synthesis, increased breakdown or both. In small animals the tracer incorporation technique is mostly used to measure protein synthesis, but for degradation measurements in vitro or ex vivo settings are required. In human and large animal studies the arteriovenous dilution technique is used because it enables the measurement of synthesis and breakdown rates simultaneously. The applicability in small animals has not yet been proven. We used a starvation model to compare both techniques. 2. A primed constant infusion of L-[2,6-(3H)]phenylalanine was given to male Lewis rats after 16, 40, 64 and 112 h starvation. Protein synthesis rates of the gastrocnemius muscle were measured by the incorporation technique and compared with hindquarter protein turnover calculated in a two- and three-compartment arteriovenous dilution model. 3. Whole-body phenylalanine rate of appearance decreased from 456 +/- 32 after 16 h to 334 +/- 34 (nmol min-1 100 g-1 body weight) after 112 h starvation. Protein synthesis rates of the gastrocnemius muscle measured by the tracer incorporation technique decreased from 3.6 +/- 0.4 after 16 h starvation to 2.2 +/- 0.3 after 64 h starvation and 1.8 +/- 0.4 (%/day) after 112 h starvation. Hindquarter protein breakdown, calculated with the tracer dilution model, increased after 112 h starvation from 28 +/- 12 to 77 +/- 15 nmol min-1 100 g-1 body weight. Using the tracer dilution model, however, the calculated protein synthesis rate across the hindquarter also increased after prolonged starvation (29 +/- 7 and 68 +/- 16 nmol min-1 100 g-1 body weight after 16 and 112 h respectively). In conjunction with this, calculated bidirectional membrane transport rates were also enhanced. Using valine and glutamine as tracers, the enhanced amino acid turnover rates were confirmed. 4. In conclusion, our results show that during short periods of starvation both methods give similar results. After prolonged starvation, however, an opposite change in disappearance rate and protein synthesis rate was observed. Assumptions made to calculate protein turnover using the arteriovenous dilution model may account for the discrepancy and care must be taken with the interpretation when using only one model in anaesthetized small animals. PMID- 8697716 TI - Fasting increases the extent of muscle necrosis in the mdx mouse. AB - 1. The effects of fasting for 48 h were investigated in C57BL/10 (wild type) and age-matched C57BL/10 dystrophin-deficient (mdx) mice. 2. Fasting resulted in an increased percentage of necrotic fibres in muscles from the hindlimb and lumbar regions of mdx mice. The percentage of necrotic fibres of forelimb and chest muscles of mdx mice was unaltered by fasting. In wild-type mice, very few necrotic fibres were observed after fasting. 3. The necrotic changes in fasted mdx muscle were not accompanied by altered energy status as evaluated by muscle ATP and phosphocreatine concentrations. 4. A significantly decreased rectal temperature was observed in mdx but not in wild-type mice after fasting. 5. Fasting would normally be expected to cause a reduction in muscle fibre size. The high prevalence of necrosis in fasted mdx mice is therefore an unusual response that may be related to disturbance of the mechanisms which, in the fed state, compensate for the dystrophin deficiency in these animals. PMID- 8697717 TI - Central and peripheral haemodynamic responses to high carbohydrate and high fat meals in human cardiac transplant recipients. AB - 1. Patients with autonomic dysfunction and elderly people with an age-related decline in autonomic function can suffer from a fall in blood pressure after eating. While the cardiovascular changes after eating and the effect of meal composition on these changes are well established, the underlying mechanisms are less clear. 2. This study assessed the cardiac, circulatory and humoral responses to ingestion of isoenergetic (2.5 MJ) high carbohydrate and high fat meals in nine orthotopic cardiac transplant recipients, who before transplantation had significant circulatory, metabolic and autonomic abnormalities and after transplantation had complete or partial extrinsic cardiac denervation, and compared them to the responses seen in nine healthy age-matched control subjects. 3. All variables were measured non-invasively. Cardiac transplant recipients, despite cardiac denervation, showed a normal heart rate response to high carbohydrate and high fat meals (maximal increase at 30 min postprandially + 7.8 +/- 1.1 and + 63 +/- 1.4 beats/min respectively), a normal cardiac output response to the high carbohydrate meal (maximal increase at 30 min + 1.16 +/- 0.25 l/min), but a significantly attenuated cardiac output response to the high fat meal. Cardiac transplant recipients had attenuated superior mesenteric artery blood flow responses after both meals (P < 0.05) and an attenuated calf vascular resistance response after the high fat meal (P < 0.01). Throughout the study after both meals, cardiac transplant recipients maintained blood pressure. 4. This study demonstrates that cardiac transplant recipients, despite partial or complete cardiac denervation, have a normal chronotropic response to food and a normal cardiac output response to a high carbohydrate meal. The attenuated cardiac output response to a high fat meal did not compromise blood pressure, due at least in part to decreased splanchnic vasodilatation. PMID- 8697718 TI - Effects of facial cooling on elderly and young subjects: interactions with breath holding and lower body negative pressure. AB - 1. The effects of convective facial cooling by cold air on arterial blood pressure, heart rate and finger blood flow and on the reflex interactions between facial cooling and respiratory and orthostatic cardiac reflexes have been examined in 28 young adults (20-39 years) and 17 elderly (66-78 years) volunteer subjects. 2. During 2 min facial cooling alone, bradycardia was smaller (P < 0.001) and reduction in finger blood flow smaller (P < 0.001) in elderly subjects than in young subjects. Increases in systolic blood pressure and mean arterial pressure were similar and diastolic pressure increased only in the young subjects. Systolic blood pressure and mean arterial pressure remained elevated in the elderly 1 min after facial cooling, but subsided in the young. 3. Arterial blood pressure increased more during a 30-s breath-hold in expiration than in inspiration (P < 0.001) in both groups, and this was exaggerated by breath-hold in expiration combined with facial cooling. The bradycardia produced by facial cooling and breath-holding in expiration was more pronounced in the young subjects than in the elderly (P < 0.002). 4. Interactions between facial cooling and orthostatic reflexes induced by lower-body negative pressure showed significantly different age-related linear trends. Facial cooling diminished the hypotension induced by lower-body negative pressure in both groups. Facial cooling had a greater effect in diminishing the lower-body negative pressure induced tachycardia in the young than in the elderly. 5. The mechanism of alteration of the facial cooling response in elderly subjects could be largely impairment of arterial baroreflexes, particularly as a result of reduced cardiac vagal activity as well as impairment of cardiopulmonary reflexes with ageing. PMID- 8697719 TI - Superficial hand vein responses to NG-monomethyl-L-arginine in post-partum and non-pregnant women. AB - 1. During human pregnancy marked vasodilatation occurs in arterial and venous vascular beds. The mechanisms responsible for this change remain unclear. The contribution of increased nitric oxide activity to vasodilatation associated with pregnancy was determined by examining superficial hand vein responses to NG monomethyl-L-arginine, an inhibitor of nitric oxide synthase, in post-partum women 24-48 h after delivery when vasodilatation remains at levels present during the third trimester. 2. Seventeen healthy women, 24-48 h post partum, and 13 healthy non-pregnant women were studied. Eight of the post-partum women underwent repeat studies 12-16 weeks after delivery. 3. NG-monomethyl-L-arginine (100 nmol/min) resulted in venoconstriction in non-constricted veins (baseline, 0%; 5 min, 26 +/- 9%; 10 min, 14 +/- 8%; 15 min, 8 +/- 7%; means +/- SEM) and noradrenaline-constricted veins (5 min, 30 +/- 7%; 10 min, 24 +/- 10%; 15 min, 14 +/- 11%). No constrictor response to NG-monomethyl-L-arginine was present in the same women 12 weeks post partum (5 min, 1 +/- 4%; 10 min, 0 +/- 3%; 15 min, 1 +/- 4%) or in the non-pregnant control subjects in non-constricted (5 min, 2 +/- 3%; 10 min, 4 +/- 3%; 15 min, 2 +/- 2%) or noradrenaline-constricted veins (5 min, -2 +/- 7%; 10 min, 1 +/- 9%; 15 min, -5 +/- 7%). 4. These findings indicate that nitric oxide activity is increased in the immediate post-partum period in venous vasculature, and support the hypothesis that increased nitric oxide activity may be responsible for the vasodilatation observed during normal pregnancy. PMID- 8697720 TI - Angiotensin receptors in myometrium and myometrial vessels from uteri of women during the follicular and luteal phases of the menstrual cycle and in late pregnancy. AB - 1. Receptors for angiotensin II were identified and characterized in membrane fractions from myometrial samples obtained at non-pregnant hysterectomy in women of reproductive age. Specific binding was also measured in paired samples of vascular and "vessel-free' myometrium. 2. A single class of high-affinity receptor sites was identified in the total myometrial preparations (n = 10), with a median equilibrium dissociation constant (Kd) of 0.122 nmol/l (range 0.065 0.465 nmol/l) and concentration of receptor sites (Bmax) of 149 fmol/mg protein (range 105-435 fmol/mg). Receptor characterization studies using losartan (an angiotensin type 1 receptor antagonist) and PD123177 (an angiotensin type 2 receptor antagonist) showed the myometrium to contain almost entirely type 2 receptors. 3. The median Kd and Bmax for specific angiotensin II binding in isolated myometrial vessel homogenates were 0.086 nmol/l (range 0.060-0.433) and 260 fmol/mg protein (range 197-737 fmol/mg) respectively. Vascular specific binding density was always higher in dissected out myometrial vessels than in paired vessel-free myometrium (median 372 compared with 120 fmol/mg protein; n = 20; P < 0.001). The specific binding in the paired samples was strongly correlated (r = 0.8904, P < 0.0001). 4. The specific binding of 125I-labelled angiotensin II in "vessel-free' myometrium was higher in samples from the follicular phase than in samples from the luteal phase (median 144 compared with 37 fmol/mg; P < 0.02). A similar trend was found in the vessels themselves, but this failed to reach statistical significance (459 compared with 225 fmol/mg; P = 0.051). 5. It is suggested that the down-regulation of the angiotensin type 2 receptors in the luteal (secretory) phase is a preparation for pregnancy, removing an inhibitory factor to uterine growth and vascularization and allowing greater prostacyclin synthesis. PMID- 8697721 TI - Use of continuous haemofiltration to assess the rate of lactate metabolism in acute renal failure. AB - 1. Whole-blood lactate levels were measured at different rates of haemofiltration in 10 patients with acute renal failure undergoing conventional continuous haemofiltration using lactate-buffered replacement fluid. 2. The results enable both basal production rates and the metabolic clearance of lactate to be estimated in man. PMID- 8697723 TI - Effect of probucol, an oral hypocholesterolaemic agent, on acute tobacco smoke inhalation in rats. AB - 1. We hypothesized that probucol, an oral hypocholesterolaemic agent, can suppress the oxidant stress induced by acute tobacco smoke inhalation in rats. We determined lung tissue glutathione (reduced and oxidized), lipid peroxide, tocopherol and plasma elastase inhibitory capacity, ferroxidase activity and lipid peroxide in rats after inhalation of tobacco smoke. 2. Rats treated with the probucol diet for 3 days or 4 weeks equally showed no suppression of plasma elastase inhibitory capacity and ferroxidase activity compared with control rats after acute tobacco smoke inhalation, although both animals treated with probucol for 3 days or 4 weeks had pharmacologically effective concentrations of probucol to lower plasma cholesterol but plasma cholesterol in rats treated with probucol for 3 days was still in the normal range. 3. Probucol treatment for 4 weeks lessened tobacco smoke-induced suppression of lung tissue glutathione, attenuated tobacco smoke-induced increases in lung tissue lipid peroxide and did not alter lung tissue tocopherol compared with control (lungs). 4. These findings demonstrate that probucol, via its antioxidant ability, confers a protective effect on lung exposed to acute tobacco smoke inhalation. PMID- 8697722 TI - Endogenous versus exogenous lithium clearance for evaluation of dopamine-induced changes in renal tubular function. AB - 1. The present randomized, double-blind cross-over study compared endogenous and exogenous lithium clearance (CLi) for estimation of the effect of dopamine on tubular sodium reabsorption. Twelve normal, salt-repleted male subjects were investigated on three different occasions with either placebo or 450 mg or 600 mg of lithium given in random order at 22.00 hours. After an overnight fast, renal clearance studies were performed during a 1 h baseline period and subsequently during the second hour of an infusion of 3 micrograms min-1 kg-1 of dopamine. 2. Baseline values of endogenous CLi and fractional excretion of lithium (FELi) [27.0 (23.5-30.5) ml/min and 24.2 (20.3-28.2)% (means with 95% confidence interval)] were lower than exogenous values [lithium, 450 mg: 32.7 (29.9-35.4) ml/min (P < 0.05) and 27.4 (25.2-29.6)% (P < 0.05); lithium, 600 mg: 33.4 (29.2 37.6)ml/min (P < 0.05) and 28.6 (26.3-31.0)% (P < 0.01)]. Both test doses of lithium increased the baseline sodium clearance (CNa), but glomerular filtration rate and urine flow rate remained unchanged. 3. Dopamine increased CNa to similar values on the three study days. CLi increased to 40.9 (35.5-46.5) ml/min (endogenous lithium, P < 0.001), 43.2 (40.8-45.6) ml/min (450 mg of lithium, P < 0.01) and 44.9 (41.3-48.4) ml/min (600 mg of lithium, P < 0.001), respectively. FELi increased to 32.2 (27.5-37.0)% (P < 0.01), 35.4 (33.0-37.7)% (P < 0.01) and 35.9 (32.8-38.9)% (P < 0.01), respectively. Values during dopamine infusion did not differ significantly. 4. The lower baseline values of endogenous CLi and FELi compared with exogenous values suggest that CLi in humans depends on the plasma concentrations of lithium. However, the effect of dopamine on CLi and FELi was expressed to the same extent with endogenous and exogenous lithium, indicating that the two methods are interchangeable for estimation of dopamine-induced changes in tubular function. PMID- 8697724 TI - Guide-lines for near patient testing: haematology. AB - These guide-lines provide a framework for the local arrangement of near patient testing (NPT) services for haematology tests. The guidance may be applied to medical and surgical units within hospitals (e.g. ITU, renal dialysis units, casualty) as well as general practitioners' surgeries, for blood counts and coagulation testing. The professional head of the central laboratory must take responsibility for all aspects of the NPT service, although there should be full discussion with the clinical departments involved and joint ownership of the results. NPT operators must be trained and accredited by the central laboratory. Equipment selected should normally have received a satisfactory evaluation report from the Medical Devices Agency (MDA), and should generate results that are comparable with those of the central laboratory. If a full MDA operation evaluation has not been performed, the purchaser should perform a local assessment according to the protocol in this document. The suitability of the equipment, imprecision, and comparability must be studied. The NPT equipment must be properly maintained and calibrated, and a record of patient identity, date and time of testing, reagent lot numbers, and operator must be kept. The central laboratory must participate in a suitable external quality assessment programme (EQA), and provide systems for EQA and internal quality control (IQC) of the NPT site. PMID- 8697725 TI - The value of gel test and ELAT in autoimmune haemolytic anaemia. AB - Three methods for detection of warm type IgG autoantibody were evaluated using 400 blood samples from 147 patients suspected of autoimmune haemolytic anaemia (AIHA). Three direct antiglobulin techniques (DAT) were used: conventional tube DAT, gel-DAT by micromethod and gel-DAT enzyme linked antiglobulin test (ELAT). Eluate examinations confirmed the presence of autoantibodies on red cells. These tests were compared directly using 126 selected blood samples from 85 patients with IgG molecules on their red cells detected by the gel test. In 106 of these samples, collected from 65 patients with clinical symptoms of AIHA, the presence of autoantibody was confirmed by acid elution. The ELAT was positive in 100 samples (94%), 87 samples for tube DAT (82%). The ELAT as well as the tube DAT was negative in 20 samples with non-reactive eluates by gel test. The gel-DAT was therefore not fully specific and detected IgG on red cells of patients with hypergammaglobulinaemia. However, due its higher sensitivity it proved useful as a screening test. The ELAT allowed changes in the number of IgG molecules per red cell to be monitored quantitatively. Both methods play a part in the diagnosis and monitoring patients with warm type IgG auto-antibody. PMID- 8697726 TI - An inappropriate erythropoietic response to iron deficiency anaemia in the elderly. AB - This study was carried out to clarify the features of iron deficiency anaemia in the elderly. Subjects were chosen from residents undergoing an annual health check in a home for the aged and the features of anaemia in the elderly were compared with those in middle-aged adults under 60 years old. The red cell count, red cell size and haemoglobin content in an elderly group with iron-deficiency anaemia did not differ from those in middle-aged adults. No significant differences of the serum ferritin and iron levels were noted between the two groups. Total iron binding capacity was higher in the middle-aged adults than in the elderly, while the reticulocyte count was significantly lower in the elderly group. Immature reticulocytes showing a considerable amount of residual RNA by flow cytometry with fluorescent staining were also lower in the elderly group than in the middle-aged adults. Serum erythropoietin levels in both groups were significantly higher than in non-anaemic age-matched controls and no difference in erythropoietin levels was noted between them. The ratio of the reticulocyte count to the log-transformed erythropoietin level was low in the elderly group with iron-deficiency anaemia compared with the middle-aged adults with iron deficiency anaemia. The same result was seen when the immature reticulocyte count was related to the log-transformed erythropoietin level. These findings suggest that the red cell production response to erythropoietin in the elderly with iron deficiency anaemia might be inappropriate compared with both non-anaemic and anaemic middle-aged adults. PMID- 8697727 TI - Circulating CD20dim T-lymphocytes increase with age: evidence for a memory cytotoxic phenotype. AB - The CD20 antigen has been regarded as a B lineage specific, 35 kDa, non glycosylated membrane phosphoprotein, which functions as either a Ca2+ ion channel or as a regulatory protein of such a channel. Weak expression of CD20 (CD20dim), however, has recently been reported on a sub-population of T lymphocytes. We present results which confirm the existence of a CD20dim T lymphocyte population and show that such cells have a reduced antibody-binding capacity, when compared to CD20bright B-cells (10337 +/- 642 and 346311 +/- 24264 respectively). In addition, CD20dim cell counts vary with age, with the highest levels occurring in octogenarians: cord blood 0.3 +/- 0.1% (n = 13), 20-60 year old group 2.1 +/- 1.1% (n = 18) and individuals > or = 61 years of age 6.9 +/- 3.2% (n = 10) (P < 0.001). Further characterization of CD20dim T cells, using three colour flow cytometry, demonstrated a predominantly memory cytotoxic phenotype, in that the cells were CD8+CD28+CD45RO+T-CR alpha beta +CD38-HLA-DR-. PMID- 8697728 TI - Evaluation of the automated leucocyte count and differential from the Cell-Dyn 3500 in sickle cell disease. AB - Erythrocytes resistant to standard lysing reagents are known to occur in sickle cell disease. These lyse-resistant erythrocytes can cause aberrant automated leucocyte counts and differentials. The ability of the Cell-Dyn 3500 automated haematology analyser to eliminate resistant erythrocytes and accurately count and differentiate leucocytes was evaluated. Samples were obtained from paediatric patients with sickle cell disease or haemoglobin SC disease. The Cell-Dyn 3500, using impedance and optical counting with a hypotonic salt "extended lyse mode', was compared to the Cell-Dyn 3000, an optical analyser that also uses a hypotonic salt lyse, the Cell-Dyn 400, a "hard detergent lyse' impedance counter, and a reference 400-cell manual white cell differential (National committee for Clinical Laboratory Standards [NCCLS] Approved Guideline H20-A). Seventy-five samples from patients with sickle cell disease or haemoglobin SC disease were evaluated for total leucocyte count, percentage of lymphocytes, percentage of neutrophils, and nucleated red blood cells (NRBC) flags. The Cell-Dyn 3500 correlated well with Cell-Dyn 400 leucocyte counts, with a correlation coefficient of 0.95. When compared to the manual differential, the correlation coefficient for lymphocytes was 0.93 and for neutrophils 0.95. The Cell-Dyn 3500 NRBC flag had a sensitivity of 47.7% and a specificity of 80.6%. The predictive value of a positive flag was 77.7%. The Cell-Dyn 3500's extended lyse mode clearly enhances the accuracy of leucocyte counts and differentials in patients with sickle cell disease. PMID- 8697729 TI - Post-splenectomy lymphocytosis. AB - We describe post-splenectomy lymphocytosis (PSL) in 23 patients, a majority (20/23) of whom have undergone splenectomy as a staging procedure for Hodgkin's disease. The absolute lymphocyte count ranged from 4.0 to 8.7 x 10(9)/l. The lymphocytosis was noted 4-242 (median 70) months after splenectomy and persisted almost unchanged in most patients on prolonged follow up (median 50 months). Immunophenotyping of the lymphocytes revealed no monoclonal B cell population. PMID- 8697730 TI - Validation of an algorithm for oral anticoagulant dosing and appointment scheduling. AB - Computer clinical decision-support systems require validation before clinical use. This study compared recommendations on warfarin dosage adjustment and timing of the next appointment made by an algorithm with those made by experienced and inexperienced clinicians. Data abstracted from the records of 125 patients seen regularly in the anticoagulant clinic were used. The algorithm recommended dose changes and next appointment for cases with INRs between 1.8 to 4.2 (therapeutic range 2.0-3.0) and between 2.3 to 5.3 (therapeutic range 3.0-4.5). Beyond these values the algorithm referred the cases to "see doctor'. Compared to experienced clinicians, the algorithm was better at "recognising' difficult patients than inexperienced clinicians (kappa = 0.43 and 0.32 respectively). There was no statistically significant difference between all decision makers in dosage recommendations for the non-difficult cases, but there was much more variation amongst the inexperienced clinicians. The interval recommendations were statistically different between and within the different decision-makers. The inexperienced clinicians tended to give relatively longer intervals for a given dose change. In conclusion, the algorithm performs better than inexperienced clinicians and as well as experienced clinicians for the non-difficult cases. PMID- 8697731 TI - Pseudoleucocytosis due to incomplete erythrocyte lysis. PMID- 8697732 TI - Essential thrombocythaemia followed by multiple myeloma in the same patient. AB - We describe a patient with essential thrombocythaemia who developed multiple myeloma 7 years after an initial diagnosis of essential thrombocythaemia. A 50 year-old white female presented in 1987 with a 2 year history of low backache, painful swollen ankles and burning feet. Her laboratory investigations suggested a diagnosis of essential thrombocythaemia. Initially she was treated with busulphan without much benefit for 6 months. Subsequently she was treated with hydroxyurea with significant relief of her symptoms and reduction in her platelet count. Seven years after her initial presentation she developed bone pains and anaemia with laboratory investigations confirming a diagnosis of multiple myeloma. PMID- 8697733 TI - Letter from America: quis custodiet ipsos custodes? PMID- 8697734 TI - Home healthcare: the role of the primary care physician. PMID- 8697735 TI - The diagnosis and treatment of infectious syphilis. PMID- 8697736 TI - Radiologic and laboratory evaluation of enhancing brain lesions in patients with AIDS. PMID- 8697737 TI - Epidemiology of candidiasis. PMID- 8697738 TI - Penicillin and multiply antibiotic-resistant Streptococcus pneumoniae. AB - The emergence of multiply antibiotic-resistant pneumococci has become a worldwide problem. To document resistance among clinical or surveillance isolates, there are a number of excellent laboratory techniques and these can be used to guide clinical decisions. All pneumococci are currently susceptible to vancomycin, an important consideration in managing patients with serious, or life threatening infection. PMID- 8697739 TI - Infectious disease indications for hyperbaric oxygen therapy. PMID- 8697740 TI - Sea monsters. PMID- 8697741 TI - Group B streptococcal infections in newborn infants. PMID- 8697742 TI - Modality specific semantic knowledge loss for unique items. AB - We report the case of a man who, following a major myocardial infarction, suffered anoxia followed by significant event memory impairment. Investigations indicated that his semantic memory for word concepts and object meanings was well preserved. However, he had great difficulty in identifying in the visual (but not verbal) modality historically known people, such as Queen Elizabeth I and Napoleon, and well known world and London landmarks, such as the Parthenon and Buckingham Palace. This selective impairment could not be accounted for in terms of prosopagnosia or high level visual perceptual deficits and we interpret it as a modality specific semantic memory loss for unique objects. PMID- 8697743 TI - Persistent post-traumatic retrograde amnesia: a neuropsychological and (18F)FDG PET study. AB - We report the case of a 48-year old woman who, after a severe closed head injury, developed a severe and persistent disruption of retrograde memory, associated with a mild impairment of learning abilities. The patient's dense amnesia spared only the childhood period and included both explicit memory (autobiographical and semantic) and procedural skills. Because of her partially spared learning ability and intact language, intensive training by family members resulted in the reacquisition and retention of many autobiographical events and of some skills she had lost after the accident. Brain CT scan and MRI were normal; a PET study with (18F)FDG revealed a significant bilateral reduction of metabolism in the hippocampus and anterior cingulate cortex, suggesting a role for these structures in memory for past events. PMID- 8697744 TI - Maximizing the bilateral field advantage on verbal and nonverbal matching tasks. AB - Research has established that response latencies are generally shorter on visual matching tasks when one target is projected to each hemifield (bilateral presentation) than when both targets are projected to the same hemifield (unilateral presentation). This effect, called the bilateral field advantage (BFA), has recently shown promise as a predictor of callosal dysfunction. As a step toward developing a reliable BFA index, the present study examined two factors that appear to influence the extent of BFA in normal subjects. Twenty seven right-handed college students performed a verbal matching task (using letter pairs drawn from the set AaBb) and a nonverbal matching task (using dot pattern pairs constructed with 4 dots in a 3 x 3 matrix). Order of task varied across subjects (dots followed by letters, or letters followed by dots, or letter trials and dot trials interleaved at random). The targets were presented either unilaterally or bilaterally. Results revealed a robust BFA for the letter matching task in all three task order conditions, suggesting that the letter task may be suitable for inclusion in a battery of tasks for clinical assessment. The dot-matching task did not yield a significant BFA when administered as the first task. The dot task BFA increased when the letter task preceded it, and became comparable to the letter task BFA in the interleaved condition. PMID- 8697746 TI - Peripheral aspects of writing can be differentially affected by sensorial and attentional defect: evidence from a patient with afferent dysgraphia and case dissociation. AB - This study reports a patient with right posterior cerebral atrophy who was affected by afferent dysgraphia, characterised by case dissociation: cursive better than upper-case print. The patient also had severe visuocostructional deficit and simultanagnosia. The hypothesis advanced to explain this dissociation is that cases are not equally dependent on visual and kinaesthetic control. Thus, if visual and kinaesthetic feedback (or the attention to them) are impaired by cerebral lesions, upper case can be expected to be more impaired than cursive. PMID- 8697745 TI - The semantic memory impairment of Alzheimer's disease: category-specific? AB - We addressed the question of whether Alzheimer's Disease (AD) causes a selective impairment for knowledge of living things. Although we replicated a previous finding that AD subjects name pictures of living things less accurately than pictures of nonliving things, we also failed to observe this selective impairment when we used two new stimulus sets, which more tightly controlled the overall naming difficulty of the living and nonliving items. We conclude that, whereas some individuals may have bona fide selective impairments in semantic memory as a result of herpes simplex encephalitis or head injury, AD does not generally give rise to selective impairments in knowledge of living things. PMID- 8697747 TI - A direct observational measure of whole body turning bias. AB - The directional preference for spontaneous turning in humans has previously been documented using an electronic device (rotometer). We used a simple, inexpensive, and well-controlled test of turning behaviour in 41 adults with no psychiatric diagnoses. In this test, the direction in which subjects turned is recorded as they complete each one of what they think is a series of evaluations of gait, in a room symmetrically spacious and free of distracters. A substantial majority of our right-handed subjects (N = 27) showed a significant leftward turning bias, while non-right handed group (N = 14) did not show this bias. Test-retest reliability for this measure in 17 individuals tested twice at different times was high (rho = 0.73). PMID- 8697748 TI - Spared retrograde memory with anterograde amnesia and widespread cognitive deficits. AB - A case is described of a young male who suffered head injuries in a motor accident and subsequently displayed a severe anterograde amnesia in the presence of a relatively intact retrograde memory. He also demonstrated marked impairment of general intellectual ability, naming, perceptual skills and executive functioning. This case demonstrates a striking dissociation between anterograde and retrograde memory. Moreover the retention of retrograde memory in the face of such severe and global cognitive impairment accentuates the dissociation or isolability of retrograde memory. It is further argued that while frontal impairment occurred in this case it lacks any of the hallmarks of frontal amnesia. The case is further evidence for the fractionation of amnesic syndromes. PMID- 8697749 TI - A role for the hippocampus in card sorting? A cautionary note. A comment to Corcoran and Upton. PMID- 8697750 TI - Semantic processing without conscious understanding in a global aphasic: evidence from auditory event-related brain potentials. AB - We report a global aphasic who showed evidence of implicit semantic processing of spoken words. Auditory event-related brain potentials (ERPs) to semantically congruous and incongruous final words in spoken sentences were recorded. 17 elderly adults served as control subjects. Their ERPs were more negative to incongruous than to congruous final words between 300 and 800 ms after stimulus onset (N400), and more positive between 800 and 1500 ms (Late Positivity). The aphasic showed an exactly similar pattern of ERP components as the controls did, but his performance in a task demanding explicit differentiation between semantically congruous and incongruous sentences was at the chance level. During follow-up, his explicit understanding recovered over the chance level but the ERPs remained fairly similar. We conclude that implicit semantic activation at the conceptual level can take place even in the absence of conscious (explicit) comprehension of the meaningfulness of linguistic stimuli. PMID- 8697751 TI - Modality specific naming and gesture disturbances: a case with optic aphasia, bilateral tactile aphasia, optic apraxia and tactile apraxia. AB - This study reports a patient who manifested optic aphasia, tactile aphasia, optic apraxia, and tactile apraxia following an operation for epidural left parietal haematoma. He could neither name nor pantomime the use of objects presented visually or tactually, but correctly performed semantic association tasks, thus demonstrating preserved recognition. He could name and pantomime the use of auditorily presented objects. Experimental results disproved that pantomime disorders were secondary to naming disorders, and suggested that modality specific aphasia and modality specific apraxia are independent clinical syndromes. CT scans showed injury to the posterior callosal radiations, the white matter of the angular gyrus, and the medial portion of the occipital lobe in the left hemisphere. We suggest that modality specific aphasia and modality specific apraxia can be explained by assuming a common semantic memory store. PMID- 8697752 TI - The representation of arithmetical facts: evidence from two rehabilitation studies. AB - We report the improvement following rehabilitation of two patients with a selective deficit on multiplication facts. The remediation experiments were conducted in specific designs to test a series of hypotheses about both the process of reacquisition and organisation of arithmetical facts in memory. The results show a significant and stable recovery and the pattern of reacquisition reflects the different strategy used by the patients to relearn the multiplication facts. Quantitative and qualitative changes in error patterns in the course of remediation reveal the underlying (re)organization of the memory network representing multiplication facts. PMID- 8697753 TI - Perseveration in two aphasic patients. AB - In this paper we report the perseverative behavior of two aphasic patients, AB and MT. They were submitted to a standardized Language Examination and to verbal and nonverbal tasks designed to elicit perseveration. Some of the features pointed out in the literature were not confirmed. Perseveration was not semantically related to the target; a correct response did not have any special status; in many instances the perseveration had not been produced as a correct response and could reappear immediately or after many stimuli; the production of two consecutive correct responses did not inhibit the spontaneous recurrences and could again be followed by the perseveration of a previous wrong response. Perseveration did not set in in the same circumstances for the two patients: in AB it set in when the patient was unable to find the correct response; MT, on the contrary, while knowing the correct response, was unable to change her perseverative behavior from one response to the other. For both patients, however, it seems as if no inhibitory system stops pre-existing motor or verbal behavior. PMID- 8697754 TI - Selective impairments within episodic memories. AB - We report the case of a patient (T.R.) who developed a severe and selective amnesia for names and dates associated with events. His amnesia was temporally limited, affecting only the last two to three decades of his life. When recalling an event he was able to evoke both its content and place, while he could not provide any information about people (names or their physical features) and the time (date/period) of its occurrence. His performance on event-memory tests was consistent across the type of material used (personal and public events) or the period of life investigated. These results suggest that knowledge of an episode is specified across multiple representations. PMID- 8697756 TI - Intensive care/intensive cure: the future of critical care? PMID- 8697755 TI - Temporal integration of events within and between the cerebral hemispheres. AB - The effect of interhemispheric transmission time (IHTT) on temporal perception was investigated by comparing simultaneity thresholds under unimanual and bimanual stimulation conditions. In the unimanual conditions the tactile stimuli were delivered to the same hand and were received by the same hemisphere, but in bimanual conditions, where stimuli were delivered to different hands, interhemispheric communication was necessary in order to compare the timing of the two stimuli. Randomised order of stimulating the fingers of the hands was compared with consistent stimulation of each hand. Previous studies have used only consistent stimulation. Thirty-two undergraduate university students (16 males and 16 females) were tested. Bimanual simultaneity thresholds were significantly higher than unimanual. Previous research showing an absence of laterality effects for simultaneity judgements was confirmed, supporting a hemispheric equivalence model of temporal processing. Simultaneity thresholds were not affected by randomisation of stimulus location, indicating that expectancy effects were not responsible for the difference between bimanual and unimanual thresholds. The implication of these findings is that temporal perceptions are affected by the process of interhemispheric transmission. PMID- 8697757 TI - A perspective from 25 years in critical care. PMID- 8697758 TI - Assumptions on LVSWI and PCWP flawed. PMID- 8697759 TI - Multiple organ failure: the final complication of critical illness. AB - The exact mechanisms responsible for the development and perpetuation of MOF are just beginning to be unraveled. Nurses must have an understanding of the progression of MOF and the physiologic and psychologic responses of the patient. Although caring for patients with MOF is not an easy task, the critical care nurse is in a pivotal role to make a difference in the outcome of these patients. PMID- 8697760 TI - Fournier's gangrene: assessment and management. PMID- 8697761 TI - Acute intermittent porphyria: a nursing case study. AB - Nursing care for a patient with AIP can be challenging. AIP is a complex disease with various signs and symptoms and is often misdiagnosed. Recognition of the signs and symptoms of AIP could be life-saving. Ways to avoid exacerbations, as well as counseling regarding possible genetic transmission, are important aspects of the nursing care of individuals with AIP. PMID- 8697762 TI - Thrombotic thrombocytopenic purpura: pathophysiology, treatment, and related nursing care. AB - The patient diagnosed with TTP presents to the critical care unit with myriad life-threatening problems. Knowledge of the pathophysiology and treatment of this rare syndrome is essential to plan care appropriately. However, despite immediate diagnosis and intervention, the outcome may not be successful. Critical care nurses play a vital role in caring for these patients, as well as helping family members deal with this devastating disease. PMID- 8697763 TI - Extracorporeal membrane oxygenation as therapy in refractory, reversible myocarditis. PMID- 8697764 TI - Meleney's synergistic gangrene: a case study. AB - Meleney's synergistic gangrene is caused by S aureus and streptococcus organisms. One of the identifying symptoms is the presence of extremely painful lesions, which usually form in the second week after surgery or minor trauma. The ulcers that form at the center of the lesion are usually covered by a black eschar and encircled by a gangrenous margin. With knowledge of the pathophysiology and characteristics of this process, nurses can aid in the recognition of this unexpected complication. Nursing interventions can be planned around the needs of these patients. The key to recovery is early identification of the infection and prompt treatment. PMID- 8697766 TI - Pain: assessment, treatment, and the coming thunder. Interview by Michael Villaire. PMID- 8697765 TI - Age-based limitation for ICU care: is it ethical? AB - Only under utilitarian analysis can age-based limitation to ICU care be justified. In all other frameworks, age is only one consideration in the decision to admit or not admit. Because Americans are reluctant to give larger shares of money to healthcare when it means excluding other social needs, the utilitarian argument will continue to be debated. PMID- 8697768 TI - Family presence--where would you want to be? PMID- 8697767 TI - The patient-driven system. Interview by Barbara Bronson Gray. PMID- 8697769 TI - Caring when curing is no longer possible. PMID- 8697770 TI - Update on interleukin-2. PMID- 8697771 TI - Credit where credit's due; it's the practitioner, not the path. PMID- 8697772 TI - Transjugular intrahepatic portosystemic shunt: an alternative. PMID- 8697773 TI - Minority attitudes toward organ donation. PMID- 8697774 TI - Ice floe. PMID- 8697775 TI - Rebleeding and vasospasm after subarachnoid hemorrhage: a critical care challenge. PMID- 8697776 TI - Meeting the needs of the dying patient's family. PMID- 8697777 TI - Assisting parents when a child dies in the ICU. PMID- 8697778 TI - Use of Passy-Muir tracheostomy speaking valve in mechanically ventilated neurological patients. PMID- 8697779 TI - Developing the nursing diagnosis of impaired oxygenation: abnormally low Svo2 value. PMID- 8697780 TI - Early heart-attack care--the critical paradigm shift toward prevention. Interview by Michael Villaire. PMID- 8697781 TI - Continuous fentanyl infusion in children following open-heart surgery. AB - Fentanyl can be an effective drug for managing sedation and blunting the stress responses in children who have pulmonary hypertension after undergoing open-heart surgery. However, expert nursing care is required to anticipate and assess complications associated with fentanyl infusion. The critical care nurse must be prepared to identify symptoms of narcotic withdrawal and intervene appropriately. In an effort to minimize the complications associated with fentanyl infusion, a care plan was developed that emphasizes the nursing diagnosis related to the care of an anesthetized infant or child in the intensive care unit (Table 2). This care plan is a guide to help critical care nurses care for an infant or child receiving a continuous fentanyl infusion. PMID- 8697782 TI - Cost vs quality of care: putting your money where your mouth is. PMID- 8697783 TI - A collaborative program for advanced practice in trauma/critical care nursing. AB - The students and faculty enrolled in the first TNP class have set a standard for future TNPs: a rigorous course of education with advanced practice and scholarship within an advanced practice collaborative model. Because of the increasingly number of trauma victims and the highly specialized care they require, nurses must come forward and provide quality care. The TNPs and their faculty must promote further recognition of the TNP role, become leaders in the field of acute care, and continue to develop and maintain collaborative relationship with physicians in support of advanced practice nursing in many areas of tertiary care. The first three graduates of the trauma/critical care practitioner class are now employed in advanced practice roles and are applying their education within trauma/critical care settings. Two of the students are trauma nurse practitioners in a community hospital, and one is a critical care nurse practitioner in a university hospital. Currently, there is an acute care nurse practitioner certification examination that is appropriate for nurses in the field of trauma/critical care. Co-sponsored by the AACN Certification Corporation and the American Nurses Credentialing Center, this examination is offered twice a year, in June and October. AACN is active in supporting and promoting the TNP role and, in conjunction with the American Nurses Association, has developed new standards of care and scope of practice to include this expanded role for the advanced practice nurse. The future for this exciting and demanding role looks bright for the advanced practice nurse interested in the care of the acutely ill patient. The time is right for this collaboration between nurses and physicians. PMID- 8697785 TI - The patient on display. PMID- 8697784 TI - Karen K Carlson: a short course on advanced cardiac life support. Interview by Michael Villaire. PMID- 8697786 TI - Pediatric pain management is a difficult issue. PMID- 8697787 TI - More on femoral artery pseudoaneurysm. PMID- 8697788 TI - Respiratory therapists are part of the team. PMID- 8697789 TI - Stunned myocardium: theoretical mechanisms of injury. AB - Stunned myocardium may occur after an episode of prolonged or transient ischemia. This phenomenon can occur in a variety of patient groups including medical, surgical, neurologic, and cardiac patients. In the stunned myocardium, myocardial contractility is temporarily depressed, causing symptoms similar to those of cardiogenic shock. When critical care nurses are familiar with the clinical characteristics and risk factors of stunned myocardium, they can start the appropriate interventions and left ventricular function returns to normal within days with no residual hypokinesis. Critical care nurses play a key role in assisting surgeons and other noncardiac physicians in the diagnosis and care of the patient with stunned myocardium. PMID- 8697790 TI - Removal of femoral sheaths by registered nurses: issues and outcomes. AB - The results of this evaluation indicate that specially trained critical care nurses can remove femoral sheaths with an acceptable margin of safety. As a result, these nurses can provide quality, cost-effective care to angioplasty patients. However, before this procedure is included as part of the RN's responsibility, written protocols are needed to identify appropriate patients, proper removal technique, and specific actions to take if complications occur. In addition, plans must be developed for initial education and ongoing competency evaluation to ensure that each nurse involved maintains an adequate knowledge base and skill level. PMID- 8697791 TI - Left ventricular diastolic dysfunction: a case report. PMID- 8697792 TI - From counterpulsation to paralysis: a case presentation. PMID- 8697793 TI - Reverse shunting through the patent foramen ovale following right ventricular infarction: nursing assessments and strategies. PMID- 8697794 TI - Intracoronary stent update: focus on patient education. PMID- 8697795 TI - Thoracoscopic surgery: a new approach to pulmonary disease. AB - VATS offers numerous advantages for patients with pulmonary disease. Diagnosis and management of numerous pulmonary and other thoracic conditions can now be treated with a less invasive approach. Because of this advance in technology, the ICU patient population is changing. With this advance, there will be fewer thoracotomies performed, resulting in fewer ICU admissions. Thoracoscopy offers hope for those critically ill patients who cannot withstand a diagnosis or interventional surgical procedure to treat their illness. PMID- 8697796 TI - Using the 12-lead ECG to detect ischemia, injury, and infarction. AB - The 12-lead ECG is extremely valuable in helping the critical care nurse detect the presence of myocardial ischemia, injury, and infarction. With an understanding of the 12-lead ECG, the nurse can relate the ECG findings to the patient's coronary artery disease and can anticipate the clinical consequences both for the functioning of the cardiac muscle and for the cardiac conducting system. PMID- 8697797 TI - Case management, critical pathways, and myocardial infarction. AB - Case management is an innovative way to simultaneously modify healthcare delivery, uphold standards of care, and reduce healthcare costs. The case manager oversees the patient's condition, progress, and consumption of resources. Information is constantly analyzed and used to regulate treatment plans in accordance with the critical pathways. The goal of this regulation is to produce outcomes that serve the patient and the healthcare system. The complexity of individualized patient care can require an unlimited number of pathways if all variances are considered. If all variances are not considered, then the quality of care is hindered, rehospitalization occurs, and the goals of the critical pathways are not achieved. Therefore, effective use of case management and critical pathways involves flexible guidelines, maintains focus on outcomes, enhances efficiency, increases cost-effectiveness, and retains a high quality of patient care. PMID- 8697798 TI - Cardiovascular toxicity with cancer chemotherapy. PMID- 8697799 TI - The three genes of the human FCGR1 gene family encoding Fc gamma RI flank the centromere of chromosome 1 at 1p12 and 1q21. AB - The high-affinity receptor for immunoglobulin G, Fc gamma RI (FCGR1), is encoded by a family of three genes within humans that share over 98% of DNA sequence homology. Efforts to define the location of the FCGR1 genes within chromosome 1 have been made to determine if they are tightly linked to the five other FCGR genes present at 1q23. Our results, obtained through both fluorescence in situ hybridization analysis of human cells and Southern analysis of cell lines containing 1p and 1q, show instead that the three genes flank the centromere of chromosome 1 at bands 1p12 and 1q21. FCGR1B was found at 1p12, whereas both FCGR1A and FCGR1C were localized to 1q21. This places the FCGR1 gene family within a large pericentric linkage group which is conserved between humans and mice. We hypothesize that the three FCGR1 genes were separated by a pericentric inversion known to have occurred on human chromosome 1, which relocated FCGR1A and FCGR1C to the long arm and left FCGR1B positioned on the short arm. We have also performed FCGR1 gene copy number experiments which indicate the existence of three FCGR1 genes within the human genome. PMID- 8697800 TI - Mapping of type I loci from human chromosome 7 reveals segments of conserved synteny on pig chromosomes 3, 9, and 18. AB - We have mapped in the pig (Sus scrofa) the genes for zona pellucida glycoprotein 3 (ZP3), erythropoietin (EPO), and malate dehydrogenase 2 (MDH2) by somatic cell hybrid analysis in the pig genome. Previously, the gene for the T-cell receptor beta cluster (TCRB) was assigned to SSC 18 and that for interleukin 6 (IL6) to SSC 9. However, statistical analysis of mapping data for ZP3, EPO, and MDH2 did not discriminate between SSC 9 and SSC 3. Porcine-specific PCR primers for ZP3 and IL6 were used to isolate probes from porcine YAC libraries. These two genes were mapped by FISH to porcine chromosome regions 3pter --> p15 (ZP3) and 9q14 - > q15 (IL6). Comparative mapping considerations permit the tentative assignment of porcine EPO and MDH2 to 3pter --> p15. PMID- 8697801 TI - The gene encoding protein-tyrosine phosphatase RPTP epsilon (PTPRE) is assigned to human chromosome 10q26. PMID- 8697802 TI - Evolution of the gonosomal heterochromatin of Microtus agrestis: rapid amplification of a large, multimeric, repeat unit containing a 3.0-kb (GATA)11 positive, middle repetitive element. AB - The sex chromosomes of Microtus agrestis are extremely large due to the accumulation of constitutive heterochromatin. We have cloned and characterized a 2,999-bp (GATA)n-positive sequence, following HaeIII digestion, that is confined to the noncentromeric heterochromatin of the X chromosome. The cloned element exhibits an accumulation of certain oligomers, which are scattered throughout its entire length, and several copies of Chi-related sequence motifs, which are thought to be implicated in recombination. The latter might have been responsible for the extensive amplification of homologous genomic elements. The sequence has been amplified to a copy number of 1-2 x 10(4) within the genome of M. agrestis. In contrast to many satellite DNAs, which are thought to be an inevitable constituent of constitutive heterochromatin, the sequence exhibits a tissue specific methylation pattern and is organized, not as a simple tandem array, but as a component of an extremely large, multimeric, higher-order repeat unit with a length of over 20 kb. This higher-order repeat accounts for at least 15-30% of the gonosomal heterochromatin in M. agrestis. Sequences homologous to pMAHAE2 are abundant in the genomes of all Microtus species. The copy number varies from approximately 100 per diploid genome in M. arvalis, M. oeconomus, and M. cabrerae to approximately 500 per diploid genome in M. guentheri and up to 1-2 x 10(4) in M. agrestis. Our molecular data indicate that the sequences of the pMAHAE2 family probably arose during the evolution of the common ancestor of Microtus and have subsequently been amplified extensively in the X chromosomes of M. agrestis in the phylogenetically very short period of less than 1 million years. PMID- 8697803 TI - A novel Kruppel-associated box containing the SSX gene (SSX3) on the human X chromosome is not implicated in t(X;18)-positive synovial sarcomas. AB - The human synovial sarcoma-specific translocation t(X;18) results in the fusion of the SYT gene on chromosome 18 with either one of the Kruppel-associated box (KRAB) containing SSX1 or SSX2 genes on the X chromosome, depending on the exact location of the breakpoint within band Xp11.2. Screening of a testis cDNA library yielded several SSX-positive clones. Subsequent sequence analysis revealed that one third of these clones represent an SSX gene that differs from both SSX1 and SSX2. This novel member of the family of KRAB containing SSX genes, which we designated SSX3, is 90% homologous to SSX1 and 95% homologous to SSX2 at the cDNA level. Somatic cell hybrid analysis indicated that SSX3 maps within Xp11.2 --> p11.1, the region that also harbors the SSX1 and SSX2 genes. However, we conclude from our RT-PCR data and from results reported in the literature that SSX3 does not act as a fusion partner to SYT in any of the 44 independent synovial sarcomas thus far tested. PMID- 8697805 TI - Karyotype and nuclear DNA content of the Australian lungfish, Neoceratodus forsteri (Ceratodidae: Dipnoi). AB - The karyotype of the lungfish, Neoceratodus forsteri, is described as 2n = 54, comprising 3 pairs of very large metacentrics, 1 pair of large submetacentrics, 13 pairs of smaller acrocentrics, and 10 pairs of microchromosomes. In addition to centromeric constitutive heterochromatin, C-bands were located on the arms of almost all of the macrochromosomes. The nuclear DNA content of N. forsteri was confirmed as being high (98.6-111.9 pg/nucleus). PMID- 8697804 TI - Seven genes from human chromosome 18 map to chromosome 24 in the bovine. AB - Bovine sequence tagged sites (STSs) were developed for seven genes and used for synteny mapping with a hybrid bovine x rodent cell line panel. The genes were thymidylate synthase (TYMS), pituitary adenylate cyclase activating peptide (ADCYAP1), and melanocortin-2 receptor (MC2R) from the short arm of human chromosome (HSA) 18 and N-cadherin (CDH2), transthyretin (TTR), gastrin-releasing peptide (GRP), and plasminogen activator inhibitor 2 (PAI2) from the long arm of HSA 18. Primers for these genes were designed with human, ovine, or bovine sequences aligned with a sequence from a second species. The bovine PCR product was cloned, and the fragment was sequenced to verify that the homologous gene was indeed amplified. A second set of bovine-specific PCR primers were developed for each gene from these sequences. These STSs were used for synteny mapping, and all seven genes were syntenic with markers of bovine chromosome (BTA) 24. The concordance with BTA 24 was at least 96.5% for all genes. PMID- 8697806 TI - The chromosomes of Nectomys (Rodentia, Cricetidae) with 2n = 52, 2n = 56, and interspecific hybrids (2n = 54) AB - Karyologic comparisons of Nectomys with 2n = 52 and 2n = 56, captured in different regions of Brazil, revealed the existence of two presumptive tandem fusions. These differences proved to represent drastic reproductive barriers between these two karyologic groups, based on an analysis of spermatogenesis in captive-bred hybrids (2n = 54). In these hybrid specimens, cytologic and histologic analyses indicated severe meiotic arrest and the presence of two trivalents in the first meiotic division, in which 26 elements were frequently observed. These findings and the sterility of crosses between F1 males and females as well as backcrosses indicated that Nectomys populations with 2n = 52 and 2n = 56 should be considered different species and that the present taxonomic arrangement of this genus must be reviewed. PMID- 8697807 TI - A somatic cell hybrid panel for pig regional gene mapping characterized by molecular cytogenetics. AB - A panel of 27 pig x rodent somatic cell hybrids was produced and characterized cytogenetically. The first step of this study consisted of hybridizing a SINE probe to GTG-banded metaphases of each hybrid clone in order to count and identify the normal pig chromosomes and to detect rearranged ones. The second step consisted of using the DNA of each clone as a probe after pIRS-PCR (porcine interspersed repetitive sequence-polymerase chain reaction) amplification to highly enrich it in pig sequences. These probes, hybridized to normal pig metaphase chromosomes, enabled the identification of the complete porcine complement in the hybrid lines. Whole chromosomes and fragments were characterized quickly and precisely, and results were compared. In addition to this cytogenetic characterization, molecular verification was also carried out by using primers specific to six microsatellites and to one gene previously mapped to pig chromosomes. The results obtained allow us to conclude that we have produced a panel that is informative for all porcine chromosomes. This panel constitutes a highly efficient tool to establish not only assignments of genes and markers but also regional localizations on pig chromosomes. PMID- 8697808 TI - Recent fusion events during evolution of pig chromosomes 3 and 6 identified by comparison with the babirusa karyotype. AB - The chromosomes of the babirusa, a species considered to have diverged from an ancestor of the pig during the Miocene epoch, about 12-26 million years ago, were studied to determine the sites of recent rearrangements during evolution of the domestic pig. It is shown that there is a pericentric inversion of the entire short arm on pig chromosome 1, compared to its counterpart in the babirusa (chromosome 15). We also present evidence suggesting that pig chromosome 3 was derived by a telomere-centromere fusion of two ancestral chromosomes homoelogous to babirusa chromosomes 12 and 17. Likewise, we conclude that pig chromosome 6 was most likely derived by a telomere-telomere fusion of ancestral chromosomes homoelogous to babirusa chromosomes 6 and 14. The detection of interstitial hybridization signals from presumptive subteloemeric repeats in the same chromosome region as the evolutionary fusion points on pig chromosomes 3 and 6 indicates that the fusion sites may still contain elements that are otherwise restricted to the telomere regions of pig chromosomes. PMID- 8697809 TI - Localization of rat K51 keratin-like locus (Krt10l) to human and animal chromosomes by in situ hybridization. AB - The rat K51 locus (gene symbol Krt10l) was mapped using isotopic in situ hybridization to rat chromosome 3, human chromosome 9, pig chromosome 6, cattle chromosome 18, and mink chromosome 1. PMID- 8697810 TI - Cloning, expression pattern and mapping to 12p 13.2 --> p13.1 of CLAPS3, a gene encoding a novel clathrin-adaptor small chain. AB - From a human fetal-brain cDNA library we isolated a novel gene encoding a peptide homologous to clathrin-adaptor small chains in rat, mouse, and yeast. The cDNA, designated CLAPS3 (clathrin-associated/assembly/adaptor protein, small 3, 22 kDa), contained an open reading frame of 579 nucleotides encoding 193 amino acids. Northern-blot analysis revealed expression of a 1.35-kb transcript in all human tissues examined. This gene was mapped to chromosome bands 12p13.2 --> p13.1 by FISH. PMID- 8697811 TI - Isolation and mapping of a human gene (SEC14L), partially homologous to yeast SEC14, that contains a variable number of tandem repeats (VNTR) site in its 3' untranslated region. AB - We have isolated a novel human gene, designated SEC14L, that contains tandemly repeated sequences in the 3' untranslated region. This gene includes an open reading frame of 2,145 bp encoding a 715-amino-acid protein. Partial homologies to yeast SEC14 and to retinal-binding protein (RALBP) of the Japanese flying squid suggest a possible role of the gene product in an intracellular transport system. As the predicted protein is also highly homologous to hypothetical proteins of C. elegans, evolutionary conservation is indicated. SEC14L, which was expressed in all human tissues examined, was localized to chromosome bands 17q25.1 --> q25.2 by fluorescence in situ hybridization. PMID- 8697812 TI - Isolation and mapping of a human gene (DIFF6) homologous to yeast CDC3, CDC10, CDC11, and CDC12, and mouse Diff6. AB - We have isolated a novel human cDNA that encodes a protein homologous to murine H5 and Diff6, and to yeast CDC10, and mapped it to chromosome region 2q37 by fluorescent in situ hybridization. Its transcript has an open reading frame of 1,218 nucleotides encoding 406 amino acids. The deduced peptide sequence contained conserved domains rich in basic residues, GXXGXGKS--DXXG--TKXD, a motif of the GTPase superfamily. Different polyA sites accounted for generation of two transcripts. The major type, 3.5 kb long, was expressed ubiquitously in all human tissues examined, but a 2.0-kb alternative transcript lacking any long AU-rich element in the 3' non-coding region was expressed abundantly only in testis, heart and skeletal muscle. PMID- 8697813 TI - Assignment of the gene for gp 130RB13-6 (Pdnpno) to rat chromosome band 1p12 by in situ hybridization. PMID- 8697814 TI - T-banding pattern of bovine chromosomes and karyotype reconstitution with physically mapped cosmids. AB - Bovine T-banded chromosomes were identified by fluorescence in situ hybridization (FISH) using 27 cosmid probes as chromosome landmarks. Pairwise combinations of probes from chromosomes of markedly different size were cohybridized to metaphase spreads of T-banded chromosomes. This confirmed the association of banding patterns to individual chromosomes. The T-banding pattern appears to be related to R-bands: 80% of T-bands were in corresponding position to R-bands, but not always conserved in size. Band assignments placed 20 probes on similar bands in both patterns. The identification of T-banded chromosomes represents a first step toward the construction of a compositional map of the bovine genome and an additional tool for its study on a comparative basis. PMID- 8697815 TI - Physical mapping of the gene for juvenile nephronophthisis (NPH1) by construction of a complete YAC contig of 7 Mb on chromosome 2q13. AB - Familial juvenile nephronophthisis (NPH) is an autosomal recessive cystic disease of the kidney that leads to end-stage renal failure in adolescence. NPH is the most common genetic cause of end-stage renal disease in children. A gene locus for nephronophthisis (NPH1) has been mapped by linkage analysis to chromosome 2q13. We report here the construction of a complete YAC contig in the minimum genetic region for NPH1 by STS content mapping using clones of the CEPH YAC libraries. A physical map of maximum distances between 32 STS markers was constructed, thereby defining the order of a total of 27 STS markers. Since D2S340 and D2S121 have previously been identified as flanking markers to the NPH1 gene, the new contig defines on a physical map the NPH1 minimum genetic region to a 6.4-Mb interval. As a novel assignment, expressed genes, some of which may be candidates for the disease, were localized to the NPH1 region. In addition, the known interstitial telomeric repeat on chromosome 2 was physically mapped to this region. This contig assembly provides the basis for closer definition of the NPH1 critical region through identification of more narrow flanking markers and for the construction of a transcriptional map of the region towards isolation of the NPH1 gene. PMID- 8697816 TI - Ordering of 66 STSs along the entire short arm of human chromosome 17 and chromosome assignment of a transcribed sequence (FMR1L2) homologous to FMR1. AB - Sixty-four PCR-markers previously assigned to the short arm of chromosome 17 and two newly established STSs were localized on a hybrid cell-YAC clone panel. The 66 STSs fell into 23 unique retention patterns, providing a map converting the entire short arm of human chromosome 17 with an average resolution of approximately 1.2 Mb. The combination of radiation-reduced hybrids, somatic cell hybrids and selected YAC clones enabled the precise localization of break-points in two cell hybrids. Since polymorphic STSs from the CEPH as well as the UTAH genetic map were used in this study, a physical link has been generated between these two high resolution genetic maps. FMR1L2, a second FMR1 autosomal homologue has been identified and assigned to a genomic interval between D17S796 and D17S799. PMID- 8697817 TI - Structures and chromosome locations of the human MEF2A gene and a pseudogene MEF2AP. AB - The MEF2 family of transcription factors control the expression of muscle specific and mitogen-induced genes. Here we describe the isolation and structure of the human MEF2A gene. The protein coding region of MEF2A is divided by 10 introns. The 3' untranslated region (UTR) is 3.7 kb in length, and it contains a region that is highly homologous with a portion of the 3' UTR of Xenopus MEF2A. A partially processed pseudogene (MEF2AP) corresponding to MEF2A was also isolated and characterized. Human MEF2A was mapped by fluorescence in situ hybridization to chromosome 15q26, and MEF2AP was mapped to chromosome 1q24 --> q25. PMID- 8697818 TI - Chromosomal mapping of the human genes CKS1 to 8q21 and CKS2 to 9q22. AB - The human cdk2/cyclin A kinase complex is a key regulator of the events of S phase. This complex contains several proteins involved in regulating its catalytic activity, including one or more of the CKS proteins, which have recently been shown to inhibit the activation of the cdk2 kinase. To investigate whether the CKS genes may be altered in human neoplasia, we mapped the chromosome locations of CKS1 and CKS2 by fluorescence in situ hybridization (FISH). CKS1 was localized to 8q21, a locus that is seldom grossly altered in cancer. The localization of CKS2 to 9q22 places it very near to a putative tumour suppressor locus suggested to be responsible for susceptibility to the Basal Cell Nervus Syndrome (BCNS or Gorlin's syndrome) familial cancer disorder. Six fibroblast cell lines isolated from patients with BCNS were demonstrated by FISH to have both copies of CKS2 present. Partial sequencing of a genomic clone of CKS2 revealed that the open reading frame lies over three exons. Examination of the six cell lines by SSCP and PCR-based sequencing of the parts of the three exons coding for the full length protein demonstrated no consistent divergence from the reported cDNA sequence in any exon. It is unlikely that CKS2 is the BCNS tumour suppressor gene. PMID- 8697820 TI - Teaching. Has the time come and gone? PMID- 8697819 TI - Update on COMPACCS. PMID- 8697821 TI - Pericardial effusion and cardiac tamponade diagnostic methods. Where are we headed? PMID- 8697822 TI - Predicting prognosis in advanced heart failure. Use of exercise indices. PMID- 8697823 TI - Ground glass attenuation on CT in patients with idiopathic pulmonary fibrosis. PMID- 8697824 TI - Protocol-driven respiratory therapy. Closing in on appropriate utilization at comparable cost and patient outcomes. PMID- 8697825 TI - Does inverse ratio ventilation predispose to pulmonary edema? PMID- 8697826 TI - Aerosolized drug delivery in the 90s. PMID- 8697827 TI - The diagnosis of pericardial effusion and cardiac tamponade by 12-lead ECG. A technology assessment. AB - OBJECTIVE: This study was designed to determine the diagnostic value of 12-lead ECG for pericardial effusion and cardiac tamponade. DESIGN: Cross-sectional study. SETTING: University hospital. PATIENTS: Hospitalized patients with and without pericardial effusion and cardiac tamponade. MEASUREMENTS AND RESULTS: In a blinded manner, we reviewed 12-lead ECGs from 136 patients with echocardiographically diagnosed pericardial effusions (12 of whom had cardiac tamponade) and from 19 control subjects without effusions. We examined the diagnostic value of three ECG signs: low voltage, PR segment depression, and electrical alternans. We found that all three ECG signs were specific but not sensitive for pericardial effusion (specificity, 89 to 100%; sensitivity, 1 to 17%) and cardiac tamponade (specificity, 86 to 99%; sensitivity, 0 to 42%). None of the ECG signs were associated with pericardial effusions of all sizes, but low voltage was associated with large and moderate pericardial effusions (odds ratio = 2.5; 95% confidence interval [CI] = 0.9 to 6.5; p = 0.06) and with cardiac tamponade (odds ratio = 4.7; 95% CI = 1.1 to 21.0; p = 0.004). In contrast, PR segment depression was associated only with cardiac tamponade (odds ratio = 2.0; 95% CI = 1.0 to 4.0; p = 0.05), while electrical alternans was not associated with either pericardial effusion or cardiac tamponade. CONCLUSIONS: Low voltage and PR segment depression are ECG signs that are suggestive, but not diagnostic, of pericardial effusion and cardiac tamponade. Because these ECG findings cannot reliably identify these conditions, we conclude that 12-lead ECG is poorly diagnostic of pericardial effusion and cardiac tamponade. PMID- 8697828 TI - The six-minute walk test predicts peak oxygen uptake and survival in patients with advanced heart failure. AB - BACKGROUND: The 6-min walk test (6'WT) is a simple measure of functional capacity and predicts survival in patients with moderate heart failure (HF). METHODS: To assess the role of the 6'WT in the evaluation of patients with advanced HF, 45 patients (age 49 +/- 8 years, mean +/- SD; New York Heart Association class 3.3 +/- 0.6; left ventricular ejection fraction 0.20 +/- 0.06; right ventricular ejection fraction 0.31 +/- 0.11) underwent symptom-limited cardiopulmonary exercise testing and the 6'WT during cardiac transplant evaluation. RESULTS: Mean 6'WT distance ambulated was 310 +/- 100 m and peak oxygen uptake (peak Vo2) was 12.2 +/- 4.5 mL/kg/min. There was a significant correlation between 6'WT distance ambulated and peak Vo2 (r = 0.64, p < 0.001). Multivariate analysis of patient characteristics, resting hemodynamics, and 6'WT results identified the distance ambulated during the 6'WT as the strongest predictor of peak Vo2 (p < 0.001). 6'WT distance ambulated less than 300 m predicted an increased likelihood of death or pretransplant hospital admission for continuous inotropic or mechanical support within 6 months (p = 0.04), but did not predict long-term overall or event-free survival with a mean follow-up of 62 weeks. Peak Vo2 was the best predictor of long-term overall and event-free survival. CONCLUSIONS: In patients with advanced HF evaluated for cardiac transplantation, distance ambulated during the 6'WT predicts (1) peak Vo2 and (2) short-term event-free survival. PMID- 8697829 TI - Corticosteroids in the treatment of tuberculous pleurisy. A double-blind, placebo controlled, randomized study. AB - Although several studies on tuberculous (TB) pleurisy suggest that the addition of corticosteroids to anti-TB therapy may have beneficial effects, these agents are not used routinely. To assess the effects of short-term oral prednisone therapy in TB pleurisy, 74 patients were randomly assigned in a double-blind fashion to treatment with either placebo or prednisone at a dose of 0.75 mg/kg/d for up to 4 weeks with gradual reduction over an additional 2 weeks. All subjects received a standard 3-drug anti-TB chemotherapy regimen for 6 months. TB pleurisy was diagnosed by histologic study and/or culture of pleural biopsy specimens obtained at thoracoscopy. Complete drainage of the effusion was performed simultaneously. Outcome measures were assessed periodically for 24 weeks, including indexes of morbidity and pleural thickening. After randomization, four patients were excluded from the final analysis. Of the 70 patients analyzed, 34 received prednisone and 36 received placebo. Demographic and clinical characteristics of the treatment groups were comparable at the time of hospital admission. Although a statistically significant improvement in symptoms occurred earlier in the prednisone group (8 weeks) than in the placebo group (12 weeks), between-group comparison showed no significant differences at any of the follow up evaluations. The proportion of subjects in the prednisone group (53.1%) with residual pleural thickening at 6 months did not differ significantly from that of the placebo group (60%). Pleural effusions did not recur in any of the patients. Initial complete drainage of the effusion was associated with greater symptomatic improvement than any subsequent therapy. We conclude that standard anti-TB therapy and early complete drainage is adequate for the treatment of TB pleurisy. The addition of short-term oral prednisone therapy neither results in clinically relevant earlier symptom relief nor confers a beneficial effect on residual pleural thickening. PMID- 8697830 TI - Miliary tuberculosis. Diagnostic accuracy of chest radiography. AB - STUDY OBJECTIVE: To assess the efficacy of the chest radiograph in identifying patients with miliary tuberculosis. DESIGN: Retrospective case-controlled review by three independent blinded chest radiologists. SETTING: Provincial tuberculosis control center. PATIENTS: Population-based sample, including all proved cases of miliary tuberculosis diagnosed in the Province of British Columbia, Canada, between November 1982 and November 1992. One hundred cases of miliary tuberculosis were identified, of which 71 had chest radiographs available for review. Forty-four normal chest radiographs and 20 chest radiographs of patients with localized pulmonary tuberculosis were also included as controls. MAIN OUTCOME MEASURES: The primary outcome of measurements was the sensitivity and interobserver variability of the chest radiograph in the diagnosis of miliary tuberculosis. The observers were also asked to describe the pattern and extent of pulmonary abnormalities based on the International Labor Organization (ILO) classification of pneumoconioses. RESULTS: The three independent observers identified 42, 44, and 49 of the 71 cases of miliary tuberculosis, respectively (sensitivity, 59 to 69%). The three observers incorrectly diagnosed miliary tuberculosis in 2, 0, and 2 of the 64 controls, respectively (specificity, 97 to 100%). There was good interobserver agreement (90%, kappa = 0.77). The nodules measured less than 3 mm in diameter in 90% of cases in which miliary tuberculosis was correctly identified. In 10% of cases, the nodules measured greater than 3 mm in diameter. The ILO profusion scores ranged from mild (profusion score 1) in 45% of cases, through moderate (profusion score 2) in 27%, and severe (profusion score 3) in 28%. CONCLUSIONS: The chest radiograph allowed identification of 59 to 69% of cases of miliary tuberculosis with a high specificity and good interobserver agreement. PMID- 8697831 TI - Interobserver reliability of the chest radiograph in community-acquired pneumonia. PORT Investigators. AB - OBJECTIVE: To evaluate the interobserver reliability of pulmonary radiographic findings in patients with community-acquired pneumonia (CAP). DESIGN: A prospective, multicenter study. SETTING: Physician offices, medical walk-in clinics, emergency departments, and inpatient wards affiliated with three university hospitals, one community hospital, and one staff model health maintenance organization in three geographic areas. METHODS: Copies of the initial chest radiograph of patients suspected of having CAP were independently read by two staff radiologists at the coordinating university hospital. Interobserver reliability for the interpretation for radiographic findings was assessed by calculation of agreement rates and the kappa statistic. PARTICIPANTS: Adults (age > or = 18 years) with symptoms or signs of CAP and a pulmonary radiographic infiltrate documented by a local study site radiologist. RESULTS: Among the 282 patients whose initial pulmonary radiographs were evaluated, there was agreement between the two staff radiologists on the presence of infiltrate in 79.4% and on the absence of an infiltrate in 6.0% (kappa = 0.37; 95% confidence interval [CI] = 0.22 to 0.52). For the 224 patients with an infiltrate identified by both radiologists, there was further agreement that the infiltrate was unilobar in 41.5% and multilobar in 33.9% (kappa = 0.51; 95% CI = 0.28 to 0.62), pleural effusion was present in 10.7% and absent in 73.2% (kappa = 0.46; 95% CI = 0.33 to 0.50), and the infiltrate was alveolar in 96.3% of patients and interstitial in no patients (kappa = -0.01; 95% CI = -0.03 to 0.00). Among the 210 patients with an alveolar infiltrate, both radiologists classified the infiltrate as lobar in 74.6% and bronchopneumonia in 2.4% (kappa = 0.09; 95% CI = -0.04 to 0.22), and agreed on the presence of air bronchograms in 7.6% and their absence in 52.9% (kappa = 0.01; 95% CI = -0.13 to 0.15). CONCLUSION: In patients with CAP, two university radiologists identified the presence of infiltrate, multilobar disease, and pleural effusion with fair to good interobserver reliability. However, interobserver reliability for the pattern of infiltrate and the presence of air bronchograms was poor. PMID- 8697832 TI - Chlamydia pneumoniae pneumonia in hospitalized patients. Clinical characteristics and diagnostic value of polymerase chain reaction detection in BAL. AB - STUDY OBJECTIVE: To evaluate the incidence and clinical characteristics of Chlamydia pneumoniae infection as detected by polymerase chain reaction (PCR) and culture of BAL in hospitalized patients with pneumonia, HIV-infected persons, and control subjects. DESIGN: Prospective, comparative clinical study. SETTING: University hospital medical center. PATIENTS: Fifty-seven hospitalized patients with acute lower respiratory tract infection (group 1); 47 HIV-positive patients (group 2); 100 patients with noninfectious bronchopulmonary disorders (group 3). INTERVENTIONS: BAL was performed in all patients at hospital admission for diagnostic purposes. In addition to semiquantitative bacterial and fungal culture, isolation and detection of C pneumoniae were performed by cell culture and PCR of the lavage fluid. MEASUREMENTS AND RESULTS: C pneumoniae was detected in 16% of group 1, 13% of HIV-positive persons, and 0% of control subjects. The sensitivity of chlamydial culture was much lower as compared with PCR (4 vs 15 cases). In contrast to group 1, in the HIV-positive patients, acute respiratory symptoms were not always present, and in 3 of 6 cases, copathogens were found in the BAL. BAL differential cell counts disclosed a significant lymphocyte elevation mostly due to the CD8 subset (group 1: 15% vs 5%; group II: 18.5% vs 4%; C pneumoniae positive vs negative cases, respectively). CONCLUSIONS: C pneumoniae is frequently detected in the BAL of hospitalized patients with pneumonia as sole pathogen. PCR detection is highly specific and far more sensitive than cell culture. Asymptomatic carriage seems to be uncommon in immunocompetent patients, but does occur in HIV-positive patients. A lymphocytic alveolitis is frequently found by BAL cytologic study and may represent a T-cell response to chlamydial infection in the lower respiratory tract. PMID- 8697833 TI - Respiratory failure in ANCA-associated vasculitis. AB - OBJECTIVE: To assess the prevalence, clinical manifestations, and course of respiratory failure in all patients who tested positive for antineutrophil cytoplasmic autoantibodies (ANCA) in our clinics in the period between January 1985 and January 1993. DESIGN: Case-series analysis. SETTING: Three teaching hospitals in the Netherlands. PATIENTS: Two hundred twenty consecutive patients suspected of having vasculitis and/or glomerulonephritis who tested positive for ANCA by indirect immunofluorescence and enzyme-linked immunosorbent assay. RESULTS: Sixty-two patients had pulmonary involvement. Acute respiratory failure developed in nine. Respiratory failure was related to infections in two of them and to ANCA-associated vasculitis in seven. These seven patients uniformly presented with pulmonary hemorrhage and diffuse pulmonary infiltrates. The diagnosis of systemic vasculitis was supported by the presence of a pulmonary renal syndrome in all patients, and by detection of antibodies to the proteinase 3 or myeloperoxidase antigen in all but one patient. Antiglomerular basement membrane antibodies were absent. The mortality was high due to hypoxic respiratory failure, pulmonary superinfections, and concomitant renal failure. CONCLUSIONS: Acute respiratory failure due to vasculitis developed in one of every nine patients with ANCA-associated pulmonary disease. Patients usually present with pulmonary infiltrates and hemoptysis. A diagnosis of vasculitis may be further supported by analysis of the urinary sediment and determination of the ANCA target antigen. It remains to be proved that early detection of ANCA favorably affects the outcome. PMID- 8697834 TI - A 12-year longitudinal study of Aspergillus sensitivity in patients with cystic fibrosis. AB - STUDY OBJECTIVE: The object of the study was to longitudinally follow immune parameters of Aspergillus fumigatus sensitization so as to predict those at risk for developing allergic bronchopulmonary aspergillosis (ABPA). DESIGN: Patients were evaluated for 5 immune parameters (skin test [ST], positive precipitating antibody [PPN], total IgE, IgE anti-A fumigatus antibody [IgE-Af], and IgG anti-A fumigatus antibody [IgG-Af]) at yearly intervals over a 12-year time period. SETTING: Patients were enrolled and evaluated during routine visits to the cystic fibrosis (CF) clinic at Cardinal Glennon Children's Hospital, St. Louis. PATIENTS: One hundred eighteen patients with documented CF participated. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Six patients were diagnosed as having ABPA. In the non-ABPA patient group, 42% had a positive ST, 42% were PPN positive, 54% had IgE-Af, 61% had IgG-Af, and 10% had an IgE greater than 1,000 IU/mL at some point in time. However, on follow-up, 18% lost skin reactivity, 54% lost-PPN, 53% lost IgE-Af, 45% lost IgG-Af, and IgE greater than 1,000 IU/mL declined more than 72% in 64% of patients. These losses were spontaneous, without systemic corticosteroid intervention. CONCLUSIONS: Spontaneous diminution and loss of immune parameters in non-ABPA CF patients prevented us from defining a profile of sensitivity likely to result in ABPA. This variability highlights the importance of obtaining follow-up studies and including clinical symptoms when considering the diagnosis of ABPA in patients with CF. PMID- 8697835 TI - Serum antibody response to influenza vaccine in pulmonary patients receiving corticosteroids. AB - OBJECTIVE: Despite the recommendation that patients with chronic lung diseases- many of whom receive corticosteroids--receive annual influenza vaccination, it is not known whether corticosteroids influence antibody response to influenza vaccine in this population. The purpose of this study was to assess whether patients with pulmonary conditions receiving long-term corticosteroid therapy develop an adequate antibody response. DESIGN: We prospectively studied 39 consecutive candidates for influenza vaccination, 25 of whom were receiving corticosteroids for underlying lung diseases. Patients with immunosuppression besides corticosteroids were excluded. Serum samples were obtained prior to and 1 month after vaccination with inactivated trivalent influenza vaccine and assayed for antibodies to the three strains using a hemagglutination inhibition assay. No patients had any intercurrent illness compatible with influenza during the study period and patients receiving corticosteroids continued treatment with them during this time. RESULTS: A fourfold rise in antibody titer at 1 month to at least one component was seen in 21 of 25 (84%) of corticosteroid-treated patients, which was similar to patients not receiving corticosteroids (11/14, 79%). There was no corticosteroid-antibody, dose-response relationship. CONCLUSIONS: Patients with pulmonary conditions receiving corticosteroids can generate an adequate antibody response to killed influenza virus vaccine. Long term therapy with corticosteroids should not preclude influenza vaccination in patients with chronic pulmonary diseases who are deemed vaccine candidates. PMID- 8697836 TI - Bronchiolitis in chronic pigeon breeder's disease. Morphologic evidence of a spectrum of small airway lesions in hypersensitivity pneumonitis induced by avian antigens. AB - We analyzed 36 open lung biopsy specimens from patients with chronic pigeon breeder's disease (PBD) to assess bronchiolar involvement and its relationship to the parenchymal pathologic abnormalities. Likewise, 21 biopsy specimens obtained from patients with usual interstitial pneumonia (UIP) were also examined. The bronchiolar abnormalities were scored by the method of Wright et al using a panel of photographs. In addition, the severity of lung fibrosis was evaluated in all samples and expressed as percentage in multiples of ten. A variable degree of epithelial cell metaplasia, bronchiolar inflammation and fibrosis, smooth muscle hypertrophy, extrinsic small airways narrowing, and intraluminal macrophages was observed in both diseases. Occasionally, hyperplasia of lymphoid follicles was also present. Bronchiolar changes were proportional in type and severity to the parenchymal damage. Spearman's nonparametric correlation between fibrosis in parenchyma and fibrosis in membranous bronchiole for the complete group (including patients with UIP and with PBD) showed a moderate but significant association (R = 0.51; p < 0.01). A significant association was also demonstrated when the score for bronchiolar fibrosis and inflammation was evaluated in relation to lung fibrosis divided in high degree (> 50%) and low degree (< 50%), respectively. In the case of patients with PBD, the correlation between bronchiolar and parenchymatous fibrosis was of 0.33 (p < 0.05). In general, bronchiolar fibrosis was less severe and inflammation more severe in PBD lungs compared with patients with UIP. Fibrosis in membranous bronchioles correlated with increased mortality in the complete group of patients, but the impact on mortality disappeared after correcting for overall fibrosis in the biopsy sample. Our findings demonstrate that a spectrum of bronchiolar lesions is usually observed in chronic PBD lungs, although the predominant pattern is similar to that found in the surrounding parenchyma, suggesting that the damage occurs in parallel. PMID- 8697837 TI - Disease progression in usual interstitial pneumonia compared with desquamative interstitial pneumonia. Assessment with serial CT. AB - OBJECTIVE: To determine the outcome of areas of ground-glass attenuation and assess disease progression on serial high-resolution CT (HRCT) scans of patients with biopsy specimen-proved usual interstitial pneumonia (UIP) and desquamative interstitial pneumonia (DIP). MATERIALS AND METHODS: Twelve patients with biopsy specimen-proved UIP and 11 patients with biopsy specimen-proved DIP who had initial and follow-up HRCT scans (median interval, 10 months) were reviewed. Eleven patients with UIP and 11 with DIP received treatment between the initial and follow-up CT scans. The scans were evaluated for the presence and extent of ground-glass attenuation, irregular linear opacities and honeycombing, and overall extent of parenchymal involvement. RESULTS: On initial CT scans, all 12 patients with UIP had areas of ground-glass attenuation (mean +/- SD extent, 30 +/- 16%) and irregular lines (mean +/- SD extent, 17 +/- 7%) and 10 patients had honeycombing (mean +/- SD extent, 10 +/- 6%). All 11 patients with DIP had areas of ground-glass attenuation on initial HRCT scans (mean +/- SD extent, 51 +/- 26%), 5 patients had irregular linear opacities (mean +/- SD extent, 5 +/- 5%), and 1 patient had honeycombing. Nine of the 12 patients with UIP showed increase in the extent of ground-glass attenuation (n = 6) or progression to irregular lines (n = 2) or honeycombing (n = 4) on follow-up as compared with only 2 patients with DIP who showed progression to irregular lines (n = 1) or honeycombing (n = 1) (p < 0.01 chi 2 test). CONCLUSION: In patients with UIP, areas of ground-glass attenuation usually increase in extent or progress to fibrosis despite treatment. Areas of ground-glass attenuation in most patients with DIP remain stable or improve with treatment. PMID- 8697838 TI - Mast cells in bronchiolitis obliterans organizing pneumonia. Mast cell hyperplasia and evidence for extracellular release of tryptase. AB - Idiopathic bronchiolitis obliterans organizing pneumonia (BOOP) is characterized by air space inflammation and fibrosis of unknown origin. The pathogenesis of the inflammatory reaction and fibrosis in fibrotic lung disorders remains unclear; however, recent attention has focused on the potential role of the mast cell in the genesis of fibrosis. To determine whether mast cells are implicated in the pathogenesis of BOOP, mast cells were identified in BAL fluid and in transbronchial lung biopsy specimens from 11 patients affected by BOOP and 17 control subjects. Mast cells and tryptase were significantly increased in BAL fluid of patients with BOOP (p = 0.001 and p = 0.03, respectively). In lung tissue of patients with BOOP, there was an increased number of mast cells per square millimeter of lung tissue with respect to control group (p = 0.001). Seventy-three percent of mast cells were found in the alveolar septa, 18% within alveoli often plunged in organizing pneumonia, 4% among alveolar lining cells, and 6% along blood vessels. No mast cells were located within alveoli in control subjects. Mast cell degranulation was evident in lung tissue specimens of patients with BOOP but not in those of control subjects (p = 0.01). This study shows the importance of mast cells and mast cell activation in the pathogenesis of BOOP. PMID- 8697839 TI - Can pulmonary angiography be limited to the most suspicious side if the contralateral side appears normal on the ventilation/perfusion lung scan? Data from PIOPED. Prospective Investigation of Pulmonary Embolism Diagnosis. AB - PURPOSE: The purpose of this investigation was to determine the frequency of pulmonary embolism (PE) in a single lung that showed a normal ventilation/perfusion (V/Q) lung scan when the V/Q scan on the contralateral side was interpreted as non-high-probability for PE. METHODS: Data are from the national collaborative study Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). PE was diagnosed or excluded in all lungs by pulmonary angiography. RESULTS: Single lungs with no V/Q abnormalities, when the V/Q scan on the contralateral side was interpreted as non-high-probability for PE, showed PE in 2 of 19 (11%) (95% confidence interval [CI], 1 to 33%). If PE was excluded by angiography on the side of the abnormal V/Q scan, then PE on the side of the normal V/Q scan was shown in only 1 of 19 (5%) (95% CI, 0 to 26%). CONCLUSION: A normal V/Q scan in a single lung, when the contralateral lung was interpreted as non-high-probability for PE, did not completely exclude PE on the apparently normal side. In such lungs, the probability of PE was in the range of low probability interpretations. If the pulmonary angiogram showed no PE on the side of the abnormal V/Q scan, the probability of PE on the side of the normal V/Q scan satisfied the definition of very low probability for PE. This observation in patients undergoing pulmonary angiography may assist in determining whether the pulmonary angiogram should be bilateral. PMID- 8697840 TI - Pulmonary embolism among patients with a nearly normal ventilation/perfusion lung scan. AB - BACKGROUND: Among patients with nearly normal ventilation/perfusion (V/Q) lung scans in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED), pulmonary embolism (PE) was diagnosed more frequently in those who underwent pulmonary angiography than in those in whom PE was diagnosed on the basis of an adverse outcome while receiving no anticoagulant therapy. This may suggest that an adverse outcome is not apparent in patients with PE of such mild severity that the V/Q scan is nearly normal. If this were the case, patients with mild PE might not require treatment. PURPOSE: The purpose of this investigation was to evaluate patients in PIOPED with nearly normal-V/Q lung scans. The V/Q scans and clinical characteristics of those in whom PE was diagnosed or excluded by pulmonary angiography (angiography group) were compared with those in whom PE was diagnosed or excluded by the presence or absence of an adverse outcome while not receiving anticoagulant therapy (outcome group). If the characteristics were the same, it would suggest that some patients with mild PE do well without treatment. If the characteristics were different, it would indicate that there is no evidence from these data that mild PE need not be treated. METHODS: Data from PIOPED were evaluated from patients with suspected acute PE who had V/Q scans interpreted as nearly normal. There were 75 patients in the angiography group and 90 patients in the outcome group. Patients with entirely normal V/Q scans were excluded. RESULTS: PE was more frequent in the angiography group than in the outcome group, 8 of 75 (11%) vs 0 of 90 (0%) (p < 0.01). In patients with nearly normal V/Q scans who were in the outcome group in comparison to the angiography group, the V/Q scan showed fewer mismatched segmental perfusion defects, a lower percentage of low-probability V/Q interpretations by one of the two V/Q readers (compared with very low or normal probability), and a generally lower clinical assessment. CONCLUSION: The observed lower frequency of PE in the outcome group in comparison to the angiography group can be attributed to a lower likelihood of PE in this group of patients with nearly normal V/Q scans in comparison to those who underwent pulmonary angiography. There is no evidence from these data that occasional patients with nearly normal V/Q scans who have PE do not require treatment. PMID- 8697841 TI - Parenchymal scarring is associated with restrictive spirometric defects in patients with chronic thromboembolic pulmonary hypertension. AB - The finding of a restrictive pulmonary defect may divert clinicians from considering the diagnosis of chronic thromboembolic pulmonary hypertension because lung volumes are usually normal in this disorder. We have, however, encountered a significant number of these patients with reduced lung volumes. Furthermore, we have observed many patients who have developed parenchymal scars and/or pleural thickening. To determine whether such findings are associated with lung volume restriction, we analyzed patients evaluated at our institution for chronic thromboembolic pulmonary hypertension over a 20-month period in whom thoracic high-resolution CT scans and pulmonary function testing had been performed. Patients with obstructive or restrictive lung disease from another cause were excluded. We compared the presence of lung restriction (total lung capacity below 80% of predicted) with the extent of parenchymal scarring, pleural thickening, and pulmonary artery diameter on CT scans. Of 191 patients evaluated, 51 met criteria for entry. Eleven patients (22%) had lung restriction. Parenchymal scarring was highly associated with lung restriction (p = 0.01). Neither pleural thickening (p = 0.08) nor pulmonary artery diameter (p = 0.80) was associated with lung restriction. CONCLUSIONS: A significant number of patients with chronic thromboembolic pulmonary hypertension may have restrictive lung defects. The restriction may be due to parenchymal scarring. PMID- 8697842 TI - Tracheobronchial constriction in asthmatics induced by isocapnic hyperventilation with dry cold air. AB - Although it is well known that isocapnic hyperventilation (IHV) with dry cold air produces airway constriction in asthmatic subjects, the site of airway narrowing is nuclear. To address this issue, we have quantified the tracheal and bronchial response to IHV with dry cold air in 15 patients with mild asthma and 7 healthy control subjects. We employed the acoustic reflection technique to evaluate changes in airway cross-sectional areas caused by IHV with dry cold air. Airway areas were measured during tidal breathing before and 5 to 10, 30, 60, and 90 min following cold air challenge. For analysis purposes, airway areas were divided into three anatomic segments: extrathoracic tracheal segment, intrathoracic tracheal segment, and main bronchial segment. These segments were assessed at a fixed volume below total lung capacity. Maximal and partial expiratory flow volume curves were also obtained before each set of area measurements. In normal subjects, IHV with dry cold air caused no significant changes in FEV1, flow at 30% of the vital capacity in the partial curve (V30p), or airway areas. In asthmatics, at 5 to 10 min after challenge, we found that FEV1 decreased by 22 +/ 5% (mean +/- SEM) (p < 0.0001), V30p by 33 +/- 8% (p < 0.003), intrathoracic tracheal area by 10.7% +/- 2% (p < 0.03), and main bronchial area by 14 +/- 3% (p < 0.003). At 30 min, tracheal and main bronchial areas were returned to baseline levels; however, FEV1 and V30p were still significantly decreased, by 13 +/- 3% and 16 +/- 4%, respectively. We conclude that in asthmatics, IHV with dry cold air causes both tracheal and bronchial constriction, and that recovery seems to occur first in the central airways. PMID- 8697843 TI - The cost of treating COPD patients with long-term oxygen therapy in a French population. AB - OBJECTIVE: In greater Paris and its surrounding (as it is in all France), oxygen is home delivered by not-for-profit (NP) associations or profit-making (PM) health organizations. Both are financed by the national health insurance. This dual context and the current economic climate justify an economic evaluation of all respiratory care for patients with COPD receiving long-term oxygen therapy (LTO). This pragmatic approach identifies the variables that have the greatest impact on direct medical costs and estimates the annual cost for respiratory care per COPD patient. DESIGN: Retrospective study. SETTING: Health insurance scheme for self-employed professionals (CANAM). PATIENTS AND METHODS: Between July 1985 and March 1994, 234 patients registered in CANAM files began LTO, 24% in the PM sector, 76% in the NP sector, mainly using concentrator (78%), mean age of 74 +/- 10 years, male predominance (74%), PaO2 of 56.2 +/- 10.5 mm Hg, FEV1/FVC of 43 +/ 15%, and 51% having 1 or more severe illness(es) associated. The economic appraisal was performed on a representative sample of 61 patients and measured the total resources consumption for respiratory care per COPD patient and per year (physician visits and tests, drugs, physiotherapy, oxygen therapy, hospitalizations for acute respiratory failure, transport costs). RESULTS: A quarter of the patients in each sector did not meet the LTO prescription guidelines (PaO2 > 60 mm Hg). For patients having their oxygen delivered by NP sector, the total ambulatory cost for respiratory care was lower ($4,506 per patient and per year vs $5,399) because they mainly used concentrator, all the other direct ambulatory costs being equal. The total annual cost for respiratory care of a COPD patient receiving LTO amounted to $11,672 (NP and PM sectors merged). Oxygen therapy represented 73% of the total ambulatory cost. In a multiple linear regression model, hospitalization represented the largest share of cost, significantly higher when PaO2 was 55 mm Hg or less ($2,287 per patient per year vs $8,717). In contrast, none of the covariates (age, sex, PaO2, FEV1/FVC) influenced at a significant level the total cost of visits, tests, drugs, and physiotherapy, amounting to $1,507. CONCLUSION: As oxygen treatment plays an important role in the variation of costs, further pragmatic studies should help to better understand what are the real motivations to choose one mode of oxygen administration more than another and should determine factors that may lead physicians sometimes not to comply with clinical guidelines. PMID- 8697844 TI - Adjusting FVC for the effect of obstruction. AB - OBJECTIVE: To derive a method of taking into account the effects of obstruction on the FVC, allowing more accurate assessment of other negative ("restrictive") influences. DESIGN: In 656 subjects with airways obstruction, defined as FEV1/FVC of 0.70 or less, regression of FVC was expressed as percentage of predicted value (FVC %PRED) on potential explanatory variables, including FEV1/FVC. The resulting equation was used to adjust FVC %PRED in 530 other obstructed men, to test whether the adjustment resulted in a different relationship of FVC %PRED to body weight. SETTING: A large occupational respiratory surveillance program utilizing rigorously quality-assured and standardized spirometry. SUBJECTS: The study included 5,188 men aged 45 to 65 years who denied fibrogenic dust exposures, including 656 with airways obstruction. RESULTS: There was a significant (p < 0.0001) linear relationship between more severe obstruction (lower FEV1/FVC) and lower FVC %PRED. Depending on which of several predictive equations is used, obstruction explains 15 to 17% of variability in FVC %PRED over the entire range of severity of obstruction. Adjusting for obstruction in the separate group of 530 subjects showed a significantly larger effect of body weight on FVC %PRED. CONCLUSION: A simple equation can be used to discount the negative effects of obstruction on FVC. This allows more accurate clinical interpretation and can be useful in the analysis of epidemiologic data. PMID- 8697845 TI - Physician-ordered respiratory care vs physician-ordered use of a respiratory therapy consult service. Results of a prospective observational study. AB - OBJECTIVE: To assess the impact of a respiratory therapy consult service (RTCS) on practices and appropriateness of ordering respiratory care services. DESIGN: Nonrandomized prospective observational cohort study with concurrent controls. SETTING: Adult non-ICU inpatient wards of an academic medical center. PATIENTS: A convenience sample of 98 adult non-ICU inpatients at the Cleveland Clinic Hospital, representing 20 inpatient clinical services. Patients whose respiratory care plans were determined by respiratory care practitioners using sign and symptom-based algorithms to specify treatment comprised the treatment group (n = 51, respiratory therapy consult group). The nonconsult group (n = 47) were patients whose respiratory care plans were specified by their own physicians. INTERVENTION: Specification of the respiratory care plan by the RTCS vs by the physicians themselves. Use of the RTCS was at the discretion of the managing physician. OUTCOME MEASURES: Types and number of respiratory care treatments, length of hospital stay, costs of the respiratory therapy provided, appropriateness of respiratory care orders (based on comparison of the actual respiratory care orders with a reference respiratory care plan generated by a study investigator who was kept blind to the actual respiratory care plan), and adverse respiratory events. RESULTS: Patients for whom the RTCS was requested by their physicians had a greater severity of respiratory illness based on having a lower triage score, but were otherwise similar at baseline. Fewer initial orders for respiratory care were discordant with the reference algorithms in RTCS patients (15% +/- 26% [SD]) than in nonconsult patients (43% +/- 36%; p < 0.001), and a smaller fraction of RTCS patients received at least one discordant initial respiratory care order (37% vs 72%; p < 0.001). Though provided to sicker patients with longer lengths of hospital stay, RTCS-directed care incurred similar respiratory care costs per patient ($335.63 +/- $272.69 [RTCS] vs $349.06 +/- $273.27; p = 0.72). CONCLUSIONS: These results suggest that the RTCS can be an effective strategy to allocate respiratory care strategies appropriately while conserving the costs of providing respiratory care. PMID- 8697846 TI - Clinical strategies to reduce utilization of chest physiotherapy without compromising patient care. AB - BACKGROUND: There is widespread interest in the evaluation of clinical strategies that safely reduce health-care costs. Elimination of inappropriate chest physiotherapy may represent one of those strategies. SETTING: An academic community hospital. METHODS: One-hundred one patients receiving chest physiotherapy were prospectively randomized to continue their chest physiotherapy or to inform their physicians that the order for the chest physiotherapy may have been inappropriate. RESULTS: Patients who were randomized to have their chest physiotherapy discontinued received 45% fewer chest physiotherapy treatments than control patients (p < 0.01). There was no increase in the mortality rate or length of hospital stay associated with the reduction in chest physiotherapy in carefully selected patients. The estimated cost savings would be $319,000, which is 50 times greater than the cost associated with the intervention. CONCLUSION: Chest physiotherapy is frequently provided to patients for inappropriate indications. Reducing chest physiotherapy for these patients may significantly reduce respiratory therapy costs without increasing length of stay or mortality rates. PMID- 8697847 TI - Elevation of interleukin-10 levels in malignant pleural effusion. AB - STUDY OBJECTIVE: Human immunity has been found to have two major components, cellular and humoral immunity. T-helper type 1 (Th1) pathway favors cellular immunity and Th2 pathway favors humoral immunity. Early determination toward Th1 and Th2 cells in the immune response is dependent on the balance between interleukin-12 (IL-12), which favors Th1 responses, and IL-4, which favors Th2 responses. IL-2 and interferon-gamma (IFN-gamma) are produced in the Th1 pathway, and IL-4 and IL-10 are produced in the Th2 pathway. Lack of cellular immunity, IL 2, and IFN-gamma had been reported in malignant pleural effusions. However, to our knowledge, there are no previous reports on other cytokine components involving Th1 or Th2 pathway. The present study was designed to answer these questions. DESIGN: Cytokine levels in peripheral blood and pleural fluid of 21 patients with malignant pleural effusion, including IL-4, IL-10, and IL-12, were analyzed with enzyme-linked immunosorbent assays. Lymphocyte subpopulations of peripheral blood and pleural effusion were also studied by using flow cytometry. MEASUREMENTS AND RESULTS: The results showed a significant increase in IL-10 level as compared with blood samples. IL-4 and IL-12 were below minimal detectable concentrations both in the blood and the effusion. The ratio of pleural helper T cells was significantly higher than in the blood (p = 0.0002). The ratio of pleural natural killer (NK) cells was significantly lower than in the blood (p = 0.0001). The ratio of pleural suppressor T cells was lower than blood with borderline significance (p = 0.0522). No significant change in B lymphocyte ratio between blood and pleural effusion was found (p = 0.2471). There was no correlation between difference in IL-10 level and lymphocyte subpopulation of pleural effusion and blood samples. CONCLUSIONS: Helper T-cell subpopulations were increased while NK and suppressor T-cell subpopulations were decreased in malignant pleural effusions. The decrease in NK cell subpopulations with elevated IL-10 and minimal IL-12 concentration in neoplastic pleural effusion would suggest the usage of IL-12 or antibody of IL-10 to improve local cellular immunity. Further study is needed. PMID- 8697848 TI - Relationship of early postoperative dysrhythmias and long-term outcome after resection of non-small cell lung cancer. AB - STUDY OBJECTIVES: To determine whether supraventricular tachydysrhythmias (SVTs) occurring early after thoracic surgery for non-small cell lung cancer (NSCLC) are associated with poor long-term survival. DESIGN: Prospective, cohort. SETTING: Referral cancer center. PATIENTS: Seventy-eight patients undergoing resection of NSCLC. INTERVENTIONS: Examination of univariate and multivariate effects of factors that might influence long-term survival: advanced age, sex, perioperative chemotherapy, extent of pulmonary resection, tumor stage, and SVT occurrence. RESULTS: In this group of patients, 10 of 78 (13%) developed early postoperative SVT. Log-rank analysis showed SVT occurrence (p = 0.01), age of 70 years or older (p = 0.04), and perioperative chemotherapy (p = 0.005) to predict poor long-term survival. Multivariate Cox regression analysis identified SVT occurrence (p = 0.007; relative risk [RR], 2.8; 95% confidence interval [CI], 1.3 to 6.1) and perioperative chemotherapy (p = 0.004; RR, 2.6; 95% CI, 1.4 to 5.1) to be independently associated with decreased survival. No other clinical or laboratory characteristic tested differentiated those patients who did or did not develop postoperative SVT. CONCLUSIONS: Early SVT occurrence after resection of NSCLC is associated with poor long-term survival. Although the etiology for this is unclear, this intriguing observation, not previously reported (to our knowledge), may be used in larger trials examining the effects of these and other factors on survival from lung cancer surgery. PMID- 8697849 TI - Pulmonary function and clinical observations in men with congenital bilateral absence of the vas deferens. AB - Congenital bilateral absence of the vas deferens (CBAVD) was once thought to be a distinct clinical entity, but genetic similarities in men with cystic fibrosis (CF) and CBAVD are described increasingly. We evaluated the clinical status, growth and nutritional state, and respiratory function of 18 men with CBAVD to determine whether these men with different CF transmembrane regulator (CFTR) genotypes may have clinical evidence of mild CF. Following a thorough history and examination, pulmonary function tests, sweat test, and renal ultrasound were performed. Genetic evaluation for 50 known CF mutations, screening for private mutations (single-strand conformational polymorphism and direct sequencing), and assay of the length of the polypyrimidine tract in the splice site acceptor of intron 8 was performed. A history of pulmonary disease was present in three, and an additional man had some features suggestive of malabsorption. Results of general physical examination and anthropomorphic measurements were unremarkable in all patients, with a mean (SD) body mass index of 26 (3). Pulmonary function tests of large and small airway function as well as lung volumes were normal in all except one whose results were consistent with moderate asthma. Five men were compound heterozygotes for CFTR mutations, four of whom had positive sweat tests (sweat chloride > 60 mEq/L). Twelve men were heterozygotes for CFTR mutations while no mutations were identified in one man. Although putative etiologic factors may suggest that men with CBAVD and CFTR mutations could be considered within the spectrum of clinical CF, the authors suggest that in men with CBAVD without any other clinical features of CF, the diagnosis of CF may not be made. PMID- 8697850 TI - Regulation of breathing and perception of dyspnea in healthy pregnant women. AB - STUDY OBJECTIVE: To examine if the perception of dyspnea during normal pregnancy may be related to an inappropriate ventilatory response to the increased metabolic rate, due to a higher chemosensitivity. PATIENTS AND INTERVENTIONS: At weeks 12, 24, and 36 of gestation and 4 months after delivery, 11 healthy pregnant women with dyspnea and 12 asymptomatic pregnant women were studied. Progesterone plasma levels, lung volumes, diffusion capacity, maximal respiratory pressures, rest oxygen uptake, breathing pattern, and mouth occlusion pressure (P0.1) were measured. Progressive isocapnic hypoxic stimulation and progressive hyperoxic hypercapnic stimulation were performed. RESULTS: Oxygen ventilation equivalent during pregnancy was significantly higher for the dyspneic group than for nondyspneic pregnant women. Dyspneic patients exhibited greater minute ventilation, tidal volume, and P0.1 than the nondyspneic group. The mean values of ventilatory and P0.1 slopes to hypoxia and CO2 during pregnancy were significantly greater in the patients with dyspnea than in asymptomatic subjects. These changes were not due to differences in progesterone plasma levels. A significant relation among the Borg score, inspiratory drive, and chemosensitivity was found. CONCLUSIONS: In some pregnant women, a higher sensitivity to CO2 and hypoxia may induce excessive ventilation to metabolic demand, which would contribute to dyspnea. PMID- 8697851 TI - Thoracoabdominal pattern of breathing in neuromuscular disorders. AB - STUDY OBJECTIVE: To assess abnormalities in thoracoabdominal pattern of breathing (TAPB) in neuromuscular disorders during spontaneous breathing, intermittent positive pressure ventilation (IPPV) with and without abdominal (AB) binder, and immediately after IPPV. DESIGN: Repeated measures design: Pre-IPPV spontaneous breathing, IPPV, IPPV with AB binder, and post-IPPV spontaneous breathing. In protocol 1, ventilator pressure was held constant at the individual value habitually adopted in sessions of IPPV. In protocol 2, it was increased stepwise from 5 to 30 cm H2O. SETTING: University hospital, Department of Pediatrics, Intensive Care, and Neuro-Ventilatory Rehabilitation. PATIENTS: Thirty-one patients with spinal muscular atrophy (SMA) and 19 patients with myopathy, mean age (+/- SD) 9.7 +/- 3 years. MEASUREMENTS: Tidal volume (VT), percent thoracic contribution to VT (%RC), the phase angle between the thoracic and the AB volume changes and the labored breathing index, which is an index of asynchrony taking into account both the phase relationships and relative volumes of rib cage and AB compartments. RESULTS: We observed marked abnormalities in TAPB during spontaneous breathing, especially in the SMA group. %RC, labored breathing index, and phase angle displayed nearly normal values during IPPV. IPPV pressures of 25 to 30 cm H2O were necessary to increase %RC above 80%. AB binding decreased VT, but led to larger thoracic volumes, especially in patients with SMA. Thoracic contribution to VT and thoracic volume after IPPV were higher than baseline levels. CONCLUSIONS: The quantitative assessment of TAPB enhances the ability to estimate pulmonary function in neuromuscular disorders, and the efficiency of mechanical ventilation. PMID- 8697852 TI - Plasma concentrations of atrial, brain, and C-type natriuretic peptides and endothelin-1 in patients with chronic respiratory diseases. AB - We measured plasma concentrations of atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP, respectively) and endothelin-1 in 20 patients with chronic respiratory diseases (CRD) to establish whether these peptides are increased in patient groups with CRD (group A, PaO2 > or = 60 mm Hg; group B, PaO2 < 60 mm Hg) and whether a correlation exists between the levels of natriuretic peptides or endothelin-1, and blood gas variables. In patients receiving long-term oxygen therapy (LTOT), plasma ANP, BNP, and endothelin-1 were compared before and after LTOT. We compared the levels of plasma ANP, BNP, and endothelin-1 in the presence or absence of right heart overloading (RHO) found in the ECG. Plasma ANP and BNP levels in group B patients were higher than those in group A and control subjects, and endothelin-1 in group B patients was higher than in control subjects. Inverse correlations were found between PaO2 and levels of plasma ANP, BNP, and endothelin-1. Plasma ANP, BNP, and endothelin-1 decreased significantly 25.4 days after LTOT. In 10 patients with RHO findings in the ECG, plasma ANP and BNP levels were significantly elevated compared with those in patients without RHO. These findings show that plasma ANP, BNP, and endothelin-1 are elevated according to the degree of hypoxemia, and they suggest that decreases in plasma ANP, BNP, and endothelin-1 may be used as indexes of the improvement by LTOT, and that plasma ANP and BNP may represent markers of RHO. PMID- 8697853 TI - Predicting the duration of mechanical ventilation. The importance of disease and patient characteristics. AB - STUDY OBJECTIVE: To analyze the determinants of an individual patient's duration of mechanical ventilation and assess interhospital variations for average durations of ventilation. DESIGN: Prospective, multicenter, inception, cohort study. SETTING: Forty-two ICUs at 40 US hospitals. PATIENTS: A total of 5,915 patients undergoing mechanical ventilation on ICU day 1 selected from the acute physiology and chronic health evaluation (APACHE) III database of 17,440 admissions. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Utilizing APACHE III data collected on the 5,915 patients, multivariate regression analysis was performed on selected patients and disease characteristics to determine which variables were significantly associated with the duration of mechanical ventilation. An equation predicting duration of ventilation was then developed using the significant predictor variables and its accuracy was evaluated. Variables significantly associated with duration of ventilation included primary reason for ICU admission, day 1 acute physiology score (APS) of APACHE III, age, prior patient location and hospital length of stay, activity limits due to respiratory disease, serum albumin, respiratory rate, and PaO2/FIo2 measurements. Using an equation derived from these variables, predicted durations of ventilation were then calculated and compared with actual observed durations for each of the 42 ICUs. Average duration of ventilation for the 42 ICUs ranged from 2.6 to 7.9 days, but 60% of this variation was accounted for by differences in patient characteristics. CONCLUSIONS: For patients admitted to the ICU and ventilated on day 1, total duration of ventilation is primarily determined by admitting diagnosis and degree of physiologic derangement as measured by APS. An equation developed using multivariate regression techniques can accurately predict average duration of ventilation for groups of ICU patients, and we believe this equation will be useful for comparing ventilator practices between ICUs, controlling for patient differences in clinical trials of new therapies or weaning techniques, and as a quality improvement mechanism. PMID- 8697854 TI - Comparison of percutaneous and surgical tracheostomies. AB - OBJECTIVE: To compare the safety and efficacy of percutaneous dilational tracheostomy (PDT) with surgical tracheostomy (ST). DESIGN: Prospective randomized trial. SETTING: Public urban teaching hospital. PATIENTS: Twenty-six patients were randomized to undergo PDT and 27 patients to ST. RESULTS: The time from randomization into the study until tracheostomy was performed was 28.5 +/- 27.9 h in the PDT group and 100.4 +/- 95.0 h in the ST group (p < 0.001). PDT was performed in 8.2 +/- 4.9 min vs 33.9 +/- 14.0 min for ST (p < 0.0001). There was no significant difference in intraprocedural complications between the groups. Postprocedural complication rates were 12% for PDT and 41% for ST (p = 0.008). CONCLUSION: PDT is superior to ST logistically. PDT can be performed at the bedside eliminating the risk of patient transport. Because operating room scheduling is not necessary, PDT can be performed earlier once the decision to do a tracheostomy is made, which will improve ICU utilization. PDT is a faster procedure to perform and has fewer postprocedural complications. PMID- 8697855 TI - Pulmonary epithelial permeability. An animal study of inverse ratio ventilation and conventional mechanical ventilation. AB - STUDY OBJECTIVE: To compare pressure-controlled inverse ratio ventilation (PCIRV) with volume-controlled ventilation with positive end-expiratory pressure (VCV PEEP) at equal levels of end-expiratory alveolar pressure. The primary focus of the study was on pulmonary epithelial permeability. Histologic and gravimetric indicators of lung injury were also studied. DESIGN: Randomized animal study. SETTING: Experimental investigation at Sodersjukhuset, Stockholm, Sweden. ANIMALS: Thirty-two New Zealand white rabbits. INTERVENTIONS: Ventilation with PCIRV or VCV PEEP for 6 h at an end-expiratory pressure level of 5 cm H2O. MEASUREMENTS AND RESULTS: Lung mechanics, heart rate, BP, and gas exchange. Measurement of pulmonary epithelial permeability by 99mTc-DTPA lung clearance. Extravascular lung water by gravimetric analysis. Morphology by light microscopy after a perfusion fixation procedure. Mean and peak airway pressures were 12.4 +/ 4.3 and 15.9 +/- 4.5 cm H2O with PCIRV and 8.6 +/- 0.8 (p < 0.001) and 19.9 +/- 4.1 cm H2O (p < 0.03) with VCV PEEP at 6 h. Mean systemic BP was lower with PCIRV (58 +/- 9 mm Hg) than with VCV PEEP (68 +/- 7 mm Hg) at 6 h (p < 0.003). At 6 h, PaCO2 was lower with PCIRV (3.2 +/- 0.6 kPa) than with VCV PEEP (4.1 +/- 0.8 kPa) (p < 0.02). There was no difference in blood oxygenation between PCIRV and VCV PEEP. 99mTc-DTPA lung clearance curves were monoexponential with both PCIRV and VCV PEEP. Mean lung clearance expressed as T 1/2 was 16 +/- 9 min with PCIRV and 107 +/- 74 min with VCV PEEP (p < 0.001). Morphologic examination revealed no differences between the groups and no evidence of significant lung injury. CONCLUSIONS: The observations reported in this article imply that PCIRV causes an alteration in lung epithelial or membrane function in comparison to VCV PEEP. This functional difference is most likely caused by the large time-adjusted lung volume produced by pressure control in combination with a prolonged inspiration. It remains to be established whether this early functional effect of PCIRV is relevant with regard to structural lung injury in mechanically ventilated subjects. PMID- 8697856 TI - Pressures required to move gas through the native airway in the presence of a fenestrated vs a nonfenestrated tracheostomy tube. AB - SUBJECT: It is occasionally desirable for patients with a tracheostomy tube to breathe through their native airway. We hypothesized that capped tracheostomy tubes with cuffs deflated would create substantial additional resistance to airflow without fenestration but would provide minimal resistance to airflow when the tube had a fenestration. METHODS: Two tracheal models were tested simulating a large (26 mm) and an average (18 mm) trachea. Tests were carried out with fenestrated and nonfenestrated tracheostomy tubes of sizes ranging from No. 4 to No. 10. Negative pressure inspiration was simulated using suction. RESULTS: With a large trachea or small tubes, the suction required to generate flows of 40 L/min or greater remained less than 5 cm H2O with or without a fenestration. However, with an average-sized trachea and no fenestration, the pressure required to generate flows of 40 L/min or greater exceeded 5 cm H2O and with No. 8 or No. 10 tubes exceeded 20 cm H2O. A fenestration routinely reduced the required pressure to less than 5 cm H2O. CONCLUSION: The effort required to move gas across the native airway in the absence of a fenestration may be substantial. If a patient is to breathe through a native airway, a fenestrated tube should be used unless the tracheostomy tube is a No. 4. PMID- 8697858 TI - Clinical applications of nitric oxide. PMID- 8697857 TI - Medication nebulizer performance. Effects of diluent volume, nebulizer flow, and nebulizer brand. AB - BACKGROUND: Medication nebulizers are commonly used to delivery aerosolized medications to patients with respiratory disease. We evaluated output and respirable aerosol available to the patient (inhaled mass) for 17 medication nebulizers using a spontaneous breathing lung model. METHODS: Three nebulizer fill volumes (3, 4, and 5 mL containing 2.5 mg of albuterol) and 3 oxygen flows (6, 8, and 10 L/min) were evaluated using the 17 nebulizers. A cotton plug at the nebulizer mouthpiece was used to trap aerosol during simulated spontaneous breathing. Following each trial, the amount of albuterol remaining in the nebulizer and the amount deposited in the cotton plug were determined spectrophotometrically. Aerosol particle size was determined using an 11-stage cascade impactor. RESULTS: Increasing fill volume decreased the amount of albuterol trapped in the dead volume (p < 0.001) and increased the amount delivered to the patient (p < 0.001). Increasing flow increased the mass output of particles in the respirable range of 1 to 5 microns (p = 0.004), but the respirable mass delivered to the patient was affected to a greater extent by nebulizer brand (p < 0.001) than flow. Although 2.5 mg of albuterol was placed into the nebulizers, less than 0.5 mg in the respirable range of 1 to 5 microns was delivered to the mouthpiece. CONCLUSIONS: The performance of medication nebulizers is affected by fill volume, flow, and nebulizer brand. When they are used for research applications, the nebulizer characteristics must be evaluated and reported for the conditions used in the investigation. PMID- 8697859 TI - New antifungal drugs for pulmonary mycoses. PMID- 8697860 TI - Pulmonary section development influences general medical house officer interests and ABIM certifying examination performance. AB - To determine whether sectional development in pulmonary and critical care medicine influences medical house officers' (HO) interests and knowledge about respiratory medicine, we reviewed HO performance on the American Board of Internal Medicine (ABIM) certifying examination during 4 years before and 5 years after reorganization of our section. After major changes in the program and introduction of new educational opportunities, HOs more often selected pulmonary consultation electives (68.6% vs 47.8%; p = 0.009) and entered pulmonary fellowships after completion of residency training (12% vs 3%; p = 0.047). Total ABIM examination score did not change, but performance on its respiratory disease component improved from a median national percentile score of 48.5% (1986 to 1989) to 80.0% (1990 to 1994) (p = 0.0365). In relation to other specialty component scores, the rank of the respiratory disease percentile improved from the lowest specialty score to the highest. ABIM examination scores correlated with the cumulative faculty effort directed toward HO teaching (r = 0.70; p = 0.04) and the total number of clinical teachers (faculty and fellows) interacting with HOs (r = 0.73; p = 0.02). Academic development in pulmonary/critical care faculty has an important influence on medical HO interests in and knowledge of that discipline. Plans for the future structure of academic pulmonary/critical care sections must take into account this impact on the training of generalists. Although institutional priorities, resources, and shifting external forces will define how, where, and by whom respiratory medicine will be taught, an appropriate number of faculty members and sufficient commitment of their time to HO education must be preserved. PMID- 8697861 TI - Endoscopic ultrasonography and real-time guided fine-needle aspiration biopsy of solid lesions of the mediastinum suspected of malignancy. AB - STUDY OBJECTIVE: The study details our preliminary experience with endoscopic ultrasonography (EUS) guided fine-needle aspiration biopsy (FNAB) of mediastinal masses suspected of malignancy. DESIGN: Prospective uncontrolled study. PATIENTS: Nine patients had lesions suspected of malignancy ranging from 1 to 9 cm in diameter in various locations of the mediastinum. INTERVENTIONS: The EUS examination was performed with a gastroscope (Hitachi/Pentax FG-32 UA) equipped with an adjustable 5- or 7.5-MHz curved array ultrasonic transducer. The scanning plane is in the long axis of the endoscope allowing endosonographically guided biopsy to be performed. A 21-gauge (0.8 mm), full-length steel needle housed in a biopsy handle (type: Hancke/Vilmann; GIP-Medizin Technik; Grassau, Germany) was used for the biopsies. RESULTS: Nine patients had biopsy specimens taken from 13 lesions. The total number of needle passes was 18 (range, 1 to 3; median, 1.4). The cytologic diagnosis was conclusive for cancer in ten lesions and consistent with a benign lesion in three lesions. All ten malignant diagnoses and two benign diagnoses were confirmed either by operation or follow-up. In the last patient with lung cancer, a final diagnosis of the EUS-guided biopsy of an enlarged lymph node could not be obtained. No false-positive or negative biopsy diagnoses were recorded. The biopsy procedure was well tolerated by all patients, and there were no complications. CONCLUSIONS: EUS-guided aspiration biopsy is a significant advance in the differentiation between malignant and benign lesions of the mediastinum carrying a high diagnostic potential. PMID- 8697862 TI - Thoracoscopic resection of an esophageal cyst in a 4-year-old girl. AB - Thoracoscopic resection of a 4-cm esophageal cyst was performed in a young child. The patient tolerated the procedure well with little chest wall trauma, and she was discharged on the second post-operative day. At 1-month follow-up, there were no associated complications. PMID- 8697863 TI - Recurrent left pleural effusion in a 44-year-old woman with a history of alcohol abuse. PMID- 8697864 TI - The case of the disappearing mass. PMID- 8697865 TI - Idiopathic pulmonary hemorrhage in infancy. Clinical features and management with high frequency ventilation. AB - STUDY OBJECTIVES: To describe the clinical characteristics of infants with severe acute pulmonary hemorrhage and the effects of mechanical ventilation on gas exchange. SETTING: Tertiary care pediatric ICU in a university hospital. PATIENTS AND DESIGN: Case records of patients with severe acute pulmonary hemorrhage from January 1992 to July 1995 were reviewed. Acute pulmonary hemorrhage was defined as hemoptysis and/or epistaxis or blood obtained from endotracheal tube which could not be attributed to cardiac or vascular malformation, infectious process, or known trauma. INTERVENTIONS: Patients were initially managed with conventional ventilation. High frequency ventilation (HFV) was utilized when hypoxemia (PaO2/PAO2 < 0.2) and/or respiratory acidosis (PaCO2 > or = 60 mm Hg with pH < 7.25) persisted. MEASUREMENTS AND RESULTS: Six African-American male infants from Detroit, with a median age 2.3 months, presented with severe acute pulmonary hemorrhage. Chest radiographs showed diffuse bilateral infiltrates or opacification with a normal sized heart. All infants were managed with HFV, four by oscillation and two by jet. The indications for HFV were persistent hypoxemia (2), respiratory acidosis (1), and a combination of both (3). There was an improvement in pH and PaCO2, and a decreased need for oxygen 6 and 24 h after initiating HFV. PaO2/PAO2 and oxygenation index showed a tendency toward improvement. All infants survived, and there were no complications. No cause for pulmonary hemorrhage was found in any of the infants. CONCLUSIONS: Idiopathic acute pulmonary hemorrhage is a potentially life-threatening disorder encountered among inner-city infants. HFV is highly effective and safe in rapidly reversing the severe oxygenation and ventilation deficits in this setting. PMID- 8697866 TI - Sulfasalazine pulmonary toxicity in ulcerative colitis mimicking clinical features of Wegener's granulomatosis. AB - The centrally accentuated antineutrophil cytoplasmic antibody test (c-ANCA) is widely regarded as a sensitive and specific marker for Wegener's granulomatosis (WG). There are increasing reports, however, of false-positive c-ANCAs, usually in the setting of other vasculidities. We report a case of a 27-year-old man with ulcerative colitis who developed pulmonary symptoms, peripheral nodular lung infiltrates, and an elevated c-ANCA suggesting WG. Chest CT and open lung biopsy specimens were consistent with WG. The symptoms and pulmonary infiltrates resolved after discontinuation of sulfasalazine therapy. The c-ANCA remained elevated due to the occurrence of false-positive values in ulcerative colitis. We conclude sulfasalazine toxicity can mimic clinical aspects of WG and that c-ANCA testing should be interpreted with caution in patients with ulcerative colitis. PMID- 8697867 TI - Hyperacute rejection following lung transplantation. AB - Although hyperacute rejection has been clinically and pathologically fully described in recipients of other solid organ transplants, to our knowledge, there have been no previous fully documented cases in recipients of lung transplants. This case of clinical hyperacute rejection is corroborated by a positive, donor antigen-specific IgG-mediated lymphocytotoxic crossmatch (LXM), and demonstrated histopathologic, immunofluorescent, and electron microscopic features consistent with hyperacute rejection as described in other organs. Features of diffuse alveolar damage, neutrophilic infiltrates, and endothelial and epithelial damage with IgG-fluorescent staining within alveolar spaces and septae were demonstrated. The management of hyperacute rejection and its outcome are reviewed. Historically a pretransplant crossmatch is not considered a routine part of lung transplantation. The outcome of this patient suggests that LXM should be performed routinely prior to lung transplant in all patients with high panel-reactive antibodies, and should be performed whenever circumstances permit. PMID- 8697868 TI - Diagnosis of cardiac sarcoidosis aided by MRI. AB - We describe herein a case of dilated cardiomyopathy. The diagnosis of myocardial sarcoid was suggested by abnormal findings on an MRI of the chest. This was subsequently confirmed by a histology of a subcutaneous nodule. MRI is well suited in imaging myocardial scarring associated with sarcoidosis. Its use should be considered where sarcoidosis is suspected. Early detection and intervention with steroids may improve function. PMID- 8697870 TI - Recent Dieulafoy's lesion bleeding and massive pulmonary emboli. Successful use of thrombolytic therapy. AB - A massive GI bleed secondary to a Dieulafoy's lesion developed in a 77-year-old woman. Fifteen days later, massive pulmonary emboli developed. We describe successful thrombolytic treatment of her pulmonary emboli without complicating GI hemorrhage. PMID- 8697869 TI - Inflammatory diseases of the lung causing false-positive 131iodine whole body scans in the evaluation of papillary thyroid carcinoma. Two case reports. AB - The 131I whole body scan is commonly used to establish the presence of metastatic disease in papillary thyroid carcinoma. False-positive scans are rare, but have been reported. We present two cases of aberrant uptake of radioiodine after thyroidectomy and 131I ablation due to inflammatory conditions of the lung, aspergilloma, and respiratory bronchiolitis. PMID- 8697871 TI - Desmoplastic malignant melanoma presenting as a lung mass. AB - A case of metastatic desmoplastic malignant melanoma is reported. The patient presented initially with a lung mass and subsequently developed facial swelling and numbness secondary to tumor involvement of the maxillary division of the trigeminal nerve. The pleomorphism, histochemistry, and schwannoid differentiation of these tumors is discussed. PMID- 8697872 TI - Cardiopulmonary bypass as an adjunct to pulmonary surgery. AB - Although performance of concomitant open heart and pulmonary operations has been described, there is general reluctance to perform pulmonary procedures in patients receiving cardiopulmonary bypass (CPB). Reasons for this include fear of excess bleeding caused by systemic heparinization, limited exposure afforded by median sternolomy, and alterations in the immune system caused by CPB that might lead to dissemination of lung cancer or infection. We have used CPB to facilitate operations on the lung in four patients who did not require concomitant cardiac surgery. In each case, lesions involving central pulmonary vessels precluded safe operation by conventional techniques. There were no complications related to the use of CPB. We believe that CPB can be a valuable adjunct in the surgical treatment of selected tumors and vascular malformations that involve large or central pulmonary vessels. PMID- 8697873 TI - Low-dose thrombolysis for thrombosed prosthetic heart valve. AB - This report describes two cases of successful fibrinolysis of thrombosed tricuspid and mitral valve prostheses (Carbomedics; Austin, Texas) with low-dose urokinase therapy corresponding to only one third of the dose usually recommended. PMID- 8697874 TI - Kaposi's sarcoma of the tip of the nose as a sentinel sign for Kaposi's sarcoma of the lung. PMID- 8697875 TI - Pulmonary toxicity during granulocyte colony stimulating factor administration and neutrophils. PMID- 8697876 TI - Reassessing the cost-effectiveness of lung transplantation. PMID- 8697877 TI - Shame on us. PMID- 8697878 TI - Video-assisted thoracoscopic surgery. Thymectomy. PMID- 8697879 TI - Bronchiectasis in an aging cohort. PMID- 8697880 TI - Determination of post-salbutamol methacholine dose shift. PMID- 8697881 TI - Physiologic dual chamber pacing in radiation-induced atrioventricular block. PMID- 8697882 TI - Pulmonary artery rupture illustrations. PMID- 8697883 TI - Outcome of in-hospital cardiopulmonary resuscitation. PMID- 8697884 TI - Comparative in vitro activity of cefodizime and other antibiotics against pathogens recently isolated in Italy. AB - In the present study we tested the susceptibility to cefodizime on 1,985 selected nosocomial pathogens isolated in five laboratories. Moreover, we evaluated the epidemiology of the resistance of the tested strains to cefodizime and to other antibiotics clinically available in Italy. The susceptibility to cefodizime was determined with both MIC (microdilution method) and the agar diffusion method (Kirby-Bauer). The Kirby-Bauer method was used to compare the antibiotics. Cefodizime was equivalent in activity to ceftazidime and ceftriaxone and was more active than piperacillin and amoxicillin + clavulanic acid. The activity of gentamicin (where tested) was generally comparable to that of cefodizime; ciprofloxacin had lower percentages of resistance against some species of Enterobacteriaceae and staphylococci. PMID- 8697885 TI - Candida glabrata: in vitro susceptibility of 84 isolates to eight antifungal agents. AB - The in vitro susceptibility of 84 isolates of Candida glabrata from patients treated at the University Hospital of the Canary islands to eight antifungal agents (amphotericin B, itraconazole, fluconazole, miconazole, clotrimazole, tioconazole and econazole) has been studied using the broth dilution micro method. Among the eight antifungal agents tested, the smaller geometric mean corresponded to tioconazole, econazole, clotrimazole and miconazole. In contrast with fluconazole, a greater geometric mean has been achieved. All the C. glabrata isolates tested were sensitive to concentrations of 3.125 micrograms/ml of clotrimazole and miconazole, 6.25 micrograms/ml of amphotericin and ketoconazole. Concentrations of 12.5 micrograms/ml were needed to obtain 100% inhibition of isolates for econazole and tioconazole and concentrations of 25 and 50 micrograms/ml, respectively for itraconazole and fluconazole. Among our C. glabrata isolates, 2.4% were found to be resistant to amphotericin B. For fluconazole and itraconazole, 19.1% and 7.9% of isolates, respectively, were resistant. With reference to imidazoles, we obtained 2.4% and 3.6% resistance for tioconazole and econazole, respectively. No isolates were found to be resistant to ketoconazole, miconazole and clotrimazole. The results have shown a high activity of amphotericin B and itraconazole, observing a similar response with the five imidazole antifungals tested. The highest rate of resistance was found when fluconazole was used. PMID- 8697886 TI - Antifungal activity of sertaconazole in vitro against clinical isolates of Candida spp.. AB - Sertaconazole is a new azolic derivative containing a benzo(b)-thiophene group, for topical use. It showed in vitro fungistatic and fungicidal activity against yeasts, dermatophytes, opportunistic filamentous fungi and Gram-positive bacteria. In this study, we have evaluated the activity of sertaconazole in vitro against 215 strains of Candida spp. Fluconazole and ketoconazole were used throughout as reference compounds. The minimum inhibitory concentration (MIC) was determined in Casitone medium and the breakpoint was obtained spectrophotometrically and visually. Visual reading of MICs correlated with the spectrophotometric determination, the values of MIC50 and MIC90 showed no difference (+/- 1 dilution) in any of the species tested (range 0.1-16 mg/l). These results show that sertaconazole is an excellent antifungal agent and fungicide in vitro against various species of Candida. PMID- 8697887 TI - Immunobiology of methicillin-resistant Staphylococcus aureus: immune response of rabbits and patients to systemic infection. AB - Teichoic acid (TA) and peptidoglycan (PG) extracted from Staphylococcus aureus strains ATCC 25923 and Lafferty as well as formalinized cells of these two strains and several clinical methicillin-resistant S. aureus (MRSA) isolates were immunogenic for New Zealand White rabbits. Rabbits which had recovered from experimental bacteremia due to MRSA seroconverted, i.e. demonstrated raised titers of antibodies against TA and PG of the S. aureus strain Lafferty and against whole cells (WC) and ultrasound cell lysates (UCL) of MRSA isolates No. 1 and 2 (representative of nosocomial MRSA strain I), as determined with enzyme linked immunosorbent assays. Furthermore, sera from 2 long-term survivor rabbits recognized four polypeptides (apparent molecular weight = 38.9, 33.9, 30.9, and 28.2 kDa) shared by UCL extracts from MRSA isolates No. 1 and 2, as determined with immunoblots. Neither normal nor immune rabbit sera augmented the bactericidal activity of fresh defibrinated human blood (65% v/v) against selected MRSA isolates and S. aureus strain ATCC 25923. Sera from 12 patients with documented systemic infection due to MRSA outbreak strain I were examined for IgM and IgG antibodies against TA, WC, and UCL antigens. Three patient sera exhibited raised IgM antibodies against TA; 7 of 12 patient sera showed increased IgG anti-TA titers. Only 1 patient had a markedly raised IgM anti-WC titer, whereas 4 and 10 of the patients had increased IgG titers against WC from MRSA isolates No. 1 and 2, respectively. However, all 12 patients had raised IgG titers against UCL from MRSA isolate No.2 versus 4 of 12 patients with elevated IgG titers against UCL from MRSA isolate No.1. Immunoblots with 3 selected patient sera revealed IgG antibodies to be more multifaceted than IgM antibodies. Sera from 11 of the 12 patients contained antimicrobial drug(s); yet only 5 of these 11 sera (used at 10% v/v in broth) killed inocula of MRSA isolate No. 43. None of the 12 patient sera (10% v/v) enhanced the bactericidal activity of human blood against selected MRSA isolates. Neither three commercial intravenously applicable IgG preparations nor an IgG anti-alpha-hemolysin formulation (employed at 10% v/v) augmented the bactericidal activity of fresh defibrinated human blood against selected MRSA isolates comprising MRSA outbreak strain I. PMID- 8697888 TI - Sparfloxacin therapy for experimental endocarditis caused by methicillin resistant Staphylococcus aureus. AB - Sparfloxacin, a new difluorinated quinolone antibiotic, was employed in the treatment of catheter-induced endocarditis in rabbits infected with a methicillin resistant strain of Staphylococcus aureus (MRSA). Animals (n = 12) in the study group received sparfloxacin, 25 mg/kg body weight every 12 h intravenously. Comparison groups were untreated controls (n = 9) and animals injected with vancomycin (n = 13) at the same dosage. MICs and MBCs of the test organism were both 1.56 mg/l for vancomycin and 0.15/0.30 mg/l for sparfloxacin. Antibiotic treatments started 24 h after bacterial challenge and lasted 4 days until sacrifice. In comparison with no treatment, both sparfloxacin and vancomycin significantly reduced the bacterial counts in aortic vegetations, while no significant difference was found between the two antibiotics. Combination of the two antibiotics, tried in a smaller group of rabbits (n = 3) showed no advantages over either single-drug therapy. Our results suggest that sparfloxacin is a potentially useful agent, at least in the rabbit model, for treating MRSA endocardial infections. PMID- 8697889 TI - Therapeutic efficacy of intravenous and oral ciprofloxacin in experimental murine infections. AB - The therapeutic efficacy of intravenous ciprofloxacin against experimentally induced systemic, respiratory tract and urinary tract infections was investigated in mice. The 50% effective dose (ED50) of intravenous ciprofloxacin against experimental systemic infections with Staphylococcus aureus Smith, Escherichia coli 444, Klebsiella pneumoniae KC-1, Serratia marcescens T-55 and Pseudomonas aeruginosa 15846 in mice, were 0.538, 0.0625, 0.0941, 0.294 and 7.76 mg/kg, respectively. These excellent results are equal to 6- to 17-fold the potency following oral administration. In murine respiratory tract infections with K. pneumoniae DT-S, the ED50 of intravenous ciprofloxacin was 20.1 mg/kg, and 26.2 mg/kg after oral administration. A marked decrease of viable bacteria count in lung was noted at doses above 7.4 mg/kg with intravenous administration. On the other hand, after oral dosing, although a marked decrease in viable bacteria count was observed with doses above 29 mg/kg, no decrease in counts was seen at 118 mg/kg and only a bacteriostatic effect could be noted. The therapeutic efficacy of intravenous ciprofloxacin against experimentally induced urinary tract infections in mice was compared to that after oral dosing by determining viable bacteria count in kidney 24h after inoculation. A dose-proportional decrease in counts was observed with both routes of administration at doses of 1.7, 5.6, 17 and 56 mg/kg. Based on these results, intravenous ciprofloxacin was found to have effects superior to those after oral administration in all infection models studied. PMID- 8697890 TI - Vancomycin plus imipenem ceftazidime or ciprofloxacin in second line therapy in patients with febrile neutropenia not responding to first line therapy. AB - 137 patients with febrile neutropenia after cytotoxic therapy not responding to ceftazidime plus or ceftriaxone plus netilmicin in received additionally to the previous combination either vancomycin alone or combined with another anti-gram negative compound: imipenem in those treated prophylactically with ofloxacin and ciprofloxacin in those without prophylaxis. The addition of vancomycin to the previously ineffective combination of a third generation cephalosporin plus aminoglycoside, and replacement of ceftriaxone plus netilmicin with ceftazidime plus amikacin plus vancomycin or with ceftazidime plus vancomycin seems to be less effective (71.8-75 vs. 87.5-90.9%, p < 0.02) and more toxic (20.5-7.2 vs. 0 5%, p < 0.0005) than vancomycin in combination with a different anti-gram negative compound as previously used: imipenem or ciprofloxacin. PMID- 8697891 TI - Comparison of oral ciprofloxacin and amoxycillin in treating infective exacerbations of bronchiectasis in Hong Kong. AB - A randomised double-blind controlled clinical trial was conducted to compare oral ciprofloxacin (500 mg b.d.) and amoxycillin (1 g t.d.s.) in the treatment of infective exacerbations of bronchiectasis. The commonest organism isolated from sputum was Pseudomonas aeruginosa, which accounted for 34% of all positive sputum cultures. Other Pseudomonas species and Haemophilus influenzae, accounted for 19%, respectively. Ciprofloxacin produced better clinical response, a higher sputum to serum antibiotic level (mean of 0.65 in the ciprofloxacin group vs. 0.18 in amoxycillin group, p = 0.0001), broader spectrum of antibacterial activity and less side-effect. It was also better tolerated by patients. The findings suggest that ciprofloxacin is an effective treatment of infective exacerbations of bronchiectasis. PMID- 8697892 TI - Breakthrough fungemia due to Hansenula anomala in a leukemic patient successfully treated with amphotericin B. PMID- 8697893 TI - Susceptibility of Haemophilus influenzae isolates with known resistance mechanisms to five cephalosporins. AB - The in vitro activities of cefaclor, cefetamet, cefixime, cefotaxime and cefuroxime were determined against 150 isolates of Haemophilus influenzae. These included 50 ampicillin-susceptible, 50 beta-lactamase-producing and 50 intrinsically ampicillin-resistant isolates. A closer relationship was apparent between the intrinsic resistance to ampicillin and reduced susceptibility to cephalosporins. Both MIC and disc diffusion methods showed that the activities of cephalosporins were reduced against most, though not all, isolates with intrinsic resistance to ampicillin. All intrinsically ampicillin-resistant isolates should be considered resistant to all cephalosporins at the present time since the clinical significance of the reduction in susceptibility is uncertain. Amongst the five cephalosporins tested, cefaclor susceptibility may facilitate the detection of intrinsic ampicillin resistance since it predicts isolates with this type of resistance mechanism. PMID- 8697894 TI - Bactericidal activity, morphological alterations, and synergistic interactions of rufloxacin, a new fluoroquinolone, alone and in combination with its N desmethylate D derivative (MF 922). AB - The in vitro activity of rufloxacin, alone and in combination with its metabolite (MF 922) against common respiratory and urinary tract pathogens and anaerobes was assessed. No synergistic interaction between rufloxacin and MF 922 was observed by the checkerboard technique against aerobic bacteria. When the time-kill system was employed, 24 synergistic interactions were noted out of 30 tests performed (80%), of which 14 (100%) were with Enterobacteriaceae isolates, 2 with Moraxella catarrhalis (50%), 4 with Haemophilus influenzae (100%), 2 with Staphylococcus aureus (50%) and 2 with Streptococcus pneumoniae and Streptococcus pyogenes (50%). Synergism was found with all Bacteroides fragilis irrespectively of the method used. Rufloxacin alone or in combination with MF 922, at concentrations achieved in vivo, induced morphological alterations in all the pathogens analyzed with the exception of M. catarrhalis and H. influenzae. Towards S. pyogenes and S. pneumoniae, the same levels of rufloxacin and MF 922 were capable of inducing only bacteriostatic rather than bactericidal effect, followed by reversible morphological modifications. The presence of 50% human serum in the test media did not affect the results. PMID- 8697895 TI - Neural connection from hippocampus to nucleus accumbens and the subpallidal area and their contribution to locomotor activity. AB - Neural connections from the hippocampus and nucleus accumbens to the subpallidal area have been implicated by behavioral observation. The locomotor activity recorded in an automated activity cage increased substantially after the bilateral injection of carbachol, a cholinergic agonist, into the dentate gyrus of the hippocampus, and this increase of activity was reduced significantly after the injection of glutamate antagonist into the nucleus accumbens. On the other hand, this hyperactivity elicited by the injection of carbachol was also reduced by the injection of GABA into the subpallidal area. In another observation, increased locomotor activity was recorded following the injection of dopamine into the nucleus accumbens. However, the increase of locomotor activity induced by dopamine was attenuated by the injection of GABA into the subpallidal area. These observations suggest that neural connections from hippocampus and nucleus accumbens to the subpallidal region may contribute to locomotor activity. PMID- 8697896 TI - Interaction of arachidonic acid with ligand binding sites of the N-methyl-D aspartate receptor in rat hippocampal membranes. AB - Ararchidonic acid, an important oxygenated metabolites of 20-carbon polyunsaturated fatty acid in cell membrane, has been implicated in potentiating the N-methyl-D-aspartate (NMDA) receptor, receptor of glutamate subtype receptors, mediated neurotransmission. We have tested the possibility that arachidonic acid may directly interact with the NMDA receptor by examining the ligand binding to this receptor/channel complex in hippocampal membrane preparation. Micromolar concentrations of arachidonic acid significantly increased both the association and dissociation of [3H]TCP binding but had no effect on the pre-equilibrated [3H]TCP binding. Arachidonic acid had no effect on the Kd and Bmax of [3H]TCP binding. Arachidonic acid also had no effect on the NMDA-displaced [3H]glutamate binding and [3H]glycine binding. In addition, docosahexanoic acid (DHA) potentiated [3H]TCP binding with similar features. However, oleic acid did not affect [3H]TCP binding. This study indicates that arachidonic acid potentiates the NMDA receptor-mediated response by directly increasing the activation of NMDA receptor-gated ion channel. PMID- 8697897 TI - Corticotropin-releasing factor injected into the lateral septum improves memory function in rats. AB - The present study investigated the role of corticotropin-releasing factor (CRF) in the lateral septum in modulating the memory process and in regulation of the rearing response in rats. Rats were bilaterally cannulated in the lateral septum and CRF was injected right after training of an inhibitory avoidance task. Retention performance and rearing measure were conducted 24 hr later. In another experiment, CRF was also injected into the lateral septum and rearing response measured immediately afterwards. Results indicated that CRF, at moderate doses, markedly enhanced memory retention and decreased rearing response in rats. The latter effect was no longer observed 24 hr after CRF injection. These findings support the notion that the lateral septum is involved in the memory process and emotional expression. These results, together with earlier reports, also suggest that CRF probably produces a consistent facilitatory effect upon memory consolidation and inhibitory effect upon exploration within the limbic system in rats. PMID- 8697898 TI - Carbachol, glycine and gamma aminobutyric acid also activate cardiovascular neurons of pontomedulla responsive to glutamate. AB - Thirty-three cats under intraperitoneal chloralose (40 mg/kg) and urethane (400 mg/kg) anesthesia were used to explore the effect of microinjections (100 nl) of carbachol (CCh, 0.5 M), a cholinergic analogue, glycine (Gly, 1 M) and gamma aminobutyric acid (GABA, 0.4 M) on the cardiovascular-reactive sites in the pontomedulla that responded to microinjection of monosodium glutamate (Glu, 0.25 M, 100 nl) resulting in changes of systemic arterial pressure (SAP). Brain sites under exploration included gigantocellular tegmental field and lateral tegmental field (FTG-FTL), the dorsomedial (DM) and ventrolateral (VLM) medulla which produced pressor responses; caudal VLM (CVLM) and paramedian reticular nucleus (PRN) which produced depressor responses. It was found that CCh produced significant fall of SAP in DM and VLM while the rise of SAP in the same site by Glu. CCh produced SAP decrease in CVLM similar to Glu. GABA significantly caused a slight to moderate increase of SAP in FTG-FTL, DM and VLM, and decrease of SAP in CVLM, all in direction similar to that of Glu. Gly produced significant and marked increase of SAP in DM and VLM similar to Glu both in magnitude and duration. Gly produced increase of SAP in CVLM but the fall of SAP by Glu. PRN was relatively non-reactive except a few microinjections of CCh which produced hypotension. In conclusion, the cardiovascular-reactive sites in the pontomedulla that respond to Glu may also react to other chemicals or neurotransmitters. It is highly possible that multiple receptors of different nature co-exist in neurons of some cardiovascular regions in the pontomedulla. PMID- 8697899 TI - Schedule-induced polydipsia increased both mesotelencephalic-dopaminergic and pontine-noradrenergic activities in the rat brain. AB - We have demonstrated previously that the activity of schedule-induced polydipsia (SIP) was persistently depressed after successive lesions of the bilateral symmetrical locus coeruleus and the ventral tegmental area. The hypothesis that central catecholaminergic neurons mediate animal behaviors in arousal or coping processes, e.g., SIP, was tested by the demonstration of concomitant changes of transmissions in regions of appropriate nerve terminals. By using the high performance liquid chromatography coupled with electrochemical detection methods, the current experiments were designed to examine the regional turnover of monoamines in the performance of SIP of the control rats by measurements of the biochemical derivatives including dopamine (DA), norepinephrine (NE), serotonin (5-HT), 3,4-dihydroxyphenylacetic acid (DOPAC), dihydroxyphenylalanine (DOPA), 4 hydroxy-3-methoxyphenylglycol-4-sulfate (MHPG-SO4) and 5-hydroxyindoleacetic acid (5-HIAA). It was found that rats in the performance of SIP, the DA levels and DA synthesis and utilization in the limbic area were increased and that the NE level and NE synthesis in the several pontine NE projected areas, e.g., limbic area, hippocampus, cortex and pons were also increased. Conversely, both NE and 5-HT metabolism in the hippocampus and the cortex were decreased. We concluded that the enhanced actions of the DA-limbic system and NE-pontine system in the rats are both important for the maintenance of SIP performance. PMID- 8697900 TI - Chronic effects of haloperidol and SCH23390 on operant and licking behaviors in the rat. AB - Behavioral effects under chronic treatment of haloperidol and SCH23390 were examined for 18 days. Water deprived rats were trained either to perform an operant response on a fixed ratio 20 (FR20) schedule of reinforcement or to lick from a tube in a separate test. Both drugs completely impaired operant responding over all chronic administration days. Whether the lick performance was significantly affected differed depending upon the variable measured in that task. In contrast to the operant results, analysis of the microstructure of licking revealed very distinctive profiles of licking for each drug. Although the lick volume was consistantly reduced by both drugs across days, the decreased numbers of licks first observed were subsequently reversed back to the control level. However, the time courses and the reversal patterns were different for each drug. Haloperidol persistantly reduced the burst size for licking, whereas SCH23390 gradually enlarged it. For interlick interval (ILI) data, haloperidol had more impact on licks with longer ILI without influencing licks of shorter ILI. Contrarily, SCH23390 tended to lengthen the licks with shorter ILI without prolonging them enough to be classified as longer ILI licks. The dissociation of behavioral effects induced by chronic treatment of haloperidol and SCH23390 can be attributed to the drugs' blockade of different DA receptor subtypes. Also, the present study illustrates that using multiple behavioral tasks can be helpful to differentiate the subtle drug actions induced by DA receptor antagonists. PMID- 8697901 TI - Carbachol but not bradykinin blocks the enkephalin-induced calcium transient in human neuroblastoma SK-N-SH cells. AB - Carbachol stimulated significantly higher increase in inositol 1,4,5 trisphosphate (IP3) generation than did leucine-enkephalin (leu-EK) and bradykinin in SK-N-SH cells. When leu-EK was concomitantly added with carbachol, an additive effect was observed in IP3 generation. However, the rise in cytosolic Ca2+ concentration ([Ca2+]i) reached the same level as that induced by carbachol alone. On the other hand, additive effects were observed in both [Ca2+]i rise and IP3 generation when leu-EK was simultaneously added with bradykinin. Furthermore, cells lost their [Ca2+]i response to leu-EK if carbachol was first added to induce a [Ca2+]i increase whereas the response was unchanged if leu-EK was added after addition of bradykinin. Our results suggest that a shared intracellular Ca2+ pool is sensitive to the opioid, bradykinin and muscarinic receptor agonists; however, a specific phospholipase C might be responsible for each receptor activation. PMID- 8697902 TI - The role of amygdala norepinephrine in memory formation: involvement in the memory enhancing effect of peripheral epinephrine. AB - The present study examined the roles of amygdala alpha 1 and beta noradrenergic receptors in memory formation as well as their involvement in the memory enhancing effect of peripheral epinephrine (E). Male Sprague-Dawley rats with cannulae implanted into the amygdala were trained on the one-trial inhibitory avoidance task and tested for retention 24 hrs later. Immediately after training, they received various treatments to alter amygdala noradrenergic functions and/or peripheral adrenergic functions. Separate groups of animals were decapitated 10 min after training for assays of monoamine levels in various brain regions by the HPLC-EC method. Results indicated that, when infused into the amygdala immediately after training, isoproterenol and 8-bromo-cAMP enhanced retention, while propranolol impaired retention. On the other hand, phenylephrine or prazosin failed to produce statistically significant effects. Posttraining intra amygdala infusion of propranolol, but not prazosin, abolished the memory enhancing effects of norepinephrine (NE) infused into the amygdala or E given subcutaneously to the adrenal demedullated rats. Depletion of amygdala NE by the selective neurotoxin DSP-4 also abolished the memory modulatory effects of E. These findings support that amygdala noradrenergic beta, but not alpha 1, receptors are involved in both central and peripheral memory modulatory processes. However, since the postmortem tissue NE levels in the amygdala and other brain regions did not differ among various groups, the inhibitory avoidance training and peripheral E may only activate a transient functional increase in the amygdala NE activity. PMID- 8697903 TI - Effect of DC-015, a novel potent and selective alpha 1-adrenoceptor antagonist, comparison with prazosin on noradrenaline-induced platelet aggregation. AB - The antiplatelet activity of DC-015, a newly synthesized quinazoline derivative was determined in human platelet-rich plasma. From the binding studies, the Ki values of DC-015 for alpha 1-, alpha 2-adrenoceptors and 5-HT1, 5-HT2 receptors were about 0.21 (nM), 0.59 (microM), 0.16 (microM) and 0.38 (microM), respectivity. On the other hand, the Ki values of prazosin for alpha 1- and alpha 2-adrenoceptors were about 0.19 (nM) and 4.8 (microM), respectivity. Experimental results indicated that DC-015 dose-dependently inhibited noradrenaline (10 microM)-induced platelet aggregation in human platelet-rich plasma. At 20 microM, DC-015 would completely inhibit platelet aggregation induced by noradrenaline. A high concentration of prazosin (> 30 mM) caused sligh inhibition of aggregation. Furthermore, DC-015 (2 microM) significantly increased the cyclic AMP level in human platelet-rich plasma, whereas, prazosin significantly increased cyclic AMP level only at higher concentrations (100 microM). We can conclude that DC-015 inhibited noradrenaline-induced platelet aggregation mainly through binding to alpha 2-receptor on platelets, resulting in inhibiting platelet aggregation. PMID- 8697905 TI - [Urgency of early treatment of ischemic cerebrovascular disease]. PMID- 8697904 TI - Complex response competition and dopamine blocking: choosing of high cost sucrose solution versus low cost water in rats. AB - The effect of DA blocking with pimozide on complex response competition involving coupling of cost and benefit was studied with a double-bottle test in lickometer: The competition occurred between two responses; licking of 2% sucrose solution requiring a high effort of standing up and licking of water requiring a low effort of crouching posture. Rats normally chose sucrose over water (76% with vehicle); however, pimozide (0, 0.25, 0.375 and 0.5 mg/kg) diminished licking of the sucrose solution dose-dependently (57% at 0.5 mg/kg) without affecting licking of water. Analysis of lick pattern suggested that this shift in choice was attributable not much to a potential effect of pimozide to hamper motor capability or to reduce rewarding impact of sucrose because (a) the difference in licking profile for sucrose and water remained intact, (b) rats remained fully capable of assuming the standing posture for sustained and efficient licking of sucrose, and (c) the integrity of licking pattern largely remained. Pimozide appeared to selectively affect the behavior that cost more but with higher reward; rats settled with behavior that cost less with lower reward. Rats became less motivated to invest effort for a better reward, a behavior pattern described as "indolent". A more complex view of incentive motivation including coupling of behavioral cost and benefit was presented as a theory to explain the DA mediation of reward-maintained behaviors. PMID- 8697906 TI - [A suggestion for unification of present limb lead systems into a single "F" system]. PMID- 8697907 TI - [Effects of thymectomy and glucocorticoid therapy on peripheral lymphocytes in myasthenia gravis]. AB - Clinical manifestations and peripheral blood lymphocyte subset changes were studied in patients with myasthenia gravis (MG) to elucidate the mechanism of clinical improvement following treatment, with thymectomy (Tx) or glucocorticoid (GC) therapy. The changes found were: 1. There was a significant increase in percentages of CD3+, CD29+ CD4+ cells and CD4/CD8 ratio and a significant decrease in percentages of CD8+ and CD16,56+ cells in patients who had never been treated with any immune therapy. 2. After Tx or GC therapy, CD3+ and CD4+, CD29+ cells were decreased, but the number CD19+ and CD16, CD56 cells did not change. 3. Tx had a special effect on CD8+ cells. In most of the patients who showed clinical improvement after Tx, CD8+ cells were increased and CD4/CD8 ratio wad decreased. 4. Anti-acetylcholine receptor (AChRAb) titers were markedly decreased after GC therapy. These results indicate that there were obvious abnormalities in cell-mediated immunity in addition to those in humoral immunity in myasthenia gravis. These abnormalities tended to be normalized after Tx or GC therapy. PMID- 8697908 TI - [An analysis on the activity status of fibrinolytic system in Chinese patients with acute cerebral infarction]. AB - The fibrinolytic activity status of the patients with cerebral infarction can affect their clinical prognosis. In this case-controlled study, the plasma fibrinolytic system activities in 30 cases of cortical artery territory cerebral infarction (CACI) and 32 cases of perforating artery territory cerebral infarction (PACI) with a disease duration less than 3 days were assayed with a comprehensive panel including the plasma tPA activity, PAI activity, tPA releasing capacity from vascular endothelium and PAI/tPA ratio values. 30 subjects without cardiovascular and cerebrovascular disorders were served as control. The results showed that the plasma fibrinolytic system activities of the patients with aforementioned two subtypes of cerebral infarction were significantly lower than those of the controls, the results provide a theoretical basis for carrying out thrombolytic therapy in patients with ischemic stroke and suggest that recurrent cerebral infarction might be related to the high activity of plasma PAI. PMID- 8697909 TI - [The effect of serum glucose level on acute cerebral infarction]. AB - The relationship between the serum glucose level and the cerebral infarct size, neurological deficits, morbidity outcome, complications and mortality was investigated in 198 acute cerebral infarction patients confirmed by computerized tomography. The results suggested that patients with hyperglycemia had larger infarct size, more neurological deficits, worse morbidity outcome, more complications and higher mortality than their normoglycemic counterparts. Our findings indicated that the elevated blood glucose level in most of the patients with cerebral infarction may be a stress response or a marifestation of latent diabetes. We considered that the hyperglycemia was a factor aggravating cerebral infarction and enhancing the degree of neurological deficit and morphological brain damage. The authors are of the opinion that insulin administration be advised in acute cerebral infarction patients with hyperglycemia so as to prevent further deterioration and improve the outcome. PMID- 8697910 TI - [Complications in multiple systems resulting from acute cerebrovascular diseases]. AB - One hundred and eighty five patients died of acute cerebrovascular diseases with complications in multiple systems were studied. Statistical analyses showed that there were no organ and system failure (NOSF) in 47 cases, single organ and system failure (SOSF) in 47 and multiple organ and system failure (MOSF) in 91. Out of 90 (50%) cases who had cerebral herniation, 39 cases were complicated with SOSF and 53 cases with MOSF. Among the patients with acute brain diseases, 25% of them (46) died of SOSF (4%, 8 cases) and MOSF (21%, 38) without herniation. Incidence of failure of organ and system was higher with stomach, metabolism and lung than with heart, kidney and blood. It took on the average 24 and 12.5 hours for the first organ and system to fail and 4 days and 24 hours for the second organ in patients with intracranial hemorrhage and cerebral infarction. Occurrence of organ and system failure was closely related to sex, previous diseases and damage of brain stem, but not to the size and number of the lesion. It is suggested that cerebrogenic organ and system failure (COSF) or cerebrogenic multiple organ and system failure (CMOSF) be referred to functional failure of more than two organs or system not including brain itself as a result of acute brain diseases. PMID- 8697911 TI - [The experimental observation on the procedure of atherosclerotic restenosis following PTCA]. AB - Angioplasty of stenotic iliac artery was performed in 23 Japanese white rabbits. Angiography and histopathology examinations were performed one day (6 rabbits), 3 days (5 rabbits), one week (5 rabbits) and one month (7 rabbits) after dilation. TXB/PGF in blood was analyzed with radio-immunologic method. TXB/6-K-PGF increased at 1st day, began to reduce at 3rd day, became almost normal after one week and returned to normal level week after one month. Restenosis occurred in all animals. Platelet aggregation and mural thrombi were observed at 1st and 3rd day. New endothelial cells covered the surface of denuded endothelium at 3rd day. At 7th day, repairing of endothelium was completed and proliferation of smooth muscle cells were prominent in new intimia. Stenosis of lumen occurred again after 1 month. The results suggested that intimia injury during the procedure initiates the process of restenosis and aggregation of platelets, imbalance of between TXA and PGI is and proliferation of smooth muscle cells play important roles in the formation of restenosis. PMID- 8697912 TI - [A study on erythrocyte membrane band 3 protein anion transport function in chronic respiratory failure patients]. AB - The changes of the structure, content and anion transport function as well as the blood gases and electrolytes inside and outside the erythrocytes were investigated in 3 groups of subjects: type I respiratory failure patients (group 1, n = 40); type II respiratory failure patients (group 2, n = 40) and controls (group 3, n = 37). The results showed that (1) anion transport function impairment of erythrocyte membrane band 3 protein and HCO3-/Cl- exchange restrain may be the reasons that aggravate CO2 retention and respiratory acidosis in cor pulmonale patients with type II respiratory failure. (2) band 3 protein anion transport function impairment in patients of cor pulmonale with type II respiratory failure is reversible. Therefore, it was necessary to supply oxygen to cor pulmonale patients with hypoxemia in time, which may contribute to the recovery of anion transport function. PMID- 8697913 TI - [Fasting and postprandial antroduodenal motility in functional dyspepsia]. AB - Fasting and postprandial antroduodenal motility was studied with manometry in 39 patients with functional dyspepsia (FD) and 15 healthy volunteers. The results showed that: (1) the interdigestive antral motility was significantly decreased with contractions of lower amplitude and less frequency and the amplitude of duodenal contractions was significantly lower in patients than that in controls; (2) the patients also had a reduced antroduodenal motor response to a solid liquid test meal; (3) the number of antroduodenal coordinated contractions was significantly less in patients and motor abnormalities such as duodenal phase III like bursts and early appearing interdigestive migrating motor complex (MMC) were recorded in a minority of patients. PMID- 8697914 TI - [Experiences in clinical diagnosis of paroxysmal nocturnal hemoglobinuria (PNH)]. AB - Two hundred and three cases of PNH diagnosed (according to the National Unified Diagnosed Criteria, 1987) and treated from 1949 to 1992 in Peking Union Medical Hospital were analyzed retrospectively in an attempt to investigate the factors leading to delayed diagnosis. The presenting manifestation was anemia in 56.7% of the patients. Next was hemorrhage (24.6%). Hemoglobinuria was seen only in 12.8% of the cases at the onset. Ham test was persistently negative in 10.4% of the patients. Only one third of all the cases was correctly diagnosed as PNH within one year after onset. Aplastic anemia or anemia of unknown cause was first diagnosed in 60.1% of cases. The heterogeneity of the manifestations and the lack of sensitive and also specific laboratory tests were the factors leading to delayed diagnosis, but negligence of PNH in differential diagnosis seem to be a major the main cause. Constant awareness of the possibility and careful follow-up accompanied with repeated laboratory examinations in a suspected case are crucial for early diagnosis of PNH. PMID- 8697916 TI - [An eight-year prospective study on 163 cases of hepatitis C]. AB - To explore the characteristics of hepatitis C in China, one hundred and sixty three cases of hepatitis C were followed for 8 years. The rates of abnormal alanine aminotransferase (ALT) were 100%, 73%, 57%, 37% and 28% in less than one, 1, 2, 5 and 8 years after the onset respectively. Abnormality of ALT might be persistent or fluctuating, and the latter type accounted for about 1/3 to 1/2 of the cases. The positive rates of anti-hepatitis C virus (HCV) were 56%, 93%, 94%, 96%, 97%, 93% and 83% in less than two, 2-6, 7-12 months and 1, 2, 5 and 8 years after the onset respectively. Negative conversion of anti-HCV was found only in a few patients whose ALT had returned to normal level and the rates of negative conversion for them were 10%, 8%, 16%, and 22% in 1, 2, 5 and 8 years after the onset. Positive rate of HCV-RNA, detected with nested PCR 8 years after the onset was 84% for patients who still showed positive anti-HCV and there was no significant difference between patients with abnormal (80%) and normal ALT (85%) levels. Genotype II accounted for 93% of the cases. No patient developed hepatocellular carcinoma or decompensated cirrhosis after a follow-up of eight years. PMID- 8697915 TI - [Expression of adhesion molecules on lymphocyte in patients with systemic lupus erythematosus]. AB - Peripheral blood lymphocyte phenotype (CD3, CD4, CD8, CD20, CD45RA and CD45RO) and adhesion molecule phenotype (CD11a/LFA-1 alpha, CD18/LFA-1 beta and CD54/ICAM 1) were investigated in 35 patients with systemic lupus erythematosus (SLE) by using flow cytometric analysis and dual immunofluorescence staining method. Results demonstrated increase in CD8+ cell and decrease in CD4+ cell, CD4+/CD8+, and CD4+/CD45RA+ cell, as well as decrease in expression of CD11a and CD18 on CD4+ cell surface, Expression of CD11a and CD18 on CD8+ cell, and CD54 on CD20+ cell increased, Moreover, increase in CD18 on CD8+ cell correlated inversely with decrease in CD4+ CD45RA+ cell (P < 0.05) and positively with increase in CD54 on CD20+ cell (P < 0.01). These data suggest that adhesion molecule LFA-1 and ICAM-1 may play an important role in the pathogenesis of SLE. PMID- 8697917 TI - [Decrease in plasma cholesterol and regression of atherosclerosis]. PMID- 8697918 TI - [Pathogenesis, diagnosis and therapy of hepatopulmonary syndrome]. PMID- 8697919 TI - [Bone density measurement for the prediction of risk of fracture in osteoporosis]. PMID- 8697920 TI - [Diabetes mellitus and heart diseases]. PMID- 8697921 TI - [Baseline hypertriglyceridemia, a risk factor for non-insulin dependent diabetes mellitus: a 6-year follow-up study of 432 nondiabetics]. AB - The relationship between baseline fasting plasma triglycerides level (FTG) and the incidence of non-insulin-dependent diabetes mellitus (NIDDM) within 6 years were investigated in 432 Chinese nondiabetics. They were identified by oral glucose tolerance test (OGTT, oral 75 g glucose) in Daqing diabetes survey in 1986. 220 subjects were men and 212 women. Among them 226 had normal glucose tolerance and 206 impaired glucose tolerance. The measurement of fasting plasma lipids and glucose were performed at the baseline examination and after 6-year follow-up. Six-year incidence of NIDDM in the highest triglycerides tertile group (top tertile Q3, mean = 2.5 mmol/L) was 2.3 times (38.6% vs 16.6%, P < 0.01) as compared with that of the lowest triglycerides tertile group (first tertile Q1, mean = 0.7 mmol/L). The difference of 2-hour blood glucose level in OGTT (OGTT BG2h level) between Q1 and Q3 was 2.4 mmol/L (mean = 7.6-10.0 mmol/L) after 6 years. Multivariate general linear regression analysis demonstrated that the FTG level was positively associated with the OGTT BG2h level after 6 years (P = 0.0335) after controlling the age, sex, fasting blood glucose (FBG) and body mass index (BMI). Therefore this result indicates that FTG level is an independent risk factor for the development of NIDDM in this population. PMID- 8697922 TI - [Analysis of luteinizing hormone pulses in men with idiopathic hypogonadotropic hypogonadism]. AB - In order to test the defect of luteinizing hormone (LH) pulses and its relationship with sexual development in patients with idiopathic hypogonadotropic hypogonadism (IHH), fourteen male IHH patients and five healthy adult men were investigated. Blood samples were withdrawn at 10 minute intervals for 24h for analysis of LH pulse. LH pulse frequency ranged from 0-13 pulses/24h. Testosterone (T) level was 1.3-8.7 nmol/L in the 14 IHH patients and higher in the 5 healthy controls (all P < 0.01). Two of the patients with IHH had no detectable LH pulsations (apulsatile pattern), no history of puberty and a small testicular volume of less than 1ml. Most of the IHH patients (n = 9) had less pulse frequency (4-13 pulses/24h) and lower mean amplitude (1.3-2.2IU/L) than the healthy controls (14-20 pulses/24h and 3.81-2.46IU/L, P < 0.01). A patient with IHH had 10 pulses/24h and more or less the same mean amplitude (4.2 +/- 1IU/L) as the healthy controls; his T level was the lowest among the 14 patients due probably to biological inactivity of LH. Two IHH patients had detectable LH pulsations with normal mean amplitude (P > 0.05) present predominantly during the night, this pattern of LH pulse resembles that of peripuberty boy. Our results indicate that (1) LH pulse pattern varies widely among IHH patients and it is related to the sex characteristics; (2) frequency of LH pulses is essential for sexual development. but adequate amplitude is more important in this respect. PMID- 8697923 TI - [Long-term results following 131I treatment of thyrotoxic heart disease: a report of 68 cases]. AB - The long-term results of 68 cases of thyrotoxic heart disease (THD) treated with 131I were analysed. 17 of 68 patients have been followed for 2-4 years, 32 for 5 9 years, 7 for 10-14 years, 8 for 15-19 years and 4 for 20-33 years. The mean period of follow up was 9 years. Of the 68 patients, 47 did not respond to antithyroid drug (ATD) therapy. Before 131I therapy, all the patients suffered from one or more of cardiac abnormalities caused by hyperthyroidism such as paroxysmal or permanent atrial fibrillation, cardiac enlargement, cardiac failure, frequent atrial or ventricular extrasystoles, angina pectoris and so on. All patients were given individualized therapeutic 131I dose of 2.59-4.44 MBq per gram of thyroid weight. The total 131I dose for patients was 85.1 MBq to 462.2 MBq. The long-term results showed that 55 cases were cured and 11 cases achieved complete remission. The total effective rate was 97 percent. There was no relapse of hyperthyroidism. Except that 4 cases of early hypothyroidism and 5 of delayed hypothyroidism were diagnosed, there were no other complications. The incidence of postradioiodine hypothyroidism at 5-9 years was 7.4 percent and at 10-33 years 20 percent. Our results indicate that 131I is a simple, safe, economic and effective treatment for THD. Pre-treatment with ATD for hyperthyroidism with cardiac complications is not necessary. 131I should be considered as the treatment of first choice for hyperthyroidism with cardiac abnormalities. PMID- 8697924 TI - [Effects of low dose aspirin on platelet function and prostaglandins metabolism in systemic and coronary circulation in patients with ischemia heart disease]. AB - Eleven patients with ischemia heart disease (IHD) were treated with low dose aspirin (ASA, 50mg/day) for more than two weeks (ASA group). 29 cases with IHD not taking ASA served as patient control (NASA group) and 13 cases without IHD not taking ASA as normal control. Blood samples for measurement of plasma (serum) TXB2 and 6-keto-PGF1 alpha were simultaneously taken from aortic root (AO) and coronary sinus (CS). The results showed: ASA group had lower plasma TXB2 level in AO blood than NASA group (P < 0.05), but there was no significant difference in plasma 6-keto-PGF1 alpha level between the two groups. Both of plasma and serum TXB2/6-keto-PGF1 alpha ratios in AO blood in ASA group were significantly lower than those in NASA group (P < 0.05 and P < 0.0005 respectively). Plasma TXB2 CS/AO ratio and 6-keto-PGF1 alpha CS/AO ratio in ASA group were significantly lower than those in NASA group (P < 0.05), but not different from those in control group. Both ASA and NASA groups had lower serum TXB2 CS/AO ratios than control group (P < 0.05). The results suggest that low dose aspirin inhibits selectively TXA2 synthesis in systemic circulation and inhibits synthesis and/or release of TXA2 and PGI2 equally (no selectivity) in coronary circulation, but could not completely inhibit intracoronary platelet activation. PMID- 8697925 TI - [Hemodynamic effects of milrinone on patients with chronic congestive heart failure: a multicenter study. Cooperative Group for Phase II Clinical Trial of Milrinone]. AB - In this multicenter, randomized, double-blind, cross-over, placebo-controlled trial, hemodynamic effects of domestic milrinone were studied in 57 patients with functional class III or IV chronic congestive heart failure. The baseline values of hemodynamic parameters were measured with standard method through Swan-Ganz catheter. During intravenous infusion of milrinone or placebo, the changes of hemodynamic parameters were monitored throughout the procedure. Compared with the baseline values, cardiac index increased from 2.20 +/- 0.64 to 2.95 +/- 0.71L/min.m2 (P < 0.05) and pulmonary capillary wedge pressure fell from 22.7 +/- 7.64 to 15.56 +/- 8.13 mmHg (P < 0.05) during intravenous infusion of milrinone. The placebo had no effects on hemodynamics in this group of patients. Milrinone has both inotropic and vasodilative effects on patients with chronic congestive heart failure. PMID- 8697926 TI - [Investigation of damage of the gastric mucosal barrier by Helicobacter pylori]. AB - Damage of the gastric mucosal barrier by Helicobacter pylori (Hp) has been investigated with estimation of antral mucosal hexosamine and phospholipid, and the degree of pathologic changes to be also evoluted in 100 cases of chronic superficial gastritis. There are 42% of 50 cases of Hp positive patients with active gastric lesions, and significantly high than 50 cases of Hp negative patients (8%). The mean value of antral mucosal hexosamine is 30.33 mg/g in Hp positive group, while in Hp negative group, the mean value is 36.98 mg/g (P < 0.005). The mean value of antral mucosal phospholipid is 31.96 mg/g in Hp positive. While in Hp negative is 36.49 mg/g (P < 0.05). So, estimation of mucosal hexosamine and phospholipid can be represent the degree of damage of gastric mucosal barrier. Hp should be considered as causative agent to break down the gastric mucosal barrier. PMID- 8697927 TI - [A clinical trial of lansoprazole in the treatment of duodenal ulcer]. AB - To evaluate the efficacy of a second generation acid pump inhibitor-lansoprazole (L) a controlled clinical trial in 72 patients of duodenal ulcer was carried out with omeprazole (O) as control. The results showed that the ulcer healing rate after 4-week treatment was 97.4% in lansoprazole group and 91.2% in omeprazole, while the effective rate was 100% and 97.1% respectively (P > 0.05). Ulcer related pain was relieved more quickly in lansoprazole group. The pain relief rate after treatment of 3 days was different significantly between the two group, being 74.3% (L) and 51.6% (O) respectively (P < 0.05). No marked side-effect was observed in lansoprazole group. It is shown that lansoprazole is effective and safe for treatment of duodenal ulcer. PMID- 8697928 TI - [A study on combined treatment with ANP and dopamine in acute renal failure in rats]. AB - Acute renal failure (ARF) model was made by intraperitoneal injection of cisplatin at a dosage of 10mg/kg. After the procedure, the rats were given atrial natriuretic polypeptide (ANP) and dopamine (DA) as well as ANP or DA individually. The results indicated that combined treatment with ANP and DA was more effective for improvement of renal function in ARF (increase of GFR) than individual treatment with either ANP or DA. Dopamine can effectively reverse the side-effect of hypotension of ANP. PMID- 8697929 TI - [Systemic manifestations of adult polycystic kidney disease: an analysis of 205 cases]. AB - Adult polycystic kidney disease (APKD) is a common genetic disease and one of the important reasons of end stage renal failure. Although renal multiple cysts are clearly an important manifestation of APKD; other systemic manifestations are both common and clinically important. The authors reviewed 205 cases from 180 APKD families (107 male 98 female). Their age ranged from 10 to 71 years. Renal cyst is one of the many renal manifestations. Hypertension, hematuria and flank pain are its major complications. Hepatic cysts, pancreatic cysts, cardiac valvular lesions, intracranial aneurysms and splenic cysts are included in the array of systemic manifestations. PMID- 8697930 TI - [A prospective study of plasma exchange in the treatment of diffuse scleroderma]. AB - A prospective randomized study to compare the efficacy between plasma exchange (PE) plus D-penicillamine (13 cases) (group I) and D-penicillamine alone (16 cases) (group II) in the treatment of diffuse scleroderma was carried out. Total skin score, the distance between finger and palm, the distance between upper and lower teeth, the index of joint tenderness, grip strength, ESR, IgG, plasma renin and angiotensin II were measured. After 6 times of PE, all parameters in group I showed significant improvement as compared with those before treatment (P < 0.05 P < 0.01). The overall effective rates evaluated by physicians and by patients were 61.1% and 69.2% respectively. One and half year after the 6 times of PE, all parameters in group I were lower than those in group II (P < 0.05). In group I there were less internal organ impairment and hypertension than in group II. The commonest side effect of PE was hypotension; it disappeared after transfusion. PMID- 8697931 TI - [A study on antimicrobial resistance of coagulase negative staphylococci]. AB - One hundred and eight strains of coagulase negative staphylococci (CNS) isolated from different clinical specimens (sputum, urine, blood, various catheters etc.) were classified into 9 species of CNS with biochemical technique. Staphylococcus epidermidis and staphylococcus saprophyticus accounted for the majority (66%). Drug susceptibility tests revealed that they were highly resistant to penicillin, oxacillin, erythromycin, chloramphenicol, compound sulfamethoxazole, tetracycline, cephazolin and ++ceftazidim but relatively sensitive to vancomycin, amikacin, gentamicin and rifapen. The MIC of oxacillin ranged from 0.125 mg/L to 128 mg/L. The MIC90 was 64 mg/L. It is suggested that vancomycin is the therapy of first choice in methicillin resistant CNS infection. PMID- 8697933 TI - [Mitochondrial gene and diabetes]. PMID- 8697932 TI - [Adrenomedullin]. PMID- 8697934 TI - [A study on antibiotic abuse in 750 children with acute respiratory infection in Tongxian County of Beijing]. AB - A study on antibiotic abuse and inappropriate use was conducted in 750 children under five years old with acute respiratory infection (ARI) in Tongxian County, Beijing, based on WHO's ARI Standard Case Management for Young Children, who sought medical care in clinics at county, township, and village levels provided by 100 physicians. Results showed 96.9% of them were defined as antibiotic abuse and 62.9% as inappropriate use. Factors that contributed to antibiotic abuse and inappropriate use were length of medical practice of physicians the ill children consulted, their education level, scores of their knowledge and attitude, their diagnostic skills, purposes for antibiotic use, whether or not to enjoy free medical care by employees' dependents, ill children's degree of fever and self prescription by parents, and so on. PMID- 8697935 TI - [Surveillance of levels of neutralizing antibodies against poliovirus among children aged 0-3 in rural areas of Anhui Province]. AB - Levels of neutralizing antibodies against poliovirus (PV) in 1,755 children aged 0-3 sampled randomly from 18 counties in Anhui Province were determined in September, 1993. Results showed the positive rates and geometric mean titer (GMT) of neutralizing antibodies against PV type 1, 2 and 3 were 96.98%, 96.01% and 96.18%, and 524.80, 323.59 and 436.50, respectively. Immune level of children was considerable high in each county sampled. No significant difference was found among different age groups and between boys and girls in positive rates and GMT of polioantibodies, but there was significant difference in them between children administered varied doses of oral polio vaccine (OPV). Children investigated took four doses of OPV in average, and their GMT was in proportion to the dose they took. Positive rate of PV antibodies was more than 95% in children who finished the full course of OPV immunization. There were very few townships or villages with a low coverage of OPV immunization in children. It indicated polio immune status was in a higher level in the Province. PMID- 8697936 TI - [Use of nutrient density in etiologic studies on stomach cancer]. AB - Role of nutrient density played in the genesis of stomach cancer was analyzed with a pair-matched case-control design to explore further the association between dietary nutrient and incidence of stomach cancer. Investigation of 88 pairs of cases with stomach cancer and controls showed high nutrient density of dietary vitamins C and A could protect from stomach cancer with OR of 0.34 and 0.46, respectively, and high of carbohydrate could increase risk of it with an OR of 2.20. Some problems in the use of nutrient density were discussed in the paper. PMID- 8697937 TI - [Serologic screening on nasopharyngeal cancer in 338,868 persons in 21 cities and counties of Guangxi Region, China]. AB - Serological screening on nasopharyngeal cancer in 338,868 persons living in 21 cities and counties of Guangxi Zhuang Autonomous Region was carried out from January 1991 to September 1993. Results showed 9367 persons were positive for IgA antibodies to Epstein-Barr virus (EBV) capsid antigen, and 306 of them positive for IgA to EBV early antigen. One hundred and thirteen cases of nasopharyngeal cancer were detected in the former with 100 cases (88.5%) in the early stage, and 63 cases in the latter with 58 (92.1%) cases in the early stage. It suggested certain relationship existed between EBV and nasopharyngeal cancer, and serologic screening could be beneficial for secondary prevention of it. PMID- 8697939 TI - [Spatial and age distribution of spermarche and its influence on development of male adolescents in China]. AB - Spatial and age distribution of spermarche, and difference of growth and development in pre- and post-spermarcheal boys were analyzed based on the data of national physique and health surveillance for school children collected in 1991 to study the relationship between spermarche and development. Generally, there existed a trend that onset of spermarche was earlier in boys living in south China than in the north, and earlier in urban than in rural areas. Physique, physiological quality and sports performance were significantly better in post spermarcheal boys aged 11 to 14 than in pre-spermarcheal ones. Discriminant analysis showed there were significant differences in development between pre- and post-spermercheal boys, especially in body height, weight, biacromial diameter, biiliocristal diameter and vital capacity, but there was no difference in type of body build. PMID- 8697938 TI - [Observational and experimental studies on relationship between domestic pigs and epidemic hemorrhagic fever investigation]. AB - Observational and experimental studies on the relationship between domestic pigs and epidemic hemorrhagic fever (EHF) were carried out during 1986 to 1994 with reverse passive hemagglutination (RPHA), reverse passive hemagglutination inhibition (RPHI), horse-radish peroxidase-staphylococcal protein A (HRP-SPA), indirect immunofluorescence assay (IFA) and reverse transcript polymerase chain reaction (RT-PCR) to understand the roles of domestic pigs played in the epidemic areas. Results showed domestic pigs could infect epidemic hemorrhagic fever virus (EHFV) naturally or experimentally, and EHFV could disseminate to many organs of the animals and caused transient pathologic changes in them. EHFV could duplicate within the animal bodies and be excreted out of the bodies with their excreta. Proportion of inapparent infection of EHF in people closely exposed to domestic pigs was significantly higher than in those without it. It indicated domestic pigs maybe played an important role in EHF as a reservoir host. PMID- 8697940 TI - [Analysis of biochemical components of seminal plasma in male workers exposed to mercury vapor]. AB - Determinations of transferrin (Tf), fructose (Fru), citric acid (CA), zinc (Zn) and copper (Cu) levels of seminal plasma in 38 male workers exposed to mercury vapor and 18 male unexposed controls showed levels of Tf and total Fru, and sperm density adjusted Fru level of seminal plasma in workers exposed were significantly lower than those in controls, and the latter lowered gradually with increase of exposure to mercury. No significant difference of levels of CA, Zn and Cu of seminal plasma between the two groups was found. It suggests chronic exposure to mercury vapor may cause adverse effects on Sertoli's cells of spermatogenic epithelium and seminal vesicle function. PMID- 8697941 TI - [Changes of lung function in ex-smokers]. AB - Lung function in 31 ex-smokers, 17 with six to eight and 14 with 11 to 15 years of cigarette smoking, and pair-matched controls were studied. Results showed smoking could cause prolongation of mean through time and partial mean through time in forced expiratory volume scheme, which increased with length of smoking, and multiple abnormal in lung function tests. Lung function could improve apparently after the cease of smoking. It suggested quitting of smoking could prevent lung function from further damage, or reverse the damaged lung function. PMID- 8697942 TI - [Inhibition of colorectal carcinoma induced by 1, 2-dimethylhydrazine in mice with tea polyphenols]. AB - Colorectal cancer was induced by subcutaneous injection of 1,2-dimethylhydrazine (DMH) in mice, and the animals were administered orally with 0.4% of tea polyphenols (TP) simultaneously for 20 weeks to study its preventive effects. Results showed incidence of colorectal cancer in mice administered with TP was significantly lower than in positive controls (P < 0.05), and average number of tumor foci and proportion of adenocarcinoma were significantly fewer in TP group than in positive controls (P < 0.01). Level of cytochrome P450 (CP450) in liver microsome of the mice administered with TP was lower than that both in negative and positive controls (P < 0.01), and activities of superoxide dismutase (SOD) in liver tissue were higher than those in positive controls (P < 0.01), but lower than in negative controls (P < 0.01). Proliferative index of epithelial cells in mice was not obviously influenced by TP. It suggested that TP could have preventive effects on experimental colorectal cancer with a possible mechanism of lowering CP450 and increasing the activity of SOD in the liver. PMID- 8697943 TI - [Inhibition of ornithine decarboxylase activity and epidermal papilloma in mice by beta-carotene]. AB - Anticarcinogenic action of beta-carotene was analyzed with determination of ornithine decarboxylase (ODC) activity induced by TPA and a two-stage model of skin papilloma-genesis in mice. Results showed increase of ODC activity induced by TPA could be significantly inhibited, onset of tumor postponed, and number of tumor foci decreased by beta-carotene. It suggested beta-carotene had an obvious chemoprophylactic effect on tumor. PMID- 8697944 TI - [Current status of the study on hepatitis C virus envelope region gene and its vaccine]. PMID- 8697945 TI - Merging PICU and MICU: expanding nurse competencies. AB - Unit mergers offer an opportunity for nurses to acquire additional skills. A model for unit mergers is presented. The authors describe how didactic and clinical competencies serve as a foundation upon which the nurse develops proficiency and expertise in a new subspecialty. PMID- 8697946 TI - Prevention of aspiration pneumonia: a research-based protocol. PMID- 8697947 TI - Management of the patient with a pituitary tumor resection. AB - The resection of a pituitary tumor represents a challenging diagnosis for the critical care nurse. There are important nursing assessments that can assist in identifying post-surgical complications. Detailed teaching instructions by the critical care nurses will also assist in minimizing the patient's postoperative complications. PMID- 8697948 TI - Atypical pneumonia in the critically ill obstetric patient. AB - The critically ill obstetrical patient is a challenging complex case for today's critical care nurse. Butterworth Hospital in Grand Rapids, Michigan, identified this emerging patient population and developed a collaborative multidisciplinary program to provide positive outcomes for these patients. The following case study illustrates the components of the program and its usefulness in providing individualized care for a particular critically ill obstetrical patient. PMID- 8697949 TI - Air mattress for post-PTCA/DCA patients: evaluating the outcome. AB - Changes in health care and the development of new technologies challenge nurses to evaluate the effectiveness of nursing practices. The application of special equipment and nursing interventions need to be researched based on desired patient outcomes. The authors report the impact on patient outcomes from the use of an air mattress during the recovery period post-Percutaneous Transluminal Coronary Angioplasty (PTCA) and Directional Coronary Atherectomy (DCA). PMID- 8697950 TI - Sperm collection in the brain-dead patient. PMID- 8697951 TI - Building a research team. AB - All diabetes healthcare professionals are involved in the research process. This involvement ranges from appraising the research literature to actually conducting a research project. Regardless of the type of involvement, collaborating with others is an effective and efficient way of introducing individuals into the world of research. Greater participation in the research process provides a greater appreciation of its roles in patient care. Forming interdisciplinary research teams contributes to the sharing and implementation of information and ideas among disciplines while building effective working relationships. PMID- 8697952 TI - The challenge of conducting clinical research in diabetes care and education. AB - The current healthcare environment requires diabetes educators to design their care and education programs around findings in scientific- and research-based literature. They must be confident that what they do makes a difference in terms of patient outcomes. Although diabetes educators recognize the importance of research as a basis for their practice, they often do not see themselves as responsible for participating in the process. Clinicians such as diabetes educators are in an ideal position to incorporate research into their practice because they are the most knowledgeable about the clinical problems that need to be solved. The challenges of conducting clinical research will be explored in this article along with ways to promote greater participation of diabetes educators in conducting research in their practices. PMID- 8697953 TI - Using focus groups to identify psychosocial issues of urban black individuals with diabetes. AB - The purpose of this focus group research was to identify issues that could serve as topics for a series of educational videos portraying psychosocial issues of urban black individuals with diabetes. Four focus groups involving 34 black adults were conducted in the Detroit area. Psychosocial issues were identified and rated in order of priority by an expert panel. The major psychosocial issues identified were the importance of food and eating in the black culture, the necessity for learning more about diabetes and its complications, learning to interact effectively with healthcare providers and systems, and the need for help and support in managing psychosocial issues related to diabetes. Black individuals with diabetes face unique psychosocial challenges. Focus groups are an effective method for obtaining relevant, culturally specific, in-depth information about living with diabetes from patients who are members of minority groups. PMID- 8697954 TI - Knowledge about hypoglycemia in young women with type I diabetes and their supportive others. AB - Hypoglycemia is a common stressful occurrence for people with type I diabetes, is disruptive to daily activities, and is a source of embarrassment, fear, and anxiety. Adequate knowledge about hypoglycemia is needed to recognize, treat, and prevent this condition. Families and friends also need adequate knowledge about hypoglycemia to provide helpful support. In this study, the Hypoglycemia Knowledge Questionnaire was used to measure knowledge about hypoglycemia in a convenience sample of 94 young women with type I diabetes and 94 supportive others. Knowledge about hypoglycemia was significantly higher for the young women with diabetes than for their supportive others, although knowledge deficits were evident for the young women on selected questionnaire items. Because normalization of blood glucose is associated with an increased risk of hypoglycemia, comprehensive evaluation of knowledge about hypoglycemia is critical to self-care. Additional studies are needed to validate the reliability and evaluate the usefulness of the Hypoglycemia Knowledge Questionnaire in clinical and research applications. PMID- 8697955 TI - Using focus groups to characterize the health beliefs and practices of black women with non-insulin-dependent diabetes. AB - The purpose of this focus group intervention was to characterize the health beliefs, self-care practices, diabetes education needs, weight-loss issues, and facilitators and barriers to diabetes health care in black women with non-insulin dependent diabetes. Major themes that emerged from the focus group were motivation to prevent complications, unrealistic weight goals set by providers, multiple barriers to diet and exercise, and a dual role of family as supporter and deterrent to diabetes management, especially related to diet. These findings suggest that culturally sensitive and appropriate patient educational programs must be provided for minority groups such as black women who have higher rates of diabetes-related complications. PMID- 8697956 TI - Strategies for teaching elders from a human development perspective. AB - Diabetes is a disease that challenges all people to learn, change, and develop. Older people can be taught about diabetes from a human development perspective using Erikson's psychosocial theory of development. Developmental changes in appearance, bodily function, and health status confront almost all persons in later years. If an individual does not have coping resources or a history of successful coping, changes in health status during aging can constitute serious crises. It is important to look at and work with individuals from the context of their entire life cycle rather than in a fixed period of time. The diabetes healthcare team can make more effective use of the theories of human development and aging to enhance the effectiveness of diabetes education for the elderly. PMID- 8697957 TI - What's your IQ on cross-cultural nutrition counseling? PMID- 8697958 TI - From the president: a tale of cost containment and chronic disease. PMID- 8697959 TI - A team approach to managing preexisting diabetes complicated by pregnancy. PMID- 8697960 TI - Spiritualcise mind-body exercise program. PMID- 8697961 TI - Physical activity in adolescents with diabetes. AB - This study investigated the physical activity and beliefs about exercise of 30 adolescents with diabetes. The Seven-Day Physical Activity Recall was used to determine the physical activity for two different recall periods that were 2 weeks apart. Forty percent of the youths engaged in 30 minutes of moderate activity 5 times per week while only 10% engaged in 20 minutes of vigorous activity 3 times per week. Forty-seven percent of the teens consistently achieved or surpassed the time equivalent of activity for one of the Healthy People 2000 Objectives for moderate or vigorous physical activity. This group had significantly higher scores on the Exercise Belief Instrument for Adolescents that was developed for this study. Strategies to encourage regular physical activity are discussed. PMID- 8697962 TI - The role of the Health Belief Model in amputees' self-evaluation of adherence to diabetes self-care behaviors. AB - This study involving 76 amputated patients with non-insulin-dependent diabetes mellitus examined the relationship between their beliefs regarding diabetes and its treatment and their self-evaluation of adherence to diabetes self-care behaviors. Descriptive results showed a high level of adherence to medication, foot care, and blood glucose testing, and a low level of adherence to diet and exercise. The correlative analysis revealed significant relationships between perceived social support and adherence to diet, and between perceived social support, barriers, and adherence to the practice of exercise. The regression analysis showed a significant influence of perceived social support on adherence to diet. The same relationship was observed for the influence of perceived social support and barriers on adherence to exercise. Findings support the importance of giving more attention to patients' needs regarding adherence to diet and exercise, improving social support, and removing barriers to patients' treatment. After an amputation it is important to provide patients with an appropriate diabetes teaching and follow-up program. PMID- 8697963 TI - Locus of control, social support, and adherence to the diabetes regimen. AB - There is a need to better understand how psychosocial factors influence regimen adherence behavior. Therefore, the purpose of this study was to assess the ability of internal diabetes locus of control and social support to predict adherence to a weight-control regimen among persons with non-insulin-dependent diabetes mellitus (NIDDM). A community-based sample of 465 patients with NIDDM was interviewed. Regression analyses revealed that internal locus of control and social support were modest but statistically significant predictors. Correlation analyses showed that internal locus of control was not related to weight control in the high social support group. In the low social support group, a stronger internal locus of control was not associated with weight management. The ways in which internal locus of control and social support work together were not clear. The findings suggest that these two factors are advantageous for promoting regimen adherence. PMID- 8697964 TI - Computer-based patient education: use by diabetes educators. AB - The purpose of this descriptive study was to identify the concerns and characteristics that distinguish diabetes educators who use computers for patient education from those who do not. Three hundred certified diabetes educators who were current members of the American Association of Diabetes Educators were surveyed using the Stages of Concern Questionnaire and a demographic questionnaire compiled by the author. Results indicated that diabetes educators are interested in computer-based patient education as an educational strategy, even though most diabetes educators are not currently using the computer for patient education. Primary barriers to using computers were identified as lack of computer availability for patients and limited financial resources. Because computers are becoming more pervasive in disseminating information about diabetes and new educational software is being developed for patients, diabetes educators need to learn more about this educational methodology for teaching their patients about diabetes. PMID- 8697965 TI - [Detection of human papilloma virus in esophageal squamous cell carcinoma and adjacent tissue specimens in Linxian]. AB - A total of 87 human esophageal tissue specimens, comprising 35 squamous cell carcinomas and 52 adjacent tissue specimens (with no gross evidence of tumors) were obtained from patients who underwent surgery for cancer of the esophagus in Lin-xian county, Henen Province. The tissue specimens were analyzed for the presence of HPV DNA by Southern blot assay with HPV type 16 and 18 probes and by polymerase chain reaction (PCR) with HPV consensus primer. The esophageal epithelial specimens of human fetus, and condyloma tissue contained HPV type 6 were used as controls. The results showed that no HPV 16, 18 and other type were detectable in any case, either in the esophageal carcinomas or adjacent tissue specimens. Thus, the role of HPV in the carcinogenesis of esophagus remains unclear. The high incidence of esophageal squamous cell carcinoma in Lin-xian is probably related to other factors such as N-nitrosamines. PMID- 8697966 TI - [Immunohistochemical characterization of CD44 molecules expressed in human brain metastases]. AB - CD44v adhesion molecules have been known to be related with carcinogenesis and metastasis of some human cancers including brain metastases of various origin. In this study, we demonstrated further that CD44v expression in brain metastases is extremely heterogeneous. Generally, v5/v6 is homogeneously expressed in the cell populations, while up-regulated v7-v10 could be usually found in a proportion of tumor cells, especially those close to necrosis, at the tumor border and with strong tendency of invasiveness. Our data thus suggest that heterogeneous CD44v expression may be determined not only by intrinsic nature of the cells but also by the surrounding micro-environment. Expression of multiple isoforms of CD44v may confer metastatic cells certain unique abilities, allowing them to localize, then to form metastatic colony in the brain. PMID- 8697967 TI - [p53 gene point mutation in human colorectal carcinoma]. AB - We introduced two modified assay systems, PCR-SSCP and PCR-direct sequencing for the identification of structure aberration at p53 exon 7 in 22 colorectal carcinomas and 1 metastatic lymph node. The data indicated that 27.2% (6/22) colorectal carcinomas and one metastatic lymph node were shown to contain the point mutations in codons 245, 251, 259 and 260 of exon 7. One half of all the mutations was G:c to A:T transition in codon 245. Other mutation patterns were base insertion and deletion. All positive point mutations of p53 exon 7 existed in colon carcinomas in this study. The point mutation in p53 exon 7 was usually associated with poorly differentiated primary carcinomas (P = 0.0178) and the mutation rate of was higher in Duckes C stage of the disease than in stage Duckes A and B (P = 0.0361). Thus p53 exon 7 point mutation in primary colorectal tumors and regional lymph nodes may identity a subgroup of colorectal cancer patients with more aggressive disease and may be as a new tumor markers for assessing the prognosis of colorectal carcinomas. PMID- 8697968 TI - [The significance of p53 gene mutations and expressions in human colorectal tumors]. AB - Using a polymerase chain reaction-single strand conformation polymorphism (PCR SSCP) approach we analyzed 18 human colorectal adenocarcinomas for mutations in exons 5, 6, 7, 8 of p53 gene. At the same time, p53 gene product expression was studied immunohistochemically in these 18 cases in frozen sections. The expression of p53 protein was also immunohistochemically studied in formalin fixed paraffin embedded specimens of 76 colorectal adenocarcinomas and 112 colorectal polyps. Eight out of 18 cases (44%) tested showed a variant band indicative of a mutation in exons 5-6 of p53 gene. Seven out of 8 cases (88%) with p53 gene mutations were positively stained for p53. There was no significant correlation between p53 expression and clinicopathological manifestations and prognosis. But the strongest staining was encountered in those cases with well differentiated and early stages of adenocarcinomas, while weaker staining was encountered in poorly differentiated and mucoid adenocarcinomas. p53 expression was not observed in proliferative polyps and adenomas with low grade dysplasia. The frequency of p53 expression reached 88% (P < 0.001) when adenoma showed malignant change. Among three types of adenomas, p53 expression was most frequent in villous type (P < 0.05). The frequency of p53 expression in adenoma, adenoma with malignant change and adenocarcinoma was 4%, 88% and 51% respectively. These indicate that genetic changes of p53 gene play an important role in the transformation from benign adenoma to adenocarcinoma. p53 immunohistochemistry can be used as a surrogate marker for p53 gene mutation for early discovery of colorectal adenocarcinomas. PMID- 8697969 TI - [Expression of ras and erbB2 in benign and malignant lesions of the stomach]. AB - The expression of P185erbB2 and P21ras was examined immunohistochemically in normal mucosa, intestinal metaplasia, dysplasia, intestinal type and diffuse type carcinoma of the stomach. The positive rates of P185 and P21 in the intestinal type carcinoma were significantly higher than those of the diffuse type. The results suggest that the two types of gastric carcinoma differ not only in histo morphology but also in molecular mechanism. P21 immunopositivity is unlikely a specific marker of malignancy in gastric mucosa because of no significant difference of immunoreactivity among intestinal metaplasia, dysplasia, and carcinoma of the stomach. The positive staining of cell membrane for P185 was observed specifically in intestinal type carcinoma, but was absent in all other lesions. So it appears to be a useful marker of malignant change in the gastric mucosa. Overexpression of erbB2 gene in gastric carcinoma was demonstrated both at the mRNA level by in situ hybridization and at the protein level by immunohistochemical staining. PMID- 8697970 TI - [Study on the reversing effect of tripiperaquine on human multidrug resistant leukemic cell line K562/A02]. AB - K562/A02 is a Cell line with multi-drug resistance established in our laboratory bey long term induction with adriamycin. In this paper, reversal of MDR in K562/A02 cell line by tripiperaquine is reported. The cytotoxicity and intracellular concentration of daunorubicin (DNR) in K562/A02 were measured by MTT colorimetric assay and spectrofluorimetry. The results showed that the sensitivity of K562/A02 to DNR was greatly enhanced by tripiperaquine at 10 micrograms/ml, with an 11-fold increase in cytotoxic activity. The intracellular concentration of DNR in K562/A02 was significantly increased after coincubation with 20 mumol/L tripiperaquine for 3 hours. Our results suggest that tripiperaquine might be used in clinical trial to reverse MDR. PMID- 8697972 TI - [Effect of calmodulin antagonist on chemosensitivity of primary cultured lung cancer cells]. AB - The effect of calmodulin antagonist trifluoperazine (TFP) on in vitro drug sensitivity of primary cultured lung cancer cells was studied in 28 cases with MTT assay. TFP was found to enhance significantly the anticancer activities of VCR, ADR and VP16 (P < 0.01 or < 0.05). But TFP could not sensitize tumor cells to DDP. TFP may therefore be useful as an adjunct in chemotherapy of lung cancer. PMID- 8697971 TI - [Mechanism of resistance to mitomycin C in a human bladder cancer cell line]. AB - This study was undertaken to determine the mechanism of resistance of a human bladder cancer cell line SCaBER to mitomycin C (MMC). The IC50 value for MMC in SCaBER cells was higher by 2.7 fold by 1-h drug exposure colony formation assay as compared to another bladder cancer cell line J82. NADPH cytochrome P450 reductase and DT-diaphorase activities were significantly lower in SCaBER cells as compared to those of J82 suggesting that relatively resistance of SCaBER cells to MMC may be due to inefficient drug activation. Further support for this conclusion derives from the observation that sensitivities of J82 and SCaBER cells to BMY25282, a MMC analogue with lower quinone reduction potential, were similar. MMC dependent lipid peroxidation (an indicator of oxygen free radical formation) was higher in SCaBER cells than in J82. The activities of anti oxsidative enzymes GSH peroxidase and catalase did not differ significantly in these cells. These results suggest that resistance of SCaBER cells to MMC may not be due to the reduced free radical formation in these cells. MMC induced DNA interstrand cross-link (ISC) formation was markedly lower in SCaBER cells than in J82. Taken together, these results suggest that SCaBER cell resistance to MMC may be due to the reduced drug activation and ISC formation in these cells. PMID- 8697973 TI - [Production and application of mouse antiserum to human estrogen receptors]. AB - An antiserum to peptide containing 15 amino acids corresponding to the region-D of human estrogen receptors (hERD) was obtained in mice by immunization with the peptide conjngated to KLH. Using this antiserum, the ER status of paraffin embeded sections of 95 human breast carcinomas (in which, sections of 31 were both frozen and paraffin-embeded ones) were studied. The corresponding rate for determination of ER status between immunohistochemical staining (IHC) and dextran coated charcoal (DCC) assay was 89.5%. The concordance rate for semiquantitative gradings was 69.3%. In addition, in situ hybridization (ISH) of 15 frozen sections of the samples using digoxigenin labeled dUTP to identify the expression of ER mRNA was also done. The result of ISH was fully consistent with that of IHC (100%). The results show that the mouse antiserum to hERD obtained in this study is specific and sensitive for IHC assay of ER and IHC is a valuable adjunct and/or alternative to the biochemical method for determination of the ER status of breast cancer. PMID- 8697975 TI - [Prevention and treatment of surgical complications of tracheobronchoplastic procedures. An analysis of 22 cases]. AB - This paper reported the surgical complications of various tracheobronchoplastic procedures in 22 cases between May 1979 to March 1994. The incidence of postoperative complication was 14.5%. The mortality rate was 1.3%. Among them, complications of the respiratory system occurred in 9 cases (41%), cardiovascular system in 4(18%), digestive system in 2(9%), chest incision infection and early recurrence of carcinoma in 1 each (5%) and those due to surgical skill in 5(23%) respectively. Tracheostomy should be done with ventilatory support should be given if early respiratory failure occurred. Particular attention should be paid to prevent fatal complications from detachment of embolus in the pulmonary vein or bronchus. Because of the surgical complications, indications of tracheobronchoplastic procedures for lung cancer should be strictly handled. PMID- 8697974 TI - [Experimental study on targeting therapy of human hepatocellular carcinoma in nude mice using adriamycin-anti-transferrin receptor conjugate]. AB - Conjugate between adriamycin and anti-transferrin receptor monoclonal antobody WuT9 was prepared with Dextran T10 as a bridge, and it was proved to retain both the drug cytotoxity and antibody activity. The conjugate or its individual components were administered to athymic mice bearing SMMC-7721 human hepato cellular carcinoma (HCC) cells. These agents were given 2, 5, 8 days after inoculation of tumor cells (1 x 10(7) per mouse). Tumor size was measured daily (geometric mean diameter, GMD) and latent period recorded. All the animals were killed on day 35 to measure tumor weight and natural killer (NK) activity of splenic lymphocytes. The results showed that the latent period in the conjugate treated group was much longer than that in Adr treated group (33.0 days vs 25.0 days), and that GMD on day 35 in the conjugate treated group was much smaller than that in Adr treated group (3.80 +/- 1.9 mm vs 6.69 +/- 2.3 mm, P < 0.05). In addition, NK activity in the conjugate treated group was higher than that in Adr treated group (28.2 +/- 8.2% vs 15.1 +/- 3.6%, P < 0.05). The results suggest that adriamycin-anti-transferrin receptor conjugate might be useful in the treatment of human HCC. PMID- 8697976 TI - [CF/5-FU-DDP therapy for esophageal carcinoma]. AB - From March 1992 to May 1994, 105 patients with esophageal carcinoma patients were treated with CF/5-Fu-DDP (group A, n = 40) or 5-Fu-DDP (group B, n = 65) protocol. The response rate (CR+PR) was 80% in group A and 60% in group B. (P < 0.01) Induction chemotherapy was followed by surgery or radiation therapy. The incidence of nausea, vomiting, cardiotoxicity and leukopenina was higher in group A than in group B. Buccal mucositis, diarrhea, abdomenal pain and skin pigmentation were noted only in group A. However, the toxic effects were tolerable. The results suggest that the CF/5-Fu-DDP regimen is more effective than 5-Fu-DDP regimen and may be one of the best chemotherapy regimens for the treatment of esophageal carcinoma. PMID- 8697977 TI - [The clinical efficacy of CAC regimen in the treatment of advanced breast cancer]. AB - Twenty seven Patients with advanced breast cancer were treated with CAC (carboplatin, adriamycin, cyclophosphamide) regimen. Eighteen patients had no prior chemotherapy. Carboplatin was given 300 mg/m2 intravenously (IV), on day 1 or 150 mg/m2 on day 1, 2, adriamycin 40 mg/m2 IV on day 3, cyclophosphamide 500 mg/m2 IV on day 3, 10. The treatment was recycled every 28 days. The overall objective response was 63% (17/27) with a CR rate of 18% (5/27). The median duration of response was 9 months and median survival time was 17 months. The response rate of soft tissue metastasis was 61% (11/18). Lung metastasis responded in 3/5, liver metastasis in 3/3, pleura metastasis in 4/4, bone metastasis in 1/10. The response rate of previously untreated patients was 72% (13/18). The gastrointestinal reaction was mild. No renal toxicity was observed. Leukopenia (WHO grade II, III) was seen in 89%. These results indicate that CAC is an effective regimen for advanced breast cancer. PMID- 8697978 TI - [Conservative surgery and radiotherapy for early breast cancer]. AB - Thirty-six patients with early stage breast cancer were treated by quadrantectomy, axillary dissection and radiotherapy (CSRT) between October 1987 and May 1990. The median follow-up was 48 months. Overall survival was 100%. 2 had local recurrence in the breast, both patients were stage IIB (T2N1), the number of positive node were 6/12 and 3/11, respectively. The cosmetic results of the breast are excellent and good in 91%. We concluded that CSRT provides good cosmetic results and better local tumor control for early breast cancer patients, but good results depend on strict adherence to indication of treatment, fair surgical techniques and radiotherapeutic measures. PMID- 8697979 TI - [Percutaneous ethanol injection therapy for the treatment of postoperative recurrent primary liver cancer]. AB - This article reported 109 cases of postoperative recurrent primary liver cancer, treated with percutaneous ethanol injection therapy (PEIT) under the guidance of conventional ultrasonic transducer, the total number of injection being 637 times. No metastasis through the needle track or other serious complications were encountered. The 1.3 and 5 year survival rates were 92.6%, 47.8%, and 19%, respectively. We noted that the key factor affecting the efficacy of treatment was the accurate localization of puncture, rather than the times of injection or the quantity of ethanol injected. Criteria for the judgement of treatment and precautions to be noted concerning the procedure were suggested. It is concluded that PEIT is the treatment of choice in the management of non-operable, single, and comparativly smalle focus of postoperative recurrent primary liver cancer. PMID- 8697980 TI - [Hepatectomy under liver normothermic ischemia in primary liver cancer patients associated with cirrhosis]. AB - From Aug 1984 to Aug 1990, under one-shot normothermic interruption of Porta Hepatis, hepatectomy was performed in 115 patients with primary liver cancer (PLC). The incidence of associated cirrhosis was 82.8% with liver function in Grade A in 59.4% of patients and in Grade B in 40.6% of patients according to Pugh's ranking criteria. Hemihepatic vascular occlusion was preferred. Due precautions were taken to prevent postoperative hepatic failure, including continuous low-pressure oxygen inhalation, the use of antioxidants and dexamethasone. Post-operative complications were: Hydrothorax (7.8%), subphrenic abscess (3.5%), bite leakage and gastrointestineal bleeding (0.9%). There was no operative mortality and hospital mortality. PMID- 8697981 TI - [Preoperative evaluation of hepatic functional reserve for patients with primary liver carcinoma]. AB - The retention rate of indocyanine green at 15 minutes (ICGR15) and routine hepatic function tests were performed preoperatively in 122 cases of patients with primary liver carcinomas in order to evaluate the hepatic functional reserve. These patients were divided into 3 groups according to the post operative changes of hepatic function. 87, 24 and 11 cases showed good recovery (group good), mild liver dysfunction (group mild) and severe liver dysfunction (group severe) respectively, after operation. The differences of Pugh's points, ALT, ALP and gamma-GT between each two groups were not significant. But, the differences of ICGR15 were very significant. We also divided all cases into 3 groups according to the value of ICGR15. The incidence of liver dysfunction was 6.0% in group A (ICGR15 < 10.0%), 27.8% in group B (ICGBR15 = 10.0%-20.0%) and 76.5% in group C (ICGR15 > 20.0%), respectively. The difference of the incidences of liver dysfunction in these 3 groups was very significant. The higher the ICGR15, the more the incidence of liver dysfunction. These results demonstrated that ICGR15 is a good indicator to judge hepatic functional reserve for patients with primary liver carcinoma. PMID- 8697982 TI - [Evaluation of combined test of sequential fecal occult blood and albumin in the screening of colorectal neoplasms]. AB - Fecal albumin test was developed and the combined use of sequential occult blood test and albumin test (SA) was evaluated and compared with sequential fecal occult blood test (S) in 365 cases diagnosed clinically and pathologically and in 883 asymptomatic individuals. In the former group, the sensitivity of detection of colorectal cancer was: 50.7% (37/73) with S and 87.7% (64/73) with SA (P < 0.001), and that of the adenoma was: 8.1% (6/74) with S and 36.5% (27/74) with SA (P < 0.001). In the latter group 2 of 3 cancer patients were detected with S while all with SA, and the detection rate of adenoma was: 4.7% (4/85) with S and 42.4% (36/85) with SA (P < 0.001) it is suggested that the additional use of fecal albumin test is of help in detecting precancerous inflammatory bowel lesions without bleeding. PMID- 8697983 TI - [Multimodality therapy of late stage lung cancer]. AB - A prospective randomized study of 80 cases of stage III lung cancer treated with different multimodality therapy was carried out. Life table and Kaplan-Meir curve were employed to calculate survival rate. Log rank-multivariate analysis and time t test were used to evaluate statistical values of the 80 cases, 40 SCLC were randomly treated with either chemotherapy (CT)-surgery-CT or CT-radiotherapy (RT) CT. The year survival rates were better in the group treated with CT-surgery-CT, a statistical difference was observed in 2yr survival rate (P < 0.05). Thus, surgical resection for SCLC was better than RT after CT. The remaining 40 cases of NSCLC were randomly treated with either CT-RT-CT or RT-CT. Multivariate analysis showed a better statistical meaning in the 20 cases treated with CT-RT CT than the other group, their 1, 2 year survival rates were 27%, 40% and 22%, 15%, respectively. Thus preradiative CT was beneficial for survival. PMID- 8697984 TI - [Lymphatic metastasis in central direction and bowel axial direction in colonic cancers]. AB - 485 lymph nodes were founded by palpation in 44 R3 resected specimens of colonic cancers. In the bowel axial direction, the rate of lymphatic metastasis was 6.8%, which accound for 9.6% of the positive lymph node metastasis. All these positive nodes were limited from 10 cm proximal to 5 cm distal to the tumor. In the central direction, the rate of mesenteric lymphatic metastasis was 20.4%, and the rate of lymphatic metastasis at the root of mesentery was 4.5%, which accounted for 38.1% of the positive lymph node metastasis. Compared to the bowel axial direction, mesenteric lymphatic metastasis in the central direction was more common and should be carefully disseted during radical operation. PMID- 8697985 TI - [Esophagogastrostomy covered by sero-muscular flap of gastric wall in the treatment of gastric cardia cancer in 100 cases]. AB - A new operative procedure-esophagogastrostmy covered by sero-muscular flap of gastric wall to treat cancer of gastric cardia was designed by the authors in order to prevent anastomotic complications. One hundred cases with cases of gastric cardiac 97 cases with adenocarcinoma and 3 cases with squamous cell carcinoma of esophago-cardiac iunction were treated with the new anastomotic method without operative mortality and anastomotic complicatins within one year after surgery. PMID- 8697986 TI - [A hot-spot mutation of p53 gene in nasopharyngeal carcinoma]. AB - Using DNA sequencing and immunohistochemical staining, p53 gene mutation and overexpression were investigated in 23 formalin-fixed and paraffin-embedded specimens of nasopharyngeal carcinoma (NPC). All patients were from regions of low NPC incidence in China. Sequencing of exon 7 and exon 8, revealed p53 gene mutation in 15 of the 23 specimens (65.2%). All the mutations were at codon 273(CGT-->CAT), so that arginine encoded by this codon was replaced by histidine. In addition, p53 overexpression was found in another NPC specimen without mutation in exon 7 or 8 of p53 gene. The results suggest that p53 gene mutation is of common occurrence in NPC. The hot-spot mutation at codon 273 might be related to some special carcinogen in the environment, or this change be essential in the multi-step process of carcinogenesis of the nasopharynx. PMID- 8697987 TI - [The relation between p53 mutations and tumor invasiveness of human hepatocellular carcinoma]. AB - We have combined the polymerase chain reaction (PCR) with the HaeIII enzyme restriction analysis to study the mutations at codon 249 of p53 gene in L02 human liver cell line, Bel-7402, SMMC-7721 human hepatocellular carcinoma cell lines and 19 surgical specimens of hepatocellular carcinoma (HCC) and their surrounding non-cancer liver tissues. None of the three cell lines and the non-cancer liver tissues was found to have p53 mutation; but 10 of 19 HCC samples (52.6%) had p53 point mutations, and the p53 gene mutated more frequently in HCC with incomplete capsule, intrahepatic metastasis, or multiple nodules than in those with well encapsulated (70% vs 33.3%, P < 0.05), no intrahepatic metastasis (71.4% vs 41.6%, P < 0.05) and single nodule (83.3% vs 38.5%, P < 0.05). These suggested that the codon 249 was a mutational hotspot of the p53 gene in human HCC seen in China, and p53 mutations may be related to invasiveness of human HCC. PMID- 8697988 TI - [Pathological studies on the anti-invasive character of IL-6 gene transfected leukemia cells]. AB - FBL-3 Leukemia cells transfected with IL-6 gene were expanded in vitro and inoculated into C57BL/6 mice subcutaneously. Tumor growth was observed and histologic analyses of the tumors in situ and the liver, spleen and bone marrow were performed at 14, 21, 28 and 35 days after inoculation. The mice inoculated with wild-type FBL-3 leukemia cells were used as the control. We found that the tumor invasiveness in the mice inoculated with FBL-3-IL-6+ occurred later than in the control group. The survival time of experimental mice was longer than in the control mice. The results demonstrated that inoculation of IL-6 high-secreting FBL-3 inhibited invasiveness of the leukemia cells, suggesting that the IL-6 gene transfected FBL-3 cells can be used as a vaccine to treat leukemia. The mechanism of the anti-invasiveness of IL-6 gene transfected leukemia cells needs further study. PMID- 8697989 TI - [Correlation between p53 nuclear protein accumulation and mutations of the p53 gene in human esophageal cancer from linxian]. AB - Thirty-three esophageal tumors were analyzed by immunohistochemistry for P53 nuclear protein accumulation, and the results were compared to p53 gene mutations by PCR-direct sequence analysis. A highly significant correlation between the presence of p53 mutations and p53 nuclear protein accumulation was found. Of 33 tumors, 23 (69.7%) that demonstrated P53 protein expression 12(36%) had p53 mutations. Of 12 tumors with p53 mutations, 9 tumors showed P53 intensive nuclear reactivity. The results reported here are consistent with the idea that p53 mutations may be an important biological event in esophageal cancer progression and P53 expression was correlated with p53 gene mutation. PMID- 8697990 TI - [Overexpression of c-myc and p53 gene in human hepato-cellular carcinoma--a study with immunohistochemistry and in situ hybridization]. AB - Immunohistochemistry (ABC method) and in situ hybridization (DNA-RNA) were used to detect c-myc and p53 gene expression in tissues of human HCC and nearby non tumorous liver (NT) from 23 patients. The results showed that the positive rates of P62c-myc were 87% (20/23) in HCC and 91% (21/23) in NT. The positive rates of P53 protein were 39% (9/23) in HCC as well as in NT. The positive rates of c-myc and p53 mRNA were 70% (16/23) and 56% (13/23) in HCC and NT respectively. The expression of c-myc and p53 at protein level was significantly correlated with that at mRNA level. These observations suggest a close association of c-myc and p53 gene overexpression with hepatocarcinogenesis. Immunohistochemistry (ABC method) on section of paraffin embedded tissue is a reliable method for detecting c-myc and p53 gene expression in HCC. PMID- 8697991 TI - [Gastric cancer with P53 overexpression and nm23 low-expression has high potential for lymph node metastasis]. AB - By using SP immunohistochemical methods, the correlation of the expression of P53 and nm23 with the biologic behavior and lymph node metastasis in gastric carcinomas was studied. Abnormalities of P53 expression were found in 49% of the 88 primary gastric carcinomas. A significant correlation was found between P53 overexpression and the depth of invasion and the proliferative activities (Pearson Contingency Coefficient P = 0.32 and 0.35, P < 0.05, respectively). The metastatic rate of tumours stained positively for P53 (93%) were higher than in those with negative P53 staining (60%, P < 0.05). Meanwhile, a significant correlation of low expression of nm23 with the depth of cancer invasion was found (Pearson Contingency Coefficient P = 0.28, P < 0.05). nm23 low-expressive tumours were associated with a higher incidence of metastasis to lymph nodes (93%) than were nm23-normal expressive (49%, P < 0.05). The contributions of P53 overexpression and nm23 low-expression to the lymph nodal metastasis were the independent joint action. It is suggested that P53 overexpression and nm23 low expression might play significant role in lymph node metastasis and invasion and proliferation in the primary gastric carcinomas. PMID- 8697992 TI - [The differentiation-inducing effect of tanshinone and retinoic acid on human cervical carcinoma cell line in vitro]. AB - The differentiation-inducing activity of tanshinone (TAN) and all-trans-retinoic acid (RA) was studied in vitro on a human cervical carcinoma cell line, ME180. The tumor cells were treated with TAN or RA in DMSO (final concentration 0.02%, V/V) on 4 successive days. Cells treated with the same concentration of DMSO alone served as control. Morphologic studies with light and transmission electron microscopy showed that the cells treated with both TAN and RA became well differentiated. The cell growth, (as revealed by cell counting and 3H-TdR incorporation) was inhibited and the tumorigenicity in nude mice was reduced. No significant difference was observed between the cells treated with TAN and RA. PMID- 8697993 TI - [Expression of the retinoic acid nuclear receptors and retinoid X receptor gene in human breast cancer]. AB - A number of studies have shown that retinoids can inhibit malignant cell growth including certain breast carcinoma cells. Its inhibitory effect is observed only in ER positive but not in ER negative breast cancer cells. We examined retinoic acid nuclear receptors (RARs) and retinoids X receptors (RXRs) levels in 6 breast carcinoma cell lines and 18 breast cancer biopsy specimens. We found that RAR alpha mRNA level was significantly higher in ER positive cell lines and samples. RAR-gamma mRNA was expressed at relatively high levels in majority of tumor samples independent of the ER-status while RAR-beta mRNA was expressed at low levels. We also found high RXR-alpha mRNA levels in all of the tumor samples examined while RXR-gamma mRNA could not be detected. Our study suggests a possibility that retinoids inhibit tumor cell growth through RAR-alpha and RAR alpha levels may serve as a potential marker to determine responsiveness of patients to retinoids therapy. PMID- 8697994 TI - [Synergistic effects of tumor necrosis factor interferon-gamma and chemotherapeutic drugs on human ovarian cancer cell lines in vitro]. AB - Three ovarian cancer cell lines, NIH: OVCAR-3, 3AO, and AO were used in this study to assess the synergistic effect of TNF-alpha, IFN-gamma and chemotherapeutic drugs (epirubicin, carboplatin, fluorouracil). It was found that NIH: OVCAR-3 and 3AO cells were resistant to the individual treatment with TNF alpha and IFN-gamma, while AO cells were sensitive to TNF-alpha but not to INF gamma. Epirubicin and TNF-alpha were the two major cytotoxic agents to NIH: OVCAR 3. 3AO cells were susceptible to epirubicin, 5-Fu, TNF-alpha and IFN-gamma, while AO cells were sensitive to TNF and epirubicin. Carboplatin did not show any synergistic effect on all these three cell lines when combined with cytokines. PMID- 8697995 TI - [Expression of oncogene and anti-oncogene in mouse lung cancer induced by coal burning smoke]. AB - Previous epidemiology studies have shown association between coal burning and human lung cancer. To confirm relationship of coal burning to lung cancer formation and progression the expression of p53 and c-myc in 13 mouse lung cancer induced by coal-burning smoke and 5 mouse lung tissue control was studied by DNA RNA in situ hybridization (ISH). Nine of 13 specimens showed c-myc overexpression but it occurred only 1 in 9 in the adjacent tissue. There was overexpression of p53 mRNA in all 13 lung cancer and 5 adjacent tissues. None in the controls was expression of p53 and c-myc detected. When compared to controls, there was significant higher expression of c-myc gene (P = 0.002) and p53 gene (P = 0.0001). The results confirm that overexpression of p53 and c-myc are common molecular events of lung cancer by coal-burning smoke and provide further evidence that smoke from coal burning is a causative agent of lung cancer. PMID- 8697996 TI - [Significance of immunohistochemical study in the diagnosis and differential diagnosis of chordoma]. AB - Seven cases of chordoma were studied immunohisto-chemically with antibodies directed to epithelium, nerve, mesenchyme, muscle and histiocyte. Six cases of chondrosarcoma and three cases of mucinous carcinoma of colon were studied as control. The results showed that the chordomas were positive for cyto-K 6/7, EMA 7/7, CEA 6/7, Vim 7/7, S-100 7/7, alpha-AT 7/7, Lyso 4/7, while negative for GFAP and Des in all 7 cases indicating that chordoma, just like notochord, had the potentiality of multidirectional differentiation. In contrast, none of the chondrosarcomas was positive for cyto-K, EMA or CEA, but positive for Vim and S 100 in 6 cases. Three cases of colon mucinous carcinoma were positive for epithelial antibodies, but none reacted with other antibodies. Thus, immunohistochemical studies are of help in the diagnosis and differential diagnosis of chordoma. PMID- 8697997 TI - [Significance of CEA and CA242 in the diagnosis of colorectal carcinoma]. AB - Carcinoembryonic antigen (CEA) is frequently used in the diagnosis of the colorectal carcinoma. CA242 is a novel unique tumor-associated antigen characterized by higher tumor specificity and sensitivity for colorectal cancer, as compared with other mucin antigens. In this study, preoperative levels of serum CEA and CA242 were measured in 63 cases of colorectal carcinoma. It was disclosed that the positive rate of CA242 was higher than that of CEA, particularly in patients with colon cancer. The combined determination of CEA and CA242 significantly increased the sensitivity and accuracy in the detection of colorectal cancer as compared with the use of CEA alone (P < 0.01). In patients with advanced disease the positive rate was markedly elevated, especially in patients with liver metastasis. The results indicate that the combined use of CEA and CA242 assays is an useful adjunct diagnostic measure for colorectal carcinoma, and is helpful in the assessment of the stage of the disease as well as in making treatment plan. PMID- 8697998 TI - [Serum hepatitis B antigen-antibody system in patients with hepatocellular carcinoma]. AB - Serum hepatitis B antigen-antibody system was detected by ELISA method in 150 patients suffering from hepatocellular carcinoma (HCC) with positive AFP. The overall infection rate of hepatitis B virus (HBV) was 86.0% (129/150). According to the antigens and antibodies to HBV, two major types of seven models could be demonstrated. In type I (including models 1 to 4) HBV infection was present in 81.9%, 74.6% among whom were considered to be of weak infectivity and 7.3% of strong one. In type II (including models 5 to 7) 18.0% (27/150) had no antigen and antibody to HBV was detected, indicating the absence of HBV infection. This study suggests that chronic infection with HBV is the major etiologic agent for human HCC and the patients with HCC often accompanied by active HBV replication. PMID- 8698000 TI - [Surgical treatment of undifferentiated esophageal carcinoma]. AB - From 1961 through 1983, a total of 3,804 cases with carcinoma of esophagus underwent surgical resection of cancer at Shanghai Chest Hospital. Thirty-nine of them were primary undifferentiated esophageal carcinoma (UEC) with an incidence of 1%. In 97% of the cases, the lesions were located at the mid- and lower esophagus. All cases underwent tumor resection and esophagogastrostomy, with an operative complication rate of 10%, and mortality rate of 13%. Follow-up until December 1994, all patients were dead. 42% of the cases died within 6 months, another 42% of the cases died within 7-24 months, with a median survival period of 7 months only. The postoperative 5-year survival rate was 15%. To improve the therapeutic results, preoperative radiotherapy and postoperative adjuvant therapy are needed. PMID- 8697999 TI - [Surgical treatment of gastric cardia cancer with fundoplication--a report of 193 cases]. AB - From December 1987 to 1994, a total of 193 patients with carcinoma of the gastric cardia were surgically treated by partial esophagectomy, partial gastrectony and end-to-side esophagogastric anastomosis with fundoplication. When compared to those patients during the same time period similarly treated but with end-to-end esophagogastrostomy, the incidences of anastomotic leakage, anastomotic stricture and esophageal reflux were all significantly decreased (P < 0.01). It is a novel surgical treatment of choice for cancer of the gastric cardia. PMID- 8698001 TI - [A new technique of esophagogastrostomy above the aortic arch--covering and suspending of the anastomotic area with mediastinal pleura flap]. AB - The postoperative anastomotic leakage is the most severe complication and the principal cause of death after resection of esophageal carcinoma. Especially, anastomosis above the aortic arch is accompanied by high incidence of anastomotic leakage usually with fatal prognosis. The authors improved the conventional method of anastomosis by using a mediastinal pleura flap to cover and suspend the anastomotic area with excellent result. From January of 1990 to April of 1995, 210 patients with esophageal carcinoma were so treated. No anastomotic leakage or stricture developed. Only one patient died of extensive myocardial infarction with an overall mortality of 0.47%. The major merit of this procedure was that the mediastinal pleura flap could cover the area of anastomosis and sustain the dragging force acting on this area, providing a better condition for the anastomosis to heal and thus reducing the possibility of anastomotic leakage. PMID- 8698002 TI - [Clinical trial of oral etoposide in the treatment of malignancies]. AB - From June 1993 to April 1994, a multi-centre prospective clinical trial was conducted to evaluate efficacy of domestic oral etoposide in the treatment of malignancies. One hundred and ten evaluable patients were assessed for both response and toxicity. Oral etoposide was given as single agent in 50 patients, including 18 patients with small cell lung cancer (SCLC), 18 with malignant lymphoma (ML), 8 with gastric cancer and 6 with ovarian cancer. The response rate was 50% in SCLC, 83.3% in ML, 16.7% in ovarian cancer and 0 in gastric cancer. Sixty patients were treated with combination chemotherapy containing oral etoposide. There were 45 patients in the control group. The response rates in the treated and control groups were 57.1% and 55.6% in SCLC, 95% and 87.5% in ML, 20% and 0 in gastric cancer, respectively. Oral etoposide was well tolerated by the majority of patients. In conclusion, oral etoposide has definite antitumor activity in SCLC, ML and ovarian cancer. PMID- 8698004 TI - [Experimental study of internal radiation with yttrium-90 microspheres in the treatment of mouse transplanted hepatoma]. AB - The effect of yttrium-90 microspheres in the treatment of mouse transplanted hepatoma H22 was studied. Seventy BALB/C mice with hepatoma H22 were randomly divided into 7 groups (A, B, C, D, E, F, G) and treated respectively with 37, 18.5, 14.8, 11.1, 7.4, 3.7 and 0 MBq/cm3 internal radiation by intratumoral injection of Y-90 microspheres. Dose-dependent therapeutic effects were observed. In group A and B, the tumor growth was markedly retarded and eventually un palpable. Histological examinations showed complete necrosis of the tumor. In groups C,D, E,F, the tumor growth was also inhibited. However, patchy necrosis could be seen amid apparently normal tumor cells. Only isolated, spotty foci of necrosis were present in the untreated control tumors. The results indicate that a tumor of 1 cm diameter can be effectively treated by internal radiation with 18.5MBq Y-90 microspheres injected into the tumor. PMID- 8698003 TI - [Results of phase III clinical trial of Pseudomonas jinanensis vaccine injection (PVI) in the treatment of malignant pleural effusion]. AB - From April 1993 to September 1994, a prospective multicenter phase III clinical trial on PVI in the management of malignant effusion was carried out. Five hundred and nine patients, including 382 with lung cancer, 54 with breast cancer, 16 with malignant lymphoma, 57 with other malignancies complicated with pleural effusion were treated with intrapleural injections of PVI. The over-all response rate was 82.7% (421/509). For comparison, 41 patients with cancer of the lung (n = 31), breast (n = 6) and other sites (n = 4) also complicated with pleural effusion were treated by intrapleural PDD. The overall response rate in the latter treatment group was 61.0% (25/41). Fever and local pain were the major adverse reactions in the PVI treated patients while nausea, vomiting and myelosuppression in the PDD-treated control patients. PMID- 8698005 TI - [Biotherapy of advanced cancer by infusion of in vitro activated autolymphocytes]. AB - Autolymphocyte biotherapy is an adoptive cellular therapy based upon the infusion of autologous lymphocytes that have been activated in vitro by anti-CD3 monoclonal antibody and depleted of suppressor T cells by cimetidine, indomethacin and low dose of gamma irradiation. The patients also receive oral cimetidine to block suppressor T cell activity in vivo. Sixty five patients received 217 autolymphocyte infusions and toxicity was minimal with transient fever and chill accompanying 18 infusions. The efficacy of treatment in patients received more than 3 infusions were evaluated. In 37 evaluable patients, the response rate (CR+PR) was 24% (9/37). As the side reactions are mild, the treatment can be done on an outpatient basis. PMID- 8698006 TI - What can be done about osteoarthritis? PMID- 8698008 TI - From trial outcomes to clinical practice. PMID- 8698007 TI - Drugs and alcohol: harmful cocktails? PMID- 8698009 TI - [102nd Congress of the German Society of Internal Medicine. Rhein-Main-Hallen, Wiesbaden, 13-17 April 1996. Abstracts]. PMID- 8698010 TI - Importance of controlled trials in medicine. PMID- 8698011 TI - A randomised controlled trial to assess the relative efficacy of chloroquine, amodiaquine, halofantrine and Fansidar in the treatment of uncomplicated malaria in children. AB - A randomised controlled trial was carried out to determine the relative efficacy of four commonly used antimalarial drugs in children aged three to twelve years presenting with uncomplicated malaria at the Eldoret District Hospital, Kenya. One hundred and eighty eight children were studied between July 1993 and July 1994. There were no significant baseline differences between treatment groups with respect to age, sex, weight, ethnicity, haemoglobin, white blood cell (WBC) counts, parasite counts, previous exposure to malaria and prior treatment. Of the 188 patients, eleven were lost to follow-up while twelve were discontinued from the study due to poor clinical response. Most of the latter (eight out of twelve) were in the chloroquine group. By day seven, there were significant differences (p = 0.004) in parasite clearance between groups. There were no significant statistical differences between the groups (p = 0.12) with regard to the fever clearance time. However, there was a significant statistical difference (p = 0.00003) between the treatment groups in the cure rates. Halofantrine was the most efficacious drug with 82% of the cases cured followed by fansidar(R)(62%), amodiaquine (55%) and chloroquine (29%). RI and RII resistance were observed in all the treatment groups, i.e. halofantrine (18%), fansidar (38%), amodiaquine (45%) and chloroquine (67%) while RIII resistance was only observed in the chloroquine group(3%). PMID- 8698012 TI - Integrated control of Onchocerca volvulus infection in a hyperendemic zone in Sierra Leone. AB - A simplified integrated method of onchocerciasis control involving mass chemotherapy with ivermectin, nodulectomy and health education was carried out in south central Sierra Leone. The prevalence of Onchocerca volvulus in the village community ranged from a low of 7.4% among the International School children to a high of 97.0% in Gbessebu. There was a significant (3-4%) overall reduction in the rate of infection after one year of ivermectin treatment (G = 2565.97, df = 11, P < 0.001). In addition, ivermectin treatment had a significant effect on the college community (G = 1168.21, df = 5, P < 0.001) and from year to year (G = 187.29, df = 1, P < 0.001), though the effect indicates the reduction varied between communities. Mass ivermectin treatment significantly (G = 1 3.79, df = 1, P < 0.005) reduced the rate of infection among school children, while the prevalence and intensity of infection was reduced by nodulectomy. Health education involving the community gave us an entry point and allowed us to gain the maximum cooperation and participation from the communities. PMID- 8698013 TI - Induced abortion in Kenya: its determinants and associated factors. AB - In a study involving 1077 women who were admitted and treated for incomplete abortion and its related problems at eight hospitals (seven district and one mission hospitals) in six of the eight provinces of Kenya, between October 1988 and March 1989, 169 (15.7%) had illegally induced unsafe abortion, based on their own history and clinical findings. The illegally induced unsafe abortions were common among both rural and urban dwellers, and women from almost all social and economic strata were involved. However, they were more common among the youth (< 25 year olds), school girls, those with high formal education, in formal employment, and not currently married. Majority (90.4%), of the induced group said their pregnancies were unwanted, as compared to only 29.1% of the non induced (p < 0.05). The main determining factor for termination of pregnancy amongst these women appeared to be the fact that it was unwanted and/or unplanned, either because of inappropriate timing, the type of man responsible, the relationship itself and the social and economic implications thereof. This is contributed to by poor contraceptive use inspite of very good awareness, and/or desire to use. There is urgent need to integrate abortion care and related services into the overall reproductive health care and as a part of the broader safe motherhood initiative in Kenya. In addition it is necessary to revise the legal provisions on abortion so as to make them more relevant. Appropriate management of adolescent fertility, should be undertaken with the aim of reducing the extent of illegally induced unsafe abortion with attendant sequealae. PMID- 8698014 TI - Return of fertility after an IUD removal for planned pregnancy: a six year prospective study. AB - This study was conducted in a series of 810 women who opted to use copper T-200 as a reliable form of contraception. The objective of the study was to determine the return of fertility after the removal of the IUD and to identify IUD related complications in an African setting. The study focused on 810 women who had requested for the removal of their IUDs at the time of planned pregnancy. Out of 810 cases, only 780 cases were analysed. In eight (1%) of the cases, the IUD was removed because of full blown pelvic infection and 22 (2.8%) of the cases lost to follow up. The mean age was 29 years. Twenty five (3.2%) of the cases were nulligravidae, 729 (93.5%) multipara, and 45 (3.3%) grand multipara. Six hundred and fifty (83.3%) were married. All the clients who entered the study could afford to go to private clinic for family planning services. Conception occurred in 160 (20.5%) in the first two cycles, 201 (25.8%) between the third and fifth cycle, 250 (32%) between the sixth and eight cycles and 60 (7.7%) between the ninth and twelfth cycle. The remaining 109 (13.9%) of the cases failed to conceive within one year after the removal of IUCD. They have unprotected sexual intercourse for a period of one year. Finally, the pregnancy out come showed the following results: spontaneous abortion 57 (7.3%), preterm birth 25 (3.2%), term delivery 589 (75.5%) and no pregnancy after the removal of the IUD in 109 (13.9%), respectively. PMID- 8698016 TI - Ten years experience with chronic prostatitis in Africans. AB - This is a prospective study of seventy three patients with chronic prostatitis over a ten year period (1984-1994. The study was carried out at various hospitals in Lagos Nigeria and Nairobi Kenya. The mean age was 39.3 years. Chronic bacterial prostatitis was diagnosed in 15 patients (20.5%) of which 11 patients (73.3%) had Escherichia coli as the causative pathogen. Four of these patients (36.4%) were symptom and culture free after 12 weeks therapy with trimethoprimsulfamethoxazole. Four of the other seven patients not responding to trimethoprim (57.1%) became symptom and culture free after four weeks therapy with ciproflaxacin. Non bacterial prostatitis including prostatodynia was diagnosed in 58 patients (79.5%). Only 15 of these patients (25.8%) reported some subjective relief of symptoms on emperic therapy with doxycycline with complete relapse on discontinuation of therapy. Further therapy with non steroidal anti inflammatory ibuprofen and anticholinergic oxybutinin chloride proved effective in alleviating symptoms in 40 patients (68.96%), but all relapsed on discontinuation of therapy emphasizing the ineffective and unsatisfactory nature of the present emperic treatment regimens as the cause of non bacterial prostatitis remains unknown. PMID- 8698015 TI - Prevalence of maxillo-mandibular fractures in mainland Tanzania. AB - In order to evaluate the current trends in maxillo-mandibular fractures, hospital records of all patients who had sustained maxillo-mandibular fractures (in Tanzania Mainland) from 1990-1992 were examined. A specially designed questionnaire was dispatched to Regional Dental Officers to be filled after examining the hospital files of patients. Factors considered were age, sex, date fracture and anatomical site of the fracture. Records of 179 patients who had sustained 187 maxillo-mandibular fractures were identified and analysed. Results showed that the greatest number of maxillo-mandibular fractures occurred in patients between the age group 21-30 years, with a male to female ratio of 3:1. Assault was found to have been the leading aetiological factor (29.9%) followed by motor vehicle and motor cycle accidents (27.3%), falls (18.2%), bar fights (9.1%), sports (8.6%), spouse abuse (3.7%) and work injuries constituted 3.2%. Mandibular fractures out-numbered maxillary fractures in a ratio of 4:1. Of the mandibular fractures, fracture of the body of the mandible occurred most followed by fracture at the angle of the mandible, symphysis, condyle, alveolar and ramus. PMID- 8698017 TI - Xerophthalmia and malnutrition among pre-school children in Agaro town south-west Ethiopia. AB - A community-based cross-sectional study was undertaken in Agaro town to determine the magnitude of xerophthalmia and malnutrition in January 1993. 434 children (aged six months to six years), were selected randomly and by using the proportionate probability sampling technique from the eight 'kebeles' of the town. Data were collected by interviewing mothers/ care-takers of index children and by ocular and anthropometric examinations. From the total subjects studied, the proportion of males (54.6%) was higher than females (45.3%). Few mothers/ care-takers (24.5%) were found to be illiterate. According to the Waterloo classification, 18.6% were either wasted, stunted or both. The overall prevalence of xerophthalmia was 6.2%. Being malnourished and earning less than 700 birr / year were significantly associated with xerophthalmia (chi 2 = 6.23; P < 0.05). Finally, children with clinical signs of xerophthalmia and other eye diseases were treated accordingly and advice was given to mothers/care-takers of malnourished children. PMID- 8698018 TI - Ocular tumours and problems in management: a Ghanaian experience. AB - Fifty eight cases of ocular tumours and forty cases of Burkitt's lymphoma with ocular involvement from the Eye and Burkitt's units of the Korle-Bu Teaching Hospital were reviewed. The tumours formed 0.1% of all the new cases seen at the Eye Clinic. Two thirds of tumours that presented at the Eye Clinic occurred in children below the age of 12 years. The three most commonly occurring tumours were retinoblastomas (50%), dermoid cysts (15.5%) and assorted conjunctival tumours (10.3%). The only secondary tumour encountered was orbital squamous cell carcinoma with the primary site in the maxillary antrum. Misconceptions and socioeconomic problems contributed immensely to late diagnosis, difficulties with management, and poor prognosis for both vision and life. Ocular involvement occurred in 40(16%) out of 248 cases of Burkitt's lymphoma from the Burkitt's Unit. PMID- 8698019 TI - Carcinoma of the male breast: a sexually transmitted disease? AB - Male breast cancer is a rare disease. In an African population, the occurrence of this cancer is high. The male/female ratio in Tanzania is 1:14 (0.071). This narrow ratio does not differ significantly in the majority of sub-Saharan African countries. The overall ratio being 0.0143 (CI = 0.0317-0.877). When this was compared with the ratio of the African American population with breast cancer in USA, it was observed to be significantly high (p < 0.05). The narrow male/female ratio amongst indigenous people with breast cancer in sub-Saharan countries was seen only in those geographical areas where cervical malignancy ranked in the leading position. There is a clear association, with a pronounced linear correlation between these two cancers (r = 0.8). In view of this association it is hypothesised that since cervical cancer behaves as a sexually transmitted disease, then possibly this could also be the case in respect to the male breast carcinoma in sub-Saharan Africa. If these results are confirmed by other investigators, an opportunity to examine the factors contributing to the oncogenesis of this disease may be invaluable in developing prevention and treatment strategies. PMID- 8698020 TI - Henoch-Schoenlein syndrome in children: experience from southern part of Saudi Arabia. AB - This is a retrospective study of 55 children with Henoch-Schoenlein syndrome (HSS) admitted to Asir Central Hospital in the southern part of Saudi Arabia from September 1988 to September 1994. Of the 55 children studied, 29 were girls and 26 were boys with the ratio of 1.1:1. The ages ranged from eight months to 18 years with a mean of 8.6 +/- 5 years. Seventy three percent of our patients were older than five years at initial presentation. Most of the cases occurred between July and January. Hundred percent had the typical rash, 78% had abdominal pain on presentation with significant gastrointestine bleed in 11%. Seventy six percent had joint pain or discomfort. Twenty percent had renal involvement on initial presentation. Recurrence of HSS occurred in 13%. Our study does not show any major regional differences, except the fact that our patients seems to be older at time of presentation. PMID- 8698021 TI - Prevalence and risk factors for warts among slaughterhouse workers. AB - This study was conducted in three animal slaughterhouses in Asir Province, southern region, Saudi Arabia. The aim of this work was to determine the prevalence of warts among the workers of slaughterhouses and to identify possible risk factors of developing warts associated with work environment and workers' characteristics. Data were collected through interview questionnaire and clinical examination. The questionnaire included items on socio-demographic, occupational and clinical characteristics of the workers. Descriptive statistics, bivariates statistics and multivariate logistic regression model were used in data analysis. All 71 workers were males with a mean age of 37 +/- 9.7 years. The overall prevalence of warts was 42.2%. Heavily exposed workers had a higher prevalence (54%) (P = 0.02). Workers with other skin lesions were at a higher risk of developing warts (OR = 4.3, 95% C.I. 1.6-11.7). It was found that exposure to meat might be necessary for development of warts. Working environment could facilitate the development and transmission of warts among slaughterers. Regular monitoring of workers with skin lesions other than warts was recommended. Workers with recurrent warts were recommended to be reassigned for jobs with lighter exposure. PMID- 8698022 TI - Validation of reagent sticks in diagnosing urinary schistosomiasis in an urban setting. AB - In view of the established potential of reagent sticks for detecting haematuria, a pilot survey to validate their use in the diagnosis of urinary schistosomiasis in an urban setting was done at Kinyerezi primary school of Ilala district in Dar es salaam. From 404 pupils screened for the disease, 273 were positive for the eggs by microscopy (filtration method), giving a prevalence of 67.6% and 253 (92.6%) of those who were positive by microscopy were also positive for haematuria by reagent sticks. Out of 131 who had no disease, 113 (86.2%) were negative for haematuria by the reagent sticks. These findings indicate a high sensitivity and specificity of microhaematuria by the reagent sticks (92.6% and 86.2%) respectively. Taking microscopy as a standard test, macrohaematuria had a sensitivity and specificity of 40.6% and 90% respectively, for urinary schistosomiasis. The accuracy of microhaematuria by reagent sticks was 90% compared to macrohaematuria which was only 56.6%. The use of reagent sticks test in detecting microhaematuria is thus recommended as a valid and rapid diagnostic test for urinary schistosomiasis in the present setting. PMID- 8698023 TI - Relative sensitivity of barium swallow examination in the diagnosis of oesophageal pathology. AB - Dysphagia is a common reason for radiographic examination of the oesophagus to assess structural or functional abnormalities. From February 1, 1989 to August 28, 1993, six hundred and sixty eight patients had barium swallow examination. Out of 668 patients complaining of dysphagia, 173 patients had either histologically confirmed diagnoses and/or surgical diagnoses or oesophagoscopic diagnoses. The histological, oesophagoscopic and surgical diagnoses were: malignant tumours of the oesophagus 137 patients, achalasia of the cardia 21 patients, diverticula of the oesophagus six patients, peptic structures, five patients and non specific oesophagitis, four patients. Barium swallow agreed with 166 (96%) histological, oesophagoscopic and surgical diagnoses. The Kappa statistic was high (> .8). The mean age for patients with malignant tumours of the oesophagus was 53.5 years (range: 32-75 years), and for achalasia of the cardia was 36 years (range: 14-58 years). Patients with malignancy are in higher age group categories in comparison to the non-malignant patients (OR = 0.07 (0.02, 0.17). The mean duration of dysphagia for achalasia of the cardia was 8.5 years. The major cause of dysphagia was found to be malignant tumour of the oesophagus. Further study is recommended to determine the pattern of oesophageal pathologies to substantiate the finding. PMID- 8698024 TI - Agglutinins for brucellae antigens in blood sera of an urban and rural population in Kenya. AB - The antibody titres for Brucella arbotus and Br. melitensis in 364 sera from healthy individuals in Nairobi and Naivasha are presented. A majority (96%) had no detectable agglutinins. Reactivity was markedly higher in the Naivasha serum samples, than in those from Nairobi. In Naivasha, seven per cent showed reactivity, whereas in Nairobi a larger majority (98%), showed no reactivity, with antibody titres ranging from 1:20-1:160. Age and sex were found to have no effect on antibody titre distribution in the two populations. The presence of brucellae antibodies in the healthy population screened (with titres upto 1:80) may be due to exposure to brucellae antigens, rather than denoting brucellosis, this titre could therefore be taken as the baseline in the healthy Kenyan population. PMID- 8698025 TI - Comparison of functional characteristics of intradental A- and C-nerve fibres in dental pain. AB - The sensory nerve fibres in the pulp consist of myelinated A- and unmyelinated C fibres which conduct nerve impulses. The A-fibres are larger in diameter and fast conducting. Most of the A-fibres are in the A-delta group, but also the existence of very fast A-beta fibres has been demonstrated. C-fibres are small and slow conducting. When natural stimuli such as heat, cold, drilling or drying of dentine with air blasts are applied on the tooth, the only sensation perceived seems to be that of pain. On the other hand perception of pain symptoms in clinical situations varies from sharp and piercing to dull and poorly localised. A- but not C-fibres respond to dentine stimulation, and therefore responsible for dentine sensitivity. When heat is applied to the tooth, there is a two-phase response. First there is an immediate A-fibre response followed by a C-fibre response. The A-fibres could be responsible for the sharp well localised pain in human subjects while C-fibres could be responsible for the dull pain radiating to other parts of the face. A-fibres are activated at a higher level of electrical stimulation than C-fibres. C-fibres, but not A-fibres respond to application of bradykinin and histamin. The functional differences in A- and C-fibres may be one explanation for the change in the pain symptoms which at the beginning of pulpitis are mediated by A-fibres and in advanced pulpitis by C-fibres. PMID- 8698026 TI - Intraocular implantation dermoid cyst of the iris: case report. AB - Secondary cysts of the iris or anterior chamber follow penetrating trauma or surgery of the cornea. These can lead to some serious complications. We describe a case of an intraocular implantation dermoid cyst of the iris that followed a perforating injury of the cornea in a seven-year old Saudi child. The cyst was surgically removed and proved histologically. PMID- 8698027 TI - Immunoglobulin and inflammatory markers profiles in mycetoma. PMID- 8698028 TI - Establishing the study of development as a dynamic force in health psychology. PMID- 8698029 TI - Preventive health psychology from a developmental perspective: an extension of protection motivation theory. AB - Theories of health psychology developed to explain adults' rational decision making were applied to 10-year-old children (n = 112), who had not reached the stage of formal operational thought; 15-year-olds (n = 67); and 20-year-olds (n = 93), extending the protection motivation theory developed by R. W. Rogers (1983). Among the adolescents and young adults, the threat appeals worked only if people believed they could cope effectively with the danger; if they believed they could not cope, higher levels of the threat resulted in decreased intentions to refrain from tobacco use. Although children elaborated and integrated the information about threat severity, personal vulnerability, and response efficacy, the fragility and malleability of the children's beliefs in self-efficacy demonstrated the importance of adding a developmental perspective to theories of preventive health psychology. PMID- 8698030 TI - When mom or dad has cancer: II. Coping, cognitive appraisals, and psychological distress in children of cancer patients. AB - Cognitive appraisals and coping were examined in children, adolescents, and young adults (N = 134) faced with the diagnosis of cancer in a parent. All 3 age groups perceived low personal control and high external control over their parent's illness and used relatively little problem-focused coping. Adolescents and young adults reported more emotion-focused coping and dual-focused coping (both problem and emotion-focused in intent) than did preadolescent children. Stage and prognosis of parent's cancer were related to appraisals of greater seriousness and stressfulness, and to more avoidance; however, only appraisals of stress were related to symptoms of anxiety-depression. Emotion-focused coping was related to greater avoidance and to higher symptoms of anxiety-depression; coping and control beliefs did not interact in their association with anxiety-depression symptoms. PMID- 8698031 TI - Restrained eating among adolescents: dieters are not always bingers and bingers are not always dieters. AB - This study examined individual differences in the relationships among 3 constructs relevant to restrained eating theory-cognitive restraint (dieting), disinhibition (binging), and hunger. Participants were 421 adolescents (158 male, 255 female, and 8 not indicated). Comparisons among subgroups based on scores on the 3 constructs indicated that there were (a) 2 types of frequent dieters-those who follow theoretical predictions and become disinhibited and those who maintain their restraint; (b) 2 types of bingers-those who engage in dieting-induced binging and those who are hungry and disinhibited; and (c) 2 types of low-hunger eaters-those who suppress their hunger and those who eat before they experience much hunger. Implications of the results for restrained eating theory are discussed. PMID- 8698033 TI - Negative affect and self-report of physical symptoms: two longitudinal studies of older adults. AB - The ability of negative affect (NA) to predict somatic complaints 6 months later was examined. State NA, including anxious affect (AA) and depressive affect (DA), was measured in 2 separate samples of older adults averaging 62 and 73 years of age. In the first study, DA reliably predicted later complaints, and a corresponding trend was noted for NA. The second study showed that state NA and its 2 constituent variables predicted somatic complaints associated with acute illness (e.g., colds) 6 months later. The second study also examined trait measures of the 3 predictor variables and found that NA and AA, but not DA, were associated with subsequent somatic complaints. However, these trait effects were less robust than those attributable to their state counterparts. The authors conclude that negative mood states are the more consistent predictors of later physical symptom reports. PMID- 8698032 TI - Individual and situational markers of condom use and sex with nonprimary partners among alcoholic inpatients: findings from the ATRISK Study. AB - Alcoholics in treatment have demonstrated increased rates of HIV risk behavior and infection. This study explored individual and situational variables associated with HIV risk behaviors such as condom nonuse and sex with nonprimary partners reported during structured interviews of 802 male and female alcoholic inpatients. Logistic regression analyses indicated that person variables, sexual history variables, and situation variables were independently associated with sexual risk behavior in the most recent episode. Results of paired t tests revealed that participants who had engaged in sex with both primary and nonprimary partners during the previous 6 months reported significantly more frequent alcohol and condom use in situations involving sex with nonprimary partners. Prevention efforts need to target alcoholic inpatients as a group and, within this group, to focus on both high-risk individuals and high-risk situations. PMID- 8698034 TI - Hostility, anger-in, and cardiovascular reactivity in white women. AB - Relations between cardiovascular reactivity and cynical hostility, aggressiveness, antagonism, and anger-in were examined in White college women for conditions of high and low interpersonal stress. High stress was created by having the participants discuss an issue on which they held a strong view with a confederate who adamantly espoused an opposing view. Participants in the low stress condition discussed an issue on which they held no strong views with a confederate who amicably expressed agreement. Participants higher in cynical hostility exhibited more systolic blood pressure reactivity than individuals lower in cynical hostility in the high interpersonal stress condition only. Also, antagonism was positively related to heart rate reactivity across conditions. However, neither aggressiveness nor anger-in was related to reactivity in either condition. Overall, cynical hostility and a disposition toward disagreeable, manipulative behaviors (i.e., antagonism) but not overt aggressive behavior were found to be related to cardiovascular reactivity. PMID- 8698035 TI - Usefulness of the protection motivation theory in explaining hearing protection device use among male industrial workers. AB - The present study examined the usefulness of personal variables: noise annoyance, and components of the protection motivation theory (R. W. Rogers, 1983) along with social-organizational factors in explaining hearing protection device (HPD) use among Israeli manufacturing workers. Participants were 281 men exposed to harmful noise levels for which routine HPD use is required by regulation. In practice, 3 HPD user groups were identified: nonusers (n = 38), occasional users (n = 125), and regular users (n = 118). HPD use was objectively verified. HPD use was primarily related to the personal variables but not to management pressure, coworker pressure, or family support. The most powerful predictors of HPD use were perceived self-efficacy (for long-term HPD use), perceived susceptibility (to hearing loss), and noise annoyance, together explaining 48% of the outcome variance. These findings have implications for interventions aimed at motivating workers to use HPDs regularly. PMID- 8698036 TI - Applications of the monitoring process model to coping with severe long-term medical threats. AB - Guided by the monitoring process model (MPM), the authors explored the illness responses of 2 samples: high monitors (who are cognitively vigilant to and amplify threat-related cues) and low monitors (who avoid them and blunt their impact). Both samples-101 women with human papillomavirus-related precancerous cervical dysplasia and 75 HIV-infected gay men-were undergoing long-term medical follow-up and management. Structural equation analysis showed an adequate fit of the MPM to the data within each sample, supporting the model's heuristic value: High monitors experienced greater disease-related intrusive ideation, which triggered greater avoidant ideation to forestall panic, particularly in the more threatened HIV-positive sample. However, efforts to avoid disturbing intrusive thoughts were ineffective, requiring increasingly extreme defensive strategies (i.e., denial and mental and behavioral disengagement). PMID- 8698037 TI - Factors predicting participant attrition in a community-based, culturally specific smoking-cessation program for Hispanic smokers. AB - Factors predicting participant attrition in a community-based, culturally specific smoking-cessation program enrolling 93 Hispanic smokers were examined. Analysis of univariate predictors showed noncompleters (n = 18) to have lower incomes, to have expressed greater initial confidence in their ability to stop smoking, and to have perceived themselves to be in poorer general health and poorer health in relation to peers, than completers. Noncompleters were also more likely to have reported cardiovascular problems. Multivariate logistic regression analysis showed that confidence in stopping smoking, health compared with that of peers, and reported cardiovascular problems contributed significantly to prediction while controlling for other significant univariate predictors. The results are discussed in terms of factors that might mitigate premature termination in community-based smoking-cessation interventions targeting Hispanic smokers. PMID- 8698038 TI - p75(NGFR) and TrkA receptors collaborate to rapidly activate a p75(NGFR) associated protein kinase. AB - The role of the low affinity nerve growth factor receptor (p75(NGFR)) in NGF mediated signaling is not yet understood. Here we show by co-immunoprecipitation that NGF activates a protein kinase that is directly associated with p75(NGFR) in dorsal root ganglion (DRG) cells and PC12 cells in culture. Two proteins of 120 and 104 kDa constitute the majority of this activity. In PC12 cells, TrkA activation was necessary to elicit p75(NGFR)-associated kinase activity. Although NGF binding to p75(NGFR) was not necessary for kinase activation, it accelerated the activation of the kinase at low NGF concentrations. Deletion analysis showed that a 43 amino acid region in the cytoplasmic domain of p75(NGFR) was responsible for this effect. These findings show that p75(NGFR) accelerates TrkA mediated signaling and, in addition, demonstrate that p75NGFR and TrkA collaborate to activate a previously undescribed p75(NGFR)-associated protein kinase. PMID- 8698040 TI - The integrity of the human gene pool. PMID- 8698039 TI - Engrailed and Hox homeodomain proteins contain a related Pbx interaction motif that recognizes a common structure present in Pbx. AB - Hox gene products have the ability to interact with either extradenticle or pbx gene products to bind cooperatively to DNA. The region in Hox proteins that is required for this interaction is located N-terminal of the homeodomain and contains a highly conserved hexapeptide. We now show that the engrailed gene products also contain a Pbx interaction motif positioned within a previously conserved region, the EH2 domain. The EH2 domain is located N-terminal of the homeodomain. Two tryptophan residues present in the Drosophila and murine Engrailed EH2 domain are required for cooperativity with extradenticle and Pbx, respectively. A second conserved domain, EH3, is required as well for cooperativity with Pbx, since deletions or an insertion in this region reduce cooperative DNA binding. Peptides containing the Pbx interaction motif of either Engrailed or Hox are capable of destabilizing Engrailed-Pbx and Hox-Pbx cooperative DNA binding. These data indicate that the Pbx interaction motifs present in Hox and engrailed gene products recognize a common structure present in the Pbx family of homeodomain proteins. PMID- 8698041 TI - Reduced proliferation rate of hypoxanthine-phosphoribosyl transferase mutant human T-lymphocytes in vitro. AB - The clonal hprt mutation assay in human T-cell is based on the assumption that wild-type cells and hypoxanthine-phosphoribosyl transferase (hprt) mutant cells survive and proliferate at the same rate during the expression phase which is required for the expression of in vitro-induced mutants. We have tested this assumption in a study of mutant frequency (MF) and proliferation rate at different time points during in vitro expansion of human T-cells in non-selective medium. Peripheral blood lymphocytes from 11 individuals were studied using standard cloning procedures to determine the cloning efficiency (CE) and the hprt MF by 6-thioguanine (TG) selection. Another cell portion from each individual was allowed to proliferate in bulk culture for 8 days in vitro, before measuring CE and MF as above. In the directly plated cell population the CE was 45% and the MF 18.7 +/- 15.3 x 10(-6) (mean +/- S.D.), whereas the in vitro expanded cell population showed a CE of 38% and a significantly reduced MF of 8.3 +/- 6.9 x 10( 6) (P = 0.0033). Thus, the mean MF was 56% lower in the in vitro expanded than in the directly plated cell population. The experiment was repeated in another group of ten individuals with essentially the same result. In a third experiment, freshly prepared cells from two donors were allowed to grow for up to 15 days in bulk culture in vitro. Cell growth, CE, and MF were determined every third day. The MF decreased gradually, and at day 12-15 it was only 25% of the initial value. The total number of clonable cells increased 13-fold during the 15 days of in vitro expansion, while the mutant, TG-resistant cell population increased only 3-fold. These results suggest that human hprt mutant T-lymphocytes have a reduced proliferation rate compared to wild-type cells during in vitro proliferation. Thus, measurements of chemical and radiation induced MF with the T-cell clonal assay may underestimate the true MF by a factor of 2 or more. PMID- 8698042 TI - Inhibition of human DNA ligase I activity by zinc and cadmium and the fidelity of ligation. AB - Heavy metals, including zinc (Zn) and cadmium (Cd), are potentially important genotoxic agents in our environment. Here we report that human DNA ligase I, the major form of the enzyme in replicative cells, is a target for Zn and Cd ions. ZnCl2 at 0.8 mM caused complete inhibition of DNA ligase I activity, whereas only 0.04 mM CdCl2 was required to achieve a similar effect. Both metals affected all three steps of the reaction, namely, the formation of ligase-AMP intermediate, the transfer of the AMP to DNA and the ligation reaction that succeeds the formation of the AMP-DNA complex. Unlike F-ara-ATP and the natural protein inhibitor of DNA ligase-I, these metals may affect different domains of the enzyme. Moreover, these metal ions did not increase the rate of misligation of F ara-A-modified DNA or mismatched DNA substrates, but considerable misligation was observed for the T:C mispairing. These data support the notion of high fidelity of the human DNA ligases and that the major action of these metal ions on the enzyme is their inhibitory function. PMID- 8698043 TI - 954 MHz microwaves enhance the mutagenic properties of mitomycin C. AB - This paper focuses on the combined effects of microwaves from mobile communication frequencies and a chemical DNA damaging agent mitomycin C (MMC). The investigation was performed in vitro by exposing whole blood samples to a 954 MHz emitting antenna from a GSM (Global System for Mobile Communication) base station, followed by lymphocyte cultivation in the presence of MMC. A highly reproducible synergistic effect was observed as based on the frequencies of sister chromatid exchanges in metaphase figures. PMID- 8698044 TI - New animals, new uses, and old issues. PMID- 8698045 TI - A computerized connectivity approach for analyzing the structural basis of mutagenicity in Salmonella and its relationship with rodent carcinogenicity. AB - We have applied a new software program, based on graph theory and developed by our group, to predict mutagenicity in Salmonella. The software analyzes, as information in input, the structural formula and the biological activities of a relatively large database of chemicals to generate any possible molecular fragment with size ranging from two to ten nonhydrogen atoms, and detects (as predictors of biological activity) those fragments statistically associated with the biological property investigated. Our previous work used the program to predict carcinogenicity in small rodents. In the current work we applied a modified version of the program, which bases its predictions solely on the most important fragment present in a given molecule, considering as practically negligible the effects of additional less important fragments. For Salmonella mutagenicity we used a database of 551 compounds, and the program achieved a level of predictivity (73.9%) comparable to that obtained by other authors using the Computer Automated Structure Evaluation (CASE) program. We evaluated the relative contributions of biophores and biophobes to overall predictivity: biophores tended to be more important than biophobes, and chemicals containing both biophores and biophobes were more difficult to predict. Many of the molecular fragments identified by the program as being strongly associated with mutagenic activity were similar to the structural alerts identified by the human experts Ashby and Tennant. Our results tend to confirm that structural alerts useful to predict Salmonella mutagenicity are generally not very strong predictors of rodent carcinogenicity. Although the predictivity level achieved for oncogenic activity improved when the program was directly trained with carcinogenicity data, carcinogenicity as a biological endpoint was still more difficult to predict than Salmonella mutagenicity. PMID- 8698046 TI - DNA sequence analysis of hprt mutations in lymphocytes from Sprague-Dawley rats treated with 7,12-dimethylbenz[a]anthracene. AB - Treatment of female Sprague-Dawley rats with the potent mammary gland carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) results in the formation of DNA adducts with dG and dA and in the induction of 6-thioguanine-resistant (TGr) lymphocyte mutants. In this study, we have examined the types of mutations induced in TGr lymphocytes from DMBA-treated rats. DNA from 263 TGr lymphocyte clones was screened for mutations in exons 2, 3, and 8 of the hprt gene by polymerase chain reaction (PCR) amplification of the exons followed by heteroduplex analysis using denaturing gradient-gel electrophoresis. Twenty-five of the clones produced heteroduplexes in exon 2, 35 produced heteroduplexes in exon 3, and 36 produced heteroduplexes in exon 8. Direct sequence analysis of the heteroduplexes revealed 96 mutations, and at least 74 of these mutations were produced independently. Eighty-five of the total mutations were simple base pair (bp) substitutions, with A --> T and G --> T transversions being the predominant types. Seven mutations were deletions, three were complex bp substitutions, and one was an insertion. The results suggest that the types of mutations produced by DMBA in rat lymphocytes are specific to the DNA adducts produced by this compound. PMID- 8698049 TI - Becquerel's legacy to nuclear medicine. PMID- 8698047 TI - Human liver S-9 metabolic activation: proficiency in cytogenetic assays and comparison with phenobarbital/beta-naphthoflavone or aroclor 1254 induced rat S 9. AB - Induced rat liver S-9 is routinely used for metabolic activation in cytogenetic assays. When a compound gives a positive test result only with rat S-9, the significance for humans should be assessed. To evaluate the use of human S-9, we used sister-chromatid exchanges (SCEs) and chromosome aberrations (Abs) in Chinese hamster ovary cells to test five pro-mutagens, each preferentially activated by a different family of P-450: benzo(a)pyrene (BP), dimethylnitrosamine (DMN), diethylnitrosamine (DEN), aflatoxin B1 (AFB), and 2 acetylaminofluorene (2-AAF). We tested two human S-9 preparations, one from a single liver and a second pooled from two livers known to have good activity for several P-450s. Concentrations and ratios of NADP and isocitrate were adjusted to optimize NADPH generation by the S-9. Abs were scored 20 hr, and SCEs 29-45 hr, after the beginning of a 3 hr treatment. P-450 enzyme activities were generally higher in rat than human S-9. With the single-liver human S-9, increase in SCEs were seen with all chemicals; with both human S-9s, increases in Abs were seen with all chemicals except BP. (The level of P-450 1A1, required for BP activation, is very low in human liver.) Compared with rat S-9, generally higher concentrations of human S-9 and of promutagens were required to see positive results. However, human S-9 effectively activated 2-AAF, whereas neither of the two types of rat S-9 produced Abs with 2-AAF. We also compared rat S-9s induced with Aroclor 1254 or phenobarbital/ beta-naphthoflavone (PB/beta NF). Although there were some differences in P-450 enzyme activities, these did not translate into differences in Abs induction. At low doses of AFB and of BP, PB/beta NF induced S-9 appeared more effective than Aroclor 1254 induced S-9. PMID- 8698048 TI - Chromium (VI) at plausible drinking water concentrations is not genotoxic in the in vivo bone marrow micronucleus or liver unscheduled DNA synthesis assays. PMID- 8698050 TI - Internal dosimetry: developments and limitations. PMID- 8698051 TI - Nuclear medicine and cardiology: the position of the Union of European Medical Specialists/Section of Nuclear Medicine. AB - This paper summarizes a communication presented at the Second International Conference of Nuclear Cardiology, held in Cannes on 23-26 April 1995. The general evolution of nuclear medicine in Europe is examined within the context of European Union Directives, and the role of the Union of European Medical Specialists/Section of Nuclear Medicine is discussed. Thereafter consideration is given to the technical aspects of cardiovascular nuclear medicine procedures, and the situation with respect to such procedures in European countries is examined. In most European countries, nuclear medicine is a recognized specialty, while "nuclear cardiology" does not exist in its own right. In general, only nuclear medicine specialists have the responsibility for radionuclide studies, and most cardiovascular studies are performed under the direct responsibility of a licensed nuclear medicine specialist. PMID- 8698052 TI - Detection of axillary lymph node metastases in breast carcinoma by technetium-99m sestamibi breast scintigraphy, ultrasound and conventional mammography. AB - Axillary lymph node status is important in the staging of breast carcinoma. To evaluate the accuracy of technetium-99m sestamibi breast scintigraphy in detecting metastatic axillary lymph nodes as compared with other accepted imaging modalities, we performed 99mTc-sestamibi breast scintigraphy, conventional mammography and ultrasound in 36 patients with primary untreated breast carcinoma. With histopathology as the gold standard, 99mTc-sestamibi breast scintigraphy was found to yield true-positive results in 7 of 11 cases (64%) of axillary lymph node metastases and true-negative results in 18 of 20 cases (90%); it has an accuracy of 81%, a positive predictive value of 77.8% and a negative predictive value of 81.8%. PMID- 8698053 TI - Early and delayed thallium-201 scintigraphy in thyroid nodules: the relationship between early thallium-201 uptake and perfusion. AB - Seventy-six patients with thyroid nodules were studied. Initially, 74 MBq of thallium-201 was injected. The thyroid gland was imaged 15 min (early) and 3 h (delayed) after the injection. Thereafter, 185 MBq technetium-99m pertechnetate was injected. Immediately after the injection, a 1-min perfusion image was acquired, followed by an image at 20 min. Increased early and delayed 201Tl uptake compared with the contralateral thyroid tissue was adopted as the criterion for malignancy. Sensitivity, specificity and negative predictive values were found to be 85%, 64% and 78%, respectively, in operated patients, but these values were 86%, 87% and 95%, respectively, in the whole group, including patients followed with fine-needle aspiration biopsy. With the purpose of investigating the relationship between perfusion and early 201Tl uptake, both perfusion and early images were graded comparing nodular activity with contralateral thyroid activity. There was a poor correlation between perfusion and 201Tl uptake. The correlation was even worse in hyperactive nodules. It is concluded that early and delayed 201Tl imaging should not be used in the differential diagnosis of cold nodules and that early 201Tl uptake seems to be more closely related to factors other than perfusion. PMID- 8698054 TI - Diastolic or systolic left and right ventricular impairment at moderate doses of anthracycline? A 1-year follow-up study of women. AB - A prospective study was carried out to assess the early and later alterations in left and right ventricular diastolic and systolic function after the termination of anthracycline therapy. In 33 women without cardiac disease who were treated by anthracycline therapy, cardiac function was evaluated by radionuclide angiography before the treatment (T0) and 1 month (T1) and 12 months (T12) after the end of the treatment. Cardiac function was assessed by radionuclide measurement throughout treatment. Analysis of ejection fraction (EF), peak ejection rate (PER), time to PER (TPER), peak filling rate (PFR) and time to PFR (TPFR) was performed before and after treatment. To normalise radionuclide measurements of the ventricular diastolic function, the ratio of the PFR and the EF and the ratio of the PFR and the PER were calculated. No patient developed symptomatic congestive cardiac failure. One-way analysis of variance showed a significant decrease in the three parameters (EF, PER, PFR) over time only for the left ventricle (LV); no significant alterations appeared for the right ventricle (RV). The EF of the LV decreased from 59%+/-5% at T0 to 57%+/-6% at T1 and 56%+/-5% at T12. The PER of the LV fell from 3.03+/-0.40 end-diastolic volume per second (EDV/s) at T0 to 2.79+/-0.47 at T1 and 2.78+/-0.43 at T12. The PFR of the LV dropped from 2.99+/-0.43 EDV/s at T0 to 2.62+/-0.44 at T1 and 2.56+/-0.42 at T12. For the normalised ratios, no differences were observed. Significant differences were found for EF, PER and PFR between T0 and T1, and between T0 and T12, but no difference was found between T1 and T12. This report shows simultaneous impairment of the systolic and diastolic LV radionuclide parameters at 1 and 12 months after anthracycline therapy without alteration in the RV function. PMID- 8698055 TI - Regional 2-[18F]fluoro-2-deoxy-D-glucose uptake varies in normal lung. AB - 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) is a promising imaging procedure for detecting primary and metastatic cancer in the lungs. We have, however, failed to detect some small tumors in the lower lobes of the lungs. This study aimed to determine whether increase 18F background activity in the dependent lower lungs is present, which could make lesion detection more difficult. We measured the standardized uptake values (SUVs) for FDG of normal lung remote from the nodular lesion in 16 patients with newly diagnosed untreated lung lesions strongly suspected to represent non-small cell lung cancers. In addition, 15 patients with known or suspected primary breast cancers without pulmonary lesions were included as control subjects. After PET transmission images of the thorax were obtained, approximately 370 MBq of FDG was injected intravenously and imaging was immediately begun. Patients were supine throughout the study. SUVs were determined with images obtained 50-70 min after FDG injection. Regions of interest (ROIs) of 6x6 pixels were positioned over normal lung in anterior, mid, and posterior portions of upper, middle, and lower lung fields. Thus, as many as 18 ROIs were positioned in each patient. The SUVs of the posterior portion were significantly higher than those of the anterior and mid portions in the population of 31 cases (P <0.001). Also, the mean SUV of the lower lung field was significantly higher than the SUVs of the upper and middle lung fields in this population (P <0.01). This pattern was seen among the two groups of 16 patients suspected of having lung cancer and 15 control subjects. Background 18F activity was highest in posterior and lower lung in these patients. The maximum value of mean SUV observed in normal posterior lower lung was 0.804+/-0.230 (41% greater than the mean SUV in the anterior upper lung), which is in the range of the apparent SUV for a 5-mm lung lesion, with higher SUV, due to recovery coefficient issues. Thus this phenomenon could contribute to occasional false-negative lesions in those areas. Increased blood flow and FDG delivery and also scatter from heart and liver may contribute to the increased lower lung background activity. Regional differences in normal lung FDG uptake are significant and should be considered when interpreting pulmonary PET studies in patients with suspected primary or metastatic lung cancer. PMID- 8698057 TI - Detection and quantification of protein-losing enteropathy with indium-111 transferrin. AB - Localisation and quantification of protein loss in protein-losing enteropathy (PLE) is useful in the clinical management of hypoalbuminaemia. Indium-111 transferrin offers the opportunity of combining localisation and quantification using a single agent. Twenty-five studies were performed in 23 patients with suspected PLE: 111In-transferrin was prepared by incubating autologous cell-free plasma with 111In chloride in vitro for 15 min. Protein loss was quantified by comparing whole-body counts recorded with an uncollimated gamma camera at 3 h and 5 or 6 days after injection of 111In-transferrin. Gamma camera imaging performed at 3 and 24 h after injection demonstrated a site of protein loss in 15 studies. Whole-body 111In excretion was abnormally elevated in 13 of these, ranging from 16% to 34% (normal <10%), was not assessed in one and was less than 10% in a patient with carcinoid syndrome. In the ten studies that were negative on imaging, whole-body 111In excretion was normal in nine and elevated at 22% in a further patient with carcinoid syndrome. Overall, the mean whole-body 111In excretion in studies with positive imaging was 21.4% (SD 6.1%) (n=14), significantly higher (P<0.01) than in studies with negative imaging, in which it was 7.5% (SD 6.7%) (n=10). This technique should be useful for the combined approach of localising and quantifying protein loss in PLE. PMID- 8698056 TI - Relationship between thallium-201 uptake by supratentorial glioblastomas and their morphological characteristics on magnetic resonance imaging. AB - Single-photon emission tomography (SPET) with thallium-201 is used in the assessment of patients with gliomas because the amount of 201Tl accumulated by the tumoral cells increases in proportion to the degree of tumour malignancy, thus making it possible to differentiate high-grade from low-grade gliomas or recurrences from radiation necrosis. However, in large areas of tissue such as those examined in 201Tl SPET studies, the uptake of 201Tl may vary considerably even in tumours with the same histological diagnosis, as occurs in glioblastomas (GBMs). In order to evaluate the possible influence of the macroscopic characteristics of tumours on 201Tl uptake, we studied a series of 13 patients with histologically proven GBMs, comparing magnetic resonance imaging (MRI) parameters such as tumour dimensions, perilesional oedema, intratumoral necrosis and contrast enhancement with the degree of 201Tl uptake. The patients underwent both 201Tl SPET and MRI before surgery. The 201Tl index (tumour/contralateral unaffected brain) was calculated using two different region of interest (ROI) methods: the first employed irregular large ROIs (3.2+/-13.9 cm2) including pixels with more than 50% maximum activity; the second employed regular square small ROIs (2.7 cm2) centered on the maximum activity of the lesion. Of the MRI morphological parameters studied, only necrosis significantly reduced the degree of 201Tl uptake in GBMs when larger ROIs were used. However, by using small regular ROIs the influence of necrosis on 201Tl uptake was found to be less relevant. Since necrosis is related to tumour proliferative activity and represents a negative prognostic factor in astrocytoma, a possible underestimation of 201Tl uptake due to intratumoral necrosis must be carefully evaluated. PMID- 8698059 TI - Tracer kinetic modelling of receptor data with mathematical metabolite correction. AB - Quantitation of metabolic processes with dynamic positron emission tomography (PET) and tracer kinetic modelling relies on the time course of authentic ligand in plasma, i.e. the input curve. The determination of the latter often requires the measurement of labelled metabolites, a laborious procedure. In this study we examined the possibility of mathematical metabolite correction, which might obviate the need for actual metabolite measurements. Mathematical metabolite correction was implemented by estimating the input curve together with kinetic tissue parameters. The general feasibility of the approach was evaluated in a Monte Carlo simulation using a two tissue compartment model. The method was then applied to a series of five human carbon-11 iomazenil PET studies. The measured cerebral tissue time-activity curves were fitted with a single tissue compartment model. For mathematical metabolite correction the input curve following the peak was approximated by a sum of three decaying exponentials, the amplitudes and characteristic half-times of which were then estimated by the fitting routine. In the simulation study the parameters used to generate synthetic tissue time activity curves (K1-k4) were refitted with reasonable identifiability when using mathematical metabolite correction. Absolute quantitation of distribution volumes was found to be possible provided that the metabolite and the kinetic models are adequate. If the kinetic model is oversimplified, the linearity of the correlation between true and estimated distribution volumes is still maintained, although the linear regression becomes dependent on the input curve. These simulation results were confirmed when applying mathematical metabolite correction to the [11C]iomazenil study. Estimates of the distribution volume calculated with a measured input curve were linearly related to the estimates calculated using mathematical metabolite correction with correlation coefficients >0.990. However, the slope of the regression line displayed considerable variability among the subjects (0.33-0.95), demonstrating that absolute quantitation of the distribution volume was impaired. Mathematical metabolite correction is a feasible method and may prove useful in cases where actual metabolite data cannot be obtained. The potential for absolute quantitation seems limited, but the method allows the quantitative assessment of regional ratios of receptor measures. PMID- 8698058 TI - Leakage measurement during selective limb perfusion using a gamma probe. AB - The objective of this study was to establish a probe system for intraoperative quantitative leakage measurement during selective limb perfusion for adjuvant high-dose chemotherapy in patients with malignant melanomas. We used a portable gamma probe with digital display and investigated the physical properties in a phantom study simulating blood pool activity at different angles of the probe to the surface and different distances. In 20 patients the limb circulation was surgically separated from the systemic blood circulation, and the limb was then selectively perfused (cytostatics added) for 60 min. Initially, 15 MBq technetium 99m labelled autologous red blood cells was injected into the limb circulation, and an equal amount was kept as a standard. Every 10 min, blood samples were drawn from the body circulation and count rates were simultaneously measured by the probe system at the lower end of the sternal body. At the end of perfusion, the circulation of the limb was reconnected, the standard injected into the systemic circulation, and a blood sample drawn after 10 min. All blood samples were counted for calculation of leakage in terms of percent of the injected dose, and the results compared with the intraoperative count rates of the probe system. In the range of leakage observed in this study (0%-86%), the count rate of the probe system (corrected for blood volume, i.e. for body surface) correlated with the results of conventional measurement (r=0.92) according to the equation: %leakage=counts per sx[1.2xbody surface (m2)-1.19]. In conclusion, the use of the described probe system is a feasible approach for leakage quantification which continuously yields data during selective limb perfusion. PMID- 8698060 TI - Interaction of metaiodobenzylguanidine with cardioactive drugs: an in vitro study. AB - Metaiodobenzylguanidine (MIBG), an analogue of noradrenaline, is used to explore the functional integrity of sympathetic nerve endings in the human heart. Various drugs inhibit noradrenaline transport systems and may block the uptake of MIBG. As in vivo studies of the effect of these drugs on myocardial [123I]MIBG uptake are often difficult to perform, we used an in vitro human blood platelet model for this purpose. A platelet preparation from healthy volunteers was incubated with [125I]MIBG alone or different concentrations of drugs currently used in cardiology. Labetalol and propranolol inhibited [125I]MIBG uptake, whereas all other drugs tested (other beta-blockers, calcium inhibitors, digoxin and amiodarone) had no effect even at doses exceeding 50 microM. The labetalol dose inhibiting 50% of [125I]MIBG uptake was lower than the plasma concentration of this drug in treated patients, whereas the propranolol dose was higher. This in vitro study of the effect of drugs on MIBG uptake by human blood platelets is predictive of their in vivo effect on myocardial uptake of [123I]MIBG in treated patients, provided that plasma concentration is taken into account. PMID- 8698061 TI - Comparison of technetium-99m sestamibi left ventricular wall motion and perfusion studies with thallium-201 perfusion imaging: in search of the combination of variables with the highest accuracy in predicting coronary artery disease. AB - Measurements of myocardial perfusion and ventricular function are expected to provide additional information in the detection of coronary artery disease (CAD). The purpose of this study was threefold: (1) to determine to what extent technetium-99m sestamibi wall motion yields different information compared with 99mTc-sestamibi and thallium-201 perfusion; (2) to test which information unique to either study is of value in diagnosing CAD; and (3) to assess the combination of variables with the highest diagnostic accuracy. Perfusion and wall motion scores (at rest and during exercise) obtained from visual and quantitative planar 201Tl and 99mTc-sestamibi scintigraphy of 60 patients with suspected CAD were compared with the angiographic results by means of a polytomous logistic regression model and the diagnostic values were compared with one another. All univariate variables were significantly related to the probability of CAD and its extent. Comparative studies revealed a large degree of correlation between 201Tl stress and redistribution variables. The rest 99mTc-sestamibi and wall motion studies contained partially different information. Stepwise logistic regression analysis showed the strongest diagnostic power for the combination of 201Tl visual analysis of the stress images with quantitative redistribution images (sensitivity 93%, specificity 71%). The diagnostic power was similar for all combinations of visual and quantitative analyses of the exercise and redistribution images. The strongest diagnostic power of the 99mTc-sestamibi variables was the score of the diastolic stress image (sensitivity 91%, specificity 79%). Comparable sensitivity and specificity estimates were found when both optimal models were compared. Wall motion studies did not have additional diagnostic power. Although 99mTc-sestamibi wall motion studies, both at rest and during exercise, provide information in addition to the 99mTc sestamibi or 201Tl myocardial perfusion variables, the information does not enhance the diagnostic power with regard to the prediction of CAD. PMID- 8698062 TI - Pharmacokinetics and biodistribution of samarium-153-labelled OC125 antibody coupled to CITCDTPA in a xenograft model of ovarian cancer. AB - The use of samarium-153 in the context of radioimmunotherapy of cancers has been limited by the instability of antibody labelling, which produces high uptake concentrations in liver and bone. This study compares the pharmacokinetics and biodistribution of 153Sm-labelled OC125 monoclonal antibody, in whole or F(ab')2 fragment form and with diethylene triamine penta-acetic acid (DTPA) or 6-p isothiocyanatobenzyl diethylene triamine penta-acetic acid (CITCDTPA) coupling, in nude mice grafted subcutaneously with an ovarian adenocarcinoma line (SHIN-3) expressing CA125 antigen. The specific activity of the immunoconjugates was 18.5 55.5 MBq/mg, and their immunoreactivity exceeded 65%. With 153Sm-DTPA OC125F(ab')2, the stability study in serum indicated that 50% of the metal remained bound to the antibody. The pharmacokinetic study showed a retention half life of 25.1 h and blood clearance of 0.72 ml/h. The biodistribution study indicated tumour uptake of 4.53%+/-0.49% of injected activity per gram (%ID/g) at 24 h and tumour-to-liver and tumour-to-bone ratios of 0.23+/-0.02 and 1.54+/-0.49 respectively at 24 h. With 153Sm-CITCDTPA-OC125F(ab')2, serum stability was greater (87% of the metal remaining bound to the antibody), retention half-life was 22.25 h and blood clearance was 2.23 ml/h. Tumour was better targeted (8.30%+/-3.56%ID/g at 24 h), and tumour-to-liver and tumour-to-bone ratios were 1.17+/-0.36 and 7.08+/-3.09 respectively at 24 h. However, renal retention remained elevated (29.76%+/-9. 41%ID/g at 24 h). With intact IgG, renal uptake decreased (1.41%+/-0. 49%ID/g at 24 h), but tumour uptake was lower than with fragments (1. 46%+/-0.58%ID/g at 24 h). Liver uptake was higher (tumour-to-liver ratio 0.10+/-0.05), and blood clearance was slower. The stability and distribution of 153Sm-CITCDTPA were more favourable than those of 153Sm-DTPA for application in radioimmunotherapy. Quantitative analysis performed using digitized images obtained by conventional autoradiography and the imaging plate system indicated that the latter system is suitable for biodistribution studies of immunoconjugates. PMID- 8698063 TI - Technetium-99m sestamibi uptake in human breast carcinoma cell lines displaying glutathione-associated drug-resistance. AB - An in vitro study was designed to evaluate the uptake of sestamibi (MIBI) in P glycoprotein (Pgp) and glutathione-associated (GSH) multidrug-resistant (MDR) cell lines. MIBI uptake was studied in various human breast carcinoma cell lines, i.e. in wild-type (MCF7/wt) cells, in adriamycin-resistant (MCF7/adr) cells which express Pgp and in melphalan-resistant (MCF7/mph) cells with increased levels of GSH. The effects of buthiomine sulphoximine (BSO) and verapamil on MIBI uptake were also studied in the MCF7/mph and MCF7/adr cells respectively. The cells were incubated for 1 h with a dose of 0.1 MBq thallium-201 and technetium-99m MIBI. Both MIBI and 201Tl uptakes were higher for MCF7/mph cells than for the other cells studied. The mean MIBI uptake in MCF7/adr cells was significantly lower than that in MCF7/wt cells (1.9%+/-0.5% vs 3. 1%.0.6%; P <0.01). Verapamil treatment increased the MIBI uptake in MCF7/adr cells (to 2.6%.0.3%; P <0.05). Treatment of MCF7/mph cells with BSO resulted in a significant reduction in GSH content (from 243.2+/-81.1 nmol/mg protein to 17.6+/-4.4 nmol/mg protein; P <0. 001). However, MIBI uptake in BSO-treated and untreated MCF7/mph cells was similar (4.43%+/-0.5% and 5.93%+/-1.7%, respectively; P >0. 1). This study suggests that the uptake of MIBI is not diminished by glutathione-associated drug resistance and that MIBI uptake in a tumour sample does not necessarily indicate that a cancer is sensitive to drugs. PMID- 8698064 TI - Standardized uptake values of fluorine-18 fluorodeoxyglucose: the value of different normalization procedures. AB - While the evident advantages of absolute metabolic rate determinations cannot be equalled by static image analysis of fluorine-18 fluorodeoxyglucose positron emission tomographic (FDG PET) studies, various algorithms for the normalization of static FDG uptake values have been proposed. This study was performed to compare different normalization procedures in terms of dependency on individual patient characteristics. Standardized FDG uptake values (SUVs) were calculated for liver and lung tissue in 126 patients studied with whole-body FDG PET. Uptake values were normalized for total body weight, lean body mass and body surface area. Ranges, means, medians, standard deviations and variation coefficients of these SUV parameters were calculated and their interdependency with total body weight, lean body mass, body surface area, patient height and blood sugar levels was calculated by means of regression analysis. Standardized FDG uptake values normalized for body surface area were clearly superior to SUV parameters normalized for total body weight or lean body mass. Variation and correlation coefficients of body surface area-normalized uptake values were minimal when compared with SUV parameters derived from the other normalization procedures. Normalization for total body weight resulted in uptake values still dependent on body weight and blood sugar levels, while normalization for lean body mass did not eliminate the positive correlation with lean body mass and patient height. It is concluded that normalization of FDG uptake values for body surface area is less dependent on the individual patient characteristics than are FDG uptake values normalized for other parameters, and therefore appears to be preferable for FDG PET studies in oncology. PMID- 8698065 TI - Technetium-99m dextran: a promising new protein-losing enteropathy imaging agent. AB - The purpose of this study was to evaluate technetium-99m dextran (99mTc-Dx; molecular weight 81000) as a prospective protein-losing enteropathy (PLE) imaging agent. Twenty-two patients with diseases commonly associated with PLE and 12 healthy control subjects underwent intravenous 99mTc-Dx scintigraphy. All of the 22 test patients showed significant radiotracer accumulation in the intestines within 3-4 h post injection. The focal, regional or generalised nature of the enteropathy and involvement of the large or small intestine could be identified in most cases. Four of the 12 apparently healthy subjects also showed minimal accumulation in the abdominal area occurring late in the study period. This could have been physiological, related to food habits or due to unsuspected intestinal worms. We attribute the high sensitivity of 99mTc-Dx to its relatively fast blood (background) clearance. The radiotracer may have several other advantages over 99mTc-labelled human serum albumin in imaging PLE. PMID- 8698066 TI - Brain mapping of median nerve somatosensory evoked potentials with combined 99mTc ECD single-photon emission tomography and magnetic resonance imaging. AB - Single-photon emission tomography (SPET) was performed during electrical median nerve stimulation and used to detect focal neuronal activation in the somatosensory pathways. Intravenously administered technetium-99m ethyl cysteinate dimer (ECD) was used as a blood flow tracer to obtain baseline and activated images in each of three subjects. After image registration, baseline images were compared voxel by voxel with the activation images. In addition, the mean summation of the activated-state images of the subjects was compared with the mean summation of the baseline-state images of ten normal subjects. Discrete brain regions occupying 0.9%-1.6% of total brain volume showed an increase in signal from 33.6% to 35.0%. For further anatomical localization of regional increases in signal, the MRI scan of each subject was registered and superimposed on the activated-state SPET image. This method may be used to localize lesions in various disorders of the central nervous system. PMID- 8698067 TI - Glucose consumption and methionine uptake in low-grade gliomas after iodine-125 brachytherapy. AB - We investigated whether 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) and carbon-11 methionine are suitable tracers to monitor the effects of therapy for low-grade gliomas. Ten patients with low-grade glioma without previous treatment were studied with FDG positron emission tomography. Additionally, l-[methyl 11C]methionine uptake was measured in five subjects before and 1 year after computerized tomography (CT)-guided stereotactic and computer-assisted implantation of iodine-125 seeds. All scans were 3D-matched to CT, isodose volumes were determined, and changes in glucose metabolism and methionine uptake were evaluated in tumour and brain tissue as a function of radiation dose. After 1 year glucose metabolism was not significantly altered up to a radiation dose of 300 Gy, whereas methionine uptake showed a significant dose-dependent decrease. Higher rates of decline were found in tumours with high basal methionine incorporation activity before therapy. These data suggest that measurement of methionine uptake is more suitable than measurement of FDG uptake for monitoring therapeutic effects in low-grade gliomas. PMID- 8698069 TI - Contracted gallbladder: a cause of false-positive hepatobiliary scan in patients with cystic fibrosis. AB - Gallbladder nonvisualization on hepatobiliary scintigraphy in cystic fibrosis is generally secondary to cystic duct obstruction from inspissated bile, mucus, or gallstones. We report gallbladder nonvisualization on hepatobiliary imaging in two patients with cystic fibrosis who had contracted gallbladders on ultrasonography. Repeat ultrasonography at 6 months revealed persistent gallbladder contraction. A contracted gallbladder therefore is a potential cause of a false-positive hepatobiliary scan which can be treated with conservative management. PMID- 8698068 TI - An update on diagnostic methods in the investigation of diseases of the thyroid. AB - Iodine deficiency and iodine-deficiency disorders continue to be problems in several parts of Europe, requiring further improvements in the techniques employed in thyroid diagnosis, and particularly in the early diagnosis and risk assessment of autonomously functioning thyroid tissue. For the latter purpose, scintigraphy with technetium-99m pertechnetate under exogenous or endogenous thyroid-stimulating hormone (TSH) suppression provides the best results. Significant methodological improvements in laboratory tests have resulted from the application of new luminescent techniques and gene technology to thyroid function tests. Especially TSH measurement using second- or third-generation assays ensures diagnostic accuracy, so that the thyrotropin-releasing hormone (TRH) test is now almost always unnecessary. The differentiation of blocking and stimulating TSH receptor antibodies is relevant when discrepant results are obtained with respect to thyroid function. Determination of glycosaminoglycans in urine may become a helpful tool in the follow-up of endocrine ophthalmopathy. Some new imaging agents have recently been applied in the scintigraphy of thyroid diseases, such as octreotide, or in thyroid diagnosis, such as fluorodeoxyglucose. Both improve the detectability of metastases of thyroid cancer, especially if the radioiodine scan is negative. PMID- 8698071 TI - Effect of tissue heterogeneity on quantification in position emission tomography: reply. PMID- 8698072 TI - Bradykinin formation during processing for cellular labelling may cause side effects. PMID- 8698070 TI - Decrease in benzodiazepine receptor binding in a patient with Angelman syndrome detected by iodine-123 iomazenil and single-photon emission tomography. AB - A receptor mapping technique using iodine-123 iomazenil and single-photon emission tomography (SPET) was employed to examine benzodiazepine receptor binding in a patient with Angelman syndrome (AS). AS is characterized by developmental delay, seizures, inappropriate laughter and ataxic movement. In this entity there is a cytogenic deletion of the proximal long arm of chromosome 15q11-q13, where the gene encoding the GABAA receptor beta3 subunit (GABRB3) is located. Since the benzodiazepine receptor is constructed as a receptor-ionophore complex that contains the GABAA receptor, it is a suitable marker for GABA-ergic synapsis. To determine whether benzodiazepine receptor density, which indirectly indicates changes in GABAA receptor density, is altered in the brain in patients with AS, we investigated a 27-year-old woman with AS using 123I-iomazenil and SPET. Receptor density was quantitatively assessed by measuring the binding potential using a simplified method. Regional cerebral blood flow was also measured with N-isopropyl-p-[123I]iodoamphetamine. We demonstrated that benzodiazepine receptor density is severely decreased in the cerebellum, and mildly decreased in the frontal and temporal cortices and basal ganglia, a result which is considered to indicate decreased GABAA receptor density in these regions. Although the deletion of GABRB3 was not observed in the present study, we indirectly demonstrated the disturbance of inhibitory neurotransmission mediated by the GABAA receptor in the investigated patient. 123I-iomazenil with SPET was useful to map benzodiazepine receptors, which indicate GABAA receptor distribution and their density. PMID- 8698073 TI - Electron probe X-ray microanalysis of rabbit ciliary epithelium. AB - Rabbit iris-ciliary bodies were preincubated in control and experimental Ringer's solutions before quick freezing, cryosectioning, dehydration and electron probe X ray microanalysis. After preincubation in a baseline bicarbonate-free Cl- Ringer's solution, the ciliary epithelial intracellular Na+, K+ and Cl- concentrations were estimated to be 15 +/- 3, 162 +/- 14 and 46 +/- 5 mmol kg-1 intracellular water, respectively. The water and elemental Na, K, Cl and P contents were similar in the non-pigmented (NPE) and pigmented (PE) ciliary epithelial cells. As expected, inhibition of the Na,K-exchange pump by preincubation with ouabain markedly increased the intracellular Na content, and markedly reduced the intracellular K content, verifying the validity of the experimental analysis. The Cl- channels of the NPE cells likely play a critical role in determining the rate of aqueous humor formation. Therefore, we have examined the effects of altering Cl- transport on the intracellular composition in this initial microprobe study of the ciliary epithelium. As expected, exposure to bicarbonate increased the intracellular Cl and water contents. Replacement of external Cl- by NO3- was twice as effective as replacement by gluconate in leaching Cl- out of the intracellular compartment. An unexpected finding was that NO3- replacement of internal Cl- substantially increased the intracellular Na and decreased the intracellular K content, possibly by stabilizing the Na,K-pump in the E1P form and inhibiting enzyme activity. PMID- 8698074 TI - The molecular chaperone alpha-crystallin inhibits UV-induced protein aggregation. AB - Solutions of gamma-crystallin, and various enzymes, at neutral pH and 24-26 degrees C, became turbid upon exposure to UV radiation at 295 or 308 nm. SDS-PAGE analysis revealed interchain cross-linking and aggregate formation compared to dark control solutions as reported previously. When alpha-crystallin was added to the protein solutions in stoichiometric amounts, UV irradiation resulted in significantly less turbidity than in the absence of alpha-crystallin. For example, addition of 0.5 mg of alpha-crystallin to 0.5 mg of gamma-crystallin in 1.0 ml solution yielded only 25% of the turbidity seen in the absence of alpha crystallin. Addition of 2.0 mg of alpha-crystallin resulted in 20% of the turbidity. Given the molecular weights of alpha- and gamma-crystallin (about 800 kDa and 20 kDa, respectively), a gamma/alpha 1:1 weight ratio corresponds to a 40:1 molar ratio, and a gamma/alpha 1:4 weight ratio corresponds to a 10:1 molar ratio. Hence, the molar ratio of alpha-crystallin needed to effectively protect gamma-crystallin from photochemical opacification was gamma/alpha = n:1, where n was in the range 10-40. In terms of subunits, this ratio is gamma/alpha = 1:m, where m = 1-4. Thus, each gamma-crystallin molecule needs 1-4 alpha subunits for protection. Similar stoichiometries were observed for protection of the other proteins studied. The protection stems in part from screening of UV radiation by alpha-crystallin but more importantly from a chaperone effect analogous to that seen in thermal aggregation experiments. PMID- 8698075 TI - Screening of the PDE6B gene in patients with autosomal dominant retinitis pigmentosa. AB - Each of the 22 exons and 140 bp of the 5' untranslated region of the gene encoding the beta-subunit of cGMP-phosphodiesterase (PDE6B) were screened by denaturing gradient gel electrophoresis for mutations in the DNAs of 54 unrelated individuals with autosomal dominant retinitis pigmentosa. Six different sequence variants were found in seven patients. Four of the sequence variants did not segregate with disease in the families of the respective probands and/or were present in control DNAs. The remaining two sequence variants, a Leu228His missense in exon 3 and a G to A transition in the tenth base of the splice acceptor site of intron 8, were both present in the same proband. One or the other of the two sequence variants was present in each affected member of the proband's small family and neither sequence variant was present in the one unaffected member nor in 75 unrelated controls. However, no effect on splicing of mRNA was observed in expression studies of DNA constructs containing the G to A transition. Therefore, mutations in PDE6B could not be shown to be the cause of adRP in this group of patients. PMID- 8698076 TI - ARPE-19, a human retinal pigment epithelial cell line with differentiated properties. AB - The retinal pigment epithelium (RPE) plays a critical role in the development and maintenance of adjacent photoreceptors in the vertebrate retina. This study describes the development and characterization of ARPE-19, a spontaneously arising human RPE cell line with normal karyology which forms polarized epithelial monolayers on porous filter supports. The cell line was established by selective trypsinization of a primary RPE culture resulting in a uniform population of highly epithelial cells which exhibit a strong growth potential. To determine the extent of biochemical differentiation, the expression of the RPE specific markers CRALBP and RPE65 was examined by Northern analysis. A single 1.6 kb CRALBP mRNA transcript and a single 2.8 kb RPE65 transcript were detected in samples of ARPE-19 total mRNA. The expression of CRALBP protein in ARPE-19 cell lysate was detected by Western blot analysis and immunocytochemistry was used to detect CRALBP throughout the cytoplasm of most, but not all, cells in confluent cultures. The essential criteria for monolayer formation were determined experimentally and it was found that ARPE-19 cells exhibit morphological polarization when plated on laminin-coated Transwell-COL filters in medium with a low serum content. The time course of tight-junction formation was determined by recording the transepithelial resistance of monolayers and reached a maximum of 50-100 omega cm2 after 4 weeks of culture. Barrier properties of ARPE-19 monolayers were evaluated by measuring the flux of 3H-inulin from the apical to the basolateral compartment of cell culture chambers. Finally, ARPE-19 clonal sublines were generated by serial dilution in an attempt to produce a subline with a high transepithelial resistance (TER). The morphology of the sublines was variable and the cloned cells exhibited a tendency to senesce in culture, confirming that this cell line is not transformed. No subline monolayers developed a TER greater than those recorded for the parent cells. Our results demonstrate that ARPE-19 has structural and functional properties characteristic of RPE cells in vivo and suggest that this cell line will be valuable for in vitro studies of retinal pigment epithelium physiology. PMID- 8698077 TI - Gap junction structures and distribution patterns of immunoreactive connexins 46 and 50 in lens regrowths of Rhesus monkeys. AB - Gap junction structures and distribution patterns of immunoreactive connexin46 (Cx46) and connexin50 (Cx50) in normal lenses and lens regrowths of rhesus monkeys were studied using electron microscopy and immunofluorescence double labeling. Lens regrowths were collected from aphakic eyes of young monkeys whose natural lenses had been surgically removed 11-34 months earlier to simulate monocular congenital cataract surgery in human infants. Approximately 90% of the lens regrowths examined was in the form of a doughnut-shaped Soemmerring's ring located behind the iris. The lens regrowth consisted of lens epithelium and lens fibers enclosed within hypertrophied capsular material. The superficial equatorial region usually contained nucleated young fibers of normal appearance. The other regions consisted of many swollen fibers. Gap junctions were readily observed between fiber cells of both normal and swollen configuration in the lens regrowth. In superficial fibers, gap junctions were not associated with cytoskeletal components. In the intermediate and the deeper cortical regions, actin filament bundles were found specifically associated with gap junctions along both of their cytoplasmic surfaces. An immunofluorescence double-labeling study showed that Cx46 and Cx50 were labeled in the same gap junctions in both superficial and deeper cortical fibers of the normal lens. In contrast, in the lens regrowth strong co-labeling of Cx46 and Cx50 was only observed in the superficial fibers. The labeling for Cx50 was very weak or absent in the deeper cortex, whereas the strong labeling for Cx46 persisted throughout the major portion of the deeper cortex. The labeling for Cx46 finally disappeared in the much deeper cortex. This study shows that (1) the same distribution pattern of actin bundle/gap junction association found in normal lenses is seen in the lens regrowth, and (2) the immunoreactive distribution of Cx46 and Cx50 differ in the lens regrowths as compared with those in the normal lenses of rhesus monkeys. PMID- 8698078 TI - Basic fibroblast growth factor: increased gene expression in inherited and light induced photoreceptor degeneration. AB - In a recent study, we reported that bFGF content and mRNA expression levels are elevated in degenerating photoreceptors in the rd mouse retina as compared to the levels in photoreceptors in age matched normal retinas (Gao and Hollyfield, 1995). To determine whether bFGF up-regulation is a general feature of degenerating photoreceptors, bFGF expression was examined with in situ hybridization in several rodent models with retinal degeneration: (a) the normal mouse retina in which cGMP metabolism had been disrupted pharmacologically using an inhibitor of phosphodiesterase or an analog of cGMP, (b) the rds mouse with an inherited photoreceptor degeneration that does not involve alterations in cGMP metabolism, (c) light-damaged BALB/c mice subjected to bright constant light, and (d) light-stressed albino rats subjected to bright cyclic light. In each of these models, we observed dramatic up-regulation of bFGF gene expression in photoreceptors, although the relative levels varied among the different models and followed different temporal patterns. We conclude that increased expression of bFGF in photoreceptors during their degeneration is a general phenomenon occurring in rd, rds, light-damaging and light-stressing conditions. These observations indicate that bFGF can be up-regulated by a variety of photoreceptor insults. We speculate that endogenous bFGF may function as a photoreceptor protection/rescue factor that is activated in response to photoreceptor stress. PMID- 8698079 TI - Role of cholesterol in the structural order of lens membrane lipids. AB - Cholesterol may order or disorder phospholipids. The physiological contribution of cholesterol to the structural order of lens membrane lipids was determined. Cholesterol and phospholipid from bovine lens nuclear and cortical tissue were separated by thin layer chromatography. The effect of cholesterol upon the trans to gauche transition of the hydrocarbon chains was assessed by measuring CH2 infrared stretching band frequencies as cholesterol was added back to the phospholipids. Although the relative cholesterol level of nuclear lipid was much higher than that of the cortex (59 vs. 36 mol%, respectively), the structural order of unfractionated nuclear and cortical lipids were similar at physiological temperature. Cholesterol added to lipids devoid of cholesterol produced a sharp biphasic effect on the structural order of nuclear lipids, increasing the trans conformation from 56% to 0 mol% cholesterol to 74% at 18% cholesterol to 41% trans at 59 mol% cholesterol. Cholesterol addition produced a shallow biphasic change in the percentage trans conformation of cortical lipids. Maximum order (about 40% trans conformation) was seen at a cholesterol level equal to that of intact cortical lipid (36 mol%). The physiological role of cholesterol is to increase the structural order of cortical membrane lipid and decrease order in nuclear lipid. The net result is a similarity in the structural order of cortical and nuclear membrane. We suggest that the different response of cortical and nuclear lipids to added cholesterol is linked to differences in the phospholipid composition between these two lens regions. In the absence of cholesterol, nuclear phospholipids are much more highly ordered than those of the cortex. PMID- 8698080 TI - Intraperitoneally injected melanin is highly uveitogenic. PMID- 8698081 TI - 25th Annual meeting of the International Society for Experimental Hematology. New York, New York, August 23-27, 1996. Abstracts. PMID- 8698082 TI - The accessory gland proteins in male Drosophila: structural, reproductive, and evolutionary aspects. AB - Recent results from biochemical and molecular genetic studies of the accessory gland proteins in male Drosophila are reviewed. The most prominent feature is the species-specific variability. However, the analysis of the sex peptide in D. melanogaster shows that there is a strong homology in the molecular structure to the closely related sibling species, and that divergence increases with increasing phylogenetic distance. For this reason the sex peptide, after being transferred to the female genital tract during copulation, reduces receptivity and increases oviposition only in virgin females belonging to the same species group and subgroup. Even though studies were hitherto limited to a small number of the secretory components, it is evident that the accessory gland proteins play a key role in reproductive success of the fruit fly by changing female sexual behavior, supporting sperm transfer, storage and displacement. Thus, genes encoding the accessory gland proteins are apparently under strong evolutionary selection. PMID- 8698083 TI - Altered axon terminals containing concentric lamellar bodies of cerebellar Purkinje cells in Mongolian gerbil. AB - Altered axon terminals containing concentric lamellar bodies were observed in cerebellar and vestibular nuclei of the Mongolian gerbil. The terminals increased in number from 30 days of age onward, and reached about tenfold at 360 days. The numbers were the same in two gerbil strains with different susceptibility to spontaneous motor seizures by various stimuli, but about threefold those in Slc:Wistar rat. PMID- 8698084 TI - In situ hybridization analysis of globin mRNAs in the primitive erythroid cells of the chick embryo. AB - The possibility that the minor embryonic chick hemoglobins might be present in a particular subgroup of primitive erythroid cells has been investigated by in situ hybridization. Probe to detect the mRNA for the alpha A globin chain of the minor embryonic hemoglobin was used, and the results of the hybridization were compared with those obtained using as probes the cDNAs for total globin mRNAs. All erythroid cells circulating in a 4-day-old chick embryo gave positive signals with both probes at an approximately constant ratio. This shows that all cells contain a similar assortment of hemoglobin types, excluding the possibility that a subgroup might contain the minor primitive hemoglobins exclusively. However, the cells are not homogeneous, since about 10% of them show a distinctly higher concentration of mRNA of all globin types. PMID- 8698085 TI - Platelet aggregation is inhibited by phycolectins. AB - Lectins from four marine algal species were examined for interaction with human platelets. The lectin designated hypnin A, from the red alga Hypnea japonica, inhibited adenosine diphosphate (ADP)- or collagen-induced human platelet aggregation in a dose-dependent manner. Complete inhibition was observed at concentrations of 100 and 5 micrograms/ml of the lectin with ADP (2 microM) and collagen (0.2 microgram/ml)-induced platelet aggregation, respectively. At the inhibitory concentration of 0.5 to 100 micrograms/ml, the lectin did not induce aggregation of resting platelets. Lectins from the other three algal species also inhibited ADP-induced human platelet aggregation. These results indicate that the algal lectins are a new group of inhibitors and may be useful to study glycoconjugates on platelet membranes and to design novel platelet aggregation inhibitors. PMID- 8698086 TI - Purification and some properties of hemagglutinin from the Myxomycete, Physarum polycephalum. AB - A new hemagglutinin was isolated from the plasmodium of Physarum polycephalum by salting out with ammonium sulphate followed by chromatography on DE-32, DEAE Toyopearl and hydroxyapatite. This hemagglutinin, named physarumin, was purified 1000-fold over crude extracts. The molecular weight of physarumin was determined to be 22,000 by size exclusion chromatography on Bio-Gel P-60 and 8,700 by SDS polyacrylamide gel electrophoresis. Physarumin agglutinated rabbit, guinea pig, horse and human erythrocytes. Physarumin-induced hemagglutination was inhibited by fetuin and alpha 1-acid glycoprotein, but not by commercially available mono- and disaccharides. Hemagglutinating activity was blocked by EDTA, and was restored by adding Ca2+ but not by Mg2+. PMID- 8698087 TI - Immunocytochemical reaction of a haemocyanin antibody in the midgut gland of Nautilus (Cephalopoda, Tetrabranchiata). AB - The branchial gland of the dibranchiate cephalopods is described as the site of haemocyanin synthesis. Because there is no equivalent to this organ in tetrabranchiate cephalopods the localization of haemocyanin synthesis remained unknown for a long time. In this study we could confirm the conclusions from preliminary investigations concerning the copper content of the midgut gland of Nautilus, which gave the first indications for a possible localization of haemocyanin synthesis in this organ. We developed a polyclonal antibody against Nautilus haemocyanin, tested its specificity, and used it on ultra-thin sections of the tissue of the midgut gland. It could be shown that there is a clear immunogold precipitation only on the triangular basal cells in the terminal alveoli. All the other types of cell in this organ were free of any immunoreactivity. It can be supposed that the triangular basal cells in the terminal alveoli of the midgut gland are the sites of haemocyanin synthesis in Nautilus. PMID- 8698088 TI - Differences in membrane ion transport between hepatocytes from the periportal and the pericentral areas of the liver lobule. AB - We studied the Na+/K+ pump, Na+/K+ ATPase activity, and oxygen consumption (QO2) in hepatocytes isolated from the periportal (PH) and pericentral (CH) regions of the liver lobule, to provide an insight into the functional properties of these cells. Na+/K+ pump activity was determined using 86Rb+ (a functional analog of K+) and ouabain, a specific inhibitor of this transport system. Our results indicate the the Na+/K+ pump and Na+/K+ ATPase activity are significantly lower in CH than in PH, although basal ouabain-sensitive (OS) QO2 was negligible in both of these cell preparations. However, OSQO2 was significantly lower in CH than in PH when the Na+/K+ pump was activated using the ionophore nystatin in a Na(+)-containing medium. These results indicate that the differences in membrane ion transport exist between hepatocytes from different locations of the liver lobule. PMID- 8698089 TI - The effect of hydrocortisone and thyroxine on development of calcium homeostasis in embryonic intestinal epithelium. AB - Cytoplasmic Ca2+ concentration of epithelial cells from 14-day embryonic chick duodena decreased during 72 h of organ culture to a value 54% of that found at 17 days in vivo. The ability of cells to maintain a constant Ca2+ concentration when challenged with high extracellular calcium was also significantly reduced. Addition of 1 microM hydrocortisone during culture restored both parameters of Ca2+ homeostasis to that of 16-day uncultured duodena, and rise in cytoplasmic Ca2+ was significant within 4 h of hormone treatment. Thyroxine influenced epithelial Ca2+ similarly, but to a lesser degree and only after 48-72 h of culture. These data indicate that glucocorticoids, and possibly thyroid hormones, influence the development of calcium homeostasis in intestinal epithelium. PMID- 8698090 TI - Inhibition of aldose reductase by dihydroflavonols in Engelhardtia chrysolepis and effects on other enzymes. AB - Astilbin and neoastilbin, dihydroflavonol rhamnosides from Engelhardtia chrysolepis, showed potent inhibition of lens aldose reductase. Kinetic analysis showed astilbin exhibited uncompetitive inhibition against both dl-glyceraldehyde and NADPH. These taxifolin glycosides were selective inhibitors of aldose reductase with no inhibition of NADH oxidase. PMID- 8698091 TI - An improved assay for UDPglucose pyrophosphorylase and other enzymes that have nucleotide products. AB - UDPglucose pyrophosphorylase catalyses the interconversion UDPglucose plus pyrophosphate and glucose 1-phosphate plus UTP. Several assay methods for this enzyme have been described but the only one that can be used to investigate the specificity with respect to various UDPsugars is based on coupling to UTP formation. This assay employs phosphoglycerate kinase to catalyse the formation 1,3- bisphosphoglycerate which is then used to oxidise NADH in the presence of glyceraldehyde 3-phosphate dehydrogenase. We have found that the activity of phosphoglycerate kinase towards UTP is low which limits the usefulness of the assay to very low rates, in agreement with the published recommendation of Hansen et al. Here it is shown that the dynamic range of the assay is increased by more than five fold on addition of nucleoside diphosphate kinase and ADP, which convert UTP to the preferred phosphoglycerate kinase substrate, ATP. It is also shown that the improved assay is suitable for enzymes with other nucleotide triphosphate products. PMID- 8698092 TI - Inhibition of lipid peroxidation by diterpenoid from Podocarpus nagi. AB - A diterpenoid, totarol (1), from Podocarpus nagi was evaluated as an antioxidant. This diterpenoid inhibited autoxidation of linoleic acid. Mitochondrial and microsomal lipid peroxidation induced by Fe(III)-ADP/NADH or Fe(III)-ADP/NADPH were also inhibited. Nagilactone E (2), a norditerpene lactone isolated from the same source, had no antioxidative activity. Furthermore, totarol protected red cells against oxidative hemolysis. This diterpene was shown to be effective in protecting biological systems against oxidative stresses. PMID- 8698093 TI - Effect of cold exposure on electrophysiological properties of rat heart. AB - Male rats exposed to the cold (4 degrees C) for five or ten days exhibited modifications in their thyroid state, as documented by increases in serum thyroid hormone levels, to which differently graded modifications of heart weight/body weight ratio, heart rate, and resting metabolic rate were associated. The values of the above mentioned thyroid state indicators returned to those of the control when the animals, kept at cold for ten days, were re-exposed to room temperature (24 degrees C) for an additional 10 days. The configuration of action potentials, recorded in vitro at 26 degrees C from fibres of anterior papillary muscles, was different in control rats of different age and was affected by prolonged cold exposure. In fact, the action potential duration (APD) increased after ten days of cold exposure. In the re-exposed group the APD was not different from that of the controls. Such a pattern was not significantly modified when the stimulation frequency increased from 1 Hz to 5 Hz. The above results suggest that in cold exposure, as in experimental hyperthyroidism, thyroid hormone might exert a cardiac chronotropic effect by modifying heart electrophysiological properties. Thus thyroid hormone should play a basic role during the exposure to cold environment, stimulating the body metabolism and increasing heart rate as a response to the requirement for greater tissue perfusion. PMID- 8698094 TI - Increased melatonin levels after hemorrhagic shock in male and female C3H/HeN mice. AB - Although hemorrhagic shock leads to significant alterations of several hormones, e.g. ACTH, corticosterone and beta-endorphin, it is not known whether plasma melatonin levels are affected under this condition and if so, whether the effects are comparable in males and females. Using a radioimmunoassay, it was found that plasma melatonin levels were significantly increased in male and proestrus female C3H/HeN mice immediately after hemorrhagic shock. However, in male mice, by two hours after hemorrhage and resuscitation, plasma melatonin returned to levels comparable to those seen in control and sham-operated animals. Proestrus female mice, on the other hand, showed significantly increased plasma melatonin levels at two hours after surgery when compared to unoperated control animals. Although the significance and biological role of the transient increased plasma melatonin levels after hemorrhagic shock remain to be determined, it appears that the pineal gland and/or an extrapineal source of melatonin, of both male and proestrus female mice responds to severe hypotension by increased release of melatonin. PMID- 8698095 TI - Resting energy expenditure in patients with cirrhosis of the liver measured by indirect calorimetry, anthropometry and bioelectrical impedance analysis. AB - Energy expenditure was investigated in 15 patients with liver cirrhosis and 20 healthy controls by three methods: indirect calorimetry, anthropometry using the Harris-Benedict equation and bioelectrical impedance analysis. The energy expenditure was expressed in kcal/day, kcal/kg BW/day (BW - body weight), kcal/kg LBM/day (LBM - lean body mass, derived by bioelectrical impedance analysis) or in kcal/m2/day. We did not find statistical differences between values of resting energy expenditure obtained in patients with cirrhosis of the liver and healthy controls whichever method we used. We also did not find statistical differences between values obtained by indirect calorimetry, anthropometry and bioelectrical impedance analysis. There was a significant correlation between indirect calorimetry and anthropometry in both groups. We found significant correlations between indirect calorimetry and anthropometry, and between indirect calorimetry and bioelectrical impedance analysis, in the control group only. We can conclude that (1) resting energy expenditure of patients with cirrhosis of the liver is not changed when compared with healthy controls, and (2) bioelectrical impedance is a useful method to calculate body composition from which energy expenditure is derived; however, it gives an appropriate result only in healthy people, and only approximate values in patients with cirrhosis. PMID- 8698096 TI - Antioxidant survey to assess antagonism to redox stress using a prokaryotic and an eukaryotic system. AB - Using a prokaryote (Escherichia coli) and a metazoa-resembling eukaryote (Ochromonas danica), we surveyed antioxidants which might overcome redox stress imposed by menadione sodium bisulphite (MD) and buthionine sulphoximine (BSO). BSO oxidant stress was evident only in O. danica; MD oxidant stress was evident in both organisms. Glutathione, its precursors, e.g. cysteine, homocysteine, and 2-oxo-4-thiazolidine carboxylic acid, and red blood cells, emerged as prime antioxidants for relieving BSO and MD oxidant stress. BSO and MD oxidant activity and antioxidant-annulling effect in O. danica were judged comparable to those found in animal cells whereas the results E. coli were not entirely equivalent. The O. danica system emerged as a practical, rapid, and useful system for pinpointing oxidant stressors and antioxidants, and shows promise for studies with mammalian systems. PMID- 8698097 TI - Antibacterial effect of 2-hydroxy-N-(3,4-dimethyl-5-isoxazolyl)-1, 4 naphthoquinone-4-imine on Staphylococcus aureus. AB - The mechanism by which a new naphthoquinone derivative, the 2-hydroxy-N-(3,4 dimethyl-5-isoxazolyl)-1, 4-naphthoquinone-4-imine (INQI-E) has antibacterial effect against Staphylococcus aureus was studied. The interaction of INQI-E with the bacteria was followed by absorption spectroscopy at 323 and 490 nm. The absorption band of INQI-E at 490 nm undergoes a hypochromic shift with a decrease of intensity. This effect was found to be reversible by oxygenation during the first hours of incubation. The participation of an oxidation-reduction process related to the respiratory chain was demonstrated by oxygen consumption. An increase in O2 uptake and inhibition of S. aureus growth was observed. Experiments with three inhibitors of the respiratory chain demonstrated that the pathway induced by INQI-E was antimycin-resistant and KCN- and salicylhydroxamic acid (SHAM)-sensitive, which suggests that INQI-E is capable of diverting the normal electron flow to an alternate superoxide-producing route. On the other hand, experiments with Tiron, a specific scavenger of superoxide, hindered the effect of INQI-E against S. aureus, indicating that the inhibitory growth effect of this quinone-imine is mainly due to the production of the cytotoxic superoxide radical. PMID- 8698099 TI - Acclimatization effect on the evening fall in core temperature under the influence of two types of clothing. AB - This paper reports the effect of acclimatization on the evening fall in core temperature under the influence of two different types of clothing. Two groups of subjects dressed in either knee-length skirts or full trousers during the daytime for the three months from April to June. To compare the circadian rhythm of core temperature, the experiments were carried out before and after the three month program of acclimatization. It was found that the subjects who had worn knee length skirts showed lower rectal temperatures during the nighttime and a bigger amplitude of circadian rhythm in July than in March. PMID- 8698098 TI - The use of cyclophosphamide as an enhancer of the vaccine against foot-and-mouth disease. AB - The immunization of biungulate animals with killed foot-and-mouth disease virus (FMDV) requires periodic vaccinations due to a low vaccine immunogenicity. Therefore, FMDV antigens need to be combined with adjuvants such as aluminium hydroxide, saponin or oil emulsions. Animal handling for periodic inoculations, and the repeated doses of vaccines that have to be administered increase the commercialization costs. Moreover, the use of adjuvants may induce adverse effects. In the present work we show that it is possible to increase the life span of neutralizing antibodies in serum when a single dose of cyclophosphamide (Cy) is administered four days before vaccination with aluminium hydroxidesaponin FMDV vaccine. PMID- 8698100 TI - Tocopheryl acetates from the pupal exocrine secretion of the squash beetle, Epilachna borealis (Coccinellidae). AB - The oily droplets on the pupal integumental hairs of the squash beetle Epilachna borealis contain a mixture of alpha-, beta-, gamma-, and delta-tocopheryl acetates as major constituents. In addition, the secretion contains a number of minor components that appear to be dehydrocongeners of the major components. This is the first report of the occurrence of acetate esters of any tocopherol in nature. PMID- 8698101 TI - Inhibition of invasion and intraerythrocytic development of Plasmodium falciparum by kinase inhibitors. AB - We have examined the effects of seven protein kinase inhibitors (staurosporine, genistein, methyl 2,5-dihydroxycinnamate, tyrphostins B44 and B46, lavendustin A and R03) on the erythrocytic cycle of the malaria parasite, Plasmodium falciparum. One (staurosporine) strongly inhibits serine/threonine kinases, but the remainder all exhibit a strong preference for tyrosine kinases. We have been able to discriminate between effects on invasion and on intraerythrocytic development. All reagents impeded development of intraerythrocytic parasites, though at widely differing concentrations, from the sub-micromolar to the millimolar. Several inhibitors, including staurosporine, also reduced invasion. The phosphatase inhibitor, okadaic acid, had a strong inhibitory effect both on invasion and development. The regulation of malaria development by phosphorylation or dephosphorylation reactions at several points in the blood stage cycle is implied. PMID- 8698102 TI - Dissociation constants of water-insoluble carboxylic acids by 13C-NMR. pK(a)s of mesobiliverdin-XIII alpha and mesobilirubin-XIII alpha. AB - High-field 13C-NMR of 13C-enriched compounds in dilute aqueous d6-Me2-SO solutions provides a simple, accurate method for measuring pK(a)s of sparingly soluble carboxylic acids. Using this method, we found the pK(a)s of mesobilirubin XIII alpha to be 4.2 and 4.9, much lower values than reported recently for bilirubin, and of mesobiliverdin-XIII alpha to be 3.9 and 5.3. PMID- 8698103 TI - Rapid development and a long life: an association expected under a stress theory of aging. AB - Life span and development time are considered in the context of the abiotic stresses to which free-living organisms are normally exposed. Under these circumstances, long life span depends upon metabolically efficient stress resistance genes, which tend to be heterozygous. Similarly, rapid development time tends to be a feature of heterozygous stress-resistant individuals. Therefore, individuals who have high inherited stress resistance should develop fastest and live longest; in addition, they should show high homeostasis in the fact of the energy costs of stress. In this way, the stress theory of aging can incorporate the developmental stage, based upon oxidative stress as an important major direct challenge. PMID- 8698104 TI - Apoptosis occurs in granulosa cells but not cumulus cells in the atretic antral follicles in pig ovaries. AB - The porcine antral follicles, 3-6 mm in diameter, were dissected from the ovaries of mature pigs, and then granulosa and cumulus cells were isolated from each follicle. In atretic follicles, high activity of neutral Ca2+/Mg2+-dependent endonuclease and DNA ladder formation, estimated by electrophoresis, were noted in granulosa cells but not in cumulus cells. Extremely low activity of the endonuclease and no DNA ladder formation were observed in both types of cells obtained from healthy follicles. Moreover, apoptotic cells were observed histochemically among granulosa cells only. A good correlation (r = 0.987) between the endonuclease activity of granulosa cells and the progesterone/estradiol ratio of follicular fluid in each follicle was found. These results suggest that apoptosis occurs in granulosa cells but not cumulus cells in the atretic antral follicles in pigs. PMID- 8698105 TI - The Na/K pump, resting potential and selective permeability in canine Purkinje fibres at physiologic and room temperatures. AB - All mammalian cells maintain a resting potential generated by ions moving down concentration gradients. In excitable cells, the inside potential is negative relative to outside. In order to maintain this electrochemical gradient, the sodium potassium (Na/K) pump actively transports out three sodium ions for every two potassium ions it brings in. This process generates a net outward current and thus hyperpolarizes the resting potential. I employed dihydroouabain (DHO) to inhibit the Na/K pump and thus measure its contribution to the resting potential. It contributed 9.0 mV at 34 degrees C and 3.8 mV at 25 degrees C. The PK/PNa ratios were calculated at both temperatures before and after subtracting the Na/K pump contribution. These ratios also suggested a decreased contribution of the Na/K pump under hypothermia. Taken together, these results suggest that the pump contribution to the resting potential is more significant at physiologic temperatures (34 degrees C) than at room temperature (25 degrees C), and that estimates of selective permeability can only be accurately obtained after assessing and eliminating the Na/K pump contribution to the resting potential. PMID- 8698106 TI - Resuscitation of cadaveric livers from non-heart-beating donors after warm ischemic insult: a novel technique tested in the rat. AB - Clinical liver transplantation has become the therapy of choice in end-stage liver disease, but the limited availability of suitable donor organs still impedes its widespread application. In order to increase the availability of donor organs for liver transplantation, it would be advantageous if ischemically damaged livers could be resuscitated from cadavers in which the heart has stopped beating. A method for doing this has been developed in a rat model. Compared to livers excised from rats in which the heart is still beating, severe deteriorations of tissue integrity and functional performance were evident in predamaged livers after cold preservation without supplementary treatment. A treatment of those livers which included an antioxidant rinse with superoxide dismutase, and venous vascular insufflation of gaseous oxygen during preservation, completely prevented tissue alterations upon reperfusion, and promoted a functional recovery of the livers, making them comparable to organs harvested from heart-beating donors. PMID- 8698107 TI - The diet and gut microflora influence the distribution of enteroendocrine cells in the rat intestine. AB - Several functions of the gut are locally influenced by peptides and biogenic amines released from enteroendocrine cells. The aim of the present study was to assess whether the luminal stimulus of diet or microbial flora or diet-microbial interactions have an influence on the distribution of enteroendocrine cells along the crypt-surface axes of the small and large intestine. The effects of diet and indigenous flora were investigated by comparing the numbers of argyrophil and serotonin immunoreactive cells in the jejunum and colon of germ free and conventional rats fed either a purified diet containing fine ingredients or a commercial diet containing crude fibre of cereal origin. The effect of human flora were analysed in germ-free rats inoculated with human faecal organisms. 1. Feeding the commercial diet reduced the number of argyrophil endocrine cells in the jejunum and serotonin immunoreactive cells in the colon of germ-free animals but increased the serotonin immunoreactive cells in the colon of conventional animals. 2. The rat flora increased the serotonin immunoreactive cells in the colon of animals fed a commercial diet and decreased in those fed a purified diet. 3. Inoculation of human flora increased the numbers of serotonin immunoreactive cells both in the jejunum and colon. The results provide evidence that the dietary changes and diet-microbial interactions can affect the regional number of enteroendocrine cells. PMID- 8698109 TI - Amylin given by central or peripheral routes decreases gastric emptying and intestinal transit in the rat. AB - The effect of rat amylin on gastric emptying and intestinal transit in the rat was examined. Amylin administered intracerebroventricularly (1, 2, 2.5 or 4 micrograms/rat) produced the maximal decrease in gastric emptying and intestinal transit at the dose of 2.5 micrograms/rat. Higher doses produced a lower effect. Peripheral administration (25, 50 or 100 micrograms/kg) produced dose-dependent effects. Pre-treatment with neostigmine blocked the effect of amylin when it was centrally injected, while the effect of amylin given peripherally was partially reduced. Pre-treatment with domperidone decreased the inhibitory effect of peripherally injected amylin, but no effect was observed when the peptide was centrally injected. PMID- 8698108 TI - Relationship of phosphatidylcholine to hydrophobic surfactant on rat intestinal chylomicron secretion. AB - Hydrophobic surfactants such as Poloxalene inhibit triglyceride secretion into lymph by enterocytes. The inhibitory effect of these agents on triglyceride secretion is reversed when lipid presented for absorption is exclusively in the form of phosphatidylcholine (PC) and not triglyceride. The present investigation performed in conscious mesenteric lymph fistula rats was designed to determine whether various mixtures of triglyceride and PC given intraduodenally with Poloxalene would also reverse the inhibitory effect of Poloxalene on triglyceride secretion into lymph. A 50-50 mixture of triolein (TO) and PC resulted in normal triglyceride secretion into lymph. However, when the mixture of lipids was 75-25, TO to PC, results for triglyceride recovery in lymph were considerably reduced. The transport rate for triglyceride into lymph was not as depressed, however, as observed for Poloxalene treated rats given lipid for absorption basically in the triglyceride form. Substitution of phosphatidylethanolamine for PC had no beneficial effect on triglyceride secretion in Poloxalene treated rats. It is concluded that PC can reverse the inhibitory effect of Poloxalene on triglyceride secretion into lymph even when considerable amounts of triglyceride along with PC are presented for absorption. PMID- 8698110 TI - Serum cholesterol level in a typical suburban commercial community in Nigeria. AB - Forty-one apparently healthy businessmen and -women and an equal number of government workers matched for age and sex underwent serum cholesterol determinations. The mean serum cholesterol levels of businessmen and -women were significantly higher than those of their government worker counterparts (p < 0.001). The marked increase in the serum cholesterol of the business subjects was attributed to their overindulgence and/or eating habits and lack of physical activity. The cardiovascular risk implications of the high cholesterol value and other risk co-factors such as obesity and alcoholism observed among the business subjects are highlighted. We advise that for communities similar to the one described here, public enlightenment programmes about the health benefits of periodic medical assessment and recreational physical activities are necessary. A further comprehensive study of lipid, lipoprotein and other risk factors in these subjects should be encouraged. PMID- 8698111 TI - Mechanism of age-dependent involution in embryonic chick notochords. AB - To study the possible mechanism of the age-dependent involution of the notochord, isolated mesenchyme-free notochords of chick embryos were cultured in vitro and compared with their counterparts in vivo. Two different aspects were evaluated: (1) DNA synthesis measured by [3H]thymidine incorporation and visualized by autoradiography and (2) cell death quantified by counting the number of pyknotic nuclei. The results demonstrate that [3H]thymidine uptake by notochords shows an age-dependent decrease in vitro as well as in vivo. The number of [3H]thymidine labelled notochord cells, however, is higher in vitro than in vivo. At the same time, there is an age-dependent increase in pyknosis in the notochord in vivo and in vitro. So, during the aging process, the number of both pyknotic nuclei and of [3H]thymidine-labelled nuclei suggest a high turnover of notochord cells in vitro. From these results, we can conclude that the process of involution in aging notochord seems to be controlled by a programmed intrinsic process, which might be influenced partially by the microenvironment in vivo. PMID- 8698112 TI - Plasma and hepatic antioxidant control and vitamin A nutritional status. AB - Twenty-seven rats were divided into three groups and fed on diets containing 0.3, 6 or 60 RE (retinol equivalent) retinyl palmitate/g food. After 7 weeks, hepatic vitamin A uptake was found to be more efficient in vitamin A-deficient rats than in rats given adequate vitamin A. We showed that during the metabolic adaptation of the animals to the level of vitamin A in the diet, extensive modifications occur in the antioxidant defences of the organism. In parallel with the increase in the level of vitamin A, the decrease in the level of alpha-tocopherol in the plasma can bring about a greater susceptibility of the lipoproteins to oxidative stress. Similarly, the decrease in the hepatic alpha-tocopherol level and in glutathione peroxidase activity leads to the weakening of the liver's antioxidant defences. PMID- 8698114 TI - Insect hormones in vertebrates: anabolic effects of 20-hydroxyecdysone in Japanese quail. AB - Ecdysteroids are hormones controlling cell proliferation, growth and the developmental cycles of insects and other invertebrates. They are occasionally present in various unrelated plants for no apparent reason; no phytohormonal function has yet been identified. In certain cases, ecdysteroids are accumulated to high levels in leaves, roots or seeds. Some ecdysteroid-containing plants have been known as medicinal plants for centuries. One of them, Leuzea carthamoides Iljin (Asteraceae), growing in Central Asia, contains 0.4% ecdysteroid in dry roots and 2% in seeds. A pharmacological preparation from this plant, "Ecdisten', is already available as a commercial preparation for its anabolic, tonic and other effects, for medical use (review). It remained problematic, however, whether ecdysteroids were truly responsible for these effects, because Leuzea contains a number of other biologically active compounds in addition to ecdysteroids. We extracted and purified ecdysteroids from the seeds of Leuzea. With 6 g of 96% 20-hydroxyecdysone (20E), we made a large-scale feeding assay with Japanese quail to find out whether ecdysteroid alone could duplicate the anabolic effects of the seeds. We found that the 96% ecdysteroid increased the mass of the developing quails in a dose-dependent manner, with the rate of increase proportional to the ecdysteroid content in the seeds; there was a 115% increase in living mass with 100 mg kg-1 of pure 20E compared with 109.5% increase with 100-180 mg kg-1 20E equivalents in the seeds. We conclude that the plethora of growth-promoting, vitamin-like effects induced in vertebrates by Leuzea is mediated by ecdysteroids. PMID- 8698113 TI - Vitamin B12 amplifies circadian phase shifts induced by a light pulse in rats. AB - Vitamin B12 (VB12) is a putative modulator of the human circadian clock, improving entrainability to the 24 h light-dark cycle. The present study was intended to elucidate the mechanism of VB12 action in an animal model. In male rats free-running under constant dim illumination, a single light pulse of 50 1000 lux for 20 min given at circadian time (CT) 20 induced a 0.28 to 1.08 h phase advance and at CT 14 induced a 0.54 to 2.10 h phase delay. A 3 h intracerebroventricular (icv) infusion of 30 nmol VB12 starting 2 h prior to a 20 min 200 lux light pulse significantly amplified phase shifts in comparison with saline-treated or untreated controls. The mean phase advance (1.13 h) was 1.8 fold greater than that of saline-infused controls, whereas the mean phase delay (2.28 h) was 2.9-fold greater. These values were comparable to the maximal phase shifts caused by 1000 lux light pulses in untreated rats. Since the same VB12 treatment alone had failed to induce a phase shift in a previous experiment, these results indicate that VB12 strongly enhanced light pulse-induced phase shifts and thus augmented the entrainability of the circadian clock to light. PMID- 8698115 TI - Experimental liver fibrosis induced in rats receiving high doses of alcohol and alternating between regular and vitamin-depleted diets. AB - Liver fibrosis was induced in rats by simulating human alcoholic eating and drinking patterns. Alcohol addiction was established by gradually increasing the ethanol concentration in the drinking water; salts were added at the terminal stage. The hepatocytes of rats receiving alcohol concentrations exceeding 50% (v/v) (similar to vodka) exhibited alcoholic hyaline (Mallory bodies). Alcoholic liver fibrosis was induced by alternating between regular and autoclaved (vitamin depleted) diets, simulating the irregular eating habits of human alcoholics. In the livers of rats receiving 70% (v/v) ethanol (comparable to absinthe) with 25% saline and fed the alternating diets, pericellular fibrosis was induced. No significant difference in calorie intake between control and alcohol rats was detected except when rats underwent drinking bouts (heavy drinking phase). This indicates that neither a high-fat diet nor a choline-depleted diet is necessary to induce the alcoholic fibrosis seen in human alcoholics. PMID- 8698116 TI - Two classes of metabolites from Theonella swinhoei are localized in distinct populations of bacterial symbionts. AB - The marine sponge Theonella swinhoei (lithistid Family Theonellidae, Order Astrophorida) has yielded many important, bioactive natural products, most of which share structural features with bacterial natural products. The presence of microbial symbionts in T. swinhoei has been reported, and it was originally suggested that the cytotoxic macrolide swinholide A and many of the bioactive cyclic peptides from T. swinhoei were all produced by simbiotic cyanobacteria. By transmission electron microscopy, we found four distinct cell populations to be consistently present in T. swinhoei: eukaryotic sponge cells, unicellular heterotrophic bacteria, unicellular cyanobacteria and filamentous heterotrophic bacteria. Purification and chemical analyses of each cell type showed the macrolide swinholide A to be limited to the mixed population of unicellular heterotrophic bacteria, and an anti-fungal cyclic peptide occurred only in the filamentous heterotrophic bacteria. Contrary to prior speculation, no major metabolites were located in the cyanobacteria or sponge cells. PMID- 8698117 TI - Heat shock enhances thermotolerance of infective juvenile insect-parasitic nematodes Heterorhabditis bacteriophora (Rhabditida: Heterorhabditidae). AB - Insect-parasitic nematodes possess many of the attributes of ideal biological control agents, but intolerance to extreme temperatures can restrict their use. We examined whether heat-shock treatments could improve nematode survival and infectivity at temperatures that normally inhibit their activity (35 and 40 degrees C). Nematodes exposed to a sub-lethal temperature (35 degrees C) for 3 h with a latency period of 1-2 h at 25 degrees C killed insects at 35 and 40 degrees C. Correlative evidence was obtained between increased thermotolerance and the synthesis of 70-kDa heat-shock proteins (hsps). These results provide the first evidence of hsp synthesis in the development of thermotolerance and biological activity in the non-feeding, developmentally arrested, infective juvenile nematodes. PMID- 8698118 TI - Cell differentiation in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is characterized by a differentiation block leading to accumulation of immature cells. Chromosomal translocations in AML affect transcription factors that are involved in regulation of myeloid differentiation. Aberrant expression of these factors interferes with differentiation events and has a role in the pathogenesis of AML through superactivation or (dominant negative) repression of genes regulating proliferation and differentiation or by interference with assembly of the transcription complex for these genes. The maturation arrest can be reversed by certain agents as judged by results from investigations of myeloid leukemic cell lines and from treatment of acute promyelocytic leukemia (APL) patients with all-trans retinoic acid. Inactivation of the p53 and retinoblastoma (Rb) tumor suppressor genes is also associated with the pathogenesis of leukemia through effects on the cell cycle, and manipulation of these genes can affect differentiation of AML cells. With differentiation therapy, when successful as in APL, the leukemic cell mass is reduced to allow restoration of normal hematopoiesis and clinical remission, but the disease is not cured. However, initial reduction of the cell mass by maturation can increase the probability for cure with chemotherapy. Overexpression of suppressor genes may increase the probability for differentiation. Most probably, particular molecular defects of subgroups of AML have to be explored to find optimal strategies for treatment including both blocking the cell cycle, promoting terminal differentiation, and inducing apoptosis as well as strengthening the immune response. PMID- 8698119 TI - Two cases of CML treated with alpha-interferon during second and third trimester of pregnancy with analysis of the drug in the new-born immediately postpartum. PMID- 8698120 TI - Nodal EBV-positive Hodgkin's disease following extranodal EBV negative non Hodgkin's lymphoma of B-cell lineage. PMID- 8698121 TI - Haemostatic markers of procoagulant imbalance in Behcet's disease. PMID- 8698122 TI - Severe anaemia as first sign of metastatic alveolar rhabdomyosarcoma. PMID- 8698124 TI - Surgical staging in Hodgkin's disease: the role of laparoscopic splenectomy. PMID- 8698123 TI - Th2 cytokines (IL-4, IL-10 and IL-13) and IL-12 mRNA expression by concanavalin A stimulated peripheral blood mononuclear cells during chronic graft-versus-host disease. PMID- 8698125 TI - Polycythaemia vera: response to treatment with angiotensin-converting enzyme inhibitor. PMID- 8698127 TI - Little evidence for clonal evolution of malignant haematopoietic cells following relapse after autologous bone marrow transplantation. AB - By screening for immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements in bone marrow samples aspirated at different time points during the course of disease from 43 patients with acute leukaemia we have analysed the extent of clonal evolution after autologous bone marrow transplantation (ABMT) and addressed the issue of whether the Southern Blot method has the power to reveal clonal proliferations representing minimal residual disease (MRD) in the autologous bone marrow grafts. Our results show that no clonal proliferations were detectable in any of the 43 bone marrow grafts analysed, even after we analysed DNA preparations in 5 cases from cells highly enriched for cells of the original malignant immunophenotype. Moreover, as judged by the Ig- and TCR gene configurations in 11 patients, relapse arose from the original clone even though minor clonal variations did occur in about half of the relapsing patients. We conclude that while the Southern Blot method can detect gene receptor rearrangements in the majority of patients with acute leukaemias and high-grade non-Hodgkins lymphomas, it is not useful for predicting relapse after ABMT. On the other hand, it is possible-by employing it-to evaluate whether or not relapse after ABMT arises from the original malignant clone and to what extent clonal evolution has taken place. PMID- 8698126 TI - Monoclonal antibody-based methods for quantitation of hemoglobins: application to evaluating patients with sickle cell anemia treated with hydroxyurea. AB - High-titer monoclonal antibodies (mAb) were raised against chromatographically purified human hemoglobin (Hb) species. These mAb were specific for either Hb A, Hb F, Hb S or Hb C. Based on these antibodies, which were directly conjugated with either fluorochromes or an enzyme (horseradish peroxidase), we developed immunoassays for determining the Hb profile in the peripheral blood; an enzyme linked immunosorbent assay (ELISA) for determining the absolute and relative quantities of various Hb species and one-step immunolabeling for fluorescence microscopic and flow cytometric analyses of the distribution of RBC with respect to their Hb types. We utilized these methods for monitoring the Hb F level and the percentage of Hb F-containing cells in patients with sickle cell anemia undergoing treatment with hydroxyurea. PMID- 8698128 TI - In vivo biological response following low-dose interleukin-2 in complete remission B-cell non-Hodgkin's lymphoma patients. Italian Lymphoma Study Group (GISL). AB - The aim of the present study is to verify whether recombinant interleukin-2 (rIL 2) at low doses is well tolerated in aggressive lymphoma in complete remission (CR), and if there may be a biological justification for its use as a remission maintenance therapy able to reduce the percentage of relapses. We treated 6 patients with B-cell non-Hodgkin's lymphoma (B-NHL) in CR following PM-Cytabom with rIL-2 3 IMU s.c. x 5 d per wk, every other wk for 8 wk. Our results show that this treatment provokes statistically significant changes in the absolute number of lymphocytes, eosinophils, CD25+ and CD122+ cells and soluble IL-2 receptors; these doses, however, are not sufficient to modify CD3+, CD16+ and CD56+ cell values or natural killer and lymphokine activated killer cell activity. Thus these findings do not appear to constitute a biological rationale for the use of rIL-2 at this dose and schedule as a remission-maintenance therapy in B-cell NHL. Nevertheless, the results are a valid basis for further study of the use of the same rIL-2 doses for a longer period of time in combination with other cytokines, in the hope that the biological effects can be augmented without increasing the toxic side effects. PMID- 8698130 TI - Intensive remission induction therapy for chronic myeloid leukemia in blast phase with a goal of post-remission bone marrow transplant--a pilot study. AB - An intensive protocol utilizing mitoxantrone, high-dose cytarabine, vincristine, etoposide and methylprednisolone as induction therapy for chronic myeloid leukemia in blast transformation is described. Fourteen patients were treated, with a remission/second chronic phase achieved in 64%. None of the 3 patients older than 50 yr responded. Complete hematological responses were seen in 9 of the 11 younger patients, 4 of whom also became BCR-ABL negative by Southern Blot analysis. Four patients went on to allogeneic bone marrow transplant. Median remission durations were 4.5 (1-5) and 8.5 (5-16) months in the non-transplanted and transplanted cohorts, respectively. Median survival is 1.5 (0.5-3), 9.5 (7 14) and 17 (14-61+) months in the non-responding, responding non-transplanted and transplanted cohorts, respectively. Toxicity, particularly gastrointestinal, was significant. This represents an aggressive protocol that should be reserved for patients who are potential transplant candidates. PMID- 8698129 TI - Deficiency of P-selectin in a patient with grey platelet syndrome. AB - Patient B.G. is a 29-yr-old female with a lifelong bleeding disorder characterized clinically by a highly increased bleeding time, menorrhagias, long lasting bleeding after cuts and tooth extractions and large post-traumatic haematomas. Her coagulation tests were within normal range, platelet count was 140,000-160,000 per microliters, but platelet function was impaired as demonstrated by the absence of collagen-induced aggregation, although no abnormalities were detected in aggregation response to ADP and ristocetin. Morphologically her platelets were characterized by gigantic size-average profile area was about 2.5 times higher than that of control donors, and severe deficiency of alpha-granules-only 16% of their number in control donors. These features taken together indicated the diagnosis of grey platelet syndrome. As has been shown by quantitative immunoblotting, patient's platelets contained small amounts of alpha-granule membrane protein P-selectin-about 15% of that in control donors. The content of plasma membrane glycoproteins IIb-IIIa and Ib was not reduced, suggesting the specific deficiency of alpha-granule membrane protein. Thus, B.G. is the second patient described in the literature (see also Lages et al, J Clin Invest 1991: 87: 919-929) with combined deficiency of alpha-granules and P-selectin. PMID- 8698132 TI - Investigation of microcytosis: a comprehensive approach. AB - Microcytosis is a highly prevalent finding during blood examination. This study investigates the causes of microcytosis (defined as mean corpuscular volume (MCV) < 82 fl) in 466 patients referred to our laboratory for suspected hemoglobinopathy. The following data were obtained: Hb, MCV, serum iron, transferrin, ferritin, HbA2, HbF, isoelectric focusing of the Hb, gene mapping of chromosome 16 with Xba I and Bgl II and hybridization with an alpha- and a zeta probe, inflammatory status. Results show that iron deficiency remains the first cause of microcytosis (35.2% of our patients), even in a selected population such as ours. Deletional alpha-thalassemia, probably the most frequent hemoglobinopathy throughout the world, represents the second most frequent cause of microcytosis (31.1%), followed by beta-thalassemia heterozygous state (18.9%). Of our patients, 1.3% had microcytosis due to the presence of an abnormal hemoglobin (HbC, Hb S/C, HbE). Three cases (0.6%) had other possible causes of microcytosis. Of the remaining 60 cases, 28 had an inflammatory state. Finally, 32 cases (6.9%) remain unexplained; taking into consideration the origin of these cases, their hematological parameters and their family history, we postulate that these cases are at high risk for non-deletional alpha-thalassemia. PMID- 8698131 TI - Functional abnormalities in granulocytes predict susceptibility to bacterial infections in chronic lymphocytic leukaemia. AB - Leukocyte functions were studied in 22 patients with chronic lymphocytic leukaemia (CLL) and were related to the patients' susceptibility to infections. In CLL patients with a history of infections, compared with CLL patients without infections or healthy controls, there were significant impairments of most granulocyte functions; random migration, N-formyl-methionylleucylphenylalanine (fMLP) and C5a stimulated chemotaxis and chemiluminescence response were decreased. No differences in these functions between CLL patients without infections and healthy controls were observed. Phagocytosis and intracellular killing of granulocytes were intact in all patients with CLL. By univariate analysis, neutrophil count and serum IgG level also predicted susceptibility to infections. By multivariate analyses, granulocyte chemotaxis and chemiluminescence remained as statistically significant predictors of infections. The lymphocyte functions (mitogen-induced lymphocyte proliferation and immunoglobulin production in vitro) were equally impaired in all patients with CLL and differed significantly from the respective functions in healthy control subjects. We conclude that impairments in granulocyte functions contribute to susceptibility to infections in CLL. PMID- 8698133 TI - Spouses of demented patients with low cobalamin levels: a new risk group for cobalamin deficiency. AB - Low serum cobalamin levels are common in conditions such as dementia and often represent mild deficiency. We surveyed serum cobalamin levels prospectively in spouses and blood relatives of demented patients to determine if any familial predisposition exists for the low levels. Cobalamin status in most of the relatives found to have low levels was assessed further by means of blood counts, metabolic tests, neurologic evaluation, absorption studies and response to cobalamin therapy. Serum cobalamin levels in 36 spouses correlated with those of the 36 demented patients related to them (r = 0.46, p = 0.004). A significant association was not seen in 34 blood relatives of 34 demented patients (r = 0.27). Most importantly, 67% of the spouses of demented patients with low serum cobalamin had low values themselves, compared with only 3% of the spouses of patients with normal levels (p = 0.001). Detailed study of 4 of the 5 spouses (and 3 blood relatives) with low cobalamin levels showed no anemia in any case. Nevertheless, 4 of the subjects had metabolic evidence of deficiency and one had electrophysiological abnormalities; all these defects improved with cobalamin therapy. These observations identify a hitherto unsuspected group of people at high risk for cobalamin deficiency and suggest that spouses of demented patients with low cobalamin levels should also have their cobalamin levels measured. The increased frequency of low serum cobalamin levels in spouses of demented patients with low levels represents in most cases a true, mild cobalamin deficiency that responds to treatment. PMID- 8698134 TI - Serum thrombopoietin and plasma glycocalicin concentrations as useful diagnostic markers in thrombocytopenic disorders. AB - Using enzyme-linked immunosorbent assays, we measured the concentrations of serum thrombopoietin (TPO) and plasma glycocalicin, a proteolytic fragment of platelet glycoprotien Ib alpha, in 13 patients with myelodysplastic syndrome (MDS), aplastic anaemia (AA) or idiopathic thrombocytopenic purpura (ITP). In the patients with AA or MDS, the TPO concentrations were remarkably increased, and their glycocalicin concentrations were decreased compared with the normal control individuals. In the patients with ITP, however, the TPO and glycocalicin levels were not changed as much as in the AA/MDS patients in spite of the same degree of thrombocytopenia. During immunosuppressive treatment of ITP patients, there was an inverse relationship between the level of TPO and the platelet count. Thus, measurements of TPO and glycocalicin levels are useful for the diagnosis of thrombocytopenia, and our results from ITP patients did not support the model which suggested the simple feedback regulation of TPO in thrombocytopenia. PMID- 8698135 TI - The use of recombinant SCF protein for rapid determination of c-kit expression in normal and abnormal erythropoiesis. AB - Stem cell factor (SCF) is the ligand for the dimeric c-kit tyrosine kinase receptor. Binding of SCF to c-kit is a crucial element in the developmental stimulus of late stem cells and early progenitor cells. In the erythroid lineage the SCF stimulus is important not only for proliferation and differentiation, but is also known to enhance later haemoglobin production. In an earlier report we described a rapid non-radioactive technique using the extended ester-attached labelled SCF protein itself for detecting c-kit expression in marrow and peripheral blood mononuclear populations. In the present study we have taken this a step further to analyse c-kit expression in developing erythroid cells in vitro, principally using normal donor samples. This was designed for use as a foundation for the comparison of haematological disorders. In this case we tested 4 patients with the congenital disorder of erythropoiesis, Diamond-Blackfan anaemia (DBA), finding that in all cases DBA c-kit expression was elevated over normal, in 1 case as high as 348% of the normal average. This may be indicative of the reduced state of progenitor development in these patients. These results show that the described technique is beneficial for analysis in the stem and progenitor compartment. PMID- 8698136 TI - Monocytic differentiation and synthesis of proteins associated with apoptosis in human leukemia U-937 cells acquiring resistance to vincristine. AB - Human leukemia U-937/WT cells were exposed to stepwise increased concentrations of Vincristine so that Vincristine-resistant cell sublines (termed U-937/RV) were developed. Established U-937/RV cell sublines have continuously propagated over a year, both in absence and presence of VCR, and have demonstrated similar features. In contrast to U-937/WT cells, U-937/RV cells have longer doubling time, and are more differentiated as determined by appearance of distinct morphological features and synthesis of mRNA that codes for the monocyte colony stimulating factor-1 receptor (c-fms). Both apoptosis-suppressing Bcl-2 and Bcl XL proteins were undectable in U-937/WT cells, whereas Bcl-2 was nearly detectable and Bcl-XL readily detectable in U-937/RV cells. The apoptosis promoting Bax protein was also absent in U-937/WT cells and readily detected in U 937/RV cells. Vincristine-resistant cells with different levels of resistance synthesize similar levels of c-fms mRNA and Bax protein. Finally, unlike U-937/WT cells, U-937/RV cells have no ability to induce tumors when xenografted in immunodeficient mice. The findings collectively suggest that development of resistance to Vincristine in U-937/WT cells may correlate with cell differentiation and synthesis of proteins that regulate apoptosis. PMID- 8698137 TI - Interleukin 1 receptor antagonist (IL1RA) in acute leukaemia: IL1RA is both secreted spontaneously by myelogenous leukaemia blasts and is a part of the acute phase reaction in patients with chemotherapy-induced leucopenia. AB - Blast cells derived from peripheral blood of patients with acute myelogenous leukaemia (AML) were cultured in vitro and interleukin 1 receptor antagonist (IL1RA) concentrations determined in culture supernatants. AML blasts derived from patients classified as AML-M4 and AML-M5 subtype showed an increased release of IL1RA. IL1 alpha and IL1 beta caused a similar increase in AML blast release of IL1RA, and addition of anti-IL1 antibodies decreased IL1RA release. IL1RA release from AML blasts was also increased by stem cell factor, tumour necrosis factor alpha (TNF alpha), granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor, whereas interleukin 3, interleukin 6, leukaemia inhibitory factor and granulocyte colony-stimulating factor did not significantly alter IL1RA release. When investigating IL1RA serum levels, serum concentrations were decreased in acute leukaemia patients with chemotherapy induced cytopenia compared with healthy controls. Serum levels of both IL1RA as well as IL1 beta and soluble TNF alpha receptors increased when the leucopenic patients developed complicating bacterial infections. PMID- 8698138 TI - Arterial and venous thrombosis in two Italian families with the factor V Arg506- >Gln mutation. AB - APC resistance, due to a point mutation in factor V at amino acid position Arg506, has been identified as a major cause of inherited thrombophilia. Here we report the presence of the factor V Arg506-->Gln mutation in 2 Italian families. In 1 family 3 subjects heterozygous and 2 subjects homozygous for the factor V Arg506-->Gln mutation were identified. The only subject who developed a thrombotic event was a 20-yr-old girl who was found to be homozygous for the factor V Arg506-->Gln mutation. In the second family 10 subjects were identified to be heterozygous for the factor V Arg506-->Gln mutation; among them 2 developed a thrombotic event. In the same family 2 individuals were found to be homozygous for the mutation: the first had a myocardial infarction at age 25 yr and the second suffered from multiple episodes of deep venous thrombosis and had a stroke at age 24 yr. These data show that the risk of developing deep venous thrombosis for the carriers of the factor V Arg506-->Gln mutation is high in the families investigated. Furthermore our data imply that the factor V Arg506-->Gln mutation in its homozygous form may relate to myocardial infarction and stroke. PMID- 8698139 TI - Charcot-Marie-Tooth disease associated with hip dysplasia: a case report. AB - A 31-year-old woman with a known history of hip dysplasia was found to have Charcot-Marie-Tooth disease following abnormal conduction studies done at the time of surgery. Physical examination in this patient was otherwise normal, and the diagnosis of Charcot-Marie-Tooth disease had not been previously considered. This report demonstrates the importance of keeping in mind the association between hip dysplasia and Charcot-Marie-Tooth disease. PMID- 8698140 TI - Hepatitis B vaccine completion among adolescents. AB - This study examined hepatitis B vaccination completion among 51 adolescents recruited from a primary care clinic. Seventy-one percent completed the series. Completion was not related to demographic characteristics or attitudinal measures at the first shot. Few opportunities for vaccination were missed. Inconvenience appears to be a factor in failure to complete the series. PMID- 8698142 TI - To sue or not to sue. PMID- 8698141 TI - Radiograph of the month. Small cell lung carcinoma with metastasis to the pituitary. PMID- 8698143 TI - An implied social contract. PMID- 8698144 TI - Cancer screening and the USPSTF. PMID- 8698145 TI - Practical procedures. PMID- 8698146 TI - Postural control in children with spastic diplegia: muscle activity during perturbations in sitting. AB - To clarify the neural mechanisms controlling equilibrium during sitting, and the implications for the optimal sitting position for children with CP, automatic postural adjustments after perturbations of the support surface during sitting were investigated in seven children with spastic diplegia and in seven age matched controls. A sudden backward sway of the body evoked brisk responses in ?ventral' muscles in both groups. However, the order of muscle recruitment, which in most non-disabled children was caudal, was reversed in the children with diplegia, whose first response was in the neck flexors. The children with diplegia also co-activated antagonistic neck and hip muscles. The authors concluded that although children with spastic diplegia may produce a basic muscle activation pattern (first level of the central pattern generator, CPG), they cannot adjust the pattern in response to external changes (second level of the CPG). PMID- 8698147 TI - Relation of gait analysis to gross motor function in cerebral palsy. AB - The Gross Motor Function Measure (GMFM) and computerized gait analysis are commonly used to assess patients with cerebral palsy (CP). The authors investigated correlations between the GMFM and gait parameters in 32 children aged 3 to 18 (mean 8.9) years with spastic CP. Of the gait parameters, cadence and normalized velocity correlated most strongly with the GMFM score, and hip knee excursion and percentage single support also correlated directly with the GMFM. In a stepwise multiple regression, cadence alone was a significant predictor of GMFM score. Time and distance parameters, hip and knee excursion in sagittal plane and GMFM value all moved consistently further from pediatric norms as functional severity increased. The study confirms that gait is representative of general motor status in CP and that the GMFM and gait analysis are complementary measures in the functional assessment of these children. PMID- 8698148 TI - How mothers and fathers view professional caregiving for children with disabilities. AB - The authors compared mothers' and fathers' perceptions of professional caregiving, using the MPOC, a self-administered questionnaire for parents. The authors looked at the aspects of caregiving 128 couples judged to be important, their perceptions of the actual caregiving received from health professionals and their stress. The data, from a relatively large sample of intact families, indicated that there were more similarities than differences between the mothers' and fathers' replies. Both valued the enabling and partnership aspect of caregiving most highly. Only one difference in reported experience was found: mothers reported experiencing significantly more coordinated and comprehensive care than did their spouses. The clinical implications of the findings are discussed, particularly with respect to the involvement of fathers in clinical intervention, and the belief that fathers are uninterested in their children's care. PMID- 8698149 TI - Biases of motion perception revealed by reversing gratings in humans who had infantile-onset strabismus. AB - Motion perception was tested by requiring adult subjects to view gratings that remained stationary but reversed in contrast several times per second. Subjects viewed monocularly and judged whether the gratings were stationary, or moving in one direction, in successive 3s trials. Subjects who had early-onset strabismus most frequently perceived vertically oriented gratings to be moving nasalward, and horizontally oriented gratings to be moving up or down. Normal subjects and subjects who had late-onset strabismus most frequently perceived the gratings to be stationary. The asymmetries of motion perception in early-onset strabismus imply that the visual motion neurons of cerebral cortex develop properly only if they receive normal binocular input during infancy. PMID- 8698150 TI - Elevated androgen, brain development and language/learning disabilities in children with congenital adrenal hyperplasia. AB - Individuals with congenital adrenal hyperplasia (CAH) provide a test population for the theory that elevated testosterone levels alter prenatal brain development and increase the risk of learning disabilities. Eleven subjects with CAH, five of their non-CAH siblings and 16 matched control subjects participated in two studies. The first study documented hand preference, verbal skills and non-verbal skills. A higher prevalence of language/learning disability was found in both the CAH subjects and their families than in the control subjects. The second study examined the prevalence of atypical perisylvian asymmetries on MRI scans. These revealed an atypical pattern of asymmetry (R = L or R > L) in the majority of the subjects with CAH and in all of their siblings. One subject with CAH also showed evidence of a neuromigratory disturbance in the posterior left hemisphere. Of the control subjects, only one showed an atypical pattern of asymmetry and none showed evidence of a neuromigratory disorder. The findings indicate that an elevated familial rate for language-based learning disabilities and altered brain asymmetries co-occur in families with the gene for CAH. PMID- 8698151 TI - Developmental changes in response to heelstick in preterm infants: a prospective cohort study. AB - Twenty-eight preterm infants of 28 weeks gestational age were observed four times over eight weeks in order to determine changes in their pain response. Both routine and sham heelstick procedures were used. Physiological (heart rate and oxygen saturations) and behavioural parameters (three upper facial actions) were used as outcomes. The responses to real heelstick were significantly greater than to sham heelstick for heart rate and all facial actions except one at 28 weeks gestational age, but not for oxygen saturation. The magnitude of response to both real and sham heelstick increased over time. Thus, the older the infant, the more robust and recognisable the response. Since even the youngest infants showed a differential response to pain, professionals caring for such infants need to be able to recognize their more subtle pain responses. PMID- 8698152 TI - Clean intermittent catheterization. PMID- 8698153 TI - Cortical dysgenesis in a patient with Turner mosaicism. AB - In a patient with Turner mosaicism who had mental retardation, epilepsy and cerebellar ataxia, MRI showed cerebellar atrophy and a bizarre cortical dysgenesis of the cerebrum, which was considered to comprise a mixture of relatively normal gyri and structures resembling pachygyria and lissencephaly. The karyotype of the patient was 45,X/47,XXX, but the brain dysgenesis could not be explained solely on the basis of this mosaicism, which is rarely associated with a gross abnormality in brain pathology. Abnormality of the X chromosome seems to have some potential for inducing cortical dysgenesis, and this case may be partially attributable to an abnormal locus on the X chromosome. PMID- 8698154 TI - Juvenile Krabbe's Leukodystrophy precipitated by influenza A infection. AB - Juvenile Krabbe's disease, a neurometabolic disorder, presented as an acute demyelinating episode characterised by an abnormal gait. The neurological presentation was preceded by influenza A infection. PMID- 8698155 TI - Chickenpox in mid-trimester pregnancy: always innocent? AB - A case of congenital varicella infection is presented, in which despite profound cerebral damage, the cardinal features of cicatricial skin lesions and limb shortening were absent. The case is compared with previously described cases, and with published series, in which this combination is uncommon. The risks of maternal varicella infection to the developing fetus are discussed in the light of recent prospective studies which demonstrate a rather lower risk than had previously been thought to be the case. PMID- 8698156 TI - The utility of acoustic reflex thresholds and other conventional audiologic tests for monitoring cisplatin ototoxicity in the pediatric population. AB - OBJECTIVE: The sensitivity of acoustic reflex threshold changes for monitoring cisplatin ototoxicity in children was compared with the sensitivity of conventional audiometric tests. DESIGN: Acoustic reflex thresholds, thresholds for audiometric frequencies 0.250 Hz to 2 kHz and 3 kHz to 8 kHz, extended high frequency (EHF) audiometry for 10 kHz to 16 kHz, and the articulation index (AI) were compared at six different cumulative dosage levels of cisplatin in 21 children, 3.08 yr to 19.25 yr of age. RESULTS: Of these 21 patients, 100% showed significant changes in at least one portion of the test battery when cumulative dosages exceeded 401 mg/m2. EHF testing was found to be the most sensitive to ototoxicity once cumulative dosage levels of 150 to 250 mg/m2 were reached. Audiometric thresholds from 3 to 8 kHz, and acoustic reflex threshold changes were found to be the next most sensitive to ototoxicity at cumulative dosages of 251 to 400 mg/m2. No significant threshold changes were noted for frequencies from 250 Hz to 2 kHz. CONCLUSIONS: Acoustic reflex threshold measures may prove to be a valuable addition to current ototoxic test protocols. Although it is currently not the most sensitive test to ototoxicity, it is one of the more objective tests. Further data must be collected to determine the clinical utility of acoustic reflex threshold testing to monitor ototoxicity. PMID- 8698157 TI - The emergence and disappearance of one subject's spontaneous otoacoustic emissions. AB - OBJECTIVE: This paper documents the appearance and disappearance of multiple, intense spontaneous otoacoustic emissions (SOAEs) in one subject who previously had no measurable SOAEs. DESIGN: A subject, who had no spontaneous otoacoustic emissions (SOAEs) from 4/24/93 to 5/24/93, displayed 10 SOAEs on 5/26/93 (day 1). The SOAEs of the subject were tracked for 342 days. RESULTS: On day 85, the SOAEs had all vanished. Thereafter, no stable SOAEs appeared. However, on days 94 and 99 one SOAE was intermittently measured in the left ear. CONCLUSIONS: These data seem to indicate that some SOAEs may be caused by reversible disturbances of active transduction mechanisms, and that not all SOAEs are heritable. Because the subject had been exposed to loud music on the night preceding the emergence of the SOAEs, the putative cause of the SOAEs may have been exposure to loud sound. PMID- 8698158 TI - Test-retest reliability of loudness scaling. AB - OBJECTIVE: Establish the test-retest reliability of loudness scaling using a bounded category rating method. DESIGN: The individual loudness functions were investigated in three groups of listeners: seven normal-hearing listeners age 18 to 35 yr, five normal-hearing listeners aged 57 to 84 yr, and five listeners aged 54 to 82 yr with bilateral sloping sensorineural hearing loss. Test-retest reliability was investigated by determining the intralistener, between-session standard deviation. RESULTS: The pattern of test-retest reliability was similar across all three groups. It improved as the intensity of the stimulus increased: 7 dB at the first quartile of the loudness function, and 3 dB at the third quartile. Two to four runs of the task appear to be sufficient to obtain a stable loudness function, and it was shown that an exponential function provided a better goodness of fit than a linear function (r2: 0.99 compared with 0.94). CONCLUSIONS: Loudness scaling is a longer test than most conventional suprathreshold measures and requires special equipment. However, it has good test retest reliability and provides more information on the loudness function that might be useful in the fitting of nonlinear hearing aids. The data show that an exponential function provides a good fit to the loudness growth data, and should probably be incorporated into fitting algorithms associated with loudness scaling. PMID- 8698159 TI - Fitting hearing aids to individual loudness-perception measures. AB - OBJECTIVE: The purpose of this study was to compare the prescribed gain, compression ratios, compression thresholds, and the relative predicted speech intelligibility (Speech Intelligibility Index [SII], American National Standards Institute 3.79, proposed) provided by four strategies proposed for selecting hearing aid parameters for low-threshold compression hearing instruments and by a traditional threshold-based hearing aid fitting procedure. The strategies used were Desired Sensation Level Input/Output (DSLTM[i/o]; Cornelisse, Seewald, & Jamieson, 1994), Visual Input-Output Locator Algorithm (VIOLA; Cox, 1994), FIG6 strategy (Killion, Reference Note 2), Ricketts and Bentler strategy (RAB), and a threshold-based hearing aid fitting procedure (National Acoustics Laboratories Revised [NAL-R]; Byrne & Dillion, 1986). These new strategies have been suggested as alternatives to threshold-based strategies, which do not provide the varying amounts of target gain, as a function of input level, necessary to fit low threshold compression hearing aids. DESIGN: The electroacoustic prescriptions and the predicted speech intelligibility were calculated across all five fitting strategies for 20 subjects. The threshold and loudness growth information used for each fitting was reported previously (Ricketts & Bentler, in press). RESULTS: Comparison across prescriptions revealed that the NAL-R strategy (due to the linear gain provided) prescribed the least gain for low-level inputs and the greatest gain for high-level inputs. Gain comparisons across fitting by loudness (FBL) strategies revealed a more shallow frequency response slope for strategies that require individual measures of loudness growth (RAB, VIOLA) in comparison with strategies that assumed average data (FIG6, DSLTM[i/o]). SII results revealed greater predicted speech intelligibility for the FIG6 and the DSLTM[i/o] compared with the NAL-R, RAB, and VIOLA. These differences were most apparent in noise backgrounds and least evident when loudness differences were minimized. CONCLUSIONS: It appears that differences in SII scores across the FBL fitting strategies are due, in part, to differences in the loudness of the output signal. It is assumed that differences in high-frequency shaping may also be a factor. These data do not appear to support the use of additional clinical time to obtain individual loudness growth measures. However, due to the fact that SII results are based on average performance, it is difficult to predict whether differences across these fitting strategies would be realized in actual measures of speech intelligibility or sound quality on an individual basis. PMID- 8698160 TI - Perceptual consequences of cochlear hearing loss and their implications for the design of hearing aids. AB - This paper provides an overview of changes in the perception of sound that result from cochlear damage. It starts with a brief introduction to the physiology of the cochlea, emphasizing the role of the "active mechanism" and describing how cochlear function is altered by cochlear damage. Then the effects of cochlear damage on various aspects of perception are described, including absolute sensitivity, frequency selectivity, loudness perception and intensity discrimination, temporal resolution, temporal integration, pitch perception and frequency discrimination, and sound localization and other aspects of binaural and spatial hearing. The possible role of each of these aspects of auditory perception in the ability to understand speech in quiet and in noise is discussed and evaluated. It is concluded that, for losses up to about 45 dB, audibility is the single most important factor. However, for greater losses, poor discrimination of suprathreshold (audible) stimuli is also of major importance. The final section of the paper describes applications of the findings to hearing aid design. It is concluded that linear amplification can be of only limited benefit in compensating for the effects of cochlear damage. Hearing aids incorporating compression can help to compensate for the effects of reduced dynamic range. Digital signal processing to enhance spectral contrast may be of some help in compensating for the effects of reduced frequency selectivity. PMID- 8698161 TI - Compression and its effect on the speech signal. AB - Compression systems are often used in hearing aids to increase the wearing comfort. A patient has to readjust frequently the gain of a linear hearing aid because of the limited dynamic hearing range and the changing acoustical conditions. A great deal of attention has been given to the static parameters but very little to the dynamic parameters. We present a general method to describe the dynamic behavior of a compression system by comparing modulations at the output with modulations at the input. The use of this method resulted in a single parameter describing the temporal characteristics of a compressor, the cut-off modulation frequency. In this paper its value is compared with known properties of running speech. A limitation of this method is the use of only small modulation depths, and the consequence of this limitation is tested. The use of this method is described for an experimental digital compressor developed by the authors, and the effects of some temporal parameters such as attack and release time are studied. This method shows the rather large effects of some of the parameters on the effectiveness of a compressor on speech. This method is also used to analyze two generally accepted compression systems in hearing aids. The theoretical method is next compared to the effects of compression on the distribution of the amplitude envelope of running speech, and it could be shown that single-channel compression systems do not reduce the distribution width of speech filtered in frequency bands. This finding questions the use of compression systems for fitting the speech banana in the dynamic hearing range of impaired listeners. PMID- 8698162 TI - Frequency-specific audiometry using steady-state responses. AB - OBJECTIVE: To evaluate the audiometric usefulness of steady-state responses to multiple simultaneous tones, amplitude-modulated at 75 to 110 Hz. DESIGN: Steady state responses to multiple tones amplitude-modulated at different rates between 75 and 110 Hz and presented simultaneously were recorded at different intensities in normal adults, well babies, normal adults with simulated hearing loss, and adolescents with known hearing losses. Response thresholds were compared with behavioral thresholds. RESULTS: In normal adults the thresholds for steady-state responses to tones of 0.5, 1, 2, and 4 kHz were 14 +/- 11, 12 +/- 11, 11 +/- 8, and 13 +/- 11 dB, respectively, above behavioral thresholds for air-conducted stimuli, and 11 +/- 5, 14 +/- 8, 9 +/- 8, and 10 +/- 10 dB above behavioral thresholds for bone-conducted stimuli. In well babies tested in a quiet environment, the thresholds were 45 +/- 13, 29 +/- 10, 26 +/- 8, and 29 +/- 10 dB SPL. In adolescents with known hearing losses, the steady-state responses thresholds predict behavioral thresholds with correlation coefficients (r) of 0.72, 0.70, 0.76, and 0.91 at 0.5, 1, 2, and 4 kHz, respectively. CONCLUSION: Steady-state responses to tone amplitude-modulated at 75 to 110 Hz can be used for frequency-specific objective audiometry. The multiple-stimulus technique allows thresholds to be estimated for eight different stimuli at the same time. PMID- 8698163 TI - Assessing the cognitive demands of speech listening for people with hearing losses. AB - OBJECTIVE: Measures of listening effort can provide a useful complement to measures of listening performance. The purpose of the present study was to measure the effort required of hearing-impaired subjects when they listen to speech. METHOD: Our subjects performed two tasks simultaneously: a speech task, which took the form of listening to connected discourse; and a digit-memorization task, which competed with the speech task for cognitive resources. Changes in speech-listening effort altered the distribution of resources between the two tasks and modulated memory performance. In two experiments, this dual-task test was given to individuals with congenital/early-onset hearing loss or with presbyacusic hearing loss. We first asked whether they could perform the dual tasks at reasonable levels. If they could, we then asked what their performance revealed about the effortfulness of speech listening, compared with the effort required of normally hearing control subjects. RESULTS: We found the dual-task test to be broadly accessible to hearing-impaired persons. We also found evidence that speech listening was abnormally effortful for both hearing-impaired groups. CONCLUSIONS: These findings encourage further study of attentional and other cognitive factors that accompany speech listening by the hearing impaired. PMID- 8698164 TI - [Importance of video display operation skills in a system of psychophysiologic selection of operators for the rolling mill automated control system]. PMID- 8698165 TI - [Parameters of alpha-rhythm and productivity of memorization]. PMID- 8698166 TI - [Hemodynamics, endurance and psychomotor parameters in residents of various latitudes in contrasting seasons]. PMID- 8698167 TI - [Hematologic parameters and factors reflecting the effect of local negative pressure on the human body]. PMID- 8698168 TI - [Sex-related differences in the levels of the major hormones in the blood and in levels of lymphocyte NAD(P)-dependent dehydrogenase]. PMID- 8698169 TI - [Effect of environmental factors and social habits on the state of the hypophyseal-adrenal system and plasma insulin in healthy people]. PMID- 8698170 TI - [Enterosorption as a method for prolonging life]. PMID- 8698172 TI - [Immunologic characteristics of the course of phlegmon of the face and neck in patients from Iakutsk and Moskow]. PMID- 8698171 TI - "Middle molecules" as probable regulators of the erythron system in competitive skiiers. PMID- 8698173 TI - [Correlation between the parameters of local and distant synchronization of brain potentials in a state of quiet wakefulness]. PMID- 8698174 TI - [Hemispheric features of spectral characteristics of background EEG and EEG during various types of cognitive activity in schizophrenic patients]. PMID- 8698176 TI - [Audio-verbal and visual-spatial memory in young schoolchildren with varying lateral profile]. PMID- 8698175 TI - [Brain bioelectric activity in children with tumors localized in the brain stem in the preoperative and early postoperative periods]. PMID- 8698177 TI - [Formation of a visual information trace. Analysis of evoked potentials]. PMID- 8698178 TI - [Positron-emission tomographic study of human brain processing of various characteristics of visually presented words. II. Brain system of word reading]. PMID- 8698179 TI - [Functional asymmetry in the cerebral hemispheres in carrying out visual-gnostic functions in people of different sexes]. PMID- 8698180 TI - [Formation of visual representations of the surrounding world in children during the first year of life]. PMID- 8698181 TI - [Evaluation of the integrity of visual objects as a function of their dimensions]. PMID- 8698182 TI - [Assessment and training of stereoscopic vision using dynamic stereovisometry]. PMID- 8698183 TI - [Detection of latent arterial hypertension using a complex of hemodynamic parameters in exercise tests]. PMID- 8698184 TI - [The peripheral heart and the mechanism of its functioning]. PMID- 8698185 TI - [Effect of dynamic compression of intrapulmonary respiratory tracts on the shape of the loop of bronchial resistance of heterogeneous lungs]. PMID- 8698186 TI - [Effect of contrasting temperatures on peripheral blood flow and microcirculation]. PMID- 8698187 TI - [Music as a means of improving the functional state of students before an examination]. PMID- 8698188 TI - Deletions at chromosome 1p by fluorescence in situ hybridization are an early event in human colorectal tumorigenesis. AB - BACKGROUND & AIMS: Deletions at chromosome 1p have been observed frequently in human colorectal adenocarcinomas, suggesting that loss of genes in this chromosome arm is relevant for tumorigenesis. The aim of this study was to investigate whether 1p deletions are already present in adenomas within selected foci of dysplasia and early cancer using two-color fluorescence in situ hybridization. METHODS: Fifty-one sectors characterized by low- and high-grade dysplasia and early cancer were microdissected from 34 adenomas, and isolated epithelial nuclei were subjected to hybridization with probes to the telomeric and centromeric regions of chromosome 1. RESULTS: Deletions of 1p were detected in 13 of 34 adenomas (38%). In particular, low/moderate and high dysplasia and foci of early cancer had 1p deletion frequencies of 31%, 44%, and 50%, respectively. CONCLUSIONS: Compared with classic cytogenetics, fluorescence in situ hybridization seems to be a particularly useful methodology to detect 1p deletions in human colorectal adenomas. The present findings indicate that loss of genes from the 1p chromosome arm may play an important role during the early steps of the colorectal carcinogenesis. PMID- 8698189 TI - Characterization of excitatory and inhibitory motor neurons to the guinea pig lower esophageal sphincter. AB - BACKGROUND & AIMS: The lower esophageal sphincter is innervated primarily by enteric motor neurons. The somata of excitatory and inhibitory motor neurons were identified and mapped. METHODS: Retrograde labeling in organotypic culture and immunohistochemistry were used to identify motor neuron somata. RESULTS: 1,1' Didodecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate (Dil) on the left side of the sphincter labeled descending motor neurons located up to 26 mm along the esophagus and locally (within 2 mm) and gastric motor neurons. Dil applied to the right side of the sphincter labeled descending and local motor neurons but very few gastric motor neurons. Inhibitory motor neuron cell bodies, identified by nitric oxide synthase immunoreactivity, accounted for 86% +/- 4% (n = 6) of descending motor neurons and 53% +/- 4% of local motor neurons labeled from the right side. Excitatory motor neurons, immunoreactive for choline acetyltransferase, accounted for 20% +/- 3% (n = 6) of descending motor neurons and for 47% +/- 4% of local motor neurons. All motor neurons were unipolar, but inhibitory motor neurons were significantly larger than excitatory neurons. CONCLUSIONS: The lower esophageal sphincter is innervated by local excitatory and inhibitory motor neurons and by descending esophageal inhibitory neurons. The oblique muscle, supplied by gastric motor neurons, is closely associated with the gastroesophageal junction. PMID- 8698190 TI - Protein kinase C isoforms in the chemopreventive effects of a novel vitamin D3 analogue in rat colonic tumorigenesis. AB - BACKGROUND & AIMS: We recently showed that dietary supplementation with an analogue of 1alpha,25-dihydroxy-vitamin D3, 1alpha,25-dihydroxy-16-ene-23-yne 26,27 F6-vitamin D3 (RO24-5531), reduced the incidence of colonic tumors in rats treated with azoxymethane (AOM). The aim of this study was to determine whether alterations in specific isoforms of protein kinase C (PKC) are involved in this phenomenon. METHODS: Protein abundance and subcellular distribution of several PKC isoforms were examined and compared in AOM-induced tumors of rats fed control and RO24-5531-supplemented diets. RESULTS: In both AOM-induced colonic adenomas and carcinomas, a significant down-regulation of PKC-alpha, -delta, and -zeta and an up-regulation of PKC-beta11 were found compared with control colonocytes. Dietary RO24-5531 preserved the expression of PKC-zeta and increased the abundance of PKC-epsilon in carcinogen-induced adenomas. CONCLUSIONS: Because identical changes in specific isoforms of PKC were found in AOM-induced adenomas and carcinomas, these alterations may be involved in the early stage(s) of colonic malignant transformation. Moreover, the ability of RO24-5531 to block the changes in PKC-zeta induced by AOM, as well as to up-regulate PKC-epsilon, may underlie its ability to prevent adenomas from progressing to carcinomas. PMID- 8698192 TI - Transjugular intrahepatic portosystemic shunts for patients with active variceal hemorrhage unresponsive to sclerotherapy. AB - BACKGROUND & AIMS: Despite urgent sclerotherapy, active variceal hemorrhage has a 70%-90% mortality rate in patients with advanced age, sepsis, renal or pulmonary compromise, tense ascites, or deep coma. The aim of this study was to test the safety and efficacy of transjugular intrahepatic portosystemic shunt (TIPS) performed semiemergently and preceded by stabilization by balloon tamponade in such patients. METHODS: Patients with actively bleeding esophageal or contiguous gastric varices despite sclerotherapy were assessed for risk of dying after emergent portacaval shunt. Those considered to be at high risk were stabilized by balloon tamponade and vasopressin/nitroglycerin and TIPS placed semiurgently within 12 hours. Balloon tamponade and pharmacological therapy were discontinued within 24 hours after TIPS in all cases. RESULTS: Thirty-two patients met entry criteria, and 2 were excluded due to portal vein thrombosis. TIPS was successfully placed in 29 of 30 patients and achieved hemostasis in all. Thirty day and 6-week survival rates were 63% and 60%, respectively; in those without aspiration, the 6-week survival rate was 90%. After a median follow-up period of 920 days, 46% of the original cohort was alive. Only 2 episodes of early rebleeding and 4 late rebleeds occurred. Eight patients developed encephalopathy. Stent stenosis requiring dilation occurred in 6 of 11 patients within 6 months. CONCLUSIONS: TIPS is highly effective as salvage therapy in high-risk patients with active variceal hemorrhage despite endoscopic sclerotherapy. PMID- 8698191 TI - Response of phenylalanine and leucine kinetics to branched chain-enriched amino acids and insulin in patients with cirrhosis. AB - BACKGROUND & AIMS: We tested the effects of branched chain-enriched, aromatic deficient amino acids with insulin to correct the altered protein turnover as well as phenylalanine (Phe) and leucine (Leu) rate of appearance in compensated cirrhotics and controls. METHODS: Phe and Leu tracers were infused both before and following intravenous amino acid administration with insulin and euglycemic clamp. RESULTS: In cirrhosis, fasting whole-body protein synthesis and protein degradation were normal; Phe rate of appearance was greater (P<0.05), whereas Leu rate of appearance/Phe rate of appearance ratio was approximately 35% less than in controls (P<0.001). Following the infusion, protein synthesis did not increase (+1% +/ 5% [NS] vs. +21% +/- 5% [P<0.05] in controls); protein degradation was more suppressed, whereas protein balance increased normally. Total Phe rate of appearance (0.91 +/- 0.13 micromol x kg-1 x min-1) and Leu/Phe disposal ratio (3.53 +/- 0.36) were nearly normalized (fasting controls, 0.68 +/- 0.07 micromol x kg-1 x min-1 and 2.87 +/- 0.14 micromol x kg-1 x min-1, respectively; P>0.05). However, Leu/Phe endogenous rate of appearance ration remained approximately 50% less (1.56 +/- 0.31 vs. 2.87 +/- 0.14; P<0.004) than in controls. CONCLUSIONS: Following this combined infusion in cirrhosis, net protein deposition increased normally despite a blunted response of protein synthesis. Phe and Leu to Phe peripheral disposal were near normalized; however, the exaggerated endogenous Phe production was not corrected entirely. PMID- 8698193 TI - Neuropsychiatric profile and hyperintense globus pallidus on T1-weighted magnetic resonance images in liver cirrhosis. AB - BACKGROUND & AIMS: Hyperintense globus pallidus on T1-weighted magnetic resonance images (MRIs) in cirrhotic patients are reported to reflect severity of liver disease; however, their consequence for hepatic encephalopathy is unknown. The aim of this study was to outline a pattern of neuropsychiatric abnormalities in chronic liver failure and its correlation with MRI findings. METHODS: Fifty-one consecutive patients were enrolled in the study. Neuropsychiatric assessment used a standardized protocol, including dichotomized neurological parameters, brief psychiatric rating and psychometric tests, as well as electroencephalography. The severity of liver failure was graded using standard laboratory parameters and the Child-Pugh's classification. Signal intensity of the globus pallidus was determined on sagittal T1-weighted MRIs. RESULTS: Two aspects of neurological dysfunction could be distinguished by principal components analysis: impairment of complex cerebral function and subcortical motor performance. Both neurological categories correlated with severity of liver failure, grade of electroencephalographic abnormalities, and psychometric test results. Additionally, prior bouts of overt encephalopathy indicate progressive dementia. T1-weighted globus pallidus signal intensity did not correlate with any clinical or laboratory test result. CONCLUSIONS: This study shows a characteristic pattern of neurological findings in patients with liver failure and hyperintense globus pallidus on T1-weighted MRIs. Although neurological dysfunction parallels hepatic failure, MRI abnormalities of basal ganglia do not indicate severity of actual hepatic encephalopathy. PMID- 8698194 TI - Apoptosis observed in peripheral T lymphocytes from patients with chronic hepatitis B. AB - BACKGROUND & AIMS: Activation-induced cell death is involved in regulating peripheral T-cell function. Understanding the kinetics of these T cells is important to elucidate the pathogenesis of chronic hepatitis B, which is mediated by cellular immune mechanisms. METHODS: Subtle apoptotic cells in CD3+ cells were discriminated by flow-cytometric assay using freshly obtained and in vitro recombinant hepatitis B core antigen-stimulated peripheral lymphocytes from patients with chronic hepatitis. RESULTS: The ratio of apoptotic cells in freshly obtained CD3+ cells was significantly higher during the decreasing phase than increasing phase of serum alanine aminotransferase activity in each patient, and apoptosis of CD3+ cells was induced by stimulation with recombinant hepatitis B core antigen. CONCLUSIONS: Activation-induced cell death in peripheral T cells was found in chronic hepatitis B virus infection, similar to some other viral infections. The apoptosis in T cells during the decreasing phase of serum alanine aminotransferase activity results in a vast amount of T-cell deletion that may weaken T-cell function of cytotoxicity over hepatitis B virus-infected hepatocytes. Thus, activation-induced cell death is considered an important modulator in down-regulating the "burst" of responding T cells in patients with chronic hepatitis B. PMID- 8698195 TI - Effects of Ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene. AB - BACKGROUND & AIMS: The mouse mdr2 gene encodes a P-glycoprotein expressed in the hepatocanalicular membrane. Inactivation of this gene causes lack of biliary phospholipid and cholesterol secretion and non-suppurative cholangitis. The aim of this study was to investigate the role of bile salt hydrophobicity in induction of liver pathology in mdr2 (-/-) mice. METHODS: Mice (+/+) wild type or (-/-) knockout for the mdr2 gene were fed with either purified control diet or this diet supplemented with cholate (0.1%) or ursodeoxycholate (0.5%) for 3, 6, or 22 weeks after weaning. Liver histology was semiquantitatively scored. RESULTS: Each mouse fed bile acid became the major constituent of the bile salt pool. The cholate diet during 22 weeks induced only very mild liver pathology in (+/+) mice. By contrast, lever histology had already deteriorated after 3 weeks in the (-/-) mice and caused pronounced inflammatory nonsuppurative cholangitis and fibrosis in the 75% of mice that survived. Dietary ursodeoxycholate had no effect on histology in (+/+) mice but improved liver pathology significantly in ( /-) mice compared with purified control diet; the decrease of ductular proliferation and portal inflammation was most prominent after 22 weeks. CONCLUSIONS: The cholangiolitis and its sequelae in the mdr2 knockout mice depend on bile salt hydrophobicity. PMID- 8698196 TI - Mechanism of collagen network stabilization in human irreversible granulomatous liver fibrosis. AB - BACKGROUND & AIMS: Cross-linking participates in the increased stability of collagen towards proteolytic degradation. Liver collagen cross-linking by pyridinoline, from the lysyl oxidase pathway, and by pentosidine, issued from glycation, was investigated to determine their respective contribution to collagen stabilization in patients with an irreversible liver fibrosis caused by the parasitic granulomatous disease alveolar echinococcosis. METHODS: Liver pyridinoline and pentosidine were analyzed by high-performance liquid chromatography, and urinary pyridinoline was analyzed by immunoassay. Cross linked type I collagen was localized by immunohistochemistry with an antibody against the C-terminal part of the molecule, involved in pyridinoline formation, that was measured in serum by radioimmunoassay. RESULTS: In contrast to pyridinoline, pentosidine decreased in fibrotic lesions. Cross-linked I collagen was located predominantly in collagen bundles in the periparasitic granuloma. Serum pentosidine and urinary pyridinoline levels did not differ significantly from controls, but the serum concentration of the C-terminal telopeptide of type I collagen increased significantly. CONCLUSIONS: Lysyl oxidase-mediated cross linking is the major process contributing to the stabilization of collagen in granulomatous fibrosis, and glycation is not significantly involved in it. The changes induced by alveolar echinococcosis in liver collagen metabolism are associated with an increase in serum C-telopeptide of type I collagen. PMID- 8698197 TI - Hepatitis B virus variants with core gene deletions in the evolution of chronic hepatitis B infection. AB - BACKGROUND & AIMS: Genomic variants of the hepatitis B virus (HBV) with core gene deletions have been identified in patients with chronic active hepatitis B, but the significance of these mutations in the course of chronic HBV infection remains unknown. The aim of this study was to longitudinally analyze the changes of HBV core gene deletion variants under the enhanced immune pressure of interferon alfa treatment and hepatitis B e antigen (HBeAg) to antibody to hepatitis B e antigen (anti-HBe) seroconversion. METHODS: HBV precore/core gene was amplified in 358 serum samples from 67 chronic HBV carriers (all HBeAg positive) followed up for a period of 2-11 years. The core gene deletions were analyzed by gel electrophoresis, cloning, and DNA sequencing. RESULTS: HBV mutants with core gene deletions (37-250 base pairs) were detected in patients with long-standing HBV replication and ongoing hepatic inflammation, always together with the wild-type strain. They were associated with a significantly lower level of viremia and a high rate of seroconversion to anti-HBe. Core gene deletion mutants were preferentially eliminated after seroconversion, in contrast to the accumulation of HBV strains with a precore stop codon. CONCLUSIONS: These data indicate that HBV variants with core gene deletions may inhibit HBV replication, do not persist in preference of the wild-type HBV under enhanced immune pressure, and do not confer resistance to interferon alfa treatment. PMID- 8698198 TI - Association between Helicobacter and gastric ulcer disease of the pars esophagea in swine. AB - BACKGROUND & AIMS: Swine present spontaneously peptic ulcer in the gastric pars esophagea and are frequently colonized by a spiral bacterium that is of the same species as Helicobacter heilmannii type 1. This organism is also observed in the gastric mucosa of patients with gastric symptoms and who present with gastritis at histology. The aim of this study was to investigate the association between the presence of H. heilmannii type 1 and lesions of the pars esophagea. METHODS: H. heilmannii type 1 infection was investigated by mouse inoculation, urease test, and carbolfuchsin stain in 20 stomachs with ulcer, 30 stomachs with preulcer lesions, and 20 stomachs with a macroscopically normal pars esophagea. RESULTS: The microorganism was more frequently found in the stomachs with ulcer (100%) and in those with preulcer lesions (90%) than in stomachs with macroscopically normal pars esophagea (35%). Histological alterations were observed in the pars esophagea and in the glandular regions of bacterium-positive stomachs. CONCLUSIONS: It has been shown that the microorganism is strongly associated with naturally occurring ulcer and preulcer lesions of the pars esophagea of swine, which raises the possibility that the bacterium is an important factor in the pathogenesis of these lesions. PMID- 8698199 TI - Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents. AB - BACKGROUND & AIMS: Pathophysiological conditions such as sepsis and hepatitis are mediated by inflammatory cytokines and frequently are associated with cholestasis. The aim of this study was to determine the effect of endotoxin (lipopolysaccharide [LPS]) and cytokine administration on hepatocellular transporters involved in bile salt transport. METHODS: LPS and cytokines were administered to Sprague-Dawley rats or C57BL/6 mice, and the expression and function of hepatocyte transporters involved in bile salt secretion were examined. RESULTS: LPS caused gene expression of the hepatocyte basolateral sodium-dependent taurocholate cotransporter (Ntcp) to decrease by more than 90%. Tumor necrosis factor alpha (TNF-alpha) or interleukin (IL) 1beta also produced a time-dependent decrease in Ntcp messenger RNA levels, whereas IL-6 had no effect. LPS administration resulted in a concordant 90% reduction of basolateral protein expression of the hepatocyte sodium taurocholate cotransporter and markedly diminished sodium-dependent taurocholate uptake. Activity of the hepatocyte basolateral Na+,K+-adenosine triphosphatase (ATPase) was also decreased by 50% in a posttranslational manner after endotoxin treatment. CONCLUSIONS: Endotoxin inhibits hepatocellular sodium-dependent bile salt uptake by decreasing both expression of Ntcp and activity of the Na+,K-ATPase. The effects on Ntcp are mediated via TNF-alpha and IL-1beta. Alterations of these transporters may contribute to the cholestasis of sepsis and inflammation. PMID- 8698200 TI - Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: a case-control study. AB - BACKGROUND & AIMS: Viral genotypes have been associated with different severity and outcome of hepatitis C virus (HCV)-related liver disease. The aim of this study was to determine whether HCV genotypes may influence the cirrhosis-related risk of the development of hepatocellular carcinoma (HCC). METHODS: Three groups of patients were studied: 593 patients with chronic hepatitis, 166 patients with HCC and cirrhosis, and 219 patients with cirrhosis but without HCC. A cross sectional study of frequency distribution and a case-control analysis were performed. HCV genotypes were detected according to Okamoto. RESULTS: HCV type 1b infection was more prevalent among patients with HCC compared with patients with cirrhosis but without HCC (P < 0.01) and chronic hepatitis (P < 0.001). Age, male sex, and HCV type 1b significantly influenced the risk of cancer in cirrhosis by univariate analysis. A pairwise comparison performed on 162 patients with HCC and an equal number of patients with cirrhosis matched by age, sex, and Child's class showed that HCV type 1b was independently associated with HCC (odds ratio, 1.7; P = 0.026). CONCLUSIONS: HCV type 1b is overrepresented in patients with cirrhosis and HCC and significantly influences the risk of HCC in cirrhosis, independent of sex, age, and Child's class. PMID- 8698201 TI - Cytochrome P4502E1 hydroxyethyl radical adducts as the major antigen in autoantibody formation among alcoholics. AB - BACKGROUND & AIMS: We have previously reported that alcoholics have increased titers of immunoglobulins reacting with protein adducts of hydroxyethyl free radicals. Because hydroxyethyl radicals are produced during ethanol metabolism by liver microsomes, the aim of this study was to determine whether such antibodies recognize microsomal proteins complexed with hydroxyethyl radicals. METHODS: Liver microsomal proteins reacting with the anti-hydroxyethyl radical antibodies were characterized by an enzyme-linked immunosorbent assay and Western blotting. RESULTS: Alcoholic cirrhotics, but not patients with nonalcoholic cirrhosis or healthy subjects, had increased serum levels of immunoglobulin G and A directed against antigens produced in microsomes incubated with reduced nicotinamide adenine dinucleotide phosphate (NADPH) and ethanol. Such immunoreactivity was completely blocked when microsomes were incubated with ethanol in the presence of the spin-trapping agent 4-pyridyl-1-oxide-t-butyl nitrone or by preincubating the sera with hydroxyethyl radical-bound human albumin. Immunoblotting of proteins from human liver microsomes incubated with NADPH and ethanol showed that 86% of the sera from alcoholic cirrhotics reacted with a 52-kilodalton protein, whereas variable reactivity was observed with proteins of 78, 60, and 40 kilodaltons, respectively, The 52-kilodalton protein was identified by immunoblotting and immunoprecipitation as ethanol-inducible cytochrome P4502E1. CONCLUSIONS: Antibodies from alcoholic cirrhotics specifically recognized hydroxyethyl radical cytochrome P4502E1 adducts, suggesting the possible implication of these antigens in the development of autoimmune reactions in alcoholic liver disease. PMID- 8698202 TI - Fasting-related hyperbilirubinemia in rats: the effect of decreased intestinal motility. AB - BACKGROUND & AIMS: Fasting increases serum bilirubin levels in both humans and rats. Because the pathogenesis of fasting hyperbilirubinemia is not fully understood, the effect of fasting on disposition of bile pigments was investigated in rats. METHODS: Bilirubin and urobilinogen were determined in excreta, bile, plasma, and liver tissues of fasted Gunn and Wistar rats. RESULTS: Fasting increased the intestinal transit time of Wistar rats. As a result, the fecal output of bile pigments was decreased by food deprivation. In contrast, the intestinal content of total bile pigments was augmented in both Wistar and Gunn rats. This finding was paralleled by the increase of serum bilirubin concentration in both rat strains. A similar increment of serum bilirubin levels was observed after injection of bilirubin into the cecum of Wistar rats. Furthermore, biliary efflux of bilirubin in Wistar rats was increased after 48 hours of fasting. Intubation of nonabsorbable bulk to fasted Wistar rats prevented the increase of serum bilirubin levels during a 48-hour period of food deprivation. CONCLUSIONS: Fasting decreases intestinal motility and elimination of bile pigments. Accumulation of bilirubin in the intestine during fasting allows enhanced enterohepatic circulation and results in an increased reflux to plasma. This seems to be a major factor involved in fasting-induced hyperbilirubinemia. PMID- 8698203 TI - Course of alcoholic chronic pancreatitis: a prospective clinicomorphological long term study. AB - BACKGROUND & AIMS: The pathogenesis of alcoholic chronic pancreatitis and its relationship to alcoholic acute pancreatitis are debated. According to our recent clinical long-term study, alcoholic chronic pancreatitis seems to evolve from severe acute pancreatits. The aim of this study was to correlate clinical findings to the pancreatic histopathology at early and advanced stages of the disease. METHODS: Morphological changes (pseudocysts, autodigestive necrosis, calcification, and perilobular and intralobular fibrosis) were recorded in 37 surgical and 46 postmortem pancreas specimens of 73 patients from our long-term series, who progressed from clinically acute to chronic pancreatitis (mean follow up, 12 years). Pancreatic function was monitored at yearly intervals. RESULTS: Surgical interventions were performed at a mean of 4.1 years from onset. Histologically, focal necrosis (49%) and mild perilobular fibrosis (54%) predominated, Pseudocysts (n = 41, mostly postnecrotic) occurred in 88% within 6 years from onset. Autopsy specimens were obtained at a mean of 12 years. These pancreata often showed severe perilobular and intralobular fibrosis (85%) and calcifications (74%), but rarely necrosis (4%). Fibrosis correlated with progressive pancreatic dysfunction (P < 0.001), particularly in the 10 patients with two histological assessments (mean interval between biopsy and autopsy, 8 years). CONCLUSIONS: The data support an evolution from severe alcoholic acute pancreatitis to chronic pancreatitis. PMID- 8698204 TI - Preneoplastic lesions and gallbladder cancer: an estimate of the period required for progression. AB - BACKGROUND & AIMS: Scarce biological information exists about the importance of preneoplastic lesions in gallbladder cancer. The aim of this study was to estimate the time required for the sequence of dysplasia (DY) to carcinoma of the gallbladder. METHODS: Eighty-four cases of DY, 60 cases of early carcinomas (ECs), 181 cases of advanced carcinomas (ACs), and 121 cases of metastatic (ME) gallbladder cancer were analyzed. Age was used as the main parameter. Statistical analysis was performed using analysis of variance and multiple regression analysis. RESULTS: Among all cases, the mean age of female patients was lower than the mean age of male patients (P = 0.001). A significant difference in mean age between sexes by specific type of lesion was also observed (P < 0.001). The mean age was 46.3 years (SD, 16) in the DY group, 57.5 years (SD, 16.7) in the EC group, 59 (SD, 13.7) in the AC group, and 61.1 (SD, 12.1) in the ME group. Multiple regression analysis showed statistically significant differences (r = 0.386; P < 0.001) in the mean age of patients with dysplastic lesions compared with the carcinoma group. CONCLUSIONS: According to these observations, the period required to progress from dysplasia to advanced gallbladder carcinoma would be around 15 years, observing a continuum in the progression of the lesions. PMID- 8698205 TI - Treatment of pediatric autoimmune enteropathy with tacrolimus (FK506). AB - Autoimmune enteropathy is characterized by chronic secretory diarrhea, villous atrophy, associated autoantibodies, and a partial response to immunosuppression. Currently available therapy (including steroids and cyclosporine) has resulted in remission only in a subset of patients. We evaluated the effects of tacrolimus (FK506) in patients with autoimmune enteropathy refractory to steroids and cyclosporine. Three patients with diagnosed autoimmune enteropathy who continued to have intractable diarrhea despite treatment with steroids and/or cyclosporine were treated with oral tacrolimus. Despite documented histological villous atrophy and poor absorption of oral cyclosporine, therapeutic tacrolimus levels were easily achieved in all 3 patients. All patients showed clinical improvement as documented by decreased stool output and ability to be weaned off parenteral nutrition; response time ranged from 1 to 4 months after tacrolimus was begun. Histological improvement was noted in all patients, and the small bowel biopsy specimens of 2 of the 3 patients showed a return to normal. All patients have been followed up for at least 6 months and are in clinical remission; 1 has received a bone marrow transplant for underlying immunodeficiency. Tacrolimus is a useful drug in the treatment of autoimmune enteropathy, even in patients who have not responded to steroids or cyclosporine. No long-term follow-up of patients with autoimmune enteropathy treated with tacrolimus is currently available. PMID- 8698206 TI - Helicobacter heilmannii (formerly Gastrospirillum): association with pig and human gastric pathology. PMID- 8698207 TI - Shedding some light on high-grade dysplasia. PMID- 8698208 TI - A role for chromosome 1 in colorectal cancer. PMID- 8698209 TI - Branched chains revisited. PMID- 8698210 TI - Neurological deficits in "awake" cirrhotic patients on hepatic encephalopathy treatment: missed metabolic or metal disorder? PMID- 8698211 TI - Role of the necrosis-fibrosis sequence in the pathogenesis of alcoholic chronic pancreatitis. PMID- 8698212 TI - Fibrosing colonopathy in cystic fibrosis: results of a case-control study. PMID- 8698213 TI - Cadherins, inflammatory bowel disease, and neoplasia. PMID- 8698214 TI - Lamivudine: a magic bullet for chronic hepatitis B? PMID- 8698215 TI - Risk factors in patients with refractory peptic ulcer. PMID- 8698216 TI - Gastrin gene products and gastrin receptors in colon cancer. PMID- 8698217 TI - Chronic unexplained diarrhea in human immunodeficiency virus infection: determination of the best diagnostic approach. PMID- 8698218 TI - Helicobacter gastritis in mice. PMID- 8698219 TI - Variant liver estrogen and response to tamoxifen. PMID- 8698220 TI - Tamoxifen treatment in hepatocellular carcinoma. PMID- 8698222 TI - The American Gastroenterological Association: second century of leadership. PMID- 8698221 TI - Epidermal growth factor promotes rapid response to epithelial injury in rabbit duodenum in vitro. AB - BACKGROUND & AIMS: Growth factors are mainly involved in the regulation of intestinal epithelial barrier function. This study investigated the effect of epidermal growth factor (EGF) and insulin-like growth factor 1 (IGF-1) on epithelial restitution of rabbit duodenum in vitro. METHODS: Rabbit duodenal mucosal strips mounted in an Ussing chamber were luminally exposed to 10 mmol/L HCl for 10 minutes and then incubated with buffer alone or luminal buffer containing various concentrations of EGF and IGF-1 for 3 hours. Resistance was calculated from potential difference and short-circuit current. Damage was assessed by morphometry on H&E-stained sections. RESULTS: HCl caused resistance to decrease from 112 +/- 2 to 51 +/- 4 ohms x cm2 10 minutes after injury (n = 6; P < 0.05). Postinjury treatment with 25 or 50 ng/mL luminal EGF for 3 hours stimulated resistance to recover to 94 +/- 3 and 104 +/- 3 ohms x cm2, respectively, vs. 81 +/- 3 omega x cm2 in controls (P < 0.05). Ten minutes after injury, 62% of the mucosa was damaged; 3 hours after injury, damage was reduced to 24% +/- 1.09% and 10% +/- 1.42% in the 25 and 50 ng/mL EGF group, respectively, vs. 38% +/- 0.93% in controls (n = 6 per group). EGF stimulated enterocyte migration. IGF-1 did not impair epithelial restitution. CONCLUSIONS: EGF, but not IGF-1, promoted epithelial restitution of rabbit duodenum in vitro. PMID- 8698223 TI - Dependence of epithelial growth of the small intestine on T-cell activation during weaning in the rat. AB - BACKGROUND & AIMS: Intestinal crypt hyperplasia is associated with local T-cell activation in both clinical and experimental examples of immunologically mediated enteropathy. This suggests that T cell-derived factors may be trophic for epithelial proliferation in the intestine postnatally. The purpose of this study was to investigate T-cell activity during weaning in the rat and to investigate immune dependence of intestinal growth on T-cell activation. METHODS: The expression of interleukin-2 receptor (IL-2R) by mesenteric lymph node T cells was investigated from days 14 to 160 of life. Rats were treated with monoclonal antibodies against the IL-2R that were nonblocking (control) or blocking (experimental) from day 7, and intestinal growth was assessed at days 19, 25, and 29 of life. RESULTS: The mean +/- SEM of T cells expressing the IL-2R during weaning (days 15-28) was 6.1% +/- 0.3% compared with 3.3% +/- 0.3% at other ages (P < 0.001). The small intestine in rats treated with blocking antibody had reduced crypt length and mitotic count compared with control animals. CONCLUSIONS: Weaning is associated with activation of T cells and blockade of the IL-2R reduces intestinal growth. PMID- 8698224 TI - Reg gene expression is increased in rat gastric enterochromaffin-like cells following water immersion stress. AB - BACKGROUND & AIMS: Reg gene has been isolated from regenerating rat pancreatic islets, and subsequent studies have shown a trophic effect of Reg protein on islet cells. However, little is known about the role of Reg protein in the stomach. The aim of this study was to clarify the localization of Reg messenger RNA (mRNA) and its product in the stomach and to examine changes in the level of their expression during regeneration of gastric mucosal cells. METHODS: Gastric lesions were experimentally induced in Sprague-Dawley rats by water immersion stress. Northern blot analysis and in situ hybridization studies were performed to examine changes in mRNA levels. Immunohistochemical studies were performed to identify the cellular localization and to investigate the change in Reg protein level. RESULTS: Reg mRNA and its product were distributed in the basal part of the oxyntic mucosa and were expressed mainly in enterochromaffin-like cells. Levels of both Reg mRNA and its product were markedly increased in the water immersion-induced gastric lesions. CONCLUSIONS: Reg mRNA and its product are expressed in gastric enterochromaffin-like cells, and their levels are increased during the healing process of water immersion-induced gastric lesions. PMID- 8698225 TI - Colitis and interleukin 1beta up-regulate inducible nitric oxide synthase and superoxide dismutase in rat myenteric neurons. AB - BACKGROUND & AIMS: Manganese superoxide dismutase (MnSOD) is rapidly induced in myenteric plexus neurons (MPNs) in acute colitis and may protect cells from nitric oxide toxicity. Inducible nitric oxide synthase (iNOS) regulation was examined in acute colitis, and MnSOD and iNOS were examined in primary cultures of MPNs. METHODS: Acute colitis in rats was induced with 5% acetic acid. iNOS messenger RNA (mRNA) was analyzed by Northern analysis, and reduced nicotinamide adenine dinucleotide phosphate diaphorase was used to identify potential NO synthase activity. MnSOD and iNOS mRNA levels were evaluated in cultured MPNs after treatment with tumor necrosis factor alpha, interleukin (IL) 1beta, or IL 6. iNOS and MnSOD protein expression in control and IL-1beta-treated neurons was evaluated by immunofluorescence microscopy. RESULTS: iNOS mRNA was detected in the mucosal and muscularis layers after the initiation of colitis. Reduced nicotinamide adenine dinucleotide phosphate diaphorase localized NO synthase activity to MPNs in controls and in epithelial cells and MPNs in the inflamed colon. In MPN cultures, tumor necrosis factor alpha and IL-1beta treatment resulted in induction of MnSOD, but only IL-1beta induced iNOS. Immunolocalization confirmed that the neurons were the primary source of iNOS and MnSOD. CONCLUSIONS: Induction of MnSOD and iNOS are coordinated and may limit NO cytotoxicity. The function of iNOS in gut neurons remains to be delineated. PMID- 8698226 TI - Role of calcium in nitric oxide-mediated injury to rat gastric mucosal cells. AB - BACKGROUND & AIMS: Perturbations in Ca2+ homeostasis as well as high levels of nitric oxide have been associated with gastric cellular injury. The purpose of this study was to examine whether high levels of endogenous or exogenous NO damage gastric cells by altering intracellular Ca2+. METHODS: Epithelial cells were isolated from the rat stomach, and cell integrity was estimated by trypan blue exclusion and alamar blue dye absorption. Cytosolic intracellular Ca2+ concentrations ([Ca2+]i) were determined by indo-1 dye fluorescence. NO synthase activity was assessed radioenzymatically. RESULTS: Induction of Ca2+-independent NO synthase in response to endotoxin challenge resulted in decreased viability and an increase in [Ca2+]i in gastric mucosal cells. These responses were ameliorated by pretreatment with NG-nitro-L-arginine methyl ester or dexamethasone. Treatment of cells with the NO donor S-nitrosoacetyl-penicillamine also decreased cell integrity and increased [Ca2+]i. The actions of S-nitroso acetyl-penicillamine could be reduced by decreasing intracellular or extracellular Ca2+, by chelating Ca2+ with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid or 1,2,-bis(2-aminophenoxy)ethane-N,N,N,N' tetraacetic acid acetoxymethyl ester, by Ca2+ channel antagonism (nifedipine), or by displacing surface-bound Ca2+ (lanthanum). Furthermore, cell damage was reduced by inhibiting protein kinase C activity with either H-7 or staurosporine. CONCLUSIONS: Excessive levels of NO from either endogenous or exogenous sources results in a reduction in gastric cellular viability. This response seems to be related causally to an increase in [Ca2+]i and protein kinase C activation. PMID- 8698227 TI - Lymphocytic gastritis and gastric permeability in patients with celiac disease. AB - BACKGROUND & AIMS: Lymphocytic gastritis is associated with celiac disease. Gastric permeability can now be assessed by a sucrose test, and intestinal permeability measured by a lactulose/mannitol test is increased in untreated celiac patients. The aim of this study was to prospectively compare gastric and intestinal permeability with histological changes of the stomach and small bowel in patients with celiac disease. METHODS: Gastric and intestinal permeability were measured by oral or duodenal (during endoscopy) administration of a triple sugar solution containing 20 g sucrose, 10 g lactulose, and 5 g mannitol in 100 mL water in 43 adult patients with celiac disease (28 without diet) and in 30 healthy controls. Endoscopical biopsy specimens were taken from the antrum and distal duodenum and investigated for intraepithelial lymphocyte counts. RESULTS: Urinary sucrose excretion decreased after duodenal administration (n = 8) as opposed to oral administration and thus measured gastric permeability in celiac disease. Gastric permeability was elevated in 60% of the celiac patients and correlated with antral intraepithelial lymphocyte counts. Intestinal permeability (measured by a lactulose/mannitol test) was also elevated in 69% of the celiac patients and correlated with duodenal intraepithelial counts. CONCLUSIONS: There is a high prevalence of lymphocytic gastritis in untreated celiac disease associated with elevated gastric permeability. Celiac disease seems to be a general disorder of the gastrointestinal tract associated with disturbed permeability. PMID- 8698228 TI - Tonic endogenous opioid inhibition of visceral noxious information in rabbits. AB - BACKGROUND & AIMS: A tonic intrinsic spinal inhibitory system on spinal motor reflexes in rabbits has been shown earlier. The aim of this study was to examine the effects of different opioid antagonists against visceral noxious stimulation in awake rabbits. METHODS: The opioid receptor antagonists examined were naloxone (nonselective), MR2266 (kappa), and naltrindole (delta). The effects on the visceromotor response thresholds induced by colorectal distention in rabbits were determined after intrathecal and intramuscular administration of the antagonists. RESULTS: Intrathecal naloxone resulted in a dose-dependent decrease of visceromotor response thresholds. The selective antagonists MR2266 and naltrindole had no significant effects. In the presence of MR2266, intrathecal naloxone reduced thresholds to the same degree as when given alone. Analysis of the data from all rabbits showed a statistically significant reduction in visceromotor response thresholds after intrathecal naloxone compared with intramuscular administration. CONCLUSIONS: In rabbits, tonic active intrinsic spinal and supraspinal endogenous opioids modulate visceral noxious information. This inhibition is exerted at the mu opioid receptor. PMID- 8698229 TI - Immunologic, functional, and morphological characterization of three new human small intestinal epithelial cell lines. AB - BACKGROUND & AIMS: Epithelial cell cultures can be used for the study of epithelial cell biology, although human small intestinal cultures have not been available to date. The aim of this study was to characterize three cell lines derived from normal human duodenum. METHODS: Cells were cultured from tissue fragments obtained from endoscopic biopsy specimens and characterized with respect to morphology and cytokine gene expression and for the presence of vectorial transport. RESULTS: All cell lines grew as polarized continuous monolayers and were mostly cuboidal in shape but were not immortalized. Cells showed junctional complexes and sparse microvilli. All cell lines showed cytokeratins and mucin antigen but not chromagranin and messenger RNA for epidermal growth factor, interleukin 6, and vascular cell adhesion molecule 1. Disaccharidase activities were low and correlated with the low proportion of cells (1%-10%), showing positive immunocytochemistry for sucrase. Monolayer resistance varied from 30 to 200 ohms. One monolayer (BN) consistently showed secretion in response to forskolin (10 micromol/L), which could b inhibited by chloride-free buffer and apical addition of the chloride channel blocker diphenylamine decarboxylate. No monolayer had evidence of glucose transport. CONCLUSIONS: These three nonimmortalized lines show morphological, phenotypic, and transport characteristics of crypt-like intestinal epithelial cells. The pattern of messenger RNA expression suggests a growth-promoting and immunomodulatory role. PMID- 8698230 TI - The endoscopic assessment of esophagitis: a progress report on observer agreement. AB - BACKGROUND & AIMS: The study and management of reflux esophagitis require an endoscopic classification system founded on esophageal lesions that can be reproducibly identified. The aim of this study was to investigate interobserver agreement for the identification of endoscopic lesions typical of reflux esophagitis. METHODS: Paired comparisons of observers' descriptions were obtained. Seventeen endoscopists assessed 100 still images, and 42 endoscopists, including 13 endoscopists in training, assessed 23 endoscopic video recordings. In a third, ancillary study, using a simpler evaluation sheet, 219 gastroenterologists recorded their assessments of 20 still images. RESULTS: The agreement between endoscopists was similar for still images and video recordings. Agreement between experienced endoscopists was acceptable to good for recognition of minimal changes (erythema, friability, mucosal edema; kappa = 0.46 to kappa = 0.8), mucosal breaks (discretely, demarcated areas of slough or erythema; kappa = 0.84), and complications (ulceration, kappa = 0.92; stricturing, kappa = 0.80; columnar metaplasia, kappa = 0.81), although there was poor agreement when the circumferential extent and number of mucosal breaks were assessed. However, total circumferential extent of the mucosal break had a kappa value of 0.59. Agreement between inexperienced endoscopists was poor for recognition of minimal changes but was good for recognition of complications (kappa, 0.70-0.90). CONCLUSIONS: Endoscopists can identify mucosal breaks confined to a mucosal fold and lesions that extend throughout the esophageal circumference. Complications of reflux disease can be reproducibly recorded. Criteria for assessing the number of mucosal breaks and their radial extent must be defined more clearly, as must the features of minimal change esophagitis. PMID- 8698231 TI - Endoscopic fluorescence detection of high-grade dysplasia in Barrett's esophagus. AB - BACKGROUND & AIMS: Early detection and treatment of esophageal cancer in Barrett's esophagus may improve patient survival if dysplasia is effectively detected at endoscopy. Typically, four-quadrant pinch biopsy specimens are taken at 2-cm intervals. This study was conducted to determine whether laser-induced fluorescence spectroscopy could be used to detect high-grade dysplasia in patients with Barrett's esophagus. METHODS: Four hundred ten-naonometer laser light was used to induce autofluorescence of Barrett's mucosa in 36 patients. The spectra were analyzed using the differential normalized fluorescence (DNF) index technique to differentiate high-grade dysplasia from either low-grade or nondysplastic mucosa. Each spectrum was classified as either premalignant or benign using two different DNF indices. RESULTS: Analysis of the fluorescence spectra from all patients collectively using the DNF intensity at 480 nm (DNF480) index showed that 96% of nondysplastic Barrett's esophagus samples were classified as benign, all low-grade dysplasia samples as benign, 90% of high grade dysplasia samples as premalignant, and 28% of low-grade with focal high grade dysplasia samples as premalignant. Using the two DNF indices concurrently, all patients with any high-grade dysplasia were classified correctly. CONCLUSIONS: Laser-induced fluorescence spectroscopy has great potential to detect high-grade dysplasia in Barrett's esophagus when using the DNF technique. PMID- 8698232 TI - Intercellular signaling and the polarization of body axes during Drosophila oogenesis. PMID- 8698233 TI - Loss of plectin causes epidermolysis bullosa with muscular dystrophy: cDNA cloning and genomic organization. AB - Plectin is a widely expressed high molecular weight protein that is involved in cytoskeleton-membrane attachment in epithelial cells, muscle, and other tissues. The human autosomal recessive disorder epidermolysis bullosa with muscular dystrophy (MD-EBS) shows epidermal blister formation at the level of the hemidesmosome and is associated with a myopathy of unknown etiology. Here, plectin was found to be absent in skin and cultured keratinocytes from an MD-EBS patient by immunofluorescence and immunoprecipitation, suggesting that plectin is a candidate gene/protein system for MD-EBS mutation. The 14800-bp human plectin cDNA was cloned and sequenced. The predicted 518-kD polypeptide has homology to the actin-binding domain of the dystrophin family at the amino terminus, a central rod domain, and homology to the intermediate filament-associated protein desmoplakin at the carboxyl terminus. The corresponding human gene (PLEC1), consisting of 33 exons spanning >26 kb of genomic DNA was cloned, sequenced, and mapped to chromosomal band 8q24. Homozygosity by descent was observed in the consanguineous MD-EBS family with intragenic plectin polymorphisms. Direct sequencing of PCR-amplified plectin cDNA from the patient's keratinocytes revealed a homozygous 8-bp deletion in exon 32 causing a frameshift and a premature termination codon 42 bp downstream. The clinically unaffected parents of the proband were found to be heterozygous carriers of the mutation. These results establish the molecular basis of MD-EBS in this family and clearly demonstrate the important structural role for plectin in cytoskeleton-membrane adherence in both skin and muscle. PMID- 8698234 TI - Interactions between wild-type and mutant prion proteins modulate neurodegeneration in transgenic mice. AB - Transgenic mice overexpressing approximately eightfold the mouse (Mo) prion protein (PrP) gene carrying the P102L mutation of GSS developed neurodegeneration between 150 and 300 days of age, while controls expressing the wild-type MoPrP-A transgene at the same level remained healthy. Mice overexpressing the wild-type MoPrP-A transgene were highly susceptible to inoculated mouse prions, exhibiting abbreviated scrapie incubation times of 45 days. After crossing the mutant transgene onto a null (Prnp 0/0) background, the resulting Tg(MoPrP-P101L)Prnp 0/0 mice displayed a highly synchronous onset of illness at 145 days of age, which was shortened to 85 days upon breeding to homozygosity for the transgene array. Besides occasional PrP plaques and modest spongiform degeneration, Tg(MoPrP-P101L) mice suffered from a myopathy and a peripheral neuropathy. Disruption of the wild-type MoPrP gene increased the number of PrP plaques and the severity of spongiform degeneration. Brain extracts prepared from spontaneously ill transgenic mice transmitted disease to Tg196/Prnp 0/0 mice, expressing low levels of the mutant transgene. Our results demonstrate that the presence of wild-type PrP genes, the level of PrP transgene expression, and the sequence of the transgene can profoundly modify experimental prion disease. PMID- 8698235 TI - Tst-1/Oct-6/SCIP regulates a unique step in peripheral myelination and is required for normal respiration. AB - The terminal differentiation of myelinating glia involves complex interactions that culminate in the formation of myelin. The POU domain transcription factor Tst-1/Oct-6/SCIP is expressed transiently during myelination, and we report here that it has a critical role in this developmental process. Deletion of the Tst 1/Oct-6/SCIP gene produces a severe defect in peripheral myelination by arresting Schwann cell maturation before axonal wrapping. Unexpectedly, the activation of major myelin-specific genes appears to be unaffected by the Tst-1/Oct-6/SCIP mutation, demonstrating that multiple, independently regulated events are required for terminal differentiation of Schwann cells. In addition, aberrant differentiation and migration of specific neurons in Tst-1/Oct-6/SCIP mutant homozygotes is associated with a fatal breathing defect, providing a model for investigating the regulation of pulmonary homeostasis. PMID- 8698236 TI - Differential splicing-in of a proline-rich exon converts alphaNAC into a muscle specific transcription factor. AB - NAC (nascent polypeptide-associated complex) was recently purified as an alpha/beta heterodimeric complex binding the newly synthesized polypeptide chains as they emerge from the ribosome. We have identified, cloned, and characterized a muscle-specific isoform of alphaNAC. The 7.0-kb mRNA arises from differential splicing-in of a 6.0 kb-exon giving rise to a proline-rich isoform that we termed skNAC. The skNAC protein was specifically expressed in differentiated myotubes but not in myoblasts. We have identified a specific DNA binding site for skNAC and shown that it can activate transcription through that element. The murine myoglobin promoter contains three putative skNAC-binding sites. skNAC was shown to activate transcription from the myoglobin promoter, and site-specific mutation of the skNAC response elements abrogated skNAC-dependent activation. We also examined the role of the NAC isoforms in the myogenic program. Whereas overexpression of alphaNAC prevented C2C12 differentiation and myotube fusion, the overexpression of skNAC in C2C12 myoblasts led to early fusion of the cells into gigantic myosacs, suggesting that skNAC may be involved in normal differentiation along the myogenic lineage and in the regulation of myoblast fusion. Our data demonstrate that differential splicing converts alphaNAC into a tissue-specific DNA-binding activator and suggest that this regulation may be an important event in the proper control of gene expression during myogenic differentiation. PMID- 8698237 TI - grim, a novel cell death gene in Drosophila. AB - A genomic interval at 75C1,2 is required for programmed cell death in Drosophila. We identified a new activator of apoptosis, grim, which maps between two previously identified cell death genes in this region reaper (rpr) and head involution defective (hid). Expression of grim RNA coincided with the onset of programmed cell death at all stages of embryonic development, whereas ectopic induction of grim triggered extensive apoptosis in both transgenic animals and in cell culture. Cell killing by grim was blocked by coexpression of p35, a viral product that inactivates ICE-like proteases, and did not require the functions of rpr or hid. The predicted grim protein shares an amino-terminal motif in common with rpr. However, grim was sufficient to elicit apoptosis in at least one context, where rpr was not. The grim gene product might thus function in a parallel circuit of cell death signaling that ultimately activates a common set of downstream apoptotic effectors. PMID- 8698238 TI - The Drosophila tamou gene, a component of the activating pathway of extramacrochaetae expression, encodes a protein homologous to mammalian cell-cell junction-associated protein ZO-1. AB - In Drosophila sensory organ development, the balance of activities between proneural genes and repressor genes defines a proneural cluster as a population of competent cells for neural development. In this study, we report the isolation and analysis of the tamou (tam) gene that encodes a cell-cell junction-associated protein, which is homologous to mammalian ZO-1, a member of the membrane associated guanylate kinase homolog family. The tam mutation reduces the transcription of a repressor gene, extramacrochaetae, and causes enlargement of a proneural cluster where supernumerary precursor cells emerge, resulting in extra mechanosensory organs in the fly. These results suggest that the membrane associated Tam protein is involved in the signaling pathway that activates emc expression. PMID- 8698239 TI - Evidence for silencing compartments within the yeast nucleus: a role for telomere proximity and Sir protein concentration in silencer-mediated repression. AB - Transcriptional repression at the silent mating-type loci in yeast requires the targeting of silent information regulator (Sir) proteins through specific interactions formed at cis-acting silencer elements. We show here that a reporter gene flanked by two functional silencers is not repressed when integrated at >200 kb from a telomere. Repression is restored by creation of a new telomere 13 kb from the integrated reporter or by elevated expression of SIR1, SIR3, and/or SIR4. Coupled expression represses in an additive manner, suggesting that all three factors are in limiting concentrations. When overexpressed, Sir3 and Sir4 are dispersed throughout the nucleoplasm, in contrast to wild-type cells where they are clustered in a limited number of foci together with telomeres. Efficient silencer function thus seems to require either proximity to a pool of concentrated Sir proteins, that is, proximity to telomeres, or delocalization of the silencing factors. PMID- 8698240 TI - Nuclear localization of the Arabidopsis APETALA3 and PISTILLATA homeotic gene products depends on their simultaneous expression. AB - The Arabidopsis APETALA3 (AP3) and PISTILLATA (PI) proteins are thought to act as transcription factors and are required for specifying floral organ identities. To define the nuclear localization signals within these proteins, we generated translational fusions of the coding regions of AP3 and PI to the bacterial uidA gene that encodes beta-glucuronidase (GUS). Transient transformation assays of either the AP3-GUS or PI-GUS fusion protein alone resulted in cytoplasmic localization of GUS activity. However, coexpression of AP3-GUS with PI, or PI-GUS with AP3, resulted in nuclear localization of GUS activity. Stable transformation with these fusion proteins in Arabidopsis showed similar results. The nuclear colocalization signals in AP3 and PI were mapped to the amino-terminal regions of each protein. These observations suggest that the interaction of the AP3 and PI gene products results in the formation of a protein complex that generates or exposes a colocalization signal required to translocate the resulting complex into the nucleus. The colocalization phenomenon that we have described represents a novel mechanism to coordinate the functions of transcription factors within the nucleus. PMID- 8698241 TI - Cap-prevented recombination between terminal telomeric repeat arrays (telomere CPR) maintains telomeres in Kluyveromyces lactis lacking telomerase. AB - Deletion of the telomerase RNA gene (TER1) in the yeast Kluyveromyces lactis results in gradual loss of telomeric repeats and progressively declining cell growth capability (growth senescence). We show that this initial growth senescence is characterized by abnormally large, defectively dividing cells and is delayed when cells initially contain elongated telomeres. However, cells that survive the initial catastrophic senescence emerge relatively frequently, and their subsequent growth without telomerase is surprisingly efficient. Survivors have lengthened telomeres, often much longer than wild type, but that are still subject to gradual shortening. Production of these postsenescence survivors is strongly dependent on the RAD52 gene. We propose that shortened, terminal telomeric repeat tracts become uncapped, promoting recombinational repair between them to regenerate lengthened telomeres in survivors. This process, which we term telomere cap-prevented recombination (CPR) may be a general alternative telomere maintenance pathway in eukaryotes. PMID- 8698242 TI - Inactivation of the mouse Brca1 gene leads to failure in the morphogenesis of the egg cylinder in early postimplantation development. AB - BRCA1 is proposed to be a tumor suppressor gene. To explore the biological function of BRCA1, a partial deletion (amino acids 300-361) of mouse Brca1 exon 11 was introduced into the genome of embryonic stem (ES) cells by homologous recombination. Mice carrying one mutated allele of Brca1 appear normal and are fertile up to 10 months of age without any sign of illness. However, no viable progeny homozygous for the Brca1 mutant allele were obtained. Detailed analysis of large numbers of embryos at different stages of development indicated that the homozygous mutant concepti are severely retarded in growth as early as embryonic day 4.5 (E4.5) and are resorbed completely by E8.5. Although the homozygotes at E5.5-E6.5 are able to synthesize DNA and display distinguishable embryonic and extraembryonic structures, they fail to differentiate and form egg cylinders. Consequently, they were unable to form primitive streaks and undergo gastrulation. Consistent with these in vivo results, blastocysts homozygous for mutated Brca1 alleles are at a considerable disadvantage when grown in vitro. These observations suggest that Brca1 has an important role in the early development of mouse embryos. PMID- 8698244 TI - [Multidisciplinary assessment of the fetus with hydrocephalus: study protocol and results]. AB - The objective was to make the confirmation-exclusion diagnosis of fetal hydrocephaly, to study its etiology and identify associated anomalies. 67 cases with suspected fetal hydrocephaly were studied at 30 weeks of mean gestational age. Serial studies of ultrasonography, TORCH serology and fetal karyotype were made. Postnatal correlation was made. 14 cases were not confirm and 53 were. 6 cases (11.3%) were classified as isolated hydrocephaly and 47 (88.7%) with associated anomalies. In this group, 15 with only intracranial anomalies and 32 intracranial and extracranial anomalies. All chromosomic anomalies were found in this latter group. Proved in all the cases of hydrocephaly and most of its associated anomalies were documented. Fetal hydrocephaly can be accurately diagnosed with the technology presently available. The diagnosis of associated anomalies is more difficult to obtain, but can be reached using serial studies and multidisciplinary approach. PMID- 8698243 TI - [Peritoneal immune response in endometriosis]. AB - The systematic analysis of immunity status in the peritoneum of women with endometriosis, is presented. Twenty five patients were studied, distributed as follows: A. Endometriosis, B. Sterility of non identified cause. In all the patients, peritoneal fluid was obtained (PF) during diagnostic laparoscopy, and a sample of peripheral blood was taken simultaneously. Both samples were processed analysis of lymphocytes subpopulations (ALS) by flux cytometry using monoclonal antibodies with reactivity to lymphocytes T total (CD+), lymphocytes B (CD19+), auxiliatory/inductory (CD3+CD4+), suppressor/cytotoxic (CD3+CD8+) and NK (CD3+CD16+ + 56+). The peritoneal ALS of both groups were characterized by a clear lymphocyte B diminution, moderate diminution of activators; a considerable increase of suppressors; altered CD4+/CD8+ relation in favour of suppression and NK diminution when comparing with its own blood compartment. All of these values were identical for both groups, and the only significant difference was found when comparing activated lymphocytes T subpopulation that was lesser in PF of women with endometriosis. This is the only fact that backs up the existence of altered immunity in the peritoneum of these patients, that affects the expression of activated lymphocytes. However, taking as a criterium the rest of subpopulations, in endometriosis as well as in ECNI the microenvironment goes for suppression and they are not distinguishable among them. On other side, it started signal characterization that conditions suppression induction for lymphocytes activation in peritoneal environment of women with endometriosis. Ten samples of PF of patients using peripheral purified lymphocytes by density gradient of voluntary donnors, normal, fertile, were analyzed. Cells were cultivated and stimulated in vitro with concanavaline A in presence of timidine 3H. In experimental holes PF was added at dose-response concentration, and it was evaluated as the difference in synthesis of radioactive ADN against the incubated cells in absence of PF. It was possible to demonstrate the presence of associated factors in PF of patients with endometriosis that inhibit proliferation of lymphocytes stimulated by Con A, and not so in samples of ECNI. With these factors one supposes the presence of soluble signals that condition local immunological suppression. PMID- 8698245 TI - [Metabolic changes in climacteric women in terms of body mass index]. AB - The objective was to identify climateric woman with cardiovasculary risk by the relation between size and weight, known as corporal mass index. Seven hundred and ninety seven postmenopausal patients, were studied; they attended the CECLIMEN, with one or two years of spontaneous menopause, and they were not receiving, nor had received replacement hormonal therapy (RHT). In all of them clinical history was taken, and blood pressure, weight, size and corporal mass index (CMI) (weight/(size)2), were evaluated; considering normal weight when CMI was < or = 27, and obesity when this index was greater than 27. Fastening and postprandial glucose at two hours, was determined, as well as total cholesterol, HDL-C, cholesterol of low density lipoproteins (LDL-C), trigliceridos (Tg), and aterogenic index was calculated by CtHDL-C. Besides, estradiol (E2) and follicle stimulating hormone (FSH) were measured in serum by radioimmunoanalysis RIA. Results were considered in the two groups, according to CMI: Group I with CMI < or = 27 (n = 566); and group II, with CMI > 27 (n = 231). Blood pressure, systolic and diastolic, triglicerides and aterogenic index were significantly greater in group II. There were higher levels of glucose in group II (tendency). CMI > 27 is useful to differentiate the postmenopausal women with a higher cardiovasculary risk. PMID- 8698246 TI - [Comparative study of the placenta from HIV+ mothers. Ultrastructural analysis]. AB - Perinatal vertical transmission has increased in all the world; it is considered that at the present time there are about one million of children with HIV. Variation goes from 12 to 40%, at different countries. During the last years antiretroviral drugs as AZT, ddI and others have been used to diminish the virus passage via transplacentary. Eighteen placentaes from HIV seropositive women, three corresponded to first trimester, and 15 to the third trimester of gestation; in four cases they were treated with AZT in weeks fourteen (two patients), 26 and 35 of gestation; and one patient received AZT and ddI at week 28. Control group was with ten normal placentaes. Ultraestructural analysis and immuno-peroxidase and immuno-oro with antibody anti gp 41, were done. Ultraestructurally there were different localizations of HIV virus, at sincitiotrophoblast, decidual cells and umbilical vessels (six cases). In 13 cases there was hyperplasia and hypertrophy of macrophages containing a great amount of lysosomes. In one case, where a girl was seropositive many viriones HIV, were identified in macrophages. With immuno-oro viral proteins were seen in cytoplasm an plasmatic membrane, in endothelium of fetal capillars and trophoblast. With immunoperoxidase, four cases were positive. Placentaes with antiretroviral treatment since week 14, trophoblast was more dense by philaments increment. Placentaes with treatment during the third trimester, showed normal morphology with slight increase of philaments. In the cases treated with AZT and ddI, there were not macrophages hyperplasia and hypertrophy, nor viral particles. It is concluded that in seropositive mothers without treatment, the virus may be present in any part of chorionic villi, and in patients with treatment, virus is not identified, but a viral proteins synthesis. PMID- 8698247 TI - [Hereditary antithrombin III deficiency. Report of an obstetric case and review of the literature]. AB - This case is a gravida 2, para 1, 21 years old, with a 36 weeks pregnancy, complicated with light toxemia, hereditary Antithrombin III (AT III) deficiency, and left iliofemoral thrombophlebitis; the patient was in labor. Two family members had thromboembolic phenomena, one of them had died because of this. The patient have had thrombophlebitis in both lower limbs during the puerperium of her previous delivery. She had received anticoagulants irregularly. Four months before the diagnosis of hereditary AT III deficiency, by laboratory. Labor was normal and had an eutocic delivery, masculine product, 3,250 g, without complications. Three hours before the effect of heparin had been reverted with protamine sulphate. Eight hours after delivery administration of heparin, was reestablished. The patient did not present other complications, and was discharged nine days after delivery. The literature about this subject was reviewed. Special emphasis is given to treatment alternatives in this type of disease that produce hypercoagulability and thromboembolic phenomena. This is the first report in Mexican literature. PMID- 8698248 TI - [Ultrastructural and immunocytochemical analysis of the synaptonemal complex at the initiation of synapsis]. AB - The synaptonemal complexes (SCs) are nuclear structures specific for meiosis. They have a central role in homolog chromosomes coupling; they are essential in crossing over events and chromosomic segregation during the first meiotic division. When its joining ends in pakiteno stage, each synaptonemal extends along the bivalent joining the ends to nuclear wrapping. The SCs are characterized by the presence of two lateral elements and a central region. The lateral elements are parallel and equidistant. The chromatine of homolog chromosomes fixes in a series of loops to these elements. The central region is between the lateral elements. It is formed by the latero-medial fibers and the medial element. The first ones are perpendicularly oriented to the longitudinal axis of CS and connect lateral elements with the medial element. The recombination modules have an active role in recombination processes and quiasma formation, they are associated, at intervals, with the central region among the homolog chromosomes. The localization and function of nucleic acids in formation and coupling of synaptonemal complex is little known, so methodologic alternatives are looked for to resolve this type of problems. In this work, ADN distribution in chicken ovocytes in cigotene, using techniques for electronic microscopy of immuno-oro, were studied. Besides, cytochemical techniques, were used as preferential contrast for ADN or preferential for ribonucleoproteins (RNPs). The combination of preferential tincture for RNPs and immunolocalization of ADN show that chromatin accumulates jointly with ribonucleoproteins in nor coupled lateral elements and the presence of numerous RNPs fibers distributed around lateral elements. Recombination nodules were found among lateral elements during the coupling, these nodules are PTA positives, which means ADN presence, and so, ADN presence among lateral elements. THe presence of a bridge of marked fibers with coloidal gold (ADN) uniting not coupled lateral elements, suggests ADN as a sort of macromollecule forming synapsis sites. PMID- 8698249 TI - [Use of fructosamine serum level measurements for diagnosis of insulin-dependent diabetic in pregnancy]. AB - In this study it has been tested the usefulness of serum glycosyl protein (fructosamine) to diagnose diabetic pregnant women requiring insulin therapy. The analysis was performed on the base of obtained results of glucose tolerance test, glycemia level in diurnal profile, fructosamine level and its relationship to albumin level and total protein amount in serum pregnant women with carbohydrates intolerance. Calculated specificity and sensitivity of above mentioned measurements was too low. We can not concluded that it is necessary to include insulin-therapy in diabetic pregnancy on the base of fructosamine serum level even corrected by protein or albumin serum level. PMID- 8698250 TI - [Nephrologic analysis of 94 women with diagnosed "primary" gestosis]. AB - Among 94 women with diagnosed "primary" gestosis during pregnancy, 67 patients demonstrated (3-6 months after delivery) chronic glomerulonephritis (25 women) or chronic pyelonephritis (28 women) or hypertension caused by others than nephrologic reasons. "Primary" gestosis was diagnosed correctly only in 29% cases. The most often reason of "secondary" gestosis was undiagnosed chronic nephropathy before and during pregnancy. Obtained results confirm other data informing that "primary" gestosis is a rare phenomenon. PMID- 8698251 TI - [Fluorides in the body of the mother and in the fetus. III. Fluorides in amniotic fluid]. AB - Fluoride concentrations in amniotic fluid as well as in venous and arterial cord blood serum were determined in 20 women during the perinatal period. The mean concentrations of fluoride from amniotic fluid, venous cord blood serum and arterial cord blood serum were 1,6 +/- 0,18 mumol/l, 3,2 +/- 0,28 mumol/l and 2,9 +/- 0,39 mumol/l respectively. Amniotic fluid fluoride concentrations were significantly higher in the older age group of pregnancies (39-42 weeks) in comparison with the younger age group of pregnancies (34-38 weeks) p < 0,01. The reasons for mentioned relations were discussed. PMID- 8698252 TI - [Effect of perinatal risk factors on treatment outcome in newborns with hypoxic ischemic encephalopathy]. AB - In 99 newborns with hypoxic-ischemic encephalopathy (22 with mild, 53 with moderate and 24 with severe stage) correlation between birth weight, low Apgar score, high-risk pregnancy and delivery and stage of encephalopathy and results of the treatment was made. Low Apgar score (< 3) had significantly influence on the development of severe encephalopathy. Most important perinatal risk factor was abnormal delivery. Especially high mortality because of moderate and severe stage of encephalopathy in prematures with intracranial hemorrhage and congenital infection was noted. Full-term babies died because of others causes. It was shown, that unfavourable outcome of neonatal encephalopathy depends mainly on high-risk delivery. PMID- 8698253 TI - [Evaluation of selected lipid metabolism parameters in premature infants with infections]. AB - In 49 prematures (25 infected and 24 healthy) serum cholesterol and triglycerides concentrations, value of alpha, pre-beta and beta serum lipoproteins (by electrophoresis) and activity of AspAt, AlAt and GGTP were estimated. It was stated, that the mean serum cholesterol concentration at the beginning of infection was significantly lower than in healthy babies, but in 2-3 week of disease the mean value of this parameter was significantly higher than in first week of life. Mean value of alpha lipoprotein was significantly lower, mean value of pre-beta and beta lipoproteins were higher in sick prematures than in control. In septic prematures positive correlation between the high serum cholesterol concentration and activity of GGTP and AspAt was found. In 30% of all septic neonates hepatitis and in 65% of dead infected prematures structural damage of liver were noted. PMID- 8698254 TI - [Evaluation of the value of clinical doppler sonography and sonographic contrast media for assessment of tubal patency]. AB - The tubal factor still remains one the most often reason of female infertility. The applying of colour Doppler sonography and up-to-date constant medium (Echovist-Schering) make possible the comparison of clinical value between colour Doppler imaging and others presently used diagnostic methods. The aim of this study was the comparison of results obtained by means of hysterosalpingography, laparoscopy and hysterosalpingosonography (HSSG) directly observing tubal flow as an estimation of tubal patency. PMID- 8698255 TI - [Clinical evaluation of the usefulness of the endometrial smear technique]. AB - On the base of dozen studies it has been estimated the usability of endometrial smear technique performed due to different clinical indications. It has been pointed on opportunity of use above mentioned method beside microcuretage or hysteroscopy. PMID- 8698257 TI - [A case of primary salpinx cancer--diagnostic difficulties]. AB - In this paper the authors presents 55-years old female patient with primary carcinoma of salpinx. The special attention is payed to the possibility of clinical misdiagnosis. The low rate of appearance and not very characteristic symptoms of that type of carcinoma makes final clinical diagnosis almost impossible without intra-or postoperative histopathological study. In presented case, in the first acute appendicitis was recognized and patient was treated surgically. During the operation the large cyst near the right uterine appendages was found and after histopathological examination the primary salpinx carcinoma was revealed. In consequences pan hysterectomy was made with cytostatic all treatment just after the operation. Now, five years has gone and the patient, temporary controlled in dispensary, is still in good condition. PMID- 8698256 TI - [Evaluation of bone loss in postmenopausal women during the first 5 years after menopause]. AB - Aim of the trial was estimation of the degree of bone loss in first 5 years of menopause. 184 postmenopausal women were evaluated. Bone status was assessed by using quantitative ultrasound. Both parameters decreased in term of 1-5 years of menopause, what was especially expressed in first 2-3 years of menopause. Densitometric values were lower in comparison to British, French and Japan women population. Also dynamic of bone loss was greater in Polish women population. Results confirm necessity of early prevention of osteoporosis in postmenopausal women. PMID- 8698258 TI - [Syndrome of the abdominal rectus muscle monitored ultrasonographically during pregnancy]. AB - It has been presented a case of pregnant woman with rectus muscle hematoma. This woman gave birth spontaneously. It has been pointed on decisive role of ultrasound examination in making diagnosis and decision concerning conservative management. PMID- 8698259 TI - [Why are we afraid of cytologic descriptions using the Bethesda method? Is it a result of unfamiliarity or a result of difficulties in presentation? Report of the XIX International Workshop on Cytology in Vienna]. PMID- 8698260 TI - Are estradiol-producing cells incompletely endowed? A chronicle of the emergence of certitude from conjecture. PMID- 8698261 TI - Ovarian effects upon maternal glucose tolerance. AB - Ovaries from homozygous diabetic (db/db) female mice were removed and transplanted into the empty left ovarian sacs of normal homozygous (m/m) female mice which had undergone left oophorectomies. To produce controls, the previously removed normal left ovaries were transplanted into the empty left ovarian sacs of other normal (m/m) left oophorectomized females. Glucose tolerance tests were done on the study and control mice before surgery, after surgery, during pregnancy, and after delivery. There were no significant differences in the glucose tolerance test results between study group and controls before or after surgery. However, the study group, when compared to the controls, had a statistically significant glucose intolerance during pregnancy. After delivery, the glucose levels returned to normal. The ovaries from diabetic (db/db) female mice may produce hormones which, by themselves or in concert with the fetal and placental hormones, may produce maternal glucose intolerance during pregnancy. PMID- 8698262 TI - Neutral and cationic amino acids in striated rectus muscle are generally in excess of those in smooth uterine muscle of term pregnant women. AB - The concentrations of 24 amino acids and four other related compounds were determined in extracts of biopsy specimens from myometrium and musculus rectus abdominis of 10 healthy term pregnant women during elective cesarean sections. The total free amino acid pool did not differ significantly between the two muscle types. There was a myometrial abundance of the two anionic amino acids glutamate and aspartate and the two aromatic amino acids tyrosine and phenylalanine, but most neutral and cationic amino acids in striated skeletal muscle tissue were found in excess of those in uterine muscle tissue. PMID- 8698263 TI - Fibronectin in the plasma during pregnancy and parturition. AB - Fibronectin can be detected in the plasma and the extracellular matrix of the uterus of pregnant women. Studies so far have compared individual observations, whilst serial investigations during pregnancy, and during and after parturition have not been carried out. Plasma fibronectin levels were measured in 153 women with healthy pregnancies in relation to the gestational age. During parturition, blood was taken from the inception of labor through to parturition, and on the 1st, 3rd, and 5th days after parturition. The investigations of the plasma fibronectin level in pregnant women show constant concentrations up to the 35th week of pregnancy. From the 36th week onward the fibronectin rises significantly before dropping to the initial values at the start of labor. The elevated fibronectin concentration in the last 4 weeks before delivery could be explained both by renewed, elevated synthesis in the uterus and placenta as well as by lower consumption. The decline in the fibronectin level with the onset of labor could be caused by an elevated enzymatic induction in the uteroplacental unit in connection with the start of parturition. PMID- 8698265 TI - Psychic and social consequences of women in relation to memories of a stillborn child: a pilot study. AB - Prevalence and determinants of long-term psychosocial morbidity among women giving birth to a stillborn child are largely unknown. Few, if any, systematic epidemiologic studies are available. In this pilot study we investigated one alternative way to collect data from relevant patient populations and formulated some hypotheses. Moreover, questions found unhelpful in this context were identified, e.g., whether the mother had bathed her dead child or not. Fruitful hypotheses found worthwhile testing were, among others: the risk of long-term anxiety-related symptoms is reduced if (1) the woman has seen her stillborn child, (2) she has an ultrasonic or photographic picture of the child, and (3) she has gone through a ritual, primarily burial of the child; moreover, (4) divorce may be a social consequence of the intrauterine loss of a child. PMID- 8698264 TI - Plasma nitric oxide levels in pregnant patients with preeclampsia and essential hypertension. AB - Nitric oxide (NO) production may be an important causal factor in hypertensive disorders during pregnancy. The plasma concentrations of NO2-(+) NO3-, stable metabolites of NO, were measured in 70 nonpregnant women, 323 normotensive pregnant women, 23 pregnant patients with preeclampsia, and 7 pregnant patients with essential hypertension. The normotensive women had higher plasma concentrations (30.0 +/- 0.6 mumol/l) than nonpregnant women (18.3 +/- 1.0 mumol/l; p < 0.0001). The plasma concentrations in the patients with preeclampsia (45.6 +/- 2.3 mumol/l) were higher than in the normotensive women (30.3 +/- 1.0 mumol/l; p < 0.0001) and were correlated with the systolic blood pressure (r = 0.442; p < 0.05). However, pregnant patients with underlying essential hypertension had significantly lower plasma concentrations (19.1 +/- 3.0 mumol/l; p < 0.005). These findings suggest that NO contributes to maternal vasodilation, the maintenance of uterine quiescence, and the pathogenesis and clinical features of hypertensive disorders during pregnancy. PMID- 8698267 TI - Studies on the detection of small endometrial implants by magnetic resonance imaging using a fat saturation technique. AB - To assess the usefulness of fat-saturated magnetic resonance (MR) imaging in detecting small endometrial implants, 258 pigmented lesions of endometriosis from 80 consecutive patients with histopathologically diagnosed pelvic endometriosis were compared using fat-saturated and conventional MR imaging. MR imaging was performed with a 1.5-tesla superconducting magnet with spin echo T1-, T2-, and fat-saturated T1-weighted images. Both conventional MR images and fat-saturated MR images permitted identification of almost all endometriomas > 10 mm in diameter. With conventional MR imaging, 29 endometrial implants measuring < 10 mm in diameter were detected. One hundred and seven lesions were detected by fat saturated MR imaging. However, conventional MR images demonstrated only 4 lesions among these 111 small endometrial implants that measured < 5 mm in diameter. The addition of fat-saturated MR imaging increased the detection rate to 55 of 111 lesions. Fat-saturated MR imaging can, therefore, be useful in detecting small endometrial implants. PMID- 8698266 TI - Use of fibrin sealant for reproductive surgery: a randomized study in the rabbit model. AB - The present study was undertaken to compare adhesion formation and reproductive outcome after reproductive surgery with or without the application of fibrin sealant. At laparotomy, the ovaries and uterine horns of 20 rabbits were longitudinally incised on the antimesenteric side using a monopolar microneedle. At random, one ovary and the ipsilateral uterine horn were covered with fibrin sealant, while those on the contralateral side were left uncovered without application of sutures. The rabbits were then mated, and 2 weeks later a second look laparotomy was performed by a blinded observer. No statistically significant differences were found in postoperative adhesions, number of corpora lutea in each ovary, number of embryos in the ipsilateral uterine horn, and nidation index for each side. Fibrin sealant for conservative surgery does not appear to significantly affect either postoperative adhesion formation or reproductive outcome. PMID- 8698269 TI - Evaluation of long-term results of surgical correction of stress urinary incontinence. AB - A total of 109 patients submitted to surgery for the correction of urinary stress incontinence (USI) by two different techniques, i.e. anterior colporrhaphy (group I, n = 57) when cystocele grade II/III was present, and Burch procedure (group II, n = 52) when cystocele grade I was present, were reevaluated an average of 5 years after surgery (range: 54-66 months). The curve constructed with the reevaluation data showed a sharp superiority of the Burch technique in terms of correction of USI and associated genital prolapses. There was a progressive recurrence rate that stabilized at 5 years, with values of 78.9% in group I and 40% in group II. Anterior colporrhaphy was ineffective for the correction of any of these parameters in group I. The data clearly show the need to improve the presurgical diagnostic methods for the selection of patients that will benefit from treatment: detailed history of the current disease and auxiliary tests such as Q-tip test, transvaginal ultrasound, and urodynamic study. Other factors were associated with ineffective treatment in both groups, such as hypoestrogenism (20/109), excessive weight gain (19/109) and chronic intestinal constipation and/or coughing present in 36 patients, with recurrence in 28 of them. PMID- 8698268 TI - Langerhans' cells and L1 antigen expression in normal and abnormal squamous epithelium of the cervical transformation zone. AB - This study evaluates the presence of Langerhans' cells and expression of L1 antigen in squamous epithelium of the normal and dysplastic transformation zone of the cervix uteri and determines the influence of tobacco smoking and pregnancy. Women who smoked and pregnant women showed a decrease of Langerhans' cell counts in normal epithelium. In cervical intraepithelial neoplasia (CIN) 1 lesions, decreased Langerhans' cell counts were noted. L1 antigen expression was significantly less in CIN of all grades. Normal squamous epithelium of smokers showed weaker staining for L1 antigen but total staining scores were not significantly different. These data suggest a decrease in epithelial cell mediated immune response in smokers, pregnant women and in low-grade CIN. Dysplastic squamous cells probably have intracellular regulatory problems independent of other immune cells. PMID- 8698270 TI - Rheumatoid factor-associated high-molecular-weight complexes in the menstrual and amniotic fluids. AB - We have previously described the identification of the human decidua-associated protein hDP200 as a rheumatoid factor [1]. Assuming that rheumatoid factor binds to Fc of immunoglobulins, the existence of high-molecular-weight complexes was studied in decidual extract, pooled uterine fluid from proliferative and early secretory phase, menstrual fluid and amniotic fluid. High-molecular-weight complexes containing hDP200 and other immunoglobulins were found only in menstrual and amniotic fluids and not in decidual extract or uterine fluid. It is possible that complexing of the immunoglobulins by hDP200 serves as one of the mechanisms that ensure suppression of the immune response to fetal antigens. PMID- 8698271 TI - Induction of ovulation with the sole use of clomiphene citrate in late-onset 21 hydroxylase deficiency. AB - Late-onset 21-hydroxylase deficiency (21-OHD) is a congenital enzymatic defect in the glucocorticoid and mineralocorticoid steroidogenic pathways. The manifestations, including hirsutism and infertility, usually occur at puberty or young adulthood. In infertile, anovulatory women with late-onset 21-OHD, the usual therapy is glucocorticoids for ovulation induction. In this case, we report the sole use of clomiphene citrate to induce ovulation in a patient with late onset 21-OHD. A hirsute and oligomenorrheic woman was diagnosed as having polycystic ovary syndrome at age 25. Her hirsutism responded to oral contraceptives. At age 31, she was given clomiphene citrate alone for ovulation induction and conceived in her fourth cycle. At age 36, because of increased hirsutism she was diagnosed with late-onset 21-OHD by an ACTH stimulation test. The induction of ovulation in late-onset 21-OHD patients has been with glucocorticoids. Given the success in inducing ovulation with clomiphene citrate alone in this patient with well-documented late-onset 21-OHD, it may be worthwhile to study the sole use of clomiphene citrate for ovulation induction in these patients. PMID- 8698273 TI - Comparison of a recombinant thromboplastin with Thrombotest for oral anticoagulant control. AB - Thrombotest results expressed in international normalized ratio (INR) values, obtained in 108 patients on oral anticoagulant treatment, were compared with prothrombin time (PT) results with a recombinant thromboplastin. The former results were obtained on an Amelung coagulometer, the latter on a photo-optical instrument. Using the Thrombotest method, performed within 2 h after sampling as the reference method, a first group of 63 patients had an INR value between 2 and 4. This group was considered as adequately anticoagulated and served as a true positive population in further analysis. The remaining 45 patients (true-negative group) had an INR value below 2 or higher than 4 and could thus be considered as inadequately anticoagulated. Using these definitions, a sensitivity of 86% and a specificity of 96% could be calculated for the PT with the recombinant thromboplastin. All tests from patients on oral anticoagulant treatment were also performed after 24 h storage of the blood or plasma samples at room temperature. When we compared the reference Thrombotest results with those of the late Thrombotest and the late PT recombinant thromboplastin, sensitivities of 86 and 86% as well as specificities of 91 and 96% were found, respectively. In conclusion, PT with a recombinant thromboplastin on a photo-optical instrument, even after prolonged storage of the plasma samples at room temperature, can be considered as suitable for oral anticoagulation control. PMID- 8698272 TI - Influence of heparin, protamine and polybrene on the time integral of thrombin generation (endogenous thrombin potential). AB - We investigated the anticoagulating and heparin-neutralizing properties of protamine and polybrene (hexadimethrine bromide), using the endogenous thrombin potential (ETP) as the parameter to access plasma coagulability. The hypocoagulability induced by high doses of heparin (3 IU/ml) could be reversed by addition of protamine to a very limited extent only. Polybrene on the other hand did neutralize heparin at the equivalent concentration and a two-fold excess did not influence the ETP parameters. In vivo neutralization of high-dose heparin with protamine should therefore be reconsidered. Our experiments suggest polybrene to be superior over protamine with respect to neutralization of high doses of heparin. PMID- 8698274 TI - Thrombin-antithrombin III complexes as an additional diagnostic aid in pulmonary embolism. AB - Plasma levels of selected coagulation and fibrinolytic parameters (activated partial thromboplastin time, prothrombin time, fibrinogen, antithrombin III, protein C, thrombin-anti-thrombin III complexes (TAT), plasminogen activator inhibitor-1 (PAI-1), plasminogen, alpha 2-plasmin inhibitor) were evaluated in 90 patients with clinical suspicion of pulmonary embolism (PE). Plasma levels of fibrinogen, PAI-1 and TAT were significantly higher in patients than in controls (p < 0.01): evaluation of TAT displayed a sensitivity of 96.1% and specificity of 30.8%, and positive and negative predictive values of 64.5 and 85.7%, respectively. The number of nonperfused lung segments correlated directly with TAT levels (p < 0.01) and inversely with arterial pO2 values (p < 0.01). No significant difference was found in the other parameters between patients and controls. Our results suggest that the finding of normal TAT plasma levels can help to exclude PE in patients with clinically suspected PE. PMID- 8698275 TI - Does glycosylation influence the experimental antithrombotic effect of a two domain tissue factor pathway inhibitor? AB - We have earlier shown that both full-length and truncated glycosylated tissue factor pathway inhibitor (TFPI) lacking the third Kunitz domain and the c terminal region has an antithrombotic effect comparable to lowmolecular-weight heparin (LMWH) in an experimental venous thrombosis model. The aim of this study was to investigate whether a recombinant truncated non-glycosylated TFPI (117QTFPI1-161) had an antithrombotic effect similar to the glycosylated TFPI1 161 and LMWH. We also followed the coagulation parameters. The thrombi were induced in rabbit jugular veins with a combination of endothelium destruction and restricted blood flow. Group 1: placebo; group 2: LMWH 60 anti-Xa IU/kg, i.v.; groups 3 and 4: TFPI1-161 0.8 and 0.2 mg/kg, i.v., respectively; groups 5 and 6: 0.8 and 0.2 mg/kg 117QTFPI1-161, i.v., respectively, in a randomized double-dummy fashion. Twelve animals were included in the placebo group and 6 in each of the other groups. The frequency of thrombosis and also of occlusive thrombosis was reduced in all groups compared to placebo. The thrombus weight was reduced (0-9.9 mg) in all groups, significantly in groups 2, 4 and 5 (p = 0.004-0.02) compared to placebo (21.1 mg). In group 3, a borderline p value was achieved (0.06 likely a beta-error). The two forms of TFPI1-161 given in the higher doses showed a significantly greater increase of anti-Xa activity, but with a shorter duration compared to LMWH (1.7-1.9 vs. 0.9 anti-Xa IU/ml). Activated partial thromboplastin time (aPTT)-analysis revealed that only LMWH (52 s) caused a significant transient elevation 2 min after injection. In the other groups, a temporary but insignificant elevation of aPTT (27-37 s) was seen. No detectable effect on anti-IIa activity and prothrombin time (PT) was seen in any TFPI group. The glycosylation of the second domain on TFPI does not substantially contribute to the antithrombotic effect of TFPI. Regardless of the glycosylation of TFPI1 161, it has a dose-dependent effect on anti-Xa, a small effect on the aPTT, but no effect on anti-Ila and PT. LMWH has a more pronounced and sustained impact on these parameters. PMID- 8698276 TI - Participation of alpha IIb beta 3 in platelet microparticle generation by collagen plus thrombin. AB - We investigated the role of alpha IIb beta 3 in microparticle generation by normal and thrombasthenic platelets stimulated with collagen plus thrombin. Microparticle generation by normal platelets was scarcely inhibited by monoclonal antibodies for glycoprotein Ib and glycoprotein IX. Although one monoclonal anti alpha IIb beta 3 antibody (NNKY1-32) partly inhibited microparticle generation, 3 other monoclonal anti-alpha IIb beta 3 antibodies had little effect. However, the combination of 4 monoclonal anti-alpha IIb beta 3 antibodies or treatment with a polyclonal anti-alpha IIb beta 3 antibody significantly inhibited microparticle generation (p < 0.05). Microparticle generation by thrombasthenic platelets also occurred after stimulation with collagen plus thrombin, although at a significantly lower level compared with normal platelets. Monoclonal antibodies for resting alpha IIb beta 3, P-selectin, activated alpha IIb beta 3 and beta 2 glycoprotein I bound to microparticles from healthy platelets. In contrast, only a monoclonal antibody for beta2-glycoprotein I bound to thrombasthenic microparticles. These results suggest that microparticle generation by collagen plus thrombin occurs via two different mechanisms which are dependent and independent of alpha IIb beta 3, respectively. The alpha IIb beta 3-dependent mechanism appears to require activation of alpha IIb beta 3. PMID- 8698277 TI - Plasma serotonin and platelet aggregation during ischemia-reperfusion in dogs: effect of dipyridamole and coenzyme Q10. AB - Platelet aggregation and plasma serotonin were studied during ischemia reperfusion of the small intestine in dogs. Blood was withdrawn from the superior mesenteric vein before and 1 h after ischemia, then 5, 30 and 60 min after reperfusion. Dipyridamole (5 mg/kg body weight) and coenzyme Q10 (CoQ10; 10 mg/kg body weight) were administered intravenously 5 min before reperfusion, following 1 h ischemia, in order to investigate their effects on platelet function and free serotonin. Ischemia-reperfusion resulted in an increased local free serotonin concentration together with an enhanced platelet response to ADP, collagen and arachidonic acid. Administration of dipyridamole and CoQ10 prior to reperfusion prevented, at least in part, augmented platelet activation and serotonin release. It appeared that dipyridamole was more potent than CoQ10. Our results may indicate a possible protective effect of dipyridamole on enhanced platelet activation during ischemia-reperfusion in dogs. PMID- 8698278 TI - Femoral artery wall morphology, hemostatic factors and intermittent claudication: ultrasound study in men at high and low risk for atherosclerotic disease. AB - The aim of this study was to examine whether there was a relationship between ultrasound-assessed morphology of the femoral artery wall and hemostatic factors, and whether these factors were associated with intermittent claudication. One hundred and thirty men at high cardiovascular risk and 51 men at low risk were examined. The subjects (high- and low-risk) with moderate/large plaque (n = 96) had higher fibrinogen, thrombin/antithrombin complex and von Willebrand factor, compared to subjects with small/no plaque. The maximum intima-media thickness of the femoral artery was significantly associated with fibrinogen. These associations were independent of current smoking habits. Clinical atherosclerosis was associated with fibrinogen, von Willebrand factor, thrombin/antithrombin complex, plasminogen activator inhibitor activity, mean and maximum intima-media thickness and plaque status of the femoral artery. In conclusion, fibrinogen, von Willebrand factor and thrombin/antithrombin complex were related to plaque occurrence in the femoral artery. Clinical atherosclerosis was associated with fibrinogen, von Willebrand factor, thrombin/antithrombin complex and plasminogen activator inhibitor activity. PMID- 8698279 TI - Tea drinking and haemostasis: a randomized, placebo-controlled, crossover study in free-living subjects. AB - The hypothesis that tea drinking may protect against coronary heart disease (CHD) through effects on clotting as measured by plasma fibrinogen, tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) was tested in 65 healthy volunteers (31 men and 34 women; aged 20-74 years) in a randomized, blind, placebo-controlled, crossover study lasting 10 weeks (run-in phase 2 weeks, tea and placebo phases 4 weeks). During the placebo phase, intakes of milk, sugar, water and caffeine were matched to those in the tea phase during which 6 mugs of tea were drunk daily. Compliance with tea intake was measured by marking tea bags with p-aminobenzoic acid and measuring recovery in 24-hour urine collections. The mean +/- SD fibrinogen level, PAI-1 activity and tPA antigen level at baseline of 2.91 +/- 0.81 g/l, 7.9 +/- 5.3 U/ml and 4.76 +/- 2.17 ng/ml, respectively, were in the normal range. No significant differences in these variables between the run-in, tea or placebo phases were observed. The putative protective effect of tea against development of CHD is not mediated through effects of black tea on fibrinogen, tPA or PAI-1. PMID- 8698280 TI - The ethosuximide-induced hyperpolarization of smooth muscle tissues--a cause of functional changes in the gastrointestinal tract of rats--is provoked by CA(2+) dependent K(+)-efflux. AB - Ethosuximide is an antiepileptic drug successfully used in the treatment of petit mal especially in childhood. Clinical investigations reveal that ethosuximide has a number of adverse side effects on the gastrointestinal tract (GIT) of patients which may include heaviness, anorexia, pains in the region of the stomach, accompanied sometimes with nausea and vomiting. In the present study we attempt to explain the mechanisms of some of the drug's adverse side effects using an experimental animal model. White rats were employed in the experiments during which they were treated daily with ethosuximide (100 mg/kg) for 100 days. We made use of the following methods in the study: 1. Contrast X-rays study of the gastrointestinal tract. 2. Recording of the bioelectric activity of isolated smooth muscle strips using the sucrose-gap method. 3. Recording of the contractile activity of isolated smooth muscle. Characteristic changes occurring after treatment of rats with ethosuximide include atony of the stomach and the intestines, hypertonus in separate duodenal segments, diminished peristaltic activity, and delayed passage at the 24th hour. The drug inhibits the spontaneous contractile activity of isolated smooth muscle strips from rat gastrointestinal tract. In some duodenal preparations is minimised in the presence of apamin, an inhibitor of Ca2+(-dependent) K+ channels (Ka+(Ca)), while in duodenal preparations this effect may undergo a reversion. In the presence of coffeine the action of ethosuximide on the smooth musculature of rat gastrointestinal tract is reduced significantly. We hypothesis that the observed functional changes in the gastrointestinal tract occur as a result of the hyperpolarizing effect of ethosuximide on the gastrointestinal musculature caused by the outcoming K+(CA) efflux. PMID- 8698281 TI - External respiration in patients with chronic renal failure in a predialysis state. AB - The purpose of this study was to make functional assessment of the external respiration in patients with chronic renal failure (CRF) in a predialysis state and to find some early indicators for uremic lung impairment. Twenty two patients (13 men, 9 women, aged 30 to 65) with different renal diseases were investigated. According to the stage of progression of CRF we allocated the patients to two groups-14 patients with stage I CRF (serum creatinine up to 353.6 mumol/I), and 8 patients with stage II CRF (serum creatinine from 353.6 to 707.2 mumol/I). The comprehensive functional study included slow spirometry, forced expiration, bodyplethysmography, and investigation of the diffusion, blood-gas and acid-base parameters. The respiratory muscle strength was measured by means of a modified device first used by Black LE and Hyatt RE. Ventilatory parameters in stage I CRF patients were found to be either normal or slightly changed while the parameters of the respiratory muscle strength worsened earlier than the ventilatory parameters. In the patients with stage II CRF the pronounced ventilatory and diffusion disorders was found to occur much more frequently. PMID- 8698282 TI - Application of one-dimensional echoencephalography to diagnosis of brain death. AB - Three groups of patients were studied by echoencephalography using a one dimensional encephalograph Eho 12. The first group consisted of 100 patients with a mild craniocerebral traumas. Good pulsations of the elements of the echoencephalogram were found during the study. The second group involved 14 people who had died as a result of craniocerebral trauma. The investigation performed postmortem revealed fixed echoencephalogram without any pulsations of its elements. The third group included 11 patients with severe craniocerebral trauma in a state of deep coma. These patients were on mechanical ventilation, their brainstem reflexes were absent, but the cardiac activity remained preserved. The echoencephalographic study in these patients showed a fixed screen curve, without pulsations of its elements. We conclude that absence of pulsations of the elements of echoencephalogram produced by one-dimensional echoencephalograph indicates brain death of the investigated patients. This investigation should be included as a component of the established diagnostic tests. PMID- 8698284 TI - Quantitative analysis of digital subtraction renal vasography in patients with autosomal dominant polycystic kidney disease correlated with clinical and paraclinical data. AB - Digital intravenous subtraction angiography (DSA) of the kidneys provides an alternative means to achieve better screening of suspected, symptomless and unclear forms of autosomal dominant polycystic kidney disease (ADPKD). The method's capabilities for a quantitative analysis makes it particularly useful in patients with arterial hypertension. We report our experience in using DSA in 36 patients of whom 11 were with proven ADPKD and 15 with suspected ADPKD. The results analysed were correlated with laboratory data obtained in 28 healthy subjects. The importance of the intravenous DSA is underscored as a possible investigation modality for a quantitative analysis in relatively normal haemodynamic conditions of imaging the two kidney's symmetrically and normal conditions for comparison. PMID- 8698283 TI - Clinical aspects of biclonal myelomas. AB - In this study, a cohort of 109 patients with multiple myeloma were followed prospectively. Eight patients (7%) were found to have biclonal M component, an occurrence rate considerably higher than that reported in literature. Biclonal myelomas were compared with the other monoclonal variants of myeloma by a number of biologic, clinical, immunological, biochemical, roentgenological, therapeutical and prognostic parameters. Among the biclonal myeloma patients there was strong male predominance, higher frequency of patients in advanced stage of the disease, combined production of predominantly kappa light chains, hypoalbuminemia and thrombocytopenia. Their response to therapy did not differ from that of the patients with monoclonal myeloma variants. The median survival of patients with biclonal myelomas was 25 months, ranking third by shortened survival after patients with light chain and D-type myelomas. PMID- 8698285 TI - Herpes zoster in infants. AB - The author reported four cases of herpes zoster in infants without history of chickenpox but with positive history of maternal varicella either in the early life or during pregnancy. One of the infants had been in a close contact with his father who had varicella. Herpes zoster in infancy develops secondary to an asymptomatic foetal varicella zoster virus infection or to an unrecognized subclinical varicella in infants born to varicella zoster virus immune mothers. PMID- 8698286 TI - Acceleration of aerobic adaptation by inclusion of appropriate additives in the diet of rats subjected to submaximal physical exercises. AB - In order to study the effect of long-term use of specific food formulas with different compositions on the aerobic adaptation of body to submaximal exercise 16 white Wistar rats were randomly assigned to two experimental groups. Group A animals were fed a mixture of 76% of standard food and 24% of a special, high-fat and high-protein formula designed for endurance athletes; Group B rats were given a mixture of 76% of standard food and 24% of the widely available low-fat formula Aufbau Konzentrat. All animals were subjected to a special training programme. Their submaximal endurance was determined at the end of weeks 2, 4, 6 and 8. During week 9 a test was performed to measure the maximum oxygen uptake (VO2 max). At the end of the experiment the submaximal running endurance of group A animals was 190.96 +/- 28.72% compared with baseline vs. 158.70 +/- 26.18% for group B animals. The maximum O2 consumption of group A animals was significantly higher than that of group B animals (85.06 +/- 8.81 and 75.77 +/- 4.91 ml O2.kg( 1).min(-1), respectively). The respiratory quotient (RQ) study showed predominant utilisation of fats as a source of energy for the physical work of group A animals after being 8 weeks on the diet. On the basis of the analysis of the composition of the consumed food we conclude that long-term (8 wk) use of combined, relatively high-fat food formulae mixed with appropriate fat-acid and amino acid ingredients as additives accelerates aerobic adaptation of the body under conditions of regular submaximal exercise. PMID- 8698287 TI - Acne tetrad in a family. AB - The authors report, for the first time in Bulgarian literature, a case of acne tetrad syndrome in a family. The patients were sisters who were found to have three of the four components of the syndrome: hidradenitis suppurativa, acne conglobata, and cysta pillaris. There was no evidence or anamnestic data for perifolliculitis capitis abscedens et suffodiens. In one of the sisters the syndrome showed a more precipitate clinical picture and was combined with other skin disorders (lichen ruber planus, neurodermitis circumscripta, hirsutismus). The patients had a familial predisposition to acne and pilar cycts. The complete blood analysis, all biochemical parameters, the cytogenetic analysis and hormonal status (testosterone and estrogens) showed no deviation from normal values. The patients did not report any disturbances during their menstrual cycles. The cellular immunity in one of the sisters was depressed. The patients and their children will be closely monitored. PMID- 8698288 TI - Thoracolumbar spine stabilization in fracture--dislocations. AB - This study analyzed a series of 35 patients with unstable fractures, with and without neurologic deficit including complete paraplegia. The patients underwent spinal stabilisation using plates and screws after sustaining fracture dislocations. Very good results were obtained in 19 patients with non-complicated fractures operated on by dorsal stabilization using Meurig-Williams plates. Complete recovery of the neurologic deficit was achieved in five out of 13 patients with neurologic deficit two of whom were paraplegic. Use of stabilization operation accompanied by dorsal vertebrodesis and post-operative immobilisation provides a reliable posterior bone block with a restored spinal canal. PMID- 8698290 TI - Morphological damage to the central nervous system (CNS) following open heart surgery. AB - We investigated 40 patients who had died following open heart surgery between January 1990 and May 1992. Between this time, 703 open heart procedures were carried out at the University Medical School of Debrecen, 2nd Department of Surgery's Cardiac Surgery Unit with a mortality rate of 8.3%. We studied each individual's clinical records, autopsy findings, and histology of defined portions of brain tissue. Clinical information used were: sex, age, clinical stage (according to New York Heart Association (NYHA) classification) at time of surgery, type of procedure performed, and duration of time of extracorporeal circulation. Autopsy records collected and studied focused on the macroscopic and microscopic alterations in the CNS. The most common morphological findings in the CNS for the 40 studies cases were, cerebral edema in all cases, reactive microgliosis and nuclear pyknosis in most cases, and in a minority of the cases focal microscopic hemorrhage or focal microscopic white emolition. Also found were, destructive brain hemorrhage and global cerebral necrosis. Of the 40 cases studied there was only one case in which brain death was diagnosed perioperatively, and which was clinically diagnosed to be caused by global cerebral hypoxia. PMID- 8698289 TI - Incidence of spinal cord injuries in Plovdiv and Plovdiv region, Bulgaria. AB - This retrospective study was conducted to evaluate the incidence of spinal cord injuries in Plovdiv and Plovdiv region, Bulgaria. The study material comprised 980 patients treated over a period of 10 years (1983-1992) in the Clinics of Traumatic and Orthopaedic Surgery and Neurosurgery, University of Medicine, Plovdiv, which are the only therapeutic establishment in this region with a population of 750,000 to admit and treat this type of injury. Conservative treatment was applied in 34.46% of the patients using various methods: the method of Gorinevska-Dreving, immobilisation in either a plaster jacket or minerva depending on the injury site, the reclination methods of Davis-Erie or Watson Jones, cranial extension by Crutchfield. Operative treatment also was used and included posterior stabilisation with or without bone plastics, anterior vertebrodesis in the cervical and thoracolumbar regions from a transpleural and retroperitoneal approaches and anterior vertebrodesis with a partial or complete replacement of the vertebral body. PMID- 8698291 TI - Risk of homicidal behavior among discharged forensic psychiatric patients. AB - We studied the risk of homicidal behavior among 281 released male forensic psychiatric patients during the 14-year period 1978-1991. Released patients were about 300 times more likely to commit a homicide than the general male population during the first year outside hospital, and the corresponding risk was 53-fold during a mean follow-up period of 7.8 years. The odds ratio for committing a homicide among all Finnish schizophrenics during the 12-year period 1980-1991 was 9.7, which indicates that previous criminality associated with schizophrenia also increases the risk of homicidal behavior remarkably when compared with schizophrenia per se. We believe that this kind of epidemiological approach is a useful method of identifying and classifying factors associated with very high risk of homicidal behavior and preventing homicidal behavior among high-risk populations. PMID- 8698292 TI - Child homicide in Cologne (1985-94). AB - Twenty five child homicides investigated in the Cologne University Institute of Forensic Medicine from 1985-94 were retrospectively analysed with special reference to the evidential value of the autopsy findings and possible peculiarities related to the infants' physiological condition. About 65% of the victims were boys younger than 3 years. About 65% of the child homicides were committed by the mother in the parental flat, predominantly in the early hours of the evening during the weekend. The mode of death were 10x blunt injury, 6x sharp violence, 6x strangulation, 3x smothering, 2x drowning, 2x gunshot and 5x neglect (starvation). The defenseless, helpless and immobile condition of the infant particularly favours a homicide by manual assault, smothering or neglect (starvation). PMID- 8698293 TI - Endogenous methanol: variability in concentration and rate of production. Evidence of a deep compartment? AB - The endogenous methanol concentration was determined in 72 men aged between 18 and 35 years in the morning after a 12-h period of fasting and abstinence from alcohol. The distribution curve was found to be skewed to the right, the concentrations ranging from '0' (below the detection threshold) to 3.4 mg/kg. The median was 0.1 mg/kg and the mean 0.35 mg/kg. Significant differences were found between three groups defined according to the duration of prior abstinence from alcohol (8 h, 30 h, and 5 days). The highest values were seen after the shortest period of abstinence and the lowest values after the longest period of abstinence. The course followed by the methanol concentration in the presence of blocking of methanol oxidation by orally or parenterally administered ethanol was observed over at least 10 h on two separate occasions in a further 8 subjects aged between 24 and 35 years. At blood ethanol concentrations of more than 0.20 g/kg, the rate of production of methanol, calculated by regression, ranged from 0.09-0.37 mg/kg/h (r = 0.970-0.554, S(y.x) = 0.227-0.565 mg/kg). The rise in methanol concentration at the start of ethanol administration was significantly more rapid than the subsequent rise. It is hypothesised that there may be a so called deep compartment for methanol that would explain the dependence of the endogenous methanol level on the duration of the preceding period of abstinence from ethanol, and the occurrence of an initial phase of faster rise in methanol concentration associated with the administration of ethanol. PMID- 8698294 TI - Estimation of the breaking of rigor mortis by myotonometry. AB - Myotonometry was used to detect breaking of rigor mortis. The myotonometer is a new instrument which measures the decaying oscillations of a muscle after a brief mechanical impact. The method gives two numerical parameters for rigor mortis, namely the period and decrement of the oscillations, both of which depend on the time period elapsed after death. In the case of breaking the rigor mortis by muscle lengthening, both the oscillation period and decrement decreased, whereas, shortening the muscle caused the opposite changes. Fourteen h after breaking the stiffness characteristics of the right and left m. biceps brachii, or oscillation periods, were assimilated. However, the values for decrement of the muscle, reflecting the dissipation of mechanical energy, maintained their differences. PMID- 8698295 TI - A study of independence between STR and conventional blood type loci. AB - Blood samples from approximately 200 Scottish Caucasian individuals were typed at conventional loci (PGM, Gc and EAP) and also with a four locus STR multiplex. Tests of the data are described which demonstrate that the assumptions of between locus independence are robust for use in forensic casework. PMID- 8698296 TI - Facial soft-tissue thicknesses in the adult male Zulu. AB - The morphometric method of forensic facial reconstruction rests heavily on the use of facial soft tissue depth measurements. In reconstructing the Negroid face, much use has been made of the tables of soft tissue thickness of American Negroid cadavers. However, the genetic complexities of American blacks are well known. In addition it is felt that measurements made on the living are of more value than those made on the dead. In view of this it was decided to set up a table of norms for facial soft tissue depths of the living Zulu, an African Negroid who has remained relatively free from genetic admixture with other populations. The tightly controlled sample consisted of 55 healthy male Zulus, aged 20 to 35. Tissue depths at established landmarks were measured from lateral and oblique cephalometric radiographs. These were then combined with ultrasonic readings at other landmarks on the subject's face to yield a comprehensive set of tissue depth data. This paper presents a set of average facial soft tissue depth measurements from the Zulu face that results in the development of a new profile. It also provides a method for linking two systems of measurement. PMID- 8698297 TI - Emerging trends and perspectives. PMID- 8698298 TI - Barriers to pain management in hospice: a study of family caregivers. AB - Cancer-related pain not only affects the patient but the family/caregiver as well. The purpose of this study was to examine concerns about reporting pain and using analgesics in a sample of primary caregivers of cancer patients receiving care from a hospice program. The Barriers Questionnaire (BQ), an instrument designed to measure eight common barriers to adequate management of cancer pain, was administered to 37 persons identified as primary caregivers. Between 62 percent and 100 percent of the caregivers reported having at least some agreement with the various concerns that are barriers to reporting pain and using analgesics, and 3 percent to 43 percent reported having strong agreement. The subscales with the highest means were fear of opioid side effects, fear of addiction, the belief that increasing pain signifies disease progression, and the fear of injections. Caregivers who were older and less educated were more likely to believe that reporting pain may distract the physician from treating or curing the cancer. In addition, caregivers with lower educational levels had higher scores on the overall BQ. Finally, caregivers of patients who reported pain was not a problem on program admission had greater concerns about tolerance and were more likely to believe that "good" patients do not complain. The caregiver, often, with time and the declining abilities of the patient, becomes the first line decision maker regarding the patient's care and treatment. Understanding caregiver perspectives is important for continued success with managing pain in hospice and, arguably, all settings. PMID- 8698299 TI - A review of the research on spiritual care and hospice. AB - This article reviews the growing body of research and literature on spiritual care in hospice. In spite of the prominent role of spirituality in the British systems, only recently has the subject received any attention within our professional literature. It is the intent of this research to update hospice professionals on the research that does exist pertaining to spiritual care in hospice and related fields, and to propose new areas of needed research. PMID- 8698300 TI - A preliminary study of the impact of terminal illness on spouses: social support and coping strategies. AB - This study examined whether social support and particular coping strategies were associated with self-reported depression, anxiety, anger, and physical symptoms in spouses of terminally ill patients recently admitted to a hospice program. Forty-four spouses were assessed within two weeks of the patients' admission. Results showed that specific types of social support (namely, socialization, guidance, and cognitive information) and the coping strategy of wishful thinking were associated with self-reported level of anxiety. In addition, cognitive information and the coping strategies of wishful thinking and express emotions were associated with self-reported level of anger. Directionality and possible explanations for these findings are discussed. PMID- 8698301 TI - Meeting the social service needs of persons with AIDS: hospices' response. AB - A national sample of 148 directors of hospice social service departments (or persons most familiar with the delivery of social services in the hospice) participated in an exploratory study investigating the effects of the acquired immune deficiency syndrome (AIDS) epidemic on the delivery of hospice social services. Findings suggest, as does the literature, that the psychosocial needs of persons dying from AIDS present different challenges than those of traditional hospice patients. Furthermore, the results indicate the need for greater collaborative efforts among community agencies as well as specific and ongoing training for staff and volunteers who work with persons with AIDS (PWAs). Implications for the delivery of hospice social services to this population are discussed. PMID- 8698302 TI - Neuropathology of human immunodeficiency virus: questions and answers. PMID- 8698303 TI - Extraosseous primary and recurrent giant cell tumors: transforming growth factor beta1 and -beta2 expression may explain metaplastic bone formation. AB - Giant cell tumor (GCT) of bone is a locally aggressive neoplasm with a high incidence of recurrence, usually at the site of previous osseous involvement. Primary and recurrent intraosseous lesions typically are lytic and do not show evidence of tumor-associated osteogenesis. Rarely, GCT recurs or is primary within soft tissue, and not infrequently, these extraosseous lesions show metaplastic bone formation that is visible radiographically. The authors report two recurrent and one primary case of extraosseous GCT, all of which exhibited significant deposits of metaplastic bone localized to the periphery of the lesions. In situ hybridization showed messenger RNA (mRNA) for transforming growth factor beta1 (TGF-beta1) and transforming growth factor beta2 (TGF-beta2) in neoplastic stromal cells and osteoclast-like giant cells within the recurrent and primary extraosseous tumors as well as in active osteoblasts on the surfaces of recently formed spicules of metaplastic bone. In situ hybridization also revealed mRNA for TGF-beta1 and TGF-beta2 in primary intraosseous tumors from these cases and from four cases in which neither extraosseous recurrence nor osseous metaplasia was identified. In the microenvironment of the extraosseous soft tissue, production of these osteoinductive growth factors by GCT may have a paracrine effect on mesenchymal progenitor cells, thereby stimulating the osteoblastic differentiation and metaplastic bone formation associated with these lesions. PMID- 8698304 TI - The immunohistochemical localization of S100 in the diagnosis of papillary carcinoma of the thyroid. AB - In general, the diagnosis of papillary carcinoma of the thyroid is readily achieved based on a defined aggregate of histopathologic features. A papillary architecture is an important but not pivotal component of the diagnosis. The recognition of classic nuclear features is the essential diagnostic element. However, both the architectural and cytological hallmarks may be encountered in other conditions and produce problems in histopathologic interpretation. A papillary architecture may be encountered in hyperplastic areas of follicular neoplasms, multinodular goiter, and Graves' disease. Moreover, there may be scattered cells within several thyroid lesions that display some of the nuclear characteristics of papillary carcinoma. The distinction of these lesions from papillary carcinoma has important implications for clinical management. Thus, the availability of supportive diagnostic evidence would be helpful. In the authors' experience, the strong expression of S100 is of value in identifying papillary neoplasia and distinguishing it from examples of papillary hyperplasia. It is of supportive but not conclusive use in distinguishing follicular adenoma from the follicular variant of papillary carcinoma. The authors stress that the overwhelming factor in the distinction remains the identification of the nuclear characteristics of a papillary carcinoma. However, the authors have encountered several cases wherein the latter are either focal or absent for reasons addressed previously and have found immunohistochemistry a valuable adjunct to diagnosis. In examining papillary foci within Graves' disease, caution must be exercised; S100 expression is a phenomenon of the hyperplastic, hyperfunctional state. PMID- 8698305 TI - Neuropathology of human immunodeficiency virus infection at different disease stages. AB - The authors studied the brains of 471 adults infected with human immunodeficiency virus type 1 (HIV-1): 123 asymptomatic carriers, 127 in an early stage of acquired immunodeficiency syndrome (AIDS) with pulmonary tuberculosis or bacterial infections, and 221 in fully developed AIDS with opportunistic infections or neoplasms. Lymphocyte infiltration of the leptomeninges and of perivascular spaces occurred at all stages, but the frequency was significantly higher in asymptomatic carriers. Microglial nodules appeared at all stages of disease; they were not an early indicator of HIV encephalitis (HIVE). The incidence of HIVE was unrelated to the stage of AIDS, suggesting that HIVE occurs before opportunistic infections and neoplasms. Drug abuse, such as cocaine and opiates, may enhance HIV replication and increase the incidence of HIVE in the early stage of AIDS. Opportunistic infections or lymphoma involved only the brain in 31.2% of persons with fully developed AIDS. Conversely, opportunistic infections or neoplasms involved only organs other than the brain in 55.7% of persons with fully developed AIDS. In 13.1% of persons with fully developed AIDS, opportunistic infections or neoplasms involved the brain and other organs. Multiple intracranial opportunistic infections and lymphoma coexisted in 4.1% of persons with fully developed AIDS. The authors identified cerebrovascular disease in 10.6% of asymptomatic carriers, 7.1% of early AIDS, and 5.0% of fully developed AIDS. The observed sequence of abnormalities may be useful in understanding the progression of HIV disease in the brain. PMID- 8698306 TI - Distribution of transforming growth factor-beta isoforms in human immunodeficiency virus-1 encephalitis. AB - The transforming growth factor-beta family of polypeptides includes three related isoforms with pervasive effects on immune system function. In this study, the authors evaluated human brains with human immunodeficiency virus (HIV)-1 encephalitis for transforming growth factor beta (TGFbeta)1, TGFbeta2, and TGFbeta3 immunoreactivity using isoform-specific polyclonal antibodies and avidin biotin immunohistochemistry. Normal brains and those with progressive multifocal leukoencephalopathy, toxoplasma encephalitis, and cryptococcal meningitis were used as controls. In normal controls, TGFbeta1, TGFbeta2, and TGFbeta3 immunoreactivity were confined to arachnoid cells and blood vessels. In 9 of 10 cases of HIV-1 encephalitis, all three isoforms were also detected in arachnoid cells. In addition, variable, predominantly TGFbeta2 and TGFbeta3 immunoreactivity were also detected in reactive astrocytes and mononuclear cells of white matter lesions. Extensive TGFbeta3 immunoreactivity was also detected in multinucleated giant cells in one case. In a case of cryptococcal meningitis, all three isoforms were detected in arachnoid cells and macrophages. Lesions of progressive multifocal leukoencephalopathy and toxoplasma encephalitis also exhibited TGFbeta1, TGFbeta2, and TGFbeta3 immunostaining in reactive astrocytes. These findings suggest that TGFbeta isoforms are present in HIV-1 encephalitis and may participate in the pathogenesis of this and other inflammatory central nervous system (CNS) lesions associated with acquired immunodeficiency syndrome (AIDS). PMID- 8698307 TI - Anaplastic variant of spermatocytic seminoma. AB - Four examples of spermatocytic seminoma with a predominant anaplastic component occurred in men 33 to 43 years of age, without histories of cyptorchidism. The seminomas presented with painless testicular masses recognized 3 to 18 months before orchiectomy. Preoperative serum measurements of human chorionic gonadotropin and alpha-fetoprotein were negative. All tumors contained areas (10% to 30% of the tumor) in which the three cell types characteristic of conventional spermatocytic seminoma could be identified under light microscopy. The predominant anaplastic component also contained the three cell types, but the nuclei had prominent nucleoli with granular and filamentous chromatin. In addition, sheets of cells with vesicular nuclei and prominent nucleoli superficially resembling embryonal carcinoma were found. There were numerous large mononuclear and multinucleated giant cells with bizarre nuclei and prominent nucleoli, but no sarcomatous elements. Many normal and abnormal mitotic figures were present. Tunical and vascular invasion and extensive necrosis were constant features. Immunohistochemistry documented p53 protein overexpression in two tumors, but neoplastic cells were negative with immunostains for placenta like alkaline phosphatase, leukocyte common antigen, neuron-specific enolase, alpha-fetoprotein, human chorionic gonadotropin, vimentin, and cytokeratins. Ultrastructural examination of the anaplastic component showed large rope-like nucleoli, but the cytoplasmic features were similar to those of conventional spermatocytic seminoma. Despite the presence of a major anaplastic component, no patient has developed metastasis. Larger series and longer follow-up are needed to understand the natural history of these neoplasms. PMID- 8698308 TI - Automated sputum screening with PAPNET system: a study of 122 cases. AB - The use of interactive, computerized PAPNET system (Neuromedical Systems, Inc, Suffern, NY) for screening of cervicovaginal smears has been favorably evaluated in several studies. In this article, the authors report on the performance of this apparatus on smears of sputum. One hundred twenty-two randomly selected, single slides of sputum specimens from an equal number of patients were subjected to PAPNET scanning. These Papanicolaou-stained slides were previously classified as inadequate, six; negative, 81; atypical, three; suspicious, one; and positive for malignant cells, 31. Images selected by PAPNET were reviewed by two observers, who were blinded to earlier interpretation and triaged into two categories: negative and review. Of the 31 smears with cancer cells, 30 were appropriately identified by PAPNET (sensitivity: 97.1%). The only case missed by PAPNET was that of small cell carcinoma that contained a single cluster of neoplastic cells. PAPNET also triggered the review of 20 of the "negative" cases, which on re-evaluation were identified as bronchial cells with squamous metaplasia and altered benign squamous cells of inflammatory type. A prospective study of PAPNET for screening of sputum samples is needed to establish the clinical value of this methodology. PMID- 8698309 TI - Centroblastic and centroblastic-centrocytic lymphomas associated with prominent epithelioid granulomatous response without plasma cell differentiation: a clinicopathologic study of 12 cases. AB - To clarify the clinicopathologic features of B-cell lymphoma associated with prominent epithelioid granulomatous responses other than immunocytomas, 12 patients were studied. There were six men and six women. The lymphoma generally affected elderly patients (median age, 58.5 years) and was mostly nodal in origin. Seven of the 12 patients had a localized lesion (stage I or II), and five had an advanced lesion (stage III or IV). Histologically, four patients showed a follicular growth pattern and eight a diffuse growth pattern. Based on the updated Kiel classification, nine patients showed centroblastic lymphomas, and three showed centroblastic-centrocytic lymphomas. The epithelioid cells were accumulated in large, poorly demarcated masses. Trabecular fibrosis compartmentalized in the lymph nodes, producing a vague nodular pattern in low power fields. Immunohistochemical studies of the tumor cells revealed positive membrane staining with L26 in all 12 patients and with LN-1 antibody in 9 of 10 patients. Expression of the bcl-2 protein was present in all seven patients tested. Genotypic investigation exhibited germline configuration of the immunoglobulin heavy chain gene, the T-cell receptor beta-chain gene and the bcl 2 gene in all three patients investigated. By in situ hybridization, Epstein-Barr virus genomes were detected in only a few tumor cells in three of the patients tested. This study indicated that most, if not all, of the B-cell lymphomas with prominent epithelioid granulomatous responses other than immunocytoma were of follicular center cell origin. PMID- 8698310 TI - Apoptotic versus proliferative activities in human benign prostatic hyperplasia. AB - Cell growth in the normal prostate is regulated by a delicate balance between cell death and cell proliferation (ie, apoptotic v proliferative activity). Disruption of the molecular mechanisms that regulate these two processes may underline the abnormal growth of the gland leading to benign prostatic hyperplasia (BPH). In this study, the incidence of programmed cell death (apoptosis) and cell proliferation was comparatively analyzed among the various cell subpopulations in the normal and benign hyperplastic human prostate. The authors also examined the relative expression of two proteins involved in the regulation of prostate apoptosis: (1) transforming growth factor (TGF)-beta1, a negative growth factor able to induce prostate apoptosis under physiological conditions; and (2) bcl-2, a potent apoptosis suppressor. Analysis of the incidence of "spontaneous" apoptosis in situ, using the end-labeling terminal transferase staining technique for the detection of nucleosomal DNA fragmentation, revealed infrequent apoptotic staining in isolated basal and secretory prostate epithelial cells. The basal level of cell proliferation was determined on the basis of the Ki-67 nuclear antigen staining, a nuclear protein that appears primarily during the proliferative phases of the cell cycle. The Ki 67-positive nuclei were equally distributed among the basal and secretory epithelial cells of the hyperplastic prostatic acini. The apoptotic index of the secretory and basal cells of the prostate epithelium was higher in the normal prostate compared with BPH tissue, whereas there was a significant increase in the proliferative index of the respective cell populations in the hyperplastic prostate. Balancing the apoptotic versus the proliferative activities revealed a substantial net decrease (fourfold) in the total number of cells dying via apoptosis in both the glandular and basal epithelial cell compartments of the hypertrophic prostate (BPH) when compared with the normal gland. TGF-beta staining was exclusively identified in the secretory epithelial cells, lining the prostatic lumen with minimal involvement of the basal cells and total lack of immunoreactivity among the stroma elements. Statistical analysis revealed a significant elevation in TGF-beta expression in the epithelial cells of BPH tissue compared with the normal prostate (P < .001). Expression of bcl-2 was topologically restricted to the glandular epithelium of the prostate. In the normal prostate, bcl-2 immunoreactivity was predominantly identified in the basal cell layer. An increase in both the intensity of immunoreactivity for bcl-2 and the number of positive epithelial cells (basal and secretory) was detected in BPH specimens relative to the normal prostate (P < .02). These results suggest a potential involvement of enhanced expression of this antiapoptosis protein in deregulation of the normal apoptotic cell death mechanisms in the human prostate, thus resulting in a growth imbalance in favor of cell proliferation that might ultimately promote prostatic hyperplasia. PMID- 8698311 TI - DNA ploidy and p53 expression correlate with survival and cell proliferative activity in male breast carcinoma. AB - DNA flow cytometry and the monoclonal antibody DO7 were applied in formalin fixed, paraffin-embedded specimens from 34 primary male breast carcinomas to verify whether DNA ploidy and p53 expression were associated with survival and proliferative activity. They were compared with tumor clinicopathologic features, sex steroid hormone receptors and cell proliferative activity, assessed by the counts of the argyrophilic nucleolar organizer regions (AgNORs), the monoclonal antibody PC10 against the proliferating cell nuclear antigen and the monoclonal antibody MIB-1. A significant correlation was found between survival and tumor ploidy (median survival, 77 months for diploid but only 38 months for aneuploid cases; P = .03) and p53 expression (median survival, 95 months for cases with p53 scores < or = 14.06% versus 33 for cases with P53 scores > 14.06%; P = .0004; median survival, 99 months for p53 negative vs 39 for positive cases; P = .007). Tumor histological grade (P = .006), AgNOR counts (P = .0001), PC10 scores (P = .002), and MIB-1 scores (P = .001) were also associated with prognosis. In the multivariate analysis, only p53 scores (P = .001) or p53 immunopositivity (P = .003) and AgNOR counts (P = .022) retained an independent prognostic significance. Aneuploid tumors had higher AgNOR counts (P = .002), PC10 (P = .007), MIB-1 (P = .006), and p53 scores (P = .01) than diploid cases. A linear relationship was observed between p53 scores and AgNOR counts (r = .41; P = .014), PC10 (r = .46; P = .005), and MIB-1 scores (r = .44; P = .011). These results indicate that DNA ploidy and p53 expression are associated with survival and cell proliferative activity in male breast carcinoma. Quantitative parameters, such as DNA ploidy, p53 scores, AgNOR counts, PC10, and MIB-1 scores substantially improve the prognostic significance of the traditional parameters in male breast carcinoma. PMID- 8698312 TI - Neuroendocrine differentiation in prostate cancer: enhanced prediction of progression after radical prostatectomy. AB - It is controversial whether neuroendocrine (NE) differentiation in adenocarcinoma of the prostate is associated with more aggressive behavior. Most studies included patients with tumors of a wide range of grades and stages and an end point of disease-specific survival, a relatively insensitive marker of progression. The authors studied completely embedded radical prostatectomy specimens from 104 patients with clinically organ-confined carcinoma and no history of adjuvant or neoadjuvant therapy. Progression was marked by a serum prostate-specific antigen (PSA) concentration greater than or equal to 0.2 ng/mL. Seventy-six men did not progress, with a mean follow-up period of 8.0 years (range = 7 to 10 years). Forty-eight men progressed at a mean time after surgery of 3.6 years (range = 1 to 8 years). Twenty-one percent of the tumors were organ confined: 79% had capsular penetration. Seminal vesicles and lymph nodes were negative in all cases. A representative section through the main tumor mass was stained for chromogranin A. Reactive neoplastic cells were counted subjectively as well as individually enumerated. Gleason grade, pathological stage, and degree of NE differentiation all correlated with progression. Only grade and extent of NE differentiation predicted progression in a multivariate analysis. NE differentiation did not correlate with stage or grade. Extent of NE differentiation separated patients (59 cases) with tumors of Gleason sum less than or equal to 6 into groups with high and low risks for progression (P < .008) independent of Gleason sum. Extent of NE differentiation provides prognostic information in addition to that provided by grade in cases of early prostate cancer treated by radical prostatectomy. PMID- 8698313 TI - Comparative analysis of mRNA and protein expression for epidermal growth factor receptor and ligands relative to the proliferative index in human prostate tissue. AB - The expression of epidermal growth factor receptor (EGF-R), transforming growth factor alpha (TGFalpha), and epidermal growth factor (EGF) was evaluated in a series of prostate cancer (CaP; n = 55) and benign prostate hyperplasia (BPH; n = 44) specimens using immunocytochemistry (ICC) and Northern blotting. In situ hybridization (ISH), performed on a subgroup of these specimens, proved to be a more informative technique for the assessment of messenger RNA (mRNA) in this heterogeneous tissue. A comparative analysis was made in relation to the proliferative index, assessed using the MIB-1 antibody. Elevated levels of EGF-R and TGFalpha, mRNA, and protein were observed in carcinoma cells compared with benign, secretory epithelium using in situ hybridization and immunocytochemistry. In carcinoma specimens evidence of an autocrine growth loop is provided by a correlation between EGF-R and TGFalpha, mRNA (P < .0001), and protein expression (P < .01). A trend toward increased expression of EGF-R and TGFalpha protein with dedifferentiation and a similar trend in the growth fraction suggest a role in tumor progression. Although there was a correlation between EGF-R and the proliferative index (P < .01), no relationship was found between this latter parameter and TGFalpha immunoreactivity (P > .05), indicating that this growth factor may be linked with other aspects of malignant activity rather than directly stimulating proliferation. PMID- 8698314 TI - The prognostic significance of tumor angiogenesis in nonaggressive and aggressive basal cell carcinoma of the human skin. AB - Basal cell carcinoma (BCC) is currently the most common cutaneous cancer found in humans. Although it generally shows a relatively benign course (BCC1), some cases of BCCs show "aggressive" behavior, rapidly infiltrating deeper structures, or metastasizing (BCC2). Until now, the traditional histological diagnostic criteria have failed to discriminate unequivocally between BCC1 and BCC2. Therefore, there is still a need to find reliable prognostic indicators that correlate with outcome and may detect patients at high risk for BCC recurrence, or metastasis and death. Recent studies have suggested that there is a significant correlation between tumor angiogenesis, expressed as the microvessel density within and toward a tumor, tumor aggressiveness, and the overall survival of patients with solid tumors. In this study, the authors examined the angiogenic rate in human cutaneous BCCs, to establish if it correlates with their biological behavior. Vessels were highlighted by immunocytochemical staining for FVIII-related antigen in formalin-fixed, paraffin-embedded tissues. All BCC2 samples of this series showed a significantly higher microvessel count than did BCC1. The existence of a significant discrepancy between the neovascularization in BCC1 and BCC2 suggests that the angiogenetic process may be an important step in the acquisition of the aggressive (malignant) phenotype in human. BCCs. The findings of the present study seem to establish a correlation between tumor vascularization and clinicobiological parameters of aggressiveness in BCC. Considering the emerging studies on the possible clinical use of substances interfering with the angiogenetic process, it is possible that the local therapy for BCCs could become less destructive, with consequent improvement in the quality of life of these patients, apart from the prolongation of the overall survival. From this view point, the assay of microvessel density might be helpful in selecting patients with cutaneous BCCs at high risk for recurrence or metastasis, who could benefit ab initio from additional therapies and closer follow-up. PMID- 8698315 TI - Differences in T-cell-receptor gene rearrangement and transcription in nasal lymphomas of natural killer and T-cell types: implications on cellular origin. AB - Although nasal lymphomas showing midfacial destructive lesions had been classified as T-cell lymphomas, their exact cellular origin is still unclear. Although they usually express a restricted number of T-cell-related antigens, namely, CD2, CD43, and CD45RO, other pan-T or subset-T-lineage antigens, such as CD3 (membrane), CD5, CD4, CD8, and CD7, are frequently absent. Conversely, they often express a natural killer (NK) cell-associated antigen, CD56, but lack other mature NK markets. To study their cellular origin further, the authors analyzed T cell receptor (TCR) gene transcription in three cases of nasal lymphomas and correlated the findings with the phenotype and gene rearrangement data. Two cases of nasal lymphomas with CD2+CD3(Leu4)-CD19-CD56+ phenotype were shown to express truncated 1.0-kb Tbeta and multiple unrearranged Tdelta transcripts with germline TCR beta, gamma, delta, and immunoglobulin heavy-chain joining region (JH) genes, consistent with NK cell lineage. In contrast, one case of nasal lymphoma with CD2+CD3(Leu4)+CD8+CD19-CD56+ phenotype expressed full-length Talpha, Tbeta, and Tgamma transcripts rearranged TCR beta, gamma, and deleted TCR delta genes, indicating T-lineage, These results support the view that nasal lymphomas can separated into NK-cell and T-cell neoplasms, based on differences genotypic characteristics. The possibility of these tumors being derived from a putative common precursor cell merits further investigation. PMID- 8698316 TI - Very early complete hydatidiform mole. AB - Recent trends toward early pregnancy ultrasound have led to evacuation of complete hydatidiform moles at a stage before the development of diffuse trophoblast hyperplasia and villous cavitation. Absence of these recognized diagnostic criteria can lead to misdiagnosis and subsequent trophoblastic neoplasia. The authors identified a case of very early complete hydatidiform mole (VECM) on review of a previous curettage specimen when the patient presented 4 weeks later with increasing human chorionic gonadotropin (HCC) titers and the typical histological features of complete mole on a subsequent curettage. DNA studies on this index case and three subsequent similar specimens confirmed the diagnosis of complete hydatidiform mole using polymerase chain reaction (PCR) amplification of eight microsatellite markers on microdissected maternal and villous tissue. VECM were compared with spontaneous abortions and elective terminations of a similar gestational age to develop diagnostic criteria. Five cardinal diagnostic features were identified: redundant bulbous terminal villi, hypercellular villous stroma, a labyrinthine network of vinous stromal canaliculi, focal cytotrophoblast and syncytiotrophoblast hyperplasia on both villi and the undersurface of the chorionic plate, and enlarged hyperchromatic implantation site trophoblast. PMID- 8698317 TI - Bronchiolitis obliterans organizing pneumonia-like reactions: a nonspecific response or an atypical form of rejection or infection in lung allograft recipients? AB - Bronchiolitis obliterans organizing pneumonia (BOOP) is a ubiquitous entity, known to occur either idiopathically or in association with various pulmonary disorders. Histologically, it is characterized by myxomatous connective tissue plugs present in the lumen of bronchioles with extension into the alveoli. Its significance in lung allograft recipients is not well documented. The authors reviewed all post-lung transplant biopsies (565 transbronchial; 19 open), explanted lungs for retransplantation (six), and autopsies (38) from 115 patients. A total of 32 patients (18 females and 14 males) showed histological evidence of BOOP-like reactions (ie, Masson bodies in 44 transbronchial and seven open lung biopsies). The mean age was 47 years (range = 14 to 69 years). Sixteen patients were recipients of single lungs, 14 received bilateral single lungs, and two had heart and double-lung transplants. BOOP-like reactions (BOOP-LRs) occurred as early as day 5 and as late as day 1,208 (40 months) posttransplantation. Twenty patients had one biopsy showing BOOP-LR, of which three patients had resolving mild acute rejection, four had ongoing minimal acute rejection, seven had ongoing mild acute rejection, one each had ongoing moderate and bronchiolar rejection, and four showed associated cytomegalovirus (CMV) pneumonitis. Seven patients had two biopsies each of BOOP-LR of which six were associated with ongoing minimal or mild acute rejection, and one had resolving mild acute rejection. Three patients had three biopsies each of BOOP-LR all associated with ongoing minimal or mild acute rejection. Two patients had four biopsies each, showing BOOP-LR, with ongoing mild or moderate acute rejection or CMV pneumonitis. Forty of the total 115 lung transplant patients (34.8%) have developed bronchiolitis obliterans syndrome (BOS) or chronic airway rejection. Twelve of these patients are from the study group, of which five have a biopsy proven histological diagnosis of obliterative bronchiolitis (OB), and the remaining seven patients have been diagnosed clinically by deteriorating lung function tests. The authors conclude that BOOP-LR in the lung transplant setting result from acute epithelial injury secondary to either allograft rejection or an ongoing infection and are not a component of, nor do they necessarily predispose to, chronic rejection. PMID- 8698318 TI - Gain and loss of chromosomes 1, 7, 8, 10, 18, and Y in 46 prostate cancers. AB - Fluorescence in situ hybridization (FISH) with centromere probes was used to investigate numerical aberrations of chromosomes 1, 7, 8, 10, 18, and Y in 46 prostate carcinoma (PC) and 11 benign prostatic hyperplasia (BPH) samples. None of the benign specimens showed any chromosomal aberration. Forty-one of 46 PC specimens showed numerical aberrations of one or more chromosomes. All investigated chromosomes showed numerical aberrations in at least 30% of the specimens, gain being more frequent than loss. Comparison of DNA flow cytometry (FCM) and FISH results showed that not only aneuploid tumors but also most diploid tumors harbored numerical chromosome aberrations. Chromosome 10 was the most frequently gained (65%), and Y the most frequently lost chromosome (14%). Nonmetastatic and metastatic tumors differed significantly (P < .05) in the number of copies for chromosomes 7, 8, and 10, but not for 1, 18, and Y. These results suggest strongly that gains of chromosomes 7, 8, and 10 are involved in PC progression. PMID- 8698319 TI - Immunohistochemical detection of parathyroid hormone-related protein in a rare variant of hepatic neoplasm (sclerosing hepatic carcinoma). AB - Sclerosing hepatic carcinoma represents an uncommon subtype of hepatic malignancy, frequently associated with hypercalcemia. We applied immunohistochemistry using the avidin-biotin-complex technique to examine the presence of parathyroid hormone-related protein (PTHrP) in formalin-fixed and paraffin-embedded sections of tissue from a case of sclerosing hepatic carcinoma obtained at autopsy. Two polyclonal antibodies against the regions 24 to 35 and 107 to 111 of human PTHrP, and a monoclonal antibody that recognizes the human sequence 38 to 64 of this protein, were used. Preabsortion tests using the corresponding synthetic peptide as antigen were done with these antibodies. The neoplastic tissue displayed cytoplasmic immunostaining, diffuse with the antibodies against the amino- or carboxy-terminal regions of PTHrP, and with a predominant peripheral pattern when using the antibody to the midregion of the molecule. Tumor cells positive for PTHrP were also positive for hepatocellular markers cytokeratins 10, 17, and 18, but negative for chromogranin A. Our findings provide the first evidence for PTHrP production in the sclerosing subtype of hepatic carcinoma. PMID- 8698320 TI - Complete hydatidiform mole with a coexistent embryo. AB - We describe a case of a complete hydatidiform mole with a coexistent embryo. A 19 year-old Hispanic woman presented with an intrauterine pregnancy at 7 weeks gestational age. An ultrasound evaluation at that time showed a gestational sac and fetal heart activity was observed. Four weeks later, subsequent ultrasound study revealed no evidence of an embryo, and a pattern consistent with a hydatidiform mole. Dilation and curettage was subsequently performed that showed a classic hydatidiform mole on histological examination. Chromosome analysis revealed a normal 46,XX karyotype. DNA was extracted from the placental tissue, as well as maternal and paternal blood. Molecular genetic analysis was; performed with four variable number of tandem repeats (VNTR) probes and showed the placental tissue to consist of only paternal DNA with two genomic copies of each allele studied. These findings are consistent with the diagnosis of complete hydatidiform mole and its origin from an empty ovum fertilized by a single sperm. This is the first reported case of a living embryo coexistent with a complete hydatidiform mole documented by genetic analysis. PMID- 8698321 TI - Cutaneous ganglioneuromas: a case report and review of the literature. AB - The occurrence of ganglioneuromas outside the sympathetic chains of the mediastinum and abdomen in the nonpediatric age group is rare. We report the case of a solitary cutaneous ganglioneuroma on the abdomen of a 52-year-old woman. The lesion, which had been present for 20 years, measured 1.2 cm in greatest dimension. Unmyelinated axons, Schwann cells, and scattered mature ganglion cells were identified by histochemistry, immunohistochemistry, and electron microscopy. Only three similar cases have been reported in the literature to date. Ganglioneuromas have also been reported as mature components of metastatic neuroblastomas and in association with plexiform neurofibromas, neither of which was present in this case. The pathogenesis of this lesion is unclear, however, aberrant migration of neural crest elements is the most likely explanation. The possible trophic role of sex steroids is also discussed. Although no follow-up series exist, local excision should he curative considering the small size and histologically benign appearance of the lesion. PMID- 8698323 TI - Ductal carcinoma in situ with periductal fibrosis -- is it in reality an invasive carcinoma? PMID- 8698324 TI - Nonisotopic in situ hybridization in the detection of integrated HPV 16/18 in cervical cancers. PMID- 8698322 TI - Cutaneous CD56+ large T-cell lymphoma associated with high serum concentration of IL-2. AB - We report the case of a patient with a clinically aggressive large cell lymphoma (LCL) which expressed several T-lymphocyte markers and, in addition, CD56 and, to a lesser degree, CD68 antigens. A marked increase in serum concentration of interleukin (IL)-2 was found (490 and 167 pg/0.1 mL in two serum samples collected 6 months apart). This increase in IL-2 appeared unique to this lymphoma because serum concentration of IL-2 was not increased in any of the cases of various types of cutaneous lymphoproliferative disorders tested: mycosis fungoides-related cutaneous T-cell lymphoma (CTCL: 28 patients), granulomatous slack-skin syndrome (GS-SS: 1 patient), anaplastic large cell lymphoma (ALCL: 2 patients), subcutaneous gamma/delta T-cell lymphoma (gamma/delta-TCL: 1 patient), adult-type leukemia/lymphoma (ATLL: 1 patient), and lymphomatoid papulosis (LyP: 4 patients). Furthermore, the increase in IL-2 serum concentration appeared selective in this CD56+ large-cell lymphoma-bearing patient, because concentration of none of the five other cytokines tested (IL-4, IL-6, IFNgamma, GM-CSF, and TNFalpha) was increased. In contrast, soluble receptors for IL-2 and two of the other cytokines (IL-6, and TNFalpha) were markedly increased not only in this patient, but also in most patients with the other cutaneous lymphoproliferative disorders that we examined except for lymphomatoid papulosis. These data indicate that increased IL-2 serum concentration may help to diagnose a unique type of cutaneous CD56(+) large (T-) cell lymphoma and suggest that IL-2 way play a role of an autocrine growth factor for this lymphoma. PMID- 8698325 TI - A pericentric inversion of chromosome six in a patient with Peutz-Jeghers' syndrome and the use of FISH to localise the breakpoints on a genetic map. AB - Karyotypic analysis in a patient with Peutz-Jeghers' syndrome demonstrated a pericentric inversion on chromosome 6. Further investigation was undertaken using fluorescence in situ hybridisation (FISH) with yeast artificial chromosome clones selected to contain genetic markers from chromosome 6, and a probe for the centromeric alphoid repeat array. This analysis located one inversion breakpoint within the alphoid array, in a 1-cM interval between D6S257 and D6S402, and the other in a 4-cM interval between D6S403 and D6S311. The oestrogen receptor gene locus (ESR) is excluded from the latter interval. PMID- 8698326 TI - The Ca(2+)-sensing receptor gene (PCAR1) mutation T151M in isolated autosomal dominant hypoparathyroidism. AB - Isolated autosomal dominant hypoparathyroidism is a heterogeneous disorder characterized by parathyroid hormone (PTH) deficiency, hypocalcemia and hyperphosphatemia. The candidate gene approach was used to study a large Norwegian family. The loci for the PTH gene, PTH receptor gene and RET protooncogene were excluded using dinucleotide markers and restriction fragment length polymorphism analysis. Complete cosegregation of this trait was found with the chromosomal region 3q13, using the short tandem repeat markers D3S1267, D3S1269, D3S1303, D3S1518, and RHO. This region contains the candidate locus for the Ca(2+)-sensing receptor (PCAR1). By single-strand conformation polymorphism (SSCP) analysis of all PCAR1 exons followed by automated sequencing, we identified a C to T transition in exon 2 (cDNA position 452) on the mutant allele in the family. The mutation predicts a substitution of Thr to Met in amino acid position 151 (T151M). A StyI restriction site created by the nucleotide substitution was used to confirm the mutation on all alleles, as well as to exclude it among 100 normal alleles (blood donors). SSCP analysis also identified a novel polymorphism of PCAR1 intron 4 (1609-88t --> c) on normal alleles. The T151M mutation is located in the extracellular N-terminal domain of PCAR1, which belongs to the superfamily of G protein-coupled receptors. We suggest that this is a gain-of-function mutation that increases the sensitivity of the receptor to [Ca2+], thereby decreasing the calcium set point. PMID- 8698327 TI - Identification of a Ser857-Asn857 substitution in DRK1 (KCNB1), population frequencies and lack of association to the low voltage alpha EEG trait. AB - A nonconservative amino acid substitution (Ser857Asn) in the human delayed rectifier potassium channel DRK1 (KCNB1 locus), a candidate gene for the low voltage alpha electroencephalogram (EEG) trait locus (LVEEG1) at 20q13.2, and its frequency in ethnic population samples are described. The frequency of Asn857 in seven different ethnic population samples, totalling more than 1600 individuals, ranged from zero to greater than 3%. However, no association was found between Asn857 and the low voltage alpha EEG trait (LVA) in a population of 105 subjects assessed for the EEG, 24 of whom actually had LVA. PMID- 8698328 TI - Small increase in triplet repeat length of cerebellum from patients with myotonic dystrophy. AB - Myotonic dystrophy (DM) is genetically characterized by abnormal expansion of an unstable CTG trinucleotide repeat, located in the 3'-untranslated region of mRNA encoding the family of serine-threonine protein kinases. DNA extracted from various organs of patients with DM was analyzed by the Southern blotting method. We identified differently expanded bands in DNAs from various tissues from patients with DM. In studying the length of the CTG repeat in different regions of the brain, we found a noticeably small increase in repeat length in the cerebellum compared with other tissues. While this phenomenon has been reported in other triplet repeat diseases such as Huntington disease, spinocerebellar ataxia type 1, and dentatorubral-pallidoluysian atrophy, we are the first to describe it in DM. Although the mechanism of expansion of the triplet repeat remains to be defined, the tissue-dependent somatic mosaicism suggests that its occurrence may depend on the differentiated state of each tissue. PMID- 8698329 TI - Pycnodysostosis: refined linkage and radiation hybrid analyses reduce the critical region to 2 cM at 1q21 and map two candidate genes. AB - Pycnodysostosis (PKND) is a rare, autosomal recessive skeletal dysplasia, which has been mapped previously to a 4-cM interval between D1S442 to D1S305 at chromosome 1q21. Only D1S498 did not recombine with the disease locus in a large, consanguineous Arab family with PKND. In the present studies, five new Genethon markers (D1S2343, D1S2344, D1S2345, D1S2346, and D1S2347) were tested against DNA from this family and against the Stanford G3 diploid radiation hybrid panel. The results permitted ordering of some loci previously mapped at no recombinant distance: D1S442-D1S2344-(D1S498/D1S2347)-(D1S2343/+ ++D1S2345)-D1S2346 D1S305.The PKND critical region was refined to the 2-cM interval from D1S2344 to D1S343/D1S2347. In addition, sequence-tagged sites were developed for the two PKND candidate genes, IL6R and MCL1. Use of radiation hybrids revealed that IL6R was tightly linked to D1S305, excluding it from the PKND critical region. MCL1 was most tightly linked to D1S498 and D1S2347, placing it within the critical region. PMID- 8698330 TI - Geographic homogeneity and non-equilibrium patterns of mtDNA sequences in Tuscany, Italy. AB - The geographical distribution of 49 mtDNA sequences from 22 localities in Southern Tuscany, Italy, was studied by molecular analysis of variance, by a new spatial autocorrelation statistic specifically designed for sequence data and by reconstructing genealogies of haplotypes. All these methods indicated a high homogeneity of populations. Nevertheless, genetic variability showed significant departure from equilibrium expectations, in agreement with the predicted effects of a population expansion. We suggest that a past population expansion that was probably associated with a migrational wave and with local gene flow between localities prevented spatial structuring in Southern Tuscany. PMID- 8698331 TI - Stability of triplet repeats of myotonic dystrophy and fragile X loci in human mutator mismatch repair cell lines. AB - At least nine human genetic diseases, including myotonic dystrophy (DM) and fragile X syndrome have been associated with the expansion of CTG or CGG trinucleotide repeats within the disease loci. Little is known about the molecular mechanisms or the genetic control of the expansion of triplet repeats. Mutations in human mismatch repair genes are associated with the increased polymorphism of many microsatellites, including dinucleotide repeats. The effect of mutations in two mismatch repair genes on the size of trinucleotide repeats in the DM and FRAXA loci has been analyzed. PCR and Southern analysis of the triplet repeat regions of the DM and fragile X mental retardation (FRAXA) loci in cell lines HTC116 and LoVo, which contain mutations in both alleles of the hMLH1 and hMSH2 genes, respectively, indicated that the size of the endogenous (CTG)n and (CGG)n tracts fall within the range observed in the normal population. This suggests that mutations in hMLH1 or hMSH2 do not result in the instability of CTG or CGG tracts to the levels observed in individuals with myotonic dystrophy or fragile X syndrome. PMID- 8698332 TI - Analysis of sex and delta F508 in single amniocytes using primer extension preamplification. AB - Reliable sex determination is an inevitable prerequisite in prenatal and preimplantation diagnosis of X-linked diseases. We report on an amelogenin-based nested polymerase chain reaction sexing method that simultaneously amplifies distinguishable fragments from both sex chromosomes. Primers matching a largely homologous region on both sex chromosomes are used that encompass a 177-bp deletion on the Y chromosome. Thus amplification results in X- and Y-specific fragments of different sizes that are resolved simply by agarose gel electrophoresis. We applied our sexing strategy to 102 single amniocytes previously subjected to primer extension preamplification. 95 showed successful amplification (93.14% sensitivity). The genotyping of all successful amplifications (from 42 male and 53 female amniocytes) was found to be correct (100% specificity). None of the media blanks showed amplification products (no false positives). Additional amplification of the locus of the most common cystic fibrosis mutation resulted in 95.1% success: 89 amniocytes (87.3%) showed no mutated allele and 7 (6.9%) were found to be heterozygous for the delta F508 mutation. PMID- 8698333 TI - Fetal cells in maternal blood: recovery by charge flow separation. AB - Fetal blood cells can be recovered from the maternal circulation by charge flow separation (CFS), a method that obviates the risks associated with amniocentesis and chorionic villus sampling. By CFS, we processed blood samples from 13 women carrying male fetuses, 2 carrying fetuses with trisomy 21, and 1 who had delivered a stillborn infant with trisomy 18. On average more than 2000 fetal nucleated red blood cells were recovered per 20-ml sample of maternal blood. Recovery of fetal cells was confirmed by fluorescence in situ hybridization with probes for chromosomes Y, 18 and 21. After culturing of CFS-processed cells, amplification by the polymerase chain reaction revealed Y-chromosomal DNA in clones from four of six women bearing male fetuses, but not in clones from three women bearing female fetuses. PMID- 8698334 TI - Mutation screening of 17 Japanese patients with neuropathic Gaucher disease. AB - Using PCR and PCR-single strand conformation polymorphism (SSCP) we have identified gene mutations in 17 Japanese patients with neuropathic Gaucher disease (type 2, 9 cases; type 3, 8 cases). The L444P, F213I, D409H, and 1447 del 20 and 1447 ins TG mutations accounted for eight (type 2, 6; type 3, 2), seven (type 2, 2; type 3, 5), three (type 3), and three (type 2) alleles, respectively. Three alleles were unique. Ten alleles (type 2, 5; type 3, 5) could not be identified. The genotypes, D409H/?, L444P/?, L444P/F213I, and F213I/?, were identified in three, three, two, and two patients, respectively. Six patients had a unique genotype and none of the mutant alleles could be identified in one patient. The data indicate that the genotypes in Japanese patients with neuropathic Gaucher disease are found to be heterogeneous and the genotype prevalence and mutated alleles are unique. PMID- 8698335 TI - X-linked dominant Charcot-Marie-Tooth neuropathy (CMTX): new mutations in the connexin32 gene. AB - X-linked dominant Charcot-Marie-Tooth (CMTX) neuropathy has been mapped to the Xq13 region. Subsequently, several mutations that could account for CMTX have been detected in the coding part of the connexin32 (Cx32) gene, which is located within this region. In order to develop more specific diagnostic tools, we have begun a systematic screening of families with dominant CMTX for mutations in the coding region of the Cx32 gene. This report describes a study of ten families and different mutations segregating with the disease were detected in five of them. In addition to the previously reported Arg22stop and Arg215Trp substitutions, three novel mutations are described, including two different missense mutations at codon Arg22 (Arg22Pro and Arg22Gly), and a nonsense mutation at codon Trp133. The identification of new CMTX-causing mutations is a critical step for carrier detection and presymptomatic diagnosis, and should provide essential information on the structure-function relationship of Cx32 in vitro as well as in vivo. PMID- 8698336 TI - The G1691A mutation of the coagulation factor V gene (factor V Leiden) is rare in Chinese: an analysis of 618 individuals. AB - To understand the allele frequency of the G1691A mutation of the coagulation factor V gene (factor V Leiden) in Chinese, 618 Chinese individuals, including 54 cases with venous thrombosis, were analyzed. Only one case in the control group was heterozygous for the 1691G allele and the 1691A allele. Our data suggest that the factor V Leiden is rare in Chinese. PMID- 8698337 TI - X-linked myotubular myopathy: refinement of the gene to a 280-kb region with new and highly informative microsatellite markers. AB - We have recently refined the localization of the myotubular myopathy (MTM1) gene to a 430-kb region between DXS304 and DXS1345 in proximal Xq28. We report two new polymorphic microsatellite markers, DXS8377 and DXS7423, that were physically mapped within the critical interval. A recombination event in a family segregating for MTM1 placed the disease gene telomeric to the trinucleotide polymorphism DXS8377. Together with the recent mapping of two microdeletions associated with MTM1, the recombination refines the critical region to 280 kb. A second recombination event was observed distal to the tetranucleotide repeat DXS7423. This recombination has occurred in the off-spring of a female with a more than 67% probability of being a carrier and very likely restricts the MTM1 gene to a 130-kb region. This physical refinement is significant for positional cloning of the disease gene. The highly polymorphic markers and the precise localization of the MTM1 gene will facilitate genetic diagnosis of the disorder. PMID- 8698338 TI - An intron 1 splice mutation and a nonsense mutation (W23X) in CYP21 causing severe congenital adrenal hyperplasia. AB - Direct DNA sequencing of the steroid 21-hydroxylase gene (CYP21) revealed two novel mutations in two patients with severe congenital adrenal hyperplasia. The nonsense mutation Trp23Stop (TGG --> TGA) was found in a woman with the simple virilizing form of the disease. She was a compound heterozygote, with the previously described Ile173Asn mutation on her other allele. A boy, who developed salt-wasting in the neonatal period, carried an allele with a novel mutation of the canonical splice acceptor site in intron 1 (AG --> GG). He was also a compound heterozygote, with the well-known splice mutation in intron 2 on his other allele. PMID- 8698339 TI - Sporadic cardiac myxomas and tumors from patients with Carney complex are not associated with activating mutations of the Gs alpha gene. AB - Cardiac myxomas are rare tumors that may be encountered sporadically or in the context of the Carney complex. The molecular basis for the development of cardiac myxomas and Carney complex tumors is unclear. Pathological myocardial function and myocardial hypertrophy have been associated with alterations in the heterotrimeric GTP-binding proteins. The postulated proto-oncogenic character of the gene encoding the alpha sub-unit of the stimulatory GTP-binding protein Gs alpha (gsp) in pituitary and thyroid tumors, the finding of identical somatic gsp mutations in the myocardium of patients with McCune-Albright syndrome, and the associated endocrine anomalies of the Carney complex prompted us to investigate the occurrence of activating missense mutations in the Gs alpha gene in 10 sporadically occurring atrial myxomas and in 8 tumors from 7 patients with Carney complex. No gsp mutations could be demonstrated by using the polymerase chain reaction and denaturing gradient gel electrophoresis complemented by direct DNA sequencing. Thus, activating Gs alpha mutations neither are associated with the development of atrial myxomas, nor can be demonstrated in other tumors from patients with Carney complex. The significance of these mutations in the myocardium of asymptomatic patients with McCune-Albright syndrome remains to be determined. PMID- 8698340 TI - Mutational spectrum in the neurofibromatosis type 2 gene in sporadic and familial schwannomas. AB - Using a heteroduplex approach and direct sequencing, we have completed the screening of approximately 88% of the neurofibromatosis type 2 (NF2)-coding sequence of DNA extracted from 33 schwannomas from NF2 patients and from 29 patients with sporadic schwannomas. The extensive screening has resulted in the identification of 33 unique mutations. Similarly to other human genes, we have shown that the CpG sites are more highly mutable in the NF2 gene. The frequency, distribution, and types of mutations were shown to differ between the sporadic and familial tumors. The majority of the mutations resulted in protein truncation and were consistent with more severe phenotype, however three missense mutations were identified during this study and were all associated with milder manifestations of the disease. PMID- 8698341 TI - DNA polymorphisms and linkage disequilibrium in the angiotensinogen gene. AB - A number of recent studies have implicated the angiotensinogen gene in the aetiology of essential hypertension in Caucasian, Japanese and African Caribbean subjects. We have genotyped 153 healthy white Caucasian subjects at a dinucleotide repeat polymorphism and seven diallelic sites in the coding or flanking regions of the angiotensinogen gene, including one polymorphism not previously studied. We have also documented patterns of linkage disequilibrium between polymorphisms. There is evidence of variation in the frequency of several mutations when compared with published results from other Caucasian control populations, possibly due to cryptic ethnic differences between these groups. This should be considered in the design and interpretation of studies of the angiotensinogen gene. PMID- 8698342 TI - Antenatal screening and fetal diagnosis of beta-thalassemia in a Chinese population: prevalence of the beta-thalassemia trait in the Guangzhou area of China. AB - In this paper beta-globin gene mutations were detected in 452 beta-thalassemia carriers from 13462 unselected individuals (6731 pregnant women and their husbands) who were screened for the beta-thalassemia trait in the Guangzhou area of China. The incidence of beta-thalassemia was calculated as 3.36%. This is higher than found in previous studies performed in southern China. Using reverse dot blot analysis, we found 11 types of mutations and identified the mutations in 446 (98.7%) of the 452 cases. Direct sequencing was carried out on the 6 unknown alleles, and a novel amber mutation in a beta 0-thalassemia gene (beta 37TGG --> TAG) was found in one of them. Thus, the prevalence and spectrum of beta thalassemia mutations were obtained for this region. Twelve couples were detected at risk for thalassemia, and prenatal diagnosis was carried out in 11 of them. This is the largest number of Chinese subjects studied by DNA analysis to date and is the first report on the prospective diagnostic trial for beta-thalassemia in a Chinese population. In addition, we have performed 80 prenatal diagnoses based on screening for beta-thalassemia retrospectively. PMID- 8698343 TI - Phenotypic variability in two families with novel splice-site and frameshift NF2 mutations. AB - Neurofibromatosis 2 (NF2) is a clinically variable autosomal dominant disorder, caused by mutations in the NF2 tumor suppressor gene on chromosome 22q12, that predisposes to nervous system tumors and ocular abnormalities. To assess intrafamilial phenotypic variability, we performed mutation analysis and clinical assessment on two multigeneration NF2 families with five patients and seven asymptomatic first-degree relatives of patients. One family had a point mutation of agCC --> ggCC at position 1447-2 at the exon 13/14 boundary predicted to lead to an altered splice acceptor sequence and exon deletion. The other family had an insertion of 2 base pairs (TC) at position 761 in exon 8, leading to a frameshift. Both mild and severe phenotypes occurred in each family, indicating that phenotypic variability in NF2 can be caused by factors other than NF2 mutations. Genetic counseling of NF2 families should include the possibility that presymptomatic NF2 mutation carriers can develop a different phenotype than previously diagnosed patients. PMID- 8698344 TI - Frequencies of cystic fibrosis mutations in the Maine population: high proportion of unknown alleles in individuals of French-Canadian ancestry. AB - Cystic fibrosis (CF) is one of the most common severe autosomal recessive disorders in Caucasian populations. A mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene causes this disorder. Reported here is the first analysis of CF mutations in the Maine population. We have screened 263 CF chromosomes for 16 previously reported mutations. Analysis of DNA from 124 apparently unrelated CF patients and 15 obligate carrier parents (whose partner and affected child were unavailable for study) resulted in the identification of 91% of the CF alleles and complete genotyping of 85% of the patients. The frequencies (%) of these mutations in the Maine population are delta F508 (75% of the chromosomes), G85E (0.76), R117H (0.76), I148T (1.1), 621 + 1G --> T (1.1), 711 + 1G --> T (3.0), A455E (1.1), 1717-1G --> A (1.1), G542X (1.9), G551D (1.9), R560T (0.76), Y1092X (0.38), W1282X (0.38), and N1303K (1.5). The exon 10 mutation, delta I507, and the exon 11 mutation, R553X, were not observed. Surprisingly, whereas only 5% of the alleles remain unidentified in the non-French population, the unidentified proportion in the French population is 19%. CF testing for the Maine population will be further improved as the as yet unidentified CF mutations in this population are characterized. PMID- 8698345 TI - Dual localization of the human gene encoding hnRNP I/PTB protein to chromosomes 19p13.3 and 14q23. AB - A cDNA probe representative of the human hnRNP I/PTB gene was used to perform fluorescence in situ hybridization (FISH) on metaphases of human chromosomes. A new localization was found on band 19p13.3 in addition to the previously reported localization to band 14q23. Identical results were obtained when FISH analysis was repeated with probes covering different parts of the hnRNP I cDNA clone. This supported the notion that most, if not all, of the sequences of the different parts of this clone are present on both chromosomes. Moreover, Southern blot analysis of DNAs from interspecies somatic hybrids containing chromosomes 19 and 14 revealed that the whole hnRNP I cDNA probe generated very similar patterns in each hybrid DNA. These data suggest that two closely related copies of the hnRNP I gene exist in the human genome. PMID- 8698346 TI - Complex segregation analysis of non-myoclonic idiopathic generalized epilepsy in families ascertained from probands affected with idiopathic epilepsy with tonic clonic seizures in Antioquia, Colombia. AB - In an attempt to identify the possible role of major genes, multifactorial inheritance, and cohort effects in the susceptibility to idiopathic epilepsy with generalized tonic-clonic seizures of the awakening type (GTCS), complex segregation analysis was performed in 196 nuclear families ascertained through affected probands with idiopathic epilepsy with GTCS belonging to the Paisa community of Antioquia (Colombia). Models postulating no transmission, single major locus (dominant and recessive) only, and multifactorial component only, were rejected. Since the codominant single major locus model could not be rejected and models that assign no major locus to transmission, no polygenic component to transmission, and no transmission of the major effect were rejected, complex segregation analysis suggested that a major autosomal codominant allele together with a multifactorial component (mixed model) best explained clustering of idiopathic epilepsy with GTCS in families of the Paisa community. The deficit of transmission of heterozygotes (0.17) is compatible with the existence of epistasis acting on a major gene whose frequency was estimated to be 0.0211. Its transmission variance accounts for 81% of the susceptibility to idiopathic epilepsy with GTCS. The complementary variance (19%) is due to the polygenic component. PMID- 8698347 TI - Analysis of the BglI restriction fragment length polymorphism in the human factor VIII gene using "virtual PCR"--a novel approach employing the polymerase chain reaction in the absence of sequence information for the locus. AB - The BglI restriction fragment length polymorphism (RFLP) of the human factor VIII (FVIII) gene is potentially useful in linkage studies in haemophilia A. The sequence at the RFLP locus is not known, therefore it is not amenable to analysis by the polymerase chain reaction (PCR) and Southern blotting is required. We present a novel approach for analysis of the BglI RFLP using the PCR targeted to known sequence downstream in exon 26 of the FVIII gene. Briefly, the size of the genomic restriction fragment carrying the PCR target depends upon whether the RFLP site is present or absent. If fragments of the required size are isolated from a genomic digest and used as substrates in the exon 26 PCR, the generation of a product in one or other fraction indicates the upstream RFLP status. We have called this approach "virtual PCR", since PCR is used to obtain information about the RFLP without amplifying the locus itself. PMID- 8698348 TI - Linkage disequilibrium between the four most common cystic fibrosis mutations and microsatellite haplotypes in the Celtic population of Brittany. AB - Microsatellite haplotypes were determined for 117 chromosomes carrying the four most frequent mutations in the cystic fibrosis (CF) gene identified in the Breton population of Celtic origin, as well as for 83 normal chromosomes (noncarriers of a CF mutation). Each of the three non-delta F508 mutations was associated with a single haplotype: 1078deIT with 16-31-13, G55ID with 16-7-17, and W846X with 16 32-13. Although these results suggest identity-by-descent for each mutation, recurrent mutations, although unlikely, could not be completely ruled out. The four most frequent haplotypes on normal chromosomes and the three most frequent haplotypes on delta F508 chromosomes are the same as those found in Ireland, Spain, and Italy. This suggests that some haplotypes, associated or not with the delta F508 mutation, were present in an ancestral population from which all four populations descended. PMID- 8698349 TI - Possible genetic heterogeneity in the Saethre-Chotzen syndrome. AB - Saethre-Chotzen syndrome is an autosomal dominant acrocephalosyndactyly syndrome whose gene has been assigned to chromosome 7p. Cytogenetic and linkage analyses have enabled the interval encompassing the disease gene to be delimited to a short region of chromosome 7p15.3-p21.2. Based on the genetic analysis of three unreported families, we confirm the location of the disease gene(s) in the interval defined by loci D7S664 and D7S493 (Zmax = 4.78 at [symbol: see text] = 0 at the D7S488 locus) but fail to decide whether one or more disease-causing genes map in this genetic interval. PMID- 8698350 TI - Cloning of contiguous genomic fragments from human chromosome 21 harbouring three trefoil peptide genes. AB - A group of small peptides with a typical cysteine-rich domain (termed trefoil motif or P-domain) is abundantly expressed at mucosal surfaces of specific normal and neoplastic tissues. Their association with the maintenance of surface integrity was suggested. The first known human trefoil peptide (pS2) was isolated from breast cancer cells (MCF7). Its oestrogen-inducible gene, and the human homologue to the porcine spasmolytic peptide gene (hSP/SML1) appear synchronously expressed in healthy stomach mucosa and several carcinomas of the gastrointestinal tract. Both genes were shown to be localised at 21q22.3. A new trefoil peptide from human intestinal mucosa (hITF/hP1.B) and its gene were described recently. By using suitable oligonucleotide primers and PCR and isolating large (110-250 kb) genomic recombinants cloned in the bacterial artificial chromosome (BAC) system, we present a genomic region from chromosome band 21q22.3 cloned in contiguous sequences and encoding all three members of human P-domain/trefoil peptides proving a physical linkage of all three trefoil peptide genes. Such genomic sequences will provide useful experimental material for analysis of gene regulation, for gene modification experiments and for establishing transgenic cells or animals. PMID- 8698351 TI - Revised transthyretin Ile 122 allele frequency in African-Americans. AB - The transthyretin (TTR) Ile 122 variant is associated with cardiac amyloidosis in individuals of African descent. To determine the prevalence of the allele encoding TTR Ile 122 in African-Americans, we have used PCR and restriction analysis to test DNA from African-Americans from various geographic areas, and found an allele frequency of 66/3376 (0.020), which is higher than the value we previously reported in a much smaller pilot study. Our data indicate that this TTR variant is present at equal frequency in African-Americans throughout the U.S., and suggest that this mutation may be a common, often unrecognized cause of cardiac disease in African-Americans. PMID- 8698352 TI - Are men carrying the apolipoprotein epsilon 4- or epsilon 2 allele less fertile than epsilon 3 epsilon 3 genotypes? AB - The epsilon 3 allele in the human gene coding for apolipoprotein E (apoE) is the most common worldwide, but epsilon 4 is probably the ancestral allele. Since apoE is involved in many important biological processes, selection forces could have favoured epsilon 3. We hypothesized that apoE genotypes may affect reproductive efficiency, and we therefore compared the distributions of 40-year-old married men with known genotypes by the numbers of their biological children. The distributions were statistically significantly different (P = 0.0026). On average, men with the epsilon 3 epsilon 3 genotype (n = 212) had 1.93 children, men with the epsilon 3 epsilon 4 or epsilon 4 epsilon 4 genotype (n = 105) had 1.50, and men with the epsilon 3 epsilon 2 or epsilon 2 epsilon 2 genotypes (n = 53) had 1.66 children. Of the men in the three groups, 6%, 26% and 19%, respectively, reported being childless. These findings are unlikely to be due to gross error in the reported prevalence of childlessness, differences in socioeconomic status or other likely sources of bias. They are compatible with higher fertility in men with the epsilon 3 epsilon 3 genotype than in those with the other common apoE genotypes. PMID- 8698353 TI - Screening for human mitochondrial DNA polymorphisms with denaturing gradient gel electrophoresis. AB - A method involving denaturing gradient gel electrophoresis (DGGE) was developed to detect mitochondrial DNA (mtDNA) polymorphisms in human peripheral T lymphocytes. DGGE analysis of 100- to 200-bp sequences of low melting temperature domains within the origin/membrane attachment site, NADH dehydrogenase subunit I, cytochrome c oxidase subunit I and two overlapping regions of the tRNA glycine/NADH dehydrogenase subunit III sequences was performed to identify sequence variants at these sites in a human B-cell line TK6 and T-cells from four individuals. A T --> C transition at position 16519 in the origin/membrane attachment site in the TK6 cell line and the T-cells from one individual was found. A sequence variant resulting in a G --> A transition at position 9966 in the tRNA glycine/NADH dehydrogenase III was identified in another individual. This method should be useful for the rapid screening of polymorphisms in a large number of samples. PMID- 8698354 TI - New mutations in the ataxia telangiectasia gene. AB - We report the detection of four new mutations in the ataxia telangiectasia gene (ATM). Reverse-transcribed RNA extracted from cultured cells was analysed for mutations by polymerase chain reaction amplifications and restriction endonuclease fingerprinting. Three deletions and a base substitution are described. The deletions reported here would result in severe disruptions of the ATM gene product by leading either to a protein truncation (a 4-bp deletion) or the loss of stretches of 53 and 58 amino acids (a 159-bp deletion and a 174-bp deletion, respectively); whereas the base substitution would lead to an amino acid change from a highly conserved glycine to an arginine residue. PMID- 8698355 TI - Combined therapy trial with interferon alpha-2a and ablative therapy in the treatment of anogenital warts. AB - OBJECTIVE: To determine whether the combination of systemically administered interferon alpha-2a and ablative surgery for the treatment of genital and/or perianal warts produces a 30% or greater improvement in lasting response rate compared with a control group receiving a combination of placebo and ablative therapy. DESIGN: Randomised, triple-blind, placebo-controlled trial using 1 or 3 MIU of interferon alpha-2a or placebo administered subcutaneously three times weekly for 10 weeks in combination with ablative surgery. SETTING: International, multicentre study in 10 genitourinary medicine clinics. PATIENTS: Two hundred and fifty patients with anogenital warts. MAIN OUTCOME MEASURES: Lasting response at week 38. RESULTS: Standard efficacy analysis at week 38 showed a lasting response in 51% (35/68) of 3 MIU interferon-treated patients, 48% (30/63) of 1 MIU interferon-treated patients and 43% (29/67) of placebo-treated patients. CONCLUSIONS: With the doses and regime described, treatment with interferon alpha 2a in combination with ablative therapy is not significantly superior in the treatment of anogenital warts than placebo and ablative therapy. PMID- 8698356 TI - Comparison of DNA probe (Gen-Probe) with culture for the detection of Neisseria gonorrhoeae in an urban STD programme. AB - BACKGROUND AND OBJECTIVES: The DNA probe assay is an alternative to culture for the detection of Neisseria gonorrhoeae which does not depend on the viability of the organism. There have been few published studies comparing the two methodologies. The majority of these studies have shown the probe assay to be comparable to culture. The goal of this study was to compare the performance of the DNA probe assay with culture in a high prevalence setting with nearly optimal culture transport conditions. METHODS: Genital specimens for culture and for DNA probe assay were collected at the time of the routine visit for STD clinic patients. Results of the two methods were compared. Discrepant results were further analysed using the results of direct patient Gram stains. RESULTS: Satisfactory matched specimens were available for 999 patients. The overall sensitivity and specificity of the DNA probe as compared with culture was 90 and 96%. Resolved values achieved by factoring in the results of direct patient Gram stains did not significantly improve the performance of the probe. CONCLUSION: Culture remains the test of choice for the detection of gonorrhoea in a high prevalence setting where culture transport conditions are adequate. PMID- 8698357 TI - Randomised double-blind trial of recombinant interferon-beta for condyloma acuminatum. AB - OBJECTIVE: To evaluate the safety and efficacy of two intralesional doses of recombinant human interferon-beta (r-hIFN-beta: Rebif, Ares Serono), given 3 times a week for 3 weeks, in the treatment of condyloma acuminatum. DESIGN: A randomised, double-blind, within-patient, placebo-controlled study. SUBJECTS: 25 patients (24 males, 1 female) with a history of condyloma acuminatum. Twenty had failed previous treatment for condyloma acuminatum. In each patient, 3 distinct lesions were selected for treatment. Each selected lesion was randomly assigned to receive intralesionally one of the following: r-hIFN-beta 33,000 IU/day, r hIFN-beta 1 x 10(6) IU/day, or matching placebo. SETTING: Institut Alfred Fournier, Paris, France. OUTCOME MEASURES: Response was evaluated colposcopically at the end of treatment (day 22) and 5 weeks later (month 2). Complete response (CR) was defined as disappearance of the treated lesion. Partial response (PR) was defined as at least a 50% reduction in size, but not disappearance of the treated lesion. RESULTS: The higher dose of 1 x 10(6) IU achieved significantly more complete and partial remissions than placebo, both by the end of treatment, and 5 weeks later. CONCLUSIONS: r-hIFN-beta appears to be safe and effective when administered intralesionally to patients with condyloma acuminatum. Most of the treated patients had failed previous treatments and were therefore a resistant population. PMID- 8698358 TI - Crusted ("Norwegian") scabies in a specialist HIV unit: successful use of ivermectin and failure to prevent nosocomial transmission. AB - A nosocomial outbreak of scabies in a specialist inpatient HIV unit resulted from a patient admitted with crusted scabies. Treatment of his infestation with topical scabicides alone failed and he remained infectious for several weeks. His infestation was then eradicated with combined topical treatment and oral ivermectin. In total, 14 (88%) out of 19 ward staff became symptomatic, and 4 (21%) had evidence of scabies on potassium hydroxide examination of skin scrapings. The ward infection control policy was changed to distinguish patients with crusted scabies from those with ordinary scabies. A second patient with crusted scabies was treated with combined oral and topical therapy early in his admission and nursed with more stringent isolation procedures. No nosocomial transmission occurred and his infestation responded rapidly to treatment. Patients with crusted scabies require strict barrier nursing if nosocomial transmission is to be avoided. Ivermectin combined with topical scabicides may be a more efficacious treatment than topical scabicides alone in such patients. PMID- 8698359 TI - Hepatitis C virus infection in a large cohort of homosexually active men: independent associations with HIV-1 infection and injecting drug use but not sexual behaviour. AB - OBJECTIVE: To determine the prevalence and risk factors for hepatitis C virus (HCV) infection in a cohort of homosexually active men, with particular reference to assessing sexual transmission. DESIGN: Prevalence based on cross-sectional testing for HCV (c100 protein) antibody in a cohort using sera stored between 1984 and 1989, and assessment of risk factors using a case-control analysis based on questionnaire data from HCV positive and negative subjects. SUBJECTS/SETTING: 1038 homosexually active men who were participating in a prospective study established to identify risk factors for AIDS. They had been recruited through private and public primary care and sexually transmissible disease (STD) services in central Sydney. MAIN OUTCOME MEASURES: Prevalence of HCV antibody and its association with human immunodeficiency virus type 1 (HIV-1) infection and other STDs, number of sexual partners, sexual practices and recreational drug use. RESULTS: Overall, 7.6% of subjects tested were seropositive for HCV antibody. In univariate analysis, HCV infection was significantly associated with injecting drug use (IDU) (OR = 8.18, p < 0.0001) and HIV infection (OR = 3.14, p < 0.0001) and with self reported history of syphilis (OR = 1.88, p = 0.016), anogenital herpes (OR = 1.93, p = 0.017), gonorrhoea (OR = 2.43, p = 0.009) and hepatitis B (OR = 1.92, p = 0.010). In case control analysis, similar sexual behaviours (partner numbers and practices) were reported by HCV positive and HCV negative subjects except that HCV negative subjects more frequently reported engaging than HCV positive subject in unprotected receptive anal intercourse without ejaculation (OR = 0.61, p = 0.034), unprotected insertive (OR = 0.59, p = 0.039) and receptive (OR = 0.56, p = 0.016) oro-anal intercourse (rimming) and insertive fisting (OR = 0.48, p = 0.034). In multiple logistic regression analyses, only HIV-1 infection (OR = 3.18, p < 0.0001) and IDU in the previous six months (OR = 7.24, p < 0.0001) remained significantly associated with the presence of HCV antibody. CONCLUSIONS: IDU was the major behavioural risk factor for HCV infection. If sexual or another from of transmission did occur, it may have been facilitated by concurrent HIV-1 infection. PMID- 8698360 TI - Changes in heterosexual university undergraduates' HIV-related knowledge, attitudes and behaviour: Melbourne, 1989-1994. AB - OBJECTIVE: To examine differences in the AIDS-related knowledge, attitudes and behaviours of first year university undergraduates in 1989 and 1994. DESIGN: Comparisons were made between cross-sectional surveys, conducted in 1989 and 1994, of first year undergraduates at three Melbourne universities. RESULTS: The 1994 cohort reported more positive attitudes toward, and better knowledge of, safe sex practices and less discrimination against perceived risk groups than did the 1989 cohort; however, this was due primarily to improvement among female undergraduates. Male undergraduates either demonstrated no improvement or a decline in pro-safe sex attitudes. A general increase was found in the proportion of respondents always using condoms for vaginal sex with casual and regular partners and for oral sex with casual and regular partners. CONCLUSIONS: While the extent of sexual behaviour among these young people has remained essentially unchanged over the past five years, the extent of self-reported condom use has increased markedly. The general decline in attitudinal measures among young men contrasts with a marked improvement among young women and suggests the need for education programs targeted specifically at this group. PMID- 8698361 TI - Epidemiology of cryptosporidiosis among European AIDS patients. AB - OBJECTIVE: To study epidemiology and possible risk factors associated with the development of cryptosporidiosis among European patients with AIDS. METHODS: An inception cohort of 6548 patients with AIDS, consecutively diagnosed from 1979 to 1989, from 52 centres in 17 European countries was studied. Data on all AIDS defining events were collected retrospectively from patients' clinical records. Kaplan-Meier estimates, log rank tests and Cox proportional hazard models were used to examine for possible risk factors associated with cryptosporidiosis. RESULTS: Cryptosporidiosis was diagnosed in 432 (6.6%) patients, 216 at time of the AIDS diagnosis and 216 during follow-up. The probability of being diagnosed with cryptosporidiosis at AIDS diagnosis was significantly lower for intravenous drug users (1.3%) than for homosexual men (4.1%) and for patients belonging to other transmission categories (4.0%) (p < 0.001). The probability was also higher for patients from Central Europe compared with patients from South Europe (4.1% versus 2.5%, p = 0.005). The rate of developing cryptosporidiosis after the diagnosis of AIDS was 3 per 100 patient years of follow-up. The rate was significantly lower for intravenous drug users than for homosexual men (relative risk 0.34, 95% confidence limits 0.22-0.54) and for women compared with men (RR 0.43 (0.21-0.87)). The risk was higher in North Europe than in South and Central Europe. In a multivariate analysis only transmission category remained a significant predictor for the development of cryptosporidiosis. CONCLUSION: The development of cryptosporidiosis in AIDS patients may be associated with sexual risk behaviour. PMID- 8698362 TI - An in vitro metronidazole susceptibility test for trichomoniasis using the InPouch TV test. AB - OBJECTIVE: An efficient anaerobic culture system, the InPouch TV test, was used to determine the susceptibility of Trichomonas vaginalis to metronidazole. Glacial acetic acid was employed as a solvent for metronidazole. METHODS: T vaginalis isolates were cultured from 16 symptomatic female patients. The 11 who responded to oral metronidazole, 250 mg tid for 7 days, were considered as having sensitive trichomonads; the 5 who remained infected after treatment were considered to have resistant organisms. All isolates were cultured for minimum lethal concentrations (MLC). Metronidazole was added to a series of pouches; two fold dilution of the most concentrated was 50 micrograms/ml and the least was 0.4 micrograms/ml. The inoculum of viable trichomonads was 1 x 105/ml in each pouch. Pouches were incubated at 37 degrees C for 48 h, examined microscopically for motile trichomonads, and then 0.5 ml was subcultured to drug free pouches. After 5 days incubation at 37 degrees C, each subculture and culture were examined microscopically for viable trichomonads. RESULTS: Eleven isolates of T vaginalis from patients responding to metronidazole treatment had MLC between 0.4 to 3.1 micrograms/ml. The MLC from the 5 treatment failure patients were between 12.5 to 50 micrograms/ml. CONCLUSIONS: For the 16 patients in this study, the MLC values determined with the InPouch TV test differentiated between infection caused by metronidazole sensitive and resistant trichomonads. The mean MLC of clinically resistant isolates was approximately eleven fold higher than the mean MLC of clinically sensitive isolates (15 micrograms/ml vs 1.32 micrograms/ml). There was a significant difference between clinically resistant and sensitive isolates (t = 5.47, p < 0.0005). This study suggests that the InPouch TV test could be used for distinguishing between metronidazole resistant and sensitive isolates. PMID- 8698363 TI - Selective culture medium failure in gonorrhoea. PMID- 8698364 TI - Antibiotic susceptibility survey of Neisseria gonorrhoeae in Tucuman, Argentina. PMID- 8698365 TI - Disseminated Toxoplasma gondii infection presenting with a fulminant pneumonia. PMID- 8698366 TI - Under-diagnosis of female genital Chlamydia trachomatis infection. PMID- 8698367 TI - Controlling chlamydial infection. PMID- 8698368 TI - Patients attending a vulval clinic in a genitourinary medicine department. PMID- 8698369 TI - Vaginal colonisation by Candida lipolytica. PMID- 8698370 TI - Should screening of genital infections be part of antenatal care in areas of high HIV prevalence? PMID- 8698371 TI - Syndromic management of genital ulcer disease--a critical appraisal. PMID- 8698372 TI - Sexually transmitted diseases control in developing countries. AB - Sexually transmitted diseases (STDs) are a major public health problem now compounded by the advent of AIDS and HIV infection. The size of the problem represented by STDs and HIV is unknown however it is estimated that there are 333 million new cases of STD per annum and currently 15-20 million people infected worldwide with HIV. Control programmes for STDs must prevent the acquisition of STDs, their complications and sequelae and interrupt and reduce transmission. They can also reduce the incidence of HIV infection. Such programmes must place emphasis on health education, condom usage, altering health seeking behaviour and providing case management. The syndromic approach currently offers the most realistic, and cost effective, way in which to treat patients. PMID- 8698373 TI - Prevention and management of tuberculosis in HIV positive patients living in countries with a low prevalence of Mycobacterium tuberculosis. AB - We have re-examined the evidence on which current British Thoracic Society recommendations for primary and secondary prophylaxis and therapy of tuberculosis are based. We suggest that in a country such as the UK with a low prevalence of tuberculosis, primary prophylaxis should be offered primarily to tuberculin positive or anergic patients from high-incidence groups, including immigrants from high-prevalence countries, intravenous drug users and those with previous tuberculosis, that secondary prophylaxis be withheld from all but very high-risk patients and that four drug regimens which include ethambutol should be used for patients originating from, or who have lived in areas of the world with more than 2% primary isoniazid resistance. PMID- 8698374 TI - Chlamydial cervicitis and urethritis: single dose treatment compared with doxycycline for seven days in community based practises. AB - STUDY GOAL: To compare the efficacy and safety of single 1 g oral azithromycin with doxycycline, 100 mg twice daily for seven days for treatment of uncomplicated urogenital chlamydial infection. STUDY DESIGN: Randomised, unblinded, comparative trial, involving 597 patients demonstrating clinical evidence of genital chlamydia and a positive non-culture assay for Chlamydia trachomatis. RESULTS: Among the azithromycin- and doxycycline-treated patients 61% and 60%, respectively, were asymptomatic within one week after the first dose. At two weeks, these figures increased to 86% and 83%, respectively. Bacteriological eradication, based on a negative assay, occurred in 338 (97%) of 347 azithromycin-treated patients and 161 (99%) of 163 doxycycline-treated patients. CONCLUSION: Treatment of uncomplicated chlamydial cervicitis and urethritis with single 1 g oral azithromycin is equivalent to standard therapy with doxycycline. Drug-related adverse events were approximately twice as common as previously reported for both drugs. PMID- 8698375 TI - Comparison of the efficacy and safety of oral fluconazole and topical clotrimazole in patients with candida balanitis. AB - One hundred fifty seven men with candidal balanitis were entered in a randomised, open-label parallel-group multicentre study comparing efficacy and safety of a single oral 150-mg fluconazole-dose with clotrimazole applied topically twice daily for 7 days. Of 64 fluconazole and 68 clotrimazole treated patients who were evaluable at short term follow up, 92% and 91% respectively were clinically cured or improved. Candida albicans was eradicated in 78% and 83% of patients respectively. Median time to relief of erythema was 6 days for fluconazole and 7 days for clotrimazole. Twelve of 15 patients who had received previous topical therapy for balanitis said they preferred oral therapy. At the one month follow up visit, 24/36 and 29/33 patients in the two groups were clinically cured or improved. Nine in the fluconazole group experienced a relapse; 6 of these 9 patients reported previous episodes of this infection during the past year. Two patients in the clotrimazole group had a relapse; neither had a history of previous episodes. Mycological eradication was noted in 26/36 and 25/33 patients in the two groups. Both treatment regimens were well tolerated. Thus a single 150 mg dose of fluconazole was comparable in efficacy and safety to clotrimazole cream applied topically for 7 days when administered to patients with balanitis. PMID- 8698376 TI - Induction of single and dual cytotoxic T-lymphocyte responses to viral proteins in mice using recombinant hybrid Ty-virus-like particles. AB - The induction of cytotoxic T-lymphocyte (CTL) responses to viral proteins is thought to be an essential component of protective immunity against viral infections. Methods for generating such responses in a reproducible manner would be of great value in vaccine development. We demonstrate here that the recombinant antigen-presentation system based on the yeast transposon (Ty) particle-forming p1 protein is a potent means of inducing CTL responses to a variety of viral CTL epitopes, including influenza virus nucleoprotein (two epitopes), Sendai virus and vesicular stomatitis virus nucleoproteins, and the V3 loop of human immunodeficiency virus type-1 (HIV-1) gp120. CTL were primed by hybrid Ty-virus-like particles (VLP) carrying the minimal epitope or as much as 19,000 MW of protein. Ty-VLP carrying two different epitopes (dual-epitope Ty VLP) were capable of priming CTL responses in two different strains of mice or against two epitopes in the same individual. Furthermore, co-administration of a mixture of two different Ty-VLP carrying single epitopes could induce responses to both epitopes in the same individual. Ty-VLP appear to represent a reproducible and flexible system for inducing CTL responses in mice, and warrant further evaluation in primates. PMID- 8698377 TI - Induction of measles virus-specific cytotoxic T-cell responses after intranasal immunization with synthetic peptides. AB - We have investigated the structural requirements for the induction of cytotoxic T cell responses (CTL) in vivo after intranasal immunization with an immunodominant CTL epitope from the nucleoprotein of measles virus (MV). For the induction of CTL responses, covalent linkage of the CTL epitope to a helper T-cell epitope was required and the orientation of the epitopes influenced the immunogenicity of the CTL epitope. The presence of two copies as compared with one copy of a T-helper epitope, rendered the CTL epitope more immunogenic and resulted in the in vivo induction of MV-specific CTLs without the need for an adjuvant. The role of CTL responses to this epitope in protection after intranasal administration was evaluated in a mouse model against challenge with a neuroadapted strain of MV. Although a decreased mortality in the peptide immunized compared with that in unimmunized mice was observed, the protection achieved was not significant. These findings highlight the importance of the rational design of synthetic immunogens for the induction of CTL responses and the potential of the intranasal route for immunization. PMID- 8698378 TI - Expression of L-selectin (CD62L) discriminates Th1- and Th2-like cytokine producing memory CD4+ T cells. AB - Human memory (CD45RO+) CD4+ T cells can be distinguished into two subpopulations on the basis of expression of the lymph node homing receptor, L-selectin (CD62L). In a prior study we showed that human L-selectin-positive memory T-helper (Th) cells promote the maturation of IgG- and IgA-producing cells by naive B cells. To further elucidate the contribution of memory CD4+ T cells to B-cell differentiation, human memory CD4+ T cells with or without L-selectin expression were evaluated for production of cytokines that participate in regulation of immunoglobulin production. It was found that L-selectin-positive human memory CD4+ T cells produce mainly interleukin (IL)-4 and IL-5, whereas L-selectin negative CD4+ T cells produce mainly interferon-gamma (IFN-gamma). This profile of cytokine expression coincides with the profile that distinguishes Th1 and Th2 subsets. In contrast to the murine system, IL-10 production was similarly contributed by human L-selectin-positive and -negative memory CD4+ T-cell subpopulations. These results suggest that the human L-selectin-negative and positive subpopulations of human memory CD4+ T cells contain Th1-like and Th2 like cytokine-producing cells, respectively. PMID- 8698379 TI - Modulation of superantigen-induced T-cell deletion by antibody anti-Pgp-1 (CD44). AB - We examined the effects of anti-Pgp-1 (CD44) antibody on the in vitro deletion of murine CD4 and CD8 single positive T cells induced by Staphylococcal enterotoxin B (SEB). Soluble anti-Pgp-1 antibody enhanced the apoptosis and decreased the proliferation of SEB-responding T cells. In contrast, cross-linked anti-Pgp-1 antibody provided costimulatory signals for the T-cell activation induced by anti CD3 antibody. Hyaluronic acid (HA), a ligand of Pgp-1, did not affect proliferation and deletion induced by SEB, whereas it mimicked the effects of the cross-linked antibody in anti-CD3-driven proliferation. T-cell Pgp-1 surface expression after 48 hr incubation with SEB was unchanged as compared to unstimulated cells. However, when the memory T cells were established, some V beta 8+ (SEB-specific) T cells Pgp-1low became Pgp-1high, displaying a bimodal character. Moreover, the Pgp-1 increased expression correlated with an increase of Pgp-1 soluble form in the supernatant. These findings suggested that signals following the triggering of the Pgp-1 molecule are important in controlling T cell survival. PMID- 8698380 TI - T-cell-receptor dose and the time of treatment during murine retrovirus infection for maintenance of immune function. AB - C57BL/6 mice were injected with different doses of human T-cell receptor (TCR) V beta 8.1 CDR1 peptide at different times after murine retrovirus (LP-BM5) infection. Injection with TCR V beta 8.1 CDR1 peptide largely prevented the retrovirus-induced reduction in B- and T-cell proliferation, and T-helper 1 (Th1) cytokines [interleukin-2 (IL-2) and interferon-gamma (IFN-gamma)] secretion. It also suppressed T-helper 2 (Th2) cytokines (IL-6 and IL-10) production, which was stimulated by retrovirus infection. These effects were accomplished using at least 100 micrograms of peptide per mouse and the most effective dose of peptide had to be given within 4 weeks after retrovirus infection. Immunization with doses above 100 micrograms/mouse as long as 4 weeks postinfection maintained natural killer (NK) cell activity during retrovirus infection. Reducing the dose of peptide or delaying it until the disease progressed towards early murine acquired immune deficiency syndrome (AIDS) allowed development of immune dysfunction. These studies provide data suggesting that immune dysfunction, induced by murine retrovirus infection, was largely prevented by TCR V beta CDR1 peptide injection. PMID- 8698381 TI - Derivation of T-cell receptor alpha-chain double expresser lines from normal murine mature T cells. AB - Because the T-cell receptor (TCR) alpha-chain locus is known to lack allelic exclusion of rearrangements, and as a recent report revealed the existence of alpha-chain double expressers among normal human peripheral blood lymphocytes (PBL), the possible existence of TCR alpha-chain double expressers among mature murine T cells was examined. Although two-colour staining analysis of normal T cell populations did not immediately reveal recognizable clusters of V alpha double expressers, alternative in vitro stimulations of normal murine T cells with antibodies to two different TCR V alpha chains reproducibly induced TCR alpha-chain double-expresser lines. TCR complexes with different alpha-chains on such T cells were both shown to be functional. The cell lines were heterogeneous with respect to V beta usage and the ratio of the expressed amounts of the two alpha-chains on the surface. The ratio of the two expressed alpha-chains was found to be very stable over a long period of time. These results are consistent with the earlier report on alpha-chain double expressers among human T cells and also show normal occurrence of TCR alpha-chain double expressers in murine T-cell populations. PMID- 8698382 TI - Developmental heterogeneity of V gamma 1.1 T cells in the mouse liver. AB - Modifications at V-(D)-J junctions increase the diversity of T-cell receptors (TCR). It has been shown that the levels of N-nucleotide insertion at the V-(D)-J junction in TCR transcripts are different between fetal and adult stages. To clarify developmental stages and pathways of gamma delta T cells in the liver, we analysed the nucleotide sequence of V gamma 1.1-J gamma 4 junctions of intra hepatic lymphocytes (IHL), spleen cells and developing thymocytes from normal and athymic nude mice. The level of N-insertion increased in thymocytes during ontogeny. The percentage of V gamma 1.1-J gamma 4 transcripts with N-insertion was 3% at day 16 of gestation, 42% at newborn, and 89% at 7 weeks. Transcripts from normal IHL showed intermediate levels of N-insertion between those of newborn and adult thymocytes. In contrast the percentage of N-insertion in nude IHL was 47%, and this value was comparable to that of newborn thymocytes. Among the transcripts of normal IHL, the sequences common with nude IHL showed a newborn level of N-insertion (38%), and the remaining sequences showed an adult level (89%). These results suggested the possibility that V gamma 1.1-expressing T cells in IHL might be a heterogeneous population consisting of the cells developed extrathymically as well as the cells developed intrathymically. The V gamma 1.1-J gamma 4 junctions from spleen cells showed less variability than those from IHL and adult thymocytes. It suggested that gamma delta T cells bearing specific V gamma 1.1 TCR develop and/or home in the spleen. PMID- 8698383 TI - CD8-deficient mice exhibit augmented mucosal immune responses and intact adjuvant effects to cholera toxin. AB - We used normal, CD4 and CD8 gene-targeted mice to investigate the role of CD4+ and CD8+ T cells in the regulation of gut mucosal immune responses following oral immunizations with cholera toxin (CT) adjuvant. Phenotypic analysis of mucosa associated tissues revealed normal CD3+ T-cell frequencies in CD4-/- and CD8-/- mice such that in CD4-/- mice the CD8+ and double-negative (DN) T cells were increased. In CD8-/- mice the CD4+ T cells were increased, with the exception that in the intraepithelial compartment the CD3+ T cells were predominantly DN gamma delta T-cell receptor (TCR)+ T cells. All mice, normal and deficient, failed to respond to oral immunization with the antigen, keyhole limpet haemocyanin (KLH), alone. In the presence of CT adjuvant, however, CD8-/- mice consistently exhibited three- to fivefold stronger gut mucosal responses compared to normal C57B1/6 mice. By contrast, no difference was observed for systemic responses between CD8-/- and normal mice. Thus the up-regulation selectively affected mucosal responses, suggesting that, contrary to the CD8-/- mouse gut, the normal gut mucosa may host CD8+ T cells that exert a local suppressive effect on T- and B-cell responses. The magnitude of the enhancing effect of CT was comparable in CD8-/- and normal mice, clearly demonstrating that the adjuvant mechanism of CT does not require CD8+ T cells. On the other hand, the adjuvant effect of CT required CD4+ T cells, because no or poor anti-KLH responses were observed in CD4-/- mice. In both normal and CD8-/- mice CT adjuvant promoted KLH specific CD4+ T-cell printing without any selective effect on the differentiation towards a T-helper type-1 (Th1) or Th2 dominance. Furthermore, CT adjuvant increased the frequency of CD4+ T cells expressing a memory phenotype, i.e. CD44high, LECAM-1low and CD45RBlow. We have shown, using gene-targeted mice, that CD8+ T cells are not required for the adjuvant effect of CT, and that CD8+ T cells may exert local mucosal down-regulation of intestinal immune responses. PMID- 8698384 TI - Human gamma/delta T-cell response to Listeria monocytogenes protein components in vitro. AB - Listeria monocytogenes is a facultative intracellular pathogen that replicates inside mononuclear phagocytes and induces specific cellular immunity. Listeriosis encompasses many clinical syndromes and meningitis is the most frequent clinical manifestation. Human alpha/beta and gamma/delta T cells have been shown to respond to L. monocytogenes antigens and to play an important role in resistance against listerial infection. We investigated the nature of listerial ligands and the influence of the major virulence factor, listeriolysin (hly), on the stimulation of human gamma/delta T cells from healthy individuals. We found that a listerial somatic protein ligand, which is sensitive to proteinase treatment, stimulated gamma/delta T cells in vitro; the majority of Listeria-responsive gamma/delta T cells expressed V gamma 9V delta 2 T-cell receptor chains and human leucocyte antigen-DR molecules; gamma/delta T-cell responses to hly+ and hly- Listeria strains were comparable; L. monocytogenes strains of different virulence stimulated gamma/delta T cells equally. Thus, protein components of L. monocytogenes unrelated to virulence activate human gamma/delta T cells in vitro. PMID- 8698385 TI - Dynamic changes in circulating and antigen-responsive T-cell subpopulations post Mycobacterium bovis infection in cattle. AB - Bovine tuberculosis is a threat to animal and human health in several countries. Greater understanding of the immunology of the disease is required to develop improved tests and vaccines. This study has used a model of bovine tuberculosis, established in the natural host, to investigate the dynamic changes that occur in the circulating T-cell subpopulations after infection. When the phenotypic composition of the peripheral blood lymphocytes was determined pre- and post experimental infection, the response to disease comprised three phases. Firstly, the WC1/gamma delta T cells decreased and then increased, suggesting localization to developing lesions and clonal expansion. Secondly, the CD4:CD8 ratio increased. Thirdly, the CD4:CD8 ratio decreased to less than pre-infection measurements. The latter changes suggested sequential involvement of CD4 and then CD8 T cells. The proportion of cells expressing interleukin-2 receptor (IL-2R) also increased. Panels of T-cell clones were established at various stages post infection and all clones that exhibited antigen responsiveness were phenotyped. T cell clones from early infection were WC1/gamma delta and CD4 in phenotype, while CD8 clones appeared later in infection, eventually becoming dominant. Therefore, from in vivo and in vitro evidence, it was suggested that there is a dynamic progression in the T-cell subpopulations involved dominantly in responses to mycobacteria. PMID- 8698386 TI - Regulation of T-cell activation in the lung: isolated lung T cells exhibit surface phenotypic characteristics of recent activation including down-modulated T-cell receptors, but are locked into the G0/G1 phase of the cell cycle. AB - Peripheral lung tissue contains large numbers of T cells, strategically located for immune surveillance at the blood-air interface. Given the intensity of antigenic exposure at this site, it is clear that local T-cell activation events require strict control, in order to maintain tissue homeostasis. How this control is achieved in this unique tissue microenvironment is unknown, and the present study sought to elucidate the process via detailed analysis of the surface phenotypic characteristics of freshly isolated lung T cells. We report below that these cells display typical characteristic of 'postactivation', notably elevated basal Ca2+ concentrations, down-modulated T-cell receptors, expression of Ia and 'late' activation antigens and concomitant CD4/CD8. However, levels of interleukin-2 receptor and CD2 expression were below those expected of 'activated' T-cell populations, and virtually all of the cells were found to be in the G0/G1 phases of the cell cycle. These properties bear a remarkable similarity to those of T cells activated in the presence of endogenous tissue (alveolar) macrophages from the lung (see accompanying paper). We hypothesize that they reflect the in vivo operation of an endogenous macrophage-mediated T cell anergy-induction process, the function of which is to limit the local clonal expansion of T cells in peripheral lung tissue after in situ activation. PMID- 8698387 TI - Regulation of T-cell activation in the lung: alveolar macrophages induce reversible T-cell anergy in vitro associated with inhibition of interleukin-2 receptor signal transduction. AB - Alveolar macrophages (AM) are recognized as archetypal 'activated' macrophages with respect to their capacity to suppress T-cell responses to antigen or mitogen, and this function has been ascribed an important role in the maintenance of local immunological homeostasis at the delicate blood:air interface. The present study demonstrates that this suppression involves a unique form of T-cell anergy, in which 'AM-suppressed' T cells proceed normally through virtually all phases of the activation sequence including Ca2+ flux, T-cell receptor (TCR) modulation, cytokine [including interleukin-2 (IL-2)] secretion and IL-2 receptor (IL-2R) expression. However, the 'suppressed' T cells fail to up-regulate CD2, and do not re-express normal levels of TCR-associated molecules after initial down-modulation; moreover, they are unable to transduce IL-2 signals leading to phosphorylation of IL-2R-associated proteins, and remained locked in G0/G1. The induction of this form of anergy is blocked by an NO-synthase inhibitor, and is reversible upon removal of AM from the T cells, which then proliferate in the absence of further stimulation. We hypothesize that this mechanism provides the means to limit the magnitude of local immune responses in this fragile tissue microenvironment, while preserving the capacity for generation of immunological memory against locally encountered antigens via clonal expansion of activated T cells after their subsequent migration to regional lymphoid organs. In an accompanying paper, we demonstrate that a significant proportion of T cells freshly isolated from lung exhibit a comparable surface phenotype. PMID- 8698388 TI - Immunosuppression and cytokine production in mice infested with Ixodes ricinus ticks: a possible role of laminin and interleukin-10 on the in vitro responsiveness of lymphocytes to mitogens. AB - T cells from BALB/c mice infested 9 days before with Ixodes ricinus nymphs had a suppressed response to in vitro concanavalin A (Con A) stimulation compared to cells from uninfested mice. When laminin (the main component of the extracellular matrix) was used as a coating agent, the Con A response of naive mice was characterized by a decrease in cell proliferation, whereas there was no significant effect on the mitogen response of cells from infested mice. In contrast, an increased response to lipopolysaccharide (LPS) was observed when assaying lymph node cells of infested mice, probably reflecting an increase in B lymphocyte number or activity. LPS cell stimulation was not modified by laminin. Supernatants of lymph node cells, taken 9 days after the first infestation of mice, stimulated with Con A in vitro, contained interleukin-10 (IL-10) but no significant levels of IL-5 as tested by enzyme-linked immunosorbent assay. At this stage of the infestation all T cells reactive with tick antigens generated in lymph nodes that drain the tick fixation site, were CD4+ cells, as determined by CD4+ depletion. With cells taken 9 days after the third infestation an increase of IL-5 and IL-10 was observed. The IL-10 levels were higher than the IL 5. According to these observations, we conclude that the reduction of T-cell proliferation in response to Con A observed in lymph node cells from infested mice, may be due to the combined effect of laminin interaction with T lymphocytes during migration and IL-10 production by these lymphocytes. PMID- 8698389 TI - Oral aspirin and ibuprofen increase cytokine-induced synthesis of IL-1 beta and of tumour necrosis factor-alpha ex vivo. AB - We investigated the effect of oral aspirin and ibuprofen on the ex vivo synthesis of interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-6, tumour necrosis factor-alpha (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) by stimulated peripheral blood mononuclear cells (PBMC) from healthy volunteers. Seven volunteers took 325 mg of aspirin daily for 14 days. Three weeks after ending aspirin medication, ex vivo IL-1 beta and TNF synthesis induced by exogenous IL-1 alpha was elevated threefold compared to the pre-aspirin value (P = 0.01 and P = 0.005, respectively). Using lipopolysaccharide (LPS) as a stimulus, no influence of oral aspirin was observed. The increase in cytokine synthesis did not parallel decreased synthesis of prostaglandin E2 (PGE2). Seven weeks after discontinuation of aspirin, cytokine and PGE-2 production returned to pre-aspirin levels. Another seven volunteers took 200 mg of ibuprofen daily for 12 days. Again, there was no effect on LPS- or Staphylococcus epidermidis-induced cytokine synthesis. However, IL-1 alpha-induced synthesis of IL-1 beta was elevated to a mean individual increase of 538% (P < 0.001) and synthesis of TNF was elevated to 270% (P < 0.001) at the end of ibuprofen medication and 2 weeks after discontinuation of ibuprofen. There were parallel increases in PGE2 and both returned to their pre-ibuprofen levels 5 weeks after stopping. Although inhibitors of cyclo-oxygenase blunt PGE2-mediated symptoms such as fever and pain, we conclude that short term use of either aspirin or ibuprofen results in a 'rebound' increase in cytokine-induced cytokine synthesis that is not observed in LPS-induced cytokines. PMID- 8698390 TI - Expression of both B7-1 and CD28 contributes to the IL-2 responsiveness of CTLL-2 cells. AB - The CTLL-2 bioassay is used frequently to determine interleukin-2 (IL-2) concentrations in experimental samples, including samples that contain reagents which affect the CD28-B7 interaction. We therefore evaluated whether the CD28-B7 pathway plays a role in the growth of CTLL-2 cells. Flow cytometry demonstrated that CTLL-2 cells express both CD28 and B7-1. CTLA4-immunoglobulin (CTLA4-Ig) inhibited the growth of CTLL-2 cells over a range of IL-2 concentrations, suggesting that the CD28-B7 interaction plays an important role in the growth of CTLL-2 cells. Anti-B7-1 antibody also inhibited CTLL-2 proliferation at all concentrations of IL-2. These results indicate that the CTLL-2 bioassay may not be a reliable means of determining IL-2 levels in experimental samples containing reagents that affect the CD28-B7 interaction. They also suggest that co expression of CD28 and B7 may contribute to the growth of malignant T cells. PMID- 8698391 TI - Impaired immunity and altered pulmonary responses in mice with a disrupted interferon-gamma receptor gene exposed to the irradiated Schistosoma mansoni vaccine. AB - A high level of protection against Schistosoma mansoni is elicited in mice by the irradiated cercaria vaccine and interferon-gamma (IFN-gamma) is a key cytokine in the pulmonary effector response. The role of this cytokine has been investigated in mice with a targeted disruption of the IFN-gamma receptor gene (IFN-gamma R-/- mice). The level of protection was impaired relative to that elicited in C57BL/6 and 129 wild-type (WT) animals. These two groups developed compact effector foci, of largely mononuclear cell composition, around individual challenge parasites migrating through the lungs. In contrast the IFN-gamma R-/- mice showed a massive and generalized leucocytic infiltration of the airways and interstitium in which eosinophils were a prominent feature. Cultures of airway leucocytes from C57BL/6 mice produced abundant IFN-gamma whilst those from IFN-gamma R-/- mice produced interleukin-4 (IL-4), IL-5 and IL-10, indicating default to the Th2 pathway; the WT animals showed an intermediate response. The pattern of cytokine gene transcripts in whole lung tissue agreed remarkably well with the level of cytokine protein detected in leucocyte cultures, with the exception of substantial IL-4 mRNA but negligible protein in C57BL/6 mice. The loose but intense infiltrate of leucocytes in the lungs of IFN-gamma R-/- mice was clearly ineffective in eliminating challenge parasites, whereas the level of IFN-gamma protein and mRNA in the lungs of C57BL/6 and WT mice correlated with the size and compactness of effector foci. On the basis of these and earlier observations, we suggest that a primary role for IFN-gamma is to promote intercellular adhesion between the leucocytes in an effector focus, promoting its ability to block parasite migration. PMID- 8698392 TI - Multiple B- and T-cell epitopes on a major allergen of Kentucky Bluegrass pollen. AB - The B- and T-cell epitopes of a recombinant grass allergen, rKBG60, were delineated using a set of overlapping synthetic peptides. Direct binding by enzyme-linked immunosorbent assay (ELISA) utilizing serum pools led to the identification of 13 murine immunoglobulin-, and nine to 13 human IgG- and five to seven human IgE-reactive overlapping peptides. Of the peptides which bound to human IgE antibodies, all but three peptides bound to human and/or murine IgG antibodies. Furthermore, eight out of 12 synthetic peptides induced antigen specific antibodies in mice, suggesting that these peptides contained epitopes that recognized and/or induced T cells. These results, in conjunction with cross recognition of different peptides at the C-terminus of rKBG60 by antibodies to neighbouring or non-overlapping peptides suggest that the C-terminus of this antigen represents a dominant antigenic and allergenic site. Peripheral blood mononuclear cell (PBMC) proliferation studies using these synthetic peptides for 13 grass allergic individuals indicated that seven potential human T-cell epitopes exist on this allergen. Taken together, the results demonstrate that multiple B- and T-cell epitopes exist on this major group of grass allergens, the majority of which are localized at the C-terminus of this antigen. PMID- 8698393 TI - CD40 antibodies defining distinct epitopes display qualitative differences in their induction of B-cell differentiation. AB - IgE production can be obtained in vitro by stimulating B lymphocytes with CD40 antibodies and interleukin-4 (IL-4). This stimulation also results in homotypic aggregation and cell proliferation. We have shown previously that IgE synthesis may be dependent on additional signals provided by the close cellular contact. Thus inhibition of the aggregation by lymphocyte function-associated antigen-1 (LFA-1) antibodies leads to a decrease in IgE production. In the present study we show that the inhibitory effect of LFA-1 antibodies is critically dependent on the CD40 antibody used for stimulation. Thus, while previously using the monoclonal antibody (mAb) S2C6, IgE production induced by the CD40 antibody mAb89 was generally higher and could be enhanced more than fivefold in the presence of LFA-1 antibodies. Similarly, the addition of the CD23 mAb MHM6, which blocked aggregation to a similar degree as the LFA-1 antibodies, inhibited S2C6-induced IgE production but enhanced that induced by mAb89. In contrast to these opposing effects on IgE synthesis, proliferation induced by the two CD40 antibodies was affected similarly by the blocking antibodies. As the interaction between CD23 and CD21 has been suggested to involve recognition of carbohydrate structures on CD21 by the lectin-like domain on CD23, we also tested the effect of some different sugars on IgE synthesis and proliferation. Addition of fucose-1 phosphate to anti-CD40 and IL-4-stimulated B cells completely inhibited IgE synthesis and proliferation. Inhibition was also seen with mannose-6-phosphate but not with glucose-1-phosphate. In contrast to the MHM6 antibody, the effect of the sugars was similar irrespective of the CD40 antibody used for stimulation. The study shows that different antibodies to CD40 may give rise to qualitatively distinct signals depending on the epitope recognized. PMID- 8698394 TI - Role of intracellular calcium as a priming signal for the induction of nitric oxide synthesis in murine peritoneal macrophages. AB - Because the role of intracellular Ca2+ in the two-signal process for the induction of nitric oxide (NO) synthesis is controversial, this study was undertaken to examine the role of Ca2+ in the transcriptional regulation of inducible NO synthase (iNOS) in murine peritoneal macrophages. Treatment of the cells with thapsigargin (TG) or 2,5-di-(t-butyl)-1,4-benzodihydroquinone (tBuBHQ), which are the specific and potent Ca(2+)-ATPase inhibitors of endoplasmic reticulum (ER), showed modest effects on tumoricidal function, whereas TG or tBuBHQ in combination with interferon-gamma (IFN-gamma) or lipopolysaccharide (LPS) showed marked effects on tumoricidal function of the cells. The tumoricidal effects of the activated macrophages were correlated with the amount of NO synthesis, and totally abrogated by the use of NOS inhibitor, NG monomethyl-L-arginine (NGMMA). The increases in NO synthesis was reflected as increased amounts of iNOS mRNA by Northern blotting. To confirm that iNOS induction was due to the changes in the intracellular Ca2+ level, the acetoxymethyl ester of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM), an intracellular Ca2+ chelator, was used. Blocking the increase of cytosolic free Ca2+ significantly decreased the induction of NO synthesis. To demonstrate that intracellular Ca2+ acts as a 'priming' signal rather than a 'triggering' signal on the induction of NO synthesis by murine peritoneal macrophages, we designed several experiments. When the cells were treated with TG 6 hr after the treatment with IFN-gamma, there was no increase in NO synthesis. In addition, when the cells were treated with TG or LPS 6 hr after treatment with tBuBHQ, a synergistic increase on NO synthesis was shown only in the case of LPS. When phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, was added to the cells 6 hr after the treatment with TG, there was a marked co operative induction of NO synthesis, even though PMA alone has no effect. Based on the results obtained in this study, we suggest that cytosolic Ca2+ might be enough for the expression of iNOS gene as a priming signal and PKC might be involved in the induction of NO synthesis as a triggering signal by post transcriptional modification of iNOS mRNA or iNOS itself in the activated murine peritoneal macrophages. PMID- 8698395 TI - A role for sialoadhesin-positive tissue macrophages in host resistance to lymphoma metastasis in vivo. AB - Sialoadhesin (SER) is a newly described macrophage-restricted adhesion molecule with a sequence similarity to CD22 on B cells and to myelin-associated glycoprotein on Schwann cells. We describe here a functional role of SER+ spleen macrophages in antigen processing and presentation to T lymphocytes. In two syngeneic murine tumour systems (ESb-MP and lacZ transduced ESbL T-lymphoma cells), the activation state of SER+ macrophages (tested by activity of marker enzymes adenosine deaminase and 5'-nucleotidase) correlated with the arrest of lymphoma metastasis. Furthermore, this macrophage subpopulation became activated upon anti-tumour immunization as well as upon adoptive transfer of immune T lymphocytes into tumour-bearing hosts. We suggest that in situ-activated SER+ macrophages contribute to host resistance against metastasis. PMID- 8698396 TI - Cultured human Langerhans' cells are superior to fresh cells at presenting native HIV-1 protein antigens to specific CD4+ T-cell lines. AB - Cultured Langerhans' cells (CLC) exhibit enhanced antigen-presenting function compared to freshly isolated LC (FLC), but they are commonly believed to be inefficient at processing intact proteins. In this study, FLC and CLC from normal, human immunodeficiency virus (HIV) seronegative volunteers were compared for their ability to present the HIV-1 envelope glycoprotein gp120 or reverse transcriptase (p66) antigens to autologous, specific CD4+ T cell lines. Epidermal cell suspensions enriched for LC were prepared from suction blister roofs. FLC stimulated T cells at lower antigen concentrations compared to unfractionated peripheral blood mononuclear cells (PBMC). CLC were more potent on a per cell basis than FLC, PBMC or adherent monocytes at presenting native gp120, native p66 or immunogenic peptides. CLC were also more efficient than FLC or PBMC in terms of the amount of antigen required for T-cell activation. Chloroquine and leupeptin inhibited presentation of intact p66, but not of an immunodominant peptide, by FLC or CLC, thus indicating that both cells utilize antigen processing mechanisms that are based on intracellular acidification and protease activity. Incubation of CLC with monoclonal antibodies against HLA-DR, CD11b, CD18, CD50, CD54, CD58 or CD80, but not anti-major histocompatibility complex class I (MHC-I), inhibited antigen-specific T-cell proliferation to varying degrees. We conclude that human CLC retain the ability to process and present protein antigens potently to CD4+ T cells. Thus, CLC have the capacity to participate actively in the generation and maintenance of T-helper cell immunity to viral antigens during HIV-1 infection. PMID- 8698397 TI - Flow cytometric analysis of cytokine receptors on human Langerhans' cells. Changes observed after short-term culture. AB - It is well established that granulocyte-macrophage colony-stimulating factor (GM CSF), interleukin (IL)-1 and tumour necrosis factor-alpha (TNF-alpha) are involved in Langerhans' cell (LC) development and dendritic cell traffic. However, little is known about the pattern of cytokine receptors on human LC and their modulation during different stages of maturation. The expression of cytokine receptors was studied by flow cytometry on both freshly isolated LC (fLC) and 72-hr cultured LC (cLC). Epidermal cell suspensions enriched in LC were obtained after skin trypsinization and Ficoll-Hypaque gradient. LC were identified by their CD1a positivity. Although the majority of fLC were positive for the alpha chain of GM-CSF receptor (GM-CSFR), the beta chain of GM-CSFR was detected only on 15% of CD1a+ cells. fLC were also positive for IL-1 receptor (IL 1R) type 1, IL-1R type 2, 75,000 molecular weight TNF receptor (TNFR) and interferon-gamma receptor (IFN-gamma R). IL-6R and its transducing signal gp130 were present in a subset of fLC. Granulocyte colony-stimulating factor receptor (G-CSFR), macrophage colony-stimulating factor receptor (M-CSFR), the alpha and beta chain of IL-2R, IL-4R, IL-7R, IL-8R and 55,000 molecular weight TNFR were not detected on fLC. After culture, LC up-regulated the expression of both the alpha and beta chains of GM-CSFR, IL-1R type 2, alpha and beta chains of IL-2R, IL-6R and gp130. In contrast, IL-1R type 1 and 75,000 molecular weight TNFR were down-modulated and the expression of IFN-gamma R was not affected by culture. These results suggest that LC undergo changes in the cytokine receptor repertory during in vitro maturation. PMID- 8698398 TI - Stem cell factor enhances immunoglobulin E-dependent mediator release from cultured rat bone marrow-derived mast cells: activation of previously unresponsive cells demonstrated by a novel ELISPOT assay. AB - Mucosal mast cells (MMC) are important effector cells in the immune response against gastrointestinal nematodes. We used cultured rat bone marrow-derived mast cells (BMMC) as an in vitro model of MMC to study the effects of the multifunctional cytokine stem cell factor (SCF) on immunoglobulin E (IgE) dependent secretion of granule mediators. SCF (< or = 1000 ng/ml) was not a direct secretagogue for these cells, but it significantly enhanced IgE-mediated secretion of the granule constituents rat mast cell protease-II (RMCP-II) and beta-hexosaminidase from mature BMMC in a dose-dependent manner (> 10 ng/ml). Maximum up-regulation of secretion occurred after cells were pretreated with SCF (50 ng/ml) for 5 minutes before challenge with anti-IgE, but the effect then declined and was absent in cells incubated with the cytokine for 3 to 24 h. In a novel ELISPOT assay developed to identify individual BMMC secreting RMCP-II, the proportion of mature BMMC responding to anti-IgE was significantly increased by treatment with SCF. To investigate this effect further, the percentage release of RMCP-II and beta-hexosaminidase from populations of mature BMMC was directly compared to the proportion of individual cells releasing RMCP-II as detected by ELISPOT. The release of both mediators was enhanced by SCF, and the increased percentage release reflected both an increased proportion of secreting cells, and enhanced mediator release from individual cells. These results suggest that SCF can enhance IgE-dependent mediator release from BMMC not only by augmenting the secretory response from individual cells, but also by activating previously unresponsive cells. PMID- 8698400 TI - Cellular and molecular determinants of ageing. AB - The highly complex nature of the process of ageing implicates both genetic and epigenetic causative factors. A progressive failure of maintenance underlines and typifies this process. The instability of the nuclear and the mitochondrial genomes is an important determinant of ageing. Infidelity and misregulation of genetic information transfer, loss of cellular proliferative capacity, altered cellular responsiveness and defective pathways of signal transduction are major aspects of the failure of homeostasis. These are also the basis of age-related diseases and impairments, such as osteoporosis, arthritis, immune deficiency, altered drug clearance and altered functioning of the brain. Studies directed towards understanding the mechanisms of interaction and inter-dependence of various genes involved in maintenance and repair networks are the most promising research strategies for identifying gerontogenes. PMID- 8698399 TI - Analysis of immunoglobulin variable region genes of a human IgM anti myeloperoxidase antibody derived from a patient with vasculitis. AB - Circulating antibodies to myeloperoxidase (MPO) are associated primarily with pauci-immune glomerulonephritis and systemic vasculitis. Anti-MPO antibodies belong to a group of autoantibodies, anti-neutrophil cytoplasmic antibodies, that may play a pathogenic role in vasculitis. We have generated a human monoclonal anti-MPO antibody (E3-MPO) using peripheral blood lymphocytes from a patient with microscopic polyarteritis. Variable region gene analysis of E3-MPO showed that the VH region had 90% homology with the germ line gene VH4-21. E3-MPO was also shown to carry the 9G4 idiotope, which so far has been associated only with human antibodies that utilize the VH4-21 gene. The 9G4 idiotope was also expressed on anti-MPO antibodies in sera from the donor patient and from 4/7 additional patients with active, untreated vasculitis. The nucleotide sequences of both the variable heavy and light chains of E3-MPO showed evidence of an antigen-driven response. PMID- 8698401 TI - Comparative immunological and genomic characterization of fowlpox virus isolates. AB - Chickens infected with fowlpox virus (FPV) IVRI vaccine strain and two field isolates collected from clinical cases of disease (Bareilly isolate and Panchmahal isolate) produced humoral antibody response after 2nd week post infection, with a noticeable variation in degree of immune response. Serum antibody titre peaked at 4th week post-infection with a titre of 25,600, 25,600 and 51,200 being detected in ELISA and neutralization index of 2.75, 2.43 and 3.12 in serum neutralization test (SNT) with IVRI vaccine strain, Panchmahal isolate and Bareilly isolate, respectively. Cellular immune response was detected as early as 1st week post-infection by leukocyte migration inhibition test (LMIT). Per cent migration inhibition too peaked at 4th week with a value of 40.30 +/- 3.45, 36.93 +/- 4.11 and 45.45 +/- 3.66 being detected with the three viruses respectively. The Hind III and Hae III restriction fragment profile of viral DNA showed almost similar pattern both in vaccine strain and two field isolates. Hind III digestion produced 47 well resolved fragments of sizes between 24.30 and 1.20 kb and the total genomic size was estimated to be between 305.81 and 306.06 kb. Hae III digestion revealed 34 well resolved fragments of sizes between 27.55 and 1.32 kb. The three viruses could not be differentiated on the basis of their genomic restriction pattern. However immunogenic and antigenic differences were noticed by ELISA and SNT tests. PMID- 8698402 TI - 2-DG induced modulation of chromosomal DNA profile, cell survival, mutagenesis and gene conversion in X-irradiated yeast. AB - Effects of post-irradiation modulation in presence of 2-deoxy-D-glucose and yeast extract, on chromosomal DNA profile, cell survival, reverse mutation (ILV+) and gene conversion (TRP+), were studied in X-irradiated stationary phase yeast cells (diploid strain D7 of Saccharomyces cerevisiae). The damage and repair in chromosomal DNA bands, resolved by using contour clamped homogeneous electric pulsed-field gel electrophoresis (PFGE) technique, was estimated by calculating intensity ratio, rho n (rho n I(n)/I(t); where I(n) is the intensity of nth band in a lane and I(t) is the sum of intensities of all bands and the well in the lane). The data indicate linear correlation between relative compactness (tau) of a chromosome [chromosome size (Kb)/length of synaptonemal complex (microns)] and DNA damage and repair. The chromosome repair kinetics were biphasic, showing initial decrease followed by an increase in rho n. Variations were observed among different chromosomes with respect to DNA damage, repair and post-irradiation repair modulation. 2-DG inhibited both components of chromosomal DNA repair and also repair of potentially lethal damage but enhanced frequencies of mutants. Relatively the effects on revertants were greater in cells irradiated with lower doses (50 Gy) of X-rays and post-irradiation incubation in presence of phosphate buffer having 2-DG (50 mM) and glucose (10 mM). Yeast extract increased frequencies of revertants and convertants thus promoting error-prone DNA repair. Yeast extract in combination with 2-DG showed complex effects on chromosomal DNA repair and enhanced mutagenesis further. PMID- 8698403 TI - Cloning of extracellular lipase gene from Xanthomonas campestris pathovar sesami on to Escherichia coli. AB - A lipase gene from X. campestris pv. sesami (strain XcS 1) causal agent of leaf spot disease of Sesamum indicum, was cloned onto E. colt. XcS showed the presence of lip+ transformants on Dye's medium with 1% glycerol as sole carbon source. The recombinant plasmids were isolated and when digested with Eco R1, yielded 2 fragments with molecular weights 4.0 and 4.8 kb. Thus a 8.8 kb insert DNA fragment was obtained which showed lipase activity. PMID- 8698404 TI - Histological changes in the spleen of BALB/C mice caused by excretory-secretory protein(s) of Setaria digitata (Von Linstow). AB - The hatching associated materials generally called the excretory-secretory material (ES) released from the filarial parasite S. digitata along with the microfilariae (mf) under in vitro conditions showed immunosuppression. However the protein from lysate of embryo zone, from which ES materials were released along with the mf showed immunopotentiation in BALB/C mice. The histological analysis of spleen of immunized BALB/C mice showed changes confirming the in vitro findings. The main changes observed in the suppressed spleen were decrease in size and number of lymph follicles and increase in number of reticuloendothelial (RE) cells and cosinophil cells, whereas the main change in the potentiated spleen was an increase in the number of lymph follicles as compared to control spleen. These results clearly indicate that there are two types of ES materials in S. digitata, the native material present in the mature embryo causes immunopotentiation, and the materials released during the hatching process into the hostile environment along with mf causes immunosuppression. The difference in the biological effect between the materials released by lysis and hatching of the embryo opens up fresh understanding about the survival strategies of filarial parasites. PMID- 8698405 TI - Antistress activity of P-GABA in experimental animals. AB - A new gamma-aminobutyric acid derivative N-phthloyl GABA (P-GABA) was found to possess anticonvulsant, antiepileptic, antiulcer and antinociceptive activities. Effect of cold restrain stress (CRS) and its modulation by P-GABA were evaluated on some biochemical and biophysical parameters in rats. CRS induced elevations in blood sugar level were unaffected by P-GABA treatment. CRS also caused an increase of Na+K+ ATPase activities, and decrease of lipid peroxidation in RBC membrane. CRS also induced (a) membrane protein clusterization, (b) increased membrane fluidity and (c) reduced thickness. CRS induced RBC membrane dynamics were reversed by P-GABA in a differential manner. However, these parameters in synaptosomal membrane were unaffected by P-GABA. PMID- 8698406 TI - Neuropharmacological studies on Panax ginseng. AB - Panax ginseng root powder is extensively used in the Far East for a wide variety of clinical ailments and to improve general physical and mental wellbeing. It is now also being used in the Occident because of the adaptogenic activity of the plant. The present investigation was conducted to evaluate the neurophamacological profile of activity of P. ginseng (ginseng), since the available data were meagre and often controversial. Ginseng had a complex profile of activity, sometimes difficult to reconcile on the available neurochemical reports on the plant. Thus, it did not appear to affect pentobarbitone sleep induction or spontaneous motor activity but potentiated amphetamine-induced increase in motility. However, ginseng attenuated the other effects of amphetamine, namely, stereotypy and lethality in aggregated mice. The drug exhibited antinociceptive activity and potentiated the antinociceptive effects of both pentazocine and aspirin. Haloperidol catalepsy was potentiated while the behavioural responses of 5-hydroxytryptophan (5-HTP) and L-DOPA were both attenuated. Ginseng had no anticonvulsant action, nor did it potentiate the anticonvulsant effects of phenobarbitone and diazepam. The drug had per se hyperthermic effect and attenuated the hypothermic response of reserpine and 5 HTP induced hyperthermia. Ginseng exhibited significant aggression-inhibiting effect in doses which had no significant effect on spontaneous motility. The results have been discussed on the neurotransmitter function basis of the experimental paradigms and the likely effect of ginseng on these actions. PMID- 8698407 TI - Influence of fowl uropygial gland and its secretory lipid components on growth of skin surface bacteria of fowl. AB - Bacterial species, which occur on the breast skin surface of adult (1 year old) white leghorn fowl with intact uropygial gland, were identified as : Staphylococcus epidermidis, Sarcina lutea, Streptomyces sp. and a facultative diphtheroid belonging to the genus Corynebacterium; S. epidermidis being the most predominant one. Two species of bacteria, namely, Staphylococcus aureus and Proteus sp. were shown to colonize the skin surface after 60 days of captivity. Extirpation of uropygial gland caused severe depletion of population of S. epidermidis, Streptomyces sp. and diphtheroid. The effect was more conspicuous after 60 days compared to that after 30 days of the gland removal. On the skin surface of glandless fowls the population of S. aureus increased significantly and a new form identified as anthracoid bacillus became the most predominant species after 60 days. Addition of total lipids from the free-flowing fowl uropygial secretion, as 0.2% suspension, to trypticase soya broth cultures of individual bacteria of fowl skin surface encouraged strongly the growth of S. epidermidis, Streptomyces sp. and Proteus sp. but suppressed the population of the anthracoid. When identical amount of diester wax or wax alcohol of the secretion was supplemented to the culture, more or less similar result was obtained. Wax alcohol also had a mild inhibitory effect on Streptomyces sp. Wax acids, added to the culture (0.2%) suppressed population of all the bacterial forms except Proteus sp., while the hydrocarbon fraction, which also contained some amount of squalene, produce an opposite effect. PMID- 8698408 TI - Specific effect of vincristine on epididymis. AB - Wistar strain male albino rats were administered with vincristine (VCR) sulphate (10 micrograms/day for 15 days); epithelial cell types of the caput (zone II) and cauda (zone V) were studied light microscopically adopting semithin sectioning. VCR caused conspicuous pathological changes in the principal and apical cells of the caput and the clear cells of the cauda. The study points to toxic effect of VCR on these cell types, suggesting impairment of epididymal function, particularly concerning sperm maturation and endocytotic removal of the contents of the cytoplasmic droplets and dead sperm. PMID- 8698409 TI - Oxidative stress in rat liver and lung induced by furanoterpenoids isolated from Fusarium solani infected sweet potatoes. AB - A crude extract containing some toxic furanoterpenoids was isolated from F. solani infected sweet potatoes. Chronic administration of the crude extract to male albino rats at a dosage of 1 mg/kg body weight/day for 21 days brought about a sharp increase in the thiobarbituric acid reactive substances and a depression of glutathione levels in the lung and liver homogenates. The antioxidant defense system was affected as evident from a significant fall in the activities of the enzymes, superoxide dismutase, catalase, glutathione peroxidase, glucose-6 phosphate dehydrogenase and glutathione-S-transferase. Such an alteration could be the reason for the lung and liver damage caused by these toxic furanoterpenoids. PMID- 8698410 TI - Toxicological evaluation of mowrah (Madhuca latifolia Macbride) seed meal. AB - Mowrah (M. latifolia) seeds yield 40-50% edible fat and the meal contains saponins besides protein and high level of carbohydrates. The toxicity of the meal was evaluated as it has a potential for use in animal feedstuffs. The meal was fed to young and adult rats at levels of 10 to 40% in diet. The animals showed marked inhibition of feed intake and loss of body weight resulting in mortalities. Histopathological examination revealed a gradation of damage from slight erosion of the tip of villi of intestinal mucous membrane to complete necrosis and destruction of it, with increasing amounts of mowrah seed meal in diets. The other significant change was a severe vacuolar degeneration of kidney tubular cells. Detoxification or complete removal of the toxins is necessary for utilization of the meal as animal feedingstuff. PMID- 8698411 TI - Role of Tamra bhasma, an Ayurvedic preparation, in the management of lipid peroxidation in liver of albino rats. AB - Hepatoprotective effect of Tamra bhasma has been studied on cumene hydroperoxide (CHP) induced peroxidation, reduced glutathione content and superoxide dismutase (SOD)-in rat liver homogenate. The drug was orally given for 8 days which showed significant reduction in the level of malondialdehyde (MDA) production at different concentrations of cumene hydroperoxide in vitro. Glutathione content was maintained upto seventy minutes and SOD activity was enhanced to 166%. These animals did not show any rise in serum GOT and GPT. On similar doses no histological changes were observed in liver. The results suggested that Tamra bhasma is a strong antioxidant drug and could be used in the management of lipid peroxidation with no detectable adverse effect. PMID- 8698412 TI - HPV 16 DNA sequences in different grades of cervical lesions. AB - A simple rapid method for isolation of genomic DNA from cervical scrape cells has been standardized. Sufficient amount of good quality genomic DNA was isolated from each cervical scrape specimen. Total 120 cervical scrape specimens from wide spectrum of cervical lesions were analysed for the presence of HPV 16 DNA by Southern hybridization using 32P labelled HPV 16 DNA as probe under stringent conditions. Viral DNA sequences were detected in 78 of the specimens. About 36% (5 out of 14) of normal cervical smears and 59% (46 out of 78) of inflammatory cervical smears had the viral DNA sequences. Except a lone sample, the rest 27 samples of different grades of dysplasia specimens and squamous cell carcinoma samples had viral DNA sequences. Due to development of sensitive Southern hybridization method, the presence of HPV 16 DNA could be detected in high percentage of specimens belonging to the inflammatory cervical specimens. PMID- 8698413 TI - Anticonvulsant activity of Albizzia lebbeck leaves. PMID- 8698414 TI - Antidiabetic activity of some oral hypoglycemic agents with metal ions on animal model. PMID- 8698415 TI - Radioprotective and antioxidant action of caffeine: mechanistic considerations. AB - Caffeine, a major constituent of coffee and other beverages has significant abilities to scavenge highly reactive free radicals and excited states of oxygen and to protect crucial biological molecules against these species. This is one of the possible reasons why caffeine acts as a radioprotector against oxygen dependent ('oxic') pathway of radiation damage and as an antimutagen/anticarcinogen under certain conditions. The possible physicochemical and molecular mechanisms of caffeine action are briefly reviewed in the light of the recent findings. PMID- 8698416 TI - Bloom syndrome: is the gene mapped to the point? AB - Bloom syndrome (BS), an autosomal recessive genetic disorder, is an instructive model to explore variety of questions in "deregulation of normal cell functioning". Most of the BS patients are homozygous for mutant BLM gene and depict high sister chromatid exchanges (SCEs) in almost all the cells. However, a few possess cells with dimorphic SCE phenotype. A majority of patients with dimorphic SCE phenotype have been suggested to be compound heterozygotes, inheriting two different mutations in the BLM locus from each parent. An intragenic somatic recombination event in a precursor stem cell in such patients is envisaged to give rise to a population of cells with functionally wild-type (BLM) gene and normal SCE phenotype. Adopting unique dual approaches of positional mapping through "homozygosity by descent" and "somatic crossover point mapping", a candidate for BLM has been identified and localized to a 250 Kb interval between polymorphic loci, DI5S1108 and D15127. The sequence has been found to encode a 1417 amino acid peptide with homology to the RecQ helicases, a sub-family of DExH box-containing DNA and RNA helicases. The presence of chain terminating mutations in the 'candidate' gene in BS patients has suggested it to be the BLM gene. Apparantly the proposed gene product does not seem to provide answer for a variety of clinical, biochemical and experimental observations made in BS or BS cells till date. Our recent observation of a significant decrease in the activity of pyruvate kinase in three BS B-lymphoblastoid cell lines when compared to a similar cell line established from a normal healthy subject presents with another possible candidate to elucidate the defects in BS. Experiments using okadaic acid, a phosphatase-2a/1 inhibitor, have depicted in our study that many of the clinical features characteristic of BS, not easily explanable by the recently proposed BLM gene, can be explained by the deficiency in the PK alone and/or PP2a/PP1 activity. PMID- 8698417 TI - Active immunization of rats with chicken egg thiamin carrier protein results in early embryonic loss at periimplantation stages. AB - Active immunization with chicken egg white thiamin carrier protein (TCP) was performed to assess the functional importance of the vitamin carrier during gestation in rats. Towards this, fertile female rats were immunized with heterologous TCP and when the circulatory titres of anti-TCP IgG were high, these animals were mated with fertile male rats. Progression of pregnancy was monitored by measuring circulatory progesterone levels. A sudden fall in the steroid hormonal levels around day 8 post coitus was observed. Histological examination of the uterine tissue sections on day 7 revealed that active immunization with TCP affected the blastocyst viability resulting in unsuccessful implantation and hence pregnancy termination. PMID- 8698418 TI - Biochemical alterations in macrophages by interaction with immune complexes. AB - The mouse peritoneal cells (MPS) were stimulated under in vitro and in vivo conditions with different compositions of bovine serum albumin (BSA)-anti BSA immune complexes (IC). The aim was to monitor the biochemical changes that may occur in macrophages and this activation was indicated by an increase in the number and protein content of the cells. The role of these complexes in inducing lysosomal hydrolases release from elicited as well as during an in vitro interaction with ICs was also studied. The insoluble immune complex at equivalence (IC-Eq) and immune complex-antibody excess (IC-Ab) registered a significant increase in number of cells and protein content as compared to soluble immune-complex antigen excess (IC-Ag) complexes. The IC elicited cells showed lesser secretory activity as compared to MPM cells stimulated in vitro. Stimulating capacity of ICs in causing hydrolase release was time and dose dependent. The complement coated complexes were the most effective in inducing enzyme release (4.5-5-fold). PMID- 8698419 TI - Fowlpox virus structural protein immunogens and characterization of single band polypeptide. AB - A fowlpox virus isolate obtained from an outbreak of disease in a vaccinated poultry flock was propagated in chicken embryo fibroblast cell culture. Analysis of purified virus polypeptide on 7.5-15% gradient polyacrylamide gel revealed 45 structural polypeptides after Coomassie blue staining. The mol.wt. of polypeptides ranged between 225.53 and 10.50 kDa with total mol.wt. of 2650 kDa. Variable numbers of immunogenic virion polypeptides were detected in immunoblot with fowlpox virus infected chicken sera collected at different time intervals. A total of 29 polypeptides reacted with sera collected at 1st week post-infection and the number gradually declined to 27, 26, 20, 17 and 15 when reacted with 2nd, 3rd, 4th, 5th and 6th week post-infection sera, respectively. Reaction with fowlpox virus hyperimmune sera revealed 35 immunogenic polypeptides. A number of major and minor immunogens were detected. Antisera against seven major single band polypeptides including one double band polypeptide showed very low reactivity both in ELISA and serum neutralization test. Involvement of multigenic components in virus neutralization is indicated. PMID- 8698420 TI - Fungitoxic action of dithanes in presence of surfactant micelles. AB - A rationale of arriving at the concentration of surfactant additives in the pesticidal formulations has been discovered. Fungitoxic activity of each of the two dithanes, Dithane M-45 (maneb) and Dithane Z-78 (zineb) has been estimated in the presence of various concentrations of three surfactants namely sodium lauryl sulphate, cetyl pyridinium chloride and Tween 80. Data reveal that the concentration of the surfactant additives in the pesticidal formulations should be at least equal to its critical micelle concentration (CMC) for enhanced biological activity. This rationale for the concentration of surfactant additives in the pesticidal formulation has so far not been clearly brought out in the literature. Since biological activity of the pesticides is enhanced in the presence of surfactant additives the present study is relevant to the reduction of environmental pollution due to pesticide residues. PMID- 8698421 TI - Development effect of technical dimethoate in rats: maternal and fetal toxicity evaluation. AB - Technical dimethoate was administered orally to pregnant rats through day 6-20 of gestation at doses 3.75, 7.5, 15 and 30 mg/kg/day. Dose of 30 mg/kg/day produced high mortality rate in dams and was not considered for developmental toxicity evaluation. Dimethoate produced enzymatic changes in liver of dams associated with mild pathomorphological changes in liver and brain. Significant fetotoxic effects were not observed at the tested dose levels as evidenced by total number of implantations, percentage resorption, and live fetuses except reduction in fetal weight. Reduced acetylcholinesterase activity in fetal brain and placenta at higher dose levels indicated possible transmigration of dimethoate from dams to fetuses. The absence of anomalies in fetal gross, visceral morphology and skeleton suggests technical dimethoate as non teratogenic in rat at tested dose levels. PMID- 8698423 TI - Effect of leaf extract of Aegle marmelose (L.) Correa ex Roxb. on histological and ultrastructural changes in tissues of streptozotocin induced diabetic rats. AB - Light and electron microscopic examination of tissues of rats rendered diabetic with a smaller dose of 45 mg/kg of body weight of streptozotocin were carried out in the present study. The dose of the drug given altered the function of pancreatic beta-cells and the acinar cells. The changes in the acinar cells were coarsening of endoplasmic reticulation (ER) and alterations in their secretory function. The changes in the liver were (1) dialation of veins, (2) loss of usual concentric arrangement of hepatocytes, (3) liver fibrosis and (4) decrease in glycogen content. The kidney tubules were thickened and the glomerulus was expanded. The leaf extract of Aegle marmelose reversed the altered parameters to near normal. The treatment of leaf extract on diabetic pancreas showed improved functional state of pancreatic beta-cells. The results indicate the potential hypoglycemic nature of the leaf extract, helping in regeneration of damaged pancreas. PMID- 8698422 TI - Hypolipidemic effect of garlic protein substituted for casein in diet of rats compared to those of garlic oil. AB - Garlic (Allium sativum Linn.) is ascribed with many therapeutic effects. For the present study, the water soluble proteins and the essential oil of garlic were investigated for their hypolipidemic effect on hyperlipidemia induced by cholesterol containing diet in albino rats. Both garlic protein (16% of diet) and garlic oil (100 mg/kg body weight/day) exhibited significant lipid lowering effects. The hypolipidemic action is primarily due to a decrease in hepatic cholesterogenesis in the treated rats. Even though garlic oil was found to be more effective, the garlic protein is more palatable and free from an obnoxious smell. PMID- 8698425 TI - Mode of action of three structurally different hypoglycemic agents: a comparative study. AB - The mechanism of dose-dependent hypoglycemic effect, the margin of safety and ED50 of three structurally unrelated compounds, tolbutamide (TB), centpiperalone (CP) and a swerchirin-containing fraction (SWI) from the plant Swertia chirayita, were investigated in experimental models. After a single oral administration of TB, CP and SWI to groups of normal and streptozotocin (STZ)-induced mild and severe diabetic rats, the blood sugar lowering effect and ED50 of the agents were determined. Plasma Immuno Reactive Insulin (IRI) levels and the degree of islet beta cell degranulation were assayed using RIA and histochemical staining, respectively, in normal rats treated with the agents. The percent blood sugar lowering, increase in IRI levels and beta cell degranulation were highest in CP treated normal rats (69, 124 and 75%, respectively). In addition, CP was the only agent found active in STZ-induced severely diabetic rats (P < 0.01). In STZ-mild diabetic rats, however, TB was more effective than CP and SWI. By analysis of data using Anova method, it is concluded that CP is more effective than SWI (P < 0.01) and TB. However, SWI an impure natural product showed better blood sugar lowering than tolbutamide which is a drug in use. PMID- 8698424 TI - Biochemical effects of garlic protein diet and garlic oil on glycosaminoglycan metabolism in cholesterol fed rats. AB - Garlic protein diet or daily administration of garlic oil to 2% cholesterol fed rats controlled significantly the increases in sulphated glycosaminoglycans in their heart and aorta. However hyaluronic acid level increased. UDPG dehydrogenase decreased and several degrading enzymes increased in the aorta on treatment. The effects of treatment were just the reverse in liver. The high percentage of cysteine in garlic protein and the reactive disulphide group in the oil may be responsible for their beneficial effects. PMID- 8698426 TI - Thermosensitive and pH mechanisms regulating urine formation. AB - The study was undertaken to investigate the effect of infusion of isotonic saline of different pH (2, 3, 9 and 10) and different temperatures (cold 4 degrees and warm 40 degrees C) in urinary bladder on rate of renal urine formation. The volume of fluid (isotonic saline) infused was 100 ml in all the cases. Presence of alkaline saline (pH-9 and pH-10) and warm saline in urinary bladder, decreased the rate of urine flow whereas acidic and cold saline increased the rate of urine flow significantly. (P < 0.05 and < 0.0001 respectively). The observed effects disappeared when 4% xylocaine in 100 ml saline was infused and evacuated prior to infusion of fluids of different pH and temperature. The observation suggests existence of chemosensitive and thermosensitive mechanisms in the vesical mucosa regulating urine formation by the kidney. PMID- 8698427 TI - Testicular lactate dehydrogenase and sorbitol dehydrogenase activity after intratesticular injection of dynorphin and morphine in male rats. AB - Testicular lactate dehydrogenase (LDH) and sorbitol dehydrogenase (SDH) activity were measured at 1 and 4 hr following intratesticular injection of morphine and dynorphin. Twenty five and 50 micrograms doses of morphine sulfate significantly reduced LDH activity at 1 hr after injection. Five and 25 micrograms doses of dynorphin reduced LDH activity both at 1 and 4 hr after treatment. Testicular SDH activity was increased by morphine at 1 hr followed by a decrease at 4 hr. Both doses of dynorphin significantly reduced SDH activity at 1 and 4 hr after treatment. These results indicate paracrine regulatory role for opioids in testicular metabolism. PMID- 8698428 TI - Alterations in the systemic acid-base status and blood gas dynamics during progressive hypocalcaemia in cow calves. AB - Hypocalcaemia, induced in cow calves by slow infusion of Na2EDTA for 6 hr, led to biphasic changes in acid-base status. Decrease in ionized plasma Ca2+ concentration upto 0.82 +/- 0.06 mmole 1(-1) was associated with metabolic alkalosis. Further decrease in ionized plasma Ca2+ concentration (0.61 +/- 0.09 mmole 1(-1)) led to metabolic acidosis, superimposed by a respiratory component. There was significant decrease in oxygen tension and saturation of arterial blood as well as impaired uptake of oxygen by peripheral tissues and pulmonary blood. PMID- 8698429 TI - Chimeric plasmid transformation in Haemophilus influenzae. AB - Fate of 32P-labelled pJ1-8N19 DNA was followed in the mutant strain N19 and wild type H. influenzae Rd, during post-uptake incubation. Integration of the insert fragment carrying novr gene into the host genome was measured at various time intervals during post-uptake incubation. Negligible amount of label transfer and no detectable transfer of biological activity (novr) was observed in mutant strain N19 compared to wild type strain Rd. These observations correlated poor extra chromosomal establishments of the donor plasmid in the mutant strain N19. PMID- 8698430 TI - Effect of storage of blood samples on DNA yield, quality and fingerprinting: a forensic approach. AB - Various storage treatments on human blood samples have been described with respect to DNA yield, quality and fingerprinting. Blood samples were stored at room temperature, 4 degrees C, -20 degrees C and -70 degrees C for different duration varying from 1, 2, 4 and 8 weeks with or without anticoagulant/preservative (EDTA or Heparin). DNA was isolated from these stored samples, quantitated by spectrophotometry and subjected to DNA fingerprinting using a human alphoid satellite DNA sequence (TRF 5.6) and a 33 mer oligonucleotide (O-chi-1) as probes. The polymorphic DNA bands were apparent between 2 to 9 kb size range and the fingerprints were individual-specific. Our results suggest that higher amount of genomic DNA can be recovered from blood samples stored at temperatures 4 degrees C or below in the presence of EDTA or heparin. PMID- 8698431 TI - Antihypertensive therapy: safety and efficacy of drugs and publications. PMID- 8698432 TI - Comparison of changes in cardiac structure after treatment in secondary hypertension. AB - To investigate the role of aldosterone and the renin-angiotensin system in cardiac structure, we performed echocardiography in patients with secondary hypertension. The relation between blood pressure or hormonal influences and left ventricular hypertrophy has not been well established in secondary hypertension. Sixteen patients with primary aldosteronism and 11 with unilateral renovascular hypertension who had completely normalized blood pressure after operation or percutaneous transluminal angioplasty were evaluated by echocardiography before and after surgery or other interventional treatment. Blood pressure was not statistically different between the groups before treatment and was normalized after treatment in both groups. Left ventricular hypertrophy was mild in both groups before treatment, and its degree was not statistically different between the groups. At the end of the follow-up period, all parameters of primary aldosteronism and left ventricular mass index in patients with unilateral renovascular hypertension were significantly reduced. In patients with primary aldosteronism, changes in end-diastolic left ventricular internal dimension correlated positively with changes in left ventricular mass index (r=.58,P<.01). In patients with unilateral renovascular hypertension, changes in mean blood pressure and left ventricular mass index were significantly correlated (r=.77,P<.01). The expanded plasma volume induced by an excess of aldosterone and high blood pressure may play an important role in the increase of left ventricular mass in primary aldosteronism. In unilateral renovascular hypertension, high blood pressure mainly contributes significantly to increased left ventricular mass. Therefore, different factors may modulate the development of left ventricular hypertrophy in patients with secondary hypertension. PMID- 8698433 TI - Exercise blood pressure predicts mortality from myocardial infarction. AB - Apparently healthy men (n=1999, 40 to 59 years old) were investigated from 1972 through 1975 to determine whether systolic blood pressure during bicycle ergometer exercise predicts morbidity and mortality from myocardial infarction beyond that of casual blood pressure taken after 5 minutes of supine rest. During a follow-up of 31 984 patient-years (average, 16 years), 235 subjects had myocardial infarctions, of which 143 were nonfatal and 92 were fatal. Exercise blood pressure was more strongly related than casual blood pressure to both morbidity and mortality from myocardial infarction. Among 520 men with casual systolic blood pressure = 140 mm Hg, 304 increased their systolic blood pressure to > or = 200 mm Hg during 6 minutes of exercise at an initial workload of 600 kpm/min. These 304 men had an excessive risk of myocardial infarction (18.8% versus 9.5% among the 1294 men with casual blood pressure < 140 mm Hg and exercise blood pressure < 200 mm Hg; P < .001). As many as 58% of those with myocardial infarction in this group died, compared with 33% (range, 26% to 35%) for all other groups (P=.0011), including those with casual blood pressure > or = 140 mm Hg and exercise blood pressure < 200 mm Hg. Thus, exercise blood pressure is a stronger predictor than casual blood pressure of morbidity and mortality from myocardial infarction, and an early rise in systolic blood pressure during exercise adds prognostic information about mortality from myocardial infarction among otherwise healthy middle-aged men with mildly elevated casual blood pressure. We suggest that blood pressure taken during standardized exercise testing may distinguish between severe and less severe hypertension. PMID- 8698434 TI - Effect of 1 year of lisinopril treatment on cardiac autonomic control in hypertensive patients with left ventricular hypertrophy. AB - In this study we evaluated in hypertensive patients the effects of drug-induced left ventricular hypertrophy regression on cardiac autonomic control, as assessed by means of heart period variability analysis. Power spectral analysis of 24-hour electrocardiographic monitoring was performed in 30 hypertensive patients with left ventricular hypertrophy at baseline, after 1 year of lisinopril treatment, and after 1 month of drug withdrawal. At the same times, patients underwent 24 hour blood pressure monitoring, echocardiographic study, and plasma renin activity assessment. Lisinopril treatment increased plasma renin activity and reduced 24-hour systolic and diastolic pressures (from 159 +/- 14 to 121 +/- 8 and from 103 +/- 7 to 80 +/- 3 mm Hg, respectively) and left ventricular mass index (from 159 +/- 33 to 134 +/- 26 g/m2); moreover, in 12 of 30 patients, left ventricular mass normalization was achieved. Drug withdrawal was followed by an increase in blood pressure without left ventricular mass modification. In the total study population, only high-frequency power was higher after lisinopril treatment. In the subgroup of patients with left ventricular mass normalization, daytime and nighttime high-frequency powers as well as nighttime total and very low-frequency powers were higher after 1 year of treatment than at baseline. In the remaining 18 patients, power spectral measures after treatment were slightly lower than at baseline and were even lower after drug withdrawal. Thus, in hypertensive hypertrophic patients, lisinopril treatment improves sympathovagal imbalance when left ventricular mass normalization is achieved. In patients without left ventricular mass normalization, drug withdrawal is followed by a worsening of neural cardiac control. PMID- 8698435 TI - Weights at birth and in early infancy, systolic pressure, and left ventricular structure in subjects aged 8 to 24 years. AB - The objective of this study was to determine whether systolic pressure and left ventricular mass in children, adolescents, and young adults are related to fetal and infant growth. Blood pressure measurements and M-mode echocardiography were performed in 210 subjects aged 8 to 24 years whose information on weights at birth and in early infancy, written by physicians, was obtained from the children's health record booklets. Systolic pressure, adjusted for sex and current height or for sex, current age, weight, and height, was the highest in subjects with low birth weight. No association was observed between systolic pressure and weight at either 9 months or 2 years. Left ventricular mass, adjusted for sex and current height or for sex, current age, weight, and height, increased with decreasing weight at 9 months or 2 years, independent of systolic pressure. Increased ventricular mass associated with reduced infant growth was concentric, resulting from a proportionate thickening of the posterior wall and interventricular septum. Left ventricular mass was not related to birth weight. These findings were observed in both sexes and in all age subgroups and were independent of gestational age, birth order, and parental risk factors. This study supports the hypothesis that systolic pressure and left ventricular mass might be partly determined during fetal life and early infancy. The mechanisms that underlie the associations of blood pressure and left ventricular structure with weights at birth and in early infancy should be studied thoroughly. PMID- 8698436 TI - Evidence for a multifactorial process involved in the impaired flow response to nitric oxide in hypertensive patients with endothelial dysfunction. AB - The assessment of endothelial function in hypertensive patients receiving acetylcholine has revealed conflicting results. Whether an impaired flow response to acetylcholine is explained solely by a diminished endothelial synthesis of nitric oxide (NO) remains unclear as yet. In the present study, we tested the hypothesis that mechanisms other than reduced NO synthesis contribute to the hypertension-associated impairment of endothelium-dependent vasodilation. Therefore, the dilatory response to endogenous and exogenous NO was measured in resistance arteries and cutaneous microvessels in the forearm circulation of 12 normotensive individuals and 17 hypertensive patients. In addition, the overall dilatory capacity was assessed by peak flow during reactive hyperemia after 3 minutes of ischemia. Forearm blood flow was quantified by venous occlusion plethysmography at rest, during application of the NO donor sodium nitroprusside, and during stimulation of endogenous NO synthesis by acetylcholine and bradykinin. Blood flow velocity in the cutaneous microvasculature was measured with laser-Doppler flowmetry in parallel. Resting forearm flow was comparable in both groups (3.1 +/- 0.2 and 3.4 +/- 0.2 mL.min-1.100mL-1 tissue), whereas blood pressure and thus peripheral vascular resistance was significantly elevated in hypertensive compared with normotensive subjects. Hyperemic peak flow was significantly blunted in hypertensive patients. Sodium nitroprusside, acetylcholine, and bradykinin increased flow in a dose-dependent manner to a comparable extent in the control group (13.3 +/- 0.8, 13.6 +/- 1.3, and 14.6 +/- 0.7 mL.min-1.100mL-1 tissue, respectively). In contrast, in hypertensive patients maximum increase in resting flow was significantly reduced (sodium nitroprusside, -36%; acetylcholine, -44%; and bradykinin, -56%). The flow response after stimulation of endogenous NO synthesis by bradykinin was significantly more blunted compared with that of exogenous NO after application of sodium nitroprusside. In the cutaneous microvasculature, bradykinin-induced increases in blood flow velocity were selectively impaired in hypertensive patients, whereas flow response to acetylcholine was preserved. Thus, we conclude that in arterial hypertension endothelium-dependent, NO-mediated dilation of resistance arteries and cutaneous microvessels of the forearm vasculature is heterogeneously impaired, depending on the type of endothelial receptor stimulated. Furthermore, the present data suggest that in hypertensive patients the impairment of NO dependent dilation of resistance arteries is caused by at least three different mechanisms: (1) a reduced endothelial synthesis of NO due to either a disturbed signal-transduction pathway and/or a reduced activity of NO synthase, (2) an accelerated NO degradation within the vessel wall, and (3) alterations in the vessel architecture resulting in an overall reduced dilatory capacity of resistance arteries. PMID- 8698437 TI - Metabolic and hemodynamic effects of a graded intracoronary insulin infusion in normal and fat anesthetized dogs: a preliminary study. AB - This study evaluated both cardiac hemodynamic and metabolic effects of a graded intracoronary artery infusion of insulin in four normal and five obese anesthetized dogs. Dogs were anesthetized with isoflurane, a catheter was advanced under fluoroscopic guidance into the coronary sinus and great cardiac vein, and a 20-MHz 3F coronary Doppler catheter was advanced into either the mid left anterior descending or circumflex coronary artery. A graded intracoronary insulin infusion was administered (starting at 0.3 mU/min and doubling every 40 minutes until a maximum dose of 2.4 mU/min was achieved). Coronary glucose extraction, coronary blood flow velocity, and coronary artery size were measured at each infusion rate. An intracoronary artery infusion of insulin stimulated myocardial glucose uptake in normal dogs. However, in high-fat-fed dogs, weight gain was associated with a reduction in the ability of insulin to promote glucose uptake by cardiac muscle and a rightward shift in the dose-response curve. In normal dogs, an intracoronary insulin infusion resulted in an increase in coronary blood flow and coronary vasodilation (with insulin coronary vascular resistance index decreases to 0.72 +/- 0.06, P<.01), whereas with weight gain the vasodilator response to insulin was lost. The loss of coronary artery vasodilation to local hyperinsulinemia in fat-fed dogs is consistent with other reports in obese or hypertensive humans that document an impairment in the action of insulin to increase skeletal muscle blood flow. PMID- 8698438 TI - Parathyroid hormone-related protein inhibits indothelin-1 production. AB - The effect of human parathyroid hormone-related protein, a powerful vasodilator, on endothelin-1 production in cultured bovine pulmonary arterial endothelial cells was studied. Treatment with parathyroid hormone-related protein(1-34) at concentrations of 10(-9) to 10(-6) mol/L for 24 hours caused dose-dependent suppression of the secretion of endothelin-1, with maximal suppression at 10(-7) mol/L to 74% of the control value. This inhibitory effect was completely abolished by coincubation with 100 ng/mL pertussis toxin, an inhibitor of GTP binding protein. Furthermore, addition of Ng-monomethyl-L-arginine, an inhibitor of nitric oxide synthase, at 10(-3) mol/L significantly blocked the suppressive effect of parathyroid hormone-related protein (1-34) on endothelin-1 secretion, and further addition of 5x10(-3) mol/L L-arginine significantly attenuated the blocking effect of N(G)-monomethyl-L-arginine. Parathyroid hormone-related protein (1-34) at 10(-7) mol/L resulted in an approximately fivefold increase in intracellular cGMP level. Northern blot analysis revealed that parathyroid hormone-related protein (1-34) inhibited both basal and thrombin-induced endothelin-1 gene expression. These findings suggest that the vasodilating property of parathyroid hormone-related protein may be mediated in part through its inhibitory effect on endothelin-1 production, which is probably mediated through nitric oxide and cGMP in endothelial cells. Thus, a feedback regulatory mechanism may exist between parathyroid hormone-related protein and endothelin-1 in the vascular wall. PMID- 8698439 TI - Effects of lisinopril on the structure of renal arterioles. AB - We investigated the effect of long-term administration of the angiotensin converting enzyme inhibitor lisinopril on renal arterioles in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) using a morphometric method and vascular cast technique. Rats were treated with lisinopril beginning at 4 weeks of age. At 15 weeks of age, the kidney vessels were fixed when maximally relaxed. Resin was perfused into the right kidney to make a cast of the renal vasculature. The opposite kidney was used for the morphometric study to evaluate structural changes of the vascular wall. The vascular cast study demonstrated a significant reduction in the lumen diameter of the afferent but not the efferent arterioles in SHR compared with those in WKY. In lisinopril-treated rats, the afferent arteriolar lumen diameters were significantly larger than those of the respective control groups in both strains. However, treatment did not affect the lumen diameter of efferent arterioles in either strain. The morphometric study revealed that the cross-sectional area of afferent arteriolar media was significantly smaller in SHR than WKY, suggesting that the impaired growth of the afferent arteriolar media was involved in the narrowed afferent arteriolar lumen in SHR. The presence of significantly smaller media-lumen ratio, greater media cross-sectional area, and larger internal as well as external diameters of the afferent arterioles in treated SHR than in untreated rats suggested that lisinopril treatment normalizes the structure of the afferent arterioles in SHR by vascular reverse remodeling and by inducing media growth. PMID- 8698441 TI - Importance of nitric oxide and prostaglandins in the control of rat renal papillary blood flow. AB - The role of nitric oxide and prostaglandins in the control of rat renal papillary blood flow has been studied in anesthetized Munich-Wistar rats by use of laser Doppler flowmeter. Acute administration of N omega-nitro-L-arginine methyl ester (L-NAME) 10 mg/kg IV (n=8) increased mean arterial pressure by 27.8 +/- 3.6%, decreased papillary blood flow by 39.4 +/- 3.8%, and decreased renal blood flow by 47.4 +/- 1.9%. The subsequent administration of indomethacin (7.5 mg/kg IV) further decreased papillary blood flow (35.2 +/- 2.5%) without significant changes in mean arterial pressure or renal blood flow. In a second group (n = 6), administration of indomethacin before L-NAME decreased papillary blood flow by 39.6 +/- 2.1% without significantly altering mean arterial ressure or renal blood flow. The subsequent injection of L-NAME further decreased papillary blood flow (32.9 +/- 1.8%) and renal blood flow (49.8 +/- 6.6%) while increasing mean arterial pressure to a level not significantly different from that found in the first group. Autoregulation studies showed that L-NAME but not indomethacin reduced the renal perfusion pressure-renal blood flow relationship without altering autoregulation. However, both nitric oxide and prostaglandins importantly affected the renal perfusion pressure-papillary blood flow relationship because L-NAME and indomethacin significantly decreased this relationship in an additive fashion. Although both drugs reduced the sensitivity of the pressure-papillary flow relationship, only L-NAME affected autoregulation so that papillary blood flow was autoregulated at higher renal perfusion pressures. Thus, the present results indicate that both nitric oxide and prostaglandins control a similar percentage of rat renal papillary blood flow, but nitric oxide seems to be more important than prostaglandins as a mediator of the pressure-blood flow relationship. In contrast, only nitric oxide modifies the renal blood flow level, although it does not disturb whole-kidney blood flow autoregulation. PMID- 8698440 TI - Effects of cilazapril on vascular structure and function in essential hypertension. AB - Hypertension is associated with an altered design of resistance vessels and decreased endothelium-dependent vasodilator response to acetylcholine. A role of angiotensin II in both defects is suggested by animal experiments in which angiotensin-converting enzyme inhibition reverted structural and functional changes. We investigated the effects of 20 weeks of therapy with the angiotensin converting enzyme inhibitor cilazapril (5 mg twice daily) on the endothelium dependent response to brachial artery infusions of acetylcholine and the endothelium-independent vascular relaxation after sodium nitroprusside in 22 subjects with mild to moderate essential hypertension. In addition, we measured minimal forearm vascular resistance (ratio of mean arterial pressure and forearm blood flow after heating, ischemia, and ischemic exercise) as an indirect estimate of vascular structure. Cilazapril decreased blood pressure (151 +/- 14/99 +/- 7 mm Hg during placebo to 138 +/- 17/89 +/- 8 mm Hg after cilazapril treatment, P<.01) and baseline (42.2 +/- 12.6 to 37.1 +/- 10.6 U, P<.05) and minimal (3.0 +/- 1.1 to 2.4 +/- 0.7 U, 15.9 +/- 20.2%; P<.05) forearm vascular resistances. The change in minimal forearm vascular resistance was unrelated to age, duration of hypertension, or changes in blood pressure. Sodium nitroprusside increased forearm blood flow from 2.6 +/- 1.0 to 11.4 +/- 5.9 mL/min per 100 mL and acetylcholine to 21.5 +/- 17.8. Both responses did not change after cilazapril. The data provide indirect evidence that cilazapril therapy may improve vascular structure in human hypertension. The lack of relationship between vascular and blood pressure changes would be compatible with experimental evidence supporting a role for angiotensin II in the development and regression of vascular changes, but this needs further study. Therapy with cilazapril for 20 weeks, like other antihypertensive therapy, does not seem to influence endothelial vasodilator function in humans to a significant degree. PMID- 8698442 TI - Preglomerular sudanophilia in L-NAME hypertensive rats: involvement of endothelin. AB - To characterize alterations of renal vessels occurring during systemic hypertension elicited in rats by 5, 10, and 25 days of treatment by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME)(20 mg/kg daily), preglomerular vasculatures, consisting of arcuate arteries and their branches, interlobular arteries, and afferent arterioles, were isolated by HCl maceration. Blockade of nitric oxide synthase significantly increased tail-cuff systolic blood pressure by 21 +/- 2% and 42 +/- 3% after 5 and 25 days, respectively. Medias of hypertensive arcuate arterial branches and interlobular arteries but not of afferent arterioles had focal deposits of Sudan black positive lipid droplets. At 25 days, vessel wall thickness increased by 72 +/- 6% along the sudanophilic areas. Immunostaining of sudanophilic lesions with a panel of antibodies unveiled medial cell proliferation, macrophage invasion, immunoreactive vascular cell adhesion molecule-1, and low-density lipoprotein. The frequency of sudanophilic lesions increased with time to affect 26 +/- 2% and 36 +/- 3% of arcuate arterial branches and interlobular arteries, respectively, at 25 days. Hypertensive L-NAME-treated rats developed glomerular injury probed by albuminuria and glomerular immunostaining for alpha-smooth muscle actin. Administration of the nonselective endothelin antagonist bosentan (30 mg/kg daily) blunted the development of sudanophilic lesions during L-NAME treatment without affecting arterial hypertension or degree of glomerular injury. Therefore, L-NAME hypertension leads to rapid development of focal, inflammatory, proliferative, and sudanophilic lesions along preglomerular vessels, suggesting atherosclerosis-like processes. Furthermore, endothelin is a likely mediator in the development of these lesions. PMID- 8698443 TI - Type 1 angiotensin II receptor subtypes in kidney of normal and salt-sensitive hypertensive rats. AB - We studied the localization and regulation of the two type 1 angiotensin II receptor subtypes AT(1A) and AT(1B) in different renal zones of the rat kidney by a reverse transcription-polymerase chain reaction amplification method. The yield of the reaction was quantified with an internal standard that was a 63-bp deleted mutant cRNA of the AT(1A) receptor. In kidneys of male Sprague-Dawley rats (n=4), the levels of AT(1A) and AT(1B) receptor mRNAs were highest in the inner stripe of the outer medulla, lowest in the inner medulla, and intermediate in the cortex and outer stripe of the outer medulla. Results (mean+/-SE) expressed in 10(5) molecules per microgram total RNA were for cortex outer stripe, inner stripe, and inner medulla, respectively, 171 +/- 15, 152 +/- 27, 322 +/- 10, and 73 +/- 3 for AT(1A), and 35 +/- 9, 26 +/- 1, 71 +/- 10, and 53 +/- 11 for AT(1B). In sabra rats sensitive (n=6) or resistant (n=6) to salt-induced hypertension and maintained on a normal salt diet, the percentage and level of each receptor subtype mRNA in cortex and outer stripe were similar in the two strains and comparable to those observed in Sprague-Dawley rats. However, AT(1A) of the inner stripe was significantly decreased in salt-resistant compared with salt-sensitive rats (166 +/- 28 and 318 +/- 58 10(5) molecules per microgram total RNA, respectively). These modifications were organ specific because no difference in the level of the receptor mRNAs was observed in the liver of the two Sabra rat strains, whereas a twofold increase in AT(1A) mRNA level but not in AT(1B) mRNA level was apparent in adrenal and in one renal zone, the inner stripe of the outer medulla, of hypertension-prone Sabra rats. PMID- 8698444 TI - Renin is expressed in rat macrophage/monocyte cells. AB - The cardiac renin-angiotensin system has been suggested to be involved in various pathological conditions, including hypertrophy and remodeling. However, direct evidence that renin synthesized in situ is really involved in the putative angiotensin II generation is still lacking because of the relatively low abundance of renin mRNA in cardiac tissues. We evaluated renin mRNA expression levels in the ventricles under various pathological conditions and found that renin gene expression was markedly increased in the ventricles of isoproterenol treated rats. Renin mRNA expression levels in the ventricles of rats that had been injected with isoproterenol (150 mg/kg SC) were transiently and markedly increased to 6-, 90-, and 4-fold compared with control expression levels at 24, 72, and 120 hours, respectively, after isoproterenol administration, Immunohistochemical analysis revealed that some of the OX-42-positive macrophage/monocyte cells had a reninlike immunoreactivity. An in vitro experiment indicated that rat peritoneal macrophage/monocyte cells expressed renin mRNA in abundance. The present study confirmed that a subpopulation of macrophage/monocyte cells could express renin. Macrophage/monocyte cells may be a source of tissue renin in some pathological conditions. PMID- 8698445 TI - Sodium intake markedly alters renal interstitial fluid adenosine. AB - Adenosine is produced locally in the kidney. Accumulating data suggest that adenosine plays a role in regulating renal functions. Using a microdialysis technique, we monitored adenosine levels in cortical and medullary renal interstitial fluid and urine after 5 days of diets containing low (0.15%), normal (0.28%), and high (4.0%) sodium. Samples were collected from anesthetized rats (n=5 for each diet). Microdialysis fluid was infused at a rate of 1 microL/min. Adenosine, measured by radioimmunoassay, was stable in the dialysate. During normal sodium intake, renal interstitial fluid adenosine estimated from the concentration in dialysate leaving the cortex was 63 +/- 6 nmol/L, which was significantly lower than in dialysate leaving the medulla (157 +/- 6 nmol/L, P<.01). The concentration of interstitial medullary adenosine was estimated to be 190 nmol/L. In rats consuming a low sodium diet, renal cortical and medullary dialysate adenosine concentrations were significantly decreased (P<.01) by 62.6% and 64.9%, respectively. Rats consuming a high sodium diet had renal cortical and medullary dialysate adenosine concentrations that were increased 18.2- and 18.9 fold, respectively (P<.01), compared with levels in rats on a low sodium diet. Similar to changes in dialysate adenosine, urinary adenosine concentration decreased during low sodium intake (P<.01) and increased during high sodium intake (P<.01). The higher adenosine levels in renal medullary than in cortical interstitial fluid may reflect its major renal site of generation. The changes in renal adenosine generation with sodium intake may reflect renal energy expenditure. PMID- 8698446 TI - Factors that affect calorie-sensitive and calorie-insensitive reduction in blood pressure during short-term calorie restriction in overweight hypertensive women. AB - This study was performed to elucidate the factors that affect the reduction in blood pressure produced by calorie restriction in overweight women with essential hypertension. Fifty-one subjects were admitted to the metabolic ward of the hospital. After being fed a standard diet (6.3 to 8.4 MJ/d) for 2 weeks, the calorie-restricted group (n=34) was fed a low-calorie diet (1.9 MJ/d) for an additional 2 weeks. The calorie-nonrestricted group (n=17) was fed the standard diet for 4 weeks. Sodium and potassium intake was kept constant, as was the level of exercise activity. The calorie-restricted group was subdivided into "calorie sensitive" and "calorie-insensitive" groups based on an average 5 mm Hg reduction in mean blood pressure during the low-calorie diet. The mean age was 51+/-6 years (mean+/-SD) in the calorie-sensitive group (n=16), which was significantly lower than the mean age of 61+/-6 years in the calorie-insensitive group (n=18). Multiple regression analysis indicated that age and change in body weight exhibited significant correlations with blood pressure reduction produced by calorie restriction among 17 parameters. Findings suggest that age can predict the extent of blood pressure reduction that would be obtained during 2 weeks of calorie restriction in overweight hypertensive women. The reduction in blood pressure may be related in part to the amount of weight loss. PMID- 8698447 TI - Ambulatory monitoring uncorrected for placebo overestimates long-term antihypertensive action. Systolic Hypertension in Europe (SYST-EUR) Trial Investigators. AB - This study compares blood pressure (BP) changes during active antihypertensive treatment and placebo as assessed by conventional and ambulatory BP measurement. Older patients (> or = 60 years, n=337) with isolated systolic hypertension by conventional sphygmomanometry at the clinic were randomized to placebo or active treatment consisting of nitrendipine (10 to 40 mg/d), with the possible addition of enalapril (5 to 20 mg/d) and/or hydrochlorothiazide (12.5 to 25 mg/d). At baseline, clinic systolic/diastolic BP averaged 175/86 mm Hg and 24-hour and daytime ambulatory BPs averaged 148/80 and 154/85 mm Hg, respectively. After 13 months (median) of active treatment, clinic BP had dropped by 22.7/7.0 mm Hg and 24-hour and daytime BPs by 10.5/4.5 and 9.7/4.3 mm Hg, respectively (P<.001 for all). However, clinic (9.8/1.6 mm Hg), 24-hour (2.1/1.1 mm Hg), and daytime (2.9/1.0 mm Hg) BPs decreased also during placebo (P<.05, except for daytime diastolic BP); these decreases represented 43%/23%, 20%/24%, and 30%/23% of the corresponding BP fall during active treatment. After subtraction of placebo effects, the net BP reductions during active treatment averaged only 12.9/5.4, 8.3/3.4, and 6.8/3.2 mm Hg for clinic, 24-hour, and daytime BPs, respectively. The effect of active treatment was also subject to diurnal variation (P<.05). Changes during placebo in hourly systolic and diastolic BP means amounted to (median) 21% (range, -1% to 42%) and 25% (-3% to 72%), respectively, of the corresponding changes during active treatment. In conclusion, expressed in millimeters of mercury, the effect of antihypertensive treatment on BP is larger with conventional than with ambulatory measurement. Regardless of whether BP is measured by conventional sphygmomanometry or ambulatory monitoring, a substantial proportion of the long-term BP changes observed during active treatment may be attributed to placebo effects. Thus, ambulatory monitoring uncorrected for placebo or control observations, like conventional sphygmomanometry, overestimates BP responses in clinical trials of long duration. PMID- 8698448 TI - 11 alpha- and 11 beta-hydroxyprogesterone, potent inhibitors of 11 beta hydroxysteroid dehydrogenase, possess hypertensinogenic activity in the rat. AB - The progesterone derivatives 11 alpha- and 11 beta-hydroxyprogesterone are potent inhibitors of 11 beta-hydroxysteroid dehydrogenase (isoforms 1 and 2) in vitro and can confer mineralocorticoid activity on corticosterone in the rat in vivo. 11 beta-Hydroxysteroid dehydrogenase metabolizes active glucocorticoids to their inactive 11-dehydro products and protects renal mineralocorticoid receptors from the high circulating levels of endogenous glucocorticoids. 11 beta-Hydroxysteroid dehydrogenase has been suggested to be important not only in the control of renal sodium retention but also of blood pressure. To assess the possible blood pressure-modulating effects of 11 alpha- and 11 beta-hydroxyprogesterone, we infused these substances into both intact and adrenalectomized Sprague-Dawley rats continuously for 14 days. Both 11 alpha- and 11 beta-hydroxyprogesterone caused a significant elevation in blood pressure within 3 days, an effect that persisted throughout the 14-day infusion. The hypertensive effects of 11 alpha hydroxyprogesterone were abolished by adrenalectomy and significantly attenuated when 11 alpha-hydroxyprogesterone was infused together with the specific mineralocorticoid receptor antagonist RU28318. In an additional series of experiments, 11 alpha-hydroxyprogesterone significantly amplified the hypertensive effects of corticosterone in adrenalectomized spontaneously hypertensive rats but had no effects by itself in this experimental animal. These results demonstrate that both 11 alpha- and 11 beta-hydroxyprogesterone are potently hypertensinogenic in the rat and that this activity depends on an intact adrenal and at least in part on the activation of mineralocorticoid receptors. 11 beta-Hydroxyprogesterone, and similar endogenous progesterone metabolites that inhibit 11 beta-hydroxysteroid dehydrogenase, may be involved in the pathology of certain hypertensive states. PMID- 8698449 TI - Antihypertensive properties of the novel calcium antagonist mibefradil (Ro 40 5967): a new generation of calcium antagonists? Mibefradil International Study Group. AB - Preclinical and initial clinical studies suggest that the novel calcium antagonist mibefradil has a unique combination of properties. Mibefredil was evaluated in a multicenter, double-blind, placebo-controlled, parallel group trial. After 4 weeks of a placebo run-in period, 202 eligible patients with mild to moderate hypertension were randomized to receive doses of 25, 50, 100, or 150 mg mibefradil or placebo once a day for 4 weeks. Blood pressure and heart rate were measured repeatedly at trough and peak (24 and 2 to 6 hours postdose, respectively) at the end of each period. Concentration-effect relationships were evaluated at trough on the last treatment day. A significant (P<.01 versus placebo) drop in blood pressure (diastolic and systolic) was observed at trough and peak in all mibefradil groups, with a trough-peak ratio greater than 0.8, high response rate, and a significant dose-response relationship (P<.001). The full antihypertensive effect of mibefradil was achieved within 1 to 2 weeks and was associated with a slight dose-dependent decrease in heart rate and increase in PQ time. Clear dissociation was observed between the effect on blood pressure and PQ time when concentration-effect relationships were evaluated. These results indicate that mibefradil is an effective and well-tolerated antihypertensive compound at doses of 25, 50, and 100 mg once daily. The incidence of treatment related adverse events observed in the 25-, 50-, and 100-mg dose groups was lower than in the placebo group, but it was slightly higher in the 150-mg dose group, and three patients from this group were prematurely withdrawn because of an adverse event. PMID- 8698450 TI - Altered c-fos in rostral medulla and spinal cord of spontaneously hypertensive rats. AB - Neurons immunoreactive for Fos, the protein product of the immediate early gene c fos, have been compared in the rostral ventral medulla and spinal cord of conscious normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) after baroreceptor unloading. Hypotension induced by a 60-minute intravenous infusion of sodium nitroprusside reduced baroreceptor activity; controls received intravenous saline. In WKY, 474 +/- 56 (n=6) Fos-positive neurons were identified in the rostral ventral medulla after nitroprusside infusion, a fivefold increase from controls; 50% of the tyrosine hydroxylase containing neurons in the rostral ventral medulla were activated by this hypotension. Sympathetic preganglionic neurons, mainly sympathoadrenal neurons, were Fos positive after nitroprusside, but Fos-positive sympathetic preganglionic neurons were not observed in control WKY. In SHR, Fos immunoreactivity in the rostral ventral medulla was elevated in the control group compared with the WKY controls (236 +/- 31 and 93 +/- 15, respectively, n=6 for both). Nitroprusside hypotension did not further increase Fos immunoreactivity in the rostral ventral medulla, although the number of Fos-positive spinal sympathetic neurons increased. Our results have identified different neuronal activities between WKY and SHR in sites that are critical to sympathetic outflow. In WKY, nitroprusside effects are consistent with an activation of rostral ventral medulla neurons, including bulbospinal neurons, that are normally inhibited by baroreceptor activity. In SHR, basal nerve activity is increased, so even at rest, rostral ventral medulla neurons and sympathetic preganglionic neurons, mainly sympathoadrenal neurons, are Fos immunoreactive. These activated neurons are likely to contribute to the elevated blood pressure in this rat strain. PMID- 8698451 TI - Acute baroreflex resetting: differential control of pressure and nerve activity. AB - This study evaluated acute resetting of carotid baroreflex control of arterial blood pressure and renal or thoracic sympathetic nerve activity in thiopental anesthetized mongrel dogs with the use of a vascularly isolated carotid sinus preparation, the experimental model used previously to characterize acute resetting in carotid baroreceptor afferent fibers. Carotid baroreceptors were conditioned with a pulsatile pressure for 20 minutes at three pressure ranges: low (50 to 75 mm Hg), mid (100 to 125), or high (150 to 175). Blood pressure and nerve activity were recorded in response to slow ramp increases in sinus pressure; nonlinear regression and best-fit analyses were used for determination of curve fit parameters of the blood pressure and nerve activity versus sinus pressure response curves. Carotid sinus pressure thresholds for blood pressure and renal nerve activity responses at all conditioning pressures were significantly different; however, only the pressure threshold for thoracic nerve activity at the low conditioning pressure was significantly different from the responses at other conditioning pressures. Average renal activity resetting (0.506 +/- 0.072) was significantly greater than blood pressure resetting (0.335 +/- 0.046) in the same dogs, and thoracic activity (0.200 +/- 0.057) was not different from blood pressure resetting (0.194 +/- 0.031) in the same dogs. In a previous investigation, our laboratory had demonstrated that type 1 carotid baroreceptors acutely reset at a value of about 0.15. These results indicate that (1) renal and thoracic nerve activities and blood pressure acutely reset to a greater degree than type 1 carotid baroreceptors and that (2) renal activity acutely resets to a greater degree than blood pressure and thoracic nerve activity. PMID- 8698452 TI - Localization of alpha 2A- and alpha 2B-adrenergic receptor subtypes in brain. AB - Recent studies have shown that all three subtypes of alpha2-adrenergic receptor (alpha2-AR) are found in brain. The purpose of this study was to map the subtype localization of the alpha2A- and alpha2B-ARs in brain structures. RNase protection shows that both the alpha2A- and alpha2B-ARs are detectable in cortex, cerebellum, pons-medulla, and hypothalamus. We tested probes derived from the alpha2A- and alpha2B-AR cDNAs on cell lines that express each of the alpha2-AR subtypes to establish the subtype specificity of these probes for in situ hybridization. Then we used the alpha2A- and alpha2B-AR probes for in situ hybridization on sagittal and coronal sections of rat brain. Both alpha2A and alpha2B mRNA were detected throughout the brain. Overall, there appears to be a greater expression of message for alpha2A- than alpha2B-AR in most brain areas, with the exception of the thalamus. Developing these probes for in situ hybridization is an important step for further studies on the exact role of the alpha2-AR subtypes in neurons that modulate cardiovascular function. PMID- 8698453 TI - Correlations of Na+-Li+ exchange activity with Na+ and Li+ binding and phospholipid composition in erythrocyte membranes of white hypertensive and normotensive individuals: a nuclear magnetic resonance investigation. AB - Enhanced Na+-Li+ exchange activity has been reported in red blood cells (RBCs) of white patients with essential hypertension compared with RBCs of normotensive individuals. To understand the factors responsible for this finding, we applied novel and conventional spectroscopic and kinetic methods to blood samples from 10 hypertensive and 10 normotensive individuals. We measured the kinetic parameters (V std, V max, and K m) for RBC Na+-Li+ exchange by atomic absorption spectrophotometry and used 23Na and 7Li nuclear magnetic resonance relaxation methods to measure Na+ and Li+ binding to RBC membranes as well as 31P nuclear magnetic resonance spectroscopy to measure membrane phospholipid compositions. We found significant differences between the two groups for the affinity of Na+ for the RBC membrane (0.202 +/- 0.054 mmol/L-1 for hypertensive patients versus 0.296 +/- 0.071 mmol/L-1 for normotensive subjects, P<.005). The kinetic parameters of RBC Na+-Li+ exchange (V std, V max, and K m) were 0.32 +/- 0.09 and 0.66 +/- 0.17 mmol Li+/L cell.h and 160 +/- 62 mmol/L, respectively, for hypertensive patients versus 0.21 +/- 0.06 and 0.32 +/- 0.14 mmol Li+/L cell.h and 86 +/- 69 mmol/L for normotensive subjects (P<.05). The fractions of phosphatidylserine and phosphatidylethanolamine were 0.153 +/- 0.009 and 0.294 +/- 0.016 for hypertensive patients versus 0.138 +/- 0.013 and 0.325 +/- 0.018 for normotensive subjects (P<.05). The Na+ binding constants were negatively correlated with the Km values for both the hypertensive (r=-.61, P=.01) and normotensive (r=-.43, P=.04) groups. Changes in lipid-protein interactions in the RBC membranes of hypertensive patients appear to be responsible for weaker Na+ binding to the membrane and for the faster rates of RBC Na+-Li+ exchange. PMID- 8698454 TI - Bacterially induced bone destruction: mechanisms and misconceptions. AB - Normal bone remodelling requires the coordinated regulation of the genesis and activity of osteoblast and osteoclast lineages. Any interference with these integrated cellular systems can result in dysregulation of remodelling with the consequent loss of bone matrix. Bacteria are important causes of bone pathology in common conditions such as periodontitis, dental cysts, bacterial arthritis, and osteomyelitis. It is now established that many of the bacteria implicated in bone diseases contain or produce molecules with potent effects on bone cells. Some of these molecules, such as components of the gram-positive cell walls (lipoteichoic acids), are weak stimulators of bone resorption in vitro, while others (PMT, cpn60) are as active as the most active mammalian osteolytic factors such as cytokines like IL-1 and TNF. The complexity of the integration of bone cell lineage development means that there are still question marks over the mechanism of action of many well-known bone-modulatory molecules such as parathyroid hormone. The key questions which must be asked of the now-recognized bacterial bone-modulatory molecules are as follows: (i) what cell population do they bind to, (ii) what is the nature of the receptor and postreceptor events, and (iii) is their action direct or dependent on the induction of secondary extracellular bone-modulating factors such as cytokines, eicosanoids, etc. In the case of LPS, this ubiquitous gram-negative polymer probably binds to osteoblasts or other cells in bone through the CD14 receptor and stimulates them to release cytokines and eicosanoids which then induce the recruitment and activation of osteoclasts. This explains the inhibitor effects of nonsteroidal and anticytokine agents on LPS-induced bone resorption. However, other bacterial factors such as the potent toxin PMT may act by blocking the normal maturation pathway of the osteoblast lineage, thus inducing dysregulation in the tightly regulated process of resorption and replacement of bone matrix. At the present time, it is not possible to define a general mechanism by which bacteria promote loss of bone matrix. Many bacteria are capable of stimulating bone matrix loss, and the information available would suggest that each organism possesses different factors which interact with bone in different ways. With the rapid increase in antibiotic resistance, particularly with Staphylococcus aureus and M. tuberculosis, organisms responsible for much bone pathology in developed countries only two generations ago, we would urge that much greater attention should be focused on the problem of bacterially induced bone remodelling in order to define pathogenetic mechanisms which could be therapeutic targets for the development of new treatment modalities. PMID- 8698455 TI - Interleukin-12-mediated resistance to Trypanosoma cruzi is dependent on tumor necrosis factor alpha and gamma interferon. AB - The aim of this study was to determine if interleukin-12 (IL-12) has a role in the immune response to Trypanosoma cruzi. Infection of BALB/c mice with the virulent Tulahuen strain of T. cruzi is characterized by a high-level parasitemia, pathology in the heart associated with the presence of amastigotes, and death during the acute phase of the disease. Administration of IL-12 to BALB/c mice infected with T. cruzi resulted in a reduced parasitemia and a significant delay in the time to death compared with those for infected controls. This protective effect was correlated with increased levels of gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in serum. To determine if these cytokines were involved in the protective effects of IL-12, we treated infected mice with IL-12 alone or in combination with monoclonal antibodies specific for IFN-gamma or TNF-alpha. These antibodies antagonized the protective effect of exogenous IL-12. Treatment of infected mice with a polygonal antibody specific for IL-12 resulted in a significant increase in parasitemia but did not affect the time to death. These latter studies demonstrate a role for endogenous IL-12 in resistance to T. cruzi. Together, our data identify an IL-12-mediated mechanism of resistance to T. cruzi, which is dependent on IFN-gamma and TNF alpha. PMID- 8698456 TI - Conservation of the C5a peptidase genes in group A and B streptococci. AB - The chromosome of group B streptococci (GBS) contains a gene which is related to the C5a peptidase gene (scpA) of group A streptococci (GAS). scpA encodes a surface-associated peptidase (group A streptococcal C5a peptidase [SCPA]) which specifically cleaves C5a, a major chemoattractant generated in serum by activation of complement. The entire scpA-like gene (scpB) was cloned from a GBS strain and sequenced. The gene encodes an open reading frame of 3,450 bp, which corresponds to a deduced protein (SCPB) of 1,150 amino acids with a molecular weight of 126,237 Da. Nucleotide and deduced amino acid sequences of SCPB were found to be highly homologous to those of SCPAs from GAS. Unexpectedly, scpA12 is more similar to scpB than to another GAS gene, scpA49. The sequence 5' of the open reading frame, including transcription start and a termination site in the signal sequence, is also similar to that of scpA, although less conserved than the coding sequences. The near identity of GBS and GAS peptidases is consistent with horizontal transmission of the scp gene between these species. Recombinant SCPB was expressed in Escherichia coli by using the expression vector plasmid pGEX-4T-1 and was shown to be identical in size to the enzyme extracted from the parental GBS strain 78-471. PMID- 8698457 TI - Ability of Escherichia coli isolates that cause meningitis in newborns to invade epithelial and endothelial cells. AB - Escherichia coli isolates that cause meningitis in newborns are able to invade the circulation and subsequently cross the blood-brain barrier. One mechanism for traversing the blood-brain barrier might involve transcytosis through the endothelial cells. The ability of the meningitis isolate E. coli IHE3034, of serotype 018:K1:H7, to invade epithelial (T24) and endothelial (EA-hy926) cells was investigated by the standard gentamicin survival assay and by electron microscopy. Human bladder epithelial and endothelial cells were efficiently invaded by strain IHE3034, whereas epithelial human colon Caco-2 cells, canine kidney MDCK cells, and the opossum [correction of opposum] epithelial kidney cell line OK were not invaded. The ability to invade human epithelial cells of the bladder could also be demonstrated for several other newborn meningitis E. coli strains and one septicemic E. coli strain. Studies utilizing inhibitors which act on eukaryotic cells revealed a dependence on microfilaments as well as on microtubules in the process of E. coli IHE3034 entry into T24 and EA-hy926 cells. These results indicated that cell cytoskeletal rearrangements are involved in bacterial uptake and suggest that there are either two pathways (microtubule dependent and microfilament dependent) or one complex pathway involving both microtubules and microfilaments. The intracellular IHE3034 organisms were contained in a host-membrane-confined compartment mainly as single microorganisms. Intracellular replication of 1HE3034 was not detected, nor did the number of intracellular bacteria decrease significantly during a 48-h period. The ability of E. coli O18:K1 to invade and survive within certain eukaryotic cells may be another virulence factor of meningitis-associated E. coli. PMID- 8698458 TI - Characterization of T cells that confer a high degree of protective immunity against tuberculosis in mice after vaccination with tumor cells expressing mycobacterial hsp65. AB - Mice vaccinated by injection with tumor cells expressing the Mycobacterium leprae gene for hsp65 acquire a remarkably high degree of protection against challenge with Mycobacterium tuberculosis. We used limiting-dilution analysis to assess the frequency of CD4+ CD8- and CD4- CD8+ splenocytes responding to mycobacterial hsp65 in such vaccinated mice. Cells of both phenotypes were present at very high and equal frequencies (approximately 1:100). Vaccination with live Mycobacterium bovis BCG also increased the frequencies of both phenotypes of hsp65-reactive cells equally (to approximately 1:2,500), whereas vaccination procedures that were not protective, with either dead BCG, hsp65 protein in incomplete Freund's adjuvant, or hsp65 mixed with tumor cells, resulted in preferential increase in CD4+ CD8- cells. Twelve CD4+ CD8- and twelve CD4- CD8+ hsp65-responsive T-cell clones were obtained and characterized. All showed conventional antigen recognition via major histocompatibility complex class II and class I pathways but differed in secretion of gamma interferon and interleukin 4 and cytotoxicity. In tests of antimycobacterial activity against M. tuberculosis, both in infected macrophages in vitro and by adoptive transfer of protection with T-cell clones injected into irradiated mice, the most effective clones were the most cytotoxic and secretion of gamma interferon made only a secondary contribution. PMID- 8698459 TI - Respiratory activity is essential for post-exponential-phase production of type 5 capsular polysaccharide by Staphylococcus aureus. AB - Capsule formation is believed to have a significant role in bacterial virulence. To examine the possible involvement of capsular polysaccharide (CP) from Staphylococcus aureus in the pathological mechanisms associated with staphylococcal infections, we investigated the influence of respiratory activity on type 5 CP production by S. aureus grown in the presence of various concentrations of dissolved oxygen or nitrate. The effects of several metabolic inhibitors (arsenite, cyanide, azide, trimethylamine N-oxide, 2-heptyl-4 hydroxyquinoline N-oxide, and 2,4-dinitrophenol) were also tested. The metabolism of the bacteria was estimated by measuring their reductive capacity and by monitoring the pH and concentrations of fermentation products. Type 5 CP was always produced by S. aureus during the exponential phase of growth under all culture conditions tested. In contrast, post-exponential-phase CP production appeared to be strictly dependent on the respiratory activity. Since post exponential-phase CP production contributes at least two-thirds of the total CP obtained, the influence of S. aureus respiration on CP production might be of some importance in the process of infection. PMID- 8698460 TI - Differential effects of the streptococcal fibronectin-binding protein, FBP54, on adhesion of group A streptococci to human buccal cells and HEp-2 tissue culture cells. AB - We have previously demonstrated that fibronectin mediates streptococcal adhesion to host cells and that streptococci interact primarily with the N-terminal domain of fibronectin. FBP54 is a 54-kDa protein from group A streptococci that binds fibronectin. In this report, we show that the N-terminal domain of fibronectin reacts with FBP54 and preferentially blocks streptococcal adhesion to buccal epithelial cells. FBP54 blocked adhesion to human buccal epithelial cells by 80% in a dose-related fashion. In contrast, FBP54 had little effect on adhesion of group A streptococci to HEp-2 tissue culture cells. The fibronectin-binding domain of FBP54 has been localized to the first 89 N-terminal residues of the protein. Experiments using affinity-purified antibodies to this region indicated that the N terminus of FBP54 is exposed on the surface of streptococci in a manner that can interact with immobilized receptors. Analysis of sera from patients with post-streptococcal glomerulonephritis and acute rheumatic fever indicated that FBP54 is expressed in vivo and is immunogenic in the human host. These data indicate that FBP54 is a streptococcal adhesin that is expressed in the human host and that preferentially mediates adhesion to certain types of human cells. PMID- 8698462 TI - Determinants of activation by complement of group II phospholipase A2 acting against Escherichia coli. AB - Prompt killing of many strains of Escherichia coli during phagocytosis in vitro by isolated polymorphonuclear leukocytes (PMN) requires the presence of nonlethal doses of nonimmune serum (B. A. Mannion, J. Weiss, and P. Elsbach, J. Clin. Invest. 86:631-641, 1990). Because this requirement is bypassed in a phospholipase A (PLA)-rich mutant (pldA ) of E. coli, we have examined the effect of serum on bacteria] phospholipid (PL) degradation during phagocytosis of wild type (pldA+) and PLA-deficient (pldA) E. coli. In parallel with increased killing, nonlethal doses of serum increased the degradation of prelabeled bacterial PL during phagocytosis by two- to fivefold, to nearly the same levels (ca. 50 to 60%) as those produced during phagocytosis of E. coli pldA in the absence of serum. The effects on the E. coli pldA mutant imply that there is a serum-mediated enhancement of granule-associated group II PMN PLA2 activity. At the same doses, serum promoted action against E. coli in the presence of purified rabbit and human group II PLA2 but did not activate bacterial PLA. Related PLA2s that lack specific structural determinants needed for optimal activity against E. coli treated with the bactericidal/permeability-increasing protein (BPI) of PMN are also less active than wild-type group II PLA2 against serum-treated E. coli. Treatment of E. coli with C7- or C9-depleted serum did not enhance bacterial killing or PL degradation during phagocytosis or the action of purified PLA2. In summary, these findings suggest that (i) nonlethal assemblies of the membrane attack complex promote intracellular killing and destruction of E. coli ingested by PMN, in part by promoting the action of granule-associated PLA2 against ingested bacteria, and (ii) structural determinants first implicated in PLA2 action against BPI-treated E. coli are also important in PLA2 action in concert with other host defense systems, such as complement. PMID- 8698461 TI - Melanin, melanin "ghosts," and melanin composition in Cryptococcus neoformans. AB - Melanin synthesis is associated with virulence for the pathogenic fungus Cryptococcus neoformans. Exposure of nonmelanized C. neoformans 4067 cells to 4 M guanidinium isothiocyanate followed by 6 M HCl at 100 degrees C resulted in complete solubilization of cellular structures. However, exposure of melanized C. neoformans 24067 to the same conditions produced a suspension of black particles. Analysis of black particles with transmission and scanning electron microscopy revealed cell "ghosts" with electron-dense walls. Electron spin resonance (ESR) spectroscopy of suspensions of black particles revealed a signal indicative of a stable free radical population. The magnitude of the ESR signal was increased by illumination, Zn2+ ions, and basic pH. Boiling the black particles produced only a small reduction in the magnitude of the ESR signal. These ESR changes are characteristic of melanin. Exposure of melanized black cells to 0.1 or 0.5% NaOCl bleached the cells white and abolished the ESR signal, consistent with melanin disruption. ESR spectroscopy was used to study the rate of stable free radical formation, taken as an index of melanization, of C. neoformans 24067 cells growing in medium with 1.0 mM L-dopa at 30 and 37 degrees C over the course of 14 days. Melanization was slower at 37 degrees C. but by day 14, cells grown at 30 and 37 degrees C. had comparable levels or melanin. ESR spectroscopy of seven melanized C. neoformans strains revealed that some strains differed by up to eightfold in melanin content. The ESR spectra of C. neoformans 24067 grown in minimal medium containing either 1.0 mM catechol, dopamine, or L-dopa revealed large differences in signal amplitude. The relative melanin contents were 0.05, 0.45, and 1.0 for C. neoformans grown in media with catechol, dopamine. and L dopa, respectively. Quantitative analysis revealed that melanin comprised 15.4% of the dry mass of the cell after 10 days of growth in medium containing 1.0 mM L dopa. The results suggest (i) a useful protocol for isolating C. neoformans melanin, (ii) a role for melanin in maintaining cell wall integrity, (iii) disruption of melanin by NaOCl, (iv) strain differences in melanin content after growth in L-dopa, and (v) quantitative and/or qualitative differences in the melanin produced after growth in various substrates. PMID- 8698463 TI - Bacterial persistence and immunity in goats vaccinated with a purE deletion mutant or the parental 16M strain of Brucella melitensis. AB - To evaluate host responses, young goats were inoculated subcutaneously with a genetic deletion mutant (deltapurE201) of Brucella melitensis (n = 6), its virulent parental strain 16M (n = 6), or saline (n = 6). No clinical evidence of brucellosis was seen in any goat. Serum antibody titers peaked at postinoculation day (PID) 14. Bacteria in lymph nodes that drained sites of vaccination reached peak numbers of >10(6) CFU/g in both infected groups at PID 7 and progressively declined to PID 84. At necropsy, bacteria were present in mammary lymph nodes or spleen of 33% of goats given virulent 16M but in none of goats given the purE mutant. Lymphadenitis, most severe in goats given 16M, involved depletion of lymphocytes and germinal centers, proliferation of lymphoblasts, and vasculitis. By PID 28, lymph node architecture was restored; there was marked germinal center formation and medullary plasmacytosis. Brucellar antigens, detected with immunoperoxidase techniques, were prominent in capsular granulomas but not in lymph node cortices. Ultrastructurally, bacteria were found in macrophages (>97%) and small lymphocytes (<3%) but not in large lymphocytes. Bacteria were intact in small lymphocytes but in macrophages were in various stages of degradation. The deltapurE phenotype of deltapurE201 was preserved during infection of goat lymph nodes. Unlike Salmonella spp. purE mutants, strain deltapurE201 may be a candidate for efficacy testing; it produced immune responses, was cleared from visceral tissues, and produced less severe pathologic changes than its wild-type parent. PMID- 8698464 TI - Use of site-directed mutagenesis to probe structure-function relationships of alpha-toxin from Clostridium perfringens. AB - The NH2-terminal domain of the alpha-toxin of Clostridium perfringens is highly homologous to the complete phospholipase C from Bacillus cereus (PC-PLC), for which a high-resolution crystal structure is available. This structural information was used as the basis of a site-directed mutagenesis strategy in which critical amino acid residues of alpha-toxin involved in zinc binding, interaction with substrate, or catalysis were replaced. Biochemical studies with the corresponding toxin variants indicate that there is probably a single active site endowed with lecithinase, sphingomyelinase, and hemolytic activities. By using a highly purified variant in which the catalytic aspartate residue at position 56 was replaced by asparagine, it was shown that phospholipase activity was essential for lethality in vivo and for mediating platelet aggregation in vitro. PMID- 8698465 TI - Colonization of gnotobiotic piglets by Helicobacter pylori deficient in two flagellin genes. AB - Helicobacterpylori possesses two flagellin molecules, MA, the major species, and FlaB, which is expressed in minor amounts. This study sought to determine if one or both flagellin species are necessary for colonization or persistence by H. pylon. Thirty-six gnotobiotic piglets from six litters were given one of four isogenic strains of H. pylon orally. The bacterial strains used were strain N6, the wild type, which produced both FlaA and FlaB and was fully motile; N6flaB::km, which produced FlaA but not FlaB and was weakly motile; N6flaA::km, which expressed FlaB but not FlaA and was nonmotile; and N6flaA::cat/flaB::km, which produced neither flagellin and was nonmotile. Strain N6 colonized all piglets and persisted for 2, 4, and 10 days after inoculation. Both N6flaA::km and N6flaB::km colonized for 2 and 4 but not 10 days, and colonization was weak. N6flaA::cat/flaB:: km colonized for 2 days but did not persist for 4 or 10 days after inoculation. These findings demonstrate that both flagellin species are necessary for full colonization by H. pylon. Colonization for up to 4 days is possible in the absence of either flagellin species but not both. PMID- 8698466 TI - Coinoculation with Hartmannella vermiformis enhances replicative Legionella pneumophila lung infection in a murine model of Legionnaires' disease. AB - The effect of inhaled amoebae on the pathogenesis of Legionnaires' disease was investigated in vivo. A/J mice, which are susceptible to replicative Legionella pneumophila infections, were inoculated intratracheally with L. pneumophila (10(6) bacteria per mouse) or were coinoculated with L. pneumophila (10(6) bacteria per mouse) and Hartmannella vermiformis (10(6) amoebae per mouse). The effect of coinoculation with H. vermiformis on bacterial clearance, histopathology, cellular recruitment into the lung, and intrapulmonary levels of cytokines including gamma interferon and tumor necrosis factor alpha was subsequently assessed. Coinoculation with H. vermiformis significantly enhanced intrapulmonary growth of L. pneumophila in A/J mice. Histopathologic and flow cytometric analysis of lung tissue demonstrated that while A/J mice inoculated with L. pneumophila alone develop multifocal pneumonitis which resolves with minimal mortality, mice coinoculated with H. vermiformis develop diffuse pneumonitis which is associated with diminished intrapulmonary recruitment of lymphocytes and mononuclear phagocytic cells and significant mortality. Furthermore, coinoculation of mice with H. vermiformis resulted in a fourfold enhancement in intrapulmonary levels of gamma interferon and tumor necrosis factor alpha compared with mice infected with L. pneumophila alone. The effect of H. vermiformis on intrapulmonary growth of L. pneumophila in a resistant host (i.e., BALB/c mice) was subsequently evaluated. While BALB/c mice do not develop replicative L. pneumophila infections following inoculation with L. pneumophila alone, there was an eightfold increase in intrapulmonary L. pneumophila in BALB/c mice coinoculated with H. vermiformis. These studies, demonstrating that intrapulmonary amoebae potentiate replicative L. pneumophila lung infection in both a susceptible and a resistant host, have significant implications with regard to the potential role of protozoa in the pathogenesis of pulmonary diseases due to inhaled pathogens and in the design of strategies to prevent and/or control legionellosis. PMID- 8698468 TI - Entry and intracellular survival of group B streptococci in J774 macrophages. AB - The mouse macrophage-like cell line J774 was used to analyze opsonin-independent entry and survival of group B streptococci (GBS). Efficient entry of GBS in J774 cells occurred within 5 min postinfection, and streptococci persisted intracellularly without loss of viability for at least 8 h. At 24 h postinfection, 30% of the total intracellular GBS was recovered from macrophages. Inhibition studies using different biochemical modulators of cellular functions showed that bacterial entry seemed to involve nonglycosylated J774 surface structures different from known receptors such as fibronectin-binding integrins. Internalization of GBS by J774 cells occurred by a microfilament-dependent phagocytosis-like process also involving participation of receptor-mediated endocytosis. Prior opsonization of GBS with human serum containing anti-GBS antibodies did not affect bacterial entry but significantly reduced the intracellular survival of GBS. Transmission electron microscopic analysis confirmed these findings and demonstrated that both opsonized and nonopsonized bacteria were contained within phagosomes during the whole infection period. Transmission electron microscopy further revealed that decreased intracellular survival rates of opsonized GBS appeared to be due to increased lysosomal activities of the macrophages. These results suggest that in the absence of opsonins, GBS are able to enter and persist efficiently in macrophages by evading intracellular antibacterial activities commonly associated with opsonin-mediated uptake. PMID- 8698467 TI - Epitope mapping of B-cell determinants on the 15-kilodalton lipoprotein of Treponema pallidum (Tpp15) with synthetic peptides. AB - The antigenicity of the 15-kDa lipoprotein of Treponema pallidum (Tpp15 or TpN15) was comprehensively evaluated in epitope-scanning studies with overlapping deca- and octapeptides and polygonal rabbit and human infant immunoglobulins (Igs) and antisera. This approach enabled us to identify potentially important regions and to determine the optimal dilutions of Igs or antisera for use in further studies. IgM and IgG from both species were capable of recognizing multiple, continuous epitopes. A total of 13 peptides, principally clustered in the central regions of the protein, were recognized by all syphilitic sera and Ig fractions. On the basis of window analyses, frequency profiles, and alanine substitution studies, five heptapeptides were selected for mimetic studies. Two of these five immunodominant, continuous epitopes initially appeared to be species specific; however, antisera elicited against mimetics of all five epitopes were polyspecific, recognizing similar motifs on several other treponemal proteins, including those of avirulent organisms. The only mimetic which yielded positive reactions with infant IgM and syphilitic sera in the absence of cross-reactions with rabbit antisera to avirulent treponemes was the variant of the VMYASSG motif. These findings are relevant to the development of simple, inexpensive assays for the serodiagnosis of active syphilis. PMID- 8698469 TI - Analysis of epithelial cell stress response during infection by Shigella flexneri. AB - Shigella flexneri-infected macrophage cells undergo an apoptotic-like death as early as one hour after infection (A. Zychlinsky, M. C. Prevost, and P. J. Sansonetti, Nature [London] 358:167-168, 1992). To determine the fate of infected epithelial cells, we characterized the viability, morphology, and several metabolic activities of HeLa cells after treatment with M90T, an invoffve isolate of S. flexneri serotype 5, or BS176, a noninvasive isolate cured of the 220-kb virulence plasmid. Using standard assays, we found that for at least 4 h after infection with M90T, HeLa cells remained viable and did not detach or lyse. The ultrastructural morphology of HeLa cells heavily infected with M90T was free of hallmarks associated with cells undergoing apoptosis. Consistent with the idea that intracellular bacterial growth is metabolically stressful to the host cell, we observed that, compared with BS176 treated-HeLa cells, M90T-treated HeLa cells showed (i) a significant decrease in the total pool size of nucleoside triphosphates, (ii) a reduced ability to incorporate extracellular radiolabeled methionine into the soluble and insoluble cell fractions, and (iii) a stimulation of glucose uptake. However, there was no detectable increase in expression of the stress-inducible hsp70 gene in M90T-infected HeLa cells or activation of the anaerobic metabolic pathway as determined by measuring total lactate levels. These results demonstrate clearly that the fate of S.flexneri-infected cells can vary dramatically between cell types and agree with the hypothesis that the destruction of epithelial cells observed in experimental models of shigellosis is due to the host inflammatory response and probably not bacterial intracellular multiplication per se. PMID- 8698470 TI - The psa locus is responsible for thermoinducible binding of Yersinia pseudotuberculosis to cultured cells. AB - Yersinia pseudotuberculosis inv mutant strains cured of the virulence plasmid exhibit thermoinducible adhesion to cultured mammalian cells. To identify the genes responsible for this phenotype, Y. pseudotuberculosis homologs of the Y. enterocolitica ail and the Y. pestis psa loci were identified. Mutations in the Y. pseudotuberculosis ail and psa loci were constructed and tested for thermoinducible binding. Results of cellular binding assays indicated that only mutations in psa, not in ail, resulted in defects for thermoinducible binding, with inv yadA psa strains showing no detectable cell adhesion. In addition, an inv psa strain was defective for hemagglutination of sheep erythrocytes, in contrast to an inv psa+ strain which was fully competent for hemagglutination. The introduction of a plasmid containing a 6.7-kb KpnI-ClaI fragment of Y. pseudotuberculosis encompassing the psa locus was sufficient to complement both the cell adhesion and hemagglutination defects of the psa mutant. Results from subcloning and transposon mutagenesis indicated that the complete 6.7-kb region was required for thermoinducible binding and hemagglutination. PMID- 8698471 TI - Cloning of a Brucella melitensis group 3 antigen gene encoding Omp28, a protein recognized by the humoral immune response during human brucellosis. AB - Brucella group 3 antigens (Ags) are outer membrane proteins (OMPs) with a molecular mass ranging from 25 to 30 kDa. The OMPs are of interest partially because of their potential use as vaccine and diagnostic reagents. We used human convalescent antibody (Ab) to clone a gene that encoded a 28-kDa protein from a lambdagt11 library of Brucella melitensis 16M genomic DNA. DNA sequence analysis revealed a single open reading frame that would encode a protein of 26,552 Da. The 28-kDa protein had a primary amino acid sequence that was 43% similar to a previously described Brucella abortus group 3 Ag, Omp25 (P. de Wergifosse, P. Lintermans, J. N. Limet, and A. Cloeckaert, J. Bacteriol. 177:1911-1914, 1995). The similarity to a known group 3 OMP, immunoreactivity with Ab prepared against B. abortus group Ags, immunolabeling of whole cells, and Southern hybridization led to our conclusion that the B. melitensis 28-kDa protein was a group 3 protein distinct from B. abortus Omp25. We designated the B. melitensis protein Omp28. Human convalescent sera from patients infected with B. abortus and Brucella suis as well as rabbit antisera prepared against killed B. abortus whole cells recognized B. melitensis Omp28 on Western blots (immunoblots). Furthermore, mice and goats infected with smooth strains of B. melitensis produced Abs against Omp28. Our results may begin to explain the variability in molecular weight seen in Brucella group Ags and point toward their possible use in vaccination against infection as well as diagnosis of the disease. PMID- 8698472 TI - Influence of smoking and race on immunoglobulin G subclass concentrations in early-onset periodontitis patients. AB - Recent data indicate that smoking is an important risk factor for the development of periodontitis. Smoking is also known to reduce serum immunoglobulin G (IgG) levels. Interestingly, patients with the localized form of early-onset periodontitis (LJP) have elevated levels of serum IgG2, and those who smoke are not clinically different from nonsmoking LJ subjects. In contrast, patients with the generalized form of early-onset periodontitis (G-EOP) who smoke have more extensive destruction than their nonsmoking counterparts. Given the effects of smoking on EOP and the association of IgG2 with less severe disease, we hypothesized that smoking might reduce serum IgG2 and that this might be most apparent in G-EOP. We therefore examined the effects of smoking on serum IgG subclass concentrations in race-matched groups: LJP, G-EOP, and age-matched periodontally healthy controls (NPs). Smoking status was established from serum cotinine levels, and serum IgG subclass concentrations were determined by using radial immunodiffusion. The data indicated that the effects of smoking were remarkably selective with respect to both IgG subclass and race. Smoking did not appear to have any effect on the concentration of IgG1 or IgG3 in either black or white subjects. In contrast, smoking was associated with depressed serum IgG2 concentrations in both white NP and G-EOP subgroups. Serum IgG2 levels in black subjects did not appear to be depressed by smoking, with the single striking exception of the black G-EOP subgroup which also had depressed serum IgG4 levels. The results here confirm that smoking has effects on serum immunoglobulin levels, but the effects were both race and serum IgG subclass specific. Furthermore, the periodontal diagnosis of EOP subjects appeared to be important, as indicated by the fact that IgG2 and IgG4 levels were reduced in smoking black G-EOP subjects whereas the IgG2 and IgG4 levels in black LJP and NP subjects were not reduced by smoking. PMID- 8698473 TI - Deletion of amino acids 29 to 81 in adhesion protein YadA of Yersinia enterocolitica serotype O:8 results in selective abrogation of adherence to neutrophils. AB - In order to analyze the multiple functions of the yersinia adhesin YadA in more detail, we constructed an N-terminally truncated YadA protein (deletion of amino acids [aa] 29 to 81) of Yersinia enterocolitica serotype 0:8. The region aa 29 to 81 of YadA is located between the signal sequence and the amino-terminal hydrophobic domain (aa 80 to 101), which is involved in surface polymerization and collagen binding. The deletion of aa 29 to 81 (resulting in YadADelta29-81) had no effect on the well-known features of YadA such as autoagglutination, serum resistance, HEp-2 cell adherence, binding of collagen, and binding of the complement-inhibiting factor H. In contrast to this, mutant WA(pYVO8-A-Delta29 81), producing the truncated YadADelta29-81 had lost the ability to adhere to polymorphonuclear leukocytes and to induce an oxidative burst. This functional deficiency was comparable to that of a yadA-null mutant (K. Ruckdeschel, A. Roggenkamp, S. Schubert, and J. Heesemann, Infect. Immun. 64:724-733, 1996). Moreover, mutant WA(pYVO8-ADelta29-81) turned out to be attenuated in virulence comparably to the yadA-null mutant, as demonstrated with orogastrically and intravenously infected mice. In summary, this study shows that specific functions of YadA (i) can be impaired by designed mutations and (ii) are important in distinct stages of the infection process. PMID- 8698474 TI - Cytotoxic-T-lymphocyte responses to epitopes of listeriolysin O and p60 following infection with Listeria monocytogenes. AB - In order to test the influence of the cell surface density of a specific H2-Kd presented epitope on the subsequent level of the cytotoxic-T-lymphocyte (CTL) response directed against the epitope, we investigated the CTL response to two secreted products of Listeria monocytogenes from mice immunized with viable L. monocytogenes. We determined the response to the H2-Kd-presented amino acid 91 to 99 (aa91-99) immunodominant peptide of listeriolysin O (LLO) and to the aa217-225 immunodominant peptide of p60. The p60-derived peptide appears at the cell surface as an H2-Kd-complexed peptide at a level sixfold higher than that of LLO aa91-99. CTL frequency analysis of anti-LLO- or anti-p60-specific CTLs from mice immunized with wild-type L. monocytogenes showed that the numbers of immune spleen cell-derived CTLs specific for the two peptides were essentially equivalent. We have also found that Listeria-specific CTL populations lyse target cells pulsed with the p60 aa217-225 peptide with a magnitude of the lytic response markedly less than that for targets pulsed with the LLO aa91-99 peptide. Additionally, immunization with mutants of L. monocytogenes which do not stimulate anti-LLO-specific CTLs does not alter the CTL frequency of anti-p60 specific effector cells, with levels of anti-p60-specific CTLs similar to those seen in mice immunized with wild-type L. monocytogenes. These results suggest that the relative cell surface density of major histocompatibility complex class I-presented L. monocytogenes-derived epitopes is but one of the criteria which determine the magnitude of the cytotoxic effector cell response that develops in antilisterial immunity. PMID- 8698476 TI - Characterization of an adherence and antigenic determinant of the ArgI protease of Porphyromonas gingivalis which is present on multiple gene products. AB - This study was performed to characterize the antigen(s) recognized by a panel of monoclonal antibodies (MAbs) produced to be specific for Porphyromonas gingivalis whole cells which we had previously shown to bind to epitopes recognized by sera from periodontitis patients. Preliminary data had suggested that the arginine specific proteases of P. gingivalis (ArgI, ArgIA, and ArgIB) contained the antigenic determinants of four of these antibodies (MAbs 1A1, 2B/H9, 7D5, and 3B1). The location of the binding sites was examined with purified P. gingivalis enzymes and recombinant regions of the ArgI polyprotein expressed by subclones of the prpR1 gene in Escherichia coli XL-1 Blue cells. All four antibodies were reactive with protein determinants within the beta subunit, a hemagglutinin and/or adhesin component, of the ArgI dimer. MAb 1A1 strongly inhibited the agglutination of human erythrocytes by P. gingivalis W50 culture supernatant, suggesting that the binding site for this antibody contains residues which are critical for the interaction with the erythrocyte surface. The determinant for MAb 1A1 was examined further by construction of a set of truncated forms of the beta component expressed as fusion proteins with glutathione S-transferase at the N terminus. Analysis of these constructs mapped the binding site for MAb 1A1 to PrpRI residues G-907 to T-931, GVSPKVCKDV TVEGSNEFAP VQNLT. Western blot (immunoblot) analysis of P. gingivalis whole-cell proteins demonstrated that MAb 1A1 reacts with several proteins in the Mr range of 20,000 to 120,000. Furthermore, an oligonucleotide probe corresponding to the coding sequence for the region of the ArgI beta component containing the MAb 1A1 binding site hybridized to multiple bands on genomic digests of P. gingivalis DNA. These data indicate that the MAb 1A1 epitope may be a component of a binding domain common to multiple gene products of this organism and may thus represent a functionally important target of the host's specific immune response to P. gingivalis in periodontal disease. PMID- 8698475 TI - Interleukin-12 production by human monocytes infected with Mycobacterium tuberculosis: role of phagocytosis. AB - Mycobacterium tuberculosis and its antigens are potent inducers of cytokine expression by mononuclear phagocytes. In this study, the ability of live M. tuberculosis to stimulate interleukin-12 (IL-12) expression by human monocytes was examined. Monocytes were purified from peripheral blood mononuclear cells by adherence and either infected with M. tuberculosis or exposed to soluble protein antigens of M. tuberculosis (purified protein derivative [PPD]). Live M. tuberculosis (10(6) to 10(7) CFU/ml) was a potent stimulus for interleukin-12 (IL 12). By using reverse transcription-PCR, p40 mRNA was detected at 3 h, peaked at 6 to 12 h, and decayed to baseline levels at 18 to 24 h following infection. Bioactive IL-12 (p70) was measured by the phytohemagglutinin blast proliferation assay and confirmed the p40 mRNA results. In contrast, soluble PPD at concentrations known to readily induce IL-1 and tumor necrosis factor alpha expression by monocytes (10 to 100 microg/ml) was a poor stimulus for IL-12 p40 mRNA expression. The different efficiencies of M. tuberculosis bacilli and PPD for IL-12 expression by monocytes was in part due to a requirement for phagocytosis. Induction of IL-12 in response to M. tuberculosis was reduced by cytochalasin D. Furthermore, phagocytosis of dead M. tuberculosis or inert 2 micron-diameter polystyrene beads by monocytes induced IL-12 p40 mRNA. In contrast, 0.5-micron-diameter beads, which can enter cells through pinocytosis, did not stimulate IL-12 expression. Functionally, IL-12 readily enhanced PPD stimulated IFN-gamma production and CD4+ T-cell-mediated cytotoxicity by peripheral blood mononuclear cells from healthy tuberculin-positive donors but induced less enhancement when live M. tuberculosis was the antigen. These results suggest that IL-12 is upregulated as part of the early cytokine response of mononuclear phagocytes to M. tuberculosis and that the cellular events associated with phagocytosis are themselves a potent signal for IL-12 production. IL-12 released by infected macrophages in turn can further upregulate M. tuberculosis specific CD4+ T-cell effector function. PMID- 8698478 TI - Identification of isp, a locus encoding an immunogenic secreted protein conserved among group A streptococci. AB - The protein Mga (mga), which is required for transcription of several virulence genes of group A streptococci (GAS), including the antiphagocytic M protein, was suggested to act as the response regulator element of a bacterial two-component pathway. To investigate whether a gene encoding a cognate sensor protein is located upstream of mga, 3.1 kb of DNA 5' of the mga translational start site was cloned from serotype M6 GAS strain JRS4. Sequence analysis of this region revealed two adjacent open reading frames, a previously described orf and a new locus, isp (immunogenic secreted protein), which could encode proteins of 9 and 59 kDa, respectively. Inactivation of either open reading frame had no significant effect on transcription of the gene encoding M protein (emm) under normal growth conditions, suggesting that neither isp nor orf is involved in the Mga regulatory circuit. A protein migrating at an apparent molecular weight of 65,000 was produced when isp was transcribed and translated in vitro. The predicted isp product (Isp) contains an amino-terminal signal sequence region homologous to that found in bacterial secreted proteins, and expression of isp in Escherichia coli resulted in the presence of Isp in the periplasmic fraction. Convalescent-phase serum from a patient with an active GAS infection recognized forms of Isp both from the periplasm of E. coli and the supernatant of a GAS strain. Both isp and orf are highly conserved among strains of GAS, as shown by hybridization analyses. PMID- 8698477 TI - Macrophages exposed to Borrelia burgdorferi induce Lyme arthritis in hamsters. AB - The mechanism(s) by which Lyme arthritis is induced has not been elucidated. In this study, we showed that macrophages have a direct, effector role in the pathogenesis of Lyme arthritis. Severe destructive arthritis was induced in recipients of macrophages obtained from Borrelia burgdorferi-vaccinated and nonvaccinated hamsters exposed to Formalin-inactivated B. burgdorferi in vitro and then challenged with the Lyme spirochete. Swelling of the hind paws was detected within 8 h of infection, increased rapidly, and peaked at 21 h. This initial swelling decreased, and by day 4 only slight swelling was detected. Severe swelling of the hind paws was detected 8 days after infection and increased rapidly, with peak swelling occurring on day 11. Histopathologic examination affirmed that macrophages exposed to Formalin-inactivated spirochetes induced a severe destructive Lyme arthritis. The onset and severity of the severe destructive arthritis were dependent on the number of macrophages transferred. By contrast, macrophages not exposed to Formalin-inactivated B. burgdorferi failed to induce severe destructive arthritis in recipients after challenge with B. burgdorferi. Similarly, severe destructive arthritis was not detected in recipients of macrophages injected with spirochetal growth medium. Our results also showed that transferred macrophages could not protect hamsters from infection with B. burgdorferi, as spirochetes were readily recovered from their tissues when cultured. These findings demonstrate that macrophages exposed to B. burgdorferi are directly involved in the induction of Lyme arthritis. PMID- 8698479 TI - Immunity to Cryptosporidium muris infection in mice is expressed through gut CD4+ intraepithelial lymphocytes. AB - The role of gut intraepithelial lymphocytes (IEL) in immunity to cryptosporidial infection was investigated with a murine infection model involving Cryptosporidium muris. Oocyst shedding was monitored in severe combined immunodeficiency (SCID) mice infected with C. muris following intravenous injection of mesenteric lymph node (MLN) cells or intestinal IEL from BALB/c donor mice which were naive or previously infected with C. muris. SCID mice receiving no lymphoid cells developed chronic infections and excreted large numbers of oocysts until the end of the experiment. SCID mice injected with IEL from immune animals, however, were able to overcome the infection, and furthermore, these animals produced fewer oocysts and recovered sooner than ones which received IEL or MLN cells from naive BALB/c donors. Similar levels of protection were obtained in SCID mice injected with either 2 X 10(6) IEL or MLN cells from immune donor mice. Depletion of CD4+ cells from immune IEL, however, abrogated the ability to transfer immunity to SCID mice, while depletion of CD8+ cells only marginally reduced the protective capacity of immune IEL. Finally, control SCID mice which received no lymphocytes had < or = 1% CD4+ cells in the IEL from the small intestine, whereas the IEL from SCID mice recovered from infection, as a result of injection with immune IEL, contained 15% CD4+ cells. Thus, the ability to control C. muris infection correlated with the presence of the protective CD4+ cells in the gut epithelium. PMID- 8698480 TI - Actinobacillus actinomycetemcomitans serotype b-specific polysaccharide antigen stimulates production of chemotactic factors and inflammatory cytokines by human monocytes. AB - Serotype b-specific polysaccharide antigen (SPA) was extracted from whole cells of Actinobacillus actinomycetemcomitans Y4 by autoclaving and purified by chromatography on DEAE-Sephadex A-25 and Sephacryl S-300. SPA induced the release of monocyte and leukocyte chemotactic factors by human monocytes. Polymyxin B had almost no effect on the release of monocyte chemotactic factor, but a monoclonal antibody against SPA markedly inhibited it. Human monocytes stimulated with SPA exhibited the increased mRNA expression of monocyte chemoattractant protein 1 (MCP-1) and a neutrophil chemotactic factor, interleukin-8 (IL-8). On the other hand, SPA induced the release of IL-1, IL-6, and tumor necrosis factor (TNF) and enhanced the expression of IL-1alpha, IL-1beta, IL-6, and TNF alpha (TNF-alpha) mRNAs. Human monocytes expressed MCP-1 and IL-8 mRNAs when stimulated by human recombinant IL-1alpha, I1-1beta, IL-6, and TNF-alpha, suggesting that these inflammatory cytokines induced by SPA might participate in the production of chemotactic factors in human monocytes. PMID- 8698481 TI - Porphyromonas gingivalis fimbrillin is one of the fibronectin-binding proteins. AB - In this study, we demonstrate that Porphyromonas gingivalis fimbrillin, a major component of bacterial fimbriae, is one of the fibronectin-binding proteins and that fibronectin is a potent inhibitor of the adherence of the bacteria to host cells and of the pathogenesis of the bacterium that acts by binding to the fimbriae. A Western blotting (immunoblotting) assay showed that fibronectin binds strongly to P. gingivalis fimbrillin. The fimbrial binding to fibronectin was also evidenced by a binding assay involving 125I-labeled fimbriae. Furthermore, fibronectin markedly inhibited the fimbria-induced expression of interleukin 1beta and neutrophil-specific chemoattractant KC genes in macrophages. The inhibitory action depended on the fimbrial interaction with heparin-binding and cell attachment domains in the fibronectin structure. The binding of P.gingivalis to mouse peritoneal macrophages via its fimbriae was inhibited by fibronectin. Fibronectin also inhibited the bacterial cell-induced expression of interleukin 1beta and KC genes in the macrophages. These results demonstrate the importance of fibronectin as a modulator of the pathogenic mechanism of P. gingivalis, a pathogen that causes adult periodontal disease. PMID- 8698482 TI - Purification and biochemical characterization of a 65-kilodalton mannoprotein (MP65), a main target of anti-Candida cell-mediated immune responses in humans. AB - A 65 kDa-constituent (MP65) of a whole-cell mannoprotein (MP) fraction of Candida albicans was purified by immunoaffinity chromatography with monoclonal antibodies directed against periodate-insensitive, protease-sensitive MP epitopes, putatively polypeptide in nature. These antibodies were obtained by immunization of mice with concanavalin A bead-coupled, low-glycosylated MP from hyphal cells of C. albicans grown in the presence of a subinhibitory dose of tunicamycin. The immunoaffinity-purified MP65 molecule had a pI of 4.1 and a protein/polysaccharide ratio of 1.8:1. It was resistant to hydrolysis by endoglycosidase H, endoglycosidase F, or N-glycoffanases but still reactive with concanavalin A. The polysaccharide moiety of MP65 was composed exclusively of mannose and glucose at a ratio of 12.7 to 1. The protein moiety showed numerous potential O-glycosidic linkage sites as suggested by the high proportion of serine and threonine (together accounting for more than 20% of the total amino acid composition) and susceptibility to diluted alkali. This treatment and digestion with alpha-mannosidase caused a reduction in the MP65 molecular mass to around 54 kDa. The N-terminal sequence of MP65 protein moiety was rich in alanine and valine (7 of 13 amino acids) and did not show any significant homology with deposited sequences in data banks. Purified MP65, at doses of a few nanograms, induced extensive T-cell proliferation of human peripheral blood mononuclear cells. This proliferation was specifically inhibited, in a dose-response fashion, by the antigen-binding fragment of the monoclonal antibody used for immunoaffinity purification. Overall, these results highlight biochemical and molecular details of MP65, a main target of human T-cell response to C.albicans. PMID- 8698483 TI - Identification of Legionella pneumophila mutants that have aberrant intracellular fates. AB - After uptake by macrophages, Legionella pneumiophila evades phagosome-lysosome fusion and replicates in a compartment associated with the endoplasmic reticulum. A collection of bacterial mutants defective for growth in macrophages were isolated, and the intracellular fate of each mutant strain was analyzed by fluorescence microscopy. To measure intracellular replication, bacteria inside macrophages were stained with the DNA dye 4',6-diamidino-2-phenylindole (DAPI). Evasion of the endocytic pathway was quantified by immunofluorescence localization of lp120 [correction of IgpI20] (LAMP-1), a membrane protein of late endosomes and lysosomes, or by measuring colocalization of bacteria with a fluorescent tracer, Texas red-ovalbumin, preloaded into lysosomes. Replication vacuoles were quantified by immunofluorescence localization of BiP, an endoplasmic reticulum protein. By these approaches, four phenotypic groups of mutants were classified. One class formed replication vacuoles less efficiently than the wild type did; another formed replication vacuoles, but replication was abortive; in another class, most phagosomes containing bacteria acquired markers of the endocytic pathway but a minority formed replication vacuoles and the bacteria replicated; finally, a fourth class, the one most defective for intracellular growth, occupied vacuoles that acquired markers of the endocytic pathway. PMID- 8698484 TI - Biofunctional domains of the Mycoplasma pneumoniae P30 adhesin. AB - The P30 adhesin genes of spontaneous, hemadsorption-negative (HA-) class II Mycoplasma pneumoniae mutants that displayed P30 adhesin-deficient protein profiles were analyzed. One subclass of P30-deficient mutants possessed the entire p3O structural gene without alterations (825 nucleotides, encoding 275 amino acids with a predicted molecular mass of 29,743 Da [S. F. Dallo, A. Chavoya, and J. B. Baseman, Infect. Immun. 58:4163-4165, 1990]). However, the second mutant subclass contained a deletion in p3O resulting in the expression of a 25-kDa peptide (681 nucleotides, encoding 227 amino acids with a calculated molecular mass of 24,823 Da). This P25-truncated peptide lacked 8 of the 13 proline-rich amino acid repeat sequences at the carboxy terminus. Whole-cell radioimmunoprecipitation of M. pneumoniae with antibodies directed against the proline-rich repeat sequences located in the carboxy terminus demonstrated their surface accessibility. In contrast, antibodies generated against N-terminal amino acid sequences upstream of the repeats did not bind to intact mycoplasmas. The amino acid sequence homologies exhibited by the P30 adhesin and eucaryotic structural proteins were corroborated by cross-reactive epitopes shared between the P30 adhesin and fibrinogen, keratin, and myosin. These data reinforce the importance of the P30 protein in cytadherence and virulence and provide a molecular basis for postinfectious autoimmunity associated with M. pneumoniae mediated pathologies. PMID- 8698485 TI - Influence of adjuvants on protection induced by a recombinant fusion protein against malarial infection. AB - Previously, we described a protective immune response induced by the carboxyl terminal region of the merozoite surface protein-1 (MSP-1) from the rodent malarial parasite Plasmodium yoelii yoelii 17XL, expressed as a fusion protein and designated glutathione S-transferase (GST)-PYC2. We also demonstrated that the humoral response induced by GST-PYC2 was the primary mechanism by which immunized animals controlled their blood-stage infections. We have now examined the influence of several adjuvants on the immune response to the GST-PYC2 fusion protein. While alum, Freund's adjuvant, Ribi adjuvant system, and TiterMax were efficacious in eliciting a protective response with GST-PYC2 in BALB/c mice, saponin failed to induce protection, although significant levels of PYC2-specific antibodies were produced in all immunized animals. This protection depended on the mouse strain since immunization of Swiss Webster mice with GST-PYC2 in alum did not produce levels of PYC2-specific antibodies comparable to those in BALB/c mice nor did it induce any demonstrable level of protection against parasite challenge. Swiss Webster mice were protected, however, when immunized with GST PYC2 in other adjuvants. Immunization with PYC2, isolated free of GST induced lower levels of antigen-specific antibody; only those animals given PYC2 in Freund's adjuvant demonstrated a significant degree of protection, suggesting the possibility (of additional cellular effector mechanisms. These findings demonstrate that adjuvant, host genotype, and the fine specificity of the response significantly influence the protection induced by the carboxyl terminus of MSP-1 in vivo and illustrate the need to consider these factors in evaluating MSP-1 as a vaccine component. PMID- 8698487 TI - A Babesia bovis 225-kilodalton spherical-body protein: localization to the cytoplasmic face of infected erythrocytes after merozoite invasion. AB - A 225-kDa Babesia bovis protein occurs on the cytoplasmic side of infected erythrocyte membranes. Here it is demonstrated that the 225-kDa protein localizes to spherical-body organelles of merozoites. Organelles consistent in size and shape with spherical bodies were isolated between 1.17 and 1.21 g/cm(3) in a sucrose density gradient. Organelles consistent with rhoptries and micronemes were also present in fractions from 1.17 to 1.19 g/cm(3). Antisera generated by immunizing mice with the fraction (1.20 to 1.21 g/cm(3)) most enriched for spherical bodies reacted predominantly with spherical bodies in B. bovis merozoites. A monoclonal antibody generated from this immunization (70/97.14) recognized an epitope that occurs in the repeat region of the 225-kDa protein (now referred to as SBP2). Monoclonal antibody 70/97.14 bound to merozoite spherical bodies, vesicles in infected-host cytoplasm, and the cytoplasmic face of the infected-erythrocyte membrane. These results indicate that spherical-body proteins become associated with the host membrane via transport through the erythrocyte cytoplasm after intracellular invasion. PMID- 8698486 TI - Candida albicans stimulates cytokine production and leukocyte adhesion molecule expression by endothelial cells. AB - Endothelial cells have the potential to influence significantly the host immune response to blood-borne microbial pathogens, such as Candida albicans. We investigated the ability (of this organism to stimulate endothelial cell responses relevant to host defense in vitro. Infection with C. albicans induced endothelial cells to express mRNAs encoding E-selectin, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, interleukin 6, interleukin 8, monocyte chemoattractant protein 1, and inducible cyclooxygenase (cox2). All three leukocyte adhesion molecule proteins were expressed on the surfaces of the endothelial cells after 8 h of exposure to C. albicans. An increase in secretion of all three cytokines was found after 12 h of infection. Cytochalasin D inhibited accumulation of the endothelial cell cytokine and leukocyte adhesion molecule mRNAs in response to C. albicans, suggesting that endothelial cell phagocytosis of the organism is required to induce this response. Live Candida tropicalis, Candida glabrata, a nongerminating strain of C. albicans, and killed C. albicans did not stimulate the expression of any of the cytokine or leukocyte adhesion molecule mRNAs. These findings indicate that a factor associated with live, germinating C. albicans is required for induction of endothelial cell mRNA expression. Furthermore, since endothelial cells phagocytize killed C. albicans, phagocytosis is likely necessary but not sufficient for this organism to stimulate mRNA accumulation. In conclusion, the secretion of proinflammatory cytokines and expression of leukocyte adhesion molecules by endothelial cells in response to C. albicans could enhance the host defense against this organism by contributing to the recruitment of activated leukocytes to sites of intravascular infection. PMID- 8698488 TI - Cloning and characterization of the catalase gene of Neisseria gonorrhoeae: use of the gonococcus as a host organism for recombinant DNA. AB - The structural gene for the catalase of Neisseria gonorrhoeae was cloned into a Kat- strain of that organism by using a recombinant vector derived from one of the beta-lactamase-specifying plasmids found in that organism. The kat gene was then successfully subcloned into both pUC8 and pGB2, transformed into Escherichia coli, and shown to complement the E. coli katE mutants UM2 and UMRl. The gene was subsequently mutagenized and returned to the gonococcus to generate a Kat- strain that was phenotypically identical to the strain originally used to clone the gene. The sequence of the gene and the derived amino acid sequence showed that the gonococcal kat gene closely resembles the hktE gene of Haemophilus influenzae. The sequence of the promoter region of the gonococcal kat gene is unusual and may explain the extremely high, loosely regulated expression of the gene. PMID- 8698489 TI - Identification and characterization of CS20, a new putative colonization factor of enterotoxigenic Escherichia coli. AB - An enterotoxigenic Escherichia coli (ETEC) strain producing a previously undescribed putative colonization factor was isolated from a child with diarrhea in India. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of bacterial heat extracts revealed a polypeptide band of 20.8 kDa when the bacteria were grown at 37 degrees C which was absent after growth at 22 degrees C. A specific rabbit antiserum raised against the purified 20.8-kDa protein bound specifically to the fimbriae, as shown by immunoelectron microscopy, and inhibited bacterial adhesion to tissue-cultured Caco-2 cells. Transformation with a recombinant plasmid harboring the cfaD gene, which encodes a positive regulator for several ETEC fimbriae, induced hyperexpression of the 20.8-kDa fimbrial subunit and a substantial increase in the proportion of bacterial cells that were fimbriated. The N-terminal amino acid sequence of the polypeptide showed 65 and 60% identity to the PCFO20 and 987P fimbriae of human and porcine ETEC, respectively. We propose the term CS20 for this new putative colonization factor of human ETEC. PMID- 8698491 TI - The major surface glycoprotein of Trypanosoma cruzi amastigotes are ligands of the human serum mannose-binding protein. AB - Trypanosoma cruzi, an obligate intracellular protozoan parasite, chronically infects mammals and causes Chagas' disease in humans. T. cruzi evasion of the mammalian immune response and establishment of chronic infection are poorly understood. During T. cruzi infection, amastigotes and trypomastigotes disseminate in the mammalian host and invade multiple cell types. Parasite surface carbohydrates and mammalian lectins have been implicated in the invasion of mammalian cells. A recent study has demonstrated that the human mannose binding protein and the macrophage mannose receptor, two mammalian C-type lectins, bind to T. cruzi (S. J. Kahn, M. Wleklinski, A. Aruffo, A. Farr, D. Coder, and M. Kahn, J. Exp. Med. 182:1243-1258,1995). In this report we identify the major surface glycoproteins, including the SA85-1 glycoproteins, as T. cruzi ligands of the mannose-binding protein. Further characterization of the interaction between the mannose-binding protein and T. cruzi demonstrates that (i) the SA85-1 glycoproteins are expressed by amastigotes and trypomastigotes but only amastigotes express the mannose-binding protein ligand, (ii) treatment of amastigotes with alpha-mannosidase inhibits the binding of mannose-binding protein, and (iii) amastigote binding of mannose-binding protein is stable despite the spontaneous shedding of some glycoproteins from its surface. Together, the data indicate that developmentally regulated glycosylation of surface glycoproteins controls the expression of ligands that affect the interactions between T. cruzi and mannose-binding protein. It has been established that the binding of mannose-binding protein to microorganisms facilitates their uptake into phagocytic cells. Preferential opsonization of amastigotes with mannose-binding proteins may account for their clearance from the circulation and may contribute to the parasite's ability to invade different cell types. PMID- 8698490 TI - Acidic pH changes receptor binding specificity of Helicobacter pylori: a binary adhesion model in which surface heat shock (stress) proteins mediate sulfatide recognition in gastric colonization. AB - The gastric pathogen helicobacter pylori is one of a number of bacteria which bind specifically to gangliotetraosylceramide, gangliotriaosylceramide, and phosphatidylethanolamine in vitro at neutral pH. Since this organism encounters an acid pH during initial infection of the stomach, we have monitored the effect of pH on receptor binding specificity and found induction of specific binding to sulfoglycolipids (sulfatide) following brief treatment at low pH. We have previously shown that heat shock proteins (hsps) bind to sulfatide, and the suspicion that this was a stress-induced response is supported by the fact that a similar change in H. pylori binding specificity was observed if the organisms were briefly exposed to heat shock treatment. Following the stress stimulus, the change in glycolipid binding specificity was prevented by the inclusion of inhibitors of protein synthesis or by incubation with anti-hsp antibodies. Expression of hsps in the surface extract and surface reactivity with anti-hsp antibodies correlated with the change in glycolipid binding specificity. Despite the presence of high levels of H. pylori cell surface urease activity which may neutralize the microenvironmental pH, the acid-induced change in binding specificity was enhanced in the presence of urea. These studies suggest that cell surface hsps mediate sulfatide recognition by this organism under stress conditions. A binary receptor model is proposed for gastric colonization by H. pylori. PMID- 8698492 TI - The major fimbrial subunit of Bordetella pertussis binds to sulfated sugars. AB - Bordetella pertussis fimbriae are composed of major and minor subunits, and recently it was shown that the minor fimbrial subunit binds to Vla-5, a receptor located on monocytes (W. Hazenbos, C. Geuijen, B. van den Berg, F. Mooi, and R. van Furth, J. Infect. Dis. 171:924-929, 1995). Here we present evidence that the major subunits bind to sulfated sugars, which are ubiquitous in the respiratory tract. Binding was observed to chondroitin sulfate, heparan sulfate, and dextran sulfate but not to dextran. Removal of the minor subunit from fimbriae did not significantly affect binding to sulfated sugars, indicating that the major subunit alone is sufficient for this binding. Fimbriae were also able to bind HEp 2 cells, which are known to display glycoconjugates on their surface. This binding was not dependent on the presence of the minor subunit. However, binding was dependent on the sulfation state of the glycoconjugates, since inhibition of the sulfation resulted in a significant reduction of fimbria binding. The specificity of fimbria binding was further characterized by using heparan sulfate derived disaccharides in inhibition assays. Two disaccharides were highly effective inhibitors, and it was observed that both the degree of sulfation and the arrangement of the sulfate groups on the disaccharides were important for binding to fimbriae. B. pertussis bacteria also bound to sulfated sugars and HEp 2 cells, and analysis of B. pertussis mutants indicated that both filamentous hemagglutinin and fimbriae were required for this binding. A host protein present in the extracellular matrix, fibronectin, has binding activities similar to those of B. pertussis fimbriae, binding to both Vla-5 and sulfated sugars. Two regions in the major fimbrial subunit were identified which showed similarity with fibronectin peptides which bind to sulfated sugars. Thus, B. pertussis fimbriae exemplify molecular mimicry and may co-opt host processes by mimicking natural ligand-receptor interactions. PMID- 8698493 TI - Monocytes of individual human subjects display heterogeneous bacterial uptake and antilisterial activity. AB - Peripheral blood monocytes (Mo) of normal human donors simultaneously exhibit two subsets differing in their functional activity towards the facultative intracellular bacterium Listeria monocytogenes. One subset (on average, 25% of total Mo) was characteristically able to ingest a large number of L. monocytogenes bacteria and permitted intracellular growth of these bacteria. The other Mo subpopulation (on average, 75% of total Mo) was far less active in phagocytosing L. monocytogenes and restricted intracellular L. monocytogenes growth. Electron microscopy revealed that the Listeria-permissive Mo subset allowed the bacteria to escape to the cytosol, a mechanism by which these bacteria evade the lethal attack of phagocytes. The Listeria-restrictive Mo subset, on the other hand, confined the bacteria to the phagolysosomes, where they were exposed to the killing mechanisms of the Mo. Permissiveness for L. monocytogenes growth was further associated with differences in the capacity of the Mo subsets to synthesize tumor necrosis factor alpha TNF-alpha), an important mediator in the defense against intracellular bacteria. Following challenge with L. monocytogenes, the Listeria-restrictive Mo subset secreted two to six times more TNF-alpha than did the Listeria-permissive Mo subset. Enhanced TNF-alpha secretion was paralleled by increased accumulation of TNF-alpha mRNA as assessed by quantitative PCR. Despite these functional differences, the two Mo subsets were indistinguishable with respect to expression of cell surface markers known to be involved in adherence and phagocytosis of microbes. A speculative physiological role of the two Mo subsets may lie in the dual function of Mo as microbicidal effector cells and accessory cells for antigen-specific immune reactions. PMID- 8698494 TI - Comparison of in vitro models for the study of Mycobacterium tuberculosis invasion and intracellular replication. AB - We recently evaluated several tissue culture model systems for the study of invasion and intracellular multiplication of Mycobacterium tuberculosis. These model systems include a human alveolar pneumocyte epithelial cell line, a murine macrophage cell line (J774), and fresh human peripheral blood-derived macrophages. Our data indicated that the initial level of association of M. tuberculosis with human alveolar pneumocyte cells (2%) was less than that observed with fresh human peripheral blood macrophages (9%) or J774 murine macrophages (13%) within 6 h of the addition of the bacteria. M. tuberculosis replicated in association with the pneumocyte cells by more than 55-fold by day 7 postinfection. In contrast, total bacteria] growth in the J774 cells and human macrophages was considerably less, with increases of only fourfold and threefold, respectively, over the same 7-day period. Amikacin, an aminoglycoside antimicrobial agent, was added to inhibit the growth of extracellular bacteria after the initial 6-h infection period. Decreases in viable counts were observed in all three cell cultures within the first 3 days after infection. However, unlike the case with either macrophage culture, intracellular bacterial CFU obtained from the infected pneumocytes increased by fourfold by day 7 after the addition of amikacin. These data indicate that M. tuberculosis infects and multiplies intracellularly in human lung epithelial cells and that these cells may be an alternative in vitro model for the study of intracellular multiplication of M. tuberculosis in the human lung. PMID- 8698495 TI - Clonal structure and virulence factors in strains of Escherichia coli of the classic serogroup O55. AB - Virulence properties and genetic variation as determined by multilocus enzyme electrophoresis were studied in 70 strains of Escherichia coli 055, a common serogroup of enteropathogenic E. coli (EPEC), a major cause of infantile diarrhea in developing countries. Nearly 40% of the strains were originally isolated in Brazil and represented serotypes 055:H6, 055:H7, and 055:H51 and nonmotile (055:H ) strains. The analysis of electrophoretic variants of 20 enzymes defined seven distinct electrophoretic types (ETs). ET 1 was represented by 41% of the strains, including strains which usually hybridized with DNA probes for the intimin gene (eaeA), the EPEC adherence plasmid (EAF), and the gene for the pilin subunit of the bundle-forming pilus (bfpA). The ET 1 strains were also typically serotype 055:H6, displayed localized adherence (LA) in tissue culture assays, and were positive in the fluorescent-actin staining test for intimate cell adherence. These same characteristics were observed in the closely related ETs 2 to 4, which clustered in the same branch as ET 1. No known virulence marker could be identified in ET 6. ET 5 included 23 strains, all of which carried the eaeA gene but otherwise displayed a striking array of distinct virulence traits. This ET was represented by 055:H7 strains with phenotypes as diverse as the simultaneous expression of LA and diffuse adherence and the ability to form a newly described adherence pattern, called LA-like adherence. The results suggest that ET 5 marks a special pathogenic clone with a propensity to acquire virulence factors which may facilitate the emergence of new pathogenic strains. PMID- 8698497 TI - Molecular cloning and characterization of Coccidioides immitis antigen 2 cDNA. AB - Previous experiments have provided evidence that Coccidioides immitis antigen 2 (Ag2) is a major T-cell-reactive component of mycelia and spherule cell walls. Here we report the identification and cloning of the cDNA that encodes Ag2 from a lambda ZAP cDNA expression library constructed from spherule-derived RNA. DNA sequence analysis established that the 1,255-bp clone contains a 174-bp 5' untranslated region, a 582-bp open reading frame which encodes for a protein consisting of 194 amino acids, and a 375-bp 3' untranslated region, including a poly(A) tail. The recombinant Ag2 protein has a predicted molecular mass of 19.5 kDa and contains an 18-amino-acid N terminus which has been tentatively identified as a signal peptide. The Ag2 cDNA was ligated into the pGEX-4T-3 vector and expressed in Escherichia coli TG-1 cells as a glutathione S transferase fusion protein. The recombinant fusion protein showed reactivity with sera from patients with coccidioidomycosis and elicited delayed-type footpad hypersensitivity responses in Coccidioides-immune mice. These results suggest that the Ag2 cDNA can be used for the large-scale production of this immunologically important protein. PMID- 8698496 TI - Pasteurella haemolytica leukotoxin induces bovine leukocytes to undergo morphologic changes consistent with apoptosis in vitro. AB - Infection of the bovine lung with Pasteurella haemolytica results in an acute respiratory disorder known as pneumonic pasteurellosis. One of the key virulence determinants used by this bacterium is secretion of an exotoxin that is specific for ruminant leukocytes (leukotoxin). At low concentrations, the leukotoxin can activate ruminant leukocytes, whereas at higher concentrations, it inhibits leukocyte functions and is cytolytic, presumably as a result of pore formation and subsequent membrane permeabilization. We have investigated the possibility that the activation-inhibition paradox is explained in part by leukotoxin mediated apoptosis (i.e., activation-induced cell death) of bovine leukocytes. Incubation of bovine leukocytes with P. haemolytica leukotoxin caused marked cytoplasmic membrane blebbing (zeiosis) and chromatin condensation and margination, both of which are hallmarks of apoptosis. The observed morphologic changes in bovine leukocytes were leukotoxin dependent, because they were significantly diminished in the presence of an anti-leukotoxin monoclonal antibody. In addition, bovine leukocytes incubated with culture supernatant from a mutant strain of P. haemolytica that does not produce any detectable leukotoxin failed to exhibit the morphologic changes characteristic of cells undergoing apoptosis. These observations may represent an important mechanism by which P. haemolytica overwhelms host defenses, contributing to the fibrinous pleuropneumonia characteristic of bovine pasteurellosis. PMID- 8698498 TI - Amino acid residues in the pro region of Escherichia coli heat-stable enterotoxin I that affect efficiency of translocation across the inner membrane. AB - Escherichia coli heat-stable enterotoxin Ip (STIp), which is a typical extracellular toxin consisting of 18 amino acid residues, is synthesized as a precursor consisting of pre (amino acid residues 1 to 19), pro (amino acid residues 20 to 54), and mature (amino acid residues 55 to 72) regions. Though the pre region functions as a conventional leader peptide that guides the following region to cross the inner membrane, the role of the pro region in the maturation pathway remains to be elucidated. We previously indicated that the sequence from residues 29 to 38 in the pro region increases the efficiency of STI translocation across the inner membrane (H. Yamanaka, Y. Fuke, S. Hitotsubashi, Y. Fujii, and K. Okamoto, Microbiol. Immunol. 37:195-205, 1993). We therefore examined the amino acid residues in the sequence that are responsible for this function. We substituted several amino acid residues in the sequence by means of oligonucleotide-directed site-specific mutagenesis. We then evaluated the effect of the substitution on the efficiency of STI translocation across the inner membrane by determining the enterotoxic activity of the culture supernatant, the amount of a fusion protein consisting of STI and nuclease A released into the periplasm, and the amount of the labeled ST released into the periplasm after pulse-labeling with [35S]cysteine. Substitution of the charged amino acid residues at positions 29 to 31 (K-E-K) with hydrophobic (I-V-L, F-W-F, or F-W-Q) or basic (K-K-K) residues significantly reduced these values in every assay. In contrast, the substitution of these amino acid residues with acidic amino acid residues (E-E-E) increased these values in all assays. This means that the negative charge near position 30 is important for STI to translocate efficiently across the inner membrane. A similar substitution of lysine residues at positions 37 and 38 showed that they are not involved in the translocation of STI across the inner membrane. PMID- 8698499 TI - Synthesis, characterization, and immunological properties in mice of conjugates composed of detoxified lipopolysaccharide of Salmonella paratyphi A bound to tetanus toxoid with emphasis on the role of O acetyls. AB - Salmonella paratyphi A, the second most common cause of enteric fever in Southeast Asia, is a habitant of and a pathogen for humans only. Lipopolysaccharides (LPS) are both essential virulence factors and protective antigens for systemic infections caused by groups A, B, C, and D nontyphoidal salmonellae. The O-specific polysaccharide of S. paratyphi A is composed of a trisaccharide, -->2-alpha-D)-Manp-(1-->4)-alpha-L-Rhap-(1-->3)-alpha-D-Galp -(1- >, with a branch of D-paratose from the C-3 of alpha-D-mannose, and the C-3 of beta-L-rhamnose is partially O acetylated (C. G. Hellerqvist, B. Lindberg, K. Samuelsson, and A. A. Lindberg, Acta Chem. Scand. 25:955-961, 1971). On the basis of data from our investigational vaccines for enteric bacterial pathogens, including group B salmonellae (D. C. Watson, J. B. Robbins, and S. C. Szu, Infect. Immun. 60:4679-4686, 1992), conjugates composed of the detoxified LPS of S. paratyphi A bound to tetanus toxoid (TT) were prepared by several schemes. LPS was detoxified with acetic acid or with hydrazine; the latter removed O acetyls from the O-specific polysaccharide. The detoxified polysaccharides were activated with cyanogen bromide (CNBr) or with 1-cyano-4-dimethylaminopyridinium tetratfluoroborate (CDAP) and bound to TT with or without a spacer. Solutions of 2.5 microgram of saccharide, alone or as a conjugate, were injected subcutaneously into young mice, and LPS and TT antibodies were measured by enzyme linked immunosorbent assaying. A conjugate synthesized with higher-molecular weight O-SP elicited the highest anti-LPS levels. Only conjugates with O acetyls elicited serum immunoglobulin G anti-LPS with bactericidal activity. There were no statistically significant differences between LPS antibody levels elicited by conjugates synthesized with or without a spacer. The conjugate with O-specific polysaccharide activated by CDAP and bound to TT without a spacer elicited the highest level of TT antibodies. Clinical evaluation (if S. paratyphi A conjugates is planned. PMID- 8698500 TI - Natural immune response to the C-terminal 19-kilodalton domain of Plasmodium falciparum merozoite surface protein 1. AB - We have characterized the natural immune responses to the 19-kDa domain of merozoite surface protein 1 in individuals from an area of western Kenya in which malaria is holoendemic. We used the three known natural variant forms of the yeast-expressed recombinant 19-kDa fragment that are referred to as the E-KNG, Q KNG, and E-TSR antigens. T-cell proliferative responses in individuals older than 15 years and the profile of immunoglobulin G (IgG) antibody isotypes in individuals from 2 to 74 years old were determined. Positive proliferative responses to the Q-KNG antigen were observed for 54% of the individuals, and 37 and 35% of the individuals responded to the E-KNG and E-TSR constructs, respectively. Considerable heterogeneity in the T-cell proliferative responses to these three variant antigens was observed in different individuals, suggesting that the 19-kDa antigen may contain variant-specific T epitopes. Among responses of the different isotypes of the IgG antibody, IgG1 and IgG3 isotype responses were predominant, and the prevalence and levels of the responses increased with age. We also found that a higher level of IgG1 antibody response correlated with lower parasite density among young age groups, suggesting that IgG1 antibody response may play a role in protection against malaria. However, there was no correlation between the IgG3 antibody level and protection. Furthermore, we observed that although the natural antibodies cross-reacted with all three variant 19-kDa antigens, IgG3 antibodies in 12 plasma samples recognized only the E-KNG and Q-KNG constructs and not the E-TSR antigen. This result suggests that the fine specificity of IgG3 antibodies differentiates among variant-specific natural B-cell determinants in the second epidermal growth factor domain (KNG and TSR) of the antigen. PMID- 8698501 TI - Differential regulation of the leukotoxin operon in highly leukotoxic and minimally leukotoxic strains of Actinobacillus actinomycetemcomitans. AB - The expression of the leukotoxin (ltx) operon varies significantly among Actinobacillus actinomycetemcomitans strains. The dual promoters driving ltx expression in the highly toxic strain JP2 have been previously characterized (J. M. Brogan, E. T. Lally, K. Poulsen, M. Kilian, and D. R. Demuth, Infect. Immun. 62:501-508, 1994), and genetic analyses of A. actinomycetemcomitans suggest that highly toxic strains like JP2 arose from minimally toxic strains, presumably by deletion of a 530-bp domain within the ltx promoter region (K. Poulsen, E. Theilade, E.T. Lally, D. R. Demuth, and M. Kilian, Microbiology 140:2049-2060, 1994). However, the ltx promoter of minimally toxic A. actinomycetemcomitans strains has not been well characterized. In this study, deletion and primer extension analyses showed that the ltx promoter of A. actinomycetemcomitans 652 is situated approximately 150 bp upstream of the ltxC gene and initiates transcription 138 nucleotides upstream of ltxC. In contrast to strain JP2, only a single promoter appears to drive ltx expression in 652. The 652 promoter resides within the 530-bp region that is absent from the JP2 promoter sequence, suggesting that the specific sequences controlling ltx expression differ in highly toxic and minimally toxic A. actinomycetemcomitans strains. In addition, ltx expression in strain 652 was shown to be induced three- to fourfold when cells were grown under anaerobic conditions. The induction of whole cell leukotoxicity, was accompanied by increases in the levels of Ltx polypeptide and the steady-state levels of ltx mRNA, suggesting that regulation occurred at the level of transcription. In contrast, the levels of leukotoxicity, Ltx polypeptide, and fix mRNA in strain JP2 were unaffected by anaerobic growth. These results suggest that the ltx operon is differentially regulated in highly toxic and minimally toxic A. actinomycetemcomitans strains and that the sequences controlling the oxygen-dependent regulation of ltx expression may reside within the 530-bp domain that is not present in highly toxic A. actinomycetemcomitans. PMID- 8698502 TI - Studies of immunity and bacterial invasiveness in mice given a recombinant salmonella vector encoding murine interleukin-6. AB - Interleukin-6 (IL-6) was expressed in Salmonella typhimurium in an attempt to increase the mucosal immune response against the bacterium. Murine IL-6 was PCR amplified from cDNA, cloned, sequenced, and found to be functionally active when expressed in S. typhimurium BRD509, the (delta)aroA (delta)aroD vaccine strain. Expression of murine IL-6 did not appear to adversely affect the growth of salmonellae, as the construct was retained in the absence of antibiotic selection and the growth rate was unaffected compared with that of the parent strain in vitro. However, IL-6 expression led to a significant reduction in bacterial invasiveness in vitro and in vivo. Splenocytes and small intestinal lamina propria lymphocytes were isolated from mice orally immunized with BRD509 expressing IL-6 (pKK233-2/IL-6), and the number of antibody-secreting cells was determined by the ELISPOT technique. No differences were observed between mice immunized with BRD509(pKK.233-2/IL-6) and those immunized with BRD509(pKK233-2) with respect to the antibody subclass-specific responses elicited despite the markedly reduced invasiveness of the former. Serum antibody responses were also examined by a kinetic enzyme-linked immunosorbent assay (ELISA), and equivalent levels of antibody response were detected in mice given BRD509(pKK233-2/IL-6) and those given BRD509(pKK233-2). The humoral immune response against bacterial lipopolysaccharides was also examined in transgenic IL-6-deficient mice given oral inocula of BRD509. Equivalent numbers of antibody-secreting cells (ELISPOTs) were observed in the spleens and laminae propriae of both IL-6-deficient (-/-) mice and control (+/+) mice harboring an intact IL-6 gene, whereas small, yet significant differences in the serum immunoglobulin A ELISA titers were observed. These data suggest that the immunoglobulin A response against Salmonella lipopolysaccharides is largely IL-6 independent. PMID- 8698503 TI - Molecular basis of size and antigenic variation of a Mycoplasma hominis adhesin encoded by divergent vaa genes. AB - The molecular basis for the size and antigenic diversity of the variable adherence-associated (Vaa) antigen, a major surface protein and a putative adhesin (of Mycoplasma hominis, is described. Size-variant alleles of the single copy vaa gene encode abundant surface lipoproteins containing one to four nearly identical, tandem repetitive units of 121 amino acids in the central region of the mature Vaa product. Gain or loss of central repeats in vaa genes gives rise to distinct size-variant Vaa antigens in clonal populations of this organism. The N-terminal and repeat regions of Vaa contain highly conserved sequences, while the C-terminal region, implicated as the adherence-mediating module, is highly variable and divergent among different strains of this pathogen. Sequence variation in this region may underlie the strain-dependent binding of some monoclonal antibodies to Vaa products. The Vaa antigen is expressed in vivo during chronic, active arthritis associated with M. hominis infection and is highly immunogenic in the human host. Size variation and C-terminal antigenic divergence of Vaa could affect the adherence of M. hominis and evasion of antibody-mediated immunity, thereby contributing to the organism's adaptive capability in the human host. Variation in vaa genes reveals a distinct pattern of mutations generating mycoplasma surface variation. PMID- 8698504 TI - Specificity of human bactericidal antibodies against PorA P1.7,16 induced with a hexavalent meningococcal outer membrane vesicle vaccine. AB - A set of isogenic strains was constructed from the meningococcal reference strain H44/76 (B:15:P1.7,16) which differed only in their outer membrane protein (OMP) compositions. First, three isogenic strains lacking the expression of either class 3 (PorB) or class 4 (RmpM) OMP or both were obtained. Second, three isogenic class 1 OMP loop-deficient strains of H44/76 lacking the predicted loop 1 or 4 or both of class 1 OMP (PorA) were obtained. Third, three isogenic class 1 OMP strains which differed by point mutations in the predicted loop 4 of subtype P1.16 were constructed. Strains were constructed through transformation with gene constructs made in Escherichia coli and their homologous recombination into the meningococcal chromosome. This study describes the contribution of one of the six class 1 OMPs, PorA P1.7,16, in the development of bactericidal antibodies after a single immunization of adult volunteers with 50 or 100 micrograms of protein within a hexavalent PorA outer membrane vesicle vaccine. PorA-, PorB-, and RpmM deficient isogenic strains were used to define the human immune response against PorA. The loop-deficient isogenic strains were used to define the contribution of loops 1 and 4 of PorA in the development of bactericidal anti-PorA antibodies. The isogenic strains carrying a point mutation in loop 4 were used to study the cross-reactivity of the induced bactericidal antibodies against target strains showing microheterogeneity. The results indicate that a single immunization with the hexavalent PorA vaccine induced a dose-dependent bactericidal immune response, which is directed mainly against PorA. The epitope specificity of antibodies is directed mostly against loop 1, although loop 4 and as-yet unidentified epitopes of PorA P1.7,16 are also involved. PMID- 8698505 TI - Infection of rabbit Peyer's patches by Shigella flexneri: effect of adhesive or invasive bacterial phenotypes on follicle-associated epithelium. AB - In order to invade the colonic mucosa, the bacterial pathogen Shigella flexneri must find a site of entry. Experiments with the rabbit ligated intestinal loop model described here confirm that M cells of the follicle-associated epithelium (FAE) that covers lymphoid structures of the Peyer's patches represent a major site of entry for invasive microorganisms. In addition, in an isogenic Shigella background, expression of an adhesive phenotype, or of an invasive phenotype, is required for bacteria to efficiently colonize the FAE. A nonadhesive, noninvasive mutant barely interacted with FAE. Adhesive and invasive strains induced dramatic but different alterations on FAE. Invasive strain M90T caused major inflammation mediated tissue destruction after 8 h of infection. Adhesive strain BS15 caused limited inflammation, but major architectural changes, characterized by an increase in the size of M cells that became stretched over large pockets containing an increased number of mononuclear cells, were observed. M cells progressively occupied large surface areas of the FAE at the expense of enterocytes. This contributed to enterocytes losing contact with the lumen. These experiments demonstrate that various remodeling patterns may occur in Peyer's patches in response to bacterial pathogens, depending on the virulence phenotype expressed by the pathogenic strain. PMID- 8698506 TI - Acidification of phagosomes containing Salmonella typhimurium in murine macrophages. AB - Salmonella species are facultative intracellular pathogens. Following entry into mammalian host cells, they reside in membrane-bound vacuoles, resist killing, and replicate. In this work, we investigated the importance of phagosomal pH in the ability of Salmonella typhimurium to survive and replicate within macrophages. Intraphagosomal pH was measured in situ by recording the fluorescence intensity of a pH-sensitive probe, DM-NERF dextran. The majority of vacuoles containing S. typhimurium (live, heat killed, or formalin fixed) acidified from pH > or = 6.0 to between pH 4.0 and 5.0 within 60 min after formation. In contrast, Mycobacterium avium-containing vacuoles failed to acidify even at later time points. Acidification of S. typhimurium-containing vacuoles was completely blocked by treatment of host cells with bafilomycin A, a specific inhibitor of vacuolar proton-ATPases. Bafilomycin inhibition of vacuolar acidification from the onset of infection significantly decreased the survival of S. typhimurium in macrophages. Furthermore, bafilomycin treatment at 2, 4, 8, or even 12 h postinfection decreased the percentage of recoverable bacteria by up to 20-fold. Loss of bacterial viability was seen with several other reagents which, like bafilomycin, raise the pH of phagosomal compartments but are not directly lethal to the bacteria or host cells. Thus, we conclude that Salmonella-containing phagosomes acidify soon after formation and hypothesize that an acidic environment is necessary for survival and replication of the bacteria within the macrophage. PMID- 8698508 TI - Tumor necrosis factor alpha and interleukin-12 contribute to resistance to the intracellular bacterium Brucella abortus by different mechanisms. AB - Both interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-alpha) are produced early in intracellular bacterial infection. Depletion of either IL-12 or TNF-alpha by a single injection of specific antibody 4 h before the injection of Brucella abortus 19 led to the exacerbation of infection 2 weeks later. Whereas the effect of IL-12 depletion on resistance was persistent and exacerbation was still significant 6 weeks later, the bacterial numbers in mice depleted of TNF alpha were similar to the bacterial numbers in control infected mice by 6 weeks postinfection. Massive splenomegaly, which is often seen in 2-week Brucella infected mice, was not observed in IL-12- or TNF-alpha-depleted mice. Both IL-12- and TNF-alpha-depleted mice showed reduced cell accumulation in the spleen compared with the massive cell accumulation in control infected mice. Granuloma formation in livers was much reduced in IL-12-depleted mice but not in TNF-alpha depleted mice. Gamma interferon (IFN-gamma) production by cells from TNF-alpha depleted mice was not significantly different from that of cells from control infected mice. In contrast, the production of IFN-gamma by both CD4+ and CD8+ T cells from IL-12-depleted mice was greatly reduced, compared with that from control infected mice. This effect was still observed when the antibody injection was delayed for up to 7 days postinfection, but injections of anti-IL-12 antibody into mice with established Brucella infection had no significant effect on IFN gamma production by T cells. Taken together, these results suggested that IL-12 contributed to resistance mainly via an IFN-gamma-dependent pathway and had a profound effect on the induction of acquired cellular resistance. In contrast, TNF-alpha was involved in resistance possibly via direct action on effector cells and may not be essential for the induction of acquired cellular resistance. PMID- 8698507 TI - Virulence properties of Pseudomonas aeruginosa lacking the extreme-stress sigma factor AlgU (sigmaE). AB - A discerning feature of Pseudomonas aeruginosa strains causing chronic endobronchial infections in cystic fibrosis is their conversion into the mucoid, exopolysaccharide alginate-overproducing phenotype. This morphologically prominent change is caused by mutations which upregulate AlgU (sigma(E)), a novel extreme-stress sigma factor with functional equivalents in gram-negative organisms. In this work, we investigated the role of algU in P. aeruginosa sensitivity to reactive oxygen intermediates, killing by phagocytic cells, and systemic virulence of this bacterium. Inactivation of algU in P. aeruginosa PA01 increased its susceptibility to killing by chemically or enzymatically generated halogenated reactive oxygen intermediates and reduced its survival in bactericidal assays with J774 murine macrophages and human neutrophils. Surprisingly, inactivation of algU caused increased systemic virulence of P. aeruginosa in mouse models of acute infection. The increased lethality of the algU-deficient strain was also observed in the endotoxin-resistant C3H/HeJ mice. Only minor differences between algU+ and algU mutant cells in their sensitivity to human serum were observed, and no differences in their lipopolysaccharide profiles were detected. Intriguingly, while inactivation of algU downregulated five polypeptides it also upregulated the expression of seven polypeptides as determined by two-dimensional gel analyses, suggesting that algU plays both a positive and a negative role in gene expression in P. aeruginosa. While the observation that algU inactivation increases systemic virulence in P. aeruginosa requires further explanation, this phenomenon contrasts with the apparent selection for strains with upregulated AlgU during colonization of the cystic fibrosis lung and suggests opposing roles for this system in chronic and acute infections. PMID- 8698509 TI - Identification of an immunoglobulin A binding motif located in the beta-antigen of the c protein complex of group B streptococci. AB - The beta-antigen of the c protein complex of group B streptococci contains two immunoglobulin A (IgA)-binding domains called A and B. A 73-amino-acid segment in domain A is responsible for most of the IgA-binding activity. To identify the IgA binding motif, the 73-amino-acid domain was divided into 60 14-amino-acid overlapping peptides spot synthesized onto a cellulose membrane. A 20-residue putative antigenic epitope was identified and expressed as a fusion protein. The fusion protein was purified by fast protein liquid chromatography and used to raise rabbit antiserum. By use of a membrane with spot-synthesized peptide amino acids of decreasing length (from 14 to 6 amino acids), the major antigenic epitope recognized by the anti-fusion protein antibodies was mapped to motif MLKKIE. Anti-fusion protein antibodies inhibited the binding of IgA to group B streptococci. This inhibition could be blocked by the peptide containing the motif MLKKIE. These results indicate that the motif MLKKIE is located in the IgA binding site. The IgA-binding domain of beta-antigen from three group B streptococcal strains reacted with the anti-fusion protein antibodies, and their coding sequences gave positive signals in Southern hybridization. The sequences of beta-antigen from these strains were amplified by PCR, and sequence analysis showed them to be identical. The results indicate that the motif MLKKIE is required for IgA binding and is present in different group B streptococcal strains. PMID- 8698511 TI - Number of specific antibody-secreting cells in the peripheral blood among children with mycoplasma pneumonia. AB - Mycoplasma pneumoniae-specific antibody-secreting cells (ASCs) in the peripheral blood were enumerated with an enzyme-linked immunospot assay in 12 children with mycoplasma pneumonia. Those cells were detected in the acute phases and declined in number in the convalescent stage. The maximum numbers of M. pneumoniae specific ASCs ranged from 0 to 478 for immunoglobulin G (IgG), 13 to 1,992 for IgM, and 0 to 53 for IgA per 106 peripheral blood mononuclear cells, whereas the total numbers (i.e., including both specific and nonspecific) of immunoglobulin secreting cells (IgSCs) were as high as 4,000 for both IgG and IgM and 1,000 for IgA per 106 peripheral blood mononuclear cells. Such a great increase in the numbers of total IgSCs in comparison with that in M. pneumoniae-specific ASCs suggests that the majority of the IgSC increase in the course of mycoplasmal infection was nonspecific to M. pneumoniae. The serum level of M. pneumoniae antibody measured by enzyme-linked immunosorbent assay remained high in the convalescent phase, while the number of specific ASCs decreased. Whereas this observation may be explained by declined degeneration or consumption of the antibody in the convalescent phase, it may be suggestive of the source of M. pneumoniae antibody other than ASCs in the peripheral blood. PMID- 8698510 TI - Decreased expression of mannose-specific adhesins by Escherichia coli in the colonic microflora of immunoglobulin A-deficient individuals. AB - Most Escherichia coli isolates can express type 1 fimbriae with mannose-specific adhesins. These adhesins bind to the oligosaccharide chains of secretory immunoglobulin A (IgA). Thus, in addition to specific antibody activity, secretory IgA possesses a broad reactivity with bacteria expressing type 1 fimbriae. The absence of secretory IgA in colonic secretions, as seen in IgA deficiency, might therefore alter the ability of type 1-fimbriated E. coli to colonize the large intestines of these individuals. In the present study, 10 E. coli isolates from each of 17 IgA-deficient and 17 age-matched control individuals were assessed for the carriage of the fim gene cluster by DNA-DNA hybridization and for the expression of type 1 fimbriae by hemagglutination of guinea pig erythrocytes. The contribution of type 1-fimbria-mediated adherence to HT-29 colonic cells was also analyzed. The proportion of fim+ E. coli isolates was lower in IgA-deficient than in control individuals (74 versus 94%, P < 0.05), as was the proportion of isolates expressing type 1 fimbriae in vitro (69% versus 85%, P < 0.05). The median mannose-sensitive adherence to HT-29 cells was lower for isolates from IgA-deficient individuals than from the controls (9 versus 26 bacteria per cell, P < 0.05). Isolates expressing type 1 fimbriae showed lower adherence to HT-29 cells when they were derived from IgA-deficient individuals than when they were derived from control individuals (15 versus 27 bacteria per cell, P < 0.05). The results suggest that the interaction of type 1 fimbriae with secretory IgA contributes to the large intestinal colonization by these bacteria. PMID- 8698513 TI - Characterization of the acid resistance phenotype and rpoS alleles of shiga-like toxin-producing Escherichia coli. AB - Shiga-like toxin-producing Escherichia coli (SLTEC) strains are an important group of enteric pathogens. In this study we have examined the abilities of 58 SLTEC isolates to survive at pH 2.5 and found 13 of these isolates to be defective in acid resistance. Introduction of rpoS on a plasmid conferred acid resistance to the majority of the acid-sensitive isolates. The rpoS genes from two of these isolates were sequenced; both isolates contained lesions in the rpoS gene resulting in a nonfunctional RpoS. These results show that mutant rpoS alleles exist in natural populations of E. coli. Such mutations may play an important role in determining the infective dose of SLTEC and suggest that isolates may vary in infectivity. PMID- 8698512 TI - Role of intercellular adhesion molecule 1 in pathogenesis of staphylococcal arthritis and in host defense against staphylococcal bacteremia. AB - Intercellular adhesion molecule 1 (ICAM-1) is a member of the immunoglobulin superfamily that interacts with two integrins, LFA-1 and Mac-1. These interactions are critical for leukocyte extravasation into inflamed tissue. To assess the role of ICAM-1 expression in the pathogenesis of bacterial infection, homozygously mutant mice lacking the ICAM-1 gene were exposed to Staphylococcus aureus. Within 6 days after inoculation 50% of the animals in the ICAM-1(-/-) group, but none of the controls, had died. Despite the high level of mortality, ICAM-1(-/-) mice developed less frequent and less severe arthritis than their wild-type littermates. In agreement, normal mice inoculated with staphylococci and administered anti-ICAM-1 antibodies exhibited a higher frequency of mortality but less severe arthritis than the controls. Our results indicate that ICAM-1 on the one hand provides protection against systemic disease but on the other hand aggravates the local disease manifestation. PMID- 8698514 TI - Role of calcium during lipopolysaccharide stimulation of neutrophils. AB - This study investigated the role of intracellular calcium concentration ([Ca]i) as a possible intermediate in the lipopolysaccharide (LPS) second messenger pathway for the activation of neutrophils (polymorphonuclear leukocytes [PMNs]). Isolated PMNs were loaded with the calcium-sensitive fluorescent dye fura-2. The PMNs were stimulated with either LPS or the positive control formyl-Met-Leu-Phe (fMLP). As expected, PMN exposure to fMLP increased [Ca]i. However, LPS stimulation did not induce any detectable changes. Depletion of intracellular Ca stores with thapsigargin, or extracellular Ca with EGTA, significantly inhibited the upregulation of the CD11b/CD18 integrin in response to fMLP but not LPS. We conclude that [Ca]i is not an early intermediate in the second-messenger pathway for the activation of PMNs by LPS. PMID- 8698515 TI - The urease enzyme of Helicobacter pylori does not function as an adhesin. AB - Helicobacter pylori urease is essential for colonization of the gastric mucosa irrespective of whether the stomach is acidic or hypochlorhydric. It has therefore been speculated that the enzyme functions as an adhesin. The aim of this study was to compare the adherence of H. pylori N6 with the adherence of an isogenic urease-negative mutant, strain N6(ureB::TnKm), to gastric cells. Strain N6 originated from a patient with gastritis. Strain N6(ureB::TnKm) is specifically modified in the gene which encodes the large subunit of urease, UreB, and hence does not form a UreA-UreB enzyme complex. We have used flow cytometry to assess the adherence of H. pylori to the cells. We have also used phase-contrast microscopy to assess the adherence of the organism to Kato III cells. In the absence of urea both strains bound to Kato III cells and to primary gastric cells. Binding of both strains to the cells occurred rapidly. The presence of urea in the incubation medium decreased the binding of strain N6 to the cells. This was due to a rise in the pH of the incubation medium, which caused loss of viability of the organism. Urea had no effect on the adherence of strain N6(ureB::TnKm). We conclude that the urease of H. pylori does not play a role in the adherence of the organism to gastric cells. PMID- 8698516 TI - T- and B-lymphocyte-independent formation of alveolar macrophage-derived multinucleated giant cells in murine Pneumocystis carinii pneumonia. AB - Multinucleated giant cells developed in Pneumocystis carinii-diseased gene disruption mutant mice deficient in major histocompatibility complex class II molecules, T-cell receptor alpha beta cells, or all mature T and B lymphocytes. These findings demonstrate lymphocyte-independent fusion of alveolar macrophages under morbid conditions. Pulmonary parasite burden seems to be a decisive factor in multinucleation. PMID- 8698517 TI - Structural and immunological characterization of Burkholderia pseudomallei O polysaccharide-flagellin protein conjugates. AB - The O-polysaccharide moiety of Burkholderia pseudomallei 319a lipopolysaccharide was covalently linked to flagellin protein isolated from the same strain. A glycoconjugate incorporating adipic acid dihydrazide as a spacer molecule elicited high-titer immunoglobulin G responses to both the protein and carbohydrate components of the construct. This immunoglobulin G was capable of protecting diabetic rats from challenge with a heterologous B. pseudomallei strain. PMID- 8698518 TI - Effect of Helicobacter pylori on gastric epithelial cell migration and proliferation in vitro: role of VacA and CagA. AB - Helicobacter pylori infection is associated with inflammation of the gastric mucosa and with gastric mucosal damage. In this study, we sought to test the hypothesis that two H. pylori virulence factors (VacA and CagA) impair gastric epithelial cell migration and proliferation, the main processes involved in gastric mucosal healing in vivo. Human gastric epithelial cells (MKN 28) were incubated with undialyzed or dialyzed broth culture filtrates from wild-type H. pylori strains or isogenic mutants defective in production of VacA, CagA, or both products. We found that (i) VacA specifically inhibited cell proliferation without affecting cell migration, (ii) CagA exerted no effect on either cell migration or proliferation, and (iii) undialyzed H. pylori broth culture filtrates inhibited both cell migration and proliferation through a VacA- and CagA-independent mechanism. These findings demonstrate that, in addition to damaging the gastric mucosa, H. pylori products may also impair physiological processes required for mucosal repair. PMID- 8698519 TI - Role of catechol siderophore synthesis in Vibrio vulnificus virulence. AB - We isolated a Vibrio vulnificus TnphoA mutant that was unable to produce catechol siderophores or to acquire iron from transferrin. This mutant showed reduced virulence in an infant mouse model. The TnphoA insertion was in an open reading frame designated venB. The venB gene cloned on a plasmid restored catechol production to the mutant. The deduced amino acid sequence of venB is 41% identical to the enzyme isochorismatase of Escherichia coli (EntB), an enzyme involved in the biosynthesis of the catechol siderophore enterobactin. PMID- 8698520 TI - Species-, serogroup-, and serovar-specific epitopes are juxtaposed in variable sequence region 4 of the major outer membrane proteins of some Chlamydia trachomatis serovars. AB - Synthetic peptides and murine monoclonal antibodies were used to map cross reactive chlamydial epitopes. A species-specific epitope in the central region of variable sequence region 4 abuts the amino-terminal end of a B-serogroup-specific or F/G-serogroup-specific epitope, which in turn abuts known serovar-specific epitopes. The carboxyl-terminal portion of variable sequence region 4 (residues 297 to 314) comprises a region of end-to-end B-cell epitopes in some serovars of the B and F/G serogroups. PMID- 8698521 TI - Repertoire of transcribed peripheral blood T-cell receptor beta chain variable region genes in acute rheumatic fever. AB - Patients with severe group A streptococcal infections have abnormalities in the Vbeta repertoire of peripheral blood T cells that are consistent with superantigen stimulation by cytoplasmic membrane proteins. The purpose of this study was to determine whether similar changes in Vbeta repertoire could be found for patients with acute rheumatic fever (ARF). The mean Vbeta repertoire of peripheral blood T cells in nine hospitalized ARF patients was similar to that of 34 controls and did not change during 6 months of follow-up in 6 of the ARF subjects. We were unable to detect changes in the Vbeta repertoire of peripheral blood T cells from patients with ARF that could be attributed to the influence of a superantigen. PMID- 8698522 TI - Purified capsular polysaccharide of Cryptococcus neoformans induces interleukin 10 secretion by human monocytes. AB - In this study, we demonstrated that purified capsular polysaccharide of Cryptococcus neoformans is a potent inducer of interleukin-10 (IL-10) secretion by human monocytes. Endogenous IL-10 was involved in regulating tumor necrosis factor alpha and IL-1beta secretion by human monocytes in response to encapsulated C. neoformans strains. Our results suggest a new immunosuppressive effect exerted by glucuronoxylomannan through the induction of IL-10, a potent downregulator of proinflammatory cytokines. PMID- 8698523 TI - Interleukin-10 protects neonatal mice from lethal group B streptococcal infection. AB - We investigated the role of interleukin-10 (IL-10) in a neonatal mouse model of lethal group B streptococci (GBS) sepsis. Plasma IL-10 levels significantly increased at 24 and 48 h after GBS inoculation. Neutralization of IL-10 with specific antibodies had no effect on lethality. Administration of recombinant IL 10 at 20 or 4 h before challenge, but not at later times, resulted in decreased tumor necrosis factor alpha levels and improved survival. IL-10 could be potentially useful for the treatment of GBS sepsis. PMID- 8698524 TI - Toxin-coregulated pilus, but not mannose-sensitive hemagglutinin, is required for colonization by Vibrio cholerae O1 El Tor biotype and O139 strains. AB - The relative contributions of toxin-coregulated pilus (TCP) and cell-associated mannose-sensitive hemagglutinin (MSHA) to the colonization ability of Vibrio cholerae O1 El Tor biotype strains and O139 Bengal strains was determined by using isogenic parental and in-frame deletion mutant pairs in the infant mouse cholera model. Both the El Tor and O139 tcpA mutant strains showed a dramatic defect in colonization as indicated by their competitive indices, whereas deletion of mshA had a negligible effect on colonization in either background. PMID- 8698525 TI - The GafD protein of the G (F17) fimbrial complex confers adhesiveness of Escherichia coli to laminin. AB - Escherichia coli IHE11088(pRR-5) expressing the G (F17) fimbria adhered to immobilized laminin as well as to reconstituted basement membranes. No adhesion was seen with the plasmidless strain IHE11088 or with the deletion derivative IHE11088(pHUB110), which expresses the G-fimbrial filament with a defective GafD lectin and lacks N-acetyl-D-glucosamine-specific binding. Adhesion of IHE11088(pRR-5) to laminin and to reconstituted basement membranes was specifically inhibited by N-acetyl-D-glucosamine, and adhesion was abolished after N-glycosidase F treatment of laminin. The results show that the GafD lectin binds to laminin carbohydrate and suggest a novel function for the F17 fimbria in binding to mammalian basement membranes. PMID- 8698526 TI - Chronic experimental Chagas' disease: functional syngeneic T-B-cell cooperation in vitro in the absence of an exogenous stimulus. AB - We have investigated CD4+ T-cell autoreactivity to normal syngeneic B cells in vitro in chronic experimental Chagas' disease. Resting B cells induced an intense proliferative response and lymphokine secretion by splenic CD4+ T cells from Trypanosoma cruzi-infected (8 months or more of infection) donors, compared to much lower responses by uninfected controls. On the other hand, lipopolysaccharide-activated B cells induced syngeneic CD4+ T-cell activation in both control and infected groups. The observed syngeneic T-B-cell cooperation was bidirectional. In the absence of any exogenous stimulus, CD4+ T cells from T. cruzi-infected animals induced much higher production of all tested immunoglobulin (Ig) isotypes (IgM, IgG1, IgG2a, IgG2b, IgG3) by syngeneic B cells, compared to T cells from uninfected donors. When lipopolysaccharide treated B cells were used, CD4+ T cells from either control or infected donors enhanced IgG1 and IgG3 production, but only CD4+ T cells of infected origin induced IgG2a production in this system without addition of exogenous gamma interferon. Enhanced T-cell proliferation and Ig production were also observed with highly purified CD4+ T cells and in serum-free medium. Both proliferation and Ig production could be blocked with anti-major histocompatibility complex class II monoclonal antibodies. Enhanced reactivity and help for Ig production were seen only in response to syngeneic BALB B cells and not in response to allogeneic B10 B cells. These results indicate that chronic infection with T. cruzi results in increased CD4+ T-cell reactivity towards syngeneic B cells, which leads to spontaneous Ig production. These autoreactive T cells might play a role in polyclonal autoantibody production in chronic Chagas' disease. PMID- 8698527 TI - Entry of Borrelia burgdorferi into macrophages is end-on and leads to degradation in lysosomes. AB - The Lyme disease spirochete, Borrelia burgdorferi, is ingested rapidly by mouse macrophages in vitro. Spirochetes attach by their ends and become progressively coiled as they move deeper into cells. From the earliest measurements, spirochetes colocalize with a marker of endosomes and lysosomes, and degradation of spirochetes occurs within lysosomes. PMID- 8698528 TI - Pulmonary damage by Vibrio vulnificus cytolysin. AB - Vibrio vulnificus is an estuarine bacterium that causes septicemia and serious wound infection. Cytolysin produced by V. vulnificus has been incriminated as one of the important virulence determinants of bacterial infection. Cytolysin (8 hemolytic units) given intravenously to mice via their tail veins caused severe hemoconcentration and lethality. Cytolysin treatment greatly increased pulmonary wet weight and vascular permeability as measured by (125)I-labeled albumin leakage without affecting those factors of other organs significantly. Blood neutrophils were markedly decreased in number after cytolysin injection, with a concomitant increase in the level of pulmonary myeloperoxidase activity, indicating that cytolysin-induced neutropenia might be due to pulmonary sequestration of neutrophils. By microscopic examination, severe perivascular edema and neutrophil infiltration were evident in lung tissues. These results suggest that increased vascular permeability and neutrophil sequestration in the lungs are important factors in lethal activity by cytolysin. PMID- 8698529 TI - Allelic exchange mutagenesis of nixA in Helicobacter pylori results in reduced nickel transport and urease activity. AB - Helicobacter pylori, an etiologic agent of gastritis and peptic ulceration in humans, synthesizes urease, a nickel metalloenzyme, as its most abundant protein. NixA, a high-affinity nickel transport protein, allows synthesis of catalytically active urease when coexpressed with H. pylori urease in an Escherichia coli host. To determine whether NixA is essential for the production of active urease in H. pylori, nixA was insertionally inactivated with a kanamycin resistance cassette (aphA) and this construct was electroporated into H. pylori ATCC 43504; allelic exchange mutants were selected on kanamycin-containing medium. The nixA mutation, confirmed by PCR, reduced urease activity by 42% (140 +/- 70 micromol of NH3/min/mg of protein in the mutant versus 240 +/- 100 micromol of NH3/min/mg of protein in the parent (P = 0.037). Rates of nickel transport were dramatically reduced (P = 0.0002) in the nixA mutant (9.3 +/- 3.7 pmol of Ni2+/min/10(8) bacteria) of H. pylori as compared with the parent strain (30.2 +/- 8.1 pmol of Ni2+/min/10(8) bacteria). We conclude that NixA is an important mediator of nickel transport in H. pylori. That residual nickel transport and urease activity remain in the nixA mutant, however, provides evidence for the presence of a redundant transport system in this species. PMID- 8698531 TI - Prospects for prostatic cancer incidence and treatment by the year 2000. PMID- 8698532 TI - High and unchanged sperm counts of Finnish men. AB - Several recent reports have suggested that the sperm counts of normal men are declining in most countries. In this study the sperm counts of Finnish men, and their possible changes during the past 28 years, were investigated. The material consisted of semen samples from 238 normal healthy men of unknown fertility and 5481 men from infertile couples. The means (medians) of semen volume, sperm density and total sperm count in normal men were 3.3 (3.0) ml, 133.9 (94.0) x 10(6)/ml and 396.6 (309.0) x 10(6), respectively. These parameters and the relative frequency distribution of the sperm density were similar to those reported elsewhere in the 1940s. Multiple linear regression analysis revealed a significant decrease in semen volume, whereas sperm density and total sperm count of infertile men had not changed significantly during the past 28 years. In addition, no change in sperm counts was associated with the year of men's birth. PMID- 8698530 TI - The Hha protein as a modulator of expression of virulence factors in Escherichia coli. AB - We constructed hha derivatives from both a clinical uropathogenic Escherichia coli isolate (strain FVL4) and a wild E. coli strain causing bovine diarrhea (strain CCB21) and analyzed the effect of the hha allele on the expression of the different virulence factors exhibited by these strains. Expression of hemolysin and of the Vir antigen was altered in hha mutants. Whereas production of hemolysin by strain FVL4 was repressed both at a low temperature and at high osmolarity, the hha allele accounted for a significant increase of hemolysin production under these conditions. Also, the low temperature-sensitive expression of the Vir adhesin was modified in hha mutants, which were able to express this adhesin at a low temperature. Expression of other virulence factors, such as cytotoxic necrotizing factor type 1 and 2 toxins, remained unmodified in hha derivatives of strains FVL4 and CCB21. PMID- 8698533 TI - Validation of a scoring method predicting the in-vitro fertilizing ability of human spermatozoa. AB - The fertilizing ability of human spermatozoa depends upon numerous functions such as motility, normal morphology, ability to bind to the zona pellucida and to undergo the acrosome reaction. Hence a lot of tests have been developed to try and predict IVF results. In a previous study we had established a scoring method, based on parameters such as sperm morphology, vitality, motility and the acrosome reaction, which was able to predict up to 83% of in-vitro fertilization results. The present study aimed to validate this score on a separate set of sperm samples. The results confirmed those of the first series. The score allowed prediction of fertilization failures with a 56% sensitivity, a 91% specificity, a 56% positive predictive value and a 91% negative predictive value. Therefore, this score could be used routinely to choose between conventional IVF and ICSI. PMID- 8698534 TI - Chromomycin A3-staining as an indicator of protamine deficiency and fertilization. AB - Mature mammalian spermatozoa have a compact and stable nuclear structure conferred by protamines instead of histones, which are present in all other cellular types. Chromomycin A3 (CMA3) is a useful tool for the detection of protamine deficiency in sperm chromatin. The purpose of this study was to correlate the percentage of spermatozoa staining positively for CMA3 with sperm parameters and in-vitro fertilization of human oocytes. Spermatozoa were collected from 56 fertile and 18 infertile men, and washed twice in PBS, fixed in two changes of methanol : acetic acid (3 : 1 v : v) spread on rinsed slides treated with APES and dried. Twenty-four of the semen samples were subjected to both Percoll and swim-up, and were stained subsequently with CMA3. CMA3-stained spermatozoa were expressed as a percentage in a count of 200 spermatozoa. A substantial variation in the percentage of CMA3-stained cells was observed in ejaculated human spermatozoa, varying between 8% and 77%. A strong negative correlation (r = -0.64, p < 0.001) was found between sperm count and the percentage of CMA3-stained spermatozoa. No correlation was found between CMA3 stained spermatozoa and their motility, while excessive sperm morphological abnormalities were related positively to CMA3-staining. Spermatozoa in samples exhibiting low (8-62%) CMA3-staining had significantly higher fertilizing rates in vitro than did samples exhibiting high (49-77%) CMA3-staining. The mean percentage of CMA3-stained spermatozoa after swim-up or Percoll preparation (26% vs 31%) did not differ significantly. These results demonstrate a close relationship between CMA3-staining, fertilization and sperm count, and suggest potential application of this marker for the prediction of sperm quality and fertilizing capacity. PMID- 8698535 TI - Long-term intracavernous self-injection with prostaglandin E1 for the treatment of erectile dysfunction. AB - Intracavernous self-injection with vasoactive drugs has become a widely accepted treatment for erectile dysfunctions (ED). Sixty-eight patients affected by ED have been followed during long-term (at least 1 year) treatment with intracavernous prostaglandin E1. Each patient underwent a penile dynamic ultrasound examination using a high-definition probe (13 MHz) before and during the treatment. The drop-out rate was 8.8%. An improvement in spontaneous erections was reported by 13% of patients. The onset of fibrotic nodules occurred in three (4.4%) patients. In one of the latter cases the occurrence of nodules could be related to the frequency and dose of the drug administered, whereas in the other two cases no such correlation could be hypothesized. These findings draw attention to this possible side-effect of long-term treatment with PGE1. PMID- 8698537 TI - Effects of progesterone on human spermatozoa prepared for in-vitro fertilization. AB - Progesterone has been tested in vitro with human spermatozoa to verify its physiological effects and its possible therapeutic use in cases of male infertility. Progesterone induced a rapid, dose-dependent influx of calcium in capacitated and non-capacitated spermatozoa with a half-maximally effective dose of 30 nM. The agonist, 19-nortestosterone, was much less potent that progesterone itself. Progesterone-induced calcium influx was not inhibited by a similar concentration (0.1 microgram/ml) of RU 486, a classical progesterone antagonist. The increase in intracytoplasmic calcium levels was unable to induce the acrosome reaction (AR) even after incubation for 5 h, when this was evaluated by double staining, using a monoclonal antibody GB24 raised against the inner acrosome membrane and ethidium homodimer as a vital probe. However, after incubation for 5 h, progesterone was able to enhance the tyrosine phosphorylation of a 95 kD sperm protein, which is phosphorylated progressively during capacitation in well defined culture media. Incubation of spermatozoa with 1 or 10 micrograms/ml progesterone for 3 or 30 min did not induce major modifications of hyperactivated movement when analysed by computer-assisted semen analysis. Progesterone secreted by cumulus cells may physiologically increase sperm intracytoplasmic free calcium during capacitation. This priming effect may facilitate the acrosome reaction, induced by binding to the zona pellucida, without enhancing spontaneous acrosome reaction prematurely. It therefore seems useful to propose progesterone as a means of accelerating capacitation during in vitro fertilization in cases of male infertility. PMID- 8698536 TI - Electrovasography in normal and vasectomized men before and after vasectomy reversal. AB - The electrical pattern of the vas deferens, or electrovasogram (EVG), was studied in 22 healthy volunteers, 20 vasectomy subjects and 18 individuals after vasectomy reversal. Their mean ages were 38.8 +/- 7.3, 44.3 +/- 7.9 and 58.6 +/- 6.6 years, respectively. Two electrodes were applied to the posterior aspect of the upper part of the scrotum. During the operation of vasectomy reversal, an electrode was applied directly to each of the two vasal segments before and immediately after vasovasostomy. The electrical activity and intravasal pressure were measured. In normal subjects, slow waves or pacesetter potentials (PP) were recorded. They had identical frequency and a regular rhythm from the two electrodes and were consistent in the individual subject on all test days. PP were followed randomly by bursts of action potentials (AP). In vasectomized subjects, PP from the proximal vasal segment exhibited an irregular rhythm (vasoarrhythmia). During operation for vasectomy reversal, the proximal vasal segment recorded vasoarrhythmia whereas the distal segment revealed a silent EVG. Intravasal pressure was normal (p > 0.05) in the distal segment but high (p < 0.05) in the proximal segment. EVG performed 1-6 years after vasectomy reversal showed a normal pattern in four subjects and diminished frequency and amplitude in three. These seven subjects had impregnated their wives and had an obstructive interval of < 3 years. The 11 subjects who did not produce a pregnancy had a vasoarrhythmic EVG and an obstructive interval of > 3 years. In conclusion, an EVG could be identified for normal subjects. Vasectomy resulted in a vasoarrhythmic EVG pattern which proved to be correctable by vasectomy reversal if the obstructive interval was short. PMID- 8698538 TI - Prolactin and testosterone: their role in male sexual function. AB - The role of androgens in the sexuality of men is still not completely clear. Men with severe hyperprolactinaemia frequently show mild hypogonadism, and many complain of loss of libido and penile erectile dysfunction (ED). We studied the night-sleep related erections and the penile response to visual erotic stimuli (VES) in 44 men: 13 with severe hypogonadism (Group 1; serum testosterone < 1.4 ng/ml), 10 with mild hypogonadism (Group 2; serum testosterone 2-3.5 ng/ml), nine with severe hyperprolactinaemia and mild hypogonadism (Group 3) and 12 control men (Group 4). All of the patients complained of loss of libido and ED. Group 1 showed significantly impaired night erections when compared with any of the other three groups, but no differences were detected between Groups 2, 3 and 4. The penile response to VES did not show any significant difference between the four groups, but was lower in Group 1 than in Group 4. These data confirm that night erections are androgen-dependent, but also suggest that there are two thresholds for serum testosterone: one below which sexual behaviour is impaired with normal night erections, and a lower threshold below which night erections are also impaired. The penile response to VES was confirmed as being only partially androgen-independent. Furthermore, hyperprolactinaemia does not affect night erections or the penile response to VES, suggesting that its effect on libido and sexual behaviour is due mainly to modulation of the psychological pattern of the patient. PMID- 8698539 TI - The combination of two semen preparation techniques (glass wool filtration and swim-up) and their effect on the morphology of recovered spermatozoa and outcome of IVF-ET. AB - The aim of this prospective study was to relate sperm quality, especially sperm morphology, to the outcome of IVF results, when glass wool filtration (GWF) and swim-up were used in combination for the preparation of spermatozoa. A total of 60 ejaculates were analysed. GWF was compared with glass wool filtration/swim-up (GWF-SU) by using aliquots from the same semen samples to increase the precision of the comparison and to establish the cumulative effect of these two semen preparation methods on the morphology of the recovered spermatozoa. Sperm parameters were examined in native semen, in semen preparation samples after GWF and GWF-SU. The mean percentages for motility, morphology and velocity were improved significantly over those in fresh semen only when GWF-SU was used. GWF alone resulted only in a significantly higher recovery of motile spermatozoa. In semen preparation, 10% of spermatozoa with normal morphology appeared to be the cut-off point as there was a significantly higher recovery in fresh semen samples containing > 10% morphologically normal spermatozoa after GWF-SU. Outcome of IVF ET following preparation with GWF-SU showed better results in comparison to the swim-up procedure alone, though this difference was not statistically significant. The cut-off point was also > 10% morphologically normal spermatozoa. Improvement in all aspects of IVF-ET occurred when native semen contained > 10% morphologically normal spermatozoa. It is concluded that GWF alone did not produce significantly better results but, in combination with swim-up, it resulted in significantly better sperm morphology and in an improved outcome of IVF-ET for fresh semen samples with > 10% morphologically normal spermatozoa. PMID- 8698540 TI - RU486 inhibits penetration of human spermatozoa into zona-free hamster oocytes. AB - Previous studies have shown that RU486 decreases the concentration of intracellular calcium ([Ca2+]i) in human spermatozoa in vitro and partially antagonizes the effect of progesterone on calcium influx and sperm acrosome reaction. The present study has examined the effect of RU486 on the penetration of human spermatozoa into zona-free hamster oocytes. RU486 (10 microM) decreased significantly the rate of penetration of zona-free hamster oocytes by human spermatozoa, and nearly abolished penetration when present in the medium at concentrations of 50 and 100 microM. RU486 must be present in the medium to exert its inhibitory effect. At the same concentration (10 microM) as RU486, progesterone was unable to reverse the inhibitory effect of RU486 on the penetration rate of human spermatozoa. PMID- 8698541 TI - Vitamin C and human health--a review of recent data relevant to human requirements. AB - The recent scientific literature indicates that beyond merely protecting against scurvy vitamin C contributes to many aspects of human health. The main areas of research reviewed include: 1. Vitamin C requirements of smokers. The data indicate that the vitamin C requirement of smokers is higher by at least 60 mg per day (up to 140 mg per day) than that of nonsmokers. 2. Important functions of the body, such as immune response, pulmonary function, and iron absorption are related to vitamin C intakes. Daily vitamin C intake of at least 150-200 mg per day enhance these functions. 3. Vitamin C may play critical roles in the prevention of CHD, cancer and cataract. Based on the available data, vitamin C intakes of at least 80-120 mg per day are associated with lowering the risk of these chronic diseases. 4. The literature documents that these and much higher intake levels of vitamin C are safe. PMID- 8698542 TI - Intermediate cancer biomarkers and their use in beta-carotene studies in humans. AB - The most effective means of avoiding the development of squamous cell carcinomas is the elimination of risk factors such as tobacco smoke and alcohol and of exposure to occupational and dietary carcinogens. In addition, chemoprevention by micronutrients such as beta-carotene may be promising. However, studies verifying such effects using cancer incidence or mortality as study endpoint are extremely costly of financial and manpower resources. Therefore, premalignant intermediate biomarkers such as histological lesions (dysplasias/leukoplakias/ polyps), genetic changes (DNA damage, mutations) or enzymatic changes (protein kinase C or ornithine decarboxylase activation) are increasingly being used as surrogate endpoints. Even though most preneoplastic biomarkers still need to be verified and shown to be linked to malignancy, their use in clusters may enhance their predictability. In human trials beta-carotene has reversed some lesions such as micronuclei, leukoplakias and dysplasias in the oral cavity, whereas other lesions, e.g. colorectal polyps (i.e. their recurrence after resection) have not been found to respond. But proliferation markers in the colon mucosa have been modified by beta-carotene. Preliminary findings are also available of a potential reduction of esophageal dysplasias in a high-risk Chinese population and of cervical dysplasias in a group of American women. The available beta-carotene data are sufficiently encouraging to justify continuation of trials using intermediate cancer markers. PMID- 8698543 TI - Absorption of retinyl acetate in laying hens. AB - Absorption of retinyl acetate (RA) was studied in hens. Animals (n = 10-10) received 12.5-,25-,50-,100-,150-,200-,250- and 300 x 10(3) IU of RA in capsules (p.os). Before treatment (0) and 2nd, 4th, 6th and 8th hours later, as well as on the following day blood samples were taken for retinoid analysis. Vitamin A peaks were detected in the blood in the 4th hour. The alterations in the plasma vitamin A levels were caused basically by the elevations of the retinyl ester (RYL) fraction. The proportion of RYL was 7-27% of the total plasma vitamin A value in all groups at the time of RA administration (0 h). This RYL ratio was elevated parallel to RA doses, and in case of higher doses reached 80-90% (4th h). It has been found that the efficiency of RA absorption, in hens, is in inverse ratio to the dose that is used. The calculated relative absorption coefficients of efficiency have a close negative correlation (r = -0.89; p < 0.01) to the doses. Relationship between the maximum plasma retinoid concentrations and the dose/metabolic body mass can be fitted to the saturation function. It seems reasonable to conclude that in hens the absorption of retinol is an enzyme dependent and/or carrier mediated process even in cases of pharmacological doses. PMID- 8698544 TI - Effect of vitamin K2 on experimental calcinosis induced by vitamin D2 in rat soft tissue. AB - The effect of vitamin K2 on calcium (Ca) and inorganic phosphorus (P) levels in the aorta and kidney obtained from experimental calcinosis induced by vitamin D2(2.5 x 10(5) I.U./ kg b.w.) of male rats was investigated. A high dose of vitamin K2 (100 mg/kg b.w.) inhibited the increase in the aortic Ca and P or in the renal Ca and P induced by vitamin D2, and a low dose of vitamin K2 (10 mg/kg b.w.) showed the same tendency, but the degree of the efficacy was small. It may be suggested that a high dose of vitamin K2 suppressed experimental calcification of soft tissues induced by vitamin D2. Therefore, a pharmacological dose of vitamin K2 might have a usefulness for the prevention and treatment of arteriosclerosis with calcification. PMID- 8698545 TI - Comparative effectiveness of vitamin D3 and dietary vitamin E on peroxidation of lipids and enzymes of the hepatic antioxidant system in Sprague--Dawley rats. AB - The vitamin D-endocrine system has mostly been studied for its role in calcium and phosphorus metabolism and its possible role as an antioxidant has been neglected. This study attempts to elucidate the antioxidative properties of the prohormone with respect to vitamin E, a membrane antioxidant. Results herein show that D3 treatment brought about similar reduction in the extent of lipid peroxidation and induction in superoxide dismutase (SOD) activity, as with vitamin E supplementation. While selenium dependent glutathione peroxidase (Sedep. GPx) activity reflected no change with vitamin D3 treatment, total GPx activity was more significantly influenced by vitamin D3 than by vitamin E. The glutathione (GSH) content in the experimental rats also reflected similar changes. Vitamin E supplementation caused 8.57% increase in glutathione reductase (GR) activity, while vitamin D3 decreased the concerned enzymes activity by 11.11%. Vitamin D3 treatment also caused 25% increase in glucose 6-phosphate dehydrogenase (G6PD) activity. These data thus suggest that vitamin D3 may function as an antioxidant in the liver in vivo and illustrate an effectiveness higher than that observed with vitamin E supplementation. PMID- 8698546 TI - Early effect of a low dose (30 micrograms) ethinyl estradiol-containing Triphasil on vitamin B6 status. A follow-up study on six menstrual cycles. AB - The objectives of the study were to follow-up six artificial menstrual cycles induced by Triphasil in order to determine: 1) the time of apparition of B6 metabolic side-effects, in the eventuality they occur, and 2) the existence or non-existence of a normalization process and if so, when it is initiated. The choice of this triphasic OC preparation was based on its current popularity among modern gynecologists. Among the selected twenty-three young women who had never used oral contraceptives (OC), fourteen consented to try a new contraceptive method. Their nutritional status including anthropometric, hematologic, biochemical and dietetic (including vitamin B6 intake) parameters was found to be adequate. A functional enzymatic test coupled to a direct measurement of vitamin B6 was employed to obtain a complete assessment of their vitamin B6 status. By using both approaches, only one case (7%) of deficiency due to OC was evidenced. This well-controlled study revealed that a short-term use of a relatively low dose estrogen-containing OC (30 micrograms) did not alter PLP concentrations in plasma and erythrocytes in the majority of our young subjects consuming adequate diets. However, a disturbance in vitamin B6 metabolism was detected. PL levels in both blood components have increased steadily and did not subside to pretreatment values at the end of the experiment. In conclusion, the single use of the PLP vitamer can be misleading as demonstrated by other investigators. To assess B6 status during oral contraception, in addition to a functional enzymatic test, it may be necessary to include the other aldehydic form of vitamin B6, to fully establish and comprehend hormone-induced adverse effects on this metabolism, particularly those of progesterone/progestin that have not yet been explored. PMID- 8698547 TI - The effect of preconceptional multivitamin supplementation on fertility. AB - A significantly higher rate of conceptions occurred after preconceptional multivitamin supplementation in comparison with a placebo-like trace element supplementation in the Hungarian randomised, double-blind, controlled trial. This difference was explained by 5% shorter time in the achievement of conception. PMID- 8698548 TI - Calcium absorption in rats with distal intestinal resection: influence of type of dietary fat, cholecalciferol and nature of the adaptative response. AB - The effects of dietary fat and supplementation with cholecalciferol on calcium absorption at different luminal concentrations (2.07 mmol/l and 2.07 mmol/l with 0.5 mmol/l 2,4-dinitrophenol and 8.20 mmol/l) were studied in vivo in the perfused duodenum, residual jejunum and proximal colon of rats with resection of 50% of the distal small intestine, as well as the nature of the adaptative response (passive or active). Changing the source of dietary fat (diet B, containing 1/3 medium chain triglycerides, 1/3 olive oil, 1/3 sunflower oil) increased calcium absorption, preferentially via active transport, in both transected and resected rats. Supplementation of diet B with cholecalciferol further enhanced intestinal calcium absorption, especially in the colon. These results suggest the importance of diet in the adaptive processes and confirm that active mechanisms of transport adapt more readily to intestinal resection than do passive mechanisms. PMID- 8698549 TI - The contribution of dietary iron to iron status in a group of elderly subjects. AB - Although it is widely accepted that body iron stores of elderly individuals are largely adequate, recent findings from our laboratory suggest that as many as 9% of a "healthy" sample showed signs of an inadequate body store of this nutrient. In an attempt to see if iron consumption may be a contributing factor, we compared dietary intakes of total iron, heme iron, nonheme iron, ascorbic acid, calcium, dietary fibre, tea and coffee between 19 healthy seniors with inadequate iron stores and 108 healthy seniors with good iron status. The daily consumption of total iron was significantly higher in those with good iron stores. Thus, dietary iron is an important contributor to iron status in old age. PMID- 8698550 TI - Micronutrient status in elderly people. Geriatrie/Min. Vit. Aux Network. AB - A biochemical assessment of the vitamin and trace element status of 756 institutionalized elderly men and women, 66-103 years old (average 83.5 +/- 7.6 y), was conducted in 26 nursing homes in different areas of France. Serum concentrations of beta- and alpha-carotene, beta-cryptoxanthin, lycopene, retinol, alpha- and gamma-tocopherol, vitamin C, zinc and selenium were measured. A difference in biochemical markers according to sex was observed for vitamins E and C: elderly women had higher levels of alpha-tocopherol and vitamin C than elderly men. When expressed as a ratio of cholesterol, the difference between sexes for alpha-tocopherol disappeared. Simple regression analysis showed that most vitamins and trace elements were significantly negatively correlated with age. A high prevalence of low concentrations of vitamin C, zinc and selenium was revealed. PMID- 8698551 TI - In vitro measurement of beta-carotene cleavage activity: methodological considerations and the effect of other carotenoids on beta-carotene cleavage. AB - In view of controversies about assessment of the beta-carotene cleavage activity, methodological aspects and problems of the dioxygenase assay are described. Using rat and hamster intestinal preparations the method was optimized on retinal formation, the only cleavage product we could demonstrate. It appeared that the cell fraction with the highest cleavage activity was the 9,000 g supernatant (S 9). Maximal retinal formation was obtained with SDS, taurocholate and egg lecithin in the buffer and 3 micrograms beta-carotene dissolved in acetone. Ethanol, THF/DMSO (1:1) or propylene glycol as solvent for beta-carotene reduced retinal formation to 55, 24, and 19%, respectively. Retinal formation increased proportionally with the amount of protein S-9 used and was linear up to 40-60 minutes of incubation. Incubation with alpha-carotene or beta-cryptoxanthin resulted in a retinal formation of 29 and 55% of the amount formed from beta carotene. Addition of 9 micrograms of lutein to an incubation with 3 micrograms beta-carotene reduced retinal formation, while lycopene had no effect. In conclusion, the beta-carotene cleavage assay with S-9 as enzyme source described in this report, seems a useful tool to study (dietary) determinants of beta carotene cleavage activity, but for other purposes adaptation of the method is required. PMID- 8698552 TI - Effects of low concentrations of dietary cobalt on rumen succinate concentration in sheep. AB - Sheep fed diets containing less than 70 micrograms Co per kg develop vitamin B12 deficiency. When sheep were fed diets containing 20 micrograms Co per kg or less, mean rumen succinate concentrations increased by more than one hundred-fold within 2 days. This increase was matched by an equimolar decrease in mean rumen propionate concentrations. When diets containing more than 20 micrograms Co per kg were fed to sheep, no such changes occurred. The synthesis of succinyl CoA from propionyl CoA in liver is impaired in ovine cobalt deficiency. We suggested that, paradoxically, accumulation of rumen succinate could reduce the effects of vitamin B12 deficiency on methylmalonyl CoA mutase and consequently result in lower plasma methylmalonic acid (MMA) concentrations than would arise by feeding diets that did not affect rumen succinate concentrations. This hypothesis was tested by feeding diets containing 4, 40 and 1000 micrograms Co per kg to sheep for 23 weeks. However, sheep fed 40 micrograms Co per kg did not have mean plasma MMA concentrations that were higher than those in the sheep fed 4 micrograms Co per kg, indicating that rumen succinate accumulation did not ameliorate the effects of Co deficiency. PMID- 8698553 TI - Radiologic evaluation of simultaneous pancreas-kidney transplantation. AB - We describe the radiographic imaging modalities that were used in the first twelve consecutive patients who have undergone simultaneous pancreas and kidney transplantation (SPK) at our institution. The total number of examinations undertaken in this study included ultrasound (n = 22), radionucleide scanning (n = 19), cystography (n = 14), computed tomography (n = 2) and magnetic resonance imaging (n = 1). Eighteen percent (5/22) ultrasound examinations were abnormal (perirenal collection [n = 4], peri-pancreatic collection [n = 1]. Two collections required aspiration and were confirmed as lymphocoeles. Cystography showed ureteric reflux in two patients and radionucleide DTPA scanning revealed a delay in the excretory phase in 20% of patients. CT was used in two patients with SPK and demonstrated large peri-pancreatic collections. No episodes of rejection or late graft pancreatitis were noted in this series. We discuss the role of radiographic imaging in detecting early graft failure and also in defining the surgical complications that may arise following transplantation. We also outline the merits and disadvantages of each imaging modality. We conclude that the most useful initial imaging techniques in the evaluation of patients following SPK are ultrasound including Doppler and nuclear medicine. PMID- 8698554 TI - Changing trends in acute peptic ulcer surgery in a district surgical unit. AB - Despite changes in management and the advances in therapeutics, surgeons are still required to treat the complications of peptic ulceration. A retrospective review of all open surgical interventions for complications of peptic ulcer disease between January 1983 and December 1993 was carried out. There were no exclusion criteria. Open gastric surgery accounted for 3% of all inpatient surgical procedures and 13% of all the major operations. There were 341 adult and 132 paediatric procedures performed in the 11 year period. Acute gastric procedures accounted for 34% of major gastric surgery in this district unit. 76 perforated ulcers and 39 bleeding ulcers required surgery. 38% of the patients were over 70 years. The perioperative mortality was 13.9% (4% for those under 70 years). The overall morbidity rate was 71% and procedure-related morbidity rate was 17%. Acute gastric surgery has a very high inpatient morbidity and is associated with a significant mortality particularly in elderly patients. PMID- 8698555 TI - The rapid reversal of profound hypothermia using peritoneal dialysis. AB - Severe hypothermia is associated with serious patient morbidity and mortality. The groups most frequently affected are the elderly, the very young and substance abusers. We describe three such cases which were successfully treated using warmed peritoneal dialysis. Two patients recovered completely and were left with no long term deficits. The third patient recovered from the acute event, but succumbed later to an underlying medical condition. Warmed peritoneal lavage is an efficient, cost effective approach which is easily performed without specialist equipment, and involves minimal risk to the patient. PMID- 8698556 TI - Infantile hypertrophic pyloric stenosis: long-term audit from a general surgical unit. AB - This article describes a 22 year experience of a general surgical unit in the treatment of infantile hypertrophic pyloric stenosis (IHPS). The hospital course of 229 IHPS patients is reviewed. The male:female ratio was 3.6:1, median age 6 weeks (range 2-26 weeks) with a positive family history in 8.3%. The diagnosis of IHPS was established clinically by palpation of a "pyloric tumour" during a pre operative test meal/clinical examination in 92.6%; in the remainder, the diagnosis was made radiologically. Ramstedt's pyloromyotomy was performed within 5 days of admission in 74% of patients and within 10 days of admission in 89%. The median post-operative hospital stay was 10 days (range 3-60 days). Wound morbidity occurred in 10.0% wound infection (7.3%) and wound dehiscence (2.6%). However, wound morbidity was reduced in the second half of the series, partly by greater utililisation of non-absorbable suture in place of chromic catgut for wound closure. Mucosal penetration was suspected in 14.8% of cases. Repeat pyloromyotomy was necessary in 1.3%. One baby died (0.4%)- this was in the early part of the series and was directly attributable to fluid and electrolyte disorder. We conclude that Ramstedt's pyloromyotomy for infantile hypertrophic pyloric stenosis can be performed with acceptable morbidity and minimal mortality in a general surgical unit. PMID- 8698557 TI - Spinal claudication versus arterial claudication. AB - Ninety-three consecutive treadmill exercise stress test were performed for the assessment of peripheral vascular function. Thirty-one were for atypical claudication-like symptoms including pain on standing, relief on sitting and back pain. Pedal pulses were palpable in 24 patients. Twenty-five patients (81%) had a negative stress test, suggesting a non-vascular aetiology and this finding was subsequently confirmed in 24 of the 25. The final diagnoses were spinal stenosis 13, [CT = 3, myelogram = 5, neurosurgeon opinion = 4, MRI = 1], myositis 2, restless leg syndrome 2 and osteoarthritis 7. Four patients had symptoms due to a combination of peripheral occlusive arterial disease and spinal stenosis; the latter was considered the predominant disorder in all four. Of the original 31 patients with atypical symptoms, spinal stenosis was present in 13 (42%). Atypia- in the common syndrome of intermittent claudication should alert the surgeon to the possibility of spinal canal disorders. Further investigation may identify significant pathology spinal stenosis in particular. PMID- 8698558 TI - Diagnostic and therapeutic ankle arthroscopy. AB - Ankle arthroscopy has grown in popularity over the past decade as a diagnostic and therapeutic procedure. We assessed 24 patients who underwent ankle arthroscopy during the two year period 1991-1993. In 18 cases a mini-arthrotomy was performed based on the arthroscopic findings. All patients were reviewed at an average of 26 months and a detailed evaluation was carried out according to an objective scoring system which grades five parameters; pain, swelling, stiffness, limp, and activity level. Twenty-two patients (92%) had good or excellent results. There were two complications transient tarsal tunnel syndrome and reflex sympathetic dystrophy. There were no neurovascular complications. This series represents an initial experience and illustrates that ankle arthroscopy provides a safe and effective method of diagnosis and treatment with few complications. Further advances in instrumentation and distraction techniques will reduce the need for open arthrotomy and should expand the indications for the procedure. PMID- 8698559 TI - Reconstruction of major nasal defects. AB - Advanced nasal skin tumours are not uncommon and can be cured with aggressive wide excision. Nasal defects can be reconstructed using a variety of surgical techniques. The principles of nose reconstruction are the creation of a new nasal lining, skeletal framework and skin cover. This paper discusses some of the procedures used in nasal reconstruction and specifically those used in the management of four patients with nasal tumours who recently had surgery in our unit. The objective in nasal cancer surgery is cure by wide excision as even total amputation can be reconstructed with very satisfactory results. PMID- 8698560 TI - Lipid profile, haemostatic variables and angiographically-defined coronary artery disease: a cross-sectional study in an Irish population. AB - More than 300 risk factors for coronary artery disease (CAD) have been described. There are important geographical and racial differences in both the prevalence of CAD and of potential risk factors. The purpose of this study was to determine the relationship between both the presence and extent of angiographically defined CAD in an Irish population and a spectrum of clinical risk factors, lipid profile and haemostatic variables. On univariate analysis, age, male gender, history of smoking, history of hypertension, total cholesterol, triglycerides, LDL, Cholesterol, the LDL:HDL ratio, apoprotein B-100 and the apoprotein B-100: A-II ratio were associated with the presence of CAD. However, in multivariate analysis only age, male gender, a history of smoking and the apoprotein B-100: A-II ratio remained significantly associated with the presence of CAD. These same risk factors and apoprotein B-100 were significantly associated with the extent of CAD on multivariate analysis. In addition, apoprotein B-100 levels appeared to be associated with disease extent. When all significant variables associated with the presence or extent of CAD were analysed together in a multivariate model, they only accounted for 28% of the variability in the distribution of CAD. Thus, advancing age, male gender, cigarette smoking and apoprotein B-100 appear to be important correlates of the presence and extent of CAD in this selected population. However, in individual patients most of the variability in the distribution of occlusive CAD remains unexplained. PMID- 8698562 TI - An unusual cause of otalgia--an ossified stylohyoid ligament. AB - Otalgia is often related to pathology in areas of the head and neck apart from the ear. This is due to the rich innervation of the ear via the fifth, seventh, ninth and tenth cranial nerves and the cervical plexus. It is estimated that 50% of ear pain is referred from non-otologic sites. A case is reported where otalgia was due to the presence of a bone in place of a ligament in the neck and was relieved by its removal. PMID- 8698561 TI - Colocalisation of human immunodeficiency virus and human cytomegalovirus infection in brain autopsy tissue from AIDS patients. AB - We have examined 26 human AIDS brains obtained at post mortem for infection by human immunodeficiency virus (HIV) and human cytomegalovirus (HCMV), and for dual infection of cells by both viruses. The techniques used were enzyme-linked immunocytochemistry for HCMV and in situ hybridisation using a cDNA probe for HIV. Using these techniques, HCMV infection was detected in 14 brains, HIV infection in 14 brains, and coinfection with HIV and HCMV in 7 brains. Four case of dual HIV/HCMV infection were found where no colocalisation could be detected. In randomly chosen dually infected areas 19.2% of infected cells were coinfected with both viruses. Although cells identified morphologically as macrophages were the most common infected cell type, astrocytes and neurons were both singly and doubly infected with HIV and HCMV. Complete clinical data were available for 4 of the 7 cases with coinfection and each had AIDS dementia complex. PMID- 8698563 TI - Appropriateness of laboratory tests: requests for atypical pneumonia serology in a teaching hospital. AB - The cost of providing medical care is ever-increasing but the resources available are at best static. Major savings can be made by reducing inappropriate investigations. Using serological testing for organisms causing atypical pneumonia as an example, we examined the appropriateness of requests and also physicians' understanding of the test. Of 119 patients tested, only 3 had titres indicative of acute infection. Most patients were tested within 2 days of hospital admission, before receipt of results excluding more likely diagnoses. Forty-five patients had no current or recent respiratory symptoms, in whom infection was highly unlikely. Titres were most often requested by the least experienced members of the clinical team. Of 70 patients with an acute illness in whom a definitive diagnosis, bacteriological or otherwise, was not made, in only 9 was a convalescent specimen sent for follow-up titres. Most requests for serology for organisms causing atypical pneumonia were inappropriate. Furthermore, in the majority of cases the test was incorrectly used. PMID- 8698564 TI - Who best assesses Crohn's disease? AB - Knowledge of the presence and the degree of inflammation in Crohn's disease would be useful in multicentre therapeutic trials. Objectives; The purpose of the present study was two fold, a) to determine the relationship between clinical assessment of activity by two clinicians with four previously published indices, the Crohn's disease activity index (CDAI), the Van Hees activity index (AI), the simple index of Harvey and Bradsaw (SI) and the Fielding index and b) for the first time, to study the internal correlation between these four indices. METHODS: A hundred and ninety-four assessments were performed on 56 patients with Crohn's disease. Following each clinical assessment, the aforementioned indices were calculated. RESULTS: Both clinicians gave the same rating of activity in 81% (157) of assessments. A good relationship was observed between the median indical values and the clinical gradings for all four indices. The best relationship was demonstrated with the AI with no overlap in 50% values with increasing grades of disease activity. All four indices demonstrated a good correlation with each other (p < 0.01). The best correlation was observed between more objective indices the AI and the Fielding index (r = 0.79) for first assessments only. Conclusion. The Van Hees AI is a reliable measure of inflammatory activity in Crohn's disease and would be useful in multicentre therapeutic trials. PMID- 8698565 TI - Trauma outcomes: a death analysis study. AB - Survival and mortality outcomes for trauma patients admitted to Liverpool Hospital, Sydney were analysed to determine the adequacy of trauma care. TRISS and ASCOT survival probabilities and peer review were utilised to determine if deaths were avoidable. Evaluation methods were compared for assessment of care. During the study period 2205 trauma patients were admitted, 518 of which fulfilled the study entry criteria. There were 38 deaths. The age and Injury Severity Score (ISS) of survivors was 34 +/- 18 years, 9.8 +/- 9 (mean +/- sd) compared to age and ISS for nonsurvivors 37 +/- 22 years and 45 +/- 22*, *p < 0.001. Peer review suggested that 32 deaths were non avoidable, 4 potentially avoidable and 2 were probably avoidable. TRISS and ASCOT survival probabilities were > 0.5 in 16 and 18 patients respectively. TRISS and ASCOT had low positive predictive value (25%) in identifying avoidable deaths. The Z Score was 1.79. The standardised mortality ratio (SMR) was 1.16. The Effectiveness (E) value for outcome was 0.91. Poor communication within the Area Trauma System was the greatest contributor to avoidable deaths. All trauma deaths need peer review rather than solely relying upon ASCOT and TRISS probabilities to identify "unexpected" deaths for detailed review. PMID- 8698566 TI - It's not science. what can science do about it? AB - Scholars describe science as one variety of organized human knowledge, characterized by its process that requires testing of theories in attempts to falsify them. Its products are descriptions and theories about the physical world that have withstood attempts at falsification. While some of these products will eventually have practical applications, all are initially interesting to other scientists. Other scientists use the products that are considered useful and that stand up to additional testing in their own research, they reject the products that do not survive testing, and they ignore most of them. Risk analyses produce informed predictions about the future likelihood that loss or injury will occur as a consequence of present actions. They are delivered not to scientists but to policymakers who, having invested in the analysis, want to use them in their work. Only rarely, and perhaps never, are the predictions testable, and they are accepted or rejected on other grounds. These contentions are the bases for a review of risk assessments about dioxin and low-level radiation exposures and some speculations about coming changes in risk assessment. PMID- 8698567 TI - Evaluation of the NESHAP radiological risk assessment. AB - The Environmental Protection Agency performed a risk assessment as a basis for the National Emission Standards for Hazardous Air Pollutants. This paper compares the Environmental Protection Agency's risk assessment with the models used by the National Research Council's fifth Committee on the Biological Effects of Ionizing Radiations, the United Nations Scientific Committee on the Effects of Atomic Radiation, and the International Commission on Radiological Protection. Comparison of the parameters used by each organization suggests that the Environmental Protection Agency could improve its own risk assessment by adopting one of the assessments done by the BEIR V Committee, the United Nations Scientific Committee on the Effects of Atomic Radiation, and the International Commission on Radiological Protection. PMID- 8698568 TI - The determination of radioisotope levels in municipal sewage sludge. AB - Sludge samples from 25 municipal waste water treatment plants have been analyzed to determine the level of environmentally present, man-made, gamma-ray emitting radioisotopes. Samples were freeze dried and separated into dried sludge, liquid soluble and liquid-insoluble components. These were counted in the low background level, whole body counter at Missouri University using a standard intrinsic Germanium spectrometer. After freeze drying, the liquid effluents from the samples were not found to have statistically significant levels of radioactivity. Using log-normal analysis, the dried sludge was found to have 0.0016 +/- 0.0022 Bq g-1 (0.04 +/- 0.06 pCi g-1) of 137Cs and 0.001 +/- 0.003 Bq g-1 (0.03 +/- 0.08 pCi g-1) of 60Co. These data can be used to determine if sewage effluents from nuclear facilities have levels of radioactivity above that expected from the environment. PMID- 8698569 TI - Plutonium in the Savannah River Site environment. AB - The Savannah River Site has produced plutonium, tritium, and other special nuclear materials for national defense, other government programs, and some civilian purposes. Plutonium has been released to the environment during the operation of five reactors, two radiochemical processing facilities, and other supporting facilities. During the period 1954-1989, 140 GBq of plutonium were released to the atmosphere and 23 GBq were released to site streams and ponds. The maximum individual effective dose equivalent at the site boundary was estimated to be 120 microSv from atmospheric releases and 2.4 microSv from liquid releases. The 80-km population dose was 7.1 person-Sv. PMID- 8698570 TI - Calculation of absorbed energy in the gastrointestinal tract. AB - One goal of this research was to reproduce the photon specific absorbed fraction calculations of Cristy and Eckerman using their gastrointestinal (GI) tract model. A second goal was to calculate photon specific absorbed fraction values for their GI tract model using electron tracking techniques. A final goal was to calculate electron absorbed fraction values for their GI tract model. This paper summarizes the work performed using the currently accepted model of the GI tract provided by Cristy and Eckerman. Their model was coded into the Electron Gamma Shower 4 (EGS4) computational package for calculation of photon specific absorbed fraction values. To benchmark the initial code, the EGS4 program was run so that all secondary particles deposited their energy at the site of the primary photon interaction (i.e., without electron tracking). The results obtained from these preliminary calculations were compared to those provided by Cristy and Eckerman to verify and benchmark the program. Next, specific absorbed fraction values were calculated for twelve discrete photon energies using the electron tracking capabilities of EGS4. These photon specific absorbed fraction values were compared to those calculated without electron tracking. Finally, absorbed fraction values were calculated for twelve discrete electron energies. The electron absorbed fraction values were compared to those calculated without electron tracking. Finally, absorbed fraction values were calculated for twelve discrete electron energies. The electron absorbed fraction values were compared to the ICRP "one-half assumption" for electron energy deposition in the wall of the GI tract. PMID- 8698571 TI - A revised model for the calculation of absorbed energy in the gastrointestinal tract. AB - The goal of this research was to develop a more complete gastrointestinal (GI) tract model for use in internal dose assessment. This paper summarizes the development of a revised mathematical model of the GI tract. The current GI tract model assumes the wall can be represented as a single soft tissue layer without regard to the radiosensitivity of the cells. The goal of the GI tract revision was to develop geometric regions that separate the radiosensitive cells from the less radiosensitive cells. Once the model was revised, it was coded into the Electron Gamma Shower 4 (EGS4) computational package for calculation of photon and electron absorbed fraction values. Photon absorbed fraction values were calculated for twelve discrete energies. For the photon absorbed fraction calculations, the EGS4 program was run so that secondary particles created in photon interactions were followed using the electron tracking capabilities of EGS4. The results of the photon absorbed fraction calculations provided better estimates of the energy deposited in the radiosensitive cells when the target organ was the source. In cases where the target organ was not the source, the photon absorbed fraction values did not provide better estimates than those obtained using the current GI tract model. An increase in the number of photon histories should provide better estimates of the photon absorbed fraction for these cases. Electron absorbed fraction values also were calculated for twelve discrete electron energies. The results of these calculations provided the expected pattern of energy deposition and better estimates than those currently available. The annual limit on intake was recalculated for a single radionuclide to demonstrate the affect of these improved absorbed fraction values on internal dose assessment. The radionuclide was selected for two reasons: 1) it was a beta emitting radionuclide; and 2) the annual limit on intake for ingestion was based on the non-stochastic committed dose equivalent limit to the lower large intestine. The calculated annual limit on intake was found to be three times greater than the annual limit on intake provided in ICRP Publication 30. There are many radionuclides that have a section of the GI tract as the limiting organ for ingestion. It is expected that the annual limit on intake value for these radionuclides would increase when the revised GI tract model is employed for internal dose assessment. PMID- 8698572 TI - On residual dose rate within particle accelerator enclosures. AB - A mathematical proof of a theorem concerning the flux density of particles at any point interior to a simple closed convex surface in which the surface emits such particles uniformly and isotropically is presented. The relationship of this theorem, which is of rather general validity, to related observations of other workers is discussed. The ramifications of the theorem are considered with particular attention devoted to conditions commonly found at particle accelerators. It is concluded that results of this theorem are directly applicable to efforts to apply the principle of maintaining dose equivalents received by personnel as low as reasonably achievable. PMID- 8698573 TI - Analysis of body-burden measurements of 137Cs and 40K in a Japanese group over a period of 5 years following the Chernobyl accident. AB - A selected group of about 20 male researchers at the NIRS that reside in Chiba, Japan, was measured for total body content of radiocesium and 40K every 3 mo from February 1986 to May 1991. A whole-body counter at the NIRS was used to measure their radioactivity in a scanning mode of 5 cm min-1 in a shielded iron room with walls 20 cm in thickness. A maximum radiocesium level of 59 Bq was observed in May 1987. The annual change in the body burden decreased with an apparent half time of 1.8 y after May 1987. The period of five years was sufficient to eliminate the effects of the accident in this group. Even in the most contaminated period, the dose from radiocesium was below 2 microSv y-1. The cumulative dose for 5 y was estimated to be 5.6 microSv, which is nearly equal to the total dose to the Japanese people caused by the artificial radionuclide fallout for the first year following the accident. It is much smaller than the committed dose of 82 microSv for internally deposited 137Cs resulting from nuclear explosions in 1961 and 1962 and the annual dose of 170 microSv from internal 40K. No detectable health risk was expected for the present group. PMID- 8698574 TI - Transfer, pathways, enrichment, and discharge of 137Cs and 90Sr in the pulp industry. AB - Natural and artificial radionuclides are transferred from terrestrial ecosystems via the forest industry to coastal sea water. The material processed, i.e., wood, fresh water, and bark, have low levels of radionuclides, but large amounts of raw materials are processed annually. Thus the annual flux of radionuclides is substantial. The purpose of this investigation was to study transfer, redistribution, enrichment, and discharges of 137Cs and 90Sr in pulp industry employing the sulphate process. 137Cs and 90Sr were measured by means of Ge detectors and a low level liquid scintillation spectrometer, respectively. 137Cs was highly enriched in the recovering process for sodium, while 90Sr was enriched in the recovering system for calcium compared to concentration levels in raw materials. The concentrations of 137Cs and 90Sr in bark were almost ten times the concentration level in conifer wood. No 137Cs or 90Sr could be identified in atmospheric discharges from the combustion processes. The products contained very low levels of these radionuclides. Only 5% of the annual input of 137Cs and 90Sr were found in the products. Discharges of radionuclides from this particular pulp production plant is nearly 40% of the annual 137Cs and 90Sr input. The contribution of 137Cs and 90Sr to coastal seawater is probably of minor importance providing that wood or fresh water from highly contaminated areas are not utilized. PMID- 8698575 TI - A gas scintillation monitor for tritium gas in argon or in nitrogen. AB - For civilian purposes tritium is presently used in quantities of tens of PBq (MCi) in laboratories for the studies of tritium technology, at the Joint European Torus plant (Abingdon, Oxon, OX143A, UK) as fuel for the process of nuclear fusion, and in the manufacture of radio-luminescent items. Given the extreme mobility of tritium in most materials, it is necessary to use systems for double containment, such as glove boxes or spaces between primary and secondary containers, in which inert gas like argon or nitrogen flows. With these systems it is possible to recover tritium that escapes from the primary containment. Presently the gas flow is monitored continuously by means of ionization chambers which may present problems in particular applications ("memory effect" with high activity, strong dependence of the response on the presence of impurity, etc.). The aim of the work here presented is to determine the prospects for the realization of a new type of monitor mainly dedicated to the measurement of gas activity in isolation space of the containing systems of the high activity tritium plants. This monitor should have sufficient sensitivity, quick response, and should be easily decontaminated. As a detection technique we chose the scintillation produced in the inert gas by radioactive decay. With the first prototype, designed in cylindrical form, it was possible to observe gaseous scintillation events in mixture of tritium and argon or nitrogen. Following that, a spherical prototype was designed, of which we studied the performances and the dependence of the response varying the pressure, the concentration of tritium, the percentage of the impurity, and the gas flow rate. The results are satisfactory and suggest that the monitor could be used in glove boxes and double containment systems. The future research program will include tests involving large quantities of tritium and a study of the ideal dimensions and geometry of the detection chamber in order to optimize the detector response. PMID- 8698576 TI - 137Cs concentration in soil samples from an early survey of Hiroshima atomic bomb and cumulative dose estimation from the fallout. AB - Low background gamma-ray measurement has been performed to determine the 137Cs content in soil samples collected in a very early survey of the Hiroshima atomic bomb. These soil samples were collected just 3 d after the explosion within 5 km from the hypocenter and were not exposed to the global fallout from nuclear weapon tests. Out of 22 samples, 137Cs was detected for 11 samples, and their radioactivities ranged from 0.16-10.6 mBq g-1 at the time of the measurement. A comparison of the 137Cs deposition with the rainfall area within Hiroshima city indicates that the rainfall area was wider than the previously proposed one. Cumulative exposure by the fallout has been estimated to be 0.31 mC kg-1 (0.12 R) in Hiroshima city except for the heavy fallout area and at most 1.0 mC kg-1 (4 R) in the heavy fallout area. PMID- 8698577 TI - A comprehensive appraisal of 241Am in soils around Rocky Flats, Colorado. AB - Soils east of Rocky Flats Plant (RFETS) near Golden, Colorado, were contaminated with actinides because of accidental release of oils laden with plutonium isotopes. Consequently, these soils were contaminated by 241Am due to radioactive decay of 241Pu (t1/2 = 14.4 y). A spatial analysis of 241Am activity in soils east of RFETS was conducted to elucidate the magnitude and the mode of 241Am dispersion in the soil environment. 241Am activity of 178 soil samples ranged from 0.037 Bq kg-1 to 10,004 Bq kg-1 with a mean of 214 Bq kg-1, median of 7.28 Bq kg-1, standard deviation of 942 Bq kg-1, and a coefficient of variation of 4.3. Spatial analysis of 241Am in soils around RFETS was conducted using indicator kriging, which is a nonparametric technique especially suitable to model a conditional cumulative distribution function (ccdf) of highly skewed environmental data such as 241Am. The ccdf was used to generate an E-type (mean of the conditional cdf) surface. The resulted surfaces were consistent with the hypothesis that the westerly winds were the dominant mechanism of americium dispersal. The spatial distribution and dispersal mechanisms of 241Am were similar to those of 239+240Pu. The ccdf was also used to construct probability of exceedence maps of 241Am in soils. For the purpose of this report two threshold values for the probability maps were selected: (1) the mean measured background activity of 241Am (0.4 Bq kg-1), and (2) the programmatic preliminary remediation goal for residential occupancy scenario (87.7 Bq kg-1). The probability-of exceedance maps provide estimates of spatial uncertainty associated with each threshold. The E-type maps in conjunction with the probability-of-exceedance maps provide a robust framework for future cleanup options and land use decisions. PMID- 8698578 TI - Environmental gamma dose measurements in Mexico City using TLD. AB - The aim of this work is to measure the gamma dose component of environmental radiation in Mexico City's metropolitan area. To perform the TL dosimetry, CaF2:Dy, CaF2:Mn, alpha-Al203:C and LiF:Mg, Cu, P crystals were used. The values of environmental gamma dose rate measured ranged between 83 and 112 nGy h-1 for the time interval going from January to August 1994. Outdoor dose rates were 85 nGy h-1 +/- 2% for city sites having soil of either volcanic or lacunar origin; this rate was 107 nGy h-1 +/- 2% at a nearby hill belonging to a volcanic chain. Indoor rates were about 20% higher than outdoor ones at the same location. PMID- 8698579 TI - Radon concentrations and exposure levels in Hungarian caves. AB - In addition to workers in uranium and coal mines, the staff of other underground workplaces, such as workers in caves, can be exposed to 222Rn and its progeny. In this study, radon and radon progeny concentrations were measured in four Hungarian caves. Two of them are used for speleotherapy, one is opened for tourist visits, and one is a reference cave used only for experimental purposes. Seasonal variation of radon levels, with summer maximums and winter minimums typical for cold karstic caves, were observed in all caves investigated. Non regular diurnal variation of radon concentration was measured in the caves where indoor air was less isolated from the outdoor atmosphere. From the measured radon concentrations, cumulative WLM exposures, bronchial dose, an effective dose equivalent values were calculated for the staff, patients and visitors. The effective dose equivalent values for the cave personnel do not exceed the 20 mSv y-1 limit. The doses for visitors and patients were one or two magnitudes lower than that of the personnel. PMID- 8698580 TI - Long-term behavior of radiocesium in dairy herds in the years following the Chernobyl accident. AB - The longterm behavior of 137Cs in milk of a Bavarian farm (farm A) deposited as a consequence of the Chernobyl accident has been followed from April 1986 until August 1994. On the basis of activity measurements in milk and feed, transfer coefficients for the different seasons have been estimated in order to see any changes in transfer behavior (aging effect) of 137Cs with time. The influence of different grazing regimes has been tested by comparison of activity concentrations in milk and pasture grass in one farm (farm A with rotational grazing regime) with that of a nearby farm (farm B with continuous grazing regime) over a complete grazing season by frequent measurements in 1993. Though the farms are located only 4 km apart, have similar soils, and were contaminated to the same extent by the Chernobyl fallout, tenfold lower 137Cs activity concentrations in milk have been observed in farm B. This finding seems to be partly due to the influence of a different grazing intensity. PMID- 8698581 TI - Elevated indoor exposure in Chinese carbon brick and cave dwellings. AB - In two rural provinces of China residents are exposed to significantly elevated levels of natural radiation: in Gansu Province millions of people have been living in earth-dug cave dwellings for several generations; in Jiangxi Province several hundred thousand inhabitants reside in carbon-brick dwellings, containing elevated levels of 238U and 226Ra. In a pilot study regional lung cancer mortality rates were investigated in the affected areas and were found to be higher than for control groups in normal dwellings in the same area. PMID- 8698582 TI - 125I aqueous waste volume reduction at a pharmaceutical research laboratory. AB - A wide variety of radioactive waste is generated by pharmaceutical research. One particularly high volume low specific activity waste stream produced by a research and development facility is aqueous 125I waste. This waste is generally held for decay and released to the sanitary sewer when the activity is low enough to ensure that concentrations are well below the appropriate regulatory limits. However, the large volume of this particular waste stream rapidly exhausted available space to store it for decay. This study investigated safe, inexpensive, and efficient methods for removing 125I from the aqueous waste, with the goal of implementing a practical process for concentrating the activity and thus reducing the stored volume. The implemented treatment (volume reduction) process used commercially available low cost activated carbon/particulate filters and inexpensive resin beds manufactured in-house. The much smaller volumes of spent filters and resin beds are then held for decay and eventual incineration. This technique has proven an effective means for managing this high volume waste stream. PMID- 8698583 TI - Environmental monitoring for a low-level radioactive waste management facility: incinerator operations. AB - An environmental monitoring program has been developed for Harvard University, Southborough campus, to assess the local environmental concentrations of radionuclides released in incinerator effluents. The campus is host to the University's low-level radioactive waste management facility, which consists of 6,000 drum capacity decay-storage buildings; a 250 drum capacity decay-storage freezer; and a controlled-air incinerator. Developmental considerations were based on the characteristics and use of the incinerator, which has a capacity of 8 tons per day and is operated 5% of the time for the volume reduction of Type 0 and Type 4 wastes contaminated with a variety of radionuclides used in biomedical research-some in microsphere form. Monitoring was established for air, leafy vegetation, leaf-litter, and surface soil media. Field sampling was optimized regarding location and time based on the action of atmospheric, terrestrial, and biotic transport mechanisms. Preliminary results indicate transient concentrations of 3H and 125I in vegetation directly exposed to the dispersing plume. Measurable particulate depositions have not been observed. PMID- 8698584 TI - Managing care, incentives, and information: an exploratory look inside the "black box" of hospital efficiency. AB - OBJECTIVE: We sought to estimate the impact of individual dimensions of hospitals' managed care strategies on the cost per hospital discharge. STUDY SETTING/DATA SOURCES: Thirty-seven member hospitals of seven health systems in the Pacific, Rocky Mountain, and Southwest regions of the United States were studied. STUDY DESIGN: Separate cross-sectional regression analyses of 21,135 inpatient discharges were performed in 1991 and 23,262 discharges in 1992. The multivariate model was estimated with hospital cost per discharge as the dependent variable. Model robustness was checked by comparing regression results at the individual discharge level with those at the level of the hospital/clinical condition pair. DATA COLLECTION/EXTRACTION METHODS: Information on hospitals' managed care strategies was provided by mail and phone survey of key informants in 1991 and 1992. Other hospital characteristics were collected from AHA Annual Survey data, and discharge data from hospital abstracting systems. PRINCIPAL FINDINGS: The pooled discharge analysis indicated three dimensions of hospital managed care strategy that consistently related to lower costs per hospital discharge: the proportion of hospital revenues derived from per case or capitation payment, the hospital's mechanisms for sharing information on resource consumption with clinicians, and the use of formalized, systematic care coordination mechanisms. CONCLUSIONS: Three strategies appear to hold promise for enhancing the efficiency of inpatient resource use: (1) "fixed price" hospital payment incentives, (2) hospital approaches to sharing resource use information with clinicians, and (3) the application of formal care management mechanisms for specific clinical conditions. PMID- 8698585 TI - Evaluation of a health promotion demonstration program for the rural elderly. AB - OBJECTIVE: This article evaluates a demonstration program that extended coverage for disease prevention/health promotion services to Medicare beneficiaries. STUDY SETTING/DATA SOURCES: Community-dwelling Medicare beneficiaries who lived in five rural counties in northwest Pennsylvania were recruited between May and December 1989. The demonstration lasted 18 months and beneficiaries were followed for an additional 18 months. Data for the evaluation came from an initial health risk assessment, Medicare administrative records, follow-up surveys, and redeemed vouchers for the waivered services. The waivered services included health screenings, influenza immunization, nutritional counseling, smoking and alcohol cessation, and depression/dementia evaluations. STUDY DESIGN: Medicare beneficiaries were randomized to one of two experimental groups and a control group. One experimental group received the newly waived services from hospitals that received a capitated fee; the other received services from providers who were paid fee-for-service. Eligibility for most waivered services was based on risk. Chi-square tests of association were used to determine if use of health promotion services and use of medical care services varied across groups. Logistic regressions were used to assess the factors associated with participation. Product-limit survival analysis was used to assess whether mortality rates varied across groups. PRINCIPAL FINDINGS: Participation rates in the new programs varied by program and by experimental group, and ranged from 16.8 percent for smoking cessation programs to 58 percent for influenza immunization. The demonstration led to an increase in influenza immunization rates relative to the control group. There were no differences in the use of medical care services or health outcomes between the experimental and control groups. CONCLUSIONS: Older rural Americans will modestly increase their use of disease prevention/ health promotion services if they are covered by Medicare. Use will be higher among those with more education. Further research is needed to assess long-term benefits of such programs. PMID- 8698586 TI - Chronic disease, functional health status, and demographics: a multi-dimensional approach to risk adjustment. AB - OBJECTIVE: The goal of this study was to develop unbiased risk-assessment models to be used for paying health plans on the basis of enrollee health status and use propensity. We explored the risk structure of adult employed HMO members using self-reported morbidities, functional status, perceived health status, and demographic characteristics. DATA SOURCES/STUDY SETTING: Data were collected on a random sample of members of a large, federally qualified, prepaid group practice, hospital-based HMO located in the Pacific Northwest. STUDY DESIGN: Multivariate linear nonparametric techniques were used to estimate risk weights on demographic, morbidity, and health status factors at the individual level. The dependent variable was annual real total health plan expense for covered services for the year following the survey. Repeated random split-sample validation techniques minimized outlier influences and avoided inappropriate distributional assumptions required by parametric techniques. DATA COLLECTION/EXTRACTION METHODS: A mail questionnaire containing an abbreviated medical history and the RAND-36 Health Survey was administered to a 5 percent sample of adult subscribers and their spouses in 1990 and 1991, with an overall 44 percent response rate. Utilization data were extracted from HMO automated information systems. Annual expenses were computed by weighting all utilization elements by standard unit costs for the HMO. PRINCIPAL FINDINGS: Prevalence of such major chronic diseases as heart disease, diabetes, depression, and asthma improve prediction of future medical expense; functional health status and morbidities are each better than simple demographic factors alone; functional and perceived health status as well as demographic characteristics and diagnoses together yield the best prediction performance and reduce opportunities for selection bias. We also found evidence of important interaction effects between functional/perceived health status scales and disease classes. CONCLUSIONS: Self-reported morbidities and functional health status are useful risk measures for adults. Risk-assessment research should focus on combining clinical information with social survey techniques to capitalize on the strengths of both approaches. Disease-specific functional health status scales should be developed and tested to capture the most information for prediction. PMID- 8698587 TI - Transitions from home to nursing home in a capitated long-term care program: the role of individual support systems. AB - OBJECTIVE: This study calculated the risk of nursing home admission for clients receiving home- and community-based (HCB) care in a capitated long-term care system. DATA SOURCES: Program administrative data for non-institutionalized elderly and physically disabled (EPD) clients who had an HCB long-term care placement in the Arizona Long-Term Care System (ALTCS) during the period from January 1989 through December 1991. STUDY DESIGN: The program experience of clients who were initially placed in HCB care (N = 2,923) was tracked from the date on which they entered the program until the end of December 1992. DATA EXTRACTION METHODS: Program administrative data were used to create spans of program experience for each client. Cox proportional hazards regression models were then used to assess the individual factors associated with the risk of nursing home entry during the study period. PRINCIPAL FINDINGS: The greatest risk of nursing home entry was observed for those who were older or white, and for those clients with Alzheimer's disease. Little significant effect was observed for support system variables. CONCLUSIONS: Study results suggest that efforts to prevent nursing home entry may be most productive if they focus on the point at which clients are first assessed for placement into the ALTCS program. Once in HCB care, subsequent risk of nursing home placement may be more related to the client's health and frailty than to support system factors. PMID- 8698588 TI - The effects of ownership and ownership change on nursing home industry costs. AB - OBJECTIVE: This study examines the effects of ownership type and ownership change on nursing home cost structures, differentiating patient care costs from plant costs. DATA SOURCES: Administrative data from the Michigan Department of Social Services, Medical Services Administration (Medicaid), and the Michigan Department of Public Health are used. Cost data are based on audited cost reports for 393 nursing care facilities in Michigan in 1989. Other facility characteristics are based on data from the 1989 annual licensing and certification survey conducted by the Michigan Department of Public Health. STUDY DESIGN: A series of ordinary least squares regressions is estimated, in which the dependent variable is either per diem patient costs or per diem plant costs. Ownership types are defined as chain, proprietary non-chain, freestanding non-profit, government-owned, and hospital-based facilities. Pooled estimation techniques, as well as separate regressions by ownership type, are presented to test for interaction effects. Key variables include whether a facility changed ownership in the preceding five years and whether chain facilities are in-state- or out-of-state-owned, in addition to size, payer mix, and case mix. PRINCIPAL FINDINGS: Behavioral differences among nursing home ownership types in respect to patient care costs tended to distinguish government-owned and hospital-based facilities from the freestanding homes rather than the usual distinction between for-profit and not for-profit classes. Variables traditionally included in nursing home cost studies, such as size, occupancy, payer mix and case mix, were found to have similar effects on per diem patient care costs for freestanding non-profit homes as well as for chain proprietary facilities. With regard to the effects of ownership change on per diem plant and per diem patient costs, however, there are few differences among ownership types. Chain and non-chain for-profit facilities, non-profit homes, and hospital long-term care units that had changed ownership reported significantly higher per diem plant costs than facilities without a change of ownership, but did not spend more on patient-related costs. Michigan Medicaid plant reimbursement system policy changes instituted in 1985 to promote continued ownership of facilities were not entirely successful. CONCLUSIONS: Non profit homes look increasingly like their for-profit counterparts with respect to spending on patient care costs. Increased competition for the more lucrative private-pay patients, coupled with declining state Medicaid reimbursement to nursing homes, may have blurred the historical distinctions between the non profit and for-profit sectors in the nursing home industry. An exception to increasing homogeneity within the nursing home industry is the tendency of proprietary homes to experience more frequent changes of ownership, which results in higher capital costs passed on to state Medicaid programs. Findings from this study indicate that while facility sales increase per diem plant costs, they do not result in increased spending for direct patient care, suggesting that state Medicaid programs may be indirectly subsidizing facility sales with no accompanying increase in expenditures for patient care. To discourage frequent facility sales, state Medicaid programs may need to consider alternative methods of reimbursing nursing home owners for capital costs. PMID- 8698589 TI - Use of care and subsequent mortality: the importance of gender. AB - OBJECTIVE: In light of recent discussions on access that have emphasized the need to relate access measures to outcomes, we examined the relationship between three self-reported utilization and access to care measures and the risk of subsequent mortality. DATA SOURCES AND DESIGN: A nationally representative sample from the first National Health and Nutrition Examination Survey that included adults 25-64 years of age without publicly funded health insurance was followed prospectively from initial interview in 1971 through 1975. DATA COLLECTION: Complete baseline and follow-up information was obtained on 4,491 persons (90 percent). Baseline access and use was assessed with answers to three questions: having a usual source of care, obtaining a general checkup, and not obtaining needed care (or forgone care). The relationships between the access and use measures and mortality by 1987 in men and women were examined using survival analyses. The analyses adjusted for race, and for baseline age, education, income, residence, insurance status, employment status, the presence of morbidity on examination, self-rated health, smoking status, leisure exercise, alcohol consumption, and obesity. PRINCIPAL FINDINGS: After adjusting for all other baseline variables, not obtaining a general checkup was associated with higher mortality in women (hazard ratio = 1.64 [95% confidence interval = 1.16, 2.32]), but not in men (hazard ratio = 1.07 [95% confidence interval = 0.80, 1.42]). Reporting a usual source of care and forgone care were not related to subsequent mortality in either women or men. CONCLUSIONS: Reporting a general checkup is an outcome related utilization measure in women only. Further development of access and use indicators should address gender differences in health care use. PMID- 8698590 TI - Interviews with home health aides caring for people with AIDS. AB - Through a phenomenological perspective, this study describes the experiences of home health aides caring for people with acquired immunodeficiency syndrome. Six home health aides were asked the question, "What is it like to be a home health aide caring for persons with acquired immunodeficiency syndrome?" The essential meanings uncovered from this study were empathy, being there, self-reflection, support and communication, and coping. This research study about home health aides caring for persons with acquired immunodeficiency syndrome will help nursing develop additional programs to educate and support the home health aide in this experience. PMID- 8698591 TI - Caring for individuals in the community who are mentally retarded/developmentally disabled. AB - Home healthcare nurses have the opportunity to care for individuals who are mentally retarded/developmentally disabled, and their families, in different types of community residences. Nursing assessments and interventions are initiated at various times in the life cycle. The goal is to help the individual and family members attain their maximum level of health, function, independence, recognition, and self-esteem. PMID- 8698592 TI - The impact of psychotherapy and self-healing techniques when coping with chronic illness: a case study. AB - This article focuses on common psychosocial issues related to chronic illness and the role psychotherapy and self-healing techniques play in coping with chronic illness. Empowerment of one's own healthcare is illustrated also. PMID- 8698593 TI - Home healthcare: the curriculum mandate. AB - Formal preparation of nursing students in home healthcare can be a reality in a college curriculum. This article describes the development and course content of a home healthcare course in the College of Nursing, Arizona State University. PMID- 8698594 TI - Health teaching for people with disabilities. AB - The authors inform nurses about their responsibility under the Americans with Disabilities Act to ensure equal access to health services and health education. This article is divided into two parts: (1) The Americans with Disabilities Act (ADA) is presented particularly in relation to health teaching. (2) Selected disabilities and helpful tips for positive interaction are discussed. PMID- 8698595 TI - Home health aide services: barriers perceived by dementia family caregivers. AB - This study explored barriers to using home health aide services as perceived by family caregivers of relatives with dementia. The authors analyzed data collected from interviews of 32 family caregivers of relatives with dementia. The major findings included the recurrent theme of cost/expectation, which emerged as a major barrier to using home health aide services. Caregivers in many cases indicated that the price paid for services outweighed benefits; however they continued to use home health aide services. Implications for home healthcare nurses are discussed. PMID- 8698596 TI - Awesome. PMID- 8698597 TI - My patient, my friend: a community health nursing experience. PMID- 8698598 TI - Transfusion reaction. PMID- 8698599 TI - Why home care needs FAT. PMID- 8698601 TI - The flavor of fieldwork in "The Big Apple". PMID- 8698600 TI - Unsung heroes. AB - This article describes learning modules developed by faculty to assist community health nursing students to care for patients with Alzheimer's disease and their caregivers. These modules were problem based using the protocol format PACES (Problem Identification, Assessment, Creative Problem Solving, Emphasis and Simplicity) to assist students and caregivers to individualize care planning. Caring theory provided the unifying thread for the project. PMID- 8698602 TI - Prevention and control of nausea and vomiting for patients with cancer. AB - Understanding the etiology and pathophysiology of nausea and vomiting help the home nurse plan interventions that relieve these symptoms in patients with cancer. Pharmacologic, self-care, and behavioral measures are presented to allow the nurse to educate and empower patients and families to be more involved in care. PMID- 8698603 TI - Healing Oklahoma's wound. PMID- 8698604 TI - Assessing and treating urinary incontinence. AB - Urinary incontinence is a problem many home care patients experience regardless of their diagnosis. Assessment and intervention strategies are presented to help the nurse creatively identify and treat this problem. PMID- 8698605 TI - Increasing student home care experiences: the client wins.... PMID- 8698606 TI - Accreditation and the nurse. Streamlining the care-planning process. PMID- 8698607 TI - Meeting the needs of home care patients 24 hours a day. AB - Meeting the patient care needs after the regular work day requires agencies to have a well-planned, comprehensive extended-hours program. This description of a large agency's approach to providing this service can be helpful to all agencies, regardless of size and location. PMID- 8698608 TI - Medicare as secondary payer. PMID- 8698609 TI - Stressors affecting hospice nurses. PMID- 8698610 TI - Get ready for OASIS. PMID- 8698611 TI - How do you measure a nurse? PMID- 8698612 TI - Development of synthetic immunoadjuvants as cytokine inducers for cancer therapy. PMID- 8698613 TI - Identification of 29 rat genetic markers by arbitrarily primed polymerase chain reaction. AB - The number of genetic markers for the rat is still limited, in spite of its wide use in cancer research. To facilitate accurate mapping of both established and novel rat genetic markers, we constructed a linkage map by genotyping 105 F2 rats from ACI/N (ACI) and BUF/Nac (BUF) crosses. This map consists of 120 genetic markers that had been previously reported, mainly by two research groups, but had not been integrated. To find new genetic markers, the arbitrarily primed polymerase chain reaction (AP-PCR) was applied to detect polymorphic bands between ACI and BUF rats. After testing 56 single primers and 12 combinations of primers, we found 36 bands produced by 16 single primers and two combinations to be reliably polymorphic between ACI and BUF rats. The 36 bands were typed in the 105 F2 rats, and 29 of them could be linkage-mapped. AP-PCR is thus useful to detect new genetic markers in laboratory strains of rats. PMID- 8698614 TI - A pilot study for a randomized controlled trial to prevent gastric cancer in high risk Japanese population: study design and feasibility evaluation. AB - Observational epidemiological studies suggest that some nutrients reduce the risk of gastric cancer and that individuals with atrophic gastritis are at high risk of developing gastric cancer. One possible measure for gastric cancer prevention is therefore nutritional supplementation for the high risk group. Before recommending this strategy for the general public, however, a randomized controlled trial (RCT) is necessary. To evaluate the feasibility of an RCT, the authors conducted a pilot study using recipients of a health check-up program in a general hospital in Japan. The subjects who were asked to participate in the trial had been diagnosed as having atrophic gastritis on the basis of serum pepsinogen I < 70 ng/ml and the ratio of pepsinogen I to II < 3.0. They were requested to ingest double-blinded capsules containing different levels of vitamin C and beta-carotene every day. Out of the 219 subjects (118 males, 101 females) who were eligible for the study and had the required pepsinogen measurement, 90 (41%) met the criteria for atrophic gastritis. Among them, 55 (61%) (35 males, 20 females) gave their informed consent to participate in the RCT. Fifty-four participants completed a 3-month course of supplementation, and all of them agreed to a 5-year supplementation period. The authors concluded that an RCT using double-blinded nutritional supplements and targeting apparently healthy individuals is feasible in an intervention study for cancer prevention in Japan. PMID- 8698615 TI - Prevention of mammary tumorigenesis in acatalasemic mice by vitamin E supplementation. AB - Adult male and female acatalasemic (C3H/AnLCsbCsb),hypocatalasemic (C3H/AnLCscCsc) and normal mice of C3H strain fed on regular laboratory chow for 15 months showed an increased incidence of spontaneous mammary tumor in the decreasing order of female acatalasemic, male acatalasemic, female hypocatalasemic and male hypocatalasemic mice. Normal mice did not develop mammary tumor. We conducted a prospective study with female acatalasemic mice, which showed the highest incidence of mammary tumor, to examine the preventive effect of vitamin E on mammary tumor. Female acatalasemic mice were fed on vitamin E-deficient (28 animals) and vitamin E-supplemented diet (25 animals) for 29 months. The incidence of mammary tumor in mice given the vitamin E supplemented diet was 47%, while that in mice given vitamin E-deficient diet was 82% (P < 0.002). Mammary tumors were apparent after 9 months of vitamin E deprivation and after 14 months of vitamin E supplementation. Female normal mice did not develop mammary tumor during a comparable period of time. The mean catalase activity of mammary gland in acatalasemic mice was 18.8% of that in normal mice. The results indicate that vitamin E protects acatalasemic mice against the development of mammary tumor. PMID- 8698616 TI - Detection of ultraviolet photoproducts in mouse skin exposed to natural sunlight. AB - In the present study, we for the first time investigated the formation of ultraviolet (UV) photoproducts, cyclobutane pyrimidine dimers (CPDs), pyrimidine pyrimidone (6-4) photoproducts (64PPs) and Dewar isomers, in vivo in shaved and depilated C3H/HeN mouse skin exposed to natural sunlight (NSL) at noon for 5 min to 1 h in mid-summer, using a highly sensitive immunohistochemical method. This method permits the quantitative analysis of UV-photoproducts in formalin-fixed, paraffinembedded sections with specific antibodies against CPDs, 64PPs and Dewar isomers. We demonstrated that the induction of CPDs in vivo in mouse skin by NSL was exposure time-dependent, but the accumulation of 64PPs or Dewar isomers was comparatively low in the skin sections from mice exposed to NSL in vivo. The results indicate that CPDs are the main photoproducts in vivo induced by sunlight and that their formation and repair may be important in connection with carcinogenesis in sun-exposed areas of human skin. PMID- 8698617 TI - Primary malignant lymphoma of the brain: demonstration of frequent p16 and p15 gene deletions. AB - The p16 (MTS-1) gene, a candidate tumor suppressor gene, was examined by means of Southern blot, PCR-SSCP (polymerase chain reaction-single-strand conformation polymorphism) and nucleotide analyses in 5 cases of primary malignant lymphoma of the brain. By Southern blot analysis, the p16 gene was found to be deleted in at least 4 cases, homozygously (3 cases) or hemizygously (1 case). The p15 (MTS-2) gene, another candidate tumor suppressor gene located in the vicinity of the p16 gene, to which it shows structural and functional similarity, was also found to be deleted in 4 cases. Our frequent detection (80%) of p16 and p15 gene deletions might suggest that these deletions are closely related to carcinogenesis in primary malignant lymphoma of the brain. SSCP and nucleotide analyses revealed no mutations of the p16 gene in any of the cases. PMID- 8698618 TI - P53 gene deficiency does not enhance instability of mouse minisatellites in somatic cells of normal tissues. AB - The effect of p53-deficiency on somatic mutation of minisatellites in normal tissues was examined using p53-deficient (-/-) mice. In total, 248 mice consisting of three different genotypes, +/+, +/ -and -/-, were obtained and DNA from their embryos was probed with two minisatellites, Pc-1 and Pc-2. The somatic mutation was detected by Southern blot hybridization as the presence of a third nonparental band reflecting mosaicism in tissues. Mutation frequency of Pc-1 for (+/+) and (+/-) was 1.3% and 1.4%, respectively, which is consistent with previous studies. On the other hand, none of the mice lacking the p53 gene (-/-) exhibited mutation. The Pc-2 probe did not show any somatic mutation in the three groups. These results suggest that the p53 deficiency does not enhance the genomic instability of the minisatellite loci in normal somatic cells. PMID- 8698619 TI - Acquisition of invasive phenotype in gallbladder cancer cells via mutual interaction of stromal fibroblasts and cancer cells as mediated by hepatocyte growth factor. AB - Growth and motility of carcinoma cells are regulated through their interactions with host stromal cells, i.e., tumor-stromal interactions. Hepatocyte growth factor (HGF), a ligand for c-Met tyrosine kinase, is a stromal-derived regulator of growth, motility, and morphogenesis. HGF stimulated proliferation and motility of GB-d1 gallbladder carcinoma cells from a patient with gallbladder cancer. HGF induced in vitro invasion of GB-d1 cells into a collagen gel matrix, and this potent, invasive effect was not seen with epidermal growth factor, transforming growth factor-beta 1, basic fibroblast growth factor, or platelet-derived growth factor. Although GB-d1 did not produce HGF, the cells did produce a factor which enhances HGF production in human skin fibroblasts, and this factor proved to be interleukin-1 beta (IL-1 beta). When GB-d1 cells were co-cultured with fibroblasts such that a collagen gel matrix was layered between the GB-d1 cells and fibroblasts, GB-d1 cells invaded the gel, but invasion of the cells in the co culture system was inhibited by antibodies against HGF and partially inhibited by antibodies against IL-1 beta. Thus, GB-d1 cell-derived IL-1 beta stimulates HGF production in stromal fibroblasts and HGF up-regulated in the fibroblasts induces invasion of GB-d1 cells. The looped interaction of carcinoma cells and stromal fibroblasts mediated by HGF and a HGF-inducer such as IL-1 beta may be one mechanism which would explain the acquisition of malignant phenotype through tumor-stromal interactions. PMID- 8698620 TI - Image quantitation of intestinal metaplasia in entire gastrectomy specimens from Swedish and Japanese patients. AB - The aim of this work was to investigate the extension of intestinal metaplasia (IM), as well as to quantitate various components of IM (namely sialomucins, sulfomucins and Paneth cells), in entire gastrectomy specimens from Swedish and Japanese patients. The length of the gastric mucosa was assessed by morphometry. The percent of sections with IM was regarded as the extension of IM in the specimens. Histochemically labeled sialomucins, sulfomucins and Paneth cells (the 3 main findings in gastric IM) were quantified in separate sections with the aid of an image analyzer. In total, 1,321 sections corresponding to 6 gastrectomy specimens were quantified. Sialomucins and sulfomucins were more extensively distributed in the 4 specimens with carcinoma than in the 2 without carcinoma (one having a peptic ulcer and the other, hereditary gastric cancer syndrome (HGCS) without carcinoma). On the other hand, quantitative analysis in Swedish specimens indicated that the highest values for sialomucins, sulfomucins and Paneth cells were present in HGCS. When Swedish and Japanese specimens with adenocarcinoma were compared, only sulfomucins (denoting Types II and III IM) were significantly higher in those carrying an intestinal-type carcinoma (ITC) than in those with diffuse-type carcinoma (DTC). The results substantiate those obtained with gastric biopsies by other authors. On the other hand, the mucosal extension and the amount of sulfomucins are not comparable parameters (since that mucin was not equally distributed, but "concentrated" in certain areas in the mucosa). One possible conclusion is that the focal distribution of acidic mucins and of Paneth cells in the gastric mucosa may strongly influence their detection rate in gastric biopsies. Thus, haphazard biopsy of the gastric mucosa may fail to sample areas with sulfomucins in population studies aiming to detect individuals at risk. Such sampling errors in gastric biopsies may explain the conflicting results on this subject appearing in the literature. PMID- 8698621 TI - Immunocytochemical detection of p53 in cultures of exfoliated cells from urine of patients with urothelial cancers. AB - Early diagnosis of urothelial cancer is critical for successful treatment. Mutation of the p53 gene together with allelic loss of chromosome 17p correlates well with high grade and invasiveness of urothelial cancer. Moreover, this mutation is reported to be an early event for carcinoma in situ of the urothelium. In order to develop a new non-invasive diagnostic method for urothelial cancer, we have established a short-term culture system for urinary exfoliated cells from patients with urothelial cancer. Immunocytochemical detection of p53 in these urine-derived cells was conducted. Short-term cultures of exfoliated cells from 50 ml samples of urine from 52 patients with urothelial cancers were made. Adequate cell growth (> 10(5) cells per flask) was followed by passage onto glass chamber slides for p53 immunocytochemical staining. Successful passage was obtained in 40 of the 52 (76.9%) patients with urothelial cancers studied. The success rate for patients with tumors immunohistochemically positive for p53 nuclear accumulation was 90.5%, and 61.3% for those with tumors negative for p53 (P < 0.05). Results of immunochemical analysis of the p53 in the urine cells and those in the tumor samples were identical in 92.1% of the patients. Culture of exfoliated cells from urine would be a good, non-invasive method for the molecular diagnosis of urothelial cancer that should prove useful for the early detection and follow-up of tumors with p53 mutation. PMID- 8698622 TI - Rejection of mouse renal cell carcinoma elicited by local secretion of interleukin-2. AB - We introduced the interleukin-2 (IL-2) gene into mouse renal cell carcinoma (RenCa) in order to examine the mechanism of tumor rejection. IL-2 gene transfected RenCa (RenCa/IL-2Hi) exhibited marked retardation of tumor growth when implanted in a syngeneic host. Growth retardation of RenCa/IL-2Hi was also observed in athymic nude mice even after depletion of natural killer (NK) cells by treatment with anti-asialo GM1 antibody. Histological analysis of RenCa/IL-2Hi tumors disclosed non-specific inflammatory changes in syngeneic hosts. Co injection of Bacillus Calmette Guerin with RenCa/IL-2Hi considerably enhanced the anti-tumor effects. Taken together, these findings strongly suggest that in situ IL-2 production leads to tumor rejection through non-specific inflammatory responses without participation of T cells and NK cells. On the other hand, the syngeneic mice that had rejected RenCa/IL-2Hi acquired immunity against parental RenCa, suggesting possible participation of memory T cells in the second rejection of the tumor. PMID- 8698623 TI - Triamterene suppresses bombesin-enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane. AB - The effects of combined administration of bombesin and the diuretic triamterene on the incidence of peritoneal metastasis of intestinal cancers induced by azoxymethane (AOM) and the labeling index of intestinal cancers were investigated in male inbred Wistar rats. From the start of the experiment, rats were given weekly s.c. injections of AOM (7.4 mg/kg body weight) for 10 weeks and s.c. injections of bombesin (40 micrograms/kg body weight) every other day, and from week 16, s.c. injections of triamterene (10 and 20 mg/kg body weight) every other day until the end of the experiment in week 45. Bombesin significantly increased the incidence of intestinal tumors and cancer metastasis to the peritoneum in week 45. It also significantly increased the labeling index of intestinal cancers. Although administration of both doses of triamterene with bombesin had little or no influence on the enhancement of intestinal carcinogenesis by bombesin, or the location, histologic type, depth of invasion, or labeling index of intestinal cancers, it significantly reduced the incidence of cancer metastasis. These findings indicate that triamterene suppresses cancer metastasis through a mechanism that does not affect the proliferation of intestinal cancers. PMID- 8698624 TI - p53 antisense oligonucleotide inhibits growth of human colon tumor and normal cell lines. AB - We examined the relationship between the expression of mutant p53 proteins and tumor cell growth using a p53 antisense oligonucleotide (5'-CCCTGCTCCCCCCTGGCTCC 3'). The oligonucleotide inhibited the growth of three human colon tumor cell lines (DLD-a, SW620 and WiDr), which produce only mutant p53 proteins with different mutation sites. Treatment of DLD-1 cells with the p53 antisense oligonucleotide caused a decrease in the level of p53 mutant protein. Synthesis of DNA in DLD-1 and SW620 cells was inhibited more potently than that of RNA or protein after antisense treatment. Furthermore, these cells were accumulated in the S phase when DNA synthesis was inhibited. Meanwhile, the antisense oligonucleotide also inhibited the growth of three human normal cell lines (WI 38, TIG-1 and Intestine 407). While treatment of WI-38 and TIG-1 cells with the antisense oligonucleotide inhibited synthesis of DNA more potently than that of RNA or protein, these normal cells were accumulated in the G0/G1 phase. These results suggest that p53 proteins, either with or without mutation, play a pivotal role in the growth of tumor and normal cells, but that mutant and wild type p53 proteins may function differently in cell growth. PMID- 8698625 TI - Antiproliferative effect of a novel cholecystokinin-B/gastrin receptor antagonist, YM022. AB - Cholecystokinin (CCK)-B and gastrin receptors are expressed on a variety of human tumor cells. Recently, we have demonstrated that the human brain CCK-B receptors are identical to the gastrin receptors derived from the stomach mucosa, and that the brain-gut peptides, CCK-8 and gastrin I are mitogenic for mouse NIH 3T3 fibroblasts expressing human CCK-B/gastrin receptors (N-hCCKBR). In this report, we evaluated the antiproliferative potency of CCK-B/gastrin receptor antagonists by using N-hCCKBR cells. Among several antagonists, a benzodiazepine derivative, YM022 had the most potent activities in competing with [125I]CCK-8 or [125I]gastrin I binding, inhibition of CCK-8- or gastrin I-induced phosphoinositide hydrolysis and increasing cytoplasmic free calcium. Interestingly, a potent antagonist for rat CCK-B/gastrin receptors did not have such activities in N-hCCKBR cells. YM022 inhibited the CCK-8- or gastrin I induced [methyl-3H]thymidine incorporation of N-hCCKBR cells in a dose-dependent manner. In the absence of exogenous peptide ligands, YM022 also inhibited the proliferation of several human cancer cell lines expressing the genes for both gastrin and its receptor. These results suggest that YM022 could intervene in the autocrine stimulation of human tumor cell lines through CCK-B/gastrin receptors. N-hCCKBR cells are an excellent tool to screen for novel human CCK-B/gastrin receptor antagonists possessing antiproliferative activity for human cancer cells. PMID- 8698626 TI - Induction of MAGE genes in lymphoid cells by the demethylating agent 5-aza-2' deoxycytidine. AB - MAGE genes encoding tumor antigens recognized by cytotoxic T lymphocytes are appropriate target molecules for specific immunotherapy of cancer. We have investigated whether the demethylating agent 5-aza-2'-deoxycytidine (DAC) induces MAGE-1, -2, -3, and -6 in normal and malignant lymphoid cells. DAC induced these MAGE genes in both PHA/interleukin-2 (IL-2)-activated T cells from healthy donors and MAGE-negative T and B cell leukemias in most cases. It also induced MAGE-1 in IL-2-dependent T cell clones and all MAGE genes tested in Epstein-Barr virus transformed B cell lines. Expression of MAGE-1 protein in the cells was confirmed by western blot analysis with anti-MAGE-1 polyclonal antibody. Therefore, demethylation is a potent stimulus to induce MAGE genes in both normal and malignant lymphoid cells. PMID- 8698627 TI - Transduction of the macrophage colony-stimulating factor gene into human multidrug resistant cancer cells: enhanced therapeutic efficacy of monoclonal anti-P-glycoprotein antibody in nude mice. AB - To develop a therapeutic modality for overcoming multidrug-resistant (MDR) cancer with anti-MDR1 antibody, we examined the effect of macrophage colony-stimulating factor (M-CSF) gene transfection into MDR AD10 cells on therapy of MDR cancer with anti-MDR1 antibody (MRK17) in nude mice. MDR human ovarian cancer (AD10) cells were transduced with the human M-CSF gene inserted into an expression vector to establish gene-modified cells capable of producing low (ML-AD10), intermediate (MM-AD10) nd high (MH-AD10) amounts of M-CSF. Systemic administration of MRK17 resulted in significant dose-dependent inhibition of subcutaneous growth of ML-AD10 tumors. In contrast, systemic administration of recombinant M-CSF in combination with MRK17 did not augment the therapeutic efficacy of MRK17 alone, but rather promoted the growth of the parent AD10 cells. To test the efficacy of in vivo M-CSF gene therapy combined with antibody, we mixed the parent AD10 cells with MH-AD10 cells producing a large amount of M-CSF, and inoculated the mixed cells subcutaneously. Treatment with MRK17 inhibited growth of the mixed cells more than that of the parent cells alone. Thus, combined therapy with anti-MDR1 mAb and M-CSF gene modification of MDR cancer cells may provide a new immunotherapeutic modality for overcoming MDR in humans. PMID- 8698628 TI - Overexpression of multidrug resistance protein gene in human cancer cell lines selected for drug resistance to epipodophyllotoxins. AB - Overexpression of either the multidrug resistance 1 (MDR1) gene or multidrug resistance protein (MRP) gene is involved in acquisition of multidrug-resistant phenotypes in human cancer cells. In this study we examined whether selection for resistance to the epipodophyllotoxins, etoposide/teniposide (VP16/VM26), could induce overexpression of MDR1 or MRP. We have previously isolated two VP16/VM26 resistant KB cell lines. Two VP16/VM26-resistant KB cell lines, KB/VM-1 and KB/ VM-4, which were selected by stepwise exposure to VM26 had decreased accumulation of [3H]VP16 and increased levels of MRP, but no apparent expression of MDR1 gene was observed. Another VP16/VM26-resistant KB cell line, KB/VP-4, which was further isolated from a VP16-resistant KB cell line, KB/VP-2, had decreased accumulation of [3H]VP16 and showed overexpression of MRP gene, but not that of MDR1 gene. We also isolated a VP16-resistant cell line, IN157/VP-1, from a human glioma cell line IN157. IN157/VP-1 cells showed decreased accumulation of [3H]VP16 and overexpression of MRP gene, but not of MDR1. These findings suggest that selection for resistance to VP16/VM26, preferentially induces overexpression of MRP gene. PMID- 8698629 TI - Biological activity and intracellular metabolism of ZD1694 in human leukemia cell lines with different resistance mechanisms to antifolate drugs. AB - The biological activity and cellular metabolism of ZD1694, a novel folate-based thymidylate synthase (TS) inhibitor, were analyzed in a human leukemia cell line, MOLT-3, and its antifolate-resistant sublines with different mechanisms of resistance to methotrexate (MTX), trimetrexate (TMQ) and N10-propargyl-5,8 dideazafolic acid (CB3717). MOLT-3/CB3717(40), which was selected for CB3717 resistance, demonstrated impaired membrane drug transport via reduced folate carrier (RFC) and lower accumulation of [3H]ZD1694-polyglutamates in the cells with a shift in the polyglutamate distribution profile to shorter chain length polyglutamates, indicating an alteration in polyglutamation capacity in this subline. Impaired RFC and reduced rate of polyglutamation could explain the cross resistance (12-fold) of this subline to ZD1694. On the other hand, there was little or no cross-resistance to this drug in a subline (MOLT-3/TMQ800) reportedly resistant to TMQ through impaired membrane transport for TMQ and an increase in dihydrofolate reductase (DHFR) activity. Total amount of ZD1694 polyglutamated to a level higher than diglutamate was approximately 1.7-fold higher in the TMQ-resistant cells than that in the parent cells, but a low degree of increase in TS activity in the cells counteracted the supposed increase in sensitivity to ZD1694. MOLT-3/TMQ800-MTX10000 cells, which were established by sequential exposure of the TMQ-resistant cells to MTX and were previously shown to amplify mutated DHFR with low affinity for MTX, showed a decreased accumulation of polyglutamated ZD1694 as compared with the parent line and this was consistent with cross-resistance to ZD1694 in this subline. Overproduction of variant DHFR scarcely influenced the sensitivity to this drug. These results indicate that ZD1694 could overcome antifolate resistance through a mechanism such as amplified DHFR activity, and the biological activity of this drug against the cells paralleled the amount of polyglutamated drug inside the cells. Determination of polyglutamation capacity in tumor cells may allow prediction of sensitivity to this drug. PMID- 8698630 TI - Determinants of myelosuppression in the treatment of non-small cell lung cancer with cisplatin-containing chemotherapy. AB - Data on 16 potential risk factors for myelosuppression were assessed in 134 patients who received either vindesine and cisplatin (VP) or mitomycin C, vindesine and cisplatin (MVP) for inoperable stage III or IV non-small cell lung cancer in a randomized trial. Determinant factors for myelosuppression were evaluated by using univariate analysis and the logistic regression model. Recursive partitioning and amalgamation (RPA) was also used to define patient subgroups frequently suffering from severe bone marrow toxicity. Overall, 33 (25%) of 134 patients experienced at least one episode of grade 4 leukopenia. In univariate analysis, age, body surface area, serum creatinine, and pretreatment hemoglobin concentration were associated with severe leukopenia. A multivariate analysis using the logistic regression method showed that only raised creatinine level was an independent predictor for grade 4 leukopenia (P = 0.049). The RPA model generated three distinct subgroups based on age, body surface area and regimen. The three subgroups were distinguished by the frequency of severe (grade 4) leukopenia (50%, 25%, and 2.4%, respectively) (P < 0.001). Grade 4 leukopenia occurred more frequently in patients in class 3 (age > or = 65 years and treatment with MVP). The RPA model was useful in identifying the risk factors for myelosuppression induced by cisplatin-based chemotherapy, and in defining patient subgroups with elevated risk of toxicity. PMID- 8698631 TI - Novel drimane sesquiterpene esters from Aspergillus ustus var. pseudodeflectus with endothelin receptor binding activity. AB - A series of novel drimane sesquiterpene esters (1-6) was isolated from fermentations of Aspergillus ustus var. pseudodeflectus and their structures elucidated by spectroscopic methods including the HMQC, HMBC and INADEQUATE NMR experiments. The major component of the fermentation, 1, was (2'E,4'E,6'E)-6-(1' carboxy-2',4',6'-trien)-9-hydroxydrim-7-ene-11 ,12-olide. Compounds 1, 2, 3 and 5 exhibited endothelin receptor binding inhibitory activity against rabbit endothelin-A and rat endothelin-B receptors with IC50 values in the range 20-150 microM. These compounds had similar levels of activity in assays for binding to human endothelin A and endothelin B receptors. The isolation of 9,11-dihydroxy-6 oxodrim-7-ene, 7, a probable biosynthetic precursor to the drimane esters is also reported. PMID- 8698632 TI - Melanoxazal, new melanin biosynthesis inhibitor discovered by using the larval haemolymph of the silkworm, Bombyx mori. Production, isolation, structural elucidation, and biological properties. AB - A new melanin biosynthesis inhibitor, melanoxazal, was isolated from the fermentation broth of Trichoderma sp. ATF-451 by successive purification procedures of carbon adsorption, ethyl acetate extraction and silica gel column chromatography. The inhibitor possesses a novel oxazole-containing structure with molecular formula, C8H9NO3. The structure was determined by means of NMR analyses to be (E)-4-(2'-formyl-3'-hydroxybuten-1'-yl) oxazole, which is related to melanoxadin. Melanoxazal inhibited melanin formation in the larval haemolymph of the silkworm, Bombyx mori; IC50 value = 30.1 micrograms/ml. Melanoxazal also showed a strong inhibitory activity against mushroom tyrosinase with IC50 value = 4.2 micrograms/ml. PMID- 8698633 TI - Further minor metabolites of staurosporine produced by a Streptomyces longisporoflavus strain. AB - From the staurosporine producing strain R-19 Streptomyces longisporoflavus various minor metabolites were isolated: They include new compounds with a keto function at carbon 4' of staurosporine and several metabolites related to TAN 1030A. The new structures were elucidated by spectroscopic methods, mainly 1H NMR and 13C NMR and by comparison with TAN-1030A. The new compounds inhibited protein kinase C with IC50 values in the micromolar range with the exception of those compounds that are alkylated at the lactam nitrogen. PMID- 8698634 TI - Novel mammalian cell cycle inhibitors, tryprostatins A, B and other diketopiperazines produced by Aspergillus fumigatus. I. Taxonomy, fermentation, isolation and biological properties. AB - Two novel diketopiperazines named tryprostatins A (1) and B (2) and a new natural product belonging to the diketopiperazine series, designated as demethoxyfumitremorgin C (3), together with four known diketopiperazines, fumitremorgin C (4), 12,13-dihydroxyfumitremorgin C (5), fumitremorgin B (6) and verruculogen (7), were isolated from the fermentation broth of Aspergillus fumigatus BM939 by the combined use of solvent extraction, silica gel column chromatography, preparative TLC and repeated-preparative HPLC. The diketopiperazines showed an inhibitory activity on the cell cycle progression of mouse tsFT210 cells in the M phase with the MIC values of 16.4 microM (1), 4.4 microM (2), 0.45 microM (3), 4.1 microM (4), 60.8 microM (5), 26.1 microM (6) and 12.2 microM (7), respectively. PMID- 8698635 TI - Novel mammalian cell cycle inhibitors, tryprostatins A, B and other diketopiperazines produced by Aspergillus fumigatus. II. Physico-chemical properties and structures. AB - Two novel diketopiperazines named tryprostatins A and B and a new natural product belonging to the diketopiperazine series, designated as demethoxyfumitremorgin C, together with four known diketopiperazines, fumitremorgin C, 12,13 dihydroxyfumitremorgin C, fumitremorgin B and verruculogen, are new M phase inhibitors of the mammalian cell cycle, which were isolated from the secondary metabolites of Aspergillus fumigatus. The structures of tryprostatins A, B and demethoxyfumitremorgin C were determined mainly by the use of spectroscopic methods especially by detailed analyses of their 1H and 13C NMR spectra with the aid of 2D NMR techniques including pulse field gradient heteronuclear multiple bond correlation (PFG-HMBC) spectroscopy. Their absolute configurations were determined on the basis of the optical rotational values and CD spectra. PMID- 8698636 TI - Novel triterpene sulfates from Fusarium compactum using a rhinovirus 3C protease inhibitor screen. AB - Two novel triterpene sulfates have been isolated from Fusarium compactum by bioactivity-directed fractionation using an assay which measures the inhibition of proteolytic activity of rhinovirus 3C protease on a fluorogenic peptide substrate. The compounds were purified by countercurrent and reverse phase chromatographies. NMR, MS, UV and IR studies revealed two triterpene sulfates, uncommon metabolites of terrestrial fungi. PMID- 8698637 TI - Ascosteroside, a new antifungal agent from Ascotricha amphitricha. I. Taxonomy, fermentation and biological activities. AB - Ascosteroside, a novel antifungal compound, was isolated from the culture broth of Ascotricha amphitricha. This compound is an alpha-linked glycoside of a lanostane type triterpenoid. It is active against yeasts such as Candida albicans and Saccharomyces cerevisiae and against filamentous fungi but shows no activity against bacteria. It is not toxic to mammalian cells at concentrations up to 150 microM. In a mouse model, the compound afforded protection comparable to that of ketoconazole. PMID- 8698638 TI - Ascosteroside, a new antifungal agent from Ascotricha amphitricha. II. Isolation and structure elucidation. AB - The novel antifungal agent ascosteroside (1) was isolated from cultured broth of Ascotricha amphitricha (ATCC 74237). The structure based on spectroscopic data was determined to be an alpha-linked glycoside of a lanostane-type triterpenoid. PMID- 8698639 TI - Epothilons A and B: antifungal and cytotoxic compounds from Sorangium cellulosum (Myxobacteria). Production, physico-chemical and biological properties. AB - An antifungal activity against Mucor hiemalis was detected in the culture broth of Sorangium cellulosum (Myxococcales) strain So ce90. The activity was excreted into the supernatant during the log and early stationary phase. When the adsorber resin XAD-16 was added to the culture, the active metabolites were quantitatively bound to the resin. The epothilons showed a high cytotoxicity for animal cells and mimic the biological effects of taxol (BOLLAG et al., Cancer Res. 55: 2325 approximately 2333, 1995). PMID- 8698640 TI - Structural determination of stevastelins, novel depsipeptides from Penicillium sp. AB - Structures of novel immunosuppressants, stevastelin A, B and B3(1) were determined by their spectroscopic and chemical studies. Three stevastelins were shown to be cyclic depsipeptides composed of a fatty acid and three amino acid moieties. The sequence of these moieties was determined to be as 3,5-dihydroxy 2,4-dimethylstearylvalylthreonyl (or O-sulfonylthreonyl in stevastelin A)-O acetylserine. Cyclic structures were shown to be formed by ester linkages between the carboxylic group of the O-acetylserine moiety and the 5-hydroxy group of the fatty acid moiety in stevastelin A and B, and the 3-hydroxy group of the fatty acid moiety in stevastelin B3. PMID- 8698641 TI - Absolute structural determination of stevastelin B. AB - Stevastelin B, obtained from a culture of a Penicillium sp. NK374186, is a novel depsipeptide containing three amino acids and 3,5-dihydroxy-2,4-dimethylstearic acid. The stereochemistry of the three amino acids was determined by HPLC analysis, and the relative configuration of the 3,5-dihydroxy-2,4-dimethylstearic acid was elucidated by chemical conversion and NMR analysis. The absolute stereochemistry of stevastelin B was determined by synthetic methods. PMID- 8698642 TI - Reductive alkylation of glycopeptide antibiotics: synthesis and antibacterial activity. AB - Reductive alkylation of the A82846 family of glycopeptide antibiotics has the potential of producing seven products. N-Alkylation of the disaccharide amino function can be accomplished selectively, and offers the greatest increase in antibacterial activity. Products resulting from N-alkylation of LY264826 (A82846B) provide the most potent derivatives as compared to other members of this class of antibiotics. Two of these derivatives, LY307599 and LY333328 are approximately 500 times more active than vancomycin against vancomycin-resistant enterococci. PMID- 8698643 TI - Cladinose analogues of sixteen-membered macrolide antibiotics. I. Synthesis of 4 O-alkyl-L-cladinose analogues via glycosylation. AB - The synthesis and biological evaluation of sixteen-membered macrolides possessing a 4-O-alkyl-alpha-L-cladinosyl moiety as the neutral sugar are described. The nine novel derivatives have been synthesized by glycosylation with 1-thio sugars. The most active derivative of them showed prolonged antibacterial activity in rat plasma in vitro and improved pharmacokinetics. PMID- 8698644 TI - New albrassitriols from Aspergillus sp. (FH-A 6357). PMID- 8698645 TI - Discovery of saricandin, a novel papulacandin, from a Fusarium species. PMID- 8698646 TI - Structure of furanocandin, a new antifungal antibiotic from Tricothecium sp. PMID- 8698647 TI - Structural features of carbapenem compounds for nephrotoxicity: effect of C-2 side chain. PMID- 8698648 TI - Deacylation of the glycopeptide antibiotic A40926 by Actinoplanes teichomyceticus ATCC 31121. PMID- 8698649 TI - Model experiments to establish behaviour of Yersinia enterocolitica O: 9 strains in various types of fresh dry sausage. AB - In model experiments different kinds of raw sausages were inoculated with liquid cultures of virulent-plasmid-carrying clinical Yersinia (Y.) enterocolitica (e.) strains of the O: 9 serotype, doses being between 10(4) and 10(5) cfu g-1. The sausage samples were stored at 3-5 degrees C and 13-16 degrees C. During the first 10 d of storage the Y.e. plate count was detected with Desoxycholate Citrate-Lactose-Sucrose Agar every day, later on in addition to it with phosphate buffer-enrichment and with enrichment according to Schiemann (1982) in intervals of several days' duration. The pH and aw values, the contents of salt and water were detected. The multitude of complexly acting factors and substances prevents obviously the proliferation of Y.e. in fresh dry sausages. Decay dynamics of Y.e. were found to be considerably affected by storage temperature. Cold storage, basically, had a conservation effect and thus delayed the dying process of model strains. Yersinia enterocolitica-contaminated fresh dry sausage may cause potential danger to consumers, because of relatively extended survival periods of the pathogen. Therefore, manufacturers are expected to observe most stringent hygienic rules of Good Manufacturing Practice. PMID- 8698650 TI - Minimum inhibitory concentrations of intestinal Escherichia coli from broiler chickens after oral administration of apramycin. AB - This study describes the influence of apramycin on minimum inhibitory concentrations (MIC) of intestinal Escherichia coli in young broiler chickens, after oral administration of the antibiotic at a dosage equivalent to a prophylactic course of treatment for 10 d. The bacteria were isolated from cloacal swabs and caecal contents. MICs were determined by agar dilution procedures. MIC of apramycin for the investigated strains ranged from 1 microgram ml-1 to 16 micrograms ml-1. Strains obtained from undosed birds mainly had MIC values of 2 micrograms ml-1. MIC values of 8 micrograms ml-1 or more were recorded only among isolates obtained from chickens which had received apramycin. Administration of apramycin resulted in a slight but statistically significant increase in the average MIC. Statistically higher average MICs were recorded among isolates from cloacal swabs 10 d after withdrawal until the end of the experiment. For strains from caecal contents, this was demonstrated only on one sampling occasion, 15 d after withdrawal. PMID- 8698651 TI - Serum survival and plasmid possession by strains of Salmonella enteritidis, Salm. typhimurium and Salm. virchow. AB - Strains of Salmonella enteritidis, Salm. typhimurium and Salm. virchow, carrying different numbers of plasmids, were examined for the ability to multiply in sera. Viable counts were performed to monitor the kinetics of growth of bacteria when in human, chicken and turkey sera. The presence of plasmids in Salm. enteritidis, Salm. typhimurium and Salm. virchow reduced considerably the ability of strains of these serotypes to multiply in serum. SDS-PAGE was used to show that growth of Salm. enteritidis in serum did not involve changes in outer membrane proteins or lipopolysaccharide. It was concluded that the carriage of plasmids may be disadvantageous for the survival in serum of certain common salmonella serotypes. PMID- 8698652 TI - Characterization of atypical Aeromonas salmonicida isolates by ribotyping and plasmid profiling. AB - A total of 38 strains of atypical Aeromonas salmonicida, three oxidase-negative but otherwise typical Aer. salmonicida, three typical Aer. salmonicida, and two reference strains, isolated from several countries and fish species were examined with respect to rRNA gene restriction patterns (ribotypes) and plasmid profiles. Most epidemiologically unrelated strains had different ribotypes, whereas isolates from the same outbreak were identical. All strains, except one, carried one or more large plasmids (> 55 kbp) and all strains, except two, additionally carried one or more smaller plasmids. Many strains isolated from the same outbreak showed different plasmid profiles although some plasmids were identical. The results suggest the existence of several atypical Aer. salmonicida. It also seems that ribotypes are stable properties for these bacteria while the plasmids are more labile. PMID- 8698653 TI - Characterization of the heterologous invertase produced by Schizosaccharomyces pombe from the SUC2 gene of Saccharomyces cerevisiae. AB - In order to gain information on the ability of Schizosaccharomyces pombe to process heterologous glycoproteins, the heterologous invertase, obtained from the expression in Schiz. pombe of the SUC2 gene of Saccharomyces cerevisiae, was characterized. In Schiz. pombe the heterologous invertase is secreted into the cell wall and seems to be firmly bound to this structure. After the isolation of the heterologous invertase the study of its enzymatic characteristics revealed that it is more similar to the Sacch. cerevisiae external invertase than to the Schiz. pombe invertase. However, it is glycosylated like the Schiz. pombe invertase since it reacts with the lectin from Bandeiraea simplicifolia seeds conjugated to fluorescein isothiocyanate, which indicates the presence of terminal galactose residues in the enzyme. Moreover, the presence of galactose in the heterologous invertase has been confirmed after analysis of the sugars present in its carbohydrate moiety by gas liquid chromatography. PMID- 8698654 TI - Foodborne disease and other hygiene issues in the home. PMID- 8698655 TI - Continuous cultivation of Saccharomyces cerevisiae at different biotin concentrations in nutrient media. AB - An increase of biotin concentration in nutrient media increased the content of protein, phosphorus, total ribonucleic acids, activity of pyruvate carboxylase and isocitrate lyase in cells and decreased the content of trehalose, glycogen and respiratory quotient of yeast cells in the course of continuous cultivation of Saccharomyces cerevisiae. PMID- 8698656 TI - Rapid estimation of Escherichia coli in live marine bivalve shellfish using automated conductance measurement. AB - Conductance measurement for quantitative estimations of Escherichia coli in live bivalve shellfish was evaluated as an alternative to the conventional most probable number (MPN) method used in France. The sensitivity of the two techniques was comparable. A single regression line (r = -0.968, P < 10(-6)) between log10 MPN and detection time (DT) was used to estimate E. coli concentrations for all shellfish examined. Estimation accuracy was +/- 0.92 log unit. Repeatability was better for DT than the log10 of MPN estimations (average coefficients of variation 2.7 and 9.3%, respectively). The conductance signal was attributable to E. coli in 96% of cases, and only 0.7% of E. coli cultures failed to exhibit a signal within 20 h. The conductance method reduces analysis handling time and is much easier to use than the MPN method. Moreover, results can be obtained within 5-9 h compared to 3 d for the MPN method. PMID- 8698657 TI - Production of brevicin 286 by Lactobacillus brevis VB286 and partial characterization. AB - Brevicin 286 was produced by Lactobacillus brevis VB286 isolated from vacuum packaged meat and was partially purified by ammonium sulphate precipitation, gel filtration and dialysis. The bacteriocin was susceptible to proteolytic enzymes, stable to heating at 100 degrees C particularly under acidic against Listeria sp. Production of brevicin 286 was optimal during exponential growth at 20 degrees C. Higher rates of cell growth occurred between 30 and 37 degrees C but with little or no expression of brevicin 286. A food-grade formulation consisting of 4% yeast extract and 1% glucose was found to be adequate for optimal brevicin 286 production and the bacteriocin-containing culture supernate was successfully spray dried with full recovery of antibacterial activity in the resultant powder. PMID- 8698658 TI - Quantification of Staphylococcus aureus and Escherichia coli in the liquid medium by fluorimetry and its use in phagocytosis assay. AB - A fluorimetric technique was compared with the plate counting method for quantification of viable cells of Staphylococcus aureus and Escherichia coli in the liquid medium. The fluorimetric assay measures the release of fluorogenic 4 methylumbelliferone (4-MU) from 4-methylumbelliferyl phosphate by the bacterial phosphatases. The increase in fluorescence was dependent on the size of bacterial inocula. Setting the fluorescence threshold at the middle of the logarithmic growth phase resulted in good linear relationship between bacterial counts and fluorescence (r = 0.99 for both Staph. aureus and E. coli). There was also an excellent correlation between the fluorimetric assay and the plate counting method in quantifying viable bacteria in saline (r = 0.99). Both methods were further compared for evaluation of extracellular bacteria following phagocytosis. The fluorimetric technique, in general, gave a higher percentage of phagocytosis than the plate counting method with statistical significance for E. coli. PMID- 8698659 TI - Interaction between fish spoilage bacteria Pseudomonas sp. and Shewanella putrefaciens in fish extracts and on fish tissue. AB - The interaction between fish spoilage bacteria, Pseudomonas sp. and Shewanella putrefaciens, was investigated using fish extract and fish tissue as model systems. Isolates of Pseudomonas that produced iron chelators, siderophores, inhibited growth of S. putrefaciens in a fish-extract-agar diffusion assay but no, or only weak, antagonistic activity was seen when the medium was supplemented with iron. Sterile-filtered supernatant fluid from a siderophore-producing Pseudomonas grown in fish extract was inhibitory to S. putrefaciens if the number of Psudomonas was above 10(8) cfu ml-1. In contrast, supernatant fluids from siderophore-negative Pseudomonas isolates did not inhibit growth of S. putrefaciens. The inhibitory effect was, except for one strain of Pseudomonas, not seen in supernatant fluids from iron-enriched cultures of Pseudomonas sp. Finally, siderophore-producing Pseudomonas sp. lowered the maximum cell level of S. putrefaciens 1-2 log units from 10(9) to 10(10) cfu g-1 when the strains were grown on fish muscle blocks at 0 degrees C but the growth rate of S. putrefaciens was not affected. PMID- 8698660 TI - Differentiation between Mycobacterium tuberculosis and Mycobacterium bovis by a multiplex-polymerase chain reaction. AB - A multiplex-polymerase chain reaction (PCR) assay, based on one-step amplification and detection of three different mycobacterial genomic fragments, was designed for differentiation between Mycobacterium bovis and Mycobacterium tuberculosis. The oligonucleotide primers were chosen from the groEL gene, present in the genus Mycobacterium sp., from the IS6110 insertion sequence, present in Myco. tuberculosis complex and from the mtp40 gene, identified as a specific-species Myco. tuberculosis genomic fragment. This amplification method allowed the detection of two fragments of 576 and 317 base pairs in Myco. bovis and three fragments of 576, 396 and 317 base pairs in Myco. tuberculosis strains, including atypical strains of Myco. tuberculosis where the copy number of the IS6110 element is low. The multiplex-PCR assay described may be a very useful tool for the rapid and specific differentiation of these related mycobacteria and easy to use in medical and veterinary microbiology laboratories. PMID- 8698661 TI - The use of an automated assay to assess phage survival after a biocidal treatment. AB - The coliphage K1-5 has been used in an automated assay to monitor the viricidal activity of various disinfectants. This indirect assay based on the spectrophotometric reading of the lysis of the host cell (Escherichia coli D837) produced encouraging results and was faster than the overlay counting method (previously studied) which relies on plaque formation. However, differences in sensitivity towards some disinfectants were observed between the two methods. PMID- 8698662 TI - Detection of Nitrosococcus oceanus in a Mediterranean lagoon by immunofluorescence. AB - The autotrophic ammonium-oxidizing bacterium Nitrosococcus oceanus was studied in the brackish lake of Ganzirri by cultural and immunofluorescent methods. The preparation of the specific antiserum in rabbits is reported. The polyclonal antiserum for Nitrosococcus oceanus cross-reacted with other ammonia oxidizing strains, but not with other marine bacteria. Temporal changes were determined by taking monthly water samples from a station 6 m deep and the distribution in sediments was investigated in four stations. Isolation of a strain of Nitrosococcus sp. was obtained from a sediment sample collected in December. The abundance of Nitrosococcus spp. bacteria correlated positively with particulate organic carbon (POC), particulate organic nitrogen (PON), temperature and total bacteria, whereas there was a negative relationship with oxygen tension. No correlation was found between immunofluorescent and MPN counts of Nitrosococcus spp. bacteria. PMID- 8698663 TI - Microbial biomass in a shallow, urban aquifer contaminated with aromatic hydrocarbons: analysis by phospholipid fatty acid content and composition. AB - The city of Perth contains a number of sites that have been contaminated with hydrocarbons due to leakage from petroleum underground storage tanks. Microbial biomass in groundwater and sediment cores from above and below the water table, and from within and outside a plume of hydrocarbon contamination, was examined using phospholipid fatty acid methyl ester analysis. Microbial numbers, calculated from the phospholipid content, ranged from 0.9 x 10(6) to 7.8 x 10(6) 'Escherichia coli equivalent cells' g-1 dry wt of sediment. Over 96% of the microbial biomass was attached to the sediment and the proportion of attached cells did not decrease within the plume of contaminants. The amount of biomass within aquifer samples seemed to be related more to the proximity of the rhizosphere to the shallow aquifer, and other unknown urban inputs, rather than to the effects of the plume of contaminants. Fatty acids common to many bacterial groups dominated within the plume, and as such the analyses gave limited insight into microbial community structure. For site assessment of intrinsic remediation of shallow aquifers in urban areas, estimates of microbial biomass may not provide information that is readily applicable to plume management. PMID- 8698664 TI - Regulation of the nisin operons in Lactococcus lactis N8. AB - The antibiotic peptide nisin produced by Lactococcus lactis is used as a food preservative due to its activity against spores and vegetative cells of Gram positive bacteria. The post-translational maturation of this secreted peptide includes dehydration of serine and threonine residues, lanthionine formation and a proteolytic processing of 23 amino acids from the N-terminus. Mutations in the nisZ, nisB and nisP genes of the biosynthetic nisZBTCIPRK nisin operon were made by gene replacement or integration of a plasmid. The mutations caused a drastic decrease of the transcription from the promoters upstream of the nisZBTCIPRK and nisFEG operons resulting in loss of nisin production and nisin immunity. The transcription of the nisin operons and nisin immunity could be partially restored by adding nisin to the growth medium of the cells. Nisin induction of the mutant strains also increased the level of the putative immunity NisI protein. These results showed that the nisZBTCIPRK operon is positively autoregulated and that the nisFEG operon is in the same regulon. PMID- 8698665 TI - Pediocin 5 production and plasmid stability during continuous free and immobilized cell cultures of Pediococcus acidilactici UL5. AB - Continuous production of pediocin 5 from Pediococcus acidilactici UL5 was investigated in MRS medium at different pH and dilution rates during continuous free cell (FC) and immobilized cell (IC) fermentations. Pediocin 5 activity from FC operated at a dilution rate of 0.31 h-1 largely increased from 128 to 2048 AU mL-1 as pH decreased from 7.0 to 5.0. Pediocin 5 activity in IC at a dilution rate of 0.93 h-1 was much less affected by pH, varying from 256 AU mL-1 at pH 7.0 to 512 AU mL-1 at pH 5.0. At the optimum pH 5.0, the dilution rate greatly influenced pediocin 5 activity both in FC and IC. Pediocin 5 production during continuous FC culture decreased with time for all dilution rates tested except 0.31 h-1 and average activity over 144 h cultures reached a maximal value of 4915 AU mL-1 at a dilution rate of 0.26 h-1. For IC, pediocin 5 production was stable with time and increased with the dilution rate from 256 to 1024 AU mL-1 in the range of 0.47-2.28 h-1. Three Listeria strains were tested for their ability to screen low bacteriocin-producing variants (Bac+v) of Bac+ cells in FC and IC cultures by using a modified deferred antagonism method. Ten to 28% of Bac+v cells appeared after 144 h of FC cultures at dilution rates in the range 0.09 0.42 h-1 and pH control set points of 5.0-7.0 while almost no Bac+v cell was detected during 192 h IC culture in the same pH range and for dilution rates varying from 0.47 to 2.28 h-1. The Bac+v cells isolated produced eight- to 64 fold less pediocin 5 than the Bac+ cells. Although electrophoresis analysis showed no apparent difference in the plasmid profiles of Bac+v and Bac+ cells, the Bac- mutant obtained by acriflavine treatment had lost the pMJ5 plasmid encoding for bacteriocin production. The decreased quantity of plasmid DNA in Bac+v cells suggests that the decreased pediocin 5 activity of Bac+v cells resulted from a decrease in plasmid copy number. PMID- 8698666 TI - A comparison of a new campylobacter selective medium (CAT) with membrane filtration for the isolation of thermophilic campylobacters including Campylobacter upsaliensis. AB - The newly developed CAT campylobacter selective medium employing the blood-free charcoal-based agar containing cefoperazone (8 mg l-1), amphotericin (10 mg l-1) and teicoplanin (4 mg l-1) was compared with the membrane filtration culture technique for isolation of Campylobacter spp. including Camp. upsaliensis. Nine hundred and fifty human, 275 dog and 65 cat faeces (in which modified CCDA medium was also compared) were tested. In addition, the recovery of Camp. upsaliensis from pure cultures and from spiked human faeces was examined after membrane filtration. A 50-fold reduction in recovery after filtration using the 0.65 micron filters and a 150-fold reduction using the 0.45 micron filters was found. Recovery of Camp. upsaliensis from spiked faeces was considerably improved using the CAT medium compared with filtration, especially with the lower concentration of organisms (approx. 10(4) cfu mL-1). Campylobacter upsaliensis was recovered from 91 specimens of animal faeces, with CCDA recovering 26 isolates (29%), CAT recovering 76 isolates (84%) and membrane filtration (0.65 microns) recovering 82 isolates (90%). CAT selective agar was found to be a suitable medium for the isolation of thermophilic campylobacters including Camp. upsaliensis from faecal samples. PMID- 8698667 TI - Use of two 16S DNA targeted oligonucleotides as PCR primers for the specific detection of Salmonella in foods. AB - A 16S DNA targeted polymerase chain reaction (PCR) method specific for the detection of Salmonella isolates with various serotypes was developed. The primers used for such a PCR method were 16SF1 and 16SIII. 16SF1 is the reverse and complementary strand of 16SI which has been shown to be able to hybridize with Salmonella and Citrobacter spp. 16III on the other hand, is able to hybridize with Klebsiella and Serratia spp. in addition to Salmonella. Although 16SF1 and 16SIII were not specific to Salmonella only, when they were used as PCR primers, only the Salmonella isolates could be specifically detected. The interference from Citrobacter, Klebsiella and Serratia spp. could be prevented. None of the other non-Salmonella isolates including strains of the family of Enterobacteriaceae closely related to Salmonella would generate the false positive reaction. When this PCR system was used for the detection of Salmonella cells artificially contaminated in food samples, results obtained were satisfactory. A detection limit of N x 10(0) cells per assay could be obtained. PMID- 8698668 TI - In vitro inhibition of Helicobacter pylori by extracts of thyme. AB - Extracts of several plants were tested for inhibitory activity against Helicobacter pylori. Among these plants thyme (aqueous extract) and cinnamon (alcoholic extract) were the most effective. Since aqueous extract of thyme is easier to produce and consume, it was further investigated. Compared with several antibacterials, the thyme extract had a significant inhibitory effect on H. pylori, reducing both its growth and potent urease activity. From the results of this study, the aqueous extract of thyme possesses a therapeutic potential which merits validation by clinical studies. PMID- 8698669 TI - Rapid physicochemical detachment, separation and concentration of bacteria from beef surfaces. AB - A simple, rapid, physicochemical treatment for the removal of viable bacteria from the surface of raw and cooked beef is described. The detachment method was linked to a differential centrifugation step which removed large amounts of particulate food matter and concentrated the detached bacteria. The method increased the numbers of bacteria released from beef surfaces and increased the numbers detected by at least one and a half orders of magnitude, when compared to the traditional 'stomaching' technique. This 1-h separation and concentration method produced cleaner suspensions of bacteria and improved the sensitivity of detection by DEFT and direct plate count. PMID- 8698670 TI - Note: development of an external quality assurance scheme for the detection and enumeration of Pseudomonas aeruginosa from water and comparison of results using modified King's A broth and a commercial agar. AB - Two trials of the isolation and enumeration of a given strain of Pseudomonas aeruginosa from water are reported. In each trial participants received concentrated samples from two batches, one with low and one with high counts, to be diluted to 500 ml in sterile distilled or deionized water and examined for Ps. aeruginosa by membrane filtration. Membranes were incubated at 37 degrees C for 48 h on pads soaked in modified King's A broth (MKAB) and Unipath Pseudomonas Agar plus CFC supplement (PCFC). The first trial involved eight Public Health Laboratories (PHL) and the organizers provided media from single batches. The second trial, involving 50 PHL, examined the feasibility of a large scale external quality assessment (EQA) distribution. Participants were invited to use the same two media and their usual medium if different. Average counts were close to expected and the spread of results was comparable to that observed from the EQA scheme for indicator organisms. From the results of the two trials a better isolation of the strain of Ps. aeruginosa under consideration was noted with PCFC compared with MKAB. PMID- 8698671 TI - Gloves: friend or foe? PMID- 8698672 TI - Tick, tock, tick, tock: have you seen any freckles with legs recently? PMID- 8698673 TI - Radiological case of the month. Sternalis muscle. PMID- 8698674 TI - New frontiers in obsessive-compulsive disorder spectrum research for psychiatry and primary care. PMID- 8698675 TI - Serotonin dysfunction disorders: a behavioral neurochemistry perspective. AB - The spectrum of efficacy of the serotonin selective reuptake inhibitor (SSRI) antidepressant drugs continues to expand. In fact, no psychiatric syndrome seems to worsen with these agents, and few studies fail to demonstrate clinical improvement in some patients, regardless of any nosologic nicety, such as precise DSM diagnosis. This suggests that the biological rubric of psychopathology is dimensional rather than categorical. New research using in vivo microdialysis shows differences in neurochemistry among SSRIs, wherein fluoxetine blocks reuptake of dopamine and norepinephrine, as well as serotonin, in medial prefrontal cortex, and fluvoxamine has a relatively more selective neurochemical profile. In the animal model of learned helplessness, which is a biobehavioral model for stress-induced anxiety causing depression, the SSRIs including fluvoxamine prevent helplessness. From these and other data, a neurotransmitter balance theory of biopsychopathology is formulated. In this hypothetical construct, dopamine, norepinephrine, and GABA modulate thought, anxiety, and mood, respectively. Serotonin is a stabilizing agent, which assists in returning the mind to its homeostatic setpoint. PMID- 8698676 TI - Serotonin selective reuptake inhibitor drug interactions and the cytochrome P450 system. AB - The article focuses on the effects of the serotonin selective reuptake inhibitors (SSRIs) on specific drug metabolizing isoenzymes: CYP2D6, CYP3A3/4, CYP1A2, CYP2C9, and CYP2C19. Both in vitro and in vivo data regarding the inhibition potential of the SSRIs at each of these isoenzyme systems are reviewed. In general, the magnitude of the in vivo interactions between the SSRIs and substrates for these isoenzyme systems mirrors to a large extent their in vitro inhibitory potencies. However, in vitro work is limited owing to pharmacokinetic considerations, the effect of metabolites on the isoenzymes, and the likelihood that several isoenzymes are co-responsible for the metabolism of a substrate. PMID- 8698677 TI - Functional neuroanatomy of obsessive-compulsive disorder. AB - Although obsessive-compulsive disorder (OCD) was once considered rare, recent epidemiologic data suggest a lifetime prevalence rate of 2% to 3%. The morbidity associated with OCD is quite high compared to other psychiatric conditions. This report reviews neurologic, neuropsychological, and psychosurgical findings relevant to the functional neuroanatomy of OCD. In addition, it describes more recent investigations of OCD using a variety of brain imaging techniques, including computed tomography, positron emission tomography, and single photon emission computed tomography (SPECT). Finally, it examines the results of an ongoing pilot study of high-resolution, full-volume, three-dimensional SPECT imaging in patients with OCD before and after treatment with fluvoxamine. PMID- 8698678 TI - Obsessive-compulsive and spectrum disorders: overview and quality of life issues. AB - Although obsessive-compulsive disorder (OCD) is among the most common of all psychiatric disorders, the diagnosis is frequently overlooked unless specific screening questions are asked by the treating physician. The obsessive thinking and compulsive behaviours that primarily characterize OCD can be found in other obsessive-compulsive "spectrum" disorders as well. These disorders affect a sizable percentage of the U.S. population and have thus become an increasing public health problem. Preliminary results from our comprehensive survey of OCD sufferers found significant impairments in quality of life and substantial costs associated with the morbidity and treatment of OCD. This is of particular interest to the primary care practitioner since these patients often present initially to primary care physicians, and early diagnosis and appropriate treatment can substantially improve outcome. PMID- 8698679 TI - An open trial of fluvoxamine therapy for panic disorder complicated by depression. AB - BACKGROUND: The efficacy of fluvoxamine in the treatment of panic disorder complicated by depression was investigated in an 8-week, single-group, open label, flexible-dose trial. METHOD: Seventeen patients having a principal diagnosis of panic disorder and scoring 16 or more on the 17-item Hamilton Rating Scale for Depression were treated with fluvoxamine at a mean final dose of 213 mg/ day. Outcome was assessed on measures of panic attacks, general and anticipatory anxiety, agoraphobic avoidance, depression, disability, and fear of anxiety symptoms. RESULTS: Subjects improved on all measures except agoraphobic avoidance. Thirteen either chose to remain on fluvoxamine treatment after the study ended or resumed taking it after a brief period without medication or on another medication. CONCLUSION: Fluvoxamine appears to be effective in this population. PMID- 8698680 TI - The characterization and treatment of trichotillomania. AB - Trichotillomania is an impulse control disorder characterized by chronic self directed hair pulling. Trichotillomania has additionally been viewed as one of the obsessive-compulsive spectrum disorders. Any body hair may be targeted, and most patients pull from more than one site. In clinical settings the disorder predominantly affects females. Onset is generally in childhood or adolescence, and a chronic course is typical. Depression and anxiety frequently accompany the disorder. An increased incidence of comorbid obsessive-compulsive disorder (OCD) has been noted. Neurobiological investigations have paralleled etiologic studies of OCD and have demonstrated both similarities and differences between these two disorders. Current treatment options include a variety of medications, particularly the serotonin selective reuptake inhibitors, the behavioral technique of habit reversal, and hypnosis. PMID- 8698681 TI - Compulsive buying: a review. AB - Compulsive buying has a long history. Described nearly a century ago by Kraepelin, and later by Bleuler, the disorder has been of interest to psychoanalysts and to the popular media. Recent interest has been rekindled by consumer behavior research that shows it to be widespread and psychiatric research that shows it to have the earmarks of a psychiatric disorder. The author reviews the history, definition, epidemiology, family history, etiology, clinical symptoms, and treatments of compulsive buying. Preliminary data from an open label study in which subjects received fluvoxamine are also presented. PMID- 8698682 TI - Fluvoxamine for premenstrual dysphoric disorder: a pilot study. AB - BACKGROUND: Serotonergic agents appear to be effective treatments for premenstrual symptoms in a number of small trials. The purpose of this open-label treatment study was to collect pilot information on the efficacy of fluvoxamine for premenstrual dysphoric disorder (PDD). METHOD: Twelve women who sought medical treatment for premenstrual symptoms were evaluated. The main outcome measure was the premenstrual score from daily symptom reports (DSRs) maintained by the subjects. After a 2-month screening period, 10 subjects who met DSM-IV criteria for PDD were treated with fluvoxamine taken daily for two menstrual cycles. The mean dose at 4 weeks was 85 mg/day; at 8 weeks, all subjects took 100 mg/day. RESULTS: The mean premenstrual DSR scores improved at 4 weeks from the pretreatment baseline (paired t test, p < .0008) and remained improved at 8 weeks at approximately the same level (p < .003). Symptoms with the greatest improvement (p < .003, significant with the Bonferroni adjustment) were irritability, anxiety, feeling out of control, and decreased interest in usual activity. Sixty percent (6/10) of the subjects reported at least a 50% reduction in the DSR scores, a conservative clinical definition of improvement. The mean premenstrual Hamilton Rating Scale for Depression scores decreased from 19 at the pretreatment baseline to 9 at the 4-week evaluation. The main side effects were insomnia (N = 6), fatigue (N = 4), dry mouth (N = 4), and nausea (N = 3) and were generally mild and transient. CONCLUSION: These promising pilot data show the importance of a controlled trial over a longer time period to provide definitive information on the efficacy of fluvoxamine for premenstrual dysphoric disorder. PMID- 8698683 TI - Body dysmorphic disorder: diagnosis and treatment of imagined ugliness. AB - Body dysmorphic disorder (BDD), a preoccupation with an imagined or slight defect in appearance, has been described for more than a century and reported around the world. However, this distressing and impairing disorder often goes undiagnosed, even though available data suggest that it is relatively common. Virtually any body part can be the focus of concern, with preoccupations most often involving the hair, nose, or skin. Most patients engage in excessive and repetitive behaviors such as mirror checking, skin picking, and reassurance seeking. Insight is generally poor, and many patients are frankly delusional. Most patients experience significant impairment in functioning, and suicide attempts are relatively common. Although the majority of patients with BDD seek often costly nonpsychiatric treatment-most often, surgical or dermatologic-such treatment usually appears to be unsuccessful. In contrast, preliminary data from open studies suggest that the serotonin reuptake inhibitors are often, and perhaps preferentially, effective for BDD. Augmentation, combination, and switching strategies may be useful in treatment-resistant cases. Preliminary data suggest that cognitive-behavioral strategies using exposure and response prevention may also be effective. Investigation of all aspects of this understudied disorder, including controlled treatment trials, is greatly needed. PMID- 8698685 TI - Obsessive-compulsive spectrum disorders in primary care: the possibilities and the pitfalls. AB - Although the serotonin selective reuptake inhibitors make the treatment of obsessive-compulsive spectrum disorders possible for primary care physicians, numerous obstacles to successful treatment in the primary care setting remain. Given the absence of studies of primary care patients in primary care settings, the generalizability of results from patients with obsessive-compulsive spectrum disorders in psychiatric settings is uncertain. The primary care physician must combat resistance and refusal by patients to accept psychiatric intervention. In addition, the primary care physician faces recognition problems--not only are patients reluctant to disclose such problems, but primary care physicians lack validated screening tools. The development of a new computerized compulsive impulsive spectrum scale should assist primary care physicians in diagnosing and treating obsessive-compulsive spectrum disorders, which may occur at a rate of 10% in the primary care setting. PMID- 8698684 TI - Open trial of fluvoxamine treatment for combat-related posttraumatic stress disorder. AB - A 10-week open-label trial of fluvoxamine was conducted for male Vietnam combat veterans with chronic PTSD. Subjects were excluded if they met full current criteria for panic disorder or agoraphobia, and lifetime criteria for psychosis, bipolar disorder, or organic mental syndrome. Repeated MANOVA was performed to determine change over time. Fluvoxamine was well tolerated; side effects were observed primarily early in treatment with headache, insomnia, sedation, and gastrointestinal distress being most frequent. Fluvoxamine was effective for treating the core intrusion, avoidance, and arousal symptoms of PTSD. Large treatment effects were seen by 4-6 weeks, and maintained at 10 weeks. The magnitude of change was greater than has been previously reported for antidepressant treatment of male Vietnam combat veterans with PTSD. PMID- 8698686 TI - Antidepressant treatment of binge-eating disorder: research findings and clinical guidelines. AB - Binge-eating disorder, characterized by recurrent eating binges without purging, affects a large number of individuals, especially among participants in weight loss programs. Recent studies have suggested that antidepressants, particularly serotonin selective reuptake inhibitors, may be effective in the treatment of binge-eating disorder. This paper reviews the findings of these studies and offers clinical guidelines for the use of antidepressants in binge-eating disorder. PMID- 8698687 TI - Diagnosis, neurobiology, and treatment of pathological gambling. AB - Pathological gambling is a disabling disorder that affects at least 2 1/2 million Americans and their families. Although pathological gambling has been characterized as an impulse control disorder, it has also been associated with compulsivity. Essential features of pathological gambling include constantly recurring gambling behavior that is maladaptive, in that personal, familial, and/or vocational endeavors are disrupted. Affective disorders and substance abuse often co-occur. Incidence of suicidality is extremely high. Despite the fact that this disorder is a widespread public health problem, few controlled studies of causes or treatment have been conducted. Preliminary neurobiological studies implicate serotonergic dysfunction in pathological gamblers. Treatment with serotonin reuptake inhibitors, such as clomipramine and fluvoxamine, may be effective in treating this disorder. Well-defined and controlled clinical trials in large samples of pathological gamblers are needed. PMID- 8698688 TI - Kinetic pathways and barriers for ligand binding to myoglobin. PMID- 8698689 TI - Effect of serum proteins on solution-induced surface transformations of bioactive ceramics. AB - The kinetics of immersion-induced surface transformation reactions of synthetic bone bioactive ceramics were studied in vitro in either protein-free or protein containing simulated physiological solutions. Both solutions had an ion content similar to that of plasma. Synthetic ceramics used for the study included Ca deficient hydroxyapatite (CDHA), stoichiometric HA either not well crystallized or well crystallized (s-HA nwc or s-HA wc), oxyhydroxyapatite (OHA), beta tricalcium phosphate (beta-TCP), and porous coralline HA (I-HA) and calcium carbonate (CC). Only CDHA and nwc s-HA led to immediate precipitation in both protein-free and protein-containing solutions. In contrast, reactions of wc HA and I-HA showed lag times to onset of precipitation in the protein-free solution and a further delay in the presence of proteins. The reactions of nonapatitic ceramics whose lag times in the protein-free solution were longer than those of apatitic, were completely blocked in the presence of proteins within the duration of the experiment (up to 3 days). CDHA and nwc s-HA were the only ceramics that, in the presence of serum proteins, led to the formation of B-type carbonated apatite, typical for calcified tissue apatite. PMID- 8698690 TI - Controlled release of antibiotics from coated orthopedic implants. AB - Chronic osteomyelitis is one of the most serious complications of orthopedic open fracture treatment. The objective of this study was to develop a biodegradable implant coating with impregnated antibiotics as an adjunct to current therapy. We used a polylactic-co-glycolic acid copolymer (PLGA) as the biodegradable carrier and gentamicin as the antibiotic. Our objectives were to establish elution characteristics of the antibiotic from the polymer, and determine if the coated orthopedic implants would inhibit bacterial growth in vitro. In the elution study, coated implants were incubated in phosphate buffered saline (PBS) at 37 degrees C and sampled daily for gentamicin levels. The in vitro model consisted of test tubes containing Mueller-Hinton culture broth inoculated with 5 x 10(6) cfu of Staphylococcus aureus and incubated at 37 degrees C. The implants were switched to a new set of inoculated tubes each day. Tubes were sampled for colony counting to determine bactericidal effects. Implant coatings consisted of 40 mg of gentamicin as a 20% mixture with PLGA. The elution curve showed an average level of 138 micrograms/mL over 15 days. This local concentration would be more than adequate to kill susceptible organisms. The in vitro study showed a significant reduction in bacterial growth in the test tubes containing coated implants. Control tubes averaged 2.5 x 10(8) cfu/mL of S.aureus over 24 days. Coated implant tubes averaged 0.9 cfu/mL. This was a reduction of greater than 99.999% (p < 0.0001). This study showed that a thin biodegradable implant coating can be developed with bactericidal activity against the organisms frequently associated with osteomyelitis in cases of open fractures. PMID- 8698691 TI - Characterization of electrolytically prepared brushite and hydroxyapatite coatings on orthopedic alloys. AB - Details of a procedure for electrolytically preparing highly pure brushite (CaHPO4.2H2O) coatings on high surface area metal substrates are provided. The influence of current density and deposition time on coating morphology is described. After a discussion of procedures used to convert the brushite coatings to hydroxyapatite, results from a preliminary animal study that demonstrate the propensity of these coatings to stimulate bony ingrowth into porous plugs are presented. PMID- 8698692 TI - In vitro platelet adhesion to nonionic and ionic hydrogels with different water contents. AB - To investigate in vitro platelet adhesion to hydrogels, using electron-beam irradiation, polymer reaction, and radical polymerization, hydrogels were synthesized to have a wide range of water content. The nonionic synthesized hydrogels include polyacrylamide (PAAm), poly(vinyl alcohol) (PVA), poly(ethylene glycol) (PEG), poly(N-vinyl pyrrolidone), and poly(methoxy-PEG methacrylate) while the ionic hydrogels were crosslinked poly(AAm-acrylic acid) and poly(AAm dimethylaminoethyl methacrylate) copolymers. Adhesion of washed rabbit platelets to these hydrogels were studied in phosphate-buffered saline for 30 min. In the case of PVA and PAAm hydrogels, platelet adhesion also was conducted in the presence of proteins. The protein sorption into PVA hydrogel was studied by fluorescent spectroscopy. It was found that all the nonionic hydrogels exhibited a lower level of platelet adhesion than did conventional hydrophobic polymers, such as medical-grade poly(vinyl chloride), polyurethane, and silicone, and they exhibited the minimum platelet adhesion at a water content of around 90%. PAAm and PEG hydrogels had the weakest interaction with platelets when the water content was lower than 90%. PVA hydrogel showed the highest platelet adhesion in the low-water-content region, but the platelet adhesion was greatly reduced in the presence of proteins. Significant protein sorption was noted when the water content of PVA hydrogel was as high as 80%. Introduction of a positive charge into the PAAm hydrogel promoted platelet adhesion whereas the negative charge introduced into the hydrogel slightly reduced the number of adhered platelets. PMID- 8698693 TI - Pillared-surface microstructure and soft-tissue implants: effect of implant site and fixation. AB - Previous work with subcutaneous implants in a rat animal model has shown that pillarlike surface microstructure will reduce fibrosis and enhance blood vessel approximation to the implant surface when compared with nontextured controls. This study was designed to determine the effect of microtissue anatomy and implant site on the observed response, as well as the effect of implant fixation. The lateral posterior sites were found to contain a fat pad which produced a dramatically reduced fibrosis for the micro-structured implants compared with smooth controls. Although significant differences between pillar-micro-structured implants and controls were found for most sites, neither fascia nor muscle reduces the level of cellular response to the same degree as fat. Suture fixation of the implants did not produce a significantly different response in these tests. The occupation of the interpillar spaces by fat and moderation of interfacial shear forces is proposed as a mechanism to explain these results. PMID- 8698694 TI - Plasticizer-level study of poly(vinyl chloride) ion-selective membranes. AB - Highly plasticized poly(vinyl chloride) (PVC) membranes (200 per hundred resin [phr]) form the basis of one class of ion-selective electrodes (ISEs). In previous work on the mechanical properties of membranes, the optimal ratio of plasticizer level employed to minimal level required for complete plasticization (phr(exp)/phrmin) was found to be 2.0. The current study was designed to determine whether this ratio is necessary or sufficient for proper ISE function. Dynamic mechanical analysis (DMA) was used to examine the effects of five plasticizers on the dynamic mechanical properties of membranes at three frequencies (110, 11.0, and 1.1 Hz) as a function of temperature (-100 degrees C to +100 degrees C); dioctyl sebacate (DOS), epoxidized propylene glycol dioleate (PGDO), ortho-nitrophenyl octyl ether (o-NPOE), epoxidized soybean oil (ESO), and epoxidized linseed oil (ELO). The glass transition temperature of PVC, which was found to be +77.1 degrees C at 11.0 Hz, was depressed by the addition of 200 phr of each plasticizer from a high of -1.4 degrees C (PGDO at 110 Hz) to a low of 70.2 degrees C (DOS at 1.1 Hz). DMA and electromotive-force (EMF) measurements on membranes plasticized with o-NPOE through a range of phr(exp)/phrmin from 0.5 to 9.3 indicated that a "transition window" occurs between phr(exp)/phrmin of 2.0 and 3.3 in which the membranes change from minimally plasticized polymer films to predictable ion-selective membranes, coinciding with the optimal mechanical properties observed previously. Based on dynamic mechanical properties and EMF response data, the optimal phr(exp)/phrmin++ ratios for membranes as a function of plasticizer were proposed: 0.8 for ESO and ELO, 1.3 for PGDO, 1.7 for DOS, and 3.0 for o-NPOE. PMID- 8698695 TI - Biocompatible coatings for luminal and outer surfaces of small-caliber artificial grafts. AB - Luminal and outer surfaces of small-caliber vascular grafts at an early implantation period may require completely opposite cellular responses: minimal cellular adhesion and fibrin formation for a luminal surface versus potent cellular adhesion and migration and matrix generation for an outer surface. Differentiated biocompatible design of luminal and outer surfaces into small caliber artificial grafts may lead to successful healing. We molecularly designed photocurable extracellular matrices (ECMs): photocurable chondroitin sulfate (CS) and hyaluronic acid (HA) for the luminal surface coating and photocurable gelatin for the outer surface coating. All of them were partially derivatized with photodimerizable groups such as thymine, cinnamate, and coumarin groups and converted to produce water-insoluble gels upon ultraviolet irradiation. In vitro study showed that platelet adhesion on photogelled CS and HA was significantly reduced, whereas endothelial cells adhered well on photogelled gelatin. These materials were individually coated and photogelled onto respective surfaces of artificial grafts (inner diameter [ID], 5 mm). During acute-phase implantation into dogs for up to 1 week, minimal cell adhesion was observed on the luminal surface, which was uniformly covered by photogelled CS or HA. Heparin impregnation of photocured ECM reduced fibrin formation. On the other hand, enhanced tissue ingrowth was noted at the outer surface. Although these ECM coated grafts need further improvement in molecular design and coating techniques, photocurable ECMs may contribute to successful healing and a high patency rate of small-caliber artificial grafts. PMID- 8698696 TI - Confocal laser-scanning microscopy for determining the structure of and keratinocyte infiltration through collagen sponges. AB - The development of artificial skin substitutes based on cultured cells and biomaterials such as collagen requires an understanding of cellular interactions with the substrate. In this study, human keratinocytes were cultured on the surface of collagen sponges, and confocal laser-scanning microscopy (CLSM) was used to assess both the microstructure of the sponge, and the cell morphology and distribution throughout the sponge. It was found that the pore size increased with increasing depth into the sponge. Both pore size and fiber thickness increased during incubation for up to 10 days at 37 degrees C in culture medium in the absence of cells. This latter effect was not observed when the sponges were incubated in distilled water. Keratinocytes penetrated into the sponge even after only 3 days in culture. By 10 days in culture, the cells had penetrated to the maximum depth that could be examined (120 microns from the sponge surface). In the presence of cells, the inner structure of the collagen sponge had altered after 10 days in culture, with the collagen fibers becoming thicker, and pore geometry less regular. The mechanism responsible for this is unknown at present. Although the presence of the keratinocytes increases distortion of the sponge structure, factors from the medium itself also contribute to this effect. CLSM is a powerful tool for assessing cellular interactions with bioimplants, providing both qualitative and quantitative information. It offers many advantages over scanning electron microscopy (SEM) and histological techniques. CLSM minimizes the time-consuming, extensive preparation of samples required with the latter two methods, and allows noninvasive serial optical sectioning of intact samples. PMID- 8698698 TI - Myoblast seeding in a collagen matrix evaluated in vitro. AB - Collagens may be used as biomaterials for soft tissue reconstruction, e.g., the abdominal wall. We previously developed a biocompatible dermal sheep collagen (DSC), which in an abdominal wall reconstruction model showed controlled biodegradation and functioned as a matrix for in-growth of fibroblasts but not of muscle. It was hypothesized that regeneration of muscle via DSC may be possible by seeding of muscle cells. Using a syringe, mouse C2C12 myoblasts were seeded in DSC disks and incubated in methylcellulose-based growth medium, changed at 24 h into differentiation medium. An estimated 85% of the cells were well distributed, especially in the top half of the DSC disks. Some 15% of the cells ended up on top. At 4 h, all cells showed a spherical morphology, sometimes with clear adhesion plaques. At 24 h, cells on the top started to form a "capsule" with well spread cells. Underneath the capsule, of the remaining 85% of the cells, approximately 30% showed adhesion and spreading on/in between collagen bundles. At day 3 after the addition of differentiation medium, the spread cells showed first indications of myotube formation. At day 7, myotube formation had proceeded, while extracellular matrix, i.e., collagen and elastin, had been deposited. This study shows that myoblast seeding into DSC is feasible, resulting in a reasonable cell distribution and survival of 45% of the cells. The surviving cells are able to differentiate into myotubes and form an extracellular matrix. PMID- 8698697 TI - Application of porous PEO/PBT copolymers for bone replacement. AB - A range of polyethylene oxide/polybutylene terephthalate (PEO/PBT) copolymers (70 30% PEO) was investigated for nonloadbearing bone replacement application. Porous PEO/PBT cylinders (d = 5 mm, h = 7 mm) were implanted transcortically in the diaphyseal femur of 10 goats, and the animals were sacrificed at 3, 6, 9, 12, and 26 weeks. Qualitative evaluation was performed using light and fluorescence microscopy, scanning electron microscopy, and back-scatter electron imaging with an attached X-ray microanalysis system. The percentage of bone ingrowth and the percentage of bone contact in the pore region were quantitatively assessed using undecalcified histological sections. The hydrogel properties of the PEO/PBT copolymers provided a rapid closure of the defect upon press-fit implantation, due to postoperative water uptake and subsequent swelling behavior of the materials. Bridging of the defect by bone and the occurrence of bone bonding were observed 6 weeks postoperatively for the material with the highest PEO content (70/30). For the 60/40 and 55/45 PEO/PBT proportions, union of the defect and bone bonding were observed at 9 and 12 weeks, respectively. The stiffer 40/60 and 30/70 PEO/PBT implants showed bridging of the 5-mm gap after 12 weeks, but did not reveal bone bonding up to 26 weeks. Peripheral fragmentation, mainly in the marrow cavity, was found for the 70/30 material at 12 weeks and had increased at 26 weeks. Degradation was not seen for the other materials. The histomorphometrical data confirmed the microscopical observations and demonstrated a direct relation between PEO content in the PEO/PBT co-polymers, the rate of bone ingrowth, and the amount of bone contact. Porous PEO/PBT copolymers are degradable, bone-bonding elastomeric substrates with favorable handling properties and a high percentage of bone ingrowth (69-78 at 26 weeks). It was therefore concluded that PEO/ PBT copolymers are highly promising materials for bone-replacement surgery. PMID- 8698699 TI - Crosslinking characteristics of porcine tendons: effects of fixation with glutaraldehyde or epoxy. AB - Anterior cruciate ligament (ACL) injuries, if left untreated, often produce significant disability in the athletically active population. Currently, autogenous tissue is the most commonly used substitute for ACL reconstruction because its immunogenicity is virtually nonexistent. However, the functional amount of autogenous tissue available for transplantation is limited. Additionally, this transplantation procedure may create a defect at the donor site, which can result in functional disability. To address these concerns, a prototype xenograft ligament prosthesis, epoxy-fixed porcine Achilles tendon, was developed. This study was intended to investigate the crosslinking characteristics of the epoxy-fixed porcine tendon. The fresh and glutaraldehyde fixed porcine Achilles tendons were used as controls. Fresh porcine Achilles tendons procured from a slaughterhouse were used to fabricate the ligament prostheses. A 4% epoxy (ethylene glycol diglycidyl ether) solution or a 0.625% glutaraldehyde solution was employed to fix the porcine tendons. Samples of each group were taken out at various elapsed fixation periods. The crosslinking characteristics- denaturation temperature, moisture content, and fixation index of each sample were then determined. In the study, it was learned that the crosslinking rate for the glutaraldehyde fixation was faster than that for the epoxy fixation. While the denaturation temperatures and the fixation indices for both studied groups were higher than for the fresh one, the denaturation temperature of the glutaraldehyde-fixed tendon was relatively higher than its epoxy-fixed counterpart. However, the fixation index and the moisture content for both studied groups were comparable. Also, it was noted that the epoxy-fixed tendon appeared more natural as compared to its glutaraldehyde-fixed counterpart. The implications of these findings for the epoxy-fixed tendon in the clinical ACL reconstruction require further investigation. PMID- 8698700 TI - Properties of collagen and hyaluronic acid composite materials and their modification by chemical crosslinking. AB - This article describes properties of composites of collagen-hyaluronic acid shaped to layered materials. According to the results, interactions of these two polymers are very strong. The properties can be influenced by chemical crosslinking using glyoxal and starch dialdehyde. The different behavior during enzymatic degradation by collagenase and in swelling experiments is discussed in relation to material composition. The valuable properties of the composites observed in this study show the possibility of their use as biomaterials. PMID- 8698701 TI - Coupled influence of substratum hydrophilicity and surfactant on epithelial cell adhesion. AB - The influence of substratum surface hydrophilicity and of a surfactant on human epithelial cell adhesion and protein adsorption was investigated. Therefore, tissue culture grade polystyrene (TCPS) and bacteriological grade polystyrene (BGPS) substrata were treated with different media, with or without Pluronic F68 [a poly(ethylene oxide) and poly(propylene oxide) triblock copolymer surfactant], and with or without type I collagen as a typical extracellular matrix protein. The conditioned substrata were submitted to XPS analysis and assayed for cell adhesion by inoculating Hep G2 cells in a chemically defined nutritive medium. The presence of collagen at the substratum surface is required to obtain attachment and spreading of Hep G2 cells. With PS substrata, treating with a solution of collagen does not promote cell adhesion if the solution contains Pluronic; XPS data show that this is due either to prevention of collagen adsorption or to its desorption by rinsing. With less hydrophobic TCPS substrata, the presence of Pluronic in the conditioning solution does not preclude cell adhesion, nor collagen adsorption. The effect of BGPS and TCPS substrata on Hep G2 cell adhesion is thus mediated by the presence of a surfactant that affects the adsorption of collagen. PMID- 8698702 TI - Studies on the biocompatibility of materials: fibroblast reorganization of substratum-bound fibronectin on surfaces varying in wettability. AB - The ability of human fibroblasts to remove and reorganize fibronectin (FN) bound on material surfaces was studied as a novel feature of material surface biocompatibility. Other traditional parameters of biocompatibility analyzed included cell spreading, clustering of fibronectin receptors into focal adhesions, development of stress fibers, and cell growth. Five different materials with surface wettability ranging from hydrophilic (underwater contact angle 25 degrees) to hydrophobic (underwater contact angle 111 degrees) were used, i.e., clean glass (GLASS), aminopropylsilane (APS), octadecylsilane (ODS), polylactate (PL), and silicone (SI). When cells were cultured on these materials in serum-containing medium, formation of FN receptor-rich focal adhesions and actin stress fibers were more evident on the hydrophilic surfaces (GLASS and APS) compared to the hydrophobic ones (PL, ODS, and SI). Cell growth showed a similar pattern, that is, increased cell proliferation with increasing material surface wettability. Preadsorption of FN on the material surfaces increased subsequent cell spreading and cytoskeletal reorganization on hydrophobic surfaces except SI. Removal and reorganization of FN from the material surfaces into extracellular matrixlike structures occurred on GLASS but not on less wettable surfaces, suggesting that this removal/reorganization process may be more sensitive to changes in surface wettability than other parameters of biocompatibility. PMID- 8698703 TI - Hydrogen peroxide toward enhanced oxide growth on titanium in PBS solution: blue coloration and clinical relevance. AB - Oxide films formed on titanium exposed to a phosphate-buffered saline solution with and without hydrogen peroxide (H2O2) addition were investigated by means of electrochemical impedance spectroscopy (EIS) and X-ray photoelectron spectroscopy (XPS). The oxide growth at the titanium/electrolyte interface was monitored in situ by daily EIS measurements during periods of several weeks. The results suggest that the oxide film can be described by a two-layer model with a barrier inner layer and a porous outer layer. H2O2 addition results in an increased dissolution/oxidation rate that leads to an enhanced oxide growth of the porous outer layer. As a result, the total oxide film can reach a thickness corresponding to an interference blue color. Based on XPS results, H2O2 addition furthermore seems to facilitate the incorporation of phosphate ions into the thicker porous layer. This observation may be related to the so-called osseointegration properties of titanium. PMID- 8698704 TI - Bacterial adhesion to orthopedic implant polymers. AB - The degradable polymers poly(orthoester) (POE), poly(L-lactic acid) (PLA), and the nondegradable polymers polysulfone (PSF), polyethylene (PE), and poly(ether ether ketone) (PEEK) were exposed to cultures of Staphylococcus epidermidis, Pseudomonas aeruginosa, or Escherichia coli. Bacteria washed and resuspended in phosphate buffered saline (PBS) adhered to polymers in amounts nearly twice those of bacteria that were left in their growth medium, tryptic soy broth (TSB). In TSB, there was variation in adhesion from species to species, but no significant variation from polymer to polymer within one species. In PBS there were significant differences in the amounts of bacteria adhering to the various polymers with the exception, of S. epidermidis, which had similar adhesion to all polymers. As a whole, P. aeruginosa was the most adherent while S. epidermidis was the least adherent. The estimated values of the free energy of adhesion (delta Fadh) correlated with the amount of adherent P. aeruginosa. When POE, PLA, and PSF were exposed to hyaluronic acid (HA) before exposure to the bacteria, there was 50% more adhesion of E. coli and P. aeruginosa on POE and PLA. With respect to bacterial adhesion, the biodegradable polymers (POE and PLA) in general were not significantly different from the nondegradable polymers. PMID- 8698705 TI - Influence of stress on calcification of delipidated bovine pericardial tissue employed in construction of cardiac valves. AB - Since the development of cardiac bioprostheses, numerous chemical treatments have been assayed to prevent mineralization. The effectiveness of chemical treatments that eliminate lipids from the tissue was tested by combining two models. First, handmade bovine pericardial bioprostheses, subjected to chemical treatment with chloroform/ methanol and glutaraldehyde or treated with glutaraldehyde alone for use as controls, were subjected to mechanical stress in a heart valve, accelerated wear tester (100 x 10(6) consecutive cycles). Then, the bioprostheses were unstitched and tissue samples were taken from the portion subjected to maximal stress (P1) and from that surrounding the sewing ring, which had not been subjected to mechanical stress (P2), for subcutaneous implantation. After 21 and 60 days of implantation, we observed calcification of the samples subjected to mechanical stress, even after delipidating treatment, with no significant differences with respect to the control group. However, the treated samples from the portion not subjected to mechanical stress presented a slighter accumulation of calcium after 60-day implantation (5.60 +/- 3.09 mg Ca2 +/g dry weight of tissue) versus the control group (47.17 +/- 20.4 mg Ca2+/g dry weight of tissue), the difference of which was statistically significant (p < 0.01). At the time of these medium-term studies, marked calcification was observed in tissue subjected to delipidating treatment in the zones that underwent mechanical stress. PMID- 8698706 TI - Users of traditional methods of contraception in Bangladesh: 1981-91. AB - This paper examines the changing patterns of knowledge, attitude and use of traditional methods of contraception, compared to modern methods, over the last five contraceptive prevalence surveys in Bangladesh (1981-91). The results show that knowledge of at least one method of family planning is universal in Bangladesh and usage is higher at all ages for women who are using modern methods than for those who are using traditional methods. Educated women and those in employment are more likely to use modern contraceptive methods. PMID- 8698707 TI - Factors affecting use of contraception in Matlab, Bangladesh. AB - This study examines the relationship between family planning, perceived availability of contraceptives, and sociodemographic factors in rural Bangladesh. Data are from the 1990 KAP survey in the Matlab treatment and comparison areas, using a sample of about 8500 married women of reproductive age. The contraceptive prevalence rate was 57% in the treatment area but substantially lower in the comparison area where mainly traditional methods of family planning were used by women who did not know of a source of supply of contraceptives. Education has no effect on contraceptive use in the treatment area but in the comparison area, modest but consistent differentials in use by level of education were found. Number of living children is the best predictor for contraceptive use, followed by number of living sons, and the attitude of respondents and their husbands towards family planning. PMID- 8698708 TI - Prior and proximate causes of infant survival in Ghana, with special attention to polygyny. AB - This study examines the role of marriage form in infant mortality and tests the relative effects and mechanisms through which polygyny affects infant survival. A sample of infants born in the 5 years preceding the 1988 Ghana Demographic and Health Survey was used. A causal model was constructed and polygyny was found to be an important mediating factor in understanding infant survival. The findings highlight the relevance of family structure (polygyny) as an intervening factor, but also reveal the complex role of ethnicity, dietary supplement and birth interval in accounting for infant survival. PMID- 8698710 TI - Biosocial perspective of consanguineous marriages in rural and urban Swat, Pakistan. AB - Consanguineous marriages in two population samples, one rural and one urban, from Swat (Pakistan) were studied. The frequency of consanguineous marriages was found to be 37.13% and 31.11%, and mean inbreeding coefficients were calculated as 0.0168 and 0.0162, for the rural and urban populations respectively. The most frequent type of marriage was between first cousins, in both samples. Among first cousin marriages, those with father's brother's daughter were predominant. Mean inbreeding coefficient was higher for higher socioeconomic groups in both samples. Differences by ethnic and educational groups were also found. Contrary to previous studies, a significant increase in the incidence of consanguineous marriages over the years has been observed. The incidence of premature mortality was significantly higher only in the offspring of first cousin marriages. Significantly higher incidence of morbidity in the offspring of consanguineous marriages was also observed. PMID- 8698709 TI - Influence of family head's reproductive behaviour on the use of modern contraceptive methods by other members of the family in rural Bangladesh. AB - A study in Bangladesh showed that the probability of use of modern contraception by eligible family members of a household increases significantly if the household head himself is a user. Multinomial logistic regression showed that contraceptive use was also significantly related with maternal age, parity, education, socioeconomic status and experience of child mortality. Inclusion of ever use of modern contraceptives by the family head or his wife, showed family head's religiosity to be a significant predictor of use, apart from his age and parity, and after controlling for socioeconomic correlates. PMID- 8698711 TI - Influence of body mass index and slimming habits on menstrual pain and cycle irregularity. AB - Using a cross-sectional sample of 1147 urban adolescents, aged between 14 and 20 years, the variability of some menstrual cycle indicators was related to weight loss. Nearly 40% of the adolescents tried to lose weight and the results showed that attempting to lose weight is significantly associated with increased prevalence of menstrual irregularity and menstrual pain. This finding is independent of body mass index. PMID- 8698712 TI - Contributions of the proximate determinants to fertility change in Botswana. AB - This study uses Bongaarts' model to examine the relative contributions of three proximate determinants (non-marriage, contraceptive use and postpartum infecundability) to fertility change using data from the 1984 and 1988 Botswana Family and Health Surveys. Breast-feeding is shown to be the most important proximate determinant of fertility, followed by contraceptive use, and finally non-marriage, both in 1984 and 1988. However, contraceptive use increased between 1984 and 1988, leading to fertility decline over this period. Marriage is the least important proximate determinant of fertility, probably due to the high prevalence of premarital childbearing. Other factors such as induced abortion could have played a major role in the fertility decline but their effect could not be estimated due to lack of accurate data. PMID- 8698714 TI - Social and economic factors related to breast-feeding durations in Tanzania. AB - Some social and economic factors related to breast-feeding durations in Tanzania are analysed using current status data taken from the 1991-92 Tanzanian Demographic and Health Survey. Proportional hazards and proportional odds models are estimated. The results show that breast-feeding durations vary according to the region of residence of the mother and child (and whether they are living in a rural or an urban area), the age of the mother at the time of the birth, the order of the birth, and the mother's religion. PMID- 8698713 TI - Sociodemographic risk factors associated with low birthweight in United Arab Emirates. AB - This case-control study was undertaken to determine sociodemographic risk factors for low birth weight in Al-Ain (United Arab Emirates) over a 12-month period in 1992-93. A total of 3485 live births occurred of which 293 (8.4%) were low birth weight. The risk factors considered were mother's occupation, house conditions, place of residence (urban or rural), maternal smoking habits, antenatal care, availability of help in the home, maternal BMI and educational status. Multiple logistic regression analysis showed that mother's occupation, maternal smoking, antenatal care, and lack of help in the home were associated with increased risk of low birth weight. PMID- 8698716 TI - Variations in Vietnamese marriages, births and infant deaths by months of the Julian calendar and years of the Vietnamese and Chinese astrological calendars. AB - The timing of births and marriages in Vietnam appears to have some statistically significant relationships with the signs of the Chinese and Vietnamese astrological calendars. Years considered to be good years have significantly more births and marriages than years that are not considered as desirable. Births and marriages also have some significant variations with seasons of the year. Infant deaths do not appear to have any significant relationships with the astrological signs although infant mortality has some significant relationships with seasons of the year. The findings indicate that there is some purposeful planning for marriages and births to coincide with optimal times defined in the astrological calendars. PMID- 8698715 TI - Using a mixture model to detect son preference in Vietnam. AB - Son preference is strong in Vietnam, according to attitudinal surveys and studies of contraceptive prevalence and birth hazards. These techniques assume a single model is valid for all families, but it is more plausible that son preference is found for some, but not all, families. Heterogeneous preferences may be addressed with a mixture model. This paper specifies and estimates a two-Weibull regression model, applied to the interval between the second and third births. The data come from the Vietnam Living Standards Survey of 1992-93. Applying information criteria, graphs, and martingale-based residuals, the two-Weibull model is found to fit better than a one-Weibull model. Roughly half of parents have son preference and, curiously, a propensity for fewer children. The other group has more children, no son preference, and is colourless in the sense that the birth interval is difficult to predict on the basis of the regressors used. PMID- 8698718 TI - Isolated rupture of the subscapularis tendon. AB - Sixteen consecutive patients were managed operatively for repair of an isolated traumatic rupture of the subscapularis tendon in the absence of avulsion of the lesser tuberosity. All of the patients were men. The diagnosis was made for each patient on the basis of the clinical examination and was confirmed by imaging studies and operative exploration. The operative treatment consisted of mobilization of the subscapularis after exploration and protection of the axillary nerve, transosseous reinsertion of the tendon to a trough created at the lesser tuberosity, closure of the rotator interval, and protection of the shoulder for six weeks postoperatively. The average duration of follow-up was forty-three months (range, twenty-four to eighty-four months). Thirteen patients subjectively rated the result as excellent or good. The average functional score of the shoulder, as assessed according to the system of Constant, was 82 per cent of the average age and gender-matched normal value. Active flexion was normal in twelve patients, was decreased by 15 degrees or less in three, and was severely limited in one patient. The capacity of the patients to work in their original occupations had increased from an average of 59 per cent of full capacity preoperatively to an average of 95 per cent postoperatively (p = 0.006). Operative treatment proved to be economically sound within the Swiss National Accident Insurance system. The quality of the result did not depend on the capacity for work at the time of the operation, on the type of work in which the patient was engaged, on the state of the biceps, or on the duration of follow-up. Conversely, the results were less successful when there was an increased delay from the time of the injury to the time of the operative repair. PMID- 8698717 TI - The effect of superior placement of the acetabular component on the rate of loosening after total hip arthroplasty. AB - A method for measurement of the true acetabular region and the approximate femoral head center as well as a classification consisting of four zones for assessment of the acetabular position of the acetabular cup were used to analyze the results of primary total hip arthroplasty with cement in 117 patients (145 hips). All patients had Crowe type-II congenital dysplasia of the hip. The mean age at the time of the arthroplasty was fifty-one years (range, fifteen to seventy-six years), and the mean duration of follow-up was fourteen years (range, two to twenty-two years). The initial position of the acetabular cup outside of the true acetabular region and outside of zone 1 (inferior and medial) was associated with an increase in the rates of loosening (p < 0.05) and revision (p < 0.04) of the femoral components. Cups that initially were more than fifteen millimeters superior to the approximate femoral head center, without lateral displacement, were associated with an increased rate of loosening (p < 0.001) and of revision (p < 0.04) of the femoral components as well as with an increased rate of loosening (p < 0.002) and of revision (p < 0.01) of the acetabular components. These findings suggest that superior positioning of the acetabular component, even without lateral displacement, leads to increased rates of loosening of the femoral and acetabular components. An attempt should be made to position the acetabular component in or near the true acetabular region. PMID- 8698719 TI - Motion of the ankle in a simulated supination-external rotation fracture model. AB - An experimental study was undertaken with use of axially loaded, unconstrained cadaver ankles to determine the motion patterns seen with progressive stages of the supination-external rotation type of fracture. As described by Lauge-Hansen, these fractures were modeled by transection of the anterior aspect of the capsule and the anterior tibiofibular ligament (stage I), followed by oblique fibular osteotomy ending at the level of the ankle joint (stage II), transection of the posterior aspect of the capsule (stage III), and sequential sectioning of the superficial and deep fibers of the deltoid ligament (stage IV). Thirteen specimens were tested on an apparatus that allowed for controlled loading while the ankle was passed through a physiological range of dorsiflexion and plantar flexion. The ankles were unconstrained about the axial (internal and external rotation) and coronal (varus and valgus angulation) axes. Measurements were made throughout the range of motion in these axes in order to define the kinematic behavior. In the intact specimens, maximum plantar flexion was associated with a mean (and standard deviation) of 1.9 +/- 4.12 degrees of internal rotation of the talus and maximum dorsiflexion, with a mean of 7.2 +/- 3.88 degrees of external rotation. Varus angulation increased slightly with plantar flexion compared with the value in dorsiflexion (2.4 +/- 2.40 compared with 0.3 +/- 1.96 degrees). Internal and external rotation was not affected by fibular osteotomy or by transection of the superficial fibers of the deltoid ligament. Transection of the deep fibers of the deltoid ligament caused a significant (p < 0.02) increase in external rotation of the talus at maximum plantar flexion; this was corrected incompletely by insertion of an anatomical fibular plate. With the numbers available for study, we could not show that varus or valgus angulation was significantly affected by any combination of sectioning of the deltoid ligament and fibular osteotomy. These experiments were repeated with the addition of fixation of the subtalar joint with a talocalcaneal screw. With the number of specimens available, we could detect no significant difference, with respect to axial rotation, due to fixation of the subtalar joint. However, along the coronal axis, increased valgus angulation (p < 0.02) was seen during plantar flexion when either the deep or the superficial fibers of the deltoid ligament had been cut. CLINICAL SIGNIFICANCE: These results indicate that stability of the loaded ankle is primarily due to the deltoid ligament, which exerts a restraining influence on external rotation of the talus. Complete fibular osteotomy did not cause abnormal motion of the ankle in the absence of a medial injury. In the presence of a complete injury, lateral reconstruction only partially restored the mechanical integrity of the ankle. The results provide justification for the non-operative treatment of isolated fractures of the lateral malleolus. The data also suggest that a lateral fracture associated with a major injury of the deltoid ligament should be treated with anatomical lateral fixation followed by immobilization without early motion, to allow adequate healing of the deltoid ligament at its resting length. PMID- 8698720 TI - Corrective osteotomy for osteonecrosis of the femoral head. AB - We reviewed the long-term results of thirty-seven corrective osteotomies that had been performed for osteonecrosis of the femoral head that was stage II or III according to the classification of Ficat and Arlet. At a mean of 11.5 years (range, five to eighteen years) postoperatively, twenty-eight hips (76 per cent) had a good or excellent result according to the Harris hip-scoring system, and nine (24 per cent) had a fair or poor result and subsequently needed a total hip arthroplasty. Six of the nine failures were in the seventeen hips of patients who had received corticosteroids. Conversely, of the twenty hips of patients who had not received corticosteroids, seventeen (85 per cent) had a good or excellent result as determined by the Harris hip score at the latest follow-up evaluation. Five of the six hips that had had a combined necrotic angle of more than 200 degrees preoperatively had subsequent collapse of the femoral head. Of the thirty one hips that had had a combined necrotic angle of less than 200 degrees preoperatively, twenty-seven (87 per cent) had a good or excellent clinical result. There were five complications. Three non-unions and one cutout of the compression screw were successfully treated, and these hips had an excellent clinical result at the time of the latest follow-up. The fifth complication was osteomyelitis and led to a poor result. The results of this study suggest that corrective intertrochanteric osteotomy is a successful treatment for Ficat and Arlet stage-II or III disease if the patient has a small or medium lesion (a combined necrotic angle of less than 200 degrees) and is not receiving continuous high doses of corticosteroids. PMID- 8698721 TI - Open fracture of the tibia in children. AB - The records of eighty-three children who had had an open fracture of the tibial metaphysis or diaphysis between January 1983 and July, 1993 were studied retrospectively. The average duration of follow-up was fourteen months (range, two to seventy-five months). There were twenty-four grade-I, forty grade-II, thirteen grade-IIIA, six grade-IIIB, and no grade-IIIC fractures, according to the classification scheme of Gustilo et al. Sixty patients (72 per cent) had sustained the fracture when they were struck by an automobile, and forty-eight patients (58 per cent) had other associated major injuries. All fractures were treated with irrigation and debridement, and antibiotics were administered parenterally for a minimum of forty-eight hours. Thirty-two patients were managed with immobilization in a cast only; forty, with transcutaneous fixation with an average of two Steinmann pins followed by immobilization in a cast; nine, with external fixation; one, with open reduction and internal fixation with two screws and two pins; and one, with delayed intramedullary nailing. Fifty-seven wounds were closed primarily (forty-four, over a Penrose drain, and thirteen, without a drain), ten were treated with delayed closure, four were allowed to heal by secondary intention, seven were covered with a soft-tissue flap, and five were treated with skin-grafting (a split-thickness skin graft was used for four, and a split-thickness and a full-thickness skin graft were used for one). The average time to union was fifteen weeks (range, five to sixty-one weeks), with the fracture healing by sixteen weeks in sixty-four patients (77 per cent). Eighteen patients (22 per cent) had delayed union, and only one patient (1 per cent) had non-union. Secondary procedures were necessary to achieve union in only two patients. Two patients had a superficial wound infection, and no patient had osteomyelitis. One patient, who had been managed with external fixation, had a pin-track infection; none of the patients who had had transcutaneous fixation had a pin-track infection. Two patients had a compartment syndrome, and two patients had a transient stretch injury of a nerve (the peroneal nerve in one and the sciatic nerve in the other). Four fractures healed with an angulatory deformity of more than 10 degrees in any plane. Five patients had overgrowth of the limb of one centimeter or more. Physeal arrest did not occur in any patient. We concluded that treatment of unstable open fractures of the tibia in children with debridement and transcutaneous fixation followed by immobilization in a cast leads to good anatomical and functional results. We prefer this technique to external fixation, which is associated with several potential complications. Loose closure of a clean open wound over a Penrose drain is effective and can be safely utilized in selected children. PMID- 8698722 TI - The teardrop in congenital dislocation of the hip diagnosed late. A quantitative study. AB - We retrospectively reviewed the radiographs of the pelvis and hips of forty-five patients who had unilateral congenital dislocation of the hip treated with closed reduction and application of a cast without subsequent operations. The radiographs were made at the time of the initial diagnosis, two years after the reduction, when the child was ten years old, and at skeletal maturity. The width, shape, and type of the teardrop; the thickness of the acetabular floor; the acetabular index; the center-edge angle; the articulotrochanteric distance; and the Severin class at maturity were measured in the dislocated and contralateral, normal hips. At the time of the initial diagnosis, a well defined teardrop was seen in thirty-six (80 per cent) of the normal hips and in seven (16 per cent) of the dislocated hips. There was no difference in the width of the teardrop in the seven dislocated hips compared with that in the normal hips, although the v shaped and crossed types of teardrops were more frequent in the dislocated hips. The v shape was not observed in the normal hips but was seen in sixteen dislocated hips two years after the reduction and in twelve dislocated hips when the children were ten years old. The superior and inferior widths of the teardrop of the dislocated hips were significantly greater than those of the normal hips (p < 0.001 and p < 0.05, respectively) when the children were ten years old. The hips with residual acetabular dysplasia had a v-shaped teardrop, widening of the superior width of the teardrop, and thickening of the acetabular floor. These hips, which were usually Severin class IV at the time of skeletal maturity, had a poor prognosis in adult life. PMID- 8698723 TI - Adolescent idiopathic scoliosis: treatment with the Wilmington brace. A comparison of full-time and part-time use. AB - We reviewed the clinical records and the radiographs of 188 patients who had adolescent idiopathic scoliosis. Our purpose was to determine whether part-time and full-time bracing had been equally effective in preventing progression of the curve. Full-time bracing had been used for ninety-eight patients; part-time bracing, for forty-nine; and electrical stimulation, for forty-one. Eighty-eight patients had had a curve of less than 30 degrees and 100 patients, a curve of 30 to 40 degrees. The treatment was considered a failure if the curve had increased 5 degrees or more. The curve progressed 5 degrees or more in thirteen (36 per cent) of the thirty-six patients who had had full-time bracing for a curve of less than 30 degrees, in thirteen (41 per cent) of the thirty-two who had had part-time bracing for such a curve, and in fourteen (70 per cent) of the twenty who had had electrical stimulation for such a curve. Compared with electrical stimulation, both full-time and part-time bracing prevented progression significantly more effectively (p < 0.02 and p < 0.04, respectively). With the numbers available, the difference in progression between the groups that had had full-time and parttime bracing was not significant (p < 0.18). The curve progressed 5 degrees or more in thirty-six (58 per cent) of the sixty-two patients who had had full-time bracing for a curve of 30 to 40 degrees, in ten of the seventeen who had had part-time bracing for such a curve, and in eighteen (86 per cent) of the twenty-one who had had electrical stimulation for such a curve. The difference in progression between each bracing program and electrical stimulation was significant (p < 0.03 for the full-time program and p < 0.05 for the part-time program). With the numbers available, the difference in progression between full-time and part-time bracing was not significant (p < 1.14). PMID- 8698724 TI - Brachioradialis transfer for wrist extension in tetraplegic patients who have fifth-cervical-level neurological function. AB - The brachioradialis tendon was transferred to the extensor carpi radialis longus and brevis tendons to restore active extension of the wrist in nine patients who had traumatic tetraplegia. The classification of neurological function was the fifth cervical level for all patients. The average time from the injury to the operation was six years (range, one to twenty years), and the average duration of follow-up was ten years (range, two to fifteen years). The evaluation of the patient included a determination of the preoperative and postoperative ranges of motion of the wrist, manual muscle-testing of the strength of the brachioradialis and the wrist extensors, a functional assessment of the ability to perform activities of daily living (eating, grooming, dressing, personal hygiene, and desktop activities [writing, typing, using a telephone, and so on]), and an assessment of functional independence. In addition, the result of the operation was evaluated subjectively by the patient. No patient had active extension of the wrist against gravity preoperatively. The strength of the wrist extensors improved postoperatively to a grade of good in six patients and to a grade of fair-plus in three. Function of the hand improved markedly in seven patients, and no patient had a loss of function. The patients had improvement in the ability to pick up objects, to feed and groom themselves, to tend to personal hygiene, to write and type, and to use a telephone. PMID- 8698725 TI - The bone-implant interface of femoral stems with non-circumferential porous coating. AB - A histological study was performed of the bone-implant interface of fifteen titanium-alloy femoral stems with porous coating limited to three proximal areas that did not cover the full circumference of the device. The specimens were obtained at autopsy from ten cadavera at a mean of forty-six months (range, one to eighty-nine months) after the implant had been inserted without acrylic cement. The volume fraction of bone within the porous spaces (the percentage of the porous space that was filled with bone) and the extent of bone ingrowth (the percentage of the porous-coated surface covered with in-grown bone that was more than one-half fiber-diameter deep, as measured from the outer surface of the porous coating), were determined with histomorphometric methods. Eleven of the fifteen stems had bone within the porous coating that was in continuity with the surrounding medullary bone. The mean volume fraction of bone ingrowth in these specimens was 26.9 per cent (range, 12.2 to 61.0 per cent), and the mean extent of bone ingrowth was 64.3 per cent (range, 28.6 to 95.2 per cent). Both of these parameters increased with time. In the other four stems, the bone lacked continuity with the surrounding trabecular bed. Two of these stems had a limited amount of bone within the porous coating, and two stems (from one patient) had no bone ingrowth. Periprosthetic membranes surrounded by a shell of trabecular bone covered the uncoated surfaces of the stems. The membranes of implants that had been in situ for eight months or more demonstrated polyethylene wear debris, and other particles generated at the level of the joint, within histiocytes throughout the length of the femoral stem. CLINICAL RELEVANCE: The findings in this study are relevant to the utilization and mechanisms of failure of femoral stems inserted without cement. Bone ingrowth and the resulting stability of the implant can be achieved with porous-coated stems. However, the extent of the surface that is porous-coated must be sufficient to prevent trabecular fracture as a secondary mechanism of loosening. Interruptions in the circumferential extent of the porous surface are associated with the formation of periprosthetic membranes, which provide a pathway for migration of particulate wear and corrosion products to the distal part of the stem. A circumferential coating may retard the access of particles and thus decrease the possibility of diaphyseal osteolysis. PMID- 8698726 TI - Long-term survival of chondrocytes in an osteochondral articular cartilage allograft. A case report. PMID- 8698727 TI - Pseudoaneurysm of the superficial palmar arch. PMID- 8698728 TI - Intra-articular penetration of the knee joint by a fragment of cortical bone during intramedullary nailing of the femur. PMID- 8698729 TI - Cellular biology of bone-resorbing cells. PMID- 8698730 TI - Prometheus and Zeus: the future of orthopaedic health care. PMID- 8698731 TI - Prometheus and Zeus: the future of orthopaedic health care. PMID- 8698732 TI - Prometheus and Zeus: the future of orthopaedic health care. PMID- 8698733 TI - Porous-coated acetabular components with screw fixation. Five to ten-year results. AB - The results of 136 consecutive primary total hip arthroplasties performed by one surgeon with the Harris-Galante-I porous-coated acetabular component were reviewed at a mean of seven years (range, five to ten years). In all hips, the outer diameter of the acetabular component was the same as the diameter of the final reamer used in the preparation of the acetabulum. However, this reamer was used only briefly at the rim of the acetabulum, and therefore the components had so-called press-fit stability. A mean of four screws (range, three to six screws) were used for additional fixation of the component. The clinical evaluation was performed with use of the Harris hip score. Standardized anteroposterior radiographs of the pelvis were assessed for migration of the component, radiolucent and radiodense lines, linear wear of the polyethylene, and osteolysis. No acetabular component had been revised for loosening and none were radiographically loose at the time of the most recent follow-up evaluation. There were no complications related to the use of the screws, and no screw had bent or broken. A non-progressive radiolucent line was seen in one acetabular zone in thirty-four hips (25 per cent) and in two acetabular zones in six hips (4 per cent). No hip had a radiolucent line in all three acetabular zones. The mean rate of linear wear of the polyethylene was 0.1 millimeter per year. There was no dissociation of the acetabular liner from the metal shell. Two hips (1 per cent) had asymptomatic osteolysis in the ischium and adjacent to the rim of the acetabular component; this was treated with grafting at the site of the lesion and exchange of the femoral head and the worn polyethylene liner. Five femoral components inserted without cement and one inserted with cement were revised because of loosening. The data suggest that, at a mean of seven years, fixation of this porous-coated component was uniformly excellent. The low prevalence of radiolucent lines and the absence of loosening are probably related, in part, to the technique of implantation. The low prevalence of polyethylene wear and pelvic osteolysis is a notable improvement compared with the results of arthroplasty with other porous-coated acetabular components. Although the results of the present study are encouraging, longer follow-up is necessary to determine the prevalence of late loosening and osteolysis. PMID- 8698734 TI - Revision of a failed cemented total hip prosthesis with insertion of an acetabular component without cement and a femoral component with cement. A five to eight-year follow-up study. AB - Sixty-one consecutive so-called hybrid revision total hip arthroplasties were performed in fifty-five patients by one surgeon, from 1986 through 1988, for mechanical failure of a cemented total hip prosthesis. In all of the patients, the acetabular and femoral components were revised to a porous-coated Harris Galante acetabular component inserted without cement and an Iowa femoral component inserted with cement. Contemporary cementing techniques were used, but structural bone graft was not. The over-all prevalence of repeat revision for aseptic loosening was 0 per cent for the acetabular components and 3 per cent (two hips) for the femoral components. In addition, 2 per cent (one) of the acetabular components and 5 per cent (three) of the femoral components demonstrated radiographic evidence of loosening. In the forty-three patients (forty-nine hips) who were alive at an average of seventy-four months (range, sixty to ninety-five months) after the revision, none of the acetabular components and 2 per cent (one) of the femoral components were revised again for aseptic loosening. An additional 2 per cent (one) of the acetabular components and 6 per cent (three) of the femoral components were radiographically loose. Ninety-eight per cent (forty-one) of the forty-two living patients (98 per cent [forty-seven] of the forty-eight hips) who had a clinical examination at least five years after the revision had increased function; 90 per cent (thirty-eight) of these patients (forty-four [92 per cent] of the hips) were satisfied with the result. The group that had a hybrid revision was compared with a group of seventy patients (seventy-four hips) who had had a revision total hip arthroplasty with use of contemporary cementing techniques for both components. These revisions had been performed by the same surgeon, before he performed the hybrid revisions, and the prevalence of repeat revision of the acetabular component was 7 per cent (five hips) and that of the femoral component was 4 per cent (three hips). In addition, 16 per cent (twelve) of the acetabular components and 3 per cent (two) of the femoral components were radiographically loose. The comparison group was not a consecutive series, as only the patients who had had radiographs made five to eight years after the revision were evaluated. In the fifty-two such patients (fifty-six hips) who were alive at five years after the revision with cement (average duration of radiographic follow-up, seventy-seven months; range, sixty to ninety-nine months), 9 per cent (five) of the acetabular components and 5 per cent (three) of the femoral components were revised again for aseptic loosening. An additional 21 per cent (twelve) of the acetabular components and 4 per cent (two) of the femoral components were radiographically loose. The results of the present study demonstrated a significant improvement (p = 0.0001) in the survival of the acetabular component of so-called hybrid revision total hip arthroplasties compared with that of revision total hip arthroplasties with cement performed by the same surgeon and followed for a comparable period. PMID- 8698735 TI - Total hip arthroplasty with cement in patients less than twenty years old. Long term results. AB - Sixty-three consecutive total hip arthroplasties were performed with cement in fifty adolescent patients from 1972 through 1980, and the results were determined after a minimum of ten years. A polyethylene cup without a metal backing and a non-modular femoral component with a collar and a fixed neck length were inserted, with use of so-called first-generation cementing techniques, in each hip. Kaplan-Meier survival analysis of all sixty-three hips demonstrated that the probability of failure (defined as revision or symptomatic loosening) increased steadily over time and reached 45 per cent after fifteen years. A number of specific variables were associated with a significantly higher probability of failure: a history of more than one previous procedure involving the hip (p = 0.0002), unilateral arthroplasty (p = 0.006), previous trauma involving the hip (p = 0.01), the absence of other disease that limited function of the ipsilateral lower extremity (p = 0.03), a high postoperative level of activity (involving moderate or strenuous manual labor) (p = 0.03), and a preoperative weight of more than sixty kilograms (p = 0.03). The probability of failure in the patients who had inflammatory arthritis (11 per cent) was significantly lower than that in those who had previous trauma involving the hip (47 per cent) (p = 0.0006). Fifty two hips (forty patients) were followed for a minimum of ten years or until revision. The mean duration of follow-up for these fifty-two hips was 12.6 years (range, 1.6 to 18.6 years). The result was evaluated clinically and radiographically with use of the Mayo hip-scoring system and was graded as excellent in ten hips (19 per cent), good in sixteen (31 per cent), fair in one (2 per cent), and poor in twenty-five (48 per cent). Most of the poor results were due to symptomatic loosening of the acetabular component. The probability of radiographic loosening after fifteen years was 60 per cent for the acetabular component and 20 per cent for the femoral component. Radiographic evidence of polyethylene wear was associated with probable loosening of the acetabular component (p = 0.03). The findings of the present study suggest that total hip arthroplasty in adolescents should be reserved for carefully selected patients for whom alternative procedures are contraindicated or unacceptable. Fixation of the acetabular component with cement is not recommended in this setting. PMID- 8698736 TI - Dexverapamil to modulate vinblastine resistance in metastatic renal cell carcinoma. AB - Multidrug resistance (MDR) in a variety of human tumours such as renal cell carcinoma (RCC) is thought to be caused by expression of the MDR1 gene and may be reversed by applying modern chemosensitisers such as dexverapamil, which inhibit the MDR1 gene product P-glycoprotein. This preliminary report gives information on a clinical study complying with good clinical practice regulations in patients with advanced RCC. The final evaluation is pending. Vinblastine, if anything the most effective chemotherapeutic agent (5-day continuous regimen), was combined with oral dexverapamil (6 times per day) as a chemosensitiser and dexamethasone to increase dexverapamil tolerance. All patients had histologically proven RCC, which was metastatic and progressive at study entry. The statistical design featured a pre-study regimen of two cycles of vinblastine alone followed by evaluation. If no response was documented, with all patients thus serving as their own control, dexverapamil and dexamethasone were added for three cycles of combination therapy. Having obtained institutional permission from the ethical review committee, we enrolled patients of whom 25 qualified for the combined treatment arm; 13 patients finished the study, 5 patients failed to complete all treatment cycles (1 because of treatment-related toxicity, 3 for personal reasons, not related to treatment, 1 for tumour-related reasons) and 7 patients were at too early a stage for evaluation. Altogether, 61% of all patients tolerated a dose of dexverapamil of at least 2400 mg/day with peak serum levels reaching, in some cases, approximately 8 microM (the sum of dexverapamil plus nordexverapamil levels). WHO grade 3 and 4 toxicities were mainly myelosuppression (5/18). The combination of 1.4 mg m-2 day-1 vinblastine plus dexverapamil was generally felt to be safe and well tolerated. One partial response and 7 stable diseases were noted in this heavily pretreated study population. Four-hourly administration of dexverapamil in combination with dexamethasone plus escalation to the individually tolerated doses have permitted increases in serum levels of dexverapamil. PMID- 8698737 TI - Randomised trial of vindesine and etoposide +/- dexverapamil in advanced non small cell lung cancer: first results. AB - To determine whether the chemotherapy resistance of non-small cell lung cancer could be modified by oral dexverapamil, the D-isomer of verapamil, 54 patients were entered into a randomised phase II study of oral dexverapamil plus chemotherapy (vindesine/etoposide) (arm B) versus chemotherapy (arm A) alone in January 1994. Chemotherapy consisted of intravenous vindesine 3 mg/m2 bolus on days one and five and etoposide 140 mg/m2 on days two and four. Dexverapamil was given for six days, 1500 mg a day divided into six doses of 250 mg every four hours starting 24 h prior to chemotherapy. According to the individual tolerability, the single dose could be increased up to a maximum of 400 mg. Cycles were repeated 3 weekly up to four courses. At this stage of the analysis, 34 patients (18 in arm A and 16 in arm B) are evaluable for toxicity and response. Cardiovascular side effects were more marked in the patient group with dexverapamil. On average, the dose of dexverapamil was 1800 mg a day. There were 5 partial remissions (31.3%) and 9 no changes (56.3%) in the group with dexverapamil as opposed to 2 partial remissions (11.1%) and 6 no changes (33.3%) in the group without dexverapamil. As far as the preliminary results show, the addition of dexverapamil to vindesine/etoposide chemotherapy in this study seems to be associated with improved outcome. PMID- 8698738 TI - Dexverapamil as resistance modifier in acute myeloid leukaemia. AB - In order to evaluate dexverapamil as a resistance modifier in acute myeloid leukaemia, we have added dexverapamil (4 x 300 mg/d orally) to DA chemotherapy (daunorubicin, cytosine arabinoside) in six patients with acute myeloid leukaemia. Two patients (1 first and 1 second relapse) achieved complete remission and two patients (1 refractory disease, 1 third relapse) showed some improvement. One patient in first relapse died due to disease progression and one drug-refractory patient remained refractory. The peak plasma levels of dexverapamil and nordexverapamil ranged from about 600 to 4100 ng/ml and from 450 to 1130 ng/ml, respectively. Major sideeffects were hypotension and sinus bradycardia. These results show the need for further evaluation of dexverapamil as a resistance modifier in acute myeloid leukaemia. PMID- 8698739 TI - Modulation of multidrug resistance by dexverapamil in EPOCH-refractory lymphomas. AB - We conducted a controlled trial of dexverapamil, an inhibitor of Pgp, in 45 Hodgkin's (HD) and 154 Non-Hodgkin's (NHL) lymphomas refractory to EPOCH chemotherapy. A total of 154 patients initially received EPOCH alone and (4.2%) with stable disease over two cycles or progressive disease "crossed over" to receive dexverapamil with EPOCH. Dexverapamil was escalated 8 dose levels, from 240 to 1200 mg/m2 per day. When possible, serial biopsies were obtained to measure MDR-1 expression by quantitative polymerase chain reaction. Median age was 44 years, 67% had stage IV disease, and median (range) prior regimens were 2 (1-12) in NHL and 1 (1-4) in HD. The maximum tolerated dose of dexverapamil was 900 mg/m2/day, and median plasma average concentrations of dexverapamil and nor dexverapamil were 1.2 and 1.4 microM, respectively. There were 3 complete and 2 partial responses (12%) and 5 minor responses in NHL, and 2 of 10 HD patients achieved partial responses. MDR-1 was measured in 44 biopsies from 19 patients. Pre-therapy, MDR-1 was low (median 2.5 U) but increased (median 12.2 U) at cross over. Among 6 patients with MDR-1 > 15, 3 responded to dexverapamil whereas only 1/8 patients with MDR-1 < 15 responded. EPOCH and dexverapamil were well tolerated. This study suggests that MDR-1 plays a role in clinical drug resistance of lymphomas, but also suggests that non-MDR-1 mechanisms are present in such patients. Earlier intervention with dexverapamil may be more effective and warrants further study. PMID- 8698740 TI - Dexverapamil to overcome epirubicin resistance in advanced breast cancer. AB - Resistance to cytotoxic chemotherapy is a major problem in the management of patients with metastatic breast cancer. Various data suggest P-glycoprotein associated multidrug resistance (MDR) to be a relevant resistance mechanism in this tumor. The purpose of this study was to evaluate feasibility and activity of combining oral dexverapamil, a second-generation chemosensitizer currently in clinical development for MDR reversal, with epirubicin in patients with epirubicin-refractory high-risk metastatic breast cancer. Patients first received epirubicin alone at 120 mg/m2. In cases of clinical refractoriness, epirubicin was continued at the same dose and schedule but supplemented with oral dexverapamil. Dexverapamil was given at 300 mg every 6 h for a total of 13 doses and commenced 2 days prior to epirubicin administration. At the time of this interim analysis, 41 patients had received epirubicin alone and 20 proceeded to treatment with epirubicin plus dexverapamil. Of the 20 patients, 14 were considered evaluable for toxicity and activity. Addition of dexverapamil resulted in a significant decrease in mean heart rate and blood pressure as well as prolongation of PQ time as compared to epirubicin alone. However, these cardiovascular effects of dexverapamil were usually mild, and subjective tolerance of treatment was good. In 7/14 patients, dose escalation of dexverapamil was feasible. Dexverapamil had no effect on epirubicin toxicities and did not require reduction of the epirubicin dose. In 2/14 patients, the addition of dexverapamil to epirubicin was able to convert progressive disease and no changes respectively, into partial responses. In 3 patients with progressive disease, addition of dexverapamil temporarily prevented further tumor progression. Analyses of dexverapamil and nor-dexverapamil plasma levels, of in vitro reversal activity of patient sera containing dexverapamil, and of epirubicin pharmacokinetics without and with dexverapamil are currently in progress. Addition of oral dexverapamil to epirubicin 120 mg/m2 proved to be feasible in a multiinstitutional setting. Patient accrual is continuing to determine whether dexverapamil is capable of overcoming epirubicin refractoriness in a significant number of patients with metastatic breast cancer. PMID- 8698741 TI - Phase I/II trial of dexverapamil, epirubicin and granulocyte/macrophage-colony stimulating factor in patients with advanced pancreatic adenocarcinoma. AB - A group of 28 previously untreated patients with locally advanced or metastatic adenocarcinoma of the pancreas were entered in this phase I/II study. Treatment consisted of oral dexverapamil 1000-1200 mg/day for 3 days, epirubicin given as an intravenous bolus injection on day 2 with a starting dose of 90 mg/m2, and 400 micrograms granulocyte/macrophage-colony-stimulating factor (GM-CSF) administered subcutaneously from day 5 through 14. Epirubicin dose escalation levels were 90, 105, 120 and 135 mg/m2. Consecutive cohorts of 4-8 patients were planned at each dose level. Treatment cycles were repeated every 3 weeks. Haematological toxicity, specifically granulocytopenia constituted the dose-limiting toxicity with a maximum tolerated dose of 120 mg/m2 for epirubicin. Despite routine supportive therapy with GM-CSF, 4, 2, and 5 patients experienced grade 4 granulocytopenia during their first two treatment courses at levels of 105, 120, and 135 mg/m2 respectively. Non-haematological toxicity was uncommon, generally modest, and did not demonstrate a clear relationship with the anthracycline dose. Dexverapamil-related cardiovascular symptoms occurred frequently, but they never resulted in serious toxicity requiring active medical intervention or permanent discontinuation of therapy. Of the 28 patients, 9 achieved partial reponses to this therapy. The recommended dose of epirubicin for this regimen with dexverapamil and GM-CSF is 120 mg/m2 every 3 weeks. Therapeutic results suggest this regimen to be an effective and tolerable treatment strategy in pancreatic cancer, which should be evaluated further. PMID- 8698742 TI - Carboplatin and cisplatin: are they equivalent in efficacy in "optimal residual" advanced ovarian cancer? PMID- 8698743 TI - Stem-cell factor regulates the expression of cyclin A and retinoblastoma gene product in the growth and differentiation pathway of human megakaryocytic cells. AB - The biological effects of c-kit ligand (stem-cell factor: SCF) on an immortalized human megakaryocytic cell line (CMK) was evaluated using methods including the 3 (4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, surface marker analysis, DNA cell-cycle analysis and immunoblotting. SCF stimulated the growth of CMK cells. Incubation with SCF resulted in increased expression of IIb/IIIa platelet-related glycoprotein (gpIIb, IIIa), indicating enhanced differentiation of CMK cells. Treatment of CMK cells with SCF resulted in a decrease in the subpopulation in the G1 phase, with a reciprocal increase in those in the S phase and the G2 + M phase. Moreover, SCF significantly increased cellular expression of cyclin A, a regulatory subunit of cyclin-dependent protein kinase (CDK), and the ratio of phosphorylated/dephosphorylated retinoblastoma gene product (RB protein). These results suggest that SCF stimulates the growth and differentiation of megakaryocytic cells possibly through mechanisms related to the activation of cell-cycle-dependent serine/threonine kinase and inactivation of the nuclear tumor-suppressor gene product. PMID- 8698744 TI - Distribution of Gs-alpha activating mutations in human thyroid tumors measured by subcloning. AB - In the search for the prevalence and distribution pattern of Gs-alpha gene mutations in differentiated thyroid tumors we examined 66 tumor tissue samples for the presence of mutations at "hot-spot" codons 201 and 227 using methods based on the polymerase chain reaction, subcloning and sequencing. The prevailing type of single-base substitution at codon 201 (71.4%) corresponded to the replacement of the wild-type sequence CGT (Arg) with TGT (Cys). The fragments of the Gs-alpha gene, including codon 201 or 227 from five follicular carcinomas and one follicular adenoma, were subcloned in Escherichia coli and it was found that the proportion of alleles with mutated codon 201 varied from 3.2% to 43%. Sequencing of the corresponding region has confirmed preliminary data indicating that the single-base changes CGT (Arg) to TGT (Cys) or CGT to CAT (His) occurred. There was only a weak correlation between the prevalence of cells bearing a mutation in the Gs-alpha gene and the level of Gs-alpha protein expression in the corresponding thyroid tumors. PMID- 8698745 TI - Analysis of T cell receptor V beta expression in rabbit T lymphocytes induced to proliferate by an HTLV-I-transformed leukemogenic T cell line. AB - Peripheral blood lymphocytes (PBL) from rabbits of the Chbb:HM strain proliferated in coculture with an X-ray-irradiated HTLV-I-transformed leukemogenic cell line of (B/J x Chbb:HM) F1 origin, whereas PBL from rabbits of the B/J and F1 strains hardly proliferated at all in co-culture with the same cell line. A proviral HTLV-I genome was detected in high-molecular-mass DNA from these proliferating cells. An analysis of T cell receptor V beta expression revealed that these lymphocytes were of restricted V beta subfamilies, suggesting that the preferential stimulation and transformation of lymphocytes occurred in this co-culture. Staphylococcal enterotoxins similarly stimulated lymphocytes and the proliferated lymphocytes were mostly of distinct V beta subfamilies depending on stimulator enterotoxins. These results suggested that the leukemogenic cell line possesses an antigen that preferentially stimulates lymphocytes of restricted V beta subfamilies. PMID- 8698747 TI - A cell-surface epitope associated with liver-preferential metastasis detected by the new monoclonal antibody 3H4 in the murine tumor model ER 15-P. AB - In the tumor model ER 15-P, a chemically induced pleomorphic myofibrosarcoma of the C57/Bl6J mouse, cell lines with liver-preferential metastatic tumor spread were selected in vivo. In order to describe cell-surface molecules relevant for hepatic metastasis, monoclonal antibodies were raised against the liver preferential variants. In a syngeneic immunization with viable tumor cells cyclophosphamide was used for augmentation of the humoral antitumor immunity. The monoclonal antibody mAb 3H4, an IgG2b isotype, reacted with a cell-surface epitope exclusively detected on the liver-preferential metastatic phenotype (Me) of the tumor model ER 15-P; no reactivity with the non-organ-specific metastatic phenotype (P) was observed. Regarding the morphological heterogeneity of different Me and P tumor cell populations, mAb 3H4 antigen expression was consistently associated with liver-preferential metastasis, not with different morphological stages of differentiation. It showed no cross-reaction with other tumor cell lines tested except MethA murine fibrosarcoma. The antibody was unreactive with normal tissue cells in C57/Bl6J mice. mAb 3H4 antigen expression was not dependent on the cell cycle. In an experimental assay of hematogenous metastasis, preincubation with mAb 3H4 significantly reduced the number of liver metastases of the liver-preferential tumor cells. Although no crossreaction of the primary ER 15-P with mAb 3H4 was observed, the antibody also significantly reduced the number of renal metastases of the P tumor cell population. The syngeneic IgG2b monoclonal antibody mAb 3H4 identified a new tumor-associated cell-surface antigen correlating with liver-preferential metastasis. mAb 3H4 antigen expression was a stable property of the liver-preferential tumor cells regardless of morphological diversity or functional cell status. In an in vivo blocking assay mAb 3H4 reduced liver colonization in vivo. PMID- 8698746 TI - Dexniguldipine hydrochloride, a protein-kinase-C-specific inhibitor, affects the cell cycle, differentiation, P-glycoprotein levels, and nuclear protein phosphorylation in Friend erythroleukemia cells. AB - Dexniguldipine hydrochloride (DNIG) is a potent antineoplastic agent with well documented anti-(protein kinase C) activity and an ability to reverse multidrug resistance. Given the importance of protein kinase C (PKC) activity in proliferation and differentiation, we examined the effect of DNIG on several parameters of Friend erythroleukemia cell (FELC) activity. Particular attention was paid to proliferation, hexamethylene-bisacetamide-(HMBA)-induced differentiation, nuclear localization of protein kinase C, and nuclear protein phosphorylation. P-glycoprotein expression was also followed as an indicator of changes in multidrug resistance. At 2.5 microM, DNIG caused a significant decrease in the rate of FELC proliferation, while maintaining a cellular viability of greater than 80%, whether exposure to the drug was continuous over 96 h or took the form of a 6-h pulse/chase. DNA synthesis was decreased in cells exposed to DNIG for 20 h. Flow cytometry showed a marked increase in the percentage of cells in S phase of the cell cycle. Phosphorylation studies revealed decreased phosphorylation of two nuclear proteins (80 kDa and 47 kDa) following a 4-h exposure to the drug. HMBA-induced differentiation was significantly inhibited with continuous exposure to DNIG, and this effect appears to be a pre-commitment one, as 6-h pulse/chase exposures also resulted in inhibition of differentiation. Cells induced to differentiate with HMBA also demonstrated a decrease in the quantity of the 80-kDa phosphoprotein. Western blotting revealed that, even in the face of decreased phosphorylation, exposure to this PKC inhibitor resulted in an increase in the amount of nuclear PKC alpha. Finally, levels of P-glycoprotein were decreased in the presence of this drug. Our work identifies several effects of the PKC inhibitor DNIG on FELC and suggests several roles for PKC in regulating FELC proliferation and differentiation. Additionally, these results suggest that this PKC inhibitor may increase the effect of other chemotherapeutic drugs, particularly S-phase specific ones, by increasing the length of S phase and decreasing multidrug resistance. The possibility of combination therapy with DNIG and other antineoplastic agents should be investigated further in light of these findings. PMID- 8698748 TI - Antioxidant and glutathione-associated enzymes in Wilms' tumour after chemotherapy. AB - The present study demonstrates the activities of antioxidant and glutathione associated enzymes and the level of glutathione in Wilms' tumour (nephroblastoma) samples after chemotherapy (mainly actinomycin D and vincristine). We observed higher activity of superoxide dismutase in Wilms' tumour compared to adjacent morphologically unchanged kidney. On the other hand, in this tumour lower activities of catalase and the glutathione-associated enzymes glutathione synthetase, gamma-glutamyl transpeptidase, glutathione reductase and total glutathione S-transferases (GST) were found. Using isoelectric focusing we separated different forms of GST in tested tissues and revealed lower activities of the basic enzymes in Wilms' tumour, which may be responsible for the decrease of total GST activity. Moreover, we found the acidic isoenzymes to be the predominant class of GST in nephroblastoma. In Wilms' tumours with unfavourable histology a high activity of these isoenzymes together with a high level of GSH were observed. We suggest that these parameters may participate in the known phenomenon of anticancer drug resistance of tumours with unfavourable histology. PMID- 8698749 TI - Immunostaining of p53 protein in ovarian carcinoma: correlation with histopathological data and clinical outcome. AB - OBJECTIVE: The objective of this study was to analyze the incidence of immunohistochemically detectable p53 protein accumulation in epithelial ovarian carcinomas and to correlate these data with the clinical outcome so as to clarify further the role of p53 mutations in prognosis with these patients. METHODS: Tumor tissues from 179 patients with epithelial ovarian carcinoma were used for immuno-histochemical analysis with monoclonal antibody DO1 and BP 53-12-1 on formalin-fixed, paraffin-embedded tissue. RESULTS: A total of 78 cases (44%) showed positive nuclear p53 staining. The p53-positive cases were found in all histological types of epithelial ovarian tumors. p53 staining was found in tumors of all stages with a higher percentage of positive cases in stage IV ovarian carcinomas (not significant). Poorly differentiated carcinomas showed a significantly higher percentage of p53 protein expression than did highly differentiated tumors (P = 0.0002). Clinical follow-up of up to 14 years (median 25 months) showed a slightly but not significantly shortened disease-free and overall survival time for patients with p53-positive epithelial ovarian carcinomas. CONCLUSIONS: We conclude from our data that p53 expression in ovarian carcinoma is associated with poor differentiation but not with the disease being in an advanced stage. There was a tendency for shortened disease-free and overall survival for patients with p53-positive tumors. PMID- 8698750 TI - Aromatase in breast cancer tissue--localization and relationship with reproductive status of patients. AB - The precise place of local estrogen production in mammary cancer is still controversial. In this investigation localization of aromatase (the key enzyme of estrogen biosynthesis) was studied in breast cancer tissue by immunohistochemical method using polyclonal rabbit antibodies. The cytoplasmic staining was found in different cell types, but the most intensive specific staining was found in malignant cells and it was stronger (P < 0.01) in postmenopausal patients than in patients of reproductive age. PMID- 8698751 TI - Carcinoembryonic antigen, tissue polypeptide antigen and neuron-specific enolase pleural levels used to classify small-cell and non-small-cell lung cancer patients by discriminant analysis. AB - The classification of lung cancer into small-cell lung cancer (SCLC) and non small-cell lung cancer (NSCLC) is essential for disease prognosis and treatment. For this purpose, we have tried to optimize the use of three tumour markers determined on pleural effusions, to differentiate SCLC from NSCLC by means of a canonic variable, generated by discriminant analysis, including subjects with histologically proven lung cancer. Discriminant analysis was performed by using carcinoembryonic antigen, neuron-specific enolase and tissue polypeptide antigen pleural levels, determined in 65 consecutive and unselected patients, histologically classified as 49 NSCLC and 16 SCLC. To validate the formula generated, a control group of 37 lung cancer patients (10 SCLC and 27 NSCLC), enrolled subsequently, was employed. Applying the discriminant analysis to SCLC and NSCLC patients a good classification was obtained (92% rate of correct classification). The aforementioned formula, applied to the validation group, showed a 92% rate of correct classification. This method, which is rapid, inexpensive and routinely applicable to malignant pleural effusions, may be reliably used to classify lung cancer patients. PMID- 8698752 TI - Factors influencing tumor cell kinetics in cervical cancer. AB - Fresh tumor tissues instead of paraffin-embedded sections were used to study the clinical significance of the tumor cell kinetics in cervical carcinomas by flow cytometry. We analyzed specimens from 153 women with cervical cancer, and DNA aneuploidy was found in 61 cases (39.9%). The mean age of patients with aneuploid tumors was significantly higher than the age of patients with diploid tumors (P < 0.001). The mean proliferation index for aneuploid tumors was significantly higher than those for diploid tumors. There was a significant correlation between the proliferation index and age. However, tumor cell kinetics is not related to the status of human papillomavirus, herpes simplex virsuses I and II, lymph nodes, histology or tumor size. The mean age and S-phase fraction for stage-II tumors were significantly higher than those for stage-I tumors (P < 0.01). The tumors of menopausal patients exhibited a relatively higher rate of lymph node metastasis, and significantly higher aneuploidy rate and proliferation index than tumors of premenopausal patients. In summary, age and, what is more important, menopausal status may significantly influence DNA ploidy and cell kinetics of tumors, and subsequently influence clinical stage and lymph node metastasis. However, tumor cell kinetics is of limited value in the prediction of lymph node metastasis and prognosis. PMID- 8698753 TI - The effect of allopurinol on interstitial purine metabolism and tissue damage in skeletal muscle I-R injury. AB - OBJECTIVE: Many studies show that allopurinol can reduce skeletal muscle I-R (ischemia-reperfusion) injury, but the mechanism of the effect is still unclear and some studies suspect the effect. In this study, we determined whether allopurinol really reaches to reperfused muscle and reduces tissue injury by inhibiting xanthine oxidase or not. EXPERIMENTAL DESIGN: In this study, microdialysis method combined with HPLC (high performance liquid chromatography) were employed and purines, MDA (malondialdehyde), allopurinol in gracilis muscle were measured continuously in I-R injury model of canine gracilis muscle. The effect was compared between Group N (no treatment: n=8), Group P (pre-ischemic treatment: n=8) and Group R (pre-reperfusion treatment: n=8). RESULTS: Allopurinol reduced the increase of xanthine, uric acid, MDA in the muscle and CPK in blood effluent from gracilis muscle after reperfusion. Tissue protecting effect of allopurinol was more effective in group R than in group P. CONCLUSIONS: By continuous measurement of purines, allopurinol and MDA in canine gracilis muscle during 5 hr ischemia and 2 hr reperfusion, it was proved that allopurinol was delivered to reperfused skeletal muscle and reduced I-R injury by inhibiting xanthine oxidase. PMID- 8698754 TI - Hemodilution in complicated high velocity vascular injuries of limbs. AB - Normovolemic hemodilution with 3,5% polygeline was carried out in fourteen ASA (American Society of Anesthesiologists) Class-I patients, who had developed false aneurysms or arteriovenous fistulas following high velocity injury on limbs. At the end of surgical procedure volume of mean blood drained was 1400.00 +/- 194.46 ml, mean surgical blood loss was 1665.71 (+/- 33.9) ml and fluid balance was 557.14 (+/- 176.40) ml. Arteriovenous oxygen content difference (C(a-v) O2), central venous pressure (CVP), heart rate and mean arterial pressure (MAP) did not show any significant variation from pre-hemorrhage value. Hematocrit (Hct%) and hemoglobin (Hb gm%) showed a highly significant fall following hemodilution and retransfusion. However on the day of discharge Hct% (37.5(+/- 3.88) and Hb gm% (12.84 (+/- 0.82) had increased from post hemodilution value of 28.96 (+/- 1.98) and 10.04 (+/- 0.87) respectively. 71% patients did not need any homologous blood transfusion. Prothrombin time index (PTI%) showed 7.5% fall at the conclusion of blood retransfusion and 3.94% fall on the day of discharge. Technique is safe, avoids use of homologous blood and is thus recommended during surgical correction of complicated high velocity vascular injury of limbs. PMID- 8698755 TI - Reconstruction of major arteries of lower extremities after war injuries. Long term follow up. AB - During 18 months' period of war in northeastern Croatia 38 wounded with injuries of lower extremity arteries were operated on in Osijek Department of Surgery demanding the use of substitute conduit for vascular reconstruction; 26 synthetic prosthesis and 12 vein grafts were applied. Ankle-brachial index and life-table method were used for the construction of the initial and cumulative limb salvage rate at 40 months. Cumulative graft patency and limb salvage rates for synthetic grafts was 87.67% +/- 6.9 and for vein grafts 91.67% +/- 8.0 respectively and did not differ significantly for both synthetic prosthesis and autologous vein grafts. PMID- 8698756 TI - Protection by coenzyme Q10 of tissue reperfusion injury during abdominal aortic cross-clamping. AB - PURPOSE: To evaluate the effect of coenzyme Q10 in reducing the skeletal muscle reperfusion injury following clamping and declamping the abdominal aorta. METHODS: 30 patients undergoing elective vascular surgery for abdominal aortic aneurysm or obstructive aorto-iliac disease were randomly divided into two groups: patients in group I were treated with coenzyme Q10 (150 mg/day) for seven days before operation, and those in group II received a placebo. We studied the hemodynamic profile in each patient during clamping and declamping of the abdominal aorta. The plasma concentrations of thiobarbituric acid reactive substances (malondialdhehyde), conjugated dienes, creatine kinase and lactate dehydrogenase were measured in samples from both arterial and inferior vena cava sites. Serial sampling was performed after induction of anesthesia, 5 and 30 minutes after abdominal aortic cross clamping, 5 and 30 minutes after aortic cross-clamp removal. RESULTS: The concentrations of malondialdehyde, conjugated dienes, creatine kinase and lactate dehydrogenase in patients who received CoQ10 were significantly lower than in the placebo group. Decrease of plasma malondialdehyde concentrations correlated positively (p < 0.01) with decrease of both creatine kinase and lactate dehydrogenase release in samples from the inferior vena cava. The hemodynamic profile during clamping and declamping the abdominal aorta was similar in both groups. CONCLUSIONS: Our findings suggest that pre-treatment with coenzyme Q10 may play a protective role during routine vascular procedures requiring abdominal aortic cross clamping by attenuating the degree of peroxidative damage. PMID- 8698757 TI - Compartment-syndrome of the lower extremity after CABG. AB - Three cases of compartment-syndrome of the lower extremity are presented as an example of a specific type of compartment syndrome of the donorleg after CABG. The possible factors contributing to this complication are being discussed, and guidelines are given to adequately diagnose and treat this problem. PMID- 8698758 TI - Ischemia of spinal cord following elective operative procedures of the infrarenal abdominal aorta. AB - OBJECTIVE: Ischemia of the spinal cord following procedures of the infrarenal abdominal aorta and the iliac arteries due to aneurysmatic or occlusive disease. DESIGN: Retrospective study, duration of follow up: two years. SETTINGS: Vascular Department of the 2nd Surgical Clinic of the University of Athens, Medical School. PATIENTS: 1,112 operative procedures to the infrarenal abdominal aorta and iliac arteries, carried out from January 1, 1976 to June 30, 1994; 665 cases were aneurysms, electively operated, to which a tube graft was placed in 390 and a bifurcated graft in the remaining 265. Similarly 457 bifurcated prostheses were placed due to stenotic disease. INTERVENTIONS: Aneurysmectomy, graft insertion. MEASURES: Death, severe disability. RESULTS: Ischemic damage to the spinal cord was noted in two cases postoperatively. The first case following placement of bifurcated prosthesis due to high occlusion of the abdominal aorta and the second case following resection of an aneurysm and placement of a tube graft. One of the patients passed away on the 43rd postoperative day, and the other 18 months after was able to stand but, however, could not walk easily without the help of another person. CONCLUSIONS: The complication seems to be multicausal, carrying a bad prognosis and cannot be foreseen. The stable hemodynamic condition of the patient during the operative and postoperative period with revascularisation of at least one hypogastric artery, reduces the time of aortic occlusion and securing collateral circulation might reduce these complications. Also preopeorative angiography of the spinal cord with more sophisticated techniques, might constitute the most reliable prognosis in the future. PMID- 8698759 TI - Twice sealed-rupture of a small abdominal aortic aneurysm with unusual computed tomography findings. A case report. AB - Small abdominal aortic aneurysm rupture is uncommon and fatal. We report a case of twice sealed-rupture small abdominal aneurysm 3.5 cm in diameter. Computed tomography showed unusual findings of a hematoma-like multiple cyst around the small aneurysm. We were bothered the diagnosis. By the intraoperative finding; an irregular pseudoaneurysm, the final diagnosis was performed. After aneurysmectomy, artificial graft replacement was made. From only this case, discussion of the indications for the small abdominal aortic aneurysm is difficult. However, the possibility of the rupture in even this [correction of thus] small abdominal aortic aneurysm should be considered. PMID- 8698760 TI - Classification of origin and proximal epicardial course of coronary arteries in transposition of the great arteries. AB - The complexity of the variability in aortic origin and epicardial course of the coronary arteries relative to the pedicles of the great arteries in hearts with transposition of the great arteries is evident in that there is no simple classification to include all the possible variations of the coronary artery patterns. Therefore, a simplified and yet all-inclusive classification is proposed in which the origin of the coronary arteries is defined as seen by an observer looking from the pulmonary artery toward the aorta. This promote and classification should expedite and promote the international exchange of data regarding coronary artery anatomy in transposition of the great arteries and should assist in the surgical management of this condition. PMID- 8698761 TI - Is surgery for aortic stenosis justified in patients over 75 years of age? AB - The upper age limit for cardiac surgery has constantly been extended since the 1980's, with the most pronounced extension observed in surgery of the calcified aortic stenosis (CAS). The aim of this study was to examine whether surgery is beneficial to the elderly population in terms of hospital mortality, long-term survival and quality of life. Between January 1989 and October 1992, 95 patients over 75 years of age underwent aortic valvular replacement (AVR) for CAS. There were 54 male and 41 female patients with a mean age of 79.7 +/- 2.8 years. All of them suffered from isolated or predominant CAS, associated with a coronary lesion requiring additional bypass procedures in 14 cases. Before surgery 67% of the patients were in NYHA class III and IV and 30% of them had suffered from acute pulmonary edema. Surgical priority was urgent in 10 patients. Mean aortic clamp time was of 55 minutes for the isolated CAS and 78 minutes for the bypass associated CAS. A Carpentier-Edwards supra-annular bioprosthesis was implanted in 95.7% of the cases, associated with coronary bypass in 14 cases, with a mean of 1.6 bypasses per patient. Global hospital mortality was 11.5%. Emergency surgery was a predictive factor of in hospital mortality in multivariate analysis. Among the 84 survivors, 12 died secondarily, 4 of them due to cardiac causes during the follow-up period (26 +/- 4 months); similar to the mortality rate of the global population for the same age. The factors responsible for this late mortality in multivariate analysis were poor left ventricular status and diabetes mellitus. Survivor's quality of life is excellent with 78.6% of patients termed class I, autonomous and free of sequelae. IN CONCLUSION: despite an operative mortality rate much higher than in patients under 70, AVR for CAS is justified even in patients over 75 years as it offers a good quality of survival and a life expectancy identical to that of the general population of the same age. PMID- 8698762 TI - Detection of myocardial ischemic injury during simple cold storage by measurement of myocardial electrical impedance. AB - The purpose of this study was to determine if graft viability during simple cold storage can be monitored from alteration of myocardial electrical impedance. Six anesthetized dogs underwent rapid cardiac extirpation and were placed in simple cold storage in saline for 12 hours. Myocardial electrical impedance was measured serially by use of a LCR meter and the changes of myocardial resistivity analyzed. Myocardial specimens were taken for myocardial ATP analysis and electron microscopic study during preservation. We investigated the correlation between myocardial resistivity and myocardial ATP content. Moreover in order to predict cardiac function after simple cold storage in saline, heterotopic cardiac transplantation in the neck was performed in mongrel dogs and left ventricular Emax (LV Emax) was measured with a micromanometer and conductance catheter method. It was then investigated whether or not it is feasible to predict cardiac function of the graft afer reperfusion from the changes in myocardial resistivity. Myocardial ATP remained above 50% of preischemic value 4 hours after preservation. Ultrastructural alterations of ischemia were observed in hearts preserved for 8 and 12 hours. In heterotopic cardiac transplantation, LV Emax at 120 minutes after reperfusion recovered to 94 +/- 13% of preischemic function in 4 hour-preserved heart, 72 +/- 10% in 8 hour-preserved heart. Percent recovery of LV Emax in the former was significantly higher than that in the latter (p<0.05). Turning points from reversible conditions to irreversible ones were between 4 and 8 hours based on myocardial ATP content, cardiac function after transplantation and morphological changes. With the time of preservation, resistivity began to increase in every dog and peaked during preservation. The time required to reach the peak point of resistivity ranged from 4 to 5.5 hours. Resistivity increase rate (RIR) decreased gradually during preservation and it was over 0.1 omega cm/min until a half-life of ATP. These results suggested that measurement of myocardial electrical impedance in the preserved heart should be feasible as an indicator of graft viability during preservation in heart transplantation. PMID- 8698763 TI - Effect of HTK solution for myocardial preservation. AB - The aim of this study was to investigate the efficacy of HTK solution for cardioplegia in the continuous 120-minute cross-clamping method in comparison with the conventional GIK method. In an experimental model, the efficacy of ketoglutarate and tryptophan in recovering cardiac function after 6 hours' preservation was evaluated. In Group A, in which ketoglutarate was excluded from the HTK solution, percent developed pressure was significantly decreased (p<0.01) and the released enzyme (CK-MB) was significantly increased, but coronary flow was not significantly changed. In Group B, in which tryptophan was excluded from the HTK solution, a significant decrease in percent developed pressure and coronary flow was seen (p<0.01). This indicated that ketoglutarate and tryptophan were effective in protecting the myocardium during the ischemia. In the clinical study, 54 open heart operations were performed with cardioplegic solution, using either HTK solution or GIK solution. In the HTK Group, the heart was exposed to 120 minutes' of ischemia after the infusion of HTK solution (3L). In the GIK group, intermittent GIK perfusion was performed every 30 minutes in association with continuous cold blood perfusion. Percent fraction shortening and cardiac index were not significantly different. However, CK-MB and HBDH were increased in the GIK group, postoperatively. Histological findings showed deterioration of the mitochondria and myocytes during ischemia in the GIK group. These data suggest that the effect of the cardioplegias in heart preservation was satisfactory in both groups, although the interval of intermittent perfusion was prolonged to 120 minutes in the HTK solution. PMID- 8698764 TI - Functional, metabolic and ultrastructure evidence for improved myocardial protection during severe ischaemic stress with MBS, a new crystalloid cardioplegic solution. AB - The duration of aortic clamping and the temperature of the arrested heart are two important factors in the overall strategy of myocardial protection with cardioplegic solutions. The isolated working rat heart was used to compare the cardioprotection effects (function, metabolism and ultrastructure) of the new "extracellular" crystalloid solution, MBS (containing glucose, aspartate and lactobionate) and St. Thomas' Hospital No. 2 (STH) during prolonged moderate hypothermic ischaemia (30 degrees C, 2 hours and 4 hours) with multidose reinfusion (2 min every 30 min interval). All MBS treated hearts (n = 9 per group) rapidly resumed spontaneous regular sinus rhythm (0.8 +/- 0.2 min) and had similar high degree of functional recovery (cardiac output: 90.2 +/- 4.5% & 80.9 +/- 3.5%, stroke volume: 89.1 +/- 4.7% & 81.9 +/- 3.4% and aortic pressure: 102.0 +/- 4.0% & 100.0 +/- 7.3% of pre-arrest values for 2 hours and 4 hours groups, respectively) during 30 min post-ischaemic reperfusion. In contrast, hearts protected with STH showed significantly (p<0.01) less recovery of left ventricular function (cardiac output: 64.3 +/- 2.9% & 5.5 +/- 3.9%, respectively) with two of the nine hearts failing to regain any cardiac pump function after 4 hours. MBS increased lactate efflux (glycolysis) and completely abolished the progressive increase in the coronary vascular resistance during 4 hours ischaemic arrest. These improvements were directly related to the significantly (p<0.01) reduced depletion of the myocardial adenosine triphosphate (13.32 +/- 1.65 vs 2.42 +/- 0.09 micromol/g dry wt) and guanosine triphosphate (1.56 +/- 0.08 vs 0.74 +/- 0.04 micromol/g dry wt) during arrest; to their enhanced repletion after reperfusion (ATP: 96% vs 36%, TAN: 90% vs 40% and GTP: 69% vs 48%); and to the absence of ultrastructural injury to cardiac myocytes and the microvasculature. We conclude that the new crystalloid cardioplegic solution MBS provides markedly improved myocardial protection particularly during severe ischaemic stress. PMID- 8698765 TI - Valve replacement with the CarboMedics bileaflet mechanical prosthesis: clinical results at midterm. AB - OBJECTIVE: We study the clinical midterm results of the valve replacement with the CarboMedics bileaflet mechanical prosthesis. EXPERIMENTAL DESIGN AND SETTING: Retrospective study. Institutional practice (National Cardiovascular Center, Osaka, Japan). PATIENTS AND INTERVENTIONS: 167 CarboMedics prostheses were implanted in 144 patients from April, 1990 and December, 1993. Of these, 77 patients underwent isolated aortic valve replacement (AVR), 45 patients underwent isolated mitral valve replacement (MVR), 21 patients underwent double (aortic and mitral) valve replacement (DVR), and one patient underwent triple (aortic, mitral and tricuspid) valve replacement (TVR). MEASURES: Events were defined in accordance with the guidelines for reporting morbidity and mortality after cardiac valve operations of the Society of Thoracic Surgeons/American Association for Thoracic Surgery. PMID- 8698766 TI - Morphological comparison of mitral and aortic bioprostheses explanted from the same patient for primary tissue failure. AB - Host factors might influence the fate of tissue prostheses. We have analyzed the tissue failure phenomenon in mitral and aortic porcine bioprostheses explanted from the same patient so as to avoid the bias of host factors. The 50 bioprostheses of this study were explanted from 25 patients reoperated on because of malfunctioning due to primary tissue failure. Bioprostheses explanted were photographed, radiographed and observed in polarizing light. All lesions analyzed received a score on the basis of morphological criteria. No difference was observed in the occurrence of pannus, tears or cells infiltrates. Calcifications occurred more extensively in mitral position (p=0.0031). Creep of the stent was significantly greater in mitral position (p=0.0324). Since the model of our study removed other individual factors, we may conclude that there is evidence for an earlier and more extensive calcific degeneration in the mitral than in the aortic position. PMID- 8698767 TI - Spirometric changes after open mitral surgery. AB - New York Heart Association (NYHA) functional classification of cardiac patients is assessed by subjective impairment of respiratory reserve. We objectively studied pulmonary function by spirometry in 31 random patients (average age 27.2 years) with rheumatic mitral valve (MV) disease undergoing open surgery (7 reconstruction, 24 replacement) preoperatively, predischarge and at 3 month follow-up. Better preoperative spirometric parameters were observed in class II nonsmoker patients with smaller cardiothoracic ratio (CTR) and normal pulmonary artery pressure (PAP). After surgery mean PAP decreased to 19.0 +/- 6.7 mmHg, MV gradient dropped to 3.4 +/- 2.9 mmHg, average CTR decreased to 52.3 /- 5.5%. MV area increased significantly from 0.8 +/= 0.49 to 2.45 +/- 1.23 cm2. Forced vital capacity (FVC), forced expiratory volume in one second FEV1), flow rates at 25% 75% of expired vital capacity (FEF 25-75%) and maximum voluntary ventilation (MVV) decreased significantly in all patients at discharge. Prolonged postoperative ventilatory support over 10 hours led to markedly reduced predischarge FVC, FEV1, FEF50, MVV and maximum mid expiratory flow rate (MMEFR). Prolonged cardiopulmonary bypass over 80 minutes caused further decrease in FVC. After 3 months all these parameters improved in all above the preoperative level but remained below the predicted values. Despite improvement in NYHA class, impaired spirometry was observed in 11 patients. Functional or hemodynamic improvement did not correlate with spirometric changes. PMID- 8698768 TI - A role for nitric oxide in the vasoplegic syndrome. AB - INTRODUCTION: Cardiopulmonary bypass (CPB) is frequently associated with hemodynamic disorders caused by a whole blood inflammatory response. In particular vasoplegic syndrome occurs in the immediate postoperative time of patients who underwent normothermic CPB. Nitric oxide (NO) was described as an endothelium derived relaxing factor (EDRF). We report changes in NO concentration occurred in patients who experienced vasoplegic syndrome following CPB. MATERIALS AND METHODS: We analyzed changes in NO concentration in 95 consecutive patients who underwent coronary artery bypass grafting under normothermic CPB. NO was measured as nitrite plasma level (NPL) by the Griess reaction. RESULTS: In all cases a significant NPL increase 30 minutes after starting CPB and 10 minutes after CPB interruption was observed (p<0.005). No significant differences were measured 60, 120 and 240 min after CPB interruption when compared with before CPB. Three patients experienced vasoplegic syndrome and NPL values measured at 60, 120 and 240 min after CPB interruption were still significantly increased when compared with before CPB (p<0.005). CONCLUSION: NO plays a role in the CPB related hemodynamic disorders. Use of NO synthase inhibitors could provide a better management of vasoplegic phenomenon following CPB. PMID- 8698769 TI - Successful surgical treatment of cardiac cirrhosis. Tricuspid surgery and plasma exchange. AB - A patient with cardiac cirrhosis due to severe tricuspid regurgitation associated with a mitral valve lesion successfully underwent mitral and tricuspid valve replacement. Preoperative rest cure with liver supporting therapy for 5 months was used to maximize hepatic and cardiac function. Postoperatively, jaundice developed despite improvements in cardiac function. Plasma exchange was performed nine times over a period of 10 days with the liver function improved. He was discharged with New York Heart Association class I symptoms and normal liver function 2 months following surgery. PMID- 8698770 TI - Surgical correction of giant patent ductus arteriosus. AB - In reviewing the literature, there was only one report having the ductus over 30 mm in width. Recently, we utilized cardiopulmonary bypass, hypothermia, and low flow through a transpulmonary approach to close 2 cases of giant patent ductus arteriosus. Both cases complicated with systemic pulmonary hypertension. Its outside diameters were 31 mm and 36 mm respectively based on the measurement from magnetic resonance imaging. To our knowledge, its seem the biggest ductus in comparison to previous reports. Both cases survived the operation and doing well for a follow-up time of 5 years and 4 years 10 months respectively. PMID- 8698771 TI - Swan-Ganz catheter induced pulmonary artery perforation during cardiac surgery concerning two cases. AB - Two case reports describing patients having cardiac operations under extra corporeal circulation are presented. At the completion of the operation, a massive hemoptysis occurred in both patients after a Swan-Ganz catheter had perforated the pulmonary artery. A hemostasis lobectomy was then immediately required. The immediate and long term prognosis seems satisfactory. This is an unusual but serious complication. The incidence of this complication varies between 0.06 and 0.2%. The more frequently related risk factors include people over the age of 60, pulmonary artery hypertension, anticoagulant therapy, hypothermia and manipulation of the heart by the surgeon. When this accident occurs, many authors suspect the balloon. An early diagnosis is essential in the case of a major or even a minor hemoptysis, because this complication may be a lethal one as the mortality rate may reach 50%. According to us, the appropriate therapy which would reduce this mortality is a surgical one (hemostasis lobectomy). PMID- 8698772 TI - Tumor embolism to LAD during pneumonectomy. A case report. AB - Arterial embolization from bronchogenic carcinoma is a rare complication and more commonly occurs intraoperatively during pneumonectomy. We report an unusual case of intraoperative tumour embolism to LAD (left anterior descending artery) and aorta during left pneumonectomy due to tumour involvement of the inferior pulmonary vein. High risk cases should be evaluated by preoperative transesophageal echocardiography. If tumour involvement of the inferior pulmonary vein is demonstrated, a modification of the surgical technique or alternative modality of treatment should be used. PMID- 8698773 TI - Pericardial cyst with partial erosion of the superior vena cava. An unusual case. AB - A case of pericardial cyst with partial erosion of the superior vena cava occasionally discovered is presented. The involvement of the vein was found on operation and the excision of the cyst was performed without cardiopulmonary bypass, repairing the vena cava by a direct suture. The pathologic examination showed multiple areas of acute and chronic inflammation without signs of infection. This exceedingly rare report indicates that both computed tomography and magnetic resonance are useful to localize the mediastinal mass and to characterize the cystic content. The cardiopulmonary bypass must be available to allow an easy repair of the structures possibly involved particularly in the case of infection. PMID- 8698774 TI - Management options for post carotid endarterectomy stroke. AB - BACKGROUND: Management of acute thrombosis of the carotid artery has been controversial. This retrospective study reviews the etiology and analyzes the management options of post carotid endarterectomy stroke. METHODS: Diagnosis was made using oculopneumop-lethysmography (OPG/Gee), duplex ultrasound, computed tomography (CT) scanning, and carotid exploration. RESULTS: The cause of stroke was identified as carotid thrombosis in 19/32 patients (59%) and non-carotid thrombosis in 13. Management options included nine patients who underwent selective carotid exploration and all had a thrombosed carotid; mandatory exploration-six were explored and three had a thrombosed carotid artery; and 17 patients had no exploration (medical treatment). Fourteen patients had a positive OPG, 13 were confirmed to have carotid thrombosis. Eight patients had a negative OPG and all were confirmed. The OPG had an overall accuracy of 95% in detecting postoperative thrombosis (89% specificity and 100% sensitivity). Patients with thrombosed carotids and patients with positive OPGs had more severe neurological deficits than those with non-thrombosed carotids. The final neurological status of the 12 patients with carotid thrombosis who underwent thrombectomy and patch angioplasty was improved (7/12) in contrast to the seven patients who did not undergo a thrombectomy (1/7). Seven of nine patients had a complete or good recovery when thrombectomy was done within two hours of the stroke in contrast to 0/3 after two hours. Seven of ten patients with Grade II stroke (moderate) had a good recovery after carotid exploration and thrombectomy in contrast to 0/2 for Grade III (severe) stroke. CONCLUSIONS: Carotid artery thrombosis, the most common cause of post carotid endarterectomy stroke, can be detected by OPG/Gee. Immediate carotid exploration for patients with Grade I or II strokes, when thrombosis is demonstrated, can improve the results of carotid endarterectomy. PMID- 8698775 TI - Validity of SEP monitoring in carotid surgery. Review and own results. AB - OBJECTIVE: The sensitivity of intraoperative monitoring by means of somatosensory evoked potentials (SEP) in carotid surgery is to be examined. EXPERIMENTAL DESIGN: Prospective clinical investigation. In addition, the influence of circulatory parameters on SEP curves will also be tested. SETTING: Department of Surgery of a university clinic. MATERIALS AND METHODS: A total of 200 patients underwent intraoperative monitoring by means of somatosensory evoked potentials (SEP) during carotid endarterectomy between March 1, 1991 and August 1, 1994. MEASURES: In order to exclude blood pressure variations as a cause for amplitude changes the blood pressure and pulse were documented during the entire phase of preparation and clamping. RESULTS: A significant correlation could not be established between parameters of circulation and amplitude changes (r = 0.0026; p = 0.62). In seven cases of intraoperative amplitude reduction of more than 50% a stroke has been avoided by inserting a shunt. Despite the lack of an amplitude reduction, a watershed stroke of A.cerebri media and A.cerebri posterior occurred in two instances. Taking this into consideration the sensitivity of monitoring is 99.0% at a specificity of 100%. CONCLUSIONS: SEP-monitoring in carotid endarterectomy is simple to execute and is superior in sensitivity to EEG analysis. To avoid artefaction by anesthesia, a standard injection anesthesia is recommended. Farfield potentials should also be derived to avoid watershed infarctions. PMID- 8698776 TI - Dilation of gelatin-sealed knitted dacron prosthesis. AB - OBJECTIVE: Postoperative dilation of gelatin-sealed knitted dacron prostheses (Gelseal, Vascutek, Scotland UK) was studied. EXPERIMENTAL DESIGN: Prospective study. SETTING: Institutional clinical research. MATERIALS AND METHODS: Ten patients who underwent aortic repair for abdominal aortic aneurysm (AAA) with the Gelseal graft were studied (Group A). Prior to and immediately following the implantation, the diameter of Gelseal was measured with slide calipers. The external diameter was examined by CT scan 4 weeks following the surgery. Another 10 patients, who had undergone AAA repair with the Gelseal graft more than 2 years earlier (Group B), also were examined by CT scan. Early and late dilation of Gelseal was estimated and the data from the two groups were compared. MEASURES: In Group A, the preimplantation external diameter was 22.6 +/- 2.3 mm while the mean package size (PS) used was 18.7 +/- 2.1 mm prior to implantation. Just after the implantation, the external diameter changed to 22.7 +/- 2.4 mm. Four weeks later, it averaged 24.0 +/- 2.2 mm. In Group B, the PS averaged 19.2 +/- 2.0 mm, while the external diameter measured by CT scan averaged 27.8 +/- 3.4 mm at a mean of 31.3 months following the surgery. RESULTS: Prior to implantation, the external diameter was 1.21 times that of the PS. Following implantation, it was 1.21 times (immediately after), 1.28 times (4 weeks later), and 1.45 times (31.3 months later) of the PS. CONCLUSIONS: At an average of 31.3 months following implantation, the external diameter was 45% larger than the PS. Considering that the external diameter was 21% larger than the PS even prior to implantation, the actual dilation rate is estimated as 24% of the PS in the late postoperative period. PMID- 8698777 TI - Experimental study on protein transmission through the human muscle fascia: preliminary results and application theory in lymphedema. AB - The presence of proteins (albumin and globulins) in lymphedematous tissue not only gives rise to colloidosmotic pressure but also produces an electrostatic charge endowing the proteins with individual features and different migration rates. The working hypothesis of the experimental study is to transfer lymph proteins from the upper fascia accumulation area to a subfascial drainage area by subjecting them to an adequate difference in potential. A double chamber, variable volume system with separation wall able to contain a 1 cm square of muscle fascia, was designed and built; the aim of the apparatus was to reproduce the subcutaneus zone separated by the fascia interposition, from the muscle vascular zone. At the system was applied a variable electric field in six different experiments: 4 using porous synthetic membranes and 2 using human muscle fascia. PMID- 8698778 TI - Deep femoral artery aneurysm rupture. A case report. AB - Primary "atherosclerotic" aneurysms of the profunda femoris are rare. Although they commonly present with rapid enlargement or rupture, only 8 ruptured cases have been found in the literature. We report a new case where the preoperative diagnosis was established by Duplex ultrasonography. Angiography was made for surgical management. Simple ligation was effective. Pathogenesis, clinical presentation, radio-graphic findings and surgical treatment are discussed. PMID- 8698779 TI - Aneurysm of a branch of the subclavian artery with multiple arteriovenous fistulae. AB - A rare case is reported of an 83-year-old woman with an aneurysm of a branch of the subclavian artery with multiple arteriovenous fistulae. The patient was admitted to our hospital with a pulsatile mass in the supraclavicular space and a prominent continuous murmur which radiated to the anterior chest, right forearm and right neck. She first noticed a pulsatile 2 cm mass in 1972, 1 year following a subtotal gastrectomy. At that time, she had intravenous therapy through a right neck vein. In 1993, the mass became larger, and she developed a shunt murmur. Digital subtraction angiography (DSA) demonstrated an aneurysm of the right subclavian artery and an arteriovenous fistula between the right subclavian artery and vein. The right common carotid artery and right subclavian artery arose from the aortic arch separately. The aneurysm arose from a branch of the subclavian artery which may be the costocervical trunk. The 5 x 4 cm aneurysm was resected and the arteriovenous fistula was divided. On postoperative day 5, a new murmur was ausculated. A repeat DSA detected a new fistula between the axillary artery and vein. Reoperation was performed to ligate and divide the fistula. Pathological examination revealed an atherosclerotic aneurysm. PMID- 8698780 TI - Post stenotic aneurysm of the inferior mesenteric artery: case report and discussion. AB - A case of post stenotic aneurysm of the inferior mesenteric artery (IMA) is reported. This case underlines the importance of a correct diagnosis by instrumental methods such as Duplex Scanner, CT and Arteriography, mainly when the first diagnosis is aneurysm of the abdominal aorta (AAA). Our patient showed, furthermore, the occlusion of the celic axis, of the superior mesenteric artery and of both hypogastric arteries; thus his intestinal vascularization was represented, from the gastric fundus until the rectum, only by the inferior mesenteric artery and its collateral network. The operation consisted in the resection and reimplantation of the vessel on the left side of the terminal abdominal aorta, after removal of the dilated segment. This location was chosen because of the coexistence of a mild dilatation of the aorta of 2.8 cm and considering possible aortic surgery for AAA in the future. PMID- 8698781 TI - Primary aortogastric fistula: a complication of ruptured aortic aneurysm. AB - An aortogastric fistula which resulted from rupture of an atherosclerotic aneurysm of the descending and supraceliac aortic segments is reported. The diagnosis was suspected preoperatively on the basis of CT and angiographic examinations. Vascular replacement was accomplished without difficulty, but a fatal outcome eventually occurred because of failure of local repair of the gastric defect. Relevant literature on primary aortoenteric fistulas has been reviewed, with particular emphasis on reports detailing management of the alimentary tract perforations. We now believe that resection should be strongly considered in situations where both resection and local repair of the enteric defect are options. PMID- 8698782 TI - Comparison of different prophylactic myocardium saving measures during heart surgery. Effects on perioperative troponin-T levels. AB - OBJECTIVE: Different prophylactic myocardium saving strategies are often routine in open heart surgery. Even if theoretically well established, they must be critically reviewed in times of limited financial resources. EXPERIMENTAL DESIGN: Troponin-T (TnT) is a valuable tool to detect even minor myocardial damages independently from concomitant muscle injuries. We measured intra- and postoperative TnT-values and ST-wave deviations on the ECG in a control group and in patients receiving one of the following prophylactic MEASURES: hypothermia during cardiopulmonary bypass (CPB), nitroglycerine ([0.5 microgram/kg/min]) or nifedipine [0.1 microgram/kg/min] after aortic cross-clamping until end of operation, or perioperative Mg2+ per os. PATIENTS AND SETTING: The study included 65 patients of a university hospital with preoperative good heart function scheduled for elective aorto-coronary bypass operation. RESULTS: TnT values increased in all groups after CPB and peaked between end of operation and first post-operative day. TnT values above the critical border of 1.0 microgram/l in the early period after CPB were less often seen in the nitroglycerine and nifedipine group. No pronounced differences could be observed after the first postoperative day. Patients of the hypothermia group had most often TnT values above 1.0 microgram/l. Maximum TnT values of the control, the hypothermia and the Mg(2+)-group correlated with the duration of aortic-crossclamping. No correlation existed between ST-deviations and TnT-values. CONCLUSIONS: The prophylactic measures failed to reduce myocardial damage as evidenced by the course of TnT values. They can therefore not be recommended as routine strategies in patients with good left heart function. Especially hypothermia should be considered carefully. PMID- 8698783 TI - Laboratory evaluation of tissue heart valves. A comparative assessment. AB - Tissue of commercially prepared tissue heart valves were evaluated and compared with aluminium treated, fixed porcine valve tissue in vitro (tensile strength, scanning and transmission electron microscopy) and in vivo (calcification potential after subcutaneous implantation in the rat model). Valve leaflets (n = 40) were divided into four groups according to the method of treatment: Group I (fixed in 0.652% glutaraldehyde, control), Group II (fixed and treated with aluminium), Group III (fixed and treated with Toluidine blue) and Group IV (fixed and treated with watersoluble alkyl sulphate). Tensile strength was not influenced in Group II and III (p > 0.05). Group IV indicated a significant (p < 0.05) reduction in tensile strength. Scanning electron microscopy revealed damage and loss of surface endothelium in Group III and IV respectively. Transmission electron microscopy indicated damage to underlying matricial cells in Group III and IV. Calcification potential was significantly (p < 0.001) reduced in Group II to IV. We conclude that damage ultrastructure could contribute to the reduced tensile strength in Group IV and that reduced tensile strength might have an influence on the long-term durability of tissue heart valves. Antimineralization treatment of tissue heart valves does retard calcification but is yet unable to inhibit the process completely. PMID- 8698785 TI - Direct coronary surgery without cardiopulmonary bypass in acute myocardial infarction. AB - From 1978 to 1995, 1420 patients underwent direct coronary surgery without cardiopulmonary bypass (CPB). Among them 32 consecutive patients (2.2%) were operated on from 1984 to 1995 for acute transmural myocardial infarction. There were 27 males and 5 females (mean age 59.2 +/- 6.7 years; range 35-72). Mean extent of coronary artery disease was 2.1 vessels/-patient. Four patients were admitted to surgery in cardiogenic shock, 5 with life-threatening ventricular arrhythmias. A mean time of 311 +/- 109 min (range 100-685 min) was recorded between the onset of symptoms and surgical reperfusion. Patients were operated on using saphenous vein or left internal mammary graft. Intraoperative transmural myocardial biopsies were taken in the area of myocardial infarction, 15 minutes before and 45 minutes after revascularization: biopsy specimens showed a marked reduction in signs of mitochondrial and myofibril damage. No in-hospital death occurred. Postoperative low cardiac output was never recorded. One patient had a mediastinitis. All patients, except one who died 8 years postoperatively, are alive at present: 1 is NYHA class II, 1 in NYHA IV and 27 are asymptomatic, with yearly treatmill test negative for recurrent myocardial ischemia. One patient underwent redo surgery 7 years after surgery for recurrent angina. First 5 consecutive patients were studied angiographically 1 to 30 days after surgery: all grafts were detected patent. In conclusion coronary surgery without CPB may be considered an alternative to conventional surgical revascularization of myocardial infarction. PMID- 8698784 TI - The incidence of significant pericardial effusion and tamponade following major aortic root surgery. AB - OBJECTIVE: To examine the hypothesis that the incidence of significant pericardial effusion following aortic root surgery is higher than anticipated after cardiac surgery. DESIGN: A retrospective data analysis. SETTING: A tertiary referral centre for cardiothoracic surgery. SUBJECTS: All patients undergoing aortic root surgery either with or without aortic valve replacement between January 1991 and July 1993. RESULTS: Three patients developed late cardiac tamponade (7-10 days post-operatively) and a further three developed clinically significant pericardial effusions as a result of post-pericardiotomy syndrome. The 31.6% (95% confidence limit: 12.5-56%) incidence of significant pericardial effusions following aortic root surgery is therefore significantly higher than anticipated after cardiac surgery (0.8-6). CONCLUSION: These data support the hypothesis that the incidence of significant pericardial effusion following aortic root surgery is higher than anticipated after cardiac surgery. We recommend that echocardiography is routinely performed during the post-operative period in these patients to exclude significant pericardial effusions. PMID- 8698786 TI - Timing of surgery in patients with acute infective endocarditis. AB - OBJECTIVE: Surgical intervention in patients with active infective endocarditis is generally considered as indicated in few high-risk patients who have developed severe complications such as heart failure, persistent septicemia or recurrent arterial embolism, but the question of when to intervene is still subject to discussion. EXPERIMENTAL DESIGN: Retrospective study. SETTING: Cardio-Thoracic Surgery Unit, University clinic. PATIENTS, INTERVENTIONS AND RESULTS: From 1984 to 1994, 130 patients (87 male, mean age 43.2 +/- 12.7 years) underwent heart valve replacement or reconstruction for infective endocarditis of native or prosthetic valves. 89 of them had acute infection requiring urgent surgical treatment. Over-all operative mortality was 12.3%. Certain preoperative factors were investigated regarding their influence on postoperative death. Statistical analysis revealed functional class according to NYHA as well as extravalvular involvement of the infection as significant risk factors or mortality. Emergency operation was not significantly associated with increased operative mortality, neither were the causative organism, a history of arterial embolism or persistent septicemia. CONCLUSIONS: In active infective endocarditis the optimal time to perform surgery is before the onset of severe end-stage heart failure or spread of the infection to extravalvular tissue. If one of these complications is imminent, urgent intervention is indicated. PMID- 8698787 TI - Changes in coagulation patterns, blood loss and blood use after cardiopulmonary bypass: aprotinin vs tranexamic acid vs epsilon aminocaproic acid. AB - Cardiopulmonary bypass (CPB) increases risk of postoperative bleeding and need for transfusion. The aim of this study was to evaluate the effects of aprotinin, epsilon aminocaproic acid and tranexamic acid on coagulation patterns and need for banked blood transfusion. Ninety-six consecutive patients who underwent coronary artery bypass surgery were randomly assigned to 4 groups (24 patients each). The following parameters were monitored before, during and after CPB: activated lotting time, hemoglobin, prothrombin time, activated prothromboplastin time, fibrinogen, antithrombin III, xDP, Factor VIII, Thrombin-Antithrombin Complex and plasminogen. Analysis of postoperative bleeding and need for transfusion showed that the aprotinin group had significantly lower mediastinal bleeding. Transfused patients were 2, 4, 12 and 18 respectively in the aprotinin, epsilon aminocaproic acid, tranexamic acid and placebo treated group. In conclusion the use of protease inhibitors significantly reduces postoperative bleeding and transfusion. The aprotinin-treated group had the lower need for transfusion. PMID- 8698789 TI - Inflammatory extracavitary right atrial mass and pulmonary thromboembolism. AB - A 40 year old male patient diagnosed as having pulmonary thromboembolism, was found to have a right atrial mass, after being subjected to an echocardiogram, a CT thoracic Scan and magnetic resonance imaging. An intracardiac exploration by cardiopul-monary bypass was performed. The mass was located and excised, but in fact found to be an extracardiac, inflammatory and cavitated mass. The wall of the right atrium was infiltrated due to the inflammatory process. This case illustrates the advantage of echocardiography, followed by surgery, in the clinical diagnosis and also shows how to treat cardiac masses and tumors. PMID- 8698788 TI - Longterm efficiency of high dose inotropic support in an infant after repair of Fallot's tetralogy. AB - A 23 month old boy with highly symptomatic tetralogy of Fallot (TOF) underwent repair. Inspite of cold Bretschneider cardioplegic solution twice the heart was beating soon after application of the cardioplegic solution each time. Soon after transfer to the intensive care unit the patient developed low cardiac output (LCO). The following days high doses of inotropic support ware necessary to maintain sufficient arterial pressure. The dosages of dobutamine (up to 49 micrograms/kg/min); norepinephrine (up to 5.28 micrograms/kg/min, and epinephrine (up to 16 micrograms/kg/min), respectively, were twice and three times as high as common maximum recommendations. After having recovered from acute renal failure requiring hemodialysis from the 5th to the 37th postoperative day the child was discharged 9 weeks after the intervention. The very unusual and interesting course of this boy is described and the form and grade of the inotropic support is discussed. PMID- 8698790 TI - Massive hemoptysis as a manifestation of fistulized thoracic aortic aneurysms into the bronchial tree. AB - Aortobronchial fistulas are an uncommon and serious cause of hemoptysis. We present three cases of aortobronchial fistulas that were diagnosed and treated at our hospital. They were presented as massive hemoptysis. The clinical suspicion of a leaking thoracic aortic aneurysm into the bronchial tree should prompt the correct diagnostic procedures since early surgery is the only way to manage this condition. PMID- 8698791 TI - Leiomyosarcoma of the pulmonary vein. AB - OBJECTIVE: We report a case of leiomyosarcoma (LMS) of the pulmonary vein and comment on the natural history and determinants for survival for this rare condition. EXPERIMENTAL DESIGN: Our retrospective review is only the fourth such case reported in the world's literature. SETTING: A teaching hospital with an active surgical residency program. PATIENT OR PARTICIPANT: A 61-year-old female who presented with a central pulmonary mass. INTERVENTIONS: Complete resection without pneumonectomy of cardiopulmonary bypass. Pathology showed low grade LMS. MEASURES: Determinants for survival include complete surgical resection and a low mitotic activity of the tumor. RESULTS: The patient remains no evidence of disease three years following initial treatment. CONCLUSIONS: One reported case of LMS of the pulmonary vein had favorable determinants for survival; complete surgical resection and low mitotic activity of the tumor. These factors may have contributed to the successful outcome. The natural history of LMS of the pulmonary vein appears similar to the more widely studied LMS of the inferior vena cava. PMID- 8698792 TI - Hepatic hydrothorax without diaphragmatic defect. An original surgical treatment. AB - A 58-year-old woman with a long history of well-compensated postnecrotic cirrhosis with acute massive ascites and right-sided pleural effusion was admitted. The injection of colorant and radioactive material into the peritoneal cavity didn't show up any passage through the diaphragm. After resuscitation therapy and insertion of abdominal and chest tube, effusions rapidly and massively re-accumulated. A LeVeen peritoneovenous shunt was inserted as an emergency measure owing to hepatorenal syndrome. Ascites completely resolved but pleural effosion was continuously and severely recharged. A Denver inverted shunt was subcutaneously inserted from pleural to peritoneal cavity. After operation CPAP was applied and pump device activated; pleural effusion gradually disappeared clearing completely the pleural space. The patient was discharged on the 10th postoperative day; her general condition and laboratory test have remained satisfactory up to one year without ascites and pleural effusion. PMID- 8698806 TI - In situ analysis of changes in telomere size during replicative aging and cell transformation. AB - Telomeres have been shown to gradually shorten during replicative aging in human somatic cells by Southern analysis. This study examines telomere shortening at the single cell level by fluorescence in situ hybridization (FISH). FISH and confocal microscopy of interphase human diploid fibroblasts (HDFs) demonstrate that telomeres are distributed throughout the nucleus with an interchromosomal heterogeneity in size. Analysis of HDFs at increasing population doubling levels shows a gradual decrease in spot size, intensity, and detectability of telomeric signal. FISH of metaphase chromosomes prepared from young and old HDFs shows a heterogeneity in detection frequency for telomeres on chromosomes 1, 9, 15, and Y. The interchromosomal distribution of detection frequencies was similar for cells at early and late passage. The telomeric detection frequency for metaphase chromosomes also decreased with age. These observations suggest that telomeres shorten at similar rates in normal human somatic cels. T-antigen transformed HDFs near crisis contained telomere signals that were low compared to nontransformed HDFs. A large intracellular heterogeneity in telomere lengths was detected in two telomerase-negative cell lines compared to normal somatic cells and the telomerase-positive 293 cell line. Many telomerase-negative immortal cells had telomeric signals stronger than those in young HDFs, suggesting a different mechanism for telomere length regulation in telomerase-negative immortal cells. These studies provide an in situ demonstration of interchromosomal heterogeneity in telomere lengths. Furthermore, FISH is a reliable and sensitive method for detecting changes in telomere size at the single cell level. PMID- 8698807 TI - Live analysis of free centrosomes in normal and aphidicolin-treated Drosophila embryos. AB - In a number of embryonic systems, centrosomes that have lost their association with the nuclear envelope and spindle maintain their ability to duplicate and induce astral microtubules. To identify additional activities of free centrosomes, we monitored astral microtubule dynamics by injecting living syncytial Drosophila embryos with fluorescently labeled tubulin. Our recordings follow multiple rounds of free centrosome duplication and separation during the cortical division. The rate and distance of free sister centrosome separation corresponds well with the initial phase of associated centrosome separation. However, the later phase of separation observed for centrosomes associated with a spindle (anaphase B) does not occur. Free centrosome separation regularly occurs on a plane parallel to the plasma membrane. While previous work demonstrated that centrosomes influence cytoskeletal dynamics, this observation suggests that the cortical cytoskeleton regulates the orientation of centrosome separation. Although free centrosomes do not form spindles, they display relatively normal cell cycle-dependent modulations of their astral microtubules. In addition, free centrosome duplication, separation, and modulation of microtubule dynamics often occur in synchrony with neighboring associated centrosomes. These observations suggest that free centrosomes respond normally to local nuclear division signals. Disruption of the cortical nuclear divisions with aphidicolin supports this conclusion; large numbers of abnormal nuclei recede into the interior while their centrosomes remain on the cortex. Following individual free centrosomes through multiple focal planes for 45 min after the injection of aphidicolin reveals that they do not undergo normal modulation of their astral dynamics nor do they undergo multiple rounds of duplication and separation. We conclude that in the absence of normally dividing cortical nuclei many centrosome activities are disrupted and centrosome duplication is extensively delayed. This indicates the presence of a feedback mechanism that creates a dependency relationship between the cortical nuclear cycles and the centrosome cycles. PMID- 8698808 TI - The Saccharomyces cerevisiae actin-related protein Arp2 is involved in the actin cytoskeleton. AB - Arp2p is an essential yeast actin-related protein. Disruption of the corresponding ARP2 gene leads to a terminal phenotype characterized by the presence of a single large bud. Thus, Arp2p may be important for a late stage of the cell cycle (Schwob, E., and R.P. Martin, 1992. Nature (Lond.). 355:179-182). We have localized Arp2p by indirect immunofluorescence. Specific peptide antibodies revealed punctate staining under the plasma membrane, which partially colocalizes with actin. Temperature-sensitive arp2 mutations were created by PCR mutagenesis and selected by an ade2/SUP11 sectoring screen. One temperature sensitive mutant that was characterized, arp2-H330L, was osmosensitive and had an altered actin cytoskeleton at a nonpermissive temperature, suggesting a role of Arp2p in the actin cytoskeleton. Random budding patterns were observed in both haploid and diploid arp2-H330L mutant cells. Endocytosis, as judged by Lucifer yellow uptake, was severely reduced in the mutant, at all temperatures. In addition, genetic interaction was observed between temperature-sensitive alleles arp2-H330L and cdc10-1. CDC10 is a gene encoding a neck filament-associated protein that is necessary for polarized growth and cytokinesis. Overall, the immunolocalization, mutant phenotypes, and genetic interaction suggest that the Arp2 protein is an essential component of the actin cytoskeleton that is involved in membrane growth and polarity, as well as in endocytosis. PMID- 8698809 TI - Bcl-2 down-regulates the activity of transcription factor NF-kappaB induced upon apoptosis. AB - Among the many target genes of the transcription factor NF-kappaB are p53 and c myc, both of which are involved in apoptosis. This prompted us to investigate the role of NF-kappaB in this process. We report that NF-kappaB is potently activated upon serum starvation, a condition leading to apoptosis in 293 cells. Similar to Bcl-2, a transdominant-negative mutant of the NF-kappaB p65 subunit partially inhibited apoptosis, indicating a direct involvement of the transcription factor in induction of cell death. As expected, the p65 mutant suppresses kappaB dependent gene expression. Surprisingly, transiently or stably overexpressed Bcl 2 had the same effect. The transcription inhibitory activity of the two proteins correlated with their cell death protective potential. Like Bcl-2, the related protein Bcl-xL but not Bcl-xS was able to suppress kB-dependent transcription. Bcl-2 inhibited NF-kappaB activity by an unusual mechanism. It did not prevent the release of IkappaB in the cytoplasm but down-modulated the transactivating potential of nuclear p65. These data show that NF-kappaB can participate in apoptosis. We suggest that at least part of the anti-apoptotic potential of Bcl-2 may be explained from a hitherto undiscovered activity of Bcl-2 in controlling nuclear gene expression. PMID- 8698810 TI - Armadillo is required for adherens junction assembly, cell polarity, and morphogenesis during Drosophila embryogenesis. AB - Morphological and biochemical analyses have identified a set of proteins which together form a structure known as the adherens junction. Elegant experiments in tissue culture support the idea that adherens junctions play a key role in cell cell adhesion and in organizing cells into epithelia. During normal embryonic development, cells quickly organize epithelia; these epithelial cells participate in many of the key morphogenetic movements of gastrulation. This prompted the hypothesis that adherens junctions ought to be critical for normal embryonic development. Drosophila Armadillo, the homologue of vertebrate beta-catenin, is a core component of the adherens junction protein complex and has been hypothesized to be essential for adherens junction function in vivo. We have used an intermediate mutant allele of armadillo, armadilloXP33, to test these hypotheses in Drosophila embryos. Adherens junctions cannot assemble in the absence of Armadillo, leading to dramatic defects in cell-cell adhesion. The epithelial cells of the embryo lose adhesion to each other, round up, and apparently become mesenchymal. Mutant cells also lose their normal cell polarity. These disruptions in the integrity of epithelia block the appropriate morphogenetic movements of gastrulation. These results provide the first demonstration of the effect of loss of adherens junctions on Drosophila embryonic development. PMID- 8698811 TI - armadillo, bazooka, and stardust are critical for early stages in formation of the zonula adherens and maintenance of the polarized blastoderm epithelium in Drosophila. AB - Cellularization of the Drosophila embryo results in the formation of a cell monolayer with many characteristics of a polarized epithelium. We have used antibodies specific to cellular junctions and nascent plasma membranes to study the formation of the zonula adherens (ZA) in relation to the establishment of basolateral membrane polarity. The same approach was then used as a test system to identify X-linked zygotically active genes required for ZA formation. We show that ZA formation begins during cellularization and that the basolateral membrane domain is established at mid-gastrulation. By creating deficiencies for defined regions of the X chromosome, we have identified genes that are required for the formation of the ZA and the generation of basolateral membrane polarity. We show that embryos mutant for both stardust (sdt) and bazooka (baz) fail to form a ZA. In addition to the failure to establish the ZA, the formation of the monolayered epithelium is disrupted after cellularization, resulting in formation of a multilayered cell sheet by mid-gastrulation. SEM analysis of mutant embryos revealed a conversion of cells exhibiting epithelial characteristics into cells exhibiting mesenchymal characteristics. To investigate how mutations that affect an integral component of the ZA itself influence ZA formation, we examined embryos with reduced maternal and zygotic supply of wild-type Arm protein. These embryos, like embryos mutant for both sdt and baz, exhibit an early disruption of ZA formation. These results suggest that early stages in the assembly of the ZA are critical for the stability of the polarized blastoderm epithelium. PMID- 8698812 TI - The adenomatous polyposis coli tumor suppressor protein localizes to plasma membrane sites involved in active cell migration. AB - Mutations in the adenomatous polyposis coli (APC) gene are linked to polyp formation in familial and sporadic colon cancer, but the functions of the protein are not known. We show that APC protein localizes mainly to clusters of puncta near the ends of microtubules that extend into actively migrating regions of epithelial cell membranes. This subcellular distribution of APC protein requires microtubules, but not actin filaments. APC protein-containing membranes are actively involved in cell migration in response to wounding epithelial monolayers, addition of the motorgen hepatocyte growth factor, and during the formation of cell-cell contacts. In the intestine, APC protein levels increase at the crypt/villus boundary, where cell migration is crucial for enterocyte exit from the crypt and where cells accumulate during polyp formation that is linked to mutations in the microtubule-binding domain of APC protein. Together, these data indicate that APC protein has a role in directed cell migration. PMID- 8698813 TI - SPC4, SPC6, and the novel protease SPC7 are coexpressed with bone morphogenetic proteins at distinct sites during embryogenesis. AB - In the present study, we screened for subtilisin-like proprotein convertases (SPCs) that potentially regulate the activation of known growth factors during embryonic development. We isolated a novel protease, SPC7, as well as several known SPCs. SPC7, like SPC1, is expressed ubiquitously throughout development. In contrast, SPC4 and SPC6 exhibit dynamic expression patterns. SPC4 transcripts were initially detected in the granulosa cells of secondary follicles. Shortly after implantation, SPC4 transcripts are localized to extraembryonic cell populations, and at later stages are detected in discrete tissues including the primitive gut, heart, neural tube, and limb buds. Within the limb buds, SPC4 mRNA is most abundant in the apical ectodermal ridge (AER). At later stages of limb development, SPC4 mRNA is strongly expressed in cartilage and in the interdigital mesenchyme. In contrast, high SPC6 mRNA levels are detected in somites, the dorsal surface ectoderm, and in vertebral cartilage primordia. In limb buds, SPC6 is strongly expressed in the AER, and at later stages in dorsal mesenchyme. A comparison of these expression patterns with those of several bone morphogenetic proteins (BMPs) indicates that processing of these growth factors may be limited by the local availability of SPCs. PMID- 8698815 TI - Growth cone collapse and inhibition of neurite growth by Botulinum neurotoxin C1: a t-SNARE is involved in axonal growth. AB - The growth cone is responsible for axonal growth, where membrane expansion is most likely to occur. Several recent reports have suggested that presynaptic proteins are involved in this process; however, the molecular mechanism details are unclear. We suggest that by cleaving a presynaptic protein syntaxin, which is essential in targeting synaptic vesicles as a target SNAP receptor (t-SNARE), neurotoxin C1 of Clostridium botulinum causes growth cone collapse and inhibits axonal growth. Video-enhanced microscopic studies showed (a) that neurotoxin C1 selectively blocked the activity of the central domain (the vesicle-rich region) at the initial stage, but not the lamellipodia in the growth cone; and (b) that large vacuole formation occurred probably through the fusion of smaller vesicles from the central domain to the most distal segments of the neurite. The total surface area of the accumulated vacuoles could explain the membrane expansion of normal neurite growth. The gradual disappearance of the surface labeling by FITC WGA on the normal growth cone, suggesting membrane addition, was inhibited by neurotoxin C1. The experiments using the peptides derived from syntaxin, essential for interaction with VAMP or alpha-SNAP, supported the results using neurotoxin C1. Our results demonstrate that syntaxin is involved in axonal growth and indicate that syntaxin may participate directly in the membrane expansion that occurs in the central domain of the growth cone, probably through association with VAMP and SNAPs, in a SNARE-like way. PMID- 8698814 TI - Interference with p53 protein inhibits hematopoietic and muscle differentiation. AB - The involvement of p53 protein in cell differentiation has been recently suggested by some observations made with tumor cells and the correlation found between differentiation and increased levels of p53. However, the effect of p53 on differentiation is in apparent contrast with the normal development of p53 null mice. To test directly whether p53 has a function in cell differentiation, we interfered with the endogenous wt-p53 protein of nontransformed cells of two different murine histotypes: 32D myeloid progenitors, and C2C12 myoblasts. A drastic inhibition of terminal differentiation into granulocytes or myotubes, respectively, was observed upon expression of dominant-negative p53 proteins. This inhibition did not alter the cell cycle withdrawal typical of terminal differentiation, nor p21(WAF1/CIP1) upregulation, indicating that interference with endogenous p53 directly affects cell differentiation, independently of the p53 activity on the cell cycle. We also found that the endogenous wt-p53 protein of C2C12 cells becomes transcriptionally active during myogenesis, and this activity is inhibited by p53 dominant-negative expression. Moreover, we found that p53 DNA-binding and transcriptional activities are both required to induce differentiation in p53-negative K562 cells. Taken together, these data strongly indicate that p53 is a regulator of cell differentiation and it exerts this role, at least in part, through its transcriptional activity. PMID- 8698816 TI - Intracellular signals direct integrin localization to sites of function in embryonic muscles. AB - In the Drosophila embryo, the alphaPS2betaPS integrin heterodimer is localized tightly at the termini of the multinucleate muscles where they attach to the alphaPS1betaPS-containing epidermal tendon cells. Here we examine the basis for alphaPS2betaPS integrin subcellular localization. We show that the betaPS cytoplasmic tail is sufficient to direct the localization of a heterologous transmembrane protein, CD2, to the muscle termini in vivo. This localization does not occur via an association with structures set up by the endogenous betaPS integrins, since it can occur even in the absence of the betaPS protein. Furthermore, the subcellular localization of the alphaPS2betaPS integrin is not dependent on any other interactions between the muscles and the tendon cells. In embryos that lack the segmental tendon cells, due to a mutation removing the related segment polarity genes engrailed and invected, alphaPS2betaPS is still localized to the muscle termini even though the ventral longitudinal muscles are not attached to the epidermis, but instead are attached end to end. Thus the alphaPS2betaPS integrin can be localized by an intracellular mechanism within the muscles. Our results challenge the view that the transmission of signals from the extracellular environment via integrins is required for the organization of the cytoskeleton and the resultant cellular polarity. PMID- 8698817 TI - Xenopus embryonic cell adhesion to fibronectin: position-specific activation of RGD/synergy site-dependent migratory behavior at gastrulation. AB - During Xenopus laevis gastrulation, the basic body plan of the embryo is generated by movement of the marginal zone cells of the blastula into the blastocoel cavity. This morphogenetic process involves cell adhesion to the extracellular matrix protein fibronectin (FN). Regions of FN required for the attachment and migration of involuting marginal zone (IMZ) cells were analyzed in vitro using FN fusion protein substrates. IMZ cell attachment to FN is mediated by the Arg-Gly-Asp (RGD) sequence located in the type III-10 repeat and by the Pro-Pro-Arg-Arg-Ala-Arg (PPRRAR) sequence in the type III-13 repeat of the Hep II domain. IMZ cells spread and migrate persistently on fusion proteins containing both the RGD and synergy site sequence Pro-Pro-Ser-Arg-Asn (PPSRN) located in the type III-9 repeat. Cell recognition of the synergy site is positionally regulated in the early embryo. During gastrulation, IMZ cells will spread and migrate on FN whereas presumptive pre-involuting mesoderm, vegetal pole endoderm, and animal cap ectoderm will not. However, animal cap ectoderm cells acquire the ability to spread and migrate on the RGD/synergy region when treated with the mesoderm inducing factor activin-A. These data suggest that mesoderm induction activates the position-specific recognition of the synergy site of FN in vivo. Moreover, we demonstrate the functional importance of this site using a monoclonal antibody that blocks synergy region-dependent cell spreading and migration on FN. Normal IMZ movement is perturbed when this antibody is injected into the blastocoel cavity indicating that IMZ cell interaction with the synergy region is required for normal gastrulation. PMID- 8698818 TI - The intracellular functions of alpha6beta4 integrin are regulated by EGF. AB - Upon ligand binding, the alpha6beta4 integrin becomes phosphorylated on tyrosine residues and combines sequentially with the adaptor molecules Shc and Grb2, linking to the ras pathway, and with cytoskeletal elements of hemidesmosomes. Since alpha6beta4 is expressed in a variety of tissues regulated by the EGF receptor (EGFR), we have examined the effect of EGF on the cytoskeletal and signaling functions of alpha6beta4. Experiments of immunoblotting with anti phosphotyrosine antibodies and immunoprecipitation followed by phosphoamino acid analysis and phosphopeptide mapping showed that activation of the EGFR causes phosphorylation of the beta4 subunit at multiple tyrosine residues, and this event requires ligation of the integrin by laminins or specific antibodies. Immunoprecipitation experiments indicated that stimulation with EGF does not result in association of alpha6beta4 with Shc. In contrast, EGF can partially suppress the recruitment of Shc to ligated alpha6beta4. Immunofluorescent analysis revealed that EGF treatment does not induce increased assembly of hemidesmosomes, but instead causes a deterioration of these adhesive structures. Finally, Boyden chamber assays indicated that exposure to EGF results in upregulation of alpha6beta4-mediated cell migration toward laminins. We conclude that EGF-dependent signals suppress the association of activated alpha6beta4 with both signaling and cytoskeletal molecules, but upregulate alpha6beta4-dependent cell migration. The changes in alpha6beta4 function induced by EGF may play a role during wound healing and tumorigenesis. PMID- 8698819 TI - Signal sequence-dependent function of the TRAM protein during early phases of protein transport across the endoplasmic reticulum membrane. AB - Cotranslational translocation of proteins across the mammalian ER membrane involves, in addition to the signal recognition particle receptor and the Sec61p complex, the translocating chain-associating membrane (TRAM) protein, the function of which is still poorly understood. Using reconstituted proteoliposomes, we show here that the translocation of most, but not all, secretory proteins requires the function of TRAM. Experiments with hybrid proteins demonstrate that the structure of the signal sequence determines whether or not TRAM is needed. Features that distinguish TRAM-dependent and -independent signal sequences include the length of their charged, NH2-terminal region and the structure of their hydrophobic core. In cases where TRAM is required for translocation, it is not needed for the initial interaction of the ribosome/nascent chain complex with the ER membrane but for a subsequent step inside the membrane in which the nascent chain is inserted into the translocation site in a protease-resistant manner. Thus, TRAM functions in a signal sequence dependent manner at a critical, early phase of the translocation process. PMID- 8698820 TI - Biology of chemokine and classical chemoattractant receptors: differential requirements for adhesion-triggering versus chemotactic responses in lymphoid cells. AB - Several chemoattractant receptors can support agonist-induced, integrin-dependent arrest of rolling neutrophils in inflamed venules in vivo, as well as subsequent crawling into tissues. It has been hypothesized that receptors of the Galpha(i) linked chemoattractant subfamilies, especially receptors for chemokines, may mediate parallel activation-dependent arrest of homing lymphocyte subsets. However, although several chemokines can attract subsets of B or T cells, robust chemoattractant triggering of resting lymphocyte adhesion to vascular ligands has not been observed. To study the biology of individual leukocyte chemoattractant receptors in a defined lymphoid environment, mouse L1/2 pre-B cells and/or human Jurkat T cells were transfected with alpha (IL-8 receptor A) or beta (MIP 1alpha/CC-CKR-1) chemokine receptors, or with the classical chemoattractant C5a (C5aR) or formyl peptide receptors (fPR). All receptors supported robust agonist dependent alpha4beta1 integrin-mediated adhesion of lymphocytes to VCAM-1. L1/2 cells cotransfected with fPR and beta7 integrin were also induced to bind MAdCAM 1, suggesting common mechanisms coupling chemoattractant receptors to activation of distinct integrins. Adhesion was rapid but transient, with spontaneous reversion to unstimulated levels within 5 min after peak binding. When observed under flow conditions, alpha4beta1-mediated arrest occurred within seconds after initiation of contact and rolling of IL-8RA transfectants on VCAM-1/IL-8 co coated surface; and arrest reversed spontaneously after a mean of 5 min with a return to rolling behavior. Each of the receptors also conferred agonist-specific chemotaxis; however, whereas strong adhesion required simultaneous occupancy of many receptors with maximal responses above the Kd, chemotaxis in each case was suppressed at high agonist concentrations. The findings indicate that alpha and beta chemokine as well as classical chemoattractant receptors can trigger robust adhesion as well as directed migration of lymphoid cells, but that the requirements for and kinetics of adhesion triggering and chemotaxis are distinct, thus permitting their independent regulation. They suggest that the discordance between proadhesive and chemoattractant responses of circulating lymphocytes to many chemokines may reflect quantitative aspects of receptor expression and/or coupling rather than qualitative differences in receptor signaling. PMID- 8698822 TI - Myosin filament structure in vertebrate smooth muscle. AB - The in vivo structure of the myosin filaments in vertebrate smooth muscle is unknown. Evidence from purified smooth muscle myosin and from some studies of intact smooth muscle suggests that they may have a nonhelical, side-polar arrangement of crossbridges. However, the bipolar, helical structure characteristic of myosin filaments in striated muscle has not been disproved for smooth muscle. We have used EM to investigate this question in a functionally diverse group of smooth muscles (from the vascular, gastrointestinal, reproductive, and visual systems) from mammalian, amphibian, and avian species. Intact muscle under physiological conditions, rapidly frozen and then freeze substituted, shows many myosin filaments with a square backbone in transverse profile. Transverse sections of fixed, chemically skinned muscles also show square backbones and, in addition, reveal projections (crossbridges) on only two opposite sides of the square. Filaments gently isolated from skinned smooth muscles and observed by negative staining show crossbridges with a 14.5-nm repeat projecting in opposite directions on opposite sides of the filament. Such filaments subjected to low ionic strength conditions show bare filament ends and an antiparallel arrangement of myosin tails along the length of the filament. All of these observations are consistent with a side-polar structure and argue against a bipolar, helical crossbridge arrangement. We conclude that myosin filaments in all smooth muscles, regardless of function, are likely to be side polar. Such a structure could be an important factor in the ability of smooth muscles to contract by large amounts. PMID- 8698821 TI - The absence of Pmp47, a putative yeast peroxisomal transporter, causes a defect in transport and folding of a specific matrix enzyme. AB - Candida boidinii Pmp47, an integral peroxisomal membrane protein, belongs to a family of mitochondrial solute transporters (e.g., ATP/ADP exchanger), and is the only known peroxisomal member of this family. However, its physiological and biochemical functions have been unrevealed because of the difficulties in the molecular genetics of C. boidinii. In this study, we first isolated the PMP47 gene, which was the single gene encoding for Pmp47 in a gene-engineerable strain S2 of C. boidinii. Sequence analysis revealed that it was very similar to PMP47A and PMP47B genes from a polyploidal C. Boidinii strain (ATCC32195). Next, the PMP47 gene was disrupted and the disruption strain (pmp47delta) was analyzed. Depletion of PMP47 from strain S2 resulted in a retarded growth on oleate and a complete loss of growth on methanol. Both growth substrates require peroxisomal metabolism. EM observations revealed the presence of peroxisomes in methanol- and oleate-induced cells of pmp47delta, but in reduced numbers, and the presence of material of high electron density in the cytoplasm in both cases. Methanol induced cells of pmp47delta were investigated in detail. The activity of one of the methanol-induced peroxisome matrix enzymes, dihydroxyacetone synthase (DHAS), was not detected in pmp47delta. Further biochemical and immunocytochemical experiments revealed that the DHAS protein aggregated in the cytoplasm as an inclusion body, while two other peroxisome matrix enzymes, alcohol oxidase (AOD) and catalase, were active and found in peroxisomes. Two peroxisome-deficient mutants, strains M6 and M13 (described in previous studies), retained DHAS activity although it was mislocalized to the cytoplasm and the nucleus. We disrupted PMP47 in these peroxisome-deficient mutants. In both strains, M6 pmp47delta and M13-pmp47delta, DHAS was enzymatically active and was located in the cytoplasm and the nucleus. We suggest that an unknown small molecule, which PMP47 transports, is necessary for the folding or the translocation machinery of DHAS within peroxisomes. Pmp47 does not catalyze folding directly because active DHAS is observed in the M6-pmp47delta and M13-pmp47delta strains. Since both AOD and DHAS have the PTS1 motif sequences at their carboxyl terminal, our results first show that depletion of Pmp47 could dissect the peroxisomal import pathway (PTS1 pathway) of these proteins. PMID- 8698823 TI - A function for filamentous alpha-smooth muscle actin: retardation of motility in fibroblasts. AB - Actins are known to comprise six mammalian isoforms of which beta- and gamma nonmuscle actins are present in all cells, whereas alpha-smooth muscle (alpha-sm) actin is normally restricted to cells of the smooth muscle lineages. alpha-Sm actin has been found also to be expressed transiently in certain nonmuscle cells, in particular fibroblasts, which are referred to as myofibroblasts. The functional significance of alpha-sm actin in fibroblasts is unknown. However, myofibroblasts appear to play a prominent role in stromal reaction in breast cancer, at the site of wound repair, and in fibrotic reactions. Here, we show that the presence of alpha-sm actin is a signal for retardation of migratory behavior in fibroblasts. Comparison in a migration assay of fibroblast cell strains with and without alpha-sm actin revealed migratory restraint in alpha-sm actin-positive fibroblasts. Electroporation of monoclonal antibody (mAb) 1A4, which recognizes specifically the NH2-terminal Ac-EEED sequence of alpha-sm actin, significantly increased the frequency of migrating cells over that obtained with an unrelated antibody or a mAb against beta-actin. Time-lapse video microscopy revealed migratory rates of 4.8 and 3.0 microns/h, respectively. To knock out the alpha-sm actin protein, several antisense phosphorothioate oligodeoxynucleotide (ODNs) were tested. One of these, 3'UTI, which is complementary to a highly evolutionary conserved 3' untranslated (3'UT) sequence of alpha-sm actin mRNA, was found to block alpha-sm actin synthesis completely without affecting the synthesis of any other proteins as analyzed by two dimensional gel electrophoresis. Targeting by antisense 3'UTI significantly increased motility compared with the corresponding sense ODN. alpha-Sm actin inhibition also led to the formation of less prominent focal adhesions as revealed by immunofluorescence staining against vinculin, talin, and beta1 integrin. We propose that an important function of filamentous alpha-sm actin is to immobilize the cells. PMID- 8698824 TI - Drosophila paramyosin/miniparamyosin gene products show a large diversity in quantity, localization, and isoform pattern: a possible role in muscle maturation and function. AB - The Drosophila paramyosin/miniparamyosin gene expresses two products of different molecular weight transcriptionally regulated from two different promoters. Distinct muscle types also have different relative amounts of myosin, paramyosin, and miniparamyosin, reflecting differences in the organization of their thick filaments. Immunofluorescence and EM data indicate that miniparamyosin is mainly located in the M line and at both ends of the thick filaments in Drosophila indirect flight muscles, while paramyosin is present all along the thick filaments. In the tergal depressor of the trochanter muscle, both proteins are distributed all along the A band. In contrast, in the waterbug, Lethocerus, both paramyosin and miniparamyosin are distributed along the length of the indirect flight and leg muscle thick filaments. Two-dimensional and one-dimensional Western blot analyses have revealed that miniparamyosin has several isoforms, focusing over a very wide pH range, all of which are phosphorylated in vivo. The changes in isoform patterns of miniparamyosin and paramyosin indicate a direct or indirect involvement of these proteins in muscle function and flight. This wide spectrum of potential regulatory characteristics underlines the key importance of paramyosin/miniparamyosin and its complex isoform pattern in the organization of the invertebrate thick filament. PMID- 8698825 TI - Forced expression of dystrophin deletion constructs reveals structure-function correlations. AB - Dystrophin plays an important role in skeletal muscle by linking the cytoskeleton and the extracellular matrix. The amino terminus of dystrophin binds to actin and possibly other components of the subsarcolemmal cytoskeleton, while the carboxy terminus associates with a group of integral and peripheral membrane proteins and glycoproteins that are collectively known as the dystrophin-associated protein (DAP) complex. We have generated transgenic/mdx mice expressing "full-length" dystrophin constructs, but with consecutive deletions within the COOH-terminal domains. These mice have enabled analysis of the interaction between dystrophin and members of the DAP complex and the effects that perturbing these associations have on the dystrophic process. Deletions within the cysteine-rich region disrupt the interaction between dystrophin and the DAP complex, leading to a severe dystrophic pathology. These deletions remove the beta-dystroglycan-binding site, which leads to a parallel loss of both beta-dystroglycan and the sarcoglycan complex from the sarcolemma. In contrast, deletion of the alternatively spliced domain and the extreme COOH terminus has no apparent effect on the function of dystrophin when expressed at normal levels. The proteins resulting from these latter two deletions supported formation of a completely normal DAP complex, and their expression was associated with normal muscle morphology in mdx mice. These data indicate that the cysteine-rich domain is critical for functional activity, presumably by mediating a direct interaction with beta-dystroglycan. However, the remainder of the COOH terminus is not required for assembly of the DAP complex. PMID- 8698826 TI - Melanophore pigment dispersion responses to agonists show two patterns of sensitivity to inhibitors of cAMP-dependent protein kinase and protein kinase C. AB - Melanophore pigment dispersion is a sensitive bioassay for activation of the adenylyl cyclase and phospholipase C second-messenger pathways. The necessity of protein kinase activation in causing pigment dispersion was confirmed for eight agonists of endogenous melanophore receptors and for two transfected receptors. All agonists and receptors previously shown to elevate intracellular cAMP in melanophores--melanocyte stimulating hormone, light, (-) norepinephrine, 5 hydroxytrptamine, and the beta2-adrenergic receptor--were able to stimulate pigment dispersion in the presence of Ro31-8220, a potent inhibitor of protein kinase C, but were blocked in the presence of H89, an inhibitor of cAMP-dependent protein kinase. The bombesin receptor, which elevates intracellular IP3 in melanophores, was unable to stimulate pigment dispersion in the presence of Ro31 8220 or H89. Agonists whose mechanism of activation of pigment dispersion are unknown were also tested. Endothelin 3 responses were blocked by both H89 and Ro31-8220, predicting coupling to phospholipase C. Vasoactive intestinal polypeptide, oxytocin, and calcitonin gene-related peptide beta responses were blocked only by H89, predicting coupling to adenylyl cyclase. PMID- 8698827 TI - Smooth muscle cells isolated from the neointima after vascular injury exhibit altered responses to platelet-derived growth factor and other stimuli. AB - A variety of evidence suggests that vascular smooth muscle cells (SMC) exhibit a more immature phenotype when stimulated by injury to replicate in the adult. One growth characteristic common to immature (embryonic, fetal, and neonatal) SMC is a markedly reduced responsiveness to platelet-derived growth factor (PDGF) and other mitogenic stimuli. Here we demonstrate that SMC isolated from the 14-day neointima of experimentally injured carotid arteries exhibit a similar growth phenotype. The proliferative responses of neointimal cells to the BB homodimer of PDGF, which interacts with both forms of the PDGF receptor, were up to twenty fold less (as assessed by BrdU immunocytochemistry) than that of adult control tunica media cells over a wide range of PDGF concentrations. Paradoxically, these cells expressed abundant mRNA for the alpha- and beta-subunits of the PDGF receptor (by RT-PCR) and expressed abundant PDGF receptor protein (by Western blotting). Addition of PDGF-BB to neointimal SMC induced significant autophosphorylation of the PDGF receptor, suggesting that the PDGF receptors were fully functional. The chemotactic responses of neointimal SMC to PDGF, in in vitro migration assays, were identical to that of control medial cells. The data further establish the existence of vascular SMC phenotypes characterized by a refractoriness to growth stimulation by specific mitogens, and provide further evidence for the reiteration of developmentally regulated programs following vascular injury in vivo. PMID- 8698829 TI - Regulation of the disassembly/assembly of the membrane skeleton in Madin-Darby canine kidney cells. AB - The effects of pH, temperature, block of energy production, calcium/calmodulin, protein phosphorylation, and cytoskeleton-disrupting agents (cytochalasin D, nocodazole) on the integrity of the membrane skeleton were studied in polarized MDCK cells. The intracellular distributions of alpha-fodrin, actin, and ankyrin were monitored by immunofluorescence microscopy. The membrane skeleton, once assembled, seemed to be quite stable; the only factors releasing alpha-fodrin from the lateral walls were the acidification of the cytoplasm and the depletion of extracellular calcium ions. Upon cellular acidification, some actin was also released from its normal location along the lateral walls and was seen in colocalization with alpha-fodrin in the cytoplasm, whereas ankyrin remained associated with the lateral walls. No accumulation of plasma membrane lipids was observed in the cytoplasm of acidified cells, as visualized by TMA-DPH. These results suggest that the linkages between the fodrin-actin complex and its membrane association sites are broken upon acidification. The pH-induced change in alpha-fodrin localization was reversible upon restoring the normal pH. Reassembly of the membrane skeleton, however, required temperatures above +20 degrees C, normal energy production, proper cell-cell contacts, and polymerized actin. Release of alpha-fodrin from the lateral walls to the cytoplasm was also observed upon depletion of extracellular calcium ions. This change was accompanied by the disruption of cell-cell contacts, supporting the role of proper cell-cell contacts in the maintenance of the membrane skeleton polarity. These results suggest that local alterations of the cytoplasmic pH and calcium ion concentration may be important in regulating the integrity of the membrane skeleton. PMID- 8698828 TI - Protein kinase C isoform expression during the differentiation of 3T3-L1 preadipocytes: loss of protein kinase C-alpha isoform correlates with loss of phorbol 12-myristate 13-acetate activation of nuclear factor kappaB and acquisition of the adipocyte phenotype. AB - The regulated expression of protein kinase C (PKC) isoforms was examined during the differentiation program of 3T3-L1 preadipocytes. In a parallel analysis, differentiation was blocked by treatment of the cells with tumor necrosis factor alpha (TNF) to determine differentiation-specific changes in isoform expression from growth or treatment-induced effects. This analysis revealed that the expression of the conventional PKC-alpha isoform was reduced by 85% as cells attained the adipocyte phenotype. PKC-beta expression was measurable only during the early stages of the differentiation process and was not detectable in fully differentiated cells. An upregulation of PKC-theta, a novel PKC isoform, occurred during the latter stage of differentiation. Expression of PKC-zeta an atypical PKC isoform suggested to participate in TNF signal transduction, occurred throughout the time course with similar levels of expression in both preadipocytes and adipocytes. Nuclear run-on analysis demonstrated an approximately 85% reduction in the transcription of the PKC-alpha gene during differentiation. The reduced expression of this isoform corresponded with the decreased ability to activate nuclear factor kapppaB (NF-kappaB) in response to phorbol 12-myristate 13-acetate (PMA) treatment in the adipocytes. These data suggest that PMA responsiveness in 3T3-L1 adipocytes is markedly diminished. PMID- 8698830 TI - Regulation of basement membrane heparan sulfate proteoglycan, perlecan, gene expression in glomerular epithelial cells by high glucose medium. AB - Proteinuria in diabetic nephropathy has been correlated with reduction in heparan sulfate proteoglycan (HSPG) content of the glomerular basement membrane. We have previously shown that the underlying mechanism probably involves reduction in the synthesis by glomerular epithelial cells. In this study we explored whether high glucose medium regulates basement membrane HSPG gene expression. Northern analysis demonstrated that rat glomerular epithelial cells in vitro constitutively express mRNA for basement membrane HSPG, similar to that observed in rat kidney glomerulus. RNase protection assay showed that incubation of glomerular epithelial cells with 30 mM glucose for 24 h and 7 days resulted in reduction in HSPG mRNA abundance. The decrease in mRNA abundance correlated with reduction in the synthesis of 35SO4-labeled basement membrane HSPG as measured by immunoprecipitation. Reduction in synthesis of HSPG could not be entirely accounted for by decrease in mRNA abundance, suggesting both transcriptional and posttranscriptional mechanisms may be involved in reduction of glomerular basement membrane HSPG synthesis by glomerular epithelial cells in diabetic nephropathy. PMID- 8698831 TI - Extracellular matrix regulation of metalloproteinase and antiproteinase in human heart fibroblast cells. AB - Following myocardial infarction, extracellular matrix (ECM) is disrupted, which leads to the generation of collagen- and elastin-derived peptides (CDPs and EDPs, respectively). To investigate whether ECM-derived peptides (i.e., CDPs and EDPs) induce extracellular proteinases in human heart fibroblast (HHF) cells, we isolated CDP and EDP using gelfiltration and antibody affinity column chromatography. The CDP and EDP were characterized by their intrinsic fluorescence due to crosslink structure (pyridinoline and desmosine, respectively) and by immunoblot analysis using anti-desmosine antibody. Neutrophil elastase and cathepsin G were identified using selective chromogenic substrates and by their specific inhibition with alpha1-proteinase inhibitor and alpha1-antichymotrypsin, respectively. Elastase and cathepsin G were elevated in the infarcted tissue. Selective inhibition of matrix metalloproteinase (MMP) by a higher concentration of tetracycline or doxycycline in zymographic gels elicited an inhibition constant (IC50) of 278 +/- 10 microM and indicated that majority of MMP in the infarcted tissue is from fibroblast cells. The HHF proliferation was measured using an acid-phosphatase assay. The EDP and CDP induce HHF cell proliferation. After EDP treatment phenotypic (formation of pseudopodia) changes were observed in HHF cells. To measure whether phenotypic changes by EDP or CDP are associated with MMP and tissue inhibitor of metalloproteinase (TIMP) expression in HHF cells, we measured MMP and TIMP expression by zymographic and Northern blot (mRNA) analyses. The expression of MMP and TIMP were upregulated at both the protein and gene transcription levels. These results suggested that during ischemic cardiomyopathy, initially neutrophil proteinase activates latent myocardial MMP which can degrade ECM, which continuously degrades if not controlled by TIMP, leading to ventricular dilatation and dysfunction. PMID- 8698833 TI - Responses of tumor cell pseudopod protrusion to changes in medium osmolality. AB - The potential involvement of osmotically generated force in protrusion of tumor cell pseudopods was examined during a micropipette assay. Experiments were performed on single A2058 melanoma cells activated by a micropipette filled with soluble type IV collagen. Previous observations suggested that tumor cell pseudopod protrusion induced by type IV collagen took place in distinct, separable phases: an initial bleb (first phase) caused by localized Ca2+ activated actin filament severing resulting in an osmotic flux followed by an extension with an irregular shape (second phase) which required G protein mediated actin polymerization (Dong et al., 1994, Microvasc. Res., 47:55-67). Presently we studied cell pseudopod protrusion in response to the changes in chemoattractant osmolality. Reduction of attractant osmolality by 20-25% from its baseline value (297 mmol/ kg) resulted in an increase in pseudopod length by 50% apparent in the initial phase. Increases in attractant osmolality by 25-30% from the baseline value arrested pseudopod protrusion significantly during both initial and later phases. Using a dual-pipette method, such osmotic influence on the cell pseudopod protrusion was shown to be only a local effect in a small region where the cell surface was stimulated by the micropipette. While forces derived from actin polymerization and osmotic pressure have been proposed to cause protrusion in general, our results suggested that osmotically generated force is more apparent in the initial phase of the pseudopod formation. PMID- 8698832 TI - Localized calcium signaling in multinucleated osteoclasts. AB - Localized intracellular Ca2+ ([Ca2+]i) pulses, fluctuations, and repetitive spikes were detected in multinucleated rabbit osteoclasts in the presence of serum and in response to calcitonin using the fluorescent calcium indicator fluo 3 and a laser scanning microscope. We observed that these [Ca2+], changes were often restricted within a region of the cell body or propagated from the initial region of occurrence to other parts of the cell body but not to all parts. These observations suggest the existence of significant barriers to Ca2+ transport between different cytoplasmic regions of the osteoclast. To further investigate this phenomenon, we mechanically perturbed different cellular regions by touching locally with a micropipette. This usually induced a local increase in cytosolic and nuclear free [Ca2+]i. In some cases there was propagation of the [Ca2+]i increase to other regions but with part of the cell body not affected. Those regions of the cell body to which the [Ca2+]i increase did not propagate had a [Ca2+]i response to a direct mechanical perturbation. Our data show that osteoclasts can have different [Ca2+]i activities in apparently equivalent cellular regions, no matter how generated. This suggests that there can be a number of spatially separate Ca2+ regulatory systems within an osteoclast cell body. PMID- 8698835 TI - Enzymatic activities affecting exogenous nicotinamide adenine dinucleotide in human skin fibroblasts. AB - The fate of nicotinamide adenine dinucleotide (NAD), AMP, and ADP-ribose supplied to intact human skin fibroblasts was monitored, and the concentrations of intra- and extracellular pyridine and purine compounds were determined by HPLC analysis. Two enzymatic activities affecting extracellular NAD were detected on the plasma membrane, one hydrolyzing the pyrophosphoric bond and yielding nicotinamide mononucleotide (nucleotide pyrophosphatase) and the other cleaving the glycoside link and releasing nicotinamide (NAD-glycohydrolase). No AMP or ADP-ribose was found in the extracellular medium of cells incubated with NAD, the former being completely catabolized to hypoxanthine and the latter degraded to adenine and hypoxanthine. PMID- 8698834 TI - Opposite regulation of thrombospondin-1 and corticotropin-induced secreted protein/thrombospondin-2 expression by adrenocorticotropic hormone in adrenocortical cells. AB - Corticotropin-induced secreted protein (CISP) is a trimeric glycoprotein secreted by primary cultures of bovine adrenortical cells in response to adrenocorticotropic hormone (ACTH). This protein was recently purified in our laboratory, and its N-terminal amino-acid sequence revealed a significant similarity with thrombospondin-2 (TSP2). We report here the nucleotide sequence of a 386 bp RT-PCR fragment specific for CISP. The deduced protein sequence shares 84% identity with the N-terminal portion of mature human TSP2, suggesting that CISP is its bovine counterpart. Northern analysis of adrenocortical cell RNA using the above cDNA fragment as a probe revealed a 6.0 kb CISP/TSP2 mRNA whose abundance was increased nearly fivefold following a 24 h cell treatment with 10( 7) M ACTH. Under the same conditions, the expression of TSP1 mRNA was reduced by tenfold. The protein levels of TSP1 and CISP/TSP2 varied accordingly with their respective mRNA levels, as shown by immunoprecipitation and immunofluorescence experiments. Taken together, these data show that ACTH induces a dramatic shift in the pattern of adrenocortical cell thrombospondin expression from TSP1 to CISP/TSP2. This observation suggests that these two members of the thrombospondin family exert distinct biological functions in the adrenal cortex. This hypothesis is further supported by the observation that anti-CISP antibodies inhibit the maintenance of the morphological changes of bovine adrenocortical cells induced by ACTH, whereas anti-TSP1 antibodies do not. PMID- 8698836 TI - Regulation of matrix metalloproteinases following cellular transformation. AB - During progression towards malignancy, many tumor cells display changes in their repertoire of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs). The recent finding that many members of the MMPs are regulated by protooncogenes may explain the frequent observation of changes in MMP gene expression during progression of many tumor types. While studies involving enzymatic assays of MMPs are usually confined to one or a few MMPs, reverse transcription-PCR (RT-PCR) permitted the analysis of seven members of the MMP family and two members of the TIMP family in several normal and transformed cell lines. RT-PCR permitted us to confirm the observation that MMP-9 is activated following transformation and also to observe the previously unreported activation of MMP-7 in SV40-transformed cells. It has previously been found that MMP-1, -2, -3, -8, and -9 are upregulated by phorbol esters; we have found that MMP-10 is also upregulated by phorbol esters. The phorbol ester upregulation of MMP-1, -3, and -10 was found to be abolished in cells transformed by SV40 virus. Several studies have shown that MMP-1 is upregulated by an integrin-mediated signal transduction pathway. This study demonstrates that MMP-3 and MMP-10 are also regulated by integrin-mediated signal transduction and that upregulation by this pathway is abolished following SV40 transformation. In summary, the more global view of MMP expression afforded by RT-PCR indicates that MMP-1, -3, and 10 are regulated by both integrin-mediated signal transduction and phorbol esters. While fibroblasts and transformed bone cells express several members of the MMP gene family, several other cell types do not express MMPs. PMID- 8698837 TI - Relationships between intermediate filaments and cell-specific functions in renal cell lines derived from transgenic mice harboring the temperature-sensitive T antigen. AB - Four renal cell lines were derived from glomeruli, proximal, distal, and cortical collecting tubules microdissected from the kidneys of transgenic mice carrying the temperature-sensitive mutant of the simian virus 40 large T antigen under the control of the vimentin promoter. All four cell lines contained large T antigen in their nuclei, grew rapidly, and contained vimentin filaments when grown in serum-enriched medium at the permissive temperature of 33 degrees C. The glomerular cell line formed multiple layers of cells and contained smooth muscle actin and desmin filaments, features of mesangial cells. The three tubule cell lines formed monolayers of polarized cuboid cells separated by tight junctions and having a patchy distribution of cytokeratins K8-K18. A shift from 33 degrees C to the restrictive temperature (39.5 degrees C) stopped cell growth in all cell lines and caused profound changes in the content of intermediate filaments. Vimentin was still present in mesangial-like cells, but the proximal, distal, and collecting tubule cells contained uniform networks of cytokeratins K8-K18 and desmoplakin I and II around the cell peripheries. Potassium transport, mediated by Na+-K+ ATPase pumps and specific cAMP hormonal sensitivities, significantly increased in proximal, distal, and collecting tubule cells when shifted from 33 degrees C to 39.5 degrees C. Thus, the temperature-dependent inactivation of large T antigen, responsible for the arrest of cell growth, did not affect the phenotype of mesangial-like glomerular cells but induced some changes in the expression of intermediate filaments and restored, at least partially, the main parental cell-specific functions in proximal, distal, and collecting tubule cultured cells. PMID- 8698838 TI - Pituitary adenylate cyclase activating peptide and its receptors are expressed in human neuroblastomas. AB - Vasoactive intestinal peptide (VIP) has been considered as an autocrine growth factor in neuroblastomas. Pituitary adenylate cyclase activating polypeptides (PACAPs) are newly recognized members of the VIP family of neurohormones. As compared to VIP, PACAP has been reported to be biologically more potent and more efficient in tissues expressing selective PACAP receptors rather than common VIP/PACAP receptors. PACAPs and VIP interact with the same affinity and stimulate adenylate cyclase activity with the same efficacy and potency on the VIP receptors, but PACAPs act also on a more selective PACAP receptor that also recognizes VIP but with a 100- to 1,000-fold lower affinity. Thus, depending on the type of receptors expressed at a cell surface, PACAP may be more potent and efficient than VIP. The capacity of 22 surgical specimens of neuroblastomas and of 5 established cell lines to synthesize PACAP and VIP and to synthesize and express PACAP receptors and VIP receptors was studied. Using the reverse transcriptase-polymerase chain (RT-PCR) method with specific primers, we detected the mRNAs coding for PACAP and VIP in 19 and 3 out of 22 samples, respectively. PACAP mRNA was expressed in 3 of the 5 cell lines studied and VIP mRNA in 4. Using the same techniques, PACAP and VIP receptors mRNA were detected in 21, and 13 of the 22 tumor samples and in 5 and 1 of the cell lines studied, respectively. The expression of the PACAP receptor was demonstrated by direct binding studies and/or by the relative potency of PACAPs and VIP to stimulate adenylate cyclase activity in 16 of the 22 tumors and in all the cell lines. In addition, there was no correlation between tumor stage and the expression of mRNA coding for the peptides and the receptors. The present results demonstrated that PACAP could also be a candidate as an autocrine regulator of neuroblastoma which a higher activity than VIP. PMID- 8698839 TI - Suppression of UV- and interferon-alpha-refractoriness by antipain in human IFr cells established from RSa cells sensitive to both stimuli. AB - The human cell line IFr is a variant with an increased resistance to cell proliferation inhibition (CPI) by human interferon (HuIFN)-alpha, established from RSa cells with unusually high-sensitivity to CPI. IFr cells were later found to have increased resistance to the cell-killing effects of far-ultraviolet (UV) irradiation. Here, in cell lysates extracted from UV-irradiated IFr cells but not in those from irradiated RSa cells, fibrinolytic protease activity was found to be elevated promptly and transiently after irradiation. Treatment of IFr cells with HuIFN-alpha alone also resulted in the elevation of protease activity, but not that of RSa cells. Both the activity elevated after UV irradiation and after HuIFN-alpha treatment was inhibited to the greatest extent by antipain in vitro. Moreover, the refractoriness of IFr cells to UV cell-killing and to HuIFN-alpha CPI was suppressed by culturing with medium containing antipain immediately after UV irradiation or during HuIFN-alpha exposure. In similarly treated RSa cells, there was no modulation of UV- or HuIFN-alpha-susceptibility. These comparative characteristics between the two cell lines suggested that antipain-sensitive proteases and/or cellular functions may be involved in increased resistance to UV and HuIFN-alpha of IFr cells. PMID- 8698840 TI - Pertussis toxin-sensitive G-proteins inhibit fibroblast growth factor-induced signaling in pancreatic acini. AB - Signal transduction of fibroblast growth factor (FGF) receptors is known to involve tyrosine phosphorylation of several substrates, including Grb2, phospholipase C-gamma, and phosphatidylinositol 3-kinase, whereas the role of G proteins in FGF receptor signaling is controversial. In the present study we investigated the role of G-proteins in FGF receptor signaling in rat pancreatic acini. Immunological analysis revealed the presence of FGF receptor and phospholipase C-gamma1 in rat pancreatic acini. Both basic fibroblast growth factor (FGF-2) and guanosine 5'-(gamma-O-thio)triphosphate (GTPgammaS) caused an increase in inositol 1,4,5-trisphosphate (1,4,5-IP3) production and amylase release. Combined stimulation of the acini with GTPgammaS and FGF-2 led to a decrease of these responses as compared to the effect of the single substances. When pancreatic acini were preincubated with FGF-2 (1 nM) or vehicle (water) ADP ribosylation of the alpha-subunit of Gi-type G-proteins by pertussis toxin was reduced in membranes prepared from FGF-2 pretreated acini as compared to control acini, suggesting functional interaction of FGF receptors with Gi-proteins. Pretreatment of acini with pertussis toxin which inhibits Gi-type G-proteins abolished the inhibitory effect of GTPgammaS on FGF-induced 1,4,5-IP3 production and amylase release, whereas the stimulatory effects of FGF-2 and GTPgammaS on these parameters remained unchanged. In conclusion, these results show communication of FGF receptors and Gi-type G-proteins and that Gi-type G-proteins exert an inhibitory influence on FGF-induced activation of phosphoinositide specific phospholipase C in pancreatic acinar cells. PMID- 8698841 TI - Changes in cytoskeletal actin content, F-actin distribution, and surface morphology during HL-60 cell volume regulation. AB - Cell volume regulation occurs via the regulated fluxes of ions and solutes across the cell membrane in response to cell volume perturbations under anisotonic conditions. Our earlier studies in human promyelocytic leukemic HL-60 cells showed that volume-dependent changes in total cellular F-actin content occur concomitantly as an inverse function of acute cell volume changes in anisotonic media (Hallows et al., 1991, Am. J. Physiol., 261:C1154-C1161). Although treatment with cytochalasin under anisotonic conditions significantly reduced total cellular F-actin levels, cytochalasin did not significantly affect the ability of cells to undergo normal volume regulation responses, which suggested that these volume-dependent changes in F-actin content may not play a critical role in HL-60 cell volume regulation. To examine more closely the possible role of the actin cytoskeleton in HL-60 cell volume regulation, we quantitated changes in Triton-insoluble cytoskeletal actin in the presence and absence of cytochalasin and also observed changes in F-actin distribution and surface morphology during volume regulation. The quantity of cytoskeletal-associated F actin, like total F-actin, shifts inversely with initial cell volume changes in anisotonic media; however, subsequent changes in cytoskeletal actin levels during volume regulation are not significant. The soluble F-actin pool in HL-60 cells may thus be more susceptible to the physicochemical effects of shifts in cell volume than the insoluble (cytoskeletal) F-actin pool. Twenty-five micromolar dihydrocytochalasin B (DHB) treatment dramatically lowers cellular cytoskeletal actin levels by approximately 75% under resting (isotonic) conditions, but there are no significant further changes in cytoskeletal actin as cells undergo anisotonic volume regulation in the presence of DHB. These results suggest that volume-dependent changes in the absolute amounts of cytoskeletal-associated F actin are not critical for HL-60 cell volume regulation. However, because some portions of the actin cytoskeleton are resistant to cytochalasin disruption during volume regulation, a role for the cytoskeleton in the sensing and signaling of HL-60 cell volume regulatory responses cannot be rigorously excluded. Particular F-actin distribution patterns, as observed using confocal fluorescent microscopy, were correlated with particular phases of volume regulation. Also, comparison of cellular F-actin distribution with surface morphology (observed by scanning electronic microscopy) of cells during volume regulation reveals a positive correlation between surface blebs and increased cortical F-actin staining intensity. PMID- 8698842 TI - Na+ transport by human placental brush border membranes: are there several mechanisms? AB - Na+ transport was evaluated in brush border membrane vesicles isolated from the human placental villous tissue. Na+ uptake was assayed by the rapid filtration technique in the presence and the absence of an uphill pH gradient. Amiloride strongly decreased Na+ uptake whether a pH gradient was present or not. In pH gradient conditions (pH 7.5 in and 9.0 out), 1 mM amiloride decreased the 10 mM Na+ uptake by 84%. In the absence of pH gradient (pH 7.5 in and out), Na+ uptake was lower but still sensitive to amiloride. The Lineweaver-Burk plot of Na+ uptake consistently showed a single kinetics. Increasing the pH gradient decreased Km values of the amiloride-sensitive Na+ uptake, leaving the Vmax unchanged. In the absence of a pH gradient, the amiloride sensitive Na+ transport was maximal at pH 7.5. Here again, a single kinetics was observed, and pH influenced exclusively the Km of Na+. Since ethylisopropylamiloride, the specific Na/H exchanger inhibitor mimicked the effects of amiloride, decreasing by 98% the 10 mM Na+ uptake, whereas benzamil, the Na+ channel blocker, had no effect, it was concluded that the amiloride sensitive Na+ uptake was predominantly or exclusively due to a Na+-H+ exchanger activity. K+ in trans-position significantly decreased the amiloride sensitive uptake. In contrast, the presence of the cation in cis-position had no effect. The amiloride resistant Na+ transport was neither influenced by pH, nor saturable. Incubation of the placental tissue with 100 microM or 1 mM dibutyryl cAMP, 0.1 or 1 microM phorbol myristate acetate, 10(-7) M insulin, 10(-10) M angiotensin II, or 10(-8) M human parathyroid hormone (PTH) did not influence Na+ transport by subsequently prepared brush border membranes. Finally, we failed to demonstrate any Na+-H+ exchange activity in the basal plasma membrane. These results indicate that (1) in the absence of cosubstrates such as phosphate and aminoacids, the Na+-H+ exchange is probably the unique mechanism of Na+ transport by the placental brush border membrane, (2) the placental isoform of the exchanger is not regulated by PTH, angiotensin, nor insulin and, therefore, is different from the isoform present in the renal brush border membrane, and (3) there is no exchanger activity in the basal plasma membrane. PMID- 8698843 TI - Entry and distribution of fluorescent antiproliferative heparin derivatives into rat vascular smooth muscle cells: comparison between heparin-sensitive and heparin-resistant cultures. AB - We studied the binding and entry of fluorescein (FITC)-labeled heparin derivatives into rat aortic smooth muscle cells (SMC) by confocal microscopy. FITC-labeled heparin fractions or FITC-labeled SR 80037A, a potent antiproliferative heparin derivative (Barzu et al., Eur. J. Pharmacol., 219:225 233 1992), were prepared and their antiproliferative activity was confirmed. By incubating SMC with FITC-labeled heparins, a specific cell-associated fluorescence was found. Cellular fluorescence was mostly located around the nucleus and at the level of cell contacts or cell adhesion. The fluorescence was displaced neither by chasing with excess of unlabeled heparins nor by washing with 1 M NaCl, which proved that labeled heparins had been internalized by SMC. Kinetics of internalization of FITC-heparins suggested receptor-mediated endocytosis of heparins by SMC. Double labeling of SMC with biotinylated Concanavalin A and FITC-SR 80037A also indicated that heparin derivative enters the endocytic pathway. The process was accelerated when serum was present in the incubation medium. Treatment of cells with chloroquine (50 microM) induced accumulation of FITC-SR 80037A in the late endosomes, around the nucleus. No fluorescence labeling could be evidenced inside the nucleus. Neither electron microscopy nor cell fractionation experiments performed with SMC previously incubated with [3H]-heparin were able to ascertain nuclear uptake of heparin, as proposed by other workers (Busch et al., Cell Biol., 116:31-42; 1992; Sing et al., Drug Dev. Res., 29:129-136 1993). The cell-associated fluorescence was very weak in SMC resistant to the antiproliferative activity of heparin, selected by long-term heparin treatment (HT-SMC) as previously shown [Barzu et al., J. Cell. Physiol., 160:239-248, 1994]. The HT-SMC differed from control SMC with regard to expression of extracellular matrix proteins. These cells exhibited very low expression of fibronectin and prevalent expression of laminin and synthesized less cell-associated glycosaminoglycans. From our results, the following conclusions can be drawn: (1) the antiproliferative heparins are bound and internalized by SMC without being taken up into the nucleus; (2) there is a correlation between the binding and/or the internalization process and the sensitivity of SMC to the antiproliferative activity of heparins; and (3) selection of heparin-resistant SMC by long treatment with heparin results in particular growth pattern of SMC (absence of focal overgrowth), associated with changes in the expression of the extracellular matrix components (fibronectin, laminin, and cell-bound glycosaminoglycans). PMID- 8698844 TI - Properties of an immortalised vascular endothelial/glioma cell co-culture model of the blood-brain barrier. AB - In an effort to obtain a useful in vitro model possessing some of the properties of the blood-brain barrier, we have investigated the properties and interactions of immortalized cell lines. Immortalised human umbilical vein endothelial cells (HUVEC-304), in co-culture with rat C6 glioma cells in a two-chambered assembly, form tight junctional complexes, and develop a permeability barrier having a high transcellular electrical resistance. The endothelial cells generate a barrier with greatest integrity in the presence of glioma cells, or in the presence of glioma cell conditioned medium. Under these conditions, the endothelial cells also display pronounced structural changes which do not occur in the absence of glioma cells. Morphological alterations include a flattening of cell shape from a cuboidal-type to a squamous-type of appearance, and a re-organization of F-actin microfilaments. The integrity of the barrier can be reversibly disrupted by osmotic shock or by tumor necrosis factor-alpha (TNF-alpha). We interpret these observations to indicate that co-cultures of immortalized vascular endothelial and C6 glioma cells provide a model for the investigation of cell-cell interactions required for the generation of a barrier having several properties of the blood-brain barrier. PMID- 8698845 TI - Nitric oxide-induced perturbations in a cell culture model of the blood-brain barrier. AB - The actions of an intracellular nitric oxide generator compound on the properties of a co-culture model of the blood-brain barrier are described. Addition of the iron-sulphur cluster nitrosyl Roussin's black salt (RBS, heptanitrosyl-tri-mu3 thioxotetraferrate (1-)) resulted in a rapid and dose-dependent (50-250 microM) decline in the electrical resistance displayed by co-cultures of vascular endothelial cells and C6 glioma cells. The breach in barrier integrity elicited by RBS (250 microM) could be prevented by either haemoglobin (100 microM), methylene blue (200 microM), or by photon-induced inactivation of RBS. In contrast, the nitric oxide synthase inhibitor nitro-L-arginine methyl ester (250 microM) caused no inhibition in the decline in resistance of RBS-exposed cultures. Addition of 8-bromo-guanosine-cyclic monophosphate (500 microM) did not mimic the actions of RBS. Exposure to intense light of co-cultures manifesting a high transcellular electrical resistance resulted in a reduction in tissue resistance which could be prevented by the presence of haemoglobin (100 microM). We conclude that nitric oxide liberated from RBS results in a reversible diminution in the integrity of the endothelial cell barrier in the co-culture system, and we suggest that light-sensitive endogenous nitric oxide generator compounds may be present in intact cells. Possible roles of nitric oxide in blood brain-barrier function are considered. PMID- 8698846 TI - Dominant negative mutants of Myc inhibit cooperation of both Myc and adenovirus serotype-5 E1a with Ras. AB - We have used dominant negative Myc mutants to analyze the Myc and E1a mechanisms of cooperation with Ras. We show that mutants of Myc with an altered basic region (BR; RR366, 367EE) or deletion of the leucine zipper (LZ; delta aa 414-439), changes which modify the DNA binding domain, or with deletions in the Myc amino terminal conserved regions box 1 (dlMB1; delta aa 46-55) and box 2 (dlMB2; delta aa 132-140) inhibit cooperation of wt Myc and activated Ras to transform rat embryo fibroblasts (REF). Expression of the amino terminal 104 aa had no effect whereas wt Myc stimulated focus formation. Mutant dlMB1 cooperated with Ras with one half wt efficiency while dlMB2 was inactive. No mutant tested was toxic during neomycin cotransformation of REF to G418 resistance. Interestingly, these Myc mutants exerted a parallel inhibition of E1a-Ras cooperation to transform REF. This suggests that the Myc-Ras and E1a-Ras cooperation pathways intersect and require common protein factors. A Myc box 2 deletion mutant which is a wt transactivator of the Myc responsive ornithine decarboxylase promoter, but unlike the wt does not repress the adenovirus-2 core promoter (Li et al., 1994, EMBO J., 13:4070-4079), inhibits Myc-Ras and E1a-Ras cooperation. This suggests that a box 2-dependent step, potentially gene repression, is required for both the E1a- and Myc-Ras cooperation mechanisms. PMID- 8698847 TI - The good side of side effects: captopril blocks vessel and tumor growth. PMID- 8698848 TI - Conditional gene targeting. PMID- 8698849 TI - IL-4 and IL-13 activate the JAK2 tyrosine kinase and Stat6 in cultured human vascular endothelial cells through a common pathway that does not involve the gamma c chain. AB - IL-4 and IL-13 each act on human endothelial cells (ECs) to induce expression of vascular cell adhesion molecule-1. On hematopoietic cells. IL-4 responses may be mediated either through a pathway involving gc, the common signaling subunit of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors, or through a gc-independent pathway that may be alternatively activated by IL-13. We find that human ECs do not express gc, as detected by indirect immunofluorescence and FACS analysis or by a reverse transcription-PCR method. Like IL-4, IL-13 activates a protein tyrosine kinase that phosphorylates the IL-4R binding protein. In addition, we find that IL-4 and IL-13 each induce tyrosine phosphorylation of the JAK2 tyrosine kinase. Furthermore, both IL-4 and IL-13 induce binding of the Stat6 transcription factor to a consensus sequence oligonucleotide. We conclude that the IL-4 response of human ECs involves the IL-13 shared pathway that is independent of gc, and uses JAK2-Stat6 signaling. PMID- 8698850 TI - Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5 fluorouracil toxicity. AB - Dihydropyrimidine dehydrogenase (DPD) deficiency constitutes an inborn error in pyrimidine metabolism associated with thymine-uraciluria in pediatric patients and an increased risk of toxicity in cancer patients receiving 5-fluorouracil (5 FU) treatment. The molecular basis for DPD deficiency in a British family having a cancer patient that exhibited grade IV toxicity 10 d after 5-FU treatment was analyzed. A 165-bp deletion spanning a complete exon of the DPYD gene was found in some members of the pedigree having low DPD catalytic activity. Direct sequencing of lymphocyte DNA from these subjects revealed the presence of a G to A point mutation at the 5'-splicing site consensus sequence (GT to AT) that leads to skipping of the entire exon preceding the mutation during pre-RNA transcription and processing. A PCR-based diagnostic method was developed to determine that the mutation is found in Caucasian and Asian populations. This mutation was also detected in a Dutch patient with thymine-uraciluria and completely lacking DPD activity. A genotyping test for the G to A splicing point mutation could be useful in predicting cancer patients prone to toxicity upon administration of potentially toxic 5-FU and for genetic screening of heterozygous carriers and homozygous deficient subjects. PMID- 8698851 TI - Activation of antigen-induced lymphocyte proliferation by interleukin-15 without the mitogenic effect of interleukin-2 that may induce human immunodeficiency virus-1 expression. AB - The newly identified cytokine, IL-15 enhanced antigen-induced proliferation of PBMC obtained from HIV-1-seropositive subjects. When compared to IL-2 which enhanced both spontaneous and antigen-induced lymphocyte proliferative responses, IL-15 rarely increased spontaneous lymphocyte proliferation. Additionally, in cultures of lymphocytes obtained from 15 HIV-1-infected patients with < 300 circulating CD4- lymphocytes/microliter IL-15 induced significant HIV-1 expression (46, 21, and 71 pg/ml) in only 3 of 15 experiments and IL-2 induced significant HIV-1 expression (range 16- > 5000 pg/ml) in 11 of 15 experiments (P < 0.01, Fischer's exact test). Simultaneous assays of cytokine-induced spontaneous lymphocyte proliferation and HIV-1 expression revealed similar dose response relationships for induction of HIV-1 and lymphocyte proliferation by IL 2. Thus, IL-15 helps to correct the impaired proliferative response of CD4+ lymphocytes from HIV-1-infected persons without the mitogenic effect of IL-2 that also may induce HIV-1 expression. PMID- 8698852 TI - Identification of an immunodominant mouse minor histocompatibility antigen (MiHA). T cell response to a single dominant MiHA causes graft-versus-host disease. AB - T cell responses to non-MHC antigens are targeted to a restricted number of immunodominant minor histocompatibility antigens whose identity remains elusive. Here we report isolation and sequencing of a novel immunodominant minor histocompatibility antigen presented by H-2Db on the surface of C57BL/6 mouse cells. This nonapeptide (AAPDNRETF) shows strong biologic activity in cytotoxic T lymphocyte sensitization assays at concentrations as low as 10 pM. C3H.SW mice primed with AAPDNRETF in incomplete Freund's adjuvant generated a potent anti C57BL/6 T cell-mediated cytotoxic activity, and T lymphocytes from AAPDNRETF primed mice caused graft-versus-host disease when transplanted in irradiated C57BL/6 recipients. These results (a) provide molecular characterization of a mouse dominant minor histocompatibility antigen, (b) identify this peptide as a potential target of graft-versus-host disease and, (c) more importantly, demonstrate that a single dominant minor antigen can cause graft-versus-host disease. These findings open new avenues for the prevention of graft-versus-host disease and should further our understanding of the mechanisms of immunodominance in T cell responses to minor histocompatibility antigens. PMID- 8698853 TI - Diverse effects of Glut 4 ablation on glucose uptake and glycogen synthesis in red and white skeletal muscle. AB - The ability of muscles from Glut 4-null mice to take up and metabolize glucose has been studied in the isolated white EDL and red soleus muscles. In EDL muscles from male or female Glut 4-null mice, basal deoxyglucose uptake was lower than in control muscles and was not stimulated by insulin. In parallel, glycogen synthesis and content were decreased. Soleus muscles from male Glut 4-null mice took up twice more deoxyglucose in the absence of insulin than control muscles, but did not respond to insulin. In females, soleus deoxyglucose uptake measured in the absence of hormone was similar in Glut 4-null mice and in control mice. This uptake was stimulated twofold in Glut 4-null mice and threefold in control mice. Basal glycogen synthesis was increased by 4- and 2.2-fold in male and female null mice, respectively, compared to controls, and insulin had no or small (20% stimulation over basal) effect. These results indicate that while EDL muscles behaved as expected, soleus muscles were able to take up a large amount of glucose in the absence (males) or the presence of insulin (females). Whether this is due to a change in Glut 1 intrinsic activity or targeting and/or to the appearance of another glucose transporter remains to be determined. PMID- 8698854 TI - Expression of the Na-K-2Cl cotransporter by macula densa and thick ascending limb cells of rat and rabbit nephron. AB - Sodium and chloride transport by the macula densa and thick ascending limb of Henle's loop participates importantly in extracellular fluid volume homeostasis, urinary concentration and dilution, control of glomerular filtration, and control of renal hemodynamics. Transepithelial Na and Cl transport across the apical membrane of thick ascending limb (TALH) cells is mediated predominantly by a loop diuretic sensitive Na-K-2Cl cotransport pathway. The corresponding transport protein has recently been cloned. Functional studies suggest that the cotransporter is expressed by macula densa cells as well as by TALH cells. The current studies were designed to identify sites of Na-K-2Cl cotransporter expression along distal nephron in rabbit and rat. Non-isotopic high-resolution in situ hybridization, using an antisense probe for the apical form of the Na-K 2Cl cotransporter identified expression throughout the TALH, from the junction between inner and outer medulla to the transition to distal convoluted tubule. Expression by macula densa cells was confirmed by colocalization using markers specific for macula densa cells. First, Na-K-2Cl cotransporter mRNA was detected in macula densa cells that did not stain with anti-Tamm-Horsfall protein antibodies. Second, Na-K-2Cl cotransporter mRNA was detected in macula densa cells that show positive NADPH-diaphorase reaction, indicating high levels of constitutive nitric oxide synthase activity. In rat, levels of Na-K-2Cl cotransporter mRNA expression were similar in TALH and macula densa cells. In rabbit, expression levels were higher in macula densa cells than in surrounding TALH cells. The present data provide morphological support for a previously established functional concept that Na-K-2Cl cotransport at the TALH is accomplished by the expression of a well-defined cotransporter. At the macula densa, this transporter may establish a crucial link between tubular salt load and glomerular vascular regulation. PMID- 8698855 TI - Rabbit sucrase-isomaltase contains a functional intestinal receptor for Clostridium difficile toxin A. AB - The intestinal effects of Clostridium difficile toxin A are inidated by toxin binding to luminal enterocyte receptors. We reported previously that the rabbit ileal brush border (BB) receptor is a glycoprotein with an alpha-d-galactose containing trisaccharide in the toxin-binding domain (1991. J. Clin. Invest. 88:119-125). In this study we characterized the rabbit ileal BB receptor for this toxin. Purified toxin receptor peptides of 19 and 24 amino acids showed 100% homology with rabbit sucrase-isomaltase (SI). Guinea pig receptor antiserum reacted in Western blots with rabbit SI and with the purified toxin receptor. Antireceptor IgG blocked in vitro binding of toxin A to rabbit ileal villus cell BB. Furthermore, anti-SI IgG inhibited toxin A-induced secretion (by 78.1%, P < 0.01), intestinal permeability (by 80.8%, P < 0.01), and histologic injury (P < 0.01) in rabbit ileal loops in vivo. Chinese hamster ovary cells transfected with SI cDNA showed increased intracellular calcium increase in response to native toxin (holotoxin) or to a recombinant 873-amino acid peptide representing the receptor binding domain of toxin A. These data suggest that toxin A binds specifically to carbohydrate domains on rabbit ileal SI, and that such binding is relevant to signal transduction mechanisms that mediate in vitro and in vivo toxicity. PMID- 8698856 TI - Paradoxical inhibition of cardiac lipid peroxidation in cancer patients treated with doxorubicin. Pharmacologic and molecular reappraisal of anthracycline cardiotoxicity. AB - Anticancer therapy with doxorubicin (DOX) and other quinone anthracyclines is limited by severe cardiotoxicity, reportedly because semiquinone metabolites delocalize Fe(II) from ferritin and generate hydrogen peroxide, thereby promoting hydroxyl radical formation and lipid peroxidation. Cardioprotective interventions with antioxidants or chelators have nevertheless produced conflicting results. To investigate the role and mechanism(s) of cardiac lipid peroxidation in a clinical setting, we measured lipid conjugated dienes (CD) and hydroperoxides in blood plasma samples from the coronary sinus and femoral artery of nine cancer patients undergoing intravenous treatments with DOX. Before treatment, CD were unexpectedly higher in coronary sinus than in femoral artery (342 +/- 131 vs 112 +/- 44 nmol/ml, mean +/- SD; P < 0.01), showing that cardiac tissues were spontaneously involved in lipid peroxidation. This was not observed in ten patients undergoing cardiac catheterization for the diagnosis of arrhythmias or valvular dysfunctions, indicating that myocardial lipid peroxidation was specifically increased by the presence of cancer. The infusion of a standard dose of 60 mg DOX/m(2) rapidly ( approximately 5 min) abolished the difference in CD levels between coronary sinus and femoral artery (134 +/- 95 vs 112 +/- 37 nmol/ml); moreover, dose fractionation studies showed that cardiac release of CD and hydroperoxides decreased by approximately 80% in response to the infusion of as little as 13 mg DOX/m(2). Thus, DOX appeared to inhibit cardiac lipid peroxidation in a rather potent manner. Corollary in vitro experiments were performed using myocardial biopsies from patients undergoing aortocoronary bypass grafting. These experiments suggested that the spontaneous exacerbation of lipid peroxidation probably involved preexisting Fe(II) complexes, which could not be sequestered adequately by cardiac isoferritins and became redox inactive when hydrogen peroxide was included to simulate DOX metabolism and hydroxyl radical formation. Collectively, these in vitro and in vivo studies provide novel evidence for a possible inhibition of cardiac lipid peroxidation in DOX-treated patients. Other processes might therefore contribute to the cardiotoxicity of DOX. PMID- 8698857 TI - Expression of type II cGMP-dependent protein kinase in rat kidney is regulated by dehydration and correlated with renin gene expression. AB - cGMP-based regulatory systems are vital for counteracting the renin-angiotensin system (RAS) which promotes volume expansion and high blood pressure. Natriuretic peptides and nitric oxide acting through their second messenger cGMP normally increase natriuresis and diuresis, and regulate renin release; however, the severe pathological state of cardiac heart failure is characterized by elevated levels of atrial natriuretic peptide that are no longer able to effectively oppose exaggerated RAS effects. There is presently limited information on the intracellular effectors of cGMP actions in the kidney. Recently we reported the cloning of the cDNA for type II cGMP-dependent protein kinase (cGK II), which is highly enriched in intestinal mucosa but was also detected for the first time in kidney. In the present study, cGK II was localized to juxtaglomerular (JG) cells, the ascending thin limb (ATL), and to a lesser extent the brush border of proximal tubules. An activator of renin gene expression, the angiotensin II type I receptor inhibitor, losartan, increased cGK II mRNA and protein three to fourfold in JG cells. In other experiments, water deprivation increased cGK II mRNA and protein three to fourfold in the inner medulla where both cGK II, and a kidney specific CI- channel shown by others to be regulated by dehydration, are localized in the ATL. Whereas additional data suggest that cGK I may primarily mediate cGMP-related changes in renal hemodynamics, cGK II may regulate renin release and ATL ion transport. PMID- 8698859 TI - Role of cortisol in the pathogenesis of deficient counterregulation after antecedent hypoglycemia in normal humans. AB - The aim of this study was to determine the role of increased plasma cortisol levels in the pathogenesis of hypoglycemia-associated autonomic failure. Experiments were carried out on 16 lean, healthy, overnight fasted male subjects. One group (n = 8) underwent two separate, 2-d randomized experiments separated by at least 2 mo. On day 1 insulin was infused at a rate of 1.5 mU/kg per min and 2 h clamped hypoglycemia (53 +/- 2 mg/dl) or euglycemia (93 +/- 3 mg/dl) was obtained during morning and afternoon. The next morning subjects underwent a 2-h hyperinsulinemic (1.5 mU/kg per min) hypoglycemic (53 +/- 2 mg/dl) clamp study. In the other group (n = 8), day 1 consisted of morning and afternoon 2-h clamped hyperinsulinemic euglycemia with cortisol infused to stimulate levels of plasma cortisol occurring during clamped hypoglycemia (53 mg/dl). The next morning (day 2) subjects underwent a 2-h hyperinsulinemic hypoglycemic clamp identical to the first group. Despite equivalent day 2 plasma glucose and insulin levels, steady state epinephrine, norepinephrine, pancreatic polypeptide, glucagon, ACTH and muscle sympathetic nerve activity (MSNA) values were significantly (R < 0.01) blunted after day 1 cortisol infusion compared to antecedent euglycemia. Compared to day 1 cortisol, antecedent hypoglycemia produced similar blunted day 2 responses of epinephrine, norepinephrine, pancreatic polypeptide and MSNA compared to day 1 cortisol. Antecedent hypoglycemia, however, produced a more pronounced blunting of plasma glucagon, ACTH, and hepatic glucose production compared to day 1 cortisol. We conclude that in healthy overnight fasted men (a) antecedent physiologic increases of plasma cortisol can significantly blunt epinephrine, norepinephrine, glucagon, and MSNA responses to subsequent hypoglycemia and (b) these data suggest that increased plasma cortisol is the mechanism responsible for antecedent hypoglycemia causing hypoglycemia associated autonomic failure. PMID- 8698858 TI - Captopril inhibits angiogenesis and slows the growth of experimental tumors in rats. AB - Captopril, an inhibitor of angiotensin converting enzyme, is widely used clinically to manage hypertension and congestive heart failure. Here captopril is shown to be an inhibitor of angiogenesis able to block neovascularization induced in the rat cornea. Captopril acted directly and specifically on capillary endothelial cells, inhibiting their chemotaxis with a biphasic dose-response curve showing an initial decrease at clinically achievable doses under 10 microM and a further slow decline in the millimolar range. Captopril inhibition of endothelial cell migration was not mediated by angiotensin converting enzyme inhibition, but was suppressed by zinc. Direct inhibition by captopril of zinc dependent endothelial cell-derived 72-and 92-kD metalloproteinases known to be essential for angiogenesis was also seen. When used systemically on rats captopril inhibited corneal neovascularization and showed the antitumor activity expected of an inhibitor of angiogenesis, decreasing the number of mitoses present in carcinogen-induced foci of preneoplastic liver cells and slowing the growth rate of an experimental fibrosarcoma whose cells were resistant to captopril in vitro. These data define this widely used drug as a new inhibitor of neovascularization and raise the possibility that patients on long term captopril therapy may derive unexpected benefits from its antiangiogenic activities. PMID- 8698860 TI - Phenylalanine kinetics in human adipose tissue. AB - Very little is known about the regulation of protein metabolism in adipose tissue. In this study systemic, adipose tissue, and forearm phenylalanine kinetics were determined in healthy postabsorptive volunteers before and during a 2-h glucose infusion (7 mg.kg-1.min-1). [3H]Phenylalanine was infused and blood was sampled from a radial artery, a subcutaneous abdominal vein, and a deep forearm vein. Adipose tissue and forearm blood flow were measured with 133Xe and plethysmography, respectively, and body fat mass was determined by dual energy x ray absorptiometry. During glucose infusion, glucose concentration increased from 86 +/- 2 to 228 +/- 13 mg/dl and insulin concentration increased from 6.6 +/- 0.6 to 35.0 +/- 3.9 mU/liter, both P < 0.001. Systemic phenylalanine appearance decreased from 40.3 +/- 1.9 to 37.0 +/- 1.6 mumol/min during glucose infusion (P < 0.05). Baseline whole body adipose tissue phenylalanine release (5.2 +/- 1.4 mumol/min) was approximately 12% of systemic phenylalanine appearance and decreased (P < 0.05) to 2.3 +/- 0.9 mumol/min during glucose infusion. In contrast, phenylalanine release from the forearm did not change during glucose infusion. These results indicate that adipose tissue is a small but significant contributor to systemic phenylalanine appearance. Phenylalanine release from adipose tissue like lipolysis, is relatively sensitive to hyperinsulinemia. PMID- 8698861 TI - Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. AB - Bisphosphonates are used with increasing frequency in the management of skeletal complications in patients with breast cancer. In this paper, we have investigated whether bisphosphonates, besides their known beneficial effects on tumor associated osteoclastic resorption, are capable of inhibiting breast cancer cell adhesion to bone matrix. For that we used two in vitro models for bone matrix (cortical bone slices and cryostat sections of trabecular bone from neonatal mouse tails). Four bone matrix-bound nitrogen-containing bisphosphonates (pamidronate, olpadronate, alendronate, and ibandronate) inhibited adhesion and spreading of breast cancer cells to bone dose-dependently, whereas etidronate and clodronate had little or no effect. Strikingly, the relative order of potency of the bisphosphonates in inhibiting the adhesion of cancer cells to cortical and trabecular bone corresponded to their relative antiresorptive potencies in vivo as well as their ranking in in vitro bone resorption assays with predictive value for their clinical efficacy. It appears that nitrogen-containing bisphosphonates alter selectively the adhesive properties of the extracellular bone matrix preventing the attachment of breast cancer cells to it. Besides the beneficial effects of bisphosphonates on tumor-induced osteoclastic resorption, the previously unrecognized effect presented in this paper makes these agents suitable for earlier pharmacologic intervention in patients with breast cancer at risk of developing bone metastases. PMID- 8698862 TI - Different clinical behaviors of acute hepatitis C virus infection are associated with different vigor of the anti-viral cell-mediated immune response. AB - The anti-viral T cell response is believed to play a central role in the pathogenesis of hepatitis C virus infection. Since chronic evolution occurs in > 50% of HCV infections, the sequential analysis of the T cell response from the early clinical stages of disease may contribute to define the features of the T cell response associated with recovery or chronic viral persistence. For this purpose, 21 subjects with acute hepatitis C virus infection were sequentially followed for an average time of 44 wk. Twelve patients normalized transaminase values that remained normal throughout the follow-up period; all but two cleared hepatitis C virus-RNA from serum. The remaining nine patients showed persistent viremia and elevated transaminases. Analysis of the peripheral blood T cell proliferative response to core, E1, E2, NS3, NS4, and NS5 recombinant antigens and synthetic peptides showed that responses to all hepatitis C virus antigens, except E1, were significantly more vigorous and more frequently detectable in patients who normalized transaminase levels than in those who did not. By sequential evaluation of the T cell response, a difference between the two groups of patients was already detectable at the very early stages of acute infection and then maintained throughout the follow-up period. The results suggest that the vigor of the T cell response during the early stages of infection may be a critical determinant of disease resolution and control of infection. PMID- 8698863 TI - IL-12 in conjunction with dendritic cells enhances antiviral CD8+ CTL responses in vitro. AB - CD8+ cytolytic T lymphocytes (CTLs) are important mediators for resistance to infections and malignant diseases. IL-12 enhances proliferative and cytolytic responses by killer cells, but its function in the generation of human antiviral CD8+ T cell responses has not been defined. We therefore evaluated the role of IL 12 in the generation of CTLs to influenza-infected dendritic cells. IL-12 was not detectable in supernatants of infected-dendritic cells, or during CTL generation. Furthermore, anti-IL-12 antibody did not block CTL generation. However, exogenous IL-12 (30-300 pg/ml) enhanced CD8+ T cell proliferative and cytolytic responses. The effect was greatest in individuals with weak reactivity to influenza virus or at antigen-presenting cell (APC):T cell ratios of 1:100 or less. IL-12 augmented interferon-gamma production during CTL generation. The CTL enhancing effects of the cytokine, however, could not be blocked by neutralizing anti-interferon-gamma antibody. Together with IL-12, antigen-pulsed dendritic cells may be a useful approach for boosting CTL responses against infectious agents and malignancies. PMID- 8698864 TI - Expression of the mouse Na-K-2Cl cotransporter, mBSC2, in the terminal inner medullary collecting duct, the glomerular and extraglomerular mesangium, and the glomerular afferent arteriole. AB - Na-K-Cl cotransport plays an important role in the kidney in NaCl reabsorption in the thick ascending limb of Henle and a less well defined role in the inner medullary collecting duct (IMCD). Two Na-K-Cl cotransporters encoded by different genes have been identified in the mammalian kidney: BSC1/NKCC2 which localizes to the apical thick ascending limb of Henle and BSC2/NKCC1 which was isolated from a mouse IMCD cell line (mIMCD-3) but its localization has not been determined. In this study we generated a polyclonal antibody (anti-mBSC2) against the mouse BSC2/NKCC1 protein in order to characterize and localize this protein in mouse kidney. Western blot analysis with affinity-purified anti-mBSC2 showed a protein doublet of 140 and 150 kD which was most abundant in the renal papilla but also seen in cortex and outer medulla. The 140-150-kD bands were not seen with preimmune serum or with anti-mBSC2 preabsorbed with specific antigen. Immunolocalization confirmed expression of mBSC2 protein on the basolateral surface of terminal IMCD segments and demonstrated expression in the papillary surface epithelium. Immunofluorescence also revealed the unexpected presence of the BSC2 protein at the juxtaglomerular afferent arteriole, in a juxtaglomerular structure probably representing the extraglomerular mesangium, and throughout the glomerular mesangium. PMID- 8698865 TI - Pathogenic and protective correlates of T cell proliferation in AIDS. HNRC Group. HIV Neurobehavioral Research Center. AB - To investigate the association of antigen specific CD4 T cell activation with HIV disease progression and AIDS-related central nervous system damage, T cell proliferation responses to HIV, CMV, and HSV were evaluated in infected individuals. CD4 T cell loss and neurocognitive impairment were assessed at 6-mo intervals. Individuals with known times of seroconversion who responded to more HIV peptides were at greater risk of progressing to < 200 CD4 T cells (P = 0.04) and dying (P = 0.03) than those with responses to fewer peptides. A positive correlation (0.52) was seen between the breadth of the HIV proliferation response and HIV plasma RNA levels. Higher proliferation responses to CMV and HSV were also associated with more rapid CD4 loss (P = 0.05). HLA phenotyped individuals (n = 150) with two HLA-DR alleles associated with response to more HIV peptides and CMV (DR-2,5,w6,10) were less likely to develop neurocognitive (P = 0.002) and neurologic impairment (P = 0.04), but were not protected from CD4 loss and death. Thus, the ability to generate a greater T cell proliferation response to HIV and opportunistic herpes viruses may lead to resistance to central nervous system damage, but also risk of more rapid HIV disease progression. PMID- 8698866 TI - Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs. AB - Suppression of hepatic glucose output (HGO) has been shown to be primarily mediated by peripheral rather than portal insulin concentrations; however, the mechanism by which peripheral insulin suppresses HGO has not yet been determined. Previous findings by our group indicated a strong correlation between free fatty acids (FFA) and HGO, suggesting that insulin suppression of HGO is mediated via suppression of lipolysis. To directly test the hypothesis that insulin suppression of HGO is causally linked to the suppression of adipose tissue lipolysis, we performed euglycemic-hyperinsulinemic glucose clamps in conscious dogs (n = 8) in which FFA were either allowed to fall or were prevented from falling with Liposyn plus heparin infusion (LI; 0.5 ml/min 20% Liposyn plus 25 U/min heparin with a 250 U prime). Endogenous insulin and glucagon were suppressed with somatostatin (1 microgram/min/kg), and insulin was infused at a rate of either 0.125 or 0.5 mU/min/kg. Two additional experiments were performed at the 0.5 mU/min/kg insulin dose: a double Liposyn infusion (2 x LI; 1.0 ml/min 20% Liposyn, heparin as above), and a glycerol infusion (19 mg/min). With the 0.125 mU/min/kg insulin infusion, FFA fell 40% and HGO fell 33%; preventing the fall in FFA with LI entirely prevented this decline in HGO. With 0.5 mU/min/kg insulin infusion, FFA levels fell 64% while HGO declined 62%. Preventing the fall in FFA at this higher insulin dose largely prevented the fall in HGO; however, steady state HGO still declined by 18%. Doubling the LI infusion did not further affect HGO, suggesting that the effect of FFA on HGO is saturable. Elevating plasma glycerol levels did not alter insulin's ability to suppress HGO. These data directly support the concept that insulin suppression of HGO is not direct, but rather is mediated via insulin suppression of adipose tissue lipolysis. Thus, resistance to insulin control of hepatic glucose production in obesity and/or non insulin-dependent diabetes mellitus may reflect resistance of the adipocyte to insulin suppression of lipolysis. PMID- 8698867 TI - Hemodialysis increases apparent diffusion coefficient of brain water in nephrectomized rats measured by isotropic diffusion-weighted magnetic resonance imaging. AB - The nature of brain edema in dialysis disequilibrium syndrome (DDS) was investigated by diffusion-weighted magnetic resonance imaging (DWI). DWI was performed on normal or bilaterally nephrectomized rats before, and immediately after, hemodialysis. Hemodialysis was performed with a custom-made dialyzer (surface area 150 cm2) against a bicarbonate-buffered bath for 90 min with or without 70 mM urea. Hemodialysis with non-urea bath decreased plasma urea by 21 mM, and plasma osmolality by 22 mosmol/kg H2O, and increased brain water content by 8.0% (all < 0.05), while hemodialysis with urea bath did not affect plasma urea, osmolality, or brain water content. Three sets of axial DWI images of the brain were obtained at different gradient weighing factors with an in-plane resolution of 0.39 mm2. The apparent diffusion coefficient (Dapp) of the brain water was not affected by bilateral nephrectomy, or by hemodialysis in normal rats. In nephrectomized rats, brain Dapp was significantly increased after dialysis with non-urea bath (1.15 +/- 0.08 vs 0.89 +/- 0.07 x 10(-9)m2/sec, P < 0.01). No significant changes of brain water Dapp could be observed after dialysis with urea bath. The increased Dapp associated with DDS indicates that brain extracellular water increases and/or intracellular water decreases after hemodialysis. Our results strongly suggest that the brain edema induced by hemodialysis in uremic rats is due to interstitial edema rather than cytotoxic edema. Furthermore, our results support a primary role for the "reverse urea effect" in the pathogenesis of brain edema in DDS.DWI may be a useful diagnostic tool for DDS in patients with end-stage renal disease. PMID- 8698868 TI - The effects of alpha tocopherol supplementation on monocyte function. Decreased lipid oxidation, interleukin 1 beta secretion, and monocyte adhesion to endothelium. AB - Low levels of alpha tocopherol are related to a higher incidence of cardiovascular disease and increased intake appears to afford protection against cardiovascular disease. In addition to decreasing LDL oxidation, alpha tocopherol may exert intracellular effects on cells crucial in atherogenesis, such as monocytes. Hence, the aim of this study was to test the effect of alpha tocopherol supplementation on monocyte function relevant to atherogenesis. Monocyte function was assessed in 21 healthy subjects at baseline, after 8 wk of supplementation with d-alpha tocopherol (1,200 IU/d) and after a 6-wk washout phase. The release of reactive oxygen species (superoxide anion, hydrogen peroxide), lipid oxidation, release of the potentially atherogenic cytokine, interleukin 1 beta, and monocyte-endothelial adhesion were studied in the resting state and after activation of the monocytes with lipopolysaccharide at 0, 8, and 14 wk. There was a 2.5-fold increase in plasma lipid-standardized and monocyte alpha tocopherol levels in the supplemented phase. After alpha tocopherol supplementation, there were significant decreases in release of reactive oxygen species, lipid oxidation, IL-1 beta secretion, and monocyte-endothelial cell adhesion, both in resting and activated cells compared with baseline and washout phases. Studies with the protein kinase C inhibitor, Calphostin C, suggest that the inhibition of reactive oxygen species release and lipid oxidation is due to an inhibition of protein kinase C activity by alpha tocopherol. Thus, this study provides novel evidence for an intracellular effect of alpha tocopherol in monocytes that is antiatherogenic. PMID- 8698869 TI - Diminished post-rest potentiation of contractile force in human dilated cardiomyopathy. Functional evidence for alterations in intracellular Ca2+ handling. AB - Post-rest contractile behavior of isolated myocardium indicates the capacity of the sarcoplasmic reticulum (SR) to store and release Ca2+. We investigated post rest behavior in isolated muscle strips from nonfailing (NF) and endstage failing (dilated cardiomyopathy [DCM]) human hearts. At a basal stimulation frequency of 1 Hz, contractile parameters of the first twitch after increasing rest intervals (2-240 s) were evaluated. In NF (n = 9), steady state twitch tension was 13.7 +/- 1.8 mN/mm2. With increasing rest intervals, post-rest twitch tension continuously increased to maximally 29.9 +/- 4.1 mN/mm2 after 120s (P < 0.05) and to 26.7 +/- 4.5 mN after 240 s rest. In DCM (n = 22), basal twitch tension was 10.0 +/- 1.5 mN/mm2 and increased to maximally 13.6 +/- 2.2 mN/mm2 after 20 s rest (P < 0.05). With longer rest intervals, however, post-rest twitch tension continuously declined (rest decay) to 4.7 +/- 1.0 mN/mm2 at 240 s (P < 0.05). The rest dependent changes in twitch tension were associated with parallel changes in intracellular Ca2- transients in NF and DCM (aequorin method). The relation between rest-induced changes in twitch tension and aequorin light emission was similar in NF and DCM, indicating preserved Ca(2-)-responsiveness of the myofilaments. Ryanodine (1 microM) completely abolished post-rest potentiation. Increasing basal stimulation frequency (2 Hz) augmented post-rest potentiation, but did not prevent rest decay after longer rest intervals in DCM. The altered post-rest behavior in failing human myocardium indicates disturbed intracellular Ca2- handling involving altered function of the SR. PMID- 8698870 TI - Estradiol-dependent uterine leiomyomas in transgenic mice. AB - Uterine leiomyomas are a major health problem for women of reproductive age. The molecular biology of these tumors is poorly understood partly because of the lack of relevant animal models. We have produced transgenic mice expressing the simian virus 40 T antigen driven by the promoter of the Calbindin-D9K (CaBP9K) gene and either -1,000 or -117 bp of regulatory sequences so as to establish in vivo, uterine smooth muscle tumor models. Six transgenic mouse lines were obtained. Leiomyomas developed in all of them, with an almost complete penetrance of the phenotype. The smooth muscle tumors arose in different parts of the female reproductive tract. Leiomyomas usually developed in the corpus of the uterus, but one mouse line developed leiomyomas in the horn of the uterus, and another in the vagina. The CaBP9K regulatory sequences directing the expression of the Tag gene possess an estradiol responsive element, and accordingly, development of the tumors was strictly under the control of estrogen. Expression of the Tag gene is not only necessary for the initiation of the tumor but also for its development and maintenance. These transgenic mouse models should be useful for studying the pathobiology of uterine leiomyomas and could be instrumental in designing new therapeutic approaches to this disease. PMID- 8698871 TI - Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. AB - The mechanism that may cause degenerative fibrotic skin lesions was studied in situ using skin biopsies from patients with systemic sclerosis (SSc), localized scleroderma, or keloids, and at the initial disease stage in the University of California at Davis (UCD) lines 200/206 chickens, which develop a hereditary systemic connective tissue disease resembling human SSc and permit study of disease stages not accessible in humans. Frozen skin sections were analyzed simultaneously for apoptosis by terminal deoxynucleotidyl transferase-mediated FITC-dUTP nick end labeling and indirect immunofluorescence staining of cell markers with tetramethylrhodamine isothiocyanate conjugates. The results showed that endothelial cells are clearly the first cells to undergo apoptosis in the skin of UCD-200/206 chickens, a process that seems to be induced by anti endothelial cell antibodies. In human fibrotic skin diseases, apoptotic endothelial cells could only be detected in early inflammatory disease stages of SSc and localized scleroderma. PMID- 8698872 TI - No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia. AB - Pain treatment with centrally acting opiates is limited by tolerance. Tolerance is a decreasing effect of a drug with prolonged administration of that drug or of a related (e.g., endogenous) compound acting at the same receptor. This is often associated with a downregulation of receptors. In peripheral inflamed tissue, both locally expressed opioid peptides and morphine can produce powerful analgesia mediated by similar populations of opioid receptors. We hypothesized that the chronic presence of endogenous opioids in inflamed joints might convey downregulation of peripheral opioid receptors and tolerance to the analgesic effects of intraarticular morphine. We assessed these effects after arthroscopic surgery in patients with and without histologically verified synovial cellular infiltration, and we examined synovial opioid peptides and opioid receptors by immunocytochemistry and autoradiography, respectively. We found that, despite an abundance of opioid-containing cells in pronounced synovitis, morphine is at least as effective as in patients without such cellular infiltrations, and there is no major downregulation of peripheral opioid receptors. Thus, opioids expressed in inflamed tissue do not produce tolerance to peripheral morphine analgesia. Tolerance may be less pronounced for peripherally than for centrally acting opioids, which provides a promising perspective for the treatment of chronic pain in arthritis and other inflammatory conditions. PMID- 8698873 TI - Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma. AB - Many reactive products may be formed when LDL undergoes lipid peroxidation, which in turn can react with lipids, apoproteins, and proteins, generating immunogenic neoepitopes. Autoantibodies recognizing model epitopes of oxidized low density lipoprotein, such as malondialdehydelysine, occur in plasma and in atherosclerotic lesions of humans and animals. Because apo E-deficient mice develop particularly high titers of such autoantibodies, we used their spleens to clone 13 monoclonal antibodies to various epitopes of oxidized LDL ("E0 antibodies"). Binding and competitive RIAs demonstrated significant differences in fine specificity even between E0 antibodies initially selected for binding to the same screening antigen. For example, some E0 antibodies selected for binding to malondialdehyde-LDL also recognized copper oxidized LDL, acrolein-LDL, or LDL modified by arachidonic or linoleic acid oxidation products. Circulating IgG and IgM autoantibodies binding to copper-oxidized LDL, 4-hydroxynonenal-LDL, acrolein LDL, and LDL modified with arachidonic or linoleic acid oxidation products were found in apo E-deficient mice, suggesting that the respective antigens are formed in vivo. Epitopes recognized by some of the E0 monoclonal antibodies were also found on human circulating LDL. Each of the E0 monoclonal antibodies immunostained rabbit and human atherosclerotic lesions, and some of them yielded distinct staining patterns in advanced lesions. Together, this suggests that the natural monoclonal antibodies recognize different epitopes of complex structures formed during oxidation of lipoproteins, or epitopes formed independently at different lesion sites. Our data demonstrate that a profound immunological response to a large number of different epitopes of oxidized lipoproteins occurs in vivo. The availability of "natural" monoclonal autoantibodies should facilitate the identification of specific epitopes inducing this response. PMID- 8698874 TI - Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein. AB - The optimal clinical management of patients with antiphospholipid antibody syndrome (APS) is uncertain because of a lack of an underlying hypothesis to explain why antiphospholipid autoantibodies (aPL) form to such ubiquitous compounds as phospholipids (PL). In this paper, we demonstrate that many, if not most, aPL are actually directed at neoepitopes of oxidized PL, or neoepitopes generated by adduct formation between breakdown products of oxidized PL and associated proteins. Each cardiolipin (CL) molecule contains four unsaturated fatty acids and is highly susceptible to oxidation, particularly upon exposure to air. Yet, standard anticardiolipin antibodies (aCL) immunoassays routinely bind CL to microtiter wells by evaporation of the ethanol solvent overnight at 4 degrees C. Using a variety of techniques, we demonstrated that rapid oxidation occurs when CL is plated and exposed to air. Sera from apo E-deficient mice, which have high autoantibody titers to oxidized low density lipoprotein, showed a striking time-dependent increase in binding to CL that was exposed to air for increasing periods of time. Monoclonal antibodies to oxidized LDL, cloned from the apo E-deficient mice, also bound to oxidized CL. Both sera and affinity purified aCL-IgG from APS patients bound to CL progressively as it was oxidized. However, the monoclonal antibodies from apo E-deficient mice, or sera or aCL-IgG from APS patients did not bind to a reduced CL analog that was unable to undergo peroxidation. These data demonstrate that many aPL are directed at neoepitopes of oxidized phospholipids, and suggest that oxidative events may be important in the pathophysiology of APS. In turn, this suggests new therapeutic strategies, possibly including intensive antioxidant therapy. PMID- 8698875 TI - Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. AB - The specificity of T cell help for B cell activation and differentiation is maintained by the brief expression on the T cell surface, following T cell receptor-mediated triggering, of CD40 ligand (CD40L). Interaction of T helper (Th) cell CD40L with B cell CD40 induces B cell activation, cell surface expression of activation antigens, proliferation, and initiation of immunoglobulin isotype switch. We predicted that in patients with systemic lupus erythematosus (SLE), in whom Th cell-dependent production of autoantibodies results in immune complex-mediated tissue damage, CD40L expression might be augmented, prolonged, or abnormally regulated. Baseline expression of CD40L was increased in some SLE patients studied, when compared with control subjects. While Th cells from normal subjects (n = 14) and rheumatic disease control patients (n = 9) showed maximal expression of CD40L, after in vitro activation with phorbol myristate acetate (PMA) and ionomycin, at 6 h of culture with diminished levels observed at 24 and 48 h, Th cells from SLE patients (n = 19) maintained high level cell surface expression of CD40L through 24 and 48 h of culture. The prolonged expression of CD40L was functionally significant, as 24 h activated SLE T cells, when cocultured with target B cells, induced greater B cell surface CD80 (B7-1) expression than did 24 h-activated normal T cells. These results document impaired regulation of CD40L expression in SLE T cells and identify an important potential target for therapy in this systemic autoimmune disease. PMID- 8698876 TI - Increased guanylate cyclase activity is associated with an increase in cyclic guanosine 3',5'-monophosphate in left ventricular hypertrophy. AB - Left ventricular hypertrophy (LVH) produced by aortic valve plication leads to increased myocardial cyclic GMP. We tested whether this was a result of increased soluble guanylate cyclase activity or nitric oxide (NO) synthase and its functional consequences. We used the nitric oxide donor 3-morpholino-sydnonimine (SIN-1) or the NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME) in 12 control and 12 LVH anesthetized open-chest mongrel dogs. L-NAME (6 mg/kg) or SIN-1 (1 microgram/kg per min) was infused into the left anterior descending coronary artery and regional segment work and cyclic GMP levels were determined. In vitro myocardial guanylate cyclase sensitivity (0.43 +/- 0.04 to 0.28 +/- 0.04 mM [EC50]) and maximal activity (10.1 +/- 2.9 to 25.5 +/- 6.5 pmol/mg protein per min) were significantly increased in LVH as compared with control animals in response to nitroprusside stimulation, but cyclic GMP-phosphodiesterase activity was similar. In LVH dogs, basal cyclic GMP was significantly elevated in vivo when compared with controls. Treatment of dogs with SIN-1 resulted in a significant increase in cyclic GMP in control (1.09 +/- 0.12 to 1.48 +/- 0.19 pmol/gram) and a greater increase in the LVH group (1.78 +/- 0.16 to 3.58 +/- 0.71 pmol/g). L-NAME had no effect on myocardial cyclic GMP levels in control or LVH dogs. Segment work decreased in the control group after SIN-1 (1,573 +/- 290 to 855 +/- 211 grams x mm/min). LVH dogs showed no decrement in work as a result of treatment with SIN-1. L-NAME did not cause significant changes in myocardial cyclic GMP, O2 consumption, or work in either control or LVH dogs, but vascular effects were evident. SIN-1 increased cyclic GMP, and with greater effect on LVH; however, this resulted in a decrement in function only in the control group. The greater increased cyclic GMP in LVH dogs is not related to increased NO production, but is related to significantly higher sensitivity and maximal activity of soluble myocardial guanylate cyclase. PMID- 8698877 TI - Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein Cl. AB - We have generated transgenic mice over-expressing human apolipoprotein CI (apo CI) using the native gene joined to the downstream 154-bp liver-specific enhancer that we defined for apo E. Human apo CI (HuCI)-transgenic mice showed elevation of plasma triglycerides (mg/dl) compared to controls in both the fasted (211 +/- 81 vs 123 +/- 52, P = 0.0001) and fed (265 +/- 105 vs 146 +/- 68, P < 0.0001) states. Unlike the human apo CII (HuCII)- and apo CIII (HuCIII)-transgenic mouse models of hypertriglyceridemia, plasma cholesterol was disproportionately elevated (95 +/- 23 vs 73 +/- 23, P = 0.002, fasted and 90 +/- 24 vs 61 +/- 14, P < 0.0001, fed). Lipoprotein fractionation showed increased VLDL and IDL + LDL with an increased cholesterol/triglyceride ratio (0.114 vs 0.065, P = 0.02, in VLDL). The VLDL apo E/apo B ratio was decreased 3.4-fold (P = 0.05) and apo CII and apo CIII decreased in proportion to apo E. Triglyceride and apo B production rates were normal, but clearance rates of VLDL triglycerides and postlipolysis lipoprotein "remnants" were significantly slowed. Plasma apo B was significantly elevated. Unlike HuCII- and HuCIII-transgenic mice, VLDL from HuCI transgenic mice bound heparin-Sepharose, a model for cell-surface glycosaminoglycans, normally. In summary, apo CI overexpression is associated with decreased particulate uptake of apo B-containing lipoproteins, leading to increased levels of several potentially atherogenic species, including cholesterol-enriched VLDL, IDL, and LDL. PMID- 8698878 TI - Quantitative trait loci influencing cholesterol and phospholipid phenotypes map to chromosomes that contain genes regulating blood pressure in the spontaneously hypertensive rat. AB - The frequent coincidence of hypertension and dyslipidemia suggests that related genetic factors might underlie these common risk factors for cardiovascular disease. To investigate whether quantitative trait loci (QTLs) regulating lipid levels map to chromosomes known to contain genes regulating blood pressure, we used a genome scanning approach to map QTLs influencing cholesterol and phospholipid phenotypes in a large set of recombinant inbred strains and in congenic strains derived from the spontaneously hypertensive rat and normotensive Brown-Norway (BN.Lx) rat fed normal and high cholesterol diets. QTLs regulating lipid phenotypes were mapped by scanning the genome with 534 genetic markers. A significant relationship (P < 0.00006) was found between basal HDL2 cholesterol levels and the D19Mit2 marker on chromosome 19. Analysis of congenic strains of spontaneously hypertensive rat indicated that QTLs regulating postdietary lipid phenotypes exist also on chromosomes 8 and 20. Previous studies in the recombinant inbred and congenic strains have demonstrated the presence of blood pressure regulatory genes in corresponding segments of chromosomes 8, 19, and 20. These findings provide support for the hypothesis that blood pressure and certain lipid subfractions can be modulated by linked genes or perhaps even the same genes. PMID- 8698880 TI - Role of CD44 in the reaction of vascular smooth muscle cells to arterial wall injury. PMID- 8698879 TI - Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody. Potential implications for the effect of c7E3 Fab treatment on acute thrombosis and "clinical restenosis". AB - The murine/human chimeric monoclonal antibody fragment (c7E3 Fab) blocks GPIIb/IIIa and alpha v beta 3 receptors, inhibits platelet aggregation, and decreases the frequency of ischemic events after coronary artery angioplasty in patients at high risk of suffering such events. Although inhibition of platelet aggregation is likely to be the major mechanism of c7E3 Fab's effects, since activated platelets facilitate thrombin generation, it is possible that c7E3 Fab also decreases thrombin generation. To test this hypothesis, the effects of c7E3 Fab and other antiplatelet agents were tested in a thrombin generation assay triggered by tissue factor. c7E3 Fab produced dose-dependent inhibition of thrombin generation, reaching a plateau of 45-50% inhibition at concentrations > or = 15 micrograms/ml. It also inhibited thrombin-antithrombin complex formation, prothrombin fragment F1-2 generation, platelet-derived growth factor and platelet factor 4 release, incorporation of thrombin into clots, and microparticle formation. Antibody 6D1, which blocks platelet GPIb binding of von Willebrand factor, had no effect on thrombin generation, whereas antibody 10E5, which blocks GPIIb/IIIa but not alpha v beta 3 receptors decreased thrombin generation by approximately 25%. Combining antibody LM609, which blocks alpha v beta 3 receptors, with 10E5 increased the inhibition of thrombin generation to approximately 32-41%. The platelets from three patients with Glanzmann thrombasthenia, who lacked GPIIb/IIIa receptors but had normal or increased alpha v beta 3 receptors, supported approximately 21% less thrombin generation than normal platelets. We conclude that thrombin generation initiated by tissue factor in the presence of platelets is significantly inhibited by c7E3 Fab, most likely in part through both GPIIb/IIIa and alpha v beta 3 blockade, and that this effect may contribute to its antithrombotic properties. PMID- 8698881 TI - Expression and localization of FGF-1 in the developing rat olfactory system. AB - Primary olfactory axons project from the nasal olfactory neuroepithelium to glomeruli in the olfactory bulb where they synapse with mitral cells, the second order olfactory neurons. We have shown that the heparin-binding growth factor FGF 1 is expressed by olfactory nerve ensheathing cells which surround fascicles of primary olfactory axons en route to the olfactory bulb. These cells are believed to modulate olfactory axon growth between the olfactory neuroepithelium and the olfactory bulb. During late embryogenesis, FGF-1 expression is turned on in the mitral cells, and the FGF-1 peptide becomes confined to layers of synaptic neuropil in the postnatal olfactory bulb. FGF-1 is selectively present in glomeruli and the external plexiform layer. In cultures of olfactory neuroepithelial cells, complexes between FGF-1 and an appropriate activating heparan sulfate proteoglycan stimulated morphological differentiation of both olfactory nerve ensheathing cells and primary sensory olfactory neurons. Thus, the spatiotemporal expression and the functional properties of FGF-1 in this system suggest that this molecule plays an important regulatory role in the formation of the olfactory pathway. PMID- 8698882 TI - Organization in the somatosensory sector of the cat's thalamic reticular nucleus. AB - This study describes the organization of cells in the thalamic reticular nucleus (TRN) that project to the somatosensory part of the dorsal thalamus in the cat. Injections of wheat germ agglutinin conjugated to horseradish peroxidase (WGA HRP) and fluorescent dyes were made into the ventrobasal complex (VB) and the medial division of the posterior complex (POm) of the thalamus. The resultant retrograde labelling in TRN was analyzed. Large injections of a tracer in VB label many reticular cells that are restricted to a centroventral, or somatosensory, sector of TRN. Small injections of a tracer in VB produce narrow zones of labelled cells in this sector. In reconstructions these zones resemble thin "slabs," which lie parallel to the plane of TRN along its oblique rostrocaudal dimension and occupy only a fraction of its thickness. In comparisons of the zones of labelled cells in TRN resulting from tracer injections in different nuclei of VB, inner cells, intermediate cells, and outer cells across the thickness of TRN project to the ventral posteromedial, the medial division of the ventral posterolateral, and the lateral division of the ventral posterolateral nuclei, respectively. Furthermore, shifts in injected areas along the dorsoventral dimension of VB produce similar shifts in zones of labelled cells in TRN. Thus, reticular cells form an accurate map on the basis of their connections with VB. Large injections of a tracer in the ventral subdivision of POm label many reticular cells that are also restricted to the centroventral sector of TRN. Small injections of a tracer in ventral POm produce broad zones of labelled cells in this sector. In comparisons of the zones of labelled cells in TRN resulting from tracer injections in different regions of ventral POm, cells that project to these regions are scattered across the thickness of TRN and occupy overlapping territories. Large injections of a tracer in either VB or ventral POm also label cells in a restricted centroventral region of the perireticular nucleus. Double injections of different tracers in VB and ventral POm produce many cells in TRN that are labelled from both of these dorsal thalamic structures and fewer cells that are labelled from only one or the other of these structures. These results indicate that there is a dual organization in the projections of cells in the somatosensory sector of TRN to dorsal thalamus: Projections to VB are topographically organized whereas those to ventral POm lack a topographical organization. Furthermore, both of these mapped and nonmapped projections can arise from single reticular cells in the somatosensory sector. PMID- 8698883 TI - Quantitative MRI of the temporal lobe, amygdala, and hippocampus in normal human development: ages 4-18 years. AB - The volume of the temporal lobe, superior temporal gyrus, amygdala, and hippocampus was quantified from magnetic images of the brains of 99 healthy children and adolescents aged 4-18 years. Variability in volume was high for all structures examined. When adjusted for a 9% larger total cerebral volume in males, there were no significant volume differences between sexes. However, sex specific maturational changes were noted in the volumes of medial temporal structures, with the left amygdala increasing significantly only in males and with the right hippocampus increasing significantly only in females. Right greater-than-left laterality effects were found for temporal lobe, superior temporal gyrus, amygdala, and hippocampal volumes. These results are consistent with previous preclinical and human studies that have indicated hormonal responsivity of these structures and extend quantitative morphologic findings from the adult literature. In addition to highlighting the need for large samples and sex-matched controls in pediatric neuroimaging studies, the information from this understudied age group may be of use in evaluating developmental hypotheses of neuropsychiatric disorders. PMID- 8698884 TI - Recruitment order and dendritic morphology of rat phrenic motoneurons. AB - The detailed morphology of rat phrenic motoneurons (PMs) was studied in 40 electrophysiologically identified cells with intracellular injection of Neurobiotin. In 15 cells, the dendritic trees were fully analyzed by using path distance analysis, and total surface area and volume were estimated. Based on their relative onset times (ROT; i.e., the time of firing onset relative to the onset of whole phrenic activity), PMs were classified into three types; early recruited (type E; ROT < 10%), late recruited (type L; ROT > 12.5%), and quiescent (type Q; not recruited under normal conditions). Dendrites constituted 93.3% of the surface area of cells and 38.9% of the cell volumes. The number of primary dendrites (nPD) averaged 10.1, and the mean number of terminations was 38.8. The combined diameters of primary dendrites of PMs correlated well with the total dendritic surface area and the number of dendritic terminations. Comparisons among cell types revealed that type Q cells had greater dendritic surface areas and volumes than type E or type L cells. With path-distance analysis, this difference was found to be due to differences between the cell types in the numbers of their dendrites, their combined dendritic lengths, and the number of their branches. The differences between these data and those available for cat motoneurons are discussed. The input resistance of PMs correlated with their total surface area but did not correlate with their somal surface area, indicating that, in rat, PM input resistance is a function of the entire neuronal membrane rather than of the somal surface alone. PMID- 8698885 TI - Regional distribution of cytochrome P450 2D1 in the rat central nervous system. AB - Cytochrome P450s are enzymes involved in the oxidative metabolism of numerous endogenous and exogenous molecules. The enzyme cytochrome debrisoquine/sparteine type monoxygenase is a specific form of cytochrome P450 and is found in the liver and the brain (in the rat the enzyme is known as CYP2D1). CYP2D1 has no established role in the brain; however, it has been shown to share substrate and inhibitor specificities with the dopamine transporter and the enzyme monoamine oxygenase B. Using CYP2D-specific deoxyoligonucleotide probes and a polyclonal antibody to CYP2D1, we have mapped the distribution of CYP2D mRNA and CYP2D1-like immunoreactivity in the rat central nervous system. CYP2D1 immunoreactivity and the CYP2D1 mRNA signal were heterogenously distributed between brain areas. There were moderate to high levels of immunoreactivity and mRNA signal in the olfactory bulb, olfactory tubercle, cerebral cortex, hippocampus, dentate gyrus, piriform cortex, caudate putamen, supraoptic nucleus, medial habenula, hypothalamus, thalamus, medial mammilliary nucleus and superior colliculus. In the brainstem, strong CYP2D1 immunoreactivity and CYP2D mRNA signal were observed in the substantia nigra compacta, red nucleus, interpeduncular nucleus, pontine grey, locus coeruleus, cerebellum, and the ventral horn of the spinal cord. This study indicates that CYP2D1 is widely and constitutively expressed in neuronal and some glial populations in the rat brain. The localization of CYP2D1 in several regions known to harbor catecholamines and serotonin may suggest a role for CYP2D1 in the metabolism of monoamines. PMID- 8698886 TI - Distribution of visual callosal neurons in normal and strabismic cats. AB - It has been suggested that synchronous activation of cortical loci in the two cerebral hemispheres during development leads to the stabilization of juvenile callosal connections in some areas of the visual cortex. One way in which loci in opposite hemispheres can be synchronously activated is if they receive signals generated by the same stimulus viewed through different eyes. These ideas lead to the prediction that shifts in the cortical representation of the visual field caused by misalignment of the visual axes (strabismus) should change the width of the callosal zone in the striate cortex. We tested this prediction by using quantitative techniques to compare the tangential distribution of callosal neurons in the striate cortex of strabismic cats to that in normally reared cats. Animals were rendered strabismic surgically at 8-10 days of age and were allowed to survive a minimum of 18 weeks, at which time multiple intracortical injections of the tracer horseradish peroxidase (HRP) were used to reveal the distribution of callosally projecting cells in the contralateral striate cortex. HRP-labeled cells were counted in coronal sections, and data from four animals with divergent strabismus (exotropia) and four with convergent strabismus (esotropia) were compared to those from four normally reared animals. Although our data from strabismic cats do not differ markedly from those reported previously, we find that the distribution of callosal cells in the striate cortex of these cats does not differ significantly from that in our normally reared control cats. These results do not bear out the prediction that surgically shifting the visual axes leads to stabilization of juvenile callosal axons in anomalous places within the striate cortex. PMID- 8698887 TI - Axon arbors and synaptic connections of hippocampal mossy cells in the rat in vivo. AB - The axon collateralization patterns and synaptic connections of intracellularly labeled and electrophysiologically identified mossy cells were studied in rat hippocampus. Light microscopic analysis of 11 biocytin-filled cells showed that mossy cell axon arbors extended through an average of 57% of the total septotemporal length of the hippocampus (summated two-dimensional length, not adjusted for tissue shrinkage). Axon collaterals were densest in distant lamellae rather than in lamellae near the soma. Most of the axon was concentrated in the inner one-third of the molecular layer, with the hilus containing an average of only 26% of total axon length and the granule cell layer containing an average of only 7%. Ultrastructural analysis was carried out on three additional intracellularly stained mossy cells, in which axon collaterals and synaptic targets were examined in serial sections of chosen axon segments. In the central and subgranular regions of the hilus, mossy cell axons established a low density of synaptic contacts onto dendritic shafts, neuronal somata, and occasional dendritic spines. Most hilar synapses were made relatively close to the mossy cell somata. At greater distances from the labeled mossy cell (1-2 mm along the septotemporal axis), the axon collaterals ramified predominantly within the inner molecular layer and made a high density of asymmetric synaptic contacts almost exclusively onto dendritic spines. Quantitative measurements indicated that more than 90% of mossy cell synaptic contacts in the ipsilateral hippocampus are onto spines of proximal dendrites of presumed granule cells. These results are consistent with a primary mossy cell role in an excitatory associational network with granule cells of the dentate gyrus. PMID- 8698888 TI - Loss of the position-dependent reinnervation of regenerated toad (Bufo marinus) glutaeus muscle. AB - The terminations of motor axons in the toad glutaeus muscle show a course dependency on the segmental origins of the axons on the spinal cord. Rostral axons in spinal nerve 8 innervate muscle fibres near the ventral surface of the muscle, while caudal axons in spinal nerve 9 innervate fibres mostly towards the opposing dorsal surface. Axons originating between these extremes tend to innervate the central regions of the muscle. A similar topographic projection is reestablished after denervation and when regenerating axons reinnervate the muscle via entirely novel pathways (Brown and Everett [1991] J. Comp. Neurol. 309:495-506). The findings are compatible with the graded expression of a determinant within the glutaeus muscle that biases the formation of synapses between positionally matched muscle fibres and motor axons. In the present work, we provide strong support for this view by showing that when the muscle is reinnervated by axons arising from only one spinal nerve, they expand their projection and form synapses in the muscle in a topographically appropriate manner. In a second experiment, we tested whether a muscle that had regenerated from its resident myogenic (satellite) cell population would be similarly reinnervated. This experiment was prompted by the work of others (Donoghue et al. [1992] Cell 69:67-77) showing that the myogenic precursor cells in adult muscle are a repository of "positional memory." In our experiments, a glutaeus muscle was removed from adult toads and soaked in bupivacaine for a brief period to destroy the muscle fibres before being sutured back into its normal position in the limb. The distribution of motor units in the muscles was determined by glycogen depletion after allowing 3-4 months for the muscles to regenerate from their satellite cell population and to become reinnervated. We found that muscle fibres belonging to single motor units were dispersed widely in the regenerated muscles and showed no topographic organisation. We conclude that the positional cues that direct topographic map formation are available to motor axons when they reinnervate a denervated mature muscle, but play no role in the reinnervation of a regenerated muscle. PMID- 8698889 TI - Rapid induction by kainic acid of both axonal growth and F1/GAP-43 protein in the adult rat hippocampal granule cells. AB - Hippocampal granule cells do not normally express the axonal growth- and plasticity-associated protein F1/GAP-43 in the adult rat. Using three different methods that lead to hypersynchronous activity in limbic circuits, expression of F1/GAP-43 mRNA can be induced in granule cells which is followed by sprouting in mossy fibers, the axons of granule cells. F1/GAP-43 mRNA expression in granule cells was induced in the temporal, but not septal, hippocampus beginning at 12 hours after kainic acid (KA) subcutaneous injection (10 mg/kg). Beginning 2 days after KA treatment, mossy fiber sprouts restricted to the temporal hippocampus were observed in the supragranular layer. In the same animal we also observed that levels of protein F1/GAP-43 immunoreactivity in this layer apparently increased at this same 2 day time point and same ventral hippocampal location. F1/GAP-43 protein levels and mossy fiber sprouting showed an increase up to 10 days after KA treatment. Sprouting was at a maximum at 40 days, the longest time point studied. These events parallel axonal regeneration with one critical difference: granule cell axons are not damaged by kainate. The rapid onset of axonal growth in the adult is striking and occurs earlier than reported previously (2 days vs. 12 days). Such growth closely associated with elevated levels of protein F1/GAP-43 may occur as a result of a) reactive synaptogenesis caused by the availability of post-synaptic surface on granule cell dendrites at the supragranular layer, b) Hebbian co-activation of the post-synaptic granule cells and their presynaptic afferents, and c) loss of target-derived inhibitory growth factor. PMID- 8698890 TI - Neuronal architecture of the dorsal nucleus (cochlear nucleus) of the frog, Rana pipiens pipiens. AB - The neuronal architecture of the dorsal nucleus of the Northern leopard frog (Rana pipiens pipiens), which is a homolog of the cochlear nucleus of mammals and birds, was investigated. Our study showed that the frog dorsal nucleus contains a number of morphologically distinct cell types that are discernible in terms of the cellular architecture as derived from Nissl-stained material and in terms of the dendritic profile as revealed by horseradish peroxidase-filled single neurons. These cell types are bushy cells, bipolar (or fusiform) cells, octopus cells, stellate cells, giant cells, radiate (or round) cells, and a variety of small cells. The different cell types occupy different regions of the nucleus. Therefore, our results suggest that the dorsal nucleus should no longer be considered to be a uniform nucleus containing a homogeneous population of neurons. Homologies of these cell types with those described in other vertebrate species, including mammals, are proposed. PMID- 8698891 TI - Morphology of the monotreme organ of Corti and macula lagena. AB - The organ of Corti and macula lagena were studied by scanning and transmission electron microscopy in two species of monotreme, the platypus and echidna. In both species, the organ of Corti had a fundamentally mammalian conformation, with distinct outer and inner hair cells, separated by a tunnel of Corti. However, unlike eutherian mammals, the monotremes had three or four rows of pillar cells, and four to five rows of inner hair cells. The organ of Corti was much shorter than in eutherian mammals, at 4.4 mm (platypus), and 7.6 mm (echidna). While the total number of outer hair cells (3,350 platypus, 5,050 echidna) was many fewer than in most eutherian mammals, the total number of inner hair cells (1,600 platypus, 2,700 echidna) was comparable with that in eutherian mammals. The stereocilia on both inner and outer hair cells underwent a systematic change in orientation across the cochlear duct, with those nearest the tunnel of Corti having their axis of symmetry oriented transversely across the duct, and those on the outer edge of the organ having the axis oriented nearly longitudinally along the duct. The macula lagena had signs of a vestibular epithelium, with tall bundles of stereocilia, a division into areas with bundles of opposing orientation and type I and type II hair cells. PMID- 8698892 TI - Pretectal projections to the oculomotor complex of the monkey and their role in eye movements. AB - The nucleus of the optic tract (NOT) is associated with the generation of optokinetic nystagmus (OKN), whereas the olivary pretectal nucleus (ol), which lies embedded in the primate NOT, is believed to be essential for the pupillary light reflex. In this anatomical study of the pretectum, projections from NOT and ol to structures around the oculomotor nucleus were traced in the monkey, to determine which cell groups they innervated. 1. 3[H]-leucine injections were placed into NOT and ol, and labelled terminals were observed just outside the classical oculomotor nucleus (nIII), in the "C-group' and midline cell clusters, both of which contain small motoneurons of the extraocular eye muscles. In addition, there were strong projections to the lateral visceral cell column of the Edinger-Westphal complex (lvc), but not to the Edinger-Westphal nucleus (EW) itself. All of these projections were mainly contralateral. 2. NOT efferents terminated over the ipsilateral medial accessory nucleus of Bechterew (nB), but not over the adjacent nucleus Darkschewitsch. 3. Injections of a retrograde tracer into the oculomotor complex showed that the pretectal afferents described above originated mainly from the dorsomedial part of NOT and from ol. 4. The use of a transsynaptic retrograde tracer, tetanus toxin fragment (BIIb), established the monosynaptic nature of the connection between dorsomedial NOT (contralaterally) and ol (bilaterally), to the small extraocular motoneurons outside classical nIII. The "C-group' motoneurons may play a role in vergence, and lvc in pupillary constriction and depth of focus. Our results imply that NOT and ol participate in the control of some aspects of the near-response, which may be important in the generation of some components of OKN in primates. PMID- 8698893 TI - Intertectal commissural projection in the lizard Gallotia stehlini: origin and midline topography. AB - The retinotectal projection of reptiles is largely crossed. The intertectal commissure is an important pathway that interconnects directly the two sides of the optic tectum. The rostrocaudal topography of intertectal commissural fibers at the dorsal midplane was examined by means of the in vitro horseradish peroxidase (HRP) labelling technique in the lizard Gallotia stehlini. Unilateral large deposits of tracer in the optic tectum as well as smaller deposits restricted to one quadrant were used to map the intertectal fibers anterogradely. Most commissural axons reached the contralateral side grouped into a dense bundle at the transition between two structurally distinct parts of the midbrain dorsal midline. The smaller rostral zone relates laterally to the griseum tectale, whereas the larger caudal zone relates to the tectum. The intertectal fibers seem to converge on the rostralmost part of the latter midline region, even though they originate throughout the optic tectum. A rough rostrocaudal tectotopic order was detected at the midline. Retrogradely labelled neurons were best obtained by depositing HRP directly within the compact commissure at the midline. These belong to pyriform cells in the periventricular layers 3 and 5. Axons labelled from the tectum did not enter the posterior commissure nor the intervening commissural region related to the griseum tectale. PMID- 8698894 TI - PNS features of rodent optic nerve axons. AB - Peripheral nerves undulate together, giving them a wavelike appearance. This axonal pattern is also found in one region of the central nervous system, the optic nerve. Undulations provide a degree of compliance, as when a nerve is stretched, they are pulled straight. In the peripheral nervous system, undulations are thought to be conditional on the presence of extrafascicular collagen, which is also present between fascicles in the mammalian optic nerve. The pattern of undulations is described in the rat optic nerve and is related to the nerve's fascicular configuration and the regions between the fascicles, the extrafascicular matrix. The stage at which the undulations appear is determined to ascertain whether they are an intrinsic feature of optic axons or whether they emerge in association with the development of other events. The waves could be traced across the width of the nerve. Their pattern was not altered at fascicular boundaries, where axon groups are segregated. The periodicity of the undulations was constant between the eye and the middle of the nerve's length. Here fascicular divisions are present. Close to the chiasm, where the glial organisation changes and fascicles disappear, the periodicity of the undulations lengthened. They disappeared in the chiasm. Although collagen is a major component of the mammalian optic nerve's extrafascicular matrix, it was not present in the rat. Hence, the wavelike trajectory is independent of connective tissue. The waves are not present during early development and hence not an intrinsic feature of these axons. They appear behind the eye at late prenatal stages, emerging in association with glia in the extrafascicular matrix. They develop caudally, mirroring glial maturation. It is probable that the glia are maturing astrocytes that provide a scaffold for this feature of optic axon trajectory. PMID- 8698895 TI - Interphotoreceptor retinoid-binding protein (IRBP): expression in the adult and developing Xenopus retina. AB - Apposition of the neural retina and pigment epithelium is critical to photoreceptor development and function. Interphotoreceptor retinoid-binding protein (IRBP) is a major component of the extracellular matrix separating these epithelia in the African clawed frog Xenopus laevis (Gonzalez-Fernandez et al., [1993], J. Cell Sci. 105:7-21). In the adult retina, IRBP appears to mediate the transport of hydrophobic molecules, particularly retinoids and fatty acids, within the hydrophilic extracellular domain. In this paper, we compare the distribution of IRBP and its mRNA in adult and embryonic Xenopus retina. Xenopus IRBP antisense RNA, labeled with tritium or digoxigenin, was used for in situ hybridizaton studies. For immunohistochemistry, we used an antiserum against Xenopus IRBP expressed in Escherichia coli. In the adult, we found that IRBP is synthesized at similar levels by both rods and cones. The protein is restricted to the interphotoreceptor matrix, with lesser amounts in the pigment epithelial cytoplasm. In the embryo, expression of the mRNA for IRBP is restricted to the central retina, where photoreceptor differentiation has taken place. By contrast, the protein is distributed throughout the embryonic subretinal space. Therefore, the presence of IRBP precedes photoreceptor differentiation. In summary, IRBP is synthesized by both rods and cones and may be internalized by the pigment epithelium. In the embryo, IRBP is synthesized by the central retina and diffuses through the matrix, reaching the undifferentiated peripheral retina. In view of its ligand-binding properties, diffusion of IRBP may provide the peripheral neural retina with a vehicle to transport retinoids and docosahexaenoic acid (molecules critical to normal retinal development) from the pigment epithelium. PMID- 8698896 TI - Localisation of NK1 receptor immunoreactivity to neurons and interstitial cells of the guinea-pig gastrointestinal tract. AB - Tachykinins, including substance P, neurokinin A, and neuropeptides K and gama, are expressed widely in the peripheral nervous system where they affect smooth muscle contraction, exocrine gland secretion, vascular permeability, and neurotransmission. Substance P, the preferred ligand for the NK1 receptor, is found in high concentrations in the enteric nervous system. In the present study, the localisation and distribution of the NK1 receptor was studied throughout the gastrointestinal tract of the guinea-pig by using a polyclonal antiserum raised against the C-terminal 15 amino acids of the NK1 receptor. Co-localisation with other neuronal markers was examined in the ileum. Nerve cell bodies reactive for the NK1 receptor were found in the myenteric plexus of all regions and the submucous plexus of the small and large intestines. In the small intestine, the interstitial cells of Cajal were also immunoreactive. Immunoreactivity was largely confined to cell surfaces. Almost all immunoreactive myenteric nerve cells had Dogiel type I morphology, and most of these were immunoreactive for nitric oxide synthase, a transmitter of inhibitory neurons to the muscle and of descending interneurons. Neuropeptide Y-containing secretomotor neurons in the submucous and myenteric plexuses also exhibited NK1 receptor immunoreactivity. NK1 receptors were present on a minority of tachykinin immunoreactive neurons of submucous ganglia. The results suggest that receptors on the longitudinal muscle might not be conventional NK1 receptors, that excitation of the circular muscle of the ileum is indirect, perhaps via the interstitial cells of Cajal, and that enteric inhibitory neurons may be excited via NK1 receptors. PMID- 8698897 TI - Neuronal localization of serotonin in the nematode Ascaris suum. AB - We have used immunocytochemical techniques to investigate the distribution of serotonin-like immunoreactivity in the nematode Ascaris suum. Antisera raised against serotonin (5-hydroxytryptamine, 5-HT) conjugated to bovine serum albumin (BSA) labelled a pair of neurons in the pharynx of both sexes and five cells in the ventral cord of the male tail. The labelling was blocked by 5-HT or by 5-HT conjugated to BSA. The 5-HT-immunoreactive cells in the pharynx resemble neurosecretory cells and are probably homologous to the neurosecretory motor neurons (NSM) in Caenorhabditis elegans; the cells in the male tail appear to be motor neurons that are homologous to CP neurons in C. elegans. Other cells that stain with 5-HT antisera have been observed in C. elegans but are not seen in Ascaris. PMID- 8698898 TI - Microglial response to N-methyl-D-aspartate-mediated excitotoxicity in the immature rat brain. AB - The intracerebral injection of N-methyl-D-aspartate (NMDA) has been proposed as a model for hypoxic-ischemic insult in the immature brain. In this light, the aim of this study was to describe the time course of the microglial reaction in the areas undergoing primary degeneration at the site of intracortical NMDA injection as well as in areas undergoing secondary anterograde and/or retrograde degeneration. Fifty nanomoles of NMDA were injected in the sensorimotor cortex of 6-day-old rats. After survival times ranging from 10 hours to 28 days, cryostat sections were stained for routine histology and for the demonstration of microglial cells by means of tomato lectin histochemistry. The areas affected by primary degeneration caused by the intracortical injection of NMDA were the neocortex, the hippocampus, and the rostral thalamus. Secondary degeneration (retrograde and anterograde) was observed in the ventrobasal complex of the thalamus. The cortical lesion also caused Wallerian degeneration of the cortical descending efferents as observed in the basilar pons. Microglial reactivity in all these areas was present at 10 hours postinjection and was restricted to the areas undergoing neuronal or axonal degeneration. Reactive microglial cells were stained intensely and showed a round or pseudopodic morphology. At 3 days, an apparent increase in the number of tomato lectin-positive cells was observed in the areas undergoing neuronal death. By 7 days after the injection, the lesion became nonprogressive, and by 14 and 28 days, microglial cells showed moderate lectin binding and a more ramified morphology. PMID- 8698899 TI - Immunohistochemical localization of mu-opioid receptors in the central nervous system of the rat. AB - Of the three major types of opioid receptors ( mu, delta, kappa) in the nervous system, mu-opioid receptor shows the highest affinity for morphine that exerts powerful effects on nociceptive, autonomic, and psychological functions. So far, at least two isoforms of mu-opioid receptors have been cloned from rat brain. The present study attempted to examine immunohistochemically the distribution of mu opioid receptors in the rat central nervous system with two kinds of antibodies to recently cloned mu-opioid receptors (MOR1 and MOR1B). One antibody recognized a specific site for MOR1, and the other bound to a common site for MOR1 and MOR1B. Intense MOR1-like immunoreactivity (LI) was seen in the 'patch' areas and subcallosal streak in the striatum, medial habenular nucleus, medial terminal nucleus of the accessory optic tract, interpeduncular nucleus, median raphe nucleus, parabrachial nuclei, locus coeruleus, ambiguous nucleus, nucleus of the solitary tract, and laminae I and II of the medullary and spinal dorsal horns. Many other regions, including the cerebral cortex, amygdala, thalamus, and hypothalamus, also contained many neuronal elements with MOR1-LI. The distribution pattern of the immunoreactivity revealed with the antibody to the common site for MOR1 and MOR1B (MOR1/1B-LI) was almost the same as that of MOR1 LI. Both MOR1-LI and MOR1/1B-LI were primarily located in neuronal cell bodies and dendrites. However, the immunoreactivities were observed in the accessory optic tract, fasciculus retroflexus, solitary tract, and primary afferent fibers in the superficial layers of the medullary and spinal dorsal horns. The presynaptic location of MOR1-LI and MOR1/1B-LI was confirmed by lesion experiments: Enucleation, placing a lesion in the medial habenular nucleus, removal of the nodose ganglion, or dorsal rhizotomy resulted in a clear reduction of the immunoreactivities, respectively, in the nuclei of the accessory optic tract, some subnuclei of the interpeduncular nucleus, nucleus of the solitary tract, or laminae I and II of the spinal dorsal horn. The results indicate that the mu-opioid receptors are widely distributed in the brain and spinal cord, mainly postsynaptically and occasionally presynaptically. Opioids, including morphine, may inhibit the excitation of neurons via the postsynaptic mu-opioid receptors, and also suppress the release of neurotransmitters and/or neuromodulators from axon terminals through the presynaptic mu-opioid receptors. PMID- 8698900 TI - Enhanced early developmental expression of the metabotropic glutamate receptor mGluR5 in rat brain: protein, mRNA splice variants, and regional distribution. AB - Glutamate stimulates phosphatidyl inositol hydrolysis and mobilizes intracellular calcium through the mediation of metabotropic glutamate receptors (mGluRs), in particular the "Group I" receptors mGluRs, mGluR1, and mGluR5. This activity is markedly enhanced in developing brain relative to the adult. To determine whether this may be due to an increased amount of mGluR5 present in the developing brain, we examined mGluR5 expression using western blotting to measure mGluR5 protein reverse transcription polymerase chain reaction (RT-PCR) to measure mGluR5 mRNA, and immunocytochemistry to assess the regional distribution of mGluR5 morphologically. Western blotting revealed that in all brain regions examined there is more mGluR5 protein present in developing brain than in the adult. In most regions, the developmental decrease was over two-fold. Total mGluR5 mRNA also decreased with development in most regions, but to a much lesser extent than the protein, suggesting that there is considerable post-transcriptional regulation of the expression of this receptor. RT-PCR analysis also demonstrated that in most regions the mGluR5a splice variant is most abundant in the young animals but mGluR5b predominates in the adult. Light microscopic immunocytochemistry indicated that expression is widespread in developing brain, and that the developmental decrease in receptor concentration is due to both an increased growth of receptor-poor tissue regions and decreased expression within receptor-rich regions. PMID- 8698901 TI - Developmental profile of GABAA-receptors in the marmoset monkey: expression of distinct subtypes in pre- and postnatal brain. AB - Gamma aminobutyric acid (GABA)A-receptors are expressed in fetal mammalian brain before the onset of synaptic inhibition, suggesting their involvement in brain development. In this study, we have analyzed the maturation of the GABAA-receptor in the marmoset monkey forebrain to determine whether distinct receptor subtypes are expressed at particular stages of pre- and postnatal ontogeny. The distribution of the subunits alpha 1, alpha 2, and beta 2,3 was investigated immunohistochemically between embryonic day 100 (6 weeks before birth) and adulthood. Prenatally, the alpha 2- and beta 2,3-subunit-immunoreactivity (-IR) was prominent throughout the forebrain, whereas the alpha 1-subunit-IR appeared in selected regions shortly before birth. The alpha 2-subunit-IR disappeared gradually to become restricted to a few regions in adult forebrain. By contrast, the alpha 1-subunit-IR increased dramatically after birth and replaced the alpha 2-subunit in the basal forebrain, pallidum, thalamus, and most of the cerebral cortex. Staining for the beta 2,3-subunits was ubiquitous at every age examined, indicating their association with either the alpha 1- or the alpha 2-subunit in distinct receptor subtypes. In neocortex, the alpha 1 -subunit-IR was first located selectively to layers IV and VI of primary somatosensory and visual areas. Postnatally, it increased throughout the cortex, with the adult pattern being established only during the second year. The switch in expression of the alpha 1- and alpha 2- subunits indicates that the subunit composition of major GABAA-receptor subtypes changes during ontogeny. This change coincides with synaptogenesis, suggesting that the emergence of alpha 1- GABAA-receptors parallels the formation of inhibitory circuits. A similar pattern has been reported in rat, indicating that the developmental regulation of GABAA-receptors is conserved across species, possibly including man. However, the marmoset brain is more mature than the rat brain at the onset of alpha 1-subunit expression, suggesting that alpha 1-GABAA-receptors are largely dispensable in utero, but may be required for information processing after birth. PMID- 8698902 TI - Serotonergic axons in monkey prefrontal cerebral cortex synapse predominantly on interneurons as demonstrated by serial section electron microscopy. AB - Anatomical approaches were used to describe the distribution, appearance, and synaptic interactions of serotonin (5-HT)-immunoreactive axons in monkey prefrontal cortex. A plexus of 5-HT axons was found throughout the gray matter, with an especially high density in layer I and a slight increase in layer IV. They were strikingly heterogeneous, with a gradient of morphologies ranging from fine and nonvaricose to highly varicose or thick and nonvaricose. Electron microscopy showed that both varicose and nonvaricose axons were typically filled with clear vesicles and less abundant dense core vesicles. A serial section analysis of 5-HT varicosities in layers I, III, and V showed consistent results across layers. Only about 23% of labeled varicosities formed identifiable synapses. These synapses were consistently asymmetric and were 2-5 serial sections (or 0.08-0.38 mu) in diameter. Targets of identified 5-HT synapses were dendritic shafts with the exception of one cell soma. Followed in serial sections, postsynaptic dendrites typically had morphological features of interneurons, i.e. they lacked spines, had a high density of synaptic inputs, and often had a varicose morphology. Only 8% of postsynaptic shafts were classified as pyramidal dendrites. This is in striking contrast to our previous study in this cortex of dopamine axons, which synapsed predominantly on pyramidal dendrites. These are the first results to indicate that interneurons are the major recipient of identifiable 5-HT synapses in the monkey prefrontal cortex. PMID- 8698903 TI - Sexually dimorphic expression of calcitonin gene-related peptide (CGRP) immunoreactivity by rat mediobasal hypothalamic neurons. AB - Although the hypothalamic arcuate nucleus is a sexually dimorphic region of the rat brain, there are no reports of sex differences in the number of neurons containing specific neuropeptides within this structure. As cells synthesizing calcitonin gene-related peptide (CGRP) have been shown to exhibit sex differences in other steroid-receptive regions of the rat brain, we examined whether the CGRP immunoreactive cells located in the mediobasal hypothalamus may also be sexually dimorphic. Immunostaining of sections from male and female colchicine-treated rats revealed a small population of CGRP-immunoreactive cells distributed throughout the arcuate nucleus. Immunoreactive cells were also detected in the lateral hypothalamic perifornical region, dorsomedial, posterior periventricular and ventral tuberomammillary nuclei, and zona incerta. Cell count analysis revealed approximately twice as many CGRP-immunoreactive cell profiles in the rostral (P < 0.01), middle (P < 0.001), and caudal (P < 0.01) thirds of the arcuate nucleus of male rats compared with females. A significant sex difference in immunoreactive cell numbers (male > female) was also detected within the caudal dorsomedial nucleus (P < 0.05) but not in the posterior periventricular nucleus, perifornical region and zona incerta. Although fibers immunoreactive for CGRP were identified in low density throughout the mediobasal hypothalamus, only female rats displayed prominent fiber staining in the periventricular region. Double-labelling immunofluorescence experiments revealed that the CGRP immunoreactive cells within the zona incerta, but not the hypothalamus, were also immunoreactive for tyrosine hydroxylase; at least 60% of the A13 dopaminergic neurons co-express CGRP. These results provide evidence that sex differences exist in the number of specific neuropeptide-synthesizing cells within the hypothalamic arcuate nucleus and provide further examples of cell populations expressing CGRP immunoreactivity in a sexually dimorphic manner. PMID- 8698904 TI - Regional distribution of neurotrophin receptors in the developing auditory brainstem. AB - Neuron survival and axonal regeneration become severely limited during early postnatal development. In conjunction with our recent organotypic analysis of regeneration in the auditory midbrain, we wished to determine whether neurotrophins could serve as a trophic substance during the postnatal period. Therefore, the current study examines the development of three neurotrophin receptor tyrosine kinases (TrkA, TrkB, and TrkC) in the gerbil auditory brainstem. Immunoreactivity to TrkA, the nerve growth-factor receptor, was observed in nonneuronal cells during the first two postnatal weeks. In the cochlear nucleus of mature animals, however, there was a TrkA-positive neuronal subpopulation. In contrast, immunoreactivity to TrkB and TrkC (the receptors for brain-derived neurotrophic factor and neurotrophin-3, respectively) displayed a widespread distribution in the auditory brainstem. At postnatal day 0, TrkB and TrkC staining was virtually absent from auditory nuclei, although immunopositive neurons were present in the mesencephalic trigeminal nucleus. By postnatal day 7, TrkB- and TrkC-positive neurons were present in most brainstem auditory nuclei. At postnatal day 15, TrkB immunoreactivity was observed throughout the inferior colliculus (IC), the cochlear nucleus, the medial and lateral nuclei of the trapezoid body, and the lateral superior olive, whereas TrkC labeled only a subpopulation of neurons within the central nucleus of the IC. The TrkB immunoreactivity was present on both neuronal somata and dendrites, whereas TrkC was generally restricted to cell bodies. At postnatal day 30, TrkB immunostaining was observed on most neurons of the IC. The medial and lateral nuclei of the trapezoid body displayed extremely strong TrkB staining, followed by the cochlear nucleus. In contrast, the TrkC immunostaining was decreased dramatically by postnatal day 21. Observations at the ultrastructural level confirmed a neuronal localization of TrkB and TrkC. Immunostaining for both receptors was restricted largely to the postsynaptic density of synaptic profiles in both dendrites and somata. In summary, this study illustrates a differential pattern of immunoreactivity between three neurotrophin receptors during development. The general increase of TrkB expression is well correlated with the onset of sound evoked activity in this system, and its synaptic localization suggests that it may be involved in the modulation or maintenance of postsynaptic physiology. PMID- 8698905 TI - Projection from the accommodation-related area in the superior colliculus of the cat. AB - Our previous study has indicated that accommodative responses can be evoked with weak currents applied to a circumscribed area of the superior colliculus in the cat. We investigated efferent projections from this area with biocytin in the present study. The accommodation area in the superior colliculus was identified by systematic microstimulation in each of five anesthetized cats. Accommodative responses were detected by an infrared optometer. After mapping the superior colliculus, biocytin was injected through a glass micropipette into the accommodation area, where accommodative responses were elicited with low intensity microstimulation. In addition, accommodative responses to stimulation of the superior colliculus were compared before and after an injection of muscimol, an agonist of inhibitory neurotransmitter, into the pretectum. Following the injection of biocytin, in the ascending projections, labeled terminals were seen mainly in the caudal portion of the nucleus of the optic tract, the nucleus of the posterior commissure, the posterior pretectal nucleus, the olivary pretectal nucleus, the mesencephalic reticular formation at the level of the oculomotor nucleus, and the lateral posterior nucleus of the thalamus on the ipsilateral side. Less dense terminals were seen in the anterior pretectal nucleus, the zona incerta, and the centromedian nucleus of the thalamus. In the descending projections, labeled terminals were observed mainly in the paramedian pontine reticular formation, the nucleus raphe interpositus, and the dorsomedial portion of the nucleus reticularis tegmenti pontis on the contralateral side. Less dense terminals were also seen in the nucleus of the brachium of the inferior colliculus, the cuneiform nucleus, the medial part of the paralemniscal tegmental field, and the dorsolateral division of the pontine nuclei on the ipsilateral side. Following the injection of muscimol into the pretectum, including the nucleus of the optic tract, the posterior pretectal nucleus, and the nucleus of the posterior commissure, accommodative responses evoked by microstimulation of the superior colliculus were reduced to 33-55% of the value before the injections. These findings suggest that the accommodation area in the superior colliculus projects to the oculomotor nucleus through the ipsilateral pretectal area, especially the nucleus of the optic tract, the nucleus of posterior commissure, and the posterior pretectal nucleus, and also projects to the pupilloconstriction area (the olivary pretectal nucleus), the vergence related area (the mesencephalic reticular formation), and the active visual fixation-related area (the nucleus raphe interpositus). PMID- 8698906 TI - Widespread cutaneous bacillary angiomatosis and a large fungating mass in an HIV positive man. AB - Bacillary angiomatosis (BA), an infection caused by a gram-negative rod, can be a multiorgan disease. The usual causative organism, Bartonella (formerly Rochalimaea) hensalae, has only recently been identified. Bartonella quintana has also been shown to cause some cases of cutaneous BA. We describe a patient with widespread cutaneous BA with probable bone involvement and a large fungating mass. PMID- 8698907 TI - Treatment of scleromyxedema with 2-chlorodeoxyadenosine. AB - Scleromyxedema is an unusual skin disease that is characterized by a proliferation of fibroblasts and an accumulation of mucin. Despite experience with multiple forms of therapy, no single agent has proved uniformly beneficial in this condition. We describe a patient with scleromyxedema who was treated successfully with 2-chlorodeoxyadenosine (2-CdA), a purine analog used mainly in the treatment of lymphoproliferative disorders. PMID- 8698908 TI - Photoaccentuated erythroderma associated with CD4+ T lymphocytopenia: successful treatment with 5-methoxypsoralen and UVA, interferon alfa-2b, and extracorporeal photopheresis. AB - We describe a 53-year-old HIV-negative white man who had chronic CD4+ T lymphocytopenia and photoaccentuated erythroderma with lymphoma-like histologic changes. The erythroderma completely responded to 5-methoxypsoralen and UVA (PUVA), interferon alfa-2b, and extracorporeal photopheresis. During therapy opportunistic skin infections, including tinea corporis, warts, and disseminated molluscum contagiosum, developed. Although the patient met the current definition of idiopathic CD4+ T lymphocytopenia (ICTL), we cannot rule out the possibility that this peripheral CD4+ T lymphocytopenia resulted from sequestration of CD4+ T lymphocytes in erythrodermic skin. PMID- 8698909 TI - Generalized melanosis caused by melanoma of the rectum. AB - Only 29 cases of generalized melanosis caused by melanoma have been described in the English-language literature since the beginning of this century. This is the first reported case in which the primary site of melanoma was the mucosal surface of the rectum and melanosis was a presenting sign of the disease. Generalized melanosis carries a dismal prognosis; none of the reported patients lived beyond 1 year after the onset of pigmentation. PMID- 8698910 TI - Hereditary progressive mucinous histiocytosis. AB - We describe hereditary progressive mucinous histiocytosis, a rare autosomal dominant non-Langerhans cell histiocytosis, in a mother and daughter. Both had similar, progressive eruptions of skin-colored to red-brown papules on the nose, hands, forearms, and thighs. Light microscopy showed small collections of epithelioid histiocytes and telangiectatic vessels in the upper dermis of early lesions. In the mid dermis of early and well-developed lesions, nodular aggregates of tightly packed spindle-shaped cells were seen. Moderate to extensive mucin production was demonstrated in epithelioid histiocytes and spindle-shaped cells. Electron microscopy of spindle-shaped cells revealed many dendritic histiocytes with abundant lysosomal storage organelles such as myelin bodies and zebra bodies. Immunohistochemistry showed expression of macrophage antigens (CD68; MS-1 high-molecular-weight protein) in epithelioid histiocytes and in some of the spindle-shaped cells. The histologic and immunohistochemical features of hereditary progressive mucinous histiocytosis most closely resemble solitary histiocytoma/cellular-type dermatofibroma. PMID- 8698911 TI - Photosensitivity from pyridoxine hydrochloride (vitamin B6). AB - We describe a 35-year-old female patient with photosensitivity due to pyridoxine hydrochloride (vitamin B6) in a multivitamin over-the-counter preparation. Photopatch and oral photochallenge tests using pyridoxine hydrochloride and UVA irradiation were positive. Larger doses for therapeutic use could cause photosensitivity. PMID- 8698912 TI - Coagulation factor V gene mutation associated with activated protein C resistance leading to recurrent thrombosis, leg ulcers, and lymphedema: successful treatment with intermittent compression. AB - Activated protein C resistance is the most frequent cause of venous thrombosis. We describe a patient with extensive ulcerations and severe lymphedema of the legs after recurrent thrombosis. Laboratory tests revealed a pathologic activated protein C resistance and a reduced functional protein S. The underlying genetic defect was identified as a heterozygous coagulation factor V mutation. A combined therapeutic approach of intermittent compression, repeated debridements and systemic antibiotics resulted in marked improvement of both lymphedema and leg ulcers. PMID- 8698913 TI - Orbital myositis, vitiligo, and giant cell myocarditis. AB - Giant cell myocarditis is a rare idiopathic inflammatory heart disease characterized histologically by multinucleated giant cells, and clinically by rapid progressive heart failure, arrhythmias, or sudden death, often within hours to days of initial symptoms. There are two previously reported cases of giant cell myocarditis with idiopathic orbital myositis. We report a similar case in a patient who also had vitiligo, a diagnostic endomyocardial biopsy, and survival because of a cardiac transplant. Giant cell myocarditis should be monitored for in the course of inflammatory orbital myopathy because of its life-threatening fulminant course. PMID- 8698914 TI - Widespread pruritic plaques in a patient with subacute cutaneous lupus erythematosus and hypocomplementemia: response to dapsone therapy. AB - We describe a patient with subacute cutaneous lupus erythematosus, widespread pruritic papulosquamous plaques, and hypocomplementemia. Skin biopsy specimens revealed liquefaction degeneration and colloid bodies and dyskeratotic cells in basal and suprabasal layers. An immunofluorescence study revealed deposits of IgG, IgM, and C3 at the dermalepidermal junction in a bandlike pattern, and particulate IgG deposition in the basal and suprabasal layers. Treatment with prednisolone (15 mg/day), chloroquine phosphate (200 mg/ day), cyclosporine (5 mg/kg daily), and gold (10 mg/day) failed to reduce pruritic plaque formation, and pulse methylprednisolone therapy led to only a transient remission. Clinical exacerbations correlated with a decrease in complement levels. The disease was successfully controlled with dapsone (75 mg/day) and prednisolone (25 mg/day). PMID- 8698915 TI - Leishmaniasis presenting as a dermatomyositis-like eruption in AIDS. AB - Three patients are described with leishmaniasis and AIDS, with cutaneous lesions mimicking dermatomyositis. Leishmania organisms were observed in great numbers in the dermis of lesional skin biopsy specimens. They were also present inside keratinocytes in all layers of the epidermis in one patient. Skin cultures from all patients and bone marrow culture in patients 1 and 3 revealed Leishmania infantum. Leishmania organisms were also found in nonlesional skin. The absence of proximal symmetric muscle weakness, elevated muscle enzymes, myopathic electromyograms, or characteristic histopathologic and immunologic features of dermatomyositis, and the rapid and complete clearance or marked improvement of the cutaneous lesions after treatment for leishmaniasis, make us consider true dermatomyositis unlikely. We suggest that leishmaniasis be included in the list of diseases capable of inducing a dermatomyositis-like eruption. PMID- 8698916 TI - Generalized multinucleate cell angiohistiocytoma. AB - Multinucleate cell angiohistiocytoma is a rare benign fibrohistiocytic vascular condition that mainly affects middle-aged women. Grouped reddish-brown papules are found in the extremities. We describe a case of multinucleate cell angiohistiocytoma occurring in a 24-year-old man who presented with multiple papules on the trunk and extremities. This is the first report of generalized multinucleate cell angiohistiocytoma. PMID- 8698917 TI - Progressive eruptive histiocytomas. AB - We describe progressive eruptive lesions that have been appearing on a 50-year old Filipino man for the past 9 years. They are characterized by smooth, brown, firm nodules mainly on the head and torso. Histologic examination shows dermal collections of lipid-filled histiocytes and Touton-type giant cells. A comparison with other types of previously described non-Langerhans cell histiocytoses is made. PMID- 8698918 TI - Widespread eruptive dermal and atypical melanocytic nevi in association with chronic myelocytic leukemia: case report and review of the literature. AB - Eruptive nevi have been associated with local skin trauma and immunosuppression, and atypical eruptive nevi preceding melanoma have been reported in immunocompromised transplant patients. We describe a 25-year-old man with widespread eruptive atypical and dermal melanocytic nevi in association with chronic myelocytic leukemia. Our patient's disease differs from earlier reports of eruptive nevi because his nevi appeared before induction chemotherapy. Eruptive nevi may have been a prodrome to leukemia in this patient. His nevi were histologically similar to eruptive atypical nevi observed in AIDS patients and may imply a link between systemic immunosuppression and melanocyte proliferation. We suggest that patients in whom eruptive nevi develop in association with immunosuppression should be carefully observed for the development of melanoma skin cancer. PMID- 8698919 TI - An unusual pustular eruption in an infant with Down syndrome and a congenital leukemoid reaction. AB - Congenital leukemia and leukemoid reactions may be indistinguishable on clinical and histologic grounds and are highly associated with trisomy 21. This report characterizes a specific vesiculopustular skin eruption in an infant with Down syndrome and a congenital leukemoid reaction. On the first day of life an unusual vesiculopustular eruption developed, starting in areas of cutaneous trauma. A biopsy revealed immature myeloid cells in an epidermal spongiotic vesiculopustule and in a perivascular distribution, suggestive of leukemia cutis. As the peripheral blood smear normalized, the eruption cleared. Myelodysplasia subsequently developed and evolved into acute myelogenous leukemia. This is the first detailed report of a specific skin infiltrate caused by the immature cells of a leukemoid reaction. Skin infiltration by immature myeloid cells during a congenital leukemoid reaction may portend an aggressive course of the myeloproliferative disorder. PMID- 8698920 TI - Pachyonychia congenita tarda. AB - Pachyonychia congenita is a rare genetic disorder classified in clinical subtypes. Late onset of the disease has recently been described and designated as pachyonychia congenita tarda. A patient in whom typical manifestations of pachyonychia congenita appeared at the age of 39 years is described. This report substantiates previous observations on the phenomenon of late-onset pachyonychia congenita. PMID- 8698921 TI - Onychomycosis caused by Scytalidium dimidiatum. AB - We report a case of onychomycosis caused by Scytalidium dimidiatum (syn., Hendersonula toruloidea) in a patient who did not live in an endemic area. This nondermatophyte mold may produce disease indistinguishable from dermatophyte fungi, but it does not respond to current systemic antimycotic therapy. Distal subungual onychomycosis, lateral onycholysis followed by lateral nail plate invasion, and chronic paronychia are common nail presentations. PMID- 8698922 TI - Liquefactive panniculitis in the inguinal area as the first sign of chronic renal brucellosis. AB - We describe an 82-year-old woman with an acute panniculitis in the left groin as the first sign of chronic renal brucellosis. She was afebrile and had a large erythematoviolaceous plaque with ulceration and liquefaction of the subcutaneous tissue. Histopathologic study showed a septal and lobular panniculitis with neutrophil infiltration, hemorrhage, and necrosis. Microbiologic cultures of a skin biopsy specimen, blood, and urine were negative. A computed tomography scan showed a left "mastic" kidney with a psoas abscess extending to the left inguinal region. The microbiologic culture of the removed renal mass and the serologic tests established the diagnosis of chronic renal brucellosis. Although the clinical picture of cold abscesses in the inguinal area classically suggests a tuberculosis, brucellosis should be included in the differential diagnosis. PMID- 8698923 TI - CD34-reactive fibrous papule of the nose. AB - In human skin, the CD34 antigen is expressed on endothelium, periadnexal cells, and a population of reticular dermal interstitial cells. CD34 expression is characteristic of dermatofibrosarcoma protuberans and several other neoplasms, but not of typical fibrous papules of the nose. We describe a 16-year-old white girl with a slowly growing papule on the nose. Histopathology showed a dermal tumor with a superficial component of branched, thin-walled blood vessels and a deeper component of benign-appearing, spindle-shaped cells. These cells uniformly and strongly expressed CD34, but not factor XIIIa or markers of melanocytic, neural, muscular, vascular, or histiocytic differentiation. We consider this lesion a CD34-reactive fibrous papule. This benign tumor must be clearly distinguished from dermatofibrosarcoma protuberans, which also is composed of bundles of CD34-reactive spindle-shaped cells in most cases but has locally aggressive behavior. PMID- 8698924 TI - Dapsone hypersensitivity syndrome. AB - We describe a 22-year-old woman with cutaneous polyarteritis nodosa in whom dapsone hypersensitivity syndrome (DHS) developed 5 weeks after initiation of dapsone therapy. She had fever and cervical lymphadenopathy, and later a widespread erythematous eruption studded with pustules developed. She also had liver involvement with mixed hepatocellular and cholestatic features. The patient was treated with prednisone 60 mg daily. Once the patient's liver function normalized, prednisone dosage was reduced by 5 mg weekly. The clinical features and treatment of DHS are reviewed. We encourage immediate discontinuation of the drug in a patient in whom a fever or flu-like illness develops, especially 4 or more weeks after the treatment is started. We also suggest routine thyroid function testing 3 months after recovery because of the possible risk of hypothyroidism. PMID- 8698925 TI - Acquired generalized hypohidrosis/anhidrosis with subclinical Sjogren's syndrome: report of a case with diffuse syringolymphoid hyperplasia and lymphocytic sialadenitis. AB - The pathogenesis and the underlying pathologic changes of acquired generalized hypohidrosis/anhidrosis (AGHA) are largely unknown. We studied a case of AGHA in a young woman suffering from heat intolerance and progressive loss of sweating. Pathologic study of affected skin revealed unique syringolymphoid hyperplasia with T cell infiltration, suggesting a T cell-mediated autoimmune disease. The patient also had subclinical Sjogren's syndrome and diffuse hair loss. The pathogenesis of the latter two conditions is believed to be related to the patient's AGHA. PMID- 8698926 TI - Primary congenital cutaneous ganglioneuroma. AB - Cutaneous ganglioneuroma is rare. Only five cases have been reported, and in all patients the lesions developed after birth. We describe a congenital cutaneous ganglioneuroma. The differential diagnosis includes well-differentiated cutaneous metastases of neuroblastoma and ganglion cells entrapped by a neurofibroma in patients with neurofibromatosis. PMID- 8698927 TI - Teaching nursing delegation: analyzing nurse practice acts. AB - Teaching delegation to nurses, especially for those nurses who have mostly practiced in primary nursing, is challenging. Many staff development and continuing education instructors are teaching delegation principles to nurses today because good delegation skills are needed to effectively implement current skill-mix and patient-focused care changes. In these courses, nurses almost always want guidelines on what they can and cannot delegate to unlicensed assistive personnel and LPN/LVNs. The best foundation for teaching what can and cannot be delegated is the nursing practice act in the state, even though analyzing state practice acts can be cumbersome. Analyzing practice acts as the basis for teaching delegation principles is a critical requirement for today's staff development/continuing educator. PMID- 8698928 TI - The challenge of cultural diversity for nurse educators. AB - By the year 2000, one in every three Americans will represent an ethnically diverse cultural group. Nurses are awaking to the critical need to become more knowledgeable and culturally competent to work with individuals from diverse cultures (Leininger, 1994). However, teaching cultural awareness in nursing education can present a major professional challenge for nurse educators. This article discusses cultural competence and presents a conceptual model of culturally competent health care. Based on this model, the article also discusses the implementation of a four-session cultural diversity program in a rural hospital setting. PMID- 8698929 TI - Factors associated with a perceived harmful outcome from medication errors: a pilot study. AB - The purpose of this pilot study was: 1) to describe factors associated with a perceived harmful outcome following medication errors made by nurses and 2) to refine the Medication Error Risk Profile (MERP) (Wolf, 1992). Ninety-four registered nurses and licensed practical nurses completed the MERP. Multiple stepwise regression analyses were used to explain the variance in the dependent variable of perceived patient harm with: 1) phases of preparation and administration; 2) categories of person responsible for the error; 3) interventions needed following the error and symptoms related to the error. The exploratory regression analysis suggests a model in which the dispensing phase of administration, the physician and pharmacist categories of persons responsible for the error, and the interventions of patient transfer to another unit and additional medications given following the error explain 53% of the variance in perceived harmful outcome for patients consequent to medication errors. A moderately strong correlation (r = .46, P < .001) existed between perceived patient harm as measured on the four-point scale and total intervention score following medication errors. PMID- 8698930 TI - Taming the "no-show" tiger: decreasing the rate of absenteeism at educational programs. AB - A multidisciplinary staff development department developed a continuous quality improvement project to study the consistently high absentee rate for scheduled training and its relationship to the class registration process. Data were collected using a 9-question survey of students who failed to attend scheduled training. Findings show that changes to the class registration process resulted in a decrease in the number of absentees under the control of the staff development department from an average of 43% to 6% by the end of the year-long review period. The overall absentee rate stabilized at 20% and has been established as the benchmark for this setting. PMID- 8698931 TI - Those who have will, those who haven't won't: caring for HIV-positive patients. AB - Nurses' willingness to care for HIV-positive patients continues to be an issue since the inception of the HIV pandemic. This descriptive correlational study found that while nurses' fear of contagion has decreased their willingness to care has not increased in the same proportion. Furthermore, while formal education demonstrated no impact on the willingness of nurses to care for HIV positive patients, provisions of hands-on care was significantly correlated with willingness to care for HIV-positive patients. PMID- 8698932 TI - The 12 1/2 minute learning session: some examples and analysis of impact. AB - Staff nurses experience time demands that frequently prevent them from attending inservice offerings. The 12 1/2 minute learning session is an innovative approach designed to meet the learning needs of the psychiatric nursing staff in spite of time constraints. The guiding principles for these sessions are: 1) "We learn what we care about," 2) preparation for sessions conveys commitment, and 3) accountability for learning is the individual's responsibility but opportunities for learning are shared. Identified outcomes of these groups are the "earthquake effect" or the shifting of one's footing; opportunity for effective debunking or uncovering of habitual patterns; and "bushfire effect" or contagiousness of enthusiasm. PMID- 8698934 TI - An approach to psychotherapy change process research: introduction to the special section. AB - This special section has a dual focus. One is on psychotherapy change research. The other is to explicate an approach to develop a program of research that builds on 2 aspects of scientific discovery: decomposition of observed phenomena and localization of specific elements that may combine to produce a complex whole. These aspects are considered within an ordered framework of 8 steps in the development and testing of a model, moving from discovery to model construction, validation, and prediction of complex outcomes. Studies on psychotherapy change processes were selected, after a masked review, to represent different levels in developing a program of research. Although it is argued that the early steps of decomposition and localization are important when developing a program of research, current editorial practices in first-tier journals, including the Journal of Consulting and Clinical Psychology, typically consider this type of study to be too preliminary for a scientific archival journal. Should this practice be revisited? PMID- 8698933 TI - So you want to host a nursing conference? AB - The increasing prevalence of nursing certification has led to a corresponding demand for nursing contact hours. The experience of a pediatric department in hosting a nursing conference that offered contact hours may assist others in successfully hosting such a conference and avoiding pitfalls of program planning. PMID- 8698935 TI - Task analysis exemplified: the process of resolving unfinished business. AB - The steps of a task-analytic research program designed to identify the in-session performances involved in resolving lingering bad feelings toward a significant other are described. A rational-empirical methodology of repeatedly cycling between rational conjecture and empirical observations is demonstrated as a method of developing an intervention manual and the components of client processes of resolution. A refined model of the change process developed by these procedures is validated by comparing 11 successful and 11 unsuccessful performances. Four performance components-intense expression of feeling, expression of need, shift in representation of other, and self-validation or understanding of the other-were found to discriminate between resolution and nonresolution performances. These components were measured on 4 process measures: the Structural Analysis of Social Behavior, the Experiencing Scale, the Client's Emotional Arousal Scale, and a need scale. PMID- 8698936 TI - The resolution of ruptures in the therapeutic alliance. AB - This article outlines some of the main features of a research program on ruptures in the therapeutic alliance and reports some of the major findings to date. A rupture in the therapeutic alliance is a deterioration in the quality of the relationship between patient and therapist; it is an interpersonal marker that indicates a critical opportunity for exploring and understanding the processes that maintain a maladaptive interpersonal schema. Following the task-analytic research paradigin, a preliminary model of the resolution process was developed and then tested and revised with 2 different data sets. A series of lag 1 sequential analyses were used to confirm the hypothesized sequences of events within resolution sessions and to demonstrate a difference between resolution and nonresolution sessions. This article describes the evolution of a model of rupture resolution and then discusses its implications for treatment development and evaluation. PMID- 8698937 TI - The relationship between vivid description, emotional arousal, and in-session resolution of problematic reactions. AB - The relationships among clients' descriptions of external events, emotional arousal, and resolution of problematic reactions was examined. Clients (n = 12) explored problematic reactions with their therapists on 2 separate occasions. It was found that (a) resolution sessions, in contrast to nonresolution sessions, were characterized by high levels of referential activity (W. Bucci, 1985) when clients described problematic situations followed immediately by the differentiation of an emotional reaction by clients and (b) clients reported a change in mood immediately after the vivid descriptions of problematic situations. The findings highlight the role that vivid description can play in promoting clients' emotional arousal during the session and provide preliminary evidence for the validity of the performance model (L. N. Rice & E. P. Saperia, 1984). PMID- 8698938 TI - Change processes in a creation of meaning event. AB - Creation of meaning events are in-therapy change episodes that occur when a patient seeks to understand the meaning of an emotional experience. A performance model of this task was developed in an earlier study. The present study was conducted to determine which client performance components distinguish successful from unsuccessful creation of meaning episodes. Measures of referential activity were also applied to the events and uncovered important features of the therapist intervention that accompanied successful meaning making. The implications of these results for psychotherapy are discussed. PMID- 8698939 TI - The interaction of the alliance and therapy microprocess: a sequential analysis. AB - The interaction of the working alliance with the therapy microprocess was explored in a sequential analytic study of brief therapy (N = 32). The alliance was largely formed within the first session and was most associated with a mutual emotional engagement process. Thereafter, log-linear modeling revealed marked alliance-related and primarily phase-specific effects on the therapy microprocesses. The alliance was associated with differing patterns of therapy activities, topics, emotions, and verbal content. High-alliance midtherapy displayed more of an alternating pattern of therapist-patient emotional engagement, although therapists also appeared to take greater charge in midtherapy. High-alliance patients were generally more emotionally engaged and responded with less dejection to therapists. The alliance-dependent differences in verbal content appeared to be secondary, with the most obvious negative effects of low-alliance levels appearing in midtherapy. Apparently, the high- and low-alliance therapies developed somewhat differently, a factor that may need to be considered in constructing theories of therapeutic change. PMID- 8698940 TI - Resolving a therapeutic impasse between parents and adolescents in multidimensional family therapy. AB - This study explored the process of resolving an in-session impasse between a parent and an adolescent in family therapy. Focusing on altering the content and affective tone of a discussion, the "shift intervention" was used to direct a family's conversation away from trying to solve behavior management problems and toward a discussion of fundamental relationship problems. Task analysis was used to specify problematic family interactions, the intervention strategy, and successful and unsuccessful outcomes. Descriptive analyses of 5 successful and 5 unsuccessful interventions yielded a detailed performance model of therapist and family behaviors involved in breaking the impasse. The Beavers Timberlawn Family Evaluation Scale was used to verify the presence of the shift intervention in the data set and to embellish the performance model. The model suggested that adolescents became more cooperative and engaged in treatment when parents shifted from trying to control them to trying to understand them. A detailed performance map for accomplishing this shift is offered. PMID- 8698941 TI - Change in early sessions of dynamic therapy: universal processes and the generic model of psychotherapy. AB - The generic model of psychotherapy is offered as a transtheoretical model of universal change processes. Session 3 change processes are examined in a naturalistic study of dynamic therapy guided by the generic model. Findings replicate and extend earlier work addressing propositions of the generic model in dynamic therapy. Openness and bond contributed to in-session realizations, whereas bond and realizations fostered session progress. Session progress, bond, use of experiential operations, and less frequent use of dynamic interventions contributed to change between Sessions 2 and 4. Discussion outlines a model of change in early dynamic therapy and highlights the usefulness of the generic model for the evaluation of change processes. PMID- 8698942 TI - Predicting the effect of cognitive therapy for depression: a study of unique and common factors. AB - The ability of several process variables to predict therapy outcome was tested with 30 depressed clients who received cognitive therapy with or without medication. Two types of process variables were studied: 1 variable that is unique to cognitive therapy and 2 variables that this approach is assumed to share with other forms of treatment. The client's improvement was found to be predicted by the 2 common factors measured: the therapeutic alliance and the client's emotional involvement (experiencing). The results also indicated, however, that a unique aspect of cognitive therapy (i.e., therapist's focus on the impact of distorted cognitions on depressive symptoms) correlated negatively with outcome at the end of treatment. Descriptive analyses that were conducted to understand this negative correlation suggest that therapists sometimes increased their adherence to cognitive rationales and techniques to correct problems in the therapeutic alliance. Such increased focus, however, seems to worsen alliance strains, thereby interfering with therapeutic change. PMID- 8698943 TI - Interpretive work in short-term individual psychotherapy: an analysis using hierarchical linear modeling. AB - "Work" and "resistance" responses to interpretation in short-term individual (STI) psychotherapy were examined using a hierarchical linear modeling (HLM) procedure. The relationships between interpretation characteristics and patient responses within therapy were considered. Process data were drawn from 60 STI therapy cases, 30 patients with low quality of object relations (QOR), and 30 patients with high QOR. In 4 instances, the relationships between technique and response were found to vary significantly across cases. One was identified for low QOR patients, and 3 were identified for high QOR patients. Individual differences in initial disturbance and outcome were used to account for the variation of technique-response relationships. Significant findings were limited to the high QOR sample. Initial disturbance was directly related to work in response to a transference-oriented approach. The transference focus-work relationship was found to be inversely related to outcome. The results extend previous findings regarding transference technique in STI therapy with high QOR patients. Through capitalizing on within-case variation, HLM can be used to illuminate process-outcome relationships in psychotherapy. PMID- 8698944 TI - Hypnosis as an adjunct to cognitive-behavioral psychotherapy for obesity: a meta analytic reappraisal. AB - I. Kirsch, G. Montgomery, and G. Sapirstein (1995) meta-analyzed 6 weight-loss studies comparing the efficacy of cognitive-behavior therapy (CBT) alone to CBT plus hypnotherapy and concluded that "the addition of hypnosis substantially enhanced treatment outcome" (p.214). Kirsch reported a mean effect size (expressed as d) of 1.96. After correcting several transcription and computational inaccuracies in the original meta-analysis, these 6 studies yield a smaller mean effect size (.26). Moreover, if 1 questionable study is removed from the analysis, the effect sizes become more homogeneous and the mean (.21) is no longer statistically significant. It is concluded that the addition of hypnosis to CBT for weight loss results in, at most, a small enhancement of treatment outcome. PMID- 8698945 TI - Hypnotic enhancement of cognitive-behavioral weight loss treatments--another meta reanalysis. AB - In a 3rd meta-analysis of the effect of adding hypnosis to cognitive-behavioral treatments for weight reduction, additional data were obtained from authors of 2 studies, and computational inaccuracies in both previous meta-analyses were corrected. Averaged across posttreatment and follow-up assessment periods, the mean weight loss was 6.00 lbs. (2.72 kg) without hypnosis and 11.83 lbs. (5.37 kg) with hypnosis. The mean effect size of this difference was 0.66 SD. At the last assessment period, the mean weight loss was 6.03 lbs. (2.74 kg) without hypnosis and 14.88 lbs. (6.75 kg) with hypnosis. The effect size for this difference was 0.98 SD. Correlational analyses indicated that the benefits of hypnosis increased substantially over time (r = .74). PMID- 8698946 TI - Prewar factors in combat-related posttraumatic stress disorder: structural equation modeling with a national sample of female and male Vietnam veterans. AB - Structural equation modeling was used to examine relationships among prewar factors, dimensions of war-zone stress, and current posttraumatic stress disorder (PTSD) symptomatology using data from 1,632 female and male participants in the National Vietnam Veterans Readjustment Study. For men, previous trauma history (accidents, assaults, and natural disasters) directly predicted PTSD and also interacted with war-zone stressor level to exacerbate PTSD symptoms for high combat-exposed veterans. Male veterans who entered the war at a younger age displayed more symptoms. Family instability, childhood antisocial behavior, and age had indirect effects on PTSD for men. For women, indirect prewar effects emanated from family instability. More attention should be given to critical developmental conditions, especially family instability and earlier trauma exposure, in conceptualizing PTSD in adults. PMID- 8698947 TI - The role of the therapeutic alliance in psychotherapy and pharmacotherapy outcome: findings in the National Institute of Mental Health Treatment of Depression Collaborative Research Program. AB - The relationship between therapeutic alliance and treatment outcome was examined for depressed outpatients who received interpersonal psychotherapy, cognitive behavior therapy, imipramine with clinical management, or placebo with clinical management. Clinical raters scored videotapes of early, middle, and late therapy sessions for 225 cases (619 sessions). Outcome was assessed from patients' and clinical evaluators' perspectives and from depressive symptomatology. Therapeutic alliance was found to have a significant effect on clinical outcome for both psychotherapies and for active and placebo pharmacotherapy. Ratings of patient contribution to the alliance were significantly related to treatment outcome; ratings of therapist contribution to the alliance and outcome were not significantly linked. These results indicate that the therapeutic alliance is a common factor with significant influence on outcome. PMID- 8698948 TI - Early-onset conduct problems: does gender make a difference? AB - Baseline assessments of 64 girls and 158 boys (aged 4-7 years) diagnosed with oppositional defiant disorder (ODD) or early-onset conduct problems, or both, were examined for gender-linked differences in behavioral symptoms. Child variables, parenting variables, and family variables were correlated with teacher reports of externalizing problems at school and independent observations of externalizing problems at home before treatment to determine whether there were any gender-specific differences in risk factors. Follow-up data (1-2 years posttreatment) were also examined for any gender differences in predictors of treatment outcome. Results indicated significant gender differences in behavioral symptoms according to independent home observations. However, reports of gender differences in behavioral symptoms were influenced by the gender of the reporting agent. The only gender-specific risk factor found was father "negativity," which was correlated with boys' behavior at home but not girls' behavior. Concerning differences in treatment outcome, variables regarding parents' psychological states and parenting style were the best predictors for girls but not for boys. PMID- 8698950 TI - Reliability of diagnosing complicated grief: a preliminary investigation. AB - Forty experienced mental health providers were asked to diagnose 4 case histories, each involving an aspect of difficult grief embedded in a larger psychopathology context. Half used the full Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev,; DSM-III-R; American Psychiatric Association, 1987); half used a forced choice from among anxiety, mood, adjustment, and personality disorders. For each case, participants also assigned 1 of 4 complicated grief labels derived from the thanatology literature or the label uncomplicated bereavement taken from the DSM-III-R. Interrater agreement was generally low using the DSM-III-R, regardless of instructional format, despite high reliance on relatively few categories. In contrast, interrater agreement was uniformly high using thanatological classifications. Results are discussed in relation to the growing literature differentiating grief from existing DSM classifications and supporting the argument for a separate taxonomy for grief reactions. PMID- 8698949 TI - Psychiatric disorder in a birth cohort of young adults: prevalence, comorbidity, clinical significance, and new case incidence from ages 11 to 21. AB - Mental health data were gathered at ages 11, 13, 15, 18, and 21 in an epidemiological sample using standardized diagnostic assessments. Prevalence of Diagnostic and Statistical Manual of Mental Disorders (3rd ed. revised; American Psychiatric Association, 1987) mental disorders increased longitudinally from late childhood (18%) through mid-(22%) to late-adolescence (41%) and young adulthood (40%). Nearly half of age-21 cases had comorbid diagnoses; and comorbidity was associated with severity of impairment. The incidence of cases with adult onset was only 10.6%: 73.8% of adults diagnosed at age 21 had a developmental history of mental disorder. Relative to new cases, those with developmental histories were more severely impaired and more likely to have comorbid diagnoses. The high prevalence rate and significant impairment associated with a diagnosis of mental disorder suggests that treatment resources need to target the young adult sector of the population. The low new-case incidence in young adulthood, however, suggests that primary prevention and etiological research efforts need to target children and adolescents. PMID- 8698951 TI - Attributions and behavior in functional and dysfunctional marriages. AB - The study examined whether spouses' attributions for partner behavior are related to their own behavior by assessing their attributions and observing the problem solving discussions of couples in which (a) neither spouse was depressed or maritally distressed, (b) the wife was depressed and both spouses were maritally distressed, and (c) the wife was not depressed and both spouses were maritally distressed. To the extent they made maladaptive attributions, wives displayed less positive behavior and more negative behavior. Husbands' attributions and behavior were unrelated, and associations between attributions and behavior were not moderated by marital distress and depression. These results highlight the need to clarify how partner behavior contributes to the attributions spouses make and to reexamine interventions designed to modify attributions in marital therapy. PMID- 8698952 TI - Acceleration of changes in session impact during contrasting time-limited psychotherapies. AB - Following the suggestion that therapeutic change is accelerated in time-limited psychotherapy, this study investigated the across-session patterns of session impact in the treatments of 117 depressed clients who were randomly allocated to 8 or 16 sessions of cognitive-behavioral (CB) or psychodynamic-interpersonal (PI) therapy. After each session, all clients completed the Session Evaluation Questionnaire and 75 of the clients completed the Session Impacts Scale. Session ratings indicated that sessions were perceived increasingly positively on most impact dimensions (e.g., session depth and smoothness, relationship with the therapist, feelings of understanding and problem solving, postsession positive mood) as treatment progressed. Early in treatment, PI therapy sessions were less smooth (i.e., more tense and uncomfortable) and less focused on problem solving, but PI sessions changed more rapidly than CB sessions on these dimensions, so that later in treatment, sessions of both treatments were equivalently positive. In both treatments, the trend toward more positive sessions was more rapid (i.e., the across-session slope was steeper) in 8-session treatments than in 16-session treatments. Such accelerated changes in session impact may reflect the suggested acceleration of therapeutic change associated with shorter time limits. PMID- 8698953 TI - Psychosocial consequences of weight cycling. AB - Participants were 130 obese women with a mean age of 41.1 +/- 8.4 years and a mean weight of 97.9 +/- 13.5 kg, who reported having undertaken a mean lifetime total of 4.7 +/- 1.2 major diets on which they had lost a mean total of 45.9 +/- 21.4 kg. Participants with a severe history of weight cycling had a significantly younger age of onset of their obesity than did mild cyclers and reported initiating dieting at a significantly younger age and lower weight. No evidence, however, was found that weight cycling was associated with greater reports of depression or other psychopathology; nor was it associated with a significantly greater frequency of binge eating disorder. The results are discussed in terms of the need to use additional measures of psychological functioning. PMID- 8698954 TI - Relaxation training and opioid inhibition of blood pressure response to stress. AB - The present study was designed to determine the role of endogenous opioid mechanisms in the circulatory effects of relaxation training. Opioid mechanisms were assessed by examination of the effects of opioid receptor blockade with naltrexone on acute cardiovascular reactivity to laboratory stress before and after relaxation training. Thirty-two young men with mildly elevated casual arterial pressure were recruited for placebo-controlled naltrexone stress tests and relaxation training. The results indicated that relaxation training significantly reduced the diastolic pressure response to mental arithmetic stress. Opioid receptor blockade with naltrexone antagonized the effects of relaxation training. These findings suggest that some of the physiological effects of relaxation training are mediated by augmentation of inhibitory opioid mechanisms. PMID- 8698955 TI - Clinical versus actuarial predictions of violence of patients with mental illnesses. AB - This study compared the accuracy of an actuarial procedure for the prediction of community violence by patients with mental illness with the accuracy of clinicians' ratings of concern about patients' violence. Data came from a study in which patients were followed in the community for 6 months after having been seen in a psychiatric emergency room. Accuracy of actuarial prediction was estimated retrospectively, with a statistical correction for capitalization on chance. Actuarial prediction had lower rates of false-positive and false-negative errors than clinical prediction. The seriousness of the violence correctly identified by the actuarial predictor (the true positives) was similar to the seriousness identified by clinicians. Actuarial predictions based only on patients' histories of violence were more accurate than clinical predictions, as were actuarial predictions that did not use information about histories. PMID- 8698956 TI - Maintenance following a very-low-calorie diet. AB - The authors posed 2 questions in this randomized study of maintenance procedures in which participants were followed for 15 months after completion of a very-low calorie diet: Would stimulus narrowing during the reintroduction of solid food, achieved by the use of prepackaged foods, improve weight losses and the maintenance of those losses as compared with the use of regular food? Would reintroduction of foods dependent on progress in losing or maintaining weight be superior to reintroduction on a time-dependent basis? Neither the stimulus narrowing condition nor the reintroduction procedure enhanced either maximum weight loss or maintenance of those losses. The stimulus narrowing condition appeared to be poorly tolerated; compliance and attendance were poorer in this condition than in the regular food condition. PMID- 8698957 TI - Determinants of research follow-up participation in an alcohol treatment outcome trial. AB - This study examined factors associated with research attrition in a long-term follow-up study (48 months). Researchers attempted to contact all randomized participants, not just those who completed treatment. The processes by which baseline characteristics, early treatment-research experiences, and short-term outcome affected subsequent participations were examined using logistic regression. The analyses deal primarily with refusal, the main reason for attrition. Baseline characteristics had small effects on likelihood of refusal; research engagement had some impact; but treatment participation had strong effect. Short-term outcome did not predict refusal. These findings, if generalizable, have implications for the conduct and reporting of outcome studies. By directly studying bias, rather than presuming its absence on skimpy evidence, researchers can achieve a better understanding of the strengths and limitations of outcome results. PMID- 8698958 TI - Effects of therapist adherence and competence on patient outcome in brief dynamic therapy. AB - The authors examined the relation between therapist process variables (adherence and competence) and subsequent symptomatic change in patients. Twenty-nine depressed patients were seen in 16 sessions of weekly supportive expressive (SE) dynamic psychotherapy. Change in depression from intake to Session 3 predicted higher ratings of adherence to expressive (interpretative) techniques during Session 3 but not their competent delivery. Partialling pretreatment psychiatric severity, therapists' adherence to use of expressive techniques, and previous symptomatic improvement, relatively competent delivery of SE-specific expressive techniques predicted subsequent improvement in depression. Secondary analyses addressing alternative explanations (such as the role of either therapeutic alliance or general therapeutic skills) did not change the results. PMID- 8698959 TI - Effectiveness of targeting the vulnerability factors of depression in cognitive therapy. AB - I. H. Gotlib and C.L. Hammen's (1992) psychopathology model of depression was used as a conceptual framework for studying the process of change in an effective course of cognitive therapy (CT) for depression. Archived CT transcripts from 30 depressed outpatients in the Cognitive-Pharmaco-therapy Treatment project (S. D. Hollon et al., 1992) were studied. An observational coding system was used to assess whether therapists focused on the cognitive, interpersonal, and developmental vulnerabilities of depression and whether these interventions were associated with symptom reduction. Therapists maintained a primarily cognitive focus, but it was interventions that addressed the interpersonal and developmental domains that were associated with improvement. A developmental focus also predicted a longer time of recovery and better global functioning over the 24-month followup period. These findings are consistent with recent theoretical developments in cognitive therapy and with the psychopathology research on depression. PMID- 8698960 TI - Resolving ethical problems in long-term care. AB - 1. End of life ethical decision-making is complex and involves many key players, each with their individual roles, responsibilities, and ethical concepts. 2. Each long-term care ethical decision which presents itself involves alternatives and choices. These must be thoughtfully evaluated to reach the best decision possible. 3. Those involved in ethical decision-making are influenced by various ethical theories as well as factors including control, legal issues, failure, coercion, obligation, advocacy, autonomy, respect, and cost. 4. Ethics committees can play a valuable role in assisting patients, families and staff through the decision-making process by providing guidelines based on ethical principles and compatible with facility mission and philosophy. PMID- 8698962 TI - Training staff to prevent aggressive behavior of cognitively impaired elderly patients during bathing and grooming. AB - 1. Cognitively impaired elderly patients often become aggressive toward caregivers who are providing assistance with bathing and grooming, but caregivers can learn methods to prevent or reduce some of the aggression. 2. The R.E.S.P.E.C.T. model describes key practices caregivers can use to better meet patient needs and reduce aggression, increasing their understanding and skill. 3. In addition to training, observation of performance and consultation are important steps in enabling caregivers to apply and maintain their skills. PMID- 8698961 TI - The use of Functional Consequences Theory in acutely confused hospitalized elderly. AB - Acute confusion is a common complication of hospitalization in the elderly that impacts on both the use of health care resources and the functional status of individuals. Providing optimum nursing care for these patients depends on three factors: 1) the nurse's ability to differentiate acute confusion from other common conditions in the hospitalized elderly, chiefly dementia or depression, 2) the nurse's ability to identify factors contributing to this condition, and 3) the implementation of interventions to minimize the effects of these factors on the patient. This article differentiates the clinical features of acute confusion from those of depression and dementia, and discusses the use of the Functional Consequences Theory, developed by Miller (1990), as a framework for nursing assessment and management of care for elderly patients with this condition. The functional consequences theory framework assists the nurse to identify risk factors associated with the development of acute confusion in the hospitalized elderly. Further it guides the development of interventions to minimize the effects of this condition in this population. The use of this framework in the clinical setting is illustrated through a case study. PMID- 8698963 TI - The confused patient: nurses' knowledge and interventions. AB - The purpose of this study was to identify nurses' knowledge and experience about confusion and its treatment. A random sample of hospital-based, medical-surgical registered nurses (N = 100) was surveyed about their contact with confused patients and their knowledge about confusion. The findings suggest that nurses have regular and frequent contact with confused patients, caring for approximately three such patients in a week. They believe they are knowledgeable about confusion, rating their own knowledge on average as 2.96 on a scale ranging from 0 to 4. Restraint is the major treatment used for confusion, with 84% of the nurses reporting that the last confused patient they cared for was restrained. The high incidence data for use of restraints raise questions about what is a necessary restraint and whether restraints are overused in hospital settings. More attention needs to be directed toward finding alternatives to the use of restraints in the acute care hospital. PMID- 8698964 TI - Partnerships meeting the challenges of informal caregiving. PMID- 8698965 TI - Assessment of urinary incontinence. AB - 1. In the past, nursing practice toward incontinence has focused on urine containment and skin protection rather than on proactive treatment-oriented therapeutic care. 2. Accurate assessment and diagnosis of urinary incontinence determine the success of treatment. 3. Efforts directed at early identification, appropriate assessment and treatment, and linkage to community agencies should be initiated by the nurse. PMID- 8698966 TI - Knowing the patient: the route to individualized care. AB - Provision of individualized care is dependent on knowing the patient as a person. Three factors contributed to individualized care: congruent societal and health care values; commonalities of patient needs in all settings; and primacy of caring through knowing the patient. Role modeling by mature nurses appears to have been of prime importance in the transmission of this way of nursing. PMID- 8698967 TI - Individualizing care: family roles in nursing home decision-making. AB - l. Family members remain fully involved in nursing home decision-making after their relative has been admitted to a facility. 2. Family involvement in nursing home decision-making serves to individualize care and provide a continuing link to the resident's personal history and preferences. 3. Family members assume an array of decision-making roles in nursing homes, including: caregiving, pampering, comforting, engaging, educating, monitoring, mediating, colluding and controlling. PMID- 8698969 TI - Maintaining cleanliness: an individualized approach. PMID- 8698970 TI - "I can do it!" Dressing: promoting independence through individualized strategies. AB - Caregivers contribute to loss of functional performance and dependency in cognitively impaired persons when they "do for," that is, dress the person instead of supporting independence in dressing. Persons with dementia have functional reserves that can be activated when caregivers use levels of assistance, standard, and problem-oriented strategies to support the person's cognitive and physical deficits. Use of these strategies requires less than one minute of additional caregiver time and leads to positive outcomes for the person and the caregiver. PMID- 8698968 TI - Mealtime in nursing homes: the importance of individualized care. AB - Malnutrition, a common problem among nursing home residents, contributes to: a) higher rates of infection, b) an impaired immune response, and c) the development of pressure sores. Eating habits are highly individualized and eating problems often occur due to a complex constellation of interacting factors such as poor oral health, medications, clinical conditions, and lack of attention to individual food likes and dislikes. By educating nursing assistants on how to provide individualized care at mealtime and ensuring that an adequate number of staff are available to assist those who need help, mealtime rather than being a task-oriented procedure will be an individualized, pleasant social event. PMID- 8698971 TI - Tales from individualized care. AB - Consistent staff assignment allows aides and residents to work out idiosyncratic ways of getting things done, rather than having battles over control, timing, and preferences. Giving nursing home residents control over small aspects of daily life is more important than staff efficiency in getting tasks accomplished. Creative approaches to solving problems arise most fruitfully from knowing the nursing home resident as a person, and this requires an investment of time as well as sensitivity that rewards both the giver and receiver of care. PMID- 8698972 TI - Individualized care. PMID- 8698974 TI - Publish or perish revisited. PMID- 8698973 TI - Individualized care for frail elders: theory and practice. AB - Individualized care for frail elders is defined as an interdisciplinary approach which acknowledges elders as unique persons and is practiced through consistent caring relationships. The four critical attributes of individualized care for frail elders are: 1) knowing the person, 2) relationship, 3) choice, and 4) participation in and direction of care. Cognitively impaired elders can direct their care through the staff's knowledge of individual past patterns and careful observation of behavior for what is pleasing and comfortable to each resident. PMID- 8698975 TI - The gift of healing in chronic illness/disability. AB - Chronic illness and disabilities are the leading health problems in North America and represent the major health challenges of this era. The traditional Western illness care model that has profoundly influenced health care and nursing practice is oppressive, inappropriate, and inadequate to meet the needs of people living with chronic conditions. What is needed is a fundamental shift in perspective, one that abandons the objective stance of the cure paradigm of Western medicine and embraces the care paradigm where the subjective experience of the person is of central concern. Such a perspective allows for the potential for healing to occur, regardless of the person's physical condition. This article presents the results of a recent study investigating the healing experience of people with chronic health challenges. An interpretive phenomenological investigation was undertaken with 8 participants, each participant living with different chronic conditions. The results of this study describe the participants' healing journey. Seven essential themes emerged to describe this experience. These themes include (a) In the Beginning, (b) Hitting the Wall, (c) Turning Around, (d) Letting Go, (e) Opening Up, (f) Letting In, and (g) the Gift. The results demonstrate a need to reconsider nursing education and practice, which shifts from the mandate of cure to a mandate of care and to one that emphasizes the promotion of health and healing. PMID- 8698976 TI - Understanding circadian rhythms: a holistic approach to nurses and shift work. AB - When night shift nurses drive home at 7:30 a.m., the daylight resets their circadian pacemakers in the retina. This daylight exposure amplifies desynchronization of the circadian rhythm. It was found that 3:00 a.m. to 3:00 p.m. and 3:00 p.m. to 3:00 a.m. shifts produced less physiological and emotional stresses. Increased awareness of circadian rhythms may help to reduce the multiple risks to nurses' health and enhance quality of life. This article presents the scientific principles of circadian rhythms and their effects on shift workers' health and illnesses. There is a significant decrease in job performance and in satisfaction and quality of patient care. Statistics indicate that errors, injuries, sick days, and accidents are higher for nurses' working rotating shifts. Eleven recommendations provide ideas to support nurses holistically. PMID- 8698977 TI - Images of caring in nursing and dance. AB - This article explores the existence of common images in nursing and dance. Nurses can look to the performing arts and music to sustain their commitment to clinical practice. The dancer must bring the whole self to the dance: history, mind, body, and spirit. The dancer creates beauty and grace and interpretive images for the audience. Nursing involves "dancing on the edge" where one must balance Roach's five elements of caring with one's self to meet the needs of the patient. For both nursing and dance, excellence begins with a centering of the self in order to create and relate to the other. Through the dance, one comes to experience beauty and grace. Images from dance can nourish one's creative caring spirits. PMID- 8698978 TI - Challenging a reductionistic paradigm as a foundation for nursing. AB - Historically, nursing practice has been grounded in the objective, analytic philosophy of the natural sciences. Over the past decades, caring--a humanistic concept--has been espoused as the essence of nursing. Paradoxically, practice based on the theme of caring remains aligned with the philosophy of the natural sciences and continues to use tools such as nursing process and nursing diagnosis, products of the natural sciences paradigm. The authors have outlined the foundation for a philosophy of caring. The encounter between caregiver and patient is the central aspect of this philosophy and is elaborated with the related concepts of openness, nonreductionism, immediacy, and meaning. In addition, holistic nursing practice requires attention by caregivers to their own self-awareness and the personal growth that is necessary for the demands of encountering patients. Practice based on such a philosophy maintains the primacy of the caregiver-patient relationship and permits the incorporation of analytic tools without depersonalizing effects. PMID- 8698979 TI - Worksite wellness programs and lifestyle behaviors. AB - Do employees who participate in worksite wellness programs differ from those who do not? What health-related lifestyle behaviors are practiced most frequently by which employees? A descriptive, correlational, comparative design was used to investigate these questions. Four hundred employees at a large public university were selected through stratified random sampling to complete a demographic sheet and the Health Promoting Lifestyle Profile (HPLP). Study findings revealed that men used self-actualization and exercise behaviors more frequently than women. Women practiced more health responsibility behaviors than men. Employees who were members of the wellness program more frequently practiced health responsibility and exercise behaviors than nonmembers. Overall, wellness program members used a greater number of the total health-related behaviors than other employees. Membership in the wellness program and the number of times per week a person exercised explained 21% of the variance in the HPLP scores. PMID- 8698980 TI - Social responsibility in nursing education. AB - Nurses will be key participants in health care reform as health care shifts from a hospital-based disease orientation to a community-centered health promotion focus. Nursing in communities, the environmental context of clients' everyday lives, requires attention to social, economic, and political circumstances that influence health status and access to health care. Therefore, nursing educators have the responsibility to prepare future nurses for community-based practice by instilling moral and professional practice obligations, cultural sensitivity, and other facets of social responsibility. In this article, social responsibility and journaling, a teaching/learning strategy suggested by the new paradigm approach of the curriculum revolution, are explored. A qualitative research study of more than 100 nursing student journal entries illustrates the concept of social responsibility and how it developed in a group of baccalaureate nursing students during a clinical practicum in a large urban homeless shelter. PMID- 8698981 TI - Hope-inspiring strategies of spouses of critically ill adults. AB - Previous research indicates that hope is an important psychosocial need of families of intensive care unit (ICU) patients. However, there is a lack of nursing research about how to inspire hope in families of the critically ill. The purpose of this study was to explore the hope-inspiring strategies that spouses of critically ill adults used while their family member was critically ill. In addition, the author explored what spouses of critically ill persons perceived to be useful sources in maintaining or increasing their hope states while their loved one was critically ill. Utilizing a qualitative methodology, 20 spouses of patients hospitalized in an ICU for the first time were interviewed. Data was categorized into eight hope-inspiring themes, including spiritual religious activities, significant others, devotion for the patient, positive relationship with caregivers, physical presence at the bedside, talking to others, and the use of distraction mechanisms. In addition, five sources of hope were identified in this population. PMID- 8698982 TI - Therapeutic touch with adolescent psychiatric patients. AB - Seven hospitalized, adolescent psychiatric patients who received a total of 31 Therapeutic Touch treatments over two 2-week periods were interviewed about their experience. Findings from the interviews were categorized within 2 overarching themes-the therapeutic relationship and the body/mind connection. The study participants enjoyed the Therapeutic Touch, and in fact, they wanted more of it. This research shows the possibility of Therapeutic Touch as a nursing intervention with adolescent psychiatric patients if all care is taken to obtain their consent and to provide them with a safe environment for touch therapy. PMID- 8698983 TI - Cultural perceptions of childbirth: a cross-cultural comparison of childbearing women. AB - The purpose of this comparative cross-cultural study was to describe the cultural/religious perception of the childbirth experiences of selected childbearing women. Finnish Lutheran women's beliefs and perceptions of childbirth were compared with those of Canadian Orthodox Jewish and American Mormon women. Methodological triangulation was achieved through semistructured, open-ended interviews and use of the Utah Test for the childbearing Year (UTCY). Canadian Orthodox Jewish women showed a significantly higher level of reliance on authority figures to ensure positive outcomes and significantly less active participation in childbirth care decisions. The Finnish Lutheran women showed less valuing of childbearing and childrearing, which may be related to a less active religious belief system and the view by Finnish women that motherhood is only one of a multiplicity of roles viewed as important. There is a need to understand and appreciate the cultural beliefs and values of childbearing women to facilitate more culturally sensitive and holistic nursing care. PMID- 8698984 TI - The adaptive value of fever. AB - There is overwhelming evidence in favor of fever being an adaptive host response to infection that has persisted throughout the animal kingdom for hundreds of millions of years. As such, it is probable that the use of antipyretic/anti inflammatory/analgesic drugs, when they lead to suppression of fever, results in increased morbidity and mortality during most infections; this morbidity and mortality may not be apparent to most health care workers because fever is only one of dozens of host defense responses. Furthermore, most infections are not life-threatening and subtle changes in morbidity are not easily detected. PMID- 8698985 TI - Fever and rash. AB - The combination of fever and rash comprises an extensive differential diagnosis. Many of the causes of this presentation are life-threatening. In this article, rashes are categorized as petechial, maculopapular, vesicular, erythematous, and urticarial. Each type of rash is then divided into infectious etiologies, both treatable and nontreatable, and noninfectious etiologies. It is usually possible to arrive at a workable differential diagnosis when clinical, historical, and epidemiologic factors are considered. PMID- 8698986 TI - Fever of unknown origin. AB - Fever of unknown origin (FUO) is defined as a temperature elevation of 101 degrees F (38.3 degrees C) or higher for 3 weeks or longer, the cause of which is not diagnosed after 1 week of intensive in-hospital investigation. This article discusses the causes, diagnosis, and treatment of FUOs. PMID- 8698987 TI - Fever in the compromised host. AB - Fever in the compromised host remains a significant clinical problem. Multiple potential pathogens, subtle physical findings, and a variety of noninfectious problems that may masquerade as infection contribute to this clinical challenge. A review of host defense defects along with a careful physical examination will begin to narrow the etiologic possibilities for fever. Recognizing that the majority of infections will represent as fevers of unknown etiology, a consistent approach to the patient who responds to empiric antibiotic therapy as well as to the patient who fails to respond should be developed. PMID- 8698988 TI - Fever in patients with HIV infection. AB - Fever is a common sign during the course of HIV infection, usually represents a superimposed opportunistic infection, and is almost always a treatable condition. Proper management generally requires detection of the underlying cause, and the diagnostic evaluation is largely driven by the clinical symptoms, associated conditions such as injection drug use, and stage of disease based largely on the absolute CD4 cell count. This article provides guidelines for the management of fever in the patient with HIV infection. PMID- 8698990 TI - Fever in the intensive care unit. AB - In the ICU, fever can be expected to accompany an extensive number of conditions of both infectious and noninfectious etiologies. It is crucial to identify the precise cause of fever, because certain conditions in either category may be life threatening, whereas others require no treatment at all. It is important to rule out the most common infections that may be present based on historical and physical signs and symptoms and epidemiologic factors. The extent of evaluation should be based on the likelihood of the disease process being present and is highly variable for each individual patient. Therefore, "routine fever work-up" should not be advocated. If overt infection is not found upon initial evaluation, antibiotics should be withheld if possible. Alternatively, in the unstable patient, empiric therapy may be started, and if no infection is evident, it may be stopped within a reasonable time frame. In no case should prolonged antibiotics be given for presumed but unproven infection. Thorough knowledge of the more common infectious and noninfectious conditions, as well as the awareness of less frequent ones and their predisposing risk factors, is essential for adequate evaluation of the febrile ICU patient. Likewise, familiarity with the techniques used for diagnosis of these infections and their appropriate interpretation and limitations in specific instances is immensely helpful to the clinician providing appropriate care for the critically ill patient. PMID- 8698989 TI - Fever in the solid organ transplant patient. AB - Fever is common in the solid organ transplant patient and may be produced by a variety of processes. The approach to the febrile transplant patient must include an extensive search for infection, which may be aided by considering the organ transplanted, time after transplantation, and the patient's immunosuppressed state. In addition, a number of noninfectious causes of fever exist in this population, including allograft rejection, drug fever, and thromboembolic disease. A review of the pathogens commonly noted in posttransplant patients is presented, emphasizing risk factors for disease, typical time of presentation, and particular organ groups affected. In addition, the authors review the noninfectious causes of fever in the solid organ transplant patient. PMID- 8698991 TI - The pharmacologic consequences of fever. AB - Despite its potential importance to the management of patients with febrile illnesses, the effect of fever on pharmacokinetics and pharmacodynamics has received little attention in the clinical literature. This article considers literature published in this potentially important area. PMID- 8698992 TI - Treatment of fever. AB - Fever is an important indicator of disease and should not be routinely suppressed by antipyretics. There is considerable evidence that fever may actually benefit the host defense mechanism. In most patients, fever is short-lived and causes only minor discomfort. Antipyretic agents are effective in lowering temperature, but have significant side effects. Routine antipyretic therapy should be avoided but may be necessary in individual patients with underlying cardiovascular or neurologic disorders. PMID- 8698993 TI - The clinical significance of fever patterns. AB - The clinical validity of fever curves remains intact. Clinicians of old were not wrong in their astute observations. The diagnostic usefulness of fever curves is best applied to difficult-to-diagnose infectious diseases where present day investigations are relatively unhelpful. Fever patterns are particularly useful in eliminating diagnoses from consideration and suggesting otherwise unsuspected disorders that may be diagnosed by further procedures. PMID- 8698994 TI - Fever in neurologic diseases. AB - In the sense that the brain houses the central mechanism for the regulation of body temperature, almost all illnesses that cause fever must interact with the central nervous system. There are far fewer diseases, however, in which the nervous system symptomatology is of prime diagnostic importance. A helpful way to view fever in association with neurologic disease is to roughly divide these disease entities into four broad categories: (1) neurologic impairment resulting from fever itself, (2) fever as the sole manifestation of a central nervous system infection, (3) systemic febrile disorders with central nervous system signs and symptoms, and (4) primary neurologic diseases, either central or peripheral in origin, with fever as a presenting sign. This article discusses the clinical presentation of disorders in each of these categories as an aid to the clinician in diagnosing and differentiating between these syndromes. PMID- 8698995 TI - Fever in rheumatic and autoimmune disease. AB - This article reviews the most common clinical conditions presenting with fever and musculoskeletal symptoms and attempts to categorize these disorders according to general etiologic categories as an aid to differential diagnosis. Although a substantial armamentarium of serologic, immunologic, and molecular laboratory studies have been developed and are available to the clinician, the most important data are obtained from a careful history and physical examination with emphasis on the musculoskeletal system. PMID- 8698996 TI - Drug fever. AB - Drug fever is the febrile response to a drug without cutaneous manifestations. Although the exact incidence of drug fever remains unknown, it has been estimated to occur in approximately 10% of inpatients. The recognition of drug fever is of great clinical importance because, if drug fever is not recognized diagnostically, patients may be subjected to prolonged hospitalization and unnecessary testing or medications. Early diagnosis and treatment of drug fevers are essential in maintaining cost-effective, high-quality medical care. PMID- 8698997 TI - Fever in the elderly. AB - Fever in elderly persons is only one clinical presentation that can be used to assist the clinician at suspecting a serious disease, such as an infection. Infections, like all other illnesses in the geriatric patient, may occur with a variety of nonspecific, atypical, nonclassic, and unusual manifestations. The clinician caring for elderly patients should be aware of these nonclassical presentations of infections in this age group. Unexplained change in functional capacity, worsening of mental status, weight loss or failure to thrive, weakness and fatigue, falls, and generalized pain are only some of the clues that may aid the clinician in considering infection in elderly persons. Key concepts of fever in older adults are: Fever generally indicates presence of serious infection, most often caused by bacteria. Fever may be absent in 20%-30% of elderly patients harboring a serious infection. Criteria for fever in elderly patients should also include an elevation of body temperature of at least 2 degrees F from baseline values. FUO in elderly persons is caused by infections (30%-35%), CTD (25%-30%), and malignancies (15%-20%) in the majority of cases. PMID- 8698998 TI - "The breastplate of righteousness": twenty-five years after Laud Humphreys' Tearoom Trade: impersonal sex in public places. AB - Twenty-five years ago, in January 1970, Laud Humphreys' Tearoom Trade was published. It generated much controversy, yet went on to win the C. Wright Mills Award of the Society for the Study of Social Problems. Today, many remember and debate its methodology and ethical issues while often overlooking its important findings and its early contributions to the emerging field of gay studies. Humphreys' findings are reviewed and commemorated and his work is assessed in light of recent studies on sex in public places. PMID- 8698999 TI - The gay librarian: a comparative analysis of attitudes towards professional gender issues. AB - Librarianship is a feminized profession, and like teaching, nursing, and social work with which it shares the occupational traits of a "semi-profession," its low status and prestige have been attributed to a negative feminine image. To date, discussion of a corresponding male librarian image, general male issues, and the broader topic of gender issues has been minimal within the profession, while serious discussion of gay male librarians and their professional identity has been virtually nil. This study compares the responses of straight and self identified gay males to an exploratory survey of male members of the American Library Association. The topics covered by the survey include reasons for entry into the field, the existence and identity of a male librarian stereotype, and gender issues generally, including gender stratification of work and sexual discrimination and/or harassment. Self-identified gay subjects share many characteristics in common with the straight cohort, including the identification of a gay male stereotype and some denial surrounding gender equity issues. On the other hand, the tentative findings of this exploratory study raise the question of whether both gay and straight male subjects overestimate the number of gay men in librarianship. The report concludes with an update on gay issues within the profession since the survey was completed, and recommendations for further research. PMID- 8699000 TI - So's your old lady: naming patterns in the gay and lesbian press. AB - This research explores the onomastic patterns of choice made by the editors of several thousand gay and lesbian newspapers, magazines, and other periodical publications issued between 1924 and 1992. Eleven categories of sources are identified and analyzed. Results indicate a highly varied background of both traditional and contemporary cultural, historical, and literary influences on the imagery of the gay and lesbian movement. PMID- 8699001 TI - The relation of job satisfaction and degree of openness about one's sexual orientation for lesbians and gay men. AB - The social environment of the workplace is an important component of job satisfaction. Different groups perceive that environment in different ways. For gay men and lesbians an important factor may be how "open" they can be about their sexual orientation in the workplace. This study assesses the relation between openness about one's sexual orientation in the workplace and job satisfaction among gay men and lesbians. Results based on responses to the Job Descriptive Index from samples in Indianapolis and San Francisco indicated a strong relationship between openness and satisfaction with co-workers. In addition, individuals who were not completely "out" in the workplace were more satisfied with their pay and tended to make more than those who were "out" to both their bosses and their co-workers. Possible implications of these results regarding job satisfaction issues for lesbians and gay men are discussed. PMID- 8699002 TI - The construct validity of the Bem Sex-Role Inventory for heterosexual and gay men. AB - This study examined the construct validity of the Bem Sex-Role Inventory (BSRI; Bem, 1978) for heterosexual and gay men. Sixty heterosexual and 63 gay male participants were recruited through networking and advertisements. These two groups were of equivalent age, socioeconomic background, race, student status, and educational level. They completed the Lifestyle Questionnaire assessing sexual orientation and the BSRI assessing sex-role orientation. The internal consistency and discriminant validity of the BSRI scales were examined by corrected item-total correlations, coefficient alphas, inter-scale correlations, and factor analysis. Results suggested that the BSRI was equally valid for heterosexual and gay men, and the psychometric data reported in the BSRI Manual (Bem, 1981) were essentially replicated. However, the short-form BSRI is recommended for use with male respondents because of the problematic non-short form Femininity items. PMID- 8699003 TI - Testing the reliability and validity of the Index of Attitudes Toward Homosexuals (IAH) in Australia. AB - Previous researchers have used a modified version of the Index of Attitudes toward Homosexuals (IAH; Hudson & Ricketts, 1980) and have reported their own reliability coefficients but relied on the authors' original validity data (Serdahely & Ziemba, 1984; Whitley, 1987; Ernulf, Innala, & Whitam, 1989; Rudolph, 1989, 1990). In order to determine if the IAH was a reliable and valid instrument in Australia, the psychometrics of this test were examined using a student population of comparable size to Hudson and Ricketts's sample. It was expected that the 150 students (92 males and 58 females) would respond in much the same way as their US counterparts. This research found the IAH to be reliable (r = .94) and valid for Australian populations and is a recommended instrument for measuring attitudes toward homosexual people. PMID- 8699004 TI - Quantification of lipoprotein lipase (LPL) by dissociation-enhanced lanthanide fluorescence immunoassay. Comparison of immunoreactivity of LPL mass and enzyme activity of LPL. AB - Lipoprotein lipase (LPL) hydrolyses triglycerides in chylomicrons and in very low density lipoproteins. In this study, a new sensitive enzyme immunoassay, the dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA), for the quantification of immunoreactive LPL mass in biological specimens was developed. In the indirect sandwich DELFIA assay polyclonal anti-human or anti-bovine LPL IgGs were used as capture antibodies, monoclonal antibody (mAb) 5D2 and Eu(3+) labelled goat anti-mouse IgG were used as detection antibodies. In the direct sandwich DELFIA assay, mAb 5D2 was used as capture and Eu(3+)-labelled mAb 5D2 as detection antibodies. Both purified bovine and human LPL proteins served as standards in the indirect and the direct DELFIA assay. Standard curves were linear between 0.1 and 1000 ng LPL/ml, assuring the sensitivity of the DELFIAs within this range. Mean values for immunoreactive LPL mass in normal individuals were found to be 40.3 +/- 14.4 ng/ml preheparin plasma and 334.1 +/- 71 ng/ml postheparin plasma. In patients affected with type I hyperlipoproteinemia 82.4 +/ 29.3 ng/ml (postheparin plasma) were determined. Coefficients of inter- and intra-assay variation were 4.3% and 6.2% on average. The correlation coefficient between the indirect and the direct DELFIA technique was 0.9694. The correlation coefficient between immunoreactive LPL mass (estimated by DELFIA) and LPL activity (estimated by the LPL activity assay) was 0.9345. Our data are consistent with the concept that LPL is active as a dimer. Dissociation of the LPL dimer into monomers is tightly coupled to both loss of immunoreactivity and enzyme activity of LPL. PMID- 8699005 TI - In vivo CTL immunity can be elicited by in vitro reconstituted MHC/peptide complex. AB - The use of peptides as a vaccine is a potentially powerful immunization strategy. We explored the possibility of inducing an efficient cytotoxic T lymphocyte (CTL) mediated immune response in mice, using in vitro reconstituted major histocompatibility complex (MHC) class I/peptide complexes as the immunogen. Recombinant derived H-2Kb and beta 2-microglobulin (beta 2m) were properly folded into an MHC class I complex using the vesicular stomatitis virus (VSV)-8mer from the natural nucleocapsid proteinN52-59 (RGYVYQGL), an immunodominant Kb epitope in C57BL/6 (B6) mice. After immunizing mice with the H-2Kb class I/VSV peptide complex and a subsequent in vitro stimulation with the VSV peptide alone, a specific CTL response was demonstrated. The method was also applicable to other peptides, for example, the Sendai virus (SV) peptideN324-332 (FAPGNYPAL). The CTL response was mediated by CD3+/CD8+ T cells and was shown to be allele specific, as only peptide loaded target cells expressing the H-2Kb allele could be recognized. It is of interest that extremely small amounts of injected MHC class I/peptide complex (i.e. 500 pg) could generate a measurable CTL response. The MHC class I/peptide complex had to be intact and properly folded to elicit an immune response, suggesting that the complex protected the peptide for internalization by antigen presenting cells (APCs) or for delivering to the proper site for peptide exchange on the cell surface of APCs. The described immunizing method can be routinely used to prime a CTL response by employing in vitro folded MHC class I/peptide complexes, without the use of adjuvants. It appears to be efficient, sensitive and specific. By using the recombinant protein system, unlimited amounts of MHC class I/peptide complex can be produced for immunization. Moreover, this protocol permits different in vitro combinations of allelic MHC class I molecules and peptide variants. PMID- 8699006 TI - Use of [35S]methionine-labelled rat lymphoblasts in micro-cytotoxic and limiting dilution assays. AB - When only limited numbers of effector cells are available for in vitro T cytotoxic determinations, standard assays cannot be performed. 51Cr is still the most commonly used marker of target cells in cytotoxicity assays but since the incorporation of this marker is low, especially in non-tumor cells such as lymphoblasts, larger numbers of both target and effector cells are required. Here we report the use of [35S]methionine-labelled rat ConA blasts in cytotoxic, micro cytotoxic and limiting dilution assays. Regardless of whether [35S]methionine or 51Cr targets were employed, cytotoxic activities were identical when large numbers of target cells (10(4)) were used. The high uptake of [35S]methionine by ConA blasts (9 cpm/cell) permitted the use of a small number of target cells without any loss of sensitivity. Therefore, the number of effectors and targets required was dramatically reduced, especially with high E : T ratios such as 100 : 1. The use of low number of [35S]methionine-labelled rat ConA blasts as targets was also suitable for the measurement of alloreactive T cell precursor frequencies. This technique illustrates the possibility of studying T cytotoxicity in animal species lacking tumor target cell lines under experimental conditions where the availability of effector cells is limited and the optimal use of such cells becomes critical. PMID- 8699007 TI - A strategy for the synthesis and screening of thiol-modified peptide variants recognized by T cells. AB - In this study we present a strategy for the identification of novel peptide conjugates which may be used to understand the molecular details of the recognition process or to potentially regulate T cell-mediated responses. The approach involves the incorporation of cysteine into a known peptide at a position of interest and subsequent chemical conjugation using thiol-specific agents. Conjugates derived from the nonapeptide QL9 that is recognized by CTL 2C had either enhanced or reduced activity compared to the original cys-peptides. Different classes of thiol-reactive agents (alkyl halides, alkylthiolsulfonates, and disulfides) were tested with increases in activity of over 100-fold. As with standard peptide analogs, the activity depended on the position of the cysteine within the peptide and the nature of the chemically linked functional group. Use of this approach in a cysteine 'scan' of all positions of the original peptide is cost effective and with the availability of many different thiol-specific functional groups will allow the screening of considerably larger libraries of chemically modified peptides than have been used to date. Additionally, these findings may provide insight into the pathogenesis of thiol agents involved in contact sensitivity reactions. PMID- 8699009 TI - A rapid and sensitive enzyme linked immunofilter assay (ELIFA) for whole bacterial cells. AB - An improved method is described for the detection of Escherichia coli by an enzyme linked immunofilter assay (ELIFA) using nitrocellulose membrane sandwiched between two 96-well plates. The incorporation of a pumping system permits a continuous flow of reagents and/or wash fluids through the membrane and provides an assay procedure capable of detecting 10(3) bacteria per well within 40 min. Quantitative bacterial detection was based on precipitated chromogen determined by scanning densitometry. The procedure represents a significant improvement in assay time and/or sensitivity over previously described ELIFA and ELISA methods for whole bacterial cells. PMID- 8699008 TI - Construction of recombinant extended single-chain antibody peptide conjugates for use in the diagnosis of HIV-1 and HIV-2. AB - The construction, expression and evaluation of recombinant scFv based HIV diagnostic reagents are described. In a whole-blood, erythrocyte agglutination assay format, recombinant scFv antibodies (expressed in Escherichia coli), linked to a spacer domain and HIV-gp36 or -gp41 peptides, were shown to be able to detect efficiently natural antibodies against HIV in human serum. Performance in trials suggests that these single chain reagents have potential as alternatives to existing Fab-peptide chemical conjugates. We also report the construction of an inducible expression vector, pGC, which can be used both in laboratory experiments and in large-scale fed-batch fermentations. It was found that while the base scFv reagent (lacking a spacer) functioned as well as the Fab peptide conjugate in assays where whole (negative) blood was spiked with mouse monoclonal anti-HIV antibodies (IgG or IgM), clinical assays using human sera showed lower sensitivities and increased false negatives. This deficiency was overcome by inclusion of the natural 1C3 kappa (light) chain domain as a spacer arm between the scFv and HIV peptide tags. This spacer was thought to overcome steric constraints which would otherwise prevent efficient interaction between the reagent (once bound to the surface of red blood cells) and the various serum antibodies against the respective C-terminal peptide epitopes. As a result of this important modification, performance of the extended scFv reagent (for both HIV-1 and HIV-2) equalled that of the current commercial technology in limited trials. PMID- 8699010 TI - Generation of novel killer hybridomas derived from proliferation-suppressed somatic cell hybrids between YACUT T cell lymphoma and normal lymphocytes activated in secondary mixed lymphocyte cultures. AB - Somatic cell hybridization between the YACUT T cell lymphoma cell line with normal lymphocytes activated in secondary mixed lymphocyte cultures (MLCs) consistently yielded IL-2-dependent CD4- CD8 alpha+ beta- Fc gamma RIII+ hybrids with cytotoxic function. The hybrids expressed T cell receptors other than that of YACUT origin, and fusion of the YACUT with a CD8 alpha+ beta+ Fc gamma RIII- T cell line also yielded hybrids with an unexpected CD8 alpha+ beta- Fc gamma RIII+ phenotype, which two observations strongly suggested that CD8+ T cells became the parental cell of the hybrids. Prolonged growth of the hybrids with IL-2 resulted in the generation of autonomously growing hybrids (hybridomas) without abrogating the cytotoxic function. The hybridomas exhibited MHC-unrestricted cytotoxicity in a Ca(2+)-dependent manner without prior stimulation and also mediated antibody dependent cellular cytotoxicity. These results indicate that novel killer hybridomas can be produced following cell transformation of proliferation suppressed cytotoxic YACUT x MLC cell hybrids. The killer hybridomas may be of value for analyzing recognition mechanisms and molecules involved in MHC unrestricted cell-mediated cytotoxicity. PMID- 8699011 TI - Determination of T cell epitopes with random peptide libraries. AB - A new approach to T cell epitope determination is presented. Critical amino acids for the induction of cytotoxic T cell responses were identified using synthetic peptide libraries with single defined sequence positions combined with randomized sequence positions. Sequences for potential T cell epitopes were deduced from scan profiles using combinations of the active amino acids. Highly potent epitopes for cytotoxic T lymphocytes were obtained. Epitopes defined by this approach are, as shown in this communication, not necessarily the natural epitopes and, therefore, were named synthetic epitopes. They can serve effectively for the development of vaccines or for the determination of T cell receptor antagonists. PMID- 8699012 TI - A simple immunomagnetic bead-based technique for the detection of surface molecules capable of inducing T cell functional polarisation. AB - Activated T cells can release lymphokines selectively towards the site of contact with the target cell. In this way the specificity of the target-effector cell interaction can be maintained in spite of signalling being mediated by soluble factors (Mosmann, 1988, Immunol. Today 9, 306). However, this polarised phenotype is not expressed in resting T cells; rather it appears to be induced in the first minutes following T cell activation. In order to analyse single molecules for their ability to induce T cell polarisation, we devised a technique based on targeting different T cell surface molecules with specific antibodies immobilised on to immunomagnetic beads. The polarised phenotype was determined from observation of the microtubule organising centre being oriented towards the site of interaction with the bead. When applied to T cell lines, the technique permitted the classification of CD3 as a polarisation-inducing molecule, while no polarisation was found when targeting CD2, CD6 and CD8 molecules. This technique has a number of potential applications since it can, in principle, be applied to any cell surface molecule or cell type. Technical details and the sensitivity of the procedure are discussed. PMID- 8699013 TI - A fluorogenic assay of endogenous phosphatase for assessment of cell adhesion. AB - Assays of cell adhesion generally require prelabeling of cells with radioactive or fluorescent probes. A new fluorogenic phosphatase assay requiring no prelabeling has been developed to quantitate cell number, which can thus serve as the basis for quantitating cell adhesion or migration. The assay uses the non fluorescent substrate 3,6-fluorescein diphosphate (FDP) whose dephosphorylation generates fluorescein. The fluorescence generated is linear with incubation time and cell number until substrate becomes limiting; the assay easily quantitates cells over a range from 10(3) to 10(6) for a variety of cell types, including resting T cells. It is as sensitive as the 51Cr assay, but has the many advantages of a non-radioactive assay, making more convenient the removal of nonadherent cells by simple 1 x g sedimentation. Unlike most other non radioactive assays, it requires no pre-incubation; this: (1) reduces cell manipulation; (2) eliminates problems of spontaneous release; and (3) avoids potential dye toxicity. This technique of cell quantitation has been adopted as standard in our laboratory for routine adhesion and migration assays. PMID- 8699014 TI - A simple chemiluminescence assay for the determination of reactive oxygen species produced by human neutrophils. AB - We show that phagocyte production of reactive oxygen species can be measured using a microtitre plate based chemiluminescence blotting technique. The production of reactive oxygen species is determined by their ability to catalyze the oxidation of luminol or isoluminol, resulting in light emission which is recorded on a photographic film. The method permits the determination of NADPH oxidase activity from as few as 9000 cells. It could be used to detect NADPH oxidase defects in neutrophils (e.g. from patients suffering from chronic granulomatous disease), and to screen pharmaceuticals with scavenging activity for reactive oxygen species. PMID- 8699015 TI - A light-scattering assay for lymphocyte shape and its application to T and B lymphocyte responses to cultured high-walled endothelial cells. AB - Lymphocyte shape changes are detectable as changes in the forward light scatter (FLS) profile of a Becton-Dickinson FACStar flow cytometer, with polar cells giving lower values of FLS. The FACScan cell analyser does not detect these changes. Freshly isolated lymph node lymphocytes are round, but when stimulated, for example by incubation with cultured high endothelial cells (HEC), a proportion change shape and become polar. The FLS profiles of lymphocytes stained for T and B cell surface markers show that both subsets change shape in response to HEC, but in a consistently different manner. Light microscopy of sorted T and B populations indicates that equal proportions of both cell types change shape, but that T cells are more likely to become highly elongated. PMID- 8699016 TI - Enhanced sensitivity of a two-site acridinium ester based immunochemiluminometric assay for rat growth hormone-releasing hormone using simple modifications in assay procedure. PMID- 8699017 TI - Assessment of variation in trypsin-sensitive neutralizable antigenic site of type O foot-and-mouth disease virus (FMDV) isolates using a Mab-binding inhibition assay. PMID- 8699018 TI - Alteration of the trypsin-sensitive antigenic site of foot-and-mouth disease virus following direct binding to an ELISA plate. PMID- 8699019 TI - Preparation and characterization of poly-(D,L-lactide-co-glycolide) and poly-(L lactic acid) microspheres with entrapped pneumotropic bacterial antigens. AB - Poly-(lactide-co-glycolide) microspheres with entrapped antigen have shown considerable promise as controlled release vaccines. To enhance the immunomodulatory effect of LW 50020, a bacterial lysate of seven common respiratory pathogens used perorally as an immunomodulator, we prepared poly-(D,L lactide-co-glycolide) (PLG) and poly-(L-lactic acid) (PLA) microspheres with entrapped immunomodulator by solvent evaporation or solvent extraction double emulsion techniques. Physical properties, such as particle size, LW 50020 entrapment rate, antigen release patterns and morphological characteristics were investigated. All preparations displayed a high degree of antigen loading up to 95%, whereas size, surface morphology and antigen release patterns were significantly influenced by the method of preparation and the polymer components used. Solvent evaporation microspheres are porous particles from 0.8 micron to 2.0 microns in diameter, that show a rapid antigen release for PLG, and a moderate antigen release for PLA microspheres within 33 days. Solvent extraction microspheres have proven to be particles from 1.1 microns to 5.0 microns in diameter showing a smooth surface and a medium antigen release rate over 33 days. SDS-PAGE and immunoblotting of extracted antigen confirmed that the molecular weight and antigenicity of the immunomodulator remained unaltered by the entrapment procedure. PMID- 8699020 TI - CTL lysis: there is a hyperbolic relation of killing rate to exocytosable granzyme A for highly cytotoxic murine cytotoxic T lymphocytes. AB - The lysis of susceptible targets by efficient cytotoxic T lymphocytes (CTL) increases both with time and with the ratio of CTL to target. Simple methods for calculating a killing rate constant from the time dependence of killing and for calculating the relation of the killing rate constant to the concentration of exocytosable granzyme A are given. Application of these methods to the killing of target cells by the highly efficient mouse CTL AR1 is presented. AR1 needed granzyme A for efficient killing. AR1 contained sufficient exocytosable granzyme A to kill at about 80% of the rate possible at infinite exocytosable granzyme A. PMID- 8699021 TI - Combined Hoechst 33342 and merocyanine 540 staining to examine murine B cell cycle stage, viability and apoptosis. AB - A procedure is described for the dual staining of lymphocytes with Hoechst 33342 (Ho342) to examine cell cycle position, and merocyanine 540 (MC540) that allows for the analysis of cells entering the early stages of apoptosis. Ho342 is a DNA specific dye and MC540 detects membrane phospholipid domain changes, some of which are associated with apoptotic cells. Flow analysis of B cells dually stained with Ho342 and MC540 allows for the discrimination of five distinct subpopulations. Two of these subpopulations represent viable, MC540 negative/dull cells with either 2n or 4n DNA. As 2n and 4n DNA B cells become MC540 bright they move into two distinct subpopulations representing cells entering and progressing through the early stages of apoptosis. As the apoptotic, MC540 bright cells move into the latter stages of apoptosis, they localize into a fifth subpopulation displaying reduced staining with Ho342 indicative of late stage apoptotic cells in the process of fragmenting their DNA. This experimental approach enables the characterization of lymphocyte populations for percentages of viable, early apoptotic, and late apoptotic cells. The cells are not fixed during this procedure, and since both dyes are viable dyes there is an additional opportunity to obtain sorted cells from any of the defined subpopulations for reculturing and functional analysis. PMID- 8699022 TI - Biodistribution of clodronate and liposomes used in the liposome mediated macrophage 'suicide' approach. AB - Clodronate (Cl2MBP; dichloromethylene-bisphosphonate)-containing liposomes are used to investigate the role of macrophages in immune and non-immune defense mechanisms by elimination of these macrophages followed by functional studies. The present studies characterize such liposomes in terms of the leakage of clodronate and the biodistribution of both the encapsulated drug and the liposomal carrier. The distribution of liposomes was studied using a radioactively labelled lipid phase marker (111In-DTPA-SA) and the distribution of the encapsulated drug was examined following injection of radioactively labelled clodronate (99mTc-Cl2MBP). Furthermore, the biodistribution of variously composed multilamellar liposomes (EPC/Chol molar ratio 7:1.3 or 7:7; EPC/Chol/PS 7:1.3:1 or 7:7:1; EPC/Chol/M 7:2:1; EPC/Chol/M-PE 7:2:1) after intravenous injection was investigated. The findings suggest that only one third of the originally entrapped clodronate was still encapsulated in the liposomes at the time of ingestion by the macrophages in the liver and spleen after intravenous injection of the clodronate containing liposomes. 3 h after injection no clodronate could be detected in the circulation. PMID- 8699023 TI - Enhancing immunoelectrochemiluminescence (IECL) for sensitive bacterial detection. AB - Immunoelectrochemiluminescence (IECL) as an alternative method versus immunochemiluminescent and immunofluorescent methods can be used for versatile applications in biological agent detection. Although IECL offered high reproducibility and sensitive detection capability for soluble antigens and nucleic acids in aqueous phase, the IECL assays are not optimal and many factors which can affect the IECL performance still remain unclear. Further IECL kinetic studies, improvement of antibody biotinylation, magnetic particle selection and reducing non-specific binding have shown that the enhanced IECL sensitivities (signal to background noise ratios) can be potentially increased at least ten fold compared to the sensitivities with general IECL assay procedures for bacterial detection. PMID- 8699024 TI - An alternative ELISA for T4 determination based on idiotype anti-idiotype interaction and a latex method for anti-idiotype monoclonal antibody selection. AB - This paper is the first report on the use of an idiotype-anti-idiotype monoclonal antibody reaction to develop an enzyme immunoassay for thyroxine (T4). We have developed a monoclonal antibody against T4, named 1F10 of IgG1 subclass and KA 5.21 x 10(8) M-1 which was used to obtain anti-idiotypic monoclonal antibodies. Anti-idiotypic antibodies were selected by a novel method, a passive agglutination assay with the idiotype monoclonal 1F10 absorbed on latex particles and subsequently characterized by RIA. One of these anti-idiotype antibodies, named 5B3--type beta antibody--of IgG1 subclass, was used to develop an enzyme linked T4 idiotype-anti-idiotype immunosorbent assay. The T4 calibration curve, using the 1F10 idiotypic antibody adsorbed to solid phase and the 5B3 anti idiotypic antibody conjugated to alkaline phosphatase (ALP), shows adequate performance in the range between 0.7-25 micrograms% of the analyte. The reliability of the proposed method is demonstrated by the correlation coefficient r = 0.74, found between T4 measured by RIA and our assay, with a panel of sera from euthyroid, hypothyroid and hyperthyroid individuals. The correlation coefficient was r = 0.93 within assays and r = 0.88 between assays. These results provide the basis for a new non isotopic assay for the study and diagnosis of T4 related human disease and provides a model to develop immunoassays for other haptens and small molecules of clinical interest. PMID- 8699025 TI - Novel monoclonal antibody, SO-MU1, against human gastric MUC5AC apomucin. AB - Human gastric mucins were chemically deglycosylated with trifluoromethanesulfonic acid. A mouse monoclonal antibody (MoAb), SO-MU1, was established against the deglycosylated mucins. SO-MU1 recognized not only the deglycosylated mucins but also the native gastric mucins. Periodate treatment of the native mucins increased the SO-MU1 reactivity. Trypsin digestion abolished the antigenicity. Human gastric cDNA expression library was screened with SO-MU1 and a mucin cDNA clone was obtained. Its sequence contained the MUC5AC tandem repeat domain. We studied gastrointestinal distribution of the SO-MU1-reactive antigen immunohistochemically. Gastric surface epithelial cells and parietal cells expressed the antigen, but the glandular cells did not. The antigen was also detected in the small intestine and biliary tract but not in the colon and pancreas. In summary, (1) MoAb SO-MU1 was raised against human gastric mucins, (2) it recognized human gastric MUC5AC apomucin, and (3) the SO-MU1-reactive antigen showed characteristic distribution in the organs of endodermal origin. MoAb SO-MU1 is the first MoAb against MUC5AC. PMID- 8699026 TI - Nitric oxide inducing factor as a measure of antigen and mitogen-specific T cell responses in chickens. AB - We describe here an assay to measure responses of T cells to in vitro stimulation with antigens and a T cell mitogen (ConA). Spleen cells from chickens immunized with live viruses and an inactivated antigen produced macrophage activating factors (MAF) in response to in vitro stimulation with homologous antigens. The production of MAF, quantitated by the induction of NO in a retrovirus transformed macrophage cell line, HD11 (Beug et al., 1979, Cell 18, 375) was antigen-specific and correlated well with T cell proliferation. Further studies showed that production of MAF was abrogated by cyclosporin A, anti-CD4 and anti-CD8 monoclonal antibodies. These data suggested that production of MAF required T cell activation and can be used as measure of antigen and mitogen-specific T cell responses in chickens. PMID- 8699027 TI - Evaluation of monoclonal antibodies with specificity for human IgA, IgA subclasses and allotypes and secretory component. Results of an IUIS/WHO collaborative study. AB - 51 monoclonal antibodies (McAb) with putative specificity for human IgA, the IgA subclasses, Am allotypes or secretory component (SC) were evaluated for immunoreactivity and specificity by nine laboratories employing immunodiffusion, agglutination, immunohistological assays, immunoblotting and direct binding and competitive inhibition enzyme immunoassays. McAbs specific for IgA PAN (n = 24), IgA1 (n = 7), IgA2 (n = 3), IgA2m(2) (n = 2), non-IgA2m(2) (n = 4) and SC or secretory IgA (n = 5) were identified that were immunoreactive and specific in the assays employed. The McAbs identified as IgA- or SC-reactive were shown to be non-reactive to human IgG, IgM, IgD, IgE, kappa and lambda by direct binding and competitive inhibition immunoassays. Interestingly, no McAbs with restricted specificity for IgA2m(1) were identified. Some McAbs displayed higher affinity and/or better performance in one or several of the assay groups. The IgA- and SC specific McAbs identified in this international collaborative study have potential as immunochemical reference reagents to identify and quantitate monomeric and polymeric IgA in human serum and secretions. PMID- 8699028 TI - Assessment of in vivo attachment/phagocytosis by alveolar macrophages. AB - Alveolar macrophages (AMs) are recognized as an important first line of cellular host defense within the lung. Although mechanisms underlying AM response to microorganisms or particulates are well characterized in vitro, experimental approaches to the study of AMs in vivo are limited. To circumvent these limitations, a new assay was developed using fluorescently labelled liposomes or Pneumocystis carinii (PC) organisms which were administered intratracheally into mechanically ventilated rats. After 30 min, the lungs were lavaged and the percentage of administered liposomes or PC bound to AMs was determined by quantifying fluorescence. Factors known to enhance attachment/phagocytosis by AMs in vitro were assayed to determine their effect in vivo. For example, vitronectin (VN)-coated liposomes increased attachment from 25.2 +/- 2.4% to 47.2 +/- 3.0% (p < 0.001), while addition of VN increased the binding of PC to AMs from 16.5 +/- 1.7% to 24.5 +/- 2.2% (p < 0.05). Confocal laser microscopy of cells obtained by lavage provided morphologic evidence of attachment/phagocytosis by AMs. This model will permit the quantitative assessment of the interaction of fluorescently labelled liposomes or microorganisms with AMs in the lower respiratory tract of living animals. PMID- 8699029 TI - Type-specific serologic diagnosis of respiratory syncytial virus infection, based on a synthetic peptide of the attachment protein G. AB - Peptides deduced from the central hydrophobic region (residues 158-189) of the G protein of bovine and ovine respiratory syncytial virus (RSV) and of human RSV subtypes A and B were synthesized. These peptides were used to develop ELISAs to measure specifically antibodies against these types and subtypes of RSV. We have evaluated the bovine RSV-G peptide in both an indirect ELISA and in a blocking ELISA. Specificity and sensitivity, relative to a routine diagnostic ELISA that detects antibodies against the RSV F-protein in bovine sera, were 98% and 92% respectively for the indirect peptide-based ELISA, and 98% and 98% for the blocking peptide-based ELISA. In paired serum samples, rises in antibody titer were detected more frequently with the indirect peptide-based ELISA than with the routine F-ELISA. Furthermore, the peptide-based G-ELISAs were able to differentiate between antibodies against BRSV and HRSV, and between those against BRSV and ORSV. In addition, the indirect peptide-based ELISA was selective for HRSV subtype A and B antibodies. This study shows that peptides, corresponding to the central hydrophobic region of the attachment protein G of several RSVs, can be used successfully as antigens in highly specific and sensitive immunoassays. PMID- 8699030 TI - A fluorescent in situ hybridization method in flow cytometry to detect HIV-1 specific RNA. AB - In HIV+ patients, the presence of HIV-RNA in plasma and circulating cells has been reported to be a marker of progression but the percentage of transcriptionally active infected cells remains unclear. We have developed a reliable fluorescent in situ hybridization method for the detection of HIV specific RNA by flow cytometry. The procedure was applied to a panel of chronically infected cell lines and to an acutely infected cell line mimicking normal peripheral blood lymphocytes in susceptibility to HIV-1. The cells were fixed in suspension and hybridized by means of an HIV-1 genomic probe labeled with digoxigenin-11-dUTP. An FITC-labeled anti-digoxigenin antiserum was then applied and the resulting fluorescence signals were analyzed both by flow cytometry and confocal microscopy. Different procedures for double staining HIV RNA together with virus induced proteins or surface markers were also developed. Flow cytometric detection of in situ hybridization offers the possibility of analyzing thousands of cells in a few seconds and of collecting multiparametric information at the single cell level, thus providing a potential tool for detecting the rare HIV-RNA expressing cells in peripheral blood samples. PMID- 8699031 TI - Analysis of the individual contributions of immunoglobulin heavy and light chains to the binding of antigen using cell transfection and plasmon resonance analysis. AB - We have cloned the Tg10 murine monoclonal antibody, which is specific for a human thyroglobulin (hTg) epitope targeted by autoantibodies in several thyroid pathologies. Transfection of COS-7 cells with plasmids expressing Tg10H and kappa chains combined with surface plasmon resonance analysis (BIAcore) of culture supernatants showed that the entire cloned Tg10 antibody displays an affinity comparable to that of the parental antibody. This approach also permitted determination of the probable role of each chain to the recognition of the cognate epitope due to the ability of COS-7 cells to secrete independently each of the two constituting immunoglobulin chains. Tg10 heavy chain recognizes hTg in the absence of the light chain, but with a ten-fold lower affinity mainly due to an increase in kappaoff. In contrast, the light chain is unable to bind hTg on its own. This suggests that the latter is probably involved in stabilization rather than in initiating the formation of the antibody/antigen complex and that the specificity of Tg10 is mostly, if not exclusively, carried by the heavy chain. The potential applications of combined cell transfection and surface plasmon resonance to our understanding of antigen/antibody interactions are discussed. PMID- 8699032 TI - Directing antigen specificity towards botulinum neurotoxin with combinatorial phage display libraries. AB - The production of antibodies towards antigens with low immunogenicity is enhanced by the intrinsic efficiency of screening combinatorial libraries of immunoglobulins. The need to isolate clones with rare binding specificities has dictated a highly efficient method of screening and isolating antibody clones. The production of recombinant immunoglobulin libraries in bacteria allows for a more controlled selection of antibody specificity and can be used in circumstances where hybridoma fusions are unable to isolate rare clones with the desired epitope specificity. Botulinum neurotoxin (NT) with associated non neurotoxin proteins (non-NT) as a complex was used to immunize mice to obtain mRNA for the production of a recombinant antibody library with a repertoire of specificities. Initial screens of the combinatorial library revealed clones which recognized the non-neurotoxin proteins of the toxin complex similar to monoclonal antibodies produced by conventional hybridoma fusions. The combinatorial library was re-screened in order to isolate antibodies that specifically recognized the neurotoxin component of the toxin complex. The ability to alter the biopanning selection process affords the researcher a measure of control in the selection process not available with traditional hybridoma fusions. PMID- 8699034 TI - Priorities in medicine. PMID- 8699033 TI - Time-resolved fluorometric assay for natural killer activity using target cells labelled with a fluorescence enhancing ligand. AB - A time-resolved fluorometric assay for the measurement of natural killer cell activity against target cells labelled with the acetoxymethyl ester of the fluorescence enhancing ligand 2,2':6',2"-terpyridine-6,6"-dicarboxylic acid (TDA) is described. The hydrophobic esterified form of TDA (bis(acetoxymethyl) 2,2':6',2"-terpyridine-6,6"-dicarboxylate, BATDA) diffuses readily through the cell membrane of viable cells. BATDA is hydrolysed by intracellular esterases resulting in accumulation of membrane impermeable TDA inside the target cells. After incubation of labelled K-562 cells with effector cells the TDA released from lysed cells into the supernatant is chelated with Eu3+. The natural killer cell activity is then quantified by measuring the intense fluorescence of the EuTDA chelates formed. Target cells are rapidly labelled when incubated with BATDA, TDA is released from target cells faster than 51Cr, the spontaneous release permits a short-term release assay to be set up and the detection of EuTDA is fast (5 min/96 well plate). Furthermore, this non-radioactive method permits the use of complex culture media since, in contrast to methods based on prompt fluorometry, the problem with autofluorescence can be avoided by the use of time-resolved fluorometry. PMID- 8699035 TI - Tear glucose estimation--an alternative to blood glucose estimation. AB - Dextrostix, being very sensitive to measure glucose level by glucose oxidase method, was chosen to measure tear glucose level to evaluate the relationship of tear glucose to blood glucose level in 94 cases. It was found that in our population the measurement of tear glucose has definite value in interpretation of glucose status of individual. So, it was suggested to use this simple method of detection of tear glucose to interpret hyperglycaemic state of the patients. The present study was undertaken (1) to sort out a definite relationship between tear and plasma glucose concentration and (2) to devise a rapid method for detection of tear glucose level semiquantitatively with glucose oxidase impregnated strips and to evaluate its role as indicator of plasma glucose level. PMID- 8699036 TI - Reproductive health behaviour of rural women. AB - The extent and nature of reproductive health problems, and the actions taken for prevention/management of these problems were studied in rural area of district Ambala, Haryana. Maternal mortality rate was found to be 230/100,000 live births. Only 31% had died in hospitals; 64% cases were not referred. Main reason for non referral was ignorance about the nature of the complication in 54%. In another study done in 4 villages, 61.2% (367/600) married women of 15-44 years reported to be suffering from symptoms suggestive of gynecological disorders. Out of the 228 who had delivered in past 2 years, 103 (45.2%) reported to have suffered from illnesses in the maternity period, 19.3% had a major maternity complication. Government doctors were consulted in 29.2%, private doctors in 43.1%, health auxiliaries in 16% and traditional birth attendants (TBAs) in 11.8% of the episodes. Average cost of treatment was Rs 211 per episode. For management of maternity related complication, 65.8% could identify a proper hospital. For conducting the delivery, 10% preferred doctors, 60.2% nurse-midwife, and 29.3% TBAs. Although 93.8% of the respondents knew about the places where pregnancy can be terminated, but only 13.8% knew that doctors conduct abortion. In view of the lack of proper understanding about the reproductive health problems, health education campaign should be launched so that maternity care facilities being upgraded in the country are utilised. Programmes for prevention and treatment of gynecological morbidity should also be initiated. PMID- 8699037 TI - Bacteria in surface infections of neonates. AB - A bacteriological work on surface infections was done among live births (study group I) and neonates admitted in hospital (study group II). Out of 134 cases of conjunctivitis in group I Gram-negative bacilli predominated (48.5%) with Escherichia coli accounting for 29 (14.9%) cases, Klebsiella species 15 (11.2%) cases, Citrobacter freundii 3 (2.2%) cases, Pseudomons aeruginosa 18 (13.4%) cases and Aeromonas hydrophila 3 (2.2%) amongst pure isolates (73.9%). Gonococcus was noted in 2 (1.5%) cases. In group II, 41.7% were Staphylococcus aureus in pure growth (75%), compared to only 9.0% in group I. Skin infections were caused by both Staphylococcus aureus and Staphylococcus epidermidis. Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa were the principal insolates from umbilical sepsis. Pseudomonas aeruginosa was isolated as pure growth from local site of noma neonatorum. Anaerobic cultures were negative in all except in 2 cases of umbilical sepsis with tetanus neonatorum revealing Clostridium tetani which however proved to be non-toxigenic. Blood cultures were positive in 4 out of 14 cases bearing 50% correlation with bacteria from surface infections. A source study established partial correlation with the cases of pseudomonas conjunctivitis. Phage typing of Staphylococcus aureus and biochemical typing failed to detect any definite marker of clinical entities, except that the skin infections were caused by group III phages predominantly (65.0%). PMID- 8699038 TI - Activated charcoal--an antidote to methyl alcohol poisoning. AB - Every year a considerable number of people die due to methly alcohol poisoning, in which most of them die even before they are given proper treatment. This report gives a simple and cheap first aid measure to those affected by methanol poisoning by the administration of activated charcoal. This study has shown that the mortality of methanol recipient rats have significantly reduced by the administration of activated charcoal. PMID- 8699039 TI - Frequency of cervical spine involvement in rheumatoid arthritis. AB - The cervical spine x-rays of a random number of patients with confirmed rheumatoid arthritis were taken. The presence of atlanto-axial subluxation, atlanto-axial impaction, subaxial subluxation and any other associated abnormalities was noted. The spinal canal diameter was also measured which was not significantly altered in rheumatoid arthritis cases. Cervical spine disorders were seen to occur in 16 cases (69.6%) out of 23 patients. Spondylosis was the most frequent disorder ie, in 10 cases (62.5%) out of 16. Obliteration of the normal lordotic curve and disc lesions occurred in 3 cases (18.7%) each out of 16. The mean spinal canal diameter was 16.30 +/- 2 mm with a range of 13-23 mm. Female patients (73.3%) had an increased cervical spine disorder than males (62.5%). Seropositive rheumatoid arthritis cases (87.5%) were mostly involved in occurrence of disorder than those of seronegative arthritis cases (46%). PMID- 8699040 TI - Prostaglandin E2 gel for cervical priming and induction of labour in unfavourable cervical state. AB - To know the safety and efficacy of intracervical prostaglandin E2 gel over conventional intravenous infusion of oxytocin for priming and induction of labour, a prospective study was undertaken in 96 cases selected at random for both study and control series consisting 48 cases in each group with definite indication for termination of pregnancy having unfavourable cervical state. Periodic clinical assessment in different groups following the procedure revealed that by the end of 12 hours, 39 cases in the study and 28 cases in the control group had uterine contraction. Foetal heart rate abnormality was more marked in the oxytocin group (1.56% in the study group and 20.31% in the control group) while increase in Bishop's cervical scoring was noticed more often in the prostaglandin group. By the end of 12 hours of initiation of therapy, 17 cases in the study group and only 3 cases in the control group had spontaneous vaginal delivery. There was significant shortening of instillation and delivery interval in PGE2 group. The number of caesarean section in the study group was only 16.66% in comparison to 25% in the control group. Analysing the efficacy of the procedures adopted, the success rate in the prostaglandin group was 91.66% in contrast to 64.58% in the oxytocin group. PMID- 8699042 TI - Present-day management of pulmonary tuberculosis. PMID- 8699041 TI - Transmission of Sarcoptes scabiei from animal to man and its control. AB - Outbreak of Sarcoptes scabiei in animals spilling over to man in close association was observed in two adjacent villages, Fewgram and Nurpur in the district of Birbhum, West Bengal, from mid-November to mid-December, 1991. Nineteen goats and one calf who did not receive any treatment died of sarcoptic manage. All infected animals got cured with external application of deltamethrin, a synthetic pyrethroid and triazapentadiene. Human cases were treated successfully with benzene hexachloride (2%). PMID- 8699043 TI - Giant cell tumour of short bones of hand. PMID- 8699044 TI - Behcet's disease: a case report. PMID- 8699045 TI - Left subdiaphragmatic kidney: a case report. PMID- 8699047 TI - General practitioners and changing scenario in drug abuse. PMID- 8699046 TI - Swyer-James-Macleod syndrome with emphysematous bulla. PMID- 8699048 TI - Looting kidney. PMID- 8699049 TI - Consumer Protection Act and the medical profession: a few corrective measures. PMID- 8699050 TI - Impact of IMA family planning training in Uttar Pradesh. Indian Medical Association. PMID- 8699051 TI - Treatment of adult varicella with sorivudine: a randomized, placebo-controlled trial. AB - The antiviral and clinical efficacy of sorivudine in adults with varicella was evaluated in a double-blind, placebo-controlled randomized trial. A total of 186 patients were hospitalized for isolation and treatment within 96 h of rash onset. The diagnosis of varicella was confirmed in 184 patients with paired sera. Patients were randomly assigned to receive 10 or 40 mg of sorivudine or an identical placebo once a day for 5 days. Treatment with 40 mg of sorivudine (compared with placebo) shortened the mean time to 100% crusting from 6.6 to 5.8 days (P = .004) and reduced the mean days that new lesion formed from 3.9 to 3.1 (P = .014). Mean days of cutaneous viral shedding were reduced from 3.3 in the placebo group to 2.6 in the 40-mg sorivudine group (P = .002). The effectiveness of therapy was not affected by the duration of rash before initiation of therapy. Sorivudine is a promising new agent for the treatment of varicella-zoster virus infections. PMID- 8699053 TI - Induction of interleukin (IL)-8 gene expression by respiratory syncytial virus involves activation of nuclear factor (NF)-kappa B and NF-IL-6. AB - Respiratory syncytial virus (RSV) preferentially infects respiratory epithelium and is an important cause of lower respiratory tract infections in young children. RSV induces the production of interleukin (IL)-8 in airway epithelial cells; however, the mechanism of this induction is not known. To define the mechanism by which RSV induces IL-8 gene activation, A549 epithelial cells were transfected with plasmids containing serial deletions of the 5'-flanking region of the IL-8 gene and then exposed to RSV for 24 h. A positive cooperative effect of the binding sites for the transcription factors, nuclear factor (NF)-kappa B and NF-IL-6, was observed. Mutations in either region abates responsiveness of the promoter to RSV infection. RSV also increases activation of the NF-kappa B and NF-IL-6 transcription factors. These data suggest that RSV may increase IL-8 production in airway epithelium partly via activation of the transcription factors NF-kappa B and NF-IL-6. PMID- 8699052 TI - Intranasal monoclonal IgA antibody to respiratory syncytial virus protects rhesus monkeys against upper and lower respiratory tract infection. AB - Respiratory syncytial virus (RSV), the major cause of lower respiratory tract disease in infants, is thought to infect the upper airways before spreading to the lower respiratory tract. A rhesus monkey model of RSV infection after upper airway inoculation was used to test the protective effect of intranasal treatment with HNK20, a mouse monoclonal IgA antibody against RSV F glycoprotein. HNK20 was administered once daily for 2 days before RSV challenge and 4 days after challenge. Treatment with 0.5 mg/kg HNK20 reduced viral shedding in the nose, throat, and lungs by 3-4 log10/mL (P < or = .002). All monkeys developed RSV neutralizing antibody in serum, even in the absence of detectable viral replication. Neutralizing concentrations of monoclonal antibody remained in nasal secretions for > 1 day after treatment. These results suggest that nose-drop application of monoclonal antibody could provide convenient and effective protection against RSV infection in human infants at risk of severe lower respiratory tract disease. PMID- 8699055 TI - Role of maternally derived circulating antibodies in protection of neonatal swine against porcine group A rotavirus. AB - The ability of maternally derived antibodies in the circulation of neonatal pigs to protect against challenge with virulent porcine group A rotavirus (OSU strain) was evaluated. Groups of neonatal pigs with nondetectable (group 1), low (group 2), or high (group 3) serum levels of OSU rotavirus-specific maternally derived antibodies were challenged with virulent OSU rotavirus at 3 days of age and monitored for infection and disease. Control pigs were sham-inoculated with diluent at 3 days of age. Although all virus-inoculated pigs shed rotavirus and developed diarrhea, group 3 pigs developed significantly less severe diarrhea and shed for significantly fewer days than group 1 and 2 pigs, and they maintained appetites and weight gains comparable to sham-inoculated controls. It was concluded that circulating maternally derived antibodies play a significant role in mitigating clinical disease following rotavirus infection in neonatal swine and that the protection afforded by these antibodies is titer dependent. PMID- 8699054 TI - Safety, immunogenicity, and protective efficacy of one and three doses of the tetravalent rhesus rotavirus vaccine in infants in Lima, Peru. AB - An oral rhesus-human rotavirus tetravalent (RRV-TV) vaccine (10(4) pfu of rhesus rotavirus [type G3] and of 3 human-rhesus reassortants [G1, G2, and G4]) was evaluated in a field trial in Lima, Peru. At 2, 3, and 4 months of age, infants received either a dose of RRV-TV, an initial dose of vaccine followed by a dose of placebo at 3 and 4 months, or a dose of placebo. Rotavirus-specific IgA responses were detected by ELISA in 75% of the three-dose vaccine group, 59% of the one-dose vaccine group (P = .05), and 24% of the placebo group (P < .001): 64%, 48%, and 12% of each group, respectively, had a neutralizing antibody response to at least 1 serotype. Both one and three doses of vaccine failed to induce a significant level of protection against rotavirus diarrhea; however, they did provide some protection (range, 35%-66%) against more severe rotavirus diarrhea, especially for episodes caused by type G1. PMID- 8699056 TI - Detection of human herpesvirus 8 DNA sequences before the appearance of Kaposi's sarcoma in human immunodeficiency virus (HIV)-positive subjects with a known date of HIV seroconversion. AB - The presence of human herpesvirus 8 (HHV-8) DNA sequences was sought by polymerase chain reaction (PCR) in peripheral blood mononuclear cells of 4 groups: 6 human immunodeficiency virus (HIV)-infected persons with well-defined dates of seroconversion, during the period between the diagnosis of HIV infection and the appearance of Kaposi's sarcoma (KS); 45 HIV-positive persons with no symptoms of HIV infection; 11 AIDS patients with KS; and 14 AIDS patients without KS. HHV-8 DNA PCR was positive in 3 of the 6 patients during HIV infection preceding the appearance of KS and in all but 1 of 11 AIDS patients with KS. HHV 8 DNA PCR was negative in all but 1 of the 45 HIV-positive persons with no symptoms of infection and in all but 1 AIDS patient without KS. These results indicate that HHV-8 DNA may be detected several years before the occurrence of KS in HIV-infected subjects. PMID- 8699057 TI - Virologic markers of human immunodeficiency virus type 1 in cerebrospinal fluid of infected children. AB - To identify virologic correlates associated with central nervous system (CNS) abnormalities in children infected with human immunodeficiency virus type 1 (HIV 1), cerebrospinal fluid (CSF) was examined for virologic markers and correlated with neurodevelopmental status and neuroimaging abnormalities. Of 30 children, 18 (60%) had at least 1 culture-positive CSF sample; in total, 21 (55%) of 38 CSF specimens were culture-positive. CSF white blood cell counts were higher in specimens that were culture-positive (P = .01). HIV-1 RNA was detected in 90% of CSF samples, and RNA levels > or = 10,000 copies/mL were found in 6 (75%) of 8 children with severe neurocognitive impairment (P = .08) and 11 (73%) of 15 children with a cognitive index < or = 85 (P = .04). Higher RNA levels were associated with abnormal brain imaging scans (P = .04) and with neurocognitive deficits (P = .04). Thus, HIV-1 is present within the CNS of most infected children, and neurocognitive impairment appears to be associated with increased HIV-1 replication. PMID- 8699058 TI - Predictive markers of AIDS dementia complex: CD4 cell count and cerebrospinal fluid concentrations of beta 2-microglobulin and neopterin. AB - A predictive marker for AIDS dementia complex (ADC) in a cohort of neurologically asymptomatic human immunodeficiency virus type 1 (HIV-1)-infected patients with < 200 CD4 cells/microL was sought. Patients were assessed neurologically and neuropsychologically at entry. Blood and cerebrospinal fluid (CSF) were taken for assay of beta 2-microglobulin (beta 2M), and neopterin and T cell subsets were assessed from blood. Patients were evaluated every 4 months. Of 37 patients recruited, 35 had sufficient follow-up data. Seventeen patients progressed to ADC stage > or = 1. In univariate analyses, concentrations of CSF beta 2M and neopterin and CD4 cell count were each significantly associated with ADC development. In a multivariate analysis, concentrations of CSF beta 2M remained significant, with levels > 5 mg/L carrying approximately 17 times the risk of ADC. CSF beta 2M and neopterin levels and CD4 cell count are useful in identifying patients at risk of ADC and as such can be used to target high-risk patients so therapy can be optimized. PMID- 8699059 TI - The effect of latent Mycobacterium tuberculosis infection on human immunodeficiency virus (HIV) disease progression and HIV RNA load among injecting drug users. AB - To examine the relationship between latent Mycobacterium tuberculosis infection and human immunodeficiency virus (HIV) disease progression, two studies were done among a cohort of HIV-infected injecting drug users. First, the decline in CD4 cell count after baseline tuberculin skin testing was prospectively compared for 37 tuberculin-positive (induration > or = 5 mm) and 284 tuberculin-negative (induration < or = 2 mm) persons. After adjustment for baseline immune function, the mean 6-month CD4 cell decline was not significantly different (34.5 vs. 45.6 cells, respectively, P = .14). Second, the plasma HIV burden at baseline skin testing was compared for 33 tuberculin-positive cases and 33 matched tuberculin negative controls. HIV RNA was detected in 8 cases and 10 controls (odds ratio = 0.67, 95% confidence interval = 0.19-2.36). Among the 14 pairs with HIV detected in > or = 1 member, the HIV concentration was higher for the case in 4 and for the control in 10 (P = .18). These findings suggest that unlike active tuberculosis, latent M. tuberculosis infection does not hasten HIV progression. PMID- 8699060 TI - An international collaborative study of the effects of coinfection with human T lymphotropic virus type II on human immunodeficiency virus type 1 disease progression in injection drug users. AB - To determine whether human T-lymphotropic virus (HTLV) type II coinfection affects progression of human immunodeficiency virus type 1 (HIV) infection, longitudinal data on 370 HIV-infected injection drug users (IDUs) with known HIV seroconversion dates from four cohort studies were pooled. HTLV infection was determined by EIA and confirmed and typed by Western blot. Proportional hazards models were used to determine whether HTLV-II infection was associated with AIDS or AIDS-related mortality. Regression analyses were used to compare declines in CD4 cell percents in singly and dually infected persons. Of 370 IDUs, 61 (16%) were HTLV-II-coinfected. During follow-up, 43 (12%) developed and 24 (6%) died of AIDS. HTLV-II coinfection was not associated with progression to AIDS (relative hazard [RH], .82; 95% confidence interval [CI], 0.34-1.94]) or AIDS mortality (RH, 1.69; 95% CI, 0.62-4.60). Rates of decline in CD4 cell percent were similar in singly and dually infected IDUs. These results suggest that HTLV-II does not affect the progression of HIV infection. PMID- 8699061 TI - Human T lymphocyte virus type I-induced myeloneuropathy in rats: implication of local activation of the pX and tumor necrosis factor-alpha genes in pathogenesis. AB - The pathogenetic roles of human T lymphocyte virus type I (HTLV-I) and cytokines were investigated in HTLV-I-induced myeloneuropathy in Wistar-King-Aptekman Hokudai rats. In the nervous system, pX messenger RNAs of HTLV-I were selectively expressed in the diseased spinal cord and peripheral nerves but not in the unaffected cerebrum and cerebellum, even though proviral DNAs were consistently identified in these tissues. Among several cytokines examined, mRNA expression and production of tumor necrosis factor (TNF)-alpha in the spinal cord and cerebrospinal fluid correlated positively with the development of spinal cord lesions. The collective evidence strongly suggests that selective activation of HTLV-I, in particular Tax expression and production of TNF-alpha induced by HTLV I infection in target spinal cord and peripheral nerves, is causally related to apoptotic death of oligodendrocytes and Schwann cells, a major pathogenetic pathway of the HTLV-I-induced myeloneuropathy. PMID- 8699062 TI - Acyclovir and prednisolone treatment of acute infectious mononucleosis: a multicenter, double-blind, placebo-controlled study. AB - Ninety-four patients with infectious mononucleosis and symptoms < or = 7 days were randomized to treatment with oral acyclovir (800 mg 5 times/day) and prednisolone (0.7 mg/kg for the first 4 days, which was reduced by 0.1 mg/kg on consecutive days for another 6 days; n = 48), or placebo (n = 46) for 10 days. Oropharyngeal Epstein-Barr virus (EBV) shedding was significantly inhibited during the treatment period (P = .02, Mann-Whitney rank test). No significant effect was observed for duration of general illness, sore throat, weight loss, or absence from school or work. The frequency of latent EBV-infected B lymphocytes in peripheral blood and the HLA-restricted EBV-specific cellular immunity, measured 6 months after onset of disease, was not affected by treatment. Thus, acyclovir combined with prednisolone inhibited oropharyngeal EBV replication without affecting duration of clinical symptoms or development of EBV-specific cellular immunity. PMID- 8699063 TI - Interleukin-6 production by human neonatal monocytes stimulated by type III group B streptococci. AB - The subcellular components of type III group B streptococci (GBS) that contribute to the host inflammatory response were determined by measuring production of the proinflammatory cytokine interleukin (IL)-6 by cord blood monocytes. Monocytes were stimulated with encapsulated (COH1) or unencapsulated (COH1-13) whole type III GBS or with purified GBS components, including type III capsular polysaccharide (III-PS), group B antigen (GB-Ag), lipoteichoic acid (LTA), or Escherichia coli lipopolysaccharide. Monocytes exposed to COH1 and COH1-13 released similar amounts of IL-6. GBS III-PS, GB-Ag, and LTA each induced IL-6. However, IL-6 release by monocytes was significantly greater after stimulation by GB-Ag than by III-PS or LTA (P < .05). Sera from 16 neonates with systemic GBS disease had IL-6 levels of 8 pg/mL to 4.28 ng/mL. GB-Ag is a potent inducer of IL 6 and may play an important role in tissue inflammation during GBS infection. PMID- 8699064 TI - Superantigen vaccines: a comparative study of genetically attenuated receptor binding mutants of staphylococcal enterotoxin A. AB - Superantigens exert their pathologic effects by direct binding to major histocompatibility complex (MHC) class II molecules and T cell antigen receptors (TCR), thus circumventing the normal, antigen-specific immune response. A direct link between disease and toxin suggests an excellent opportunity for vaccine intervention. Site-directed mutants of staphylococcal enterotoxin A (SEA) that have attenuated binding to either the TCR or the MHC class II molecule were developed. Both kinds of SEA mutants induced high levels of antibody against SEA when used as vaccines, and the immunized animals were fully protected when challenged with wild type toxin. However, a residual lethality was associated with the attenuated TCR-binding mutant. These results, combined with an understanding of the molecular nature of superantigen and receptor interactions, indicate that targeting MHC class II binding by site-directed mutagenesis will produce the most effective vaccine. PMID- 8699065 TI - Serodiagnosis of Lyme disease: accuracy of a two-step approach using a flagella based ELISA and immunoblotting. AB - An ELISA containing a purified flagellar antigen from Borrelia burgdorferi (FLA ELISA) was evaluated. The FLA-ELISA, detecting IgM and IgG together, did not have adequate specificity by itself. Good accuracy was obtained, however, when the FLA ELISA was the first step in a two-step protocol that used immunoblotting as a conditional second test. Samples that scored positive or equivocal by the FLA ELISA were evaluated with separate IgM and IgG immunoblots. The sensitivity of the two-step process for patients with erythema migrans or with later manifestations of Lyme disease was 64% and 100%, respectively. The specificity for health blood donors was 100% and was 90% for the aggregate of all persons with illness that may cause serologic cross-reactivity (98% if the samples from relapsing fever patients were excluded). Test precision was 96% overall, 99% for Lyme disease case serum samples, 100% for specimens from blood donors, and 88% for samples from persons with other illness. PMID- 8699066 TI - Molecular mechanisms of clarithromycin resistance in Mycobacterium avium: observation of multiple 23S rDNA mutations in a clonal population. AB - The peptidyltransferase region of the 23S rRNA gene (the probable target site for the macrolides) was investigated in blood isolates of Mycobacterium avium recovered from 38 patients before and after the development of clarithromycin resistance. Point mutations were identified in 100% of the 74 resistant relapse blood isolates but in none of 69 susceptible pretreatment isolates. Multiple mutations were identified in isolates from 23 (61%) of 38 patients. Of the 63 identified mutations, 95% involved adenine at bp 2058. Single-colony clones from cultures that were mixtures of more than one mutation revealed a single mutation within each clone. Pulsed field gel electrophoresis of genomic DNA restriction fragments revealed that 13 (81%) of 16 multiple mutations identified in the same patient were derived from a single infecting strain. In vitro investigation revealed the same point mutations observed in vivo. This study defines the probable mechanism of clarithromycin resistance in M. avium and provides in vivo evidence that mutational resistance is random and selection-directed. PMID- 8699067 TI - Safety, immunogenicity, and efficacy of Plasmodium falciparum repeatless circumsporozoite protein vaccine encapsulated in liposomes. AB - Seventeen malaria-naive volunteers received a recombinant Plasmodium falciparum vaccine (RLF) containing the carboxy- and the amino-terminal of the circumsporozoite protein (CSP) antigen without the central tetrapeptide repeats. The vaccine was formulated in liposomes with either a low or high dose of 3 deacylated monophosphoryl lipid A (MPL) and administered with alum by intramuscular injection. Both formulations were well tolerated and immunogenic. MPL increased sporozoite antibody titers measured by ELISA, Western blot, and immunofluorescence assay. One high-dose MPL vaccine formulation recipient developed a CSP-specific cytotoxic T lymphocyte response. After homologous sporozoite challenge, immunized volunteers developed patent malaria. There was no correlation between prepatent period and antibody titers to the amino- or carboxy terminal. The absence of delay in patency argues against inclusion of the amino terminal in future vaccines. A significant cytotoxic T lymphocyte response may have been suppressed by the inclusion of alum as an adjuvant. PMID- 8699068 TI - Duration of protection and age-dependence of the effects of the SPf66 malaria vaccine in African children exposed to intense transmission of Plasmodium falciparum. AB - The SPf66 synthetic vaccine is safe and partly efficacious against Plasmodium falciparum malaria among children 1-5 years old. The estimated vaccine efficacy [VE] for all clinical episodes over a period of 18 months after the third dose is 25% (95% confidence interval [CI], 1%-44%; P = .044). The observed temporal variations in efficacy could have been due to chance (likelihood ratio chi 2 = 13.8, 8 df; P = .086). Efficacy against clinical malaria did not vary significantly with age (chi 2 = 1.07, 4 df; P = .90). Overall parasite density was 21% lower in vaccine recipients than in the placebo group (95% CI, 0%-38%; P = .044). Further development of SPf66 may require trials to evaluate safety, immunogenicity, and efficacy when administered in the first year of life, together with other vaccines contained in the Expanded Programme of Immunization schedule. PMID- 8699069 TI - Molecular analysis of strains of Plasmodium vivax from paired primary and relapse infections. AB - Relapse infections are an important obstacle to the successful treatment and control of Plasmodium vivax malaria, but the molecular basis of relapse remains poorly understood. To provide insight into the molecular mechanisms of relapse, paired primary and relapse isolates of P. vivax were subjected to single-strand conformational polymorphism (SSCP) and sequence analysis of the circumsporozoite and merozoite surface protein 1 genes. All unrelated isolates were unique by both SSCP and sequence analysis, but 5 of 6 relapse isolates were identical to or were clones of their matched primary isolates. These results indicate that most relapses are caused by the same parasite populations that circulate during the primary infection and do not arise from a genetically distinct subpopulation. PMID- 8699070 TI - Immunoregulation in onchocerciasis: persons with ocular inflammatory disease produce a Th2-like response to Onchocerca volvulus antigen. AB - To examine the role of specific cytokines in mediating the clinical manifestations of human onchocercal disease, microfilariae-positive Ghanaian subjects with inflammatory ocular disease were compared with microfilariae positive subjects without ocular disease. Onchocerca volvulus antigen (OvAg) stimulated peripheral blood mononuclear cells (PBMC) from subjects with disease produced significantly more interleukin (IL)-10 (with disease = 447.34 vs. without disease = 292.22 pg/mL; P < .01) and IL-5 (with disease = 33.36 vs. without disease = 27.26 pg/mL; P = .02). OvAg-stimulated IL-4 and interferon (IFN)-gamma levels were essentially undetectable in either group. When cytokine mRNA levels were measured by reverse transcriptase-polymerase chain reaction ELISA, persons with disease produced significantly more OvAg-stimulated IL-4, IL 5, and IL-10 mRNA (P = .03, < .01, .05, respectively). No difference in IFN-gamma mRNA production by either group was seen. Addition of neutralizing alpha IL-10 antibody to OvAg-stimulated PBMC increased TFN-gamma production to detectable levels in 20 of 24 persons. PMID- 8699071 TI - Mucosal antibodies to human cytomegalovirus glycoprotein B occur following both natural infection and immunization with human cytomegalovirus vaccines. AB - Because antibodies against human cytomegalovirus (HCMV) glycoprotein B (gB) neutralize, levels of IgG, secretory IgA (sIgA), and mucosal IgA1 antibodies to HCMV were measured in saliva and nasal washes. Ten seronegative adults lacked these antibodies, but of 10 naturally seropositive adults, 10 had IgG to gB, 5 had sIgA, and 0 had mucosal IgA. Among 12 recipients of a live HCMV vaccine, 8 had IgG to gB, 4 had sIgA, and 2 had mucosal IgA in samples collected 10-20 months after immunization; of 10 recipients of a gB vaccine, 8 had IgG to gB, 7 had sIgA, and 7 had mucosal IgA in samples collected just before or 1 month after a booster. IgG to gB and neutralizing titers in serum correlated with IgG to gB in mucosal samples. IgG to gB was in the saliva of 25 of 26 subjects with serum neutralizing titers > 1:64. Serum neutralizing titers > 1:64, whether induced by vaccine or wild type virus, are associated with mucosal IgG to HCMV. PMID- 8699072 TI - Once-weekly intraocular injections of ganciclovir for maintenance therapy of cytomegalovirus retinitis: clinical and ocular outcome. AB - The clinical course and the outcome of treatment were studied in 40 patients with primary cytomegalovirus (CMV) retinitis in 57 eyes. All had received one 14-day course of intravenous ganciclovir and all were free of other end-organ CMV disease. All afficted eyes received weekly intravitreal injections of 400 micrograms of ganciclovir for maintenance therapy. Median survival of patients was at least 13 months. Fifteen patients had 19 new opportunistic infections during the observation period, but none developed new nonocular CMV disease. Active retinitis recurred in 68.4% of the eyes while receiving maintenance therapy, with a median time to progression of 14.7 weeks. CMV retinitis occurred in 30.4% of the previously uninvolved eyes (follow-up, 3.1 years). Bacterial endophthalmitis complicated treatment in 1 eye, and 5 eyes developed a retinal detachment. Thus, the long-term treatment of CMV retinitis with weekly intraocular injections of ganciclovir was associated with survival and ocular outcome similar to those reported with systemic ganciclovir. PMID- 8699073 TI - Measurement of human herpesvirus 7 load in peripheral blood and saliva of healthy subjects by quantitative polymerase chain reaction. AB - Qualitative and competitive-quantitative nested polymerase chain reaction (PCR) assays were developed for human herpesvirus 7 (HHV-7). These assays amplify a DNA sequence encoding part of the HHV-7 homologue of the human herpesvirus 6 (HHV-6) U42 gene. The PCR assays were used to analyze peripheral blood DNA (pbDNA) and saliva from 24 healthy volunteers. The prevalence of HHV-7 in saliva was 96%, with a median virus load of 1.1 x 10(6) copies/mL. Longitudinal analysis revealed sustained virus load, suggesting continued active viral replication. Analysis of 1 microgram of pbDNA showed the prevalence of HHV-7 to be 83%, with a median virus load of 40 copies (267 copies/10(6) cells). Analysis of sequential pbDNA samples showed individuals to have stable levels of HHV-7 virus load. These data demonstrate persistence of HHV-7 at two distinct sites and provide baseline data allowing comparisons with HHV-7 load in immunocompromised patients. PMID- 8699074 TI - Changes in virus load markers during AIDS-associated opportunistic diseases in human immunodeficiency virus-infected persons. AB - Human immunodeficiency virus (HIV) load markers are being used increasingly to monitor disease progression and evaluate antiretroviral therapy. This study examined plasma HIV RNA and p24 antigen levels before, during, and after 15 AIDS associated opportunistic disease events in patients with AIDS (median CD4 cell count = 65/microL). Plasma HIV RNA was detected during 13 of the 15 events (median level before an event = 21,000 copies/mL). There was an increase in the level of plasma HIV RNA with the onset of an AIDS-associated opportunistic disease during 11 of 13 events for which HIV RNA was detectable (median level during an event = 145,000 copies/mL). There was a decline in the level of HIV RNA with the recovery from disease (median level after an event = 29,700 copies/mL). In contrast, there was no consistent or significant change in p24 antigen levels or CD4 cell counts with either the onset of or recovery from an event. Clinical interpretation of plasma HIV RNA changes must take into account this reversible elevation during AIDS-associated opportunistic disease. PMID- 8699075 TI - Human immunodeficiency virus type 1 kinetics in lymph nodes compared with plasma. AB - As lymphoid organs are the major reservoir of human immunodeficiency virus type 1 (HIV-1), the rates at which HIV-1 RNA decreases from the plasma and from a series of lymph node biopsies from 4 patients treated with a combination of zidovudine, didanosine, and lamivudine were measured. The concentrations of HIV-1 RNA in the plasma and in lymph nodes declined exponentially, with mean half-lives of 1.88 +/ 0.86 days for plasma and 6.01 +/- 3.44 days for lymph nodes. These data show that most of the HIV-1 in lymphoid organs is due to the infection of new cells and demonstrate that a triple-drug combination is able to target this compartment. PMID- 8699076 TI - Direct genetic detection of Dobrava virus in Greek and Albanian patients with hemorrhagic fever with renal syndrome. AB - Blood samples were collected from an Albanian and a Greek patient with hemorrhagic fever with renal syndrome and tested by reverse transcriptase polymerase chain reaction. The genetic detection assay amplified hantavirus specific DNA fragments from RNA extracted from the blood of the patients; nucleotide sequence analysis revealed that the causative agent of the disease was Dobrava virus. These findings suggest that Dobrava virus (which was originally isolated from the lungs of an Apodenws flavicollis mouse in Slovenia) is endemic throughout the Balkan States and causes overt human disease. PMID- 8699077 TI - Phylogenetic analysis of GB virus C: comparison of isolates from Africa, North America, and Taiwan. AB - A group of flavi-like GB viruses (GBV-A, -B, and -C) has been discovered and partially characterized. Only GBV-C is found in humans. Nucleotide sequences of the putative helicase gene of the GBV-C genome were determined in 21 Taiwanese patients and compared with isolates from Africa and North America by phylogenetic analysis. The average similarities of Taiwanese isolates to those from West Africa, East Africa, Canada, and United States were 83%, 85%, 78%, and 82%, respectively. Phylogenetic analysis of the NS3 region showed that 81% of the Taiwanese isolates were more closely related to the East African isolate. GBV-C isolates from Taiwan could be classified into at least 3 groups. These data suggest that GBV-C isolates cloned from different geographic areas have genetic heterogeneity. PMID- 8699078 TI - A new model of experimental prosthetic joint infection due to methicillin resistant Staphylococcus aureus: a microbiologic, histopathologic, and magnetic resonance imaging characterization. AB - Partial knee arthroplasty was done in rabbits with a silicone-elastomer implant. Immediately after closing the surgical wound, 5 x 10(6) cfu of methicillin resistant Staphylococcus aureus was injected into the joint. Disease evolution was studied at different stages of infection up to 8 weeks. Prosthetic infection developed in all animals. Gross pathology and histopathologic changes were characteristic of joint and bone infection. Quantitative bacterial counts from infected bone confirmed disease chronicity. The mean number of colony-forming units per gram of bone +/- SD 1 week after infection was 4.84 +/- 0.24 log10 cfu/g and remained stable from week 1 to week 8. Magnetic resonance imaging showed evidence of prosthetic infection as of week 1, while only mild radiologic changes of bone were seen 2 weeks after infection. This model produces a prosthetic infection that is reproducible and close to that of human prosthetic infection. PMID- 8699079 TI - Effect of granulocyte colony-stimulating factor on the course of infection with gram-positive bacteria in mice during granulocytopenia induced by sublethal irradiation or cyclophosphamide. AB - This study assesses the effect of granulocyte colony-stimulating factor (G-CSF) on the outcome of infection with Listeria monocytogenes or Staphylococcus aureus in mice during leukocytopenia induced by sublethal total body irradiation or cyclophosphamide treatment. The role of granulocytes during infection was assessed in the thigh muscle, spleen, and liver. G-CSF treatment in naive mice increased the number of blood granulocytes; upon infection, these numbers increased further, but G-CSF did not affect the outgrowth of bacteria in the tissues. Cyclophosphamide treatment and sublethal irradiation decreased the number of blood granulocytes, which was not affected by G-CSF treatment. However, during infection in cyclophosphamide-treated mice, G-CSF increased the number of granulocytes in the circulation and at the site of infection and decreased the number of bacteria in the tissues. Treatment with G-CSF did not affect the number of granulocytes or the course of infection in irradiated mice. PMID- 8699080 TI - Etiology of the acrodermatitis chronica atrophicans lesion in Lyme disease. AB - Spirochete diversity in acrodermatitis chronica atrophicans lesions in a closely defined central European site was compared to that in the local vector population, in human erythema migrans lesions, and in cerebrospinal fluid by amplifying and sequencing a segment of the gene of outer surface protein A directly from sampled tissues. Borrelia garinii, Borrelia afzelii, and Borrelia burgdorferi acutely infect human skin and invade internal tissues. Only B. afzelii, however, is associated with acrodermatitis chronica atrophicans lesions, persisting chronically where the skin has atrophied. PMID- 8699082 TI - An immunohistochemical analysis of naturally occurring chancroid. AB - Haemophilus ducreyi is a major cause of genital ulcer disease in many developing countries and is associated with augmented transmission of human immunodeficiency virus (HIV). However, the mechanisms through which H. ducreyi produces ulceration are poorly understood. The characteristics of the host response to H. ducreyi and the pathobiology of its potential contribution to increased HIV susceptibility are not known. Chancroid ulcer biopsies from 8 patients were analyzed histologically and immunohistochemically. All biopsies had perivascular and interstitial mononuclear cell infiltrates that extended deep into the dermis. The infiltrate, which contained macrophages and CD4 and CD8 lymphocytes, was consistent with a delayed hypersensitivity type cell-mediated immune response. The recruitment of CD4 T lymphocytes and macrophages may in part explain the facilitation of HIV transmission in patients with chancroid. PMID- 8699081 TI - Characteristics of Lyme disease spirochetes in archived European ticks. AB - To determine whether the characteristics of the Lyme disease spirochete (Borrelia burgdorferi) in Europe may have changed during the past century, DNA was amplified from archived Ixodes ricinus ticks. Tick DNA could be amplified, even when ticks had been stored under museum conditions for nearly a century. Spirochetal DNA was detected by polymerase chain reaction in 6 ticks preserved for as long as a century; the oldest was collected in 1884. Borrelia garinii, which predominates in modern ticks in the region, infected 3 of these older ticks, and the presently infrequent B. burgdorferi sensu stricto infected 2. These data indicate that residents of Europe have been exposed to diverse Lyme disease spirochetes at least since 1884, concurrent with the oldest record of apparent human infection. PMID- 8699083 TI - Immune response to recombinant mycobacterial proteins in patients with tuberculosis infection and disease. AB - The capacity of four Mycobacterium tuberculosis recombinant antigens to elicit proliferation and cytokine production by human T cells was evaluated. Proliferative responses of peripheral blood mononuclear cells (PBMC) to all antigens were greater in healthy tuberculin reactors than in pulmonary tuberculosis patients, and proliferative responses of pleural fluid cells were greater than those of PBMC from patients with tuberculous pleuritis. The proliferative responses to the four recombinant antigens were similar in all patient groups, and there was no selective unresponsiveness to any antigen in pulmonary tuberculosis patients. The 38-kDa antigen induced less interferon-gamma than did the 10-, 30-, and 65-kDa antigens, and all four antigens induced similar amounts of interleukin-10. These results suggest that none of the four recombinant antigens are immunodominant, and that the 10-, 30-, and 65-kDa antigens are similar in their capacity to induce a potentially protective Th1 like response. PMID- 8699084 TI - Host defenses against disseminated candidiasis are impaired in intercellular adhesion molecule 1-deficient mice. AB - Genetically engineered mice, which lack normal expression of intercellular adhesion molecule 1 (ICAM-1), were used to study the role of ICAM-1 in the host defense against disseminated candidiasis. The responses of ICAM-1-deficient mice and normal wild type mice were compared following an intravenous challenge with Candida albicans. ICAM-1-deficient mice lost more weight (P < .001) and had a significantly higher mortality (P < .001). Quantitative cultures revealed a greater tissue fungal burden in ICAM-1-deficient mice compared with normal mice, in both the kidney (P < .001) and the brain (P = .007). Extensive inflammation, composed primarily of histiocytes admixed with lymphocytes and occasional neutrophils, was present in the renal tissue of ICAM-1-deficient mice; this contrasted with a more localized and predominantly neutrophilic infiltrate in normal mice. This work suggests that the loss of ICAM-1 significantly impairs host defense against C. albicans, by impairing either neutrophil migration or phagocyte activation or both. PMID- 8699085 TI - Cytokine production by peripheral blood mononuclear cells in human coccidioidomycosis. AB - The production and mRNA expression of the cytokines interferon-gamma (IFN-gamma) and interleukin (IL)-4, -10, and -12 by peripheral blood mononuclear cells (PBMC) after incubation with the coccidioidal antigen toluene spherule lysate (TSL) from various subjects were measured. The IFN-gamma concentration in PBMC supernatants incubated for 72 h from 8 subjects with disseminated coccidioidomycosis was significantly less than that from 7 healthy, coccidioidal-immune subjects (P = .015). No differences were seen among the subject groups in the concentrations of IL-4, -10, or -12. By use of competitive polymerase chain reaction, PBMC from subjects with disseminated coccidioidomycosis also expressed less mRNA for IFN gamma and IL-12 than did cells from healthy, immune subjects. These data suggest that patients with disseminated coccidioidomycosis have a diminished T helper lymphocyte type 1 response. PMID- 8699086 TI - Anti-human cytomegalovirus effects of breast milk. PMID- 8699088 TI - Human immunodeficiency virus (HIV) type 1-specific B cell response in seronegative subjects at risk for HIV exposure. PMID- 8699087 TI - Genital ulcers associated with human immunodeficiency virus-related immunosuppression. PMID- 8699089 TI - Zidovudine resistance reverse transcriptase mutations during didanosine monotherapy. PMID- 8699090 TI - [Clinical studies of fluconazole in patients with deep-seated fungal infection in intravenous hyperalimentation (IVH)]. AB - Clinical efficacy of fluconazole on fungal infections was evaluated. Fluconazole was administrated orally or intravenously to 16 cases with fungal infections (chronic renal failure 4, congestive heart failure 2, cerebral infarction 2, etc). All cases were suspected of mycosis. The details of those administrated were 16 cases of pneumonia 3 cases, fungemia 9 cases (suspected 7 cases) and urinary tract infection 3 cases. Clinical efficacy rate was 71.4%. Side-effects were observed in only 1 case, and this consisted of transient increase of leukocytes and thrombocytes. Fluconazole is considered to be a potent, safe antifungal agent for the treatment of suspected fungal infection during intravenous hyperalimentation. PMID- 8699091 TI - [Effect of prolonged administration of erythromycin on the drug sensitivity and the biological properties of Streptococcus pneumoniae]. AB - From April 1990 to February 1992 two hundred and ten strains of Streptococcus pneumoniae were isolated in the laboratory of Nara Medical University Hospital. Frequency of erythromycin resistant Streptococcus pneumoniae, prescription mode of macrolide antibiotics and biological properties were investigated. 1. Erythromycin resistant Streptococcus pneumoniae was predominantly isolated from the wards of the respiratory unit of Inter- nal Medicine and Pediatrics. 2. Patients with erythromycin resistant Streptococcis pneumoniae were treated with macrolide antibiotics frequently in the respiratory unit of Internal Medicine and Pediatrics. 3. MIC90 of EM, CLDM, MINO and ABPC for Streptococcus pneumoniae was 8.0, 8.0, 8.0 and 1.0 micrograms/ml, respectively, indicating moderate resistance to penicillin derivatives and high resistance to macrolides, particularly EM; some strains showed high levels of MIC over 400 micrograms/ml. 4. Investigations on biological properties using VITEK GPI cards revealed that some erythromycin resistant strains showed less responsiveness to DEX, LAC, PUL and MEL. 5. The survival rate of mice infected with erythromycin resistant strains was longer than that with erythromycin sensitive strains. These findings suggested that the prolonged administration of erythromycin causes a virulence reduction of the organism. PMID- 8699092 TI - [An outbreak of influenza A (H3N2) in a nursing home]. AB - In the nursing home belonging to our hospital, an outbreak of influenza A (H3N2) occurred in January 1995, and we studied 23 elderly residents with influenza A infection. Twenty three residents with influenza A (8 males and 15 females) ranged in age from 67 to 95 years (average 83.1 years), 91.3% of them were bedridden. And all had underlying medical conditions with neurologic, cardiac, orthopedic, being the most frequent. The most common complaints were fever (100%), followed by cough (95.7%), sputum (60.9%), but sore throat was significantly less frequent. Influenza A virus was isolated from throat swab specimens from 6 of 18 ill patients. Fourteen persons were hospitalized and 2 of them had pneumonia, but nobody died. The levels of CRP, WBC were significantly high in the influenza group, as compared to the non influenza group. So this result suggested that influenza A infection among elderly subjects was apt to cause bacterial infection such as bronchitis and pneumonia. This outbreak was caused by contact from the staff to residents, so we think the health care of the staffs and prevention of influenza should be a high priority in nursing homes. PMID- 8699093 TI - [Clinical study on bacteremia in patients with liver cirrhosis]. AB - Infections and fever are frequent in patients with liver cirrhosis. Study on bacteremia in cirrhotic patients has not been reported in Japan. In a 16 year period from 1979 to 1994, we collected 39 cases with 40 episodes and 44 microorganisms of bacteremia for this study. The incidence of bacteremia in cirrhotic hospital admissions was 4.8% (39/808). Gram negative bacteria were the predominant microorganisms of bacteremia (66%, 29/44). Among them, Escherichia coli, Klebsiella pneumoniae, Vibrio sp. were the three most commonly detected microorganisms. Pseudomonas aeruginosa bacteremia has not been detected. Laboratory data of cirrhotic patients showed that positive blood culture patients had significantly lower serum albumin, prothrombin time and hepaplastin test than negative patients. Focal infection could be diagnosed in only 45% (20/44). The mortality rate was 28% (11/39), but the bacteremia related death (by septic shock) were only 2 cases. The other causes of death were hepatic failure in 9 cases. In conclusion, bacteremia is a important complication of liver cirrhosis. Blood culture is necessary in cirrhotic patients with fever. PMID- 8699094 TI - [Suppression of anti-Candida activity of human neutrophils by glucose and diminishment of the glucose effect by an amino acid mixture]. AB - Effects of a glucose and amino acid mixture prescribed for parenteral alimentation on anti-Candida activity of neutrophils were examined. Neutrophils obtained from peripheral blood of healthy humans inhibited the growth of Candida albicans in vitro. More than 1.0% of glucose inhibited the anti-Candida activity of the neutrophils in a dose-dependent manner. This glucose effect was reduced by the addition of an amino acid mixture clinically prescribed with a carbohydrate solution (PN-twin) in Japan. The amino acid mixture neutralized the suppression of anti-Candida activity of neutrophils by dexamethasone. These results suggest that an amino acid mixture prescribed in an alimentation solution may play a role as a neutralizer of the suppressive action of glucose for anti-Candida activity of neutrophils in a limited area near the top of a catheter in a blood vessel. PMID- 8699095 TI - [The etiology of acute lower respiratory tract infections in infants]. AB - The etiology of acute lower respiratory tract infections (ALRI) was studied in pediatric inpatients under 2 years of age admitted to Chiba Municipal Hospital between June 1994 and March 1995. Eighty-seven patients, 99 episodes were investigated for bacterial infection with the use of blood culture and washed sputum culture, for viral infection with the use of virus isolation, antigen detection and antibody assays, for Mycoplasma pneumoniae infection with the use of antibody assay and for Chlamydia infection with the use of antigen detection. Pathogens were identified in 71 (71%) of the 99 episodes. Evidence of bacterial infection was detected in 43 episodes (43%), viral infection in 37 episodes (37%), Mycoplasma pneumoniae infection in 4 episodes (4%) and Chlamydia infection 3 episodes (3%). The major bacterial pathogens were H. influenzae, M. (B) catarrhalis and S. pneumoniae. RS virus and influenza virus epidemics occurred during the winter. A mixed bacterial and viral infection was documented in 13 episodes (13%). RS virus infection was common in infants up to 6 months old. Mixed bacterial and influenza virus infections were common in 1 or more year old children. Virus isolation was useful for the grasp of the viral epidemic. Bacterial associated infections were common in children under 2 years of age with ALRI. Washed sputum culture and sputum gram stains' were useful for the treatment of infant ALRI. PMID- 8699096 TI - [A novel RNA capture method for the extraction of HCV-RNA]. AB - A novel method for the extraction of HCV-RNA by using DNA probe coated-latex microparticle (AmpliTex) was developed. This high density particle, with a large surface area, could be dispersed uniformly in a guanidium lysate of the serum. The DNA probe on the particles could hybridize with a few copies of HCV-RNA in the lysate. The RNA thus extracted on the particle can be subjected to the reverse-transcription and PCR reaction. Analytical sensitivity to detect HCV in serum was approximately 20 copies per ml. AmpliTex and the conventional organic extraction gave the same sensitivity and specificity (both 100%) to detect the HCV-RNA from fifty clinical specimens. It was also possible to extract the HCV RNA from heparinated plasma. PMID- 8699097 TI - A comparative study of detection of hepatitis E virus RNA by RT-PCR and digoxin probe techniques. AB - Techniques for detecting hepatitis E virus nucleic acid by RT-PCR and digoxin probe spot hybridization tests were developed. The examination by RT-PCR test of 250 stored stool specimens from patients with acute hepatitis E gave a positive rate of 40.9% and was positive in one stool specimen collected 28 days after the patient had contracted the illness. Serologic examination yielded a positive rate of 66.7%, and also utilizing the DIG probe labelled with PCR product it was 66.6%. RT-PCR with the digoxin probe proved to be suitable for clinical diagnosis and basic research on hepatitis E. PMID- 8699098 TI - [Two cases of gram-positive sepsis successfully treated with vancomycin in combination with imipenem or cilastatin]. AB - Against gram-positive sepsis, vancomycin (VCM) was administered in combination with imipenem or cilastatin (IPM/CS). Its excellent efficacy was confirmed in 2 cases, one affected with methicillin resistant Staphylococcus aureus and another with Gemella morbillorum. By calculating the FIC index according to a checkerboard technique, the in vitro synergistic effect was also demonstrated. At the present state multi-drug resistant gram-positive infections prevailed, the combination of VCM with IPM/CS can be expected as an effective measure for treating these diseases. PMID- 8699099 TI - [A case report: horizontal infection of typhoid fever from daughter to mother (by suppository maneuver)]. AB - A 22-year-old female was admitted to our hospital because of general fatigue and continuous high fever. Salmonella Typhi was detected from her blood. Her mother, 44-year-old female was admitted to our hospital a few days later because of high fever. She had nursed to her daughter and inserted suppositories to her daughter several times. S. Typhi was also detected from her blood. No other member of her family was infected with S. Typhi. From the study of the route of the infection, we are confident that S. Typhi was delivered from daughter to mother by insertion of suppositories. PMID- 8699100 TI - [A 12-year-old girl with acute respiratory disease with pneumonia caused by adenovirus type 7]. AB - We have encountered a 12-year-old girl with acute respiratory disease including pneumonia caused by adenovirus type 7. While being followed-up for bronchial asthma, she developed this disease with dyspnea accompanied by high fever, pharyngalgia and a dry cough subsequent to a slight fever. Adenovirus type 7 was separated and identified from the pharyngeal smear. Additionally, perfusion scintigraphy of the lungs presented evidence of interstitial pneumonia. with these findings and the clinical course put together, this case was diagnosed as having acute respiratory disease with pneumonia caused by adenovirus type 7. Thereafter, perfusion scintigraphy of the lungs continued showing interstitial shadows, which suggested the presence of severe sequlae of the lung. Formerly the separation rate of adenovirus type 7 was low in Japan, but the rate has tended to increase in cities in recent years. Cases presenting such acute, severe respiratory symptoms are expected to increase in the future, and clinically we consider to be our case important enough to be reported. PMID- 8699101 TI - [Prevention of infections in a case with myelodysplastic syndrome by an intermittent subcutaneous administration of G-CSF]. AB - An 83-year-old male was admitted to our hospital because of pancytopenia and low grade fever on April 19, 1993. On admission, hematological data were as follows: WBC 1,000/microliters with 19% neutrophils, RBC 367 x 10(4)/microliters, Hb 9.5 g/dl and platelets 6.7 x 10(4)/microliters. Bone marrow examination revealed 6.6% myeloblasts and 33.5% erythroblasts. Morphological abnormalities included hypersegmentation, degranulation and pseudo-Pelger's nuclear anomaly in neutrophils. Based on these findings the diagnosis of refractory anemia with excess of blasts (RAEB) of the myelodysplastic syndrome (MDS) was made and therapy with low dose Cytarabine (Ara-C) was initiated in April 1993. The patient had two episodes of severe pneumonia in June and July. Therefore, 75 micrograms/day of G-CSF was given in addition to antibiotic therapy for the second episode of infection in July. Thereafter the severe infection subsided, and G-CSF administration was switched to an intermittent schedule (75 micrograms twice a week) since September. Cytarabine ocfosfate (100 mg/day) was added for 10 14 days at interval 1-2 months from October,1993. He has been well with no episode of infection for more than two year. One major concern regarding the clinical application of G-CSF in MDS patients is related to the possible stimulation of leukemic cell proliferation. Frequent hematological monitoring is necessary in patients with RAEB who are prone to develop acute myeloid leukemia. However, we administered G-CSF at a relatively low dose twice a week for over two year and could successfully prevent infections without inducing the leukemic changes. PMID- 8699102 TI - [A case of the greater omentum abscess due to Peptostreptococcus ssp]. AB - A case of the greater omentum abscess due to Peptostreptococcus ssp. is reported. A 63-year-old male was admitted to Heisei Memorial Hospital with a complaint of abdominal pain. An intraperitoneal mass measuring 6 cm in diameter was detected by CT and ultrasonogram. He was diagnosed as having an intraperitoneal abscess. After antibiotics therapy by cefotiam, laparotomy was performed and an abscess about 7 cm in diameter at the edge of the greater omentum was found. There was no evidence of perforation in the intestine wall. The abscess was removed and Peptostreptoccocus spp. was isolated from the dark red pus drained from the abscess. PMID- 8699103 TI - [A case of Tsutsugamushi disease infected by mountain climbing in the Republic of Korea]. AB - A 47-year-old male was infected with Tsutsugamushi disease showing typical findings after mountain climbing in the Republic of Korea (ROK). Immunoserological examinations suggested that he had been infected in ROK. In this case, detection of the characteristic sting was useful for early diagnosis and treatment. Until now, Tsusugamushi disease has not been reported in Hokkaido. It is the first case registered in Hokkaido. With extensive international intercourse these days, this case suggests that Tsutsugamushi disease can occur potentially all over Japan. PMID- 8699104 TI - ECG of the month. Hindsight. Electrolyte disturbance. PMID- 8699105 TI - Management of orbital fractures. AB - Motor vehicle accidents have a high association with orbital injuries. A thorough clinical examination is essential, especially an ophthalmic examination. Radiographic analysis is an important aspect of diagnosis. Plain films can be obtained emergently, but high resolution CT scans with axial and coronal planes provide more accurate information. Zygomatic complex fractures are the most common injuries involving the orbits, with naso-orbito-ethmoid fractures and internal orbital fractures following. Autogenous bone, allografts, or synthetic material can be used for repair of defects located in the anterior or middle part of the orbital floor. Multi-team approach is important in the comprehensive management of these complex injuries. PMID- 8699106 TI - An 82-year-old woman with carcinomatosis. AB - An 82-year-old woman with breast carcinoma died with carcinomatosis, confirmed at autopsy. An unexpected finding was the "linitis plastica" aspect of the stomach, resulting from diffuse tumor infiltration. The coexistence of two different primary tumors was ruled out with data obtained by immunohistochemistry and presented at Tulane Pathology Grand Rounds. PMID- 8699107 TI - Radiology case of the month. Expansile lesion of bone. Aneurysmal bone cyst (ABC); MRI is the best modality to evaluate this lesion. PMID- 8699108 TI - The journal 150 & 100 years ago. June 1846 and 1896. PMID- 8699109 TI - Prevalence of drugs and alcohol in autopsied homicide cases in St. John Parish, Louisiana. AB - This article presents a retrospective review of all autopsies conducted by the St. John Parish coroner's office between January 1992 and June 1995. The overall prevalence of illicit drugs or alcohol detectable in the autopsied homicide cases for that time period was 60%. Cocaine was the most prevalent substance, detected in 40% of homicide victims. This study also describes a preponderance of firearm violence among homicide cases, and an overrepresentation of young black men with detectable blood levels of drugs or alcohol at time of death. The data from this rural/suburban parish closely parallels that collected from larger urban areas in recent years. These trends in less urban areas will likely further come to resemble those in large cities, and continue to tax health care and community service resources. PMID- 8699110 TI - Mortality experience among Louisiana chemical manufacturing employees, 1957-1992. AB - A cohort mortality study was undertaken of persons ever employed at BASF's Geismar, Louisiana chemical manufacturing facilities for 3+ months prior to 1992. The 1,870 men and 263 women employees were traced through 1992 (99% follow-up) using employment and pension records, National Death Index searches, social security record matching, and credit bureau checks. Death certificates were obtained and coded for 92% of the 128 decedents. Overall and total cancer deaths among short-term ( < 10 years of site employment) and long-term hourly and salaried employees were fewer than expected based on comparisons to US general population death rates. Deaths due to external causes were higher than expected among short-term hourly employees (23 observed compared to 16 expected deaths). Among all employees, three accidental deaths occurred at work, the most recent in 1981. Four deaths each, due to urinary and brain cancers, exceeded expectation; however, there was no pattern of job assignments suggesting a work-related etiology for these occurrences. PMID- 8699111 TI - HIV, TB, and mental illness in a health clinic for the homeless. AB - The authors reviewed the medical records of both mentally ill and non-mentally ill patients in a clinic for the homeless population of New Orleans. The records of all psychiatric patients (n = 52) and a randomly selected comparison group (n = 236) of clinic patients without mental illness were chosen for review. Five of the 52 homeless mentally ill who were tested for HIV had a positive test (9.6%), as did 7 of the 129 homeless people without mental illness (5.4%). Regarding TB, only 5 of the 29 mentally ill tested for TB were PPD positive (17.2%), as compared to 34 (29.3%) of the non-mentally ill, a strong trend (r = 0.11, p = 0.09). Differing trends were found regarding HIV and TB in the two homeless groups under study. Further work with a larger sample is needed to determine the factors, if any, which facilitate the spread of HIV and inhibit that of TB. PMID- 8699112 TI - The nerve growth factor/tumor necrosis factor receptor family. AB - Receptors in the nerve growth factor/tumor necrosis factor receptor family are characterized by the presence of cysteine-rich motifs of approximately 40 amino acids in the extracellular domain. The ligands are type II transmembrane proteins with beta-strands that form a jelly-roll beta-sandwich. The receptors recognize soluble or cell-surface-bound ligands and mediate diverse cellular responses. Activation of intracellular signals is mediated at least in part by the association of proteins with a RING finger motif or a death domain to the cytoplasmic domains of the receptors. In addition to cell-membrane-bound receptors soluble forms have been described for most of the receptors. Activation of intracellular signals not only occurs through ligand binding to the receptors but cross-linking of at least some members of the ligand family can regulate cell functions. PMID- 8699113 TI - Rat eosinophils: isolation and characterization of superoxide production. AB - Studies with isolated cells are important to the understanding of mechanisms by which eosinophils participate in allergic inflammation. Due to species variability, isolation techniques and cell biology need to be defined for each source. We developed methods to obtain rat eosinophils with purity and viability exceeding 90%, characterized the superoxide anion production of these cells in response to standard activators, and compared these results with those previously obtained in our laboratories with the use of human eosinophils. Rat eosinophils responded vigorously to phorbol myristate acetate and poorly to platelet activating factor and to N-formyl-methionyl-leucyl-phenylalanine, parallel to the responses of human eosinophils. In contrast, rat eosinophils responded unlike human eosinophils to other activators, having a larger response to calcium ionophore A23187, a smaller response to serum-treated or serum-opsonized zymosan, and a negative rather than positive modulatory effect of cytochalasin B. We conclude that rat eosinophils can be obtained in high purity and with intact responsiveness to a number of different activators. PMID- 8699114 TI - CD66a, CD66b, CD66c, and CD66d each independently stimulate neutrophils. AB - Four members of the carcinoembryonic antigen family, CD66a, CD66b, CD66c, and CD66d, are expressed on human neutrophils. In neutrophils these proteins are activation antigens in that their surface expression is increased following stimulation. To examine their potential role in neutrophil signaling, the effects on neutrophil adhesion to human umbilical vein endothelial cells of a panel of well-characterized CD66 mAbs was tested. CD66a, CD66b, CD66c, and CD66d antibodies each increased neutrophil adhesion to human umbilical vein endothelial cell monolayers. This increase in neutrophil adhesion caused by CD66 antibodies was blocked by a CD18 antibody and associated with up-regulation of CD11/CD18 on the neutrophil surface. This increase in neutrophil adhesion required physiological extracellular calcium concentrations at or near the time of CD66 antibody binding to the neutrophil. The incubation of CD66 antibodies with neutrophils in the absence of calcium for 10 min before repletion of calcium resulted in no increase in neutrophil adhesion. The data suggest that CD66a, CD66b, CD66c, and CD66d antibody binding to the neutrophil surface triggers a transient activation signal that requires extracellular calcium and regulates the adhesive activity of CD11/CD18. Sequential desensitization experiments indicated that CD66a, CD66b, CD66c, and CD66d can each independently transmit signals in neutrophils. PMID- 8699115 TI - Effects of fungal beta-glucan and interferon-gamma on the secretory functions of murine alveolar macrophages. AB - We investigated the effect of a fungal component, soluble beta-glucan, on secretory functions of murine alveolar macrophages (AMs) in vitro. Stimulation by beta-glucan (500 microg/mL) or interferon-gamma (IFN-gamma; 100 U/mL) alone had a slight effect on AM functions, but when AMs were incubated together with beta glucan and IFN-gamma, the production and secretion of some immune mediators, such as nitric oxide, interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF alpha), were markedly augmented. This combined effect of beta-glucan and IFN gamma was based on a priming effect of IFN-gamma, because prestimulation with IFN gamma followed by beta-glucan induced high nitric oxide production of AMs, but reversal of the sequence of treatments had only a slight effect. We also found that preincubation of AMs with IFN-gamma enhanced the binding of fluorescein labeled beta-glucan on the AM surface, and this increased binding was abrogated to the control level by the addition of three species of soluble unlabeled (1- >3)-beta-D-glucans but not by soluble alpha-glucan. These data imply that the priming effect of IFN-gamma on the AM response to beta-glucan was dependent, at least in part, on the enhancement of beta-glucan specific binding sites on the AM surface. It was suggested that IFN-gamma is one of the principal factors controlling the pulmonary immune system against both severe fungal infection and inflammation via AM activation at the alveoli. PMID- 8699116 TI - Cytokines induced by Sendai virus in human peripheral blood leukocytes. AB - Human peripheral blood leukocytes (hPBL) are a rich source of natural leukocyte interferon (IFN-alpha) when treated with Sendai virus. Sendai virus treatment of hPBL will also result in significant production of several chemokines and cytokines such as macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, RANTES, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-8, in a time-dependent way. A significant amount of MCP-1 is constitutively produced in overnight culture of leukocytes. The most abundant cytokine is IFN-alpha, which is induced to its maximum level approximately 11-15 h after addition of Sendai virus. The amount of IFN-alpha induced at 15 h after Sendai virus treatment is more than 16-fold higher than those of MIP-1alpha, MIP-1beta, and RANTES. IFN-alpha is also induced more than 60-fold higher than TNF-alpha and IL 8. The amount of IL-6 induced is approximately 400-fold less than IFN-alpha. Limited amounts of other cytokines such as IL-1alpha, IL-1beta, macrophage colony stimulating factor, TNF-beta, and IFN-gamma are also induced in Sendai virus treated hPBL. No measurable amount of granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, leukemia inhibitory factor, IL-2, IL-3, IL-4, IL-5, IL-7, IL-10, IL-11, or IL-12 was induced in the supernatant of Sendai virus-treated hPBL. PMID- 8699117 TI - Focal effects of mononuclear leukocyte transendothelial migration: TNF-alpha production by migrating monocytes promotes subsequent migration of lymphocytes. AB - In many inflammatory diseases, mononuclear leukocytes (MNLs) accumulate as focal infiltrates in perivascular spaces. We postulated that MNLs migrating through endothelium modify the microenvironment to promote the subsequent migration of additional MNLs into the same area. We found that as monocytes adhere to and migrate spontaneously through an endothelial monolayer, they secrete tumor necrosis factor-alpha (TNF-alpha) and interleukin-1. These cytokines stimulate endothelial cell expression of CD54 (intercellular adhesion molecule-1) and CD106 (vascular cell adhesion molecule-1). Consequently, when freshly isolated MNLs are added to that endothelial monolayer four or more hours later, significantly greater numbers of lymphocytes bind to and migrate through these endothelial monolayers. In addition to its ability to activate endothelial cell adhesion molecules, TNF-alpha induced directed migration of lymphocytes through collagen pads. These results illustrate a potential amplification mechanism by which MNLs moving through a vessel wall may secrete TNF-alpha, leading to the recruitment of additional leukocytes into the same perivascular locus. PMID- 8699118 TI - Constitutive expression of specific interferon isotypes in peripheral blood leukocytes from normal individuals and in promonocytic U937 cells. AB - Constitutive expression of IFN-alpha5 and IFN-beta was detected in different lymphoid cells including peripheral blood mononuclear cells from normal individuals following amplification of IFN mRNA by reverse transcriptase polymerase chain reaction and direct sequencing of the amplified product. The activated form of the interferon-induced transcription factor complex ISGF3 was also detected in nuclear extracts from uninduced cells. Culture supernatants from uninduced U937 cells were also found to activate an ISRE cloned upstream of the luciferase reporter gene, indicating the presence of endogenous IFN activity equivalent to approximately 0.3 to 0.5 IU/mL. This endogenous IFN was also shown to play a role in maintaining the basal level of expression of the major histocompatibility class I genes in lymphoid cells. These results suggest that IFN-alpha5 and IFN-beta are produced at low levels in normal tissues and play an important role in the regulation of cell function and in the maintenance of homeostasis. PMID- 8699119 TI - Cloning and functional expression of CC CKR5, a human monocyte CC chemokine receptor selective for MIP-1(alpha), MIP-1(beta), and RANTES. AB - We have cloned a human cDNA for a novel CC chemokine receptor (CC CKR) designated CC CKR5 that has 48-75% amino acid identity to other CC CKRs. CC CKR5 mRNA was detected constitutively in primary adherent monocytes but not in primary neutrophils or eosinophils. Macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and RANTES were all potent agonists for CC CKR5 (EC50 = 3-30 nM) when calcium flux was measured in transfected HEK 293 cells, yet the apparent binding affinities of the corresponding iodinated chemokines to intact cells expressing the receptor were low (IC50 approximately 100 nM). The calcium flux responses were completely blocked by treatment of transfected cells with pertussis toxin. These data suggest that CC CKR5 is a G(i)-coupled receptor that may mediate monocyte responses to MIP-1alpha, MIP-1beta, and RANTES. PMID- 8699120 TI - The inflammatory potential of IL-2: local induction of a specific chronic granulomatous lesion in mice. AB - Subcutaneous injection of recombinant human interleukin-2 (rhuIL-2) at 10(2) 10(4) U/mouse induced delayed (48 h) accumulation of mononuclear leukocytes with diffuse granulocytes, including eosinophils. Subcutaneous local infusion of rhuIL 2 or recombinant murine IL-2 (10(2)-10(4) U/mouse) via implanted Alzet miniosmotic pumps in mice induced chronic inflammatory lesions characterized by infiltration of large vacuolated mononuclear leukocytes, lymphoid cells, and eosinophil foci; neovascularization, with high endothelial-like cells, was prominent, exhibiting intravascular trapping and migration of large mononuclear leukocytes. Leukocyte infiltrates comprised T lymphocytes (CD4+; CD8+), B lymphocytes, and macrophages. Control infusions of bovine serum albumin (BSA) induced weak fibrotic lesions with sparse macrophage infiltration and minimal accumulation of lymphocytes; VLA4+ and ICAM-1+ leukocyte infiltrates were significantly greater in IL-2-induced lesions compared with BSA-induced lesions. Quantitative image analysis showed significantly increased lesion size in the IL 2-induced lesions compared with those induced by BSA infusion. The vascularity of IL-2-induced lesions assessed by immunostaining for platelet-endothelial cell adhesion molecule was increased compared with control, BSA-induced lesions mainly due to neovascularization. ICAM-1 and VCAM-1 expression was significantly enhanced in IL-2 lesions. No systemic pathological changes were observed following IL-2 infusion. We conclude that local slow-release of IL-2 causes the evolution and maintenance of a specific chronic inflammatory lesion. PMID- 8699121 TI - Effects of spaceflight on rat peripheral blood leukocytes and bone marrow progenitor cells. AB - The white blood cell (WBC) elements and the bone marrow myeloid progenitor cell populations were analyzed to ascertain adaptation to micro-gravity and subsequent readaptation to 1 G in rats flown on the 14-day Spacelab Life Sciences-2 (SLS-2) mission. Bone marrow cells were harvested from one group of rats killed inflight (FD13) and blood was drawn from three other groups at various times. The WBC level was normal on FD14 with the exception of neutrophilia. On FD13, numbers of colony-forming units-granulocyte (CFU-G), CFU-GM, and CFU-M from flight animals were decreased compared with ground controls when incubated with recombinant rat interleukin-3 (rrIL-3) alone or in combination with recombinant human erythropoietin (rhEpo). On recovery (R + 0), flight rats had decreased numbers of total leukocytes and absolute numbers of lymphocytes and monocytes with elevated neutrophils compared with control rats. They had lower numbers of CD4, CD8, CD2, CD3, and B cells in the peripheral blood but no differences in spleen lymphocytes. PMID- 8699122 TI - The inflammatory macrophage response to MCMV in mice with a retroviral immunodeficiency syndrome (MAIDS). AB - We have shown that normal C57BL/6J mice are moderately resistant to infection with murine cytomegalovirus (MCMV) and that this resistance is impaired by prior infection with LP-BM5 MuLV, which causes a disease (MAIDS) similar to early HIV induced disease. This study investigates macrophage function in MAIDS+ mice challenged with MCMV. MAIDS reduces the influx of cells into the peritoneal cavity seen in normal C57BL/6J mice 6 days after MCMV infection. The infiltrates contained cells that resembled activated macrophages, as they took up colloidal gold, expressed the macrophage marker Mac-1, had high levels of acid phosphatase activity, and were lymphocytostatic when co-cultured with activated T cells. MAIDS+ mice had a higher percentage of cells able to take up colloidal gold and higher acid phosphatase activity per cell. The cells were also more lymphocytostatic and produced higher levels of interleukin-1 and tumor necrosis factor-alpha on days 4 and 6 after MCMV infection. Hence, MAIDS enhances baseline and induced macrophage activity, but depresses infiltration into the site of inflammation. PMID- 8699123 TI - Interleukin-10 inhibits interleukin-2-induced tumor necrosis factor production but does not reduce toxicity in C3H/HeN mice. AB - Immunotherapy with interleukin-2 (IL-2) is limited by severe side effects thought to be mediated by the activation of immune effector cells and the induction of secondary cytokines including tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). In C3H/HeN mice the primary IL-2 toxicity is the production of pleural effusion with subsequent respiratory compromise. IL-10 is a cytokine that has been shown to inhibit the generation of secondary cytokines in vitro and in vivo. In this study, in C3H/HeN mice, we tested the ability of IL-10 to inhibit IL-2-induced mononuclear cell and alveolar macrophage activation and IL-2-induced increases in serum TNF-alpha and IFN-gamma, all of which may contribute to the generation of toxicity. IL-10 was ineffective at reducing IL-2 induced pleural effusion. However, IL-10 did inhibit IL-2-induced increases in serum TNF-alpha, which was accompanied by a decrease in Golgi apparatus and rough endoplasmic reticulum in alveolar macrophages. In addition, IL-10 combined with IL-2 increased mononuclear cell activation, which may limit the ability of IL-10 to inhibit IL-2-induced IFN-gamma production and pulmonary injury. PMID- 8699124 TI - Platelets enhance Fc(gamma) receptor-mediated phagocytosis and respiratory burst in neutrophils: the role of purinergic modulation and actin polymerization. AB - The interaction of platelets with neutrophil granulocytes is considered to play an important role in the inflammatory process, and the present study was focused on platelet-induced modulation of Fcgamma receptor-mediated functions in neutrophils. We found that phagocytosis and the respiratory burst (measured as luminol-enhanced chemiluminescence), triggered in neutrophils by immunoglobulin G (IgG)-opsonized yeast particles, were potentiated by platelets and that maximal enhancement was achieved at a physiological neutrophil/platelet ratio of about 1:50 to 1:100. Platelets both increased the intra- and extracellular generation of oxygen radicals as well as the release of myeloperoxidase from stimulated neutrophils. The presence of platelets also induced a cortical actin polymerization in neutrophils, which might explain the increased phagocytic capacity. Platelets appear to affect neutrophil function in a contact-independent manner that most likely involves ATP, indicated by the following: (1) platelet supernatants, but not fixed platelets, affected neutrophil function in the same way as viable platelets; (2) platelets raised the extracellular ATP level four- to fivefold; (3) exogenous ATP mimicked the effects of platelets on actin polymerization, phagocytosis, and the respiratory burst in neutrophils; (4) hydrolysis of extracellular ATP with apyrase or blocking of ATP receptors with suramin reversed the platelet-induced enhancement of neutrophil function. An increased accumulation of extracellular adenosine, induced by inhibiting endogenous adenosine deaminase or adding exogenous adenosine, reversed the effects of platelets. The platelet-induced potentiation of the respiratory burst was inhibited by the tyrosine kinase inhibitor genistein, suggesting that tyrosine phosphorylation is involved. However, platelets did not significantly affect the Fcgamma receptor-triggered calcium response in neutrophils. In conclusion, we show that platelets, through an ATP-dependent mechanism, potentiate IgG-mediated ingestion and production of oxygen metabolites in neutrophils. PMID- 8699125 TI - Effect of spaceflight on human stem cell hematopoiesis: suppression of erythropoiesis and myelopoiesis. AB - Humans subjected to periods of microgravity develop anemia, thrombocytopenia, and abnormalities in red blood cell structure. The causes of these abnormalities are complex and unclear. The in vitro effects of spaceflight on hematopoietic cell proliferation and differentiation were investigated during the space shuttle missions STS-63 (Discovery) and STS-69 (Endeavour). CD34+ bone marrow progenitor cells were cultured in liquid suspension culture and on hematopoietic supportive stromal cells using hollow-fiber culture modules. One set of cultures was maintained at microgravity (flight cultures) for the last 8-10 days of culture and a second control was at full gravity (ground control). Over the 11- to 13 test-day period, ground control culture total cell number increased 41.0- to 65.5 fold but flight culture total cell number increased only 10.1- to 17.6-fold (57 84% decrease). Comparing ground control cultures and microgravity cultures, respectively, for progenitor cell content, myeloid progenitor cell numbers expanded 2.6- to 17.5-fold compared with 0.9- to 7.0-fold and erythroid progenitor cell numbers expanded 2.0- to 4.1-fold in ground control cultures but actually declined at microgravity (>83% reduction). Moreover, microgravity cultures demonstrated accelerated maturation/differentiation toward the macrophage lineage. These data indicate that spaceflight has a direct effect on hematopoietic progenitor cell proliferation and differentiation and that specific aspects of in vitro hematopoiesis, particularly erythropoiesis, involve gravity sensitive components. PMID- 8699126 TI - Effects of released products from platelets on neutrophilic adhesion to endothelial cells and nylon fibers. AB - In this study, the effects of platelet release products (PRPr), ATP, and ADP on the adhesion of human neutrophils to human umbilical vein endothelial cells (HUVEC) and nylon fibers (NF) are described and the implications of various adhesion molecules are considered. Adhesion of neutrophils to HUVEC and NF was increased by PRPr, ATP, and ADP, while their adhesion-increasing actions were cancelled or considerably repressed by apyrase treatment. When anti-CD11a or anti CD11b was added to neutrophils with PRPr, ATP, or ADP, the adhesion-increasing action was cancelled or considerably repressed. On the other hand, anti-ICAM-1 and anti-CD35 had no significant effects on this action. The above results indicated that platelets, through ATP and ADP in PRPr, increased the adhesion of neutrophils to endothelial cells and foreign bodies. Although it was suggested that the adhesion-increasing action was at least partially based on CD11a and CD11b, ICAM-1 and CD35 had no part in the enhancement of the adhesion. PMID- 8699127 TI - Endotoxin signal transduction in macrophages. AB - Through its action on macrophages, bacterial lipopolysaccharide (LPS) or endotoxin can trigger responses that are protective or injurious to the host. This review examines the effects of LPS on macrophages by following events from the cell surface to the nucleus. The involvement of protein tyrosine kinases, mitogen-activated protein kinases, protein kinase C, G proteins, protein kinase A, ceramide-activated protein kinase, and microtubules in this process are reviewed. At the nuclear level, rel, C/EBP, Ets, Egr, fos, and jun family members have been implicated in activation of LPS-inducible gene expression. PMID- 8699128 TI - Beta-1,2-linked oligomannosides inhibit Candida albicans binding to murine macrophage. AB - Interaction of Candida albicans with cells of the macrophage lineage was examined by using heat-killed (HK) and live yeast cells. Laminarin, an analogue of the cell wall beta-glucans, strongly inhibited HK yeasts adherence to J774 cell line but had no effect on live yeast binding. Phosphopeptidomannan (PPM) from Saccharomyces cerevisiae had a limited effect on the binding of both HK and live yeasts but significant inhibition was achieved by the use of C. albicans PPM. The role of beta-1,2-oligomannosides was examined with regard to their exclusive presence within C. albicans PPM. PPM acid labile beta-1,2-oligomannosides or a synthetic beta-1,2-mannotetraose, inhibited yeasts binding in a manner comparable to the original PPM. These latter results were confirmed by using mouse peritoneal macrophages, thus suggesting a general role for beta-1,2 oligomannosides in the adherence of the yeast to the macrophage membrane. PMID- 8699129 TI - Unidirectional heterologous receptor desensitization between both the fMLP and C5a receptor and the IL-8 receptor. AB - During inflammation neutrophils receive multiple signals that are integrated, allowing a single modified response. One mechanism for this discrimination is receptor desensitization, a process whereby ligand-receptor binding is disassociated from cell activation. We examined the effect of heterologous receptor desensitization on neutrophil chemotaxis, calcium mobilization, and arachidonic acid production, using interleukin-8 (IL-8), C5a, and N-formyl methionyl-leucyl-phenylalanine (fMLP). We observed reciprocal inhibition with respect to chemotaxis. We demonstrated that homologous desensitization, with respect to the mobilization of intracellular calcium stores, lasted approximately 15 min. Heterologous desensitization between the fMLP receptor and the C5a receptor was reciprocal; either stimulant would diminish the cells' response to stimulation by the other for approximately 3-5 min. However, we observed a unidirectional heterologous desensitization of the IL-8 receptor by both the fMLP and the C5a receptor. This unidirectional heterologous desensitization was observed with respect to both calcium mobilization and arachidonic acid production (i.e., prestimulation of the IL-8 receptor had no effect on subsequent stimulation by either fMLP or C5a). PMID- 8699130 TI - Modulation of neutrophil migration by exogenous gaseous nitric oxide. AB - We studied the effect of exogenous nitric oxide (NO) on migration of rabbit peritoneal neutrophils. Exogenous NO enhanced random migration of neutrophils in a concentration-dependent way. An optimally stimulatory effect was observed with 0.5 microM NO, whereas at higher NO concentrations the enhancing effect decreased again. NO caused a rapid and transient increase in intracellular guanosine-3',5' cyclic monophosphate (cGMP) levels. The enhancing effect of NO on random migration was largely reversed by the inhibitors of cGMP accumulation, LY-83583 and methylene blue, and by the antagonists of cGMP-dependent protein kinase, 8 bromoguanosine-3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-8-Br-cGMPS) and 8 (4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphorothioate (Rp-8-pCPT cGMPS). These observations strongly suggest that the enhancement of random migration by NO is mediated by cGMP and cGMP-dependent protein kinase. The effect of NO on migration did not occur in the absence of extracellular calcium. Although NO did not induce a measurable elevation of intracellular free calcium, pre-incubation with the intracellular calcium chelator Fura-2/AM abolished the enhancing effect of NO. It appears therefore that a small change in the level of cytoplasmic free calcium does play a role in the enhancement of random migration by NO. High concentrations of NO were found to inhibit chemotaxis induced by an optimal concentration of the chemotactic peptide N-formyl-methionyl-leucyl phenylalanine (fMLP). This inhibitory effect was also dependent on the presence of extracellular calcium. A role for cGMP in the inhibition of fMLP-induced chemotaxis by NO is not supported by our measurements of intracellular cGMP levels. In contrast to the effects on fMLP, NO did not affect chemotaxis induced by the phorbol ester PMA. In conclusion, we show that NO, not derived from NO donors but applied directly, may stimulate or inhibit neutrophil migration, dependent on the concentration. The enhancing effect of NO on random migration is mediated by cGMP, which emphasizes the importance of this second messenger as a modulator of neutrophil functional. PMID- 8699131 TI - Growth hormone-releasing factor expression is discordantly regulated in the hypothalamus and testis of streptozotocin-diabetic rats. AB - Growth hormone-releasing factor (GRF) mRNA expression in male rats occurs predominantly in the hypothalamus (mainly in the arcuate nucleus), and among extraneural sites primarily in the testis. Hypothalamic GRF is the physiological tropic stimulus to growth hormone secretion. However, the role of GRF in the testis is unknown. We have shown previously that hypothalamic GRF mRNA expression is significantly reduced in streptozotocin (STZ)-diabetic rats. This reduction is confined to the arcuate nucleus and probably accounts for the suppression of growth hormone pulsatility. The present studies were performed to evaluate GRF expression in the testis of streptozotocin (STZ)-diabetic rats. Diabetes was induced by injection of STZ (100 mg/kg i.p.). Seventeen to twenty days later diabetic rats were hyperglycemic compared with vehicle-injected controls and demonstrated growth failure. Insulin treatment reduced the glycemia and increased body weight towards normal. Total RNA was extracted from the hypothalamus and testis, and GRF mRNA levels estimated by solution hybridization/nuclease protection assay. Levels of hypothalamic somatostatin mRNA were measured to serve as control values. GRF mRNA was significantly (P < 0.001) decreased in the hypothalamus of STZ-diabetic rats (0.2 +/- 0.07 mean relative densitometric units, n = 8) compared with controls (1.0 +/- 0.19, n = 8) with no change in somatostatin mRNA expression. In contrast, testicular GRF mRNA was increased 70% (P < 0.05) in STZ-diabetic rats. Insulin treatment resulted in normalization of hypothalamic GRF mRNA levels (1.1 +/- 0.17, n = 5) with no effect on testicular GRF mRNA expression. In conclusion GRF gene expression is discordantly regulated in tissues of male STZ-diabetic rats. While reduced GRF expression may account for the low growth hormone state in this model, increased testicular GRF mRNA (with the previously reported reduction of insulin-like growth factor-I mRNA) resembles the response seen in growth hormone-sensitive tissue (especially the hypothalamus) to this growth hormone-deficient state. PMID- 8699132 TI - Effects of TRH, prolactin and TSH on cell proliferation in the intermediate lobe of the rat pituitary gland. AB - The effect of TRH on cell proliferation in the anterior lobe of the pituitary is well known and documented. On the other hand, there are no data on the effects of TRH on the intermediate lobe of the pituitary gland. The aim of this study was to investigate the effect of TRH and its analogues (pGlu-HIs-Gly, pGlu-His-Gly-NH2) on cell proliferation in the intermediate pituitary lobe. The bromodeoxyuridine technique was used to detect the proliferating cells. It was found that TRH stimulated cell proliferation 24 h after a single injection at a dose of 100 micrograms/kg body weight. The TRH analogues did not exert any significant stimulatory effect either 12 h or 24 h after the injection. The second experiment was carried out to distinguish the probable mechanism of the action of TRH. The effects of TSH and prolactin (PRL) on intermediate lobe cell proliferation were examined. It was found that both PRL and TSH exerted a significant stimulatory effect 24 h after a single s.c. injection of PRL at a dose of 150 IU/kg body weight or TSH at a dose 20 IU/kg body weight. It therefore appears that the stimulatory effect of TRH on intermediate pituitary lobe cell proliferation is mediated by PRL and TSH. PMID- 8699133 TI - The effects of GH-releasing peptide-6 (GHRP-6) and GHRP-2 on intracellular adenosine 3',5'-monophosphate (cAMP) levels and GH secretion in ovine and rat somatotrophs. AB - The mechanism of action of GH-releasing peptide-6 (GHRP-6) and GHRP-2 on GH release was investigated in ovine and rat pituitary cells in vitro. In partially purified sheep somatotrophs, GHRP-2 and GH-releasing factor (GRF) increased intracellular cyclic AMP (cAMP) concentrations and caused GH release in a dose dependent manner; GHRP-6 did not increase cAMP levels. An additive effect of maximal doses of GRF and GHRP-2 was observed in both cAMP and GH levels whereas combined GHRP-6 and GHRP-2 at maximal doses produced an additive effect on GH release only. Pretreatment of the cells with MDL 12,330A, an adenylyl cyclase inhibitor, prevented cAMP accumulation and the subsequent release of GH that was caused by either GHRP-2 or GRF. The cAMP antagonist, Rp-cAMP also blocked GH release in response to GHRP-2 and GRF. The cAMP antagonist did not prevent the effect of GHRP-6 on GH secretion whereas MDL 12,330A partially reduced the effect. An antagonist for the GRF receptor, [Ac-Tyr1,D-Arg2]-GRF 1-29, significantly diminished the effect of GHRP-2 and GRF on cAMP accumulation and GH release, but did not affect GH release induced by GHRP-6. Somatostatin prevented cAMP accumulation and GH release responses to GHRP-2, GRF and GHRP-6. Ca2+ channel blockade did not affect the cAMP increase in response to GHRP-2 or GRF but totally prevented GH release in response to GHRP-2, GRF and GHRP-6. These results indicated that GHRP-2 acts on ovine pituitary somatotrophs to increase cAMP concentration in a manner similar to that of GRF; this occurs even during the blockade of Ca2+ influx. GHRP-6 caused GH release without an increase in intracellular cAMP levels. GH release in response to all three secretagogues was reduced by somatostatin and was dependent upon the influx of extracellular Ca2+. The additive effect of GHRP-2 and GRF or GHRP-6 suggested that the three peptides may act on different receptors. In rat pituitary cell cultures, GHRP-6 had no effect on cAMP levels, but potentiated the effect of GRF on cAMP accumulation. The synergistic effect of GRF and GHRP-6 on cAMP accumulation did not occur in sheep somatotrophs. Whereas GHRP-2 caused cAMP accumulation in sheep somatotrophs, it did not do so in rat pituitary cells. These data indicate species differences in the response of pituitary somatotrophs to the GHRPs and this is probably due to different subtypes of GHRP receptor in rat or sheep. PMID- 8699134 TI - Effects of hormone replacement therapy on platelet membrane fatty acid composition. AB - Oestrogen replacement therapy has been shown to protect postmenopausal women from ischaemic heart disease, strokes and hypertension. The mechanism of protection conferred by oestrogen, although partly attributable to changes in serum lipoproteins, is not fully understood. The present study was undertaken to assess the effect of hormone replacement therapy on the composition of platelet membrane fatty acids in postmenopausal women. These were analysed by gas-liquid chromatography before and six weeks after continuous conjugated equine oestrogen therapy (0.625 mg daily) combined with cyclical therapy with 75 micrograms L norgestrel from day 17 to 28 of a 28-day cycle. Each subject acted as her own control. The principal findings of the study were that, following treatment, there was a 16.2% reduction in platelet membrane polyunsaturated fatty acids (P < 0.001), an increase of 9.1 and 7.1% in saturated fatty acids and monounsaturated fatty acids respectively (P < 0.001) and a 17.8% reduction in arachidonic acid (P < 0.003). There was no correlation between changes in membrane fatty acids and serum lipoproteins. This suggests that the changes in membrane composition noted in this study may be a primary effect of hormone replacement therapy, especially oestrogen. PMID- 8699136 TI - Relationship between calbindin-D28K levels in the A and B cells of the rat endocrine pancreas and the secretion of insulin and glucagon: influence of vitamin D3 deficiency and 1,25-dihydroxyvitamin D3. AB - The pancreatic B cell is equipped with specific receptors for 1,25 dihydroxyvitamin D3 (1,25-(OH)2D3) and contains vitamin D-dependent calcium binding proteins (calbindin-D). Insulin secretion is impaired by vitamin D deficiency and is restored by 1,25-(OH)2D3 (concomitantly with an improved calcium handling within B cells) but the effect of 1,25-(OH)2D3 on the pancreatic B cell via calbindin-D is unclear. Therefore we examined the relationship between calbindin-D28K or calbindin-D9K and the activity of the endocrine pancreas in normal (N), four week vitamin D-deficient (-D) and one week 1,25-(OH)2D3-replete (+D) rats. Calbindin-D9K was not found in the pancreas, neither in the islets nor in the exocrine part, of any of the groups of rats (N, -D, or+D). Surprisingly, total islet calbindin-D28K content was increased by vitamin D deficiency and partly restored by 1,25-(OH)2D3. Calbindin-D28K immunostaining was observed only on A and B cells in the endocrine part of the pancreas, the greatest staining being found in A cells. This difference in staining density was increased by vitamin D deficiency and decreased by 1,25-(OH)2D3 treatment. In vitro, 1,25 (OH)2D3 also produced a negative influence on calbindin-D28K staining in A cells, as demonstrated using pieces of pancreas incubated with the steroid for 2 h. No significant influence on labeling intensity of B cell calbindin-D28K could be shown. Plasma insulin and islet insulin release in response to 10 mM arginine stimulation were decreased in -D rats and enhanced in +D rats towards N values. In contrast, plasma glucagon and the amount of glucagon secretion, stimulated in vitro by 10 mM arginine or by low (1.7 mM) glucose concentration, was increased in -D rats and attenuated by 1,25-(OH)2D3. Thus there appears to be no relationship between the steady state level of B cell calbindin-D28K and the regulation of insulin secretion by 1,25-(OH)2D3 in vitamin D-deficient rats. However there is a correlation between A cell calbindin-D28K and glucagon secretion, which are both negatively regulated by 1,25-(OH)2D3. The predominance of calbindin-D28K in A cells raises the question as to how A and B cells interact and the role of calbindin-D28K in calcium handling. PMID- 8699135 TI - Inhibin and activin differentially regulate androgen production and 17 alpha hydroxylase expression in human ovarian thecal-like tumor cells. AB - Activin and inhibin are structurally related dimeric glycoproteins belonging to the transforming growth factor-beta superfamily of proteins which are synthesized and secreted by the granulosa cells of the ovary. Although initially characterized by their ability to influence FSH secretion from pituitary cells, paracrine regulatory roles of these factors on neighboring ovarian theca interna have been suggested. While inhibin has been shown to increase and activin to decrease the production of androgens, the mechanisms of action are not well defined, partly due to difficulties in obtaining adequate numbers of thecal cells from individual patients or animal models. Using a unique human ovarian thecal like tumor (HOTT) cell culture model system we investigated the biochemical and molecular mechanisms controlling C19 steroidogenesis and the effects of activin and inhibin on the activity and expression of key ovarian thecal steroidogenic enzymes, cholesterol side-chain cleavage cytochrome P450 (P450scc), 3 beta hydroxysteroid dehydrogenase (3 beta HSD) and 17 alpha-hydroxylase/17,20 lyase cytochrome P450 (P450c17). Steroid production, level of steroidogenic enzyme mRNA expression, and enzyme activity following treatment with forskolin, inhibin-A and activin-A were examined. Basal steroid production, enzyme activities, and steroidogenic enzyme mRNA levels were not markedly different following treatment with activin (25 ng/ml) or inhibin (25 ng/ml) alone. Forskolin (10 microM) markedly increased production of both androstenedione (fivefold) and progesterone (threefold) as well as the activity of 3 beta HSD (sevenfold), and P450c17 (sevenfold) over basal. Forskolin stimulated the expression of mRNA for P450scc (fourfold), 3 beta HSD (threefold), and P450c17 (eightfold) over basal. Androstenedione accumulation was decreased by 60% in the forskolin plus activin group compared with forskolin alone, while progesterone production was maintained. This was attributed to a reduction of P450c17 mRNA (45% of forskolin alone) and activity (45% of forskolin alone). In contrast, co-treatment with forskolin and inhibin increased androstenedione production by 40% while decreasing progesterone by 40% compared with forskolin alone. Concomitantly, this was associated with a higher P450c17 mRNA expression (1.5-fold) and activity (twofold) but with minimal effects on the mRNA for 3 beta HSD and P450scc. HOTT cell responses to activin (0.05-50 ng/ml) and inhibin (0.05-50 ng/ml) in the presence of forskolin demonstrated dose-dependent effects on the steroid accumulation, enzymatic activity and mRNA expression of P450c17. Additionally, the differences seen on mRNA expression of steroidogenic enzymes in response to these factors were time-dependent. In summary, forskolin stimulated C19 steroid production from HOTT cells by increasing the expression of all steroidogenic enzymes examined. Inhibin and activin exerted differential effects on the expression of these enzymes which resulted in alterations in the steroid profile toward production of C19 steroids in the case of inhibin and away from C19 steroids in the case of activin. The influence of these important intraovarian factors on the expression of P450c17, a pivotal enzyme in thecal cell production of C19 steroids, could impact greatly on the follicular milieu of a normal developing follicle as well as in pathophysiological disorders such as polycystic ovarian syndrome. PMID- 8699137 TI - Possible mechanism for the first response to short captivity stress in the water frog, Rana esculenta. AB - To clarify the endocrine mechanism involved in the short captivity stress in the water frog, Rana esculenta, the activity of 9-ketoreductase, the enzyme which converts prostaglandin E2 (PGE2) into prostaglandin F2 alpha (PGF2 alpha), and aromatase, which converts testosterone into oestradiol-17 beta, were studied. Adult male and female frogs were sacrificed 0, 1.5, 3, 6, 12, 24, 48, 72, 168 and 336 h after capture in the field. PGE2, PGF2 alpha, progesterone, testosterone, oestradiol-17 beta and corticosterone plasma levels were detected by RIA at each time point. 9-Ketoreductase (conversion of [3H]PGE2 into [3H]PGF2 alpha) and aromatase (conversion of [3H]testosterone into [3H]oestradiol-17 beta) activities in the brain, testis, ovary and interrenal were also determined at each time point. After capture, levels of plasma PGF2 alpha increased (male: 228%; female: 288%) and PGE2 decreased (male: 68%; female: 81%) at 1.5 h, oestradiol-17 beta increased (male: 399%; female: 425%) and testosterone decreased (male: 87%; female: 83%) at 6 h, and corticosterone increased (male: 421%; female: 426%) at 72 h. 9-Ketoreductase activity in the brain was enhanced at 1.5 h after capture (male: 249%; female: 262%); aromatase activity increased at 6 h in the testis (261%), ovary (273%) and interrenal (male: 227%; female: 267%). These results indicate that short captivity stress could induce an increase in plasma PGF2 alpha through activation of brain 9-ketoreductase. In turn, PGF2 alpha might enhance the levels of circulating oestradiol-17 beta through activation of gonadal and interrenal aromatase. PMID- 8699138 TI - Characterisation of acyltransferase activity in ovine placental tissue during pregnancy and at the time of labour. AB - Although it is well established that the formation of eicosanoids by ovine intrauterine tissues increases during pregnancy and at the time of labour, the biochemical mechanisms involved remain to be clearly established. In this study, we tested the hypothesis that the gestational and labour-associated increases in eicosanoid formation are associated with a reduction in the activity of the reacylating enzyme, acyl Coenzyme A lysophosphatide acyltransferase (LAT). To evaluate this proposal, in vitro LAT activity was quantified in ovine placenta (cotyledons) obtained during pregnancy (85-147 days of gestation and at the time of labour). Ovine placental LAT increased from 1.81 +/- 0.06 nmol/min per mg protein at 85 days of gestation to 2.34 +/- 0.10 nmol/min per mg protein at 142 days of gestation (P < 0.005; n = 15). The apparent Km did not vary significantly between the 85- and 142-day groups. Vmax, however, was significantly greater in the late-gestation group (2.98 +/- 0.02 nmol/min per mg protein) than in the mid gestation group (2.38 +/- 0.13 nmol/min per mg protein, P < 0.05). In association with labour, placental LAT activity decreased by 16% (1.96 +/- 0.13 nmol/min per mg protein) when compared with that observed in tissue obtained from the non labouring ewe (P < 0.01). The data obtained are consistent with the hypothesis that changes in LAT activity in ovine placenta do not contribute to the gestational increase in prostaglandin formation, but a contribution to the labour associated increase in non-esterified arachidonic acid availability and eicosanoid formation cannot be negated. PMID- 8699139 TI - Ontogeny of GH receptor and GH-binding protein in the pig. AB - The present study was undertaken to examine the developmental pattern of GH receptor (GHR) and GHR gene expression in skeletal muscle (longissimus dorsi and trapezius (TR)) and liver from the last third of gestation until 1 year of age in male Large White (LW) and Meishan (MS) pigs. Plasma GH-binding protein (GHBP) levels were also measured. 125I-Labelled bovine GH (bGH) specific binding (not determined in foetal TR) and GHR mRNA were detected in skeletal muscle from 75 days of gestation until the adult stage with no clear age-related changes. By contrast, 125I-labelled bGH specific binding and GHR mRNA were undetectable or barely detectable in foetal liver. After birth, 125I-labelled bGH specific binding (P < 0.001) and GHR mRNA in liver increased with age. The level of bGH binding to liver membranes was higher in MS than in LW pigs at 1, 45, 80 and 120 days of age and did not differ between breeds at the other ages. Specific binding of 125I-labelled human GH (hGH) to plasma GHBP was easily detected as early as 75 days of gestation and increased with age (P < 0.001). The level of hGH binding to plasma GHBP was higher in MS than in LW pigs at 1, 80 and 120 days of age. It can be concluded that (1) the developmental expression of the GHR is tissue-specific, (2) the presence of GHBP in foetuses despite the absence of GHR in liver suggests that other tissues such as skeletal muscle could contribute to the generation of GHBP and (3) the presence of GHR in skeletal muscle as early as 75 days of gestation suggests that GH may play a role in foetal muscle growth. PMID- 8699140 TI - Vitamin A is involved in estrogen-induced cell proliferation but not in cytodifferentiation of the chicken oviduct. AB - We examined vitamin A-deficient chicks to determine whether vitamin A affects the estrogen-induced development of the chick oviduct. When oviduct development was stimulated for 5 days with the synthetic estrogen, diethylstilbestrol, the wet weight of the oviduct in vitamin A-deficient chicks was only half that in control chicks. The DNA content in this tissue showed that the decreased oviduct weight in the vitamin A-deficient chicks was caused by the decreased proliferation of oviduct cells. However, the estrogen-induced expression of the ovalbumin gene was not affected by the vitamin A deficiency, suggesting that estrogen-induced cytodifferentiation is not affected by vitamin A. To clarify the vitamin A action on estrogen-induced development in the oviduct, transcripts of nuclear estrogen receptor (ER) and all-trans-retinoic acid (RAR alpha, beta and gamma) receptors, which exert the effects of estrogen and vitamin A, were measured. The ER, RAR alpha and RAR beta genes, but not that of RAR gamma, were expressed during oviduct development, indicating that estrogen and vitamin A may control the expression of target genes through their cognate receptors. Thus, we have shown that vitamin A is involved in estrogen-induced cell proliferation but not in cytodifferentiation of the chicken oviduct. PMID- 8699141 TI - Development and application of a two-site enzyme immunoassay for the determination of 'total' activin-A concentrations in serum and follicular fluid. AB - The performance of existing immunoassays and bioassays for activins is compromised by the presence of activin-binding proteins such as follistatin and alpha 2 macroglobulin (alpha 2M) in biological fluids. To overcome this problem we have developed a novel two-site enzyme immunoassay procedure for activin-A which incorporates an analyte denaturation and oxidation step. The optimized assay is sensitive (detection limit approximately 10 pg/well), precise (mean within- and between-plate coefficients of variation 4.9 and 9.1% respectively) and accurate (activin-A recovery values of 102 +/- 3 and 96 +/- 5% for bovine follicular fluid (FF) and human serum respectively). In specificity tests, high concentrations of follistatin (500 ng/ml) and alpha 2M (100 microgram/ml) did not interfere with the response signal to activin-A. In addition, no significant cross-reactivity was observed with a range of related molecules including inhibin A, inhibin-B, activin-B (all < 0.5%), bovine pro-alpha C and follistatin (both < 0.1%). Response curves parallel to the activin-A standard curve were obtained for a variety of test samples including bovine, human, ovine and porcine FF, human sera and conditioned medium from cultured bovine and human granulosa cells. Fractionation of bovine FF by SDS-PAGE confirmed assay specificity since only one peak of activin-A immunoreactivity was detected (M(r) approximately 25 k) in eluted gel slices. However, gel-permeation chromatography showed that under physiological conditions all of the detectable activin-A in bovine FF eluted with apparent M(r) values of > 700 and 60-200 k reflecting its association with binding protein(s). Analysis of bovine FF samples (n = 76) from morphologically dominant follicles during the luteal phase showed that activin-A levels were positively correlated with inhibin-A (r = +0.54; P < 0.001) and total beta subunit immunoreactivity (r = +0.32; P < 0.005) but not with total alpha subunit immunoreactivity (r = -0.09). Classification of these follicles according to oestrogenic status showed that activin-A, inhibin-A and total beta subunit levels were highest in oestrogen-inactive follicles (P < 0.01) whereas total alpha subunit levels were lowest in these follicles (P < 0.001). Activin-A levels were measurable in all human serum samples analysed, ranging from 128 pg/ml during the normal menstrual cycle, 210 pg/ml in women undergoing ovarian hyperstimulation and approximately 500 pg/ml in postmenopausal women to over 4000 pg/ml during pregnancy. In conclusion, the present assay provides a reliable method for quantitating total (i.e. bound+free) activin-A concentrations in a variety of biological samples and should prove useful for further in vivo and in vitro studies in a range of species including man. PMID- 8699142 TI - Peripheral and ovarian IGF-I concentrations during the ovine oestrous cycle. AB - IGF-I was measured by RIA in plasma samples collected 8-hourly for 24 days which included two consecutive preovulatory surges of LH. In a separate study, ovarian venous blood was collected from animals undergoing ovariectomy on day 10 of the oestrous cycle, or 36 h later after being treated with prostaglandin with or without steroid-free bovine follicular fluid. Jugular venous blood samples were collected before, during and after surgery. Follicles were dissected from ovaries of these animals and sorted into categories of small, intermediate and large, non atretic or atretic, and the follicular fluid was pooled and assayed for IGF-I. From another population of ovaries recovered from the slaughterhouse, granulosa, theca and corpora lutea were isolated, homogenized and assayed for IGF-I. Finally ovarian corpora lutea and granulosa cells were each incubated with tritiated amino acids overnight at 37 degrees C. Thereafter the tissues and media were sonicated, IGF-I extracted from the supernatant and tritiated IGF-I precipitated using a specific IGF-I antibody. The absence of any significant change in peripheral IGF-I concentrations following ovariectomy and the finding that the ovarian venous IGF-I concentrations (161 +/- 10 micrograms/l) were not significantly different from levels seen in peripheral blood (157 +/- 10 microgram/l) indicated that the ovary is not a net exporter of IGF-I. However, the ovary does synthesize IGF-I, as evidenced by granulosa and luteal synthesis, but probably not in quantities in excess of that utilized by ovarian tissues per se. Although the plasma IGF-I levels increased around the second preovulatory LH surge, the results overall indicated that the IGF-I concentrations in plasma are not strictly related to any major ovarian event during the oestrous cycle in the sheep. This view is based on the findings that the concentration of IGF-I in follicular fluid was not related to follicular health but correlated with those in peripheral plasma and that the ovarian venous concentrations did not vary between left and right ovaries irrespective of whether the ovaries contained a corpus luteum, dominant follicle or neither. Collectively, these results are consistent with the notion that IGF-I of ovarian origin fulfils an autocrine/paracrine function and does not have an endocrine role. Moreover, the results show that the concentrations of IGF-I in follicular fluid reflect those in peripheral plasma. PMID- 8699143 TI - Prolactin- and testosterone-induced inhibition of LH secretion after orchidectomy: role of catecholaminergic neurones terminating in the diagonal band of Broca, medial preoptic nucleus and median eminence. AB - Central catecholaminergic neurones projecting to specific hypothalamic structures are involved in stimulating and inhibiting the activity of the GnRH-containing neurosecretory neurones. Both testosterone and elevated circulating prolactin (PRL) levels inhibit postcastration LH release. Three groups of adult male rats were orchidectomized and adrenalectomized, received corticosterone replacement and were: (i) administered purified ovine PRL (oPRL; 2400 microgram/s.c. injection) or (ii) its diluent, polyvinylpyrrolidone (PVP), every 12 h, or (iii) received physiological testosterone replacement for 2 days. At 0, 2 and 6 days postcastration, norepinephrine (NE), epinephrine (E) and dopamine (DA) turnover were estimated by the alpha-methyl-p-tyrosine method in three micro-dissected hypothalamic structures: the diagonal band of Broca at the level of the organum vasculosum of the lamina terminalis (DBB(ovlt)), the medial preoptic nucleus (MPN) and the median eminence (ME). In control (PVP-treated) rats, serum LH concentrations increased eightfold at 2 and 6 days postcastration and this rise was prevented by testosterone. oPRL treatment transiently suppressed LH secretion at 2 but not 6 days postcastration. Castration significantly decreased basal rat PRL (rPRL) levels at 2 and 6 days and testosterone administration partially prevented this effect. NE turnover in the ME and E turnover in the MPN increased markedly at 2 and 6 days postcastration, and testosterone replacement for 2 days prevented these increases. Thus, noradrenergic neurones innervating the ME and adrenergic neurones innvervating the MPN may drive postcastration LH secretion by providing stimulatory afferent input to the GnRH neurones. It was striking to observe that oPRL blocked the increases in both ME NE and MPN E turnover at 2 but not 6 days postcastration. Hence, oPRL may transiently suppress LH release by an inhibitory action on these NE and E neurones. DA turnover in the DBB(ovlt) was significantly decreased by 6 days postcastration. Testosterone-treated (2 days postcastration) and oPRL-treated (2 and 6 days postcastration) rats exhibited turnover values indistinguishable from day 0 controls. Hence, the A14 dopaminergic neurones, which synapse on GnRH neurones in the rostral preoptic area and may exert an inhibitory effect on them, are positively regulated by PRL and perhaps by testosterone as well. Autoregulatory feedback suppression of endogenous rPRL secretion by oPRL was observed both 2 and 6 days postcastration. In contrast to the A14 dopaminergic neurones, turnover in the A12 tuberoinfundibular dopaminergic (TIDA) neurones innervating the ME increased significantly by 6 days postcastration in control rats while oPRL administration further increased ME DA turnover at both 2 and 6 days. Hence, autofeedback regulation of rPRL secretion persists through at least 6 days of oPRL exposure temporally associated with markedly increased turnover in the TIDA neurones. In summary, our results support the hypothesis that the inhibitory effect of PRL on postcastration LH release is mediated by suppression of the activity of NE neurones innervating the ME and E neurones terminating in the MPN which, with time, become refractory to continued PRL exposure. PMID- 8699144 TI - Circulating levels of IGF-I and IGF-binding protein-1 throughout pregnancy: relation to birthweight and maternal weight. AB - Serum levels of IGF-I and IGF-binding protein (IGFBP-1) have been determined in the maternal circulation between 11 and 42 weeks of gestation in women not in labour (n = 335) and in the maternal and fetal circulations at the time of delivery between 37 and 42 weeks (n = 55). Maternal serum (MS) IGF-I levels increased during pregnancy and showed a significant positive correlation with maternal weight (P = 0.0033) but no correlation with birthweight. The MS IGFBP-1 levels did not change during the second and third trimesters and showed a negative correlation with birthweight, maternal weight, placental weight and MS glucose (P = 0.0002, P < 0.0001, P = 0.047, P = 0.024 respectively). MS IGFBP-1 levels were higher in small-for-gestational age babies than in average-for gestational weight babies (P = 0.026) and lower in the large-for-gestational weight group (P = 0.048). There was a significant rise in mean MS IGFBP-1 levels during labour (P = 0.0005). These findings suggest that IGFBP-1 may be an important factor in pathological growth retardation. PMID- 8699145 TI - Pressor doses of angiotensin II increase hepatic glucose output and decrease insulin sensitivity in rats. AB - The metabolic effects of angiotensin II (AII) were studied under steady-state conditions of euglycaemic hyperinsulinaemia in anaesthetized rats. Pressor doses of AII (50 and 400 ng/kg per min) had dose-dependent hypertensive and hyperglycaemic effects during glucose clamp studies. Glucose turnover measurements showed that hepatic glucose output (HGO) increased equally at both pressor doses compared with either saline infusion or AII infusion at a dose without a pressor effect (20 ng/kg per min); however, glucose disposal increased significantly only at 50 ng/kg per min. Infusion of the AII receptor antagonist, saralasin, did not itself alter glucose output or disposal significantly, but it abolished the effects of a simultaneous infusion of AII. It is concluded that pressor doses of AII increase HGO by a receptor-mediated mechanism that is not related to the pressor response to the hormone. The hyperglycaemic reaction to this metabolic effect of AII is partially offset by increased glucose disposal at lower doses. The physiological significance of these metabolic actions of AII remains to be established, but they raise the possibility that AII could potentially play a role in glucose homeostasis in vivo. PMID- 8699146 TI - Identification of epidermal growth factor-secreting cells in the anterior pituitary of lactating female rats. AB - Epidermal growth factor (EGF) is synthesized and secreted by mammalian anterior pituitary cells. It stimulates GH and prolactin (PRL) secretion, but the cellular origin of EGF is relatively unexplored. The objective of this study was to characterize the cells that secrete EGF in the anterior pituitary of lactating rats. An EGF reverse haemolytic plaque assay (RHPA) was used to identify EGF secreting cells and this RHPA was combined with immunofluorescence using antibodies to the six major adenohypophysial hormones (i.e. PRL, GH, LH, FSH, TSH and ACTH). Approximately 20% (20.33 +/- 2.96%) of the cells in the pituitary of lactating rats secrete EGF. The EGF-secreting cell population was composed of the following labelled cells: PRL (27%), GH (20%), LH (18%), FSH (14%), TSH (14%) and ACTH (5%). The present study showed that EGF is released by a subpopulation of anterior pituitary cells composed of all the classic hormone-containing cells. PMID- 8699148 TI - Regulation of type 1 insulin-like growth factor (IGF) receptors and IGF-I mRNA by age and nutrition in ovine skeletal muscles. AB - The relative abundance and location of type 1 IGF receptors in sheep muscles have been measured to determine whether changes occur during post-natal growth and nutritional stress. Using the technique of histological autoradiography, specific binding of 125I-IGF-I in muscle fibre and connective tissue of M. biceps femoris and M. gastrocnemius was demonstrated, as was specific binding to the tendon of M. gastrocnemius and the surrounding connective tissue. The binding site in both muscles was characterised as the type 1 IGF receptor in membrane preparations using competitive binding assay and SDS-PAGE. Type 1 receptors were more abundant in connective tissue than muscle fibre or tendon (P < or = 0.001). Levels changed significantly with age in all tissues (P = 0.054 to P < or = 0.001), while change as a result of fasting was limited to a receptor increase in the connective tissue of M. gastrocnemius (P = 0.034). IGF-I mRNA in M. biceps femoris, as assessed by in situ hybridisation, showed changes in expression with increasing age (P < or = 0.025) but no change with fasting. These data indicate that the distribution, relative abundance and nutritional sensitivity of type 1 receptors are related to cell type in vivo. The overall decline of receptors with increasing age may be a feature of transition from linear animal growth to cell maintenance in adult animals. Connective tissue appears to be more sensitive than muscle fibre to nutrition, possibly allowing the reduction of non-essential metabolism during fasting. PMID- 8699147 TI - Studies on the role of TRH and corticosterone in the regulation of prolactin and thyrotrophin secretion during lactation. AB - This study describes the effects of litter size and acute suckling on the synthesis and release of hypothalamic TRH, as indirectly estimated by determination of hypothalamic prothyrotrophin-releasing hormone (proTRH) mRNA and median eminence TRH content. The effects of litter size (five or ten pups) were studied throughout lactation, while suckling-induced acute changes were analyzed on day 13 of lactation in dams with ten pups. In view of the enhanced adrenal activity during lactation and recent evidence that corticosteroids have negative effects on hypothalamic TRH, we also studied adrenalectomized (ADX) dams treated with corticosterone to maintain basal plasma corticosterone levels. In addition to an increased plasma level of prolactin (PRL), adrenal weight and plasma corticosterone increased, while plasma TSH, tri-iodothyronine (T3), thyroxine (T4) and free T4 (FT4) levels decreased during lactation. Litter size correlated positively with plasma PRL, adrenal weight and plasma corticosterone. No effect of litter size was observed on plasma T3, but rats with ten pups had lower plasma TSH, T4 and FT4 than rats with a five-pup litter. Compared with dioestrous rats, lactating rats showed an increased hypothalamic proTRH mRNA content on day 2, but not on days 8 and 15 of lactation. Median eminence TRH in lactating rats gradually increased until day 15 and decreased thereafter. Acute suckling, after a 6-h separation of mother and pups, rapidly increased plasma PRL and corticosterone in the mothers, but had no effects on plasma TSH and thyroid hormone levels. Hypothalamic proTRH mRNA increased twofold after 0.5 h of suckling, and then gradually returned to presuckling values after 6 h. Compared with sham-operated rats, corticosterone-substituted ADX rats with ten pups had increased plasma PRL and TSH, hypothalamic proTRH mRNA and pituitary TSH beta mRNA on day 15 of lactation. Moreover, while acute suckling did not enhance TSH release in sham-operated rats, it provoked not only PRL but also TSH release in corticosterone-substituted ADX dams. It is concluded that suckling exerts a rapid, positive effect on hypothalamic proTRH mRNA content. However, the concurrent enhanced adrenal activity has negative effects on hypothalamic proTRH gene expression resulting in a suppressed hypophysial-thyroid axis during lactation. While TRH appears to play a role in PRL release during the first days of lactation and during acute suckling, TRH seems not important in maintaining PRL secretion during continued suckling. PMID- 8699149 TI - Characterization of the hypothalamo-pituitary-IGF-I axis in rats made obese by overfeeding. AB - Obesity is coupled to several disturbances of the endocrine axes. It has previously been shown that genetically obese Zucker male rats have an impaired secretion of growth hormone (GH), probably originating from a primary reduction of hypothalamic GH-releasing hormone (GHRH) function and resulting in a decrease of GH gene expression and release. We sought to evaluate the somatotropic function in another model of experimental obesity. Normal male Sprague-Dawley rats were fed an energy-rich highly palatable diet for 7 months until they reached body weights overlapping those reported for obese Zucker rats. They were then evaluated for different indices of the hypothalamo-pituitary-somatomedin-C (IGF-I) axis. At the end of the overfeeding period, rats were divided into overtly obese (obese group) and overweight (overweight group) rats according to the degree of overweight and the Obesity Lee Index, while rats fed ad libitum with the standard pellet chow served as controls. Acute administration of a supramaximal dose of GHRH (2 micrograms/rat i.v.) elicited a significantly (at least P < 0.05) lower plasma GH rise in the overweight and obese groups compared with the controls although no difference was seen in the pituitary GH content and gene expression and plasma concentrations of free IGF-I in the two experimental groups vs the controls. In addition, evaluation of hypothalamic GHRH and somatostatin mRNAs (slot-blot hybridization) did not show any significant differences between the three groups. Of the different metabolic indices investigated, plasma glucose and insulin concentrations were significantly (P < 0.01) higher in the obese than in the overweight and control groups. A sharp decrease in plasma testosterone levels, together with a reduction in testis weight, was seen in both groups of rats fed the palatable diet compared with the controls. These findings underline the 'peripheral' feature of the hyposomatotropinism of rats chronically fed an energy-rich diet, and may account for the reversibility of the GH impairment in many obese subjects once a normal body weight has been restored. Moreover, the peripherally-driven hyposomatotropinism of these rats is in sharp contrast with the hypothalamic driven GH secretory impairment of the obese Zucker rats. PMID- 8699150 TI - Transcriptional and post-translational regulation of insulin-like growth factor binding protein-5 in rat articular chondrocytes. AB - The aim of this study was to assess the regulation of insulin-like growth factor binding proteins (IGFBPs) by IGFs in primary cultures of rat articular chondrocytes (RAC). Employing Western ligand blotting, immunoprecipitation and Northern blot analysis, RAC were found to secrete IGFBP-5 (29 kDa) and IGFBP-4 (24 kDa) as the predominant IGFBPs, as well as IGFBP-2 (32-30 kDa) and IGFBP-3 (43-39 kDa) as the minor species. Treatment of cells with IGF-I and IGF-II resulted in a dose-dependent increase of IGFBP-5 and a small increase in IGFBP-4 in conditioned media (CM). Des(1-3) IGF-I and [Gln6, Ala7, Tyr18, Leu19] IGF-II ([QAYL] IGF-II), which bind to the type 1 IGF receptor but not to IGFBPs, also induced IGFBP-5 peptide, although the increase was less than with IGF-I or IGF-II treatment of RAC. [Leu27] IGF-II, which does not bind to the type 1 IGF receptor but binds to IGFBPs, resulted in little induction of IGFBP-5, while [QAYL-Leu27] IGF-II, which has reduced affinity for both the type 1 IGF receptor and IGFBPs, did not increase IGFBP-5. These data suggest that the increase in IGFBP-5 in CM is modulated by both the type 1 IGF receptor and the interaction between IGFs and IGFBPs. Northern blotting analysis showed that IGF-I, IGF-II and des(1-3) IGF-I treatment of RAC increased steady state levels of IGFBP-5 mRNA, suggesting that the IGF-mediated increase in IGFBP-5 is transcriptionally modulated. Interestingly, the increase in IGFBP-5 peptide levels and mRNA were not parallel, suggesting the possibility of post-translational modifications of IGFBP-5, such as those seen with IGFBP-5 protease. IGFBP-5 protease activity was detectable in untreated CM, whereas treatment with IGF-I and IGF-II partially protected IGFBP-5 from proteolysis. In summary, treatment of RAC with IGF-I and IGF-II results in dose-dependent increases in both IGFBP-5 peptide in the CM and mRNA levels. These changes are mediated by interactions via the type 1 IGF receptor as well as IGFBPs, both transcriptionally and post-translationally. PMID- 8699151 TI - Mediation by the central nervous system is critical to the in vivo activity of the GH secretagogue L-692,585. AB - To investigate the effect of hypophyseal transection (HST) on GH secretagogue activity of the non-peptidyl GH secretagogue L-692,585 in the conscious pig, male castrated swine were randomly assigned to either a hypophyseal stalk transection group (HST; n = 3) or to a sham-operated control group (SOC; n = 3). Treatments administered were L-692,585 (100 micrograms/kg), human GH-releasing factor(1 29)NH2 (GRF; 20 micrograms/kg) or L-692,585 (100 micrograms/kg) + GRF (20 micrograms/kg) on days -7 to -3 before surgery and days +3 to +8 after surgery. To evaluate the integrity of the pituitary gland, the animals were challenged with corticotropin-releasing hormone (CRH; 150 micrograms) or GnRH (150 ng/kg) both before and after surgery. Blood was collected from -60 to +180 min post treatment and assayed for GH, cortisol and LH. Before surgery, no significant difference (P > 0.05) in peak GH response (ng/ml) was present between the two groups (SOC vs HST) in response to L-692,585 (101 +/- 12 vs 71 +/- 9) or L 692,585 + GRF (171 +/- 21 vs 174 +/- 21). Only two out of three SOC vs three out of three HST pigs responded to GRF (13 +/- 2 vs 25 +/- 3) resulting in a significant difference between groups. Following surgery, significant differences were present in peak GH response (ng/ml) between SOC and HST groups following L 692,585 (79 +/- 6 vs 13.8 +/- 1.0); however, the response to L-692,585 + GRF was similar (115 +/- 8 vs 94 +/- 7). All animals responded to GRF; however, a significant difference was present between groups due to the magnitude of the responses. Whereas the cortisol responses (ng/ml) to L-692,585 in the SOC and HST groups were similar before surgery, a significant difference was present after surgery (44.4 +/- 6.4 vs 14.6 +/- 2.1). No significant difference was noted between the HST and SOC groups in response to CRH or GnRH either before or after surgery. These results indicated that L-692,585 induced an immediate GH response in the intact animal in contrast to GRF where the GH release was variable. L 692,585 also stimulated an immediate increase in cortisol levels. Transection of the hypophyseal stalk dramatically decreased but did not ablate the GH or cortisol response to L-692,585. Co-administration of L-692,585 + GRF induced an immediate GH response of similar magnitude in the intact and HST animal. We conclude that L-692,585 has a direct but limited action at the level of the pituitary and that an intact hypophyseal stalk is required for a maximal GH and cortisol response. L-692,585 acts with GRF at the level of the pituitary to induce a maximal GH response. These findings suggest that L-692,585 stimulates GH secretion by acting in combination with GRF and interrupting the inhibitory tone of somatostatin on the somatotroph. PMID- 8699152 TI - Membrane energization by proton pumps is important for compartmentalization of drugs and toxins: a new type of active transport. AB - Many organelles are energized by proton pumps: mitochondria form an inside negative membrane potential by means of the respiratory chain and endomembrane structures, such as lysosomes and synaptic vesicles, establish an internal acidic pH by means of a vacuolar-type H(+)-ATPase (V-ATPase). Various amphipathic drugs such as local anesthetics and neuron blockers are accumulated in acidic organelles upon energization by proton pumps. However, this process does not require any transporters specific for the drugs: these drugs penetrate through the lipid bilayer against a concentration gradient so as to accumulate inside the energized organelles. Essentially the same transport process takes place in liposomes that have been reconstituted with purified V- or F-ATPase. Various hydrophobic cations are also accumulated in mitochondria by a similar mechanism. The energy-dependent but transporter-independent accumulation does not belong to the known transport categories and seems to represent a new type of transport which may be important for understanding the mode of action of drugs and toxins. PMID- 8699153 TI - Function of the intercostal muscles in trotting dogs: ventilation or locomotion? AB - Although the intercostal muscles play an important role in lung ventilation, observations from fishes and ectothermic tetrapods suggest that their primary function may be locomotion. To provide a broader understanding of the role these muscles play in locomotion, I measured ventilatory airflow at the mouth and activity of the fourth and ninth intercostal muscles in four dogs trotting on a treadmill. During rest and thermoregulatory panting, activity of the intercostal muscles was associated with inspiratory and expiratory airflow. However, during trotting, activity of the interosseous portions of the intercostal muscles was correlated with locomotion. When ventilation and stride cycles were not synchronized, activity of the interosseous intercostal muscles stayed locked to the locomotor events and drifted in time relative to ventilation. In contrast, activity of the parasternal portion of the internal intercostal muscles was always associated with inspiratory airflow. These observations suggest that, in dogs, locomotion is the dominant function of the interosseous portions of the intercostal muscles. However, the parasternal intercostal muscles are primarily inspiratory in function. PMID- 8699154 TI - Characterization of the atrial natriuretic factor system in lungs of the toad Bufo paracnemis. AB - Blood pressure in the amphibian pulmonary circulation is relatively high because a single ventricle serves both the systemic and pulmonary circulation, creating a high degree of plasma filtration from pulmonary capillaries. Previous studies have shown that lung atrial natriuretic factor (ANF) may have an important physiological function in preventing edema in mammals. In this study, we report the presence of the complete ANF system in the lungs of the toad Bufo paracnemis. Radioimmunoassay of tissue homogenates revealed that toad lung ANF concentration was approximately twice as high (928.5 +/- 83.0 pg mg-1 protein) as that of lung tissue in mammals of a similar size. The amount of ANF was significantly higher in the left than in the right atrium (15.0 +/- 1.2 versus 1.9 +/- 0.8 ng mg-1 protein; N = 4, P < 0.001), while the ventricle contained 488.3 +/- 41.8 pg mg-1 protein. In extracts of both lungs and atria, high-performance liquid chromatography revealed two forms of the peptide; prohormone and a carboxy terminal peptide of low molecular mass, which is the biologically active form of peptide. The presence of the prohormone suggests that ANF is synthesized in toad lungs and atria. Characterization of toad lung receptors by a competitive binding assay demonstrated three different subtypes of ANF receptors: the guanylyl cyclase (GC) receptors, GC-A and GC-B, as well as clearance (C) receptors. We conclude that the toad Bufo paracnemis has a well-developed complete ANF system in the lung, suggesting that it has a role in toad lung physiology. PMID- 8699155 TI - The time-dependent mechanical properties of the human heel pad in the context of locomotion. AB - Previous measurements of the mechanical properties of the heel pad, especially of the energy loss during a cycle of compressive loading and unloading, have given contrasting values according to whether the investigators used isolated single impacts (e.g. pendulum tests; energy loss approximately 48%) or continuous oscillations (energy loss approximately 30%). To investigate this discrepancy, rest periods were inserted between single compressive cycles, giving intermittent loading as in locomotion. The energy loss, measured as the percentage area of the hysteresis loop, was found to change linearly with the logarithm of the rest time. It was approximately 33% when the rest time was 1 s. Each 10-fold increase in the rest time added approximately 3.7% to the energy loss. Thus, with rest times appropriate to locomotion, the pad is far from fully relaxed. The springy heel pad may help to reposition the foot during the transfer of load from the heel to the forefoot. Information is also included on the load-deformation curves for the heel pad and the way in which these change with rest time. This is presented as equations which may be useful in future models relating the mechanical properties of the heel to either its structure or its function. PMID- 8699156 TI - Is chemosensory input essential for the rapid rejection of toxic foods? AB - Herbivorous insects often rapidly reject foods containing toxic plant compounds. While the functional significance of this rejection response is clear, the mechanistic basis is not. The role of peripheral chemoreceptors in the rapid rejection of toxic foods was examined using a model system consisting of nicotine and the tobacco hornworm (Manduca sexta), which is a pest of tobacco plants. When offered diets containing naturally occurring concentrations of nicotine, larvae initially fed readily, but abruptly stopped feeding within 30s. A high percentage of larvae also exhibited toxic responses mediated by the central nervous system (twitching and writhing) to the ingested nicotine within 30s, indicating that nicotine could have been absorbed within the same time as the rejection response. Two lines of evidence are provided against a role of peripheral chemoreceptors in this rapid rejection response. First, all mouthpart chemoreceptors were ablated from the larvae, and they were then subjected to feeding tests with diets containing either nicotine or a compound (caffeine) that is known to stimulate deterrent taste receptors in M. sexta. Whereas the ablations virtually eliminated the rejection response to caffeine, they had no measurable impact on the rejection response to nicotine. Second, sensory recordings from two important gustatory sensilla (the medial and lateral styloconica) failed to demonstrate a plausible role of sensory input from either sensillum in the rapid rejection of nicotine. The most parsimonious interpretation of these results is that the nicotine rejection response was mediated by a rapidly acting post-ingestive mechanism. PMID- 8699157 TI - Comparison of the expression patterns of five developmentally regulated genes in Manduca sexta and their regulation by 20-hydroxyecdysone in vitro. AB - A previous study, using subtractive hybridization, identified five genes (esr16, esr20, Mng10, Mng14 and tps9) whose transcripts were up-regulated prior to metamorphosis in Manduca sexta nervous tissue. The developmental time points chosen for subtraction suggested that expression could be coordinately regulated and should be negatively regulated by the steroid hormones, the ecdysteroids. In the present paper, we present an analysis of the expression patterns of these five genes, using reverse transcription-polymerase chain reaction (RT-PCR), at various times during development and assess the effects of 20-hydroxyecdysone and cycloheximide on their expression in vitro. This analysis revealed that with the exception of esr20 all transcripts were detectable at all times and that all but one of the genes were up-regulated in vivo and in vitro in the absence or in the presence of low levels of the ecdysteroids. In the absence of ecdysteroids, cycloheximide blocked the accumulation of only two transcripts, esr16 and esr20. These results reveal a much more complex pattern of gene expression in the central nervous system prior to metamorphosis than previously imagined. PMID- 8699158 TI - Autonomic nervous control of heart rate in muskrats during exercise in air and under water. AB - Neural control of the cardiac responses to exercise in air (running) and under water (diving) was studied in the muskrat (Ondatra zibethicus) by means of acute pharmacological blockade with the muscarinic blocker atropine and the beta adrenergic blocker nadolol. Saline injection was used as a control. Controls running on a treadmill showed a marked increase in heart rate with exercise. Atropine-treated animals had a higher resting heart rate than controls, but heart rate still increased with running. Nadolol-treated animals had a lower resting heart rate than controls and displayed a less pronounced increase in heart rate with running than controls. Animals treated with a combination of atropine and nadolol had a resting heart rate similar to that of controls but their heart rate was unaffected by running. Thus, exercise tachycardia in muskrats is due to activation of the sympathetic system and also to a reduction in parasympathetic tone. Heart rate decreased markedly during voluntary submergence in controls but rose as muskrats swam submerged against increasing water flows. Nevertheless, diving bradycardia was still present. Free-diving bradycardia and the relative increase in heart rate with underwater exercise were abolished by atropine and unaffected by nadolol. Hence, unlike the cardiac response to exercise in air, the cardiac response to underwater exercise is due only to a reduction in parasympathetic tone. Injection of the beta-adrenergic agonist isoproterenol markedly increased heart rate in air but had little effect during voluntary and forced dives, indicating a marked decrease in the sensitivity of cardiac cells to adrenergic stimulation during submergence. These results strongly suggest that accentuated antagonism between the two branches of the autonomic nervous system occurs during diving so that parasympathetic influences on the heart predominate and inhibit any chronotropic response to adrenergic stimulation. PMID- 8699159 TI - Salinity change and cell volume: the response of tissues from the estuarine mussel Geukensia demissa. AB - The response of cell volume to changes in external salinity was assessed in four tissues (gill, mantle, hemolymph cells and ventricle) of the estuarine mussel Geukensia demissa by using one or more of the following three indicators of cell volume response: changes in cell dimensions, cell water space and cell solute content. All three techniques indicated that short-term volume regulation was generally absent from gill tissue. Lateral cell height in gills, measured using differential interference contrast (DIC) microscopy, increased by approximately 20% after an abrupt exposure to reduced salinity (60% artificial sea water, ASW). There was significant variability in the observance of a regulatory volume decrease (RVD) subsequent to the initial swelling; cells remained swollen for 1 h after low-salinity exposure in two-thirds of the trials, while there was a return of cell volume towards control values in the remaining one-third of the trials. Lateral cell height increased linearly when salinity was gradually decreased from 100 to 60% ASW over 135 min. Cell height then returned to control values when the salinity was abruptly returned to 100% ASW, indicating that an RVD was not elicited by a slow change in salinity of the type normally encountered by estuarine mussels. Cumulative cell water space in gills increased by 47% after exposure to 60% ASW and the cells remained swollen for at least 4 h, returning to control values when gills were returned to 100% ASW. Consistent with the overall lack of an RVD, there was only a small decrease (approximately 5%) in cumulative osmolyte content (primarily taurine, betaine and K+) after 4 h in 60% ASW. Decreases in both cell water space and osmolyte content after 3 weeks of acclimation to 60% ASW indicated a long-term RVD of approximately 60%. Individual cells in the mantle epithelium also generally lacked an RVD in response to lowered salinity. Both abrupt and gradual decreases in salinity caused an increase in mantle cell height to a maximum of 25-30%, and cell height returned to the control height when salinity was abruptly returned to 100% ASW. Corresponding with the lack of an RVD in individual mantle cells, there was no change in solute content of the mantle tissue after 4 h of exposure to low salinity. The response of the volume of spherical hemolymph cells to 1 h of abrupt exposure to low salinity, calculated from measured cell diameters, likewise indicated that an RVD is generally lacking in these hemolymph cells. In the ventricle, however, there was a significant decrease in amino acid and betaine content after 4 h of exposure to low salinity, suggesting tissue-specific variability in the cellular response to salinity change. The consistent lack of a short-term RVD in many tissues may serve to avoid large energetic expenditures associated with repeated volume regulation in the face of the frequent, short term changes in salinity encountered by estuarine mussels. PMID- 8699160 TI - "Cytomegalovirus disease" in renal allograft recipients: is human herpesvirus 7 a co-factor for disease progression? AB - Fifty-six renal allograft recipients were studied prospectively for 3 months or longer after transplant. The polymerase chain reaction (PCR) was used to screen peripheral blood leucocyte (PBL) specimens for CMV, human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7) DNA (DNAemia) in 67 healthy controls and in serial (fortnightly) PBL specimens from the 56 allograft recipients. None of the healthy controls had detectable CMV DNAemia, although HHV6 and HHV7 DNAemia was found in 7% and 9% of individuals respectively. In contrast, DNAemia due to CMV, HHV6 and HHV7 was found in 50%, 36% and 39% of patients respectively, at some time during the post-transplant period. Of the 28 patients who had CMV DNAemia, eight developed "CMV disease". The risk of progression to "CMV disease" was increased in patients with concurrent DNAemia to all three viruses (relative risk 3.7; 95% CI 1.3-10.5). The relative risk of "CMV disease" for patients with concurrent CMV and HHV7 was also increased (RR = 3.5; 95% CI = 1.1-11.6), while the association between CMV and HHV6 was inconclusive (RR = v2.1; 95% CI = 0.7-6.6). The first 26 patients recruited to the study also had serial serum samples tested for antibody responses to the three viruses. "CMV disease" was associated with rising antibody titres to HHV7 (Fisher's exact test, P = 0.02), and weakly so with HHV6 (P = 0.07). It is concluded that in patients with CMV DNAemia, concurrent infection/reactivation HHV7 (and possibly HHV6) is associated with an increased risk of progression to "CMV disease". PMID- 8699161 TI - Overexpression of the proto-oncogene c-jun in association with low-risk type specific human papillomavirus infection in condyloma acuminata. AB - Infection with different types of human papillomavirus (HPV) is associated with neoplasia at different anatomic sites. The "low-risk" HPVs (LR-HPV) are responsible for benign genital lesions such as condyloma acuminata. In order to clarify the tumorigenic mechanism of LR-HPV, the HPV infection status was investigated and the expression of the c-jun proto-oncogene in different HPV related skin and genital lesions analyzed. Of the 17 condyloma specimens analyzed by Western blotting, 13 cases (76.5%) exhibited overexpression of the c-jun gene. All 13 cases harbored high copy numbers of the LR-HPV genome with an average of 926 copies per cell, whereas the other four cases had an average of 12 copies of LR-HPV per cell (P < 0.001). Further typing of HPV by Southern blotting revealed that HPV-6 and HPV-11 infections predominated in c-jun positive cases. The c-jun protein was detected much less frequently in cervical cancers (three of 29, or 10.3%) and skin warts (one of 10), and was not detected in five genital polyps or in five normal cervical tissues. These findings suggest a type 6/11-specific induction of c-jun gene expression in HPV-related neoplastic lesions. PMID- 8699162 TI - Investigation of murine cytomegalovirus latency and reactivation in mice using viral mutants and the polymerase chain reaction. AB - Studies with 6 ts mutants of mouse cytomegalovirus indicated that mutants tsm1, tsm2, tsm3, and tsm6, like wild-type (wt) virus, produced acute infection in mice, became latent, and were reactivated as infectious virus immunosuppression. Using PCR, all five viruses expressed immediate-early (IE)-1, early (E)-1, and late (L, gB) genes during acute infection in all tissues examined (salivary glands, lung, spleen, liver, kidney, and heart). DNA was present in most tissues during latent infection with all five viruses, but transcription was restricted to the IE-1 gene in the salivary glands of wt infected mice only, suggesting true molecular latency rather than low level virus persistence. Similarly, mutant tsm5 expressed all three genes following primary inoculation. Although no detectable virus was produced, tsm5 subsequently entered the latent state as evidenced by DNA detection without RNA transcription indicating that productive infection is not required to initiate latency. This mutant also failed to reactivate from latency, although all three marker genes were expressed in most tissues. In contrast, tsm4 expressed all three marker genes and produced infectious virus during acute infection, then became latent. However, upon immunosuppression to reactivate tsm4, IE-1 and E-1 transcription occurred but neither gB transcription nor infectious virus was detectable in salivary glands, lung, spleen, liver, kidney, heart, or blood. The significance of this with regard to reactivation from latency is discussed. PMID- 8699163 TI - Characterization of antisense RNA-mediated inhibition of SIV replication. AB - Antisense RNA-mediated inhibition of HIV showed mixed success in previous experiments. In order to elucidate the parameters influencing the efficacy of an antisense RNA approach, retroviral vectors encoding 4.5 kb, 3.5 kb, or 2.5 kb antisense RNA of the gag-pol region of SIV (simian immunodeficiency virus) were constructed and used to transduce a CD4-positive CEM174 cell line. The growth rate of transduced cells was measured, and results showed that antisense RNAs have no detrimental effect on cell growth. Similar levels of antisense RNA expression were observed in all transduced cells by Northern analysis. The transduced cells were challenged with uncloned SIVmac239 at a m.o.i. (multiplicity of infection) of 1.0, 0.1, or 0.01. At a m.o.i. of 1.0 or 0.1, no significant inhibition of viral replication was observed in any antisense construct transduced cells up to 9 days postinfection. At a lower m.o.i. (0.01), viral replication was effectively inhibited in 3.5 kb antisense transduced cells as compared to 4.5 kb and 2.5 kb antisense transduced cells at 15 days postinfection. These data suggest that the size of antisense RNA and the challenge dose play a significant role in achieving effective inhibition. PMID- 8699164 TI - Isolation of varicella-zoster virus from vesicles in children with varicella. AB - Varicella-zoster virus (VZV) was isolated from 29 samples of the vesicular fluid in 13 otherwise healthy children with varicella who were aged from 7 months to 7 years. Human embryonic lung cells were used for viral isolation, and VZV was identified by a characteristic cytopathic effect and an indirect immunofluorescence assay. VZV was found in 17 samples; in two (12%) of which it was also detected after filtration (0.45 microns). The rate of isolation was 100% in the first two days after the onset of the disease. It declined gradually with time to 1 of 6 in the samples 6 days after the clinical onset. Specific IgG antibody to VZV was investigated in the same materials. The positive rate was 0% (0/13) in the first 3 days and increased to 7 of 16 in the following 3 days after the onset. VZV was not isolated from samples with specific antibody. In conclusion, VZV can be isolated easily from vesicles within the first 3 days of onset, but the filtration of samples affects its isolation. Infective VZV disappears gradually in vesicles after the first 3 days, and this may be related to the establishment of immune reactions including specific antibody. PMID- 8699165 TI - Identification of antigenic regions in the GB hepatitis viruses GBV-A, GBV-B, and GBV-C. AB - The genomes of two novel members of the Flaviviridae associated with GB agent hepatitis (GB viruses A and B) were cloned and sequenced recently. The genome of a third novel virus (GB virus C), related to but distinct from GB viruses A and B, has also been identified and characterized. Overlapping clones encompassing the large open reading frames of these three viruses have been expressed in E. coli as CTP:CMP-3-deoxy-D-manno-octulosonate cytidylyltransferase (CKS) fusion proteins. Bacterial lysates were subjected to Western blot analyses using sera from GB agent-infected tamarins and human sera from various individuals with or "at risk" for non-A, non-B, non-C, non-D, non-E hepatitis. Antigenic regions were identified in the putative NS3, NS4, and NS5 proteins from all three viruses. An antigenic region was also identified in the putative core protein of GB virus B. Many of the clones identified originally as encoding antigenic proteins were quite large. To map these regions more narrowly, smaller overlapping clones were generated by polymerase chain reaction (PCR), expressed as recombinant CKS fusion proteins and tested by Western blot. Additionally, a lambda gt11 expression library was generated from infectious tamarin sera and immunoscreened. These studies have identified at least three epitopes in GB virus A, five epitopes in GB virus B and four epitopes in GB virus C. PMID- 8699166 TI - Hepatitis C plasma viral load is associated with HCV genotype but not with HIV coinfection. AB - The influence of human immunodeficiency virus (HIV) coinfection and hepatitis C virus (HCV) genotype distribution on HCV viral load and alanine amino transferase (ALT) levels in chronically infected patients remains unclear. In the present study, serum samples from a group of haemophiliac patients were investigated retrospectively. HCV geno- and subtyping was carried out using the Inno line probe assay (Inno LIPA, Innogenetics, Zwijnaarde, Belgium) in 87 patients positive by HCV RT PCR. Of these patients, 31 (35.6%) were HIV coinfected. HCV RNA was quantified with the HCV Monitor kit (Roche, Basel, Switzerland) in 43 patients (22 HIV-negatives, 21 HIV-positives). The most prevalent genotypes were 1 (n = 52) and 3a (n = 16) followed by genotype 2 (n = 9) and 4 (n = 3). Mixed infections were detected in 7 patients. Of genotype 1 positive samples, 24 and 23 were classified as subtype a and b, respectively. Five samples could not be subtyped. Although higher mean values of ALT were observed in genotype 1 infected patients, there was no statistically significant association between HCV genotype or subtype and liver enzymes (P > 0.05). On the other hand, statistically significant higher HCV RNA titres were observed in haemophiliacs infected with HCV genotype 1 in comparison to those infected with other genotypes (P < 0.01). No relationship was found between the presence of HIV coinfection and viral load of HCV RNA. There was no evidence that HCV infection had a more severe outcome in HIV-positive patients who had been infected with HIV and HCV more than ten years ago, even in those with very low CD4+ cell counts. No clear association between high ALT levels and large amounts of viral RNA was observed. In conclusion, a large viral load is associated with HCV genotype 1 infection; HIV coinfection has no clear effect on the intensity of HCV replication. An ongoing prospective study will evaluate the respective role of viral load, genotype, HIV coinfection and ALT level in the response to interferon therapy. PMID- 8699167 TI - Human herpesvirus 6 in human immunodeficiency virus-infected individuals: association with early histologic phases of lymphadenopathy syndrome but not with malignant lymphoproliferative disorders. AB - Preliminary evidence suggested that human herpesvirus-6 (HHV-6) may act as a cofactor in acquired immunodeficiency syndrome (AIDS) and may contribute to the pathogenesis of lymphoproliferative disorders occurring in individuals infected with the human immunodeficiency virus (HIV). To understand better the biological and clinical significance of HHV-6 infection in the context of HIV-related immunosuppression, the polymerase chain reaction was used to study the frequency and variant distribution of HHV-6 in peripheral blood mononucleated cells (PBMCs) from HIV-seropositive individuals, either asymptomatic or with lymphadenopathy syndrome (LAS) or with overt AIDS. Non-neoplastic and malignant lymphoproliferative disorders from both HIV-infected and HIV-seronegative patients were also investigated using the same series of samples for the presence of Epstein-Barr virus (EBV). When compared with healthy blood donors (12/42, 29%), HHV-6 prevalence in PBMCs showed a progressive decline in HIV-seropositive individuals with asymptomatic HIV infection (3/26, 11%) and in patients with LAS (1/13, 8%) and a significant reduction in patients with overt AIDS (1/20, 20%; P = 0.02). The decrease correlated with the number of CD4+ cells at the time of examination. In addition, HHV-6 DNA sequences were significantly more prevalent in LAS biopsies (13/20, 65%) than in HIV-unrelated reactive lymphadenopathies (2/10, 20%; P = 0.02) and the presence of HHV-6 sequences correlated closely with a histologic pattern of follicular hyperplasia (13/16, 81%; P = 0.003). Strikingly, HHV-6 prevalence decreased in PBMCs of LAS patients, suggesting that the likelihood of interactions between HHV-6 and HIV varies in different body districts. In particular, the demonstration that all HHV-6-carrying LAS samples were also positive for HIV infection suggests that LAS lymph nodes constitute one of the sites where biologically relevant interactions between the two viruses might occur. Also, the prevalence of EBV was higher in LAS (14/20, 70%) than in non-neoplastic lymph nodes from HIV-seronegative individuals (4/10, 40%), although the difference was not statistically significant. EBV was associated strongly with HIV-related malignant lymphoproliferative disorders, being detected in 100% of patients with Hodgkin's disease (HD) and 53% of B-cell non-Hodgkin's lymphomas (NHL). In contrast, the prevalence of HHV-6 DNA in HD and B-cell NHL arisen in HIV-infected patients (30% and 6% respectively) was remarkably lower and similar to that observed in lymphoproliferative disorders from HIV seronegative patients. Finally, as observed in healthy individuals, HHV-6 variant B was more prevalent than variant A in benign and malignant lymphoproliferative disorders from bot HIV-infected and HIV-seronegative patients. These results suggest that the interactions between HHV-6 and HIV could be different in the various phases of HIV disease and in different districts; HHV-6 has probably no direct role in the pathogenesis of HIV-associated B-cell NHL and HD cases, and behave differently from EBV; and HIV-related immunosuppression does not alter the distribution of HHV-6 variants in these tissues, as observed in the case of EBV. PMID- 8699168 TI - Comparison of serum hepatitis C virus RNA concentration by branched DNA probe assay with competitive reverse transcription polymerase chain reaction as a predictor of response to interferon-alpha therapy in chronic hepatitis C patients. AB - A study was carried out to assess the correlation between the serum concentration of hepatitis C virus RNA (HCV-RNA) in patients with chronic hepatitis, as measured by competitive reverse transcription polymerase chain reaction (cRT-PCR) and branched DNA probe assay (bDNA), and response to interferon-alpha (IFN alpha) therapy. The serum HCV-RNA concentration was evaluated by both cRT-PCR and bDNA in 54 patients who had received a total dose of 480 MU of IFN alpha. HCV subtypes were also identified in all patients. The measurement of serum HCV-RNA concentration by bDNA correlated significantly with that of cRT-PCR. The concentration of HCV-RNA in subtype 1 patients was significantly higher than that in subtype 2 patients when measured by bDNA, but not when measured by cRT-PCR. The correlation of HCV-RNA concentration between bDNA and cRT-PCR was associated with both subtypes 1 and 2. The difference in serum HCV-RNA concentration between complete and incomplete responders was more significant when measured by bDNA probe assay than by cRT-PCR. Moreover, only 1 of 26 patients with a HCV-RNA concentration of more than 1 x 10(6) eq/ml as measured by bDNA probe assay attained a complete response, while 19 of 28 patients with that of less than 1 x 10(6) eq/ml achieved it. Measurement of serum HCV-RNA concentration by bDNA probe assay was a better predictor of clinical response of IFN alpha therapy than measurement by cRT-PCR. PMID- 8699169 TI - Viral safety of a new highly purified factor VIII (OCTATE). AB - The inactivation of both transfusion-relevant and model viruses by modified pasteurisation (10 hours at 63 degrees C in solution) has been evaluated following the established guidelines of the EU CPMP Ad Hoc Working Party on Biotechnology/Pharmacy. This heat treatment was introduced into the manufacturing process of OCTAVI, a very high purity factor VIII concentrate stabilized only by von Willebrand factor, in the presence of a proprietary mixture of low molecular weight stabilizers. Both enveloped (human immunodeficiency virus, Sindbis virus, herpes simplex virus, pseudorabies virus) and nonenveloped viruses (poliovirus, Coxsackievirus, hepatitis A virus) were inactivated by this heating step by more than 4.7 log10. The combination of the solvent/detergent step used in the manufacture of OCTAVI with this modified pasteurization leads to a double virus inactivated factor VIII concentrate (OCTATE) with a viral safety distinctly superior to monoinactivated products. PMID- 8699171 TI - Glycylsarcosyl-L-histidylglycine, A peptide with a "breakpoint" in complex formation: hydrolysis of the complex [CuH-1L]. AB - Coordination of CU(II) with glycylsarcosyl-L-histidylglycine to form the series of [CuL] and [CuH-1L] was studied potentiometrically and spectroscopically. [CuL] includes the Cu(N2O)O chromophore, in which Cu(II) coordinates with nitrogens from the terminal amino and imidazole groups and a carbonyl oxygen of the Gly-Sar bond, and shows a d-d transition band at 696 nm in the absorption spectrum and at 648 nm in the CD spectrum. The predominant species around pH 8 was [CuH-1L] with Cu(N3O) chromophore, in which Cu(II) coordinates with three nitrogens from a terminal amino, a deprotonated Sar-His peptide bond, and an imidazole of a histidyl residue, and shows the d-d transition band at 652 and 580 nm in the absorption and CD spectra, respectively. This species was hydrolyzed at the Gly Sar peptide bond, yielding the Cu(II) complex of sarcosyl-L-histidylglycine. PMID- 8699170 TI - Metal-ion discrimination by phage T7. AB - The discovery of new metal-selective complexing agents may be facilitated by applying an in vitro selection strategy. Such a strategy was recently devised to identify and enrich populations of bacteriophage that rely on Mg(II)-, Zn(II)-, or Au(III)-selective stabilization for survival in the presence of denaturing urea. The potential for extension of the strategy to other metal ions is investigated here. The kinetics of phage inactivation in 5 M urea was measured for a spectrum of metals. At a concentration of 1 mM, Mg(II), Ca(II), Co(II), and Ni(II) were found to be the most stabilizing, followed by Cd(II), Cu(II), and Zn(II), respectively. K(I) had virtually no effect. In contrast, Al(III) and Au(III) significantly destabilized the phage, even at concentrations of 0.25 mM. PMID- 8699172 TI - Specific interactions of Cu2+ ions with fragments of envelope protein of hepatitis B virus. AB - Potentionmetric and spectroscopic (EPR, CD and absorption spectra) data have shown that a fragment of envelope proteins of the hepatitis B virus could be very specific bind molecules for Cu2+ ions using arginine lateral NH2 donor sites. The presence of Pro and Asp residues makes Arg binding not only very specific, but also very efficient. PMID- 8699173 TI - Synthesis, characterization, and DNA modification induced by a novel Pt-berenil compound with cytotoxic activity. AB - In the present paper, we show that the reaction of the antipyranosomatid berenil drug with K2PtCl4 resulted in the synthesis of a covalent (Pt(II)-berenil compound of formula [Pt2Cl4(berenil)2]Cl4.4H2O as shown by IR, 1H, 13C, and 195Pt NMR. The Pt-berenil compound was tested for in vitro antitumor activity against HL-60 and U-937 human leukemic cells. The results show that the LC70 values of the Pt-berenil are about two-fold lower than those of cis-DDP in both HL-60 and U 937 cell lines. Melting data of Pt-berenil:DNA and berenil:DNA complexes indicate that the platinated compound produces on a DNA secondary structure higher compaction than the berenil ligand. The mobility in agarose gels and the circular dichroism spectra of the compounds:DNA complexes revealed, moreover, that both induce drastic changes on a DNA secondary and tertiary structure. The total reflection X-ray fluorescence data showed, in additIon that DNA platination in Pt berenil:DNA complexes occurs within minutes after addition of the drug, in contrast to what that observed in cis-DDP:DNA complexes. On the basis of these results, we propose that in Pt-berenil, the berenil ligand acts as a carrier of the active cis-P(II) centers towards DNA. PMID- 8699174 TI - The iron environment in heme and heme-antimalarial complexes of pharmacological interest. AB - Mossbauer spectroscopy has been utilized to probe the electronic environment of iron in a number of Ferriprotoporphyrin IX complexes of relevance to malaria. The markedly different iron environments found for the complexes of hemin with quinine, chloroquine, and the Chinese herbal antimalarial artesunate suggest that these compounds act by protecting the heme from polymerization to insoluble hemozoin, and by facilitating the transport of the protected heme to the food vacuole membrane where it is able to exercise its cytotoxic redox catalytic activity. Mossbauer parameters determined here for purified malaria pigment and synthetic beta-hematin confirm the chemical identical-ness of these species. The Mossbauer spectra of the complexes are discussed in light of the proposed structures of the complexes. PMID- 8699175 TI - A circular dichroism study of ethidium bromide binding to Z-DNA induced by dinuclear platinum complexes. AB - Dinuclear bis(platinum) complexes have been shown previously to induce the B-->Z transition in synthetic DNAs (Nucleic Acids Res. 7, 1697-1703, J. Inorganic Biochem. 54, 207-220). In this paper, the reversibility of the Z conformation back to the B form was assessed by treatment of the induced Z form in poly(dG dC).poly(dG-dC) with ethidium bromide (Etd). Z-DNA induced by the tetra-amine cations [{Pt(NH3)3}2(H2N(CH2)nNH2)]4+, which are capable of only electrostatic interactions with the polynucleotide, was readily reversible. The spectroscopic data mirrored that of ethidium bromide/poly(dG-dC).poly(dG-dC) in the presence of 4.4 M NaCl. In contrast, Z-DNA induced by the bifunctional complexes [{trans PtCl(NH3)2}2(H2N(CH2)nNH2)]2+ did not produce spectra typical of Etd intercalation and reversal to B-form DNA. The original Z-form CD spectra of DNA treated with the bifunctional complexes could be reobtained following removal of Etd by extensive dialysis. The bifunctional complexes are very effective interstrand cross-linking agents. The data suggest that interstrand cross-linking by dinuclear complexes can stabilize or "lock" the Z-conformation prohibiting its reversal to the B-form. The implications for the biological activity of the dinuclear complexes are briefly discussed. PMID- 8699176 TI - Palladium(II) complexes of dialkyl alpha-Anilinobenzylphosphonates. Synthesis, characterization, and cytostatic activity. AB - The new palladium (II) halide complexes with diethyl and dibutyl esters of (alpha anilino-N-benzyl) phosphonic acid and diethyl and dibutyl esters of [alpha-(4 benzeneazoanilino)-N-benzyl] phosphonic acid have been prepared and studied. All organophosphorus ligands form dihalide complexes, trans-Pd(L)2X2(X = Cl or Br), with monodentate N-bonded ligand through the anilinobenzyl nitrogen in (alpha anilino-N-benzyl) phosphonate complexes and through the azo nitrogen in [alpha-(4 benzeneazoanilino)-N-benzyl] phosphonate complexes, respectively, without participation of the phosphoryl group. Azobenzene containing ligands by ortho metallation also form binuclear organo-palladium complexes, [Pd(L-H)Cl]2, with the metal-metal chloro bridge. The complexes have been identified and characterized by elemental analysis, infrared and 1H NMR, as well as by magnetic and conductometric measurements. All were tested in vitro for their cytostatic activity against KB and L1210 tumor cell lines. The results show that these complexes inhibit the multiplication of these tumor cells, but only the dichloro adduct of diethyl [alpha-(4-benzeneazoanilino)-N-benzyl] phosphonate was found to have activity comparable to that of the antitumor drug cisplatin. PMID- 8699178 TI - 3rd Meeting of the Asian-Pacific Society for Neurochemistry, 5th meeting of the Chinese Society for Neurochemistry. Beijing, China, October 8-10, 1996. Abstracts. PMID- 8699177 TI - Interaction of bivalent copper, nickel, manganese ions with native DNA and its monomers. AB - UV differential spectroscopy is applied to study the interaction of Cu2+, Ni2+, Mn2+ ions with deoxyribonucleotides of canonic bases (dGMP, dAMP, dCMP, dTMP) and native DNA. Heteroatoms of the bases, coordinating ions, and binding constants which characterize the formation of metal complexes are found. The affinity of the ions is lower for the deoxyribonucleotide bases than for the ribonucleotide ones. This indicates that 02' of ribose participates in the stabilization of the metal complex even under conditions close to the neutral one (pH 6). Unlike the Cu2+ ions, Ni2+ and Mn2+ ions do not interact with N3C both in monomers and polymers. This seems to be the main factor explaining why copper makes DNA transform into a structure with a quasi-Hoogsteen pairing of GC pairs. No transformations of this kind of helix-coil transitions are caused by manganese and nickel up to concentrations 4 X 10(-2) M. PMID- 8699179 TI - Isolation of 20 glycosides from the starfish Henricia downeyae, collected in the Gulf of Mexico. AB - Thirteen new (1-13) and seven known (14-20) steroid glycosides were isolated from Henricia downeyae, collected from the offshore waters of the northern Gulf of Mexico. Ethanolic extracts of these starfish caused growth inhibition in bacteria and fungi, potent antifouling activity against barnacle and bryozoan larvae, and feeding deterrent activity against a marine fish. The known compounds are typical glycosides found in several species of the family Echinasteridae, i.e., Echinaster sp. and Henricia laeviuscola. One of the new compounds belongs to this group, whereas the remaining 12 new compounds represent a novel series of steroid glycosides which have aglycons with structural similarities to the "asterosaponins". They possess a delta 9(11) 3 beta, 6 alpha-dihydroxysteroidal aglycon with 23-oxo or 22,23-epoxy functionalities and often a 20-hydroxyl group in the side chain. The sulfate is located at C-6 and the saccharide moiety at C 3, in contrast with the asterosaponins which have the sulfate at C-3 and the oligosaccaride moiety at C-6. All the new compounds contain a glucuronic acid unit, which is uncommon among steroid glycosides from echinoderms. The structures of the new compounds, isolated in amounts ranging from 3.4 to 0.9 mg, were determined by interpretation of their spectral data and by comparison with spectral data of known compounds. PMID- 8699180 TI - Triterpenoid saponins from Bellis sylvestris. 2. Structures of partially deacylated saponins. AB - Four saponins have been isolated from the herbal parts of Bellis sylvestris and the same, together with three further compounds, from the underground parts. The structures were elucidated by electrospray ionization mass spectrometry, including tandem mass spectrometry, and by 1D and 2D homonuclear and heteronuclear NMR spectroscopy. Two of the compounds are new saponins with the structures 3-O-beta-D-glucopyranosyl-2 beta, 3 beta, 23-trihydroxyolean-12-en-28 oic acid 28-O-beta-D-glucopyranosyl (1-->3)-[alpha-L-rhamnopyranosyl (1-->2)] beta-D- glucopyranoside and 3-O-beta-D-glucopyranosyl-2 beta, 3 beta,16 alpha, 23 tetrahydroxyolean-12-en- 28-oic acid 28-O-alpha-L-rhamnopyranosyl (1-->3)-beta-D xylopyranosyl(1-->4)-alpha-L- rhamnopyranosyl(1-->2)-[(E)-2-butenoic acid (1- >3)]-beta-D-fucopyranoside. Taxonomically these data provide significant evidence of a link between the Bellis genus and Bellium bellidioides. PMID- 8699181 TI - Diterpenoid alkaloids from Delphinium davisii. AB - Three new hetisane-type diterpenoid alkaloids, davisinol (6), 18-benzoyldavisinol (7), and Davisin (9) have been isolated from Delphinium davisii Munz. and their structures established by detailed spectroscopic studies. Accurate 1H- and 13C NMR assignments have been made for kobusine (8), a related hetisane-type alkaloid, and karakoline (5), a norditerpenoid alkaloid. The known norditerpenoid alkaloids 14-acetylperegrine (4), 6-deacetylperegrine (3), and karakoline (5) and the diterpenoid alkaloids hetisine and hetisinone were also isolated. PMID- 8699183 TI - Antitumor germacranolides from Anvillea garcinii. AB - The aerial parts of Anvillea garcinii yielded two new germacranolides, 9 alpha hydroxy-1 beta, 10 alpha-epoxyparthenolide (4) and parthenolid-9-one (5), in addition to the known 9 alpha-hydroxyparthenolide (1), 9 beta-hydroxyparthenolide (2), and 9 beta-hydroxy-1 beta, 10 alpha-epoxyparthenolide (3). The structures of the new compounds were elucidated from their spectral data (IR, MS, 1H- and 13C NMR, 1H-1H COSY, and 1H-13C HETCOR) and by chemical derivatization. The hitherto unreported 13C-NMR data and carbon atom assignments of the previously isolated lactones 1, 2, and 3 were given. The in-vitro antitumor and anti-HIV activities were evaluated for the isolated compounds. PMID- 8699182 TI - Comparative study of the vasodilatory effects of three quinazoline alkaloids isolated from Evodia rutaecarpa. AB - The vasoreactivity of dehydroevodiamine (1), evodiamine (2), and rutaecarpine (3), quinazoline alkaloids isolated from Evodia rutaecarpa, to aorta smooth muscle demonstrated that they produce a vasodilatory effect on endothelium-intact rat aorta with equal potency. Compound 3 produced a full (100%) nitric oxide dependent vasodilatation, whereas 2 and 1 produced a partially endothelium dependent effect, 50% and 10%, respectively. At the same time, I and 2 may also act by other mechanisms, including probably an alpha1-adrenoceptor blocking action and a 5-HT antagonizing action, respectively. PMID- 8699184 TI - New prenylflavones from the leaves of Epimedium saggitatum. AB - Five new prenylflavones, yinyanghuo A (1), yinyanghuo B (2), yinyanghuo C (3), yinyanghuo D (4), and yinyanghuo E (5), along with six known flavonoids, chrysoeriol, quercetin, apigenin, apigenin 7,4'-dimethyl ether, kaempferol, and luteolin, were isolated from the leaves of Epimedium sagittatum. Their structures were determined from spectral analysis. Compounds 1 and 2 showed significant antiplatelet induced by arachidonic acid. PMID- 8699185 TI - Triterpenoid saponins from Cephalaria transsylvanica. AB - Two new triterpenoid saponins, transsylvanosides G and H, were isolated from Cephalaria transsylvanica and their structures established as 3-O-[beta-D glucopyranosyl(1-->4)-beta-D-glucopyranosyl(1-->3)-alpha-L- rhamnopyranosyl(1- >2)-beta-D-xylopyranosyl] hederagenin 28-O-[beta-D-glucopyranosyl(1-->4)-beta-D xylopyranosyl] ester (1) and 3-O-[beta-D-xylopyranosyl(1-->3)-alpha-L rhamnopyranosyl-(1-->2)-beta-D- xylopyranosyl] hederagenin (2), respectively. A novel prosapogenin (3) was obtained on the alkaline hydrolysis of 1 and its structure defined as 3-O-[beta-D-glucopyranosyl(1-->4)-beta-D-glucopyranosyl(1- >3)-alpha-L- rhamnopyranosyl(1-->2)-beta-D-xylopyranosyl] hederagenin. The structures of compounds 1-3 were established by spectral and chemical methods. PMID- 8699186 TI - Barbamide, a chlorinated metabolite with molluscicidal activity from the Caribbean cyanobacterium Lyngbya majuscula. AB - The lipid extract from a Curacao collection of the marine cyanobacterium Lyngbya majuscula was toxic to the mollusc Biomphalaria glabrata. Subsequent bioassay guided fractionation of this extract yielded a novel lipopeptide, barbamide, as the active compound (LC100 = 10 micrograms/mL). The structure of barbamide was determined by spectroscopic methods and was found to contain several unique structural features, including a trichloromethyl group and the methyl enol ether of a beta-keto amide. PMID- 8699187 TI - Antifungal and molluscicidal saponins from Serjania salzmanniana. AB - An investigation of Serjania salzmanniana for biologically active substances has led to the isolation of two novel saponins, salzmannianoside A (3-O-[[beta-D- glucopyranosyl-(1-->4)]-[alpha-L-rhamnopyranosyl-(1-->2)]-alpha-L- arabinopyranosyl] gypsogenin) [3] and salzmannianoside B (3-O-[[beta-D glucopyranosyl-(1-->4)]-[alpha-L- arabinopyranosyl-(1-->3)-alpha-L rhamnopyranosyl-(1-->2)] -alpha-L-arabinopyranosyl] hederagenin) (4). Two known saponins, pulsatilla saponin D (3-O-[[beta-D- glucopyranosyl-(1-->4)]-[alpha-L rhamnopyranosyl-(1-->2)]-alpha-L- arabinopyranosyl] hederagenin) (1) and 3-O [[beta-D-glucopyranosyl-(1-->4)]-[alpha-L-rhamnopyranosyl-(1-->2)]-a lpha-L- arabinopyranosyl] oleanolic acid (2) were also isolated from this plant. The structures of 3 and 4 were elucidated by FABMS and 2D NMR techniques. All these four saponins were mollusicidal, causing 70-100% mortality at 10 ppm against Biomphalaria alexandrina, a vector of Schistosoma mansoni in the Nile Valley. The saponins also showed antifungal activity against Cryptococcus neoformans and Candida albicans at minimal inhibitory concentrations of 8 and 16 micrograms/mL, respectively. PMID- 8699188 TI - Pessoine and spinosine, two catecholic berbines from Annona spinescens. AB - The trunk bark and roots of Annona spinescens have been investigated for their alkaloid content. Two new berbine alkaloids, pessoine (1) and spinosine (2), have been isolated from the bark, and their structures were elucidated by spectroscopic methods. Eight known isoquinoline alkaloids were also obtained. The trypanocidal and antileishmanial activities of these isolated compounds have been investigated. PMID- 8699189 TI - (all trans)-2,4,6,8,10,12-tetradecahexene-1,14-dial, a new pigment from Conidiobolus paulus. AB - A study of the coloring matter produced by Conidiobolus paulus Drechsler NRRL 2648 on potato-dextrose medium led to the isolation of a new dialdehyde unsaturated metabolite, (all trans)-2,4,6,8,10,12-tetradeca-1,14-hexenedial. The structure was characterized by MS and by 1H- and 13C-NMR. The compound inhibited the growth of the Gram-positive bacterium, Bacillus cereus, and the Gram-negative bacterium, Escherichia coli (MIC values of 10 micrograms and 50 micrograms, respectively). PMID- 8699190 TI - Effect of Polygonum hydropiper sulfated flavonoids on lens aldose reductase and related enzymes. AB - The sulfated flavonoids in Polygonum hydropiper showed potent inhibiton against lens aldose reductase. Among these flavonoids isorhamnetin 3,7-disulfate (5) was most potent. Kinetic analysis showed that 5 exhibited noncompetitive inhibition against both dl-glyceraldehyde and NADPH. PMID- 8699191 TI - Isolation and structure of isoculmorin from the marine fungus Kallichroma tethys. PMID- 8699192 TI - Induction of mature neuronal properties in immortalized neuronal precursor cells following grafting into the neonatal CNS. AB - RN33B, a conditionally-immortalized neuronal cell line, survives and differentiates following grafting into the neocortex and hippocampus of adult and neonatal rat hosts. We have previously shown that these cells assume shapes characteristic of endogenous neurons at the integration site and persist up to 24 weeks post-grafting. In the present study we use electron microscopy and immunohistochemistry to characterize such cells. Differentiated RN33B cells were identical in size to endogenous neurons and their sizes depended on the specific location of integration. RN33B cells in the granule cell layer of the dentate gyrus and CA3 and CA1 pyramidal layers were 9.0, 15.3, and 12.6 microns in diameter, respectively. Grafted RN33B cells received synapses from fibres of host origin. Differentiated cells expressed neuronal markers, but not glial markers. Some differentiated cells expressed glutamate both in vitro and in vivo whereas undifferentiated cells did not. Grafted RN33B cells that differentiated with morphologies similar to CA3 pyramidal neurons and pyramidal cortical neurons expressed Py antigen, a neuronal marker that is differentially expressed in endogenous large pyramidal neurons of the cerebral cortex and large pyramids of hippocampal field CA3. This Py immunoreactivity was region-specific and corresponded to the endogenous pattern of Py immunostaining. Collectively, these data indicate that RN33B cells are capable of region-specific differentiation and have the potential to integrate functionally into the host CNS. PMID- 8699193 TI - Neuropeptides and neurotransmitter-synthesizing enzymes in intrinsic neurons of the human urinary bladder. AB - The expression of neuropeptides, and the enzymes nitric oxide synthase and tyrosine hydroxylase were examined in intramural ganglia of human urinary bladder using single label immunocytochemistry. Scattered ganglia composed of between 1 36 neurons (median 4) were observed in all layers of the lateral wall of the bladder. These contained immunoreactivity to vasoactive intestinal peptide, nitric oxide synthase, neuropeptide Y, and galanin. Neurons within the bladder were heterogeneous with regard to their content of these antigens, with the proportion of immunopositive cells ranging from 58-84%. Occasional neurons with immunoreactivity to the catecholamine-synthesizing enzyme, tyrosine hydroxylase, were also observed. No cell somata, however, were immunoreactive for enkephalin, substance P, calcitonin gene-related peptide or somatostatin. Varicose terminals entering the ganglia were seen to form pericellular baskets surrounding some of the principal ganglion cells. The most prominent pericellular varicosities were those containing calcitonin gene-related peptide- or vasoactive intestinal peptide-immunoreactivity, followed by those with immunoreactivity for enkephalin, neuropeptide Y, or galanin. Less common were pericellular varicosities with substance P-immunoreactivity, which may represent collateral processes of unmyelinated primary sensory fibres, and presumptive noradrenergic processes containing tyrosine hydroxylase. Some calcitonin gene-related peptide immunoreactive varicosities constituted a distinct type, terminating as large pericellular boutons 2-4 microns in diameter. Fibres containing nitric oxide synthase- or somatostatin-immunoreactivity were not associated with the intramural neurons. The results demonstrate that intrinsic neurons within the human urinary bladder express a number of neuroactive chemicals, and could in principle form circuits with the potential to support integrative activity. PMID- 8699194 TI - Tyrosine hydroxylase, neuropeptide Y, substance P, calcitonin gene-related peptide and vasoactive intestinal peptide in nerves of rat periovarian adipose tissue: an immunohistochemical and ultrastructural investigation. AB - Rat periovarian adipose tissue contains unilocular adipocytes and some multilocular adipocytes that, following acclimation to cold, become more numerous and give rise to periovarian brown fat areas. We studied the occurrence and distribution of tyrosine hydroxylase, neuropeptide Y, substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, methionine enkephalin, neurotensin, galanin, and cholecystokinin 9-20 in the nerves of rat periovarian tissue maintained at 20 degrees C (control rats), acclimated at 4 degrees C (cold acclimated rats) and at 28 degrees C (warm-acclimated rats). In the periovarian tissue of control and warm-acclimated rats, tyrosine hydroxylase-like, neuropeptide Y-like, substance P-like and calcitonin gene-related peptide-like immunoreactive elements (putative nerves) were present in the blood vessels. In the periovarian tissue of cold-acclimated rats, we found: (1) a more widespread vascular distribution of these neuropeptides; (2) tyrosine hydroxylase-like and calcitonin gene-related peptide-like immunoreactive elements among paucilocular and multilocular adipocytes (parenchymal-like nerves); (3) vasoactive intestinal peptide-like immunoreactive elements in some arteries. Investigation by EM showed the presence of heterogeneous non-myelinated axons both associated with capillaries and among paucilocular and multilocular adipocytes (parenchymal fibres) in periovarian brown fat areas. In conclusion, periovarian brown fat contains the same neuropeptides, with the same vascular and parenchymal distribution, already seen in typical depots of brown fat. PMID- 8699195 TI - Age-related reduction of the satellite cell sheath around spinal ganglion neurons in the rabbit. AB - The volumes of the nerve cell bodies and those of the enveloping satellite cell sheaths from spinal ganglia of young adult and aged rabbits were determined by morphometric methods using the electron microscope. The mean volume of the nerve cell bodies was greater in the old rabbits than in young adults; this is probably related to the larger body size of the old animals. The mean volume of the satellite cell sheaths was, however, smaller in the aged rabbits than in the young adults. Consequently the volume ratio between the satellite cell sheaths and the related nerve cell bodies was significantly smaller in the aged animals. Since satellite cells play an important role in the support of the neuron, the reduction in volume of the perineuronal sheath could be associated with a decrease in the trophic activity of satellite cells towards the enveloped neuron with consequences for neuronal activity. Furthermore, in the satellite cell sheaths of old rabbits, the number and extension of gaps that leave the neuronal surface directly exposed to the basal lamina were significantly increased. Since spinal ganglia lack a blood-nervous tissue barrier, only the satellite cell sheath controls the traffic of material to the nerve cell body. Because the neuronal surface unprotected by the satellite cell envelopment is significantly more extensive in the spinal ganglia of old rabbits than in those of young adults, the nerve cells of the former are more exposed to potential damage by harmful substances. A dense undercoating was seen very frequently beneath the portions of the neuronal plasma membrane not covered by satellite cells. PMID- 8699196 TI - Peripheral nerve explants grafted into the vitreous body of the eye promote the regeneration of retinal ganglion cell axons severed in the optic nerve. AB - We have conducted experiments in the adult rat visual system to assess the relative importance of an absence of trophic factors versus the presence of putative growth inhibitory molecules for the failure of regeneration of CNS axons after injury. The experiments comprised three groups of animals in which all optic nerves were crushed intra-orbitally: an optic nerve crush group had a sham implant-operation on the eye; the other two groups had peripheral nerve tissue introduced into the vitreous body; in an acellular peripheral nerve group, a frozen/thawed teased sciatic nerve segment was grafted, and in a cellular peripheral nerve group, a predegenerate teased segment of sciatic nerve was implanted. The rats were left for 20 days and their optic nerves and retinae prepared for immunohistochemical examination of both the reaction to injury of axons and glia in the nerve and also the viability of Schwann cells in the grafts. Anterograde axon tracing with rhodamine-B provided unequivocal qualitative evidence of regeneration in each group, and retrograde HRP tracing gave a measure of the numbers of axons growing across the lesion by counting HRP filled retinal ganglion cells in retinal whole mounts after HRP injection into the optic nerve distal to the lesion. No fibres crossed the lesion in the optic nerve crush group and dense scar tissue was formed in the wound site. GAP-43 positive and rhodamine-B filled axons in the acellular peripheral nerve and cellular peripheral nerve groups traversed the lesion and grew distally. There were greater numbers of regenerating fibres in the cellular peripheral nerve compared to the acellular peripheral nerve group. In the former, 0.6-10% of the retinal ganglion cell population regenerated axons at least 3-4 mm into the distal segment. In both the acellular peripheral nerve and cellular peripheral nerve groups, no basal lamina was deposited in the wound. Thus, although astrocyte processes were stacked around the lesion edge, a glia limitans was not formed. These observations suggest that regenerating fibres may interfere with scarring. Viable Schwann cells were found in the vitreal grafts in the cellular peripheral nerve group only, supporting the proposition that Schwann cell derived trophic molecules secreted into the vitreous stimulated retinal ganglion cell axon growth in the severed optic nerve. The regenerative response of acellular peripheral nerve-transplanted animals was probably promoted by residual amounts of these molecules present in the transplants after freezing and thawing. In the optic nerves of all groups the astrocyte, microglia and macrophage reactions were similar. Moreover, oligodendrocytes and myelin debris were also uniformly distributed throughout all nerves. Our results suggest either that none of the above elements inhibit CNS regeneration after perineuronal neurotrophin delivery, or that the latter, in addition to mobilising and maintaining regeneration, also down regulates the expression of axonal growth cone-located receptors, which normally mediate growth arrest by engaging putative growth inhibitory molecules of the CNS neuropil. PMID- 8699197 TI - Ultrastructural association of hyaluronan with rat unmyelinated nerve fibres. AB - A potential association between hyaluronan and unmyelinated nerve fibres in the PNS (rat skin and iris) and CNS (rat retinal inner plexiform and nerve fibre layers) was investigated at the ultrastructural level using two different hyaluronan-binding probes (link protein-gold and aggrecan-gold). Neuronal and glial cell plasma membranes, as well as the periaxonal space in between, were specifically labelled, suggesting that hyaluronan is secreted by these cells and utilized locally. Intracelluarly, weak labelling of mitochondrial profiles was observed. PMID- 8699198 TI - Morphology of diaphragm neuromuscular junctions on different fibre types. AB - We hypothesize that the morphology of the neuromuscular junction on different muscle fibre types varies, reflecting differences in activation history. In the rat diaphragm muscle, we used a three-colour fluorescent immunocytochemical technique to simultaneously visualize (1) innervating axons and presynaptic nerve terminals, (2) motor endplates, and (3) myosin heavy chain isoform expression (muscle fibre type). Laser-scanning confocal microscopy was then used to optically section the triple-labelled muscle fibres, and create three-dimensional views of the neuromuscular junction. Type I fibres were innervated by the smallest axons, and type IIa, IIx and IIb fibres by progressively larger axons. Absolute planar areas of nerve terminals and endplates progressively increased from type I, IIa, IIx to IIb fibres. When normalized for fibre diameter, planar areas of nerve terminals were largest on type I fibres, with no difference among type II fibres. The normalized planar area of endplates were larger for type I and IIb fibres, compared to type IIa and IIx fibres. The three-dimensional surface area of endplates was largest on type I fibres, with no differences across type II fibres. When normalized for fibre diameter, endplate surface areas increased progressively from type I, IIa, IIx to IIb fibres. The branching patterns of both nerve terminals and endplates varied across fibre types. The number of nerve terminal and endplate branches increased progressively from type I, IIa, IIx to IIb fibres. Conversely, individual branch length was longest on type I fibres, and shortest on type IIb fibres. The extent of overlap of pre- and postsynaptic elements of the neuromuscular junction decreased progressively on type I, IIa, IIx and IIb fibres. We conclude that these morphological differences at the neuromuscular function of different fibre types reflect differences in activation history and may underlie phenotypic differences in neuromuscular transmission. PMID- 8699199 TI - Development of a clinical asthma score for use in hospitalized children between 1 and 5 years of age. AB - The objective of this study was to develop a clinical asthma score (CAS) for use in hospitalized children between 1 and 5 years of age. Formal approaches to item selection and reduction, reliability, discriminatory power, validity, and responsiveness were used. The final CAS consisted of five clinical characteristics: respiratory rate, wheezing, indrawing, observed dyspnea, and inspiratory-to-expiratory ratio. Interrater reliability was high (weighted kappa = 0.82), and the CAS was discriminatory (Ferguson's delta = 0.92). The CAS was valid, with a strong correlation with length of hospital stay (Spearman's correlation = 0.47, p < 0.05) and drug dosing interval (Spearman's correlation = 0.58, p < 0.01). The CAS was responsive, with a significant change in CAS from admission to discharge (Wilcoxon signed rank test, p < 0.01). This score, for use in hospitalized preschool children, is reliable, discriminatory, valid, and responsive. PMID- 8699200 TI - Psychosocial adjustment and quality of life in women with breast cancer and benign breast problems: a controlled comparison. AB - Comparison of psychosocial adjustment in women with breast cancer (BC) and women with benign breast problems (BBP) has been hampered by a failure to control for age differences between these groups, as well as a failure to assess positive psychosocial adaptation in addition to psychological distress. Age-matched women with breast cancer (n = 80) and benign breast problems (n = 80) completed measures of psychological distress, positive psychosocial adaptation, and general quality of life (QOL). Breast cancer patients had completed primary treatment for breast cancer a mean of 24.6 months prior to participation (range, 6-57 months). Comparison of the BC and BBP groups indicated that the BC group reported (1) poorer physical health and functioning, (2) no differences in psychological distress, and (3) greater positive psychosocial adaptation, such as improved life outlook, enhanced interpersonal relationships, and deeper spiritual and religious satisfaction. Results support the theoretical position that cancer is a transitional event, that is, a traumatic event that alters an individual's assumptive world with the potential to produce long-lasting changes of both a positive as well as negative nature. This underscores the importance of using measures of both psychological distress and positive psychosocial adaptation when assessing psychological adjustment following transitional events such as breast cancer. PMID- 8699201 TI - Generalizability of clinical studies conducted at tertiary care medical centers: a population-based analysis. AB - The Marshfield Epidemiologic Study Area (MESA), a geographically defined population registry at one of the participating sites in SUPPORT (a multicenter study of the care of seriously ill hospitalized patients) permitted assessment of generalizability in that study. On the basis of age- and sex-specific rates of enrollment of SUPPORT patients in MESA, we estimate that about 400,000 patients per year would fulfill SUPPORT eligibility criteria in the United States. However, an estimated 925,000 patients, particularly the elderly and those with impairments in their activities of daily living (ADLs), have SUPPORT-like illnesses annually, but do not receive the aggressive care required for study enrollment. The absence of patients not interested in aggressive care in tertiary care-based studies is compounded by the overrepresentation of patients referred from distant areas to the tertiary care center. Such patients tended to be older and to have different diseases than patients in MESA. Care should be taken in generalizing results from clinical and epidemiologic studies conducted at tertiary care centers. PMID- 8699202 TI - Regional variation in survival following the diagnosis of cancer. AB - Recent studies have documented substantial geographical variation in patterns of treatment of cancer and other diseases. Because cancer treatment is not uniform nationwide, survival following the diagnosis of cancer might also be expected to vary geographically. Survival data from the nine population-based registries in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program were analyzed for cancers of the stomach, colon, rectum, lung, breast, uterus, ovary, prostate, and bladder (n = 401,861). The patients included all non-Hispanic white patients diagnosed with cancer of one of the selected sites during 1983-1991. Regional variation in crude five-year survival rates across the nine SEER areas was most marked for cancers of the uterus and prostate. For uterine cancer, for example, five-year survival ranged from 73.2% in Connecticut to 84.0% in Hawaii. Less marked variation was observed for cancers of the colon, rectum, and breast. For cancers of the bladder, ovary, stomach, and lung, survival rates five years after diagnosis were relatively invariant across the SEER areas. Observed differences in survival rates, although statistically significant, were relatively modest from the standpoint of the practicing physician. Nonetheless, the general pattern of regional variation was unchanged after adjustment for sex, age, stage, and surgical treatment and when analysis was limited to patients younger than 70 years, who would be anticipated to have the least comorbidity. PMID- 8699203 TI - Measures of adiposity and coronary heart disease mortality in the Chicago Western Electric Company Study. AB - Associations of body mass index (BMI), two measures of percent body fat derived from skinfolds, body weight adjusted for height, triceps and subscapular skinfolds, and their sum, with 22-year coronary heart disease (CHD) mortality were compared in 1707 white men ages 40-55 years at baseline (1958) and free of CHD and cancer in 1961 in the Western Electric Study. Because associations of adiposity measures with CHD mortality differed by length of follow-up, analyses were conducted separately for the first 14 years of follow-up and years 15 through 22. In Cox regression analyses, none of the adiposity measures was significantly related to CHD mortality for the first 14 years of follow-up. For years 15-22, all adiposity measures, except triceps skinfold, were significantly related with adjustment for age, as well as eight other covariates. These results indicate that a positive relation of adiposity to CHD risk may not become apparent until several years after the assessment of adiposity. PMID- 8699204 TI - Insulin sensitivity and blood pressure in a biethnic sample: the Miami Community Health Study. AB - An association between blood pressure and insulin sensitivity among normotensive African-Americans has not been demonstrated consistently in epidemiologic studies. Part of the discrepancy may be due to studying persons with profound obesity-an insulin-resistant state itself. The association between insulin mediated glucose uptake (i.e., insulin sensitivity) and blood pressure was examined among 25 nondiabetic African-American and 28 white non-Hispanic persons aged 25-44 years who ranged from normal weight to obese, using the hyperinsulinemic euglycemic clamp technique. In bivariate analyses, insulin sensitivity was inversely related to systolic (p < 0.01) and diastolic blood pressure (p = 0.08) among African-American persons and to diastolic blood pressure among white non-Hispanic subjects (p < 0.05). Covariate adjustment for age and sex had only a marginal effect on these results. When the data were pooled and further adjusted for ethnicity, insulin sensitivity remained significantly associated with both systolic and diastolic blood pressure (p < 0.01 for each). To consider the effect of obesity, body mass index (BMI) was divided at the sample median (26.5 kg/m2) and the analyses were repeated within each stratum. Among those whose BMI was below the median value, each increment in insulin sensitivity was associated with a 2-mmHg decrease in systolic blood pressure (p = 0.02). These results suggest that ethnicity was not a strong effect modifier in this sample and indicated that insulin sensitivity was inversely related to blood pressure level in these normotensive African-American and white, non-Hispanic participants. PMID- 8699205 TI - Out-of-hospital sudden death referring to an emergency department. AB - Over an 11-year period, autopsies were performed on 957 of 1038 nontraumatic deaths in the Emergency Department of the Central Hospital in Ferrara, Italy. Of these 957 cases, 732 (76.5%) met criteria for sudden death. In 100 (14%) of these cases, the death could be attributed to pulmonary embolism (55 cases), stroke (17), or rupture of aortic aneurysm (28). Acute myocardial infarction accounted for 403 (55%) of all sudden deaths. Severe coronary artery disease was found in 340 (84%) of these 403 deaths, with plaque fissuring or thrombi in 189 or 151 cases, respectively. Among the 229 sudden deaths for whom no immediate cause could be determined (31% of the total population), all had evidence of heart disease: 147 individuals had severe coronary artery disease, with plaque fissuring or thrombi found in 72 or 43, respectively. The remaining cases with no immediate cause of death had evidence of a cardiomyopathy (61) or valvular disease (21). We conclude that acute myocardial infarction accounts for the majority of cases of nontraumatic sudden death in our Emergency Department. Altogether, 84% of these patients had severe coronary artery disease. In approximately one-third of cases for whom no immediate cause of sudden death could be determined, all had evidence of heart disease, and about two-thirds had severe coronary artery disease. PMID- 8699206 TI - Standardization of blood pressure measurement in an international comparative study. AB - In the context of a collaborative study on the epidemiology of hypertension in populations of West African origin procedures for standardization of the measurement of blood pressure were evaluated. Comparisons of mean levels of blood pressure, which in large part determine prevalence rates, are highly sensitive to differences in technique. While rotating a single field team may be the ideal approach to multisite studies, it is not practical in international collaborative research. Appropriate techniques to standardize multiple teams over a long period of time have not been well developed, however. In the present study 8981 individuals were examined in eight sites in six countries with the standard mercury sphygmomanometer. An evaluation of the effectiveness of central training, site visits, monitoring of digit preference, and the use of an electronic device for internal standardization is described. In all but one of the sites reliability was high and comparable to the observers at the Coordinating Center. Digit preference for the entire set of measurements was limited (frequency of terminal zero = 23.5% for systolic and 28.9% for diastolic readings) and could be shown to have virtually no effect on prevalence rates or correlation estimates. Mean differences among observers within a given site and between sites were small (+/- 0-5 mmHg). While logistically complex, these methods can provide the basis for standardization in international comparative blood pressure surveys. PMID- 8699207 TI - Applying the realized probability of dying to cancer survival. AB - Age comparisons of survival in cancer cohorts generally utilize relative survival rates, which are based on indicators of the probability of survival for a given number of years after diagnosis. Cancer relative survival rates for the same number of years tend to decline as age at diagnosis increases. However, the same number of years of survival reflects higher relative longevity at older ages than at younger ages. The realized probability of dying (RPD) is a survival measure that expresses individual survival time after diagnosis relative to the survival distribution of an age-, race-, and sex-specific reference population, in effect weighing individual survival time more heavily as age at diagnosis increases. The purpose of this study was to apply the RPD as a survival measure in cancer epidemiology. Two cohorts of cancer patients, white males with prostate cancer and white females with breast cancer, aged 55 years and over at diagnosis, were followed for 15 years. Although older subjects survived less time after diagnosis than younger subjects, they achieved more favorable RPD values. We present survival analysis methods for analyzing the RPD in this population, an approach not previously used with this measure. The implications for use of the RPD in cancer epidemiology are discussed. PMID- 8699208 TI - Smoking prevalence in neighborhood and hospital controls: implications for hospital-based case-control studies. AB - It is widely believed that the prevalence of smoking among hospital patients is greater than that of the general population because many conditions for which patients are hospitalized are caused by or associated with smoking, and that this increased prevalence may bias results of case-control studies of tobacco-related diseases. For this reason, many authors have suggested excluding from the control series patients hospitalized for tobacco-related illnesses. The present study investigated potential selection bias for hospital compared to neighborhood controls in studying tobacco-related diseases. The 709 cases from six U.S. cities had tobacco-related cancers or myocardial infarction. They were individually matched to one hospital control and to one neighbor. After excluding patients with tobacco-related diseases, hospital controls were less often current smokers and more often former smokers than neighborhood controls. Among male ever smokers, hospital controls tended to smoke more cigarettes per day than neighborhood controls. Compared with the U.S. population, there was an overrepresentation of smokers in neighborhood controls rather than an under representation of smokers in hospital controls. Relative risk estimates varied according to type of control. Choosing between hospital and neighborhood controls in case-control studies should be dictated by criteria related to the study hypothesis, participation, or cost. In particular, exclusion of hospital controls with diseases known to be tobacco-related seems to be a successful strategy for reducing selection bias. PMID- 8699209 TI - Carcinogenic effects of diesel emissions and lung cancer: the epidemiologic evidence is not causal. AB - The effects of diesel engine exhaust in lung carcinogenesis have been evaluated by several scientific organizations and government agencies. This complex issue has required a multidisciplinary approach including atmospheric measurements, toxicology, chemical carcinogenesis, epidemiology, and risk assessment. One important aspect of the epidemiological studies that deserves further attention is the confounding effects of cigarette smoking. Only some epidemiological studies have statistically adjusted for cigarette smoking, usually by years of smoking, cigarettes per day, or pack-years. Some studies obtained smoking information from proxy interviews. However, differences in "tar" intake, interpuff interval, depth of inhalation, and other smoking behavior patterns were not evaluated. These smoking parameters are rarely collected for occupational data analysis, yet the inability to adjust statistically for such parameters may result in a small degree of residual confounding. Because the highest odds ratios for lung cancer associated with diesel engine exhaust are usually less than 2 or 1.5, possible residual confounding effects of smoking may have resulted in spurious associations. PMID- 8699210 TI - Validation of the Danish Birth Registration. AB - We assessed validity and reliability of data on four serious pregnancy complications and gestational age in two national registers, the Medical Birth Register (MBR) and the National Register of Hospital Discharges (NRHD). From a cohort of all women in Denmark who gave birth to their first and second singleton infant in 1982-1987, a review was made of a selected sample of 1662 medical records. Regarding registration of pregnancy complications, there was good agreement (kappa above 0.6) between medical records and the registers, and between the registers. However, there was a tendency toward understatement evidenced by low sensitivity of three of four pregnancy complications. The level of agreement (43%) for length of gestation was disappointing. The number of systematic and nonsystematic errors indicate that there was about 52% more singleton preterm deliveries in Denmark in 1982 than previously reported (6.9% instead of 4.5%). It is concluded that the validity of the Danish birth registers should be improved by explicit definitions, increased use of raw data, and data collection by motivated professionals at birth. PMID- 8699211 TI - On the use of auxiliary data to estimate the survival function and its variance: an application to acquired immunodeficiency syndrome. AB - Prospective studies have as their goal the estimation of the survival function when the time to the specified event may be censored due to loss to follow-up or to the termination of the study before the event of interest occurs. In such a study, information about an auxiliary event, correlated to the event of interest, is often available. An example of such an auxiliary event in cancer studies is remission or relapse. A stochastic model was proposed by Lagakos, which utilizes this type of information in the analysis of survival studies [1]. The primary objective of using an auxiliary information is to improve the estimation of survival. This article proposes a method to estimate the variance of the estimator of the survival function S(t) for the model including such auxiliary information. Thus, we compute for different situations the relative efficiency of the estimator of S(t) using the stochastic model to the estimator of S(t) using only survival data. The method is applied to data from a prospective study of 379 HIV-seropositive homosexual men, of whom 31 developed AIDS. In our example, the auxiliary event is defined by the level of CD4 lymphocyte counts using distinct threshold values, for instance 200 cells/mm3, while the event of interest is the time to development of AIDS. PMID- 8699212 TI - Inappropriate use of bivariable analysis to screen risk factors for use in multivariable analysis. AB - The use of bivariable selection (BVS) for selecting variables to be used in multivariable analysis is inappropriate despite its common usage in medical sciences. In BVS, if the statistical p value of a risk factor in bivariable analysis is greater than an arbitrary value (often p = 0.05), then this factor will not be allowed to compete for inclusion in multivariable analysis. This type of variable selection is inappropriate because the BVS method wrongly rejects potentially important variables when the relationship between an outcome and a risk factor is confounded by any confounder and when this confounder is not properly controlled. This article uses both hypothetical and actual data to show how a nonsignificant risk factor in bivariable analysis may actually be a significant risk factor in multivariable analysis if confounding is properly controlled. Furthermore, problems resulting from the automated forward and stepwise modeling with or without the presence of confounding are also addressed. To avoid these improper procedures and deficiencies, alternatives in performing multivariable analysis, including advantages and disadvantages of the BVS method and automated stepwise modeling, are reviewed and discussed. PMID- 8699213 TI - Sampling distributions of p(pos) and p(neg). AB - In the absence of a gold standard, assessment of clinimetric properties of dichotomous variables should include reporting of the proportions of positive agreement (ppos) and negative agreement (pneg). For example, for a patient considering whether or not to undergo elective surgery, ppos represents the probability that a second physician would concur with a recommendation to undergo surgery and pneg represents the probability that a second physician would concur with a recommendation not to undergo surgery. This article uses a conditional binomial distribution to derive the sampling distributions of ppos and pneg. The sampling distribution can be used as a basis for confidence intervals and hypothesis tests. PMID- 8699214 TI - Age and severe adverse drug reactions caused by nifedipine and verapamil. Gruppo Italiano di Farmacovigilanza nell' Anziano (GIFA). AB - The association of age with risk for severe adverse drug reactions (SADRs) was studied in 2371 and 862 hospitalized patients taking nifedipine and verapamil, respectively. Nifedipine caused hypotension (n = 22), tachycardia (n = 3), and acute renal failure (n = 1) (total SADR rate, 1.1%, 26/2371). Verapamil caused hypotension (n = 3), bradycardia (n = 9), and atrioventricular blocks (n = 2) (total SADR rate, 1.6%, 14/862). The mean age of patients with and without SADRs was for nifedipine 77.1 +/- 1.7 and 71.8 +/- 0.8 years, respectively (p < 0.05), and for verapamil 73.4 +/- 2.9 and 73.1 +/- 0.4 years, respectively. Sex, length of stay, comorbidity, polypharmacy, intake of slow-release preparations, daily dosage, and new intake of calcium antagonists were examined as potential confounders of the age-SADR association. After adjusting for potential confounders, age was significantly and independently associated with SADRs caused by nifedipine, but not with SADRs caused by verapamil (OR = 1.69, 95% CI = 1.05 2.72 and OR = 1.06, 95% CI = 0.63-1.68 for 10-year increase, respectively). Although nifedipine and verapamil did not have significantly different rates of SADRs, an age-related gradient was found only for nifedipine. PMID- 8699215 TI - Distribution of prescription drug exposures in the elderly: description and implications. AB - Using data from a comprehensive prescription drug benefit program in British Columbia, we studied the distribution of prescription drug expenditures and exposures in the community-dwelling elderly over a 1-year period. Overall, 84% of the population was exposed to at least one prescription drug. The 11% of individuals with the highest level of use accounted for 50% of total drug expenditures. Individuals 65 to 74 years of age were exposed to a median of 2.2 different drugs during the year compared to a median of 3.8 for those 75 years of age and over. Twenty-four percent of the 65- to 74-year-old population were exposed to six or more different drugs during a 1-year period compared to 37% of the 75 years and over population. Central nervous system and cardiovascular drugs were most commonly responsible for multiple drug exposures. Forty-eight percent of the individuals exposed to six or more different drugs received prescriptions from three or more different physicians. In British Columbia, 98% of the elderly receiving six or more different drugs received at least one prescription from a general practitioner or a family practitioner. PMID- 8699216 TI - On biases in a study of the effects of occupational and individual factors on the risk of neck trouble. PMID- 8699217 TI - Problems in the use of aggregate measures. PMID- 8699218 TI - Persistent problems in acronyms. PMID- 8699219 TI - Comments on a pragmatic trial. PMID- 8699221 TI - Proliferation and motility responses of primary and recurrent gliomas related to changes in epidermal growth factor receptor expression. AB - Astrocytic neoplasms show a high incidence of elevated or mutated epidermal growth factor receptor (EGFR) expression. Although proliferative effects from EGFR activation are well described, the role that changes in this receptor play in glioma growth and migration remain poorly addressed. This report characterizes changes in the levels of EGFR expression in three glial tumors at initial presentation (resection) and at the time of recurrence. By quantitative flow cytometry the mean level of EGFR expression increased, decreased, or remained the same in different recurrent astrocytomas relative to their primary tumor cells. Immunocytochemistry for EGFR on monolayer cells corroborated the level of expression in the recurrent tumors relative to their matched primary specimen. Immunoprecipitation indicated that 170 kd EGFR was expressed in each of the tumors, and showed normal down regulation following treatment with EGF. Proliferation response to EGF was seen in only 1/6 instances, but was concentration-dependent when observed. Stimulated migration of the cells was frequently seen and was also concentration-dependent on EGF; the magnitude of response was related to the relative level of 170 kd EGFR expression in the cells. EGFR immunostaining of tissue sections from the tumors confirmed the levels of EGFR expressed in primary and recurrent astrocytomas as was seen in the cultured cells. These results indicate that the relative levels of EGFR in early passage cell cultures from glioma specimens concurs with the measured tissue levels of expression. Human glioma cells are more responsive to migration induction than proliferation induction by EGF. PMID- 8699220 TI - Effect of calcium antagonists on regional cerebral blood flow in transplanted rat brain tumors. AB - We studied the effect of intracarotid infusion of various calcium antagonists on regional CBF (rCBF) in the C6 rat glioma by a hydrogen clearance method. Nimodipine at doses of 0.1, 0.5 and 1 microgram/kg/min was found to produce tumor specific increases in the rCBF (40.2 +/- 18.4%, p < 0.01, 67.8 +/- 32.6%, p < 0.001 and 37.3 +/- 37.2%, p < 0.05, respectively) without affecting systemic blood pressure. Regarding the time course of the nimodipine effects, at a dose of 0.5 micrograms/kg/min, rCBF in the tumor showed maximum value at fifteen minutes after the start of the intracarotid infusion. Diltiazem at doses of 5, 20, and 40 micrograms/kg/min also increased tumor rCBF in a dose-dependent manner (27.9 +/- 12.5%, p < 0.001, 52.0 +/- 21.8%, p-AN 0.001 and 54.5 +/- 18.4%, p < 0.001, respectively). Both nifedipine and flunarizine significantly increased the rCBF in the tumor, while they did not cause a higher percent increase of the rCBF when compared with those of nimodipine and diltiazem. No significant percent increase of the rCBF in the tumor was observed in verapamil treated rats. These results indicate that tumor vessels may have an altered response to calcium antagonists, especially to nimodipine and diltiazem, when compared to normal brain capillaries. The varied responses to calcium antagonists could be explained by their differences in tissue selectivity and affinity to calcium channels. PMID- 8699222 TI - Reconstituted basement membrane (matrigel) enhances the growth of human glioma cell lines in nude mice. AB - Transplantation of human cancers into immunologically deficient mice is widely used to study potential therapeutic interventions in vivo. For brain tumor research, however, several factors limit more widespread application of this animal model. First, only a minority of human glioma-derived cell lines are tumorigenic in nude mice. In addition, even for tumorigenic cell lines, tumor take is variable and growth is often slow for tumors derived from cell inoculums. Reconstituted components of tumor basement membrane (matrigel) have been found to improve the growth in nude mice of several types of human tumors originating outside the central nervous system when premixed with the tumor cells before subcutaneous inoculation. We investigated the ability of matrigel to enhance the growth in nude mice of tumors derived from the human glioma cell lines U-251 MG, U-373 MG, SNB-78 and SNB-101. Athymic nude mice (NIH Swiss background, nu/nu genotype) were inoculated subcutaneously with 1.0 x 10(6) tumor cells alone or after premixing with an equal volume of liquid matrigel. U-251 and U-373 cells were tumorigenic, with palpable tumors present by about 2 to 3 weeks. Co injection of these cell lines with matrigel resulted in higher tumor-take rates, from 6/10 to 8/8 animals for U-251 at 60 days, and from 9/12 to 11/11 animals for U-373 at 60 days. Matrigel also enhanced tumor growth, with tumors at 45 days significantly larger than those formed in the absence of matrigel, for both cell lines (p < 0.01). SNB-78 and SNB-101 cells did not give rise to progressively enlarging solid tumors with or without matrigel. Matrigel enhances the growth of tumorigenic human gliomas in athymic nude mice. This technique provides a model with more consistent tumor take and more rapid growth kinetics for human glioma cell lines that are tumorigenic in nude mice. PMID- 8699223 TI - Granulocyte colony-stimulating factor (G-CSF) production by astrocytoma cells and its effect on tumor growth. AB - We investigated the expression of granulocyte colony-stimulating factor (G-CSF), G-CSF mRNA, and G-CSF receptor mRNA in astrocytoma cell lines, G-CSF in astrocytoma cyst fluid, and the effect of recombinant G-CSF on the proliferation of astrocytoma cells in vitro and in vivo. We first examined supernatants from astrocytoma cell lines for the presence of G-CSF by ELISA. G-CSF was expressed by 6 of 14 astrocytoma cell lines constitutively, and, was detected after stimulation with tumor necrosis factor-alpha (TNF-alpha) in four of eight cell lines which did not produce G-CSF constitutively. G-CSF mRNA was detected by reverse-transcriptase polymerase chain reaction (RT-PCR) in all cell lines studied, suggesting that astrocytoma cells have the potential to produce G-CSF. We also analyzed the presence of G-CSF by ELISA in five astrocytoma cyst fluids. G-CSF was detected in one case. Although, in vitro study, the growth of glioma cells was not affected by rG-CSF, in a mouse model, the administration of G-CSF significantly shortened the time to tumor appearance and accelerated tumor growth. These data suggest that G-CSF has a stimulatory effect on the proliferation of astrocytoma cells in vivo through the mediation of host factors. PMID- 8699224 TI - Fabrication and testing of a device capable of reducing the incidence of ventricular shunt promoted metastasis. AB - PURPOSE/OBJECTIVE: Some malignant brain tumors shed cells into the cerebrospinal fluid (CSF). These tumors may implant throughout the neuroaxis via the CSF. With the placement of a ventriculoperitoneal (VP) or ventriculoatrial (VA) shunt, tumor cells free-floating in the CSF may be carried through the shunt to the remainder of the body. Mechanical filtration devices to prevent this are not reliable. We report the development of a new device capable of reducing the incidence of shunt promoted metastasis. MATERIALS & METHODS: The device exposes the draining CSF, as it passes through a baffle system, to a localized high intensity radiation field adequately shielded from surrounding normal tissue. The prototype consists of geometrically fixed iodine-125 (125I) sources. The device accommodates the maximum CSF flow rate of 500 ml/24 hours. Radiation exposure to clonogenic cells occurs as they transit through the baffle system. Since the volume of the prototype device is 14 ml, a tumor cell floating through the device will be exposed to radiation for 40 minutes. Utilizing the human medulloblastoma cell line D425 MED, a limiting dilution clonogenic assay was performed. Suspensions of tumor cells in liquid medium were pumped through the device at the maximum anticipated CSF production rate of 0.35 ml/min. After the cells, with their tissue culture medium, were received from the device, a series of nine 5 fold dilutions were prepared from the suspensions which initially contained 10(6) tumor cell/ml. Plates were then incubated and growth was demonstrated by visual scoring of colonies of more than 20 cells. Limiting dilution data analysis was performed. Radiation surveys of the fully loaded (approximately 1.8 Ci) 125I prototype were conducted. A well calibrator was used to measure the activity of the fully loaded device. RESULTS: When the device was loaded with 125I seeds providing a dose of 364-479 cGy the probability of clonogen survival was 0.033. Radiation exposure levels at the exterior surface of the shielded device were in the range of 2-5 mR/hr and thus fell within guidelines for acceptable normal tissue exposure. Attenuation of radiation by the shielding case for the fully loaded device was 10(-5). CONCLUSION: The device kills medulloblastoma cells as they are pumped through it. If the risk of metastasis is linearly related to the number of clonogenic cells, then the device would, we infer, reduce the risk of shunt-born metastasis by a factor of 0.033 and merits further investigation. PMID- 8699225 TI - Solitary metastasis to the choroid plexus of the lateral ventricle. Report of three cases and a review of the literature. AB - Three cases of cancer metastasis to the choroid plexus of the lateral ventricle are reported. The metastases were from sigmoid colon cancer, renal cell carcinoma and pulmonary cancer, and were located in the trigone in two cases and the right inferior horn in one. Total removal was accomplished in all cases without any complications. In addition, eight reported cases of single brain metastasis to the choroid plexus of the lateral ventricle, including clinical and radiological features, are discussed. Peritumoral edema on computed tomographic (CT) scan or magnetic resonance (MR) imagining was found to be an important feature of metastasis developing at this site. PMID- 8699226 TI - Cisplatin-induced autonomic neuropathy: does it really exist? AB - The neurotoxic side-effects of cisplatin affect predominantly the large, myelinated fibres of peripheral nerves, leading to a sensory neuropathy. Several reports of cisplatin-associated autonomic neuropathy have been published. Autonomic dysfunction however, is caused by a neuropathy of small unmyelinated nerve fibres. By using the absolute pupil diameter as a parameter of autonomic nervous system function, we studied autonomic neuropathy in the eye of cisplatin intoxicated rats. In addition, we examined autonomic cardiovascular function by measuring the change in heart rate (HR) and mean arterial blood pressure (MAP) in response to intravenous phenylephrine (PHE) and tyramine (TYR). No significant differences in mean pupil diameter developed in cisplatin-intoxicated rats (n = 12) in the course of 9 weeks (total cumulative dose cisplatin 18 mg/kg) compared with normal controls (n = 9) MANOVA, F1,19 = 0.88, P < 0.36). The PHE- and TYR induced changes in MAP and HR were virtually the same in cisplatin-intoxicated rats when compared with normal controls. We conclude that cisplatin probably does not cause autonomic dysfunction, at least not in rats, in doses commonly used and which are known to cause a peripheral sensory neuropathy. PMID- 8699227 TI - Multiple brain metastases: a rare manifestation of adenoid cystic carcinoma of the parotid gland. AB - A rare case of multiple hematogenous brain metastases from adenoid cystic carcinoma of the parotid gland is reported. The patient had a parotid tumor that was treated ten years prior to the appearance of the brain metastases. Magnetic resonance imaging (MRI) and histological findings, as well as the radiation therapy response, of this tumor are presented. PMID- 8699228 TI - Prognostic significance of preoperative MRI scans in glioblastoma multiforme. AB - Tumor necrosis, enhancement, and associated edema in patients with glioblastoma multiforme (GBM) represent biological variables that can be quantitated on preoperative MRI scans. We reviewed 48 highly selected patients, all of whom had supratentorial lesions, had undergone gross total tumor resection, and had received adjuvant treatments (radio- and chemotherapies). None of these patients had had surgery for recurrent tumor resection and none had harbored multifocal tumors. The median age was 50 years. The median Karnofsky performance score was 80. Multivariate analysis using the Cox regression model revealed that the strongest prognostic variable was the amount of tumor necrosis on preoperative scan (P < 0.001), with median survivals of 42, 24, 15, and 12 months for tumor necrosis grades of 0 (7 'pts'), I (11 'pts'), II (9 'pts'), and III (21 'pts'), respectively. The intensity of enhancement of the tumor nodule was another prognostic factor (P = 0.003), with median survivals of 35, 18, and 13.5 months for enhancement grades of 0 (2 'pts'), I (22 'pts'), and II (24 'pts'), respectively. The extent of peritumoral edema had a quadratic effect (P = 0.001), with grades I (19 'pts'), II (22 'pts'), and III (7 'pts') surviving for 24, 12, and 20 months respectively. Location and volume of tumors were not statistically significant predictors of survival (P < 0.05). In conclusion, in this highly selected group, GBM patients with little or no necrosis and with less tumor nodule enhancement on preoperative MRI survive longer than patients with greater amounts of necrosis and greater degrees of tumor enhancement. In addition, a moderate degree of peritumoral edema is associated with worse prognosis. PMID- 8699229 TI - A grading study of gliomas using computer aided malignancy classification and histologic morphometry. AB - Forty three cases of astrocytic tumors and mixed gliomas were studied with the aim of evaluating the reproducibility of the Kernohan grading system vis a vis (a) grading using computer-aided malignancy classifier TESTAST 268 and (b) grading by quantitative morphometric evaluation of the various histological parameters of TESTAST 268. These patients were then followed up for variable periods with a maximum of forty months. High inter and intra-observer variability were observed in the Kernohan grading system. TESTAST 268 was found to be simpler, rapid and more reproducible. However, one drawback observed of this system was that it did not completely eliminate inter-observer variability because there was still some subjectivity in assignment of the categorical values against the histological features. Morphometric evaluation of the semi quantitative assignment values of the 4 histological variables in the TESTAST 268 classifier using Zeiss Morphomat-30 revealed a statistically significant difference between the clusters of the measured quantitative values. A repeat grading using TESTAST 268 and categorical assignment values of histological features derived from the absolute values obtained by morphometry resulted in complete elimination of inter-observer variability. Thus, this study highlights the importance of objectivisation using TESTAST 268 and histologic morphometry in the grading of gliomas. However, since this is a preliminary study on a small number of cases, no cut off values of these measurements have been proposed. PMID- 8699230 TI - Will high dose chemotherapy followed by autologous bone marrow transplantation supplant cranio-spinal irradiation in young children treated for medulloblastoma? AB - Cranio-spinal irradiation is the gold standard treatment used in non metastatic medulloblastoma as prophylaxis against central nervous system (CNS) metastases. However, given the severe late effects caused by this procedure in children under 3 years of age, most pediatric oncologists are currently treating these patients with conventional chemotherapy in order to postpone or even avoid irradiation. In the French Society of Pediatric Oncology (SFOP) this attitude has been adopted since 1987. Among the patients treated without radiotherapy, 20 relapsed while on conventional chemotherapy and were entered in a study of high-dose chemotherapy (HDC) followed by ABMT. Their median age at diagnosis was 23 months (R5-71) and the relapse occurred at a median time of 6.3 months after the initiation of chemotherapy. Complete surgical removal of the local relapse was the first treatment in 4/20 patients who were not evaluable for response. Sixteen of the twenty patients had measurable disease at the primary site (9 patients), or at metastatic sites (3 patients) or both (4 patients). The conditioning regimen consisted of combination Busulfan 600 mg/m2 over 4 days and Thiotepa 900 mg/m2 over three days. After recovery from aplasia, patients with a local relapse received local radiotherapy limited to posterior fossa. RESULTS: among the 16 patients with measurable disease, 6 CR, 6 PR, 3 NR, were observed following HDC (response rate 75%). One patient was not evaluable. For the 20 patients, the EFS is 50%. Among the surviving patients, the median follow up is 31 months post BMT (R12-82). Ten patients who developed a local relapse or local progression are alive with NED without craniospinal irradiation. Among the 7 patients who developed metastases or progression of metastases, only one is alive. Toxicity was high but manageable: the median duration of granulocytopenia < 0.5 x 109/l and thrombocytopenia < 50 x 10(9)/l was 13 and 41 days respectively. Bacteremia was documented in 4 cases. Grade > 2 mucositis and diarrhea were observed in 60% of patients. One complication-related death occurred 1 month post BMT. CONCLUSION: With a 75% response rate, this HDC proved to be very efficient in relapsed medulloblastoma. A longer follow up is necessary to demonstrate whether, after a local relapse, HDC could replace craniospinal irradiation as prophylaxis against CNS metastases. PMID- 8699232 TI - Infrequency of p53 gene mutations in ependymomas. AB - Ependymomas, which comprise 5% of central nervous system tumors, have not been extensively characterized genetically. The p53 tumor suppressor gene is frequently mutated in human cancer, and is important in the pathogenesis of other central nervous system (CNS) tumors. Chromosomal DNA corresponding to the p53 tumor suppressor gene was amplified by the polymerase chain reaction (PCR) from 31 archival ependymoma specimens. DNA was screened for the presence of p53 mutations by single strand conformational polymorphism (SSCP) analysis; samples with altered mobility were further tested for the presence of mutation by direct DNA sequence analysis. Of the 31 ependymomas tested, one contained a detectable DNA sequence change in the p53 gene. Sequencing revealed a silent mutation in exon 6, at codon 213, which represents a known p53 sequence polymorphism. These finding suggest that in contrast to many other human cancers, p53 mutation is not important in the pathogenesis or progression of ependymomas. PMID- 8699231 TI - Bcl-2 distribution in neuroepithelial tumors: an immunohistochemical study. AB - Bcl-2 proto-oncogene prevents apoptosis in many conditions. First detected in lymphomas, it has been also described in non-lymphoid tissues. The immunohistochemical distribution of bcl-2 protein in 100 neuroepithelial tumors is presented. Bcl-2 was positive in some neurons of normal nervous tissue, in reactive astrocytes and variably in all neuroepithelial tumor. The reaction product was either diffuse or granular, due to bcl-21 protein localization on cytoplasmic, nuclear and mitochondrial membranes. The positivity was high in medulloblastomas and in astrocytic tumors. In the latter, the strongest staining was found in cells retaining the astrocytic aspect. Oligodendroglial cells were minimally stained. No correlation of bcl-2 staining with survival was found in each tumor type. The interpretation of the results is based on the one side on the constitutive role played by bcl-2 in the nervous tissue and its neoplastic derivatives. On the other side, in tumors bcl-2 acts by preventing tumor cells from undergoing apoptosis. BCl-2 expression in brain tumors, therefore, receives a dual interpretation. For this reason and for the lacking of correlation with survival, bcl-2 expression cannot be regarded as a prognostic factor. PMID- 8699233 TI - Immunohistochemical evaluation of erbB-2 and p53 protein expression in benign and atypical human meningiomas. AB - Meningiomas arise from the arachnoidal cells surrounding the brain and are one of the most common tumors of the central nervous system. These tumors are known to be hormonally modulated and may occur in association with breast carcinoma. Overexpression of the erbB-2 oncogene product and mutation of the tumor suppressor p53 gene are considered causal driving forces in the pathogenesis of adenocarcinomas of the breast. To determine whether abnormal expression of these genes also plays a role in the pathogenesis of meningiomas, we analyzed the expression of the erbB-2 and p53 proteins in 17 atypical and 35 typical meningioma tissue specimens by immunohistochemistry. The staining intensity was assigned a relative value of 0 to 5+, where 5+ denoted confluent immunoreactivity, 4+ to 1+ denoted varying degrees of focal positivity, and 0 denoted no evidence of staining. Levels of p53 and erbB-2 immunohistochemical staining were then correlated with tumor histology. For p53 immunoreactivity, typical meningiomas had a median staining score of 1.0, compared to 4.0 for atypical meningiomas (P < 0.0001, Mann-Whitney U test). For erbB-2 immunoreactivity, typical meningiomas had a median staining score of 5.0 compared to 1.0 for atypical meningiomas (P < 0.0001, Mann-Whitney U test). The inverse relationship between levels of erbB-2 and p53 immunoreactivity was found to be statistically significant (P < 0.0001, ANOVA). Expression of the erbB-2 protein was not associated with gene amplification or the presence of activating mutation in the transmembrane region of the protein. These findings may improve our understanding of the molecular events that occur in the neoplastic transformation of meningothelial cells. The patterns of erB-2 and p53 immunoreactivity may prove to be useful markers with which to identify potentially more malignant meningiomas. PMID- 8699234 TI - Reversion of phenotype of endothelial cells in brain tissue around glioblastomas. AB - With the aim of studying the putative involvement of peritumoral microvessels in the formation of brain edema, small pieces of peritumoral brain tissue were removed from six patients with glioblastoma multiforme submitted to surgery. All patients had cerebral edema, as shown by preoperative C.T. and N.M.R. Control specimens were obtained from four patients undergoing ventriculo-peritoneal shunt. The tissue fragments were fixed in glutaraldehyde-osmium and embedded in Epon. In semi-thin sections observed under light microscopy peritumoral endothelial cells exhibited voluminous cytoplasm and nucleus. Under the electron microscope, capillary cells from glioblastoma patients differed from controls mainly by showing nuclei rich in euchromatin, cytoplasm rich in pinocytotic vesicles and with occasional fenestrations. All these morphological characteristics are compatible with a process of reversion of phenotype of capillaries around glioblastomas to that of periphery as well as an increase in permeability. Both events may be due to diffusion of a tumoral vascular permeability/endothelial growth factor. This peripheral vessel phenotype of peritumoral microvessels supports their participation in the formation of brain edema and may provide a new clue for therapeutic intervention: for example it fits quite well to the known increase in permeability by leukotrienes and decrease in permeability by corticosteroids in tumoral edema. PMID- 8699236 TI - Intra arterial chemotherapy with ACNU and radiotherapy in inoperable malignant gliomas. AB - For the non-operable malignant glioma patients, prognosis remains poor, with a survival of 8 months for the glioblastomas (G), and 15 months for anaplastic astrocytomas (AA). 27 histologic proven malignant gliomas (17 AA and 10 G) were treated between April 1991 and June 1992. Median age was 48 years. The therapeutic protocol consisted of three courses of intra arterial chemotherapy (IAC) with ACNU, at intervals of six weeks, and a localised 60 Gy radiotherapy between the first and the second IAC course. 72 courses of IAC were delivered (2.4 per patient). Response rate was 51.8%. Median survival (MS) was 13 months, with a survival rate of 28% at 24 months. For the AA, MS was 21 months, with a survival rate of 37% at 24 months. For the G, median survival was 10 months. Responders were 65% for AA, 30% for G. Non responders all died before 24 months had relapsed with a MS of 9 months. 54% of responding patients had a 2 years survival. Toxicity were acceptable with 7% of haematological toxicity and partial loss of visual acuity in 11% of the case. No chronic neurological sequellae were noted. We compare theses results with two previous trials, concerning inoperable patients, treated by association of radiotherapy and systemic chemotherapy. Survival seems to be equivalent with HeCNU and with this treatment, but toxicity decrease with ACNU. Early radiotherapy does not increase complications. This treatment can be used for patients with inoperable malignant gliomas. PMID- 8699235 TI - Adoptive immunotherapy using lymphokine-activated killer (LAK) cells and interleukin-2 for recurrent malignant primary brain tumors. AB - Ten patients with recurrent malignant primary brain neoplasms were treated with adoptive immunotherapy using lymphokine-activated killer (LAK) cells and interleukin-2 (IL-2). Nine patients had supratentorial glioma and they received multiple intratumoral instillations of LAK cells through reservoir-catheter system or burrhole. The other patients with disseminated subarachnoid metastases from posterior fossa medulloblastoma received immunotherapy via lumbar subarachnoid route. A partial and transient clinical response was observed in two patients. following the therapy, and a cystic transformation of the essentially solid tumour was noted on the CT scans of these two patients. No significant clinical or radiological response to the treatment was observed in the remaining 8 patients. The results of this preliminary study reveal limitations of the regional intratumoral adoptive immunotherapy using currently available techniques and provide sufficient evidence of its effectiveness to warrant further investigations. PMID- 8699237 TI - Phase II study of prolonged oral therapy with etoposide (VP16) for patients with recurrent malignant glioma. AB - Because the percentage of dividing cells in malignant gliomas is small, cell cycle specific drugs such as VP16 are most effective if given continuously over prolonged periods. In this study, we chose a dose of 50 mg/day to minimize therapy interruptions for myelosuppression. VP16 was given until the neutrophil count dropped to < 1.0 x 10(9)/L or the platelets fell to < 75 x 10(9)/L and resumed when the counts rose to normal levels. We treated 46 patients with supratentorial malignant glioma (15 anaplastic astrocytoma, 21 glioblastoma multiforme, 9 anaplastic oligodendroglioma, 1 undifferentiated primary malignant brain tumor) at the time of tumor progression. All had KPS > or = 70 at study entry. All patients had prior RT, 13 with adjuvant nitrosourea. Twenty-four had prior nitrosourea chemotherapy for tumor progression, 7 had no prior chemotherapy. We treated 20 patients with VP16 at first progression and 26 at second or later progression. All patients had CT or MR scans and clinical evaluation every 8 weeks. Median time to tumor progression (TTP) was 8.8 weeks for all evaluable patients, 8.6 weeks for those treated at first progression and 8.4 weeks for those treated at second progression, 9.1 weeks for anaplastic astrocytoma, 7.5 weeks for glioblastoma multiforme and 17.1 weeks for anaplastic oligodendroglioma. There were 8 responses and 11 patients with stable disease for at least 8 weeks (R + SD = 42%). Prolonged low-dose oral VP15 is well tolerated, with minimal myelosuppression. Prolonged low-dose oral VP16 is modestly effective treatment for patients with recurrent malignant glioma and is more effective for anaplastic astrocytoma and anaplastic oligodendroglioma than glioblastoma multiforme. PMID- 8699238 TI - Interstitial chemotherapy with mitoxantrone in recurrent malignant glioma: preliminary data. AB - We undertook a phase I-II trail of loco-regional mitoxantrone in 12 patients affected by malignant gliomas. Mitoxantrone was delivered at tumor recurrence by Ommaya reservoir, with 2 cycles and a 1 month interval between each cycle, in conjunction with systemic chemotherapy (8 pts) or not (4 pts). Treatment tolerability was good, and 9 of the patients showed either response or stable disease at the end of the treatment schedule. Regardless of associated chemotherapy, time to further tumor progression was at 6 months. A combination of early systemic and loco-regional chemotherapy with surgery and radiotherapy seems worth while pursuing in the therapeutic approach to malignant gliomas. PMID- 8699239 TI - Association of rubidium and C-methionine uptake in brain tumors measured by positron emission tomography. AB - Positron emission tomography (PET) studies have indicated that alteration of active transport contributes to increased net amino acid accumulation into human brain tumors. We compared the uptake of 11C-methionine (MET) and the K+ analog 82Rubidium (RUB) in 30 patients suffering from various brain tumors using PET. MET and RUB accumulated rapidly in tumor tissue and remained on average at a stable level thereafter from which normalized uptake values calculated (tissue radioactivity over injected radioactivity x body weight (NU). K1 (RUB) and K1, k2, k3 (MET) were also estimated using non-linear rate constant fitting in 17/30 patients. NU and K1 values for MET and RUB were higher in meningiomas compared to gliomas and were significantly correlated for the whole spectrum of tumors (p < 0.0001). When meningiomas were excluded, the correlation was maintained. K3 values for MET (metabolic rate) in tumors were in the range of normal brain. No correlation between RUB and MET was found for normal brain. with increasing rub intake the ratio of Nu MET over Nu RUB approached the value of 1.0. These results suggest that apart from active transport, also passive diffusion across the blood brain barrier (BBB) may account for MET uptake from blood into tumor tissue. This probably limits the use of MET in the differential diagnosis of brain lesions where BBB disruption is present. PMID- 8699240 TI - Low-grade pure and mixed cerebral astrocytomas treated in the CT scan era. AB - From 1974 to 1992, 63 patients diagnosed with low-grade pure or mixed oligo astrocytoma were seen and treated at our institution. All patients underwent CT scan pre-operatively. There were 20 female and 43 males ranging in age from 12 to 73 years (median age of 33 years). 15 patients had a stereotactic biopsy as the only surgical procedure. 34 had a partial tumor resection and 14 a gross total tumor resection. 43 patients were treated with post-operative radiotherapy whereas 20 patients underwent surgery only as part of the initial management. 50 to 60 Gy (median 59.4 Gy) were given with daily fractions of 1.8 to 2 GY. Tumor volume ranged from 3.4 to 441 cm3. Median tumor volume was larger for radiotherapy treated patients. Median follow-up was 54 months (range of 4 to 240 months). The overall 10 and 15 actuarial survival rates were 37% and 25% respectively. The 5 years survival rate for patients treated at initial diagnosis with surgery alone was 66% and it was 67.3% for patients treated with radiation therapy (P = NS). Prognostic factors having independent significant impact on survival were: extent of surgery, age gender and tumor volume. As well, survival for patients with low-grade astrocytoma in the CT scan era appears to be improved compared to historical controls in the literature. PMID- 8699242 TI - C-erbB2/neu transfection induces gap junctional communication incompetence in glial cells. AB - Astrocytes form functional networks that participate in active signaling in which external stimuli are generated and amplified in many of the same ways as in neurons. Gap junctions between astrocytes offer the structural avenue by which the electrical and metabolic signals are propagated from one cell to another. Little is known about the trafficking, assembly, and degradation mechanisms of the major astrocytic gap junction protein connexin43. We have studied a glial cell line transfected with the C-erbB2/neu oncogene (neu+), finding severe interruption of gap junctional communication after stable transfection. Evidence from Western blotting and phosphorylation studies showed that the processing of connexin43 to its higher phosphorylated isoforms is disturbed. Confocal laser imaging indicates that the major deficit in the neu+ cells is attributable to a lack in plaque assembly of connexin43. Because the neu+ cells also lack N-CAM proteins and because work from others has indicated a close relationship between communication competence and constitutive CAM expression, our data suggest that expression of C-erbB2/neu oncogene alters cell-cell association via CAM proteins, which thereby affects gap junction plaque assembly and appropriate phosphorylation of connexin43. PMID- 8699241 TI - Autologous tumor cell vaccination combined with adoptive cellular immunotherapy in patients with grade III/IV astrocytoma. AB - Brain tumors are highly resistant to treatment. Their diffuse infiltrative nature and the relative inaccessibility of the brain to blood and lymph are barriers to surgical and cytotoxic treatments alike. Preclinical animal studies demonstrated that intravenously administered tumor antigen-specific T lymphocytes will reject tumors growing in the brain. Specifically activated effector T lymphocytes may be generated by in vivo immunization followed by restimulation of antigen-primed T cells with autologous tumor cells in vitro. In order to apply these findings to humans, feasibility studies of combined active immunization and specific adoptive cellular immunotherapy were performed on fifteen patients with recurrent astrocytoma. The objective was to determine whether; 1) T cells could be grown from peripheral blood of patients immunized with autologous tumor cells, and 2) whether stimulated cells could be safely readministered to patients. Patients were immunized with a combination of their own irradiated tumor cells and Bacillus of Calmette and Guerin. Two weeks later a mononuclear cell-rich fraction of blood was obtained by leukapheresis. Mononuclear cells were cultured with irradiated autologous tumor cells and interleukin-2. Selective expansion of CD4+ and CD8+ T lymphocytes occurred. Intravenous transfer of stimulated cells to the fifteen patients on twenty-four separate occasions with or without systemic administration of interleukin-2 was tolerated with limited toxicity. The studies established the feasibility of conducting controlled studies of the anti-tumor effects of tumor antigen-specific cellular immunotherapy. PMID- 8699243 TI - Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. AB - Activation of cannabinoid receptors inhibits voltage-gated Ca2+ channels and activates K+ channels, reminiscent of other G-protein-coupled signaling pathways that produce presynaptic inhibition. We tested cannabinoid receptor agonists for effects on excitatory neurotransmission between cultured rat hippocampal neurons. Reducing the extracellular Mg2+ concentration to 0.1 mM elicited repetitive, transient increases in intracellular Ca2+ concentration ([Ca2+]i spikes) that resulted from bursts of action potentials, as measured by combined whole-cell current clamp and indo-1-based microfluorimetry. Pharmacological characterization indicated that the [Ca2+]i spikes required glutamatergic synaptic transmission. Cannabinoid receptor ligands inhibited stereoselectively the frequency of [Ca2+]i spiking in the rank order of potency: CP 54,939 > CP 55,940 > Win 55,212-2 > anandamide, with EC50 values of 0.36, 1.2, 2.7, and 71 nM, respectively. CP 55,940 was potent, but not efficacious, and reversed the inhibition produced by Win 55,212-2, indicating that it is a partial agonist. Inhibition of [Ca2+]i spiking by Win 55,212-2 was prevented by treatment of cultures with active, but not heat-treated, pertussis toxin. Win 55,212-2 (100 nM) inhibited stereoselectively CNQX-sensitive excitatory postsynaptic currents (EPSCs) elicited by presynaptic stimulation with an extracellular electrode, but did not affect the presynaptic action potential or currents elicited by direct application of kainate. Consistent with a presynaptic site of action, Win 55,212 2 increased both the number of response failures and the coefficient of variation of the evoked EPSCs. In contrast, cannabimimetics did not affect bicuculline sensitive inhibitory postsynaptic currents. Thus, activation of cannabinoid receptors inhibits the presynaptic release of glutamate via an inhibitory G protein. PMID- 8699244 TI - Modulation of conduction block in leech mechanosensory neurons. AB - Conduction block is a mechanism of activity-dependent neuronal plasticity, but little is known about its possible neuromodulation. Extensive activity in leech touch (T), pressure (P), and nociceptive (N) mechanosensory neurons results in conduction block of their minor receptive fields. We have examined whether the duration of conduction block could be modulated by the serotonergic Retzius neurons or by application of serotonin (5-HT). Activation of one Retzius cell reduced the duration of conduction block in T and P cell posterior fields, but their anterior fields and N cell fields were unaffected. Perfusion with 5-HT had stronger effects, reducing the duration of conduction block in T, P, and lateral N cells in the posterior fields and either reducing or more often enhancing the expression of conduction block in anterior fields. The effects of 5-HT on posterior fields were blocked by the nonspecific 5-HT antagonist methysergide and were partly suppressed by the 5-HT2 antagonist ketanserin. To determine the site of 5-HT action, the central ganglion or peripheral skin was perfused independently. T and to a greater extent P cells showed a preferential sensitivity to application of 5-HT onto the central ganglion. Interestingly, medial N cells exhibited a progressive decrease in the duration of conduction block during repeated trials ("wind-up") that was unaffected by 5-HT. We conclude that secretion of 5-HT by the Retzius cells has a central modulatory effect on the duration of conduction block in T, P, and lateral N cells. PMID- 8699245 TI - [Ca2+]i elevations detected by BK channels during Ca2+ influx and muscarine mediated release of Ca2+ from intracellular stores in rat chromaffin cells. AB - Submembrane [Ca2+]i changes were examined in rat chromaffin cells by monitoring the activity of an endogenous Ca(2+)-dependent protein: the large conductance Ca(2+)-and voltage-activated K+ channel (also known as the BK channel). The Ca2+ and voltage dependence of BK current inactivation and conductance were calibrated first by using defined [Ca2+]i salines. This information was used to examine submembrane [Ca2+]i elevations arising out of Ca2+ influx and muscarine-mediated release of Ca2+ from intracellular stores. During Ca2+ influx, some BK channels are exposed to [Ca2+]i of at least 60 microM. However, the distribution of this [Ca2+]i elevation is highly nonuniform so that the average [Ca2+]i detected when all BK channels are activated is only approximately 10 microM. Intracellular dialysis with 1 mM or higher EGTA spares only the BK channels activated by the highest [Ca2+]i during influx, whereas dialysis with 1 mM or higher BAPTA blocks activation of all BK channels. Submembrane [Ca2+]i elevations fall rapidly after termination of short (5 msec) Ca2+ influx steps but persist above 1 microM for several hundred milliseconds after termination of long (200 msec) influx steps. In contrast to influx, the submembrane [Ca2+]i elevations produced by release of intracellular Ca2+ by muscarinic actetylcholine receptor (mAChR) activation are much more uniform and reach peak levels of 3-5 microM. Our results suggest that during normal action potential activity only 10-20% of BK channels in each chromaffin cell see sufficient [Ca2+]i to be activated. PMID- 8699246 TI - Structure and evolution of neurexophilin. AB - Using affinity chromatography on immobilized alpha-latrotoxin, we have purified a novel 29 kDa protein, neurexophilin, in a complex with neurexin l alpha. Cloning revealed that rat and bovine neurexophilins are composed of N-terminal signal peptides, nonconserved N-terminal domains (20% identity over 80 residues), and highly homologous C-terminal sequences (85% identity over 169 residues). Analysis of genomic clones from mice identified two distinct neurexophilin genes, one of which is more homologous to rat neurexophilin and the other to bovine neurexophilin. The first neurexophilin gene is expressed abundantly in adult rat and mouse brain, whereas no mRNA corresponding to the second gene was detected in rodents despite its abundant expression in bovine brain, suggesting that rodents and cattle primarily express distinct neurexophilin genes. RNA blots and in situ hybridizations revealed that neurexophilin is expressed in adult rat brain at high levels only in a scattered subpopulation of neurons that probably represent inhibitory interneurons; by contrast, neurexins are expressed in all neurons. Neurexophilin contains a signal sequence and is N-glycosylated at multiple sites, suggesting that it is secreted and binds to the extracellular domain of neurexin l alpha. This hypothesis was confirmed by binding recombinant neurexophilin to the extracellular domains of neurexin l alpha. Together our data suggest that neurexophilin constitutes a secreted glycoprotein that is synthesized in a subclass of neurons and may be a ligand for neurexins. PMID- 8699247 TI - Expression of a kinesin-related motor protein induces Sf9 cells to form dendrite like processes with nonuniform microtubule polarity orientation. AB - The microtubules (MTs) within neuronal processes are highly organized with regard to their polarity and yet are not attached to any detectable nucleating structure. Axonal MTs are uniformly oriented with their plus ends distal to the cell body, whereas dendritic MTs are of both orientations. Here, we sought to test the capacity of motor-driven MT transport to organize distinct MT patterns during process outgrowth. We focused on CHO1/MKLP1, a kinesin-related protein present in the midzonal region of the mitotic spindle where MTs of opposite orientation overlap. Insect ovarian Sf9 cells induced to express the N-terminal portion of the molecule form MT-rich processes with a morphology similar to that of neuronal dendrites (Kuriyama et al., 1994). Nascent processes contain uniformly plus-end-distal MTs, but these are joined by minus-end-distal MTs as the processes continue to develop. Thus, this CHO1/MKLP1 fragment establishes a nonuniform MT polarity pattern and does so by a similar sequence of events as occurs with the dendrite, the antecedent of which is a short process with a uniform MT polarity orientation. Two lines of evidence suggest that these results are elicited by motor-driven MT transport. First, there is a depletion of MTs from the cell body during process outgrowth. Second, the same polarity pattern is obtained when net MT assembly is suppressed pharmacologically during process formation. Collectively, these findings provide precedent for the idea that motor driven transport can organize MTs into distinct patterns of polarity orientation during process outgrowth. PMID- 8699248 TI - Functional correlation of NMDA receptor epsilon subunits expression with the properties of single-channel and synaptic currents in the developing cerebellum. AB - NMDA receptor (NMDAR) subunits epsilon 1-epsilon 4 are expressed differentially with respect to brain region and ontogenic period, but their functional roles still are unclear. We have compared an epsilon 1 subunit-ablated mutant mouse with the wild-type to characterize the effect of epsilon subunit expression on NMDAR-mediated single-channel currents and synaptic currents of granule cells in cerebellar slices. Single-channel and Western blot analyses indicated that the epsilon 2 subunit disappeared gradually during the first postnatal month in both wild-type and mutant mice. Concomitantly, the voltage-dependent Mg2+ block of NMDAR-mediated EPSCs (NMDA-EPSCs) was decreased. Throughout the developmental period studied, postnatal day 7-24 (P7-P24), the decay time course of NMDA-EPSCs in epsilon 1 mutant (-/-) mice was slower than in wild-type mice. We suggest that the expression of the epsilon 3 subunit late in development is responsible for a reduction in the sensitivity of NMDA-EPSCs to block by extracellular Mg2+ and that receptors containing the epsilon 1 subunit determine the fast kinetics of the NMDA-EPSCs. PMID- 8699249 TI - Protein kinase A activation increases sodium current magnitude in the electric organ of Sternopygus. AB - The inactivation kinetics of the Na+ current of the weakly electric fish Sternopygus are modified by treatment with androgens. To determine whether phosphorylation could play a role in this effect, we examined whether activation of protein kinase A by 8 bromo cyclic AMP (8 Br cAMP) altered voltage-dependent properties of the current. Using a two-electrode voltage-clamp procedure, we found no effect of 8 Br cAMP on inactivation kinetics or other voltage-dependent properties of the Na+ current of the electrocytes. However, treatment with 8 Br cAMP did produce a dose-dependent increase in the Na+ current compared with saline controls: 17.6% at 100 microM, 42.4% at 1 mM, and 43.1% at 5 mM. This effect was blocked by 30 microM H89, a PKA inhibitor, indicating that the observed effect was attributable to 8 Br cAMP activation of PKA. We conclude that androgen-induced changes in Na+ current inactivation are not mediated by PKA and suggest that PKA-mediated increases in Na+ current underlie increases in the amplitude of the electric organ discharge observed in social interactions or with changes in water conductance. PMID- 8699250 TI - The behavior of optic axons on substrate gradients of retinal basal lamina proteins and merosin. AB - To study the behavior of optic axons to continuously changing concentrations of their substrate, explants from embryonic retina were placed across gradients of retinal basal lamina proteins and merosin. The following growth patterns of axons in response to the substrate gradients were found: (1) Axons that grew up gradients, i.e., from low to high substrate concentrations, became longer and less fasciculated with increasing concentration of the substrate. On shallow basal lamina gradients, the axons also showed a directional response that resulted in guidance to higher substrate concentrations. (2) Axons that grew down gradients, i.e., from high to low substrate concentrations, became shorter and more fasciculated with decreasing concentrations of the substrate. On gradients of merosin, a significant alteration in the axonal growth direction toward higher substrate concentrations was detected. Axons heading down gradients never U turned to higher substrate concentrations. (3) Axons confronted with discontinuous substrates were confined to the borders of the substrate exclusively, whereas axons confronted with substrate gradients were able to cross into the territory beyond the substrate. (4) The growth patterns of axons on substrate gradients of basal lamina proteins and merosin were similar but not identical, indicating that axons may respond to substrate gradients dependent on its chemical composition. The present results show that substrate gradients can regulate length and fasciculation of neurites and have a limited capability to direct axons to higher substrate concentrations. PMID- 8699251 TI - Neurotrophin-3 antibodies disrupt the normal development of the chick retina. AB - When chick embryos are treated with a monoclonal antibody specifically blocking the activity of neurotrophin-3 (NT-3), the development of the retina is profoundly affected. Fewer axons are found in the optic nerve, and the retina shows abnormalities in all layers. Early during retinogenesis, the proportion of dividing cells is higher in NT-3-deprived embryos compared with age-matched controls and that of differentiated neurons is smaller. The NT-3 receptor trkC is expressed early by a majority of retinal cells, and NT-3 is present in the retina at the earliest stage studied. Initially, it is located mainly in the pigmented epithelium, with a shift toward the neural retina as development proceeds. Thus, NT-3 seems to be an essential intrinsic signal acting early in development to promote the differentiation and survival of many retinal neurons. PMID- 8699252 TI - Upregulation of BDNF mRNA expression in the barrel cortex of adult mice after sensory stimulation. AB - Upregulation of brain-derived neurotrophic factor (BDNF) mRNA expression by neuronal activity has been reported in cultured hippocampal cells and in different in vivo excitotoxic paradigms. The aim of the present study was to determine whether sensory stimulation of the whisker-to-barrel pathway alters BDNF mRNA expression in the cortex and, if so, to evaluate the specificity of this effect. To this end, a set of mystacial whiskers was unilaterally stimulated by mechanical deflection, and the expression of BDNF mRNA was analyzed in the barrel cortex by in situ hybridization (ISH) using a 35S-labeled antisense BDNF riboprobe and emulsion autoradiography. A clear-cut and specific upregulation of the BDNF mRNA expression was found at the level of the somatosensory cortex after the increased peripheral stimulation. In the barrel cortex of control mice, BDNF mRNA was present in a few cells in layers II/III and VI, whereas it was almost undetectable in layer IV. After 6 hr of whisker stimulation, increased levels of BDNF mRNA were found in layers II to VI of the contralateral barrel cortex. In layer IV, BDNF upregulation was confined to the barrels corresponding to the stimulated follicles. ISH combined with immunocytochemistry against the three calcium-binding proteins parvalbumin, calretinin, and calbindin-D28K revealed that BDNF mRNA-expressing cells do not belong to the GABAergic cell population of the barrel cortex. The present results support a role for BDNF in activity dependent modifications of the adult cerebral cortex. PMID- 8699253 TI - The structure of spatial receptive fields of neurons in primary auditory cortex of the cat. AB - Transient broad-band stimuli that mimic in their spectrum and time waveform sounds arriving from a speaker in free space were delivered to the tympanic membranes of barbiturized cats via sealed and calibrated earphones. The full array of such signals constitutes a virtual acoustic space (VAS). The extra cellular response to a single stimulus at each VAS direction, consisting of one or a few precisely time-locked spikes, was recorded from neurons in primary auditory cortex. Effective sound directions form a virtual space receptive field (VSRF). Near threshold, most VSRFs were confined to one quadrant of acoustic space and were located on or near the acoustic axis. Generally, VSRFs expanded monotonically with increases in stimulus intensity, with some occupying essentially all of the acoustic space. The VSRF was not homogeneous with respect to spike timing or firing strength. Typically, onset latency varied by as much as 4-5 msec across the VSRF. A substantial proportion of recorded cells exhibited a gradient of first-spike latency within the VSRF. Shortest latencies occupied a core of the VSRF, on or near the acoustic axis, with longer latency being represented progressively at directions more distant from the core. Remaining cells had VSRFs that exhibited no such gradient. The distribution of firing probability was mapped in those experiments in which multiple trials were carried out at each direction. For some cells there was a positive correlation between latency and firing probability. PMID- 8699254 TI - Electrographic seizures and new recurrent excitatory circuits in the dentate gyrus of hippocampal slices from kainate-treated epileptic rats. AB - Mossy fiber sprouting has been proposed to lead to new excitatory connections between dentate granule cells, which in turn cause electrographic seizures. We tested this hypothesis in hippocampal slices from rats made epileptic-by kainate injections. The Timm's histological method revealed intense staining of the inner molecular layer in slices from all kainate-treated rats. In bicuculline (10 microM) and 6 mM [K +]o, antidromic stimulation of the granule cells evoked bursts of population spikes superimposed on long-lasting negative shifts in all slices tested from all kainate-treated rats. Long-duration (2-47 sec), seizure like bursts with tonic and clonic components occurred spontaneously (53%) or in response to antidromic stimulation (81%). Under identical conditions, prolonged bursts were never seen in slices from controls or from kainate-injected rats 2-4 d after treatment. Glutamate microdrops applied in the granule cell layer evoked abrupt increases in the frequency of excitatory postsynaptic potentials (EPSPs) in two thirds of the cells tested. Glutamate microstimulation was effective at several sites in the granule cell layer but ineffective in the hilus. The proportion of granule cells responding to local application of glutamate by an increase in EPSPs was higher in slices with long bursts (80% with bursts of > 3 sec) than in slices with shorter bursts (33% with bursts of < 3 sec). Glutamate microstimulation did not affect EPSPs in granule cells from control preparations. These results support the hypothesis that kainate-induced mossy fiber sprouting forms new excitatory connections between granule cells and can lead to increased seizure susceptibility in the dentate gyrus. PMID- 8699255 TI - Double transduction with GTP cyclohydrolase I and tyrosine hydroxylase is necessary for spontaneous synthesis of L-DOPA by primary fibroblasts. AB - Gene transfer of tyrosine hydroxylase (TH) in animal models of Parkinson's disease (PD), using either genetically modified cells or recombinant virus vectors, has produced partial restoration of behavioral and biochemical deficits. The limited success of this approach may be related to the availability of the cofactor, tetrahydrobiopterin (BH4), because neither the dopamine-depleted striatum nor the cells used for gene transfer possess a sufficient amount of BH4 to support TH activity. To determine the role of BH4 in gene therapy, fibroblast cells transduced with the gene for TH were additionally modified with the gene for GTP cyclohydrolase l; an enzyme critical for BH4 synthesis. In contrast to cells transduced with only TH, doubly transduced fibroblasts spontaneously produced both BH4 and 3, 4-dihydroxy-L-phenylalanine. To examine further the importance of GTP cyclohydrolase I in gene therapy for PD, in vivo micro-dialysis was used to assess the biochemical changes in the dopamine-denervated striatum containing grafts of genetically modified fibroblasts. Only denervated striata grafted with fibro-blasts possessing both TH and GTP cyclohydrolase I genes displayed biochemical restoration. However, no significant differences from controls were observed in apomorphine-induced rotation. This is partly attributable to a limited duration of gene expression in vivo. These differences between fibroblasts transduced with TH alone and those additionally modified with the GTP cyclohydrolase I gene indicate that BH4 is critical for biochemical restoration in a rat model of PD and that GTP cyclohydrolase I is sufficient for production of BH4. PMID- 8699256 TI - Organization of AMPA receptor subunits at a glutamate synapse: a quantitative immunogold analysis of hair cell synapses in the rat organ of Corti. AB - Sensitive and high-resolution immunocytochemical procedures were used to investigate the spatial organization of AMPA receptor subunits (GluR1-4) at the synapse between the inner hair cells and the afferent dendrites in the rat organ of Corti. This is a synapse with special functional properties and with a presynaptic dense body that defines the center of the synapse and facilitates its morphometric analysis. A quantitative postembedding immunocytochemical analysis was performed on specimens that had been embedded in a metachrylate resin at low temperature after freeze substitution. Single- and double-labeling procedures indicated that GluR2/3 and GluR4 subunits were colocalized throughout the postsynaptic density, with a maximum distance of 300 nm from the presynaptic body and with higher concentrations peripherally than centrally. No receptor immunolabeling was found at extrasynaptic membranes, but some GluR4 subunits appeared to be expressed presynaptically. The synapses between outer hair cells and afferent dendrites were devoid of labeling. The present data indicate that AMPA receptor subunits are inserted into the postsynaptic membrane in a very precise manner and that their density increases on moving away from the center of the synapse. PMID- 8699257 TI - Localization of the somatostatin receptor SST2A in rat brain using a specific anti-peptide antibody. AB - Biological actions of somatostatin are exerted via a family of receptors, for which five genes recently have been cloned. However, none of these receptor proteins has been visualized yet in the brain. In the present-study, the regional and cellular distribution of the somatostatin sst2A receptor was investigated via immunocytochemistry in the rat central nervous system by using an antibody generated against a unique sequence of the receptor protein. Specificity of the antiserum was demonstrated by immunoblot and immunocytochemistry on rat brain membranes and/or on cells transfected with cDNA encoding the different sst receptor subtypes. In rat brain sections, sst2A receptor immunoreactivity was concentrated either in perikarya and dendrites or in axon terminals distributed throughout the neuropil. Somatodendritic labeling was most prominent in the olfactory tubercle, layers II-III of the cerebral cortex, nucleus accumbens, pyramidal cells of CA1-CA2 subfields of the hippocampus, central and cortical amygdaloid nuclei, and locus coeruleus. Labeled terminals were detected mainly in the endopiriform nucleus, deep layers of the cortex, claustrum, substantia innominata, subiculum, basolateral amygdala, medial habenula, and periaqueductal gray. Electron microscopy confirmed the association of sst2A receptors with perikarya and dendrites in the former regions and with axon terminals in the latter. These results provide the first characterization of the cellular distribution of a somatostatin receptor in mammalian brain. The widespread distribution of the sst2A receptor in cerebral cortex and limbic structures suggests that it is involved in the transduction of both pre- and postsynaptic effects of somatostatin on cognition, learning, and memory. PMID- 8699258 TI - Immunocytochemical localization of the GABAc receptor rho subunits in the mammalian retina. AB - Polyclonal antibodies against the N terminus of the rat rho 1 subunit were generated to study the distribution of GABAc receptors in the mammalian retina. The specificity of the antibodies was tested in Western blots and transfected HEK 293 cells. No cross-reactivity with the GABAA receptor subunits alpha 1-3, beta 1 3, gamma 2, delta or with the glycine receptor subunits alpha 1 and beta could be detected. In contrast, the rho 1, rho 2, and rho 3 subunits were all recognized by the antibodies. In vertical sections of rat, rabbit, cat, and macaque monkey retinae, strong punctate immunoreactivity was present in the inner plexiform layer. Weaker immunoreactivity was also present in the outer-plexiform layer, and cell bodies of bipolar cells were faintly labeled. Double immunostaining of vertical sections and immunostaining of dissociated rat retinae showed the punctate immunofluorescence to colocalize with bipolar cell axon terminals. The puncta possibly represent clustering of the rho subunits at postsynaptic sites. PMID- 8699259 TI - Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. AB - The entorhinal cortex (EC) plays a crucial role as a gateway connecting the neocortex and the hippocampal formation. Layer II of the EC gives rise to the perforant pathway, the major source of the excitatory input to the hippocampus, and layer IV receives a major hippocampal efferent projection. The EC is affected severely in Alzheimer disease (AD), likely contributing to memory impairment. We applied stereological principles of neuron counting to determine whether neuronal loss occurs in the EC in the very early stages of AD. We studied 20 individuals who at death had a Clinical Dementia Rating (CDR) score of 0 (cognitively normal), 0.5 (very mild), 1 (mild), or 3 (severe cognitive impairment). Lamina specific neuronal counts were carried out on sections representing the entire EC. In the cognitively normal (CDR = 0) individuals, there were approximately 650,000 neurons in layer II, 1 million neurons in layer IV, and 7 million neurons in the entire EC. The number of neurons remained constant between 60 and 90 years of age. The group with the mildest clinically detectable dementia (CDR = 0.5), all of whom had sufficient neurofibrillary tangles (NFTs) and senile plaques for the neuropathological diagnosis of AD, had 32% fewer EC neurons than controls. Decreases in individual lamina were even more dramatic, with the number of neurons in layer II decreasing by 60% and in layer IV by 40% compared with controls. In the severe dementia cases (CDR = 3), the number of neurons in layer II decreased by approximately 90%, and the number of neurons in layer IV decreased by approximately 70% compared with controls. Neuronal number in AD was inversely proportional to NFT formation and neuritic plaques, but was not related significantly to diffuse plaques or to total plaques. These results support the conclusion that a marked decrement of layer II neurons distinguishes even very mild AD from nondemented aging. PMID- 8699260 TI - The effects of superior temporal cortex lesions on the processing and retention of auditory information in monkeys (Cebus apella). AB - Three monkeys with extensive preoperative training on visual and auditory memory tasks (delayed matching-to-sample), an auditory pattern-discrimination task, and a visual serial-order task, received bilateral lesions of the superior temporal (ST) cortex in two stages, with testing after each lesion. Unilateral ST cortex lesions resulted in only moderate auditory memory impairments, whereas bilateral ST cortex lesions resulted in severe auditory memory impairments. The bilateral ST cortex lesions also resulted in severe impairments in the ability to relearn the auditory pattern-discrimination task. In contrast to the auditory impairments, neither unilateral nor bilateral ST cortex lesions had any effect whatsoever on either visual memory or visual serial-order behavior. These findings indicate that the ST cortex plays a role in auditory processing and retention similar to that played by the inferior temporal cortex for visual processing and retention. PMID- 8699261 TI - A pair of identified interneurons in Aplysia that are involved in multiple behaviors are necessary and sufficient for the arterial-shortening component of a local withdrawal reflex. AB - A bilateral pair of cerebral interneurons, called CC5, contribute to the generation of a number of different behaviors involving head movements. Each cell sends its axon to the ipsilateral and contralateral pedal and pleural ganglia. A weak tactile stimulus to the head excites the ipsilateral CC5; a strong stimulus excites both the ipsilateral and contralateral cells. Firing of CC5 produces powerful shortening of the ipsilateral pedal artery (PA) by means of monosynaptic excitation of the pedal artery shortener (PAS) neuron, the single motor neuron for the artery. A weak touch to a tentacle excites the ipsilateral PAS and evokes a local withdrawal response accompanied by shortening of the ipsilateral PA. In vivo recording of the pedal artery nerve (PAn) showed that PAS was activated bilaterally during defensive head withdrawal elicited by a strong stimulus and was activated unilaterally by a weak stimulus. The responses were eliminated by cutting the ipsilateral cerebral-pleural connective (C-PLC). Electrical stimulation of the cerebral-pleural connective provided evidence that all of the excitatory input to PAS via this connective is provided by CC5. A variety of experimental results indicates that during a local withdrawal reflex of the tentacle, CC5 is necessary and sufficient for the unilateral PA-shortening component of the response and therefore functions as a command neuron for a component of the behavior. The data suggest that during defensive head withdrawal, the two CC5 neurons may act conjointly as a two-neuron command system that is necessary and sufficient for the bilateral arterial-shortening component of the behavior. PMID- 8699262 TI - Synaptogenesis and Fos expression in the motor cortex of the adult rat after motor skill learning. AB - Recent work has suggested that changes in synapse number as well as changes in the expression of the Fos protein may occur within the motor cortex in association with motor learning. The number of synapses per neuron and the percentage of Fos-positive neurons within layer II/III of the rat motor cortex was measured after training on a complex motor learning task. Adult female rats were allocated randomly to either an acrobatic condition (AC), a motor control condition (MC), or an inactive control condition (IC). AC animals were trained to traverse a complex series of obstacles, and each AC animal was pair matched with an MC animal that traversed an obstacle-free runway. IC animals received no motor training. Animals from each condition were killed at various points during training, and unbiased stereological techniques were used to estimate the number of synapses per neuron and the percentage of Fos-positive cells within layer II/III of the motor cortex. AC animals exhibited an overall increase in the number of synapses per neuron in comparison to MC and IC animals at later stages of training. AC animals also had a significantly higher overall percentage of Fos positive cells in comparison to both controls, with a trend for the increase to be greater during the acquisition versus the maintenance phase. These data suggest that Fos may be involved in the biochemical processes underlying skill acquisition and that motor learning, as opposed to motor activity, leads to increases in synapse number in the motor cortex. PMID- 8699263 TI - Future of AHCPR threatened. PMID- 8699264 TI - Changing behaviors. Nurse educators and clinical nurse specialists design a discharge planning program. AB - In this article, the authors describe a discharge planning program developed for geriatric and maternal-child nurses at Mount Sinai Medical Center. King's theory of goal attainment was used in the program design and teach strategies were selected that matched behavioral objectives in the cognitive, psychomotor, and affective domain. Evaluation methods include participants' pre- and post-surveys regarding their comfort in implementing discharge planning and concurrent review of their documentation 1 month after the program. After participating in the program, staff nurses displayed a change in behavior in terms of increased documentation relating to discharge planning. PMID- 8699265 TI - Float pool orientation. AB - Orienting new staff members to competently deliver care on a single unit is a challenging endeavor. This challenge escalates when orienting float staff members to 10 medical/surgical and 2 parent-child units. In this article, the authors describe the process for development and implementation of a competency-based orientation for float pool staff members. These principles also may be used to cross-train nursing staff members who occasionally float. PMID- 8699266 TI - Factors affecting the delegation of tasks by the registered nurse to patient care assistants in acute care settings. A selective review of the literature. AB - Nursing shortages and issues of fiscal accountability have compelled nurse executives to restructure nurses' work. Because proficiency in delegation is central to the success of redesigned patient-focused models of nursing care, nurses must change their behavior and delegate to perform more effectively. Using Lewin's field theory of change, the authors examined the delegation of tasks by registered nurses in acute care settings. A comprehensive review of the literature suggests that factors related to successful delegation have not been examined systematically. In this article, the authors provide information for use in future research on delegation. PMID- 8699267 TI - Computerization of standards and patient education material. AB - In this article, the authors describe the evolution, design, implementation, and evaluation of a computer system for presentation of Nursing Standards and Patient Education Materials at The Presbyterian Hospital in the City of New York. PMID- 8699268 TI - Fear of AIDS, homophobia, and occupational risk for HIV. A staff development challenge. AB - Nursing is committed to providing quality care; however, nursing practice has been challenged by patients with AIDS. In this pilot study, the authors investigated the relation among nurses' homophobia, fear AIDS, and occupational risk for contracting HIV. With their findings, they found that a positive attitude toward homosexuality, more clinical experience, and more experience with HIV patients contribute to a positive attitude toward AIDS. The authors recommend that staff development programs focus on the affective domain of nursing, universal precautions and infection control, and precepted experiences for new graduates. PMID- 8699269 TI - Clinical rounds: a measure of competence. PMID- 8699270 TI - Using structure, process, and outcome for total program evaluation in continuing nursing education. PMID- 8699271 TI - A peer review program for professional nurses. AB - Within the past 3 years, the Division of Nursing in a large medical center implemented a career ladder and a professional practice model. Peer review was identified as a critical component for the success of these two initiatives and maturation of the model. Limitations in the conduct of peer review among the professional nursing staff centered around the lack of a coherent process. The Coordinating Council, the governing body of the professional nursing staff, formally recognized the accomplishments of a Quality Improvement team and directed the team to implement and evaluate a process of peer review. The development and implementation of peer review as experienced by this Quality Improvement team is described in this article. The process and structure of peer review and specific continuous improvement tools used by the team in developing this process are reviewed. PMID- 8699273 TI - Identifying the learning needs of nurse managers. application of the critical incident technique. AB - Accurate identification of learning needs is the most important component of the staff development process. The critical incident technique is shown to be a valuable tool in identifying the learning needs of nurse managers in a long-term care facility. This technique addresses the real work issues and concerns affecting nurse managers. A step-by-step process is provided to help nurse educators develop a comprehensive inventory of learning needs. PMID- 8699272 TI - Effect of three teaching methods on a nursing staff's knowledge of medication error risk reduction strategies. AB - The authors' purpose in this study was to (1) compare the effects of three teaching methods on registered nurses' and licensed practical nurses' knowledge of medication error risk reduction strategies, and (2) to compare registered nurses' and licensed practical nurses' knowledge of medication error risk reduction strategies using a pretest/posttest design. Registered nurses (n = 129) and licensed practical nurses (n = 21) employed by two hospitals constituted the study sample. Subjects were assigned alternately to three intervention groups: videotape (n = 50); instructional booklet (n = 50); and lecture (n = 50). A 38 item test, including true-false, multiple choice, matching items and dosage calculation problems, was administered to subjects in each group before and after the teaching intervention. On the basis of the results, there was no statistically significant difference in total knowledge scores for the three intervention groups (F = 2.07, P = 0.130). Staff development instructors should consider the advantages of a videotape and instructional booklet over the time intensive lecture strategy. PMID- 8699274 TI - Delegation in nursing staff development. AB - Delegating work, responsibility, and authority in a staff development department is difficult because it means letting others make decisions. Delegation, however, is necessary because it allows competent educators to perform and to get work done proficiently. Delegation is perhaps the hardest job directors have to learn. It requires planning, skill, and the use of available resources. When carried out effectively, delegation is the key to a successful department. PMID- 8699275 TI - Staff development through international cooperation. The Kenya experience. AB - International cooperation in nursing enables nurses to share, exchange, and develop knowledge and experience, increase tolerance and sensitivity, expand horizons, make new friends, and contribute to the advancement of professionalism. International cooperation exists in many fields and is carried out through governments, international organizations, public and academic institutions, and professional associations. The authors were sent by the Center for International Cooperation of Israel's Ministry of Foreign Affairs to teach a course entitled "The Nurse Educator Role: Aspects in Nursing Education and Management." The learners were senior nurses in Kenyatta National Hospital, Nairobi, Kenya. The course was designed to meet two main objectives: (1) to emphasize the educational role as an essential dimension of the professional nursing practice, and (2) to expand the knowledge base and skills to enable participants to improve their function as educators. PMID- 8699276 TI - How much is enough? Agency nurse orientation. PMID- 8699277 TI - Preparing staff members for the JCAHO survey: adding the important ingredient of "fun". PMID- 8699278 TI - Off to a successful start! The use of self-study for hospital-wide nursing orientation. AB - Introducing speaker after speaker and providing lecture after lecture is a standard method for delivering nursing orientation in many hospitals. However, this is not always the most effective method of orientation for new nurses. In this article, the author outlines the process used to convert a traditional, lecture-style orientation to one alternative method, self-study, and shows how the change decreases the time orientees spend in nursing orientation and lowers the cost per person. PMID- 8699279 TI - Nursing research and patient outcomes: tools for managing the transformation of the health care delivery system. AB - This paper outlines strategies for all nurses to participate in nursing's research agenda, which aims to enhance the scientific basis of nursing practice. The emphasis here is on generating data for the outcomes movement as a tool for transforming the American health care delivery system. PMID- 8699280 TI - Revisiting New York State's proposed surrogate decision-making legislation. AB - More than 2 years have passed since legislation was first proposed in New York to remedy the absence of legal authority for family members who must make important health care decisions for incapacitated loved ones who have left no advance directives. This legislation, the "Family Health Care Decisions Act," included standards for surrogate decision-making and safeguards for surrogate decisions about the use of life-sustaining treatments. This article argues in favor of the legislation and discusses the concerns presented in opposition. PMID- 8699281 TI - Survey of nursing research in New York State: XVII. PMID- 8699282 TI - Bibliography: critical paths. PMID- 8699283 TI - Health care reform activities. PMID- 8699284 TI - Use of educational gaming to enhance theory learning. AB - Using educational games in the classroom can increase enthusiasm and reinforce previously presented didactic information in an innovative way. This article presents a game format for teaching and learning components of nursing theories. A discussion of the teaching objectives, the development of the game, rules of play, and an evaluation of the experience are presented. The use of educational games in the classroom can be a positive, interactive, alternative method of teaching and information sharing. Engaging students in a game that is structured to reinforce information presented in lectures and reading assignments can help students test and apply their knowledge of key concepts. PMID- 8699285 TI - Medicaid managed care: a brief analysis. AB - Many states have begun to implement Medicaid managed care programs as a means of reducing costs and improving access for Medicaid recipients. This paper presents a review of the debate surrounding Medicaid managed care programs gathered from the literature, professional meetings, and correspondence. PMID- 8699287 TI - Nursing practice: the regulatory arena. AB - State nursing laws and boards of nursing significantly impact nurses, nursing education, and practice. As healthcare delivery systems continue to change, roles of boards of nursing and the value of licensure will be questioned. In this article, the purpose of nursing laws and licensure, and the mission, authority, and functions of boards of nursing are reported. A decision-making model to guide nurses in determining scope of practice matters is provided. The delegation of nursing tasks and use of unlicensed assistive persons under nurse supervision is addressed. PMID- 8699286 TI - Pediatric peripherally inserted central catheter program report: a summary of 4,536 catheter days. AB - Data were collected on all peripherally inserted central catheters (PICCs) inserted by one i.v. nurse clinician from July, 1989 to June, 1992 in an urban pediatric teaching hospital of more than 100 beds. Growth of this PICC program, as well as outcome of patients with PICCs, was recorded and compared to published reports. During the surveillance period, 269 PICCs were successfully inserted in 226 patients out of 330 patients referred for PICC placement. This article contains the outcome of that program. Catheter duration and rate of PICC complication at St. Christopher's Hospital for Children (Philadelphia, Pennsylvania) was comparable to eight other published reports. PICCs are an efficacious and safe method of i.v. access for intermediate to long-term use in children. PMID- 8699288 TI - Emerging problems in antimicrobial resistance. AB - The ability of many different species of bacteria to resist the inhibitory action of antimicrobial agents has become a global problem. As the magnitude of the problem continues to increase, it is imperative that healthcare professionals, particularly nurses who administer antimicrobial agents on a daily basis, become familiar with the causes of antibiotic resistance and the ways in which the emergence of resistance can be prevented or minimized. It also is important that the proper use of antimicrobial agents and the problems associated with misuse be conveyed to patients receiving intravenous therapy, particularly those receiving therapy outside of traditional healthcare settings. This article will highlight some of the factors leading to the development of resistance in bacteria and the problems facing the medical community and the public regarding the spread of resistant bacteria in hospital and community settings. PMID- 8699289 TI - Inotropic therapy in the home care setting: criteria, management, and implications. AB - The home care clients of today are requiring more intensive i.v. therapies in their home setting. The cardiac compromised patient is a prime target for this emerging trend in home infusion therapy. The end-stage cardiac patient has been traditionally treated in the hospital acute-care setting through frequent readmissions. However, there is an increasing desire by cardiac patients and their families to administer inotropic therapies in the home. Cardiac patients receiving inotropic therapy can be successfully treated in the home using specific admission criteria and monitoring guidelines. PMID- 8699290 TI - Patient-focused care: a response to the healthcare crisis. AB - During this time of major challenges and transitions in the healthcare industry, as both healthcare professionals and consumers, nurses are in a pivotal position to become active, informed advocates for reasonable, rational changes within a system in which we have a truly unique perspective. In this environment, it is critical that nurses understand the need for change so that we can critically analyze work redesign initiatives for their likelihood to positively or negatively impact the healthcare system at a global or local level. It will then be possible to explore the transformation of the healthcare delivery system, the concept of patient-focused care, and the impact on the healthcare workforce of the future with particular attention to the practice of intravenous nursing. PMID- 8699291 TI - Color me yellow: caring for the infant with hyperbilirubinemia. AB - When caring for the neonate with hyperbilirubinemia, discerning between physiologic jaundice and non-physiologic jaundice is important in determining the needed management techniques. The causes of neonatal jaundice are examined along with contributing factors. Based on these findings, management techniques are discussed including nutrition, fluid support, advice to the breast-feeding mother, and options for in-house or home care management. PMID- 8699292 TI - Careless hospitals cut too close to the bone. AB - In 1994, with U.S. hospitals adopting managed care as the new competitive edge, Assistant Professor of Nursing Judith Shindul-Rothschild decided to repeat a 1989 survey of hospital nurses to determine the impact on patient care. She surveyed nearly 900 Massachusetts nurses, producing a study that raises disturbing questions about the quality of hospital care. An interview with senior writer John Ombelets. PMID- 8699293 TI - Polyurethane and silicone: myths and misconceptions. PMID- 8699294 TI - Psychosocial assessment in the general pediatric population: a multiple-gated screening and identification procedure. AB - This article describes a screening and assessment procedure to identify the need for psychologic and psychiatric services within the general pediatric population. This procedure is additionally designed to facilitate timely and focused treatment planning. It begins with a brief, user friendly instrument, the Pediatric Symptom Checklist (PSC), to routinely screen all pediatric patients. The procedure continues by asking parents of children who are identified as meeting cutoff criteria (on the PSC) or at-risk for psychosocial problems to complete a more sophisticated instrument, the Child Behavior Checklist. Using the PSC and the Child Behavior Checklist in this multiple-gated manner allows for screening and then identification of problem child behaviors, providing data necessary to complete an initial treatment plan. The procedure is proposed as an efficient means of routinely screening for, and then identifying, child psychosocial problems in general pediatric populations. PMID- 8699295 TI - Primary care of adolescents with bulimia nervosa. AB - Adolescents with bulimia nervosa present a challenge to pediatric nurse practitioners. These adolescents have a disorder that is secretive and difficult to diagnose, chronic, multifaceted, and difficult to treat. However, armed with the proper knowledge and skills, pediatric nurse practitioners are the ideal primary health care providers for this population. PMID- 8699296 TI - President's message: AAP and NAPNAP working together. PMID- 8699297 TI - Cultural considerations in Cambodian childrearing. AB - INTRODUCTION: The purpose of this study was to explore childrearing practices and beliefs of Cambodian refugees. Cambodians, a culturally distinct group, are increasing in number in the United States. They are in need of health care and childrearing advice, but Cambodian childrearing practices and beliefs are not well documented. METHOD: A descriptive study was conducted to investigate Cambodian families' cultural childrearing practices and beliefs. Participant observation techniques were used, and interviews were conducted with a convenience sample of 28 Cambodians. RESULTS: Three themes emerged: Buddhism is deeply embedded in Cambodian culture; the family is the basic, most important structure in the life and identity of a Cambodian; and life is set and ordered within a hierarchical structure. Childrearing practices are set up to teach and reinforce these beliefs. DISCUSSION: Nurses offering advice regarding childrearing practices must respect the client's value system. Nurses must continue to ask and share cultural information while developing mutually acceptable guidelines for care. PMID- 8699298 TI - Labial adhesions in childhood. PMID- 8699299 TI - Protein-energy malnutrition (kwashiorkor and marasmus). PMID- 8699300 TI - Infant born to a mother with a positive tuberculin skin test result. PMID- 8699301 TI - Medication-induced esophagitis. PMID- 8699302 TI - Children and tobacco. PMID- 8699303 TI - What's "new" in street drugs: "illy". PMID- 8699304 TI - Policy and position statement. Pediatric HIV disease. National Association of Pediatric Nurse Associates and Practitioners. PMID- 8699305 TI - President's message. Advanced practice nurse. PMID- 8699306 TI - The importance of being nice. PMID- 8699307 TI - Health outcomes of children receiving EPSDT checkups: a pilot study. AB - This pilot study used medical records to examine the health outcomes of children receiving care in Medicaid's Early and Periodic Screening, Diagnosis and Treatment (EPSDT) program. Medical records from 76 children seen for EPSDT visits during a 6-month period were reviewed to assess whether health problems were identified and whether treatment, follow-up, or referral care was provided. Health problems were identified for 43% of the children; 22% received treatment, and 18% were referred for specialty care. Checkups uncovered fewer problems than would be expected in a poor, largely minority population. Almost one third of the children referred for specialty care apparently did not receive such care. The study verified the need for further research and provides direction for future study. PMID- 8699308 TI - The lifestyle questionnaire for school-aged children: a tool for primary care. AB - The Lifestyle Questionnaire for School-Aged Children can be used by nurse practitioners in the primary care setting to enhance assessment and focus health teaching. A survey of 75 school-aged children seen for well child examinations is highlighted, illustrating how nurse practitioners can use the Lifestyle Questionnaire to assess lifestyle patterns and promote healthy behaviors and habits. PMID- 8699309 TI - Adolescents and sexually transmitted diseases: diagnosis, developmental issues, and prevention. AB - Sexually transmitted diseases (STDs) continue to be a public health priority; adolescents are the highest risk group for nearly all STDs. Health care providers play an important role in addressing the problem of STDs among teenagers. This article reviews diagnostic approaches, developmental aspects of adolescents, and prevention efforts. Findings related to the STD epidemic in adolescents and the theoretic and pragmatic issues regarding prevention efforts, are presented. PMID- 8699310 TI - An innovative model of community collaboration in pediatric nursing. AB - Collaboration among nurses can lead to improved education and clinical practice and increased opportunities for nursing research. Although numerous descriptions of interinstitutional collaboration among nurses can be found, many projects are limited in scope or purpose. A more comprehensive approach can facilitate excellence in practice, education, and research throughout the community. By pooling professional resources, nurses across organizational lines can achieve common goals and reduce costs associated with services and programs. The purpose of this article is to describe an interinstitutional nursing model that supports collaboration while promoting standards of excellence. PMID- 8699311 TI - Family violence. PMID- 8699312 TI - Pediatric dosing information for health care providers. PMID- 8699313 TI - Alopecia in an adolescent. PMID- 8699314 TI - The federal role in motor vehicle safety issues. PMID- 8699315 TI - A minor's consent to treatment: an ethical dilemma. PMID- 8699317 TI - [Heterogeneity of GTPase-activating proteins for Ras in the regulation of Ras signal transduction pathway]. AB - The proto-oncogene ras is an essential gene for the growth and the differentiation for various types of cells. Ras, ras gene product, is a GTP binding protein which controls the signal transduction by GTP hydrolysis. The ras gene is frequently activated by point mutations in various types of human cancers, which results in a decrease in the GTPase activity of its product. A GTPase-activating protein p120 (p120GAP) was identified as a factor which stimulates the GTPase of normal ras gene product p21 but not of the mutated. An NF1 gene was identified as a gene whose loss of function causes an onset of human disorder, neurofibromatosis type I. The NF1 gene encodes a protein which contains a region with a similarity to the catalytic domain of p120GAP. We recently purified a novel Ras GAP whose molecular weight and immunogenecity are different from those of p120GAP and NF1. We named the novel mammalian Ras GAP as Gap1m. Isolation and sequencing of Gap1m cDNA revealed that Gap1m is indeed a novel Ras GAP. We also succeeded in isolation of another novel Ras GAP gene, GapIII/Gap1IP4BP, which is closely related to Gap1m. Recently, it is shown that GapIII/Gap1IP4BP binds inositol-tetrakis phosphate compounds. The overview of these Ras GAP molecules is described. PMID- 8699316 TI - [Synthesis of lactone ring-containing bioactive natural products. Cardiotonic steroids, naphthoquinone antibiotics, and tetronic acid ionophore antibiotics]. AB - Achievements in the synthestic study on cardiotonic steroids, pyranonaphthoquinone antibiotics, and tetronic acid ionophore antibiotics from author's laboratory are reviewed. PMID- 8699318 TI - [Studies on solid phase extraction of bile acids from biological matrix]. AB - To quantify bile acids in biological samples, a solid phase extraction method was examined. This method is known as simpler procedures with less contamination compared with solvent extraction methods. Rat bile, feces and urine were used as biological samples. Since Bond Elut C18 and C8 were proved to be more suitable than the other phases (CH and SAX) so far examined using standard bile acids, Bond Elut C18 was used for biological samples. Quantification of biological sample was carried out by gas chromatography after the extracted sample was derivatized to methyl ester by treatment with trimethylsilyldiazomethane then to trifluoroacetyl ester by trifluoroacetic anhydride. On the gas chromatography, two columns (Rtx-50 and Rtx-200) were connected to the injector with Y-tube for elimination of interference. Except for a few bile acids, high recovery with less biological contamination was obtained by this solid phase extraction method. PMID- 8699319 TI - [Studies on the synthesis of cholecystokinin A receptor antagonists. I. synthesis and cholecystokinin A receptor inhibitory activities of malonamide derivatives]. AB - 2-Substituted malonamide derivatives were synthesized and tested for cholecystokinin A (CCK-A) receptor inhibitory activity. Significant CCK-A receptor inhibitory activities were found in only three compounds (4g-i) which have carboxyl group. In order to study structure-activity relationships, carboxyethyl group was selected for 2-substituent and a number of N-substituted malonamides were prepared. After these compounds were tested for CCK-A receptor inhibitory activity, 4-(3,4-dichlorophenylcarbamoyl)-N,N-dipentylglutaramic acid (4h) was selected as the most preferred compound. PMID- 8699320 TI - [A simultaneous determination of evodiamine and rutaecarpine in oriental pharmaceutical decoctions containing Evodia fruit by ion-pair high-performance liquid chromatography]. AB - A simple and precise method was established for the simultaneous determination of evodiamine and rutaecarpine in oriental pharmaceutical decoctions containing Evodia Fruit using high-performance liquid chromatography with sodium dodecyl sulfate (SDS) as an ion-pair reagent. Evodiamine and rutaecarpine were eluted within 60 min without interference from co-existing components using an ODS column and a mixture of water-methanol-acetonitrile-SDS-phosphoric acid (600:330:70:5:0.01, v/v/v/w/v, pH 5.0) as a mobile phase. PMID- 8699321 TI - [Stability of phenyl salicylate in alcoholic-aqueous solution]. AB - The stability and degradation pathways of phenyl salicylate (PS) in 50 v/v% aqueous ethanol were investigated over the pH range of 3.2-8.4. The experiments were performed at three different temperatures (5, 23 and 50 degrees C) for four months by the use of high performance liquid chromatography. The degradation of PS was observed as a pseudo first-order kinetics not only in the alkaline region but in the acidic region and shown to proceed via transesterification (k1) and hydrolysis (k2) processes. The transesteified product, ethyl salicylate (ES), further underwent hydrolysis (k3) (k1 > k2 > k3). On the basis of kinetic studies, it was found that the degradation rate of PS decreased with decreasing pH and temperature. The half-lives of PS at pH 6.3 were 6.6 d (50 degrees C), 178 d (23 degrees C) and 2934 d (5 degrees C), respectively, and PS was stable at below ca. pH 4. On the other hand, PS in 100% ethanol also underwent the breakdown to ES by k1 process and its half-lives were 2.5 d (50 degrees C), 31.5 d (23 degrees C) and 257 d (5 degrees C), respectively. The present results is useful for the integrity of pharmaceutical formulations and delivery profiles. PMID- 8699322 TI - Epidermal enzymes as penetration enhancers in transdermal drug delivery? AB - Epidermal enzymes play an important role in the process of differentiation of keratinocytes. The present preliminary in vitro study was undertaken to observe if topical enzyme treatment influenced permeation of compounds across the skin. Due to the noted function and importance of phosphatidylcholine metabolism during maturation of the barrier lipids, the effects of topical application of the phosphatidylcholine dependent phospholipase C enzyme (not present in epidermis) on skin penetration of three model drugs, viz. benzoic acid, mannitol and testosterone, were studied. Similar studies were also carried out using epidermal enzymes like triacylglycerol hydrolase, acid phosphatase, and phospholipase A2 (present in epidermis). Pretreatment of skin with phospholipase C significantly enhanced permeation of benzoic acid, mannitol, and testosterone relative to untreated skin. Triacylglycerol hydrolase (neutral) increased the penetration of mannitol 3-fold and had no effect on benzoic acid penetration. Topical application of acid phosphatase did not alter the permeation of any of these compounds. Phospholipase A2 significantly enhanced permeation of benzoic acid and mannitol while it did not have any effect on the penetration of testosterone. These results for the first time demonstrate that enzymes may remarkably affect and/or regulate the permeation of topically applied compounds. PMID- 8699323 TI - Absorption of Cam-2445, and NK1 neurokinin receptor antagonist: in vivo, in situ, and in vitro evaluations. AB - Cam-2445 is a selective, high-affinity NK1 receptor antagonist that is a potentially useful treatment for arthritis, asthma, migraine, anxiety, psychosis, and emesis. Cam-2445 exhibits low aqueous solubility and high lipophilicity and has a molecular weight of 470. Cam-2445 has poor oral bioavailability and the purpose of this research was to examine the potential barriers to the oral bioavailability of Cam-2445. Cam-2445 was relatively stable at 37 degrees C in 0.1 N HCl, 5 microM alpha-chymotrypsin, rat intestinal perfusate, and in rat jejunal brush border membrane suspension. High permeability was observed from CACO-2 cells and from rat single-pass intestinal perfusions. Cam-2445 was administered as a solution to rats by intravenous (i.v.), oral (p.o.), intraduodenal (i.d.), and intraportal (i.p.v.) routes. The total oral bioavailability was poor at 1.4%. Absorption appeared to be rapid after i.d. dosing; bioavailability was 26%, and 54% of the dose was absorbed intact into the portal system. After i.p.v. dosing, 48% of the dose was available to the systemic circulation. The elimination t1/2 after i.d. dosing (2.91 h) was comparable to that i.v. dosing (2.93 h), whereas it was significantly longer after p.o. dosing (12.4 h). The p.o. dose apparently precipitated in the gastrointestinal (GI) tract, resulting in low oral bioavailability. These results indicated that neither stability in the GI tract nor membrane transport were major obstacles to the absorption of Cam-2445. While hepatic extraction of 52% was significant, the low aqueous solubility of Cam-2445, as well as the differences noted between p.o. and i.d. studies, strongly support GI dissolution and/or precipitation as the limiting factor for the oral bioavailability of the compound. PMID- 8699324 TI - Synthesis and antihypertensive activity of N-(alkyl/alkenyl/aryl)-N-heterocyclic ureas and thioureas. AB - A variety of N-(alkyl/alkenyl/aryl-N-heterocyclic ureas and thioureas were synthesized as potential antihypertensives. The selected heterocyclic nuclei were the 6-substituted quinoline and the pyridine. Eleven synthesized compounds and seven related compounds in the series were evaluated orally at a dose of 100 mg/kg in conscious deoxycorticosterone acetate/saline-treated hypertensive rats by the tail-cuff method. Seventeen out of the eighteen tested compounds possessed significant antihypertensive activity (p < 0.05). 1-n-Propyl-3-[2'-(6 methoxy)quinolyl]urea (9), showing 29.1% reduction in systolic blood pressure, was the most active compound in the series. Two other compounds producing a fall in systolic blood pressure of the same magnitude were 1-allyl-3-[2'-(6 methyl)quinolyl]thiourea (4) and 1-n-propyl-3-[(2'-pyridyl)methyl]urea (17). Compound 17 with rapid onset caused significant relaxation (p < 0.01) of isolated rabbit femoral artery and guinea pig atrium but had no effect on heart rate. However, none of these exhibited higher potency than prazosin (5 mg/kg). The potency, onset, and duration of action improved when the heterocyclic nucleus was pyridine. PMID- 8699325 TI - Partitioning of ifosfamide and its metabolites between red blood cells and plasma. AB - A recently developed GC-MS analytical method for the quantitative determination of oxazaphosphorines and their metabolites in blood plasma, using stable trifluoroacetyl derivatives and electron capture negative chemical ionization detection, was applied to measure the partitioning of the antitumor drug ifosfamide and its metabolites between plasma and red blood cells for four cancer patients. The separation of a constant volume of red blood cells was performed using a special instrument, MESED, through centrifugation of blood samples. The measured compounds were ifosfamide, 2- and 3-dechloroethylifosfamide, 4 ketoifosfamide, carboxyifosfamide, ifosfamide mustard, 2-chloroethylamine and 1,3 oxazolidin-2-one. Concentration-time profiles for the metabolites in the two blood fractions and partitioning factors between erythrocytes and plasma were obtained. For ifosfamide itself, and metabolites with an intact ring system, a partitioning factor between 1 and 2 was observed for the concentration ratio between red blood cells and plasma in the patients studied. However, for the compounds with an open structure, carboxyifosfamide and ifosfamide mustard, partitioning factors higher than 3 were obtained. The active antitumor metabolite ifosfamide mustard showed a strong preference for the red blood cells in the measured patient samples. This means that erythrocytes may play an important role in the transport and the subsequent release of the active alkylating agent to the tumor cells. PMID- 8699326 TI - Boronic acids facilitate the transport of ribonucleosides through lipid bilayers. AB - Boronic acids were found to facilitate the transport of various ribonucleosides in and out of liposomes (artificial cells). Most experiments were conducted with large unilamellar vesicles composed of dipalmitoylphosphatidyl choline, cholesterol, and phosphatidic acid in the ratio 20:15:2. Rates of nucleoside efflux were determined by a UV assay, whereas the influx experiments used a radiotracer method. Five boronic acids were studied: 3,5 bis(trifluoromethyl)phenylboronic acid (1), 3,5-dichlorophenylboronic acid (2), 4 tert-butylphenylboronic acid (3), 1-butylboronic acid (4), and 4 carboxyphenylboronic acid (5). The order of carrier effectiveness was found to be 1 > 3 > 2 >> 4 >> 5. Efflux and influx experiments with mixtures of nucleosides and sucrose showed virtually complete transport selectivity in favor of the nucleosides. Mechanistic studies indicate that the nucleoside transport mechanism involves transient formation of a lipophilic, trigonal boronate ester. PMID- 8699327 TI - Transport properties are not altered across Caco-2 cells with heightened TEER despite underlying physiological and ultrastructural changes. AB - Selected properties of Caco-2 cells were examined after disparate transepithelial electrical resistance (TEER) measurements were observed in two populations of Caco-2 cells. Comparisons were made between the early passages of Caco-2 cells (Caco-2E, passages 35-47) and the later passages of cells (Caco-2L, passages 87 112). Transmission electron microscopy revealed that regions of Caco-2L cells were composed of multiple cell layers rather than the monolayers observed in Caco 2E cells. Epithelial cell height (or barrier thickness) was not significantly different between the two cell populations. Intercellular and intracellular lumina were observed in the Caco-2L cells, but not in the Caco-2E cells. Results of [3H]thymidine incorporation assays showed significantly higher cell proliferation rates in Caco-2L cells relative to Caco-2E cells. Despite morphological and physiological changes, there were no significant differences in the apparent permeabilities for D-mannitol (paracellular diffusion marker), hydrocortisone (transcellular diffusion marker), or dipeptide, Gly-Sar (carrier mediated transcellular transport marker) between the two populations of cells. The higher TEER values in Caco-2L cells may be the results of a slight perturbation of tight junctions associated with both the multiple cell layers and the presence of intercellular lumina. PMID- 8699328 TI - Synthesis of human globin polypeptides mediated by recombinant adeno-associated virus vectors. AB - Adeno-associated virus, serotype 2 (AAV2)-based chimeric plasmids that harbored a near-full-length human alpha- or beta-globin cDNA were constructed. The cDNAs were spliced into an AAV plasmid, pAAV delta K, downstream from the viral P40 promoter, substituting the capsid gene region. The correctness of the insertion with regard to the transcription polarity was ascertained by both restriction enzyme analysis and DNA sequencing. One of the constructs, pAAVcHBBLCR, contained the erythroid-specific enhancer elements, the locus control region, HS1 and HS2, to ensure an efficient and tissue-specific gene expression. Use of a defective complementing helper, pAVXB (Dixit, M.; et al. Gene 1991, 104, 253-257.) and adenovirus 2 made it possible to prepare recombinant AAVs (rAAVs). Infection of human 293 cells (embryonal kidney cell line) with the resultant rAAV (AAVcHBB) and cotransfection of mouse erythroleukemia (MEL) cells with the beta-globin construct (pAAVcHBBLCR) and an alpha-globin construct (pAAVcHAB) triggered efficient synthesis of human globin polypeptides in the cells, as analyzed by biochemical and immunohistochemical means. The LCR made the construct respond to an inducer, N,N-hexamethylenebisacetamide, the amount of expressed human beta globin reaching a similar level as the endogenous mouse beta-globin in MEL cells. Electrotransfection of mouse bone marrow hematopoietic stem/progenitor cells with the constructs dramatically increased the number of benzidine-positive cells in liquid suspension culture, indicating expression and synthesis of a human hemoglobin in these cells. Thus, the rAAV constructs may be useful for gene therapy of hemoglobinopathies. PMID- 8699329 TI - Distribution of the dipeptide transporter system along the gastrointestinal tract of rats based on absorption of a stable and specific probe, SQ-29852. AB - Peptidic drugs such as beta-lactam aminocephalosporin antibiotics (e.g., cephalexin) and the ACE inhibitors lisinopril, quinapril, and benzazepril are apparently absorbed, at least in part, by the intestinal dipeptide transporter system (DTS). Although many properties of the DTS have been elucidated, including isolation of the carrier protein, little is known about the distribution of this transporter along the gastrointestinal (GI) tract. The objectives of the present study were to (1) validate that SQ-29852 (a lysylproline ACE inhibitor) is a stable and specific probe for evaluation of the DTS in rats and (2) provide fundamental in vivo information on the distribution of the DTS along the GI tract of rats. Most of the previous studies that explored the location of the DTS typically involved either in vitro uptake or in situ disappearance of unstable or nonspecific probes. SQ-29852, on the other hand, is an ideal probe for evaluation of the DTS because it is chemically and metabolically stable and it is absorbed almost exclusively by the DTS. SQ-29852 appears to be a specific probe for the DTS because the dose-dependent reduction in absorption from about 60% to less than 8% (3 and 3000 mg/kg, respectively) suggests that at least 85% of an orally administered low dose of SQ-29852 is absorbed by a saturable process, which was shown previously to be the DTS. [14C]SQ-29852 was administered by gavage to intact rats and via an indwelling cannula in one of the following sections of the intestine: duodenum, jejunum, ileum and proximal colon (n = 4 for each site). On the basis of the recovery of [14C]SQ-29852 in urine, the DTS is apparently distributed throughout the entire GI tract of rats, including the proximal colon. The present results are consistent with previously reported results on the absorption of natural dipeptides in humans and rats and immunohistochemical evaluation in rats; however, they disagree with a recent report in humans with amoxicillin. This difference is discussed in terms of the specificity and stability of various drugs that have been used as probes of the DTS. PMID- 8699330 TI - A sensitive high-pressure liquid chromatography/particle beam/mass spectrometry assay for the determination of all-trans-retinoic acid and 13-cis-retinoic acid in human plasma. AB - A highly sensitive assay for the measurement of all-trans-retinoic acid (tretinoin) and 13-cis-retinoic acid (isotretinoin) has been developed. Collected plasma samples were protein precipitated with 2-propanol followed by solid phase extraction. The retinoic acids were subsequently derivatized to their pentafluorobenzyl esters followed by separation and isolation by reverse phase high-pressure liquid chromatography. The HPLC eluate was directed to a mass spectrometer via a particle beam interface. Selected ion monitoring (299 m/z) for the retinoic acid's carboxylate anion produced by negative chemical ionization using methane reagent gas achieved minimum detection limits of 25 pg injected. Endogenous blood levels in 19 male and 9 female subjects were measured. It was found that females have significantly more all-trans-retinoic acid than males and that both sexes demonstrate significantly more all-trans-retinoic acid then 13 cis-retinoic acid. PMID- 8699331 TI - A comprehensive investigation of plasma and brain regional pharmacokinetics of imipramine and its metabolites during and after chronic administration in the rat. AB - The relationship between the serum imipramine concentration and its antidepressant effects remain undefined despite > 30 years of clinical investigation. No study to date has assessed the kinetic relationships between the concentrations of imipramine and its metabolites in plasma and in various brain structures. In this study, we examine the pharmacokinetics of imipramine (IMI) and its desmethylated and hydroxylated metabolites in rats given IMI chronically (20 mg/kg, intraperitoneally twice a day for 14 days). The concentrations in serum, cerebrospinal fluid, and six brain structures were measured by high-performance liquid chromatography at 13 different times from 0.5 to 120 h after the end of treatment. The concentrations of IMI, desipramine (DMI), and didesmethylimipramine (DDMI) in brain tissue were much higher than in the serum; concentrations were maximal at 1-2 h in the serum and the brain, which is indicative of the rapid metabolism of IMI with immediate and massive entry of the metabolites into the brain. The elimination halflives of desmethylated compounds increased with the degree of desmethylation, and DDMI was still present in brain tissue 96 h after the end of treatment. These results suggest that DDMI should be taken into account in clinical investigations of the effects of serum concentrations of IMI. The hydroxylated metabolites 2-OH imipramine (2-OH IMI) and 2-OH desipramine (2-OH DMI) were detected in serum, but not in cerebral tissue. The 10-OH metabolites were detected in both serum and brain, but the antidepressant action of these metabolites have not been clearly established. Finally, there were significant differences in the distributions of IMI and several of its metabolites in brain structures. Such differences may have clinical relevance if they also occur in humans. PMID- 8699332 TI - A pharmacokinetic study of intravenous CTLA4Ig, a novel immunosuppressive agent, in mice. AB - Three skin-intact mice in each group received a single 0.07-, 0.29-, or 0.57-mg dose of CTLA4Ig intravenously (i.v.). Three skin-grafted mice received a single 0.29-mg dose i.v. and another three skin-grafted mice received a 0.29-mg dose once daily for 7 days (the dose was administered via the tail vein). Serial blood samples (0.15 mL) were obtained by retro-orbital bleeds up to 240 h after all single doses and up to 360 h after the last multiple dose. Serum samples were analyzed for CTLA4Ig by a validated enzyme immunoassay method. The concentration data were subjected to noncompartmental pharmacokinetic analysis. Both Cmax and AUCinf values increased in a dose-proportional manner in skin-intact mice. The CLT values were dose independent. The MRT, t1/2, and Vdss values at the 0.07-mg dose level were significantly lower than those obtained for both the 0.29- and 0.57-mg dose levels; however, the respective values between the 0.29- and 0.57-mg dose levels were not significantly different. No significant differences were found in the pharmacokinetic parameters between the skin-intact and skin-grafted mice. PMID- 8699333 TI - Bioequivalence of two tablet formulations of nadolol using single and multiple dose data: assessment using stereospecific and nonstereospecific assays. AB - Nadolol, a nonspecific beta-blocker, is a racemate composed of equal amounts of four stereoisomers, namely, SQ-12148, SQ-12149, SQ-12150, and SQ-12151. In an open-label, randomized, four-period crossover study, the pharmacokinetics of nadolol and its stereoisomers and the bioequivalence of two formulations of nadolol were assessed in 20 healthy male subjects following a single dose (80 mg) and multiple doses (80 mg; once daily for 7 days). A standard granulated tablet and direct compressed tablet formulations, each containing 80 mg of nadolol, with different in vitro dissolution profiles that met current USP requirements were used. The four treatments were single and multiple doses of granulated tablet, and single and multiple doses of compressed tablet. There was a 7 day washout period between successive treatments. All doses of nadolol were administered after an overnight fast. Serial blood samples were collected up to 72 h following the single dose and during multiple dose treatments, following day 6 and 7 doses. Validated high-performance liquid chromatographic assays were applied to measure nadolol and its stereoisomers in the study samples. Plasma concentration data were subjected to noncompartmental pharmacokinetic analysis. Both C(max) and AUC values were significantly greater for SQ-12150 when compared to other nadolol stereoisomers obtained after a single dose or at steady state. However, T(max) and T1/2 values were similar among the four isomers. The observed steady state AUC tau values for nadolol (2278-2331 ng h/ML) or its stereoisomers (550-874 ng h/ML) were significantly greater than those predicted from the single dose AUCinf values (nadolol, 1840-1845 ng h/ML; isomers, 450-713 ng h/ML). The intrasubject variability, computed from multiple dose data, was generally greater for the stereoisomers (17-40%) than for nadolol (10-32%). The two formulations were bioequivalent for nadolol (C(max) = 0.98 [84%, 117%]; AUCinf = 1.03 [93%, 116%]) and SQ-12150 (C(max) = 1.12 [89%, 122%]; AUCinf = 0.98 [82%, 119%]) after a single dose, and only for nadolol (C(max) = 1.07 [84%, 118%]; AUCinf = 1.02 [91%, 113%]) at steady state. PMID- 8699334 TI - Albumin binding and time action of acylated insulins in various species. AB - Insulins acylated with fatty acids at the epsilon-amino group of LysB29 constitute a new class of insulin analogs, which are prolonged-acting due to albumin binding. In the present study it is shown that the affinity of fatty acid acylated insulins for albumin varies considerably (> 50-fold) among species. The relative affinities of acylated insulin for albumin in human, pig, and rabbit serum are about 1:1:5:35. The several fold higher binding affinity in rabbit serum than in pig serum is reflected in a relatively more protracted effect after sc injection in rabbits than in pigs. Due to the similar binding affinities in pig serum and human serum, the pig model should provide a useful estimate of the degree of protraction of acylated insulin in humans. The results emphasize that species differences in ligand binding can be of major importance in the preclinical evaluation of highly albumin bound drugs. PMID- 8699335 TI - Chronokinetics of liposomal encapsulated ampicillin in fasting and nonfasting rats. AB - The chronobiological effect on the pharmacokinetics of liposomal encapsulated ampicillin (LEA) was compared at noon (1200) and midnight (2400) after intravenous injection of 50 mg/kg of LEA in rats. The effects of fasting on the circadian rhythms of LEA were also investigated. Serial blood samples were collected for 2 h. Bile and urine were collected during the entire study. Plasma data was analyzed by noncompartmental methods. Dosing of LEA at 2400, when the animals were active, resulted in a 50% decrease in mean residence time (MRT) and a 20% increase in systemic clearance (Cltotal). The increase in Cltotal was reflected by increases in biliary (Clbile) and renal (Clrenal) clearance at 2400. In addition, the steady-state volume of distribution (Vss) at 2400 was also decreased by about 50% as compared to dosing at 1200. Interestingly, no difference in the pharmacokinetic parameters were observed in fasting animals at 1200 and 2400. Since rats consume very little food during their sleep cycle, restriction of food intake did not have any affect on the pharmacokinetics of LEA at 1200. However, fasting rats had an approximately 36% decrease in Cltotal as compared to nonfasting rats at 2400. This decrease in systemic clearance was paralleled by a 60% and 24% decrease in Clbile and Clrenal, respectively. These variations could be attributed to changes in bile composition and/or lipoprotein concentrations in the plasma as a result of "forced" fasting at 2400 when the animals are generally more active and food intake is high. PMID- 8699336 TI - Control of poorly soluble drug dissolution in conditions simulating the gastrointestinal tract flow. 1. Effect of tablet geometry in buffered medium. AB - The dissolution rate of a solid drug from the gastrointestinal (GI) tract is affected by the properties and flow dynamics of the liquid medium surrounding the tablet, as well as by the chemical nature of the drug. In this study, naproxen was used as a poorly soluble model drug. The dissolution medium was buffered with acetate, citrate, or phosphate buffer of varied concentrations and pH. GI flow conditions around a stationary tablet were simulated in a laminar flow device by anchoring the tablet on the floor of its channel having a rectangular cross section. Fresh, buffered solution was passed across the tablet and the effluent was collected for analysis and calculation of the dissolution rate. The dissolution rate was found to vary nonlinearly with the exposed tablet height, reaching a maximum at a tablet height approximately half the channel height. This maximum rate was attributed to an optimal combination of (1) eddy mixing and local turbulence generated by the flow impingement on the bluff object (tablet) and (2) the exposed tablet surface area available for dissolution. This effect was further confirmed by using dye-enhanced visual analysis of flow patterns at varied flow rates and exposed tablet heights. Elevation of the tablet to approximately the channel half-height significantly magnified the dissolution rate increase observed on exposure to buffered medium. Thus, tablet height and exposed surface area are major factors in determining dissolution rate, especially in conditions where the dissolving species reacts with the solvent. These results suggest that standard in vitro dissolution rate methods do not qualitatively indicate incremental changes in rate with altered tablet geometry or dissolution medium. PMID- 8699337 TI - Quantitative evaluation of aqueous isopropyl alcohol enhancement on skin flux of terbutaline (sulfate). 2. Permeability contributions of equilibrated drug species across human skin in vitro. AB - This paper demonstrates the usefulness of an equilibria-cotransport model for understanding the isopropyl alcohol-enhanced transport of an ionizable model compound, terbutaline in its sulfate salt form, through human skin in vitro. With the same isopropyl alcohol concentrations (0 - 80% v/v) present at both sides of skin, the permeation experiments were conducted using split-thickness skin and dermis membranes. The equilibria-cotransport model was consistent with total terbutaline flux and a terbutaline-to-sulfate flux ratio, both increased with increasing isopropyl alcohol and/or terbutaline sulfate concentrations. From the saturated drug solutions, aqueous isopropyl alcohol enhanced terbutaline skin flux about 10 - 100-fold with the maximum at 60 - 80% isopropyl alcohol. This overall flux enhancement was qualitatively separated into the contributions of isopropyl alcohol effects on both equilibrated donor concentrations and skin permeabilities of protonated terbutaline, terbutaline-sulfate ion pair anion, and neutral terbutaline-sulfate (2:1) ion triplet. In addition to altering the species equilibria, isopropyl alcohol was found to enhance the transport of both neutral and ionic species of terbutaline sulfate across stratum corneum. PMID- 8699338 TI - Interactions between drug substances and excipients. 1. Fluorescence and HPLC studies of triazolophthalazine derivatives from hydralazine hydrochloride and starch. AB - The strength of hydralazine hydrochloride (I) 10 mg tablets, containing starch as an excipient, decreases significantly with time. An investigation to determine the basis for the drop in strength showed that starch exposed to the drug exhibited fluorescence at 414 nm. As model compounds IIIa and V, which contain a triazolophthalazinyl moiety, also fluoresce at about 414 nm, it is proposed that the emission is due to a triazolophthalazine derivative (IIIc) resulting from hydralazine hydrochloride and starch. Degradation of IIIc generates s triazolo[3,4-a]phthalazine (IIIb), and a small amount of IIIb is detected in aged tablets. IIIc in aged tablets can be converted to IIIb by acid-catalyzed hydrolysis. The quantity of IIIb determined by HPLC amounts to most of the "missing" hydralazine hydrochloride. The reaction between hydralazine hydrochloride and starch is believed to cause the unexpected drop in the strength of hydralazine hydrochloride tablets. PMID- 8699339 TI - Influence of pH on the release of propranolol hydrochloride from matrices containing hydroxypropylmethylcellulose K4M and carbopol 974. AB - The dissolution of propranolol hydrochloride from matrices containing hydroxypropylmethylcellulose K4M (HPMC K4M) and carbopol 974 has been investigated using 0.1 M hydrochloric acid or phosphate buffer at pH 4.5 or pH 7.5. In 0.1 M hydrochloric acid, HPMC K4M predominantly controlled release since carbopol has a low solubility at this pH. As the pH increased, the carbopol became increasingly ionized and interacted with propranolol hydrochloride to form an insoluble complex which retarded the release of the drug. In addition, the nature of the interaction between carbopol 974 and HPMC K4M altered. DSC and viscometric studies indicated that the two polymers contributed synergistically to the gel network at pH 7.5. Thus at pH 7.5 polymers contributed to matrix integrity and to the control of drug release. PMID- 8699340 TI - Pharmacokinetics of mycophenolate mofetil, a new immunosuppressant, in rats. AB - Mycophenolate mofetil (MPM), a new immunosuppressant, is the morpholinoethyl ester of mycophenolic acid (MPA). The distribution in blood and pharmacokinetics of MPA after administration of MPM were examined. The plasma to erythrocyte concentration ratio was low (0.10-0.15). MPA existed in rat plasma as the highly bound form (bound fraction was 9.79 +/- 0.57%). MPA disappeared from the systemic circulation with biexponential decay. After i.v. administration of MPM at the doses of 8.3, 16.7, and 33.3 mg/kg, the total clearance of MPA was 0.241 +/- 0.056, 0.321 +/- 0.126, and 0.317 +/- 0.092 L/h/kg, respectively. The terminal elimination half-live were 5.17 +/- 1.44, 8.89 +/- 2.76, and 7.94 +/- 2.94 h, respectively. After i.d. administration of MPM at the doses of 8.3, 16.7, 33.3, and 50.0 mg/kg, the terminal elimination half-live were 6.41 +/- 4.16, 4.49 +/- 2.20, 7.58 +/- 3.72, and 8.18 +/- 1.32 h, respectively. The mean peak times were within 30 min. The systemic availability of MPA after i.d. administration of MPM (at 8.3, 16.7, and 33.3 mg/kg) was calculated using the corresponding mean AUCiv, and the values were 84.3 +/- 35.0%, 69.9 +/- 25.7%, and 63.6 +/- 8.8%, respectively. PMID- 8699341 TI - Assessment of tumor cell proliferation using [18F]fluorodeoxyadenosine and[18F]fluoroethyluracil. AB - This study was to develop radiofluorinated ethyluracil (FEU) and deoxyadenosine analogues (FAD) for noninvasive assessment of tumor proliferative potential by positron emission tomography (PET). 5-(2-Fluoroethyl)uracil ([18F]FEU) was prepared by treating 2,4-dimethoxy-5-(2-hydroxyethyl)pyrimidine with K18F, followed by hydrolysis with HBr. Fluorodeoxyadenosine ([18F]FAD) was prepared by treating a triacetylated analogue of adenosine with K18F. In vitro cell proliferation assay of [18F]-FEU was performed using human peripheral blood mononucleus cells. Tissue distributions were studied in breast tumor-bearing rats at 0.5, 1, 2 and 4 h along with autoradiography at 45 min postinjection. PET imaging studies were conducted in VX-2 tumor-bearing rabbits. In vitro assay indicated that [18F]FEU incorporated into DNA/RNA during cell proliferation. Tumor-to-tissue count density ratios of [18F]FAD and [18F]-FEU increased as a function of time. [18F]FAD had higher tumor-to-nontumor tissue count density ratios than [18F]FEU. Autoradiograms of [18F]FEU and [18F]FAD, and PET images of [18F]FEU, showed that the tumors could be well visualized. The results suggest that [18F]FEU and [18F]FAD have potential use in evaluating tumor cell proliferation by PET. PMID- 8699342 TI - Importance of glass transition temperature in accelerated stability testing of amorphous solids: case study using a lyophilized aspirin formulation. PMID- 8699343 TI - A new linear solvation energy relationship for the solubility of liquids in water. AB - From a comparison between the linear solvation energy relationship (LSER) and the extended solubility parameter model, it has been found that the solute-solute interaction energy term is missing in the LSER equation. A new LSER equation with the supplementary interaction energy term has been proposed for the solvation process. It is shown that the new LSER equation yields the correct solute-solvent interaction terms for the solubilities of liquids in water. PMID- 8699344 TI - Genetics of split hand and split foot. A case study. AB - Split hand and split foot is an autosomal dominant disorder that displays several genetic phenomena. These include variable expressivity, reduced penetrance, and segregation distortion. Although not fully understood at the molecular level, all are important in determining transmission of the gene thought to be mapped to the long arm of chromosome 7 (7q21.3-q22.1). These phenomena, therefore, have significant implications for inheritance of split hand and split foot and for proper referral for genetic counseling. PMID- 8699345 TI - Microembolization from atheroembolic disease or aneurysm. A case study. AB - Cyanosis of the digits may have several etiologies ranging from trauma to connective tissue disease; however, the most common cause of the so-called blue toe syndrome is atheroembolic disease or aneurysm and is frequently misdiagnosed on initial presentation. Pedal pulses are often palpable which may misdirect the physician from a diagnosis of vascular pathology. Furthermore, the proximal source of embolic shower may be far from the sight of symptoms. Noninvasive vascular testing, peripheral angiography, abdominal and popliteal ultrasonography, and echocardiography are all techniques that may be beneficial in discovering the origin of emboli. Atheroembolisms and aneurysms can be limb threatening or life-threatening and hence early diagnosis is imperative. PMID- 8699346 TI - Use of the Cam Walker in treating diabetic ulcers. A case report. AB - This case study shows how a Cam Walker when equipped with an arch filler can be another tool the physician may use to help heal diabetic ulcerations. Even after other methods of conservative care have failed, the Cam Walker with an arch filler has been shown to gradually decrease and heal diabetic ulcerations on the plantar aspect of the foot. It accomplishes this by decreasing the pressure on the ulcerative areas and by decreasing the velocity with which the foot strikes the ground. PMID- 8699347 TI - Hand-foot-and-mouth disease. AB - Hand-foot-and-mouth disease is a highly contagious disease most often seen in children during the summer. It is caused most commonly by the virus coxsackie A16, but other enteroviruses have been implicated. It presents with low grade fever, and a vesicular eruption on the hands, feet, and mouth. More serious manifestations are seen less commonly. Diagnosis is most often clinical and treatment is symptomatic in nature. The infection in a male adult is presented. PMID- 8699348 TI - Kaposi's sarcoma versus bacillary angiomatosis. AB - Persons with acquired immune deficiency syndrome (AIDS) are subject to a host of pathologic entities secondary to a depressed immune system. Kaposi's sarcoma frequently presents in this immunocompromised population and, therefore, diagnosis seems clinically straightforward. However, because of the prevalence of a strikingly similar infectious disease known as bacillary angiomatosis, skin biopsy of one or more lesions is crucial. PMID- 8699349 TI - Practical classification for the use of nonsteroidal anti-inflammatory drugs. AB - The podiatric physician is faced with a multitude of nonsteroidal anti inflammatory drugs from which to choose. Podiatric physicians are overwhelmed with advertisements in the literature, outlining the safety and efficacy of one or another of these medications. This article will categorize the nonsteroidal anti-inflammatory drugs to aid in their selection. PMID- 8699350 TI - Rickets. A study with case report. AB - Rickets is a pediatric disorder not commonly encountered by physicians in the US. Nevertheless, the podiatric physician should be aware that it persists and may exist in children who initially present with gait disturbances or failure to thrive. By using routine plain film radiography of the child's foot, the podiatric physician can screen one of the child's most rapid sites of secondary osseous growth, ie, the distal tibia. A brief overview of the rachitic and osteomalacic disorders is presented, followed by a discussion centered primarily on the plain film radiologic diagnosis of rickets. PMID- 8699351 TI - "Stand down for the homeless". Podiatric screening of a homeless population in Cleveland. AB - Health care for the homeless is a major public health concern. With the rise in antibiotic-resistant tuberculosis, the increase of human immunodeficiency virus (HIV) diseases, and other health risks, the medical community has begun to recognize the urgency of taking a proactive role in providing care for this population. Lower extremity pathology can result in limb-threatening and, in some cases, life-threatening sequelae for homeless populations. This patient group has limited access to regular hygiene, appropriate shoes, and podiatric medical care. Participation in the "Stand Down for the Homeless" projects provided an opportunity to evaluate the podiatric needs of a homeless population and to project a response to those needs. The authors define and compare this homeless population with the national homeless population, compare the podiatric needs of this homeless populations versus the general population, and respond to those needs. PMID- 8699352 TI - Mycobacterial skeletal infection of the foot. A case report. AB - Peripheral skeletal infections caused by Mycobacterium are widely reported in the literature. Unfamiliarity with this disease, or oversight caused by inexperience may result in failure to thoroughly investigate the presence of this organism. An unusual case of tuberculous osteomyelitis involving the second digit of the foot is presented. The authors emphasize the importance of including cultures of acid fast bacillus in the work-up of atypical infectious processes of the foot and ankle, and include Mycobacterium in their differential until it is positively ruled out. An in-depth radiologic review is included. PMID- 8699354 TI - Tallor's bunion. PMID- 8699353 TI - Rewards of entering podiatric medicine and attitudes toward older adults. AB - This study examined the relationships between social and demographic characteristics (ie, gender, race, year in school, desired residency choice, and socioeconomic background), motivations for entering the profession of podiatric medicine (extrinsic and intrinsic rewards), and negative attitudes toward treating elderly patients. The study used ordinary least squares multiple regression models to analyze data from a random, national sample of 448 podiatric medical students. In particular, the ordinary least squares models were developed to determine the independent effect of intrinsic and extrinsic rewards on negative attitudes toward treating elderly patients. Consistent with the study hypotheses, after adjusting for social and demographic characteristics, the study found extrinsic rewards to have strong positive relationships with negative attitudes toward treating elderly patients, and intrinsic rewards to have strong negative relationships with negative attitudes toward treating elderly patients. The authors discussed the implications of the findings for podiatric physicians and educators training podiatric medical students. PMID- 8699355 TI - Challenging questions for the advanced practice of nurse midwifery. PMID- 8699356 TI - The role of the nurse practitioner in ambulatory women's health. AB - The role of the nurse practitioner emphasizes health maintenance and prevention. In the climate of health care reform, interest in this advanced practice nurse is growing, particularly as health care moves predominantly into ambulatory care and home settings. Collaborative practice, the clinical and educational role of the nurse practitioner in ambulatory obstetrics and gynecology, is examined. PMID- 8699357 TI - A new advanced practice role focused on outcomes management in women's and children's health. AB - Outcomes management involves goal-directed coordination of transdisciplinary teams. It focuses on achieving measurable outcomes for select populations of patients. The article presents a new advanced practice role focused on outcomes management for the perinatal population. Practice pattern reforms accomplished during 3 years of work and the associated favorable clinical, functional, service, quality, and financial outcomes are described. Supports required for the success of an outcomes management program as well as lessons learned from 2 years work are presented. PMID- 8699358 TI - High-risk obstetric nursing role: perinatal nurse practitioner. AB - This article chronicles the development of the perinatal nurse practitioner (PNNP) role in providing care to high-risk obstetric patients in ambulatory and inpatient settings. Factors in the health care delivery system as well as the philosophic basis of the role are discussed. This role was modeled after neonatal nurse practitioners. Curriculum examples and role competencies are identified. Four programs are currently in existence with several more in the planning stages PMID- 8699359 TI - Role of the genetic counselor: an overview. AB - Nonphysician genetic counselors have been in practice only since 1971. Since that time such professional have integrated themselves into many medical settings, and established both a professional society and a certification board. Genetic counselors strive to be nondirective in their approach, allowing patients autonomy in decision making. This article will highlight some of the concepts inherent in the process of genetic counseling, as well as touch upon some of the ethical concerns faced by counselors. PMID- 8699360 TI - Combining the roles of clinical nurse specialist and neonatal nurse practitioner: the experience in one academic tertiary care setting. AB - The roles of clinical nurse specialist (CNS) neonatal nurse practitioner (NNP) have originated and evolved to meet specific needs in the nursing and medical community. The CNS role was developed in response to the perception that patient care needed to be improved; the NNP role resulted from an acute shortage of physicians to provide neonatal medical management. While on the surface these two roles may appear to be vastly different, many facets of each may be effectively interfaced. The NNP-CNS practice at Doernbecher Neonatal Care Center is an example of successful convergence of the two roles. The implementation of the combined practice is described in this article. PMID- 8699361 TI - Creating a successful environment for neonatal nurse practitioners. AB - Factors that contribute to the neonatal nurse practitioner (NNP) practice environment have emerged from research grounded in the results of a nonexperimental, descriptive, and correlational study that described the role and nursing identity of 258 NNPs. These factors may be used as prescriptions for developing successful NNP environments or to strengthen a current practice. Nursing management has a responsibility to identify factors that enhance nursing identity of NNPs and to plan strategies to operationalize those factors to provide an optimal environment in which NNPs can practice to their fullest potential. Implications are raised for nursing administration and education to address the issues of role differentiation, socialization, and identity of advanced practice nurses in tertiary care. PMID- 8699362 TI - Expanding the caregiving environment for advanced practice neonatal nurses. AB - Advanced practice neonatal nurses (APNNs) have participated as crucial care providers during the past two decades in supporting the development and implementation of safe, therapeutic interventions for critically ill infants in the neonatal intensive care unit (NICU). This role has been limited primarily to the NICU environment, however, and there has been minimal opportunity for APNNs to participate in caregiving that extends beyond this boundary. This boundary based practice may no longer be practical as a result of significant changes in health care financing and health care reform. It is important for all neonatal health care providers to consider an expanded scope of practice for the APNN that extends beyond the NICU into the community and home and encompasses caregiving for the neonate and infant within the first year of life. PMID- 8699363 TI - Pharmacologic therapy for pregnancy-induced hypertension. AB - Complications of pregnancy-induced hypertension (PIH) remain a leading cause of maternal mortality in the United States. The etiology of the disease is not fully understood, but pathologic effects of PIH on maternal organ systems are well documented. Present strategies for management emphasize prevention and control of eclamptic seizure and hypertensive crisis and correction of fluid imbalance. The article reviews current trends in drug therapy for the acute management of PIH. Topics discussed include evaluation of magnesium sulfate as an anticonvulsant, hydralazine versus labetalol for management of hypertension, and the role of colloid osmotic pressure in fluid therapy. PMID- 8699364 TI - Pharmacologic intervention in the management of preterm labor: an update. AB - Preterm birth accounts for the majority of neonatal morbidity and mortality not associated with congenital anomalies. Its incidence has remained relatively unchanged over the past 15 to 20 years. Tocolytic therapy has been shown to be ineffective in the prevention of preterm labor but can delay delivery by approximately 48 hours. Four major drug groups are currently available. The article reviews each drug group, including mechanism of action, pharmacology, side effects, efficacy, and nursing implications. PMID- 8699365 TI - Medical management of the patient with an ectopic pregnancy. AB - Ectopic pregnancies are the leading cause of pregnancy-related death during the first trimester. Historically, the treatment for an ectopic pregnancy was emergency laparotomy, which included salpingectomy. In 1987, research began at the Regional Medical Center at Memphis, in conjunction with the University of Tennessee, examining early detection and medical treatment for ectopic pregnancy. Pharmacologic management of an unruptured, size-appropriate ectopic pregnancy is now an established standard of care. The present protocol recommends single-dose methotrexate. This form of methotrexate has proven to be a successful, cost effective alternative to traditional surgical management of ectopic pregnancies. PMID- 8699366 TI - Pregnancy and immunosuppressive drug therapy. AB - Pregnancies in women who have previously received an organ transplant are becoming more common. This is evidenced by the growing number of case reports and published studies of pregnancy outcomes involving transplant recipients. Perinatal nurses must expand their knowledge base to provide comprehensive care to this growing population. An understanding of immunosuppressive therapy and its implications for the mother and her unborn infant is necessary in providing care. The effects of the pregnancy on the therapy and vice versa need to be understood. PMID- 8699367 TI - Pharmacologic management of apnea of prematurity. AB - Apnea of prematurity is one of the most common problems in the neonatal intensive care unit. Management of premature infants with apnea involves pharmacologic and nonpharmacologic therapies. Drugs such as theophylline and caffeine are used when nonpharmacologic measures are ineffective. The article discusses the different types of apnea seen in premature infants, how these drugs affect premature infants, how to recognize early signs of toxicity, and implications for nursing assessment and management. PMID- 8699368 TI - Intravenous immunoglobulin: what nurses need to know. AB - Neonatal sepsis continues to be a major source of morbidity and mortality among preterm infants. Although traditional antibiotic therapy continues to be the mainstay of treatment for sepsis, intravenous gammaglobulin (IVIG) is being used in both prevention and treatment of neonatal sepsis as a means to boost the infant's immunocompetence. The article explores the conflicting results of clinical trials testing the efficacy of IVIG for neonatal sepsis. IVIG is discussed with regard to its mechanism of action, pharmacokinetics, dosage and administration, adverse reactions, and nursing implications. PMID- 8699369 TI - Pharmacologic management of neonatal abstinence syndrome. AB - Substance abuse among pregnant women has become a national health issue. As a result of the increase in maternal consumption of illicit drugs during pregnancy, many more infants are experiencing signs and symptoms of withdrawal during the immediate newborn period. In many instances, pharmacologic management is required to alleviate the signs and symptoms of withdrawal experienced by these infants. The article provides a review of the common drugs of abuse consumed by women during pregnancy, identifies the common signs and symptoms of infant withdrawal, describes the onset and duration of these symptoms, and discusses potential pharmacologic agents that can be used to treat infant withdrawal or neonatal abstinence syndrome. PMID- 8699371 TI - Proceedings of the Nephrology 1994 Janus and the Workshop on Peritoneal Dialysis. Bombay, India, May 15-17, 1994. PMID- 8699370 TI - Neonatal nurses' knowledge of and attitudes toward caring for cocaine-exposed infants and their mothers. AB - The knowledge, attitudes, and backgrounds of 215 nurses employed in the nurseries of six hospitals were studied by means of a questionnaire survey. The nurses' attitudes toward the mothers of cocaine-addicted infants were found to be generally negative and/or judgmental and their knowledge to be low. More experience with nursing cocaine-addicted infants and greater acuity of the neonatal unit in which the nurse worked correlated with more positive attitudes toward the infants but not toward their mothers. Knowledge and attitude correlated positively with formal education, inservice education, and self education, but the correlations were weak. PMID- 8699372 TI - Three decades of nephrology. PMID- 8699373 TI - The development of nephrology. PMID- 8699374 TI - Some aspects of acute renal failure in the tropics. PMID- 8699375 TI - Thrombotic microangiopathy with hypertension and acute renal failure in children (a typical hemolytic uremic syndrome). AB - Thus I would like to conclude by saying that an idiopathic form of obliterative renal arteriopathy account for the rare presentation of severe hypertension and progressive renal failure with or without overt hemolytic anemia and thrombocytopenia in children. It can be labelled as primary malignant nephrosclerosis (NScl) or atypical HUS, based on primary thrombotic angiopathy. This, essentially intimal changes, is seen in diverse conditions and appears to result from primary endothelial injury followed by intimal exudation, thrombosis, and repair by fibrosis. Persistent or recurrence of this process form the basis of progressive obliterative arteriopathy. The result is renal ischemia and renin angiotensin mediated hypertension. Establishment of a vicious circle would further accelerate HT and lead to end stage renal failure. Early recognition and prompt therapeutic intervention might prove beneficial. PMID- 8699376 TI - Acute renal failure following poisonous snake bite. PMID- 8699377 TI - Renal involvement in leptospirosis--our experience in Madras City. PMID- 8699378 TI - Renal involvement in malaria. PMID- 8699379 TI - The role of renal biopsy in nephrotic syndrome. PMID- 8699380 TI - Should we treat all patients of glomerulonephritis? PMID- 8699381 TI - Water treatment for hemodialysis. PMID- 8699382 TI - Ethical issues in nephrology. PMID- 8699383 TI - Peritoneal dialysis update 1994. AB - Each year there are over 400 papers published in the field of peritoneal dialysis. In this review I have touched on only a few highlights of some of the more active areas of investigation and development. The advances in controlling peritonitis rates with the Y-set have been dramatic and have resulted in peritonitis rates in many centers less than one episode per 24 patient months. Technique survivals have also improved with lower peritonitis rates. The enormous literature on new approaches to treatment and new understandings of host defenses are beyond the scope of this review. There are also many advances in peritoneal access. We now have many new types of catheters under investigation such as the Swan-Neck Missouri catheter and the Moncrief-Popovich catheter, with complete burial of the catheter until eventual externalization for CAPD training. There have been major advances in understanding the normal healing of exit sites and the early diagnosis and treatment of exit-site infections. All the extensive literature on catheter development in the management of exit sites will be reviewed elsewhere. I have focused primarily on an update of worldwide demographics, some of the new findings in peritoneal transport, the use of low calcium solutions, experiences with EPO, new thinking about adequacy and nutrition, and finally, on recent comparisons of CAPD and hemodialysis. PMID- 8699384 TI - Status of renal transplant in India--May 1994. PMID- 8699386 TI - The value of the graft biopsy in the care of renal transplant patients. PMID- 8699385 TI - The role of fine needle aspiration cytology in the management of renal allograft dysfunction. PMID- 8699387 TI - Renal transplantation in children. PMID- 8699388 TI - Peritoneal access. PMID- 8699389 TI - Connecting devices in CAPD and their impact on peritonitis. PMID- 8699390 TI - Ultrafiltration failure in CAPD. PMID- 8699392 TI - Effect of radon exposure on superoxide dismutase (SOD) activity in rats. AB - Effect of radon exposure on the activities of superoxide dismutase (SOD) in blood, kidney, liver and spleen of male Wistar rats were investigated. Radon exposure was carried out in a newly developed chamber with 226Ra as the radon source. SOD activity, measured by the spin trap method using an electron spin resonance spectrometer, increased greatly in liver and kidney after 4 hour exposure whereas it decreased significantly after 16 hour exposure. Despite approximately same total doses by the radon exposure, the stimulated SOD activity after 4 hour exposure was not observed after 16 hour exposure in kidney, liver and spleen except blood, suggesting that the stimulating effect could last for a short period. PMID- 8699391 TI - Identification and characterization of a protein found after X-irradiation in human T cell leukemia. AB - An X-ray-induced protein in human T cell leukemia MOLT-4 cells is described. It was detected 4 hrs after irradiation by two dimensional gel electrophoresis and silver staining. The location is 41 kDa in the mass and 4.0 of pI. Its spots were collected from the gels and microsequenced. The protein was identified from its partial sequences as a set gene product, whose gene translocation previously was found in a case of acute undifferentiated leukemia. Polyclonal rabbit antibodies stained two spots, the 41 kDa (p 41) and the 42 kDa (p 42) proteins. Photoimage analyses of the silver-stained gels and Western blots indicated that the induction of p 41 was time dependent, starting 4 hrs after irradiation and reaching a plateau by 10 hrs, and was dose dependent between 1 and 10 Gy. p 41 appeared somewhat ahead of cell death, as determined by the dye exclusion test, but the role in that cell process has yet to be clarified. PMID- 8699393 TI - Molecular dynamics (MD) simulation of DNA dodecamer with 5-hydroxy-6-cytosinyl radical. AB - Molecular dynamics (MD) simulation of DNA dodecamer d (CGCGAATTC*GCG)2 with a primary radiation damage represented by 5-hydroxy-6-cytosinyl radical (C*) in position 9 was performed with AMBER 4.0 force field with periodic boundary conditions for the solvent. The temperature, potential energy of the system, energetic contributions from groups and RMS deviation from original positions were examined throughout the course of the simulation up to 140 ps. The stabilized structure (after 100 ps) was distorted and bent near the damaged site, which is similar to that observed in the MD of DNA with thymine glycol (Miaskiewicz, K. et al (1994) Radiat. Protection Dosimetry, 52, 149-153). The results suggest that a small and local damage in DNA may cause a large and global conformational change in DNA. Water molecules form two layers at distance 2.5 A and 5.5 A around the DNA. The MD simulation is a new approach to study radiation damages in molecular level. PMID- 8699394 TI - Effect of NaN3 on oxygen-dependent lethality of UV-A in Escherichia coli mutants lacking active oxygen-defence and DNA-repair systems. AB - Escherichia coli mutants which lack defence systems against such active oxygen forms as OxyR (delta oxyR), superoxide dismutase (SOD) (sodA and sodB) and catalase (katE and katG) are sensitive to UV-A lethality under aerobic conditions, whereas OxyR- and SOD-mutants have resistance under anaerobic conditions and in the presence of sodium azide (NaN3) during irradiation. UV-A induces lipid peroxidation in the delta oxyR mutant, which is suppressed by NaN3. These results suggest that UV-A generates 1O2 or the hydroxyl radical to produce lipid peroxides intracellularly in the delta oxyR mutant and that O2- stress may be generated in the sodAB mutant after 8hr of exposure to UV-A. The sensitivities of such DNA repair-deficient mutants as recA(ind-) and uvrA to UV-A also were examined and compared. These mutants are sensitive to UV-A lethality under aerobic conditions but show only slight resistance under anaerobic conditions or in the presence of NaN3 during irradiation. We conclude that NaN3 protects these mutant cells from oxygen-dependent UV-A lethality. PMID- 8699395 TI - Morphological profiles of neutron and X-irradiated small intestine. AB - This paper describes the response of mouse small intestine, at several time points after treatment with neutron or X-irradiation, using doses expected to give similar effects in terms of crypt/microcolony survival. Using resin histology, the effects of radiation on the numbers of duodenal cell types and measurements of tissue areas were assessed. The results for individual parameters and for an estimate of overall damage are given in a data display, which summarises the morphological profile of the organ after both types of radiation. Damage and recovery were seen for many of the parameters studied but there was no standard response pattern applicable for all parameters. In particular, the response of individual crypt cell types could not be predicted from knowledge of the change in crypt numbers. With regard to the holistic response of the gut, neutron irradiation appeared to have caused more damage and produced more early effects than the X-irradiation. More specifically, neutron treatment led to more damage to the neuromuscular components of the wall, while X-irradiation produced early vascular changes. PMID- 8699396 TI - Accumulation of cells at G2/M stage by low dose-rate irradiation renders the cell population more susceptible to the subsequent induction of 6-thioguanine resistant mutations by 252Cf fission neutrons. AB - A previous study on mutagenesis by 252Cf radiation in mouse L5178Y cells showed that the frequency was higher when the dose was delivered chronically, which was in sharp contrast to the results by gamma-rays (Nakamura and Sawada, 1988). A subsequent study using synchronized cells revealed that the cells at G2/M stage were uniquely sensitive to mutation induction by 252Cf radiation but not so by gamma-rays (Tauchi et al, 1993). We carried out the present study to test the possibility that radiation-induced G2 block may be a major determinant of the inverse dose-rate effect following chronic 252Cf radiation. Growing cell population was first subjected to conditioning gamma or 252Cf radiation with different dose-rates, followed by cell cycle distribution analysis and 252Cf mutagenesis. We found that G2/M fraction increased by 3- to 4-fold when the conditioning doses (2 Gy of gamma or 1 Gy of 252Cf radiation) were delivered chronically over 10 hours but only slightly so when the same doses were delivered for 1 hour or less. Subsequent 252Cf irradiation gave higher mutation frequencies in the cells pre-irradiated with gamma-rays over a protracted period of time than in those with higher dose-rate gamma-rays. These results suggest that radiation induced G2 block would be at least partly (but can not be totally) responsible for the inverse dose-rate effect. PMID- 8699397 TI - Influence of culture system and oxygen tension on the development of ovine zygotes matured and fertilized in vitro. AB - The development and quality of ovine zygotes matured and fertilized in vitro were compared after coculture with oviductal cells (CZB-199 system) and culture in synthetic oviduct fluid medium without cells (SOF system). The effect of two oxygen concentrations (5% and 20%) on the development of ovine zygotes in SOF medium was also studied. More ovine zygotes reached the blastocyst stage when culture in SOF medium was performed in 5% O2 rather than 20% O2. A greater number of blastocysts was obtained after culture in the SOF system than coculture in the CZB-199 system. Proportions of grade I (excellent), II (good), III (fair) and IV (poor) blastocysts did not differ significantly between the SOF and CZB-199 systems. Histological examination of hatched blastocysts revealed a superiority of the SOF system for the following: a greater number of total and trophoblastic cells in grade I and II blastocysts; more endodermic cells in grade I blastocysts, higher mitotic index in the inner cell mass of grade II blastocysts and in total and trophoblastic cells of grade I, II and III blastocysts; more grade III blastocysts with mitosis in the inner cell mass; and a lower pyknotic index in the inner cell mass of grade I, II and III blastocysts. Culture in the SOF system improved the rate and quality of blastocysts in comparison with the CZB-199 system. Furthermore, culture in SOF medium with 5% O2 provided more blastocysts than culture in the presence of 20% O2. PMID- 8699398 TI - Glucose controls sex-related growth rate differences of bovine embryos produced in vitro. AB - The objective of this study was to determine whether the presence of glucose in the culture medium causes more growth of male embryos than of female embryos in cows. Oocytes matured and fertilized in vitro were cultured from 24 to 48 h after insemination in CR1aa medium with or without 5.56 mmol glucose l-1. At the end of culture the mean numbers of cells of the cleaved embryos were 5.07 (+/- 0.16) in glucose-free medium and 5.29 (+/- 0.17) in medium with glucose (P = 0.86). Without glucose in the medium, the least square mean was 0.22 cells higher in males than in females. This difference was not significant (P = 0.44). However, in the presence of glucose this difference was 1.25 cells in favour of males (P = 0.0001). The possibility that the sex difference is linked with growth stimulating effects of oxygen radicals is discussed. PMID- 8699399 TI - Changes in secretory status, cell height and percentage ciliation of epithelial lining of sheep fimbria oviduct during early pregnancy. AB - Studies have shown that the biosynthetic activity of the fimbria oviduct in the sheep changes during the first few weeks of pregnancy. The objective of the present study was to determine whether the secretory epithelial lining of the fimbria undergoes pregnancy-associated morphological alterations in a concordant manner. Oviducts obtained from ovariectomized, oestrous (day 0) and pregnant (day 1.5, 2, 3, 4, 6 and 16) ewes were analysed quantitatively and qualitatively using light and electron microscopy. The epithelium was low cuboidal in fimbria from ovariectomized sheep, significantly increased in height at day 1.5 of pregnancy, immediately decreased at day 2, and underwent an additional slight reduction at day 6 and day 16 of pregnancy. Ciliated and nonciliated cells were present in the epithelium at all reproductive stages. The proportions of ciliated and nonciliated cells varied during pregnancy and ciliated cells were always the major cell type. Consistent with previous data, the secretory organelles of nonciliated epithelial cells obtained from ovariectomized ewes were poorly developed. Maturation of secretory organelles in nonciliated cells occurred at oestrus and was maintained until days 2-3 of pregnancy; regressive changes were then observed, characterized by atrophy of the Golgi apparatus and rough endoplasmic reticulum, and increases in heterochromatin and pronounced nuclear folds. Large, electron-dense lipid droplets were present throughout the cytoplasm of ciliated and nonciliated epithelial cells, beginning at day 1.5 of pregnancy and increasing at later stages of pregnancy. Apical protrusions and microvilli were observed at the luminal domains of nonciliated cells and were reduced in extent after day 3 of pregnancy. Cells were extruded from the epithelial lining at day 16 of pregnancy. These data show that the epithelial lining of the fimbria oviduct in the sheep undergoes distinct changes in cell height, percentage ciliation and secretory organelle development during the first few weeks of pregnancy. PMID- 8699400 TI - The ovarian follicular wave pattern and induction of ovulation in the mated and non-mated one-humped camel (Camelus dromedarius). AB - Ovarian follicular wave patterns were studied ultrasonographically in three groups of dromedary. Group 1 camels (n = 20) were teased daily with a vasectomized male but mating was prevented; group 2 camels (n = 8) ran freely with a vasectomized male camel for 10 h each day and group 3 camels (n = 8) were kept completely separate from any males. In a second experiment (n = 63), when the diameter of the dominant follicle reached 0.5-0.9 cm, 1.0-1.9 cm, 2.0-2.9 cm or > 3 cm, the camel was given one of three treatments to induce ovulation: (i) natural mating; (ii) 20 micrograms of the GnRH analogue, buserelin; or (iii) 3000 iu hCG. The ovaries were re-scanned regularly to monitor ovulation, and daily blood samples were assayed for progesterone and oestradiol concentrations. The follicular cycle was divisible into a growth phase (10.5 +/- 0.5 days), a mature phase (7.6 +/- 0.8 days) and a regression phase (11.9 +/- 0.8 days). The dominant follicle reached a mean +/- SEM maximum diameter of 2.0 +/- 0.1 cm (range 1.5-2.5 cm) in 34 cycles (52%) before it began to regress. In the other 32 cycles (48%), however, the dominant follicle continued to grow to 4.2 +/- 0.2 cm (range 4.0-6.0 cm) before regression commenced. Group 2 camels were mated when their follicles reached 1.3 +/- 0.1 cm in diameter and the mean interval between successive matings was 13.8 +/- 1.0 days. Mean +/- SEM serum concentrations of oestradiol reached peak values at 39.0 +/- 1.8 pg ml-1, when the dominant follicle measured 1.7 +/- 0.1 cm and, after ovulation, mean serum concentrations of progesterone reached peak values at 2.6 +/- 0.3 ng ml-1 on day 8, before decreasing to < 1 ng ml-1 by day 10 or 11. When the dominant follicle measured 0.5-0.9 cm in diameter, 70%, 60% and 60% of them ovulated in response to mating, or treatment with buserelin or hCG, respectively. These ovulation rates increased to 85% (mating), 81% (buserelin) and 67% (hCG) when the follicle measured 1-1.9 cm, but they decreased again to 12.5% (mating), 29% (buserelin) and 13% (hCG) when the diameter had increased to 2.0-2.9 cm at the time of treatment. No follicles measuring > 3.0 cm ovulated in response to any of the treatments. These results indicated that the optimum time to mate or attempt to induce ovulation in the female dromedary is when the growing follicle measures 0.9-1.9 cm in diameter. PMID- 8699401 TI - Oocyte quality in small antral follicles in the presence or absence of a large dominant follicle in cattle. AB - The aim of these experiments was to determine whether the presence of a dominant follicle affects the developmental competence of oocytes from small antral follicles of cattle. In Expt 1, oocytes or follicular fluid samples were collected from follicles 2-7 mm in diameter before (day 3 of the oestrous cycle; n = 4) or after (days 6 and 7 of the oestrous cycle; n = 6) emergence of the first wave dominant follicle (verified by rectal ultrasonography). Five to ten follicles were aspirated for the determination of individual follicular fluid concentrations of oestradiol, progesterone, testosterone and dimeric inhibin; oocytes from the remaining follicles from each cow were pooled and developmental capacity assessed by in vitro fertilization and maturation. In Expt 2, ovaries containing a young corpus luteum and with or without a large oestrogen-active follicle were collected from the abattoir. Follicular aspirates from small follicles in each pair of ovaries were pooled, and oocyte quality and steroid concentrations were determined. In Expt 1, small follicles obtained before emergence of the dominant follicle contained significantly more oestradiol than they did after emergence (19.5 +/- 1.5 versus 0.7 +/- 1.1 ng ml-1, respectively; P < 0.05), but there were no significant differences in concentrations of progesterone, testosterone or dimeric inhibin. The percentage of blastocysts obtained from oocytes collected before (12.1 +/- 9.0) or after emergence (11.8 +/ 7.0) of the dominant follicle did not differ significantly (P > 0.05). In Expt 2, follicular steroid concentrations did not differ in small follicles taken in the presence versus the absence of a large oestrogen-active follicle, and there were no differences in the developmental capacity of the oocytes. There were significant negative correlations between follicular oestradiol concentration and the percentage of blastocysts formed from two-cell (r = -0.90; P < 0.01) and eight-cell embryos (r = -0.65; P < 0.05). These data suggest that in cattle the developmental competence of oocytes from small antral follicles is not adversely affected by the presence of a dominant follicle. PMID- 8699402 TI - Lipid and antioxidant changes in semen of broiler fowl from 25 to 60 weeks of age. AB - Spermatozoa and seminal plasma from cockerels at the beginning and end of their reproductive periods were examined for their lipid composition and associated antioxidant capacities. The significant reduction in concentration of spermatozoa with age was associated with a large increase in lipid concentrations in spermatozoa and in seminal plasma. This change in lipid concentration was accompanied by increases in the proportions of phospholipid and free cholesterol; in contrast, the proportions of these lipid moieties in seminal plasma were reduced. The major phospholipid fractions in the spermatozoa and seminal plasma were phosphatidyl choline and phosphatidyl ethanolamine. There was a large decrease with age in the proportion of phosphatidyl ethanolamine and a commensurate increase in that of phosphatidyl choline in the spermatozoa and seminal plasma. These major changes in phospholipid content were accompanied by a decrease in the amount of phosphatidyl serine in the spermatozoa and increases in phosphatidyl inositol and cardiolipin in both spermatozoa and seminal plasma. The reductions in the proportions of phosphatidyl ethanolamine were accompanied by considerable reductions in the content of the major polyunsaturated fatty acids 20:4 (n-6) and 22:4 (n-6). The changes in lipid composition owing to ageing were associated with a marked reduction within the spermatozoa of the major antioxidant enzyme glutathione peroxidase. The role of these changes in the specific combinations of polyunsaturated lipids and in antioxidant capacity in the reduction in fertility with age are discussed. PMID- 8699403 TI - High androgen production by ovarian thecal interstitial cells: a mechanism for delayed ovulation in a tropical vespertilionid bat, Scotophilus heathi. AB - The steroid hormone profile of Scotophilus heathi, and Indian tropical vespertilionid bat, was studied, with special reference to the period of delayed ovulation. The results show unusually high concentrations of circulating androstenedione and testosterone during the first half of the period of delayed ovulation, whereas the concentrations of progesterone and oestradiol were relatively low during this period. Androstenedione, testosterone and oestradiol concentrations were high during the period of ovarian recrudescence (October November). The oestradiol concentration increased, whereas androstenedione and testosterone declined significantly, before ovulation. Studies in vitro showed that the ovary secrets more androstenedione and testosterone than does the adrenal. A histological study showed that a major part of the ovary of S. heathi was occupied by hypertrophied interstitial cells. An immunocytochemical study showed ovarian thecal interstitial cells as the major site of high androgen synthesis in the ovary. During the period of delayed ovulation the bat ovaries thus resemble the ovaries from women with polycystic ovaries in which abnormally high androgen secretion from hypertrophied interstitial cells prevent ovulation. PMID- 8699404 TI - Regulation of reproductive seasonality in the red deer hind: oestradiol-dependent and -independent influences on the patterns of LH concentrations. AB - The control of reproductive seasonality was studied in farmed adult red deer hinds that had been either ovariectomized or ovariectomized and oestradiol treated (s.c. implants). The breeding season, delineated by progesterone secretion in intact hind herdmates, was characterized by high (mean 0.6, range 0.1-2.5 ng ml-1 plasma) LH concentrations in ovariectomized oestradiol-treated hinds. In contrast, during the non-breeding season plasma LH concentrations in these animals were significantly lower (mean 0.1, range 0-0.9 ng ml-1 plasma). LH secretion in ovariectomized untreated hinds also displayed a marked seasonal pattern, approximately the inverse of daily photoperiod (that is, a winter peak and summer trough). The pituitary LH response to 10 micrograms exogenous GnRH was also maximal during the breeding season in ovariectomized (mean 7.4, range 1.2 14.6 ng ml-1) and ovariectomized, oestradiol-treated (mean 16.4, range 1.4-32.3 ng ml-1) hinds. These results indicate that LH secretion in the hind is regulated by both steroid-dependent and -independent mechanisms. PMID- 8699405 TI - Developmental regulation and partial characterization of growth factors in the bovine mammary gland. AB - Bovine mammary gland secretions from several developmental stages were shown to stimulate [3H]thymidine incorporation into AKR-2B mouse embryo fibroblast cells. In virgin heifers, mammary secretions at 1% concentration stimulated thymidine incorporation into AKR-2B cells more than threefold compared with 10% (v/v) fetal calf serum. The growth-promoting activity peaked at an early stage of the last trimester (7-8 months) of gestation and declined after this until the colostrum forming stage. At this point, the activity was one- to twofold that induced by 10% (v/v) fetal calf serum. At parturition the activity dropped abruptly to virtually undetectable values in milk. The developmental change in activity could be mimicked by hormonal priming of the mammary gland. The partial characterization of the growth promoting activities in secretions at the seventh month of gestation revealed at least two major growth-promoting activities: bovine mammary derived growth factor 1 (bMDGF-1), an epidermal growth factor-like growth factor with a molecular weight of 30,000, which is trypsin sensitive and heat stable, and bMDGF-2, which eluted under gel filtration conditions at a molecular weight of 50,000 and 150,000. bMDGF-1 is predominant in pregnant, precolostric, and colostric secretions, and is not detected in milk. bMDGF-2 is the major growth factor in milk. These results show developmental regulation and modulation of growth-promoting factors during the different stages of mammary gland development and suggest that growth factors are involved in regulating growth during gestation. PMID- 8699406 TI - Influence of oral administration of ornidazole on capacitation and the activity of some glycolytic enzymes of rat spermatozoa. AB - The chlortetracycline fluorescence assay was used to study the status of capacitation and the extent of induced acrosome reactions in cauda epididymidal spermatozoa from fertile and infertile rats fed, respectively, with vehicle or ornidazole (400 mg kg-1 day-1) for 10 days. Uniform bright fluorescence over the whole head was classified as the uncapacitated pattern, whereas a postacrosomal dark band, and a uniformly weaker fluorescence over the acrosome, reflected patterns intermediate between the uncapacitated and acrosome-reacted states. Acrosome-reacted spermatozoa displayed a dark head but always retained fluorescence at their tip. There was no difference between experimental and control groups of rats with regard to the development of the chlortetracycline fluorescence patterns during incubation. Under basal incubation conditions, the acrosome reaction was slightly delayed in spermatozoa from ornidazole-treated animals. In contrast, more spermatozoa were acrosome reacted in this group after incubation for 5 h when the concentration of BSA was increased from 4 to 20 mg ml 1. The Ca(2+)-ionophore A23187 induced a similar stimulation of capacitation and acrosome reactions in spermatozoa from control and ornidazole-fed animals, but in the latter group A23187 caused strong immobilization of spermatozoa. In the capacitation medium containing 5 mmol lactate l-1 and 5 mmol glucose l-1, the straight-line velocity of spermatozoa from ornidazole-treated rats was reduced by 50% compared with controls, irrespective of the concentration of BSA. Two glycolytic enzymes, triose phosphate isomerase and glyceraldehyde 3-phosphate dehydrogenase, displayed reduced activity (48% and 68% of controls, respectively) in cauda epididymidal spermatozoa from ornidazole-fed rats, whereas the activities of hexokinase and lactate dehydrogenase remained unchanged. This finding suggests that the fertility-compromising action of ornidazole is due to a disturbed glycolytic pathway. PMID- 8699407 TI - Decidual sialylation shows species-specific differences in the pregnant mouse and rat. AB - Biotinylated lectins from Sambucus nigra (SNA) and Maackia amurensis (MAA), which bind to alpha 2,6-linked and alpha 2,3-linked sialyl residues, respectively, were used as probes to study glycan terminal modifications associated with decidualization in the uterine stroma of pregnant rats and mice. Binding of lectins from Erythrina cristagalli (ECA), Phaseolus vulgaris (leukoagglutinin, L PHA), Triticum vulgaris (WGA) and Bandeiraea simplicifolia (BSA-1B4) was also examined. Tissues from rats between day 5 and day 8 of gestation and mice between day 5 and day 7 of gestation were fixed in Bouin's solution and embedded in wax prior to lectin histochemistry. On day 7 in rats and day 6 in mice, there was a marked reduction in the binding of SNA in the subluminal decidua surrounding the implantation site. In rats, MAA binding to enlarged decidual cells around the implantation chamber was increased markedly, but there was no change in mice. In both species there was de novo binding of ECA in the SNA-negative area, suggesting that the loss of alpha 2,6-linked sialyl residues unmasks terminal N acetyl lactosamine. These findings are consistent with previous evidence of a close structural and functional similarity between the artificially induced deciduoma and true decidua of rats and show identical changes to the glycosylation patterns previously found in differentiating rat deciduoma. In both species, therefore, decidua exhibits regionally specific terminal glycosylation. However, the species-specific expression of alpha 2,3-linked sialyl residues suggests distinct patterns of steroidally modulated sialyl transferase expression. PMID- 8699408 TI - Ultrastructural validation of an improved culture system for boar efferent duct epithelium. AB - A tissue culture system in which cells retain defined ultrastructural and functional characteristics was established to provide a basis for functional investigations of the efferent ductules in boars. A currently used culture protocol for rat epididymal epithelium was used as a starting point and was subsequently modified because of unsatisfactory results. Epithelial plaques were isolated by mechanical uncoiling of the ductules and two sequential enzymatic digestion steps. Plaques were seeded onto extracellular matrix-coated permeable membranes and maintained in a two-chamber system. Samples taken before seeding and after 7 days in culture were processed for transmission and scanning electron microscopy. Perfusion-fixed material from earlier studies served as a reference to assess ultrastructural preservation. In addition, endocytotic activity was investigated by adding cationized ferritin to the culture medium on day 8 before fixation. At the end of the disaggregation procedure, cells were cuboidal, while cilia, microvilli and cell organelles were well preserved. After 7 days in culture, three types of cell formation were observed: cysts, pseudotubules and epithelial sheets. Cell sheets were made up of closely juxtaposed cells bearing motile kinocilia and exhibiting well-developed polar differentiation, as judged from the localization of cell junctions and organelles. Although it did not return to the values of native material, cell height was greater than that of cells grown according to the pre-existing protocol. Furthermore, preferential uptake of ferritin by principal cells after 7 days in culture was demonstrated. Preservation of these fundamental characteristics of the in vivo state corroborates that our in vitro system will furnish reliable information. PMID- 8699409 TI - Chromatin defects in normal and malformed human ejaculated and epididymal spermatozoa: a cytochemical ultrastructural study. AB - Cytochemical defects in chromatin were examined by transmission electron microscopy (TEM) after the staining by alcoholic phosphotungstic acid (PTA) of normal and malformed ejaculated spermatozoa from 35 male partners of infertile couples, and in six sperm samples retrieved from the caput epididymidis of men affected by obstructive azoospermia. PTA staining was also analysed in normal ejaculates of fertile men after incubation of the washed spermatozoa with dithiothreitol (DTT) to reduce disulfides to thiols, or with DTT followed by iodoacetamide, a blocking agent for thiol groups. PTA stained 63 (27-100)% of malformed heads and 25 (10-100)% of normal sperm heads (median (range) n = 35; P = 0.0001, Wilcoxon matched pairs test). The percentage of normal heads stained by PTA was negatively correlated with the percentage of heads of normal form, with condensed chromatin and a normal acrosome (Spearman r = 0.75; P = 0.0001), and positively correlated with the percentage of malformed heads after conventional TEM analysis (Spearman r 0.60; P = 0.0001). Staining with PTA in normal heads was not correlated with the presence of non-condensed chromatin in otherwise normal sperm heads evaluated by conventional TEM analysis. In spermatozoa recovered from the caput epididymidis, 15% of normal heads were stained with PTA, significantly fewer than in ejaculated sperm samples (P = 0.014). The reduction of disulfides to thiols was associated with PTA staining of all normal heads, and this was prevented by incubation with iodoacetamide. We conclude that PTA staining of the nuclei of human ejaculated spermatozoa may indicate a defect of chromatin condensation, owing to an excess of free thiol groups. The lower percentage of normal epididymal sperm heads that stained with PTA in cases of obstructive azoospermia compared with ejaculated sperm may be related to an overoxidation of thils owing to the ageing of spermatozoa. PMID- 8699410 TI - Disruption of early pregnancy by direct and indirect exposure to novel males in mice: comparison of influences of preputialectomized and intact males. AB - Inseminated female CF-1 mice (Mus musculus) were exposed on days 1 to 5 of pregnancy to unfamiliar outbred males. In the first experiment, inseminated females were each housed directly with the sire, a preputialectomized male, or an intact male. Both types of novel male attempted to mate with the female during this period, unlike the sire. Reinsemination occurred in a significant proportion of the females that were exposed to novel males; this effect was equivalent for preputialectomized and intact males. In two subsequent experiments, we refined a paradigm of indirect exposure to novel males through a wire-mesh grid, which prevents mating and reinsemination. Two or three males housed directly above each female through a grid disrupt pregnancy in most cases, but housing the males below the females is much less likely to do so. In a final experiment, each inseminated female was housed below two males that were either preputialectomized or sham-preputialectomized. Whereas 29 of 33 undisturbed controls were parturient, only eight of 32 females exposed to sham-preputialectomized males and six of 32 exposed to preputialectomized males were parturient. These results suggest that nonvolatile pheromones are involved in novel-male-induced pregnancy disruptions, but that preputial gland emissions are not necessary for such disruptions. PMID- 8699411 TI - Suppression of oocyte release in rats by local administration of the noradrenergic neurotoxin DSP4. AB - The presence of noradrenergic neuronal innervation in the ovaries and cyclic alterations in ovarian noradrenaline suggest a role for such innervation in oocyte release. The current experiments evaluated the relationship between ovulation and alterations in ovarian concentrations of noradrenaline induced by unilateral, intrabursal administration of the specific noradrenergic neurotoxin DSP4. Intrabursal injections of DSP4 (0-10 mumoles per ovary) given at 19:00 h at pro-oestrus induced a prompt, dose-related reduction in ovarian noradrenaline on the injected and non-injected sides. Although this result suggests that injected material was reaching the contralateral ovary, ovulation was suppressed only on the injected side. This suppression was persistent, and lasted through at least the next two cycles following either unilateral or bilateral treatment. The reductions in noradrenaline could be mostly, if not entirely, attenuated by prior administration of desipramine which blocks re-uptake of noradrenaline, while the ipsilateral ovulatory effects remained unchanged. Although it has been reported that DSP4 binds the opiate receptor, intrabursal co-administration of the antagonist naloxone was ineffective in altering ovulatory suppression. These results suggest that while decreases in ovarian noradrenaline in response to local exposure to a noradrenergic neurotoxin may accompany a reduction in oocyte release or a block in ovulation, the anti-ovulatory effect of DSP4 is independent of the changes in noradrenaline concentrations and may be due to some other ovarian response. PMID- 8699412 TI - Cellular localization and steroid hormone regulation of mRNA encoding tumour necrosis factor receptor I in mouse uterus. AB - Signals transduced by binding of tumour necrosis factor alpha (TNF) and lymphotoxin alpha (LT-alpha) trimers to high-affinity cell membrane receptors, TNF-RI (p55/p60) and TNF-RII (p75/p80), affect many cell functions. In this study, expression of the gene encoding TNF-RI in uteri of cyclic mice was mapped using in situ hybridization. TNF-RI hybridization signals fluctuated during the cycle. Signal intensity was highest during dioestrus-II, when mRNA encoding TNF RI was present in endometrial epithelial and stroma cells, as well as in myometrial smooth muscle and connective tissue cells. The ability of oestradiol and progesterone to modulate steady state concentrations of mRNA encoding TNF-RI in uterine cells was assessed by using in situ and northern blot hybridization procedures. Seven days after ovariectomy, low concentrations of mRNA encoding TNF RI were detected by northern analysis and weak in situ hybridization signals were identified in epithelia and some myometrial connective tissue cells. Administration of oestradiol, progesterone or oestradiol plus progesterone to ovariectomized animals stimulated temporal and cell type-specific changes in steady state concentrations of mRNA encoding TNF-RI that were unique to each hormonal regimen. Maximal induction of mRNA encoding TNF-RI required 24 h of oestradiol stimulation and 72 h of progesterone stimulation. In uteri treated with oestradiol plus progesterone, the oestradiol pattern predominated over the progesterone pattern. Thus, multiple cell types in cyclic mouse uteri express the gene encoding TNF-RI, and expression in specific cells is controlled by female steroid hormones. PMID- 8699413 TI - Effects of selenium deficiency on testicular morphology and function in rats. AB - For four generations rats were fed a low selenium diet (2-7 micrograms Se kg-1) or the same diet with 250 or 300 micrograms Se kg-1 added as selenite. In male rats of the first generation that had been fed the diets from the age of 20 days onwards, selenium depletion led to slightly delayed testis growth during pubertal development that was compensated for in the later stages of maturation. In adult rats fed the low selenium diet for nearly a year no changes in testicular mass and morphology were observed. The serum concentration of testosterone of 6-month old, selenium-depleted animals was, however, slightly lower than that of adequately supplied controls, and the stimulation of testosterone secretion by administration of GnRH or LH resulted in a significantly less marked rise in the serum concentration of testosterone. From the second generation onwards the testis mass, expressed as a percentage of the body mass, decreased and in the fourth generation was less than 50% of that of the controls. The male gonads of fourth generation animals showed a severe bilateral atrophy, in which the seminiferous tubules were considerably reduced in diameter and almost entirely lined by Sertoli cells and a few stem cells. Differentiated spermatozoa could not be detected. The alterations were reversible and spermatogenesis was restored by feeding the selenium-adequate diet. The findings indicate that testicular morphology and functions are affected by severe selenium deficiency and that the element is necessary for testosterone biosynthesis and the formation and normal development of spermatozoa. PMID- 8699414 TI - Oxygen uptake and carbohydrate metabolism by in vitro derived bovine embryos. AB - The consumption of oxygen, uptake of pyruvate and glucose and production of lactate were determined for groups of bovine embryos produced in vitro from the one-cell to the blastocyst stage (day 0-6 of culture). Measurements were made in Hepes-buffered synthetic oviduct fluid medium supplemented with 1.0 mmol pyruvate l-1, 10 mmol D,L-lactate l-1 and 1.5 mmol glucose l-1 and also 3 mg BSA ml-1 and, from day 5 of development, 10% (v/v) fetal calf serum. The amount of ATP production was determined from oxygen consumption and the proportion of glucose taken up that could be accounted for by lactate production. The data revealed that oxygen consumption was relatively constant from days 0-4 of culture (0.24 0.27 nl per embryo h-1), but increased with the initiation of compaction (0.39 nl per embryo h-1) and continued to increase with the formation and expansion of the blastocoel (0.9 nl per embryo h-1). Both pyruvate and glucose uptake followed similar patterns. Furthermore, when plotted against oxygen consumption, both pyruvate and glucose uptake increased significantly (P < 0.001) in a linear relationship (R2 = 0.61 and 0.49, respectively). Lactate production also increased with development and accounted for 40% of glucose uptake at day 0 of culture (putative zygotes), increasing to 70% by day 2 (eight-cell stage) and 100% of glucose uptake from day 4 of culture onwards. ATP production followed a similar pattern to that of oxygen consumption (60-85 pmol per embryo h-1 from day 0 to day 4) increasing with compaction (124 pmol per embryo h-1) and blastulation (221 pmol per embryo h-1). For precompaction stages, 93-96% of ATP production was derived from oxidative phosphorylation, decreasing to 82% with compaction. ATP produced by oxidative phosphorylation could be accounted for by the uptake of pyruvate, suggesting that bovine embryos produced in vitro utilize little endogenous substrates when appropriate exogenous substrates are present in the culture medium. The data revealed that bovine embryos were dependent on oxidative phosphorylation for energy (ATP) production at all stages of pre-elongation development, with perhaps a shift in dependence towards glycolysis in conjunction with compaction. It follows that oxidizable substrates, such as pyruvate and certain amino acids, are preferred in embryo culture medium during development in vitro. PMID- 8699415 TI - Association of disproportionate growth of fetal rats in late gestation with raised systolic blood pressure in later life. AB - In human populations, patterns of disproportionate fetal growth are associated with cardiovascular disease in later life. Protein restriction of pregnant rats is known to impair fetal growth and is also associated with increased systolic blood pressure in later life. Growth of fetuses exposed to maternal low protein diets was found to be accelerated between day 14 and day 20 of gestation, but this growth appeared to falter in late gestation, resulting in low or normal birthweights. Placental growth was also accelerated by protein restriction. Day 20 fetuses from rats fed low protein diets were heavier but had proportionally smaller brains than did control fetuses. These animals were also longer in proportion to body mass. Between day 20 and full term (day 22), growth of the brain was spared at the expense of the trunk and at birth, pups exposed to low protein were short in relation to body mass. At weaning, rats exposed to low protein diets in utero had significantly higher systolic blood pressure relative to control animals. These data indicate that increased blood pressure in rats is linked to disproportionate patterns of growth in middle and late gestation. PMID- 8699416 TI - Lectin histochemistry in the human epididymis. AB - A histochemical study using lectins to identify glycoconjugates present in the efferent ducts and ductus epididymidis of men without testicular or related disease was carried out. The lectins used and the oligosaccharide residues linked were: wheat germ agglutinin (WGA) for beta-N-acetylglucosamine and sialic acid, concanavalin A (ConA) for alpha-mannose, Ulex europaeus agglutinin (UEA-I) for alpha-fucose, Dolichos biflorus agglutinin (DBA) for alpha-N-acetylgalactosamine, soy bean agglutinin (SBA) for beta-N-acetylgalactosamine, and peanut agglutinin (PNA) for beta-galactose. The lectin-binding pattern in the human epididymis presents similarities and differences to those observed in other mammals which also showed differences between species. The present results revealed that regional differences along the human ductus epididymidis were less pronounced than those reported in other mammals. The epithelial cells in the efferent ducts reacted positively to WGA. All along the length of the ductus epididymidis, the principal cells and the luminal content showed staining affinity for WGA and ConA. The epididymal principal cells and luminal content also reacted positively to DBA for alpha-N-acetylgalactosamine but only in the cauda epididymidis. A positive reaction to UEA-I was observed only in the luminal content of the cauda epididymidis. This finding suggests that changes in the oligosaccharide chains of secretions leading to a positive UEA-I reaction occur in the cauda epididymidis. The epididymal principal cells showed positive reactions to SBA and PNA over the apical microvilli but not in the cytoplasm. The reaction was observed in the caput and corpus epididymidis but not in the cauda. Positive reactions to SBA and PNA were also detected in the epididymal fluid and in the cytoplasm of mitochondria-rich cells (a minor population of epididymal epithelial cells). These cells also reacted to other lectins such as WGA, ConA and DBA, which were also detected in the principal cells. PMID- 8699417 TI - Metabolism of glycerol 3-phosphate by mature boar spermatozoa. AB - Under anaerobic conditions boar spermatozoa metabolized fructose and glucose to lactate but did not produce ATP to the extent of that produced under aerobic conditions; the ketogenic amino acids leucine, tryptophan, phenylalanine and tyrosine were not oxidatively metabolized. Glycerol 3-phosphate was metabolized rapidly in the presence or absence of the glycolytic inhibitor, 3-chloro-1 hydroxypropanone (CHOP). In the absence of CHOP, glycerol 3-phosphate was converted to CO2, lactate, glucose 6-phosphate and fructose 6-phosphate, and ATP was produced. In the presence of CHOP, glycerol 3-phosphate did not produce CO2, lactate or ATP, but formed fructose 1,6-bisphosphate and dihydroxyacetone phosphate. With dihydroxyacetone phosphate as substrate, fructose 1,6 bisphosphate, lactate, glucose 6-phosphate, fructose 6-phosphate and ATP were produced. Accumulation of glucose 6-phosphate and fructose 6-phosphate from glycerol 3-phosphate appeared to depend on the production of ATP; if ATP was not produced, dihydroxyacetone phosphate and fructose 1,6-bisphosphate accumulated. The conversion of glycerol 3-phosphate to glycolytic intermediates appeared to be a mechanism for the conversion of substrates for the ultimate production of lactate. PMID- 8699418 TI - Localization of mRNA encoding c-kit during the initiation of folliculogenesis in ovine fetal ovaries. AB - The c-kit protein is a transmembrane tyrosine kinase receptor that binds the growth factor stem cell factor. Mutant alleles of the genes coding for both the receptor (c-kit) and its ligand (stem cell factor) affect gametogenesis, development of melanoblasts and some aspects of haematopoiesis. The aim of this study was to examine expression of the c-kit gene during folliculogenesis in fetal sheep ovaries using in situ hybridization. A 422 bp cDNA encoding the extracellular domain of the c-kit protein was amplified from sheep ovarian RNA using reverse-transcription-polymerase chain reaction (RT-PCR), cloned and sequenced. Riboprobes transcribed from the ovine cDNA encoding c-kit were used to detect the presence of mRNA encoding c-kit within the ovaries of fetal sheep on days 90, 100, 120 and 135 of gestation (term = 147 days). In day 90 and 100 fetal ovaries, mRNA encoding c-kit was not detected in association with oogonia during the period of meiosis (to prophase I) but was present in some of the isolated oocytes. In ovaries from day 90 to day 135, mRNA encoding c-kit was detected in the oocytes at every stage of follicular growth--primordial through to antral follicles. This pattern of localization is consistent with that demonstrated in mice. PMID- 8699419 TI - Reproductive activity in captive female cheetahs (Acinonyx jubatus) assessed by faecal steroids. AB - Faecal oestradiol and progestogen metabolite excretion was monitored in adult, female cheetahs (Acinonyx jubatus) (n = 26) for 1-24 months. Increased faecal oestradiol excretion was associated with mating or equine chorionic gonadotrophin (eCG) administration for artificial insemination, whereas increased progestogen metabolites were observed during natural and human chorionic gonadotrophin (hCG) induced pregnant and nonpregnant luteal phases. On the basis of oestradiol excretory patterns, duration of the oestrous cycle (mean +/- SEM) was 13.6 +/- 1.2 days with high oestradiol concentrations lasting for 4.1 +/- 0.8 days. In non gonadotrophin-treated cheetahs, 75% showed evidence of oestrous cyclicity; however, none evaluated for 1 year or longer were continuously cyclic. Rather, cyclicity was interrupted by periods of anoestrus, often exceeding several months in duration. These inactive ovarian periods were unrelated to season and were not synchronous among females. Mean duration of gestation (breeding to parturition) was 94.2 +/- 0.5 days, whereas duration of faecal progestogen metabolite excretion during the nonpregnant luteal phase was 51.2 +/- 3.5 days. On the basis of progestogen metabolite evaluations, spontaneous ovulation (non-mating induced) occurred only once in two females (2 of 184 oestrous cycles; 1.1%). Peak eCG stimulated, preovulatory oestradiol concentrations were similar to those associated with natural oestrus, whereas progestogen metabolite profiles after hCG resembled those during pregnant and nonpregnant luteal phases after natural mating. In summary, results confirm that the cheetah is polyoestrus and ovulation is almost always induced. However, new evidence suggests that many females inexplicably experience periods of anoestrus unrelated to season, while 25% of the cheetahs examined expressed no ovarian activity during the study period. PMID- 8699420 TI - Relaxin in peripheral plasma of boars during development, copulation, after administration of hCG and after castration. AB - Seventy-two Yorkshire boars were used in five experiments to evaluate the temporal changes in relaxin concentrations in peripheral blood plasma during prepubertal development, copulation, after castration and after treatment with hCG. High concentrations of relaxin (484 +/- 27 pg ml-1) were detected at 11 weeks of age but there was no positive correlation with testicular development. Relaxin concentrations fluctuated in mature boars but the results do not suggest a diurnal rhythm, although there is the possibility of pulsatile secretion. A decrease (P < 0.05) in circulating relaxin was observed before and immediately after copulation. Castration of boars at 90, 115, 160 and 200 days of age did not significantly decrease relaxin concentrations within 48 h. Administration of hCG significantly depressed relaxin secretion at 90 days of age but not at 160 days of age. These studies suggest a non-gonadal source of boar relaxin that is not correlated with testicular growth or testosterone concentrations, is modulated by copulation and by hCG but only at specific stages of development. PMID- 8699421 TI - Regulation of granulosa cell-derived ovarian metalloproteinase inhibitor(s) by prolactin. AB - Increased prolactin concentrations are known to inhibit the ovarian proteolytic enzyme cascade associated with follicular rupture. It is not known whether there is also an effect of prolactin on endogenous proteinase inhibitors such as the tissue inhibitors of metalloproteinases (TIMPs). We sought to study the effect of prolactin on ovarian metalloproteinase inhibitors in cultured rat granulosa cells. Granulosa cells were cultured for 24 h with prolactin (0-1000 ng ml-1) in the absence or presence of LH. Metalloproteinase inhibitor activity in the conditioned culture media was measured by a colorimetric assay. Prolactin at 1000 ng ml-1 increased inhibitor activity by 2.86 +/- 0.63 times. Expression of mRNA encoding TIMP-1 measured by Northern analysis increased by 2.34 +/- 0.34 times with 100 ng prolactin ml-1 and by 2.43 +/- 0.42 times with 1000 ng prolactin ml-1 compared with control cultures (no LH, no prolactin). In the presence of LH, expression of mRNA encoding TIMP-1 and inhibitor activity increased by 2.60 +/- 0.6 and 4.60 +/- 0.54 times, respectively. However, no further change in mRNA expression or inhibitor activity was apparent with the addition of prolactin to LH-treated cultures. Prolactin had no effect on expression of mRNA encoding TIMP 3 in the absence or presence of LH, although LH stimulated a 1.7-fold increase in mRNA encoding TIMP-3 compared with controls. Addition of prolactin had no effect on media concentrations of oestradiol or progesterone. These data demonstrate that metalloproteinase inhibitor activity increases with increasing doses of prolactin; however, when LH was added, this effect was no longer seen. With an increase in metalloproteinase inhibitor activity, tissue metalloproteinase action could be decreased, providing a possible explanation for the local inhibition on pre- and peri-ovulatory pathways by hyperprolactinaemia. PMID- 8699422 TI - Stimulatory effect of insulin-like growth factor I and epidermal growth factor on the maturation of rabbit oocytes in vitro. AB - The effects of different combinations of epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) on cumulus expansion and meiotic maturation were examined in rabbit oocytes. Selected rabbit follicular oocytes were matured in vitro and were classified as cumulus-oocyte complexes or denuded oocytes. They were cultured in TCM 199, and were treated with growth factors at different concentrations: EGF at 0, 1, 10, 50 and 100 ng ml-1, IGF-I at 0, 50, 100 and 200 ng ml-1 and EGF plus IGF-I at 10 + 50; 10 + 100; 50 + 50 and 50 + 100 ng ml-1, respectively. After 6 h of culture, the oocytes were assessed for nuclear maturation and after 16 h of culture, for cumulus expansion and maturation stage. After culture for 6 h, the incidence of germinal vesicle breakdown was higher (P < 0.05) in all of the growth factor treatments tested compared with controls. After culture for 16 h, EGF enhanced the incidence of cumulus expansion at all of the concentrations tested. Cumulus expansion was greatest with 50 mg EGF ml-1 plus 100 ng IGF-I ml-1 (72.0% versus 2.4% in controls). Treatment with IGF-I significantly increased (P < 0.05) the incidence of metaphase II stage, and maximum stimulation occurred at 100 ng IGF-I ml-1 (84.5% versus 31.1% in controls). However, IGF-I did not affect cumulus expansion. When denuded oocytes were used, no positive effects on nuclear maturation rates were observed for any treatment. These results suggest that: (1) EGF, either alone or with IGF-I, stimulates cumulus expansion; (2) the addition of IGF-I or EGF plus IGF-I significantly enhances nuclear maturation in immature rabbit oocytes; and (3) this effect is mediated by the presence of cumulus cells. PMID- 8699423 TI - Appearance and cellular distribution of lectin-like receptors for alpha 1-acid glycoprotein in the developing rat testis. AB - A histochemical avidin-biotin technique with three different alpha 1-acid glycoprotein glycoforms showed pronounced alterations in the cellular localization of two alpha 1-acid glycoprotein lectin-like receptors during cell differentiation in the developing rat testis. The binding of alpha 1-acid glycoprotein glycoforms to their receptors is inhibited by steroids. Testosterone, oestradiol and progesterone inhibited the binding of alpha 1-acid glycoprotein glycoform A to its receptor. Cortisone, aldosterone, oestradiol and progesterone inhibited the binding of alpha 1-acid glycoprotein glycoforms B and C to their receptor. A difference in the cellular content of alpha 1-acid glycoprotein glycoforms and alpha 1-acid glycoprotein receptors separates the spermatocytes and the early spermatids from the late spermatids. The difference in receptor composition implies a difference in the effect of different steroid hormones. The Leydig cells contained alpha 1-acid glycoprotein and lectin-like receptors for one of the glycoforms of alpha 1-acid glycoprotein from birth. The interaction between alpha 1-acid glycoprotein glycoforms and their receptors may modulate the actions of testosterone and other steroids in the testis. PMID- 8699424 TI - Ovulatory cycles and anovulatory periods in the addax (Addax nasomaculatus). AB - Changes in serum oestradiol and progesterone were measured to study their dynamics during ovulatory cycles in six female addax, an endangered antelope. Blood was collected three times per week, during chute restraint, for 3 months (November to February) before introduction of a male, and continued until pregnancy was diagnosed with ultrasound. Serum was analysed by enzymeimmunoassay. Mean luteal phase, interluteal phase, and cycle durations were 22.7 +/- 2.0, 8.78 +/- 0.5 and 32.3 +/- 1.7 days, respectively. Ultrasonography revealed coiled uterine horns and maximum follicle and corpus luteum diameters of 15 and 27 mm, respectively. Each female experienced an anovulatory period, during which oestradiol continued to fluctuate, but progesterone remained below 2 ng ml-1. These periods ranged from 39 to 131 days and were not synchronous; ovulatory cycles resumed spontaneously in all females. All four females placed with a male conceived. Because addax give birth all year round, they are not considered seasonal breeders. The sporadic periods of anovulation that occurred during the winter months of this study suggest a possible seasonal effect. However, systematic sampling has not been conducted during summer and early autumn and will be necessary to address this question. PMID- 8699425 TI - Proliferation of granulosa and thecal cells in germinal disc and non-disc regions during follicular growth in Japanese quail (Coturnix coturnix japonica): bromodeoxyuridine incorporation in situ. AB - Proliferation of granulosa and thecal cells was analysed during ovarian follicular growth in laying Japanese quail. The birds were injected intraperitoneally with bromodeoxyuridine (BrdU) 10 or 4 h before ovulation, that is, before or after a preovulatory LH surge, respectively, and incorporation of BrdU by follicular tissues was detected immunocytochemically. Cells labelled with BrdU were seldom seen in the most immature follicles in the ovarian cortex, whereas many granulosa and thecal cells were labelled with BrdU in medium-sized white yolky follicles (approximately 13.3% and 14.4% in granulosa and theca layers, respectively). Ten and four hours before ovulation, the granulosa cells in the germinal disc and non-disc regions of the third largest yellow yolky follicle (F3) were labelled with BrdU (approximately 8.4% and 9.4% in germinal disc; 6.1% and 9.0% in the non-disc region), but only those in the germinal disc region were labelled (approximately 5.4% and 4.0%) in the largest yellow yolky follicle (F1). The percentage of thecal cells labelled with BrdU 4 h before ovulation was significantly higher than the percentage labelled 10 h before ovulation, and was higher in F3 (approximately 11.7%) than in F1 follicles (approximately 5.4%) 4 h before ovulation. These results show that proliferation of granulosa and thecal cells occurs in both germinal disc and non-disc regions in growing follicles, but when a follicle matures proliferation is reduced and in the case of granulosa cells it is restricted to the germinal disc region. PMID- 8699426 TI - Bovine luteal cell production in vitro of prostaglandin E2, oxytocin and progesterone in response to pregnancy-specific protein B and prostaglandin F2 alpha. AB - A study was conducted to determine the effects of pregnancy-specific protein B (PSPB) and prostaglandin F2 alpha (PGF2 alpha) on bovine luteal cell progesterone, prostaglandin E2 (PGE2) and oxytocin production in vitro. Corpora lutea were enucleated from multiparous cows with normal oestrous cycles during the mid-luteal (days 10-12; n = 5) or late-luteal (days 17-18; n = 5) stage. Mixed large and small cells (1.5 x 10(5) cells per well) were incubated in 500 microliters modified Ham's F-12 medium. Cells were incubated for 18 h before treatments were added. Cells were treated with PSPB (0, 2.5, 5.0 micrograms) and PGF2 alpha (0, 100, 200 ng) in a 3 x 3 factorial arrangement. After treatments were added, media samples were collected at 6 and 12 h. During the 18 h pretreatment incubation, progesterone, PGE2 and oxytocin production was similar between the prospective treatment groups. Progesterone production was greater (P < 0.001) by mid-stage than by late-stage cells. In addition, progesterone decreased (P < 0.001) as incubation time increased. Progesterone production was not affected by PGF2 alpha, but PSPB increased (P < 0.02) progesterone at the 5.0 micrograms dose. Late-stage luteal cells produced more (P < 0.001) PGE2 than did mid-stage cells; PGE2 production decreased (P < 0.001) with increased incubation time. Luteal PGE2 production increased in response to PSPB treatment (P < 0.01) and PGF2 alpha treatment (P < 0.001). Luteal oxytocin production was greater (P < 0.01) by mid-stage compared with late-stage cells. Oxytocin production decreased (P < 0.001) with incubation time in mid-stage cells, but in late-stage cells oxytocin production was similar over time. Neither PSPB nor PGF2 alpha had an effect on oxytocin. These results indicate that PSPB does not affect luteal oxytocin, but does increase progesterone and PGE2 production. In addition, PGF2 alpha increases luteal PGE2, but does not affect progesterone or oxytocin production. These data do not show an interaction between PSPB and PGF2 alpha in regulating bovine luteal cell endocrine function. PMID- 8699427 TI - Number and function of Sertoli cells, number and yield of spermatogonia, and daily sperm production in three breeds of boar. AB - The objective of this study was to determine the number of Sertoli cells per boar, daily sperm production, and germ cell yield per type A spermatogonium in mature Whitecross, Meishan, and West African boars. The paired parenchymal mass was greatest in the Whitecross boars and greater in Meishan than in West African boars. Daily sperm production per boar (x 10(9)) differed significantly (P < 0.05) among breeds (Whitecross: 12.5 +/- 1.5; Meishan: 6.0 +/- 0.5; West African: 2.9 +/- 0.3). Daily sperm production per boar was positively (P < 0.01) correlated with parenchymal mass (r = 0.97), number of A spermatogonia per testis (r = 0.88), and Sertoli cells per testis (r = 0.87). Daily sperm production per gram of testis was similar among breeds. Number of Sertoli cells and number of type A spermatogonia per boar were greater for the Whitecross but similar in the Meishan and West African boars. The number of Stage VII germ cells per Sertoli cell was greater (P < 0.05) in the Meishan (39.08 +/- 5.07), but similar in the Whitecross (19.91 +/- 1.62) and West African boars (15.81 +/- 2.43). The number of type A spermatogonia per testis was highly and positively (P < 0.01) correlated with number of Sertoli cells per testis (r = 0.95), and parenchymal mass (r = 0.88). There was a trend for the spermatid yield per type A spermatogonium to be greater in the Meishan boars, and this ratio was positively correlated with spermatid:Sertoli cell ratio (r = 0.62) but not with daily sperm production per boar or Sertoli cells per testis. No significant germ cell degeneration occurred during the long meiotic prophase, but the loss of progeny during postprophase of meiosis averaged 32.62% across all breeds. Germ cell degeneration was similar (P > 0.05) across breeds during spermiogenesis, and on average amounted to 8.6%. The increased number of type A spermatogonia and of Sertoli cells associated with larger testes for the Whitecross over West African or Meishan boars is sufficient to explain the higher sperm production in the Whitecross. However, the lower index of degeneration and more efficient Sertoli cell function in Meishan boars results in the daily sperm production being intermediate between that of the Whitecross and West African boars. PMID- 8699428 TI - Commentary: standardization of nonsteroidal regulators of gonadotrophin secretion. PMID- 8699430 TI - Preferential esterification of arachidonic acid into ethanolamine phospholipids in epithelial cells from ovine endometrium. AB - In sheep, the pulsatile release of prostaglandin F2 alpha by the endometrium is necessary to achieve luteolysis which occurs at the end of the oestrous cycle. The production of prostaglandins is known to depend upon the availability of arachidonic acid, the fatty acid precursor of prostaglandin biosynthesis. Consequently, the mechanisms controlling intracellular amounts of arachidonate may be involved in the regulation of prostaglandin synthesis. Since arachidonic acid is mostly found in phospholipids and the endometrial epithelium is the primary source of prostaglandin F2 alpha during luteolysis, the fate of arachidonic acid when incorporated into epithelial cells from the ovine uterus was investigated. Endometrial epithelial cells isolated from cyclic ewes at day 15 after oestrus were cultured in the presence of [3H]arachidonic acid. Incorporation and distribution of the radiolabelled arachidonic acid into the various phospholipid classes were examined using HPLC. We observed that ethanolamine glycerophospholipids contained 61% of the total tritiated arachidonic acid incorporated into cellular lipids, whereas phosphatidylinositols, phosphatidylcholines and phosphatidylserines contained 17%, 13% and 4.7%, respectively. In addition, the radioactivity measured within phosphatidylethanolamines was preferentially detected in the 1-alkenyl-2-acyl (44%) forms of ethanolamine phospholipids, also called plasmalogens. The kinetic study of arachidonic acid uptake into ethanolamine phospholipids showed that arachidonic acid was rapidly esterified into the diacyl forms and then uptake decreased, whereas the incorporation increased continuously into the plasmalogen forms for at least 24 h. These results demonstrate that the primary pool of esterified arachidonic acid is found in ethanolamine plasmalogens of epithelial cells from the ovine endometrium. The high arachidonate content of ethanolamine plasmalogens suggests that these phospholipids play a crucial role in the control of arachidonic acid availability and ultimately in the regulation of prostaglandin synthesis. PMID- 8699429 TI - Effect of continuous infusion of thyrotrophin-releasing hormone on plasma prolactin and on ovarian activity in melatonin-treated ewes. AB - Twelve anoestrous ewes maintained under natural photoperiod at 57 degrees N received an oral dose of 3 mg melatonin daily at 15:00 h from 1 May. Starting 41 days later and extending from 11 June until 5 September, six of the ewes were also infused continuously with 0.8 mg thyrotrophin-releasing hormone (TRH) day-1 via subcutaneous osmotic minipumps. The remaining six ewes acted as controls. Behavioural oestrus, ovulation rate and luteal function were determined by exposure to a vasectomized ram, laparoscopy and the measurement of progesterone in peripheral plasma, respectively. TRH infusion stimulated a sustained increase (P < 0.001) in plasma concentrations of thyroxine, tri-iodothyronine and prolactin (thyroxine: 158 +/- 9.3 and 65 +/- 7.7 nmol l-1 for TRH-infused and control ewes, respectively; tri-iodothyronine, 2.6 +/- 0.12 and 1.1 +/- 0.19 nmol l-1 and prolactin, 57 +/- 12 and 11 +/- 2 micrograms l-1). No ewes were in oestrus before TRH infusion and the mean number of behavioural oestrous cycles per ewe during the infusion period was 1.3 +/- 0.33 and 2.5 +/- 0.34 for TRH infused and control ewes, respectively (P < 0.05). Corresponding mean intervals from 1 May to the onset of the first luteal phase (progesterone > 1 ng ml-1) were 88 +/- 8.9 and 79 +/- 3.5 days (not significant). TRH infusion had no effect on the mean numbers of corpora lutea (1.7 +/- 0.14 and 1.6 +/- 0.20 for TRH-infused and control ewes, respectively), but was associated with a lower mean incidence of normal luteal phases (1.5 +/- 0.43 versus 2.7 +/- 0.21, P = 0.052). Abnormalities in luteal function included delayed initial expression, extended ovarian cycles, suprabasal periovulatory progesterone concentrations and protracted periods of low progesterone secretion between successive ovarian cycles. Thus continuous TRH infusion suppressed plasma prolactin, doubled the circulating concentrations of thyroxine and tri-iodothyronine, and was associated with a wide range of abnormalities in ovarian function and endocrine status, the nature of which varied between ewes. PMID- 8699431 TI - Remotely delivered immunocontraception in free-roaming feral burros (Equus asinus). AB - Regulation of local overpopulations of free-roaming feral equids is in demand worldwide for ecological balance and habitat preservation. Contraceptive vaccines have proven effective in feral horses, which breed seasonally, but no data are available for equids such as the burro, which is reproductively active all year round. In the present study, 27 individually identified female feral burros (Equus asinus) roaming free in Virgin Islands National Park (St John, US Virgin Islands; Lesser Antilles) were remotely treated with pig zonae pellucidae (PZP) vaccine. Between January and May, 16 burros were darted with a 1 ml emulsion of PZP plus Freund's adjuvant. Ten to twelve months later each treated burro was given a single booster injection of PZP plus adjuvant to maintain contraception through a second year. Eleven adult untreated jennies served as controls. Beginning one year after initial vaccination, these burros were monitored for pregnancy and foal production. Collection of data to determine treatment effect was not begun until 12 months after initial treatment to ensure that pregnancies existing before vaccination were not included. Pregnancy was assessed using previously validated methods for steroid metabolite measurement in fresh faecal samples. None of the PZP-treated burros produced foals between 0 and 12 months after the last inoculation. One PZP-treated burro tested positive for pregnancy at 10 months after the final inoculation. During this same period, six of 11 untreated burros tested pregnancy-positive, and four were observed with foals. There was no difference in pregnancy rates among treated, control and randomly sampled jennies between 12 and 24 months after the last inoculation. The results demonstrate that, in free-roaming feral burros that are reproductively active all year round: (1) burros can be accessed for remotely delivered PZP vaccination; (2) PZP contraception is effective; (3) PZP contraception is reversible; and (4) pregnancy can be reliably detected by faecal steroid analysis. PMID- 8699432 TI - Cryopreservation of zona-hatched mouse blastocysts. AB - Experiments were conducted to determine the conditions for successful and efficient cryopreservation of hatched mouse blastocysts, using simple vitrification procedures. Hatched blastocysts were obtained by culture of morulae in vitro. Vitrification solutions used were EFS40 and GFS40, which were 40% (v/v) ethylene glycol and 40% (v/v) glycerol, respectively, diluted in PB1 medium containing 30% Ficoll (w/v) and 0.5 mol sucrose l-1. In the one-step method, embryos were directly exposed to the vitrification solutions at 25 degrees C for 0.5 or 2 min; in the two-step method, embryos were equilibrated with a dilute (10 20%, v/v) ethylene glycol or glycerol solution for 5-10 min, before a 0.5 min exposure to EFS40 or GFS40, respectively. They were then vitrified in liquid nitrogen. When the embryos were vitrified in EFS40, the post-warming survival rates, assessed by the re-expansion of the blastocoel during 16 h of culture, were higher in embryos that had hatched from the zona earlier (120-132 h after hCG) than in those hatched later (142-150 h after hCG); however, the highest survival rate was only 65%, which was obtained by a one-step method. When embryos were vitrified in GFS40, a high survival rate (89-94%) was obtained especially by the two-step methods. Vitrified blastocysts developed into live young just as well as did fresh blastocysts; survival was highest after transfer to recipients on day 3 or day 4 of pseudopregnancy. These findings show that hatched mouse blastocysts can be successfully cryopreserved by a simple vitrification method, and that a glycerol-based vitrification solution is more suitable than the corresponding ethylene glycol-based solution for the vitrification, probably because slower permeation of glycerol avoids toxic injury. PMID- 8699433 TI - Immunolocalization of the matrix metalloproteinases gelatinase B and stromelysin 1 in human endometrium throughout the menstrual cycle. AB - Immunolocalization techniques were used to examine the distribution of the matrix metalloproteinases gelatinase B and stromelysin 1 in human endometrial specimens, taken across the normal menstrual cycle. Gelatinase B was produced by glandular epithelial cells for approximately 7 days during the proliferative phase, with polymorphonuclear leucocytes, macrophages and eosinophils providing most of this enzyme at menstruation. There was no evidence that gelatinase B is produced by stromal cells or mast cells during the cycle. Immunoreactive gelatinase B in glandular epithelial cells was greatest during the late proliferative phase and just after ovulation; its presence in glandular secretion and the uterine fluid was optimal during the peri-implantation phase. Gelatinase B was clearly associated with an influx of polymorphonuclear leucocytes, macrophages and eosinophils just before, and during, menstruation. In contrast, immunostaining for stromelysin 1 was much weaker than that for gelatinase B, and was present only around stromal cells and limited to microfocal locations at times coincident with stromal oedema (days 8-10 and 21-22). Both enzymes were widely distributed in specimens just before and during menstruation, and were particularly prominent in connective tissue stroma and vascular basement membranes. Specimens at the early proliferative stage were devoid of both enzymes. The data provide further evidence supporting a role for metalloproteinases in endometrial biology, not only in matrix remodelling during the cycle, but also in glandular secretions potentially relevant to blastocyst recognition and implantation. Our observations emphasize the functional importance of specific cell types and the temporal regulation of gelatinase B and stromelysin 1 throughout the normal menstrual cycle. PMID- 8699434 TI - Timing of ovulation after gonadotrophin induction and its importance to successful intrauterine insemination in the tiger (Panthera tigris). AB - The ovarian response to equine chorionic gonadotrophin (eCG) and human chorionic gonadotrophin (hCG), the effect of timing of ovulation relative to hCG injection and the use of laparoscopic intrauterine artificial insemination (AI) were examined in two subspecies of tiger (Panthera tigris). Adult female tigers were subjected to the same eCG/hCG treatment followed by laparoscopy under xylazine/diazapam/ketamine HCl anaesthesia at 39-42 h (Group I, n = 9), 46-49 h (Group II, n = 5) or 51-55 h (Group III, n = 5) after hCG. Six of these females, observed to be postovulatory at the time of laparoscopy (Group II, n = 3; Group III, n = 3), were subjected to intrauterine AI. The number of preovulatory follicles observed on the ovaries of Group I females was twofold greater (P < 0.05) than the number observed on ovaries of females in Group II and III. Fewer (P < 0.05) corpora lutea were observed on ovaries of Group I females (1.3 +/- 0.6) compared with the number of corpora lutea in Group II and III (combined average, 7.8 +/- 0.8 corpora lutea per female). Only one of ten females in Groups II and III failed to ovulate by the time of laparoscopy. Four Group I females never ovulated, based on a laparoscopic re-evaluation 4 weeks later. One female inseminated 46 h after hCG (Group II) became pregnant and delivered a healthy cub after a normal gestation. There were no apparent differences between subspecies in response to the same ovulation induction protocol. Results demonstrate the importance of the relationship between exogenous gonadotrophin treatment and onset of anaesthesia for laparoscopic examination and AI in tigers. Data clearly indicate that anaesthesia/laparoscopy conducted too early (39-42 h after hCG) compromises the number of females and proportion of follicles ovulating. In contrast, ovulation success is high if anaesthesia/laparoscopy is performed after this time, and intrauterine insemination can result in healthy young. PMID- 8699435 TI - Socioendocrine and morphological correlates of paternity in rhesus macaques (Macaca mulatta). AB - When females mate with several males, problems arise in identifying sire and in determining factors contributing to differential male reproductive success. Three potential primary correlates of differential reproduction in males include fighting ability, sperm competition, and body condition. We collected a variety of socioendocrine and morphological measurements from sexually mature rhesus macaques to determine corollaries of paternity. We studied a troop of about 150 rhesus macaques living in a 0.3 ha corral and identified the sires of 70% of infants using multilocus DNA fingerprints. Eight of 21 males sired offspring, and dominant males were more successful than subordinate males. Neither canine size nor age influenced the probability of siring offspring. Male reproductive success was primarily an outcome of the number of females mated with, which was associated with an ensemble of traits including high dominance rank, large body size, relatively voluminous testicles and good body condition. Testes size was significantly larger in sires than in non-sires, but among sires the number of progeny produced was not correlated with testicle size. Sires began the mating season with more body fat than non-sires, but the energetic costs of mating resulted in a 50% reduction in abdominal skinfold thickness during the mating season. We conclude that social status exerts a major impact on paternity by affecting the number of females mated with, that male quality is a critical factor modulating paternity, and that male feeding strategies have a direct influence on variation in male reproductive success. PMID- 8699436 TI - Analysis by two-dimensional electrophoresis of proteins secreted by sheep ovarian follicles: effects of the FecB gene, follicle size and atresia. AB - Proteins secreted by sheep ovarian follicles at different stages of maturation (small healthy, large healthy or large atretic) and originating from ewes with different ovulation rates (homozygous carriers or noncarriers of the FecB gene) were analysed by two-dimensional electrophoresis (PAGE) followed by computerized image analysis. Follicles were incubated intact for 1 h to assess steroidogenesis, and then incubated for 24 h in the presence of [35S]methionine. Secreted proteins were then resolved by iso-electric focusing followed by migration on 10% acrylamide slab gels and fluorography. Incorporation of label into proteins was similar irrespective of genetic type or health status of the follicles (4-6%). Small follicles incorporated significantly less (P < 0.05) label. Over 100 spots were detected on the fluorographs. The presence of the FecB gene induced qualitative and quantitative changes in the follicular protein patterns. Frequency of detection of spots 116 and 129 was significantly higher (P < 0.01) in Fec+Fec+ compared with FecBFecB follicles (80% versus 8%). In addition, amounts of proteins present in spots 2 and 12 were increased in FecBFecB follicles, while those in spots 9 and 21 were decreased. Size and atresia affected protein patterns only quantitatively. Increased amounts of proteins in spots 1, 10, 38, 44 and 113 were associated with atresia (P < 0.05). Follicle enlargement was associated with increased (P < 0.05) amounts of proteins in spots 5 and 6 and decreased amounts of proteins in spot 16. Amounts of three proteins (33, 40 and 58) were related positively to oestradiol production in vitro before labelling. PMID- 8699438 TI - Effects of oviductal fluid on sperm penetration and cortical granule exocytosis during fertilization of pig oocytes in vitro. AB - The effects of oviductal fluid on sperm penetration and cortical granule exocytosis in pigs were examined. Cortical granule exocytosis in oocytes matured in vivo and in vitro was observed by staining with fluorescent-labelled lectin and laser-scanning confocal microscopy. Exocytosis of matured oocytes was classified into three categories after in vitro fertilization: complete cortical granule exocytosis and even distribution of exudate in the entire perivitelline space (type I); complete exocytosis and partial distribution of exudate (type II) and incomplete cortical granule exocytosis (type III). The incidence of oocytes with type I exocytosis was higher in oocytes matured in vivo than in those matured in vitro. The addition of oviductal fluid at a concentration of 1% or 10% to the fertilization medium decreased sperm penetration and the mean number of spermatozoa present in penetrated eggs. The distribution of cortical granule exudate was not different in the presence of 1% oviductal fluid after sperm penetration from that of control groups. When oocytes were cultured for 1.5 h in medium containing 10% or 30% oviductal fluid before insemination, the incidence of monospermy increased without a decrease in sperm penetration. Preculture of oocytes in medium containing 30% oviductal fluid increased type I cortical granule reaction and increased resistance of the zona pellucida to dissolution by 0.1% (w/v) pronase at the time of sperm penetration. These results suggest that a factor(s) from the oviductal secretion is required for the complete cortical granule reaction and in the modification of the zona pellucida. PMID- 8699437 TI - Anti-Mac-1 antibodies and early pregnancy loss in mice. AB - This study focused on the role of adhesion molecules in early pregnancy in mice. Injection of anti-Mac-1 antibodies during early pregnancy resulted in early pregnancy loss (only 30.7% of mice in the group injected with anti-Mac-1 antibody were pregnant compared with 87.5% of controls), while mice treated with anti-Mac 1 antibodies during late pregnancy did not show a significant abortive effect (68.8% mice in the treated group were pregnant compared with 92.9% of control mice). Anti-LFA-1 alpha, LFA-1 beta or mouse Ag-Eb antibodies, when injected during early pregnancy, caused a nonsignificant decrease in pregnancy rate ranging between 15% and 25% (P > 0.05), while anti-Thy-1.2 antibodies demonstrated a marginal effect only. Staining of uterine tissue sections, collected on days 4-6 of pregnancy, with anti-Mac-1 antibodies, demonstrated antibody bound to cells in the deep endometrium and in the myometrium but not in the uterine area close to the lumen or on the surface of the blastocyst. These results indicate a possible role for the Mac-1 antigen in early pregnancy. PMID- 8699439 TI - Osmotic properties of boar spermatozoa and their relevance to cryopreservation. AB - A series of six experiments was conducted to determine the fundamental cryobiological properties of boar spermatozoa to develop optimal approaches for cryopreserving this important cell type. In the first experiments, boar spermatozoa samples were diluted in various osmolalities of experimental solutions (185-900 mOsmol kg-1) to provide hypo-, iso-, and hyperosmotic conditions. Equilibrium cell volumes (Expts 1 and 2) were measured after exposure for 3 min and the change in cell volume was measured over time using an electronic particle counter (Expt 3). The isosmotic cell volume was found to be 26.3 +/- 0.39 microns 3 (mean +/- SEM; n = 5). Over this range of osmolalities, boar spermatozoa behaved as linear osmometers (a linear volume versus 1/osm plot, r2 = 0.99) with an osmotically inactive cell fraction of 67.4 +/- 4.5%. The rate of water permeability (Lp) was determined to be 1.03 +/- 0.05 microns min-1 atm 1, which was consistent within and among donors (P > 0.130). A second series of experiments was performed to determine the effect of temperature and osmolality on boar sperm motility (Expt 4), and the effect of osmolality on the integrity of the sperm plasma membrane and its temperature dependence. Plasma membrane integrity was measured before and after boar spermatozoa were returned to an isosmolality (Expt 6). Motility was not affected at 30 degrees C, relative to that at room temperature, but was significantly decreased (P < 0.05) at 8 degrees C and 0 degree C (yielding a relative reduction to 85% and 35% of original motility, respectively; n = 6). Sperm motility was not significantly decreased (P > 0.05) until the osmolality reached 210 mOsmol kg-1, at which time motility began to decrease from 95% to 10% of the original value at 90 mOsmol kg-1. The integrity of the plasma membrane of boar spermatozoa was found to be dependent on temperature, donor and osmolality, decreasing significantly (P < 0.05) below room temperature, and below 185 mOsmol kg-1 (P < 0.05). There was no significant difference (P > 0.10) in the integrity of the plasma membrane of the samples before and after returning to 290 mOsmol kg-1, indicating that osmotic damage occurs during the initial change from isosmotic to hyposmotic media. These osmotic characteristics could be used to determine optimal conditions for cryopreservation of boar spermatozoa. PMID- 8699441 TI - Society for the Study of Fertility, annual conference. Nottingham, July 1996. Abstracts. PMID- 8699440 TI - Penetration by field vole spermatozoa of mouse and hamster zonae pellucidae without acrosome reaction. AB - Spermatozoa of the field vole (Microtus montebelli) that bound to the zona pellucida of field vole oocytes underwent the acrosome reaction before passing through it. In contrast, vole spermatozoa that bound to the zonae of mouse and hamster oocytes penetrated the zonae without any sign of the acrosome reaction. The presence or absence of proteinase/hyaluronidase inhibitors in the medium did not make any difference to zona penetration by acrosome-intact vole spermatozoa. These observations suggest that field vole spermatozoa can cross mouse and hamster zonae mechanically without assistance from zona-hydrolysing enzymes. PMID- 8699442 TI - Laboratory and field evaluation of deet, CIC-4, and AI3-37220 against Anopheles dirus (Diptera: Culicidae) in Thailand. AB - Laboratory and field tests of the repellents diethyl methylbenzamide (deet), 1-(3 Cyclohexen-1-yl-carbonyl)-2-methylpiperidine (AI3-37220), and (2 hydroxymethylcyclohexyl) acetic acid lactone (CIC-4) were conducted against Anopheles dirus Peyton & Harrison, the principal malaria vector in Thailand. In the laboratory, An. dirus was more sensitive to CIC-4 than either AI3-37220 or deet. The duration of protection provided by each repellent in laboratory tests increased with higher concentrations of repellents and when exposed in cages containing fewer mosquitoes. A field study in Chanthaburi Province, southeastern Thailand, during November 1993 tested 25% (wt:wt) ethanol solutions of each repellent against An. dirus. In contrast to the laboratory experiments, protection provided by AI3-37220 was significantly better than either deet or CIC 4 and there was no significant difference between deet and CIC-4. Protection provided by deet and CIC-4 fell to below 95% 2 h after repellent application, whereas AI3-37220 provided > 95% protection for 4 h. The protection provided by all repellents fell to < or = 65% 7 h after repellent application. PMID- 8699443 TI - Behavior of Wuchereria bancrofti (Filariidea: Onchocercidae) infective larvae in the vector Aedes polynesiensis (Diptera:Culicidae) in relation to parasite transmission. AB - In French Polynesia, Aedes polynesiensis Marks is the major vector of human filariasis caused by subperiodic Wuchereria bancrofti (Cobbold). Factors affecting transmission of infective larvae from vector to humans were assessed. The 66-100% loss of infective larvae during a blood meal was independent of the initial vector parasite burden. Infective larvae were able to migrate to the mouthparts during a blood meal. Blood feeding by mosquitoes to repletion was one important aspect in the escape of larvae. Infective larvae were not transmitted (lost) without a blood meal and may move in the vector's body. Ae. polynesiensis may retain infectivity potential during several days and may infect several hosts during one blood meal session or on several gonotrophic cycles. In terms of parasite transmission, these findings were interpreted as efficient adaptations of the filaria to the Ae. polynesiensis biting habits. PMID- 8699444 TI - Mosquitoes (Diptera:Culicidae) breeding in brackish water: female ovipositional preferences or larval survival? AB - Four species of mosquitoes were abundant in concrete reservoir tanks containing brackish water that ranged from 16 to 39% sea water. The ability of the larvae to survive in various salinities was compared for each species with the ovipositional preferences of the adult females to determine whether the 2 traits were correlated. Southern house mosquito, Culex quinquefasciatus Say, normally was not present in the tanks but survived well in salinities up to 25% sea water. However, gravid females almost always oviposited in fresh water. Culex sitiens Weidemann larvae survived best in saline water (66% sea water), but oviposition was greatest in 28% sea water; both larval survival and the frequency of oviposition were low in fresh water. Culex sinaiticus Kirkpatrick survived salinities up to 50% sea water, but the females refused to blood-feed; therefore, their ovipositional preferences were not tested. Larvae of Anopheles stephensi Liston and An. culicifacies Giles survived best in fresh water, but some An. stephensi were able to tolerate up to 50% sea water. The females had a similar ovipositional preference for fresh water. The preferred salinity for oviposition did not correspond with larval survival for Cx. quinquefasciatus and Cx. sitiens, but did compare well in An. stephensi and An. culicifacies. PMID- 8699445 TI - Genetic structure of Aedes albifasciatus (Diptera:Culicidae) from a marsh ecosystem in Cordoba, Argentina. AB - Allozymic variability was analyzed for 8 samples of the floodwater mosquito Aedes albifasciatus (Macquart) obtained in October and November 1993 from marsh and pasture habitats along the Mar Chiquita ecosystem in central Argentina. Expected mean heterozygosity among 17 loci was low. Fls values were negative for all polymorphic loci, and mean FST values were low, indicating high levels of gene exchange and the absence of subpopulations within the 25-km-wide study area. Genetic homogeneity throughout the area suggests that outcrossing occurs frequently as a result of dispersal among sampled sites. PMID- 8699446 TI - Theoretical dynamics of experimental populations of introduced and native blowflies (Diptera:Calliphoridae). AB - Equilibrium dynamics in experimental populations of Chrysomya megacephala (F.) and C. putoria (Wiedemann), which have recently invaded the Americas, and the native species Cochliomyia macellaria (F.), were investigated using nonlinear difference equations. A theoretical analysis of the mathematical model using bifurcation theory established the combination of demographic parameters responsible for producing shifts in blowfly population dynamics from stable equilibria to bounded cycles and aperiodic behavior. Mathematical modeling shows that the populations of the 2 introduced Chrysomya species will form stable oscillations with numbers fluctuating 3-4 times in successive generations. However, in the native species C. macellaria, the dynamics is characterized by damping oscillations in population size, leading to a stable population level. PMID- 8699447 TI - Enzyme polymorphisms in the Anopheles gambiae (Diptera:Culicidae) complex related to feeding and resting behavior in the Imbo Valley, Burundi. AB - A cellulose acetate electrophoresis system was used to study the Anopheles gambiae complex at 2 villages in Central Imbo Valley and at 1 village in South Imbo Valley (Burundi). In South Imbo, only An. gambiae Giles sensu stricto was present. In the drier Central Imbo, the dominant species was An. arabiensis Patton (97.5%); An. gambiae s.s. represented only 2.5%. Both species were separated readily by Odh and Mpi, because they did not share alleles at those loci. Indoor resting An. gambiae s.s. from South Imbo differed significantly from outdoor resting females at 2 Ioci, Mpi, and Got-2. In Central Imbo, total An. arabiensis did not differ between adjacent villages. Endophagic An. arabiensis significantly differed at loci alpha-Gpd, and Idh-1 between the 2 villages, whereas no difference was observed between exophagic females. Allelic and genotypic frequencies at the locus Mdh-2 were significantly different between indoor and outdoor biting An. arabiensis. Active choice for the best place to bite or to rest seemed to be associated with specific genotypes. The Nei genetic distance values were typical of conspecific populations, ranging from 0.154 to 0.160 between An. gambiae s.s. and An. arabiensis. Even though vector populations were structured at spatial and behavioral levels, they were panmictic, and thus selection of exophilic or exophagic vectors, or both, by insecticide pressure is not likely to occur. PMID- 8699448 TI - Dispersal of blacklegged tick (Acari:Ixodidae) nymphs and adults at the woods pasture interface. AB - Marked nymphal and adult blacklegged ticks, Ixodes scapularis Say, were released in 4 host-exclusion cages and 4 similar control areas, all straddling the woods pasture interface. Both nymphs and adults were recaptured by flagging at regular intervals outside the cages, having therefore actively dispersed > 4.5 m (i.e., without involvement of vertebrates). Nymphs were recaptured much more often ( > 90%) in the woods than pastures, whereas 62.8% of recaptured adults were taken in pastures. Females were recaptured in equal numbers in pastures and woods, but 75.4% of recaptured males were in pastures. Adults that dispersed into pastures were recaptured an average of 1.6 and 3.7 m from the woods edge in 1992 and 1993, respectively, and as far as 7-8 m from the woods edge. Nymphs dispersed shorter distances than adults with 66% of the recaptured nymphs found 2-3 m from their release points, and > 46% of recaptured adults found > 5 m from their release points. Twice as many nymphs were recaptured from the caged than uncaged sites. The lower numbers of nymphs recaptured from control sites compared with caged sites are probably the result of host acquisition; the absence of this discrepancy with the adults may reflect by their ability to move relatively quickly from the host-exclusion cages and become available for host contact. PMID- 8699449 TI - Immunity induced by vaccination with Rhipicephalus appendiculatus salivary gland antigens does not augment protective immunity acquired naturally by exposing rabbits to adult ticks. AB - A study was conducted using rabbits to ascertain the effects of immunity induced with salivary gland antigens (SGA) on naturally acquired host resistance, which was confirmed by exposing groups of rabbits to adult Rhipicephalus appendiculatus (Neumann) ticks. A reciprocal experiment was conducted to establish the effect of naturally acquired resistance on vaccination with SGA. After the acquisition of resistance by either method of vaccination, rabbits were then challenged with the 3 life stages of the tick. Results of the experiment demonstrated 3 phenomena: infestation of rabbits with 60 adult ticks leads to high protection in terms of reduction in the engorged weight against adult ticks, larvae, and nymphs (88.6, 31.5, and 55.9%, respectively); vaccination alone provides 53.9, 29.7, and 35.7% reduction in adult, larval, and nymphal ticks, respectively; and vaccination of rabbits already exposed to adult tick infestation appeared to have no additive immunological benefit above that already provided by adult ticks. Sodium dodecyl polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting analyses revealed that antibodies with high avidity to SGA were directed to a 39-kDa polypeptide. This polypeptide was not revealed by sera from rabbits that were first infested with adult ticks. Sera from rabbits that were first vaccinated with SGA consistently reacted with the 39-kDa polypeptide. Sera from rabbits that were infested recognized strongly a 42-kDa polypeptide among 5 polypeptides in the SGA. Results of the experiment show that resistance resulting from adult tick infestation is not augmented by immunity caused by vaccination with SGA. PMID- 8699450 TI - Arthropod succession on exposed rabbit carrion in Alexandria, Egypt. AB - In 1988 and 1989, seasonal field studies on exposed rabbit carcasses were conducted in Alexandria, Egypt, to describe the decomposition process and arthropod succession patterns. Four decomposition stages were recognized: fresh, bloated, decay, and dry. Carcasses in summer and spring decayed at a much faster rate than those in fall and winter. The bloated stage in summer lasted longer than in spring because of the difference in breeding biology of the primary flies infesting carcasses in these seasons. Dipterous larvae of the family Calliphoridae, and to a lesser extent of the families Sarcophagidae and Muscidae, were responsible for the process of carrion degradation. Carrion-arthropod communities in cooler seasons were distinguished from those in warmer seasons by the presence of certain dipterous (muscids and fanniids) and coleopterous larvae, and by adults of small flies such as sphaerocerids and scatopsids. The presence of adult psychodids, sciarids, and phorids was unique to the winter carrion arthropod community. Eleven species of carrion-breeding Diptera were found to coexist in the study site. The coexistence of the 2 calliphorids Chrysomya albiceps (Wiedemann) and Lucilia sericata (Meigen) in carrion in fall and spring is a new record for the Palaearctic Region. In spring, 3rd instars of C. albiceps were observed preying on the pupae of their own species. Although the carcasses were of equal size and simultaneously exposed, there was considerable variation in the rate of decay among fall carcasses only, which was attributed to unknown reasons at the beginning of the experiment and to heavy rains later on. This affected oviposition and the feeding period of maggots. Approximately 100 arthropod species were recovered on carcasses throughout the study. Diptera was the predominant group, whereas Coleoptera ranked 2nd. Carcasses in cooler seasons were richer in species than in warmer seasons. PMID- 8699451 TI - Spring migratory birds (Aves) extend the northern occurrence of blacklegged tick (Acari:Ixodidae). AB - Birds that had migrated northward across Lake Superior were captured upon reaching landfall at Thunder Cape (48 degrees 18' N, 88 degrees 56' W) at the southwestern tip of the Sibley Peninsula, northwestern Ontario, from 9 May to 9 June 1995. Twenty-one of 530 birds examined (6 of 55 species) had a total of 34 ticks; 1 blue jay, Cyanocitta cristata, had a northern fowl mite, Ornithonyssus sylviarum (Canestrini & Fanzago). Four blacklegged tick, Ixodes scapularis Say, larvae were found on an American robin, Turdus migratorius, and 2 on a chipping sparrow, Spizella passerina. This tick was not found on small mammals at Thunder Cape. Twenty-six larvae and a nymph of the rabbit tick, Haemaphysalis leporispalustris (Packard) were found on 1 American robin, 2 Swainson's thrushes, Catharus ustulatus, 1 white-throated sparrow, Zonotrichia albicollis, 1 common yellowthroat, Geothlypis trichas, 1 blue jay, and 12 chipping sparrows. A nymph of H. chordeilis (Packard) occurred on 1 chipping sparrow. Results demonstrate that northward migrating birds transport larvae of I. scapularis to areas of Ontario where the tick does not appear to have become established in small mammal populations. Spring migrants may be more involved in the dispersal of I. scapularis larvae than previously thought. Cooler temperatures and shorter seasons experienced in the more northerly, continental parts of the established distribution of this tick may extend the life cycle, resulting in a predominance of larvae rather than nymphs being acquired by northward-bound birds in early spring. Consequently, the role of spring migrating birds in the northward spread of I. scapularis and of borreliosis should be reevaluated. PMID- 8699452 TI - In vivo rearing and development of Wohlfahrtia magnifica (Diptera: Sarcophagidae). AB - Wohlfahrtia magnifica (Schiner, 1862) has a seasonal cycle from May to September. The main objective of the current study is the rearing and development in the laboratory, outside its natural life cycle. The free and obligate parasite phases were reared in the laboratory during 7 mo, from 16 September to 26 March. Between 97.49 and 98.27% of the third instars reached the pupal stage (at 24 degrees C and under natural light cycle). Between 73.98 and 92.24% of the pupae developed into adults (at 70% RH and 22 degrees C). In the induced cycle the ratio of females to males was between 1.87:1.00 and 1.40:1.00, at 70% RH and 24 degrees C. In the trials involving the diapause pupae, 35.29% emerged as adults during a period of 53 d (from 23 January to 20 March), when held at an average storage temperature of 18 degrees C. Eighty-five percent emerged during 2 d (23 and 24 February) when the storage temperature was 4 degrees C. PMID- 8699453 TI - Seasonal variations in density of questing Ixodes ricinus (Acari: Ixodidae) nymphs and prevalence of infection with B. burgdorferi s.l. in south central Sweden. AB - Seasonal variations in the density of questing Ixodes ricinus (L.) nymphs and their prevalence of infection with Borrelia burgdorferi s.l. Johnson, Schmid, Hyde, Steigerwalt & Brenner were studied during 1991-1993 at a locality in southcentral Sweden. The seasonal pattern of the density of questing I. ricinus nymphs was variable; there was a bimodal pattern with peaks of similar magnitude in 1991, a bimodal pattern with a small spring peak and a greater autumn peak in 1992, and a unimodal pattern with a spring peak and lower values during summer and autumn in 1993. The seasonal pattern of prevalence of Borrelia infection in questing nymphs was similar during all 3 yr, with a peak infection prevalence in late spring or early summer, followed by lower infection prevalences in late summer and autumn. There was a significant correlation between the monthly density of Borrelia-infected nymphs and the monthly density of nymphs. This suggests that, within a certain range of nymphal densities, it may be possible to assess the density of Borrelia-infected I. ricinus nymphs without examining nymphs for B. burgdorferi s.l. PMID- 8699454 TI - Relative abundance and species composition of mosquito populations (Diptera:Culicidae) in a La Crosse virus-endemic area in western North Carolina. AB - Container surveys were conducted in 5 communities on the Cherokee Indian Reservation, an area of western North Carolina endemic for transmission of La Crosse (LAC) virus, to determine the potential for peridomestic mosquito breeding, the relative abundance of mosquito species, and the standing crop of mosquitoes per residence. Eleven species of mosquitoes were collected, but 80.9% of all mosquitoes reared from containers were Aedes triseriatus (Say). All communities averaged > 6 containers per residence, indicating that the potential for mosquito production was high. The Breteau index and mean standing crop of adults per residence in the 5 communities were highly concordant. LAC virus was isolated from 2 pools of 56 female and 36 male Ae. triseriatus adults that were reared from eggs collected by ovitraps. The minimum field infection rate was 0.26 per 1,000 adults tested. Aedes triseriatus, the most frequently collected blood fed mosquito (98/112 blood-engorged specimens), fed predominantly on dogs (40.4%), rabbits (26.6%), and turtles (22.3%). Only 7.5% of the blood-fed mosquitoes had fed on eastern chipmunks. Peridomestic conditions on the Reservation appear to contribute to the maintenance of LAC virus transmission. Production of Ae. triseriatus occurs in artificial containers discarded around residences, and wooded areas immediately adjacent to residences provide resting cover for mosquitoes as well as suitable habitat for LAC virus reservoir hosts. PMID- 8699455 TI - Effects of sugar availability on the blood-feeding behavior of Anopheles gambiae (Diptera:Culicidae). AB - Blood-feeding behavior and survivorship of individual Anopheles gambiae Giles females were observed daily in cohorts with either access to sugar (n = 76) or without sugar (n = 80). Individual mosquitoes were allowed to feed daily on an anesthetized mouse. Mosquitoes provided with sugar lived on average almost 3 d longer than females without sugar (19.0 versus 16.2 d). After stratification by age, mosquitoes in the youngest (5-12 d) and middle (13-19 d) age strata showed no differences in blood-feeding patterns relative to sugar availability. However, mosquitoes from the oldest age group and no access to sugar had more total blood feeds than long-lived females ( > or = 20 d) with access to sugar (9.8 versus 6.5). Furthermore, mosquitoes > or = 20 d old and without sugar available had a higher blood-feeding frequency than females that had sugar available (0.36 versus 0.25 blood meals per female per day). The enhanced blood-feeding capability among older sugar-deprived An. gambiae emphasized the close association between sugar feeding and blood-feeding behavior and the potential consequences for the transmission of malaria parasites and other pathogens. PMID- 8699456 TI - Frequent blood-feeding and restrictive sugar-feeding behavior enhance the malaria vector potential of Anopheles gambiae s.l. and An. funestus (Diptera:Culicidae) in western Kenya. AB - Natural blood-feeding and sugar-feeding behaviors were investigated for populations of Anopheles gambiae s.l. and An. funestus Giles at 2 sites in western Kenya. During peak levels of malaria parasite transmission, > 85% of 1,569 indoor-resting females contained fresh blood meals. Findings that up to 55.4% of blood-fed resting females and 72.0% of host-seeking females had either stage IV or V oocytes provided strong evidence that females were refeeding before oviposition. Such gonotrophic discordance was common throughout the year for both An. gambiae s.l. and An. funestus. Determinations of gonotrophic cycles for freshly blood-fed mosquitoes collected inside houses indicated that only 60.0% of 1,287 An. gambiae s.l. and 60.0% of 974 An. funestus oviposited eggs after a single blood meal. The timing of oviposition was irregular as indicated by relatively high coefficients of variation for An. gambiae s.l. (44.0%) and An. funestus (35.9%). Associated with frequent blood feeding was a surprisingly low rate of sugar feeding; only 6.3% of 1,183 indoor-resting and only 14.4% of 236 host-seeking anophelines were positive for fructose. Natural patterns of frequent blood feeding, year-round gonotrophic discordance, irregular oviposition cycles, and limited sugar feeding illustrate that anopheline mosquitoes have complex behavioral and physiologic means for adapting to their environment. In western Kenya, for example, adaptations for frequent blood feeding by An. gambiae s.l. and An. funestus potentiates their ability to transmit malaria parasites, well beyond that predicted by standard measures of vectorial capacity. PMID- 8699457 TI - Microclimate-dependent survival of unfed adult Ixodes scapularis (Acari:Ixodidae) in nature: life cycle and study design implications. AB - Microclimate and other abiotic factors may be important in determining the survival of arthropod vectors, yet the impact of such variables rarely has received careful examination. The impacts of habitat, microclimate, and experimental confinement on survival rates of unfed adult blacklegged ticks, Ixodes scapularis Say, were studied in field enclosures in southcentral and northwestern Connecticut. At both locations, 2 enclosures were placed in each of 3 different habitats (field, forest canopy, and forest/field edge). Forty wild caught adult ticks (20 males, 20 females) were placed in each enclosure. At one site, another 40 ticks were confined to nylon mesh bags placed inside each enclosure. Soil temperature, ground-level air temperature and relative humidity were measured within each habitat. The number of ticks surviving within each enclosure was monitored 1 or 2 times per week. Ticks that were confined in nylon bags had a lower survival rate than ticks that were able to move freely within the enclosures. Ticks survived longer in edge and forest habitats than in open fields, which were characterized by greater extremes in air temperature, soil temperature, relative humidity, and vapor pressure deficit than the other 2 habitats. The mean daily survival rates of free-ranging I. scapularis were negatively related to air temperature, vapor pressure deficit, and the coefficient of variation of relative humidity. PMID- 8699459 TI - Potential colonization of the peridomicile by Triatoma guasayana (Hemiptera:Reduviidae) in Santiago del Estero, Argentina. AB - Sylvatic triatomines might use the peridomicile as a 1st step in the process of domiciliation. Therefore, we evaluated the capability of sylvatic species to colonize the peridomicile of a rural area in the Province of Santiago del Estero, Argentina. The research was carried out in 6 houses in the village of Trinidad. The person per hour capture method was employed to determine the presence of triatomines in all the buildings (n = 44). Dispersing adults were collected by means of light traps and by villagers when approaching their houses. Triatoma infestans (Klug) was the most abundant species followed by the sylvatic Triatoma guasayana Wygodzinsky & Abalos. The branch pens, which included cacti, Opuntia quimilo, and bromeliads in their structure, were significantly associated with T. guasayana. Most of these insects had fed on domestic blood sources. With the exception of 1 Triatoma sordida (Stal), dispersing adults were T. guasayana; among those approaching houses, 12 were females (2 of which were infected with Trypanosoma cruzi Chagas) and 3 were males. T. guasayana was found to be capable of intensively invading the intradomicile and the peridomicile, showing a high tendency to settle in the ecotopes which included nontransformed raw material from the wild and where T. infestans was less abundant. PMID- 8699458 TI - Salivary gland changes and host antibody responses associated with feeding of male lone star ticks (Acari:Ixodidae). AB - The goal of this study was to demonstrate that male lone star ticks, Amblyomma americanum (L.), actively feed on rabbits during attachment and that the host is capable of mounting an immune response against male salivary gland proteins. During attachment, it was shown that male ticks salivary glands hypertrophy. An enzyme-linked immunosorbent assay was used to detect rabbit serum proteins in the midgut of previously attached male ticks. SDS-polyacrylamide gel electrophoresis showed that the proteins expressed in the male tick salivary gland changed during feeding, with several new proteins in the 15- to 50-kDa range synthesized during attachment. Rabbits mounted a detectable antibody response against male tick salivary gland proteins after 2 sequential feedings of male ticks. The antibodies were directed against a spectrum of male salivary gland proteins ranging from 18 to 160 kDa. Several of these proteins were not recognized by antibodies directed against female tick saliva proteins, and thus may be specific male salivary gland components. This evidence indicates that male A. americanum ticks actively feed during attachment, that their salivary gland proteins change during feeding, and that male salivary gland proteins are immunogenic. PMID- 8699460 TI - Field and laboratory responses of adult Ixodes scapularis (Acari: Ixodidae) to kairomones produced by white-tailed deer. AB - In a field test, adult blacklegged ticks, Ixodes scapularis Say, of both sexes exhibited an arrestant response to substances associated with external glands on the legs of white-tailed deer, Odocoileus virginianus (Zimmermann), their principal host. Substances rubbed from the pelage covering tarsal and interdigital glands were applied to artificial vantage points simulating vegetation on which I. scapularis adults wait for host contact. A combination of tarsal substances (applied to the apex of the simulated vantage point) and interdigital gland substances (applied to the horizontal base) elicited a greater response than either treatment alone. A minimal response was observed on untreated vantage points. In laboratory bioassays using glass tubing as vantage points, substances associated with preorbital glands of deer elicited a strong arrestant response among I. scapularis females, whereas samples rubbed from the forehead, back, and a nonglandular area on deer tarsi evoked weak arrestant responses. These results support the hypothesis that the kairomonal properties of host-generated residues, either in conjunction with or in lieu of the effects of carbon dioxide, help account for the prevalence of host-seeking ticks along animal trails. PMID- 8699461 TI - Salivary gland anticoagulants in culicine and anopheline mosquitoes (Diptera:Culicidae). AB - Female salivary gland extracts from 9 mosquito species representing the 2 hematophagous subfamilies delayed coagulation of human plasma. All extracts significantly delayed recalcification time, prothrombin time, and activated partial thromboplastin time, indicating an effect on the common coagulation pathway. Chromogenic assays to determine the coagulation inhibition site were performed for coagulation factor Xa (FXa) and thrombin, the major components of the common pathway. Although variation existed in the degree of inhibition, all anophelines have thrombin-directed anticoagulants, and culicine mosquitoes have FXa-directed anticoagulants. Differences in the site of action of the anticoagulants most likely reflected the long period of independent adaptation of the 2 subfamilies to the challenges presented by vertebrate hemostasis. PMID- 8699462 TI - Egg production and emergence of adult cat fleas (Siphonaptera: Pulicidae) exposed to different photoperiods. AB - Laboratory cats were infested with a known number of cat fleas, Ctenocephalides felis (Bouche), to determine the effects of photoperiod on flea egg production. Photoperiods of 8:16, 12:12, and 16:8 (L:D) h were chosen to represent winter, spring/fall, and summer, respectively. There were no significant differences in daily or total flea egg production among the 3 photoperiods. To determine the effects of photoperiod on development of immature stages and subsequent adult emergence from cocoons, eggs collected during each photoperiod experiment were reared under the 3 described light and dark conditions. Resulting differences suggest that photoperiod may influence the emergence behavior of adults from cocoons. PMID- 8699464 TI - Dispersal and distribution of Calliphoridae (Diptera) immatures from animal carcasses in southern Louisiana. AB - Spatial distributions of calliphorid pupae (based on adult emergence) from swine carcasses located in woods and pasture were determined during 4 seasons in southern Louisiana. Adult emergence was substantially greater in pastures than woods for all seasons except winter. Secondary screwworm, Cochliomyia macellaria (F.), was the predominant calliphorid species collected ( > 95%) during summer and fall; whereas, black blow fly, Phormia regina (Meigen), was the primary species (86%) during spring. The highest densities of calliphorid pupae per square meter were located within 0.9 m of the animal carcasses in the woods and the pasture (summer); however, the number of calliphorid pupae per square meter during the summer was substantially greater in the pastures than in the woods (2,370/m2 compared with 77/m2). Postfeeding calliphorid larvae preferred to disperse toward the southeastern quadrant during summer and spring and toward the southeastern to southwestern quadrants in fall. The winter evaluation period was the most prolonged (85 d), had the least number of emergent adults (only 6-11% of the populations that emerged in the other seasons), and consisted of predominantly, Phaenicia sericata (Meigen). PMID- 8699463 TI - Establishment of the tick (Acari:Ixodidae)-borne cattle pathogen Anaplasma marginale (Rickettsiales:Anaplasmataceae) in tick cell culture. AB - Anaplasma marginale is a tick-borne rickettsia that causes bovine anaplasmosis worldwide. Despite its importance, A. marginale has thus far not been established in a continuous culture system. We have propagated A. marginale continuously for the 1st time in a tick cell line derived from the black-legged tick, Ixodes scapularis Say, using infected bovine blood as the inoculum. Erythrocytic stages invaded the tick cells and multiplied in membrane-lined vacuoles to form colonies typical of those observed in naturally infected ticks as demonstrated by light and electron microscopy. The rickettsiae have been passaged serially for 3 yr and have been cryopreserved in liquid nitrogen. Antigens present in A. marginale from tick cell culture were recognized by bovine immune serum against the blood stages of A. marginale. A. marginale grown in this tick cell line was infective for calves, and male ticks fed on the calves transmitted A. marginale to a susceptible calf. The ability to culture A. marginale removes a major impediment to the study of Anaplasma biology in vitro, and will enhance development of vaccines and diagnostic tests. PMID- 8699465 TI - Toxicity and histopathology of the growth regulator pyriproxyfen to adults and eggs of the cat flea (Siphonaptera:Pulicidae). AB - Adult cat fleas, Ctenocephalides felis (Bouche), exposed continuously to pyriproxyfen died within 8-10 d. Microscopic examination of 7-d-old adults indicated death was caused by histopathological damage to fat body, Malpighian tubules, midgut epithelia, salivary gland cells, and other internal tissues. Fleas were killed by pyriproxyfen regardless of whether they were held as unfed adults on treated filter paper or as feeding adults on treated dog hair. In addition to these toxic effects on adults, pyriproxyfen also induced formation of large autophagic vacuoles in maturing oocytes leading to partial reabsorption of yolk, degeneration of the nucleus, and lysis of the follicular epithelium. Consequently, most of the eggs laid by treated fleas lacked a nucleus, had a poorly formed chorion, and were ruptured during ovulation. These laboratory results suggest that continuous exposure of fleas to pyriproxyfen on a host animal could prevent deposition of viable eggs and eventually kill adults, thereby controlling all stages of flea development. PMID- 8699466 TI - Release of Romanomermis iyengari (Nematoda:Mermithidae) to control Aedes taeniorhynchus (Diptera:Culicidae) in Punta del Este, Isla de la Juventud, Cuba. AB - Preparasites of Romanomermis iyengari Welch were applied at the rate of 1,000 preparasites per square meter of surface area in 5 natural breeding sites in carbonate rock depressions to control Aedes taeniorhynchus Wiedeman larvae. Larval parasitism averaged 100, 97, 81, and 80% in 1-4 instars, respectively. Three of 5 sites produced parasitism in excess of 90%. The range of salinity and water depth had little influence on the levels of parasitism. Ae. taeniorhynchus density was reduced from 78 to 96% at the 5 sites 8 d posttreatment. PMID- 8699467 TI - Abundance and parity rate of Lutzomyia cruciata (Diptera:Psychodidae) in an endemic focus of localized cutaneous leishmaniasis in southern Mexico. AB - Human bait catches were carried out from 5 through 27 March 1994 in an endemic focus of cutaneous leishmaniasis in the state of Campeche, Mexico. Females of Lutzomyia cruciata (Coquillet) were dissected and 67% were parous. The number of total and parous females collected per day was analyzed by time series, but neither the gonotrophic cycle length nor survivorship could be estimated. However, a survival rate per oviposition cycle of 0.68 was estimated from the least square regression of parous on total females. Additional evidence for L. cruciata as a vector of human leishmaniasis is discussed. PMID- 8699468 TI - Diel rhythms of oviposition and fecundity of Anopheles aquasalis (Diptera:Culicidae) under laboratory conditions. AB - The oviposition patterns of Anopheles aquasalis Curry collected from a grass swamp in Gloudon, Caroni Swamp, Trinidad, were studied in the laboratory by recording the egg-laying performance of 30 individuals and a group of 150 females at 2-h intervals. Oviposition was nocturnal, with a peak between 2400 and 0400 hours when 72% of the eggs were laid. Wild-caught females engorged on human blood matured 89.8 +/- 21.3 follicles (range, 50-118). These findings provide vector control workers with the opportunity to maximize the effect of adulticides on An. aquasalis populations by restricting their operations to the time of peak flight activity. PMID- 8699469 TI - Yellowfever mosquito (Diptera:Culicidae) introduced into Landi Kotal, Pakistan, by tire importation. AB - Although the recent distribution of yellowfever mosquito, Aedes aegypti (L.), in Pakistan has been restricted to the port city of Karachi, adult and immature mosquitoes breeding in imported tires in warehouses at Landi Kotal (North-West Frontier Province) were identified as Ae. aegypti. The patterns of tire trade and the current disjunct distribution of Ae. aegypti indicated that the introduction into Landi Kotal may have been either from Karachi or India. Thermal fog application of pirimiphos-methyl and residual spray of malathion during 1993 reduced abundance in October-November. Living larvae or adults were not found during January 1994, apparently because of cold weather. However, Ae. aegypti reappeared during May-June 1994, most probably from eggs that overwintered. Population increased during late August when another round of spray using the same insecticides and fenthion as an additional larvicide again reduced abundance. Although this mosquito apparently has not spread into neighboring areas, its survival at Landi Kotal through all seasons despite control measures indicates its potential of becoming established in other areas of Pakistan. PMID- 8699470 TI - Infection of Ixodes ricinus (Acari:Ixodidae) by Borrelia burgdorferi in Ile de France. AB - Free-living nymphs and adults from Rambouillet and Fontainebleau, 2 major forests of Ile de France, were collected to determine the infection rates of Ixodes ricinus L. by Borrelia burgdorferi (Johnson, Schmid, Hyde, Steigerwalt & Brenner). Field-collected I. ricinus nymphs and adults were screened for the presence of B. burgdorferi using direct fluorescent antibody assay. The infection rates of nymph, male and female were 12.4% (314), 2.8% (35), and 2.9% (34). No difference in infection rates of nymphs among sites were detected. Spirochetes was isolated from both sites. Isolates from Rambouillet and Fontainebleau were identified as B. burgdorferi sensu stricto and B. garinii, respectively (Baranton, Postic, Saint-Girons, Boerlin, Piffaretti, Assous, and Grimont). PMID- 8699471 TI - Survival of newly emerged Culex tritaeniorhynchus (Diptera:Culicidae) adults in field cages with or without predators. AB - A field experiment was conducted to estimate the survival of Culex tritaeniorhynchus Giles adults before 1st blood feeding under conditions with or without predators in a rice field in central Japan. Adults were counted for 5 d after emerging in cages (2 by 2 and 1.5 m high), which were placed in rice fields during the midseason drying period. Only 10% of the adults survived until day 4 after emergence when exposed to predation, whereas > 60% of the adults survived until day 4 without predation. Lycosidae, hunting spiders, may be an effective predator of Cx. tritaeniorhynchus adults. PMID- 8699472 TI - Cuticular plasticization induced by copulatory stimuli in female Haemaphysalis longicornis (Acari:Ixodidae). AB - Partially engorged adult female ticks, Haemaphysalis longicornis Neumann, received complete, incomplete, or no copulatory stimuli. Subsequently, they were inflated with physiological saline by injection into the haemocoel. Ticks that copulated received both preinseminational and inseminational stimuli and increased their body volume > 10-fold. Ticks that incompletely copulated received only preinseminational stimuli and expanded slightly, whereas ticks that did not copulate did not expand. These results show that the soft integument of H. longicornis only expanded after complete copulation. Therefore, copulatory stimuli induced cuticular plasticization. PMID- 8699473 TI - Cold-hardiness of a laboratory colony of lone star ticks (Acari: Ixodidae). AB - The cold-hardiness of a lone star tick, Amblyomma americanum (L.), laboratory colony was characterized. Fed and unfed larvae, fed and unfed nymphs, and unfed adults did not survive exposure to -17 degrees C for 7 d. After an 8-d exposure to -10 degrees C, adults tolerated cold better than immatures and unfed specimens fared better than fed ticks. Exposing unfed 6-wk-old (postmolt) adult males and females to -15 degrees C for increasing intervals up to 2 h suggests that males were more tolerant to cold than were females. Half of all adults were alive 3 d after the 2-h low-temperature treatment. Males may have survived because of a significantly higher hemolymph osmotic pressure, although the solute concentration increased for both sexes after a 2-h exposure to 0 degree C. Acclimation to 5 degrees C for 7 d had no influence on supercooling points for unfed males and females, engorged nymphs and larvae, and eggs. None of the life stages survived supercooling, which strongly suggests that this species is freeze intolerant. Intolerance of immature stages to chilling may be a limiting factor in the northern distribution of lone star ticks in North America. PMID- 8699474 TI - Computing the field in proteins and channels. PMID- 8699475 TI - A nonselective high conductance channel in bovine pigmented ciliary epithelial cells. AB - An ion channel activated by hyperpolarization was identified in excised patches of bovine pigmented ciliary epithelial cells using the single channel patch clamp technique. In symmetrical NaGluconate, the channel had a maximum conductance of 285 pS. The channel was characterized by frequent flickery transitions between the fully open and closed levels. The channel did not discriminate very clearly between anions and cations; when the cytoplasmic face of excised patches was bathed in a dilute NaCl solution, the channel had a chloride-to-sodium permeability ratio (PCl/PNa) of 1.3. However, the channel showed a small anion selectivity (PCl/PNa = 3.7) when bathed in a concentrated NaCl solution. Gd3+ blocked the channel reversibly. Channel kinetics were characterised by slow (approximately min) voltage-dependent activation and inactivation rate constants. The channel was most active in the range-60 to -140 mV and showed a peak at -120 mV. A similar time- and voltage-dependent activation was also observed in cell attached recordings. In conclusion, hyperpolarization of pigmented ciliary epithelial cell membrane patches activated a large conductance, nonselective ion channel. This combination of nonselectivity and hyperpolarizing activation is consistent with the involvement of this channel in ion loading from the blood into pigmented ciliary epithelial cells-the first phase in the secretion of aqueous humor. PMID- 8699476 TI - Heart and T-lymphocyte cell surfaces both exhibit positive cooperativity in binding a membrane-lytic toxin. AB - Cobra venom cytotoxins (CTX) have been shown to disrupt cells as different as immunocytes, skeletal myocytes, erythrocytes and tumor cells. Nevertheless, even subpopulations of tumor cells are differentially susceptible to CTX by an order of magnitude. In the present study, our objective was to compare CTX-specific binding with cytolytic potency for two disparate cell types in vitro. We investigated the lytic activity of cytotoxin-III from Naja naja atra (NNA, fraction D) using heart cells and human leukemic T-cells (CEM cells). For both cell types, 50% cytolysis, assessed by tetrazolium dye conversion, occurred with microM concentrations of toxin (EC50 = 2.2 microM). We examined the binding of radiolabeled CTX III to both heart cells and CEM cells and found the apparent dissociation constant (KDapp) to be 0.69 microM and 0.75 microM, for CEM and heart cells respectively. The Bmax for the CEM cells was 1.0 fmoles/cell and that for heart cells was 5.2 fmoles/cell, both exhibiting positive cooperativity between the sites (Hill coefficients 1.4, T-cells; 1.6, heart). Relatively modest dissociation constants plus high numbers of binding sites per cell are consistent with a model of CTX binding to plasma membranes by interaction with phospholipids in the bilayer. Our results suggest that the lytic activity of this cytotoxin follows its binding to a population of sites on the cells in a cooperative fashion. PMID- 8699477 TI - Characterization of a large conductance, cation-selective channel from sea urchin eggs that is sensitive to sulfhydryl reducing agents. AB - Vesicles containing large conductance cation selective channels were isolated from sea urchin (Strongylocentrotus purpuratus) eggs. Addition of the vesicles to one side of lipid bilayer led to the rapid appearance of 200 or more identical channels. These channels would then inactivate within 2 to 10 min. The inactivation could be prevented by the addition of sulfhydryl reducing agents (e.g., dithiothreitol or glutathione) to the cis side of the membrane. Only one channel type is present. The channel is cation selective, with a conductance of 572 ps in symmetrical 0.5 M KCl. The relative cation selectivity is K (1.0) > Cs (0.53) approximately < Na (0.52) > Li (0.2). The permeability ratio (Px/Pk) is 1.37 (Li) > 1.27 (Na) > 0.57 (Cs). Most organic cations (choline, tetraethylamine, tetrabutylamine, gallamine, lysine, histidine, arginine, etc.) and multivalent cations (La+3, alkali earth family, Zn+2, Eu+3, etc.) produced a significant channel block. The highest observed affinity was for La+3 which produced a 50% decrease in conductance in 500 mM KCl at a concentration of 8 microM. The biophysical properties of this channel are similar to those of a non selective channel found in ascidian egg plasma membrane (Dale & DeFelice, 1984). A soluble extract of the egg supernatant can also prevent the inactivation of the channels. Using deactivated channels reconstituted into a planar lipid bilayer as an assay, this factor was partially purified. It is heat and acetone stable with a molecular weight of between 10 and 20 K. One of the major bands remaining in the purest fraction cross reacted with antibodies raised against E. coli thioredoxin. PMID- 8699478 TI - Pore formation by S. aureus alpha-toxin in liposomes and planar lipid bilayers: effects of nonelectrolytes. AB - Nonelectrolytes such as polyethylene glycols (PEG) and dextrans (i) promote the association of S. aureus alpha-toxin with liposomes (shown by Coomassie staining) and (ii) enhance the rate and extent of calcein leakage from calcein-loaded liposomes; such leakage is inhibited by H+, Zn2+ and Ca2+ to the same extent as that of nonPEG-treated liposomes. Incubation of liposomes treated with alpha toxin in the presence of PEG with the hydrophobic photo-affinity probe 3 (trifluoromethyl)-3-m-[125I]iodophenyl) diazirine (125I-TID) labels monomeric and predominantly-hexameric forms of liposome-associated alpha-toxin; in the absence of PEG little labeling is apparent. At high concentrations of H+ and Zn2+ but not of Ca(2+)-all of which inhibit calcein leakage-the distribution of label between hexamer and monomer is perturbed in favor of the latter. In alpha-toxin-treated planar lipid bilayers from which excess toxin has been washed away, PEGs and dextrans strongly promote the appearance of ion-conducting pores. The properties of such pores are similar in most regards to pores induced in the absence of nonelectrolytes; the differ only in being more sensitive to "closure" by voltage (as are pores induced in cells). In both systems, the stimulation by nonelectrolytes increase with concentration and with molecular mass up to a maximum around 2,000 Da. We conclude (i) that most of the alpha toxin that becomes associated with liposome or planar lipid bilayers does not form active pores and (ii) that the properties of alpha-toxin-induced pores in lipid bilayers can be modulated to resemble those in cells. PMID- 8699479 TI - A novel, volume-correlated Cl- conductance in marginal cells dissociated from the stria vascularis of gerbils. AB - Using the whole-cell patch-clamp technique, we examined Cl-selective currents manifested by strial marginal cells isolated from the inner ear of gerbils. A large Cl-selective conductance of approximately 18 nS/pF was found from nonswollen cells in isotonic buffer containing 150 mM Cl-. Under a quasi symmetrical Cl- condition, the "instantaneous' current-voltage relation was close to linear, while the current-voltage relation obtained at the end of command pulses of duration 400 msec showed weak outward rectification. The permeability sequence for anionic currents was as SCN- > Br- approximately = Cl- > F- > NO3- approximately = I- > gluconate-, corresponding to Eisenmann's sequence V. When whole-cell voltage clamped in isotonic bathing solutions, the cells exhibited volume changes that were accounted for by the Cl- currents driven by the imposed electrochemical potential gradients. The volume change was elicited by lowered extracellular Cl- concentration, anion substitution and altered holding potentials. The Cl- conductance varied in parallel with cell volume when challenged by bath anisotonicity. The whole-cell Cl- current was only partially blocked by both 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB, 0.5 mM) and diphenylamine-2-carboxylic acid (DPC, 1.0 mM), but 4-acetamido-4'-isothiocyanato stilbene-2,2'-disulfonic acid (SITS, 0.5 mM) was without effect. The properties of the present whole-cell Cl- current resembled those of the single Cl- channel previously found in the basolateral membrane of the marginal cell (Takeuchi et al., Hearing Res. 83:89-100, 1995), suggesting that the volume-correlated Cl- conductance could be ascribed predominantly to the basolateral membrane. This Cl- conductance may function not only in cell volume regulation but also for the transport of Cl- and the setting of membrane potential in marginal cells under physiological conditions. PMID- 8699480 TI - Calcium-dependent enhancement of depletion-activated calcium current in Jurkat T lymphocytes. AB - We have obtained evidence that the Ca(2+)-selective current activated by Ca2+ store depletion (Ca2+ release-activated Ca2+ current; Icrac) in Jurkat T lymphocytes is augmented in a time-dependent manner by Ca2+ itself. Whole cell patch clamp experiments employed high cytosolic Ca(2+)-buffering conditions to passively deplete Ca2+ stores. Rapidly switching to nominally Ca(2+)-free extracellular buffer instantaneously reduced Icrac measured at -100 mV to leak current level. Unexpectedly, readmission of 2 mM Ca2+ instantaneously restored only 38 +/- 5% (mean +/- SEM, n = 9) of the full Icrac amplitude. The remainder reappeared in a monotonic time-dependent manner over 10 to 20 sec. Rapid vs. slow intracellular Ca2+ chelators did not alter this process, and inorganic Icrac blockers did not regenerate it, arguing against an intracellular site of action. The effect was specific to Ca2+: introduction of the permeant ions, Ba2+ or Sr2+, failed to invoke time-dependent Icrac reappearance. Moreover, equimolar substitution of Ba2+ for Ca2+ initially produced Ba2+ current of similar magnitude to the full Ca2+ current, but the Ba2+ current decayed monotonically to < 50% of its initial amplitude in < 20 sec. Conversely, return to Ca2+ produced a time-dependent increase in Icrac to its larger Ca2+ permeation level. Thus Ca2+ appears to selectively promote a reversible transition of Icrac that results in larger current flux, and at least partially explains the selectivity of this current for Ca2+ over other divalent ions. PMID- 8699482 TI - Short-chain fatty acid (SCFA) volume regulation in proximal and distal rabbit colon is different. AB - SCFAs increase the volume of many different cell types rarely exposed to significant concentrations of these weak electrolytes. SCFAs swell isolated cells from colonic carcinoma cell lines, but the-mechanism(s) of volume regulation in normal colonocytes, which are generally exposed to > 100 mM SCFAs, has not been well characterized. AIMS. To determine the effect of SCFAs on volume regulation in proximal and distal rabbit colonocytes. METHODS. Isolated colonocytes were plated on coverslips and placed in a perfusion apparatus that permitted fluid changes. Cells were continuously monitored by video-microscopy; volume was estimated by measured changes in the radius of individual cells. RESULTS. Distal colonocytes (DC) consistently had a slightly greater basal volume than proximal colonocytes (PC): [14.2 pl/fl:9.8 pl/fl] In HEPES-buffered solutions, an isotonic change to a 90 mM NaCl/50 mM Na propionate solution elicited a significant increase in cell volume within 10 min, but no noticeable regulatory volume decrease over 30 min: V/Vo in DC: 1.29 +/- .09; in PC: 1.25 +/- .05. In HCO3 buffered solutions, 50 mM PROP caused significantly greater cell swelling; in DC: 1.74 +/- .21; in PC: 1.52 +/- .08. In DC both amiloride and EIPA blocked the SCFA induced increase in cell volume. A hypotonic challenge confirmed that these cells were capable of swelling. In contrast, amiloride did not significantly inhibit SCFA-induced swelling in PC: control, 1.25 +/- .05; amiloride, 1.36 +/- .10. Cell volume increased in PC perfused with an isosmotic 50 mM propionate, Na-free solution: 1.22 +/- .04. CONCLUSIONS. (i) SCFAs induce significant cell swelling, but no regulatory volume decrease, in isolated colonocytes; (ii) HCO3 augments SCFA-induced cell swelling; (iii) volume increase in DC is dependent on Na-H exchange, but in PC appears to be Na-independent. SIGNIFICANCE. There are fundamental differences in how proximal and distal colon respond to isosmotic volume challenge of SCFAs. PMID- 8699481 TI - Phosphorylation is involved in the regulation of the taurine influx via the beta system in Ehrlich ascites tumor cells. AB - The role of 3',5'-cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), protein kinase C (PKC) and phosphatases in the regulation of the taurine influx via the beta-system in Ehrlich ascites tumor cells has been investigated. The taurine uptake by the beta-system in Ehrlich cells is inhibited when PKC is activated by phorbol 12-myristate 13-acetate (PMA) and when protein phosphatases are inhibited by calyculin A (CLA). On the other hand, taurine uptake by the beta system is stimulated by an increased level of cAMP or following addition of N6,2' O-dibutyryl-3',5'-cyclic adenosine monophosphate (dbcAMP). The effect of dbcAMP is partially blocked by addition of the protein kinase inhibitor H-89, and suppressed in the presence of CLA. It is proposed that the beta-system in the Ehrlich cells exists in three states of activity: State I, where a PKC phosphorylation site on the transporter or on a regulator is phosphorylated and transport activity is low. State II, where the PKC phosphorylation site is dephosphorylated and transport activity is normal. State III, representing a state with high transport activity, induced by an elevated cellular cAMP level. Apparently, cAMP preferentially stimulates taurine transport when the beta-system is in State II. PMID- 8699484 TI - Quantitative distribution of muscle fiber types in the scup Stenotomus chrysops. AB - Because the mass-specific power generated by myotomal muscle during swimming varies along the length of the fish, a realistic assessment of total power generation by the musculature requires integrating the product of mass-specific power and muscle mass at each position over the length of the fish. As a first step toward this goal, we examined the distribution of red, pink, and white muscle along the length of Stenotomus chrysops (scup) using histochemical and image analysis techniques. The largest cross-sectional area of red fibers occurs at 60% of total fish length and declines both anteriorly and posteriorly. By contrast, white fibers have the largest cross-sectional area in the anterior and decline dramatically moving posteriorly. The proportion of the fishes' cross section occupied by red fibers increases from 1.37% to 8.42% moving posteriorly along the length of the fish. In contrast, the proportion of cross-sectional area occupied by pink fibers is constant (1.19%), while the proportional cross sectional area of white fibers falls from 82.5% to 66.3%. The red, pink, and white fibers comprise 2.09, 0.73, and 51.1%, respectively, of total fish weight. We also compared the distribution of muscle in 10 degrees C- and 20 degrees C- acclimated animals. The value for red fiber volume, though slightly higher (13%) in cold-acclimated fish, is not statistically different. No difference was found in pink or white fibers. Finally, the finding that most of the red muscle is in the posterior half of the fish further supports the notion that most power for steady swimming at moderate speeds comes from posterior rather than anterior musculature. PMID- 8699483 TI - Dye transfer between cells of the lens. AB - Dye transfer between lens fiber cells and between lens epithelial cells and underlying fiber cells was studied using a wide dynamic range-cooled CCD camera, H2O immersion objectives and image analysis techniques. Each lens was decapsulated by a new technique which leaves the epithelial cells adherent to the lens fiber mass. Lucifer Yellow CH was injected into either single epithelial cells or single fiber cells using the standard whole cell configuration of the patch voltage clamp technique. The results demonstrate extensive dye communication between fiber cells at the lens posterior surface, anterior surface, and equatorial surface. Dye transfer between deep fiber cells was also observed. Dye transfer between approximately 10% of epithelial cells and their underlying fiber cells was apparent when care was taken to yield wide dynamic range images. This was required because the relatively high concentration of dye in the epithelial cell masks the presence of much lower dye concentrations in the underlying fiber cell. A mathematical model which includes dye concentration, time, and spatial spread suggests that those epithelial cells that are coupled to an underlying fiber cell are about as well dye coupled as the epithelial cells themselves. The relatively low dye concentration in a fiber cell is due to its larger volume and diffusion of the dye along the axis of the fiber away from the fiber/epithelial junction. PMID- 8699485 TI - Dental Implants. Part I: Biological basis, implant types, and the peri-implant sulcus. AB - Dental implantology is a rapidly advancing area of dentistry providing a number of alternative treatment possibilities for patients with partially or fully edentulous mouths. The following article is the first in a series of three dealing with various aspects of dental implantology, with a particular emphasis on those areas related to field of periodontology. In this paper we shall consider the biological basis of dental implants, different implant systems, and the peri-implant sulcus. Forthcoming articles will cover the diagnosis and treatment of peri-implantitis and failing implants, guided bone regeneration around implants, immediate implant placement, the placement of implants in the posterior maxillae, and implant maintenance. PMID- 8699486 TI - PSR and CPITN charting: the need for documentation in patients records. PMID- 8699487 TI - The role of the dental hygienist. PMID- 8699488 TI - A landmark in New Zealand dental history. PMID- 8699489 TI - A study comparing the efficacy of a toothpaste containing extract of Salvadora persica with a standard fluoride toothpaste. PMID- 8699490 TI - Dental implants. Part II: Guided bone regeneration, immediate implant placement, peri-implantitis, failing implants. AB - In the first part of this article the biological rationale and the use of different implants was considered. In this second part, guided bone regeneration (GTR) around implants, immediate placement of implants, peri-implantitis, and failing implants will be discussed. PMID- 8699491 TI - Continued recession affecting a successful free gingival graft. PMID- 8699492 TI - Knowledge, awareness and use of interdental cleaning aids by dental school patients in New Zealand. PMID- 8699493 TI - A new treatment for premature ejaculation: the rehabilitation of the pelvic floor. AB - This study evaluated pelvic floor rehabilitation as a possible treatment for premature ejaculation. In this treatment it is assumed that the pelvic muscles are involved in the control of the ejaculatory reflex. The treatment avails itself of a method already used for fecal and urinary incontinence. Eighteen patients with premature ejaculation were recruited. Fifteen (83%) of them had suffered from this disturbance for at least five years. Most of them had experienced other therapies without success. After 15-20 sessions of pelvic floor rehabilitation, 11 (61%) patients were cured and are able to control the ejaculatory reflex; seven (39%) patients had no improvement. All patients were followed for a minimum of 6 months to a maximum of 14 months. This therapy is easy to perform, has no side effects, and can be included among the therapuetic options for patients with premature ejaculation. PMID- 8699494 TI - The reliability and validity of a sexual functioning questionnaire. AB - The present study assessed the reliability and validity of a measure of sexual functioning, the CMSH-SFQ, for male patients and their partners. The CMSH-SFQ measures erectile and orgasmic functioning, sexual drive, frequency of sexual behavior, and sexual satisfaction. Test-retest reliability was assessed with 19 males and 19 females for the baseline CMSH-SFQ. Criterion validity was measured by comparing the answers of 25 male patients to those of their partners at baseline and follow-up. The majority of items had acceptable levels of reliability and validity. The CMSH-SFQ provides a reliable and valid device that can be used to measure global sexual functioning in men and their partners and may be used to evaluate the efficacy of treatments for sexual dysfunctions. Limitations and suggestions for use of the CMSH-SFQ are addressed. PMID- 8699495 TI - An 18-month follow-up on the effectiveness of a sexuality workshop: some methodological pitfalls. AB - Students from four health sciences programs (Medicine, Nursing, Occupational Therapy and Physiotherapy) participated in a two-day Sexuality Workshop and completed pre- and post-workshop questionnaires dealing with sexual attitudes, comfort, and knowledge. Eighteen months later, these students were asked to complete the same questionnaires. Not only had they sustained the gains made during the workshop, but they continued to show improvement in the three areas during this interval. However, of greater importance than the positive finding is the need to understand the range of methodological problems encountered in carrying out this type of follow-up educational inquiry and in seeking measures for improving the validity and generalizability of such research. PMID- 8699496 TI - Report of a case of male genital self-mutilation and review of the literature, with special emphasis on the effects of the media. AB - Genital self-mutilation is seldom reported; fewer than 100 cases have been reported in the literature to date. Few studies have examined the factors that may lead susceptible individuals to undertake this act. We report here on a case of genital self-mutilation by a 22-year-old man who cut off his penis with an electric chain saw. This patient, who also demonstrated borderline intellectual functioning as evidenced by psychological testing, was likely influenced by the popular media, which was showcasing the criminal trials of John and Lorena Bobbitt at the time of the patient's act. PMID- 8699498 TI - Teaching sex education in the Arab sector in Israel: an approach for working with a traditional population. AB - While the Israeli Arab population includes a plurality of cultures, all Arabs share a very traditional, conservative view of sexuality. Family Life and Sex Education has only recently been considered possible within the Arab school system. This paper describes an approach that has been developed for the design of teacher training courses and that is grounded in an understanding of and respect for the Arab cultural environment as distinct from the Jewish majority culture. PMID- 8699497 TI - Auto-erotic asphyxiation: three case reports. AB - Men who indulge in auto-erotic asphyxial practices are rarely encountered by psychiatrists. More often, they come to light at a coroner's inquest, and a verdict of "accidental death" is usually rendered (e.g., from hanging/suffocation). This paper describes and contrasts three cases of auto erotic asphyxial practices. The first case, of accidental death by hanging, was an apparently highly successful young man who functioned at a high level and was without "serious psychopathology." In contrast, the other two, both survivors of asphyxial practices, manifested multiple paraphilias and other types of psychopathology. The syndrome may be extremely diverse, and survivors who consult psychiatrists require holistic assessment and treatment tailored to multifarious needs. PMID- 8699500 TI - AIDS prevention in high-risk African American women: behavioral, psychological, and gender issues. AB - A three-year longitudinal intervention study was implemented to reduce high-risk drug and sexual behaviors in methadone-dependent African American women. Participants were recruited from four inner-city methadone maintenance programs and randomly assigned either to an eight-week peer counseling and leadership training group or to a control group. The 107 trainees and 97 controls completed pretests and posttests at two, four, and seven months. This paper focuses on final data related to the subjects' sexual beliefs, attitudes, knowledge, and behaviors that put them at risk for HIV/AIDS. Reasons for not using condoms are categorized and discussed. Despite the women's awareness of the seriousness of AIDS, perceived powerlessness to negotiate condom use, negative attitudes about the use of condoms, influence of drugs, and unavailablility of condoms interfered with safer sex practices. The inability of education alone to prevent many high risk sexual behaviors suggests that more serious consideration be given to expanded distribution of condoms as well as needle exchange programs and legalization of illicit drugs. PMID- 8699499 TI - Who benefits from couple therapy? A comparison of successful and failed couples. AB - Two years after couple therapy, a group of successful couples was compared with a group of failed couples. The successful group was younger and had a higher level on Positive Regard at the start of therapy. PMID- 8699502 TI - Nifedipine-induced gingival enlargement around dental implants: a clinical report. AB - Calcium channel-blocking agents are used extensively for the management of cardiovascular conditions, including angina pectoris, coronary artery spasm, cardiac arrhythmias, and hypertension. Gingival overgrowth around natural teeth has been previously reported in the literature with patients taking calcium channel-blocking agents. This clinical report describes hyperplasia of tissues around titanium dental implants in a patient taking Nifedipine along with the multiphasic approach to treating this medication-induced hyperplasia of the peri implant tissues. PMID- 8699501 TI - A new animal model for molecular biological analysis of the implant-tissue interface: spatial expression of type XII collagen mRNA around a titanium oral implant. AB - The objective of this study was to develop an animal model to investigate the molecular biological healing events at the tissue-implant surface occurring in the alveolar bone. Newly designed mini-titanium implants (2mm in length and 1 mm in diameter) were placed in the maxilla of retired-breeder male Sprague-Dawley rats. The implants were placed in freshly drilled holes in the maxillary bone, or in an area close to the roots of the maxillary first molar. The healing phase in each group was studied histologically at 28 days and at 56 days by means of non decalcified polymethylmethacrylate-embedded sections and decalcified paraffin embedded sections. Initial osseointegration was observed at 28 days, with mature osseointegration seen at 56 days. Specimens with implants placed immediately adjacent to the root showed fibrous healing at the implant-tissue surface. As a pilot study, the expression of type XII collagen, a molecular marker specific to the mature periodontal ligament (PDL), was studied by in situ hybridization. There was an absence of type XII expression close to the implant surface, whereas there was a zone of type XII collagen expression closest to the bony wall. Our preliminary results indicated a significant molecular variation in the fibrous implant interface. This model will be useful in studies of the wound-healing patterns of the extracellular matrix around oral implants specifically relevant to alveolar bone osseointegration and potential formation of PDL. PMID- 8699503 TI - Unsplinted crowns on implants in the subantral augmented region: an evolution. AB - Excluding the wisdom teeth, the average human being is supplied by nature with a total of 42 tooth roots (24 in the maxilla and 18 in the mandible). After the loss of any tooth root, bone resorbs at that site due to the lack of endosseous stress. With this article, the author supports the idea of a new concept: keeping the individual alveolar bone site alive with endosteal root-form implants by imitating the natural dentition as closely as possible--even in the subantral region. PMID- 8699505 TI - Use of dental implants for rehabilitation of mandibulectomy patients prior to radiation therapy. AB - The use of dental implants can aid in prosthetic rehabilitation of patients after ablative cancer surgery of the oral cavity. Biological effects of radiation therapy and the enhancement of radiation by metal implants have limited the use of dental implants. This article presents a case of dental implants used prior to radiation therapy for rehabilitation of a mandibulectomy patient and discusses the current understanding of radiation effects on bone and metal implants. PMID- 8699506 TI - Effects of chemotherapy in patients with dental implants. AB - Endosseous implant placement is generally considered to be contra-indicated in patients undergoing chemotherapy for the treatment of cancer. A case is presented where a patient was diagnosed with cancer and began chemotherapy four weeks after endosseous implants were placed. The impact of chemotherapeutic agents on endosseous implant acceptance as well as upon oral tissue is examined. PMID- 8699507 TI - Implant surgery: our experience in performing second stage surgery by a punch approach. PMID- 8699504 TI - A surgical perspective: immediate placement of blade-/plate-form and self-tapping vent-plant screw implants into fresh extraction sites. PMID- 8699508 TI - Contradictions of commerce and how it confounds the clinician. PMID- 8699509 TI - Evaluation of a high-density polytetrafluoroethylene (n-PTFE) membrane as a barrier material to facilitate guided bone regeneration in the rat mandible. AB - The purpose of this investigation was to evaluate the use of high-density polytetrafluorethylene (n-PTFE) membranes to facilitate guided tissue regeneration (GTR) in the rat. The concept of guided tissue regeneration is based on the hypothesis that if the non-osteogenic connective tissue cells are mechanically blocked from entering a bone defect, selective re-population of the defect by osteoblasts will occur. Bilateral through-and-through defects of critical size were created in the mandibular angle of 12 rats. The experimental side was covered on both the medial and lateral aspects of the mandible with high density n-PTFE membrane, with the opposite side serving as a control. Histological analysis revealed osteogenic tissue completely bridging the defect by two weeks. After six weeks of healing, osteogenic repair was observed at the margins of the defects, with islands of woven bone seen in the central areas. After 10 weeks of healing, complete ossification was observed on the n-PTFE treated side. The control defects exhibited very little osseous regeneration, and rounding of the defect margins was observed after 10 weeks of healing. These results indicate that high-density n-PTFE can serve effectively as a guided tissue regeneration barrier in certain bone defects. PMID- 8699510 TI - Histologic observations of bone remodeling adjacent to endosteal dental implants. AB - To examine bone morphology associated with endosteal dental implants at various time intervals, we inserted 20 one-stage and 20 two-stage titanium blade implants and 20 one-stage and 20 two-stage titanium root-form implants into 30 dog mandibles. Sixteen implants in 6 control (c) dogs (in situ five months) did not receive bridgework. Sixty-four implants in 24 dogs supported bridges for six, 12, 18, or 24 months. The entire area of the mandible containing the implants was examined by routine light and Nomarski differential interference microscopy (NM) for bone morphology (including osteon orientation) at the implant surface and at regions away from the implant. Control root-form implants were apposed by woven bone, with homogenous compact bone in the cortical plate distant to the implant. After 6 mo of load, immature bone was predominant apposing the implant, but initial osteonal maturation was apparent. NM clearly demonstrated the interstitial and concentric lamellae of the bone. Surprisingly, compact bone formed internal to the cortical plate, an area where trabecular bone is expected. At later periods of load, more mature osteons were seen apposing the implants; however remodeling events were still apparent. These remodeling events extend further away from the implant than was expected if the events resulted only from surgical repair. Also, when the implant inclined so that half was totally in the cortical plate and half in the marrow (in trabecular patterns), osteonal bone appeared to remodel in both areas. Control blade implants and blades loaded for six months were apposed by immature osteons when the implant was placed into the cortical plate. A trabecular meshwork was inferior to the osteonal bone. At 12 mo of load, the bone internal to the cortical plate appeared similar to the lamina dura supporting teeth; however, no PDL existed; the lamina-dura-like pattern directly apposed the implant. Even after 24 mo of load, extensive bone remodeling was apparent adjacent to the implant, markedly different from the bone making up the existing cortical plate. From these data, remodeling activities to blade implants may involve the development of a lamina-dura-like bone morphology after longer periods of load. Osteonal bone was apparent, but only at regions where the implant was inserted into the cortical plate. Further, bone remodeling was apparent even after long periods of load. PMID- 8699511 TI - Preliminary evaluation of titanium-coated PEEK dental implants. AB - A total of 40 titanium-coated and uncoated polyetheretherketone (PEEK) cylindrical implants was placed in unicortical sites in the femurs of four mongrel dogs. The implants were evaluated mechanically and histologically at periods of four and eight weeks. Interface attachment strength was determined for each specimen, as were measurements of bone contact, porosity, bone ingrowth, inflammatory response, and mode of failure. Statistical analysis revealed that the uncoated implants had a significantly higher interface shear strength at four weeks, but that there was no significant difference from the coated implants at eight weeks. At both four and eight weeks, the titanium-coated specimens had significantly higher percentages of bone contact. There was no significant increase in bone contact between four and eight weeks for either the coated or uncoated specimens. PMID- 8699512 TI - In vivo evaluation of CSTi dental implants in the presence of ligature-induced peri-implantitis. AB - The histology of a CSTi (cancellous-structured titanium) porous-coated cylindrical dental implant was compared with that of a solid control HA (hydroxylapatite)-coated dental implant with the same geometry. A particular concern with the use of porous-coated implants in dental applications is the possibility of infection due to direct exposure to the outside environment. Three implants of each type were placed in healed mandibular sites of 14 canines, and after eight weeks of healing, an abutment was placed on each implant. In one half of the implants, ligature-induced peri-implantitis was introduced. The implants were evaluated at four, eight, 16, and 26 weeks post-ligature placement. Bone ingrowth percentages were relatively high for both ligated and non-ligated CSTi specimens, with mean values ranging from 59% to 71%. There was no significant difference in bone ingrowth percentages between ligated and non-ligated specimens at any of the evaluation periods. For the HA-coated specimens, there was also no significant difference in bone contact percentages between ligated and non ligated implants. There was not a significant decrease in bone contact of bone ingrowth with time for either the ligated or non-ligated implants. No loss of bone along the porous coating or coating-bone interface was observed due to the peri-implantitis, although HA failure was seen primarily in ligated specimens. When crestal bone loss was evaluated on histologic sections and radiographs, it was found that there was no significant difference in loss between CSTi- and HA coated implants at all time periods for ligated and non-ligated specimens. Histological inspection of the CSTi implants did not reveal any migration of infection or inflammation through the porous coating resulting in bone ingrowth loss. PMID- 8699513 TI - Fixed provisional restorations for extended prosthodontic treatment. AB - During extensive and extended prosthodontic treatment, there is need for a durable esthetic fixed provisional restoration that can be easily modified as treatment is completed and that is cost-effective. The needed strength of provisional restorations can be underestimated, and the management of complex treatment is then more difficult and the prosthetic results less predictable. Knowledge of the criteria for treatment restorations and the adequacies of their construction is essential for the prevention of catastrophic failures, patient management problems, and compromised results. Many times in complex prosthodontic treatment, changes are needed in esthetics, the plane of occlusion, incisal edge position, lip support, and type of occlusion, or the soft and/or hard tissues need to be altered or grafted surgically. In addition, after first- and second stage implant surgery and extractions, there is a need for immediate tooth replacement with extended time between prosthodontic treatments. These prosthodontic changes and challenges can be addressed with reinforced acrylic provisional restorations that are adequately cemented and retained during the interim stage of healing and treatment. In addition, the provisional restoration should serve as a guide for the final restoration while esthetics and phonetics are evaluated for patient acceptance. This article describes the materials used with an indirect technique for fabrication of an extended-treatment acrylic provisional restoration that uses an internal cast metal support system for strength. This support system consists of metal bands or copings with extensions into edentulous areas and that have been opaqued to neutralize the metallic color. A matrix of vinyl polysiloxane made from the diagnostic wax-up simplifies construction of the acrylic, resulting in a strong, ridged, yet esthetic result. PMID- 8699514 TI - Oral bacterial attachment to titanium surfaces: a scanning electron microscopy study. AB - Despite the wide use of dental implants, the understanding of the mechanism(s) of bacterial attachment to implant surfaces and of the factors that affect such attachment is limited. In this study, the attachment of oral bacteria--including Streptococcus sanguis, Actinomyces viscosus, and Porphyromonas gingivalis--to titanium (Ti) discs with different surface morphology (smooth, grooved, or rough) was examined by scanning electron microscopy (SEM). The most bacterial attachment was observed on the rough BSA-coated Ti surfaces. The smooth surfaces promoted poor attachment for S. sanguis and A. viscosus. However, P. gingivalis attached equally well to both the smooth and grooved coated Ti surfaces, based on direct cell quantitation and examination with SEM. Cell-surface fimbriae (which may play a role in adhesion) of both A. viscosus and P. gingivalis observed were associated with the Ti surfaces. Ti implant surface characteristics appeared to influence oral bacterial attachment in vitro. The in vitro attachment system has proven its usefulness for future bacterial attachment studies with model implant surfaces. PMID- 8699515 TI - Anatomy and histophysiology of the periosteum: quantification of the periosteal blood supply to the adjacent bone with 85Sr and gamma spectrometry. AB - The periosteum or periosteal membrane is a continuous composite fibroelastic covering membrane of the bone to which it is intimately linked. Although the bone cortex is the main beneficiary of the principal anatomical and physiological functions of the periosteal membrane, the behavior of the entire bone remains closely influenced by periosteal activity. These principal functions are related to the cortical blood supply, osteogenesis, and muscle and ligament attachments. Through its elastic and contractile nature, it participates in the maintenance of bone shape, and plays an important role in metabolic ionic exchange and physiologic distribution of electro-chemical potential differences across its membranous structure. It has also been suggested that the periosteum may have its own specific proprioceptive property. This paper presents a study of the anatomy and histophysiology of the periosteum, and discusses in detail its main functions of cortical blood supply and osteogenesis. It also presents the third intermediary report on a current study of the quantification of cortical vascularization of femoral bone via the periosteum, using an isotonic salt solution containing 85 Strontium. The afferent-efferent (arterio-venous) flows of this solution in the thigh vascular system of guinea pigs were measured by gamma spectrometry after a series of selective macro- and micro-injections of radioactive salt into the femoral arterial system was carried out. Each vascular territory was meticulously selected and the injections were made according to size, starting with the larger vessels, with or without ligatures of neighboring vessels, going progressively to smaller and smaller vessels with diameters not exceeding 100 microns. The principal technical difficulty at this stage of experimentation was related to the identifying and acquiring of appropriate microcatheters. The study also includes a series of measurements after blockage of the transmuscular blood flow and the corresponding periosteal vascular system by selective ligation of the thigh muscles. The results clearly show the fundamental predominance of periosteal blood circulation to the bone cortex (70 to 80% of the arterial supply and 90 to 100% of venous return) compared with centromedullary vascularization. A quantitative formula related to the general blood circulation in the bone cortex and marrow, taking into account the two pathways, is presented. Although the application of these results (which concern a long-bone site in an animal) to the alveolar and maxillo-mandibular periosteum requires the conception of an appropriate human experimental model, the extrapolation of the findings seems plausible in the case of the mandible, where the osseous structures and the vascular network are comparable with those found in long bone. However, in the maxilla, where the general blood supply is more intense and anastomotic, the periosteal contribution may legitimately be considered less important than the centro-medullary circulation. Finally, the presentation analyzes the physio-pathology of an experimentally damaged periosteum either directly (by thermodestruction, squashing, and chemodestruction), or indirectly (by muscular pull and tear), leading to the inevitable chain reaction, i.e., "ischemia-necrosis-atrophy and partial regeneration" of the underlying bone and very frequently compromising the survival of an implant that had been placed within it. The report emphasizes the importance of impeccable soft tissue and periosteum management at the time of implant surgery and indicates a number of technical precautions that should be observed in order to avoid periosteal damage. PMID- 8699516 TI - Bone scintigraphy and osseointegration (preliminary report). PMID- 8699517 TI - In vivo evaluation of a CSTi dental implant: a healing time course study. AB - The in vivo interface attachment strength and histology of CSTi (cancellous structured titanium)-coated cylindrical dental implants were compared with those of solid HA-coated dental implants of the same dimensions and geometry. The implants were placed in healed extraction sites in the mandibles and prepared unicortical sites in the femurs of canines. The mandibular implants were evaluated at two, four, eight, and 12 weeks post-implantation, and the femoral implants were evaluated at two, four, eight, 12, 16, 24, and 34 weeks post implantation. The interface attachment strength of the CSTi implants placed in the mandible at two, four, eight, and 12 weeks was not significantly different from that of the control HA-coated implants. In the femurs, the CSTi implants were significantly stronger than the HA-coated implants at all time periods except 12 weeks (two, four, eight, 16, 24, and 34 weeks). The CSTi implants were able to achieve high percentages of bone ingrowth in the mandible and femur of up to 92% at the later time periods, thus providing a sound interface bond. PMID- 8699518 TI - Interim clinical study report: a threaded, hydroxylapatite-coated implant--five year post-restoration safety and efficacy. AB - An ongoing prospective clinical trial is being conducted at three study sites to evaluate the safety and efficacy of a threaded, hydroxylapatite-coated implant (Steri-Oss Inc., Yorba Linda, CA) in a patient population reflective of the investigators' overall population of implant candidates. The 2062 implants placed and restored among 720 patients over the five-year period up to the study interim analysis cut-off date (November, 1994) include over 600 implants and 200 patients at each study site. Mean age and sex distribution of patients were comparable among the study sites. Study design attributes included well-defined patient selection criteria, standardized study procedures, standardized measurement and observation methodology, complete data accountability, and rigorously applied implant success/failure criteria. Thirty-five implants were considered failures at exposure, and the surgical success rate was 98.3%. Of 65 implants that failed post-restoration, three were removed, while 62 remained functional and in service. The five-year post-restoration follow-up success rate, determined by means of life table methodology, was 96.0%. By region, the five-year life table success rates post-restoration were 94.3% in the anterior maxilla, 96.6% in the posterior maxilla, 97.2% in the anterior mandible, and 95.6% in the posterior mandible. Adverse events occurred in association with less than 1% of the implants placed. PMID- 8699519 TI - Comparison between planned prosthetic trajectory and residual bone trajectory using surgical guides and tomography--a pilot study. AB - Implant treatment is a highly technical and complex form of dentistry. Research and experience have shown that the success of dental implant treatment relies on a well-developed treatment plan approach that takes into account factors such as systemic condition, anatomical landmarks, occlusion, shape and density of the jawbone, and type of implant system. Historically, once the tissue was reflected, implant placement was guided by residual bone height and width, using the trajectory that was compatible with the location and direction of available bone, at times compromising prosthetic needs. The purpose of this study was to measure the amount of deviation between planned prosthetic trajectory (PPT), perpendicular to the plane of occlusion, and residual bone trajectory (RBT) in different areas of the maxillary and mandibular dental arches, using tomography in conjunction with surgical guides. Twenty-five patients with a total of 66 implant sites were selected for this study. A surgical guide with a radiopaque indicator was constructed to determine the PPT. Cross-sectional tomograms were taken through the indicator at each implant site. The outlines of the available bone, PPT and RBT, were traced, and the difference in the angulation between the two trajectories was determined. Results showed discrepancies between the PPT and the RBT to be greater in the mandibular molar areas. Further study of such pre implant diagnostic procedures is needed to understand the relation between the PPT and RBT, thus increasing the predictability of implant success. PMID- 8699520 TI - Evaluation of recombinant human osteogenic protein-1 (rhOP-1) placed with dental implants in fresh extraction sites. AB - This study used the canine mandibular model to evaluate the efficacy of recombinant human osteogenic protein-1 (rhOP-1) for accelerating the healing of fresh dental extraction defects and in encouraging osseointegration of dental implants. Eight implants, four hydroxylapatite (HA)-coated and four non-coated, were placed in each mandible of four adult male mongrel dogs immediately after extraction of the eight premolars. The rhOP-1 was placed in all extraction sites with and without implants on the left side of the mandible. All animals were killed at 12 weeks postoperatively; histologic analysis was performed, including measurement of the new bone formation within the extraction defects, implant incorporation, and implant-bone interface characteristics, including percent bone and fibrous tissue apposition. Extraction sites treated with rhOP-1 were completely filled with new bone and were well incorporated with the host bone at 12 weeks post-operative. New bone had filled the untreated defect sites; however, the amount, density, and degree of remodeling were less than was observed in rhOP 1 sites. Small increases in osseointegration and adjacent new bone formation were apparent surrounding implants placed with rhOP-1. However, good initial implant fit and the small amount of rhOP-1 delivered to the site in this model may have mitigated any large differences. The results of this study demonstrate that new bone formation can be induced around and adjacent to a dental implant placed in a fresh extraction site with a recombinantly produced bone inductive protein. PMID- 8699521 TI - Comparative stress analyses of fixed free-end osseointegrated prostheses using the finite element method. AB - We investigated the designs of osseointegrated prostheses in cases of free-end partial edentulism using comparative stress analyses interpreted with the two dimensional finite element method. Seven free-end fixed osseointegrated prosthesis models with various connection designs (i.e., rigidly connected to an abutment tooth, not connected to an abutment tooth, connected to an abutment tooth with a non-rigid attachment) were studied. The stress values of the seven models loaded with vertical force were analyzed. When the prosthesis was not connected to natural abutment tooth but was supported instead by two free standing implant abutments, lowest levels of stress in bone were noted. On the other hand, non-rigid attachments, when incorporated into a prosthesis, did not significantly reduce the level of stress in bone. PMID- 8699522 TI - A light and scanning electron microscopic evaluation of electro-discharge compacted porous titanium implants in rabbit tibia. AB - This study used light and scanning electron microscopic (SEM) histomorphometric methods to quantitate the rate of osseointegration of totally porous titanium alloy (Ti-6Al-4V) implants prepared by a novel fabrication technique- electrodischarge compaction (EDC). EDC was used to fuse 150-250-micrometer spherical titanium alloy beads into 4 X 6 mm cylindrical implants through application of a 300-microsecond pulse of high-voltage/high-current density. Two sterilized implants were surgically placed into each tibia of 20 New Zealand white rabbits and left in situ for periods corresponding to 2, 4, 8, 12, and 24 weeks. At each time point, 4 rabbits were humanely killed, and the implants with surrounding bone were removed, fixed, and sectioned for light and SEM studies. The degree of osseointegration was quantitated by means of a True Grid Digitizing Pad and Jandel Scan Version 3.9 software on an IBM PS/2 computer. The total pore area occupied by bone was divided by the total pore area available for bone ingrowth, and a Bone Ingrowth Factor (BIF) was calculated as a percent. The light microscopic results showed BIFs of 4% at week 2, 47% at week 4, 62% at week 8, 84% at week 12, and greater than 90% at week 24. The SEM results showed BIFs of 5% at week 2, 34% at week 4, 69% at week 8, 75% at week 12, and in excess of 90% at week 24. The results of this study show that EDC implants are biocompatible and support rapid osseointegration in the rabbit tibia and suggest that, after additional studies, they may be suitable for use as dental implants in humans. PMID- 8699523 TI - A maxillary subperiosteal implant design that maximizes bone support and accomodates a cemented, low-profile parallel guiding planes Hader bar. AB - A design for the maxillary subperiosteal implant is detailed that (1) simplifies construction, (2) maximizes underlying bone support, (3) minimizes posterior forces to the "egg-shell"-thin bone under the maxillary sinuses, and 4 (accommodates the low-profile, cemented, parallel guiding planes Hader bar. This implant design maximizes bony support for the maxillary overdenture. It places the Hader bar superstructure within a precise envelope that maximizes esthetics, proper phonetics, and acrylic bulk for long-term serviceability. PMID- 8699524 TI - Treatment of a microvascular reconstructed mandible using an implant-supported overdenture: case report. AB - Oral rehabilitation of patients with mandibular discontinuity defects is a challenging problem facing both the surgeon and the dentist. Advances in microvascular surgery have provided the surgeon with methods to repair the partially resected mandible with vital bone grafts. Often, however, reconstruction of the bony defect alone does not guarantee an adequate foundation for successful conventional prosthetic rehabilitation. Osseointegrated implants placed into the microvascularized grafted bone offer an opportunity for improved function and patient satisfaction. The following case presentation reports the use of an implant-supported overdenture in a vascularized iliac bone graft to reconstruct a partially resected mandible. PMID- 8699525 TI - Pilot-hole preparation for proper implant positioning and the enhancement of bone formation. AB - We have demonstrated a new insertion technique, "pilot-hole preparation", for proper implant positioning. The purpose of this study was to investigate the histological and biomechanical efficacies of the technique. We analyzed the influence of implant position on the stress distribution to the bone by the two dimensional finite element method (FEM). In addition, we studied the influence of the pre-operative pilot-hole preparation on the bone tissue in vivo using histological examination. PMID- 8699526 TI - T cell receptor peptides in treatment of autoimmune disease: rationale and potential. AB - The natural tendency in T cell-mediated autoimmune conditions to develop focused antigen-specific responses that over-utilize certain T cell receptor (TCR) V region segments prompts the induction of anti-TCR-specific T cells and antibodies that can inhibit the pathogenic T cells and promote recovery from disease. This natural regulatory network can be manipulated by injecting synthetic peptide vaccines that correspond to segments of the over-expressed V genes. In experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis (MS), the pathogenic T cells are directed at myelin components, including basic protein (MBP). In some strains such as the Lewis rat and the PL/J mouse, the encephalitogenic BP-specific T cells overexpress a particular V region gene (V beta 8.2) in the TCR. In vivo administration of V beta 8.2 peptides in rats or mice can prevent and treat EAE by boosting regulatory anti-V beta 8.2-specific T cells that inhibit but do not delete the encephalitogenic specificities. This regulation is mediated by soluble factors, suggesting that the presence of regulatory TCR-specific T cells within the target organ (the central nervous system) may inhibit not only the stimulating V beta 8.2 + T cells, but also bystander T cells bearing different V genes. Parallel studies in MS patients have revealed striking V gene biases among BP-specific T cell clones from some patients that provided a rationale for TCR peptide therapy. Injection of V beta 5.2 and V beta 6.1 peptides boosted the frequency of TCR peptide-specific T cells and reduced responses to BP, in some cases with clinical benefit, indicating the presence of an anti-TCR regulatory network in humans that may also be manipulated with TCR peptide therapy. PMID- 8699527 TI - STAT proteins are activated by ciliary neurotrophic factor in cells of central nervous system origin. AB - Neuropoietic cytokines, including ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF), have survival effects on cells of the peripheral and central nervous systems (PNS and CNS). CNTF and LIF also produce differentiation in some cells of the PNS. We have shown previously that CNTF activates the signal transducers and activators of transcription (STAT) family of transcription factors, and that this signaling pathway may be one of several employed by CNTF to regulate the expression of the vasoactive intestinal peptide (VIP) gene in cells of the PNS (Symes et al.: Proc Natl Acad Sci USA 90:572-576, 1993; Symes et al.: Mol Endocrinol 8:1750-1763, 1994). To investigate the mechanisms of action of CNTF in the CNS, we have analyzed the activation of STAT proteins in a septal derived cell line, SN48, and in primary CNS cultures. CNTF treatment of SN48 cells produces a sustained activation of Stat3. CNTF treatment of SN48 cells also activated transcription mediated by the VIP cytokine responsive element (CyRE) which contains a STAT binding site. Mutation of the STAT site in the CyRE attenuated transcriptional activation by CNTF, indicating the importance of STAT proteins to CNTF-dependent transcriptional activation of SN48 cells. In cultures of embryonic rat septum and other brain areas, in addition to Stat3, CNTF also activates Stat1. As in cells of the PNS and non-neuronal cells, the Janus kinase (Jak)-STAT pathway is activated in CNS cells by cytokines. The SN48 cell line may be valuable in further characterization of regulation of the Jak-STAT pathway by neuropoietic cytokines. PMID- 8699528 TI - Assembly of microfilaments and microtubules from axonally transported actin and tubulin after axotomy. AB - The slow component (SC) of axonal transport conveys structural proteins, regulatory proteins, and glycolytic enzymes toward the axon tip at 1-6 mm/day. Following axon interruption (axotomy), the rate of outgrowth corresponds to the rate of SCb-the fastest subcomponent of SC. Both axonal outgrowth and SCb accelerate 20-25% after axotomy. Tubulin and actin are the major proteins being carried by SCb. To further characterize the acceleration of SCb, we measured the equilibrium between subunits and polymers for both actin and tubulin. We radiolabeled newly synthesized proteins in rat motor neurons by microinjecting [35S]methionine into the spinal cord 7 days after crushing the sciatic nerve (85 mm from the spinal cord). Nerves were removed 7 days later for homogenization in polymer-stabilizing buffer (PSB) and centrifugation, followed by SDS-PAGE of supernatants (S) and pellets (P). We removed beta-tubulin, actin, and the medium weight neurofilament protein (NF-M) from each gel by using the fluorogram as a template. After solubilizing gel segments for liquid scintillation spectrometry, we expressed counts as a polymerization ratio: P/[S+P]. In the nerve segments that contained radiolabeled Scb proteins, located 24-36 mm from the spinal cord, axotomy increased the polymerization ratio of SCb actin from 0.23 to 0.36 (P < 0.05) but had no effect on SCb beta-tubulin. In a separate experiment, we added 12 microM taxol to PSB to stabilize newly assembled microtubules. Adding taxol did not alter the polymerization ratio for SCb beta-tubulin in sham-axotomized nerves but aid increase the ratio in axotomized nerves, from 0.44 to 0.63 (P < 0.05); polymerization ratios for SCb actin were unaffected. We conclude that the assembly of microfilaments and microtubules increases to provide cytoskeletal elements for axon sprouts. The resulting loss of actin and tubulin subunits may play a role in the acceleration of SCb. PMID- 8699529 TI - Distinct effects of recombinant tenascin-C domains on neuronal cell adhesion, growth cone guidance, and neuronal polarity. AB - Using a set of recombinantly expressed proteins, distinct domains of the mouse extracellular matrix glycoprotein tenascin-C, hereafter called tenascin, have been identified to confer adhesion, anti-adhesion, and changes in morphology of neuronal cells. In short-term adhesion assays (1 hr), cerebellar and hippocampal neurons adhered to several domains, encompassing the fibronectin type III-like (FN III) repeats 1-2 and 6-8, as well as to the alternatively spliced FN III repeats and to tenascin itself. Although no short-term adhesion to the EGF repeats containing fragment could be detected under the conditions used, it was anti-adhesive for neuronal cell bodies and repellent for growth cone advance and neuritogenesis. FN III repeats 3-5 were repellent only for growth cones but not for neuronal cell bodies. Neurite outgrowth promoting activities at early stages and induction of a polarized neuronal morphology at later stages of differentiation were associated with the EGF repeats and the FN III repeats 6-8. These observations suggest differential effects of particular domains of the tenascin molecule on distinct cellular compartments, i.e., cell body, axon and dendrite, and existence of multiple neuronal receptors with distinct intracellular signaling features. PMID- 8699530 TI - Dopamine receptors mediate differential morphological effects on cerebral cortical neurons in vitro. AB - A morphogenic role of neurotransmitters during cellular differentiation in vitro has been demonstrated in recent years. Using in situ hybridization, we confirm the presence of the D1 receptor at E16 and show additionally that the transcript is relatively widespread and present in both proliferative and differentiating areas of the cerebral wall. Because DA receptor expression precedes the arrival of presynaptic terminals during forebrain development, we examined the role of DA in cerebral cortical neuron differentiation in vitro, using immunohistochemical markers of dendrites, microtubule-associated-membrane protein 2 (MAP2) and axons, neurofilament protein (NF-H). Neurite length, cell size, and cell viability in response to D1 and D2 receptor agonists SKF38393 and quinpirole, respectively, and to DA were analyzed in neurons obtained from embryonic (E) day 16 rats. We have shown that 1) paradoxically, DA at different concentrations can either stimulate or inhibit neurite outgrowth; 2) there is a bimodal pattern of DA induced axonal outgrowth, i.e., at low and high doses; 3) D2 receptor activation induces neurite outgrowth while D1 receptor activation is inhibitory; 4) D2 mediated neurite elongation is preferentially axonal while D1 receptor activation reduces both axonal and dendritic outgrowth; 5) low doses of DA promote the expression of cytoskeletal components of axonal maturation; and 6) D1 receptor activation decreases neuronal size. We suggest that DA may influence cellular differentiation and circuitry formation early in development of the cerebral cortex through receptor-mediated effects on process outgrowth, which could lead to effects on circuit formation. PMID- 8699532 TI - Removal of serum from primary cultures of cerebellar granule neurons induces oxidative stress and DNA fragmentation: protection with antioxidants and glutamate receptor antagonists. AB - Cerebellar granule neurons undergo apoptosis when deprived of chronic depolarization; serum deprivation has not been considered as a trigger of apoptosis in this culture. Here we report that serum removal triggers cell injury, which is characterized by signs of apoptosis. Actual cell death (trypan blue permeability) occurred 24 and 48 hr after serum removal. At earlier times (6 and 8 hr after serum removal) we found significant impairment of mitochondrial functioning [3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay] and an increase in the percentage of neurons showing signs of DNA fragmentation (insitu terminal deoxynucleotidyl transferase assay, fluorescent assay). Protection was obtained by inhibiting RNA synthesis with actinomycin D and by antioxidants [1mM: 1,4-diazobicyclo(2.2.2)octane, histidine, mannitol; 1% dimethyl sulfoxide; 0.01-1 microM ascorbic acid]. We also measured neuronal oxidation utilizing the oxidation-sensitive fluorescent dye 2', 7'-dichloro- fluorescin diacetate, and found a significant increase in the rate of neuronal oxidation as early as 15 min after serum deprivation. The blockade of glutamate receptors by (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801) and 6-cyano-7-nitroquinoxaline-2,3-dione also provided neuroprotection. However, oxidative stress appears to precede glutamate receptor activation: within the 8 hr period of serum deprivation, mannitol was protective when present either during only the first or last 4 hr; MK-801 was protective only when present for the entire 8 hr period or in the last, but not first 4 hr of serum deprivation. Serum deprivation of mature cerebellar granule neurons can be used to study mechanisms of oxidative stress-induced apoptosis. PMID- 8699531 TI - Transforming growth factor-beta 3, glial cell line-derived neurotrophic factor, and fibroblast growth factor-2, act in different manners to promote motoneuron survival in vitro. AB - Developing chick motoneurons depend on as yet unidentified factors from the periphery and the central nervous system for their survival. Using cultures of purified embryonic motoneurons, we show that basic fibroblast growth factor (FGF 2) or transforming growth factor-beta 3 (TGF beta 3) each have only low survival promoting activity when tested alone, but act synergistically to keep motoneurons alive for at least 3 days. Glial cell line-derived neurotrophic factor (GDNF), another member of the TGF beta family, was itself sufficient to maintain a population of motoneurons. However, its effect was not significantly increased by the addition of FGF-2. These results suggest that FGF-2, TGF beta 3, and GDNF, which are all present in the environment of developing motoneurons, may act different mechanisms as physiological survival factors for this population of central neurons. PMID- 8699533 TI - Dopamine-stimulated changes in activated calpain I in rat hippocampal slices. AB - Activated calpain I immunoreactivity (76 kDa band) was detected in membranes prepared from rat brain hippocampal slices using a polyclonal antiserum raised against an N-terminus peptide of the cleaved subunit of calpain I. While basal levels of activated calpain I were stable over incubation times, 1 nM dopamine (DA) produced an initial 32% increase (5 min) in the 76 kDa protein followed by a 53% decrease in this band at 20 min of incubation. The DA-induced changes in activated calpain I immunoreactivity were blocked by the calpain inhibitor peptide, N-acetyl-Leu-Leu-norleucinal(100 microM) or by EGTA. Basal levels of the 76 kDa band were not affected by the calpain inhibitor. These changes in activated calpain I, elicited by DA, are in accord with the DA-induced decreases in the levels of the calpain substrate, gamma PKC (Yurko-Mauro and Friedman; J Cell Biochem [Abstr] 180:80, 1994; J Neurochem 65: 1622-1630, 1995) and suggest that DA activates this Ca(++)-dependent protease in its regulation of neuronal signal transduction. PMID- 8699534 TI - Immunohistochemical evidence of neuroprotection by R(-)-deprenyl and N-(2-hexyl) N-methylpropargylamine on DSP-4-induced degeneration of rat brain noradrenergic axons and terminals. AB - DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] is a potent neurotoxin highly selective to the locus coeruleus noradrenaline (NA) system. Previous biochemical studies have shown that the monoamine oxidase-B (MAO-B) inhibitors, R(-)-deprenyl and (+/-)2-HxMP [N-(2-hexyl)-N-methylpropargylamine], are able to prevent DSP-4 induced NA depletion in the mouse hippocampus. It is not quite certain, however, whether this actually represents neuroprotection of NA axons or a metabolic effect due to inhibition of MAO activity. Employing dopamine-beta hydroxylase immunohistochemical and image analysis methods, we have shown that 92% and 84% of NA nerve fibers in the rat hippocampus are spared from DSP-4 neurotoxicity by a single pretreatment dose of either R(-)-deprenyl or (+/-)2 HxMP respectively. Similar neuroprotective effects of R(-)-deprenyl and (+/-)2 HxMP were also observed in the cerebral cortex, thalamus, amygdaloid complex and cerebellum. This is the first morphological evidence demonstrating that R(-) deprenyl and (+/-)2-HxMP can indeed protect noradrenergic axons of locus coeruleus origin against DSP-4 neurotoxicity. PMID- 8699536 TI - Vasoactive intestinal peptide: mediator of laminin synthesis in cultured Schwann cells. AB - To learn more about neuropeptide-induced glial responses which accompany axon regeneration, we studied effects of VIP on laminin production by cultured Schwann cells. Schwann cells were isolated from sciatic nerves of neonatal mice, purified, and incubated for 5 days in either control medium (DMEM + 15% FCS) or control medium containing 10-7 -10-11 M VIP. At 10-7 and 10-8 M VIP, laminin levels measured by enzyme-linked immunosorbent assay were significantly higher (55% and 35%) than those in control cultures. Lower VIP concentrations (10-9 -10 11 M) produced smaller increases which were not significant. Low-affinity VIP receptors which mediated this effect were demonstrated on Schwann cells by radioligand binding studies. The increased Schwann cell synthesis of laminin induced by VIP was blocked when either a VIP antagonist or a VIP receptor antagonist was added to the VIP-containing incubation medium. In contrast to astrocytes, when Schwann cells were loaded with fura-2, VIP did not increase cytosolic Ca2+. This indicates that Schwann cells and astrocytes may have different intracellular transduction pathways; their receptor subtypes also may differ. We suggest that the VIP-induced increase in laminin synthesis which we have observed in cultured Schwann cells may also occur in vivo and might be an important component of axon-Schwann cell interactions during nerve regeneration. PMID- 8699535 TI - Characterization of L-DOPA transport in cultured rat and mouse astrocytes. AB - The present work studied the transport of L-DOPA in cultured rat and mouse astrocytes. Results indicated that the uptake of L-[14C]DOPA in both rat and mouse astrocytes was Na+ independent and temperature sensitive. It was mediated by a carrier-mediated mechanism with Km values of 36 and 60.3 microM, and V(max) values of 2.4 and 1.9 nmol/min/mg protein for rat and mouse cells, respectively. L-DOPA uptake was potently inhibited by aromatic or branched-chain amino acids. Interestingly, the release of intracellular L-[14C]DOPA was also trans stimulated by competitors that affect L-DOPA uptake. The 14C recovered in the 2-min uptake process was identified as L-[14C]DOPA. However, [14C]dopamine (DA) was also detected in both rat and mouse astrocytes after 30 min L-DOPA incubation, indicating the existence of aromatic L-amino acid decarboxylase (AADC). Taken together, L-DOPA was uphill transported into rat and mouse astrocytes by a (Na+) independent exchanger with preference for aromatic and branched-chain amino acids. Rat astrocytes possessed higher affinity for L-DOPA uptake than mouse astrocytes. Both cells synthesized DA from exogenous L-DOPA. Thus, astrocytes serve not only as a temporary storage site for L-DOPA but also as a DA-producing machinery. These results may be of particular importance to parkinsonian patients under L-DOPA medication. PMID- 8699537 TI - Different mechanisms of glutamate-induced neuronal death between dopaminergic and non-dopaminergic neurons in rat mesencephalic culture. AB - Parkinson's disease is characterized by dopaminergic neuronal degeneration, but its pathogenic mechanism is still unknown. In the dopaminergic neurons, oxygen radicals such as hydrogen peroxide are released through dopamine oxidation. Many factors are involved in radical formation, but glutamate and nitric oxide (NO) are the major effectors of the radical-induced neurotoxicity mediated primarily through calcium influx. In the cultured embryonic rat mesencephalon, we investigated the dopaminergic and non-dopaminergic neuronal death induced by glutamate and by NO-generating agents. Although glutamate had a neurotoxic effect on both dopaminergic and non-dopaminergic neurons, it showed slightly greater effect in the dopaminergic neurons. In contrast to glutamate, NO-generating agents (S-nitrosocysteine and sodium nitroprusside) showed neurotoxic effects restricted exclusively to non-dopaminergic neurons. Although N omega-nitro-L arginine, and NO synthase inhibitor, had no significant effect on the glutamate induced cytotoxicity in dopaminergic neurons, it had a significant antagonistic effect on that in non-dopaminergic neurons. These findings indicate the presence of two different mechanisms of glutamate-induced neuronal death, one being neurotoxicity not mediated by NO, found in dopaminergic neurons, and the other being that mediated via NO, found in non-dopaminergic neurons. PMID- 8699539 TI - Community mobile treatment. What it is and how it works. AB - In 1984, Paul Hanki of Prince George, British Columbia, Canada, developed community mobile treatment, an innovative approach to substance abuse treatment in Native communities. The feature that distinguishes community mobile treatment from most other forms of treatment is the strong emphasis on community involvement. Before an actual treatment program is implemented, the community must acknowledge that a substance abuse problem exists and be committed and involved in addressing the problem. Once a community is mobilized, a 21 to 28 day intensive alcohol and drug treatment program for substance abusers and their families is brought into the community. Since its inception in 1984, community mobile treatment has been implemented in approximately 17 Canadian communities. The few evaluations that have been conducted suggest that this approach holds much promise in reducing alcohol and drug-related problems. This article reviews the existing documentation and provides a comprehensive description of this unique approach. PMID- 8699538 TI - Group cognitive-behavioral therapy for women with PTSD and substance use disorder. AB - This paper describes a model of group cognitive-behavioral therapy (CBT) for women with posttraumatic stress disorder (PTSD) and substance use disorder (SUD). The need for specialized treatment derives from the high incidence of these comorbid disorders among women as well as from their particular clinical presentation and treatment needs. The treatment educates patients about the two disorders, promotes self-control skills to manage overwhelming affects, teaches functional behaviors that may have deteriorated as a result of the disorders, and provides relapse prevention training. The program draws on educational principles to make it accessible for this population: visual aids, education for the patient role, teaching for generalization, emphasis on structured treatment, testing of acquired knowledge of CBT, affectively engaging themes and materials, and memory enhancement devices. PMID- 8699541 TI - Group intervention with pre-recovery patients. AB - This article examines treatment outcomes of alcohol and drug abusing patients admitted to a university-based alcohol and drug outpatient clinic. Treatment effectiveness of two treatment models were evaluated. The psycho-educational approach utilized a teacher-student model with the goal of imparting information about drugs and consequences of use. The recovery-oriented approach utilized a patient-counselor collaborative model where patients were encouraged to be active in progressing through sequential stages of pre-recovery tasks. Patients in the psycho-education group stayed in treatment longer and were more likely to rate treatment as useful. Results showed minimal differences between the two groups in terms of Addiction Severity Index scores, Drug Attitude, and urine drug screen results. PMID- 8699540 TI - Psychosocial treatments for cocaine abuse. 12-month treatment outcomes. AB - The 12-month posttreatment outcome results for a randomized clinical trial that tested the effectiveness of various combinations of 4-month psychosocial treatment interventions are reported for 184 clients who used cocaine. Clients primarily used crack (93%), and the majority were African American (95%). Overall, clients exhibited substantial pre-post treatment gains: reduced regular cocaine use, reduced other drug use, reduced regular alcohol use, and reduced involvement in illegal activities. Logistic regression models produced significant odds ratios showing that those who used cocaine regularly during the year after treatment were more likely to have attended fewer treatment sessions, to be female, to be less educated, to have been regular cocaine users prior to treatment, and to have spent fewer days incarcerated during the 12-months after treatment. It was concluded that treatment positively impacted posttreatment gains, and it was suggested that selective tailoring of additional treatment services may produce additional treatment gains. PMID- 8699542 TI - Preferences for clinic privileges, retail items and social activities in an outpatient buprenorphine treatment program. AB - This study evaluated preferences for various clinic privileges, retail items, and social activities for use in an outpatient opioid dependence treatment program. Fifty-three opioid-dependent patients who received treatment with buprenorphine for at least 30 days rank ordered 11 clinic privileges, 19 retail items, and 8 social activities from the most desirable (a rank of 1) to the least desirable (a rank equal to the number of items in that category). Additional questions determined preference for counseling frequency and dosing levels. The top three mean rankings for clinic privileges were $50 cash for opioid-negative urines (2.8), take-home doses of buprenorphine (3.6), and voucher points for opioid negative urines (4.7). The top three mean rankings for retail items were restaurant gift certificates (4.1), movie passes (4.9), and videotape movie and player rentals (6.8). The top three mean rankings for social activities were movies (2.4), barbecues (3.8), and hiking trips (4.3). There was no preference reported for increases or decreases in counseling frequency. Seventy-four percent of subjects preferred to increase their buprenorphine dose by an average of 60.84% independent of their present dose. Consistent with previous findings from methadone treatment, cash payments for opioid-negative urines and take-home medication were the highest ranked clinic privileges. These results suggest that various retail items and social activities may also be useful for reinforcing positive treatment outcomes during outpatient opioid treatment. PMID- 8699543 TI - Women in recovery. Their perceptions of treatment effectiveness. AB - Research with chemically dependent women over the past two decades indicates that women substance abusers have special characteristics and needs that warrant gender-sensitive drug-treatment approaches. While the potential benefit of such treatment seems clear, little empirical data is available on how women perceive the effectiveness of gender-sensitive specialized drug treatment. This article presents findings from an exploratory study of the present and past treatment experiences of 24 women in recovery. Results indicate that while some specialized services such as child care and women-only therapy groups are increasingly available, many drug-treatment programs fail to provide these services in a context which supports and promotes women. As a result, women in drug treatment continue to experience negative stereotyping and sexual harassment as their gender-specific needs remain ignored, silenced, or deemed pathological. Major gaps in drug treatment for women are discussed as are implications for the provision of effective gender-sensitive treatment. PMID- 8699544 TI - The effect of anxiety and depression on completion/withdrawal status in patients admitted to substance abuse detoxification program. AB - A large proportion of patients entering substance abuse treatment carry psychiatric diagnoses, and some studies have found that those with psychopathology are more likely to withdraw before treatment is completed. We performed a prospective study of patients entering an inpatient substance abuse detoxification program to determine if the degree of anxiety and/or depression correlated with higher dropout rates. On entry to the unit, all patients were administered the Hamilton Rating Scales for Depression and Anxiety. Of the 148 patients studied, 97 (65.5%) completed treatment and 51 (34.5%) withdrew prematurely. There were no significant differences in Hamilton Depression and Anxiety Rating Scale scores between completers and withdrawers. This was true for the total study population, as well as for subgroups of patients based on primary drug abused (heroin or cocaine). Although anxiety and depression are common in substance abusers, we were unable to detect differences on validated anxiety and depression rating scales between those completing and those withdrawing from substance abuse detoxification. PMID- 8699545 TI - A retrospective study of the concept of spirituality as understood by recovering individuals. AB - In 62 individuals recovering from substance abuse, materialism and spiritualism and cognitive patterns were quantified, before (retrospectively) and after recovery with the Mathew Materialism Spiritualism Scale (MMSS) and a Cognitive Patterns Questionnaire (CPQ). MMSS was also administered once to 61 general controls. Recovering individuals showed highly significant prerecovery to postrecovery increases in spirituality on most subscales of MMSS and changes in cognitive patterns. Sixteen controls who met the criteria for alcoholism on the Michigan Alcoholism Screening Test (MAST-positive) were separated from the others. Prerecovery MMSS scores did not differentiate the recovering individuals from MAST-positive controls. However, the prerecovery MMSS scores obtained by recovering individuals were significantly lower than the scores obtained by the MAST-negative controls. On the other hand, after recovery, recovering individuals showed higher MMSS spirituality scores in comparison to MAST-positive controls. The only MMSS item that differentiated recovering individuals after recovery from MAST-negative controls was mysticism with the recovering group obtaining higher scores. PMID- 8699546 TI - Recovering substance abuse staff members' beliefs about addiction. AB - This study of 329 substance abuse treatment staff assessed how recovery status, in combination with other variables, influences beliefs about the causes and treatment of substance abuse. About 15% (n = 47) of participants were "in recovery" from substance abuse problems; these staff members were not significantly different than nonrecovering staff members on education, age, race/ethnicity, years of clinical experience, or amount of client contact. When examined in a multiple regression equation that also included age, education, and treatment program goals and activities, staff members' recovery status was not associated with endorsement of disease and psychosocial models of substance abuse. However, being in recovery was associated with endorsing an eclectic approach to substance abuse treatment. The importance of recognizing the diversity of beliefs about substance abuse among recovering staff and of acknowledging that multiple influences affect all staff members viewpoints on treatment is discussed. PMID- 8699547 TI - Compulsory supervision and methadone maintenance. AB - Treatment outcomes of 296 subjects admitted to methadone maintenance while on probation or parole are compared to those of 314 subjects admitted without such compulsory supervision. Equivalent treatment services were offered to both groups. The pretreatment differences between groups were small except for time incarcerated. All subjects were followed for one year. The compulsory supervision group had worse outcomes with respect to retention, productive activity, and incarceration. The differences were small except for incarceration. The mean number of months incarcerated was 2.1 for the compulsory supervision group and 0.7 for the voluntary group. Of subjects discharged from treatment, a higher percentage of the compulsory supervision group was discharged because of incarceration, but a higher percentage of the voluntary group was discharged for noncompliance with program requirements. The findings do not support a policy of exclusion of opioid users from methadone maintenance because they are on probation or parole. PMID- 8699548 TI - Benefits of extracorporeal membrane oxygenation for hydrocarbon pneumonitis. AB - OBJECTIVE: To review the therapeutic benefits of extracorporeal membrane oxygenation for the management of hydrocarbon pneumonitis. METHODS: A search of the medical literature was conducted through Medline and the bibliographies of relevant articles and a search of patient databases maintained by the Extracorporeal Life Support Organization and the American Association of Poison Control Centers was performed. All articles and case reports on the use of extracorporeal membrane oxygenation in patients with hydrocarbon pneumonitis were selected. The data were abstracted without judgments about study design. RESULTS: There is some evidence that pulmonary parenchymal tissue can recover from hydrocarbon pneumonitis, but the degree of injury and recovery are variable. In the Extracorporeal Life Support Organization Registry 19 children with hydrocarbon pneumonitis were treated with extracorporeal membrane oxygenation during 1985 to 1994 and 68% survived compared to the 52% overall survival of 883 pediatric cases who had a diagnosis of a respiratory condition. A review of the American Association of Poison Control Centers data for 1993 and 1994 identified five cases of hydrocarbon pneumonitis in which extracorporeal membrane oxygenation was used and two survived. There are two full case descriptions in the literature with both children surviving, but one child developed persistent moderate left hemiparesis and seizure activity. CONCLUSIONS: The need for extracorporeal membrane oxygenation is rare owing to the generally good outcome of most cases of hydrocarbon ingestions and pneumonitis. Only with further research on the nature and clinical course of severe hydrocarbon pneumonitis, refinement of extracorporeal membrane oxygenation criteria, and evaluation of alternative therapies, will the benefits of extracorporeal membrane oxygenation be better defined. PMID- 8699549 TI - Risks of extracorporeal membrane oxygenation: is there a role for use in the management of the acutely poisoned patient? AB - OBJECTIVE: To review the use of extracorporeal membrane oxygenation in the support of poisoned patients and provide a basis for comparison to other methods of respiratory support for these patients. METHODS: The medical literature was reviewed and selected cases of poisoning supported by extracorporeal membrane oxygenation and mechanical ventilation highlighted. Data from published outcome studies were reviewed. All cases found were included in the database. Case experiences were critiqued based on available clinical literature. Outcome studies were critiqued with respect to relevancy and bias. Many cases do not provide strong evidence of direct patient benefit. There are no data to support an improvement in outcome among poisoned patients. CONCLUSION: The use of extracorporeal membrane oxygenation for respiratory failure following ingestion has the same limited indications as for other patients with respiratory failure. Data supporting an improvement in outcome are not available. Extracorporeal membrane oxygenation support for reversible cardiac toxicity has a sound basis but clinical experience is limited. Good supportive care for the poisoned patient is essential before considering extracorporeal membrane oxygenation. PMID- 8699550 TI - 4-Methylpyrazole and hemodialysis in ethylene glycol poisoning. AB - CASE REPORTS: Two patients severely intoxicated with ethylene glycol became anuric and were treated by hemodialysis and the antidote, 4-methylpyrazole. On admission, their plasma ethylene glycol concentrations were 0.42 and 3 g/L respectively and no alcohol was detected. The elimination of 4-methylpyrazole in the dialysate represented 45% of the total body elimination. Clearances of 4 methylpyrazole by hemodialysis were 80 mL/min and 52 mL/min respectively. RESULTS: In such cases, the authors propose infusion of a 4-methylpyrazole loading dose of 10-20 mg/kg before dialysis and intravenous infusion of 1-1.5 mg/kg/h during the 8-12 hours of hemodialysis to compensate the loss in dialysate. PMID- 8699551 TI - 4-Methylpyrazole--present status. PMID- 8699552 TI - Nasal pathology and ultrastructure in patients with chronic airway inflammation (RADS and RUDS) following an irritant exposure. AB - BACKGROUND: Reactive airways dysfunction syndrome is a chronic asthma-like condition developing after an acute irritant exposure, and chronic inflammation has been seen on endobronchial biopsy. Reactive upper-airways dysfunction syndrome is chronic rhinitis developing in temporal association with a toxic inhalation exposure, but the pathophysiology is unknown. OBJECTIVES: To study biopsies of the nasal mucosa in patients with reactive upper-airways dysfunction syndrome and in some cases reactive airways dysfunction syndrome developing in temporal association with a chlorine dioxide exposure, to see if a histologic basis for the persistent rhinitis and sensitivity to chemical irritants could be determined. METHODS: Specimens were stained with hematoxylin-eosin and immunoperoxidase stains for substance P, vasointestinal peptide, and S-100 (nerve fibers), and fixed in glutaraldehyde for electron microscopy. Biopsies of three nonexposed subjects were performed for comparison. A pathologist blinded to clinical data interpreted the specimens. RESULTS: Inflammation ratings of exposed individuals were higher than for the nonexposed individuals. The number of nerve fibers stained was greater for patients vs controls. Substance P and vasointestinal peptide staining was nonspecific. Electron microscopy showed desquamation of the epithelium and permeability of epithelial cell junctions. CONCLUSION: This study suggests a mechanism by which ongoing low level exposures perpetuate airway inflammation after an inducing toxic inhalation. A possible overlap between reactive airways dysfunction syndrome, reactive upper-airway dysfunction syndrome and the multiple chemical sensitivity syndrome is suggested. PMID- 8699553 TI - Pharmacokinetics of hydroxocobalamin in smoke inhalation victims. AB - OBJECTIVE: Hydroxocobalamin has been proposed as a cyanide antidote. Little is known, however, about its pharmacokinetics in human cyanide poisoning. METHODS: We prospectively studied the pharmacokinetics of hydroxocobalamin in 11 smoke inhalation victims of whom all but one had objective evidence of cyanide exposure. Serum hydroxocobalamin levels were followed from just before drug administration to six days after a single 5 g dose of hydroxocobalamin. RESULTS: The results (mean +/- standard error) suggest a two compartment model. Distribution half-life is on the order of 1.86 +/- 0.34 h and the elimination half-life 26.2 +/- 2.7 h. The apparent volume of distribution is 0.45 +/- 0.03 L/kg. Renal and total body clearance are 0.31 +/- 0.06 and 0.83 +/- 0.07 L/h, respectively. CONCLUSION: The apparent volume of distribution suggests a predominantly extracellular partitioning of the antidote, even in the presence of cyanide, an important factor in terms of its antidotal effect. Hydroxocobalamin's elimination half-life in these cyanide-exposed patients far exceeds those found in previous studies of dogs and minimally-exposed humans. If confirmed, this half life suggests that a single dose of hydroxocobalamin, sufficiently large enough to bind the cyanide present, should be adequate. PMID- 8699554 TI - Retrospective study of mistletoe ingestion. AB - BACKGROUND: There are limited data concerning accidental exposure to Phoradendron flavescens (Phoradendron serotinum, American Mistletoe). The only published reports include a review of 14 cases which revealed no symptoms and a single fatality from an intentional ingestion of an unknown amount of an elixir brewed from the berries. The risk of serious toxicity from accidental exposure to this plant appears to be minimal, yet it continues to be regarded as a dangerous plant. We reviewed charts for four years (1990-1993) from three poison centers where Phoradendron flavescens is indigenous. RESULTS: Ninety-two human cases were located. Age ranged from four months to 42 years, with a mean of six years (SD 8.8) and median of two years. There were 14 symptomatic cases of which 11 were determined to be related to mistletoe exposure. There were six gastrointestinal upset, two mild drowsiness, one eye irritation, one ataxia (21 months), one seizure (13 months). Treatments included gastrointestinal decontamination in 54 patients (59%), ocular irrigation in one and IV benzodiazepine in one. Decontamination did not appear to affect outcome. Amount ingested ranged from one berry or leaf to more than 20 berries or five leaves. In cases with a known amount ingested, eight of ten cases with > or = 5 berries remained symptom free. In the 11 cases with leaf-only ingestion (range 1-5 leaves), three patients had gastrointestinal upset. The one case with five leaves ingested remained asymptomatic. The infant with seizures was an unwitnessed exposure, found with both berries and leaves in the crib. No arrhythmias or cardiovascular changes were reported in any case. All symptomatic cases had onset of symptoms in < or = 6 hours. DISCUSSION: Symptoms are infrequent and in all but one case would not require direct medical supervision. Seizures have not previously been reported with Phoradendron flavescens exposure. CONCLUSION: Symptoms from Phoradendron flavescens exposure are infrequent, even with ingestion of 5-20 berries or 1-5 leaves, but may include seizures. Cardiovascular effects were not seen. PMID- 8699555 TI - Naloxone--for intoxications with intravenous heroin and heroin mixtures--harmless or hazardous? A prospective clinical study. AB - BACKGROUND: Naloxone is standard medication for the treatment of heroin intoxications. No large-scale studies have yet been carried out to determine its toxicity in heroin intoxications. METHODS: We have undertaken an investigation as to the frequency, type and degree of severity of complications attributable to naloxone administration. Subjects treated between 1991 and 1993 with naloxone for intravenous drug intoxications were prospectively evaluated. MAIN OUTCOME MEASUREMENTS: Development of ventricular tachycardia or fibrillation; atrial fibrillation; asystole; pulmonary edema; convulsions; vomiting; and violent behavior within ten minutes after parenteral administration of naloxone. RESULTS: Six of 453 intoxicated subjects (1.3%; 95% confidence interval 0.4%-3%) suffered severe adverse effects within ten minutes after naloxone administration (one asystole; three generalized convulsions; one pulmonary edema; and one violent behavior). After the ten minute period, no further complications were observed. CONCLUSIONS: The short time between naloxone administration and the occurrence of complications, as well as the type of complications, are strong evidence of a causal link. In 1000 clinically diagnosed intoxications with heroin or heroin mixtures, from 4 to 30 serious complications can be expected. Such a high incidence of complications is unacceptable and could theoretically be reduced by artificial respiration with a bag valve device (hyperventilation) as well as by administering naloxone in minimal divided doses, injected slowly. PMID- 8699557 TI - Blood lead of intravenous drug users. AB - OBJECTIVE: A common method of illegal methamphetamine production uses lead acetate as a reagent. Production errors may result in methamphetamine grossly contaminated with lead. Three reports have documented outbreaks of acute lead poisoning in intravenous methamphetamine users. METHODS: This study measured blood lead concentrations in intravenous drug users of methamphetamine, cocaine or heroin presenting to the emergency department to determine the prevalence of subclinical lead poisoning in intravenous methamphetamine users. RESULTS: Mean blood leads for methamphetamine users (n = 92) were 6.22 micrograms/dL or 0.30 mumol/L (range 0.10-1.15, SD 0.20) and 7.25 micrograms/dL or 0.35 mumol/L (0.10 0.80, SD 0.15) for the nonmethamphetamine users (n = 53) with no significant difference between groups. CONCLUSIONS: The data suggest that previous outbreaks of acute intravenous lead poisoning among methamphetamine users were probably related to episodic contamination of methamphetamine. Subclinical lead poisoning was not found among the methamphetamine users presenting to the emergency department. PMID- 8699556 TI - Lead poisoning associated with the use of Ayurvedic metal-mineral tonics. AB - OBJECTIVE: The aim of this study was to confirm the connection between lead poisoning and the use of traditional Ayurvedic metal mineral tonics. METHODS: The study group comprised 29 subjects (26 adults and three children) who had previously taken Ayurvedic metal mineral tonics. All subjects were tested for lead absorption by blood lead, erythrocyte delta-aminolevulinic acid dehydratase activity and erythrocyte protoporphyrin. RESULTS: Eighteen samples of Ayurvedic preparations were obtained from 15 subjects and analyzed for lead content. Five adult subjects with established lead poisoning received chelation therapy. In Ayurvedic preparations a wide range of lead content was found (0.9-72,990 micrograms Pb/g; 0.35-29,900 micrograms Pb/capsule or tablet). The blood lead, erythrocyte delta-aminolevulinic acid dehydratase and erythrocyte protoporphyrin of the subjects, grouped according to the remedies used, correlated with the lead content in the preparations (p < 0.001). Chelation therapy was successful in normalization of laboratory findings and clinical recovery. CONCLUSION: Ayurvedic metal-mineral tonics are again identified as a potential source of high lead. The import of such tonics should be strictly controlled. PMID- 8699558 TI - Salicylism from topical salicylates: review of the literature. AB - BACKGROUND: Although topical salicylates are widely used, toxicity from this route is rare. CASE REPORT: We present an unusual case of salicylism from a topical salicylate preparation in an 80-year-old woman. The patient was admitted to the dermatology service with a diagnosis of erythroderma and was treated with salicylate containing ointments. After six days of treatment the patient became confused and paranoid. A serum salicylate was 3.36 mmol/L (46 mg/dL). The patient was admitted to the intensive care unit were she was rehydrated and treated with bicarbonate and activated charcoal. RESULTS: Her serum salicylate fell to 1.90 mmol/L (26 mg/dL) over a two day period and she regained a normal mental status. PMID- 8699559 TI - Gabapentin, valproic acid, and ethanol intoxication: elevated blood levels with mild clinical effects. AB - CASE REPORT: A suicidal, epileptic patient ingested ethanol, valproic acid, and gabapentin, a new antiepileptic drug. He did well clinically despite elevated blood gabapentin, valproic acid, and ethanol. CONCLUSIONS: Preliminary data from this case and one previous report indicate relatively mild clinical signs and symptoms with gabapentin poisoning. PMID- 8699560 TI - Herbicide: fatal ammonium thiocyanate and aminotriazole poisoning. AB - OBJECTIVE: To describe fatal herbicide poisoning with Radoxone TL composed of aminotriazole and ammonium thiocyanate. CASE REPORT: A 54-year-old man was hospitalized because of unexplained coma with myoclonic jerks and vascular collapse. Despite symptomatic treatment with mechanical ventilation and vascular filling, life-threatening shock occurred with oliguria, profound metabolic acidosis and cardiac arrest. Hyperchloremia (141 mmol/L) with reversed anion gap (-19) suggested interference with chloride measurement caused by halogens (Br,F,I) or other anions such as thiocyanate. Eventually a weed killer, Radoxone TL containing ammonium thiocyanate, was found at the patient's house. Thiocyanate and aminotriazole blood levels were 750 mg/L and 138 mg/L respectively more than 12 hours after ingestion. After prolonged cardiopulmonary resuscitation, continuous venovenous hemodiafiltration was performed. Despite hemodynamic recovery the patient died 48 hours later of postanoxic coma. CONCLUSION: Aminotriazole, a systemic nonselective herbicide, is often associated with ammonium thiocyanate which enhances its activity. Experimental studies and previous fatal cases suggest a predominant toxicity of thiocyanate. Early diagnosis is important. PMID- 8699561 TI - Intravenous thiodan (30% endosulfan in xylene). AB - OBJECTIVE: We report the first case of intravenous self-poisoning with Thiodan (30% endosulfan in xylene). CASE REPORT: A 28-year-old woman with a past history of epilepsy presented with refractory grand mal seizures after injecting 1 mL of Thiodan intravenously. She developed liver dysfunction, proximal myopathy secondary to rhabdomyolysis and renal failure. INTERVENTIONS AND OUTCOMES: The seizures were terminated with midazolam and thiopentone. Mechanical ventilation was required for nine days. Renal and liver dysfunction resolved with supportive measures only. Hemodialysis was not required. Pulmonary complications and neurological sequelae were minimal with the patient making a full recovery over three months. CONCLUSION: The intravenous adminis-tration of a small dose of endosulfan in xylene caused the rapid onset of severe grand mal seizures. The absence of pulmonary edema in this case suggests aspiration to be the cause of pulmonary toxicity due to oral endosulfan poisoning. PMID- 8699562 TI - Clinical course of severe poisoning with thiomersal. AB - CASE REPORT: A 44-year-old man ingested 83 mg/kg Thiomersal. He developed gastritis, renal tubular failure, dermatitis, gingivitis, delirium, coma, polyneuropathy and respiratory failure. Treatment was symptomatic plus gastric lavage and the oral chelating agents dimercaptopropane sulfonate and dimercaptosuccinic acid. The patient recovered completely. Maximum mercury concentrations were blood 14 mg/L, serum 1.7 mg/L, urine 10.7 mg/L, and cerebrospinal fluid 0.025 mg/L. Mercury concentration in blood declined with two velocities: first with half-time 2.2 days, then with half-time 40.5 days. The decline of mercury concentration in blood, urinary mercury excretion, and renal mercury clearance were not substantially influenced by chelation therapy. PMID- 8699563 TI - Hepatitis, rash and eosinophilia following trichloroethylene exposure: a case report and speculation on mechanistic similarity to halothane induced hepatitis. AB - CASE REPORT: A previously healthy 30-year-old male began work as a degreaser. The solvent used in the degreasing operation was trichloroethylene. Over the next month he experienced symptoms of weakness, dizziness, decreased appetite, nausea, abdominal pain, diarrhea, fever, chills, dry skin, red rash with bumps, peeling face, and itching. At that time he had marked liver enzyme elevation without evidence of cholestasis. CBC was remarkable for a significant number of atypical lymphocytes. Two weeks later his liver enzymes showed a marked reduction in ALT from a peak of 1250 IU to 717 IU. Tests for Hepatitis A, B, and C, CMV, HIV1 were all negative. The night following his first day back at work he had a recurrence of a red, diffuse rash without any consumption of alcohol. The rash caused tremendous itching. Over the next few days off work the rash continued and peeled. Physical examination one week after re-exposure was remarkable for diffuse, erythematous rash; some peeling skin and pitting edema to the knees. ALT was 517 IU/L. White blood cell count was 10,100/mm3 with 27% eosinophilia. CONCLUSION: This patient had possibly experienced sensitization to trichloroethylene, or more likely, to one of its metabolites. Similar symptoms attributed to trichloroethylene have been reported in only a few other patients. Patch testing with trichloroethylene and its metabolites may better clarify a causal relationship in future patients. If an immune mechanism is involved it may be similar to one postulated for halothane induced hepatitis. PMID- 8699565 TI - Suicide attempt by ingestion of potassium ferricyanide. PMID- 8699564 TI - Falsely elevated lithium levels in plasma samples obtained in lithium containing tubes. AB - CASE REPORT: We present a case of lithium poisoning in a 15-month-old child. Delayed elevation of the plasma lithium concentration at 13 hours after admission to a hospital was noted. This appeared to be factitiously related to the collection of samples in a speckled green top tube which contains lithium heparin as an anticoagulant. CONCLUSION: This type of false elevation has not been reported in the medical literature. A follow-up study in five healthy volunteers showed that the lithium concentrations of plasma samples obtained in speckled green top tubes are increased by approximately 1.5 mEq/L (1.5 mmol/L). PMID- 8699566 TI - Nicotine poisoning as a cause of cardiac arrest? PMID- 8699567 TI - [The investigation of the immunomodulatory effect of san-hwang-sei-sin-tang]. AB - San-Hwang-Sei-Sin-Tang is a famous ancient Kampo. In order to investigate the immunomodulatory effect of this Kampo, we can stimulate lymphocytes with PHA to study the lymphocyte transformation and IL-2 production as indicators of effect. In this study, we found that the extract of San-Hwang-Sei-Sin-Tang at the concentration of 0.1 mg/ml and 1 mg/ml could effectively inhibit the index of lymphocyte transformation. San-Hwang-Sei-Sin-Tang at the concentration of 0.01 mg/ml, 0.1 mg/ml and 1 mg/ml also have the tendency of inhibition of IL-2 production. In the future, San-Hwang-Sei-Sin-Tang may be developed as an effective immunosuppressant. PMID- 8699568 TI - [Gastric emptying in non-insulin dependent diabetic patients]. AB - Disordered gastrointestinal motility is an often overlooked clinical problem. Delayed gastric emptying of solid and/or liquid meal in patients with both type 1 and type 2 diabetes mellitus occurs in approximately 50% of these patients. Gastric emptying time (GET) was studied in seventy four non-insulin dependent (type 2) diabetic out-patients by using radionuclide gamma-photography with Tc 99m phytate solid experimental meal. Thirty nine of them received Tc-99m phytate liquid test meal on the next day. Forty six normal healthy volunteers acted as controls. The results showed that solid GET in patients with type 2 diabetes mellitus was significantly delayed (149.44 +/- 64.0 min) as compared with that in the control group (88.7 +/- 14.2 min) (p < 0.001). Fifty three among these 74 diabetic patients had delayed solid GET, accounting for 71.6%. Only 5 of 39 (12.8%) diabetic patients showed delayed liquid GET (average 38.7 +/- 35.3 min; control 46.2 +/- 11.1 min). There were no differences in sugar control, duration of the disease, and upper gastrointestinal symptoms between patients with delayed GET and those with normal GET. We concluded that delayed gastric emptying is very common in patients with non-insulin dependent diabetes mellitus and which has no direct correlation to blood sugar control, duration of the disease, and upper gastrointestinal symptoms. Radionuclide solid gastric emptying test is a both safe (low radioactivity) and convenient (non-invasive) diagnostic tool in non insulin dependent diabetic gastroparesis. PMID- 8699569 TI - [A study on survival rates of oral squamous cell carcinoma]. AB - Oral squamous cell carcinoma is seen predominantly after the fourth decade of life. We have retrospectively reviewed 103 patients (92 males and 11 females) with squamous cell carcinoma, which were confirmed by histopathologic examination and treated by surgical excision at Kaohsiung Medical College Hospital from 1987 to 1991. The age of the patients ranged from 23 to 87 years. 39.8% of cases occurred on the buccal mucosa, 27.2% on the tongue, 15.5% on the gingiva of mandible, 8% on the maxilla, 7.8% on the lower lip and 1% on the floor of the mouth. 23.3% of the patients had stage I disease, 14.6% were stage II, 43.7% were stage III and 18.4% stage IV. Of 103 patients treated with wide excision, about 65% (17/103) of patients treated with wide excision and radical neck dissection or suprahyoid neck dissection, and 41% (42/103) were treated by a combination of radiation and surgery. 96% (99/103) of our cases have completed a minimum follow up period of 3 years. The sex and age of the patients did not influence survival significantly. The 5-year survival rates were 62% for patients with stage I disease, 80% for patients with stage II disease, 42% for patients with stage III, and 19% for patients with stage IV disease. Stage at initial presentation was an important factor influencing survival. The location of the primary tumor did not significantly influence survival for early stage tumors (stage I & II). In terminal stage tumors (stage III & IV). those with carcinomas of the floor of the mouth, gingiva of the mandible, lip, and maxilla had a 5-year survival of 15%, those with carcinomas of the tongue had a 5-year survival of 47%, and those with carcinomas of the buccal mucosa had a favorable survival rate of 53%. The differences were significant (P = 0.017). PMID- 8699570 TI - [The bonding mechanisms of base metals for metal-ceramic crown microstructure analysis of bonding agent and gold bond between porcelain and base metals]. AB - The use of base metal alloys for porcelain fused to a metal crown and bridges has increased recently because of lower price, high hardness, high tensile strength and high elastic modulus. The addition of beryllium to base metal alloys increased fluidity and improved casting fitness. Beryllium also controlled surface oxidation and bonding strength. The bonding agent and gold bonding agent also affected the bonding strength between porcelain and metal alloys. Four commercially available ceramic base alloys were studied (two alloys contained beryllium element, another two did not). The purpose of this investigation was to study the microstructure between porcelain matrix, bonding agent and alloy matrix interfaces. A scanning electron micro-probe analyzer and energy dispersive X-ray spectroscopy (EDXS) were used to study the distribution of elements (Ni, Cr, Mo, Cu, O, Si, Sn, Al) in four base alloys. The following results were obtained: 1. The thickness of the oxidized layer of Rexillium III alloy and Unitbond alloy (contained beryllium) was thinner than Unibond alloy and Wiron 88 alloy (no beryllium). 2. The thickness of the oxidized layer of alloys in air (10 minutes and 30 minutes) was thinner in Unitbond (2.45 microns and 3.80 microns) and thicker in Wiron 88 (4.39 microns and 5.96 microns). 3. The thickness of the oxidized layer occurring for a duration of ten minutes (in vaccum) showed that the Rexillium III alloy was the thinnest (1.93 microns), and Wiron 88 alloy was the thickest (2.30 microns). But in thirty minutes (vacuum), Unitbond alloy was the thinnest (3.37 microns), and Wiron 88 alloy was the thickest (5.51 microns). 4. The intensity of Cr elements was increased obviously near the interface between Unitbond alloy, Wiron 88 alloy (no beryllium) and oxidized layer, but the intensity of Ni and Mo elements was slightly increased. The intensity of Cr element was not increased markedly between Rexillium III alloy, Unitbond alloy (beryllium) and oxidized layer. 5. A white-grayish oxidized layer appeared at the metal-ceramic interfaces but the thickness of oxidized layer was not obviously different. 6. The use of bonding agent at metal-ceramic interface leads to the deposition of many Sn elements at about 40 microns range within the porcelain surface. 7. Second interaction phases at the porcelain layer appeared when gold bonding agent was used, and a 50-100 microns microleakage occurred at the metal ceramic interface. PMID- 8699572 TI - [The participation of physical activity and its associated factors in the elderly]. AB - The purpose of this study was to explore the participation of physical activity and its related factors in the elderly in the community. Five hundred elderly ( > or = 65 yrs) living in the San-Min district of Kaohsiung city was taken as study subjects. A structured questionnaire was used to gather data including the following items: (1) the participation of physical activity (2) modifying factors: demographic data, biological characteristics, previous experience in exercise and exercise knowledge (3) cognitive-perceptual factors: perceived health status, perceived self-efficacy, perceived benefits and perceived barriers to exercise (4) cues to action. The results showed 19.2% of the elderly never exercised, 15.9% had exercised previously but not now, 20.4% exercised intermittently, 1% exercised only on holidays and 43.8% exercised regularly. Within the elderly who exercised regularly, 89.2% exercised more than three times a week and at least 20 minutes each time, walking was the most popular exercise pattern. The participation of physical activity had significant relationship with modifying factors, cognitive-perceptual factors and cues to action. After logistic stepwise multiple regression, those who totally self-care, without a history of exercise injury during youth, male, higher perceived self-efficacy score, lower perceived barriers score and those with higher cues to action score tended to exercise regularly. PMID- 8699571 TI - [The influence of job characteristics and workplace subculture on individuals' drinking behavior--an exploratory pilot study]. AB - The purpose of this study was to explore how individuals' drinking behavior was associated with their jobs in terms of the amount consumed and its consequences. The researchers attempted to analyze the characteristics of job and workplace from structural, psychological, and cultural perspectives. The structural dimension referred to years serving in a company, years serving in a department, work position, work characteristics, and shift. The psychological dimension was addressed on perceived stress and work hazards. The cultural dimension of one's job consisted of formal and informal norms regarding one's drinking within the workplace. The result showed the occurrence of drinking-related problems was significantly associated with workplace subculture among the non-aboriginal Chinese males. However, none of the three perspectives as job characteristics was significantly associated with drinking amount. The findings imply that the workplace subculture plays a determinant role in affecting individual's drinking behavior, moreover, it could result in one's problem drinking. PMID- 8699573 TI - [Community-based integrated home care model for the demented patients and their families]. AB - The purposes of this research project were to establish an integrated home care model and understand the influence of an integrated home care model on demented elders and their families. The changes in cognitive function and self-care ability of demented elders were also explored longitudinally. The disciplines involved in the integrated home care model included doctors, home care nurses and social workers. The integrated home care model was developed according to the functions and roles of different disciplines in their actual working process. Services provided included home nursing care, telephone consultation and a support group. Home care nurses played the role of case manager in this model. Twenty-five families participated in this study. Among them, 22 received home care service, and 20 of them participated in a caregiver support group. The cognitive function of the demented elders did not significantly decrease over the 6-month period. Among their self-care ability, grooming and eating dependency were found significantly increased during this period. Overall, 81% families reported that home nursing care services could help them to develop care skills, care knowledge and provided emotional support. However, the caregiver burden did not significantly decrease after the home nursing care services. Seventy percent of caregivers reported that telephone consultation could support them emotionally and provided them with information concerning care. Over half of the caregivers reported that in getting related information and receiving emotional support was helpful. This integrated model developed from this research project can be adapted and used in networking home care agencies, the community and health care resources. The small and convenient sample was one of the limitations of this study. The insignificance of some of the findings might be due to the short time period (6 months) and some effects of the model might appear later than 6 months. For further research, larger and random samples and a longer period of follow-up with more health disciplines involved were suggested. PMID- 8699574 TI - [Body image, cognition, behavior and social support of married pregnant adolescents during the third trimester]. AB - In an attempt to compare the body image, cognition, behavior and social support in the third trimester of pregnancy between the pregnant adolescent and pregnant adult in the Tainan area, seventy-five pregnant adolescents during the third trimester were enrolled and matched to seventy-five pregnant adults who were also selected for this study. The results were as follows: The two groups were similar in their body image, cognition, and behavior. The order of sources from which the pregnant adult got information about infant's requirements was books, the neighborhood, friends, their mother, sisters, mother-in-law, and nurses. That for the pregnant adolescents was books, their mother, mother-in-law, neighborhood, friends, sisters, and nurses. The order of the preference for food of the pregnant adult was rice, pizza, sour food, sweet food, noodles, cookies, cola, hamburgers, and chocolates. That for the pregnant adolescents was noodles, sour food, pizza, sweet food, rice, hamburgers, cola, chocolates, and cookies. Both groups suffered from insomnia. However, the sleeping status of the pregnant adolescents was significantly worse than that of the pregnant adults. In both case, economic support came from spouse's income, but it was more obvious that pregnant adolescents relied on their parents' economic support more often than did normal pregnant women, the difference was statistically significant. The pregnant adult had a much higher score on social support than did the pregnant adolescents with a significant difference. Adolescents with unexpected pregnancies have lower social support scores than their adult counterparts. PMID- 8699575 TI - The new public health. PMID- 8699576 TI - Cerebrospinal fluid adenosine deaminase activity for the diagnosis of tuberculous meningitis in children. AB - Adenosine deaminase (ADA) activity was measured in the cerebrospinal fluid (CSF) of 27 subjects suffering from tuberculous meningitis (TBM), 19 from bacterial meningitis, 10 from encephalitis, and 10 control subjects. The mean CSF ADA level was significantly raised (P < 0.001) in TBM patients as compared to other study groups. A cut-off CSF ADA level of > 5 IU/1 was considered for the diagnosis of TBM, and the test had sensitivity and specificity of 89 and 92 per cent, respectively. Overall, it was found to be a better test in comparison to any other single test for the diagnosis of TBM. Confirmed TBM patients had significantly higher CSF ADA activity when compared with clinical TBM (P < 0.01) and the levels did not differ significantly among different stages of disease. The ADA level in TBM cases had significant correlation with CSF cell count (P < 0.01), lymphocyte percentage (P < 0.02) and protein concentration (P < 0.02). Thus, the CSF ADA activity assay was found to be a simple, useful and rapid diagnostic test for the early recognition of TBM in children. PMID- 8699577 TI - Efficacy of traditional rice-lentil-yogurt diet, lactose free milk protein-based formula and soy protein formula in management of secondary lactose intolerance with acute childhood diarrhoea. AB - Secondary lactose intolerance is often a cause of prolongation of diarrhoeal episodes. As appropriate management of lactose intolerance is elimination of lactose from diet, expansive lactose free formulae are often prescribed in acute childhood diarrhoea without establishing diagnosis of lactose intolerance. Since cheap weaning diets made from locally available cereals have been found effective in management of persistent diarrhoea, we postulated that same weaning diet made of rice lentil and yogurt (K-Y diet) could be effectively used in management of acute childhood diarrhoea associated with secondary lactose intolerance. We compared this K-Y diet with milk protein-based lactose free and soy-protein formula. Thirty children between 3-18 months of age completed dietary trial for 72 h. Of these nine children received K-Y diet (Group A), four children received milk protein-based formula (Group B) and 11 children received soy protein formula (Group C). Stool frequency was significantly reduced in children in Group A (13 +/- 6 on day 1 to 6 +/- 5 on day 3) and in Group B (13 +/- 5 on day 1 to 7 +/- 4 on day 3), but not in Group C (13 +/- 4 on day 1 to 10 +/- 8 on day 3). No significant difference was observed in intake of diet, total calories intake, and fluid intake among the three groups. It is concluded that cheap weaning diet made of locally available cereals and yogurt can be used effectively in management of secondary lactose intolerance associated with acute childhood diarrhoea. PMID- 8699578 TI - Acute respiratory tract infection: a community-based intervention study in Malaysia. AB - A community-based intervention trial was conducted in Kelantan, Malaysia with the aim of reducing severe acute respiratory tract (ARI) infection in children. Interventions included health education of mothers on childhood pneumonia and training of health staff on case management. In a house-to-house survey 1382 and 1107 children less than 5 years of age in the intervention and control areas, respectively, were followed up every 2 weeks over a 62-week period. The reduction in the incidence of severe ARI cases in the intervention area was significantly greater than in the control area (P < 0.05). The ARI mortality rates were low in both the intervention and control areas ( < 0.1%). Our results indicate that with relatively inexpensive methods and simple interventions, reduction of severe ARI may be effectively achieved. This has important implications for an ARI control programme in Malaysia and other developing countries. PMID- 8699579 TI - Response of Egyptian infants with protein calorie malnutrition to hepatitis B vaccination. AB - The response to recombinant hepatitis B vaccine was assessed in 31 seronegative infants (2-26 months old) with protein calorie malnutrition (PCM), compared with 13 seronegative age- and sex-matched healthy infants. Both groups received three 10 micrograms vaccine doses at 0, 1, and 6 months. At month 8, all healthy infants and 87 per cent (27 out of 31) of PCM infants were seroprotected. Thus, hepatitis B vaccination (Engerix-B, SmithKline Beecham Biologicals) can be used effectively in PCM for mass vaccination in developing communities. PMID- 8699580 TI - Head and chest circumferences as predictors of low birth weight in Indian babies. AB - This study attempts to select predictors for indirect estimation of low birth weight from three important anthropometric measurements (viz. body length, head and chest circumferences) taken at birth. The data of 422 Indian low birth weight babies have been used to select the best combination of predictors by examining the separate effect of each of the three concomitant variables on birth weight using the technique of multivariate regression analysis. The combination of head and chest circumferences was found to be the best combination of predictors for estimation of birth weight in view of the simplicity and non-invasiveness of measuring these two body circumferences. A nomogram has also been constructed to predict low birth weight from head and chest circumferences. This nomogram will serve as a simple and quick procedure for predicting low birth weight from head and chest circumferences whenever the direct weighing at birth is not feasible. PMID- 8699581 TI - Role of viruses in acute gastroenteritis in infants and young children at Vellore, south India. AB - The aetiological contribution of viral agents in the causation of acute diarrhoea was studied prospectively in 915 infants and young children aged 1-35 months. This was a hospital-based study, selection being carried out by proportionate random sampling; 587 matched controls were also investigated simultaneously. Methods of detection included direct electron microscopy, ELISA for rotaviruses and immune electron microscopy. Rotaviruses emerged as the single most important cause with highest prevalence in the 6-11-month age group. The contribution of other agents was negligible. Electron microscopy, though a "catch-all' technique, is not a cost-effective diagnostic method for developing countries. PMID- 8699582 TI - Maternal and neonatal prevalence of toxoplasma and cytomegalovirus (CMV) antibodies and hepatitis-B antigens in an Egyptian rural area. AB - To determine the seroprevalence of maternal and neonatal toxoplasmosis and cytomegalovirus (CMV) antibodies and hepatitis-B (HB) antigenaemia in a rural Egyptian area, a prospective serological study was done on a randomly selected sample of pregnant women (n = 150) and their newborn infants (n = 150). Sera were collected from the mothers during the first antenatal visit, and at the time of delivery and cord blood specimens (paired samples) taken from their infants to be tested for toxoplasma-IgG and IgM antibodies, CMV-IgG and IgM antibodies surface antigen (HBsAg) and HBe antigen (HBeAg). Maternal infection was indicated in cases where specific IgM antibody was present or where an initial maternal specimen gave negative result for IgG antibody, but the second blood specimen gave positive result. Specific IgM antibody in a cord blood specimen indicated fetal infection. Out of the 150 pregnant women, 64 (43 percent) were toxoplasma immune at their first antenatal visit and their newborns were toxoplasma IgG positive. Toxoplasma specific IgM antibody was detected in only three mothers at the time of deliver. The rate of maternal infection in susceptible pregnancies was 4 percent and the maternal-fetal transmission rate was estimated to be 33 percent, as only one newborn infant had toxoplasma-IgM antibody at birth. This denoted a prevalence of congenital toxoplasma infection = < 1.0 percent to non immune mothers. There were no clinical features of congenital infection in the infant with toxoplasma-IgM antibody, but he will require long-term follow-up. All the mothers infected during pregnancy had known risk factors for toxoplasma infection. One-hundred-and-forty-three (96 percent) of the pregnant women were CMV-IgG seropositive at their first antenatal visit. At the time of delivery 143 (96 percent) of the mothers and their newborn infants were CMV-IgG seropositive. None of the mothers or their infants was CMV-IgM seropositive. HBsAg was detected in 8 per cent of pregnant mothers (n = 12) and in two (17 percent) of their newborn infants. None of the mothers was HBeAg positive. In conclusion, the prevalence of toxoplasma infection during pregnancy and its transplacental transmission rate in a rural Egyptian area are high compared to other countries. A toxoplasmosis antenatal screening and public education programmes for pregnant mothers is justifiable in rural Egypt. However, it appears that an antenatal screening programme for CMV is, at present, not warranted. PMID- 8699583 TI - Significance of very low retinol levels during severe protein-energy malnutrition. AB - In developing countries, severe vitamin A deficiency is associated with increased child mortality. In Kivu, Zaire, child mortality rate is approximately 50 per 1000 per year and protein calorie malnutrition is endemic. To evaluate vitamin A status in this population, we measured plasma retinol levels in 28 severely malnourished hospitalized children (plasma albumin level below 3 g/dl), and in 153 outpatients (mean plasma albumin level: 3.19 +/- 0.7 g/dl) as controls. Sixty percent of inpatients and 37 percent of out-patients had retinol levels below 10 micrograms/dl (P = 0.02) suggesting a high prevalence of severe vitamin A deficiency in this population. We found that plasma retinol levels were correlated with low retinol binding protein plasma levels (r = 0.77). We conclude that although vitamin A deficiency probably exists in this malnourished population, low retinol levels could at least partly be related to decreased levels of its carrier protein. PMID- 8699584 TI - Lactobacillus GG and acute diarrhoea in young children in the tropics. AB - A prospective, placebo controlled, triple blind clinical trial was undertaken in Thailand to determine the effect of Lactobacillus GG on recovery from acute diarrhoea in children. Thirty-nine children (mean age = 8 months) were enrolled and following rehydration received either oral Lactobacillus GG (n = 20) as a freeze-dried preparation or placebo (n = 19) twice daily for 2 days. The clinical characteristics of the study groups were similar. There was no significant difference overall in clinical response detected between the study groups. When only those with acute non-bloody diarrhoea (n = 26) were considered, the mean duration of diarrhoea was significantly shorter in the lactobacillus group (1.9 days) than in the placebo group (3.3 days) (P < 0.055). Stool frequency was less on the second day in the lactobacillus group (P < 0.05). The results suggest that Lactobacillus GG accelerates recovery from acute watery diarrhoea in young children in a tropical setting. PMID- 8699585 TI - Effect of passive smoking on frequency of respiratory illnesses and serum immunoglobulin-E (IgE) and interleukin-4 (IL-4) concentrations in exposed children. AB - We studied the relationship of serum immunoglobulin-E (Ig-E) and interleukin-4 (IL-4) concentrations, eosinophil counts, and frequency of respiratory illness with passive smoking in 70 randomly selected children of smoking parents. Fifty randomly selected age-matched children of non-smoking parents served as controls. Children of smoking parents had higher frequency of respiratory illnesses per year (P < 0.01), significantly higher total leucocytic and eosinophil counts, higher percentage of eosinophils (P < 0.01), and higher serum IgE and IL-4 concentrations (P < 0.05) compared to the control group. Serum IgE level was correlated positively with the average number of smoked cigarettes/day, number of siblings, and total leucocytic count. Interleukin-4 concentrations were significantly correlated with the number of smoked cigarettes and IgE levels. Although IgE levels were higher in children of smoking parents (587 +/- 359 IU/ml) compared to controls (189 +/- 21 IU/ml), they did not differ significantly between children with and those without frequent respiratory illness (605 +/- 365 and 557 +/- 354 IU/ml, respectively). Interleukin-4 concentrations were significantly higher in children of smoking parents with frequent respiratory illness (1.8 +/- 0.5 pg/ml) v. those without frequent respiratory illness (1.3 +/ 0.45 pg/ml). Multiple logistic regression analysis revealed that the overall positivity of the risk factors predisposing to respiratory diseases in the study children was 79 percent, and the highest odds ratio was that for IL-4 (OR = 5.15). In conclusion, there is a significant increase in IL-4 and Ig-E concentrations, high eosinophil count and frequent respiratory symptoms in children of smoking parents. It remains that the current state of knowledge on health risks associated with passive smoking warrants that strong preventive action be promoted. PMID- 8699586 TI - Early complementary feeding is associated with low nutritional status of young infants recovering from diarrhoea. AB - Young infants admitted to hospital for diarrhoea were studied to identify and understand the reasons for early complementary feeding and to examine its effect on nutritional status. Of 132 infants, 71 percent were being breastfed, 24 percent had already stopped, and 5 percent had never been breastfed. Complementary feeds were started by the mothers when infants' median age (range) was 27 (1-180) days. Mothers' perceptions regarding breastmilk being insufficient (53 per cent) or causing diarrhoea (19 percent), were the major reasons for complementary feeding. The mean weight-for-age of the infants given complementary feeds before the age of 2 months was 72 percent of the National Centre for Health Statistics (NCHS) standards, compared to 82 percent in those starting after 2 months of age (P = 0.01). Similarly, the mean weight-for-length in these two groups were 86 and 91 percent, respectively (P = 0.04). Initiation of early complementary feeding is associated with infant malnutrition and this alarming trend should be strongly discouraged. PMID- 8699587 TI - An investigation into feeding errors of 0-4-month-old infants. AB - This study was carried out on 206 infants seen consecutively at the Pediatric Clinic of our hospital. The feeding errors investigated were: The proportion of infants not exclusively breastfed, incorrect dilution of formula milk, incorrect dilution of cow's milk, rice flour feed prepared with water, and the use of rice water as a feed. The feeding methods of the infants were compared with their weight for height. Of those infants exclusively breastfed 83 percent were found to be above the median standard of weight-for-height. In those receiving supplementary feeds this ratio was significantly lower (P < 0.05). In 20 percent of cases where the infant had received formula milk and in 14 percent of cases where the infant had received cow's milk, the milk was found to be overdiluted by more than 40 percent. PMID- 8699588 TI - Addiction among high school pupils in Holon (Israel) and their attitudes towards drugs: a pilot study (1993-1994). AB - One-hundred-and-twenty-five high school pupils aged 14-17 years had completed anonymous questionnaires dealing with smoking habits and alcohol consumption, as well as with the knowledge and attitudes towards drug addiction. Twenty-four percent of the pupils smoked regularly; the age of onset of smoking was 13.93 +/- 1.53 years. Thirty-one percent of the pupils admitted to the regular drinking of alcoholic beverages (including beer, wine, and other alcoholic beverages); the age of onset of drink was 14.65 +/- 0.79 years. The pupils' knowledge concerning drugs was relatively low (scoring of 37.78 +/- 16.87 percent). Pupils in the 16 17-year age group proved to have the highest knowledge. Pupils who used to take drugs received a higher score for their knowledge than other pupils in their classes. Most pupils presented conservative attitudes towards drugs; pupils in the 16-17-year age group received the highest (most liberal) scores; higher (liberal) scores correlated with parental familial status (cohesion) (P = 0.029) and inversely correlated with the behavior marks (r = 0.294; P = 0.03). The attitude of addicted pupils (to cigarettes, alcohol and drugs) was more liberal in comparison with their peers (P < 0.003). PMID- 8699589 TI - Breastfeeding pattern in Jos, Nigeria, before baby-friendly hospital initiative. AB - Interviews were conducted amongst 800 mothers attending Jos University Teaching Hospital, Nigeria, to obtain information on prenatal care, knowledge, attitudes, and practices relating to breastfeeding. Of the 653 women who had antenatal care, 75 per cent had breastfeeding education, though devoid of practical demonstration of breastfeeding techniques. Breastfeeding was universal, but only 439 (55 per cent) mothers started breastfeeding within 24 hours of delivery with a mean initiation time of 1.9 days. Prelacteal feeds were often offered. Only 51 (6 per cent) mothers exclusively breastfed at 3 months while early supplementation was common. Acquisition of secondary or post-secondary education was associated with significantly shorter duration of breastfeeding, P < 0.01 and P < 0.001, respectively, when compared with those with or without primary education. These problems are being effectively countered by appropriate health education, training of health workers, and effective lactation management. PMID- 8699590 TI - Awareness claims versus actual knowledge of oral rehydration therapy and the salt sugar solution in northeastern Nigeria. AB - Focus group discussions involving rural and urban residents drawn from Kanuri and Bura settlements, were conducted as part of an on-going survey of the perception and treatment of diarrhoea among major ethnic groups in northeastern Nigeria. Awareness of oral rehydration therapy (ORT) was universal among participants, but knowledge of its function and the preparation of the sugar salt solution (SSS) was markedly deficient among the Kanuris, especially in rural areas. Reported SSS use parallel the knowledge of ORT function/SSS preparation and seemed heightened by church-fellowship activities among the rural Buras. Surprisingly, tasting was apparently not realised by participants to be an important step in SSS preparation. These preliminary results suggest that knowledge of ORT function and SSS preparation need further emphasis in ORT awareness campaigns, and that religion-based activities could be a potent and actualizable method of ORT promotion. PMID- 8699591 TI - About the French language breastfeeding literature. PMID- 8699592 TI - Single-dose secnidazole versus 10-day metronidazole therapy of giardiasis in Iranian children. PMID- 8699593 TI - Clinico-radiological follow-up study of empyema thoracis in children. PMID- 8699594 TI - The relationship between admission electrolyte levels and rehydration time in moderately dehydrated children with diarrhoea. PMID- 8699595 TI - The Dr Albert Dubois Prize of tropical pathology. PMID- 8699596 TI - The clinically negative neck in patients with early oral cavity carcinoma: a decision-analysis approach to management. AB - Despite improvements in both diagnostic and therapeutic techniques in recent decades, the prognosis for oral cavity squamous cell carcinoma has not improved. Patients presenting with overt regional metastases necessarily undergo therapeutic intervention directed to both the primary site and the neck. However, controversy persists regarding the best management for patients without clinical evidence of nodal disease. Would these patients best be managed with elective treatment of the neck, with no neck treatment unless overt nodal metastases are detected, or would some diagnostic test be beneficial in determining which patients are at highest risk of having occult nodal disease and, therefore, most likely to benefit from elective treatment? We performed a decision analysis to address this question. Baseline probability assumptions were made based on the evidence available in the literature for the parameters of interest. A decision tree was constructed and analyzed. In the final analysis, two options, elective functional neck dissection for all patients and a supraomohyoid neck dissection, were equally beneficial and were significantly better than the remaining options tested. Either of these surgical treatment strategies shifted the survival distribution curve significantly to the right. PMID- 8699597 TI - Pneumatization and otitis media in Greenlandic Inuit before European colonization. AB - A total of 127 Greenlandic Inuit crania from before the European colonization of Greenland and deriving from the West (W), Southeast (SE), and Northeast (NE) coast of Greenland were examined for sequelae of infectious middle ear disease (IMED) and for a relationship between the size of the pneumatized cell area in the temporal bones and cranial morphology. IMED was inferred from the area size of the pneumatized cell system as seen on x-rays. The crania were classified into IMED or non-IMED by applying a statistical model on the distribution of areas. The model designated six crania (4.7%, 95% CI: 1.8-10.0%) as having had IMED, four from the W, one from the SE, and one from the NE. This is lower than the present frequency of IMED in Greenland. One cranium revealed pathology resembling that caused by chronic inflammation (e.g., from cholesteatoma or cancer). The area sizes differed significantly between sexes and between regions, as did some of the cranial measures. This indicated a relationship between cranial morphology and the area size. However, in a multiple regression analysis, cranial morphology only explained 5 to 7% (R2) of the variability in the areas. PMID- 8699598 TI - Age and hearing function in patients with chronic otitis media. AB - The effect of age on hearing function was assessed in 897 patients with chronic otitis media. Preoperatively, 3% of chronic ears were found to be totally deaf, anacusis being most frequent in patients over 60 years of age. Severe sensorineural hearing loss (preoperative bone conduction threshold worse than 30 dB) was observed in 10% of the patients, and the mean bone conduction thresholds elevated with increasing age. Sensorineural hearing loss was significantly more common in patients with cholesteatoma than in patients with chronic otitis media without cholesteatoma. Conductive hearing loss was less severe in paediatric patients than in patients over 30 years of age. Postoperative hearing results of paediatric patients did not differ significantly from those of adults. In contrast to some earlier studies, average postoperative hearing gain was as good in elderly patients as in younger patients. PMID- 8699599 TI - Intratympanic gentamicin therapy for Meniere's disease: preliminary comparison of two regimens. AB - Selective chemical ablation of the vestibular endorgan using intratympanic gentamicin is an effective and safe treatment for incapacitating vertigo in patients with unilateral Meniere's disease. A major risk of the treatment is sensorineural hearing loss. In this retrospective study, two different regimens of intratympanic gentamicin therapy are compared. In one group, multiple daily doses were administered in hospital over 4 consecutive days. The other group received single treatments at weekly intervals on an outpatient basis, following pretreatment audiometric and clinical assessment. We adopted the weekly protocol to theoretically reduce the incidence of treatment-related hearing loss by a more controlled titration of dosing. Preliminary results indicate that the weekly interval treatment offers equivalent efficacy with considerably less risk to hearing. PMID- 8699600 TI - Comparison of botulinum toxin injection procedures in adductor spasmodic dysphonia. AB - This study compares the effects of unilateral and bilateral thyroarytenoid muscle injections of botulinum toxin in 50 patients with adductor spasmodic dysphonia. Patients were randomly assigned to two treatment groups of 25 patients each and a group of 15 normal control subjects was also included. Using a standard electromyographic guidance procedure, one patient group received unilateral thyroarytenoid muscle injections of 15 units of botulinum toxin, while the second patient group received bilateral thyroarytenoid muscle injections of 2.5 units of botulinum toxin on each side. Follow-up data were obtained at 2- and 6-week intervals. Acoustic and perceptual measures of vocal performance included maximum phonation time, fundamental frequency, standard deviation of fundamental frequency, jitter, shimmer, signal/noise ratio, voice break frequency, spasm severity rating, and vocal breathiness rating. Unilateral and bilateral group comparisons at 2-weeks postinjection revealed no significant difference on any of the measures examined. At 6-weeks postinjection, maximum phonation time was significantly lower in the bilateral group. All other measures failed to differentiate the two patient groups. These results suggest that standard unilateral and bilateral botulinum toxin injections provide equivalent degrees of improvement in the symptoms of spasmodic dysphonia. However, bilateral injections appear to be associated with a longer period of excessive phonatory airflow than do unilateral injections. PMID- 8699601 TI - Evaluation of criteria for uvulopalatoplasty (UPP) patient selection using acoustic analysis of oronasal respiration (SNAP testing). AB - This study was designed to evaluate the acoustic parameters of sleeping oronasal respiration as determined by the SNAP system, to identify those that might aid in identifying appropriate candidates for uvulopalatoplasty (UPP). Eighteen UPP patients who completed preoperative and postoperative SNAP testing and assessment interviews were analyzed. Significant multiparametric changes subsequent to UPP were identified. These parameters were then correlated with subjective outcomes and predictive parameters were defined that may aid in the identification of patients who would be the most appropriate candidates for UPP. Predictive correlation with relief of snoring was noted when the relative loudness of velum like snoring was greater than 12 dB and the snoring distribution was dominated by low-frequency (velum-like) snoring (> 85%). Objective and more accurate UPP candidate selection may be possible using SNAP testing. PMID- 8699602 TI - The aesthetic nose: do we agree? AB - The surgeon and patient use the preoperative consultations to develop an agreement regarding the aesthetic goals of a rhinoplasty. This study was designed to evaluate whether people do agree on what makes a nose attractive. Computerized video-imaging technology was used to create nine case studies. The graphics software permitted precise modification to either tip projection, tip rotation, or size of the dorsal hump. Only one parameter was altered in each case. Two hundred fifty judges were asked to identify the most attractive image in each case study. Significant trends were observed in each case, but every image received the preference of some judges. Most judges preferred midrange values in eight of nine cases, but overrotation of the tip was preferred to tip droop, overremoval of the dorsal hump was preferred to underremoval, and overprojection of the tip was preferred to underprojection. The discrepancy in what constitutes an aesthetic nose reinforces the need for the surgeon to clearly understand the patient's specific requests rather than to aim to produce a "standard nose.". PMID- 8699603 TI - Gelfoam/Gelfilm patching following the removal of ventilation tubes. AB - A follow-up study to document the rate of tympanic membrane perforation following surgical removal of ventilation tubes with Gelfoam/Gelfilm patching in paediatric patients is presented. The initial study performed at The Hospital for Sick Children with no patching following ventilation tube removal had a perforation rate of 10.3%. This follow-up study used Gelfoam/Gelfilm patching of perforations at the time of ventilation tube removal performed between January 1993 and May 1994 at the same hospital. There was sufficient follow-up on 155 ears with (4.5%) documented perforations, a significant difference from the the no-patching technique. PMID- 8699604 TI - Intraparotid facial nerve schwannoma. AB - Intraparotid facial nerve schwannomas have been documented sporadically throughout the medical literature. These benign tumours of neurogenic origin should be considered in the differential diagnosis of parotid region masses. A case report is presented, followed by a brief literature review and discussion of appropriate diagnostic and treatment modalities. PMID- 8699605 TI - Oropharyngeal burns from microwave ovens: case report and review of the literature. AB - We present a case of a child suffering oropharyngeal burns consequent on the inappropriate use of a microwave oven. The literature on such burns is reviewed, and the pathophysiology discussed. PMID- 8699606 TI - The "temporocele". AB - This article reports a case of spontaneous extracranial pneumatocele and introduces a new simple terminology for this clinical entity. A 10-year-old Saudi girl presented with left tympanoparietomastoid swelling. It was found to be fluctuant and full of air. On exploration, bony septae were found arising from the skull aponeurosis, the cranial boundary was elevated, and an ivory, cancellous bony swelling was over the root of the zygoma. No naked eye anatomic communication to the mastoid air cell was found. The mastoid pneumatization was within normal limits. All preoperative, operative, and postoperative investigations are presented. The authors introduce temporocele as a new term applied to this extracranial spontaneous pneumatocele. PMID- 8699607 TI - The case of the disappearing fish bone. AB - This article reports the 9-month follow-up CT scan of a patient with a pharyngeal fish bone that had migrated into the soft tissues of the neck. The patient had been managed conservatively and remains well, the fish bone having disappeared completely and presumed to have been resorbed. PMID- 8699608 TI - New aspects in the pathogenesis of dialysis-related amyloidosis: pathophysiology of advanced glycation end products in renal failure. AB - It has been demonstrated that beta 2-microglobulin is a major constituent of amyloid fibrils in dialysis-related amyloidosis, a serious complication leading to bone and joint destruction in long-term hemodialysis patients. However, the molecular pathogenesis of this complication remains unknown. Several lines of evidence suggest that beta 2-microglobulin plays an active role in the development of dialysis-related amyloidosis. It is unlikely that intact beta 2 microglobulin per se contributes to the pathogenesis, because no difference in the plasma levels of intact beta 2-microglobulin has yet been found between hemodialysis patients with and without this complication. Some investigators, therefore, have focused on the modification of this molecule. Recent studies have revealed a new modification of beta 2-microglobulin in amyloid fibrils: advanced glycation end products (AGEs) formed by a nonenzymatic reaction between aldoses and proteins. Further studies have suggested that the interaction of AGE-modified beta 2-microglobulin with monocyte/macrophage and osteoclast/osteoblast gives a plausible, albeit partial, explanation for the mechanism of bone and joint destruction in dialysis-related amyloidosis. This article focuses on the modification of beta 2-microglobulin with AGEs, especially on their structure and pathological role in dialysis-related amyloidosis. Furthermore, the implication of renal failure in the pathophysiology of AGEs is also discussed. PMID- 8699609 TI - Effect of herbimycin A on renal cancer cell growth. AB - We investigated the effect of herbimycin A on the monolayer growth of 4 human renal cell carcinoma (RCC) cell lines and a normal renal tubular cell line (RTC 13) using MTT [3-(4,5-dimethylthiszol-2,5-diphenyl tetrazolium bromide)] assay. Herbimycin A induced remarkable growth inhibition in each RCC cell line tested, without any morphological changes of the cells. At the concentration of 500 ng/ml, herbimycin A caused more than a 30% growth inhibition in all RCC cells (p < 0.005 vs RTC 13), while less than 7% growth inhibition was observed in RTC 13 at the same herbimycin A concentration. The cell cycle was estimated by analysing DNA (deoxyribonucleic acid) content using a FACS. A DNA histogram of RCC cells treated at herbimycin A showed a block in the cell cycle at the S and G2M phases. However, little effect by herbimycin A on RTC 13 cells was observed. Our results suggest that protein tyrosine kinases inhibitors, like herbimycin A, may offer a new treatment option for RCC patients. PMID- 8699610 TI - Effect of acteoside on mesangial proliferation in rat anti-Thy 1 nephritis. AB - We investigated whether acteoside can inhibit mesangial matrix expansion or mesangial cell proliferation in mesangioproliferative anti-Thy 1 nephritis. Untreated control rats were compared to the rats treated with acteoside either during early (day 1 to 8) or late (day 4 to 12) period after the induction of anti-Thy 1 nephritis. The result showed that acteoside and prednisolone treatments (in either early or late period) significantly reduced proteinuria, mesangial matrix expansion (the index of matrix expansion) and mesangial proliferation as determined by the number of proliferating nuclear cell antigen (PCNA)-positive cells. Acteoside also reduced glomerular macrophage infiltration and ICAM-1 expression in glomeruli of anti-Thy 1 nephritic rats. Furthermore, acteoside treatment markedly increased the activities of matrix metaloproteinases (MMP) in glomeruli. These results suggest that acteoside can inhibit mesangial cell proliferation and extracellular matrix overproduction by either inhibiting ICAM-1 expression or increasing activities of MMP. PMID- 8699611 TI - Expression of tenascin in normal and diseased human kidneys. AB - Expression of tenascin was studied in normal human adult and fetal kidney specimens, and in renal tissues biopsied from patients with several types of glomerulonephritis. Immunofluorescent staining of the normal kidneys showed that tenascin was present weakly in the mesangial area and interstitium, but was absent from the glomerular capillaries. In the fetal kidney, tenascin was detected in the interstitium, but not in the immature glomeruli. In kidney tissues biopsied from patients with various renal diseases, expression of tenascin was associated with increased mesangial expansion and tubulointerstitial changes. In situ hybridization showed that tenascin mRNA was expressed in the renal tissues, but tenascin mRNA and tenascin protein were occasionally dissociated. These findings indicate that expression of tenascin is associated with mesangial expansion and also with tubulointerstitial changes in human glomerulonephritis. Tenascin expression may contribute to repair of injured glomeruli and interstitium. PMID- 8699612 TI - High postprandial plasma remnant-like particles-cholesterol in patients with coronary artery diseases on chronic maintenance hemodialysis. AB - The aim of this study was to determine the levels of postprandial plasma remnant like particles-cholesterol (RLP-C) in patients with coronary artery disease (CAD) on chronic maintenance hemodialysis (HD). Forty-two patients on chronic maintenance HD with and without CAD were studied. The subjects took a meal within 1 hr before HD then underwent HD for 4 hr with heparin infusion. The plasma level of RLP-C was monitored before and during HD and its biochemical characteristics were analysed. In the CAD group, the RLP-C level was 5.9 +/- 3.5 mg/dl before HD and 6.9 +/- 4.6 mg/dl after HD. In patients without CAD, RLP-C levels before and after HD were 2.1 +/- 0.8 mg/ dl and 2.7 +/- 1.2 mg/dl respectively (within the normal range). The RLP-C levels between CAD and non-CAD were highly significant (p < 0.001). HPLC analysis of RLP revealed that VLDL remnants were reduced to smaller size, cholesterol rich particles within 1 hr of HD and a marked increase in chylomicron (CM) remnants was observed at the end of HD. These observations suggest that a latent metabolic disorder of chylomicrons and VLDL during HD after a meal can be detected by plasma RLP-C assay. The association between the frequency of latent metabolic lipoprotein disorders and CAD found in HD patients may require appropriate dietary intervention together with drugy therapy for the control of CAD. PMID- 8699613 TI - Serum carnitine concentrations in different glomerular diseases with normal renal function. AB - Serum carnitine concentrations are known to decrease in patients on regular hemodialysis and to increase in chronic renal failure. However, there is little information available concerning serum levels of carnitine in different glomerular diseases in patients whose renal functions have not yet deteriorated. In this study, we measured serum carnitine concentrations in 40 pediatric patients with idiopathic nephrotic syndrome, IgA nephropathy, non-IgA glomerulonephritis, focal segmental glomerular sclerosis, and normal controls. The results showed that there were no significant differences in the serum-free and total carnitine concentrations (S-FCC and S-TCC, respectively) between patients with different glomerular diseases and the controls. Of interest was the statistically weak correlations of both S-TCC and S-FCC with BUN in these patients, despite their normal renal functions. The ratio of S-FCC to S-TCC was significantly higher as compared with that of the controls. These findings suggest that serum carnitine concentrations are not affected by the types of glomerular lesions and that serum levels of carnitine depend mostly on the glomerular excretory capacity of urea nitrogens, even when the renal functions have not yet deteriorated. The increase in the ratio of S-FCC to S-TCC may be an early reflection of changes in the serum carnitine profiles of these patients. PMID- 8699614 TI - Hereditary nephritis associated with low-tone sensorineural hearing difficulty: a case report. AB - The proband was a 14-year-old girl with hematuria and proteinuria. Many members of her maternal pedigree had hematuria and proteinuria. Her mother, younger brother (age 12 years) and younger sister (age 9 years) had microscopic hematuria and proteinuria with normal renal function. Her mother had nephrotic syndrome during pregnancy and a renal biopsy was performed. Light microscopic findings of the renal biopsy specimen revealed mild mesangial proliferation and irregularity of glomerular basement membrane. The pedigree showed no chronic renal failure and no deafness. The proband had experienced microscopic hematuria and occasionally macroscopic hematuria since 3 years of age. Proteinuria increased steadily and at the age of 14 years, she had nephrotic syndrome and renal dysfunction (creatinine clearance of 57.9 ml/min/1.48 m2). Renal biopsy was performed and light microscopic findings showed segmental mesangial cell proliferation and numerous interstitial foam cells without significant findings by immunofluorescent study. Electron microscopic examination showed splitting into many layers and thinning of the glomerular basement membrane. She had no complaint of hearing. However, audiological studies detected bilateral low-tone (from 125 Hz to 1000 Hz) sensorineural hearing difficulty, ranging from 30 to 40 dB. High scores on the short increment sensitivity index (SISI) test suggested inner ear hearing difficulty. Audiogram of her brother revealed also low-tone sensorineural hearing loss. Hereditary nephritis with the characteristic lesion of the glomerular basement membrane and sensorineural hearing difficulty has been known as Alport syndrome. Alport syndrome associated with familial low-tone hearing difficulty has not been reported previously. PMID- 8699615 TI - [Exposure to the technologists from radioactive patients during nuclear medicine studies]. AB - In order to evaluate the exposure to the nuclear medicine technologists from patients who had been administrated with radiopharmaceuticals, we measured the exposure in 5 common diagnostic procedures (bone, lung, tumor scan, and brain, myocardial SPECT, n = 8 to 52) using a silicon semiconductor pocket dosimeter. We also measured the spatial dose rates at 5 cm, 50 cm, and 100 cm from skin surface of the patients (n = 10 to 21) using an ionization chamber, both 5 min after injection and right before the studies with the same procedures above. We further measured the spatial dose rate distributions around the patients in the 4 procedures (bone, renal, blood pool scan, and brain SPECT, n = 2 to 3). In results, the exposure to the technologists in each procedure was small (0.5, 0.5, 0.7, 1.6, and 0.3 muSv in each bone, lung, tumor scan, and brain, myocardial SPECT, respectively), compared with the dose limits of the medical workers. However, the dose-response relationships in cancer and hereditary effects, referred to as the stochastic effects, have been assumed linear and no threshold models; therefore, the exposure should be minimized. For this purpose, the measurements of spatial dose rates and spatial dose rate distributions were thought to be useful. The differences of these results among procedures were caused by the differences of dose distributions and physical and biological half lives of the radiopharmaceuticals. The results of the measurements in 7 consecutive weeks suggested that the direct measurement of the exposure using a high sensitive digital pocket dosimeter might result a reduced exposure to the technologists. PMID- 8699616 TI - [111In-labeled leukocyte scintigraphy in patients with inflammation of unknown focus]. AB - This study evaluates the usefulness of 111In-labeled leukocyte scintigraphy to localize inflammatory foci that cannot be determined by clinical symptoms and other imaging studies. Patients with persistent fever following abdominal surgery (n = 20), suspected post-traumatic osteomyelitis associated with multiple fractures (n = 5), and fever of unknown origin (n = 22) were recruited. In all patients, the exact location of inflammatory foci could not be determined by clinical symptoms and conventional imaging studies. In patients with post surgical fever, leukocyte scintigraphy localized responsible foci in 65% of patients and provided clinically useful information for the treatment. In patients with multiple fractures, the location of osteomyelitis was diagnosed confidently in only one case (20%). In patients with fever of unknown origin, responsible foci were detected in 18% of patients. Although in those patients positive leukocyte studies provided clinically useful information, overall usefulness seemed to be limited. Leukocyte scintigraphy is able to detect inflammatory foci in patients with post-surgical fever, but less likely to localize responsible foci for post-traumatic osteomyelitis or fever of unknown origin when patients have been examined carefully by clinical symptoms and conventional imaging studies. PMID- 8699617 TI - [Characteristics of regional sympathetic innervation in diabetic patients with silent myocardial ischemia assessed by 123I-metaiodobenzylguanidine imaging]. AB - The purpose of this study was to clarify any association between clinically detectable silent myocardial ischemia (SMI) and myocardial 123I-metaiodobenzyl guanidine (MIBG) uptake. Subjects of this study were (1) patients with SMI with diabetes (n = 15), (2) patients with angina pectoris with diabetes (n = 15), (3) patients with SMI without diabetes (n = 8) and (4) normal subjects (n = 23). Subjects underwent planar and single photon-emission-computed tomography (SPECT) imaging 15 min and 3 hours after injection of 123I-MIBG. H/M ratio was significantly lower in diabetic SMI (2.1 +/- 0.3) and non-diabetic SMI (2.3 +/- 0.3) than control subjects (2.6 +/- 0.3). The inferior-to-anterior wall count ratio (I/A) in diabetic SMI group was the lowest among all groups (p < 0.05). A significant difference was observed in relative regional uptake in the inferior segment of the distal left ventricle between SMI and angina group in patients with diabetes mellitus (p < 0.05). The decreased MIBG uptake in the inferior wall may be an important sign of cardiac sympathetic dysfunction, suggesting the abnormalities in cardiac nervous system play an important role in the mechanism of diabetic silent myocardial ischemia. PMID- 8699619 TI - [Pharmacokinetics of 99mTc-MAG3 and 131I-OIH: comparative study based on 2 compartment model analysis]. AB - We studied 50 patients with mild to moderate renal dysfunction to compare pharmacokinetics of 99mTc-MAG3 with that of 131I-OIH. After simultaneous bolus injection of both 99mTc-MAG3 and 131I-OIH, 8-point venous blood sampling was performed from 2 to 44 min post injection. Aliquoted plasma samples were counted for radioactivity along with the injected standard to obtain % injected dose/ml plasma for each tracer. Using obtained time-concentration data, classical 2 compartment model analysis was performed for both tracers to obtain various pharmacokinetic parameters, including distribution volumes (Vds), inter compartmental rate constants, and plasma clearance. In these parameters, Vd of central compartment, Vd at steady state, central to peripheral inter compartmental rate constant, and plasma clearance were significantly larger for 131I-OIH. In all parameters, significant correlation was found between 99mTc-MAG3 and 131I-OIH. The best correlation was seen in plasma clearance (r = 0.891, p < 0.0001). Plasma clearance ratio (99mTc-MAG3/131I-OIH), however, showed weak but significant negative correlation with serum creatinine, although this correlation was not likely to affect the overall correlation of clearance between 131I-OIH and 99mTc-MAG3. From these results, we confirmed that 99mTc-MAG3 clearance could be used as an alternative to 131I-OIH clearance, although pharmacokinetic behavior of 99mTc-MAG3 was not exactly the same as that of 131I-OIH. PMID- 8699620 TI - [Evaluation of the clinical usefulness of super dynamic 99mTc-HM-PAO SPECT in ischemic cerebrovascular disease--detection of hypo- and hyperperfusion area]. AB - The purpose of this study is to assess the clinical usefulness of super dynamic SPECT of 99mTc-HM-PAO. Six patients with unilateral occlusion of middle cerebral artery (MCA) or internal carotid artery (ICA) in the chronic phase, and 5 patients with subacute cerebral infarction were studied. We used a ring-type SPECT "HEADTOME." Two types of collimator were used: a high sensitivity (HS) collimator for super dynamic scan and a high resolution (HR) collimator for static scan. First, the intravenous constant infusion of 99mTc-HM-PAO (925-1480 MBq) for 1 minute was started. After 30 seconds from the beginning of the injection, we performed the 12 seconds/frame super dynamic SPECT for 2 minutes. Then, the static SPECT for 10 minutes was done. For semiquantitative analyses, differential percentage of regional activity between affected and non-affected hemispheres was calculated in the 6th frame image of super dynamic SPECT and static SPECT image. In all 6 patients with unilateral occlusion of MCA and ICA, super dynamic SPECT images showed the better contrast of low perfusion areas in comparison with the static SPECT images. In 5 patients with subacute cerebral infarction who showed focal hyperactivities on static SPECT, focal hyperactivities (hyperperfusion or hyperemia) were displayed in 3 cases, whereas, focal hypo- or isoactivities (hypo- or isoperfusion) were shown in 2 cases on super dynamic SPECT. However, all patients with subacute cerebral infarction showed hyperfixation on static SPECT as compared with super dynamic SPECT. Although the image quality on super dynamic SPECT is not as high as that on static SPECT, cerebral hemodynamics would be detected with less backdiffusion of 99mTc-HM-PAO from the brain to blood, and with less accumulation of hydrophilic components in subacute infarct region. In conclusion, super dynamic SPECT in early distribution of 99mTc-HM-PAO using dedicated SPECT device might be helpful to detect cerebral perfusion close to true cerebral blood flow distribution. PMID- 8699618 TI - [Comparative evaluation of 99mTc-MIBI (hexakis2-methoxy isobutyl isonitrile) and 201Tl-chloride in primary lung cancer]. AB - We performed comparative study, using 99mTc-MIBI and 201Tl-chloride in patients with primary lung cancer. There were 42 patients with primary lung cancer. All patients underwent dual radionuclide imaging with 201Tl-chloride and 99mTc-MIBI. Regions of interest were placed over the tumor area (T) and contralateral normal lung area (N). A tumor to normal lung ratio (T/N ratio) and retention index were calculated by early and delayed ratios. In the SPECT images, the positive rate was 98% in both the early and delayed images for 201Tl-chloride and 95% in the early and 88% in the delayed images for 99mTc-MIBI. Both early and delayed T/N ratios of 201Tl-chloride were significantly higher than those of 99mTc-MIBI. The retention index of 201Tl-chloride was higher than that of 99mTc-MIBI. T/N ratio and retention index did not significantly correlated with reference to histological types. We conclude that 99mTc-MIBI SPECT can be helpful in localizing primary lung cancers. However, in our study the tumor accumulation of 99mTc-MIBI was significantly lower compared with 201Tl-chloride. PMID- 8699622 TI - [Evaluation of pulmonary perfusion in a patient with agenesis of the left pulmonary artery: usefulness of radionuclide angiography]. AB - We reported a case with agenesis of the left pulmonary artery, in which radionuclide angiography with 99mTc-HSA and time activity curve (TAC) were useful in evaluating pulmonary perfusion in the effected lung. The case involved a 32 year-old male, who underwent nuclear medicine examination including 99mTc-MAA scanning, 81mKr scanning and 99mTc-HSA angiography. 99mTc-MAA and 81mKr scanning showed the perfusion defect and decreased ventilation in the effected lung, respectively. On the other hand, the delayed images of 99mTc-HSA angiography showed the existence of perfusion in the effected lung, although the early images showed the perfusion defect in the same lung. The TAC whose region of interest was placed on the hilus showed that the effected lung was gradually filled with the blood flow through the collateral pathways. In addition, the ratio of area under the TAC on the contralateral lung versus the effected lung was 4.6, while the volume ratio of the contralateral lung versus the effected lung obtained from X-ray CT images was 2.7. Therefore, it was suggested that the perfusion per volume in the effected lung was decreased, compared with that in the contralateral lung. It was concluded that 99mTc-HSA angiography was useful in evaluating the perfusion of the effected lung in a patient with agenesis of the left pulmonary artery. PMID- 8699621 TI - [Two cases of breast cancer detected by 99mTc-tetrofosmin myocardial scintigraphy]. AB - Breast cancer ranks the second position among the cancer of women in Japan. We report two cases of breast cancer detected by 99mTc-tetrofosmin. First case was 51 years old female with breast cancer (invasive papillotubular carcinoma) and dextrocardia. She received 99mTc-tetrofosmin myocardial scintigraphy to evaluate dextrocardia and suspicious coronary artery disease. A planar image of 99mTc tetrofosmin myocardial scintigraphy showed myocardium at the right side, gall bladder at the left lower side and abnormal uptake on the left chest wall. Transaxial images of 99mTc-tetrofosmin myocardial SPECT showed myocardium at the right side and abnormal uptake on the left chest wall. Second case was 78 years old female with breast cancer (intracystic papillary carcinoma) and arrhythmia. 99mTc-tetrofosmin myocardial scintigraphy was performed to evaluate arrhythmia and suspicious coronary artery disease. A planar image of 99mTc-tetrofosmin myocardial scintigraphy shows hot nodule at the lateral side of the myocardium. Transaxial images of 99mTc-tetrofosmin myocardial SPECT showed abnormal uptake at the left lateral side on the chest wall. Both cases appeared illed foci as abnormal uptake with 99mTc-tetrofosmin scintigraphy, although histological diagnosis was different. We conclude that 99mTc-tetrofosmin scintigraphy is helpful for evaluating breast cancer. PMID- 8699623 TI - [A case of metastatic gastrinomas in the liver visualized by 111In-DTPA-D-Phe octreotide (111In-pentetreotide)]. AB - A 51-year-old woman with metastatic gastrinomas in the liver was intravenously injected with 80.3 MBq of 111In-DTPA-D-Phe-octreotide (111In-pentetreotide). Planar images were obtained at 4 hr, 24 hr and 48 hr after the injection. SPECT was also performed at 24 hr after the injection. Two metastatic lesions in the liver were visualized on each imaging occasion. 111In-pentetreotide imaging is useful to visualize gastrinomas. PMID- 8699624 TI - [Comparison of cerebral vasoreactivity to acetazolamide in normal volunteer among 123I-IMP, 99mTc-ECD and 99mTc-HMPAO]. AB - We studied the difference in the cerebral vasoreactivity to acetazolamide among three cerebral blood flow tracers, N-isopropyl-p-123I-iodoamphetamine (123I-IMP), 99mTc-ethyl cysteinate dimer (99mTc-ECD), 99mTc-hexamethylpropylene amine oxime (99mTc-HMPAO). Subjects were 4 healthy male adult volunteers at ages respectively of 30, 30, 35 and 41 years. Each subject underwent SPECT total 6 times. The three tracers were each used in the tests during rest and during acetazolamide loading, which were performed on different days. At least three days were allowed to intervene between one test and another, and all tests were completed within 2 months. The blood flow was calculated on the microsphere model with 123I-IMP, and Patlak plot method with 99mTc-ECD and 99mTc-HMPAO, to perform quantitative assessment. In the acetazolamide loading test, 1 g acetazolamide was intravenously administered, and each tracer was administered at 15 minutes after that. mCBF and BPI data on total 8 sides, one side representing the right or left side of each subject, were statistically analyzed. For rCBF, the region of interest was set up on the right and left sides of the frontal, temporal and occipital lobes on the slice passing through the third ventricle. The percent increase in mCBF with IMP was 29.3 +/- 10.5% (Mean +/- SD), significantly higher than 10.4 +/- 3.9% (p < 0.05) with ECD or 8.9 +/- 6.9% (p < 0.02) with HMPAO. The percent increase in rCBF with IMP was 30.8 +/- 13.4%, significantly higher than 14.3 +/- 13% (p < 0.001) with ECD or 8.7 +/- 14.8% (p < 0.001) with HMPAO. The percent increase in rCBF with ECD was higher than that with HMPAO, but not significantly. The percent increase in BPI calculated by Patlak plot method with ECD (26.4 +/- 14.3%) was higher than that with HMPAO (13.9 +/- 12.8%), but not significantly. It has been pointed out that 99mTc-ECD and 99mTc-HMPAO underestimate blood flow in the high blood flow area, which seemed to account for the underestimation of acetazolamide reactivity. The extent of underestimation in the high blood flow area is less with 99mTc-ECD than with 99mTc-HMPAO, while the stability of the preparation under acetazolamide is maintained, which seemed to explain difference in the reactivity. PMID- 8699625 TI - Recent progress in human molecular biology and expression profiling of active genes in the body. AB - Recent progress in molecular biology based upon rapidly developing DNA technology is reviewed. Emphasis is placed on the developing human genome project that includes structural as well as functional analyses of the genome. Expression profiling of active genes in the body helps construct a data-base for the functional aspects of the human genome. PMID- 8699626 TI - No relation of plasma morphine level to the severity of naloxone-induced withdrawal in acute morphine-dependent rats. AB - Plasma morphine concentration and naloxone-precipitated withdrawal body weight loss and plasma corticosterone (PCS) increase were determined at 12, 18 and 24 hr after i.v. infusion of morphine at a constant rate of 10 mg/kg/hr for 4 hr in Sprague-Dawley rats. Plasma morphine concentration declined 98.0% within 12 hr and further declined 58.8% during 12-24 hr after morphine infusion. There was a significant difference between plasma morphine concentrations at 12 and 24 hr after the morphine infusion. Naloxone (0.5 and 2.0 mg/kg)-precipitated withdrawal, but not spontaneous withdrawal, was elicited at 12-24 hr after the morphine infusion, and the severity of withdrawal precipitated by 2.0 mg/kg naloxone was the same at 12-24 hr after the morphine infusion. Furthermore, there was no significant correlation between plasma morphine concentration and body weight loss or PCS increase. The results suggest that a constant degree of morphine dependence is sustained during 12-24 hr after the morphine infusion and the severity of naloxone-precipitated withdrawal is not related to the plasma morphine concentration at the time of naloxone injection, that is, the rate of morphine removal from its receptor sites. PMID- 8699627 TI - Effect of phorbol ester, 12-deoxyphorbol 13-isobutylate (DPB), on muscle tension and cytosolic Ca2+ in rat anococcygeus muscle. AB - Effects of phorbol ester, 12-deoxyphorbol 13-isobutyrate (DPB), on muscle tension and cytosolic Ca2+ ([Ca2+]i) level was investigated in rat anococcygeus muscle in comparison with other smooth muscles. 1) DPB (10(-6) M) induced a large contraction and an elevation of [Ca2+]i level in rat aorta and small and rhythmic changes in tension and [Ca2+]i level in guinea pig ileum. However, DPB did not change either of the parameters in rat anococcygeus muscle. 2) DPB caused tension development without changing the [Ca2+]i level elevated by high K+, ionomycin or beta-escin in the anococcygeus muscle. 3) In the beta-escin permeabilized muscles of guinea pig ileum and urinary bladder, rabbit mesenteric artery and rat anococcygeus muscle, DPB enhanced the Ca(2+)-developed tension. Moreover, the enhancement was inhibited by H-7 (3 x 10(-5) M). 4) DPB did not cause muscle tension to develop in the muscle of rat aorta, guinea pig ileum and rat anococcygeus muscle, pretreated with phorbol 12-myristate 13-acetate for 24 hr. In conclusion, DPB showed different contractile effects on the aorta, ileum and anococcygeus muscle, respectively. The initiation of muscle tension by DPB probably requires [Ca2+]i and the DPB-induced enhancement may be due to a Ca2+ sensitization of contractile elements in the anococcygeus muscle. Therefore, the difference between the DPB-induced response of the anococcygeus muscle and those of the other muscles seems to be due to a different Ca2+ movement caused by DPB. Moreover, it is suggested that DPB develops muscle tension by increasing [Ca2+]i and enhances it through the mediation of protein kinase C in the anococcygeus muscle as well as the other smooth muscles. PMID- 8699628 TI - Effect of serotonin (5-HT)3-receptor antagonists YM060, YM114 (KAE-393), ondansetron and granisetron on 5-HT4 receptors and gastric emptying in rodents. AB - We investigated the effects of YM060 [(R)-5-[(1-methyl-3-indolyl)carbonyl] 4,5,6,7-tetrahydro-1H-benzimidazol e hydrochloride] and YM114 (KAE-393) [(R)-5 [(2,3-dihydro-1-indolyl)-carbonyl]-4,5,6,7-tetrahydro-1H- benzimidazole hydrochloride] on 5-HT4 receptors and gastric emptying in normal and cisplatin treated rats and compared results with those for ondansetron and granisetron. YM060, YM114, ondansetron and granisetron dose-dependently inhibited the specific binding of [3H]-GR113808 ([[1-[(2-methylsulphonyl)amino]ethyl]-4-piperidin yl]methyl 1-methyl-1H-indole-3-carboxylate) in guinea pig striatum, with pKi values of 5.53, 5.13, 5.21 and 5.63, respectively. According to the pKi values reported in 5-HT3-receptor binding of [3H]GR65630 to rat cortical membranes, the affinity of YM060, YM114, ondansetron and granisetron for 5-HT4 receptors was approximately 5, 5, 3.5 and 3.5 log units lower than that for 5-HT3 receptors, respectively. In the guinea pig longitudinal muscle with myenteric plexus and rat esophageal tunica muscularis mucosae, YM060 and YM114 showed neither 5-HT4 agonistic nor antagonistic properties. Although ondansetron produced concentration-dependent increases in the magnitude of the twitch response in longitudinal muscle, it did not possess 5-HT3- and 5-HT4-agonistic activity. Granisetron antagonized 5-HT-induced relaxation of the rat esophagus with an apparent pA2 value of 5.39. Intravenous YM060, YM114, ondansetron and granisetron significantly enhanced gastric emptying of glass beads and improved cisplatin induced slowing of gastric emptying in rats. These results indicate that the selectivity of YM060 and YM114 for 5-HT3 receptors is higher than that of ondansetron and granisetron and that these 5-HT3 antagonists have gastroprokinetic activity in normal and cisplatin-treated rats without affecting 5-HT4 receptors. PMID- 8699629 TI - Antihypertensive effect of chronic KT3-671, a structurally new nonpeptide angiotensin AT1-receptor antagonist, in stroke-prone spontaneously hypertensive rats. AB - KT3-671 (2-propyl-8-oxo-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]-4,5,6, 7 tetrahydrocycloheptimidazole), a structurally new nonpeptide angiotensin AT1 receptor antagonist, was administered orally and repeatedly to 15-week-old stroke prone spontaneously hypertensive rats for 7 weeks; and its effects on blood pressure, heart rate, renal function, plasma renin concentration (PRC), plasma aldosterone concentration (PAC) and hypertension-related tissue damage in the brain, heart, kidney and mesenteric artery were investigated. KT3-671 at a dose of 3 or 10 mg/kg, p.o. per day prevented development of hypertension and produced a significant and consistent reduction of blood pressure in a dose-dependent manner. Enalapril at a dose of 10 mg/kg per day produced cardiovascular effects similar to those of KT3-671 at 10 mg/kg. Despite marked reduction in blood pressure, neither KT3-671 nor enalapril affected the heart rate. KT3-671 at 10 mg/kg produced a transient and significant reduction of urinary sodium excretion in the second week, but did not affect renal function at any other time during the experimental period. Both KT3-671 at 10 mg/kg and enalapril at 10 mg/kg produced a significant increase in PRC and showed a tendency to decrease PAC. Repeated administration of KT3-671 reduced the severity of the pathological changes in the kidney. These results suggest that KT3-671 is a potentially useful antihypertensive drug. PMID- 8699630 TI - Irsogladine inhibits ionomycin-induced decrease in intercellular communication in cultured rabbit gastric epithelial cells. AB - Effects of irsogladine on ionomycin-induced decrease in intercellular communication and increase in intracellular concentration of Ca2+ ([Ca2+]i) were investigated in cultured rabbit gastric epithelial cells. Ionomycin (10(-7)-10( 6) M) transiently and concentration-dependently inhibited intercellular communication concomitantly with the elevation of [Ca2+]i in the presence and absence of extracellular Ca2+. Irsogladine (10(-5) M), which has been shown to facilitate intercellular communication, suppressed the ionomycin-induced elevation of [Ca2+]i and decrease in intercellular communication. The suppression of the ionomycin effects by irsogladine was independent of extracellular Ca2+. TMB-8 [8-(diethylamino)octyl-3,4,5-trimethoxy-benzoate hydrochloride] (10(-6) M) also suppressed the ionomycin-induced elevation of [Ca2+]i and decrease in intercellular communication. These results indicate that the ionomycin-induced decrease in intercellular communication may be due to Ca2+ mobilization from intracellular stores. Inhibitory effects of irsogladine and TMB-8 on the ionomycin-induced decrease in intercellular communication may be produced by suppressing Ca2+ mobilization. PMID- 8699632 TI - Mechanism and properties of inhibition of purified rat brain adenylate cyclase by G protein beta gamma-subunits. AB - The mode of the inhibition of purified rat brain adenylate cyclase by the beta gamma-subunits of G protein (beta gamma) was studied. These subunits inhibited the catalytic activity of the cyclase with the maximal inhibition of 85% and the half-maximal inhibition at about 0.7 nM beta gamma. The complex of beta gamma and adenylate cyclase isolated by density gradient centrifugation contained 1.8-2.0 mol beta gamma per mol of the cyclase when beta gamma was assayed by immunoblotting and by its inhibitory activity on adenylate cyclase. However, the beta gamma concentration-inhibition curves suggest that one of the two beta gamma molecules bound may be essential for the inhibition. The role for the second beta gamma molecule is unknown. As a tentative estimate, 70% of the adenylate cyclase activity remained inhibited by beta gamma when the complex was isolated. The inhibition was not dependent on G alpha s or calmodulin. Although purified adenylate cyclase contained a protein (0.06-0.08 mol/mol of adenylate cyclase) that reacted with anti-G alpha s antibody, this protein was not liberated from the cyclase when it formed a complex with beta gamma. In addition, guanine nucleotide analogs little affected the cyclase activity or the inhibition by beta gamma. The inhibition by beta gamma was reversed by the dilution of the complex, and the following re-addition of beta gamma suppressed the enzyme activity to about 15% of the initial activity again. These findings provide strong evidence that beta gamma inhibits adenylate cyclase directly and reversibly through the formation of the complex. PMID- 8699631 TI - Cardiovascular effects of the combination of OPC-18790 and dopamine in halothane anesthetized dogs. AB - OPC-18790, (+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-quin olinone, is a novel positive inotropic agent, and its mechanism of positive inotropic action involves not only phosphodiesterase inhibition, but also a prolongation of action potential duration in ventricular muscle. Prolongation of action potential duration is also a property of class III antiarrhythmic agents; therefore, we examined the cardiohemodynamic effects and arrhythmogenicity of a combination of OPC-18790 and dopamine in halothane-anesthetized dogs. Dopamine (5 micrograms/kg/min) alone increased the peak of the first derivative of left ventricular pressure (LVdP/dtmax) and cardiac output (CO) by 43-48% and 16-20%, respectively, while OPC-18790 (10 micrograms/kg/min) increased these parameters by 56% and 22%, respectively. The combination of OPC-18790 (10 micrograms/kg/min) and dopamine (5 micrograms/kg/min) and dopamine alone at an increased dose of 10 micrograms/kg/min further increased LVdP/dtmax and CO by 104-113% and 29-30%, respectively. Thus, positive inotropic effects were equally observed in both groups, and the effects of OPC-18790 and dopamine seemed to be additive. The other hemodynamic effects were similar among all groups. Arrhythmias such as premature ventricular contraction developed in 5 out of 7 dogs (71.4%) in the 10 micrograms/kg/min dopamine group, while only one premature ventricular contraction was observed in 1 of 7 dogs (14.3%) in the OPC-18790 (10 micrograms/kg/min) and dopamine (5 micrograms/kg/min) combination group. These results suggest that the combination of OPC-18790 and dopamine may provide new therapeutic options for the treatment of heart failure. PMID- 8699634 TI - Comparison of effects of famotidine on vagally and field-electrically stimulated acid secretion in the isolated mouse whole stomach. AB - Effects of famotidine on neuronally evoked acid secretion were investigated by means of vagal (at the lower esophagus level) and field-electrical stimulation (around the stomach) in the isolated mouse whole stomach preparation. Each of the electrical stimulations caused a frequency-dependent (1 to 20 Hz) increase in acid output, and the secretory response was abolished by tetrodotoxin or atropine. In the case of field stimulation, the acid secretion was not completely inhibited by hexamethonium. When 10 Hz frequency was applied with either vagal or field-electrical stimulation, the acid secretion was only partly inhibited by famotidine at doses of up to 30 microM. In contrast, the acid response to 2 Hz stimulation was almost completely inhibited by 1 microM famotidine. In the presence of neostigmine (30 nM), the 2 Hz vagally stimulated acid secretion became partly resistant to the effect of famotidine (10 microM). These results suggest that both vagally and field-electrically stimulated acid secretions have essentially the same characteristics and that the secretory mechanism through histamine release is exclusively dominant with weak stimulation, while the cholinergic mechanism on parietal cells is sufficient for reaching the maximal secretory response with strong stimulation. PMID- 8699633 TI - A novel adrenaline derivative, AZ002, and its hypoglycemic action in yellow KK mice. AB - AZ002 (L-threo-(3,4-dihydroxy phenyl)-N-methyl serine methyl ester) is a newly synthesized adrenaline derivative. AZ002 caused relaxation of rat jejunum (beta 3 receptors) (ED50 = 18 microM), but did not affect the atrial rate (beta 1) or tracheal relaxation (beta 2) at a concentration of 0.3 mM. The pA2 values for propranolol in inhibiting the isoproterenol- and AZ002-stimulated relaxation of rat jejunum were 6.27 and 6.33, respectively. Thus, AZ002 is a selective agonist for beta 3-adrenoceptor. AZ002 stimulated lipolysis (ED50 = 10 microM) and glucose uptake (ED50 = 1 microM) in rat adipocytes. In both cases, stimulation was antagonized by high concentrations of the beta-adrenoceptor antagonist propranolol, but not by the alpha-adrenoceptor antagonist phentolamine. The effect of AZ002 on glucose uptake was synergistic with that of insulin. AZ002 was also assessed in vivo by using genetically obese mice (KK/Ay strain) with hyperglycemia. Administration of AZ002 in the diet for a week decreased blood glucose and non-esterified fatty acids. PMID- 8699635 TI - KW-5092, a novel gastroprokinetic agent, reverses the norepinephrine-induced decline of the gastric mucosal blood flow in rats. AB - We examined the effects of KW-5092 ((1-[2-[[[5-(piperidinomethyl)-2 furanyl]methyl]-amino]ethyl]- 2-imidazolidinylidene) propanedinitrile fumarate), a novel gastroprokinetic agent, on gastric mucosal blood flow (GMBF) in anesthetized rats. Intravenous infusion of KW-5092 (0.1 mg/kg/min for 30 min), which did not affect the basal GMBF, reversed the norepinephrine (1 microgram/kg/min, i.v. infusion for 30 min)-induced decline of GMBF in the corpus and the antrum. The improvement by KW-5092 of the GMBF was abolished by atropine (0.1 mg/kg/min, i.v. infusion for 30 min). These results suggest that KW-5092, via cholinergic activation, could counteract the decline of GMBF induced by adrenergic activation. PMID- 8699636 TI - Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on thyrotropin releasing hormone-like immunoreactivity in the cerebral cortex and hippocampus of aged rats. AB - We investigated the effects of a novel prolyl endopeptidase inhibitor, JTP-4819 ((S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N- (phenylmethyl)-1 pyrrolidinecarboxamide), on thyrotropin-releasing hormone (TRH)-like immunoreactivity (TRH-LI) in the cerebral cortex and hippocampus of aged rats. The TRH-LI content of both brain regions in aged rats was significantly lower than that in young rats. A single oral dose of JTP-4819 (3 mg/kg) restored the cortical TRH-LI content in aged rats, while doses of 0.3-3 mg/kg restored it in the hippocampus. Repeated oral administration of JTP-4819 at a dose of 1 mg/kg for 21 days produced a significant increase of TRH-LI in the cerebral cortex, while it did so in the hippocampus at doses of 0.3 and 1 mg/kg. Our findings suggest that JTP-4819 may improve the functioning of TRHergic neurons, which deteriorate with senescence. PMID- 8699637 TI - A xanthine derivative denbufylline inhibits negative inotropic response to verapamil in guinea pig ventricular papillary muscles, independent of its phosphodiesterase inhibitory activity. AB - A phosphodiesterase (PDE) III inhibitor, amrinone, inhibited both the negative inotropic actions of verapamil and nicardipine in guinea pig ventricular papillary muscle; this effect was canceled by the protein kinase A inhibitor H 89. The PDE IV inhibitor 1,3-di-n-butyl-7-(2'-oxopropyl)xanthine (denbufylline), which elicited a negative inotropic action by itself, attenuated the action of verapamil up to 10 microM, without any interaction with nicardipine. The attenuation by denbufylline was not influenced by H-89. This suggests that in the ventricular papillary muscle, denbufylline acts on some verapamil-sensitive site(s) in the membrane and interferes with the calcium channel function without involvement of its PDE inhibitory activity. PMID- 8699638 TI - Complementary effects of paeoniflorin and glycyrrhizin on intracellular Ca2+ mobilization in the nerve-stimulated skeletal muscle of mice. AB - Effects of paeoniflorin (PF) and glycyrrhizin (GLR), contained in paeony and licorice roots, respectively, on contractile and non-contractile Ca2+ mobilization were examined by measuring the Ca(2+)-aequorin luminescence (Ca2+ transients) of the nerve-stimulated skeletal muscle of mice in the presence of neostigmine (0.3 microM). PF (0.1-1 mM) prolonged the duration of non-contractile Ca2+ transients, which may induce the desensitization of nicotinic acetylcholine receptor, but did not affect contractile Ca2+ transients. GLR (0.3-1 mM) depressed contractile Ca2+ transients without affecting non-contractile transients. These results suggest that PF and GLR may have complementary effects on intracellular Ca2+ mobilization to block the neuromuscular transmission. PMID- 8699639 TI - Selective inhibition of inducible nitric oxide synthase by agmatine. AB - Agmatine was about as potent as aminoguanidine to inhibit the activity of the inducible form of nitric oxide synthase (iNOS) in isolated rat aorta. Like aminoguanidine, agmatine was devoid of significant activity on the constitutive form of NOS. Agmatine inhibited the conversion of [3H]L-arginine in [3H]L citrulline in partially purified iNOS from macrophages (IC50 = 262 +/- 39.9 microM). Thus, our data suggest that agmatine may act as endogenous inhibitor of iNOS. PMID- 8699640 TI - Induction of cyclooxygenase type-2 (COX-2) in rat endometrium at the peak of serum estradiol during the estrus cycle. AB - We investigated the induction of cyclooxygenase (COX) in rat endometrium during the estrus cycle. The estrus cycle was divided into five stages (proestrus, estrus, diestrus-1, diestrus-2, diestrus-3) by cytological observation of vaginal smears. COX-1 was detected in the endometrium during all five stages of the estrus cycle. In contrast, COX-2 in the endometrium was detectable only in three stages (diestrus-3, proestrus, estrus) and showed a peak at diestrus-3, coinciding with the peak in serum estradiol level, suggesting the estradiol dependent induction of COX-2. PMID- 8699641 TI - [The effect of stimulus-driven factor on attentional capture: evidence from visual search paradigm containing static and dynamic stimuli]. AB - The present study investigated the nature of attentional control when the stimulus display contained both static and dynamic items. Subjects searched for a target defined by color presented among nontargets, one of which was a distractor with a unique feature in a different stimulus dimension. Experiment 1 showed that the presence of a distractor with a task irrelevant form hindered identification of the color-defined target. When it was easy to distinguish the target from the other items, this attentional capture was not observed even if the display contained a motion distractor (Experiment 2). Decreasing the saliency of a target color yielded the attentional capture by a motion distractor and interfered target identification performance (Experiment 3). These results suggest that the attentional control mainly depends on the stimulus-driven activations caused by differences between features in stimulus dimensions whether the target and the distractor are defined by static or dynamic features. In order to explain these findings of the attentional capture, a possibility for proposing the single activation map model was discussed. PMID- 8699642 TI - [The effects of social support reciprocity on mental and physical health of young adults]. AB - The present study examined the effects that reciprocity of social support has on mental and physical health of young adults from the viewpoint that an individual is both an active and passive support provider as well as receiver. The questionnaire, completed by 505 young adults, included items that measured four kinds of support: requested by and provided to others, and requested and received by them. It also asked about the affects associated with support relationships, in addition to the level of adjustment and mental and physical health. Correlational analyses showed that young adults felt their support relationships were fairly reciprocal. ANOVA and multiple regression indicated that lack of reciprocity was in general associated with negative affects and poor health. Providing more support than receiving lead to dissatisfaction, and receiving more than providing to a feeling of indebtedness. Finally, the data supported the prediction that there was a path from support equity to affective state to mental and physical health. PMID- 8699643 TI - [Self-assessment of ability and expectation of self-enhancement]. AB - This study examined how the level of desire to acquire an ability and the perceived probability that it may be acquired affect self-assessment of the ability. From three categories, (1) desire to acquire is strong and desired level of acquisition is high, (2) desire is strong and desired level of acquisition is average, and (3) desire is weak, ten abilities each were chosen by each of 77 undergraduates. They also indicated the perceived probability that each ability might be acquired. Then, self-assessment behavior for each ability was measured with the choice and preference among four tasks that differed in terms of ability diagnosticity. The main results were as follows: (a) High-diagnostic tasks were chosen more often than the others, regardless of the desire to acquire and the probability. (b) Preference for high-diagnostic tasks was stronger when the desired acquisition level was high or average and the perceived probability was high. (c) Subjects' reason for self-assessment was their need to acquire accurate self-knowledge. The results suggest that expectation of future self-enhancement affects the likelihood of self-assessment behavior. PMID- 8699644 TI - [A Japanese version of inventory of orientation toward privacy]. AB - Marshall (1974) and Pedersen (1979) theorized and studied Orientation toward Privacy, but the concept has not been explored extensively in this country. In this study, a Japanese version of their Inventory of Orientation toward Privacy was constructed. In Study 1, translated items of the inventory were examined to see whether they had the same dimensions as the original scale. The results indicated that the dimensions were similar, except an "Anonymity" factor. In Study 2, excluding anonymity items, a 21-item Japanese version was constructed, incorporating Iwata's (1987) findings as well. Factor analysis revealed seven factors, Free will, Intimacy with Friends, Reserve, Intimacy with Family, Seclusion, and Isolation. Finally, in Study 3, the new Inventory was administered to another sample, and its factor structure re-examined. The structure proved to be reasonably stable, and it therefore may be concluded that the scale meaningfully measured Orientation toward Privacy. PMID- 8699645 TI - [A study on the mechanism of anxiety reduction through training: a comparison and examination of the stress-model and the distraction-model]. AB - This study was carried out on the basis of Wolpe's principle of reciprocal inhibition. The stress-model asserts that the essence of anxiety reduction is the shift from the ergotropic to the trophotropic state, while the distraction-model asserts that distraction is the essence of anxiety reduction. The present experiment brings light to the following points not clarified in previous studies: (1) the effects of training vary with the symptoms of clients suffering from generalized anxiety disorders. The anxiety reducing effects of relaxation training is higher among those who complain of emotional syndromes than in those who complain of behavioral syndromes; (2) in both generalized anxiety disorders and social phobias, the mechanism of anxiety reduction matches the distraction model more than the stress model; (3) the effects of anxiety reduction by relaxation training and stress-relieving training carried out in the counseling room or in the client's home is higher in cases of generalized anxiety disorders than in social phobias. PMID- 8699646 TI - President's Message: How to they get there? On quality equipment and personnel for patient transport. PMID- 8699647 TI - The growing need for emergency nurse practitioners. PMID- 8699648 TI - Emergency/ambulatory care nurse practitioner programs: the emphasis and the need. PMID- 8699649 TI - More on evidence collection. PMID- 8699652 TI - Comprehensive program to improve care leads to reduced ED use by patients with asthma: one hospital's experience. PMID- 8699651 TI - Thrombolytic therapy in a 79-year-old man with massive pulmonary embolism and unstable hemodynamic status. PMID- 8699650 TI - A look back: concussion of the brain. PMID- 8699653 TI - Recognizing infective endocarditis: case study of a 28-year-old. PMID- 8699654 TI - An overview of latex allergy and its implications for emergency nurses. PMID- 8699655 TI - "That will look good on a resume!": Padding, fluffing, or maintaining our values? PMID- 8699656 TI - Bereavement protocols. PMID- 8699657 TI - Use of unlicensed assistive personnel: anecdotes and antidotes. PMID- 8699658 TI - The good, bad, and ugly: using ketamine for ED pediatric patients. PMID- 8699659 TI - Breaking the silence: what emergency nurses can do about battering. PMID- 8699660 TI - Flight crew safety: a compelling case example. PMID- 8699661 TI - Developing a graduate forensic nursing elective. AB - The forensic nursing and trauma nursing courses can be presented as individual or complementary graduate courses. Knowledge of forensic principles enhances the nurse's assessment and documentation skills that can serve to support and substantiate his or her suspicions of criminal or abusive situations. Clearly, nurses educated in the forensic sciences can better serve the public who come to their agencies in search of help, compassion, and safety--and sometimes even justice. PMID- 8699662 TI - Wireless bedside registration in the emergency department. PMID- 8699663 TI - Latex allergy: one emergency department's response. PMID- 8699664 TI - Cocaine abuse case review: a few comments. PMID- 8699665 TI - The case of the blue baby: ED management of tetralogy of Fallot. PMID- 8699666 TI - Ear temperatures: making research-based clinical decisions. PMID- 8699667 TI - Date rape drug alert. PMID- 8699668 TI - Glasgow Coma Scale: a quick review. PMID- 8699669 TI - An adult female with furuncles and formication. PMID- 8699670 TI - Annie O'Connor, NP, MS: domestic violence survivor and community advocate. Interview by Marlene Jezierski. PMID- 8699671 TI - An important job. PMID- 8699672 TI - Believing the child. PMID- 8699673 TI - More on TennCare: the impact of state health care reform on emergency patients and caregivers. PMID- 8699674 TI - [Medical topics, IVH and intestinal feeding]. PMID- 8699675 TI - [Perspective: counseling service in the work place]. PMID- 8699676 TI - [Development of independent nursing practice: services we provide]. PMID- 8699677 TI - [The nursing shortage and the 1990s: realities and remedies: nursing shortage outside hospitals]. PMID- 8699678 TI - [Nursing day forum. Beginning of human life]. PMID- 8699679 TI - [Survey of evaluation by nursing schools of the 1990 revision of the curriculum of nursing education. JNA Curriculum Review Committee]. PMID- 8699681 TI - [Nursing administrators' course I studied at Kanagawa Nursing School]. PMID- 8699682 TI - [Outline of proposed revision of health insurance law]. PMID- 8699680 TI - [Translation, interpretation and nursing]. PMID- 8699683 TI - [Physician's orders and nursing service. An analysis of doctor-nurse relationship according to the provisions of the law]. PMID- 8699684 TI - [Physician's order and nursing service. Doctors and nurses as coworkers through doctors' orders]. PMID- 8699685 TI - [Physician's order and nursing service. Scope of nursing practice carried out by physicians' order]. PMID- 8699686 TI - [Physician's order and nursing service. Physicians' orders need to be interpreted by nursing department]. PMID- 8699688 TI - [New minister of health and welfare--welfare and care plan for the elderly and sick]. PMID- 8699687 TI - [Physician's order and nursing service. Ethical issues related to physicians' order]. PMID- 8699689 TI - [Report of director of nursing: emergency medicine and life saving activities]. PMID- 8699690 TI - [We admire nurses: informed consent and communication training using SP as I observed in the US hospitals]. PMID- 8699691 TI - [Baccalaureate programs in nursing]. PMID- 8699692 TI - [Report of director of nursing: nurses labor market is changing]. PMID- 8699693 TI - [We admire nurses: communication training with simulated patients]. PMID- 8699695 TI - [Be strong but also be gentle]. PMID- 8699694 TI - [Development of independent nursing practice: home health service as business]. PMID- 8699696 TI - [Survey of evaluation by nursing schools of the 1990 revision of the curriculum of nursing education. JNA Curriculum Review Committee]. PMID- 8699697 TI - [Survey of nursing research conducted by members of Kawaga Prefecture Nursing Association]. PMID- 8699699 TI - [Informed consent as it should be. Informed consent improves QOL of patients]. PMID- 8699698 TI - [Nursing should be made an attractive work]. PMID- 8699700 TI - [Informed consent as it should be. Informed consent for hospice patients]. PMID- 8699701 TI - [Informed consent as it should be. Problems of informed consent of organ donors and their family]. PMID- 8699702 TI - [Informed consent as it should be. Patients need nurses' help to give informed consent]. PMID- 8699703 TI - [Informed consent as it should be. Informed consent as patients' rights]. PMID- 8699705 TI - [Informed consent as it should be. Breast cancer patients are denied informed consent in Japan]. PMID- 8699704 TI - [Informed consent as it should be. Informed consent and blood transfusion]. PMID- 8699707 TI - [Outline of the National Health Budget Proposal for 1995]. PMID- 8699706 TI - [The nursing shortage and the 1990s: realities and remedies--nursing shortage and nursing education]. PMID- 8699709 TI - [We admire nurses: students' symposium on team medicine]. PMID- 8699708 TI - [Report of director of nursing: staffing level at Mayo Medical Center]. PMID- 8699710 TI - [Brain death and organ transplantation]. PMID- 8699711 TI - [Development of independent nursing practice: enterostomal therapy nurse]. PMID- 8699712 TI - [Bone marrow transplantation: transplants from non-kin donors]. PMID- 8699713 TI - [10th International Conference on AIDS in Yokohama]. PMID- 8699714 TI - [Nursing care of patients with AIDS and education of nurses at Hospital Cochin in Paris: hospital organization]. PMID- 8699715 TI - [Modification of forms of birth certificates and death certificates]. PMID- 8699716 TI - [Study of community health service provided by hospital nurses]. PMID- 8699717 TI - [We decided to care our mother who is senile at our home rather than at a nursing home]. PMID- 8699718 TI - [Provision of enjoyable hospital meals for patients. Providing hospital meals in a home-like atmosphere]. PMID- 8699719 TI - [Provision of enjoyable hospital meals for patients. There are choices for foods]. PMID- 8699720 TI - [Provision of enjoyable hospital meals for patients. Cultural background of meals]. PMID- 8699721 TI - [Provision of enjoyable hospital meals for patients. An art of serving enjoyable meals]. PMID- 8699722 TI - [Provision of enjoyable hospital meals for patients. Serving vegetable meals]. PMID- 8699723 TI - [Provision of enjoyable hospital meals for patients. Viking style breakfast]. PMID- 8699724 TI - [Provision of enjoyable hospital meals for patients. Meals that combine cure and care]. PMID- 8699725 TI - [Provision of enjoyable hospital meals for patients. Swallowing training for post operative esophageal cancer patients]. PMID- 8699726 TI - [Provision of enjoyable hospital meals for patients. Past and future of hospital meals]. PMID- 8699727 TI - [History of Japanese nursing that I lived: social status and nursing education (1926-1937)]. PMID- 8699729 TI - [Report of director of nursing: expanding role of nurses in the US]. PMID- 8699728 TI - [Social security policy related to nurses and nursing]. PMID- 8699730 TI - [We admire nurses: encouraged by the staff of Kasai City Hospital]. PMID- 8699731 TI - [Amenities in the hospital]. PMID- 8699732 TI - [Report on people and food around the world]. PMID- 8699733 TI - [Development of independent nursing practice: enterostomal therapy nurse]. PMID- 8699734 TI - [History of Japanese nursing that I lived: student life at Keio University Hospital Nursing School]. PMID- 8699735 TI - [Bone marrow transplantation: legal aspect of informed consent of donors]. PMID- 8699736 TI - [Nursing care of patients with AIDS and education of nurses at Hospital Cochin in Paris: telling diagnosis, wearing gloves]. PMID- 8699738 TI - [Pros and cons of telling patients their diagnosis]. PMID- 8699737 TI - [A color scale for bloody urine]. PMID- 8699739 TI - [Human rights of AIDS patients and international collaboration. WHO Nursing Collaborative Center]. PMID- 8699740 TI - [China-Japan Nursing Research Conference in Beijing]. PMID- 8699741 TI - [Using nursing diagnosis. Nursing diagnosis as a part of the nursing process]. PMID- 8699743 TI - [Using nursing diagnosis. Enabling nurses to make judgments as specialists]. PMID- 8699742 TI - [Using nursing diagnosis. Using nursing diagnosis for quality assurance]. PMID- 8699744 TI - [Using nursing diagnosis. Enabling nurses to concentrate on nursing]. PMID- 8699745 TI - [Using nursing diagnosis. Continuity and individualization of care made possible]. PMID- 8699746 TI - [Using nursing diagnosis. Helping patients to attain their goals]. PMID- 8699747 TI - [Using nursing diagnosis. Function of nursing made clear by nursing diagnosis]. PMID- 8699748 TI - [Using nursing diagnosis. Development of nursing diagnosis in Japan]. PMID- 8699749 TI - [Using nursing diagnosis. Development and current issues of nursing diagnosis in the U.S]. PMID- 8699750 TI - [Nurses' views expressed at the Committee to Discuss Nursing Issues in an Aging Society]. PMID- 8699751 TI - [Report of director of nursing: hospital meetings I attended]. PMID- 8699752 TI - [We admire nurses: my experience of "be-a-nurse-for-a-day" and informed consent]. PMID- 8699753 TI - [Medical topics. Limits of data from simulation]. PMID- 8699754 TI - [Perspective: animal behavior and human morals]. PMID- 8699755 TI - [Development of independent nursing practice: establishing a corporation to sell home nursing services]. PMID- 8699756 TI - [I love my nurses at the diabetes clinic]. PMID- 8699757 TI - [Bone marrow transplant: nursing in aseptic dust-free wards]. PMID- 8699758 TI - [The nursing shortage and the 1990s: realities and remedies: nursing shortage outside the hospital]. PMID- 8699760 TI - [Responses from the "be-a-nurse-for-a-day" participants]. PMID- 8699759 TI - [Visit to nursing department of National University Hospital in Beijing]. PMID- 8699761 TI - [JNA report. Donations to nursing scholarships and activities]. PMID- 8699762 TI - [Reports of JNA Annual General Convention and Professional Assemblies of Public Health Nurses, Midwives and Nurses]. PMID- 8699763 TI - [Issues and problems of proposed community health law. Outline and significance of the proposed community health law]. PMID- 8699764 TI - [Issues and problems of proposed community health law. Purpose of the proposed law as discussed at the task force]. PMID- 8699765 TI - [Issues and problems of proposed community health law. Roles expected of public health nurses under the proposed law]. PMID- 8699766 TI - [Issues and problems of proposed community health law. Community health initiatives of our town in Kumamoto Pref]. PMID- 8699767 TI - [Issues and problems of proposed community health law. Background paper of the proposed community health law]. PMID- 8699768 TI - [Neural mechanisms in infantile esotropia--what is not functioning?]. PMID- 8699769 TI - [Dermal fat transplant as autologous orbital implant]. AB - BACKGROUND: The use of orbital implants after an enucleation is the pre-condition for an adequate fitting of the prosthesis and gives the best functional and cosmetic results. The autogenous dermofat graft is an alternative to the widely used alloplastic orbital implants. It can be used as a primary implant or as a secondary implant for the correction of a contracted socket or a post enucleation socket syndrome. METHOD: Deepithelialized skin with subcutaneous fat is implanted into the socket. The rectus muscles, Tenon's capsule and conjunctive are fixed to the transplant separately. Surgical technique, possible complications and their therapy are presented. CONCLUSIONS: Disadvantages of the method are the more extensive surgery, some minor complications and the possible shrinkage of the transplant. Advantageous is the fact, that typical complications of all alloplastic implants, like migration and extrusion, can be avoided, heterologous materials like donor sclera are unnecessary and the functional and cosmetic results are very good. PMID- 8699770 TI - [Risk factors in patients with amaurosis fugax]. AB - BACKGROUND: In the diagnosis of retinal and cerebral vascular occlusion and migraine amaurosis fugax may be an important symptom. To evaluate the relation between cardiovascular diseases and amaurosis fugax we investigated the risk factors in patients with amaurosis fugax. MATERIALS AND METHODS: Twenty-four patients (14 m, 10 f; aged 22 to 84 years; mean: 55 +/- 19 years) with amaurosis fugax were included in this study. All patients underwent a detailed clinical and ophthalmological examination, including video fluorescein angiography shortly after the event. RESULTS: The duration of symptoms ranged from 30 seconds to 30 minutes (median: 3 minutes). Additional acute symptoms were headache in eight patients and tinnitus in one patient. Visual acuity showed no difference between the effected and the fellow eye. Intraocular pressure was normal in all eyes. Video fluorescein angiography revealed normal retinal perfusion times in all cases (arm-retina-time: 12.9 +/- 3.8 s; arteriovenous passage time: 1.8 +/- 0.7 s). Cardiovascular risk factors were present in all patients: 58% of the patients suffered from arterial hypertension, 8% of the patients from diabetes mellitus. Hyperlipidaemia was diagnosed in 17% of the patients, 46% of the patients were smokers. A history of cardiovascular disease (e.g. myocardial infarction, vitium, arrhythmia) was found in 58% of the patients. Cerebrovascular disease was diagnosed in 54% of the patients (migraine: 33%). CONCLUSIONS: The ophthalmologic examination especially the fluorescein angiography revealed no pathologic findings in patients with amaurosis fugax. The risk factor distribution corresponded to data found in patients with retinal artery occlusion. PMID- 8699771 TI - [Keratoplasty with scleral rim after the most severe chemical eye burns of the anterior eye segment]. AB - BACKGROUND: Corneo-scleral ulcerations and perforations are severe complications after most severe eye burns. One possibility to handle this situation is a keratoplasty with a scleral rim. This retrospective study was carried out to show the outcome after total replacement of the cornea after most severe eye burns. PATIENTS: Between 1986 and 1991 we carried out 12 keratoplasties with a scleral rim in 9 most severely burnt eyes of 7 patients. In 9 cases this intervention was the first transplantation. In 3 eyes a re-keratoplasty had to be carried out. RESULTS: All eyes could be saved after this surgical intervention, although all but two transplants failed. In eight cases the transplant decompensated and/or was replaced by scar tissue. Two transplants remained clear. Visual acuity was light perception in five cases, intact light projection in two cases, 1/35 in one case because of cataract formation and 0.8 in another case at the end of the observation period. The reasons for graft failure were multifactorial. Epithelial problems were the reason for graft failure in eight cases. Two of these also showed shrinkage of the eye lids with incomplete lid closure. In six cases severe vascularisation with scar formation was observed. It is remarkable that immunoreactions occurred only in four cases. This may be due to the fact that all patients were treated systemically with cyclosporin A. In one case the transplant failed after extensive surgery of the anterior segment. CONCLUSION: Our results show that the keratoplasty with a scleral rim can save the eye in the difficult situation of corneo-scleral ulceration or perforation. Nevertheless a visual rehabilitation could not be achieved in seven of nine cases. But all eyes were in a satisfying condition for further smaller transplants to achieve better visual acuity. PMID- 8699772 TI - [Retinal hemodynamics in diabetic retinopathy before and after laser coagulation]. AB - PATIENTS AND METHODS: By means of video-fluoresce in angiography arm-retina-time (ART) and retinal arteriovenous passage time (AVP) were measured in order to determine the effect of panretinal laser-coagulation on retinal circulation in patients with diabetic retinopathy. 55 patients with either preproliferative (n = 29) or proliferative (n = 26) retinopathy we reexamined before, 3-9 weeks after panretinal laser-coagulation (mean: 848 burns, 0.5 mm diameter), and 0.5-3 years later. RESULTS: The ART of the diabetic patients was in the normal range and showed no differences among the three measuring times. The retinal AVP was significantly prolonged in the three measuring times (nasal and temporal) when compared to normals. Laser-coagulation showed no significant effect on AVP in the temporal branches, whereas in the nasal branches AVP decreased from 2.38 +/- 0.69 s (before laser-coagulation) to 2.11 +/- 0.68 s (3-9 weeks after treatment) and 2.06 +/- 0.67 s (0.5-3 years after treatment) (p < 0.01). In branches with neovascularisation (n = 24) a pronounced decrease of AVP from 2.60 +/- 0.70 s to 1.96 +/- 0.61 s and 2.09 +/- 0.64 s (p < 0.01) was detected. CONCLUSIONS: Thus, laser-coagulation leads to a faster circulation in areas with laser burns within 3-9 weeks post-treatment. PMID- 8699773 TI - [Increased possibility for HIV-associated retinal microangiopathy syndrome in patients with concomitant hepatitis C infection]. AB - BACKGROUND: The etiology of HIV-related retinal microangiopathy syndrome is yet unknown. Several authors postulate direct endothelial-cell infection, an immunocomplex vasculitis caused by HIV-related hypergammaglobulinemia or an increased serum concentration of endothelin as its origin. PATIENTS: 118 patients infected by HIV-1 have been examined (CDC I: 1; CDC II: 42; CDC III: 7; CDC IV: 68). 49 out of them were also infected by hepatitis-C-virus (CDC I: 0; CDC II: 16; CDC III: 4; CDC IV: 29). RESULTS: 26 out of 49 patients with hepatitis-C-co infection showed HIV-related retinal microangiopathy syndrome (CDC I: 0/0; CDC II: 8/16; CDC III: 2/4; CDC IV: 16/29). In 69 patients without hepatitis-C infection, HIV-related retinal microangiopathy syndrome was found five times (CDC I: 0/1; CDC II: 2/26; CDC III: 0/3; CDC IV: 3/39). CONCLUSION: Co-infection with hepatitis-C-virus is supposed to enhance the development of retinal microangiopathy syndrome in patients infected by HIV-1. PMID- 8699774 TI - [Anti-inflammatory effects and aqueous humor concentration of various nonsteroidal anti-inflammatory drugs in extracapsular cataract surgery]. AB - BACKGROUND: Within the spectrum of anti-inflammatory drugs, the preference of nonsteroidal anti-inflammatory drugs (NSAID) is definitely increasing. In the present study, we compared the anti-inflammatory effects and aqueous humour concentrations of 3 topical NSAID (indomethacin, diclofenac, and flurbiprofen) during extracapsular cataract surgery. PATIENTS AND METHODS: We examined 90 patients (52-89 yrs of age) without pre-existing deficiencies of the blood aqueous barrier. In 60 of these patients (series 1), and examination using the laser flare-cell meter was performed prior to and following extracapsular cataract surgery with intraocular lens implantation. In 30 patients (series 2), aqueous humour was drawn intraoperatively, and the NSAID concentration was determined using high-pressure liquid chromatography (HPLC). Patients were randomly assigned to one of the following three treatment protocols with commercially available NSAID: protocol A: indomethacin 1% eyedrops (Chibro-Amuno 3); protocol B: diclofenac 0.1% eyedrops (Voltaren ophtha); protocol C: flurbiprofen 0.03% eyedrops (Ocuflur). 2 drops of either drug were administered as follows: day before surgery (4:00 p.m., late night), day of surgery (2, 1, and 1/2 hrs preop, end of operation, 4:00 p.m., late night), and days 1-3 postoperatively (5 times per day). RESULTS: Under indomethacin therapy (protocol A), the flare [in photon counts/ms] increased from a preoperative value of 8.0 +/ 2.8 (means +/- SE) to 20.1 +/- 2.2 on day 1 postoperatively, and decreased to 16.9 +/- 2.5 on day 3. Under diclofenac therapy (protocol 2), the flare averaged 25.8 +/- 3.8 and 16.9 +/- 2.8 on postoperative days 1 and 3, respectively. Under flurbiprofen therapy (protocol C), the flare amounted to 31.4 +/- 6.6 and 26.2 +/ 3.4 on days 1 and 3, respectively. On day 1 postoperatively, there was a significant difference (p < 0.01) between all three treatment protocols. Postoperative fibrin exsudation was observed in 1 of 20 indomethacin- and 1 of 20 flurbiprofen-treated patients (5%), and in 4 of 20 diclofenac-treated patients (20%). The highest individual aqueous humour concentration of indomethacin was 430 micrograms/1, the lowest 30. The concentrations of flurbiprofen lay between 42 and 31, those of diclofenac between 80 and 30 micrograms/1. All patients treated with indomethacin had detectable aqueous humour concentrations, whereas 3 flurbiprofen- and 7 diclofenac-treated patients had no HPLC-detectable concentrations (detection limit: 30 micrograms/1). CONCLUSIONS: After extracapsular cataract surgery, the anti-inflammatory potency of topical indomethacin 1% is superior to that of flurbiprofen 0.03% and diclofenac 0.1%, as demonstrated by the laser flare-cell meter. The rate of postoperative fibrin exsudation is lower under treatment with topical indomethacin or flurbiprofen compared to diclofenac. Using the commercially available substances (with different drug concentrations and vehicles), indomethacin exhibits a higher aqueous humour concentration than flurbiprofen, and diclofenac shows the lowest concentration. PMID- 8699775 TI - [Detection and diagnosis of small ocular misalignment with the Purkinje reflex pattern method]. AB - BACKGROUND: Application test for an automatic classification strategy for ocular alignment data for the detection of ocular misalignment in strabismic patients. METHODS: Photographic Purkinje Reflection Pattern Evaluation was used a) with a handheld device for the detection and measurement of ocular misalignments in near fixation (group 1, n = 64 strabismic patients) and b) with a stationary device for the detection and measurement of ocular misalignments in near fixation (group 2, n = 38 patients) and in distance fixation (group 3, n = 36 patients). The orthoptic diagnoses were mostly primary and secondary microtropia with manifest angles of strabismus from naught or 0.25 degrees to 3-4 degrees, with maximum angles up to 6-9 degrees. The ocular alignment data were classified using the computer based strabismus index procedure. This strategy relies on thresholds derived from means and standard deviations in orthotropic control populations. In this way the data sets were classified automatically as "no referral" or "referral". In addition, an automatic diagnosis of the type of misalignment was given and the results were compared to the orthoptic gold standard. RESULTS: The sensitivity for the detection of a manifest ocular misalignment was a ca. 80% in group 1 and 2, and 90% in group 3, with specificities from 90% to 100%. All manifest angles of strabismus larger than 1 degree were correctly classified as "referral". There was good agreement between the diagnoses of the type of misalignment in most cases. Discrepancies were observed with very small ocular misalignments or with incomplete data sets, or they could be explained by a switch of fixation. The amount of the misalignment varied markedly as compared to the orthoptic measurement in a number of cases. CONCLUSIONS: The examination allows for a detection of small manifest ocular misalignments with a very high sensitivity. The deviated eye and the type of the misalignment in the primary position are evaluated automatically by a data base computer algorithm. The differences between the measured angles of strabismus indicate that the photographic examination conditions and the orthoptic simultaneous prism and cover test conditions are not exactly alike. Purkinje Reflection Pattern Evaluation represents a step towards an examiner-independent measurement of the angle of strabismus. PMID- 8699776 TI - [Establishing human, conjunctival fibroblast cultures as a test system for evaluating ophthalmic drugs]. AB - BACKGROUND: Chronic inflammation of the anterior eye segment caused by severe burns has to be treated by several drugs. Often it is very difficult to recognize the relationship between drug and side effects. Although the results were usually satisfying, proliferation of the conjunctival tissue was observed. Therefore the question was raised whether these proliferations might have been a side effect of the drugs. To answer this question, we established cultures of human conjunctival fibroblasts for ocular toxicity testing of drugs used in the therapy of severe eye burns. MATERIALS AND METHODS: Conjunctival fibroblasts from young donors were cultured under standard conditions (37 degrees C, 5% C02, 95% RH) in Medium 199 supplemented with 20% FCS without antibiotics. At the time of inoculation the following drugs were added: aprotinin, prednisolone, chloramphenicol and methylhydroxypropylcellulose. Cell growth was observed and growth kinetics were estimated by hemocytometer over a period of 7 days. RESULTS: The investigations of prednisolone showed the well-known dose-dependent anti-proliferative effect. The application of methylhydroxypropylcellulose resulted in decreased cell growth and in total cell detachment. Experiments with aprotinin and chloramphenicol showed no effects on the growth behaviour. The application of a drug mixture lead to similar results as in experiments with prednisolone. DISCUSSION: The presented cell-culture system is able to reproduce specific effects, especially the toxicity of ophthalmic drugs but a complex interaction of an inflammatory reaction, e.g. after severe eye burns, cannot be simulated. The network of reactions and the interaction of many substances playing an important role during this process are too complex. PMID- 8699777 TI - [Effect of the vasodilator isosorbide dinitrate on ocular circulation]. AB - BACKGROUND: Vasodilator drugs are increasingly being discussed as possible antiglaucomatous substances. Aim of the present study is to evaluate, from a hemodynamic point of view, the vasodilator drug isosorbide dinitrate (ISDN) regarding its suitability for glaucoma therapy. METHODS: 20 healthy subjects (mean age: 28 yrs) volunteered to participate in the study. In randomized order, each subject received one tablet containing 40 mg ISDN (sequels) or--in a second trial--one tablet placebo (+500 mg of the analgetic metamizol, respectively, for prophylaxis of nitrate headache). 1 h before as well as 1, 3, 5, and 7 hrs after medication, the following variables were determined using oculo-oscillo dynamography: systolic ophthalmic artery pressure (SOAP), systolic ocular perfusion pressure (SOPP), ocular pulsation amplitude (OPA) and the product OPA x heart rate (HR). Intraocular pressure (IOP) as well as systolic and diastolic brachial artery pressures (SBAP, DBAP) were also measured. RESULTS: After administration of ISDN (+analgetic), the variables SBAP, SOAP and SOPP were significantly (p = 0.01) lowered compared to placebo (+analgetic), and also the IOP tended to be lower (p = 0.08). The maximum reduction was found 3-5 hrs after medication: SBAP 10.9 mm Hg (9%), SOAP 12.5 mm Hg (14%), SOPP 11.3 mm Hg (14.5%), and IOP 1.5 mm Hg (12%). The relation SOAP vs. SBAP was significantly (p = 0.0004) linear, the correlation coefficient amounted to 0.39. DBAP remained unchanged, HR was increased by 4-7 beats/min (p = 0.08). OPA and the product OPA x HR showed highly significant decreases by maximum values of 44% and 40%, respectively. CONCLUSION: ISDN (+analgetic) caused a reduction of SOAP and SOPP, which can be accounted for by the reduced systolic systemic blood pressure. In addition, there was a decrease of OPA and of the product OPA x HR (a measure of pulsatile ocular blood flow), which finding may be explained by a cardiac stroke volume reduction that is typical for nitrates. Due to these hemodynamic effects and due to the only weak IOP reduction, ISDN does not appear to be suitable for glaucoma therapy. PMID- 8699778 TI - [Severe perforating eye injury caused by an air bag in a traffic skid accident]. AB - BACKGROUND: After a penetrating injury of the eye following a car accident the driver demanded accurate investigations by the Institute for Legal Medicine of Zurich concerning the security of the equipment, especially the airbag. This led to an astonishing explication of the mechanism of the injury, not without consequences for safety measures for drivers and front seat passengers in air bag equipped cars. CASE REPORT: Due to a relatively harmless accident, the driver suffered from a severe penetrating injury of the right eye after the airbag deployed. The front seat passenger, having the seat belts fastened, was not injured. The accident was investigated by the Institute of Legal Medicine of Zurich. RESULTS: The analysis of the accident showed that the airbag had deployed properly. The cover of the airbag showed no defects of substance. With the precise examination of the interior of the car a broken tobacco pipe came to light. CONCLUSIONS: In this case not the airbag itself but a tobacco pipe held in the hand by the driver during the airbag ignition caused a severe injury of the eye. This case report illustrates the hazard of having any rigid object between the occupant and the deploying air bag. In conclusion, the drivers and front seat passengers of an airbag equipped car can only profit from the considerable security gain, if they know about these risks and adapt their behaviours to the new surroundings, but also the car manufactures have to instruct the customers properly. PMID- 8699779 TI - [Mobilization of intraocular foreign bodies by magnetic resonance tomography]. AB - A 49-year-old patient suffered from a binocular perforating trauma with metal foreign bodies in 1974. During an MRI examination in 1992 for a lumbar spine herniation a metal foreign body was mobilised from the deeper vitreal and retinal area, now causing optical disturbances freely floating in the anterior vitreous. Refusing an operation, the patient, an electrical engineer, tried himself to remove the foreign body out of the optical axis by exposing his head to the electro-magnetic field of an induction coil (pulsed magnetic induction B at t0 of 0.26 Tesla). The foreign body was split into multiple small parts no longer disturbing the patient. To early detect a siderosis regular ophthalmological controls including ERG are necessary. This example stresses that even small intraocular metal foreign bodies are a contraindication for the usually applied field strength of MRI examinations. PMID- 8699780 TI - [Ophthalmological surgery education. 23. Evisceration]. PMID- 8699781 TI - A case of the bilateral superficial brachial arteries which continued to the radial arteries in the forearms. AB - During the dissection course of Kobe University School of Medicine, we found the bilateral superficial brachial arteries that continued to the radial arteries in a 90-years-old female cadaver. Each superficial brachial artery is classified Arteria brachialis superficialis lateralis inferior. This artery directly continued to the radial artery in the forearms on each side. Anomalous branching patterns of the (proper) brachial artery in this case belong to the type 7 of Adachi's classification. The incidence and embryological aspects of this anomalous arterial branching are discussed. PMID- 8699782 TI - Glial fibrillary acidic protein expression in the developing human retina. AB - We have studied the expression of glial fibrillary acidic protein(GFAP), an astrocyte specific protein in the normal developing human retina using anti-GFAP antibody. GFAP positive cells were first detected at 24 gestational weeks(GW) in the nerve fiber and ganglion cell layers in the vicinity of the optic disc. Over subsequent weeks, GFAP positive cells covered larger regions of the retina. Some of the processes of these cells terminated in sucker like end-feet upon blood vessels of the nerve fiber layer. A second population of GFAP positive cells existed as perivascular glia in the nerve fiber layer in the early stage of fetal development. In the adult retina perivascular glia were found on vessels throughout the nerve fiber and in the inner portion of the inner plexiform layers. Staining of Muller cells end-feet was obtained only in the adult retina. These results support the views that in the human retina, GFAP positive cells first appear at 24 GW in the region near the optic disc, covering the whole retina at subsequent ages. PMID- 8699783 TI - Prediction of maximal oxygen uptake by squat test in men and women. AB - To examine the reproducibility of simple tests including step, squat and double quick tests, the respective tests were performed twice in 242 college women. The step test for 1, 2 or 3 min and the squat test for 1 or 1.5 min were adopted as simple endurance tests with superior reproducibility. Then 30 men (18-26 yr) and 32 women (18-34 yr) participated in a maximal O2 uptake (VO2max) test and the simple endurance tests. The scores (the sum of heart beats for 30-60, 90-120, 150 180 seconds in a sitting posture following the exercise) in the respective simple endurance tests were significantly correlated (P < 0.001) with VO2max per kilogram body weight in the men and women. For example, the equation relating VO2max to the score (X) of the squat test for 1.5 min in men was: VO2max (ml. kg 1. min-1) = -0.261X + 85.19 (r = -0.820, P < 0.001). The discrepancies between VO2max predicted by using the respective estimation equations and that determined by the direct method were 6.3% (by the step test for 3 min) approximately 8.1% (by the squat test for 1 min) in men and 4.7% (by the step test for 2 min) approximately 6.1% (by the squat test for 1 min) in women. Significant correlations were observed between the respective scores in the simple endurance tests (P < 0.001) and between % body fat and the scores (P < 0.01) in both men and women, but not for height vs. the scores. These results suggest that VO2max can be estimated not only by the step test for 1, 2 or 3 min but also the squat test for 1 or 1.5 min. PMID- 8699785 TI - Factors affecting performance of PACS. AB - We experimentally constructed a personal-computer-based Picture Archiving and Communication System (PACS) for color images of dermatology clinics. This system should especially satisfy such a demand as to be able to retrieve an image within a few seconds from the database residing in a remote server. Our two objectives in the experiment were: To examine how much time was consumed in each part of PACS while it does a series of jobs, from the requesting of an image to its display on the screen of the workstation of the user. The other objective was to see if a personal-computer-based PACS could satisfy our criteria. Total retrieving time, data reading time, data transporting time and image displaying time were measured. Total retrieving time can be divided into three procedures: Data reading time, data transporting time, image displaying time. Data reading time was about 0.6 second for reading an image with the size of 1 mega bytes (MB). Data reading time and the size of data were linearly correlated. Data transporting time was about 11 seconds for transporting an image with the size of 1 MB through EtherTalk, and 66 seconds through LocalTalk. Data transporting time and the size of the data were also linearly correlated. Data reading time and data transporting time was able to be reduced largely by compression technique. However, smaller data give other important effects to the network system besides reducing the time of data reading, data transporting and data displaying. Most Local Area using image Network (LAN) systems, such as EtherTalk, adopt Carrier Sense Multiple Access with Collision Detection (CSMA/CD) for the way of accessing to other computer. In CSMA/CD, transporting performance suddenly declines if the congestion of signal in a network gets beyond a critical level. This situation fatally impairs the performance of a network. We concluded that data compression plays an important role to improve the performances of PACS, especially those of a server and the network system. A personal-computer-based PACS with EtherTalk and an image compression/decompression hardware, e.g., CL550A chip, satisfies our criteria. PMID- 8699784 TI - The role of nitric oxide metabolites during pregnancy. AB - Nitric Oxide (NO) is a potent vascular endothelial cell derived vasorelaxant with important effects on vascular tone. This study was initiated to clarify the role of urinary metabolites of nitric oxide (NOx) during pregnancy. Twenty four normal pregnant women and 12 patients with preeclampsia were studied. Urinary NOx levels were determined with the Greiss reagent and spectrophotometry methods after enzymatic reduction of nitrate to nitrite in the samples. Urinary excretion of nitric oxide (NOx) were elevated in normal pregnant women and decreased in preeclamptic women. A significant correlationship was observed in the urinary excretion of cyclic guanosine monophosphate (cGMP) level in between the normal and preeclamptic puerperial groups (p < 0.05). Positive correlationships were found between urinary excretion of nitrate level and either of fractional excretion of sodium (FENa) (r = 0.702, p < 0.005) or fractional excretion of calcium (FECa) (r = 0.570, p < 0.04) in normal and preeclamptic subjects. Also a positive correlationship was observed between the level of urinary NOx excretion and high density lipoprotein cholesterol (HDL-cholesterol) (r = 0.681, p < 0.005). Our results suggest that nitric oxide may play an important role in the mechanism to modulate circulatory physiology of normal and preeclamptic pregnant women. PMID- 8699786 TI - Pancreas transplantation using non-suture cuff technique in the neck. AB - To get a successful pancreas transplantation in a rat model, we performed heterotopic pancreas transplantation with non-suture cuff technique to neck vessels. As the graft was placed in the neck, we could avoid the clamping of systemic circulation which is essential but detriment to the rat during vascular anastomosis in intraabdominal grafting. The diameter of the portal vein was enlarged to prevent outflow block after transplantation. The cuff was fixed by fat clay during anastomosis to perform vascular anastomosis easily. As a result the success rates was 16/20, 80%. 16 rats survived more than 30 days and maintained serum glucose level within 200 mg/dl throughout the experiment. The heterotopic pancreas transplantation using non-suture cuff technique to the neck vessels is safe, reliable and recommended as the experimental model using the rat. PMID- 8699787 TI - [Parliament is struggling for appropriate remuneration for night work. Time or money--that is the question]. PMID- 8699789 TI - [Thoughtless functioning is supplanting visions]. PMID- 8699788 TI - [Risk is increasing--prognoses still positive]. PMID- 8699790 TI - [Influencing health policies globally]. PMID- 8699792 TI - [I am never lonely with my dog]. PMID- 8699791 TI - [Interview with ICN president Margretta Styles. "It was my wish to be useful to others"]. PMID- 8699794 TI - [Interdisciplinary work procedures]. PMID- 8699793 TI - [A day in the operating room]. PMID- 8699795 TI - [Home care. A mobile team at your service]. PMID- 8699796 TI - [Dispute among experts about psychotropic drugs]. PMID- 8699797 TI - [From the job of patient guardian to the nursing profession. 2. Introduction to the places of decision making]. PMID- 8699798 TI - [Psychiatric care of people from foreign cultures. "I am sick with nerves"]. PMID- 8699799 TI - [Controversy about the inability to work]. PMID- 8699800 TI - [Nobody can escape: laughter is contagious]. PMID- 8699801 TI - [Payment of salary in case of accident or illness. Which one counts: the grade of employment or the amount of service?]. PMID- 8699802 TI - Multiple splenic myelolipomas in a ferret (Mustela putorius furo). PMID- 8699803 TI - Chronic excretion of coronavirus-like particles in laboratory guinea pigs. PMID- 8699804 TI - Development of a laboratory colony of the musk shrew (Suncus murinus, insectivora) exhibiting a high incidence of spontaneous diabetes mellitus. PMID- 8699805 TI - Effect of sex and dexamethasone dose on the experimental host for Pneumocystis carinii. PMID- 8699806 TI - Ivermectin toxicity in young mice. PMID- 8699807 TI - Rapid way to identify the cilia-associated respiratory bacillus: tracheal mucosal scraping with a modified microwave Steiner silver impregnation. PMID- 8699808 TI - Survey of Cryptosporidium and Giardia spp. in a captive population of common marmosets. PMID- 8699809 TI - Resumption of fertility after myomectomy for uterine leiomyoma in a rhesus macaque. PMID- 8699810 TI - Benign cutaneous mast cell tumor in a rhesus monkey. PMID- 8699811 TI - Histologic examination of the NOD-mouse lacrimal glands, a potential model for idiopathic autoimmune dacryoadenitis in Sjogren's syndrome. PMID- 8699812 TI - Reproductive abnormalities associated with a coronavirus infection in rats. PMID- 8699813 TI - Inflammatory large bowel disease in immunodeficient mice naturally infected with Helicobacter hepaticus. AB - Large bowel disease detected clinically by rectal prolapse was studied in 64 immunodeficient mice (37 athymic NCr-nu/nu, 12 BALB/c AnNCr-nu/nu, 9 C57BL/6NCr nu/nu, and 6 C.B17/Icr-scid/NCr) naturally infected with Helicobacter hepaticus. Rectal prolapse was found in approximately 5% of immunodeficient mice maintained in a research facility over a period of 3.5 years. All mice had various degrees of chronic proliferative typhlitis, colitis, and proctitis, usually without concomitant hepatitis. Some mice had severe proliferative proctitis with cystic hyperplasia. Histologic study of the large bowel of 48 athymic NCr-nu/nu mice without H. hepaticus infection and housed in another clean facility revealed only 12% of the mice with minimal-to-mild large bowel inflammation. Helicobacter hepaticus infection is associated with large bowel disease in immunodeficient mice but is not seen in H. hepaticus-infected immunocompetent mice. This new pathogenic bacterial infection should be considered as another potential cause or co-factor for rectal prolapse and large bowel disease in mice. PMID- 8699814 TI - A novel presentation of Clostridium piliforme infection (Tyzzer's disease) in nude mice. AB - Clostridium piliforme infection (Tyzzer's disease) was diagnosed in a colony of nude mice. Because spontaneous Tyzzer's disease had not been reported in nude mice, a study was undertaken to better define the clinicopathologic features of this disease outbreak. Sixty homozygous nude (nu/nu) females, 10 nu/nu males, and 10 heterozygous nude (nu/+) females were observed for signs of disease. Over a 3 month period, 43% of the nu/nu mice died or manifested clinical signs of disease and were euthanized, but nu/+ mice remained healthy. Clinical signs of disease were infrequently observed in nu/nu mice and, when evident, were followed by rapid deterioration and death. Gross and histologic lesions, including severe hepatic and intestinal necrosis associated with C. piliforme, were observed only in clinically affected animals. Clostridium piliforme isolated from diseased livers had marked cytotoxicity in in vitro assays. This outbreak is unique in that, contrary to a previous experimental report, nu/nu mice had increased susceptibility to Tyzzer's disease, suggesting that T cells may play an important role in host defenses against C. piliforme infection. In addition, this is the first report of a toxigenic isolate of C. piliforme recovered from mice. The cytotoxin produced by the isolate may have contributed to the severity of clinical disease and lesions. PMID- 8699815 TI - Genetic analysis of serum alanine transaminase activity in normal and hepatitis C virus-infected chimpanzees: an application of research-oriented genetic management. AB - The hepatic enzyme alanine transaminase (ALT) is a diagnostic marker for liver damage but has a considerable degree of normal variation. We used complex segregation analysis to determine whether evidence exists for major genic determination of normal ALT values in an important animal model, the chimpanzee (Pan troglodytes). Normal ALT values were available for 212 chimpanzees. Available genealogical data allowed assignment of 165 animals to a total of 19 pedigrees; 47 animals were treated as independent. A major gene explaining 60% of the phenotypic variance in normal alanine transaminase (ALT) activity was detected by complex segregation analysis. The allele for high ALT activity had a frequency of 0.20. Polygenes accounted for an additional 20% of the variation. The observation that 80% of the total phenotypic variance is attributable to genetic factors has important implications for studies that use ALT activity in assessments. Genetic analysis of change in ALT activity after inoculation with hepatitis C virus (HCV) in a subset of animals indicated that approximately 30% of the variation in response may also be attributable to genetic factors and that the estimated major locus genotypes differ in their responses. This suggests that genetic components can exert substantial influences on experimental parameters in hepatitis research. PMID- 8699817 TI - Diabetes mellitus and islet amyloidosis in cynomolgus monkeys. AB - Six 15- to 20-year-old obese cynomolgus monkeys were determined to have diabetes mellitus. These monkeys were hyperglycemic and hypertriglyceridemic, yet remained nonketotic for several years before requiring clinical intervention. A significant decrease in glucose disappearance and an increased area under the glucose disappearance curve were found in response to intravenous glucose tolerance testing. Basal hyperinsulinemia was found in three animals that, in response to glucose stimulation, had a blunted insulin response, resulting in an overall decrease in the area under the insulin curve. Two animals died during the study and had extensive amyloid infiltration of pancreatic islets. The combined findings of old age, obesity, hyperinsulinemia, improvement in response to caloric restriction, and islet amyloidosis are consistent with type 2 diabetes mellitus. PMID- 8699816 TI - Increased glycation of plasma lipoproteins in diabetic cynomolgus monkeys. AB - Hyperglycemia associated with diabetes mellitus increases glycation of hemoglobin and serum proteins in human and nonhuman primates. It also has been documented that numerous other circulating proteins may be glycated. In this study we found that most of the major subclasses of lipoproteins (low-density, very low-density, and high-density) from diabetic cynomolgus monkeys were significantly more glycated than were lipoproteins from age- and sex-matched controls. Correlations between levels of glycemic control and glycation of lipoproteins also were significant. Because glycation of lipoproteins has been shown to affect their normal metabolism, this animal model may be useful in determining the interaction between lipoproteins, diabetes mellitus, and the increased risk of atherosclerosis. PMID- 8699818 TI - Tumor necrosis factor-alpha and interleukin-1 alpha expression in a murine model of allergic bronchopulmonary aspergillosis. AB - Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) are two important proinflammatory cytokines that may be involved in allergic inflammatory processes. We recently developed a murine model of allergic bronchopulmonary aspergillosis characterized by eosinophilic and lymphocyte lung infiltration and increased serum and bronchoalveolar lavage immunoglobulin E concentration. In this study we examined the expression of TNF-alpha and IL-1 alpha in the lung tissue sections of C57BL/6 mice that were intranasally challenged with Aspergillus fumigatus antigen or saline on the first 3 days of each week and sacrificed on days 4, 7, 14, and 21. Compared with the control mice, A. fumigatus treated mice had a remarkable increase of TNF-alpha and IL-1 alpha expression in the lung on days 4, 14, and 21, with a slight increase on day 7. The major types of cells expressing TNF-alpha and IL-1 alpha included alveolar macrophages, endothelial cells, and bronchiolar and alveolar epithelial cells. Consistent with increased expression of TNF-alpha and IL-1 alpha, intercellular adhesion molecule-1 expression also was upregulated in the lung of A. fumigatus treated mice; its time course and cell types were similar to those of TNF-alpha and IL-1 alpha expression. These results suggest that TNF-alpha and IL-1 alpha may be involved in the A. fumigatus induced inflammatory process and that upregulated intercellular adhesion molecule-1 expression may represent one of the roles played by TNF-alpha and IL-1 alpha in this murine model. PMID- 8699819 TI - Antigen-specific humoral immune responses to a hapten-carrier conjugate in SCID mice engrafted with bovine fetal hematopoietic tissues. AB - We describe the conditions necessary to reconstitute a bovine immune system in SCID mice that supports the generation of antigen-specific serum antibody responses to a hapten-carrier (DNP-KLH) conjugate. Sublethally irradiated SCID mice were engrafted with fetal bovine liver, lymph node, and thymus. Treatment groups were established in which human recombinant interleukin 7, autologous bovine bone marrow, and engraftment site (omentum or abdominal wall) were evaluated for their ability to enhance the reconstitution of the bovine immune system in SCID mice. Engrafted SCID mice were inoculated at approximately 6 and 12 weeks after engraftment with DNP-KLH. Vaccinated mice were evaluated by enzyme linked immunosorbent assay for serum antibody specific for DNP-KLH and total concentrations of bovine serum immunoglobulin biweekly through 20 weeks after engraftment. The SCID mice with fetal tissues engrafted onto the abdominal wall from two different donors produced microgram quantities of bovine immunoglobulins and had >70% reconstitution rate. Administration of human interleukin 7 and/or fetal bovine bone marrow did not significantly increase the frequency of reconstitution. Subclass analysis of serum from mice receiving the abdominal implants suggested that class-switching occurred to a predominant non-IgM isotype response after the second inoculation. Pooled thymic and splenic cell populations obtained 20 weeks after engraftment from abdominally engrafted groups yielded 38 to 90% bovine cells, as determined by polymerase chain reaction in situ hybridization with bovine satellite DNA-specific primers. These results indicate that an antigen-specific bovine immune response can be generated in heterochimeric SCID-bo mice. PMID- 8699820 TI - Seminar on procedures for carrying out rat surgery. PMID- 8699822 TI - Pathologic study of a rabbit model for shigellosis. AB - A nonsurgical rabbit model of enteric Shigella infection was developed for studying the pathogenesis and immunology of shigellosis and for evaluating Shigella vaccine candidates. In this model, rabbits are made susceptible to Shigella infection by a pre-inoculation conditioning procedure consisting of a 36 h nonfeeding period, with 250 mg of tetracycline administered in 250 ml of drinking water, 75 mg of cimetidine given intravenously, and two 15-ml doses of 5% sodium bicarbonate given orally immediately before orogastric administration of the bacterial inoculum. Lastly 2 ml of tincture of opium is administered intraperitoneally. With a virulent strain, Shigella flexneri 2a, the clinical and pathologic characteristics of shigellosis in this rabbit model were studied. Twenty hours after oral inoculation of 10(10) bacteria, all six experimental rabbits developed diarrhea and were lethargic or moribund, whereas the four control rabbits inoculated with sterile broth remained healthy. Histologic examination revealed severe, diffuse, necrotizing ileitis with hemorrhage in experimental rabbits, whereas no lesions were found in the controls. Although the major site of necrosis in this rabbit model was the ileum, as opposed to the colon in humans and nonhuman primates, the histologic morphology of the lesion was the same in the various hosts. Because it is relatively inexpensive and convenient, this model should facilitate study of the pathophysiology and immunology of shigellosis, thereby speeding development of oral vaccines, which can be tested in this animal model. PMID- 8699821 TI - Inherited prolonged bleeding time and platelet storage pool deficiency in the subtle gray (sut) mouse. AB - A high proportion of mouse mutants with diluted pigmentation have severely prolonged bleeding times due to platelet storage pool deficiency. The deficiency is associated with concomitant abnormalities in platelet dense granules and coat pigment granules. The coat color of the subtle gray (sut) mouse is diluted to a relatively minor degree. Analysis of platelet serotonin concentration established that this dense granule component similarly is reduced a relatively small amount in this mutant. The subtle gray mouse thus allowed a test of the hypothesis that relatively small changes in platelet dense granule contents may cause discernible increases in bleeding times. Bleeding times of mutant mice were significantly prolonged (3.4-fold) in comparison with those in normal sut/+ controls. These bleeding times were significantly reduced in comparison with other mouse pigment dilution mutants with more severe storage pool deficiency. These results establish the subtle gray mouse as an appropriate animal model for mild storage pool deficiency and human Hermansky-Pudlak syndrome. They indicate, together with related experiments, that bleeding times are highly sensitive to concentrations of platelet dense granule components such as serotonin. PMID- 8699823 TI - Body weight and composition in the Sprague Dawley rat: comparison of three outbred sources. AB - Body weight with age and final composition for water, fat, and protein, were measured in three outbred stocks derived from the Sprague Dawley rat. Three groups of 10 individually housed male rats from three outbred colonies (Crl:CD[SD]BR, Hsd:SD[SD], and Tac:N[SD]fBR) provided with standard rodent chow and water ad libitum were weighed weekly for 56 consecutive weeks. Rats in each group were born on the same day, and each group was born within a 4-day period. Significant group effects were found for upper weight limit, carcass weight, water, and fat content (P < 0.05). The Hsd:SD(SD) and Tac:N(SD) rats grew, in proportion to their upper weight limits, at a faster rate (P < 0.01) and contained a greater percentage of body protein (P < 0.05) than did heavier, reportedly shorter-lived Crl:CD(SD)BR rats. PMID- 8699824 TI - Sequential changes in the harderian gland of rats exposed to high intensity light. AB - We examined sequential changes in histology, fluorescent microscopy, and porphyrin content in the Harderian glands of 55 male Wistar rats exposed to fluorescent light of 2,500 or 1,600 lux for 12 h a day up to 8 days and of 10 control rats. After exposure for 1 day there was severe necrosis of the glandular cells, with edema and cellular infiltration of the Harderian gland adjacent to the retina. After exposure for 4 and 8 days these changes regressed and glandular cells regenerated. Red fluorescence in frozen sections of glands from control rats was interpreted to be due to porphyrins. The red fluorescence was faint in glandular acini injured by exposure to light for 4 and 8 days, and porphyrin content of the gland decreased after 4 and 8 days. Homogenates of the Harderian glands from five control rats caused marked hemolysis after exposure to sunlight. Thus exposure to high-intensity light induced necrosis of the glandular cells in the Harderian glands. The injury appeared to be a direct effect of light on the glandular cells, probably as a result of photodynamic action on the porphyrins in the gland.(ABSTRACT TRUNCATED) PMID- 8699825 TI - Ileal cannulation and associated complications in dogs. AB - Accurate measurement of small intestinal digestibility is important in dogs because it allows the formulation of pet foods that provide optimal nutrition at minimal cost. Digestibility measured by comparing nutrient intake to fecal excretion in intact animals does not distinguish small intestinal digestion from large intestinal bacterial fermentation. Ileal cannulation allows small intestinal digestion to be measured alone by comparing nutrient intake with ileal excretion of chyme. Nevertheless, ileal cannulation and its associated complications are not well documented in dogs. We describe the implantation of a simple T-cannula in the ileum of nine dogs for an average duration of 26 weeks. Established cannulas were well tolerated, and one dog retained the cannula for 14 months. Nevertheless, ileal effluent proved extremely caustic, and the incidence of complications in the immediate postoperative period was high. Only one dog had an unremarkable postoperative course. Complications included abscessation and cannula extrusion, followed by severe excoriation and ulceration of the skin. This excoriation could be prevented only by immediate surgical closure of the fistula. Chronic ileal cannulation is therefore a viable technique in dogs, but careful monitoring of the cannula site is essential. Dogs should be subjected to this procedure only if adequate veterinary and nursing care is available. It is preferable to maintain a colony of long-term cannulated dogs rather than to implant cannulas as needed. PMID- 8699826 TI - Recombinant antibodies: alternative strategies for developing and manipulating murine-derived monoclonal antibodies. AB - Since the introduction of hybridoma technology 20 years ago, numerous monoclonal antibodies with specificity to cellular, bacterial, and viral proteins have been developed. Application of monoclonal antibodies in biomedical research has substantially contributed to our understanding of the structural and physiologic components of intra- and extracellular protein interactions. Monoclonal antibodies that target antigens specific to infective agents or tumor cells may also be used as therapeutic agents. Despite the versatility of these molecules, monoclonal antibody/hybridoma production is labor-intensive and requires the use of live animals. The fact that monoclonal antibodies are derived from animals limits their use as systemic therapeutic agents in humans. This can be attributed to the human anti-mouse antibody response that is mounted against these therapeutically administered foreign proteins. Recent advances in our understanding of immunoglobulin structure through three-dimensional studies- using nuclear magnetic resonance and X-ray crystallography and increased computer assisted molecular modeling capabilities, combined with the application of recombinant approaches--has led to the evolution of a new class of antibody-like molecules or man-made antibodies. The potential of recombinant antibodies has been realized globally by academic and industrial institutions; the efficacy, toxicity, and pharmacokinetics of these antibody-derived compounds are being tested in a variety of animal models. This review summarizes various approaches for producing recombinant antibodies and discusses their potential as anti-cancer compounds so that those who are involved in relevant experimental animal protocols may gain a better understanding of this rapidly growing area. Additionally, by mimicking the affinity maturation of antibodies in vitro, phage display strategies have the potential to reduce or eliminate the use of animals in antibody production protocols. PMID- 8699827 TI - Detection of Pasteurella pneumotropica in laboratory mice and rats by polymerase chain reaction. AB - A 16S rDNA-based polymerase chain reaction (PCR) method specific for Pasteurella pneumotropica was developed. The PCR product, a 395-base pair DNA fragment, was amplified from P. pneumotropica and not from 42 other bacterial species tested, including four other Pasteurella species and Actinobacillus ureae. The PCR method was used to identify 13 previously isolated strains that had been identified as P. pneumotropica by conventional methods: 12 were confirmed by PCR; one that was PCR-negative was re-examined by biochemical methods and determined to be A. ureae. The PCR detection of P. pneumotropica in nasopharyngeal swab specimens from 121 surveillance animals (15 inbred mice and 5 inbred rats from 20 animal rooms) had a high carrier state in healthy laboratory animals; for example, rat swab specimens were 89.6% (43/48) positive by PCR, 8.3% were positive by the direct culture-biochemical method, and 16.7% were positive by the enrichment culture-biochemical method. The positive rate for mice (21.9% [16/73]) was lower than that for rats. PMID- 8699828 TI - Dorsal laminectomy in the adult mouse: a model for nervous system research. AB - Animal strains with specific genetic mutations can serve as powerful tools to study normal and pathologic cellular and molecular processes. The mammalian species with the largest number of known genetic mutations is the mouse. In spinal cord research, mice have not been used as extensively as other species because of the difficulty in accessing and manipulating their spinal cord. We describe the technique of exposing and manipulating the spinal cord of normal mice and of mice with the severe combined immunodeficiency (scid) mutation. Surgical outcome and complications are discussed. We conclude that dorsal laminectomy with subsequent access and manipulation of the spinal cord and its roots can be accomplished consistently with practice. PMID- 8699829 TI - Fetal surgical protocols in Yucatan miniature swine. AB - Thirty-nine Yucatan miniature swine were used in three fetal surgical experimental protocols. They involved antiarrhythmic administration, pacemaker implantation, and in-utero diagnosis of ventricular septal defect by intraoperative echocardiography. Because of problems encountered with surgical protocols in the initial stages, modifications were made to prevent fetal hypothermia and intraoperative mortality. These modifications included environmental temperature support, staple surgical techniques to reduce operative time, and development of fetal catheters designed to facilitate cannulation of small vessels. Postoperative care protocols were intensive and included antibiotics, analgesics, and supportive care designed to reduce discomfort and prevent abortion and sepsis. Thirty-seven of 39 sows survived the surgical procedures; experiments were performed on 117 fetuses. Twenty-two fetuses died either intraoperatively or postoperatively because of complications related to the experimental protocols. Modification of surgical and postsurgical protocols for these projects demonstrates the feasibility of using miniature swine as a model for fetal surgery, when their use was appropriate for anatomic and physiologic reasons. PMID- 8699830 TI - Diagnostic exercise: megacolon in a cynomolgus monkey. PMID- 8699831 TI - Diagnostic exercise: kidney masses in Wistar rats. PMID- 8699832 TI - Metabolic and ventilatory response to cross-country skiing classical and double arm poling exercise. AB - Nordic skiers place great emphasis on upper body endurance. Therefore, the purpose of this study was to compare oxygen uptake (VO2), minute ventilation (VE), tidal volume (VT), breath frequency (fB), heart rate (HR), and ventilatory anaerobic threshold (Tvan) responses to upper body classical poling (CP) and double poling (DP). Sixteen male master class cross-country ski racers performed DP and CP at similar incremental power outputs at 45 strokes/min on a modified Biokinetic swim bench variable-resistance arm ergometer. Leg VO2peak was measured during a Monark bicycle ergometer graded exercise test. Mean CP VO2peak was 34.8 +/- 9.0 ml kg-1 min-1 compared to 40.3 +/- 10.5 ml.kg-1 for DP (p < 0.05). CP and DP VO2peak was 70 +/- 3.4% and 81 +/- 3.8% respectively of the bicycle test VO2peak. DP VO2peak, and HR peak were significantly (p < 0.05) higher than for CP. CP Tvan appeared at 30.1 +/- 6.9 ml.kg-1.min-1 or 86 +/- 3.2% of CP VO2peak and DP Tvan occurred at 36.6 +/- 9.0 ml.kg-1.min-1 or 92 +/- 3.6% of DP VO2peak (p < 0.01). HR at Tvan was significantly higher for DP than for CP (< 0.05). Values for VT, fB, and VE measured at Tvan for both arm exercise modes were not significantly (p > 0.05) different. At submaximal exercise values for VO2, and HR were significantly different between the arm exercise modes. It is concluded that the mechanisms responsible for these observations may be increased active upper body muscle mass involvement for DP and that Tvan adaptations occur specifically to the exercise mode and recruited muscle groups. PMID- 8699833 TI - Submaximal running economy in run-trained pre-pubertal boys. AB - There is an increasing tendency for young children to participate in training and competitive running. The impact long-term training has upon stimulating functional physiological adaptation has yet to be fully understood. In this study cardio-respiratory and kinematic differences were assessed at submaximal and maximal exercise intensities in run-trained and non-run-trained boys. Thirty three pre-pubertal boys volunteered to take part in the study. The subjects were in two groups: 15 run-trained subjects [age 11.7 +/- 1.06 yrs, mean +/- SD] and 18 non-run-trained (control) subjects [age 11.3 +/- 0.90 yrs]. Two separate (4 x 3 min) submaximal protocols were used for the trained and non-run-trained groups, with two of the speeds overlapping for comparison purposes. In addition, all boys also performed a maximal oxygen consumption test. Mean VO2max value for the run trained group was 60.5 +/- 3.3 ml/kg/min and for the control group 51.1 +/- 4.3 ml/kg/min, (p < 0.001). No significant differences were found for submaximal running economy at either comparison speed. In addition, no significant (p > 0.05) differences were noted between the groups for any of the kinematic variables at the two comparison speeds. However, selected physiological differences did exist at the submaximal running speeds. The source of the differences that did exist between the two groups may be the result of training, genetic pre-selection or developmental differences between the groups. PMID- 8699834 TI - Maximal lactate values following competitive performance varying according to age, sex and swimming style. AB - Peak blood lactate concentration for a given individual in a given event could be considered as indicator of exercise effort, especially if the race is fast as it occurs following competitive swimming events. The present study attempts to describe the postcompetition lactate profile across all the swimming distances and strokes according to the age and sex of the swimmer. Blood samples (100 micro lambda) were taken from an arterialized fingertip of a total of 337 swimmers (171 males and 166 females) at the end of 3rd and 6th minutes of competition over 50 to 1500 meter distances and for the following 3 age group divisions: AGE1 = > 18 years of age, AGE2 = 16-17 years of age and AGE3 = 14-15 years of age. For AGE1 group the subjects who were picked up for testing were all the first three who met the criteria for this age category in the OPEN winter and summer National and Provincial Championships. For AGE2 and AGE3 groups the subjects who were picked up for testing were ranked among the first three in their age group winter and summer National and Provincial Championships. Results showed that the highest mean peak lactate values for groups AGE2 and AGE3 were recorded in 200 medley event for both sexes while for group AGE1 the highest mean peak lactate value was recorded in 200 and 400 meter medley events for males and females respectively. On the other hand, the lowest mean lactate value was recorded in long distance events of 1500 and 800 meters for males and females respectively and for all the age group divisions. Furthermore, swimming performance was related to peak lactate values which subsequently was independent of sex but dependent on age with higher lactate values and older age documented by the subjects with faster times. PMID- 8699835 TI - Determination of the heart rate deflection point by the Dmax method. AB - OBJECTIVE: Conconi et al. proposed that the point where heart rate departed from linearity in an incremental exercise test was a good indicator of the anaerobic threshold. However, the heart rate deflection points (HRDPs) can not be determined in many subjects. The aim of this study was to determine the heart rate deflection point by the Dmax method and to compare it with the conventional linear method. SETTING: The study was performed in the Exercise Physiology Laboratory in the Faculty of Medicine, Selcuk University. PARTICIPANTS: Thirty two untrained males (aged 18-22) performed a maximal exercise test on a cycle ergometer. RESULTS: The deflection from linearity of HR could not be detected in nine subjects (28%) by the linear method. The HRDPs could be detected in all subjects by the Dmax method. It was observed that the HR values in the HRDPs determined by both methods were close to the maximal HR values (approximately 90% of maximum). There were high correlations and no differences (p more than 0.05) between the deflection points expressed as oxygen uptake, HR and work rate determined by two methods (correlation coefficients 0.93, 0.93, 0.97, respectively, p less than 0.001). CONCLUSIONS: The Dmax method is more useful than linear method. The HRDPs of all the people can easily and objectively be found by this method. PMID- 8699836 TI - Landing models for volleyball players: a longitudinal evaluation. AB - The purpose of the study was to longitudinally evaluate lower extremity landing performance of elite volleyball players. Seven female members of a Division 1 NCAA volleyball team completed three data collection sessions (pre-, post-, off season) during which they performed block-jumps on a dual force platform system (1000 Hz) while being simultaneously videotaped from the right sagittal view (200 Hz). Selected kinetic and lower extremity kinematic variables were calculated. Three dependent variables representing landing impact were identified: first (F 1) and second (F 2) maximum vertical force and knee joint range of motion (K(ROM)). A non-landing performance measure, jump height was also evaluated. Results of repeated measures univariate ANOVAs identified a significant (p < 0.05) difference for test session for K(ROM) suggesting a kinematic change in landing performance across the season. Multiple regression models to predict landing impact identified 88.1 and 98.3% explained variance for F1 and F2 with no significant K(ROM) model identified. F1 was predicted by ankle joint angular velocity during the jump while F2 was best predicted by jump phase braking impulse. Application of the group prediction equations to individual athletes produced differential results across subjects, suggesting the need to tailor the model to the athlete. The results further suggest training/practice-related kinematic differences and have implications for training and assessment of individuals who perform dynamic landing activities. PMID- 8699837 TI - Sports injuries in children and adolescents treated at a sports injury clinic. AB - This study presents the results of a three-year (1989-1991) retrospective survey of sports injuries to children and adolescents (5-17 years of age) treated at a sports injuries clinic (Crystal Palace, London). Of the total of 394 injuries, 178 (45.2%) were to females and 216 (54.8%) were to males. In both females and males the frequency of injuries showed a unimodal relationship with increasing age; the peak frequency in females occurred at age 13-14 years and in males at age 15-16 years. Fifty per cent of the injuries (197) were acute, 49.5% (195) were chronic and 0.5% (2) were inconclusive in diagnosis. Most of the acute injuries were muscle/tendon/ligament sprains, strains or contusions (62%) whereas most of the chronic injuries affected articular cartilage, epiphyseal and apophyseal growth plates (53%). Injuries to knees and ankles accounted for 51% of all injuries. The sports responsible for most injuries were characterised by i) explosive and/or high speed movements and/or ii) physical contact with apparatus, equipment or other players. PMID- 8699838 TI - Gymnasts, distance runners, anorexics body composition and menstrual status. AB - Ten top class female distance runners, ten female anorexics and twenty female gymnasts of a similar age were compared for height, mass, %fat, fat mass, lean body mass, age of menarche and incidence of amenorrhoea. The mean age of the distance runners, anorexics, and gymnasts was 13.6 years, 14.7 years, and 13.3 years respectively. In comparison to normal data on females of a similar age they were shorter, lighter, had lower fat masses, and %fat, and the gymnasts and anorexics had lower lean body masses. However, the gymnasts and runners had higher lean body masses compared with the anorexic group. There were no significant differences in body composition by hydrostatic weighing but of these three groups the anorexics tended to have the highest total skinfold, %fat and fat masses. Only 20% of the gymnasts, 40% of the runners and 70% of the anorexics had started menstruating compared with 95% of girls of a similar age. Of the girls in our study who had started menstruating one gymnast, (25% of sub-group) two runners (50% of sub-group) and seven anorexics (100% of sub-group) had developed secondary amenorrhoea. The low body masses, low fat masses, delayed menarche and secondary amenorrhoea in athletes are discussed in relation to low caloric intake, stress, hormone levels, high training loads and genetic factors. Our data demonstrating no significant differences in body composition variables between the three groups of young girls, support the main contention that this type of physique may arise through different mechanisms leading to a common outcome, but without a proven causal link between anorexia and athletic performance. PMID- 8699839 TI - Lipid and lipoprotein changes in women following 6 months of exercise training in a worksite fitness program. AB - It was the purpose of this investigation to examine the influence of a worksite aerobic training program on serum lipid and lipoproteins and cardiovascular fitness in female employees. Thirty-seven healthy but previously untrained, female employees (Ss) from Westinghouse Corporation, (College Station, Texas) volunteered for the study. Ss were randomly assigned to either an exercise group (Ex) (n = 20) or control group (C) (n = 17). Prior to training (PRE) and following training (POST), all Ss were measured for weight (WT), body composition (%FAT) and tested for maximal oxygen consumption (VO2 max). PRE and POST Lipid analysis included: total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), and triglycerides (TG). Following PRE testing, the Ex group aerobically trained by walking, jogging and/or cycling, at least 3 days per wk for 24 wks. Exercise training resulted in an improvement in VO2 max (p < 0.0006) and a 2 kg WT loss in Ex (p < 0.025) with no change in C. Both Ex and C Ss exhibited a loss in %-FAT (p < 0.0001), and a decrease in TC (p < 0.0001) and LDL-C (p < 0.0001). No differences were observed between groups or over the training period for VLDL-C or TG. Although HDL-C increased 6 mg/dl in the Ex group but not in C, this difference did not reach statistical significance (p < 0.0625). These results demonstrate that aerobic training by females in a worksite fitness program significantly improves cardiovascular fitness without altering lipids or lipoproteins. PMID- 8699840 TI - Exercise-induced bronchodilatation in asthmatic athletes. AB - In most asthmatics muscular effort induces bronchial spasms. However, despite this limitation many of them carry on sports activities even at a high level. It has already been shown that training reduces the bronchial obstruction response while heightening a bronchodilator response. The purpose of this study is to monitor these changes in bronchial calibre under effort condition. To this aim, 14 high-level athletes effected by asthma with chronic bronchial obstruction, but clinically silent, were studied. Under the maximal effort test these athletes displayed very high peak ventilation and peak oxygen uptake. At the end of the effort bronchodilatation was found to occur in all of them, and during recovery a slow return of bronchial patency toward the basal values was noticed: in no case was there any aggravation of bronchial obstruction. It is surely this persistent bronchodilatation that makes it possible for these athletes to achieve high ventilation levels and to carry on sports activities without any respiratory related limitation. The inhalation of salbutamol before the effort test increases tha amount of bronchodilatation over that already measured during the test without administering the drug. It can be supposed that in these athletes an increase in the number or density of the adrenergic betareceptors occurs, thus promoting the action of the catecholamines. The increase in bronchial calibre that is found under effort, without the use of salbutamol, is such that any prophylaxis using bronchodilator drugs would be hardly useful under favorable climatic conditions. PMID- 8699841 TI - Maximal inspiratory pressure in elite soccer players. AB - The respiratory muscle strength of elite athletes has been assessed only for some competitive sports and different conclusions have been reported. The aim of this study was to evaluate the inspiratory muscle strength in a group of professional soccer players in comparison with a group of sedentary subjects. Maximal Inspiratory Pressure (PImax) was measured both at Functional Residual Capacity (FRC) and at Residual Volume (RV) in 130 subjects: 27 of these were elite soccer players (all males, aged 22 +/- 3 years) and 103 were normal sedentary subjects (77 males and 26 females, aged 44 +/- 19 years). Predictive linear models were produced by a stepwise regression analysis in the whole sample of subjects. Both PImaxFRC and PImaxRV models included female gender and ageing as negative predictors, and Body Mass Index (BMI) as positive predictor of the inspiratory pressures. The model predicting PImaxFRC was slightly more accurate than the model predicting PImaxRV (r-squared: 0.38 vs 0.36, respectively). After adjustment for the variables entered in these models, PImaxFRC and PImaxRV were respectively 1.54 KPa and 1.08 KPa higher in soccer players than in sedentary subjects but this result was statistically significant (p < 0.02) only for PImaxFRC. We conclude that the inspiratory muscle strength is increased in soccer players and PImax measured at FRC seems more sensitive in order to discriminate between subjects with different level of physical activity. PMID- 8699842 TI - Running economy, preferred step length correlated to body dimensions in elite middle distance runners. AB - The purpose of this research was to study the relationship between running economy, step length, and body dimensions. Elite middle distance runners were tested for one high submaximal volocity very close to usual training speeds, near the anaerobic threshold (15 km.h-1) and one low submaximal velocity very different to usual training speeds, near the speed transition between walking and running (9 km.h-1). All the subjects were selected after a maximal protocol to be homogeneous on VO2max (65.7 +/- 2.3 ml.kg-1.min-1). Then they were monitored during two submaximal tread-mill tests at 54.4 +/- 2.2% (9 km.h-1) and 78.5 +/- 3.9% VO2max (15 km.h-1). Body weight, body fat, height, sitting height, low extremity length (height - sitting height), relative low extremity length, leg length, thigh length, foot length were determined. The results indicate an effect of the running speed on the relationship between body dimensions, step length and VO2. The relation was inverse between running economy, body dimensions at 9 and 15 km.h-1 and no significant correlation was found for running economy between these two speeds. Furthermore, the mode of expressing VO2 in ml.kg-0.75.min-1 affects these relations. Thus, this result allows us to make the assumption that mechanisms of adaptation can be different according to the running speed, and the specific constraints that it represents for each subject. PMID- 8699843 TI - Fatal rhabdomyolysis during mountaineering. AB - We treated two rare cases of acute rhabdomyolysis induced by heat stroke encountered during mountaineering. The clinical findings were complicated by severe acute renal failure and disseminated intravascular coagulation (DIC), respectively. Though heat-related disorders occur frequently in mountain medicine in summer, severe and fatal rhabdomyolysis due to heat stroke is rare. It was also noteworthy that both patients had received treatment with antipsychotic drugs including phenothiazine. Even in a moderate exercise activity such as mountaineering, the possibility of rhabdomyolysis should be considered for all cases of heat stroke, especially those with a history of antipsychotic neuroleptics. PMID- 8699844 TI - From Cyclic AMP to Cytokines. Pentoxifylline: Present and Future. Proceedings of an International Congress. Budapest, Hungary, July 7-9, 1994. PMID- 8699845 TI - Lipopolysaccharide signal transduction, regulation of tumor necrosis factor biosynthesis, and signaling by tumor necrosis factor itself. AB - In recent years, the chain of events that connects introduction of bacterial endotoxin (lipopolysaccharide; LPS) into a mammalian host, and the syndrome of organ damage and vascular collapse that ensues, have come into sharper focus. Several of the molecules that engage LPS, and a rough outline of the signaling cascade that leads to cytokine release from mononuclear cells, have been elucidated. The principal cytokines that mediate the untoward effects of LPS have also been identified. The most important of these is tumor necrosis factor (TNF), which elicits biologic responses from virtually every type of cell to which it binds. Two distinct receptors transduce the TNF signal. Mechanisms of TNF receptor action are becoming increasing clear, and there is reason to hope that, through intervention at many distinct levels, the devastating effects of LPS might be attenuated or averted. PMID- 8699846 TI - Expression of elastase and fibrin in venous leg ulcer biopsies: a pilot study of pentoxifylline versus placebo. AB - The pathogenesis of venous leg ulcers is based on the leakage of fibrinogen leading to a pericapillary fibrin cuff and plugging of capillaries by white blood cells. On the basis of a previous work, we had assumed that the key event in the pathogenesis of venous leg ulcers is related to inflammation generated by activated white blood cells that accumulate under unrelieved blood pressure, because in ulcer biopsies we had detected the presence of tumor necrosis factor alpha (TNF-alpha) in intracapillary monocytes, elastase in the polymorphonuclear leukocytes near the vessels, and a pericapillary undegraded fibrin cuff causing a diffusion barrier to oxygen. This concept was developed because TNF-alpha synthesized by activated monocytes is responsible for many deleterious effects. It has a potent mitogenic effect on fibroblasts, leading to new collagen deposition and angiogenesis, it induces an increase in collagenase production, it acts through upregulation of an intracellular adhesion molecule (ICAM-1), leading to leukocyte sequestration and consequently a release of toxic metabolites by the polymorphonuclear cells, an early step in chronic inflammation, it activates the coagulation pathway via a marked increase in monocyte-associated tissue factor (TF) procoagulant activity, and it inhibits fibrinolysis by promoting the release of PAI-1, contributing to undegraded fibrin deposition. Therefore, we were interested in evaluating, in patients with venous leg ulcers, the effect of pentoxifylline administered at 1,200 mg daily (versus placebo) for 2-months, as this drug induces a decrease in TNF-alpha synthesis and also blocks its activity. This pilot assay was performed in blind. Evolution of several parameters in ulcer biopsies are analyzed: TNF-alpha, intact fibrin, fibrin degradation products, ICAM-1, TF, and elastase. Pentoxifylline administration induced a decrease of local elastase and of fibrin deposit. These results support the hypothesis that accumulation of activated leukocytes is the key event in venous leg ulcers. PMID- 8699847 TI - Pharmacologic control of intracellular signaling pathways: from research to therapy. AB - Intracellular signaling pathways mediate the main events in a cell's life cycle, such as growth, proliferation, differentiation, performance of specialized functions, and apoptosis. Intracellular signaling is initiated either by extracellular signals or by intracellular gene products, e.g., those resulting from appropriately or inappropriately activated oncogenes. Extracellular signals either are generated by the general environment or are secretory products of other cells (e.g., growth factors, cytokines, hormones). Both act on specific receptors and, with some similarities to endogenous products, activate intracellular signaling and cell functional responses. Extracellular and intracellular signals coordinate the activities of the various cells in multicellular organisms. Dysregulation of signaling pathways by extracellular stimuli such as pathogens, or by gene abnormalities such as oncogene activation or loss of tumor suppressor gene activity, induces disease. The usual therapeutic targets of drugs are the stimuli and, in cancer, the oncogene or its direct product, the mRNA. Molecular components of cell signaling pathways are candidate targets for therapy. This approach may itself be sufficient to modify the positive or negative effects of a molecule in the signaling pathway. Drugs targeting cell signaling molecules can be combined with drugs acting on oncogenes, extracellular stimuli, or receptors. The main molecules involved in intracellular signaling are those of the transduction pathways and the second messengers and transcription factors. These molecules and their interactions are first recalled and are then analyzed to determine how, by the use of "specific" inhibitors, antisense methods, and directed mutagenesis, their functionality has been established. Finally, we will consider whether or not these methods can be adapted to clinical use. PMID- 8699848 TI - Pentoxifylline: a potential treatment for thrombosis associated with abnormal tissue factor expression by monocytes and endothelial cells. AB - Tissue factor (TF) is a transmembrane glycoprotein that acts as the cell receptor for factor VII and activated factor VII (VIIa) and as the co-factor for VIIa. Because binding of factor VII/VIIa to its receptor is the first step in the activation of the coagulation process, TF is not normally expressed by circulating cells. Monocytes and endothelial cells are, however, capable of producing TF in response to diverse stimuli. TF expression is believed to be responsible for thrombotic complications associated with certain diseases. In vitro, pentoxifylline (PTX) inhibits monocyte production of TF in response to endotoxin, as well as endothelial cell production of TF in response to tumor necrosis factor-alpha (TNF-alpha). In vivo, injection of PTX into primates prevents the activation of coagulation by endotoxin. The potential benefit of this treatment in patients with septic shock and disseminated intravascular coagulation, as well as in other clinical conditions in which TF expression is increased, remains to be determined in well-designed clinical trials. PMID- 8699849 TI - Leukocyte adherence in an ischemic muscle perfused by a collateral circulation. AB - Leukocyte adherence was studied in an original experiment that allowed study of the microcirculation in an ischemic muscle perfused by a collateral circulation. In this model, the artery feeding the cremaster muscle was ligated. Then the muscle homolateral to the ligation and its contralateral muscle were both studied by intra-vital-microscopy at 4 h, 1, 3, 7, and 21 days after the ligation. Rats were treated or not with 20 mg/kg/day pentoxifylline (PTX) i.m. In untreated rats, we found that both short-lasting and long-lasting leukocyte adherence was largely increased in the postcapillary venules of the ischemic muscle but not in its contralateral control. This dramatic increase was not limited to the hours immediately after the arterial ligation but was also found up to 3 weeks after the ligation when blood flow was almost restored to normal. This suggested that when muscle blood flow was chronically reduced, some changes promoting leukocyte adherence may occur in the endothelium. In rats treated with PTX, we found very effective inhibition of leukocyte adherence. PMID- 8699851 TI - Cytokines and thrombosis. AB - Cytokines are pleiotropic mediators of inflammation and immunity. Leukocytes and vascular cells are both sources of cytokines and targets for them. Several cytokines affect key functions of vascular wall cells. Several clinical acute or chronic inflammatory situations associate modifications of the cytokine network and a prothrombotic state. Many experimental data support the hypothesis that endothelial cells have an active role in these situations. Endothelial cells activated by cytokines such as tumor necrosis factor and interleukin-1 have decreased antithrombotic or prothrombotic properties and express leukocyte adhesion molecules to a greater extent. Cytokines, chemokines, and colony stimulating factors modulate the recruitment and activation of leukocytes. Activated platelets aggregate and bind to endothelial cells and to immobilized leukocytes, thus causing vascular occlusion accompanied by coagulation and leading to thrombosis. Cytokine activation may be limited by natural inhibitors or by therapeutic agents such as monoclonal antibodies, recombinant proteins, and drugs that alter cytokine synthesis, which may be of benefit in infection, inflammation, and possibly atherosclerosis. PMID- 8699850 TI - Neutrophil degranulation related to the reperfusion of ischemic human heart during cardiopulmonary bypass. AB - Activation of polymorphonuclear neutrophils (PMNs) during cardiopulmonary bypass (CPB) is a wellknown phenomenon. This study aimed to determine if activated PMNs are sequestered and degranulated within the myocardium at reperfusion in patients undergoing coronary artery bypass grafting (CABG). Nineteen patients undergoing elective CABG were included in a prospective randomized study. Blood samples were obtained simultaneously from the radial artery (RA) and the coronary sinus (CS) at the following times: T0 (5 min after onset of CPB), T1 (2 min after aortic unclamping), and T2 (10 min after aortic unclamping). Neutrophil function was evaluated by PMN count and by elastase and lactoferrin concentrations. All patients survived. Neutrophils increased significantly from T0 to T1 and T2 in both RA and CS (p < 0.001 between T0 and T1 or T2). Pre-ischemia and reperfusion were associated with a significantly lower neutrophil count in CS compared with RA blood (p < 0.001), suggesting that PMNs were trapped within the myocardium at the onset of the CPB. Elastase and lactoferrin concentrations increased significantly from T0 to T1 and from T1 to T2 for each site, with greater concentrations (p < 0.001) in the CS compared with the RA, suggesting that activated neutrophils released their granular content into the plasma milieu only after reperfusion of the ischemic heart. This study establishes that neutrophil sequestration seems to be secondary to PMN activation by CPB but that the ischemia-reperfusion sequence induces specific degranulation of the PMNs trapped within the ischemic myocardium. PMID- 8699852 TI - Pentoxifylline and lung ischemia-reperfusion injury: application to lung transplantation. Universite Paris-Sud Lung Transplant Group. AB - Pentoxifylline (PTX) attenuates neutrophil-mediated lung injury in several models of acute lung inflammation. Because pulmonary neutrophil sequestration is the main determinant of ischemia-reperfusion (IR) injury in lung transplantation, we sought to determine whether or not PTX prevented IR injury in isolated perfused rat and rabbit lungs submitted to IR, and in pigs after left lung allotransplantation. In rat lungs after IR, the coefficient of lung endothelial permeability (Kfc) increased by 112 +/- 12% in controls and by 27 +/- 8% (p < 0.001) in PTX-treated lungs. After IR, lung myeloperoxidase and blood neutrophil count decrease were lower with PTX than in controls, and the changes in Kfc were correlated with the percentage decrease in blood neutrophils during reperfusion. In rabbit lungs, endothelium-dependent relaxation in isolated pulmonary arterial rings was decreased in the control group and normal in the PTX group. In pigs ventilated with pure oxygen, the PaO2 was greater in the PTX group than in the control group (423 +/- 49 vs. 265 +/- 43 mm Hg; p < 0.05), whereas the total pulmonary vascular resistance was lower (15 +/- 1 vs. 30 +/- 9 mm Hg/L/min; p < 0.02). After reperfusion, the decrease in circulating leukocyte count fell by 35 +/- 3% in the control group and remained unchanged in the PTX group, and the leukocyte count per microscopic field in the transplanted lung was lower in the PTX group than in the control group (p < 0.02). In conclusion, PTX prevented IR lung endothelium injury and improved post-IR lung function by decreasing neutrophil lung sequestration, and this agent might be useful in clinical lung transplantation. PMID- 8699853 TI - Pentoxifylline in severe inflammatory response syndrome. AB - It is increasingly evident that sepsis triggers a complex host reaction that is responsible for a variety of pathophysiologic changes during the inflammatory process. Pentoxifylline (PTX) is a methylxanthine with selective anti inflammatory activity. Because of the current concept of an exaggerated immune response during severe inflammatory response syndrome (SIRS), this drug has received interest as a potential beneficial modulator of SIRS. Animal studies suggest that randomized clinical trials should be carefully planned with regard to dose-response relationship, disease severity, etiologic pathogens, and mechanisms that result in SIRS. The efficacy of PTX has been promising in human malaria. It is probably also effective in other hyper-tumor necrosis factor (TNF) states. The effective dosage is unclear to date, and its use is restricted by intolerance. Potential adverse effects may be related to the selective depression of TNF expression and to the depression of granulocyte phagocytic activity and the neutrophil/endothelium interaction. However, it is unlikely that any single agent will prove to be the magic bullet in the therapy of sepsis and SIRS. Multiple agents, perhaps tailored to individual circumstances, will most probably be needed, raising dramatic economic and ethical challenges. PMID- 8699854 TI - Pentoxifylline for the treatment of HIV infection and its complications. AB - The increased levels of tumor necrosis factor-alpha (TNF-alpha) seen in patients with acquired immune deficiency syndrome (AIDS) may contribute to the AIDS related wasting syndrome. TNF also induces expression of human immunodeficiency virus (HIV) through activation of the transcription factor NF-kappa B, which binds to the viral long terminal repeat (LTR). Because TNF can decrease the antiretroviral activity of zidovudine (AZT) in vitro, pentoxifylline (PTX) may increase the efficacy of AZT. PTX decreases HIV replication in acutely infected cells and inhibits gene expression controlled by the HIV-1 LTR. The antiretroviral activity of PTX is associated with decreased binding of NF-kappa B to its recognition sequences. Therefore, PTX may inhibit HIV expression indirectly by diminishing TNF production and directly, by decreasing activity of NF-kappa B. PTX, and an inhibitor of the viral transactivator TAT, Ro24-7429, may inhibit HIV gene expression in a cooperative fashion. The first clinical study of PTX in AIDS patients was conducted by us through the AIDS Clinical Trial Group of the National Institutes of Health. AIDS patients on antiretroviral therapy received PTX 400 or 800 mg three times daily for 8 weeks. TNF assays included TNF mRNA levels in peripheral blood mononuclear cells (PBMCs) and inducible TNF protein levels in the supernatant of PBMCs cultured in the presence of 0.1 microgram/ml lipopolysaccharide (LPS). The median change in TNF mRNA was a 30% decrease. There was a median and significant 40% decrease in the production of inducible TNF protein. HIV load decreased in 10 patients and increased in four patients, but did not change in the group as a whole. Others have extended our initial observations in HIV-infected patients. In a placebo-controlled trial, TNF production by unstimulated PBMCs decreased by 52% in the PTX arm and increased by 7.2% in the placebo arm. In a study comparing AZT, PTX, or a combination of the two, viral load after treatment was ninefold above baseline in the AZT or PTX alone arm, compared to only twofold in the combination arm. In a quality of life trial, PTX was associated with improvement in depression, anger, and social and cognitive function: a placebo effect, however, was not ruled out. PTX 400 mg three times daily is safe and well tolerated. PTX decreases PBMC TNF expression in HIV-infected patients, measured as protein in culture supernatant or as mRNA, and may decrease viral replication. Further studies of HIV-infected persons are needed to ascertain the benefit of PTX as an adjunct either to inhibitors of reverse transcriptase (e.g., AZT) or of transcription (e.g., TAT inhibitor). PMID- 8699855 TI - Prevention studies with pentoxifylline: new clinical projects. AB - Pentoxifylline (PTX) is a methylxanthine derivative whose diverse mechanisms of action are now extensively documented. It may play a role in various diseases via a pharmacologic modification of cytokine dysregulation. Despite many encouraging results in animal models, it has not yet been demonstrated that PTX could have beneficial effects in other diseases than intermittent claudication. We selected three clinical conditions that may benefit from PTX and are trying to clarify its potential for use in these disorders. The use of allogeneic bone marrow transplantation is limited by its toxicity, although this form of therapy is able to cure many hematologic malignancies. We are performing a placebo-controlled trial to evaluate the ability of PTX to decrease transplant-related toxicity. In severe chronic respiratory insufficiency, a study is ongoing to compare the number of infectious exacerbations under PTX or placebo. Finally, we have planned a long-term prevention study in patients with peripheral arterial disease. We present here the rationale and design of these trials. PMID- 8699856 TI - Cytokines, phagocytes, and pentoxifylline. AB - Phagocytic cells, such as polymorphonuclear neutrophils, monocytes, and macrophages, are essential for defense against infection caused by a variety of microorganisms. The mechanisms used by these cells to destroy microbes comprise a potent oxidative armamentarium including superoxide, hydrogen peroxide, and hypochlorous acid. In addition, granule contents such as proteolytic enzymes, lysozyme, lactoferrin, and myeloperoxidase are released into the phagosome to destroy ingested microorganisms. Inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and IL-6, enhance the phagocytic and microbicidal activity of the cells and increase their stickiness. It has been demonstrated in a variety of animal and clinical studies that activated phagocytes can damage the host they are designed to protect, using the mechanisms described above. Alkylxanthines, including pentoxifylline, are potent inhibitors of this inflammatory damage by two major actions: (a) reduction of the production of inflammatory cytokines (especially TNF) by phagocytes stimulated with a variety of microbial products (e.g., endotoxin); and (b) reversal of the effect of these cytokines on phagocytes. Thus, pentoxifylline counteracts the following effects of inflammatory cytokines on phagocytes: increased adherence, shape change resulting in larger size and rigidity, increased oxidative burst, priming for an enhanced oxidative burst, increased degranulation, and decreased chemotactic movement. In addition, these activities synergize with the normal anti-inflammatory mediator adenosine. Alkylxanthines have the potential to be effective therapy for conditions in which inflammatory cytokines and phagocytes cause damage, including the sepsis syndrome, ARDS, AIDS, and arthritis. PMID- 8699857 TI - Neutrophil activation, tumor necrosis factor, and survival after endotoxic and hemorrhagic shock. AB - Polymorphonuclear neutrophils (PMNs) may contribute to organ injury in both hemorrhagic and endotoxic shock. Both models of shock exhibit a "flight of the leukocytes," but the mechanisms for entrapment of leukocytes in the microcirculation differ. The objective of this study was to investigate lipopolysaccharide (LPS)-induced shock and hemorrhagic shock with similar survival rates, in terms of circulating PMNs, activated circulating PMNs, plasma tumor necrosis factor (TNF) activity, and PMN adhesion. In the LPS protocol, rats received 6.5 mg/kg E. coli LPS i.v., which resulted in 50% survival. In the hemorrhagic shock protocol, rats were maintained for 3 h at 40 mm Hg mean arterial pressure, and survival during a 24-h observation period was 40%. LPS injection and hemorrhage caused rapid neutropenia in survivors and nonsurvivors. Low circulating PMN counts persisted during hypotension in the hemorrhagic protocol and among nonsurvivors in the LPS protocol, but in both protocols a tendency toward significantly higher circulating PMN counts in survivors compared with nonsurvivors was found. In both protocols, survivors had significantly lower fractions of circulating activated PMNs and lower adhesion of circulating PMNs to nylon fibers. In the LPS protocol, higher plasma TNF activity was found in nonsurvivors than in survivors, but no TNF activity in plasma could be found throughout the hemorrhagic protocol. These results indicate that nonsurvivors in both shock models exhibit higher levels of PMN activation. No correlation was detected between PMN activation and plasma TNF activity to suggest that TNF serves as the primary mediator of circulating PMN activation. PMID- 8699858 TI - Pentoxifylline selectivity inhibits tumor necrosis factor synthesis in the arterial wall. AB - Pentoxifylline (PTX) has been reported to potentially inhibit tumor necrosis factor (TNF) synthesis by monocytes/macrophages. Because inflammatory processes involve both leukocytes and vascular cells, we tested the effects of PTX on TNF and interleukin-6 (IL-6) production by the vessel wall in response to lipopolysaccharide (LPS). Rings of rat thoracic aorta were incubated for 24 h in DMEM containing antibiotics and 1% fetal calf serum in the presence of 1 microgram/ml LPS. TNF and IL-6 were biologically assayed using L-M fibroblast cytotoxicity and B9 hybridoma cell proliferation, respectively. Maximal LPS induced production of TNF and IL-6 by the aorta was 0.77 +/- 0.04 and 23.3 +/- 3.5 x 10(3) U/mg dry weight, respectively. The addition of PTX dose-dependently suppressed the production of TNF by 26 +/- 7%, 58 +/- 6%, and 85 +/- 9% at 10, 100, and 1,000 microM, respectively. This effect was selective for TNF, because the production of IL-6 was not affected by any dose of PTX, suggesting a selective gene regulation of TNF and IL-6 in vascular cells. These results may have clinical implications. PTX may be useful in vascular inflammatory diseases, in which serum TNF levels have been shown to be correlated with the severity of the disease. PMID- 8699859 TI - Activated leukocytes, endothelial cells, and effects of pentoxifylline: observations by VEC-DIC microscopy. AB - Using video-enhanced contrast (VEC)-differential interference contrast (DIC) microscopy, ultrastructural observations were made of the activation of polymorphonuclear leukocytes (PMNLs), the interaction between activated PMNLs and endothelial cells (ECs), and the effects of pentoxifylline (PTX). The ECs were obtained from a commercial source as human umbilical cord vein endothelial cells (HUVECs) or were obtained from pig or rat brains. They were cultured on a coverglass with DMEM for about 1 week. The human PMNLs were obtained from the authors' venous blood. The control appearance of the PMNLs resembled an elastic ball covered with fine villi. The PMNL was activated spontaneously and became flattened on the glass surface within 10 min in the observation chamber. The activation of the PMNLs was estimated arbitrarily from the polymorphous changes in cell shape, agitation of the intracellular granules, and apparent increase in adhesiveness. Preadministered PTX prevented such PMNL activation, and the PMNLs remained round for more than 15 min. PMNL activation was accelerated by chemoattractants (PAF, fMLP, and PMA). In one case, a PMNL that had been activated by PMA tended to recover its round shape with PTX, but finally ended by swelling and bursting. When PMNLs were introduced into the EC-containing chamber, they became entrapped by the ECs and activated, with degranulation followed by release of a smoke-like material. After about 3 h, the EC with an attached PMNL shrank and fell into a state of coagulation necrosis. When PTX was introduced at the time of adhesion of the flattened PMNL, the PMNL appeared to be deactivated, becoming smaller and assuming its previous round shape, and detached from the EC. PTX prevented the spontaneous activation of PMNLs, and of deactivated PMNLs even after their adherence to the endothelium. PMID- 8699860 TI - Pharmacologic approaches to the treatment of atherosclerotic arterial obstruction. AB - Three consecutive periods in the natural history of atherosclerosis are amenable to medical treatment. Plaque development is the main target of prevention, which also aims at slowing the progression of already existing plaques. The control of several established risk factors (high blood cholesterol, high blood pressure, diabetes mellitus, tobacco smoking) has already yielded encouraging benefits, especially in the field of secondary prevention. More efficient prophylaxis is to be expected, either from the further improved control of these classic risk factors with earlier, stronger, and longer interventions or from the correction of newly established causal determinants of atherosclerosis. A plaque manifests itself clinically through progressive or abrupt obstruction of the arterial lumen, which can be avoided or retarded by interventions aimed at reducing thrombosis, at controlling plaque instability (the major cause of thrombosis), and at enhancing arterial remodeling (which allows compensatory enlargement of the arterial lumen). When ischemia has occurred, a third wave of palliative treatments aims at improving energy supply to the organ with compromised vascularization. Classic treatments reduce oxygen consumption or improve oxygen extraction by ischemic tissues. In addition, the design of drugs to enhance the development of collateral channels appears to be promising therapeutic approach. PMID- 8699861 TI - Pentoxifylline and intermittent claudication: review of clinical trials and cost effectiveness analyses. AB - Intermittent claudication (IC) is common in the elderly; the prevalence is approximately 6% in 50- to 60-year-old patients and 10-20% in those over the age of 70. Several risk factors, especially smoking, are associated with increased prevalence. Disease progression results in increasingly debilitating and costly surgical intervention for about 20% of patients. This report reviews findings from some of the clinical studies that demonstrated the efficacy of pentoxifylline, the only U.S.-approved medical therapy for IC. Findings from a recently published cost-effectiveness analysis are presented. IC is difficult to study clinically because pain is both variable and subjective. In two multicenter, randomized, placebo-controlled studies, carefully monitored treadmill testing showed that pentoxifylline-treated patients had significantly improved walking distances even in the presence of a placebo effect. The pentoxifylline effect was pronounced in patients from a clinical target population defined by low baseline resting pressure ratios (< or =0.8) and long disease duration ( > 1 year). To understand the social implications of these findings, treadmill distances were converted to comparable distances on flat ground. Improvements on pentoxifylline therapy translate to walking distances that enable greater daily function. This improvement has significant practical benefit to the quality of life of IC patients. Using Medicare expenditure data, it was found that pentoxifylline therapy reduced average hospital costs per patients by $1,173. Direct medical cost savings of $69 to $3,090 were suggested by sensitivity analyses. In analyses of practical aspects of walking distance as well as cost-effectiveness analyses, pentoxifylline appears to be a highly useful treatment for IC. PMID- 8699862 TI - National study of obliterative arterial disease of the lower limbs involving general practitioners in France: Artemio study. AB - A national survey was performed in France from May to June, 1993. The aim of this study was to evaluate general practitioners' attitudes and behaviors when diagnosing and managing patients with lower extremity arterial disease (LEAD). One thousand general practitioners, randomly drawn from an exhaustive list, were contacted to participate in a telephone interview concerning the last patient with intermittent claudication seen in their practice. Four hundred seventy-six general practitioners participated. Risk factors noted for these 476 patients with intermittent claudication were in agreement with the literature: 86% were men aged 64 +/- 10 years (mean +/- SD) and 14% were women aged 73 +/- 8 years. Sixty-two percent had a pain-free walking distance of between 100 and 500 meters at diagnosis. Forty-five percent were former smokers and 37% currently smoked; 55% had hypertension, 14% diabetes, and 56% disturbances of lipid metabolism. A majority of them were hypercholesterolemic. The diagnosis of the disease was based primarily on a clinical assessment, confirmed for 33% by Doppler or echo Doppler. The mean duration of diagnosis was 4.4 +/- 4.1 years. Management of the disease was mainly by prescription of vasodilators (91%), antiplatelet agents (59%), and anticoagulants (8%). Use of Doppler or echo Doppler was recommended once a year. Infection was observed in 27% of patients. Thirty-eight percent had had a cardiac incident (angina pectoris or myocardial infarction) and 10% a cerebrovascular accident. They differed significantly from those with LEAD alone for the following parameters: age (68.5 +/- 9.2 vs. 63.2 +/- 10.3 years; p < 0.001); duration of LEAD (5.6 +/- 4.6 vs. 3.6 +/- 3.5 years; p < 0.001); hypertension (65% vs. 50%; p < 0.01); and current smoking (29% vs. 43%; p < 0.01). This survey confirmed the feasibility of telephone interviewing, on a large sample of general practitioners in France. The high level of association with other cardiac incidents was, for these patients, a much higher risk of mortality and morbidity than LEAD alone. It would be interesting to validate the associations observed with a prospective study of comorbidity. PMID- 8699863 TI - Pentoxifylline and critical leg ischemia. AB - The annual incidence of critical leg ischemia has been estimated at 500-1,000 patients per million population/year. In critical ischemia there is a breakdown in the microvascular flow-regulating system and inappropriate activation of the microvascular defense system, with resultant endothelial damage and activation of platelets and leukocytes, which leads to further damage of the capillary network. The mainstay of treatment until recently has consisted of interventional procedures. However, these are not always feasible and are not without significant mortality and morbidity. Therefore, attention has been directed towards pharmacologic management. Pentoxifylline inhibits leukocyte aggregation and activation, and improves red cell deformability and oxygen release to tissue. On the basis of these properties, several pilot studies were undertaken, and most have confirmed the benefits of pentoxifylline in the management of critical ischemia. These positive results led to the initiation of a multicenter, double blind, placebo-controlled study of intravenous pentoxifylline in the acute management of critical ischemia. Results showed a significant reduction in rest pain with pentoxifylline, and outcome was not influenced by various prognostic factors. Research to date suggests that pentoxifylline could have a definite role in the management of patients with critical ischemia. PMID- 8699864 TI - Pharmacologic treatment of venous leg ulcers. AB - In terms of prevalence, total cost and morbidity, venous leg ulcers are probably by far the most important type of ulcerations in the leg. The macrocirculatory defect leading to a raised ambulatory venous pressure is now accepted as a common initial pathologic pathway. Most current treatment modalities, such as surgery or external compression, are designed to control the macrovascular defect. However, it is the microcirculatory consequences of the venous hypertension that give rise to the trophic skin changes and ultimately to ulceration. At this microcirculatory level, pharmacotherapy may be a useful adjunct in the treatment of venous leg ulcers. The microcirculatory pathophysiologic changes include decreased fibrinolytic activity, elevated plasma fibrinogen, microcirculatory thrombi, and inappropriate activation of the white blood cells. The oxidative burst from the activated white cells probably plays a key role by releasing locally leukocyte-derived free radicals, proteolytic enzymes, cytokines, platelet activating factor, and a number of other noxious mediators. An important additional component in recalcitrant venous ulcers is co-existing arterial disease, which is probably present in 15-20% of cases. Decreased arterial perfusion pressure will further aggravate the ischemic changes caused by the venous hypertension. Pentoxifylline downregulates leukocyte activation, reduces leukocyte adhesion, and also has fibrinolytic effects. A number of clinical studies have therefore been carried out to examine the clinical efficacy of pentoxifylline in treatment of venous leg ulcers. Probably the largest published placebo-controlled, double-blind randomized study was reported in 1990. In this study, 80 patients received either pentoxifylline 400 mg three times a day orally or matching placebo for 6 months or until their reference ulcer healed if this occurred sooner. Complete healing of the reference ulcer occurred in 23 of the 38 patients treated with pentoxifylline compared to 12 of the 42 patients treated with placebo. The odds ratio in favor of pentoxifylline was 1.81 (95 confidence intervals 1.20-2.71). PMID- 8699865 TI - Impairment of polymorphonuclear neutrophil function in HIV-infected patients. AB - Impaired polymorphonuclear neutrophil (PMN) function may contribute to the onset of certain bacterial and fungal infections and to tissue damage in human immunodeficiency virus (HIV)-infected patients. Published data on PMN function in HIV infection are controversial, possibly because most studies have involved PMNs isolated from the normal blood environment by various procedures that may modify PMN responses. We therefore used flow cytometry to study the expression of adhesion molecules at the PMN surface, actin polymerization, and the oxidative burst of whole-blood PMNs in 42 HIV-infected patients at different stages of the disease. These PMNs were activated in vivo, as shown by increased expression of the adhesion molecule CD11b/CD18, reduced L-selectin antigen expression, increased actin polymerization, and increased H2O2 production. The alterations were present in asymptomatic patients with CD4+ cell counts above 500/microliters and did not increase with progression of the disease. This PMN activation could contribute to the oxidative stress described in HIV infection. Stimulation by bacterial N-formyl peptides showed dysregulation of L-selectin shedding and decreased H2O2 production after cx vivo priming with tumor necrosis factor-alpha or interleukin-8. These latter impairments, which correlated with the decrease in CD4+ lymphocyte numbers, could contribute to the increased susceptibility of HIV infected patients to bacterial infections. PMID- 8699866 TI - Effect of pentoxifylline on apoptosis of cultured cells. AB - Apoptosis or programmed cell death (PCD) was measured in two human cell models by flow cytometric analysis. Blood neutrophils underwent spontaneous apoptosis in short-term culture. Pentoxifylline (PTX) inhibited spontaneous neutrophil PCD. We confirmed that granulocyte/macrophage colony-stimulating factor (GM-CSF) inhibited apoptosis of polymorphonuclear neutrophils. Treatment with both GM-CSF and PTX did not increase the inhibition of PCD by either GM-CSF or PTX alone. Because apoptosis could be due to the accumulation of H2O2 in the culture medium, and because PTX has been described to reduce peroxide production, we studied the effect of adding catalase to the medium. Catalase reduced the neutrophil apoptosis and this effect was cumulative with the effect of PTX. Camptothecin, an inhibitor of topoisomerase I, induces a block in the S-phase of the cell cycle followed by apoptosis of the U937 cell line. This drug-induced apoptosis was partially inhibited by PTX, whereas the S-phase cell block was not affected. In conclusion, PTX was found to inhibit apoptosis in two different human cell types. In neutrophils, this effect appears to occur regardless of the inhibition of phosphodiesterase activity and inhibition of H2O2 release. PMID- 8699867 TI - Regulatory effects of pentoxifylline on T-helper cell-derived cytokine production in human blood cells. AB - Pentoxifylline (PTX), a methyl xanthine derivative, was examined for its regulatory effect on Th1-and Th2-cell-derived cytokines in human whole blood and peripheral blood mononuclear cells stimulated with phytohemagglutinin (PHA) and phorbol myristate acetate (PMA). Cytokine production was analyzed by enzyme linked immunosorbent assay and cytokine mRNA expression was examined by the polymerase chain reaction (PCR) after reverse transcription (RT). The results showed that PTX at 5 x 10(-4) M concentration selectively suppressed Th-1 cytokines [interleukin-2 (IL-2) and interferon-gamma (IFN-gamma)] but not IL-4, as observed by the measurement of protein secretion. Using sensitive RT-PCR assays, data show that at this same PTX concentration (5 x 10(-4) M), these cells also exhibited inhibition in the expression of IL-4 and IL-10 mRNA, together with inhibition of IL-2 and IFN-gamma mRNA expression. At 1 x 10(-4) M, no apparent change in IL-4 and IL-10 mRNA expression was observed, whereas IL-2 mRNA was still inhibited. It was noted that PTX at 1 x 10(-3) M induced a generalized inhibition of all cytokines. Our findings showed that PTX at the appropriate concentrations could induce selective suppression of IL-2 and IFN-gamma, whereas at high concentrations this drug could act as a suppressive agent of both Th1- and Th2-derived cytokines. Moreover, these data provide further evidence that the induction of IL-2 gene transcription is highly sensitive to an elevation of cAMP, whereas IL-4 gene transcription appeared to be less affected. PMID- 8699869 TI - Influence of pentoxifylline on membrane thrombomodulin levels in endothelial cells submitted to hypoxic conditions. AB - Thrombomodulin (TM) expression at the surface of endothelial cells is upregulated by cAMP analogues, whereas hypoxic conditions induce a decrease in this expression. Pentoxifylline (PTX) enhances the intracellular levels of cAMP in human umbilical vein endothelial cells (HUVECs). We therefore investigated the influence of this drug on TM expression in cells submitted to hypoxia. TM expression was quantified at the surface of HUVECs in the presence or absence of PTX during 18 h of incubation. Membrane TM was immunolabeled with a fluorescent monoclonal antibody and the expression was quantified by flow cytometric analysis. Our preliminary data revealed that PTX at 0.01 microM significantly increased TM expression levels compared with cells in hypoxia without the drug. Therefore, at this low dose PTX appears able to counterbalance the procoagulant effect of hypoxia. PMID- 8699868 TI - Production of proinflammatory cytokines and cytokines involved in the TH1/TH2 balance is modulated by pentoxifylline. AB - The modulation of cytokine release induced by pentoxifylline (PTX) has recently been demonstrated not to be restricted solely to tumor necrosis factor (TNF) alpha. This prompted us to study the influence of PTX on a larger spectrum of cytokines with proinflammatory actions [TNF-alpha, interleukin-6, (IL)-6, IL-1 beta, IL-8] or with implied actions in the TH1 (IL-2, IFN-gamma)/TH2 (IL-10) balance. The IL-1RA was also explored. This work was performed using a whole blood model in which cytokine production is measured after stimulation by lipopolysaccharide (LPS) (25 micrograms/ml) and phytohemagglutinin (PHA) (5 micrograms/ml) in 1:10 diluted whole blood. The stimulation test was performed in blood from healthy controls and from septic patients (without septic shock) in the presence or absence of PTX at 10(-6), 10(-5), 10(-4), or 10(-3) M. In controls and septic patients, at a 10(-4) M PTX concentration the production of IL-2 is strongly diminished (26-32% of the basal level), followed by diminution of IFN-gamma (30-40%). As expected, of the proinflammatory cytokines TNF was the most strongly suppressed (50% of baseline) followed by IL-1 (about 80% of basal production). Finally, IL-10 was also influenced by PTX (65% of baseline). At 10( 4) M, IL-1RA and IL-6 were unaffected by PTX. Taken altogether, our data demonstrate that PTX possesses a much broader spectrum of activity on cytokine production than was initially described, and it appears to be a potential and promising immunotherapeutic agent. PMID- 8699870 TI - Inhibitors of phosphodiesterase (pentoxifylline, trequinsin) inhibit apical and subcellular matrix expression of tissue factor in cultured human endothelial cells. AB - Exposure of endothelial cells (ECs) to thrombin or cytokines leads to major changes in their biochemical properties, which confer procoagulant activities. Stimulated ECs express the procoagulant glycoprotein tissue factor (TF). Although some TF is expressed on the apical surface of the cells, most is deposited as a cryptic pool in the subendothelial matrix. This matrix-associated TF may play a role in thromboembolic complications associated with alterations in the integrity of the EC monolayer. We have measured TF activity on the surface and in the subcellular matrix of human saphenous vein ECs in culture, by assaying the TF dependent formation of activated factor X in the presence of factor VII. The subcellular matrix was prepared by exposure of ECs to ammonium hydroxide. Incubation of ECs for 4 h with 1 U/ml human thrombin induced TF expression on the apical cell surface and in the matrix. Activity in the matrix was 4.1 +/- 0.5 times greater than on the cell surface. Pentoxifylline inhibited the expression of TF both on the cell surface and in the matrix. The EC50 was on the order of 3.9 mM in both cases. No signs of cell toxicity were observed at this concentration of pentoxifylline. Similar effects were obtained with trequinsin (HL 725), a phosphodiesterase inhibitor, with an EC50 of 40 microM. This suggests that an increase in cAMP may be involved in the mechanism of action of pentoxifylline. Inhibition of TF deposition in the matrix may be important in the prevention of thromboembolic episodes in conditions where ECs either retract or are removed by major injury. PMID- 8699871 TI - Cytokines regulate vascular functions related to stability of the atherosclerotic plaque. AB - The cytokines are multipotent mediators of inflammation and immunity that can affect key functions of vascular wall cells. Growing evidence suggests that cytokines participate as autocrine or paracrine mediators in atherogenesis, as cells in lesions can both produce and respond to these mediators. The functions of vascular wall cells regulated by cytokines may influence lesion initiation, progression, or complication. For example, cytokines can regulate the expression of adhesion molecules crucial to the recruitment of leukocytes to lesions, including vascular cell adhesion molecule-1 (VCAM-1). Cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) can regulate the production of monocyte chemoattractant protein-1 (MCP-1), a potential signal for directed migration of monocytes into the intima. Cytokines can also regulate genes that encode other growth factors and cytokines themselves. TNF-alpha can induce IL-1 mRNA in human endothelial (EC) and smooth-muscle cells (SMC). IL-1 and TNF-alpha can augment the production by vascular cells of macrophage-colony stimulating factor (M-CSF), which may promote growth and activation of mononuclear phagocytes. Cytokines can exert both pro-and antiatherogenic actions. Activated T cells in human atheroma may secrete the lymphokine IFN-gamma, an inhibitor of SMC proliferation. Cytokines influence vasomotor tone in arteries, e.g., by inducing a form of nitric oxide synthase, the enzyme that synthesizes the vasodilatory nitric oxide radical. The cytokines also modulate endothelial functions that govern the formation and stability of blood thrombi. Finally, in the late stages of the disease, matrix metalloproteinases derived from macrophages or smooth-muscle cells themselves may contribute to weakening of the fibrous cap in the vulnerable shoulder area, promoting plaque rupture and occlusive thrombosis, culminating in the dramatic clinical manifestations of atherosclerosis, including myocardial infarction and stroke. Thus, cytokines can influence multiple aspects of atherogenesis and provide new and interesting targets for therapeutic intervention. PMID- 8699872 TI - Effects of pentoxifylline on the adherence of polymorphonuclear neutrophils to oxidant-stimulated human endothelial cells: involvement of cyclic AMP. AB - Cultured human umbilical vein endothelial cells (HUVECs) treated with reactive oxygen species (ROS) show increased adherence of polymorphonuclear leukocytes (PMNs). Because pentoxifylline (PTX) is known to inhibit cell interactions, we studied PMN adherence to ROS-stimulated HUVECs pretreated with PTX. ROS were generated by the oxidation of hypoxanthine by xanthine oxidase, giving rise to superoxide anion and hydrogen peroxide. Human PMNs were then added to HUVEC monolayers. After various times, the cultures were washed and the number of adherent PMNs was estimated by measuring myeloperoxidase in the total cell homogenate. PTX inhibited adherence in a concentration-dependent manner. Moreover, the increase in intracellular cAMP content varied with the PTX concentration. Isobutylmethylxanthine (IBMX) and isoproterenol (ISO) which increase intracellular cAMP content, also inhibited the adherence of PMNs to ROS stimulated HUVECs. We conclude that cAMP is probably involved in the intracellular regulation of ROS-mediated PMN adherence to endothelial cells. PMID- 8699873 TI - Leukocyte activation study during occlusive arterial disease of the lower limb: effect of pentoxifylline infusion. AB - Granulocytes play a significant role in vascular diseases. The mechanisms of neutrophil-mediated vascular injury include their increased endothelial adhesion and activation with release of inflammatory mediators. Pentoxifylline (PTX) has a well-demonstrated ability to act on the activated neutrophils. It increases chemotaxis and decreases their adherence to endothelial cells, oxidative burst, and enzyme release. In this preliminary study, we investigated the effects of PTX on ischemia-induced changes in polymorphonuclear neutrophils (PMN) activation and cytokine release. A double-blind, randomized, placebo-controlled trial was carried out in 14 patients (age range 46-86 years) suffering from critical ischemia, as defined by the European Consensus Document, or subacute ischemia due to occlusive arterial disease of the lower limb. Femoral and antecubital venous blood samples on the side of the ischemic leg were obtained from patients immediately before (TO) and after infusion (T24) of PTX or placebo. PMN activation was evaluated by study of cell migration, beta 2 integrin expression (CD11b/ CD18), oxidative burst, and elastase release. Inflammation proteins were analyzed, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6), C-reactive protein (CRP), and fibrinogen. Before treatment, our results demonstrate an important activation in both femoral and antecubital venous blood. PMN activation markers, cytokine release, and other inflammation proteins were significantly increased compared with normal subjects. In the experimental group there was no significant difference between femoral and antecubital venous blood. Six patients received PTX infusion and seven patients were in the placebo group. The effect of PTX was evaluated after 24 h of treatment (1,200 mg). In the PTX group the following variables were improved compared with the placebo group: CD11b expression on PMNs, elastase released from PMNs, fibrinogen, CRP, TNF-alpha, and IL6 in plasma. These preliminary results should be interpreted with caution because of the small sample size. Further trials may contribute to more complete understanding. PMID- 8699874 TI - The behavioral neurochemistry of motivation: methodological and conceptual issues in studies of the dynamic activity of nucleus accumbens dopamine. AB - Considerable experimental and clinical evidence links forebrain dopamine (DA) systems to the performance of motor activities and to motivational processes. Much of the support for this conclusion was obtained from studies utilizing lesions or drugs to manipulate aspects of central dopaminergic function. Although such experiments yield important information concerning the behavioral consequences of interference with DA systems in brain, they do not demonstrate any relation between the dynamic activity of DA neurons and the level or type of motor function exhibited by the organism. This review discusses the emerging field of behavioral neurochemistry, and provides an overview of recent studies investigating the relation between nucleus accumbens DA release and behavior. Particular emphasis is placed upon current research involving microdialysis, voltammetry and electrophysiology. These different methods are viewed as complementary techniques for investigating the activity of DA systems in behaving animals. Evidence indicates that DA activity is most reliably activated by stimuli that trigger instrumental behavior and during the preparatory or instrumental phase of motivated behavior. The effects of consummatory reactions to positive reinforcers are somewhat equivocal; with food consumption, dialysis studies have yielded inconsistent results, while some voltammetric and electrophysiological studies have shown that DA activity in accumbens or ventral tegmental area actually decreases during consumption of food reinforcement. Moreover, the responsiveness of accumbens DA activity during behavioral stimulation is not unique to appetitive conditions, as several studies have shown that aversive or stressful conditions also stimulate accumbens DA release or metabolism. It is reasonable to suggest at this time that accumbens DA neurons are activated by a variety of different motivational conditions, but that the consequence of that activation is to modulate the behavioral reactivity of the organism. This type of function is seen as representing an area of overlap between motor and motivational processes. PMID- 8699875 TI - Brain regional levels of adenosine and adenosine nucleotides in rats killed by high-energy focused microwave irradiation. AB - A high-energy focused microwave system for killing experimental animals was used to rapidly inactivate enzymes and prevent postmortem breakdown of adenine nucleotides and adenosine, thereby enabling accurate measurements of AMP, ADP, ATP and adenosine in rat brain. For comparison, purine levels were measured in brains of rats killed by decapitation, decapitation into liquid nitrogen, or in situ freezing of the brain with liquid nitrogen. Of the three microwave irradiation power levels used, 10, 6.0 or 3.5 kW, rats killed by 10 kW had the highest ATP levels (28.8 nmol/mg protein) and cellular energy charge value (0.8), and the lowest levels of AMP (2.2 nmol/mg protein) and adenosine (19.7 pmol/mg protein). Of the 6 brain regions studied, adenosine levels (pmol/mg protein) ranged from 10 in cerebral cortex to 170 in cerebellum of rats killed using 10 kW microwave irradiation and, for comparison, ranged from 840 in cerebral cortex to 2498 in striatum of rats killed by decapitation. Focused microwave killing permits precise and accurate measurements of purines in discrete regions of rat brain. PMID- 8699876 TI - A microcomputer-based system for real-time analysis of animal movement. AB - A microcomputer-based video system for tracking, recording, and analyzing the movement of animals in two dimensions on variegated background in real-time has been developed and validated, both mechanically and with moving animals. Hardware and software (donationware) costs are low. Specimens visualized as small as 3 pixels long may be tracked in an arena that is 240 x 320 pixels in size. The results of tracking a mechanical moving spot are compared with a theoretical circular path. Comparisons between frame-by-frame human observation and computer generated X-Y coordinates are also presented. Applications of the tracking system include insect toxicology and pheromone bioassay, vertebrate locomotion studies, and basic research on taxes and kineses. PMID- 8699877 TI - Multiple source localization using genetic algorithms. AB - We present a new procedure for localizing simultaneously active multiple brain sources that overlap in both space and time on EEG recordings. The source localization technique was based on a spatio-temporal model and a genetic algorithm search routine. The method was successfully applied to the localization of two dipole sources from several sets of simulated potentials with various signal-to-noise ratios (SNR). The different SNR values resembled evoked responses and epileptic spikes as commonly seen in the laboratory. Results of the simulation studies yielded localization accuracy ranging from 0.01 to 0.07 cm with an SNR of 10; from 0.02 to 0.26 cm with an SNR of 5; and from 0.06 to 0.73 cm when the SNR was equal to 2. Additionally, two sets of simulations were based on the dipole arrangements and time activities of data obtained during electrical stimulation of the median nerve in human subjects. These studies yielded localization accuracy within 0.1 cm. We also studied the localization accuracy of the algorithm using a physical model incorporating potential measurements of two current dipoles embedded in a sphere. In this situation the algorithm was successful in localizing the two simultaneously active sources to within 0.07 0.15 cm. PMID- 8699878 TI - Methylcellulose during cryopreservation of ventral mesencephalic tissue fragments fails to improve survival and function of cell suspension grafts. AB - Cryopreservation may allow long-term storage of fetal ventral mesencephalon (VM) for transplantation in patients suffering from Parkinson's disease (PD). We investigated whether the polymer methylcellulose protects fetal rat VM during cryopreservation in liquid nitrogen and improves survival and function of this tissue as intrastriatal suspension grafts in the 6-hydroxydopamine (6-OHDA) rat model. VM tissue fragments (E14-E15) were either immediately dissociated and grafted as a cell suspension (FRESH) or cryopreserved under controlled conditions for 7 days in a conventional cryoprotective medium (CRYO) or a medium containing 0.1% methylcellulose (mCRYO) and then dissociated and grafted. Rats from the cryo groups showed only limited behavioral compensation in contrast to complete compensation observed in rats from the FRESH group. Cryopreservation of fetal rat VM decreased the viability of cell suspensions in vitro to about 70%, survival of grafted tyrosine hydroxylase-immunoreactive (TH-IR) neurons to 11% and 20%, and transplant volume to 8% and 17% (mCRYO and CRYO, respectively, compared to FRESH). The addition of 0.1% methylcellulose to tissue fragments during freezing did neither improve in vitro viability nor survival of TH-IR neurons nor behavioral compensation when compared to the control CRYO group. These results suggest that methylcellulose failed to improve survival of cryopreserved dopaminergic ventral mesencephalic neurons. PMID- 8699879 TI - A neural network approach to real-time spike discrimination during simultaneous recording from several multi-unit nerve filaments. AB - A multi-channel, real-time, unsupervised spike discriminator was developed in order to reconstruct single spike trains from several simultaneously recorded multi-unit nerve filaments. The program uses a Self Organising Map (SOM) algorithm for the classification of the spikes. In contrast to previous similar techniques, the described method is made for use on a PC, and the method may thus be implemented at relatively low cost. In order to test the accuracy of the program, a robustness test was performed, where noise with different RMS levels was superimposed on the spikes. Furthermore, the maximal classification rate was determined. The program is easy to use, since the only manual inputs needed are the voltage threshold for spike detection, and the number of units present in each recorded nerve filament. PMID- 8699880 TI - A biplanar slice preparation for studying cerebellar synaptic transmission. AB - Unlike certain other brain areas, notably the hippocampal formation, synaptic transmission in the cerebellum, a 3-dimensional anatomical structure, is no ideally studied in a 2-dimensional slice preparation. We describe a method for cutting a cerebellar slice that incorporates two planes of section: one sagittal (in the plane of the Purkinje cell dendrites and of afferent and efferent fibres running in the white matter), and the other in the plane of the parallel fibres (granule cell axons). Details are given of how neurotransmission in the parallel fibre-to-Purkinje cell pathway and in the mossy fibre-to-granule cell pathway can be studied by applying a specially designed grease-gap recording technique to the biplanar slice. We further demonstrate the utility of the slice for intracellular recording. PMID- 8699882 TI - Tri-axial, real-time logging of fly head movements. AB - We present a method to record and simultaneously display the three rotatory components of arbitrary head turns of an insect flying stationarily in a wind tunnel or walking on a treadmill. An elongated marker, placed on the fly's forehead, is video-recorded from ahead under deep red stroboscopic illumination, invisible to the insect. A fast on-board image processor of a PC video-adapter (True Vision, AT-Vista), programmed in its native code, extracts position and orientation of the marker in the video-image. The host PC transforms these data into calibrated head angles and displays stimulus and response components after 40 ms processing time at a rate of 50 frames per second. Head turns are measured relative to the fly's trunk even when the fly is rotated around its body axis provided that it is aligned with the video-axis. Technical tests, as well as recordings from live flies responding to various stimuli, illustrate the performance and accuracy of the procedure. This minimally invasive method of motion recording should be easily adaptable to other insects and to similar movements of small parts. PMID- 8699881 TI - A quantitative fluorescence-imaging technique for studying acetylcholine receptor turnover at neuromuscular junctions in living animals. AB - We have developed a technique to measure changes in the amount of fluorescently labeled acetylcholine receptors in living muscles over long time periods. The measurements of fluorescence are made relative to a novel, photolytically stable fluorescence standard (Spectralon) which allows changes in fluorescence to be followed over days, even months. The method compensates for spatial and temporal variations in image brightness due to the light source, microscope, and camera. We use this approach to study the turnover of fluorescently labeled acetylcholine receptors at a single neuromuscular junction in a living mouse by re-imaging the same junction in situ over a period of 3 weeks. In addition we show that the SIT video camera, which is generally considered inadequate for quantitative imaging (in comparison to CCD cameras), is actually a very good quantitative device, especially in situations requiring both fast acquisition and high resolution. PMID- 8699883 TI - Cross-correlation and microstimulation: complementary tools in the extracellular analysis of synaptic interactions. AB - The utility of extracellular microstimulation as an ancillary tool to compliment cross-correlation analyses is explored. This technique aims at demonstrating the "sufficiency' of the spike train generated by the "reference' neuron in eliciting spikes in the "target' neuron. It involves activating the reference neuron with very low-intensity current pulses (1-10 microA) delivered through the recording microelectrode. Microstimulation can provide independent evidence that can either support or refute notions of synaptic connectivity generated by correlation analyses. Data are presented from antidromically identified descending corticofugal neurons and putative inhibitory interneurons of S1 "barrel' cortex of the rabbit and from simultaneously recorded neurons in the topographically aligned "barreloid' of ventroposterior medial thalamus (VPM). A very strong relationship was seen between brief, statistically significant peaks in the cross correlograms (CCGs) suggestive of monosynaptic excitatory input and the responses of cortical neurons to VPM microstimulation. Thus, 18/19 cortical neurons that responded to microstimulation pulses of < 6 microA showed a significant CCG with the VPM neuron. Conversely, each of 16 cortical neurons that failed to respond at 10 microA also failed to show a significant CCG. CCGs compiled from independent data sets collected before and after hundreds of microstimulation pulses were very similar, showing that such stimulation can be relatively benign. The method has many limitations, which are discussed. The most serious problem is that the effects of extracellular current pulses cannot be limited to the reference neuron. Nevertheless, microstimulation can provide independent experimental support or refutation of hypotheses of synaptic connectivity that are generated by cross-correlation analyses. In addition, since the technique is rapidly implemented and has considerable power to predict significant cross-correlations, it can be useful in deciding which neuron pairs to study when limited time is available for data collection. PMID- 8699884 TI - A computerized system for the simultaneous monitoring of place conditioning and locomotor activity in rats. AB - Place conditioning is one of the most popular behavioral methods for assessing the rewarding properties of various substances. Many substances that are rewarding also influence motor activity. This report describes a computerized system designed to simultaneously monitor both place conditioning and locomotor activity. The system consists of 4 independent conditioning boxes, each equipped with 6 pairs of photosensors connected to an Experiment Controller, an electronic board containing a microprocessor, a programable timer, and 16 K of RAM used to store both instructions and data. The effects of the stimulant (+)-amphetamine were assessed using this system and found to produce a place preference comparable to that obtained from a previously utilized mechanical timer system. The computerized system also demonstrated that amphetamine increased unconditioned activity. There are a number of advantages and broader applications of the new methodology. PMID- 8699885 TI - A system for the accurate measurement of pointing responses. AB - We present an accurate, yet relatively inexpensive, system for measuring the direction of pointing responses. This system utilizes off-the-shelf business presentation components in a novel way to help detect and quantify the pointing measurements. The system configuration, measurement features, and procedures to enhance measurement accuracy are described. PMID- 8699886 TI - Intra-vitreal injection of substance P antibodies as an antagonist in the vertebrate (fish) retina. AB - A method is described for using substance P (SP) antibodies as an antagonist in the retina of a cyprinid fish, the roach (Rutilus rutilus). Antibody solution (10 microliters) injected into the vitreous was found by immunohistochemical localization to penetrate the neural retina up to the level of the inner margin of the inner nuclear layer. Thus, the inner plexiform layer, where SP would normally be released, was well infiltrated. Similar penetration patterns were observed 2 or 24 h after injection. The physiological effectiveness of the antibody was demonstrated indirectly by measuring its effect upon the spatial coupling of the horizontal cells. Previous work suggested that SP stimulates dopamine release which normally uncouples the horizontal cell somata but not the syncytium of their axon terminals. In retinae isolated from antibody-injected eyes, the horizontal cell somata (but not axon terminals) were indeed found to be significantly more strongly coupled, consistent with the blockage of SP-induced, presumably tonic, release of dopamine. The results suggest that peptide antisera can be useful as pharmacological tools to investigate electrophysiological effects of neuropeptides in the retina as in other parts of the central nervous system. PMID- 8699887 TI - Whole-cell recording from non-dissociated taste cells in mouse taste bud. AB - A method for the whole-cell recording from non-dissociated taste cells within mouse taste bud is described. The lingual epithelial sheet containing the taste buds was peeled free from the tongue by injecting a proteolytic enzyme, elastase, under the lingual epithelium and by incubating it in normal Tyrode solution at 30 degrees C. The preparation consisting of a taste bud and a small piece of the lingual epithelium was obtained by further the incubation in divalent cation-free Tyrode solution. After holding the small piece of the epithelium by a holding pipette loaded with continuous negative pressure for keeping the orientation of the taste bud, whole-cell configuration was established in a non-dissociated taste cell within the taste bud with a patch pipette containing Lucifer Yellow. Taste stimuli or blockers were applied from the third pipette placed near the taste pore under the continuous flow of bathing solution. Under this condition, we could simultaneously accomplish patch-clamping, visualization of taste cell morphology, localized taste stimulation and maintenance of microenvironment around the taste organ. Rapid responses to a relatively high concentration of salt stimuli were also obtained. PMID- 8699888 TI - A computer-controlled apparatus for measuring and analysing myoclonic jerk activity in guinea pigs. AB - Guinea pigs respond to 5-hydroxytryptophan (5-HTP) with a complex behavioural syndrome which includes distinctive whole-body jerks (myoclonic jerks). These are species-specific, involve all major muscle groups, are highly rhythmic and can occur with relatively high frequency (1-2/s). Current methods of quantifying the response, which rely on observer ratings are unsatisfactory. We report the development of a fully automated, PC-based system for detecting and analysing myoclonic jerks. Floor-mounted accelerometers generate a movement signal and detection is performed by an algorithm based on a detailed analysis of the topography of myoclonic jerk responses. The system can monitor the output from 10 purpose-built test enclosures and it provides for pseudorandom treatment allocation, flexible control of experimental parameters and automated data output to a spreadsheet which generates appropriate graphs, statistical summaries and data analysis. This robust response provides a useful means of exploring the role of novel 5-HT receptor subtypes in guinea-pig behaviour. PMID- 8699889 TI - Cerebrospinal fluid drainage in the management of CSF leak following acoustic neuroma surgery. AB - A retrospective analysis was performed on 174 patients operated on from 1992 to 1995 to evaluate the safety and efficacy of continuous lumbar cerebrospinal fluid drainage (CLCFD) in the management of cerebrospinal fluid (CSF) leaks following acoustic neuroma surgery. There was a 17% incidence of CSF leak. CLCFD stopped the leak in 87% of cases. There were no cases of meningitis associated with CLCFD. One deep vein thrombosis was treated without sequelae. It is concluded that CLCFD is safe and efficacious. The authors recommend that CLCFD be implemented immediately when indicated, foregoing a trial of conservative therapy. Indications and precautions are discussed. PMID- 8699890 TI - Patterns of sinusitis in cystic fibrosis. AB - It has been pediatric dogma that most children with cystic fibrosis (CF) have pansinusitis and few are symptomatic. To reassess this premise, we compared symptoms, clinical examinations, radiographic and surgical findings, and results of treatment in 19 children with cystic fibrosis who had undergone computed tomography at St. Christopher's Hospital (Philadelphia) from 1991 to 1994. We found two distinct patterns of sinus disease: chronic sinusitis (n = 3) and polyposis (n = 12). Two of the patients with polyposis had ethmoid mucoceles and 1 child had no sinus disease at all. Children with chronic sinusitis had headache as a major complaint, while those with polyposis suffered nasal obstruction alone unless a mucocele was present. Surgery provided marked and lasting improvement in the 14 patients who were operated on. PMID- 8699891 TI - Microbiology of subperiosteal orbital abscess and associated maxillary sinusitis. AB - Aspirate of pus from eight subperiosteal orbital abscesses (SPOAs) and their corresponding infected sinuses were studied for aerobic and anaerobic bacteria. Polymicrobial flora was found in all instances, and the number of isolates varied from two to five. Anaerobes were recovered from all specimens. The predominant isolates were Peptostreptococcus spp, Prevotella spp, Fusobacterium spp, Staphylococcus aureus, and microaerophilic streptococci. Concordance in the microbiological findings between SPOA and the infected sinus was found in all instances. However, certain organisms were only present at one site and not the other. Fourteen beta-lactamase-producing organisms were present in nine specimens. These data confirm the importance of anaerobic bacteria in sinusitis and demonstrate their predominance in the associated SPOA. PMID- 8699892 TI - Management of airway obstruction in cicatricial pemphigoid. AB - Cicatricial pemphigoid is a chronic vesiculobullous disease of the mucosal epithelium that primarily involves the oral cavity and the eyes. The clinical and histologic features are identical to those of bullous pemphigoid, and these features often can be nonspecific for other disease processes. It is not unusual for a period of 1 year or more to elapse before a diagnosis is made. The diagnosis of cicatricial pemphigoid requires characteristic lesions and histopathologic evidence of immunoglobulin deposition along the basement membrane, as well as a high index of suspicion. The authors detail a case of cicatricial pemphigoid resulting in airway obstruction and present the treatment required for both stabilization of the airway and resolution of the disease process. PMID- 8699893 TI - Inflammation in the uvula mucosa of patients with obstructive sleep apnea. AB - This study was conducted to determine whether inflammation is present in the uvula mucosa of patients with obstructive sleep apnea (OSA). Uvulas were obtained by uvulopalatopharyngoplasty in 21 patients with moderate OSA (mean apnea/hypopnea index and standard error of the mean: 32 +/- 4) and by autopsy in 5 individuals not known to have OSA. Using point counting in five randomly selected high-power microscopic fields (X100), the authors found that the number of leukocytes in the lamina propria of the uvula mucosa was significantly higher in patients with OSA than in the controls (179 +/- 12 cells vs. 71 +/- 4 cells, respectively; P < .05). This was due to a significant increase in the number of plasma cells in patients with OSA as compared with controls (89 +/- 15 cells vs. 21 +/- 5 cells, respectively; P < .05). The thickness of the lamina propria (an index of interstitial edema) was also significantly increased in patients with OSA compared with controls (0.99 +/- 0.12 mm vs. 0.27 +/- 0.02 mm, respectively; P < 0.05). The authors conclude that inflammation, characterized by plasma cell infiltration and interstitial edema, is present in the uvula mucosa of patients with moderate OSA. They also suggest that soft palate inflammation contributes to upper airway occlusion observed during sleep in these patients. PMID- 8699894 TI - Nitric oxide: a mediator of endotoxin-induced middle ear effusions. AB - Using a rat model, the authors investigated the role of nitric oxide (NO) in endotoxin-induced middle ear effusion (MEE). After the eustachian tube was obstructed, the middle ear was transtympanically injected with 35 microL of either 1 mg/mL lipopolysaccharide (LPS) or LPS and 1 mmol/L N-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NO synthase. Over the next 6 hours, the fluid within the middle ear was collected every 2 hours, and the quantity of albumin in the fluid, an index of vascular leakage, was determined using enzyme-linked immunosorbent assay. L-NAME significantly reduced LPS-induced vascular extravasation into the middle ear. Inoculation of the ear with L arginine, the substrate for NO synthase, reversed the effects of L-NAME. These results indicate that NO is a mediator of LPS-induced MEE. Therefore, inhibition of NO synthase may represent a novel approach to the treatment of otitis media with effusion. PMID- 8699895 TI - Reduction of endotoxin-induced inflammation of the middle ear by polymyxin B. AB - Endotoxin (ET) is an aggregate of lipo-oligosaccharide and protein found in the cell wall of gram-negative bacteria. A potent mediator of inflammatory responses, ET has been detected in middle ear effusions from patients with otitis media with effusion and chronic suppurative otitis media and used to induce inflammation of the middle ear mucosa and disruption of mucociliary transport in experimental animals. Polymyxin B, a polypeptide antibiotic, has been shown to bond to and inactivate the ET molecule. This study investigated the efficacy of polymyxin B as a modulator of the inflammatory response to endotoxin in the middle ear. In a guinea pig model, cellular infiltrate, effusion volume, and mucosal edema in response to ET were reduced in the presence of polymyxin B. These results suggest a potential role for the use of polymyxin B in the management of middle ear effusion. PMID- 8699896 TI - Age-related alterations in the auditory brainstem responses and the compound action potentials in guinea pigs. AB - The auditory brainstem response (ABR) and the eight nerve compound action potential (CAP) were measured using click click stimuli to investigate the age related alteration in the auditory function in 66 guinea pigs consisting of four age groups. With advancing age, a gradual elevation of the thresholds in both the ABR and CAP was clearly seen, together with the prolonged latencies for waves I, II, III, and IV to clicks at 95 dBpeSPL in the ABR. There were some individual differences in either threshold elevation or latency prolongation of both the ABR and CAP in aged guinea pigs. These findings suggest that the effect of individual differences on degenerative aging processes of the auditory system should be considered in selected aged animals, although a significant elevation of the neural auditory threshold is clearly found with advancing age as a whole. PMID- 8699897 TI - Residual mesenchyme in temporal bones of children. AB - The role of mesenchyme in the temporal bone is still poorly understood. A microscopic study of residual mesenchyme was undertaken in temporal bones of children from birth to 5 years of age. Residual mesenchyme was found to be located in the mastoid antrum and epitympanum more often than in the mesotympanum. The amount of mesenchymal tissue remaining in the temporal bones decreased with increasing age. Persistence of mesenchyme in the temporal bone was related to congenital morphologic ear anomalies and syndromes. There was also an association evident with pulmonary disease, but not with congenital heart defects. Persistent mesenchyme was also found to be significantly associated with chronic middle ear inflammation, and in cases of unilateral otitis media the ear with otitis media had more residual mesenchyme than the non-otitis media ear. PMID- 8699898 TI - Surgicel in the control of post-tonsillectomy bleeding. PMID- 8699899 TI - The turbinate flap for reconstruction of nasal septal mucosal defects. PMID- 8699900 TI - Examination room design for the pediatric otolaryngology practice. PMID- 8699901 TI - What's all the fuss about?: The Laryngoscope pages cause an international incident. PMID- 8699902 TI - Advertisements in The Laryngoscope. Arsenauro, 1901-1904. PMID- 8699903 TI - The evolution of head and neck surgery. PMID- 8699904 TI - Jako: "Laser surgery of the vocal cords; an experimental study with carbon dioxide lasers on dogs." (Laryngoscope, 1972; 82:2204-2216) PMID- 8699905 TI - Laryngoscopy and laryngoscopes--who's first?: the forefathers/four fathers of laryngology. PMID- 8699906 TI - Transpharyngeal approach to base of tongue tumors: a comparative study. AB - Tumors of the tongue base have been traditionally removed by resecting the mandible or using a translabial transmandibular approach. These procedures involve significant morbidity including lip and chin scars, malocclusion, compromised deglutition, chronic aspiration, and altered speech articulation. Therefore alternative techniques have been described to minimize the morbidity associated with transmandibular tongue resection. A retrospective analysis of patients with base of tongue tumors treated at the University of California, Los Angeles, Medical Center between 1981 and 1994 was undertaken. Thirteen patients were treated using a transpharyngeal approach compared with 18 patients who underwent a transmandibular resection. There was no difference in terms of survival or tumor-free margins. However, there was a significant difference in function (P < .05). Patients who underwent transpharyngeal resection had significantly better speech and swallowing and less aspiration compared with those who underwent transmandibular resection of tumors. PMID- 8699907 TI - Endoscopic staple-assisted esophagodiverticulostomy for Zenker's diverticulum. AB - We have used a new technique, endoscopic staple-assisted esophagodiverticulostomy (ESED), for the treatment of Zenker's diverticulum. This technique is a modification of the endoscopic approach first described by Mosher in 1917 and popularized by Dohlman and Mattsson in which the common wall between the esophagus and diverticulum was divided without mucosal closure. ESED differs in that an endosurgical stapler is used to create an esophagodiverticulostomy by dividing the common wall between the esophagus and diverticulum, with the mucosal and muscular edges sealed by the staples. We have performed this procedure in six patients, with no perioperative morbidity in any patient. All patients resumed oral intake on either the first or second postoperative day, with no evidence of fistula formation or mediastinitis. Hospital stay has averaged 2 days (range, 1 to 3 days). Patient follow-up after ESED averages 6 months and is available for five of the six patients treated. There has been complete resolution of pretreatment symptoms in these five patients, with resumption of regular diet between postoperative day 3 and day 14 (average, day 9). Our results demonstrate that ESED is a safe and effective treatment for Zenker's diverticulum. This endoscopic approach offers a number of advantages over previously used treatments for Zenker's diverticulum, including reduced morbidity, rapid convalescence, short hospitalization, brief operative time, and predictable resolution of symptoms. PMID- 8699908 TI - Effect of hyperbaric oxygenation on existing oral mucosal carcinoma. AB - Hyperbaric oxygen therapy (HBO) is used to treat some complications of head and neck carcinoma treatment. Several patients treated with HBO have had rapid growth of a clinically cured squamous cell carcinoma. Prior studies have produced conflicting evidence about the effect of HBO on tumor growth. This study was undertaken to determine the effects of HBO on established squamous cell carcinoma. Forty Golden Syrian hamster cheek-pouch carcinomas were induced with the established chemical carcinogen 9,10-dimethyl-1,2-benzanthracene. Twenty hamsters underwent 30 HBO dives for 60 minutes each to 2.81 atm, while 20 served as controls. At necropsy, animals receiving HBO therapy had significantly smaller tumors (P < .05) and showed a trend toward fewer cervical metastases (P < .06). HBO therapy with coexistent carcinoma inhibited the established tumor's growth. PMID- 8699909 TI - Familial large vestibular aqueduct syndrome. AB - The large vestibular aqueduct syndrome (LVAS) is a distinct clinical entity characterized by stepwise progressive sensorineural hearing loss associated with isolated enlargement of the vestibular aqueduct. A correlative clinical, audiologic, vestibular, cytogenetic, and radiographic analysis of a family with inherited LVAS was performed. The male proband and his affected brother are offspring of unaffected parents, and have no other abnormalities. Pedigree analysis suggests autosomal recessive or X-linked inheritance with variable expressivity of LVAS in this family. This study is the first description of familial inheritance of LVAS. LVAS may account for a significant number of patients with nonsyndromal, genetic sensorineural hearing loss. Future molecular analyses of this study family may identify the causative gene(s) in LVAS. PMID- 8699910 TI - Microsporidian sinusitis in patients with the acquired immunodeficiency syndrome. AB - Sinusitis in patients with human immunodeficiency virus (HIV) infection usually arises from the same organisms that are infective in the nonimmunosuppressed population. The authors of this article report that optimal antimicrobial treatment and functional endoscopic sinus surgery failed to eradicate sinonasal disease in three of five patients with acquired immunodeficiency syndrome (AIDS) and refractory sinusitis. The sinonasal disease was manifested by congested, edematous, and polypoid mucosa, often with a superimposed bacterial infection from ostial obstruction. After tissue was sent for electron microscopy (EM), the patients were eventually diagnosed with microsporidiosis of the sinonasal cavities. Microsporidia are obligate intracellular protozoans that have been seen in AIDS patients with diarrhea. These protozoans have only recently been identified in sinonasal tissue. Microsporidia are often missed on routine histopathology. The authors present case reports on their five AIDS patients with refractory sinusitis. The management of refractory sinusitis in the HIV-infected population, including mandatory EM of sinonasal tissue, is also discussed. PMID- 8699911 TI - Determination of the efficacy of topical oral pilocarpine for postirradiation xerostomia in patients with head and neck carcinoma. AB - Pilocarpine hydrochloride suspended in a candy-like pastille was evaluated as a topical treatment for radiation-induced xerostomia in head and neck cancer patients. This local delivery system, which differs from systemically administered pilocarpine preparations, was developed to hopefully maximize the local response and minimize the systemic side effects. A prospective, randomized, double-blind, placebo-controlled trial was undertaken to determine objective and subjective efficacy in reversing the decrease in salivation. Forty previously irradiated patients received increasingly higher pilocarpine dosages in pastilles for 5 successive weeks. At each successive dose of pilocarpine, no significant increased salivation was noted. However, 25 (74%) of 34 patients reported that pilocarpine alleviated their subjective xerostomia. Topical pilocarpine administration has shown similar results to previous systemic delivery methods for radiation-induced xerostomia, but with improved patient tolerance. PMID- 8699912 TI - Endoscopic sinus surgery with partial middle turbinate resection: effects on olfaction. AB - Few studies have investigated the effects of endoscopic sinus surgery (ESS) on olfaction. In particular, the effect of surgical manipulation of the middle turbinate on olfaction has not been established. Using the University of Pennsylvania Smell Identification Test (UPSIT) and patient questionnaires, the authors performed a prospective study of olfaction in 64 patients undergoing ESS. Thirty-eight patients (59%) underwent partial middle turbinate resection; in the remaining 26 patients (41%), the middle turbinate was preserved. All patients were reevaluated approximately 8 weeks after surgery by endoscopic examination, questionnaire, and the UPSIT. Patients who underwent no resection had a median decrease in UPSIT score of 1.4, and those who underwent resection had a median decrease of 0.5; this difference was not statistically significant. Further, no correlation was found between changes in UPSIT score and follow-up time, sex of the patient, or the patient's subjective assessment of postoperative olfaction. It is concluded that middle turbinate resection has no effect on olfaction. PMID- 8699913 TI - Safety awareness for the otolaryngologist caring for the HIV-positive patient. AB - The alarming increase in human immunodeficiency virus (HIV) infection, expected to reach 40 million cases worldwide by the year 2000, has enormous impact on the otolaryngologist, since up to 70% of HIV-positive patients present with head and neck symptoms. Parenteral and nonparenteral acquisition of HIV has been documented with seroconversion from needle sticks estimated at 1 for every 200 exposures. The rate of compliance with universal precautions is found to be reported as low as 16%. In 1993, over 1400 patients with HIV were admitted to Kings County Hospital Center. There were 165 reported cases of sharp injuries of which 4 were scalpel related and 17 were suture needle related. We surveyed HIV safety experiences at five hospitals emphasizing operating room procedures, including instrument handling, gloving, elimination of excess equipment and personnel, utilization of nonsharp instruments, and team discipline. Preventive measures are recommended to help minimize inadvertent sharp injuries. PMID- 8699914 TI - The incidence of micrometastases in neck dissection specimens obtained from elective neck dissections. AB - Although modern imaging techniques become more accurate for the assessment of lymph node metastases in the neck as criteria and technology evolve, micrometastases remain occult with any technique. Even the routine histopathological examination of neck dissection specimens is unable to detect all micrometastases. Because knowledge on the incidence of micrometastases in the clinically NO neck might be of importance for decision making regarding elective treatment, a retrospective study on 96 elective neck dissections was conducted. Meticulous histopathological examination of the neck dissection specimens yielded 3092 lymph nodes of which 67 (2.2%) were tumor-positive. Twenty-six of these 67 lymph node metastases were micrometastases. Of the 36 tumor-positive neck dissection specimens, 21 contained micrometastases. In 9 tumor-positive specimens only micrometastases were found. This high incidence of micrometastases has important implications for the diagnostic work-up, the treatment, and histopathological examination of the NO neck. PMID- 8699915 TI - Hearing loss in Turner syndrome. AB - A retrospective study was undertaken to answer the following questions: Is the sensorineural hearing loss (SNHL) in Turner syndrome progressive? Can the occurrence of hearing loss be explained by the parental origin of the intact X chromosome? Twenty-four individuals recruited through the Turner Syndrome Society completed a questionnaire and submitted sufficient medical records to determine their otologic status. The majority (21/24) have had problematic otitis media (OM), and two thirds (16/24) have SNHL. In seven of the Turner subjects (age range: 12 to 51 years), gradual progressive SNHL began in late childhood or early adulthood. Molecular techniques showed no correlation between parental origin of the retained X chromosome and hearing status in 17 Turner subjects and at least one of their parents. SNHL and frequent OM appear to be independent variables that are both present in Turner syndrome. It is postulated that the presence of unpaired genes on the X chromosome may account for hearing loss and other phenotypic abnormalities seen in this syndrome. PMID- 8699916 TI - Regional spread of auricular and periauricular cutaneous malignancies. AB - Over 90% of all cutaneous malignancies occur in the head and neck. Malignancies involving the external auditory meatus, auricle, and periauricular region are notoriously difficult to control. The morbidity and mortality associated with extension of these malignancies underscore the importance of complete initial removal. We present 14 patients who underwent excision of periauricular lesions. All lesions were less than 2 cm in diameter and previously excised with negative margins. These patients were subsequently referred for regional disease. Twenty nine percent of the patients failed definitive surgical therapy. We examine the indications for regional lymphadenectomy in the treatment of auricular and periauricular cutaneous malignancies. PMID- 8699917 TI - Lack of binding of acetaminophen to 5-HT receptor or uptake sites (or eleven other binding/uptake assays). AB - The mechanism of analgesic action of acetaminophen (paracetamol) remains unknown. However, a central component distinct from that of the NSAIDs (non-steroidal antiinflammatory drugs) seems likely. A recent report (NeuroReport 6:1546-1548, 1995) suggests the involvement of 5-HT3 receptors. In the present study, we measured the affinity of acetaminophen at 5-HT3, as well as 5-HT1A, 5-HT1B, 5 HT1D, 5-HT2, 5-HT2C, 5-HT4, 5-HT6, 5-HT7 and eleven other receptor sites and at serotonin and norepinephrine reuptake sites. At 10 microM, acetaminophen inhibited less than 10% specific radioligand binding at any site. These findings: (i) suggest that acetaminophen's effect on serotonergic pathways is indirect, and (ii) circumscribe acetaminophen's possible central analgesic mechanism(s). PMID- 8699918 TI - Capsaicin-induced biphasic oxygen uptake in rat muscle: antagonism by capsazepine and ruthenium red provides further evidence for peripheral vanilloid receptor subtypes (VN1/VN2). AB - Previous studies with the vanilloid spice principle capsaicin have demonstrated a biphasic VO2 response, with vasoconstriction, in the perfused rat hindlimb that has led to suggestions of vanilloid receptor subtypes (VN1/VN2) in this preparation (1). In the present study, the known competitive vanilloid antagonist capsazepine inhibited the above capsaicin-mediated effects in a manner that was indicative of binding at specific vanilloid recognition sites. Low concentrations of capsazepine selectively inhibited the increased VO2 produced by the putative VN1 receptor at submicromolar concentrations of capsaicin, while the inhibition of VO2 produced by high concentrations of capsaicin (putative VN2) was enhanced. These observations, showing different susceptibilities to blockade by capsazepine, further support the presence of two vanilloid receptor subtypes in the rat hindlimb. Schild plots of the data yielded variable slopes that approach unity at greater responses to capsaicin (mean KB = 8.44 +/- 2.08 microM and 7.28 +/- 0.78 microM for VO2 and perfusion pressure curves, respectively). Low concentrations of the capsaicin antagonist ruthenium red selectively blocked the putative VN2 receptor-mediated effects produced by high concentrations of capsaicin. The noncompetitive nature of this inhibitor suggests an operation through separate receptor-coupled ion channel complexes at high and low concentrations of the vanilloid. Tetrodotoxin failed to attenuate any changes produced by capsaicin, suggesting that the mechanism of action of capsaicin in the rat hindlimb may differ from other tissues. PMID- 8699919 TI - Effect of chronic cocaine exposure on carotid artery reactivity in neonatal rabbits. AB - Chronic cocaine abuse by pregnant women results in chronic neonatal drug exposure. In adults, chronic cocaine use alters neurotransmitter concentrations and receptor dose-response relationships. Similar changes may also occur in the neonatal cerebrovasculature after in utero cocaine exposure. This study examined the effect of chronic cocaine exposure on internal carotid artery reactivity to norepinephrine, serotonin, acetylcholine, sodium nitroprusside, adenosine, and cocaine in neonatal rabbits. Internal carotid artery rings were isolated from 16 to 20 day old rabbits that had received cocaine (20 mg/kg IP BID, n = 8) or saline (n = 8) from 5 days of age and were studied in organ baths using standard in vitro techniques. Chronic treatment with cocaine decreased the half-maximal relaxant response (ED50) to adenosine (control 6.9 +/- 1.8 vs cocaine 3.5 +/- 0.99 microM, p = 0.05). The half-maximal contractile responses (EC50) to norepinephrine and serotonin and the half-maximal relaxant responses (ED50) to acetylcholine and sodium nitroprusside were similar between groups. The threshold concentration of cocaine that induced vessel contraction was altered by chronic cocaine exposure (control group 10(-6) M vs chronic cocaine group 10(-4) M). We conclude that chronic cocaine exposure sensitizes carotid arteries to the relaxant effects of adenosine. In addition, chronic cocaine exposure desensitizes carotid arteries to the contractile effects of acute cocaine. These vasoreactivity changes may underlie altered cerebrovascular responses to asphyxia and play a role in the pathogenesis of postnatally acquired brain injury in critically ill "crack" babies. PMID- 8699920 TI - Norepinephrine release during vasoconstriction induced by cross-linked hemoglobin. AB - The pressor effect of hemoglobin-based blood substitutes is due partly to their capacity to scavenge nitric oxide (NO), a potent vasodilator. NO also appears to modulate the release of norepinephrine (NE) from sympathetic nerve endings in some blood vessels. Thus studies were designed to determine if contraction occurring in response to alpha alpha-cross-linked hemoglobin (XL-Hb) is due in part to increased exit of NE from vascular nerve endings. Helical strips of canine femoral artery were superfused in vitro with Krebs-Ringer solution and, for each strip, the overflow of NE into the superfusate as well as contractile responses were measured concurrently during basal conditions, during nerve stimulation and during tyramine-evoked release of NE. XL-Hb (10 microM) contracted unstimulated strips without affecting NE overflow. NE overflow also was unchanged by NG-monomethyl-L-arginine (L-NMMA; 300 microM), an inhibitor of NO synthesis; by sodium nitroprusside (SNP; 1 microM) an NO donor; by a combination of XL-Hb and L-NMMA; or of XL-Hb and SNP. These treatments contracted the strips to the same degree as did XL-Hb alone, except for SNP, which induced relaxation. Transmural stimulation of the strips at 2 and 10 Hz induced NE overflow and contraction, neither of which was affected by any treatment except SNP which significantly (P < 0.05) increased NE overflow while inhibiting contraction. In other experiments, XL-Hb augmented contractions induced by tyramine (10 microM) although the resulting NE release was unaffected. These results suggest that, in the femoral artery, contractions induced by XL-Hb are not due to increased efflux of NE from vascular nerve endings but are consistent with inhibition of the the actions of NO. PMID- 8699921 TI - The effect of anoxia on cardiomyocyte glucose transport does not involve an adenosine release or a change in energy state. AB - The action of anoxia on glucose transport was investigated in isolated resting rat cardiomyocytes. Incubation of these cells in the absence of oxygen for 30 min resulted in a 4- to 5-fold increase in glucose transport (with a lag period of 5 10 min). Up to 40 min of anoxia failed to alter the cellular concentrations of ATP, phosphocreatine, and creatine. Adenosine deaminase (1.5 U/ml), the A1 adenosine receptor antagonist 1,3-diethyl-8-phenylxanthine (1 microM), or the A2 selective antagonist 3,7-dimethyl-1-propargylxanthine (20 microM) had no effect on anoxia-dependent glucose transport. Moreover, adenosine (10-300 microM, added under normoxia) did not stimulate glucose transport. Wortmannin (1 microM) did not influence the effect of anoxia, but completely suppressed that of insulin. On the other hand, the effects of anoxia and insulin were not additive. These results indicate (i) that the effect of anoxia on cardiomyocyte glucose transport is not mediated by a change in energy metabolism, nor by an adenosine release; (ii) that it probably does not involve a phosphatidylinositol 3-kinase, in contrast to the effect of insulin, and (iii) that the signal chains triggered by anoxia or insulin may converge downstream of this enzyme, or, alternatively, that anoxic conditions may impair the action of the hormone. PMID- 8699922 TI - Effects of in vitro 5-HT1 receptor activation in guinea pig trachea. AB - 5-hydroxytryptamine (5-HT) has been reported to show some effects in respiratory tissues by activation of different subtype receptors. It has been demonstrated that 5-HT2 receptor activation causes in vivo and in vitro airways contraction and enhances effects of cholinergic nerve-mediated responses, whereas 5-HT1 receptor activation seems to be related to a relaxant effect. Moreover, in isolated guinea pig ascendens colon preparations 5-HT1 activation causes relaxation by involvement of nitric oxide (NO). The aim of this study was to investigate the effects of 5-HT1 receptor activation in guinea pig trachea as well as NO probable role in this activation. In tissues pretreated with both ketanserin (10 microM), an antagonist of 5-HT2 receptors, and ondansetron (10 microM), an antagonist of 5-HT3 receptors, 5-HT (from 10 nM to 10 mM) relaxed guinea pig trachea precontracted with acetylcholine (ACh, 100 microM). Carboxamidotryptamine (5-CT, from 10 nM to 10 mM), an agonist of 5-HT1 receptors, as well relaxed guinea pig trachea precontracted with ACh (100 microM). A pretreatment with NAN-190 (from 10 nM to 100 microM), a 5-HT1A selective antagonist, reduced the 5-HT and 5-CT relaxant effects but only at very high concentrations. Finally, a pretreatment with L-nitro-arginine-methyl-ester (L NAME, 1 mM), an inhibitor of NO-synthase, and L-arginine (L-ARG, 1 mM), a precursor of NO synthesis, did not modify 5-HT and 5-CT responses in guinea pig trachea. In conclusion, this study suggests a 5-HT relaxant activity in guinea pig trachea via a 5-HT1 receptor activation without any NO pathway involvement. However, further investigations are needed to clarify which 5-HT1 receptor subtype is involved in 5-HT relaxant effect. PMID- 8699923 TI - Bone mineral density at the metaphysis is specifically reduced in STZ-treated diabetic rats. AB - Bone length (L), dry weight (DW) and ash weight (AW) were determined for the femur bone of 9-15 week old female rats with or without streptozotocin (STZ) treatment. Matrix weight (MW) was obtained by subtracting AW from DW. AW/L3 and MW/L3 were taken as measures indicating overall bone mineral density and bone matrix density, respectively. Regional changes such as metaphyseal bone mineral density (MBD) and diaphyseal mineral density (DBD) were determined by single photon absorptiometry (SPA). In the control rats, MW/L3 and MBD stayed constant in spite of a time-dependent increase in L, whereas the other bone parameters correlated positively with L. Thus MW/L3 and MBD were compared between rats with different L, and the other parameters were compared with the expected values calculated for L by regression equation. STZ-treatment virtually stopped the growth of L, significantly reduced MBD, but hardly affected MW/L3. Although DW, AW and AW/L3 in the STZ-treated rats were significantly smaller than in the control, they were almost identical with the expected values excepting at 6 weeks when the observed values were less than the expected values. DBD in the STZ treated rats was even larger than the expected values, DW, AW and MBD decreased with time, and MW/L3 stayed rather constant; only DBD increased time-dependently in these animals. These results suggest that bone mineralization at the metaphysis is specifically reduced in STZ-treated diabetic rats. PMID- 8699924 TI - Interleukin-1 signal transduction. AB - Interleukin-1 (IL-1) is primarily an inflammatory cytokine, although it is capable of mediating a wide variety of effects on many different cell types. Nearly every known signal transduction pathway has been reported to be activated in response to IL-1. However, the significance of many of these signaling events is unclear, due to the use of different and sometimes unique cell lines in studying IL-1-initiated signal transduction. Complicating matters further is the lack of association in many studies between identified IL-1-induced signals and subsequent biological responses. In this article, we review what is known about IL-1 receptor signaling and, whenever possible, correlate signaling events to biological responses. PMID- 8699925 TI - Effects of lipopolysaccharide on the expression of fibrinolytic factors in an established cell line from human endothelial cells. AB - Human endothelial cells express antithrombotic properties by producing prostacyclin, heparan sulphate and plasminogen activator (PA). Bacterial extract, such as lipopolysaccharide (LPS), damaged the blood vessels and destroyed the balance between the antithrombotic and thrombotic functions of endothelial cells. The fibrinolytic system is involved in antithrombotic functions. The TKM-33 cell line was established from human endothelial cells. In order to determine whether TKM-33 is a good fibrinolytic system endothelial cell expression model, the expression of fibrinolytic factors in TKM-33 cells treated with or without LPS was studied. The endothelial cells which had not been treated with LPS produced and secreted a large amount of urokinase-type PA (u-PA), and small amounts of tissue-type PA (t-PA) and PA inhibitor-1 (PAI-1), which were identified immunohistochemically and by electrophoretic enzymography. Diisopropylfluorophosphate-treated 125I-u-PA bound specifically to acid-treated monolayered endothelial cells with a Kd of 2.83 +/- 0.61 nM, and Bmax of (0.11 +/ 0.01) x 10(6) sites/cell. u-PAR expression was detected in endothelial cells by Northern blot analysis. Thus, endothelial cells was shown to express u-PAR which binds u-PA specifically. In the binding assay, the stimulation of endothelial cells with 0.1, 1.0 and 10 micrograms/ml of LPS altered the Kd values to 6.04 +/- 0.71, 7.03 +/- 1.55 and 7.38 +/- 1.03 nM, respectively. However the Bmax values did not change significantly. Although LPS treatment increased u-PAR expression in endothelial cells in a dose-dependent manner, the expression of u-PA and t-PA mRNAs was not altered significantly. LPS stimulation (10 micrograms/ml) increased the expression of PAI-1 mRNA, significantly. The PA activity recovered from the cell surface fraction was not affected by LPS stimulation, but the PAI-1 activity was increased. These findings suggest that the established endothelial cell line, TKM-33, possesses the characteristics of endothelial cells and they express u-PAR on their cell surface, which is occupied by intrinsic u-PA secreted from the cells, and that treatment of endothelial cells with LPS changes the cell surface characteristics and inhibited the u-PAR expression thus promoting the prothrombotic function concomitantly with increased PAI-1 activity. PMID- 8699926 TI - Involvement of D-aspartic acid in the synthesis of testosterone in rat testes. AB - D-Aspartic acid (D-Asp) is an endogenous amino acid which occurs in many marine and terrestrial animals. In fetal and young rats, this amino acid occurs prevalently in nervous tissue, whereas at sexual maturity it occurs in endocrine glands and above all in pituitary and testes. Here, we have studied if a relationship exists between the presence of D-Asp and the hormonal activity. The following results were obtained: 1) Both D-Asp and testosterone are synthesized in rat testes in two periods of the animal's life: before birth, about the 17th day after fertilization and, after birth, at sexual maturity. 2) Immunocytochemical studies have demonstrated that this enantiomer is localized in Leydig and Sertoli cells. 3) In vivo experiments, consisting of i.p. injection of D-Asp to adult male rats, demonstrated that this amino acid accumulates in pituitary and testis (after 5 h, the accumulation was of 12 and 4-fold over basal values, respectively); simultaneously, luteinizing hormone, testosterone and progesterone significantly increased in the blood (1.6-fold, p < 0.05; 3.0-fold, p < 0.01 and 2.9-fold, p < 0.01, respectively). 4) Finally, in vitro experiments, consisting of the incubation of D-Asp with isolated testes also demonstrated that this amino acid induces the synthesis of testosterone. These results suggest that free D-Asp is involved in the steroidogenesis. PMID- 8699927 TI - Vibrio vulnificus hemolysin dilates rat thoracic aorta by activating guanylate cyclase. AB - Hemolysin produced by Vibrio vulnificus caused hypotension and tachycardia in rats and dilated rat thoracic aorta. Hemolysin-induced vasodilatation of the aorta was not affected by N omega-nitro-L-arginine methyl ester and aminoguanidine, NO synthase inhibitors, whereas the vasodilatation was inhibited by LY 83,583, a guanylate cyclase inhibitor. Hemolysin elevated cGMP levels, and the elevation was abolished by LY 83,583. These results suggest that V. vulnificus hemolysin activates guanylate cyclase independently of NO synthase, and the subsequent increase in cGMP levels results in vasodilatation. PMID- 8699928 TI - Inhibition by triptoquinone-A of LPS- and IL-1 beta-primed induction of NO synthase in rat thoracic aorta. AB - We investigated the effect of triptoquinone-A (TQA), an active principal of Triptergium wilfordii, on the induction of nitric oxide synthase (NOS) promoted by endotoxin (LPS) and interleukin-1 beta (IL-1 beta). Prophylactic application of TQA selectively prevented LPS-primed initiation of L-arginine (Arg)-induced relaxation, and cGMP formation of rat thoracic aorta, and LPS-stimulated nitrite production by cultured aortic smooth muscle cells, which appear to be mediated by NOS expressed by LPS in vascular smooth muscle. TQA also prevented IL-1 beta triggered initiation of Arg-induced relaxation and nitrite accumulation. These results suggest that TQA prevents LPS-or IL-1 beta-promoted induction of NOS in vascular smooth muscle, thus inhibiting development of Arg-induced vasorelaxation. PMID- 8699929 TI - Pharmacology of barbiturate tolerance/dependence: GABAA receptors and molecular aspects. AB - Barbiturates are central nervous system depressants that are used as sedatives, hypnotics, anesthetics and anticonvulsants. However, prolonged use of the drugs produces physical dependence, and the drugs have a high abuse liability. The gamma-aminobutyric acidA (GABAA) receptor is one of barbiturates' main sites of action, and therefore it is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates. Recent advances in the study of the GABAA receptor/chloride channel complex allow us to examine possible mechanisms that underlie barbiturate tolerance/dependence in a new light. In this minireview, we mainly focus on molecular and cellular aspects of the action of barbiturates and the possible mechanisms that contribute to development of tolerance to and dependence on barbiturates. PMID- 8699930 TI - Stability of epidermal growth factor in the gastrointestinal lumen of suckling and weaned pigs. AB - The stability of epidermal growth factor (EGF) in the gastrointestinal humen of 3 day-old suckling and 45-day-old weaned pigs was examined by incubating iodine labeled recombinant human EGF (hEGF) in the gastrointestinal fluids at 37 degrees C and monitoring the generation of acid soluble radioactivity. Chromatographic analysis and receptor binding study were also undertaken. The results showed that hEGF was quite stable in the gastric fluids in both suckling and weaned pigs with less than 20% degradation after 20 min incubation. The degradation rate in the intestinal fluids varied with the region of the small intestine and the age of the animals. At the proximal and mid regions of the small intestine in suckling pigs the degradation rate of hEGF after 20 min incubation was 5 and 20% respectively, while the degradation rate at the distal region was up to 50%. In the small intestinal lumen in weaned pigs the degradation rate of hEGF was much greater than that in suckling pigs, and the degradation rates at the proximal, mid and distal regions were 33, 51 and 56% respectively. Addition of acid soluble or casein fractions of porcine colostrum markedly reduced the degradation of hEGF in the intestinal fluids. These results indicate that milk-borne EGF is stable in the gastric and proximal intestinal humen in suckling pigs, and may play a role in regulating postnatal development in the suckling young. PMID- 8699931 TI - Cold swim stress leads to enhanced splenocyte responsiveness to concanavalin A, decreased serum testosterone, and increased serum corticosterone, glucose, and protein. AB - This study extends previous observations of the conditions under which enhancement of lymphocyte activity occurs following cold swim stress and presents a possible explanation for the enhancement observed. Eight- to twelve-week old male Sprague-Dawley rats swam for 10 minutes daily for one, three, or five days in cold water at 15 degrees C and were killed 0, 30, or 240 minutes following the last swim. Apparatus control animals were placed into an empty swim tank for 10 minutes and then returned to their home cages. Home cage control animals were not manipulated experimentally at all. Splenocyte but not thymocyte responses to concanavalim A were significantly enhanced after one, three, and five days of stress. This enhancement was seen after 0, 30, and 240 minutes of recovery and also in the apparatus controls! The number of splenocytes did not change significantly, but thymocyte number declined following the swims. The blood displayed no changes in leukocyte percents. Serum corticosterone levels were significantly higher and serum testosterone levels were significantly lower after one, three, and five days of stress. The drop in testosterone levels may have released the lymphocytes from inhibition by this hormone, resulting in increased responsiveness. There were significant elevations in levels of blood glucose and protein following one, three, and five days of stress sessions, correlated with the increases in serum corticosterone. PMID- 8699932 TI - Constitutive expression and structural diversity of inducible isoform of nitric oxide synthase in human tissues. AB - Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) plays a major role in immune responses to bacteria and tumors, and the gene is induced by endotoxin and cytokines. However, we have detected iNOS cDNA sequences expressed constitutively at low level from human retinal, cerebellar and skeletal muscle tissues using northern-blot and RT-PCR analyses. In northern-blot analysis, two types (4.5 kb and 4.2 kb) of iNOS mRNA have been observed in retinal tissue, whereas only one type of mRNA was observed in cerebellum (4.5 kb) and skeletal muscle (4.2 kb). This result indicates that the presence of differential expression and/or structural diversity of the iNOS gene in various tissues, and some cells can express iNOS gene constitutively. We have also demonstrated a structural diversity formed by alternative splicing in the open reading frame sequence of the iNOS cDNA cloned from retinal tissue, which may reflect functional differences of iNOS gene. PMID- 8699933 TI - Effect of growth hormone, insulin and dexamethasone on 11 beta-hydroxysteroid dehydrogenase activity on a primary culture of rat hepatocytes. AB - 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) is a microsomal enzyme present in the peripheral tissues of the rat, including the liver, and is mediated by a number of factors in animal in vivo studies. However, the effect of peptide hormones and glucocorticoids on the activity of 11 beta-HSD in isolated rat hepatocytes is not clear. To investigate these effects, we determined 11 beta-HSD activity in a primary culture of rat hepatocytes by adding various concentrations of growth hormone, insulin and dexamethasone (Dex). 11 beta-HSD activity increased significantly after treatment with Dex (10(-9)M-10(-6)M) for 48h. Dex (100nM) treated hepatocytes, incubated for 12h to 48h, resulted in a significant two-to four-fold rise in 11 beta-HSD activity compared to control (p < 0.01), which was in contrast to GH (10(-9)M-10(-6)M) and insulin (10(-8)M-10(-5)M), which inhibited 11 beta-HSD activity (p < 0.05). These results suggest that the 11 beta-HSD of rat hepatocytes is under multifactorial regulation; Dex stimulates and GH and insulin inhibit 11 beta-HSD activity in primary cultures of rat hepatocytes. PMID- 8699934 TI - Characterization of the alpha 1-adrenoceptors of cat liver. Predominance of the alpha 1A-adrenergic subtype. AB - The alpha 1-adrenoceptors present in the liver of cats were characterized using [3H]prazosin. This radioligand binds to cat liver membranes with high affinity ((KD 0.79 nM) to a moderately abundant number of sites (160 fmol/mg of protein). This sites were characterized pharmacologically, by binding competition, observing the following orders of potency: a) for agonists: oxymetazoline > epinephrine = norepinephrine >> methoxamine, and b) for antagonists: WB4101 > or = prazosin > or = (+) niguldipine > or = benoxathian > or = spiperone = 5-methyl urapidil > phentolamine > BMY 7378. These data suggested that cat liver expresses alpha 1A-adrenoceptors. Expression of the mRNA for this receptor was confirmed by RT-PCR. PMID- 8699935 TI - Atrial natriuretic peptide increases adrenomedullin in the circulation of healthy humans. AB - Adrenomedullin (ADM) is a new 52 amino acid peptide originally isolated from extracts of human pheochromocytoma. ADM's biologic properties are nearly identical to those of atrial natriuretic peptides. Thus, the 4 peptide hormones originating from amino acids 1-30 [long acting natriuretic peptide], 31-67 [vessel dilator], 79-98 [kaliuretic peptide] and 99-126 [atrial natriuretic factor; ANF] of the 126 amino acid ANF prohormone as well as ADM have blood pressure lowering and diuretic properties. The present investigation was designed to determine if one or more of these 4 atrial natriuretic peptides increase adrenomedullin within the circulation of healthy humans. Infusion of 100 ng/kg body weight/minute for 60 minutes of the respective atrial peptides resulted in a 4-fold (P < 0.001) increase in the circulating concentration of adrenomedullin secondary to the ANF infusion but no increase in adrenomedullin with the long acting natriuretic peptide, vessel dilator, or kaliuretic peptide infusions. The four-fold increase of adrenomedullin in the circulation persisted throughout the infusion of ANF, but returned to pre-infusion levels within 30 minutes of stopping the ANF infusion. Infusion of 10 pg/kg body weight/minute for 60 minutes of ANF resulted in a 2 1/2-fold increase (P < 0.05) in the circulating concentration of adrenomedullin. There was a significant (P < 0.01) diuresis and blood pressure lowering effect with each of the atrial natriuretic peptides in the present investigation. This investigation suggests that 1) atrial natriuretic factor increases the release of adrenomedullin and 2) that the diuretic and blood pressure lowering effects previously attributed to atrial natriuretic factor may be partially due to adrenomedullin since both increased during the ANF infusion and both have similar biologic effects. As opposed to atrial natriuretic factor, adrenomedullin was not increased by long acting natriuretic peptide, vessel dilator, or kaliuretic peptide suggesting that their biologic effects do not involve adrenomedullin. PMID- 8699936 TI - Inhibition of phospholipase D and superoxide generation by glucose in diabetic neutrophils. AB - Diabetics are prone to infection, in part, due to neutrophil dysfunction and impaired superoxide generation. The mechanism of impaired superoxide generation in diabetes remains unknown. We report herein that neutrophils from poorly controlled diabetics have impaired ability to generate superoxide in response to N-formyl-Met-Leu-Phe (FMLP) but not to 4 beta-phorbol 12-myristate 13-acetate (PMA). Phosphatidic acid, a phospholipase D (PLD) -mediated product of membrane phosphatidylcholine is decreased in response to FMLP. The impaired superoxide generation and activation of phospholipase D are readily reversible once the diabetic neutrophils are incubated in normal glucose concentration. These data show that decreased superoxide generation by neutrophils in insulin-dependent diabetics is, in part, due to impaired activation of phospholipase D and is solely due to high glucose concentrations. PMID- 8699937 TI - Lack of an EMF-induced genotoxic effect in the Ames assay. AB - A few epidemiological studies have linked exposure to electromagnetic fields (EMF) and the incidence of cancer. Since many carcinogens are mutagens in the Ames assay, the purpose of this study was to determine if exposure of four tester strains of Salmonella typhimurium (TA97a, TA98, TA100, and TA102) to EMF would increase their rate of mutation. Parallel plate electrodes and Helmholtz coils were used to create uniform field properties (300 V/in., 0.3 mT). Separate and combined alternating electric and magnetic fields effects were studied at a combined field frequency of 60, 600, and 6000 Hz at room temperature. These fields did not elevate the temperature of the culture plates above room temperature, Petri dishes containing each tester strain in top agar were exposed to an electric field (E), magnetic field (M), combined electric and magnetic field (EM), or no additional field above ambient conditions in the lab (control). Four plates containing each strain were exposed in each condition: two plates had the appropriate positive-control mutagen for each strain included in the top agar and two plates did not. Plates were exposed to either E, M, EM, or control conditions at room temperature for 48 hr. and then incubated an additional 24 hr. at 37 deg. C. The plates containing mutagen in the top agar showed an increased number of colonies consistent with mutagenesis. However, the rate of mutation in the S. typhimurium strains TA97a, TA98, TA100, and TA102 in either the presence or absence of mutagen was not affected by 48 hr. exposure at room temperature to E, M, or EM fields at 60, 600, or 6000 Hz. PMID- 8699938 TI - Estimation of the iron concentration in excised gray matter by means of proton relaxation measurements. AB - To validate their correlation with tissue iron concentration, proton transverse relaxation measurements have been made at 2.35 T (100 MHz) in 25 samples of excised, frozen, but unfixed human gray matter tissue obtained from the globus pallidus, putamen, caudate, thalamus, and cortex of five postmortem brains free of neurological disease. The iron concentration was independently measured, using atomic absorption spectroscopy. The proton transverse relaxation measurements exploited the interecho time dependence of the apparent transverse relaxation rate, R2app, obtained from a Carr-Purcell-Meiboom-Gill (CPMG) sequence. An empirical semilogarithmic relationship between R2app and the interecho time provided a measure of the relaxation enhancement due to iron, namely, a slope p, which demonstrated a significant correlation (r = 0.78, P < 0.001) with tissue iron concentration. Moreover, a simple rate difference, delta R2app, determined between interecho time values of 6 and 60 ms, was also found to correlate significantly with iron concentration (r = 0.81, P < 0.001). Both of the foregoing correlations were better than that of R2app itself. When the tissue samples were subdivided into brain structure groups, the intergroup differences in rho reflected their known differences in iron accumulation and correlated with those of the mean group iron content, determined by atomic absorption spectrometry. PMID- 8699939 TI - Retrospective estimation and correction of physiological artifacts in fMRI by direct extraction of physiological activity from MR data. AB - A physiological artifact reduction method based on extracting respiratory motion and cardiac pulsation directly from functional MR data is described. In fast low angle shot (FLASH), respiratory cycles are derived utilizing the phase of the center of a navigator echo, in echo-planar imaging (EPI) from the phase of the center k-space point. Cardiac cycles are determined from projections obtained from the navigator echo (FLASH) and the center k-space line (EPI). Because direct extraction of physiological parameters eliminates the need for external monitoring, the method can be more readily implemented. Experimental results illustrate that the technique provides effective compensation for physiology related signal fluctuations in functional MRI and performs as well as the retrospective technique using external physiological monitoring. PMID- 8699940 TI - Decomposition of inflow and blood oxygen level-dependent (BOLD) effects with dual echo spiral gradient-recalled echo (GRE) fMRI. AB - Image contrast with gradient-recalled echo sequences (GRE) used for fMRI can have both blood oxygen level-dependent (BOLD) and inflow components, and the latter is often undesirable. A dual-echo technique can be used to differentiate these mechanisms, because modulation of signal from inflow is common to both echoes, whereas susceptibility and diffusion-related signal losses are larger in the second echo. An efficient dual-echo interleaved spiral sequence was developed for use with a conventional scanner. It uses a k-space trajectory that spirals out from the origin while the first echo is collected, then spirals back in while collecting the second echo. Decomposition of the data provides separate images of the inflow and T2-weighted components. Results demonstrate the decomposition with phantom experiments and with photic stimulation in normal volunteers. PMID- 8699941 TI - Simultaneous magnetic resonance phase and magnitude temperature maps in muscle. AB - Noninvasive magnetic resonance temperature maps that are used to monitor thermal ablation of tissue are described. In magnetic resonance images, thermally induced proton nuclear magnetic resonance frequency shifts, and changes in the longitudinal relaxation time produce both phase and magnitude changes in the MR signal. Temperature maps with improved sensitivity are derived from the complex difference nuclear magnetic resonance signal. Bovine muscle specimens were heated with focused ultrasound to model thermal surgery and create a known thermal distribution to test the method. Resulting MR images acquired in 2 s produce temperature maps with 1 min resolution and 2 degrees C temperature sensitivity. The temperature sensitivity was increased by extending the acquisition to 5 s, by decreasing the receiver bandwidth, and increasing the echo time. PMID- 8699942 TI - A forward-subtraction procedure for removing hyperfine artifacts in electron paramagnetic resonance imaging. AB - The potential for using electron paramagnetic resonance (EPR) imaging in biological applications has been limited by the lack of ideal single-line imaging probes. The commonly used nitroxides exhibit multiple lines, causing either hyperfine-based limitations in the maximum obtainable image resolution or hyperfine-based artifacts in the reconstructed image. The application of a numerical method, based on forward-subtraction principles for removing hyperfine artifacts in the measured projections is reported. It is demonstrated by using computer simulations, imaging of phantoms, and imaging of rat hearts, that marked enhancement in image quality and resolution can be obtained by removing the hyperfine-imposed limit on the gradient magnitude and performing postacquisition corrections for removing hyperfine artifacts in the image. PMID- 8699943 TI - Three-dimensional gated EPR imaging of the beating heart: time-resolved measurements of free radical distribution during the cardiac contractile cycle. AB - In vivo or ex vivo EPR imaging, EPRI, has been established as a powerful technique for determining the spatial distribution of free radicals and other paramagnetic species in living organs and tissues. While instrumentation capable of performing EPR imaging of free radicals in whole tissues and isolated organs has been previously reported, it was not possible to image rapidly moving organs such as the beating heart. Therefore instrumentation was developed to enable the performance of gated-spectroscopy and imaging on isolated beating rat hearts at L band. A synchronized pulsing and timing system capable of gated acquisitions of up to 256 images per cycle, with rates of up to 16 Hz was developed. The temporal and spatial accuracy of this instrumentation was verified using a specially designed beating heart-shaped isovolumic phantom with electromechanically driven sinusoidal motion at a cycle rate of 5 Hz. Gated EPR imaging was performed on a series of isolated rat hearts perfused with nitroxide spin labels. These hearts were paced at a rate of 6 Hz with either 16 or 32 gated images acquired per cardiac contractile cycle. The image enabled visualization of the time-dependent alterations in the free radical distribution and anatomical structure of the heart that occur during the cardiac cycle. PMID- 8699944 TI - Evaluation of intracellular diffusion in normal and globally-ischemic rat brain via 133Cs NMR. AB - The question of whether the apparent diffusion coefficient (ADC) of intracellular water changes after brain injury was addressed by using 133Cs as an indicator to report on the state of the intracellular environment. Cesium is an NMR-detectable potassium analog that accumulates in the intracellular space and is detectable in rat brain after being added to the animal's diet. The ADC of cesium was measured before and after the death of the rat. The cesium ADC fell from 0.91 +/- 0.05 x 10(-3) mm2/s (mean +/- SEM, n=5) in the alive rat to 0.71 +/- 0.05 x 10(-3) mm2/s within 20 min (the best time resolution of the experiment) of the death of the animal and stayed at this value for at least 3 h (p < 0.001). Assuming that the ADC of cesium reflects motion in the intracellular environment, these results support the idea that there are changes associated with cell injury that would cause a reduction in the ADC of intracellular water. Hence, one factor contributing to the decrease in water ADC after brain injury is a change in the ADC of intracellular water. PMID- 8699945 TI - Evaluation of triple-quantum-filtered 23Na NMR in monitoring of Intracellular Na content in the perfused rat heart: comparison of intra- and extracellular transverse relaxation and spectral amplitudes. AB - Multiple-quantum filtered (MQF) NMR offers the possibility of monitoring intracellular (IC) Na content in the absence of shift reagents (SR), provided that (i) the contribution from IC Na to the MQF spectrum is substantial and responds to a change in IC Na content, and (ii) the amplitude of the extracellular (EC) MQF component remains constant during a change in IC Na content. The validity and basis for these conditions were examined in isolated perfused rat hearts using SR-aided and SR-free triple-quantum filtered (TQF) 23NaNMR. Despite a myocardial Na content that was only approximately 1/70 that of EC Na. IC Na contributed to over 25% of the total TQF spectrum acquired in the absence of SR. Transverse relaxation times (T2) were approximately twice as long for EC compared to IC Na, despite SR-induced relaxation of T2 for the former pool. However, the efficiency of generation of the TQF signal was similar for IC and EC Na, indicating that a much greater percentage of IC relative to EC Na exhibits TQ coherence. During constant perfusion with ouabain (0.2 mM for 25 min) or with a hypoxic and aglycemic solution (50 min), the amplitude of the IC TQF spectrum increased by approximately 330% and -280%, respectively. In contrast, the amplitude of the EC TQF spectra remained essentially constant for both interventions. The amplitude for IC Na increased approximately 250% relative to baseline during no-flow ischemia (60 min), whereas the amplitude of the EC TQF spectra decreased by approximately 33% before stabilizing. In SR-free experiments, the TQF spectral amplitude increased approximately 2-fold during the constant perfusion interventions, but did not change significantly during no-flow ischemia. These data suggest that the change in the TQF spectral amplitude during constant perfusion interventions is from IC Na, and that TQF techniques in the absence of SR may be useful in monitoring IC Na during these interventions. The fall in the amplitude of the EC TQF spectral amplitude during no-flow ischemia complicates the use of TQF techniques without SR during this intervention. PMID- 8699946 TI - Movement-related effects in fMRI time-series. AB - This paper concerns the spatial and intensity transformations that are required to adjust for the confounding effects of subject movement during functional MRI (fMRI) activation studies. An approach is presented that models, and removes, movement-related artifacts from fMRI time-series. This approach is predicated on the observation that movement-related effects are extant even after perfect realignment. Movement-related effects can be divided into those that are a function of position of the object in the frame of reference of the scanner and those that are due to movement in previous scans. This second component depends on the history of excitation experienced by spins in a small volume and consequent differences in local saturation. The spin excitation history thus will itself be a function of previous positions, suggesting an autoregression-moving average model for the effects of previous displacements on the current signal. A model is described as well as the adjustments for movement-related components that ensue. The empirical analyses suggest that (in extreme situations) over 90% of fMRI signal can be attributed to movement, and that this artifactual component can be successfully removed. PMID- 8699947 TI - Quantitative proton MR spectroscopic imaging of the human brain. AB - Multislice proton MR spectroscopic images (SI) of the brain were quantitated, using the phantom replacement technique. In 16 normal volunteers, ranging in age from 5 to 74 years, average "whole brain" concentrations of choline (Cho), creatine (Cr), and N-acetylaspartate (NAA) were found to be 2.4 +/- 0.4, 7.9 +/- 1.3, and 11.8 +/- 1.0 (mM, mean +/- SD), respectively. These values are in good general agreement with those previously determined by single-voxel localization techniques. Cortical gray matter was found to have lower Cho and NAA levels, compared to those of white matter, corpus callosum, and basal ganglia. Cho was also found to increase significantly with age in several locations. Quantitative multislice proton Si is feasible in the clinical environment, and regional and age-dependent variations occur that must be accounted for when evaluating spectra from pathological conditions. PMID- 8699949 TI - Criteria for analysis of multicomponent tissue T2 relaxation data. AB - Monte Carlo simulations were performed to determine whether the multicomponent T2 distribution of tissue can be estimated accurately from T2 decay data acquired in vivo. Simulated data were generated for white matter, fast twitch muscle, and breast tissue. The signal-to-noise ratio, number of data samples, and minimum echo time were varied from the experimental conditions currently achievable with MRI to those achievable for in vitro experiments. Data were fitted by a distribution of T2 values using the T2NNLS algorithm, and statistics characterizing the estimated T2 components were determined. Current MRI techniques were found to provide conditions insufficient for accurate multicomponent T2 analysis on a pixel-by-pixel basis. However, volume localization methods that measure T2 decay from a large volume of interest have potential for this analysis. These results illustrate a general framework for development of new techniques to measure T2 decay accurately in vivo. PMID- 8699948 TI - Noninvasive temperature measurement in vivo using a temperature-sensitive lanthanide complex and 1H magnetic resonance spectroscopy. AB - A new lanthanide complex, praseodymium-2-methoxyethyl-DO3A, was tested as a temperature indicator for 1H magnetic resonance spectroscopy under in vivo conditions, using a 2-T imaging system. The chemical shift of the methoxy group of the compound is strongly temperature dependent. In vitro, a shift change of 0.131 ppm/degree C was found. The signal was shifted by about -24 ppm relative to the water signal, allowing easy water suppression and signal identification in vivo. The body temperatures of eight anesthetized rats were measured in the liver after intravenous administration of 1 mmol/kg of the praseodymium complex under different heating conditions of the animal. The temperatures calculated from the spectra were in good agreement (deviation < +/- 1 degree C) with values obtained simultaneously with a thermocouple placed in the rectum of the animals. PMID- 8699950 TI - New method for contrast manipulation in DNP-enhanced MRI. AB - The magnetization subtraction technique (MS), which is equivalent to the inversion recovery technique in strong magnetic fields, has been implemented in dynamic nuclear polarization-enhanced magnetic resonance imaging (DNPI). The general theoretical basis of the MS method, which can be applied to DNPI or to prepolarized MRI in weak magnetic fields (such as Earth's magnetic field), is introduced. Details are provided about the signal amplitude, dynamic range of the method, and conditions required to observe signal void in samples with specific T1 relaxation times. The experimental results obtained with MS DNPI are presented and discussed. In the experiments, electron spin resonance irradiation frequencies of 199 MHz and 16.2 MHz were employed. Also, T1 contrast manipulation in the polarizing and in the detection magnetic field is discussed and demonstrated for MS DNPI. PMID- 8699951 TI - Three-dimensional MR image registration of the human brain. AB - An automatic three-dimensional technique for registration of MR images of human brain is described. The algorithm was tested, using MR images of human brain, and was found to estimate angular offsets to within 0.5 degrees and translational offsets to within about 1 pixel. The quality of final registration was evaluated by histogram analysis. The algorithm was found to be computationally efficient and robust. PMID- 8699952 TI - Phase-encode reordering to minimize errors caused by motion. AB - A new method for suppressing the effects of motion in MR images by reordering the acquisition of k space has been developed. Existing reordering methods suffer from image blurring. The method presented here applies specifically to translation along the phase-encoding direction, in which case it reduces both ghosting and blurring. The method is conceptually similar to a linear phase shift of k space, except that it has the advantage of not corrupting stationary structures inadvertently. The method is intended for anatomic sites in which substantial translational motion occurs along the phase-encoding direction, such as the cranial-caudal motion of the liver and kidneys. The reordering method is motivated from an analysis of factors affecting the severity of motion artifacts. The theory behind the reordering method is described and validated experimentally by imaging a moving phantom. PMID- 8699953 TI - Encoding of anisotropic diffusion with tetrahedral gradients: a general mathematical diffusion formalism and experimental results. AB - A diffusion imaging method with a tetrahedral sampling pattern has been developed for high-sensitivity diffusion analysis. The tetrahedral gradient pattern consists of four different combinations of x, y, and z gradients applied simultaneously at full strength to uniformly measure diffusion in four different directions. Signal-to-noise can be increased by up to a factor of about three using this approach, compared with diffusion measurements made using separately applied x, y, and z gradients. A mathematical formalism is presented describing six fundamental parameters: the directionally averaged diffusion coefficient D and diffusion element anisotropies eta and epsilon which are rotationally invariant, and diffusion ellipsoid orientation angles theta, phi, and omega which are rotationally variant. These six parameters contain all the information in the symmetric diffusion tensor D. Principal diffusion coefficients, reduced anisotropies, and other rotational invariants are further defined. It is shown that measurement of off-diagonal tensor elements is essential to assess anisotropy and orientation, and that the only parameter which can be measured with the orthogonal method is D. In cases of axial diffusion symmetry (e.g., fibers), the four tetrahedral diffusion measurements efficiently enable determination of D, eta, theta, and phi which contain all the diffusion information. From these four parameters, the diffusion parallel and perpendicular to the symmetry axis (D and D) and the axial anisotropy A can be determined. In more general cases, the six fundamental parameters can be determined with two additional diffusion measurements. Tetrahedral diffusion sequences were implemented on a clinical MR system. A muscle phantom demonstrates orientation independence of D, D, D, and A for large changes in orientation angles. Sample background gradients and diffusion gradient imbalances were directly measured and found to be insignificant in most cases. PMID- 8699954 TI - Transesophageal cardiac pacing during magnetic resonance imaging: feasibility and safety considerations. AB - The feasibility and safety of transesophageal cardiac pacing during clinical MRI at 1.5 Tesla is considered. An MRI compatible pace catheter was developed. In vitro testing showed a normal performance of the pulse generator, image artifacts that extended less than 11 mm from the catheter, and a less than 5% increase in noise. Cardiac stimulation induced by MRI was not observed and, theoretically, is not expected. Potentially, tissue around the catheter tip may become heated. This heating (delta tau) was monitored. Eight dogs were exposed to MRI during pacing. For low RF radiation exposure, a time-averaged squared B1 field below 0.08 p tau 2 (SAR < 0.03 W/kg), delta tau was below 1 degree C. For high RF radiation exposure, but at normal RF radiation specific absorption rate (0.4 W/kg) delta tau was 5 degrees C. Thus, transesophageal atrial pacing during MRI at low RF exposure seems to be possible to perform cardiac stress studies or to correct unstable heart rates. PMID- 8699955 TI - A method for generating magnetic resonance microimaging T2 maps with low sensitivity to diffusion. AB - Generating T2 maps in magnetic resonance microimaging is often complicated by the self-diffusion of water molecules. A modification of the standard spin-echo pulse sequence is proposed which minimizes this effect. Experiments with doped water confirmed that the T2 values obtained with the modified sequence were equal within the experimental error to the value obtained by the spectroscopic Carr Purcell-Meiboom-Gill method. The applicability of the technique is demonstrated by generating T2 maps of porcine articular cartilage. PMID- 8699956 TI - Multiple breathhold 3D time-of-flight MR angiography of the renal arteries. AB - A technique is described for angiographic imaging of the renal arteries with acquisition performed over several periods of suspended respiration. The 3D Fourier transform (FT) gradient-echo angiographic sequence uses magnetization preparation and appropriately chosen delay times for background nulling and time of-flight enhancement of the vasculature. The sequence was applied to 10 volunteers, each of whom was imaged in three ways: (i) over a series of breathholds in which feedback was provided to enable reproducible breathholding; (ii) over a series of breathholds with no feedback; and (iii) over continuous respiration. Results were evaluated by measuring the transverse extent of the well-delineated renal vasculature and by noting the distal extent of the vasculature branching (main, segmental, and interlobar branches). The transverse extent of renal vasculature visible with breathhold feedback, breathholding, and free breathing was 6.1 +/- 0.9 cm, 5.0 +/- 1.8 cm, and 4.0 +/- 1.4 cm, respectively (mean +/- SD). Breathhold feedback enabled visualization of segmental renal arteries bilaterally in all 10 volunteers. PMID- 8699957 TI - Brain alcohol detectability increase with repeated administration in humans: a proton spectroscopy study. AB - Proton MRS was used to detect brain alcohol after repeated alcohol exposure in human subjects. MRS detectability measurements were made after administration of an alcoholic drink (0.6 g/kg alcohol) and after an identical drink administrated 6 h later. Between-drink differences in the methyl proton triplet resonance of ethyl alcohol were assessed at statistically equivalent and near-peak blood alcohol concentrations (reflecting brain alcohol concentrations) and statistically equivalent internal standard N-acetyl resonance areas after Drinks 1 and 2, respectively. Brain alcohol detectability was not altered in TE 30-ms spectra but was increased in all five subjects after Drink 2 by an average of 70% in TE 270-ms spectra (p < 0.01). This was accompanied by significant between drink differences in subjective ratings of alcohol's effects, suggestive of induction of acute alcohol tolerance. These findings suggest increased brain alcohol detectability in TE 270-ms spectra after repeated alcohol exposure that may reflect acute alcohol tolerance. PMID- 8699958 TI - Clinical implications of genetic defects in G proteins. The molecular basis of McCune-Albright syndrome and Albright hereditary osteodystrophy. AB - Inactivating and activating mutations in the gene encoding G alpha s (GNAS1) are known to be the basis for 2 well-described contrasting clinical disorders, Albright hereditary osteodystrophy (AHO) and McCune-Albright syndrome (MAS). AHO is an autosomal dominant disorder due to germline mutations in GNAS1 that decrease expression or function of G alpha s protein. Loss of G alpha s function leads to tissue resistance to multiple hormones whose receptors couple to G alpha s. By contrast, MAS results from postzygotic somatic mutations in GNAS1 that lead to enhanced function of G alpha s protein. Acquisition of the activating mutation early in life leads to a more generalized distribution of the mosaicism and is associated with the classic clinical triad of polyostotic fibrous dysplasia, endocrine hyperfunction, and cafe au lait skin lesions described in MAS. Acquisition of a similar activating mutation in GNAS1 later in life presumably accounts for the restricted distribution of the gsp oncogene, and is associated with the development of isolated lesions (for example, fibrous dysplasia, pituitary or thyroid tumors) without other manifestations of MAS. Tissues that are affected by loss of G alpha s function in AHO are also affected by gain of G alpha s function in MAS, thus identifying specific tissues in which the second messenger cAMP plays a dominant role in cell growth, proliferation, or function. Further investigations of the functions of G alpha s and other members of the GTPase binding protein family will provide more insight into the pathogenesis and clinical manifestations of human disease. PMID- 8699959 TI - Sulfadiazine-associated nephrotoxicity in patients with the acquired immunodeficiency syndrome. AB - We performed a computerized search on sulfadiazine-associated nephrotoxicity reported in human immunodefiency virus (HIV)-infected patients in the international literature. Including an original case report, we summarized 35 acquired immunodefiency syndrome (AIDS) patients from 1987 to 1995 in an analysis comparing their features to historical HIV-negative controls from the 1940s and 1950s. Likely due to a high prevalence of potential risk factors, incidence of sulfadiazine-associated renal impairment was 1.9%-7.5% in AIDS patients and 1%-4% in HIV-negative controls. Its occurrence appeared to be delayed in HIV-infected patients with a median of about 3 weeks of medication compared with about 10 days in HIV-negative subjects. Correspondingly, the cumulative sulfadiazine dose at manifestation doubled in AIDS patients with a median of 84 g versus 40 g in controls. Patients usually presented with flank or lumbar pain, oliguria, and (macro) hematuria. Urinalysis showed typical "sheaves of wheat" crystalluria, erythrozyturia, and, less commonly, leukozyturia and proteinuria. Echogenic (mostly peripelvic) densities, renal stones, and hydronephrosis are frequent findings on ultrasound examination, whereas X-ray examination possesses a low diagnostic sensitivity. The principle aim of therapy in these patients is to (re)institute the physicochemical urinary solubility of sulfadiazine and its metabolites. For this purpose, forced rehydration and, most importantly, urine alkalinization proved to be effective measures without an absolute need to withhold the drug. Provided prophylactic and therapeutic recommendations are complied with, outcome of this drug-related side effect is usually excellent, and rare relapses will similarly respond well. PMID- 8699960 TI - Complications associated with Brucella melitensis infection: a study of 530 cases. AB - We carried out a prospective study of 530 patients older than 14 years of age with brucellosis. We describe the incidence and clinical features of the focal forms of the disease, analyzing some of the possible factors associated with their appearance. One hundred sixty-nine patients (31.9%) had a focal form or complication. Osteoarticular complications were the most frequent, totaling 113 cases (66%), followed by genitourinary with 18 cases (5.1% of males), hepatic (2.5%), neurologic (1.7%), and heart (1.5%). Nine patients (1.7%) had more than 1 complication. In a multivariate analysis, diagnostic delay greater than 30 days (OR 2.0), ESR > 40 mm/hr (OR 1.9), and levels of alpha-2 globulin > 7.5 g/L (OR 6.8) were statistically significant independent variables associated with the presence of focal forms. Twenty-five patients with complications (14.8%) required surgical treatment. The relapse rate was 3.6% for those patients without complications and 4.1% for patients with focal forms (p > 0.05). However, when therapeutic failure, relapses, and mortality were considered together, the risk of an unfavorable evolution was significantly greater in patients with focal forms (10.6% versus 3.6% in patients without complications; OR 1.9, 95% CI 1.4 7.1, p < 0.005). Given the worse prognosis, knowledge and early diagnosis of the focal forms of B. melitensis infection is especially important. PMID- 8699961 TI - Paracoccidioidomycosis of bones and joints. A clinical, radiologic, and pathologic study of 9 cases. AB - Paracoccidioidomycosis is a systemic fungal infection endemic to Central and South America. It is associated with a broad spectrum of clinical manifestations and has been classified into acute and chronic forms. The latter is the most common type and usually affects male agricultural workers in rural communities. The disease typically begins in the lungs producing varying degrees of parenchymal damage, and in a significant number of cases the organism spreads through bronchogenic, lymphatic, or hematogenous routes to involve 1 or more organs. Bone and joint infection is relatively uncommon and has not been well described in the English literature. Much of the information on this form of the disease has been derived from radiographic and autopsy studies on patients with severe or fatal infections in whom skeletal involvement was a minor or incidental finding. We describe our experience with 9 cases in which osteoarticular manifestations were the sole or 1 of the few major complications of the disease. All 9 patients were male, from 9 to 49 years of age (mean, 36.6 yr). Six were farmers. Evidence of visceral infection was present in 6 patients, in all of whom the lungs were considered the primary site of disease. The osteoarticular lesions were symptomatic in all cases, with the duration of symptoms ranging from 1 week to 2 years. The lesions were centered in bone in 2 cases: they manifested radiographically as circumscribed areas of lysis with or without a rim of sclerosis. The disease was centered in joints in 7 cases; the associated radiographic changes included evidence of joint effusion, periarticular bony erosions, and narrowing of the joint space. Biopsy of the involved skeletal site revealed compact or loose granulomas containing variable numbers of fungi. Although follow-up information was not available for all patients, those treated with TMP-SMX (and 1 patient who also received amphotericin B) and who were followed had prompt resolution of their signs and symptoms. Our findings substantiate some of what is known about the epidemiology of bone and joint involvement in chronic paracoccidioidomycosis. Our patients exhibited features of skeletal infection that have not been emphasized previously, however, including 1) frequent involvement of large joints or long bones of the extremities, 2) presentation with relatively rapidly developing musculoskeletal symptoms, and 3) manifestation as a solitary joint or bone lesion with or without concurrent clinically detectable pulmonary disease. Bone and joint paracoccidioidomycosis should be considered in the differential diagnosis in patients who have skeletal lesions with or without pulmonary involvement and have either lived in or traveled through endemic areas. Early diagnosis and treatment with antifungal medications can achieve an excellent outcome with limited local sequelae. PMID- 8699962 TI - Acute arterial obliteration: a new feature of the POEMS syndrome? AB - The POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammapathy, and skin changes) syndrome is a rare variant of plasma cell dyscrasia with multisystemic manifestations. We present 4 cases with arterial symptoms typical of acute arterial obliteration (AAO) and review 9 similar cases in the literature. The clinical course of AAO was unusual and particularly severe when affecting the lower limbs; recurrent events required amputations. As demonstrated by angiographic and histologic studies, thrombotic and atheromatous lesions were the main pathologic features of AAO. Atherosclerotic risk factors were absent or moderate in 3 of our cases, and no cause of thrombosis other than the POEMS syndrome was found. A high production of cytokines was found in all cases, with elevated serum levels of interleukin-1 beta (9/9 samples), interleukin-6 (7/9 samples), and tumor necrosis factor-alpha (6/9 samples). We suggest that arterial manifestations should be added to the spectrum of manifestations of the POEMS syndrome. Cytokines may mediate the POEMS syndrome-associated AAO, as previously proposed for the other systemic manifestations of this disorder. PMID- 8699964 TI - Efficacy of disinfectants against biofilm cells of methicillin-resistant Staphylococcus aureus. AB - The effect of disinfectants on biofilm cells of methicillin-resistant Staphylococcus aureus (MRSA) was evaluated. Eradication of biofilm cells of MRSA by chlorhexidine gluconate, benzalkonium chloride, alkyldiaminoethyl glycine and sodium hypochlorite required a much longer time than that of planktonic cells in suspensions. Benzalkonium chloride (0.1%) and alkyldiaminoethyl glycine (0.1%) were ineffective for eradication of biofilm cells even after 1 h, but were effective for eradication of planktonic cells within 20 s. Sodium hypochlorite (0.01%) was also ineffective for eradication of biofilm cells even after 30 min, but was lethal to planktonic cells within 20 s. PMID- 8699963 TI - Recovery of soluble protein after expression in Escherichia coli depends on cellular disruption conditions. AB - Proteins overproduced in Escherichia coli are frequently recovered from bacterial extracts as insoluble material. The influence of different cell disruption procedures on the recovery of soluble protein, after recombinant protein expression in E. coli, was assessed using two beta-tubulin derivatives. Nonionic detergents such as Triton X-100 and Nonidet P-40 promote aggregation when present in the lysis buffer. The effect of Triton X-100 is reversed by the addition of 1 M NaCl in the lysis buffer indicating that the recombinant protein aggregation is probably caused by interactions with membrane proteins. The importance of the cellular disruption method on the recovery of potentially soluble recombinant proteins is discussed. PMID- 8699965 TI - Investigations into the microbial contamination of toothbrushes. AB - Used brushes (28 in toto) were assessed for microbial contamination. The micro organisms removed from the toothbrush heads were plated onto a range of selective media. The total number of micro-organisms isolated per brush varied from 0 to 10(8) CFU. Staphylococci, coliforms, pseudomonads and yeasts were isolated from 64, 57, 28 and 39% of brushes, respectively. Identification tests on representative colonies indicated that media for streptococci, staphylococci, yeasts and pseudomonads were selecting for appropriate growth with > 90% efficiency. Of those tested on MacConkey agar eight from eleven colonies were oxidase negative, Gram-negative rods; the remainder were oxidase positive. No black pigmented obligate anaerobes were isolated. None of the seventeen colony types on Helicobacter selective agar proved to belong to that genus. Scanning electron microscopy of bristles revealed toothpaste debris, but micro-organisms were not evident. PMID- 8699966 TI - Effects of tunicamycin on glycoprotein antigens of Aspergillus fumigatus. AB - Tunicamycin, which inhibits N-glycosylation of proteins, was used as a tool to determine the type of linkage which occurs in glycoprotein antigens of Aspergillus fumigatus. When A. fumigatus extracts were electrophoretically separated and blotted then probed with anti-Aspergillus patients' sera, differences in antigenic profiles were noted when tunicamycin-treated samples were compared with controls. Tunicamycin had no detectable effect on the cellular proteinases of A. fumigatus, most of which are glycosylated. Some enzymatic components were lacking when extracellular proteinases were compared with those of control samples. The major catalase component of A. fumigatus is a concanavalin A (ConA)-binding glycoprotein. In cultures grown in the presence of tunicamycin, partially-deglycosylated catalase components were obtained which could be distinguished from the native catalase by altered mobilities in polyacrylamide gels. The effect of deglycosylation on catalase antigens was monitored using an antiserum raised to a ConA-binding fraction of A. fumigatus mycelium. These antibodies bound both to the native glycoprotein and the partially deglycosylated material. These latter two were largely unaffected when incubated with an antiserum raised to a non-ConA-binding fraction of A. fumigatus which is essentially carbohydrate free. The ability to produce partially glycosylated antigens of A. fumigatus offers a model to study the effect of basic structural modifications on both the enzymatic and antigenic activities of these molecules. PMID- 8699968 TI - Multidisciplinary education. PMID- 8699967 TI - Tetranitromethane as a broad spectrum disinfectant. AB - Tetranitromethane (TNM), a protein nitrating reagent, was shown to be effective in killing Gram-positive and Gram-negative bacteria, bacterial endospores and fungi. The killing action was greater in alkaline media, where nitration was most effective. TNM has a high affinity for hydrophobic solvents, and it is suggested that the reagent killed micro-organisms by nitrating critical membrane proteins. PMID- 8699969 TI - A structured panel interview and group exercise in the selection of medical students. AB - The selection of entrants for medical school, as now widely agreed, should include measurements of non-academic as well as academic attributes. The authors have developed a process to assess the personal attributes of applicants. This included a structured panel interview carried out twice on each applicant by independent interviewers and a group exercise in which several applicants were observed whilst discussing a problem. Training for interviewers took the form of a half-day interactive workshop. One hundred and forty-one school-leaving applicants completed the new assessment. No relationship was found between academic achievement as reflected by marks in a national examination and scores in the panel interview, the group exercise, or the school principal's report. However, significant intercorrelations were found between the panel interview, group exercise and school report. The results of this experience have encouraged the Auckland School to continue to explore methods to measure these attributes in a carefully controlled study. PMID- 8699970 TI - Embarking upon a medical career: psychological morbidity in first year medical students. AB - This study was undertaken to measure the prevalence of psychological morbidity, and the nature and source of stress, in first year medical students. Two hundred and four first year medical students at a university in the north of England were sent a postal, self-report questionnaire. They were asked to complete the General Health Questionnaire (GHQ), the Stress Incident Record and to give details of their alcohol consumption. A total of 172 students (84.3%) replied. Thirty-six per cent of the students scored above the threshold of the GHQ, indicating probable psychological disturbance. There was no difference between men and women. Approximately half of the students described a stressful incident, the majority of which were related to medical training rather than to personal problems. Male students reported drinking significantly more alcohol than female students, but there was no relationship between levels of alcohol consumption and either psychological disturbance or reporting of stress. The findings suggest that even at the preliminary stages of medical training, many students find aspects of the medical course very stressful. The psychological well-being of medical students needs to be more carefully addressed, and closer attention paid to the styles of medical teaching that may provoke avoidable distress. PMID- 8699971 TI - The value of medical student research: the experience at Stanford University School of Medicine. AB - At Stanford University School of Medicine, students are encouraged to conduct research, requiring a substantial amount of funding and effort on the part of teaching staff. We questioned one graduating class and all medical teachers to determine the value of the research experience to students, as well as staff satisfaction. Seventy-three per cent of students and 80% of teaching staff responded. Ninety per cent of students had performed research resulting in at least one published manuscript for 75% and a presentation at a national meeting for 52%. Almost all thought the experience taught them to ask questions, review the literature critically, and analyse data. Three-quarters responded that the experience motivated them to pursue further research, and 60% indicated that they plan a full-time academic career. The majority of teaching staff who worked with students found it rewarding and thought the student had had a valuable experience. We conclude that our curriculum provides a positive opportunity for students to develop an investigative approach to medical problems. PMID- 8699972 TI - Clinical problem-solving using video simulation: an investigation. AB - This paper examines the use of videotape simulation as a research method for the exploration of clinical problem-solving. The challenges posed and the strategies employed to overcome the difficulties encountered are discussed. The simulation forms part of a larger comparative study of outcomes of pre-registration nurse education programmes, commissioned by the English National Board for Nursing, Midwifery and Health Visiting. PMID- 8699973 TI - An instrument to evaluate clinical instructional skills. AB - A questionnaire, which consisted of 10 statements dealing with the attributes of effective clinical instruction, was designed for use by medical students. Three groups of trainees who followed consecutive clinical rotations in paediatrics assessed the instructional skills of their tutors using the instrument. Summary reports on students' perceptions were made available to the teachers soon after each rotation. The results showed that although individual instructors exhibited varying degrees of the desired skills, they maintained a consistent pattern through the assessments. When considered on an overall basis, teacher behaviours such as allowing the students to ask questions and giving satisfactory answers, and helping in students' learning problems with relevant feedback, received a higher percentage of positive ratings than emphasizing problem-solving, demonstrating and supervising physical examinations and procedures, and stimulating the students' interest in the subject. It appears that the instrument developed is suitable for obtaining feedback from the students to identify the strengths and weaknesses of the instructional skills of their clinical teachers. Such feedback would become useful when modifying programme presentation and in planning and conducting faculty development activities. PMID- 8699974 TI - Mandatory HIV testing of patients and professionals: bringing ethics into practice. AB - A contemporary health dilemma, that of mandatory HIV testing of patients and professionals, is used as a focus for an ethics class. Background material which is given to students is described and referenced. The interjection of ethical theory is described. The exercise has provided an effective focus for medical and health professional undergraduate and postgraduates. It combines contemporary material with ethical theory, and so brings ethics into practice for students. PMID- 8699975 TI - A skin cancer training programme: evaluation of a postgraduate training for family doctors. AB - This study aimed to evaluate the effectiveness of a postgraduate skin cancer training programme in improving family doctors' levels of knowledge and clinical practice. Forty-one of 59 family doctors (69% consent) who enrolled in the training programme agreed to participate in its evaluation. Approximately half of the doctors were allocated to the 'intervention' group, and the others were in the 'waiting-list' control group. Pre- and post-test data were collected to assess changes in doctors' knowledge, perceived confidence and clinical practice. The training programme involved three sessions, including an information/education session, a practical session at the local Melanoma Unit, and a practical surgical procedures session. There were significant improvements in the proportion of (i) accurate diagnoses, which were made when lesions were presented on colour slides with an accompanying case history; (ii) lesions presented on colour slides in which the correct management of the lesion was identified; and (iii) doctors who felt very or extremely confident in their ability to advise patients on screening frequency, to advise patients on the signs of skin cancer, and to decide whether changes in lesions were malignant. The only improvement observed in the doctors' clinical practice was a significant increase from pre- to post-test in the proportion of pathology request forms on which a diagnosis of the specimen was attempted by doctors in the intervention group compared to those in the control group. The results of this study indicate that whilst significant improvements in knowledge are achievable through postgraduate programmes, clinical practice is much more difficult to change. PMID- 8699976 TI - Women consultants, their background and training: some myths explored. AB - This paper aims to show what choices (both personal and professional) the many women who achieve National Health Service (NHS) consultant status make, and how some of the factors that affect this also influence merit awards. Over 2200 women and 200 men holding consultant contracts within the NHS were asked (through an anonymous postal questionnaire) about the personal choices they had made and other factors that had influenced their career. Findings from the 1654 respondents show that women reach consultant grade at about the same time as their male contemporaries, but are more likely to be in anaesthetics, radiology, pathology or psychiatry. Many women choose these specialities because they fit best with family commitments. The remaining women are more likely to work in the female-orientated specialities of paediatrics and obstetrics and gynaecology than other medical or surgical specialities. They are less likely to receive a merit award. PMID- 8699977 TI - The feminization of the medical profession in Israel. AB - Two factors have caused major changes in the gender composition of the Israeli medical profession in recent years: (i) a wave of immigration from the former USSR, which increased the doctor population by approximately 70% and which included a majority of women physicians, and (ii) the entry of more Israeli women into medical school. This report presents the current gender status of the Israeli medical profession, regarding students and physicians, and the choice of medical specialty and academic seniority, and compares gender differences in Israel with those in other countries. Traditional patterns of specialization persist in Israel, with women still concentrated in primary care (family medicine, paediatrics and psychiatry). In addition, women still face obstacles in entering the more prestigious (mainly surgical) specialties. Whilst the number of women in academic medicine has increased over the last decade, women are still concentrated in the lowest echelons of academic medicine. However, the steady trend towards the feminization of medicine will inevitably lead to an increase of women in all areas of the medical profession. Because cross-cultural studies have repeatedly revealed that women doctors have a more humanistic and personalized approach to patient care, a higher ratio of women in the profession should have a qualitative effect in this direction, despite the bureaucratic and fiscal constraints incumbent upon practising doctors. As more women become role models for medical students, their approach will influence the education of the doctors of the future. PMID- 8699978 TI - The epidemiological information system of the French national electricity and gas company: the SI-EPI project. AB - SI-EPI is epidemiological information system set up in 1978 in the national electricity and gas company, Electricite de France-Gaz de France (EDF-GDF). The worker population comprises about 150,000 individuals, involved in production, transmission and distribution of energy. SI-EPI was developed by the epidemiologists of the Occupational Health Department (180 physicians), and of the Securite Sociale Department (120 physicians). Several data bases constitute SI-EPI. The population data base contains demographic, socioeconomic and professional data about each worker. The health data base is an exhaustive register of sick leave, accidents, permanent disabilities, compensated diseases, causes of death and cancer incidence among active workers. The Occupational Exposure and Working Conditions data base includes the MATEX job-exposure matrix (30 potentially carcinogenic agents) and FINDEX files which record data obtained from the systematic individual surveillance of workers. The GAZEL cohort data base concerns a sample of more than 20,000 volunteer workers, followed since 1989; in addition to data from the data bases, it contains information collected from other different sources, including self-questionnaires. Numerous epidemiological studies based on SI-EPI data have been conducted by in-house epidemiologists as well as by external research groups. They include mortality and morbidity studies and address various topics and health problems. Their results are used for internal information, as well as for epidemiological research purposes. PMID- 8699979 TI - A cross-sectional study on nerve conduction velocities among workers exposed to carbon disulphide. AB - We examined nerve conduction velocities (NCVs) in the ulnar nerve (motor, slower motor fiber and mixed), the peroneal nerve (motor, MCV) and the sural nerve (sensory, SCV) among 46 Japanese workers exposed to carbon disulphide (CS2, CS2 exposed group) and 28 normal control workers (group C). The subjects had not suffered from diseases or injuries of the peripheral or central nervous system. MCV in the peroneal nerve and SCV in the sural sural nerve in the CS2-exposed group were significantly reduced compared with those of group C (p < 0.05 in both), but no significant difference in NCVs of the ulnar nerve was noted between the two groups. In the two subgroups of the CS2 exposed group (currently exposed: group E n = 24; removed from exposure: group R n = 22), NCVs of group E tended to be lower than those of group R in spite of the younger age of group E. MCV in the peroneal nerve and SCV in the sural nerve in group E were significantly reduced compared with those in group C, but not significantly in group R. These findings indicate the existence of a toxic effect of CS2 exposure on the NCV, predominantly evident in the lower limbs in those workers. On removal from CS2 exposure, NCV recovery seemed to be possible. PMID- 8699980 TI - [Respiratory function in a group of railway car repair workers]. AB - A study was performed on respiratory function in 875 railways workers employed in an Italian Railways repair workshop, formerly exposed to asbestos. Workers were interviewed on personal and occupational histories and personal habits. They underwent physical examination and spirometry. Analysis of covariance was performed for FVC, FEV1/FVC, and FEF25-75%. FEV1/FVC and FEF25-75% were reduced in the most heavily exposed group. No reduction in the FVC corrected mean value was found in the exposed workers but an interaction between age and smoking was observed in the most exposed group. PMID- 8699981 TI - [An experimental evaluation of the efficacy of 4 types of detergents for 3 types of dyes to which workers in color-printing plants are exposed]. AB - The efficacy of 4 commercial cleansing products was tested with 3 colouring agents widely used in the dyeing industry in a randomised double blind trail involving 8 workers each time. A between-detergents statistically significant difference was observed; the interaction (detergents x colouring agents) was significant. The efficacy of type A detergent was higher for type I-III dyers, while the efficacy of type C detergent, which widely used was lowest. PMID- 8699982 TI - Epidemiological aspects of cancer risk associated with exposure in the occupational environment. AB - The contribution of epidemiological research to the definition of cancer risk from the occupational environment is reviewed and evaluated on the basis of the systematic approach adopted by the Monograph Program of the International Agency for Research on Cancer. The importance of cancer risk from industrial environments and its historical pattern are discussed along with the presentation of an updating on the available knowledge in this field. PMID- 8699983 TI - Evaluation of the predictive value of Fanger's PMV index study in a population of school children. Predicted mean vote. AB - Fanger's PMV index has been widely used in the last ten years even if it has not yet been sufficiently tested in children. Furthermore recent studies have expressed doubts on the utilization of the index in real situations. We therefore studied the applicability of the PMV index via a survey that involved school children from 8 to 11 years old. The study was conducted comparing the individual objective quantification of thermal comfort (values of PMV index) and the feeling of subjective thermal comfort of people involved (by answering a standardized questionnaire). The PMV index values within the interval +/- 0.5 were grouped in 2 degrees C operative temperature classes; the percentages of subjects who expressed thermal comfort were calculated within these groups. Considering Fanger's assumption (as foreseen by ISO 7730), the percentage of subjects in a condition of thermal discomfort could not be higher than 10% in each group. On the contrary a percentage of dissatisfied persons was obtained that was significantly higher (p < 0.01) than 10% over all the temperature values considered. The number of discrepancies, analyzed even with respect to operative temperature values, was so high that it could not be attributed to the thermal variation that can be measured in the classrooms. Variations due to differences in the thermal resistance of clothing can be excluded since this was taken into consideration individually during the elaboration of the index. PMID- 8699985 TI - [The sleep of statistics is generating monsters]. PMID- 8699987 TI - Umbilical cord blood for bone marrow transplantation. PMID- 8699984 TI - [Biological monitoring of exposure to solvents: a method for the gas chromatographic determination of aromatic hydrocarbons in the blood and urine]. AB - A gas chromatographic procedure with dynamic head-space purge and trap preconcentration (HSGC) and FID detection for blood and urinary benzene, toluene, ethylbenzene and xylenes (BTEX) determination at low level exposure is described. Critical steps (sample collection, calibration, HSGC conditions, contamination control) are discussed. The calibration curve is linear in the range 50 ng/l-500 micrograms/l; the calculated detection limit is 50 ng/l for all the considered aromatic hydrocarbons (AH) both in blood and urine; the within-day precision, calculated as variation coefficient (CV) at 400 ng/l and 40 micrograms/l (n = 6) was respectively CV = 13% and CV = 6% for all the studied analytes. The recovery rate was in the range 29-70%, depending on the hydrocarbon and matrix (blood or urine) considered. The procedure was applied to the biological monitoring of 151 workers occupationally or environmentally exposed to BTEX. Occupationally exposed subjects showed blood AH levels of 2-4 order of magnitude higher than environmentally exposed subjects. In white-collar workers exposed to BTEX urban pollution a significant difference in blood and urine levels of AH was observed between nonsmokers and smokers. Nonsmokers showed blood AH median values of respectively benzene = 241 ng/l, toluene = 759 ng/l, ethylbenzene = 140 ng/l, xylenes = 604 ng/l. Significatively higher BTEX blood values were observed in smokers after a median consumption of 5 cigarettes in 5 hours; observed median values were respectively: benzene = 365 ng/l toluene = 1327 ng/l, ethylbenzene = 233 ng/l, xylenes = 794 ng/l. PMID- 8699986 TI - [The prevention of work risks deriving from the use of chemotherapeutic antineoplastics in the health environment: the consensus document (November 1995)]. PMID- 8699988 TI - Terbinafine for onychomycosis. PMID- 8699989 TI - Induction toxicity of a modified Memorial Sloan-Kettering-New York II Protocol in children with relapsed acute lymphoblastic leukemia: a single institution study. AB - Although the chance of cure for children with acute lymphoblastic leukaemia (ALL) is high, their outlook with subsequent relapse is poor. Bone marrow transplantation may be an option for some, but the need for intensive reinduction chemotherapy regimens remains the best hope for effecting cure in the majority of relapsed children. The authors report the experience of using an intensive chemotherapy protocol (Memorial Sloan-Kettering-New York II Protocol, MSK-NY-II) in a series of relapsed children with ALL. Thirty children presenting to the Royal Alexandra Hospital for Children, Sydney, in their first relapse of ALL were treated according to a modification of the original MSK-NY-II protocol. Three children (10%) died during induction therapy, two from overwhelming Gram-negative sepsis, and one from intracerebral haemorrhage. Of 27 children completing induction, two children failed to enter remission; however, both had planned deviations from the protocol. Infectious complications were prominent with a total of 55 admissions for febrile neutropenic episodes. Eight children required the support of the intensive care unit for infectious complications. A total of 36 microbiological isolates were obtained from the patients during induction therapy. Ten bone marrow transplant procedures have been subsequently performed in these children, of whom five are alive and disease free at the time of writing. The MSK-NY-II protocol is an intensive regimen but with encouraging early remission rates in relapsed childhood ALL. Early sepsis in previously immunosuppressed children is an important cause of induction death. PMID- 8699990 TI - Response of pediatric malignant solid tumors following ifosfamide or ifosfamide/carboplatin/etoposide: a single hospital experience. AB - One hundred thirty-eight pediatric patients have received treatment for malignant solid tumors with ifosfamide with mesna, and 71 have received a combination with ifosfamide/carboplatin/etoposide (ICE). Responses were obtained in many types of pediatric tumors, yet comparison of responses was not possible because of inadequate numbers of tumors of differing histiotypes. Comparison of results between patients with all tumors treated with ifosfamide or ICE indicated that there was a higher response rate for patients treated with ICE, with an estimated odds ratio of 2.74 (95% C.I. 1.45-5.179). Excluding patients without prior chemotherapy and radiotherapy, the odds ratio for 2.801 (95% C.I. 1.45-5.4) suggests a similar result. There remain no guarantees that the more costly treatment with ICE, which requires cytokine support, will offer therapeutic benefits against resistant solid tumors. PMID- 8699991 TI - Progressive glomerular toxicity of ifosfamide in children. AB - Glomerular toxicity following ifosfamide (IFO) is not as well recognized as renal tubular damage. Following a case of ifosfamide-induced renal failure with histological evidence of glomerular changes, we undertook a retrospective study of all IFO-treated children to assess the extent and severity of its glomerular toxicity and to identify possible predisposing factors. Thirty-seven children with a follow-up of 6 months or more from the end of chemotherapy were studied. They were a median of 10.8 years old (range 3.25-18.5), had received a median of 54 g/m2 (range 9-135) of IFO, and had a median follow-up of 29 months (range 6 68). The criteria to identify glomerular dysfunction were raised plasma creatinine (Pc) values on two occasions or a low glomerular filtration rate (GFR) measured by Tc-99-DTPA clearance. Detailed assessment was carried out to identify other nephrotoxic influences in these children. Subjects in whom glomerular dysfunction could be causally linked to IFO were compared with the rest of the group for a variety of predisposing factors. Of eight children with glomerular dysfunction, two had other nephrotoxic influences and were excluded from further analysis. In six (17.1%) children, glomerular dysfunction appeared to be causally linked to IFO. Their median GFR was 61.9 ml/min/1.73 m2(range 33-85) and Pc was 123 mumol/l (range 85-216). Five of the six had normal glomerular function at the end of therapy and the raised Pc values were first noted 19, 21, 26, 29, and 36 months later. Children with glomerular toxicity had a significantly longer median follow-up (41.5 vs. 19 months; P = 0.04) than the rest of the group, suggesting late onset of this problem. They were older at the time of the study and had received nearly twice the dose of IFO, though the differences in age and dose did not reach statistical significance. The earliest signs of renal toxicity were seen in the index case, who had had prior nephrectomy. All affected children had coexistent and preceding tubular toxicity. The inadequacies of tests commonly used to assess glomerular function and the possibility of underestimation of dysfunction are discussed. Glomerular dysfunction following IFO is poorly recognized and evidence from this study of its later onset and progressive nature is a cause for concern. The index case is described with histological findings. PMID- 8699992 TI - Non-Hodgkin's lymphoma after liver transplantation: response to chemotherapy. AB - An increased incidence of lymphoproliferative disorders in immunosuppressed organ transplant recipients has long been recognised. Lymphoproliferative disorders occur in 2% of orthotopic liver transplant patients. Different therapies have been used, but the optimal treatment remains unknown. Relatively little information is available on experience with cytotoxic chemotherapy. Three children who developed Burkitt-like, non-Hodgkin's lymphomas after liver transplantation are described. The disease failed to regress after initial management, which included a reduction in immunosuppression. With cytotoxic chemotherapy all three achieved complete remission, which continued 36+, 35+, and 16+ months after diagnosis. Results suggest that in selected cases chemotherapy can be safe in late-onset lymphomas appearing after solid organ transplantation. PMID- 8699993 TI - Outcome of children treated for cancer in the Republic of Namibia. AB - The data of a survey undertaken to record all cases of childhood cancer in Namibia from 1983 to 1988 were analyzed to estimate 5-year survival rates. The projected survival rate for 150 children with cancer was 37% with no difference between boys and girls. The calculated survival rates for most of the tumor groups were poor with the exception of Wilms' tumor which had a 5-year survival rate of 76%. The zero survival rate of children with malignant bone disease may have been due to inadequate treatment. Neuroblastoma and retinoblastoma presented with advanced disease which contributed to the poor survival rates of 13% and 46%, respectively. The overall survival rate for lymphoma of 53% and 39% for all leukemias compares poorly with the rates obtained in industrialized countries. The relatively poor 25% survival rate in tumors of the central nervous system (CNS) may partly be due to the long delay between the initial diagnosis and the institution of appropriate treatment for raised intracranial pressure and for the tumor. Both cure and long-term follow-up are difficult to achieve in a developing country. Improved early diagnosis and appropriate treatment are necessary to improve survival rates. PMID- 8699994 TI - Phase I trial of extracellular adenosine 5'-triphosphate in patients with advanced cancer. AB - Adenosine 5'-triphosphate (ATP) has antineoplastic activity in vitro and in murine tumor systems, but there are no data in humans defining its potential use as an antineoplastic agent. We conducted a phase I study to determine the spectrum of toxicity, maximum safely tolerated dose (MTD), and pharmacokinetics of intravenous ATP. Fourteen men with advanced cancer received 96-hour infusions of ATP once monthly in doses ranging from 50 to 100 micrograms/kg/minute. Toxicity was assessed by standard National Cancer Institute (NCI) criteria, cardiac function was monitored serially by two-dimensional echocardiography, and whole blood ATP was measured serially in a subset of patients. ATP was generally well tolerated and no significant hematologic toxicity was noted. The dose limiting toxicity was a cardiopulmonary reaction characterized by chest tightness and dyspnea that resolved within seconds of discontinuing ATP. Dose-limiting cardiopulmonary toxicity occurred in 3 of 3 patients at 100 micrograms/kg/minute, in 3 of 6 patients at 75 micrograms/kg/minute, and 4 of 11 patients at 50 micrograms/kg/minute. Whole blood ATP levels significantly increased with treatment, reaching a steady state by 24 hours and returning to or near baseline by 1 week after treatment. Plateau levels were 63%, 67%, and 116% above base-line at 50, 75, and 100 micrograms/kg/min, respectively. We conclude that prolonged infusions of ATP are feasible with acceptable toxicity and that 50 micrograms/kg/minute is both the MTD and the most appropriate dose rate for subsequent Phase II testing of 96-hour infusions of ATP in patients with advanced cancer. PMID- 8699995 TI - Rhabdoid tumor of the kidney: a report of two cases with respective tumor markers and a specific chromosomal abnormality, del(11p13). AB - Malignant rhabdoid tumor is a rare, aggressive, invariably lethal tumor that is resistant to multimodal treatment. In this report, two patients with malignant rhabdoid tumor of the kidney (RTK) are described. The first patient is the first case of RKT with hyperreninemia, and the second case is also the first case with a specific chromosomal abnormality, del 11p13. The first patient presented with hematuria and a mass in the left kidney. Plasma renin, angiotensin, and aldosterone levels were elevated and paralleled the tumor progression. The karyotype of the tumor cells was normal (46,XX). In the second patient, who presented with a mass in the right kidney, the concentration of plasma tissue polypeptide antigen was elevated and paralleled the tumor progression. The karyotype of the tumor cells was 46,XX, del(11)(pter-p13::p12-qter). RTK with a cytogenetic abnormality of del(11p13), which is usually found in aniridia-Wilms' tumor syndrome, has not been known. Both patients died of metastatic disease within 7 months of diagnosis in spite of the multimodal therapy. The clinicopathology of RTK and the differences between Wilms' tumor and RTK raise compelling questions which should be the subject of future studies. PMID- 8699996 TI - Multimodal management of recurrent Wilms' tumor: the role of radiation therapy. PMID- 8699997 TI - Paclitaxel-induced radiation recall dermatitis. AB - The authors present a case of radiation recall dermatitis occurring in a patient receiving paclitaxel shortly after completion of radiation therapy. A brief review of previously reported taxane-induced radiation recall reactions is provided. PMID- 8699998 TI - Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): response to methotrexate and mercaptopurine. AB - We report a 3-year-old girl presenting with bilateral cervical lymph node enlargement persisting for > 3 months. Leukocytosis, elevated erythrocyte sedimentation rate, a marked hypergammaglobulinemia, and a moderate hepatosplenomegaly were also found. The diagnosis of sinushistiocytosis with massive lymphadenopathy (SHML), also known as Rosai-Dorfman disease, was established histologically by the demonstration of characteristic sinushistiocytosis with lymphocytophagocytosis. Treatment was started with high dose steroids, and a decline of lymph node size and a normalization of laboratory parameters occurred. However, when steroids were tapered, lymph node size rapidly reincreased. Chemotherapeutic treatment was started using etoposide, which was completely ineffective. Therefore, treatment was changed to a combinatory low dose methotrexate therapy and 6-mercaptopurine for 4 months. Whereas a prompt and complete remission was reached, single 6-mercaptopurine therapy was maintained and treatment has been discontinued after a total of 2 years. The child has remained healthy for 7 years. This case would recommend the use of methotrexate and 6-mercaptopurine for treatment of complicated SHML. PMID- 8699999 TI - Pancreatoblastoma: case report and review of treatment in the literature. AB - A case of pancreatoblastoma arising from the body-to-tail of the pancreas in a 5 year-old boy is presented. The patient underwent exploratory laparotomy and, 11 days later, resection of the tumor (partial pancreatectomy, pyloroplasty, and splenectomy). Before resection, cyclophosphamide and vincristine were administered. Because of tumor spillage during resection, a combination of chemotherapy (administration of cyclophosphamide and adriamycin on that day) and postoperative radiotherapy was given. Nine months after resection, partial hepatectomy was performed for liver metastasis and consolidated by a more intensive chemotherapy regimen using cisplatin, adriamycin, vincristine, and cyclophosphamide. After completion of the chemotherapy, the patient had a 14 month uneventful course, and a locally recurrent tumor was treated by the fourth surgery (extirpation of the recurrent tumor, partial hepatectomy, partial colectomy, and partial gastrectomy) and intraoperative radiation. Thereafter, the boy has shown no evidence of disease at 3 years 8 months. The literature of pancreatoblastoma is reviewed from the therapeutic viewpoint. PMID- 8700000 TI - Multiple inflammatory fibrosarcoma of the abdominal cavity in a child. AB - Inflammatory fibrosarcoma is a rare condition in childhood. In the abdominal location, its behaviour is often aggressive and potentially metastasizing. We report a case of a 3-year-old female with abdominal inflammatory fibrosarcoma who relapsed after 1 month from radical surgery. Chemotherapy was ineffective, and we registered a brief stabilisation of disease only with alpha-IFN. Our case confirms the potential malignancy of this tumour and its resistance to treatment. It is noteworthy that the therapy with alpha-IFN improved the quality of life in this child for 4 months. PMID- 8700001 TI - Central venous catheter infection by Aspergillus fumigatus in a patient with B type non-Hodgkin lymphoma. AB - Invasive Aspergillus infection is still a major problem in immunocompromised patients. A central venous catheter infection by Aspergillus fumigatus, however, has not yet been reported. We describe the case of a 10-year-old female patient with B-type non-Hodgkin lymphoma treated according to the German chemotherapy protocol NHL-BFM 90. Isolation of Aspergillus fumigatus from the blood was the first hint of invasive aspergillosis. A central venous catheter-associated infection was suggested, since Aspergillus was also isolated from the thrombotic tip of the removed catheter. Secondary pulmonary aspergillosis was documented radiologically. The patient was treated successfully by Ampho-thericin B and Itraconazol and explantation of the central venous catheter under conditions of complete hematopoietic regeneration of the bone marrow with omission of the final chemotherapeutic cycle. PMID- 8700002 TI - International Society of Pediatric Oncology, SIOP XXVIII meeting. Vienna, Austria, October 1-5, 1996. Abstracts. PMID- 8700003 TI - [The characteristics of the topographical distribution of leishmaniasis in Turkmenistan]. AB - Long-term studies of the spread zoonotic cutaneous leishmaniasis (ZCL) and visceral leishmaniasis (VL) have revealed that the prevalence of the disease is associated with definite landscapes. ZCL is constantly notified in the valley delta, undermountainous (lowland) landscapes. VL is common in the sandy desert areas of the southeastern Kara-Kum, in the valley on Murgab, in the piedmont and low-mountainous areas of the Kopet-Dagh. The spread of ZCL coincides with the landscape P .papatasi distribution and that of VL with P.turanicus. There is cyclic recurrence in activation of a VL natural focus and an association of case histories with definite administrative areas in particular periods. PMID- 8700004 TI - [Ca++ ion transport blockers as reversants of the drug resistance of malarial parasites. 1. The effect of verapamil on the resistance to chloroquine in vivo of Plasmodium berghei and in vitro of Plasmodium falciparum]. AB - The reversing action of verapamil on the effect of chloroquine was found in in vivo experiments by using a model P. berghei resistant to chloroquine, an LNK65 isolate having a naturally lower resistance to the agent, and its polyresistant strain with the acquired resistance to chloroquine and fansidar, as well as by employing the chlorine-resistant P. falciparum isolates from the south of the Socialist Republic of Vietnam. The magnitude of this effect was related to the dose of verapamil, the frequency of administration of a combination of the agents in vivo, while that was associated to the concentration of verapamil and the level of isolate resistance to chloroquine in vitro which was the most pronounced. Taking into account the dose-dependent effect of verapamil, it can be suggested that increasing its concentration in combination with chloroquine can provide a more marked reversing action with lower chloroquine concentrations. The parameters accepted by the authors in evaluating the combined effect enable the effect of the verapamil/chloroquine concentration to be regarded as potentiation. PMID- 8700005 TI - [The effect of the dispersity of tegalid on its bioavailability]. AB - The impact of the new helminthicide Tegalide, a dibromobenzamide derivative, on its pharmacology was investigated. The agent given as a fine-dispersed form was found to be more intensively absorbed by the body and to be in animals' blood for a longer period of time (MRT fine-dispersed and MVR coarse-dispersed were 88.5 and 50.4 hours, respectively). As the fine-dispersed fraction of Tegalide increased, its bioavailability showed an equivalent increase. PMID- 8700006 TI - [The search for new antiparasitic agents. 16. A study of the anti-Fasciola activity of N-[(chloro-naphthyloxy)phenyl]benzamides]. AB - The study was undertaken to examine the fasciolacidal activity of the agents G 1411, G-1423, and G-1439. Tested, G-1439 was chosen for detailed investigations as a non-toxic fasciolacide. PMID- 8700007 TI - [The technology for manufacturing antiparasitic preparations. 5. The development of a technology for producing the anthelmintic triclonate and the evaluation of its therapeutic efficacy in monieziasis]. AB - A procedure has been developed to manufacture the anthelminthic Triclonate. The agent was tested for the treatment of sheep's natural monieziasis infection and it was found to have a high activity. PMID- 8700009 TI - [Parasitological monitoring in Russia (the bases of the concept)]. PMID- 8700008 TI - [The attraction of the female urban mosquito Culex pipiens (Diptera, Culicidae) for oviposition by different attractants]. AB - For urban female mosquitoes to lay eggs, the following potential attractants were dark containers, larval feed, ammonia solutions, larval culture medium and hay infusion were tested. The latter was found to be the best attractant since it was the most attractive and cheaper. The combination of the attractants did not enhance their efficiency. It is recommended that egg traps should be used to detect and measure the number of the mosquitos. The possibility of suppressing the quantity of the urban mosquitos by using the method is limited. PMID- 8700010 TI - [The insecticidal activity of the new combined dust Malcord]. AB - A formulation of 0.5% Malcord dust, which contains carbofos and permethrin (a 1:1 ratio) as active agents, was designed and examined. LC99 against synanthropic insects by the active ingredient was 0.01-0.005 g/m2. The effective application rate of the dust ranged 5 to 10 g/m2 in the treatment of various objects. The residual insecticidal effect of the dust on the treated surfaces remained 1.5-2.0 months (depending upon the type of an object). The dust Malcord has been permitted by the health care authorities of the Russian Federation for its usage by specialists and the population. PMID- 8700011 TI - [A histological and electron microscopic study of the kidneys in migrating ascariasis]. AB - Histological and electron microscopic techniques were used to study the structure of the kidney in migration ascariasis caused by the single or double infection of white mice with Ascaris at an interval of 14 days. The animals were autopsied on days 5-7 after single or double infection. It was found that double infection changes occur earlier (on day 2). The kidneys were ascertained to restore their structure by day 21, suggesting the reversibility of the detected changes. Such regularity has been defined before while examining the structure of the liver in ascariasis. PMID- 8700012 TI - [Immunoenzyme analysis in the diagnosis of opisthorchiasis. I. The development of an immunoenzyme method for determining IgM antibodies to the Opisthorchis antigen]. AB - An assay was developed to determine IgM antibodies to Opisthorchis felineus antigens for the diagnosis of acute infection. The method is based on indirect solid-phase enzyme immunoassay. Optimal conditions were elaborated for analysis and its high specificity and specifications are shown in the paper. PMID- 8700013 TI - [A case of Dirofilaria repens migration in man]. AB - The paper reports a case of Dirofilaria repens subcutaneous parasitism with the larva migrans phenomenon in the North Causasus area where epidemiological prerequisites are available for spread of dirofilariasis. The clinical picture, surgical intervention, and the diagnosis of the infection are presented. The parasite is defined by the authors as Dirofilaria repens. PMID- 8700014 TI - [The duration of the persistence of the plaque microbe in the body of the flea Citellophilus tesquorum altaicus]. AB - Experiments have established that the plague bacillus persists long in the flea C. tesquorum altaicus in the Tuva natural foci. Experimentally, 64.2 to 77.3% of the fleas inoculated in autumn survived winter. More than one-half preserved the plague bacillus. From 0.7 to 19.4% of the inoculated fleas survived from one summer to another. The plague persisted in 30% of the insects. Individual C. tesquorum altaicus females survived two winters, preserving the bacillus for 21.5 22.0 months. The fact that the fleas has survived both one and two winter periods in coma transmitted the plague bacillus to healthy sousliks has been recorded. Rather late periods (278-411 days) of blocking the fleas after the insects' inoculating feeding have been defined. PMID- 8700015 TI - [The epidemiological and epizootiological characteristics of leptospirosis in the Republic of Sakha (Yakutia)]. AB - Among zoonotic infections with natural foci in the Republic of Sakha (Yakutia), leptospiroses have assumed greater importance. Their morbidity is sporadic, mainly afflicting rural adults. The serogroups pomona, grippotyphosa, and icterohaemorrhagiae are prevalent in the etiological structure of leptospiras. An epizootiological survey has revealed natural and anthropurgic leptospirosis foci which present a hazard primarily to rural inhabitants who deal with animal husbandry, fur-bearer breeding, hunting, and fishing. The vole (Microtis) and root vole (Microtis oeconomus) serve as the major reservoir and source of leptospiroses in the natural foci, while cattle and caged Arctic foxes do in the anthropurgic ones. High sizes of house and grey mice which are carriers of the Leptospira javanica and icterohaemorrhagiae, have been recorded in the residential and domestic constructions of localities. A complex of antileprospirotic measures that limits the influence of the leading factors of infection transmission and the risk of human infection is substantiated. PMID- 8700016 TI - [The spread of the principal socially important parasitic disease on the territory of the Chukot Autonomous Okrug (ChAO)]. AB - The paper provides the examination findings of helminthiases in the population of the town of Anadyr, the settlements of Kanchalan, Krasneno, and in the reindeer breeding teams of the Anadyr District, CAD. The children infected with enterobiasis were shown to amount to 15.1 to 22.9%, diphyllobothriasis was detected in 12.9 - 33.7% of the examinees. Single cases of ascariasis were revealed. Analysis of 232 cases with echinococcosis demonstrates that the infection is prevalent over the whole Chukotka territory. Infection with Echinococcus multilocularis is more common in the indigenous population in the north-east of the District and that with Echinococcus granulosus in the central and northern regions. High extensive and intensive parasitic contamination rates of environmental objects, such as soil, sewage, household appliances, fish, etc., were noted, indicating a constant risk for Chukotka population's infection with parasites. PMID- 8700017 TI - [The information value of a method of examining for helminthiasis using an ocular spatula with an adhesive layer]. AB - The paper outlines a new method for examining the population and animals for some helminthiases and results of its testing in different cities and towns of the Russian Federation and Kazakhstan. The recommended method is shown to be of high informative value, easy-to-use, hygienic, and efficient. It should be more widely used to diagnose enterobiasis, Taeniarhynchus infection in human beings and taeniasis and nematodiases (toxocariasis) in animals. The method has been approved by the Ministry of Health of the Russian Federation and recommended for its use at the Health care institutions and centers of sanitary and epidemiological surveillance. PMID- 8700018 TI - [American trypanosomiasis (Chagas disease)]. PMID- 8700019 TI - [Parasitoses of the wild, domestic and agricultural animals of the Moscow megapolis]. PMID- 8700020 TI - Generation of arbitrary intensity profiles by combining the scanning beam with dynamic multileaf collimation. AB - An algorithm, which combines the scanning beam with dynamic collimation to generate any arbitrary intensity profile, is presented. The desired intensity profile is assumed to be piecewise linear. The dynamic collimation method used is the "sliding window." The algorithm can be used either for a given scanning beam profile or to simultaneously determine the scanning beam profile and the leaf motions required to generate the desired intensity profile, which minimize the total treatment time. The limitations imposed by the physics of an elementary beam are taken into account. The algorithm is an iterative one, with typical calculation times being of the order of a few milliseconds. PMID- 8700021 TI - A new way of averaging with applications to MRI. AB - Averaging is often used to increase the quality of an image degraded by noise or artifacts. A method is developed in which several degrees of freedom are introduced in the averaging process, this freedom making possible the choice of different weighting factors for different portions of the Fourier space. If a weighting factor is associated with each line of a magnetic resonance acquisition, we show that we obtain some freedom to eliminate motion artifacts. The process minimizes a quantity called the gradient energy over a region of interest in the image plane. A processed image is obtained from a mosaic of such regions of interest scanned over the whole image plane. The method is shown to yield greater motion artifact suppression in magnetic resonance images than that achieved with regular averaging. The main strength of the method is probably its ability to diminish the intensity of unstructured artifacts which are usually poorly managed by other postprocessing methods of artifacts suppression. PMID- 8700022 TI - Quantification of multiple sclerosis lesion volumes in 1.5 and 0.5 T anisotropically filtered and unfiltered MR exams. AB - Recently, guidelines for the use of MRI in the monitoring of MS have recommended the use of imaging systems with mid-field (0.5-1.0 T) or high-field (greater than 1.0 T) strengths. Higher field strengths provide many advantages, including increased signal-to-noise ratios (SNR). SNR also may be increased by post processing algorithms that reduce noise. In this paper we evaluate the impact on operator variability of (a) lesion quantification in high-field (1.5 T) versus mid-field (0.5 T) exams; and (b) an anisotropic diffusion filter algorithm that reduces image noise without blurring or moving object boundaries. Inter- and intra-operator reliability and variability were studied using repeated quantification of lesions in 1.5 and 0.5 T filtered and unfiltered MR exams of a MS patient. Results indicate that inter-operator variability in 1.5 T unfiltered exams was 0.34 cm3 and was significantly larger than that in 1.5 T filtered (0.27 cm3), 0.5 T unfiltered (0.26 cm3), and 0.5 T filtered (0.24 cm3) exams. Similarly, intra-operator variability in 1.5 T unfiltered exams was 0.23 cm3 and was significantly larger than that in 1.5 T filtered (0.19 cm3), 0.5 T unfiltered (0.19 cm3), and 0.5 T filtered (0.18 cm3) exams. In addition, the minimum significant change between two successive measurements of lesion volume by the same operator, was 0.64 cm3 in 1.5 T unfiltered exams, but 0.53 cm3 or less in other exams. For two different operators making successive measurements, the minimum significant change was 0.94 cm3 in 1.5 T unfiltered exams, but only 0.75 cm3 or less in other exams. Finally, the number of lesions to be monitored for an average change in volume at a given power and significance level was greater by 30%-60% for quantification in 1.5 T unfiltered exams. These results suggest that inter- and intra-operator variability are reduced by anisotropic filtering, and by quantification in 0.5 T exams. Reduced operator variabilities may result from higher detail signal-to-noise ratios (dSNRs) in 0.5 T and filtered exams. PMID- 8700023 TI - The effects of lossy compression on the detection of subtle pulmonary nodules. AB - We examined the ability of radiologists to detect pulmonary nodules in computed radiographic (CR) chest images subjected to lossy image compression. Low-contrast 1-cm diameter targets simulating noncalcified pulmonary nodules were introduced into clinical images and presented to ten radiologists in a series of two alternative forced-choice (2AFC) observer experiments. The percentages of correct observer responses obtained while viewing noncompressed images (1:1) were compared with those obtained for the same images compressed 7:1, 16:1, 44:1, and 127:1. The images were compressed using a standard full-frame discrete cosine transform (DCT) technique. The degree of compression was determined by quantizing Fourier components in various frequency channels and then Huffman encoding the result. The data show a measurable decline in performance for each compression ratio. Through signal-to-noise ratio (SNR) analysis, we found that the reduction in performance was due primarily to the compression algorithm that increased image noise in the frequency channels of the signals to be detected. PMID- 8700024 TI - Automatic correction of biplane projection imaging geometry. AB - A novel method is presented for correcting errors in measurements of biplane projection imaging geometry without prior identification of corresponding points in the two images. For imaged objects that project onto both images, a constraint equation is obtained that relates weighted integrals along corresponding epipolar lines. The integrals are computed to first order in the angular beamwidth, which is assumed to be small. Starting from measured or estimated values, geometrical parameters are computed iteratively in order to maximize the correlation between epipolar line integrals in the two images. Improvement in the computation of corresponding epipolar lines is demonstrated on images of a wire phantom. The root mean square distance of the epipolar lines from the corresponding reference points is improved from 15 pixel widths to less than 4 pixel widths (1.3 mm). Convergence is demonstrated on phantom images for individual parameter variations up to 70% in relative magnification, a relative shift of the imaging planes by 50 pixels, or a relative rotation of at least 35 degrees around either of two axes. Applicability to clinical images is demonstrated by using a biplane angiogram of a pig to align corresponding points determined from images of a Perspex cube acquired with the same geometry. PMID- 8700025 TI - Mammography fixed grid versus reciprocating grid: evaluation using cadaveric breasts as test objects. AB - In this study we use unfixed cadaveric breasts to obtain mammography images with fixed and reciprocating grids. Sheets of acrylic, containing one or more clusters of simulated calcifications and masses, were superimposed on two fresh cadaveric breasts (3.4 and 6.5 cm thick), and were imaged with a fixed grid and a reciprocating grid. Six radiologists, working independently, attempted to identify the number of clusters and/or masses in 114 images containing 139 clusters of simulated calcifications and 42 simulated masses. Thirty-four of these images were normal, containing no lesions. For the thinner breast, no statistically significant difference was found in the detection of clusters of calcifications in the images produced with the fixed grid compared to those produced with the reciprocating grid. However, for the detection of calcifications in images of the thicker breast, sensitivity of 74% for detection of calcifications when a fixed grid was used was significantly less than sensitivity of 86% when a reciprocating grid was used (P = 0.006). The mass detection sensitivity was 91% for images made with a fixed grid compared to 96% for images made with a reciprocating grid, but the difference was not statistically significant (P = 0.346). The use of cadaveric breasts as test objects was well accepted by radiologists. Only for the thick cadaveric breast were differences between the two grids significant, and these differences were restricted to the task of finding calcifications. PMID- 8700026 TI - Frequency-domain optical mammography: edge effect corrections. AB - We have investigated the problem of edge effects in laser-beam transillumination scanning of the human breast. Edge effects arise from tissue thickness variability along the scanned area, and from lateral photon losses through the sides of the breast. Edge effects can be effectively corrected in frequency domain measurements by employing a two-step procedure: (1) use of the phase information to calculate an effective tissue thickness for each pixel location; (2) application of the knowledge of tissue thickness to calculate an edge corrected optical image from the ac signal image. The measurements were conducted with a light mammography apparatus (LIMA) designed for feasibility tests in the clinical environment. Operating in the frequency-domain (110 MHz), this instrument performs a transillumination optical scan at two wavelengths (685 and 825 nm). We applied the proposed two-step procedure to data from breast phantoms and from human breasts. The processed images provide higher contrast and detectability in optical mammography with respect to raw data breast images. PMID- 8700027 TI - Chelator effect on ion diffusion in ferrous-sulfate-doped gelatin gel dosimeters as analyzed by MRI. AB - Ferrous-sulfate-doped gelatin gel dosimeters are useful tools for the measurement of three-dimensional absorbed radiation dose distributions. The diffusion of ferric ions through these gels causes degradation with time of the dose distribution image. It would be useful to reduce ferric ion diffusion without decreasing gel sensitivity. The amount of ferric ion diffusion is a function of the time delay after radiation, the gel temperature, and the gel concentration. These effects can be quantified by measuring the ferric ion diffusion coefficient. Determination of the diffusion coefficient by irradiating the lower section of a cylinder of gel, which was then imaged repeatedly over time with a clinical magnetic resonance imager, is described. Analysis of the edge spread function formed at each of several times after irradiation by drawing a profile over the imaged junction between the irradiated and unirradiated halves of the cylinder, gave estimates of the variance of the edge spread function. These variances were used to obtain an estimate of the ferric ion diffusion coefficient for the gel. A method of reducing ferric ion diffusion by adding a chelator and the cross linkage agent formaldehyde is suggested. The chelators investigated were 1,10 phenanthroline, xylenol orange, and bathophenanthroline disulfonic acid. These reduced diffusion to varying extents, and influenced the gel sensitivity. The diffusion coefficient in gels containing xylenol orange was found to be 0.44 mm2h-1. The gel sensitivity was 0.0093 s-1Gy-1. This compared with a diffusion coefficient of 0.82 mm2h-1 for the base line gel that did not contain formaldehyde or chelators. The sensitivity of this base line gel was 0.0129 s-1Gy-1. The addition of xylenol orange produced the most improved gel dosimeter of the gels studied. This gel had a decreased ferric ion diffusion coefficient and a decreased sensitivity. It was still sensitive enough to be useful. PMID- 8700028 TI - Dosimetry of [15O]water: a physiologic approach. AB - Earlier dosimetry estimates for [15O]water assumed its instantaneous equilibrium with total body water. This assumption leads to an underestimation of the absorbed doses to organs with high blood flows, since the biodistribution of this short-lived radiopharmaceutical is dependent upon blood flow to organs. We have developed a physiologically based whole body blood flow model (WBBFM) using a commercially available icon-driven mathematical simulation software package and applied it to the reevaluation of [15O]water dosimetry in humans. The WBBFM uses multiple parallel compartments to represent organs, heart chambers, the injection site for [15O]water, and blood sampling sites (arterial and venous). Input values to the WBBFM include organ blood flows, organ masses, organ water volumes, organ:blood partition coefficients, injected activity and S-values of [15O]. The WBBFM is based on the same assumptions that are used in calculating regional blood flow using [15O]water and simulates the human body closely in its physiologic response. The activity in each organ is derived from the simulation and is used to calculate absorbed doses. The WBBFM calculated absorbed doses in microGy/MBq (mrad/mCi) to various organs are as follows: heart--2.66 (9.84), kidneys--2.20 (8.15), thyroid--1.83 (6.78), brain--1.66 (6.13), ovaries--1.25 (4.61), breast--1.24 (4.59), and small intestine--1.03 (3.83). These values are approximately two- to threefold higher than the earlier estimates of Kearfott [J. Nucl. Med. 23, 1031-1037 (1982)] and similar to the recent findings of Herscovitch et al. [J. Nucl. Med. 34, 155P (1983)]. We believe this approach yields more realistic dosimetry estimates for [15O]water. Accordingly, we have revised the amount of [15O]water administered during regional blood flow studies at our institution. The relative ease and accuracy of this approach suggests its usefulness in dosimetry estimation for other freely diffusible radiopharmaceuticals. PMID- 8700029 TI - A bound on the energy resolution required for quantitative SPECT. AB - Scattered radiation is one of several physical perturbations that limit the accuracy of quantitative measurements in single-photon emission computed tomography (SPECT). Improvement in detector energy resolution leads to a reduction of scatter counts and a corresponding improvement in the quantitative accuracy of the SPECT measurement. In this study, simulated SPECT projections of a simple myocardial perfusion phantom were used to investigate the effect of detector energy resolution on the data. The phantom consists of a spherical shell of radionuclide within a 15 cm radius water-filled cylinder. Each projection contains on the order of 3 x 10(5) counts. The results demonstrate that a full width, half-maximum energy resolution of 3-4 keV is sufficient to render the error due to scatter insignificant compared to the uncertainty due to photon statistics in this case. Further simulations verify that because smaller objects produce less scatter, they can be imaged accurately with degraded energy resolution. These results are useful when designing prototype systems that utilize solid-state detectors and low-noise electronics to achieve improved energy resolution. PMID- 8700030 TI - kQ factors for ionization chamber dosimetry in clinical proton beams. AB - We discuss a formalism for clinical proton beam dosimetry based on the use of ionization chamber absorbed dose-to-water calibration and beam quality correction factors. A quantity kQ, the beam quality correction factor, is defined which corrects the absorbed dose-to-water calibration factor ND,w in a reference beam of quality Q0 to that in a user's beam of quality Q1. This study of proton beam quality correction factors used 60Co (kQ gamma) and proton (kQp) reference beams. The kQ gamma factors were measured using combined water calorimetry and ionometry for PTW and Capintec-Farmer-type ionization chambers, and were computed from standard dosimetry protocols. Agreement between measured and calculated kQ gamma values for both chambers was found within 1.2% in the plateau region for a monoenergetic 250-MeV beam and within 1.8% at the spread-out Bragg peak for a 155 MeV range-modulated beam. Comparison of absorbed doses to water determined in the range-modulated 155-MeV beam was performed with the PTW chamber using three calibration methods: Ngas calibration (AAPM Report 16), ND,w,gamma calibration in a 60Co beam in conjunction with a kQ gamma factor, and ND,w,p calibration in a proton beam in conjunction with a kQp factor. Absorbed doses to water obtained with the three methods agreed within 2% when ionization chamber dosimetry data were analyzed using the proton W-value for air from the AAPM Report 16 and the ICRU 49 proton stopping powers. The use of the proton-calibrated reference ionization chamber, in conjunction with the beam quality correction factor kQp, significantly reduced the systematic uncertainty of the absorbed dose determination. PMID- 8700031 TI - Electron dose profile shaping by modulation of a scanning elementary beam. AB - The use of multiple high energy electron beams has been limited in the treatment of deep seated tumors. This is principally because of the rapid increase in the physical electron beam penumbra as a result of the rise in large angle scattering with depth in the patient. This decreases the transverse dose gradient between the target volume and sensitive dose limiting structures and diminishes the ability to conform electron isodose lines to the target volume. If the beam is flat in air, then its profile will become progressively more rounded with depth, due to the increase of scatter out of the beam edges. With a scanning elementary electron beam, such as produced by the Microtron MM50, the characteristics of a broad beam profile are determined by the scan pattern. Using an appropriate scan pattern one can create, at any depth within the range of electrons, various dose profiles with the sharpness not exceeding that of the elementary beam. The objective of this work was to study methods that produce the desired electron beam profile at the depth of the target volume, and to derive the surface fluence profile required. Two approaches were explored to modulate the elementary beam distribution: "amplitude modulation" (AM) and "frequency modulation" (FM). We calculated coordinate and intensity distributions of the 25, 40, and 50 MeV elementary beam pulses at the surface that would yield a flat field at various prescribed depths. The results are in good qualitative agreement with iterative deconvolution calculations by Brahme et al. [Acta Radiol. Oncol. 19, 305-319 (1980)]. The scattering penumbra between the 50%-90% isodose lines can be reduced by up to 40% by beam modulation. The modulation should also enable the combination of multiple electron beams so as to achieve the desired conformal isodose profile as is customarily seen with photon beam planning, but with greater normal tissue sparing due to higher electron longitudinal depth--dose gradients. The results can be also used for electron accelerators that do not use a scanning elementary beam. PMID- 8700032 TI - A new miniature x-ray source for interstitial radiosurgery: device description. AB - A device that generates low-energy x rays at the tip of a needle-like probe was developed for stereotactic interstitial radiosurgery. Electrons from a small thermionic gun are accelerated to a final energy of up to 40 keV and directed along a 3 mm outside diameter drift tube to a thin Au target, where the beam size is approximately 0.3 mm. All high-voltage electronics are in the probe housing, connected by low-voltage cable to a battery-operated control box. X-ray output, which is nearly isotropic, consists of a bremsstrahlung spectrum and several lines between 7 and 14 keV, with characteristic radiation contributing 15% of the total energy output. To date, 14 patients with metastatic brain tumors have been treated with this device. PMID- 8700033 TI - A new miniature x-ray device for interstitial radiosurgery: dosimetry. AB - A miniature, battery operated 40 kV x-ray device has been developed for the interstitial treatment of small tumors ( < 3 cm diam) in humans. X rays are emitted from the tip of a 10 cm long, 3 mm diameter probe that is stereotactically inserted into the tumor. The beam, characterized by half-value layer (HVL), spectrum analysis, and isodose contours, behaves essentially as a point isotropic source with an effective energy of 20 keV at a depth of 10 mm in water. The absolute output from the device was measured using a parallel plate ionization chamber, modified with a platinum aperture. The dose rate in water determined from these chamber measurements was found to be nominally 150 cGy/min at a distance of 10 mm for a beam current of 40 microA and voltage of 40 kV. The dose in water falls off approximately as the third power of the distance. To date, 14 patients have been treated with this device in a phase I clinical trial. PMID- 8700034 TI - Scattered radiation in portal images: a Monte Carlo simulation and a simple physical model. AB - The scattered radiation in 6 MV radiotherapy portal images is analyzed. First, a quantity SPR* is studied, by means of Monte Carlo (MC) modeling. SPR* is defined as the ratio, on the central axis, of the signal due to scattered radiation to that due to the primary radiation. The detector model mimics a high-energy photon detector in the context of transit dosimetry. Second, a physical model of SPR* has been developed from first principles. For a cylindrical phantom, placed symmetrically about the isocenter, it predicts that SPR* depends on the area A at the isocenter of the circular field and the phantom thickness d as follows. SPR* = k0Ad(1 + k1d)(1 + k2A), where k0 = 0.0266(L1 + L2)2/(L1L2)2, k2 = - [L1(-2) + L2(-2) + (L1(-1) + L2(-1))2((2/3) + (3 kappa/2))]/2pi, L1 is the source-to isocenter distance, L2 is the isocenter-to-detector distance, and kappa is the mean energy of the radiation beam (MeV/0.511). Constant k1, for which there is no simple expression, depends on L2. Comparison to the MC data shows that for 60 or= 50 cm. Third, experimental measurements of the scatter-to-primary ratio were obtained using our custom built imaging system mounted on a Philips SL25 linear accelerator. In the first experiment, A was varied from 40 to 400 cm2 with L1 = L2 = 100 cm with d = 20 cm. In the second experiment water depth d was varied from 0 to 28 cm with L1 = L2 = 100 cm and A = 200 cm2. The rms agreements between the MC data and the experiments were 0.0015 and 0.0045, respectively. PMID- 8700035 TI - A grey-level image alignment algorithm for registration of portal images and digitally reconstructed radiographs. AB - An algorithm for automatic registration of pairs of portal images based on image correlation is presented. It uses a fast-Fourier-transform-based cross correlation operator to find the optimal registration, accounting for both in plane translations and rotations. Different cross-correlation operators have been tested: the Pearson linear correlation coefficient has been implemented by fast Fourier transform and its performance has been compared to that of the more conventional normalized cross-correlation. A sequential approach has been applied to speed up the registration considerably without degrading the performance of the algorithm. The algorithm has also been applied to the automatic registration of portal images to digitally reconstructed radiographs (DRRs), which have been modified to resemble megavoltage images. The results are indicative of the feasibility of this approach to the inspection of patient setup in radiation therapy. PMID- 8700036 TI - The variability of manual and computer assisted quantification of multiple sclerosis lesion volumes. AB - The high resolution and excellent soft tissue contrast of Magnetic Resonance Imaging (MRI) have enabled direct, noninvasive visualization of Multiple Sclerosis (MS) lesions in vivo. This has allowed the quantification of changes in the appearance of lesions in MR exams to be used as a measure of disease state. Nevertheless, accurate quantification techniques are subject to inter- and intra operator variability, which may hinder monitoring of disease progression. We have developed a computer program to assist an experienced operator in the quantification of MS lesions in standard spin-echo MR exams. The accuracy of assisted and manual quantification under known conditions was studied using exams of a test phantom, while inter- and intra-operator reliability and variability were studied using exams of a MS patient. Results from the phantom study show that accuracy is improved by assisted quantification. The patient exam results indicate that assisted quantification reduced inter-operator variability from 0.34 to 0.17 cm3, and reduced intra-operator variability from 0.23 to 0.15 cm3. In addition, the minimum significant change between two successive measurements of lesion volume by the same operator was 0.64 cm3 for manual quantification and 0.42 cm3 for assisted quantification. For two different operators making successive measurements, the minimum significant change was 0.94 cm3 for manual quantification, but only 0.47 cm3 for assisted quantification. Finally, the number of lesions to be monitored for an average change in volume at a given power and significance level was reduced by a factor of 2-4 by assisted quantification. These results suggest that assisted quantification may have practical applications in clinical trials, especially those that are large, multicenter, or extended over time, and therefore require lesion measurements by one or more operators. PMID- 8700037 TI - Analytic representation of the dose from a 32P-coated stent. AB - The dose along the radial direction located at the midplane of a radioactive stent, simulated by a uniform cylinder of 32P, is represented by an analytical function consisting of the sum of two modified exponentials. This procedure reproduces values obtained from numerical integration, for which no closed form exists, to within 5% for distances up to 6 mm from the wall and for stent diameters from 2-6 mm. PMID- 8700038 TI - Robust three-dimensional object definition in CT and MRI. AB - This work describes the application of an object definition algorithm to the medical imaging environment for the task of automated detection of anatomical boundaries in three dimensions in the presence of low spatial frequency nonstationarities. We have chosen the Liou-Jain algorithm and have modified it for use with 3D medical image datasets and extended it by including a recruitment operator that corrects for the algorithm's inherent volume underestimation. The algorithm avoids problems in both traditional statistical segmentation and 2D techniques and elegantly bridges the gap between traditional gradient-based edge finding and regression-based segmentation techniques. Results are shown for MRI datasets from the human abdomen and brain and for a CT dataset of a liver tumor, as well as an MRI scan of a glioma in a rat brain. For comparison, the human abdomen dataset was processed by a multivariate, statistical classifier. The results demonstrate the statistical technique's susceptibility to low spatial frequency nonstationarities due to rf field inhomogeneity; the Liou-Jain algorithm is shown to be immune to this effect. Further, the results show spatial consistency as a result of inherent characteristics of the algorithm. Volumes identified by the algorithm are visualized and assessed qualitatively in three dimensions. Quantitative accuracy of the algorithm's volume estimates is assessed by the use of a phantom. This work demonstrates that this technique is effective in automatically detecting anatomical organ and lesion surfaces in 3D medical datasets that are corrupted by low spatial frequency nonstationarity and in obtaining volume estimates. PMID- 8700039 TI - Lead effects on the brain stem auditory evoked potential in monkeys during and after the treatment phase. AB - Rhesus monkeys were pre- and postnatally exposed to either 0, 350, or 600 mg lead acetate/kg diet continuously until the age of about 9.75 years. At the age of 8 8.25 years (Experiment 1) and 9.25-9.5 years (Experiment 2) brain stem auditory evoked potentials (BAEPs) were recorded. Blood lead levels at the time of testing were about 5, 35, or 55 micrograms/dl for controls, the 350-mg group and the 600 mg group, respectively. There were no clinical signs of intoxications. Clicks varying in sound pressure level (SPL) and rate were used to elicit BAEPs. In addition, the influence of different levels of masking noise was explored in Experiment 1. Four early prominent waves were detected in accordance with other studies of the monkey BAEP. The most reliable wave was No. II. Latencies in the BAEP exhibited the known dependencies on parametric variation for SPL, stimulus rate, and masking level. The 600-mg group exhibited the longest latencies at all stimulus conditions. Analysis of wave II and IV latencies revealed a significant main effect for lead on wave II. At the rate condition there were also signs of latency decreases in the 350-mg group that did not reach significance. Therefore, repetition rate was varied on all SPLs in Experiment 2 to assess the reliability of this effect because similar observations were reported in lead-exposed children. There was no indication of reduced latencies using this extended design. In contrast, significant lead-induced increases in latencies of waves I, II, and IV were revealed by multivariate ANOVA. The purpose of Experiment 3 was to examine whether these results were dependent on current exposure or persisted after cessation of lead treatment. It started 18 months after the end of lead feeding, when blood lead levels had declined to nearly normal values. The same lead-related effects were detected as in the previous experiments. Taken together, these results indicate consistent prolongations of latencies in the BAEP due to subtoxic lead exposure that are not dependent on current treatment. The results are compared to the effects found in epidemiological studies in lead exposed children. PMID- 8700040 TI - An in-depth analysis of lead effects in a delayed spatial alternation task: assessment of mnemonic effects, side bias, and proactive interference. AB - This study examined the effects of chronic postweaning lead (Pb) exposure in Long Evans rats on a series of spatial alternation tasks. All tasks were administered in automated testing chambers, with a nosepoke as the critical response. While neither Pb-exposed group (median blood lead levels: 19 and 39 micrograms/dl, respectively) was impaired in learning the alternation rule, both groups performed more poorly than controls on the alternation task with variable intertrial delays (0, 10, 20, and 40 s). The deficit was constant across delays, arguing against memory dysfunction. Analyses of the responses on individual trials shed further light on the impaired and spared processes in the Pb-exposed rats. First, these analyses revealed stronger side biases in the higher exposure group. One interpretation is that these animals experienced impatience when the longer delays were included, making it more difficult for them to inhibit a prepotent response to a preferred side. In contrast, these trial-by-trial analyses revealed that several other factors-retention interval, semantic proactive interference, and temporal discriminability-exerted similar effects on performance in the control and lead-exposed animals. The use of logistic regression for these trial-by-trial analyses provided a means of simultaneously assessing the influence of several variables on performance, a significant advantage when there is confounding or interactions between variables. PMID- 8700041 TI - In utero lead exposure in squirrel monkeys: motor effects seen with schedule controlled behavior. AB - Timed-pregnant squirrel monkeys were exposed orally to lead during the last 1/2 to 2/3 of gestation such that maternal lead levels ranged from 21 to 70 micrograms/dl in blood. Offspring of these lead-exposed monkeys were compared to gender-matched, untreated controls (blood-lead levels from 4 to 9 micrograms/dl), born at about the same time. When the monkeys were 3 to 7 years old they were trained to pull a T-shaped bar against 1 kg spring through a displacement of 1 cm. This performance was examined during acquisition of different fixed-ratio (1, 5, and 20) and fixed-interval (120", 300", and 600") schedules of reinforcement and during steady state under the fixed-ratio 5 and fixed-interval 600". Monkeys exposed prenatally to lead showed an increased number of responses failing to meet the requirement of pulling against 1 kg spring through a 1 cm displacement when behavior was maintained by a fixed-ratio schedule, which engenders a vigorous, high-rate pattern of responding. This increased number of incomplete responses first appeared in the acquisition of a fixed-ratio 5 and fixed-ratio 20 schedules of reinforcement, remained after the fixed-ratio 5 schedule was allowed to reach steady state, and did not appear under the fixed-interval schedule. Neither body weight not response rate were affected by lead, but it was necessary to control for these variables using multiple regression to isolate lead's effect. The appearance of incomplete responses while the monkeys pulled vigorously against a 1 kg spring suggests that lead exposure during gestation produced subtle motor impairments years after exposure has ended. Deficits in the acquisition of behavior (learning) under Concurrent Random Interval schedules of reinforcement have also been reported with these monkeys. Together, these reports reveal prolonged deficits in learning and motor function resulting from in utero exposure to lead at maternal blood lead levels (21-70 micrograms/dl) that could result from exposure to ambient air in heavily polluted urban environments or in occupational settings meeting current World Health Organization standards. PMID- 8700042 TI - Effects of prenatal ethanol exposure on dopamine systems in C57BL/6J mice. AB - Young rats prenatally exposed to ethanol exhibit heightened responses to dopaminergie (DA) drugs, altered brain concentrations of dopamine, and its metabolite dihydroxyphenylacetic acid (DOPAC), and transient reductions in DA receptor binding. Adult mice exposed to ethanol prenatally also exhibit increased responses to DA drugs; however, brain concentrations of DA and DOPAC are unaltered. The effects of prenatal ethanol exposure on DA or DOPAC concentrations in young mice or on DA receptor binding in mice of any age are unknown. Therefore, to determine if the different effects of prenatal ethanol exposure on rats and mice are due to age at time of testing or species, we determined its effects on DA concentrations and turnover in young mice under conditions previously reported for adult offspring and on DA D1 and D2 receptor binding in both young and adult offspring. Consistent with our previous report for adult offspring, prenatal ethanol exposure did not alter DA concentrations or turnover. The treatment did, however, diminish periadolescent growth as previously reported and produced a transient increase in DA D1, but not DA D2 receptor binding. DA receptor binding was not altered in adult offspring. Although unrelated to prenatal ethanol exposure, the sexes differed on all of the DA measures. Combined with previous reports, the present study suggests that species rather than age is more likely to account for the different effects of prenatal ethanol exposure on DA systems, and that sex differences in DA systems should be further examined. PMID- 8700043 TI - Prenatal haloperidol reduces the number of active midbrain dopamine neurons in rat offspring. AB - The dopamine (DA) receptor antagonist, haloperidol (HAL, 1.25 or 5 mg/kg), or vehicle, dimethyl sulfoxide (DMSO), was administered (SC) daily to pregnant Sprague-Dawley dams from gestational day (GD) 8 to GD 20. The average body weight of 2-week-old male offspring was significantly lower in all of the HAL-treated groups relative to controls. In extracellular electrophysiological studies, the male 2-week-old offspring from all HAL treatment groups were found to have significantly reduced average numbers of spontaneously active midbrain dopamine (DA)-containing neurons in both the substantia nigra (A9) and the ventral tegmental area (A10) relative to controls. In DA neurons classified as bursting neurons, HAL exposure (5 mg/kg) caused a significantly increased level of burst activity in A10 but not A9 DA neurons relative to controls. For both the A9 and A10 regions, the proportion of DA neurons classified as bursting or nonbursting was unaffected by HAL treatment. These results suggest that prenatal HAL exposure influences the development of midbrain DA neurons. PMID- 8700044 TI - Effects of prenatal ethanol exposure and early experience on home-cage and open field activity in mice. AB - -C57BL/6 mice were intubated from gestational day 14-18 twice daily with 1.58 g/kg ethanol, 4.2 g/kg sucrose, or remained untreated. Offspring of ethanol treated or lab chow control groups were raised either by group-housed dams and weaned on postnatal day (PND) 28 or by individually housed dams and weaned on PND 21. Offspring of the sucrose control group were raised by individually housed dams and weaned on PND 21. Groups did not differ in pup weight or litter size. Offspring were assessed for home-cage activity (PND 36-38) and open-field behavior (PND 40-42). Mice prenatally exposed to ethanol showed increased activity in their home cages, whereas open-field behavior was generally not different from that of control groups. Conversely, different preweaning rearing conditions had affected open-field behavior, but not home-cage activity. In conclusion, home-cage behavior was a sensitive paradigm for detecting hyperactivity subsequent to a relatively low dose of prenatal ethanol in mice, and communal nesting/late weaning vs. individual nesting/ standard weaning may be a useful preweaning environmental manipulation to study possible modifications of prenatal neurobehavioral effects. PMID- 8700045 TI - Dearomatized white spirit inhalation exposure causes long-lasting neurophysiological changes in rats. AB - Exposure for 6 h per day, 5 days per week, during a period of 6 months to the organic solvent dearomatized white spirit (0, 400, and 800 ppm) was studied in rats that were 3 months old when the repeated exposure was initiated. After an exposure-free period of 2-6 months duration, neurophysiological, neurobehavioral, and macroscopic pathologic examinations were performed. The study revealed exposure-related changes in sensory evoked potentials and a decrease in motor activity during dark (no light) periods but no white spirit-induced changes in learning and memory functions. The measurements of the flash evoked potential (FEP), somatosensory evoked potential (SEP), and auditory brain stem response (ABR) all demonstrated dose-dependent increases of the amplitudes of the early latency peaks of the sensory evoked potentials (EPs). Furthermore, an increase of the dose showed that the measurements of FEP and SEP revealed changes in the later-latency peaks, which reflect the more associative aspects of sensory processing. The results demonstrated that 6 months of exposure to dearomatized white spirit induced long-lasting and possible irreversible effects in the nervous system of the rat. PMID- 8700046 TI - Effects of inhaled 1,1,1-trichloroethane on locomotor activity in mice. AB - To quantify the motoric effects of an abused solvent, photocells were added to two exposure systems. The first system utilized a static exposure chamber that recirculated vapor-laden air. A second dynamic system allowed for removal of waste gases with replenishment of fresh air combined with test vapors. In the present studies, male mice were examined for effects on locomotor activity following 30-min inhalation exposures to several concentrations of 1,1,1 trichloroethane (TCE), a widely used and abused solvent. TCE produced significant increases in locomotor activity at intermediate concentrations. Minimally effective concentrations for activity-increasing effects in the dynamic and static systems were 1,250 ppm and 2,500 ppm, respectively. At higher concentrations, motor activity was decreased with the highest dynamic system concentration (10,000 ppm), resulting in 26% of baseline control values. Biphasic, motor activity increasing and decreasing effects of TCE as a function of exposure concentration may reflect the CNS-depressant drug-like effects of abused solvents. PMID- 8700047 TI - A comparison of standing steadiness measurements from two devices: covariates and normal values. AB - Quantifying standing steadiness may be a useful method of detecting neurotoxicity in epidemiological studies. Unfortunately, use of quantitative standing steadiness outcomes in epidemiologic studies has been limited by lack of standardization of methods, insufficient availability of normative data, and inadequately characterized effects of covariates. Additionally, the current gold standard method, the force platform (FP), has been expensive and unwieldy for use in field studies. A relatively inexpensive and portable head position monitor (HPM) has been introduced as an alternate method for measuring standing steadiness. In this study 211 subjects were tested with one or both devices using a common testing protocol. The correlations between measurements obtained with the FP and the HPM were high and similar to those obtained during repeated measurements with each device separately. The effects of potential covariates on outcome measures were investigated. There was significant age x sex interaction in the FP standing steadiness measurements in this population with decreased steadiness among older men but not older women. Information for estimating normal values for the outcome measures is provided. This study suggests that measures of standing steadiness obtained with the HPM are similar, but not identical, to measures obtained with a conventional FP and that the HPM may be useful in field studies of occupational exposure to neurotoxicants. PMID- 8700048 TI - Effects of inhalation of cadmium on the rat olfactory system: behavior and morphology. AB - To investigate the effects of cadmium on olfaction, two separate studies were conducted in which male adult rats were exposed to CdO, via inhalation, for 5 h per day, 5 days a week for 20 weeks. Target exposure values of 250 and 500 micrograms/m3 were measured at 200 and 325 micrograms/m3 for the low concentration in two experiments, and 550 and 660 micrograms/m3 for the high concentration. Prior to exposure, olfactory thresholds were obtained using a conditioned suppression technique. After 20 weeks of cadmium exposure, there was no evidence of anosmia in any of the rats nor were there any significant changes observed in olfactory thresholds. Although olfaction was not impaired, cadmium levels in the olfactory bulbs of exposed rats were significantly elevated compared to controls. Cardiac and respiratory histopathology were observed at all exposure levels, but there was no evidence of nasal pathology related to exposure to cadmium. Failure of cadmium to produce olfactory dysfunction may be due to the protective effects of metallothionein and/or to the highly resilient nature of the rodent olfactory system. PMID- 8700050 TI - The 1995 A.S.P.E.N. Standards for Nutrition Support: Hospitalized Patients. PMID- 8700049 TI - Acute trimethyltin exposure produces nonspecific effects on learning in rats working under a multiple repeated acquisition and performance schedule. AB - Previous research has explored the adverse effects of trimethyltin (TMT) on learning and memory in laboratory animals. Virtually all studies of TMT effects on learning have not, however, included appropriate controls to establish a selective effect on learning. This experiment investigated the effects of TMT on the repeated acquisition (learning) and performance of response sequences. Adult male Long-Evans rats, maintained at 300 g b.wt., were trained with food reinforcement under a multiple repeated acquisition (RA) and performance (P) schedule. The RA component required rats to learn a different three-member response sequence during each session (Center Right Left, RLC, RCL, LCR, or LRC); the correct response sequence remained constant in the P component (CLR). RA and P components alternated twice during a session. Rats were given 0, 4, or 8 mg/kg TMT IV after 30 sessions of stable baseline performance, and an additional 40 sessions were conducted following TMT. Prior to TMT, all groups maintained comparable accuracy levels in both RA and P components. Following TMT, significant decreases in both accuracy and response rate were obtained in the 8 mg/kg group. Thereafter, response rate and accuracy both recovered to near baseline levels, although large individual differences were observed. No selective effects of TMT were obtained on RA when compared to P. These data suggest that TMT-induced impairments on learning may be due to a generalized performance decrement rather than a specific effect on learning. PMID- 8700051 TI - Standards for Nutrition Support: Hospitalized Patients. The American Society for Parenteral and Enteral Nutrition. PMID- 8700052 TI - Nutrition support teams: past, present, and future. AB - Nutrition support teams have evolved rapidly and grown in numbers since the early 1970s. While not all hospitals have or need nutrition support teams, the team approach has been demonstrated to be an excellent mechanism for identifying patients in need of nutrition support, reducing the complications associated with enteral and parental nutrition, and providing cost-effective nutrition support in a variety of hospital environments. The organization of a nutrition support team is reviewed, and suggestions are outlined for team survival in this uncertain era of health care reform. New JCAHO standards are reported which require performance based interdisciplinary delivery of nutrition support, and make it more likely that efficiently organized nutrition support teams will thrive and continue to make important contributions to safe and cost-effective health care now and in the immediate future. PMID- 8700053 TI - Formulaic methods of estimating calorie requirements in mechanically ventilated obese patients: a reappraisal. AB - A variety of formulae are used by clinicians to estimate calorie requirements in hospitalized obese patients. Many of these formulae have been validated by determining their correlation to calorie requirements as determined by indirect calorimetry (IC). The use of correlation coefficients (CC) in this manner may be misleading. A more appropriate statistical methods, limits of agreement (LA), for comparing clinical measurements has recently been described by Bland and Altman. We obtained a total of 188 IC measurements on 113 obese (> 120% IBW), mechanically ventilated patients. These were compared by CC and LA to seven formulaic methods of determining calorie requirements. All formulae correlate significantly with IC. Analysis by LA indicated acceptable bias in several formulae (eg, 21 kcal/kg, Ireton-Jones obese patients (IJ), Ireton-Jones ventilatory patients, (VEE); however, the uniform lack of precision demonstrated by all formulae renders their clinical utility questionable. PMID- 8700054 TI - Taking your show on the road: the concept of a mobile nutrition support team. AB - Nutrition support teams (NSTs) have been in existence since the 1970s and remain an enduring concept of how nutrition support should be provided. The basic model of a NST who serves one institution has changed little over the past two decades. With the expansion of managed care, development of integrated hospital networks, decreasing inpatient census, and downsizing in hospital staff, a new model for the NST that anticipates and addresses these changes in the healthcare environment is needed. This article presents a model for a NST who is mobile and can function within an integrated system to improve the utilization, management, and quality of specialized nutrition therapy. PMID- 8700055 TI - Generic enteral formulas: a new idea for the 1990s. AB - Generic equivalent enteral formulas are now commercially available. The purpose of this article is threefold: (1) to define generic equivalents and compare both their nutritional and monetary differences with brand name products, (2) to provide the clinician with factors to consider when evaluating generic formulas- the source and distribution of macronutrients and micronutrients, and patient tolerance, nutritional status and outcome--and (3) to provide information on how to incorporate generic enteral formulas onto an institution's enteral formulary. In today's environment of diminishing health care budgets, generic enteral formulas can play a role in cost containment without sacrificing quality nutritional care. PMID- 8700056 TI - Intradialytic parenteral nutrition after small bowel resection. AB - Malnutrition is frequently observed in the hemodialysis patient population. It may be associated with increased morbidity and mortality as well as affect overall quality of life, which may already be compromised from dialytic physical and psychological demands. In the past, intradialytic parenteral nutrition (IDPN) has been available to hemodialysis patients as an adjunct to their dietary intake. In this time of cost containment and the increasing need to scientifically justify the benefit of such therapies to have them paid for by third party reimbursers, IDPN is coming under much scrutiny. This report describes a case of inadequate enteral nutrient absorption in a malnourished hemodialysis patient. This is a case in which IDPN was beneficial and without which other alternatives would have proven more costly physically, emotionally, and economically to the patient. PMID- 8700057 TI - Nutrition support clinical pathways. AB - With growing concerns over cost containment, hospitals are using clinical pathways to standardize health care and reduce costs. Clinical pathways designate the actions and services that patients should receive at specified time intervals throughout the hospital stay. Although most clinical pathways have been created for specific diseases or diagnoses, the nutrition support team at Tallahassee Memorial Regional Medical Center has developed clinical pathways for enteral and parenteral therapies. These pathways allow the team to track patient outcomes related to nutrition and to document variances when provisions fall outside the pathways. Variances are tallied on a quarterly basis and reported to the hospital Nutrition Support Committee. As data collection continues, trends emerge that guide the team to take appropriate corrective actions. Patient care is continuosly improved by incorporating these corrective actions into the pathways. PMID- 8700058 TI - Certification of staff nurses to insert enteral feeding tubes using a research based procedure. AB - Nutrition Support Nurse Clinicians at a Central Texas tertiary care facility have developed a research-based nasoenteric feeding tube insertion procedure that minimizes the potential for inadvertent passage of a feeding tube containing a stylet into the respiratory tract and maximizes placement of the feeding tube in the desired gastric or duodenal location. The first 79 staff nurses to be certified to use the technique had a 90% duodenal placement success rate under supervision. No bedside feeding tube insertion complications have been noted since the initiation of the certification program 6 years ago. This article describes the feeding tube insertion technique used in the certification process and the research on which it is based. PMID- 8700059 TI - How to minimize interaction between phenytoin and enteral feedings: two approaches. PMID- 8700060 TI - Treatment decisions: opinions or data? PMID- 8700061 TI - New guidelines for intravascular device-related infections. PMID- 8700062 TI - Intradialytic parenteral nutrition: a useful therapy? AB - Malnutrition in hemodialysis patients is common and may affect as much as 40% of this population of patients. There are many causes of malnutrition and all must be considered before utilizing nutrition support to reverse the malnutrition. Intradialytic parenteral nutrition (IDPN) is a therapy that has become popular among US nephrologists despite the fact that there are no clear data that support its use or efficacy. A thorough review of published articles suggests a relationship between the use of IDPN and improved patient outcome measured by hospitalization rate and a decrease in mortality in certain subgroups. However, these studies have many confounding factors that prevent a definitive conclusion concerning the true efficacy of IDPN. This is very problematic since reimbursement changes for parenteral and enteral nutrition have been proposed by HCFA. The best recommendation that can be made for IDPN is that it may represent a useful form of nutrition support in the malnourished hemodialysis patient who has no other active disease processes, cannot ingest adequate nutrition by mouth, and has a contraindication to or a serious complication from enteral feeding. It is clearly not a therapy to be considered as the first line of nutrition support in these patients. PMID- 8700063 TI - A view of nursing education in Scotland. PMID- 8700064 TI - Career guidance for student nurses: an unmet need. AB - Career guidance is important both organizationally and for the individual, especially at a time of re-emerging concerns about retention, and increasing complexity of nursing careers due to rapidly changing systems of health care provision. A questionnaire survey of 1015 newly qualified registered general nurses explored their experiences of career guidance whilst students, in relation to three areas: . applying for first post . taking post-basic courses . longer term plans. Findings revealed that few students were provided with guidance. Furthermore, a substantial unmet need was demonstrated, especially in relation to discussions about individual career planning. PMID- 8700065 TI - How can nurse teachers be more effective in practice settings? AB - This paper reports on selected aspects of a research project commissioned by the English National Board for Nursing, Midwifery and Health Visiting (ENB) to investigate the relationship between teaching, support, supervision and role modelling in clinical areas, within the context of Project 2000 diploma courses. The paper will focus upon findings which related to the role of the nurse teacher in practice settings. These were derived from interviews with students, practitioners and nurse teachers in three Project 2000 centres in England, and from a series of case studies in practice settings providing learning experiences for students undertaking the adult and mental health branches of Project 2000 diploma courses. Findings are discussed in relation to four broad areas: establishing a role for nurse teachers within the practice team; preparation of practitioners for their role in student learning; helping students to link theory and practice; and the nurse teacher's role in developing practice. PMID- 8700066 TI - Basic life support skill acquisition and retention in student nurses undertaking a pre-registration diploma in higher education/nursing course. AB - Many studies have investigated the ability of health care professionals to provide competent Basic Life Support (BLS) and all results indicate that the majority of staff fail to demonstrate competence. However, it has not yet been shown whether this poor performance is due to deterioration of skill or the nonacquisition of the skill during BLS training. This study seeks to identify aspects of BLS acquisition and retention by student nurses during their three years of training. The two issues under consideration are the effect of teacher student ratio and the effect of regular practice on BLS performance. This paper provides a review of the methodology and the initial findings. PMID- 8700067 TI - An approach to the facilitation and assessment of critical thinking in nurse education. AB - Problems around the production of written work to a given level, i.e. critical analysis, have dominated discussion of course standards in recent months since the introduction of the higher award pathway in post-registered nurse education. This paper seeks to address these concerns by suggesting a model for teachers to use in course planning and by use of an action research approach indicates to what extent: 1. The model works with two specific courses. 2. It is possible to assess student performance by an examination of their written work. The paper attempts to address issues related to why nurses have difficulty with the concepts and to what extent issues of power and culture play a part in such difficulty. The action research itself is based around two cycles of the research model using examples of student work to explain results. Overall the results are mixed but show that the adoption of a problem solving approach to lesson planning together with tutorials sustained throughout the course can bring about the required level in students final written work. PMID- 8700068 TI - Enlightenment, empowerment and emancipation: the case for critical pedagogy in nurse education. AB - This paper explores the notion that nurse education is a political activity which is value laden and has multiple social meaning. As long as teachers continue to pursue liberal and andragogical theories of learning, students will fail to develop a critical consciousness. The implications are vast as nursing prepares to enter the next millennium: notions such as the reflective practitioner and the knowledgeable doer feature highly on the profession's educational agenda, both of which implicitly require critical thinking skills. By using Habermas' definition of 'critique' as a framework and Paulo Freire's concept of 'conscientisation' as an educational model, it is argued that nurse teachers can expose the oppressive structures which confine and limit the nursing experience. Only then, when our oppression, both as women and nurses has been recognised, and a critical consciousness achieved, can true humanistic care be given. Through the development of emancipatory nursing actions can the profession stop colluding with the social structures which keep many people and groups in oppressive conditions. We should, in short, be teaching for 'peaceful revolution'. PMID- 8700069 TI - Teaching spiritual care to nurses. AB - In this paper a number of issues related to the teaching of spiritual care to nurses are considered. The spiritual dimension influences health and well-being. Research shows that patients considered their spiritual needs of importance. Nurses held a similar view but felt the need for further education to help them give spiritual care. The nursing literature suggests that spiritual care is part of the nurse's role and guidelines for nurse education state that it should be taught to nurses. It is not clear, however, if or how the subject is taught or how effective such teaching is in helping nurses to give spiritual care. The ways in which spiritual care could be taught are explored. PMID- 8700070 TI - Why teach ethics to nurses? AB - The Project 2000 diploma course has established ethics as a core component of the nursing curriculum. As a consequence there has been a plethora of nursing ethics books which justify their existence on the notion that nurses are recognizing the ethical nature of their work and seeking ethical guidance. It remains to be seen, however, whether the texts fulfil the perceived need. Ethics, it may be argued, is the current vogue; and the teaching of ethics to nurses is being given prominence. The aims of such teaching would appear to vary both between and within institutions but broadly seem to reflect the notions highlighted above. However, nurses do not approach this subject with one voice and much criticism has suggested that current approaches to the teaching of ethics to nurses do little more than frustrate students in their attempt to deal with matters ethical, and produce a generation of moral sceptics (Baier 1985). It is the aim of this paper to examine the rationale for teaching ethics to nurses. PMID- 8700071 TI - The analysis and application of peer assessment in nurse education, like beauty, is in the eye of the beholder. AB - Recent nursing literature has illustrated an increasing interest in the use of peer assessment in nurse education programs. An examination of this mode of assessment has revealed that the way in which peer assessment is both analysed and applied in the educational domain in general, and in the nursing education domain in particular, is dependent upon the philosophy or theoretical framework that explains and directs the context in which it takes place. This influence may originate from the guiding philosophy of a curriculum, the regulatory constraints of a professional body, the mission statement of an educational institution, or the prevailing values and beliefs of society at large. Underpinning each of these influences are the particular interests of the empirical, the interpretive and the critical paradigms. This paper will examine the concept of peer assessment from the perspectives of its purpose in the development of the professional nurse and the particular interest(s) it serves. PMID- 8700072 TI - Issues in designing a student database. AB - Many larger colleges of nursing have centralized student databases in which all elements of students' records are collated. The smaller department or college may leave the design of such databases to course leaders. This paper highlights stages and considerations in the development of student databases. It offers definitions of flat-file and relational databases; it identifies issues in prior planning and then of direct plannings of the database. It offers a discussion of a number of issues related to what sort of information is stored in a student database. It closes with a discussion of the training needs of those staff who are going to use such a database. The principles described in this paper can also be adapted for use in the designing of any health care related database system. The paper also addresses the question of why all colleges are not, already, using such systems. PMID- 8700073 TI - Nursing curriculum content: an innovative decision-making process to define priorities. AB - Curriculum planning in the health sciences is becoming increasingly complex due to rapid societal change and scientific discovery. The half-life of most curricula is 5 years, which necessitates a periodic close examination and revision of both content and process. For nursing faculty, this exercise is often viewed as an arduous one and traditionally can lead to endless hours of circular debate. Planning is usually in two stages; the first stage being the development of or agreement about a theoretical framework and the second stage is deciding on core content and teaching methodologies. This article focuses on decisions in the second stage. Traditionally, decisions around curriculum are arrived at by much debate. Some argue that all health issues should be addressed in the curriculum in order that the graduate be prepared to deal with a breadth of issues. However, this approach often leads to what has been referred to as 'curriculum hypertrophy', where, in an attempt to be all-inclusive, the curriculum grows without bounds. Rarely is anything dropped from the curriculum when this approach is used. Sometimes priorities are established on the basis of what the individual teaching staff deems important. In other cases a consensus approach is chosen. PMID- 8700074 TI - Recognition and assessment of teaching quality. AB - As colleges of nursing and midwifery move into higher education they will be shaped by the 'quality ethos' of their parent university, where in the past, excellence in teaching has in practice been less valued than other (e.g. research) activities. Application of the principles of standards, quality and competitiveness now underlie the quality assessment and quality audit procedures of the University Funding Councils. Colleges of nursing and midwifery have a culture that considers and values excellence in teaching. It is therefore essential that teachers of nursing and midwifery can clearly define their criteria for teaching quality, and more significantly, how this might be achieved, recognized and rewarded. This article discusses the nature of quality in education and suggests different models for consideration. The nature of teaching, teaching quality and competence is reviewed and analysed; with characteristics of good teaching given, in the context of higher education. The assessment of teaching is debated; and a range of criteria are suggested by which teaching activities might be evaluated and judged. By being clear and explicit about these issues nurse and midwifery teachers, as they move into higher education, can work with their higher education colleagues to shape the 'quality ethos' to one that values excellence in teaching on a par with that of research. PMID- 8700075 TI - Has nursing sold its soul? A response to Professor Banks. PMID- 8700076 TI - Professor Barbara Banks presented her 'uncompromising view of nurse education, England, 1995'. PMID- 8700077 TI - Opinions about nurse education. PMID- 8700078 TI - Increasing staff nurse awareness of postoperative pain management in the NICU. AB - Infants must have effective pain management in the postoperative period. A Level III NICU evaluated its current practice and identified barriers to effective pain management. Action was then taken to eliminate the identified barriers. This included developing a pain management team, testing and implementing an objective postoperative pain tool, employing a new flow sheet that incorporates the pain tool, offering multidisciplinary educational activities, and involving nurses in research. These actions have broken down the barrier to effective postoperative pain management and provided direction for a new standard of care. PMID- 8700079 TI - Choices of neonatal nurses in ambiguous clinical situations. AB - This article reports a study of the nurse's choice of level of management and factors influencing that choice in three ambiguous clinical situations related to neonatal nursing. A nationwide mail survey, using a Likert scale, was conducted on a random sample of the membership of the National Association of Neonatal Nurses. The findings of this research suggest that nurses have clearly defined choices related to the degree of intensity of management of infants, based on consideration of the information available to the nurse in the neonatal setting. These findings have implications for nursing practice and education and consequences for the quality of nursing care provided to infants and their families. PMID- 8700080 TI - Gestational age assessment. AB - A six-pound infant may be 33 weeks, 43 weeks, or term, each with a different set of medical and developmental needs, requiring different nursing care. Gestational age determination is important for anticipating each infant's medical risks, preventing complications, distinguishing the infant's developmental capabilities in feeding, sleep, and interactive behaviors with the parents, and establishing the infant's nursing care needs on a timely basis. This article reviews the history of gestational age assessment, gestational age classifications and associated risks, and the accuracy of current tools and provides instruction for performing a gestational age assessment. PMID- 8700081 TI - Minimizing epidermal stripping in the very low birth weight infant: integrating research and practice to affect infant outcome. AB - As smaller infants are cared for in our NICUs, maintaining skin integrity and preventing epidermal stripping have become key aspects of neonatal nursing care. This article describes a research utilization project in which research-based knowledge, expert information, and scientific practice guided a practice change in one NICU. The implementation process, based on the Iowa model, included the following steps: identification of triggers; review, critique, and evaluation of the literature; determination of the soundness of the research base; identification of alternate strategies; making the practice change; and evaluation of the outcomes. Initial monitoring suggests that the recommended interventions can be successful with very low birth weight infants. PMID- 8700082 TI - The effect of soothing music on neonatal behavioral states in the hospital newborn nursery. AB - Most newborns born in Western countries spend their first transitional hours in hospital nurseries. Noxious noise levels in the nursery can interfere with neonatal efforts to achieve physiological and behavioral homeostasis. Literature indicates that music has been used to induce relaxation states and reduce stress responses. This study used a one-group, pretest, posttest design. A convenience sample of 20 term, Caucasian neonates was recruited. The number of high arousal behavioral states and the number of state changes of the newborns was recorded for a control and an experimental period. Soothing, lyrical music was played in the baby's bed during the experimental period. The data was compared using McNemar's test statistic. A significant difference (p < .01) was observed. The results suggest that soothing music may be a feasible intervention to help newborns demonstrate fewer high arousal states and less state lability. PMID- 8700083 TI - Making choices to ease the stress. PMID- 8700084 TI - Congenital anomalies of the gastrointestinal tract. Part II: The small bowel. PMID- 8700085 TI - Developmental care: is it working? PMID- 8700086 TI - Seat belt safety education: when informing the public about the law isn't enough. PMID- 8700087 TI - Dinosaurs in the bath. PMID- 8700088 TI - Secret fears of a pregnant NICU nurse. PMID- 8700089 TI - One Touch II hospital system for neonates: correlation with serum glucose values. AB - A correlation study was conducted to examine the relationship between results from LifeScan's One Touch II blood glucose monitoring system and laboratory analysis of serum glucose values in neonates. A total of 327 blood samples was obtained from newborn infants in a Level III NICU. The comparison of the paired results showed that the r value was .902. The overall results suggest that the LifeScan One Touch II set in the neonatal mode gives results showing good agreement with standard serum glucose values in neonates with serum glucose values < 100 mg/dl (5.6 mmol/liter). PMID- 8700090 TI - Patent ductus arteriosus in the preterm infant. AB - The ductus arteriosus is a communication between the main pulmonary trunk and the descending aorta. In utero, the ductus arteriosus allows blood flow to be diverted from the high-resistance pulmonary circulation to the descending aorta and the low-resistance placental bed. Functional closure of the ductus arteriosus occurs soon after birth but can be delayed in premature infants and in certain situations. Patency of the ductus arteriosus results in alterations in blood flow to many different organ systems. This article describes the physiologic effects, as well as symptoms, diagnosis, and management of a patent ductus arteriosus in the preterm infant. PMID- 8700091 TI - Mothers' perceptions of the quality of their infants' back transfer: pilot study results. AB - This pilot study was designed to test an instrument measuring mothers' perceptions of the quality of the back-transfer experience from a neonatal intensive care unit in a tertiary medical center to a community hospital. Forty one mothers completed a questionnaire that contained the 24-item NICU/Community Hospital Transfer Quality Scale, a 1-item measure of stress associated with the overall experience, and other variables that might affect the transfer experience. Transfer quality was strongly correlated with the overall stress of the transfer (r = .61, p < .001). That is, the higher the perceived transfer quality, the less stress the mother associated with the transfer. This instrument had a test-retest reliability of r = .82 (p < .001, n = 23) and a Chronbach's alpha of .84. Comments made by mothers indicated that communication with health care providers is a very important but sometimes inadequately addressed component of the transfer experience. Nurses can play a key role in facilitating communication between the family and health care providers in both the tertiary and community settings. Four goals for enhancing communication between parents and health care providers are described. PMID- 8700092 TI - Effects of gentle human touch on preterm infants: pilot study results. AB - A pilot study was conducted to evaluate the effects of gentle human touch (GHT) provided for 15 minutes a day to preterm infants from day 7 to day 12 of life. The study suggested that GHT has no adverse effects on the oxygen saturation or heart rate levels of small preterm infants and that GHT has a soothing effect as evidenced by decreased levels of active sleep, motor activity, and behavioral distress. These results can provide NICU nurses with a basis for guiding parents in their early interactions with preterm infants in the NICU. PMID- 8700093 TI - Controversial aspects of umbilical artery catheters. PMID- 8700094 TI - Position statement on minimum staffing in NICUs. PMID- 8700095 TI - Postconceptional age as the basis for neonatal case management. AB - Managing the care of the very preterm infant can become a maze of diagnoses, treatments, and tests that blur progress and expectations along an infant's extended course in the NICU. Yet the health care environment demands that comprehensive, high-quality, cost-effective care be provided each infant and family entrusted to our care. Critical pathways based on gestational age at birth and postconceptional age throughout the hospital stay facilitate the necessary goal-oriented, interdisciplinary approach to infant care by providing consistency, flexibility, and quality management. PMID- 8700096 TI - Testing for group B streptococcus latex particle agglutination. PMID- 8700097 TI - Congenital anomalies of the gastrointestinal tract. Part III: The colon and rectum. PMID- 8700098 TI - Temperature control: servo versus nonservo--which is best? PMID- 8700099 TI - And death shall set ye free. PMID- 8700100 TI - Characterization of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one as a heme-site inhibitor of nitric oxide-sensitive guanylyl cyclase. AB - Nitric oxide (NO) binds with high affinity to the heme of soluble guanylyl cyclase (sGC), resulting in accumulation of the second messenger cGMP in many biological systems. 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) was recently described as potent and selective inhibitor of sGC, providing an invaluable tool with which to settle the function of the cGMP pathway in NO mediated signal transduction [Mol. Pharmacol. 48:184-188 (1995)]. The present study investigated the mechanism of ODQ-induced inhibition of purified bovine lung sGC. The drug induced a rightward shift of the concentration-response curves recorded with two different NO donors and a reduction of maximal sGC activity, pointing to a mixed type of inhibition. The time course of NO-stimulated sGC activity determined in the presence of 0.3 microM ODQ showed that the inhibitory effect was time-dependent (half-time approximately 3 min) and virtually complete after about 10 min. The cyclase did not recover from ODQ-induced inhibition upon extensive dilution, pointing to an apparently irreversible inactivation of the enzyme by the quinoxalin. Light absorbance spectroscopy showed that ODQ (0.3 mM) induced a shift of the Soret band of the heme from 431 nm to 393 nm, indicating that ODQ oxidizes the ferrous form of the enzyme to the ferric species, which is though to exhibit only poor NO sensitivity. Together, our results suggest that inhibition of sGC by ODQ is NO-competitive and results in an apparently irreversible oxidation of the prosthetic heme group. PMID- 8700101 TI - Trans-species gene transfer for analysis of glucocorticoid-inducible transcriptional activation of transiently expressed human CYP3A4 and rabbit CYP3A6 in primary cultures of adult rat and rabbit hepatocytes. AB - Interindividual variation in the spontaneous and in the glucocorticoid-or rifampicin-inducible expression of the CYP3A cytochromes P450, the dominant froms of this supergene family that catalyze the oxidation of numerous drugs and environmental chemicals in human liver, remains largely unexplained, due in part to the lack of a validated animal model. We analyzed the 5'-flanking sequences of CYP3A genes from the rat (CYP3A23, CYP3A2), rabbit (CYP3A6), and human (CYP3A4, CYP3A5, CYP3A7) and found variable regions separated by three areas (consensus I, II, and III) of sequence homology immediately upstream of their respective promoters. We used trans-species gene transfer in cellulo as a new approach for determining the basis for qualitative differences among species in liver expression of different forms of CYP3A. When we transfected into cultured rat hepatocytes vectors containing 5'-flanking DNA from CYP3A23, CYP3A4, or CYP3A6 genes, we found that CAT activity was induced on treatment with dexamethasone or pregnenolone-16 alpha-carbonitrile only if consensus II sequences were included. Rifampicin treatment had no effect. When the same constructions containing consensus II were transfected into rabbit hepatocytes, increased activity was observed on treatment of the cells with dexamethasone or with rifampicin but not with pregnenolone-16 alpha-carbonitrile. These results suggest that the host cellular environment rather than the structure of the gene dictates the pattern of CYP3A inducibility. The application of this new model system will provide a unique technique for identifying mechanisms of induction and advancing the development of appropriate toxicological models for human safety assessment. PMID- 8700102 TI - Effects of long-term treatment with the allosteric enhancer, PD81,723, on Chinese hamster ovary cells expressing recombinant human A1 adenosine receptors. AB - In this study, desensitization and down-regulation of A1 adenosine receptors (A1AR) by the allosteric enhancer PD81,723 (PD) and by N6-cyclopentyladenosine (CPA) were investigated after 24-hr pretreatment of CHO-K1 cells stably expressing recombinant human A1AR. Pretreatment with 20 microM PD and 10 microM CPA caused a 1.5- and 4.0-fold, respectively, desensitization (reduced potency of CPA to lower cAMP). Pretreatment with PD and/or CPA did not modify the acute effect of PD to increase (5-fold) the potency of CPA. Radioligand binding was used to measure receptor down-regulation in cell membranes and in intact cells. Pretreatment of cells with PD had no effect on the number of membrane binding sites for the agonist [125I] N6-(3-iodo-4-aminobenzyl) adenosine or for the antagonist, [3H]8-cyclopentyl-1,3-dipropylxanthine, but the binding of these radioligands to intact cells was modestly reduced (20-37%), possibly reflecting an effect of pretreatment on receptor subcellular distribution. Pretreatment of cells with CPA produced large ( > 40%) reductions in the binding of radioligands to both membranes and intact cells. Pretreatment of cells with CPA also increased the number of presumed internalized receptors measured as [3H]8-cyclopentyl-1,3 dipropylxanthine binding sites in intact cells insensitive to blockade by the charged antagonist 8-sulfophenyltheophylline. The relatively small degree of functional desensitization and down-regulation of A1AR caused by long term exposure of cells to PD is considered to be encouraging in terms of the therapeutic potential of the allosteric enhancer class of compounds. PMID- 8700103 TI - Characterization of the peptide binding requirements for the cloned human pancreatic polypeptide-preferring receptor. AB - Traditionally, neuropeptide Y (NPY) receptors have been divided into Y1 and Y2 subtypes based on peptide pharmacology and synaptic localization. Other receptor subtypes have been proposed based on preferences for NPY, peptide YY (PYY), or pancreatic polypeptide (PP). Recently, we discovered a novel human member of this receptor family exhibiting high affinity for PP and PYY. In the current study, we expressed a DNA clone encoding this human PP-preferring receptor [hPP1 (or Y4)] in Chinese hamster ovary cells and performed a peptide structure-activity study. [125I]pPYY bound to homogenates of hPP1-Chinese hamster ovary cells with a Kd of 0.064 +/- 0.006 nM and a Bmax of 244 +/- 12 fmol/mg protein. Human PP inhibited binding with a Ki of 0.023 nM, whereas human PYY (Ki = 0.31 nM) and human NPY Ki = 12 nM) were significantly less potent. Rat, porcine, and bovine PP inhibited binding with similar affinities to human PP, whereas avian PP was substantially less potent (Ki = 1 nM). Deletion of the first four amino acids reduced the affinity of bovine PP to 1 nM. Carboxyl-terminal fragments of NPY and PYY also had reduced potency compared with the native peptides. In addition, deletion of Tyr36-amide produced a substantial reduction in affinity. Pro34-substituted NPY and PYY had modestly increased affinity compared with the native peptides, although Gln34-bPP had similar affinity compared with bovine PP. The carboxyl terminally derived Y1 antagonist 1229U91 was a very potent (Ki = 0.042 nM) inhibitor of binding to hPP1. Thus, the carboxyl-terminal region of PP seems to be the most important part of the peptide for high affinity binding to hPP1. A few key residues (amino acids 2 and 3) in the amino-terminal region of PP contribute to the high affinity of the native peptide. Thus, features required for peptide recognition by the hPP1 receptor seem to be distinct from the Y1 and Y2 receptor. PMID- 8700104 TI - Properties of recombinant gamma-aminobutyric acid A receptor isoforms containing the alpha 5 subunit subtype. AB - The cDNAs encoding alpha 5 and gamma 2L subunit subtypes of the gamma aminobutyric acid (GABA) type A receptor (GABAR) were transfected into L929 cells together with cDNAs encoding either the beta 1, beta 2, or beta 3 subunit subtype. Properties of expressed recombinant alpha 5 beta X gamma 2L (where X = 1,2, or 3) GABARs were studied with the use of whole-cell, patch-clamp techniques. In cells voltage-clamped at -70 mV with equlvalent bath and pipette chloride concentrations, the application of GABA produced a concentration dependent inward chloride current with all three alpha 5 beta X gamma 2L isoforms. Minimal or no responses were recorded from cells transfected with only two subunit cDNAs, demonstrating that all three subunits were required for functional receptor assembly in these cells. The GABA concentration producing a half-maximal current was similar for beta 2 and beta 3 subtype-containing receptors (6 microM) but higher for beta 1 subtype-containing receptors (26 microM). alpha 5 beta 3 gamma 2L receptors were zinc and diazepam sensitive but zolpidem insensitive. In response to low GABA concentrations, beta 1 and beta 3 subtype-containing receptors showed outward rectification of the current-voltage relationship, whereas current-voltage responses of beta 2 subtype-containing receptors were relatively linear. Likewise, at high GABA concentrations, beta 1 and beta 3 subtype-containing receptors showed less desensitization at positive than at negative membrane potentials. Beta 2 subtype-containing receptors displayed faster desensitization at depolarized potentials. These voltage dependent properties were characteristic of alpha 5 but not alpha 1 or alpha 6 subtype-containing receptors and were similar to responses recorded from hippocampal CA1 pyramidal neurons. Based on the pharmacological and biophysical similarities to hippocampal GABAR responses, the alpha 5 beta 3 gamma 2L isoform could represent a native GABAR subtype. PMID- 8700105 TI - B1 and B2 kinin receptors mediate distinct patterns of intracellular Ca2+ signaling in single cultured vascular smooth muscle cells. AB - Stimulation of B1 and B2 kinin receptors on cultured rabbit superior mesenteric artery smooth muscle cells with des-Arg9-bradykinin (DBK) and bradykinin (BK), respectively, results in significantly different patterns of intracellular Ca2+ mobilization. Single-cell fluorescence imaging of Fura-2-loaded cells revealed that although both DBK and BK initially triggered similar rapid increases in cytosolic free Ca2+, the DBK response was biphasic and sustained, whereas the BK response was transient. The DBK response was maintained for > or = 20 min with the second phase characterized by an elevated plateau and/or base-line oscillations. The BK response was limited to an initial transient peak with the exception of a few cells, which after a prolonged latency period, exhibited weak but regular base-line oscillations. The initial BK- and DBK-stimulated rises in cytosolic free Ca2+ were dependent on the release of Ca2+ from intracellular stores that seemed to be common for the two agonists. On the other hand, the continuation of the sustained phase of the DBK response required the influx of extracellular Ca2+, as well as continuous receptor occupancy by the agonist. Stimulation of cells with DBK followed by washing and restimulation with the same agonist within < or = 2 min resulted in a second B1 receptor response that was not significantly different from the first response. In contrast, the same protocol with BK yielded a dramatically decreased second B2 receptor response. This attenuation did not seem to be due to a lack of Ca2+ in the agonist sensitive intracellular stores because DBK elicited a full response after BK stimulation. This study shows that in single cultured RSMA smooth muscle cells, agonist stimulation of B1 receptors generates a sustained intracellular Ca2+ signal, whereas stimulation of B2 receptors promotes rapid and homologous desensitization, resulting in a transient Ca2+ signal. These distinct receptor specific patterns of Ca2+ mobilization imply significantly different roles for B1 and B2 kinin receptors in vascular smooth muscle cells. PMID- 8700106 TI - Alanine scanning mutagenesis of conserved arginine/lysine-arginine/lysine-X-X arginine/lysine G protein-activating motifs on m1 muscarinic acetylcholine receptors. AB - Alanine scanning mutagenesis of B-B-X-X-B motifis (where B is a basic residue and X is any nonbasic residue) in m1 muscarinic acetylcholine receptors was performed to determine the relative roles of basic amino acids in receptor coupling. This conserved motif is found in many G protein-coupled receptors and has been implicated in G protein activation. The KKAAR365 motif, located at the carboxyl terminal third intracellular loop of m1 receptors, was mutated to AAAAA365, thereby generating a triple-substitution mutant devoid of ability to stimulate either phosphoinositide (PI) hydrolysis or cAMP accumulation. In contrast, a triple-alanine substitution of the KRTPR140 motif in the carboxyl-terminal second intracellular loop, yielding mutant AATPA140, had no effect on receptor coupling to the two independent second messenger pathways. Analysis of a series of single- and double-substitution mutants demonstrate that all three basic residues of the KKAAR365 motif participate in efficient m1 receptor coupling. The presence of second and third basic residues in this motif was absolutely critical for full agonist recognition of a high and low affinity state of the receptor. Mutation of either Lys362 or Lys365, but not-Lys361, abolished guanine nucleotide-dependent conversion of agonist affinity states and correlated with an inability of full agonists to fully activate PI hydrolysis. The different combinatorial double substitution mutants also revealed that Lys365 was necessary but not sufficient, in the context of the KKAAR365 motif, for efficient receptor coupling. This residue cannot facilitate full agonist-stimulated Pl hydrolysis in the absence of both Lys361 and Lys362. In comparison, the critical residue Lys362 was both necessary and sufficient. Substitution of nearby basic residues Lys361 and Lys365 with alanine yielded mutant AKAAA365, which exhibited partial ability to couple PI hydrolysis after full agonist stimulation. Therefore, Lys365 seems to function in a hierarchal (interdependent) manner with nearby basic residues, whereas Lys361 and Lys362 can act independent of surrounding basic residues to facilitate partial m1 receptor coupling after full agonist stimulation. In contrast, all three residues must be present for stimulation of PI hydrolysis by a partial agonist. PMID- 8700107 TI - Glutathione-associated enzymes in the human cell lines of the National Cancer Institute Drug Screening Program. AB - The steady state expression of glutathione S-transferases (GSTs) at both the protein and mRNA level is reported for the 60 tumor cell lines that are used for the National Cancer Institute Drug Screening Program. Individual GST isozymes were separated, identified, and quantified (with reverse-phase calibration curves) through a novel high performance liquid chromatographic procedure. GSTP1 was the predominant isozyme and was found at quantifiable levels in all but two of the cell lines. This isozyme ranged from 0.03% to 2.7% of the total cytosolic protein. For the mu family, 90% of the lines had GSTM2, 68% had GSTM3, but only 28% were positive for the M1 phenotype. The M1 proportion is lower than would be expected from the standard M1 null phenotype for human populations. Isozymes of the alpha family were detected only at very low levels in 35% of the lines. Significant quantitative correlations among enzyme activity, total enzyme protein, and mRNA were shown for GSTP1. However, such relationships were not apparent for the mu or alpha families. Levels of glutathione (GSH), and the transcript levels of other enzymes involved in GSH homeostasis were determined. gamma-Glutamyl cysteine synthetase (gamma-GCS) was present in all cell lines, but did not correlate with levels of intracellular GSH. Glyoxalase-I and gamma glutamyl transpeptidase, both involved in GSH salvage, were found in 100% and 70% of the cell lines, respectively. Using a pattern-matching computer program, COMPARE, we compared and correlated the arrays of mRNA and protein levels with the pattern of chemosensitivity or chemoresistance of the 60 cell lines with 175 agents constituting a standard agent database. This database is composed of compounds to which a putative mechanism of action has been assigned. Although Pearson correlation coefficients relating the target and drug patterns were generally modest, when the patterns for the enzyme protein and mRNA levels for GST pi were correlated to drug sensitivity patterns, the list of 30 agents most closely matching (for which P < 0.05) was enriched with alkylating agents. gamma GCS also showed an enrichment of alkylating agents in the COMPARE correlations, indicating that high levels of gamma-GCS may be an important determinant of resistance. In contrast, none of the other enzymes or GSH had patterns of expression that resulted in an obvious correlation to the sensitivity or resistance of alkylating agents. PMID- 8700108 TI - 2',3'-Didehydro-3'-deoxythymidine: regulation of its metabolic activation by modulators of thymidine-5'-triphosphate biosynthesis. AB - The anti-human immunodeficiency virus (anti-HIV) agent 2',3'-didehydro-3' deoxythymidine (D4T), like other 2',3'-dideoxynucleosides, requires conversion to its 5'-triphosphate to exert its pharmacological effect. Although D4T triphosphate is unusually potent as an inhibitor of HIV-1 reverse transcriptase, the phosphorylation of the drug at low dose levels is inefficient because of its low affinity as an alternate substrate for the initial phosphorylation enzyme thymidine kinase. Because thymidine kinase is under feedback regulatory control by the physiological deoxynucleoside-5'-triphosphate dTTP, we examined the effect on D4T phosphorylation and thus, potentially, on its antiviral activity, of a variety of agents that lower intracellular dTTP pools. We found that agents that inhibit the de novo pyrimidine biosynthetic pathway have the ability to increase D4T phosphorylation, the most effective being two inhibitors of thymidylate formation, methotrexate and 5-fluoro-2'-deoxyuridine, compounds that block the enzymes dihydrofolate reductase and thymidylate synthetase, respectively. Because HIV itself lacks the capacity to synthesize dTTP and the other deoxynucleoside triphosphates essential for viral replication, combinations of D4T with modulatory agents that deplete host-cell dTTP, unlike conventional anti-HIV drug monotherapy directed solely at viral enzymes, have the ability to inhibit replication of mutant HIV strains as well as of wild-type virus. PMID- 8700109 TI - Characterization and regulation of the human ML1A melatonin receptor stably expressed in Chinese hamster ovary cells. AB - The human ML1A melatonin receptor is expressed in the suprachiasmatic nucleus of the hypothalamus and is believed to regulate circadian rhythms. We report the kinetic characteristics and pharmacological profile of 2-[125I]iodomelatonin binding and the signaling pathway and agonist regulation of the human ML1A melatonin receptor stably expressed in Chinese hamster ovary cells. Association of 2-[125I]iodomelatonin binding was maximal by 1.5 hr at 37 degrees and fully dissociated on the addition of 1 microM melatonin. The binding of 2 [125I]iodomelatonin was saturable and of high affinity (KD = 74 +/- 14 PM, Bmax = 679 +/- 88 fmol/mg protein; three experiments). The pharmacological profile of various melatonin analogues revealed a profile (2-iodomelatonin > or = melatonin > N-acetyl serotonin > luzindole) characteristic of an ML1 subtype. Competition of melatonin for 2-[125I]iodomelatonin binding to the human ML1A receptor in lysed or intact cells resulted in biphasic curves revealing the existence of super high (approximately 20%) and high (approximately 80%) affinity states of the receptor. Guanosine-5'-0-(3-thio)triphosphate (100 PM-30 microM) when added alone inhibited 2-[125I]iodomelatonin binding (IC50 = 0.87 +/- 0.12 microM; three experiments), suggesting uncoupling of the receptor from G proteins. In addition, guanosine-5'-O-(3-thio)triphosphate (3 microM) produced a right-ward shift in both the super high and high binding melatonin affinities for 2 [125I]iodomelatonin resulting in monophasic curves. Melatonin (0.1 fM-1 nM) inhibited forskolin-induced cAMP formation in a concentration-dependent and biphasic manner. Low concentrations of melatonin (0.01 fM-1 PM) inhibited forskolin (100 microM)-stimulated cAMP formation with an IC50 of 0.1 +/- 0.05 PM (four experiments) and a maximal inhibitory effect (26%) at 1 PM. Higher concentrations of melatonin (1 PM-1 nM) inhibited forskolin-induced cAMP formation with an IC50 of 64 +/- 1.8 PM (four experiments) and a maximal inhibition (74%) at 1 nM. Luzindole (1 microM), a competitive melatonin receptor antagonist, antagonized the effect of melatonin at the higher concentrations only (IC50 = 1.5 +/- 0.22 nM, pKB = -7.3; three experiments). Pretreatment with pertussis toxin completely abolished melatonin-mediated inhibition of forskolin induced cAMP formation through these receptors. Pretreatment with various concentrations of melatonin (0.1 PM-1 microM) for different periods of time (1, 6, 18, and 24 hr) did not decrease 2-[125I]iodomelatonin binding. However, competition by melatonin for 2-[125I]iodomelatonin binding to cells pretreated with melatonin and washed was only to a single population of super high affinity sites (IC50 = 1.1 +/- 0.28 nM; three experiments) as revealed by monophasic curves. Cells pretreated with melatonin revealed a persistent inhibition (approximately 20%) of forskolin-induced cAMP formation that was not reversed by extensive washes (up to 1 hr) or when luzindole (1 microM) was added together with melatonin during pretreatment. These results suggest that tight binding of melatonin to the super high affinity state of the human ML1A melatonin receptor may be the mechanism by which low concentrations of circulating hormone in vivo regulates signaling in the suprachiasmatic nucleus of the hypothalamus. PMID- 8700110 TI - Effect of phorbol myristate acetate on alpha 1-adrenergic action in cells expressing recombinant alpha 1-adrenoceptor subtypes. AB - We studied the ability of norepinephrine to stimulate [3H]inositol trisphosphate production and calcium mobilization in rat-1 fibroblasts stably expressing the cloned alpha 1-adrenergic subtypes and their sensitivity to phorbol-12-myristate 13-acetate (PMA). It was observed that the three subtypes were able to activate this signal transduction process, but marked differences in efficacy were noted. The order of efficacy was alpha 1a > alpha 1b > alpha 1d in cells with similar receptor densities. The use of PMA blocked the alpha 1d responses at lower concentrations than those needed to block the alpha 1b action; little effect of PMA was observed on effects mediated through alpha 1a-adrenoceptors. These effects of PMA were not observed in cells preincubated overnight with the tumor promoter, suggesting that such actions were mediated through isoform or isoforms of protein kinase C subjected to down-regulation. The repetitive addition of norepinephrine induced desensitization of the alpha 1-adrenergic action in cells expressing any of the three subtypes, and this effect was not altered by overnight pretreatment with PMA. Our data indicate that there are differences in sensitivity to PMA among the alpha 1-adrenoceptor subtypes stably expressed in rat-1 fibroblasts. PMID- 8700111 TI - Inducible expression of beta 1- and beta 2-adrenergic receptors in rat C6 glioma cells: functional interactions between closely related subtypes. AB - We examined the role of beta 1- and beta 2-adrenergic receptor (AR) density and ratio in catecholamine-stimulated cAMP responses in rat C6 glioma cells. These cells, which normally express both subtypes, were stably transfected with an isopropylthio-beta-D-galactoside-inducible vector containing either beta 1AR or beta 2AR coding sequences, and receptor expression was controlled by the time and concentration of isopropylthio-beta-D-galactoside exposure. Induction of the dominant beta 1AR subtype increased the potencies of isoproterenol (ISO) and other agonists in stimulating cAMP accumulation by 20-40-fold without changing maximal response. Induction of beta 2AR expression caused 7-13-fold increases in the potency of ISO, epinephrine, and zinterol, but not of norepinephrine, and a 20-40% loss in maximal response to all agonists. Selective antagonists showed that both subtypes contributed in a nonadditive manner in the response to ISO under different conditions. After beta 2AR induction, the effects of ISO were not blocked by the beta 1-selective antagonist CGP 20712A but were shifted 100-fold to the right by the beta 2-selective antagonist ICI 118,551. However, in the presence of ICI 118,551, CGP 20712A caused an additional 100-fold decrease in ISO potency, and Schild analysis revealed complex interactions between the two subtypes. Each antagonist alone caused smaller shifts to the right in the dose response curve to NE and, when present simultaneously, completely abolished the NE response. We conclude that beta 1ARs and beta 2ARs have different efficiencies in activating cAMP accumulation in C6 glioma cells. Activation of coexisting subtypes results in complex and sometimes synergistic interactions between the two subtypes, which vary with agonist concentration, selectivity, subtype density, and ratio. PMID- 8700112 TI - Enhancement of recombinant alpha 1 beta 1 gamma 2L gamma-aminobutyric acidA receptor whole-cell currents by protein kinase C is mediated through phosphorylation of both beta 1 and gamma 2L subunits. AB - The gamma-aminobutyric acidA (GABA)A receptor (GABAR) beta 1 and gamma 2L subtypes have been shown to be phosphorylated in vitro by protein kinase C (PKC) [J. Biol. Chem. 267:14470-14476 (1992); Neuron 12:1081-1095 (1994)]. To determine the physiological consequences of phosphorylation of GABAR isoforms containing the beta 1 and gamma 2L subtypes, the specific serine residues phosphorylated by PKC (beta 1 S409, gamma 2L S327 and S343) were changed to alanines through site directed mutagenesis. Wild-type (alpha 1 beta 1 gamma 2L GABARs) and three mutant GABAR isoforms [alpha 1 beta 1 gamma 2L(S327A, S343A), alpha 1 beta 1(S409A) gamma 2L, and alpha 1 beta 1(S409A) gamma 2L(S327A, S343A) GABARs) were expressed in mouse L929 fibroblasts through transient cotransfection. Recordings were obtained from each cell with the use of the whole-cell patch-clamp technique. The initial recording was made with the use of control intrapipette solution, and a second recording from the same cell was obtained with pipettes containing either constitutively active PKC [protein kinase M (PKM)] or control solution to obtain paired GABA concentration-response relationships. All GABAR isoforms studied had equivalent maximal GABA currents and similar GABA concentration-response profiles under the control condition. Intracellular PKM treatment increased the maximal current and EC50 value in cells expressing wild-type GABARs. However, PKM reimpalement did not significantly change these parameters in cells expressing any of the mutant GABAR isoforms, indicating that the mutation of either the beta 1 or gamma 2L subtype alone was sufficient to prevent enhancement of GABAR current by PKM. No significant changes were obtained during control reimpalement recordings of wild-type or mutant receptors. Furthermore, PKM treatment did not after the time constants of GABA current desensitization kinetics measured from cells expressing wild-type or mutant receptors. These data thus suggest that PKC phosphorylation of the beta 1 and gamma 2L subtypes enhances GABAR current and that both subtypes are required for complete PKC-mediated enhancement of alpha 1 beta 1 gamma 2L GABAR current. PMID- 8700113 TI - A novel irreversible antagonist of the A1-adenosine receptor. AB - We determined the effects of 8-cyclopentyl-3-[3-[[4 (fluorosulfonyl)benzoyl]oxy]propyl]-1-propylxanth ine (FSCPX), a putative irreversible antagonist of the A1-adenosine receptor, on cardiac A1-adenosine receptor-mediated responses and on the specific binding of [3H]-8-cyclopentyl-1,3 dipropylxanthine ([3H]CPX) to guinea pig cardiac and brain membranes. FSCPX (5 microM) completely reversed the increase in K+ current of guinea pig atrial myocytes caused by 100 microM adenosine (259 +/- 30 to 20 +/- 7 pA) but had no significant effect on K+ currents caused by either 0.5 microM carbachol or 100 microM GTP gamma S. The attenuation of K+ current by FSCPX was both time and concentration dependent and persisted after washout of the antagonist. Pretreatment of atrial myocytes with FSCPX (50 nM) markedly attenuated the activation of K+ current and the inhibition of isoproterenol-stimulated I(Ca,L) caused by adenosine by 90.1% and 84.2%, respectively, but did not alter the responses of atrial myocytes to carbachol. FSCPX (1 microM) irreversibly antagonized the A1-adenosine receptor-mediated increase in atrioventricular nodal conduction time of isolated perfused guinea pig hearts from 10.5 +/- 0.5 to 0.7 +/- 0.6 msec but did not significantly alter the A2-adenosine receptor-mediated decrease in coronary resistance. Preincubation of guinea pig cardiac membranes with 0.1, 1.0, or 3.0 microM FSCPX for 30 min reduced the Bmax of [3H]CPX binding by 41 +/- 10%, 67 +/- 6%, and 80 +/- 1% (mean +/- standard error, three experiments), respectively, with no significant change in the Kd. Similarly, 0.1 and 1.0 microM FSCPX irreversibly reduced the binding of [3H]CPX to guinea pig forebrain membranes by 65 +/- 5% and 83 +/- 2% (four experiments), respectively, but did not reduce the binding of [3H]CGS 21680, an A2a-adenosine receptor agonist, to striatal membranes. FSCPX did not affect the potency of 5' guanylylimidodiphosphate to inhibit the binding of [3H]CCPA, an A1-adenosine receptor agonist, to brain membranes. The results indicate that FSCPX is a specific, irreversible, A1-adenosine subtype-selective receptor antagonist. PMID- 8700114 TI - Effects of channel modulators on cloned large-conductance calcium-activated potassium channels. AB - Through expression of the cloned mouse (mSlo) or human (hSlo) large-conductance (BK) Ca(2+)-activated K+ channel in Xenopus laevis oocytes and HEK 293 cells, we characterized the effects of reported blockers and openers of BK channels to initiate the study of the molecular determinants of BK channel modulation. In oocytes, iberiotoxin and charybdotoxin, peptidyl scorpion toxins, were both equally effective blockers of BK current, although iberiotoxin was significantly more potent than charybdotoxin. The structurally related peptide kaliotoxin was not a potent blocker of BK current. Paxilline, a fungal tremorgenic alkaloid, was an effective but complex blocker of BK current. Tetrandrine, a putative blocker of type II BK channels, and ketamine were relatively ineffective. The putative BK openers NS004 and NS1619, phloretin, niflumic acid, flufenamic acid, and 5-nitro 2-(3-phenylpropylamino)benzoic acid (NPPB) increased BK current in oocytes at microM concentrations; many of these produced biphasic concentration-response relationships. Coapplication of representative blockers and openers revealed several patterns of interaction, including competitive and noncompetitive antagonism. NS1619, niflumic acid, and phloretin were tested by using excised inside-out membrane patches from HEK 293 cells and were found to increase the activity of hSlo BK channels and produce a leftward shift in the G/Gmax-versus voltage relationship of these channels. These results represent the first comprehensive examination of the molecular pharmacology of BK channels. PMID- 8700115 TI - Alpha 6 and gamma 2 subunit antisense oligodeoxynucleotides alter gamma aminobutyric acid receptor pharmacology in cerebellar granule neurons. AB - To characterize the role of the alpha 6 subunit in gamma-aminobutyric acid (GABA) receptors in cerebellar granule cells, primary cerebellar cultures were treated with antisense oligodeoxynucleotides (ODNs) complementary to and overlapping the initial codon of the alpha 6 subunit cDNA. The specific reduction in the expression of the alpha 6 receptor subunit protein after a 48-hr antisense ODN treatment was assessed with the use of immunoblot assays. Sister cultures were treated in parallel with mismatched (scrambled) ODNs. Inhibition of GABA-gated currents by furosemide, a selective inhibitor of GABAA receptors containing alpha 6 subunits, was attenuated after the alpha 6 antisense treatment. Furosemide was tested in parallel in transfected cells expressing various combinations of the alpha 1 and alpha 6 subunits, which showed that the relative abundance of these subunit mRNAs determines the extent of furosemide-induced inhibition of GABA gated currents. Compared with control or mismatched ODN-treated cell cultures, treatment of granule neurons with alpha 6 antisense ODNs caused a decrease in GABA-induced maximal current density and increased the half-maximal concentration derived from GABA dose-response curves. Furthermore, the depletion of alpha 6 subunits from cerebellar granule cells enhanced flunitrazepam-induced potentiation of GABA-activated currents. In contrast, gamma 2 antisense ODN treatments of cell cultures increased the receptor sensitivity to GABA and potently decreased the response to flunitrazepam. Our results show that alpha 6 and gamma 2 subunit expression can be blocked with the use of synthetic ODNs and that these subunits are crucial determinants of the pharmacological properties of native GABAA receptors in cerebellar granule cells. PMID- 8700116 TI - Contribution of a helix 5 locus to selectivity of hallucinogenic and nonhallucinogenic ligands for the human 5-hydroxytryptamine2A and 5 hydroxytryptamine2C receptors: direct and indirect effects on ligand affinity mediated by the same locus. AB - An important determinant of the neurobehavioral responses induced by a drug is its relative receptor selectivity. The molecular basis of ligand selectivity of hallucinogenic and nonhallucinogenic compounds of varying structural classes for the human 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors was investigated with the use of reciprocal site-directed mutagenesis. Because these two closely related receptor subtypes differ in the amino acid present at position 5.46 (residues 242 and 222 in the sequences, respectively), the effects of corresponding substitutions in the 5-HT2A[S5.46(242)-->A] and 5-HT2C[A5.46(222)- >S] receptors were studied in tandem. By studying both receptors, the direct and indirect effects of mutations on affinity and selectivity can be distinguished. The ergolines studied, mesulergine (selective for the 5-HT2C receptor) and d lysergic acid diethylamide (selective for the 5-HT2A receptor), reversed their relative affinity with mutations in each receptor, supporting a direct role of this locus in the selectivity of these ligands. However, interchange mutations in either receptor led to decreased or unchanged affinity for (+/-)-1-)(2,5 dimethoxy-4-iodophenyl)-2-aminopropane and ketanserin, which have higher affinity for the 5-HT2A receptor, consistent with little contribution of this locus to the selectivity of these ligands. The indoleamines studied were affected differently by mutations in each receptor, suggesting that they bind differently to the two receptor subtypes. Mutation of this locus in the 5-HT2A receptor decreased the affinity of all indoleamines, whereas the interchange mutation of the 5-HT2C receptor did not affect indoleamine affinity. These results are consistent with a direct interaction between this side chain and indoleamines for the 5-HT2A receptor but not for the 5-HT2C receptor. Furthermore, this analysis shows that the higher affinity of 5-HT and tryptamine for the 5-HT2C receptor than for the 5 HT2A receptors is not due to the difference at this locus. The hallucinogens studied [d-lysergic acid diethylamide, psilocin, bufotenin, and (+/-)-1-(2,5 dimethoxy-4-iodophenyl)-2-aminopropane] fell into different classes in this analysis. For the classes of ligand studied, the side-chain difference at this position directly determines relative ligand selectivity only for ergolines and may contribute to the specific effects of hallucinogens in this class. PMID- 8700117 TI - mu-Opioid receptors inhibit dopamine-stimulated activity of type V adenylyl cyclase but enhance dopamine-stimulated activity of type VII adenylyl cyclase. AB - The introduction of D1A dopamine receptors and mu-opioid receptors into HEK 293 cells that were also transiently transfected with adenylyl cyclase cDNA imparted to dopamine and to mu-opioid receptor agonists the ability to modulate the activity of the expressed adenylyl cyclase. Dopamine added to cells expressing D1A receptors and type V adenylyl cyclase significantly stimulated type V enzyme activity. The concomitant addition of morphine produced a dose-dependent inhibition of dopamine-stimulated type V adenylyl cyclase activity. On the other hand, if the HEK 293 cells were transfected with cDNA for type VII adenylyl cyclase instead of the type V isoform, morphine stimulated this adenylyl cyclase activity beyond the stimulation produced by dopamine. Both the inhibitory and stimulatory effects of morphine were blocked by naloxone or pretreatment of the transfected HEK 293 cells with pertussis toxin. When expressed in the HEK 293 cells, the alpha subunit of transducin, which is considered to be the putative scavenger of the beta gamma subunits of G proteins, suppressed the stimulatory effect of morphine on type VII adenylyl cyclase. We also expressed the adenylyl cyclases in cells that were transfected with D1A receptor and G beta 1 and G gamma 2 cDNAs. Dopamine was more efficacious in stimulating type VII adenylyl cyclase activity in cells concomitantly transfected with the beta gamma subunit cDNAs than in cells not transfected with these G protein subunits. Transfection with beta gamma subunit cDNAs did not affect dopamine stimulation of type V adenylyl cyclase activity, and morphine-induced inhibition of type V adenylyl cyclase activity was still evident in cells cotransfected with the alpha subunit of transducin. These data support the contention that the effects on type VII adenylyl cyclase activity mediated through the G1/G(o) proteins may depend on the actions of the beta gamma subunits. The same is not the case for type V adenylyl cyclase. Our data demonstrate that both qualitative and quantitative responses to mu-opioid receptor stimulation depend on the isoform of adenylyl cyclase expressed in neurons or other cells of the body. PMID- 8700118 TI - Bimodal distribution of renal cytochrome P450 3A activity in humans. AB - It has been proposed that excessive intrarenal conversion of cortisol to 6 beta hydroxycortisol by CYP3A may mediate increased tubular reabsorption of sodium, leading to a state of mild volume expansion and the clinical phenotype of salt sensitive hypertension. Therefore, we characterized CYP3A activity in a bank of microsomes from human kidneys using the formation of 1'-hydroxymidazolam (1'-OHM) as a prototypical CYP3A-catalyzed reaction. Maximal rates of metabolite formation occurred at midazolam concentrations of 12.5-50 microM; higher concentrations resulted in dramatic substrate inhibition. At 12.5 microM midazolam, 4 of 27 kidneys exhibited relatively high mean +/- standard deviation 1'-OHM formation rate (184.0 +/- 14.4 pmol/hr/mg) compared with the remaining 23 samples, which had a mean formation rate of (10.1 +/- 6.4 pmol/hr/mg). Triacetyloleandomycin and anti-CYP3A antibody inhibited midazolam hydroxylation by 53% and 57%, respectively. The correlation between CYP3A5 content, determined through immunoblotting, and 1'-OHM formation rate was high (r2 = 0.84, 24 experiments). The expressions of mRNA corresponding to CYP3A3, CYP3A4, CYP3A5, and CYP3A7 were determined through polymerase chain reaction with specific oligonucleotides as primers. All kidneys examined (25 experiments) expressed CYP3A5 protein and contained the corresponding CYP3A5 mRNA. CYP3A4 mRNA was detected in 40% of the kidney samples, and 70% of those that contained detectable CYP3A4 mRNA also expressed detectable levels of the corresponding protein. Therefore, in contrast to hepatic tissue, in which CYP3A4 is universally expressed, CYP3A5 is the ubiquitously expressed member of the CYP3A family in renal tissue. The distribution of enzyme activity and protein content suggests bimodality and may represent induction of CYP3A5 in a select population and/or a genetically determined organ-specific pattern of expression. PMID- 8700119 TI - (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine, a potent and selective antagonist of type 2 metabotropic glutamate receptors. AB - The pharmacological profile of (2S,1'S,2'S,3'R)-2-(2'-Carboxy-3' phenylcyclopropyl)glycine (PCCG-IV) at metabotropic glutamate receptor (mGluR) subtypes mGluR1a, mGluR2, mGluR4a, and mGluR5 was examined. PCCG-IV potently antagonized glutamate-induced inhibition of forskolin-stimulated cAMP formation in baby hamster kidney cells expressing mGluR2 in a competitive manner (KB = 8.2 +/- 0.4 microM). PCCG-IV was a weak agonist at mGluR4a but inactive at the cloned phosphoinositide-coupled mGluRs (mGluR1a and mGluR5a). PCCG-IV was significantly more potent and selective as an antagonist at mGluR2 compared with previously described mGluR2 antagonists, including alpha-methyl-4-carboxyphenylglycine. In mice cortical neurons, PCCG-IV antagonized the neuroprotective effects of a selective mGluR2 agonist, (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine, at low doses (0.2-20 microM), whereas a higher dose of PCCG-IV (80 microM) was similarly neuroprotective to L-2-amino-4-phosphonobutanoate. The neuroprotective effect of PCCG-IV was blocked by an antagonist of mGluR4a, alpha-methyl-4 phosphonophenylglycine. Thus, PCCG-IV is a novel and useful tool for delineating the physiological roles of group II mGluRs in the central nervous system. PMID- 8700120 TI - Pituitary adenylate cyclase activating polypeptide prevents apoptosis in cultured cerebellar granule neurons. AB - The two forms of pituitary adenylate cyclase-activating polypeptide, PACAP27 and PACAP38, are two neuropeptide hormones related to the vasoactive intestinal peptide/secretin/ glucagon family of peptides. PACAP receptors that are positively coupled to adenylyl cyclase and phospholipase C have been identified in cultured cerebellar granule cells. Using the reverse transcription-polymerase chain reaction methodology, we demonstrated the expression of the PACAP-R and PACAP-R-hop mRNAs in cultured granule cells. When grown in the absence of serum or in low K+ concentrations, these neurons underwent apoptosis, a naturally occurring process characterized by cell shrinkage and internucleosomal DNA cleavage. We used these models of programmed cell death to study the relationship between PACAP receptor activation and neuronal apoptosis. Treatment with PACAP27 and PACAP38 reduced the development of apoptosis in a dose-dependent manner. The neuroprotective activity of PACAP was mimicked by high concentrations of vasoactive intestinal peptide or forskolin but not by carbamylcholine. Thus, we suggest that the activation of type I PACAP receptors may contribute to the survival of cerebellar granule neurons. PMID- 8700121 TI - Peroxisome proliferator-activated receptor alpha required for gene induction by dehydroepiandrosterone-3 beta-sulfate. AB - Peroxisome proliferator-activated receptor alpha (PPAR alpha) mediates the effects of foreign chemical peroxisome proliferators on liver and kidney, including the induction of peroxisomal, mitochondrial, and microsomal enzymes involved in beta-oxidation of fatty acids. However, the role of this receptor in the peroxisome proliferative effects of the endogenous steroid dehydroepiandrosterone (DHEA) is not known. DHEA-3 beta-sulfate fd(DHEA-S) is shown to induce a liver peroxisome proliferative response in rats in vivo at a dose at which DHEA is much less active, which is consistent with cultured hepatocyte studies indicating a requirement for sulfation for the activation of DHEA. Transient transfection experiments demonstrated that in contrast to the prototypic foreign chemical peroxisome proliferator pirinixic acid, DHEA-S and its 17 beta-reduced metabolite, 5-androstene-3 beta, 17 beta-diol-3 beta-sulfate, are inactive in mediating trans-activation by PPAR alpha in COS-1 cells. Two other mammalian PPAR isoforms, gamma and delta/Nucl, were also inactive with respect to DHEA-S trans-activation. To test whether PPAR alpha mediates peroxisomal gene induction by DHEA-S in intact animals, we administered DHEA-S or clofibrate to mice lacking a functional PPAR alpha gene. Both peroxisome proliferators markedly increased hepatic expression of two microsomal cytochrome P450 4A proteins as well as six mRNAs known to be associated with the peroxisomal proliferative response in wild-type mice. In contrast, neither DHEA-S nor clofibrate induced these hepatic proteins and mRNAs in PPAR alpha-deficient mice. Clofibrate-induced expression of kidney CYP4A mRNAs was also blocked in the PPAR alpha gene knockout mice. Thus, despite its unresponsiveness to steroidal peroxisome proliferators in transfection assays, PPAR alpha is obligatory for DHEA-S-stimulated hepatic peroxisomal gene induction. DHEA-S, or one of its metabolites, may thus serve as an important endogenous regulator of liver peroxisomal enzyme expression via a PPAR alpha-mediated pathway. PMID- 8700122 TI - Ligands of the antiestrogen-binding site are able to inhibit virion production of human immunodeficiency virus 1-infected lymphocytes. AB - Since the discovery of human immunodeficiency retrovirus, the drug arsenal against retrovirus has rapidly increased. Concomitantly, new challenges in the therapy of acquired immune deficiency syndrome have arisen, including drug toxicities, drug resistance, and the development of various cancers as effective therapies prolong survival. Tamoxifen, a nonsteroidal antiestrogen with a low incidence of side effects, is widely used in cancer therapy; it is known to exert pleiotropic activities by binding essentially to the estrogen receptor and other unidentified proteins. In the present work, quantification of the p24 core protein of human immunodeficiency virus 1 produced by infected lymphocytes shows an inhibitory effect of tamoxifen on virion production. Moreover, we assume that this effect is not mediated by the estrogen receptor because antiestrogen ligands interacting with the antiestrogen-binding site exhibit efficacy related to their affinity for this site, although specific antiestrogens of the estrogen receptor are ineffective. PMID- 8700124 TI - KINFIT II: a nonlinear least-squares program for analysis of kinetic binding data. AB - We describe a versatile computer program for least-squares fitting of ligand/receptor association and dissociation curves from several experiments simultaneously. The program is designed to handle any number of classes of binding sites reacting with a single ligand that may have two forms: labeled and unlabeled. For a single class of binding sites, the exact, analytical solution is used to generate the computed curves. For more than one class of sites, the computed curves are generated through numerical solution of a set of ordinary differential equations. The parameters determined with this procedure are the on- and off-rate constants and the concentrations of each binding site class. An extensive selection of experimental designs can be processed. The times of observation may be freely chosen, although that choice will affect the quality of the results. Starting with a sample material (e.g., cells, membranes, macromolecules), one can preincubate (to equilibrium) with any combination of labeled and unlabeled ligand. One can then perturb the system by adding any combination of labeled and cold ligand or simply diluting the sample; such an experiment can be continued through several perturbations. A variety of such runs may be combined for analysis as a single data set. PMID- 8700123 TI - k-Opioid receptor activation of a dendrotoxin-sensitive potassium channel mediates presynaptic inhibition of mossy fiber neurotransmitter release. AB - Activation of kappa-opioid receptors on mossy fiber terminals in the hippocampus inhibits excitatory amino acid release. The mechanism of presynaptic inhibition at the mossy fiber synapse was investigated through whole-cell voltage-clamp of CA3 pyramidal cells. The application of a kappa-opioid agonist, U69593, reduced the amplitude of the excitatory postsynaptic current response, and this effect was reversed with a k receptor antagonist. Presynaptic potassium channels were blocked by bath application of channel toxins, and the effect of kappa receptor activation was tested. The inhibition caused by U69593 was blocked by low doses of 4-aminopyridine (30 microM) and the selective peptide toxins dendrotoxin and mast cell degranulating peptide. The inhibition was not blocked by low doses of tetraethylammonium chloride (1 mM), barium, or glibenclamide. Thus, we conclude that presynaptic kappa-opioid receptors are coupled to a Shaker-type voltage dependent potassium channel that is sensitive to dendrotoxin and mast cell degranulating peptide. An increase in presynaptic potassium conductance would enhance the rate of repolarization after action potential invasion, thereby limiting calcium influx and neurotransmitter release. This is the first physiological demonstration of the involvement of a dendrotoxin-sensitive potassium current in presynaptic inhibition mediated by a G protein-coupled receptor. PMID- 8700125 TI - Genetic evidence for involvement of multiple effector systems in alpha 2A adrenergic receptor inhibition of stimulus-secretion coupling. AB - The alpha 2A-adrenergic receptor (alpha 2AAR), via its interaction with the pertussis toxin-sensitive Gi/G(o) class of G proteins, modulates multiple effector systems, including inhibition of adenylyl cyclase and Ca2+ channels and activation of K+ channels. Mutation of a membrane-embedded aspartate residue, highly conserved among G protein-coupled receptors, in the alpha 2AAR to asparagine (D79N alpha 2AAR) results in selective uncoupling of the receptor to K+ currents but retention of inhibition of cAMP production and of voltage sensitive Ca2+ currents when expressed in AtT20 anterior pituitary cells in culture. It is known that attenuation of cAMP synthesis alone cannot account for alpha 2AAR suppression of stimulus-secretion coupling; thus, the D79N alpha 2AAR provides a unique tool with which to assess the relative contribution of K+ current activation and Ca2+ current suppression in mediating the cellular responses of alpha 2AAR. The wild-type alpha 2AAR suppresses basal and secretagogue-evoked adrenocorticotropic hormone (ACTH) release in a manner indistinguishable from response to the endogenous somatostatin receptor. In contrast, the D79N alpha 2AAR does not attenuate basal ACTH release and is only partially effective in suppressing ACTH secretion evoked by the secretagogue isoproterenol. Regulation of ACTH release evoked by 8-bromo-cAMP, which bypasses receptor regulation of cAMP synthesis, suggests that attenuation of cAMP production, although not sufficient for inhibition of ACTH secretion, nevertheless participates in a functionally relevant manner. Taken together, the present findings indicate that alpha 2AAR-mediated suppression of neuropeptide secretion requires concomitant regulation of K+ and Ca2+ currents in parallel with attenuation of cAMP production. PMID- 8700126 TI - Differential expression of sumatriptan-sensitive 5-hydroxytryptamine receptors in human trigeminal ganglia and cerebral blood vessels. AB - The efficacy of sumatriptan in migraine relief has been attributed to its interaction with 5-hydroxytryptamine1D (5-HT1D) receptors in cerebral blood vessels and/or on nerve endings of the trigeminovascular system in the dura mater. Using the high sensitivity of polymerase chain reaction (PCR) amplification, we investigated the expression of the sumatriptan-sensitive 5-HT receptors, namely, the 5-HT1D alpha, 5-HT1D beta, and 5-HT1F subtypes in human trigeminal ganglia (10 experiments) and cerebral blood vessels (seven experiments) obtained postmortem. Messages for the 5-HT1D alpha and 5-HT1D beta receptors were expressed in all except one of the 10 trigeminal ganglia studied. Expression of the 5-HT1F receptor was detected by gel electrophoresis of the PCR products in six ganglia and by Southern blot hybridization in two additional cases. In human brain vessels, message for the 5-HT1D beta receptor was present in all samples, whereas specific PCR products corresponding to the 5-HT1D alpha receptor could hardly be detected in only two preparations. PCR products indicative of the 5-HT1F receptor message were detected by gel electrophoresis in three brain vessel preparations and confirmed in the other four by Southern blot hybridization. Restriction mapping and sequence analysis of all PCR products identified the expected human 5-HT receptor DNA sequences. The data confirm that the 5-HT1D beta receptor is the dominant species in human cerebral blood vessels and further show that this receptor and the 5-HT1F are expressed in both neural and vascular tissues. In contrast, the data point to a preferential expression of 5-HT1D alpha receptors in neural versus vascular tissues and strongly reemphasize the need for selective 5-HT1D alpha agonists in the identification of the target tissue(s) for antimigraine drugs. Moreover, the data stress the importance to better understand the role of 5-HT1F receptors in cerebrovascular functions and dural inflammation and further raise interest regarding their possible involvement in migraine therapy. PMID- 8700127 TI - Uridine nucleotide selectivity of three phospholipase C-activating P2 receptors: identification of a UDP-selective, a UTP-selective, and an ATP- and UTP-specific receptor. AB - Observation that the G protein-coupled P2U receptor (P2Y2 receptor) is activated by UTP as well as ATP provided the first indication that a class of uridine nucleotide-responsive receptors might exist. This hypothesis was confirmed by our identification of a uridine nucleotide-specific receptor on C6-2B rat glioma cells and by the recent cloning of two uridine nucleotide-responsive receptors, the P2Y6 receptor [J. Biol. Chem. 270:26152-26158 (1995)] and the P2Y4 receptor [J. Biol. Chem. 270:30849-30852 (1995) and J. Biol. Chem. 270:30845-30848 (1995)]. The relative nucleotide selectivities of these uridine nucleotide activated receptors have not been established. Therefore, we cloned and expressed the P2Y6 and P2Y4 receptors in 1321N1 human astrocytoma cells and compared their relative selectivities for UDP, UTP, and other uridine and adenine nucleotides with that of the P2Y2 receptor expressed in the same cells. These comparisons were made by measuring inositol phosphate accumulation under conditions in which the initial purity and stability of agonists were rigidly ensured and quantitatively assessed. The data indicate that the P2Y2 receptor is activated with similar potencies by ATP and UTP but not by ADP or UDP; the P2Y6 receptor is activated most potently by UDP but weakly by UTP, ATP, and ADP; and the P2Y4 receptor is activated most potently by UTP, less potently by ATP, and not at all by nucleotide diphosphates. Furthermore, the P2Y6 receptor, which displays a uridine nucleotide selectivity essentially identical to that of the uridine nucleotide-specific receptor in C6-2B cells, was shown to be natively expressed in C6-2B cells and to account for the uridine nucleotide responses originally identified in these cells. These results define the uridine nucleotide selectivity of three phospholipase C-linked receptors: a receptor that is selectively activated by UDP (P2Y6 receptor), selectively activated by UTP (P2Y4 receptor), and activated by UTP and ATP but not by diphosphate nucleotides (P2Y2 receptor). PMID- 8700128 TI - Leptin, the obese gene product, rapidly modulates synaptic transmission in the hypothalamus. AB - We examined the effects of leptin, the product of the obese gene, on synaptic transmission in the arcuate nucleus in rat hypothalamic slices. Both leptin and neuropeptide Y (NPY) reduced the evoked glutamatergic excitatory postsynaptic current in the arcuate nucleus. NPY also depressed the GABAergic inhibitory postsynaptic current, although leptin had no effect. Leptin also decreased the input resistance of arcuate neurons, and this was accompanied by the activation of an outward current at depolarized potentials. Leptin modulated Ca2+ signals in acutely isolated arcuate neurons. In some cells, the intracellular calcium concentration rise produced by 50 mM K+ was decreased, whereas in others it was increased. However, leptin produced no effects on synaptic transmission and little or no effect on Ca2+ signaling in the hypothalamus of Zucker fatty rats that contain mutated leptin receptors. On the other hand, NPY exhibited synaptic modulatory effects in Zucker lean and fatty rats. These data suggest that leptin can produce rapid synaptic modulatory effects in the arcuate nucleus, which may contribute to its effects on food intake. PMID- 8700129 TI - Treatment of glioblastoma U-87 by systemic administration of an antisense protein kinase C-alpha phosphorothioate oligodeoxynucleotide. AB - Glioblastoma multiforme is the most common form of malignant brain cancer in adults and, unfortunately, is not amenable to treatment with current therapeutic modalities. Human glioblastoma U-87 has many of the distinguishing phenotypic features of primary glioblastoma, including an autocrine form of proliferation, high levels of protein kinase C alpha (PKC alpha), and infiltration via white matter tracts. We show that treatment of mice bearing U-87 xenografts with an antisense phosphorothioate oligodeoxynucleotide (S-oligodeoxynucleotide) against the 3'-untranslated region of PKC alpha mRNA results in suppression of tumor growth. Growth was inhibited in both subcutaneous and intracranial tumors, and in the latter instance, treatment with the antisense PKC alpha S oligodeoxynucleotide resulted in a doubling in median survival time ( > 80 days), with 40% long term survivors. The antisense S-oligodeoxynucleotide did not produce systemic toxicity in mice with subcutaneous or intracranial tumors after daily intraperitoneal injection for 21 or 80 days, respectively, and a scrambled S-oligodeoxynucleotide with the same nucleotide composition as the antisense S oligodeoxynucleotide did not produce an antitumor effect. The intratumoral levels of both antisense and scrambled S-oligodeoxynucleotide in subcutaneous tumors were 2 microM after 21 daily doses of 20 mg/kg S-oligodeoxynucleotide. The antisense S-oligodeoxynucleotide selectively reduced the levels of PKC alpha in subcutaneous tumors but not those of protein kinase C epsilon or protein kinase C zeta. This is the first demonstration that the growth of glioblastoma multiforme can be suppressed by an antisense PKC alpha S-oligodeoxynucleotide and suggests that this may represent an effective therapy for this type of malignancy. PMID- 8700130 TI - Resistance to etoposide in human leukemia HL-60 cells: reduction in drug-induced DNA cleavage associated with hypophosphorylation of topoisomerase II phosphopeptides. AB - Tumor cell resistance to anthracyclines and epipodophyllotoxins can be due to reduced drug accumulation and/or alterations in the activity of topoisomerase II (TOPO II). HL-60 cells selected in 0.05 micrograms/ml doxorubicin (DOX) are 10 fold and > 20-fold resistant to DOX and etoposide (VP-16), respectively. The accumulation of [3H]VP-16 was 2-3-fold lower in the resistant cells (HL-60/DOX 0.05) than in similarly treated parent-sensitive cells (HL-60/S). However, compared with HL-60/S cells, the HL-60/DOX 0.05 cells required > 20-fold higher concentrations of VP-16 to produce equivalent damage to DNA. The reduced formation of VP-16-stabilized DNA cleavable complex in the HL-60/DOX 0.05 cells was not due to differences in the amount of 170-kDa TOPO (alpha) II protein or enzyme catalytic activity between HL-60/S and HL-60/DOX 0.05 cells. Metabolic labeling with [32P]orthophosphoric acid and immunoprecipitation indicated that the level of phosphorylated 170-kDa TOPO II alpha protein in the HL-60-/S cells was 2.2 +/- 0.4-fold higher than that in HL-60/DOX 0.05 cells. Hypophosphorylation (3-fold) of 170-kDa TOPO II protein in HL-60/S cells treated with the calcium chelator 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester produced a > 2-fold reduction in VP-16-induced TOPO II mediated DNA cleavable complex formation. Two-dimensional mapping of phosphopeptides in complete tryptic digests demonstrated that the reduced phosphorylation of the 170-kDa TOPO II alpha in HL-60/DOX 0.05 cells was due to the hypophosphorylation of at least three phosphopeptides characteristic of HL 60/S cells. Thus, the attenuated ability of TOPO II to form drug-stabilized DNA cleavable complex is related to the phosphorylated state of 170-kDa TOPO II, and in HL-60/DOX 0.05 cells, resistance may be related to hypophosphorylation of three phosphopeptides characteristic of HL-60/S cells. PMID- 8700131 TI - Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced ornithine decarboxylase activity by genistein, a tyrosine kinase inhibitor. AB - The effects of the protein tyrosine kinase inhibitor genistein on 12-O tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) activity in monkey kidney epithelial CV-1 cells were determined. CV-1 cells were pretreated with genistein for 2 hr before treatment with 100 nM TPA. ODC activity was determined 9 hr after TPA treatment. Genistein inhibited TPA-induced ODC activity at 0.1, 1, 10, 25, 50, 100, 200, and 400 microM by 0%, 0%, 42%, 59%, 62%, 81%, 91%, and 100%, respectively (IC50 = 20 microM). Genistein inhibited TPA induced mitogen-activated protein kinase (MAPK) tyrosine phosphorylation and the accumulation of steady state levels of ODC mRNA at 400 microM but not at 25 microM. Genistein, at 25 microM, did not alter the TPA-induced phosphorylation of p90 ribosomal S6 kinase but caused a approximately 50% decrease of the TPA induced phosphorylation of p70 S6 kinase (p70S6K), a protein kinase involved in the control of translational efficiency. Taken together, these data indicate that genistein may inhibit TPA-induced ODC activity at the transcriptional and translational levels through the inhibition of MAPK and p70S6K activation, respectively. The regulation of MAPK and p70S6K may be mediated through different protein tyrosine kinases that have differential sensitivity to genistein. PMID- 8700132 TI - A novel G protein-coupled P2 purinoceptor (P2Y3) activated preferentially by nucleoside diphosphates. AB - A partial cDNA was isolated by hybridization screening of an embryonic chick brain library for P2Y purinoceptors. After extension to full length, it revealed an open reading frame that encoded a protein, P2Y3, of 328 amino acids that is nearest in sequence identity to the G protein-coupled P2 purinoceptors obtained by DNA cloning. Expression of P2Y3 in cRNA-injected Xenopus oocytes confirmed that this cDNA encodes a member of the metabotropic purinoceptor family, with a novel order for the relative activities of nucleotides. At 100 microM concentrations, ADP gave the highest activity, and UTP and UDP were also strongly active. When expressed in the human T cell line Jurkat, P2Y3 mediated transient increases in intracellular Ca2+ in response to various nucleotides. Again, an unusual agonist rank order was revealed, with uridine nucleotides being more potent than adenosine nucleotides and UDP being the most potent agonist tested (half-maximal concentration, 0.13 microM) and 10-fold more potent than UTP. 2 Methylthlo-ATP was of relatively low activity in both systems. The receptor transcript is expressed in brain, spinal cord, kidney, and lung and is highly abundant in the spleen but not in other peripheral tissues that we tested. The results indicated that P2Y3 is a previously unknown P2 purinoceptor subtype with a preference for nucleoside diphosphates. PMID- 8700133 TI - Inability to N-glycosylate the human norepinephrine transporter reduces protein stability, surface trafficking, and transport activity but not ligand recognition. AB - The role of N-glycosylation in the expression, stability, and ligand recognition by the cocaine- and antidepressant-sensitive human norepinephrine transporter (hNET) was assessed in stably and transiently transfected cell lines. The use of hNET-specific antibodies and the membrane-impermeant biotinylating reagent sulfosuccinimidobiotin establishes that treatment of stably transfected LLC-PK1 cells with tunicamycin depletes surface membranes of mature hNET glycoproteins, which is consistent with a failure of less stable, nonglycosylated subunits to replenish surface compartments. To determine whether N-glycosylation plays a direct role in hNET stability, surface expression, and ligand recognition, we mutated the three hNET canonical N-glycosylation sites (hNETN184, 192, 198Q) and transiently expressed the mutant cDNA in parallel with the parental hNET construct in HeLa and COS cells. hNETN184, 192, 198Q protein exhibited increased electrophoretic mobility (approximately 46 kDa), similar to that of enzymatically N-deglycosylated hNET protein, which confirms the use of canonical sites in the second extracellular loop of the transporter. hNETN184, 192, 198Q protein in HeLa and COS extracts was reduced approximately 50% relative to hNET protein in parallel transfections, demonstrated to arise from a reduction in transporter half-life, which is consistent with the proposed role of N-glycosylation in hNET stability. Both HeLa and COS cells transfected with hNETN184, 192, 198Q exhibit a significantly greater reduction in transport activity than can be accounted for by losses in either total or surface NET protein. Furthermore, sensitivity of catecholamine transport to unlabeled substrate and antagonists was unchanged in the mutant, suggesting that residual nonglycosylated surface hNETs execute a key step in the transport cycle after ligand recognition with reduced efficiency. PMID- 8700134 TI - Characterization of hepatic nitric oxide synthase: identification as the cytokine inducible form primarily regulated by oxidants. AB - Induction of hepatic nitric oxide synthase (NOS) by tumor necrosis factor-alpha (TNF alpha), interleukin-1 beta (IL-1 beta), interferon-gamma (IFN gamma), interleukin-6 (IL-6), and lipopolysaccharide was assessed as activity and immunoreactive protein. Hepatic NOS activity was cytosolic and had cofactor requirements consistent with inducible nitric oxide synthase (NOS2). NOS induction by TNF alpha was dose dependent from concentrations of 0.06 to 60 nM and was increased 2-3-fold by IFN gamma. NOS induction was reflective of total TNF alpha binding to hepatocyte receptors. Hepatocyte TNF alpha binding fit a biphasic curve with high affinity (K(d) = 1.4 nM, Bmax = 3157 sites) and low affinity (K(d) = 157 nM, Bmax = 204,948 sites) elements. NOS2 activity was induced by lipopolysaccharide, IL-1 beta, TNF alpha, and IFN gamma but not by IL 6. All cytokine stimuli were inhibited by antioxidants. Oxygen radical generation was directly measured as dichlorofluoroscein fluorescence in isolated mitochondria. Mitochondria from TNF alpha-treated hepatocytes generated more oxygen radicals than did controls. Antioxidants reduced mitochondrial generation of oxygen radicals. Activation of the transcription factor nuclear factor-kappa B by TNF alpha, IFN gamma, and IL-1 beta was assessed by gel shift analysis. Cytokine treatment increased nuclear factor-kappa B binding, and the addition of antioxidants or rotenone inhibited cytokine activation. Taken together, these data suggest that oxygen radicals, possibly generated by mitochondria, play a major role in NOS2 induction by cytokines. PMID- 8700135 TI - Neuropeptide Y and the nonpeptide antagonist BIBP 3226 share an overlapping binding site at the human Y1 receptor. AB - Neuropeptide Y (NPY) is a 36-amino acid peptide that exhibits actions on the cardiovascular system and the central nervous system. NPY can regulate blood pressure, psychomotor function, anxiety, food intake, and endocrine secretions. BIBP 3226, the first potent and selective nonpeptide antagonist at the NPY Y1 receptor, was designed by mimicking the carboxyl-terminal structure of NPY. We investigated the interaction of NPY and BIBP 3226 with the human Y1 receptor at the molecular level. Alanine mutants at positions Y100, D104, W288, and H298 of the human Y1 receptor showed no or significantly reduced binding for NPY but were not affected in their ability to bind BIBP 3226. Receptors with alanine mutations at positions W163, F173, Q219, N283, F286, and D287 showed reduced binding for both NPY and BIBP 3226. Mutations at other positions were tested (H105, S170, L174, V178, D200, D205, S206, H207, S210, T212, T280, T284, N289, H290, and Q291) and did not affect the binding of NPY or BIBP 3226. The human Y1 receptor mutant Y211A showed no affinity for BIBP 3226 but retained wild-type affinity for NPY. Based on these experimental results, a detailed model for the interaction of BIBP 3226 with the human Y1 receptor was developed using a Y1 receptor model and a three-dimensional model of BIBP 3226. The experimental results, supported by modeling studies, clearly suggest that the native ligand (NPY) and the antagonist (BIBP 3226) share an overlapping binding site. PMID- 8700136 TI - Differential blockade of opioid analgesia by antisense oligodeoxynucleotides directed against various G protein alpha subunits. AB - Antisense oligodeoxynucleotides directed against various G protein alpha subunits differentially block the analgesic actions of mu-, delta-, and kappa-opioid agonists in mice. Intracerebroventricular administration of oligodeoxynucleotides targeting Gi alpha 2, G(o) alpha, and Gs alpha block supraspinal mu-opioid analgesia, whereas Gi alpha 2 and Gx/z alpha antisense probes block spinal mu analgesia. Although supraspinal and spinal morphine-6 beta-glucuronide (M6G) analgesia also is sensitive to these antisense treatments, its sensitivity profile differs from that of morphine, implying the existence of a different analgesic system. Gi alpha 1 and Gx/z alpha antisense probes block supraspinal M6G analgesia, whereas Gi alpha 1, Gi alpha 3, G(o) alpha, and Gx/z alpha antisense probes block spinal M6G analgesia. Spinal delta-opioid analgesia is blocked by antisense probes to all of the G protein alpha subunits tested, whereas kappa 1-opioid analgesia is sensitive to only Gq alpha. The kappa 3 agonist naloxone benzoylhydrazone produces its analgesia through supraspinal mechanisms and is blocked by Gi alpha 1, Gi alpha 3, Gs alpha, Gq alpha, and Gx/z alpha antisense oligodeoxynucleotides. Together, these results support the presence of seven different analgesic systems for these various opioid agonists. PMID- 8700137 TI - Irreversible inhibition of forskolin interactions with type I adenylyl cyclase by a 6-isothiocyanate derivative of forskolin. AB - Forskolin (Fsk) has been demonstrated to interact directly with the enzyme adenylyl cyclase (EC 4.6.1.1) in diverse tissues. However, the ability of Fsk to bind to and activate adenylyl cyclase varies depending on the tissue being studied. Different adenylyl cyclase subtypes have been cloned and expressed in a recombinant Sf9 expression system. This provides an opportunity to study the effects of chemically reactive derivatives of Fsk on individual adenylyl cyclase subtypes in the absence of Gs alpha. Reaction of type I adenylyl cyclase with an isothiocyanate derivative of Fsk (6-[[N-(2 isothiocyanatoethyl)amino]carbonyl]forskolin) causes irreversible inhibition of Fsk binding with an IC50 of 300 nM and irreversible inhibition of Fsk activation with an IC50 of 10 microM, suggesting that there are two sites of 6-[[N-(2 isothiocyanatoethyl)amino]carbonyl]forskolin interaction. These studies establish the usefulness of the isothiocyanate derivative of Fsk in localizing the site(s) of Fsk interaction with type I adenylyl cyclase. PMID- 8700138 TI - Rapid agonist-induced internalization of the 5-hydroxytryptamine2A receptor occurs via the endosome pathway in vitro. AB - The mechanism by which agonists induce 5-hydroxytryptamine2A (5-HT2A) receptor internalization was investigated in a clonal cell line stably transfected with the 5-HT2A receptor cDNA. Confocal laser microscopy of immunolabeled 5-HT2A receptors in control (untreated) cells demonstrated that most of the immunoreactivity was associated with the cell surface. After quipazine administration, a significant increase in intracellular immunofluorescence was measured. Time course studies demonstrated rapid agonist-dependent internalization of 5-HT2A receptors, with significant internalization occurring as early as 5 min after agonist administration at 37 degrees. In GF-62 cells, agonist-induced internalization was blocked by preincubation with the 5-HT2A receptor antagonist ketanserin. Internalization was also temperature sensitive because agonist-induced internalization did not occur at 4 degrees. Dual-label experiments disclosed that 5-HT2A and transferrin receptors were internalized via the same endocytotic vesicles. These results suggest that 5-HT2A receptors and transferrin receptors are internalized via the endosomal pathway in GF-62 cells. Although 5-HT2A receptors were internalized, down-regulation, or loss of radioligand binding sites, did not occur. Our results demonstrate that agonists rapidly induce 5-HT2A receptor internalization via the endosomal pathway and that internalization can be dissociated from down-regulation. PMID- 8700139 TI - A nonantisense sequence-selective effect of a phosphorothioate oligodeoxynucleotide directed against the epidermal growth factor receptor in A431 cells. AB - The overexpression of epidermal growth factor receptor (EGFr) has been implicated as a causative factor and a poor prognostic marker in a number of carcinomas. Therefore, strategies that down-regulate EGFr expression may be therapeutically useful. We designed antisense ODNs complementary to the initiation codon region of the EGFr mRNA and evaluated their efficacy in several tumor-derived cells, including the A431 cell line, that express amplified levels of EGFr. A 15-mer phosphorothioate (PS) antisense ODN (erbB1AS15) induced a concentration-dependent reduction in proliferation that was accompanied by a change in the morphology of A431 cells into more tightly clustered and discrete colonies. A 15-mer sense (PS) control oligodeoxynucleotide (ODN) and a phosphodiester (PO) version of erbB1AS15 had little or no effect on cell number of morphology, and erbB1AS15 (PS) did not induce these effects in control cell lines expressing lower levels of EGFr. The effects of erbB1AS15 (PS) on A431 cells were not mediated by a true antisense mechanism in that there was no reduction in the level of EGFr mRNA or protein over a 24-hr period, as determined by Northern and Western blotting, respectively. However, autophosphorylation of the receptor was significantly reduced by erbB1AS15 (PS) and not by control ODNs. The results of further studies suggested that this effect was mediated by a direct, dose-dependent inhibition of the EGFr tyrosine kinase enzyme and was not due to impairment of either ligand binding or receptor dimerization. These data suggest that erbB1AS15 (PS) can inhibit proliferation and alter the morphology of A431 cells by a sequence selective, but nonantisense, mechanism affecting receptor tyrosine kinase activity. PMID- 8700140 TI - Tienilic acid-induced autoimmune hepatitis: anti-liver and-kidney microsomal type 2 autoantibodies recognize a three-site conformational epitope on cytochrome P4502C9. AB - Tienilic acid-induced hepatitis is characterized by the presence of anti-liver and -kidney microsomal (anti-LKM2) autoantibodies in patient sera. Cytochrome P4502C9(CYP2C9), involved in the metabolism of tienilic acid, was shown to be a target for tienilic acid-reactive metabolites and for autoantibodies. To further investigate the relationship between drug metabolism and the pathogenesis of this drug-induced autoimmune disease, the specificity of anti-LKM2 autoantibodies toward CYP2C9 was first determined, and the antigenic sites on CYP2C9 were localized. By constructing several deletion mutants derived from CYP2C9 cDNA and by probing the corresponding proteins with different anti-LKM2 sera, we defined three regions (amino acids 314-322, 345-356, and 439-455); they interacted to form a major conformational autoantibody binding site. This binding site was immunoreactive with 100% of sera and allowed removal of the entire reactivity of the sera tested by immunoblotting. Epitope mapping studies have been performed for CYP2D6, CYP17, CYP21A2, and, recently, CYP3A. Those data were compared with the results obtained in the current study with CYP2C9 in an attempt to elucidate one of the mechanisms by which CYP becomes immunogenic. PMID- 8700141 TI - Attenuation of inducible nitric oxide synthase gene expression by delta 9 tetrahydrocannabinol is mediated through the inhibition of nuclear factor- kappa B/Rel activation. AB - delta 9-Tetrahydrocannabinol (delta 9-THC) a prototypic compound belonging to the family of agents known as cannabinoids, produces a wide variety of biological effects, including inhibition of immune function. The putative mechanism for cannabinoid biological action involves binding to cannabinoid receptor types 1 and 2 (CB1 and CB2) to negatively regulate adenylate cyclase and inhibit intracellular signaling via the cAMP cascade. In the current study, we show that delta 9-THC produces a marked inhibition of inducible nitric oxide synthase (iNOS) transcription and nitric oxide production by the macrophage line RAW 264.7 in response to lipopolysaccharide (LPS). Analysis of RAW 264.7 cell RNA demonstrated transcripts for CB2 but not CB1. Treatment of RAW 264.7 with delta 9 THC inhibited forskolin-stimulated cAMP production in a dose-related manner, verifying the expression of functional cannabinoid receptors by this cell line. iNOS transcription, which is regulated in part by the nuclear factor-kappa B/Rel (NF-kappa B/Rel) family of transcription factors, has been shown to be under the control of the cAMP signaling cascade. We demonstrate that delta 9-THC inhibits the activation and binding of NF-kappa B/Rel proteins to their cognate DNA site, kappa B, in response to LPS stimulation. LPS treatment of RAW 264.7 cells also induced the activation of the cAMP cascade, as indicated by an increase in binding of nuclear factors to the cAMP response element. Activation of CRE binding proteins was inhibited by delta 9-THC. Forskolin treatment of RAW 264.7 cells induced both kappa B and cAMP response element binding activity and was likewise inhibited by delta 9-THC. Collectively, this series of experiments indicates that NF-kappa B/Rel is positively regulated by the cAMP cascade to help initiate iNOS gene expression in response to LPS stimulation of macrophages. This activation of iNOS is attenuated by delta 9-THC through the inhibition of cAMP signaling. PMID- 8700142 TI - Cytochrome P4502D4 in the brain: specific neuronal regulation by clozapine and toluene. AB - Twenty-four hr after a single dose of the neuroleptic drug clozapine, cytochrome P4502D4 (P4502D4) immunoreactivity, which was barely detectable in the brains of untreated rats, was clearly evident in neurons of the substantia nigra pars compacta, ventral tegmental area, granular neurons of the olfactory bulb, and Purkinje and granular neurons of the cerebellum. Induction was maintained with daily administration for 3 weeks. The mRNA for P4502D4 was detected by Northern blotting and localized by in situ hybridization in neurons throughout the brain and in the Bergman glia in the cerebellum. There were no detectable changes in the distribution or quantity of P4502D4 mRNA after treatment with clozapine. The overall P450 content of the brain increased with daily administration to a approximately 7-fold induction by 3 weeks of clozapine treatment. No induction of 2D4 was observed with the dopamine D2 receptor blockers haloperidol, chlorpromazine, and sulpiride or with the serotonin receptor blocker mianserin. A clozapine-like induction of P4502D4 was obtained on administration of toluene to rats. The specificity of the induction of P4502D4 in the brain with respect to both the drugs that induce it and the cells in which it is induced suggests that induction of this enzyme could be involved in the therapeutic action of clozapine. The similarity of induction of P4502D4 elicited by clozapine and by the neurotoxin toluene suggests that more information is needed before a beneficial or toxicological role can be assigned to this isozyme. PMID- 8700143 TI - Structural requirements for G(o) activation by receptor-derived peptides: activation and modulation domains of the alpha 2-adrenergic receptor i3c region. AB - Synthetic peptides are important tools for understanding the sites and mechanisms of receptor/G protein interactions. We examined the structural determinants of receptor-fragment peptides for G protein binding and activation. A dimer of peptides from the carboxyl-terminal (i3c) and amino-terminal (i3n) regions of the alpha 2A-adrenergic receptor is most potent in stimulating guanine-nucleotide exchange of any peptides studied. Stimulation of GTPase by i3n is partially blocked by pertussis toxin treatment, whereas stimulation by i3c is not, which is consistent with action of i3c at the amino terminus of Gi. Both peptides inhibit adenylyl cyclase in Chinese hamster ovary cell membranes, but only the i3c effect is consistent with a pure Gi stimulation. We also examined the mechanism and defined a minimal structural subset of i3c required for G protein activation. Residues 361-365 from the receptor were essential for GTPase stimulation, whereas determinants in the region 368-373 modulated that activity. A specific role for arginines is defined beyond just their positive charge. Complex effects of modifications of Thr373 suggest a regulatory or conformational role of that residue in the previously defined constitutive activation of the alpha 2 adrenergic receptor [J. Biol. Chem. 268:16483-16487 (1993)]. Thus, our data plus recent mutagenesis results support a role for hydrophobicity in the i3n region and a positively charged/arginine-rich region approximately 15-20 residues from the sixth transmembrane span in G protein activation. In contrast, the immediate perimembrane region of i3c seems to have largely conformational effects in producing constitutive activation of the receptors. PMID- 8700144 TI - Potent inhibition of human immunodeficiency virus and herpes simplex virus type 1 by 9-(2-phosphonylmethoxyethyl)adenine in primary macrophages is determined by drug metabolism, nucleotide pools, and cytokines. AB - The efficacy of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) against the replication of human immunodeficiency virus (HIV) and herpes simplex virus type 1 (HSV-1) and its cellular metabolism were investigated in human primary macrophages from seronegative donors. PMEA potently inhibited the replication of both HIV and HSV-1 in macrophages, with similar EC50 values (0.025 and 0.032 microM, respectively), whereas the EC50 values of PMEA in lymphocytic C8166 cells and fibroblastoid Vero cells were 150-200-fold higher (3.5 and 7.9 microM, respectively). Granulocyte/macrophage colony-stimulating factor and macrophage colony-stimulating factor, two cytokine enhancers of the replication of HIV (and HSV-1), decreased the activity of PMEA against both viruses, yet EC50 values were still lower than in lymphocytes and fibroblasts. Thus, the selectivity index of PMEA in macrophages was > 2 orders of magnitude higher than that in lymphocytes and fibroblasts and still > 1 log higher under conditions of enhancement of virus replication in macrophages. The intracellular levels of 2'-deoxyadenosine-5' triphosphate, the natural competitor of PMEA-diphosphate at the level of viral DNA polymerase (either RNA or DNA dependent), were 5-12-fold lower in macrophages than in other cells. Furthermore, intracellular concentrations of PMEA diphosphate (the active metabolite of PMEA) were unusually much higher in macrophages (with or without cytokines) than in lymphocytes and fibroblasts. Consequently, the ratio of PMEA-diphosphate to 2'-deoxyadenosine-5'-triphosphate in monocytes/macrophages was approximately 2 orders of magnitude higher in macrophages than in the other cells and correlated closely with the pronounced antiviral potency of PMEA. The dual potent activity of PMEA against HIV and HSV-1 stresses the importance of clinical trials to assess the role of this drug in the therapy of HIV-related disease. PMID- 8700145 TI - Thrombin-stimulated phospholipase C activity is inhibited without visible delay by a rapid increase in the cyclic GMP levels induced by sodium nitroprusside. AB - Different drugs that elevate the cGMP levels inhibit the agonist-induced platelet activation. The mechanisms of action of cGMP probably include inhibition of both phospholipase C and the increase in intracellular Ca2+ concentration, and these effects seem to be mediated by cGMP-dependent protein kinases. However, in most studies, cells were preincubated with nitrovasodilators before stimulation. The effect of the preincubation with sodium nitroprusside before stimulation or the simultaneous addition of sodium nitroprusside and thrombin has been compared. The simultaneous addition of sodium nitroprusside and thrombin was able to inhibit without any significant delay the platelet aggregation. This rapid effect was correlated with an inhibition of both the maximum increase in intracellular Ca2+ concentration and the phospholipase C activity. Also, the simultaneous addition of sodium nitroprusside and thrombin clearly accelerated the decline in the Ca2+ signal, which was not observed in platelets preincubated with sodium nitroprusside. The rapid inhibition induced by sodium nitroprusside was correlated with a rapid and significant increase in the cGMP levels and reversed when platelets were pretreated with methylene blue. The inhibitor of cAMP dependent protein kinase Rp-8-(4-chlorophenylthio)-adenosine-3',5'-cyclic monophosphorothioate was able to abolish nearly completely the inhibitory effect induced by sodium nitroprusside independent of the protocol used. Thus, the rapid inhibition induced by sodium nitroprusside seems to be induced by a rapid phosphorylation-dependent mechanism. In addition, both cGMP- and cAMP-dependent protein kinase seem to be involved; however, the cAMP-dependent protein kinase seems to be more important. PMID- 8700146 TI - Mapping the block of a cloned human inward rectifier potassium channel by dofetilide. AB - Dofetilide, a methanesulfonanilide derivative, is a potent class III antiarrhythmic drug. Like other members of this class of K+ channel blockers, the sites in the channel to which the drug binds are unknown, although high and low affinity binding has been reported in cardiomyocytes. The most sensitive K+ channel target for dofetilide seems to be IKr, the rapid component of the repolarizing delayed rectifier K+ current. However, block of other K+ channels occurs at higher concentrations and is of special interest in regard to toxicity. Recently, we have demonstrated that hIRK, a cloned inward rectifier K+ channel (IRK) isolated from human atrium and expressed heterologously in Xenopus oocytes, is blocked by dofetilide. We report the localization of a site that is critical for dofetilide block in hIRK. We used chimeric constructs between hIRK and ROMK1, a related inward rectifier that is drug resistant. Substitution of hIRK-M2, the second putative transmembrane spanning segment of IRKs, with ROMK1-M2 increased unblocking of dofetilide by 10-20-fold in hIRK. Site-directed mutagenesis further pinpointed the effects to a single hydrophobic residue (I177) in M2. A reduction in hydrophobicity by the point mutation I177C increased recovery from block > 10 fold (1.17 sec in wild-type to 0.112 sec at -80 mV at physiological K+ concentrations), leading us to suggest that hydrophobic interactions are essential for dofetilide block in hIRK. A similar mechanism may explain dofetilide block in other ion channels, including IKr. PMID- 8700147 TI - Transport of the antiviral nucleoside analogs 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine by a recombinant nucleoside transporter (rCNT) expressed in Xenopus laevis oocytes. AB - Expression screening in Xenopus oocytes has been used to isolate a cDNA from rat jejunal epithelium encoding an intestinal/kidney Na(+)-dependent nucleoside transporter protein named rCNT1 [J. Biol. Chem. 269:17757-17760 (1994)]. rCNT1 is predicted to have 648 amino acid residues (relative molecular mass, 71,000) with 14 potential transmembrane domains and belongs to a new family of transporter proteins. Recombinant rCNT1 transports physiological pyrimidine nucleosides and adenosine. In the current investigation, functional expression in Xenopus oocytes was used to determine whether recombinant rCNT1 also transports antiviral pyrimidine nucleoside analogs. The recombinant protein mediated Na(+)-dependent transport of both 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC). Apparent K(m) values of '0.5 mM were obtained for both [3H]AZT and [3H]ddC influx compared with 37 microM for [3H]uridine influx, with Vmax/Km ratios of 0.048, 0.039, and 0.57 for AZT, ddC, and uridine, respectively. Extracellular AZT and ddC stimulated rCNT1-mediated efflux of [3H]uridine from preloaded oocytes. These experiments provide direct evidence for Na(+)-dependent transport of AZT and ddC and suggest that members of the cNT family may be involved in the intestinal absorption and renal handling of pyrimidine nucleoside analogs used to treat acquired immune deficiency syndrome. PMID- 8700148 TI - Highly favorable antiviral activity and resistance profile of the novel thiocarboxanilide pentenyloxy ether derivatives UC-781 and UC-82 as inhibitors of human immunodeficiency virus type 1 replication. AB - The novel human immunodeficiency virus type 1-specific thiocarboxanilide derivatives that contain either a substituted furanyl (UC-781) or thienyl (UC-82) ring linked to the thiocarboxy group and a pentenyloxyether chain linked to the 4 chlorophenyl ring in meta position show highly favorable antiviral properties. Compounds UC-781 and UC-82 discovered by scientists at Uniroyal Chemical Ltd. proved to be > or = 5-10-fold more inhibitory to wild-type human immunodeficiency virus type 1 strains (EC50 approximately 0.002 microgram/ml) than the thiocarboxanilide oxime ether UC-10 and other non-nucleoside reverse transcriptase inhibitors such as nevirapine, bis(heteroaryl)piperazine, and tetrahydroimidazo[4,5,l-jk][1,4]-benzodiazepin-2(1H)-one. In addition, the compounds were able to knock out virus replication in cell culture at concentrations that were 20-50-fold lower than those of nevirapine or bis(heteroaryl)piperazine. They were also highly efficient (EC50 < or = 0.02 microgram/ml) in suppressing the replication of mutant virus strains that contained mutations in their reverse transcriptase that conferred resistance to other non-nucleoside reverse transcriptase inhibitors (i.e., Tyr181 to Cys, Lys103 to Asn, Val106 to Ala, and Leu100 to Ile). The compounds selected for virus mutants that were only marginally resistant to the thiocarboxanilides ( < 10-20-fold). The antiviral activity of the compounds was only slightly affected by the presence of high concentrations of human serum, and the compounds were shown to be highly stable in the presence of human serum for at least 24 hr at room temperature. PMID- 8700149 TI - A single amino acid determines differences in ethanol actions on strychnine sensitive glycine receptors. AB - Effects of ethanol on strychnine-sensitive glycine receptors were studied in Xenopus laevis oocytes expressing alpha 1 wild-type, alpha 2, or mutant alpha 1(A52S) homomeric glycine receptors. This alpha 1(A52S) mutant, in which a serine residue substitutes for alanine at amino acid 52, is responsible for the spasmodic phenotype in mice and alters the ability of glycine to activate the receptor. Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations. Homomeric alpha 1 glycine receptors were more sensitive to the effects of ethanol than were alpha 2 or the mutant alpha 1(A52S) receptors. No differences were found in ethanol sensitivity between alpha 2 and the mutant alpha 1(A52S) receptors. The alpha 2 subunit has a threonine residue, a conservative substitution for serine, at amino acid 52. The general anesthetic propofol was also tested in homomeric alpha 1, alpha 2, or the mutant alpha 1(A52S) receptors. Propofol, at unaesthetic concentrations (1-5 microM), reversibly potentiated the glycine receptor function in a concentration dependent manner and to an equal extent in the three subunits tested. These data suggest that the mutation of an alanine to serine at amino acid 52 of the alpha subunit is responsible for the difference in ethanol sensitivity seen in homomeric receptors composed of alpha 1 and alpha 2 subunits. PMID- 8700150 TI - Alpha 2-adrenergic receptors activate phospholipase C in renal epithelial cells. AB - The effects of alpha 2-adrenergic receptors are usually attributed to inhibition of adenylyl cyclase through pertussis toxin-sensitive Gi coupling. In kidney distal convoluted tubule (DCT) cells, stimulation of Na+/K(+)-ATPase by alpha 2 receptors involves activation of protein kinase C (PKC). To identify the signal pathways coupled to alpha 2 receptors, we measured cAMP production and show that the alpha 2 agonist B-HT 933 had no effect on basal or stimulated (forskolin, parathyroid hormone) cAMP accumulation in DCT cells but inhibited parathyroid hormone-stimulated cAMP accumulation in proximal tubule cells. I tested whether alpha 2 receptors on DCT cells stimulate PKC through second messengers generated from phospholipase C (PLC) activation. In DCT cells, B-HT 933 increased inositol 1,4,5-trisphosphate formation by 4-6-fold over control and increased diacylglycerol formation by 46%. Basal intracellular calcium concentration in single DCT cells averaged 114 nM and increased within 2 min to 196 nM with B-HT 933. Treatment with the PLC inhibitor U-73122 but not pertussis toxin blocked B HT 933-induced rises in inositol-1,4,5-trisphosphate and intracellular calcium concentration. B-HT 933 increased PKC activity by 45% over control in DCT cells. These findings provide evidence that alpha 2-adrenergic receptors activate PLC in DCT cells through a pertussis toxin-insensitive mechanism. PMID- 8700151 TI - Inhibition of receptor/G protein coupling by suramin analogues. AB - Suramin analogues act as direct antagonists of heterotrimeric G proteins because they block the rate-limiting step of G protein activation (i.e., the dissociation of GDP prebound to the G protein alpha subunit). We have used the human brain A1 adenosine receptor and the rat striatal D2 dopamine receptor, two prototypical Gi/G(o)-coupled receptors, as a model system to test whether the following analogues suppress the receptor-dependent activation of G proteins: 8-(3 nitrobenzamido)-1,3,5-naphthalenetrisulfonic acid (NF007), 8-(3-(3 nitrobenzamido)-benzamido)-1,3,5-naphthalenetrisulfonic acid (NF018); 8,8' (carbonylbis(imino-3,1-phenylene))bis-(1,3,5-naphthalenetr isulfonic acid) (NF023); 8,8'-(carbonylbis(imino-3,1-phenylene)carbonylimino-(3,1- phenylene)) bis(1,3,5-naphthalenetrisulfonic acid) (NF037); and suramin. Suramin and its analogues inhibit the formation of the agonist-specific ternary complex (agonist/receptor/G protein). This inhibition is (i) quasicompetitive with respect to agonist binding in that it can be overcome by increasing receptor occupancy but (ii) does not result from an interaction of the analogues with the ligand binding pocket of the receptors because the binding of antagonists or of agonists in the absence of functional receptor/G protein interaction is not affected. In addition to suppressing the spontaneous release of GDP from defined G protein alpha subunits, suramin and its analogues reduce receptor-catalyzed guanine nucleotide exchange. The site, to which suramin analogues bind, overlaps with the docking site for the receptor on the G protein alpha subunit. The structure-activity relationships for inhibition of agonist binding to the A1 adenosine receptor (suramin > NF037 > NF023) and of agonist binding to the inhibition D2 dopamine receptor (suramin = NF037 > NF023 > NF018) differ. Thus, NF037 discriminates between the ternary complexes formed by the agonist-liganded D2 dopamine receptors and those formed by the A1 adenosine receptor with > 10 fold selectivity. Therefore, our results also show that inhibitors can be identified that selectively uncouple specific receptor/G protein tandems. PMID- 8700152 TI - Receptor internalization delays m4 muscarinic acetylcholine receptor resensitization at the plasma membrane. AB - We analyzed the role of receptor internalization and recycling in muscarinic acetylcholine receptor (mAChR) desensitization and resensitization. Incubation of Chinese hamster ovary cells stably expressing the m4 mAChR with 1 mM carbachol for 1 hr reduced cell surface receptor number by 50-60% with no change in total receptor number. Pretreatment of the cells with 450 mM sucrose, which did not affect the ability of m4 receptors to inhibit forskolin-stimulated cAMP accumulation, completely blocked receptor internalization. On the other hand, the carbachol treatment reduced the ability of m4 receptors to inhibit cAMP accumulation in both sucrose-treated and untreated cells, with a similar onset and to a similar extent. The EC50 value for carbachol was increased approximately 10-fold, and maximal inhibition determined at 100 microM carbachol was reduced approximately 50%. In contrast, thrombin-induced inhibition of cAMP accumulation was not affected. Recycled receptors in cells not treated with sucrose remained refractory to carbachol stimulation for > or = 2 hr after agonist removal, even though cell surface receptor number had recovered completely within 1 hr. In contrast, resensitization of receptor function was very rapid in cells treated with sucrose. Ten minutes on removal of agonist, mAChRs in the plasma membrane of sucrose-treated cells were fully resensitized. Also, an internalization-defective m4 mAChR mutant, T399A, that was found to desensitize similar to the wild-type receptor, resensitized more rapidly than the wild-type receptor. We conclude that desensitization and resensitization of m4 mAChRs in Chinese hamster ovary cells can occur at the plasma membrane and that receptor internalization strongly delays the process of resensitization of desensitized receptors. PMID- 8700153 TI - Novel natriuretic peptide receptor/guanylyl cyclase A-selective agonist inhibits angiotensin II- and forskolin-evoked aldosterone synthesis in a human zona glomerulosa cell line. AB - We report the production of a novel human natriuretic peptide receptor/guanylyl cyclase A (hNPR-A)-selective agonist ANP [G9T, R11S, G16R] (sANP). This agonist has similar affinity to ANP for hNPR-A and 1,000-10,000-fold reduced affinity for the human natriuretic peptide clearance receptor (hNPR-C). sANP was used to directly test the hypothesis that hNPR-A mediates the inhibitory effect of natriuretic peptides on aldosterone generation in a human zona glomerulosa cell line, H295R. Human type A natriuretic peptide and sANP (10(-11) to 10(-6) M) resulted in concentration-dependent increases in cGMP levels and decreases in forskolin (100 nM)- and angiotensin II (5 nM)-induced aldosterone and pregnenolone production. These results revealed an inhibitory effect of both peptides on the agonist-stimulated conversion of cholesterol to pregnenolone (i.e., cytochrome P-450 cholesterol monooxygenase side-chain cleaving enzyme, EC 1.14.15.6). H295R cells also exhibited angiotensin II- and forskolin-evoked conversion of [3H]cortico-sterone to [3H]aldosterone (i.e., cytochrome P-450 steroid 11 beta-monooxygenase/aldosterone synthase, EC 1.14.15.4). Human type A natriuretic peptide and sANP (10(-7) M) inhibited the angiotensin II-stimulated late pathway but did not affect forskolin-facilitated conversion of corticosterone to aldosterone. Our results directly demonstrate inhibitory effects of hNPR-A-mediated signal transduction on cytochrome P-450 cholesterol monooxygenase side-chain cleaving enzyme and steroid 11 beta monooxygenase/aldosterone synthase complex depending on the steroidogenic agonist used. PMID- 8700154 TI - Identification of cholecystokinin-B/gastrin receptor domains that confer high gastrin affinity: utilization of a novel Xenopus laevis cholecystokinin receptor. AB - A hallmark of the mammalian brain cholecystokinin (CCK) receptor, CCK-B/gastrin (CCK-BR), is its high affinity for two structurally related peptides, CCK and gastrin. Previous radioligand binding experiments suggested that the predominant CCK receptor from Xenopus laevis brain shares high affinity for sulfated cholecystokinin octapeptide but has > or = 1000-fold lower affinity for gastrin. To determine the molecular basis for this pharmacological divergence between mammalian and lower vertebrate receptors, we isolated a cDNA encoding the X. laevis brain CCK receptor (CCK-XLR). CCK-XLR shares approximately 50% homology at the amino acid level with both the human CCK-BR and the peripheral CCK-A receptor subtypes. The recombinant X. laevis receptor has a distinct pharmacological profile of agonist and antagonist affinities and as such offers a useful tool for structure-function studies. We used CCK-XLR to map the human CCK-BR domains that confer high affinity for gastrin. A series of chimeric CCK-BR/CCK-XLR constructs was generated and pharmacologically characterized. While maintaining wild-type affinity for sulfated cholecystokinin octapeptide, receptors with increasing amino-terminal contributions from CCK-BR demonstrated a stepwise increase in gastrin affinity. Further dissection of the amino-terminal third of the human receptor, a domain that confers a > 250-fold increase in gastrin affinity, revealed the importance of interactions among at least three subdomains. Additional structural requirements for gastrin affinity mapped to a segment spanning transmembrane domains IV and V. PMID- 8700155 TI - Steroid hormonal regulation of calcium-binding protein regucalcin mRNA expression in the kidney cortex of rats. AB - The effect of various steroid hormones on the expression of calcium-binding protein regucalcin mRNA in the kidney cortex of rats was investigated. The change of regucalcin mRNA levels was analyzed by Northern blotting using rat liver regucalcin complementary DNA (0.9 kb of open-reading frame). Regucalcin mRNA was expressed in the kidney cortex but not the medulla. Rats received a single subcutaneous administration of steroid; the animals were sacrificed 60 min after the treatment of aldosterone (2.5, 5.0 and 10 micrograms/100 g body weight) or 6 h after the treatment of estrogen (17 beta-estradiol; 0.05, 0.1 and 0.2 mg/100 g), hydrocortisone (0.5, 1.0 and 3.0 mg/100 g) and dexamethasone (50, 100 and 150 micrograms/100 g). Regucalcin mRNA levels in the kidney cortex were clearly diminished by the administration of aldosterone or estrogen, while hydrocortisone administration had no effect. The administration of dexamethasone (100 micrograms/100 g) caused a remarkable increase of regucalcin mRNA levels in the kidney cortex. The dexamethasone-induced increase in regucalcin mRNA levels was completely blocked by the simultaneous administration of cycloheximide (150 micrograms/100 g), although the drug administration had no effect on the mRNA levels in control rats. Meanwhile, the dexamethasone administration did not cause an appreciable alteration of calcium content in the kidney cortex. The present study demonstrates that, of the various steroid hormones used, dexamethasone uniquely has a stimulatory effect on regucalcin mRNA expression in the kidney cortex of rats. The steroid effect may be mediated through a newly synthesized protein. PMID- 8700156 TI - Fatty acid double bond orientation alters interaction with L-cell fibroblasts. AB - Relatively little is known of fatty acid specificity in cellular fatty acid uptake. In this study L-cells, a fibroblastic cell line with very low levels of endogenous cytosolic fatty acid binding protein, were used to examine the role of cis and trans unsaturation on fatty acid uptake. The fluorescent fatty acids, trans-parinaric acid and cis-parinaric acid, were used as analogs of straight chain saturated, and kinked-chain unsaturated fatty acids, respectively, in order to evaluate the fatty acid specificity of the uptake system. Parinaric acid is poorly metabolizable; greater than 97% was unesterified while 3H-oleic acid was almost totally metabolized after 30 min uptake. Cis- and trans-parinaric acid uptake was saturable and dependent on the concentration of fatty acid. However, the initial rate and maximal amount of trans-parinaric acid taken up by the L cells was greater than for cis-parinaric acid under the same conditions. The affinity of L-cell uptake for trans-parinaric acid (Km = 0.12 uM) was 35-fold higher than that for cis-parinaric acid (Km = 4.17 uM). Based on competition studies with oleic and stearic acids, it was concluded that the cis- and trans parinaric acid were taken up by the same L-cell fatty acid uptake system. The results suggest that the L-cell fatty acid uptake system has selectivity for straight chain rather than kinked chain unsaturated fatty acids. PMID- 8700157 TI - The uptake of calcium by isolated chromaffin granules of the adrenal medulla. AB - Bovine chromaffin secretory granules were purified by isopycnic Metrizamide gradient centrifugation and their Ca2+ sequestration pathways were characterized. The rate of Ca2+ sequestration at 37 degrees C was first order, with a maximal uptake of 26.9 +/- 0.46 (mean +/- S.D., n = 3) nmol Ca2+/mg protein and a first order rate constant (k) of 0.046 +/- 0.002 min-1. At 4 degrees C the rate of uptake was substantially attenuated, with only 2.47 +/- 0.2 (mean +/- S.D, n = 3) nmol Ca2+/mg protein sequestered in 60 min. Ca2+ sequestration was 93% inhibited by 180 mM NaCl [I50% of 78.7 +/- 9.3 mM NaCl (mean +/- S.D., n = 11)] but only slightly inhibited by KCl or MgCl2. Ca2+ sequestration was not stimulated by incubation with MgATP but was inhibited by 57% after incubation with 30 microM monensin. Ca2+ sequestration was dependent on extravesicular Ca2+ with half maximal sequestration at pCa2+ 6.81 +/- 0.028 (mean +/- S.D., n = 3). Sequestered Ca2+ could be exchanged with external 45Ca2+, the exchange rate was first order (k of 0.042 +/- 0.004: mean +/- S.D., n = 3) and saturated at 27.7 +/- 1.1 nmol Ca2+/mg (mean +/- S.D., n = 3). The Ca2+/Ca2+ exchange system was totally inhibited by NaCl or KCl but only slightly by MgCl2. About 75% of sequestered 45Ca2+ could be released by incubation with NaCl, but only 8% was released by incubation with KCl. Half-maximal release of sequestered 45Ca2+ required 69.3 +/- 12.2 mM NaCl (mean +/- S.D., n = 3). The Na+-induced release of sequestered 45Ca2+ was rapid, t0.5 of 2.80 +/- 0.63 min (mean +/- S.D., n = 3) and inhibited at 4 degrees C. The concurrent incubation of chromaffin granules with 45Ca2+ and either annexin proteins V or VI resulted in attenuated uptake of 45Ca2+. These results suggest that Ca2+ uptake in adrenal chromaffin granules is regulated by Na+ and Ca2+ gradients and also possibly by annexins V and VI. PMID- 8700158 TI - Characterization of the HeLa cell 35 kDa Alu-element binding protein. AB - Human Alu-elements are short interspersed DNA sequences that comprise approximately 5% of the human genome. The physiological role of Alu-elements are unknown, although they are proposed to be involved in DNA replication, transcriptional regulation and nuclear transport of signal recognition particle RNA. Proteins that bind to Alu-element and Alu RNA have been identified in human cells. In HeLa cells, two proteins of 120 kDa and 35 kDa specifically bind to Alu elements. We find that the 35 kDa protein is localized exclusively to the nucleus, while the 120 kDa protein is distributed between nucleus and cytoplasm. The 35 kDa protein is regulated by phosphorylation. Upon dephosphorylation, its DNA binding activity is significantly enhanced. Contrary to the recent identification of the smaller Alu-element binding protein as annexin II, we find that annexin II is not an Alu-element binding protein. Using a variety of techniques, we demonstrate that the 35 kDa Alu-element binding protein is distinct from annexin II. PMID- 8700159 TI - Superinduction of mouse epidermal ornithine decarboxylase activity by repeated 12 o-tetradecanoylphorbol-13-acetate treatments. AB - A correlation of the levels of epidermal protein kinase C (PKC) isozymes, steady state levels of ornithine decarboxylase (ODC) mRNA, and ODC antizyme with the induction of ornithine decarboxylase (ODC) activity by a second repeat 12-O tetradecanoylphorbol-13-acetate (TPA) treatment to mouse skin was determined. A single application of TPA to female CD-1 mouse skin leads to a dramatic induction of ODC activity (approximately 3 nmol CO2/60 min/mg protein) which peaks at about 5 h after treatment. However, a superinduction of ODC activity (approximately 13 CO2/60 min/mg protein) is observed upon the second TPA application at 48 or 72 h after the first TPA treatment. Prior application of a tumor initiating dose of 7,12-dimethylbenz[a]anthracine to mouse skin did not influence the degree of induction of ODC by a repeat TPA treatment. Western Blot analyses using antibodies specific to PKC alpha, beta, gamma, delta and epsilon indicate detectable levels of PKC alpha, beta, delta and epsilon in mouse epidermal extracts. A time course of the effects of a single topical application of 20 nmol of TPA to the mouse skin indicate that none of PKC isozymes (alpha, beta, gamma, delta and epsilon) were completely downregulated at times (72 h) when ODC was overinduced by TPA. TPA-induced steady state levels of ODC mRNA did not correlate with the degree of superinduction of ODC activity by TPA. The second TPA treatment, 72 h after the first TPA treatment, which leads to superinduction of ODC activity did not decrease the levels of the ODC-antizyme. The results indicate that superinduction of mouse epidermal ODC activity is regulated in part post-transcriptionally and may not be the result of either a loss of PKC isoform(s) or a decrease in the levels of ODC antizyme. PMID- 8700160 TI - Regulation of the apolipoprotein E by dietary lipids occurs by transcriptional and post-transcriptional mechanisms. AB - The aim of the present investigation was to study the regulation of apolipoprotein E by two dietary nutrients, saturated fat and cholesterol, known to raise plasma cholesterol levels. ApoE is a protein component of several classes of lipoproteins including VLDL and HDL, and dietary lipids may regulate VLDL and apoE-containing HDL particles through their effects on apoE gene. Male rats and mice were fed the following 4 diets: control diet (C); high cholesterol diet with 0.5% cholesterol (HC); high fat diet with 20% hydrogenated coconut oil (HF); and high fat plus high cholesterol diet with 0.5% cholesterol and 20% fat (HF/ C). Plasma cholesterol levels remained unchanged on HC diet, but in mice VLDL-cholesterol increased by 31%. HF diet increased VLDL and LDL by 15-17% in rats, and 21% in mice. A combination of fat and cholesterol diet showed pronounced effects on plasma lipoprotein concentrations, raising apoB-containing particles by 21% and 44% in mice and rats, respectively. Plasma apoE levels increased significantly on all diets. The mechanism of regulation of increased plasma apoB and apoE levels was examined. Quantification of hepatic apoB mRNA showed a lack of correlation between plasma apoB and hepatic apoB mRNA levels, suggesting that posttranscriptional regulation increased plasma apoB-containing lipoproteins in animals fed saturated fat diets. Hepatic apoE mRNA levels increased significantly in animals fed cholesterol-rich diets. However, despite increased plasma apoE levels on diet containing only saturated fat, hepatic apoE mRNA did not change. Synthesis of apoE on the liver polysomes increased selectively on cholesterol-rich diets. These results suggest that cholesterol rich diets altered apoE, in part, by transcriptional mechanism, and saturated fat rich diets increased plasma apoE levels by posttranscriptional mechanism, possibly decreased receptor-mediated uptake of apoE-containing particles. The regulation of LDL receptor was also studied since plasma apoB and E levels may be altered by LDL receptor-mediated uptake by the hepatocytes. As expected, high cholesterol diet decreased LDL receptor mRNA by 30-40%. However, the LDL receptor protein on liver membranes did not change on any of the test diets in both animal species. Hepatic cholesterol content increased several fold selectively on high cholesterol diets. These findings suggest that: 1) both transcriptional and posttranscriptional mechanisms are important in regulating plasma apoB and E containing lipoproteins; 2) dietary cholesterol regulates apoE gene by a transcriptional mechanism and dietary saturated fat by posttranscriptional mechanism; and 3) changes in the hepatic apoE and LDL receptor mRNA are associated with the changes in intracellular cholesterol concentrations. PMID- 8700161 TI - Hypoglycemia-induced AP-1 transcription factor and basic fibroblast growth factor gene expression in multidrug resistant human breast carcinoma MCF-7/ADR cells. AB - We investigated the effect of hypoglycemic treatment on the activation of the AP 1 transcription factors and the regulation of basic fibroblast growth factor (bFGF) gene expression in multidrug resistant human breast carcinoma MCF-7/ADR cells. Northern blot and gel mobility shift assays showed that hypoglycemic treatment induced c-jun and c-fos gene expression, AP-1 binding activity, as well as bFGF gene expression. Moreover, transfected cells expressing high levels of abnormal c-Jun protein exhibited a reduction in the bFGF protein levels compared to parental cells. A potent protein kinase C (PKC) inhibitor, H-7 (60 micrograms/ml) suppressed the stress-induced bFGF gene expression. Our study also demonstrated that H-7 did not facilitate the decay of bFGF mRNA. Thus, the suppression of bFGF gene expression by treatment with H-7 was due to the effect of the drug on the synthesis of bFGF mRNA rather than the stability of bFGF mRNA. Our data suggest that hypoglycemia-induced bFGF gene expression is mediated through the activation of PKC and the AP-1 transcription factors. PMID- 8700162 TI - Analysis of mRNA expression and cloning of a novel plasma membrane Ca(2+)-ATPase splice variant in human heart. AB - Four different plasma membrane Ca(2+)-ATPase (PMCA) genes and three sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) genes have been previously cloned and characterized. In this study we have investigated the expression of the mRNA encoding the various PMCA and SERCA proteins in fetal and adult human heart and placenta by the reverse-transcriptase-polymerase-chain-reaction (RT PCR) and cDNA cloning. We have found that PMCA1 and PMCA4 genes were expressed in 8-, 12- and 20-week fetal heart and in adult heart. PMCA2 gene was expressed at low levels in adult heart but was not detected in fetal heart. PMCA3 mRNA was not detected in the heart nor placenta. In contrast, the mRNA encoding SERCA2a, SERCA2b and SERCA3 were expressed in all cardiac developmental stages. Multiple alternatively spliced mRNA transcripts which differ at splice site A and B/C of the PMCA1, PMCA2 and PMCA4 genes were detected in the human heart. Interestingly, a novel tissue specific variant of the PMCA4 gene was detected in both fetal and adult human heart but not in placenta that accounts for about 30% of the total PMCA4 mRNA variant expression. DNA sequence analysis of this novel variant revealed that it corresponds to the equivalent of the PMCA1d variant and accordingly we have named it PMCA4d. We cloned and sequenced eight cDNA inserts encoding for the PMCA1 and PMCA4 variants from a fetal human heart cDNA library confirming that these are the two main PMCA genes expressed in cardiac muscle. PMID- 8700163 TI - Phosphorylation of cardiac junctional and free sarcoplasmic reticulum by PKC alpha, PKC beta, PKA and the Ca2+/calmodulin-dependent protein kinase. AB - Phosphorylation of cardiac junctional and free sarcoplasmic reticulum (SR) by protein kinase C (PKC) isoforms alpha and beta was investigated. Both SR and PKC were isolated from canine heart. Junctional and free SR vesicles were prepared by calcium-phosphate-loading. The substrate specificities of PKC alpha and PKC beta were found to be similar in both SR fractions. A high molecular weight junctionally-associated protein was phosphorylated by PKA, PKC and an endogenous Ca2+/calmodulin-dependent protein kinase activity: the highest levels of phosphate incorporation being catalysed by the latter kinase. In addition to this high molecular weight junctionally-associated protein, PKC induced phosphorylation of 45, 96 kDa and several proteins of greater than 200 kDa in junctional SR. A protein of 96 kDa was phosphorylated by both isoforms in junctional and free SR. The major substrate for PKA, PKC alpha, PKC beta and the Ca2+/calmodulin-dependent protein kinase, in both junctional and free SR, was phospholamban. Although the phosphorylation of phospholamban by PKC was activated by Ca2+, a component of this activity appeared to be independent of Ca2+. PKC mediated phosphorylation of phospholamban was fully activated by 1 microM Ca2+ whereas the Ca2+/calmodulin dependent kinase required concentrations in excess of 5 microM Ca2+. In the in vitro system employed in these studies, the concentrations of either PKC alpha or the catalytic subunit of PKA required to phosphorylate phospholamban were found to be similar. In addition, in the presence of a 15 kDa sarcolemmal-associated protein, which becomes phosphorylated upon activation of PKC in vivo, phosphorylation of phospholamban by PKC was unaffected. These results demonstrate that, although substrates for both subtypes are found in both junctional and free SR, PKC alpha and PKC beta do not show differences in selectivity towards these substrates. PMID- 8700164 TI - Biodegradable microparticles as a delivery system for measles virus cytotoxic T cell epitopes. AB - Cytotoxic T-cell (CTL) responses are likely to be important for the clearance of a measles virus (MV) infection. To induce CTL responses. replicating vectors have generally been used but the use of such vectors in humans mav be problematic, and immunization with synthetic peptides may be more appropriate. We have investigated the potential of poly(lactide-co-glycolide)(PLG) microparticles as a delivery system for a CTL epitope representing residues 51-59 from MV nucleoprotein. After a single intraperitoneal injection in saline of the encapsulated epitope, CTL responses to the homologous peptide and MV were detected over a period of 4 months. Responses reached a maximum 30 days after priming and were maintained at high levels for 120 days. These responses were higher than those observed when the CTL epitope was administered in saline or as an emulsion in Incomplete Freund's Adjuvant. The pronounced immunostimulatory effect of microparticles, combined with their excellent tissue compatibility and biodegradability suggests that they represent a valuable delivery system for synthetic peptide immunogens. PMID- 8700165 TI - A novel and efficient route for the isolation of antibodies that recognise T cell receptor V alpha(s). AB - Studies of the T cell repertoire have been hindered by the lack of antibodies that recognise V region families, particularly for V alpha regions. In this report, single chain Fv (scFv) fragments have been isolated that recognise both recombinant V alpha(s) and native V alpha(s) on the surface of T cells. Mice have been immunised with purified soluble T cell receptors (TCRs) and antibody heavy and light chain variable domain (VH and VL, respectively) genes isolated from splenocytes using the polymerase chain reaction (PCR). The VH and VL genes have been assembled as scFv gene libraries and a bacteriophage display system used to isolate scFvs that recognise a soluble V alpha. Five scFvs have been purified and characterised in detail using enzyme-linked immunosorbent assays (ELISAs) and flow cytometry. Three of these five scFvs recognise native V alpha(s) on the surface of T cell hybridomas. This method therefore offers a rapid route to the generation of scFvs that recognise native TCRs and can readily be extended to the production of anti-human TCR antibodies for use in therapy and diagnosis. PMID- 8700166 TI - Molecular characterization of a monoclonal antibody produced in response to a group C meningococcal polysaccharide peptide mimic. AB - We have developed a monoclonal antibody, designated anti-anti-Id Ab3-2C4 which reacts with Neisseria meningitidis serogroup C polysaccharide (MCPS). Anti-anti Id Ab3-2C4 was produced by immunizing Balb/C mice with a peptide mimic of MCPS. This monoclonal antibody reacts with native polysaccharide and its anti-idiotype antibody Ab2-6F9 by ELISA. The synthetic peptide mimic was constructed based on the sequence of the VHCDR3 region of the anti-idiotype Ab2-6F9. We compared the cDNA sequence of Ab3-2C4 to the sequence of idiotype antibody Ab1-1E4 produced in response to native MCPS. The predicted amino acid sequence of the unique VHCDR3 of anti-anti-Id Ab3-2C4 is similar to that of idiotype Ab1-1E4. Also the VHCDR3 of both antibodies is similar to some of the known or suggested carbohydrate binding motifs. A different VH gene family was utilized by Ab3-2C4 than by Ab1 1E4. These results suggest that immunization with the anti-idiotype-derived peptide mimic of the MCPS antigen stimulates the production of antibodies with a binding site structurally related to idiotype antibodies, even though the antibodies Ab1-1E4 and Ab3-2C4 are not related in gene families. Our results support the premise that the use of peptide antigens which are mimics of carbohydrates is an alternate vaccine strategy for polysaccharide antigens and results in an appropriate response. PMID- 8700167 TI - A complement factor B-like cDNA clone from the zebrafish (Brachydanio rerio). AB - An important molecule in the activation of the complement system in vertebrates is factor B, a serine protease with a molecular mass of 95,000. Factor B and the complement component C2 are thought to have arisen by gene duplication. In mammals and in Xenopus the factor B gene is linked to the major histocompatibility complex (MHC), whereas in domestic fowl it segregates independently of the MHC. Here we describe the isolation of a cDNA clone coding for factor B in the zebrafish, Brachydanio rerio. The deduced protein sequence exhibits a characteristic mosaic structure consisting of the short consensus repeat (SCR), the von Willebrand factor, and the serine protease domains. The estimated time of factor B and C2 divergence (approximately 350 million years ago), combined with the fact that C2 has thus far been found only in mammals, suggest that the factor B-C2 gene duplication occurred after the divergence of mammal-like reptiles from other reptiles and hence also birds. After the duplication, the C2 component evolved significantly faster than factor B. PMID- 8700168 TI - The stoichiometry and affinity of the interaction of murine Fc fragments with the MHC class I-related receptor, FcRn. AB - The binding of recombinant wild type and mutant Fc-hinge fragments to soluble, FcRn expressed in insect cells has been analysed. The mutant Fc-hinge fragments are derived from murine IgG1 with mutation of residues located at the CH2-CH3 domain interface (Ile253, His31O, Gln311, His433 and Asn434; EU numbering). These mutant Fc-hinge fragments have previously been shown to be deficient in neonatal transcytosis in suckling mice and also have abnormally short serum half lives. The mutated residues are highly conserved in human and rodent gammaglobulins (IgGs) and are also involved in binding to staphylococcal protein A. This study demonstrates that the Fc mutants have lower binding affinities for recombinant FcRn and mutations in the CH2 domain have a greater effect than those in the CH3 domain. There is an excellent correlation between affinity and transcytosis or the control of catabolism, and this provides further evidence in support of the close overlap of the sites of IgG/Fc involved in these processes. The stoichiometry of the FcRn:Fc interaction has also been investigated and has been found to be 1:1, indicating that binding of FcRn to one CH2-CH3 domain interface site precludes an FcRn:Fc interaction at the second site. PMID- 8700169 TI - Increase in the specific activity of p50csk in proliferating T cells correlates with decreased specific activity of p56lck and p59fyn and reduced phosphorylation of CD3 subunits. AB - Depending on their prior antigen recognition history, mature T cells respond with different functional outcomes to T cell receptor (TCR) stimulation. These functional outcomes include proliferation, anergy and cell death. The biochemical basis underlying differential responses by mature T cells at different stages of their developmental pathway to TCR stimulation remains to be determined. We have previously shown that proliferating but not naive T cells were susceptible to apoptosis after TCR stimulation and that the tyrosine phosphorylation of TCR zeta, CD3 gamma, and CD3 epsilon in proliferating T cells was decreased after TCR stimulation. In this study. We determined whether differences in phosphorylation between naive and proliferating T cells were due to altered regulation of p56lck (Lck) or p59fyn (Fyn) by their positive or negative regulators, CD45 or p5Ocsk (Csk), respectively. We found that Lck was expressed at the same level and had the same phosphotyrosine content in naive and proliferating T cells. However, its autophosphorylation activity was lower in proliferating cells, corresponding to a 2-fold decrease in its specific kinase activity. Similarly, the specific kinase activity of Fyn was also decreased by about 2-fold in proliferating T cells. In contrast, although Csk was expressed at the same level in both cell types its specific kinase activity was increased by 6-fold in proliferating T cells. The tyrosine phosphatase CD45, a positive regulator of src-family kinases, was overexpressed by 3- to 6-fold in proliferating cells. However, the specific activity of CD45 in naive and proliferating T cells was the same. Therefore, although the protein expression level of CD45 was increased in proliferating T cells it only partially compensated for the hyperactivity of Csk resulting in a 2 fold reduction in the specific activity of Lck and Fyn in proliferating T cells. PMID- 8700170 TI - Induction of costimulatory molecules B7-1 and B7-2 in murine B cells. the CBA/N mouse reveals a role for Bruton's tyrosine kinase in CD40-mediated B7 induction. AB - The binding of CD40 ligand on activated T cells to CD40 on resting B cells induces the expression of costimulatory molecules B7-1 (CD80) and B7-2 (CD86). The induction of B7 molecules by CD40 ligand-CD40 interaction represents a critical step in rendering B cells competent for antigen presentation. The CBA/N mouse has a defect in CD40 signalling which has been attributed to a mutation in Bruton's tyrosine kinase. We have compared the ability of murine CD40 ligand to induce B7-1 and B7-2 expression on B cells isolated from CBA/N and wild-type CBA/J mice. We find that the CBA/N defect partially impairs both B7-1 and B7-2 induction via CD40. Subsequent experiments investigated the roles of different second messenger systems in B7-1 and B7-2 induction in normal B cells. In M12 B lymphomas either CD40 cross-linking or cAMP treatment can induce B7 molecules. Here we report that treatment with dibutyryl-cAMP also induces B7 molecules in normal B cells provided that they have been preactivated by CD40 cross-linking. We also find that PMA and ionomycin treatment of B cells induces B7-2 but not B7 1 expression. Our data therefore show roles for BTK, cAMP and PMA/ionomycin in B7 induction, as well as providing further evidence for differential regulation of B7-1 and B7-2 induction in B cells. PMID- 8700171 TI - Non-stochastic utilization of Ig V region genes in unselected human peripheral B cells. AB - Limited evidence based on a few subjects suggests that human peripheral blood B cells may express a non-stochastic assortment of V region genes. To determine if non-stochastic utilization was a generally applicable rule, the identities of rearranged V region gene segments were determined in unselected peripheral blood B cells from 12 subjects (five male, seven female), ranging in age from 35 to 72 years. The analysis was limited to V region genes belonging to the VH3 gene family. More than 4500 independent VH3-containing rearrangements were analysed. The frequency of occurrence of eight individual VH3 gene segments contained in rearrangements was assessed using gene specific oligonucleotide probes. Usage of elements was not uniform. Three elements, which have been known to encode autoantibodies as well as to be frequently rearranged during fetal development, were represented among rearrangements more frequently than were other members of the VH3 family, and in aggregate, accounted for the majority of rearrangements. These three predominant loci are clustered in an 80 kb region suggesting an influence of chromosomal location on efficiency of rearrangement. The results document a clear, statistically significant, preference for the occurrence of specific V region genes among rearrangements. The modest amount of variation observed between subjects was not associated with either age or gender. Duplications which increased gene dose may have contributed to increased gene usage. These data indicate that, in caucasians, the immunoglobulin rearrangements in adult human B cells are dominated by a few heavy chain V region genes to the exclusion of other putatively equally functional genes. Thus, the conventional notion that the adult repertoire is normalized with respect to family complexity is not confirmed by analysis of individual VH genes. PMID- 8700172 TI - Biochemical analysis of the interaction of fibronectin with IgG and localization of the respective binding sites. AB - Fibronectin (Fn), a mosaic protein composed of multiple copies of three different module types (Fl, F2 and F3), has been found associated with circulating immune complexes (ICs) and immunoglobulin (Ig) aggregates in a variety of IC diseases and myeloproliferative disorders. We have previously shown that a proteolytic fragment of Mr = 25,900 Da, from the NH2-terminal domain of Fn, composed of five type 1 modules (1Fl -5Fl) binds to the major Ig classes under physiologic conditions, suggesting that the presence of Fn in ICs and cryoglobulins results from a physicochemical binding interaction between these two molecules. Using an ELISA, we now show that the interaction between Fn and IgG is: (1) not influenced by any other constituent of plasma; (2) unaffected by temperature; and (3) has an estimated Kd of 3.77 x 10(-9) M. In addition, we have further delineated the respective sites involved in the interaction between Fn and IgG. Recombinant type l module pairs (1Fl.2Fl and 4Fl.5Fl) from the NH2-terminus of Fn, expressed in yeast, were employed in an ELISA and affinity chromatography and compared with the 25.9 kDa (1Fl - 5Fl) fragment and intact Fn for binding to IgG. The 4Fl.5Fl and the 25.9 kDa fragment bound to immobilized IgG and inhibited Fn binding to IgG to nearly the same extent as the intact molecule (IC50: Fn = 6.77 x 1O(-9) M; 25.9 kDa fragment = 5 x 10(-9) M; 4Fl.5Fl = 7.6 x 10(-9) M). Thus, the binding site for IgG on the Fn molecule is localized to and completely conferred by the 4Fl.5Fl module pair (residues 151-244). Similar experiments using papain generated Fab and Fc fragments of IgG localized the Fn binding site on IgG to the Fe region of the IgG molecule. Fn bound to the Fc fragment with a nearly identical Kd of 3.69 x 10(-9) M, as to intact IgG (3.77 x 10(-9) M). These studies support the hypothesis that the interaction between Fn and Ig may contribute to the pathophysiology of immune complex related disorders. PMID- 8700173 TI - Direct detection of peptide-dependent HLA variability by surface plasmon resonance. AB - Cytotoxic T lymphocytes (CTL) recognize antigens as peptides associated with molecules of the major histocompatibility complex (MHC). The accurate characterization of antigenic peptides requires knowledge of how peptides bind to MHC molecules, and hence the conformational changes they can induce. Several reports have indicated that the conformation of the MHC class I molecule plays a role in T cell recognition. We therefore studied the interaction of a series of viral epitopes with HLA-A2, -A3, -B7 and -B8 molecules to determine how peptides could induce conformational changes in HLA molecules. This was done either directly with class I heavy chains in lysates of peptide-loading deficient T2 cells, or with purified material from B-EBV transformed cell lines. The peptide induced HLA conformations were assessed using monoclonal anti-HLA antibodies (mAbs) and detected by surface plasmon resonance (SPR). Antigenic peptides specifically bound to the HLA molecule, even when assembly occurred in a mixed solution of HLA molecules. Distinct patterns of reactivity to a given peptide bound class I molecule were obtained with monomorphic and allele-specific anti HLA mAbs. PMID- 8700174 TI - Comparison of chemically induced DNA breakage in cellular and subcellular systems using the comet assay. AB - The alkaline comet assay, employing a single cell gel electrophoresis, is a rapid, simple and sensitive technique for visualizing and measuring DNA damage leading to strand breakage in individual mammalian cells. In this report, we describe a modified version of this assay which we used to assess DNA damage as a result of treating lysed cells with genotoxic and antimetabolic agents. By means of this modified assay, DNA is no longer held under the regulation of any metabolic pathway or membrane barrier. Using 3 direct-acting agents, hydrogen peroxide, N-methyl-N-nitrosourea, and bleomycin, we were able to induce increased DNA migration by both the standard and modified comet assays. In contrast, with 4 nitroquinoline 1-oxide, 5-fluorouracil, and methotrexate, which require cellular enzymatic activity to induce DNA damage, we succeeded in inducing increased DNA migration using the standard comet assay conditions only. In some cases, the modified comet assay might be helpful in analyzing chemical and biological characteristics of genotoxic agents when performed in combination with the standard comet assay. PMID- 8700175 TI - Mutagenic activity of some coal-derived humic compounds evaluated by the Ames test. AB - Two coal-derived humic substances (Sulcis and South Africa, Eniricerche, Italy) have been evaluated for their mutagenic activity on TA98 and TA100 Salmonella typhimurium strains, either in presence or in absence of metabolic activation (S9). Both compounds showed no effect on the two strains, as observed with natural humic acid (Fluka). After chlorination, coal-derived humic acids induced a strong dose-related increase in the number of revertants on TA100 without S9, whose extent was directly proportional to the chlorination ratios. Such effect was completely suppressed when a sodium thiosulfate solution (10%) was added at the end of the chlorination period (about 90 h). The analogies with natural humic acid mutagenicity are discussed. PMID- 8700176 TI - Sister chromatid exchange analysis in workers exposed to noise and vibration. AB - Workers chronically exposed to whole-body vibration and noise are known to develop pathophysiological and psychological disturbances. The frequencies of sister chromatid exchanges (SCEs) and of cells with high frequencies of SCEs (HFCs) were analyzed in lymphocytes of 50 workers occupationally exposed to vibration and noise and of 34 controls. The exposed group included: individuals operating hand-vibrating tools (group 1), 'test-cell operators' (group 2) and 'run-up' operators (group 3) from an air base and helicopter pilots (group 4). The statistical analysis of the mean SCE count per cell was carried out by multiple regression analysis, comparing various predictor variables: exposure group, duration of exposure, age and cigarette consumption. Only cigarette consumption and exposure group were found to be significantly correlated with the mean SCE frequency. After allowing for the effects of smoking, the analysis indicates that: (1) there was no significant difference between group 1 and controls (p > 0.05); (2) the differences between group 2 and group 0, group 3 and group 0 and group 4 and group 0 were all highly significant (p < 0.001); (3) there was no significant difference between groups 2 and 3 (p > 0.05), nor between groups 2 and 3 combined and group 4 (p > 0.05); (4) exposure groups 2, 3 and 4 combined, had a significantly elevated mean SCE frequency compared to the control group (p < 0.0001). Statistical analysis of the proportion of HFCs was consistent with these results. Our data suggest that chronic exposure to whole body vibration and noise may lead to an increase in the level of SCEs in man. The observed effects may not reflect a direct action of these physical agents on DNA. Alternative explanations may include some of the whole-body vibration and noise induced or stress-induced pathophysiological alterations which may indirectly induce SCE formation. PMID- 8700177 TI - Spontaneous micronuclei in peripheral blood erythrocytes from 35 mammalian species. AB - In this paper we report the results of a study to determine the frequencies of spontaneous micronucleated erythrocytes (MNE) in peripheral blood of 35 mammalian species. The main goal was to find mammals with a high spontaneous frequency of MNE that could, therefore, be good candidates for biomonitoring genotoxic agents in their natural habitat. We obtained 187 peripheral blood samples, but in 13 of the species we could only sample one individual. A wide range in the number of MNE (1/434 to 0/40,000 erythrocytes) was observed. Since the number of individuals per species is not high enough, this results should be cautiously considered. The cat, mouse, giraffe, pig, opossum and capuchin monkey seem to be suitable species for biomonitoring for genotoxic events. PMID- 8700178 TI - Interlaboratory validation of a new assay for DNA-protein crosslinks. AB - In 1992, a simple and sensitive assay for detecting DNA-protein crosslinks was developed [1]. In an effort to facilitate the greater use of the assay, a number of studies were conducted to evaluate its reliability and reproducibility. During this work, the assay was used to assess whether various metals and other compounds could induce crosslinks in cultured human lymphocytes (Epstein-Barr virus-transformed Burkitt's Lymphoma cell line). Potassium permanganate, mercury chloride, lead nitrate, magnesium perchlorate, aluminum chloride, and cadmium chloride did not induce DNA-protein crosslinks at either cytotoxic or non cytotoxic levels. Copper sulfate, arsenic trioxide, and potassium chromate induced DNA-protein crosslinks only at cytotoxic concentrations. Acute lethality of the cells was assessed immediately after exposure to metals by trypan blue exclusion while long-term lethality was assessed by cell proliferation and trypan blue exclusion following an incubation period of 5 days after exposure to the metal compound. All metals exhibited more toxicity in the long-term lethality assay compared to the short-term assay. The cultured human lymphocytes treated with various doses of lead acetate, cadmium chloride, arsenic trioxide and copper sulfate, as well as cis-platinum and chromate, were sent to four different laboratories to compare the reliability and reproducibility of the DNA-protein crosslink assay. Depending on the chemical studied, there were quantitative differences in the results observed among the various laboratories using the assay. However, all laboratories generally showed that cis-platinum, chromate, arsenic trioxide and copper sulfate induced DNA-protein crosslinks at levels that produced acute cytotoxicity, whereas cadmium chloride and lead acetate did not. PMID- 8700179 TI - The Ames test: the two-fold rule revisited. AB - Mutagenicity in the Ames assay is evaluated by comparing the number of revertants observed in treated cultures to those in untreated cultures. Often, some form of the '2-fold rule' is employed, whereby a compound is judged mutagenic if a 2-fold or greater increase is seen in a treated culture. In order to understand the underpinnings of this approach, we study some of its statistical properties. We assume that the number of revertants on any plate from a given two-group experiment follows a Poisson distribution and we address the following questions: (1) what is the false-positive error probability of observing at least a doubling of the number of colonies from the control to the treatment group?; (2) if a given mean number of colonies is postulated for a control group, what number of colonies above the observed control mean provides a false-positive rate of 5%? We also present results for question 1 in the case where the number of revertants follows a negative binomial distribution. PMID- 8700180 TI - Base analog 6-N-hydroxylaminopurine mutagenesis in the yeast Saccharomyces cerevisiae is controlled by replicative DNA polymerases. AB - Genetic control of mutagenesis by the base analog 6-N-hydroxylaminopurine (HAP) was studied in a set of isogenic yeast strains carrying null or point mutations in DNA repair and replication genes. Null alleles of the PMS1, RAD6, REV3 and RAD52 genes did not affect HAP mutagenesis. Defects in 3'- > 5' exonucleases associated with DNA polymerases epsilon and delta led to 2- to 3-fold increases in HAP-induced forward Can(r) mutant frequency. A similar increase was observed for FOAr mutants but only in the strain with a defective exonuclease of the polymerase epsilon (mutation pol2-4). The polymerase epsilon mutations, pol2-9 and pol2-18, which lead to temperature-sensitivity, and pol2-1 (insertion of URA3 at the position coding for amino acid 1134 in the POL2 gene) substantially reduced HAP mutagenesis. The polymerase delta mutation, cdc2-2, slightly reduced HAP mutagenesis. Enhanced proofreading was not the cause of the antimutator effect in the pol2-18 bearing strain, inasmuch as antimutator effect was observed in the pol2-4,18 mutant strain lacking proofreading. From the data obtained, we conclude that both DNA polymerase epsilon and delta participate in mutation generation by HAP. PMID- 8700181 TI - Organ variation in the mutagenicity of MeIQ in Big Blue lacI transgenic mice. AB - 2-Amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), which is a heterocyclic amine found in food and the potent mutagen in S. typhimurium TA98, was examined for its genotoxic potential using lacI transgenic mice (Big Blue, C57BL/6N lineage). Female mice, at 7 weeks of age, were given a diet containing 0.03% MeIQ for 1, 4 and 12 weeks, and mutant frequencies (MF) were analyzed in the bone marrow, liver, forestomach, colon and heart. The MF increased in a feeding period dependent manner. Relative to untreated mice, the MF after a 12-week-feeding of MeIQ was 38 times higher in the colon, 5.8 times higher in the bone marrow, 4.6 times higher in the liver, and 2.6 times higher in the forestomach. No increase in MF was detected in the heart, where no tumors develop. PMID- 8700182 TI - Detection of neocarzinostatin-induced translocations in human sperm chromosomes using fluorescence in situ hybridization of chromosome 2. AB - Mature sperm and late spermatid are known to be sensitive stages to clastogens in mammalian spermatogenesis. Certain types of chromosomal damage induced in these stages will pass to successive generations as heritable translocations. In the present study, we employed whole chromosome 2 painting with the fluorescence in situ hybridization (FISH) technique to detect the chemically induced translocations in human sperm. Mature human sperm were treated in vitro with an antitumor drug, neocarzinostatin (NCS), and fertilized in vitro with golden hamster oocytes. Sperm pronuclear chromosome slides were prepared at the first cleavage metaphase. To compare the characteristics of translocations between somatic and germ cells, human lymphocytes in peripheral blood treated with NCS in vitro were analyzed at first round metaphase after PHA-stimulation. From the analysis of translocations by whole chromosome 2 painting, frequencies of the haploid genomic translocations (FhG) were predicted for both sperm and lymphocytes. At 1.0 micrograms/ml, the actual percentages of sperm and lymphocytes with chromosome 2 translocations were almost identical (11.9% and 12.0%). At the same dose, however, the FhG of the sperm (1.15) was considerably higher than that of the lymphocytes (0.58), indicating that complex translocations having two or more rearranged sites were induced by NCS more frequently in sperm than in lymphocytes. PMID- 8700183 TI - Cytogenotoxicities of sublimed urethane gas to the mouse embryo. AB - Urethane (ethyl carbamate) which has long been used for commonly used drugs and has proven to be useful in the formation of products in every-day use, is volatile, and small amounts sublime spontaneously. Pregnant ICR mice were maintained in the vinyl chamber (45 liter) which was ventilated 4 times per hour. To inhale urethane gas, air was passed first through a glass bottle containing 500 g of crystalline urethane and then into the vinyl chamber. Concentration of the sublimed urethane gas in the chamber was 1.28 +/- 0.08 mg/l, and sublimed urethane gas produced significantly high incidence of chromosomal aberrations in the cells of whole embryo, when mice inhaled it for 48 h from day 9 to day 11 of pregnancy. High and significant incidence of chromosomal aberrations (36.0%) was detected in the embryo 3 h after urethane gas inhalation, but decreased to 5.3% at 24 h after exposure and showed no significant differences from controls after 48 h, while the incidence in bone marrow cells from the adult (pregnant) mice was lower (21.5%) at 3 h after exposure but a significant increase remained until 72 h after exposure. A majority of chromosomal aberrations was chromatid types. As a consequence of cellular damages by urethane gas inhalation during pregnancy, significantly high incidence of fetal deaths and congenital malformations (cleft palate, polydactyly, tail anomaly etc.) was induced in the offspring. Thus, we must be aware of the risk of volatile chemicals, because it is difficult to perceive and avoid hazardous exposure via respiration. PMID- 8700184 TI - Comparative in-vivo genotoxicity of antiviral nucleoside analogues; penciclovir, acyclovir, ganciclovir and the xanthine analogue, caffeine, in the mouse bone marrow micronucleus assay. AB - Three purine nucleoside analogues, penciclovir (PCV), acyclovir (ACV) and ganciclovir (GCV), were assessed for in-vivo genotoxicity in the mouse bone marrow micronucleus assay, together with the xanthine (purine) analogue, caffeine (CAF). All these compounds exhibit anti-viral properties and the first three are marketed anti-viral drugs. All have been shown to be genotoxic in separate in vitro and in-vivo studies. Because of their widespread use, we considered it important to directly compare their relative in-vivo genotoxic potencies as an aid to assessing their relative genotoxic risk to humans. Accordingly, two-dose (0 and 24 h)/single sample mouse micronucleus assays were performed on all four compounds. PCV and ACV appeared to give essentially arithmetic increases in induction of micronucleated polychromatic erythrocytes (MNPCE) with arithmetic increases in dose with apparent thresholds at approx. 1078 mumols/kg per day and 316 mumols/kg per day, respectively. The dose-response curve for GCV appeared more exponential, without a threshold, but with a no-effect dose of around 150 mumols/kg per day. With CAF, systemic toxicity allowed the assessment of only very weak effects, such that our estimate of a no-effect dose of 388 mumols/kg per day is subject to large errors. Taking into account magnitude of response, slope of dose-response curve and no-effect doses, the order of potency was GCV > ACV > (CAF?) > PCV. The relevance of these findings in terms of risk is uncertain. PMID- 8700185 TI - Retrospective dose estimates in Estonian Chernobyl clean-up workers by means of FISH. AB - The present study deals with retrospective estimation of radiation doses, among Estonian Chernobyl clean-up workers, by means of scoring stable translocations using the FISH technique. All persons investigated in this study were sent to the area in 1986 and the majority of them were selected to be among those with the presumably highest exposure doses. In spite of the selection the estimated average dose is between 0.2-0.3 Gy, thus not clearly above the officially permitted dose level of 0.25 Gy. Due to unforseen conditions during transport of the blood samples, both the number of persons available for analysis and the number of metaphases available for scoring were substantially reduced. However, unless this selection is linked with the potential aberration frequency of the cells involved, no bias is expected. PMID- 8700186 TI - Genotoxicity in vivo of phenazine and aminophenazines assayed in the wing spot test and the DNA-repair test with Drosophila melanogaster. AB - The genotoxicity and DNA-damaging activity of 6 phenazine and aminophenazine derivatives were assayed in the wing spot and DNA-repair tests in Drosophila melanogaster. Phenazine (Pz), and all aminophenazines tested, namely, 1 aminophenazine (APz), 2-APz, 2,3-diaminophenazine (DAPz), 2,7-DAPz and 2,7 diamino-3,8-dimethylphenazine (DADMPz), exhibited mutagenicity significantly in the wing spot test. The activities in the wing spot test were ranked in a sequence DADMPz > (2,7-DAPz, 2,3-DAPz) > (2-APz, 1-APz, Pz). In the DNA-repair test, 2,3-DAPz, 2,7-DAPz, and DADMPz clearly showed DNA-damaging activity, but Pz, 1-APz and 2-APz were inactive. Based on these results, we predict that DADMPz, 2,3-DAPz and 2,7-DAPz are likely to be more carcinogenic than 2-APz, 1 APz or Pz. PMID- 8700187 TI - Cytogenetic effects of Metalaxyl on human and animal chromosomes. AB - The purpose of this study was to assess the cytogenetic effects in vitro and in vivo of a commonly used fungicide, Metalaxyl. Chromosome damage in vitro, quantified by cultured human peripheral blood lymphocytes, demonstrated dose related effects not associated with mitotic inhibition or cell death. Significant induction of chromosomal aberrations was observed with between 300 and 1000 micrograms/ml Metalaxyl in the absence of microsomal activation. Incubation in the presence of S9 mix produced less cytogenetic damage. Single i.p. injections of 75-300 mg/kg Metalaxyl had no effect on the frequency of micronuclei, detected in murine polychromatic erythrocytes. Micronuclei results were not compromised by direct evidence of cytotoxicity in the bone marrow of treated animals. The results in the present study indicated that genotoxicity of Metalaxyl was detected only in vitro and not in vivo. Available data reported that Metalaxyl was non-carcinogenic and gave negative results in a battery of genotoxicity tests. So, clastogenicity of Metalaxyl may not be evidence for DNA reactivity, but it may indicate alterations in cell homeostasis which are well implicated in the process of carcinogenesis. PMID- 8700188 TI - Effect of eugenol on the mutagenicity of benzo[a]pyrene and the formation of benzo[a]pyrene-DNA adducts in the lambda-lacZ-transgenic mouse. AB - To study the possible reduction by eugenol of the mutagenicity and genotoxicity of benzo[a]pyrene (B[a]P) in vivo, the lambda-lacZ-transgenic mouse strain 40.6 (Muta Mouse) was used. Male mice were fed a diet containing 0.4% (w/w) eugenol or a control diet for 58 days. On day 10, half of the mice received an i.p. dose of 100 mg/kg b.w. B[a]P. The lacZ mutants were recovered by packaging of DNA isolated from liver into lambda phage, and expressed in E. coli C lacZ-recA-galE- bacteria. In both control mice and mice fed the eugenol diet, B[a]P treatment resulted in a similar, significant increase in lacZ mutant frequency. Eugenol was not mutagenic by itself. By 32P-postlabelling analysis of the liver DNA using an analysis method with chromatographic conditions for B[a]P-DNA adducts, no effect of eugenol on the formation of B[a]P-DNA adducts in the lambda-lacZ-transgenic mouse was found. By 32P-postlabelling analysis using an alkenylbenzene solvent system the amount of B[a]P-DNA adducts was lower in mice fed the eugenol diet than in mice fed the control diet but the decrease was not statistically significant. However, one spot indicative of an eugenol-associated DNA adduct was detected. The present data provide no evidence for antimutagenic or antigenotoxic potential of eugenol in vivo. Furthermore, they suggest genotoxicity in vivo of eugenol per se. PMID- 8700189 TI - Inhibition by quercetin and luteolin of chromosomal alterations induced by salted, deep-fried fish and mutton in rats. AB - Previous studies from our laboratory have shown the clastogenic effects of long term feeding on deep-fried fish and mutton in rat bone marrow cells. We report the chemopreventive action of two flavanoids, quercetin (Qn) and luteolin (Ln) against the induced mutagenicity by fish and mutton extracts. Groups of rats were treated with flavanoids through pre-, simultaneous- and post-treatment regimens and killed at the end of treatment. The bone marrow was removed and analysed for the presence of micronuclei (MN) and chromosome aberrations (CA). Pre-treatment showed most effectively a good inhibition of mutagenicity at every dose tested. Luteolin was a better protective agent than quercetin. It protected the cells against genetic damage to 93% in the micronucleus assay and to 95% in the chromosome aberrations induced by fish extract (p < 0.001 in both the groups). Mutton extract-induced micronuclei and chromosome aberrations were protected 85% and 90%, respectively, by luteolin and 79% and 76%, respectively, by quercetin. Our results tend to suggest that quercetin and luteolin are potential chemopreventive compounds. PMID- 8700190 TI - Roche fails to get European patent on Taq polymerase. PMID- 8700191 TI - US panel established to coordinate work on endocrine disrupters. PMID- 8700192 TI - 'Beware of hype,' AIDS conference told. PMID- 8700193 TI - Brain science benefits from budget plan. PMID- 8700194 TI - Patents versus transplants. PMID- 8700195 TI - Mad cows, bats and baby milk. PMID- 8700196 TI - Aptly named aptamers display their aptitude. PMID- 8700197 TI - Fat regulation. Prime time for neuropeptide Y. PMID- 8700198 TI - Tumour suppressors. Dispatches from patched. PMID- 8700199 TI - Circadian rhythms. Ion channels get the message. PMID- 8700200 TI - Positive effects of pollution. PMID- 8700201 TI - Oxidative damage in Alzheimer's. PMID- 8700202 TI - Integration of positional signals and regulation of wing formation and identity by Drosophila vestigial gene. AB - Appendage formation is organized by signals from discrete sources that presumably act upon downstream genes to control growth and patterning. The Drosophila vestigial gene is selectively required for wing-cell proliferation, and is sufficient to induce outgrowths of wing tissue from eyes, legs and antennae. Different signals activate separate enhancers to control vestigial expression: first, in the dorsal/ventral organizer through the Notch pathway, and subsequently, in the developing wing blade by decapentaplegic and a signal from the dorsal/ventral organizer. Signal integration must be a general feature of genes like vestigial, that regulate growth or patterning along more than one axis. PMID- 8700203 TI - Trichromatic colour vision in New World monkeys. AB - Trichromatic colour vision depends on the presence of three types of cone photopigment. Trichromacy is the norm for all Old World monkeys, apes and humans, but in several genera of New World monkeys, colour vision is strikingly polymorphic. The difference in colour vision between these New and Old World primates results form differing arrangements of the pigment genes on the X chromosome. In Old World primates the three photopigments required for routine trichromatic colour vision are encoded by two or more X-chromosome pigment genes and an autosomal pigment gene. New World monkeys typically have only one X chromosome pigment gene; multiple alleles allow different types of dichromatic colour vision and, in female heterozygous at this locus, variant forms of trichromatic colour vision. Here we report that multiple X-chromosome pigment genes and trichromatic colour vision are the norm for one genus of platyrrhine monkey, the howler monkey, Alouatta. PMID- 8700204 TI - A PET study of the neural systems of stuttering. AB - The cause of stuttering is unknown. Failure to develop left-hemispheric dominance for speech is a long-standing theory although others implicated the motor system more broadly, often postulating hyperactivity of the right (language nondominant) cerebral hemisphere. As knowledge of motor circuitry has advanced, theories of stuttering have become more anatomically specific, postulating hyperactivity of premotor cortex, either directly or through connectivity with the thalamus and basal ganglia. Alternative theories target the auditory and speech production systems. By contrasting stuttering with fluent speech using positron emission tomography combined with chorus reading to induce fluency, we found support for each of these hypotheses. Stuttering induced widespread overactivations of the motor system in both cerebrum and cerebellum, with right cerebral dominance. Stuttered reading lacked left-lateralized activations of the auditory system, which are thought to support the self-monitoring of speech, and selectively deactivated a frontal-temporal system implicated in speech production. Induced fluency decreased or eliminated the overactivity in most motor areas, and largely reversed the auditory-system underactivations and the deactivation of the speech production system. Thus stuttering is a disorder affecting the multiple neural systems used for speaking. PMID- 8700205 TI - Decapentaplegic restricts the domain of wingless during Drosophila limb patterning. AB - Signalling proteins in the BMP-decapentaplegic (dpp), WNT-wingless (wg) and Shh hedgehog (hh) families have been implicated in limb and appendage development in both invertebrates and vertebrates. In Drosophila, dpp protein (Dpp) induces distal outgrowth and patterning of legs and wings, but the molecular responses to Dpp are not well characterized. Analysis of clones mutant for the Dpp receptors encoded by punt or thickveins (tkv) reveals that repression of wg expression is one critical function of Dpp signalling in leg and wing discs. Distal clones that lie on the anterior edge of the anterior-posterior compartment boundary ectopically express wg and cause pattern abnormalities, suggesting that Dpp represses Hh activation of wg in the distal primordia of the leg and wing. By repressing wg expression in the leg, Dpp signalling limits the region that responds to high levels of Wg and Dpp to the site of distal outgrowth. Such negative regulatory feedback loops between signalling molecules are likely to be critical for limb patterning in other species. PMID- 8700206 TI - A cationic channel regulated by a vertebrate intrinsic circadian oscillator. AB - Secretory cells of the chicken pineal gland exhibit light-sensitive circadian rhythms in melatonin release that persist in vitro. Melatonin secretion is positively regulated by cyclic AMP and intracellular Ca2+ (refs 8, 10-15). Cyclic AMP analogues are more effective at stimulating melatonin secretion during the circadian night owing in part to increased Ca2+ influx at those times. However, this cannot be attributed to increased activity of L-type Ca2+ channels. Here we describe an unusual 40-pS cationic channel (ILOT) in cultured chicken pineal cells that is permeable to Ca2+ and active in the night but not during the day. ILOT is not voltage- or stretch-activated, it has a characteristically long open time, and its gating persists in excised inside-out patches in the absence of Ca2+ or cyclic nucleotides. Daily rhythms in ILOT gating are also observed in previously entrained chicken pineal cells free-running under constant dark conditions. Nighttime ILOT activity is not suppressed by brief light pulses. PMID- 8700207 TI - A receptor subtype involved in neuropeptide-Y-induced food intake. AB - Neuropeptide Y (NPY) is a powerful stimulant of food intake and is proposed to activate a hypothalamic 'feeding' receptor distinct from previously cloned Y-type receptors. This receptor was first suggested to explain a feeding response to NPY and related peptides, including NPY2-36, that differed from their activities at the Y1 receptor. Here we report the expression cloning of a novel Y-type receptor from rat hypothalamus, which we name Y5. The complementary DNA encodes a 456 amino-acid protein with less than 35% overall identity to known Y-type receptors. The messenger RNA is found primarily in the central nervous system, including the paraventricular nucleus of the hypothalamus. The extent to which selected peptides can inhibit adenylate cyclase through the Y5 receptor and stimulate food intake in rats correspond well. Our data support the idea that the Y5 receptor is the postulated 'feeding' receptor, and may provide a new method for the study and treatment of obesity and eating disorders. PMID- 8700208 TI - Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. AB - Signal transducers and activators of transcription (STATs) are activated by tyrosine phosphorylation in response to cytokines and mediate many of their functional responses. Stat4 was initially cloned as a result of its homology with Stat1 (refs 4, 5) and is widely expressed, although it is only tyrosine phosphorylated after stimulation of T cells with interleukin (IL)-12 (refs 6,7). IL-12 is required for the T-cell-independent induction of the cytokine interferon (IFN)-gamma, a key step in the initial suppression of bacterial and parasitic infections. IL-12 is also important for the development of a Th1 response, which is critical for effective host defence against intracellular pathogens. To determine the function of Stat4 and its role in IL-12 signalling, we have produced mice that lack Stat4 by gene targeting. The mice were viable and fertile, with no detectable defects in haematopoiesis. However, all IL-12 functions tested were disrupted, including the induction of IFN-gamma, mitogenesis, enhancement of natural killer cytolytic function and Th1 differentiation. PMID- 8700209 TI - Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. AB - Interactions between cytokine and receptor lead to the activation of multiple signalling molecules, including the family of signal transducer and activator of transcription (STAT) proteins. STAT4 is one member of this family, and is activated only in response to the cytokine interleukin (IL)-12 (refs 5, 6). By gene targeting, we have generated mice deficient in STAT4 to determine whether the function of this transcription factor is redundant with other signalling molecules activated by IL-12. IL-12-induced increases in the production of interferon (IFN)-gamma cellular proliferation and natural killer (NK) cell cytotoxicity are abrogated in lymphocytes from STAT4-deficient mice. The development of Th1 cells in response to either IL-12 of Listeria monocytogenes is also impaired in the absence of Stat4. Furthermore, Stat4-deficient lymphocytes demonstrate a propensity towards the development of Th2 cells. These results demonstrate that Stat4 is essential for mediating responses to IL-12 in lymphocytes, and regulating the differentiation of both Th1 and Th2 cells. PMID- 8700210 TI - Regulation of receptor-mediated endocytosis by Rho and Rac. AB - Pinocytosis and membrane ruffling are among the earliest and most dramatic cellular responses to stimulation by growth factors or other mitogens. The small Ras-related G proteins Rho and Rac have a regulatory role in membrane ruffling and activated Rho has been shown to stimulate pinocytosis when microinjected into Xenopus oocytes. In contrast to these well established effects of Rho and Rac on plasma membrane morphology and bulk pinocytosis, there has been no evidence for their involvement in the regulation of receptor-mediated endocytosis in clathrin coated pits. Here we show that activated Rho and Rac inhibit transferrin-receptor mediated endocytosis when expressed in intact cells. Furthermore, we have reconstituted these effects in a cell-free system and established that Rho and Rac can regulate clathrin-coated vesicle formation. PMID- 8700211 TI - NMR structure of the mouse prion protein domain PrP(121-231). AB - The 'protein only' hypothesis states that a modified form of normal prion protein triggers infectious neurodegenerative diseases, such as bovine spongiform encephalopathy (BSE), or Creutzfeldt-Jakob disease (CJD) in humans. Prion proteins are thought to exist in two different conformations: the 'benign' PrPcform, and the infectious 'scrapie form', PrPsc. Knowledge of the three dimensional structure of PrPc is essential for understanding the transition to PrPsc. The nuclear magnetic resonance (NMR) structure of the autonomously folding PrP domain comprising residues 121-231 (ref. 6) contains a two-stranded antiparallel beta-sheet and three alpha-helices. This domain contains most of the point-mutation sites that have been linked, in human PrP, to the occurrence of familial prion diseases. The NMR structure shows that these mutations occur within, or directly adjacent to, regular secondary structures. The presence of a beta-sheet in PrP(121-231) is in contrast with model predictions of an all helical structure of PrPc (ref. 8), and may be important for the initiation of the transition from PrPc to PrPsc. PMID- 8700213 TI - US company comes under fire over patent on umbilical cord cells. PMID- 8700212 TI - Structural basis of RNA folding and recognition in an AMP-RNA aptamer complex. AB - The catalytic properties of RNA and its well known role in gene expression and regulation are the consequence of its unique solution structures. Identification of the structural determinants of ligand recognition by RNA molecules is of fundamental importance for understanding the biological functions of RNA, as well as for the rational design of RNA Sequences with specific catalytic activities. Towards this latter end, Szostak et al. used in vitro selection techniques to isolate RNA sequences ('aptamers') containing a high-affinity binding site for ATP, the universal currency of cellular energy, and then used this motif to engineer ribozymes with polynucleotide kinase activity. Here we present the solution structure, as determined by multidimensional NMR spectroscopy and molecular dynamics calculations, of both uniformly and specifically 13C-, 15N labelled 40-mer RNA containing the ATP-binding motif complexed with AMP. The aptamer adopts an L-shaped structure with two nearly orthogonal stems, each capped proximally by a G x G mismatch pair, binding the AMP ligand at their junction in a GNRA-like motif. PMID- 8700214 TI - BSE transmission data pose dilemma for UK scientists. PMID- 8700215 TI - German institute renews east-west unease. PMID- 8700216 TI - Transcription. A fate worse than death. PMID- 8700217 TI - Human genetics. Woman's meat, a man's poison. PMID- 8700218 TI - Self-replication. Even peptides do it. PMID- 8700219 TI - Cortical neurophysiology. Attention is everywhere. PMID- 8700220 TI - Frameshift mutator mutations. PMID- 8700221 TI - Direct dating of Florisbad hominid. PMID- 8700222 TI - Denial of disabilities in anosognosia. PMID- 8700223 TI - Biological activity of interleukin-16. PMID- 8700224 TI - Cdc25 cell-cycle phosphatase as a target of c-myc. AB - The product of the proto-oncogene c-myc, in partnership with Max, forms a transcription factor that can promote either oncogenic transformation or apoptosis. The Myc/Max heterodimer binds to elements in the cdc25A gene and activates transcription. Like myc, cdc25A, itself a proto-oncogene, can induce apoptosis in cells depleted of growth factor, and Myc-induced apoptosis also requires cdc25A. These findings indicate that cdc25A is a physiologically relevant transcriptional target of c-myc. PMID- 8700225 TI - A self-replicating peptide. AB - The production of amino acids and their condensation to polypeptides under plausibly prebiotic conditions have long been known. But despite the central importance of molecular self-replication in the origin of life, the feasibility of peptide self-replication has not been established experimentally. Here we report an example of a self-replicating peptide. We show that a 32-residue alpha helical peptide based on the leucine-zipper domain of the yeast transcription factor GCN4 can act autocatalytically in templating its own synthesis by accelerating the thioester-promoted amide-bond condensation of 15- and 17-residue fragments in neutral, dilute aqueous solutions. The self-replication process displays parabolic growth pattern with the initial rates of product formation correlating with the square-foot of initial template concentration. PMID- 8700226 TI - A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. AB - A pheromone-induced neurosecretory pathway in Caenorhabditis elegans triggers developmental arrest and an increase in longevity at the dauer diapause stage. The gene age-1 is required for non-dauer development and normal senescence. age-1 encodes a homologue of mammalian phosphatidylinositol-3-OH kinase (PI(3)K) catalytic subunits. Lack of both maternal and zygotic age-1 activity causes dauer formation, whereas animals with maternal but not zygotic age-1 activity develop as non-dauers that live more than twice as long as normal. These data suggest that phosphatidylinositol signalling mediated by AGE-1 protein controls lifespan and the dauer diapause decision. PMID- 8700227 TI - Attentional modulation of visual motion processing in cortical areas MT and MST. AB - The visual system is constantly inundated with information received by the eyes, only a fraction of which seems to reach visual awareness. This selection process is one of the functions ascribed to visual attention. Although many studies have investigated the role of attention in shaping neuronal representations in the visual cortex, few have focused on attentional modulation of neuronal signals related to visual motion. Here we report that the responses of direction selective neurons in monkey visual cortex are greatly influenced by attention, and that this modulation occurs as early in the cortical hierarchy as the level of the middle temporal visual area (MT). Our finding demonstrates a stronger and earlier influence of attention on motion processing along the dorsal visual pathway than previously recognized. PMID- 8700228 TI - Reversal of apoptosis by the leukaemia-associated E2A-HLF chimaeric transcription factor. AB - The E2A-HLF (for hepatic leukaemia factor) fusion gene, formed by action of the t(17;19) (q22;p13) chromosomal translocation, drives the leukaemic transformation of early B-cell precursors, but the mechanism of this activity remains unknown. Here we report that human leukaemia cells carrying the translocation t(17;19) rapidly died by apoptosis when programmed to express a dominant-negative suppressor of the fusion protein E2A-HLF, indicating that the chimaeric oncoprotein probably affects cell survival rather than cell growth. Moreover, when introduced into murine pro-B lymphocytes, the oncogenic E2A-HLF fusion protein reversed both interleukin-3-dependent and p53-mediated apoptosis. The close homology of the basic region/leucine zipper (bZIP) DNA-binding and dimerization domain of HLF to that of the CES-2 cell-death specification protein of Caenorhabditis elegans suggests a model of leukaemogenesis in which E2A-HLF blocks an early step within an evolutionarily conserved cell-death pathway. PMID- 8700229 TI - Transcriptional regulator of programmed cell death encoded by Caenorhabditis elegans gene ces-2. AB - The ces (for cell-death specification) genes of the nematode Caenorhabditis elegans control the cell-death fate of individual cell types and are candidates for being the regulators of an evolutionarily conserved general pathway of programmed cell death. Here we present what we believe is the first molecular characterization of a ces gene. We cloned the gene ces-2, which is required to activate programmed cell death in the sister cells of the serotoninergic neurosecretory motor (NSM) neurons, and found that ces-2 encodes a basic region leucine-zipper (bZIP) transcription factor. The CES-2 protein is most similar to members of the PAR (proline- and acid-rich) subfamily of bZIP proteins and has DNA-binding specificity like that of PAR-family proteins. An oncogenic form of the mammalian PAR-family protein, hepatic leukaemia factor (HLF), is reported to effect programmed cell death in mammalian cells. On the basis of these observations, we suggest that some CES-2/PAR family transcription factors are evolutionary conserved regulators of programmed cell death. PMID- 8700230 TI - smoothened encodes a receptor-like serpentine protein required for hedgehog signalling. AB - Members of the Hedgehog family of secreted proteins control a number of important inductive interactions in the development of both vertebrates and Drosophila, but little is known about the ways in which their signalling activities are transduced. In Drosophila, hedgehog is one of the segment-polarity genes, mutations of which disrupt the pattern and polarity of individual embryonic segments and their adult derivatives; several of these genes have been implicated in transduction of the hedgehog signal. Here we show that the segment-polarity gene smoothened is required for the response of cells to hedgehog signalling during the development of both the embryonic segments and imaginal discs. Sequence analysis of the smoothened transcription unit reveals a single open reading frame encoding a protein with seven putative transmembrane domains. This structure is typical of G-protein-coupled receptors, suggesting that the Smoothened protein may act as a receptor for the Hedgehog ligand. PMID- 8700231 TI - Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. AB - The DNA-dependent protein kinase (DNA-PK) is a mammalian serine/threonine kinase that is implicated in the repair of DNA double-strand breaks, DNA replication, transcription, and V(D)J recombination. To determine the role of the DNA-binding subunit of DNA-PK in vivo, we targeted Ku80 in mice. In mutant mice, T and B lymphocyte development is arrested at early progenitor stages and there is a profound deficiency in V(D)J rearrangement. Although Ku80-/- mice are viable and reproduce, they are 40-60% of the size of littermate controls. Consistent with this growth defect, fibroblasts derived from Ku80-/- embryos showed an early loss of proliferating cells, a prolonged doubling time, and intact cell-cycle checkpoints that prevented cells with damaged DNA from entering the cell-cycle. The unexpected growth phenotype suggests a new and important link between Ku80 and growth control. PMID- 8700232 TI - Structural basis for inhibition of receptor protein-tyrosine phosphatase-alpha by dimerization. AB - Receptor-like protein-tyrosine phosphatases (RPTPs), like their non-receptor counterparts, regulate the level of phosphotyrosine-containing proteins derived from the action of protein-tyrosine kinases. RPTPs are type-I integral membrane proteins which contain one or two catalytic domains in their cytoplasmic region. It is not known whether extracellular ligands regulate the activity of RPTPs. Here we describe the crystal structure of the membrane-proximal catalytic domain (D1) of a typical RPTP, murine RPTP alpha. Significant structural deviations from the PTP1B fold reside within the amino-terminal helix-turn-helix segment of RPTPalphaD1 (residues 214 to 242) and a distinctive two-stranded beta-sheet formed between residues 211-213 and 458-461. The turn of the N-terminal segment inserts into the active site of a dyad-related D1 monomer. On the basis of two independent crystal structures, sequence alignments, and the reported biological activity of EGF receptor/CD45 chimaeras, we propose that dimerization and active site blockage is a physiologically important mechanism for downregulating the catalytic activity of RPTPalpha and other RPTPs. PMID- 8700234 TI - Meeting patient needs through multiskilling. PMID- 8700233 TI - Recognition of DNA by designed ligands at subnanomolar concentrations. AB - Small molecules that specifically bind with high affinity to any predetermined DNA sequence in the human genome would be useful tools in molecular biology and potentially in human medicine. Simple rules have been developed to control rationally the sequence specificity of minor-groove-binding polyamides containing N-methylimidazole and N-methylpyrrole amino acids. Two eight-ring pyrrole imidazole polyamides differing in sequence by a single amino acid bind specifically to respective six-base-pair target sites which differ in sequence by a single base pair. Binding is observed at subnanomolar concentrations of ligand. The replacement of a single nitrogen atom with a C-H regulates affinity and specificity by two orders of magnitude. The broad range of sequences that can be specifically targeted with pyrrole-imidazole polyamides, coupled with an efficient solid-phase synthesis methodology, identify a powerful class of small molecules for sequence-specific recognition of double-helical DNA. PMID- 8700235 TI - Some of the people, some of the time: customer service in the real world. PMID- 8700236 TI - Caring in nursing education: reducing anxiety in the clinical setting. AB - It has been well-documented that the clinical experience is one of the most anxiety-producing aspects of nursing education. When feelings of anxiety become severe, they present a clear threat to the student's success in the program. This article explores the role of "caring" in nursing education as a means of reducing student anxiety. Caring, described at length by Jean Watson, has become one of the most popular trends in the education of young nurses. When caring behaviors are demonstrated in a meaningful way by clinical instructors, the student may experience a sense of comfort and belonging, which may in turn be effective in reducing anxiety and enabling the student to successfully complete a clinical rotation. The aim of this article is to inspire nurses, not only those in the educational setting but in all settings and at all levels of their careers, to reconsider the effects and benefits of displaying a caring attitude. PMID- 8700237 TI - Be careful what you wish for.... PMID- 8700238 TI - Health insurance: impact on hospitalization rates for asthma. AB - Recent studies have shown that hospitalization rates for asthma have increased. Data from the 1991 National Health Interview Survey were analyzed to show the relationship between insured and uninsured persons who self-identify as having asthma. Having health insurance was found to decrease the number of hospitalizations associated with asthma, particularly at low and high income levels. A collateral finding demonstrated an inverse relationship between doctor visits and hospitalizations. This suggests that having health insurance will result in patients' seeking physician contact for preventive care; this leads to better control, infrequent hospitalizations, and, ultimately, decreased health care costs. PMID- 8700239 TI - Politics: the neglected ethical dimension of an ethic of care. PMID- 8700240 TI - Interdisciplinary research: evaluating writing to learn in the nursing curriculum. AB - A 3-year collaborative study was conducted by the department head of baccalaureate nursing and the director of writing at a southern university in Louisiana. The research was designed to test the effectiveness of an intense writing-to-learn curriculum intervention incorporated into a required introductory nursing course. Writing-to-learn strategies used in this study were designed to foster personal involvement in the subject matter, improve data comprehension, and encourage critical thinking (Dobie & Poirrier, 1995). The findings reported in this study represent Part III of a 3-year investigation into the effectiveness of using writing-to-learn strategies in freshman nursing classes. PMID- 8700241 TI - Competencies of new registered nurses: a survey of deans and health care agencies in the state of Hawaii. AB - In Hawaii, a survey of schools of nursing and health care agencies revealed significant differences in the perceived competencies of new registered nurse graduates. When directors of nursing were asked if new graduates meet expectations, more than 42% said no. This survey identifies that numerous discrepancies exist between agency expectations and what is actually practiced in the clinical setting. Suggestions for achieving competencies in both academic and agency settings are offered. PMID- 8700242 TI - Accepting and delegating care tasks: is the sky the limit? PMID- 8700243 TI - The art of working with number two. PMID- 8700244 TI - Measuring nursing intensity in ambulatory care. Part I: Approaches to and uses of patient classification systems. AB - Part I of this two-part series summarizes medical and nursing approaches to patient classification in ambulatory care. The conceptual basis for the Patient Intensity for Nursing: Ambulatory Care (PINAC) also is described as are important contemporary uses of data from Patient Classification Systems (PCS). Part two of this series, which will appear in the March/April 1996 issue, will present data on the reliability and validity of the PINAC. PMID- 8700246 TI - Cost analysis: initiation of HBMC and first CareMap. AB - The start-up costs incurred when instituting Hospital Based Managed Care (HBMC) and using CareMaps in a large mid-western teaching hospital are analyzed. The complete cost analysis of developing the first CareMap, Cesarean Section, is included. Cost analysis of an additional CareMap, Normal Vaginal Delivery, is available for comparison for the developmental phase of the CareMap. The CareMaps were designed by the same multidisciplinary team though 18 months apart. PMID- 8700245 TI - Nurses' use and delegation of indirect care interventions. AB - One hundred seventy one nurses were surveyed about their use of 26 indirect care interventions. They indicated that they would not delegate to others the majority of the interventions. Their estimations of the time to perform each intervention were, for the most part, the same, regardless of size of hospital, shift work, and illness level of the patient. The results demonstrate the importance of defining the nurse's indirect care, or role as manager of the care environment role. The indirect care interventions in this study are included in the second edition of the Nursing Interventions Classification (NIC). PMID- 8700247 TI - On risk-taking and role-breaking. PMID- 8700248 TI - Nurses' and other experts' views of health care fraud and abuse. AB - This study examines the perceptions of a Florida panel of experts regarding the effectiveness and cost effectiveness of changes in law related to health care fraud and abuse. The panel was established as a task force under Florida health reform initiatives. The panel first defined fraud and abuse, then studied a variety of proposed initiatives, and finally rated each initiative as to its effectiveness and cost-effectiveness. Findings show significant perceptual differences between the nurses' perceptions and those of other panelists. PMID- 8700249 TI - The challenge of change: allowing for the learning curve. PMID- 8700250 TI - An interview with John Kitzhaber. Interview by Connie R Curran. AB - Oregon Governor John Kitzhaber has been instrumental in developing a blueprint for universal access to basic and affordable health coverage. The Oregon Health Plan is a bipartisan plan, created by the people of Oregon through community, business, labor, and government participation. In this interview, Gov. Kitzhaber discusses the challenges and opportunities facing patients and providers in the U.S. health care system. PMID- 8700251 TI - Medicaid to Medigrant: states prepare for change. PMID- 8700252 TI - Opportunities for nursing innovation in a changing health care system: a case analysis. AB - Opportunities for nursing leadership and innovation have emerged as a result of the reorganization of health systems. A case study illustrates such opportunities, with reference to the related literature of health care redesign. The creation of a new department and a new role for nursing as a response to current market forces are presented as an exemplar in organizational redesign and nursing leadership. PMID- 8700253 TI - The emotional side of leadership: the nurse manager's challenge. PMID- 8700254 TI - Case management: implementing the vision. AB - Case management is a strategy for restructuring the health care delivery system. The system requires critical planning and implementation steps to achieve quality care at reduced cost. PMID- 8700255 TI - Effects of shared governance on perceptions of work and work environment. AB - This quasi-experimental study examined the effects of shared governance on nurse/non-nurse perceptions of work and work environment. Initiating shared governance did not significantly influence job satisfaction, anticipated turnover, and perceived effectiveness. Increases in autonomy were not sustained over time. PMID- 8700256 TI - Case management--a vital link to performance improvement. AB - A pilot program in the cardiac surgical service resulted in a $ 1.3 million reduction in patient charges while quality patient outcomes were sustained. Pivotal to the success of the program was the implementation of the case manager role. PMID- 8700257 TI - Transprofessional patient care--the nurse manager's challenge. PMID- 8700258 TI - Ambulatory care series praised. PMID- 8700259 TI - Mentoring: executive responsibility? PMID- 8700261 TI - Preparing nurse managers for a managed care future. PMID- 8700260 TI - Budget and appropriations status report. PMID- 8700262 TI - The bed is dead. PMID- 8700263 TI - An interview with Rick Scott. Interview by Connie R Curran. AB - Richard (Rick) L. Scott is president and chief executive officer of Columbia/HCA Healthcare Corporation, the nation's largest health care services provider. In this interview, he discusses principles of patient care, measuring and sharing systems, the future of academic health centers, and the importance of information dissemination. PMID- 8700264 TI - Take charge: managing six transformations in health care delivery. AB - Changes occurring in the health care industry are substantive and constitute a paradigm shift. Nurse managers can participate in shaping the health care organization of the future by understanding six critical areas of transformation and their driving forces. PMID- 8700265 TI - Measuring nursing intensity in ambulatory care. Part II: Developing and testing PINAC. AB - Measures of nursing intensity are needed for a variety of administrative, clinical, research, and quality management purposes. The Patient Intensity for Nursing: Ambulatory Care (PINAC) is a new measure designed and tested for use in ambulatory care. Reliability and validity testing of the PINAC are described in this second part of a two-part series. PMID- 8700266 TI - Benchmarking for clinical pathways in hospitals: a summary of sources. AB - Benchmarks are criteria and standards for resource expenditure, as well as other variables, derived from organizations or communities which have been identified as models of the most effective and efficient practices. The development of benchmarks is crucial to reducing lengths of stay and related costs in hospitals. Useful sources for benchmarking data and how to access them are summarized. PMID- 8700267 TI - The impact of unlicensed assistive personnel on nursing care delivery. AB - Besieged with fiscal and political constraints in acute care, the addition or substitution of less expensive nursing personnel is quickly gaining popularity. The evolution of nursing care delivery systems in the acute care setting, the factors associated with the increased use of unlicensed assistive personnel, examination and evaluation of the current literature surrounding unlicensed assistive personnel, and recommendations for a future strategy are described. PMID- 8700268 TI - [Limited joint movement; a little known complication of diabetes mellitus]. PMID- 8700269 TI - [Levonorgestrel capsules: a big leap forward in intrauterine contraception]. PMID- 8700270 TI - [Estrogen agonists, especially raloxifene, in the treatment of osteoporosis]. PMID- 8700271 TI - [What is somatization?]. PMID- 8700272 TI - [Criteria for somatization studied in an outpatient clinic for general internal medicine]. AB - OBJECTIVE: To compare the evolution of bodily symptoms and the frequency of medical consultation using three different operational definitions of 'somatization'. DESIGN: Descriptive follow-up study. SETTING: General Internal Medicine Outpatient Clinic of Leiden University Hospital, the Netherlands. METHOD: Information about physical and psychic symptoms and about the somatic medical diagnosis was collected in a group of 158 newly referred patients. The concept of 'somatization' was operationalized in three ways: a) seeking medical consultation for somatically unexplained symptoms; b) seeking medical consultation for somatically unexplained symptoms combined with an anxiety disorder or a depressive disorder according to the 'present state examination'; c) seeking medical consultation for somatically unexplained symptoms combined with a somatization disorder or hypochondria according to the Diagnostic and statistical manual of mental disorders (DSM) III R criteria. After a follow-up period of 1.2 years, information was collected from the entire study group about the evolution of the physical symptoms and the frequency of medical consultation. RESULTS: Patients with somatically unexplained symptoms combined with a somatization disorder or hypochondria were characterized in the follow-up by numerous physical symptoms and a high frequency of medical consultation. Compared with the other patients with unexplained symptoms, they visited the general practitioner during the follow-up period 2.5 times as often, saw specialists twice as often and were admitted to a 'somatic' hospital, 6 times as often. CONCLUSION: Using criteria of low restrictiveness for somatization, a large group of patients were identified with a relatively normal (average) illness behaviour. Using more restrictive criteria led to identification of a smaller group with more extreme illness behaviour. PMID- 8700273 TI - [Moderate results of the treatment of femoral shaft fractures in children using intramedullary fixation]. AB - OBJECTIVE: To evaluate the results of treatment of femoral shaft fractures in children with intramedullary nailing. DESIGN: Retrospective. SETTING: Department of Surgery, University Hospital Utrecht, Department of Paediatric Surgery, Wilhelmina Children's Hospital, Utrecht. METHOD: Between 1982 and 1993, 27 femoral shaft fractures in 27 patients under the age of 16 were treated by intramedullary nailing. The charts and radiographs of these patients were reviewed and 24 patients were seen for follow-up examination (mean 7.5 years). Leg length was measured radiographically and anteversion of the affected and normal femora was determined by a standard computed tomography (CT) study. RESULTS: The average hospital stay was 34 days. There were no postoperative complications. At follow-up 10 patients had a leg length discrepancy < 1 cm and a rotational deformity < 10 degrees. Three patients had a shortening of the injured leg > 1 cm (max. 1.7 cm), in 6 patients the injured leg was more than 1 cm longer (max. 3.5 cm). The difference in rotation between fracture side and unaffected side was > 10 degrees in 9 patients. In 6 patients this was due to increased exorotation (max. 22 degrees) and in 3 patients to increased endorotation (max. 27 degrees). Iatrogenic injury of the epiphyseal line was not seen. CONCLUSION: Regarding leg length differences and rotational deformities intramedullary nailing was not superior to the known results of conservative treatment. The indication for operation should be carefully considered and during an operation there should be perfect control of reduction. PMID- 8700274 TI - [Soft-tissue swelling of the foot not always benign]. AB - Two men aged 17 and 23 years had a swelling on the foot which was neither an abscess nor a ganglion. Histological study revealed Ewing's sarcoma and synoviosarcoma, respectively. In both patients amputation under the knee was performed; nevertheless both developed metastases. In case of a swelling of the foot the possibility of malignancy has to be considered in order to shorten the diagnostic period. Consultation of the 'Commissie voor Beentumoren' may be desirable because of the low incidence and often difficult diagnostic process. PMID- 8700275 TI - [Progressive partial lipodystrophy; an external problem with internal anomalies]. PMID- 8700276 TI - [Laparoscopic inguinal hernia surgery: (for the time being) marking time]. PMID- 8700277 TI - [Timing of elective delivery and the possibility of respiratory problems in the infant]. PMID- 8700278 TI - [Spongiform encephalopathy in cattle and humans]. PMID- 8700279 TI - [Immunotherapy in rheumatoid arthritis; current status]. PMID- 8700280 TI - [Cerebrospinal fluid diagnosis using polymerase chain reaction]. PMID- 8700281 TI - [Medical language based on literature references of original articles in the Nederlands Tijdschrift voor Geneeskunde (1930-1995)]. AB - OBJECTIVE: To describe and analyse the frequency of use of the various languages in the bibliographical references in the original articles published in Nederlands Tijdschrift voor Geneeskunde (NTvG) during the past 65 years (1930 1995). DESIGN: Descriptive. SETTING: Hoffmann-La Roche, Basle, Switzerland. METHODS: The language of publication of 10,462 references from 700 original articles published in NTvG between 1930 and 1995 were determined (50 articles a year at intervals of five years). RESULTS: The proportion of references in English increased sharply in 1950, and has continued to increase more slowly since then (15% in 1935; 20% in 1945; 58% in 1955; 64% in 1965; 75% in 1975; 80% in 1985, and 79% in 1995). The proportion of references in Dutch decreased from 1945 to 1975, but has increased since then (20% in 1935; 29% in 1945; 15% in 1955; 16% in 1965; 12% in 1975; 15% in 1985, and 20% in 1995). The proportion of references in German decreased fairly steadily from 1945 onward (51% in 1935; 43% in 1945; 19% in 1955; 15% in 1965; 9% in 1975; 4% in 1985, and 1% in 1995). CONCLUSIONS: In 1950, English supplanted German as the undisputed main language of medicine in the Netherlands. The importance of English, increasing from 1945, has stabilised by 1975. The importance of Dutch slowly decreased from 1945, but has increased substantially since 1975. PMID- 8700282 TI - [Future prospects for children with spina bifida aperta]. AB - OBJECTIVE: To determine the prospects for independent functioning in society of children born with meningomyelocele who are receiving maximal treatment. DESIGN: Retrospective descriptive. SETTING: University Hospital Groningen, the Netherlands. METHODS: Data were collected in 1994 regarding personal care, mobility, education, living conditions and employment of 163 patients alive and born in 1966-1990. They were divided into three groups according to their age, corresponding to the primary school period (n = 47), secondary school period (n = 37) and subsequent education or employment period (n = 79). All data were related to the level of the neurological lesion. RESULTS: A higher level of the neurological deficit corresponded with a lower probability of functioning independently in society. This was mainly caused by the concomitant mental handicap that occurs frequently in children with a high neurological deficit. Nine out of 46 adult patients with a deficit higher than LIII were living independently. Eleven of these 46 patients were (or had been) capable of attending regular education, and 7 of these 11 patients had a regular job. CONCLUSION: The prospects of children born with a meningomyelocele of reaching independence are relatively poor, depending on the level of neurological deficit. PMID- 8700283 TI - [Systemic mastocytosis as a cause of osteoporosis]. AB - Out of 21 male patients with osteoporosis who visited an outpatient clinic for endocrine diseases in two years (1994-1995), three had systemic mastocytosis as diagnosed histopathologically. Two of these had characteristic features of urticaria pigmentosa, consisting of multiple brown nodules on the skin of trunk and extremities, and a positive Darier sign. In all of them the excretion of the histamine metabolites methylhistamine and methylimidazoleacetic acid in a 24-hour urine specimen was increased. When osteoporosis is diagnosed in men or premenopausal women, underlying pathology could be considered. Cautious investigation of signs and symptoms of systemic mastocytosis in such patients might prove this disease be less rare than is often assumed. PMID- 8700284 TI - [Obstetric care in The Netherlands; a lead or in arrears?]. PMID- 8700285 TI - [Psychiatric admissions in Amsterdam according to ethnic background and diagnosis]. PMID- 8700287 TI - What is nursing informatics? The newest nursing specialty. PMID- 8700286 TI - [Infections caused by Listeria monocytogenes]. PMID- 8700288 TI - Nursing must name quality indicators. Interview by Sue Bristol. PMID- 8700289 TI - Always a nurse. PMID- 8700290 TI - Health care systems in flux. PMID- 8700291 TI - A physician's perspective on nurse practitioner legislation. PMID- 8700292 TI - Every woman matters. PMID- 8700293 TI - Nursing: outcomes for the future. PMID- 8700294 TI - License assistance program: intervening for a chemically dependent colleague. PMID- 8700295 TI - Healing touch: its importance in the art of nursing. PMID- 8700296 TI - Over 700 Nebraska nurses heat "Why every patient deserves a licensed nurse". PMID- 8700297 TI - The healthcare revolution: a struggle to maintain equality. PMID- 8700298 TI - ANA introduces 'survival kit' in face of massive hospital restructuring. PMID- 8700299 TI - Power napping and work performance. PMID- 8700301 TI - Nevada Nurses Association position statement on unlicensed assistive personnel. PMID- 8700300 TI - A 'round-the-clock' profession: coping with the effects of shift work. PMID- 8700302 TI - Health care reform project. PMID- 8700303 TI - Neonatal seizures in the United States: results of the National Hospital Discharge Survey, 1980-1991. AB - We present nationally representative estimates of neonatal seizure risk by gender, race and geographic region of the United States. National Hospital Discharge Survey data were analyzed for the period 1980-1991. Birth-weight adjusted risks of neonatal seizures were calculated by the direct method for each gender or race group and for each census region by 4-year intervals. The overall risk of neonatal seizures was 2.84 per 1,000 live births. Risk estimates were consistently higher in low-birth-weight infants (relative risk 3.9). Unadjusted risks were similar across race and gender groups; birth weight adjustment had very little effect. No clear temporal trend was apparent over the 12-year study period. National Hospital Discharge Survey data provide reasonable, although conservative, estimates of neonatal seizure risks nationwide. Underascertainment of neonatal seizures, particularly among sick low-birth-weight infants, is likely due to data collection limitations of the National Hospital Discharge Survey. PMID- 8700304 TI - Epidemiological and genetic studies of Huntington's disease in the San-in area of Japan. AB - After the DNA diagnosis, we evaluated the prevalence of Huntington's disease (HD) in the San-in area of Japan, and confirmed the founder effect. There were 10 patients with HD in the San-in area, who were diagnosed clinically. The expansion of the CAG repeat was observed in 9 patients with HD members in their families, although those family members of the patients had already died. In the patient who had no positive family history, expansion of the CAG repeat was not seen. The prevalence of HD was 065/100,000 in this area. The common haplotype studied by the polymorphism marker of D4S136 was shown in all 9 HD patients, although they were observed in only 2.7% of the normal population. These results suggested a common ancestor of these HD patients. PMID- 8700305 TI - Review of the contribution of twin studies in the search for non-genetic causes of multiple sclerosis. AB - Data are reviewed on the sib risk, the dizygotic twin concordance rate and the prevalence rate of multiple sclerosis (MS) in twins. Concordant affected twin pairs are so rare that it is unlikely that a single study (no matter how large) will establish whether they nevertheless are more common than expectation based on the null hypothesis of sib risk. For this reason, it is necessary to consider all the studies in which twin pairs were ascertained in series. There now seem enough data to cast doubt on this null hypothesis. Moreover, the prevalence of MS in twins seems low. Both these suggestions would be explained by the hypothesis that MS is a rare sequel of late exposure to common childhood infection. PMID- 8700306 TI - An epidemic-like cluster of motor neuron disease in a Swedish county during the period 1973-1984. AB - We have tried to find all cases of motor neuron disease (MND) with onset during the study period 1961-1990 in the county of Skaraborg, Sweden, and in this retrospective study we have identified 168 cases, 107 men and 61 women. Fifty percent of them were alive 2 years after onset. The number of MND cases in consecutive 5-year intervals during the study period was shown to be statistically significantly elevated for males in the period 1981-1985 (Knox test disjoint procedure, p = 0.02). During the period 1973-1984, 70 males had onset of MND, corresponding to an average annual incidence of 4 per 100,000 person-years. This epidemic-like cluster was compared to the MND morbidity in a neighbouring county and was shown to be statistically significantly elevated even when the p value was adjusted for multiple comparisons. Agricultural work was significantly more common among the cases compared to the rest of the population. PMID- 8700307 TI - Survival prediction in sporadic amyotrophic lateral sclerosis. Age and clinical form at onset are independent risk factors. AB - Amyotrophic lateral sclerosis is a progressive neurological disease of unknown etiology and fatal outcome. Patient management can be aided by careful assessment of prognostic factors. A prospective study of 158 patients was carried out to examine the prognostic significance of age and clinical form at onset. The overall 5-year survival rate was 14.7%. The higher the age was at first symptoms, the worse the prognosis. The bulbar and common forms had a worse prognosis than the pseudo-polyneuritic forms. After adjustment for age, the clinical form at onset remained a prognostic factor. In a multivariate analysis using the Cox model, these two factors remained independent despite the later onset of the bulbar forms. In view of the discrepancies between the different published studies, the evaluation of the survival of an individual patient is of doubtful value. PMID- 8700308 TI - Sleepiness in clinical and nonclinical populations. AB - Sleepiness is a commonplace experience for all individuals at some point in their daily lives. Whether such a ubiquitous experience has utility in discriminating a diseased population from the general population has yet to be determined. The purpose of this study was to determine the accuracy of reports of sleepiness across different situations by identifying individuals with sleep apnea. We compared a clinical population of 630 patients aged 50-65 with polysomnographically diagnosed sleep apnea with a randomly sampled population of 1,877 individuals of similar age from a nearby community. Sleepiness while watching television was the most prevalent behavior (about 36% of the reference population and 90% of the apnea patients), but potentially better discrimination occurred with items inquiring about sleepiness in other situations. The data suggest that discrimination between diseased and nondiseased populations may be more successful with sleepiness items involving relatively low, rather than high, rates of endorsement. PMID- 8700309 TI - Comparison of seven sets of criteria used for the diagnosis of vascular dementia. AB - At least seven different sets of criteria are commonly used for the diagnosis of vascular dementia (VaD). These are the ischemic scales (IS) of Hachinski, Rosen and Loeb, the criteria from the DSM-III-R, those outlined by Erkinjuntti et al., the State of California Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC) and the international workgroup of the American National Institute of Neurological Disorders and Stroke (NINDS) and the European "Association Internationale pour la Recherche et l'Enseignement en Neurosciences'. To investigate the differences and similarities of these criteria, we applied them to a sample of 124 demented patients from the Maastricht Memory Clinic. Only 8 patients were diagnosed as having VaD by all criteria. Depending on which criteria were used, the frequencies of VaD and Alzheimer's disease (AD) ranged from 6 to 32%, and from 48 to 56%, respectively. The IS of Hachinski and Rosen resulted in the highest frequencies of VaD, whereas the criteria of Erkinjuntti and those from the ADDTC and the NINDS workgroup yielded the lowest. The number of patients with VaD was reduced substantially when neuroradiological data and the temporal relationship between stroke and dementia were taken into consideration. We conclude that the seven sets of criteria cannot be regarded as interchangeable. Differences in the criteria for VaD and AD may be an overlooked source of interstudy variance PMID- 8700310 TI - Cine-magnetic resonance imaging evaluation of communication between middle cranial fossa arachnoid cysts and cisterns. AB - Cine-magnetic resonance (MR) imaging examinations were performed in 10 patients with middle cranial fossa arachnoid cysts to evaluate communication between the cysts and the normal cerebrospinal fluid (CSF) space. Eight of 10 patients were evaluated by time of flight cine-MR imaging, and two by phase contrast cine-MR imaging. Two patients underwent membranectomy of the cysts, and were evaluated both pre- and postoperatively. Computed tomography cisternography was used to confirm communication between the cysts and the surrounding cisterns. Pulsatile fluid motion within the cysts was present in all patients. However, marked fluid motion and jet flow between the cysts and the surrounding cisterns were only observed in communicating cysts. In the two patients who underwent membranectomy, postoperative examination found greater fluid motion and jet flow not previously present. Cine-MR imaging demonstration of marked pulsatile fluid motion accompanied by jet flow suggests that a cyst communicates with the normal CSF space. PMID- 8700311 TI - Gamma knife radiosurgery for brain tumors: postirradiation volume changes compared with preradiosurgical growth fractions. AB - The postradiosurgical volume changes were compared with preradiosurgical growth fractions defined as the tumor doubling time and/or MIB-1 staining index in 14 patients who underwent gamma knife radiosurgery for treatment of various brain tumors. The mean preradiosurgical observation period using neuroimaging techniques was 750 days (range 80-2967 days), and the mean follow-up period after radiosurgery was 664 days (range 328-1100 days). There were four neurinomas, three meningiomas, two craniopharyngiomas, two gliomas, one hemangioblastoma, one pituitary tumor, and one intracranially infiltrative lacrimal gland tumor. The mean patient age at the time of radiosurgery was 52 years (range 8-81 yrs). There were eight males and six females. Following gamma knife radiosurgery, the mean tumor half time was estimated to be 789 days (range 124-2101 days), and the volume reduction against the preradiosurgical tumor volume ranged from 6.3% to 76.1%. This study demonstrates that gamma knife radiosurgery can control tumor growth despite the lack of a correlation with preradiosurgical tumor growth or staining indices for MIB-1. Analyses of this type are essential to show that an "unchanged tumor volume" as demonstrated by postradiosurgery follow-up neuroimaging can be regarded as showing successful radiosurgery. PMID- 8700312 TI - Comparison of whole brain radiation therapy and locally limited radiation therapy in the treatment of solitary brain metastases from non-small cell lung cancer. AB - The benefit and risk of whole brain radiation therapy (WBRT) compared to locally limited radiation therapy was assessed in 61 patients with solitary brain metastases from non-small cell lung cancer without an unresectable active primary lesion or systemic dissemination in the other organs. Twenty-three patients received local irradiation (Group A), and 38 patients received whole brain irradiation with or without local irradiation (Group B). The survival was significantly better in Group A than in Group B (p < 0.05), with median survivals of 83.1 and 30.7 weeks, respectively. One-year local recurrence rates were 7% in Group A and 21% in Group B, but the difference was not statistically significant. The 1-year distant recurrence rate was similar at 18%. Radiation-induced dementia occurred in two patients in Group A (8.7%) and seven in Group B (18.4%), but was not statistically significant (p = 0.30). There is no obvious benefit and possible disadvantages of WBRT compared to local irradiation for the population of patients investigated in this study. Intraoperative radiation therapy or stereotactic radiosurgery without WBRT should be considered in the patients with solitary brain metastases. PMID- 8700313 TI - Perioperative antimicrobial prophylaxis in neurosurgery: clinical trial of systemic flomoxef administration and saline containing gentamicin for irrigation. AB - The efficacy of a new protocol consisting of a prophylactic antibiotic regimen of peri- and postoperative intravenous administration of flomoxef and irrigation of the operative field with saline containing gentamicin was assessed by comparing infection rates in two consecutive series of patients who underwent neurosurgical procedures. Group A received postoperative flomoxef administration, with saline containing no antibiotics for irrigation, from July 1988 to December 1989. Group B received the new protocol from January 1990 to December 1991. For further evaluation, this protocol was continued in most patients who underwent surgery from January 1992 through December 1993 (Group C). Only adult or adolescent patients who underwent clean neurosurgical procedures were included. The number of patients and procedures in each group were: 76 patients (97 procedures) in Group A, 103 (133) in Group B, and 107 (137) in Group C. There were no significant differences between Groups A and B in age, sex, clinical category, coexistent disease, clinical outcome, surgical procedures, general anesthesia, emergency operation, steroid administration, and the timing (season), duration, and frequency of surgery. Meningitis developed in three patients and subcutaneous infection in one in Group A. None of the patients in Group B experienced postoperative infection. This difference in infection rates (4.1% vs. 0%) was statistically significant (p = 0.0305). Furthermore, no postoperative infections developed in the Group C patients. The most appropriate interval for multiple dose administration was determined by analyzing intraoperative time-related changes in the serum flomoxef concentration during surgery in 21 recent patients. Serum flomoxef concentrations fell below therapeutic levels (3.0 micrograms/ml) by the 6th post-administration hour in 70% of patients. We conclude that this antibiotic regimen significantly reduces the postoperative infection rate following neurosurgical procedures. Multiple dose administration of flomoxef is recommended when the duration of surgery is 6 hours or more. PMID- 8700314 TI - Traumatic acute subdural hematoma localized on the superior surface of the tentorium cerebelli--two case reports. AB - An 8-year-old boy, who fell downstairs and struck his head, and a 62-year-old female, who hit her head in the automobile accident, presented with unusual traumatic acute subdural hematoma localized on the superior surface of the tentorium cerebelli. Magnetic resonance imaging was useful for determination of the anatomical location of the hematoma, and confirmation of absence of significant parenchymal contusion. Injury of the variant bridging vein possibly caused subdural hematoma over the tentorium. PMID- 8700315 TI - Acoustic neurinoma with a large organized hematoma--case report. AB - A 66-year-old female presented with a large organized hematoma within an acoustic neurinoma. She had suffered from diminished hearing for 20 years and had headache 1 week before presentation. Computed tomography demonstrated an inhomogeneously high density cerebellopontine angle mass, and magnetic resonance imaging showed a mass with heterogeneous intensity and gadolinium-diethylenetriaminepenta-acetic acid enhancement of only the peripheral surface of the mass and the inner parts of the internal auditory meatus. At operation the majority of the mass was soft and feature-less with a firm capsule, and a yellowish soft tumor was removed from the perimeatal area. Histological examination showed the mass was an acoustic neurinoma with a large organized hematoma. Extensive hemorrhage from an abnormal vascularity in the tumor had repeated followed by granulomatous organization. PMID- 8700316 TI - Intracranial hypoglossal neurinoma without preoperative hypoglossal nerve paresis -case report. AB - A 46-year-old female presented with an intracranial hypoglossal neurinoma manifesting only as spasticity in the lower extremities without hypoglossal nerve paresis. Magnetic resonance imaging greatly aided in the early detection of the tumor with this atypical presentation. Unilateral suboccipital craniotomy with resection of the occipital condyle allowed us to approach the tumor in front of the medulla from an inferolateral direction and to remove it successfully. We emphasize the need to pack dead space with fatty tissue to prevent cerebrospinal fluid leakage. PMID- 8700317 TI - Solitary plasmacytoma of the skull vault--case report. AB - A 55-year-old female presented with a rare solitary plasmacytoma restricted to the skull vault without systemic myelomatosis. She had a 9-month history of a slowly growing soft mass in the right temporal region. Neuroradiological examination revealed a skull defect and an extradural tumor. The whole layer of the skull was destroyed by the tumor, but the dura was not involved. The tumor was totally removed, and postoperative radiotherapy was given. Follow-up examination after 2 years showed she was free from local recurrence or evidence of systemic involvement. Complete surgical resection with adjuvant radiation therapy is the treatment of choice. Although the prognosis is good, regular lifelong examinations for myelomatosis are required. PMID- 8700318 TI - Extensive extraaxial blastomycosis granuloma at the skull base--case report. AB - A 37-year-old female presented with a rare case of intradural, extraaxial Blastomyces dermatitidis granuloma involving a large part of the skull base. She had the principal complaint of worsening vision, but was otherwise healthy. The lesion mimicked an en-plaque meningioma on radiological examination and in gross appearance during surgery. This is a very unusual presentation for a blasto mycosis granuloma. PMID- 8700320 TI - Visual screening of mobility personnel. PMID- 8700319 TI - Cystplastic cyst-subarachnoid shunt procedure for arachnoid cyst of the middle cranial fossa--technical note. AB - A cystplastic cyst-subarachnoid shunt procedure using a ventricular catheter of Denver type shunt system was performed in seven patients with non-communicating middle cranial fossa arachnoid cyst. The operation technique consists of: linear incision of the outer membrane of arachnoid cyst and intrusion into the cyst; followed by a 5 mm incision of both the inner membrane of the arachnoid cyst and the arachnoid membrane; insertion of a 2-3 cm length of the ventricular catheter, cut as required with silk thread bound around the midpoint of the tube, into the subarachnoid space; fixation of the tube to the arachnoid membrane by a silk thread with Weck clips; and finally suturing of the outer membrane of arachnoid cyst by a nylon thread. During the follow-up period of 3 months to 3 years after the operation, the symptoms were relieved in all patients, and no recurrence or complication was observed. PMID- 8700321 TI - Peacetime trauma experience. PMID- 8700322 TI - Unpublished findings not intended for reference. PMID- 8700323 TI - Causes of death among U.S. military personnel: a 14-year summary, 1980-1993. AB - Data extracted from the Report of Casualty (DD Form 1300) of the Department of Defense's Worldwide Casualty System were used to describe the 27,070 deaths among active duty personnel for the 14-year period 1980 through 1993. Ninety-five percent of all military deaths occurred among males and 84% among enlisted personnel. Unintentional injuries were the leading cause of death among both males (61%) and females (52%). Diseases accounted for about 20% of all death and represented the second most significant cause of death for both male and female service personnel. Suicide was the third leading major cause of death among males (13%), followed by homicide (5%); among females this order was reversed, with homicide (14%) exceeding suicide (12%). About 2% of all deaths resulted from combat. The findings presented here are useful in identifying cause-specific high risk groups in each of the four service branches and directing appropriate prevention strategies. PMID- 8700324 TI - Prevalence of tobacco use among first-term Air Force personnel before and after basic military training. AB - To support the goal of a tobacco-free Air Force, a longitudinal study of 3,531 first-term airmen was conducted during basic military training (BMT) at Lackland Air Force Base, Texas. Tobacco use is currently prohibited during the 6-week period of BMT. Three self-reported surveys to determine tobacco use prevalence and behaviors were administered at the beginning, end, and 90 days post-BMT. Results indicate that 36% of men and 29% of women used some form of tobacco prior to BMT. Within 90 days after completing BMT, 74% of matched males and females resumed tobacco use and 6% of matched males and females initiated tobacco use. Regression analysis found that several survey questions could predict 85% of tobacco use and 88% of non-tobacco use after BMT. We conclude that tobacco prohibition during BMT has a small, beneficial effect on post-BMT tobacco use. Further efforts, however, are needed to meet the goal of a tobacco-free Air Force. PMID- 8700325 TI - Demographic, clinical, and military factors related to military mental health referral patterns. AB - This study examined 693 cases of active duty members from all service branches seen in an Air Force outpatient mental health clinic over a 3-year period. Age, gender, rank, marital status, duty status, presence of special duty status, diagnostic category, and recommendations to the member's unit were examined across referral sources (i.e., self-referred, referred by others in authority, and command-ordered). Results showed significant differences across all variables, with self-referred members being more likely to be older, higher ranking, and married. Permanently assigned members were more likely than students to self-refer. Members with special duty status were less likely to self-refer. Self-referred members were less likely to have recommendations made with negative career impacts. The implications of these findings in terms of targeting interventions to increase self-initiated help-seeking behavior as well as recommendations for future research are discussed. PMID- 8700326 TI - Medicolegal aspects of breast cancer in U.S. federal medical facilities: analysis of 80 claims. AB - Eighty malpractice claims were taken against the U.S. government alleging negligence and delay in the diagnosis of breast cancer in federal medical facilities during the period from 1980 to 1989. Medical records and claim documents were reviewed together with the opinions of expert witnesses, journal articles, and opinions of the Department of Legal Medicine of the Armed Forces Institute of Pathology. The radiology and pathology reports were reviewed. Of the 80 claims, 68 were closed; compensation amounts ranged from $6,000 to $1 million. There was no correlation between the length of delay in diagnosis and the amount of compensation paid. The reasons for delayed diagnosis are considered in detail, and recommendations are made in an attempt to minimize the number of such claims in the future. PMID- 8700327 TI - Eyeglass MEDRETE: practical considerations (a user's guide). AB - This article presents the experiences of two independent practitioners who participated in eyeglass-dispensing medical readiness training exercises (MEDRETEs) in Central America. It explains the importance of defining personnel policies, having the proper equipment, utilizing the retinoscopists optimally, and having an adequate supply of eyeglasses with plus lens power for indigenous persons in this geographic area. To maximize the effectiveness of a MEDRETE, a dispensing optician and two teams of translators are needed. Triage of patients will permit the optimal number of refractions and distribution of corrective lenses to those most in need. Fitting indigenous patients with corrective lenses in one of the more tangible and lasting effects of a MEDRETE. It contributes not only to patient satisfaction but possibly to improved relationships with the host nation. PMID- 8700328 TI - Severe systemic reactions attributed to the acetone-inactivated parenteral typhoid vaccine. AB - Typhoid vaccine is recommended for people traveling to areas where they may be exposed to contaminated food and/or water. Two different parenteral forms of the vaccine have been utilized. We report five active duty patients with severe systemic reactions to the acetone-inactivated form of typhoid vaccine. The patients presented with very similar physical exam findings and laboratory abnormalities. Alternative typhoid vaccines that are less reactogenic are now available for use. PMID- 8700329 TI - The measurement of childhood trauma among male and female soldiers in the U.S. Army. AB - One thousand three hundred sixty-five soldiers from the U.S. Army completed a 30 item version of the Childhood Trauma Questionnaire (CTQ) together with four questions on sexual abuse developed for a national survey of U.S. adults. A four factor solution to the CTQ produced four subscales that were similar to those found in the original study, namely (1) emotional neglect, (2) physical and emotional abuse, (3) sexual abuse, and (4) physical neglect. We found that half of female soldiers reported a childhood history of sexual abuse, compared with one-sixth of male soldiers. Half of both male and female soldiers reported a childhood history of physical abuse. Combined abuse histories were noted in 34% of female and 11% of male soldiers. Abused soldiers reported more psychological symptoms on the Brief Symptom Inventory than nonabused soldiers. The CTQ and screening questions are discussed as possible tools for eliciting histories of abuse from soldiers. PMID- 8700330 TI - Command of military medical units: grounding the paradigm. AB - Proper command of medical units is central to their effectiveness. For many years the majority of commands have been available only to physicians. This paper suggests a concept for structuring the way in which individuals are considered suitable for command assignments. In this regard, there is an ongoing process within the Army Medical Department working toward delinking command from specific corps and substituting branch immaterial commands. Some ideas are presented to clarify this issue and contribute toward the resolution of a crucial and potentially divisive area. PMID- 8700331 TI - Millon Clinical Multiaxial Inventory profiles and maladjustment in the military: preliminary findings. AB - The Millon Clinical Multiaxial Inventory (MCMI) profiles of 69 active duty male soldiers who presented to an outpatient mental health clinic for a broad range of problems are compared to a local normative sample of 84 males. The clinical and comparison groups differed significantly on all 20 scales. In agreement with previous findings, the mean profile for the clinical group was a 2 (Avoidant)-8 (Passive-Aggressive) codetype, whereas the comparison group showed a 5 (Narcissistic)-6 (Antisocial) codetype. Findings offer specific codetypes that effectively discriminate functional versus dysfunctional individuals in a military setting and provide an empirical foundation on which to base future, and critically important, prospective studies of the predictive validity of the MCMI with military personnel. The potential role of the MCMI as a screening and assessment tool in military settings is discussed. PMID- 8700332 TI - Health behavior correlates of hazardous drinking by Army personnel. AB - The current investigation determined that military personnel who drink heavily differ from those who drink moderately in the practice of nine behaviors often associated with unhealthy lifestyle. In particular, excessive drinkers were found to smoke more, drive dangerously more frequently, and consume saturated fats more often. The project further found that the relationship of excessive drinking to these activities is mediated by age, marital status, and race, although not by gender or rank. Implications of the findings for prevention and treatment are suggested. PMID- 8700334 TI - Obsessive-compulsive disorder symptoms associated with military duty. PMID- 8700333 TI - Serum prostate-specific antigen concentration before and after vasectomy. AB - Recent epidemiologic studies have suggested that a risk factor for the development of carcinoma of the prostate may be previous vasectomy. As a majority of prostate cancer cases diagnosed in the U.S. are detected by an elevation in prostate-specific antigen (PSA), an elevation in PSA due to vasectomy may underpin this association. There have been no published reports on the relationship between PSA before and after vasectomy. To study this relationship, this study was undertaken to determine the effects of vasectomy on PSA. Twenty five men undergoing vasectomy were studied with serial PSA determinations prior to and following vasectomy. Analysis of data suggests that PSA is not affected by previous vasectomy and that other causes for an increased detection in this cohort may be operational. PMID- 8700335 TI - Trans-jugular extraction of bullet embolus to the heart. AB - Bullet emboli to the heart are rare and are typically treated by operative extraction through a median sternotomy and cardiotomy. This report details the case of an 18-year-old male who sustained two gunshot wounds, one of which lodged in his left renal vein. At laparotomy, the bullet embolized to the right atrium via the inferior vena cava. Under fluoroscopic guidance the bullet was retrieved with a snare introduced percutaneously through the right internal jugular vein. Sternotomy and possible cardiopulmonary bypass were avoided. PMID- 8700336 TI - Obstructive sleep apnea presenting during infantry field exercises: does the Army Weight Control Program protect soldiers from obstructive sleep apnea? AB - We report two cases of obstructive sleep apnea (OSA) that presented during infantry field exercises as snoring so loud as to risk betraying the unit's position. Both patients exceeded the height-weight standards of the Army Weight Control Program (AWCP). Since high body mass is a strong risk factor for OSA, we asked whether the AWCP reduces the risk of OSA. We found that it should for women in all age groups and for men over 40, but it is less protective for younger men (who constitute a large portion of Army personnel). In light of this and of previous estimates that up to 1.5% of all Army personnel exceed the AWCP standards, we conclude that there may be a significant number of unrecognized cases of OSA in the Army. Additionally, tightening of the AWCP standards may be warranted for women under 30 and men under 50, who currently are permitted to significantly exceed ideal body weight. PMID- 8700337 TI - [Neoadjuvant chemotherapy in malignant fibrous histiocytoma of the limbs: 10 years of experience (1983-1992) at the Rizzoli Orthopedic Institute]. AB - During the period September 1983 to December 1991, 47 patients with nonmetastatic malignant fibrous histiocytoma (MFH) of the limbs were treated using 3 different protocols of neoadjuvant chemotherapy activated at successive intervals. Surgery consisted of limb salvage in 41 cases and amputation in 6. After a mean follow-up of 6.5 years 33 patients (70%) had been continuously disease-free and 14 had undergone relapses. In the latter group the first sign of recurrence was metastasis in 12 cases and local recurrence in 2 cases. These results are distinctly better than those obtained in 20 patients treated during the same period using surgery alone (24% of disease-free survival and 30% local recurrence), and compared to those obtained in an earlier study in which surgery was associated with postoperative chemotherapy alone (59% of disease-free survival and 25% of local recidivation). The authors conclude that, as already observed in the case of osteosarcoma, neoadjuvant chemotherapy can significantly improve prognosis even in patients with bone MFH localised in the limbs. Moreover, given that, contrary to adjuvant chemotherapy, associated chemotherapy is effective not only in controlling the microscopic disease but also reducing the incidence of local recurrence, it enables amputation to be avoided in the majority of patients. PMID- 8700338 TI - [Mepartricin 150.000 (40 mg) vs mepartricin 50.000 U (13 mg) in the treatment of BIP. Double blind clinical trial]. AB - A group of 25 patients with uncomplicated BPH was treated mepartricin 150,000 U (40 mg) once in the evening for 60 days and the results were compared with those obtained in 25 patients treated with mepartricin 50,000 U (13 mg) t.d.s. Efficacy and tolerance of both treatment schemes were good. In the group treated with on single dose at night some symptoms such as nocturia and pollakiuria regressed more rapidly. PMID- 8700339 TI - [Clinical evaluation of 30 mg cinnoxicam in patients with osteoarthrosis. Double blind controlled trial]. AB - We tested the therapeutic response of osteoarthrosis subjects to 30 mg piroxicam cinnamate (Sinartrol). The double-blind study was conducted in 2 homogeneous groups of 30 patients each treated with piroxicam cinnamate one 30-mg tablet twice daily for 2 days followed by 1 tablet daily for further 13 days and with piroxicam cinnamate 20 mg tablets (according to the same posologic scheme) respectively. The results obtained demonstrate the efficacy of this new piroxicam cinnamate formulation which led to a significant clinical improvement, already evident after 2 days of treatment and even more evident at the end of therapy. Patients compliance to treatment was good and side effects were scarce and spontaneously subsiding. PMID- 8700340 TI - [Short term assessment of anthropometric indices and metabolic parameters in obese subjects treated with acarbose]. AB - Acarbose represents the first of a new class of oral antidiabetic drugs: the alpha-glucosidases inhibitors. This drug in fact delays the production of monosacchtarides inhibiting the alpha-glucosidases of the small bowel, that are responsible of digestion of complex polysaccharides and sucrose. In patients with insulin dependent diabetes mellitus (IDDM) acarbose, significantly reduces the postprandial blood glucose levels, and improves the symptoms associated with nocturnal hypoglycaemia reducing the daily insulin dosage. Furthermore acarbose ameliorates the glycemic control of obese patients when associated with hypocaloric diet. The aim of our study has been to value the effectiveness of acarbose 300 mg/day for 12 weeks in patients affected by moderate obesity (30 < - BMI < 40) and with impaired glucose tolerance (IGT). We have studied 12 patients, 6 have been treated with acarbose and hypocaloric diet, while the other 6 have been treated only with diet, these last formed the control group. Before and after the treatment, anthropometric indexes and haematologic parameters have been observed. Patients treated with acarbose presented a significative decrement of body weight, BMI, fat free mass, fat mass and of basal and peak glycaemic values after oral glucose tolerance test (OGTT). Serum lipid values, insulin levels during OGTT and blood pressure presented a not significative improvement. Gastrointestinal symptoms such as flatulence and borborygmus have been reported only in the patients treated with acarbose. The incidence of these reactions usually decreases with time. PMID- 8700341 TI - [New strategies in the acute and chronic treatment of the patient with Alzheimer's dementia]. PMID- 8700342 TI - [Changes in the heart conduction system in a case of Wegener's granulomatosis]. AB - Since the initial description by Klinger in 1931 and confirmation by Wegener in 1936, Wegener's granulomatosis has emerged as an uncommon disease entity of unknown aetiology. This disease is characterized by a granulomatous-necrotizing general vasculitis, which most frequently affects the respiratory tract, and by a usually focal necrotizing glomerulonephritis. We report one case of Wegener's granulomatosis with reference to heart conduction system involvement and to nervous plexuses localized in the heart. Specialized conduction system of the heart is little investigated in Wegener's granulomatosis. The blocks of tissue containing the sinoatrial node, the atrio-ventricular node, His bundle, the bifurcation and both bundle branches were fixed in buffered formalin 10% and embedded in paraffin, cut serially at 150 mu intervals and stained alternately with hematoxylin-eosin and Heidenhain trichromic (azan). This heart showed fibrosis near distal His bundle, coronaric arteriolar severe stenosis and fibrotic involvement of the root of the left branch. This histological picture is plausibly and result of scarring of arteriolar specific granulomatous process, also in relation to the low grade of coronarosclerosis. Sclerosis of specific conduction tissue, in addition to cardiac intramural arteriolar subocclusion and to aspecific inflammation of nervous plexuses, can be considered as a plausible arrhythmogenic base of death. PMID- 8700343 TI - [Appendicitis]. PMID- 8700344 TI - Four year study of the risk factors of surgical wound infection in 5260 traumatological patients. AB - We carried out a four-year prospective study in the rehabilitation and traumatology center of the Hospital La Paz, where a total of 5260 patients were included. The objective of the study was to know the main risk factors that could influence the development of an infection of surgical wound, and get a predictive equation of infection of surgical wound in our patients. We utilized logistic regression for it, following the patient by means of active epidemiological surveillance; the main risk factors found were: immunodeficiency (OR = 8.3) wrong scaring (OR = 14.4), more than one intervention (OR = 3.5), type of surgical intervention (OR = 4.8) and incorrect use of prophylaxis (OR = 6.3). We considered that this knowledge could permit us to diminish the incidence of infections, specially if there is some of these factors, like the antimicrobial prophylaxis, that could be easily modified. Finally, upon applying to our patients the gotten equation, we get a ROC curve with 85% of the area under it, and if we take the point of cut of greater sensibility and specificity in this situation of very low prevalence of illness, it determines we could use it better in order to mark patients that don't suffer infection (high negative predictive value), making this possible to improve the efficacy of our work. PMID- 8700345 TI - [Longitudinal study of fractures in institutionalized elderly]. AB - AIM: Evaluation of fracture incidence in the institutionalized elderly and analysis of associated risk factors. EXPERIMENTAL DESIGN: Longitudinal and prospective study with 3-year follow-up. SETTING: Old people's home in Turin for patients who are no longer self-sufficient. PARTICIPANTS: 197 subjects (47 males and 150 females) aged between 61-98 years old, dependent in at least two basic daily activities. PARAMETERS: At the time of enrollment, the following parameters were evaluated: age, weight, height, degree of walking autonomy, bone mineral density at proximal and distal radius. The number of falls and fractures were recorded during follow-up. RESULTS: A total of 46 fractures (22 femoral and 24 in other sites) were recorded with an annual incidence of 7.8%. Femoral fractures only occurred in females. The following risk factors were associated with femoral fractures: very old age (relative risk = 2.6; 95% confidence interval = 1.1-6.4), low body mass index levels (RR = 3.3; 95% CI = 1.3-8.7), low bone mineral density levels at the proximal radius (RR = 2.6; 95% CI = 1.1-6.3), autonomous walking capacity (RR = 3.7; 95% CI = 1.1-12.0) and recurrent falls (RR = 2.7; 95% CI = 1.2-6.2). The following risk factors were associated with non-femoral fractures: autonomous deambulation (RR = 5.7; 95% CI = 1.4-23.7) and recurrent falls (RR = 6.4; CI = 2.3-18.3). CONCLUSIONS: Institutionalized elderly patients present numerous risk factors for femoral fractures. Fractures in other sites are only associated with risk factors that express a tendency to fall. PMID- 8700346 TI - [Alcohol consumption and coronary disease in men]. AB - It has been recently suggested by many epidemiological studies, and emphasized by a nonspecialistic press, that a moderate alcohol intake may exert a protective role in coronary heart diseases. In our study, by means of a questionnaire, the consumption of alcohol in 100 male patients, less than 70 years old, affected by myocardial infarction and/ or angina pectoris, has been evaluated during a period before and after the admission to our Coronary Care Unit. On the basis of their alcohol intake, patients were divided into five categories: abstainers (8%), daily intake lower than one drink (7%), between one and two drinks (8%) between three and four drinks (46%) and equal or higher than five drinks (31%). In the light of these results, we suggested that, in our region (a country area in the north-east of Italy), there are higher levels of ethanol intake compared to those reported by other authors, that these parameters are only slightly modified by the occurrence of coronary heart diseases and that alcohol consumption, although low and moderate, must be therefore emphasized with extreme caution. PMID- 8700347 TI - [Neurocardiogenic (or vasovagal) syncope]. AB - Syncope is a common clinical problem in a general population that is responsible for a significant number of emergency department visits (3%) and hospitalizations (1%) each year. The clinical spectrum of etiologies of syncope includes disorders classified as cardiovascular, noncardiovascular and unexplained. A majority of syncopal events are believed to be caused by vasovagally mediated episodes by hypotension and bradycardia. Although vasovagal syncope is essentially equivalent to simple fainting, the physiologic events that lends to this phenomena are complex. Although not completely understood, the most commonly held theory explaining vasovagal syncope involves a series of reflexive interactions between cardiac mechanoreceptors and the autonomic nervous system. Until the advent of head upright tilt table testing, diagnosis of vasovagal syncope has been an assumption, made when all other causes have been eliminated. Frequently an accurate history, a physical examination and a standard ECG are enough to formulate a correct diagnosis. Head-up tilt test must be considered in patients with an unknown diagnosis, before starting invasive investigation. Tilt table testing, either alone or with a graded-dose infusion of isoproterenol, allows reproduction of the syncopal event in susceptible individuals and monitoring of the patients physiologic responses during the episode. Direct observation and documentation of symptoms permit accurate diagnosis and yield information vital to treatment and symptom control. This article reviews our current understanding of the mechanisms involved in the development of neurally mediated syncope. PMID- 8700348 TI - [Familial Marfan's syndrome. A critical review and presentation of a clinical case]. AB - Aim of this paper is to describe and discuss, on the basis of an exhaustive review of literature, the case of a 14-year-old girl with familiar Marfan's syndrome. This disease is a generalized inherited disorder with involvement of connective tissue and symptoms affecting ocular, skeletal and cardio-vascular systems, usually diagnosed in young age and associated with a poor prognosis because of late severe aortic complications (dissection, dilation or aneurysms, regurgitation, etc.). The young patient sought to our medical attention because of severe leanness, delayed menarca and irregular menstruations; physical examination disclosed the typical "morphotype of Marfan" with long limbs, slenderness of hands and feet, severe kyphoscoliosis, narrow chest with "pectus excavatum", marked hyperextensible joints, and high arched palate with malocclusion. Echocardiography demonstrated a mild mitral valve prolapse. The 43 year-old patient's mother presented an undiagnosed Marfan's syndrome, despite typical morphotype, muscle-skeletal alterations and moderate dilation of ascending aorta. The maternal grand-mother deceased prematurely for cardiopathy of unknown origin. It is stressed that the disease should not be underestimated, because the early diagnosis is important for the patient's prognosis, allowing the early preventive surgical intervention for correcting aortic or valvular alterations. The echocardiography represents a sensitive and noninvasive mean, useful to manage the patients with proven or suspected aortic dilation. The subjects with Marfan's syndrome who exhibit rapid progression of aortic dilation, or an aortic diameter in excess of 50 mm, should be considered for an elective surgical intervention (at low mortality and suitable to increase remarkably the lifetime expectation). Women with syndrome of Marfan should be advised on the high cardio-vascular risk during pregnancy. PMID- 8700349 TI - [Familial combined hyperlipidemia with particularly severe and premature arteriosclerotic lesions. Description of a case]. AB - The case is reported of a 44 year old male patient admitted to our Department for left pyramidal hemisyndrome. Familial anamnesis was positive for premature cardiovascular complications and the patient, who was a heavy smoker, had suffered from arterial hypertension and claudicatio intermittens for 10 years. Laboratory investigations showed increased plasma levels of triglycerides, cholesterol and apolipoprotein B, with a sharp decrease in apo A/apo B ratio. Ultrasound and angiographic scans showed severe and diffuse atherosclerotic lesions. A diagnosis was made of familial combined hyperlipidemia and treatment was begun with simvastatin, which produced a progressive normalization of lipidic picture, without any effect of the symptoms related to lower limb occlusive arteriopathy. Two apparently healthy sisters of the patient have also been studied. The first was found to be affected by familial combined hyperlipidemia with isolated increase in cholesterol plasma levels, the second was perfectly normal. This case demonstrates that subjects with similar alterations in lipidic metabolism may present with completely different clinical pictures, even within the same inherited disorder. Different hypotheses are discussed to explain the particularly severe and precocious atherosclerotic lesions of our patient: sex, smoking habit and arterial hypertension, which would have been caused, at least in part, by the observed congenital malformation of renal circulation. PMID- 8700350 TI - Langerhans' cell granulomatosis and Hodgkin's lymphoma. Report of a case. AB - A 48-year-old female with a history of accentuated dyspnea, pleural thickening in anteromedial portion with left patchy parenchymal shadowing invading adjoining parasternal structure of the rib cage, presented 13 months later marked superclavicular, anterior mediastinic and parahilar left lymphadenopathy. Open surgical biopsies on the pleural lesion invading the hypodermic tissues of parasternal region showed morphological and immunocytochemical patterns of Langerhans' cell histiocytosis (LCH). 13 months later the superclavicular lymph node biopsy diagnosed Hodgkin's lymphoma (HD), mixed cellularity type II, stage AE. On a total of 29 cases with association of LCH and HD, the described case in the second case that shows morphologically demonstrated LCh with subsequent development of HD. It is postulated that the development of HD in a patient with LCH, might represent malignant evolution of this hyperplastic process. PMID- 8700351 TI - [Multiple cutaneous leishmaniasis after a stay in Central America]. AB - Leishmaniasis is a protozoal disease affecting at least 12 millions persons, with 400,000 new cases per year. It is transmitted by a small insect, the phlebotomine sand fly. Clinical syndromes include visceral leishmaniasis and various cutaneous affections. We describe here the case of a patient affected by a multiple lesions New World cutaneous leishmaniasis, after staying in Costa Rica for tourism; we discuss the differential diagnosis and make a short summary of the principles of treatment. PMID- 8700352 TI - [Multiple cerebral infarctions in Crohn's disease. Report of a case]. AB - Cerebrovascular occlusions are rare but well-documented complications of Crohn's disease. We report the case of a young man with regional enteritis and a history of three ischemic strokes, two of them preceded the occurrence of the bowel disease. PMID- 8700353 TI - [Unstable bladder and Sjogren syndrome. Clinical case]. AB - A female patient developed severe detrusor instability years after a diagnosis of Sjogren syndrome. A common etiology could be possible if an association with viral demyelinization in Sjogren patients is confirmed. Vaginal Sicca syndrome was present and responded to a topical androgen-oestriol association with definite cytologic improvement. Anticholinergics were tolerated and moderately effective. Low initial dose were slowly increased (over three months) to avoid excessive mouth dryness and avoid gastrooesophageal symptoms. PMID- 8700354 TI - [Effect of specific immunotherapy on peripheral T-lymphocytes in atopic patients]. AB - Specific hyposensitising therapy for IgE mediated respiratory allergopathies is recognised as an effective therapy able to improve clinical symptoms and bronchial hyperreactivity. IgE synthesis, which is altered in atopic subjects, is regulated by CD4 and partly CD8 lymphocytes. This paper examines the changes in the main T lymphocyte subpopulations in peripheral blood in 10 atopic subjects undergoing specific immunotherapy. The results highlight a significant reduction (p = 0.028) in mean CD4 levels after 6.3 months of treatment. Changes in the other T lymphocyte components and total IgE serum levels were not significant. PMID- 8700355 TI - [Procollagen type I C-propeptide in kidney transplant recipients]. AB - The excessive production of parathormone may persist or return after renal transplantation, so that latent hyperparathyroidism in time may lead to loss of bone mass and of the new kidney; a precocious diagnosis of this disease represents the best preventive measure. On a group of 50 successfully undergone kidney transplant patients (group A: 38 immunosuppression therapy with corticosteroids, azathioprine and cyclosporine A patients; group B: 12 immunosuppression therapy with azathioprine and ciclosporine A patients) we have evaluated also the most common markers of hyperparathyroidism, C-propeptide of procollagen of type I (PICP), that is a product of procollagen degradation and it represents in the serum a direct measure of osteoblastic bone activity. Our results showed alkaline phosphate, osteocalcin and PICP increase, which are index of osteoblastic activity and urinary collagen cross-links pyridinoline and deoxypyridinoline increase which are index of bone osteoclastic activity. The survey revealed a linear significant correlation only between PICP and pyridinoline and cross link deoxypyridinoline (p < 0.05). In this group of patients the only PICP could not have a diagnostic meaning. Owing to the particularly bone metabolism of our patients, that probably feel the effects of hyperparathyroidism of the pre-transplant period, PICP turns out insufficient to study the persistent or returned hyperparathyroidism. PMID- 8700356 TI - [Diagnosis of drug allergy. Role of specific IgE and IgG determination]. AB - In the diagnosis of drug allergies, the anamnesis and, in some cases, prick tests are without doubt indispensable approaches but they are not always able to provide optimal prognostic levels. Moreover, prick tests are sometimes contraindicated owing to their potential danger. This study evaluated the diagnostic efficacy of a test in vitro--the assay of IgE- and IgG-specific (RAST) -for a group of 16 drugs in 88 patients referred for allergological consultancy after clinical manifestations attributable to the administration of a drug (30/88 cases) or more than one drug (58/88). Disorders had appeared at least one week after the start of drug treatment, an interval that is compatible with the development of an immune response. In 17/88 (19.3%) patients the in vitro test confirmed the presence of IGe and/or IgG against at least one of the drugs suspected in the anamnesis. In this series it was also found that there was a higher incidence of ADR in females (60/88) compared to males (28/88). Reactions to several drugs were more frequent than reactions to a single drug (58 cases vs 30). The association of ADR and the presence of other allergies in a particular individual was relatively rare (13/88 = 14.7%). These results confirm the value of RAST as a useful aid to improve the overall diagnosis of drug allergies and to make it safer. PMID- 8700357 TI - [Various personality traits of patients with psoriatic arthropathy]. AB - It is well known that patients affected by rheumatic diseases may present specific pathological trends in personality structure, as has been extensively reported in literature. Our study was aimed at investigating several aspects of the personality traits of 20 patients with psoriatic arthropathy, compared with a group of 20 patients with rheumatoid arthritis. All patients were evaluated with appropriate rating scales assigned in auto and hetero-administration. The study results points to a personality trait disturbance in psoriatic arthritis patients, which can be clearly differentiated from the anxious habitus and/or reactive-depressive state observed in patients with rheumatoid arthritis. PMID- 8700358 TI - [Progression of renal insufficiency and platelet activating factor (PAF)]. AB - An unresolved question of many medical nephropathies is the progression of chronic renal failure to end-stage renal insufficiency: every year many patients must be submitted to extracorporeal haemodialysis with a high cost for society. The control of so-called risk factors of progression, such as arterial hypertension, persistent proteinuria, renal infection etc. is not sufficient to prevent the progression to end-stage renal failure. The hypoproteic diet may retard this progression So currently the ability of physicians to alter the inexorable course of the disease is limited. In recent years medical research has shown that many mediators of phlogosis may play an important role in renal glomerular pathology. PAF seems to have a preeminent role. The aim of this study is to present the actual knowledge about the role played by PAF in renal physiology and pathophysiology with future perspectives on renal insufficiency progression. PMID- 8700359 TI - [Liver cirrhosis and cardiovascular system]. AB - The patient with hepatocellular disease shows marked vasodilatation, accompanied by hyperdynamic circulation and opening of arteriovenous shunts. The effect of these circulatory changes and especially the profound vasodilation has only recently been investigated in detail. In patients with hepatocellular failure the extremities are flushed, the pulses bounding, the cardiac output increased and the blood pressure low. The circulation resembles what found with systemic arteriovenous fistulae. The peripheral vasodilatation and splanchnic venous pooling reduce the effective blood volume so activating baroreceptors. The secondary events which follow the vasodilation include stimulation of the sympathetic nervous system. This serves to counteract the tendency to arterial hypotension and probably contributes to renal hypoperfusion and to the hepatorenal syndrome development. The nature of the concerned vasodilators remains speculative, but is likely to be multiple. Whatever its nature, the substance might be formed by the sick hepatocyte, fail to be inactivated by it or bypass it through intra- or extra-hepatic portal systemic shunts. In cirrhosis the cardiac index and reduced systemic vascular resistance correlate with the Child's grade of liver failure. This article provides an overview of the general vasodilatory state and its effects on various organs. The mechanisms and the different vasoactive substances that might be responsible are also discussed. PMID- 8700360 TI - [Sexuality of elderly women]. AB - Physiological aging in older women it is not necessarily the cause of a change in their sexual attitudes. The organic changes, during concomitant illness, is often known to be the cause of sexual dysfunction, when present. Psychosocial factors are also very important in determining sexual dysfunction. Successful management of sexual dysfunction in older women is totally dependent on clinical history, physical examination of genitalia, personal interview. A multidisciplinary team approach is required for otimal management of sexual problems in elderly women. PMID- 8700361 TI - [Visceral leishmaniasis in patients with HIV infection. Our experience]. AB - The authors describe a case of visceral leishmaniasis in an intravenous drug abuser, HIV seropositive patient. Visceral leishmaniasis was the first opportunist infection and diagnosis was based on smear from bone marrow. A treatment with N-methylglucamine and allopurinol was successful. The authors stress to take into account visceral leishmaniasis in HIV-infected patient in act resident or in past lived in endemic for Leishmania areas even in presence of atypical clinical features and propose to include visceral leishmaniasis as an opportunist infection in the IVC-2 group of clinical classification of HIV infection. PMID- 8700362 TI - Identification of a gene for autosomal dominant polycystic kidney disease: implications for understanding the pathogenesis and treatment of the disease. PMID- 8700363 TI - Prognostic factors in acute renal failure due to sepsis. Results of a prospective multicentre study. The French Study Group on Acute Renal Failure. AB - BACKGROUND: Sepsis is a major cause of acute renal failure in hospital patients, but its incidence and the associated prognostic factors have rarely been assessed prospectively by multivariate analysis. METHODS: We conducted a prospective 6 month study in 20 multidisciplinary intensive care units to assess the prognosis of patients hospitalized with acute renal failure due to sepsis. Sepsis syndrome and septic shock were defined according to the criteria of the Society of Critical Care Medicine Consensus Conference. Severity scoring indexes (SAPS, APACHE II, and organ system failure (OSF)) were measured on ICU admission and on inclusion. The end-point was hospital mortality. RESULTS: Acute renal failure had a septic origin in 157 patients (Group 1), comprising 68 with septic shock and 89 with sepsis syndrome, and did not result from infection in 188 patients (Group 2). Patients with septic acute renal failure were older (mean age: 62.2 versus 57.9 years, P<0.02) and had on inclusion a higher SAPS (19.3 versus 16.1, P<0.001), APACHE II (29.6 versus 24.3, P<0.001), and OSF (2.07 versus 1.52, P<0.001) than patients with non-septic acute renal failure. They had a higher need for mechanical ventilation (69.1% versus 47.3%, P<0.001), and acute renal failure was more often delayed during the ICU stay than was present on admission (47.7% versus 32.4% respectively, P<0.005). Hospital mortality was higher in patients with septic acute renal failure (74.5%) than in those whose renal failure did not result from sepsis (45.2%, P<0.001). Mortality was influenced by the presence of a septic shock (79.4%) or of a sepsis syndrome on inclusion (70.8%). Using a stepwise logistic regression model, sepsis was an independent predictor of hospital mortality (OR, 2.51; 95% CI, 1.44-4.39) as well as a delayed occurrence of acute renal failure, oliguria, an altered previous health status hospitalization prior to ICU, need for mechanical ventilation, age and severity scoring indexes on inclusion. In total patients, mortality was higher in dialyzed than in non-dialyzed patients (P<0.001), and in those treated by continuous compared to intermittent techniques (P<0.01). Patients dialyzed with biocompatible membranes had a lower mortality than those treated with cellulose membranes (P<0.005). CONCLUSIONS: Patients with acute renal failure due to sepsis have a worse prognosis than those with non-septic acute renal failure. Sepsis and the above-defined predictive factors are to be considered in studies on prognosis of ARF patients. Our results suggest that the use of biocompatible membranes may reduce significantly mortality in these patients. PMID- 8700364 TI - Primary purulent pericarditis in an immunocompromized patient - an unusual cause of acute renal failure. PMID- 8700365 TI - Improvement of a toxaemic pregnancy with molsidomine, a nitric oxide donor. PMID- 8700366 TI - Effects of defibrotide treatment in patients with IgA nephropathy and reduced renal function. PMID- 8700367 TI - Ciprofloxacin-induced acute interstitial nephritis. PMID- 8700368 TI - End-stage renal failure due to diabetic nephropathy in Spain. PMID- 8700369 TI - How to treat primary oxalosis. PMID- 8700370 TI - Renal oncocytoma in a short-term renal transplant patient. PMID- 8700371 TI - Unresponsiveness to recombinant human erythropoietin in haemodialysis patients: possible implications of angiotensin-converting enzyme inhibitors. PMID- 8700372 TI - L-arginine has no effect on erythropoietin-induced hypertension in the excision remnant kidney model. PMID- 8700373 TI - Regression of a brown tumour after 3 years of treatment with intravenous calcitriol in a haemodialysis patient. PMID- 8700374 TI - Potential role of cytokines in renal osteodystrophy. PMID- 8700375 TI - Successful trial of steroids in two haemodialysis patients with inflammatory disease and anaemia unresponsive to recombinant erythropoietin. PMID- 8700376 TI - Interdialysis blood pressure control by long haemodialysis sessions. PMID- 8700377 TI - Failure of AVP and other pressor hormones to increase in severe recurrent dialysis hypotension. PMID- 8700378 TI - Reply to the letter of Professor A Bensman. PMID- 8700379 TI - What contributions would the clinical background of the nurse make to the executive team? PMID- 8700380 TI - The skill sets, experience, and criteria for future nurse leaders. PMID- 8700381 TI - The capitation revolution in health care: implications for the field of nursing. AB - Health care is being reformed in the United States. However, rather than the reform taking the course of the rejected Clinton health care plan, the invisible hand of the free market is reshaping America's health care sector through the spread of a system known as capitation. This article looks at capitation and its effect on hospitals, which are rapidly adopting this practice. Then it explores the implications for both nurses and nursing administration as hospitals seek to transform themselves into health care delivery systems. It is suggested that hospitals bring nurses and nurse administrators to the forefront on their concerns in setting up such capitated systems. PMID- 8700382 TI - Trust: key to acculturation in corporatized health care environments. AB - Widespread restructuring of health care organizations often results in corporatization and associated cultures to which nurse administrators must adapt. Acculturation may be facilitated through understanding key aspects of traditional and emerging corporate cultures. One of these aspects is trust, which is requisite for persistently successful organizational performance in dynamic environments. This article defines trust, assesses its significance within organizational settings, delineates specific ways in which it affects organizations, and discusses the implications for nurse administrators of varying levels of trust associated with organizations. PMID- 8700383 TI - A theoretical approach to studying work empowerment in nursing: a review of studies testing Kanter's theory of structural power in organizations. AB - Although work empowerment is a common theme in the current nursing systems literature, few systematic programs of research have studies the phenomenon from an explicitly theoretical framework. The author summarizes the results of a series of studies in a program of research designed to test Rosabeth Moss Kanter's Structural Theory of Organizational Behavior in the nursing population. Future directions for theory and research are proposed. PMID- 8700384 TI - Integrating care delivery. AB - Mergers and acquisitions, multibillion dollar profit margins, and hospital chains that boast more than 400 sites all reflect the fact that health care is no longer a cottage industry but a corporate giant. The forms and structures that will provide care will continue to disintegrate and then evolve as we face a crisis in Medicare funding and as the ranks of uninsured continue to grow. The challenge for nursing leaders to stay centered on the core product and the core process of our industry--caring for patients. Integration is the key strategy that must be applied to achieve that end. We must strive for integration in three levels: within ourselves, between persons, and within our organization. Only then will nursing leadership be able to bring wholeness and influence to the corporate health care world through our individual roles and collectively through our profession. PMID- 8700385 TI - The role of the nurse executive: in the corporatization of health care. AB - This article describes one of the changing roles of the executive nurse. It attempts to sketch the environment, the changing politics, possible role expectations, and perceived barriers of the system role. A brief list of additional skills that may be helpful in assuring greater success is also detailed. This article is an account of "a" perspective and experience. PMID- 8700386 TI - Patient care leadership within an emerging integrated delivery network. AB - The emergence of integrated delivery networks provides an opportunity for leaders of patient care services to reach into our tool bags and refine the key leadership skills of strategist, facilitator, coach, and mentor. Shifting the focus from management to leadership is the hallmark of our success. As patient care leaders we will facilitate the achievement of the organization's strategic initiatives to improve clinical care delivery while decreasing cost. This article will explore the role of the patient care executive as part of the leadership team developing an integrated/organized delivery network. PMID- 8700387 TI - Clinical integration: an interdisciplinary approach to a system priority. AB - Clinical integration, a Mercy Health Services (MHS) system-wide priority, addresses MHS's ability to provide appropriate, effective clinical care across the continuum and to improve care outcomes. MHS chartered a Clinical Integration Priority Team (CIPT) that developed a common language for clinical integration; began to build infrastructure for coordinated systems of care in such areas as information systems and pharmacy; improved methods and technology for clinical decision making and care delivery; and educated clinicians to improve care processes, manage care for populations, and measure outcomes. Clinical professionals in corporate staff roles have supported clinicians' efforts across the system by providing direction, coaching, educating and supporting in activities to improve patient care. PMID- 8700388 TI - The role of the corporate nurse executive: providing balance and perspective for patient care and the corporate structure. AB - The nurse executive at the corporate level is in a pivotal position to provide balance between the provision of integrated patient care and success of the corporate mission. In this role, the nurse executive shifts the spotlight from a solely nursing perspective to the systems approach in support of patient care. The response that follows is often a redoubling of the efforts of health care providers to render more efficient and cohesive care to patients. In the end, success is an outgrowth of strong teamwork combined with the ability of the executive to connect the corporate business strategy with the provision of patient care wherever it is delivered. PMID- 8700389 TI - Transitions in nursing leadership roles. AB - Today's turbulent, chaotic health care environment necessitates dramatic changes in the roles of nurse executives. These role changes are rapidly being cast upon individuals who are pressured to react, accept, and adapt quickly. Previously successful leadership styles no longer serve nurse executives as they assume nonoperational roles without line authority and power. No prescriptive strategies will be effective to assist nurse leaders in their new roles. One nurse executive's story of her own journey will be shared to illustrate how she is creating a successful transition. PMID- 8700390 TI - The 21st century nurse executive. PMID- 8700391 TI - The effects of an AIDS diagnosis on undergraduate nursing students' care of dying patients. AB - Nurse educators frequently deal with nursing students' discomfort in learning to care for dying patients. However, teaching students how to care for dying patients with acquired immune deficiency syndrome (AIDS) presents unique and interesting challenges. The authors describe the influence an AIDS diagnosis has on students' comfort levels in touching and talking to dying patients. Recommendations and teaching strategies to assist nurse educators are provided. PMID- 8700392 TI - Changing associate degree nursing curricula to meet evolving healthcare delivery system needs. AB - Curricular change for evolving healthcare delivery: everyone says to do it, but how, and what do you do? The authors explore the need for curricular change, a process to use in making the changes, essential elements to explore, and what changes one community college made. Included in the curricular revision is the hardest part-what was deleted-as well as what was added, and how nurse educators can continue to evolve. PMID- 8700393 TI - Stepfamilies. An "ostrich" concept in nursing education. AB - Little attention has been given to the concept of stepfamilies in nursing literature. However, nurse educators can help their students to assist natural parents and stepparents create a more supportive and loving environment for themselves and their biological children and their stepchildren. The author identifies key issues that nurse educators need to teach student nurses related to stepfamilies based on research and a review of the literature, offering interventions that include material resources and referrals to national organizations whose focus is on stepfamilies. PMID- 8700394 TI - Incoming nursing students' perceptions of their caring behaviors. AB - What are the caring attitudes and abilities of incoming nursing students? This phenomenologic study used the Colaizzi method to analyze descriptions of caring interactions written by 15 incoming nursing students on orientation day. It indicates that students have definite attitudes and values about caring and established patterns of caring behaviors. Educators need to start where the learners are-namely, recognizing and valuing their inherent caring behaviors. Using these threads, nurse educators can begin to weave the fabric of professional caring. PMID- 8700395 TI - Restructuring registered nurse curricula. AB - National initiatives in higher education, health reform, and the nursing curriculum revolution are applied to five curricular patterns for registered nurse (RN) upward mobility baccalaureate education. American Association of Higher Education principles for quality baccalaureate education are applied to the curricular models. The patterns described are: community model, health promotion model, nursing diagnosis model, case management model, and caring model. Three educational strategies for prompting paradigm shifts in RNs who return to school are discussed: collaborative learning, portfolios, and self assessments. These learning strategies are designed to move the adult student through Perry's phases of cognitive development from duality to relativism. The combination of fresh new curriculum patterns and collaborative learning strategies can empower nurses to discover new paradigms with which to transform the profession. PMID- 8700396 TI - Effects of touch on stress reduction in nursing students during a clinical experience. PMID- 8700397 TI - Innovative teaching of management skills. PMID- 8700398 TI - A conceptually focused postconference. PMID- 8700399 TI - Holistic healthcare highlighted in student tour to Great Britain. PMID- 8700400 TI - Using a challenge examination to demonstrate a student-centered philosophy. PMID- 8700401 TI - Differentiated nursing practice in all care settings. PMID- 8700402 TI - An introduction to nursing on the Internet. Part One. AB - The Internet is a global resource connecting millions of computers. The author discusses the hardware and software needed to access the Internet and how to use one of the main Internet tools, electronic mail. PMID- 8700403 TI - Humor in the testing situation. PMID- 8700404 TI - Nursing education and healthcare reform. AB - What and how we teach, how we learn, and how we practice nursing are fundamentally changing. Perspectives on Assessment invites dialogue on assessment's central role in the paradigm shifts currently occurring in nursing education and nursing practice. Programs of assessment in educational and practice institutions offer the opportunity for continuous feedback on the quality and effectiveness of our efforts to prepare nurses who are competent to practice in a healthcare environment that is continuously changing and increasingly community based. The assessment process itself offers the opportunity for us to engage in an ongoing conversation about our progress with these two paradigm changes. PMID- 8700406 TI - Nursing information systems: applications in nursing curricula. AB - America's healthcare system is being transformed to meet a new set of priorities: cost-effectiveness, quality, and access. To meet these priorities, health practitioners of the 21st century will rely heavily on computer information systems to provide complete, easily accessed patient data. Incorporation of this technology in nursing programs will enhance the quality of the graduates who will then strengthen the availability of a qualified work force to employers. PMID- 8700405 TI - Exposure to bloodborne pathogens in the academic setting: prevention, reporting, and management issues. AB - Management of nursing students exposed to bloodborne pathogens in the academic setting continues to challenge nurse educators. Management issues include nonreporting by students, lack of established policies and procedures, and inconsistent application of postexposure policies. The authors confirmed previously identified 50% nonreporting rates by students. Development of a postexposure management plan is discussed, emphasizing the need for psychological and medical interventions. PMID- 8700407 TI - Reading ability and success in nursing. PMID- 8700408 TI - The use of color in the work setting. AB - Color impacts many areas of life. Although it is impossible to establish any hard and fast rules about which colors are most suitable for a particular decor and setting, some colors create a more restful and peaceful atmosphere. The author explores the use of color in the academic work setting. PMID- 8700410 TI - Helping students understand substance abuse. PMID- 8700409 TI - An interdisciplinary educational model for health professions students in a family practice center. AB - Health professions students have little or no opportunity to practice together during their formative stages of development. Therefore, can we realistically expect them to practice together as professionals? This is an important area for educators to address, given the current emphasis on interdisciplinary collaboration. The authors describe an interdisciplinary education program model for nursing, medicine, and social work students in a family practice center. PMID- 8700411 TI - Teaching from a treetop. AB - Development of a curriculum using a conceptual model of a tree is described. With roots in knowledge and caring and a trunk composed of fundamental content, courses grow from three main branches. Equal emphasis is given to client, socialization, and environment. A critical-thinking/learning model developed by the author promotes self-directed, active, collaborative learning and is the basis of teaching methodology within the curriculum tree. PMID- 8700412 TI - Global gladiators: a model for international nursing education. AB - Vietnam is a beautiful country with many needs related to the achievement of optimal healthcare and the role of nurses in the country. The authors describe a U.S. Agency for International Development funded project sponsored by Health Volunteers Overseas. Nursing educators involved in the project share their experiences to help readers gain insight into the coordination necessary to make an international nursing education project successful. PMID- 8700413 TI - Strategies for teaching critical thinking in pharmacology. AB - The author presents six strategies that have been used successfully to teach and assess critical-thinking skills in a pharmacology course. Within the context of pharmacology content, the strategies were designed to develop student abilities in making critical distinctions, critical decision making, analysis of assessment findings, and the anticipation of intervention results and possible side effects/consequences. PMID- 8700414 TI - The student process for success: the nursing care plan. AB - Written nursing care plans are designed to focus students on individualizing nursing care, which promotes critical thinking and decision making. In actual practice, emphasis has shifted from care plans toward standards of care. The authors discuss a concise, simplified care plan format that includes both standards of care and collaborative problems. This plan of care is compatible with healthcare regulations and requires less time to produce and evaluate. PMID- 8700415 TI - Teaching communication techniques with the flash card method. PMID- 8700416 TI - Nursing students' attitudes: cynical or humanitarian. PMID- 8700417 TI - Making of a cross-cultural videotape. PMID- 8700418 TI - Tic TAc Test Ready. PMID- 8700420 TI - An introduction to nursing on the Internet: Part Two. PMID- 8700419 TI - Appointment, promotion and tenure. PMID- 8700421 TI - Assessing outcomes of community-based nursing education. AB - Assessing community-based, community-focused nursing education outcomes is a continuing conversation about the teaching/learning process between faculty, students, and communities. No longer is the focus primarily on the content and competencies that nursing faculty members believe students need to master. Rather, this conversation is now expanded, and thus fundamentally changed, by its focus on the development of new relationships requisite to community-focused practice which is characterized by quality and competency. The authors explore the role and process of assessment in helping faculty and students identify and clarify competencies needed to practice community-focused, community-based nursing. PMID- 8700422 TI - Nursing students working with the homeless. AB - In a program funded by the Wisconsin Area Health Education Center System, four nursing students were placed with nurse preceptors working with homeless people. The overall intent of the program was to provide students with stipend incentives to promote working with clients in underserved areas after graduation. The author discusses the program and its outcomes. PMID- 8700423 TI - Healthcare for the future: caring for populations in alternative settings. AB - The healthcare environment integrates rapid changes in healthcare delivery, educational approaches to professional role preparation, and professional relationships with others. To meet these challenges, faculty members developed a new course for baccalaureate students. Students are exposed to innovative strategies and models for healthcare delivery with an emphasis on critical thinking related to their experiences in alternative healthcare settings. PMID- 8700425 TI - The index card scenario postclinical conference. PMID- 8700424 TI - An innovative, interdisciplinary educational experience in field research. AB - Although interdisciplinary practice is necessary to meet the complex health needs of populations, there are few planned interdisciplinary learning experiences within educational programs for the health professions. The authors describe an interdisciplinary learning experience in field research for students and faculty members from schools of nursing and medicine. PMID- 8700426 TI - Public education programs in the nursing curriculum. AB - The author describes the integration of a structured public education program of the American Cancer Society with didactic and clinical experiences in the nursing curriculum. Sixty-five nursing students and their clinical instructors were trained as public education speakers for the breast health program. This experience integrated concepts of public education, community health, health behavior, professional role development, and community volunteerism, and served as an excellent learning opportunity for undergraduate nursing students. PMID- 8700427 TI - Teaching portfolios for faculty evaluation. AB - Teaching portfolios are stimulating much discussion as more comprehensive approaches to evaluating teaching are sought. Portfolios can be used effectively for both formative and summative evaluative purposes. The content of a portfolio may vary greatly, but commonly includes material that reflects student learning, evaluative materials, and a personal statement on the faculty's philosophy of education. Professional growth often accompanies developing a personal teaching portfolio. PMID- 8700428 TI - Assisting students at risk: using computer NCLEX-RN review software. AB - In response to a decline in the success rate on the National Council Licensure Examination for Registered Nurses (NCLEX-RN) examination, the authors developed a program to identify and assist students at risk for failure. The use of a computerized NCLEX-RN practice examination and an individualized student review and study process is described. PMID- 8700429 TI - "Prep" for class and class activity: key to critical thinking. AB - Using guidelines, students independently complete a written preparation for class assignment to develop a knowledge base needed for active participation in one or more class activities. The authors present a two-part method that is key to developing critical-thinking skills, using case studies. PMID- 8700430 TI - Promoting critical thinking in the classroom. AB - Although nurse educators have designed many techniques for enhancing critical thinking skills in clinical and seminar settings, lectures also remain an integral part of nursing education. The author offers practical active learning strategies for promoting critical thinking in large classroom instruction. PMID- 8700431 TI - Bridging a gap between nursing education and administration: a teaching strategy. PMID- 8700432 TI - Reconceptualizing scholarship for graduate nursing education. PMID- 8700433 TI - Computer conferencing: communication for distance learners. AB - Computer conferencing enables the user to easily and quickly communicate and access information from a remote site. The Nurse Practitioner Outreach program at the University of Texas School of Nursing at Galveston pilot-tested a program in which students at remote locations used computer conferencing to receive course assignments and interact with faculty members and one another. This program has provided valuable insights into the advantages and challenges of using computer conferencing in a nursing educational setting. PMID- 8700434 TI - Proceedings of conference on nutrition and physical activity to optimize performance and well-being. Atlanta, Georgia, April 5-7, 1995. PMID- 8700435 TI - Dietary intake and physical activity as "predictors" of weight gain in observational, prospective studies of adults. PMID- 8700436 TI - Peak bone mass and physical activity: a short review. PMID- 8700437 TI - Physical inactivity and metabolic factors as predictors of weight gain. PMID- 8700438 TI - Is weight loss hazardous? PMID- 8700439 TI - Can obesity be prevented? PMID- 8700440 TI - Clinical applications of diet and physical activity in weight loss. PMID- 8700441 TI - Carbohydrates and exercise performance. PMID- 8700442 TI - Effects of exercise on daily energy expenditure. PMID- 8700443 TI - Vitamin and mineral supplements as nutritional aids to exercise performance and health. PMID- 8700444 TI - Reproductive performance and nutrition during childhood. PMID- 8700445 TI - Fluid balance for optimal performance. PMID- 8700446 TI - Is increased dietary protein necessary or beneficial for individuals with a physically active lifestyle? AB - For most of the 20th century, scientists have believed that protein needs are not altered by physical exercise. In contrast, athletes are typically convinced that additional dietary protein can significantly enhance exercise performance. Until recently, the opinion of the athletes has been largely unsubstantiated in the scientific literature. However, since the 1970s, an increasing number of studies have appeared that indicate dietary protein needs are elevated in individuals who are regularly physically active. Together, these data suggest that the RDA for those who engage in regular endurance exercise should be about 1.2-1.4 g protein/kg body mass/d (150-175% of the current RDA) and 1.7-1.8 g protein/kg body mass/d (212-225% of the current RDA) for strength exercisers. Fortunately, the typical North American diet contains protein near these quantities, so most individuals who decide to begin an exercise program will obtain sufficient protein as long as their diet is mixed and they are careful to consume adequate energy. Populations at greatest risk for consuming insufficient protein include any group that restricts energy intake (those on diets) or high quality protein sources (vegetarians) as well as any group that has a requirement higher than normal due to another existing condition (growing individuals). Future studies should focus on these groups. Moreover, few exercise performance measures have been made, so any negative effect of insufficient dietary protein on athletic success needs to be determined. Supplementation of several individual amino acids may be beneficial for physically active individuals, but considerable potential risk is also present. Intake of large quantities of individual amino acids is not recommended until much more information is available. PMID- 8700447 TI - An eastern perspective on nutrition and performance. PMID- 8700448 TI - School breakfast and cognition among nutritionally at-risk children in the Peruvian Andes. PMID- 8700449 TI - Physical activity and performance in children. PMID- 8700450 TI - Bone mass, nutrition, and other lifestyle factors. PMID- 8700451 TI - Habitual physical activity and academic performance. PMID- 8700452 TI - Exercise, physical activity, nutrition, and the brain. PMID- 8700453 TI - Habitual physical activity, psychomotor performance, and older workers. PMID- 8700454 TI - Physical activity and psychological well-being: knowledge base, current issues, and caveats. PMID- 8700455 TI - The role of nutrition in economic development. PMID- 8700456 TI - The benefits of adequate iodine intake. PMID- 8700457 TI - Measuring nutrition status, physical activity, and fitness, with special emphasis on populations at nutritional risk. PMID- 8700458 TI - Trends in body weight and overweight in the U.S. population. PMID- 8700459 TI - Administering oxygen by nasal cannula. PMID- 8700460 TI - Making the transition to home health care charting. PMID- 8700461 TI - Defending against diarrhea. PMID- 8700462 TI - Venlafaxine. PMID- 8700463 TI - Self-test: understanding the gastrointestinal system. PMID- 8700464 TI - Understanding paclitaxel therapy. PMID- 8700465 TI - Managing escalating pain. PMID- 8700466 TI - Reviewing Zollinger-Ellison syndrome ... from A to Z.E.S. PMID- 8700467 TI - Knowing how to manage complications of tube feeding. PMID- 8700468 TI - What you should know about hepatitis B. PMID- 8700469 TI - Action stat. Heparin-induced thrombocytopenia and thrombosis. PMID- 8700470 TI - Diabetes in the elderly, Part I. Unmasking a hidden disorder. PMID- 8700471 TI - Diabetes in the elderly, Part II. Finding the balance for drug therapy. PMID- 8700472 TI - Lumbar punctures: helping a "sticky" procedure go smoothly. PMID- 8700473 TI - First aide. PMID- 8700475 TI - Warding off Mr. Pond. PMID- 8700474 TI - Caring for patients with heart failure. PMID- 8700476 TI - How to smooth the way for cyclic tube feedings. PMID- 8700477 TI - Emergencies handbook. PMID- 8700478 TI - Myths & facts ... about Down's syndrome. PMID- 8700479 TI - Facing the music. PMID- 8700480 TI - Courageous followership... PMID- 8700481 TI - Corporate liability: security and violence--Part I. AB - Violence in the workplace is becoming one of the nation's top killers. It is like an Equal Opportunity Employer--it does not discriminate on the basis of race, color, religion, age, sex, national origin, disability or sexual orientation. A few regulatory agencies and legislators are requiring health care facilities to take steps to improve safety and security. PMID- 8700482 TI - The changing marketplace: are subacute care providers ready? AB - In 1995, subacute care providers focused much attention on program development, marketing, managed care contracting and outcomes measurements. As the move to balance the federal budget continues to occupy center stage in the health care arena, subacute care providers need to rapidly shift gears and develop a blueprint for managing the changing marketplace. Without such a blueprint, subacute care providers may find themselves struggling for survival in the years ahead, instead of strategically positioned to remain competitive. PMID- 8700483 TI - Capitating mental health services. AB - Many employers are contracting mental or behavioral health services separately from other types of health care. Capitation rates are paid for a defined set of benefits. Mental health services are capitated in two ways; both approaches are discussed. PMID- 8700484 TI - Coping with downsizing: stress, self-esteem and social intimacy. AB - As health care system continue to downsize, nurses will experience organizational changes, change in positions or sudden terminations. Acute care surgical nurses were surveyed to determine their perceptions of work-related stress, self-esteem and social intimacy during downsizing. PMID- 8700485 TI - The effects of threat appraisal. AB - A study determines if perceived threat negatively affects female staff nurses. Research questions were asked to determine the degree and category of perceived threats reported by the study participants. PMID- 8700486 TI - Nursing care plans: issues and solutions. AB - Through necessity, nurses have found practical ways to incorporate physicians' orders into practice. Yet, nursing care orders have not been given the same degree of importance in delivery of documentation as physician orders. Thus, care plans often become half-hearted attempts at appeasing accreditors. A nursing care plan is described that addresses some of the issues involved in the care plan debate. PMID- 8700487 TI - Overreacting: a manager's dilemma. AB - Time-proven strategies assist nurse managers to react confidently, coolly and effectively when others are overreacting. Each person is responsible for his/her own feelings. Nevertheless, managers can teach others better coping mechanisms so that overreactions are replaced with sophisticated coping strategies. PMID- 8700488 TI - Vision: a professional model for nursing practice. AB - The creation of Vision: A Professional Model for Nursing Practice followed an evolutionary process of development over a 20-year time span. The nurse/patient relationship was the central theme of this practice model and implies that nursing excellence, driven by knowledge, research, empowerment and accountability, would result in positive outcomes for patient care and create a culture of independent, caring professional nurses. PMID- 8700489 TI - Teaching managers to appraise performances. AB - To accomplish effective performance reviews and appraisals that respect employee dignity, managers must cultivate a wide range of competencies. Systems are required to observe and collect data, cue and measure observations, then interpret behavior. PMID- 8700490 TI - Interdisciplinary documentation in the NICU. AB - A continuous quality improvement (CQI) project focused on documentation within the Newborn Intensive Care Unit (NICU) at Primary Children's Medical Center. The task force developed and implemented an interdisciplinary patient care documentation system that reduces duplication, increases compliance, improves communication and is fiscally responsible. PMID- 8700491 TI - QI study in the ICU: bedside testing of gastric contents. AB - Quality improvement (QI) studies must use valid and reliable tools to measure patient outcomes. This study identified daily nursing practices related to the prevention of stress ulcer syndrome (SUS) in a medical intensive care unit (ICU). The QI study: (1) compared the "gold" standard bedside test for gastric pH and fecal occult blood with an inclusive measurement tool that was created specifically to measure gastric pH and occult blood at the bedside; (2) assessed nursing knowledge of SUS; and (3) analyzed cost. PMID- 8700492 TI - Establishing a team-based coaching process. AB - As our organization moved toward implementing self-managed work teams and decreased management hierarchy, the need arose to revise our performance development structure. A team-based coaching process has been implemented successfully on all patient care units and is being modified for use in other areas. PMID- 8700493 TI - The latex dilemma: an actual case. AB - Health care institutions across the country are dealing with a relatively new phenomenon: staff sensitivity to latex. This article presents the issues involved through an actual case and the response of one institution. PMID- 8700494 TI - Conflict management in nursing administration. AB - Identifying the causes of conflict and the effective measures to negotiate successful solutions encourages win-win situations. The situations that cause stress are discussed and the methods used to resolve conflict are identified. PMID- 8700495 TI - Ethics, discipline and discharge. AB - Discipline in today's workplace focuses on a collegial "training that corrects, molds, strengthens or perfects." It requires self-discipline, which is possible only if each team member (1) knows the rules, (2) understands their purpose and (3) agrees that they deserve compliance. Only when all else fails is discharge justifiable--and then the burden of proof rests on the employer. PMID- 8700496 TI - Computer-based patient records--hype versus reality. AB - Although growing in capacity, few of today's computer-based patient records (CPR) systems satisfy all the key requirements defined by the Institute of Medicine. This current vacuum, however, should not frustrate us but rather stimulate our personal interest and creativity as to ways to best accomplish an optimal CPR solution in a very dynamic health care environment. PMID- 8700497 TI - Job satisfaction and intent to stay: RNs' perceptions. PMID- 8700498 TI - Effects of personality types on nursing management teams. PMID- 8700499 TI - A nursing service--nursing education collaboration. PMID- 8700500 TI - Hurry up and wait. PMID- 8700501 TI - Focus on care not insurance. PMID- 8700502 TI - Managing a large staff. PMID- 8700503 TI - A community case management model. PMID- 8700504 TI - Scarce graduate nurse jobs: an opportunity. PMID- 8700505 TI - The health of populations. PMID- 8700506 TI - Genetic change in actinic keratoses. AB - Actinic keratoses (AKs) are small scaly red areas of skin characterised histologically by dysplasia, a minority of which are thought to be precursors of squamous cell carcinoma (SCC), and which show a high frequency of regression. Surprisingly, in view of their benign clinical course, they show a high frequency of loss of heterozygosity (LOH) with a median loss of four loci with almost 20% of lesions showing loss of eight or more alleles, as well as frequent p53 mutation. Loss was common on 3p (31%), 9p (39%), 9q (22%), 13q (52%), 17p (64%) and 17q (46%), and allele loss correlated with dysplasia. Topological disturbance of p21WAF1/CIP1 expression correlated with allele loss but was also seen together with increased wild-type p53 expression and an increase in the fraction of cycling cells in the absence of allele loss or p53 mutation, and is likely to represent an early change. P21WAF1/CIP1 expression appeared independent of p53 status. The frequency of LOH in AKs exceeded that of (invasive) SCCs suggesting that the relation between the accumulation of genetic change and behaviour for non-melanoma skin cancer is not straightforward. PMID- 8700507 TI - Networks of interaction of p120cbl and p130cas with Crk and Grb2 adaptor proteins. AB - P120cbl, the product of the c-cbl proto-oncogene, has previously been shown to become tyrosine phosphorylated following EGF stimulation of cells, and to bind constitutively to the SH3 domain of the adaptor protein Grb2. Here we show that another adaptor protein, Crk, binds through its SH2 domain to tyrosine phosphorylated p120cbl. In addition, Crk becomes phosphorylated on tyrosine and serine following EGF treatment of PC12 and other cell lines. In unstimulated cells, while Grb2 is not bound to any tyrosine phosphoprotein, Crk is bound via its SH2 domain to tyrosine phosphorylated p130cas, the Crk-associated v-Src substrate. Following EGF treatment, Crk dissociates from p130cas, possibly due to a higher affinity of Crk SH2 for p120cbl compared with p130cas. Interaction between Grb2 and p120cbl increases threefold following EGF treatment of cells; in vitro, this induction of Grb2 association with unphosphorylated p120cbl can be mimicked by the addition of tyrosine phosphorylated Shc, suggesting a transfer of information between the SH2 and SH3 domains of Grb2. These data indicate that adaptor proteins can exchange binding partners in response to stimuli, and that different adaptor proteins can bind to the same partners by different mechanisms. PMID- 8700508 TI - Expression of p53 in normal and gamma-irradiated rat testis suggests a role for p53 in meiotic recombination and repair. AB - In testis, the expression of tumor suppressor protein p53 is stronger than in other tissues suggesting a role for it in spermatogenesis. We have studied the expression of p53 in both unirradiated and gamma-irradiated rat testis using the stage-specific model of rat seminiferous epithelium. Our results show that p53 is expressed during meiosis in normal rat spermatogenesis and its expression is localized to the preleptotene-early pachytene spermatocytes. The most prominent expression is in zygotene - early pachytene spermatocytes (stages XIII-I of seminiferous epithelium). After irradiation p53 levels increased in a time and a dose-dependent manner being highest with the doses of 6.0 and 12.0 Gy and 4 h after irradiation. This increase occurs in the same cells that normally express elevated levels of p53. These results support the view that p53 is involved in meiosis of the male rat and we suggest that p53 has a role in recombinational processes and/or formation of the synaptonemal complex. We also demonstrate that p53 takes part in the response of primary spermatocytes to irradiation gamma induced DNA damage. PMID- 8700509 TI - The 5' end of the BRCA1 gene lies within a duplicated region of human chromosome 17q21. AB - To begin to address the hypothesis that abnormal regulation of the breast/ovarian cancer susceptibility gene BRCA1 is a critical step in sporadic breast/ovarian tumorigenesis, we have determined the detailed structure of the BRCA1 genomic region. We show that this region of the genome contains a tandem duplication of approximately 30 kilobases, which results in two copies of BRCA1 exons 1 and 2, of exons 1 and 3 of the adjacent 1A1-3B gene and of the previously reported 295 base pair intergenic region. Sequence analysis of the duplicated exons of BRCA1 and 1A1-3B and flanking genomic DNA reveals maintenance of the intron-exon structure and a high degree of nucleotide sequence identity, suggesting that these are non-processed pseudogenes and that the duplication is a recent event in evolutionary terms. We also show that a processed pseudogene of the acidic ribosomal phosphoprotein P1 (ARPP1) is inserted directly upstream of pseudo-BRCA1 exon 1A. We believe that these findings could not only confound BRCA1 mutation analysis, but could have implications for the normal and abnormal regulation of BRCA1 transcription, translation and function. PMID- 8700510 TI - Analysis of the role of v-rel in transcriptional regulation of high mobility group 14. AB - The oncogene, v-rel is a member of the rel/NF-kappaB family of transcription factors. It causes a rapidly fatal lymphoma in young chicks and is capable of transforming both fibroblasts and primitive hematopoietic cells in culture. To understand the role of v-rel in transformation we constructed an inducible form of v-rel and used it to identify potential cellular target genes for v-rel regulation. In this paper we show that High Mobility Group Protein 14 (HMG 14) is expressed in a wide variety of v-rel transformed cell types. In addition we show that v-rel participates in the transcriptional regulation of HMG 14 and that extracts from v-relER cells interact with the HMG 14 promoter. These experiments suggest a role for v-rel in the regulation of a unique gene whose protein product may influence gene transcription in a global fashion. PMID- 8700511 TI - Isolation and characterization of genes associated with chromosome-6 mediated tumor suppression in human malignant melanoma. AB - Melanocytic transformation is thought to occur by the sequential accumulation of genetic alterations. Evidence implicating human chromosomes as a site for a gene(s) involved in melanoma suppression comes from studies of LOH [loss of heterozygosity], cytogenetics and biologic reversion of tumorigenicity following the introduction of a normal chromosome 6 by microcell-mediated chromosome transfer (Trent et al., 1990). Using a tumorigenic melanoma cell line (UACC 903) and a chromosome-6 suppressed melanoma subline [UACC 903 (+6)], we have isolated a series of genes uniquely expressed in the suppressed subline. A modified PCR based cDNA subtraction technique was used to generate subtracted cDNA sublibraries for both the parental and (+6) suppressed cells. A total of 32 randomly selected clones from the suppressed sublibrary were isolated and examined, with 24 detecting a transcript by Northern analysis. Of these 24 clones, 21 (88%) demonstrated elevated expressed by Northern analysis in the suppressed subline relative to the tumorigenic parental cell line. In 6/21 differentially expressed clones (29%), expression was exclusive to the suppressed subline. Partial sequence analysis and database searching of these clones indicated that 5/6 were novel with one representing a previously characterized gene. Chromosomal localization of the five novel clones was performed following PCR amplification of a human/rodent somatic cell hybrid mapping panel or fluorescent in situ hybridization. One cDNA (termed AIM1) was localized to a band region of chromosome 6 frequently deleted in melanomas (6q21). This novel approach should facilitate the identification of genes whose expression is causally related to the suppressed phenotype. PMID- 8700513 TI - S-phase induction by adenovirus E1A requires activation of cdc25a tyrosine phosphatase. AB - Adenovirus E1A proteins can induce quiescent cells to enter S-phase and also affect the expression of cellular genes including various cell cycle regulators. Here we show that human cdc25A, a tyrosine phosphatase involved in regulation of the G1/S-phase transition of the cell cycle, is a target of the adenovirus E1A protein in virus-infected human fibroblasts. Expression of E1A in quiescent fibroblasts leads to a rapid increase in cdc25A phosphatase activity and also increases both cdc25A and cyclin E gene expression. Inhibition of cdc25A function by antibody injection prevents virus-induced entry into S-phase. These results indicate that induction of high levels of cdc25A and its potential positive regulator cyclin E mediates the ability of E1A to induce S-phase in the presence of antiproliferative signals. PMID- 8700512 TI - Neu differentiation factor (Heregulin) activates a p53-dependent pathway in cancer cells. AB - Previously we reported that neu differentiation factor (NDF)/heregulin (HRG) elevates tyrosine phosphorylation of its receptors erbB-3, erbB-4, and erbB-2 (through heterodimer formation). We also showed that both NDF/HRG and antibodies to erbB-2 can arrest growth and induce differentiation in breast cancer cells. In this study, we report on the mechanism of NDF/HRG-induced cellular effects. We show that NDF/HRG and antibodies to erbB-2 receptors up-regulate expression of p53 by stabilizing the protein. This is accompanied by up-regulation of the p53 inducible gene, p21CIP1/WAF1, in a variety of cell lines: MCF7 and their derivatives (MCF7/HER2, MN1 and MCF-7-puro), ZR75T and LnCap cells. The induction of p21 is further enhanced when cells are treated with both NDF/HRG and DNA damaging chemotherapeutic agents (i.e. doxorubicin). The NDF/HRG mediated induction of p21 is dependent on wildtype p53, as it fails to occur in cells expressing dominant negative p53 (MDD2). Furthermore, p21 induction is capable of inactivating cdk2 complexes as measured by Histone H1 phosphorylation assays. Finally, we show that in primary cultures of breast and other cancers, p21 is significantly induced in response to NDF/HRG treatment. Collectively, these observations suggest that the mechanism of breast cancer cell growth inhibition and differentiation via erbB receptors activation is through a p53-mediated pathway. PMID- 8700514 TI - Characterization of PCP-2, a novel receptor protein tyrosine phosphatase of the MAM domain family. AB - DNA sequences encoding a novel member of the receptor protein tyrosine phosphatase (R-PTP) family, termed PCP-2, were identified in a human pancreatic adenocarcinoma cDNA library. Human PCP-2 cDNA predicts a protein of 1430 amino acids with a calculated Mr of 160 kDa. The predicted PCP-2 enzyme consists of a 740 amino acid extracellular region, a single transmembrane domain, and a 666 amino acid intracellular portion. The extracellular sequence contains a MAM (meprin/A5/PTPmu) domain, an immunoglobulin-like domain and four fibronectin type III-like repeats, suggesting that it is a member of the PTPkappa and PTPmu subfamily. The intracellular region contains two tandemly-repeated protein tyrosine phosphatase domains. Northern blot analyses revealed a single transcript of 5.5 kilobases, which is expressed at different levels in many human tissues except spleen and placenta. Upon transfection of PCP-2 cDNA into human embryonic kidney fibroblast 293 cells, a protein with an apparent Mr of 180 000 was detected by immunoblot analysis. This size was reduced to the predicted Mr upon treatment with endoglycosidase F, indicating that PCP-2 is glycosylated and, hence, expressed at the cell surface. A potential role of PCP-2 in cell-cell recognition and adhesion is supported by its co-localization with cell adhesion molecules, such as catenin and E-cadherin, at sites of cell-cell contact. PMID- 8700515 TI - RN-tre identifies a family of tre-related proteins displaying a novel potential protein binding domain. AB - Eps8 is a recently identified SH3-containing substrate for tyrosine kinase receptors. To understand the role of eps8 in receptor-mediated signaling, we cloned cDNAs encoding proteins that bind to its SH3 domain. One of these cDNAs predicts the synthesis of an 828 amino acid protein with homology to the N terminal region of the tre oncogene. We designated this protein RN-tre for Related to the N-terminus of tre. RN-tre is ubiquitously expressed and maps to 10p13, a region known to be involved in translocations in various leukemias. In addition, a 10p13 monosomy syndrome, characterized by developmental alterations, has been reported. The regional homology between RN-tre and tre, which is limited to their N-terminal portion, prompted us to investigate the origin of the tre oncogene transcriptional unit. We were able to show that tre is the fusion product of a 5' genetic element, homologous to RN-tre and a 3' element, encoding a de-ubiquinating enzyme. Moreover, we identified, within the N-terminus of RN tre and tre, a domain (named TrH, for Tre Homology), which is conserved within several proteins from yeast to mammals and has protein-binding properties in vitro. PMID- 8700516 TI - Formation of undifferentiated mesenteric tumors in transgenic mice expressing human neurotropic polymavirus early protein. AB - The human polyomavirus, JCV, is the established etiologic agent of the human demyelinating disease, progressive multifocal leukoencephalopathy (PML) seen in immunosuppressed individuals. In PML patients, the viral early protein, which is produced exclusively in glial cells is responsible for initiation of the viral lytic cycle. The JCV early protein, T-antigen, has greater than 70% homology to the well characterized SV40 early protein which has established oncogenic properties. To investigate the role of JCV T-antigen in tumorigenesis, transgenic mice containing the viral early genome were produced. Of the four positive transgenic animals, one developed severe neurological abnormalities and succumbed to death at 3 weeks of age. Another animal died with no visible gross pathology and the cause of death was not determined. The remaining two founders developed massive, undifferentiated, solid mesenteric tumors with no obvious neurological symptoms. Results from histologic analysis demonstrated the presence of highly cellular, poorly differentiated neoplastic cells in the tumor tissue. Electron microscopic evaluation of the tumor revealed the presence of a small blue cell like tumor of epithelial/neuroectodermal origin. Results from RNA analysis by non quantitative and highly sensitive RT-PCR indicated the presence of the JCV early transcript in various tissues, including kidney, liver, spleen, heart, lung, and brain, as well as in the tumors. However, analysis of the viral early protein by Western blot and immunohistochemistry indicated high level production of JCV early protein in the tumor tissue, but not in any other tissues. These observations present the first evidence for the development of inheritable neuroectodermal tumors induced by the human polyomavirus, JCV, early protein in a whole animal system. PMID- 8700517 TI - The differentiation primary response gene MyD118, related to GADD45, encodes for a nuclear protein which interacts with PCNA and p21WAF1/CIP1. AB - Towards dissecting the regulation of terminal differentiation, including growth arrest and apoptosis, myeloid differentiation primary response (MyD) genes, induced in the absence of de novo protein synthesis following induction of M1 myeloblastic leukemia cells for terminal differentiation have been isolated. MyD118 was one of the novel MyD genes cloned, subsequently observed also to be a primary response gene to TGF-beta, which induces M1 cells for growth arrest and apoptosis uncoupled from differentiation. The MyD118 encoded protein was observed to be remarkably similar to the protein encoded by Gadd45, a growth arrest and DNA damage induced gene, regulated in part by the tumor suppressor p53. Though evidence has accumulated that MyD118 functions as an important modulator of negative growth control both in hematopoietic and non-hematopoietic cells, its mechanism of action is unknown. To better understand the role(s) of MyD118 in negative growth control, we have analysed the expression and biological characteristics of the MyD118 protein, compared to the Gadd45 protein, in distinct pathways of growth arrest and apoptosis, including p53 dependent and independent pathways either coupled or uncoupled from differentiation. It is shown that MyD118 and Gadd45 differentially accumulated upon induction of distinct pathways of growth arrest and apoptosis; notably, MyD118, but not Gadd45, was induced by TGF-beta, whereas Gadd45, but not MyD118, was induced by activating wild type (wt) p53 function. It is also shown that MyD118 is a nuclear protein, which regardless of the pathway induced, predominantly localized within the cell nucleus, and interacted with the DNA replication and repair protein PCNA and the cyclin dependent kinase inhibitor P21WAF1/CIP1. MyD118 also modestly stimulated DNA repair in vitro. All of these characteristics were shared with Gadd45. Finally, it is demonstrated that MyD118, Gadd45 and p21 synergized in the suppression of colony formation by NIH3T3 cells. Taken together, these findings demonstrate that MyD118 and Gadd45 are representative of a new protein family that share remarkable functional similarities in the control of distinct pathways of negative growth, including the suppression of cellular growth and programmed cell death. PMID- 8700518 TI - Synergistic stimulation of avian I kappa B alpha transcription by rel and fos/jun factors. AB - Rel/NF-kappa B transcription factors and I Kappa B alpha function in an autoregulatory network. Avian I kappa B alpha transcription is increased in response to both c-Rel and v-Rel. This study shows that I kappa B alpha transcription is synergistically stimulated by Rel and AP-1 factors (c-Fos and c Jun). However, the response to v-Rel and the AP-1 factors was not as vigorous as that of c-Rel and AP-1. A 386 bp region of the I kappa B alpha promoter (containing two NF-kappa B and one AP-1 binding sites) was shown to be both necessary and sufficient for response to both Rel factors alone or Rel factors in conjunction with the AP-1 proteins. In addition, an imperfect NF-kappa B binding site was found to overlap the AP-1 binding site. Mutation of either of the NF kappa B binding sites or the AP-1 binding site dramatically decreased the response of the I kappa B alpha promoter to Rel proteins alone or Rel and AP-1 factors. Overexpression of c-Rel or v-Rel resulted in the formation of DNA binding complexes associated with the imperfect NF-kappa B binding site which overlaps the AP-1 site. v-Rel associated with the imperfect NF-kappa B site stronger than c-Rel, and overexpression of v-Rel also resulted in the formation of a v-Rel containing complex bound to a consensus AP-1 site. These studies address the difference in c-Rel and v-Rel's ability to synergistically stimulate I kappa B alpha expression in conjunction with the AP-1 factors. PMID- 8700519 TI - 30 KDa phosphorylated form of Bcl-2 protein in human colon. AB - Bcl-2 expression was studied in a human colon cell line (HT-29) and in human colonic biopsies by Western and Northern blotting. Polyclonal antibodies raised against the Bcl-2 protein detected the expected 26 KDa protein in human colon. However, although Bcl-2 mRNA was present, the 26 KDa Bcl-2 protein was absent in HT-29 cells. Instead, a 30 KDa protein band strongly reacting with anti-Bcl-2 antibodies was found in HT-29 cells, and also in human colon, tonsil, and some other tissues. Alkaline phosphatase shifted the 30 KDa protein to the 26 KDa position in a time-dependent manner. 32P-labeling of HT-29 cells showed that the 30 KDa protein was phosphorylated. A 27 KDa phosphorylated protein was also immunoprecipitated by anti-Bcl-2 antibody. Phosphopeptide mapping showed that the 27 KDa protein contained a minimum of 3 and the 30 KDa protein at least an additional four phosphorylation sites. Phosphoamino acid analysis revealed that both the 30 KDa and 27 KDa proteins were phosphorylated on serine residues. These findings strongly suggest that the 30 KDa protein is a phosphorylated form of Bcl 2, which is widely distributed in human tissues. PMID- 8700520 TI - Comparative analysis of the structure and function of the chicken c-myc and v-myc genes: v-myc is a more potent inducer of cell proliferation and apoptosis than c myc. AB - To gain a more complete understanding of c-myc regulation in chickens, we have completed the structural characterization of the chicken c-myc gene and have begun to investigate c-myc transcription and protein expression. A comparison of c-myc structure and expression between mammals and birds presents an enigma: there are striking similarities in the pattern of gene expression in the absence of obvious sequence similarities in the controlling elements. We have begun to investigate c-myc and v-myc function using retroviral vectors that differ solely in the Myc proteins that they express. We show that while the overexpression of the smaller c-Myc protein is sufficient to induce morphological transformation in chicken embryo fibroblasts, overexpression of v-Myc provides a stronger signal for cells to enter the cell cycle and is a more potent inducer of apoptosis than c-Myc. PMID- 8700521 TI - Heterogenous point mutations in the BRCA1 breast cancer susceptibility gene occur in high frequency at the site of homonucleotide tracts, short repeats and methylatable CpG/CpNpG motifs. AB - Heterogeneous mutations in the BRCA1 tumour suppressor gene are responsible for a large percentage of inherited breast cancers as well as breast/ovarian cancers in families with a high incidence of both cancer types. Over a hundred BRCA1 mutations have been reported, but little is known of the mechanism(s) responsible for BRCA1 mutagenesis. To determine the significance of specific nucleotide sequences at mutational sites within the BRCA1 gene, we assessed how frequently independent BRCA1 mutations occur at the site of short direct repeats, single nucleotide repeats (homonucleotides) and at CpG and CpNpG motifs. We found that homonucleotide and short direct repeats are commonly associated with small deletions and insertions. Substitution mutations are frequently associated with homonucleotide repeats and with methylatable CpG dinucleotides and CpNpG trinucleotides. Our methylation and sequencing experiments show that CpG and certain CpNpG motifs are methylated, supporting the hypothesis that DNA methylation specificity at these sites may be an important contributor to BRCA1 mutagenesis. We suggest that BRCA1 mutations are acquired by replication errors and are retained by cells through an intricate balancing of replication and repair mechanisms. Such mutations may provide a proliferative advantage for a cell, leading to the tumour phenotype. PMID- 8700522 TI - Cyclin C/CDK8 is a novel CTD kinase associated with RNA polymerase II. AB - A number of cyclin/kinase complexes have been identified in mammalian cells that are essential for controlled cell proliferation. Cyclin C was isolated by virtue of its ability to rescue the triple CLN mutation in yeast; however, until now its function has remained unclear. Cyclin C associates with a novel cyclin dependent kinase, CDK8, and we demonstrate that this complex is associated with kinase activity towards the carboxy-terminal domain (CTD) of RNA polymerase II. We have identified at least two distinct cyclin C/CDK8 containing complexes within the cell, a larger complex over 500 kD in size, that also contains the largest subunit of RNA polymerase II, and a smaller 170 kD species. Both of these cyclin C complexes retain potent CTD kinase activity. We further demonstrate that the cyclin C/CDK8 complex associates with the large subunit of RNA polymerase II in vivo, implicating a potential role for cyclin C/CDK8 in regulating its activities. PMID- 8700523 TI - Microsatellite instability and the role of hMSH2 in sporadic colorectalcancer. AB - Microsatellite instability (MSI) occurs in most tumours from patients with hereditary non-polyposis colorectal cancer (HNPCC) and in around 17% of sporadic colorectal cancers. Germline defects in mismatch repair (MMR) genes are responsible for the majority of large HNPCC families, with hMSH2 accounting for at least 50%. MMR gene defects also occur in a small proportion of sporadic colorectal tumours with MSI. Here we report a systematic analysis of mismatch repair deficiency in 215 Scottish patients with sporadic colorectal tumours. We found that 16.4% of tumours exhibited MSI; survival analysis by Cox proportional hazards method showed a substantial survival advantage for patients with tumours showing MSI, independent of other prognostic factors. Tumours with MSI were screened for hMSH2 mutations and although 61% were found to have alterations, of these only 1/24 was exonic. The majority of these changes were reductions in length at intronic mononucleotide tracts and we postulate that these alterations are the result of a genetic defect elsewhere, although they may compromise hMSH2 function as a second step in tumourigenesis. Our findings indicate that instability confers an improved prognosis in colorectal cancer and, despite the fact that these two groups of tumours share similar biological characteristics, the genetic basis of HNPCC and sporadic colorectal cancer with MSI is different. PMID- 8700524 TI - Ras- and Raf-mediated regulation of transforming growth factor beta 1 gene expression by ligands of tyrosine kinase receptors in PC12 cells. AB - Different ligands of tyrosine kinase receptors have neurotrophic or mitogenic effects in PC12 cells. NFG and FGF, which cause morphological differentiation, as well as EGF, that induces cell growth, produce a significant increase of TGF beta1 transcripts in PC12 cells. Sequences responsible for the transcriptional effects of the growth factors are located in the 5'-flanking region of the TGF beta1 gene. The TGF-beta1 gene has two promoters and the growth factors significantly enhance the activity of constructs containing either the first or the second promoter. A functional p21ras is required for the regulation of TGF beta1 by ligands of tyrosine kinase receptors since expression of oncogenic ras in PC12 cells also increases TGF-beta1 transcripts, and a dominant inhibitory ras mutant blocks activation of TGF-beta1 gene expression by NGF. Oncogenic raf stimulates the activity of both promoters and a dominant negative raf also significantly inhibits growth factor activation. As determined by Mv1Lu cell proliferation inhibition assay, PC12 cells release a significant amount of TGF beta1 in a latent form and incubation with growth factors or expression of oncogenic ras further increase TCF-beta1 production. These results suggest that during proliferation or growth factor-induced differentiation of sympathetic neurons there is an increase in TGF-beta1 that could be an important mediator of neural cells function. PMID- 8700526 TI - Transgenes encoding both type I and type IV c-abl proteins rescue the lethality of c-abl mutant mice. AB - Mice carrying homozygous mutations in the c-abl gene (abl-(m1) or abl2) exhibit severe, though variable phenotypes, including a high rate of postnatal mortality, runting, morphological abnormalities, a susceptibility to infections, and selected immune system defects. To further determine the role of the c-Abl protein in vivo, we have generated three lines of mice expressing c-abl transgenes. These minigenes encode the two major forms of the c-abl gene product (c-Abl types I and IV) and a kinase defective type IV c-Abl. The transgenic lines, in Abl-positive genetic backgrounds, were phenotypically almost indistinguishable from their non-transgene littermates and expressed the c-abl transgene in a variety of tissues at levels comparable to that of the endogenous c-abl gene. When the transgenes were introduced into a mutant c-abl strain by mating, the mutant c-abl phenotype was almost completely rescued by either of the c-abl type I or type IV transgenes, but not by the kinase-defective transgene. These findings suggest that either of the two alternatively spliced c-abl gene products can provide the in vivo functions of c-Abl, and that these functions are dependent on kinase activity. PMID- 8700525 TI - Loss of transactivation and transrepression function, and not RPA binding, alters growth suppression by p53. AB - The tumor suppressor protein p53 activates transcription from promoters with specific p53 binding elements, represses transcription from promoters without such elements and interacts with and inhibits the single-stranded DNA binding activity of the human DNA replication factor RPA. All these activities involve the N terminal 70 amino acids of p53. Dissection of the domains of p53 which bind RPA suggest that multiple sub-domains of the protein synergize to give strong RPA binding. Point-mutations in one of these sub-domains of p53 significantly diminish its ability to interact with RPA. A multimer of a peptide from p53 which includes these residues, or of a peptide from the acidic activation domain of the prototypic trans-activator protein VP16, can itself bind to RPA. Comparison of sequences of these multimeric peptides suggests that aromatic amino acids flanked by negatively charged residues are important for binding RPA. Several alleles of p53 with point mutations in the N terminal region were analysed for their relative abilities to bind RPA, activate or repress transcription, and suppress growth of p53 null SaOs2 and H1299 cells. Both mutants of p53 with decreased RPA binding suppressed cell growth as well as wild-type p53, suggesting that p53 can suppress growth without interacting with RPA. The allele that lost most of the transcription activation function also lost most of its transcription repression activity suggesting that interaction with the same basal transcription factors are involved in both functions. This same allele bound RPA well but was defective in growth suppression. Therefore, transcription activation and/or repression appear to be more important for the growth suppression function of p53 than RPA binding. PMID- 8700527 TI - RN-tre specifically binds to the SH3 domain of eps8 with high affinity and confers growth advantage to NIH3T3 upon carboxy-terminal truncation. AB - We isolated a cDNA encoding a protein, RN-tre, which shows homology to the N terminus of the tre oncogene product and has SH3-binding ability as well as an evolutionarily conserved domain, termed TrH, with protein-binding ability in vitro. In the present study, we identify the product of the RN-tre gene as a 97 100 kDa protein. We demonstrate stable association in vivo and in vitro between RN-tre and eps8, mediated by the SH3 domain of the latter. In vitro, RN-tre displayed remarkable preference for binding to the eps8-SH3, as compared to eight other SH3s. The Kd for the in vitro interaction between RN-tre and eps8-SH3 was between 10(-8) and 10(-7) M. A role for RN-tre in cell proliferation was suggested by the finding that a C-terminal truncated mutant was able to confer proliferative advantage and reduced serum-requirement to NIH3T3 fibroblasts. Finally, comparison of the structure and biological activities of RN-tre and of the tre oncogene product, provided insight into the mechanism of oncogenic activation of tre. PMID- 8700528 TI - Targeted proteolysis of the focal adhesion kinase pp125 FAK during c-MYC-induced apoptosis is suppressed by integrin signalling. AB - The product of the c-myc proto-oncogene has a central role in induction of apoptosis, a physiological form of cell death characterised in vitro by morphological rounding, detachment and nuclear disintegration. Induction of apoptosis by serum withdrawal from c-Myc-transformed chicken embryo fibroblasts (CEF) results in early proteolysis of focal adhesion kinase (ppl25FAK), a tyrosine kinase implicated in the conversion of integrin signals into their biological responses. Proteolysis of pp125 FAK occurs in adherent cells prior to commitment to death, suggesting that it contributes to c-Myc-induced apoptosis, rather than being a consequence of it. Furthermore, c-Myc-induced detachment, cell death and cleavage of pp125FAK are coordinately suppressed by treating with insulin or plating on the extracellular matrix components collagen and fibronectin. In addition, proteolysis of pp125FAK is suppressed by a beta1 specific integrin antibody, which promotes cell survival in the face of the oncoprotein-induced signal for apoptosis. These results provide compelling evidence that the c-Myc-induced cell death programme in CEF requires disruption of the integrin signalling pathways which normally function when cells are spread on ECM, and that maintaining cellular pp125FAK, which couples integrins to their downstream effectors, is closely linked to cell survival. PMID- 8700529 TI - The brain specific Ras exchange factor CDC25 Mm: modulation of its activity through Gi-protein-mediated signals. AB - CDC25Mm is a mouse guanine nucleotide exchange factor specific for Ras, exclusively expressed in the brain. We used a reporter gene containing a Ras responsive fos-promoter in order to gain information on the role played by this exchange factor in signal transduction. Transient expression of CDC25Mm in CHO cells activates Ras. Moreover serum, but not insulin, can upregulate the response mediated by CDC25Mm and this modulation requires that the CDC25Mm maintains its N terminal region. NIH3T3 fibroblasts, stably overexpressing this exchange factor, show a partially transformed phenotype, suggesting that the Ras-dependent pathway is constitutively active. In these cells serum and lysophosphatidic acid (LPA) stimulate Ras activity above the basal level while PDGF does not. Both serum and LPA-induced Ras activations in CDC25Mm overexpressing cells can be completely inhibited by pertussis toxin. Moreover, these responses are strongly reduced by coexpression of a truncated version of CDC25Mm lacking the C-terminal catalytic portion. This construct behaves in a dominant negative manner suggesting that it may compete with CDC25Mm by sequestering in an unproductive way signalling components activated by these factors. The data presented indicate that CDC25Mm does not participate in connecting tyrosine kinase receptors with Ras, while it could mediate Ras activation induced by pertussis toxin sensitive Gi-coupled receptors. PMID- 8700530 TI - Murine WNT11 is a secreted glycoprotein that morphologically transforms mammary epithelial cells. AB - Wnt genes encode a set of structurally related cell surface glycoproteins that appear to have roles in cell-cell signalling. The ectopic expression of several murine Wnt genes has been implicated in the transformation of mammary epithelial and the onset of mammary tumours. Wnt11 is expressed in the developing embryo in a variety of structures including the dermatome/myotome junction of the somites, the truncus ateriosus region of the heart and limb mesenchyme. Here we report that Wnt11 encodes a glycoprotein that is secreted from expressing cells and becomes associated with the extracellular matrix. In addition, Rat2 fibroblasts expressing WNT11 (which are not morphologically altered themselves) are able to induce the transformation of adjacent C57MG mammary epithelial cells in co culture experiments. These results suggest that WNT11 functions via a paracrine signalling mechanism to have a direct effect on the morphology and growth characteristics of mammary epithelial cells. PMID- 8700531 TI - Tissue-specific expression, evolutionary conservation and localization of the cph proto-oncogene on Syrian hamster chromosome X. AB - Treatment of Syrian hamster embryo fibroblasts with a single dose of 3 methylcholanthrene caused the activation of the transforming potential of cellular sequences (Notario et al, Oncogene 5: 1425-1430, 1990), which were subsequently isolated by cosmid rescue techniques, and further identified as a novel oncogene, termed cph because of its involvement in the carcinogenic progression of hamster embryo cells (Velasco et al, Oncogene 9: 2065-2069, 1994). We have analysed the expression of the cph proto-oncogene in adult Syrian hamster tissues by northern hybridization using cph-specific genomic probes. The three cph transcripts expressed in normal and neoplastic Syrian hamster embryo cells in culture (5.0, 3.5 and 2.0 kb) were also present in most adult tissues, although different mRNA species, most likely resulting from alternative splicing events, were expressed in testes. The highest steady-state level of cph mRNA was found in kidney, whereas cph expression was nearly undetectable in skin and skeletal muscle. Southern blot analyses of DNAs from other eucaryotic organisms were performed under moderate stringency conditions with a Syrian hamster-specific cph probe. Discrete cph-hybridizing sequences were present in genomes from yeast to mammalian species, including humans, thus demonstrating that cph is a highly conserved gene in eucaryotic evolution. Using fluorescence in situ hybridization (FISH), we have determined also the chromosomal localization of the cph proto oncogene in the hamster genome. FISH experiments demonstrated that cph is a single copy gene, localized on the euchromatic short arm of the X chromosome, at region Xpa7. Because chromosome X is frequently involved in structural alterations in neoplastic Syrian hamster cells transformed by chemical carcinogens and oncogenic viruses, the localization of the cph locus on this chromosome supports the notion that the cph oncogene plays a role in the malignant conversion of chemically transformed hamster fibroblasts. The wide range of tissue-specific expression and species-specific distribution of cph strongly suggest that the normal function of the cph protein product(s) may be essential for metabolic processes involved in the regulation of cell proliferation and survival. PMID- 8700532 TI - Deletion mapping identifies loss of heterozygosity at 5p15.1-15.2, 5q11 and 5q34 35 in human male germ cell tumors. AB - Cytogenetic and loss of heterozygosity (LOH) studies of chromosome 5 in male germ cell tumors (GCTs) previously reported suggested the presence of one or more tumor suppressor genes (TSGs) on this chromosome which may play a role in the development of these tumors. In an attempt to further characterize allelic deletions on chromosome 5, we performed a detailed deletion mapping utilizing 66 normal-tumor DNAs from male GCTs assaying 24 polymorphic markers mapped to both the short and long arms. Thirty-seven (56%) tumors exhibited LOH at one or more loci. Loss of one allele at all informative loci was found in 15 of 37 (40.5%) cases suggesting monosomy of chromosome 5. The pattern of LOH in the remaining 22 (59.5%) tumors revealed regional losses identifying three common sites of deletions at 5p15.1-15.2, 5q11, and 5q34-35, respectively. The distribution of allelic deletions was found to be similar in all histologic subtypes with predominance of monosomy in teratomas. Thus, the present study revealed 2 types of chromosome 5 abnormalities in male GCTs, genetic monosomy and regional deletion, the latter identifying three novel sites of candidate TSGs. These data suggest that loss of genetic information on chromosome 5 plays an important role in male GCT development. PMID- 8700533 TI - HER-2/c-erbB2 is phosphorylated by calmodulin-dependent protein kinase II on a single site in the cytoplasmic tail at threonine-1172. AB - Calmodulin-dependent protein kinase II (Cam kinase II) is known to desensitise epidermal growth factor receptor (HER-1) tyrosine kinase activity by a process involving phosphorylation at serines 1046/47 in the cytoplasmic tail. We have developed an experimental system to investigate phosphorylation of the related HER-2/c-erbB2 proto-oncogene utilising purified Cam kinase II and recombinant glutathione-S-transferase (GST) fusion proteins. The cDNA for rat Cam kinase II alpha was transfected into human embryonic kidney (HEK) 293 fibroblasts and the expressed protein purified to homogeneity by calmodulin-agarose affinity chromatography. A GST fusion protein comprising residues 1126-1255 of HER-2 was phosphorylated by purified Cam kinase II, in contrast to a GST protein comprising residues 1005-1125. Phosphoamino-acid analysis and site-directed mutagenesis indicated that HER-2 was phosphorylated on a single site at threonine-1172 which resides within a consensus Cam kinase II phosphorylation site (RAKT). HER-2 (threonine-1172-alanine), in the form of a ligand-inducible chimaera HER-1/2, was co-transfected into HEK-293 fibroblasts with a constitutively active form of Cam kinase II, followed by in vivo labelling of these cells with 32 P-orthophosphate. Immunoprecipitation of ligand-activated receptors followed by two-dimensional phosphopeptide mapping indicated that threonine-1172 in HER-2 is a newly identified in vivo site which can be hyper-phosphorylated by constitutively active Cam kinase II. In addition, when over-expressed in HEK-293 fibroblasts, HER-1/2 (threonine-1172-alanine) showed a defect in desensitisation and underwent a more sustained EGF-induced receptor autophosphorylation compared to wild-type HER-1/2. PMID- 8700534 TI - Abrogation of p53-induced G1 arrest by the HPV 16 E7 protein does not inhibit p53 induced apoptosis. AB - Wild type (wt) p53 expressed from a temperature-sensitive construct (ts p53) can induce both G1 cell cycle arrest and apoptosis in the p53-negative J3D mouse T lymphoma line (Wang et al, 1995). The human papillomavirus (HPV) 16 E7 protein has been shown to prevent p53-induced G1 cell cycle arrest following DNA damage. We asked whether inhibition of p53-induced G1 arrest by overexpression of the HPV16 E7 protein in the ts p53-transfected J3D cells would interfere with p53 induced apoptosis. Whereas a majority of the ts p53-expressing J3D cells were arrested in the G1 phase 22 h after induction of wt p53 by temperature shift to 32 degrees C, the E7/ts p53-expressing cells showed only a minor increase in the number of cells in G1 at this time point. In addition, the E7/ts p53-expressing cells showed a much less dramatic reduction in number of cells in S phase than the ts p53-expressing cells. This demonstrates that E7 at least partially rescues the cells from p53-induced G1 arrest. In contrast, overexpression of HPV16 E7 did not have any effect on the kinetics nor the frequency of p53-triggered apoptotic death, as shown by FACS analysis, trypan blue exclusion, and DNA fragmentation analysis. These findings support the notion that p53-induced G1 arrest and p53 induced apoptosis are two separate independent pathways. PMID- 8700535 TI - Induction of apoptosis by the tumor suppressor protein BRCA1. AB - The breast and ovarian cancer susceptibility gene BRCA1, is a nuclear phosphoprotein which functions as a tumor suppressor. To investigate the role of BRCA1 in apoptosis, we have developed mouse fibroblast cell lines and human breast cancer cell lines expressing BRCA1. The expression of BRCA1 protein in the BRCA1 transfectants were analysed by immunofluorescence and immunohistochemistry. The BRCA1 transfectants showed a flattened morphology compared to the parental cells. We show that serum deprivation or calcium ionophore treatment of BRCA1 transfectants resulted in programmed cell death. These results indicate that BRCA1 genes may play a critical role in the regulation of apoptosis. Thus, since a wide variety of human malignancies like breast and ovarian cancers have a decreased ability to undergo apoptosis, this could be due to lack/decreased levels of functional BRCA1 proteins. Treatments that are aimed at increasing the apoptotic threshold by BRCA1 gene therapy may have the potential to prevent the progression of these malignancies. PMID- 8700536 TI - A bcl-2/IgH antisense transcript deregulates bcl-2 gene expression in human follicular lymphoma t(14;18) cell lines. AB - The 14;18 chromosome translocation, characteristic of most human follicular B cell lymphomas, juxtaposes the bcl-2 gene with the IgH locus, creating a bcl 2/IgH hybrid gene. By mechanisms that are still under investigation, this event increases the cellular levels of the bcl-2 mRNA and thereby induces an overproduction of the antiapoptotic BCL-2 protein which is likely responsible for neoplastic transformation. In an effort to identify potential upregulators of bcl 2 activity in t(14;18) cells, we found, by strand-specific RT-PCR, a bcl-2 antisense transcript that is present in the t(14;18) DOHH2 and SU-DHL-4 but not in the t(14;18)-negative Raji and Jurkat lymphoid cell lines, and thus appears to be dependent on the bcl-2/IgH fusion. This antisense transcript is a hybrid bc1 2/IgH RNA, that originates in the IgH locus, encompasses the t(14;18) fusion site and spans at least the complete 3' UTR region of the bcl-2 mRNA. To achieve some insight into its biological function, we treated the t(14;18) DOHH2 cell line with oligonucleotides (ODNs) by specifically targeting the bc1-2/IgH antisense strand. These ODNs lowered bcl-2 gene expression, inhibited neoplastic cell growth by inducing apoptosis. We would like to propose the hypothesis that the bc1-2/IgH antisense transcript may contribute, by an unknown mechanism, to upregulation of bcl-2 gene expression in t(14;18) cells. The possibility has been considered that the hybrid antisense transcript mask AU-rich motifs present in the 3' UTR of the bcl-2 mRNA characterized in other genes as mRNA destabilizing elements. PMID- 8700537 TI - An abundance of p53 null mutations in ovarian carcinoma. AB - Ovarian cancers from 64 midwestern US women were screened for p53 dysfunction both by immunohistochemical staining (IHCS) and single strand conformation polymorphism (SSCP) analysis of the entire open reading frame (ORF). Forty SSCP abnormalities in 39 tumors included nine deletion, one insertion, two splice junction, two nonsense, one silent and 25 missense mutations were confirmed by direct genomic sequencing. Eight of the insertion/deletion defects may have occurred due to slippage during the course of DNA replication. This observation suggests that genomic instability may play an important role in ovarian carcinogenesis. Fifteen percent of the mutations encountered were located outside exons 5-9 and four of these were null. The sensitivity of IHCS was 96% for missense mutations but only 14% for null mutations. This contrasted with 100% sensitivity of the SSCP screening methodology. The 21% overall incidence of null mutations in the present study far exceeds the reported 6.8% incidence in the world literature (P=0.0003). Explanations for this difference include: (1) our complete analysis of the entire ORF of the p53 gene; (2) the tendency of others to rely upon IHCS to screen tumors prior to mutation analysis; and (3) environmental or endogenous genetic influences. PMID- 8700538 TI - Dimerization of a chimeric CD4-interferon-alpha receptor reconstitutes the signaling events preceding STAT phosphorylation. AB - Interferon-alpha induces the rapid tyrosine phosphorylation of a number of molecules, including the cognate receptors, JAK-family kinases (Jak1 and tyk2), and latent transcription factors (STATs 1 and 2). Here, we describe the use of chimeric molecules composed of the extracellular domain of CD4 fused to the intracellular domain of the interferon-alpha receptor subunit 1 (IFNaR1). Antibody mediated crosslinking dimerizes the transfected chimeras, activates tyk2 and induces a tyk2-dependent tyrosine phosphorylation of the intracellular domain of the chimera. We further define the major site of IFNaR1 phosphorylation, and show that phosphorylation of this site is required for association with STAT2. Finally, we show that homodimerization of IFNaR1 is not sufficient to activate the STATs, suggesting a role for the IFNaR2 subunit and Jak1 in the transduction of the interferon-alpha signal. PMID- 8700539 TI - Constitutively activated JNK is associated with HTLV-1 mediated tumorigenesis. AB - Human T cell leukemia virus type I (HTLV-1) is the etiologic agent of adult T cell leukemia (ATL) and HTLV-1 associated myelopathy, also called tropical spastic paraparesis (HAM/TSP). Both clinical and in vitro evidence have demonstrated that the virus or its transactivator Tax, are transforming. However, transformation appears to require additional, as yet poorly characterized, genetic changes in infected cells. JNK is a recently characterized member of the MAP kinase family. Its signaling cascade is distinct from other members and has been demonstrated to play an important role in T-cell activation, at least partially through its downstream targets, c-jun and ATF-2. Here we demonstrate constitutive activation of the JNK cascade in human lymphocytes transformed in vitro by HTLV-1 and also in Tax transformed murine fibroblasts. Such activation is not induced by Tax expression alone, and occurs only when infected lymphocytes become IL-2 independent or immortalized. Constitutive JNK activation was also found in leukocytes isolated from ATL patients. The acquisition of constitutive JNK activation may represent an important later event in HTLV-1 tumorigenesis. PMID- 8700540 TI - Oxamflatin: a novel compound which reverses malignant phenotype to normal one via induction of JunD. AB - In the course of screening for inhibitors of tumorigenic phenotype of K-ras transformed NIH3T3 cells (DT cells), we found a novel compound, oxamflatin, an aromatic sulfonamide hydroxamate derivative, which induces flat phenotype in these cells and suppresses their anchorage-independent growth. In contrast to DT cells, in v-raf-transformed NIH3T3 cells, no change in their morphology and no specific inhibition of their anchorage-independent growth was observed. Interestingly, oxamflatin was effective to NIH3T3 cells transformed by constitutively activated mutant of MEK, indicating the possibility that oncogene induced morphological change is not necessarily induced by common signaling pathway such as MAP kinase cascade. In oxamflatin-treated DT cells, the expression of transcription factor junD was highly augmented, resulting in trans activation of fibronectin gene by junD via cyclic AMP responsive element in its promoter. This behavior of junD was confirmed to correlate well with partial blocking of malignant phenotype in DT cells. Thus, oxamflatin can be categorized as the first reagent which induces genes whose products can interfere with oncogene-dependent transformation. PMID- 8700541 TI - The kinase-inactive PDGF beta-receptor mediates activation of the MAP kinase cascade via the endogenous PDGF alpha-receptor in HepG2 cells. AB - The PDGF beta-receptor in which the active-site lysine in the kinase domain has been mutated to arginine (K634R) tacks intrinsic kinase activity. When expressed in HepG2 cells, the kinase-inactive PDGF beta-receptor was tyrosine phosphorylated in response to PDGF-BB. Previously, HepG2 cells were thought to be devoid of PDGF alpha-receptor primarily due to lack of specific antibody which precluded detection of the PDGF alpha-receptor. In fact, these cells express low levels of PDGF alpha-receptor. In HepG2 cells that express the kinase-inactive PDGF beta-receptor, PDGF-BB activates the PDGF alpha-receptors to trans phosphorylate the kinase-inactive PDGF beta-receptor in an intermolecular fashion. As a result, stimulation of HepG2 cells that express the kinase-inactive receptor leads to activation of serine/threonine kinases of the MAP kinase cascade which include RAF-1, MEK-1 and p42 MAP kinase. In contrast, the kinase inactive receptor does not activate any signaling pathways when it is expressed in PC12 cells which do not express the endogenous PDGF alpha-receptor. Thus, the kinase-inactive K634R PDGF beta-receptor is able to enhance PDGF-BB signaling in HepG2 cells that express the PDGF alpha-receptor. PMID- 8700542 TI - Telomerase activity in human renal cell carcinoma. AB - Telomeres have a vital role in maintaining chromosome stability and are essential for long term viability. Since the very ends of linear chromosomes cannot replicate, telomeres shorten in normal somatic cells eventually resulting in growth inhibition. However, most immortal cell lines maintain stable telomeres indicating that mechanisms exist to compensate for the end replication problem. Telomerase activity, leading to synthesis of telomeric DNA repeats, has been proposed to be an important step in the immortalization process of tumor cells. In the present study, 56 renal cell carcinomas were tested for telomerase activity using the sensitive TRAP (telomeric repeat amplification protocol). Forty of the analysed tumors (71%) were positive for telomerase activity, whereas none of the 56 corresponding normal kidney samples showed telomerase activity. All telomerase negative tumors had a reduction in mean telomere restriction fragment (TRF) length and a decrease in total telomere repeat hybridization signal, though cases were observed with an increase in peak TRF lengths. No obvious association between the presence of telomerase activity and clinicopathological parameters (histopathologic grade, DNA-ploidy, stage and clinical outcome) was found. The high frequency of detection of telomerase activity in the renal cell carcinomas indicates that this enzyme is likely to be an important factor involved in the evolution of this tumor type. PMID- 8700543 TI - Differentiation of mouse keratinocytes is accompanied by PKC-dependent changes in AP-1 proteins. AB - The conversion of cultured basal keratinocytes to the spinous and granular cell phenotypes seen in the skin can be stimulated by raising the levels of extracellular calcium. Here we show that AP-1 DNA binding activity is very low in primary cultures of basal keratinocytes, but that this activity is induced 24-48 h after increasing the concentration of extracellular calcium from 0.05 to 0.12 mM. As such, the induction of AP-1 DNA binding activity correlates with events occurring during the terminal stages of keratinocyte differentiation. Calcium induced AP-1 DNA binding complexes consist of Fra-1, Fra-2, c-Jun, JunB and JunD and are independent of c-Fos, since the induction of DNA binding activity and the composition of the AP-1 binding complexes are identical in differentiating keratinocytes derived from c-fos null and wild type mice. The formation of calcium-induced AP-1 binding complexes is regulated by protein kinase C (PKC) and requires a functional PKCalpha isozyme, as determined through pharmacological down-modulation of specific PKC isozymes in differentiating keratinocytes. Moreover, PKC activation is required for the increased expression of Fra-2, JunB and JunD in the nucleus of differentiating cells in vitro. This observation provides a link between the obligate activation of PKC during keratinocyte differentiation and the nuclear response required to alter gene expression. In vivo expression patterns suggest that the predominant AP-1 heterodimer in the granular layer consists of Fra-2 and JunB while a JunD and Fra-1 complex predominates the spinous layer of mouse epidermis. These findings suggest distinct functions for different AP-1 proteins in the regulation of events related to keratinocyte maturation. PMID- 8700544 TI - Variation in the sequence of Epstein Barr virus nuclear antigen 1 in normal peripheral blood lymphocytes and in Burkitt's lymphomas. AB - We have examined sequence variations in the EBNA-1 protein of EBV in normal peripheral blood lymphocytes (PBL) and Burkitt's lymphomas (BL). We find two EBNA 1 strains P (prototype) and V (variant) which differ by 15 amino acids. Each strain has two subtypes defined by the amino acid at position 487 (P-ala, P-thr, V-pro and V-leu). In PBLs from 32 normal individuals, up to three of these subtypes were found in each sample, but the V strain did not occur in the absence of P strain viruses, nor was the V-leu subtype ever observed in normal PBL. In BLs only a single subtype was observed in each tumor. The P-thr and V-leu subtypes were more frequently seen than the P-ala and V-pro subtypes, which occurred in only two and one of the 36 tumor samples respectively. The P-thr was the most commonly observed subtype in peripheral blood of both American and African lymphocytes as well as in African tumors. However, in 11 of 12 American tumors, the EBNA-1 subtype was V-leu. These data indicate that some EBNA-1 subtypes are more likely to lead to oncogenesis, and one subtype, V-leu, appears only to occur in tumors. PMID- 8700545 TI - Structurally altered Evi-1 protein generated in the 3q21q26 syndrome. AB - Overexpression of the Evi-1 gene appears to be a consistent feature of the 3q21q26 syndrome, an association of myeloid leukemias/myelodysplastic syndrome with a specific chromosomal aberration involving both 3q21 and 3q26, such as t(3;3)(q21;q26) or inv(3)(q21q26). The rearrangement in 3q26 has been reported to occur near the Evi-1 locus, implicating that it is the critical gene deregulated in the 3q21q26 syndrome. Here we present a structural abnormality of Evi-1 protein in a case with the 3q21q26 syndrome. In this case carrying typical inv(3)(q21q26), the 3q26 breakpoint is located within an intron of the Evi-1 gene, and resulted in overexpression of normally unexpressed, an aberrant form of Evi-1 protein, in which the C-terminal 44 amino acids of wild-type Evi-1 protein were truncated and replaced by five amino acids. The truncated Evi-1 protein is shown to increase AP1 activity when expressed in NIH3T3 cells as its wild-type counterpart. We also show that the origin of this peculiar type of rearrangement of the Evi-1 gene is not an artifact during establishment of the cell line, but is the event that occurred in the primary leukemic cells. Our results strongly support that the primary target for the 3q21q26 syndrome is the Evi-1 gene, and provide the first evidence that the structurally altered Evi-1 gene may be involved in the 3q21q26 syndrome. PMID- 8700546 TI - Subcellular localization of the Arg protein tyrosine kinase. AB - Arg and c-Abl are ubiquitously expressed proteins which represent the mammalian members of the Abelson family of nonreceptor protein tyrosine kinases (PTKs). In contrast to most nonreceptor PTKs, c-Abl is located in the nucleus and cytoplasm. In this study the subcellular localization of Arg was examined to gain insight into its possible functions. Using indirect immunofluorescence, Arg was detected in the cytoplasm but not the nucleus of both transiently transfected COS cells and stable NIH3T3 transfectants. Arg is expressed as IA and IB isoforms which bear alternative amino termini, with the IB isoform containing a potential myristic acid acceptor sequence. Modification of ArgIB by myristic acid was confirmed by the detection of [3H]myristic acid labeling and the observation that labeling was abolished by mutating Gly-2. These results indicate that the subcellular localization of Arg is distinct from that of c-Abl and thus suggest that the two proteins have different functions in intracellular signaling. In addition, Arg, like c-Abl, is expressed as myristoylated and nonmyristoylated isoforms, suggesting that it may have dual cytoplasmic subcellular localizations, and possibly participate in diverse signaling pathways. PMID- 8700547 TI - Impaired development of CD4+ CD8+ thymoyctes by csk-'knock-in' into fyn locus. AB - p59fyn is one of the Src-family kinases thought to play an important role in signaling through T cell receptor. However, Fyn deficiency has caused no overt defects in vivo on T cell development, nor has it caused any changes in the phosphorylation status of molecules such as ZAP-70 which have been proposed as p59fyn substrates. This could be explained as being due to compensation of Fyn deficiency by other Src-family kinases. Here, we have 'knocked-in' the csk gene, a negative regulator of Src-family kinases, into fyn locus to challenge the problem of redundant functions among Src-family kinases. The csk-'knock-in' mice displayed atrophy of the thymic cortex and impaired development of CD4+ CD8+ thymocytes. This was concomitant with decrease in tyrosine phosphorylation of ZAP 70 and p120cbl. PMID- 8700548 TI - Murine p53 is phosphorylated within the PAb421 epitope by protein kinase C in vitro, but not in vivo, even after stimulation with the phorbol ester o tetradecanoylphorbol 13-acetate. AB - The p53 tumour suppressor protein is thought to play a major role in the defence of the cell against agents which damage DNA. p53 is phosphorylated at multiple sites in vivo and by several different protein kinases in vitro. In this report, we have examined the phosphorylation of murine p53 by protein kinase C (PKC). Phosphopeptide mapping, phosphoamino acid analysis and radiosequence analysis of p53 phosphorylated by PKC in vitro indicated that serine 370 and threonine 377 were the major targets for phosphorylation and suggested that serine 372 and threonines 365 and 371 were minor phosphorylation sites. Site-directed mutagenesis confirmed that residues 370-372, all of which lie within the epitope for monoclonal antibody PAb421, were phosphorylated in vitro. The p53 from 32P labelled SV3T3 cells showed a phosphopeptide pattern which includes peptides with mobilities similar to those arising from phosphorylation of residues 370-372 by PKC in vitro. Only two of these in vivo-labelled phosphopeptides co-migrated in two dimensions with peptides labelled in vitro within the PAb421 epitope and their phosphorylation was not stimulated by the addition of the PKC activator o tetradecanoylphorbol 13-acetate (TPA) to the cells, even though this treatment led to a fourfold stimulation of p53 phosphorylation by MAP kinase. Moreover, when the p53 proteins containing mutations at residues 370-372 were expressed in COS cells, there was no loss of any of the in vivo phosphopeptides, indicating that phosphorylation within the PAb42I epitope was undetectable in the cell. These data suggest that p53 and PKC may not interact in vivo. The two-dimensional migration pattern of the novel group of peptides is consistent with phosphorylation of previously uncharacterised sites within the central DNA binding region of p53. PMID- 8700549 TI - Bcl-2 blocks loss of mitochondrial membrane potential while ICE inhibitors act at a different step during inhibition of death induced by respiratory chain inhibitors. AB - Bcl-2, Bcl-xL, CrmA and tetrapeptide ICE inhibitor reduce the extent of necrotic cell death induced by cyanide, which primarily damages mitochondria. Although none of them affects the drastic decrease in ATP levels induced by cyanide, Bcl-2 and Bcl-xL but not CrmA or ICE inhibitor inhibit the cyanide-induced decrease in mitochondrial membrane potential. A similar blocking effect is observed on necrotic cell death induced by other respiration inhibitors, rotenone and antimycin A, and on apoptotic cell death induced by etoposide or calcium ionophore. These results indicate that Bc1-2 and Bcl-xL protect mitochondria against the loss of function during both apoptosis and at least some forms of necrotic cell death. The ICE family proteases act at a different step other than the loss of mitochondrial membrane potential. PMID- 8700550 TI - Isolation of expressed sequences that include a gene for familial breast cancer (BRCA2) and other novel transcripts from a five megabase region on chromosome 13q12. AB - A proportion of familial breast cancer has recently been shown by genetic linkage analysis to map to chromosome l3q12 (Wooster et al, 1994). This locus contains a tumor suppressor gene BRCA2, mutations in which lead to tumorigenesis. Genetic alterations at this locus have also been shown in pancreatic adenocarcinoma and in hepatocellular carcinoma. In an effort to isolate the BRCA2 gene, we have cloned 73 non overlapping cDNAs from a set of nine YACs spanning 6 cM interval on chromosome 13q12 by using a direct cDNA selection method. One of the selected cDNAs corresponds to a region of the 3' portion of BRCA2 mRNA, the sequence of which was published recently (Wooster et al, 1995). Northern analysis of BRCA2 transcripts from a variety of cell lines showed altered sizes of the mRNA in a breast cancer cell line (MCF7) and a prostate carcinoma cell line (DU145). Furthermore, BRCA2 transcript was present in cDNA libraries from total fetus as well as adult human tissues. Fifteen unique cDNA fragments encode genes/ESTs that are already known, of which only two have been mapped to this region. The other 12 cDNAs include genes for RPL6/mRNA for TAX REB 107, elongation factor-1 delta, 26S protease S4 regulatory subunit, small cytoplasmic 7SL RNA, a full length open reading frame (ORFU), brain thiol specific antioxidant protein, ribosomal protein, L35, and lipoxygenase activating protein. Six cDNAs represent human homologs of genes known in other species, namely, mouse HSPE71, Rat RhoGAP protein, S cerevisiae leucyl tRNA synthetase and S cerevisiae chromosome II ORF YBLO44W. The remaining 52 cDNAs showed either weak similarity or no similarity to sequences in the nucleotide data base and hence would represent novel genes. The plausible functions of some of these genes based on their sequence similarity to other known genes is discussed. PMID- 8700551 TI - Down regulation of Bcl-2 is the first step on Fas-mediated apoptosis of male reproductive tract. AB - Suppression of apoptosis by Bcl-2, an oncogene product, has been previously reported. Although the down regulation of Bcl-2 has been encountered in various types of apoptosis, the time course of changes in the expression of Bcl-2 has yet to be determined. In the present study, we established and analysed an in vivo model of apoptosis. The mouse male reproductive tract, specifically the prostate and epididymis, which is regulated by sex steroid hormones, especially testosterone, showed regression induced by chromosomal DNA fragmentation, apoptotic cell death, after gonadectomy. Following this apoptosis, down regulation of Bcl-2 and the new expression of Fas were seen. Using functional Fas lacking mice, we demonstrated that this regression of the male reproductive tract is triggered by Fas-mediated apoptosis. In addition, time course experiments revealed that down regulation of Bcl-2 when apoptosis occurs heralds Fas expression. We propose here that apoptotic death signal transduction in total involve, a number of steps, the first and most important of which is down regulation of Bcl-2. PMID- 8700552 TI - Chromosome 22 complements apoptosis in Fas-and TNF-resistant mutant UK110 cells. AB - Fas and p55 tumor necrosis factor receptor (TNFR) transfer an apoptosis signal when they are crosstinked with their ligands or agonistic antibodies. However, the signal transduction mechanism of apoptosis via Fas and p55 TNFR has not yet been elucidated. We previously described a recessive mutant UK110 from the human monocytic leukemia U937 cell line, that showed resistance against Fas- and p55 TNFR-mediated apoptosis. By cytogenetic analysis and microcell-fusion method, we demonstrate here that introduction of chromosome 22 can specifically restore the sensitivity to Fas- and TNF-mediated apoptosis in UK110 cells. Moreover, introduction of chromosome 22 into UK110 can complement the processing of interleukin-1 beta converting enzyme (ICE)-like proteases, such as CPP32/Yama/Apopain and ICH-1L, after treatment with anti-Fas and anti-p55 TNFR antibodies. These results suggest that the product of a gene located on chromosome 22 participates in the Fas-and p55 TNFR-mediated apoptosis at a point upstream of ICE-like proteases. PMID- 8700553 TI - The human FGF-8 gene localizes on chromosome 10q24 and is subjected to induction by androgen in breast cancer cells. AB - Androgen-induced growth factor (AIGF or FGF-8) was originally isolated from the conditioned medium of an androgen-dependent Shionogi carcinoma, SC-3, cell line. It shares structural similarity with other members of the FGF family. The temporal and spatial expression patterns of the FGF-8 gene suggest its involvement in gastrulation, regionalization of the brain, and organogenesis of the limb and face as an embryonic epithelial factor. In the adult, expression of FGF-8 is restricted to gonads including testes and ovaries. Since FGF-8 is identified as a corroborating gene in MMTV-induced mammary tumors in Wnt-1 transgenic mice and because FGF-8 manifested its autocrine mitogenic activity in SC-3 cells, it is possible that aberrant expression of FGF-8 may be present in human cancers which are hormone dependent. However, very little is known about human FGF-8. To determine whether FGF-8 plays a role in human breast cancer, we have isolated the full-length cDNA from SK-BR-3 breast cancer cells. We have also isolated the corresponding genomic DNA in a P1 cloning vector. The FGF-8 gene has been mapped to chromosome 1Oq24 using both somatic cell hybrid genetic analysis and fluorescence in situ hybridization. Finally, we show that FGF-8 gene expression in a human breast cancer cell line, MDA-MB-231, is inducible by androgen. The findings presented here will facilitate our understanding of the molecular mechanism underlying hormone-responsive breast and prostate cancers. PMID- 8700554 TI - Ganciclovir-induced ablation non-proliferating thyrocytes expressing herpesvirus thymidine kinase occurs by p53-independent apoptosis. AB - In adult mice of the transgenic strain TG66.19, in which expression of herpes simplex type 1 virus thymidine kinase (HSVI-TK) is driven in thyrocytes from the thyroglobulin promoter, the drug Ganciclovir causes the death (ablation) of thyrocytes. Ablation occurred in the absence of thyrocyte proliferation or nuclear DNA synthesis, but was accompanied by transient expression of proliferating cell nuclear antigen and the dying thyrocytes exhibited the ultrastructural features of apoptosis. Control experiments show that the apoptosis is a result of the production of Ganciclovir phosphates in thyrocytes that express HSV1-TK. However, cell death was not dependent upon the presence of a functional copy of the oncosuppressor gene p53. We conclude that the apoptosis is probably not mediated by induction of DNA damage and occurs via a pathway that is independent of p53. The fact that Ganciclovir phosphate can kill cells by a p53-independent apoptotic pathway is encouraging in relation to tumour ablation by methods based on transfection with HSV1-tk genes and administration of Ganciclovir. PMID- 8700555 TI - Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescence in situ hybridization. AB - Amplification and overexpression of the HER-2/neu gene occurs in 25-30% of human breast cancers. This genetic alteration is associated with a poor clinical prognosis in women with either node negative or node positive breast cancers. The initial studies testing this association were somewhat controversial and this controversy was due in large part to significant heterogeneity in both the methods and/or reagents used in testing archival material for the presence of the alteration. These methods included a number of solid matrix blotting techniques for DNA, RNA and protein as well as immunohistochemistry. Fluorescence in situ hybridization (FISH) represents the newest methodologic approach for testing for this genetic alteration. In this study, FISH is compared to Southern, Northern and Western blot analyses as well as immunohistochemistry in a large cohort of archival human breast cancer specimens. FISH was found to be superior to all other methodologies tested in assessing formalin fixed, paraffin embedded material for HER-2/neu amplification. The results from this study also confirm that overexpression of HER-2/neu rarely occurs in the absence of gene amplification in breast cancer (approximately 3% of cases). This method of analysis is rapid, reproducible and extremely reliable in detecting presence of HER-2/neu gene amplification and should have clinical utility. PMID- 8700556 TI - Neurofibromatosis 2 antisense oligodeoxynucleotides induce reversible inhibition of schwannomin synthesis and cell adhesion in STS26T and T98G cells. AB - Mutations in the neurofibromatosis 2 (NF2) gene are the predominant cause in the development of sporadic schwannomas and are also involved in the pathogenesis of meningiomas and ependymomas. The product of the NF2 gene, termed merlin or schwannomin, is thought to act as a tumor suppressor protein. Although its protein sequence shows homology to proteins that are known to link the cytoskeleton to the cell membrane, no direct evidence for this function has been obtained. We used antisense phosphorothioate oligodeoxynucleotides (pODNs) complementary to the human NF2 cDNA sequence and transfected them into Schwann like STS26T cells permeabilized by streptolysin 0. Changes in cell morphology and attachment were observed at 12 to 24 h and continued up to 48 h post transfection. Cells were rounded and easily dislodged from the substratum at 12 24 h. These changes were reversible and cells became bipolar with thin protrusions and began to reattach to the substratum after 48 h. Normal morphology and adhesion were observed at 72 h post transfection. Morphological changes were due to suppression of schwannomin synthesis. Immunoprecipitations with antischwannomin antibodies showed schwannomin to be almost absent 3 h after treatment with antisense pODNs and to be significantly suppressed up to 12 h post transfection whereas beta-actin levels remained unchanged. The morphological changes were not the result of cell death, but resulted in increased cell proliferation. These data demonstrate that antisense oligonucleotides can be successfully employed to suppress schwannomin synthesis and indicate that schwannomin may belong to a class of tumor suppressor genes that provide a link between cell adhesion and tumorigenesis. PMID- 8700557 TI - Transformational and altered signal transduction by a naturally occurring mutant EGF receptor. AB - An amino-truncated variant form of the epidermal growth factor receptor (EGFRvIII) has been identified in human brain, breast, lung and ovarian tumors. We have found that overexpression of this mutant EGF receptor in NIH3T3 cells results in transformation as a result of the activation of the receptor kinase via ligand-independent dimerization. Transformation was correlated with tyrosine phosphorylation of only a subset of the proteins observed in cells overexpressing the normal EGF receptor. This suggested that further studies on cells expressing the EGFRvIII might provide insights into the pathways most relevant to transformation. In clones expressing high levels of mutant EGF receptor, the levels of both Grb2 and SHC were decreased. Despite this decrease, much of the endogenous Grb2 immunoprecipitated with EGFRvIII. Interestingly, no increase in ras-GTP loading was found in clones expressing the EGFRvIII and MAP kinase assays indicated only a small increase in activity. These results indicate that high level expression of the EGFRvIII induces down-regulation of the ras-MAP kinase pathway and that other components involved in EGF receptor signal transduction may play a greater role in neoplastic transformation by the EGFRvIII. PMID- 8700558 TI - HST-1/FGF-4 stimulates proliferation of megakaryocyte progenitors synergistically and promotes megakaryocyte maturation. AB - Megakaryocyte (MK) development is dependent on the complex interaction of MK progenitors, various cytokines and stromal elements. We previously reported that an injection of replication-deficient adenovirus containing HST-1/FGF-4 cDNA (Adex1HST-1) into mice caused a twofold increase in peripheral platelet count for 30 days without any other hematological or histological abnormality. In the present study using Adex1HST-1-infected human megakaryocytic Dami cells, we demonstrated for the first time that HST-1/FGF-4 promoted MK maturation, inducing increases in DNA ploidy, cytoplasmic and membrane maturation, and platelet-like particle release. Moreover, HST-1/FGF-4 acted on megakaryocytic cells to induce secretion of IL-6 and TNF-alpha, and increased adhesion of megakaryocytic cells to human endothelial cells primarily via VLA-4 and LFA-1 molecules; both mechanisms have been shown to lead to MK maturation. We also showed that HST 1/FGF-4 stimulates the proliferation of MK progenitors not alone but synergistically with IL-3 via IL-6 and with c-mpl ligand (thrombopoietin) not via IL-6. This result supports the hypothesis of the presence of two distinct populations of MK progenitors: IL-3-dependent and Tpo-dependent. All these results suggest that HST-1/FGF-4 can regulate MK development not only as an MK potentiating factor, but also as an inducer of cytokine secretion from MK, and as a modulator of adhesive interactions with endothelial cells. PMID- 8700560 TI - Nurses are a political force. PMID- 8700559 TI - The identification of osteopontin as a metastasis-related gene product in a rodent mammary tumour model. AB - The rat mammary epithelial cell line, Rama 37, yields benign, non-metastasizing adenomatous tumours in syngeneic Furth-Wistar rats. Transfection of this stably diploid cell line with genomic DNA fragments from a human metastasizing breast cancer cell line yields cells which, when injected subcutaneously in syngeneic rats, give rise to secondary tumours in a number of the animals. From one such secondary lung tumour, a cell line was established designated Ca2-5-LT1. This cell line, when introduced into the syngeneic rat host, also showed the ability to metastasise. To determine key changes in gene expression that occur during the progression from Rama 37, the benign tumour-inducing cell line, to the metastatic derivative Ca2-5-LT1, a general method of subtractive hybridization has been employed. This procedure in conjunction with Northern blotting and nucleic acid sequencing has been used to identify mRNAs expressed differentially between the metastatic and nonmetastatic cell lines described above. So far, of the subtracted cDNAs that have been identified which represent differentially expressed mRNAs, a large proportion of these cDNAs corresponded to the mRNA for rat osteopontin (OPN). The mRNA for OPN was expressed at a ninefold higher level in the metastatic Ca2-5-LT1 cell line when compared to the nonmetastatic parental Rama 37 cell line. Rama 37 cells transfected with DNA from a human benign cell line failed to show elevated levels of OPN mRNA. Following transfection of Rama 37 cells with an expression-construct producing elevated levels of OPN, the newly transfected cells, when introduced into the rat host, developed metastases in 55% of the animals that produced primary tumours. These experiments show that increasing the expression of OPN in a previously benign cell tine is sufficient to produce a metastatic phenotype in this particular rat mammary model. PMID- 8700562 TI - Choosing the right resume format. PMID- 8700561 TI - Nursing museum connects past, present, future. PMID- 8700563 TI - Transfer techniques of the lower extremity with an external fixator. AB - This article describes the uses of external fixation for lower extremity problems and addresses some issues related to the correct way to lift an extremity with an external fixator. The differences in opinions between nurses and among physicians is discussed, followed by suggestions for solving this confusion within the settings in which people work. The article then pictorially demonstrates how to lift an extremity with an external fixator. It proceeds through a series of photographs depicting how to transfer a patient into a chair by supporting the extremity, and again by supporting the external fixator itself. PMID- 8700564 TI - Developing continuing education for contact hour approval. AB - Developing quality nursing continuing education for contact hour approval requires a basic understanding of the nursing continuing education system and the application process. The Regional Education Approver Unit (REAU) of the National Association of Orthopaedic Nurses (NAON) helps providers (i.e., members, chapters, corporate members) develop educational activities and grants contact hour approval. This article reviews terminology used in nursing continuing education and the application process for contact hour approval through NAON. PMID- 8700565 TI - Steroids: a breakfast of young champions. AB - Anabolic-androgenic steroids (AAS) may, unfortunately, be the breakfast of some youngsters aspiring to become champions. Awareness of this problem by health care providers is important so youngsters tempted to take, or taking, AAS may be identified and counseled. PMID- 8700566 TI - Telephone triage of upper extremity problems. PMID- 8700567 TI - Tears of the rotator cuff. AB - Pain and loss of motion, the results of rotator cuff tears, can be disabling. Initially, treatment is conservative, but surgical repair may be indicated after failed nonoperative management. Rotator cuff anatomy is reviewed in this article as well as clinical and radiographic assessment of the patient with presumed rotator cuff pathology. Nonoperative and surgical treatment strategies are outlined. The rate of motion and functional recovery after repair is presented on the basis of a prospective study. Although most patients are able to perform work and daily activities 3 months after surgery, motion recovery can continue for at least a year. PMID- 8700568 TI - Managed care and the nurse's ethical obligations to patients. AB - The goal of managed care is to control health care costs by such means as keeping people healthy and decreasing the length of hospital stays. This change in health care delivery has resulted in work redesign programs, lay-offs, cross-training, and the use of an increasing number of nonprofessional care providers. The challenge for nursing, as a result of these changes, is how to fulfill its obligations of fidelity and due care. The authors discuss these ethical responsibilities and the impact that managed care is having on the fiduciary relationship between nurse and patient. Four strategies that nurses can use to fulfill their obligations include engaging in personal reflection, communicating and collaborating, protecting patient's rights, and evaluating patient outcomes. PMID- 8700569 TI - Models of care using unlicensed assistive personnel. Part II: Perceived effectiveness. AB - This article describes the results of a NAON-funded descriptive design research project developed to gather data on how clinical nursing assistants are being used in the practice setting by examining the role responsibilities, extent of delegation, training effectiveness, and evaluation measures designed by agencies to evaluate the effectiveness of this model of care. Fifty-three hospitals from 31 states participated in the investigation, with 53 nurses managers, 620 staff nurses, and 305 nursing assistants responding to questionnaires. Overall results indicated that models of care using unlicensed assistive personnel are not working. Primary impediments were identified as lack of role clarity, ineffective educational preparation of nursing assistants, ineffective educational preparation of staff nurses, lack of an adequate infrastructure to support the model, and lack of evaluation systems. PMID- 8700570 TI - Jones Fracture. Lisfranc Fracture. PMID- 8700571 TI - Highway safety and the 104th Congress. PMID- 8700572 TI - From the president: networking. PMID- 8700573 TI - Complications of trauma: the nurse's role in prevention. AB - Trauma is the leading cause of death in the United States for persons less than 40 years of age. It is the fourth leading cause of death in persons of all ages. Over 60 million injuries occur annually, therefore multiply injured patients represent a large portion of hospital admissions (Cordona, Hurd, Mason, et al., 1994; Geerts, Code, Jay, et al., 1994) Due to the complexity of patient care, and the potential for complications, nurses caring for these patients must be knowledgeable of their role in the patient's management and recovery. The following case scenario represents a typical multiply-injured patient and discusses common potential complications and how the nurse can intervene to prevent these complications from occurring. PMID- 8700574 TI - Anterior cruciate ligament reconstruction as an outpatient procedure. AB - With the demands of insurance companies and the need for cost containment, more and more surgeons are performing the anterior cruciate ligament reconstruction (ACL) procedure on an outpatient basis. The shorter hospital stay has increased the demands of nurses to provide appropriate nursing care, while also meeting the educational needs of patients receiving an ACL reconstruction as an outpatient. This article reviews the preoperative, intraoperative, and the postoperative phases of the care for patients undergoing anterior cruciate ligament reconstruction on an outpatient basis. It also emphasizes the role of the nurse in assessing, implementing, and coordinating care for patients having an ACL reconstruction. PMID- 8700575 TI - Bosworth fracture. Shephered fracture. PMID- 8700576 TI - Basic tools for the orthopaedic staff nurse. Part I: Assertiveness. AB - Organizational restructuring and expanded settings of health care delivery provide opportunities for the orthopaedic staff nurse to review basic communication tools that are useful with clients and families, managers, and other health care providers. It is critical for the staff nurse to build a repertoire of skills that support leadership and encourage enlightened followers. This two-part article addresses assertiveness, conflict management, and negotiation skills that are basic to providing professional care with confidence and competence in a changing health care environment. PMID- 8700577 TI - Cervical spondylosis: diagnosis, symptomatology, and treatment. AB - This article reviews in detail cervical anatomy and pathophysiology. It then details appropriate workup including x-rays and other diagnostic studies. It concludes with a brief description on nonoperative and operative management. PMID- 8700578 TI - Promoting normalcy in chronically ill children. AB - Chronic orthopaedic conditions or orthopaedic conditions associated with other chronic conditions affect an estimated 150,000 children in the United States. The ultimate cost in human and financial resources depends upon the success of habilitation efforts throughout childhood. This article identifies major areas of concern to the continuing care of the child and family who must cope with chronic problems and proposes nursing approaches to resolve them. PMID- 8700579 TI - Factors influencing postoperative urinary retention following orthopaedic surgical procedures. AB - This study was designed to identify factors contributing to postoperative urinary retention in patients undergoing hip and knee replacements and reconstructive surgeries. The clinical literature links post-operative urinary retention to various factors including a history of postoperative urinary problems, advanced age, the total amount of fluid replacement over a 24-hour postoperative period, type of anesthesia, pain management medications, and the route and length of medication administration. PMID- 8700580 TI - What is a t-test? PMID- 8700581 TI - Orientation to the orthopaedic operating room. Chapter 7: Shoulder. PMID- 8700582 TI - The ROBODOC clinical trial: a robotic assistant for total hip arthroplasty. AB - Operating room teams at three U.S. hospitals are participating in a controlled clinical trial to evaluate the use of a surgical robot in total hip arthroplasty. The robot, called the ROBODOC Surgical Assistant System, precisely prepares the femoral canal for the placement of a "press fit" cementless prosthesis. The Food and Drug Administration (FDA) requires that the robot, as an investigational device, be tested in a controlled clinical trial to demonstrate safety and efficacy. The clinical trial will include 300 patients who must meet specific criteria before enrollment and randomization. This article describes the need for new surgical technology, ROBODOC's development history, hardware and software components of the system, the patient population and surgical protocol for the clinical trial, special nursing care requirements, and considerations for patient rehabilitation. PMID- 8700583 TI - [Change in lipid composition and lipid peroxidation rate in brain tissue under conditions of thymic hormone deficiency]. AB - Experiments on mature male rats have shown that 3 and 6 months after removal of the brain thymus, the level of total lipids in all cell centrifugate fractions (homogenate, supramitochondrial and mitochondrial fractions), which was followed by the higher rate of lipid peroxidation and the lower activity of cellular compartments, the spectrum imbalance of lipid fractions with predominant increases in the levels of phospholipids and free cholesterol. It is suggested that these changes make a contribution to the dysfunction of brain structures and participate in regulatory processes in thymectomy. PMID- 8700584 TI - [Effect of essentiale on the cardioprotective action of anapriline, nitroglycerin and their combinations in acute total myocardial ischemia]. AB - The pattern of changes in myocardial energy metabolism and antioxidative enzyme activities was examined in acute total myocardial ischemia treated with anapriline, nitroglycerin, and essentiale. There was an increase and prolongation of the metabolic effects and activity of antianginal agents along with the animal saturation with polyunsaturated phospholipids. In early and late acute total myocardial ischemia, the most pronounced effect was observed during administration of a combination of anapriline, nitroglycerin, and essentiale. PMID- 8700585 TI - [Immunomodulating action of essentiale during prolonged intake of dietary cholesterol]. AB - Light red blood cells from the rabbits on cholesterol diet were found to have immunosuppressing properties. The extracorporeal treatment of red blood cells with essentiale, heavy erythrocytes acquired immunostimulating properties. Light red blood cells lost their immunosuppressive capacity. The administration of linetol caused no changes in the immunomodulating properties of red blood cells from the rabbits taking cholesterol for a long time. PMID- 8700586 TI - [Immunomodulating action of hyaluronic acid and its hydrolysis products in health and in Staphylococcus infection]. AB - Potassium hyaluronate was found to suppress the development of a humoral response and delayed hypersensitivity, while hyaluronidase and the incubate of potassium hyaluronate and hyaluronidase enhanced the manifestations of the humoral response and delayed hypersensitivity. The suppressive effect of potassium hyaluronate was mediated by light erythrocytes, whereas the stimulating effect of hyaluronidase the incubates of potassium hyaluronate and hyaluronidase was mediated by heavy erythrocytes. In Staphylococcus infection, hyaluronidase and the incubates of potassium hyaluronate and hyaluronidase enhanced the development of a humoral response and failed to affect the manifestations of delayed hypersensitivity. PMID- 8700587 TI - [Interrelationship between splenocyte immunomodulating factors in animals undergoing combined exposure to ethanol and tetrachloromethane]. AB - On concomitant exposure to ethanol and tetrachloromethane, the nature and direction of a humoral immune response depend on the accumulation of immunosuppressive and immunostimulating factors of splenocytes. The accumulation of either factors is most likely to be in turn regulated by negative feedback systems, which should be borne in mind in applying immunocorrective therapy. PMID- 8700588 TI - [Development of immunosuppression and its correction with cell membrane stabilizers in burn trauma]. AB - Degree IIIB burn suppresses the development of an immune response to T-dependent antigen. Following burn, substances having immunosuppressive active and inducing the emergence of suppressive properties in light erythrocytes occur in blood. Essentiale, alpha-tocopherol acetate and lidocaine enhance the development of an immune response to T-dependent antigen in burn injury. The administration of the drugs reduced the immunosuppressive activity of the sera from the burnt animals. Essentiale attenuated the immunosuppressive properties of red blood cells, while alpha-tocopherol acetate and lidocaine abolished them. Essentiale induced the occurrence of immunostimulating properties in heavy red blood cells from the burnt animals while alpha-tocopherol acetate and lidocaine enhanced the resistance of light erythrocytes to the burnt rat serum compounds that induced the emergence of immunosuppressive properties in the animals. PMID- 8700589 TI - [Effectiveness of the use of synthetic opioid peptide in rats with traumatic shock]. AB - Experiments were conducted on 80 male Wistar rats. Traumatic shock was simulated by applying clamps to lower extremity soft tissue for 6 hours. After removing the clamps, experimental animals were intraperitoneally injected the synthetic leucine-enkephalin dalargin. The blood ionogram, the levels of urea, glucose, phosphorus, creatinine, lactic and pyruvic acids, blood plasma osmolarity, LDH activity were determined. In the animals untreated with dalargin, plasma concentrations of ions of potassium, phosphorus, creatinine, urea, osmolarity, LDH activity increased and the levels of glucose decreased when shock developed. At the same time the rat death rates were 70-80% 24 hours later. The administration of dalargin corrected the majority of the above-mentioned parameters and the death rates were decreased to 20%. It is concluded that dalargin has an early antishock effect. PMID- 8700590 TI - [Effect of resection of the proximal part of the small intestine on inhibition of gastric secretion as affected by pituitrin, gastrozepin and histodil]. AB - Semichronic experiments on rats with gastric fistula have revealed that the resection of the proximal third of the small intestine results in impairments of the gastric secretion inhibition induced by gastrozepin or histodil blockade of M choline- and H2-receptors. At the same time the operation has no noticeable impact on the gastric secretion inhibition caused by pituitrin (vasopressin) on V1-receptors. The difference found is accounted for by a relative specialization of the enterogastric influences that regulate the sensitivity of gastric secretory mechanisms to inhibitory signals. PMID- 8700591 TI - [Role of stress-limiting systems in the pathogenesis of stress-induced myocardial damage]. AB - The role of GABAergic and serotoninergic system (stress-limiting systems) in the changes occurring in the activity of blood and myocardial pro- and antioxidative systems, as well as in stress-induced cardiac structure damages was studied in 103 rabbits by using a model of long-term emotional stress induced by 24-hour hour electrostimulation of the hypothalamic dorsomedial nucleus during 12 days. The experiment alternated with relaxations of the same duration. A total of 5 sessions were conducted within 120 days. During early emotional stress, the increased activity of the hypothalamic stress-limiting systems was demonstrated to be followed by higher lipid peroxidation rates along with the activation of antioxidative enzymes. From electrostimulation cycle 3, there was exhaustion of the functional activity of the stress-limiting systems, followed by intensive increases in blood and myocardial primary and secondary lipid peroxidation products. After termination of the investigation, myocardial necrotic and ischemic changes were detected in all the animals. PMID- 8700592 TI - [Age-related features of inflammatory and immune responses of the gastric mucosa in women with chronic gastritis]. AB - The paper presents the results of studies of the specific features of an inflammatory reaction of the mucosa in the gastric body and antrum in chronic gastritis associated with Helicobacter pylori (HP) in females of reproductive age and in menopause. In the gastric body, there were prevalent chronic inflammatory processes with developed mononuclear infiltration in reproductive females whereas there were predominant elements of exudative and destructive inflammation in older females. The antral mucosa of young females showed predominantly destructive changes. The magnitude of HP seeding in the superficial and fossular mucosa was much higher both in the fundum and antrum in menopausal than reproductive females. There was great differences in the nature of inflammatory and immune reactions in either females with HP-associated chronic gastritis. PMID- 8700593 TI - [Enzymatic activity of the pancreas and small intestinal mucosa in modelling of toxic hepatitis by administration of heliotrine]. AB - The activity of pancreatic (alpha-amylase, protease, and lipase) and enteral (maltase, glycyl-L-leucine dipeptidase, monoglyceride lipase) was studied in the experiments on adult male Wistar rats weighting 350 +/- 35 g 1-3, 7, 10, 30, 60, and 90 days after injection of a single dose of 25 mg per 100 g body weight. Acute heliotrine intoxication (in a toxic hepatitis model) was shown to lead to a marked decrease in the activities of both pancreatic and intestinal enzymes. It is suggested that the changes may be associated with the direct action of heliotrine on the pancreas and small intestinal mucosa or with hepatic failure. PMID- 8700594 TI - [Dynamics of biliary prostaglandin secretion in patients with dyskinesia of the biliary tracts]. AB - The time course of biliary secretion of prostaglandins (PG)E1 and F2 alpha was studied in 20 patients with primary dysfunctions in the cholepoietic system. The studies indicated that baseline high PGE1 levels and slow increases in PGF2 alpha during vesical reflex might be one of the factors predisposing to biliary hypokinesia. In patients with Oddi's sphincter spasms, the period of active PGE1 synthesis coincides with that of sphincter spasm. It is suggest that the latter is due to PGE1-induced muscle spasm of the duodenum whose fibers are an integral part of the intricate muscle system of Oddi's sphincter. In Oddi's sphincter spasm concurrent with biliary dyskinesia, the curve of PGF2 alpha virtually little differs from that in Oddi's sphincter spasm alone. PGE1 increases at the closed sphincter stage in the same way as that elevates in isolated sphincter spasm, but in patients with biliary hypokinesia contaminant with Oddi's sphincter spasm PGE1 shows its concentration in the vesical reflex phase, which appears to result in biliary hypokinesia. PGE1 and PGF2 alpha imbalance is one of the links in the pathogenesis of biliary dyskinesia. PMID- 8700595 TI - [Elimination of asialoorosomucoid and its catabolism in liver of rats with toxic CCl4-induced cirrhosis]. AB - Human 125I-acyaloorosomucoid was intravenously injected to male Wistar rats. Hepatic cirrhosis was induced by oily CCl4 solution (0.04 ml toxin per 100 g body weight, twice a week for 2 months). Cirrhosis was found not to prevent blood elimination of 125I-acyaloorosomucoid (t1/2 = 2.53 versus 2.50 in the control). Ten minutes after injection, there was 75.2% of the administered radioactive dose in the liver versus 77.1% in the control. The 60-minute hepatic elimination of substrate in rats with cirrhosis was even more intensive than in the control animals, which is in agreement with the high levels of acid-soluble radioactivity (for 10 minutes). By large, CCl4-induced hepatic cirrhosis did not lead to disturbances of the hepatocytic function aimed at endocytosis and catabolism of acyaloorosomucoid. PMID- 8700596 TI - [Acute renal insufficiency in rats in compensatory renal hypertrophy]. AB - Sodium bichromate and glycerol were administered to compare the course of acute renal failure in uninephrectomized rats and rats with two kidneys. The blood serum levels of creatinine, urea, sodium, potassium and osmotically active agents were found to be rather similar in the rats with one and two rats two days after the administration of nephrotic compounds. The concentration of electrolytes in the renal cortex and papilla of these animal groups. It is concluded that acute renal failure caused by glycerol and bichromate runs virtually similarly both in animals with one and two kidneys. Thus, in emergency, such as acute renal failure, the compensatorily hypertrophied kidney ensures the same elimination of nitrogen metabolic-waste products and maintains the electrolytic composition of the internal environment as in the animals with two working kidneys. PMID- 8700597 TI - [Effect of induction of enzymes of the cytochrome p-450 system on the survival of rats after acute hemorrhage]. AB - The effect of acute hemorrhage on the functional status of microsomal cytochrome P-450-dependent hepatic monoxygenases and the impact of induction of these monoxygenases on the survival of posthemorrhagic male Wistar rats. Acute blood loss of the rats, which caused 50% deaths led approximately to a double decrease in the hepatic activity of 77-ethoxycoumarin-O-deethylase (ECOD). Induction of hepatic monoxygenases by phenobarbital in a dose of 80 mg/kg for 3 days, which caused a 2.4-fold increase in the activity of ECOD as compared with the controls, prolonged the survival rate of posthemorrhagic rats from 50 to 85%. PMID- 8700598 TI - [Effect of dalargin on healing of a bullet wound of the soft tissues in rabbits]. AB - Reparative processes were studied by using an experimental model based on a bullet wound in the rabbit's leg soft tissue. The effect of dalargin (10 mg/kg for a 14-day course) was shown in its reducing posttraumatic edema, hemorrhages, and tissue inflammation, as well as conductive demarcation of necrosis. Dalargin was found to stimulate the proliferation of epidermal cells, the formation and transformation of granulations. With the peptide, the phagocytic functions of neutrophils were restored and hyperfermentemia was reduced. The findings suggest that dalargin is a promising agent in stimulating the reparative processes in the gun-shot wound. PMID- 8700600 TI - [Level of double bonds in lipids in human plasma and erythrocytes]. AB - The unsaturation of plasma and red blood cell lipids and their total content of blood were determined in 212 donors. There was a significant individual variability of double binds in human blood lipids. A correlation was found between the magnitude of lipid unsaturation and the total blood lipid levels. The levels of double binds and total lipids did not depend upon the donors' sex and age. There were seasonal variations in the levels of double binds and lipid in plasma and red blood cells. PMID- 8700599 TI - [Lipid peroxidation and protein glycosylation in the aorta of rabbits with alloxan diabetes during insulin correction]. AB - The pathogenesis of angiopathic complications was studied in rabbits with alloxan diabetes treated with insulin. The latter was found to affect lipid peroxidation, while the levels of glycosylated proteins remained increased in the aortic wall and red blood cells. It is concluded that enhanced nonenzymatic protein glycosylation in a patient with diabetes mellitus may be one of the factors predisposing to angiopathic complications in diabetes mellitus, irrespective of insulin therapy. PMID- 8700602 TI - Pediatric nursing--not "med-surg" nursing on little people. PMID- 8700601 TI - Approaching the RSV season with a nursing plan of action. AB - As the statistics show with year-in, year-out regularity, during November through March in the United States, approximately 90,000 infants and young children will be hospitalized with a severe lower respiratory infection attributable to the respiratory syncytial virus (RSV). This virus, discovered only as recently as 1956, appears to be ubiquitous, infecting virtually 100% of children by age 4. For most of them the resulting illness will be mild and easily vanquished by an intact immune system. For some, however, RSV infection confers considerable morbidity, and these infants and children are the concern of the symposium held in conjunction with Pediatric Nursing's 11th annual conference. The symposium addressed several aspects of RSV infection: Who is at risk and should be hospitalized? How can nurses contribute to the care of hospitalized patients? Are there environmental risks to health-care personnel from ribavirin aerosol, the antiviral treatment approved for RSV infection? Are there special considerations for mechanically ventilated patients? Speakers generally concluded that symptomatic treatment and antiviral therapy with ribavirin aerosol can reduce severe morbidity in severely infected patients with minimal occupation risk to health-care personnel. PMID- 8700603 TI - Chronic renal disease: the mother's experience. AB - In a qualitative study, mothers (N = 4) of children with chronic renal disease were asked to share the meaning they assigned to their child's illness. The central theme of "uncertainty" emerged from the data and was described in three phases: (a) finding out, (b) learning to live with chronic illness, and (c) worries and dreams about the future. In this article phase three, labeled "learning to live with chronic illness," is presented. PMID- 8700604 TI - Therapeutic effects of music and mother's voice on premature infants. AB - Aversive environment auditory stimuli is a common concern in neonatal intensive care. Recently, interest has developed regarding the use of music applications to mask such stimuli and to reduce the high risk for complications or failure to thrive. In this study of 20 oxygenated, low birth weight infants in a Newborn Intensive Care Unit of a regional medical center in the Southeastern United States, 10 infants listened to lullabies and 10 infants to recordings of their mother's voice through earphones for 20 minutes across three consecutive days. Oxygen saturation levels and frequency of oximeter alarms were recorded. Results indicated a differential response to the two auditory stimuli as listening time progressed. On Day 1, the infants listening to music had significantly higher oxygen saturation levels, but these effects disappeared by Days 2 and 3. On Days 2 and 3, however, the babies hearing music had significantly depressed oxygen saturation levels during the posttest intervals after the music was terminated. Infants hearing music had significantly fewer occurrences of Oximeter alarms during auditory stimuli than did those listening to the mothers' voice. Implications for the therapeutic use of auditory stimuli in the Newborn Intensive Care Unit are discussed. PMID- 8700605 TI - Baby bottle tooth decay: a concern for all mothers. AB - Health care professionals often inappropriately separate dental health from other health functions. Baby bottle tooth decay (BBTD) should be a concern for all professionals who work with expectant or new mothers and very young children. Research indicates that even though many mothers are aware of the etiology of the condition, they continue to allow prolonged nursing with milk or liquids other than water. Nurses can help promote good oral health for children by educating and training expectant and new mothers, children, and others who work with mothers and children in preventing BBTD. PMID- 8700606 TI - Living related liver transplantation (LRLT) in children: focus on issues. AB - Living-related liver transplantation (LRLT) aims to reduce the mortality of children with end-stage of liver disease who could possibly die while waiting for a cadaver organ. While there are many advantages of LRLT for potential candidates, there are clearly also numerous psychosocial and ethical concerns for those individuals undergoing these procedures. Families struggle with the decision and care involved with these children who may be quite ill. Careful consideration for both the LRLT recipients and their families is needed. PMID- 8700607 TI - Nurses in early intervention. AB - The number of children from ages birth to 3 in need of early intervention services has increased over the past decades. A family-centered approach to early intervention services is essential. The family-centered approach emerged from early intervention philosophy developed by professionals in response to the needs of children and families. The historical perspective of early intervention and family-centered care, the role of nurses in early intervention and suggested focus of future research are outlined. PMID- 8700608 TI - Indoor environmental allergy: a guide to environmental controls. AB - Indoor environmental allergy is a significant problem in the pediatric population. Allergen exposure is a major risk factor for the development of asthma. Avoidance is one approach to allergy management and asthma prevention. Environmental controls are a series of allergen avoidance measures to decrease exposure to allergens. PMID- 8700609 TI - Standards and guidelines for pediatric prelicensure nursing education published. PMID- 8700610 TI - Alternative methods for newborn urine sample collection. AB - PURPOSE: To investigate the accuracy of laboratory results of urine samples collected from cotton balls as compared with paired samples collected from catheterization, Preemie Pampers, and Newborn Pampers. METHOD: Urine samples were collected from 30 infants by aspirating urine from a cotton ball placed over the meatus. An additional urine sample was obtained from the same infants by aspiration from the diaper. The samples were tested by labstik analysis and results were compared by t-test. An additional sample of 20 infants had urine collected by cotton ball and catheterization for detection of Group B strep antigen and the results were correlated. FINDINGS: Samples obtained from cotton balls and Preemie Pampers yielded equivalent results. Significant differences were found in the pH and specific gravity of Newborn Pampers and Preemie Pampers. No redness nor skin breakdown was observed with the cotton ball application. Three positive Group B strep results were detected by both methods of urine collection. The remainder of the samples were negative by both methods. CONCLUSIONS: Urine samples collected by the cotton ball method were accurate for pH and specific gravity and were atraumatic to the skin of newborns. The sample size of positive Group B strep antigen was small (n = 3) and results should be replicated with further research. PMID- 8700611 TI - Republican budget proposal: a budget that hurts children? Let the reader decide! PMID- 8700612 TI - Parent education for mothers in prison. AB - The over 26,700 mothers in U.S. prisons are a nursing concern. Incarceration disrupts families and affects mothers, children, and caregivers alike. Outcomes of prison parenting programs include improved self-esteem, behavioral expectations, empathy, discipline, family roles, relationships, and a commitment to avoid substance abuse and reincarceration, all beneficial to families and society. Nurses can voice support for prison policies that support the mother child relationship and can help to meet the needs both of children whose mothers are incarcerated and women who were previously incarcerated. PMID- 8700613 TI - Adolescent tattoos: educating vs. pontificating. AB - Tattooing is a contemporary teen issue and a flourishing risk-taking behavior, whether the tattoos are amateur markings or studio designs. In order to assist teen clients, nurses in primary health settings need to focus on two important tasks. First, they must examine their own feelings toward tattooed adolescents before they take on the second task, the essential role of health education. Health education is important to assist adolescents become informed decision makers about tattooing. PMID- 8700614 TI - Tuberculosis and multi-drug resistant tuberculosis in children. AB - Infection and disease caused by Mycobacterium tuberculosis remain a hugh global problem, and are not well controlled in several areas within the United States. Co-infection with the human immunodeficiency virus (HIV) and immigration from areas with high rates of tuberculosis contribute to the problem in the United States. Organisms resistant to the two main drugs, isoniazid and rifampin, known as multidrug-resistant M. tuberculosis or MDR-TB, present serious therapeutic challenges. Strategies for the management of such cases are presented. PMID- 8700615 TI - Developing a competency-based curriculum for tracheostomy and ventilator care. AB - Advances in technology and medical practice have enabled children with special health needs, such as tracheostomy and ventilator care, to be discharged to their families while continuing to require specialized care. Yet, corresponding increases in the availability and competence of home care providers have not kept pace with this trend. The authors set a goal to design, develop, implement, validate, and disseminate a competency-based curriculum to prepare adults to care for these children in the home and community. This article is Part 1 of a two part series. PMID- 8700616 TI - Pediatric management problems: a significant head injury. PMID- 8700617 TI - Are there circumstances that justify deceitful placebo use? PMID- 8700618 TI - Are there circumstances that justify deceitful placebo use? PMID- 8700619 TI - The Internet and pediatric nursing: guide to the information superhighway. AB - Today's health care providers are learning the technologies available on the Internet and Worldwide Web and becoming more proficient at accessing information. Pediatric nurses are at a point where they, too, need to be able to use the information technologies that are available to them. The Internet contains resources such as directories, on-line medical and nursing texts, graphics and databases that are invaluable to nurses and all health professionals. PMID- 8700620 TI - Computerized approaches to teaching nurse practitioner students. AB - Personal computer in clinical and educational environments have proliferated and offer users new opportunities for individualized learning. Computerized patient management problems are an innovative resource for the teaching clinical content and problem-solving skills. This article describes two computerized applications and highlights one such personal computer program, NP Clinic, which was designed for use with pediatric and family nurse practitioner students. NP Clinic software is also suitable for providing continuing education to nurses in primary care settings. A discussion of the advantages and disadvantages of computer-assisted instruction is included along with ideas for effective implementation of this learning strategy. PMID- 8700621 TI - What are blood counts? A computer-assisted program for pediatric patients. AB - The diagnosis of cancer in a child leaves the parents and child faced with a life threatening illness in addition to the need to learn about how the illness will impact their lives. Education about the disease process, treatment regimen, and possible side effects of therapy must occur. The educational process, often consisting of didactic teaching sessions, often does not lend itself well to the individual learning needs of the child. A more individualized and developmentally appropriate method of educating children was developed, consisting of the development of a computer-assisted instructional (CAI) program on blood counts. PMID- 8700622 TI - Attention deficit hyperactivity disorder. AB - Attention Deficit Hyperactivity Disorder is found in a significant number of children. The symptoms of the disorder can cause problems in learning, socialization, and behavior for those individuals afflicted with it and put them at high risk for serious psychopathology in adulthood. This article describes the causes, neurobiology, symptoms, and treatment for ADHD and the pediatric nurse's role in identification, referral, and symptom management of this disorder. PMID- 8700623 TI - Imagine the possibilities! Guided imagery with toddlers and pre-schoolers. AB - Guided imagery, a form of relaxed, focused concentration is a natural and powerful coping mechanism. Easily learned, guided imagery can be used as an adjunct to the care of toddlers and preschool children who are experiencing anxiety and pain. The nurse must first prepare him/herself, the parent, and the child for the experience. Techniques of joining, leading, pacing, and word choice facilitate the process, informed by an understanding of child development. This low tech, cost-effective intervention can promote children's personal coping abilities and increase their sense of self-esteem. PMID- 8700624 TI - Genome research: implications for children. AB - New discoveries from genetic research may benefit children through increased knowledge of genetic causes of diseases, and new methods of diagnosis and treatment including presymptomatic diagnoses, carrier diagnoses, and gene therapy. However, these discoveries are also creating ethical, legal, and social dilemmas regarding children's health. Inaccurate interpretation of carrier test results, a limited understanding of implications of genetic information, emotional implications of testing, and potential insurance denials are examples. Ways in which pediatric nurses will apply knowledge of genome research in their practice include: education, counseling, advocacy, clarification of values and feelings, and referral for information, support, and assistance. PMID- 8700625 TI - Part 2: using a competency-based curriculum to train experienced nurses in ventilator care. AB - As pediatric nurses, we are caring for increasing numbers of children with special health needs such as tracheostomy and ventilator care. These children are being discharged to their families requiring specialized care, including in-home skilled nursing services. In Part I of this two-part series, the authors described the development of a training curriculum for nurses caring for ventilator-assisted children at home. The next step was to validate that the curriculum was effective, feasible, and replicable. Part 2 describes the initial validation efforts with hospital and home care nurses. PMID- 8700626 TI - Pediatric management problems: orbital cellulitis. PMID- 8700627 TI - "Mastering uncertainty:" mothering the child with asthma. AB - PURPOSE: To describe the meaning childhood asthma has for mothers of afflicted children. METHOD: The qualitative method, ethnography, was used in this study. Participant observation and indepth interviewing took place in the homes of the participants. Using a method adapted from Spradley (1979), the analysis included uncovering domains, taxonomies, components of meaning, and finally cultural themes. FINDINGS: The overall theme that emerged was "mastering uncertainty." The mothers expressed their experiences in terms of self by describing "internal self" and "actions" during a "passage of time." CONCLUSIONS: These themes can assist nurses and other health care professionals in understanding the meaning of childhood asthma to mothers. PMID- 8700628 TI - Parent Partners: a parent-to-parent support program in the NICU. Part 1: Program development. AB - Neonatal intensive care units (NICU) face the challenge of developing family centered systems of service delivery. An important component of family-centered care is parent-to-parent support. A parent-to-parent support program that meets the needs of both parents and staff can be successfully established in the NICU if the principles of planned change are used to guide the process of program development, implementation, and evaluation. PMID- 8700630 TI - Your PC can enhance staff and patient education. AB - Obtaining education materials for both staff and patients can be expensive. Tracking staff certification requirements and available references for individual units can be time consuming and awkward. Using a regular home personal computer and inexpensive software applications, the staff nurse, educator, and manager can produce quality education products, maintain records, and graph representation of administrative trends. PMID- 8700629 TI - The language of miracles: ethical challenges. AB - In the context of health care decision making, the language of miracles is expressed by both parents and professionals. Without mutual understanding of the meaning of miracles, parents and professionals may experience conflict about treatment goals. Understanding the dynamics of appeals to miracles, examining caregiver responses, and employing strategies to assess parental knowledge, understanding the meaning of miracles and faith, and allowing for hope are essential for respectful and mutual accommodation. PMID- 8700631 TI - Riding the technology surf or caught in a tidal wave? PMID- 8700632 TI - NPs and nurses must promote health maintenance examinations. PMID- 8700633 TI - Questions raised regarding double blind comparison research. PMID- 8700634 TI - Synopsis book. Best articles relevant to pediatric allergy and immunology. 1994 1995. PMID- 8700635 TI - Health systems: opportunities for nursing practice, education and research. PMID- 8700636 TI - Subacute care in New Jersey's hospitals. PMID- 8700637 TI - Nurses and pain. PMID- 8700638 TI - Chronic pain and insomnia focus of conference. PMID- 8700639 TI - Peer assistance: Department of Health grant focuses on needs of long term care facilities. PMID- 8700640 TI - [Public health science--an old field expanding rapidly]. PMID- 8700641 TI - [Atrial fibrillation and apoplexy--risks and prevention]. AB - The annual incidence of ischemic stroke among patients with chronic non-valvular atrial fibrillation is about 4.5 percent. In five controlled trials, oral anticoagulant therapy with warfarin reduced the annual incidence of stroke by 68 percent to 1.4 percent. The effect of aspirin has not been unequivocally determined. Aspirin reduced the annual risk of stroke by 18 percent (n.s.) in one trial, and by 44 percent in another, though the two trials differed both in mean age of the patients and in aspirin doses. Direct comparison of warfarin and aspirin revealed no difference in efficacy. Advanced age, previous stroke or transient ischemic attack (TIA), hypertension and diabetes were all found to be risk factors for stroke in patients with atrial fibrillation. In patients under 65 years of age without risk factors, the annual risk of stroke was 1 percent. After TIA or minor stroke, warfarin reduced the annual risk of a second stroke from 12 percent to 4 percent. Aspirin had no such effect. The annual incidence of major bleeding episodes was 0.2-2.0 percent in the warfarin-treated subgroup, 0.2 1.5 percent in the aspirin subgroup and 0-1.6 percent in the placebo subgroup. Based on findings in the above mentioned trials, warfarin (INR 2.0-3.0) is recommended for stroke prevention in patients over 60 years of age with non valvular atrial fibrillation. Trials are under way to ascertain whether conventional warfarin treatment can be replaced by less complicated and safer treatments in patients with chronic atrial fibrillation. PMID- 8700642 TI - [Man's own antibiotics--an innate immune system]. AB - In 1981, Steiner and co-workers of Stockholm described a newly discovered type of potent antibacterial peptides which lack cysteine, so called cecropins, which are spiral-formed molecules of 30-40 amino acids found to kill bacteria within a few minutes by disintegration of the bacterial cell wall, but to do no damage to the membrane of insect or mammalian cells. To date, descriptions have been published of about a hundred peptide antibiotics from various mammals (including man), birds, frogs, many types of insects. Peptide antibiotics exert a bacteriostatic effect on the normal flora of the skin and of the oral cavity and other orifices. It is also possible that peptide antibiotics protect us against many pathogenic organisms. PMID- 8700643 TI - [Creutzfeldt-Jakob disease--a human prion disease]. AB - The human prion diseases, Creutzfeldt-Jakob disease, Gerstmann-Stroaussler Scheinker syndrome and kuru, are neurodegenerative disorders sharing clinical features of rapidly progressive neurodegenerative dementia and cerebellar symptoms of marked ataxia and tremor, resulting in death within one year after onset. Similar diseases have been described in animals, such as scrapie in sheep and goats, and bovine spongiform encephalopathy in cattle (mad cow disease). The very long incubation period, the lack of a host immune response, and a neurological triad of spongiosis, astrocytosis and amyloid plaque formation have suggested these diseases to have a common aetiology. A highly effective transmissible agent, fundamentally different from viruses, has been identified and the term prion adopted to distinguish it from viruses and viroids. CJD is unique in occurring both in inherited, sporadic and acquired forms. PMID- 8700644 TI - [Confusional states in the elderly--an underdiagnosed syndrome with a poor prognosis]. AB - Confusion in the elderly, ie, delirium, is an organic mental disorder often associated with severe somatic disease. Approximately 20-60 per cent of elderly in-patients are afflicted with transient confusion states during hospitalisation, and in more than 50 per cent of cases this escapes the notice of the attending physician. The disorder is characterised by a remarkably poor prognosis; even among those whose confusion state is transient, 20-30 per cent die before discharge, and approximately one third remain hospitalised. The occurrence of confusion in the elderly patient should alert the physician to the need of investigation to detect underlying severe disease without delay. Despite the otherwise poor prognosis, improved diagnosis and treatment should not only yield better results but also economic gain to the community. PMID- 8700645 TI - [Dangerous health]. PMID- 8700646 TI - [Public health science education in Scandinavia and in Europe]. PMID- 8700647 TI - [Medical societies in Europe]. PMID- 8700648 TI - [Medical science theory. Copenhagen-model]. PMID- 8700649 TI - New insights into directed cell migration: characteristics and mechanisms. AB - The present article describes how it is possible to elucidate the essential cellular machines controlling directed migration. Investigations are performed with cells like granulocytes, fibroblasts or neural crest cells and these cells are found to contain two independent types of machines, a steerer (controller without feedback) for the speed and an automatic controller (controller with feedback) for the angle of migration. The first intracellular signal is the distribution of membrane bound receptors occupied by kinesis stimulating molecules from the extracellular space. Motile force is produced by a linear motor supplied by the chemically amplified first intracellular signal (total number of occupied receptors). When properties of the cellular steering device are investigated, results show the angle of migration to be corrected by an automatic controller and an asymmetric distribution of occupied receptors to be the first intracellular signal for directed migration. Properties of the goal seeking device are also investigated. As in many different types of technical machines, the cellular machinery operates in a cyclic manner which in the case of granulocytes a measuring cycle of 8 s and a response cycle of approximately 60 s. These cellular machines may be understood in terms of a self-ignition mechanism where the renewal of membrane bound receptors is the essential step. PMID- 8700650 TI - Localized stage non-Hodgkin's lymphoma of the testis: a retrospective study of 16 cases. AB - The present report concerns a retrospective study of 16 patients with localized intermediate- or high-grade non-Hodgkin's lymphoma of the testis treated in one institution from 1973 to 1990. Ann Arbor stage of disease was IE in 11 and IIE in 5 cases. All except one patient underwent initial inguinal orchidectomy, 11 were disease free after surgery and 12 received inverted Y radiation therapy. All patients achieved a complete remission (CR). Relapse occurred in 8 of 9 patients who did not receive initial chemotherapy, but in only 3 of 7 patients initially treated with chemotherapy including anthracyclins. In 3 cases relapse was confined to the CNS, while diffuse relapse in 8 others included 4 cases of CNS involvement. Eight patients are now alive in CR (5 in first CR, 1 in second CR and 2 in third CR) with a median follow-up of 68.5 months (range 54-101). Chemotherapy thus emerges as the initial treatment of preference for localized testicular lymphoma. Therapy should be preceded by a thorough assessment of the stage of disease and due to the high frequency of CNS relapse, CNS prophylaxis should be considered for all patients. PMID- 8700651 TI - Intra-abdominal localization of acute leukaemia: report of six cases. AB - Clinical findings leading to the diagnosis of acute leukaemia result from the consequences of both pancytopenia and tumoral manifestations. Although leukaemic infiltration of hematopoietic organs is common, the involvement of non hematopoietic abdominal organs remains rare. The authors report a series of six cases, where intra-abdominal localization of acute lymphoblastic or myeloblastic leukaemia was detected at diagnosis or relapse. Chemotherapy may lead to remission or cure if the early abdominal complications are managed with care. PMID- 8700652 TI - Incremental threshold loading in patients with chronic obstructive pulmonary disease. AB - The purpose of this research was to study the reproducibility of incremental threshold loading, a test of inspiratory muscle endurance, in patients with mild to severe chronic obstructive pulmonary disease. Twenty-seven patients completed four weekly visits. A significant difference was noted between the first visit and subsequent visits for the maximum absolute load that patients could tolerate, but no difference was noted in the load relative to inspiratory strength. Breathing pattern did not change significantly among visits to account for the differences in absolute load. Patients had a tendency to use rapid shallow breathing at the end of the test, suggesting that they approached the limits of their endurance and thus nearly fatigued their inspiratory muscles. PMID- 8700653 TI - Reliability and validity of the 12-minute distance walk in patients with chronic obstructive pulmonary disease. AB - Validity and test-retest liability of the 12-minute distance (12MD) walk, a measure of functional status, were examined in patients with chronic obstructive pulmonary disease. Four tests were administered at weekly intervals. Performance increased (p < .01) over the first three tests. Test-retest reliability was r34 = .98 (df = 46) for tests 3 and 4. The 12MD walk correlated with the Sickness Impact Profile, Physical Dimension (r = -.45); forced expiratory volume in 1 second % predicted ( r = .40); maximal inspiratory pressure (PImax) (r = .52); and exercise-related breathlessness (r = -.49). Exercise-related breathlessness and PImax accounted for 42% of the variance. The validity and reliability of the 12MD walk were supported. PMID- 8700654 TI - Epilepsy self-management: a test of a theoretical model. AB - This study examines the role of social support, self-efficacy, outcome expectancy, and anxiety as predictors of medication management in persons with epilepsy. A model based on social cognitive theory was constructed to explain managing medications under conditions of scarcity. A survey instrument was sent to 450 individuals who participated in job training programs for persons with epilepsy. One hundred ninety-five completed questionnaires were returned and met the inclusion criteria. The proposed structural model was tested using structural equation modeling procedures. The assistance aspect of social support was positively related to regimen-specific support. The paths from self-efficacy to outcome expectancy and anxiety were significant and in the predicted directions, as was the path from anxiety to self-management. PMID- 8700655 TI - Gastric emptying and gastric-intestinal transit in rats with varying ovarian hormone status. AB - Basal and stimulated gastric emptying and gastrointestinal (GI) transit in rats of varying ovarian hormone status were compared to define direct ovarian hormone effects on GI function. Thyrotropin-releasing hormone (TRH) was used to evoke vagal GI motility stimulation. Adult female Sprague-Dawley rats were anesthetized (equithesin), ovariectomized, and implanted with 28-day estrogen (E), progesterone, (P), E+P, or vehicle (V) pellets; males were also studied. On Day 26, fasted rats were anesthetized (urethane). Nonabsorbable 14C polyethylene glycol-4000 in saline was gavaged at t = 0. At t = 5 minutes, TRH or saline was administered intracisternally. At t = 30 or 60 minutes, the GI tract was removed, ligated, sectioned, and counted. Gastric emptying was expressed as 100% minus the ratio of gastric to total counts; GI transit was expressed as geometric center of radioactivity. In saline-treated rats, gastric emptying and GI transit at 60 minutes varied significantly among ovarian hormone-treated groups, with E lower and males elevated. TRH-significantly increased both variables at both times in all groups. Results are consistent with acceleration of upper GI function in the absence of E, possibly contributing to GI symptoms during menopause and late luteal phase. PMID- 8700656 TI - A meta-analysis of the relationship between postpartum depression and infant temperament. AB - A meta-analysis of 17 studies was conducted to determine the magnitude of the relationship between postpartum depression and infant temperament during the infant's first year. Interrater reliabilities for coding of substantive and methodological characteristics for each study ranged from 87% to 100%. The meta analytic combinations were calculated in three different ways: unweighted, weighted by sample size, and weighted by a quality index score. A significant, moderate correlation between postpartum depression and infant temperament was found. The mean r index of effect size was .31 when the studies were weighted by sample size; .36 when the studies were unweighted; and .35 when they were weighted by the quality score. All three r indexes were in Cohen's range of moderate effect sizes. The calculated 95% confidence interval ranged from .261 to .369, indicating a significant relationship between postpartum depression and infant temperament. Sample size and year of publication were significantly correlated with the effect size of temperament in infants of postpartum depressed mothers. PMID- 8700657 TI - Self-esteem as a mediator of the effects of stressors and social resources on depressive symptoms in postpartum mothers. AB - The purpose of this study was to examine the role of self-esteem as a mediator of the effects of stressors and social resources on mothers' postpartum depressive symptoms. Data were collected during in-home interviews with 738 women 1 to 2 months postpartum. Forty-two percent of the women had high depressive symptoms. Self-esteem mediated the effects of everyday stressors and the quality of primary intimate relationships on depressive symptoms. However, everyday stressors also exhibited direct effects. Mothers with low self-esteem were 39 times more likely to have high depressive symptoms than those with high self-esteem. Interventions to decrease postpartum mothers' chronic stressors and to improve the quality of their primary intimate relationships may enhance their self-esteem, which in turn may decrease the likelihood of high depressive symptoms. PMID- 8700658 TI - Mammography in older women: one-time and three-year adherence to guidelines. AB - A survey examined self-reported mammography use in a convenience sample of 1,083 women 50 years of age and over. Relationships were examined between ever having mammography; 3-year adherence to mammography guidelines; the predisposing variables of attitudes, knowledge, health history factors, and selected demographics; and the enabling variables of income, health insurance, source of regular medical care, and type of regular physician. Logistic regression analysis for ever having a mammogram identified significant odds ratios (OR) > 1 (p < or = .05) for doctor recommendation for mammography (OR = 14.26), satisfaction with way of living (OR = 2.77), perceived benefits of mammography (OR = 1.35), and knowledge (OR = 1.21). Odds ratios < 1 were found for scaled variables of barriers and control (OR = .81 and .65, respectively). For 3-year adherence, significant odds ratios > 1 were annual Pap tests (OR = 3.36), willingness to pay > or = $50 for mammography (OR = 2.00), benefits (OR = 1.20), and knowledge (OR = 1.18). The odds ratio for control was significant at .85. PMID- 8700660 TI - Management of poisoning. PMID- 8700659 TI - The influence of stress management training in HIV disease. AB - A pretest-posttest design (with a 6-week wait-list control and a 6-month comparison group) was used to compare the effectiveness of a 6-week stress management training program with standard outpatient care for 45 men with HIV disease. Outcomes included stress levels, coping patterns, quality of life, psychological distress, illness-related uncertainty, and CD4+ T-lymphocyte levels. At 6 weeks, intervention was associated with increases in the emotional well-being dimension of quality of life. After 6 months, the intervention group had a relative decline in HIV-related intrusive thinking, indicating that stress management training may have buffered illness-related psychological distress over time. PMID- 8700661 TI - Professional development. Breast cancer: the role of the nurse (continuing education credit). PMID- 8700662 TI - A hard pill to swallow. PMID- 8700663 TI - Who wants to know? PMID- 8700664 TI - Charter for care. Interview by Adam Legge. PMID- 8700665 TI - Quality of care in A&E is the issue--not speed. AB - The Audit Commission's new report into A&E services has produced a strong case for enhancing nursing's role in A&E. This paper, by a nurse member of the commission's study team, explains how the influential report backs nurses' efforts to extend their scope of practice. The report criticises the Patient's Charter's initial assessment standard, saying attention should be focused on how well, rather than simply how quickly, A&E patients are assessed and treated. PMID- 8700666 TI - Ways of reducing the waiting times for patients in A&E. AB - This paper reflects the current debate surrounding the Patient's Charter standard for initial assessment within the A&E department and suggests ways of improving the quality of the assessment and reducing waiting times for patients in A&E. PMID- 8700667 TI - Systems of life. Hormones and sexual puberty. PMID- 8700668 TI - Winning ways with research proposals and reports. AB - This paper is the first of a series of six on the evaluation of clinical treatments. It explains the steps involved in drawing up research proposals and reports, with emphasis on the importance of planning. Later papers will cover literature searches, setting aims, designing the evaluation and presenting results. PMID- 8700669 TI - Extending the midwives' role in perineal management. AB - More than 70% of women in the western hemisphere undergo perineal suturing following childbirth. But there is no audit system developed to monitor subsequent healing. At London's Whittington Hospital Trust it was decided that midwives should be enabled to follow up their perineal management. PMID- 8700670 TI - Entering the world of disability. PMID- 8700671 TI - Disability: traumatic transitions. PMID- 8700672 TI - The care alliance. PMID- 8700673 TI - Telling it like it is. PMID- 8700674 TI - Joint initiative. PMID- 8700675 TI - Wound care. Diabetic foot ulceration. PMID- 8700676 TI - Wound care. An Ethiopian experience. PMID- 8700677 TI - Wound care. Holistic pressure care. PMID- 8700678 TI - Wound care. Setting up a foot clinic. PMID- 8700679 TI - Wound care. Waterlow revisited. PMID- 8700680 TI - Wound care. Treating lymphoedema. PMID- 8700681 TI - Breakdown of trust. PMID- 8700682 TI - On duty. Interview by Brigid McConville. PMID- 8700683 TI - The aftermath of tragedy. PMID- 8700684 TI - Evaluating a nebuliser service to improve patient care. AB - This article describes the results of a postal questionnaire completed by 32 adults with home nebuliser equipment. The author found that patients had a limited understanding of the care and maintenance their equipment required. She puts forward a number of recommendations, including the provision of information for patients to control their problems. PMID- 8700685 TI - Fat is an occupational issue. PMID- 8700686 TI - Staff knowledge of inhaler technique improved by survey. AB - This paper looks at a small project that examines nurses' knowledge of inhaler technique and related issues using a range of inhalers. It identified a lack of knowledge in a specific group of hospital nurses in the range of inhalers available, user techniques and the care and management of such devices. This resulted in individual tuition for nurses on inhaler technique and relevant information being made available. PMID- 8700687 TI - The effective mentor: a model for student-centred learning. AB - This paper is concerned with the relationship between student and clinical supervisor (known as a mentor) and its influence on nursing students' development of professional knowledge during his or her clinical practice. The paper is based on the results from a longitudinal naturalistic study of eight nursing degree students during their four-year programme. The study was concerned with investigating and describing how nursing students develop their professional knowledge while working in clinical areas. During the data collection and analysis it became evident that the influence of the clinical mentor and the nature of the relationship were central to students' knowledge growth. By undertaking a content analysis for the relevant data and using an inductive approach, five key aspects of the student-mentor relationship emerged. These five aspects will be presented and discussed along with the implications for nurse education and the role of clinical staff. PMID- 8700688 TI - An analysis of blood malignancies and disorders. AB - This penultimate paper in our series on haematological malignancies looks at the rare types of leukaemia. The epidemiology, pathophysiology, treatment and prognosis for each group is described. The signs and symptoms are also highlighted. PMID- 8700689 TI - Learning disabilities. Special families, special needs. PMID- 8700690 TI - Managed change or management speak? PMID- 8700691 TI - Uphill struggle. PMID- 8700692 TI - Womens health. Pause for thought. PMID- 8700693 TI - Fluid forces. PMID- 8700694 TI - Diabetes: a guide to new developments. PMID- 8700695 TI - Critical masses. PMID- 8700696 TI - Professional development. Termination of pregnancy: knowledge for practice (continuing education credit). PMID- 8700698 TI - Acute discomfort. PMID- 8700697 TI - Long-term care set to be a lottery. PMID- 8700699 TI - On a special mission. Interview by Ian McMillan. PMID- 8700700 TI - Special solutions. PMID- 8700701 TI - Media madness. PMID- 8700702 TI - Junior doctors' hours and the expanding role of the nurse. AB - This paper describes the development of an educational programme designed to support nurses in expanding their role, while maintaining the focus on the patient. Developments leading to changes in nurses' roles are also highlighted. The paper shows how the initiative was undertaken and discusses the philosophy behind it, which was to preserve the caring role of the nurse while developing technical skills. PMID- 8700703 TI - The named nurse in Scotland: time for action runs short. AB - The implementation of the named-nurse standard for Scotland takes place in 1997. Scottish nurses therefore have the opportunity to learn from the successes and pitfalls experienced by their English colleagues. This article examines the change process in one Lanarkshire hospital which saw a marked change in the extent to which patients could identify their named nurse. At the start of the project 72% of 50 patients surveyed could identify who their named nurse was. After a structured change programme involving planning, training implementation and evaluation, 100% of patients in the first eight wards that took part in the project could identify their named nurse, with 75% saying that they spoke with their named nurse on a regular basis. PMID- 8700704 TI - How to avoid mistakes in medicine administration. AB - This article examines factors that may contribute to errors in drug administration. These can range from the omission of a single dose of a non essential drug to a major overdose resulting in serious harm to a patient. It concludes that a combination of being observant and well-informed can help to prevent errors. PMID- 8700705 TI - Making sense of tonicity and intravenous therapy. AB - The body maintains homeostasis by controlling the movement of fluid between different internal areas. Intravenous therapy assists when imbalance occurs because of injury or illness. The nurse needs to be aware of the appropriate solutions to administer in various situations. PMID- 8700706 TI - Paths to effective teamwork in primary care settings. AB - Effective teamworking does not automatically follow the creation of primary health-care teams. This article identifies some of the barriers to effective teamworking in primary care. It considers the limitations of the Health Education Authority's team-building workshop programme and charts the progress of an alternative model, which initially focuses on the nursing team rather than the multidisciplinary team. The success of the model in offering team members a goal in profiling and planning to meet community health needs is described. Also highlighted is the need for team-building throughout primary care disciplines which involves health-needs profiling and service planning. PMID- 8700707 TI - Complementary medicine. Moving experiences. PMID- 8700708 TI - Midwifery. Human values. PMID- 8700709 TI - Old-timer's lament. PMID- 8700710 TI - The bitterest pill. PMID- 8700712 TI - Children first? PMID- 8700711 TI - A forum for discontent. PMID- 8700713 TI - Is our obsession with physical beauty creating an underclass of less-than-perfect people?. Interview by Daloni Carlisle. PMID- 8700714 TI - Specialist unit improves outcome after acute stroke. AB - Stroke rehabilitation units are associated with reduced mortality, morbidity and length of stay, in much the same way that coronary care units are known to improve the acute care of patients who have had a heart attack. Such units have facilitated the development of drugs that may improve the outcomes following a heart attack. The acute stroke unit at King's Healthcare, London, was set up to improve the early management of stroke and facilitate the development of new treatments. The unit has just celebrated its first anniversary and this paper evaluates its work one year on, plus the implications for nursing practice. PMID- 8700715 TI - Stroke. Communication difficulties. AB - This paper highlights the problem of non-fluid dysphasia and provides an overview of the complex physical, psychological and social dimension to consider when caring for this client group. PMID- 8700716 TI - Continuing education: how well is PREP working? AB - It is nearly a year since the UKCC's standards for post-registration education were implemented. This paper reviews some of the issues resulting from post registration education standards and introduces a combined Nursing Times/Queen's Nursing Institute study looking at practitioner's access to continuing education. PMID- 8700717 TI - Setting clinical standards for care in schizophrenia. AB - A clinical standards advisory group spent more than two years developing a protocol for assessing standards of care for people with a diagnosis of schizophrenia. The results of its site visits have major implications for nursing practice. There is a clear need for attention to be paid to physical health, medication management and the greater involvement of users and carers. Training in psychosocial interventions needs to be developed as a matter of urgency. PMID- 8700718 TI - Systems of life. Glands, gender and sexuality. PMID- 8700719 TI - Skin graft. PMID- 8700720 TI - International perspectives. Facing the future. PMID- 8700721 TI - Family matters. PMID- 8700722 TI - Travels of my aunt. PMID- 8700723 TI - Good, but could do better. PMID- 8700726 TI - HIV/AIDS predictions proved wrong. PMID- 8700725 TI - Continence. Help for a peaceful night. PMID- 8700724 TI - Continence. Survey shows hidden problem. PMID- 8700727 TI - Professional development. Myocardial infarction: revision notes (continuing education credit). PMID- 8700728 TI - Evaluation of shared care for people with HIV. PMID- 8700729 TI - Reversion therapy. PMID- 8700730 TI - Waiting for guidance. PMID- 8700731 TI - The whistle stop. PMID- 8700732 TI - Part-time working. Balancing act. PMID- 8700733 TI - Part-time working. Level the playing field. PMID- 8700734 TI - Part-time working. Defective agency. PMID- 8700735 TI - How nurses view emotional involvement with patients. AB - This paper explores the concept of involvement within the nurse-patient relationship. The development of involvement and the notions of being involved, over-involvement and not being involved are all explored. The effect of the care environment on relationships formed and patients' individual needs for involvement are also considered. PMID- 8700736 TI - Nursing management of oral care in older patients. AB - Oral care is one of the most important nursing activities and it is essential to ensure patient comfort, maintain nutritional status and prevent infection. This paper, the first in a four-part literature review series, looks at oral care in older adults. PMID- 8700737 TI - Clinical outcomes for nurse-led in-patient care. AB - An earlier paper described an in-patient population that was identified as potentially able to benefit from nurse-managed in-patient care. This paper describes a pilot experimental study aimed at measuring the impact of transfer to a nurse-led unit. Outcomes for 71 patients considered for transfer to the nurse led ward were compared with a control group of 48 patients who remained under medically managed care for the duration of their stay. Large but non-significant improvements in length of stay were found in the treatment group. There was a significantly lower incidence of pressure sores, urinary tract infections and chest infections. There were no differences in mortality. The author urges a cautious interpretation of results and emphasises the need for replication. PMID- 8700739 TI - Nappies: a guide to what's on offer. PMID- 8700738 TI - Lymphomas: aetiology, classification and treatment. AB - This paper continues our series on haematological malignancies by describing the classification, epidemiology and aetiology of lymphomas and outlining clinical approaches. PMID- 8700740 TI - Talk is cheap. PMID- 8700741 TI - Learning disabilities. Independent means. PMID- 8700742 TI - Learning disabilities. Brave new world? PMID- 8700743 TI - Exploring music intervention with restrained patients. AB - Roy's Adaptation Model is used in a case study approach to begin examining the potential of music intervention in hospitalized, restrained patients. Restraints were removed during the time in which the patient listened to a musical tape through a headset. Mr. D, presented in this case study, was one of the 30 medical surgical patients who participated. His observable positive behaviors increased from 10 during the preintervention period to 12 during the musical intervention. Mr. D displayed no negative behaviors during the entire study period. PMID- 8700744 TI - The quest for cultural competence in nursing care. AB - Conducting a culturally sensitive cultural assessment is a critical factor in rendering culturally relevant services to our growing ethnically diverse patient population. The author examines issues affecting the process of conducting culturally sensitive cultural assessments. A review of several cultural assessment tools is presented, along with suggestions for conducting effective cultural assessments. PMID- 8700745 TI - Associate degree nursing education: challenging premonitions with resourcefulness. AB - The demise of associate degree nursing education is greatly exaggerated. Most nurses enter nursing through associate degree programs. However, external forces- including changes in the structure of healthcare delivery models, changes in practice settings, and the public's demand for decreased healthcare cost--are forcing associate degree nursing educators to provide a different type of product. The authors offer strategies for educators to meet the challenge of equipping associate degree nursing students with the skills needed for the 21st century. PMID- 8700746 TI - Bring back the nurse's cap. PMID- 8700747 TI - Utilizing the home setting to teach Watson's theory of human caring. AB - Watson's theory of human caring serves as a framework in assisting RN/BSN completion students caring for dying patients at home. Through personal journals and case conferences, students incorporated Watson's 10 carative factors of human caring as the basis of their nursing interventions with clients and families. In this required course students visited patients, saw them through the dying process, and helped families with grieving. Students learned principles of home care, hospice, and what the differences and similarities can mean in the home and hospital setting. PMID- 8700748 TI - Advanced practice nurses: starting an independent practice. AB - Independent or private practice is the delivery of nursing services provided by nurses over which nurses have full control. With a changing healthcare system, nurses are in a prime position to negotiate the delivery of appropriate, acceptable, and cost-effective health care as independent practitioners. This article addresses the mission and goals of independent practice, community need, business structure of the practice, housing the practice, legal considerations, financing the practice, marketing issues, clientele, record keeping, and reimbursement. PMID- 8700750 TI - Critical pathways: a wolf in sheep's clothing? PMID- 8700749 TI - Under assault: the experience of work-related anger in female registered nurses. AB - This article is Part I of a three part article. Part I describes work-related experiences of anger of female registered professional nurses (N = 9) who participated in phenomenological interviews. Participants ranged in age from 29 to 56 and had practiced nursing for a period of 7 to 34 years. Nurses described being "under assault" in a hostile environment. Military metaphors and similes permeated all the interviews. Subtheme of "under assault" included scapegoating, disrespectful treatment, and lack of support. Anger was a weapon used by the nurse to defend or advocate for patients or self, as well as to attack doctors, peers, patients, and self. Factors within the self such as control versus powerlessness influenced nurses' anger experience and expression. Infighting within the profession prevents mobilization of resources to confront the larger issues of healthcare reform. Nurses must reframe anger as a constructive means of empowerment, rather than a weapon to defend against assault. Part II addresses anger experiences of male registered nurses, and Part III provides recommendations for channeling anger constructively. PMID- 8700751 TI - A response to associate degree nursing education: challenging premonitions with resourcefulness. PMID- 8700752 TI - Research implications for alternative health therapies. AB - Nontraditional health practices have gained in popularity during the past 10-15 years. Unfortunately, the effectiveness of many nontraditional approaches have been inadequately investigated. Furthermore, tradition research protocols often have fallen short in providing satisfactory strategies for these types of investigations because the nature of the personal belief system between patient and provider has not been examined. The authors discuss the implications for triangulation techniques in nursing research related to nontraditional treatments. Six types of triangulation are defined and methods for utilizing these techniques are explained. PMID- 8700753 TI - All the right reforms? PMID- 8700754 TI - Periodontal complications following use of the rubber dam: a case report. PMID- 8700755 TI - Depth of composite polymerization within simulated root canals using light transmitting posts. AB - In this study, the depth of cure of composite resins cured within simulated root canals by means of light-transmitting plastic posts was compared to that achieved by the conventional light-curing method. Six sizes of posts with diameters of 1.05 mm, 1.20 mm, 1.35 mm, 1.50 mm, 1.65 mm, and 1.80 mm were investigated. In general, the larger the post diameter, the greater was the depth of cure. There were significant differences in the depth of cure between the control and all sizes of posts investigated. There were also significant differences between the various post diameters except for the 1.35 mm and 1.50 mm diameter posts. It was possible to achieve a depth of cure exceeding 11 mm using these light transmitting posts. PMID- 8700756 TI - Effects of dentin air abrasion with aluminum oxide and hydroxyapatite on adhesive bond strength. AB - Shear bond strengths to dentin were determined with six current-generation resin adhesive systems following air abrasion of the dentin surface with aluminum oxide and hydroxyapatite. In addition, scanning electron microscopy was used to examine the effects of air abrasive techniques and conditioners/primers on the dentin surfaces. Altering the dentin surface with air abrasion using aluminum oxide and hydroxyapatite did not enhance dentin bond strengths with current-generation adhesive systems. Air abrasion of dentin with aluminum oxide created more surface irregularity than hydroxyapatite. Dentin surfaces air abraded with aluminum oxide and the treated with conditioners that removed the smear layer appeared more irregular than flat ground dentin surfaces treated with the same conditioners. PMID- 8700757 TI - Retention of paraposts cemented with dentin-bonded resin cements. AB - The main purpose of this study was to assess the retention of Paraposts cemented with dentin-bonded resin cements in single-rooted teeth with elliptical canals. Forty-two mandibular premolars and canines were used in this study. The crowns of these teeth were removed 1 mm above the cementoenamel junction and the root canals instrumented to a depth of 8 mm to receive size 5 Paraposts. Prepared teeth were divided into six equal groups. Each group was assigned to a different cementation system at random. The six cementation systems used were: Fleck's Cement, Universal Post Cementation Kit, Prisma Universal Bond 3/Biomer, Scotchbond 2/Resiment, All-Bond 2/All-Bond C & B Cement, and Scotchbond Multi Purpose/Resiment. Following post cementation, the teeth were stored in water at 37 degrees C for 24 hours, after which the posts were subjected to uniaxial tensile force on a testing machine until post separation occurred. Paraposts cemented with Prisma Universal Bone 3/Biomer or with Scotchbond Multi Purpose/Resiment had significantly greater separation forces than posts cemented with any of the other cementation systems. Adhesive failure of the posts occurred in all of the specimens of the resin cement groups, whereas cohesive failure of the cement occurred in the majority of the specimens of the zinc phosphate cement group. The effects of thermocycling and post length (5 mm versus 8 mm) on the retention of Paraposts cemented with dentin-bonded resin cements were also investigated. Neither thermocycling nor post length had a significant effect on post separation force. PMID- 8700758 TI - Secondary caries formation in vitro around fluoride-releasing restorations. AB - Secondary caries is one of the most important factors leading to replacement of dental restorations. This investigation assessed the capacity of fluoride releasing restorative materials to resist caries in vitro. Class 5 cavities were prepared in buccal and lingual surfaces of 18 extracted premolars. The six materials used were: high-copper amalgam (Dispersalloy), fluoride-containing amalgam (Fluor-Alloy), composite resin (Valux), fluoride-containing composite resin (Heliomolar), glass-ionomer cement (Fuji), and glass-ionomer cement with silver particles added (Ketac-Silver). After 15 weeks in an acid gel for caries like lesion formation, the teeth were sectioned longitudinally and examined with polarized light. The results showed that restoration of caries with glass-ionomer materials and fluoride-containing amalgam may be of great importance in the prevention of both secondary caries around the restorations and primary caries in surface enamel adjacent to the restoration. PMID- 8700759 TI - Microleakage of five dentinal adhesives. AB - This study compared the microleakage characteristics of four dentinal adhesives against Scotchbond 2 as a control and discusses the results in light of recently reported bond strengths for these same materials. Dentin specimens from 100 caries-free extracted human molar teeth were used in a matched pair design. In each of the four test materials, 25 tooth sides were treated along with the matching control, subjected to 500 thermocycles (5 to 55 degrees C), followed by AGNO3 dye penetration, specimen sectioning, and evaluation by low-power stereomicroscopy. Mean microleakage values were as follows (microns): Scotchbond Multipurpose, 498.0; All-Bond 2, 530.8; Syntac, 748.0; X-R Bond, 844.9; and the Scotchbond 2 control (a composite score created by averaging four sets of 25 tooth sides), 1095.2. Paired t-tests showed that Scotchbond Multipurpose, Syntac, and All-Bond 2 had significantly lower microleakage than the control (P=0.0001); however, X-R Bond had no significant difference from the control (=0.4634). PMID- 8700760 TI - The effect of various surface coatings on fluoride release from glass-ionomer cement. AB - To protect glass-ionomer cement from moisture contamination and dehydration during initial setting, immediate application of a surface coating agent is recommended. This study compared the effect of various surface coatings on F release from glass-ionomer cement. Twenty glass-ionomer cement (Ketac Fil Aplicap) disks (4.52 cm2) were prepared from a Teflon mold. The control group was uncoated, while the experimental groups were coated with Visiobond, Scotchbond II, and Ketac Varnish. In addition, five specimens of Variglass were similarly prepared and remained uncoated as per the manufacturer's instructions. F release was measured each day during week 1 and on the last day of weeks 2, 3, and 4. The results indicated that the application of the surface coatings did not completely inhibit F release from glass-ionomer cements, and that F release during the first week for all groups was significantly greater than in the subsequent 3 weeks. Visiobond-coated glass-ionomer cement allowed significantly more F release than Scotchbond II-coated glass-ionomer cement, Ketac Varnish-coated glass-ionomer cement, or Variglass. PMID- 8700762 TI - Nanoleakage: leakage within the hybrid layer. AB - Most microleakage studies involve quantitating the magnitude of movement of a tracer molecule through a gap between restorative materials and the wall of cavity preparations. The present microscopic study examined the migration of silver nitrate into the interface between dentin and five different dentin bonding agents used to restore class 5 cavities, in the absence of gap formation. Several different leakage patterns were seen, but they all indicated leakage within the hybrid layer when viewed by SEM. The ranking of microleakage from most to least was: All-Bond 2 > Suberbond C&B > Scotchbond Multi-Purpose > Clearfil Liner Bond System > Kuraray Experimental System, KB-200. To distinguish this special type of microleakage within the basal, porous region of the hybrid layer in the absence of gap formation, we propose the term nanoleakage. PMID- 8700761 TI - Alcohol-containing mouthwasheses: effect on composite color. AB - This study investigated whether commercially available mouthwashes could affect or change the color of a hybrid composite resin. Twenty-four disks were fabricated and divided into eight equal groups for testing. At baseline, six colorimetric recordings and color parameters (L*, a*, b*) were recorded for each grouping of disks using a Chroma Meter CR-300 in reflectance mode. The groups of disks were immersed in their respective mouthwashes for 2 minutes a day in a vibratory fashion over a 6-month period. At the end of 6 months, color differences, delta E, were calculated between the base line and test recordings. The results indicate that rinsing with mouthwashes for 6 months can cause a hybrid resin to undergo color variations. Except for one product the color variations were not clinically significant. PMID- 8700763 TI - Increases in cavity volume associated with the removal of class 2 amalgam and composite restorations. AB - Removal of amalgam restorations from class 2 cavities has been shown to cause increases in cavity volume. The aim of this study was to test whether the removal of composite resin from class 2 cavities was associated with greater increases in cavity volume compared to that produced during removal of amalgam. Class 2 cavities were prepared in previously extracted human molar teeth and the cavity volumes calculated. The teeth were restored with either amalgam or a composite resin and appropriate dentin bonding agent (APH/Optibond). Two dentists removed the restorations, and the resultant cavity volumes were calculated. The results were analyzed using a standard t-test, ANOVA, and a Scheffe F-test. Removal of composite from class 2 cavities resulted in significantly increased cavity volumes compared to that when amalgam was removed. While there was significant interoperator difference in cavity volumes following removal of amalgam from class 2 cavities, there was no significant interoperator difference in cavity volumes following the removal of composite. These differences were related to the methods used to eliminate the restorations from the cavities. PMID- 8700764 TI - The effect of setting time on the clinical performance of a high-copper amalgam alloy. AB - The purpose of this clinical study was to evaluate the factor of the setting rate/Eames working time on fracture at the margins of amalgams. One batch of a high-copper amalgam was modified to obtain two setting rates, one fast and one slow setting. Two dentists originally placed 134 amalgam restorations in 23 patients. Both dentists used a rubber dam throughout the restorative procedure and prepared cavities as conservatively as possible. The amalgams were condensed by hand and carved with sharp instruments. At 1 year 124 restorations and at 2 years 115 restorations were evaluated for fracture at the margins. Results indicated that there was no significant clinical difference between a slow- and fast-setting alloy, nor was there a difference between the operators. PMID- 8700765 TI - Influence of irradiation sequence on dentin bond of resin inlays. AB - The relationship between the order in which a dual-cured resin cement is light activated and the bond strength of resin inlay materials to dentin was examined. Also evaluated was the setting time with various irradiation sequences. Lite-Fil CR/Imperva Bond (Shofu) and Clearfil CR/CR Cement (Kuraray) were employed. Ten specimens, 4 mm in diameter by 4 mm deep, were made with each material for each condition and bonded to bovine dentin with the respective bonding agent and cement. Order of light activation was: 1) no light activation; 2) premix activation of only the liquid prior to mix, 3 seconds for Lite-Fil and 25 seconds for Clearfil; 3) postplacement activation, 30 seconds for Lite-Fil and 40 seconds for Clearfil; and 4) premix and postplacement activation, 3 seconds and 30 seconds for Lite-Fil and 25 seconds and 40 seconds for Clearfil. Samples were stored in water for 24 hours and shear strength tested. The setting time with no activation and premix activation was measured according to the ISO #7489 standards. Bond strengths (MPa) were 1) 4.41, 2) 13.07, 3) 6.34, and 4) 14.81 for Lite-Fil, and 1) 0.37, 2) 2.44, 3) 0.52, and 4) 2.51 for Clearfil. No light activation or only postplacement activation resulted in lower bond strengths with a 4.0 mm-thick specimen. The setting time of the cement mix with premix activation was shorter than with no activation. Light activation of these dual cure cements is essential. Premix activation of only the liquid resulted in bond strengths similar to those obtained with combined pre- and postplacement activating. PMID- 8700766 TI - Placement and replacement of composite restorations in Germany. AB - From 15 September to 15 October 1991, 102 dentists practicing in a rural area of Germany provided information on 3375 composite resin fillings. The purpose of this cross-sectional study was to record the reasons for placement and replacement of composite resin restorations, including any change of material when replacing a filling, and to register the age of any failed restoration. First placements because of primary caries were made in 50.6% of all cases; 49.4% were replacements of failed restorations. Composite resins were used as a material for the first placement of a restoration in 19.2% of primary teeth and in 47.8% of permanent teeth. More amalgams were replaced by composites than vice versa. Secondary caries was the most frequent reason for replacement in permanent teeth and in restorations with less than four surfaces, whereas fracture caused most failures in primary teeth and in fillings with four surfaces. The median age of the replaced restorations was 43.5 months. Failed restorations with four surfaces had the lowest median age. PMID- 8700767 TI - Factors associated with clinical success of cervical abrasion/erosion restorations. AB - The purpose of this study was to evaluate the clinical performance of class 5 restorations according to USPHS criteria. Twenty-five patients and 116 abrasion/erosion lesions were restored with either a glass-ionomer cement restoration (Ketac-Fil), a composite resin restoration with a dentin bonding agent (Silux Plus, Scotchbond 2), or a composite resin restoration with a dentin bonding agent and a glass-ionomer liner (Silux Plus, Scotchbond 2, Vitrebond). At 3 years, 24 patients and 110 teeth were evaluated. All restorations were rated clinically acceptable for color match, cavosurface discoloration, surface texture, and caries development. Glass-ionomer cement restorations demonstrated a slightly rougher surface texture than the composite restorations (Friedman Two way ANOVA, P=0.000). Significant differences were found with retention (Cochran Q test, P=0.012). Percentages retained were: glass ionomer, 97.3% (36/37); composite/dentin bonding agent, 75.7% (28/37); composite/dentin bonding agent/glass-ionomer liner, 100% (36/36). At 3 years class 5 restorations of glass ionomer cement or composite with a dentin bonding and a glass-ionomer liner demonstrated significantly better retention than restorations of composite with a dentin bonding agent. Increased occlusal function, mobility, and mandibular arch were associated with a decrease in retention rate. PMID- 8700768 TI - Is there a future for gold foil? PMID- 8700769 TI - Direct esthetic restoration of anterior root canal-treated teeth. AB - The esthetic restoration of anterior root canal-treated teeth with significant loss of tooth structure is a challenging clinical situation. For younger patients or for patients requiring interim treatment plans, restoring badly broken-down anterior teeth with composite resin provides an expedient and esthetic solution. Current visible-light-activated composite resin materials require an incremental build-up to ensure adequate depth of cure. With the use of custom-contoured, stabilized, thin crown forms and strategically placed vent holes, the clinician can efficiently provide cost-effective direct composite resin restorations that meet the patients' esthetic needs. PMID- 8700770 TI - Shear bond strengths of composite to dentin using six dental adhesive systems. AB - The development of adhesive agents for bonding composite to dentin has rapidly evolved in recent years. It is postulated that dentin bond strengths in the range of 17 MPa are sufficient to resist the polymerization shrinkage of composite resins. The purpose of this study was to evaluate the shear bond strengths of the following dentin adhesive systems: All-Bond 2 (Bisco), Imperva Bond (Shofu), Optibond (Kerr), Permagen (Ultradent), ProBond (Caulk/Dentsply), and Scotchbond Multi-Purpose (3M). Sixty human molars (10 per group) were mounted in phenolic rings, and the occlusal surfaces were flat ground in dentin to 600 grit. The prepared dentin bonding sites were treated according to the directions for each of the systems evaluated. A gelatin capsule technique was used to bond Bis-Fil composite cylinders to the teeth. The specimens were stored in water at 37 degrees C for 24 hours. Mean shear bond strengths were as follows: Scotchbond Multi-Purpose: 23.1 +/- 2.6 MPa, All-Bond 2: 21.4 +/- 7.8 MPa, Imperva Bond: 19.8 +/- 6.1 MPa, Optibond: 19.7 +/- 3.6 MPa, ProBond: 16.3 +/- 4.5 MPa, and Permagen: 16.2 +/- 3.0 MPa. There was not a significant difference (P<0.05) in the bond strengths of Scotchbond Multi-Purpose, All-Bond 2, Imperva Bond, and Optibond. The bond strengths of Scotchbond Multi-Purpose and All-Bond 2 were significantly greater (P<0.05) than ProBond and Permagen. Current-generation dentin adhesive systems have approached or exceeded the theoretical threshold value to resist contraction stresses during polymerization of resin materials. PMID- 8700771 TI - In vitro and clinical evaluations of a dentin bonding system with a dentin primer. AB - The purpose of this study was to investigate the effect of a dentin primer in improving dentin-to-composite bond strengths mediated by a dentin adhesive. The investigation consisted of both an in vitro tensile bond test, in which fresh bovine dentin was used, and clinical evaluation. In the in vitro bond test, bovine dentin surfaces were treated with the primer (an aqueous solution of HEMA) for different durations (10, 20, 30, and 60 seconds) prior to bonding of the light-cured adhesive and placement of a light-cured composite material. For the clinical evaluation, a total of 33 cervical erosion lesions were restored with the combination of the primer, the adhesive, and the composite. To comply with ADA requirements for the acceptance program of dentin-bonding agents, no enamel etching nor any mechanical retentive locks were performed in those restorations. Significant increases in bond strength were obtained in specimens treated with the primer. Regarding the clinical evaluations in which 30 restorations were available for the 6-month recall and 15 restorations were also available for the 1-year recall, all samples demonstrated a retentive rate of 100%. PMID- 8700772 TI - Shear bond strength of composite resin to microetched metal with five newer generation bonding agents. AB - The purpose of this study was to determine the shear bond strength of a hybrid composite resin to a nickel-chrome-beryllium (Ni-Cr-Be) alloy, using five of the newer-generation bonding agents: Optibond, All-Bond 2, Prisma Universal Bond 3, Restobond 4, and Amalgambond Plus with HPA. For each bonding system 10 samples of metal were microetched with 50-micron aluminum oxide prior to the placement of the bonding agent and resin. The shear bond strength was tested, and the results showed that Amalgambond Plus with HPA developed the strongest bond at 18.81 +/- 3.924 MPa, followed by All-Bond 2 at 14.33 +/- 3.408, Optibond at 13.97 +/- 1.508, Prisma Universal Bond 3 at 12.51 +/- 1.845, and Restobond 4 at 10.29 +/- 1.407. PMID- 8700773 TI - Microleakage of class 2 Superbond-lined composite restorations with and without a cervical amalgam base. AB - The purposes of the present study were: 1) to assess the microleakage at the cervical margin of Superbond-lined composite restorations with and without a cervical amalgam base and compare the results to cervical margins of composite restorations lined with Scotchbond 2, and 2) to compare the quality of the occlusal margins of Superbond-lined P-50 restorations with those bonded with Scotchbond 2. Forty-eight class 2 cavities were prepared in extracted or exfoliated primary molars. The teeth were randomly divided into three groups and restored as follows: Group A, amalgam + Superbond + P-50 (sandwich); Group B, Superbond + P-50; Group C, Scotchbond 2 + P-50 (control). Marginal leakage was assessed by the degree of dye penetration on sections of the restored teeth. The occlusal margins presented no or minimal leakage (degrees 0 and 1) in 53% of Group A restorations, 60% of Group B, and 44% of Group C. These differences were not statistically significant (P<0.05). The cervical margins showed moderate to severe dye penetration (degrees 2 and 3) in 94% of Group A, 47% of Group B, and 87% of Group C. These differences were statistically significant (P<0.05). The amalgam/Superbond/composite interface exhibited no leakage in 70% of the restorations. Although marginal leakage was not completely eliminated, Superbond exhibited significantly less leakage (P<0.05) at the cervical margins than Scotchbond 2 or amalgam with Superbond. PMID- 8700774 TI - Shear bond strength of composite resin to fresh amalgam. AB - The shear bond strength between fresh amalgam and composite resin using three adhesive systems was assessed. Amalgambond (5.19 MPa), All-Bond (3.45 MPa), and Clearfil New-Bond (4.37 MPa) had comparable shear bond strengths higher than Enamel Bond (1.27 MPa) after 48 hours of water immersion. This bond was hydrolytically degraded during 100 days of immersion in water. The greatest deterioration was observed for Clearfil New-Bond (0.81 MPa). Amalgambond provided the best results, whereas All-Bond and Clearfil New-Bond had comparable bond strength to Enamel Bond at the end of the experiment. PMID- 8700775 TI - Influence of different factors on bond strength of hybrid ionomers. AB - A new generation of filling materials, the hybrid-ionomer cements, has been introduced recently. In many clinical situations these hybrid ionomers may be an alternative to conventional glass-ionomer cements and resins bonded with dentin bonding agents. During the past years research has focused on factors influencing bond strength of dentin bonding systems, but there is not much knowledge about the bond strength of hybrid- and glass-ionomer filling materials under different conditions. Bond strengths of four hybrid ionomers, one conventional glass ionomer cement, and one cermet cement were determined in superficial and deep, dry and moist dentin using a simplified pulp chamber model. All materials showed significantly higher bond strength to superficial compared to deep dentin. Moisture showed no significant influence on any material neither in deep nor in superficial dentin. Bond strengths of Fuji II LC, Variglass, and Vitremer were distinctly higher than those of the conventional glass-ionomer cement (Ketac-Fil) and the cermet cement (Ketac-Silver), while that of Photac-Fil was not significantly different. Ionomer samples failed cohesively in superficial dentin in over 60% of the samples. The bonding interfaces between Fuji II LC and Variglass and the treated dentin surface showed tags but no distinct hybrid layer. Bond strength is not only dependent on the pretreatment of the dentin, but also on the glass-ionomer resin composition of the material. PMID- 8700776 TI - Award of Excellence. PMID- 8700777 TI - Hollenback Prize for 1995. PMID- 8700778 TI - Is it too late to modify reality? PMID- 8700779 TI - Coolant evacuation: a solution for students working without dental assistance. PMID- 8700780 TI - The effect of air thinning on dentin adhesive bond strength. AB - The purpose of this study was to determine if air thinning three dentin adhesives would affect bond strength to dentin. Ninety human molars were mounted in acrylic and the occlusal surfaces ground to expose a flat dentin surface. Thirty teeth were randomly assigned to one of the following dentin bonding agent/composite combinations: A) Universal Bond 3/TPH (Caulk), B) All-Bond 2/Bis-Fil-P (Bisco), and C) Scotchbond Multi-Purpose/Z-100 (3m). The primers were applied following the manufacturers' instructions. The adhesives were applied by two methods. A thin layer of adhesive was applied with a brush to 15 specimens in each group and light cured. Adhesive was brushed on to the remaining 15 teeth in the group, air thinned for 3 seconds, and then polymerized. The appropriate composite was applied in 2 mm increments and light cured utilizing a 5 mm-in-diameter split Teflon mold. Following 3 months of water storage, all groups were shear tested to failure on an Instron Universal Testing Machine. Bond strength was significantly higher in all groups when the dentin bonding agent was painted on without being air thinned. Scotchbond Multi-Purpose had significantly higher bond strength than All-Bond 2, which had significantly higher bond strength than Universal Bond 3. PMID- 8700781 TI - Shear bond strengths of resin-modified glass-ionomer restorative materials. AB - The purpose of this study was to evaluate the shear bond strength of resin modified glass-ionomer restorative materials to dentin. The materials tested were Fuji II LC, Geristore, Photac-Fil, VariGlass VLC, and Vitremer. Ketac-Fil, a conventional glass ionomer, was used as the control. The occlusal surfaces of 60 extracted molars were ground flat in dentin using 600-grit silicon carbide abrasive paper. Dentin surfaces were treated according to manufacturers' instructions, and restorative materials were applied using gelatin capsule matrices. Shear bond strengths were determined after the specimens were thermocycled 500 times. Mean bond strengths of the resin-modified glass ionomers ranged from 1.4 MPa (Photac-Fil) to 12.3 MPa (Fuji II LC). Except for Photac-Fil, all values were significantly higher than the control. Pairwise comparisons between the means for Fuji II LC and Vitremer, Vitremer and Geristore, and Geristore and VariGlass were not significantly different. PMID- 8700782 TI - Fracture toughness ov conventional or photopolymerized glass ionomer/dentin interfaces. AB - Several new light-cured glass-ionomer materials have been developed for restorative use. It is not yet clear, however, whether the ability of the conventional glass ionomers to bond chemically to dentin has been preserved in the new light-cured glass ionomers whose chemical compositions have been modified. The fracture toughness test was recently introduced as an appropriate method of measuring the fracture resistance of an interface. We have applied this test to the glass ionomer/dentin interface for the first time. Ten mini short-rod fracture-toughness specimens were fabricated for each group. Each specimen contained a chevron-shaped glass ionomer/dentin interface along its midplane. After 24 hours in 37 degrees C water, the specimens were tested by loading at 0.5 mm/min. The interfacial Kic results (MPa X m (1/2)) (SD), analyzed by ANOVA and Fisher's LSD test (P<0.05), were: Chem-fil II, 0.17 (0.04); Vitremer, 0.18 (0.15); Fuji II LC, 0.33 (0.16). There were no significant differences in interfacial Kic between the conventional and light-cured glass ionomers. Interfacial Kic's for a light-cured glass ionomer were, however, significantly higher when an intermediary dentin bonding agent was used. SEM examinations of the fractured surfaces indicated that crack propagation generally occurred along the bond interface, and indicated the formation of a resin-infiltrated layer when the dentin bonding agents were used. It was concluded that the fracture-toughness test could be a useful measure of the integrity of the glass ionomer/dentin interface. The clinical effect of an intermediary layer between the glass ionomer and the tooth structure is, however, unknown and requires further investigation. PMID- 8700783 TI - Reduction of marginal gaps in composite restorations by use of glass-ceramic inserts. AB - The objective of this study was to evaluate the effects of glass-ceramic inserts on reducing the marginal gaps caused by polymerization shrinkage in composite restorations. A light microscope was used to measure the largest gap at margins around restorations made in glass cylinders and tooth cavities with and without adhesion promoters. Where the cylinder was not silanated, the average gap was less in samples containing an insert than in those without. Two preparations were made in the dentin of 20 human molars. In each molar one cavity was restored with a dentin bonding agent and composite and the other with a dentin bonding agent and an insert seated in the composite. The average maximum gap width of restorations containing inserts was statistically less than for those with only composite (paired t-test, P<0.0001). When considering the volume of composite displaced by the insert, these results that the use of a glass-ceramic insert decreased the marginal gaps resulting form polymerization shrinkage. PMID- 8700784 TI - Shear bond strength of resin to acid/pumice-microabraded enamel. AB - The effect of enamel microabrasion techniques consisting of either 18% hydrochloric acid in pumice or a commercially available abrasive/10% hydrochloric acid mixture, PREMA, on composite/enamel shear bond strengths was investigated. Sixty extracted third molars had the bonding surface flattened and were divided into six treatment groups (n=10) with the enamel treated prior to bonding as follows: Group 1-- untreated; Group 2--37% phosphoric acid etched for 30 seconds; Group 3--18% hydrochloric acid/pumice mixture applied for five 20-second treatments; Group 4--similar to Group 3 with additional 37% phosphoric acid etch; Group 5--treated with PREMA compound applied for five 20-second treatments; Group 6--similar to Group 5 treatment with additional 37% phosphoric acid. Herculite XR composite resin was then bonded to all samples using a VLC unit. Samples were tested in shear, and fractured enamel surfaces were evaluated using light microscopy to determine the enamel-to-resin failures. Resin bond strengths to microabraded and H3PO4-etched enamel were similar to bond strengths of untreated H3PO4-etched enamel and were significantly better than bond strengths to PREMA treated or unetched enamel. PMID- 8700785 TI - Comparative SEM and TEM observations of nanoleakage within the hybrid layer. AB - Most adhesive interface studies have involved SEM demonstration of the penetration of adhesive resins into demineralized dentin surfaces with subsequent creation of hybrid layers. Nanoleakage is a term that describes the diffusion of small ions or molecules within the hybrid layer in the absence of gap formation. The present microscopic study examined the nanoleakage of the hybrid layer using a silver nitrate staining technique. Adhesive dentin sandwiches, which were immersed in a silver nitrate solution, were prepared for both SEM and TEM examination using both the Clearfil Liner Bond and All-Bond 2 adhesive systems. Both systems demonstrated silver accumulation within the hybrid layers. Clearfil Liner Bond System showed scattered silver particles at the bottom two-thirds of the hybrid layer by both SEM and TEM observation, whereas All-Bond 2 revealed stained fiber-like structures within the full thickness of the hybrid layer. To evaluate the quality of the hybrid layer, the utilization of tracer molecules such as silver nitrate that are detectable by both SEM and TEM is proposed. It is important to determine the location and morphology of these nanometer-sized porosities that may permit the hydrolysis of collagen fibers and degradation of adhesive monomers. PMID- 8700786 TI - The health status of adults with epilepsy compared with that of people without chronic conditions. AB - STUDY OBJECTIVES: To examine the feasibility of administering and the psychometric properties of a general health status questionnaire in adults with epilepsy, and to assess the health status of these patients. DESIGN: Prospective, cross-sectional, observational study. SETTING: Neurology clinic of a tertiary care medical center. PATIENTS: One hundred forty-eight ambulatory adults with epilepsy. INTERVENTIONS: Patients completed the SF-36, a general health status questionnaire. Respondent burden and data quality as well as psychometric characteristics were evaluated. Patients' SF-36 scale scores, adjusted for comorbidities, were compared with those of 641 people without chronic conditions with the same sociodemographic characteristics. MEASUREMENTS AND MAIN RESULTS: Administering the SF-36 to adult outpatients with epilepsy is feasible and results are psychometrically sound. Compared with those who were not ill, patients had significantly (p < 0.001) lower (0 = worst, 100 = best) scores in six of the eight SF-36 domains: general health perceptions (57.7 vs 82.1), mental health (61.3 vs 79.6), vitality (53.5 vs 67.8), role limitations owing to physical (69.6 vs 95.0) and emotional problems (67.2 vs 88.4), and social functioning (75.2 vs 89.9). CONCLUSIONS: Lower SF-36 scores may reflect patients' assessments of the balance among epilepsy, seizures, and antiepileptic drug therapy-related effects. Incorporating health status information into therapeutic decision making may help to attain the ultimate goal of improving patients' health. PMID- 8700787 TI - Effects of nicotinic acid on poloxamer 407-induced hyperlipidemia. AB - We attempted to determine the mechanism(s) of poloxamer (P)-407-induced hyperlipidemia in rats by administering a lipid-lowering drug with a known mechanism of action. Five weight-matched animals were assigned to each of four treatment groups. Two groups received P-407 300 mg/ml and two received saline 1 ml. One of the P-407 and one of the saline groups were administered nicotinic acid 100 mg/kg by intraperitoneal injection at 6-96 hours after blood sampling. Blood samples were collected at 7 points from time zero to 120 hours and analyzed for triglyceride and cholesterol concentrations. The detergent produces hypertriglyceridemia (HTG) increasing from 53.4 +/- 7.0 mg/dl (time zero) to 4026.9 +/- 42.1 mg/dl by 24 hours. The HTG response was significantly attenuated by nicotinic acid (at t = 24 hrs). This, however, was followed by an average triglyceride concentration increase of 2.8-fold from 72 to 120 hours. The detergent produces a dramatic hypercholesterolemia (HCHO), increasing cholesterol from 47.5 +/- 1.8 mg/dl to 468.5 +/- 27.9 mg/dl by 48 hours. The HCHO was significantly affected by nicotinic acid administration during the accumulation phase. Nicotinic acid reduced cholesterol concentration from 364.4 +/- 16.1 mg/dl to 276.8 +/- 16.4 mg/dl at 24 hours (p < 0.05). It is a potent antilipolytic agent, limiting the free fatty acids available for the synthesis of triglyceride and cholesterol. These data suggest that P-407 may act by stimulating the release of free fatty acids from the adipocyte for at least 24 hours after injection. PMID- 8700788 TI - Pharmaceutical marketing: implications for medical residency training. AB - An educational intervention was developed to improve family practice residents' ability to obtain useful information from pharmaceutical representatives. The curriculum is based on the traditional one-on-one drug detail. The objectives are to develop residents' skills in controlling the interview, promote skills for critically analyzing drug-promotional material, and discuss ethical issues. The contents include an assessment tool, suggested readings, and interview questions with rationale. After 5 years, residents' confidence in all areas of the curriculum improved significantly. PMID- 8700789 TI - ASHP-ACCP supplemental standard and learning objectives for specialized residency training in pharmacotherapy practice. PMID- 8700790 TI - Insights into mechanisms of cisplatin resistance and potential for its clinical reversal. AB - Cisplatin in combination with other cytotoxic agents is the backbone for a potential cure of testicular germ cell neoplasms and is a critical factor in the substantial activity observed in the treatment of small cell lung cancer, bladder cancer, and ovarian germ cell tumors. Resistance to cisplatin at the onset of treatment or at relapse limits its curative potential, however. Laboratory studies using both cells selected for cisplatin resistance by exposure to sublethal concentrations and biopsy specimens from patients' tumors provide insights for the potential mechanisms of resistance. The mechanisms identified in vitro include a complex and wide array of related and unrelated pathways such as alterations in cellular drug transport, enhanced DNA repair dependent and independent of signal transduction pathways, and enhanced intracellular detoxification such as glutathione and metallothionein systems. Studies of these mechanisms have identified a number of agents with known potential for administration to humans and that reverse cisplatin resistance in vitro; for example, reversal of cellular accumulation defects by dipyridamole; inhibition of DNA repair by hydroxyurea, pentoxifylline, and novobiocin; inhibition of the glutathione system by ethacrynic acid and buthionine sulfoximine; and inhibition of signal transduction pathways by cyclosporine, tamoxifen, and calcium channel blocking agents. Current phase I clinical trials are focusing on the most effective doses and schedules to administer these agents in combination with cisplatin. Initial uncontrolled trials in limited numbers of patients suggest that the addition of modulators of cisplatin has the potential to reverse resistance in patients previously failing therapy. Another promising avenue for circumventing cisplatin resistance is the development of noncross-resistant platinum analogs. PMID- 8700791 TI - Dornase alfa: a new option in the management of cystic fibrosis. AB - Recombinant human DNase I, or dornase alfa, is the first new therapy developed specifically for cystic fibrosis in almost 30 years. It selectively digests extracellular DNA and reduces the viscosity of purulent sputum. In clinical trials dornase alfa modestly improved pulmonary function, slightly decreasing the number of respiratory exacerbations requiring parenteral antibiotics compared with placebo. Phase III studies suggest that patients receiving dornase alfa also spend slightly fewer days in the hospital than those treated with placebo. The aerosolized preparation is safe and generally well tolerated. Voice alteration and sore throat are the most commonly reported adverse effects. Further research is necessary to determine the optimum time to initiate therapy and to evaluate the agent's pharmacoeconomic impact on the treatment of cystic fibrosis. Aerosolized dornase alfa should always be given in conjunction with standard cystic fibrosis therapies including antibiotics, chest physiotherapy, and pancreatic enzyme supplementation. PMID- 8700792 TI - Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease. AB - Alcohol withdrawal syndrome (AWS) may result in nausea, vomiting, diarrhea, weakness, sweating, tremors, tachycardia, hypertension, agitation, delirium, hallucinations, seizures, and death beginning 6 hours after alcohol cessation in alcoholics. Benzodiazepines are cross-tolerant with ethanol and are considered first-line therapy for treating AWS. Chlordiazepoxide and diazepam are first metabolized by hepatic oxidation, then glucuronidation. Lorazepam and oxazepam undergo only hepatic glucuronidation. Benzodiazepine oxidation is decreased in persons with liver disease and the elderly. Accumulation with resultant excessive sedation and respiratory depression may be significant when administering chlordiazepoxide or diazepam to patients with impaired oxidative metabolism. Lorazepam and oxazepam metabolism is minimally affected by age and liver disease. Chlordiazepoxide and diazepam are erratically absorbed by the intramuscular route. Lorazepam is predictably absorbed by the intramuscular route. Oxazepam is not available in parenteral form. Lorazepam appears to be the safest empiric choice among the various benzodiazepines for treating AWS in the elderly and in patients with liver disease, or those who require therapy by the intramuscular route. PMID- 8700793 TI - Enhanced oral cyclosporine absorption with water-soluble vitamin E early after liver transplantation. AB - We evaluated the effect of Liqui-E, a water-soluble vitamin E preparation, on cyclosporin A (CyA) whole blood concentration in liver transplant recipients, and its impact on the cost of CyA. Patients were 26 liver transplant recipients (19 adults, 7 children) who were unable to achieve and maintain therapeutic CyA whole blood concentrations with the standard recommended oral daily dose in the early post-transplant period. Liqui-E 6.25 IU/kg orally was administered with CyA every 12 hours (median time of starting Liqui-E day 14.5). With Liqui-E, the daily oral CyA requirements (mean +/- SD) were decreased in adults from 22.6 +/- 8.9 to 16.2 +/- 7.3 mg/kg/day (p < 0.001) and in children from 78.6 +/- 34.1 to 53.7 +/- 35.0 mg/kg/day (p < 0.02); intravenous administration of CyA was unnecessary. The CyA trough concentrations (mean +/- SD) before and after Liqui-E were 670 +/- 186 and 1012 +/- 216 ng/ml, respectively, in adults (p < 0.001) and 732 +/- 187 and 1052 +/- 166 ng/ml, respectively, in children (p < 0.01). When given with Liqui-E, the daily cost of CyA decreased by 26% in both adults and children. No clinical or biochemical evidence of Liqui-E toxicity was observed. Thus its administration in the early post-transplantation period can enhance CyA absorption in adults and children who are unable to achieve adequate whole blood concentrations with the usual recommended oral dosages. In addition, a significant cost saving can be realized by coadministration. PMID- 8700794 TI - Intranasal desmopressin-induced hyponatremia. AB - Desmopressin is a commonly used, well-tolerated agent for the treatment of primary nocturnal enuresis and central diabetes insipidus. Intranasal desmopressin provides symptomatic relief with few serious complications. A 29 year-old woman with a long history of primary nocturnal enuresis began treatment with intranasal desmopressin. Although the enuresis ceased, she developed throbbing headaches, nausea, vomiting, paresthesia, lethargy, fatigue, and altered mental status over the next 7 days. When she came to the emergency room her sodium concentration was 127 mmol/L. The history of desmopressin use was not obtained at that time. She was treated with intravenous fluids and discharged. The symptoms returned and worsened over the next 4 days, and she returned to the emergency room stuporous. A repeat sodium was 124 mmol/L, and she was admitted. The history of desmopressin use was still not available. Medical evaluations included computerized tomography, lumbar puncture, complete blood counts, serum chemistries, and serologies. The next morning the woman was improved and informed clinicians of her desmopressin use. Without other causes for the hyponatremia, she was diagnosed with the syndrome of inappropriate antidiuretic hormone, presumably caused by desmopressin. Within 24 hours of fluid restriction and cessation of desmopressin, her symptoms and hyponatremia resolved. A review of the literature found 11 children and 2 adults in whom intranasal desmopressin was associated with hyponatremia, all of whom experienced seizures or altered mental status. Our patient illustrates the importance of early recognition and treatment of hyponatremia before the onset of seizures. When vague symptoms develop during desmopressin therapy, hyponatremia must be considered as part of the differential diagnosis. It may also be prudent to screen for electrolyte abnormalities in patients taking this agent to prevent serious iatrogenic complications. PMID- 8700795 TI - Intravenous ketorolac for pain management in a ventilator-dependent patient with thermal injury. AB - A patient with a long-standing history of chronic obstructive pulmonary disease suffered a thermal injury over 20% of his total body surface area. He required opiates for pain management and benzodiazepines for anxiety associated with dressing changes. The narcotics compromised his pulmonary function and level of consciousness, and interfered with several attempts to wean him from ventilator support. Intravenous ketorolac instead of narcotics before dressing changes alleviated the respiratory depression and returned his partial pressure of carbon dioxide-mediated respiratory drive to normal. With these changes, including changes in respiratory rate to tidal volume, he was successfully weaned from ventilatory support. In addition, the patient's level of consciousness improved. These changes increased his participation in his daily physical therapy sessions. PMID- 8700796 TI - Alopecia associated with zidovudine therapy. AB - Alopecia has been described in patients infected with the human immunodeficiency virus (HIV). Zidovudine reportedly influences hair growth in these patients, causing regrowth or thickening. A 33-year-old HIV-infected man developed alopecia areata after beginning zidovudine therapy. The alopecia reversed after the drug was discontinued. PMID- 8700797 TI - A review of NMDA receptors and the phencyclidine model of schizophrenia. AB - Current models of drug-induced psychosis insufficiently describe the symptoms of schizophrenia. Phencyclidine-induced psychosis is a model that more completely reflects the pathophysiology of the disease. By decreasing glutamatergic neurotransmission, phencyclidine decreases gamma-aminobutyric acid release from the nucleus accumbens, striatum, and hippocampus (manifested by MK-801); may inhibit tonic release of dopamine from the nucleus accumbens and striatum, resulting in increased dopamine phasic reactivity; and decreases long-term potentiation. Glutamatergic system dysfunction may be involved, but pharmacologic manipulation has not revealed a clear mechanism of this dysfunction. PMID- 8700798 TI - Extent of community-based delivery of pharmaceutical care in Virginia. AB - This study attempted to define the characteristics and process components of pharmaceutical care, and to quantify the extent to which they compare in community pharmacists' perception of practice. Published literature and personal interviews were synthesized into a 75-question, cross-sectional, self-evaluated survey that was sent to all in-state members of the Virginia Pharmacists Association. A Community-based Pharmaceutical Care Index (CPCI) was developed to categorize and compare respondents. Individuals with scores greater than 1 standard deviation above (CPCI > or = 72.6, 14%, n = 91) and below (CPCI < or = 44.3, 16%, n = 106) the mean (CPCI = 58.4) were defined as high- and low-CPCI pharmacists, respectively. The response rate for the survey was 58% (972/1672). The high-CPCI pharmacists practiced predominantly in independently owned pharmacies in rural Virginia and appeared to have good rapport with their patients and local physicians. The presence of high-CPCI pharmacists working in chain-owned pharmacies indicated that the setting was not the only factor determining the decision to practice pharmaceutical care. As the prescription volume increased beyond 150/day, the number of high-CPCI pharmacists able to maintain their practice style rapidly declined. The CPCI allows differentiation and comparison of individual pharmacists along the spectrum of patient care. PMID- 8700799 TI - Expression and processing of peptidylglycine alpha-amidating monooxygenase messenger RNA in rat prostate. AB - The prostate gland contains neuroendocrine cells and amidated neuroendocrine peptides whose presence has been related to aggressive forms of prostate cancer. The enzyme peptidylglycine alpha-amidating monooxygenase (PAM) is critical to the bio-synthesis of amidated peptides and is commonly present in neuroendocrine cells. By northern blot hybridization analysis, PAM mRNA was detected in similar quantities in dorsolateral and ventral prostates of 3-month-old and 13-month-old rats. Multiple forms of PAM mRNA were present whose size distribution was more similar to PAM mRNAs found in pituitary than atrium. Alternative splice sites in PAM mRNA were investigated by reverse-transcriptase polymerase chain reaction. Similar alternatively spliced forms of PAM mRNA were found in both prostate lobes, pituitary, and atrium. However, the distribution of forms in the prostate most resembled that of pituitary. Multiple forms of PAM mRNA are present in prostate and may serve as markers of neuroendocrine differentiation. PMID- 8700800 TI - Evidence of stem cells in the adult prostatic epithelium based upon responsiveness to mesenchymal inductors. AB - Ductal tips approximately 300 microM in length from adult rat dorsal (DP), lateral type 1 (L1), and lateral type 2 (L2) prostates were combined with mesenchyme from the embryonic urogenital sinus (UGM), neonatal seminal vesicle (SVM), or neonatal bulbourethral gland (BUGM) and grafted underneath the renal capsule of syngeneic male hosts. Following 1 month of in vivo growth, all tissue recombinants formed large masses of prostatic ductal tissue, which represented massive growth of the original population of prostatic epithelial cells. Examination of secretory protein expression in these tissue recombinants indicated that each mesenchyme influenced secretory function in the adult prostatic epithelium in a characteristic way. SVM maintained expression of DP-1 and probasin in prostatic ducts of DP, L1, and L2, which normally express these proteins. BUGM induced expression of C3 in prostatic ducts of the DP, L1, and L2, which normally do not express C3. UGM induced the expression of DP-1, probasin, and C3 in prostatic ducts from all dorsal-lateral lobes. Mesenchymal induction of massive epithelial growth, new ductal branching morphogenesis, and change in prostatic lobe identity are indicative of the presence of stem cells in adult prostatic epithelium because high proliferative capacity, tissue regeneration, and pluripotency (change in functional differentiation) are hallmarks of stem cells. PMID- 8700801 TI - Molecular biology of prostatic intraepithelial neoplasia. AB - High-grade PIN is the most likely precursor of prostatic adenocarcinoma, according to virtually all available evidence to date. The clinical importance of recognizing PIN is based on its strong association with prostatic carcinoma. PIN has a high predictive value as a marker for adenocarcinoma. Its identification in biopsy specimens of the prostate warrants further search for concurrent invasive carcinoma. PIN is associated with progressive abnormalities of phenotype and genotype intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis. There is progressive gain or loss of a wide variety of biomarkers, including morphometric markers, differentiation markers, stromal markers, growth factors and associated receptors, oncogenes, tumor suppressor genes, and chromosomes. Abnormalities in expression of most biomarkers are amplified in the progression from high-grade PIN to localized cancer, metastatic cancer, and hormone-refractory cancer. Oncogenesis of prostatic carcinoma probably occurs through the selection of several genetic changes, each modifying the expression or function of genes controlling cell growth and differentiation. Further studies are needed to evaluate the function and prognostic value of oncogene expression in the normal, preneoplastic, and neoplastic prostate. PMID- 8700802 TI - Induction of apoptosis in prostatic tumor cell line DU145 by staurosporine, a potent inhibitor of protein kinases. AB - We are interested in studying the possibility of modulating prostatic cell growth by manipulating apoptosis. Here we show that 1 microM staurosporine (STS) induces a human androgen-independent prostatic tumor cell line, DU145, to undergo dramatic changes in morphology and results in programmed cell death. Several genes involved in apoptosis were analyzed for expression in STS-treated and untreated DU145 cells. It was observed that these genes were differentially regulated. The expression level of bcl-2, bcl-xL, Ich-1L remains unchanged in treated and untreated cells. On the other hand, DAD1 and interleukin-1 beta converting enzyme (ICE) were downregulated while bcl-xs and Ich-1s were upregulated. By blocking bcl-2 gene expression using antisense oligonucleotides, it was determined that the anti-bcl-2 oligonucleotides have no effect on the proliferation of DU145 or STS-treated DU145 cells. These results demonstrate that programmed cell death can be induced in an androgen-independent prostatic cancer cell line and BCL-2 was found not to play an important role in preventing STS induced apoptosis in the DU145 cell line. PMID- 8700803 TI - Relative and total volume of histological components in benign prostatic hyperplasia: relationships between histological components and clinical findings. AB - To investigate the correlation between histological differences and clinical findings in patients with benign prostatic hyperplasia (BPH), quantitative morphometrical analysis on prostate was performed on 26 specimens obtained by TURP. The relative and total volume of each histological component were obtained. In this series, the proportion of fibrous tissue element showed a weak positive correlation with prostatic volume (r = 0.499, P = 0.0087). The relative volume of the smooth muscle component showed an inverse correlation with prostatic volume (r = -0.488, P = 0.0105). Patient age and symptom score showed no relationship with the relative volume of histological components. The total volume of all histological components increased with prostatic volume. However, an increase in the fibrous tissue element appeared to be predominant in prostatic enlargement (r = 0.970, P < 0.0001). Although the total volume of all histological components increased with prostatic size, fibrous tissue appeared to play a major role in prostatic enlargement in BPH. PMID- 8700804 TI - Effects of finasteride on health-related quality of life in men with symptomatic benign prostatic hyperplasia. Finasteride Study Group. AB - The effects of urinary symptoms on health-related quality of life (HRQL) are important in therapeutic decision making. Few have evaluated the treatment effects on HRQL in men with benign prostatic hyperplasia (BPH), even though increased urinary symptoms are associated with greater worry, bother, and interference with living activities. We report on patient assessments of such disease-specific measures as well as general HRQL measures from two placebo controlled clinical trials of finasteride in the treatment of symptomatic BPH. Patients treated with finasteride appeared to have greater improvement than placebo-treated patients in disease-specific measures and in patient global assessment. The treated group appeared to have a greater mean increase in sexual domain scores. As expected, general measures (health rating, life satisfaction, ladder of life) changed little. Thus, treatment with finasteride appears to reduce bother, worry, and activity interference due to symptoms but in a small percentage of men may lead to slightly reduced sexual function. PMID- 8700806 TI - [Immunologic reactions in the male and female reproductive system]. AB - This review describes presence and significance of antisperm antibodies (ASA) in male and female reproductive compartments. We described their relevance to infertility in humans. A structure and function of cervical mucus as the environment of females defensive reactions against all the invasive factors is outlined. There are also briefly characterized techniques of ASA detection. PMID- 8700805 TI - Expression and regulation of metallothionein mRNA levels in the prostates of noble rats: lack of expression in the ventral prostate and regulation by sex hormones in the dorsolateral prostate. AB - The rat prostate is composed of two anatomically well-defined regions designated as the ventral prostate (VP) and the dorsolateral prostate (DLP). VP and DLP are known to exhibit marked cytological, biochemical, and functional differences including differential susceptibilities to carcinogens. While the VP is uniquely susceptible to cadmium carcinogenicity [1,2], the DLP is sensitive to sex hormone induced cancer [3,4]. The role played by the heavy metal binding protein, metallothionein (MT), in the prostate is largely unknown. It is still controversial as to whether MT is expressed in the rat gland. The aim of the present study is to examine the expression pattern of MT mRNA in the rat gland and its probable regulation by heavy metal ions and sex hormones, in order to gain insight into the biological function of MT in the prostate. Northern hybridization and reverse transcriptase-polymerase chain reaction analyses revealed constitutive expression of MT mRNA in the DLP and a lack of expression of the transcript in the VP. In situ hybridization localized the transcript to the epithelium of the DLP, with the lateral prostate epithelium exhibiting the highest level of expression. Administration of cadmium and zinc failed to induce MT transcription in the VP, nor were these treatments effective in elevating levels of MT mRNA in the DLP. A 60% reduction in MT message levels was observed in the DLP following orchiectomy. MT transcript levels in the DLPs of castrates were restored by readministration of androgen to the animals. Long-term treatments (16 weeks) of rats with estradiol-17 beta (E2) or testosterone (T) plus E2 induced a 2.8-fold and a 5-fold increase in MT message content in the DLP, respectively. In sum, MT mRNA was shown to be absent in the VP and was not inducible by heavy metal ions or hormones in this prostatic lobe. These findings substantiate the belief that MT plays a role in heavy metal detoxification and deficiency in its expression may contribute to the unique susceptibility of the VP to cadmium carcinogenicity. By contrast, constitutive expression of MT was demonstrated in the DLP, which was shown to be regulated by androgen and not by exogenously administered heavy metal ions. These results suggest a participatory role of MT in the normal functioning of the DLP. The fact that high levels of MT mRNA were induced in the DLP following long-term estrogenic or conjoint androgenic-estrogenic action alludes to the possibility that MT may serve as an intracellular antioxidant in DLP cells. PMID- 8700807 TI - [Glutamate receptors in the central nervous system]. AB - A lot of clinical processes following excessive stimulation of glutamate receptors seem to participate in pathophysiology of numerous acute and chronic neurological disorders. The whole of these reactions has been named as "glutamate cascade", because of the central role of glutamate in initiation and intensification of these processes. In this article, classification of different types of glutamate receptors and several hypotheses concerning mechanisms of glutamate neurotoxic activity are presented. A wide variety of neurological diseases, which etiologies are more or less connected with glutamate toxicity are discussed. At last, the future perspectives for treatment by drugs which action is thought to be mediated through glutamate receptors are presented. PMID- 8700808 TI - [The role of free radicals in pathogenesis of insulin dependent diabetes mellitus]. AB - The role of free radicals as well as cytokines (IL-1, tumor necrosis factor alpha, interferon gamma) and nitric oxide in the immune-mediated processes leading to the beta-cell destruction during IDDM is described. It is also pointed that the excess of IL-1ra in relation to IL-1 prevents IL-1 toxicity to beta cells. PMID- 8700809 TI - [Interaction of free radicals with proteins]. AB - This review describe the generation of free radicals in the cells under the influence of exogenously and endogenously acting factors. The interactions of free radicals with proteins and amino acids and the consequences of these effects are also presented. PMID- 8700810 TI - [Prevention and treatment of uremic autonomic neuropathy]. AB - The autonomic impairment, which is the frequent complication of end-stage renal failure, may eventually trigger numerous crippling consequences. It is doubtful if standard dialysis techniques may effectively treat once developed autonomic lesions. Renal transplantation seems to be much more efficient. The article points out the discrepancies in symptoms attributable to autonomic impairment and results of autonomic testing, discusses also differences between somatic and autonomic nervous system involvement in uremic patients. The one of the most important part of the article describes the practical approach to the patient with severely symptomatic uremic autonomic neuropathy. Finally the authors articulate their proposals for further research on uremic autonomic neuropathy. PMID- 8700811 TI - Asthma. Specific preventive strategies. AB - Asthma can be a destructive disease over time, resulting in partially irreversible obstruction. Early intervention is essential, and preventive strategies are preferred to treatment for flare-ups. These strategies include intensive patient education and constant monitoring of airflow as well as effective pharmacotherapy and management of concomitant disorders and side effects. Because allergy is a component in half or more of patients, consultation with an allergist is recommended. New agents for both oral use and inhalation are either in development or will soon be available. PMID- 8700812 TI - Safe allergen immunotherapy. The correct allergen, the appropriate patient, the adequate dose. AB - Effective immunotherapy has been shown to be allergen-specific, dose-dependent, and duration-dependent. Patients must receive adequate doses of the relevant allergen to obtain benefit, and most require 3 to 5 years of injections to maintain prolonged benefit after injections are stopped. Concurrently, patients must cooperate by modifying their environment and using some medications during difficult seasons. Although serious reactions to immunotherapy are relatively rare, a physician must be readily available whenever injections are administered, and office staff need to recognize and be ready to respond to systemic reactions. PMID- 8700813 TI - Unstable angina. Strategies to minimize myocardial injury. AB - The primary goals in treatment of unstable angina are to relieve pain and prevent or limit myocardial infarction or ischemia. Patients with distinct, rapid progression of their usual angina pattern should be admitted to a coronary care unit and given heparin and intravenous nitrates as well as aspirin. Cardioselective beta blockers should also be administered when there are no contraindications. Intravenous thrombolytic agents are indicated in patients with objective evidence of ischemia who fit criteria for this therapy. However, thrombolysis is not advocated for routine treatment of unstable angina. Percutaneous transluminal coronary angioplasty or coronary artery bypass grafting should be considered--depending on the location, age, and morphology of the culprit lesion and the degree of left ventricular dysfunction--in patients who have refractory or recurrent ischemia despite aggressive medical therapy. However, in general, high-technology interventions are not a substitute for long term regimens, such as risk-factor and lifestyle modification, daily aspirin, and pharmacologic therapies aimed at maximizing cardiac function. PMID- 8700814 TI - Feeling hopeless and helpless. When anxiety symptoms coexist with depressive disorder. AB - Among patients with psychiatric disorders, a significant number have a depressive disorder and coexisting symptoms of anxiety. The overlapping conditions present physicians with a confusing array of symptoms that, in the past, has made diagnosis and therapy difficult. Although the anxiety symptoms may not be sufficient to meet diagnostic criteria for an anxiety disorder, they can have a profound influence on the severity of and prognosis for the depressive illness. To clarify diagnosis when symptoms of both depression and anxiety are present, it is important to consider elements such as predominant mood, sleep patterns, psychomotor signs, and suicidal ideation, which serve to differentiate between the two disorders. Once a diagnosis is established, appropriate use of pharmacotherapy (especially antidepressant agents that have anxiolytic side effects) and psychotherapy can help relieve symptoms and lead to a favorable outcome. PMID- 8700815 TI - Narrowing the gray zone. How clinical practice guidelines can improve the decision-making process. PMID- 8700816 TI - Low-frequency magnetic fields and cancer. What you should know and what to tell your patients. AB - Although the available scientific data that low-frequency magnetic fields play a role in the etiology of cancer are inconclusive, this link has been suggested by epidemiologic data and proliferated in the nonscientific literature. Electric power lines, cellular phones, and personal computers are examples of sources that have been blamed for medical problems, particularly cancer. Since exposure to low frequency magnetic fields is universal and practically unavoidable, what can physicians advise their patients? In light of the controversy surrounding this issue, the best advice may be to minimize such exposure. Future research on the health implications of low-frequency magnetic fields appears to be warranted. PMID- 8700817 TI - Infectious myositis. A tropical disease steals out of its zone. AB - Infectious myositis is an acute infection of skeletal muscle that is increasing in prevalence with the increased incidence of HIV disease. Typical presentation is asymmetric swelling of an isolated muscle, with exquisite pain and fever. Results of laboratory studies are usually nonspecific, but magnetic resonance imaging of the affected area suggests the diagnosis. Muscle biopsy and direct identification of the pathogen on tissue culture are required, because the list of potential pathogens is long. With prompt treatment, most patients achieve complete resolution and return to their preinfection level of health. PMID- 8700818 TI - Bowel preparation before colonoscopy. Choosing the best lavage regimen. AB - A review of the relevant English-language literature on bowel cleansing before colonoscopy yielded results of randomized trials comparing a variety of regimens, including polyethylene glycol (PEG)-electrolyte lavage, 3-day clear liquid diet with laxatives or prokinetics, and oral sodium phosphate, as well as these regimens combined with agents such as metoclopramide, cisapride, and senna. Balancing the importance of such factors as cleansing effectiveness, safety, ease of completion, side effects, patient tolerance, and cost, the authors recommend four methods: (1) PEG-electrolyte solution (eg, CoLyte, GoLYTELY, NuLytely) in combination with senna (eg, X-Prep), (2) PEG-electrolyte solution alone (either single dose or split dose), (3) oral sodium phosphate (Fleets Phosphosoda) given in split dose, and (4) oral magnesium citrate in combination with rectal pulsed irrigation. PMID- 8700819 TI - Bladder cancer. Current diagnostic methods and treatment options. AB - The incidence of bladder cancer has grown over the years, presumably in part because of increasing exposure to carcinogenic agents in modern-day life. Drs Badalament and Schervish outline the latest diagnostic and staging methods for the disease and summarize treatment options for superficial, invasive, and metastatic cancers, including discussion of various methods for urinary diversion following cystectomy. PMID- 8700820 TI - Eyelid dermatitis. A common, often confounding rash. AB - Five common conditions and several less common ones cause eyelid dermatitis. Diagnosis and treatment depend on recognizing their characteristics, obtaining a good history, performing a careful skin examination, administering and interpreting patch tests, prescribing the proper medications at the right time, and teaching the patient how to avoid trouble in the future. A case report illustrates the importance of integration and progression of diagnostic and therapeutic steps in resolving the management challenges of eyelid dermatitis. PMID- 8700821 TI - Patellar tendon rupture. The importance of timely recognition and repair. AB - Patellar tendon rupture is not uncommon in active adults, although it occurs less often than rupture of the ligaments. The diagnosis is easily missed on initial examination. Delay of surgical treatment leads to a complicated repair and a less functional outcome. The key physical finding is inability to actively extend the affected leg. Patients may also have severe, rapid swelling and depression in the infrapatellar region. The mechanism of injury usually involves forced hyperflexion or rapid extension from a weight-bearing position. Radiographic findings include patella alta and possible subluxation. This case report described an infrapatellar tendon rupture in a patient with no underlying systemic disease or history of repetitive trauma. PMID- 8700822 TI - 'I need a referral'. PMID- 8700823 TI - Surplus of physicians. PMID- 8700824 TI - Surplus of physicians. PMID- 8700825 TI - Allergic and nonallergic rhinitis. Directing medical therapy at specific symptoms. AB - Rhinitis is a common complaint, especially during the allergy season. Physicians can often identify the probable allergen or irritant with history taking, and skin tests may be helpful in confirming the clinical impression. Often, environmental control measures can provide significant relief. Successful drug treatment hinges on selection of the proper class of medication for a given patient's type and severity of symptoms. Antihistamines remain a mainstay for reducing sneezing, itching, and nasal discharge. New oral agents are nonsedating, and an eyedrop form is available for bothersome eye symptoms. Decongestants reduce nasal blockage and are often especially beneficial when used in combination with antihistamines, In moderate to severe rhinitis, intranasal corticosteroids are the most effective treatment. PMID- 8700826 TI - Urticaria. The diagnostic challenge of hives. AB - Hives pose a diagnostic challenge to physicians. With an acute episode, a careful look for possible triggers and relief of symptoms with H1 antihistamines are usually sufficient. For both urticaria and angioedema, the most helpful diagnostic tool may be a carefully taken medical history, including a family history. When a patient's urticaria lasts for more than 6 weeks, further physical and laboratory evaluation is warranted. Treatment of chronic urticaria generally involves the use of antihistamines first. Corticosteroids are to be avoided, if possible. PMID- 8700827 TI - Anaphylaxis. How to recognize, treat and prevent potentially fatal attacks. AB - Anaphylaxis is a potentially fatal condition. Causes range from bee stings to drugs, foods, and exercise. Onset is usually sudden, and a delayed reaction may occur hours after the initial reaction. Treatment consists of airway maintenance and support of the blood pressure with fluid expanders, epinephrine, and oxygen. Additional agents, such as corticosteroids, antihistamines, vasopressors, glucagon, atropine sulfate, and isoproterenol hydrochloride, can be useful. Prevention is the most important part of anaphylaxis management. In patients with known allergies, self-administration of epinephrine plays a key role in reducing mortality. PMID- 8700829 TI - The catalytic mechanism of beta-lactamases: NMR titration of an active-site lysine residue of the TEM-1 enzyme. AB - Beta-Lactamases are widespread in the bacterial world, where they are responsible for resistance to penicillins, cephalosporins, and related compounds, currently the most widely used antibacterial agents. Detailed structural and mechanistic understanding of these enzymes can be expected to guide the design of new antibacterial compounds resistant to their action. A number of high-resolution structures are available for class A beta-lactamases, whose catalytic mechanism involves the acylation of a serine residue at the active site. The identity of the general base which participates in the activation of this serine residue during catalysis has been the subject of controversy, both a lysine residue and a glutamic acid residue having been proposed as candidates for this role. We have used the pH dependence of chemical modification of epsilon-amino groups by 2,4,6, trinitrobenzenesulfonate and the pH dependence of the epsilon-methylene 1H and 13C chemical shifts (in enzyme selectively labeled with [epsilon-13C]lysine) to estimate the pKa of the relevant lysine residue, lysine-73, of TEM-1 beta lactamase. Both methods show that the pKa of this residue is > 10, making it very unlikely that this residue could act as a proton acceptor in catalysis. An alternative mechanism in which this role is performed by glutamate-166 through an intervening water molecule is described. PMID- 8700828 TI - Going mobile: microtubule motors and chromosome segregation. AB - Proper chromosome segregation in eukaryotes depends upon the mitotic and meiotic spindles, which assemble at the time of cell division and then disassemble upon its completion. These spindles are composed in large part of microtubules, which either generate force by controlled polymerization and depolymerization or transduce force generated by molecular microtubule motors. In this review, we discuss recent insights into chromosome segregation mechanisms gained from the analyses of force generation during meiosis and mitosis. These analyses have demonstrated that members of the kinesin superfamily and the dynein family are essential in all organisms for proper chromosome and spindle behavior. It is also apparent that forces generated by microtubule polymerization and depolymerization are capable of generating forces sufficient for chromosome movement in vitro; whether they do so in vivo is as yet unclear. An important realization that has emerged is that some spindle activities can be accomplished by more than one motor so that functional redundancy is evident. In addition, some meiotic or mitotic movements apparently occur through the cooperative action of independent semiredundant processes. Finally, the molecular characterization of kinesin related proteins has revealed that variations both in primary sequence and in associations with other proteins can produce motor complexes that may use a variety of mechanisms to transduce force in association with microtubules. Much remains to be learned about the regulation of these activities and the coordination of opposing and cooperative events involved in chromosome segregation; this set of problems represents one of the most important future frontiers of research. PMID- 8700830 TI - DNA strand breakage, activation of poly (ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite. AB - The free radicals nitric oxide and superoxide anion react to form peroxynitrite (ONOO-), a highly toxic oxidant species. In vivo formation of ONOO- has been demonstrated in shock and inflammation. Herein we provide evidence that cytotoxicity in cells exposed to ONOO- is mediated by DNA strand breakage and the subsequent activation of the DNA repair enzyme poly(ADP ribose) synthetase (PARS). Exposure to ONOO- (100 microM to 1 mM) inhibited mitochondrial respiration in cultured J774 macrophages and in rat aortic smooth muscle cells. The loss of cellular respiration was rapid, peaking 1-3 h after ONOO- exposure, and reversible, with recovery after a period of 6-24 h. The inhibition of mitochondrial respiration was paralleled by a dose-dependent increase in DNA strand breakage, reaching its maximum at 20-30 min after exposure to ONOO-. We observed a dose-dependent increase in the activity of PARS in cells exposed to ONOO-. Inhibitors of PARS such as 3-aminobenzamide (1 mM) prevented the inhibition of cellular respiration in cells exposed to ONOO-. Activation of PARS by ONOO--mediated DNA strand breakage resulted in a significant decrease in intracellular energy stores, as reflected by a decline of intracellular NAD+ and ATP content. 3-Aminobenzamide prevented the loss of NAD+ and ATP in cells exposed to ONOO-. In contrast, impairment of cellular respiration by the addition of the nitric oxide donors S-nitroso-N-acetyl-DL-penicillamine or diethyltriamine nitric oxide complex, was not associated with the development of DNA strand breaks, in concentrations up to 1 mM, and was largely refractory to PARS inhibition. Our results suggest that DNA damage and activation of PARS, an energy-consuming futile repair cycle, play a central role in ONOO--mediated cellular injury. PMID- 8700831 TI - A quantitative test to estimate neutralizing antibodies to the hepatitis C virus: cytofluorimetric assessment of envelope glycoprotein 2 binding to target cells. AB - Hepatitis C virus (HCV) is a major cause of chronic hepatitis. The virus does not replicate efficiently in cell cultures, and it is therefore difficult to assess infection-neutralizing antibodies and to evaluate protective immunity in vitro. To study the binding of the HCV envelope to cell-surface receptors, we developed an assay to assess specific binding of recombinant envelope proteins to human cells and neutralization thereof. HCV recombinant envelope proteins expressed in various systems were incubated with human cells, and binding was assessed by flow cytometry using anti-envelope antibodies. Envelope glycoprotein 2 (E2) expressed in mammalian cells, but not in yeast or insect cells, binds human cells with high affinity (Kd approximately 10(-8) M). We then assessed antibodies able to neutralize E2 binding in the sera of both vaccinated and carrier chimpanzees, as well as in the sera of humans infected with various HCV genotypes. Vaccination with recombinant envelope proteins expressed in mammalian cells elicited high titers of neutralizing antibodies that correlated with protection from HCV challenge. HCV infection does not elicit neutralizing antibodies in most chimpanzees and humans, although low titers of neutralizing antibodies were detectable in a minority of infections. The ability to neutralize binding of E2 derived from the HCV-1 genotype was equally distributed among sera from patients infected with HCV genotypes 1, 2, and 3, demonstrating that binding of E2 is partly independent of E2 hypervariable regions. However, a mouse monoclonal antibody raised against the E2 hypervariable region 1 can partially neutralize binding of E2, indicating that at least two neutralizing epitopes, one of which is hypervariable, should exist on the E2 protein. The neutralization-of-binding assay described will be useful to study protective immunity to HCV infection and for vaccine development. PMID- 8700832 TI - A role for the Msx-1 homeodomain in transcriptional regulation: residues in the N terminal arm mediate TATA binding protein interaction and transcriptional repression. AB - In a previous study we showed that the murine homeodomain protein Msx-1 is a potent transcriptional repressor and that this activity is independent of its DNA binding function. The implication of these findings is that repression by Msx-1 is mediated through its association with certain protein factors rather than through its interaction with DNA recognition sites, which prompted investigation of the relevant protein factors. Here we show that Msx-1 interacts directly with the TATA binding protein (TBP) but not with several other general transcription factors. This interaction is mediated by the Msx-1 homeodomain, specifically through residues in the N-terminal arm. These same N-terminal arm residues are required for repression by Msx-1, suggesting a functional relationship between TBP association and transcriptional repression. This is further supported by the observation that addition of excess TBP blocks the repressor action of Msx-1 in in vitro transcription assays. Finally, DNA binding activity is separable from both TBP interaction and repression, which further shows that these other activities of the Msx-1 homeodomain are distinct. Therefore, these findings define a role for the Msx-1 homeodomain, particularly the N-terminal arm residues in protein-protein interaction and transcriptional repression, and implicate a more complex role overall for homeodomains in transcriptional regulation. PMID- 8700833 TI - Nuclear/cytoplasmic localization of the von Hippel-Lindau tumor suppressor gene product is determined by cell density. AB - The product of the von Hippel-Lindau (VHL) tumor suppressor gene, the gene inactivated in VHL disease and in sporadic clear-cell renal carcinomas, has recently been shown to have as a functional target the transcription elongation complex, elongin (also called SIII). Here it is shown that there is a tightly regulated, cell-density-dependent transport of VHL into and/or out of the nucleus. In densely grown cells, the VHL protein is predominantly in the cytoplasm, whereas in sparse cultures, most of the protein can be detected in the nucleus. We have identified a putative nuclear localization signal in the first 60 and first 28 amino acids of the human and rat VHL protein, respectively. Sequences in the C-terminal region of the VHL protein may also be required for localization to the cytosol. These findings provide the initial indication of a novel cell density-dependent pathway that is responsible for the regulation of VHL cellular localization. PMID- 8700834 TI - Peroxynitrite-mediated nitration of tyrosine residues in Escherichia coli glutamine synthetase mimics adenylylation: relevance to signal transduction. AB - Treatment of Escherichia coli glutamine synthetase (GS) with peroxynitrite leads to nitration of some tyrosine residues and conversion of some methionine residues to methionine sulfoxide (MSOX) residues. Nitration, but not MSOX formation, is stimulated by Fe-EDTA. In the absence of Fe-EDTA, nitration of only one tyrosine residue per subunit of unadenylylated GS leads to changes in divalent cation requirement, pH-activity profile, affinity for ADP, and susceptibility to feedback inhibition by end products (tryptophan, AMP, CTP), whereas nitration of one tyrosine residue per subunit in the adenylylated GS leads to complete loss of catalytic activity. In the presence of Fe-EDTA, nitration is a more random process: nitration of five to six tyrosine residues per subunit is needed to convert unadenylylated GS to the adenylylated configuration. These results and the fact that nitration of tyrosine residues is an irreversible process serve notice that the regulatory function of proteins that undergo phosphorylation or adenylylation in signal transduction cascades might be seriously compromised by peroxynitrite-promoted nitration. PMID- 8700835 TI - Observation via one-dimensional 13Calpha NMR of local conformational substates in thermal unfolding equilibria of a synthetic analog of the GCN4 leucine zipper. AB - Synthesis of a 33-residue, capped leucine zipper analogous to that in GCN4 is reported. Histidine and arginine residues are mutated to lysine to reduce the unfolding temperature. CD and ultracentrifugation studies indicate that the molecule is a two-stranded coiled coil under benign conditions. Versions of the same peptide are made with 99% 13Calpha at selected sites. One-dimensional 13C NMR spectra are assigned by inspection and used to study thermal unfolding equilibria over the entire transition from 8 to 73 degrees C. Spectra at the temperature extremes establish the approximate chemical shifts for folded and unfolded forms at each labeled site. Resonances for each amino acid appear at both locations at intermediate T, indicating that folded and unfolded forms interconvert slowly (> >2 ms) on the NMR time scale. Moreover, near room temperature, the structured form's resonance is double at several, but not all, sites, indicating at least two slowly interconverting, structured, local conformational substates. Analysis of the dynamics is possible. For example, near room temperature at the Val-9, Ala-24, and Gly-31 positions, the equilibrium constant for interconversion of the two structured forms is near unity and the time scale is > or= 10-20 ms. PMID- 8700837 TI - Human stanniocalcin: a possible hormonal regulator of mineral metabolism. AB - We have isolated a human cDNA clone encoding the mammalian homolog of stanniocalcin (STC), a calcium- and phosphate-regulating hormone that was first described in fishes where it functions in preventing hypercalcemia. STC has a unique amino acid sequence and, until now, has remained one of the few polypeptide hormones never described in higher vertebrates. Human STC (hSTC) was found to be 247 amino acids long and to share 73% amino acid sequence similarity with fish STC. Polyclonal antibodies to recombinant hSTC localized to a distinct cell type in the nephron tubule, suggesting kidney as a possible site of synthesis. Recombinant hSTC inhibited the gill transport of calcium when administered to fish and stimulated renal phosphate reabsorption in the rat. The evidence suggests that mammalian STC, like its piscine counterpart, is a regulator of mineral homeostasis. PMID- 8700836 TI - The nucleation of receptor-mediated endocytosis. AB - A theory of the mechanical origins of receptor-mediated endocytosis shows that a spontaneous membrane complex formation can provide the stimulus for a local membrane motion toward the cytosol. This motion is identified with a nucleation stage of receptor-mediated endocytosis. When membrane complexes cluster, membrane deformation is predicted to be most rapid. The rate of growth of membrane depressions depends upon the relative rates of approach of aqueous cytosolic and extracellular fluids toward the cell membrane. With cytosolic and extracellular media characterized by apparent viscosities, the rate of growth of membrane depressions is predicted to increase as the extracellular viscosity nears the apparent viscosity of the cytosol and then to decrease when the extracellular viscosity exceeds that of the cytosol. To determine whether these trends would be apparent in the overall endocytosis rate constant, an experimental study of transferrin-mediated endocytosis in two different cell lines was conducted. The experimental results reveal the same dependence of internalization rate on extracellular viscosity as predicted by the theory. These and other comparisons with experimental data suggest that the nucleation stage of receptor-mediated endocytosis is important in the overall endocytosis process. PMID- 8700838 TI - Correlation between kinetics and RNA splicing of alpha-amino-3-hydroxy-5 methylisoxazole-4-propionic acid receptors in neocortical neurons. AB - In the cortex fast excitatory synaptic currents onto excitatory pyramidal neurons and inhibitory nonpyramidal neurons are mediated by alpha-amino-3-hydroxy-5 methylisoxazole-4-propionic acid (AMPA) receptors exhibiting cell-type-specific differences in their kinetic properties. AMPA receptors consist of four subunits (GluR1-4), each existing as two splice variants, flip and flop, which critically affect the desensitization properties of receptors expressed in heterologous systems. Using single cell reverse transcription PCR to analyze the mRNA of AMPA receptor subunits expressed in layers I-III neocortical neurons, we find that 90% of the GluR1-4 in nonpyramidal neurons are flop variants, whereas 92% of the GluR1-4 in pyramidal neurons are flip variants. We also find that nonpyramidal neurons predominantly express GluR1 mRNA (GluR1/GluR1-4 = 59%), whereas pyramidal neurons contain mainly GluR2 mRNA (GluR2/GluR1-4 = 59%). However, the neuron-type specific splicing is exhibited by all four AMPA receptor subunits. We suggest that the predominance of the flop variants contributes to the faster and more extensive desensitization in nonpyramidal neurons, compared to pyramidal cells where flip variants are dominant. Alternative splicing of AMPA receptors may play an important role in regulating synaptic function in a cell-type-specific manner, without changing permeation properties. PMID- 8700839 TI - Retinoid X receptor-selective ligands produce malformations in Xenopus embryos. AB - Retinoids exert pleiotropic effects on the development of vertebrates through the action of retinoic acid receptors (RAR) and retinoid X receptors (RXR). We have investigated the effect of synthetic retinoids selective for RXR and RAR on the development of Xenopus and zebrafish embryos. In Xenopus, both ligands selective for RAR and RXR caused striking malformations along the anterior-posterior axis, whereas in zebrafish only ligands specific for RAR caused embryonic malformations. In Xenopus, RAR- and RXR-selective ligands regulated the expression of the Xlim-1, gsc, and HoxA1 genes similarly as all-trans-retinoic acid. Nevertheless, RXR-selective ligands activated only an RXR responsive reporter but not an RAR responsive reporter introduced by microinjection into the Xenopus embryo, consistent with our failure to detect conversion of an RXR selective ligand to different derivatives in the embryo. These results suggest that Xenopus embryos possess a unique response pathway in which liganded RXR can control gene expression. Our observations further illustrate the divergence in retinoid responsiveness between different vertebrate species. PMID- 8700840 TI - Steel mutant mice are deficient in hippocampal learning but not long-term potentiation. AB - Mice carrying mutations in either the dominant white-spotting (W) or Steel (Sl) loci exhibit deficits in melanogenesis, gametogenesis, and hematopoiesis. W encodes the Kit receptor tyrosine kinase, while Sl encodes the Kit ligand, Steel factor, and the receptor-ligand pair are contiguously expressed at anatomical sites expected from the phenotypes of W and Sl mice. The c-kit and Steel genes are also both highly expressed in the adult murine hippocampus: Steel is expressed in dentate gyrus neurons whose mossy fiber axons synapse with the c-kit expressing CA3 pyramidal neurons. We report here that Sl/Sld mutant mice have a specific deficit in spatial learning. These mutant mice are also deficient in baseline synaptic transmission between the dentate gyrus and CA3 but show normal long-term potentiation in this pathway. These observations demonstrate a role for Steel factor/Kit signaling in the adult nervous system and suggest that a severe deficit in hippocampal-dependent learning need not be associated with reduced hippocampal long-term potentiation. PMID- 8700841 TI - Immune response of HLA-DQ8 transgenic mice to peptides from the third hypervariable region of HLA-DRB1 correlates with predisposition to rheumatoid arthritis. AB - The major histocompatibility complex class II genes play an important role in the genetic predisposition to many autoimmune diseases. In the case of rheumatoid arthritis (RA), the human leukocyte antigen (HLA)-DRB1 locus has been implicated in the disease predisposition. The "shared epitope" hypothesis predicts that similar motifs within the third hypervariable (HV3) regions of some HLA-DRB1 alleles are responsible for the class II-associated predisposition to RA. Using a line of transgenic mice expressing the DQB1*0302/DQA1*0301 (DQ8) genes in the absence of endogenous mouse class II molecules, we have analyzed the antigenicity of peptides covering the HV3 regions of RA-associated and nonassociated DRB1 molecules. Our results show that a correlation exists between proliferative response to peptides derived from the HV3 regions of DRB1 chains and nonassociation of the corresponding alleles with RA predisposition. While HV3 peptides derived from nonassociated DRB1 molecules are highly immunogenic in DQ8 transgenic mice, all the HV3 peptides derived from RA-associated DRB1 alleles fail to induce a DQ8-restricted T-cell response. These data suggest that the role of the "shared epitope" in RA predisposition may be through the shaping of the T cell repertoire. PMID- 8700842 TI - A recombinant antibody with the antigen-specific, major histocompatibility complex-restricted specificity of T cells. AB - Specific recognition of peptide/major histocompatibility complex (MHC) molecule complexes by the T-cell receptor is a key reaction in the specific immune response. Antibodies against peptide/MHC complexes would therefore be valuable tools in studying MHC function and T-cell recognition and might lead to novel approaches in immunotherapy. However, it has proven difficult to generate antibodies with the specificity of T cells by conventional hybridoma techniques. Here we report that the phage display technology is a feasible alternative to generate antibodies recognizing specific, predetermined peptide/MHC complexes. PMID- 8700843 TI - Cellular aging, destabilization, and cancer. AB - Three major characteristics of aging in animals are a slowdown of cell proliferation, an increase in residual bodies associated with age pigments, and a marked increase in the likelihood of neoplastic transformation. The 28 L subline of the NIH 3T3 line of mouse embryo fibroblasts exhibits all these characteristics when held at confluence for extended periods. The impairment of proliferation is the first behavioral characteristic detected in low density subcultures from the confluent cultures, and it persists through many cell generations of exponential multiplication. There is an equal degree of growth impairment among replicate cultures (lineages) recovered after each of 2 successive rounds of confluence, although heterogeneity appears after the third round. The growth impairment pervades the entire cell population of each lineage. The degree and duration of impairment increase with repeated rounds of confluence. A marked increase of residual bodies characteristic of age pigments occurs in the cytoplasm of all the cells kept under prolonged confluence. Neoplastic transformation first appears as foci of multilayered cells on a monolayered background of nontransformed cells. The transformed cells arise at different times in the lineages and originate from a very small fraction of the population. The transformed cells selectively overgrow the entire population in successive rounds of confluence leading to an increase in saturation density of each lineage at different times. Under cloning conditions, isolated colonies of transformed cells develop more slowly than colonies of nontransformed cells but eventually reach a higher population density. The regularity of persistent growth impairment among the lineages and the appearance of large numbers of residual bodies in all the cells of each population are more characteristic of an epigenetic process than of specific local mutations. although random chromosomal lesions cannot be ruled out. By contrast, the low frequency and stochastic character of neoplastic transformation are consistent with a conventional genetic origin. The advent in long-term confluent NIH 3T3 cultures of three cardinal characteristics of cellular aging in vivo recommends it as a model for aging cells. PMID- 8700844 TI - Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins. AB - In gene therapy to treat cancer, typically only a fraction of the tumor cells can be successfully transfected with a gene. However, in the case of brain tumor therapy with the thymidine kinase gene from herpes simplex virus (HSV-tk), not only the cells transfected with the gene but also neighboring others can be killed in the presence of ganciclovir. Such a "bystander" effect is reminiscent of our previous observation that the effect of certain therapeutic agents may be enhanced by their diffusion through gap junctional intercellular communication (GJIC). Herein, we present the evidence, from in vitro studies, that gap junctions could indeed be responsible for such a gene therapy bystander effect. We used HeLa cells for this purpose, since they show very little, if any, ability to communicate through gap junctions. When HeLa cells were transfected with HSV tk gene and cocultured with nontransfected cells, only HSV-tk-transfected HeLa cells (tk+) were killed by ganciclovir. However, when HeLa cells transfected with a gene encoding for the gap junction protein, connexin 43 (Cx43), were used, not only tk+ cells, but also tk- cells were killed, presumably due to the transfer, via Cx43-mediated GJIC, of toxic ganciclovir molecules phosphorylated by HSV-tk to the tk- cells. Such bystander effect was not observed when tk+ and tk- cells were cocultured without direct cell-cell contact between those two types of cells. Thus, our results give strong evidence that the bystander effect seen in HSV-tk gene therapy may be due to Cx-mediated GJIC. PMID- 8700845 TI - Anti-idiotypic antibodies mimicking glycoprotein D of herpes simplex virus identify a cellular protein required for virus spread from cell to cell and virus induced polykaryocytosis. AB - Glycoprotein D (gD) of herpes simplex virus 1 (HSV-1) is required for stable attachment and penetration of the virus into susceptible cells after initial binding. We derived anti-idiotypic antibodies to the neutralizing monoclonal antibody HD1 to gD of HSV-1. These antibodies have the properties expected of antibodies against a gD receptor. Specifically, they bind to the surface of HEp 2, Vero, and HeLa cells susceptible to HSV infection and specifically react with a Mr 62,000 protein in these and other (143TK- and BHK) cell lines. They neutralize virion infectivity, drastically decrease plaque formation by impairing cell-to-cell spread of virions, and reduce polykaryocytosis induced by strain HFEM, which carries a syncytial (syn-) mutation. They do not affect HSV growth in a single-step cycle and plaque formation by an unrelated virus, indicating that they specifically affect the interaction of HSV gD) with a cell surface receptor. We conclude that the Mr 62,000 cell surface protein interacts with gD to enable spread of HSV-1 from cell to cell and virus-induced polykaryocytosis. PMID- 8700846 TI - Measurement of muscle protein synthesis by positron emission tomography with L [methyl-11C]methionine. AB - Positron emission tomography (PET) with L-[methyl-11C]methionine was explored as an in vivo, noninvasive, quantitative method for measuring the protein synthesis rate (PSR) in paraspinal and hind limb muscles of anesthetized dogs. Approximately 25 mCi (1 Ci = 37 GBq) of L-[methyl-11C]methionine was injected intravenously, and serial images and arterial blood samples were acquired over 90 min. Data analysis was performed by fitting tissue- and metabolite-corrected arterial blood time-activity curves to a three-compartment model and assuming insignificant transamination and transmethylation in this tissue. PSR was calculated from fitted parameter values and plasma methionine concentrations. PSRs measured by PET were compared with arterio-venous (A-V) difference measurements across the hind limb during primed constant infusion (5-6 h) of L-[1 13C, methyl-2H3]methionine. Results of PET measurements demonstrated similar PSRs for paraspinal and hind limb muscles: 0.172 +/- 0.062 vs. 0.208 +/- 0.048 nmol 1.min-1.(g of muscle)-1 (P = not significant). PSR determined by the stable isotope technique was 0.27 +/- 0.050 nmol-1.min-1.(g of leg tissue)-1 (P < 0.07 from PET) and indicated that the contribution of transmethylation to total hind limb methionine utilization was approximately 10%. High levels of L-[methyl 11C]methionine utilization by bone marrow were observed. We conclude that muscle PSR can be measured in vivo by PET and that this approach offers promise for application in human metabolic studies. PMID- 8700847 TI - Expression of the fructose transporter GLUT5 in human breast cancer. AB - The primary metabolic characteristic of malignant cells is an increased uptake of glucose and its anaerobic metabolism. We studied the expression and function of the glucose transporters in human breast cancer cell lines and analyzed their expression in normal and neoplastic primary human breast tissue. Hexose uptake assays and immunoblotting experiments revealed that the breast carcinoma cell lines MCF-7 and MDA-468 express the glucose transporters GLUT1 and GLUT2, isoforms expressed in both normal and neoplastic breast tissue. We also found that the breast cancer cell lines transport fructose and express the fructose transporter GLUT5. Immunolocalization studies revealed that GLUT5 is highly expressed in vivo in human breast cancer but is absent in normal human breast tissue. These findings indicate that human breast cancer cells have a specialized capacity to transport fructose, a metabolic substrate believed to be used by few human tissues. Identification of a high-affinity fructose transporter on human breast cancer cells opens opportunities to develop novel strategies for early diagnosis and treatment of breast cancer. PMID- 8700848 TI - The multiple phenotypes of allosteric receptor mutants. AB - Channel-linked neurotransmitter receptors are membrane-bound heterooligomers made up of distinct, although homologous, subunits. They mediate chemo-electrical signal transduction and its regulation via interconversion between multiple conformations that exhibit distinct pharmacological properties and biological activities. The large diversity of functional properties and the widely pleiotropic phenotypes, which arise from point mutations in their subunits (or from subunit substitutions), are interpreted in terms of an allosteric model that incorporates multiple discrete conformational states. The model predicts that three main categories of phenotypes may result from point mutations, altering selectively one (or more) of the following features: (i) the properties of individual binding sites (K phenotype), (ii) the biological activity of the ion channel (gamma phenotype) of individual conformations, or (iii) the isomerization constants between receptor conformations (L phenotype). Several nicotinic acetylcholine and glycine receptor mutants with complex phenotypes are quantitatively analyzed in terms of the model, and the analogies among phenotypes are discussed. PMID- 8700849 TI - An ATP-activated, ligand-gated ion channel on a cholinergic presynaptic nerve terminal. AB - ATP has recently been identified as a fast neurotransmitter in both the central and peripheral nervous systems. Several studies have suggested that ATP can also affect the release of classical neurotransmitters, including acetylcholine with which it is co-released. We have searched for ATP receptors on a cholinergic presynaptic nerve terminal using the calyx-type synapse of the chicken ciliary ganglion. ATP was pulsed onto the terminals under voltage clamp and induced a short latency cation current that exhibited inward rectification and marked desensitization. This current was not seen with adenosine but was mimicked by several sterically restricted ATP analogs and was blocked by suramin. ATP activated single ion channels exhibited prominent flickering and had a conductance of approximately 17 pS. Our results demonstrate a ligand-gated P2X like purinergic receptor on a cholinergic presynaptic nerve terminal. PMID- 8700850 TI - Antisense oligodeoxynucleotide inhibition of a swelling-activated cation channel in osteoblast-like osteosarcoma cells. AB - By patch-clamp analysis, we have shown that chronic, intermittent mechanical strain (CMS) increases the activity of stretch-activated cation channels of osteoblast-like UMR-106.01 cells. CMS also produces a swelling-activated whole cell conductance (Gm) regulated by varying strain levels. We questioned whether the swelling-activated conductance was produced by stretch-activated cation channel activity. We have identified a gene involved in the increase in conductance by using antisense oligodeoxynucleotides (ODN) derived from the alpha 1-subunit genes of calcium channels found in UMR-106.01 cells (alpha1S, alpha1C, and alpha1D). We demonstrate that alpha 1C antisense ODNs abolish the increase in Gm in response to hypotonic swelling following CMS. Antisense ODNs to alpha1S and alpha1D, sense ODNs to alpha1C, and sham permeabilization had no effect on the conductance increase. In addition, during cell-attached patch-clamp studies, antisense ODNs to alpha1c completely blocked the swelling-activated and stretch activated nonselective cation channel response to strain. Antisense ODNs to alpha1S treatment produced no effect on either swelling-activated or stretch activated cation channel activity. There were differences in the stretch activated and swelling-activated cation channel activity, but whether they represent different channels could not be determined from our data. Our data indicate that the alpha1C gene product is involved in the Gm and the activation of the swelling-activated cation channels induced by CMS. The possibility that swelling-activated cation channel genes are members of the calcium channel superfamily exists, but if alpha1c is not the swelling-activated cation channel itself, then its expression is required for induction of swelling-activated cation channel activity by CMS. PMID- 8700851 TI - Structure of a gene encoding a cytosolic acetyl-CoA carboxylase of hexaploid wheat. AB - An entire gene encoding wheat (var. Hard Red Winter Tam 107) acetyl-CoA carboxylase [ACCase; acetyl-CoA:carbon-dioxide ligase (ADP-forming), EC 6.4.1.2] has been cloned and sequenced. Comparison of the 12-kb genomic sequence with the 7.4-kb cDNA sequence reported previously revealed 29 introns. Within the coding region, the exon sequence is 98% identical to the known wheat cDNA sequence. A second ACCase gene was identified by sequencing fragments of genomic clones that include the first two exons and the first intron. Additional transcripts were detected by 5' and 3' RACE analysis (rapid amplification of cDNA ends). One set of transcripts had a 5' end sequence identical to the cDNA found previously and another set was identical to the gene reported here. The 3' RACE clones fall into four distinguishable sequence sets, bringing the number of ACCase sequences to six. None of these cDNA or genomic clones encodes a chloroplast targeting signal. Identification of six different sequences suggests that either the cytosolic ACCase genes are duplicated in the three chromosome sets in hexaploid wheat or that each of the six alleles of the cytosolic ACCase gene has a readily distinguishable DNA sequence. PMID- 8700852 TI - Q/R site editing in kainate receptor GluR5 and GluR6 pre-mRNAs requires distant intronic sequences. AB - RNA editing by adenosine deamination in brain-expressed pre-mRNAs for glutamate receptor (GluR) subunits alters gene-specified codons for functionally critical positions, such as the channel's Q/R site. We show by transcript analysis of minigenes transiently expressed in PC-12 cells that, in contrast to GluR-B pre mRNA, where the two editing sites (Q/R and R/G) require base pairing with nearby intronic editing site complementary sequences (ECSs), editing in GluR5 and GluR6 pre-mRNAs recruits an ECS located as far as 1900 nucleotides distal to the Q/R site. The exon-intron duplex structure of the GluR5 and GluR6 pre-mRNAs appears to be a substrate of double-stranded RNA-specific adenosine deaminase. This enzyme when coexpressed in HEK 293 cells preferentially targets the adenosine of the Q/R site and of an unpaired position in the ECS which is highly edited in brain. PMID- 8700853 TI - The joining (J) chain is present in invertebrates that do not express immunoglobulins. AB - Joining (J) chain is a component of polymeric, but not monomeric, immunoglobulin (Ig) molecules and may play a role in their polymerization and transport across epithelial cells. To date, study of the J chain has been confined to vertebrates that produce Ig and in which the J chain displays a considerable degree of structural homology. The role of the J chain in Ig polymerization has been questioned and, since the J chain can be expressed in lymphoid cells that do not produce Ig, it is possible that the J chain may have other functions. To explore this possibility, we have surveyed J-chain gene, mRNA, and protein expression by using reverse transcriptase-coupled PCR, Northern blot analysis, and immunoblot analysis in invertebrate species that do not produce Ig. We report that the J chain gene is expressed in invertebrates (Mollusca, Annelida, Arthropoda, Echinodermata, and Holothuroidea), as well as in representative vertebrates (Mammalia, Teleostei, Amphibia). Furthermore, J-chain cDNA from the earthworm has a high degree of homology (68-76%) to human, mouse, and bovine J chains. Immunohistochemical studies reveal that the J chain is localized in the mucous cells of body surfaces, intestinal epithelial cells, and macrophage-like cells of the earthworm and slug. This study suggests that the J chain is a primitive polypeptide that arose before the evolution of Ig molecules and remains highly conserved in extent invertebrates and vertebrates. PMID- 8700854 TI - Embryonic expression patterns of the neural cell adhesion molecule gene are regulated by homeodomain binding sites. AB - During development of the vertebrate nervous system, the neural cell adhesion molecule (N-CAM) is expressed in a defined spatiotemporal pattern. We have proposed that the expression of N-CAM is controlled, in part, by proteins encoded by homeobox genes. This hypothesis has been supported by previous in vitro experiments showing that products of homeobox genes can both bind to and transactivate the N-CAM promoter via two homeodomain binding sites, HBS-I and HBS II. We have now tested the hypothesis that the N-CAM gene is a target of homeodomain proteins in vivo by using transgenic mice containing native and mutated N-CAM promoter constructs linked to a beta-galactosidase reporter gene. Segments of the 5' flanking region of the mouse N-CAM gene were sufficient to direct expression of the reporter gene in the central nervous system in a pattern consistent with that of the endogenous N-CAM gene. For example, at embryonic day (E) 11, beta-galactosidase staining was found in postmitotic neurons in dorsolateral and ventrolateral regions of the spinal cord; at E14.5, staining was seen in these neurons throughout the spinal cord. In contrast, mice carrying an N CAM promoter-reporter construct with mutations in both homeodomain binding sites (HBS-I and HBS-II) showed altered expression patterns in the spinal cord. At E11, beta-galactosidase expression was seen in the ventrolateral spinal cord, but was absent in the dorsolateral areas, and at E 14.5, beta-galactosidase expression was no longer detected in any cells of the cord. Homeodomain binding sites found in the N-CAM promoter thus appear to be important in determining specific expression patterns of N-CAM along the dorsoventral axis in the developing spinal cord. These experiments suggest that the N-CAM gene is an in vivo target of homeobox gene products in vertebrates. PMID- 8700855 TI - Midcycle administration of a progesterone synthesis inhibitor prevents ovulation in primates. AB - Progesterone receptors appear in granuloma cells of preovulatory follicles after the midcycle gonadotropin surge, suggesting important local actions of progesterone during ovulation in primates. Steroid reduction and replacement during the gonadotropin surge in macaques was used to evaluate the role of progesterone in the ovulatory process. Animals received gonadotropins to induce development of multiple preovulatory follicles, followed by human chorionic gonadotropin (hCG) administration (day 0) to promote oocyte (nuclear) maturation, ovulation, and follicular luteinization. On days 0-2, animals received no further treatment; a steroid synthesis inhibitor, trilostane (TRL); TRL + R5020; or TRL + dihydrotestosterone propionate (DHT). On day 3, ovulation was confirmed by counting ovulation sites and collecting oviductal oocytes. The meiotic status of oviductal and remaining follicular oocytes was evaluated. Peak serum estradiol levels, the total number of large follicles, and baseline serum progesterone levels at the time of hCG administration were similar in all animals. Ovulation sites and oviductal oocytes were routinely observed in controls. Ovulation was abolished in TRL. Progestin, but not androgen, replacement restored ovulation. Relative to controls, progesterone production was impaired for the first 6 days post-hCG in TRL, TRL + R5020, and TRL + DHT. Thereafter, progesterone remained low in TRL but recovered to control levels with progestin and androgen replacement. Similar percentages of mature (metaphase II) oocytes were collected among groups. Thus, steroid reduction during the gonadotropin surge inhibited ovulation and luteinization, but not reinitiation of oocyte meiotic maturation, in the primate follicle. The data are consistent with a local receptor-mediated role for progesterone in the ovulatory process. PMID- 8700856 TI - Nonclathrin coat protein gamma, a subunit of coatomer, binds to the cytoplasmic dilysine motif of membrane proteins of the early secretory pathway. AB - Coatomer, a cytosolic heterooligomeric protein complex that consists of seven subunits [alpha-, beta-, beta'-, gamma-, delta-, epsilon-, and zeta-COP (nonclathrin coat protein)], has been shown to interact with dilysine motifs typically found in the cytoplasmic domains of various endoplasmic-reticulum resident membrane proteins [Cosson, P. & Letourneur, F. (1994) Science 263, 1629 1631]. We have used a photo-cross-linking approach to identify the site of coatomer that is involved in binding to the dilysine motifs. An octapeptide corresponding to the C-terminal tail of Wbp1p, a component of the yeast N oligosaccharyltransferase complex, has been synthesized with a photoreactive phenylalanine at position -5 and was radioactively labeled with [125I]iodine at a tyrosine residue introduced at the N terminus of the peptide. Photolysis of isolated coatomer in the presence of this peptide and immunoprecipitation of coatomer from photo-cross-linked cell lysates reveal that gamma-COP is the predominantly labeled protein. From these results, we conclude that coatomer is able to bind to the cytoplasmic dilysine motifs of membrane proteins of the early secretory pathway via its gamma-COP subunit, whose complete cDNA-derived amino acid sequence is also presented. PMID- 8700857 TI - Chemical specificity and physical properties of the lipid bilayer in the regulation of protein kinase C by anionic phospholipids: evidence for the lack of a specific binding site for phosphatidylserine. AB - The association of protein kinase C (PKC) with membranes was found not to be specific for phosphatidyl-L-serine (PS). In particular, a synthetic phospholipid, dansyl-phosphatidylethanolamine, proved to be fully functional in the association of PKC with lipid bilayers and in mediating the interaction of this enzyme with diacylglycerol. Dansyl-phosphatidylethanolamine was also able to activate the enzyme in a Ca2+-dependent fashion. Differences in the ability to bind and activate PKC observed for an array of anionic lipids were not larger than alterations caused by changes in acyl chain composition. Thus, although different lipids interact to different extents with PKC, there are no specific binding sites for the PS headgroup on the enzyme. We found that lipids with a greater tendency to form inverted phases increased the binding of PKC to bilayers. However, these changes in lipid structure cannot be considered separately from the miscibility of lipid components in the membrane. For pairs of lipids with similar acyl chains, the dependence on PS concentration is sigmoidal, while for dissimilar acyl chains there is much less dependence of binding on PS concentration. The results can be explained in terms of differences in the lateral distribution of components in the membrane. PMID- 8700858 TI - Detection of sub-8-nm movements of kinesin by high-resolution optical-trap microscopy. AB - Kinesin is a molecular motor that transports organelles along microtubules. This enzyme has two identical 7-nm-long motor domains, which it uses to move between consecutive tubulin binding sites spaced 8 nm apart along a microtubular protofilament. The molecular mechanism of this movement, which remains to be elucidated, may be common to all families of motor proteins. In this study, a high-resolution optical-trap microscope was used to measure directly the magnitude of abrupt displacements produced by a single kinesin molecule transporting a microscopic bead. The distribution of magnitudes reveals that kinesin not only undergoes discrete 8-nm movements, in agreement with previous work [Svoboda, K., Schmidt, C. F., Schnapp, B. J. & Block, S.M. (1993) Nature (London) 365, 721-727], but also frequently exhibits smaller movements of about 5 nm. A possible explanation for these unexpected smaller movements is that kinesin's movement from one dimer to the next along a protofilament involves at least two distinct events in the mechanical cycle. PMID- 8700859 TI - FM1-43 dye ultrastructural localization in and release from frog motor nerve terminals. AB - Previous work has shown that the fluorescent styryl dye FM1-43 stains nerve terminals in an activity-dependent fashion. This dye appears to label the membranes of recycled synaptic vesicles by being trapped during endocytosis. Stained terminals can subsequently be destained by repeating nerve stimulation in the absence of dye; the destaining evidently reflects escape of dye into the bathing medium from membranes of exocytosing synaptic vesicles. In the present study we tested two key aspects of this interpretation of FM1-43 behavior, namely: (i) that the dye is localized in synaptic vesicles, and (ii) that it is actually released into the bathing medium during destaining. To accomplish this, we first photolyzed the internalized dye in the presence of diaminobenzidine. This created an electron-dense reaction product that could be visualized in the electron microscope. Reaction product was confined to synaptic vesicles, as predicted. Second, using spectrofluorometry, we quantified the release of dye liberated into the medium from tubocurarine-treated nerve-muscle preparations. Nerve stimulation increased the amount of FM1-43 released, and we estimate that normally a stained synaptic vesicle contains a few hundred molecules of the dye. The key to the successful detection of released FM1-43 was to add the micelle forming detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), which increased FM1-43 quantum yield by more than two orders of magnitude. PMID- 8700860 TI - The thyroid hormone-induced tail resorption program during Xenopus laevis metamorphosis. AB - Genes that are up- and down-regulated by thyroid hormone in the tail resorption program of Xenopus laevis have been isolated by a gene expression screen, sequenced, and identified in the GenBank data base. The entire program is estimated to consist of fewer than 35 up-regulated and fewer than 10 down regulated genes; 17 and 4 of them, respectively, have been isolated and characterized. Up-regulated genes whose function can be predicted on the basis of their sequence include four transcription factors (including one of the thyroid hormone receptors), an extracellular matrix component (fibronectin) and membrane receptor (integrin), four proteinases, a deiodinase that degrades thyroid hormone, and a protein that binds the hypothalamic corticotropin-releasing factor, which has been implicated in controlling thyroid hormone synthesis in Xenopus tadpoles. All four down-regulated genes encode extracellular proteins that are expressed in tadpole epidermis. This survey of the program provides insights into the biology of metamorphosis. PMID- 8700861 TI - Evolution of chlorophyll and bacteriochlorophyll: the problem of invariant sites in sequence analysis. AB - Competing hypotheses seek to explain the evolution of oxygenic and anoxygenic processes of photosynthesis. Since chlorophyll is less reduced and precedes bacteriochlorophyll on the modern biosynthetic pathway, it has been proposed that chlorophyll preceded bacteriochlorophyll in its evolution. However, recent analyses of nucleotide sequences that encode chlorophyll and bacteriochlorophyll biosynthetic enzymes appear to provide support for an alternative hypothesis. This is that the evolution of bacteriochlorophyll occurred earlier than the evolution of chlorophyll. Here we demonstrate that the presence of invariant sites in sequence datasets leads to inconsistency in tree building (including maximum-likelihood methods). Homologous sequences with different biological functions often share invariant sites at the same nucleotide positions. However, different constraints can also result in additional invariant sites unique to the genes, which have specific and different biological functions. Consequently, the distribution of these sites can be uneven between the different types of homologous genes. The presence of invariant sites, shared by related biosynthetic genes as well as those unique to only some of these genes, has misled the recent evolutionary analysis of oxygenic and anoxygenic photosynthetic pigments. We evaluate an alternative scheme for the evolution of chlorophyll and bacteriochlorophyll. PMID- 8700862 TI - Expression of the human acute myeloid leukemia gene AML1 is regulated by two promoter regions. AB - The human chromosome 21 AML1 gene is expressed predominantly in the hematopoietic system. In several leukemia-associated translocations AML1 is fused to other genes and transcription of the fused regions is mediated by upstream sequences that normally regulate the expression of AML1. The 5' genomic region of AML1 was cloned and sequenced. The two 5' untranslated regions (UTRs) previously identified in AML1 cDNAs were located in this region and the distance between them was established. The distal 5' UTR maps over 7 kb upstream of the proximal one. Using primer extension with mRNA, transcription start sites were identified at two distinct sites above these 5' uTRs. Sequence analysis revealed the absence of a TATA motif and the presence of Sp1, PU.1, Oct, CRE, Myb, Ets, and Ets-like binding sites in both upstream regions. Several initiator elements (Inr) that overlap the transcription start sites were also identified. These proximal and distal upstream regions and their deletion mutants were cloned in front of a luciferase reporter gene and used in transfection assays. We demonstrate that both upstream regions function as promoters in hematopoietic (Jurkat) and nonhematopoietic (HEK) cell lines. The activity of both promoters was orientation dependent and was enhanced, in a cell-type specific manner, by a heterologous enhancer sequence. These results indicate that additional control elements, either negative or positive, regulate the tissue-specific expression of AML1. PMID- 8700863 TI - ARD1, a 64-kDa bifunctional protein containing an 18-kDa GTP-binding ADP ribosylation factor domain and a 46-kDa GTPase-activating domain. AB - The alpha subunits of the heterotrimeric guanine nucleotide-binding proteins (G proteins) hydrolyze GTP at a rate significantly higher than do most members of the Ras family of approximatelly 20-kDa GTP-binding proteins, which depend on a GTPase-activating protein (GAP) for acceleration of GTP hydrolysis. It has been demonstrated that an inserted domain in the G-protein alpha subunit, not present in the much smaller Ras-like proteins, is responsible for this difference [Markby, D. W., Onrust, R. & Bourne, H. R. (1993) Science 262, 1895-1900]. We report here that ARD1, a 64-kDa protein with an 18-kDa carboxyl-terminal ADP ribosylation factor (ARF) domain, exhibited significant GTPase activity, whereas the ARF domain, expressed as a recombinant protein in Escherichia coli, did not. Addition of the 46-kDa amino-terminal extension (similarly synthesized in E. coli) to the GTP-binding ARF-domain of ARD1 enhanced GTPase activity and inhibited GDP dissociation. The kinetic properties of mixtures of the ARF and non ARF domains were similar to those of an intact recombinant ARD1. Physical association of the two proteins was demonstrated directly by gel filtration and by using the immobilized non-ARF domain. Thus, like the alpha subunits of heterotrimeric G proteins, ARD1 appears to consist of two domains that interact to regulate the biological activity of the protein. PMID- 8700864 TI - A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice. AB - While most effects of dopamine in the brain are mediated by the D1 and D2 receptor subtypes, other members of this G protein-coupled receptor family have potentially important functions. D3 receptors belong to the D2-like subclass of dopamine receptors, activation of which inhibits adenylyl cyclase. Using targeted mutagenesis in mouse embryonic stem cells, we have generated mice lacking functional D3 receptors. A premature chain-termination mutation was introduced in the D3 receptor gene after residue Arg-148 in the second intracellular loop of the predicted protein sequence. Binding of the dopamine antagonist [125I]iodosulpride to D3 receptors was absent in mice homozygous for the mutation and greatly reduced in heterozygous mice. Behavioral analysis of mutant mice showed that this mutation is associated with hyperactivity in an exploratory test. Homozygous mice lacking D3 receptors display increased locomotor activity and rearing behavior. Mice heterozygous for the D3 receptor mutation show similar, albeit less pronounced, behavioral alterations. Our findings indicate that D3 receptors play an inhibitory role in the control of certain behaviors. PMID- 8700865 TI - A large-capacity memory system that recognizes the calls and songs of individual birds. AB - Auditory responses in the caudomedial neostriatum (NCM) of the zebra finch (Taeniopygia guttata) forebrain habituate to repeated presentations of a novel conspecific song. This habituation is long lasting and specific to individual stimuli. We here test the acoustic and ethological basis of this stimulus specific habituation by recording extracellular multiunit activity in the NCM of awake male and female zebra finches presented with a variety of conspecific and heterospecific vocalizations, white noise, and tones. Initial responses to conspecific song and calls and to human speech were higher than responses to the other stimuli. Immediate habituation rates were high for all novel stimuli except tones, which habituated at a lower rate. Habituation to conspecific calls and songs outlasted habituation to other stimuli. The extent of immediate habituation induced by a particular novel song was not diminished when other conspecific songs were presented in alternation. In addition, the persistence of habituation was not diminished by exposure to other songs before testing, nor was it influenced by gender or laterality. Our results suggest that the NCM is specialized for remembering the calls and songs of many individual conspecifics. PMID- 8700866 TI - Role of oxidation in the neurotoxic effects of intrastriatal dopamine injections. AB - We have examined the biochemical and histological effects of high concentrations of dopamine (0.05-1.0 micromol) injected into the rat striatum. Twenty-four hours after such injections, the oxidation products of dopamine and dihydroxyphenylacetic acid were detected as both free and protein-bound cysteinyl dopamine and cysteinyl dihydroxyphenylacetic acid. Protein-bound cysteinyl catechols were increased 7- to 20-fold above control tissue levels. By 7 days postinjection, the protein-bound cysteinyl catechols were still detectable, although reduced in concentration, whereas the free forms could no longer be measured. Histological examination of striatum at 7 days revealed a central core of nonspecific damage including neuronal loss and gliosis. This core was surrounded by a region containing a marked reduction in tyrosine hydroxylase immunoreactivity but no apparent loss of serotonin or synaptophysin immunoreactivity. When dopamine was injected with an equimolar concentration of either ascorbic acid or glutathione, the formation of protein-bound cysteinyl catechols was greatly reduced. Moreover, the specific loss of tyrosine hydroxylase immunoreactivity associated with dopamine injections was no longer detectable, although the nonspecific changes in cytoarchitecture were still apparent. Thus, following its oxidation, dopamine in high concentrations binds to protein in the striatum, an event that is correlated with the specific loss of dopaminergic terminals. We suggest that the selective degeneration of dopamine neurons in Parkinson's disease may be caused by an imbalance between the oxidation of dopamine and the availability of antioxidant defenses. PMID- 8700867 TI - Single-amino acid substitutions eliminate lysine inhibition of maize dihydrodipicolinate synthase. AB - Dihydrodipicolinate synthase (DHPS; EC 4.2.1.52) catalyzes the first step in biosynthesis of lysine in plants and bacteria. DHPS in plants is highly sensitive to end-product inhibition by lysine and, therefore, has an important role in regulating metabolite flux into lysine. To better understand the feedback inhibition properties of the plant enzyme, we transformed a maize cDNA for lysine sensitive DHPS into an Escherichia coli strain lacking DHPS activity. Cells were mutagenized with ethylmethanesulfonate, and potential DHPS mutants were selected by growth on minimal medium containing the inhibitory lysine analogue S-2 aminoethyl-L-cysteine. DHPS assays identified surviving colonies expressing lysine-insensitive DHPS activity. Ten single-base-pair mutations were identified in the maize DHPS cDNA sequence; these mutations were specific to one of three amino acid residues (amino acids 157, 162, and 166) localized within a short region of the polypeptide. No other mutations were present in the remaining DHPS cDNA sequence, indicating that altering only one of the three residues suffices to eliminate lysine inhibition of maize DHPS. Identification of these specific mutations that change the highly sensitive maize DHPS to a lysine-insensitive isoform will help resolve the lysine-binding mechanism and the resultant conformational changes involved in inhibition of DHPS activity. The plant-derived mutant DHPS genes may also be used to improve nutritional quality of maize or other cereal grains that have inadequate lysine content when fed to animals such as poultry, swine, or humans. PMID- 8700868 TI - Protein degradation and increased mRNAs encoding proteins of the ubiquitin proteasome proteolytic pathway in BC3H1 myocytes require an interaction between glucocorticoids and acidification. AB - In rats and humans, metabolic acidosis stimulates protein degradation and glucocorticoids have been implicated in this response. To evaluate the importance of glucocorticoids in stimulating proteolysis, we measured protein degradation in BC3H1 myocytes cultured in 12% serum. Acidification accelerated protein degradation but dexamethasone did not augment this response. To reduce the influence of glucocorticoids and other hormones and cytokines in 12% serum that could mediate proteolysis, we studied BC3H1 myocytes maintained in only 1% serum. Acidification of the medium or addition of dexamethasone at pH 7.4 did not significantly increase protein degradation, while acidification plus dexamethasone accelerated proteolysis. The steroid receptor antagonist RU 486 prevented this proteolytic response. Acidification of the medium with 1% serum did increase the mRNAs for ubiquitin and the C2 proteasome subunit, but when dexamethasone was added the mRNAs were increased significantly more. The steroid receptor antagonist RU 486 suppressed this response to the addition of dexamethasone but the mRNAs remained at the levels measured in cells at pH 7.1 alone. Thus, acidification alone can increase the mRNAs of the ubiquitin proteasome proteolytic pathway, but both acidosis and glucocorticoids are required to stimulate protein degradation. Since these changes occur without adding cytokines or other hormones, we conclude that the proteolytic response to acidification requires glucocorticoids. PMID- 8700869 TI - Proteolytic activation of the cell death protease Yama/CPP32 by granzyme B. AB - The serine protease granzyme B, which is secreted by cytotoxic cells, is one of the major effectors of apoptosis in susceptible targets. To examine the apoptotic mechanism of granzyme B, we have analyzed its effect on purified proteins that are thought to be components of death pathways inherent to cells. We demonstrate that granzyme B processes interleukin 1beta-converting enzyme (ICE) and the ICE related protease Yama (also known as CPP32 or apopain) by limited proteolysis. Processing of ICE does not lead to activation. However, processing by granzyme B leads directly to the activation of Yama, which is now able to bind inhibitors and cleave the substrate poly(ADP-ribose) polymerase whose proteolysis is a marker of apoptosis initiated by several other stimuli. Thus ICE-related proteases can be activated by serine proteases that possess the correct specificity. Activation of pro-Yama by granzyme B is within the physiologic range. Thus the cytotoxic effect of granzyme B can be explained by its activation of an endogenous protease component of a programmed cell death pathway. PMID- 8700870 TI - Nucleotide binding-promoted conformational changes release a nonnative polypeptide from the Escherichia coli chaperonin GroEL. AB - The Escherichia coli chaperonins GroEL and GroES facilitate the refolding of polypeptide chains in an ATP hydrolysis-dependent reaction. The elementary steps in the binding and release of polypeptide substrates to GroEL were investigated in surface plasmon resonance studies to measure the rates of binding and dissociation of a normative variant of subtilisin. The rate constants determined for GroEL association with and dissociation from this variant yielded a micromolar dissociation constant, in agreement with independent calorimetric estimates. The rate of GroEL dissociation from the nonnative chain was increased significantly in the presence of 5'-adenylylimidodiphosphate (AMP-PNP), ADP, and ATP, yielding maximal values between 0.04 and 0.22 s(-1). The sigmoidal dependence of the dissociation rate on the concentration of AMP-PNP and ADP indicated that polypeptide dissociation is limited by a concerted conformational change that occurs after nucleotide binding. The dependence of the rate of release on ATP exhibited two sigmoidal transitions attributable to nucleotide binding to the distal and proximal toroid of a GroEL-polypeptide chain complex. The addition of GroES resulted in a marked increase in the rate of nonnative polypeptide release from GroEL, indicating that the cochaperonin binds more rapidly than the dissociation of polypeptides. These data demonstrate the importance of nucleotide binding-promoted concerted conformational changes for the release of chains from GroEL, which correlate with the sigmoidal hydrolysis of ATP by the chaperonin. The implications of these findings are discussed in terms of a working hypothesis for a single cycle of chaperonin action. PMID- 8700871 TI - A general two-process model describes the hydrogen exchange behavior of RNase A in unfolding conditions. AB - When NMR hydrogen exchange was used previously to monitor the kinetics of RNase A unfolding, some peptide NH protons were found to show EX2 exchange (detected by base catalysis) in addition to the expected EX1 exchange, whose rate is limited by the kinetic unfolding process. In earlier work, two groups showed independently that a restricted two-process model successfully fits published hydrogen exchange rates of native RNase A in the range 0-0.7 M guanidinium chloride. We find that this model predicts properties that are very different from the observed properties of the EX2 exchange reactions of RNase A in conditions where guanidine-induced unfolding takes place. The model predicts that EX2 exchange should be too fast to measure by the technique used, whereas it is readily measurable. Possible explanations for the contradiction are considered here, and we show that removing the restriction from the earlier two-process model is sufficient to resolve the contradiction; instead of specifying that exchange caused by global unfolding occurs by the EX2 mechanism, we allow it to occur by the general mechanism, which includes both the EX1 and EX2 cases. It is logical to remove this restriction because global unfolding of RNase A is known to give rise to EX1 exchange in these unfolding conditions. Resolving the contradiction makes it possible to determine whether populated unfolding intermediates contribute to the EX2 exchange, and this question is considered elsewhere. The results and simulations indicate that moderate or high denaturant concentrations readily give rise to EX1 exchange in native proteins. Earlier studies showed that hydrogen exchange in native proteins typically occurs by the EX2 mechanism but that high temperatures or pH values above 7 may give rise to EX1 exchange. High denaturant concentrations should be added to the list of variables likely to cause EX1 exchange. PMID- 8700872 TI - Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. AB - The tyrosine kinases Flt4, Flt1, and Flk1 (or KDR) constitute a family of endothelial cell-specific receptors with seven immunoglobulin-like domains and a split kinase domain. Flt1 and Flk1 have been shown to play key roles in vascular development; these two receptors bind and are activated by vascular endothelial growth factor (VEGF). No ligand has been identified for Flt4, whose expression becomes restricted during development to the lymphatic endothelium. We have identified cDNA clones from a human glioma cell line that encode a secreted protein with 32% amino acid identity to VEGF. This protein, designated VEGF related protein (VRP), specifically binds to the extracellular domain of Flt4, stimulates the tyrosine phosphorylation of Flt4 expressed in mammalian cells, and promotes the mitogenesis of human lung endothelial cells. VRP fails to bind appreciably to the extracellular domain of Flt1 or Flk1. The protein contains a C terminal, cysteine-rich region of about 180 amino acids that is not found in VEGF. A 2.4-kb VRP mRNA is found in several human tissues including adult heart, placenta, ovary, and small intestine and in fetal lung and kidney. PMID- 8700873 TI - Molecular cloning and characterization of SCaMPER, a sphingolipid Ca2+ release mediating protein from endoplasmic reticulum. AB - Release of Ca2+ stored in endoplasmic reticulum is a ubiquitous mechanism involved in cellular signal transduction, proliferation, and apoptosis. Recently, sphingolipid metabolites have been recognized as mediators of intracellular Ca2+ release, through their action at a previously undescribed intracellular Ca2+ channel. Here we describe the molecular cloning and characterization of a protein that causes the expression of sphingosyl-phosphocholine-mediated Ca2+ release when its complementary RNA is injected into Xenopus oocytes. SCaMPER (for sphingolipid Ca2+ release-mediating protein of endoplasmic reticulum) is an 181 amino acid protein with two putative membrane-spanning domains. SCaMPER is incorporated into microsomes upon expression in SO cells or after translation in vitro. It mediates Ca2+ release at 4 degrees C as well as 22 degrees C, consistent with having ion channel function. The EC50 for Ca2+ release from Xenopus oocytes is 40 microM, similar to sphingosyl-phosphocholine-mediated Ca2+ release from permeabilized mammalian cells. Because Ca2+ release is not blocked by ryanodine or La3+, the activity described here is distinct from the Ca2+ release activity of the ryanodine receptor and the inositol 1,4,5-trisphosphate receptor. The properties of SCaMPER are identical to those of the sphingolipid gated Ca2+ channel that we have previously described. These findings suggest that SCaMPER is a sphingolipid-gated Ca2+-permeable channel and support its role as a mediator of this pathway for intracellular Ca2+ signal transduction. PMID- 8700874 TI - Discontinuous epitopes of hepatitis B surface antigen derived from a filamentous phage peptide library. AB - The structure of the small hepatitis B virus surface antigen (HBsAg) was investigated by epitope mapping of four anti-HBsAg monoclonal antibodies (mAbs). Amino acid sequences of epitopes were derived from affinity-enrichment experiments (biopanning) using a filamentous phage peptide library. The library consists of 10(9) different clones bearing a 30-residue peptide fused to gene III. Sequence homologies between peptides obtained from panning the library against the antibodies and the native HBsAg sequence allowed for precise description of the binding regions. Three of four mAbs were found to bind to distinct discontinuous epitopes between amino acid residues 101 and 207 of HBsAg. The fourth mAb was demonstrated to bind to residues 121-124. The sequence data are supported by ELISA assays demonstrating the binding of the HBsAg-specific peptides on filamentous phage to mAbs. The sequence data were used to map the surface of HBsAg and to derive a topological model for the alpha-carbon trace of the 101-207 region of HBsAg. The approach should be useful for other proteins for which the crystal structure is not available but a representative set of mAbs can be obtained. PMID- 8700875 TI - Antiangiogenic therapy of transgenic mice impairs de novo tumor growth. AB - Angiogenesis is activated during multistage tumorigenesis prior to the emergence of solid tumors. Using a transgenic mouse model, we have tested the proposition that treatment with angiogenesis inhibitors can inhibit the progression of tumorigenesis after the switch to the angiogenic phenotype. In this model, islet cell carcinomas develop from multifocal, hyperproliferative nodules that show the histological hallmarks of human carcinoma in situ. Mice were treated with a combination of the angiogenesis inhibitor AGM-1470 (TNP-470), the antibiotic minocycline, and interferon alpha/beta. The treatment regimen markedly attenuated tumor growth but did not prevent tumor formation; tumor volume was reduced to 11% and capillary density to 40% of controls. The proliferation index of tumor cells in treated and control mice was similar, whereas the apoptotic index was doubled in treated tumors. This study shows that de novo tumor progression can be restricted solely by antiangiogenic therapy. The results suggest that angiogenesis inhibitors represent a valid component of anticancer strategies aimed at progression from discrete stages of tumorigenesis and demonstrate that transgenic mouse models can be used to evaluate efficacy of candidate antiangiogenic agents. PMID- 8700876 TI - Foldons, protein structural modules, and exons. AB - Foldons, which are kinetically competent, quasi-independently folding units of a protein, may be defined using energy landscape analysis. Foldons can be identified by maxima in a scan of the ratio of a contiguous segment's energetic stability gap to the energy variance of that segment's molten globule states, reflecting the requirement of minimal frustration. The predicted foldons are compared with the exons and structural modules for 16 of the 30 proteins studied. Statistical analysis indicates a strong correlation between the energetically determined foldons and Go's geometrically defined structural modules, but there are marked sequence-dependent effects. There is only a weak correlation of foldons to exons. For gammaII-crystallin, myoglobin, barnase, alpha-lactalbumin, and cytochrome c the foldons and some noncontiguous clusters of foldons compare well with intermediates observed in experiment. PMID- 8700877 TI - T-cell epitope analysis using subtracted expression libraries (TEASEL): application to a 38-kDA autoantigen recognized by T cells from an insulin dependent diabetic patient. AB - Studies on circulating T cells and antibodies in newly diagnosed type 1 diabetic patients and rodent models of autoimmune diabetes suggest that beta-cell membrane proteins of 38 kDa may be important molecular targets of autoimmune attack. Biochemical approaches to the isolation and identification of the 38-kDa autoantigen have been hampered by the restricted availability of islet tissue and the low abundance of the protein. A procedure of epitope analysis for CD4+ T cells using subtracted expression libraries (TEASEL) was developed and used to clone a 70-amino acid pancreatic beta-cell peptide incorporating an epitope recognized by a 38-kDa-reactive CD4+ T-cell clone (1C6) isolated from a human diabetic patient. The minimal epitope was mapped to a 10-amino acid synthetic peptide containing a DR1 consensus binding motif. Data base searches did not reveal the identity of the protein, though a weak homology to the bacterial superantigens SEA (Streptococcus pyogenes exotoxin A) and SEB (Staphylococcus aureus enterotoxin B) (23% identity) was evident. The TEASEL procedure might be used to identify epitopes of other autoantigens recognized by CD4+ T cells in diabetes as well as be more generally applicable to the study low-abundance autoantigens in other tissue-specific autoimmune diseases. PMID- 8700878 TI - Pathogenic autoantibodies are routinely generated during the response to foreign antigen: a paradigm for autoimmune disease. AB - The immune system's ability to distinguish self and nonself is essential for both host defense against foreign agents and protection of self-antigens from autoimmune destruction. Such discrimination is complicated by extensive structural homology shared between foreign and self antigens. One hypothesis to explain the development of an autoimmune response is that some B cells activated by foreign antigen acquire, through somatic mutation, specificity for both the eliciting foreign antigen and self antigen. If such clones arise frequently, there must be a mechanism for their elimination. We have analyzed the extent of autoreactivity arising in a nonautoimmune host during the response to a foreign antigen. To overcome the process of apoptosis in primary B cells that might routinely eliminate autoreactive clones, we generated B-cell hybridomas from spleen cells of immunized mice by using a fusion partner constitutively expressing bcl-2. Multiple lines were obtained that recognize simultaneously the hapten phosphorylcholine and the self antigen double-stranded DNA. This dual specificity was not present early but was detected by day 10 after immunization. Some of these cross-reactive antibodies deposit in kidneys in a pattern similar to what is seen in autoimmune disease. These results demonstrate that autoantibodies arise at a high frequency as part of a response to foreign antigen. It has previously been shown that autoreactivity is regulated by central deletion; these data demonstrate a need for negative selection in peripheral lymphoid organs also, to regulate autoantibodies acquiring their self-specificity by somatic mutation. PMID- 8700879 TI - Long-term in vitro correction of alpha-L-iduronidase deficiency (Hurler syndrome) in human bone marrow. AB - Allogeneic bone marrow transplantation is the most effective treatment for Hurler syndrome but, since this therapy is not available to all patients, we have considered an alternative approach based on transfer and expression of the normal gene in autologous bone marrow. A retroviral vector carrying the full-length cDNA for alpha-L-iduronidase has been constructed and used to transduce bone marrow from patients with this disorder. Various gene-transfer protocols have been assessed including the effect of intensive schedules of exposure of bone marrow to viral supernatant and the influence of growth factors. With these protocols, we have demonstrated successful gene transfer into primitive CD34+ cells and subsequent enzyme expression in their maturing progeny. Also, by using long-term bone marrow cultures, we have demonstrated high levels of enzyme expression sustained for several months. The efficiency of gene transfer has been assessed by PCR analysis of hemopoietic colonies as 25-56%. No advantage has been demonstrated for the addition of growth factors or intensive viral exposure schedules. The enzyme is secreted into the medium and functional localization has been demonstrated by reversal of the phenotypic effects of lysosomal storage in macrophages. This work suggests that retroviral gene transfer into human bone marrow may offer the prospect for gene therapy of Hurler syndrome in young patients without a matched sibling donor. PMID- 8700880 TI - Betidamino acids: versatile and constrained scaffolds for drug discovery. AB - Betidamino acids (a contraction of "beta" position and "amide") are N' monoacylated (optionally, N'-monoacylated and N-mono- or N,N'-dialkylated) aminoglycine derivatives in which each N'acyl/alkyl group may mimic naturally occurring amino acid side chains or introduce novel functionalities. Betidamino acids are most conveniently generated on solid supports used for the synthesis of peptides by selective acylation of one of the two amino functions of orthogonally protected aminoglycine(s) to generate the side chain either prior to or after the elongation of the main chain. We have used unresolved Nalpha-tert butyloxycarbonyl-N'alpha-fluorenylmethoxycarbonyl++ + aminoglycine, and Nalpha (Nalpha-methyl)-tert-butyloxycarbonyl-N'alpha-fluo renylmethoxycarbonyl aminoglycine as the templates for the introduction of betidamino acids in Acyline [Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(Ac)-D4Aph(A c)-Leu-Ilys-Pro-DAla-NH2, where 2Nal is 2-naphthylalanine, 4Cpa is 4-chlorophenylalanine, 3Pal is 3-pyridylalanine, Aph is 4-aminophenylalanine, and Ilys is Nepsilon-isopropyllysine], a potent gonadotropin-releasing hormone antagonist, in order to test biocompatibility of these derivatives. Diasteremneric peptides could be separated in most cases by reverse-phase HPLC. Biological results indicated small differences in relative potencies (<5-fold) between the D and L nonalkylated betidamino acid-containing Acyline derivatives. Importantly, most betide diastereomers were equipotent with Acyline. In an attempt to correlate structure and observed potency, Ramachandran type plots were calculated for a series of betidamino acids and their methylated homologs. According to these calculations, betidamino acids have access to a more limited and distinct number of conformational states (including those associated with alpha-helices, beta-sheets, or turn structures), with deeper minima than those observed for natural amino acids. PMID- 8700881 TI - Characterization of small nontranslated polyadenylylated RNAs in vaccinia virus infected cells. AB - Host protein synthesis is selectively inhibited in vaccinia virus-infected cells. This inhibition has been associated with the production of a group of small, nontranslated, polyadenylylated RNAs (POLADS) produced during the early part of virus infection. The inhibitory function of POLADS is associated with the poly(A) tail of these small RNAs. To determine the origin of the 5'-ends of POLADS, reverse transcription was performed with POLADS isolated from VV-infected cells at 1 hr and 3.5 hr post infection. The cDNAs of these POLADS were cloned into plasmids (pBS or pBluescript II KS +/-), and their nucleotide composition was determined by DNA sequencing. The results of this investigation show the following: There is no specific gene encoding for POLADS. The 5' ends of POLADS may be derived from either viral or cellular RNAs. Any RNA sequence including tRNAs, small nuclear RNAs and 5'ends of mRNAs can become POLADS if they acquire a poly(A) tail at their 3' ends during infection. This nonspecific polyadenylylation found in vaccinia virus-infected cells is probably conducted by vaccinia virus poly(A)+ polymerase. No consensus sequence is found on the 5' ends of POLADS for polyadenylylation. The 5' ends of POLADS have no direct role in their inhibitory activity of protein synthesis. PMID- 8700882 TI - Purification and physical properties of the male and female double sex proteins of Drosophila. AB - The double sex gene (dsx) encodes two proteins, DSX(M) and DSX(F), that regulate sex-specific transcription in Drosophila. These proteins bind target sites in DNA from which the male-specific DSX(M) represses and the female-specific DSX(F) activates transcription of yolk protein (Yp) genes. We investigated the physical properties of these DSX proteins, which are identical in their amino-terminal 397 residues but are entirely different in their carboxyl-terminal sequences (DSX(F), 30 amino acids; DSX(M), 152 amino acids). DSX(M) and DSX(F) were overexpressed in cultured insect cells and purified to near homogeneity. Gel filtration chromatography and glycerol gradient sedimentation showed that at low concentrations both proteins are dimers of highly asymmetrical shape. The axial ratios are approximately 18:1 (DSX(M), 860 X 48 angstroms; DSX(F), 735 X 43 angstroms). At higher concentrations, the proteins form tetramers. Through use of a novel, double crosslinking assay (protein-DNA plus protein-protein), we demonstrated that a DNA regulatory site binds to both monomers of the DSX dimer and to only two monomers of the tetramer. Furthermore, binding another DNA molecule to what we presume is the second and identical site in the tetramer dramatically shifts the equilibrium from tetramers to dimers. These oligomerization and DNA binding properties are indistinguishable between the male and female proteins. PMID- 8700883 TI - A set of genes expressed in response to light in the adult cerebral cortex and regulated during development. AB - Activity-dependent plasticity is thought to underlie both formation of appropriate synaptic connections during development and reorganization of adult cortical topography. We have recently cloned many candidate plasticity-related genes (CPGs) induced by glutamate-receptor activation in the hippocampus. Screening the CPG pool for genes that may contribute to neocortical plasticity resulted in the identification of six genes that are induced in adult visual cortical areas in response to light. These genes are also naturally induced during postnatal cortical development. CPG induction by visual stimulation occurs primarily in neurons located in cortical layers II-III and VI and persists for at least 48 hr. Four of the visually responsive CPGs (cpg2, cpg15, cpg22, cpg29) are previously unreported genes, one of which (cpg2) predicts a "mini-dystrophin like" structural protein. These results lend molecular genetic support to physiological and anatomical studies showing activity-dependent structural reorganization in adult cortex. In addition, these results provide candidate genes the function of which may underlie mechanisms of adult cortical reorganization. PMID- 8700884 TI - Arrest of endotoxin-induced hypotension by transforming growth factor beta1. AB - Septic shock is a cytokine-mediated process typically caused by a severe underlying infection. Toxins generated by the infecting organism trigger a cascade of events leading to hypotension, to multiple organ system failure, and frequently to death. Beyond supportive care, no effective therapy is available for the treatment of septic shock. Nitric oxide (NO) is a potent vasodilator generated late in the sepsis pathway leading to hypotension; therefore, NO represents a potential target for therapy. We have previously demonstrated that transforming growth factor (TGF) beta1 inhibits inducible NO synthase (iNOS) mRNA and NO production in vascular smooth muscle cells after its induction by cytokines critical in the sepsis cascade. Thus, we hypothesized that TGF-beta1 may inhibit iNOS gene expression in vivo and be beneficial in the treatment of septic shock. In a conscious rat model of septic shock produced by Salmonella typhosa lipopolysaccharide (LPS), TGF-beta1 markedly reduced iNOS mRNA and protein levels in several organs. In contrast, TGF-beta1 did not decrease endothelium-derived constitutive NOS mRNA in organs of rats receiving LPS. We also performed studies in anesthetized rats to evaluate the effect of TGF-beta1 on the hemodynamic compromise of septic shock; after an initial 25% decrease in mean arterial pressure, TGF-beta1 arrested LPS-induced hypotension and decreased mortality. A decrease in iNOS mRNA and protein levels in vascular smooth muscle cells was demonstrated by in situ hybridization and NADPH diaphorase staining in rats treated with TGF-beta1. Thus these studies suggest that TGF-beta1 inhibits iNOS in vivo and that TGF-beta1 may be of future benefit in the therapy of septic shock. PMID- 8700885 TI - A developmental timer regulates degradation of cyclin E1 at the midblastula transition during Xenopus embryogenesis. AB - We have analyzed cyclin E1, a protein that is essential for the G1/S transition, during early development in Xenopus embryos. Cyclin E1 was found to be abundant in eggs, and after fertilization, until the midblastula transition (MBT) when levels of cyclin E1 protein, and associated kinase activity, were found to decline precipitously. Our results suggest that the reduced level of the cyclin E1 protein detected after the MBT does not occur indirectly as a result of degradation of the maternally encoded cyclin E1 mRNA. Instead, the stability of cyclin E1 protein appears to play a major role in reduction of cyclin E1 levels at this time. Cyclin E1 protein was found to be stable during the cleavage divisions but degraded with a much shorter half-life after the MBT. Activation of cyclin E1 protein turnover occurs independent of cell cycle progression, does not require ongoing protein synthesis, and is not triggered as a result of the ratio of nuclei to cytoplasm in embryonic cells that initiates the MBT. We therefore propose that a developmental timing mechanism measures an approximately 5-hr time period, from the time of fertilization, and then allows activation of a protein degradative pathway that regulates cyclin E1. Characterization of the timer suggests that it might be held inactive in eggs by a mitogen-activated protein kinase signal transduction pathway. PMID- 8700886 TI - Two-hybrid system as a model to study the interaction of beta-amyloid peptide monomers. AB - The kinetics of amyloid fibril formation by beta-amyloid peptide (Abeta) are typical of a nucleation-dependent polymerization mechanism. This type of mechanism suggests that the study of the interaction of Abeta with itself can provide some valuable insights into Alzheimer disease amyloidosis. Interaction of Abeta with itself was explored with the yeast two-hybrid system. Fusion proteins were created by linking the Abeta fragment to a LexA DNA-binding domain (bait) and also to a B42 transactivation domain (prey). Protein-protein interactions were measured by expression of these fusion proteins in Saccharomyces cerevisiae harboring lacZ (beta-galactosidase) and LEU2 (leucine utilization) genes under the control of LexA-dependent operators. This approach suggests that the Abeta molecule is capable of interacting with itself in vivo in the yeast cell nucleus. LexA protein fused to the Drosophila protein bicoid (LexA-bicoid) failed to interact with the B42 fragment fused to Abeta, indicating that the observed Abeta Abeta interaction was specific. Specificity was further shown by the finding that no significant interaction was observed in yeast expressing LexA-Abeta bait when the B42 transactivation domain was fused to an Abeta fragment with Phe-Phe at residues 19 and 20 replaced by Thr-Thr (AbetaTT), a finding that is consistent with in vitro observations made by others. Moreover, when a peptide fragment bearing this substitution was mixed with native Abeta-(1-40), it inhibited formation of fibrils in vitro as examined by electron microscopy. The findings presented in this paper suggest that the two-hybrid system can be used to study the interaction of Abeta monomers and to define the peptide sequences that may be important in nucleation-dependent aggregation. PMID- 8700887 TI - Targeted gene correction of episomal DNA in mammalian cells mediated by a chimeric RNA.DNA oligonucleotide. AB - An experimental strategy to facilitate correction of single-base mutations of episomal targets in mammalian cells has been developed. The method utilizes a chimeric oligonucleotide composed of a contiguous stretch of RNA and DNA residues in a duplex conformation with double hairpin caps on the ends. The RNA/DNA sequence is designed to align with the sequence of the mutant locus and to contain the desired nucleotide change. Activity of the chimeric molecule in targeted correction was tested in a model system in which the aim was to correct a point mutation in the gene encoding the human liver/bone/kidney alkaline phosphatase. When the chimeric molecule was introduced into cells containing the mutant gene on an extrachromosomal plasmid, correction of the point mutation was accomplished with a frequency approaching 30%. These results extend the usefulness of the oligonucleotide-based gene targeting approaches by increasing specific targeting frequency. This strategy should enable the design of antiviral agents. PMID- 8700888 TI - Different interleukin 2 receptor beta-chain tyrosines couple to at least two signaling pathways and synergistically mediate interleukin 2-induced proliferation. AB - One of the earliest events induced by interleukin 2 (IL-2) is tyrosine phosphorylation of cellular proteins, including the IL-2 receptor beta chain (IL 2Rbeta). Simultaneous mutation of three tyrosines (Y338, Y392, and Y510) in the IL-2Rbeta cytoplasmic domain abrogated IL-2-induced proliferation, whereas mutation of only Y338 or of Y392 and Y510 inhibited proliferation only partially. While Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc. Thus, activation of both Jak-STAT and Shc-coupled signaling pathways requires specific IL-2Rbeta tyrosines that together act in concert to mediate maximal proliferation. In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510, suggesting that the role for this Jak kinase may extend beyond the Jak-STAT pathway. PMID- 8700889 TI - Human immunodeficiency virus type 1 and 2 Tat proteins specifically interact with RNA polymerase II. AB - The Tat-responsive region (TAR) element is a critical RNA regulatory element in the human immunodeficiency virus (HIV) long terminal repeat, which is required for activation of gene expression by the transactivator protein Tat. Recently, we demonstrated by gel-retardation analysis that RNA polymerase II binds to TAR RNA and that Tat prevents this binding even when Tat does not bind to TAR RNA. These results suggested that direct interactions between Tat and RNA polymerase II may prevent RNA polymerase II pausing and lead to Tat-mediated increases in transcriptional elongation. To test this possibility, we performed protein interaction studies with RNA polymerase II and both the HIV-1 and the closely related HIV-2 Tat protein. These studies indicated that both the HIV-1 and HIV-2 Tat proteins could specifically interact with RNA polymerase II. Mutagenesis of both HIV-1 and HIV-2 Tat demonstrated that the basic domains of both the HIV-1 and HIV-2 Tat proteins were required for this interaction. Furthermore, "far Western" analysis suggested that the largest subunit of RNA polymerase II was the site for interaction with Tat. The interactions between Tat and RNA polymerase II were of similar magnitude to those detected between RNA polymerase II and the cellular transcription factor RAP30, which stably associates with RNA polymerase II during transcriptional elongation. These studies are consistent with the model that RNA polymerase II is a cellular target for Tat resulting in Tat-mediated increases in transcriptional elongation from the HIV long terminal repeat. PMID- 8700890 TI - Cloning the expression of a mammalian gene involved in the reduction of methionine sulfoxide residues in proteins. AB - An enzyme that reduces methionine sulfoxide [Met(O)] residues in proteins [peptide Met(O) reductase (MsrA), EC 1.8.4.6; originally identified in Escherichia coli] was purified from bovine liver, and the cDNA encoding this enzyme was cloned and sequenced. The mammalian homologue of E. coli msrA (also called pmsR) cDNA encodes a protein of 255 amino acids with a calculated molecular mass of 25,846 Da. This protein has 61% identity with the E. coli MsrA throughout a region encompassing a 199-amino acid overlap. The protein has been overexpressed in E. coli and purified to homogeneity. The mammalian recombinant MsrA can use as substrate, proteins containing Met(O) as well as other organic compounds that contain an alkyl sulfoxide group such as N-acetylMet(O), Met(O), and dimethyl sulfoxide. Northern analysis of rat tissue extracts showed that rat msrA mRNA is present in a variety of organs with the highest level found in kidney. This is consistent with the observation that kidney extracts also contained the highest level of enzyme activity. PMID- 8700891 TI - Inhibition of G-protein betagamma-subunit functions by phosducin-like protein. AB - Phosducin is a cytosolic protein predominantly expressed in the retina and the pineal gland that can interact with the betagamma subunits of guanine nucleotide binding proteins (G proteins) and thereby may regulate transmembrane signaling. A cDNA encoding a phosducin-like protein (PhLP) has recently been isolated from rat brain [Miles, M. F., Barhite, S., Sganga, M. & Elliott, M. (1993) Proc. Natl. Acad. Sci. USA 90, 10831-10835. Here we report the expression of PhLP in Escherichia coli and its purification. Recombinant purified PUP inhibited multiple effects of G-protein betagamma subunits. First, it inhibited the betagamma-subunit-dependent ADP-ribosylation of purified alpha(o) by pertussis toxin. Second, it inhibited the GTPase activity of purified G(o). The IC50 value of PhLP in the latter assay was 89 nM, whereas phosducin caused half-maximal inhibition at 17 nM. And finally, PhLP antagonized the enhancement of rhodopsin phosphorylation by purified betagamma subunits. The N terminus of PhLP shows no similarity to the much longer N terminus of phosducin, the region shown to be critical for phosducin-betagamma-subunit interactions. Therefore, PhLP appears to bind to G-protein betagamma subunits by an as yet unknown mode of interaction and may represent an endogenous regulator of G-protein function. PMID- 8700892 TI - Protein kinase cross-talk: membrane targeting of the beta-adrenergic receptor kinase by protein kinase C. AB - The beta-adrenergic receptor kinase (betaARK) is the prototypical member of the family of cytosolic kinases that phosphorylate guanine nucleotide binding-protein coupled receptors and thereby trigger uncoupling between receptors and guanine nucleotide binding proteins. Herein we show that this kinase is subject to phosphorylation and regulation by protein kinase C (PKC). In cell lines stably expressing alpha1B- adrenergic receptors, activation of these receptors by epinephrine resulted in an activation of cytosolic betaARK. Similar data were obtained in 293 cells transiently coexpressing alpha1B- adrenergic receptors and betaARK-1. Direct activation of PKC with phorbol esters in these cells caused not only an activation of cytosolic betaARK-1 but also a translocation of betaARK immunoreactivity from the cytosol to the membrane fraction. A PKC preparation purified from rat brain phospborylated purified recombinant betaARK-1 to a stoichiometry of 0.86 phosphate per betaARK-1. This phosphorylation resulted in an increased activity of betaARK-1 when membrane-bound rhodopsin served as its substrate but in no increase of its activity toward a soluble peptide substrate. The site of phosphorylation was mapped to the C terminus of betaARK-1. We conclude that PKC activates betaARK by enhancing its translocation to the plasma membrane. PMID- 8700893 TI - Neural tube defects and abnormal brain development in F52-deficient mice. AB - F52 is a myristoylated, alanine-rich substrate for protein kinase C. We have generated F52-deficient mice by the gene targeting technique. These mutant mice manifest severe neural tube defects that are not associated with other complex malformations, a phenotype reminiscent of common human neural tube defects. The neural tube defects observed include both exencephaly and spina bifida, and the phenotype exhibits partial penetrance with about 60% of homozygous embryos developing neural tube defects. Exencephaly is the prominent type of defect and leads to high prenatal lethality. Neural tube defects are observed in a smaller percentage of heterozygous embryos (about 10%). Abnormal brain development and tail formation occur in homozygous mutants and are likely to be secondary to the neural tube defects. Disruption of F52 in mice therefore identifies a gene whose mutation results in isolated neural tube defects and may provide an animal model for common human neural tube defects. PMID- 8700894 TI - A polygenic mouse model of psoriasiform skin disease in CD18-deficient mice. AB - Previously, a hypomorphic mutation in CD18 was generated by gene targeting, with homozygous mice displaying increased circulating neutrophil counts, defects in the response to chemically induced peritonitis, and delays in transplantation rejection. When this mutation was backcrossed onto the PL/J inbred strain, virtually all homozygous mice developed a chronic inflammatory skin disease with a mean age of onset of 11 weeks after birth. The disease was characterized by erythema, hair loss, and the development of scales and crusts. The histopathology revealed hyperplasia of the epidermis, subcorneal microabscesses, orthohyperkeratosis, parakeratosis, and lymphocyte exocytosis, which are features in common with human psoriasis and other hyperproliferative inflammatory skin disorders. Repetitive cultures failed to demonstrate bacterial or fungal organisms potentially involved in the pathogenesis of this disease, and the dermatitis resolved rapidly after subcutaneous administration of dexamethasone. Homozygous mutant mice on a (PL/J x C57BL/6J)F1 background did not develop the disease and backcross experiments suggest that a small number of genes (perhaps as few as one), in addition to CD18, determine susceptibility to the disorder. This phenotype provides a model for inflammatory skin disorders, may have general relevance to polygenic human inflammatory diseases, and should help to identify genes that interact with the beta2 integrins in inflammatory processes. PMID- 8700895 TI - Expression of protein encoded by varicella-zoster virus open reading frame 63 in latently infected human ganglionic neurons. AB - The ganglionic cell type in which varicella-zoster virus (VZV) is latent in humans was analyzed by using antibodies raised against in vitro-expressed VZV open reading frame 63 protein. VZV open reading frame 63 protein was detected exclusively in the cytoplasm of neurons of latently infected human trigeminal and thoracic ganglia. This is, to our knowledge, the first identification of a herpesvirus protein expressed during latency in the human nervous system. PMID- 8700896 TI - Cloning, expression, and properties of the microtubule-stabilizing protein STOP. AB - Nerve cells contain abundant subpopulations of cold-stable microtubules. We have previously isolated a calmodulin-regulated brain protein, STOP (stable tubule only polypeptide), which reconstitutes microtubule cold stability when added to cold-labile microtubules in vitro. We have now cloned cDNA encoding STOP. We find that STOP is a 100.5-kDa protein with no homology to known proteins. The primary structure of STOP includes two distinct domains of repeated motifs. The central region of STOP contains 5 tandem repeats of 46 amino acids, 4 with 98% homology to the consensus sequence. The STOP C terminus contains 28 imperfect repeats of an 11-amino acid motif. STOP also contains a putative SH3-binding motif close to its N terminus. In vitro translated STOP binds to both microtubules and Ca2+ calmodulin. When STOP cDNA is expressed in cells that lack cold-stable microtubules, STOP associates with microtubules at 37 degrees C, and stabilizes microtubule networks, inducing cold stability, nocodazole resistance, and tubulin detyrosination on microtubules in transfected cells. We conclude that STOP must play an important role in the generation of microtubule cold stability and in the control of microtubule dynamics in brain. PMID- 8700897 TI - Enhanced and accelerated lymphoproliferation in Fas-null mice. AB - Fas is a 45-kDa membrane protein that transduces an apoptotic signal. The mouse lymphoproliferation (lpr) mutation is a leaky mutation of Fas. In this study, we examined lymphocyte development in Fas-null mice generated by gene targeting. The Fas-/- mice progressively accumulated abnormal T cells (Thy1+, B220+, CD4-, and CD8-) and developed lymphadenopathy and splenomegaly, which were much more accelerated and pronounced than those in lpr mice. In addition, the Fas-null mice showed lymphocytosis, accompanied by lymphocytic infiltration in the lungs and liver. The number of apparently normal B cells also increased, and large amounts of immunoglobulins, including anti-DNA antibodies, were produced. Thymic clonal deletion, assessed by deletion of T cells reactive to mouse endogenous superantigens, was apparently normal in the Fas-/- mice, whereas the peripheral clonal deletion of mature T cells against a bacterial superantigen was impaired. These results suggested that Fas plays a decisive role in peripheral clonal deletion but not in negative selection in the thymus. PMID- 8700898 TI - Transgenic mice that overexpress the human trefoil peptide pS2 have an increased resistance to intestinal damage. AB - pS2 is a member of the trefoil peptide family, all of which are overexpressed at sites of gastrointestinal injury. We hypothesized that they are important in stimulating mucosal repair. To test this idea, we have produced a transgenic mice strain that expresses human pS2 (hpS2) specifically within the jejunum and examined the effect of this overexpression on proliferation and susceptibility to indomethacin-induced damage. A transgenic mouse was produced by microinjecting fertilized oocytes with a 1.7-kb construct consisting of rat intestinal fatty acid binding protein promoter (positions -1178 to +28) linked to full-length (490 bp) hpS2 cDNA. Screening for positive animals was by Southern blot analysis. Distribution of hpS2 expression was determined by using Northern and Western blot analyses and immunohistochemical staining. Proliferation of the intestinal mucosa was determined by assessing the crypt cell production rate. Differences in susceptibility to intestinal damage were analyzed in animals that had received indomethacin (85 mg/kg s.c.) 0-30 h previously. Expression of hpS2 was limited to the enterocytes of the villi within the jejunum. In the nondamaged intestine, villus height and crypt cell production rate were similar in transgenic and negative (control) litter mates. However, there was a marked difference in the amount of damage caused by indomethacin in control and transgenic animals in the jejunum (30% reduction in villus height in controls vs. 12% reduction in transgenic animals, P < 0.01) but the damage sustained in the non-hpS2-expressing ileal region was similar in control and transgenic animals. These studies support the hypothesis that trefoil peptides are important in stimulating gastrointestinal repair. PMID- 8700899 TI - Azotobacter vinelandii NIFL is a flavoprotein that modulates transcriptional activation of nitrogen-fixation genes via a redox-sensitive switch. AB - The NIFL regulatory protein controls transcriptional activation of nitrogen fixation (nif) genes in Azotobacter vinelandii by direct interaction with the enhancer binding protein NIFA. Modulation of NIFA activity by NIFL, in vivo occurs in response to external oxygen concentration or the level of fixed nitrogen. Spectral features of purified NIFL and chromatographic analysis indicate that it is a flavoprotein with FAD as the prosthetic group, which undergoes reduction in the presence of sodium dithionite. Under anaerobic conditions, the oxidized form of NIFL inhibits transcriptional activation by NIFA in vitro, and this inhibition is reversed when NIFL is in the reduced form. Hence NIFL is a redox-sensitive regulatory protein and may represent a type of flavoprotein in which electron transfer is not coupled to an obvious catalytic activity. In addition to its ability to act as a redox sensor, the activity of NIFL is also responsive to adenosine nucleotides, particularly ADP. This response overrides the influence of redox status on NIFL and is also observed with refolded NIFL apoprotein, which lacks the flavin moiety. These observations suggest that both energy and redox status are important determinants of nif gene regulation in vivo. PMID- 8700900 TI - Anticoagulant repertoire of the hookworm Ancylostoma caninum. AB - Hookworms are hematophagous nematodes that infect a wide range of mammalian hosts, including humans. There has been speculation for nearly a century as to the identity of the anticoagulant substances) used by these organisms to subvert host hemostasis. Using molecular cloning, we describe a family of potent small protein (75-84 amino acids) anticoagulants from the hookworm Ancylostoma caninum termed AcAP (A. caninum anticoagulant protein). Two recombinant AcAP members (AcAP5 and AcAP6) directly inhibited the catalytic activity of blood coagulation factor Xa (fXa), while a third form (AcAPc2) predominantly inhibited the catalytic activity of a complex composed of blood coagulation factor VIIa and tissue factor (fVIIa/TF). The inhibition of fVIIa/TF was by a unique mechanism that required the initial formation of a binary complex of the inhibitor with fXa at a site on the enzyme that is distinct from the catalytic center (exo-site). The sequence of AcAPc2 as well as the utilization of an exo-site on fXa distinguishes this inhibitor from the mammalian anticoagulant TFPI (tissue factor pathway inhibitor), which is functionally equivalent with respect to fXa dependent inhibition of fIIa/TF. The relative sequence positions of the reactive site residues determined for AcAP5 with the homologous regions in AcAP6 and AcAPc2 as well as the pattern of 10 cysteine residues present in each of the inhibitors suggest that the AcAPs are distantly related to the family of small protein serine protease inhibitors found in the nonhematophagous nematode Ascaris lumbricoides var. suum. PMID- 8700901 TI - Recognition of diverse sequences by class I zinc fingers: asymmetries and indirect effects on specificity in the interaction between CF2II and A+T-rich elements. AB - The Drosophila CF2II protein, which contains zinc fingers of the Cys2His2 type and recognizes an A+T-rich sequence, behaves in cell culture as an activator of a reporter chloramphenicol acetyltransferase gene. This activity depends on C terminal but not N-terminal zinc fingers, as does in vitro DNA binding. By site specific mutagenesis and binding site selection, we define the critical amino acid-base interactions. Mutations of single amino acid residues at the leading edge of the recognition helix are rarely neutral: many result in a slight change in affinity for the ideal DNA target site; some cause major loss of affinity; and others change specificity for as many as two bases in the target site. Compared to zinc fingers that recognize G+C-rich DNA, CF2II fingers appear to bind to A+T rich DNA in a generally similar manner, but with additional flexibility and amino acid-base interactions. The results illustrate how zinc fingers may be evolving to recognize an unusually diverse set of DNA sequences. PMID- 8700902 TI - Tumor dormancy and cell signaling: anti-mu-induced apoptosis in human B-lymphoma cells is not caused by an APO-1-APO-1 ligand interaction. AB - Signal transduction initiated by crosslinking of antigen-specific receptors on T- and B-lymphoma cells induces apoptosis. In T-lymphoma cells, such crosslinking results in upregulation of the APO-1 ligand, which then interacts with induced or constitutively expressed APO-1, thereby triggering apoptosis. Here we show that crosslinking the membrane immunoglobulin on human lymphoma cells (Daudi) (that constitutively express APO-1) does not induce synthesis of APO-1 ligand. Further, a noncytotoxic fragment of anti-APO-1 antibody that blocks T-cell-receptor mediated apoptosis in T-lymphoma cells does not block anti-mu-induced apoptosis. Hence, in B-lymphoma cells, apoptosis induced by signaling via membrane IgM is not mediated by the APO-1 ligand. PMID- 8700903 TI - Function of the pre-T-cell receptor alpha chain in T-cell development and allelic exclusion at the T-cell receptor beta locus. AB - The pre-T-cell receptor, composed of the T-cell receptor (TCR) beta chain (TCRbeta), pre-Talpha (pTalpha) chain, and CD3 molecules, has been postulated to be a transducer of signals during the early stages of T-cell development. To examine the function of the transmembrane pTalpha chain during tbymocyte development, we generated pTalpha-/- embryonic stem cells and assayed their ability to differentiate into lymphoid cells in vivo after injection into recombination-activating gene (RAG)-2-deficient blastocysts. Thymocytes representing all stages of T-cell differentiation were detected in the thymus of pTalpha-/- chimeric mice, indicating that thymocyte development can occur without pTalpha. However, greatly reduced thymocyte numbers and substantially increased percentages of both CD4-CD8- thymocytes and TCRgammadelta+ thymocytes suggest that pTalpha plays a critical role in thymocyte expansion. To investigate the role of the pTalpha chain in allelic exclusion at the TCRbeta locus, a functionally rearranged TCRbeta minigene was introduced into pTalpha-/- and pTalpha+/- embryonic stem cells, which were subsequently assayed by RAG-2 deficient blastocyst complementation. In the absence of pTalpha, expression of the transgenic TCRbeta inhibited rearrangement of the endogenous TCRbeta locus to an extent similar to that seen in normal TCRbeta transgenic mice, suggesting that pTalpha may not be required for signaling allelic exclusion at the TCRbeta locus. PMID- 8700904 TI - Factor XII-induced mitogenesis is mediated via a distinct signal transduction pathway that activates a mitogen-activated protein kinase. AB - Clotting factor XII (Hageman factor) contains epidermal growth factor (EGF) homologous domains and is reported to be a potent mitogen for human hepatoma (HepG2) cells. In this study, we tested whether factor XII exhibits growth factor activity on several other EGF-sensitive target cells, including fetal hepatocytes, endothelial cells, alveolar type II cells, and aortic smooth muscle cells. We found that factor XII significantly enhanced [3H]thymidine incorporation in aortic smooth muscle cells (SMCs) and all other cells tested. Tyrphostin, a growth factor receptor/tyrosine kinase antagonist, inhibited both EGF- and factor XII-induced responses. However, differences in the levels of magnitude of DNA synthesis, the observed synergism between EGF and factor XII, and the differential sensitivity to tyrphostin suggest that the EGF receptor and the factor XII receptor may be nonidentical. The factor XII-induced mitogenic response was achieved at concentrations that were 1/10th the physiologic range for the circulating factor and was reduced by popcorn inhibitor, a specific factor XII protease inhibitor. Treatment of aortic SMCs with factor XII, as well as activated factor XII, resulted in a rapid and transient activation of a mitogen-activated/extracellular signal-regulated protein kinase with peak activity/tyrosine phosphorylation observed at 5 to 10 min of exposure. Taken together, these data (i) confirm that clotting factor XII functions as a mitogenic growth factor and (ii) demonstrate that factor XII activates a signal transduction pathway, which includes a mitogen-activated protein kinase. PMID- 8700905 TI - Expression of the C terminus of the amyloid precursor protein alters growth factor responsiveness in stably transfected PC12 cells. AB - The amyloid precursor protein (APP) is a molecule centrally involved in Alzheimer disease pathology, but whose normal function is still poorly understood. To investigate the consequences of increased intracellular production of various regions of APP on cellular physiology, we stably transfected PC12 cells with the C-terminal 100 amino acids of the human APP. In eight transfected clones that express the APP(C100) protein, exposure to nerve growth factor (NGF) did not promote differentiation. Transfectants continued to divide and failed to elaborate extensive neurites, whereas control PC12 cells, mock-transfected PC12 cells, and a nonexpressing transfected cell line did develop neurites and stopped dividing after NGF stimulation. Unlike NGF treatment, treatment with basic fibroblast growth factor profoundly accelerated neurite outgrowth in transfected cells. Also, a dramatic increase in a tyrosine phosphatase activity was noted. Expression and accumulation of APP C100 protein in PC12 cells results in an abnormal response to growth factor stimulation. PMID- 8700906 TI - Peptides from conserved regions of paramyxovirus fusion (F) proteins are potent inhibitors of viral fusion. AB - The synthetic peptides DP-107 and DP-178 (T-20), derived from separate domains within the human immunodeficiency virus type 1 (HIV-1) transmembrane (TM) protein, gp4l, are stable and potent inhibitors of HIV-1 infection and fusion. Using a computer searching strategy (computerized antiviral searching technology, C.A.S.T.) based on the predicted secondary structure of DP-107 and DP-178 (T-20), we have identified conserved heptad repeat domains analogous to the DP-107 and DP 178 regions of HIV-1 gp41 within the glycoproteins of other fusogenic viruses. Here we report on antiviral peptides derived from three representative paramyxoviruses, respiratory syncytial virus (RSV), human parainfluenza virus type 3 (HPIV-3), and measles virus (MV). We screened crude preparations of synthetic 35-residue peptides, scanning the DP-178-like domains, in antiviral assays. Peptide preparations demonstrating antiviral activity were purified and tested for their ability to block syncytium formation. Representative DP-178-like peptides from each paramyxovirus blocked homologous virus-mediated syncytium formation and exhibited EC50 values in the range 0.015-0.250 microM. Moreover, these peptides were highly selective for the virus of origin. Identification of biologically active peptides derived from domains within paramyxovirus F1 proteins analogous to the DP-178 domain of HIV-1 gp4l is compelling evidence for equivalent structural and functional features between retroviral and paramyxoviral fusion proteins. These antiviral peptides provide a novel approach to the development of targeted therapies for paramyxovirus infections. PMID- 8700907 TI - An ATP-dependent As(III)-glutathione transport system in membrane vesicles of Leishmania tarentolae. AB - Membrane preparations enriched in plasma membrane vesicles prepared from promastigotes of Leishmania tarentolae were shown to accumulate thiolate derivatives of 73As(III). Free arsenite was transported at a low rate, but rapid accumulation was observed after reaction with reduced glutathione (GSH) conditions that favor the formation of As(GS)3. Accumulation required ATP but not electrochemical energy, indicating that As(GS)3 is transported by an ATP-coupled pump. Pentostam, a Sb(V)-containing drug that is one of the first-line therapeutic agents for treatment of leishmaniasis, inhibited uptake after reaction with GSH. Vesicles prepared from a strain in which both copies of the pgpA genes were disrupted accumulated As(GS)3 at wild-type levels, demonstrating that the PgpA protein is not the As(GS)3 pump. These results have important implications for the mechanism of drug resistance in the trypanosomatidae, suggesting that a plasma membrane As(GS)3 pump catalyzes active extrusion of metal thiolates, including the Pentostam-glutathione conjugate. PMID- 8700908 TI - Prevention of diabetic alterations in transgenic mice overexpressing Myc in the liver. AB - Recent studies have demonstrated that the overexpression of the c-myc gene in the liver of transgenic mice leads to an increase in both utilization and accumulation of glucose in the liver, suggesting that c-Myc transcription factor is involved in the control of liver carbohydrate metabolism in vivo. To determine whether the increase in c-Myc might control glucose homeostasis, an intraperitoneal glucose tolerance test was performed. Transgenic mice showed lower levels of blood glucose than control animals, indicating that the overexpression of c-Myc led to an increase of blood glucose disposal by the liver. Thus, the increase in c-Myc might counteract diabetic hyperglycemia. In contrast to control mice, transgenic mice treated with streptozotocin showed normalization of concentrations of blood glucose, ketone bodies, triacylglycerols and free fatty acids in the absence of insulin. These findings resulted from the normalization of liver metabolism in these animals. While low glucokinase activity was detected in the liver of diabetic control mice, high levels of both glucokinase mRNA and enzyme activity were noted in the liver of streptozotocin treated transgenic mice, which led to an increase in intracellular levels of glucose 6-phosphate and glycogen. The liver of these mice also showed an increase in pyruvate kinase activity and lactate production. Furthermore, normalization of both the expression of genes involved in the control of gluconeogenesis and ketogenesis and the production of glucose and ketone bodies was observed in streptozotocin-treated transgenic mice. Thus, these results suggested that c-Myc counteracted diabetic alterations through its ability to induce hepatic glucose uptake and utilization and to block the activation of gluconeogenesis and ketogenesis. PMID- 8700909 TI - Calmodulin controls adaptation of mechanoelectrical transduction by hair cells of the bullfrog's sacculus. AB - Deflection of the mechanically sensitive hair bundle atop a hair cell opens transduction channels, some of which subsequently reclose during a Ca2+-dependent adaptation process. Myosin I in the hair bundle is thought to mediate this adaptation; in the bullfrog's hair cell, the relevant isozyme may be the 119-kDa amphibian myosin I beta. Because this molecule resembles other forms of myosin I, we hypothesized that calmodulin, a cytoplasmic receptor for Ca2+, regulates the ATPase activity of myosin. We identified an approximately 120-kDa calmodulin binding protein that shares with hair-bundle myosin I the properties of being photolabeled by vanadate-trapped uridine nucleotides and immunoreactive with a monoclonal antibody raised against mammalian myosin I beta. To investigate the possibility that calmodulin mediates Ca2+-dependent adaptation, we inhibited calmodulin action and measured the results with two distinct assays. Calmodulin antagonists increased photolabeling of hair-bundle myosin I by nucleotides. In addition, when introduced into hair cells through recording electrodes, calmodulin antagonists abolished adaptation to sustained mechanical stimuli. Our evidence indicates that calmodulin binds to and controls the activity of hair bundle myosin I, the putative adaptation motor. PMID- 8700910 TI - Spectrum of HERG K+-channel dysfunction in an inherited cardiac arrhythmia. AB - Long QT syndrome (LQT) is an autosomal dominant disorder that can cause sudden death from cardiac arrhythmias. We recently discovered that mutations in HERG, a K+-channel gene, cause chromosome 7-linked LQT. Heterologous expression of HERG in Xenopus oocytes revealed that HERG current was similar to a well-characterized cardiac delayed rectifier K+ current, IKr, and led to the hypothesis that mutations in HERG reduced IKr, causing prolonged myocellular action potentials. To define the mechanism of LQT, we injected oocytes with mutant HERG complementary RNAs, either singly or in combination with wild-type complementary RNA. Some mutations caused loss of function, whereas others caused dominant negative suppression of HERG function. These mutations are predicted to cause a spectrum of diminished IKr and delayed ventricular repolarization, consistent with the prolonged QT interval observed in individuals with LQT. PMID- 8700911 TI - Z-membranes: artificial organelles for overexpressing recombinant integral membrane proteins. AB - We have expressed a fusion protein formed between the avian infectious bronchitis virus M protein and the bacterial enzyme beta-glucuronidase in transgenic tobacco cells. Electron microscope images of such cells demonstrate that overexpression of this fusion protein gives rise to a type of endoplasmic reticulum membrane domain in which adjacent membranes become zippered together apparently as a consequence of the oligomerizing action of beta-glucuronidase. These zippered (Z ) membranes lack markers of the endoplasmic reticulum (NADH cytochrome c reductase and ribosomes) and accumulate in the cells in the form of multilayered scroll-like structures (up to 2 micrometers in diameter; 20-50 per cell) without affecting plant growth. The discovery of Z-membranes has broad implications for biology and biotechnology in that they provide a means for accumulating large quantities of recombinant membrane proteins within discrete domains of native membranes. PMID- 8700912 TI - The contagion indicator hypothesis for parasite-mediated sexual selection. AB - Hamilton and Zuk [Hamilton, W. D. & Zuk, M. (1982) Science 218, 384-387] proposed that females choosing mates based on the degree of expression of male characters obtain heritable parasite resistance for their offspring. Alternatively, the "contagion indicator" hypothesis posits that females choose mates based on the degree of expression of male characters because the latter indicate a male's degree of infestation of parasites and thus the risk that choosing females and their offspring will acquire these parasites. I examined whether parasite transmittability affects the probability that parasite intensity and male mating success are negatively correlated in intraspecific studies of parasite-mediated sexual selection. When females risk infection of themselves or their future offspring as a result of mating with a parasitized male, negative relationships between parasite intensity and male mating success are significantly more likely to occur than when females do not risk such infection. The direct benefit to females of avoiding parasitic infection is proposed to lead to the linkage between variable secondary sexual characters and the intensity of transmittable parasites. The direct benefits of avoiding associatively transmittable parasites should be considered in future studies of parasite-mediated sexual selection. PMID- 8700913 TI - Cleavage of actin by interleukin 1 beta-converting enzyme to reverse DNase I inhibition. AB - Three of the predominant features of apoptosis are internucleosomal DNA fragmentation, plasma membrane bleb formation, and retraction of cell processes. We demonstrate that actin is a substrate for the proapoptotic cysteine protease interleukin 1beta-converting enzyme. Actin cleaved by interleukin 1beta converting enzyme can neither inhibit DNase I nor polymerize to its filamentous form as effectively as intact actin. These findings suggest a mechanism for the coordination of the proteolytic, endonucleolytic, and morphogenetic aspects of apoptosis. PMID- 8700914 TI - Preventing malnutrition in patients on CAPD. AB - Malnutrition is not uncommon in patients on CAPD. Thorough assessment and accurate records are essential for recognition of early indicators. Dietary advice can improve compliance. Intraperitoneal infusion of amino acids may be useful in some patients. PMID- 8700915 TI - Handwashing practice in nurse education. AB - Handwashing is the single most important clinical procedure. There is a discrepancy between nurses' knowledge of handwashing and their practice. The selection of an appropriate teaching method is important and should be reflected within the curriculum. PMID- 8700916 TI - Living wills: making patients' wishes known. AB - Writing a living will allows patients to issue an advance directive on their care. Should an individual become unable to communicate or lose the mental capacity to make treatment decisions, staff can refer to the living will. Nurses have an important role as patient advocates. In future, living wills may serve to strengthen and formalise this important aspect of nursing care. PMID- 8700917 TI - Paediatric community nursing: doctors' views. AB - Children should always be cared for at home if possible. Plans to expand the paediatric community nursing service need to take the views of doctors into account. Liaison between the service, referring doctors and the hospital services is essential. PMID- 8700918 TI - Implications of severe trauma to the hand. AB - Assessment of hand injury should ensure that planning of care is tailored to individual needs. A rehabilitation programme is vital to achieve maximum potential function in the long term. Patients should be prepared for long-term problems. PMID- 8700919 TI - Ambulatory suction equipment for home use. AB - People requiring life-supporting technology should be able to live at home. Funding is often the main obstacle to discharge for highly dependent individuals. Care in the home environment can greatly improve quality of life. Specialist nurses are ideally positioned to evaluate highly technical home care. PMID- 8700920 TI - Neurological observations. PMID- 8700921 TI - The care of older women with uterine prolapse. PMID- 8700922 TI - Coronary heart disease. PMID- 8700923 TI - Occupational skin disorders. PMID- 8700924 TI - Sequential compression to treat lymphoedema. AB - There is no consensus on the most appropriate treatment for lymphoedema. Patients are often confused--and may have been misinformed--about treatment options. The breast care specialist nurse should be able to offer a range of treatments, including sequential compression. PMID- 8700925 TI - Attitudes to drug users according to age of staff. AB - The attitudes of professionals working with intravenous drug users, and their perceptions of service delivery, are likely to be affected by age. Younger professionals tend to be more positive in their attitudes towards intravenous drug users. Older professionals tend to be less concerned about the risks from HIV infection than younger ones. More research is needed into the effects of age group on attitudes. PMID- 8700926 TI - PREPared professionals. PMID- 8700927 TI - Promoting continence with electrostimulation. AB - Electrostimulation can be used to treat urinary and faecal incontinence. Women with urinary stress and/or urge incontinence, detrusor instability and a weak anal sphincter may be helped. Nursing support is needed to encourage compliance over a long period. PMID- 8700928 TI - The right to die: the dilemma for A&E nurses. AB - Older people have the highest suicide rate of any age group. A&E staff are faced with patients who have taken an overdose and ask to be allowed to die. Care of such patients in A&E should not only be concerned with the physical aspects but must respond to the individual's needs and problems. PMID- 8700929 TI - Intravenous drug therapy. PMID- 8700930 TI - Using reflective practice in clinical supervision. AB - Supervision is a key aspect of quality assurance. Clinical supervision should not be confused with managerial monitoring. Supervision takes time and commitment. PMID- 8700931 TI - Identifying problems in the operating theatre. AB - The management of change requires consultation with those affected. Prioritising problems can be a more objective process if opinions are appropriately weighted. PMID- 8700932 TI - Dealing with complaints: procedural changes. AB - Many complaints can be dealt with by the staff immediately concerned. Complaints procedures have been criticised as being too complicated. New procedures will extend the terms of reference of the Health Service Commissioner and should simplify the complaints procedure. PMID- 8700933 TI - Genetics. PMID- 8700934 TI - Delivering care. Part I: delivery systems. PMID- 8700935 TI - Fluids used in total parenteral nutrition. AB - Parenteral nutrition is indicated for patients who cannot eat normally and for whom enteral feeding is inappropriate. TPN has an increasing role in home care for long-term conditions. The costs associated with TPN need to be considered in the context of patient benefits. PMID- 8700936 TI - Plague. PMID- 8700937 TI - Developing a leg ulcer management programme. AB - Compression therapy is an essential component in the treatment of venous leg ulcers. Comprehensive education and training and support of district nurses in leg ulcer management is essential. PMID- 8700938 TI - Effects on regional cerebral blood flow of transcendental meditation. AB - Previous blood flow measurements in this laboratory have indicated increased nonrenal nonhepatic blood flow during behaviorally induced rest states, especially during the stylized mental technique of transcendental meditation (TM). We have hypothesized that increased cerebral blood flow (CBF) may account for most of the increased nonrenal nonhepatic blood flow during TM. In this report we describe increased frontal and occipital CBF in TM determined by the electrical impedance plethysmographic methodology known as rheoencephalography (REG), which allows noninvasive, nondisturbing, continuous CBF monitoring. We also report high correlation between increased CBF and decreased cerebrovascular resistance (CVR) during TM, suggesting that a contributing vascular mechanism to the increased CBF may be decreased CVR. Because only a small amount of stage 1 sleep was observed during TM and because stage 1 sleep has been reported to be accompanied by decreased CBF, we believe that sleep did not contribute to the CBF increase. The data of this study are consistent with the hypothesis that blood flow changes during TM comprise a patterned response subserving needs of increased cerebral activity. PMID- 8700939 TI - Individual patterns of food intake development in children: a 10 months to 8 years of age follow-up study of nutrition and growth. AB - Individual patterns of food intake development have been investigated on the basis of a longitudinal study of nutrition and growth carried out in 112 children at the ages of 10 months, and 2, 4, 6, and 8 years. On the average, energy intake increased steadily with age. However, individual subjects sometimes followed a different pattern. Approximately 1 out of 5 subjects decreased their intake between two examinations. Besides, less than half the children (43%) were in the same category of energy intake (defined as tertiles) at 10 months and 8 years of age. Similarly, 47% of the children were in the same weight/height (BMI) category at 10 months and 8 years. Correlations computed between early intakes (10 months, and 2, 4, and 6 years) and intakes at 8 years were better for energy and protein intake than for fat and carbohydrates (CHO), showing that intake of energy or protein early in life has a better predictive value of intake at later ages. Energy intake development has been examined in those children who were found to be lean, medium, and fat at the age of 8 years; it increased more between the ages of 4 and 6 years, in children who were fat at 8 years. Individual variations of anthropometric measurements during growth are well documented. The present study points out that similar individual variations of intake also exists. These variations could reflect regulatory processes acting during growth and should be taken into account in investigating the child's appetite. PMID- 8700940 TI - Stress induced disorganization of circadian and ultradian rhythms: comparisons of effects of surgery and social stress. AB - Persistent autonomic disturbances following stressful events suggest that the rhythmical nature of homeostatic functioning may be disrupted by these experiences. We assessed the effects of two different stressors on circadian and ultradian rhythms of Long-Evans rats by using nonlinear multi-oscillator cosinor analysis. Heart rate and intraperitoneal temperature were monitored continuously in 5-min intervals in two groups of animals via radio-telemetry for 15 days after surgery (n = 9) and 15 days following social defeat (n = 6). Circadian amplitude of heart rate and temperature increased significantly for the first nine days of the recovery from surgery but only circadian temperature amplitude increased following social defeat. Circadian acrophase of temperature but not heart rate changed significantly for a similar period following the surgery but not after the social defeat. A mathematical model incorporating the first five harmonics of the circadian rhythm was found to fit the data significantly better than a circadian model alone with rhythms of 3 and 5 cycles/day in temperature and heart rate entraining significantly to the light-dark schedule. Full recovery of the circadian and ultradian rhythms did not occur until a minimum of nine to twelve days after surgery or social defeat. The results suggest that rhythms with multiple periodicities are involved in homeostatic functioning and that models incorporating these rhythms may aid in understanding an organisms adaptive response to surgical intervention and social defeat, long after the challenges have terminated. PMID- 8700941 TI - Field observations of yawning and activity in humans. AB - Rates of wrist activity and yawning were recorded continuously for 7-15 days in adult human male and female subjects. In the 15 min following 747 yawns wrist motion increased reliably in all subject records. The data were consistent with an hypothesis that yawning is predictive of an increase in activity level. In a second study, data from daily logs kept by 45 subjects confirmed previous findings that yawning frequency is unrelated to prior amount of sleep, or to times of awaking or retiring. More yawning occurred during the week than during weekends. PMID- 8700942 TI - Physiological measures of conduction velocity and refractory period for putative reward-relevant MFB axons arising in the rostral MFB. AB - Extracellular recordings were obtained, in urethane-anesthetized rats, from 44 neurons in the rostral bed nuclei of the medial forebrain bundle (MFB). These cells were antidromically activated by stimulation of MFB sites that typically support self-stimulation. Recording sites included the magnocellular preoptic nucleus, substantia innominata, ventral pallidum, olfactory tubercle, and horizontal limb of the diagonal band. Refractory period estimates ranged from 0.35 to 1.20 ms (mean +/- SD = 0.72 +/- 0.30 ms, n = 15) for stimulation sites in the lateral hypothalamic and ventral tegmental areas when using currents of twice threshold and procedures designed to estimate excitability at or near the site of stimulation. Interelectrode conduction velocity estimates ranged from 1.48 to 20.0 m/s (mean +/- SD = 9.26 +/- 7.22 m/s, n = 11) and were obtained by dividing the interelectrode distance by the difference in the response latency from the two MFB stimulation sites. The refractory period and conduction velocity estimates for these neurons overlap the psychophysically derived estimates for MFB reward neurons. These data are consistent with the hypothesis that neurons arising in the rostral bed nucleus of the MFB compose at least part of the directly activated substrate for MFB self-stimulation. PMID- 8700943 TI - Arm width and brightness modulation of spontaneous behaviour of two strains of mice tested in the elevated plus-maze. AB - Amongst the nonpharmacological variables that may influence spontaneous behaviour in the elevated plus-maze, at least two (namely, the width and brightness level of the maze arms) have not been evaluated for possible consequences on baseline activity. We therefore investigated the effect of width (5, 7, or 9 cm) and brightness level (grey vs. white) of the maze arms on the activity patterns of NMRI and C57/BL 10j mice in a plus-maze based on that described by Lister. Results indicated a clear strain difference in spontaneous behaviour in the open/closed arms with C57/BL mice making no visits on the open arms of the maze. In the NMRI strain, enlarging the arms resulted in significantly increased running in open arms but brightness level did not affect behavioural parameters. In the C57/BL mice, no significant behavioural changes were detected after increasing the arm width; however, the maze with a white floor significantly increased the latency to move and decreased ambulation. Finally, employing a maze with white closed arms and open grey arms resulted in ambulation by C57/BL mice into the open arms, a behaviour not normally observed in this strain using a uniformly bright maze. The results are discussed in terms of their putative effects in pharmacological testing. PMID- 8700944 TI - Analgesic effects of cranial laser treatment in two rat nociception models. AB - The present experiments sought to establish dose dependency and time course for effects of cranial laser irradiation in two rodent models of pain. These were the hot plate and tail flick tests, which are both widely used to quantify analgesic drug effects. The laser used was an Omega Biotherapy 3ML (wavelength 820 nM, average power output 100 mW, pulse frequency 5 kHz) and irradiation was applied to rats' shaved heads above the midbrain. In the first experiment, four groups of 10 rats received doses of 0, 6, 12, 18, and 24 J/cm2 in random orders prior to hot plate testing either immediately, 30 min, 1 h or 24 h postlaser. The second study employed three groups of 10 rats receiving 0, 12, and 18 J/cm2 in random orders prior to tail flick testing at the three shorter times above. Latency to lick hind paws on the hot plate was highly significantly prolonged by laser treatment across all doses and time periods, F(4, 126) = 4.51, p < 0.01. There was good dose dependency for immediate observations, but at 24 h 18 J/cm2 was the most effective dose. Laser treatment also delayed tail flick responses at both doses and all time periods, F(2, 54) = 10.60, p < 0.001, but 12 and 18 J/cm2 doses were similar in efficacy. PMID- 8700945 TI - Iron nutritional status in female karatekas, handball and basketball players, and runners. AB - The iron nutritional status was studied in 84 sportswomen (19 karatekas, 20 handball players, 20 basketball players, and 25 middle and long distance runners) and in 82 nonathletic females of similar characteristics (control group). After a 7-day nutritional survey by means of the food weighing method, it was found that iron intake was significantly higher in the handball players (p < 0.05), basketball players (p < 0.01), and runners (p < 0.01) with regard to the control group; the basketball players were the only ones to cover the recommended minimum intake (15 mg/day). The heme iron intake was significantly greater in the handball and basketball players (p < 0.01), who, together with the runners, reached the value of 1.5 mg/day, which is considered to be optimal. In relation to the control group, the karatekas and handball and basketball players had lower levels of serum ferritin, although their iron intake was greater, whereas the runners had higher values that were very similar to those of the control group, due to the iron supplementation they had received. Despite finding a marked prevalence of inadequate iron intake, both in the sportswomen and in the control group, the manifest cases of anemia are relatively scarce. The organic iron stores do not seem to depend exclusively on the iron intake but also on intimate mechanisms of intestinal absorption and diverse causes of iron loss. PMID- 8700946 TI - Cardiorespiratory effects of electrical stimulation of the globus pallidus in cats. AB - Increase in the arterial blood pressure (BP), heart rate (HR), and respiratory rate (RR) was regularly evoked by electrical stimulation of the globus pallidus (GP) in awake, freely moving cats. The somatomotor responses to GP stimulations consisted of either slow movements, localized mainly on the head, or contraversive circling. Both the peak and the shape of the BP curve were related to the stimulus intensity. Stimulations repeated under blockade of the adrenergic alpha-receptors failed to increase BP whereas the somatomotor responses occurred as in drug-free animals. Intra-arterious injection of procaine did not interfere with the electrically elicited elevation of BP. GP stimulations also caused arterial blood pressure changes under chloralose anesthesia. It is concluded that the globus pallidus has a role in connecting somatomotor activities with the appropriate cardiorespiratory changes. PMID- 8700947 TI - Serum NGF levels increase during lactation and following maternal aggression in mice. AB - In the present study, serum levels of nerve growth factor (NGF) were assessed in virgin and in lactating female CD-1 mice. In the case of the lactating females, NGF levels were assessed both under basal conditions and 60 and 180 min following a 10 min encounter with a male or a nonlactating female mouse. Basal serum NGF levels of lactating females were higher than those of virgin females but did not increase significantly above base after an aggressive encounter with a male or a female conspecific. Female intruders were attacked in a ritualized manner. In contrast, males received numerous bites to vulnerable regions of their body. A positive correlation was found between serum NGF levels and pattern of aggression in females confronting male conspecifics. Thus, in lactating mice, serum NGF levels following an aggressive encounter relate to the specific pattern of behavior the female uses to defend the offspring. PMID- 8700948 TI - Carbohydrate- and protein-conditioned flavor preferences: effects of nutrient preloads. AB - Food-deprived rats were trained to associate one flavor (CSProt) with intragastric (IG) infusions of protein (PROT; 10% calcium caseinate), a second flavor (CSCHO) with IG infusions of carbohydrate (CHO; 10% protein), and a third flavor (CS-) with IG water infusions during 30 min/day training sessions. (The CS flavors were cherry, grape, and orange saccharin solutions.) In subsequent two bottle tests the rats reliably preferred both the CSProt 2nd CSCHO to the CS- and equally preferred the CSProt and CSCHO. The preference for the two nutrient paired flavors was not altered by IG preloads of PROT or CHO delivered as three loads 120, 40, and 5 min prior to testing. However, single oral + gastric preloads of CSCHO + IG CHO and CSProt + IG PROT 45 min prior to test selectively increased the preference for the CSProt and CSCHO, respectively. In subsequent gastric-only and oral-only tests single IG preloads of PROT and CHO, but not CSProt and CSCHO preloads, selectively altered the rats' preference for CSCHO vs. CSProt. In a second experiment with new rats, oral + gastric preloads again selectively altered the preference for the CSCHO vs. CSProt, but gastric-only preloads failed to have this effect. These results demonstrate that rats can learn to associate different flavors with the postingestive effects of different nutrients, and modify their flavor preferences after nutrient preloads. Oral + gastric preloads were most effective in altering flavor preferences, whereas gastric-only preloads had inconsistent effects and oral-only preloads were ineffective. PMID- 8700949 TI - Role of olfaction in the formation of preference for high-fat foods in mice. AB - Male albino mice were given access to both high- and low-fat food mixtures in the home cage for 4 days. Mice were then divided into three groups and given a choice test in which all groups demonstrated a significant preference for the high-fat food mixture. One group was then bilaterally olfactory nerve sectioned. Seven days following surgery, all groups were given a second choice test. Olfactory nerve-sectioned mice (while anosmic) showed no preference, whereas high-fat food preference in the two control groups strengthened. However, high-fat food preference returned to recovered nerve-sectioned mice by 21 days postsurgery. It appears that preference for many high-fat foods in mice requires olfaction. This is in good agreement with earlier work that reported the loss of the novel food effect in olfactory nerve-sectioned mice while anosmic, and points to an important role for olfaction in the formation of preference for many high-fat foods. PMID- 8700950 TI - Male reproductive systems under chronic fluoxetine or trimipramine treatment. AB - Adult male Long-Evans rats (n = 9 per group) received daily exposure for 4 weeks to fluoxetine (0.75 mg FLUOX/kg body weight) or trimipramine (1.6 mg TRIMI/kg body weight). Separate tests of copulation, sexual motivation, and intermale aggressive behaviors were used to evaluate functional changes during chronic exposure to either typical or atypical antidepressant drugs with more or less serotonin specificity. Circulating hormones, primary and secondary sex structures, and concentrations of dopamine (DA) and serotonin (5-HT) from mesolimbic tissue were assessed at necropsy. Results of tests with estrous females and untreated males revealed progressive disruption to sexual performance and aggressive responsiveness over time of treatment with TRIMI and, to a lesser extent, with FLUOX. By contrast, motivation, testosterone, and all measures of reproductive physiology were indistinguishable from controls. Ratios of transmitter metabolites relative to the parent compounds indicated similar reductions of 5-HT turnover with FLUOX and TRIMI. However, influences on DA turnover were significantly less with FLUOX than with TRIMI. Conclusions are that long-term intervention with antidepressant drugs may disrupt sociosexual exchanges without compromising male rats' interest in sexual contact or integrity of their reproductive physiology. Lessened disruption of sociosexual behaviors with this regimen of chronic FLUOX treatment may be related to the greater selectivity on serotonin relative to dopamine turnover. PMID- 8700951 TI - Sensitization and desensitization to capsaicin and menthol in the oral cavity: interactions and individual differences. AB - It was reported in a recent study that, like capsaicin, menthol is capable of producing a desensitization to sensory irritation in the oral cavity. Whereas capsaicin is known to be able to cross-desensitize with other chemical irritants, no such information exists for menthol. To address this question, the first experiment was designed to reveal whether cross-desensitization would occur between menthol and capsaicin. After a pretest on the tongue tip in which subjects rated the intensity of irritation and cold produced by 3.5 ppm capsaicin or 0.3% l-menthol, five samples of the same stimuli were sipped and swished at 1 min intervals for 5 min. Fifteen minutes later subjects were tested on the tongue tip with either capsaicin or menthol. The results 1) confirmed self desensitization for both chemicals, 2) demonstrated cross-desensitization of menthol by capsaicin, and 3) revealed cross-sensitization of capsaicin by menthol. This series of outcomes suggests that menthol produces much of its sensory irritation via capsaicin-sensitive pathways, but that it excites and/or desensitizes those pathways via different mechanisms than does capsaicin. Analysis of the individual data revealed large differences in sensitization, and desensitization that were significantly correlated across chemicals, which suggests the possibility that the perceptual response to repeated exposures to irritants may be idiosyncratic. Contrary to earlier findings, the first experiment also revealed apparent self- and cross-desensitization of the menthol sensation of coolness. The latter outcome was investigated in a second experiment in which the effect of capsaicin desensitization on the perception of physical as well as chemical (menthol) cooling was measured when the stimuli were presented as oral rinses. No desensitization was found for either form of stimulation, which implied the apparent desensitization of coolness in Experiment I may have been due to the difficulty of discriminating sensations of cold from sensations of chemical irritation. The overall findings are discussed in terms of the complex sensory and perceptual interactions that take place within the chemesthetic modality. PMID- 8700952 TI - Cyclic AMP tastes aversive, not sweet, to rats. AB - Electrophysiological and biochemical evidence suggests that cAMP mediates sweet taste transduction. Neural recordings from anesthetized rats and in vitro preparations demonstrate that membrane-per-meable cAMP analogues mimic the effects of sucrose and artificial sweetners. We presented solutions of sodium 8 (4-chlorophenylthio)-adenosine 3'-5'-cyclic monophosphate (8cpt-cAMP), a water soluble, membrane-permeable cAMP analogue to freely behaving rats in short-term lickometer tests. Rats licked significantly less to 8cpt-cAMP than to sucrose or palatable saccharin solutions. Rats could taste 8cpt-cAMP solutions, however, because they licked less to 8cpt-cAMP in mixture with sucrose than to sucrose alone. Because 8cpt-cAMP decreased licking when mixed with sucrose, we conclude that the taste of 8cpt-cAMP is aversive, not sweet, to freely behaving rats. PMID- 8700953 TI - Lipopolysaccharide and IL-1 alpha activate CNS pathways as measured by NK cell activity. AB - The effect of lipopolysaccharide (LPS) on murine unstimulated and prestimulated natural killer (NK) cells and its ability to serve as an unconditioned stimulus was investigated. LPS injection induced a statistically significant increase in NK cell activity when compared with saline-treated control groups. To demonstrate the existence of communication between the peripheral immune system and the central nervous system (CNS), we used a single-trial conditioning paradigm in which camphor served as the conditioned stimulus (CS) and LPS as the unconditioned stimulus (US). Once a CS/US association is made, exposure of animals to the CS alone results in the conditioned response (i.e., increase in NK cell activity). Using 50 micrograms of LPS as the US produced a low but significant increase in NK cell activity when compared to control groups. However, 10 micrograms of LPS did not show a significant increase in NK cell activity. We also observed that interleukin-1 alpha (IL-1 alpha) injected intracisternally can serve as a US to condition a central neuroendocrine pathway. Because the dose of IL-1 alpha employed was too small to raise NK cell activity in the spleen, the NK cells themselves were formally not subjected to conditioning. These observations suggest that LPS and IL-1 alpha conditions the brain and that NK cell activity can be used as an indicator system to detect neuroendocrine signals arising from the activated pathway(s). PMID- 8700954 TI - Analysis of polysaccharide taste in hamsters: behavioral and neural studies. AB - A series of studies was carried out in hamsters (Mesocricetus auratus) to determine whether polysaccharides have behavioral and neurophysiological characteristics that distinguish them from simple sugars. Behavioral studies utilized solutions of glucose, maltose, sucrose, Polycose, and glycogen in two bottle preference tests and in tests of generalization of conditioned taste aversions. Multiunit and single-unit responses of the chorda tympani nerve were studied with the same stimuli. Neural responses to Polycose and glycogen were found to be generated primarily by ionic contaminants. Dialysis or deionization dramatically reduced electrophysiological responses, a result consistent with occurrence of Polycose and glycogen sensitivity in electrolyte-sensitive nerve fibers. Effects of treatment with the Na + -channel blocker amiloride and cross adaptation were also consistent with neural responses generated by ionic contaminants. Hamsters showed strong preferences for the sugars and Polycose, a mixture of glucose polymers with alpha-1,4 linkages, and even stronger preferences for a glycogen preparation. Conditioned flavor aversions were established to glycogen, sucrose, and maltose, but no aversion was learned to 3.2% Polycose. The learned aversion to maltose partly generalized to glycogen and sucrose, but sucrose and glycogen did not cross-generalize. Deionization did not affect the preferences for Polycose and glycogen but removal of contaminants of mol.wt. < or = 7000 Da greatly reduced preference for glycogen. In conclusion, glycogen itself, after removal of low molecular weight contaminants, is a poor taste stimulus in hamsters, both behaviorally and neurophysiologically. However, Polycose is highly preferred by hamsters but gives little chorda tympani response after removal of ionic contaminants. In alert animals, the action of salivary amylase on polysaccharides may produce simpler, detectable taste stimuli. PMID- 8700955 TI - P3(00) habituation from auditory and visual stimuli. AB - The P3(00) event-related brain potential (ERP) was elicited with auditory and visual stimuli using an oddball task in which the subject indicated with a button press response the occurrence of a target stimulus that occurred randomly on 20% of the trials and refrained from responding to a standard stimulus. A total of four trial blocks were collected for each stimulus modality condition. P3 amplitude from the target stimuli decreased reliably across trial blocks for both the auditory and visual stimulus condition, with no interaction obtained between stimulus modality and trial block. P3 latency was shorter for the auditory compared to visual stimulus conditions, but did not vary with trial block. No changes in amplitude or latency independent of the P3 effects were obtained for the other ERP components with trial block, although the usual modality differences were observed. The results suggest that P3 components elicited by auditory and visual stimuli both habituate for actively discriminated target stimuli. The theoretical implications are discussed in the context of previous findings. PMID- 8700956 TI - Aging and the hypothalamus: research perspectives. AB - There are several hypothalamic theories of aging, none of which has been validated. An approach to validation is to search for consequences of anatomic ablations of hypothalamic regions that are functional hallmarks of aging, or consequences of ablation that postpone the appearance of hallmarks of aging or extend longevity. Ablation of the hypothalamic ventromedial nucleus (VMN) in the weanling rat is associated with subsequent increased body fat, glucose intolerance, hyperlipidemia, and decreased renal function. Each of these consequences is characteristic of aging in humans and in several animal models of aging. Ablation of the hypothalamic dorsomedial nucleus (DMN) in the weanling rat leads to a symmetrically smaller animal with normal glucose and lipid metabolism, decreased body fat for size, and reduced risk of decreased renal function and circulating IGF-I levels. These are findings consistent with calorie restriction models in rodents that significantly extend life span. This review compares outcomes of lesions in the VMN, DMN, and lateral hypothalamic area (LHA) for relevance to aging. To establish a relationship between these anatomic areas of the hypothalamus and aging, it is concluded that the VMN, DMN, and LHA lesions should be examined for impact on longevity and compared with data obtained from simultaneously studied intact ad-lib-fed and 40% calorie-restricted animals. Lesioned animals also should be rigorously studied for neurotransmitters (e.g., neuropeptide Y, beta-endorphin, serotonin, corticotropin-releasing factor, and galanin), and for behavioral changes consistent with aging, for accumulation of specific tissue lipofuscin and amyloid that are associated with normal aging and for other age-dependent findings, such as incidence of tumors and cataract. PMID- 8700957 TI - Effects of sympathetic inhibition on receptive, proceptive, and rejection behaviors in the female rat. AB - The present investigation was designed to examine the effects of sympathetic nervous system (SNS) inhibition on sexual behavior in ovariectomized, steroid treated female rats. Clonidine, an alpha2-adrenergic agonist, guanethidine, a postganglionic noradrenergic blocker, and naphazoline, an alpha2-adrenoreceptor agonist were used to inhibit SNS activity. Intraperitoneal injections of either 33 micrograms/ml or 66 micrograms/ml clonidine significantly decreased receptive (lordosis) and proceptive (ear wiggles) behaviors and significantly increased rejection behaviors (vocalization, kicking, boxing). Either 25 mg/ml or 50 mg/ml guanethidine significantly decreased receptive and proceptive behavior and had no significant effect on rejection behaviors. Naphazoline significantly inhibited lordosis behavior at either 5 mg/ml or 10 mg/ml doses, significantly inhibited proceptive behavior at 5 mg/ml, and had no significant effect on rejection behaviors. These findings support the hypothesis that SNS inhibition decreases sexual activity in the female rat. PMID- 8700958 TI - Changes in pain threshold during the reproductive cycle of the female rat. AB - Responsiveness to pain was determined in female rats across the whole reproductive cycle using the tail-flick test. When tested immediately after mating, pain thresholds were unaltered, whereas 10 min later animals typically demonstrated hyperalgesia (Experiment 1). They also demonstrated hyperalgesia during most of pregnancy, and had significantly lower pain thresholds than the unmated controls except for the 24 h before parturition, when a sudden increase in tail-flick latencies was recorded (Experiment 2). Pain thresholds were also significantly lower throughout the nursing period but increased significantly when dams were separated from their litters for 6 h, and returned to premating baseline values within 24 h of weaning (Experiment 3). These findings confirm and extend earlier reports that female reproductive state may significantly modify responsiveness to noxious stimuli, and it is suggested that differences between the results of this and previous studies may be at least partly explained by the relatively stress-free test procedure adopted here. PMID- 8700959 TI - Changes in taste responsiveness in patients with anorexia nervosa during behavior therapy. AB - We evaluated the changes in taste responsiveness of anorexia nervosa (AN) patients during behavior therapy. Taste responsiveness of AN patients was lower at admission when compared to controls but it improved significantly over the course of treatment (p < 0.01). Taste responsiveness improved prior to increase in body weight. No significant correlation was noted between weight gain and improvement in taste responsiveness. The period required to reach a food intake of 1600 Kcal/day and the duration of hospitalization were highly correlated (r = 0.72, p < 0.05). Those who reached 1600 Kcal/day earlier showed more rapid improvements in taste responsiveness. These results suggest that decreased taste responsiveness in AN patients can rapidly improve and such early improvement may result in better progression of treatment. PMID- 8700960 TI - Effects of pyruvate and lactate on food intake in rat strains sensitive and resistant to dietary obesity. AB - We have investigated the effects of peripherally administered pyruvate and lactate on the intake of high fat (HF) and low fat (LF) diets by a strain of rat either sensitive (Osborne-Mendel, OM) or resistant (SSB/Pl) to high fat-induced obesity. Both pyruvate and lactate inhibited the intake of HF and LF diets by OM rats and these effects were blocked by selective hepatic vagotomy. In contrast, in S5B/Pl rats fed an LF diet the responses to pyruvate and lactate were attenuated and were absent in S5B/Pl rats fed the HF diet. These data suggest that OM and S5B/Pl rats differ either in their metabolism of pyruvate and lactate or in their responses to these metabolites. PMID- 8700961 TI - MidnightSun: software for determining light exposure and phase-shifting schedules during global travel. AB - The application of circadian principles has the potential to alleviate jet-lag in global travelers, but their application is hampered by the difficulty of determining light exposure along international flight routes. Computerized tools can solve this problem algorithmically. We have developed a program for Macintosh computers, called MidnightSun, which allows researchers to display ambient lighting conditions at any geographical location at any time of the year. The program contains a data base with the latitudes and longitudes of over 3000 airports. It calculates flight paths and durations, and prints a graphical itinerary indicating times of daylight during flights and layovers. Given a travel itinerary and a user-defined phase response curve (PRC) for light, it recommends light exposure times that may accelerate the reentrainment of circadian rhythms to new time zones and reduce the deleterious effects of jet-lag (depending on the efficacy of the PRC and the compliance of the traveler). Other potential applications include determining lighting protocols for photoperiodism experiments and providing data sets for mathematical circadian simulations under naturalistic lighting conditions. PMID- 8700962 TI - Investigation of the effects and aftereffects of naturally occurring upper respiratory tract illnesses on mood and performance. AB - This study examined the effects and aftereffects of naturally occurring upper respiratory tract illnesses on mood and performance. Twenty-six subjects (12 males, 14 females, mean age 23 years 10 months, age range 18-39 years) were tested once a week for a period of a month. Fifteen subjects were suffering from a common cold on the first week and the other 11 subjects were matched healthy controls. Subjects attended for an initial 3-h testing period that consisted of a set of practice trials and two test sessions involving mood rating and performance of a battery of tests measuring psychomotor functions, attention, and memory. Sessions 3, 4, and 5 took place 1, 2, and 3 weeks later, respectively. In addition to measuring mood and mental performance, symptom severity was rated on a subjective checklist. The results showed that subjects with a cold reported an increase in negative mood and that this was only significant in the first week. Impairments of psychomotor function (simple reaction time and tracking) were also observed at this time. Performance of sustained and selective attention tasks was also impaired in subjects with colds but this effect was only significant in the second week. Other functions such as working and semantic memory were unimpaired in subjects with colds at any point in the experiment. Overall, the present results confirm many of the earlier results obtained in studies of experimentally induced upper respiratory tract illnesses. Indeed, these results are both of great practical importance and theoretical interest and further studies must now elucidate the mechanisms underlying these effects. PMID- 8700963 TI - Higher-protein foods produce greater sensory-specific satiety. AB - The objectives of this study were to determine if high-protein versions of the same food systems show more sensory-specific satiety than lower-protein versions, and to determine the effect of these protein differences on hunger levels following a meal. Subjects ate a high-protein and a low-protein version of a food system (either strawberry yogurt or a sandwich) as test meals. The high-protein strawberry yogurt test meal consisted of a serving of strawberry yogurt that contained whey protein isolate; the low-protein yogurt test meal consisted of a close-to-commercial strawberry yogurt. The high-protein sandwich meal consisted of a ham sandwich; the low-protein sandwich meal consisted of a bacon sandwich. Subjects tasted small portions of a set of foods (which included a sample of the test meal), and rated their liking of these foods before and after eating a test meal. Sensory-specific satiety occurred for all test meals. The decreases in liking when the high-protein versions of the test meals were eaten were significantly greater than the decreases in liking for the paired low-protein test meals. Higher-protein versions of the test meals also decreased hunger more than the lower-protein versions. PMID- 8700964 TI - Characterization of bacteriophage T4 early promoters in vivo with a new promoter probe vector. AB - We report on the construction of promoter probe vector pKWIII, useful in cloning and analyzing strong promoters for Escherichia coli RNA polymerase. Also T4 early promoters that proved to be difficult to clone with other vectors could be tested. The promoter activities obtained with this convenient and nonradioactive system largely correspond to those determined by pulse-labeling of transcripts in the same system. Results with well-characterized control promoters are in good agreement with values given by other authors. We present relative activities of several early promoters of phage T4 and compare these to promoter activities of other phages. Sorting the T4 promoters according to strength suggests the importance of distinct sequence elements to promoter functioning. They are centered around positions -52, -42, and -15. PMID- 8700965 TI - A region of a Sym plasmid of Rhizobium leguminosarum biovar phaseoli has similarity to prokaryotic insertion sequences and to eukaryotic integrases. AB - Near the nod and nif genes of the Sym plasmid pRP2JI of Rhizobium leguminosarum biovar phaseoli are three open reading frames whose deduced polypeptide products have similarities to those of genes in bacterial insertion sequences. The similarity of one of these ORFs was significantly greater to that of the integrase region of pol proteins of eukaryotic retroviruses and transposable elements in animals and plants than it was to the transposases of prokaryotic insertion sequences. In the noncoding region of the IS-like element, there was a sequence similar to that which had been identified close to nod genes in Azorhizobium caulinodans. PMID- 8700966 TI - Nucleotide sequence and analysis of pWC1, a pC194-type rolling circle replicon in Lactococcus lactis. AB - A 2.8-kb cryptic plasmid showing no homology to either pFX3 (rolling circle, pE194-type) or pCI305 (theta-type) lactococcal replicons was identified in Lactococcus lactis subsp. cremoris 2204. The plasmid, pWC1, was compatible with both pCI3340 (a pCI305 derivative) and pFX3 in L. lactis subsp. cremoris 2204. Sequence analysis of pWC1 showed one major ORF encoding a protein with a deduced size of 316 amino acids (aa). Database comparisons showed that the protein was distinct from the pFX- and pCI-type replication proteins (less than 21% aa identity), but shared significant homology (up to 57% aa identity) with the replication proteins from a different group of rolling circle plasmids (pC194 type) commonly found in gram-positive bacteria. A pC194-type rolling circle plasmid has not been previously described in L. lactis. Further sequence analysis showed a conserved double-stranded origin of replication in pWC1 preceded by a large (118-bp) direct repeat. The chloramphenicol-resistance gene from pC194 was inserted into a nonessential region of pWC1 to give pCP12. The host range of pCP12 included Streptococcus thermophilus, Enterococcus faecalis, and Staphylococcus aureus, but not Escherichia coli. Both pCP12 and to a lesser extent pWC1 generated single-stranded DNA (ssDNA) in L. lactis. A possible single stranded origin of replication was identified by sequence analysis of pWC1 and by comparing levels of ssDNA produced by pCP12 deletion derivatives. The pWC1 replicon may be a useful addition to other replicons currently available for vector construction. PMID- 8700967 TI - Complete nucleotide sequence of the Sulfolobus islandicus multicopy plasmid pRN1. AB - The complete sequence of the 5350-bp plasmid pRN1 from the crenarchaeote Sulfolobus islandicus has been determined. This plasmid is the first to be sequenced from this group of thermoacidophilic archaebacteria (Archaea) and its high copy number and wide host range make it a good candidate for a cloning vector. pRN1 contains several open reading frames, including one that spans over half the plasmid and has significant similarity to the helicase domain of viral primase proteins. Directly upstream of this putative primase is a homologue of Cop, a family of small proteins from promiscuous eubacterial plasmids which control copy number by repressing the expression of the replication initiation protein. In eubacterial plasmids cop is found upstream of the replication initiator protein. The location of a cop homologue upstream of a primase-like gene in pRN1 suggests that it controls DNA replication in a manner similar to these eubacterial plasmids, but does so using a mixture of components from plasmids and viruses. PMID- 8700968 TI - A novel tetracycline-resistant determinant, tet(U), is encoded on the plasmid pKq10 in Enterococcus faecium. AB - Nine tetracycline (Tc)-resistant clinical isolates of Enterococcus faecium were screened for plasmid content using agarose gel electrophoresis. pKQ10, a 1.9-kb plasmid carrying a novel Tc resistance determinant, was isolated from one of the isolates. The nucleotide sequence of this plasmid revealed an open reading frame corresponding to an 11.8-kDa protein and containing 105 amino acid residues. There was some limited similarity between this protein and tet(M), tet(O), tet(Q), tet(S), tetB(P), and otr(A), which overlapped, but did not include, the consensus GTP-binding sequences. The low-level, Tc-resistant determinant of pKQ10, named tet(U), does not appear to correspond to any other known Tc resistance determinant. PMID- 8700969 TI - Sequences found on staphylococcal beta-lactamase plasmids integrated into the chromosome of Enterococcus faecalis CH116. AB - We have previously reported the presence of the staphylococcal beta-lactamase gene in chromosomes of Enterococcus faecalis strains CH19 and CH116. CH116 also harbors a 26-kb mobile element, designated Tn5384, which confers resistance to erythromycin and gentamicin. Sequence analysis of the rightmost 9 kb of Tn5384 indicates that this element lies immediately upstream of the beta-lactamase determinant in E. faecalis CH116. This 9-kb region consists of sequences highly homologous to those previously described in staphylococcal beta-lactamase plasmids, including a beta-lactamase transposon indistinguishable from Tn552, an open reading frame encoding a deduced amino acid sequence 94% identical to a previously described potential staphylococcal invertase, an intact copy of staphylococcal insertion-like element IS257, and the major portion of the staphylococcal organomercurial lyase (merB) gene. These data are consistent with the hypothesis that several of the resistance genes encoded within the large transferable region of the CH116 chromosome were originally components of a staphylococcal beta-lactamase plasmid. PMID- 8700970 TI - Structural organization of pRAM4, a cryptic plasmid from Prevotella ruminicola. AB - A total of 530 strains of rumen bacteria were screened for the presence of plasmid DNA. The percentage of plasmid-bearing strains was found to be the highest among the Bacteroides/ Prevotella group (9.9%), while it was less than 1% in the Butyrivibrio (0.2%) and Clostridium (0.6%) genera. A small cryptic plasmid pRAM4 from Prevotella ruminicola T31 was subcloned in Escherichia coli and completely sequenced. Two open reading frames, encoding potential polypeptides of M(r) 32,322 (ORF1) and 32,122 (ORF2) with limited sequence similarity to replication initiation and mobilization proteins, respectively, could be identified within the sequence. The region upstream from ORF1 had an AT-rich (75%) region followed by four 22-bp direct repeats, a structure characteristic of replication origins. The plasmid hybridized at high stringency with plasmids from Bacteroides/Prevotella and Butyrivibrio, and with pBR322, suggesting that at least regions of the plasmid are widespread. PMID- 8700971 TI - Molecular analysis of closely related copper- and streptomycin-resistance plasmids in Pseudomonas syringae pv. syringae. AB - The genetic relationship of a group of copper (Cur) and streptomycin (Smr) resistance plasmids and their Pseudomonas syringae pv. syringae hosts was examined. Each of these plasmids contained sequences homologous to the oriV and par sequences from pOSU900, a cryptic P. syringae pv. syringae plasmid. Analysis of restriction digest patterns of plasmid DNA indicated that the plasmids could be clustered into four groups; two of the groups contained multiple members which differed by only a few fragments. An analysis of the host P. syringae genotypes using the arbitrarily primed PCR technique and genomic DNA indicated that the host strains could be placed in groups similar to those resulting from analysis of plasmid DNA. Southern hybridization analyses of plasmid DNA indicated that each Smr plasmid contained sequences homologous to probes specific for the strA strB Smr genes and the transposase and resolvase genes from Tn5393. All plasmids hybridized to two additional probes derived from P. syringae plasmid DNA, but none of the plasmids contained IS51 or IS801 sequences. Furthermore, Tn5393 was mobilized, presumably by transposition, between the incompatible plasmids pPSR5 and pPSR4 in P. syringae pv. syringae FF5. The variation in molecular structure of the closely related plasmids in this study is similar to that observed with antibiotic-resistance plasmids from clinical bacteria. PMID- 8700972 TI - Autogenous soft-tissue procedures and osseointegrated alloplastic reconstruction: their role in the treatment of complex craniofacial defects. AB - Between 1990 and 1994, twenty-seven patients with extraoral craniofacial defects were treated at the Craniofacial Osseointegration and Maxillofacial Prosthetic Rehabilitation Unit in Edmonton. Fourteen patients required management by a combination of alloplastic and autogenous techniques to optimize their reconstructive result. Autogenous soft-tissue procedures were performed almost twice as often in patients whose deformity was the result of trauma. Autogenous soft-tissue procedures included soft-tissue expansion, static facial slings, free and pedicled vascularized bone grafts, eyebrow reconstruction, brow lifts, and scar revisions. These reconstructive procedures are illustrated in three cases. PMID- 8700973 TI - Stability of fronto-orbital advancement in nonsyndromic bilateral coronal synostosis: a quantitative three-dimensional computed tomographic study. AB - Fronto-orbital dysmorphology in nonsyndromic bilateral coronal synostosis includes frontal flattening, supraorbital recession, and ocular globe protrusion. Surgical advancement of the supraorbital region ("bandeau") is performed to correct these deformities. A retrospective analysis of 10 consecutive patients with nonsyndromic bilateral coronal synostosis was performed to assess the effect of two types of bandeau fixation at the nasion. The advanced bandeau was fixed medially at the nasion with a calvarial bone graft and polyglycolic acid sutures (bone graft/suture group, five patients) or with a microplate (plate group, five patients) and bilaterally at pterion with calvarial bone grafts and polyglycolic acid sutures (all patients). The cranio-orbital dysmorphology and the surgical results were studied using pre-, peri-, and post-operative three-dimensional computed tomographic (CT) data. Reformation, manipulation, editing, and quantitative measurements of the CT data were performed on a computer workstation and Analyze imaging program. Four measurements performed to evaluate the fronto orbital morphology: the length:width ratio of anterior cranial fossa, ventral globe index, cornea position, and supraorbital rim lag. The ventral globe index assessed the degree of eyeball protrusion out of the orbit cavity. Measurements of the cornea position and supraorbital rim lag were performed on the longitudinal orbit projections of the CT data. Six normal skull CT scans were available for same measurement and comparison. Measurements of the preoperative fronto-orbital dysmorphology in bilateral coronal synostosis were significantly different from those of normal subjects. One year after the surgery, the length:width ratio of the anterior cranial fossa was normalized in both groups. The ventral globe index was improved but not normalized in both groups, whereas the cornea position and supraorbital rim lag were improved in the bone graft/suture group but were normalized in the plate group. Based on the quantitative data, the surgical outcomes in the plate group were significantly better than those in the bone graft/suture group. Major relapse of surgical advancement in the bone graft/suture group seemed to occur in perioperative period. In summary, at 1 year postoperatively, the bandeau advancement improved but did not entirely normalize the fronto-orbital dysmorphology of nonsyndromic bilateral coronal synostosis in either group. We conclude that plate rigid fixation at the nasion provides superior stability for bandeau advancement compared with bone graft/suture fixation. PMID- 8700974 TI - Craniofacial growth in rabbits after rigid or semi-rigid fixation of the frontonasal suture. AB - Treatment of craniofacial dysostosis involves complex remodeling of the cranium and facial bones. Maintenance of the newly positioned segments may be achieved by rigid fixation using plates; however, there is concern that, over time, these plates may interfere with normal growth. The purpose of this study was to test a method of "semi-rigid" fixation of an osteotomy of the frontonasal suture in juvenile rabbits by comparing standardized parameters of craniofacial growth after conventional suture plating with the experimental plating method and with growth after sham operation. Forty-five, 6-week-old, weanling rabbits were divided into three groups of 15 each (12 for cephalometry, 3 for histological examination): (group 1) control, sham operated; (group 2) rigid fixation; (group 3) semi-rigid fixation. Rabbits were maintained for 14 weeks. Craniofacial growth was assessed using three-dimensional image analysis techniques. Measurements were subjected to statistical analysis (one-way analysis of variance) to compare the three treatment groups. Pairwise comparison of means between the treatment groups was done using Bonferroni's method at the 0.05 significance level. Semi-rigid fixation permitted significantly more normal growth of the developing rabbit head than rigid fixation in total snout length, total vault length, left and right midface height, and left orbital length. Both semi-rigid and rigid fixation significantly restricted growth compared with sham operated animals in left and right posterior midface height, right orbital length, right and left nasal bone length, and left parietal width. There were no significant differences in the growth of all other parameters measured. PMID- 8700975 TI - Evaluation of a novel osteogenic factor, bone cell stimulating substance, in a rabbit cranial defect model. AB - A novel osteogenic factor, bone cell stimulating substance (BCSS), was recently isolated from bovine bone. Unlike the bone morphogenetic proteins, which are generally 20- to 40-kDa glycoproteins belonging to the transforming growth factor beta superfamily, BCSS is a 2.5-kDa, water-soluble polypeptide. This study evaluated the osteogenic potential of BCSS in combination with coralline-derived porous hydroxyapatite to reconstruct a large, nonhealing cranial defect in the rabbit. Twenty-four rabbits underwent a 16 x 20 mm full-thickness (extradural) excision of the parietal bones and were divided into six groups of four rabbits each. Group 1 through 5 were reconstructed with 16 x 20 x 1.5 mm hydroxyapatite implants treated with: (1) 20 osteogenic units (424 micrograms) BCSS, (2) 8 osteogenic units (170 micrograms) BCSS, (3) 4 osteogenic units (85 micrograms) BCSS, (4) 0 osteogenic units (424 micrograms) inactive BCSS analog, or (5) left untreated. Group 6 was left unreconstructed. Implants were harvested at 12 weeks and analyzed for percentage of lamellar bone formation by a computerized microscope video image analysis system. Groups reconstructed with BCSS-treated hydroxyapatite implants demonstrated more bone ingrowth than did the control hydroxyapatite groups not treated with BCSS (inactive BCSS analog or untreated). Linear regression dose-response analysis indicated an average 3.2 percent increase in bone ingrowth for a 10-U increase in BCSS (p = 0.043). The unreconstructed control group demonstrated no healing. With a molecular mass of only 2.5 kDa and its identity not completely known, BCSS is a novel factor that seems to possess osteogenic potential similar to that of previously investigated osteogenic proteins. PMID- 8700976 TI - Prevention of facial herpetic infections after chemical peel and dermabrasion: new treatment strategies in the prophylaxis of patients undergoing procedures of the perioral area. AB - A proposed clinical strategy is offered for the prevention and treatment of facial herpetic infection associated with phenol chemical peel or dermabrasion of the perioral area. A retrospective evaluation of 181 consecutive patients undergoing perioral chemical peel or dermabrasion from 1983 to 1990 was performed. No patients were excluded and the minimum follow-up was 6 to 24 months. All procedures were done at a private practice ambulatory surgery center. Patients with any history of oral herpetic lesions were pretreated with oral acyclovir. The vast majority of these patients received dosages far exceeding previously described regiments. A subset of patients (n = 12) whose procedures predated acyclovir's commercial availability received no prophylactic treatment and allowed for a comparison group. The incidence of postoperative infection was measured to determine the effectiveness of prophylactic acyclovir treatment. In patients reporting previous herpetic infection, postoperative herpetic outbreaks were far more likely to occur (50 percent infection rate) in the absence of prophylactic acyclovir. An 8.3 percent infection rate was noted in patients with a similar history who received standard acyclovir prophylaxis. Once high dose prophylactic treatment was initiated, no further herpetic outbreaks were observed. Even among patients with a negative history of oral herpes (no treatment), 6.6 percent developed postoperative infections. Pretreatment with high dose acyclovir clinically minimizes the incidence and severity of postoperative herpetic infection in patients undergoing perioral chemical peel or dermabrasion. All patients should be treated preoperatively with acyclovir regardless of past history, because even those patients reporting no previous outbreaks of oral herpes may develop postoperative infections. PMID- 8700977 TI - Rhinoplasty patients' critical self-evaluations of their noses. AB - Many applicants for cosmetic rhinoplasty do not appear to have grossly deformed noses. This study was undertaken to determine the accuracy of nasal evaluations in a group of 20 female cosmetic rhinoplasty patients, before and after surgery, relative to a matched nonrhinoplasty control group composed of 25 subjects. Self assessments and surgeon assessments were obtained for both groups. Compared with those of controls, the noses of patients were found to be more deformed before and better shaped after the operation, according to both self-assessments and surgeon assessments. Rhinoplasty patients, in contrast to controls, tended to downgrade the shape of their noses compared with surgeon assessments both before and 4 months after surgery. Faulty evaluation was not associated with sociodemographic parameters, brief symptoms index (BSI) scores, or the degree of patient satisfaction from surgical outcome. Replication and longer-term follow-up studies are needed and are anticipated. PMID- 8700978 TI - Cutaneous malignant melanoma in children and adolescents in Scotland, 1979-1991. AB - All cases of cutaneous malignant melanoma in Scotland have been registered by the Scottish Melanoma Group since 1979, and there are currently more than 4700 cases on the registry. Of these, only 50 cases are in patients 18 years of age and younger (1.04 percent of all melanomas); 15 of these were prepubertal, i.e., 14 years or younger (0.3 percent of all melanomas). The nine cases of documented metastases occurred in children with tumor thickness of 1.50 mm or more, with only one of these metastases occurring in a prepubertal child. Eight of these patients with metastatic disease died, with a maximum survival of 4 years. A reliable clinical history was obtained from the families of 23 patients. Eight of them had a history of preexisting congenital nevocellular nevus. In this series, no case arose in a large congenital nevocellular nevus. Histological review showed that the majority of cases (58 percent) exhibited typical cytological and architectural features of malignant melanoma. In the remaining cases, the lesions were difficult to fit into any of the classic patterns of malignant melanoma or of the known benign nevocellular lesions. PMID- 8700979 TI - Preservation of the inframammary fold: what are we leaving behind? AB - Preservation of the inframammary fold (IMF) at the time of mastectomy facilitates immediate breast reconstruction. Twenty-four IMF specimens were removed separately after mastectomy for cancer, were serially sectioned, and were examined histologically. Computer image analysis was used to calculate the percentage of breast tissue in each specimen. The mean volume of IMF tissue removed was 99 cm3 (27.3-205.2 cm3), and the mean area examined histologically was 3,036.3 mm2 (294-11,755 mm2). Breast tissue was identified in 13 of the 24 specimens. All cases were negative for carcinoma, but one case had a focus of ductal hyperplasia, usual type. The mean percent breast tissue in those positive for breast tissue was 0.04 percent and 0.02 percent overall. Preservation of the IMF leaves a minimal amount of breast tissue and does not appreciably effect the completeness of a mastectomy. PMID- 8700980 TI - Outcome analysis of reduction mammaplasty. AB - In an attempt to obtain objective analysis of outcome in reduction mammaplasty patients, a retrospective study was done for women having elective bilateral reduction mammaplasty. Participants were chosen from a pool of over 200 consecutive reduction mammaplasty patients at the University of Missouri Columbia. Of those eligible for inclusion, 72 met the criteria and were available for long-term follow-up. These patients answered a panel of questions regarding weight change, brassiere size, exercise, activity level, symptoms, and a personal appraisal of appearance. Statistical analysis was done to evaluate the change in each variable in relationship to the time of surgery, i.e., before surgery, 6 months after surgery, and at the present time. The findings revealed a significant stable reduction of breast mass. The women reported a significant reduction of symptoms that had been associated with their macromastia. They also reported a significant increase in exercise and other physical and social activities. PMID- 8700981 TI - Determining the safety of the silicone envelope: in search of a silicone antibody. AB - In the controversy surrounding breast implants, one of the crucial questions is whether patients ca form antibodies directed against the silicone shell of the implant. If this were the case, implications for current breast implant development, indeed, for all silicone medical devices, are far-reaching. To evaluate this hypothesis, sera from 18 patients who had tissue expanders and 15 control patients who had no silicone implant exposure were tested retrospectively for antibodies to the silicone using an enzyme-linked immunosorbent assay previously documented as a case report in the literature. Contrary to previous studies, no significant difference in antibody levels was found between test subjects and the controls. Additionally, this enzyme-linked immunosorbent assay for silicone antibodies was poorly reproducible. This study calls into question the existence of specific antibodies to the silicone shell. It also provides further data that the enzyme-linked immunosorbent assay may not be reliable as a silicone antibody test. PMID- 8700982 TI - Choice of flap and incidence of free flap success. AB - A review of 854 consecutive free flaps was performed to determine whether the choice of flap used for the reconstruction influenced the probability of a successful outcome. Flaps were grouped into nine categories: rectus abdominis, free transverse rectus abdominis myocutaneous, radial forearm, jejunum, latissimus dorsi, fibula, scapula, iliac crest, and other. There were significant differences among the success rates of different flaps (p < 0.0001). Rectus abdominis-based flaps used for breast or head and neck reconstruction had lower failure rates (0.9 percent) than did non-rectus abdominis flaps (6.6 percent; p < 0.0001). Flaps requiring vein grafts had a higher rate of flap loss (18.4 percent) than did flaps that did not require vein grafts (2.9 percent; p < 0.0001). There was a strong trend favoring survival of flaps without a bone component (compared with osteocutaneous flaps), and a weaker trend favoring survival of flaps in nonobese patients (compared with flaps in obese patients). Smoking, age, and previous irradiation had no significant effect on flap failure rates. Surgeons should consider the flap success rate as one (but not necessarily the most important) factor in choosing the best reconstruction for any individual patient. PMID- 8700983 TI - Sliding myofascial flap of the rectus abdominus muscles for the closure of recurrent ventral hernias. AB - Despite a reported incidence of up to 11 percent of incisional/ventral hernias following celiotomies, there is no universally applicable preventive or reconstructive technique in practice. Among patients undergoing repair of ventral incisional herniation, the reported recurrence rates are typically in the 30- to 50-percent range. This study concentrates on the patient with a large, recurrent abdominal incisional hernia in whom conventional surgical repair has failed. We report our recent 4-year experience with the use of "components separation" of the myofascial layers of the abdominal wall for repair of these recurrent herniations. During 4-year period, 35 patients with large, recurrent ventral hernias underwent repair by the same surgeon (J. H. M.) using the method described below. Abdominal defects as large as 875 cm2 were repaired, with a median defect size of 255 cm2. The repair was based on the compound flap of the rectus muscle with its attached internal oblique-transversus abdominus muscle with advancement to the midline to recreate the linea alba. Any repairs that were attenuated were supported with either ePTFE (8.6 percent) or Vicryl mesh (34 percent). The study group consisted of 35 patients, 34 percent male and 66 percent female; mean age was 55 years. Length of follow-up ranged from 1 to 43 months, with a mean follow-up of 22 months. Overall recurrence rate for herniation was 8.5 percent (3/35). Additional complications, namely seroma, wound infection, and hematoma, occurred at rates of 2.8, 5.7, and 5.7 percent, respectively. There were no mortalities. The compound flap of the rectus and internal oblique-transversus can be advanced medially to recreate the linea alba to provide dynamic, stable support for defects as large as 875 cm2. A recurrence rate of 8.5 percent was achieved in a relatively high-risk population with acceptable morbidity and no mortalities. In our 4-year experience, the sliding rectus abdominus myofascial flap has proved to be a safe and effective tool for dealing with patients in whom conventional means of repair have failed. PMID- 8700984 TI - Fingertip replantations: clinical evaluation of 135 digits. AB - From July 1985 to February 1993, 135 digits in 119 patients with complete amputations at or distal to the distal interphalangeal joint (zone I for amputations distal to the nail base of zone II for amputations between the distal interphalangeal joint and the nail base) were replanted using a microsurgical technique at Korea University Guro Hospital. Because of the high social value placed on body form and function, the indication for replantation was extended to cases with severe soft-tissue injuries and attempted replantation as a routine procedure in nearly all distal amputation cases. The overall survival rate was 78 percent, with the survival rate for zone I being 70 percent and that for zone II reaching 86 percent. Even in cases with severe soft-tissue injury, the survival rate was high, with viability in avulsion injuries and crush injuries reaching 75 percent each. The most common type of vascular repair in zone I cases was revascularization of one artery only and no vein repair (87 percent). Of these cases, interpositional vein grafts were used in 65 percent. In zone II cases, the most common combination repair was one artery and one vein anastomosis (70 percent), with interpositional vein grafts for arterial anastomosis in 49 percent; most of the venous repair was feasible by the direct method (78 percent). The follow-up period ranged from 1 month to 5 years with a mean of 14.8 months; 52 patients were followed-up for more than 6 months. In 52 long-term follow-up patients, the average two-point discrimination was 8 mm. Patient satisfaction, aesthetically and functionally, was high (91 percent). PMID- 8700985 TI - Eight cases of nine-digit and ten-digit replantations. AB - Amputations involving nine and all ten digits are very rare because of the different lengths of the digits, and it is also unusual to have all digits suitable for replantation. At Korea University Guro Hospital, from March 1987 to April 1992, three cases of 10-digit and five cases of 9-digit complete amputations were replanted by microsurgical technique. All eight cases involved young, healthy male patients, and the causes of amputation were either a cutter of press machine. The replantations were done under general anesthesia simultaneously on both hands by eight microsurgeons divided into a total of four teams. The operating times ranged from 19 to 31 hours, and the total amounts of transfused blood ranged from 6 to 38 pints. The warm ischemic times ranged from 10 minutes to 15 hours, and the cold ischemic times ranged from 3 to 29 hours. The sequence of replantation was radial digit to ulnar digit. In five of the eight patients, all of the replanted digits survived. Necrosis occurred in one and two digits in two patients with nine-digit replantations. Also, necrosis occurred in three digits in a patient who had had nine digits amputated by a press machine, sustaining severe crush injuries. The overall survival rate was 92 percent. In multidigit replantations involving 9 or 10 digits, there are a number of problems that must be overcome, including a long operating time, long ischemic times, and a large amount of blood loss. The long ischemic times were not critically related to survival rate. The total amount of blood transfused was reduced from 38 pints in one of the initial cases to 6 pints by intermittent use of the pneumatic tourniquet and venous anastomosis before arterial anastomosis. Static two-point discrimination ranged from 3 to 22 mm, and palm to pulp distance ranged from 0 to 7 cm, 1 to 5 years postoperatively. Grasping power ranged from 13 to 65 lb, and pinching power ranged from 5 to 26 lb, which was 42 and 50 percent of the average power of a Korean adult male, respectively. All eight patients returned to work and are satisfied with the result, functionally and aesthetically. PMID- 8700986 TI - Aesthetic refinements in toe-to-hand transfer surgery. AB - Techniques for aesthetic refinement are as important as those for functional improvement in toe-to-hand transfer. The appearance of the thumb reconstructed using various types of great toe transfer can be improved by reduction of the soft tissue, bone, interphalangeal joint, and nail and by secondary pulp reduction and contouring procedures. Finger and thumb reconstructions using lesser toes can be improved aesthetically by minimal inclusion of adipofibrous tissue under the plantar skin flap especially at the metatarsophalangeal joint region, thus decreasing the anterior-posterior bulkiness. Tight extensor repair, temporary K-pin fixation of the proximal and distal interphalangeal joint in extension, followed by prolonged use of a nighttime extension splint and secondary pulp reduction help to avoid the claw and drumstick appearances of the transferred lesser toe. Adequate soft-tissue coverage, cruciate skin incisions, extensive mobilization, and thinning and trimming of the skin flaps of the digital amputation stump lead to a smooth junction between the amputated digit and the transferred toe. In the distal digital reconstruction, skeletonization of medial and lateral neurovascular bundles of the harvested toe helps primary closure of the digital wound, thus avoiding the unsightly skin graft on the sides of the reconstructed digit. Regarding the donor foot, preservation of the proximal 0.5 to 1 cm of the proximal phalangeal stump of the great toe maintains the span of the foot, thus improving donor site appearance. In single lesser toe or combined second and third toe transfer, the proximal phalanx should not be preserved but an optimal web space should be reconstructed. Primary closure without skin graft is essential for aesthetic appearance of the donor foot. PMID- 8700988 TI - The future of the surgical subspecialist. PMID- 8700987 TI - Possible contributions of mastocytosis, apoptosis, and hydrolysis in pathophysiology of randomized skin flaps in humans and guinea pigs. AB - To understand better the pathophysiology of random skin flaps, randomized skin flaps of human (3 cases) and guinea pig (53 cases) were investigated. Proximal (normal), proximomedial (viable), mediodistal (between viable and necrotic parts), and distal (necrosis) locations of the skin flaps were biopsied. Lipid peroxidase, hydrolytic enzymes of cytosol (Ca(2+)-dependent cysteine protease: calpain), and lysosome (acid phosphatase) of skin were used as markers. Measurements were taken of the flap blood flow; the numbers of capillaries, postcapillary venules, pericapillary arterioles, leukocytes, and mast cells per unit square of dermis. Apoptotic cells were identified by specific staining. Flaps were sampled at postoperative weeks 1 and 3 (human) and hours 1 and 6, and days 1 to 7 (guinea pig). The values for normal skin were regarded as the control. Obstruction (by leukocytes) of venous microvessels, rather than arterial microvessels, was the major cause of temporary hypoxia in the proximomedial location, constant hypoxia (venous stasis) in the mediodistal location, and ischemia in the distal location. Increases in the number of mast cells (mastocytosis) and microvessels (angiogenesis) were significant only in the viable parts of the flaps. This phenomenon and the rate of blood flow increased with time in viable locations (guinea pig). Epidermal necrosis, dermal fibrosis, and apoptosis were evident mostly in the mediodistal location. Elevated levels of leukocytes, lipid peroxidase, acid phosphatase, and calpain, combined with necrotic changes, were seen mostly in the distal skin location. There is a strong possibility that the following factors are involved: lipid piroxidation and hydrolysis in necrosis of the distal flap location after ischemia; constant hypoxia in fibrosis and apoptosis in the mediodistal location; and initial or temporary hypoxia in mastocytosis-induced angiogenesis in the viable location. The results presented here indicate that guidelines for further investigations include combined suppression of leukotaxis, lipid peroxidase, and hydrolysis, or the application of mast cell growth factors in an effort to salvage the flap maximally. PMID- 8700989 TI - CO2 laser resurfacing: why all the fuss? PMID- 8700990 TI - Multiple occurrence of pilomatrixoma. AB - Multiple occurrences of pilomatrixoma are rare. Although it has been known as a benign lesion, there are reports of some tumors that have histopathologic features of malignancy. A case of a 68-year-old Caucasian women with multiple pilomatrixoma is presented. She was operated on to remove three other pilomatrixomas on the arms 3 years after the initial excision from the face. Two years after excision of the lesions on the arms, no recurrences were evident. PMID- 8700991 TI - Treatment of recurrent cerebrospinal fluid rhinorrhea with a free vascularized omental flap: a case report. AB - Cerebrospinal fluid fistulas after pericranial surgery are a major source of morbidity. A patient who underwent transsphenoidal sinus surgery for a recurrent pituitary adenoma was presented. The patient developed a chronic CSF leak despite standard management, including subarachnoid CSF drainage and transnasal endoscopic closure of the dura. Successful closure of the CSF fistula was obtained using a free omental flap to the sphenoid sinus. This case is the first reported use of a free microvascularized omental flap in an intracranial position for treating chronic CSF rhinorrhea. A description of the indications and the surgical technique for free omental closure of CSF fistulas was provided. The etiology, diagnosis, and management of CSF rhinorrhea are reviewed for the reconstructive surgeon. PMID- 8700992 TI - Use of a new anchoring device for tendon reinsertion in medial canthopexy. AB - This paper describes the use of the Mitek Mini GII Anchor System for tendon reinsertion in medial canthopexy. The system is simple, fast to insert, and easy to use. It allows precise placement with minimal dissection, which is limited to the ipsilateral orbit. PMID- 8700993 TI - Surgical management of axillary bromidrosis--a modified skoog procedure by an axillary bipedicle flap approach. AB - We developed a modified Skoog procedure to treat axillary bromidrosis and hyperhidrosis that creates a bipedicle flap over the axillary fold with two parallel incisions to achieve a complete excision of the sweat glands. If necessary, the flap can be extended by making another parallel incision for a larger axillary hair-bearing area. Between 1988 and 1992, 110 patients were operated on using this method, but only 92 of the 110 patients, with an average follow-up period of 29.5 months, were available for this follow-up study. In this series, 86.9 percent of patients gave a family history of axillary bromidrosis. This follow-up review demonstrated that 93.5 percent of patients experienced no odor or occasional very mild axillary odor postoperatively. Postoperative scar formation was either nonvisible or excellent in 95.1 percent of patients, and 82.6 percent of patients reported either a hairless axilla or a marked decrease of axillary hair. Most importantly, 92.4 percent of patients reported a marked decrease in axillary sweat. Four axillary fossae developed postoperative subcutaneous hematomas, and six wounds had mild dehiscence. All of the wounds eventually healed satisfactorily after minor procedures. We concluded that for the treatment of extensive axillary apocrine bromidrosis, this new method achieves complete excision of the sweat glands and provides excellent functional and cosmetic results. PMID- 8700994 TI - Treatment of vaginal agenesis with an expanded vulval flap. AB - We propose a vaginal reconstruction method using an expanded vulval flap. This technique avoids long-term dilation and combines the advantages of commonly used methods of treatment for vaginal agenesis, resulting in good functional outcome. PMID- 8700995 TI - Reconstruction of incomplete syndactyly of the toes using both dorsal and plantar flaps. AB - A new modified method for surgical correction of simple incomplete syndactyly of the toes has been devised. This procedure involves both a dorsal and a plantar skin flap and does not require a skin graft. Reconstruction of syndactyly using only skin flaps situated near the toes almost always results in skin deficiency. Use of a plantar flap from the sole provides sufficient skin for one toe and can be closed primarily. Fourteen cases involving 11 patients have been treated by this method, which is described herein. PMID- 8700996 TI - Calcaneal fillet flap: a new osteocutaneous free tissue transfer for emergency salvage of traumatic below-knee amputation stumps. AB - Traumatic below-knee amputations do not always leave enough soft tissue of bone with which to fashion a stump of sufficient length and durability to support a prosthesis. Composite free flaps can often be harvested from the amputated limb to provide immediate one-stage stump salvage and to preserve knee function. We report a new technique to increase stump length by incorporating the calcaneus into a foot fillet flap as a vascularized bone transfer. The calcaneal fillet flap is a useful addition to the inventory of available composite flaps. It is recommended for knee joint salvage when there is less than 11 cm of tibial remnant length. PMID- 8700997 TI - The prefabricated combined scapula flap for bony and soft-tissue reconstruction in maxillofacial defects--a new method. AB - A concept for improving the precision of reconstruction of the maxilla in terms of form and function, including gnathologic, functional, and prosthetic aspects, is presented with a prefabricated combined scapula flap. In four cases, a bony flap from the lateral border of the scapula with osseointegrated titanium implants, covered with skin grafts and encapsulated with a Goretex sheet to create a stable soft-tissue coverage, was performed. Three months later, the prefabricated combined scapula flap was harvested and transferred to reconstruct a maxillary bony and soft-tissue defect in the face using microsurgical vascular anastomoses to the facial vessels. One flap was lost because of vascular thrombosis and was repeated successfully 1 year later. In each of the four cases, full dental rehabilitation and marked improvement of the facial contour was achieved in a single surgical intervention of the face. For this purpose, new radiodiagnostic methods for precise correlation between the maxillofacial defect and the donor area were use. With this new concept, an organ-specific reconstruction of soft-and bony-tissue defects of the alveolar ridge and the hard palate, with a pseudogingiva and teeth, is possible in an optimal way. PMID- 8700998 TI - Development of alternative breast implant filler material: criteria and horizons. AB - The introduction of the silicone gel-filled breast implant more than 30 years ago changed the nature of alloplastic breast augmentation and reconstruction. Over the last three decades, it is estimated that one million American women have undergone implantation with some variation of these devices. Recent medical, legal, and regulatory developments have forced a moratorium on the unrestricted uses of the silicone gel-filled implants, and it appears unlikely that its general use will return. However, there is a continued need for some type of breast implant in both aesthetic and reconstructive surgery. The Food and Drug Administration has proposed testing guidelines for the development of any new breast implant before unrestricted clinical use. These guidelines will direct the creation of new filler materials from their earliest stages, through long-term postimplantation follow-up studies. This article succinctly examines the central issues in the breast implant controversy in relation to the FDA's recommendations for the development of new implants, discusses breast implant filler materials currently under development, and offers guidelines fro the development of breast implant fillers that are safe and effective. PMID- 8700999 TI - The hazards of using supplemental oxygen. PMID- 8701000 TI - Complications of harvesting cranial bone grafts. PMID- 8701001 TI - Another area of risk avoidance. PMID- 8701002 TI - A simplified procedure for locking the plunger during syringe-assisted liposculpturing. PMID- 8701003 TI - Gagged care. PMID- 8701004 TI - On the genesis of managed care. PMID- 8701005 TI - An unusually avulsed penis successfully replanted by using microsurgical technique. AB - An unusually avulsed penis and its successful microsurgical replantation is reported. The penis was self-avulsed between the superficial fascia of the shaft, and the shaft was cut distally, just proximal to the glans, with the whole glans and a short part of the shaft hanging in the avulsed skin of the penis. According to our search in the literature, this is the first successful replantation of such a case by microsurgery. The blood circulation of the replant was reestablished, after 15 hours of tissue ischemia, by means of microsurgical vascular anastomosing of the minimal subcutaneous vessels in the skin. Both the skin and the glans survived, indicating the alternative possibility of replantation of avulsed penile skin by microsurgery, rather than by skin grafting. PMID- 8701006 TI - Reattachment of the temporalis muscle to methacrylate in secondary surgery for craniosynostosis. PMID- 8701007 TI - How to handle rigid endoscopes in office surgical facilities. PMID- 8701008 TI - Patient selection caveats. PMID- 8701009 TI - Placebo effects. Issues for clinical practice in psychiatry and medicine. AB - Placebo effects are integral to everyday clinical practice; therefore, they should be well understood by all health care practitioners. Despite the rich literature on the topic, placebo effects receive only passing mention in major textbooks of psychiatry and medicine. The authors clarify the placebo construct and offer a selective review of its history, definitions, mechanisms, and relation to experimental methodology and statistics. Also considered are the concept of nocebo, variation in placebo response rates, and some economic and ethical problems with placebos in clinical trials. Directions are suggested for future research. PMID- 8701010 TI - Screening for somatizing patients in the pulmonary subspecialty clinic. AB - Somatizing patients present a history of vague, unexplained medical symptoms. This study compared somatizing patients with pulmonary control subjects by using the Diagnostic Interview Schedule (DIS-III-R), the Illness Attitude Scales (IAS), and the Minnesota Multiphasic Personality Inventory (MMPI-2). The groups differed in the number of somatization symptoms reported and in the frequency of somatization disorder diagnoses when the screening criteria were used. The somatizing group obtained higher scores on the bodily preoccupation and hypochondriacal beliefs subscales of the IAS; no differences were found on the MMPI-2. These findings indicate that the DSM-III-R somatization screening items can be useful for detecting somatization when patients present with unexplained respiratory complaints. PMID- 8701011 TI - Death anxiety, locus of control, and purpose in life of physicians. Their relationship to patient death notification. AB - This study explored gender and specialty differences in death anxiety, locus of control, and purpose in life of physicians, and if these variables might influence the clinical behavior of physicians regarding death notification. The subjects were 155 attending and house staff physicians who responded to mailed questionnaires. The female physicians scored higher in death anxiety than the male physicians. The psychiatrists scored higher in death anxiety than surgeons. There was a trend for the internists to have scores indicating a more external locus of control. Purpose in life was inversely correlated with death anxiety and external locus of control. Death anxiety was related to the physicians' preferred mode of conveying the news of an unexpected patient death to the next of kin. PMID- 8701012 TI - A psychiatric appraisal of "glossodynia". AB - "Glossodynia" is a diagnostic rubric that includes patients enduring pain or a burning sensation in the tongue without any oral pathology or systemic disease. Psychiatric profiles of 50 women patients with "glossodynia" were compared with those of control subjects. The patients scored significantly lower on the Extraversion Scale of the Eysenck Personality Questionnaire and higher on the Toronto Alexithymia Scale than the control subjects, whereas there was no significant difference in the mean General Health Questionnaire score. The psychopathology of "glossodynia" may be more markedly associated with personality trait characteristics than with neurotic or depressive symptoms. PMID- 8701013 TI - Famotidine-associated delirium. A series of six cases. AB - Famotidine is a histamine H2-receptor antagonist used in inpatient settings for prevention of stress ulcers and is showing increasing popularity because of its low cost. Although all of the currently available H2-receptor antagonists have shown the propensity to cause delirium, only two previously reported cases have been associated with famotidine. The authors report on six cases of famotidine associated delirium in hospitalized patients who cleared completely upon removal of famotidine. The pharmacokinetics of famotidine are reviewed, with no change in its metabolism in the elderly population seen. The implications of using famotidine in elderly persons are discussed. PMID- 8701014 TI - Practice patterns in the diagnosis and treatment of anxiety and depression in the medically ill. A survey of psychiatrists. AB - By use of a survey that assessed practice patterns and responses to case vignettes of anxiety and depression in the medically ill, 38 psychiatrists were compared with 10 national leaders in consultation-liaison psychiatry. On the case vignettes, percentage agreement with the experts varied significantly by case and by question. Fifty-eight percent of the time the psychiatrists agreed with the experts on whether to order laboratory tests as compared with an 81% agreement level on whether to use psychotherapy. Multiple regression analysis revealed that the best model to predict lower agreement with the experts was years in practice plus percentage of time spent in solo (vs. group) practice (r2 = 0.40). This study extended previous data-based pharmacoepidemiology by assessing multiple aspects of psychiatrists' practice patterns. Psychiatrists who are more distant from training years and more isolated from the current stimulation of colleagues may be particularly appropriate targets for continuing education. PMID- 8701015 TI - Constant observation in a medical-surgical setting. The role of consultation liaison psychiatry. AB - Constant observation (CO) is commonly used in general hospital settings to protect patients who are at risk for harming themselves or others. The role of consultation-liaison psychiatry in the implementation of this procedure is often assumed, but has not been well studied. The authors report the findings of a 6 month study of the use of CO in a general hospital and discuss its implications for quality of care and, possibly, cost-effectiveness. PMID- 8701016 TI - The use of electroconvulsive therapy in pain patients. AB - Twenty-one patients with primary chronic pain received electroconvulsive therapy (ECT) for concurrent affective symptoms. Twenty of the 21 patients experienced improvement in the level of their pain. ECT can be an effective treatment modality for patients who have chronic pain complicated by affective symptoms. PMID- 8701017 TI - Major depression in Alzheimer's disease. An interaction between gender and family history. AB - Major depression afflicts from 15% to 31% of patients with Alzheimer's disease (AD). The charts of 137 patients with AD were reviewed to assess the association between several variables and the risk of developing major depression. Thirty eight patients (28%) had major depression. A family history of mood disorder was associated with a significantly increased risk for major depression, but this was only true in women (relative of odds = 2.82,95 confidence interval from 1.19 to 6.69). There was no relationship between major depression and a personal history of depression, younger age at onset of AD, history of substance use disorder, institutionalization, and marital status. These results suggest that the relationship between family history and depression in AD is more complex than previously thought. PMID- 8701018 TI - The prevalence of symptoms of irritable bowel syndrome among acute psychiatric inpatients with an affective diagnosis. AB - An interview study of 87 inpatients with affective diagnoses, according to the International Classification of Diseases (9th Edition), yielded a prevalence of irritable bowel syndrome (IBS) of 39.7%, approximately twice that found in the general population. The IBS symptoms almost invariably preceded the onset of the affective disorder, but were exacerbated by it. The consultation rate for bowel symptoms (41.9%) was greater than that in the general population. In this study, 69.2% of consulters and 55.5% of nonconsulters had experienced an exacerbation of their IBS symptoms since the onset of their emotional disorder. These findings suggest that such disorders may influence the subjective severity of IBS and also consultation behavior, but do not play a major part in the etiology of the gastrointestinal symptoms. PMID- 8701019 TI - Iatrogenic (physician-induced) hypochondriasis. Four patient examples of "chemical sensitivity". PMID- 8701020 TI - ECT in a patient receiving prophylactic CNS irradiation for an intraocular lymphoma. PMID- 8701021 TI - Multifetal pregnancy reduction. PMID- 8701022 TI - Bioactive peptides from lizard venoms. PMID- 8701023 TI - Insulin-like growth factors in chick embryo retina during development. AB - Evidence exists supporting an important role for insulin-like growth factors (IGFs) during fetal growth. In the present report we performed studies to define whether developing chick retina contains IGFs and whether IGFs play a role in the growth of this tissue. We have shown that both IGF-I and IGF-II are present in chick embryo retina throughout development (7th-18th day). The highest values, when expressed as ng/g of tissue, were found in the youngest retinas studied (7th 9th day) and at 16th-18th day of development. During whole development the content of IGF-II was about two to three times higher than that ascertained for IGF-I. The tissue also contains cell-surface binding for IGFs. However, the developmental pattern of IGF-I binding was quite different from that found for IGFs, showing the highest values during the second week of development. Competitive studies showed that this receptor has a high affinity for IGF-I, a lower affinity for IGF-II, and a very much lower affinity for insulin. Also anti IGF-I receptor antibody (alpha IR3) inhibited 125I-labeled IGF-I binding to the receptor. Such results indicate the presence of type I IGF receptor in chick embryo retina. Affinity labeling experiments have confirmed this hypothesis. We have also shown that cultured retinal explants contain, synthesize and release into the medium appreciable amounts of IGFs. Both exogenous IGF-I and IGF-II added to the culture medium stimulated DNA synthesis of retinal explants. Evidence that the retinas produce IGFs and possess IGF-IR together with the growth-promoting effect of IGFs suggests that these factors play an important role as regulators of retinal growth. PMID- 8701024 TI - Calcitonin gene-related peptide (CGRP) in the circular muscle of guinea-pig colon: role as inhibitory transmitter and mechanisms of relaxation. AB - In the presence of 1 microM tetrodotoxin (TTX), human alpha calcitonin gene related peptide (CGRP) produced a concentration-dependent relaxation (EC50 1.1 nM; Emax 86% of the relaxation to 1 microM isoprenaline) of mucosa-free circular muscle strips from the guinea-pig proximal colon. In the presence of TTX, the C terminal fragment CGRP(8-37) produced a concentration (0.3-3 microM)-dependent rightward shift of the curve to CGRP. The TTX-resistant, receptor-mediated, CGRP induced relaxation was unaffected by apamin (0.3 microM) and L-nitroarginine (L NOARG, 100 microM), alone or in combination, as well as by glibenclamide (3 microM) or (S)-ketoprofen (10 microM). Tetraethylammonium (TEA, 1-10 mM) and cyclopiazonic acid (CPA, 3-10 microM) produced a concentration-dependent partial inhibition of the relaxant response to CGRP. The inhibitory effect of TEA on the maximal relaxation produced by CGRP was prevented by nifedipine (1 microM) which did not affect the CGRP-relaxation of its own. In the presence of atropine (1 microM), guanethidine (3 microM), SR 140,333 (0.3 microM), MEN 10,627 (1 microM), apamin (0.3 microM) and L-NOARG (100 microM), the application of 1 microM capsaicin produced a transient relaxation of the strips. This response was not reproduced upon a second application of capsaicin, 60 min later, indicating complete desensitization. CGRP(8-37) (0.3-1.0 microM) produced a partial inhibitory effect (about 50% inhibition) of the relaxant response to capsaicin. In the presence of atropine (1 microM), guanethidine (3 microM), SR 140,333 (0.3 microM), MEN 10,627 (1 microM), apamin (0.3 microM), L-NOARG (100 microM) and after capsaicin in vitro pretreatment (10 microM for 15 min), electrical field stimulation (EFS, 10 Hz for 5 s) produced a transient relaxation which was unchanged by CGRP(8-37) (1 microM) while being abolished by TTX. In sucrose gap, brief superfusion with 0.3 microM CGRP produced a TTX (1 microM)- resistant membrane hyperpolarization and relaxation: the hyperpolarization produced by CGRP was inhibited by about 50% by either TEA (10 mM) or CPA (10 microM), while being unaffected by glibenclamide (3 microM). The combined application of TEA and CPA was not more effective (65% inhibition) in inhibiting the CGRP-induced hyperpolarization than each drug alone. We conclude that CGRP produces a direct relaxation of the circular muscle of the guinea-pig proximal colon by activating receptors sensitive to blockade by CGRP(8-37). Activation of Ca-dependent potassium channels and Ca release/reuptake from internal store(s) appear both to be involved in the action of CGRP. Endogenous CGRP mediates part of the relaxant response evoked by stimulation of capsaicin-sensitive primary afferent nerves in the circular muscle of guinea-pig colon, while it is not involved in the apamin and L-NOARG-resistant nonadrenergic noncholinergic (NANC) relaxation produced by electrical field stimulation of intrinsic inhibitory nerves. PMID- 8701025 TI - Changes in enkephalin and neuropeptide Y-like immunoreactivity in rabbit chromaffin tissues during perinatal development. AB - Enkephalin-like immunoreactivity (ENK-LI), neuropeptide Y (NPY)-LI and dopamine beta-hydroxylase (DBH)-LI were found within the chromaffin cells of both the paraaortic body and the adrenal medulla of the newborn rabbit using immunohistochemistry. Cells positive to DBH-LI were abundant in both the paraaortic body and the adrenal medulla. ENK-LI positive cells were frequent in the paraaortic body, but more sparse in the adrenal medulla. A few cells staining for NPY-LI could be detected in both organs. Some nerve fibers within these organs also contained substance P-LI and calcitonin-gene related peptide-LI. The tissue contents of ENK-LI and NPY-LI, as measured by radioimmunoassay, increased after birth in the adrenal glands and were significantly higher than the fetal levels from 1 week of age. In the paraaortic body the lowest content of ENK-LI was found around birth, whereas the content of NPY-LI was highest at that time. With advancing postnatal age, the content of ENK-LI increased, whereas the content of NPY-LI decreased. At each age, there was a higher content of ENK-LI as compared to NPY-LI in both organs. This indicates that the synthesis of ENK-LI and NPY-LI in the paraaortic body is differently regulated during perinatal development. PMID- 8701026 TI - Histamine release induced by human natriuretic peptide from rat peritoneal mast cells. AB - We have been interested in the effects of some popular peptides on tracheal smooth muscle. Previously, we reported that atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) had dose dependent relaxant effects on guinea pig tracheal smooth muscle. In this study, we compared the effects of ANP, BNP and CNP on histamine release from rat peritoneal mast cells. ANP and BNP were more potent than CNP, dose-dependently increasing histamine release at a concentration of 10(-7) M or higher. CNP induced histamine release at a concentration of 10(-6) M or higher. Extracellular calcium inhibited the histamine release induced by all 3 peptides. In conclusion, the effects of these 3 peptides in rat peritoneal mast cells demonstrated adverse reactions for respiratory diseases, although our previous results showed that these peptides caused relaxation of guinea pig tracheal smooth muscle. We should note that the drugs have different actions in each organ. PMID- 8701027 TI - Inhibition of adenylyl cyclase activity by the cholecystokinin analog SNF 9007 in neuroblastoma x glioma NG108-15 hybrid cells. AB - The effect of the cholecystokininB (CCKB) receptor-selective cholecystokinin octapeptide (CCK-8) analog SNF 9007 on forskolin-stimulated adenylyl cyclase activity in NG108-15 hybrid cells was measured. The activity of SNF 9007 was compared to the delta opioid agonists D-Pen2-D-Pen5-enkephalin (DPDPE, delta 1 receptor-selective) and Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2, (D-Ala2-deltorphin II, delta 2-receptor-selective) because SNF 9007 binds with moderate affinity to delta opioid receptors. SNF 9007 inhibited forskolin-stimulated adenylyl cyclase activity with efficacy similar to DPDPE. IC50 determinations showed that D-Ala2 deltorphin II was the most potent, followed by DPDPE, then SNF 9007 (IC50 values = 0.013, 0.21 and 4.8 microM, respectively). CCK-8 had no effect on adenylyl cyclase activity. The delta 1 receptor-selective antagonist 7 benzylidenenaltrexone hydrochloride (BNTX, 10 nM) had no effect on the activity of any of these agonists, but the delta 2 receptor-selective antagonist naltriben methanesulfonate (NTB, 10 nM) increased IC50 values of all the agonists. Combinations of BNTX and NTB (10 nM each) increased the D-Ala2-deltorphin II IC50 value 12-fold, the DPDPE IC50 value 18-fold and the SNF 9007 IC50 value 26-fold. The effect of the combined delta antagonists on SNF 9007 activity was different from the effect on DPDPE or D-Ala2-deltorphin II activity. These data suggest that the interaction of the CCK-8 analog SNF 9007 with opioid receptors in NG108 15 hybrid cells is different from the interaction of opioid peptides with these receptors. PMID- 8701028 TI - Characterization of binding sites for calcitonin gene-related peptide in the mollusc gill. AB - Target organs for calcitonin gene-related peptide (CGRP) were investigated in Pecten maximus using 125I-labelled human CGRP. CGRP was shown to interact specifically with mantle and gill tissue. Receptor studies using branchial membrane preparations indicated that the binding was time dependent. Scatchard analysis of binding data showed that there was a single class of binding sites. The affinity constant was found to be 0.7.10(8) M-1 and the number of binding sites 2600.10(8)/mg of protein. Salmon CT inhibited the binding of 125I-labelled CGRP to branchial membranes with a lesser efficiency than that of the unlabelled hormone. A 40% inhibition of the 125I-labelled CGRP binding was observed in the presence of 2.6 and 26 nM CGRP and salmon CT, respectively. In addition, 200 nM human CGRP inhibited 25 and 10% of the basal branchial and mantle adenylate cyclase activity, respectively. These data suggest that CGRP participates in the regulation of the branchial function in molluscs probably via a vasoconstrictor role. PMID- 8701029 TI - Vasopressin potentiation of the melatonin synthetic pathway via specific V1a receptors in the rat pineal gland. AB - The pineal gland releases the "time-keeping' hormone melatonin following a rhythmic sympathetic input which translates light information. The aim of this work was to study the role and mechanism of action of the central vasopressinergic input on pineal cAMP-dependent melatonin synthesis in the rat. The pineal was found to display vasopressin receptors of the V1a subtype, as the V1a antagonist [125I]HO-LVA bound in a saturable manner to pineal membranes with a high affinity (kd = 10 pM) and a maximal binding capacity (B(max)) of 13 fmol/mg protein. Vasopressin was able to displace [125I]HO-LVA binding in a dose dependent manner (k(i) = 1.9 nM). Vasopressin had no effect on the basal cAMP level and melatonin secretion in cultured rat pinealocytes. However, it clearly and dose-dependently (EC50 = 7 nM) potentiated by 2-3 times cAMP accumulation and by 1.5-2.5 times melatonin secretion induced by moderate noradrenergic stimulation. On strongly stimulated pinealocytes, however, vasopressin could potentiate cAMP accumulation, but not melatonin secretion. The potentiatory effect of vasopressin was inhibited in the presence of the V1a antagonist. These results indicate that vasopressin is a potent modulator of rat pineal synthetic activity. PMID- 8701030 TI - Inhibition of pentagastrin-induced pressor response in conscious rats by the CCK B receptor antagonist CI-988 and chlordiazepoxide. AB - Elevation of blood pressure is a characteristic feature of spontaneous and pharmacologically induced panic attacks in man. We examined whether this symptom could be reproduced in conscious rats and, if so, whether the cardiovascular changes induced by anxiogenic agents could be employed as a functional in vivo screen for CCK-B receptor antagonists which might be predictive of anxiolytic activity. Bolus i.v. administration of pentagastrin (0.1-100 micrograms/kg) or the beta-carboline FG-7142 (0.001-3 mg/kg) caused transient ( < or = 5 min) dose dependent increases in arterial blood pressure of up to 41 mmHg. The benzodiazepine receptor agonist chlordiazepoxide (10 mg/kg i.v, 15 min previously) attenuated the pressor response induced by either pentagastrin (1 microgram/kg i.v.) or FG-7142 (0.3 mg/kg i.v.). In contrast, the CCK-B receptor antagonist CI-988 (3 mg/kg i.v., 15 min previously) inhibited the pressor response induced by pentagastrin, but not FG-7142. Antagonism of the pressor response elicited by pentagastrin in animals provides a simple method to establish the active dose range for CCK-B receptor antagonists in vivo. Since cardiovascular parameters can be readily monitored in man, this approach may assist in guiding clinical dose ranging studies to establish therapeutically beneficial effect of these compounds in panic disorder. PMID- 8701031 TI - Differential increase in neuropeptide Y-like levels and myenteric neuronal staining in diabetic rat intestine. AB - Neuropeptide Y is a regulatory peptide found in adrenergic and non-adrenergic neurons. Diabetes, which may cause autonomic neuropathy, induces an increase in hypothalamic neuropeptide Y (NPY) levels; thereby we measured the effects of chronic diabetes on neuropeptide Y in the intestine. Rats were injected with streptozotocin (65 mg/kg) and maintained for up to 20 weeks. Another group of rats was injected with 6-hydroxydopamine (50 mg/kg) x 2 to induce sympathectomy. Ileum and colon were harvested and both whole and microdissected intestine were (1) stained with antibodies to neuropeptide Y, vasoactive intestine polypeptide, and neurofilaments or (2) extracted for neuropeptide Y radioimmunoassay. Neuropeptide Y levels were similar under all conditions in the colon, but there was a trend toward an increase in the diabetic whole ileum. NPY levels were significantly increased in the dissected myenteric plexus ileal layer in diabetics. We noted an increase in the number of neuropeptide Y and vasoactive intestine polypeptide immunoreactive myenteric neurons in diabetics and after 6 hydroxydopamine-induced sympathectomy. Diabetes, and to a lesser extent sympathectomy, induced an increase in ileal neuropeptide Y levels and neuropeptide Y-staining myenteric but not submucosal neurons. Altered tissue levels of neuropeptide Y may account for certain of the gastrointestinal disturbances commonly seen in diabetes. PMID- 8701033 TI - Inhibitory effects of gastrin releasing peptide on gastric emptying in rats. AB - Gastrin-releasing peptide (GRP) has a wide range of biological actions, including stimulation of the frequency of antral contractions and delaying gastric emptying. The present study was designed to evaluate the role of GRP in the control of gastric emptying of liquid test meals in the rat. The emptying of methyl cellulose given by gavage to fasted rats, or of saline given via the fistula to conscious gastric fistula rats was not influenced by the GRP antagonists, NC-8-89 (Leu13-psi-(CH2NH)-Leu14-bombesin) and 2258U89 ((de NH2)Phe19, D-Ala24, D-Pro26 psi (CH2NH)Phe27(-GRP (19-27)), at 2 mg/kg, s.c. However, both antagonists (0.02, 0.2 and 2 mg/kg) reversed the inhibitory effect of HCI on gastric emptying in gastric fistula rats (P < 0.05-0.001). When peptone was administered after a preload, but not otherwise, the inhibition of emptying was also partly reversed by both antagonists at all doses used (P < 0.05-0.001). Interestingly, the delay in the emptying of hyperosmolal saline compared to saline, was enhanced at a dose of 0.2 mg/kg of both antagonists (P < 0.05 and P < 0.01). Food intake did not change significantly with the two lower doses of antagonists, but was decreased by the highest dose of NC 8-89. We conclude that GRP specifically inhibits gastric emptying of acid and peptone solutions in the conscious rat. PMID- 8701032 TI - Localization and characterization of neuropeptide Y/peptide YY receptors in the brain of the smooth dogfish (Mustelis canis). AB - Multiple receptor subtypes specific for the neuropeptide Y (NPY)/peptide Y (PYY) family of peptides exist in mammals, but little is known about the distribution of this receptor family in other vertebrates. Saturable binding sites for 125I labeled porcine PYY were localized in frozen sections of the brain of the smooth dogfish (Mustelis canis) by radioligand binding and autoradiography. Saturable 125I-porcine PYY binding sites were distributed widely in the cerebral hemispheres, optic lobes, hypothalamus, cerebellum and hindbrain. Binding was saturable, specific for PYY and related peptides, and of high affinity (Kd = 2.53 nM). The specificity of the binding site was analyzed by performing competitive inhibition experiments with nonradioactive PYY, NPY, and [Leu31, Pro34]-NPY and NPY13-36, synthetic peptide analogs specific for the mammalian Y1 and Y2 receptor subtypes, respectively. Saturable 125I-porcine PYY binding sites in all regions of the dogfish brain closely resembled the mammalian Y1 NPY receptor subtype in specificity for these substances. There was no evidence for expression of multiple receptor subtypes. We conclude that a single receptor specific for the NPY/PYY family of peptides is widely expressed in the smooth dogfish brain and that this receptor closely resembles the mammalian Y1 receptor subtype, suggesting that the Y1 receptor is the ancestral receptor in this family. PMID- 8701034 TI - Effect of peptide YY on gastric motor and secretory activity in vagally innervated and denervated corpus pouch dogs. AB - In this study, we examined the mechanism by which constant intravenous infusion of physiological doses of PYY affects gastric secretion and motility in the vagally innervated (Pavlov) and denervated (Heidenhain) corpus pouch. As a result, only in the Heidenhain pouch, PYY at a dose of 100 pmol/kg-h significantly inhibited gastric secretion in the interdigestive and postprandial states. A dose of 300 pmol/kg-h inhibited the gastric secretion in both types of pouch, but inhibition in the Pavlov pouch was less than in the Heidenhain pouch. The inhibitory effect of PYY on phase III contractile activity was dose-dependent and significant, except in the Heidenhain pouch, and no dose of PYY had any effect on postprandial gastric motility. After all, vagal denervation enhanced the inhibitory effect of PYY on gastric secretion, but abolished the inhibitory effect on phase III contractile activity. Our findings strongly suggest that the inhibitory effect of PYY on gastric secretion is in part mediated by a non-vagal pathway and the inhibitory effect of PYY on gastric motor activities is completely dependent on vagal innervation, but the vagus nerve acts as an inhibitory modulator of the inhibitory effect of PYY on gastric secretion. PMID- 8701035 TI - Developmentally regulated expression of IGF binding protein-3 (IGFBP-3) in human placental fibroblasts: effect of exogenous IGFBP-3 on IGF-1 action. AB - Preterm, human, placental fibroblasts exhibit growth rates, in vitro, that vary with gestational age. The observed increase in proliferation rate is associated with enhanced mitogenic responsiveness to IGF-I. IGFBPs can either potentiate or inhibit IGF action at the cellular level. The production of IGFBPs by placental fibroblasts was studied as potential modulators of their responsiveness to IGFs. Human placental fibroblasts were obtained at various gestational ages and maintained in culture. IGFBP-3 protein and mRNA expression were assessed by Northern and ligand blot analyses. First, media conditioned by fibroblasts, in culture, were subjected to ligand blot analysis. Multiple species of IGFBPs were present in each cell line tested. IGFBP-3, migrating as a doublet at approx. 38/42 kDa, was the predominant IGFBP species present. Other IGFBPs of 22-35 kDa were also present. The secretion of IGFBP-3 exhibited a marked decrease at 10-15 weeks gestation relative to 8-9 week fibroblasts but began to increase again by 19 weeks. We next studied the expression of IGFBP-3 mRNA. Total cellular RNA was obtained from rapidly growing cells and subjected to Northern analysis. Placental fibroblasts exhibited decreased steady state levels of IGFBP-3 mRNA at 10-15 weeks gestation consistent with its decreased protein expression. The ability of IGFBP-3 to influence IGF-1 stimulated DNA synthesis was studied in 10 week placental fibroblasts as measured by [3H]thymidine incorporation. IGFBP-3 inhibited IGF-1 (3.3 nM) stimulated DNA synthesis in a dose-dependent manner when added simultaneously with IGF-1 or preincubated with the cells for 48 h prior to the addition of IGF-1. By contrast, maximum effective concentrations of IGFBP-3 (52 nM) potentiated the effect of IGF-1 50-200% when preincubated with bovine fibroblasts for 48 h prior to the addition of IGF-1. These data suggest that IGFBP-3 production is developmentally regulated in human placental fibroblasts and inhibits their mitogenic response to IGF-1. The regulated expression of IGFBP 3 may contribute to the altered growth rate and IGF responsiveness exhibited by placental fibroblasts, in vitro. PMID- 8701036 TI - Pituitary adenylate cyclase activating polypeptide (PACAP): occurrence and vasodilatory effect in the human uteroplacental unit. AB - Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide which was originally isolated from ovine hypothalamus. PACAP exists in at least two biologically active forms, PACAP-38 and PACAP-27. The aim of this study was to establish the distribution, localization and smooth muscle effects of PACAP-38 and PACAP-27 in the human uteroplacental unit. For this purpose we used radioimmunoassay, immunocytochemistry and in vitro studies of the effect of the peptides on smooth muscle activity. RESULTS: By radioimmunoassay both peptides were detected throughout the uteroplacental unit. The concentrations of PACAP-27 were in general low, ranging from 1/6-1/25 of the corresponding PACAP-38 concentrations. PACAP-immunoreactivity was localized in nerve fibres of the lower segment of the pregnant uterus, but the number of PACAP-immunoreactive nerves was very clearly reduced compared to the corresponding isthmic region of non-pregnant myometrial tissue. PACAP-immunoreactive fibres were not observed in placenta or in the umbilical cord. Both PACAP-38 and PACAP-27 caused a concentration dependent relaxation on stem villous arteries and on the intramyometrial arteries. Neither of the peptides displayed any effect on non-vascular smooth muscle specimens from the term pregnant myometrium. In conclusion the findings suggest a vasoregulator role of PACAP in the human uteroplacental unit. PMID- 8701037 TI - Cationic lipid-mediated delivery and expression of prepro-neuropeptide Y cDNA after intraventricular administration in rat: feasibility and limitations. AB - The utility of in vivo lipofection for delivery and expression of a neuropeptide gene in the adult rat brain was explored. Prepro-neuropeptide Y (NPY) cDNA was cloned into the episomal eucaryotic expression vector pCEP4. This construct was complexed to lipofectamine or lipofectin. Complexed DNA was injected into the lateral ventricles of adult rats. Brains were removed for analysis following various time intervals. Polymerase chain reaction (PCR) reactions were designed for specific detection of endogenous and vector derived NPY sequence, respectively. PCR of DNA preparations from 5 major brain regions (frontal and parietal cortex, striatum, hypothalamus, brain stem) demonstrated presence of vector DNA up to 1 month (longest interval studied) in all brain regions. Reverse transcription (RT-) PCR of DNase treated RNA-preparations from brain tissue demonstrated presence of both vector-derived and endogenous NPY mRNA in treated animals, while only endogenous mRNA was detected in controls. In situ hybridization histochemistry indicated scattered patches of vector uptake into tissue in the vicinity of the CSF compartment, but not into deeper located structures. Weight gain was not affected, indicating that the expression levels achieved may not be sufficient to play a functional role, and/or may need to be targeted to specific brain areas. These findings suggest a potential for cationic lipid mediated gene transfer in the brain as an experimental tool and as a possible future therapeutic principle, but also indicate the need for optimization of delivery strategies in order to achieve functionally relevant expression levels. PMID- 8701038 TI - Localization and quantitation of angiotensin AT1 and AT2 receptors in the pregnant and non-pregnant sheep uterus. AB - The two angiotensin II receptor subtypes, AT1 and AT2, have been reported to be differentially expressed in the myometrial membrane preparations of nulliparous and pregnant sheep, however, their distribution in the sheep reproductive tract has not been reported. The aim of this study is to map the distribution of AT1 and AT2 receptors in the anoestrus reproductive tract of the sheep by quantitative in vitro autoradiography and to investigate if the density and distribution of the receptors change during pregnancy. The AT2 receptor is abundant in a discrete layer in the myometrium of the anoestrus sheep uterus, whilst the AT1 receptor is expressed at lower levels, predominantly in the endometrium. Near-term pregnant uteri, show a marked change in the expression of angiotensin II receptors: the myometrium no longer expresses detectable AT2 receptors but rather, expresses low levels of AT1 receptors. Angiotensin converting enzyme is found in high concentrations in the blood vessels of the pregnant and non-pregnant sheep reproductive system and on the epithelial cells of the fallopian tubes of the non-pregnant sheep. These studies reveal marked reciprocal changes of angiotensin II receptors, with myometrial AT1 receptors increasing during pregnancy, whilst AT2 receptors fall markedly. These changes suggest that angiotensin II may be involved in regulating changes of uterine structure and function during pregnancy by interaction with multiple receptor subtypes. PMID- 8701039 TI - Octreotide differentially modulates human Caco-2 intestinal epithelial cell proliferation and differentiation by decreasing intracellular cAMP. AB - Somatostatin modulates gastrointestinal mucosal growth and differentiation indirectly via inhibition of bioactive peptides and directly by less well understood mechanisms. We studied the direct effects of the somatostatin analog octreotide on proliferation, brush-border enzyme activity, cell-matrix interactions and intracellular cAMP in Caco-2 human intestinal epithelial cells. Proliferation was assessed by cell counting and [3H]thymidine uptake. The brush border enzymes alkaline phosphatase (AP) and dipeptidyl dipeptidase (DP) were quantitated by synthetic substrate digestion. Adhesion and migration on purified matrix proteins were also measured. Octreotide (10(-9)-10(-5)M) shortened doubling time (46.5 +/- 6.2% at 10(-5) M, n = 20, P < 0.0001) and stimulated [3H]thymidine uptake. Octreotide decreased intracellular cAMP by 19.4 +/- 5.0% (n = 7, P < 0.0001) while dibutyryl-cAMP (10(-6) M) prolonged doubling time by 10.1 +/- 1.5% (n = 8, P < 0.0001), and blocked the octreotide effect. Octreotide decreased AP and DP with maximal effect at 10(-6) M (36.8 +/- 8.3% and 20.5 +/- 9.1%, n > 7, P < 0.0005 respectively). However, mitomycin proliferative blockade prevented octreotide inhibition of AP and DP, suggesting that the mitogenic effects of octreotide had simply decreased average maturity of the cells. Octreotide did not alter Caco-2 adhesion, EGF-or matrix-modulated motility, or integrin surface expression. Octreotide appears to directly stimulate Caco-2 proliferation by decreasing cAMP. These proliferative effects modulate Caco-2 differentiation but do not affect cell-matrix interactions. PMID- 8701040 TI - Polycystic hydatid disease in Brazil. Report of five new human cases and a short review of other published observations. AB - This paper describes five additional Brazilian human cases of polycystic hydatid disease due to Echinococcus vogeli, reviews the previous cases reported in Brazil, including one report of E. oligarthus (20 in total), and some epidemiological aspects of this disease which is no longer a curiosity but rather a problem that is not medically easy to handle. Its presence should be expected in any rural area of the New World where humans have not eliminated wild felids/canids, bush dogs, pacas, agoutis and other wild rodents. PMID- 8701042 TI - [The epidemiological determinant aspects in the maintenance of visceral leishmaniasis in the state of Maranhao, Brazil]. AB - The authors analysed the visceral leishmaniasis (VL) aspects in the state of Maranhao, Brazil, from 1982 to 1993. The disease happens to occur predominantly in Sao Luis Island (MA) and during the epidemic period, town of Sao Luis was pointed out as the main endemic area. The greatest frequency of cases occurred in 1993, despite the use of insecticide and dogs control. There was predominance of age between 0- to 4-year-old population with 58.04% of cases. Neither the human disease nor the rainfall index had significant seasonal variation. However they were correlated moderately, with high number of cases after the period of great precipitation of rain. After this study, the data obtained will allow a better control of the disease, despite some factors such as: the urbanization, localization and dynamic of transmission in endemic areas in the Maranhao state. PMID- 8701043 TI - [Bone involvement in chronic disseminated paracoccidioidomycosis. A report on the first cases in Rio Grande do Sul]. AB - The first cases of bone involvement in paracoccidioidomycosis observed in the state of Rio Grande do Sul (Brazil) are reported. Clinical and radiological findings are commented and some peculiarities are pointed out. PMID- 8701041 TI - Plants used in the treatment of leishmanial ulcers due to Leishmania (Viannia) braziliensis in an endemic area of Bahia, Brazil. AB - This paper records the plants used in the treatment of cutaneous leishmaniasis due to Leishmania (Viannia) braziliensis (L(V)b) among the rural population of a cocoa-producing coastal area of Bahia state, Brazil. An enquiry conducted among a hundred patients identified 49 plants species used to treat skin ulceration caused by this Leishmania species. The principal plants used are caju-branco (Anacardium occidentale, Anacardiaceae), used by 65% of the population, folha fogo (Clidemia hirta,Melastomataceae) 39%, alfavaca-grossa (Plectranthus amboinicus, Lamiaceae) 33%, mastruz (Chenopodium ambrosioides, Chenopodiaceae) 31%, erva-de-santa-maria (Solanum americanum, Solanaceae) (25%) and transagem (Plantago major, Plantaginaceae) 2%. PMID- 8701044 TI - [Helicobacter pylori gastric infection in symptomatic patients from Sao Luis Island, MA: endoscopic, anatomicopathologic and microbiological correlations]. AB - With previously defined criteria of inclusion and previous consent, twenty six consecutive patients (19 to 64 years old), with upper digestive symptoms, were submitted to endoscopy, with biopsy, constant of eight samples of the antropyloric region (four of the anterior aspect and four of the posterior aspect). Two samples were been for culture; two for free urease test, two for smears; all gathered in adequate transport medium over refrigeration. Two samples immersed in formaline to 10% for histopathologic exam. 25/26 (96%) of the patients showed infection by H. pylori by means of one or more methods utilized. In 16/26 (61%), alterations were observed in endoscopy (gastric inflammation in eleven, peptic ulcer in two and ulcer scars in three cases). Of the patients with endoscopic gastric inflammation, presented positive as well as all (100%) bearers of scar or peptic ulcer. A close relationship was observed between the presence of H. pylori and chronic gastric inflammation 24/25 (96%). Histopathologic slices stained by hematoxilin-eosin was the test of highest diagnostic sensitivity 24/25 (96%), followed by urease test 23%25 (92%), stained smears 19/25 (76%) and culture 18/25 (72%). Our conclusion is that the prevalence of gastric infection for H. pylori in symptomatic patients is high, correlated with chronic gastric inflammation and ulcers. Histopathologic slices stained by hematoxilin-eosin and free urease test are the most sensitive indicators of the presence of H. pylori. This study should proceed for further elucidation of questions realised and include a control group of symptomatics individuals paired for sex and age. PMID- 8701045 TI - [An efficacy and tolerance study of oral artesunate alone and in combination with mefloquine in the treatment of uncomplicated falciparum malaria in an endemic area of Para, Brazil]. AB - With the objective to evaluate the efficacy and tolerance of artesunate in the treatment of noncomplicated falciparum malaria in endemic area of the State of Para, 153 patients were randomized and studied in three groups, distributed by therapeutical scheme (I received mefloquine 1000 mg, II used artesunate 600 mg followed by mefloquine 500 mg). Evaluation was made by daily clinical and parasitological examination, in the first 7 days, and weekly until the 35th day of the follow-up. Biochemical and hematological analysts previously done and on the 7th day, targeting cure control and identification of possible effects related to drugs administration. As to sex, parasitemia and fever, studied groups were homogeneous. Time for parasitemia disappearance was shorter in the groups II and III respectively, whose therapeutical schemes had artesunate. Fever disappearance was quicker in the group treated with the combination of drugs. Clinical and biochemical alterations associated with drugs administration did not show significant differences among the studied groups. Early disappearance of fever and parasitemia, and absence of important side effects suggest that artesunate, isolated or administrated in combination with mefloquine, constitutes an able therapeutical procedure to constitutes and able therapeutical procedure to contribute for disease control in that region. PMID- 8701046 TI - SPf66 vaccine trial in Brazil: conceptual framework study design and analytical approach. AB - This paper describes the study population and the study design of the phase III field trail of the SPf66 vaccine in Brazil. Assessment of validity and precision principles necessary for the appropriate evaluation of the protective effect of the vaccine are discussed, as well as the results of the preliminary analyses of the gathered data. The analytical approach for the estimation of the protective effect of the vaccine is presented. This paper provides the conceptual framework for future publications. PMID- 8701047 TI - [Subcutaneous phaeohyphomycosis in the state of Para: a report of 3 cases]. AB - Three cases of subcutaneous phaeohyphomycosis from the state of Para, Brazil are reported. This is the first time that this form of phaeohyphomycosis is described in northern Brazil. The etiologic agents could not isolated, and the diagnosis in all cases was established only on histopathological basis, particularly through the demonstration of fungal elements in tissue sections. Hyphal fragments and vesicular cells were very numerous and conspicuous in special (Grocott and Fontana-Masson methods) stained sections, in contrast to their apparent scarcity in routine hematoxilin-eosin preparations. The difference was certainly due to the aspect in the latter of the invasive tissue forms: the thin-walled and light brown pigmented organisms stained poorly and were very difficult to distinguish from the tissue components. PMID- 8701048 TI - Acute exacerbation in chronic hepatitis B virus infection. AB - A case of an acute exacerbation of liver injury in a chronic HBV infected young male is reported. The correlation between the severe symptomatic hepatitis is done with the histopathologic findings of extensive areas of bridging necrosis on the liver biopsy. The serological pattern for markers of HBV (HBsAG +, anti HBs-, HBeAg-, anti HBe+, anti HBc IgG + and IgM-) confirm a chronic infection, and the authors propose that the episode of severe hepatitis relates to the recent spontaneous seroconversion of HBeAg to anti HBe. Other causes of hepatitis were excluded, and the control liver biopsy (6 months later) showed normalization of hepatic architecture and absence of markers of viral replication in tissue and serum. A review of literature is done in an attempt to elucidate the diagnostic possibilities in this case, with emphasis on new immunoassays useful in differentiating between acute hepatitis B and acute exacerbation of a chronic hepatitis by the same virus. PMID- 8701049 TI - [The occurrence of the autochthonous transmission of visceral leishmaniasis in Mato Grosso]. PMID- 8701050 TI - [Rotavirus studied in the feces of 10 patients with the acquired immunodeficiency syndrome (AIDS)]. PMID- 8701051 TI - Delayed skin healing of cutaneous leishmaniasis after clinical cure of mucosal surfaces. PMID- 8701052 TI - The Second Buriti Workshop on Transfection of Parasites. PMID- 8701053 TI - [Central nervous system involvement in the chronic form of Chagas' disease]. PMID- 8701054 TI - [In defense of Trypanosoma (tripanossoma)]. PMID- 8701055 TI - Intrarectal glucantime. PMID- 8701056 TI - [Cytomegalovirus retinitis in patients with AIDS]. PMID- 8701057 TI - [Intravitreal ganciclovir in cytomegalovirus retinitis in AIDS]. AB - A retrospective study was made of 26 patients with AIDS who initially presented with retinitis as the only clinical manifestation of cytomegalovirus infection (39 eyes). Sixty-five induction or re-induction therapeutic courses were administered with intravitreal ganciclovir. The efficiency rate of therapy was 93.8%. Thirty-eight maintenance therapeutic courses (200 micrograms/week) were evaluated. The non-compliance rate was 23%. Bilateral retinitis occurred in 44.4% of cases. The systemic administration of therapy had to be substituted for the intravitreal administration in 32% of patients during the clinical course of their conditions. The mean survival rate was 9.5 months. Both retinal detachment and vitreal hemorrhage occurred in 5% of patients. When retinitis is the first clinical manifestation of cytomegalovirus infection, therapy with intravitreal ganciclovir is efficacious to inactivate lesions. Although bilateral retinitis and extraocular dissemination are common, the mean survival rate is high. PMID- 8701058 TI - [Usefulness of bone marrow examination in patients with advanced HIV infection]. AB - A bone marrow investigation is a common examination in HIV infected patients for the study of cytopenia, febrile syndromes of unknown origin and extension of neoplastic disorders. A study was made of bone marrow specimens from 35 patients with advanced HIV infection (stage IC or C, CDC, Atlanta) for morphologic and culture investigations (aerobes, anaerobes, fungi, and mycobacteria). In nine patients cytopenia accounted for the investigation of bone marrow specimens (9 aspirates and 3 biopsies); in only two cases did the investigation orientate towards a possible etiology: in the first patient a parvovirus B19 infection and in the second patient a hemophagocytic syndrome. In twenty-five patients the bone marrow specimen was studied because of fever of unknown origin (23 aspirates and 10 biopsies) and only in one case was the identification of Mycobacterium tuberculosis obtained. The other patient was studied for lymphoma staging and aspirate and biopsy examinations were normal. A high percentage of patients had eosinophilia, plasmacytosis, increased iron reserves, fibrosis, and changes consistent with myelodysplasia. In conclusion, in our experience the investigation of bone marrow specimen was of little help to clarify the possible etiology of cytopenia and febrile syndromes of unknown origin in patients with advanced HIV infection. PMID- 8701059 TI - [Hashimoto toxicosis: diagnostic criteria and a 10-year follow up]. AB - An study was carried out of the association of Basedow disease (B) and Hashimoto toxicosis (H), the response to the usual therapeutic regimens and prognostic factors for the clinical course. Seventy-one patients with the diagnosis of autoimmune hyperthyroidism were included. Sixty-one of them were prospectively followed for 8.4 +/- 2.2 years (range: 5-10 years). All patients were treated following the same criteria with antithyroid drugs and aggressive therapy (radioiodine or surgery). Two groups were differentiated: group H (62%), with titers of antimicrosomal antibodies (AMSA) > or = 1/6,400 and a positive perchlorate discharge test (PDT), and group B, with AMSA titers < 1/6,400 and negative PDT. During follow-up a three-fold number of relapses was observed in group H compared with group B, a higher frequency towards spontaneous hypothyroidism in the evolution (23% in H versus 0% in B), and higher requirements of radioiodine in H than in B. In our experience, H makes up and important percentage of autoimmune hyperthyroidism (62%) with a clinical course characterized by a higher number of relapses, higher requirements of radioiodine and a higher rate towards spontaneous hypothyroidism. PMID- 8701060 TI - [Cellular immune response in tuberculosis: analysis of T-lymphocytes and their subsets, B-lymphocytes and natural cytotoxic cells in different tuberculosis states and body fluids]. AB - BACKGROUND: The immune response to Mycobacterium tuberculosis is primarily mediated by T lymphocytes. In this study an investigation was made of T lymphocytes and their subsets, B lymphocytes and natural cytotoxic cells (Natural Killer, NK) in blood and organic fluids in different tuberculosis conditions. METHODS: Patients with localized pulmonary tuberculosis (LPT, n = 12), extensive pulmonary tuberculosis (EPT, n = 24), pleural tuberculosis (PLE, n = 14), disseminated tuberculosis (DIS, n = 10), recent Mantoux converters (MAN, n = 15) and healthy subjects (CON, n = 19) were studied. HIV+ and immunosuppressed patients were excluded. Total lymphocytes and T subsets (CD3, CD4, CD8, TCR alpha beta and gamma delta), B (CD19) and NK cells (CD56) in blood and pleural fluid (n = 7) and ascitic fluid (n = 3) were determined. RESULTS: An increase was observed in total lymphocytes and all T subsets (CD3, CD4, CD8, alpha beta and gamma delta) in MAN group compared with CON group (p < 0.05 for all determinations). A progressive lymphopenia of total lymphocytes and CD4 was observed with more extensive disease, particularly in the DIS group (p < 0.05). No differences were observed between groups regarding B lymphocytes and NK cells. In pleural effusions and ascitic exudates an accumulation of T lymphocytes, mainly CD4, was observed, with no increase in gamma delta T lymphocytes. CONCLUSIONS: 1) In patients with recent tuberculosis infection T lymphocytosis (total and subsets) occurs. 2) In the absence of HIV infection, a progressive lymphopenia occurs, particularly CD4, with extending disease. 3) In tuberculous pleural effusions and ascitic exudates and accumulation of CD4 T lymphocytes occurs, but not TCR gamma delta lymphocytes. PMID- 8701061 TI - [Retinopathy in patients with insulin-dependent diabetes mellitus of short duration]. AB - To evaluate the role of metabolic control at the beginning of insulin-dependent diabetes mellitus (IDDM) in the development of diabetic retinopathy (DR) a cross sectional study was performed with a retrospective analysis of 24 patients followed for at least seven years. The following parameters were investigated: 1) At IDDM diagnosis, age, sex, metabolic control (basal serum glucose, HbA1, cholesterol, triglycerides) and endogen insulin secretion (EIS). 2) At one year in the follow-up: EIS. 3) Since IDDM diagnosis and every 3-4 months: body mass index, dose and pattern of insulin administration and metabolic control. 4) At seven years in the follow-up: direct ophthalmoscopy, fluorescein angiography, microalbuminuria and blood pressure. In the seventh year of follow-up five patients (23.8%; 95% CI: 8.2%-47.2%) developed changes in fluorescein angiography secondary to IDDM. Compared with patients with normal fluorescein angiography their metabolic control was poorer (mean HbA1--seven years--: 11.7 +/- 0.5 versus 9.8 +/- 0.3%; p = 0.01); mean basal glycemia--seven years--: 214 +/- 13.3 versus 174 +/- 7.7 mg/dl; p = 0.03) and their systolic blood pressure (SBP) higher (124 +/- 5.5 versus 111 +/- 2.8 mmHg; p = 0.04). Logistic regression revealed that mean HbA1 values for seven years was the only independent risk factor significantly associated with the development of DR (p = 0.04). The conclusion is that in patients with IDDM of short duration, the development of DR is associated with a deficient glucose control and a higher SBP. PMID- 8701062 TI - [Acute cervical ischemic myelopathy: anterior spinal artery syndrome]. AB - Acute ischemic myelopathy is an uncommon cause of spinal lesion. Its most common location is the thoracic-lumbar region in the territory of the anterior spinal artery. The involvement of the cervical segment is occasional and with certain etiologic features that differentiates it from the involvement of other spinal segments. We report here two patients with no vascular risk factors who had an infarction in the territory of the cervical anterior spinal artery after physical exertion in one of the patients. We suggest the compression of anterior radicular medullary arteries or the cervical anterior spinal artery against the anterior bone wall of the spinal canal as possible pathogenic mechanism. PMID- 8701063 TI - [Mounier-Kuhn syndrome. 2 representative cases of its clinical spectrum]. AB - Tracheobronchomegaly is characterized by tracheal and main bronchial dilatation usually associated with pulmonary parenchymatous disease. It is a rare condition and less than a hundred cases have been reported so far. Two cases of tracheobronchomegaly are here reported, one of them in an asymptomatic patients who came to medical attention because of pneumothorax (a previously non reported association); the other case was in a female patient with advanced age and history of recurrent pneumonic episodes and with marked parenchymatous involvement. In both cases the diagnostic confirmation was made by CT. PMID- 8701064 TI - [Prevention of cytomegalovirus in organ transplantation]. PMID- 8701065 TI - [Treatment of neutropenia in HIV infection with hematopoietic growth factors]. PMID- 8701066 TI - [71-year-old man with a palpable mass in the right flank]. PMID- 8701067 TI - [Increased abdominal perimeter and pain the right hypochondrium and both iliac fossa]. PMID- 8701068 TI - [A young woman with dermopathy and thoracic pain]. PMID- 8701069 TI - [Imported pruriginous cutaneous lesions]. PMID- 8701070 TI - [Cerebral embolism of cardiac origin]. PMID- 8701071 TI - [Primary medullary tumor]. PMID- 8701072 TI - [Surgical abdomen in a patient with human immunodeficiency virus infection]. PMID- 8701073 TI - [Non-organ dependent generalized edemas as a presentation form of systemic lupus erythematosus]. PMID- 8701074 TI - [Disseminated xanthoma with diabetes insipidus: therapeutic failure of thalidomide]. PMID- 8701075 TI - [Acute bacterial parotitis caused by Serratia marcescens]. PMID- 8701076 TI - Genetic analysis of thyroid hormone receptors in development and disease. AB - Thyroid hormone (T3) fulfills diverse functions in vertebrate development and physiology. These functions are thought to be mediated by two genes encoding the related T3 receptors. TR alpha and TR beta. The use of homologous recombination in embryonic stem cells to generate defined, single-gene mutations provides a powerful means to investigate the individual functions of TR alpha and TR beta in mice. We have shown that targeted inactivation of the TR beta gene results in goiter and elevated levels of thyroid hormone. Thyroid stimulating hormone (TSH), which is released by pituitary thyrotropes and is normally suppressed by increased levels of thyroid hormone, was present at elevated levels in homozygous mutant (Thrb-/-) mice. These findings suggest a unique role for TR beta that cannot be substituted by TR alpha in the T3-dependent feedback regulation of TSH transcription. Thrb-/- mice provide a recessive model for the human syndrome of resistance to thyroid hormone (RTH). Typically, RTH is associated with dominant mutations in TR beta. It is unknown whether TR alpha, TR beta, or other receptors are targets for inhibition in dominant RTH; however, the analysis of Thrb-/- mice suggests that antagonism of TR beta-mediated pathways underlies the disorder of the pituitary-thyroid axis. Thrb-/- mice also display defective maturation of auditory function, demonstrating that TR beta is essential for the development of hearing. Interestingly, hearing defects are generally absent in dominant RTH, indicating that in the auditory system, a dominant TR beta mutant cannot mimic the defect caused by loss of TR beta. This suggests the existence of tissue specific mechanisms that modulate the activity of TR beta. These results define in vivo functions for TR beta and indicate that specificity in T3 signaling is conferred by distinct receptor genes. PMID- 8701077 TI - Transgenic models to study the roles of inhibins and activins in reproduction, oncogenesis, and development. AB - With the advent of gene targeting in pluripotent mouse embryonic stem cells, it is now possible to modify the mammalian genome to generate mutant strains of mice with precise genetic mutations. The major goal of my laboratory is to generate transgenic mice to use as physiologic models to study mammalian reproduction and development. The initial focus of our research has been to generate mice deficient in inhibins, activins, activin binding proteins (i.e., follistatin), and activin receptors (i.e., activin receptor type II) to understand their interactions and roles in the hypothalamic-pituitary-gonadal axis and mammalian development. Inhibins and activins, dimeric members of the TGF-beta superfamily, were discovered due to their role in pituitary follicle stimulating hormone homeostasis. However, these proteins have later been shown to have diverse endocrine, paracrine, and autocrine functions. Activins have been shown to mediate their signals through type I and type II serine/threonine kinase receptors. The high interspecies conservation of activins, inhibins, and activin receptors and the universal presence of activins in mammals, birds, amphibians, and fish suggest an evolutionarily conserved role of these proteins in animal development. Our initial studies have demonstrated a tumor suppressor role of inhibin in the gonads and adrenals and have also suggested a role of activins in cancer cachexia-like syndrome. To further study the gonadal tumor development and the cancer cachexia-like syndrome in these mice, we have begun to generate mice with multiple genetic alterations (e.g., mice deficient in both inhibin and Mullerian inhibiting substance). We have also generated mice deficient in other components of this complex system (e.g., activin beta A, activin receptor type II, follistatin). Analysis of these transgenic mutant models has aided our overall understanding of the critical roles these proteins play in the development of the reproductive system, in the modulation of the endocrine milieu that regulates reproductive function, and in mammalian development. PMID- 8701078 TI - Estrogen receptor gene disruption: molecular characterization and experimental and clinical phenotypes. AB - The estrogen receptor (ER) is thought to play a crucial role in the regulation of many life processes, including development, reproduction and normal physiology. Because there have been no known mutations of the estrogen receptor in normal tissue of humans and animals, its presence and tissue distribution is thought to be essential for survival. Using the techniques of homologous recombination, we have disrupted the ER gene and have produced a line of transgenic mice possessing the altered ER gene (ERKO). The mouse ER gene was disrupted by inserting a 1.8 kb PGK-Neomycin sequence into exon 2, approximately 280 bp downstream of the transcription start codon. The correct targeting of the disruption was demonstrated by Southern blot analysis and PCR. Western blot analysis of uterine preparations from ERKO females showed no detectable ER protein. Heterozygotes had one half the level of ER protein compared to wild-type animals. Estrogen insensitivity was confirmed using estrogen agonists, estradiol, hydroxy tamoxifen, diethylstilbestrol treatment for 3 days which resulted in a 3-4-fold increase in uterine wet weight and vaginal cornification in wild-type females, while ERKO mice were totally unresponsive. These data were further supported by the failure of estrogen or EGF treatment to induce DNA synthesis in uterine tissue of similarly treated mice. Lactoferrin, an estrogen-responsive gene in the uterus, was also assayed by Northern blot. Wild-type mice treated with a single estradiol injection showed a 350-fold induction in lactoferrin mRNA. while ERKO females showed no detectable response. Both male and female animals survive to adulthood with normal gross external phenotypes. As expected, females are infertile and demonstrate hypoplastic uteri and hyperemic ovaries with no apparent corpora lutea. Males are also infertile, with atrophy of the testes and seminiferous tubule dysmorphogenesis. Although the reproductive capabilities have been altered with a dramatic effect on the gonads, prenatal development of the reproductive tracts of both sexes appear to be independent of an ER-mediated response. Analysis of the mammary glands of the ERKO females at 4 months of age showed a primitive ductal rudiment rather than the fully developed ductal tree seen in wild-type siblings. Also absent were the terminal end buds seen during normal ductal morphogenesis. Both sexes show a decrease in skeletal bone density, supporting a direct role for ER action in bone. A single patient is described who is homozygous for a point mutation in the human ER gene at codon 157. The mutation produces a truncation of the ER protein and results in estrogen insensitivity syndrome. Most significant of the clinical findings are effects on skeletal bone density and retarded bone age. Findings from the patient and mice suggest that the absence of functional ER is not lethal. Mutation in the ER gene is present in the human population. Further characterization of the mice and identification of additional patients will be required to more fully understand the consequences of ER gene mutations. PMID- 8701079 TI - IGF-I receptor signalling: lessons from the somatotroph. AB - Insulin-like growth factor 1 (IGF-I) is a major feedback regulator of pituitary GH secretion, with defined actions occurring at both the hypothalamus and pituitary. The IGF-I gene is expressed in the anterior pituitary in a GH dependent manner thus providing for both endocrine-as well as autocrine-mediated GH regulation. In turn, IGF-I selectively and specifically inhibits GH gene transcription and secretion, its attenuating effects on nascent GH mRNA synthesis being demonstrable within 1 h. Binding of IGF-I to its pituitary cell surface receptor is followed by rapid activation of the intrinsic tyrosine kinase activity of the receptor beta-subunit and phosphorylation of insulin receptor substrate 1 (IRS-1). Structure-function studies of the human IGF-I receptor were performed in stable, GH-secreting transfectants expressing either the cDNA encoding the wild-type (WT) human IGF receptor and exhibiting enhanced IGF-I responsiveness, or cDNAs encoding IGF-I receptor mutants and a truncated, kinase deficient receptor (952STOP). 950Tyr situated on the submembrane receptor domain was found to be critical for transducing the IGF-I signal to the GH gene. IGF-I failed to suppress GH secretion by signalling endogenous rat IGF-I receptors when hybrid receptors were formed with kinase-deficient human receptors and rat hemi receptors. This dominant negative effect on hormone secretion was also evidenced when mitogenic IGF-I signals were blocked in vitro and in vivo by these hybrid receptors. Using similar doses of IGF-I, the IGF-I receptor cell transfectants also demonstrated ligand-dependent activation of ERKs in pituitary cells. In conclusion, the pituitary IGF-I receptor mediates the negative feedback regulation of GH. Thus, IGF-I receptor mass may determine GH responses to malnutrition, pregnancy, and refeeding. IGF-I receptor mutations may also prove useful to abrogate the growth of IGF-I-dependent tumors. These structure-function studies of the human IGF-I receptor provide mechanistic insights into both metabolic control of the GH axis, as well as target tissue proliferative characteristics. PMID- 8701080 TI - Transcriptional control of cell phenotypes in the neuroendocrine system. AB - A fundamental aspect of the development of complex organ systems is a requirement for precise temporal and spatial coordination in the genesis of tissues of distinct embryonic origins, in order to form functional units required for physiological homeostasis and survival. Such a requirement is particularly well exemplified in mammalian development in the formation of the hypothalamic pituitary axis. Neuronally expressed POU domain factors might exert effects on terminal differentiation events similar to those of Pit-1 in the maturation of anterior pituitary gland cell phenotypes. Neurons comprising the endocrine hypothalamus develop in tandem with their ultimate target, the pituitary gland, and arise from a primordium in which three related class III POU domain factors Brn-2, Brn-4, and Brn-1-are initially co-expressed. These factors subsequently exhibit stratified patterns of ontogenic expression, correlating with the appearance of distinct neuropeptides that define three major endocrine hypothalamic cell types. Deletion of the Brn-2 genomic locus affects terminal differentiation and/or maintenance of hypothalamic neurosecretory neurons and development of the posterior pituitary gland. Thus, both neuronal and endocrine components of the hypothalamic-pituitary axis are critically dependent upon the action of specific POU domain factors at a penultimate step in the sequential events that underlie the appearance of mature cellular phenotypes. PMID- 8701081 TI - The gonadotropin genes: evolution of distinct mechanisms for hormonal control. AB - The glycoprotein hormones (TSH, FSH, LH, CG) are structurally related proteins with diverse physiologic functions. This family of hormones offers an opportunity to address fundamental questions concerning how gene expression is regulated in a cell-specific manner and in response to different hormones. For example, the alpha-subunit gene is expressed in several different pituitary cell types (gonadotropes and thyrotropes) as well as in the placenta. Because it must be coordinantly expressed with the different beta-subunit genes, the alpha-gene provides an interesting model for multihormonal control which varies in a cell type specific manner. Many of the promoter regulatory DNA sequences and cognate transcription factors in the alpha-gene have been identified. These studies reveal a remarkable series of composite regulatory elements that interact with families of transcription factors that are still being characterized. In contrast, the beta-subunit genes are notable for restricted cell-type expression and more limited hormonal regulation that reflects their individual physiologic roles. The TSH beta gene is expressed only in thyrotropes where, in conjunction with the alpha-gene, it is subject to transcriptional repression by thyroid hormone. The FSH beta gene is expressed in gonadotropes where its expression is controlled primarily by activin and inhibin, with additional regulation by GnRH. The LH beta gene is also expressed in gonadotropes, but it is more dependent upon GnRH input and its expression is unaffected by the activin/inhibin system. The CG beta gene evolved recently from the LH beta gene and in the process, the CG beta promoter acquired new regulatory elements that favor its expression in the placenta rather than the pituitary gland. Less is known about the regulatory elements in the beta genes, in part because highly differentiated cells are required for their normal regulation. This chapter reviews the regulation of this family of genes with an emphasis on recent studies from our laboratory involving the gonadotropins (LH, FSH, CG). Concomitant with our advancing understanding of how the gonadotropin genes are regulated, we are also learning about genetic causes of gonadotropin deficiency syndromes. PMID- 8701082 TI - The gene responsible for adrenal hypoplasia congenita, DAX-1, encodes a nuclear hormone receptor that defines a new class within the superfamily. AB - X-linked adrenal hypoplasia congenita (AHC) is an inherited disorder of the development of the adrenal cortex. The gene responsible for this genetic disorder has been identified using positional cloning methods and has been named DAX-1 based on its localization within the dosage-sensitive sex reversal (DSS) locus and the AHC locus on the X chromosome. The DAX-1 gene consists of two exons separated by a 3.4 kb intron. Analysis of DNA from patients with deletions in the AHC critical region in the X chromosome provided strong indication for the involvement of the DAX-1 gene in X-linked AHC. A number of intragenic mutations within the DAX-1 gene have also been identified in patients with isolated AHC. The DAX-1 gene product belongs to the nuclear hormone receptor superfamily based on the presence of an entire ligand binding domain present in the carboxy terminal region of the receptor. However, DAX-1 has a domain structure which is very unusual with respect to other nuclear hormone receptor superfamily members. The amino-terminal portion of DAX-1 contains a novel domain consisting of 3.5 repeats of a 65-67 amino acid motif that contains two putative zinc finger structures in place of the more usual amino-terminal domain, DNA binding domain, and hinge region of the typical nuclear hormone receptors. It has been proposed that the amino-terminal portion of the DAX-1 protein is the DNA binding domain. The expression pattern of DAX-1 suggests that it may play a role in the regulation of steroidogenesis. Not only is DAX-1 expressed in the adrenal glands, but it is also expressed in the ovaries and testes. Most recently, we demonstrated that DAX-1 is also expressed in the hypothalamus and pituitary gland. The expression of DAX-1 in the neuroendocrine system suggests that interruption of the expression in these tissues may be the cause of the hypogonadotropic hypogonadism (HH) that is frequently associated with AHC. Interestingly, hybridization of a human DAX-1 cDNA probe with genomic DNA from various species indicated that a DAX-1 homologue may exist in yeast. Thus, DAX-1 or a DAX-1-like transcription factor may be the most primitive member of the nuclear hormone receptor superfamily. Although the molecular mechanism of action of DAX-1 is not yet characterized, its importance for the development and physiology of the adrenal gland and gonads is indicated by its involvement in AHC and HH. Analysis of the functions of DAX-1 along with its regulation of expression will not only provide information concerning the actions of this new member of the nuclear hormone receptor superfamily, but will also yield insight into the pathogenesis of AHC and HH and may allow for the development of gene therapy protocols for the treatment of these diseases. PMID- 8701083 TI - Modulation of pulsatile GH release through a novel receptor in hypothalamus and pituitary gland. AB - Hormone replacement should provide a serum hormone profile similar to that found in normal physiology. This is generally impractical because hormones are usually released episodically and therefore require frequent administration. However, rather than replacing the hormone directly, in theory, one could administer a mimic or amplifier of the pulse generator that controls pulsatile release of the particular hormone. Using growth hormone (GH) as a paradigm we sought such a mimetic that would provide episodic GH release when administered by the oral route. A GH secretagogue MK0677, is described that has these ideal properties; following oral administration MK0677 amplifies episodic GH release. Mechanistically, it synergizes with growth hormone releasing hormone (GHRH) through a receptor and signal transduction pathway distinct from that of GHRH and is a functional antagonist of somatostatin (SRIF). MK0677 also acts on the arcuate nucleus and appears to stimulate GHRH release. By using 35S-MK0677, a new G-protein coupled receptor for MK0677 was characterized in the plasma membrane fraction of pituitary and hypothalamic tissue. The receptor is present in very low abundance and couples to phospholipase C. Other ligands selective for this receptor also cause synchronization of well-defined pathways leading to GH release. Repeated oral treatment of dogs once daily with MK0677 initiates amplified pulsatile GH release accompanied by increases in IGF-1 that are sustained. The unique biological properties of MK0677 and other synthetic ligands that bind to the same receptor force us to predict that these ligands mimic a naturally occurring hormone that regulates pulsatile GH release. Understanding the regulatory mechanisms involved in this paradigm has broad implications for the control of pulsatile rhythms in the endocrine system. PMID- 8701084 TI - The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. AB - Molecular cloning experiments have led to the identification and characterization of a family of five receptors for the melanocortin (melanotropic and adrenocorticotropic) peptides. The first two members of the family cloned were the well-characterized melanocyte-stimulating hormone receptor (MSH-R) and adrenocorticotropin receptor (ACTH-R). The three new melanocortin receptors have been termed the MC3-R, MC4-R, and MC5-R, according to the order of their discovery, and little is known at this point concerning their function. Agouti and extension are two genetic loci known to control the amounts of eumelanin (brown-black) and phaeomelanin (yellow-red) pigments. Chromosomal mapping demonstrated that the MSH-R, now termed MCI-R, mapped to extension. Extension was shown to encode the MCI-R, and mutations in the MCI-R are responsible for the different pigmentation phenotypes caused by this locus. Functional variants of the MCI-R, originally characterized in the mouse, have now also been identified in the guinea pig and cow. Dominant constitutive mutants of the MCI-R are responsible for causing dark black coat colors while recessive alleles result in yellow or red coat colors. Agouti, a secreted 108 amino acid peptide produced within the hair follicle, acts on follicular melanocytes to inhibit alpha-MSH induced eumelanin production. Experiments demonstrate that agouti is a high affinity antagonist, acting at the MCI-R to block alpha-MSH stimulation of adenylyl cyclase, the effector through which alpha-MSH induces eumelanin synthesis. The MCI-R is thus a unique bifunctionally controlled receptor, activated by alpha-MSH and antagonized by agouti, both contributing to the variability seen in mammalian coat colors. The variable tan and black coat color patterns seen in the German Shepherd, for example, can now be understood on the molecular level as the interaction of a number of extension and agouti alleles encoding variably functioning receptors and a differentially expressed antagonist of the receptor, respectively. PMID- 8701085 TI - Desensitization of G protein-coupled receptors. AB - Waning responsiveness to continuous or repeated stimulation constitutes the phenomenon of desensitization, which pervades biological systems. Over the last several years, molecular mechanisms for desensitization of cellular signaling through G protein-coupled receptors have been delineated, particularly at the level of the receptors themselves. This review focuses on those aspects of G protein-coupled receptor desensitization which occur within minutes of agonist exposure. Agonist-dependent desensitization of these receptors can reduce their signaling responsiveness to maximum stimulation by up to 70-80%; indeed, in some receptor systems, the process of receptor desensitization appears to effect the termination of the cellular signaling response. Agonist-induced desensitization involves phosphorylation of G protein-coupled receptors by two currently recognized classes of serine/threonine protein kinases. Second messenger dependent kinases, phosphorylating a variety of proteins, mediate a generalized cellular hyporesponsiveness termed heterologous desensitization. G protein coupled receptor kinases (GRKs) phosphorylate specifically agonist-occupied, or activated, receptors, and thereby initiate receptor-specific, or homologous, desensitization. GRK-mediated receptor phosphorylation facilitates the binding of an inhibitory arrestin protein to the phosphorylated receptor, an event which substantially impairs receptor signaling. The GRK family comprises six, and the arrestin family comprises four known members. Each GRK demonstrates the ability to phosphorylate a limited number of model receptor substrates, but the widespread expression of several GRKs and the two somatic arrestins suggest that GRK-initiated homologous desensitization is of general importance to a wide range of G protein-coupled receptors. Exploration of the substrate specificity for GRKs and the ligand specificity for arrestins remains in its early stages. Currently, GRKs can most readily be differentiated by the mechanisms each employs to associate with the plasma membrane. Accumulating data from human disease states and transgenic mice attest to the physiologic significance of GRK-initiated receptor desensitization. PMID- 8701086 TI - Modulator and messenger functions of cyclic ADP-ribose in calcium signaling. AB - Cyclic ADP-ribose (cADPR), a Ca+2 mobilizing cyclic nucleotide derived from NAD+, is emerging as an endogenous modulator of the Ca(+2)-induced Ca+2 release (CICR) mechanism in cells. cADPR was discovered because of the prominent delay in the initiation of Ca+2 release by NAD+ in sea urchin egg homogenates, which was due to enzymatic conversion to cADPR. In addition to the egg, an invertebrate cell, amphibian neurons, a variety of mammalian cells and plant vacuoles are found to be responsive to cADPR, indicating its generality. The cyclic structure of cADPR has been determined by X-ray crystallography. A series of analogs has been synthesized, which includes cyclic GDP-ribose, a fluorescent analog, a series of specific antagonists, a photoaffinity label and caged cADPR. The use of these analogs of cADPR has provided definitive evidence for the authenticity of its Ca+2 mobilizing activity and insights for understanding its mechanism and biological functions. Results show that its action requires a soluble protein which is identified as calmodulin. The effect of calmodulin is synergistic with cADPR and both act to sensitize CICR to Ca+2. Together, the Ca+2 sensitivity of CICR can be increased by several orders of magnitude. In addition to being a modulator of CICR. cADPR can also function as a messenger. Activation of its synthetic enzyme can lead to large increases in cellular concentrations of cADPR, which would sensitize CICR to such an extent that even basal levels of cellular Ca+2 are sufficient to trigger further release. This is operationally equivalent to being a Ca+2 messenger. Three types of enzymes are involved in the metabolism of cADPR, a soluble ADP-ribosyl cyclase; a bifunctional ecto-enzyme, CD38, which is also a lymphocyte antigen; and an intracellular enzyme activable by a cGMP dependent process. The importance of two cysteine residues in the bifunctionality of CD38 has been shown by site-directed mutagenesis. Both ADP-ribosyl cyclase and CD38 can catalyze the exchange of the nicotinamide group in NADP+ with nicotinic acid, leading to the formation of another Ca+2 mobilizing metabolite, nicotinic acid dinucleotide phosphate (NAADP). Pharmacological and desensitization studies show that the NAADP-mechanism is totally independent of the cADPR- and inositol trisphosphate-mechanisms and the Ca+2 stores responsive to NAADP are separable from those sensitive to the other two Ca+2 agonists. Microinjection studies show that all three mechanisms are present and functional in cells. The emerging picture of multiplicity in Ca+2 signaling mechanisms underscores the versatility of Ca+2 in regulating diverse cellular functions. PMID- 8701087 TI - The JAK-STAT pathway: summary of initial studies and recent advances. AB - Polypeptides redirect cells by causing immediate changes in gene transcription. A direct connection between polypeptide receptors on the cell surface and genes in the nucleus has been provided by the recognition of the JAK-STAT pathway. Results leading to our present understanding of this pathway are reviewed. PMID- 8701088 TI - Protein tyrosine phosphatases: their roles in signal transduction. AB - Protein tyrosine phosphatases play critical roles in a number of cellular signal transduction pathways. Receptor-like PTPases such as CD45 are essential for antigen-induced proliferative responses of T-cells. Intracellular PTPases have been shown to associate with specific growth factor receptors and this association has a dramatic effect on receptor signaling mechanisms. Other phosphatases (e.g., the product of the CDC25 gene) are essential for cell cycle progression. It appears that the cellular location of the intracellular PTPases plays an important role in defining the substrate specificity. Phosphatases are also present in both pathogenic bacteria and viruses. These PTPases most likely function to disrupt important signal transduction pathways present in the host. More than 30 different phosphatases have been cloned and characterized. A detailed understanding of their catalytic properties suggests that all PTPases use a common mechanism for removing phosphatase from various phosphoproteins. Two PTPase structures recently have been determined. The structural information along with biochemical and kinetic data provides a basis for understanding the catalytic properties of these enzymes. PMID- 8701090 TI - Gonadal cell apoptosis. AB - Apoptosis is an important cellular process by which superfluous or unwanted cells are deleted from an organism during tissue remodeling and differentiation. Recent studies have demonstrated the role of this programmed cell death or "controlled cell suicide" in the physiological function of an organism. Suppression of apoptosis increases the susceptibility of an individual to malignancy whereas uncontrolled cell death is associated with degenerative diseases. Normal development of both female and male gonads is characterized by massive cell death. More than 99% of ovarian follicles endowed at early life are destined to undergo apoptosis and the exhaustion of these follicles serves as a "clock" for female reproductive senescence. In the testis, up to 75% of male germ cells also undergo apoptosis, perhaps as a mechanism to delete superfluous or defective germ cells. Gonadal cell apoptosis provides valuable models to study hormonal regulation of apoptosis. In the ovary, gonadotropins, estrogens, growth hormone, growth factors (IGFI, EGF/TGF-alpha, basic FGF), cytokine (interleukin-1 beta) and nitric oxide act in concert to ensure the survival of preovulatory follicles. In contrast, androgens, interleukin-6 and gonadal GnRH-like peptide are apoptotic factors. Developmental studies further indicate that fractions of endowed follicles are recruited throughout the reproductive life whereas most of the primordial follicles are "arrested" at the initial stage of development for a prolonged time. Because a transcriptional factor WT1 is expressed in high levels in follicles at early stages of development and because WT1 over-expression represses the promoter activity of inhibin-alpha gene, this nuclear protein may be important in the maintenance of follicles at early stages of development. Once a cohort of follicles is recruited to grow, it is destined to undergo apoptosis unless rescued by survival factors. After puberty onset and under gonadotropin stimulation, some of the growing antral follicles are "selected" to continue their final maturation and secrete high levels of estrogens to trigger ovulation. Following repeated cycles of recruitment, atresia or ovulation, the follicle reserve is exhausted, thus signaling the onset of reproductive senescence. Although the somatic granulosa cell is the major cell type undergoing apoptosis in the ovary, the germ cells in the testis also exhibit signs of apoptotic cell demise. In the testis, gonadotropins and androgens act as survival factors whereas exposure to elevated temperature in cryptorchid testes increases apoptosis. In the seasonally breeding hamster model, photoperiod-entrained regression and recrudescence of testis tissue serves as a unique natural model of apoptosis. With recent advances in our understanding of the cellular mechanism of apoptosis, including the elucidation of the Ced9/bc12 and Ced3/ICE family of proteins, further investigation of gonadal apoptosis may lead to a better understanding of gonadal degenerative disorders (such as premature ovarian failure and oligospermia), reproductive senescence and tumorigenesis. The gonadal model should also be valuable in studying the regulation of intracellular apoptosis genes by external hormonal signals. PMID- 8701089 TI - Extracellular matrix signaling from the cellular membrane skeleton to the nuclear skeleton: a model of gene regulation. AB - It is well established that cells must interact with their microenvironment and that such interaction is crucial for coordinated function and homeostasis. However, how cells receive and integrate external signals leading to gene regulation is far from understood. It is now appreciated that two classes of cooperative signals are implicated: a soluble class including hormones and growth factors and a class of insoluble signals emanating from the extracellular matrix (ECM) directly through contact with the cell surface. Using 3-dimensional culture systems and transgenic mice, we have been able to identify some of the elements of this ECM-signaling pathway responsible for gene regulation in rodent mammary gland differentiation and involution. Our major observations are 1) the requirement for a laminin-rich basement membrane; 2) the existence of a cooperative signaling pathway between basement membrane and the lactogenic hormone prolactin (PRL);3) the importance of beta 1-integrins and bHLH transcription factor(s) and the presence of DNA response elements (exemplified by BCE-1, located on a milk protein gene, beta-casein); and 4) the induction of mammary epithelial cell programmed cell death following degradation of basement membrane. We hypothesize that this cooperative signaling between ECM and PRL may be achieved through integrin- and laminin-directed restructuring of the cytoskeleton leading to profound changes in nuclear architecture and transcription factor localization. We postulate that the latter changes allow the prolactin signal to activate transcription of the beta-casein gene. To further understand the molecular mechanisms underlying ECM and hormonal cooperative signaling, we are currently investigating ECM regulation of a "solid-state" signaling pathway including ECM fiber proteins, plasma membrane receptors, cytoskeleton, nuclear matrix and chromatin. We further postulate that disruption of such a pathway may be implicated in cell disorders including transformation and carcinogenesis. PMID- 8701091 TI - The biochemistry and molecular biology of glucocorticoid-induced apoptosis in the immune system. AB - Apoptosis is a form of programmed cell death that occurs under numerous developmental and physiological conditions that require the selective elimination of cells from tissues and organs without the production of an inflammatory response. The initiation of apoptosis is controlled by a regulation of the balance between death and life signals perceived by the cell. A typical response of cells to an apoptotic stimulus includes a reduction in cell volume, compaction of intracellular organelles, chromatin condensation, and the generation of apoptotic bodies which contain degraded cellular components. Apoptotic bodies are often engulfed by neighboring cells or macrophages, preventing the occurrence of an inflammatory response in the region of the dying cells. Although the molecular basis for this cellular suicide is poorly understood, evidence indicates that apoptosis is an active process, requiring energy for its effective completion. We have sought to define the catabolic "effector" molecules that carry out the apoptotic process using glucocorticoid-induced apoptosis in rodent and human lymphocytes as model systems. These cells respond to dexamethasone with an arrest of cell growth, chromatin condensation, cell shrinkage, and the selective degradation of DNA, RNA, and protein. These effects are dependent on the presence of functional glucocorticoid receptors and require gene expression. The fragmentation of DNA and its associated cell shrinkage has been a focus of our efforts, because these effects reflect an irreversible commitment to death. Accordingly, we have developed assays to study apoptosis at the single cell level and to identify, purify, and clone the nuclease(s) that cause DNA damage in apoptotic cells. Using these approaches, we have identified and characterized a novel low molecular weight nuclease (NUC18) whose activity correlates with the DNA degradation occurring during apoptosis. NUC18 requires calcium for optimal activity in vitro and is inhibited by zinc and aurintricarboxylic acid, two known inhibitors of apoptosis. The amino acid sequence of pure NUC18 reveals a surprising homology to the cyclophilin family of proteins. Furthermore, recombinant cyclophilins have biochemical and pharmacological properties identical to those of NUC18. We have also studied the molecular basis for the catabolism of RNA and proteins that occurs during lymphocyte apoptosis. Recent experiments have identified selective cleavage of 28S ribosomal RNA and a novel nonlysosomal protease, both of which contribute to the demise of the cell. In summary, we present an evolving model that unifies the activation of apoptosis in lymphocytes by glucocorticoids with the counter-balancing effect of inhibitors such as Bcl-2. PMID- 8701092 TI - Programmed cell death in human breast cancer cells. AB - The need for improved systemic therapy for breast cancer is great. Cancer growth represents an imbalance between cell proliferation and cell death: thus, effective anti-cancer therapies may act to decrease cell proliferation or increase cell death, or both. This chapter delineates the role of the programmed cell death process in maintaining homeostasis in normal mammary tissues. The preservation of such death pathways in malignant mammary cells and the ability of chemotherapeutic agents to initiate the programmed cell death process in these cells is reviewed. Finally, ongoing research exploring new ways to take advantage of these death pathways in the clinical setting is examined. PMID- 8701093 TI - A nuclear matrix acceptor site for the progesterone receptor in the avian c-myc gene promoter. AB - It has been the goal of this project to determine the location, composition, and biological function of the nuclear acceptor sites (i.e., the nuclear binding sites) for the avian oviduct progesterone (Pg) receptor (PR). Many laboratories have demonstrated a native-(in vivo) like cell-free binding of steroid receptor complexes to specific acceptor sites in nuclei/chromatin in a variety of target tissue systems. These sites appear to involve protein-DNA complexes and some of these have been shown to reside in the nuclear matrix, including the chromatin acceptor sites for the avian oviduct PR. We have purified a nuclear matrix "acceptor protein" for the avian PR. termed receptor binding factor-1 (RBF-1), based on its ability to generate specific, high-affinity PR binding on avian genomic DNA. This 10 kD nuclear matrix protein was found to be unique with minimal homology to a couple of other proteins. Using immunohistochemical techniques and antibodies against the purified RBF-1, the RBF-1 was localized to the nuclei of many avian and rat tissues. Co-localizations of RBF-1 and PR in select cell types in the avian oviduct and rat reproductive organs were also reported. A tissue specificity was found with regard to RBF-1 concentrations. The full length cDNA to RBF-1 has been isolated and used to identify a 0.7 kb mRNA whose levels in various avian tissues reflect the protein levels. Genomic sequences of RBF-1 have been isolated and characterized. Preliminary studies indicate that the over-expression of the RBF in human MCF-7 cells results in an inhibition of the c-myc gene promoter activity which is further inhibited by steroid hormone treatments of the cells. Past studies in our laboratory demonstrated that the c-myc mRNA steady state levels are rapidly (approximately 15 min) reduced by Pg and glucocorticoids in the avian oviduct. Further, partially purified fractions of RBF-1 were shown to generate specific PR binding sites only on the genomic DNAs of certain animal species and on the c-myc gene, but not ovalbumin gene. Using Southwestern blot analyses, the purified RBF-1 was shown to bind specifically to sequences in the 5' end of c-myc, c-jun proto oncogenes but not to genomic sequences of the ovalbumin gene. A specific DNA binding element in the promoter region of the c-myc proto-oncogene has been identified as AT-rich domain of homopurine/pyrimidine stretches flanked by GC rich sequences. Southern blot analyses using 200 bp matrix DNA fragments protected by the nuclear matrix structure indicate that the matrix is attached on either side of the RBF-1 binding element. A model is described for a nuclear matrix acceptor site attached to the c-myc promoter which may mediate the Pg induced down-regulation of the c-myc gene expression. PMID- 8701094 TI - Resistance to thyrotropin and other abnormalities of the thyrotropin receptor. PMID- 8701095 TI - Taking off the rose-colored glasses: the need to find remedies for toxic workplaces. PMID- 8701096 TI - Painting a mural and writing an article: creative rehabilitation strategies. AB - In this article, the authors describe a creative rehabilitation process that used painting a mural and writing for publication as interventions. The successful rehabilitation process is described from the perspective of the patient as well as the rehabilitation nurse. Creative strategies often are needed when a patient does not readily respond to traditional rehabilitation methods. A patient's interests, talents, and concerns often can be creatively aligned with the rehabilitation goals of the nurse and can result in unique interventions that have successful outcomes. Painting a mural and coauthoring this article became the primary rehabilitation interventions for a patient with expressive aphasia and impaired mobility, secondary to his stroke in 1987. PMID- 8701097 TI - Family relationships and adaptation to spinal cord injury: a qualitative study. AB - To study adaptive processes following spinal cord injury, unstructured audiotaped interviews were conducted on an almost daily basis with a 30-year-old divorced male during the first 3 months of his initial comprehensive inpatient rehabilitation. Analysis of the transcribed tapes identified a number of important themes, including the theme of social relationships, recurring throughout the data. Family relationships are the focus of this article. The role of the rehabilitation nurse in promoting family involvement in the rehabilitation process is discussed. PMID- 8701098 TI - Assessing the functional level of rehabilitation teams and facilitating team development. AB - This article describes a research-based method for assessing team effectiveness and for facilitating the development of rehabilitation teams. The authors used a 60-item self-report instrument to measure the developmental level of a group or a team. Two examples of the use of this instrument with rehabilitation teams are discussed. PMID- 8701100 TI - Operationalizing a comprehensive neurobehavioral plan. AB - The formulation and implementation of a workable and effective plan of care for the complex rehabilitation patient are nursing challenges. Even more challenging, however, is putting the plan into operation over a 24-hour period. Staffing variations, patients' circadian rhythms, and visiting hours are only a few of the factors that require consideration when formulating a viable plan of care. The purpose of this article is to discuss strategies that have been effective in providing consistent, safe, therapeutic care for the patient population on a 39 bed neurobehavioral unit that treats mostly individuals with traumatic brain injuries. PMID- 8701099 TI - Educational interests of individuals with spinal cord injury living in the community: medical, sexuality, and wellness topics. AB - As a component of Baylor College of Medicine study of the life status of people with spinal cord injury (SCI), this study determined the educational topics of interest to a cohort of 590 adults with SCI living in the community. Thirty-five items in nine topic areas were included in the inventory. Three topic areas- medical, sexuality, and wellness--are discussed in this article. Across the three topic areas, the five topics of greatest interest were exercise programs, testing of nerve and muscle function, bladder or kidney problems, pain, and sexuality issues. Information about smoking cessation and alcohol or drug abuse was of interest to very few participants. Ten grouping variables were analyzed and individual differences, such as educational level and whether an individual had paraplegia or quadriplegia, were found to account for differences in the topics of interest. The results of this study can be used in setting priorities for the development of educational activities and learning experiences for individuals with SCI living in the community. PMID- 8701101 TI - Patient transfer to rehabilitation: just another move? AB - Although relocation stress syndrome (RSS) is not a diagnosis that is unique to rehabilitation patients, it is important for nurses practicing in rehabilitation environments to be knowledgeable about this phenomenon. Rehabilitation patients are at high risk for RSS. Nursing care planning should incorporate interventions that aim to prevent or reduce RSS. While various relocations are inherent in the rehabilitation process, emphasis should be placed on predictability of care and on patients and families having as much control over decision making as possible. The authors describe how appropriate assessment and management of RSS can facilitate smoother transitions throughout the rehabilitation process and permit a stronger focus on rehabilitation therapies and on patient and family teaching. PMID- 8701102 TI - Life began with a loss. PMID- 8701103 TI - On-site triage of avalanche victims with asystole by the emergency doctor. AB - Asystole in avalanche victims is generally due to asphyxia and not primarily to hypothermia. Hence, on-site establishment of death by asphyxiation would avoid evacuation risks to the rescue party, as well as high costs of transport to, and treatment at, frequently distant specialist centres in cases with a hopeless prognosis. This paper presents a novel differential diagnosis scheme based on burial duration (critical time 45 min) and core temperature (critical level 32 degrees C) of the person on extrication, as well as the presence or absence of an air pocket, facilitating on-site identification of asphyxiated victims. When information regarding an air pocket is uncertain in victims buried longer than 45 min, determination of serum potassium (critical level 10 mmol/l) at the nearest hospital becomes an alternative criterion for triage. The proposed guidelines aim to clarify field decision-making for the emergency doctor with respect to discontinuation of resuscitation and limitation of transferral for cardiopulmonary bypass core rewarming to those patients with presumptive reversible hypothermia. PMID- 8701104 TI - Response to cardiac arrests in a hospital setting: delays in ventilation. AB - The outcome following a cardiac arrest is affected by the length of time that elapses before cardiopulmonary resuscitation is initiated. Only 10-15% of patients experiencing cardiac arrest in hospital settings survive to discharge. Therefore, the time between cardiac arrest and administration of cardiopulmonary resuscitation in a metropolitan hospital was examined. All cardiac and respiratory arrests that occurred in the adult non-intensive care areas of a medical center over a period of 16 months were evaluated within 12 h to determine how much time had elapsed before resuscitation was initiated, the devices utilized for initial airway management, and the outcome. To initiate ventilation, bag-valve-masks (BVMs) were used in the majority (76%) of the efforts to resuscitate while mouth-to-mask resuscitation was performed in another 18%; however, in only 37% of the codes was ventilation initiated within 1 min and in 18% ventilation was started after 3 min. Mouth-to-mask resuscitation resulted in more rapid time to onset of ventilation than BVM. In only 18% of the arrests studied was a 'lay-on' mask available in the room and utilized. In 11%, a bag valve-mask was at the patient's bedside, and in 53% a BVM was taken from the crash cart outside the room. In 63% of the cases where using a lay-on mask was appropriate, it was either not looked for or not present in the patient's room. Also in 37% of the cases where a BVM was needed, one was not readily present because of difficulty in locating the crash cart immediately. Although initiation of cardiopulmonary resuscitation within a minute of a cardiac or respiratory arrest is the standard of care, in the non-intensive care in-patient cases surveyed, typically more than a minute elapsed, and frequently 3 or more minutes, before resuscitation was started. If the time elapsing before an arresting in patient is ventilated can be shortened, which is easily and effectively achieved by mouth-to-mouth or mouth-to-mask resuscitation, an increase in both the survival rate and the number of good neurological outcomes should be expected. PMID- 8701105 TI - Optimal defibrillation strategy and follow-up of out-of-hospital cardiac arrest. The Belgian CPCR Study Group. AB - In the current climate of rising healthcare cost, resuscitation efforts performed outside the hospital are critically evaluated because of their limited success rate in some settings. As part of a quality assurance program between the 1st January 1991 and 31st December 1993, six centres of the Belgian CPCR study group prospectively registered cardiac arrest (CA) patients and their treatment according to the Ustein Style recommendations. In the group (n = 511) of patients initially found in ventricular fibrillation (VF) a significantly better survival rate was observed for those patients who received a 1st defibrillatory shock by the 1st tier (n = 142 (27.8%)) as compared to those defibrillated after arrival of the 2nd tier (n = 369 (72.2%)). Median time to delivery of the first shock was significantly shorter (5 min) in the 1st tier group. In a second part of the study we describe long-term management of the 28 surviving VF patients, treated by the single EMS system of Brugge between 1st January 1991 and 30th April 1995: only 6 patients eventually received an implantable cardioverter defibrillator (ICD), whereas coronary revascularization was performed in 9 patients, and 3 patients were discharged on amiodarone only. Satisfactory long-term survival after out-of-hospital VF can be achieved by an early shock followed by advanced life support and appropriate definitive treatment. PMID- 8701106 TI - Controversies in resuscitation: to infuse or not to infuse (1) PMID- 8701107 TI - Teaching schoolchildren cardiopulmonary resuscitation. AB - Forty-one children aged 11-12 years received tuition in cardiopulmonary resuscitation (CPR) and subsequently completed questionnaires to assess their theoretical knowledge and attitudes their likelihood of performing CPR. Although most children scored well on theoretical knowledge, this did not correlate with an assessment of practical ability using training manikins. In particular only one child correctly called for help after the casualty was found to be unresponsive, and none telephoned for an ambulance before starting resuscitation. These omissions have important implications for the teaching of CPR and the resulting effectiveness of community CPR programmes. PMID- 8701108 TI - Automatic external defibrillators in the hospital as well? AB - When a cardiac arrest occurs in a non-intensive area of the hospital, the emergency response is not always adequate from the point of view of timeliness and technical quality. The aims of this study were evaluate an experimental programme to improve the CPR skills of staff operating in non-intensive areas of our general hospital and to test the usefulness of placing automatic external defibrillators (AEDs) within these areas. In the experimental phase, two AEDs were placed in 2 non-intensive wards of our hospital for 8 months. The staff of these wards received specific training in CPR and early defibrillation (CPR-D). The devices were used in 19 cases; for defibrillation in four cases of ventricular fibrillation (VF) (three patients were discharged alive from hospital), and for monitoring three supraventricular arrhythmias, one bradyarrhythmia and 11 cardiac rhythms during critical situations. In the implementation phase, four AEDs were indefinitely assigned to as many non intensive awards. Periodical CPR-D courses and refresher exercises were run; the cardiology staff co-operated in the maintenance of the AEDs and in the registration of technical and clinical data. In the first period of this phase (9 months), AEDs were utilized in 24 cases by the ward-staff: in nine cases for VF (three patients were discharged alive from hospital) and in 15 cases for other rhythm detection in critical conditions. The number and the quality of these uses seem to confirm the favourable impact of the adoption of a more user-friendly defibrillator, such as an AED. The active co-operation between intensive and non intensive staff was important to facilitate a quick activation of the chain of survival outside the intensive care units. We conclude that AEDs, which were developed for out-of-hospital use by non-physician operators, are suitable for use inside the hospital as well. PMID- 8701109 TI - Effects of various degrees of compression and active decompression on haemodynamics, end-tidal CO2, and ventilation during cardiopulmonary resuscitation of pigs. AB - The effects of various degrees of compression and active decompression during cardiopulmonary resuscitation were tested in a randomized cross-over-design during ventricular fibrillation in eight pigs using an automatic hydraulic chest compression device. Compared with 4/0 (compression/decompression in cm), mean carotid arterial blood flow rose by 60% with 5/0, by 90% with 4/2 and 4/3, and 105% with 5/2. Two cm active decompression increased mean brain and myocardial blood flow by 53% and 37%, respectively, as compared with 4/0. Increasing standard compression from 4 to 5 cm caused no further increase in brain or heart tissue blood flow whether or not combined with active decompression. Tissue blood flow remained unchanged or decreased when active decompression (4/3) caused that 50% of the pigs were lifted from the table due to the force required. Myocardial blood flow was reduced with 5/0 vs. 4/0 despite no reduction in end decompression coronary perfusion pressure ((aortic-right atrial pressure) (CPP), (7 +/- 8 mmHg with 4/0, 14 +/- 11 mmHg with 5/0)(NS)). End decompression CPP increased by 186% with 4/2 vs. 4/0, by 200% with 4/3, and by 300% with 5/2. Endo-tracheal partial pressure of CO2 was significantly increased during the compression phase of active decompression CPR compared with standard CPR. Active decompression CPR generated an significantly increased ventilation compared with standard CPR. CONCLUSION: Carotid and tissue blood flow, ventilation, and CPP increase with 2 cm of active decompression. An attempt to further increase the level of active decompression or increasing the compression depth from 4 to 5 cm did not improve organ blood flow. PMID- 8701110 TI - Effect of mild hypothermia on ischemia-induced release of endothelin-1 in dog brain. AB - Endothelin-1 (ET-1) plays an important role in the physiologic or pathophysiologic regulation of cerebral circulation. To evaluate the effect of mild hypothermia on the cerebral concentration of ET-1 and on the cerebral metabolism of oxygen after complete global cerebral ischemia, we occluded the ascending aorta and caval veins of 9 dogs for 15 min. A fiberoptic catheter was inserted into the sagittal sinus to monitor venous oxygen saturation (S(SO)2) continuously. Blood samples were collected 30 min before and 30 min, 1 h, 2 h, 4 h and 6 h after the ischemic insult. Concentrations of ET-1 were assayed in the blood of the sagittal sinus and abdominal aorta. Before, during and after the aortic occlusion, we compared findings in a normothermic control Group 1 (pulmonary artery temperature 38.5 degrees C) (n = 4) with those in the mildly hypothermic Group 2 (pulmonary artery temperature 34.0 degrees C) (n = 5) by surface cooling induced before and maintained during and after ischemia for 6 h. Following ischemia, the plasma concentration difference of ET-1 (sagittal sinus- arterial) was significantly decreased in Group 2 (P < 0.05). Differences in S(SO)2 between the two groups were not statistically significant. Mild hypothermia reduced the ET-1 release in the cerebral circulation but did not improve cerebral oxygen metabolism after complete cerebral ischemia. Findings indicated that the decrease in ET-1 induced by mild hypothermia contributes to the improvement of the cerebral microcirculation after ischemia. PMID- 8701111 TI - Effects of epinephrine and vasopressin on median fibrillation frequency and defibrillation success in a porcine model of cardiopulmonary resuscitation. AB - OBJECTIVE: This study was designed to assess whether median frequency of ventricular fibrillation (VF) correlates with myocardial blood flow and defibrillation success during cardiopulmonary resuscitation (CPR) after epinephrine or vasopressin administration. METHODS AND RESULTS: After 4 min of VF and 3 min of CPR, 14 pigs received 0.045 mg/kg epinephrine or 0.4 U/kg vasopressin. Using radio-labeled microspheres, median myocardial blood flow during CPR before, and 90 s and 5 min after drug administration (DA) was 15.5 (12.6, 23.1; 25th percentile, 75th percentile), 26.4 (18.5, 29.1), 16.9 (14.9, 19.1) mL min-1 100 g-1, respectively, in the epinephrine, and 16.9 (15.4, 18.9), 48.1 (36.9, 68.9) (P < 0.05 vs. before DA), 52.3 (38.5, 65.0) mL min-1 100 g-1, respectively, in the vasopressin group. Using spectral analysis of VF, median frequency of VF was 11.0 (10.7, 11.8), 11.3 (9.6, 13.1), 10.2, (8.8, 11.4) Hz, respectively, in the epinephrine, and 10.1 (10.0, 10.5), 11.7 (11.1, 14.2) (P < 0.05 vs. before DA), 13.2 (11.5, 13.9) Hz, respectively, in the vasopressin group at the same points in time. Median frequency correlates significantly with myocardial blood flow in the epinephrine (n = 21); rs = 0.772; P < 0.001) and in the vasopressin group (n = 21; rs = 0.905; P < 0.001). Median fibrillation frequency before the first defibrillation was 13.0 (12.2, 13.2) Hz in resuscitated (n = 8) and 9.2 (8.3, 10.2) Hz (n = 6) in non-resuscitated animals (P < 0.01). CONCLUSIONS: We conclude that median frequency of VF reflects myocardial blood flow and the chance of successful defibrillation during closed chest CPR after vasopressor treatment in a porcine model of VF. PMID- 8701112 TI - Controversies in resuscitation: to infuse or not to infuse (2) PMID- 8701113 TI - [The association of self-rated health and mortality--a 7-year follow-up study of a Japanese community]. AB - This study aims to examine whether self-rated health is an independent predictor of cause-specific mortality even after the influence by a variety of factors in relation to mortality reported by previous studies have been excluded. This study included randomly selected 4,259 inhabitants (1,827 men and 2,432 women) in Y city, Fukuoka prefecture, Japan, aged from 30 to 79 in 1987. These subjects were surveyed in 1987 by self-administered questionnaires regarding self-rated health as well as life habits, and followed up for their vital status and underlying causes of death. After excluding the individuals who were lost to follow up or who didn't respond to the question on self-rated health, 4,046 individuals were analysed to see the relationship between self-rated health and cause-specific mortality by Cox proportional hazard models, controlling for sex, age, smoking, BMI, medical care use and ADL. It was shown that relative risks for all causes, cancer, circulatory disease and other causes among the unhealthy group were 2.95 (95% CI: 1.93-4.50), 2.96 (1.53-5.73), 2.32 (0.86-6.26) and 4.09 (2.12-7.89), relatively. In the analyses of the subgroup (subjects without diseases in 1987 or subjects excluding deceased cases within first 3 years after follow-up), to avoid selection bias, the association between self-rated health and mortality was substantially similar to the results obtained in the former analysis, even the association was weakened. Even after excluding both of the subjects with diseases in 1987 and the subjects who died in the first 3 years after follow-up, self rated health could be associated with mortality from all causes (RR = 1.89, 95%CI; 0.91-3.94). From the results it is suggested that self-rated health itself can be the independent predictor of mortality. PMID- 8701114 TI - [A sero-epidemiological study on atrophic gastritis and Helicobacter pylori infection]. AB - The aim of this study is to clarify the relationship between the incidence of atrophic gastritis and Helicobacter pylori infection. A case control study was conducted in 1995. Cases and controls were selected among those who took an annual health examination in a rural area of Fukuoka Prefecture. Cases are those who were not diagnosed as having atrophic gastritis in 1991 or 1992 but were diagnosed as having atrophic gastritis in 1995 by the examination of serum pepsinogens. Controls are those who were not diagnosed as having atrophic gastritis between 1991, or 1992 and 1995. Helicobacter pylori infection was evaluated by anti Helicobacter pylori IgG in 1995. The odds ratio for atrophic gastritis was calculated using Logistic regression analysis. The odds ratio of age and sex was not significant, but the odds ratio of Helicobacter pylori infection was significantly elevated (5.2, 95% confidence interval: 2.08-13.17). As for the influence of sex difference on the incidence of atrophic gastritis by Helicobacter pylori infection, the odds ratio among males was not significant (1.4, 95% confidence interval: 0.30-6.10), but the odds ratio among females was significantly high (9.8, 95% confidence interval: 2.82-34.11). These results suggest that Helicobacter pylori infection is associated with the incidence of atrophic gastritis. There may be a risk difference between males and females in the incidence of atrophic gastritis caused by Helicobacter pylori infection. PMID- 8701115 TI - Comprehensive care for hemophiliacs--activities of North Kyushu Hemophilia Center at the University Hospital of Occupational and Environmental Health, Japan. AB - One of our objectives in establishing the Hemophilia Center was to create a model of a total care system for chronic diseases which develop in the childhood and continue through adulthood. We also believe that the comprehensive medical care system should be introduced not only for the care of hemophiliacs but also for those with every chronic refractory disease. It may be a surprise that in a university hospital, which is likely to lack cooperation between departments, this kind of cross sectional support system, even extending to activities outside the hospital, has been continued. This success owes much to the understanding and consideration by successive Directors of the Hospital and the Professors (Directors) of every department, the enthusiastic efforts by members of the Center who have continued their volunteer work for the purpose of improving the QOL of patients, and the cooperation by students of the Volunteer Study Club. We also have to mention the advice and guidance by Dr. Minoru Inagaki (now at the National Children's Hospital) who established the first substantial hemophilia center in Ogikubo Hospital, and Dr. Kaneo Yamada, present Visiting Professor in the Faculty of Medicine, St. Marianna University. We would like to thank every one who has supported the activities of the Center. Finally, we strongly hope that this total care system will become popular among those responsible for caring of patients with other chronic refractory diseases. PMID- 8701116 TI - [Analysis of financial statements of Japanese private hospitals (1982-1991)]. AB - In order to clarify the financial situation of Japanese private hospitals, the financial statements provided by the Social Welfare and Medical Service Corporation were analyzed for the period from 1982 to 1991. The results clarified the low growth rate and low profitability of the Japanese private hospitals, although their financial situation was relatively stable. However, the efficiency of cost has been stalled in recent years and profitability has been declining due to the low turnover rate of capital. According to the CVP analysis, the Profit volume ratio of the investigated hospitals has been increased to the level of 95%. This situation means that, in the current financial situation, more than half of the Japanese private hospitals will go into the red if revenue declines 5% due to some short term change in the managerial environment. PMID- 8701117 TI - [50th anniversary...]. PMID- 8701118 TI - [Hematopoietic growth factors]. PMID- 8701119 TI - [Cyclosporin A (Sandimmun)]. PMID- 8701120 TI - [Corticotherapy: half a century of fortune and misfortune]. PMID- 8701121 TI - [Calcitonin]. PMID- 8701122 TI - [Biphosphonates]. PMID- 8701123 TI - [Nonsteroidal anti-inflammatory drugs]. PMID- 8701124 TI - [Morphine]. PMID- 8701125 TI - [Anesthetics]. PMID- 8701126 TI - [35 years of estrogen-progestagen pills: where is the vascular risk?]. PMID- 8701127 TI - [The therapeutic contribution of prostaglandins in obstetrics]. PMID- 8701128 TI - [Retinoids]. PMID- 8701129 TI - [Topical corticoids]. PMID- 8701130 TI - [Beta-blockers]. PMID- 8701132 TI - [Angiotensin-converting enzyme inhibitors]. PMID- 8701131 TI - [Calcium channel blockers in the treatment of arterial hypertension]. PMID- 8701133 TI - [History and trends in the treatment with diuretics]. PMID- 8701134 TI - [Fibrinolytics. Development and current application]. PMID- 8701135 TI - [Antitubercular agents]. PMID- 8701136 TI - [From penicillin to the progress in beta-lactams. Chronicle of a 50th anniversary]. PMID- 8701137 TI - [Fluoroquinolones]. PMID- 8701138 TI - [Antiepileptic drugs]. PMID- 8701139 TI - [L-dopa and antiparkinson agents]. PMID- 8701140 TI - [Neuroleptics or antipsychotic agents]. PMID- 8701141 TI - [Aspirin, an always current drug]. PMID- 8701142 TI - [Benzodiazepines]. PMID- 8701143 TI - [Antidepressive agents]. PMID- 8701144 TI - [H2 inhibitors and protein pump inhibitors]. PMID- 8701145 TI - [Insulin: 1921-1996]. PMID- 8701146 TI - [Hypoglycemic sulfamides, 50 years after Loubatiere]. PMID- 8701147 TI - [Growth hormone, therapeutic with unclear limitations]. PMID- 8701148 TI - [Statins. From LDL receptor to cardiovascular protection]. PMID- 8701149 TI - [Digestive system endoscopy and ultrasonography]. PMID- 8701150 TI - [Endoscopic retrograde cholangiopancreatography]. PMID- 8701151 TI - [Endoscopic retrograde cholangiopancreatography: management of a hospitalized patient]. PMID- 8701152 TI - [Endoscopic sphincterotomy: treatment of common bile duct lithiasis]. PMID- 8701153 TI - [Biliary-pancreatic endoscopy: other therapeutic indications]. PMID- 8701154 TI - [Neoplastic stenoses of the biliary ducts: palliative endoscopic treatment]. PMID- 8701155 TI - [Laparoscopic colectomy: history of a hospitalization]. PMID- 8701156 TI - [Endoscopy by nurses?]. PMID- 8701157 TI - [Surgical practice: staggering changes in practice]. PMID- 8701158 TI - [Uterus and adnexa: abdominal surgical approach]. PMID- 8701159 TI - [Common bile duct lithiasis: diagnosis and treatment]. PMID- 8701160 TI - [What is your diagnosis? Right bundle-branch block]. PMID- 8701161 TI - [Rhythmology in clinical practice]. PMID- 8701162 TI - [Diagnostic electrophysiological studies]. AB - Clinical cardiac electrophysiology has evolved over the last decades as a technique to study arrhythmias. Programmed stimulation is a potent tool in assessing the detailed mechanisms of most brady- and tachyarrhythmias as well as a method to judge the efficacy of antiarrhythmic therapy and to stratify patients at risk for the development of life-threatening sustained ventricular arrhythmias. We give an overview of the physiologic mechanisms responsible for paroxysmal supraventricular tachycardias, pre-excited tachycardias as well as sustained ventricular tachycardia in coronary artery disease. Benefit and limitations in assessing the risk for life-threatening tachyarrhythmias in clinically important situations are briefly discussed. PMID- 8701163 TI - [Therapeutic electrophysiology]. AB - Due to tremendous technical progress during the last decade, electrophysiology offers now a therapeutic option to patients suffering from cardiac arrhythmias owing to radiofrequency catheter ablation. This article focuses particularly on the different radiofrequency ablation approaches used in the most common encountered supraventricular arrhythmias. PMID- 8701164 TI - [Atrial fibrillation]. AB - Atrial fibrillation is the most common arrhythmia the general practitioner as well as the physician in the hospital has to deal with. Even if it is said to be benign, heart failure and embolism may be deleterious consequences of this arrhythmia. In this article we well discuss the management of this arrhythmia, taking into consideration the etiologic factors, the pathophysiology of atrial fibrillation and therapeutic aspects from cardioversion to prevention of embolism. PMID- 8701165 TI - [Late ventricular potentials: significance, electrophysiology and clinical importance in coronary disease]. AB - Ventricular late potentials are high-frequency, low-amplitude abnormal electrical signals occurring in the terminal QRS complex or on the ST segment of the electrocardiogram during sinus rhythm. They are thought to represent delayed activation of some areas of a diseased myocardium and are therefore considered as a marker of an arrhythmogenic substrate, especially in patients after myocardial infarction. An association between the presence of ventricular late potentials and the occurrence of malignant re-entrant ventricular arrhythmias has been clearly demonstrated, and the prognostic value of late potentials after myocardial infarction has been confirmed by several large prospective trials. Because it is a simple and noninvasive technique, the detection of ventricular late potentials allows a first risk stratification of postmyocardial infarction patients, together with the Holter recording, the exercise stress test, the echocardiography and the radionuclide ventriculography. Such a risk stratification strategy is essential because the empirical use of antiarrhythmic drugs has been associated with an adverse prognosis and because significant advances have been made in the management of malignant ventricular arrhythmias. The clinical value of ventricular late potentials is mainly related to their negative predictive value (93 to 98%), and their positive predictive value has been shown to be low (6 to 19%). But even if the prognostic value of late potentials after myocardial infarction is now well established, their exact role for the management of individual patients still needs to be defined. PMID- 8701166 TI - [Role of calcium antagonists in the treatment of acute coronary syndromes]. PMID- 8701167 TI - [Comparison between ski and snowboarding accidents. Current overview from the ski area Arosa (Switzerland) (1988/89 to 1994/95)]. AB - The ski resort of Arosa (Switzerland) is geographically isolated and has recorded it winter sports accidents since 1969. Based on this reliable data, the ski (3877 in total) and snowboard (512 in total) accidents of the last seven years were statistically analyzed. The study showed that snowboarding isn't much more dangerous than skiing the number of accidents was about the same in both groups, whereas snowboarders were less likely to be admitted to a hospital or to get injured by collision. The average age of snowboarders was 21.6 years, almost 20 years lower than that of the skiers. Both sexes were about equally represented. Most snowboarders had injuries of the upper extremity (14% fractures of the radius, 9% distortions), particularly because of falling backward after losing balance. In both groups (skiers and snowboarders) 60% of all injuries were of low grade, which did not lead to long absence from work. The results are discussed and compared with already existing publications. PMID- 8701168 TI - [Prevalence of tuberculosis in Swiss hospitals in the years 1990 to 1993]. AB - The medical statistics of VESKA (Association of Swiss Hospitals), MSV, comprise and include the spectrum of all diseases in patients admitted to Swiss hospitals which are members of the association. Documentation is carried out in accordance with the WHO ICD code. Tuberculosis is registered under the main figures 010 to 018. The MSV makes an essential contribution in a special area to the recording of tuberculosis in Switzerland. The ICD code classes the disease either in positions 1 to 3 as the category of "all (TB) diagnoses' or as "principal diagnosis' in the first place. The numerical values are either recorded individually for the years 1990 to 1993 or as mean values of these four years. Tuberculosis occupies a small space within the overall statistics. Of a total of 722 868 and 369 840 coded diagnoses (1990 to 1993, averages), 1100 and 627, respectively, fall under tuberculosis in the two categories. This corresponds to a proportion of 0.15% and 0.17%, respectively. Tuberculosis becomes more important because the general average hospital stay of 12.7 days is almost doubled with an average of 24.7 days for tuberculosis patients. If the costs per case generally stand at Sfr. 7353.-, then, for tuberculosis patients, they rise to Sfr. 14 301.-. The overall costs for tuberculosis patients per calendar year total Sfr. 15 731 430.- and Sfr. 8 966 915.-, respectively, in the two categories. Tuberculosis is, therefore, a disease which is still of economic significance even in Switzerland. In the category of types of tuberculosis, pulmonary tuberculosis (011) still today occupies first position compared to previous analyses with current figures of 65.1% and 67.7% respectively. In the case of the extra-pulmonary types, uro-genital tuberculosis (016) stands in second place with 5.7% and 3.5% in the two categories, after the group of tuberculosis of other organs (017) with 5.9% and 6.1%, respectively. There was a constant preponderance of male over female patients (64.3% vs. 35.6%). If decades ago tuberculosis shifted to and was spread over more advanced age groups in Switzerland, the proportion of foreigners now within the whole population has brought about a change. Almost twice as many tuberculosis cases occur within the 20-year to 40-year age group than in the other age groups, in which a certain degree of levelling off is apparent. From comparisons of notifications to authorities in Switzerland and from hospitalization rates, it can be deduced that there is no increased need for hospitalization for any particular age group. PMID- 8701169 TI - [Our knowledge is patchwork. Survey on the adherence to international guidelines concerning acute and long-term therapy in recurrent depressions and diseases in the schizophrenic field]. AB - In order to assess the observance of international guidelines, 88 psychiatrists and 88 general practitioners (GPs) were asked about their pharmacotherapeutic concepts for depressive and schizophrenic patients with a questionnaire. 47% of the psychiatrists and 72% of the GPs returned their answers. 29% of the psychiatrists and 24% of the GPs treat their depressive patients after an acute episode for six months (in accordance with WHO consensus). 32% of the psychiatrists and 47% of the GPs would suggest prophylactic treatment after two or more depressive episodes as proposed by the WHO. After one or more episodes within the last five years 2.7% of the psychiatrists and 12% of the GPs would start prophylactic treatment as suggested by the WHO. 16% of the psychiatrists and 17% of the GPs would treat a schizophrenic patient after a first episode for 12 to 24 months as proposed by the International Consensus Conference. After two or more psychotic episodes, 16% of the psychiatrists and 31% of the GPs would treat their patients in accordance with international guidelines. The consensus of the WHO for the treatment of depression and the international guidelines for relapse prevention in schizophrenics are hardly known by the examining psychiatrists and GPs and rarely used as treatment guidelines. PMID- 8701170 TI - [Check-up at 40 years of age]. AB - A chest radiograph performed on a 40-year-old patient revealed a smoothly contoured right posterosuperior opacity. CT scans demonstrated a sharply defined homogeneous mass without enhancement. In a transbronchial FNA specimen, ciliated cells were found. Transesophageal ultrasound showed a hypoechoic structure, distinct from the esophagus. The patient underwent surgical excision. The postoperative finding confirmed the diagnosis of a bronchogenic cyst. PMID- 8701171 TI - [A case from practice (353). Burning-mouth syndrome of obscure etiology: psychogenic cause in suspected generalized anxiety attack]. PMID- 8701172 TI - [Livia is not a poisoner]. PMID- 8701173 TI - [What is your diagnosis?]. PMID- 8701174 TI - [Cardiovascular diseases in the elderly]. PMID- 8701175 TI - [Orthostatic hypotension in the elderly]. AB - Orthostatic hypotension is observed in 10 to 20% of all patients aged 65 or over. The elderly is thus at an elevated risk for orthostatic hypotension; however, the relative contributions of normal ageing, of diseases and their respective treatments to its development are unknown. Orthostatic hypotension discovered by chance in a symptomatic or asymptomatic elderly patient has to be considered as risk for falls or syncopes. The most common reversible causes are side effects of various drugs and hypovolemia. Next to a specific therapy of the underlying causes, symptomatic measures are proposed. Pharmacotherapy is limited to patients incapacitated by symptoms. PMID- 8701176 TI - [Diagnosis and treatment of arterial hypertension in the elderly]. AB - The incidence of hypertension increases with age and becomes very high in the seventh decade. The increase of the blood pressure may be systolic, diastolic or both. Various controlled studies have shown that the treatment of hypertension in the elderly reduces the incidence of myocardial infarction and of stroke. It appears today that also patients with isolated systolic hypertension benefit from antihypertensive treatment. All classes of antihypertensive agents, including beta-blocking drugs, may be used in the elderly. PMID- 8701177 TI - [Diagnosis and treatment of cerebrovascular accidents of cardioembolic origin]. AB - Compared to the normal population, patients with atrial fibrillation are at a significantly enhanced risk for cerebrovascular insults, in particular when the fibrillation is of recent occurrence, chronic rather than paroxysmal, and when it is associated with cardiopathy. Several studies have documented the efficacy of anticoagulation in prevention of cerebrovascular insults. Aspirin may be a valid alternative in young patients without cardiopathy; however, anticoagulation is more effective in patients which have experienced thromboembolism. In elderly patients (over 75 years) the situation is unclear, because the favorable effects of anticoagulation are offset by an increased risk for intracerebral hemorrhage. The treatment must thus be individualized by assessment of a risk/benefit ratio. PMID- 8701178 TI - [Preventive treatment of cerebrovascular accidents of arterial origin]. AB - Inhibitors of platelet aggregation are in use for prevention of cerebrovascular insults (CVI). Aspirin at a dose of 250 +/- 100 mg/day is the most common regimen for patients at an elevated risk for vascular complications. Aspirin and ticlopidine (500 mg/day) are the best drugs for secondary prevention of arterio arterial cerebrovascular incidents. Efficacy of inhibitors of platelet aggregation in prevention of primary cerebral infarcts has not been demonstrated. An analogue of ticlopidine, clopidogrel is presently under comparison with aspirin in the prevention of CVI. Endarterectomy of the carotid has been evaluated in several studies for prevention of CVI. In patients with symptomatic carotid stenosis (70 to 99%), endarterectomy decreases the risk for cerebral infarcts by 20 to 44%. The indication for endarterectomy in patients with asymptomatic stenosis has to be posed reluctantly because of controversial interpretations of recent study results. PMID- 8701179 TI - [Cardiac insufficiency: therapeutic aspects in the elderly person]. AB - Heart failure is at the same time a muscular and a neurohormonal disease. This explains the current therapeutic choices: in particular digitalis, ACE inhibitors, spironolactone and in certain patients even beta-blocking agents. Two different types of heart failure are distinguished today: systolic failure with pump failure and diastolic failure with deranged ventricular filling. In the elderly, the two entities occur either together or individually. A precise and early diagnosis is important for an appropriate treatment to be instituted as early as possible, even in the case of asymptomatic or subclinical heart failure. PMID- 8701180 TI - [Coronary angioplasty in elderly patients]. AB - Percutaneous transluminal coronary angioplasty (PTCA) is a widely accepted treatment of symptomatic coronary heart disease providing prompt and prolonged clinical, improvement in most patients. We have examined the value of this therapy in a group of 91 patients in their eighth decade treated by 133 consecutive angioplasties. Most patients had refractory or instable angor in spite of optimal pharmacotherapy. Multivessel disease was present in 67% and maintained left-ventricular function in 92% of the patients. The angiographic success rate of PTCA was 84%; technical failures occurred in 12% and adverse events in 14%. Two patients died. The rate of symptomatic restenosis was 24%. Survival and patients free of myocardial events were at 89% and 60%, respectively, estimated by Kaplan-Meier analysis. PTCA is an efficient and acceptable treatment for the elderly patient with severe and drug-resistant angina. Two years after PTCA the majority of patients was asymptomatic. PMID- 8701181 TI - [Physical exercise and its effects on the cardiovascular system in elderly subjects]. AB - Physical capacity and exercise tolerance decrease in the elderly because of derangements of the cardiovascular and musculoskeletal systems. It is increasingly apparent that many of these alterations are not necessarily connected to ageing but rather to physical inactivity. Rehabilitation programs adapted to the individual capacities of each patient permit prevention and even reversal of organic and functional deficits of the two systems, which are sometimes at the onset of serious invalidity. The recognition of the usefulness of such programs should lead the practitioner to persuade his elderly patients to sustain a physical activity adapted to their state of health. PMID- 8701182 TI - [Assessment of ventricular arrhythmias]. AB - In the evaluation of patients with ventricular arrhythmias, those patients with asymptomatic ventricular arrhythmias, who usually comprise a low-risk population, have to be differentiated from patients with symptomatic ventricular arrhythmias (presyncopal symptoms, syncope, cardiac arrest). In general, patients with asymptomatic ventricular arrhythmias should not be treated with antiarrhythmic drugs; however, patients with recent myocardial infarction and asymptomatic ventricular arrhythmias, which may indicate an increased risk of sudden death, should undergo further risk stratification, since some of them might benefit from preventive antiarrhythmic therapy with a beta-blocking agent of amiodarone. In contrast to asymptomatic patients, patients with symptomatic ventricular arrhythmias are at high risk for sudden death, and, if functional status does not mandate against active therapy, these patients should undergo coronary angiography and electrophysiologic evaluation. Revascularization procedures and specific antiarrhythmic measures such as antiarrhythmic drug therapy, ablative therapy (surgical resection or transcatheter radiofrequency ablation of the arrhythmogenic focus) or the implantation of a cardioverterdefibrillator (ICD) are frequently needed in such patients. Consequently, in this high-risk population, early referral to a cardiac center with an electrophysiologic laboratory is recommended, whereas it should be strongly mandated against empirical antiarrhythmic drug therapy. PMID- 8701183 TI - [Sudden cardiac death: definition, mechanisms and risk factors]. AB - Sudden cardiac death is defined as natural death due to cardiac causes, heralded by abrupt loss of consciousness within one hour after the onset of symptoms. The mechanisms are the following: 1. ventricular fibrillation, 2. ventricular tachycardia and flutter with subsequent ventricular fibrillation, 3. torsade de pointe, 4. bradyarrhythmias and asystolic arrest. White the main risk factor is the presence of coronary artery disease, any organic or functional disease of the heart can predispose for sudden cardiac death. To evaluate the risk of sudden cardiac death noninvasive (Holter, echocardiography, exercise test and signal averaged (ECG) and often invasive (electrophysiological study) tests are necessary. The therapy is based on drugs (mainly beta blockers and amiodarone), coronary revascularization, catheter ablation techniques and the implantation of a cardioverter defibrillator; the latter appears to be the most promising approach. PMID- 8701184 TI - [Prevertebral cervical phlegmon with spinal epidural abscess as complication of diabetes mellitus]. PMID- 8701185 TI - [Jaundice, anemia and mitral valve insufficiency following mitral valve reconstruction]. AB - A 33-year-old man was admitted because of jaundice. Five months ago a reconstruction of the mitral valve was performed because of mitral valve insufficiency. There was a history of heroin dependence until three years ago. Laboratory tests showed normochromic normocytic anemia, increased nonconjugated serum bilirubin, decreased plasma haptoglobin, hemoglobinuria and hemosiderinuria. The peripheral blood smear contained numerous fragmented red cells, and the bone marrow showed a markedly increased erythropoiesis and absent iron stores. The clinical examination as well as echocardiography revealed severe mitral valve insufficiency; therefore, a mitral valve replacement was performed. Introperatively the mitral valve showed ruptured chordae tendineae of the posterior leaflet and a leaking stitch of the anterior leaflet. We diagnosed a macrovascular hemolytic anemia with subsequent mechanical injury and fragmentation of red cells on a dysfunctioning mitral valve. PMID- 8701186 TI - [A case from practice (342). Neuroendocrine tumor of the anterior mediastinum. Atypical nevocellular nevus]. PMID- 8701187 TI - [Left-ventricular hypertrophy and left heart insufficiency: towards cause oriented therapy]. PMID- 8701188 TI - [From left hypertrophy to heart insufficiency: hemodynamic and clinical findings]. AB - The pathophysiology of left-ventricular hypertrophy is characterized by structural remodeling with increasing content of collagen and development of ventricular dilatation ('Gefugedilatation'). According to recent clinical view points, three stages may be distinguished: first stage, compensation, second stage, diastolic dysfunction with delayed relaxation and decrease of the passive elastic properties, third stage, systolic and diastolic dysfunction with decreasing pump function and signs of left-ventricular failure. Diastolic dysfunction is linked to delayed rotation during isovolumetric relaxation (delayed 'untwisting') which leads to decreased ventricular filling. These changes of the myocardial adaptation process may be prevented and the vicious circle interrupted by appropriate therapeutic strategies. PMID- 8701189 TI - [Left-ventricular hypertrophy as a cardiac risk factor: role of the renin angiotensin-aldosterone system]. AB - Left-ventricular hypertrophy is the result of cardiac adaptation to global or regional overstress and represents an important cardiovascular risk factor, increasing the risk for development of congestive heart failure and incidence of sudden death. This review describes the pathophysiological and biochemical mechanisms involved in the development of left-ventricular hypertrophy and cardiac fibrosis with particular emphasis on the role of angiotensin II and aldosterone. Central to the cascade of cardiac fibrosis is the increased production or reduced degradation of collagen proteins in fibroblasts. Collagen proteins are proteins needed for the alignment of cellular compartments and the development of forces, contraction and relaxation of the heart. If overexpressed, an important rise of wall stiffness is observed in addition to a reduced capacity to provide oxygen to the cardiac tissue. This latter explains why in areas of histologically hypertrophied heart muscle atrophied muscle cells are observed. The characterization of the second-messenger systems involved in the regulation of cardiac cells as well as the identification of angiotensin-II receptor subtype and angiotensin IV is described. Both of these receptors are present on cardiac fibroblasts and stimulate these to collagen production, which can be inhibited by antagonists or the generation of angiotensin II by ACE inhibitors. In some forms of left-ventricular hypertrophy and in patients with congestive heart failure in addition to elevated angiotensin-II levels, increased aldosterone levels are observed. Aldosterone raises upon stimulation by angiotensin II and upon reduction of angiotensin-II generation subsequent to ACE inhibition through an escape mechanism. The contribution of aldosterone to left-ventricular hypertrophy and cardiac fibrosis can be prevented and reduced by the administration of its antagonist, spironolactone. Further and larger clinical trials are needed and in progress to evaluate if the combination of an ACE inhibitor with spironolactone potentiates the reduction of left-ventricular hypertrophy and if this translates in a reduction of the cardiovascular risk. PMID- 8701190 TI - [Sympathetic nervous system and endothelial function in heart failure]. AB - Congestive heart failure is a frequent cardiovascular disease with a poor prognosis in advanced stages. Activation of neurohumoral systems such as the renin-angiotensin system and the sympathetic nervous system as well as impairment of local regulatory mechanisms (i.e. adrenoceptors, endothelial factors) play an important role in the pathogenesis and prognosis of the disease. The increase in peripheral resistance is due to imbalance of vasoconstrictors and vasodilators in favour of the vasoconstrictors and to changes in endothelial function, i.e. impaired production of nitric oxide, increased production of endothelin. Sodium and volume retention as well as the activation of the renin-angiotensin system increase preload. The sympathetic nervous system, which is known to be an independent negative prognostic factor, is activated and interacts with the renin angiotensin system; however, up to now it is uncertain, whether these pathophysiological findings contribute to the development of congestive heart failure or if they are only secondary phenomena. PMID- 8701191 TI - [Therapy-oriented assessment of heart failure in the hospital and clinical practice]. AB - Heart failure represents a complex of symptoms caused by heart disease. The understanding of the underlying pathophysiological changes due to myocardial damage are crucial for an optimal diagnostic evaluation and treatment. The use of vasodilators and ACE inhibitors has led us to realize that the modulation of the neurohumoral system plays an eminent role in the morbidity and for survival of heart failure patients; therefore, the goal must be to recognize as early as possible myocardial damage, preventing the devastating effects of neurohumoral activation. This paper illustrates this aspect and discusses the clinically available therapeutic approaches. PMID- 8701192 TI - [Medical treatment of sleep apnea syndrome]. PMID- 8701193 TI - [Medical practitioner's attitude in case of suspected pulmonary embolism]. PMID- 8701194 TI - [Asthma in children: practical aspects of inhalation techniques]. PMID- 8701195 TI - [Endo-orbital decompression on Basedow exophthalmia]. PMID- 8701196 TI - [Breakfast--composition and nutrients. Intermediate effects]. PMID- 8701197 TI - [Nature and antibiotic sensitivity of bacterial species isolated in secretory otitis in a cohort of children]. PMID- 8701199 TI - [Tell me how you suffer and I will tell you...]. PMID- 8701198 TI - [Evolution of bacterial species and their sensitivity to antibiotics in the laboratory of a small hospital]. PMID- 8701200 TI - [The beginnings of anesthesiology in Lausanne. Observations concerning Rene Bussien's article in RMSR, 115:925-930, 1995]. PMID- 8701201 TI - [Small-cell bronchial cancer]. PMID- 8701202 TI - [Non-small-cell bronchial cancer: medical approach]. PMID- 8701203 TI - [Non-small-cell lung cancer: surgical approach]. PMID- 8701204 TI - [Obstructive sleep apnea syndrome: various diagnostic aspects]. PMID- 8701205 TI - [Sleep apnea syndrome and snoring: the ENT approach]. PMID- 8701206 TI - Biology, Biochemistry and Clinical Usefulness of Tumor Markers. The 23rd Meeting of the International Society for Oncodevelopmental Biology and Medicine. September 10-13, 1995. Montreal, Canada. Abstracts. PMID- 8701207 TI - Ethics in action. A cardiac patient has just signed a consent form agreeing to participate in a clinical trial. PMID- 8701208 TI - Laparoscopic bowel resection? PMID- 8701209 TI - A road map for stroke recovery. PMID- 8701210 TI - Chemo quick guide: antimetabolites. PMID- 8701211 TI - In this issue: battling the super bugs! PMID- 8701212 TI - An easy way to document patient ed. PMID- 8701213 TI - Restoring electrolyte balance: calcium & phosphorus. PMID- 8701214 TI - Day care consulting: it isn't kids' stuff. PMID- 8701215 TI - The legal risks of managed care. PMID- 8701216 TI - Studies and more studies. PMID- 8701217 TI - OTC NSAIDs: patients need to know about side effects. PMID- 8701219 TI - We cut costs without cutting staff. PMID- 8701218 TI - Coming through the fire. PMID- 8701220 TI - Spotting an MI before it's an MI. PMID- 8701221 TI - CAPD with only one arm? PMID- 8701222 TI - Chemo quick guide. Antitumor antibiotics. PMID- 8701223 TI - Assessing children--it's different. PMID- 8701224 TI - Take action before anger builds. PMID- 8701225 TI - On the road with a home health nurse. PMID- 8701226 TI - Nurses are embracing holistic healing. PMID- 8701227 TI - When communication breaks down. PMID- 8701228 TI - Can melatonin cause severe headaches? PMID- 8701229 TI - My car, myself. PMID- 8701230 TI - Longitudinal studies of dependence in daily life activities among elderly persons. AB - Ability in activities of daily living (ADL), use of assistive devices, and relation to functional limitations and impairments were studied among persons between 70 and 76 years of age within the Inter-Vention study of Elderly in Goteborg (IVEG) Sweden. An ADL index was developed including instrumental activities (I-ADLs) (cleaning, shopping, transportation and cooking), which was combined with Katz' Index of personal daily life activities (P-ADLs) (bathing, dressing, going to the toilet, transfer, continence and feeding). Independence of and dependence on assistance from another person was assessed and it was possible to classify performance according to an ordinal scale of ADL-steps. The reliability and validity of the scale were tested in an out-patient sample (n = 85) as well as in a population of 76-year-olds (n = 659) and were found to be sufficient (coefficients of reproducibility and scalability, internal consistency, inter- observer reliability, content, construct, and criterion validity). The "Staircase of ADL" can be used for observation and documentation of different levels of ability/disability for individuals, groups and for population studies. Most persons (83%) were independent in all activities at age 70 (n = 617). Among survivors followed longitudinally, the incidence of disability was 8% between 70 and 73 and 26% between 73 and 76 years of age. Dependence at age 70 could predict mortality as well as institutionalization. No sex differences were found in the proportion with overall disability. Assistance given by relatives dominated both at 70, 73 and 76 years of age. One fifth at age 70 and almost half of the population at age 76 used assistive devices (AD) in daily life activities, and the use was more frequent in women (52%) than men (37%) at age 76 (n = 595). During the studied age interval, 39% "new users" were found, while 22% were "temporary users". The usage rate was high and the effectiveness of ADs increased the person's ability to master the situation, especially evident as increased safety and reduction of effort in activities of daily living, implying a reduced degree of handicap. Physical impairments and functional limitations had a considerable impact on dependence in daily life activities as persons dependent in ADL had lower maximal walking speed, grip strength, knee extensor strength, stair-climbing capacity and forward reach than those who were independent in ADL (n = 602). Walking speed in both women and men and sight impairment in men had the greatest influence on dependence in ADL. Women and men who stayed independent over the period (70-76) had significantly higher maximal walking speed and knee extensor strength at the age of 70 than those who became dependent or were dependent on both occasions. PMID- 8701231 TI - Prevention of occupational musculo-skeletal injuries. Labour Inspectorate investigation. AB - The present study was undertaken to investigate the effect on ergonomic conditions by Labour Inspectorate intervention at the work place and to follow health and employment among occupationally injured. 195 reports on occupational musculo-skeletal injury (accidents and diseases) from men and women with different occupations were collected consecutively at three Labour Inspectorate offices. Fifteen Labour Inspectors volunteered to investigate half of the reports by work place visits within three months. The other half was kept for control. The inspectors were trained in ergonomics and also got complementary training in ergonomic work place assessment. A check-list was designed for the purpose and tested for validity and reliability. Eighteen months after the time of the injury reports, all work places were visited by ergonomists to evaluate possible improvements in ergonomic conditions. Due to turnover and prolonged sick-leaves, evaluations were performed for only 92 of the injured. At 160 work places other employees had performed similar tasks as the injured at the time of the injury report. Evaluations of possible improvements in ergonomic conditions were performed also for these employees. As regards changes at the work place there were no differences between the injured in the study and control groups. The inspectors had delivered 11 inspection notices to the employers demanding improvements for the injured and 14 notices regarding the conditions of work mates. For this latter group there was a significant association between delivered notices and improved ergonomic conditions eighteen months after the reports. Three years after the time of the reports a postal questionnaire on health, psychological well-being and employment was distributed to the injured. The response rate was 93%. Questionnaire answers were compared to results from other studies, where identical questions were used. There was a significantly higher prevalence of musculo-skeletal and psychological symptoms in the study group compared to data from population groups. Activities in daily life were more restricted in the study group. 109 persons were in active employment. The association between the two effect measures improved ergonomic conditions and active employment, and both individual and work-related characteristics was analysed. The odds for improved working conditions were increased where the employer had given an informative injury description in the injury report, probably indicating that an understanding of the mechanisms of injury is a prerequisite for effective prevention. Sick-leaves for more than 6 months during the year following the report had a significant negative association with active employment, whereas male sex and higher education, respectively, had a positive association. The studied musculo-skeletal injuries were associated with a high prevalence of physical and psychological symptoms. Identification and investigation of ergonomic hazards, as appearing in informative reports on the origin of injuries and in inspection notices, seemed to have a positive influence on the process of prevention. PMID- 8701232 TI - Aphasia, dichotic testing and defective hearing. AB - Cerebral lesions causing aphasia are often found close to auditory areas. The aphasia may therefore sometimes be aggravated by hearing problems, which are concealed by communicative restrictions. Unilateral lesions of the cerebral auditory system influence the functional ear preference disclosed by dichotic tests. For that reason we have examined aphasic patients with recent, initial, unilateral brain infarctions for ear preference with regard to dichotically presented two syllable words. In a consecutive series of 114 patients who could cope with the test, 29 showed signs of an acquired left ear advantage (LEA). All were offered, and 22 accepted a full scale audiological examination including pure tone, speech and phase-audiometry. Nine of these patients showed retrocochlear or central hearing disturbances, which added to their communicative predicaments. The LEA of 11 patients lacked audiological rationales and a compensatory shift of cerebral speech-lateralization cannot be excluded. PMID- 8701233 TI - A 5-year psycho-medical follow-up study of coronary by-pass artery graft patients. AB - This is a 5-year follow-up study of coronary artery by-pass graft (CABG) patients. Our aim was: To study the development of previously rated psycho medical aspects, with special reference to depression among the CABG patients. The patients were sent two questionnaires, one of which focused on psycho-medical factors and the other on depression. The average rate of participation was 80%. The most important results were that previously high levels of depression were no longer to be found and that post-operative depression among the CABG patients clearly disappears over time. PMID- 8701234 TI - A criterion for stability of the motor function of the lower extremity in stroke patients using the Fugl-Meyer Assessment Scale. AB - A test-retest reproducibility study was performed to define a criterion for stability as opposed to change of motor function of the lower extremity in stroke patients. Forty-nine patients with stroke were examined twice by the same physiotherapist, using the Fugl-Meyer Assessment Scale. The interval between both measurements was three weeks. The mean differences between the first and the second measurement were small, with 0.04 points for the lower extremity scale and 0.92 points for the balance scale, respectively. Intraclass correlation coefficient for the lower extremity scale was 0.86, and 0.34 for the balance scale. The standard error of measurement for each scale was 1.76 and 1.17 points, respectively. The standard error of measurement can be transformed in an 'error threshold', which is a criterion to differentiate real changes from changes due to chance variation or measurement error. As the absence of real change is a parameter for stability, a change of less than 5 points for the lower extremity scale and of less than 4 points for balance confirms stability of motor function. PMID- 8701235 TI - Connection between smoking and back pain--findings from an Icelandic general population study. AB - The association between pain in general, back pain and smoking was studied in a sample of subjects from the general public (n = 862). The results show that smoking men had pain problems more frequently than women (p < 0.0001). In comparison with non-smokers, smokers were found to have back pains more frequently (p < 0.01). Male smokers were also found to have a higher frequency of intervertebral disc problems than female smokers (p < 0.009). The frequency of disc problems encountered by the smoking subjects indicates a possible connection between smoking and back pain. PMID- 8701236 TI - Long-term sickness absence due to musculoskeletal disorders: the necessary intervention of work conditions. AB - To make rehabilitation of musculoskeletal disorders effective it is crucial to identify circumstances that tend to support the persistence of sickness absence. A total of 93 patients with recently developed disorders in the neck and shoulders were followed for one year after rehabilitation, in order to identify factors associated with recovery and chronicity, respectively. Health status was evaluated before rehabilitation and after 12 months in terms of sickness absence, pain ratings and self-rated quality of life, the Sickness Impact Profile. The study group was divided into tertiles based on their number of days of sickness absence during the follow-up period (short: < 25 days, medium: 25-101 days, long: > 101 days). Those with long-term sickness absence perceived higher physical and mental load in their jobs. There was also a higher proportion of persons who were not born in Sweden in this group and on average they had more sick-leave days the preceding year. Other background characteristics and personality ratings were similar between the groups. Long-term sickness absence was associated with worse ratings in quality of life after one year, and pain did not diminish during the follow-up year. Multiple regression analysis indicated that long-term sickness absence was largely associated with work conditions rather than with individual characteristics. Therefore, the results underscore the importance not only of treating the individual with musculoskeletal disorders, but in particular of improving his or her work conditions. PMID- 8701237 TI - A pilot study of rehabilitation at home after stroke: a health-economic appraisal. AB - This study aimed at describing the health-economic implications and organisational issues of rehabilitation at home in south-west Stockholm of 15 acute stroke patients, mean age 68.2, male:female ratio 9:6, independent in feeding and continent one week after their stroke. Average patient satisfaction with different dimensions of care was 92%. Perceived dysfunction, by means of the Sickness Impact Profile, 3 months after stroke was highest for Recreation-and Pastime, Home Management and Ambulation. Between 3-12 months after stroke, functional improvement was particularly seen in Home Management, Recreation-and Pastime and Emotional Behaviour. Three fourths of the patients received help with different ADL tasks from a family caregiver and 1/5 from home service assistants. According to the scores for subjective health of the spouses and time used to help the patient, the burden that the programme put on the patient's family was modest, temporary and in accordance with preferences reported by the elderly in Sweden. The mean duration of hospital stay for patients under rehabilitation at home was 14 days and for a selected comparison group with similar ADL-grade, 27 days. The mean number of therapy sessions at home was 11. Each home visit took 3.2 hours, 60% of which were direct patient time. In the selected comparison group, 1/3 was referred to other departments for rehabilitation and care, and 40% had contacts with day-care and paramedical professionals after discharge from the hospital. During the first year after stroke, the average, direct, per capita cost for rehabilitation at home amounted to SEK 127,730 divided between hospital care (50%), followed by contribution by family caregivers (18%), rehabilitation at home (10%), out-patient visits to physicians and nurses (8.8%), home-help service (7%), auxiliary equipment (2%), medication (1.5%), home adaptation (1%) and transportation service (0.3%). This organisational model of home-based rehabilitation of stroke patients constitutes a feasible, possibly less expensive alternative and complement to current rehabilitation in hospital and primary care, which could be further developed and evaluated. PMID- 8701238 TI - [ARDS caused by military zinc fumes exposure]. AB - A previously healthy 19-year-old male was exposed to concentrated hexite smoke (ZnCl2) for several minutes during military training. The initial symptoms (vomiting, cough, dyspnea) disappeared after a few hours. After 48 hours the patient developed acute respiratory distress syndrome requiring tracheal intubation and mechanical ventilation for 8 days. He left hospital 10 days after extubation. Spirometry at this time revealed a restrictive defect (vital capacity 50% predicted). Four months after the accident the patient had returned to work without symptoms of respiratory insufficiency. Lung function tests had normalized with the exception of a slight reduction in carbon monoxide diffusion. This case illustrates the typical course of inhalative intoxication with hexite. It underlines the importance of prolonged clinical surveillance in view of the latency between the initial symptoms of hexite intoxication and possible later development of ARDS. PMID- 8701239 TI - [Risk stratification following myocardial infarct]. AB - In recent decades, early mortality of acute myocardial infarction has decreased from above 30% to below 10%. Many survivors of acute myocardial infarction are at increased risk for cardiac death and/or nonfatal recurrent ischemic events. This has not changed with the introduction of thrombolysis. How can high risk patients be identified who would benefit from coronary revascularization and/or from antiarrhythmic treatment? Based on clinical findings such as a large infarction, infarction of the anterior wall, congestive heart failure, cardiogenic shock during the acute phase, post-infarct angina and a history of previous infarctions, high risk patients who should undergo coronary angiography and--if feasible--revascularization can be defined. Patients with symptomatic arrhythmias should receive medical or interventional antiarrhythmic treatment. All patients who are clinically considered not to be at high risk should undergo risk stratification with signal averaged ECG, non-invasive stress testing and non invasive quantification of left ventricular function. In the presence of late potentials, ischemia during stress testing and impaired left ventricular function, further evaluation with Holter ECG or an electrophysiologic study and coronary angiography is indicated. In infarct survivors over 75 years old, the therapeutic goal is improvement of quality of life, i.e. relief of symptoms, rather than improvement of prognosis. Invasive procedures should therefore be considered only in individual patients. However, in all postinfarct survivors the assessment and treatment of cardiovascular risk factors and secondary medical prevention is mandatory. PMID- 8701240 TI - [Cerebral ischemic events: when and how to look for a cardiac embolism source?]. AB - In industrialized countries, cerebral ischemic events rank third among the most frequent causes of death. In survivors, long-term disability may result. The diagnosis and therapy of preventable causes is therefore a major task. Echocardiography has proven to be most helpful in the search for cardioembolic sources, and the transesophageal approach (TEE) is superior to the transthoracic (TTE) in this specific indication. In patients in whom a cardioembolic source can be identified by clinical examination, 12-lead surface ECG or chest X-ray, an additional echocardiographic examination is not necessary. Patients under 50 with cerebral ischemic events should undergo TEE. In patients over 70 with a contraindication for long-term anticoagulant therapy, TEE has no therapeutic consequences and should therefore not be performed. In patients aged between 50 and 70 the diagnostic procedure of choice must be considered in each individual patient. It should be kept in mind that a more aggressive approach using TEE, from which therapeutic conclusions are drawn, has not clearly been shown to improve the prognosis of patients with cerebral ischemic events. PMID- 8701241 TI - [Factor XI deficiency: do patients with hemorrhagic diathesis also have hemostasis defects?]. AB - It is well known that the extent of bleeding in patients with a deficiency of factor XI does not parallel the residual factor activity. Therefore, additional hemostatic aspects must be taken into consideration. 27 patients of 18 different families--6 with severe (FXI < 0.01 to 0.09 U/ml) and 21 with moderate (FXI 0.20 to 0.252 U/ml) factor XI deficiency--were reinvestigated regarding hemostasis including bleeding time and platelet function. 16 had an enhanced bleeding tendency, while the others--including 3 with severe FXI deficiency of < 0.01 U/ml -never suffered from bleeding complications despite delicate surgery in some. All 16 of the symptomatic patients had, besides the reduction of factor XI activity to various extents, an additional hemostatic defect: 3 had a moderate alpha/delta storage pool detect of the platelets, 11 a platelet anomaly mainly characterized by reduced ADP aggregation and 2 an isolated prolonged bleeding time of unknown cause. Synthesis of platelet thromboxane was unimpaired in all patients as tested by formation of malondialdehyde after stimulation with N-ethyl maleimide. Hence, in patients with a known factor XI deficiency diagnostic and prophylactic measures before surgery should concentrate on such additional findings. Preoperative administration of desmopressin, and not replacement of factor XI, will be the treatment of choice in these cases. PMID- 8701242 TI - [Expenses and risk of artificial knee joint: a look backward to a 20-year clinical experience]. AB - Costs and risks of implantation of prosthetic knee joints are analyzed in this retrospective study. From 1974-1993 514 primary and 34 revision arthroplasties were done in this hospital, all by the same surgeon. 98% of the patient protocols were available and analyzed, but no systematic follow-up was attempted. 82% of the patients were female; mean age at operation was 74 years. Joint destruction was caused by osteoarthritis in 75%, aseptic osteonecrosis in 10%, rheumatoid arthritis in 9% and posttraumatic arthritis in 3.5%. 75% of the patients were obese and had a body mass index > 25 kg/m2. Non-constrained unicompartmental type prostheses were used in 66%, the non-constrained multicompartmental type in 10% and the constrained total rotation knee (Engelbrecht) in 24%. Hospital mortality rate was 0.55% due to myocardial infarction and pulmonary embolism. 3 patients died of septic prosthetic joint infections 5, 7 and 71/2 years after surgery. Perioperative morbidity, typical of the age group above 70 years, was mainly due to cardiovascular and thromboembolic events and gastrointestinal bleeding. Early infection during the first postoperative year was encountered in 3 constrained total knees, but none in nonconstrained type. The calculated operative infection rate was 2.4% for the constrained type, zero for the non-constrained type, and 0.5% for the whole series. Late prosthetic infections occurred in 8 patients up to 12 years after surgery. In comparing non-constrained unicondylar and hinged types of joint replacement, the non-constrained sledge prosthesis involves considerably lower costs in terms of duration of surgery, hospital stay, blood loss, price of the implant, infection rate and difficulties of revision arthroplasty. Lower costs and risks favour the smaller unicondylar implant for use in localized degenerative or necrotic destruction, particularly of the medial compartment of the knee. Semi-constrained total condylar systems are used for more extensive degeneration without evident instability. The indication for hinged endoprostheses is restricted to revision arthroplasty and grossly unstable knees. PMID- 8701243 TI - [Reduced sympathetic nervous system activity during the cluster period of cluster headache]. AB - Cluster headache is a rare, very severe disorder that is clinically well characterized with a relatively poorly understood pathophysiology. Alterations of the hypothalamic-pituitary axis due to chronobiological changes, such as typical temporal pattern of both cluster periods and attacks, point to a central etiopathogenesis. Multiple local and systemic autonomic symptoms are compatible with an altered balance of the sympathetic and parasympathetic nervous system. In this connection, too, a central etiology is postulated. To evaluate the activation of the sympathetic nervous system, in 12 cluster headache patients we investigated the plasma catecholamines norepinephrine and epinephrine four times a day (7.00, 12.00, 17.00, 23.00) in the cluster period. In the cerebrospinal fluid we determined the transmitters norepinephrine, epinephrine, dopamine and the metabolites homovanillic acid (HVA), vanillymandelic acid (VMA) and 5 hydroxyindoleacetic acid (5-HIAA). Values of plasma norepinephrine in the morning (p < 0.01), in the evening (p < 0.01) and the daily mean value (223.8 = 58.3 nmol/ml) were significantly decreased in the cluster headache group in comparison to the control group (328.8 = 53.0 nmol/ml, p < 0.01). The plasma epinephrine showed no significant changes. In the CSF of cluster headache patients norepinephrine (p < 0.05), HVA (p < 0.01), and 5-HIAA (p < 0.01) were significantly decreased. Plasma norepinephrine was correlated with CSF values of HVA and 5-HIAA. The longer the duration of the disease, the lower the values of HVA and 5-HIAA in the CSF of cluster headache patients. Moreover, plasma norepinephrine showed a significant correlation with the duration, the intensity and the frequency of the attacks. The results of this study implicate decreased activity of the sympathetic nervous system with alteration of circadian rhythmicity during the cluster period. The decreased CSF transmitter values may support the hypothesis of a central etiopathogenesis of cluster headache. Moreover, plasma norepinephrine seems to be involved in triggering and continuing the attacks. The anatomical region in which this interface of sympathetic and neurogenic inflammatory processes might be located is the trigemino-vascular system. PMID- 8701244 TI - [Disseminated infection with Mycobacterium celatum]. AB - A 29-year-old patient with AIDS was hospitalized with weight loss, fever and cough. Mycobacterial cultures from sputum, blood and bronchoalveolar lavage became positive after 3 weeks' incubation. When using a DNA probe for identification of Mycobacterium tuberculosis complex, a weakly positive signal was obtained. Tuberculosis was suspected and treatment was started with isoniazid, ethambutol and ciprofloxacin. Sequencing of the gene of the 16S rRNA, however, identified the isolates as belonging to a new, slow-growing atypical mycobacterial species, Mycobacterium celatum (M. celatum). Treatment was modified to take into account the previously described primary resistance of M. celatum to antituberculous drugs, whereupon the patient improved. PMID- 8701245 TI - [Portal hypertension-induced stomach disease]. AB - After esophageal and fundus varices, portal hypertensive gastropathy (PHG) is the second most frequent cause of bleeding in cirrhotic patients. It accounts for 1 8% of primary upper gastrointestinal hemorrhage and 30-60% of secondary acute or chronic bleeding in the first 12 months, mainly after sclerosing therapy of varices. Endoscopy is diagnostic by showing either a typical "mosaic pattern" (mild form) or single or confluent "cherry red spots" (severe form). Helicobacter pylori or NSAID-induced gastropathy are to be distinguished. The therapeutic principles are the same as in drug therapy of esophageal varices. Secondary prophylaxis with propranolol, especially after sclerosing therapy, is recommended, but not primary prophylaxis. PMID- 8701246 TI - [Schoenlein-Henoch purpura: course in 139 children]. AB - We evaluated the records of 139 pediatric patients with Schonlein-Henoch purpura (aged 0.4 to 15.1 years, median 5.4 years), referred from 1974 to 1993 to the University Children's Hospital, Berne. An acute febrile illness preceded Henoch Schonlein purpura in 83 (60%) out of the 139 children. The purpuric papules were distributed over the lower extremities and the buttocks in 68 patients (49%), and more extensively in the remaining 71 (51%). Joint tenderness or swelling was observed in 110 patients (79%). Abdominal involvement occurred in 92 patients (66%): abdominal pain (n = 63), melena or hematemesis (n = 23), and intussusception (n = 6). The following rather rare features were observed: scrotal swelling (n = 11), neurologic involvement (n = 3), and stenosing ureteritis (n = 1). A remission lasting at least 4 weeks occurred within 4 weeks in 84, within 5-8 weeks in 19, and within 9-53 weeks in 18 out of 121 patients. A relapse was observed in 10 subjects. Renal involvement occurred in 60 patients. Severe renal involvement, defined as proteinuria exceeding 40 mg/[m2 X h], occurred in 18 of the patients with renal involvement. Progredient renal failure developed in one male. Children with renal involvement tended to be older (6.6 versus 4.1 years) and to have more prolonged extrarenal manifestations (6 versus 3 weeks). It is concluded that in children with Schonlein-Henoch purpura extrarenal involvement often lasts more than one month. Its outcome is almost always favourable. Children with heavy proteinuria tend in some cases to develop renal failure. For these patients, new treatment regimens aimed at preventing renal failure warrant evaluation in prospective controlled studies. PMID- 8701247 TI - [Coronary fistula in adults. Review with reference to personal experience]. AB - A consecutive series of 5384 coronary arteriograms was retrospectively investigated for the presence of coronary artery fistulas. 15 fistulas were found in 14 patients, corresponding to a prevalence of 0.26%. All the fistulas were small and hemodynamically insignificant. There were no fistula-associated complications. Most of the fistulas were discovered as incidental findings during an otherwise indicated coronary angiography (8 patients). In the 6 patients without other cardiac pathology, the investigation was performed because of a systolo-diastolic murmur in 2 cases, myocardial ischemia caused by a "coronary steal phenomenon" in 2 cases, and chest pain in 2 cases. With the exception of a fistula between two coronary arteries and a postoperative fistula, all of them originated from the proximal part of the coronary arteries (9 from the right, 6 from the left). Most of the fistulas drained into the main pulmonary artery (73%). PMID- 8701248 TI - [Exacerbation of pseudoparalytic myasthenia gravis following azithromycin (Zithromax)]. AB - We report the case of a 25-year-old female patient with severe aggravation of myasthenia gravis due to azithromycin which was prescribed for an influenza syndrome. One hour after the intake of 500 mg azithromycin the patient developed weakness of the legs and respiratory distress due to respiratory muscle failure. She was hospitalized in a comatose state and required intubation and mechanical ventilation for six days. Acute worsening of myasthenia gravis was observed in this patient in 1986 after parenteral administration of erythromycin. Erythromycin causing aggravation of myasthenia gravis by interfering with neuromuscular transmission is reported in the literature. The close temporal relationship between the intake of azithromycin and severe worsening of myasthenia gravis in our patient suggests that azithromycin, a new azalid antibiotic of the macrolid group, can exacerbate myasthenia gravis. We conclude that azithromycin should be added to the list of drugs to be used with caution in patients with myasthenia gravis. PMID- 8701249 TI - [Haemophilus aphrophilus as a rare cause of bacterial spondylitis]. AB - We report a case of lumbar spondylitis due to Haemophilus aphrophilus in a 36 year-old man with monoclonal gammopathy of undetermined significance. Haemophilus aphrophilus is a gram-negative capnophilic, slow growing coccobacillus, a component of the normal human flora of the oropharynx. This organism is considered an uncommon human pathogen and has been reported in the literature in only 10 cases of bacterial spondylitis. We review the bacteriological and clinical findings, predisposing conditions and the previously reported infections caused by Haemophilus aphrophilus. The patient responded well to antibiotic treatment with ciprofloxacin. PMID- 8701250 TI - [Pelvic pain of proctological origin]. AB - Pelvic pain of anorectal origin should be carefully investigated. The detailed clinical history may be sufficient to establish diagnosis and determine the etiology of anorectal pain. The diagnosis should be confirmed by complementary clinical investigations. The diagnosis of essential anorectal pain can be established only after failure of measures instituted to correct organic lesions and if pain persists. Among types of essential anorectal pain, coccygodinia and nervus pudendus entrapment are responsive to precise and effective management. PMID- 8701251 TI - [Skin manifestations of graft-versus-host reaction following bone marrow transplantation]. AB - We review the cutaneous manifestations of acute and chronic graft versus host disease (GvHD). Acute GvHD is characterized by initial itching, pain on pressure and erythema which begins on posterior auricular skin, palms and soles. The disease evolves into a typical but nonspecific maculopapular rash. Confluent rashes and follicular erythema may occur. Erosive oral lesions usually develop. The most severe variant of GvHD is toxic epidermal necrolysis, which often has a fatal outcome. The onset of chronic GvHD usually occurs more than 100 days after bone marrow transplantation and may be preceded by the acute form. The spectrum of skin changes includes lichenoid pruritic lesions with violaceous color and scleroderma-like skin involvement. Investigation of unknown rashes in these patients includes skin biopsy, which clearly differentiates leukocytoclastic vasculitis and erythema exsudativum multiforme with lymphocytic vasculitis from cutaneous manifestations of GvHD. Special stains may reveal bacteria and fungus in septicemic patients. The therapeutic options are discussed. PMID- 8701252 TI - [Mobilization and transplantation of autologous hematopoietic stem and progenitor cells from peripheral blood: principles and applications]. AB - The use of peripheral blood progenitor cells instead of bone marrow to rescue hematopoiesis has dramatically reduced the morbidity and costs of high-dose chemo/radiotherapy. The time of aplasia after the myeloablative regimen is now only 8-14 days, reducing hospital stay and use of antibiotics and red cell or platelet transfusions. Sufficient progenitor and stem cells can be obtained with a small number of leukaphereses after mobilization in the blood by chemotherapy and hematopoietic growth factors or by growth factors alone. This method constitutes the treatment of choice for patients with relapse of Hodgkin's disease and of high-grade non-Hodgkin's lymphoma. Future developments will include the definition of new indications and the search for ways to eliminate tumor cells from the graft. PMID- 8701253 TI - [Transplantation of allogeneic peripheral hematopoietic progenitor cells instead of bone marrow]. AB - In a pilot study we tested the feasibility and safety of peripheral blood precursor cells instead of bone marrow cells for allogeneic transplantation. 13 patients, 7 male and 6 female between 24 and 52 years of age with hematological malignancies (10 with acute leukemias, 3 with myeloproliferative syndromes-were conditioned for bone marrow transplantation with VP-16, cyclophosphamide and total body irradiation followed by graft-versus-host disease prophylaxis with cyclosporin and methotrexate. Precursor cells were mobilized in the donors by granulocyte colony stimulating factor (G-CSF, Neupogen) 10 micrograms/kg s.c. from day-5 on. A total of 14.05 x 10(8) nucleated cells/kg recipient body weight (range 9.52-20.23 x 10(8)/kg), corresponding 6.82 x 10(6)/kg CD 34+ cells (range 1.43-15.84 x 10(8)/kg) or 113.9 x 10(4) CFU/kg (range 45.15-431.64 x 10(4)/kg) were collected by 3 phereses (1 patient 5 phereses) of 27-45 liters and infused without further manipulation. All patients engrafted with a recovery of total white blood cell count > 1 x 10(9)/l on day 15 (day 10-26) and of platelets > 20 x 10(9)/l on day +18 (day 12-39). 11 of the 12 patients developed aGvHD, 8 with grade II, 3 with grade > or = II. 9 of 13 patients are alive and well +4 to +16 months posttransplant, 3 patients died of aGvHD, one of veno-occlusive disease. These preliminary results confirm the capacity of peripheral blood precursor cells for rapid and complete engraftment in the allogeneic setting. Whether they induce more or equal aGvHD is an open question. Their value in allogeneic transplantation is currently under investigation in prospective randomized trials. PMID- 8701254 TI - [Successful syngeneic transplantation using G-CSF-stimulated peripheral hematopoietic progenitor cells combined with post-transplant administration of G CSF in a patient with acute lymphatic leukemia]. AB - A 45-year-old male with acute lymphoblastic leukemia in first remission was successfully transplanted with G-CSF (filgrastim)-mobilized syngeneic PBPC (peripheral blood progenitor cells). Conditioning regimen consisted of high-dose etoposide, cyclophosphamide and total body irradiation. For PBPC mobilization the patient's healthy syngeneic brother was subcutaneously stimulated with 16 micrograms/kg/day G-CSF for 5 consecutive days. Only mild adverse effects (myalgia, transient changes of laboratory test) were observed. PBPC-apheresis was performed three times without complications on days 4, 5 and 6 after the start of G-CSF application. The unmanipulated PBPC (total 5.75 x 10(8)/kg mononucleated cells) were transfused immediately after each collection. Engraftment under administration of G-CSF (5 micrograms/kg/day subcutaneously) from day 0 to +12 was very rapid. Neutrophils exceeded 1.0 x 10(9)/l on day +9, platelet counts reached 50 x 10(9)/l on day +13. On day +27 the patient was discharged from the hospital with normal blood counts except mild anemia (Hb 9.5 g%). Bone marrow aspiration was repeatedly normocellular with normal differential count and no leukemia. We demonstrate that G-CSF-mobilized syngeneic PBPC transplantation after myeloblative chemoradiotherapy results in rapid and so far stable hematologic reconstitution with an actual follow-up of more than 15 months. This experience may be of relevance for future allogeneic G-CSF-mobilized PBPC transplantation. PMID- 8701255 TI - [Chronic inflammatory bowel diseases and nutrition]. AB - The etiology of inflammatory bowel disease is still unknown. Several potential mechanisms are discussed. The etiological and therapeutic importance of nutrition is controversial. Though changes in dietary habits and incidence of inflammatory bowel disease during the last century were in parallel, no specific nutritional factor has been isolated. No dietary prophylaxis of inflammatory bowel disease is yet known; all dietary therapies in inflammatory bowel disease aim to improve nutritional support and to diminish inflammation by bowel rest. Children and adolescents gain in weight and height. Total parenteral nutrition will not substantially reduce disease activity and operation rates. Total parenteral nutrition can only be recommended in ulcerative colitis patients with severe disease in the initial phase and in Crohn's patients with severe malnutrition and intestinal complications. Enteral nutrition support is less effective in ulcerative colitis than in Crohn's disease. Reported remission rates on enteral nutrition are 25% for ulcerative colitis and up to 80% for Crohn. However, in active Crohn's disease enteral nutrition is less effective than standard therapy with methylprednisolone and sulfasalizine. It is generally believed that nutrition therapy in combination with drugs is the best treatment modality. There is no evidence to support the importance of any combination of the formula diets such as elemental, oligopeptide, or polymeric formulations. Administration of formula diets by nasogastric tubes all show similar remission rates. Whether newer diets supplemented with arginine, glutamine, omega-3-fatty acids or short chain fatty acids increase remission rates is not known. Further studies in this field are warranted. PMID- 8701256 TI - [Isolation and cryopreservation of human islets of Langerhans]. AB - Islet transplantation represents an alternative to whole pancreas transplantation for the treatment of patients suffering from diabetes type I. The transplantation of a sufficient number of islets is an essential condition for successful allograft. Islet cryopreservation allows the storage of islet preparations for subsequent pooling, at the time of transplantation, of cryopreserved islets with a fresh preparation in order to increase the mass of transplanted pancreatic endocrine tissue. From May 1994 to April 1995, islets were isolated from 22 human pancreases using a modified automated method, and 19 preparations were cryopreserved. The function of cryopreserved islets was tested in vitro (static incubation and perifusion). The results of static incubation experiments confirmed that the insulin secretion of cryopreserved human islets in response to glucose stimulation was comparable to the response of islets that have not been frozen. In static incubation experiments, the mean (+/- SEM) insulin secretion of islets, prior to cryopreservation, was 239.3 (+/- 58.9) and 479.5 (+/- 59.5) pg/islet/15 min at 2.8 mM glucose and 16.7 mM glucose respectively. The mean (+/- SEM) insulin secretion of cryopreserved islets was 274 (+/- 103.2) and 468.5 (+/- 191.9) pg/islet/15 min at 2.8 mM and 16.7 mM glucose respectively. The perifusion experiments also demonstrated a significant increase of insulin secretion from cryopreserved islets perifused with a stimulating glucose concentration. Our experiments allow us to envisage the use of cryopreserved islet preparations for allotransplantation in diabetic patients. PMID- 8701257 TI - [Virus titre and histological inflammation activity in chronic hepatitis C]. AB - We determine the correlation between viremia in serum specimens, transaminase activity (ALT and AST) and histological grading in 37 patients with chronic hepatitis C. In addition we compared two PCR methods for hepatitis C virus (HCV) RNA in serum specimens. For the histological grading we used a modified Knodell score. For detection and quantification we measured the viremia (HCV-RNA titer) with a standardized "nested primer" PCR (end-point dilution method) and the commercially available Amplicor HCV Monitor. The mean HCV-RNA and AST level was significantly higher in patients with a histologically active inflammation. In the individual patient we could not conclude from the titer of HCV-RNA on the histologic grading because of the wide range of the results. We did not find a significant difference in ALT in patients having varying histological gradings. HCV-RNA titer and transaminases (ALT and AST) did not correlate significantly. The HCV-RNA titer was significantly marked in older patients (above 40 years) and patients having sporadic hepatitis than in younger patients and patients with chronic hepatitis after drug abuse. The "nested primer" PCR (end-point dilution method) was more sensitive for detection of HCV-RNA in serum specimens than Amplicor HCV Monitor. The lack of HCV-RNA with Amplicor HCV Monitor in 12 of 37 patients (32%) did not rule out viremia. We conclude that in patients with a chronic hepatitis C marked viremia points to a histologically active inflammation. In the individual patient we could not conclude from the titer of HCV-RNA on the histological grading. Because of the lower sensitivity of Amplicor HCV Monitor it is necessary to confirm negative results with a "nested primer" PCR. PMID- 8701258 TI - [Role of hepatotropic viruses in liver pathology in Southwestern Cameroon]. AB - Between 1990 and 1992 (2 years), 102 patients with clinical liver pathology underwent standardized clinical, pathological, sonographic and serologic investigations (HAV, HBV, HCV, HDV autoantibodies and tumor markers). During the same period seroepidemiological studies with the same parameters as above were performed on the following control groups: healthy pregnant women (n = 383), blood donors (n = 85), HIV-positive individuals (n = 93), and hospitalized patients in all age groups with minor ailments unrelated to liver pathology (n = 108). The results are discussed in detail. Virtually all adults had HAV infection. HBV and HCV infection appears to play a major role in chronic liver pathology in southern Cameroon. The two infections frequently occur together (over 40% of liver cases) and correlate significantly with liver cirrhosis. The marked prevalence of HBV and HCV markers in healthy pregnant women is of epidemiological concern due to the potential for vertical transmission of the infection (immunization). Endemic infections such as falciparum malaria are probably responsible for unspecific stimulation of the immune system, which is reflected in a generally marked prevalence of autoimmune markers in liver patients and controls, since histologically there was no evidence of autoimmune liver disease. PMID- 8701259 TI - [Significance of ursodeoxycholic acid in the eradication of Helicobacter pylori]. AB - In this pilot study we investigated the value of a fourteen-day regimen with amoxicillin (1 g bid), ranitidine (300 mg/d) and ursodeoxycholic acid (300 mg tid) in eradicating Helicobacter pylori. 15 patients with non-ulcer dyspepsia (reactive CLO test, positive histology or 13C urea breath test) were enrolled. Helicobacter pylori was eradicated in 6 of 13 patients (13C urea breath test 4 weeks after the end of treatment). 2 patients were not followed up because of too short treatment (< 1 week). Only 5/15 patients had no side effects (33%). These results strongly suggest that ursodeoxycholic acid in this application regimen is not of use in eradicating Helicobacter pylori. PMID- 8701260 TI - [2 cases of Whipple disease with different outcomes]. AB - Whipple's disease is a rare infectious disease with systemic manifestation on different organs. In 1992 the typical rod-shaped bacillus was identified as a gram-negative actinomycete with distinctive morphologic characteristics and named as Tropheryma whippelii. The diagnosis is established by demonstrating the presence of PAS-positive macrophages in the mucosa, with large cytoplasmatic granules. We present two cases of Whipple's disease with different outcomes. Both were treated with the same antibiotics (penicillin/streptomycin). With this treatment one patient recovered completely. In a follow-up over 7 years no relapse occurred. The second patient died only 4 weeks after the diagnosis was established. PMID- 8701261 TI - Cancer surveillance colonoscopy in ulcerative colitis: sense or nonsense? AB - Surveillance in patients at risk for the development of cancer in the setting of ulcerative colitis is a common part of the management of these patients. There is controversy as to the efficacy of surveillance, the key issues relating to cost and reduction of cancer risk. Colonoscopic surveillance makes sense when it can be shown to detect cancers at a curable stage or be used to prevent cancer. The use of "low grade dysplasia" as an indication for early colectomy may have a favorable impact on survival statistics. The costs for surveillance compared favorably to the costs for flexible sigmoidoscopy surveillance for colo-rectal cancer. The negative answer to the question relates to studies suggesting that the cancer risk is overestimated and that "low-grade" dysplasia is of little prognostic value. Advocates of this policy recommend a non-surveillance or "follow-up" program. Two approaches that may improve efficacy are to target the high risk population for an increased frequency of surveillance and to enhance the accuracy of the dysplasia marker. Studies with flow cytometry are encouraging with DNA aneuploidy in colonic biopsies shown to have predictive value for the development of dysplasia in ulcerative colitis. Overall, surveillance seems warranted due to the risk, fear of cancer among patients, and the excess mortality among the entire inflammatory bowel disease population. The availability of the newer molecular tools could provide improvement in the surveillance approach. PMID- 8701262 TI - [Indications for, results and consequences of 24-hour esophageal pH monitoring]. AB - Gastroesophageal reflux disease accounts for approximately 75% of esophageal pathology. Accurate diagnosis can be complicated by the absence of endoscopic esophagitis in about 40% of patients with typical symptoms or atypical symptoms such as chest pain, chronic cough or wheezing. A number of tests have been developed to aid diagnosis, but 24-hour pH monitoring has emerged as the standard in reflux diagnostics. Although this method has been known for a long time, it has only become popular since small, portable digital recorders have been available. The aim of this retrospective study was to analyze our first experience with this method. Included in the study were the first 50 consecutive patients in our hospital who had undergone endoscopy of the upper GI tract followed by 24-hour pH monitoring. As a recorder we used the "GastrograpH Fresenius Mark II". In agreement with the literature we considered the following findings as abnormal: esophageal acidity below pH 4 > 5% of total time or > 8% of upright time or > 3% of supine time, more than 4 reflux episodes of > 5 minutes, duration of the longest reflux episode more than 20 minutes. With this definition there were 24 patients (48%) with reflux disease. The reflux episodes chiefly occurred in daytime (68%), as known from the literature. The indications for this examination were chiefly given by pneumologists (50%), followed by gastroenterologists (22%) and cardiologists (14%). Acid block therapy was performed in 83%, with success in 42% and failure in 8%. In 50% of the patients the necessary data were lacking. Based on these results we conclude that 24-hour pH monitoring has shown itself reliable for the diagnosis of reflux disease and should always be performed in patients with negative endoscopic examination but typical or atypical symptoms of gastroesophageal reflux. PMID- 8701263 TI - [Value of abdominal ultrasonography in deep venous thrombosis. Retrospective study of 104 patients]. AB - An association between venous thrombosis and cancer was first suggested by Armand Trousseau in 1865 and subsequently confirmed by a number of studies. It was therefore concluded that laboratory tests, chest radiograph and abdominal ultrasonography should be routinely performed on all patients with deep venous thrombosis. The aim of our retrospective study was to detect the clinical relevance of abdominal ultrasonography findings, especially tumors, in patients with deep venous thrombosis of the lower extremities. All patients with deep venous thrombosis hospitalized between 1990 and 1994 in the department of internal medicine of our hospital were registered. Only patients were included in the study who (1) underwent abdominal ultrasonography in our department; (2) had confirmed acute deep venous thrombosis; (3) had no known malignancy. Malignancies which appeared after hospital stay were detected by telephone inquiry among patients and general practitioners in February 1995. Of the 371 patients with deep venous thrombosis 104 were included in the study. We found abnormal ultrasound findings in 68 patients (65%), but only in 23 patients were the findings of clinical relevance, in 12 of whom (12%) there was a connection with deep venous thrombosis. Ultrasound detected 3 malignancies (3%). The overall rate of newly detected malignancies was 10 (10%), of which 6 were detected during hospitalization and 4 afterwards. Based on these results we can recommend routine performance of abdominal ultrasonography on patients with deep venous thrombosis. A literature overview is given. PMID- 8701264 TI - [Value of endo-anal ultrasonography in the assessment of anal incontinence]. AB - Endoanal ultrasonography with a Bruel and Kjaer 7 mHz rotative probe allows precise evaluation of the different structures of the anus, the anal canal and the rectum. The integrity, thickness and length of the muscle layers can be measured in a reproducible way during contracture and at rest. In addition to the classic images, video recording can be carried out. We examined 96 consecutive patients with anal incontinence, comprising 82 female and 14 male patients. In 76 cases the origin were an obstetrical lesion, 7 were surgical lesions, in 9 cases the lesion was posttraumatic and in 2 cases a malformation. In 2 cases a rectal prolapse was associated. We found that endoanal ultrasonography permits a precise diagnosis of anal incontinence. The nature and the extent of sphincteric lesions can be determined and the surgical procedure can thus be planned. In the absence of organic lesions this examination serves to avoid unnecessary surgical treatment. PMID- 8701265 TI - [Ectopic varices, a rare cause of digestive hemorrhage]. AB - From January 1986 to September 1995, 4 patients were hospitalized in our ward for gastrointestinal bleeding from ectopic varices. The patients were all female, aged 30 to 65 years. The etiology of portal hypertension in these patients was alcoholic cirrhosis, cirrhosis in Wilson's disease and previous alveolar echinococcosis treated by right hepatectomy, complicated by post-operative portal thrombosis. Clinical presentation in all 4 cases was lower gastrointestinal bleeding. Diagnosis was by emergency arteriography in 3 cases; no source was found in one case with recurrent hemorrhage. The 4 patients had a history of abdominal surgery. The location of the ectopic varices was small bowel and cecum. 3 patients were treated surgically: right colectomy, partial small bowel resection and porto-caval shunt with complete lysis of adhesions. One patient was treated conservatively with emergency placement of a TIPS (transjugular intrahepatic porto-systemic shunt), with simultaneous embolization of cecal varices. Upon laparotomy, all 3 surgical cases presented ectopic varices in post operative adhesions. In conclusion, in a patient with portal hypertension presenting with lower gastrointestinal bleeding, hemorrhage from ectopic varices should be kept in mind and investigated by arteriography. A history of abdominal surgery seems to be a predisposing factor in development of ectopic varices by adhesion formation. PMID- 8701266 TI - Combined islet-lung transplantation in a cystic fibrosis patient. AB - The prevalence of insulin-dependent diabetes mellitus (IDDM) in cystic fibrosis patients ranges from 2 to 8% and glucose intolerance up to 15%. In recent years, lung transplantation has helped to prolong life expectancy of cystic fibrosis patients and represents 10 to 30% of all indications for lung transplantation. The postoperative need for immunosuppressive therapy using diabetogenic agents has decompensatory effects on glucose regulation and will probably increase the number of insulin-dependent cystic fibrosis patients. We report the case of an insulin-dependent cystic fibrosis patient transplanted with a combined islet-lung allograft. The pre-transplantation C-peptide level was below 0.04 nmol/l and preoperative insulin requirement was some 100 U per day. A sequential bipulmonary lung transplantation was performed and, using the pancreas of the same donor, we isolated and purified the islets of Langerhans by a modified automated method. We obtained 232,200 islets equivalent, which were injected into the liver by portal embolization. The postoperative course was uncomplicated, the insulin requirement decreased to 50% of the preoperative need and the C-peptide value increased to normal values and remained with the normal range during a follow-up period of 15 months. In conclusion, we believe that, besides type I diabetic patients, insulin dependent cystic fibrosis patients with a negative C-peptide value could also be good candidates for combined islet-lung allotransplantation. PMID- 8701267 TI - [Results of surgical treatment of hepatic metastasis of colorectal origin]. AB - Surgery is the only treatment which can achieve long-term survival of patients with colorectal liver secondaries. This study reports the results in 71 patients with liver metastases who underwent hepatic resection from January 1980 to December 1994. The mean age was 60 years (range 37 and 80 years). Operations included 33 right hepatectomies, 5 extended right hepatectomies, 6 left hepatectomies, 11 left lobectomies,. Surgery was macroscopically and microscopically curative in 61 patients. Information was not available in 2 patients. Significant morbidity was observed in 37% of patients. Actuarial survival at 1, 3 and 5 years was 83%, 27% and 20% respectively. At the end of the follow-up, 50 patients had died and 6 were lost to follow-up. Techniques of hepatic resection for secondaries are well established and postoperative mortality is low. Pending advances in chemotherapy, we recommend surgery as being the only way of improving long-term survival in patients with colorectal hepatic metastases. PMID- 8701268 TI - [Treatment of rectum adenoma. Retrospective study of the treatment of inpatients (1987-1991)]. AB - In carrying out an evaluation prior to acquisition of equipment for transanal endoscopic microsurgery (TEM), we wished to examine current concepts in the treatment of rectal adenoma, i.e.: What form of surgery was chosen in relation to the dimension and localization of the adenoma? Should the indications for the particular procedure be changed to render it less invasive? Should the new endoscopic surgical method TEM be introduced? 134 inpatients covering a 5-year period were evaluated. We analyzed the correlation between localization of the adenoma in the rectum (42% low, 22% middle, 36% high position), diameter of the tumor (37% < 2 cm, 38% 2-4 cm, 11% 4-6 cm, 10% > 6 cm) and type of surgery (endoscopic 27%, transanal 45%, anterior resection 25%). We found a high percentage of anterior resections in the middle rectum which could be reduced by introduction of the less invasive TEM. 29 (22%) of our patients could have been treated with TEM. PMID- 8701269 TI - [Technique and results of laparoscopic rectum resection]. AB - The general principles of oncologic operations for colorectal cancer are the same for both open and laparoscopic surgery. Isolation of the tumor by occlusion of the intestinal lumen, early blockage of venous outflow, complete resection of the lymph node bearing mesenterium, high ligation of the artery and prevention of tumor cell dissemination during extirpation of the specimen are the most important factors. We present our technique for laparoscopic abdominoperineal resection, which fulfills the above mentioned criteria. From June 1993 to October 1994 we operated on 19 patients (median age 68 [47-91] years; male/female ratio 10/9). Laparoscopic abdominoperineal resection of the rectum was palliative in 3 patients and curative in 16. Tumors were located 3 (1-8) cm from the anal verge. In 3 patients the operation was converted to open surgery. Intraoperative complications were encountered in 3 patients. Median operation time was 300 (200 400) minutes and postoperative morbidity 8/19 (42%) leading to reoperation in one patient. 30-day mortality was nil. Three patients died 5, 8, and 14 months postoperatively due to metastatic disease (all 3 after initial palliation). One patient had local recurrence and liver metastasis and died 14 months after operation. Another patient died from liver metastases. In one patient a single liver metastasis was successfully removed. 14 patients were tumor-free after a median follow-up of 10 (3-14) months. There was no implantation metastasis on a trocar site. Laparoscopic abdominoperineal resection of the rectum is feasible and the results are comparable with those of open surgery. Local recurrence rate and incidence of liver metastases are comparable with open surgery after this short follow-up. However, 5-year survival is needed to judge the oncological radicality of laparoscopic abdominoperineal resection of the rectum. PMID- 8701270 TI - [Endoscopic therapy of bile leakage following laparoscopic cholecystectomy]. AB - Biliary leakages are more frequent in laparoscopic than in open cholecystectomy. The aim of our study was to evaluate the diagnostic and therapeutic value of endoscopic retrograde cholangiography (ERC) in the management of bile leakages after laparoscopic cholecystectomy. The primary management was endoscopic sphincterotomy and extraction of remaining gallstones in the common bile duct to provide a decrease of biliary pressure, allowing closure of the fistulas. We report on 20 patients with bile leakage at ERCP, presenting between January 1991 and October 1995 with persistent bile discharge out of drainages, increasing fluid collections subhepatic (termed bilomas) or in the free peritoneal cavity (cholascos), abdominal pain, fever, cholestasis, intraoperatively diagnosed choledocholithiasis, and subhepatic abscess in one case. In 19 cases, after fluoroscopic visualization of the biliary tree and the leak, endoscopic sphincterotomy was performed. The biliary leaks were located at the cystic duct remnant (n = 12), at the gallbladder fossa (n = 5), or at lesions at the hepatic or common bile duct (n = 2). In 7 patients residual common bile duct stones were endoscopically removed. Most patients had localized small subhepatic fluid collections (n = 13) and the others had cholascos (n = 6). The leaks closed with endoscopic sphincterotomy alone in 11 patients, 4 patients had endoscopic sphincterotomy plus percutaneous or laparoscopic drainage of the bile collections, and 4 patients underwent laparotomy. All 6 cases with cholascos but only 2 of the 13 patients with localized collections underwent a second therapeutic procedure (drainage, laparotomy). Five of these procedures were performed within 7 days of ERCP, in most cases due to persistent bile leak. We conclude that biliary leakages after laparoscopic cholecystectomy require laparotomy only exceptionally. Endoscopic sphincterotomy, combined with percutaneous drainage in the case of large collections, represents a safe and successful strategy ensuring closure of the leaks in most cases. PMID- 8701271 TI - [Malnutrition in the hospital]. AB - It can be expected that every fifth patient in an internal medical ward in our hospitals is malnourished. Reasons for this are consuming underlying diseases as well as psychological and social factors. The association of malnutrition and hypoalbuminemia is a marker of poor prognosis; malnutrition associated with hypoalbuminemia has also been named "protein malnutrition". However, this term is misleading and "dysproteinemic malnutrition" would be more appropriate, because hypoalbuminemia is usually not caused by protein malnutrition but rather by an underlying severe illness. The nutritional state should be assessed in all patients with suspected malnutrition; not only body composition but also body function should be determined. Elderly patients have an increased prevalence of malnutrition; among individual micronutrients vitamin D, B12 and B6 in particular are frequently diminished. Nutritional therapy should be a component of all comprehensive treatment programmes for diseases which may lead to malnutrition. PMID- 8701272 TI - [Physician-patient relations and stress caused by coloscopy in patients with chronic inflammatory bowel disease]. AB - The relationship between doctors and patients with inflammatory bowel disease is usually considered complex and difficult. We analyzed the quality of this relationship and the stress inflicted on the patients by endoscopy. 76 patients with Crohn's disease or ulcerative colitis answered a questionnaire. More than three quarters considered their relationship to their doctors good or very good. The patients expressed a wish for more information on the pathophysiology and treatment options of their disease. The stress placed on the patients by endoscopy was considered severe or very severe by 57%. We conclude that the relationship between doctor and patients with inflammatory bowel disease is generally considered good or very good. Endoscopies are highly stressful for most patients and we recommend appropriate sedation. PMID- 8701273 TI - [Social consequences and quality of life in patients with chronic inflammatory bowel disease]. AB - We conducted a survey on the quality of life and social consequences for patients with inflammatory bowel disease. Questionnaires of 41 patients with Crohn's disease, 28 patients with ulcerative colitis and 7 patients with overlap colitis were evaluated. All the patients had been hospitalized in the past. 15 patients (20%) were unable to work due to inflammatory bowel disease. 9 (12%) of these 15 patients received a disability pension. 11 patients (15%) had to change a place of work and 16 (21%) had had financial problems due to inflammatory bowel disease. 4 patients (5%) had had to give up a partnership due to the disease. For 16% of the patients their perceived quality of life during the past 4 weeks was poor or very poor, while 35% of the patients perceived their overall quality of life as poor or very poor since the beginning of the disease. We conclude that inflammatory bowel disease affects job and financial matters rather than partnerships. The quality of life is judged by many patients as considerably diminished. PMID- 8701274 TI - Is hormone replacement therapy a risk? PMID- 8701275 TI - Advances in cancer detection. PMID- 8701276 TI - Is genetic testing premature? PMID- 8701277 TI - Advances in tumor imaging. PMID- 8701278 TI - Should women in their 40s have mammograms? PMID- 8701279 TI - Does screening for prostate cancer make sense? PMID- 8701280 TI - Advancing current treatments for cancer. PMID- 8701281 TI - When are bone marrow transplants considered? PMID- 8701282 TI - Twelve major cancers. PMID- 8701283 TI - Immunotherapy for cancer. PMID- 8701284 TI - New molecular targets for cancer therapy. PMID- 8701285 TI - Fighting cancer by attacking its blood supply. PMID- 8701286 TI - Cancer's psychological challenges. PMID- 8701287 TI - HIV's Achilles' heel. Drugs and education are starting to slow the AIDS virus. PMID- 8701288 TI - Alternative cancer treatments. PMID- 8701289 TI - Controlling the pain of cancer. PMID- 8701290 TI - What are obstacles to ideal care? PMID- 8701291 TI - World birth-control use. PMID- 8701292 TI - New chip off the old block. Can DNA microprobes do for genetics what microprocessors did for computing? PMID- 8701293 TI - Artificial blood quickens. Several short-term substitutes approach final clinical trials. PMID- 8701294 TI - Making headway against cancer. PMID- 8701295 TI - How cancer arises. PMID- 8701296 TI - How cancer spreads. PMID- 8701297 TI - What causes cancer? PMID- 8701298 TI - Why community cancer clusters are often ignored. PMID- 8701299 TI - Strategies for minimizing cancer risk. PMID- 8701300 TI - Chemoprevention of cancer. PMID- 8701301 TI - Arsenic burden among children in industrial areas of eastern Germany. AB - The internal burden of arsenic among 5- to 14-year-old eastern German children in the heavily polluted areas of Hettstedt, a region of smelting and copper mining, and Bitterfeld, a center of chemical production and coal mining, was compared with that in a control area (Zerbst) by means of urinary arsenic concentrations in 1992-94. The unadjusted geometric mean among the 950 children was significantly higher in Hettstedt (5.1 micrograms/l; 95% C.I. 4.8-5.5) but not in Bitterfeld (4.3 micrograms/l; 95% C.I. 3.7-4.9) compared with the control area (4.0 micrograms/l; 95% C.I. 3.5-4.5). This difference persisted after adjustment for relevant confounders. Despite these regional differences, recent fish consumption was as strongly associated with urinary arsenic levels (42% increase, 95% C.I. 18-71%). Additionally, although the geometric mean among the children in Hettstedt (4.8 micrograms As/g creatinine; 95% C.I. 4.5-5.1) was higher than that found in an environmental survey of eastern German children (3.60 micrograms As/g creatinine; 95% C.I. 3.06-4.24), it was similar to that found among western German children (4.59 micrograms As/g creatinine; 95% C.I. 4.20-5.02). This suggests that the arsenic contamination in Hettstedt is not substantially increasing the internal burden of arsenic among children above that found in other German children. PMID- 8701302 TI - NIH rating system. PMID- 8701303 TI - Risks from low doses of radiation: continued. PMID- 8701304 TI - German genome program. The right mix of form and function. PMID- 8701305 TI - Reports bolster viral cause of KS. PMID- 8701306 TI - Chemical shackles for genes? PMID- 8701307 TI - Does nature drive nurture? PMID- 8701308 TI - Ancient remedy performs new tricks. PMID- 8701309 TI - Putting the brakes on bone growth. PMID- 8701311 TI - CO in the early universe clouds cosmologists' views. PMID- 8701310 TI - Yeast prions: DNA-free genetics. PMID- 8701312 TI - Computational molecular biology. Software matchmakers help make sense of sequences. PMID- 8701314 TI - Do Java users live dangerously? PMID- 8701313 TI - Bioinformatics. Working the Web with a virtual lab and some Java. PMID- 8701315 TI - Which came first, protein sequence or structure? PMID- 8701316 TI - Shaking out the cause of addiction. PMID- 8701317 TI - Pharmaceuticals based on biotechnology. PMID- 8701318 TI - Fetal immune response. PMID- 8701319 TI - Peopling the Americas. PMID- 8701320 TI - Despite anxiety, NIH begins merging neuroscience panels. PMID- 8701321 TI - Forging a path to cell death. PMID- 8701322 TI - New experiments underscore warnings on maternal drinking. PMID- 8701323 TI - The public health risk of animal organ and tissue transplantation into humans. PMID- 8701324 TI - Is the new variant of Creutzfeldt-Jakob disease from mad cows? PMID- 8701325 TI - Why stress is bad for your brain. PMID- 8701326 TI - STATs find that hanging together can be stimulating. PMID- 8701328 TI - Innovations in prostate disease education. PMID- 8701327 TI - Urinary incontinence among primiparous women. AB - OBJECTIVE: The purpose of this study was to explore the symptoms of urinary incontinence among primiparous women. METHODS: This descriptive study used a paper and pencil mail survey. A sample of 300 primigravida mothers (aged 16 to 45 years; 10 weeks to 8 months postpartum) was garnered from a university-affiliated city-county hospital. RESULTS: Most respondents (53%, n = 65/122) reported urinary incontinence (UI) symptoms sometime before, during, or after pregnancy. Few respondents (6.2%, n = 4) had UI symptoms continuously across all time periods surveyed. Age did not contribute to UI when a comparison was made among mothers who were very young (aged 16 to 19 years), young (aged 20 to 29 years), and mature (aged 30 to 36 years). None of the respondents with persistent or current UI had reported the symptoms to a health care provider. Of those who had reported their symptoms (n = 11), only four mothers received any recommendations for treatment. CONCLUSIONS: However common UI may be during pregnancy, it is commonly overlooked as a problem amenable to simple and effective behavioral treatments. This study shows that UI is equally problematic for very young mothers and more mature mothers. Additional studies are indicated among very young mothers to document factors related to prevalence and incidence. PMID- 8701329 TI - Bridging the cultural gap. PMID- 8701330 TI - Easy disinfection of urine after BCG bladder instillation. PMID- 8701331 TI - Percutaneous nephrostomy tubes: nursing care. PMID- 8701332 TI - Guess where else you can use nasogastric tape? PMID- 8701333 TI - 1995 SUNA resource directory. PMID- 8701334 TI - The medication minute. PMID- 8701336 TI - Re: "Electric stimulation: does nursing have a role in the treatment of adult urinary incontinence". PMID- 8701335 TI - Getting ready for certification. PMID- 8701337 TI - [Urinary infections]. PMID- 8701338 TI - [Bacterial skin infections]. PMID- 8701339 TI - [Viral hepatitis]. PMID- 8701340 TI - [The psycho-affective dimension]. PMID- 8701341 TI - [The world of bacteria and viruses]. PMID- 8701343 TI - [Nutrition and bone marrow transplantation]. PMID- 8701344 TI - [Hepatobiliary infections]. PMID- 8701342 TI - [Psychotropic drug consumption in prison]. PMID- 8701345 TI - [A sacred fire for nurses]. PMID- 8701347 TI - [Ovarian cancers]. PMID- 8701346 TI - [Antiandrogens: medical treatment of prostate cancer]. PMID- 8701348 TI - [Advanced ovarian cancer]. PMID- 8701350 TI - [Malignant epithelial ovarian tumors]. PMID- 8701349 TI - [Ovarian cancer. The new chemotherapeutic agents]. PMID- 8701352 TI - [Nursing records in pediatric hematology]. PMID- 8701351 TI - [Patient education ... from idea to reality]. PMID- 8701353 TI - [I'm eating less ... Why? What should I do?]. PMID- 8701354 TI - [Ovarian cancer epidemiology]. PMID- 8701355 TI - [Silence on the irreductibles]. PMID- 8701356 TI - [Gene therapy service]. PMID- 8701357 TI - [Drugs for prostatic adenoma]. PMID- 8701358 TI - [The specificity of the pre-admission]. PMID- 8701359 TI - [Day hospital for adolescents]. PMID- 8701360 TI - [Psychic and somatic]. PMID- 8701361 TI - [Adolescents in the acute phase]. PMID- 8701362 TI - [Institutional staff and nursing staff]. PMID- 8701364 TI - [Therapeutic field trips]. PMID- 8701363 TI - [Anorexia and nursing care]. PMID- 8701365 TI - [The vase opens to the interior]. PMID- 8701366 TI - [The Dupre Clinic]. PMID- 8701367 TI - [Multidisciplinary nursing care]. PMID- 8701368 TI - [A Pantagruelian meal]. PMID- 8701369 TI - [The nurses of the Dupre Clinic]. PMID- 8701370 TI - [A long awaited decree! August 20, 1995]. PMID- 8701371 TI - [Nurses and student nurses around the patient-student]. PMID- 8701372 TI - Management of cancer pain. AB - Pain is often the first symptom of cancer. Pain and fear of pain are concerns of most cancer patients and their families. The therapeutic options available to control pain are numerous, allowing practitioners to better individualize treatment. We present an overview of the pathophysiology of cancer pain, the current theories of pharmacologic opioid management, advantages of adjuvant drugs, and the range of invasive and noninvasive procedures that practitioners can offer their patients who have cancer-related pain. PMID- 8701373 TI - Migraine: definitions, mechanisms, and treatment. AB - Although ubiquitous, migraine remains incompletely understood and thus often ineffectively managed. Fortunately, new advances in our understanding of migraine's origins have led to identification and application of therapeutic intervention that is unparalleled in its specificity and clinical efficacy. We present a unified model of migraine genesis and explain how application of the model to clinical practice may improve therapeutic management of this common disorder. PMID- 8701374 TI - Patient understanding of emergency department discharge instructions. AB - Patients were interviewed immediately after discharge outside the emergency department to determine whether they could read their discharge instructions and recall their diagnosis and treatment plan. The association between frequency of correct responses and various characteristics of the patients was assessed. Of the patients completing the interview, 72% could read the discharge instructions. The illiteracy rate was higher for patients with less than 9 years of education and for patients aged 50 to 59 years. There was no association between patient race, sex, or literacy. The correct diagnosis was given by 79% of patients, correct treatment information by 49%, and correct follow-up information by 82%. Overall, 37% of patients answered all questions correctly and 8% answered all questions incorrectly. No association was found between frequency of correct responses and variables examined. Miscommunication of discharge information occurs frequently; illiteracy does not completely account for the observed low rates of recall. PMID- 8701375 TI - Efficacy of ciprofloxacin in the eradication of Helicobacter pylori. AB - In small preliminary trials, ciprofloxacin has failed to eradicate Helicobacter pylori. Since fluoroquinolones have a marked reduction in bactericidal activity at acidic pH, we altered the gastric pH using omeprazole and investigated the efficacy of ciprofloxacin in eradicating H pylori. Forty-four consecutive patients infected with H pylori were prospectively studied in a randomized, double-blind, controlled trial comparing ciprofloxacin with a placebo for 2 weeks. Both treatment groups received bismuth and omeprazole. In 36 patients, follow-up endoscopy was done 4 weeks after the cessation of all study drugs. The H pylori infection cleared in 13 of 17 patients (76%) in the ciprofloxacin group versus 5 of 19 (26%) in the placebo group. Concurrent administration of omeprazole with ciprofloxacin resulted in increased bactericidal activity against H pylori. Ciprofloxacin when combined with omeprazole and bismuth is efficacious for eradication of H pylori. PMID- 8701377 TI - The effect of high-dose right upper quadrant lithotripsy on normal swine tissue. AB - To assess the effects of high doses of shock waves to organs in the right upper quadrant of the abdomen, 36 adolescent swine were given one treatment of either 2,000 (2k), 6,000 (6k), or 10,000 (10k) shock waves at 24 kV peak pressure using a spark-gap lithotriptor. Shock waves were sonographically focused on the lumen of the gallbladder. Blood and tissue were examined for each group at 48 hours, at 35 days, and at 6 months. This study showed that administration of up to five times the accepted upper limit of shock waves produced no permanent damage. Transient injury, most commonly hematoma, was encountered. No posttreatment intra abdominal catastrophes occurred. Although no renal injury was seen, it should be noted that the focus of maximum energy was 5 cm cephalad to the right kidney. This study suggests that an increased number of shock waves may be administered safely to this area of the abdomen. PMID- 8701376 TI - Intravenous amiodarone for therapy of atrial fibrillation and flutter in critically ill patients with severely depressed left ventricular function. AB - A retrospective review was done to determine the efficacy and hemodynamic effects of slow intravenous amiodarone administration on invasively monitored patients with acute onset of atrial fibrillation or atrial flutter and left ventricular ejection fractions < 15%. Eight patients met predefined inclusion criteria. All received 300 mg amiodarone intravenously over 1 hour. Seven reverted to sinus rhythm within 1 hour, with return of most hemodynamic variables to baseline. Before reversion, each patient experienced a beneficial slowing of heart rate (mean, 28%) resulting in significant improvement of stroke volume index (mean, 49%) and left ventricular stroke work index (mean, 61%). No patient had hemodynamic deterioration attributable to amiodarone infusion. Slow intravenous infusion of amiodarone appears to be an effective and hemodynamically well tolerated therapy for atrial fibrillation and atrial flutter in critically ill patients with marked depression of left ventricular systolic function. PMID- 8701378 TI - Use of Texas birth certificate data to predict measles immunization status. AB - Inadequate immunization has been a major cause of epidemic measles, but risk factors for inadequate immunization are poorly characterized. By using measles data bases and computerized birth certificate files, we identified a retrospective cohort of 1,070 Texas-born children who were aged 15 months to 10 years when they had measles during the 1988 to 1991 epidemics. We used measles and birth certificate data, including prenatal care and demographic information, to determine immunization status and risk factors for inadequate measles immunization. Risk factors predicting lack of immunization in children with measles in stepwise logistic regression were black ethnicity, urban residence, poor prenatal care, preschool age, and an unknown father. Birth certificates contain information that can predict inadequate measles vaccination and should be evaluated prospectively. PMID- 8701379 TI - Fracture and migration of a pacemaker atrial lead retention wire found by fluoroscopic screening in an asymptomatic patient. AB - We present the case of a woman who had an Accufix atrial "J" pacemaker lead implanted in 1990. Subsequently, Telectronics Pacing Systems recalled two models of the atrial leads after problems with fracture and malfunction were reported. One of these models was used in our case. Fifty-two months after implantation, following recommended fluoroscopic screening, our patient was found to have a complete fracture of the "J" retention wire with one fragment protruding from the sheath in the right atrium and another fragment of the wire lodged in the right ventricle. The pacemaker had continued to function normally and there was no clinical evidence to suggest such a potentially disastrous fracture. Our report emphasizes the importance of fluoroscopic screening of all patients with atrial leads involved in the recall. PMID- 8701380 TI - Pulmonary alveolar proteinosis: an unusual association with Mycobacterium avium intracellulare infection and lymphocytic interstitial pneumonia. AB - Pulmonary alveolar proteinosis is a nonspecific alveolar response to various forms of injuries. Many cases have been associated with hematologic malignancies. The most commonly reported complication of pulmonary alveolar proteinosis is superinfection with fungal, bacterial, and viral infections. We report a case of a 33-year-old man with alveolar proteinosis complicated by Mycobacterium avium intracellulare complex infection. The additional presence of diffuse lymphocytic interstitial pneumonitis is an association that has not been previously reported. PMID- 8701381 TI - Levels of therapeutic antivenin and venom in a human snakebite victim. AB - An enzyme-linked immunosorbent assay was used to measure the levels of therapeutic antivenin (Antivenin [Crotalidae] Polyvalent, Wyeth-Ayerst) in serum and the levels of venom in the urine of a patient bitten by a western diamondback rattlesnake (Crotalus atrox). Serum and urine samples were taken on admission, during hospitalization, and during follow-up until 5 months after the bite. Photographs were taken of the bite site on admission to the hospital and during follow-up. Serum levels of therapeutic antivenin were highest between 1 and 3 days after the bite but were still detectable 46 days as well as 4 months after the bite. Crotalus atrox venom was detectable in the urine 4 days after the bite and was still measurable 6 days after the bite. PMID- 8701382 TI - Mesenteric lymphangioma causing bowel obstruction in a child. AB - Mesenteric lymphangioma was manifested as a bowel obstruction in a child with cerebral palsy. Diagnosis was not confirmed until the time of laparotomy. Mesenteric lymphangioma is rare but should be considered in a child with bowel obstruction and no other known abdominal disease. PMID- 8701383 TI - Systemic lupus erythematosus diagnosed during interferon alfa therapy. AB - We describe a patient who had clinical manifestations of several autoimmune disorders: Sjogren's syndrome, benign hypergammaglobulinemic purpura of Waldenstrom, and systemic lupus erythematosus (SLE). The SLE was diagnosed during therapy with interferon alfa. Testing for anti-Ro and anti-La antibodies was negative until the serum was diluted to eliminate a possible prozone phenomenon of antibody excess. PMID- 8701384 TI - Pseudoaneurysm of the superficial temporal artery. AB - Ours is the first report of pseudoaneurysm of the superficial temporal in a 90 year-old woman. Although falls with associated head and scalp injuries in the geriatric population are common, pseudoaneurysm of the superficial temporal artery is rarely reported, probably due to the generally protected course of the superficial temporal artery across the skull. Clinicians' familiarity with this entity is important for early diagnosis and intervention. PMID- 8701385 TI - Fragmentation hemolysis: an unusual indication for valve replacement in native valve infective endocarditis. AB - Intravascular mechanical fragmentation of erythrocytes is an uncommon occurrence in native valve infective endocarditis. We report a case of fragmentation hemolysis in a patient with tricuspid valve endocarditis due to Staphylococcus aureus. She received transfusion of multiple units of packed red blood cells and ultimately required surgical removal of the affected valve to control the hemolytic process. We believe this to be only the fifth such reported case and the first in which surgical therapy was necessary to control the hemolytic process. PMID- 8701386 TI - Clinical and postmortem outcome of "no-reflow' phenomenon in a patient treated with rotational atherectomy. AB - In the 77-year-old woman described, atherectomy of a circumflex artery with the Rotablator device was complicated by "no reflow." Ten days later, a 75% right coronary artery stenosis was successfully managed by balloon angioplasty. On the following day, acute closure of this vessel resulted in death. Gross examination of the heart showed features of recent posterior infarction, and microscopic study revealed atheroemboli in myocardial arterioles. We conclude that high-speed pulverization of atherosclerotic plaque can cause clinically significant emboli. PMID- 8701387 TI - Left hilar mass in a 62-year-old man: severe pulmonary valvular stenosis with a poststenotic aneurysm. AB - We describe a patient who had a left hilar mass initially diagnosed as probable bronchogenic carcinoma. When a paradoxic arterial embolus led to further investigation, the hilar mass was found to be a poststenotic dilatation due to a severe pulmonary valve stenosis. Percutaneous balloon valvuloplasty of the pulmonary valve was successfully done, and the patient is well 2 years after the procedure. PMID- 8701388 TI - Sting of the puss caterpillar: an unusual cause of acute abdominal pain. AB - We report the case of a 41-year-old man with abdominal pain after envenomization by a puss caterpillar. The patient's medical history and physical examination revealed classic symptoms, leading to the correct diagnosis and appropriate therapy with intravenous calcium gluconate. Although severe, local reactions to puss caterpillar envenomization have been previously described, to our knowledge this is the first report of a patient with severe, acute abdominal pain caused by a puss caterpillar's sting. PMID- 8701389 TI - Cisapride as a successful treatment for acute intestinal pseudo-obstruction. AB - Cisapride has been used in the treatment of chronic intestinal pseudo-obstruction with some success; however, the use of cisapride in the treatment of acute pseudo obstruction has not been adequately studied. We describe a case of acute intestinal pseudo-obstruction successfully treated with cisapride. To our knowledge, this is the second such case reported in the English language literature. Our patient's acute intestinal pseudo-obstruction was probably precipitated by pneumonia and sepsis, and the prompt resolution of his intestinal pseudo-obstruction after initiation of cisapride therapy (despite progressive deterioration of his overall clinical status) implicates cisapride as the cause of the improved intestinal function. Therefore, we suggest that a trial of cisapride be considered for patients with acute intestinal pseudo-obstruction when other therapeutic maneuvers have failed. PMID- 8701390 TI - Pathophysiologic information and therapy for non-insulin-dependent diabetes mellitus. PMID- 8701391 TI - Gouty arthritis in a patient with Ivemark syndrome. PMID- 8701392 TI - The Ehlers-Danlos syndrome: a heritable collagen disorder as cause of bleeding. PMID- 8701393 TI - The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S deficient women. AB - Hereditary deficiencies of the naturally occurring anticoagulants are well recognized conditions predisposing to recurrent venous thromboembolism. Since thrombotic phenomena have been implied as a cause of abortion and stillbirth, we hypothesized that these deficiencies increase the risk of fetal demise. A group of 129 female subjects who had been pregnant at least once and who had a family member with documented venous thrombosis associated with a deficiency of AT, PC or PS were studied. We first assessed the obstetric history and subsequently determined the deficiency status. In the 60 deficient subjects 42 (22.3%) of the 188 pregnancies resulted in miscarriage or stillbirth as compared to 23 (11.4%) of the 202 pregnancies in the 69 non-deficient subjects. The relative risk of abortion and stillbirth per pregnancy for deficient women as compared to non deficient women was 2.0 (95% C.I. 1.2-3.3). PMID- 8701394 TI - Tissue factor induces migration of cultured aortic smooth muscle cells. AB - Tissue factor (TF) plays a key role as a primary initiator on the extrinsic coagulation cascade. Recently, upregulation of TF has been reported in human atherosclerotic lesions. We investigated the effects of TF on migration and proliferation of cultured smooth muscle cells (SMCs) from rabbit aortas. We tested three kinds of recombinant human TF (L-TF: the full length of TF with relipidation, NL-TF: the full length of TF without relipidation, and S-TF: a soluble form of TF1-219). Only L-TF had coagulant activity. All kinds of TF showed the chemotactic migration activity for SMCs. The migration ability of TFs was comparable to those of platelet-derived growth factor (PDGF)-BB and basic fibroblast-growth factor (bFGF), and was inhibited by anti-TF polyclonal and monoclonal antibodies. On the other hand, none of the forms of TF induced SMC proliferation. These results indicate that TF is not only a coagulation factor but also a strong chemotactic factor for vascular SMCs, and suggest that TF could play an important role in atherogenesis as well as in hemostasis and thrombosis. PMID- 8701395 TI - Factor V gene mutation is a risk factor for cerebral venous thrombosis. AB - To evaluate the association between coagulation defects and cerebral venous thrombosis, a case-control study was conducted in 25 patients who had no autoimmune, neoplastic or infections disease and 75 healthy individuals. There were no patients with deficiency of protein C or protein S. Four had resistance to activated protein C (APC) and one had APC resistance associated with antithrombin deficiency. APC resistance was investigated by DNA analysis, and diagnosed by the presence of a point mutation in the factor V gene, which predicts replacement of Arg506 with Gln at one of the two APC cleavage sites in activated factor V. The prevalence of APC resistance was 20% in patients and 2.7% in controls. This difference was statistically significant (p = 0.01) and the odds ratio was 9.1. A circumstantial factor predisposing to cerebral venous thrombosis (such as oral contraceptive intake, pregnancy, puerperium, trauma or prolonged immobilization) was reported in 72% of cases. In conclusion, APC resistance is the most frequent coagulation abnormality associated with cerebral venous thrombosis. PMID- 8701396 TI - Increased plasma levels of tissue factor pathway inhibitor (TFPI) after n-3 polyunsaturated fatty acids supplementation in patients with chronic atherosclerotic disease. AB - This double-blind, randomised, controlled study examined the effect of a daily dosage of 3 g n-3 polyunsaturated fatty acids (n-3 PUFA) on plasma lipids and some haemostatic factors in 40 patients with chronic atherosclerotic diseases. Serum lipids, factor VII, tissue factor pathway inhibitor (TFPI) and prothrombin activation fragment 1 + 2 (F1 + 2) were measured at baseline and after 2, 8, and 16-week supplementation of either n-3 PUFA or corn oil. Administration of n-3 PUFA promptly lowered serum triglycerides and increased LDL-cholesterol (-32% and +33%, respectively, after 2 weeks of treatment) while a significant increase (+31%) in HDL-cholesterol was documented at the end of the observation period. Treatment with n-3 PUFA induced a progressive significant increase of TFPI plasma levels (+21% after 16 weeks; p = 0.029). TFPI activity was significantly correlated with LDL-cholesterol, and multiple stepwise regression analysis showed that LDL-cholesterol was the most important predictor of TFPI activity. Plasma levels of the inhibitor showed also a very high parallelism in their trend over time (ANOVA model for homogeneity of slopes) with both HDL-cholesterol (p = 0.82) and LDL-cholesterol (p = 0.67). Patients treated with n-PUFA also showed a significant reduction of F1 + 2 plasma levels (p = 0.016) while no significant changes were detected in plasma factor VII clotting activity. Lipid and haemostatic parameters were not modified at any study time in patients receiving corn oil as placebo. The results of this study confirm the effects of n-3 PUFA administration on plasma lipids and show that in patients with chronic atherosclerotic disease a 16-week supplementation with these compounds induces a small but statistically significant increase of TFPI plasma levels with a parallel down-regulation of the extrinsic pathway of blood coagulation which may be relevant to the antithrombotic activity of fish diet and fish oil derivatives. PMID- 8701397 TI - Factor VII gene polymorphisms, factor VII:C levels and features of insulin resistance in non-insulin-dependent diabetes mellitus. AB - The macrovascular complications of non-insulin-dependent diabetes mellitus (NIDDM) are related to the features of insulin resistance (IR). High Factor VII:C (FVII:C) levels are associated with increased cardiovascular risk and relate to a base change in the FVII gene detected by Msp I endonuclease, and also to an insertion polymorphism in the promoter region. To examine the association between FVII:C levels, genotype and features of IR, 95 NIDDM patients were studied. Genotype was related to FVII:C levels (M1M1 137%, n = 75; M1M2 and M2M2 114%, n = 20, p < 0.005; AA 136%, n = 71; Aa 119%, n = 21, p < 0.05), which is consistent with previous studies in healthy populations. FVII:C correlated with cholesterol (r = 0.51, p < 0.0005), insulin (r = 0.36, p = 0.002), triglycerides (r = 0.34, p = 0.001), age (r = 0.23, p < 0.005) and body mass index (r = 0.23, p < 0.05). When analysed by Msp I genotype, the stronger predictor of FVII:C levels, these correlations remained, with no difference in regression slopes. In a multiple regression model, genotype, cholesterol, insulin, and gender remained as independent predictors of FVII:C levels. In conclusion, FVII:C concentrations are elevated in NIDDM in relation to both FVII genotypes and features of IR. PMID- 8701398 TI - Markers of hemostatic system activation during thromboprophylaxis with recombinant hirudin in total hip replacement. AB - Coagulation activation markers were studied in 148 patients undergoing total hip replacement under recombinant-hirudin (Desirudin, Revasc) prophylaxis with the aim of investigating the efficacy and safety of this anticoagulant compared with heparin in terms of biological effects on coagulation variables and bleeding. Hirudin (10, 15 or 20 mg s.c. b.i.d.) or unfractionated heparin (5000 IU s.c. t.i.d.) was administered immediately before surgery and continued for 8-12 days. Activated partial thromboplastin time (aPTT), prothrombin activation fragment F1 + 2 (F1 + 2), thrombin-antithrombin III complexes (TAT) and D-dimer were measured at baseline and on postoperative days 1,3 and 6, immediately before the morning injection. In comparison with baseline values, heparin had little effect on aPTT whereas the three hirudin doses prolonged aPTT significantly with no differences among the three doses. Moreover, there were no group differences in perioperative or cumulative blood loss or transfusion requirements. F1 + 2 fragment, TAT and D dimer plasma levels were higher than at baseline during the entire postoperative period, with different trends (F1 + 2 increasing, TAT decreasing, D-dimer increasing, decreasing and then increasing again), but without significant differences among the four treatment groups. Our findings suggest that specific inhibition of thrombin seems a safe and efficacious mode of blocking thrombin activity after hip surgery although it does not prevent thrombin generation. PMID- 8701399 TI - Evaluation of a new rapid quantitative D-dimer assay in patients with clinically suspected deep vein thrombosis. AB - The sensitivity and specificity for deep vein thrombosis (DVT) of a new rapid, quantitative and precise (total imprecision < 10%) D-dimer assay suitable for individual measurements (VIDAS D-DIMER, bio-Merieux, France) were evaluated in a consecutive series of 103 in- and out-patients submitted to serial compression ultrasonography (C-US) for the clinical suspicion of DVT (n = 66) or of DVT recurrence (n = 37) and symptoms lasting from 1 to 15 days. DVT was found in 22 patients at baseline testing and no patient with an initially negative C-US developed vein incompressibility at follow up. The time elapsed from the onset of symptoms was negatively associated with D-dimer levels both in patients with and in those without DVT. In the entire series of patients, the sensitivity of a positive D-dimer test ( > or = 1.0 microgram/ml) for the presence of DVT was 96% (21/22 patients, 95% confidence interval 75-100%) with a specificity of 75% (64 84%), a negative predictive value of 98% (90-100%), a positive predictive value of 51% (35-67%), and an overall accuracy of 80% (70-87%). A normal D-dimer value (0.22 microgram/ml) was observed in one patient with DVT and symptoms lasting from 15 days. The approach of withholding C-US testing in patients with symptoms lasting from less than 11 days and D-dimer levels below the cut-off value was compared to serial C-US testing alone in a cost-effectiveness analysis subdividing the 66 patients with a first episode according to their clinical pretest probability of DVT. Thrombosis was detected in 6.7% of the patients in the low probability group (n = 15), 16.7% of the patients in the moderate probability group (n = 24), 51.9% of the patients in the high probability group (n = 27) and 8.1% of patients with suspected DVT recurrence. Calculated cost savings for each DVT diagnosed ranged from 5% in the high pretest probability group to 55% in the low pretest probability group and to 77% in patients with suspected DVT recurrence. The safety of avoiding C-US testing in symptomatic patients with a negative D-dimer test should be evaluated in clinical management studies. PMID- 8701400 TI - Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency. AB - We investigated the presence of the gene mutation of factor V, FV R506Q or factor V Leiden, responsible for activated protein C resistance, in DNA samples of 127 probands and 188 relatives from 128 families with antithrombin deficiency. The factor V mutation was identified in 18 families. Nine families were available to assess the mode of inheritance and the clinical relevance of combined defects. The factor V and antithrombin genes both map to chromosome 1. Segregation of the defects on opposite chromosomes was observed in three families. Co-segregation with both defects on the same chromosome was demonstrated in four families. In one family a de novo mutation of the antithrombin gene and in another a crossing over event were the most likely explanations for the observed inheritance patterns. In six families with type I or II antithrombin deficiency (reactive site or pleiotropic effect), 11 of the 12 individuals with both antithrombin deficiency and the factor V mutation developed thrombosis. The median age of their first thrombotic episode was 16 years (range 0-19); this is low compared with a median age of onset of 26 years (range 20-49) in 15 of 30 carriers with only a defect in the antithrombin gene. One of five subjects with only factor V mutation experienced thrombosis at 40 years of age. In three families with type II heparin binding site deficiencies, two of six subjects with combined defects experienced thrombosis; one was homozygous for the heparin binding defect. Our results show that, when thrombosis occurs at a young age in antithrombin deficiency, the factor V mutation is a likely additional risk factor. Co segregation of mutations in the antithrombin and factor V genes provides a molecular explanation for severe thrombosis in several generations. The findings support that combinations of genetic risk factors underly differences in thrombotic risk in families with thrombophilia. PMID- 8701401 TI - "Pseudo homozygous" activated protein C resistance due to double heterozygous factor V defects (factor V Leiden mutation and type I quantitative factor V defect) associated with thrombosis: report of two cases belonging to two unrelated kindreds. AB - Two unrelated patients belonging to two Italian kindreds with a history of thrombotic manifestations were found to have a double heterozygous defect of factor V (F. V), namely type I quantitative F.V defect and F.V Leiden mutation. Although DNA analysis confirmed the presence of a heterozygous F.V Leiden mutation, the measurement of the responsiveness of patients' plasma to addition of activated protein C (APC) gave results similar to those found in homozygous defects. It has been recently reported in a preliminary form that the coinheritance of heterozygous F. V Leiden mutation and type I quantitative F. V deficiency in three individuals belonging to the same family resulted in the so called pseudo homozygous APC resistance with APC sensitivity ratio (APC-SR) typical of homozygous F.V Leiden mutation. In this study we report two new cases of pseudo homozygous APC resistance. Both patients experienced thrombotic manifestations. It is likely that the absence of normal F.V, instead of protecting from thrombotic risk due to heterozygous F.V Leiden mutation, increased the predisposition to thrombosis since the patients became, in fact, pseudo-homozygotes for APC resistance. DNA-analysis is the only way to genotype a patient and is strongly recommended to confirm a diagnosis of homozygous F.V Leiden mutation also in patients with the lowest values of APC-SR. It is to be hoped that no patient gets a diagnosis of homozygous F.V Leiden mutation based on the APC-resistance test, especially when the basal clotting tests, i.e., PT and aPTT; are borderline or slightly prolonged. PMID- 8701402 TI - Platelet-derived microvesicles in thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. AB - Thrombotic thrombocytopenic purpura (TTP) and the related hemolytic uremic syndrome (HUS) are disorders characterized by thrombocytopenia, microangiopathic hemolytic anemia, a variable degree of impairment of renal function and fluctuating neurological symptoms, which are thought to be due to platelet activation and subsequent formation of thrombi in the microcirculation. Since platelet activation is accompanied by the generation of microvesicles (PMPs), we determined their presence in patients with TTP and HUS by flow cytometry. The analysis was performed in whole blood, using FITC-conjugated monoclonal antibodies (CD 42b and/or CD 61a). PMPs were discriminated from platelets on the basis of size and fluorescence profiles. Their levels in 21 normal controls ranged between 2.4% and 9.4% (mean +/- SD: 5.2 +/- 1.99%). No correlations were found with platelet number. PMPs were then evaluated in 13 patients with TTP and 2 cases of HUS. In all patients they were found higher than in controls, ranging from 11.0 to 91.1% (45.0 +/- 26.0%; p = 0.0001 vs controls). PMPs were serially measured in patients with TTP: at diagnosis a correlation between PMPs and platelet number was found (R]2 = 0.669) and the time-course showed that the improvement of both microangiopathy and clinical manifestations of cerebral and renal involvement was accompanied by a progressive normalization of PMP levels and platelet count. PMP levels were measured also in patients suffering from other forms of thrombocytopenia: they were 17 patients with idiopathic thrombocytopenic purpura and 10 patients with acute leukemias and severe thrombocytopenia during the aplastic phase following chemotherapy. PMP ranges were: 2.0-79.6% (21.6 +/- 20.8%; p = 0.001 vs controls) and 4.6-12.5% (8.8 +/- 2.4%; p = 0.0001 vs controls), respectively. No correlations were found between platelet number and the absolute number of PMPs in these 2 groups of patients. These findings show that increased levels of PMPs may be found in peripheral thrombocytopenias and suggest that their presence may be clinically relevant, particularly in the microangiopathic forms. PMID- 8701403 TI - Feasibility of using recombinant factor VIIa in continuous infusion. AB - Recombinant factor VIIa (rFVIIa; NovoSeven) is a recent addition to the hemostatic alternatives for the treatment of hemophiliacs with inhibitors. A drawback in the use of rFVIIa has been its half-life of only about 2 h, which necessitates very frequent and punctual injections. We evaluated the stability of reconstituted, but not further diluted, rFVIIa in 3 infusion systems (WalkMed 350 and CADD-Plus minipumps and Meddex 2001 syringe pump). The factor VII (F VII) activity was maintained for at least 3 days at room temperature with only a minor and clinically insignificant increase in oxidized forms of rFVIIa and minimal leaching of the plastic softeners dibutylphthalate and di-octylphthalate after 24 48 h. Addition of heparin, 5-10 U/ml, to reconstituted rFVIIa caused a loss of about 50% of the activity within 4 h of storage in the infusion system, whereas low molecular weight heparin had no such effect. Repeated samples showed that the infusion systems maintained sterility. Reconstituted rFVIIa did not support bacterial growth when inoculated with Staphylococcus aureus or Escherichia coli to any greater extent than did reconstituted factor VIII, lidocaine in saline or heparin in saline. Two patients were treated with continuous infusion of rFVIIa on 4 occasions (total knee arthroplasty, wound revision, and twice straightening of a 90 degrees contracture of the knee under general anaesthesia). A preoperative pharmacokinetic evaluation was performed, and the clearance was used to calculate the maintenance dose, aiming at a FVII level of 10 U/ml, which proved to be a hemostatic level. The first patient had no change in the clearance during the two treatment episodes. He suffered from repeated thrombophlebitis at the infusion site. The second patient had a progressive decrease of the clearance from 86.4 to 24.7 ml/h/kg. He received during the first treatment a parallel infusion with heparin (approximately 250 U/24 h) to the same venous access and did not develop thrombophlebitis during 3.5 days of therapy. For the second episode low molecular weight heparin was added directly to the infusion bag, and no adverse effects were observed. Continuous infusion with rFVIIa is thus feasible with the minipumps used by us, eliminates the need for 2 h injections and reduces the total dose of rFVIIa by 50-75%, depending on the behaviour of the clearance. PMID- 8701404 TI - Five novel mutations of the protein S active gene (PROS 1) in 8 Norman families. AB - To further elucidate the molecular basis for hereditary thrombophilia, we screened the protein S active gene in 11 families with type I deficiency, using a strategy based on denaturing gradient gel electrophoresis (DGGE) of all the coding sequences. Fragments with an abnormal DGGE pattern were sequenced, and 5 novel mutations were identified in 8 families. The mutations were a 7-nucleotide deletion in exon II, a 4-nucleotide deletion in exon III, a T insertion in exon VII, a C to T transition transforming Leu 259 into Pro and a T to C transition transforming Cys 625 into Arg in 4 families. These mutations were the only sequence variations found in the propositus' gene exons and co-segregated with the plasma phenotype. A total of 28 members of these 8 families were heterozygous for one of the 5 mutations. Twenty-four (58,5%) of the 41 deficient subjects over 18 years of age had clinical thrombophilia, whereas the 13 subjects under 18 were asymptomatic. Of the 28 subjects, 6 (21,5%) were also found to bear the factor V Arg 506 Gln mutation. PMID- 8701405 TI - Factor XIa induced activation of the intrinsic cascade in vivo. AB - Coagulation factor XI is a glycoprotein of the contact factor system. Its deficiency is associated with a highly variable bleeding tendency, thus a role in relation to hemostasis appears to exist. However, the importance of factor XI for stimulating intrinsic coagulation in vivo has not yet been determined. To study the procoagulant effects of human factor XIa in vivo, we infused the purified enzyme into normal chimpanzees (100 micrograms) in the absence or presence of the thrombin inhibitor rec-hirudin (1.0 mg/kg loading dose plus 0.3 mg/kg body wt continuous infusion). Factor XIa elicited an immediate activation of factors IX, X, and prothrombin, as measured by their respective activation fragments. However, whereas the activation of factors IX and X was immediate and shortlasting, (peak increments of 6- and 1.4-fold of baseline at 5 minutes after injection), the conversion of prothrombin gradually increased, reaching a summit of 6-fold baseline values after 60 min, and remaining elevated during the course of the experiments. Thrombin-antithrombin complexes also remained elevated during the study period. In the presence of hirudin, the initial activation of factors IX, X, and prothrombin was unchanged, however the further increment in prothrombin fragment F1 + 2 was markedly inhibited. These results demonstrate that factor XIa is a potential agonist of the intrinsic cascade in vivo, which activity is enhanced in the presence of thrombin. PMID- 8701406 TI - Isolation and characterization of canine factor IX. AB - Canine plasma factor IX was purified to homogeneity by a combination of barium citrate precipitation and three-step column chromatographies of DEAE sepharose, heparin agarose and a monoclonal antifactor IX antibody-linked agarose. Canine factor IX has an apparent molecular size of 61 kDa, which is slightly smaller than that of human factor IX, as determined by denatured polyacrylamide gel electrophoresis. Its amino acid composition, amino-terminal and carboxyterminal amino acid sequences agreed well with those predicted from the reported cDNA. Unlike purified human factor IX, canine factor IX preparation often showed a discrete smaller molecular species (approximately 50 kDa) which was generated by a specific proteolytic cleavage between Arg310 and Val311. When purified canine factor IX was utilized as a standard for enzyme linked immunosorbent assay, the concentration of canine factor IX in the pooled normal dog plasma was determined to be 5.3 micrograms/ml with 11.2% carbohydrate content (or 4.7 micrograms/ml for its polypeptide chain moiety). Concentration of plasma factor IX antigen was measured in six severely affected, unrelated hemophilia B dogs. Four had factor IX antigen of less than 1% of the normal, and two had undetectable levels. The latter two had gross molecular abnormalities in their factor IX genes. Three obligate carrier females had variable but proportionately reduced factor IX antigen and factor IX coagulant activity levels. These results provide a quantitative method for measuring canine factor IX antigen which is a prerequisite for studying hemostasis and development of gene transfer approaches in the canine model of hemophilia B. PMID- 8701407 TI - Antibodies to prothrombin imply a risk of myocardial infarction in middle-aged men. AB - Antiphospholipid antibodies in patients with "antiphospholipid syndrome" may be directed at least in part against plasma phospholipid-binding proteins, such as beta 2-glycoprotein I or prothrombin, which are involved in the control of thrombosis and haemostasis. IgG-class antibodies against prothrombin and beta 2 glycoprotein I were measured by enzyme-linked immunoassay in initially healthy middle-aged dyslipidaemic men (non-high-density lipoprotein > 5.2 mml/l). Serum samples had been drawn at entry to a 5-year coronary primary-prevention trial with gemfibrozil from 106 subjects who experienced either a non-fatal myocardial infarction or cardiac death during the follow-up and from 106 subjects without coronary episodes, matched for treatment group (gemfibrozil/placebo) and geographical area. The antiprothrombin antibody level, as expressed in optical density units, was significantly higher in patients than in controls (0.26 +/- 0.17 versus 0.22 +/- 0.09; p < 0.02). A high level of antiprothrombin antibodies (highest tertile of distribution) predicted a 2.5-fold increase in the risk (95% confidence interval 1.2-5.3) of myocardial infarction or cardiac death. The distribution of IgG-class antibodies against beta 2-glycoprotein I did not differ significantly between cases and controls. The joint effect of antiprothrombin antibodies and other factors associated with hypercoagulative state: triglyceride level, lipoprotein(a) and smoking, was multiplicative for the risk. Antiprothrombin antibodies are a new immunological predictor of myocardial infarction and the effect of these antibodies may be mediated by hypercoagulative mechanisms. PMID- 8701408 TI - Technical and biological conditions influencing the functional APC resistance test. AB - Poor anticoagulant response to APC is conveniently screened by a commercially available functional test (Coatest APC Resistance) allowing identification of APC resistant patients. These patients may then be genotyped with respect to factor V, the Arg -> Gln mutation being the principle cause of APC resistance. However, determination of phenotype generally precedes that of genotype, and the need for an "abnormality threshold" prompted a study of inter-batch variations and the clinical conditions associated with an altered APC response. The response to APC was assessed twice in plasma from 111 patients using two of four successive kit batches. A modest but significant inter-batch variability was observed. At the same time, we also tested 130 patients with retinal venous occlusion (RVO), 28 patients with glaucoma and 24 normal volunteers. The APCaPTT/aPTT ratio was found to be lower in the presence of elevated thrombin-antithrombin complexes (r = 0.167, p < 0.02) and low blood viscosity (at high shear rate: r = 0.305, p < 0.0001) independently of any alteration in genotype. PMID- 8701409 TI - Identification and biosynthesis of fibrinogen in human uterine cervix carcinoma cells. AB - Fibrinogen has been detected in ME-180 human uterine cervix carcinoma cells, and synthesis of fibrinogen by ME-180 cells has been measured using [35S] L methionine incorporation. Expression of mRNA for the B beta-chain of the fibrinogen in ME-180 cells has been identified by PCR-assisted mRNA amplification. The A alpha-, B beta-, and gamma-chains of fibrinogen synthesized by ME-180 cells were chemically and immunologically identical to those of plasma fibrinogen. These findings suggest that fibrinogen is present and synthesized in ME-180 human uterine cervix carcinoma cells, and that fibrinogen plays a role in these malignant tumor cells. PMID- 8701411 TI - Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential medroxyprogesterone acetate: a 1-year, double-blind, placebo controlled study. The Writing Group for the Estradiol Clotting Factors Study. AB - After menopause the haemostatic balance shifts towards a latent hypercoagulable state. To evaluate the effects of two regimens of transdermal estradiol (E2) combined with progestin on the balance between procoagulant factors and inhibitors, 255 women in physiological menopause for 1-5 years were randomly allocated to 1 year of treatment with cyclic transdermal E2 (50 micrograms/day for 21 days) plus medroxyprogesterone acetate (MPA) (10 mg/day from days 10 to 21), continuous transdermal E2 (50 micrograms/day for 28 days) plus MPA (10 mg/day from days 14 to 25), or placebo. Fibrinogen, factor VII (FVII), factor VIII:C (FVIII:C), antithrombin III (ATIII), protein C, protein S, heparin cofactor II (HCII) and plasminogen activator inhibitor (PAI-1) levels were measured at baseline and after 6 and 12 cycles. 167 women who took the treatment for at least 6 cycles were evaluable. The continuous treatment group had significantly lower final values of fibrinogen, FVII, ATIII, protein S and HCII than the placebo group; the cyclic treatment reduced fibrinogen in comparison with placebo but the difference was not significant. In conclusion, both regimens produce a clinically relevant decrease of fibrinogen levels; the continuous regimen affects also the levels of FVII and inhibitors suggesting that the haemostatic balance is shifted to a more physiological state. PMID- 8701410 TI - DDAVP reduces bleeding during continued hirudin administration in the rabbit. AB - Hirudin is a potent thrombin inhibitor derived from the leech Hirudo medicinalis salivary gland which has considerable potential for therapeutic use in thrombotic disease. The major risk attendant its use is hemorrhage. This study investigates the hypothesis that the prohemostatic effects of DDAVP infusion can curtail the hemorrhagic effect induced by ongoing hirudin administration. In a randomized and blinded manner, rabbits were exposed to a 15-min intravenous infusion of DDAVP or saline midway through a continuous two-h intravenous infusion of hirudin. Bleeding time was monitored by full thickness ear punctures performed before, during and after hirudin exposure. Hirudin induced a significant hemorrhagic state, manifest as a 7-10-fold prolongation of the primary bleeding time. DDAVP reduced the mean duration of primary bleeding from 10.8 min to 5.9 min (p = 0.001) as well as the number of sites which bled for longer than 6 or 20 min (46% vs 27%, p = 0.002; and 18% vs 5%, p = 0.002, respectively). Although there was no difference in the incidence of spontaneous rebleeding from these sites (44 vs 36%, p = 0.21), rebleeding did not persist as long in animals that received DDAVP (8 vs 16 min, p = 0.005), and fewer sites rebled for longer than 20 min (8 vs 27%, p = 0.027). Results were essentially the same for two different commercial recombinant hirudin preparations. DDAVP appears to attenuate the bleeding caused by continuous hirudin infusion in rabbits and establishes a foundation for clinical assessment in patients. PMID- 8701413 TI - Comparison between recombinant and rabbit thromboplastin in the management of patients on oral anticoagulant therapy. AB - The aim of this study was to compare recombinant thromboplastin (rTF, ISI = 0.82) with rabbit thromboplastin (RT, ISI = 1.46) in order to evaluate which performed better in our thrombosis centre. To this purpose we randomized 67 patients to be double-blind monitored in two groups for three months either with PT performed with RT or with PT performed with rTF. After this period each patient was shifted to the other group. We considered the following as end points of the study: percentages of PT results within the therapeutic range, number of visits and therapeutic dose adjustments per patient. The "last check in file" method was used to evaluate the laboratory quality of oral anticoagulation for both thromboplastins. The results show that there was no difference in the number of visits per patient between the two groups: 6.9 +/- 1.7 in the rTF group versus 7.3 +/- 1.9 in the RT group (p = 0.19). The variations of therapeutic dose per patient were not different in the two groups: the dose was changed once (range 0 8) in the rTF group and once (range 0-11) in the RT group (p = 0.15). The percentages of PT results within the therapeutic range were not different between the two groups. The "last check in file" method showed similar percentages in both groups: PT results in the therapeutic range were 67.2% in the RT group and 68.8% in the rTF group. We conclude that the two thromboplastins had a similar effect on the end points of the study in spite of the relatively high ISI of the RT. PMID- 8701412 TI - Characterization of a cDNA encoding murine coagulation factor VII. AB - The cDNA encoding murine coagulation factor VII (mfVII) was isolated and reconstructed from a lambda Zap cDNA library generated from murine liver mRNA. The cDNA contains 1903 nucleotides spanning 15 bases upstream of the 5' translation initiation codon, an open reading frame of 1338 nucleotides, 550 nucleotides downstream of the first stop codon and a 3' poly(A) tail. The translation product is composed of a 41-amino acid signal/propeptide region followed by a 405-residue mature protein. The latter is highly homologous to that of human, rabbit, bovine, Rhesus monkey, and canine fVII. All protein domains of hfVII are strictly conserved in mfVII. PMID- 8701414 TI - Physico-chemical properties and the structure of dermatan sulfate fractions purified from plasma after oral administration in healthy human volunteers. AB - Dermatan sulfate (DS) was administered by oral route in healthy human volunteers. The structure, physico-chemical properties and biological activity of DS purified from human plasma after oral administration were studied and compared with those of native DS. DS extracted and purified from pig mucosa has a relative molecular mass (Mr) of about 23,100 and is composed of about 10% nonsulfated disaccharide, 80% monosulfated disaccharides and about 10% disulfated disaccharides, with a sulfate to carboxyl ratio of 1.00 and a heparin cofactor II (HCII) activity of about 160 units/mg. This native polysaccharide is composed of about 94% iduronic acid. One gram of native DS was orally administered to five healthy human volunteers, and 50 ml of blood were collected after 4 h. DS possibly present in plasma after oral administration was extracted and purified. About 130 +/- 42 micrograms of DS per 50 ml of blood were detected by agarose-gel electrophoresis and DMB assay. This DS shows a broad Mr range. After oral absorption, substantial amounts of species with a Mr of about 7,500 are detected in blood but chains with Mr ranging from 7,500 to 20,000 are also found. Moreover, some very low-Mr species are detected, with a prevalence of disaccharides. After oral absorption, DS is sulfated above all in position 4 of the N-acetyl-galactosamine (60%), with a sulfate to carboxyl ratio of about 0.64, demonstrating that DS is desulfated during or after oral absorption by about 30-40%, A small amount of disulfated disaccharide (in particular 2,4-disulfated, 1.4%) is preserved from catabolic processes, as DS extracted from human plasma is able to inhibit thrombin activity mediated by HCII (about 16 U/mg). PMID- 8701415 TI - Effect of lipoprotein(a) and LDL on plasminogen binding to extracellular matrix and on matrix-dependent plasminogen activation by tissue plasminogen activator. AB - Lp(a) is an LDL-like lipoprotein plus an additional apolipoprotein apo(a). Based on the structural homology of apo(a) with plasminogen, it is hypothesized that Lp(a) interferes with fibrinolysis. Extracellular matrix (ECM) produced by human umbilical vein endothelial cells was used to study the effect of Lp(a) and LDL on plasminogen binding and activation. Both lipoproteins were isolated from the same plasma in a single step. Plasminogen bound to ECM via its lysine binding sites. Lp(a) as well as LDL were capable of competing with plasminogen binding. The degree of inhibition was dependent on the lipoprotein donor as well as the ECM donor. When Lp(a) and LDL obtained from one donor were compared, Lp(a) was always a much more potent competitor. The effect of both lipoproteins on plasminogen binding was reflected in their effect on plasminogen activation. It is speculated that Lp(a) interacts with ECM via its LDL-like lipoprotein moiety as well as via its apo(a) moiety. PMID- 8701416 TI - Pentamidine is a specific, non-peptide, GPIIb/IIIa antagonist. AB - Pentamidine was previously shown to act on glycoprotein (GP) IIb/IIIa (Cox et al., Thromb Haemost 1992; 68: 731). In this paper we study the effect of pentamidine on other RGD-dependent receptors. In a cell adhesion assay, pentamidine was 500 times more potent than RGDS at inhibiting platelet adhesion to fibrinogen. While RGDS inhibited platelet adhesion to fibronectin, endothelial cell adhesion to vitronectin or fibronectin, 293 cell adhesion to vitronectin, IMR 32 cell adhesion to fibronectin and C32 cell adhesion to vitronectin; pentamidine failed to inhibit these interactions at doses as high as 1 mM. Resting platelets fixed in the presence of 1 mM RGDS had increased binding of fibrinogen, i.e., RGDS activated GPIIb/IIIa, while pentamidine at 100 microM had no effect. Similarly, RGDS induced the binding of an anti-LIBS monoclonal antibody, while pentamidine had no effect. Pentamidine partially, but significantly, inhibited lysosome and alpha-granule release induced by the thrombin agonist peptide, while RGDS had no effect. Neither pentamidine nor RGDS affected ADP-induced Ca2+ influx. Pentamidine had no effect on ADP-induced intracellular pH changes while RGDS prevented the pH from returning to normal. Thus, pentamidine is a non-peptide GPIIb/IIIa antagonist that is non-activating and is specific for GPIIb/IIIa. PMID- 8701417 TI - A prostacyclin-sparing effect of indobufen vs. aspirin. AB - Indobufen ((+/-)-2-[p-(1-oxo-2-insoindolinyl)-phenyl]-butyric acid, indo) is a drug inhibiting platelet function by a reversible block of the arachidonic acid metabolism at the level of cyclooxygenase. Since tolerability profile of such drugs is mostly linked to extra-platelet cyclooxygenase inhibition, we prospectively evaluated the extent of platelet and extra-platelet cyclooxygenase inhibition by in vivo administration of indo in comparison with ASA. We assessed the effects of the two drugs on the ex vivo generation of TXB2 and 6-keto-PGF1 alpha in whole blood, as indices of the production of TXA2 and PGI2 (prostacyclin), respectively, either after spontaneous clotting at 37 degrees C for 1 h (Study 1) or after the addition of 2 micrograms/ml collagen (Study 2). Generation of 6-keto-PGF1 alpha in whole blood is a mixed index of platelet and extra-platelet cyclooxygenase activity, deriving from both platelet and white blood cell arachidonic acid metabolization. Fifteen patients with ischemic heart disease and baseline serum TXB2 levels > 300 ng/ml were allocated to receiving one single administration of either indobufen 200 mg (n = 6) or aspirin 500 mg (n = 9). Whole blood prostanoid generation was assessed at 0, 1, 2, 4, 6, 8, 12 and 24 h after drug administration (Study I). Ten healthy male volunteers were allocated to a double-blind, randomized crossover comparison of indo 200 mg b.i.d. vs. ASA 300 mg/d for 7 days (Study 2). Prostanoid generation and whole blood platelet aggregation were performed before and at the end of each study period (Day 0 and Day 7). At each time-point after single dose administration (Study 1), indobufen caused less % inhibition of whole blood 6-keto-PGF1 alpha than of TXB2. At 2 h, TXB2 was reduced to a similar extent after ASA (98 +/- 4%) and indo (97 +/- 6%) (p = N.S.), while inhibition of 6-keto-PGF1 alpha was clearly different ( > 98% after ASA, 81 +/- 2.5% after indo, p < 0.01). After one week of ASA or indo (Study 2) the maximum extent of whole blood platelet aggregation was similarly inhibited (from 17.2 +/- 1.4 ohms to 3.6 +/- 1.3 ohms with ASA; from 18.3 +/- 1.0 ohms to 1.6 +/- 0.7 ohms with indo (p ASA vs. indo = N.S.). Despite equal inhibition of whole blood TX production after collagen (from 49.0 +/- 4.3 ng/ml to 1.1 +/- 0.6 ng/ml with ASA, from 49.8 +/- 1.3 ng/ml to 1.4 +/- 0.6 ng/ml with indo), again, however, 6-keto-PGF1 alpha production was less affected by indo than by ASA (from 409 +/- 30 pg/ml to 37 +/- 13 pg/ml with ASA, inhibition = 91%; from 396 +/- 35 to 318 +/- 40 with indo, inhibition = 20%). These differential effects of indo and ASA might lead to a better platelet selectivity, tolerability and benefit/risk profile of indo vs. ASA, which are worthy of further assessment. PMID- 8701418 TI - Interventional thermal injury of the arterial wall: unfolding of von Willebrand factor and its increased binding to collagen after 55 degrees C heating. AB - PURPOSE: Thermal angioplasty alters the thrombogenicity of the arterial wall. In previous studies, platelet adhesion was found to increase after heating human subendothelium to 55 degrees C and decrease after heating to 90 degrees C. In the present electron microscopic study, the mechanism of this temperature-dependent platelet adhesion to the heated arterial wall is elucidated by investigating temperature-dependent conformational changes of von Willebrand factor (vWF) and collagen types I and III and the binding of vWF to heated collagen. METHODS: Purified vWF and/or collagen was applied to electron microscopic grids and heated by floating on a salt-solution of 37 degrees C, 55 degrees C or 90 degrees C for 15 s. After incubation with a polyclonal antibody against vWF and incubation with protein A/gold, the grids were examined by electron microscopy. RESULTS: At 37 degrees C, vWF was coiled. At 55 degrees C, vWF unfolded, whereas heating at 90 degrees C caused a reduction in antigenicity. Collagen fibers heated to 37 degrees C were 60.3 +/- 3.1 nm wide. Heating to 55 degrees C resulted in the unwinding of the fibers, increasing the width to 87.5 +/- 8.2 nm (p < 0.01). Heating to 90 degrees C resulted in denatured fibers with an enlarged width of 85.1 +/- 6.1 nm (p < 0.05). Heating of collagen to 55 degrees C resulted in an increased vWF binding as compared to collagen heated to 37 degrees C or to 90 degrees C. Incubation of collagen with vWF, prior to heating, resulted in a vWF binding after heating to 55 degrees C that was similar to the 37 degrees C binding and a decreased binding after 90 degrees C. CONCLUSIONS: After 55 degrees C heating, the von Willebrand factor molecule unfolds and collagen types I and III exhibit an increased adhesiveness for von Willebrand factor. Heating to 90 degrees C denatures von Willebrand factor and collagen. The conformation changes of von Willebrand factor and its altered binding to collagen type I and III may explain the increased and decreased platelet adhesion to subendothelium after 55 degrees C and 90 degrees C heating, respectively. PMID- 8701419 TI - Improved Method for factor V Leiden typing by PCR-SSP. PMID- 8701420 TI - Detection of the factor V Leiden mutation using whole blood PCR. PMID- 8701421 TI - The modified APC resistance test in the presence of factor V deficient plasma can be used in patients without oral anticoagulant. PMID- 8701422 TI - Lack of activated protein C resistance in healthy Hong Kong Chinese blood donors- correlation with absence of Arg506-Gln mutation of factor V gene. PMID- 8701423 TI - Warfarin induced skin necrosis associated with activated protein C resistance. PMID- 8701424 TI - Oral contraceptives and screening for factor V Leiden. PMID- 8701425 TI - Purpura fulminans in a patient homozygous for a mutation in the protein C gene- prenatal diagnosis in a subsequent pregnancy. PMID- 8701427 TI - [Growth promotors in animal husbandry: between fancy and fact]. AB - The use of growth promotors, such as steroid hormones, beta-agonists and somatotropins, may result in animal health and welfare risks and raise ethical questions. From this point of view some fundamental statements are discussed. Growth promotors do not contribute to an efficient production of essential nutritional needs for man. There is a need for a consistent policy aiming at sustainable agriculture and world food supply. Animal husbandry cannot be regarded as a simple technical-economical enterprise because of the intrinsic biological values involved. If growth promotors are almost exclusively judged on safety criteria than questions of principle are avoided. The choice to use growth promotors cannot be left to self-regulation based on self-interest and/or be made subject to international trade agreements governed by economic considerations only. In the production of food the price for the protection of the environment and the animals ought to be paid. It is time to make future oriented choices. PMID- 8701426 TI - [Insight in SVD epidemiology. Specimen collection Regulation Farm Surveillance Animal Diseases]. AB - Periodic (4-monthly) surveillance of pig herds for antibodies against swine vesicular disease (SVD) is obligatory in the Netherlands since 1993. Samples should be collected "at random' in as many compartments as possible, with a maximum of one pig per pen. This prerequisite for a sensitive surveillance will be elucidated using four examples of SVD outbreaks in the Netherlands. PMID- 8701428 TI - [Farewell Andries van Foreest combined with Specialists' Day. Zoo-veterinarian relationship central in Ouwehand]. PMID- 8701429 TI - [Communication: fast - faster......too late?]. PMID- 8701430 TI - [Double-muscled heifer]. PMID- 8701431 TI - [Prof. Pijpers talks. Members benefit form expansion specialty pharmacy. Interview by Jan Hulsen]. PMID- 8701432 TI - Glycosomes--the organelles of glycogen metabolism. AB - This article reviews the data concerning the electron microscopical interpretation of glycogen. It demonstrates that glycogen in the cell is associated with the enzymes involved in its metabolism and that the glycogen protein complex forms morphologically distinct cell organelles called glycosomes. Glycogen can be visualized in the electron microscope (EM) by histochemical procedures, or by negative staining, but it does not react with heavy metals such as uranium and lead. The protein component of glycosomes, stainable by heavy metals, appears in EM as 20-30 nm granules. While biochemical findings have long indicated the association of glycogen and protein in the cell, morphological interpretation traditionally defined the protein component of glycosomes as particles of glycogen. Accordingly, the term alpha or beta particles, introduced to define particles of glycogen, became subsequently applied to the protein component visible in sections stained by heavy metals. The history of microscopic research reveals the conditions which led to such interpretation. Morphological analysis of the reaction of glycosomes to the acids shows that glycosomes deposited free in the cytosol (lyoglycosomes) are acid labile, whereas the others (desmoglycosomes), intimately associated with different cellular structures, are acid-resistant. These 2 groups correspond to lyo- and desmoglycogen distinguished in early biochemical studies on the basis of their different resistance to the cold trichloroacetic acid. The theory of glycosomes provides a new paradigm which clarifies numerous unexplained data in the microscopic literature on glycogen, and opens a vast field for the research on the cellular metabolism of glycogen, with the use of modern molecular and cellular biology techniques. PMID- 8701433 TI - Quantitative analysis of glycogen content in hepatocytes of portal and central lobule zones of normal human liver and in patients with chronic hepatitis of different etiology. AB - Glycogen content was determined in hepatocytes of different lobule zones of the normal human liver (23 patients without any liver pathology) and the liver of patients with chronic viral B hepatitis (30 patients) and chronic alcohol hepatitis (28 patients). All the patients were males and aged between 17-50 years. Quantitative analysis of the glycogen content in hepatocytes of portal and central lobule zones was carried out in sections of the human liver (material of functional biopsies) stained with PAS-reaction. The measurements were carried out using an image analyser 'Magiscan' which allows combined cytophotometric analysis of a substance in cells and determination of the cell localization in tissue. The results showed significant differences of the glycogen content in different lobule zones in the normal liver and in the liver in chronic viral and alcohol hepatitis. Ratios of glycogen content in hepatocytes of the portal and the central zones of liver lobule were 1.128 +/- 0.004 and 1.061 +/- 0.003 in normal human liver, and liver of patients with chronic viral hepatitis respectively, i.e. the glycogen content in hepatocytes of the portal lobule zone was much higher than in the central lobule zone in the normal liver and in the liver of patients with chronic viral B hepatitis. The ratio in patients with chronic alcohol hepatitis was less than 1.0 (0.930 +/- 0.003), i.e. a significantly higher glycogen content was found in hepatocytes of the central liver lobule zone. Possible mechanisms of this phenomenon are discussed. Thus, the pattern of the glycogen content in hepatocytes of different lobule zones can be used as an indicator of etiology of chronic hepatitis. PMID- 8701434 TI - Further studies on the organization of the hydrogenosome in Tritrichomonas foetus. AB - The fine structure of the hydrogenosome of Tritrichomonas foetus was analysed using different approaches: routine transmission electron microscopy, quick freezing techniques followed by freeze-fracture, deep-etching and freeze substitution, cryo-ultramicrotomy, serial sectioning followed by three dimensional (3D) reconstruction and cytochemical detection of carbohydrates, Ca++ and phosphates. The presence of two closely apposed unit membranes surrounding the hydrogenosome, as well as its internal vesicle, was shown both in thin sections of well-preserved cells and in freeze-fracture replicas. Analysis of light micrographs, thin serial sections used to 3-D reconstruction and freeze fracture replicas, show that the hydrogenosome of T. foetus resembles a sphere, but presents a protusion towards the cytoplasm. The vesicle varies in size from organelle to organelle and represent about 8.5% of the volume of the organelle. Based on the fact that the vesicle (a) presents a distinct morphological appearance from the hydrogenosome matrix, (b) was the main site of Ca++ accumulation, (c) presents phosphatase activity and (d) its membrane presents N acetyl-glucosamine-containing glycoconjugates, as revealed by incubation of cryosections in the presence of gold-labeled WGA, we conclude that it represents a specialized sub-compartment of the hydrogenosome. Freeze-fracture followed by deep etching showed the presence of large number of particles, probably correspondent to macromolecules, within the hydrogenosomal matrix. These structures were not randomly distributed. PMID- 8701435 TI - Immunohistochemical and histochemical characterisation of epithelial cells of rabbit lacrimal glands in tissue sections and cell cultures. AB - The purpose of this study was to establish conditions for isolation and long term culture of acinar cells from the Harderian gland, and superior and inferior lacrimal glands of the rabbit and to compare the in vitro growth patterns of cultured cells from these glands. In order to determine the predominant cell type in the cultures, cells and tissue sections were stained using a variety of antibodies to cytokeratins, smooth muscle actin, and neuron specific enolase. Similarly, PAS and alcian blue histochemistry were used to test for the presence of mucins. The glands were excised and cells isolated using enzymatic digestion and then established in long term culture. Different media and substrata were trialed for suitability. When cultured on uncoated Costar plastic in DMEM/10%FBS, the pattern of cell growth was similar for all glands with distinct phases involving aggregation and migration out from the aggregates before cells died between 20 to 30 days. Immunohistochemical staining indicated that the cultures were of acinar cells with a small percentage of ductal cells. The acinar cells of the lacrimal glands in situ and in vitro stained with antibody MNF116 directed against cytokeratins 5, 6, 8 and 17 but did not stain for antibodies to cytokeratin 18. The reverse staining pattern was true for the Harderian gland. Sections from the white lobe of the Harderian gland showed islets of serous secreting cells which showed positive staining when MNF116 was used. In situ, PAS positive cells were found in a small number of demilunes in the superior and inferior lacrimal glands and also in cells of the intercalated ducts. Surprisingly, in culture nearly all cells, including those isolated form the Harderian gland became PAS positive. In this study we have demonstrated that acinar cells from the Harderian and lacrimal glands of rabbit can be isolated and maintained in culture for 20 to 30 days, and that despite dramatic morphological changes, these cells retain their distinctive phenotype as indicated by antibody staining to specific cellular structural proteins such as cytokeratins and actin. However, the cultured cells also begin to produce mucins as indicated by PAS staining. PMID- 8701436 TI - Identification of two types of smooth muscle cells from rabbit urinary bladder. AB - Cells from the muscular layer of neonatal (3-day-old) rabbit urinary bladders were dissociated with collagenase, and cultured in M199 supplemented with 10% fetal bovine serum and antibiotic-antimycotic. Cells in culture were of two types: long and short. The short cells were thick and spindle-shaped, and the long cells were flat and elongated. The long cells can be about 15 times longer than the short cells. The short cells do not divide, but the long cells divide readily. Expressions of smooth muscle and non-muscle myosins, alpha-smooth muscle actin, vimentin, and h-caldesmon were determined by immuno-fluorescence microscopy using specific antibodies. Both types of cells react strongly with antibodies against smooth and non-muscle myosins. Unlike the short cells, the long cells also contain alpha-actin and vimentin. The expression of h-caldesmon was very weak in both cell types. Also, cells dissociated from the smooth muscle layers of adult (6-month-old) rabbit bladder were cultured under the same conditions as the cells from the neonatal bladders to see if the heterogeneity of smooth muscle cells, exhibited by cells from neonatal rabbits, is also shown by cells from adult bladder. Two types of cells were also identified. The cells were then fixed and examined with the same panel of antibodies that we used for the neonatal cells. The long cells from adult bladder muscle express similar proteins to those in the neonatal long cells, and the short cells were stained positively with smooth muscle myosin, non-muscle myosin, alpha-smooth muscle actin, and lightly with caldesmon. Although the absence of vimentin in the short cells from adults is similar to that from neonatal, the strong expression of alpha-actin in the adult short cells is unlike the short cells from neonatal rabbits, in which their expression is barely detectable. PMID- 8701437 TI - Duration of spermatogenesis and relative frequency of each stage in the seminiferous epithelial cycle of the chimpanzee. AB - To determine the duration of 1 spermatogenic cycle, a single pulse of tritiated thymidine was infused into a branch of the spermatic artery in each of 3 chimpanzees (Pan troglodytes). Samples were recovered surgically prior to infusion, at 1 h, and at 3, 8, 14, 16, 17, 28, 30, 33, 40, 44, and 48 days postinfusion. Tissues were fixed in Bouin's solution, dehydrated, paraffin embedded, sectioned at 5 micrometers, and stained. Pre-infusion samples were used in morphometric studies to estimate the percentage frequency of area occupied by each of the 6 cellular associations (stages I-VI) characteristic of chimpanzee spermatogenesis, and thus, to estimate the days duration of each stage. To estimate the duration of 1 spermatogenic cycle, pre- and post-infusion, tissue sections were coated with undiluted Kodak NTB2 liquid autoradiographic emulsion and incubated at 4 +/- 1 degree C. At optimum exposure times, slides were processed with Kodak D-19 and Fixer; light microscopic analyses were conducted to determine the most mature labeled cell in stage III for each of the sample times. The duration of the 6 stages (I-VI) are 4.2, 2.0, 4.3, 1.5, 1.3 and 0.6 days, respectively, and the duration of 1 spermatogenic cycle is approximately 14 days. Thus, the duration of spermatogenesis from the Ap spermatogonium to mature Sd2 spermatid is approximately 62.5 +/- 1.5 days or 4.46 spermatogenic cycles. PMID- 8701438 TI - Significant induction of a 54-kDa protein in rat liver with homologous alignment to mouse selenium binding protein by a coplanar polychlorinated biphenyl, 3,4,5,3',4'-pentachlorobiphenyl and 3-methylcholanthrene. AB - A 54-kDa protein in rat liver cytosol was significantly induced by treatment with 3,4,5,3',4'-pentachlorobiphenyl (25 mg/kg, single i.p.) and 3-methylcholanthrene (20 mg/kg, once a day for 3 days, i.p.). The protein exhibited pI of 6.8 on two dimensional gel electrophoresis. The amino acid sequences of peptide fragments from the protein digested in situ were highly similar to a selenium binding protein in mice and to the isoform acetaminophen binding protein in mice. The present result clearly demonstrates that a coplanar polychlorinated biphenyl and 3-methylcholanthrene are responsible for induction of selenium binding protein homologues. The physiological role of the mouse proteins, however, is not yet elucidated. PMID- 8701439 TI - In vitro and in vivo effects of lead, methyl mercury and mercury on inositol 1,4,5-trisphosphate and 1,3,4,5-tetrakisphosphate receptor bindings in rat brain. AB - In vitro and in vivo effects of mercury (Hg), methyl mercury (MM) and lead (Pb) on [3H]inositol 1,4,5-trisphosphate (IP3) and [3H]inositol 1,3,4,5 tetrakisphosphate (IP4) receptor binding in the Sprague-Dawley rat brain cerebellar membranes were studied. In vitro studies indicate that binding of [3H]IP3 and [3H]IP4 to cerebellar membranes was inhibited by Hg while they were stimulated by MM or Pb in a concentration-dependent manner. MM was more potent (EC50 3.4 microM) than Pb (EC50 18.2 microM) in stimulating the [3H]IP3 receptor binding activity whereas Pb (IC50 30 microM) was more potent than MM (IC50 133 microM) in stimulating the [3H]IP4 receptor binding. When the rats were treated (i.p) with Hg (5 mg/kg body wt.) or MM (5 mg/kg body wt.) or Pb (25 mg/kg body wt.) for 3 or 24 h, no significant alterations in [3H]IP3 receptor binding were observed in cerebellum and cerebral cortex. But the above treatment of Pb or MM for 3 or 24 h to rats resulted in an increase of [3H]IP4 receptor binding in the membranes of cerebral cortex. However, the rats treated with Hg (1 mg/kg body wt./day) or Pb (25 mg/kg body wt./day) for 7 days did not show any alteration in binding of [3H]IP3 to its receptors in cerebellar membranes but an increase in this receptor binding was noticed with the treatment of MM (2.5 mg/kg body wt./day) for 7 days. The cerebellum and cerebral cortex of rats with the above treatment of MM or Pb for 7 days exhibited an increase in [3H]IP4 receptor binding. These in vitro and in vivo data suggest that alterations in inositol polyphosphate receptor binding by metals could result in alterations in intracellular calcium levels which may influence neuronal activity. PMID- 8701440 TI - Antagonistic effect of melatonin against cyanide-induced seizures and acute lethality in mice. AB - The effect of melatonin on potassium cyanide-induced neurotoxicity was investigated in vivo. The ED50 value of potassium cyanide, as measured by induction of tonic and clonic seizures, was significantly increased by 1.5- or 1.8-fold by s.c. preinjection of melatonin (20, 100 or 345 mg/kg) in mice. The preventive effect of melatonin against potassium cyanide-induced seizures was dose dependent. The LD50 value of potassium cyanide, based on 24-h mortality, was also significantly increased by 1.3-fold by preinjection of melatonin. Potassium cyanide (8 mg/kg, s.c.) increased lipid peroxidation in whole brain of mice, and the increased lipid peroxidation was completely abolished when cyanide-induced seizures were stopped by preadministration of melatonin. These results suggest that melatonin, a pineal hormone, may protect against cyanide-induced neurotoxicity with its free radical scavenging effects in mice. PMID- 8701441 TI - Effect of sulfamethazine on phenobarbital and benzo[a]pyrene induced hepatic microsomal mixed function oxidase system in rats. AB - Administration of sulfamethazine (300 mg/kg, i.p., single dose) to phenobarbital (80 mg/kg, i.p., 3 days) pretreated rats showed significant decrease in microsomal protein, electron transport components and drug metabolizing enzyme activities, compared with phenobarbital administration alone. Induction of mixed function oxidase enzymes due to phenobarbital was not affected by the pretreatment of sulfamethazine. Sulfamethazine administration to benzo[a]pyrene (20 mg/kg, i.p., 2 days in oil) pretreated rats showed no significant change, but there was a slight decrease in cytochrome P450 and aminopyrine N-demethylase activity, compared with benzo[a]pyrene administration alone. A significant inhibition was observed in aminopyrine N-demethylase activity due to in vitro addition of sulfamethazine (3.5 mM) to microsomal incubations from untreated, sulfamethazine, phenobarbital and benzo[a]pyrene-treated rats. The results indicate that the phenobarbital induced cytochrome P450 is more susceptible to sulfamethazine than benzo[a]pyrene induced cytochrome P450. PMID- 8701442 TI - Kinetics of Cu2+ inhibition of Na+/K(+)-ATPase. AB - The interaction of Cu2+ with enzymatic activity of rabbit kidney Na+/K(+)-ATPase was studied in media with buffered, defined free Cu2+ levels. The IC50-values are 0.1 mumol/l for Na+/K(+)-ATPase and 1 mumol/l for K(+)-pNPPase. Dithiothreitol (DTT) reverses the inhibitory effect of Cu2+ in vitro. Cu2+ exerts non competitive effects on the enzyme with respect to Na+, K+, ATP or pNPP, but has a mixed-type inhibitory effect with respect to Mg2+. It is concluded that the appreciation of the inhibitory effect of Cu2+ on this enzyme requires carefully composed assay media that include a buffer for Cu2+, and that the IC50-values calculated according to this model indicate that Cu2+ may be more toxic than previously anticipated. PMID- 8701443 TI - Suitability of different cytotoxicity assays for screening combination effects of environmental chemicals in human fibroblasts. AB - Cytotoxicity screening assays measuring survival, growth, colony forming ability, DNA and protein synthesis in human fibroblasts were tested for their suitability to determine combination effects. Thereby, the dose-response curves of a hydrophilic substance A alone and after pretreatment with a membrane damaging substance B were compared. Substances B were applied at concentrations which did not induce toxic effects in the assays (noec). Synergistic combination effects were demonstrated by reduction of the EC20 value of substances A in the combination in comparison to substances A alone. The following substance pairs (substance B/substance A = membrane damaging/hydrophilic) were tested: n dodecylbenzenesulfonic acid/2,4-dichlorophenoxyacetic acid, 2,4,6 trichlorophenol/2,4-dichlorophenoxyacetic acid, 1,1,2,2-tetrachloroethane/4 chloroaniline, pentachlorophenol/CrCl3. While survival, growth, and DNA synthesis assays were suitable methods for detecting synergistic combination effects, the growth assay was the most sensitive. Here, all four substance pairs showed synergistic combination effects. PMID- 8701444 TI - Riboflavin can decrease the nephrotoxic effect of chromate in young and adult rats. AB - The influence of 5 mg vitamin B2/100 g b.wt. (B2, riboflavin) on the nephrotoxic effect of 1 or 2 mg Na2Cr2O7/100 g b.wt. (Cr) was investigated in 55- and 10-day old rats, respectively. Nephrotoxic effect was evaluated by the determination of urinary volume and protein excretion as well as the concentration of blood urea nitrogen (BUN). The concomitant administration of Cr and B2 only in 55-day-old rats increased the nephrotoxicity shown by enhanced proteinuria and BUN. B2, administered 3 h after Cr, was able to diminish Cr nephrotoxicity significantly in 55- and 10-day-old rats. The effect of B2 on Cr nephrotoxicity could be interpreted not by the stimulatory effect of B2 on GSSG reductase, which was abolished by Cr; but by its antioxidant effect. PMID- 8701446 TI - [Screening tests for dementia: agreement between CST14 and ADS3 is incomplete (Cognitive Screening Test and Amsterdam Dementia Test)]. AB - The agreement between two screening tests for the detection of dementia was tested by comparing a 14-item orientation questionnaire (Cognitive Screening Test or CST14) and the short version of the Amsterdam Dementia Screening Test (ADS3: Visual Memory, Orientation and Fluency. All 106 consecutive patients (71% female) of a psychogeriatric day care center were tested in two sessions. Their mean age was 77,7 (range 52-89). Taking the advised cutting-scores into account, we found consistent results for 74% of the patients (95%-confidence interval: 65%-82%): 60 patients were positive for dementia on both tests, and 18 were negative. For 28 patients the results were inconsistent, in that more patients scored in the impaired range for ADS3 than for CST14. PMID- 8701445 TI - Methyl parathion activation by a partially purified rat brain fraction. AB - Organophosphorus pesticides are one of the most commonly used insecticide classes. They act through a potent inhibition of acetylcholinesterase (AChE). Many of them must undergo transformation into the corresponding oxon analogs to inhibit AChE. This study showed that a brain tissue subfraction transformed methyl parathion (O,O-dimethyl O-p-nitrophenyl phosphorothioate) in vitro. Methyl parathion activation was assayed by solvent extraction of the products followed by HPLC and GC-MS analyses and, indirectly, by the inhibition of AChE present in the incubation mixture. The lack of impairment of AChE after 2 h of incubation of the brain subfraction with methyl parathion and, alternatively, with NADPH, CO, SKF 525-A, piperonyl butoxide or nitrogen indicated that this brain subfraction transformed methyl parathion without the involvement of a mixed-function oxidative pathway. The results from HPLC analysis did not show a peak corresponding to methyl paraoxon (O,O-dimethyl O-p-nitrophenylphosphate), but showed the production of an unidentified peak which eluted nearby standard methyl parathion (retention times of 10.65 and 8.86 min, respectively). GC-MS analysis suggested that the unidentified product could be a methyl parathion isomer. PMID- 8701447 TI - [Effects of technical aids on the utilization of professional care. A study among single 75-year olds]. AB - In this paper we describe the results of a project, in which occupational therapists visited 83 independently living, single, elderly people (clients of organisations providing care) and advised them about technical aids. Subsequently some technical aids were provided. The intervention group received, on average, three out of five advised technical aids. The effect of this intervention was an increase in the use of technical aids (people used, on average, two technical aids more at the end of the project), which means that the provided technical aids were being used. This effect was stronger in the group of the 75-84 old persons than in the above 85 year old ones. This effect led to a change in people's attitudes towards technical aids: at the beginning of the project 80% of the elderly believed technical aids could help them to remain independent and at the end this percentage was 90%. There was a slight, non-significant, decrease in the number of hours home help (from 5,4 to 4,7 hours per week). However, we were unable to ascertain an effect on the percentage of elderly using community care or waiting for institutional care. This may have been due to the heterogeneity of the intervention, the small research population and the relatively short intervention period. Elderly should be assessed as being in need of technical aids at an earlier stage. PMID- 8701448 TI - [Locomotive limitations in the elderly; something to consider]. AB - A clinimetric method was used to investigate subjective and objective gait disabilities in 339 persons of 65 years and older in Valkenburg aan de Geul, the Netherlands. Because this study deals with disabilities rather than with medical diagnoses an interview by telephone was considered sufficient. A short, simple and broadly applicable questionnaire was made in order to assess gait disabilities in an objective way. In this random sample 43% of the elderly persons experienced difficulties with walking and 30% experienced objective gait disabilities. The non-response was 30%. The predominant complaint that hampered walking was pain, followed by tiredness and short of breath. The respondents attributed their gait disabilities to cardiovascular problems (23%) and to arthrosis (16%). 15% had no explanation for the cause of the gait problems. PMID- 8701449 TI - [Effects of some factors in the development of locomotive disorders in the elderly]. AB - 267 Persons over 65 years were interviewed by telephone to investigate the influence of some factors on the occurrence of gait disabilities. These factors are: sex, fractures, operations of the lower extremities, overweight, underweight, decreased sight, parity, medication use, smoking and occupation. The gait disabilities were objectivated by a short questionnaire. RESULTS: Male and female respondents reported gait disabilities in equal numbers. No relation occurred between fractures of the lower extremities and gait disabilities in the respondents. More people with than without gait disabilities have had an operation of the lower extremities, particularly when the operation indication was a vascular one. A relation was found between gait disabilities in the elderly respondents and smoking (ns), decreased sight and medication use. PMID- 8701450 TI - [Nature turned away from us. Viewpoint of the Commission Medical Ethics of the KNMG (Royal Dutch Medical Society) concerning postmenopausal IVF (in-vitro fertilization)]. PMID- 8701451 TI - [Failure in self care and heart failure, thiamine deficiency in geriatric patients]. AB - In two patients admitted to a geriatric ward cardiac failure was based on a thiamine deficiency (wet beri-beri). After supplementation with thiamine they recovered completely. The first patient had a insufficient diet of only canned food, whereas the second patient suffered from both alcoholism and insufficient nutrients. These geriatric patients suffered from a serious illness due to a combination of somatic, psychological, functional en social factors. Thiamine is a co-enzyme in many metabolic processes. A thiamine deficiency is defined as a serum concentration below 95 nmol/1. Other diseases associated with thiamine deficiency are the Wernicke-Korsakoff syndrome and peripheral polyneuropathy (dry beri-beri). Not only alcoholics but also elderly patients with malnutrition are at risk of thiamine deficiency and associated diseases. Do not hesitate to supplement thiamine in case of cardiac failure because of possible thiamine deficiency. PMID- 8701452 TI - Allogeneic marrow reconstitution using peripheral blood stem cells: the dawn of a new era. PMID- 8701453 TI - Clinical toxicity and laboratory effects of granulocyte-colony-stimulating factor (filgrastim) mobilization and blood stem cell apheresis from normal donors, and analysis of charges for the procedures. AB - BACKGROUND: Apheresis of granulocyte-colony-stimulating factor (filgrastim) mobilized blood stem cells from normal donors is now being used in place of a marrow harvest in transplantation. How the adverse effects of and charges for this procedure compare with those of the standard marrow harvest is not known. STUDY DESIGN AND METHODS: Forty consecutive normal subjects who received filgrastim 96 micrograms/kg) subcutaneously twice daily for 4 to 6 days in preparation for apheresis were monitored prospectively by clinical and laboratory evaluation. RESULTS: Sixty-two percent of the subjects required oral analgesics. None discontinued filgrastim prematurely. Bone pain (82%), headache (70%), fatigue (20%), and nausea (10%) were reported. Filgrastim caused a mean eightfold increase in neutrophil counts, a mean twofold increase in lymphocyte counts, a mean twofold rise in alkaline phosphatase and lactate dehydrogenase levels, and minor changes in serum potassium, magnesium, and uric acid. Adverse events and laboratory effects resolved within 7 days after apheresis. No apheresis stem cell donor required transfusion or hospitalization, and only one required an additional clinic visit after completion of apheresis. By comparison, a retrospective analysis of 33 normal marrow donors demonstrated that all received transfusion(s), 3 were hospitalized, 3 required additional clinic visits after the marrow harvest. The median total charges related to the two procedures were comparable (p = 0.43), although the charges were significantly lower for donors requiring only one apheresis procedure (p = 0.002). CONCLUSION: Filgrastim mobilization and apheresis of blood stem cells constitute a safe, well-tolerated, and comparable or less expensive alternative to the traditional marrow harvest. PMID- 8701454 TI - Changes in blood counts after the administration of granulocyte-colony stimulating factor and the collection of peripheral blood stem cells from healthy donors. AB - BACKGROUND: After the collection of granulocyte-colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells from healthy donors, the donor platelet counts fall. However, the magnitude and duration of this decrease are not known. STUDY DESIGN AND METHODS: Sixty healthy people were given G-CSF (5, 7.5, or 10 micrograms/kg/day) for 5 days (Days 1-5), and 1 peripheral blood stem cell component was collected on Day 6. The platelet count, white cell count, absolute neutrophil count, hematocrit, and red cell count were measured before administration of G-CSF (Day 0), before collection of peripheral blood stem cells on Day 6, and on Days 8, 10, 13, 16, and 20. RESULTS: The platelet count fell from 261 +/- 47 x 10(9) cells per L on Day 0 to 159 +/- 30 x 10(9) cells per L on Day 8 (p < 0.0001) and reached its lowest level on Day 10 (146 +/- 30 x 10(9)/L; p < 0.001). Compared to Day 0 levels, the platelet count was lower on Day 13 (185 +/- 49 x 10(9)/L, p < 0.001), was the same on Day 16 (270 +/- 53 x 10(9)/L), and was greater on Day 20 (333 +/- 60 x 10(9)/L, p < 0.0001). The white cell count returned to pretreatment values on Day 13, and the absolute neutrophil count returned to pretreatment values on Day 10 (Day 0 white cell count = 6.05 +/- 1.59 x 10(9)/L and Day 0 absolute neutrophil count = 3.97 +/- 1.52 x 10(9)/L). On Day 20, both were less than pretreatment values (white cell count = 5.14 +/- 1.24 x 10(9)/L, p = 0.0007 and absolute neutrophil count = 3.20 +/- 1.24 x 10(9)/L, p = 0.0036). The red cell counts on Day 16 (4.52 +/- 0.41 x 10(12)/L) and Day 20 (4.42 +/- 0.39 x 10(12)/L) were less than Day 0 values (4.73 +/- 0.43 x 10(12)/L, p = 0.008 and p < 0.0001, respectively). The hematocrit on Day 20 (39.2 +/- 3.2%) was also less than that on Day 0 (41.2 +/- 4.8%; p = 0.01). The changes in these blood counts were not affected by the dose of the G-CSF. CONCLUSION: After stimulation with granulocyte-colony-stimulating factor and the collection or peripheral blood stem cells, the platelet counts in normal donors were decreased for at least 7 days (Days 6-13). Two weeks after collection of peripheral blood stem cells (Day 20), platelet production was increased, but the production of neutrophils and red cells was decreased. If two or more peripheral blood stem cell components are collected, then the platelet count should be measured after the second and subsequent collections. Further studies on the long-term effect of G-CSF on blood counts are needed. PMID- 8701456 TI - Peripheral blood progenitor cells for marrow reconstitution: mobilization and collection strategies. AB - Previous studies of PBPC BMR have found evidence supporting its safety, feasibility, and efficacy when used in a wide range of patients. Although the optimal regimen for mobilization remains a focus of debate, data from the use of combinations of chemotherapy and cytokines suggest that there is more rapid white cell and platelet engraftment than with BMT, which leads to decreased transfusion requirements and, possibly, reduced patient care costs. Recent advances in the field include allogeneic PBPC BMR, negative selection of tumor cells to reduce contamination, and positive selection of CD34+ cells. These new strategies are anticipated to enhance the therapeutic effectiveness of PBPC BMR while minimizing toxicity. Still, the ultimate comparison of PBSC BMR and medullary BMT will depend on the results of well-designed, randomized, controlled clinical trials with long-term outcome analysis. However, the refinement and improvement of mobilization and collection techniques for PBPC BMR continue to add to the armamentarium of current therapeutic approaches for cancer and related nonmalignant conditions and will enable future strategies for ex vivo expansion of progenitor cells and use in gene transfer studies. PMID- 8701457 TI - Royal College of Physicians of Edinburgh Consensus Conference on Autologous Transfusion. Edinburgh, 4-6 October 1995. PMID- 8701455 TI - Treatment of normal individuals with granulocyte-colony-stimulating factor: donor experiences and the effects on peripheral blood CD34+ cell counts and on the collection of peripheral blood stem cells. AB - BACKGROUND: Granulocyte-colony-stimulating factor (G-CSF) has been used in patients to increase the level of circulating hematopoietic progenitors. Although G-CSF has been administered to some healthy individuals, the kinetics of mobilization of peripheral blood stem cells (PBSCs), the optimum dose schedule and the incidence and nature of adverse reactions in normal individuals are not completely defined. STUDY DESIGN AND METHODS: Normal individuals (n = 102) who received G-CSF for 5 or 10 days at doses of 2, 5, 7.5, or 10 micrograms per kg per day were studied. The subjects were observed for symptoms and physical changes, and blood samples were obtained for a variety of laboratory tests. After 5 or 10 days of G-CSF treatment, PBSCs were collected by apheresis and analyzed. RESULTS: Overall, 89 percent of the individuals completed the 5-day treatment protocol and 88 percent completed the 10-day protocol without modification of the dose of G-CSF administered. Ninety percent of donors experienced some side effect of G-CSF. The most frequent effects noted were bone pain (83%), headache (39%), body aches (23%), fatigue (14%), and nausea and/or vomiting (12%). The dose of G CSF administered directly affected the proportion of people with bone pain (p = 0.025) or body aches (p = 0.045) or who were feeling hot or having night sweats (p = 0.02) or taking analgesics (p = 0.01). With the 5-day dose schedule, several changes in serum chemistries occurred, including increases in alkaline phosphatase (p = 0.001), alanine aminotransferase (p = 0.0013), lactate dehydrogenase (p = 0.0001), and sodium (p = 0.0001). Decreases occurred in glucose (p = 0.045), potassium (p = 0.0004), bilirubin (p = 0.001), and blood urea nitrogen (p = 0.0017). In donors who received G-CSF for 5 days, the absolute neutrophil count was increased after one G-CSF dose, and it reached a maximum on Day 6, as did the number of CD34+ cells (64.6 +/- 55.9 x 10(6) cells/L). In those same donors, the platelet count after apheresis on Day 6 was 32 +/- 13 percent lower than pretreatment values (250 +/- 42 x 10(9) cells/L). In donors receiving G-CSF for 10 days, the neutrophil count reached a maximum on Day 8, but the number of CD34+ cells peaked on Day 6 (58.3 +/- 52.1 x 10(5) cells/L) and then declined. The platelet count decreased from pretreatment values by 28 +/- 12 percent prior to apheresis on Day 11. When individuals were treated for 5 days with G-CSF, the quantity of CD34+ cells collected was directly related to the G CSF dose. When 5 micrograms per kg per day was given, 2.80 +/- 1.81 x 10(8) cells were collected, compared with collection of 4.67 +/- 3.11 x 10(8) cells when 10 micrograms per kg per day was given (p = 0.04). More important, PBSCs collected after 10 days of G-CSF administration (5 micrograms/kg/day) had significantly fewer CD34+ cells (0.82 +/- 0.37 x 10(8) cells, p = 0.01) than did PBSCs collected after 5 days of G-CSF (5 micrograms/kg/day). CONCLUSION: Most normal donors receiving G-CSF experience side effects, but these are mild to moderate in degree. Some alterations in blood chemistries occur, but none were clinically serious. Because of the symptoms associated with G-CSF, these individuals must be monitored closely. The treatment of normal donors with G-CSF for more than 5 days significantly decreased the number of circulating CD34+ cells and the quantity collected by apheresis. PMID- 8701458 TI - Consensus conference on autologous transfusion. An organisers' view. PMID- 8701459 TI - Consensus conference on autologous transfusion. General background paper. PMID- 8701460 TI - Consensus conference on autologous transfusion. Preoperative autologous donation. PMID- 8701461 TI - Consensus conference on autologous transfusion. Acute normovolaemic haemodilution. AB - ANH is a relatively cheap and logistically straightforward method of autologous transfusion which is attractive in that it may be applied to a wide cross-section of patients, many of whom will not be suitable for pre-deposit. There are, however, concerns about the safety of the procedure, and doubts have been expressed about its efficacy in reducing allogeneic transfusion requirements and, therefore, its cost-effectiveness. Assessment of the value of the procedure is hampered by the lack of large scale prospective, controlled trials. In the present state of knowledge it seems that ANH is most likely to be safe, efficacious and cost-effective when undertaken aggressively (target haematocrit < 0.20) in otherwise healthy, young patients undergoing elective surgery with large expected blood losses. PMID- 8701462 TI - Consensus conference on autologous transfusion. Perioperative red cell salvage. PMID- 8701463 TI - Thrombocytopenia in allogeneic peripheral blood stem cell collections. PMID- 8701464 TI - Infection with hepatitis GB virus among Japanese hemophiliacs. PMID- 8701465 TI - Photosynthesis: the Z-scheme revised. PMID- 8701466 TI - Post-translational protein translocation: not all hsc70s are created equal. AB - Hsc70s in the yeast endoplasmic reticulum (ER) and mitochondria interact with membrane-associated components of the translocation machinery and are required for post-translational protein import. Although it has been proposed that the mitochondrial and ER machines function similarly, a variety of experiments suggest that BiP, the ER hsc70, might play a more elaborate role. PMID- 8701467 TI - "Outlier' lipocalins more than peripheral. PMID- 8701468 TI - Ancient duplication of DNA polymerase inferred from analysis of complete bacterial genomes. PMID- 8701469 TI - The ethylene signal transduction pathway in Arabidopsis: an emerging paradigm? AB - In the plant Arabidopsis, ethylene signaling involves at least two putative receptors, both of which resemble the "two-component' regulators known almost exclusively in bacteria. Downstream in the pathway is a putative serine/threonine protein kinase related to the animal Raf protein kinases. This novel combination of signaling proteins has parallels with the postulated osmolarity-response pathway in yeast. PMID- 8701470 TI - The S100 family of EF-hand calcium-binding proteins: functions and pathology. AB - Calcium lons as second messengers control many biological processes, at least in part, via interaction with a large number of Ca(2+)-binding proteins. One class of these proteins shares a common Ca(2+)-binding motif, the EF-hand, Here, we describe some functional aspects of EF-hand proteins, which have been found recently in different cellular compartments. Novel links between EF-hand proteins, particularly S100 proteins, and specific diseases are now emerging. PMID- 8701472 TI - Strategies for RNA folding. AB - RNAs are surprisingly adept at folding into specific shapes capable of ligand recognition and catalysis. Thermodynamic analysis of the unfolding of several different RNAs suggests that there are at least three strategies an RNA might use to achieve a very stable and compactly folded structure: hydrogen bonding between irregular complementary surfaces (as in transfer RNA tertiary structure); monovalent and divalent lons bound to specific sites (as found in a ribosomal RNA fragment) and pseudoknot folds (exemplified by a messenger RNA fragment with extensive non-canonical structure). PMID- 8701471 TI - The biology of HMG-CoA reductase: the pros of contra-regulation. AB - Hydroxymethylglutaryl-CoA reductase (HMG-R) is a key enzyme in the mevalonate pathway, from which thousands of molecules are derived including cholesterol and prenyl moieties. The regulation of HMG-R is complex and includes feedback control, cross-regulation by independent bio-chemical processes and contra regulation of separate isozymes. From studies in yeast, these separate modes of regulation can be considered in an integrated fashion. PMID- 8701473 TI - EMBnet: an institute without walls. PMID- 8701474 TI - Methods and reagents. Is there any sense in antisense terminology? AB - Methods and reagents is a unique monthly column that highlights current discussions in the newsgroup blonet.molbio.methds-reagnts, available on the internet. This month's column reviews a recent debate held over the present sense and antisense terminology when referring to DNA. For details on how to partake in the newsgroup, see the accompanying box. PMID- 8701475 TI - The Nomenclature Committee of the IUBMB comment. PMID- 8701476 TI - 'Nothing to laugh at at all': humor in biochemical journals. PMID- 8701477 TI - The prevalence of asthma and other allergic diseases in a province of Turkey. AB - To document the prevalence of asthma and other allergic disorders among children, a questionnaire study involving 3,118 children aged six to 14 years was done. The overall prevalence of allergic diseases was 27.4 percent and the prevalence of each disorder was as follows: rhinitis 11 percent, asthma 10.2 percent, conjunctivitis 7.1 percent, and skin diseases 6.3 percent. Atopic diseases were reported most commonly among the families of children with allergic rhinitis. When compared with internal regions of Turkey, the prevalence of allergic diseases was found to be very high. It was concluded that allergic diseases are an important health problem among children in our region. PMID- 8701478 TI - Efficacy of oxybutynin, pseudoephedrine and indomethacin in the treatment of primary nocturnal enuresis. AB - The efficacy of oxybutynin, pseudoephedrine and indomethacin treatment was investigated in 29 patients with primary nocturnal enuresis. Patients were randomly assigned to either oxybutynin (1st group, n = 9), pseudoephedrine (2nd group, n = 11) or indomethacin (3rd group, n = 9) treatments. Oxybutynin and indomethacin did not cause a statistically significant difference in the number of dry nights (p > 0.05), but patients treated with pseudoephedrine had a significant increase in the number of dry nights (p < 0.05). Five patients in the oxybutynin and one patient in the indomethacin group experienced side effects. None of the patients in the pseudoephedrine group had any complaints with the drug. We therefore conclude that pseudoephedrine can be an alternative in the treatment of primary nocturnal enuresis. PMID- 8701479 TI - The frequency of IgG subclass deficiency in children with recurrent respiratory infections. AB - We studied the frequency of IgG subclass deficiency in 61 children (ages 1-7 years, mean 3.8 years) with recurrent respiratory tract infections by using the radial immunodiffusion method. The overall frequency of IgG subclass deficiency was found to be 39.3 percent (24 patients). Among 26 children who had major immunoglobulin abnormalities, we found IgG subclass deficiency in 11 patients (42.3%). In children with normal immunoglobulin levels, the frequency of IgG subclass deficiency was 37.1 percent (13 patients). PMID- 8701480 TI - Inhalation therapy with magnesium sulfate and salbutamol sulfate in bronchial asthma. AB - Inhalation therapy with magnesium sulfate and salbutamol sulfate was applied to two groups, each consisting of 20 patients with acute asthma. The effects of inhaled magnesium sulfate and salbutamol sulfate were compared. The evaluation of patients was done using respiratory score, peak expiratory flow rate with a Wright peak flow meter, respiration rate, heart rate and blood pressure. Although magnesium sulfate's bronchodilating effect continued for approximately one hour, treatment of acute asthma using salbutamol sulfate inhalation was found to be more successful and its effect continued for six hours. PMID- 8701482 TI - Convulsions in childhood shigellosis and antimicrobial resistance patterns of shigella isolates. AB - Drug resistance patterns of 68 shigella strains were investigated prospectively in Kayseri during a period of approximately two years. The resistance was highest with ampicillin (58.8%) followed by co-trimoxazole (50%) and ampicillin-sulbactam (13%). Only 2.8 percent of cases were resistant to gentamicin, and all serogroups were sensitive to ceftriaxone. We conclude that in children with severe shigellosis, treatment with ceftriaxone is effective and better than ampicillin and co-trimoxazole for obtaining a clinical cure. We followed 18 children who experienced convulsions associated with shigellosis. Only one child had a history of febrile convulsions, and two children had histories of convulsive disorders. The majority of the children had generalized, self-limited convulsions which lasted less than ten minutes. Due to the benign and self-limited nature of most of the convulsions, neither diagnostic procedures nor drug therapy are usually necessary. These measures should, however, be considered in complicated cases characterized by focal or prolonged seizures. PMID- 8701483 TI - Juvenile rheumatoid arthritis: cervical spine involvement and MRI in early diagnosis. AB - Magnetic resonance imaging (MRI) of the cervical spine was performed on 20 patients (mean age 10 years) with a preliminary diagnosis of juvenile rheumatoid arthritis (JRA). In all patients conventional x-rays of the cervical spine were obtained, and the relationship between clinical status and MRI findings were evaluated. Two patients with clinical manifestations, including neck pain and diminished range of motion, exhibited significant pathologic features on radiogram and MRI, the latter providing more detailed information. Among 18 patients who had no complaints about their cervical spines, 3 patients (65%) had either soft tissue involvement, pannus formation or erosions on the surface of atlantoaxial joints; only four patients (20%) had erosions on plain x-ray views. Since the early diagnostic ability of MRI in JRA allows early therapeutic intervention, every patient with a probable diagnosis of JRA would benefit from MRI. PMID- 8701481 TI - "Acquired" subvalvular aortic stenosis after repair of several congenital cardiac defects. AB - Discrete subvalvular aortic stenosis is a progressive lesion. In this report we presented nine patients who had no significant left ventricular-aortic obstruction at initial cardiac catheterization or echocardiographic examination, but later developed significant subvalvular aortic stenosis. Associated lesions included ventricular septal defect in three, patent ductus arteriosus in two, aorticopulmonary window in one, tetralogy of Fallot in one, supramitral membrane in one, and ventricular septal defect and patent ductus arteriosus in one case. Nine patients were diagnosed with subvalvular aortic stenosis 18 months to eight years after surgical correction. Eight of the patients required surgery for subvalvular obstruction. In conclusion, discrete subaortic stenosis is a rare, late complication of the surgical repair of several congenital heart defects. It is a progressive lesion after surgery; therefore these patients require careful follow-up. PMID- 8701484 TI - Plasma plasminogen levels in early respiratory distress syndrome. AB - The serum plasminogen status in 35 preterm infants with or without respiratory distress syndrome (RDS) was determined in the first few hours of life. Blood samples for plasminogen testing (Synthetic chromogenic substrate method; Stachorm PLG. Diagnostica Stago) were obtained from a peripheral vein within six hours after birth. Among 35 infants, 20 infants who were in stable clinical condition served as the control group. Fifteen developed RDS with clinical, laboratory and radiological findings. The mean plasma plasminogen levels were found to be similar in the two groups (p > 0.05 by Mann-Whitney U test). These findings are discussed along with our previous findings showing normal tissue plasminogen activator (tPA) but lower D-dimer and higher plasminogen activator inhibitor (PAI) levels within the first few hours of life in preterm infants who later developed RDS compared to the control group. PMID- 8701485 TI - The risk of bilirubin encephalopathy in neonatal hyperbilirubinemia. AB - Jaundice is the most common and one of the most annoying problems that can occur in the newborn. Although most jaundiced infants recover without any serious problem, there is always a risk of bilirubin encephalopathy during the period of hyperbilirubinemia. The relationship between encephalopathy and serum free bilirubin levels was investigated in 83 newborn infants (40 premature, 43 mature) with unconjugated hyperbilirubinemia. A complete physical examination was done in all patients, and signs of bilirubin encephalopathy were noted if present. The serum free bilirubin level exceeded 0.1 mg/dl in 13 infants, and 12 of them showed signs of encephalopathy. On the other hand, none of the infants whose serum free bilirubin levels were below 0.1 mg/dl showed signs of encephalopathy. Although there is a significant positive correlation between serum total and free bilirubin levels, it is not clear at what total bilirubin level free bilirubin will appear. Serial determinations of free bilirubin appear to be more helpful in the management of hyperbilirubinemia in infants with an increased risk of bilirubin toxicity. PMID- 8701486 TI - Publication potential in pediatrics in Turkey. AB - In this article, the publication potential in pediatrics in Turkey was investigated. In this context, native pediatric journals, publication activities of medical faculties as the main source of scientific publication and certain data obtained from some of the international indexes' sources were analyzed. The Turkish Journal of Pediatrics (Turk J Pediatr) and Cocuk Sagligi ve Hastaliklari Dergisi are two native pediatric journals which have been published without interruption for 36 and 37 years, respectively. Both are indexed in BIOSIS (Bioscience information Service) and Excerpta Medica. In addition, Turk J Pediatr is indexed in Index Medicus and Current Contents, and is the only Turkish medical journal indexed in Index Medicus at present. Eighty percent of papers submitted to both journals are from medical faculties all over the country (60% of these from Hacettepe Faculty of Medicine), while 15% are from the teaching hospitals of the Ministry of Health and 5% from outside the country. In 1994, Hacettepe University School of Medicine was the leader with 244 (21%) of the 1165 articles published in the health sciences from 22 medical faculties in Turkey. In the same year, 32 percent of all International medical publications by Hacettepe Faculty of Medicine were in the field of pediatrics. In addition, of 353 papers by Turkish authors appearing in Current Contents during the three-month period July September 1993, 70 (20%) were pediatric articles. All of these findings may indicate that publications in the field of pediatrics have increasing potential and an important impact on the scientific medical publication's platform in our country. PMID- 8701487 TI - Treatment of X-linked lymphoproliferative disease (Duncan disease) with high-dose methylprednisolone and etoposide (VP-16). AB - A five-year-old boy in the acute phase of X-linked lymphoproliferative (XLP) syndrome (Duncan disease) with high fever and hepatosplenomegaly was treated successfully with high-dose methylprednisolone and VP-16 for 15 months. He had been alive for four years after diagnosis as of this writing. We recommend high dose methylprednisolone and VP-16 in patients with XLP who have to wait for a suitable donor before bone marrow transplantation. PMID- 8701488 TI - Severe acute thinner intoxication. AB - Thinner which contains aromatic hydrocarbons such as xylene, toluene and N-hexane is widely used in industrial plants manufacturing dyes, plastic, varnishes and glues. Chronic intoxication due to abuse of solvents, including thinner, by workers who inhale the solvent vapor is frequently encountered. Acute intoxication with ingestion of excessive amounts is relatively rare and usually fatal. It is reported that 45-50 ml of orally ingested thinner is enough to cause severe complications. The case reported here was forced to drink 200 ml of thinner by an older friend, and presented with severe complications such as rhabdomyolysis, polyneuropathy, chemical pneumonia and coma. To the best of our knowledge this is the first case reported in the literature to survive acute thinner intoxication with such complications. PMID- 8701489 TI - Spontaneous complete remission in a child with acute lymphoblastic leukemia. AB - A five-year-old girl was admitted to the hospital with fever and tender lymphadenopathy. She was diagnosed with acute lymphoblastic leukemia (ALL-L3). Because of infection she was given antibiotics and a blood transfusion. Her bone marrow was in remission after 15 days without chemotherapy. This case emphases the role of transfusion and/ or infection in obtaining complete remission without chemotherapy. PMID- 8701490 TI - Systemic lupus erythematosus presenting with thrombocytopenia. Report of a child with positive anticardiolipin antibodies. AB - We report a case of systemic lupus erythematosus initially presenting with thrombocytopenia and diagnosed as immune thrombocytopenic purpura. The patient subsequently developed lymphadenopathy, arthritis and cardiac involvement along with anticardiolipin antibodies. We would like to emphasize the fact that these autoantibodies have a role in the pathogenesis of thrombocyte destruction, and that patients with immune thrombocytopenic purpura should be followed for signs of systemic lupus erythematosus. PMID- 8701491 TI - Congenital chloride diarrhea in a Turkish boy. AB - Congenital chloride diarrhea (CCD), first described in 1945, is a rare, autosomal recessively inherited disease. It is characterized by chronic, watery diarrhea with a high fecal chloride concentration, hyponatremia, hypokalemia, and hypochloremic metabolic alkalosis. In this report, a 7.5-year-old boy with CCD diagnosed by high fecal chloride concentration is presented. Until now CCD had not been reported from Turkey, although consanguineous marriages are common. PMID- 8701492 TI - The management of renal candidiasis in the newborn. AB - Renal candidiasis in the neonate is encountered infrequently. We report a newborn with ichthyosis, who during the hospital course had five episodes of culture proven sepsis, probably due to skin lesions. For these infections various antibiotic combinations were used. During the therapy of the last sepsis attack, unilateral hydronephrosis developed secondary to renal candidiasis. Percutaneous nephrostomy with amphotericin B irrigation, coupled with five weeks of intravenous amphotericin B therapy was successful. We believe that with this approach the mortality and morbidity of renal candidiasis could be reduced. PMID- 8701493 TI - Transcatheter embolization of a residual congenital coronary arteriovenous fistula with a detachable balloon; superiority of interventional cardiology? AB - A ten-year-old girl who presented with a continuous murmur was diagnosed with a right coronary to right ventricular fistula with colored Doppler echocardiography and selective arteriography. She underwent traditional treatment-ligation of the fistula by sternotomy. Afterwards, the systolic component of the murmur persisted and repeat arteriography showed a residual shunt through the fistula, with no change in the diameter of the right coronary artery. We describe the first case in which a residual fistula was treated with a detachable balloon embolization. PMID- 8701494 TI - Gyrate atrophy of the choroid and retina. AB - Gyrate atrophy of the choroid and retina is characterized by autosomal recessive inheritance, progressive chorioretinal atrophy beginning in late childhood, and hyperornithinemia with ornithinuria caused by deficient ornithine aminotransferase activity. In this paper, four patients with gyrate atrophy are described. All patients had visual impairment, mental retardation, hyperornithinemia, hypolysinemia, ornithinuria and lysinuria. The first case had hypermetropic astigmatism in contrast to other reported gyrate atrophies. These are the first reported cases from Turkey, but gyrate atrophy may not be rare in Turkey since the frequency of some other metabolic disorders has also been reported to be high. It is suggested that gyrate atrophy must be considered in all patients with chorioretinal atrophy. PMID- 8701495 TI - Fatal intracranial hemorrhage in a newborn with factor VII deficiency. AB - Factor VII deficiency is a rare congenital coagulopathy. Prolonged prothrombin time with normal partial thromboplastin time indicates factor VII deficiency. For the definitive diagnosis, the specific factor VII level should be investigated. We report a seven-day-old, male, full-term newborn who was admitted with the diagnosis of sepsis. Hematological tests revealed prolonged prothrombin time and a factor VII level of five percent. After antibiotic therapy and fresh frozen plasma replacement his clinical status improved but the prothrombin time continued to be prolonged. On the 14th day, just before the end of antibiotic therapy, the infant died of sudden intracerebral hemorrhage. In this article, the clinical features and management of factor VII deficiency are discussed. PMID- 8701496 TI - Association of xeroderma pigmentosum with thrombasthenia. AB - Xeroderma pigmentosum (XP) is an autosomal recessive disorder characterized by severe sun-sensitivity, early skin cancers and abnormal DNA repair. XP has a worldwide distribution with an approximate frequency of 1/250,000. It is classified into nine complementation groups, and distribution of patients among the various groups is related to ethnic origin. To our knowledge, the association of XP with thrombasthenia has not been reported previously; here a 12-year-old girl with this combination is reported. She was first noted to have skin erythema on exposure to sunlight at the age of six months and was diagnosed with XP. At the age of one she had the complaints of easy bruising and epistaxis. A diagnosis of thrombasthenia was made based on the absence of platelet aggregation response to ADP, collagen and adrenaline and reduced clot retraction. In clinical management, oral isotretinoin was given in order to suppress tumor formation. PMID- 8701497 TI - Ossifying fibroma. A case report. AB - Ossifying fibroma is a benign tumor of connective tissue origin which occurs in fibro-osseous lesions. The lesion is seen most commonly in children and young adults. It is asymptomatic and slow-growing, but in some cases may show aggressive behavior. Though it has a slight predilection for the mandible, it may involve both jaws. The lesion is generally asymptomatic until it produces noticeable swelling, and mild deformity and migrations of teeth may be an early clinical feature. Pediatricians and dentists must be aware when asymmetry of the face occurs, and the lesion must be well diagnosed as it has a cancer-like radiographic appearance. In this article a nine-year-old patient with a massive mandibular ossifying fibroma is presented. PMID- 8701498 TI - Asymmetric crying facies: an index of other malformations. AB - Congenital hypoplasia or absence of the depressor anguli oris muscle is a minor congenital anomaly causing asymmetrical crying facies (ACF). The interesting aspect of this abnormality lies in the frequently associated abnormalities. Cardiac, urogenital, musculoskeletal, respiratory and cervicofacial defects have been described in cases with ACF. Therefore it is suggested that ACF can be used as an index of other congenital malformations. We report three cases with ACF who had varied congenital anormalites. PMID- 8701499 TI - Klippel-Trenaunay-Weber syndrome with hemimegalencephaly. Report of a case. AB - A case of Klippel-Trenaunay-Weber Syndrome (KTWS) in a 2.5-year-old girl with congenital hemihypertrophy, nevus flammeus and liver hemangioma is presented. In addition, this report describes the rare association of hemimegalencephaly with KTWS. PMID- 8701500 TI - About Salmonella typhi infections. PMID- 8701501 TI - Rice for diarrhea. PMID- 8701503 TI - [Markers of vitamin deficiencies]. PMID- 8701502 TI - [Science and practice--thoughts when changing editors]. PMID- 8701504 TI - [Cellular biology of neutrophil granulocytes]. PMID- 8701505 TI - [P-methylmalonate and P-homocysteine: metabolic markers of vitamin deficiencies. Background, validity and applications]. AB - The clinical value of measuring concentrations of methylmalonate and total homocysteine in plasma as an aid in the diagnosis of cobalamin, folate and pyridoxine deficiencies has recently aroused interest. This review describes factors which affect the validity and interpretation of plasma (p-) methylmalonate and p-homocysteine. P-methylmalonate is not affected by preanalytical variables, there are no age- or sex-related differences and the intra-individual variation is negligible. The only important limitation to the specificity of an increased p-methylmalonate for cobalamin deficiency appears to be secondary accumulation due to impaired renal function. However, an elevated p methylmalonate, which normalizes following cobalamin injections proves cobalamin deficiency, irrespective of renal function. P-homocysteine is affected by several preanalytical factors, so the utmost care is required in blood collection. Furthermore, p-homocysteine is dependent on age and sex. An elevated p homocysteine is a less specific parameter for cobalamin deficiency, for which reason measurement in patients with suspected cobalamin deficiency is indicated only if p-methylmalonate is normal. Homocysteine is also increased in folate and pyridoxine deficiencies. Recently, moderate hyperhomocysteinaemia has become an established independent and significant risk factor for premature atherosclerotic cardiovascular diseases, suggesting a large future demand for p-homocysteine determinations. PMID- 8701506 TI - [Atrial fibrillation after coronary artery bypass surgery. The significance of preoperative vagus modulation and ectopic atrial activity]. AB - To investigate the impact of pre-operative autonomic balance and atrial ectopic activity on the risk of atrial fibrillation or flutter after aorto-coronary artery bypass surgery 24-hour Holter monitoring was analyzed in 102 patients before coronary artery bypass grafting. Index for vagal tone was calculated as % successive RR-interval differences > 6%. Twenty-nine (28%) of the 102 patients developed atrial fibrillation or flutter. Independent predictors (90% confidence interval) of postoperative atrial fibrillation or flutter were identified by logistic regression analysis: the independent predictors were older age, relative risk 1.07/year (1.02-1.12), vagal index < 10%, relative risk 4.50 (1.40-14.5), > or= 10 ectopic supraventricular beats/24 hour, relative risk 3.03 (1.05-8.72), and one or more event of non-sustained supraventricular tachycardia, relative risk 3.02 (1.11-8.22). Thus, age of the patient, attenuated preoperative cardiac vagal modulation, ectopic supraventricular beats, and paroxysmal non-sustained supraventricular tachycardia are independent risk factors for the development of atrial fibrillation or flutter after coronary artery bypass surgery. PMID- 8701507 TI - [Blood loss during transurethral resection of the prostate]. AB - Measurement of the perioperative blood loss during transurethral resection of the prostate was performed using the modern HemoCue photometer in 100 men. The measurement lasts only 5-10 minutes. The median weight of the removed prostate was 28 grams and the operating time 60 minutes. The median blood loss was 393 ml (range 8-1843 ml) and was positively correlated to operating time, change in the peroperative blood pressure, volume of the irrigating fluid and the drop in the postoperative serum sodium. Perioperative measurements of the blood loss draw the surgeons' attention to the haemostasis, provide an objective measure of the most important factor for morbidity during TURP and allow a rational policy for blood transfusion. It is an advantage to place this measurement in the hands of professionals, i.e. laboratory technicians, who are trained to quality-secure the measurement and preserve the photometer. PMID- 8701508 TI - [The effect of Ginkgo biloba extract in patients with intermittent claudication]. AB - Eighteen patients with stable intermittent claudication were randomized in a double blind cross-over study comparing the effects of the Ginkgo biloba extract GB-8 at a dose of 120 mg o.d. with placebo. All patients were treated for three months with the active extract and three months with placebo. The effects of treatment on arterial insufficiency were quantified by measurements of systemic and peripheral systolic blood pressures, and pain-free and maximal walking distances on a tread-mill. Questionnaires based on visual analogue scales were used to quantify the severity of leg pain, impairment of concentration, and inability to remember. Short-term memory was objectively assessed. We did not find any significant changes in either peripheral blood pressures, walking distances or the severity of leg pain. Systemic blood pressure was reduced both by placebo and GB-8. The impairment of concentration and the inability to remember were both reduced, when comparing results during active treatment to placebo. Short-term memory did not change significantly. In conclusion, our study has shown that treatment with the Ginkgo biloba extract GB-8 improves some cognitive functions in elderly patients with moderate arterial insufficiency, whereas the extract did not change signs and symptoms of vascular disease in the patients. PMID- 8701509 TI - [Hot water irrigation in the treatment of posterior epistaxis]. AB - Tamponade treatment in epistaxis is painful and the patient needs hospitalisation. Irrigation with hot water was introduced as a treatment of epistaxis 100 years ago. This study compares the two treatments with respect to effect, recurrence, pain, and length of hospital stay. Forty-four consecutive patients with posterior epistaxis were randomized to receive treatment with either hot water (HWI) or tamponade. In the group of patients treated with HWI, the treatment had to be stopped in seven patients (33%) because of lack of cooperation; nine patients (43%) could be discharged from hospital with no need for further treatment, whereas five patients (24%) had recurrent epistaxis requiring additional tamponade treatment. Among patients treated with tamponade, 14 patients (61%) could be discharged from hospital with no need for further treatment, while nine patients (39%) had recurrent epistaxis requiring additional tamponade treatment. Compared with the tamponade treatment, HWI is almost as effective, the hospital stay is shorter, and the treatment is significantly less painful. PMID- 8701510 TI - [Toxoplasmosis-chorioretinitis: clinical course and treatment of seven patients]. AB - Toxoplasmosis is a major and preventable cause of severe visual loss and blindness in young people. Ocular toxoplasmosis is the leading cause of posterior uveitis and in most cases it represents a late manifestation of a congenital infection. The clinical picture and anti-Toxoplasma therapy of seven patients referred to the Department of Infectious Diseases, Hvidovre Hospital is described. All patients had clinical ocular toxoplasmosis at initial examination with unilateral focal necrotizing retinitis associated with typical old, pigmented scars. All patients had anti-toxoplasmosis IgG antibodies. After anti Toxoplasma therapy with sulfadiazine, pyrimethamine and corticosteroid the ocular lesions were healed to atrophic scars and the inflammatory activity disappeared. We conclude that when the clinical picture is compatible with toxoplasmosis, antibodies to Toxoplasma gondii are demonstrated and there is no other diagnosis, anti-Toxoplasma treatment should be considered. It is important to inform pregnant women about prophylactic measures, and to perform a serological screening of newborns, since treatment of congenital toxoplasmosis from birth improves the prognosis. PMID- 8701512 TI - [Caroli's disease]. AB - Caroli's disease (CS) is a rare malformation of the bile duct with multiple segmental communicating dilatations of intrahepatic bile ducts affecting the whole of or parts of the liver. The disease is presumably of autosomal recessive hereditary character. Caroli described two types: the rare isolated variety (type 1), is characterized by recurring episodes of cholangitis. The more frequently occurring type 2 is associated with congenital hepatic fibrosis, and consequently there are also symptoms of portal hypertension. Both types may make their first appearance at a very early age. A case story is presented. In the light of the development of carcinoma in 7% of the patients, the authors recommend that patients who cannot be operated radically should have regular, clinical follow ups including ultrasonography and biopsies if necessary. PMID- 8701511 TI - [Salmeterol improves the control of disease in patients with moderate asthma. A comparative study of inhaled salmeterol 50 mg and salbutamol depot tablets 8 mg, both administered twice daily]. AB - In a randomized, double-blind, double-dummy, cross-over study the efficacy and safety of inhaled salmeterol 50 mcg (b.i.d.) was compared with oral salbutamol controlled release 8 mg (b.i.d.). Fifty-nine patients with moderate asthma were randomized to two four-week periods of treatment with a two-week washout period. During the study period the patients were allowed to use inhaled Salbutamol on a prn. basis. Inhaled steroids, if any, were continued. On diary cards patients recorded peak expiratory flow rate (PEFR) morning and evening before medication, asthma symptom score, and use of inhaled salbutamol. Salmeterol was more effective than salbutamol CR in decreasing daily symptoms (p = 0.001) and increasing morning-PEFR (p = 0.004). Salmeterol resulted in significantly more days without symptoms (p = 0.0004) and days and nights without need for rescue medication (p = 0.01 and p = 0.01). Salmeterol was better tolerated than salbutamol CR. PMID- 8701513 TI - [Postbulbar duodenal ulcer. A rare cause of icterus]. AB - Post bulbar location of a duodenal ulcer is a rare condition associated with a greater than normal incidence of complications. Bleeding is a major problem, but also perforation, strictures, choledochoduodenal- and pancreaticoduodenal fistulas are found as complications of post bulbar duodenal ulcers. In spite of the close relation of the second part of the duodenum to the common bile duct, jaundice is remarkably rare with a prevalence of about 0.14%. We present a case of benign jaundice caused by a juxtapapillary duodenal ulcer treated by temporary biliary stenting and medical anti-ulcer treatment. PMID- 8701514 TI - [Taxans in the treatment of ovarian cancer]. PMID- 8701515 TI - [Chlamydia trachomatis]. PMID- 8701516 TI - [A comment on vitamin C]. PMID- 8701518 TI - [Prion diseases]. PMID- 8701517 TI - [Vitamin C and cancer]. PMID- 8701519 TI - [Treatment of anus cancer]. PMID- 8701520 TI - [Protein structure and pathology of the erythrocyte membrane]. PMID- 8701521 TI - [Human spongiform encephalopathies. Diseases caused by prions]. AB - Spongiform encephalopathies or prion diseases are common denominators for a group of diseases, all fatal, which show characteristic neuropathological changes. In man the group includes four diseases: kuru, Creutzfeldt-Jakob's disease (CJD), Gerstmann-Straussler-Scheinker's disease (GSS) and fatal familial insomnia (FFI). In animals it comprises the following six: scrapie (sheep and goats), transmissible mink encephalopathy (mink), chronic wasting disease (mule/elk), exotic ungulate encephalopathy (antelopes) and feline and bovine spongiform encephalopathy (cats and cattle). The diseases can be transmitted to other animal species, including mice, hamsters, rats, monkeys and chimpanzees. The diseases show common histopathological changes in both animals and man, which are restricted to the CNS, in none of them are there signs of an inflammatory process or fever, and the cellcount in the CSF is normal. Disease symptoms are characterized by loss of higher levels of brain functions resulting in dementia and ataxia as the most pronounced symptoms. All prion diseases are associated with accumulation of an abnormal, partially proteinase-resistant isoform of a host-coded protein, the prion-protein (PrP), which is a cell surface sialoglycoprotein of unknown significance. PrP is highly conserved among mammals and is expressed in most tissues. Diseases caused by prions are exceptional as they can occur sporadically and are transmissible both genetically and infectiously. This review attempts to elucidate the present knowledge of the natural history of these diseases in man. PMID- 8701522 TI - [Anus cancer]. AB - The pathology, etiology and epidemiology of anal cancer (CA) and the treatment and prognostic factors are reviewed. CA is a rare disease. However, the incidence is rising and is now 0.7 per 100,000 women and 0.4 per 100,000 men in Denmark. The median age is 60 years. Smoking and infection with human papillomavirus or HIV increases the risk of CA. The most important prognostic factors are tumour size, depth of invasion, inquinal lymph node involvement, differentiation and DNA ploidy. Previously CA was treated with abdominoperineal resection. Now sphincter preserving treatment with radiotherapy either alone or in combination with chemotherapy is preferred in most centers. Its is unsettled whether combined treatment is superior to radiotherapy only. Careful follow-up is warranted in order to perform salvage surgery in case of recurrent disease. PMID- 8701523 TI - [Nasal catheters versus Hudson face mask in oxygen therapy]. AB - Thirty-two females, ASA class I, scheduled for termination of pregnancy before the 13th week participated in the study. After induction of anaesthesia, a soft plastic catheter was inserted in the oropharynx and the patients were postoperatively monitored with a capnograph, which sampled in- and expired air from the catheter. In a randomized cross-over design the patients received oxygen therapy by the Hudson face-mask and a nasal cannula. Humidified and heated oxygen was given in both cases, using a flow of 15 litres per minute. The nasal cannula resulted in a significantly higher expired end-tidal O2-fraction (FETO2) compared to the Hudson mask. During the nasal cannula period the respiratory rate was significantly lower than during the face mask period. The end-tidal CO2 pressure (PETCO2) remained constant. PMID- 8701525 TI - [Lateral humeral epicondylitis. A postoperative evaluation]. AB - From 1.1.1982 to 31.12.1941 45 patients with 50 elbows were operated at Holstebro Central Hospital under the diagnosis epicondylitis lateralis humeri. The material consisted of 29 females and 16 males with an average at operation of 41.1 years (21-61 years). At that time the patients had had symptoms for approximately 2.8 years (0.5-25 years), and they had all received conservative treatment without effect. Forty-seven patients were operated with a tenotomy of caput commune extensorum, and three patients had a lengthening of the m. extensor carpi radialis performed. At follow-up at an average of 83.1 months postoperatively (16 127 months) 61% were working whereas none of them had been working preoperatively. Forty-six per cent were satisfied with the result. These results do not differ from what other authors have found, and today it seems that everybody agrees that only patients who have tried conservative treatment without improvement should be offered an operation. In a study recently published, histopathologic examination of the tissue of those patients who had no effect of conservative treatment showed degenerative changes rather than inflammatory changes, and this could be a reason why some patients have no effect of immobilisation and treatment with nonsteroidal antiinflammatory drugs. PMID- 8701524 TI - [Continuous monitoring of end-tidal CO2-tension in non-intubated patients]. AB - We describe and evaluate a method for continuously monitoring end-tidal CO2 (PETCO2) in non-intubated, spontaneously breathing patients. In 18 ASA I patients scheduled for minor surgery a 3.3 mm (10 CH) soft plastic catheter was preoperatively inserted through one nostril placing the tip at the level of the epiglottis. In the recovery room a capnograph was connected to the catheter for monitoring PETCO2. We found no significant differences between arterial carbon dioxide tension (PaCO2) and PETCO2 obtained by the catheter (0.2 +/- 2.2 mmHg) or obtained by a maximal expiration through a mouthpiece (-0.8 +/- 2.8 mmHg). We tested the possibility of mixing expired air with supplementary oxygen via the other nostril at a flowrate of 15 litres min-1, and found no significant difference in PETCO2 with or without flow (0.0 +/- 0.9 mmHg). Values are mean +/- SD. In conclusion we find that this method allows accurate monitoring of PETCO2 in non-intubated, spontaneously breathing patients even at supplementary oxygen flow-rates of up to 15 litres min-1. PMID- 8701526 TI - [Treatment of brain tumors investigation by positron emission tomography]. AB - The effects of glucocorticoids (GC) on the blood-to-tumour barrier transport (BTT) and tissue blood volume (Vb) and aspects of brain tumour acid/base balance were studied in patients with brain tumours using positron emission tomography (PET). BTT was assessed by 82Rb/PET and quantitated as K1 (unidirectional transport constant), tissue blood volume was also measured by 82Rb/PET. The parameters were evaluated following start of GC. The pH was assessed with 11C DMO/PET as a single measurement in patients receiving GC. GC treatment reduced the tumour K1 20% to 30%, within 6 to 24 hours following start of treatment. Brain tumours were in the alkalotic range compared to normal brain. The studies have helped to explain GC's antioedema effect and mechanisms behind the observed tumor alkalosis. The 82Rb/PET model seems useful for quantitative measurements of such parameters as pharmacological blood-tumour barrier opening, allowing continuous assessment of the potential for tumour chemotherapeutic uptake, thereby improving anti-cancer chemotherapy. PMID- 8701527 TI - [Acute porphyria and multiple organ failure during treatment with lamotrigine]. AB - A 38-year-old female suffered from an acute porphyric attack, multi-organ failure and disseminated intravascular coagulation (DIC) within two weeks of starting lamotrigine, a new antiepileptic drug. The porphyric attack was characterized by excess urinary excretion of aminolevulinic acid (ALA), porphobilinogen (PBG) and coproporphyrin III, a pattern similar to that seen in hereditary coproporphyria, however the diagnostic criteria for this specific porphyria were not fulfilled. We suggest that the observed clinical picture represents a rare adverse reaction to lamotrigine. PMID- 8701529 TI - [High-dose chemotherapy in solid tumors--a therapeutic breakthrough?]. PMID- 8701530 TI - [Can MR scanning replace diagnostic arthroscopy of the knee joint?]. PMID- 8701528 TI - [Torsade de Pointes tachycardia during sotalol treatment of a patient with normal potassium levels]. AB - Proarrhythmia in the form of Torsade de Pointes tachycardia (TdP) is a well-known complication of sotalol treatment. It most often occurs in the setting of sotalol overdosing, renal impairment, bradycardia, hypokalaemia, hypomagnesiaemia or lengthening of the QT-interval due to other drugs. TdP is reported without these predisposing factors. In the described case, TdP might be facilitated by bradycardia and by potassium depletion without concomitant hypokalaemia after diuretic treatment. PMID- 8701531 TI - [Erythropoiesis and use of hematopoietic growth factors in children]. PMID- 8701532 TI - [High-dose chemotherapy and autologous bone marrow transplantation in solid tumors. A review]. AB - This review deals with high-dose chemotherapy plus haematopoietic stem cell support as treatment to patients with chemosensitive solid tumours, breast-, testicular-, small cell lung-, and ovarian cancer. Dose-intensification of cytotoxic agents without stem cell support has not increased survival in these patients. High-dose chemotherapy plus stem cell support is a promising treatment strategy as adjuvant therapy in patients with high-risk breast cancer, i.e. more than 6-10 metastatic axillary lymph nodes, and there are several on-going randomized studies investigating conventional versus high-dose therapy in this situation both in Europe and in the US. Another international randomized study concerns patients with testicular cancer, where high-dose therapy is given as relapse treatment and as initial therapy in high-risk patients. High-dose therapy is an experimental treatment in all solid tumours, but there are no data supporting randomized studies in other solid tumours. PMID- 8701533 TI - [Evaluation of trainees' stay in general practice by the young physicians and their tutors]. AB - In 1991 a new reform for postgraduate trainees was introduced in Denmark. Since the reform all young doctors-as a compulsory part of their vocational training have had to work for six months as general practice trainees, no matter their wishes for future specialization. The reform furthermore led to the general practice trainees being considerably younger than previously-the average length of postgraduate experience before working as a trainee declined from six to seven years to one to two years. In this light an investigation was conducted from August 1992 to July 1993. Seven hundred and fifty-eight questionnaires were sent to general practice trainees and their tutors in Denmark. Ninety-five percent of the questionnaires were returned, thus it was possible to evaluate the new compulsory training in general practice. In conclusion, the main part of the trainees had a positive assessment of the work conditions in general practice. However, a large part of the trainees indicated that their tutor doctors had set aside too short a time for supervision. PMID- 8701534 TI - [It is still beneficial to be a tutor physician]. AB - In 1991 a new reform for postgraduate trainees was introduced in Denmark. As a result of the reform the average postgraduate experience of trainees in general practice declined from six to seven years to one to two years and the training in general practice became compulsory for all. It was expected that these changes would require more supervision of the trainees by their tutor doctors, and some general practitioners no longer wished to receive trainees. In this light an investigation was conducted from August 1992 to July 1993. Questionnaires were sent to tutors who had employed a trainee with less than 25 months of postgraduate experience since 1990. As a precondition questionnaires were only sent to tutors who had also employed trainees before the reform. Two hundred and twenty-eight of the questionnaires were returned. The tutors were asked to compare their assessments of the pre- and post-reform arrangements. According to the answers the young trainees contributed less to the everyday work and they earned the same as or less for the practice than their more experienced predecessors. The tutors were furthermore asked to give a specific assessment of the young trainee working at the moment in general practice. The tutors found sufficient skills in the trainees, they found relief in their workload and a neutral or improved economics due to the trainees In spite of the trainees being less experienced and a need for more supervision and education as compared to the time before the reform, the tutors still agreed that having a trainee in their practice was an overall benefit. PMID- 8701535 TI - [Prognosis in familial adenomatous polyposis. Results from the Polyposis Registry]. AB - Regional and national polyposis registries have been established all over the world over last decades, with the aim to improve survival in patients with familial adenomatous polyposis (FAP). The Danish Polyposis Register was founded in 1971 and coordinates screening and prophylactic treatment. At the end of 1992 the register included 321 histologically verified FAP patients: 142/205 probands (69%) had colorectal cancer at the time of diagnosis of FAP versus only 2/116 call-up cases (2%). The 10-year cumulative crude survival was 94% among call-up cases versus only 41% among probands (p < 0.00001), and the survival increased significantly after establishment of the Polyposis Register in 1971. We conclude that centralized registration with identification and prophylactic examination of relatives at risk results in a substantial improvement of the prognosis. PMID- 8701536 TI - [Occupational exposure to formaldehyde and risk of cancer]. AB - Formaldehyde is a widespread animal carcinogen with limited evidence of carcinogenesis in humans. We investigated the occupational risk of cancer (1970 84) among men and women in Denmark. Relative risks (RR) were estimated from standardized proportionate incidence ratios among patients whose longest employment had been held since 1964, at least 10 years before diagnosis, in 265 companies in which exposure to formaldehyde was identified. The only biologically plausible increased risk was for nasal cancer, for which relative risks of 2.3 (95% confidence interval = 1.3-4.0) and 2.4 (0.6-6.0) appeared for men and women, respectively. In the subgroup of blue-collar men with no probable exposure to wood-dust, the major confounder, the relative risk for this cancer was 3.0 (1.4 5.7). It is concluded that occupational exposure to formaldehyde may increase the risk of nasal cancer, but formaldehyde does probably not affect other cancers. PMID- 8701537 TI - [Painful menstruation and low intake of n-3 fatty acids]. AB - Menstrual pain, dysmenorrhea, which is known to be prostaglandin mediated, can possibly be influenced by the dietary ratio of omega-3 and omega-6 polyunsaturated fatty acids. The prostaglandins derived from marine omega-3 fatty acids are normally less aggressive and therefore expected to be associated with milder menstrual symptoms. This hypothesis was surveyed in an epidemiological study in Danish women based upon self administered questionnaires concerning menstrual history, present symptoms, general health, socio-economic factors, and general dietary habits. Two prospective four-day dietary records were used to estimate average daily nutrient intake. The subjects were recruited by advertising, they were 20-45 years of age, not pregnant, and did not use oral contraceptives. No correlations were found between socioeconomic or anthropometric data and menstrual problems. However, certain dietary habits e.g. low intakes of animal and fish products, and low intakes of specific nutrients (omega-3 PUFA, B12 and omega-3/omega-6 ratio) were correlated with menstrual pain. The other nutrients in the diet were not significantly related to menstrual pain. The results were highly significant and mutually consistent and supported the hypothesis that a higher intake of marine, omega-3 fatty acids correlate with milder menstrual symptoms. PMID- 8701538 TI - [Magnetic resonance imaging of the knee joint after trauma with intra-articular accentuation]. AB - Two male adolescents with direct trauma to the knee and haemarthrosis were followed up with MR imaging (MAI). No fractures were detected on plain films and both patients had extensive bone marrow lesions in MRI. The lesions were located within the metaphysis and the lateral tibial and femoral condyle respectively. In one patient MRI demonstrated additional soft tissue lesions of the femoral muscles. One patient had almost no clinical symptoms, while the other patient suffered from severe pain, inability to walk, and delayed recovery. The present report emphasizes the potential of MRI for the detection of occult injuries of bone and soft tissue, and calls for prospective studies of their clinical significance. PMID- 8701539 TI - [Acute arsenic poisoning]. AB - We report three cases of arsenic poisoning in a chemical factory. Three workers were exposed to vinyzene 10,10'-oxydephenarsine and developed mild symptoms of acute poisoning. All patients were treated with dimercaprol, and recovered after a few days. Urine analysis did not show increased arsenic excretion, but this could be due to the large urine samples taken. It is recommended that a urine sample is taken right after admission to hospital and new samples after eight and 16 hours. PMID- 8701540 TI - [Ion generators and bronchial asthma]. PMID- 8701541 TI - Proceedings of Ultrasonics International 1995. Edinburgh, 5-7 July 1995. PMID- 8701542 TI - Application of neural networks to quantitative nondestructive evaluation. AB - This paper concentrates on the quantitative analysis of reflection and transmission characteristics of structural waves in notched beams using neural networks. At one end of a rod a piezoelectric transducer excites a flexural guided wave, which propagates through the structure and is reflected from the notch as well as from the ends of the rod. At another point, a laser interferometer measures the resulting displacement versus time, which is recorded and serves as the digital fingerprint of the experiment. Our aim is to obtain quantitative information about the notch characteristics, i.e. its location and depth, on the basis of these digital recordings. This requires an inverse problem to be solved using neural networks. For the training of the network, synthetically produced wave patterns are used. The results of the corresponding wave experiment simulations compare well with experimental data. For fixed location, the calculated wave patterns could be quantitatively analysed to yield the depth of the notch if it is greater than a twentieth of the diameter. Another network could be trained for the localization with an accuracy of 2 cm for 93% of the training patterns. On the basis of these results a strategy is formulated on how neural networks could be trained to evaluate quantitatively both of the notch characteristics. PMID- 8701543 TI - Ultrasonic characterisation of inhomogeneous materials: some problems with measurements of forward scattered fields. AB - Measurements of the complex pressure fields transmitted by scattering specimens consisting of glass beads in silicone rubber and of in vitro samples of ox myocardium, liver and kidneys have been carried out by point-by-point mapping of the amplitude and phase of the fields, using a new design of PVDF needle hydrophone in a high precision scanning tank. The results show that disruption of the phase fronts by the specimens is small and the measured values depend on the choice of measurement distance and frequency, and spatial sampling interval. As a result, there is little difference between phase sensitive and phase insensitive measurements at frequencies below 5 MHz. It is therefore unlikely that the proposed method could be applied successfully to the characterisation of such materials at low megahertz frequencies. PMID- 8701544 TI - Bioeffects of diagnostic ultrasound in vitro. AB - Biological effects induced by ultrasound were frequently reported for continuous wave (cw) mode. Thresholds for the onset of bioeffects of pulsed ultrasound, starting from diagnostic conditions, have not yet been defined by standardized in vitro models. We therefore investigated the effects of pulsed ultrasound on cultured cells using diagnostic ultrasound devices, a selfmade transducer and a sonochemical laboratory reactor tunable from pulsed diagnostic conditions to cw ultrasound. Additionally, we determined physical parameters of the ultrasonic field by different types of hydrophones. Sonochemical reactions and the effects induced by the ultrasonic fields in cultured cells indicated a threshold for bioeffects. PMID- 8701545 TI - Ultrasonic velocities of concentric laminated uric acid stones. AB - In concentric laminated uric acid samples two different sound velocities are observed with very different values, the one in the organic matrix varies from 670 to 1170 m s(-1), the other in the crystalline layers between 3200 and 5300 m s(-1). This large difference illustrates the importance of the internal stone structure on the fracture behaviour of urinary stones and reveals the weakness of the actual disintegration models, attributing the destructive effect of shock waves on the differences in acoustical impedance at the water/stone interface and not on the differences in acoustical impedance at the matrix/crystalline interfaces inside the urinary calculus. PMID- 8701546 TI - Modelling of a photoacoustic probe designed for medical applications. AB - A model is presented describing the thermoelastic photoacoustic interaction in a layered medium within a transparent fluid, where a polymer transducer is used for the detection of ultrasonic pulses. By taking the optical absorption coefficient and finite layer thickness into account, the amplitude and shape of photoacoustic transients are calculated for both forward and backward travelling directions. Additionally, photoacoustic transient interaction with the PVDF transducer has been characterised using a discrete-time algorithm for the transducer response. Good agreement with experimental waveforms are demonstrated, so that this may form the basis of system characterisation when miniature laser-ultrasound probes are used in various applications. PMID- 8701547 TI - Physics of ultrasonic surgery using tissue fragmentation. AB - The ultrasonic surgical aspirator employs a vibrating metal tip to fragment tissue and then aspirates the debris through the hollow center of the tip. The mechanism of interaction has been stated to be poorly understood, most likely related to cavitation, possibly acting in concert with other mechanical actions. The role of stroke, suction, frequency, tissue type, and tip area have been examined with regard to tissue fragmentation rate. Suction is shown to make a significant contribution to the interaction. Photographic and acoustic data from experiments in water and on a range of fresh pig tissues are used to investigate the fragmentation effect. A model for the primary mechanism for tissue fragmentation is presented. This involves the horn-tip impact and other mechanical forces, operating in combination with hydrodynamic forces applied to the tissue on the forward stroke in each cycle. No evidence of cavitation in tissue was observed. PMID- 8701548 TI - New ultrasound contrast agents and technological innovations. AB - Further development of clinical diagnostic procedures, as well as new diagnostic techniques, requires ultrasound specific contrast agents as well as technological innovations. This paper reviews contrast agents developed in the last decade, which are all based on free gas or encapsulated gas bubbles. PMID- 8701550 TI - History, physical examination, and classification of neurogenic voiding dysfunction. AB - Although exceptions exist, clinical and urodynamic findings can be predicted on the basis of the location of the neurologic lesions. Conversely, these findings can be used to predict the location of the lesion. Recognition of similar patterns allows for classification, and classification allows the physician more readily to devise a diagnostic and therapeutic plan. Furthermore, a simple and practical classification system facilitates communication between physicians. PMID- 8701549 TI - An in vitro study on the influence of limited frequency resolution on contrast agent-enhanced Doppler signals. AB - Ultrasound contrast agents for vascular use are gas-filled microspheres and will increase the backscatter from blood and therefore enhance the Doppler signal. Studies have shown that Doppler enhancement may result in an increased maximum velocity when observed as the envelope of the spectral Doppler screen. Change in observed velocity may be due to biological or instrumentational effects. The purpose of this study was to investigate the possible instrumentational effects on the Doppler signal after injection of the contrast agent (Infoson). By performing the measurements on a Doppler phantom, the biological effects was eliminated. Computer simulations of limited frequency resolution were compared to measurements. The conclusion was that the increase in detected maximum velocity after Infoson injection is due to the combined effect of signal enhancement and limited frequency resolution. It is shown that a large change in signal strength can change the estimated maximum frequency from the spectral Doppler whether this is due to a contrast agent or instrument settings. It is therefore important in a clinical situation to have an adequate, but not too strong or too weak signal in order to make the best velocity estimates. PMID- 8701551 TI - Ambulatory urodynamics: extramural testing of the lower and upper urinary tract by Holter monitoring of cystometrogram, uroflowmetry, and renal pelvic pressures. AB - This article elucidates the clinical applicability and state of the art of ambulatory urodynamics. Ambulatory urodynamics have evolved into practical investigations like EAC, HFM, and EAC combined with renal pelvimetry. EAC has been shown to be the method of preference if detrusor overactivity is involved. Conventional filling cystometry has proved to be an unreliable way to exclude detrusor instability. De novo instability after suspension surgery often indicates that an existing detrusor overactivity was not identified preoperatively. EAC including flowmetry has shown considerable variance in obstructive and contractility parameters in males with LUTS indicative for BPH. This raises doubt whether the clinical flow analysis is the suitable "gold standard" as advocated by the ICS. For a real break through of EAC, less complex automatic analysis is necessary. HFM is a newer method within the range of ambulatory urodynamic tests. It has not yet been completely evaluated. But, because the technique is analogous to the office flowmetry, noninvasive and very well accepted by the patients, it is expected to be widely used. This expectation is strengthened by the fact that HFM seems to show individual therapeutic efficacy of drugs, such as alpha-blockers. As a research tool to evaluate efficacy, it is far more powerful than conventional methods because of the reduction of within-patient standard deviation to about 10%. Finally, EAC combined with pelvimetry offers a promising method for the clinical evaluation of a combined dysfunction of upper and lower urinary tract. PMID- 8701552 TI - Obstructive uropathy in the male. AB - BPH is not synonymous with prostatic obstruction. The cause of symptoms in men with prostatism is multifactorial, comprising four conditions: (1) prostatic urethral obstruction, (2) impaired detrusor contractility, (3) detrusor instability, and (4) sensory urgency. Some men have an isolated obstruction at the vesical neck, termed primary vesical neck obstruction, that may have a different cause from that of BPH, and others have a learned voiding dysfunction wherein they are unable to relax completely during micturition. There is no simple means of distinguishing the various conditions that underlie voiding symptoms in men. Neither simple cystometry nor uroflow suffice. Detrusor pressure and uroflow studies usually are definitive, but more sophisticated analysis may be necessary. PMID- 8701553 TI - Bladder outlet obstruction in women. AB - While voiding dysfunction is relatively common in women, true bladder outlet obstruction is a rare condition and may be present in a misleading manner. To make an accurate diagnosis and tailor appropriate treatment, urodynamic investigation is required. However, even sophisticated urodynamic studies have limitations in predicting obstruction as a complication of anti-incontinence surgery and response to ureterolysis. PMID- 8701554 TI - Computer-assisted pressure-flow analysis. AB - Infravesical obstruction can only be diagnosed objectively from a urodynamic pressure-flow study. Analysis of the resulting data is not straightforward. Recently,many methods have been proposed for such analysis. Inevitably most of these methods for pressure-flow analysis are discussed in this contribution, and some results of clinical application of calculated urethral resistance factors are presented. PMID- 8701555 TI - Diagnosis of stress urinary incontinence. An overview. AB - This article represents an overview of the evaluation and diagnosis of stress urinary incontinence. Lower urinary tract anatomy in women is reviewed with particular attention to the salient features contributing to stress incontinence. Also discussed is the relevance of the distinction between anatomic incontinence and intrinsic sphincter deficiency in the classification of stress urinary incontinence. Various diagnostic techniques are described with emphasis on the importance of urodynamic evaluation in complex cases. PMID- 8701556 TI - Urge incontinence. AB - This article discusses the management of patients presenting with urge incontinence as the main symptom. The etiological factors, though not understood completely, are grouped into logical subsets and discussed. The incidence and the implications of urge incontinence on the quality of life of patients is considered. A summary of available treatment methods is presented in an algorithm. PMID- 8701557 TI - Evoked potential testing. AB - Electrophysiologic tests of the sacral neuromuscular system and its suprasegmental control may be divided into EMG and methods involving stimulation (i.e., evoked potential and sacral reflex testing). The latter group of methods tests the function of defined parts of the motor or sensory nervous system, or reflex arcs. There already is ample experience with testing the somatic sensory pathways (pudendal SEP) and the (somatic) sacral reflex arc, whereas other methods (testing the motor system and tests involving visceral afferents and sympathetic efferents) need further study to establish their proper place in everyday clinical diagnostics. The application of these methods in research has led to important advances in our understanding of nervous system involvement in different pathologic conditions leading to neurogenic sacral dysfunctions. If applied in individual patients, these methods should however, be used and interpreted with restraint; they should be considered in patients with probable or proved nervous system lesions, those in whom additional clarification regarding proof of, localization of, and the nature (i.e., axonal versus demyelinative) of the lesion is relevant for diagnosis and prognosis. If applied in patients with central nervous system involvement, evoked potential studies may be used on their own; but, in the author's opinion, in patients with putative peripheral nervous system involvement these tests should be considered, as a rule, only as an extension of a needle EMG exploration. It is expected that further experience will clarify the sensitivity and specificity of the available methods. The already available methods certainly will gain a place in the operating room helping the surgeon in selected procedures involving the pelvis and particularly conus and cauda equina better to identify neuromuscular structures and to monitor their function throughout the operation in order to prevent subsequent development of lesions. PMID- 8701558 TI - Postprostatectomy incontinence. AB - Post-prostatectomy incontinence is a devastating complication that is frustrating for the patient and the surgeon. Bladder dysfunction with or without sphincteric incompetence is the main cause for post-prostatectomy incontinence. Treatment based on the urodynamic evaluation is effective in restoring continence and improving the patient's quality of life. PMID- 8701559 TI - Urodynamics of spinal cord injury. AB - Historically, urologic complications have been the major source of morbidity and mortality among spinal cord injured (SCI) patients. All SCI patients should undergo urodynamic evaluation, with the initial urodynamics study done after the patient is beyond the spinal-shock phase. Management of the urinary tract in SCI individuals should be based on urodynamic principles and findings rather than on the neurologic history. PMID- 8701560 TI - Urodynamics and multiple sclerosis. AB - Multiple sclerosis is an enigmatic and devastating neurologic disease. Voiding dysfunction is common and the irritative and obstructive symptoms can be disabling to the patient. Voiding symptoms alone are unreliable predictors of bladder and urethral dysfunction secondary to multiple sclerosis. This article focuses on the central role played by urodynamic studies in the initial assessment and management of the lower urinary tract. Detrusor hyperreflexia is the most common urodynamic finding. However, a variety of urodynamic patterns can be seen and voiding function may change over time with this chronic neurologic disorder. PMID- 8701561 TI - Effects of cerebrovascular accident on micturition. AB - A functionally oriented approach to acute stroke care should take place in conjunction with traditional medical management, because the medical care provided during the first days and weeks after a stroke affects the ultimate disability status of the patient.10 New onset voiding dysfunction after a stroke is a difficult problem for all involved in the care of the patient. Urinary incontinence and retention are socially unacceptable and can be very embarrassing for the patient. They can interfere with patient discharge and complicate patient rehabilitation.13 With the high incidence of stroke, geriatricians and urologists will come across many patients with this condition, and they must approach the problem of voiding dysfunction in concert if they expect to achieve the optimal outcome for the patient. Therefore, proper diagnosis and management of voiding dysfunction in the poststroke patient are important for improved patient well being, increased patient survival, and decreased disability as well as a reduction in the national health care expenditures. PMID- 8701562 TI - Peripheral neuropathy and peripheral nerve injury. AB - The peripheral nerves to the bladder can be altered by several disease processes. Voiding symptoms alone are not reliable in predicting the exact neurogenic bladder dysfunction. Urodynamic evaluation is crucial to optimize therapy and to rule out concomitant pathology. PMID- 8701563 TI - Pediatric neurourology. AB - Children with voiding disturbances or neurologic dysfunction of the lower urinary tract present challenges to the practicing clinician. With careful clinical and radiologic evaluation, many of these disturbances can be managed. Complex situations, however, generally require expert urodynamic evaluation to delineate the cause of the bladder dysfunction and to guide management. These investigations combined with long-term follow up should provide new insights for further improvement in the management of neurogenic bladders in children. Urodynamic studies also have given us insights into the pathophysiology of abnormal voiding states secondary to dysfunctional bladders in children with posterior urethral valves, the prune belly syndrome, and the Hinman syndrome. PMID- 8701564 TI - Percutaneous bladder neck suspension. AB - The early results after PBNS are extremely encouraging. The procedure is easy to learn, is performed rapidly on an outpatient basis under local anesthesia if desired, and has minimal postoperative morbidity. Continued objective follow up is critical to define the long-term efficacy of this promising technique. PMID- 8701565 TI - An experimental ovine foot abscess model using a Fusobacterium necrophorum biotype AB. AB - An experimental procedure is described for the production of foot abscess in sheep that mimics the natural disease. Lesions were produced by the intradermal inoculation of suspensions of Fusobacterium necrophorum biotype AB containing from 5 x 10(2) to 5 x 10(8) bacteria, into interdigital skin devitalized by freezing with liquid nitrogen. A dose of 5 x 10(5) bacteria induced the development of foot abscess in 3 of 4 and 8 of 8 inoculated feet. It was found that to produce foot abscess in devitalized tissue required between 10(3) and 10(6) fewer bacteria than were necessary to produce similar lesions in healthy tissue. PMID- 8701566 TI - Infection of cattle with Yersinia enterocolitica O:9 a cause of the false positive serological reactions in bovine brucellosis diagnostic tests. AB - During the last four years, an increasing number of cattle herds were classified positive by brucellosis screening tests in areas of Belgium and France free of the disease. No clinical symptom of brucellosis was reported in these animals and no Brucella abortus strains were isolated. After two years, no brucellosis outbreak was registered in all of the herds concerned. On this basis, all the serological reactions observed were classified as false positive. An ELISA using Yersinia Outer membrane Proteins (YOPs) as antigens was developed in order to discriminate between a Yersinia enterocolitica O:9 infection and a Brucella abortus infection. Antibodies against YOPs were detected in sera from Y. enterocolitica O:9 experimentally infected cattle (n = 4) but not in sera from B. abortus experimentally infected cattle (n = 4). In a field study, 66.7% of the 174 serum samples from cattle presenting false positive serological reactions showed anti-YOPs antibodies whereas only 10% of 454 sera, classified negative by the brucellosis screening tests, showed anti-YOPs antibodies. Our results suggest that infections with Y. enterocolitica O:9 may cause false positive reactions in brucellosis testing. PMID- 8701567 TI - Serogroups of Escherichia coli isolated from piglets in Spain. AB - Serogroups of 1334 E. coli colonies isolated in Spain between 1986 and 1991 from piglets with diarrhoea, oedema disease and from healthy piglets, were determined. The serogroups determined in E. coli from diarrhoea were: O1, O2, O4, O5, O7, O8, O9, O12, O20, O21, O23, O25, O26, O32, O39, O45, O54, O75, O78, O80, O83, O91, O92, O101, O103, O113, O115, O116, O118, O125, O127, O138, O139, O141, O149, O153 and O157; from pigs with oedema disease: O8, O101, O138, O149 and O157; and from healthy piglets: O1, O2, O5, O7, O8, O9, O20, O21, O26, O29, O45, O64, O71, O80, O81, O91, O101, O105, O113, O115, O116, O126, O128, O132, O138, O139, O142, O146, O149, O152, O153, and O168. Serogroups O138, O141 and O149 were found to be statistically associated with enteric porcine colibacillosis (diarrhoea and oedema disease) (0.025 > P < 0.01). In addition, enterotoxigenic (ETEC) strains belonged to serogroups: O8, O9, O20, O101, O138, O141 and O149; verotoxigenic (VTEC) strains (VTEC) strains to serogroups 091 and 0138; and necrotizing (NTEC) strains to serogroups O2, O4, O8, O54, O78 and O83. Furthermore, 91.2% (249 out 273) of the ETEC (LT and/or STa) and/or VTEC strains belonged to only seven different serogroups. These major serogroups to which the ETEC and VTEC strains belonged, were determined in a lower percentage (21.2%) among non-toxigenic E. coli colonies isolated from sick and healthy piglets. PMID- 8701568 TI - Replication of bovine respiratory syncytial virus in ovine peripheral blood lymphocytes and monocytes in vitro. AB - Adherent and non-adherent mononuclear cells obtained from the peripheral blood of normal lambs supported the replication of bovine respiratory syncytial virus in vitro. Sequential treatment of monocytes with phorbol ester acetate (PMA) enhanced their ability to support viral replication. After exposure in vitro for 24 h, viral antigens were present in 47 +/- 4.5% of monocytes and 32 +/- 3% of lymphocytes. Treatment of monocytes with PMA resulted in the increase of the proportion of cells expressing viral antigen and in the titre of infectious virus. PMID- 8701569 TI - The distinction of serologically related ruminant alphaherpesviruses by the polymerase chain reaction (PCR) and restriction endonuclease analysis. AB - The amplification and analysis of a 468bp fragment from the gB gene of the serologically related ruminant alphaherpesviruses bovine herpesvirus-1.1 and 1.2 (BHV-1.1 and BHV-1.2), caprine herpesvirus-1 (CapHV-1), cervine herpesvirus-1 (CerHV-1) and rangiferine herpesvirus-1 (RanHV-1) by PCR and restriction endonuclease analysis is described. As primers, 22bp oligomers selected from the BHV-1 gB gene sequences were used for the amplification of the DNA from the five viruses. The amplification product from each virus was analysed by the restriction endonuclease enzymes BglI, HinfI, SmaI and AvaI. The specific amplification obtained demonstrate the existence of the gB gene sequences for each of the five alphaherpesviruses. However, sequences from some of the fragments were found to be different from those predicted from the gB gene following restriction endonuclease analysis. All five amplification products generated the same number of fragments after digestion with HinfI except for two additional bands evident in CapHV-1. The CerHV-1 and RanHV-1 fragments contained slightly different BglI restriction sites from those of the other three. While BHV-1.1, BHV-1.2, CapHV-1 and CerHV-1 contained SmaI and AvaI restriction sites, the RanHV-1 amplification product lacked both SmaI and AvaI restriction sites. PMID- 8701570 TI - Virulence and immunogenicity in calves of thymidine kinase- and glycoprotein E negative bovine herpesvirus 1 mutants. AB - A deletion was introduced into the thymidine kinase (TK) gene of the BHV1 strain Lam and, or, the complete coding region of the glycoprotein E (gE) gene was deleted to reduce virulence and to make serological differentiation possible. The virulence and immunogenicity of these three BHV1 mutants (TK-, gE- and TK-/gE) were studied in specific-pathogen-free calves. Although inactivation of TK strongly reduced the virulence of the Lam strain, deletion of the gE gene alone sufficed to yield complete attenuation of the Lam strain for seven-week-old calves. The three mutants induced protective immunity against disease after challenge with a virulent BHV1 strain. The reduction of virus shedding after challenge was related to the virulence of the various strains. The immunogenicity of the mutants was also evidenced by the reduction of challenge virus shedding after dexamethasone treatment. None of the mutant viruses could be isolated after dexamethasone treatment. The results demonstrate that the gE- and TK-/gE- mutants are good candidates for incorporation in a BHV1 marker vaccine. PMID- 8701571 TI - Comparison by restriction enzyme analysis of three fowl adenoviruses of varying pathogenicity. AB - Restriction enzyme studies have been used to divide the fowl adenoviruses (FAV) into 5 groups - A, B,C,D and E. More detailed restriction enzyme studies of a series of group E FAV field isolates showed that these methods could differentiate between mildly and hypervirulent FAV belonging to this group. We have mapped the genomes of the hypervirulent (CFA 40) and two of the mildly virulent FAV (CFA 44 and CFA 3), using 11 different restriction enzymes: HindIII, BglII, XbaI, NdeI, SpeI, DraI, NotI, StuI, NheI, SfiI, and AvrII. Comparison of the three maps showed that the CFA 3 genome was approximately 3.5 kb smaller than that of CFA 44 and CFA 40. This size difference was discounted as a likely cause of the reduced pathogenicity of CFA 3 as the other mildly virulent virus, CFA 44, was the same size as the hypervirulent CFA 40. Other variations between the three viruses occurred in the region of the hexon and 100 K genes, but further studies are required to determine the significance of these variations in pathogenicity. PMID- 8701572 TI - Serologic evidence for bovine immunodeficiency virus infection in France. AB - We report herein on the first serologic detection of antibodies to bovine immunodeficiency virus (BIV) in France. Serum samples from dairy and beef cattle from southwestern and western France (Landes and Vendee) were tested using a western blot assay with a recombinant 53 kDa gag precursor derived from the Louisiana BIV R29 isolate. We performed our study on the oldest animals from 37 different herds that were under serologic follow up for previous bovine leukemia virus infection. Overall, 398 selected bovine sera were assayed and 15 serum samples from 8 herds reacted with the recombinant 53 kDa BIV R29 gag. Interestingly, reactions obtained with French sera were weaker than with positive Louisiana sera, a finding that may indicate the occurrence of distinct French and Louisiana BIV variants. PMID- 8701573 TI - Serological response of cattle to Brucella allergen after repeated intradermal applications of this allergen. AB - A study was conducted to determine whether an allergen that has been prepared from a mucoid strain of Brucella abortus triggers a serum antibody response that interferes with the interpretation of serologic tests results. Fifteen cattle seronegative for Brucella antigen were tested with the SDTH test several times. Blood samples were collected weekly and tested with the serum agglutination test and complement fixation test. Results show that some cattle tested seronegative after each of the SDTH tests while other cattle tested weakly positive with the serum agglutination test or the complement fixation test. All seropositive cattle tested seronegative 4-7 weeks after the last SDTH test indicating an antibody response of a transient nature. We conclude that serologic tests results indicating infection are reliable when recorded four weeks after a single SDTH test. If cattle are tested with the SDTH test several times an interval of seven weeks should be observed after the last test to ensure a reliable interpretation of the serologic test results. PMID- 8701574 TI - Studies on natural transmission of Bordetella bronchiseptica in cats. AB - Two pregnant specific-pathogen-free (SPF) cats, from a colony endemically infected with Bordetella bronchiseptica, were housed under barrier conditions in the latter stages of pregnancy in order to study the possible transmission of the organism to their kittens. Both queens had antibody titres to Bordetella bronchiseptica of 1 in 320 at the start of the experiment but did not shed Bordetella bronchiseptica until 9 days and 6 weeks after parturition, respectively. Five of the nine kittens had detectable maternally-derived-antibody to Bordetella bronchiseptica which declined to < or = 1 in 40 by two weeks of age. Kittens were weaned at 12 weeks of age. No Bordetella bronchiseptica was isolated from any of the kittens and none seroconverted over this time. At 15 1/2 weeks of age, half of each litter were housed separately and inoculated intra nasally with 10(8) colony-forming-units B. bronchiseptica. Mild signs of upper respiratory tract disease were seen and the organism was isolated for 19 weeks following inoculation when the experiment ended. Seroconversion occurred at 4 weeks postinoculation. Oral treatment of two clinically-recovered kittens with doxycycline once a day did not eliminate shedding. PMID- 8701575 TI - The humoral immune response of turbot to recently isolated pathogenic Enterococcus strains. Cross-reactivity with other Gram-positive bacteria. AB - An Enterococcus sp. causing severe mortalities among farmed turbot (Scophthalmus maximus) has recently been detected in northwest Spain. We found that specific turbot serum antibodies raised against isolate RA-99.1 of the new pathogen by intraperitoneal immunization, did not cross react in enzyme-linked immunosorbent assay (ELISA) with other enterococcal or non-enterococcal Gram-positive bacteria. In immunoblotting, antibodies raised against strain RA-99.1 recognized the same components in the homologous total soluble antigen preparation (TSA) as in TSA of two other isolates of the pathogen obtained from different farms. Anti-RA-99.1 serum also recognized some components of the TSA of several other Gram-positive bacteria. Immunogold labelling indicated that the antigens which provoke the humoral immune response to this pathogen are located mainly on the bacterial surface. PMID- 8701576 TI - Characterization of tetracycline and erythromycin resistance in Actinobacillus pleuropneumoniae. AB - Minimum inhibitory concentrations to tetracycline and erythromycin were determined for nineteen isolates of Actinobacillus pleuropneumoniae of Norwegian origin. The isolates were screened for rRNA methylase determinants (Erm genes) and for the tetracycline resistance Tet B determinant, using oligonucleotide probes, polymerase chain reaction and hybridization. Ten isolates (53%) carried the Erm C determinant, two isolates (10%) carried the Erm A determinant, four isolates (21%) carried both the Erm A and the Erm C determinants, and three isolates (16%) carried none of the Erm determinants examined. Eight isolates (45%) carried the Tet B determinant. Selected isolates were shown to transfer the Erm C and Erm A determinants at a frequency of 10(-7)-10(-9) per recipient cell. This is the first description of A. pleuropneumoniae carrying either Erm A, Erm C or/and Tet B determinants. PMID- 8701577 TI - Genotyping by PCR, of Staphylococcus aureus strains, isolated from mammary glands of cows. AB - A total of 71 Staphylococcus aureus strains isolated from bovine mammary glands were identified and subtyped. The methods used to differentiate between the S. aureus isolates were the DNA polymorphism pattern after amplification with a Polymerase Chain Reaction using several primer combinations and phage typing. The DNA fingerprinting technique using RAPD, ERIC1R and ERIC primers proved to be useful in differentiating isolates of S. aureus. Differentiation of isolates using phage typing gave no additional information compared to the DNA technique. The outbreak of S. aureus in the herd studied was mainly caused by one S. aureus strain. Other strains were only found on three occasions, twice in subclinical infections and once from a case of clinical mastitis. In the latter case the dominant strain was isolated from a different quarter of the same cow. Four of the ten cows studied suffered from clinical mastitis. From those four cows, three remained infected with the same S. aureus strain despite antibiotic treatment. PMID- 8701578 TI - Isolation and characterisation of dog uropathogenic Proteus mirabilis strains. AB - Proteus mirabilis strains isolated from the urine of dogs with urinary tract infections, were characterised with respect to the production of haemolysin and fimbriae. In contrast to healthy dogs, P. mirabilis was also isolated in high numbers from the faeces of dogs suffering from recurrent urinary tract infections. Production of fimbriae was demonstrated by electron microscopy and the presence of genes for two different types of major fimbrial subunits (MR/P like or UCA-like) was demonstrated by Southern hybridisation. These genes were absent in the Proteus vulgaris, Providentia rettgeri and Morganella morganii strains tested. All but one P. mirabilis strains were haemolytic and most strains produced fimbriae albeit in different amounts. The UCA fimbrial subunits from dog and human isolates have identical molecular weights and N-terminal sequences and are immunologically cross reactive. It was concluded that dog uropathogenic P. mirabilis strains are very similar to human uropathogenic P. mirabilis strains. PMID- 8701579 TI - Identification and characterization of genus-specific epitopes of Serpulina species using monoclonal antibodies. AB - Four murine monoclonal antibodies (mAbs) designated as C9E8, A10, G12, and G8 which recognized both Serpulina hyodysenteriae and S. innocens were produced and characterized. The mAbs reacted with whole cell antigens in ELISA, indirect immunofluorescence and immunoblot assays. The mAbs did not show any cross reactivity in rapid dot ELISA or immunoblot assay with Leptospira icterohemorrhagiae, Campylobacter jejuni and Escherichia coli. Treatment of whole cell suspension with proteinase K and sodium periodate indicated that the reacting epitopes of the mAbs were protein in nature. The genus-specific antigens were identified as heat-stable proteins with molecular weight in the range of 26 to 45 kDa. Immunofluorescence and immunogold labelling studies showed that the antibody-binding epitopes were exposed on the outer-surface of the spirochaetal cell wall. The mAbs inhibited growth of reference strains of both S. hyodysenteriae and S. innocens in vitro but failed to cause agglutination. The detection of spirochaetal forms directly in fecal smears or paraffin-embeded tissue sections from experimentally infected pigs indicated that such mAbs were potentially useful for the diagnosis of swine spirochaetosis. This is the first report of mAbs identifying and characterizing common antigens of porcine Serpulina. PMID- 8701580 TI - Characterization of transmissible gastroenteritis coronavirus S protein expression products in avirulent S. typhimurium delta cya delta crp: persistence, stability and immune response in swine. AB - The spike protein from transmissible gastroenteritis virus (TGEV) was expressed in attenuated S. typhimurium delta cya delta crp delta asd chi 3987. Three partially overlapping fragments of TGEV S gene, encoding the amino-terminal, intermediate, and carboxy-terminal end of the protein, as well as the full length gene were inserted into the asd+ plasmid pYA292 to generate recombinant plasmids pYATS-1, pYATS-2, pYATS-3, and pYATS-4, respectively, which were transformed into S. typhimurium chi 3987. Recombinant S. typhimurium chi 3987 (pYATS-1) and chi 3987 (pYATS-4) expressing constitutively a 53 kDa amino-terminal fragment of the S protein and the full length protein (144 kDa), respectively, showed high stability. After 50 generations in vitro 60% and 20% of the bacteria transformed with pYATS-1 and pYATS-4, respectively, expressed the S-protein antigen. Since S. typhimurium chi 3987 (pYATS-1) showed a better level of expression and stability in vitro, this recombinant strain was selected as a potential bivalent vector to induce both immunity to Salmonella and TGEV in swine. In order to study colonization of swine tissues by S. typhimurium delta cya delta crp, a gene conferring resistance to rifampicin was cloned into the chromosome of S. typhimurium chi 3987, generating chi 4509 strain. Both S. typhimurium chi 4509 (pYA292) and chi 4509 (pYATS-1) colonized the ileum of orally inoculated swine with clearance of bacteria between days 10-20 post-infection. The expression of the amino-terminal fragment of the S protein diminished the ability of S. typhimurium chi 4509 (pYATS-1) to colonize deep tissues. The recombinant strain S. typhimurium chi 3987 (pYATS-1) induced TGEV specific antibodies in both serum and saliva of orally inoculated swine. PMID- 8701581 TI - Correlation between occurrence of exudative epidermitis and exfoliative toxin producing ability of Staphylococcus hyicus. AB - Staphylococcus hyicus was isolated from healthy pigs and pigs affected with exudative epidermitis (EE). Thirty seven strains (P-7 to P-43) were isolated from pigs affected with EE on 8 farms while 131 strains were isolated from healthy pigs bred on 2 farms in Japan. Isolation rate for pigs affected with EE was 100% while that for healthy pigs was 35.4%. The biochemical and cultural characteristics of the isolates from healthy and diseased pigs were identical except for the Voges-Proskauer reaction. The culture supernatant of many isolates caused skin exfoliation in 1-day-old chickens. Therefore, many isolates were considered to produce S. hyicus exfoliative toxin (shET). The rate of shET production by the isolates from piglets affected with EE was 87.5%, while that of the isolates from healthy pigs was 76.1%. shETs were divided in two serotypes by immunodiffusion. Piglets experimentally infected with shET-producing and nonproducing strains were observed. Local skin erythema at the inoculation site was observed with nonproducing strains and disappeared within 48 h, while the skin erythema at the sites inoculated with shET-producing strains did not disappear until 7 days after inoculation. Typical clinical signs, such as exfoliation, exudation and crusting were observed only in the piglets inoculated with shET-producing strains. PMID- 8701582 TI - [Interspecific protoplast fusion between Bacillus thuringensis Bt-3701 and Bacillus megaterium Bm-107]. AB - The results of the interspecific protoplast fusion between B. thuringensis sub. kurstaki Bt-3701 which has pesticide ability, and B. megaterium var. phosphaticum Bm-107 which has decomposing phosphate activity, were reported. High frequency of protoplast formation and regeneration was obtained with 4h activated Bm-107 treated by 100 micrograms/ml lysozyme, and with 2h activated Bt-3701 treated by 3% glycin and mild temperature. Using 40% PEG and 5% nascent Ca2+ to treat the parential protoplast mixture for 3 min at 37 degrees C, 4 stable fusants were obtained. Biological tests show that they have both pesticide ability and decomposing phosphate activity, but which are weaker than that of parential strains. PMID- 8701583 TI - [Sequencing of polyhedrin gene of Leucania separata multiple capsid nuclear polyhedrosis virus by silver sequencing system]. AB - The genome of LsNPV was digested with EcoRV and cloned into pBluescript. With the partial polyhedrin gene of Autographa californica as a probe, positive recombinants were screened by colony in situ hybridization, further characterized by sequencing, and designated as pLsEV and pLsPH5. The intact 741 bp polyhedrin gene of LsNPV is located on the two recombinants revealed by Silver Sequencing System, and shares 80.0% and 97.0% nucleotide identity of the coding sequence, 87.8% and 97.5% amino acid identity with AcMNPV and MbMNPV respectively. Glu is the richest amino acid, and Gln and Trp the poorest amino acid in the polyhedrin of LsNPV. The codons ended with pyrimidine were higher in the codon usage. There was a signal-peptide-like hydrophobic region of 26 amino acids in the N end of polyhedrin. PMID- 8701584 TI - [Production and characterization of sterigmatocystin]. AB - Two strains of Aspergillus versicolor producing ST at 550.8 mg.kg-1 substrate and 1160.8 mg.kg-1 substrate were selected to inoculate 4 kg solid ST-producing media. After 35 days stationary incubation at 28 degrees C in the dark, 2271.6 mg of pale-yellow needle-shaped crystals were isolated and purified from the culture with a procedure applying column chromatography and recrystallization method. The crystal was proved to be sterigmatocystin by spectroanalysis and some physico chemical analysis. The purity of the final material obtained were more that 99.9% as shown by HPLC and TLC detection. With this procedure, ST was obtained at about one tenth of its commercial cost. PMID- 8701585 TI - [Cloning of a cluster of genes encoding coli-surface antigen 6(CS6) of human enterotoxigenic E. coli]. AB - A gene library was constructed from large plasmid DNA of wild strain E519/66A of human enterotoxigenic Escherichia coli (ETEC). Positive colonies containing CS6 antigen were obtained. The CS6 gene fragment was identified by restriction endonuclease mapping. It was approximately 4.6 kb in length and responsible for encoding CS6 genes and regulating the CS6 antigen. Two forms of fimbriae protein with different molecular weight were produced by the selected clones. Both of them could react with the same CS6 antiserum. So we expect to use the recombinant strain as candidate for human ETEC vaccine development, and it is also useful for further research on the expression and regulation of genes encoding CS6 fimbriae protein. PMID- 8701586 TI - Overview: practical insights from comparative immunology and pathogenesis of AIDS, hepatitis B, and measles for developing an HIV vaccine. AB - Combined effects of viral mutation, beneficial and adverse host immune responses, and alterations in immune function strongly fashion the pathogenesis and outcome of HIV infection. Understanding HIV can be aided by understanding hepatitis B and measles. Clinical remission and exacerbation in persistent hepatitis B virus infection is determined by the triad of viral mutation, induction of anergy, and host immune responses. Measles virus infects many of the same kinds of cells as HIV and causes an immunodeficiency as well that usually is spontaneously reversible. Lessons learned from comparative studies can assist in plotting approaches and strategies for immunoprophylactic and therapeutic interventions in HIV infections and AIDS. PMID- 8701587 TI - Immunization with a soluble recombinant HIV protein entrapped in biodegradable microparticles induces HIV-specific CD8+ cytotoxic T lymphocytes and CD4+ Th1 cells. AB - One of the major obstacles to the development of successful recombinant vaccines against human immunodeficiency virus (HIV) and other intracellular pathogens is the identification of a safe and effective vaccine delivery system for the induction of cell mediated immunity with soluble protein antigens. In this study it was demonstrated that immunization with a recombinant HIV envelop (env) protein entrapped in biodegradable poly(lactide-co-glycolide) (PLG) microparticles induced consistent HIV-specific CD4+ and CD8+ T-cell responses in mice. Major histocompatibility complex (MHC) class I-restricted cytotoxic T lymphocytes (CTL) responses were detected following a single systemic immunization with gp120 entrapped microparticles and when given by the intranasal (i.n.) route induced HIV-specific CD8+ CTL and secretory IgA. Furthermore immunization with gp120 entrapped in microparticles generated CD4+ T cells that secreted moderate to high levels of IFN-gamma. Therefore, PLG microparticles are a safe and effective means of delivering antigen to the appropriate processing site for the generation of class I-restricted CTL, and are also capable of inducing Th1 cells. PMID- 8701588 TI - Ability of synthetic peptides representing epitopes of outer membrane protein F of Pseudomonas aeruginosa to afford protection against P. aeruginosa infection in a murine acute pneumonia model. AB - Three synthetic peptides (Nos 9, 10 and 18) representing surface-exposed, linear B-cell epitopes of outer membrane protein F of Pseudomonas aeruginosa were each conjugated to the carriers keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA), with the conjugates being used to immunize mice intranasally. Mice were also immunized intranasally with a KLH/BSA carrier control or with a peptide No. 8 conjugate as a negative control. An immunoglobulin G response reactive with P. aeruginosa whole cells was demonstrated by enzyme-linked immunosorbent assay (ELISA) of sera from mice immunized with peptide 9, 10 or 18, whereas no whole cell reactivity by ELISA was detected in sera from mice immunized with peptide 8. Upon pulmonary challenge of immunized mice with a Fisher-Devlin immunotype 4 strain of P. aeruginosa, only those mice immunized with peptide 9 or peptide 10 had a significantly greater survival rate compared to control mice immunized with the carriers alone. Peptides 9 (TDAYNQKLSERRAN) and 10 (NATAEGRAINRRVE) have potential for further development as a protective vaccine against P. aeruginosa infections. PMID- 8701589 TI - Optimization of the intestinal lavage procedure for determination of intestinal immune responses. AB - Optimal conditions to process, concentrate and store intestinal lavage fluid were studied in samples collected from volunteers before and after oral immunization with a prototype vaccine against enterotoxigenic Escherichia coli (ETEC) diarrhoea. Total IgA and specific IgA antibody titres against enterotoxin and colonization factor antigen were determined in 22 lavage samples which were either enzyme-inhibited or heat-inactivated and then subjected to different long term storage conditions. Samples were analysed within 1 month of collection and also after 3, 6 and 24 months of storage. Total IgA concentrations and specific IgA antibody levels were higher in lavage samples treated with enzyme inhibitors (soybean trypsin inhibitor and phenylmethylsulfonyl fluoride) than in those heat inactivated. Similarily, concentration of the lavage fluid by freeze-drying was superior to concentration against polyethylene glycol. Specific antibody titres remained elevated after storage for at least 6 months but declined after 2 years in frozen compared with freeze-dried samples. PMID- 8701590 TI - Immunity to rubella before and after vaccination against measles, mumps and rubella (MMR) at 12 years of age of the first generation offered MMR vaccination in Sweden at 18 months. AB - In 1982, a two-dose programme of vaccination against measles, mumps and rubella (MMR) at the ages of 18 months and 12 years was introduced in Sweden. In 1992-3, the first group of children vaccinated at 18 months reached the age of 12, i.e. the time for a second dose. In connection with this 12-year vaccination, 376 children were recruited, investigated concerning earlier MMR vaccination and bled prior to and 2 months after the immunization. Two hundred and twenty of them had a documented, earlier MMR vaccination and 156 had not. The latter were classified as unvaccinated. The antibody status against rubella was measured by the haemolysis-in-gel method. Prior to the present vaccination, 3% of the earlier vaccinated group totally lacked any sign of antibodies. In the presumably unvaccinated group, this figure was 76%. After the vaccination all children showed signs of antibody activity and reached the antibody level of > or = 15 international units, i.e. in our tests a zone dia. of approx 8 mm. However, the secondly vaccinated children ended up with a mean antibody level of 10.7 mm which was slightly lower than the level, i.e. 11.0 mm of those lacking earlier vaccination history and prevaccination seronegative. The earlier unvaccinated but pre-immune children reached a mean level of 11.2 mm. In general, those with relatively high, pre-vaccination, antibody levels reacted less to the booster than those with low or no pre-vaccination immunity. The booster thus appeared to restore the antibody levels of the low-titre children. PMID- 8701591 TI - Experimental quantification of transmission of genetically engineered pseudorabies virus. AB - There is concern that live pseudorabies virus (PRV) vaccine or PRV vector vaccine strains may spread from vaccinated to unvaccinated pigs. Moreover, it is feared that recombining PRV vaccine strains with related vaccine or wild-type strains may lead to spread and survival of recombinant PRV. To learn more about to what extent different PRV vaccine strains could spread we used a previously described experimental model to study the transmission of intranasally inoculated PRV mutant strains under experimental conditions. We used PRV strains that lacked glycoprotein E (gE) or thymidine kinase (TK), and a PRV vector vaccine (gE-, TK-, gG-) that expresses the glycoprotein E1 (E1) of hog cholera virus. In addition, we investigated whether intranasally co-inoculated gE-negative and gE-positive PRV strains competed in transmission among pigs. The extent of transmission was estimated using the reproduction ratio R. This ratio has a threshold property; when R1, the infection can spread; when R < 1, the infection will disappear. We found that R for a gE-negative strain was 10.1, and R for a TK-negative strain was 5. Furthermore, the R for the vector vaccine (gE-, TK-, gG-) expressing E1 was 0.18, and did not differ significantly from the R for the control strain without E1. The R of gE-negative strain was significantly 1 (P = 0.0005). Co inoculation with a gE-positive field strain did not prevent the transmission of a gE-negative strain. This study shows that a small-scale experiment can be used to estimate the transmission of genetically engineered organisms in their host species. The results of this study indicate that the deletion of gE alone or TK alone is not enough to prevent spread of PRV among susceptible pigs, and that transmission of gE-negative PRV is not firmly limited by co-presence of a gE positive strain. PMID- 8701592 TI - Recombinant antibodies containing an engineered B-cell epitope capable of eliciting conformation-specific antibody responses. AB - The immunogenicity of a soluble, non-self protein or peptide can be greatly enhanced by injecting this antigen coupled to an antibody specific for class II MHC molecules in the recipient. This adjuvant-independent immunization strategy is known as immunotargeting. We have investigated the ability of a mouse anti class II MHC antibody to provide the three-dimensional framework for the reconstitution of a heterologous conformational B-cell epitope, specifically the A loop epitope from the influenza virus hemagglutinin (HA). From a panel of three anti-class II MHC immunoglobulin (Ig)-A loop constructs, we found that one of these, an insertion into the FR3 region of the Ig molecule, retained its specificity for mouse I-Ak. Although mouse monoclonal antibodies specific for the A loop region in the HA molecule were unable to react with the Ig-A loop variants, we did find that the heavy chain CDR3 insertion construct was able to elicit an A loop-specific, HA-reactive antibody response when used as an immunogen in rabbits. These results demonstrate the potential for the Ig molecule to function successfully as a structural framework for the reconstitution and presentation of heterologous conformational B-cell epitopes. PMID- 8701593 TI - Experimental anthrax vaccines: efficacy of adjuvants combined with protective antigen against an aerosol Bacillus anthracis spore challenge in guinea pigs. AB - The efficacy of several human anthrax vaccine candidates comprised of different adjuvants together with Bacillus anthracis protective antigen (PA) was evaluated in guinea pigs challenged by an aerosol of virulent B. anthracis spores. The most efficacious vaccines tested were formulated with PA plus monophosphoryl lipid A (MPL) in a squalene/lecithin/Tween 80 emulsion (SLT) and PA plus the saponin QS 21. The PA+MPL in SLT vaccine, which was lyophilized and then reconstituted before use, demonstrated strong protective immunogenicity, even after storage for 2 years at 4 degrees C. The MPL component was required for maximum efficacy of the vaccine. Eliminating lyophilization of the vaccine did not diminish its protective efficacy. No significant alteration in efficacy was observed when PA was dialyzed against different buffers before preparation of vaccine. PA+MPL in SLT proved superior in efficacy to the licensed United States human anthrax vaccine in the guinea pig model. PMID- 8701594 TI - Caseous lymphadenitis vaccine development: site-specific inactivation of the Corynebacterium pseudotuberculosis phospholipase D gene. AB - Vaccines for ovine caseous lymphadenitis (CLA) are currently formulated using partially purified, formalin inactivated phospholipase D (PLD) derived from Corynebacterium pseudotuberculosis culture supernatants. Chemical treatment has been a common and effective way of inactivating bacterial toxins for use in toxoid vaccines. Genetic inactivation of toxin genes using site-specific mutagenesis has the potential to improve this process by providing a safer and more cost-effective product. In the present study amino acid substitutions at the putative catalytic site and metal binding domain of the PLD protein had a profound affect upon PLD activity and secretion from C. pseudotuberculosis. Two mutated PLD analogues that were secreted to a level of 40% compared to the wild type and retained minimal activity showed promise for development as recombinant CLA vaccines. Further work will be required to establish their suitability for commercialization. PMID- 8701595 TI - Preparation and characterization of a purified influenza virus neuraminidase vaccine. AB - Influenza virus neuraminidase (NA) has been shown to induce protective but infection-permissive immunity in experimental animals. Challenge infection following such immunization is attended by decreased viral replication and disease manifestations but is sufficient to provide antigenic stimulation and definitive immunity to the virus. The present report describes the preparation and characterization of a purified NA vaccine (NAV) used in Phase 1 (immunogenicity and toxicity) trials in humans. In essence, virion NA was isolated from detergent-disrupted virus by affinity chromatography on oxamic acid agarose, treated with formalin and tested for its enzymatic activity and for its immunogenicity in Balb/c mice and New Zealand rabbits. The preparation was essentially free of viral hemagglutinin but contained residual NP and M1 proteins. Both dispersed and aggregated NA tetrameric heads were seen in electron micrographs. Enzymatic activity was preserved, and minimal immunogenic doses in mice and rabbits, respectively, were 3.7 and 0.027 micrograms per kg. PMID- 8701596 TI - Purified influenza A virus N2 neuraminidase vaccine is immunogenic and non-toxic in humans. AB - The immunogenicity and toxicity of a purified influenza virus (N2) neuraminidase vaccine (NAV) were investigated in 88 human subjects aged 18-40, and compared to response to a conventional trivalent influenza vaccine, Fluogen (Parke-Davis). NAV doses ranged from 2.6 to 69.9 micrograms and were given intramuscularly. Serologic neuraminidase-inhibiting (NI) and neuraminidase-specific ELISA responses in this N2-primed population were roughly proportional to the dose administered. Maximal response was seen in 14-21 days and NI antibody titers persisted unabated for the 6-month post-vaccination follow-up period. All doses were well tolerated with respect to local and systemic reactions. NI tests performed with the putative (1975) priming N2 antigen demonstrated anamnestic response but did not reveal responses not already shown with the homologous (1992) antigen. Response to this purified, non-adjuvanted preparation encourages continuing investigation of the induction of infection-permissive immunity with influenza virus neuraminidase. PMID- 8701597 TI - Effect of vaccination with a recombinant Bm86 antigen preparation on natural infestations of Boophilus microplus in grazing dairy and beef pure and cross-bred cattle in Brazil. AB - Current methods for the control of the cattle tick Boophilus microplus infestations are not effective and the parasite remains a serious problem for the cattle industry in tropical and sub-tropical areas. Recent advances have introduced the possibility for the immunological control of the parasite through the use of recombinant vaccines. Recently, it was shown that the recombinant vaccine Gavac (Heber Biotec S.A.) is able to control B. microplus populations in artificially infected grazing dairy cattle in Cuba. To assay the effect of the vaccine on a different B. microplus strain and under different ecological conditions, we conducted a trial in Brazil on grazing dairy and beef pure and cross-bred cattle under natural infestation conditions. A farm in the northeast of the state of Sao Paulo was selected and two groups of animals per breed were included in the experiment and were maintained grazing on separate but similar pastures. For each breed, one group was vaccinated with the vaccine Gavac and the second group was not vaccinated and was employed as a control. In vaccinated cattle, during 36 weeks of experiment, the average infestation rate was maintained below 78 ticks per animal while average infestation peaks (mean +/- S.E.) of 144 +/- 44 ticks per animal (for dairy cross-bred cattle) and 195 +/- 42 ticks per animal (for beef cross-bred cattle) were recorded in the control groups. Tick infestation rates showed statistical significant differences (p = 0.04) between both experimental groups throughout the experiment. These results clearly showed, as in the Cuban study, that the vaccine controlled tick numbers in successive generations in the field. PMID- 8701598 TI - Interferon-gamma inductive effect of liposomes as an immunoadjuvant. AB - Adjuvant effect of liposomes was compared to that of aluminium hydroxide (Alum) using ovalbumin (OVA) as a model antigen, and the difference in adjuvanticity of liposomes from Alum has been evaluated on the basis of cytokine production. Both adjuvants enhanced the IgG levels, but a remarkable difference was observed in the production of IgG subclass; Alum enhanced IgG1 levels, and liposomes enhanced IgG2a, IG2b, and IG3 levels. Further, Alum enhanced antigen-specific IgE levels, whereas liposomes did not. To clarify the difference in adjuvant effect of these adjuvants, secretion of cytokines, especially interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) which regulate IgE production, was estimated ex vivo. Overnight culture of splenic cells obtained from mice immunized with liposomes encapsulating OVA elicits IFN-gamma secretion, but not IL-4 secretion. On the other hand, the production of both cytokines was elevated by the immunization with OVA-Alum complex. The results indicate that the difference of adjuvant activity between liposomes and Alum may come from the difference in the secretion of IL-4 and that, consequently, a different class of antibody response is developed. More importantly, negatively charged liposomes containing phosphatidylserine remarkably promoted IFN-gamma secretion compared to neutral liposomes. PMID- 8701599 TI - [Diabetes and pregnancy]. AB - Diabetes and pregnancy are associated with an increased incidence of preeclampsia. The pathogenesis is not exactly known. However endothelial factors and more special the prostacyclin-thromboxane system may be involved. Perinatal morbidity and mortality is increased in a diabetic pregnancy implicated with preeclampsia. Prevention and a curative approach is necessary. PMID- 8701601 TI - [Towards greater involvement by the Academy in health policy]. AB - The essential tasks of the "Koninklijke Academie voor Geneeskunde van Belgie" include, next to the scientific aspects, the rules concerning the practice of medicine. Therefore a close cooperation with the authorities is an absolute must. In former days propositions and positive considerations were already formulated in that sense. We may think of the evaluation of the fast development of science, of the specialization in medical branches, genetics and informatics. On the one hand and on the other hand the need of a pluridisciplinarian approach associated with the medical development. With regard for existing advisory organs, the Academy's efforts must offer an added value, considering the control, the reevaluation and the reconsideration of problems. That is the reason why the Academy should be informed about these institutions and their mandates. The fundamental redistribution of the federal competences concerning public health is also extremely important. Finally a closer dialogue with our sister-institution, the "Academie royale de Medecine de Belgique" is indispensable to the consequent national influence and to our common international echo. PMID- 8701600 TI - Therapeutic potential of Cidofovir (HPMPC, Vistide) for the treatment of DNA virus (i.e. herpes-, papova-, pox- and adenovirus) infections. AB - (S)-1-(3-Hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC, Cidofovir, Vistide) is an acyclic nucleoside phosphonate with broad-spectrum activity against a wide variety of DNA viruses including herpesviruses [Herpes simplex virus type 1 (HSV 1) and type 2 (HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus type 6 (HHV-6) and equine and bovine herpesviruses], papovaviruses [human polyoma virus and human papilloma virus (HPV)], adeno-, irido-, hepadna-, and poxviruses. HPMPC has proved effective against these viruses in different cell culture systems and/or animal models. The mechanism of action of HPMPC is based upon the interaction of its active intracellular metabolite, the diphosphorylated HPMPC derivative HPMPCpp, with the viral DNA polymerase. HPMPCpp has been shown to block CMV DNA synthesis by DNA chain termination following incorporation of two consecutive HPMPC molecules at the 3'-end of the DNA chain. HPMPC confers a prolonged antiviral action, which lasts for several days or weeks, thus allowing infrequent dosing (i.e. every week or every two weeks). This prolonged antiviral action is probably due to the very long intracellular half-life of the HPMPC metabolites, particularly the HPMPCp choline adduct. In clinical studies, HPMPC has proved efficacious in the treatment of CMV retinitis, following both intravenous injection (3 or 5 mg/kg, every other week) and intravitreal injection (single dose of 20 micrograms per eye). Initial clinical trials also point to the efficacy of both systemic (intravenous) and topical HPMPC (1% ointment) in the treatment of acyclovir resistant HSV infections, and of topical HPMPC (ointment or injection) in the treatment of pharyngeal, laryngeal and anogenital HPV infections. HPMPC is now being pursued in the topical and/or systemic (intravenous) treatment of various infections due to CMV, HSV, VZV, EBV, HPV, polyoma-, adeno- and poxviruses. PMID- 8701602 TI - Effect of chemoprophylaxis on immunity to gastrointestinal nematodes in cattle. AB - Control of gastrointestinal nematodes in calves is largely based on either strategic anthelmintic treatment or the use of anthelmintic-release devices. Control is evolving towards more efficacious anthelmintics and delivery systems, almost annihilating host-parasite contact. Recent studies have demonstrated the inverse relationship between the intensive use of modern anthelmintics and the build-up of immunity to gastrointestinal nematodes. A study performed by the Department of Parasitology, Faculty of Veterinary Medicine, Merelbeke, Belgium did provide further support for the finding that the development of immunity can be impaired by the implementation of preventive control measures. PMID- 8701603 TI - [Incidence and course of acute coronary events in the population of Ghent from 1983 to 1990]. AB - In the framework of the W.H.O.- MONICA project, a register for acute coronary events was established in the adult population aged 25-69 years of the city of Ghent. One of the objectives is to collect on an annual basis precise and valid information on the frequency of the disease. Fatal and non-fatal coronary events were monitored through the population-based register, using a standardized protocol and rigid diagnostic criteria. These criteria were evaluated by the research group on the basis of available information that was collected in collaboration with family doctors, hospital physicians, the city hall services and the district medical structure. Lethality was defined as deaths occurring within 28 days after initial symptoms. From 1993 to 1990, 2.626 events were registered. The age standardized annual event rates in men varied from 32.2 to 41.7/10.000; in women the corresponding values were 9.2 and 16.6/10.000. The attack rate declined over time at a rate of -13% over 5 years in men and -23% over 5 years in women. Attack rates of fatal coronary events declined even stronger. The incidence was calculated only in hospitalized cases in whom the antecedents of heart attacks were known in 93%. The age standardized annual incidence rates in hospitalized men varied from 15.5 to 22.4/10.000 and from 4.0 to 6.8/10.000 in hospitalized women. Over time no significant changes in incidence rates were observed. In both sexes there was a trend towards a decline in the incidence of fatal cases and towards an increase in the incidence of non fatal cases. Lethality was dependent on age, sex and declined over time; the maximal case fatality rate was 57.9% and the minimal 42.3%. The lethality in hospitalized cases was 23.8% on average and declined significantly over time. In hospitalized cases with a first heart attack the lethality was 18.5%. All patients who entered the register from 1983 to 1985 for a non-fatal event (n = 465) were followed as to vital status until the end of 1991. The five years survival was 80.4 and 77.0% in respectively men and women. The long term prognosis was not different between sexes, strongly dependent on age and slightly different in the presence of antecedents of heart attacks. These results illustrate how precise and valid information on the frequency of acute coronary events can be collected through a population-based register. The results indicate high attack and incidence rates, a high case-fatality but favorable time trends from 1983 to 1990. PMID- 8701604 TI - DNA-binding properties of the yeast transcriptional activator, Gcr1p. AB - In Saccharomyces cerevisiae the GCRI gene product is required for high-level expression of genes encoding glycolytic enzymes. In this communication, we extend our analysis of the DNA binding properties of Gcr1p. The DNA-binding domain of Gcr1p binds DNA with high affinity. The apparent dissociation constant of the Gcr1p DNA-binding domain for one of its specific binding sites (TTTCAGCTTCCTCTAT) is 2.9 x 10(-10) M. However, competition experiments showed that Gcr1p binds this site in vitro with a low degree of specificity. We measured a 33-fold difference between the ability of specific competitor and DNA of random sequence to inhibit the formation of nucleoprotein complexes between Gcr1p and a radiolabeled DNA probe containing its binding site. DNA band-shift experiments, utilizing probes of constant length in which the positions of Gcr1p-binding sites are varied relative to the ends, indicated that Gcr1p-DNA nucleoprotein complexes contain bent DNA. The implications of these findings in terms of the combinatorial interactions that occur at the upstream activating sequence elements of genes encoding glycolytic enzymes are discussed. PMID- 8701605 TI - Identification of a class of Saccharomyces cerevisiae mutants defective in fatty acid repression of gene transcription and analysis of the frm2 gene. AB - Exogenous fatty acids transcriptionally control the expression of a wide variety of eukaryotic genes, many of which encode proteins involved in lipid metabolism. To identify gene products involved in the lipid signalling pathway, a reporter plasmid containing the 5'-upstream region of a gene demonstrated to be repressed by unsaturated fatty acids (OLE1) was fused in frame to the Escherichia coli gene lacZ encoding beta-galactosidase. Saccharomyces cerevisiae mutants defective in transcriptional control by lipids were identified and this class of mutants has been named frm (fatty acid repression mutant). The mutants were organized into six complementation groups designated frm1-6. Mutants from two of the complementation groups, frm1 and frm3, were also defective in their ability to activate a reporter construct containing the 5'-upstream region of POX1. POX1 has been shown to be transcriptionally activated in the presence of unsaturated fatty acids. frm2 was rescued by a region of DNA localized to chromosome III. This region contained an open reading frame of 579 nucleotides predicted to encode a M(r) 21 116 polypeptide. The upstream region of FRM2 contained a number of potential response elements which have previously been identified as important in regulating gene expression in response to glucose and certain fatty acids. Consistent with this observation, lacZ activity driven by FRM2 or frm2 promoters was induced two- to three-fold dependent upon the carbon and fatty acid source utilized. The properties of FRM2 suggest that it functions in the fatty acid signalling pathway and that it is itself regulated by fatty acids. PMID- 8701606 TI - Candida maltosa NADPH-cytochrome P450 reductase: cloning of a full-length cDNA, heterologous expression in Saccharomyces cerevisiae and function of the N terminal region for membrane anchoring and proliferation of the endoplasmic reticulum. AB - A full-length cDNA for NADPH-cytochrome P450 reductase from Candida maltosa was cloned and sequenced. The derived amino acid sequence showed a high similarity to the reductases from other eukaryotes. Expression in Saccharomyces cerevisiae under control of the GAL10 promoter resulted in an approximately 70-fold increase in NADPH-cytochrome c reductase activity in the microsomal fraction. The functional integrity of the heterologously expressed reductase as an electron transfer component for alkane hydroxylating cytochrome P450 from C. maltosa was shown in a reconstituted system containing both enzymes in a highly purified state. The signal-anchor sequence of the reductase was identified within the N terminal region of the protein by means of constructing and expressing fusion proteins with the cytosolic form of yeast invertase. The first 33 amino acids turned out to be sufficient for stable membrane insertion, wild-type membrane orientation and retention in the endoplasmic reticulum. As shown by immunoelectron microscopy, the heterologously expressed reductase was integrated into the endoplasmic reticulum of the host organism. It triggered a strong proliferation of the membrane system. This membrane-inducing property of the reductase was transferable to the cytosolic reporter protein with the same N terminal sequences that confer membrane insertion. PMID- 8701607 TI - Effects of a novel DNA-damaging agent on the budding yeast Saccharomyces cerevisiae cell cycle. AB - We have investigated the effects on Saccharomyces cerevisiae of a novel antitumour agent (FCE24517 or Tallimustine) which causes selective alkylations to adenines in the minor groove of DNA. Tallimustine, added to wild-type cells for short periods, reduced the growth rate and increased the percentage of budded cells and delayed the cell cycle in the late S + G2 + M phases. In the rad9 delta null mutant cells, Tallimustine treatment did not affect growth rate and the percentage of budded cells but greatly reduced cell viability compared to isogenic cells. Consistent with a role of RAD9 in inducing a transient delay in G2 phase which preserves cell viability, the potent cytotoxic effect of the drug on rad9 delta cells was alleviated by treatment with nocodazole. Tallimustine was also found to delay the resumption from G1 arrest of wild-type but not of rad9 delta cells. These data indicate that the effects of Tallimustine on cell cycle progression in yeast are mediated by the RAD9 gene product. From our data it appears that yeast could be a valuable model system to study the mode of action of this alkylating drug and of minor groove alkylators in general. PMID- 8701608 TI - Candida albicans homologue of GGP1/GAS1 gene is functional in Saccharomyces cerevisiae and contains the determinants for glycosylphosphatidylinositol attachment. AB - The GGP1/GAS1/CWH52 gene of Saccharomyces cerevisiae encodes a major exocellular 115 kDa glycoprotein (gp115) anchored to the plasma membrane through a glycosylphosphatidylinositol (GPI). The function of gp115 is still unknown but the analysis of null mutants suggests a possible role in the control of morphogenesis. PHR1 gene isolated from Candida alibicans is homologous to the GGP1 gene. In this report we have analysed the ability of PHR1 to complement a ggp1 delta mutation in S. cerevisiae. The expression of PHR1 controlled by its natural promoter or by the GGP1 promoter has been studied. In both cases we have observed a complete complementation of the mutant phenotype. Moreover, immunological analysis has revealed that PHR1 in budding yeast gives rise to a 75 80 kDa protein anchored to the membrane through a GPI, indicating that the signal for GPI attachment present in the C. albicans gene product is functional in S. cerevisiae. PMID- 8701609 TI - Discrimination between fortuitous and biologically constrained open reading frames in DNA sequences of Saccharomyces cerevisiae. AB - The systematic sequencing of the yeast genome has raised the problem of the biological significance of the open reading frames (ORFs) revealed: it is possible that some of these are fortuitous. To avoid the analysis of such fortuitous ORFs, a minimum length of 100 sense codons was adopted. Nevertheless, the presence of fortuitous ORFs of more than 100 codons cannot be excluded. Thus, in the context of functional analysis, a method for discrimination between fortuitous and biologically active ORFs may be useful. The discrimination method described here is based on multiple criteria: ORF length, codon bias, and both amino-acid and dipeptide composition of the corresponding polypeptide. The thresholds for each criterion are based on the comparison between two learning sets: one drawn from random DNA sequences and the second from known genes. The method was validated by two test sets (one random and one biological) and then applied to the ORFs of chromosomes I, II, III, V, VIII, IX and XI. This method predicts 123 fortuitous ORFs among the 1773 identified on these chromosomes. PMID- 8701610 TI - Sequence analysis of the 43 kb CRM1-YLM9-PET54-DIE2-SMI1-PHO81-YHB4-PFK1 region from the right arm of Saccharomyces cerevisiae chromosome VII. AB - The nucleotide sequence of a 43 118 bp fragment from chromosome VII of Saccharomyces cerevisiae has been determined and analysed. The fragment originates from the right arm of chromosome VII. It starts approximately 11 kb centromere-proximal to the per54 marker and ends in the middle of the PFK1 gene. The sequence contains a small nuclear RNA gene (SNR7) and 29 open reading frames (ORFs) larger than 100 amino acids. Six of these were completely internal to or partially overlapped other ORFs. Six previously described genes, YLM9/MRPL9, CRM1, DIE2, SMI1, PHO81 and YHB4, were mapped to this region in addition to pet54 and PFK1. Of the remaining 17 ORFs, four showed homology with other S. cerevisiae genes and four, including one of the partially overlapping ORFs, with genes from other organisms. Eight ORFs had no homology with any sequence in the databases. PMID- 8701611 TI - Sequencing a cosmid clone of Saccharomyces cerevisiae chromosome XIV reveals 12 new open reading frames (ORFs) and an ancient duplication of six ORFs. AB - A sequence of 31431 bp located on the left arm of chromosome (chr.) XIV from Saccharomyces cerevisiae was analysed. A total of 18 open reading frames (ORFs) could be identified. Twelve ORFs are new, two of which are most likely ribosomal protein genes, leaving ten ORFs of unknown function. Nine of the 18 ORFs show either at least 20% overall amino acid identity or significant regional homology to other S. cerevisiae ORFs. Additionally, six of these nine ORFs have homologues of similar size and the same transcriptional orientation within a stretch of 50 kb on chromosome IX. The degree of homology ranges from 90% overall identity to 23% in 375 amino acids. The homologues on chromosome IX are grouped in two blocks that are separated by relatively long ORFs. This is the first example of a multi gene duplication in S. cerevisiae not linked to a centromere or subtelomere region. PMID- 8701612 TI - The sequence of a 21.3 kb DNA fragment from the left arm of yeast chromosome XIV reveals LEU4, MET4, POL1, RAS2, and six new open reading frames. AB - The nucleotide sequence of a fragment of 21 308 bp from the left arm of Saccharomyces cerevisiae chromosome XIV has been determined. Analysis of the sequence revealed 13 open reading frames (ORFs) longer than 300 bp, four of which correspond to the previously identified genes LEU4, MET4, POL1 and RAS2. One putative protein, N2160, shares considerable homology (32% identity) with a hypothetical protein encoded by a gene located on chromosome XV as well as with human OCRL protein (36% identity), involved in Lowe's syndrome. N2185 contains ten predicted transmembrane segments and is similar to another putative protein (YKL146) from yeast. PMID- 8701613 TI - Physical mapping of a centromere-proximal region of chromosome IV-L defines the placement of genes USO1, MBP1, PSA1 and SLC1. AB - A physical map of a 14.5 kb region close to the centromere on the left arm of chromosome IV of Saccharomyces cerevisiae is presented. This map has been constructed by restriction analysis of a clone from a YCp50 genomic library and by use of pre-existing and new sequence data from this region. The map reveals the following gene order (reading from the most centromere-distal to the most centromere-proximal locus): USO1/INT1-MBP1-PSA1-SLC1-YLA1 and defines the size of the open reading frames and intergenic regions. PMID- 8701614 TI - [AIDS prevention in homosexuals in Switzerland: adaptation to risks according to type of partner]. AB - OBJECTIVE: To evaluate the effectiveness of AIDS prevention and modes of adaptation to risk among gay men. Swiss results are presented from an international study conducted in 8 European countries. METHOD: A self administered questionnaire was published in gay magazines and distributed by gay organizations and clubs. 934 questionnaires were returned in Switzerland. RESULTS: More than 80% of the respondents report no risk behaviours in the last 12 months. Among all respondents three main modes of adaptation to risk were found: avoidance (no partner, no penetration), protection (condom use), non-use of condoms by stable couples (this assumes an agreement between partners). With casual partners 39% avoid penetration, 49% use condoms and 12% do not use them consistently. With stable partners penetration is more frequent; protection and non use of condoms are found with equal frequency. Nevertheless, 10% of those who report always using condoms say that they have been exposed to a risk, while a third of those who do not always use condoms admitted having taken such a risk. CONCLUSIONS: Prevention campaigns must continue and focus especially on factors linked to the non use of condoms in couples in stable relationships (poor communication, exaggerated trust). PMID- 8701615 TI - [Occupational status and prevalence of cardiovascular risk indicators in employed men in German-speaking Switzerland]. AB - Based on a sample of 623 employed men from the Berne Workplace Health Project ("Harz-As-Project") we studied the relationship between the occupational status and prevalence of cardiovascular risk indicators. Besides "biological" risk indicators, like high total cholesterol, low HDL-cholesterol, hypertension, and overweight, we also studied two behavioral risk indicators (current smoking, physical inactivity in leisure time) and a summary risk score. Odds ratios for several risk indicators controlled for age, were markedly different among different occupational status groups. High cholesterol/HDL-cholesterol ratios were more common in lower occupational status groups, while the likelihood for hypertension and high total cholesterol was highest among qualified workers. There was a strong association between occupational status and the behavioral risk indicators smoking and physical inactivity in leasure time. Similarly, 1 or more risk indicators, and more than 2 risk indicators, respectively, were also found to be strongly related to occupational status. Our results confirm former findings of unequal distribution of cardiovascular disease risk indicators among groups of different occupational status. Future studies will have to focus upon the underlying causes for these inequities. PMID- 8701616 TI - [Drunkenness in traffic in Geneva: distribution and detection]. AB - All cases of inebriety (up to the Swiss Legal BAC: 0.8 gr/kg) in traffic (pedestrians and drivers) recorded by the police during one year are the object of the study. Their frequency and blood alcohol levels are related to individual variables (sex, age, nationality) and also to environmental variables (vehicle, month, day, time). Clinical appreciation of intoxication levels by physicians taking blood samples is also verified. Inherent difficulties of methodological bias coupled to the use of official data, are examined by systematically taking into account the way in which intoxication was detected (with or without accident). In all, 951 cases of alcohol intoxication were studied. PMID- 8701617 TI - [Drunkenness in traffic in Geneva: occasional abuse or alcoholism?]. AB - The main aim of the study is to measure the importance of alcoholism amongst alcohol intoxication (up to the Swiss legal BAC: 0.8 gr/kg) in traffic. The method used describes the characteristics of all cases of inebriety (amongst pedestrians and drivers) recorded by the police during one year and relates this with complementary data such as the determination of a biological marker of alcohol consumption (Gamma Glutamyl Transferase), or DWI recidivism. Results of general interest are: 22% of recorded cases of alcohol intoxication are recidivists; about one third of the cases of alcohol intoxication registered are due to alcoholism rather than to social drinking. A preventive policy in road traffic safety must integrate the problems, caused by alcoholism, on Public Health. PMID- 8701618 TI - [Age, health status and the utilization of general practitioners and specialists]. AB - Data collected by mailed survey and a random sample of 2552 German adults, are analyzed via stepwise regression for the relationship between age and visits to GPs and Specialists. Contrary to common opinion and descriptive analysis the relationship is weak and non-linear. The total effect shows that contacts with GPs do not increase with age much an more. Analysis also shows that effects for both groups of physicians are not only biological but also cohort effects, the latter measured via education. Older people collectively have less education, show consequently 1. worse health and 2. more contacts with GPs than specialists. Results in light of debates about rationing and the cost saving behavior of older people have immediate importance for the policies of health care. PMID- 8701619 TI - [Current models in health insurance and health care delivery]. AB - Health care organizations similar to American HMOs have recently appeared in Switzerland. They elicit many reactions, both in the general public and among the medical profession. In contrast to traditional health insurance, HMOs organize and actively manage health care delivered to their members. This paper reviews the historical background of similar organizations in Europe and in the United States, and focuses in particular on the recent evolution and fragmentation of the concept of "managed care". Follows a discussion of the mechanisms and the side-effects of various tools used to manage care, both in managed care settings and by traditional health insurance plans. It appears that all of health care is managed, that all management tools have potential side effects, and that use of some management tools implies a redistribution of the respective roles of plan members, administrators, and physicians. The authors suggest that the complexity of health care management requires a more active implication of the health professions in that process. PMID- 8701620 TI - [1st Congress of the newly founded German Menopause Society]. PMID- 8701621 TI - Estrogen replacement therapy in the elderly. AB - A woman spends about one-third of her life in her postmenopausal years. Some women supplement this period of decreased estrogen production with estrogen replacement therapy (ERT). Since the 1970s, we have evaluated the long-term risks and benefits of ERT in one population of women, the Leisure World retirement community. ERT is the most effective method for preventing osteoporotic bone loss and fractures in postmenopausal women. In Leisure World, ERT reduced the risk of hip fractures about 50 %. The effect is greatest in long-term users but may be lost after discontinuation. Postmenopausal osteoporosis affects the bones of the jaws as well as other skeletal bones. Bone loss in the jaws may result in tooth loss. In Leisure World, estrogen users retain more natural teeth than nonusers. Cardiovascular disease is the leading cause of hospitalization and death in women. In Leisure World, ERT reduced the risk of fatal and nonfatal myocardial infarction, ischemic heart disease, other heart disease, and stroke by 20-40 %. The reduction is greatest in long-term and/or current users. ERT is effective in women with and without cardiovascular disease risk factors. A most feared aspect of aging is Alzheimer's disease. In Leisure World, women who had used ERT had a reduced risk of Alzheimer's disease. Risk both increaseng dose and decreased with increasing duration of use. Estrogen use, however, is not without risk. Unopposed estrogen increases risk of endometrial cancer. Risk increases with increasing years of use and remains high after discontinuation. The most important potential risk of ERT is breast cancer. In Leisure World, women who had used a total accumulated estrogen dose of 1500 mg or more had nearly twice the risk of breast cancer compared with nonusers. Short-term low-dose users showed no substantial increased risk. The Leisure World Study shows risks and benefits of ERT similar to other reports in the literature. For postmenopausal women generally, the benefits of ERT--preventing osteoporotic fractures, reducing heart disease, decreasing mortality, and possibly reducing risk of Alzheimer's disease-out-weigh the risks of endometrial and breast cancers. A woman must be fully informed of the risks and benefits of hormone therapy and play an important role in deciding whether to take hormones and which regimen to use. PMID- 8701622 TI - [Significance of hereditary thrombophilia for risk of thrombosis with oral contraceptives]. AB - Oral contraceptives increase the natural incidence of venous thromboses of 1 2/10,000 women per year 3-to 4fold. Recent investigations have shown that during intake of desogestrel or gestodene containing formulations the risk is twice that with older low-dose ovulation inhibitors. This difference is larger in first time users than in women who had previously used an oral contraceptive. During pregnancy, the incidence of thromboses rises up to 10/10,000 women-years and post partum up to 40/10,000 women-years. In about 60 % of thromboses no causal explanation can be found. It is suggested that in 40 % of all cases an inherited thrombophilia is present. Among the hereditary types of thrombophilia, the resistance against activated protein C (APC-resistance) represents nearly 50 %, while altogether 15 to 20 % is based on a deficiency of antithrombin III, protein C or protein S. APC-resistance the prevalence of which is 3-5 % in the general population, increases the risk of thrombosis 8fold and in users of oral contraceptives 35fold. Protein C-deficiency (prevalence 0.1-0.5 %) increases the risk of thrombosis 9fold and in users of oral contraceptives 15fold, while antithrombin III-deficiency (prevalence 0.02-0.05 %) enhances the risk in pill users 8fold. Ovulation inhibitors do not influence risk of thrombosis in women with protein S-deficiency. Antiphospholipid-antibodies the concentration of which may increase during treatment with oral contraceptives, represent a considerably enhanced risk of thrombosis, too. A positive family history (before age of 40 years) indicates an inherent thrombophilia. In these risk groups, the cost/benefit ratio of a selective screening is unfavorable, as at most 70 % of the hereditary thrombophilias can be diagnosed by laboratory analysis, and only very few patients will actually experience a thrombotic event: only 3 of 1000 carriers of APC-resistance will suffer from thrombosis during oral contraception per year. On the other hand, a negative result of laboratory tests does not exclude a hereditary thrombophilic disorder which as yet cannot be substantiated. It is not yet clarified whether a selective screening is superior to a careful assessment of individual and family history. A general screening cannot be justified because of the unfavorable cost/benefit ratio. If the individual or family history or pathological laboratory parameters indicate an enhanced risk of thrombosis, this risk has to be carefully weighed against the consequences of discontinuation of pill use. Those few individuals with risk factors who will experience a thrombosis, cannot be identified in advance. If in patients with thrombophilic disorders and/or other risk factors the use of oral contraceptives represents a particularly high risk, other contraceptive methods should be taken into consideration. If a patient with risk factors decides for the use of oral contraceptives, she has to be informed that in the case of symptoms indicating a thrombosis, the physician has to be consulted immediately. The earlier an appropriate therapy is initiated, the more effectively an acute pulmonary emboli or permanent damages, e.g. the post-thrombotic syndrome, can be prevented. PMID- 8701623 TI - [Comparison of the cytostatic effect of epirubicin and mitoxantrone on native breast carcinoma cells using the ATP tumor chemosensitivity assay]. AB - This trial was conducted to compare the cytotoxic efficacy of epirubicin (EPI) and mitoxantrone (MX) in clinical tumor samples derived from 34 chemotherapy native women suffering from breast cancer by utilizing an in vitro ATP tumor chemosensitivity assay (ATP-TCA). An assay evaluability rate of 32/34 (94 %) was achieved. There was no significant difference between EPI and MX when regarding the mean IC90 and IC50 values corresponding to nearly identical overall in vitro response rates observed for both drugs (EPI: 62.5 %; MX 59.4 %). Individual IC90 values showed a weak correlation which was lacking for IC50. Accordingly, a lack of cross-resistance was found in 11/32 tumors (34 %) with 6 tumors showing sensitivity to EPI and resistance to MX and 5 tumors showing resistance to EPI and sensitivity to MX. At lower drug concentrations, a steep slope of the cumulative dose response curves for IC50 could be observed for both cytostatics with an apparent shift to higher concentrations at the IC90 level. For both drugs, a loss of linearity of the IC90 and IC50 dose-response curves was found at maximum concentrations. In conclusion, our results demonstrated an overall equality of EPI and MX in previously untreated breast cancers which already has been found clinically in metastatic disease. Nevertheless, we were able to show that approximately one third of chemotherapy-naive breast carcinomas are not cross-resistant to both EPI and MX. These findings could have implications on planning adjuvant chemotherapy for an individual breast cancer patient. PMID- 8701625 TI - [Results of long-term follow-up in treatment of endometriosis with the GnRH agonist leuprorelin acetate depot (Enantone-Gyn monthly depot)]. AB - In a previous study 198 patients with histologically confirmed endometriosis underwent a "three-step" therapy, where surgical removal of endometriosis implants was followed by a 6 months treatment with 3.75 mg leuprorelinacetate depot as monthly subcutaneous injections and a second look laparoscopy with removal of residuals. In the following report long-term follow-up data generated in 112 of the above 198 patients on the post-treatment effect in respect to symptoms and pregnancy outcome in infertility are reported. For this purpose a special questionnaire was used. The follow-up period was up to 60 months with a median time of 33.5 months. Out of 112 patients 91 complained of infertility. 43 out of these 91 (47.3 %) became pregnant during the follow-up period, resulting in 55 pregnancies and 36 newborns. More than half of these patients conceived spontaneously, whereas in the rest stimulation programs became necessary. Recurrence of dysmenorrhoea, dyspareunia and pelvic pain was defined as recurrence of disease. During the follow-up period 70/112 (62.5 %) of the patients complained recurrence of symptoms with median first onset at 11 months. In two third symptoms were still less severe than at admission and classified as mild and moderate. The r-AFS score at first and second look laparoscopy did not differ in patients with and without recurrence of disease (p = 0.311 and 0.750). Only 28.6 % (20/70) of patients required an additional medical or surgical treatment. A subgroup of 51 patients could be evaluated in respect to quality of life and improvement of subjective conditions. Regain of quality of life and improvement of subjective conditions were reported in 54.9 % (28/51) and 52.9 % (27/51) respectively. The study results suggest that although the physiological effects of leuprorelin acetate treatment as suppression of ovarian function is rapidly reversible, the therapeutic effects linger, as evidenced by ongoing reduction of symptoms from baseline, leaving many patients asymptomatic or much improved longer than 1 year after treatment has ended. Besides long term relief and/or sustained reduction in symptom severity, the high pregnancy rate in infertility, as well as regain of quality of life and well being favour this therapeutic approach in endometriosis. PMID- 8701624 TI - [Perioperative antibiotic prophylaxis in breast surgery: cefotiam versus clindamycin]. AB - 97 patients undergoing breast surgery received either 2 g cefotiam or 1200 mg clindamycin as i.v. singleshot application in the course of an open randomised comparison of parallel groups to evaluate the efficacy and tolerability of both antibiotic regimens. Both regimens proved to be well to-lerated and equally suitable for the prophylaxis of postoperative infections in breast surgery. PMID- 8701626 TI - [Hormonal premedication in endometrium ablation--results of a prospective comparative study]. AB - In a prospective study in 40 patients the pretreatment for endometrial ablation with a gestagen (Orgametril 10 mg/die), danazol (600 mg/die) and an injection of a GnRH-analogon (Decapeptyl-Depot) was compared with a control group without pretreatment. The subjective estimation of the surgeon (endometrial thickness and depth of coagulation) showed a sufficient pretreatment in 90 % of all cases following danazol- and GnRH-analogon-pretreatment. In 90 % of the danazol- and GnRH-analogon pretreated group the histological findings showed also an atrophic or little proliferative endometrium. In a follow up of 6 months after endometrial ablation the highest amenorrhoea-rates were reached following danazol- and GnRH analogon pretreatment. These two regimes should be used for the pretreatment for endometrial ablation. PMID- 8701627 TI - [Primary angiosarcoma of the breast]. AB - We report on a 39 year old woman with a biopsy diagnosed angiosarcoma of the breast. Surgical treatment consisted of a modified radical mastectomy with axillary lymph node dissection (level I and II). The size of the tumor was 4.5 x 3.5 x 2.3 cm with G II grading. In addition the patient was put on postoperative chemotherapy (EC). Soft tissue sarcomas of the breast are very rare tumors (0.04 to < 1 % of all malignant breast tumors). The etiology of most of the vascular neoplasias of the breast is therapy associated such as preexisting surgery and radiotherapy. We found a primary angiosarcoma of the breast and tried to demonstrate aspects of the morphological diagnosis, prognosis and treatment of this disease. PMID- 8701628 TI - [Sarcoid tumor of the breast]. AB - We report on a 56 years old women with an enlarging breast mass in the region of an old scar due to a former diagnostic excision. Mammography and sonography were without value while MRT was suspicious for breast cancer. In the frozen section of the excised tissue a carcinoma was diagnosed and therefore a mastectomy performed. This diagnosis was in correct, instead a granulomatous process in the breast and the axillary lymph nodes took place. In respect to a pulmonary sarcoidosis and to laboratory results a true breast sarcoidosis may be supposed. It was also discussed whether it could be a lipogranulomatous pseudosarcoidosis. PMID- 8701630 TI - [A new modification of the neovagina reconstruction with peritoneum technique]. AB - There are several surgical methods designed to construct a vagina when it is congenitally absent. Davidov has described a technique for correcting this condition, using the pelvic peritoneum to line the vaginal space. We performed new modifications to prevent disadvantages of this technique. An operative vagina was constructed in eight patients with vaginal agenesis, the vaginal surface were covered, using parietal peritoneum flaps with abdominovaginal approach. One year later, we found that four of them had an anatomically and functionally sufficient vagina. The remaining four patients can't be controlled yet, because not enough time has passed after the operation. PMID- 8701629 TI - [Vaginal reconstruction in vaginal aplasia by a Vecchietti modified laparoscopic operation--further simplification of the method]. AB - We describe on a case of a patient with Mayer-v. Rokitansky-Kuster-syndrome the formation of a vagina by a laparoscopic modification of the Vecchietti-procedure. A further simplification of this procedure is the use of a laparoscopic needle holder to tense the strings above the abdominal wall. We even abandoned the use of a prothesis after finishing the tension phase. Instead, we allowed early intercourse on the third day of extraction of the vaginal phantom. PMID- 8701631 TI - Echocardiographic study of mitral valve prolapse in dachshunds. AB - In this prospective echocardiographic study, we investigated the occurrence of mitral valve prolapse (MVP) in 60 dachshunds: 30 with mitral regurgitation (MR), 15 age-matched and 15 3-year-old controls without heart murmurs. To assess the MVP, video recorded sequences from the right parasternal long axis 4-chamber view were blindly evaluated by three observers. Of the 30 dogs with MR, 12 (40%) had severe MVP, 10 (33%) had mild MVP, and eight (27%) had a normal mitral valve. The clinical status of the dogs with MR correlated significantly with the severity of MVP, and these dogs had significantly worse MVP than age-matched controls, among which seven (47%) had mild MVP and eight (53%) had a normal mitral valve ( P < 0.01). In the group of 15 young dachshunds without heart murmurs, seven (47%) had mild MVP and eight (53%) had a normal mitral valve. The degree of MVP correlated significantly with the occurrence of arrhythmias, particularly severe sinus arrhythmia. We conclude that dachshunds with MR have a higher prevalence of MVP than controls, and that the severity of MVP is correlated with clinical status. The dogs with MVP and marked sinus arrhythmia might have autonomic dysfunction, analogous to findings in humans. Whether young dachshunds with MVP are predisposed to MR later in life must await the results of a longitudinal study. PMID- 8701632 TI - Characterization of camel leukocytes by flow cytometry and microscopic evaluation of granulocyte phagocytosis of fluorescent bacteria. AB - Peripheral blood was obtained from four lactating camels (Camelus bactrianus) and flow cytometry was used to characterize cell populations. The ability of the granulocytes to engulf fluorescent bacteria was studied in vitro using fluorescence microscopy. Three clusters of blood cells (mononuclear cells, neutrophils and eosinophils) were identified by flow cytometry and fluorescent microscopy. Milk, on the other hand, was dominated by cell fragments and no distinct cluster formation was found. The mean yield of blood granulocytes and monocytes isolated on Ficoll gradient was 92.2 +/- 5.4% and 7.9 +/- 5.7%, respectively. Cell viability was 95%. The mean percentage of phagocytic cells was 71.8 +/- 5.9% at 10 min and increased to 97.3 +/- 0.5% at 60 min when observation was terminated. The average number of bacteria per phagocyte was 8.7 +/- 2.1 and 13.1 +/- 0.9 at 10 and 60 min incubation time. PMID- 8701633 TI - Exercise-induced changes in the activities of beta-glucuronidase and N-acetyl beta-D-glucosaminidase in plasma and muscle of standardbred trotters. AB - The activities of lysosomal enzymes, such as beta-glucuronidase and N-acetyl-beta D-glucosaminidase, have been shown to increase in muscle after endurance exercise. We examined whether measurable activities of lysosomal enzymes are present in equine plasma and whether the exercise-induced changes in the muscle are reflected in plasma. Six trained Standardbred trotters performed three exercise bouts with 1 h intervals and the same procedure was repeated 3 days later. Venous blood samples and muscle biopsies from the middle gluteal muscle were taken before and after exercise. The activities of beta-glucuronidase and N acetyl-beta-D-glucosaminidase were measured both from plasma and muscle specimens. Cell infiltration into the muscle after exercise was evaluated by the DNA content and histochemically by haematoxylin stain. The activity of N-acetyl beta-D-glucosaminidase in plasma was increased immediately after exercise, but had returned to the basal level at 4 h. N-acetyl-beta-D-glucosaminidase in muscle and beta-glucuronidase in muscle and plasma increased 2 days after exercise and returned to the basal level on day 3. A similar pattern was seen when the exercise protocol was repeated 3 days later, except that the activities continued to increase during the 3 days after exercise. The DNA content in muscle correlated with beta-glucuronidase in muscle and plasma and with the N-acetyl beta-D-glucosaminidase in muscle indicating that the activities reflect the infiltration of phagocytes into the exercise-injured muscle. It can be concluded that the activities of the lysosomal enzymes in plasma increase after exercise and that the changes are mainly due to a simultaneous increase in the number of neutrophils. Therefore, plasma activities of the lysosomal enzymes are poor indicators of exercise-induced muscle damage. PMID- 8701634 TI - Determination of canine prolactin by use of a commercial heterologous enzymeimmunoassay kit. AB - The present study evaluated a commercial heterologous enzymeimmunoassay (EIA) method for the determination of prolactin (PRL) in canine blood plasma and compared the results found with this heterologous method to the PRL concentrations measured by use of a commercial homologous PRL EIA. The heterologous PRL EIA was characterized by intra-assay coefficients of variation (CV %) of 3-5 % for replicate determinations, and inter-assay CV %'s of 5-7 % between means of duplicate determinations. The least detectable concentration was 0.1 microgram/L. A satisfying accuracy was settled by a recovery of added PRL not different from 100 % at varying PRL levels. The cross-reactivity (CR) to canine growth hormone (GH) was 5 %. Both methods outlined equally well the changes in PRL concentrations induced by administration of metoclopramid and bromocriptin; the specificity of both methods was further confirmed by a lack of response to clonidin GH stimulation test. The results achieved with the two methods were not identical despite of identical dose response relations. This difference in test results was, however, considered to be of minor practical importance if locally established reference ranges are used for evaluation of test results. PMID- 8701635 TI - Effects of dietary soybean and cowpea on gut morphology and faecal composition in creep and noncreep-fed pigs. AB - The effects of creep feeding and different levels of soybean meal (SBM) and cowpea meal on the intestinal morphology and faecal characteristics were investigated in weaners. Prior to the feeding trial, one group of piglets was creep-fed and the other noncreep-fed. The two groups of piglets were weaned at 28 days and randomly assigned to four different diets whose main sources of protein were: T1-skimmed milk powder (control); T2-31 % soybean meal; t(3)-15% soybean meal and 12 % skimmed milk powder; and T(4)-100% raw cowpea meal. Live weight gain was highest in the T1 group, and least in the T(4) group. At weaning only the noncreep-fed weaners showed villus atrophy and crypt hyperplasia, but at 7 days postweaning these changes were evident in all groups except the control and were more severe in the noncreep (T2,T3) and cowpea-fed groups. At 21 days postweaning, only noncreep cowpea-fed pigs showed a reduced villus height when compared to the T1 group. A mild diarrhoea was generally observed in all noncreep fed weaners but its onset was more rapid (P < 0.01) and the duration longer (P < 0.05) in the T2 and T4 pigs than in T3 and T1 groups. A lower faecal pH was observed in weaners that had diarrhoea when compared with a pH of 7.1 in pigs with normal moisture. The glucose content of the faeces was found to be significantly higher (P<0.05) in the T2 and T4 groups. The observations of enteropathology and low growth performance in the T4 group suggest that feeding raw cowpea to weaners is capable of inducing considerable antigenicity in the intestinal mucosa, causing damage and a consequent decrease in productivity. However, the introduction of creepfeeding before weaning appears to have some ameliorative effects. PMID- 8701636 TI - [Estimation of the heritability of abomasal displacement in German black-pied cattle in Hesse]. AB - The degree of heritability of displacement of the abomasum was estimated in 30 Hessian herds breeding German Black Pied cattle in which displacement of the abomasum occurred more frequently than normal. Estimation was made by investigating the similarity between mothers and daughters. A total of 2626 pairs were used for this investigation, based on the absence or occurrence of abomasal displacement in the mothers and daughters. The fourpoint correlation coefficient was determined for each herd using a quadrant square. The arithmetic means were then calculated from the correlation coefficients. The number of herds examined was limited by assuming the correlation coefficient to be stable when it varied by less than 0.02 units during the investigation of more than 15 herds. Heritability was then calculated using the correlation coefficient. The correlation coefficient was stable after examining 15 herds; for the examination of the last six herds, it was 0.12 (0.117-0.124) units. Based on this, the heritability of displacement of the abomasum in the herds was taken to be h2 = 0.24. PMID- 8701637 TI - Studies on in vivo endotoxin plasma disappearance times in cattle. AB - Endotoxin plasma disappearance (EPDT) times were determined by a modified Limulus amoebocyte lysate (LAL) assay technique after the intravenous administration of 25 micrograms E. coli 055:B5 endotoxin per kg b.w. to 22 Jersey cows. Clinically healthy cows (n = 6) cleared endotoxin from the plasma within 30 min. Cows pretreated with flunixin meglumine (n = 6) had 2-3 times longer plasma disappearance times, while cows pretreated with phenylbutazone (n = 6) had plasma disappearance times which were 6-12 times longer than the healthy control group. A fourth group comprised clinical cases of spontaneously developed hepatic lipidosis (n = 4). None of these cows were able to clear the injected endotoxin dose and one died before the end of the experiment. The acute phase response, described by leukocyte and thrombocyte counts and plasma glucose and zinc concentrations, was not statistically different between the four groups. PMID- 8701638 TI - [The capacity of avirulent forms of Francisella tularensis for dissemination and proliferation in the host body]. AB - In this investigation isogenic avirulent variants obtained from F. tularensis standard virulent strain 503 were used. The capsule-deficient variants (cap-) were shown to have no species-specific capsular antigens and to be capable of producing R-LPS having no the polysaccharide part of the molecules. The capsule defective forms (cap +/- ) were found to synthesize capsular antigens and S-LPS whose polysaccharide part essentially differed from the O-lateral chains of LPS of the virulent strain. The study of bacterial dissemination revealed that virulent bacteria rapidly spread in the macroorganism, and their subsequent proliferation shortly led to the death of animals. Avirulent mutants (cap- and cap +/- ) appeared in the organs of animals later and proliferated slower, parasitizing in the macroorganism without fatal outcome. The cap- variants were not capable of inducing the synthesis of antitularemic antibodies and possessed no protective properties. The cap +/- mutants were capable of inducing the synthesis of antitularemic antibodies in mice. These antibodies facilitated the elimination of avirulent strains from the macroorganism, but did not ensure protection from infection with virulent strains. PMID- 8701640 TI - [The adhesive activity of clinical strains of Klebsiella]. PMID- 8701639 TI - [Pathogenic bacteria common to man and plants: the problem and the facts]. PMID- 8701642 TI - [World cholera pandemics as mono- and polycyclic phenomena]. PMID- 8701641 TI - [Francisella tularensis persistence in the body of highly sensitive animals]. PMID- 8701643 TI - [The current problems of streptococcal infection]. PMID- 8701644 TI - [An unusual epidemic outbreak of food poisoning in a children's health-promotion camp (epidemiological practice No. 8. Conclusion)]. PMID- 8701645 TI - [An outbreak of intestinal infection of unestablished etiology in a boarding school (epidemiological practice No. 9. Conclusion)]. PMID- 8701646 TI - [The characteristics of the interaction of Bacillus anthracis with host phagocytes in relation to the plasmid spectrum of the causative agent]. AB - The study revealed that after the intraperitoneal inoculation of spores of B. anthracis strains with different plasmid composition into guinea pigs the active germination of the spores both outside and inside the cells of the host occurred as early as on hour 2 of their interaction with the macroorganism. The further fate of the infective agent and the character of its interaction with peritoneal exudate cells depended on the plasmid composition of the bacilli. Thus, the presence of toxin-formation plasmid PXO1 and capsule-formation plasmid PXO2 in B. anthracis permitted the successful adaptation of these bacilli to the conditions of the macroorganism, while the absence of such plasmids made them nonviable in this environment. The presence of plasmid PXO1 in B. anthracis permitted the manifestation of their cytopathic effort on the cells and the presence of plasmid PXO2 only gave the bacilli incomplete protection from phagocytosis. PMID- 8701648 TI - [The hydrophobicity of Streptococcus pyogenes as a possible marker of its virulence]. AB - The hydrophobicity of 366 S. pyogenes cultures isolated from the pharynx of tonsillitis and scarlet fever patients and healthy children, as well as museum strain of type M29, was studied. The study revealed that the hydrophobicity of cultures isolated from scarlet fever patients exceeded that of cultures isolated from healthy carriers and tonsillitis patients. Among S. pyogenes cultures isolated in cases of prolonged carriership a considerable proportion of highly hydrophobic cultures was detected, which was probably indicative of an important role played by the hydrophobicity of streptococci in retaining them on the barrier epithelium. This was confirmed by the presence of correlation between the hydrophobicity of culture of S. pyogenes, type M29, and its adhesion to the fibronectin receptor and HEp-2 cells. For S. pyogenes of type M6, epidemic in the group of children under observation during the period of 1987-1988, the values characterizing its hydrophobicity were registered which significantly exceeded average hydrophobicity values. At the period of a rise in morbidity S. pyogenes cultures were characterized by significantly higher hydrophobicity. The variability of the hydrophobicity index and its relationship with the dissociation of cultures were established. The hydrophobicity index may be used as one of the virulence markers of S. pyogenes strains. PMID- 8701647 TI - [The wound microflora of patients with gunshot injuries to the extremities during a mass hospitalization]. AB - The dynamic study of the microflora of bullet wounds in 32 patients was carried out. In cases of mass hospitalization coccal microflora (staphylococci and streptococci) was mainly isolated from wounds, at the period of treatment hospital infections with enterobacteria, Pseudomonas and Enterococcus occurred. Before cleaning the wound a decrease in the contamination rate for all microbial species was observed. As the disease progressed an increase in the amount of antibiotic-resistant bacterial strains was registered. The results of sanitary microbiological investigations made in the wards where the wounded patients were treated correspond to the structure of the causative agents of purulent processes in patients. PMID- 8701649 TI - [The characteristics of the spread of diphtheria in Russia against the background of the mass immunization of children]. PMID- 8701651 TI - [The characteristics of a natural attenuated isolate of Francisella tularensis]. AB - The natural isolate of F. tularensis subsp. holarctica 268 was detected and studied. The isolate possessed the properties of the vaccine strain: residual virulence for white mice, avirulence for guinea pigs and high immunogenicity for experimental animals. A significant decrease in its virulence for animals, highly sensitive to tularemia, was noted. In contrast to most virulent strains circulating in natural foci, F. tularensis strain 268 was characterized by the absence of growth at a cultivation temperature of 42 degrees C and had stable biological properties after 10-fold passage through white mice. PMID- 8701650 TI - [The risk of becoming infected with hepatitis B and C viruses in the pupils of children's boarding schools]. AB - The risk of contamination of 487 inmates of 5 boarding schools at northwestern Ukraine with hepatitis B (HB) and hepatitis C (HC) viruses was analyzed and the role of some factors facilitating the spread of these infections among the inmates of such schools was shown. In 28.3 +/- 2.2% of the inmates the presence of HB markers was detected, while these markers occurred only in 7.2 +/- 1.9% of children attending open schools. During the survey of the child population the presence of HB markers was detected in 8.0 +/- 1.1%, which was significantly lower than among the inmates of boarding schools (p < 0.001). Among such markers, HBsAg was detected in 8.3 +/- 0.5% of the inmates and in 1.6 +/- 0.5% of other children living in the area. Among inmates with CNS pathology the sum of markers was significantly higher than in inmates without such pathology (52.9 +/- 3.8%). The occurrence of the markers was shown to depend on the duration of staying in a boarding school and on the presence of the source of infection in the collective. Anti-HCV were detected in 1.4 +2- 0.6% of the inmates of boarding schools and in 0.5 +/- 0.3% of the whole child population. PMID- 8701652 TI - [The phenotypic characteristics of healthy carriers of the antigenic structures of the influenza A virus]. AB - Highly sensitive methods for the detection of viral antigens with the use of monoclonal or polyclonal enzyme immunoassay test systems, as well as virus specific nucleic sequences (NS-gene) in polymerase chain reaction, made it possible to establish the fact of long-term asymptomatic virus carriership (AVC) in some of adolescent schoolchildren in a closed group. The occurrence of AVC varied at different phases of the epidemic process. The tendency to AVC was observed in individuals having blood group B (III) and HLA-A9 antigen of the major histocompatibility complex. The development of AVC occurred in the presence of a decreased level of humoral immunity. AVC was mainly registered among individuals, relatively resistant to relapsing clinically pronounced forms of respiratory virus infections. PMID- 8701653 TI - [An epidemiometric model of viral hepatitis A and its use]. AB - The mathematical model of viral hepatitis A has been developed. The model is the system of 7 boundary differential equations which describe changes occurring in the course of time in the main epidemiological groups of the population. On the basis of the proposed model quantitative experiments on the epidemiological effects of a hypothetic program of immunization at hypothetic power of infection have been carried out. PMID- 8701654 TI - [The epidemiological patterns of yersiniosis in the Republic of Sakha (Yakutia)]. AB - On the basis of complex studies, carried out over the period of 21 years, the epidemiological characterization of Yersinia infections in the Republic of Sakha (Yakutia) is presented. The average monthly morbidity rate (per 100,000 persons) was 5.8 +/- 0.002 for pseudotuberculosis and 0.61 +/- 0.001 for enteric yersiniosis. In the time course of pseudotuberculosis morbidity 2 periods were established. The first period (1974-1987) was characterized by the prevalence of epidemic outbreaks with a pronounced spring-summer rise in morbidity, mainly among children aged 3-6 years and 7-14 years in closed groups. The reasons of these epidemic outbreaks were established. The second period (1988-1994) was characterized by sporadic morbidity with seasonal winter-spring and summer-autumn rises involving children of all age groups both in closed groups and at home. The main trends in the system of epidemiological surveillance on Yersinia infections were determined, depending on the level and character of morbidity. PMID- 8701655 TI - [The characteristics of the autoimmune reactions in donors immunized with influenza vaccine and staphylococcal anatoxin]. AB - Regularities in the formation of autoantibodies to human IgA, IgM, IgG and their fragments, such as F(ab')2, Fab, Fc, in donors immunized with influenza vaccine (44 subjects) and staphylococcal toxoid (15 subjects) were studied with regard to the dynamics of specific immune response. After immunization with staphylococcal toxoid autoimmune reactions were registered only in the precipitation tests during 3-5 weeks of observation. In donors immunized with influenza vaccine the induction of isotypically heterogeneous autoimmune reactions was established. These reactions were represented mainly by IgA and IgG autoantibodies to immunoglobulins of different classes and their fragments. The duration of autoimmune reactions registered in this group of donors was specially noteworthy. The levels of autoantibodies to most of the antigens under study remained significantly elevated for 6 months. After immunization with influenza vaccine the presence of direct correlation between the level of specific immune response and the level of autoantibody formation was established. PMID- 8701656 TI - [A comparative evaluation of different immunological reactions in the diagnosis of pseudotuberculosis]. AB - To study humoral response in patients with the generalized form of pseudotuberculosis, the agglutination test, the passive hemagglutination test and the complement fixation test with antigen obtained from "Virion" (Switzerland) were used. The study of the dynamics of antibody formation to outer membrane proteins (OMP) and Yersinia pseudotuberculosis (pYV+ and pYV-) lipopolysaccharide (LPS) revealed that the synthesis of antibodies to OMP, controlled by inv gene, exceeded the synthesis of antibodies to LPS at all periods of the disease, which determined the necessity of further study of the role of OMP in pathogenesis and in the formation of humoral response. On the basis of the study of the occurrence of antigens a high diagnostic effectiveness the enzyme immunoassay for the detection of Y. pseudotuberculosis antigens, mainly at the first stage of the disease, was noted. PMID- 8701657 TI - [The use of a new strain of Vibrio cholerae O139 as a producer of an enteric chemical vaccine]. AB - Conditions for the submerged cultivation of a strain of V. cholerae O139, were worked out. These conditions ensured a high yield of biomass, soluble O-antigen and exoenzymes (proteinase, phospholipase A) into the culture medium, which exceeded their production by strains of serovar O1, respectively, 2, 3, 4 and 8 times. The preparation, isolated from the culture fluid and lyophilized, contained up to 50% of O-antigen and exoenzymes. In experiments on white mice the preparation exhibited low toxicity (LD50 was equal, on the average, to 1.2 mg) and immunogenicity (ED50 was equal to 3-5 micrograms) with respect to V. cholerae O139, which corresponded to the protective potency of commercial vaccine against V. cholerae O1 infection. PMID- 8701658 TI - [The vaccinal prophylaxis of hepatitis B among children born to mothers with persistent HBs-antigenemia]. AB - In Uzbekistan and Moldova 542 children born of HBsAg carriers were immunized against hepatitis B (with vaccine Engerix B according to the immunization schedule of 4 injections). Anti-HBs antibodies in protective titers were detected by EIA and RIA techniques in 76.7% of children aged 4-5 months after the 3rd injection, in 95.7% of children aged 15-16 months and in 90.0% of children aged 2 2.5 years after the 4th (booster) injection. In the control group (117 nonimmunized children born of HBs carriers) observed during the same period anti HBs antibodies were detected significantly less frequently (in 7.3%, 11.6% and 12.9% of these children respectively). 1-2 months after the course of immunization was completed 74.1% of the immunized children had high anti-HBs antibody titers (exceeding 1000 IU/ml) with their subsequent decrease by 2-2.5 years of age. In the control group these figures were 27.1% and 29.0% respectively. The index of immunization effectiveness obtained by the comparison of the hepatitis B morbidity rates in both groups was 7.8. No postvaccinal complications were registered. PMID- 8701659 TI - [The effect of the conditions for Neisseria meningitidis cultivation on the protein composition in the protein-polysaccharide complex--the base of meningococcal serogroup B vaccine]. AB - New data concerning the influence of cultivation conditions on the synthesis aimed at producing immunologically active antigens of group B Neisseria meningitides were obtained. The combination of conditions (deficiency in ions of iron, pH of the medium, growth phase of the culture) capable of essentially increasing (9- to 28-fold) the content of iron-dependent protein with a mol. wt. of 75-76 kD, was selected. At the same time the content of other immunologically active proteins with mol. wt. of 92-94 kD, 100-102 kD and 141-144 kD perceptibly increased (1.5 to 2.2-fold). Group B meningococcal vaccine prepared on the basis of native protein-polysaccharide complex with a higher content of the above mentioned species-specific proteins may be expected to have a wider spectrum of immunological action. PMID- 8701660 TI - [The development of species-specific test systems for the rapid diagnosis of staphylococcal infections]. AB - Highly purified teichoic acids (TA) were isolated from Staphylococcus aureus and S. epidermidis and characterized. The preparations of TA were highly species specific. For the first time monospecific sera to S. aureus and S. epidermidis were obtained. From these monospecific sera immunoglobulins were isolated and used for the preparation of reagents for the passive hemagglutination (PHA) test and the enzyme immunoassay (EIA). The sensitivity of the PHA test and EIA was 15 micrograms/ml when S. aureus and S. epidermidis were used and 10(6)-10(7) cells/ml when whole microbial cells were used. The diagnostic preparations proved to be highly specific and did not react with other preparations isolated from S. aureus and S. epidermidis, as well as from bacteria belonging to other taxa. Experiments on rabbits, carried out with the use of newly developed test systems, demonstrated that staphylococci could be detected in the blood as early as 10 minutes after the intravenous infection of the animals and until day 12. PMID- 8701661 TI - [The immune reactivity of patients with chronic bronchitis on vaccinal therapy]. AB - The treatment of 17 patients having chronic obstructive bronchitis with a combined vaccine resulted in a rise in the number of T lymphocytes and T suppressors, as well as a simultaneous increase in their functional activity, in these patients. Moreover, an increase in the ingestive activity of neutrophils and in the concentration of immune complexes was registered. Treatment with the vaccine containing Staphylococcus aureus, Klebsiella pneumoniae, Proteus and Escherichia coli antigens facilitated an increase in the titers of antibodies to most antigens contained in the vaccine and in the resistance of the body to infection. Vaccinal therapy made it possible to achieve a significant prolongation of the period of remission. PMID- 8701662 TI - [An immunological study of the cell wall proteins of Pseudomonas aeruginosa]. AB - A preparation containing P. aeruginosa cell-wall proteins with a mol. wt. of 9-55 kD has been obtained from P. aeruginosa by the method of extraction with the use of tris-EDTA buffer. In experiments on mice this protein preparation has shown pronounced protective properties, but, according to the data of Shwartzman's local reaction, proved to be toxic, perhaps due to the admixture of LPS. The purification of the protein preparation from the admixture of LPS will make it possible to obtain an effective vaccine against P. aeruginosa infection. PMID- 8701663 TI - [The effect of streptococcal group A polysaccharide on PHA-induced T-cell proliferation]. AB - The influence of group A streptococcal polysaccharide (A-PS) on the proliferation and functional activity of subpopulations CD4+ and CD8+ of human peripheral blood lymphocytes has been studied. As revealed in this study, A-PS, though having no mitogenic activity of its own, is capable of influencing the process of proliferation of two main T-cell subpopulations in the presence of PHA. Its action has a regulatory character and is manifested by the maintenance of the ration of lymphocytes CD4+ and CD8+ in the culture at a constant level (approximating 1). This effect is seemingly linked with changes in the functional activity of lymphocytes in both subpopulation CD4+ and subpopulation CD8+. The detected properties of A-PS make it possible to regard it as a pathogenic factor playing an important role in immunoregulatory disturbances in diseases connected with infection caused by group A streptococcus. PMID- 8701664 TI - [The effect of an experimental staphylococcal infection on the morphofunctional characteristics of tissue basophils and mast cells]. AB - In the process of staphylococcal infection in mice an increase in the number and functional activity of peritoneal, mesenterial and dermal basophils occurs. The preliminary activation of tissue basophils with equine serum albumin has favorable influence on the course of the infectious process, enhances the reaction of mast cells and phagocytes on the causative agent. The role played by tissue basophils in anti-infectious protection may be linked with the increased secretion of histamine producing a stimulating effect on the phagocytic mechanism of immunity. PMID- 8701665 TI - [The Fc-dependent binding of gram-negative bacterial endotoxins by human blood polymorphonuclear leukocytes]. AB - The treatment of thin blood smears with antibodies to glycolipid of chemotype Re, conjugated with horseradish peroxidase, revealed that under physiological conditions about 3.5% of leukocytes bound endotoxin of gram-negative bacteria by means of the Fc-dependent mechanism. In addition, about 4.9% of leukocytes may bind endotoxin as the result of the treatment of blood smears with the preparation of glycolipid of chemotype Re. At the acute period of bacterial cerebrospinal meningitis leukocytes capable of binding endotoxin in the body or during the treatment of blood smears are practically absent. The conclusion was made that the binding of endotoxins by leukocytes had a protective character. PMID- 8701666 TI - [The indices of interleukin 1, 2 and 4 production and the specific antibody titers in mice with an opposite sensitivity to staphylococcal infection]. AB - The data on a high level of interleukin production in mice, resistant to staphylococcal infection (CBA), in comparison with that in mice, sensitive to this infection (C3HA), are presented. The production of interleukin 1 in intact and infected mice of different strains exhibited no differences between these strains, but its level considerably increased after the inoculation of the animals. A the same time differences in the synthesis of IgM and IgG1 in intact and infected mice of different strains were noted. PMID- 8701667 TI - [The antibody spectrum after the inoculation of sensitive animals with Yersinia pestis and Yersinia pseudotuberculosis bacteria]. AB - Antibody spectra in the sera of guinea pigs and white mice infected with Y. pestis and Y. pseudotuberculosis, the causative agents of plague and pseudotuberculosis, were determined with the use of immunoblotting. The amount of antigens, found to produce humoral immune response both in plague and in pseudotuberculosis was, on the whole, considerably less (5-6 times) in white mice than in guinea pigs. The animals were found to produce antibody response to plasmid-specific (Yop) Y. pestis antigens with with molecular weights 76, 41 and 34 kD and Y. pseudotuberculosis antigens with molecular wt of 41, 34 and 25 kD. Differences in the character of humoral immune response induced in guinea pigs by killed and live Y. pseudotuberculosis were determined. In the animals inoculated with killed bacteria these differences consisted in the absence of antibody formation to the immunodominant antigen with a molecular weight of 62 kD and in the increase of antibody response to antigens with molecular weights of 36 and 21 kD, supposed to be related to Y. pseudotuberculosis pathogenicity factors and to possess protective properties. PMID- 8701668 TI - [The morphometric characteristics of the immune system organs in dynamic experimental Salmonella infection]. AB - Quantitative and morphological changes in the immune system (CBA x C57BL/6)F1 mice after their enteral (group 1) and intraperitoneal (group 2) inoculation with Salmonella typhimurium in a dose of 2 x (10)6 microbial cells per mouse were studied. The study revealed that on day 28 after inoculation the death rate of the animals was 12.5 +/- 6.75% in group 1 and 57.84 +/- 4.89% in group 2. The same type of changes in the organs of the immune system was observed in both groups of mice, but in the animals of group 2 these changes were more pronounced. This was manifested by leukocytosis, exhaustion of thymic cells, hyperplasia, hypertrophy of the spleen and an increase in the proliferative activity in its B zone, a decrease in the number of myelokaryocytes. Such changes are indicative of their importance in the resistance of the body to Salmonella infection. PMID- 8701669 TI - [The probiotic correction of microecological and immune disorders in gastroduodenal pathology in children]. AB - The state of microbiocenosis was studied and the level of immunoglobulins was determined in the gastric juice and feces of children with chronic diseases of the digestive system. In 20% of patients an increase in the contamination of the gastric biotope with opportunistic microflora was established. The isolation rate of Helicobacter pylori was 56%. The detection of H. pylori was found to be accompanied by the aggravation of the form and course of gastritis. In cases of Helicobacter-associated pathology the deficiency of Lactobacillus sp. in the stomach was established, which was accompanied by their deficiency and absence in feces. The study also revealed a decrease in the population level of Bifidobacterium sp. with a simultaneous increase in the population of opportunistic enterobacteria and changes in the state of local immunity: the decreased level of SIgA in most samples and the decreased level of IgG in the presence of H. pylori. The correction of microecological and immune disturbances with probiotic preparations, containing bifidobacteria (bifidumbacterin-forte) and lactobacilli, yielded good results. PMID- 8701670 TI - [Microbiological monitoring of suppurative-septic hospital infections in newborn infants and puerperae]. AB - The microbiological monitoring of obstetric institutions revealed essential changes in the microbiological structure of hospital purulent septic infections in newborns and parturient women during the period of 1987-1992. An increase in the role of gram-negative microflora, mainly the representatives of the family Enterobacteriaceae, was registered. The specific proportion of gram-negative microorganisms in the etiology of hospital infections increased from 43.7% to 95.1% in newborn infants and from 33.3% to 61.3% in parturient women, which differently affected on the structure of the main nosological forms of these diseases. PMID- 8701671 TI - [The clinical picture and pathogenesis of complications in food poisonings (salmonellosis)]. AB - Observation on 32,448 salmonellosis patients was carried out. In 653 cases (2.01%) the complicated course of the disease was observed. It was caused by generalized disturbances in blood circulation, or shock, in 0.09% of cases, or by regional disturbances in blood circulation (myocardial infarction in 0.4%, acute disturbances in cerebral circulation in 0.4%, thrombosis of mesenterial vessels in 0.1% of cases). In addition, infectious complications developed in the form of pneumonia (0.5%) and acute renal insufficiency (0.6% of cases). Acute adrenal insufficiency, observed in the past, did not practically occur during the recent 20 years, having lost its importance due to the use of adequate therapy with polyionic crystalloid solutions. PMID- 8701672 TI - [The pathogenetic characteristics of the development of a bacterial carrier state]. PMID- 8701673 TI - [Early prognosis of free venous autograft in common bile duct reconstruction. Experimental study--first phase]. AB - Experiments were carried out on 25 grown-up dogs of both sex in general anesthesia. The supraduodenal part of the choledochus was excised and the reconstruction of the defect with a free venous autograft was made by an end to end anastomosis without use of a transitory or permanent prosthesis. The experimental animals were observed for 60 days, during which period they were checked clinically, biochemically and radiologically. After this period the animals were sacrificed and surgical peroperative control and sampling of material for histological study were made. Out of 25 experimental animals 18 (72%) survived a period of 60 days and 7 dogs died. On autopsy it was found that the cause of death in all animals was biliary peritonitis, but in only one case due necrosis of the graft. The values of bilirubin concentration at the end of the experiment showed almost normal level, but the values of the alkaline phosphate activity and transminase showed significant increased values. Intravenous biligraphy showed significant excretion of the contrast material, freely passing the graft, which was dilated due to stenotic changes of the distal anastomosis. After sacrificing the animals we found: the graft increased length, diameter, thickness wall and stenosis of the distal anastomosis. By histological exploration we found in the liver the signs of the biliary stasis and in the grafts substitution of its endothelium by biliary epithelium. Free venous autograft used as a substitute in the reconstruction of the bile duct which survived 60 days postoperatively, remained transient but with changes in the sense of elongation and dilatation caused by the stenosis od distal anastomosis. Histologically the grafts were entirely bridged by biliary epithelium. PMID- 8701674 TI - [Complications in reconstructive procedures on arteries in the lower extremities]. AB - During a year (1987/88) a study was performed at he Clinic of Thoracal and Vascular Surgery, supervised by Prof. dr J. Vollmar. Analysis of all cases with complications after reconstruction of the lower limbs arteries necessitating reoperation was performed. There were 56 patients in all. They were retrospectively analysed for establishing risk factors, clinical stage (by Fonstine), and time lapse from the surgery to the occurrence of complications. There were 12(21,4%), 23 (41,1%) and 21 (37,5%) of immediate, early and late complications, respectively. The following causes of complications following reconstruction of the lower limbs arteries were recorded: graft trombosis (41,1%), pseudoaneurism of anastomosis (17,8%), progressive arteriosclerosis (12,7%), proximally or distally to the operated segment. The following reoperations were applied: graft prolongation due to distal occlusion (35,7%), desobstruction of the graft and patch plasty (21,2%), partial or total replacement of the graft (17,9%), correction of the supplying vascular tree (7,1%). More than one reoperation were performed in 22 cases (39,2%) and amputation of the limb was necessitated in 4 (7,1%) cases. PMID- 8701675 TI - [Diffuse adenomyomatosis of the gallbladder]. AB - Adenomyomatosis is a rare benign proliferative disease of the gallbladder characterized by epithelial proliferation and formation of mucosal pouches through the thickened muscular layer of gall bladder wall. It appears in three different types: diffuse, segmental and localised adenomyomatosis. Diffuse type is the rarest. Etiology is unknown. Patients sometimes feel a dull pain in the upper right abdominal quadrant. Preoperative diagnosis is based on cholecystography and ultrasonography. Cholecystectomy is a method of treatment. Diagnosis is confirmed on histology. Very rarely, adenomyomatosis seems to bee a premalignant condition. We present four patients treated during the last two years, a woman and three men, 27-41 years old (average 37 years). All these patients had a dull pain in the right subcostal region, approximately 6 months before the diagnosis was established. One patient had chronic alcoholic pancreatitis with dilated pancreatic duct. Diagnosis of diffuse adenomyomatosis was made preoperatively on ultrasonography in all patients. Cholecystectomy was carried out Diagnosis was confirmed on histology. There was no carcinoma. In a patient with chronic pancreatitis Wirsungojejunostomy (Puestow) and choledochojejunostomy were also carried out. PMID- 8701676 TI - [Tracheal and laryngeal resection and anastomosis in the treatment of chronic obstruction]. AB - Prolonged intubation and inadequate management of acute injuries of the larynx are the most common causes of increasing number of tracheal and laryngeal stenosis. Different conservative procedures are not sufficient in a large number of severe stenosis of the laryngotracheal tree. The author presents a single stage procedure of surgical resection of the trachea for 3-4 cm with anastomosis for managing severe circular stenosis of different etiologies. Out of five successfully operated patients stenosis resulted from prolonged intubation in two cases, and from malignant tumor, benign tumor and inflammation of undetermined etiology in the three respective cases. Several years postoperatively, patency of the trachea at the site of the anastomosis remains normal. Stenosis of the subglottis or the initial part of the trachea at the site of anastomosis remains normal. Stenosis of the subglottis of the initial part of the trachea were managed by resections of the cricoid or half of the larynx with reconstruction of the new larynx in the same procedure by an open and elevated trachea. The reconstruction was initially evaluated experimentally and afterwards applied clinically as laryngotracheoplasty-Successful decannulation was performed in six patients subjected to this type of surgery, and normal breathing, speech and swallowing functions were maintained. One patient died after the operation owing to hepatic coma induced by unrecognized liver metastases. The importance of preserving blood vessels for prevention postoperative necrosis and dehiscence of the anastomosis has been pointed out. In both types of reconstruction anastomoses were performed by subucosal sutures making in possible to heal with no associated granuloma and restenosis, avoiding complicated endoscopic removal of the sutures and granulomas in the postoperative course. The new method of cricoid nad laryngeal reconstruction by a trachea provides a vide neolaryngeal lumen, successful decannulation and preservation of all laryngeal functions. PMID- 8701677 TI - [Biliary ileus]. AB - In the period 1946-1987 at the former Second Surgical Clinic of the Medical Faculty in Belgrade 25 patients with a biliary ileus were Surgically treated, 20 females (80%), and 5 males (20%), aged from 53 to 87 years, (mean 67 years). Six patients were decade, 7 in 7th, 9 in 8th, and 3 in 9th decade. In only 8 patients biliary calculosis had been confirmed earlier. Preoperative troubles in the Bowel Passage lasted 1-7 days, (mean 3 days), mostly as in incomplete gut occlusion. Preoperative diagnosis of the biliary ileus, using x-ray, was exact only in 3 cases (12%), while other remaining patients underwent Surgery diagnosed as ileus of the small bowel or acute abdomen. In 7 patients a stone obstructed the jejunum, in 6 ones its widpart and in 10 cases the terminal ileum. In 23 patients an enterotomy distally to the obstruction with an expulsion-extraction was done, in one patient a partial resection of the gut and in another patient a manual stone expulsion into the colon, with no enterotomy, was carried out, and after operation the stone was removed from the rectum. The Bilio-digestive fistula was never treated either the surgery itself, or later. Complications arised in 13 patients: wound infection in 11, deep thrombophlebitis in one and a pneumonia in two patients. An average hospitalization was 27 days, and all patients Survived. PMID- 8701678 TI - [Extra-articular fractures of the distal humerus]. AB - In our study we examined the patients with extraarticular fractures in five years period: from 1984 to 1987. Most of them were treated operatively (76%). The good results highly correlated with the early timing of operation, the best results are seen in cases, which are operated urgently or in the first week after injury. PMID- 8701679 TI - [Pancreatic pleural effusion. Diagnosis and therapy]. AB - Pancreaticopleural fistula is an uncommon complication of chronic pancreatitis or pancreatic trauma. Clinical features include pleural effusion and resulting pulmonary symptoms. Abdominal pain and other clinical manifestations of pancreatitis may be minimal or absent. As in this case, computed tomography and endoscopic retrograde cholangiopancreatography may provide complementary diagnostic information in the evaluation of this condition. A discussion of the pathophysiology, diagnosis and management of pancreaticopleural fistula is presented. PMID- 8701680 TI - [Splenorrhaphy and partial splenectomy as an alternative to splenectomy in trauma -overview]. AB - For many year splenectomy was considered to be the only possible surgical treatment for all laceration of the spleen, whether resulting from abdominal contusion or not. Such factors have led to changes in practical attitudes to splenic lacerations but it would seem that indications for a conservative approach must be based upon the underlaying condition and the precise nature of the lesions. Splenectomy should be done promptly in cases of concomitant splenic and cerebral injury and in patients with injury of multiple organ systems. Present knowledge of the complications of anesplenia has led to new surgical techniques for conservation of splenic tissue. Splenorrhaphy was a frequently used treatment in the non-complicated traumatic lesions. The decision of whether or not to remove an injured spleen is one which must be made intraoperatively by the surgeon. Operative splenic repair and preservation of the spleen often requires considerable experience. We conclude that surgical splenic preservation is a viable and safe procedure, especially in infants and young children. PMID- 8701681 TI - [Fractures of the radius in the typical site, conservative and surgical treatment -comparison of results]. AB - In the years 1987-1988, 372 fractures of the radius in the typical zone were treated at the trauma station. 178 were included into our study, the remaining 194 did not return for check-ups. 123 cases were treated conservatively and 55 operatively. According to statistical data, more women than men were injured (p < 0.01). More patients aged over 60 were treated conservatively. In operative and conservative treatment, the types of fractures were similar (p < 0.01). In comparing the results of operative treatment with those from 1985, we establish that the present results are better (p < 0.0001), owing above all to the shorter period of time elapsing between injury and operation. In conservative treatment, the results are also better owing to a change in the method of plaster casting. All unstable fractures must be treated operatively. Among the applied operative methods, transcutaneous fixation with Kierschner's wires under X-ray monitoring proved to be the best. Etiologically, injuries listed under other hold the first place, followed by occupational and traffic injuries. Treatment and control must be managed by a surgeon who is acquainted with problems of bone tissue injuries. Continuous cooperation with the physiotherapist is of extreme importance. PMID- 8701682 TI - [The effect of the duration of the surgical procedure on the appearance of surgical wound infection]. AB - In order to search the influence of longitudiness of surgical intervention in the appearance of the surgical wound, there were analysed 90 operations. There were 32 operations of the "clean" group out of which 19 took longer than one hour and with the infection of 10,5% and 13 less than one hour, without infection. In the "potentially contaminated" wound there were 22 operations. Out of 22 operations, 12 took longer than one hour with the frequency of infections 50% and 10 operations took less than one hour with frequency of infections of 10%. In the "contaminated" group there were 36 operations out of which 25 took longer than one hour with the infection frequency of 72% and 11 operations that took no longer than one hour with the infection frequency of 27,7%. We come to conclusion that the frequency of wound infection grow in all groups of patients if the operations takes longer than one hour, and even more if the surgical intervention is done upon potentially contaminated or contaminated wound. PMID- 8701683 TI - [The St. Jude biopolymeric graft in reconstruction of peripheral arteries]. AB - The authors present their preliminary results of St. Jude Bio Polymeric graft application in the periphery arteries reconstruction. This biograft like all the previous ones (Soleo, CB.S., human umbilical veins) was introduced with the aim of creating a better substitute for autovenous Graft, which has been irreplacible ever before, especially in cases of crural reconstruction. The operated patients were classified into the II stadium of occlusive disease (claudication) and indications for surgery have been based on Doppler sonography and arteriography. In three cases crural femoro-popliteal reconstruction was carried out, because of an occlusion of the superficial femoral artery, in one case a femoro-femoro cross over bypass due to an occlusion of the iliac artery. Postoperative follow-up ranged from 6 to 12 months and the control of the graft passage by. Doppler sonography and arteriography confirmed patency of all grafts. I.e. the preliminary results are excellent. PMID- 8701684 TI - [Rare anomalies in the development of the appendix]. AB - Anomalies of the appendix are extremely uncommon. Cases of complete agenesia have been reported only few times. Even "lucky" surgeons usually do not have the opportunity of seeing in more than once in ca career. Abnormal development of the appendix usually takes the form of a double appendix. About 60 such cases have been reported so far describing several types of the abnormality. Type A is described as a single appendix with the body or tip branching, or, alternatively, completely divided like a double-barreled gun. Type Bis described as occurrence of completely separated appendices with bases also being located on different sites of the cecum (the avian type) or with both bases springing from the intestinal tenia (tenia-coli type). Type C is a doubled cecum, each containing its own appendix. Type D is a horseshoe appendix with two openings at the common cecum All these anomalies are of great practical importance, and a surgeon has to bear them in mind during an operation, since in case he overlooks them the operated patient may experience grave consequences. They also may be the forensic issue in cases when repeated explorative laparotomy reveals "previously removed" vermiform appendix. We report a case of a horseshoe appendix with mesenterial incarceration of the terminal ileum and resulting partial intestinal gangrene necessitating intestinal resection and terminolateral ileotransversostomy. The postoperative course was characterised with partial gangrene of the cecom and fistula of the intestines on a completely intact part of the intestinal wall which could be explained by possible presence of anomalous vascularization in the area. PMID- 8701685 TI - [Gentamycin-polymethylmethacrylate in the treatment of osteoarticular panaritium]. AB - The authors present treatment results by Gentamicin-polymethyl methacrylate in severe forms of osteoarticular panaritium in the duration of three years when 16 patients with the age ranging form 19 to 64 Years were studied. Serial pearls 7 mm and 5 x 3 mm in diameter were used. The application of pearls was done in pale stasis, upon completing surgical treatment of the fingers and filling of the created cava. The immobilization was placed and 14 days later pearls extracted. Inflammatory process was restrained in all patients with a complete reparation of the fingers' soft tissue. In five patients who had through destruction of the phalangealarticular surfaces developed functional ankylosis in the period of rehabilitation. There were no amputations of the phalanges. Our initial experience in treating destructive inflammatory changes in phalanges by Gentamicin-polymethyl methacrylate points to the shorter treatment period and lower degree of disability when compared to the conventional treatment methods. PMID- 8701686 TI - [Injury of the left hepatic vein by a large hepatic echinococcal cyst]. AB - While different sorts of affection of the biliary tree by the hydatide cysts of the liver are frequent (20-30%), vascular complications are rare. That is why serious peroperative bleedings are usually caused by surgical mistakes. Bleeding caused by hydatide cyst itself is very rare, sudden, abundant, dramatic and usually lethal on the operative table. We present a 76-years-old man in whom during the operation of a huge hydatide liver cyst, sudden and abundant bleeding from the defect (2 x 0.5 cm) of the left hepatic vein caused by the cyst itself, appeared. The bleeding was successfully solved by direct suture of the defect. Three months later hepatitis B viral infection manifested apparently after numerous blood and plasma transfusions during surgery, and patient died in hepato renal syndrome. PMID- 8701687 TI - [Use of taurolin in the prevention of septic complications in emergency abdominal surgery]. AB - The purpose of the study was to evaluate effectiveness of local application of Taurolin in prevention of septic complications after abdominal emergency surgery. Group A included 30 patients in whom intraoperative peritoneal lavage was performed with 0.5% solution of taurolin. In the first 12 postoperative hours peritoneal lavage was repeated through the drain. Group B included 30 patients in whom intraoperative lavage was performed with either physiologic saline or Povidon solution. All patients had suppurative peritonitis provoked by perforation of some of the abdominal organs. Intraoperatively samples of abdominal pus were taken for bacteriological analysis, while postoperatively samples were taken from drains placed abdominally and subcutaneously. Twelve hours after the surgery therapy was conducted according to the operative findings, postoperative course, x-ray and laboratory findings and results of sensitivity testing. Analysis of the results revealed significant differences in postoperative morbidity and mortality between the two groups. No fatal outcomes were recorded in the immediate postoperative course in group A where only one case of recurrent intraperitoneal infection occurred and three cases of wound infection. In group B, however, three patients died in the immediate postoperative course, recurrent intraperitoneal infection developed in four cases and wound infection in 12. Intraoperative and early postoperative local application of Taurolin in addition to appropriate surgical treatment and postoperative care has an important role in prevention of postoperative septic complications and decrease of postoperative mortality. PMID- 8701688 TI - [The Edward method of subfascial resection in communicating vein insufficiency in the calf]. AB - The purpose of this study was to identify the operative method that gives the best immediate and remote results. The study includes: a retrospective study, a prospective study and remote results. In the retrospective and prospective studies the immediate complication and the results of surgical treatment were evaluated. The total number of immediate complications amounts to 30% and the least of them has Edwards section (3.8%). The best immediate results have been achieved by Edwards method, too (the curing rate of insufficient perforating veins and varix is 93.3%, and of insufficient perforating veins and ulcer is 90.9%). The best remote results have been established at the subfascial section, combined with stripping of insufficient superficial veins and extirpation of varix (the curing rate at 71.4%). This operative procedure can be considered as a selective method in surgical treatment of blood reflux through insufficient perforating veins, and particularly in those regions of the calf characterised by strong indurative and sclerotic changes, as well as by cured and fresh ulcers. PMID- 8701689 TI - [3 case reports of unsuccessful cadaveric pancreas transplantation]. AB - Pancreas transplantation, according to the experiences of USA and Europe, must be done persistently, as only in this way can be acquired the precious experiences. By the gradual preparation one can acquire criticism for this more complicated explantation of graft than its implantation. Three our cases, two of which ended with exitus letalis and one with the successful kidney transplantation only, speaks in favor of the fact that the experiences must permanently be enlarged on the own casuistics, with the readiness, that in the beginning results can also be discourageous, what, unfortunately has happened in our case. In the paper was presented the clinical flow, surgical technique, immunobiological monitoring and some important complications of our first transplantations of the whole pancreas. PMID- 8701690 TI - [Occurrence of thyroid gland carcinoma in Graves-Basedow disease]. AB - Among 319 patients with Graves-Basedow disease who were operated upon in surgical department of The Institute of Endocrinology in Belgrade between 1978 and 1990, thyroid carcinoma was found in 15 cases (4.7%). In 10 patients carcinoma was suspected before operation because of the node in diffuse goiter, while in 5 patients carcinoma was found unexpectedly. Tumor was smaller than 1 sm in only one patient. Nine patients had papillary carcinoma, 4 had follicular and 2 had medullary carcinoma. One patient with medullary carcinoma had been treated previously with radioactive iodine. In 2 patients carcinoma was found in recurrent goiter after primary operation, patients with thyroid carcinoma in Graves-Basedow disease were averaging about 10 years older than other patients with Graves-Basedow disease treated surgically. PMID- 8701691 TI - [Intra-articular fractures of the distal humerus]. AB - The authors analysed 79 patients with intraarticular fracture of the distal end of the humerus, treated during the past 5 years. Seventeen patients were treated by conservative methods, and 62 by surgery. Of the latter, 23 required emergency operations. In the majority of cases, open reduction was accomplished by special plates for the distal end of the humerus and by Y-plates. Screws, Kirschner wires and suture of bone fragments were rarely used. The most frequently employed approach was osteotomy of the olecranon. The results were excellent, except in 13 patients. PMID- 8701692 TI - [Recurrent acute pancreatitis and biliary microlithiasis]. AB - The ease with which biliary microcalculi migrate through the cystic duct and their frequent involvement in choledochus, may be a high risk for developing of recurrent acute pancreatitis, especially if papilla of vater is blocked. The concomitant presence of acute pancreatitis becomes an indication for litothomy, thorough lavage and surgical or endoscopic sphincterotomy. Twenty-one patients with biliary microlithiasis are reviewed in this article. The authors stress the importance of thorough pre and intraoperative investigation whenever the presence of biliary microlithiasis is suspected and confirm the indications for radical treatment of the disease. PMID- 8701693 TI - [External fixators combined with other methods]. AB - Problems in the treatment of injured persons, especially if lesions of larger organs or organ systems exist, are great. Each method of treatment has some deficiency respectively dark side. In such cases a combination of methods of treatment is a necessity and a rule. In combining various methods, special care must be taken to cover these deficiencies up resp. to improve the methods. Regarding the fact that the method of external fixation has in its indications for treatment numerous combinations, it is also more easily combined with other surgical methods. It proved successful in combinations such as: minimal osteosyntheses acc. to the AO method, additional immobilization in unstable osteosyntheses, in covering of extensive skin defects and soft parts with cross leg and free grafts, in temporary osteosynthesis in extensive bone defects, in large diastases of public bones and lesion of the posterior urethra, in polytrauma for temporary bone immobilisation, in bone fractures and "compartment syndrome". The analysis of 38 cases shows that our decision was correct, since no unfavourable results were obtained. PMID- 8701694 TI - [Surgical treatment of diabetic foot syndrome]. AB - This is a review of 365 diabetic cases with severe forms of syndrome of diabetic foot (SDF) surgically treated in period of 20 yrs (1970-1989) at the Surgical Hospital, University Clinical Center in Nis. Comparative analysis of the clinical material, divided into two groups, the former and the latter periods of ten yrs, revealed essential difference in surgical treatment of SDF where advantages of modern surgical approach to treatment of this acute and severe problem have been clearly evidenced. After establishing the role and importance of surgical therapy in a complex, multidisciplinary treatment of SDF; practical guidelines for everyday surgical practice have been recommended for achieving better results to be reflected in decrease of mortality, increased number of spared legs and feet, or, in cases where amputation cannot be avoided, successful rehabilitation and application of prosthesis in severe diabetic patients. PMID- 8701695 TI - [Correction of hypospadias with a preputial flap--personal experience]. AB - In the period 1985-1989 correction of hypospadia was performed in 187 children aged 2-14 yrs. Praeputial flap was used in 54 patients with penile and scrotal hypospadia. Ombredanne's operation in one or two stages was used in 35 cases, while Perovis's method vas used in 19 patients. Fistulas occurred in 8% of the cases. However, the achieved results did not differ significantly. Cases of meatal or neourethral stenosis were not recorded. Both techniques resulted in satisfactory cosmetic and functional outcome. PMID- 8701696 TI - The role of high dose methylprednisolone and splenectomy in the accelerated phase of Chediak-Higashi syndrome. AB - The Chediak-Higashi syndrome (CHS) is a rare autosomal recessive immunodeficiency disorder. Some cases with CHS develop the accelerated phase characterized by pancytopenia, high fever and lymphohistiocytic infiltration of liver, spleen and lymph nodes. The treatment of the accelerated phase of CHS is difficult. We describe a case with CHS in the accelerated phase who had multiple polyposis and pulmonary infiltration that was probably due to involvement of CHS. She was successfully treated with high-dose methylprednisolone at her first admission. At her second admission, splenectomy was performed to remove hypersplenism, and her clinical, radiological and hematological findings improved significantly. PMID- 8701697 TI - A de novo deletion causing epsilon gamma delta beta-thalassemia in a Dutch patient. PMID- 8701698 TI - Development of factor VIII:C inhibitors following vaccination. PMID- 8701699 TI - Bilateral submandibular salivary gland enlargement during chemotherapy for acute myeloid leukaemia--beneficial effect of propranolol. PMID- 8701700 TI - Development of polycythaemia rubra vera following treatment for centroblastic lymphoma. PMID- 8701701 TI - Transfer of human adenine deaminase gene into murine hematopoietic stem cells: sequential study of spleen colony-forming units from bone marrow of living mice and the requirement of the microenvironment. AB - Irradiated female mice were reconstituted with male hematopoietic stem cells (HSCs) retrovirally marked with human adenine deaminase (hADA) complimentary DNA. HSCs were incubated with interleukin-6 and stem cell factor before coculture with GP+E86-producing cells. Bone marrow HSCs were infused intravenously to irradiated mice and spleen colony-forming units (CFU-S) were evaluated for hADA marked clones by Southern blot analysis. 45 of 54 CFU-S were marked by the hADA gene sequence with multiple copies integrated per genome. Oligoclonal hematopoiesis evolved over time with 1-2 clones demonstrated 5-11 months after reconstitution. Comparable results were obtained with embryonic fetal liver HSCs. Incubation of bone marrow HSCs with adherent stromal cells rather than growth factors produced less efficient gene transfer, and polyclonal hematopoiesis was not observed. Donor origin was established by the Y chromosome probe. These results support the clonal succession model of hematopoiesis. PMID- 8701702 TI - Short-course intravenous antibiotics with oral quinolone prophylaxis in the treatment of neutropenic fever in autologous bone marrow or peripheral blood progenitor cell transplant recipients. AB - The effectiveness of short-course intravenous antibiotics concurrent with prophylactic oral ciprofloxacin in the treatment of neutropenic fever was studied in 81 patients undergoing autologous bone marrow or peripheral blood progenitor cell transplantation (ABMT or PBPCT). During the neutropenic period following ABMT or PBPCT, 10/81 (12%) patients did not require treatment with intravenous antibiotics. Seventy-one patients required antibiotics. Forty-seven of the 71 (66%) responded to 72 h treatment with gentamicin, azlocillin or ceftazidime, and vancomycin. Thirty-three of the 47 (70%) responders had a complete resolution of their fever with no further recurrence. Fourteen of the 47 responders developed a second fever between 2 and 25 days after stopping first-line antibiotics. Eleven of the 14 patients responded to a second course of intravenous antibiotics. Twenty-four of the 71 patients did not respond to intravenous antibiotics and were treated with intravenous amphotericin and the intravenous antibacterial agents were discontinued. Eighteen of the 24 patients responded to amphotericin. The 6 patients who had persistent fever resolved their temperature when their neutrophil count recovered. There were no deaths due to infection during the study. Short-duration intravenous antibiotics in conjuction with oral ciprofloxacin prophylaxis are a safe and effective treatment for neutropenic fever. PMID- 8701703 TI - Hypocomplementemia and hematological abnormalities in immunoblastic lymphadenopathy and immunoblastic lymphadenopathy-like T cell lymphoma. AB - Serum complement levels and hematological data were evaluated in five patients with immunoblastic lymphadenopathy (IBL) and four with IBL-like T cell lymphoma (IBL-T). Anemia with Hb values below 10.0 g/dl was seen in four patients. A direct Coombs test was positive in five patients and the bone marrow of two of these showed features of pure red cell aplasia. Seven patients were thrombocytopenic with platelet counts below 100 x 10(9)/l. Six of the seven patients had splenomegaly. Platelet-associated IgG was elevated in all three thrombocytopenic patients examined. Whole complement activity (CH50) was reduced in eight patients (89%) at presentation and subsequently normalized in five who were treated either with prednisolone (two patients with IBL) or with multidrug combination chemotherapy (three with IBL-T). One patient achieved complete remission and four partial remission. Remission was accompanied by normalization of hematological abnormalities and elevation of complement activity to the normal range in all cases. These results suggested that complement-mediated mechanisms are responsible, at least in part, for some of the hematological abnormalities observed in IBL and IBL-T and that hypocomplementemia is a common abnormality with significance as a laboratory marker for the disease activity. PMID- 8701704 TI - Tuberculosis-associated haemophagocytic syndrome: a report of two cases and a review of the literature. AB - The haemophagocytic syndrome (HS) is an uncommon reactive proliferation of mature histiocytes, and is more frequently but not exclusively associated with infections in individuals with pre-existing immunologic abnormalities. As far as we know, only 13 cases of tuberculosis-associated HS have previously been reported. We present here two cases of disseminated tuberculosis-associated HS. Both of the cases recovered with antituberculosis therapy. High-dose methylprednisolone and intravenous immunoglobulin were added in one case because of the extremely severe clinical presentation. This therapy seemed to contribute to the favourable outcome of the patient. The similarities in HLA phenotypes of this patient and others reported in the literature may provide evidence for an underlying immune dysregulation in some cases of infection-associated HS. PMID- 8701705 TI - Combination therapy with recombinant human erythropoietin, interferon-alpha-2b and granulocyte-macrophage colony-stimulating factor in idiopathic myelofibrosis. AB - Seven patients, 3 men and 4 women 48-72 years of age and suffering from idiopathic myelofibrosis were given a combination of recombinant human erythropoietin (r-hu-Epo), interferon-alpha-2b (IFN) and GM-CSF, in an attempt to treat their pancytopenia and marrow fibrosis. The dose of r-hu-Epo was 200 U/kg 3 times weekly, that of IFN was 3 x 10(6)/U 3 times weekly, and that of GM-CSF was 250 micrograms/m2/daily. The duration of therapy ranged from 3 to 6 months for r hu-Epo and IFN and was 3 weeks for GM-CSF. The treatment regimen had a beneficial effect on all patients. The levels of hemoglobin increased in all patients but particularly in 5 (2 of whom had been dependent on red blood cell transfusions). Splenomegaly decreased significantly in 4 patients. Fibrosis in the bone marrow decreased in 2 patients. Three patients also had an increase in the number of white blood cells during the therapy with GM-CSF. We observed mild side effects in 6 of our patients. One patient had severe side effects from IFN and treatment was discontinued. In conclusion, the combination of r-hu-Epo, IFN and GM-CSF may improve the anemia (due to r-hu-Epo), increase the white blood cell count (due to GM-CSF) and reduce the marrow fibrosis (probably due to IFN) in patients with idiopathic myelofibrosis. PMID- 8701706 TI - Detection of acute myeloid leukemic cells in complete remission and in extramedullary sites by clonal analyses. AB - We report the case of a 49-year-old woman with acute myeloid leukemia (AML, M5b). The leukemic cells expressed blast as well as myelomonocytic antigens and were characterized by a clonal gene rearrangement of the immunoglobulin (Ig) JH gene. During the course of the disease in clinical/cytological complete remission (CR) the persistence of leukemic cells was shown by surface marker analyses on bone marrow (BM) cells or BM clones grown in agar. Moreover, clonal leukemic cells could be detected by Southern blot analyses indicating the persistence of blasts. Occasionally BM cells obtained in CR showed a cytologically, immunologically differentiated phenotype, but nevertheless DNA-rearranged cells indicated differentiated blasts ('clonal remission'). Five years after diagnosis the patient presented with an isolated pleural effusion. Southern blot analysis identified the original leukemic clone because pleural cells showed the same clonal Ig gene rearrangement as the cells at diagnosis. The patient died 6 years after diagnosis during her fourth relapse of AML. This shows the value of Southern blot analyses, immunophenotyping and culture techniques to monitor the course of leukemic tumor burden even if it is not cytologically identifiable. PMID- 8701707 TI - Bilateral osteonecrosis of the head of the femur complicating acute promyelocytic leukemia: a sequel to treatment of retinoic acid syndrome with dexamethasone. AB - The complication of 'retinoic acid syndrome' occurs in 25-30% of patients with acute promyelocytic leukemia (APL) treated with all-transretinoic acid (ATRA). Early dexamethasone therapy has reduced mortality from this complication. No long term sequel of the syndrome or its treatment with dexamethasone has been described. We report a patient with APL treated with ATRA who developed avascular necrosis of both femoral heads following treatment of retinoic acid syndrome with short-duration, high-dose dexamethasone. PMID- 8701708 TI - AILD-like dysplasia transformed in AILD-type T cell lymphoma in an HTLV-1 carrier: usefulness of interferon-alpha. AB - A 61-year-old Japanese woman who was an HTLV-1 carrier had angioimmunoblastic lymphadenopathy with dysproteinemia (AILD)-like dysplasia that transformed into AILD-type lymphoma after 3 years. Complete remission was achieved with interferon alpha (IFN-alpha) treatment following a previous combination of anticancer drugs. IFN-alpha was also effective for maintenance therapy after this complete, albeit transient, remission. From clinical and pathological studies on AILD patients, it appears that AILD may in some cases be the consequence of an immune dysfunction caused by HTLV-1 infection and that AILD-type lymphoma is a malignant disorder of peripheral T cell clones different from those T cells incorporating the HTLV-1 virus. PMID- 8701709 TI - Acute leukemias expressing p210-and p 190-type bcr/abl mRNAs: report of two cases and review of the literature. AB - We report two patients with acute leukemias who expressed two types of bcr/abl mRNA. The first case was an 8-year-old boy with acute mixed leukemia in whom the Ph1 chromosome and p210/p190 types of bcr/abl mRNAs were detected at diagnosis. The second case was a 39-year-old male with acute nonlymphocytic leukemia transformed from myelodysplastic syndrome (refractory anemia with excess of blasts). In the latter case, the p210-type mRNA appeared after leukemic transformation, and the p190-type transcript was detected only during the late stage when the Ph1 chromosome was first observed. The leukemias in these two patients were aggressive in their clinical courses. We conclude that the dual expression of p210 and p190 types of bcr/abl is a factor indicating a poor prognosis, and that, in some patients, p190-type bcr/abl may contribute to disease progression. PMID- 8701711 TI - Making a difference: the value of choices for institutionalized elders. PMID- 8701710 TI - Improving functional mobility in elderly patients: a nursing program. PMID- 8701712 TI - Involving nurses in their own education: a novel idea? PMID- 8701713 TI - Predicting falls: risk assessment tool versus clinical judgement. PMID- 8701714 TI - The registered nurse referral network. PMID- 8701715 TI - The grass is only as green as you make it. PMID- 8701716 TI - Independent practice: legal considerations. PMID- 8701717 TI - Myths and facts about paying privately for health care. PMID- 8701718 TI - Change, it affects us all. PMID- 8701720 TI - Dr. Gail Mitchell: an interview. Interview by Eve Henderson and Wendy Duggleby. PMID- 8701719 TI - PACS--a system for measuring patient activity and costs. PMID- 8701721 TI - Teambuilding: a positive force in times of change. AB - The health care system continues to undergo revolutionary changes in the 90's. Never before in this area have we seen so many changes occur so quickly in such a short period of time. Funding changes and decreases to hospitals are only one of the critical factors ultimately effecting patient care and the direction of health in the future. Staffing changes because of bumping due to seniority and redesign efforts have had an even greater impact on the day to day operation of a hospital unit. This article attempts to address some of these concerns with one practical process that is universally accepted and can be readily implemented. This process which is springing up in the literature and is fast becoming the popular term of this decade is that of "TEAMBUILDING". In the next few pages an interdisciplinary team will describe their successful efforts at teambuilding in one clinical program. PMID- 8701722 TI - Videotaping: a creative strategy for patient education. PMID- 8701723 TI - 48th Congress of the Nordic Orthopedic Federation. Bergen, Norway, June 12-15, 1996. Abstracts. PMID- 8701724 TI - [Multiple primary tumors in patients with laryngeal carcinoma: incidence and prognostic factors]. AB - An a series of 1.053 treated surgically for laryngeal cancer, a noteworthy incidence of secondary tumors (S.T.) was observed. This occurrence was correlated to various oncological parameters of primitive laryngeal tumors in order to reveal any eventual predictive factors. A S.T. occurred in 80 patients (7.6%): in 22 cases (27.5%) in the upper aero-digestive tract; in 23 (28,8%) in the lungs; in 15 (18.7%) in the gastro-intestinal tract (stomach, intestines, liver, esophagus); in 9 (11.2%) in the genitourinary tract (bladder, prostate); in 4 (5%) on the skin; in 3 (3.8%) in the thyroid; in 2 (2.5%) in the skeletal system; in one case each in the nervous system and in the mediastinum (1.2% respectively). On slightly more than one half of the cases (56.3%) diagnosis was made in the first 5 years following laryngeal surgery; in 26.2% in the following 6-10 years; in 26.2% in the 17.5% after 10 years. Only in two cases (stomach and thyroid) a S.T. appear within 6 months (simultaneous S.T.). No predictive correlation was revealed with regard to site or laryngeal tumor extension; to the presence of lymph node metastases or capsular rupture. However, in patients that had undergone functional surgery, S.T. incidence was double that of those who had been treated with total laryngectomy. Furthermore, in comparing the incidence of pulmonary metastases with that of a pulmonary S.T., it appeared that these is a higher probability of occurrence of the former in cases of supraglottic carcinomas, of laterocervical lymph node metastases or of capsular rupture. This findings clearly demonstrate that during pre-operative staging and post-operative follow-up an extremely accurate clinical and instrumental examination, aimed furthermore at revealing any eventual second neoplasms which, on the basis of our observations, may strike anywhere in the body, is absolutely indispensable. PMID- 8701725 TI - [Study of pharmacokinetics of liver targeting antimalarial agent neoglycoalbumin primaquine conjugate (NGA-PQ) and primaquine phosphate in mouse]. AB - A normal phase high-performance liquid chromatography process was used to separate and detect primaquine in blood and liver after a single intravenous dose of the hepatic targeting agent neoglycoalbumine-primaquine conjugate (NGA-PQ) and primaquine phosphate (PQP) in mice. 6-Methoxy-8-(4-amino-butyrylamino) quinoline synthesized and identified by us was used as an internal standard to be added to biologic samples obtained from mice at different times after given NGA-PQ or PQP. The mixture was extracted with ether after alkalinization in the PQP group. In the NGA-PQ group, the biological samples must be hydrolized by heating under nitrogen and acid condition in a domestic pressure cooker before extraction. The extracts were evaporated to dryness under nitrogen, then dissolved in the mobile phase (chloroform-methanol-amonium hydroxide = 86.8: 12.5: 0.7). The results showed that the hepatic PQ collecting ratio and the retention time of PQ in liver in the NGA-PQ group were higher and longer than those in the PQP group. The results also point out that NGA-PQ has liver targeting property. PMID- 8701726 TI - Determination of age-related changes of cytochrome P-450 sensitive to mepyramine in rat hepatic microsomes. AB - The cytochrome P-450 (Cyt P-450) sensitive to mepyramine (HP-450) in liver microsome is a protein that possesses properties of both H1 receptor and cytochrome P-450. We used [3H]mepyramine radioligand binding assay and enzymological technique to study the kinetic properties of HP-450 and Cyt P-450. Age-related changes in the Bmax, Kd of HP-450 and Cyt P-450 in rat hepatic microsome were demonstrated. The levels of Bmax for both HP-450 and the Cyt P-450 dramatically increased in the postnatal period from the second to the eighth week, and reached maximum steady status during the eighth to tenth week. The values of Bmax of HP-450 correlated well with the content of Cyt P-450 in rat liver microsome (r = 0.625). The affinity of HP-450 (Kd) decreased with the growth of rats during postnatal. No sexual-related difference was observed in this experiment. PMID- 8701727 TI - [Protective effect of salvianolic acid a on ischemia-reperfusion induced injury in isolated rat heart]. AB - The protective effect of salvianolic acid A (Sal A) on cardiac ischemia reperfusion induced injury was studied on the isolated rat heart. The results indicate that Sal A can reduce the occurence of ventricular fibrillation, decrease the cellular LDH leaking and reduce the concentration of lipid peroxidation product-MDA significantly in ischemia-reperfused cardiac tissue. The possible machenism in decreasing ischemia-reperfusion injury of Sal A was discussed. PMID- 8701728 TI - [Potassium channel openers antagonize 4-aminopyridine induced histamine release from rat peritoneal mast cells]. AB - 4-Aminopyridine (4-AP) was shown to promote histamine release from isolated rat peritoneal mast cells (PMC) in a dose-dependent manner. Potassium channel openers, minoxidil (Min) 200 mg.kg-1 ig, diazoxide (Dia) 500 mumol.L-1 in vitro and calcium antagonist nifedipine (Nif) 125 mg.kg-1 ig were found to inhibit 4-AP induced histamine release from rat PMC. Electron microscopy revealed that 4-AP caused partial degranulation of PMC and extrusion of granules and Min 200 mg.kg-1 ig retarded this phenomenon. These results provide evidence that potassium channels are present in rat mast cell membrane and indicate that the mechanism of histamine release by 4-AP may be related to its potassium channel blocking effect. As a result of this effect, the calcium channels open and Ca2+ influx to the mast cells increases, thus eliciting histamine release. Potassium channel openers seemed to be a new group of inhibitors of histamine release from mast cells. PMID- 8701729 TI - [Effect of DL-butylphthalide (NBP) on mouse brain energy metabolism in complete brain ischemia induced by decapitation]. AB - The effects of NBP on gasping and brain energy metabolism after complete brain ischemia in mice subjected to decapitation were investigated. The levels of ATP, phosphocreatine (PCr) and lactate were determined by the method of Lowry. The data indicated that NBP at 112.5 or 250 mg.kg-1 sc can significantly prolong the duration of gasping and at the dose of 150 or 200 mg.kg-1 sc reduce the level of lactate and increase the levels of ATP and PCr after complete brain ischemia. The results suggest that NBP may have brain protective action and improve ischemic brain energy metabolism. PMID- 8701730 TI - [Synthesis and antifertility activity of a-nor-5 alpha-androstane derivatives]. AB - In order to study the relationship between the structure of A-nor-5 alpha androstane derivatives and their antifertility activity, we designed and synthesized 16 A-nor-5 alpha-androstane compounds through several reaction steps with dehydroepiandrosterone acetate as a starting material. Their structures were confirmed by IR, 1HNMR, MS, elemental analyses, etc. Preliminary pharmacological tests showed that compounds 8, 9, 10 and 16 possess antiimplantation activity to some extent (2.5 mg.kg-1, administered po, gave 67-75% antiimplantation rate). Other compounds showed low activity. The possible relationship between compound structures and their activities is analysed briefly. PMID- 8701731 TI - High-performance liquid chromatographic determination of free ferulic acid in serum of rabbits with blood stasis. AB - A Simple, rapid and sensitive reversed phase high performance liquid chromatographic (RP-HPLC) method for the analysis of free ferulic acid in serum of rabbits with blood stasis has been developed. Coumarin was used as internal standard. 0.2 ml of serum containing ferulic acid was deproteinized with acetonitrile which contained the internal standard (coumarin). The supernatant was evaporated to dryness. The residue was dissolved in 60 microliters of acetonitrile. A Du Pont Zorbox C18 column was used. A mixture of acetonitrile and 0.10 mol.L-1 phosphoric acid (3:7, v/v, pH 2.5) was used as the mobile phase, and UV detection was performed at 320 nm. The detection limit (signal-to-noise ratio = 3) and the mean recovery from serum were 1 ng and 97.0 +/- 1.8%, respectively. The method was linear within the range of 20-800 ng.ml-1 (r = 0.9986). The relative standard deviation were all less than 7%. The method was applied to pharmacokinetic studies in healthy rabbits and rabbits with blood stasis. Through this experiment we have found significant difference in the pharmacokinetic parameters between healthy rabbits and rabbits with blood stasis. The results obtained are coincident with syndrome and pharmacokinetics. PMID- 8701732 TI - [HPLC determination of 4-[4"-(2",2",6",6"-tetramethyl-1"-piperidinyloxy) amino] 4'-demethylepipodophyllotoxin in rat plasma and studies of its pharmacokinetics]. AB - 4-[4"-(2",2",6",6"-tetramethyl-1"-piperidinyloxy) amino]-4'- demethylepipodophyllotoxin (GP-7) is a new podophyllotoxin spin-labeled derivative. Its primary effect is the antitumor activity on transplanted mouse tumors and cultured tumor cells. This paper describes a method for its determination using HPLC with UV detection and the determination of its pharmacokinetic parameters in rats. A Shimadzu LC-6A liquid chromatograph equipped with a Shimadzu SPD-6AV multiwavelength detector and a Chromatopac C-R3A data processor was used. The separation was performed on a Zorbax-ODS column (5 microns, 4.6 mm x 150 mm) with a mobile phase of methanol--water--glacial acetic acid (59:41:0.6). The flow-rate was 1.0 ml.min-1 and detection was made at 285 nm. A plasma specimen (0.2 ml) was spiked with 22.6 micrograms.ml-1 internal standard (podophyllic acid piperidinyl hydrazone nitroxide radical, GP-1) and extracted with ether--dichloromethane (3:1). The extract was evaporated at 45 degrees C. The residue was taken up with 0.1 ml of the mobile phase and 20 microliters aliquots were injected into the system. The calibration curve was linear in the range from 2 to 200 micrograms.ml-1 with r = 0.9997. The detection limit was 0.2 microgram.ml-1 and the recovery of GP-7 from rat plasma was 94.3% 100.9%. The relative standard deviations for within- day and between-day were 2.29%-4.64% and 5.55%-7.70%, respectively. After iv injection of GP-7 10, 20 and 30 mg.kg-1, the concentrations of the drug in rat plasma were determined. The pharmacokinetic parameters of GP-7 were obtained by using MCPKP program on a COMPAC-486 computer. The data obtained fitted a two-compartment open model, and the mean T1/2 beta value was 39.8 +/- 10.8 min. PMID- 8701734 TI - [Comparison of morphological and microscopical diagnostic characters of Hawthorn fruits (Crataegus species)]. AB - This paper deals with studies on morphological and microscopical diagnostic characters of Chinese Hawthorn fruits. Their similarities and differences in morphological and microscopical characters among eight species of Crataegus (C. pinnatifida Bge., C. pinnatifida var. major NE Br., C. cuneata sieb. & Zuce., C. scabrifolia (Franch.) Rehd., C. hupehensis Sarg., C. kansuensis Wils, C. maximowiczii Schneid. and C. sanguinea Pall.) fruits are compared and illustrated with diagrams. PMID- 8701733 TI - [Transdermal iontophoresis of insulin: effect of penetration enhancers on blood glucose level in diabetic rats]. AB - The effects of many usual penetration enhancers such as azone (AZ), oleic acid (OA), poloxamer 188 (POL 188) and propylene glycol (PG) on the blood glucose level in diabetic rats after transdermal iontophoresis of insulin were studied. The change of blood glucose level (D%), defined as the percent ratio of the concentration of blood glucose in rats after the iontophoretic application of insulin to that before administration of insulin, was used to present the data. The results showed that following iontophoretic application of insulin for 3 h, the D% in diabetic rats treated with 100% AZ and 5% AZ/PG was 38.58% and 25.28% respectively, and the D% in diabetic rats untreated with enhancers was 45.48%. The D% in diabetic rats treated with 100% OA, 10%-OA/PG, 10% POL 188/PG and 100% PG was 66.28%, 60.47%, 76.75% and 57.93% respectively. So, AZ showed a synergistic effect on the ability of iontophoresis to promote skin permeation of insulin, and PG further increased this effect. The combination of AZ, PG and iontophoresis increased the permeation of insulin significantly. OA, POL 188 and PG did not display synergistic effect on iontophoresis enhancement. The combination of iontophoresis and some enhancers provided a novel idea and possibility for the administration of polypeptide drugs. PMID- 8701735 TI - [Increase of 3H-GABA release from rat cultured cortex neurons after chronic exposure to MK801]. AB - Excitatory amino acids are involved in acute and chronic neurodegenerative diseases. Little is known about the potential consequences of chronic blockade of NMDA receptors (one subtype of excitatory amino acid receptors). Receptor function measured as 3H-GABA release in culture media after pretreatment with MK801 was studied in rat cortical neurons in primary cultures. Cultured neurons were exposed to 1 mumol.L-1 MK801 for 4 days since the 14th day. Glutamate (1 mmol.L-1) evoked 3H-GABA release was shown to be significantly increased (control 0.2174/1000 +/- 1.40/1000; MK801 treatment 0.763% +/- 0.192%). KCl 40 mmol.L-1 stimulation showed no such effect. This result suggests that the NMDA receptor function of releasing neurotransmitters changed after chronic treatment with noncompetitive antagonists. PMID- 8701736 TI - [Studies of drugs for osteoporosis (3): synthesis of quinolinone derivatives and their treatment of osteoporosis]. AB - In order to obtain more effective drugs with less side effects for the treatment of osteoporosis, we designed and synthesized fourteen quinolinone derivatives. The 14 title compounds have not been reported in literature. Their structures were confirmed by elemental analysis, IR, MS and 1H-NMR. Initial pharmacological test showed that target compound TM-11 could stimulate bone formation in Wistar rat embryo in culture and showed higher activity in stimulating bone formation than ipriflavone. PMID- 8701737 TI - [Protective effect of polysaccharide sulfate on human umbilical vein endothelial cell (HUVEC) injury in vitro]. AB - The influence of four kinds of polysaccharide sulfate [heparin (Hep), low molecular weight heparin (LMWH), proglylene glucol mannate sulfate (MS871), chondroitin A sulfate (CAS)] on HUVEC injured by polycations and oxygen free radicals was investigated. The degree of injury was determined by checking the release of LDH to medium and 3H-TdR incorporation. The four kinds of polysaccharide sulfate were shown to protect cells from injury caused by polylysine concentration-dependently. The study also showed that the effects of Hep and CAS were stronger than those of LMWH and MS871 at the same dose level. In view of the level of LDH, the four kinds of polysaccharide sulfate can protect cells from oxygen free radical injury. The effects of Hep and CAS were more active than those of LMWH. PMID- 8701738 TI - [Effects of dynorphin A (1-8) on cell cycle and total cellular protein during neuronal aging in vitro]. AB - Serum-free culture of mouse neuroblastoma cells was used as the experimental model for the study of neuronal aging, with flow cytometry of cell cycle, DNA and total cellular protein as the indices of neuronal aging. After addition of dynorphin A (1-8) 10(-7) mol.L-1 into the culture medium, the following general tendencies were obtained: (1) The number of S and G2 + M phase cells was increased and the number of G1 phase cells decreased. (2) The total cellular protein in aged experimental neural cells decreased. The results implies that Dyn A (1-8) Produced effects on cell cycle, DNA and total cellular protein in the direction of delaying neuronal aging. The relation between Dyn A (1-8) and neuronal aging merits further investigation. PMID- 8701739 TI - [Protective effects of tetrandrine on ischemic myocardia in anesthetized dogs]. AB - The present study indicates that iv tetrandrine may transiently decrease blood pressure, while other hemodynamic parameters such as LVP, +/- dp/dtmax, LVEDP, HR and CO may not be significantly altered. During coronary occlusion three of five dogs developed ventricular fibrillation (VF) and died in the control group, i.e. incidences of VF and mortality were 60%. While tetrandrine (Tet) appeared to reduce the severity of ischemic injury. It may alleviate arrhythmia and prevent VF and death in four of the five dogs. Tet also attenuated Ca2+ accumulation in myocardial cell, reduced melondialdehyde (MDA) production in ischemic myocardial and decreased CPK release in comparison with the control. It appears that Tet may have significant protective effects against ischemia induced cardiac damage in anesthetized dogs. PMID- 8701740 TI - [Determination of N-demethyldiazepam and its metabolite oxazepam in plasma by HPLC and their pharmacokinetics in rats]. AB - A simple rapid and sensitive HPLC method for simultaneous determination of N demethyldiazepam and its metabolite oxazepam in both human and rat plasma was described. A reversed phase C18 column equipped with a 240 nm detector were selected. Diazepam was used as internal standard. The mobile phase consisted of acetonitrile--0.01 mol.L-1 sodium acetate buffer (pH 3.8, 33.3: 66.6 v/v). The retention time for N-demethyldiazepam, oxazepam and internal standard were 4.85 min, 2.8 min and 8.5 min, respectively. The lower detection limits for oxazepam and N-demethyldiazepam were 10 ng.ml-1 and 7 ng.ml-1, respectively. The precisions (RSD%, n = 5) of within-day and day-to-day were less than 6% and 10% and their absolute recoveries were 74% and 86%, respectively. The pharmacokinetic characteristics of N-demethyldiazepam in Sprague-Dawley rats after a single oral dose of 2.5 mg.kg-1 was investigated by this method. The concentration-time curve was fitted to a two-compartment open model. Its main pharmacokinetic parameters were: Tmax = 0.24 h, Cmax = 1211.78 ng.ml-1, T1/2 beta = 2.84 h, AUC = 1264 ng.ml 1.h-1. PMID- 8701741 TI - [A rat middle cerebral artery thrombosis model for evaluation of thrombolytic and antithrombotic agents]. AB - The purpose of this study was to develope a rat model of cerebral artery thrombosis by adding FeCl3 to the surface of right middle cerebral artery (MCA) for 30 min. After 4 h, 8 h, 24 h, 48 h, 72 h, 1 week and 2 week, the extent of neurologic deficits of rats was evaluated and after 24 h and 48 h the size of cerebral infarction was measured. The results indicate that the features of neurologic deficits and infarction were similar to those of the rat focal cerebral ischemia model established by Tamura et al (1981). The nature of thrombus formed in our experiment is combined-thrombus. The antithrombotic effect of aspirin and the thrombolytic effect of urokinase were also examined. Aspirin (50 mg.kg-1) was given by duodenum 30 min before adding FeCl3 to the surface of the right MCA and urokinase (4000 U.kg-1, iv) was given 30 min after thrombosis. After operation, the behavior of rats were observed. The cerebral infarction was evaluated 24 h after thrombosis. The infarcted areas in the aspirin and the urokinase groups were reduced to 20% and 11% those of the control group, respectively. The neurologic deficits were also attenuated. These studies suggest that this rat model may be used for testing not only antithrombotic but also thrombolytic agents. PMID- 8701742 TI - [Minocycline potentiates the antimetastatic effect of boanmycin]. AB - Boanmycin (bleomycin A6, BAM) was found to markedly inhibit the spontaneous pulmonary metastasis of Lewis carcinoma in mice. Compared at equitoxic doses (1/9 LD50), BAM was more effective than mitomycin. Minocycline (MNO) at 5 mg.kg-1 showed no inhibition on the growth of sc transplanted Lewis primary tumor; however, it markedly potentiated the antimetastatic effect of BAM. Treated with BAM (5 mg.kg-1) alone, the number of total metastatic foci and that of large foci (> 2 mm in diameter) in the lung were suppressed by 67% and 85%, respectively. When BAM was used in combination with MNO, the number of those foci was further reduced by 88% and 100%, respectively. By NAG enzyme assay, MNO was not cytotoxic and showed no synergism with BAM against PG cells, a cell line derived from a highly metastatic human giant cell carcinoma of the lung. Determined by ELISA with a monoclonal antibody, the expression of type IV collagenase in PG cells was remarkably inhibited by MNO. The intracellular free Ca2+ level in PG cells was reduced from 76.7 nmol.L-1 to 42.2 nmol.L-1 by MNO treatment. The study suggests that the combination of boanmycin and minocycline may be useful for control of tumor metastasis and the inhibition of type IV collagenase expression may be involved in the mechanism of minocycline potentiation. PMID- 8701743 TI - [Protective effects of ginsenoside Rb1 and Rg1 on cultured hippocampal neurons]. AB - It has been well documented that ginsenoside Rb1 and Rg1 are important active principles of ginseng. In the present studies, Rb1 and Rg1 were found to prolong the duration of neuronal life and provided partial protection against the excitotoxic effect of glutamate in primary hippocampal cultures. Since excitotoxic neuronal injury of glutamate is considered to be caused by the increase of intracellular Ca2+ concentrations, the effects of Rb1 and Rg1 on [Ca2+]i elevated by glutamate were measured in cultured hippocampal cells using Fura-2/AM as a calcium indicator. The results showed that Rb1 and Rg1 could selectively inhibit the high level glutamate (500 mumol.L-1) induced increase of [Ca2+]i, suggesting that the neuroprotective activities of Rb1 and Rg1 were mediated by blocking calcium over-influx into neuronal cells. PMID- 8701744 TI - [Studies on the synthesis and structure-activity relation of deltorphin I analogues]. AB - Endogenous opioid deltorphin I (DEL I) and its three analogues (progressive, stepwise repositioning of Asp from 5 to 7) were synthesized by solid phase method. DEL I at 10(-14)-10(-10) mol.L-1 in vitro and at 0.5-5 micrograms.kg-1 in vivo was found to increase the percentages of erythrocyte rosette forming cells (E-RFC) and red blood cell C3b receptor garland (RBC-CR1). This augmentative effect of DEL I was antagonized by naloxone. The results indicate that DEL I enhanced the immune function of rats. The order (from strong to weak) of the analgesic and immune activity was shown to be Asp4, Asp7, Asp5, Asp6 and Asp4, Asp7, Asp6, Asp5 respectively. PMID- 8701745 TI - [Simultaneous determination of verapamil and its major metabolite in human plasma by high performance liquid chromatography]. AB - A sensitive high-performance liquid chromatographic assay suitable for the simultaneous determination of verapamil (I) and its major active metabolite norverapamil (II) in human plasma is described. After adding internal standard ethmosine, plasma samples were extracted using a mixture of n-hexane and n-butyl alcohol (12:1) to give mean recoveries of > 92% of both I, and II. The extracts were chromatographed on a C18 reversed phase column with a mobile phase composed of methanol, water and triethylamine (67: 33: 0.4, pH 6.7), with UV (lambda, 279 nm) detection. The calibration curves were linear over a wide range of concentrations (25-1000 ng.ml-1), and the limits of determination was 2.5 ng.ml-1 for I and 5.0 ng.ml-1 for II. The method showed good precision: the within-day RSD were < 7.6% for both I and II; the day-to-day RSD were < 8.6% for both I and II. Using this assay, plasma concentrations of both I and II were simultaneously determined in six volunteers after a single oral dose of 120 mg of verapamil.HCl. PMID- 8701746 TI - [Analysis of penbutolol and its metabolites in human body fluid by gas chromatography--mass spectrometry]. AB - A method for the detection and identification of penbutolol and its metabolites in human body fluid by using gas chromatography-mass spectrometry was established. The urine was extracted with diethyl ether-isopropanol and the plasma was extracted with Sep-Pak column. After TMS derivatization the sample was analyzed with GC-MSD. Six metabolites of penbutolol were found in urine sample. The recovery was 90.83% for urine and 85.88% for plasma. The detection limit of penbutolol was 5 pg. PMID- 8701747 TI - [Study on the specific killing activity of albumin nanoparticles containing adriamycin targeted by monoclonal antibody BDI-1 to human bladder cancer cells]. AB - A highly specific immuno-nanoparticle (ADR-NP-Ab) has been constituted by chemically coupling a monoclonal antibody BDI-1 to albumin nanoparticle containing adriamycin (ADR-NP). Different molecular ratios of antibody to ADR-NP were tried to determine the optimal condition for preparing the immuno nanoparticle. The results of immunoflurecence and microphotographic analysis showed that the activity of ADR-NP-Ab was well preserved. The result of the cytotoxicity of ADR-NP-Ab in vitro assay showed strong killing activity of ADR-NP Ab to bladder cancer cells (EJ), while no apparent cytotoxic activity to non targeted human colon carcinoma cells (Lovo) was observed. PMID- 8701748 TI - [Radioprotective effect of gamma-harmine and its carboline analogues]. AB - gamma-Harmine (I), harmine (II) and harmaline (III) were isolated from Peganum harmala L. (Zygophylaceae). Tests were conducted with mice to detect whether gamma-harmine (a new compound), harmine, harmol (IV) and harmalol (V) are effective radioprotective compounds against gamma-ray irradiation. Intraperitoneal injection of the hydrochlorides of the four alkaloids 50-80 mg.kg 1 X 1 in NIH male mice 30-45 minutes before 8.6-9.7 Gy whole body 60Co irradiation significantly increased the survival effects (1.33-2.61) and 30-day survival survival rate in comparison with control mice. The results indicate that gamma-harmine exhibited relatively good radioprotective effect. gamma-harmine is the first alkaloid isolated from a plant having protective effects against whole body lethal irradiation in mice. PMID- 8701749 TI - beta-Adrenoceptor activates endothelium-dependent release of nitric oxide in rat aorta. AB - AIM: To examine the possible role of agents elevating cAMP to release NO from aortic endothelial cells. METHODS: NG-nitro-L-arg inine methylester (L-NAME), an inhibitor of NO synthase, partially inhibited endothelium-dependent relaxation evoked in phenylephrine-precontracted rings by isoproterenol and abolished relaxation mediated by forskolin 0.2 mumol L-1. RESULTS: In rings without endothelium, isoproterenol and forskolin were less effective relaxants and L-NAME had no effect on the responses. In methylene blue-treated rings isoproterenol- and forskolin-induced relaxation were prevented in both endothelium-intact and denuded rings, but the inhibitory effect of methylene blue were significantly more in rings with endothelium than in those without. On the other hand, relaxation induced by sodium nitroprusside was not inhibited by L-NAME, but was inhibited by methylene blue in both the endothelium-intact and -denuded rings. The concentration-relaxation curves to sodium nitroprusside after methylene blue were identical for rings with and without endothelium. CONCLUSION: beta Adrenoceptors or any agent which raises cAMP elevate NO release from endothelial cells. PMID- 8701750 TI - Efficacy of tablet huperzine-A on memory, cognition, and behavior in Alzheimer's disease. AB - AIM: To evaluate the efficacy and safety of tablet huperzine-A (Hup) in patients with Alzheimer's disease. METHODS: Using multicenter, prospective, double-blind, parallel, placebo controlled and randomized method, 50 patients were administered orally 0.2 mg (4 tablets) Hup and 53 patients were given po 4 tablets of placebo bid for 8 wk. All patients were evaluated with Wechsler memory scale, Hasegawa dementia scale, mini-mental state examination scale, activity of daily living scale, treatment emergency symptom scale, and measured with BP, HR, ECG, EEG, ALT, AKP, BUN, Cr, Hb, WBC, and urine routine. RESULTS: About 58% (29/50) of patients treated with Hup showed improvements in their memory (P < 0.01), cognitive (P < 0.01), and behavioral (P < 0.01 functions. The efficacy of Hup was better than placebo (36%, 19/53) (P < 0.05). No severe side effect was found. CONCLUSION: Hup is a promising drug for symptomatic treatment of Alzheimer's disease. PMID- 8701751 TI - Pharmacokinetics of tablet huperzine A in six volunteers. AB - AIM: To study pharmacokinetics of tablet huperzine A (Hup-A) in Chinese volunteers to help establishing its drug administration schedule. METHODS: For 6 volunteers after a single oral dose of 0.99 mg, drug concentrations in plasma were assayed by reverse phase high pressure liquid chromatography (HPLC) at 0.5, 0.75, 1.0, 1.25, 1.5, 2, 4, 6, 8, and 10 h. The pharmacokinetic parameters were calculated with a 3P87 program by computer. RESULTS: The time course of plasma concentrations conformed to a one-compartment open model with a first order absorption. The pharmacokinetic parameters were as follows: T 1/2ka = 12.6 min, T 1/2ke = 288.5 min, Tmax = 79.6 min, Cmax = 8.4 micrograms L-1, AUC = 4.1 mg L-1 min. CONCLUSION: Hup-A was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate. PMID- 8701752 TI - Effects of Panax notoginseng saponins on posthypoxic cell damage of neurons in vitro. AB - AIM: To study cerebral protective mechanism of Panax notoginseng saponins (PNS). METHODS: Cultured neurons of chick embryo cerebral hemisphere were used as an in vitro system for investigating the effects of PNS. The hypoxic cell damage of neurons cultured were induced by NaCN. The levels of adenosine triphosphate (ATP) were determined with HPLC. PNS was added 30 min before, beginning or after hypoxia. RESULTS: PNS 50 and 100 mg L-1 retarded the break down of ATP of cultured neurons after 2-h hypoxia for 11.3 +/- 1.5 (P < 0.05) and 12.8 +/- 2.2 mumol/g protein (P < 0.01), respectively and accelerated the restoration of ATP during 30-min reoxygenation for 21.0 +/- 2.0 (P < 0.05) and 22.7 +/- 2.6 mumol/g protein (P < 0.01), respectively. PNS also reduced the release of creatine kinase (CK) from 75 +/- 8 kU L-1/g protein to 52 +/- 6 (P < 0.05) and 41 +/- 3 kU L-1/mg protein (P < 0.01), respectively and promoted the restoration of ATP of neurons 20 h after hypoxia when administered in the beginning of hypoxia from 13.0 +/- 0.9 mumol/g protein to 18.1 +/- 1.4 and 20.5 +/- 2.1 mumol/g protein (P < 0.01), respectively. PNS still promoted the restoration of ATP from 13.0 +/- 0.9 nmol/mg protein to 14.9 +/- 1.0 and 18.3 +/- 0.7 nmol/mg protein (P < 0.01), respectively and reduced (PNS 100 mg L-1) the CK release of neurons 20 h after hypoxia even when added in the recovery. CONCLUSION: The protection against hypoxic damage of PNS was related to improving energy metabolism, preserving the structural integrity of neurons. PMID- 8701753 TI - Pharmacokinetics of ceftizoxime in renal failure patients without dialysis. AB - AIM: To investigate the pharmacokinetics of ceftizoxime (Cef) in renal failure patients without any dialysis and supply the basis for a suitable clinical regimen. METHODS: Cef in plasma and urine was assayed by HPLC. RESULTS: After injecting Cef 16.7 mg kg-1, Cef concentration in blood was described as a 2 compartment open model. The main pharmacokinetic parameters were Vd 0.55 +/- 0.17 L kg-1; AUC 879 +/- 460 mg L-1 h; Cl 27 +/- 11 mL kg-1 h-1. T1/2 beta was 15 +/- 4 h. CONCLUSION: T1/2 beta in renal failure patients was about 10 times longer than that in normal volunteers. The clinical regimen should be adjusted in renal failure patients with infection, either prolonging the interval between Cef administration, or decreasing Cef dosage. PMID- 8701754 TI - Effects of hemodynamic changes on taurine release from posterior hypothalamus of freely moving rats. AB - AIM: To study the effects of blood volume and vascular resistance on taurine release. METHODS: We used push-pull superfusion technique in the posterior hypothalamus of conscious freely moving rats. Taurine was determined in the superfusate by HPLC with fluorescence detection following automatic precolumn o phthaldialdehyde (OPA) derivatization. RESULTS: Hypervolemia increased the release of taurine in the hypothalamus. Intravenous infusion of levarterenol (3 micrograms kg-1 min-1) elicited a pronounced pressor response and an increase in the release of taurine. Conversely, a controlled hemorrhagic hypotension or iv infusion of nitroprusside (30 micrograms kg-1 min-1) elicited a hypotension and a decrease in the release of taurine from the posterior hypothalamus. CONCLUSION: In the posterior hypothalamus, taurine might play an important role in central blood pressure regulation. PMID- 8701755 TI - Relationship between muscarinic receptor subtypes and cyclic nucleotides in pons medulla oblongata. AB - AIM: To study the relationship between muscarinic receptor (M-R) subtypes and cyclic nucleotides in pons-medulla oblongata (MeOb). METHODS: The contents of cGMP and cAMP in Sprague-Dawley rat pons-MeOb, cerebellum and cerebral cortex were assayed by radioimmunoassay and competitive protein-binding assay, respectively, after ip injections of drugs. Control rats were given ip normal saline. RESULTS: M1-R agonist pilocarpine (6, 15 mg kg-1, ip) increased the content of cGMP in the pons-MeOb and cerebral cortex, but did not bring about any noticeable change in the cAMP content. The increase of cGMP was antagonized by ip pirenzepine or scopolamine. On the other hand, ip M2-R agonist 6 beta-acetoxy nortropane (6 beta-AN) 25 micrograms kg-1 reduced not only cAMP contents in the pons-MeOb and cerebellum but also cGMP contents in the pons-MeOb and cerebral cortex, while 6 beta-AN 12 micrograms kg-1 only lowered cAMP content. The decreases of cGMP and cAMP induced by 6 beta-AN were antagonized by ip AF-DX 116 or atropine, respectively. CONCLUSION: Stimulation of M1-R causes the increase of cGMP and that of M2-R induces the decreases of both cGMP and cAMP in the pons MeOb. PMID- 8701756 TI - Effects of tetrandrine and chlorpromazine on synthesis of collagen and hyaluronic acid in cultured human lung fibroblasts. AB - AIM: To study the effects of tetrandrine (Tet) and chlorpromazine (Chl) on synthesis of collagen and hyaluronic acid (HA) in cultured human lung fibroblasts (HLF). METHODS: The synthesis of collagen and HA was assessed by measuring the incorporation of [3H]proline and radioimmunoassay. RESULTS: Both Tet (5-80 mumol L-1) and Chl (10-40 mumol L-1) diminished the collagen synthesis in a concentration-dependent manner. The suppression was aggravated at 36-48 h. The HA content in the supernatant of culture also decreased gradually with the increasing dosage of Tet or Chl after 24-h exposure. There was no obvious toxic effect of Tet on HLF cells at 5-20 mumol L-1. CONCLUSION: Tet 5-20 mumol L-1 decreased the production of collagen and HA without obvious toxity on HLF, suggesting that Tet could be a hopeful anti-fibrosis drug. PMID- 8701757 TI - Molecular structure alteration of IgG increased anticomplementary activity of intravenous immunoglobulin. AB - AIM: To study the cause of anticomplementary activities (ACA) of intravenous immunoglobulins (IVIG). METHODS: ACA were determined by two assays (limit test and 100CH50 test), distributions of IgG molecular size (polymer, dimer, monomer and fragment) by HPLC, IgG subclasses and IgA contents by radial immunodiffusion, prekallikrein activator (PKA) and kallikrein (KK) activities by chromogenic assay, potency of antibody against hepatitis B surface antigen (Anti-HBs) by enzyme-linked immunosorbent assay (ELISA). RESULTS: The two ACA assays showed good correlation. However, ACA levels were not associated with distributions of IgG molecular size, IgG subclasses and IgA contents, PKA and KK activities. After heating incubation, ACA levels increased markedly and Anti-HBs decreased notably, distributions of IgG molecular size remained relatively constant. CONCLUSION: Molecular structure alteration of IgG increased spontaneous complement activation of IVIG. PMID- 8701758 TI - Effect of ginsenosides against anoxic damage of hippocampal neurons in culture. AB - AIM: To study the protective effect of ginsenosides (Gin) against anoxic injury in brain cells. METHODS: On d 12 after plating of the hippocampal cells from newborn rat, the cultures were exposed to anoxic atmosphere (95% N2 + 5% CO2) for 4-24 h. The cellular morphology, survival rate, and effluxes of lactate dehydrogenase (LDH) and K+ from cells were observed. RESULTS: After 24-h anoxia, the survival rate of cells was decreased from 92% +/- 4% before anoxia to 1.0% +/ 2.0%; the effluxes of LDH and K+ were increased from 2.3 +/- 0.6 U L-1 and 5.56 +/- 0.16 mmol L-1 before anoxia to 36 +/- 5 U L-1 and 8.5 +/- 0.7 mmol L-1, respectively. In the Gin group exposed anoxia for 24 h, the survival rate of cells was 4% +/- 4%; the effluxes of LDH and K+ were 30 +/- 3 U L-1 and 7.9 +/- 0.8 mmol L-1, respectively. All these changes were lower in Gin group than those of control. CONCLUSION: Under anoxia the cultured hippocampal neurons were seriously damaged, which may be protected by Gin. PMID- 8701759 TI - Agonistic actions of pergolide on firing activity of dopamine neurons in substantia nigra compacta area. AB - AIM: To study the potency of pergolide as a D2 receptor agonist on the firing activity of substantia nigra compacta (SNC) dopamine (DA) neurons compared with that of bromocriptine and to determine whether pergolide has the nature of D1 receptor agonist in vivo. METHODS: Extracellular single unit recording techniques. RESULTS: Both pergolide and bromocriptine decreased the spontaneously firing rate of "sensitive" and "insensitive" DA cells. In regard of ID50 values, pergolide (11.9, 95% fiducial limits, 5.7-25.1 micrograms kg-1) was more potent than bromocriptine (7.8, 95% fiducial limits, 3.3-18.5 mg kg-1). The discharge inhibition of pergolide was attenuated following the injection of selective D2 receptor antagonist spiperone 0.25 mg kg-1 or selective D1 receptor antagonist Sch-23390 1-2 mg kg-1. However, the inhibition caused by bromocriptine was not always attenuated by spiperone. CONCLUSION: Pergolide is 650 times more potent than bromocriptine at D2 receptors, and possesses D1 receptor agonist characteristics in vivo. PMID- 8701760 TI - Effects of toquipidine on ionic channels of cultured embryonic Xenopus laevis myoblasts and neurons. AB - AIM: To study the effects of toquipidine (1-p-methyl-phenyl-2-(alpha piperidinoacetyl)-1, 2, 3, 4-tetrahydroisoquinoline hydrochloride, Toq), a new anti-arrhythmic agent first synthesized in China, on ionic channels. METHODS: Ionic channel currents were recorded by whole-cell patch clamp technique in cultured embryonic Xenopus laevis myoblasts and neurons. RESULTS: Toq (0.1, 1, 10, and 100 mumol L-1) caused a concentration-dependent inhibition of the Na+ currents with IC50 7.2 mumol L-1 (5.3-9.8 mumol L-1). Toq (10 mumol L-1) also suppressed the high-voltage-activated Ca2+ currents in neurons. But the steady state outward K+ currents in myoblasts were activated by Toq (10 mumol L-1). CONCLUSION: Toq blocked the Na+ and Ca2+ channels and opened the steady-state outward K+ channels. PMID- 8701761 TI - Expressions of preproenkephalin mRNA during electroacupuncture analgesia enhanced by fenfluramine. AB - AIM: To study the changes of preproenkephalin (PPE) mRNA in rat brain in response to electroacupuncture (EA) combined with fenfluramine (Fen), a releaser of 5-HT. METHODS: In situ hybridization histochemistry technique was used to observe the expression of PPE mRNA in rat brain during EA analgesia potentiated by Fen. RESULTS: The greatest relative increase of PPE mRNA was seen in lumbar spinal cord (laminae I & II), nucleus raphe magnus, dorsal raphe nucleus, periaqueductal gray, interpeduncular nucleus, preoptic lateral area, amygdala nucleus and caudate-putamen (P < 0.01, vs NS + EA). Moderate increases were found in lateral septal, preoptic medial area, hypothalamus ventromedial nucleus, lumbar spinal laminae III & IV (P < 0.05, vs NS + EA). Thalamus showed no statistical significant change in PPE mRNA. CONCLUSION: The enhancing of PPE mRNA in relative brain nuclei is involved in potentiating action of Fen on EA. PMID- 8701762 TI - Effect of pineal body and melatonin on chemiluminescence of peritoneal macrophages via hypothalamus in rats. AB - AIM: To study whether the hypothalamus was a major relay for the action of melatonin (Mel) on peritoneal macrophage (PM subliminal diameter of) function. METHODS: Pinealectomy, luminol-dependent chemiluminescence (CL), hypothalamic dinoprostone radioimmunoassay, and intrahypothalamic injection of Mel were done in rats kept under light:dark 12h:12h. RESULTS: CL value of PM subliminal diameter of was decreased and hypothalamic dinoprostone content was elevated after pinealectomy, which were restored by Mel (10 micrograms kg-1 d-1 ip at 16:00 for 7 d). The same treatment of Mel increased CL value of PM subliminal diameter of and depressed hypothalamic dinoprostone production in intact rats. CL value of PM subliminal diameter of showed negative relation to hypothalamic dinoprostone with r = -0.78 (P < 0.01). Intrahypothalamic injection of Mel (2 micrograms) enhanced CL value of PM subliminal diameter of in normal and pinealectomized rats. CONCLUSION: The hypothalamus is a main site of pineal Mel action upon PM subliminal diameter of function. PMID- 8701763 TI - Hippocampal quinolinic acid concentrations in epileptogenesis in rats. AB - AIM: To study the changes of hippocampal quinolinic acid (QA) concentrations during acute and chronic seizures induced by ip injection of kainic acid (KA, 12 mg kg-1) in rats. METHODS: The extraction and measurement of QA in the hippocampus were performed using a gas chromatography-mass spectrometry method. RESULTS: When acute seizures were fully established 3 h after KA injection, no significant changes of hippocampal QA were found. During chronic seizures observed on d 30 after KA injection, there was even a 55 +/- 8% significant decrease. When neither acute nor chronic seizures were detectable but astroglial proliferation in the hippocampus and secondary neuronal degeneration in extrahippocampal regions became gradually prominent 2 d and 7 d after KA injection, there were 56 +/- 13% and 156 +/- 13% dramatic increases of hippocampal QA concentrations, respectively. CONCLUSION: The increase of hippocampal QA hardly plays any key role in the initiation of KA-induced seizures but may contribute to astroglial proliferation and neuronal degeneration by activation of N-methyl-D-aspartate receptors. PMID- 8701764 TI - Effects of artesunate on immune function in mice. AB - AIM: To study the effects of artesunate (dihydroartemisinine-12-alpha-succinate, Art) on immune function in mice. METHODS: Hemolysin concentration was determined by colorimetric method. Serum IgG and C3 contents were measured by single immunodiffusion method. Percentage of lymphocyte transformation, phagocytosis percentage and phagocytic index were counted under microscope. RESULTS: Art im 75 mg kg-1 bid x 7 d decreased the humolysin-forming capacity and levels of serum IgG of mice sensitized with sheep red blood cell. The serum complement 3 level rose remarkably, when Art was given im to Plasmodium berghei-infected mice. Art enhanced the PHA-induced lymphocyte transformation rate (in vivo) in mice and increased the weight of spleen but reduced that of thymus in mice. Art elevated the DNFB-induced delayed-type hypersensitivity. Art im 75 mg kg-1 bid x 5 d reduced the percentage of phagocytosis of peritoneal macrophages and the phagocytic index. CONCLUSION: Art suppressed the humoral immune responses but enhanced the cell-mediated immunity. PMID- 8701765 TI - Morphine inhibited respiratory burst of neutrophils and scavenged oxygen free radicals. AB - AIM: To study the effects of morphine on active oxygen free radicals. METHOD: Chemiluminescence method was used to measure (a) active oxygen generation induced by respiratory burst of neutrophils from human blood stimulated with phorbol myristate acetate (PMA), (b) Superoxide anion (O2.-) induced by xanthine-xanthine oxidase system, (c) hydroxyl radical (.OH) generated by ascorbic acid (AA)-Cu(2+) zymosan, and (d) the release of H2O2. RESULTS: The (a), (b), (c), and (d) were scavenged by morphine and their median inhibitory concentrations (IC50 and 95% confidence limits) were 21.1 (13.0-34.0), 54.1 (50.0-58.5), 224.0 (128.2-390.8), and 66.9 (62.9-71.0), nmol L-1, respectively. CONCLUSION: The immunosuppressant effect of morphine was related to its free radicals scavenging action. PMID- 8701766 TI - Effect of morphine on interleukin-1 and tumor necrosis factor alpha production from mouse peritoneal macrophages in vitro. AB - AIM: To study the influence of morphine on lymphokine production from mouse peritoneal macrophages (PM phi). METHODS: The productions of interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha) from PM phi under various concentrations of morphine with or without naloxone were measured by testing thymocyte proliferation and L929 cell lysis in vitro. RESULTS: Both morphine (1 x 10(-8) - 1 x 10(-3) mol L-1) and naloxone (50 mumol L-1) inhibited IL-1 production from mouse PM phi primed by sodium thioglycolate. Naloxone did not block the inhibitory effect of morphine. TNF-alpha production from PM phi was inhibited by only high concentration (1 mmol L-1) of morphine which was not blocked by naloxone. CONCLUSION: Morphine had a direct inhibitory effect on PM phi, which was not mediated by opioid receptor of PM phi. PMID- 8701767 TI - Alterations of subtypes of cardiac adrenoceptors in old rat. AB - AIM: To determine alterations of subtypes of myocardial adrenoceptors in senescence. METHODS: Heart membrane preparations were made from 3- and 25-month old Wistar rats. Alpha 1- and beta-adrenoceptors were measured by radioligand, 125I-BE2254 and 125I-pindolol, binding assays, respectively. RESULTS: In the old rat heart, alpha 1- and beta-adrenoceptor densities were declined from the young rats of 119 +/- 4 and 45.9 +/- 1.9 pmol L-1 to 70 +/- 6 and 36.4 +/- 1.6 pmol L-1 (P < 0.01), with a greater change in alpha 1-AR and in beta-AR. The ratio of alpha 1A/alpha 1B subtypes was decreased from the young rats of 39/61 to the old rats of 26/74 (P < 0.05). CONCLUSION: The cardiac adrenoceptors are decreased with different extents in the different subtypes in old rats. PMID- 8701768 TI - Restraint stress changes heart sensitivity to arrhythmogenic drugs. AB - AIM: To study the effects of acute restraint stress on ventricular electric stability (VES) and its mechanisms of action. METHODS: VES was evaluated both in vivo and in vitro by the changes of arrhythmogenic responses to icv or ip aconitine in rats and iv BaCl2 or adrenaline in rabbits following restraint stress for different durations. Pretreatments and the assay of heart-specific enzymes were made. RESULTS: The heart sensitivity to these drugs was promoted after stress for 2 h, but obtunded after stress for 8 h (the latency of ventricular arrhythmia to icv aconitine was shortened from 4.1 +/- 0.9 min in control rats to 2.9 +/- 0.9 min after stress for 2 h, P < 0.05; but prolonged to 9.3 +/- 3.8 min after stress for 8 h, P < 0.05). In Langendorff heart, the changes of VES induced by stress were similar to those in vivo, but to lesser degree. Pretreatment with adrenalectomy inhibited the descending phase of VES, while pretreatment with both aminophylline and vagotomy remarkably depressed the ascending phase at 8 h. In addition, the serum activities of lactate dehydrogenase (LDH), creatine kinase (CK), and aspartate aminotransferase and their isozymes, LDH1 and CK-MB, were elevated at 2 h, and rose continuously at 8 h. CONCLUSION: Acute restraint stress causes biphasic changes of VES. The initial decrease of VES was related to adrenal catecholamine release, whereas the following increase of VES was ascribed to adaptive decrease of cAMP and vagal activation. The changes of VES did not always parallel the injury of heart. PMID- 8701769 TI - Effects of Panax notoginseng saponin Rg1 on cardiac electrophysiological properties and ventricular fibrillation threshold in dogs. AB - AIM: To study the effects of Rg1 isolated from saponins of Panax notoginseng on cardiac electrophysiological properties and ventricular fibrillation threshold (VFT). METHODS: Seventeen open-chest dogs were randomly allocated into a Rg1 group (20 mg kg-1, iv) and a control group. The electrophysiological variables and VFT were evaluated by standard electric stimuli and monophasic action potential (MAP) recording. RESULTS: Rg1 prolonged sinus node recovery time (SNRT) by 19.1%, AV conduction Wenckebach cycle length (AVWCL) by 7.1%, and ventricular effective refractory period (VERP) by 7.9%. It prolonged ventricular MAPD30, MAPD50, and MAPD90 by 25.5%, 24.2%, and 13.5%, respectively. VFT was increased by 19.2%. CONCLUSION: Rg1 prolonged ventricular refractoriness and repolarization, and increased VFT. It was indicated that cardiac electrophysiological effects of Rg1 were similar to those of amiodarone. PMID- 8701770 TI - Depressant effect of taurine on triggered activity induced by cesium chloride in rabbit hearts in vivo. AB - AIM: To study the effects of taurine (Tau) and tetrodotoxin (Tet) on cesium chloride (CsCl)-induced triggered activity and arrhythmia in anesthetized rabbits. METHODS: With a cuffed endotracheal tube, the rabbit ventilation was maintained by a respirator. A Franzy's contact electrode catheter was advanced into the right ventricle through the right external jugular vein and positioned against the anteroapical endocardial surface to record the monophasic action potential (MAP). A catheter was placed into femoral vein for systemic drug administration. RESULTS: CsCl (1 mmol L-1 iv) produced a decrease in the amplitude of MAP from 42.2 +/- 2.1 to 37.0 +/- 3.8 mV (P < 0.01), a prolongation of MAPD50 (156 +/- 22 to 209 +/- 26 ms, P < 0.01) or MAPD90 (205 +/- 25 to 250 +/ 20 ms, P < 0.01) and an early afterdepolarization (EAD) developed within 30 s after CsCl injection. The ventricular premature (VP) resulted from EAD triggered by CsCl. In the Tau (100 mg kg-1)- or Tet (10 micrograms kg-1)-pretreated group, not only was the amplitude of EAD decreased (Tau, 4.2 +/- 2.7; or Tet, 5.2 +/- 2.6, respectively vs 16.1 +/- 8.3 mv, P < 0.01), but also the duration of EAD was shortened (Tau, 695 +/- 164; or Tet, 492 +/- 172, respectively, vs 1068 +/- 166 ms, P < 0.01). The severity of triggered arrhythmia (TA) was alleviated and the incidence of TA was lowered within 30 min after iv CsCl by either Tau or Tet. CONCLUSION: The depressant effects of Tau and Tet on EAD and VP induced by CsCl were involved in an increase of outward current or a decrease of an inward current. PMID- 8701771 TI - Sex differences in pharmacokinetics of oral propranolol in healthy Chinese volunteers. AB - AIM: To determine if the gender-based dimorphism of the distribution and metabolism of oral propranolol (Pro) exists in the healthy Chinese volunteers. METHODS: Twelve subjects (6 M and 6 F) were given an 80 mg single oral dose of Pro. Plasma Pro levels were determined by HPLC with fluorescence detector and the pharmacokinetic parameters were calculated by using the MCPKP program. RESULTS: AUC and Cmax in females were about 74% and 99% higher than those in males (P < 0.05), whereas oral clearance and apparent distribution volume were 109% and 120% lower in females than in males (P < 0.05), respectively. The T1/2 tended to be longer in females (P > 0.05). No differences in any other kinetic parameters were found between the sexes. CONCLUSION: The higher oral bioavailability (AUC and Cmax) of Pro in Chinese women is in part caused by their lower oral clearance and volume of distribution. PMID- 8701772 TI - Anti-implantation activity of 2 derivatives of o-hydroxy naphthaquinones in rats. AB - AIM: To search for female contraceptive agents. METHODS: 2-Hydroxy-3-methyl-1, 4 naphthoquinone monosemicarbazone (HMNQS) and 2-hydroxy-1, 4-naphthoquinone monothiosemicarbazone (HNQTS) were screened for anti-implantation activity in rats. RESULTS: Both compounds showed a dose-dependent activity, and HNQTS was more potent. An 100% anti-implantation activity was observed with HNQTS 150 mg kg 1 ig. Its LD50 was found to be > 2 g kg-1 ig in mice. CONCLUSION: HNQTS was more potent than HMNQS for anti-implantation activity in rats. PMID- 8701773 TI - [Microdialysis sampling and microbore liquid chromatography with electrochemical detection for determination of serotonin in rat brain striatum]. AB - AIM: To develop a sensitive method for determination of serotonin in biological samples. METHODS: A combination of microdialysis sampling and microbore liquid chromatography with electrochemical detection (LCEC) was established. RESULTS: Changes of serotonin in fg or pg in microdialysates from brain striatum of the free moving rat were easily determined. CONCLUSION: This developed method was useful for living animal research. Serotonin level in corpus striatum healthy rats was quite stable. PMID- 8701774 TI - [Effects of nicorandil on spontaneous beating and action potentials of cultured myocardial cells of neonatal rats]. AB - AIM: To study the anti-arrhythmic mechanism of nicorandil (Nic). METHODS: The myocardial cells of neonatal rats were cultured and effects of Nic on spontaneous beating and action potential of cultured myocardial cells were observed. RESULTS: Nic 32 mumol L-1 and 160 mumol L-1 decreased the spontaneous beating rates of cultured myocardial cells of neonatal rats. Nic 64 mumol L-1 prevented the beating rats induced by CaCl2 1 mmol L-1 and isoproterenol 2 mumol L-1. Nic 32 and 160 mumol L-1 reduced the amplitude, maximal rate of rise, and shortened APD50 and APD90 repolarization. Nic prolonged the spontaneous sinus cycle length. CONCLUSION: The antiarrhythmic mechanism of Nic is related to its direct effects on the myocardial cells. PMID- 8701775 TI - IgA2 genotyping by polymerase chain reaction (PCR) using allele-specific amplification primers. AB - A method of genotyping IgA2 alleles in the human immunoglobulin alpha 2 heavy chain constant region (C alpha 2 gene) was developed by using the polymerase chain reaction (PCR). By this method, the genotype was determined by discriminating base substitution in the 3'-flanking region of alleles, A2m*1 and A2m*2, which manifest A2m serum types, by nested PCR using allele-specific primers. Three types, IgA2*1/IgA2*1, IgA2*2/IgA2*1, and IgA2*2/IgA2*2, were detected from DNA extracted from lymphocytes. Genotyping was possible from 100 pg of DNA by this method. The estimated allele frequency in 318 Japanese subjects was 0.561 for IgA2*1 and 0.439 for IgA2*2. Analysis of 29 cases of paternity tests suggested that the data follow Mendel's law of inheritance. This genotype could also be detected in whole blood, blood stains, saliva stains, and various organs and tissues. These results suggest the usefulness of the present method for paternity testing and individual identification in forensic medicine. PMID- 8701776 TI - Enhancement of experimental metastasis by gamma-interferon in a murine adenocarcinoma. AB - This study was conducted to examine the effect of gamma-interferon (IFN-gamma) on experimental metastasis formation by murine colon 26 adenocarcinoma in BALB/c mice. We found that the number of experimental lung metastases was increased after colon 26 cells were pretreated for 1 h with as little as 1 OIU/ml of IFN gamma. 5-[125I] iodo-2'-deoxyuridine-radiolabeled colon 26 cells pretreated with IFN-gamma remained at higher level in the lung at 24h after intravenous injection than when the cells were not pretreated. In vivo elimination of asialo GM1 positive cells increased the number of lung metastases and, in such mice, there was no longer a difference in metastatic ability between control and IFN-gamma treated cells. Colon 26 cells were completely resistant to lysis by isolated splenocytes. Splenocytes incubated in vitro with interleukin 2 exhibited moderate cytotoxicity against colon 26 cells, but there were no significant differences between control and IFN-gamma-treated cells. Colon 26 cells pretreated with IFN gamma demonstrated resistance to tumor necrosis factor alpha-mediated growth inhibition. The enhancement of metastases by IFN-gamma was dependent on de novo protein synthesis since the enhancement was abolished by cycloheximide. Taken together, the data suggest that the metastatic ability of colon 26 cells pretreated with IFN-gamma is significantly higher due to the resistance to asialo GM1-positive cells accompanied with de novo protein synthesis. PMID- 8701777 TI - Transplantation of the cadaver heart harvested one hour after hypoxic cardiac arrest using the core-cooling technique in dogs. AB - A shortage of donor organs in clinical transplantation prompted us to study whether resuscitated dead hearts could be utilized for successful orthotopic heart transplantation. After 60 min of hypoxic cardiac arrest, one group of canine hearts was resuscitated (Res group, n = 6). The other group was harvested directly (Non-Res group, n = 6). In the Res group, cardiopulmonary bypass was utilized for resuscitation at 37 degrees C and the animals were then core-cooled to 15 degrees C. The hearts then were preserved in University of Wisconsin solution and orthotopically transplanted. Stable prostacyclin analogue (OP2507) and verapamil, a calcium antagonist, were added to the cardioplegia, and substrate-enriched warm blood cardioplegia and a hydroxy radical scavenger (EPC) were administered at the time of reperfusion of the transplanted heart. All animals in each group were successfully weaned from cardiopulmonary bypass with dopamine (5 micrograms/kg/min). Cardiac function without dopamine was better preserved in the Res group than the Non-Res group (Emax: 130.6 +/- 41.5% vs. 47.1 +/- 24.7%; mean +/- SD, as percent of postbrain death values, P < 0.01 by unpaired t-test). Cadaver hearts 60 min after anoxic arrest can be successfully re-animated and orthotopically engrafted. In addition, the core-cooling technique is useful. We believe this study serves as the key step in the clinical application of dead hearts to successful cardiac transplantation. PMID- 8701778 TI - Spinal schwannomas: a review of 42 cases. AB - In this study, 42 cases of spinal schwannomas are reviewed. We analyzed the therapeutic results of patients with spinal schwannomas in order to investigate the factors which affect the clinical outcomes. Early diagnosis and treatment could help procure a good result for the patient. The delay in diagnosis and the subsequent duration of symptoms was significantly longer in cases of lumbar lesions compared to cervical and thoracic lesions. Tumor recurrence was rare, but in some cases where complete resection was not possible, close follow-up of the patients postoperatively with MRI was indicated. PMID- 8701779 TI - Surgical treatment for metastatic tumors of the spine. AB - We report herein the results of anterior or posterior neural decompression with spinal stabilization in 16 patients with spinal metastases. Intractable back pain was relieved in 14 patients (87.5%) and 4 had complete pain relief. Neurologic recovery was observed in 8 out of 13 patients (61.5%) who had some neurologic deficits before surgery. The activities of daily living improved in 7 of 9 (77.7%), and 5 out of 8 patients (62.5%) who had been unable to walk before surgery became ambulatory after surgery. The average operation time was 3h 15 min with an average blood loss of 2150 ml. No patient died within 1 month after surgery and the median survival was 19.1 months. The results indicated that, if properly indicated, anterior or posterior neural decompression and spinal stabilization is a safe and effective treatment for patients with spinal metastases to improve the quality of life for the patients' remaining years. PMID- 8701780 TI - Factors affecting prognosis of idiopathic interstitial pneumonia. AB - Idiopathic interstitial pneumonia (IIP) is a progressive and often fatal pulmonary disorder, and evaluating the prognosis of patients with IIP has never been sufficient. Accordingly, factors including clinical features, laboratory data, cellular components in bronchoalveolar lavage (BAL) fluid and response to corticosteroid therapy were analyzed in 35 patients with IIP whose median age of respiratory onset was 60 years (range; 37-77 years). Nineteen patients (54.3%) were in the active stage of IIP and 16 of them were treated with corticosteroids. Significant prognostic factors were the neutrophil percentage in BAL fluid, interstitial shadows on chest radiograph, pulmonary function, blood oxygen level, grade of dyspnea, and disease activity at the initial examination. Patients in the active stage showed higher proportions of neutrophils and eosinophils in BAL fluid than those in the non-active stage. Despite corticosteroid therapy, the survival of patients in the active stage was significantly shorter than those in the non-active stage. Fifty percent of the patients treated with corticosteroids were regarded as responders at 1 month after the initiation of therapy; however, there was no significant difference between responders and non-responders in terms of survival time. In conclusion, disease activity and neutrophils in BAL fluid may be important predictors of the prognosis of IIP. PMID- 8701781 TI - Effect of intracellular free calcium mobilization on aggregation of umbilical cord blood platelets. AB - Aggregation activity of platelets in umbilical blood is lower than that in adult blood, but the reason for this is not well understood. It has recently been clarified that calcium plays a role as a second messenger of platelet aggregation, and that glycoproteins of platelet surface membrane such as glycoprotein I b and IIb/IIIa are receptors for agonists inducing aggregation. We examined the concentrations of intracellular calcium and the membrane glycoproteins of platelets in umbilical and adult blood. The increase of intracellular calcium in umbilical platelets was lower than that in adult platelets when the aggregation was induced by ADP, collagen, thrombin and epinephrine. Only calcium ionophore A23187 induced aggregation of both umbilical and adult platelets. On the other hand, there were no qualitative differences between glycoproteins I b and IIb/IIIa of these two groups. Therefore, the low aggregation activity of umbilical platelets seems to be due to low responsiveness of the intracellular calcium system, not to the disorder of functional surface membrane glycoprotein. PMID- 8701782 TI - cDNA cloning of rat major AP endonuclease (APEX nuclease) and analyses of its mRNA expression in rat tissues. AB - APEX nuclease is a mammalian DNA repair enzyme having apurinic/apyrimidinic (AP) endonuclease, 3'-5'-exonuclease, DNA 3' repair diesterase and DNA 3'-phosphatase activities. It is also a redox factor (Ref-1), stimulating DNA binding activity of AP-1 binding proteins such as Fos and Jun. In the present paper, a cDNA for the enzyme was isolated from a rat brain cDNA library using mouse Apex cDNA as a probe and sequenced. The rat Apex cDNA was 1221 nucleotides (nt) long, with a 951 nt coding region. The amino acid sequence of rat APEX nuclease has 98.4% identity with mouse APEX nuclease. Using the rat Apex cDNA as a probe for Northern blot analysis, the size of rat Apex mRNA was shown to be approximately 1.5 kb. Its expression was compared in 9 rat organs on postnatal days 7 and 28. Although Apex mRNA was expressed ubiquitously, the levels varied significantly, suggesting organ- or tissue-specific expression of the Apex gene. The highest level was observed in the testis, relatively high levels in the thymus, spleen, kidney and brain, and the lowest level in the liver. The level of expression at postnatal day 28, with the exception of the testis, was almost the same as or lower in respective organs than that at postnatal day 7. Postnatal developmental changes of Apex mRNA expression in the testis and thymus were further studied. The expression in testis was markedly increased on postnatal days 21 and 28. The expression in thymus increased once at postnatal day 14, and then decreased. The developmental changes of Apex mRNA expression in testis and thymus suggest that APEX nuclease is involved in processes such as recombinational events. PMID- 8701783 TI - Effects of growth hormone and growth hormone-releasing hormone on steroid synthesis in cultured human luteinizing granulosa cells. AB - To assess the direct effect of growth hormone and growth hormone-releasing hormone on gene expression of steroidogenic enzymes and production of progesterone, 17-hydroxyprogesterone (17-OHP) and estradiol, we cultured luteinizing granulosa cells with or without follicle-stimulating hormone (FSH), growth hormone and growth hormone-releasing hormone at different concentrations. Luteinizing granulosa cells were obtained from women undergoing an in vitro fertilization program in the Department of Obstetrics and Gynecology, S. Raffaele Scientific Institute, Milan, Italy. At a concentration of 1 microgram/ml, FSH significantly increased estradiol production (2.1 +/- 0.7-fold the control value; p < 0.05 vs. control) and progesterone production (3.5 +/- 2.0-fold the control value; p < 0.05 vs. control). Growth hormone was effective on estradiol, progesterone and 17-OHP at 1 microgram/ml, enhancing estradiol production (1.3 +/ 0.2-fold the control value; p < 0.05 vs. control), progesterone production (2.5 +/- 1.0-fold the control value; p < 0.05 vs. control), and 17-OHP (1.4 +/- 0.2 fold the control value; p < 0.05 vs. control). Growth hormone-releasing hormone increased estradiol production (1.5 +/- 1.2-fold the control value) and progesterone production (1.3 +/- 0.8-fold the control value), but not significantly. No effects by growth hormone-releasing hormone were seen on 17-OHP production. FSH, growth hormone and growth hormone-releasing hormone did not increase P450scc and P450 aromatase mRNAs, whereas FSH increased P450c17 mRNA to 150% at 100 ng/ml and 1 microgram/ml, growth hormone increased it to 230% at 100 ng/ml and to 200% at 1 microgram/ml, and growth hormone-releasing hormone increased it to 140% at 100 ng/ml and to 190% of control values at 1 microgram/ml. These results indicate a direct effect of growth hormone on steroidogenesis by increasing P450c17 mRNA accumulation and progesterone, 17-OHP and estradiol production. PMID- 8701784 TI - Estrogen induces expression of c-fos and c-jun via activation of protein kinase C in an endometrial cancer cell line and fibroblasts derived from human uterine endometrium. AB - Endometrial fibroblasts derived from uterine endometrium as controls and endometrial cancer cell lines (Ishikawa and HHUA cells) were analyzed for the induction manner of c-fos and c-jun transcripts in endometrial cancers, some of which are estrogen-dependent in growth. Estrogen increased c-fos expression and protein kinase C (PKC) activity in fibroblasts and Ishikawa cells, but not in HHUA cells. Progesterone diminished c-fos and c-jun expression and PKC activity induced by estradiol in the fibroblasts, but not in Ishikawa cells, which persistently overexpressed c-fos and c-jun. In these cells, 12-0-tetra decanoylphorbol-13-acetate (TPA) increased c-fos and c-jun expression as did estradiol. Pretreatment with 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) abolished estrogen-inducible over-expression of c-fos and c jun. The combination of both estradiol and TPA at maximum effective concentration exerted no additive and synergistic effect on induction of c-fos and c-jun expression. In conclusion, persistent activation of PKC might lead to overexpression of c-fos and c-jun in some endometrial cancers with an estrogen predominant milieu, which might be, at least in part, associated with the transformation or growth potential. PMID- 8701785 TI - Comparison of flutamide and cyproterone acetate in the treatment of hirsutism: a randomized controlled trial. AB - The objective of this study was to compare the efficacy of flutamide and cyproterone acetate in the treatment of hirsutism. Twenty-two women with idiopathic hirsutism were randomized to receive either flutamide or cyproterone acetate. Each patient underwent a complete gynecological examination as well as an endocrinological profile and hematological, hepatic and renal function analyses. Hirsutism scores were determined using a modified Ferriman-Gallwey scoring system. These tests were then repeated at 3 and 9 months of therapy. Eleven patients received 250 mg of flutamide twice daily and 11 patients received 100 mg of cyproterone acetate on days 5-14 of the menstrual cycle. Ferriman Gallwey scores were decreased significantly in both groups at the end of 9 months. There was a trend towards a better response with flutamide, that did not achieve significance. Another significant difference was the increased sex hormone-binding globulin in both groups. A statistically significant decrease was also observed for the levels of testosterone on both drugs. No subject withdrew from the study due to a side-effect. The data suggest that both flutamide and cyproterone acetate were similarly effective in treatment of hirsutism, and that the pure antiandrogen flutamide is a safe, well-tolerated and effective alternative in treatment. PMID- 8701786 TI - Inverted skin changes induced by estrogen and estrogen/glucocorticoid on aging dermis. AB - To evaluate hormone replacement therapy effects at the peripheral level, the present trial explored the oral effects of mestranol (80 micrograms/day for 10 days) and mestranol plus paramethasone (80 micrograms + 6 mg/day for 10 days) on the skin of postmenopausal women. This double-blind study included 13 patients. Skin biopsies were obtained from the thigh area by a single punch, 5 mm in diameter, before and after treatment, and the sections, six per sample, were micrometrically evaluated. Various features of the epidermis and dermis layers were stained using the hematoxylin and eosin, Masson, Verhoeff's and Gomori techniques. Statistically significant changes were found in the papillar dermis thickness; mestranol reduced it and mestranol plus paramethasone increased it. The current results encourage widening these observations of the possible advantage of this estrogen/glucocorticoid combination, in order to alleviate the cellular degenerative process. PMID- 8701787 TI - Ureteral obstruction due to retroperitoneal endometriosis: a conservative approach including surgery and GnRH analogs. AB - Ureteral obstruction due to endometriosis is an infrequent condition which can be asymptomatic for a long time. Irreversible loss of renal function may result in cases with delayed diagnosis. Our report concerns a case of unilateral hydronephrosis and hypertension due to retroperitoneal endometriosis occurring in a 24-year-old woman. The management of patients bearing obstructive uropathy caused by endometriosis is discussed. In the present case, a conservative operation followed by medical treatment, including GnRH analogs, was used to preserve reproductive capacity. PMID- 8701788 TI - Basal body temperature curves and endocrine pattern of menstrual cycles in Down syndrome. AB - We examined the basal body temperature curves and the endocrine pattern of 20 cycles from women with Down syndrome with regular menstrual cycles. Data were compared with those obtained from an age-matched population of healthy women with regular menses. Growth hormone deficiency was excluded for women with Down syndrome by pharmacological tests. Women with Down syndrome showed a significantly higher incidence of anovulation and luteal defects than controls (p < 0.001). Overall, and in ovulatory cycles, estradiol and progesterone plasma levels were greater in controls than in women with Down syndrome. No difference was observed for gonadotropin and androgen circulating levels between the two groups. It is concluded that in women with Down syndrome with regular menses, ovulatory events were less frequent and often characterized by luteal defects. This could be ascribed to an impairment of both follicular and luteal functions. However, reproduction is possible in such patients. PMID- 8701789 TI - Catamenial epilepsy: gynecological and hormonal implications. Five case reports. AB - The aim of this study was to analyze the gynecological and hormonal condition of five patients with catamenial epilepsy and to establish a relationship with the presence of convulsive crises. The clinical profiles of five patients were obtained and their serum levels of anticonvulsants and sex steroids were determined. Four patients showed obvious signs of premenstrual tension syndrome (PMTS), with retention of fluid and reduction of the serum levels of anticonvulsants, which were restored to therapeutic levels after treatment of the PMTS. The fifth patient presented with chronic anovulation, which was treated by administration of progesterone during the second phase of the menstrual cycle, resulting in an improvement in the frequency of convulsions. In the cases studied, the low levels of progesterone and their rapid fall in PMTS, as well as the raised levels of circulatory estrogens in the anovulatory menstrual cycle, appear to be implicated in the convulsive disorder of catamenial epilepsy. PMID- 8701790 TI - Estrous cycle- and acute stress-related changes of rat ovarian immunoreactive corticotropin-releasing factor. AB - Corticotropin-releasing factor (CRF), the major regulator of the stress response within the central nervous system, is also present at peripheral sites, including the gonads, and the gene encoding its own receptor can be finely induced in selective ovarian compartments in both control and stressful conditions during the gonadal life cycle. The present study, therefore, investigated the influence of both gonadal function and estrous cycle on the immunoreactive CRF (irCRF) contents in the immature and adult rat ovary. In addition, the effect of an acute (5 min) or chronic intermittent (twice a day for 4 days) cold swimming stress on ovarian irCRF contents was evaluated. High-performance liquid chromatography (HPLC), gel-chromatography (Sephadex G-75, 45 x 1 cm) and a direct radioimmunoassay were performed to measure irCRF ovarian contents. The HPLC elution profile of irCRF in ovarian tissues of adult rats was superimposable on that of synthetic rat/human CRF and gel-chromatograms performed according to the phase of the estrous cycle revealed higher irCRF contents at proestrus. Total irCRF ovarian content was undetectable both in control and acute stressed immature rats, while adult rats showed the highest values at proestrus (p < 0.0001). The acute stress exposure induced a significant increase (p < 0.0001) of irCRF ovarian contents only at proestrus, without affecting irCRF at the other phases of the estrous cycle. Finally, no significant changes were found in ovarian irCRF after chronic intermittent stress. The proestrus-related changes of ovarian irCRF, confirming the adult ovary as an extrahypothalamic source of CRF, may constitute a neuropeptidergic signal involved in the gonadal reproductive cycle. Furthermore, the stress-related changes of ovarian irCRF indicated that the gonad may be locally sensitive to acute stressful stimuli. PMID- 8701791 TI - Prolactin response to metoclopramide and thyrotropin-releasing hormone in normoprolactinemic and hyperprolactinemic women: a comparison of diagnostic validity. AB - The objective was to define the diagnostic validity of prolactin response tests by comparing the stimulating effect of thyrotropin-releasing hormone (TRH) and metoclopramide on prolactin secretion in patients with and without functional hyperprolactinemia. Prolactin response studies were performed in 18 patients with functional hyperprolactinemia (defined as prolactin serum levels > or = 16 and < 50 ng/ml during the follicular phase without evidence of prolactinoma) and 18 controls with similar age who had normal serum prolactin levels. Tests were done on the 7th, 8th or 9th day of the follicular phase under standardized conditions (at 08.00-09.00, after a 1-h rest and overnight fasting) with 200 micrograms TRH or 10 mg metoclopramide i.v. After metoclopramide, higher maximal prolactin levels were observed in the study group as well as in the control group than after TRH (metoclopramide mean: 243 +/- 62 ng/ml vs. 181 +/- 100 ng/ml, U-test: p = 0.0019; TRH mean: 101 +/- 23 ng/ml vs. 41 +/- 20 ng/ml, U-test: p = 0.0001). There was no significant difference in the relative increment of prolactin serum levels between both groups, neither after metoclopramide nor after TRH (after metoclopramide, mean: 13.5 +/- 5.8 vs. 17.2 +/- 9.2, U-test: p = 0.137; after TRH, mean 3.6 +/- 1.1 vs. 3.8 +/- 1.9, U-test: p = 0.899). No correlation between prolactin basal and peak levels, either after TRH or after metoclopramide, could be found, neither in the study (metoclopramide test: p = 0.738; TRH test: p = 0.076) nor in the control group (metoclopramide test: p = 0.331; TRH test: p = 0.360). While significantly higher prolactin peaks were recorded after metoclopramide than after TRH in both groups, no difference in the response to TRH and metoclopramide, regarding absolute and relative increment, could be found. PMID- 8701792 TI - Relative resistance of a macroprolactinoma to bromocriptine therapy during pregnancy. AB - A woman presented with a pituitary macroadenoma with extensive suprasellar extension. Her initial response to bromocriptine therapy was good, allowing subsequent trans-sphenoidal surgical treatment. The tumor grew during pregnancy despite continued bromocriptine therapy, but it returned to prepregnancy size postdelivery. There have been conflicting reports regarding the growth of pituitary tumors in pregnancy. Most recognize that some growth may occur, but only a small percentage of patients are reported to become symptomatic from the growth. Resistance to bromocriptine has been reported in non-pregnant patients. Patients who have had surgery or radiation therapy and did not receive bromocriptine treatment during pregnancy have been reported to have symptomatic growth of their residual tumor. This case demonstrates an unusual tumor that became resistant to bromocriptine during pregnancy, but whose sensitivity to the drug returned postdelivery. PMID- 8701794 TI - Intracellular survival of protozoan parasites with special reference to Leishmania spp., Toxoplasma gondii and Trypanosoma cruzi. PMID- 8701793 TI - Role of leukotriene C4 in follicle-stimulating hormone (FSH) secretion in female rat pituitary. AB - Leukotriene C4, at doses of 0.01 and 0.1 nmol/l added to superfused cells in pulse of 4-min duration, evoked follicle-stimulating hormone (FSH) release up to 12- to 26-fold of basal secretion. Higher and lower concentrations of leukotriene C4 were not able to induce FSH secretion. Gonadotropin-releasing hormone (GnRH) induced FSH release was reduced by 38-57% by the leukotriene receptor antagonist FPL 55712 (10 mumol/l). Moreover, we have shown that FSH release occurs parallel to leukotriene C4 synthesis in rat anterior pituitary cells. Mellitin (100 nmol/l), an activator of phospholipase A2, induced FSH and radioactivity secretion in rat anterior pituitary cells previously preincubated for 24 h with [3H]arachidonic acid (AA). PMID- 8701795 TI - Mouse-parasite interactions: from gene to population. PMID- 8701796 TI - Detection, screening and community epidemiology of taeniid cestode zoonoses: cystic echinococcosis, alveolar echinococcosis and neurocysticercosis. PMID- 8701797 TI - Human strongyloidiasis. PMID- 8701798 TI - The Biology of the intestinal trematode Echinostoma caproni. PMID- 8701799 TI - Regulation of infectivity of Plasmodium to the mosquito vector. PMID- 8701800 TI - Nephrectomy for metastatic renal cell carcinoma and surgery for distant metastases. AB - Renal cell carcinoma has a very heterogeneous behavior. Nearly 30% of the patients are metastatic at the time of diagnosis and approximately 50% of the patients will develop metastases or recurrence after nephrectomy for an apparently localized disease. No prognostic factor is at the moment absolutely reliable in predicting the outcome for an individual patient. Nephrectomy in the presence of metastases is often performed by urologic surgeons in an attempt to prolong life or to improve the quality of life. Induction of spontaneous regression of metastases is very rare and it is still not proven that nephrectomy enhances the response to any systemic therapy. The resection of a solitary metastasis can be beneficial to a few patients although cure remains uncommon. Since no other effective treatment is actually available, metastasectomy can be advocated in a selected group of patients. PMID- 8701801 TI - Superficial bladder cancer--treatment approach. PMID- 8701802 TI - BCG treatment: current status. PMID- 8701803 TI - A combined analysis of EORTC/MRC randomized clinical trials for the prophylactic treatment of TaT1 bladder cancer. Eortc Genito-Urinary Tract Cancer Cooperative Group and the Medical Research Council Working Party on Superficial Bladder Cancer. PMID- 8701804 TI - Cytokines in superficial bladder cancer. PMID- 8701805 TI - Metastatic renal cell carcinoma: systemic treatment. PMID- 8701806 TI - Innovative approaches for superficial bladder tumors. PMID- 8701807 TI - Neo-adjuvant and adjuvant chemotherapy in locally advanced bladder cancer. PMID- 8701808 TI - Adjuvant chemotherapy for non-organ confined bladder transitional cell carcinoma. PMID- 8701809 TI - Neoadjuvant treatment for invasive bladder cancer: is it worthwhile? PMID- 8701810 TI - Chemotherapy for advanced bladder carcinoma: new molecules and regimens. PMID- 8701811 TI - New generation of prognostic factors in muscle invasive bladder cancer. PMID- 8701812 TI - Gene therapy. PMID- 8701813 TI - Molecular research in cancer: future clinical applications. PMID- 8701815 TI - Carcinoma of the prostate: neoadjuvant hormonotherapy followed by radiotherapy. PMID- 8701814 TI - Neoadjuvant hormonal deprivation in locally advanced prostate cancer: does it make sense? PMID- 8701816 TI - Adjuvant radiation therapy for pT3 prostate cancer. PMID- 8701817 TI - Prostate cancer--treatment of disseminated disease. PMID- 8701818 TI - Complete hormonal blockage--antiandrogens. PMID- 8701819 TI - Controversies surrounding hormonal deprivation. PMID- 8701820 TI - Canary-pox (ALVAC) virus-mediated cytokine gene therapy induces tumor specific and non-specific immunity against mouse prostate tumor. PMID- 8701821 TI - Carcinoma of the prostate: treatment of bone metastasis. PMID- 8701822 TI - Renal cell carcinoma (RCC). Place of chemotherapy either alone or in combination regimens. PMID- 8701823 TI - Intermittent androgen therapy. PMID- 8701824 TI - Quality of life and intermittent hormonal therapy. PMID- 8701826 TI - Neo-adjuvant and adjuvant treatment in penile squamous cell carcinoma. PMID- 8701825 TI - New molecules and treatment modulation in advanced prostatic cancer. PMID- 8701827 TI - 10 steps to keep the children in your practice nonsmokers. PMID- 8701828 TI - An approach to correction of hyperkalemia. PMID- 8701829 TI - Availability of part-time family practice faculty positions. PMID- 8701830 TI - Chiropractic therapy for relief of back pain. PMID- 8701831 TI - Management of patients with abnormal cervical cytology. PMID- 8701832 TI - Reliability of serum B12 levels in the diagnosis of B12 deficiency. PMID- 8701833 TI - Continuing family medicine's unique contribution to rural health care. PMID- 8701834 TI - Office evaluation of pulmonary function: beyond the numbers. AB - Pulmonary function testing is useful in evaluating dyspnea, wheezing and cough, determining the severity of pulmonary disease, monitoring the response to therapy and assessing preoperative pulmonary risk. Accurate office spirometry requires routine preventive maintenance, cleaning and calibration of equipment and quality control measures. To obtain a flow-volume loop, the seated or standing patient is instructed to inspire maximally to total lung capacity, exhale as hard, fast and completely as possible (forced vital capacity [FVC]), and inhale quickly and deeply to total lung capacity (TLC). Spirometry reveals both obstructive and restrictive airway disease. Obstruction is characterized by reduced forced expiratory volume in one second (FEV1) and FEV1/forced vital capacity (FEV1/FVC%), and normal to increased TLC and residual volume. Restriction is characterized by reduced TLC and residual volume and normal FEV1/FVC%. Spirometry may also reveal abnormalities of the upper airway, including the nasopharynx, vocal cords, trachea and proximal large airways. PMID- 8701835 TI - Home blood pressure monitoring. AB - Blood pressure measurements made in the physician's office have been the standard for diagnosing hypertension and determining the efficacy of antihypertensive drug therapy. However, these measurements do not necessarily reflect a patient's usual blood pressures in other circumstances, such as at work or in the home. Accurate blood pressure measurements performed by the patient or a family member in an out of-office setting can be integrated with office readings to assist in the management of hypertension. PMID- 8701836 TI - Diagnostic imaging to identify the cause of jaundice. AB - Imaging studies can be helpful in identifying the etiology of conjugated (direct) hyper-bilirubinemia. An elevated direct bilirubin level suggests obstructive jaundice, and ultrasound or computed tomographic (CT) imaging may identify the responsible structural lesion. Imaging can also be used to guide percutaneous biopsy. A cost-effective strategy for determining the cause of direct hyperbilirubinemia rests on ultrasound as the primary modality. Endoscopic retrograde cholangiopancreatography and CT are performed as follow-up studies only when necessary. Magnetic resonance imaging is rarely useful. PMID- 8701837 TI - Pyomyositis. AB - In the past, most cases of pyomyositis occurred among persons living in tropical climates, with the most common pathogen being Staphylococcus aureus. Increased numbers of cases have been reported more recently in North America, particularly in immunocompromised persons, such as those infected with the human immunodeficiency virus (HIV) and those with diabetes mellitus. These patients present with a wider variety of pathogens, including gram-negative bacteria, Streptococcus groups B, C and G, and Mycobacterium avium. Therefore, it seems prudent to consider pyomyositis in the differential diagnosis of persons with HIV infection, diabetes mellitus or other immunocompromising conditions, who present with persistent or worsening muscle aches and pains. Antibiotic treatment with a pencillinase-resistant penicillin is recommended for up to six weeks. PMID- 8701838 TI - Antiretroviral drug treatment for HIV/AIDS. AB - As new antiretroviral drugs for the treatment of human immunodeficiency virus (HIV) infection and new tests to measure HIV infection have become available, primary care clinicians now have more management options than ever before. Viral load measurements are becoming more accepted as a means of assessing HIV disease and estimating the efficacy of specific drug regimens. Clinical status changes also mark times to review antiretroviral regimens. Potential benefits of combination drug therapy, including the new protease inhibitor class of drugs, have added a new sense of optimism to the care of patients with HIV. Whether combination therapy and protease inhibitor treatment will live up to their promise by inducing better long-term clinical results remains to be seen. PMID- 8701839 TI - Evaluation of pediatric foot problems: Part I. The forefoot and the midfoot. AB - Foot problems in children can be the result of infection, trauma or overuse. Ingrown toenails, bunions, sesamoid disease, congenital overriding of the fifth toe, and fractures may occur in both adults and children. Some disorders, such as Freiberg's infarction and Kohler's disease, however, are unique to the pediatric population. The potential for adverse sequelae is greater in children than in adults. A thorough understanding of the anatomy of the pediatric foot and a systematic examination will facilitate the diagnosis of pediatric foot problems. A conservative approach to management will improve both compliance and outcome. PMID- 8701840 TI - Constipation in children. AB - Constipation is a common childhood condition, estimated to occur in 5 to 10 percent of children. In most cases, the cause is functional. However, constipation may occasionally indicate a significant organic disorder, which can usually be determined by a thorough history and physical examination. Constipation that is present from birth or that begins in the neonatal period is most likely to be congenital in origin. Acute constipation usually has an organic cause, while chronic constipation usually has a functional cause. Failure to thrive and gross distention of the abdomen suggest the diagnosis of Hirschsprung's disease. Rectal examination of a child with constipation usually reveals a distended rectum that is full of stool. In patients with Hirschsprung's disease, the rectum is usually empty and tight. Laboratory investigations are usually not necessary in patients with mild constipation. Treatment should be directed at the underlying cause. Functional constipation can be managed by changes in diet, regular bowel habits and, if necessary, pharmacologic therapy and biofeedback training. PMID- 8701841 TI - Assessment of the post-term pregnancy. AB - A post-term pregnancy is one that lasts beyond 42 weeks of confirmed gestational age. The goal of management in the post-term pregnancy is to avoid stillbirth, meconium aspiration and neonatal death. Ultrasonography obtained at term does not accurately predict gestational age. In pregnancies that progress beyond 41 weeks of confirmed gestational age, fetal well-being has been assessed by ultrasound evaluation of amniotic fluid volume, fetal breathing, fetal tone and fetal movement, in addition to nonstress testing. A definitive assessment plan for the post-term pregnancy should reduce the risk of maternal, fetal and neonatal morbidity. PMID- 8701842 TI - Maximizing function in Alzheimer's disease: what role for tacrine? AB - As the number of elderly persons continues to increase, family physicians will be caring for more patients with Alzheimer's disease. The treatment plan for patients with this incurable illness should be directed at optimizing their physical and psychosocial functioning and supporting their caregivers. Tacrine is the first medication proven to ameliorate the symptoms of Alzheimer's disease. This drug has been approved by the U.S. Food and Drug Administration for use in patients with mild to moderate Alzheimer's disease as evidenced by a score between 10 and 26 on the Mini-Mental State Examination. Tacrine can produce modest dose-related improvements in cognitive function and global measures of patient function. Such improvements only occur in 25 percent of patients treated with tacrine. On discontinuation of the drug, the patient's cognitive function returns to the level that would be expected if no treatment had been given. Both the degree of cognitive improvement and the severity of cholinergic symptoms increase with higher doses of tacrine. Thus, patients receiving tacrine therapy must be monitored for both clinical efficacy and adverse effects of the medication. PMID- 8701843 TI - Alcohol withdrawal syndrome. AB - Hundreds of thousands of significant alcohol withdrawal episodes are encountered by primary care physicians every year. If the situation is appreciated at an early stage, most patients can be managed successfully on an outpatient basis with benzodiazepines. Patients with seizures, concurrent medical illnesses and severe withdrawal signs should be hospitalized. Fewer than 5 percent of patients withdrawing from alcohol progress to delirium tremens. Mortality from delirium tremens has been reduced to less than 5 percent of patients, through early diagnosis, supportive nursing care, treatment of coexisting medical conditions and aggressive pharmacologic therapy. Patients with a history of multiple detoxification episodes are more likely to experience seizures and severe withdrawal symptoms. PMID- 8701845 TI - NIH develops consensus statement on the role of physical activity for cardiovascular health. PMID- 8701844 TI - Pharmacotherapy of urinary incontinence. AB - Aging is associated with many changes that may predispose an individual to urinary incontinence. An appropriate pharmacologic treatment plan depends on identification of the type of incontinence and minimization of aggravating factors. Stress incontinence is caused by incompetence of the internal urethral sphincter and is most common in postmenopausal women. This type of incontinence may respond to estrogen therapy and/or alpha-adrenergic agonists. Urge incontinence may occur in both men and women as a result of inappropriate detrusor muscle contraction. This condition may be treated with estrogens, anticholinergics or smooth muscle relaxants. Hypertonicity of the detrusor muscle, usually secondary to a neurologic problem, leads to overflow incontinence. Although overflow incontinence is difficult to control, cholinergic agonists and beta-adrenergic blockers may be helpful. Finally, any obstruction of bladder outflow may cause overflow incontinence and is best treated by amelioration of the cause. However, alpha-adrenergic blockers and 5-alpha reductase inhibitors may be useful in selected cases. PMID- 8701847 TI - Conditions of the musculoskeletal system. American Academy of Family Physicians. PMID- 8701846 TI - ACIP issues recommendations for the prevention and control of influenza in the 1996-97 season. PMID- 8701848 TI - Alterations in circulating intercellular adhesion molecule-1 and L-selectin: further evidence for chronic inflammation in ischemic heart disease. AB - Atherosclerosis is increasingly thought to be a chronic inflammatory disease. Inflammation requires transmigration of leukocytes from the circulation to the tissues. Adhesion of leukocytes to endothelial calls is the initial event in an inflammatory response and is mediated by expression of several adhesion molecules. In this study we characterize the contribution of intercellular adhesion molecules (ICAM-1) and L-selectin in patients with different coronary artery disease syndromes. Serum concentrations of cICAM-1 and sL-selectin were measured by enzyme-linked immunosorbent assay in 31 patients with stable angina, 30 patients with unstable angina, 18 patients with acute myocardial infarction and 20 healthy subjects in a control group. All patients underwent coronary angiography. Mean (+/-SE) cICAM-1 levels were higher (p < 0.05) in patients with stable angina (249 +/- 6 ng/ml), unstable angina (260 +/- 16 ng/ml), or acute myocardial infarction (261 +/- 24 ng/ml) compared with those in subjects in the control group (171 +/- 11 ng/ml). In contrast, levels of sL-selectin were lower (p < 0.01) in patients with stable angina (1.2 +/- 0.1 microg/ml), unstable angina (1.1 +/- 0.6 microg/ml), or acute myocardial infarction (1.1 +/- 0.1 microg/ml) compared with those in subjects in the control group (1.8 +/- 0.1 microg/ml). No difference was found in cICAM-1 or sL-selectin levels among patients with stable angina, unstable angina, or acute myocardial infarction. No correlation was seen between cICAM-1 or sL-selectin levels and extent (or severity) of coronary artery disease or leukocyte count. L-selectin expression was observed to be depressed in patients with severe angina compared with that in members of the control group. To examine the mechanism of reduction in sL selectin levels and L-selectin expression on leukocytes, leukocytes from the control group were stimulated in vitro. Stimulation of leukocytes resulted in a rapid downregulation of surface L-selectin expression, measured by flowcytometry, similar to the suppressed expression of L-selectin found on leukocytes from patients with coronary artery disease. In conclusion, altered cICAM-1 and sL selectin levels in patients with coronary artery disease reflect the presence of a chronic inflammatory process. This inflammatory process results in downregulation of leukocyte expression of L-selectin and thus lower circulating sL-selectin levels. PMID- 8701849 TI - Increased plasma levels of B-type natriuretic peptide in patients with unstable angina. AB - This study was designed to examine the plasma levels of B-type or brain natriuretic peptide (BNP), as well as A-type or atrial natriuretic peptide (ANP) in patients with unstable angina as compared with those in patients with stable exertional angina and control subjects. We measured the plasma levels of BNP and ANP in 33 patients with unstable angina, 20 patients with stable exertional angina, and 20 control subjects. The plasma levels of BNP were significantly increased in patients with unstable angina compared with those in patients with stable exertional angina and control subjects, respectively (39.5 +/- 29.4 pg/ml vs 15.1 +/- 8.0 pg/ml; p < 0.01 and 39.5 +/- 29.4 pg/ml vs 10.3 +/- 6.4 pg/ml; p < 0.01, respectively). On the other hand, there was no significant difference in the plasma levels of ANP among the three groups. Furthermore, in patients with unstable angina, the plasma levels of BNP decreased significantly after the medical treatment (from 39.5 +/- 29.4 pg/ml to 15.8 +/- 11.0 pg/ ml; p < 0.01), whereas the plasma levels of ANP did not change. We conclude that the plasma levels of BNP are increased in the majority of patients with unstable angina and that the increased levels decrease toward normal after treatment. PMID- 8701850 TI - Technetium 99m-Q12 kinetics in perfused rat myocardium: effects of hypoxia and low flow. AB - Technetium 99m-Q12 is a new cationic myocardial perfusion imaging agent that produces excellent images in human beings. The purpose of this study was to examine the separate effects of hypoxia and low flow on myocardial clearance kinetics. After a 1 mCi bolus injection, myocardial 99mTc-Q12 clearance was monitored for 1 hour by using an Nal detector in 24 isolated perfused rat hearts. In 6 control hearts, flow was 12 ml/min, and oxygenation was normal. In 6 hypoxic hearts, flow was normal, but oxygenation was reduced (<5% 02). In 6 low-flow hearts, flow was 3 ml/min, and oxygenation was normal. In 6 very low flow hearts, flow was 1 ml/min, and oxygenation was normal. 99mTc-Q12 myocardial clearance was biphasic in all four groups, consisting of a rapid early phase and a second slow phase that began after 10 minutes. Myocardial retention between 1 and 10 minutes was 56.8% +/- 1.8% for control, 49.2% +/- 2.2% (p < 0.05 compared with control) for hypoxic, 56.8% +/- 2.6% (p = NS compared with control) for low flow (3 ml/min), and 63.7% +/- 2.1 % (p < 0.05 compared with control) for very low flow hearts (1 ml/min). Myocardial retention between 10 and 60 minutes was 90.5% +/- 0.2% for control, 90.2% +/- 1.6% for hypoxic, 90.0% +/- 0.8% for low-flow hearts (3 ml/min), and 87.6% +/- 0.3% (p < 0.05 compared with other groups) for very low flow hearts (1 ml/min). In conclusion, 99mTc-012 demonstrates biphasic clearance from normal, hypoxic, low-flow, and very low flow ischemic myocardium. Early phase myocardial retention is decreased by hypoxia and increased by very low flow. PMID- 8701851 TI - Effect of parenteral d-sotalol on transvenous atrial defibrillation threshold in a canine model of atrial fibrillation. AB - In an effort to reduce energy requirements for atrial defibrillation to a level low enough to perform painless electrical cardioversion with an implantable atrial defibrillator, we tested the hypothesis that drug therapy with the class III agent d-sotalol, when used concurrently with a low-energy shock, reduces atrial defibrillation threshold. In a nonthoracotomy canine model of atrial fibrillation, intracardiac shocks were delivered between the distal coronary sinus and the mid-right atrium. Based on a step-up energy delivery protocol the atrial defibrillation threshold was defined as the least amount of energy that resulted in a >10% and <90% rate of successful defibrillation. At a dose associated with class III antiarrhythmic effects (5 mg/kg), d-sotalol significantly reduced atrial defibrillation threshold from 1.72 +/- 1.12 J to 0.59 +/- 0.60 J (p < 0.01). These results support the feasibility of using antiarrhythmic drug therapy with d-sotalol to minimize energy requirements for intracardiac electrical cardioversion of atrial fibrillation. PMID- 8701852 TI - Lack of proarrhythmia as assessed by Holter monitor after atrial radiofrequency ablation of supraventricular tachycardia in children. AB - The purpose of this study was to assess the short-term arrhythmogenicity of atrial radiofrequency (RF) ablation lesions in children. Patients with the greatest exposure to RF energy comprised the study group. Holter data on 35 RF ablation procedures in 31 patients with a median age of 13.2 years (range 3 months to 20 years) was retrospectively analyzed. Patients received an average of 19.9 (SD = 13.6) RF lesions, all delivered by an atrial approach. Supraventricular ectopy and ventricular ectopy were compared immediately before and after and 4 to 9 weeks after RF ablation by serial Holter monitoring. Factors thought to possibly predispose patients to a proarrhythmic effect were used to define subgroups for separate analysis. No increase in ambient supraventricular ectopy or ventricular ectopy was observed either immediately after or 4 to 9 weeks after RF ablation compared with the baseline Holter recordings. Children exposed to relatively large doses of RF energy may demonstrate transient and asymptomatic nonsustained tachycardias in the short term. However, no new sustained tachycardias and no increase in supraventricular or ventricular ambient ectopy are detected by short-term Holter monitoring. PMID- 8701853 TI - Long-term outcome after radiofrequency catheter ablation of atrioventricular nodal reentrant tachycardia with the anterior-approach method. AB - Previous studies have reported only short-term (6 to 10 months) follow-up after ablation of atrioventricular (AV) nodal reentrant tachycardia by using the anterior approach. The objective of this study was to determine the long-term efficacy and safety of radiofrequency catheter ablation of AV nodal reentrant tachycardia with the anterior-approach method. In 56 patients (16 men and 40 women; mean [+/-SD] age, 44 +/- 19 years) with symptomatic AV nodal reentrant tachycardia. In 53 patients, ablation was performed initially by using a standard 7F, 2 mm-tipped tripolar His bundle catheter when the large-tip electrode was not as available, and in the remaining 3 patients, ablation was performed with a 7F, 4 mm-tipped catheter. Ablation was successful in the short term in 53 (95%) patients after a median of 7 radiofrequency applications. Three (5%) patients developed complete AV block immediately after ablation. Six (11 %) patients had recurrence of tachycardia within 3 months (n = 5) and 13 months (n = 1) after ablation. Repeated ablation resulted in successful outcome in 4 patients and in complete AV block in 1 patient; the other patient refused a repeated ablation attempt. A total of 51 patients was monitored for 36 +/- 12 months (range, 25 to 72 months), and none had tachycardia recurrence or delayed AV block. In conclusion, our results show that the anterior approach to radiofrequency catheter ablation can be used successfully to treat patients with AV nodal reentrant tachycardia with a good long-term efficacy and safety. PMID- 8701854 TI - Vascular repair mechanisms after directional atherectomy or percutaneous transluminal coronary angioplasty in atherosclerotic rabbit iliac arteries. AB - Although directional atherectomy (DA) reduces the plaque burden, successful revascularization is not associated with a reduced restenosis rate when compared with percutaneous transluminal coronary angioplasty (PTCA). The purpose of this study was to compare and contrast the vascular response to DA-induced and PTCA induced injury. Six to 8 weeks after induction of atherosclerosis, PTCA (n = 34) was performed in one iliac artery and DA in the other (n = 30). Arteries were obtained at 6 time points: 1, 3, 5, 7, 14, and 28 days. Eleven arteries that did not undergo an intervention acted as controls. Radiograms obtained before and after intervention and at euthanization were compared. Morphometric, histologic, and immunohistochemical analyses were performed. Both PTCA and DA resulted in an immediate increase in luminal diameter that subsequently decreased over the ensuing month. PTCA caused deep dissection (7 of 8 arteries), often extending to the adventitia, whereas stand alone DA resulted in deep cleft formation (4 of 5). Of the 30 arteries that underwent DA, 4 exhibited an increase in luminal diameter in the absence of tissue retrieval. Thrombus was observed in both the dissection planes and the clefts within the first 7 days, and cellular ingrowth was appreciated at 5 to 7 days. By 7 days the artery was repaired, and the histologic appearance of the arteries that had undergone PTCA could not be differentiated from the arteries that had undergone DA. Increased intimal and medial collagen and elastin was noted at 14 and 28 days. An increase in the area bordered by the external elastic lamina was observed in both groups. Although successful DA results in tissue removal and the production of a deep tissue cleft and PTCA causes a dissection, both produce a condition in which the arterial injury exposes the arterial media to blood, causing thrombus formation and inflammation with subsequent cellular accumulation into the thrombotic framework. PMID- 8701856 TI - Quantitative assessment of stenotic aortic valve area by using intracardiac echocardiography: in vitro validation and initial in vivo illustration. AB - Quantitative assessment of aortic stenosis (AS) is subject to the limitations of all current noninvasive and invasive methods. The ability to obtain a direct measure of aortic valve area with high resolution by intracardiac echocardiography (ICE) could be of great benefit to catheterized patients. To provide a fixed AS area as an ideal standard for comparison, we performed ICE in 12 sheep hearts with experimentally created AS and five human AS hearts from autopsies. ICE catheters were passed retrograde across the aortic valve, and the minimal orifice area on pullback was planimetered and compared with calibrated video imaging. The entire orifice circumference could be successfully recorded in 16 (94%) hearts. Orifice area from ICE correlated well with actual values (r=0.98; standard error of the estimate [SEE] = 0.06 cm2). To illustrate the applicability in vivo, two canine models and 10 patients with AS were studied. The limiting orifice could be imaged in both animals and in 8 of 10 patients, in whom values agreed well with invasive data (r= 0.95; SEE = 0.04 cm2). ICE can therefore accurately measure AS orifice area in vitro; it can be applied in vivo as well. These validation studies laid the foundation for subsequent clinical studies and applications. PMID- 8701855 TI - Importance of assessing changes in ventricular response to atrial fibrillation during evaluation of new heart failure therapies: experience from trials of flosequinan. AB - This study evaluated the effects of flosequinan on ventricular rate in patients with congestive heart failure and atrial fibrillation to determine whether this agent has a facilitatory effect on atrioventricular conduction and whether such an effect may be deleterious. Flosequinan is known to have a dose-dependent positive chronotropic effect on the sinus node, but its effect on atrioventricular conduction has not been evaluated. An excessive increase in ventricular rate during the treatment of heart failure could raise a safety concern and counterbalance beneficial responses. Data were analyzed from 338 patients participating in three similarly designed placebo-controlled exercise trials with flosequinan who also underwent ambulatory electrocardiographic monitoring. The effects of two doses of flosequinan on supine, standing, ambulatory, and exercise heart rates and on exercise capacity in patients in sinus rhythm and atrial fibrillation were compared. Flosequinan increased heart rate in a dose-dependent manner, in patients both with sinus rhythm and atrial fibrillation. A 100 mg once daily dose produced significant increases, in both rhythms, ranging from 6 to 11 beats/min, in supine and standing heart rate, ambulatory heart rate, and exercise heart rate. With a dose of 75 mg twice daily, heart rates under these conditions increased by >20 beats/min in flosequinan treated patients in atrial fibrillation, a change significantly greater than that observed with placebo or flosequinan, 100 mg once daily and also more than in patients in sinus rhythm treated with the same dose. These results indicate that flosequinan facilitates atrioventricular nodal conduction, increasing the ventricular response in atrial fibrillation, especially at higher dosages. This finding could result from a direct drug action, such as phosphodiesterese inhibition, or reflex sympathetic activation. This response is of sufficient magnitude potentially to impair left ventricular function and interfere with clinical benefit. The effect of heart-failure drugs on ventricular responses in atrial fibrillation should be examined to provide insight into potential mechanisms of both action and safety in this common patient group. PMID- 8701857 TI - Spectrum of structural abnormalities in floppy mitral valve echocardiographic evaluation. AB - Posterior displacement of the mitral valve with billowing into the left atrium has been the major echocardiographic criterion used for the diagnosis of mitral valve prolapse (MVP). However, the current criteria are limited by the influence of hemodynamic factors on the degree of prolapse, whereas complications such as mitral regurgitation, endocarditis, and need for surgery have been associated with redundancy or thickening of the leaflets. Sixty-eight normal subjects (mean age, 40 years; range, 18 to 76 years) were compared with 58 patients with MVP (mean age, 37 years, range, 18 to 83 years). Leaflet displacement across the annular plane in the parasternal long-axis view was mandatory for the diagnosis of MVP. Transthoracic echocardiographic measurements of anterior and posterior leaflet thickness, leaflet length, and chordal length were made from the parasternal long-axis view and the mitral annular diameter, from the apical four chamber and two-chamber views. The MVP group had greater anterior thickness (4.1 +/- 0.4 mm vs 5.3 +/- 0.7 mm; p = 0.0001), posterior thickness (3.2 +/- 0.4 mm vs 4.7 +/- 0.9 mm; p = 0.0001), anterior length (22.8 +/- 2.0 mm vs 25.7 +/- 1.7 mm; p = 0.0001), posterior length (12.8 +/- 1.0 mm vs 15.7 +/- 2.5 mm; p = 0.0001), chordal length (25.6 +/- 2.7 mm vs 28.0 +/- 2.5 mm; p = 0.0001), and annular diameter (29.1 +/- 1.5 mm vs 31.3 +/- 2.6 mm; p = 0.0001). Of the MVP group, >80% had at least one abnormality identified and >50% had at least two abnormalities. In addition, patients with MVP with significant regurgitation had greater anterior thickness (5.2 +/- 0.7 mm vs 5.8 +/- 0.8 mm; p = 0.015), posterior thickness (4.5 +/- 0.9 mm vs 5.3 +/- 0.7 mm; p = 0.024), posterior length (15.1 +/- 1.6 mm vs 17.9 +/- 4.2 mm; p = 0.004), and annular diameter (36.0 +/- 2.0 mm vs 33.3 +/- 2.1 mm; p = 0.0001). The majority of patients with floppy mitral valves resulting in MVP have structural abnormalities that may be defined by echocardiography. A spectrum of floppy valve structure is demonstrated by echocardiography, with mitral regurgitation occurring more frequently in patients with multiple and more severe anatomic abnormalities. In addition to the presence of prolapse and regurgitation, the assessment of leaflet thickness, leaflet length, annular diameter, and chordal length is fundamental to the definition and stratification of patients with MVP associated with the floppy mitral valve. PMID- 8701858 TI - Electrocardiograms of Wolff-Parkinson-White syndrome simulating other conditions. PMID- 8701859 TI - Magnetic resonance imaging in ischemic heart disease. AB - The clinical use of MR imaging in ischemic heart disease is still limited, although this is the major cardiac disease afflicting populations of many countries. However, with the recent development of faster MR techniques, MR imaging provides multiple capabilities for the evaluation of most aspects of ischemic heart disease. We described the potential application of MR imaging for identifying and quantifying morphologic and functional alterations caused by myocardial infarction and ischemia; the contribution of MR contrast media to improve tissue characterization and to identify ischemic myocardium; and the application of fast MR imaging techniques for assessing anatomy and blood flow in the native coronary arteries and bypass conduits. With continued development of these capabilities, MR imaging has the potential to be a comprehensive noninvasive imaging modality in ischemic heart disease. PMID- 8701861 TI - Use of miniature biplane transesophageal echocardiography during pediatric atrial catheter interventional procedures. AB - We reported the use of a new miniature biplane TEE probe during pediatric cardiac interventional catheterization procedures. Use of this imaging modality provided significant advantages during dilation of obstructed venous pathways and closure of interatrial defects. Procedural characteristics and specific congenital heart lesion-related advantages were discussed. PMID- 8701860 TI - Epidemiologic assessment of angina before and after myocardial infarction: The Framingham study. AB - Angina pectoris before and after MI was evaluated in a sample of 729 men and women from a general population in whom MI developed during a 36-year period of follow-up. Relations of AP to subsequent CHD events and mortality after initial MI were analyzed by proportional hazards regression models and were adjusted for covariates (age, sex, blood pressure, serum cholesterol, body mass index, glucose intolerance, cigarette smoking, and antihypertensive medications) obtained from routine biennial examinations preceding the initial MI. Comparisons of the influence of angina were made between pre-MI angina, post-MI angina, and absence of AP. The sample had 484 men and 245 women (mean ages, 63 and 69, respectively) who survived greater than / equal to 30 days after MI. The initial MI was clinically unrecognized in 165 (34%) men and 115 (47%) women. Data on covariates were complete for 622 subjects, among whom 30% had pre-Ml angina, 18% had post-MI angina, and 52% did not have AP. Angina was half as common in persons with unrecognized MIs as in those with clinically recognized MIs. During an average of 8.7 years of follow-up, 57% of subjects developed subsequent CHD events, including recognized and unrecognized MI, coronary insufficiency, and CHD death, and 74% died. Both pre-MI angina (hazard ratio, 1.49; 95% CI, 1.17 to 1.91) and post-MI angina (hazard ratio, 1.43; 95% CI, 1.06 to 1.94) adjusted for accompanying risk factors were associated with increased risk for subsequent CHD events compared with those without AP. Neither pre-MI nor post-MI angina was associated with excess overall mortality. PMID- 8701862 TI - Early increase of vasoactive intestinal peptide in acute myocardial infarction. PMID- 8701863 TI - Multiple early percutaneous transluminal coronary angioplasty failures related to lupus anticoagulant. PMID- 8701864 TI - Bailout stenting for extensive dissection complicating direct infarct angioplasty. PMID- 8701865 TI - Verapamil-induced acute right heart failure. PMID- 8701866 TI - Recurrent syncope after successful aortic valve replacement. PMID- 8701867 TI - Nonhemorrhagic cardiac tamponade after penetrating chest trauma. PMID- 8701868 TI - Radiofrequency ablation of ventricular tachycardia in an infant with cardiac tumors. PMID- 8701869 TI - Treatment of spontaneous coronary artery dissection with intracoronary stenting. PMID- 8701870 TI - Endomyocardial biopsy in arrhythmogenic right ventricular cardiomyopathy. PMID- 8701871 TI - Coronary microvascular abnormalities in Chagas' disease. PMID- 8701872 TI - Preventive effects of probucol on restenosis after percutaneous transluminal coronary angioplasty. AB - This protocol was performed to elucidate the preventive effects of probucol on restenosis after percutaneous transluminal coronary angioplasty (PTCA). A total of 118 patients with 134 vessels undergoing successful PTCA was randomly and prospectively assigned to the probucol group (group P) or the control group (group C). The subjects consisted of 91 men and 27 women, with a mean age of 63.4 +/- 2.3 years. Sixty-six vessels of 59 patients in group P and 68 vessels of 59 patients in group C were evaluated by coronary angiography at 3 months after PTCA. Probucol (0.5 mg/day) was administered between >7 days before PTCA and 3 months after PTCA. The serum total cholesterol (TC) level and the formula low density lipoprotein cholesterol (formula LDL-C) in group P decreased from 203.8 +/- 43.1 to 169.6 +/- 39.4 mg/dl and from 131.4 +/- 0.7 to 108.7 +/- 2.5 mg/dl, whereas in group C, the levels decreased only from 202.3 +/- 32.1 to 194.2 +/- 29.8 mg/dl and from 129.2 +/- 38.1 to 124.3 +/- 31.7 mg/dl, respectively. The restenosis rate was significantly lower in group P (19.7%; 13 of 66 vessels) than in group C (39.7%; 27 of 68 vessels; p < 0.05). In group P, the probucol blood concentration was significantly higher in the subjects without restenosis (31 +/- 9 microg/ml) than in those with restenosis (18 +/- 8 microg/ml; p < 0.01), but the serum TC and formula LDL-C levels were not significantly different between these two groups. In summary, long-term administration of probucol significantly reduces the incidence of restenosis after PTCA. it was suggested that the mechanism of this preventive effect was not reducing the serum TC or formula LDL C levels, but rather an inhibitory action on smooth muscle cell proliferation. PMID- 8701873 TI - Intravascular imaging of serial changes of disease in saphenous vein grafts after coronary artery bypass grafting. AB - To clarify the structural changes of saphenous vein grafts after coronary artery bypass grafting, intravascular ultrasound and angioscopic images were obtained from 23 grafts in vivo and 5 grafts and 3 new veins in vitro; the images were compared with histologic findings. Intravascular ultrasound demonstrated a single layered appearance at new veins and all of the angiographically normal grafts within 6 months after surgery. A triple-layered appearance that might be related to the remarkably proliferative and degenerated intima was revealed histologically at 73.3% of the normal sites of grafts between 5 and 10 years after operation. In 83.3% of the stenoses at several years after operation, angioscopy showed yellow atheromatous plaques, often with a friable surface; a heterogeneous, lucent echo pattern was revealed on intravascular ultrasound. Thus intravascular ultrasound and angioscopy may be used to identify the morphologic changes of graft at different points after implantation more precisely than conventional angiography. PMID- 8701874 TI - Detection of regional perfusion abnormalities during adenosine stress echocardiography with intravenous perfluorocarbon-exposed sonicated dextrose albumin. AB - Although perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles produce myocardial contrast after intravenous injection, it is unknown whether their use can accurately identify myocardial blood-flow abnormalities during stress echocardiography. Accordingly, we compared the background-subtracted peak myocardial videointensity (PMVI) after intravenous injections of PESDA before and during adenosine stress (100 to 140 units/kg/min) in 10 open-chest dogs with angiographically significant left circumflex artery disease. The ratios of PMVI in the ischemic region compared with the adjacent normal left anterior descending perfusion bed were measured, as were wall-thickening and coronary-flow ratios. In the dogs with a >50% diameter stenosis, there was a decrease in PMVI ratio during adenosine stress by >0.20 in 9, whereas wall-thickening ratios decreased in only 5. PMVI in the ischemic zone increased by <1.5 units during adenosine infusion in 8 of 10 dogs, whereas it increased by >1.5 units in 8 of 1O adjacent normal zones. We conclude that regional myocardial-perfusion abnormalities can be detected with intravenous PESDA during adenosine stress echocardiography. PMID- 8701875 TI - Effect of percutaneous transluminal coronary angioplasty on exercise ventilation in patients with coronary artery disease and normal left ventricular function. AB - We evaluated the ventilatory response to exercise before and after percutaneous transluminal coronary angioplasty (PTCA) in 22 patients with coronary artery disease (CAD) and normal left ventricular systolic function to determine the effect of exercise-induced myocardial ischemia on the ventilatory response. Subjects performed a symptom-limited maximal ergometer exercise test in the sitting position. The ventilatory response was evaluated in terms of the slopes of minute ventilation (VE) and carbon dioxide production (VCO2) during exercise (slope 1 and slope 2, defined as below and above the respiratory compensation threshold, respectively). Slope 1 of the correlation between (VE) and (VCO2) was significantly greater in patients with CAD (27.3 +/- 2.6) than in the age-matched control group (23.7 +/- 2.6; p < 0.01). Slope 2 was also significantly greater in patients (41.0 +/- 4.8) than in the control group (29.7 +/- 2.9; p < 0.01). Slope 1 of the correlation between (VE) and (VCO2) decreased significantly in the 14 patients in whom PTCA was successful but did not decrease in the 8 patients in whom PTCA failed. Our results suggest that myocardial ischemia increases exercise ventilation in patients with CAD and normal left ventricular systolic function and that its effect is reversible. PMID- 8701876 TI - Myocardial integrated ultrasonic backscatter in patients with old myocardial infarction: comparison with radionuclide evaluation. AB - The purpose of our study was to clarify whether the abnormalities in integrated backscatter may be used to assess myocardial viability in patients with old myocardial infarction by comparing these integrated backscatter parameters with conventional radionuclide and echocardiographic estimates of myocardial viability. Two myocardial integrated backscatter parameters, the magnitude of cyclic variation in integrated backscatter and the myocardial integrated backscatter calibrated with the power of Doppler signals from the blood along the same ultrasound beam (calibrated myocardial integrated backscatter), were measured in 21 normal persons and 33 patients with old anteroseptal myocardial infarction. Calibrated myocardial integrated backscatter was higher and the magnitude of cyclic variation in integrated backscatter was lower in the infarct septum compared with the septum of normal subjects. Percent thallium uptake, as assessed in scintigraphic images taken at rest or after reinjection, correlated well with the calibrated myocardial integrated backscatter (r = -0.72, p < 0.01) and more weakly but significantly with the magnitude of cyclic variation in integrated backscatter (r = 0.55, p < 0.05) in 16 of 33 patients. The measurement of calibrated myocardial integrated backscatter, in addition to the magnitude of cyclic variation of integrated backscatter, may likely be valuable in the noninvasive assessment of myocardial viability. PMID- 8701877 TI - Effects of exercise training on left ventricular filling at rest and during exercise in patients with ischemic cardiomyopathy and severe left ventricular systolic dysfunction. AB - The aim of our study was to determine whether exercise training can augment left ventricular diastolic filling at rest and during exercise in patients with ischemic cardiomyopathy and whether any correlation exists between changes in diastolic filling and changes in exercise tolerance. Forty-three consecutive patients (mean age, 54 +/- 8 years) with ischemic cardiomyopathy and severe left ventricular systolic dysfunction (election fraction <30%) were studied. Group T (29 patients) was exercised on a cycle ergometer 3 times a week for 8 weeks at 60% of peak oxygen uptake. Group C (14 patients) was not exercised. All patients underwent an exercise test and a radionuclide ventriculography at baseline and after 8 weeks. At the end, no changes were found in group C. In group T, exercise training increased peak oxygen uptake (1 5%; p < 0.0001), work rate (1 5%; p < 0.005), peak early filling rate (10%; p < 0.02), and peak filling rate (1 1%; p < 0.03). At submaximal exercise, peak filling rate increased at all matched heart rates. The increase in peak filling rate was correlated with the increase in cardiac index (r= 0.72; p < 0.0001) at peak exercise. The independent predictors of the increase in peak oxygen uptake were changes in work capacity and peak early filling rate. The data demonstrate that exercise training can improve the exercise capacity of patients with ischemic cardiomyopathy and severe systolic dysfunction. The increase in early diastolic filling at rest and during exercise may contribute to the improvement in peak oxygen uptake. PMID- 8701878 TI - Benefit of converting enzyme inhibition on left ventricular volumes and ejection fraction in patients receiving beta-blockade after myocardial infarction. CONSENSUS II multiecho study group. AB - Beta-blockers reduce infarct size and improve survival after acute myocardial infarction (MI). Post-MI angiotensin-converting enzyme inhibition also improves survival and may attenuate left ventricular (LV) dilatation. We evaluated the effect of early enalapril treatment on LV volumes and ejection fraction (EF) in patients on concomitant beta-blockade after MI. Intravenous enalaprilat or placebo was administered <24 hours after MI and was continued orally for 6 months. LV volumes were assessed by echocardiography 3 +/- 2 days, 1 and 6 months after MI. Change in LV diastolic volume during the first month was attenuated with enalapril (2.7 vs placebo 6.5 ml/m2 change; p < 0.05), and significantly lower LV diastolic and systolic volumes were observed with enalapril treatment compared with placebo at 1 month (enalapril 47.21 23.9 vs placebo 53.1/29.2 ml/m2; p < 0.05) and at 6 months (enalapril 47.9/24.8 vs placebo 53.8/29.6 ml/m2; p < 0.05). EF was also significantly higher 1 month after MI in these patients (enalapril 50.4% vs placebo 46.4%; p < 0.05). Our date demonstrate that early enalapril treatment attenuates LV volume expansion and maintains lower LV volumes and higher EF in patients receiving concurrent beta-blockade after MI. A possible additive effect of combined therapy should be evaluated prospectively. PMID- 8701879 TI - Ventricular premature beat-driven intermittent restoration of coronary blood flow reduces the incidence of reperfusion-induced ventricular fibrillation in a cat model of regional ischemia. AB - With a cat model of regional cardiac ischemia, we examined whether the incidence of reperfusion-induced ventricular fibrillation (VF) could be reduced by ventricular premature beat (VPB)-driven intermittent reperfusion. In addition, we assessed whether the effect of the intermittent reperfusion was comparable with that of ischemic preconditioning in suppressing the VF. Of 15 cats subjected to uninterrupted reperfusion after 20-minute occlusion of the left anterior descending coronary artery, 13 (86.70%) had VF, whereas only 1 (7.1%) of 14 cats subjected to the VPB-driven intermittent reperfusion had VF. This incidence of VF was significantly lower than that of the animal group subjected to uninterrupted reperfusion. However, it was not statistically different from that (3 of 15) of the group subjected to a 10-minute episode of the coronary artery occlusion before the 20-minute occlusion (i.e., "ischermic preconditioning"). Our results suggest that the VPB-driven intermittent reperfusion (i.e., "postconditioning") is very effective in preventing reperfusion-induced VF and as good as, if not better than, ischemic preconditioning. PMID- 8701880 TI - Endothelin-1 and myocardial preconditioning. AB - This study attempted to define the role of endothelin (ET) in preconditioning. We previously showed that ET Is produced during myocardial ischemia and reperfusion. Because both preconditioning and ET act through protein kinase C, ET could play a role in preconditioning. Dogs were randomized to three groups subjected to 40 minutes of ischemia, with (groups A and B) or without (group C) preconditioning, followed by 4 hours of reperfusion. Groups A and C received saline infusions; group B received continuous infusions of the ETA-selective antagonist FR139317. Both preconditioned groups had smaller infarct sizes (group A, 7.9% +/- 2.5%; group B, 8.4% +/- 2.6%) than the nonpreconditioned group (group C, 16.2% +/- 3.3%). Administration of the ETA antagonist FR139317 did not alter infarct size. This study demonstrated that ETA-receptor blockade did not alter infarct size in preconditioned animals and suggests that endothelin does not play a significant role in this process. PMID- 8701881 TI - Band neutrophil count and the presence and severity of coronary atherosclerosis. AB - It has been consistently shown that the total blood leukocyte count is an independent risk factor for coronary artery disease. Few studies, however, have addressed the relation between differential leukocyte counts and coronary artery disease. We investigated the relation of total and differential leukocyte counts to angiographically determined coronary atherosclerosis. The study included 486 subjects (335 men, 151 women) who underwent coronary angiography for suspected coronary artery disease. Band neutrophil count was significantly positively related to coronary atherosclerosis (p = 0.004) after adjustments for age, sex, body mass index, cigarettes per day, serum total cholesterol, and hypertension. Although sex and age-adjusted total blood leukocyte count was significantly positively related to coronary atherosclerosis (p = 0.04), this relation did not reach significant levels (p = 0.08) after adjusting for other risk factors. The positive association with band neutrophil counts was at least as strong as that with serum total cholesterol concentrations. This study indicates that band neutrophil counts serve as an independent risk factor for coronary atherosclerosis. PMID- 8701882 TI - L-arginine decreases infarct size in rats exposed to environmental tobacco smoke. AB - This study examined the effects of L-arginine on myocardial infarct size, hemodynamics, and vascular reactivity in environmental tobacco smoke (ETS) exposed and non-ETS-exposed rats. We previously demonstrated that exposure to ETS increased myocardial infarct size in a rat model of ischemia and reperfusion. If reduced reperfusion was caused by endothelial cell damage and increased vascular tone, L-arginine (ARG) would increase nitric oxide and better protect the heart. Sixty Sprague-Dawley rats were randomly divided into four groups: ETS or non-ETS (control) with and without ARG (2.25% ARG in drinking water). The ETS groups were exposed to passive smoking (4 Marlboro cigarettes per 15 minutes, 6 hours a day) for 6 weeks. After 6 weeks, all rats were subjected to 35 minutes of left coronary artery occlusion and 120 minutes of reperfusion, with hemodynamic monitoring. Aortic rings were harvested to evaluate vascular reactivity. Average air nicotine, carbon monoxide, and total particulate concentrations were 1304 +/- 215 microgram/m3, 78 +/- 2.0 ppm, and 31 +/- .7 mg/m3 (mean +/- SEM) for the ETS exposed rats. Infarct size (infarct mass/risk area x 100%) increased with ETS exposure but decreased significantly in the ETS-with-ARG group compared with the ETS-without-ARG group (42% +/- 6% vs 64% +/- 6%, mean +/- SEM; p = 0.043). The benefit of ARG was dependent on ETS exposure (ETS x ARG interaction, p = 0.043). There were no significant differences between groups in heart rate, systolic pressure, and rate-pressure product. ARG significantly decreased myocardial infarct size after ischemia and reperfusion in ETS-exposed rats. Neither the adverse effects of ETS on infarct size nor the blockage of this effect by ARG appears to be the result of ETS-induced alterations in hemodynamics. PMID- 8701883 TI - Distal coronary flow velocity immediately after direct angioplasty for acute myocardial infarction. AB - To evaluate coronary flow dynamics after direct angioplasty and to define the determinants of flow-velocity variables in the infarct artery, we measured coronary flow velocity in 36 infarct arteries and 64 normal coronary arteries by using a Doppler guide wire. Flow-velocity variables in the infarct arteries did not return to normal even after successful direct angioplasty, and phasic coronary flow in infarct arteries varied considerably. Normal phasic flow was calculated as the ratio of diastolic to systolic flow ratio (DSVR) of greater than or equal to mean DSVR - 1 SD in normal coronary arteries. Infarct-related arteries were divided into two groups: normal DSVR (n = 28) and low DSVR (n = 8). Reduced diastolic peak velocity with a relative preservation of systolic velocity contributed to a low DSVR flow. Angiographic slow flow and late recanalization were significantly related to low DSVR flow. Thus the extent of disturbed microcirculation can be evaluated by assessing phasic flow after direct angioplasty for acute infarction. PMID- 8701884 TI - beta-Estradiol, but not alpha-estradiol, reduced myocardial necrosis in rabbits after ischemia and reperfusion. AB - Recent studies in several animal models have suggested that estrogen, given for the short term, may protect ischemic myocardium. Our objective was to test the effect of exogenous estradiol on the development of myocardial necrosis. Twenty minutes before coronary occlusion, rabbits were given an IV bolus of either 17 beta-estradiol, a form of the hormone that stimulates the estrogen receptor (10 micrograms) or 17 alpha-estradiol, a natural form of the hormone lacking estrogenic effects (1 mg), or vehicle. Regional myocardial blood flow (RMBF) was measured after treatment and during occlusion and reperfusion, and heart rate and blood pressure were monitored throughout. All rabbits underwent 30 minutes of coronary artery occlusion and 4 hours of reperfusion. Estradiol levels were 6 +/- 2 pg/ml in untreated rabbits, 392 +/- 78 pg/ml in rabbits given 17 beta estradiol, and 413 +/- 68 pg/ml in rabbits given 17 alpha-estradiol. The size of the ischemic region was similar in all groups, but rabbits treated with 17 beta estradiol developed significantly less necrosis than did control rabbits (0.33 +/ 0.04 vs 0.53 +/- 0.05 of the area at risk; p < 0.05), whereas rabbits treated with 17 alpha-estradiol did not (0.43 +/- 0.03; p = NS vs control group). Heart rate, systemic pressure, and RMBF were comparable among groups throughout the protocol. In conclusion, 17 beta-estradiol exerts a protective effect on ischemic myocardium, reducing infarct size. This beneficial effect is not associated with an increase in myocardial blood flow or alteration in hemodynamics. Because 17 alpha-estradiol did not affect infarct size, the cardioprotective effect of 17 beta-estradiol is probably receptor mediated. PMID- 8701885 TI - Comparison of elective Wiktor stent placement with conventional balloon angioplasty for new-onset lesions of the right coronary artery. AB - This study compared the clinical and angiographic outcome, during a 6-month follow-up period, of 84 patients with new-onset lesions of the right coronary artery randomized to either Wiktor stent implantation (42 patients) or conventional balloon angioplasty (42 patients). At hospital discharge, three patients in each group (7%, p = not significant [NS]) reached a clinical end point. At 6 months, these proportions were 24% (10 patients with stents) and 29% (12 patients with angioplasty) (p = NS). There were no incidents of death or myocardial infarction. Despite a larger minimal luminal diameter after stenting (2.87 mm [95% confidence interval; 2.66 to 2.96 mm] vs 2.37 mm [2.23 to 2.61 mm for angioplasty] [p = 0.001]), no difference was observed at 6 months of follow up (1.75 mm [1.43 to 2.18 mm] vs 1.74 mm [1.45 to 2.03 mm] [p = NS], respectively). Accordingly, angiographic restenosis rates were 47.5% (19 of 40 patients with stents) and 35% (14 of 40 patients with angioplasty) (p = NS). Elective stenting with the Wiktor stent and conventional balloon angioplasty are safe and immediately effective therapeutic options for symptomatic, obstructive right coronary artery disease. At 6 months of follow-up, clinical and angiographic outcome did not differ. The role of Wiktor stent placement in primary restenosis prevention remains to be determined for lesions of the right coronary artery. PMID- 8701886 TI - High serum concentration of lipoprotein(a) is a risk factor for restenosis after percutaneous transluminal coronary angioplasty in Japanese patients with single vessel disease. AB - To determine the relation between the concentration of lipoprotein(a) [Lp(a)] and restenosis after percutaneous transluminal coronary angioplasty (PTCA) in Japan, we studied 80 consecutive patients with single-vessel disease who successfully underwent PTCA. All were evaluated by follow-up angiography a mean of 6.9 months after PTCA and were divided into the restenosis (30 patients) and the non restenosis (50 patients) groups. The serum Lp(a) concentration of 29 +/- 17 mg/dl in the restenosis group was significantly higher than that of 17 +/- 14 mg/dl in the nonrestenosis group (p < 0.01). Multiple logistic regression analysis for risk factors revealed a significant correlation between restenosis and Lp(a) (p < 0.003). The serum Lp(a) concentration was positively correlated with the coronary artery percent stenosis at the time of follow-up angiography (r = 0.32, p < 0.01). High serum concentration of Lp(a) is therefore a risk factor for restenosis after PTCA in Japan. PMID- 8701887 TI - Characterization of spontaneous recurrent ventricular arrhythmias detected by electrogram-storing defibrillators in sudden cardiac death survivors with no inducible ventricular arrhythmias at baseline electrophysiologic testing. AB - This retrospective study characterized the recurring ventricular arrhythmias with an electrogram-storing defibrillator in survivors of sudden cardiac death who had no inducible sustained ventricular arrhythmias at baseline electrophysiologic testing (EPS). The study group was composed of 24 selected patients with documented ventricular fibrillation (VF) without need of revascularization or chronic antiarrhythmic therapy. The EPS protocol usually consisted of three extrastimuli at two drive cycles at two right ventricular sites. Nonischemic cardiomyopathy was the most frequent structural abnormality (n = 11) followed by coronary artery disease (n = 7). The mean ejection fraction was 0.37 +/- 0.13. Cardiac status did not appear to change during a mean follow-up period of 16.4 +/ 12.5 months, and eight (33%) patients received appropriate shocks in that time period. On the basis of intracardiac electrograms, 7 (88%) patients experienced VF and 1 (12%) patient had ventricular tachycardia as the first recurring arrhythmia. Four patients had additional recurrences and all were VF episodes. VF was usually present from the onset of the arrhythmia. In addition, 9 (38%) patients had nonsustained ventricular arrhythmias that were solely VF in 6 (67%). In conclusion, VF of sudden onset was the most frequent recurring sustained ventricular arrhythmia in this group. PMID- 8701888 TI - Reciprocating supraventricular tachycardia in children: low rate at rest as a major factor related to propensity to syncope during exercise. AB - Reciprocating supraventricular tachycardia may have several clinical presentations, with symptoms often more severe during exercise or emotional stress. This study shows by using transesophageal atrial pacing, the factors related to syncope during exercise. Between May 1989 and June 1994, transesophageal atrial pacing was performed at rest and during exercise in 75 children aged > 6 years with suspected or documented episodes of paroxysmal supraventricular tachycardia. Reciprocating supraventricular tachycardia could be induced both at rest and during exercise in 22 patients (8 girls, 14 boys; mean age 10.6 +/- 2.7 years, range 7 to 15 years) with ventriculoatrial interval < 70 msec in 11 patients and > 70 msec in 11. At rest, all patients had palpitations caused by the induction of tachycardia. After conversion to sinus rhythm, when tachycardia was induced during exercise, symptoms did not change in 14 patients (group A), whereas symptoms worsened (presyncope) in eight (group B). The statistical analysis showed a significant difference of mean reciprocating supraventricular tachycardia rate at rest between the two groups (group A, 211 +/ 23 beats/min; group B, 173 +/- 33 beats/min; p = 0.0057) and reciprocating supraventricular tachycardia rate variation from rest to exercise (group A, 62 +/ 18 beats/min; group B, 105 +/- 24 beats/min; p = 0.0001). These data suggest that children with low tachycardia rate during normal activities may have syncope more frequently, independently of the tachycardia rate during exercise or emotional stress. PMID- 8701889 TI - Characterization of left atrial appendage Doppler flow in atrial fibrillation and flutter by Fourier analysis. AB - The aim of this study was to characterize left atrial appendage mechanical function in atrial fibrillation and flutter by Fourier analysis to analyze frequency and regularity of flow. Left atrial appendage function is central to a patient's risk for thromboembolism. Although the function of the appendage can be analyzed by Doppler echocardiography in sinus rhythm, its mechanical function in atrial fibrillation and flutter has not been well characterized. This lack of adequate definition is caused by the complexity and temporal variability of the Doppler flow profiles. We assessed left atrial appendage function in 21 cases of atrial fibrillation (n - 11) and flutter (n = 10) and five in sinus rhythm with transesophageal Doppler echocardiography. Doppler profiles were examined by Fourier analysis, and the power spectra compared and analyzed between patients with atrial fibrillation and flutter. Left atrial appendage Doppler flow in atrial fibrillation produced Fourier spectra over a narrow band of frequencies with a peak frequency of 6.2 +/- 1.0 Hz, significantly higher than in atrial flutter (3.9 +/- 0.6 Hz, p < 0.00001). Additionally, a significant difference in subharmonic modulation (spectral power below the peak frequency) was observed between atrial appendage flow in atrial fibrillation and flutter, because 37% +/- 16% of the total spectral power was achieved before the dominant frequency in atrial fibrillation compared with 20% +/- 14% in atrial flutter (p = 0.02). Conversely, patients in sinus rhythm exhibited broad-banded Fourier spectra with most of the power in discrete frequency spikes at harmonics above the fundamental frequency with very little subharmonic modulation (1% +/- 0.05%). Left atrial appendage function in atrial fibrillation and flutter can be well characterized by Fourier analysis of Doppler flow. Atrial fibrillation has higher dominant frequencies and greater subharmonic modulation compared with flutter. Moreover, atrial fibrillation demonstrated quasiperiodic contraction patterns typically found in chaotic systems. Fourier analysis of left atrial appendage contraction patterns may therefore have significant promise in providing insights into mechanisms of atrial fibrillation and thromboembolism. PMID- 8701890 TI - Twenty-four-hour ambulatory electrocardiography in elderly subjects: prevalence of various arrhythmias and prognostic implications (report from the Bronx Longitudinal Aging Study). AB - Functional, ambulatory, community-dwelling subjects (n = 423, aged 75 to 85 years) underwent baseline 24-hour ambulatory electrocardiography (ECG) examinations as part of the Bronx Aging Study, a 10-year prospective cohort study designed to identify risk factors and disease markers for cardiovascular, cerebrovascular, and dementia illnesses in old people. Premature ventricular contractions were the most commonly observed arrhythmia noted (93% of subjects), with a low prevalence of nonsustained ventricular tachycardia (5%), paroxysmal atrial tachycardia (13%), atrial fibrillation (4%), and atrioventricular blocks (4%). A 24-hour sinus rate of < 60 beats/min was noted in 13% of subjects, and 11% of subjects were noted to have transient episodes of severe bradycardia (< 40 beats/min). In a multivariate analysis, nonsustained ventricular tachycardia was an independent predictor of death (p = 0.015; relative risk [RR] 2.8; 95% confidence interval [CI] 1.4 to 5.8) and myocardial infarction (p = 0.031; RR 3.2; CI 1.2 to 9.4). Transient atrioventricular block was an independent predictor of stroke (p - 0.0006; RR 9.7; CI 3.3 to 28.9), as was sinus bradycardia over a 24-hour period (p = 0.033; RR 2.7; CI 1.2 to 6.4). Ventricular tachycardia approached significance as an independent predictor of multiinfarct dementia (p = 0.052; RR 6.3; CI 1.4 to 28.7). Episodes of paroxysmal atrial fibrillation, a trial tachycardia, and severe bradycardia were not associated with adverse outcomes. Some arrhythmias found on the ambulatory ECG in very old subjects can predict an increased risk for subsequent death, myocardial infarction, stroke, and multiinfarct dementia. PMID- 8701891 TI - Potential clinical implications of abnormal myocardial perfusion patterns immediately after reperfusion in a canine model: a myocardial contrast echocardiography study. AB - During myocardial infarction, lack of myocardial opacification after reperfusion has been associated with poor or no recovery of function. We have previously documented the presence of perfusion abnormalities after brief coronary occlusions without infarction and the absence of perfusion abnormalities after prolonged occlusions with infarction. To characterize myocardial perfusion patterns immediately after reperfusion, we studied 53 animals in two groups in a coronary occlusion-reperfusion model. Temporary occlusions (group 1, 15 minutes; group 2, 30 to 360 minutes) were performed, followed by reperfusion with and without dobutamine. Myocardial contrast echocardiography was performed with aortic root injections of sonicated 5% serum human albumin (Albunex) during each intervention. Group 1 dogs showed no evidence of myocardial infarction. In group 2, 26 of 40 dogs had infarctions. After reperfusion, no perfusion abnormalities were seen in 13 of 26 group 2 dogs with infarctions; perfusion abnormalities were identified after reperfusion in 2 of 13 group 1 and in 8 of 14 group 2 dogs without infarctions. In animals subjected to prolonged ischemia, the absence of perfusion abnormalities after reperfusion did not rule out the presence of necrosis. Similarly, in animals without infarction subjected to ischemia, the presence of a perfusion defect after reperfusion did not represent the presence of necrosis but an abnormal microvascular reserve. These results suggest that early after reperfusion, assessment of perfusion by myocardial contrast echocardiography has significant limitations in the evaluation of myocardial viability and salvage. PMID- 8701892 TI - Bolus recombinant urokinase versus heparin in deep venous thrombosis: a randomized controlled trial. AB - Bolus urokinase (Abbokinase ) is effective for initial treatment of deep venous thrombosis but is associated with a high rate of rigors. This randomized controlled trial was undertaken among patients with deep venous thrombosis to evaluate the efficacy and safety of a novel thrombolytic agent, recombinant urokinase (rUK), administered as three bolus infusions of 1 million U over a 24 hour period versus heparin alone. Of 361 patients with DVT screened, 17 (5%) were enrolled. Recent surgery was the most common reason for exclusion (n = 113, 31%). Images of the patients were obtained at baseline, 24 to 48 hours after randomization, and before hospital discharge. Two patients in each treatment group had minor clot progression. One patient in the heparin group had no change; all other patients showed mild (< 50%; n = 5 in each group) or moderate (> 50%; n = 1 in each group) improvement. No bleeding complications or rigors developed in patients randomized to rUK. Mean bleeding times among patients given rUK were not significantly different from mean values of patients given heparin at any of the measured time points available for comparison (331 vs 387 seconds at baseline and 381 vs 416 seconds at 24 hours). However, mean fibrinogen levels declined with successive urokinase boluses and were significantly lower than levels in patients treated with heparin at 24 (233 mg/dl vs 466 mg/dl, p = 0.01) and 48 hours (270 mg/dl vs 474 mg/dl, p = 0.02). Although bolus rUK had a favorable safety profile, rUK was no more effective than heparin in achieving clot lysis at the doses used in this trial. PMID- 8701893 TI - Effects of aging per se on arterial stiffness: systemic and regional compliance in beagles. AB - Although previous studies have suggested that aging results in an increase in vascular stiffness, diseases that increase in prevalence with advanced age may have confounded the results of some of this past research. The purpose of this investigation was to determine whether aging per se results in reduced arterial compliance by using animals that are resistant to atherosclerosis and do not develop hypertension or hyperlipidemias with advanced age. We evaluated systemic and regional (femoral) arterial compliance in older (110 +/- 8 months old) and in younger (27 +/- 2 months old) female beagle dogs by using a computer-based assessment of the diastolic decay of arterial pressure waveforms and a modified Windkessel model of the circulation. Although systemic arterial pressure was very similar in both age groups, cardiac output was 29% lower (p = 0.03) and systemic vascular resistance was 24% higher (p = 0.02) in the older dogs. Moreover, there was an age-related reduction in systemic arterial compliance, derived both from the exponential decay in the arterial pulse (C1) (p = 0.05) and that derived from the oscillatory component of the diastolic pulse wave (C2) (p = 0.04). By contrast, although femoral vascular resistance was 25% higher in the older dogs (p = 0.04), regional (femoral) vascular compliance measured after femoral arterial occlusion was also 25% reduced but was not significantly changed with age (p = 0.14). These results demonstrate that systemic arterial compliance is reduced with age in dogs, extending this finding to animals without age-related diseases that frequently occur in older human beings. Regional compliance, evaluated in the isolated femoral vascular bed, also tends to be reduced with age, but variability in this parameter in dogs reduces the significance of this finding. PMID- 8701894 TI - Distortion of intravascular ultrasound images because of nonuniform angular velocity of mechanical-type transducers. AB - The purpose of this study was to quantify nonuniform rotation in a current mechanical intravascular ultrasound (IVUS) instrument and its effect on arc, area, and diameter measurements. The accurate reconstruction of IVUS two dimensional images is dependent on uniform rotation of the catheter tip. Prior investigations suggested that bends in the catheter driveshaft may be responsible for poor torque transmission, nonuniform rotation, and consequent errors in IVUS measurements. Eight 30 MHz mechanically driven IVUS catheters were evaluated in a model simulating the catheter course through the aorta and coronary ostium in a clinical study. Angular velocity and posi-ion profiles of the transducer, image angle, and diameter and area measurement errors were obtained from each catheter by imaging a vascular phantom with eight equispaced echogenic markers from concentric and eccentric positions. Six catheters also were tested for comparison in a simple curvature model. Rotational error was found in all catheters tested and worsened in the aortic model. Maximal angular error, defined as the largest angle between actual and presumed transducer direction, increased when measured in the aortic model as compared with the simple curvature model (17 +/- 12 degrees to 45 +/- 25 degrees; p < 0.05). Angles of 45 degrees were misrepresented with a mean range of values of 26 to 63 degrees. With eccentric catheter placement, area and diameters had average maximal absolute errors of 26% +/- 7.8% and 23% +/- 10%, respectively. In conclusion, nonuniform rotation of mechanical IVUS transducers constitutes a significant potential source of error in IVUS measurement of arcs of calcification, and lumen shape, area, and diameter. PMID- 8701895 TI - Doppler transesophageal echocardiographic determination of aortic valve area in adults with aortic stenosis. AB - Two-dimensional transesophageal echocardiography has been shown to be an accurate method of measuring aortic valve area in patients with aortic stenosis. The accuracy of Doppler transesophageal echocardiography for this purpose is unknown. Thus 86 consecutive adult patients (mean age 68 +/- 11 years) with calcific (n = 79) or congenital bicuspid (n = 7) AS were studied by biplane or multiplane transesophageal echocardiography. From the transgastric long-axis view, continuous wave Doppler of peak aortic valve velocity and pulsed Doppler of left ventricular outflow tract velocity were determined. Left ventricular outflow tract diameter was measured from a transesophageal echocardiography long-axis view, and cross-sectional area was calculated. Aortic valve area was calculated by the continuity equation. Two-dimensional transesophageal echocardiography was used to directly measure aortic valve area by planimetry of the minimal orifice from a short-axis view. Aortic valve area determination was less feasible by Doppler (62 of 86 patients, or 72%) versus two-dimensional transesophageal echocardiography (81 of 86 patients, or 94%; p < 0.0025) because of the inability to align the continuous wave Doppler beam with the aorta in 24 patients. The feasibility of obtaining aortic valve area by Doppler transesophageal echocardiography improved from the first 43 patients (24 of 43 patients, or 56%) to the latter 43 patients (38 of 43 patients, or 88%; p < 0.0025) and suggests a significant learning curve. In 62 patients, aortic valve area by Doppler and two dimensional transesophageal echocardiography did not differ (1.30 +/- 0.54 cm2 vs 1.23 +/- 0.46 cm2, p = not significant) and correlated well (r = 0.88; standard error of the estimate = 0.26 cm2; intercept = 0.02 cm2; slope = 1.04; p = 0.0001). Absolute and percent differences between aortic valve area measured by Doppler and two-dimensional transesophageal echocardiography were small (0.18 +/- 0.20 cm2 and 15% +/- 15%, respectively). Mild, moderate, and severe aortic stenosis by two-dimensional transesophageal echocardiography was correctly identified in 93% (28 of 30), 79% (15 of 19), and 77% (10 of 13) of patients by Doppler transesophageal echocardiography, respectively. Doppler transesophageal echocardiography is an accurate method to measure aortic valve area in patients with aortic stenosis and should complement two-dimensional transesophageal echocardiography. The feasibility of Doppler transesophageal echocardiography for aortic valve area determination has a significant learning curve. PMID- 8701896 TI - Combined rest and exercise electrocardiographic repolarization findings in relation to structural and functional abnormalities in asymptomatic aortic regurgitation. AB - The relationship of combined rest and exercise electrocardiographic (ECG) repolarization abnormalities to left ventricular geometry and function was examined in 48 patients with asymptomatic chronic pure aortic regurgitation and no recent use of digitalis. Echocardiographic and radionuclide cineangiographic findings were compared in groups defined by the presence or absence of the "strain" pattern of repolarization abnormality on the resting ECG and also by the presence or absence of standard positive repolarization changes during upright treadmill exercise ( > 0.1 mV additional horizontal or downsloping ST depression). These hierarchic groups demonstrated trends toward progressively abnormal left ventricular dimensions, mass, wall stress, and change in ejection fraction with exercise. Although the presence of the strain pattern on the resting ECG alone was most strongly correlated with underlying functional and geometric abnormalities, an abnormal exercise test response was independently associated with abnormal left ventricular systolic dimension. The large group of patients with no symptoms and normal resting repolarization had only 0% to 4% prevalences of markedly increased systolic dimension (> 55 mm), reduced ejection fraction at rest (< 45%), or reduced ejection fraction during exercise (< 40%), whereas the small group of patients with abnormal resting repolarization and a positive exercise test response had 50% to 83% prevalences of these findings. These data suggest a possible role for rest and exercise ECG in the serial evaluation of patients with aortic regurgitation. PMID- 8701897 TI - Relationship between severity of mitral regurgitation and prognosis of mitral valve prolapse: echocardiographic follow-up study. AB - We investigated the relation between the severity of mitral regurgitation and the development of complications and cardiac events by using two-dimensional and color Doppler echocardiography in 229 consecutive patients with mitral valve prolapse. The frequency of moderate and severe mitral regurgitation was significantly higher in patients with a prolapsed posterior leaflet (61%) than in patients with a prolapsed anterior leaflet (25%), and the older the patient, the greater the severity of mitral regurgitation. The occurrence of complications, such as atrial fibrillation, congestive heart failure, and chordal rupture, was significantly greater in prolapsed posterior leaflet cases than in prolapsed anterior leaflet cases, and the occurrence was closely associated with the degree of severity of mitral regurgitation. Multiple logistic regression analysis showed that the severity of mitral regurgitation is a strong prognostic indicator for developing complications. Furthermore in a subgroup of 49 patients tracked for a mean of 4.8 years, the new development of complications was significantly higher in patients who showed a progression in the severity of mitral regurgitation (52%) that in patients without progression in severity (8%). The initial severity of mitral regurgitation was related to the occurrence of cardiac events (mitral valve replacement, infective endocarditis, cerebral embolism and death). The data indicated that the progression of mitral regurgitation is closely associated with the development of complications and cardiac events and suggest that the severity of mitral regurgitation is an important prognostic indicator for the development of complications and cardiac events in patients with mitral valve prolapse. PMID- 8701898 TI - Immediate and long-term effect of mitral balloon valvotomy on left ventricular volume and systolic function in severe mitral stenosis. AB - To determine the immediate and long-term effect of mitral balloon valvotomy (MBV) on left ventricular (LV) volume and function, we studied 17 patients (mean age 27 +/- 9 years) with severe mitral stenosis undergoing MBV by cardiac catheterization and angiography before and immediately after MBV and at mean 12 months later. At baseline, LV end-diastolic volume index (EDVI) was reduced. Ten patients had EDVI < or = 55 ml/m2, and four patients (23.5%) had LV ejection fraction < 50%. EDVI increased from 60 +/- 17 ml/m2 to 66 +/- 17 ml/m2 (p < 0.05) immediately after MBV and increased further to 72 +/- 16 ml/m2 (p < 0.05) later. Stroke volume index increased from 34 +/- 10 ml/m2 to 41 +/- 12 ml/m2 (p < 0.05) immediately after MBV and increased further to 50 +/- 11 ml/m2 (p < 0.001) later. LV end diastolic pressure increased from 12 +/- 5 mm HG to 16 +/- 4 mm HG (p < 0.05) immediately after MBV and fell to 13 +/- Hg at follow-up. LV ejection fraction increased from 57 +/- 7% to 62 +/- 6% (p < 0.05) immediately after MBV and 71 +/- 8% later (p < 0.001). Mean systolic ejection rate increased from 82 +/ 35 ml/sec to 101 +/- 48 ml/sec (p < 0.05) immediately after and 165 +/- 81 ml/sec later (p < 0.05). Systemic vascular resistance fell from 1887 +/- 525 dyne/sec/cm-5 to 1280 +/- 231 dyne/sec/cm-5 (p < 0.001) at follow-up. We conclude that the LV end-diastolic volume and systolic function are reduced in patients with mitral stenosis, and the LV end-diastolic volume is increased immediately after MBV and continues to increase at follow-up 12 months later; the LV ejection performance improves after successful MBV because of an increase in end-diastolic LV volume (preload) and reduction of SVR. PMID- 8701899 TI - A novel inotropic vasodilator, OPC-18790, reduces myocardial oxygen consumption and improves mechanical efficiency with congestive heart failure. AB - We analyzed the left ventricular (LV) pressure-volume relation and obtained direct measurements of myocardial oxygen consumption (MVO2) before and after drug administration in 21 patients with New York Heart Association functional class II to III congestive heart failure to compare the mechanoenergetic effects of OPC 18790, a novel inotropic agent, and dobutamine. Pressure-volume data were obtained by the conductance method, and MVO2 measurements were obtained with a double-thermistor coronary sinus catheter before and after administration of OPC 18790 and dobutamine. The LV end-diastolic volume index decreased significantly without an increase in the heart rate after administration of OPC-18790, unlike that after administration of dobutamine. Both drugs significantly increased the LV contractility index (Emax) and caused similar improvements in ventricular arterial coupling. OPC-18790 significantly reduced MVo2, whereas dobutamine increased MVo2. The ratio of the pressure-volume area to myocardial oxygen consumption (PVA/MVo2) remained unchanged after administration of OPC-18790 and decreased after administration of dobutamine. The ratio of external work to the pressure-volume area (EW/PVA) was similarly increased by both drugs, resulting in an improvement in mechanical efficiency (EW/MVo2) with OPC-18790 (p < 0.05) and in a deterioration with dobutamine (p < 0.05). OPC-18790 had an energetic advantage over dobutamine in spite of its positive inotropic effect. Our findings suggest that OPC-18790 may be useful for the treatment of patients with congestive heart failure. PMID- 8701900 TI - Effects of beta-blockade with bisoprolol on heart rate variability in advanced heart failure: analysis of scatterplots of R-R intervals at selected heart rates. AB - The effect of beta-blockade on heart-rate variability was assessed at different heart rates in 52 patients with heart failure included in the randomized, placebo controlled, Cardiac Insufficiency Bisoprolol Study (CIBIS). Scatterplots of R-R intervals display beat-to-beat variability by plotting each R-R interval against the preceding interval. Scatterplot dispersion at different R-R intervals provides a measure of beat-to-beat heart-rate variability at different heart rates. A 24-hour Holter tape was performed at baseline and after 2 months of treatment with bisoprolol or matched placebo. Geometric measurements of scatterplots were used to determine beat-to-beat dispersion for different R-R intervals. Bisoprolol and placebo groups were well matched at base-line. After 2 months of treatment, bisoprolol significantly increased beat-to-beat variability at the longest R-R intervals (p < 0.05); however, there was no change in scatterplot dispersion at the shortest R-R intervals. This suggests that beta blockade increases parasympathetic or decreases sympathetic tone or both in heart failure patients only at the slowest heart rates. PMID- 8701901 TI - Volume-rendered, three-dimensional echocardiographic determination of the size, shape, and position of atrial septal defects: validation in an in vitro model. AB - Accurate evaluation of atrial septal defect (ASD) size and shape is very important for the selection of patients for transcatheter occlusion. The ability of volume-rendered, three-dimensional echocardiography (3DE) in displaying ASDs in a dynamic mode has been demonstrated; however, its accuracy in sizing ASDs is unknown. To assess this, we performed 3DE of 10 explanted pig hearts in which ASDs of various locations, sizes, and shapes had been experimentally created. From en face 3DE views of the atrial septum containing the defects, major and minor diameters of the defect were measured by a blinded observer, and these data were compared to direct anatomic measurements. The correlations between 3DE and anatomy for the major and minor ASD diameters were y = 0.83x + 3.4 (r = 0.97, p < 0.0001) and y = 0.92x + 1.3 (r = 0.92, p < 0.0001) respectively. The correlation between the measures for major and minor axis ratio was y = 1.06 x - 0.052, r = 0.91, p < 0.0002. Good agreement between both methods of measurements was demonstrated for all measurements. In addition, 3DE portrayed the location and shape of the defects accurately. Thus 3DE provides excellent visualization of ASD and is able to accurately define the size of the defects. These qualitative and quantitative capabilities enhance the clinical potential of this technique in the appraisal of ASDs for decisions regarding application of closure devices. PMID- 8701902 TI - Juxtaposition of the morphologically right atrial appendage in solitus and inversus atria: a study of 35 postmortem cases. AB - Juxtaposition of the atrial appendages has previously been classified positionally, left sided being more frequent than right sided. In our study of 35 postmortem cases, juxtaposition was analyzed morphologically for the first time. Juxtaposition of the morphologically right atrial appendage (JRAA) was always left sided with solitus atria (34 cases) but was right sided with inversus atria (1 case), the latter patient being the first documented case of JRAA with atrial inversion. Thus in patients with JRAA, the sidedness of the juxtaposition depends on the type of atrial situs that coexists. Frequent associated malformations included tricuspid valve anomalies (21 [60%] of 30), hypoplasia of the right ventricular sinus (26 [74%] of 35), and an abnormal conus (subaortic or bilateral) in 100%. Hypoplasia of the right ventricular sinus, plus malformation of the conus, appears to be important in the morphogenesis of JRAA. PMID- 8701903 TI - Juxtaposition of the morphologically left atrial appendage in solitus and inversus atria: a study of 18 postmortem cases. AB - Juxtaposition of the morphologically left atrial appendage (JLAA) was analyzed for the first time primarily morphologically, rather than primarily positionally. In a series of 18 postmortem cases, JLAA with solitus atria occurred in 16 (89%) cases, and JLAA with inversus atria was found in 2 (11%) cases. JLAA with solitus atria was always right-sided, whereas JLAA with inversus atria was left-sided. Thus the sidedness of the malposed (juxtaposed) LAA depended on the atrial situs, not on the type of ventricular loop (contrary to what was formerly thought). The anatomic features associated with JLAA are essentially the opposite of those with JRAA. JLAA was characterized by left atrial outlet obstruction (69%), left ventricular hypoplasia (67%), and aortic outflow tract obstruction (39%). JLAA usually has a hypoplastic left ventricle and normal conus, whereas JRAA typically has a hypoplastic right ventricle and abnormal conus. PMID- 8701904 TI - Feasibility and effectiveness of repeated balloon dilatation of restenosed congenital obstructions after previous balloon valvuloplasty/angioplasty. AB - Balloon dilatation of congenital stenotic lesions of the heart and great vessels has been used for more than a decade. Varying incidence of residual obstruction or recurrence, hereafter referred to as restenosis, has been observed at follow up. The purpose of this study was to evaluate the feasibility and effectiveness of repeated balloon dilatation of restenosed lesions after previous balloon dilatation for pulmonic (PS) and aortic (AS) stenosis and native aortic coarctation (AC). Neonates, infants, and children (n = 178) underwent balloon valvoplasty/angioplasty with reduction (p < 0.001) or peak-to-peak systolic pressure gradients from 91 +/- 41 (mean +/- SD) mm Hg to 25 +/- 19 mm Hg, from 70 +/- 20 mm Hg to 26 +/- 12 mm Hg, and from 48 +/- 17 mm Hg, to 11 +/- 9 mm Hg in patients with PS, AS, and AC, respectively. Repeated catheterization or echo Doppler studies or both were performed from 3 months to 5 years after initial balloon dilatation. Residual gradients at follow-up were 26 +/- 26 mm Hg, 34 +/- 20 mm Hg, and 16 +/- 15 mm Hg, respectively, for PS, AS, and AC and remained significantly lower (p < 0.01) compared with gradients before the balloon dilatation. However, when results of individual patients were scrutinized, 9 (11%) of 80 patients with PS, 6 (23%) of 26 patients with AS, and 16 (27%) of 60 patients with AC had restenosis, on the basis of standard criteria. Repeated balloon dilatation was performed with reduction (p < 0.05 to < 0.001) of peak-to peak gradients from 89 +/- 40 mm Hg to 38 +/- 20 mm Hg in 9 patients with PS, from 77 mm Hg to 13 mm Hg and 66 mm Hg to 6 mm Hg, respectively, in 2 patients with AS, and from 38 +/- 11 mm Hg to 10 +/- 6 mm Hg in 12 patients with AC. Echo Doppler studies, 2 to 6.5 years after repeated balloon dilatation, indicated excellent results, with residual peak instantaneous Doppler gradients of 24 +/- 13 mm Hg in PS, 43 +/- 20 mm Hg in AS, and 11 +/- 6 mm Hg in AC groups, respectively. This improvement is irrespective of the cause of restenosis after initial balloon valvuloplasty/angioplasty. From this experience, we conclude that repeated balloon dilatation is feasible and effective in relieving restenosis after initial balloon valvuloplasty/angioplasty. PMID- 8701905 TI - Progression of valvular aortic stenosis in adults: literature review and clinical implications. PMID- 8701906 TI - Remodeling cardiac rehabilitation into secondary prevention programs. PMID- 8701907 TI - Management of restenosis after coronary intervention. AB - Coronary restenosis has proven to be the "Achilles heel" of percutaneous coronary interventions, frequently leading to repeated procedures. The pathogenesis of restenosis can be divided into four phases: early elasic recoil (hours to days), mural thrombus formation (hours to days), neointimal proliferation and extracellular matrix formation (weeks), and chronic geometric arterial changes (months). Restenosis is device nonspecific except for intravascular stents, which can eliminate elastic recoil and prevent geometric vessel changes, leading to decreased restenosis. Of all antithrombotics tried so far, only an inhibitor of the platelet IIb/IIIa integrin, which may lead to early vessel wall passivation, has shown reduction of clinical restenosis. Trapidil (antiproliferative agent) and angiopeptin (somatostatin analog) have also resulted in improved restenosis rates. The field of local drug delivery is currently under investigation in association with radiation or molecular therapy. The current specific target of these approaches is the neointimal proliferation, especially because this is the most dominant mechanism of restenosis after stent placement. Evaluation of these novel methods is complex and interrelates the delivery system with the therapeutic agent administered. However, they provide the means for very specific and timely interruption of the pathogenic process that may lead to better understanding and, ultimately, elimination of restenosis. PMID- 8701908 TI - The Holmes heart: historic associations and pathologic anatomy. AB - In 1824, Andrew F. Holmes, later to become the first Dean of the Medical Faculty of McGill University, published the autopsy findings of a 21-year-old man who had died with chronic cyanosis and congestive heart failure. Autopsy revealed the first documented case of single ventricle. Reinspection and detailed photographs published for the first time show absence of the sinus (body or inflow tract) of the morphologically right ventricle (RV) and hence a single (unpaired) morphologically left ventricle (LV), double-inlet LV, infundibular outlet chamber (IOC), and normally related great arteries, with the pulmonary artery arising from the IOC and the aorta from the single LV. In view of its rarity, William Osler urged Maude Abbott to republish this case, which she did in 1901. Republication of the Holmes heart catalyzed the career of Maude Abbott, who then proceeded to become the world's authority on congenital heart disease until her death in 1940. PMID- 8701909 TI - Suppression of ventricular tachycardia by sotalol in myotonic dystrophy. PMID- 8701910 TI - Anomalous sinus node artery originating from the left main coronary artery. PMID- 8701911 TI - Exercise-induced neurocardiogenic syncope. PMID- 8701912 TI - Right atrial thrombus mimicking myxoma in a heart transplant recipient. PMID- 8701913 TI - Intramural left atrial hematoma complicating mitral annular calcification. PMID- 8701914 TI - Intravascular ultrasonographic characterization of calcification of the patent ductus arteriosus in adults. PMID- 8701915 TI - Training in cardiac catheterization at high-volume and low-volume centers: is there a difference in case mix? AB - Current guidelines recommend that cardiology trainees participate+ in a minimum of 100 cardiac catheterization procedures during their clinical training (volume minimum level 1 training). To examine the differences in case mix seen by cardiology trainees during their training in cardiac catheterization, we examined the first 100 cases done by two trainees at different hospitals. One hospital was a high-volume center performing > 5500 procedures/year, and the other was a low volume center performing < 1500 procedures/year. Demographic and clinical characteristics of the patients undergoing cardiac catheterization were similar at the two hospitals. Indications were also similar, with the only exception being a higher rate of urgent/emergent cases among patients seen at the low volume center (8% vs 1%). Minor differences in procedural techniques were present at the two hospitals, with the trainee at the high-volume center having more experience with arm cases (4% vs 0%) and left ventriculograms (77% vs 48%) and the trainee at the low-volume center having more experience with right-heart catheterizations (36% vs 11%) and temporary pacing wires (5% vs 2%). Neither trainee had significant experience with valvular or adult congenital heart disease (2%, low-volume center; 1%, high-volume center). These results suggest that current volume minimums may ensure relatively uniform case mix among physicians who are training in cardiac catheterization at different centers. However, training may be deficient in several areas such as valvular heart disease, congenital heart disease, and arm cases. PMID- 8701916 TI - Beneath the surface of the mud... PMID- 8701917 TI - Factor V R506Q gene mutation analysis by PCR-RFLP: optimization, comparison with functional testing for resistance to activated protein C, and establishment of cell line controls. AB - Resistance to activated protein C (APC) has been recently identified as a highly prevalent risk factor for the development of venous thrombosis. In the majority of cases, APC resistance correlates with the presence of a single point mutation in the factor V gene (FV R506Q). The mutation is present in 3% to 5% of the general population and in up to 50% of patients with a personal and family history of venous thrombosis. In the current study, the authors have optimized and implemented for clinical diagnosis a method for detection of FV R506Q using the polymerase chain reaction coupled with restriction fragment length polymorphism analysis (PCR-RFLP). Forty-one healthy adults and 139 patients referred for hypercoagulability testing were genotyped and their APC resistance ratios determined using commercially available reagents (COATEST APC Resistance Kit). Comparative analysis indicated that if functional APC resistance was defined as per manufacturer's guidelines, a significant number of individuals with a normal factor V genotype were categorized as APC resistant and conversely, a significant number of individuals heterozygous for FV R506Q were categorized as non-APC resistant. These results indicate that comparative functional and genotypic analyses in the individual clinical laboratory setting are critical for establishing normal ranges and cut-off values for functional APC resistance due to FV R506Q. To facilitate molecular evaluation of APC resistance, Epstein-Barr virus (EBV) immortalized B-lymphocyte cell lines were established from individuals heterozygous and homozygous for FV R506Q. PMID- 8701918 TI - Sensitivity and specificity of the APC resistance assay in detection of individuals with factor V Leiden. AB - Resistance to activated protein C (APC) is the most common cause of familial thrombophilia. The partial thromboplastin time (PTT)-based test for resistance to APC has been widely employed as a screening test for this disorder. However, the utility of this test for screening is not well characterized. More than 90% of patients with resistance to APC have the G1691A mutation in factor V (factor V Leiden). The authors studied the ability of a commercial APC resistance assay to correctly identify the factor V Leiden genotype in 130 individuals. At the recommended assay cut-off value of 2, the sensitivity of the APC resistance assay was 50%, with a specificity of 98%. Increasing the cut-off value increased the sensitivity but decreased the specificity of the test. Receiver operating characteristic (ROC) curve analysis indicated that the test was of intermediate utility. There was considerable overlap in APC ratios in the range of 2 to 3 between subjects with a normal factor V genotype and heterozygotes for factor V Leiden. The authors conclude that the APC resistance assay in its present form is not a useful screening test for factor V Leiden heterozygotes. Until the performance of this assay is improved, patients should have molecular diagnostic testing performed to determine their factor V Leiden status. PMID- 8701919 TI - Clinical laboratory investigation of the Sanofi ACCESS CK-MB procedure and comparison to electrophoresis and Abbott IMx. AB - This evaluation was undertaken to verify the application protocol for the CK-MB assay on the ACCESS Immunoassay Analyzer (Sanofi Diagnostics Pasteur, Chaska, MN). The results show that the ACCESS CK-MB assay total imprecision was 6.8% to 9.1%. Analytical linearity of the ACCESS CK-MB assay was excellent in the range of < 1-214 micrograms/L. A comparison of the ACCESS CK-MB assay with the IMx (Abbott Laboratories, Abbott Park, IL) method shows good correlation r = 0.990 (n = 108). Linear regression analysis yielded Y = 1.36X-0.3, Sx/y = 7.2. ACCESS CK MB values also correlated well with CK-MB by electrophoresis with r = 0.968 (n = 132). The linear regression equation for this comparison was Y = 1.08X + 1.4, Sx/y = 14.1. The expected non-myocardial infarction range of CK-MB determined by the ACCESS system was 1.3-9.4 micrograms/L (mean = 4.0, n = 58). The ACCESS CK-MB assay would appear to be rapid, precise and clinically useful. PMID- 8701920 TI - Cardiac troponin T is elevated in asymptomatic patients with chronic renal failure. AB - Patients with chronic renal failure (CRF) are at increased risk for myocardial events that are difficult to evaluate due to atypical symptoms and chronically elevated protein markers of cardiac damage. This study evaluated cardiac troponin T (cTnT), a sensitive marker of cardiac injury, in patients with CRF without myocardial infarction symptoms, and assessed potential causes for elevated cTnT. Blood was obtained from 38 patients with CRF immediately before hemodialysis and from 16 of them post-dialysis, from 21 peritoneal dialysis patients, 10 patients with CRF not on dialysis, 11 patients with cardiomyopathy, and 10 adolescent patients with CRF undergoing hemodialysis. Samples were analyzed for myoglobin, creatine kinase, creatine kinase isoenzyme-MB (CK-MB), lactate dehydrogenase, lactate dehydrogenase isoenzyme-1 (LD-1), and cTnT. Cardiac TnT was elevated in: 71% of patient with CRF undergoing hemodialysis with no significant differences between pre- and post-dialysis values, 57% of patients with CRF on peritoneal dialysis, 30% of patients with CRF without dialysis, 18% of patients with cardiomyopathy, and 20% of adolescent patients with CRF undergoing hemodialysis. Myoglobin was elevated in almost all patients with CRF undergoing hemodialysis and without dialysis, whereas CK-MB and LD-1 were rarely elevated. Cross-reacting dialyzable substances and myocardial stretch were not major causes for elevated cTnT. Until future studies clarify the etiology of elevated cTnT in patients with CRF, results should be interpreted cautiously. PMID- 8701921 TI - Recommendations for the reporting of resected large intestinal carcinomas. Association of Directors of Anatomic and Surgical Pathology. AB - The Association of Directors of Anatomic and Surgical Pathology (ADASP) has named several committees to develop recommendations regarding the content of the surgical pathology report for common malignant tumors. A committee of individuals with special interest and expertise write the recommendations, and they are reviewed and approved by the council of ADASP and subsequently by the entire membership. The recommendations have been divided into four major areas: (1) Items that provide an informative gross description; (2) Additional diagnostic features that are recommended to be included in every report if possible; (3) Optional features that may be included in the final report; and (4) A checklist. The purpose of these recommendations is to provide an informative report for the clinician. The recommendations are intended as suggestions and adherence to them is completely voluntary. In special clinical circumstances, the original recommendations may not be applicable. The recommendations are intended as an educational resource rather than a mandate. PMID- 8701922 TI - Precision, accuracy, and managed care implications of a hand-held whole blood analyzer in the prehospital setting. AB - Hand-held portable clinical analyzers permit the rapid measurement of whole blood electrolytes, glucose, blood urea nitrogen (BUN) and hematocrit. Knowledge of these values in the field might aid radio telemetry emergency department physicians in the field treatment and triage of patients. The purpose of this study was determine if the analyzer could function in the hostile prehospital environment. In phase 1, analyses of control electrolyte (n = 30) and hematocrit (n = 28) solutions were performed in a moving ambulance by paramedics to determine precision performance. The F-statistic was used to compare variances against reference values and no significant differences were found. In phase 2, prospective split-sample testing of 57 whole blood samples drawn in the field were analyzed on 2 machines by paramedics in a moving ambulance, and then again within 10 minutes of arrival at the receiving hospital emergency department. Regression analysis between ambulance and emergency department venues revealed high correlation (r) values: sodium (Na)+ (0.93), potassium (K)+ (0.99), chloride (Cl)- (0.89), BUN (0.99), glucose (0.99), hematocrit (0.95), and hemoglobin (0.92). A hand-held whole blood analyzer can be reliably used in the field to obtain blood chemistry and hematocrit values. There was excellent correlation between field and hospital emergency department values. Clinical pathologists extend their oversight and consider encouraging emergency physicians to obtain field blood chemistry values in research studies aimed at improving medical treatment and patient triage in the prehospital setting. We speculate that these results might be important to managed care groups because knowledge of blood chemistry values in the field might provide physicians with objective, criteria based data on which to triage patients to the emergency department, to an ambulatory care setting, or to a community health center with attendant cost savings. PMID- 8701923 TI - A practical approach to the laboratory diagnosis of dyslipidemia. AB - Disorders in lipoprotein metabolism (dyslipidemia) can result in premature atherosclerosis or pancreatitis. Dyslipidemias can be classified as hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, and low levels of high density lipoprotein (HDL) cholesterol. All of the dyslipidemias can be primary or secondary. Both elevated levels of low density lipoprotein cholesterol and decreased levels of HDL cholesterol predispose to premature atherosclerosis. Triglyceride levels greater than 1,000 mg/dL increase the risk for pancreatitis. In the appraisal of the dyslipidemias, measurement of serum cholesterol, triglycerides, HDL-cholesterol and obtaining the LDL cholesterol by Friedewald equation is usually sufficient in the majority of patients. However, in some cases, such as the diagnosis of the Type III dyslipidemia and when triglycerides are > or = 400 mg/dL, ultracentrifugation is required to determine the VLDL or LDL cholesterol. Lipoprotein electrophoresis can be useful in the diagnosis of Type III dyslipidemia (broad beta band) and also to detect chylomicrons. In young subjects with coronary artery disease with a normal LDL cholesterol an apolipoprotein B-100 level may be a useful test. In children and young adults with severe hypertriglyceridemia, measurement of lipoprotein lipase activity or assaying apolipoprotein C-II levels can be useful in elucidating the cause. Also, laboratory tests are useful in excluding a secondary cause of dyslipidemia (urinalysis, plasma creatinine, TSH, glucose, protein electrophoresis, alkaline phosphatase and transaminases). Thus, laboratory investigations play an important role in the management of dyslipidemia. PMID- 8701924 TI - Proliferation markers in breast carcinoma. PMID- 8701925 TI - Results of autopsy survey. PMID- 8701926 TI - Application of catalyzed signal amplification in immunodetection of gonadotropin subunits in clinically nonfunctioning pituitary adenomas. AB - Pituitary adenomas that are characterized by the absence of a particular clinical syndrome and the absence of excessive hormone secretion have been classified as nonfunctioning adenomas. Recent development of immunohistochemical analysis and hormonal assay have suggested that many of these tumors have function to secret the gonadotropin subunits. A novel procedure biotin amplification in immunohistochemistry, catalyzed signal amplification (CSA) has been reported recently. In this study, the authors applied this new method to tissues from 50 cases of clinically nonfunctioning adenomas. These cases had no evidence of endocrinological signs by hormone secretion. When the CSA system was applied in normal pituitary gland, each of subunits was positive even when the antibody was diluted 1:1,000,000, which is 1,000 folds of standard indirect immunoperoxidase method. Immunohistochemical staining by indirect immunohistochemical method revealed that all 50 adenomas were negative for all the anterior hormones, including growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH), beta-subunit of luteinizing hormone (LH beta), follicle-stimulating hormone (FSH beta), thyroid stimulating hormone (TSH beta), and a-subunit of glycoprotein (alpha SU). Using avidin-biotin complex (ABC) method, two cases were positive for FSH beta and four cases were positive for alpha SU, respectively, and the immunopositivities were observed weakly in scattered cells. By CSA system, 26 cases of 50 nonfunctioning adenoma were positive for FSH beta, 16 cases were positive for LH beta, and 29 cases were positive for alpha SU, respectively. The immunoreactivities were clearly observed in cytoplasm of many adenoma cells. This amplification procedure provides a means of greatly increasing the sensitivity of the immunohistochemistry including subunits of glycoproteins that are difficult to detect by previous indirect immunoperoxidase method or ABC method. This amplification procedure provides a great increase in the sensitivity of the immunohistochemistry for the detection of gonadotropin subunits and suggest that significant proportion of the nonfunctioning adenomas are gonadotropin subunit producing adenomas. PMID- 8701929 TI - The role of the hemostasis laboratory in cardiopulmonary bypass surgery. PMID- 8701927 TI - DNA ploidy, cell cycle kinetics, and low versus high grade atypia in endometrial hyperplasia. AB - There have been few studies of DNA ploidy and cell cycle kinetics in endometrial hyperplasia. The authors studied archival cases of proliferative endometrium, simple, complex and atypical endometrial hyperplasia and well, moderately, and poorly differentiated endometrial adenocarcinoma by flow cytometry and also evaluated the significance of the degree of cytologic atypia (low versus high) in endometrial hyperplasia relative to the occurrence of carcinoma. All proliferative endometria, all types of hyperplasia and well and moderately differentiated carcinomas were diploid. Two-thirds of poorly differentiated adenocarcinomas were aneuploid. Neither S-phase fractions or proliferative fractions (S+G2M) could distinguish among the different types of hyperplasia or predict which hyperplasias were associated with carcinomas. The degree of cytologic atypia in atypical hyperplasia was not predictive of the occurrence of carcinoma. Poorly differentiated carcinomas showed significant differences in DNA ploidy, S-phase, and proliferative fractions from endometrial hyperplasia and lower grade carcinoma. These results support the concept that there are two fundamentally different types of endometrial carcinoma. PMID- 8701928 TI - Secondary pericardial malignancies: a critical appraisal of the role of cytology, pericardial biopsy, and DNA ploidy analysis. AB - The authors studied 112 pericardial fluids (45 malignant, and 67 benign) from 63 men and 33 women. All cytologic (n = 112) and histologic (n = 61) specimens were reviewed. Statistical analysis was conducted in 61 paired cytology and histology specimens (45 malignant and 16 benign) and correlated with available ploidy analysis of fluid specimens (n = 34). In cases of malignancy (41 patients), the primary site was known in 34 patients, whereas no origin for metastatic disease was apparent in 3 patients. Pericardial cytology yielded the initial diagnosis in four patients. After careful review of all cytology and histology specimens, seven truly discrepant cases were noted, six of which had positive cytology. Tissue biopsy sampling error was the cause for such discrepancies. DNA diploidy obtained by flow cytometry correlated with benign cytology, whereas aneuploidy was associated with malignant cytology in a total of 32 of 34 cases (94%). Cytologically malignant effusions rendered diploid DNA in 2 of 10 cases (20%). In conclusion, cytology is the single most important parameter in the evaluation of secondary pericardial malignancy and should be considered the gold standard. Causes for false-negative cytologic diagnoses include scant cellularity and obscuring blood. Hence, careful screening is recommended. The low sensitivity of flow cytometric DNA analysis does not favor its routine use. PMID- 8701930 TI - Basal cell (monomorphic) and minimally pleomorphic adenomas of the salivary glands. Distinction from the solid (anaplastic) type of adenoid cystic carcinoma in fine-needle aspiration. AB - Cytologic features of the cell-stroma interface are useful in distinguishing between monomorphic adenomas of the basal cell type and adenoid cystic carcinoma. In basal cell adenomas, the collagenous stroma interdigitates with adjacent cells, whereas in adenoid cystic carcinoma, the two are separated by a sharp smooth border. Furthermore, the stroma of basal cell adenomas can contain rare spindle cells or capillaries, but the cylinders of adenoid cystic carcinoma are acellular. The authors review their experience with five cases of basal cell adenoma, and three cases that were designated "minimally pleomorphic adenomas." The latter group showed the small blue cell pattern of basal cell adenoma at the time of fine-needle aspiration, and histology revealed only small foci of typical pleomorphic adenoma. With the exception of one cystic case, the cell-stroma interface of basal cell adenoma was observed in all eight cases. These cases are contrasted with three adenoid cystic carcinomas with extensive solid (anaplastic) areas. All showed the small blue cell pattern and cell-stroma interface features of basal cell adenoma. Neither showed the smooth-bordered cylinders of adenoid cystic carcinoma. Two of these three were incorrectly interpreted as benign at the time of fine-needle aspiration. The authors suggest that the stroma aspirated from solid adenoid cystic carcinoma represents desmoplastic tumor stroma that mimics the pattern of basal cell adenoma in smear material. Distinction between basal cell adenoma and the solid type of adenoid cystic carcinoma at the time of fine-needle aspiration remains a very difficult problem. PMID- 8701931 TI - The differential expression of a novel intestinal epithelial glycoprotein in various forms of inflammatory bowel disease. AB - A13D8 is a monoclonal IgM antibody that identifies an as yet unknown antigen that is expressed intensely and ubiquitously in enterocytes. Immunohistochemically, it was shown that A13D8 has a granular supranuclear staining pattern in columnar epithelial cells of normal small intestine and the colon. In ulcerative colitis, this staining pattern was retained. However, during active inflammation, staining also was evident in goblet cells. To test whether this feature of goblet cell staining was unique to ulcerative colitis, tissue sections from a variety of colitides were examined. Crohn's disease, infectious colitis, and ischemic colitis had similar staining patterns to that seen with ulcerative colitis. There was significantly more inflammation in the biopsies from patients with ulcerative colitis and Crohn's disease with positive goblet cell staining than in the biopsies from those patients with negative goblet cell staining. Almost all positive goblet cell staining in ulcerative colitis and Crohn's disease occurred in biopsies that were actively inflamed, whereas there was rare staining in biopsies that were noninflamed (regardless of whether or not there was active inflammation elsewhere in the colon). Ileal goblet cells stained positively with A13D8 only in cases of active ileitis. In cases of collagenous colitis, with comparable degrees of inflammation to that seen in ulcerative colitis and Crohn's disease, there was rarely goblet cell staining and in graft-versus-host disease goblet cell staining of A13D8 was not observed. The binding of A13D8 to tissue sections was completely inhibited by N-acetyl-D-galactosamine. These results, in conjunction with immunochemical studies, suggest that the antibody recognizes an N-acetyl-D galactosamine-containing epitope on a glycoprotein(s). In conclusion, these data suggest that A13D8 recognizes a glycoprotein expressed by intestinal columnar epithelial cells and during specific inflammatory states, particularly those associated with a neutrophilic infiltrate, becomes evident in goblet cells. Further work is required to establish the exact nature of this molecule and whether it is a pro- or anti-inflammatory factor. PMID- 8701932 TI - Human papillomavirus types 16 and 18 infection in infiltrating adenocarcinoma of the cervix: PCR analysis of 138 cases and correlation with histologic type and grade. AB - The authors investigated by PCR 138 infiltrating cervical adenocarcinoma (27 grade 1, 76 grade 2, and 35 grade 3) for the presence of human papillomavirus (HPV) 16 and 18 infection. They included 95 (68.8%) mucinous and 43(31.2%) non mucinous tumors. The overall prevalence of HPV infection was 84.8%; 28.3% of the cases were positive for HPV 16, 29.7% for HPV 18, and 26.8% for both HPVs. Amplification of HPV 16 and 18 negative cases with consensus primers MY09/MY11 failed to yield any additional tumors with HPV DNA sequences. Patients with HPV infection were younger than the patients who were HPV-negative (P = .001). The type of HPV was unrelated to age. Human papillomavirus infection was found in 95.8% mucinous and in 60.5% non-mucinous tumors (P < .001), with even distribution among grade 1, 2 and 3 adenocarcinoma. Our findings confirm the key role of HPV 16 and 18 in the development of cervical adenocarcinoma, particularly in mucinous histotypes. The absence of HPV infection, the old age of patients and the non-mucinous differentiation may identify a subset of cervical adenocarcinoma with different etiopathogenesis. PMID- 8701933 TI - Neutrophil nuclear segmentation in mild cobalamin deficiency: relation to metabolic tests of cobalamin status and observations on ethnic differences in neutrophil segmentation. AB - Neutrophil hypersegmentation is considered the most sensitive peripheral blood cell marker of cobalamin deficiency. However, its diagnostic value in the mild deficiency states that accompany most low cobalamin levels and its relation to metabolic test of cobalamin status are unknown. The authors compared neutrophil lobe averages and percent neutrophils with 5 or more lobes (%5+ lobes) in 169 subjects with their mean corpuscular volume (MCV) and serum cobalamin, methylmalonic acid (MMA), homocysteine, and folate levels and, in 65 cases, with the deoxyuridine suppression test (dUST). Only 9 subjects had hypersegmentation by lobe average and 20 subjects by %5+ lobes. They were not more often cobalamin deficient than subjects without hypersegmentation. Moreover, only one of 34 subjects with dUST results diagnostic for cobalamin deficiency had neutrophil hypersegmentation. Both indices of neutrophil segmentation in the 169 subjects correlated significantly with homocysteine levels. They also showed weak inverse correlation with cobalamin levels, but did not correlate with MMA, folate, or MCV values. Cobalamin therapy for 6 months did not significantly change neutrophil lobe averages in 35 subjects with mild deficiency, compared with 8 nondeficient controls, and only marginally improved the %5+ lobes. A surprising, incidental observation was that blacks had significantly greater neutrophil segmentation by both criteria than did whites and others. This difference was unrelated to cobalamin or folate status. Our results indicate that dUST abnormalities precede all morphologic changes of deficiency, including hypersegmentation. Although a tendency exists for neutrophil segmentation to increase very slightly as some serum values, especially homocysteine, start to worsen in mild cobalamin deficiency, the metabolic changes precede overt hypersegmentation. Neutrophil nuclear segmentation is insufficiently sensitive in relation to metabolic evidence of deficiency to be used as a clinical tool in the diagnosis of mild cobalamin deficiency. PMID- 8701934 TI - Use of irradiated blood components: practice parameter. AB - Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare but fatal potential complication of transfusions. It is mediated by immunocompetent donor lymphocytes that cannot be eliminated by the recipient. Patients at risk for developing TA-GVHD are those who have a profound deficiency in cell-mediated immunity or those who share histocompatibility antigens with the donor and do not recognize the donor cells as foreign. Irradiation of cellular blood components is currently the only acceptable method for prevention of TA-GVHD. This practice guideline identifies the patient population who should receive irradiated blood components and describes the technical aspects of blood component irradiation that may affect the safety of the final product. PMID- 8701935 TI - Characterization of myeloma cells by means of labeling index, bone marrow histology, and serum beta 2-microglobulin. AB - The relationship between two cellular prognostic parameters of multiple myeloma, the plasma cell labeling index (LI%) and bone marrow histology was studied. The LI% as the percentage of monoclonal plasma cells in the S-phase was measured by bromodeoxyuridine incorporation using the anti-bromodeoxyuridine antibody BU-1. The histologic classification was based on six plasma cell types that allow prognostic grading as the Marschalko, small cell, cleaved, polymorphous, asynchronous, and blastic types. The biopsies also were used for estimating the degree of infiltration. Beta 2-microglobulin (IMx assay, Abbott, North Chicago, IL), the most significant serum parameter for myeloma also was measured for comparison. Bone marrow specimens and sera were obtained from 50 myeloma patients. Fourteen patients with smoldering myeloma were characterized by well differentiated Marschalko or small cell type cells, a low LI% and a low beta 2 microglobulin concentration. Considering all myeloma patients, plasma cell type and degree of infiltration showed a significant correlation with LI% and beta 2 microglobulin concentration. Patients with plasma cells that were not mature cells of the Marschalko or small cell type revealed a high LI% or high beta 2 microglobulin level in 16 of 19 cases. However, a high LI% or high beta 2 microglobulin level could be detected in only 8 of 31 patients with plasma cells of the Marschalko or small cell type. Three of 21 stage I patients did not show the typical finding of a low LI%, low beta 2-microglobulin level, and a favorable grade. Stage II patients were not uniformly characterized by LI%, beta 2 microglobulin and plasma cell morphology. The percentage of nucleolated plasma cells was not associated with the LI%. Bone marrow histology, LI%, and beta 2 microglobulin concentration appear to be supplementary prognostic factors. If LI% and beta 2-microglobulin levels are not measured, a higher risk could be overlooked in cases with mature plasma cells. PMID- 8701937 TI - CD20 (pan-B cell antigen) expression on bone marrow-derived T cells. AB - Antibodies directed against CD20 (L26, Leu 16, and B1) are frequently used to determine the presence of B lymphocytes. However, recent publications describe the unexpected presence of CD20-positive T cells in the peripheral blood of normal subjects and occasional T-cell neoplasms that express CD20. To determine the presence of CD20-positive T cells in bone marrow, flow cytometric analysis was performed on 34 aspirate specimens (14 normal, 5 acute lymphoblastic lymphoma [ALL], 5 acute myelogenous leukemia [AML], 4 HIV positive, 2 myelodysplastic/myeloproliferative, 2 chronic myelogenous leukemia [CML], 1 chronic lymphocytic lymphoma [CLL], 1 multiple myeloma). A small population of cells coexpressing CD3 (Leu 4) and CD20dim (Leu 16) was identified in 94% of the specimens, representing 0% to 11% (mean 1.77%) of marrow mononuclear cells and 0% to 22.2% (mean 6.54%) of marrow lymphoid cells. There was no correlation between the percentage of CD20-positive T cells and the CD4:CD8 ratio, patient age, gender, or diagnosis. CD20dim positive cells included immature B cells and CD20 positive T cells. Although evaluation of CD20 expression is useful in delineating B-cell processes, caution should be exercised in interpreting its expression on bone marrow T-lymphoid cells. CD20 expression on T cells may be seen in either normal, reactive, or neoplastic processes. PMID- 8701936 TI - Angiocentric immunoproliferative lesions of the lymph node. AB - Clinicopathologic features in 14 cases of lymph node-involved angiocentric immunoproliferative lesions (AILs) are reported. They were selected from 900 cases of lymphoproliferative disorders registered at the Department of Pathology, Fukuoka University. Four cases showed a histologic feature of AIL grade II (AIL II) and 10 had angiocentric lymphoma (AIL-III). Immunohistologically, transformed B cells were mixed with a large number of small T cells in AIL-II. In AIL-III, there were five cases with B-cell lymphoma, and three had peripheral T-cell lymphoma with no expression of natural-killer (NK)-associated antigens. In the remaining two cases, lymphoma cells expressed both T-cell- and NK-associated antigens. These findings indicate that lymph node-involved AILs are rarely occurring (1.6%) and phenotypically different from sinonasal and cutaneous AILs. Furthermore, NK-associated antigen-positive AILs were found to rarely involve the lymph node. For Epstein-Barr virus (EBV) infection, seven cases of AILs showed many atypical lymphocytes that were positive for EBV-encoded RNA (EBER-1) by using the in situ hybridization analysis. Among them, six cases had latent membrane protein (LMP) positive and EBV nuclear antigen 2 (EBNA-2) negative atypical lymphocytes. The pattern of latent EBV infection was similar to that of Hodgkin's disease, but differed from those of sinonasal T-cell lymphoma and other subtypes of non-Hodgkin's lymphoma. Clinically, 12 patients, including all 4 AIL II, died within 22 months of the onset of the disease, despite intensive therapy, suggesting that lymph node-involved AILs have a poor prognosis. PMID- 8701938 TI - A survey of current practices in clinical flow cytometry. AB - In mid-1995, a 40-question survey was distributed to determine the current practices of clinical flow cytometry laboratories. Forty-seven responses were received. Included in the survey were questions regarding the affiliation and size of the laboratory, the qualifications of the staff, the nature and number of assays performed, whether laboratory resources and specimen loads were changing, and how data were analyzed and interpreted. The results indicate considerable variability in many aspects of clinical cytometry, such as number of markers used for immunophenotyping leukemias and lymphomas, types of specimens analyzed for DNA-ploidy, and charges for specific tests. PMID- 8701940 TI - Prenatal and molecular diagnosis of hemophilia B. AB - Prenatal diagnosis was carried out on a woman who had previously given birth to a son with a spontaneous mutation of C-->T transition at nt 31133 of the factor IX (F.IX) gene. The diagnosis was performed on chorionic villi sampling by the method of amplification-created restriction site (ACRS). It revealed a female fetus with a normal F.IX gene, as confirmed by DNA sequencing after delivery. Meanwhile, a survey using the ACRS method to evaluate the inheritance of 63 individuals from 8 hemophilia B families was done. A different single-point mutation in each family was proved by DNA sequencing. One individual had a mutation with a naturally-created restriction site. In each of the remaining patients, we were able to show an enzyme-cutting site in their DNA amplification product for ACRS with the designed mutagenesis primers. All patients and carriers could be diagnosed accurately by comparing ACRS results with clinical and laboratory findings. There were new novel mutations among the patients. PMID- 8701939 TI - Changes in blood coagulation during and following cardiopulmonary bypass: lack of correlation with clinical bleeding. AB - Although previous studies have documented a wide variety of derangements in laboratory measurements of blood coagulation and platelets during cardiopulmonary bypass, limited data are available concerning the magnitude of these changes and any association with excessive bleeding. To determine whether abnormalities in commonly available laboratory tests for the evaluation of coagulation, fibrinolysis and hemostasis correlate with postoperative blood loss and transfusion requirements as measures of clinical outcome, 47 consecutive patients undergoing coronary artery bypass grafting with hypothermic cardiopulmonary bypass (CPB) were studied prospectively at 12 time points before, during, and following CPB. Routine blood coagulation tests, coagulation factor levels (fibrinogen, V, VII, VIII, and IX) and fibrinolysis (FDP) became abnormal within 15 minutes after patients were placed on CPB, remained abnormal for the duration of CPB, and recovered at varying rates after discontinuation of CPB. Mean factor V levels declined by the greatest percentage, to 15% of normal, followed by factor VIII which decreased to 30%. Platelet counts declined to below 100 x 10(9)/L after the initiation of CPB and remained low in the postoperative period. Twenty-eight percent of patients had mediastinal output > or = 100 mL per hour during the immediate postoperative period, and were considered to be "bleeders." There were no clinically relevant differences in any of the laboratory measurements between patients with normal postoperative blood loss and those defined as bleeders. Thus, the absence of significant correlations between various laboratory measurements of hemostasis and actual postoperative bleeding indicates that these laboratory derangements are transient, are not predictive of clinically important hemostatic abnormalities, and should not be used in isolation to guide the use of blood components in these patients. Furthermore, although bleeders received more blood components, there was surprisingly little effect on the coagulation factor levels measured. PMID- 8701941 TI - Isolated recombinant domain of von Willebrand factor displaying increased sensitivity to ristocetin. AB - Type 2B von Willebrand disease is characterized by an abnormal von Willebrand factor molecule with increased affinity for the platelet glycoprotein (GP) Ib-IX receptor. A diagnostic feature of type 2B von Willebrand disease is a characteristic loss of von Willebrand factor high molecular weight multimers. In vitro, the soluble interaction of normal von Willebrand factor with platelets can be initiated with exogenous modulators, the most common being the antibiotic ristocetin. The variant molecules resulting in type 2B von Willebrand disease can sustain binding to platelets at subnormal levels of ristocetin. We characterized the von Willebrand factor gene of an individual with type 2B von Willebrand disease and identified a nucleotide transition resulting in an Arg543-->Trp amino acid substitution within the GP Ib-IX binding domain of von Willebrand factor. In this study we demonstrate that a recombinant plasmid capable of expressing the isolated GP Ib-IX binding domain of von Willebrand factor, and containing the Arg543-->Trp amino-acid substitution, secretes a dimeric molecule that supports platelet agglutination using subnormal levels of ristocetin. These results demonstrate that the mutation at position 543 increases the affinity between the variant molecule and platelet GP Ib-IX as an intrinsic feature of the isolated von Willebrand factor domain. Thus, structural perturbations within the GP Ib-IX binding domain that are independent of the von Willebrand factor multimeric structure can sufficiently increase the affinity of von Willebrand factor to sustain platelet aggregation, using subnormal levels of ristocetin. PMID- 8701942 TI - Vincristine-induced alterations in Schwann cells of mouse peripheral nerve. AB - The sciatic nerve of C57Bl mice was examined with a transmission electron microscope to study the ultrastructural alterations in Schwann cells following treatment with escalating doses of vincristine. Results indicated that the drug exerts a dose-related effect. Total doses up to 8 micrograms/mouse did not cause any visible damage to Schwann cells. Higher doses induced not only damage to individual cells, but also affected a greater percentage of them. The myelin sheath was the most affected organelle. Schwann cells of myelinated fibers showed greater damage than those of unmyelinated fibers. PMID- 8701943 TI - MRNA analysis in reticulocytes of subjects with Hb D, Hb Porto Alegre, Hb E, and different types of unstable hemoglobin variants. AB - Using a reverse transcription-polymerase chain reaction (RT-PCR) technique we determined the alpha 2/alpha 1, alpha/beta, and gamma/beta mRNA ratios in reticulocytes of 11 patients with seven different unstable beta chain variants, of 4 patients with two unstable alpha chain variants, in hemoglobin (Hb) D, Hb Porto Alegre, and Hb E heterozygotes, and in 8 patients with Hb X-beta 0 thalassemia (thal) (three D-beta 0-thal, one Porto Alegre = beta 0-thal, one Lulu Island-beta 0-thal, and three E-beta 0-thal). In addition, we determined the beta X/beta A mRNA ratios (X = unstable) in some Hb D heterozygotes and in 6 subjects with an unstable beta chain variant. Normal alpha/beta and beta X/beta A mRNA ratios were found in all heterozygotes tested, indicating that the respective mutations did not alter the stability of the mRNAs. The alpha/beta mRNA ratio in four Hb E heterozygotes averaged 4.21 (normal, 4.47), and that in 2 patients with Hb E-beta 0-thal and four alpha-globin genes (alpha alpha/alpha alpha) averaged a high 22.4. The gamma mRNA level in the Hb E heterozygotes was < 1% but varied greatly in patients with Hb E-beta 0-thal; the alpha/(gamma + beta) mRNA ratios in the 2 patients were 15.5 and 16.7, respectively. The large differences in alpha/beta and alpha/(gamma + beta) mRNA ratios in reticulocytes of subjects with AE and with E-beta 0-thal may be due to differences in the levels of normally spliced beta E and abnormally-spliced beta E mRNAs. Only the latter is unstable and is preferentially produced in bone marrow and reticulocytes of Hb E-beta 0 thal patients, where it is rapidly degraded. PMID- 8701944 TI - Deficiency of CD34+ c-kit+ and CD34+38- hematopoietic precursors in aplastic anemia after immunosuppressive treatment. AB - To characterize the persistent abnormalities of hematopoiesis in aplastic anemia (AA) after immunosuppression with antilymphocyte globulin (ALG), we analyzed the quantity, phenotype, and growth properties of hematopoietic progenitor cells in 13 patients who received ALG treatment. Flow cytometry (FACS) revealed a deficiency of CD34+ cells in bone marrow (BM) of all patients. This deficiency was most severe (40-fold) in 4 patients in AA relapse. In 9 patients in remission, CD34+ cells were reduced 2-10-fold and showed no correlation with the ALG-induced improvement of peripheral blood cell counts. The proportion of CD34+ cells carrying c-kit receptors was abnormally low (2-10-fold below normal) in 5 of 13 AA patients. These patients also displayed low levels of c-kit mRNA by reverse transcription-polymerase chain reaction (RT-PCR). Furthermore, the CD34+ cell population was almost completely depleted of CD34+CD38- early hematopoietic progenitors in all AA patients. The proportion of CD34+ cells expressing lineage differentiation antigens CD33, CD71, and CD45RA in AA was increased, as compared to control BM. Formation of hematopoietic colonies by FACS-purified CD34+ cells was nearly absent in 4 relapsed patients, normal in 4 of 9, and decreased (up to 10-fold) in 5 of 9 patients in remission. The degree of impairment of colony forming ability by AA progenitors correlated well with the reduction of CD34+ c kit+ cells. The best proliferative response of CD34+ cells was observed in the presence of stem cell factor and, in some cases, fit3 ligand. Our results indicate that the disease process in AA depletes immature BM progenitors, thus providing a plausible explanation for persistent defects in colony-forming ability and long-term regenerative capacity of AA marrow after immunosuppression. Analysis of the immunophenotypes and the proliferative properties of purified progenitors may be useful for estimating degree of hematopoietic recovery in ALG treated patients. PMID- 8701945 TI - Intensive brief chemotherapy with hematopoietic growth factors as hematological support and adjuvant radiotherapy improve the prognosis in aggressive malignant lymphoma. AB - An intensive brief chemotherapy and radiotherapy regimen including high doses of cyclo-phosphamide (5 g/m2), etoposide (1 g/m2), epirubicin (180 mg/m2), and ifosfamide (5 g/m2) administered in a period of 30 days followed by involved field radiotherapy to sites of initial bulky disease was administered to 46 untreated patients with high-intermedium and high-risk malignant lymphoma. G- or GM-CSF were used as hematological support instead of bone marrow transplantation. All patients had more than 3 adverse prognostic factors at diagnosis. Forty-one patients (89%) achieve complete response (33 after chemotherapy and 8 partial responses were converted to complete response after adjuvant radiotherapy). Acturial failure-free survival at 3 years is 83% and 37 of all patients started on therapy remain alive and in first remission at a median of 24.3 months from completion of treatment. Nearly all patients developed granulocytopenia grade IV; only 13 episodes of bacterial infection were documented. Because hematological recovery was very short (mean 13.6 days) no death related treatment and opportunistic infections were observed. Other non-hematological toxicities were scarce and well tolerated. No decrease > 10% was observed in the left ventricular ejection fraction. None have developed clinically evident congestion heart failure or other late side effects. These results showed that G- or GM-CSF can act as hematological support instead of bone marrow transplantation during intensive and brief chemotherapy. These regimens produce higher complete remission rate, and adjuvant radiotherapy will improve the outcome in patients with bulky disease. PMID- 8701946 TI - Detection of chimerism and early engraftment after allogeneic peripheral blood stem cell or bone marrow transplantation by short tandem repeats. AB - Chimerism can be monitored after HLA-matched allogeneic bone marrow transplantation (BMT) or allogeneic peripheral blood stem cell transplantation (PBSCT) by detecting polymorphisms in short tandem repeats (STR). The purpose of our study was to document early complete chimerism in BMT and PBSCT recipients using STR, and to determine whether the initial WBC recovery correlated with the days required to attain complete chimerism. A total of 5 patients (2 PBSCT and 3 BMT) were followed by STR after transplantation. Peripheral blood obtained prior to transplantation was used to determine the 2 most informative STR probes for each donor/recipient pair. STR were amplified by polymerase chain reaction (PCR) with 8 commercial probes, and PCR products were visualized with silver staining. Peripheral blood was evaluated daily post-transplantation for WBC counts and to identify the presence of mixed or full chimerism by STR. The sensitivity of the STR technique varied from 0.05 to 1%, depending on the probe. Full chimerism was documented between day 9 and 14 in PBSCT recipients and on day 14 and 16 in BMT recipients. The initial rise in WBC occurred within 3 days of the onset of full chimerism, indicating that full chimerism is a more sensitive indicator of early engraftment. Periodic recipient monitoring using STR after complete chimerism identifies those patients who revert to mixed chimeras. The STR method may be useful in future studies to determine the significance of early engraftment and the clinical implications of sustained complete chimerism or mixed chimerism. PMID- 8701947 TI - Conditions influencing release of granule contents from human platelets in citrated plasma induced by ADP or the thrombin receptor activating peptide SFLLRN: direct measurement of percent release of beta-thromboglobulin and assessment by flow cytometry of P-selectin expression. AB - Contrary to a recent report [Rinder et al.: Blood 82:505, 1993], aspirin does inhibit the release of alpha-granule contents as well as inhibiting the release of dense granule contents by human platelets during ADP-induced aggregation in citrated platelet-rich plasma (PRP). Measurements were: percent release of 14C serotonin from prelabeled platelets, radio-immunoassay of beta-thromboglobulin (beta TG), and expression on the platelet surface of the alpha-granule constituent, P-selectin, by flow cytometry. During the second phase of ADP induced aggregation, 69.0 +/- 8.3% of beta TG and 54.1 +/- 4.6% of 14C-serotonin were released (mean +/- SEM, n = 13); aspirin treatment reduced these values to 6.0 +/- 1.2 and 1.0 +/- 0.3%, respectively. In contrast, incubation of platelets with ADP without stirring caused only 6.7 +/- 1.7% release of beta TG and 2.1 +/- 0.4% release of 14C-serotonin; these low values were not appreciably affected by aspirin. During ADP-induced primary aggregation in PRP anticoagulated with FPRCH2CI (PPACK), only 4.7 +/- 0.9% release of beta TG and no detectable release of 14C-serotonin occurred; aspirin had no effect. In both stirred and unstirred PRP, the thrombin receptor activating peptide, SFLLRN (50 microM), caused at least 75% release of the contents of both granules, which was partially inhibited by aspirin. Upon incubation of platelets with ADP (2-10 microM), the mean fluorescence intensity due to P-selectin was < 14% of that induced by SFLLRN. In this unstirred system used for flow cytometry, aspirin treatment caused no significant inhibition of P-selectin expression. Thus, under conditions in which ADP does not cause secondary aggregation (physiological Ca2+ concentration or unstirred citrated PRP) release of the contents of both types of granules is less than 7% and aspirin is not inhibitory; the P-selectin expression associated with this low percent release is also unaffected by aspirin. However, aspirin does strongly inhibit the extensive release of both alpha-granule and dense granule contents during ADP-induced secondary aggregation in citrated PRP. PMID- 8701948 TI - A family inheriting different subtypes of acute myelogenous leukemia. AB - Rare inherited cancer syndromes have proven invaluable for the identification of genes involved in the more frequent corresponding noninherited cases. We report on a family with an adult onset, incompletely penetrant, autosomal dominant syndrome of myelodysplasia and acute myelogenous leukemia, affecting at least eight, and probably ten, individuals from three generations. The patients have developed leukemias differing in morphologic subtype, tumor cytogenetics, and abruptness of presentation. Some have presented with acute onset and others with protracted myelodysplasia. This family does not have an unusual incidence of other malignancies; however, one person at 50% risk of inheriting this gene developed atypical mycobacterium infection in the absence of leukemia, but also without appreciable risk factors for acquired deficiencies in cellular immunity. Features common to affected family members, including the individual with mycobacterium infection, are the early presence in the bone marrow of red cell and platelet maturation defects. A search for mutations in diseased marrows fails to detect abnormalities of p53 or N-ras. Two of the affected family members, third degree relatives, have co-inherited a constitutional chromosomal banding variation of 9p21-22, potentially suggesting linkage to this locus. The variable penetrance and expressivity of this syndrome support a multistep model of leukemia evolution, in which the gene defined by this family's syndrome is the signal step. PMID- 8701949 TI - Hemoglobin S/hemoglobin Osler: a case with 3 beta globin chains. DNA sequence (AAT) proves that Hb Osler is beta 145 Tyr-->Asn. AB - A 13-year-old African-American female with erythrocytosis and three different beta globins on electrophoresis beta A, beta S, and beta Osler, raised the possibility that one chromosome 11 might contain a duplicated beta globin gene, since there are normally only 2 beta globin genes. DNA sequence analysis showed GTG at codon 6 in exon 1, corresponding to Hb S and AAT at codon 145 in exon 3, indicating a substitution of Asn for Tyr. Thus, Hb Osler undergoes spontaneous post-translational deamidation, beta 145 Asn-->beta 145 Asp. Unmodified Hb Osler (Asn) co-migrates with Hb A on electrophoresis and co-elutes with Hb A on HPLC; therefore it has not been identified previously. All previous studies have incorrectly identified the mutation as being beta 145 (HC 2) Tyr-->Asp. PMID- 8701950 TI - Microangiopathic hemolytic anemia complicating FK506 (tacrolimus) therapy. AB - We describe 3 episodes of microangiopathic hemolytic anemia (MAHA) in 2 solid organ recipients under FK506 (tacrolimus) therapy. In both cases, discontinuation of FK506 and treatment with plasma exchange, fresh frozen plasma replacement, corticosteroids, aspirin, and dipyridamole led to resolution of MAHA. In one patient, reintroduction of FK506 led to rapid recurrence of MAHA. FK506 associated MAHA is probably rare but physicians must be aware of this severe complication. In our experience and according to the literature, FK506 does not seem to cross-react with cyclosporin A (CyA), an immuno-suppressive drug already known to induce MAHA. PMID- 8701951 TI - Neutropenias following allogeneic bone marrow transplantation: response to therapy with high-dose intravenous immunoglobulin. AB - Cytopenias following bone marrow transplantation may be severe and life threatening. These have been described post-allogeneic Klumpp, 1991: Bone Marrow Transplant 8:159-171. or post-autologous bone marrow transplants Khouri et al., 1994: J Clin Oncol 12:748-758. as well as with peripheral blood stem cell transplantation Klumpp et al., 1992: Am J Hematol 41:215-217. It can be immune mediated, associated on occasions with graft-versus-host disease (GVHD) Anasetti et al., 1989: Blood 4:1054-1058; however, in most cases, the underlying mechanism is uncertain. The treatment of post-transplant cytopenias is not well established, and they are often refractory to immunosuppressive therapy with steroids. Herein we describe two cases of neutropenia after allogeneic bone marrow transplantation that improved after therapy with high-dose intravenous immunoglobulin. PMID- 8701952 TI - Hairy cell leukemia is infrequent in Mexico and has a geographic distribution. AB - Considering that the prevalence of some hematologic malignancies may have a geographic distribution that could be related with its etiology, a group of 2,387 patients with acute leukemia (1,968 adults and 419 children) was studied along a 5-year period in six different locations within Mexico. Twenty-seven patients (16 males and 11 females) with hairy cell leukemia (HCL) were identified. The adjusted overall proportion of HCL, after excluding data from centers reporting only adults, was 1.12% of all leukemia cases; this figure is lower than that reported in the United States or England. The proportion of adult leukemic patients with HCL was significantly higher in the northern region of the country where there are more people devoted to farming and agricultural activities-as compared with the central or southeastern regions (3.07 vs. 1.03% vs. 0%; P < 0.05); possible explanations for these differences are briefly discussed. PMID- 8701953 TI - Influence of purified apoprotein E on platelet activation induced by serotonin. AB - Serotonin induces platelet activation. Purified apoprotein E of 300 micrograms/ml prevented morphological alterations of blood platelets stimulated with serotonin (5 microM). Lower concentrated apoprotein E showed no such clear effects. These findings suggest that apoprotein E may liter atherosclerosis by suppressing agonist-induced platelet activation. PMID- 8701954 TI - Different adhesion types and active sensitivity of platelet subpopulations. AB - Two different adhesion patterns of blood platelets with different sensitivity to adenosine were demonstrated by means of reflection contrast microscopy with consecutive image analysis and cell affinity chromatography. High-performance liquid chromatography revealed that thrombin-induced serotonin release of adenosine-sensitive platelets was lower than that of adenosine-resistant cells. Our results indicate platelet heterogeneity and suggest that the platelets with lower adenosine sensitivity may be actively involved in the early interaction between platelets and injured endothelium. PMID- 8701956 TI - Bradycardia due to mitoxantrone exacerbated by previous anthracycline therapy. PMID- 8701955 TI - Direct detection of Hb C (B6 Glu-Lys) by BseRI analysis. AB - Hemoglobin C (B6 Glu-Lys) can be identified by different techniques. Here we describe a restriction enzyme digestion protocol (BseRI GAGGAG N10) for direct detection of this variant. PMID- 8701957 TI - Translocation T(4;21) associated with the Pelger-Huet anomaly in a patient with Ph chromosome-negative CML. PMID- 8701958 TI - Quantitative analysis of MDR-1 gene expression in acute myeloid leukemia by reverse transcription polymerase chain reaction. PMID- 8701959 TI - Refractory pancreatitis associated with graft-versus-host disease in Fanconi anemia. PMID- 8701960 TI - Central nervous system involvement in multiple myeloma. PMID- 8701961 TI - When is selection bias not selection bias. PMID- 8701962 TI - Childbearing age patients with essential thrombocythemia: should they be placed on interferon? PMID- 8701964 TI - Leukopenia, thrombocytopenia, and acute autoimmune hemolytic anemia associated with an unusual (type 2/4) Hodgkin's disease: case report. PMID- 8701963 TI - Acquired factor V inhibitor in a patient with acquired human immunodeficiency syndrome. PMID- 8701965 TI - Thrombotic thrombocytopenic purpura and 17 beta-estradiol transdermal skin patch. PMID- 8701966 TI - Acute esophageal stricture after induction chemotherapy for acute leukemia. PMID- 8701968 TI - Temporal alterations in basement membrane components in the pulmonary vasculature of the chronically hypoxic rat: impact of hypoxia and recovery. AB - The hypoxic model of pulmonary hypertension was used to examine temporal alterations in the deposition of the basement membrane (BM) and components of fibronectin, laminin, and Type IV collagen within vascular, airway, and gas exchange compartments of the lung. Because hypoxic pulmonary hypertension is a reversible model of hypertension, changes in fibronectin and laminin synthesis/deposition in the recovering lung were also examined. Long-term hypoxic exposure produced decreases in body weight, increased right ventricular and lung dry weights and elevations in pulmonary arterial pressure. Immunohistochemical analysis revealed consistent and progressive increases in the deposition of fibronectin and laminin, but not type IV collagen, in the subendothelial and medial BMs of large and small pulmonary arteries, but not in airways or lung parenchyma. These changes were observed by day 4 of hypoxia and were most prominent in the conducting vasculature. Northern analysis showed a biphasic pattern of alterations in steady-state levels of BM component mRNA in hypoxic rats with early reductions at days 4 and 7 followed by increases at day 12. Recovery from 12 days of hypoxia resulted in regression of pulmonary hypertension and right ventricular hypertrophy but not increased lung weight. Immunohistochemical analysis of fibronectin, laminin, and type IV collagen levels in the vasculature showed a temporal regression to levels that were not remarkably different from time-matched controls at day 30 of recovery. Northern analysis of lungs from hypoxic-recovery rats revealed increased steady-state levels of mRNA for fibronectin, laminin, and type IV collagen at all time points. These data indicate that long-term hypoxic exposure elicits marked alterations in the synthetic capacity and deposition of the important cell attachment BM glycoproteins fibronectin and laminin. In addition, recovery from hypoxia appears to be characterized by a lack of increased fibronectin and laminin levels in the conducting vasculature, suggesting a marked and rapid reorganization of the vascular BMs on both hypoxic exposure and recovery from hypoxia. PMID- 8701967 TI - Reconstitution of human red blood cell Na/H and Na/Na exchange transport. AB - Na/H and Na/Na exchange transport was measured using human erythrocyte membrane proteins solubilized with octyl glucoside and reconstituted into voltage clamped soybean phospholipid membrane vesicles. The uptake of Na in exchange for either H or Na was: 1) 8 to 10 times higher in proteoliposomes that contained erythrocyte proteins than in proteoliposomes that contained heat denatured proteins or in liposomes that contained no proteins; 2) not affected by ouabain, bumetanide, or 4.4'-diisothiocyanostilbene-2-2'-disulfonic acid (DIDS); 3) inhibited by amiloride, 5-(n-ethyl-n-isopropyl)amitoride (EIPA), and 5-(n-ethyl-1-n isobutyl)amiloride (MIA) but not phenamil; and 4) inhibited by lithium (Li) in a concentration-dependent manner. Incubation of erythrocyte proteins with a low concentration of immobilized trypsin resulted in a significant increase (52%) in Na/Na transport, but no change was seen in Na/H transport. A higher concentration of trypsin increased Na/H transport by more than 2.5 times but did not increase Na/Na transport further. Examination of these studies indicates that, as assayed in reconstituted proteoliposomes that contained erythrocyte proteins, there is a differential response between Na/H and Na/Na transport to trypsin. PMID- 8701969 TI - "Lifestyle" interventions for promoting physical activity: a kilocalorie expenditure-based home feasibility study. AB - The Centers for Disease Control and Prevention and the American College of Sports Medicine in cooperation with the President's Council of Physical Fitness and Sports recommended short periods of daily kilocalorie (calorie) expenditure with moderate-intensity physical activities to complement the currently existing recommendations. In this study the feasibility (adherence and safety) of employing calorie expenditure as the basis for prescribing a home-based walking program to healthy, community-dwelling men and women was examined. This was a 16 week pretest-posttest feasibility study of a home-based calorie-expenditure walking program conducted in an outpatient clinic in an academic medical center. Participants included 20 healthy, elderly, community-dwelling men and women. A 16 week home-based walking program was individually prescribed as a weekly amount of calorie expenditure increasing from an initial 300 calories per week to 1,200 calories per week (approximately 30 minutes of walking daily) during the final 6 weeks of the study. Adherence to the program was recorded individually in a diary (kept daily and reviewed at each visit), body weight, and walking pace. All but one participant were able to complete this 16-week program (95 percent adherence). That a calorie-based approach to promote physical activity among the elderly has a high adherence rate is suggested by these findings. Additional studies are necessary to define the potential role for this approach in promoting physical activity and improving health outcomes among the elderly. PMID- 8701970 TI - Review: the effects of antihypertensive agents on serum lipids. AB - Because various antihypertensive drugs adversely affect lipid metabolism, these drugs may increase associated risks for coronary artery disease and thus offset some of the beneficial effects of blood pressure reduction. In this paper the current literature regarding the effects of antihypertensive agents on serum lipids is reviewed. Differing effects of various classes of antihypertensives are assessed to further our understanding of this very important subject. PMID- 8701971 TI - Case report: polymyositis-induced myoglobinuric acute renal failure. AB - Polymyositis rarely leads to myoglobinuric acute renal failure. One such case is reported here, and certain common features in reported cases are discussed. Given therapeutic advances, these patients should do well despite the dismal prognosis reported in the literature, but early diagnosis and prompt treatment are essential. PMID- 8701972 TI - Case report: late relapse in a case of mesangioproliferative glomerulonephritis. AB - A case of atypical proliferative glomerulonephritis (PGN) without mesangial immunoglobulin (Ig) A deposition (so-called non-IgA PGN) showing exacerbation of heavy proteinuria under long-term observation is reported. Examinations of first renal biopsy specimens revealed membranoproliferative glomerulonephritis (MPGN) like findings. Urinary protein excretion completely disappeared after treatment with prednisolone (PSL) and an antiplatelet drug, i.e., dipyridamole. Negative reaction for urinary protein continued for more than 10 years. Fourteen and a half years after the first biopsy, the patient had heavy proteinuria again. Results of the second renal biopsy showed marked proliferation of glomerular mesangial cells. Under electron microscopy, lobulation and double contours of the glomerular capillary walls were also observed segmentally. Depositions of IgG, IgM, IgA, and C3 were observed mainly in the glomerular capillary walls, but not in the mesangial areas; however, these findings were not compatible with IgA nephropathy or MPGN. No hypocomplementemia was observed during the clinical course. The patient was treated with 30 mg of PSL and 75 mg of dipyridamole daily and showed a good response to such treatment. It appears that this patient had a rare case of atypical non-IgA PGN. PMID- 8701973 TI - Case report: severe hyponatremia after water intoxication: a potential cause of rhabdomyolysis. AB - A 28-year-old woman, treated for schizophrenia, developed severe hypotonic hyponatremia (serum Na: 109 mEq/L) after several days of compulsive water drinking. The patient was admitted in a coma and required intensive supportive therapy. Rhabdomyolysis quickly followed with high serum creatine phosphokinase levels and myoglobinuria. A high volume alkaline diuresis was initiated. Renal failure or compartment syndrome did not complicate the clinical picture. The mechanisms causing water intoxication and hyponatremia are discussed as are the possible pathogenetic explanations behind acute hyponatremia and rhabdomyolysis. PMID- 8701974 TI - Case report: diclofenac-induced rhabdomyolysis. AB - A case is described in which, after administration of diclofenac for 13 days for arthritis attributed to gout, the patient experienced erythema multiforme followed by muscle weakness, elevation of serum creatine phosphokinase (CPK) level from 101 to 83,770 U/L, 100% muscle isoenzyme, blood urea nitrogen (BUN) level from 15 to 87 mg/dL, creatinine level from 1.0 to 2.1 mg/dL and urine myoglobin level to 1,190 micrograms/dL (N < 1.2). The diagnosis was rhabdomyolysis due to diclofenac, with myoglobinuria resulting in mild renal failure. Treatment consisted of discontinuing diclofenac and administering sufficient fluids to prevent progression of myoglobinuric renal failure. Serum CPK level gradually returned to normal by day 50, BUN and creatinine levels by day 28, and muscle strength between day 90 and 180. Rhabdomyolysis due to diclofenac or to other nonsteroidal antiinflammatory drugs has not been reported. PMID- 8701975 TI - Immunology of atherosclerosis: the promise of mouse models. PMID- 8701976 TI - Evidence for a local immune response in atherosclerosis. CD4+ T cells infiltrate lesions of apolipoprotein-E-deficient mice. AB - It has been suggested that immune responses are involved in the development of atherosclerosis. We have evaluated this possibility by analyzing immunocompetent cells in a murine model of the disease. Apolipoprotein E knockout (apoE -/-) mice are genetically hypercholesterolemic due to targeted disruption of the apolipoprotein E gene and develop severe atherosclerosis. Such mice were fed either standard pellets or a diet containing 1.25% cholesterol. Lesions were analyzed from mice at 9 and 16 weeks of age. Immunohistochemical staining of fatty streaks showed that CD4+ T cells were frequent, both in clusters and as single cells. In advanced atherosclerotic plaques, CD4+ T cells were prominent in the fibrous cap and subendotbelially, whereas CD8+ T cells were sparse. The CD25 subunit of the interleukin-2 receptor, which is a marker for activated T cells, was expressed in CD4-rich areas and the major histocompatibility complex class II antigen, I-A(b), which is induced by cytokines released from activated T cells, was also found in the lesions. These data indicate that CD4+ T cells participate in the formation of atherosclerotic lesions in genetically hypercholesterolemic apoE -/- mice. They suggest that immune activation is part of the disease process, and we speculate that a direct link may exist between cholesterol accumulation and T cell activation, possibly by autoimmune responses to modified lipoproteins. PMID- 8701977 TI - Apoptosis is abundant in human atherosclerotic lesions, especially in inflammatory cells (macrophages and T cells), and may contribute to the accumulation of gruel and plaque instability. AB - Death of intimal tissue may lead to plaque rupture with thrombosis, which is the basis of the most severe clinical consequences of atherosclerosis. Little is known about the mechanisms that promote intimal cell death or its nature. This work was undertaken to elucidate the extent to which, the cell types in which, and where programmed cell death, apoptosis, might occur in atherosclerotic lesions. The material was fibrous or fibro-fatty non-ulcerated lesions from the human thoracic aorta and coronary arteries. Apoptosis was indicated by the in situ labeling of internucleosomally degraded DNA with the TUNEL technique, which has a preference for apoptosis as compared with cell necrosis and was combined with the immunohistochemical typing of cells. Apoptosis was corroborated by morphological criteria on the light and electron microscope levels and by the presence of an apoptosis-specific protein. It was common in the lesions and virtually absent in non-atherosclerotic regions. It occurred in smooth muscle cells subendothelially, in places of the fibrous cap, and in the underlying media, which may destabilize the plaque and promote rupture. Inflammatory cells, ie, macrophages and T cells, appeared abundantly subendothelially, in the fibrous cap, and in the shoulder regions, and apoptosis was common, maybe reflecting a means for quenching of the inflammatory reaction. Many macrophages contained abundant apoptotic material indicative of phagocytosis of apoptotic cells, but the occurrence of apoptosis, even in some of these cells, and of apoptotic material extracellularly and the very high numbers of apoptotic cells that were encountered may indicate insufficient mechanisms for the removal of apoptotic cells in the atherosclerotic lesion. It is not possible to decide as yet whether this is due to overloading with cellular material by inflammation and cell multiplication, to an increased frequency of apoptosis, to a reduction of the removal/degradation of apoptotic material by macrophages, or a combination of these factors. PMID- 8701978 TI - Early alteration of cell-cycle-regulated gene expression in colorectal neoplasia. AB - Aberrant crypt foci with dysplasia are thought to be the first detectable lesions of colorectal neoplasia. Because cell cycle disruption appears crucial for tumorigenesis, we analyzed the immunohistochemical expression patterns of the prototype cyclin-dependent kinase inhibitor p21 WAF1/CIP1 and the proliferation marker Ki67 in the early stages of colorectal tumorigenesis. In colorectal epithelium, p21 WAF1/CIP1 expression was undetectable in the lower third of the crypts, where Ki67 was expressed, but then sharply increased as cells passed out of the proliferating zone and migrated toward the humen. Hyperplastic polyps retained this normal compartmentalized pattern. In contrast, markedly decreased p21 WAF1/CIP1 immunostaining was observed in dysplastic aberrant crypt foci as well as in small adenomas. Moreover, the compartmentalization of Ki67 and p21 WAF1/CIP1 was lost, as Ki67 expression extended into the small p21-expressing zone at the top of the crypts. These data suggest that the dysregulated expression of cell-cycle-controlling genes and the consequent release from normal cell cycle controls may represent an essential early step in colorectal neoplasia. PMID- 8701979 TI - Chronic iron overload in rats induces oval cells in the liver. AB - Liver damage induced by a variety of agents including hepatocarcinogens, alcohol, and virus induces proliferation of oval cells. In this study, iron overloading of the liver is used as a means of inducing liver damage over an extended period to ascertain whether it promotes the appearance of oval cells. Rats were fed a 2% carbonyl-iron-supplemented diet for 3 or 6 months. Extensive iron deposits appeared periportally in hepatocytes and some Kupffer cells. Iron deposition was less pronounced pericentrally. Small oval-like cells, morphologically and immunocytochemically similar to CDE-derived oval cells, were identified and quantified. They first emerged periportally and subsequently in small tracts or foci nearer central regions and stained positively for alpha-fetoprotein, pi class glutathione S-transferase, and the embryonic form of pyruvate kinase. They contained very few iron deposits and were classified as iron free. The major difference between CDE- and iron-overload-derived oval cells was that the latter were negative for transferrin. This study shows that cellular changes occurring in iron-overloaded rat liver are similar to those observed in rats placed on a hepatocarcinogenic diet and in rats chronically exposed to alcohol. PMID- 8701980 TI - Feasibility of using decades-old archival tissues in molecular oncology/epidemiology. AB - Archival tissues are a bountiful resource for various studies. Polymerase chain reaction permits the use of such tissues for molecular biological analyses of disease causation. However, a comprehensive study using a large number of decades old samples (20 or more years) for molecular oncology/epidemiology has never been shown to be feasible. We have relied upon the unique tumor registry of atomic bomb survivors to show that such studies are possible using 275 hepatocellular carcinoma and 41 skin cancer cases. We used 23 relatively recent thyroid papillary carcinoma cases from persons living in the vicinity of the Chernobyl nuclear reactor accident for comparison. Degradation of DNA is severe in autopsy hepatocellular carcinoma samples but can be compensated for by decreasing the polymerase chain reaction product size. Increasing the amount of DNA that is used by a factor of 8 improved amplification efficiency from approximately 60 to 80%. Age of the samples was not as great a problem as was the source of procurement. The extracted DNA can be used for all types of assays that require polymerase chain reaction amplification, such as restriction fragment length polymorphism, single-strand conformation polymorphism, and direct sequencing. PMID- 8701981 TI - Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-alpha. AB - We have previously shown that co-expression of c-myc and transforming growth factor (TGF)-alpha as transgenes in mouse liver results in major enhancement of neoplastic development in this organ as compared with expression of either of these transgenes alone. In this report we describe in detail the progression from liver cell dysplasia to hepatocellular carcinomas (HCCs) occurring in the liver of c-myc/TGF-alpha and c-myc transgenic mice. Despite morphological similarities in the sequence of events between the two transgenic lines, the dramatic acceleration, extent, and severity of hepatic lesions in c-myc/TGF-alpha mice clearly demonstrated the synergistic effects of this transgenic combination. Although c-myc/TGF-alpha and c-myc females displayed longer latency and lower tumor incidence, the pathological changes were the same as those seen in the male mice, including the formation of HCCs, which are absent in TGF-alpha single transgenic females. Tumors in single- and double-transgenic mice showed induction of the endogenous c-myc and TGF-alpha and, most frequently, unchanged or decreased epidermal growth factor receptor, further indicating the collaborative role of c-myc and TGF-alpha in providing a selective growth advantage to tumor cells independently of the epidermal growth factor receptor levels. To identify possible tumor precursors, we focused particularly on the dysplastic changes preceding and accompanying the appearance of preneoplastic and neoplastic lesions in the double-transgenic mice. Early on, these changes were characterized by the appearance of large dysplastic hepatocytes, mostly pericentrally, expressing high levels of TGF-alpha and uPA, as well as TGF-beta 1, particularly in apoptotic cells. After a short period of replication and expansion into the liver parenchyma, as well as penetration into the central veins, these cells underwent apoptotic cell death while preneoplastic and neoplastic lesions were forming. The peritumorous tissues also contained small dysplastic hepatocytes and oval-like cells, similar to those found in the tumors. Transplantation of the transgenic liver tissues harboring only dysplasia with or without vascular lesions onto nude mice was able to yield HCCs composed of small diploid cells, suggesting that initiated cells are generated during the early dysplastic phase and can progress to HCC. It is therefore likely that large dysplastic hepatocytes undergo apoptosis, which may be closely associated with the up-regulation of TGF-beta 1 and uPA, whereas other cells evolve into the precursor population for HCC. Due to the simultaneous presence of c-myc, TGF-alpha, and dysplasia in premalignant human liver diseases, our transgenic mouse system appears to be an appropriate model for studying human hepatocarcinogenesis. PMID- 8701982 TI - Fas antigen expression and its relationship with apoptosis in human hepatocellular carcinoma and noncancerous tissues. AB - Apoptosis, a programmed cell death, can be observed in the tissues of viral or autoimmune hepatitis and of hepatocellular carcinoma. Fas antigen (Fas) was proposed as a protein that triggers apoptosis. To elucidate the relationship between Fas expression and its location in hepatocellular carcinoma cells, we histochemically examined Fas expression by using 25 hepatocellular carcinoma tissues and their corresponding noncancerous tissues, which were surgically obtained from the same patients. In addition, the relationship between Fas expression and apoptotic cell numbers was examined in the hematoxylin-and-eosin stained specimens obtained from 23 of the 25 patients. Hepatocellular carcinoma tissues expressed Fas less frequently and more weakly than noncancerous tissues. The majority of noncancerous specimens expressed Fas both on the surface and in the cytoplasm, whereas the majority of hepatocellular carcinoma expressed Fas only in the cytoplasm. Apoptotic cell counts were significantly higher in Fas expressing tissues than in Fas-negative tissues. Among Fas-expressing tissues, the counts were higher in surface Fas-expressing tissues than in tissues that expressed only cytoplasmic Fas (P < 0.01 to 0.05). Our findings indicate that the development of apoptosis in hepatocellular carcinoma tissues relates to not only Fas expression but also its location. PMID- 8701984 TI - Cell-type-specific expression of neural cell adhesion molecule (N-CAM) in Ito cells of rat liver. Up-regulation during in vitro activation and in hepatic tissue repair. AB - Ito cells (lipocytes, stellate cells) are regarded as the principle matrix producing cell of the liver and have been shown recently to express glial fibrillary acidic protein, an intermediate filament typically found in glia cells of the nervous system. The present study examines 1) whether Ito cells of rat liver express central nervous system typical adhesion molecules, namely, neural cell adhesion molecule (N-CAM), in a cell-type-specific manner and 2) whether N CAM expression is affected by activation of Ito cells in vitro and during rat liver injury in vivo. As assessed by reverse transcriptase polymerase chain reaction, Northern blotting, Western blotting, and immunocytochemistry of freshly isolated and cultivated hepatic cells, N-CAM expression was restricted to Ito cells and was absent in hepatocytes, Kupffer cells, and sinusoidal endothelial cells. Ito cells expressed predominantly N-CAM-coding transcripts of 6.1 and 4.8 kb in size and 140-kd isoforms of the N-CAM protein, which was localized on the cell surface membrane of Ito cells. In parallel to glial fibrillary acidic protein down-regulation and smooth muscle alpha-actin up-regulation, N-CAM expression was increased during in vitro transformation of Ito cells from resting to activated (myofibroblast-like) cells and by the fibrogenic mediator transforming growth factor-beta 1. By immunohistochemistry, N-CAM was detected in normal rat liver in the portal field as densely packed material and in a spot as well as fiber-like pattern probably representing nerve structures. However, after liver injury, N-CAM expression became detectable in mesenchymal cells within and around the necrotic area and within fibrotic septae. In serially cut tissue sections, N-CAM-positive cells were predominantly co-distributed with smooth muscle alpha-actin-positive cells rather than glial fibrillary acidic protein positive cells, especially in fibrotic livers. The experimental results illustrate that N-CAM positivity in the liver cannot be solely ascribed to nerve endings as, among the different types of resident liver cells, Ito cells specifically express N-CAM in vitro and presumably in vivo. In addition to its role as potential cell-type-specific marker protein for activated Ito cells, the induction of N-CAM expression might illustrate a mechanism by which mesenchymal cell proliferation might be inhibited when tissue repair is concluded. PMID- 8701983 TI - Ductular reaction after submassive necrosis in humans. Special emphasis on analysis of ductular hepatocytes. AB - The ductular reaction to acute submassive necrosis was studied in human livers removed at the time of orthotopic liver transplantation. Single, double, and triple immunohistochemical labeling in combination with morphometry was used to analyze the phenotype and proliferative and apoptotic rates of various epithelial cell compartments. These were divided on the basis of immunohistochemistry and morphology into three subtypes: 1) CK19+/AE1+ mature bile duct epithelium, 2) HEP PAR+ mature hepatocytes (HEPs), and 3) CK19+/AE1+ ductular hepatocyte (DH) cells lying at the interface between the portal tract connective tissue and the hepatic lobules. Cycling cells were defined as those showing Ki-67+ (MIB-1) nuclear labeling. Apoptotic cells were identified with in situ labeling using the terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling assay. Special emphasis was placed on DHs that appeared at the interface between the portal tracts and hepatic lobules. During the recovery phase from submassive hepatic necrosis, subtraction of the rate of cell death from the proliferative index shows that all of the epithelial compartments experience a net increase in the number of cells. The highest proliferation rate occurs in the DHs, which is significantly (P < 0.0001) higher than the proliferation rate seen in either the HEP or bile duct epithelium compartments. Immunohistochemical analysis of the highly proliferative DH compartment shows it to be a heterogeneous population with unique phenotypic features. Like epithelial cells in the ductal plate of fetal liver and cholangiocarcinomas, DHs are positioned on a laminin-rich matrix and focally express vimentin and Lewis(x) and show up-regulation of bcl-2 and type IV collagenase. However, unlike ductal plate cells, DHs are CD34 and alpha fetoprotein negative. Although a subpopulation of DHs share phenotypic features with mature bile duct epithelium (AE1/cytokeratin 19 and type IV collagenase positive) or HEP (HEP-PAR, albumin, and alpha-1-antitrypsin positive), they are also clearly separate from both populations; DHs are negative or only weakly stain for glutathione-S-transferase-pi and are type IV collagenase positive. Moreover, occasional DHs also co-expressed HEP-PAR or alpha-1-antitrypsin and AE1, indicative of both hepatocyte and ductular differentiation. These findings suggest that DHs seen in human livers after submassive necrosis may represent a transient amplifying population arising from a progenitor population located in or near the canals of Herring. In addition, injured hepatocytes can express cytokeratin 19 and AE1, which normally are biliary intermediate filaments. PMID- 8701985 TI - Translocation t(2;5) is not a primary event in Hodgkin's disease. Simultaneous immunophenotyping and interphase cytogenetics. AB - A number of neoplastic disorders are characterized by recurrent chromosome aberrations. One of these is the translocation t(2;5), which is found in a considerable percentage of large-cell anaplastic lymphomas. This translocation results in the fusion of two genes, alk and npm. The recent discovery of alk/npm mRNA in 11 of 13 cases of Hodgkin's disease has caused a controversial discussion concerning the question of whether t(2;5) is also present in Hodgkin and Reed Sternberg cells. We tackled this problem on the molecular cytogenetic level by combined CD30 immunophenotyping and interphase cytogenetics. Using a pair of DNA probes flanking both sides of the npm gene breakpoint at 5q35 we were able to prove, at least in 12 of 13 cases of Hodgkin's disease, that all CD30-positive Hodgkin and Reed-Sternberg cells lacked the translocation t(2;5). Fifteen to forty-five Hodgkin/Reed-Sternberg cells were analyzed per case (mean, 27). Our findings indicate that this translocation is not a primary event in the development of Hodgkin's disease. PMID- 8701986 TI - CD30 ligand expression in nonmalignant and Hodgkin's disease-involved lymphoid tissues. AB - The CD30 ligand (CD30L) is a type II transmembrane glycoprotein of the tumor necrosis factor ligand superfamily. Recent cloning of CD30L has enabled studies to explore its function and tissue distribution. For instance, recombinant CD30L has been shown to co-stimulate T cells and to act as mitogen for Hodgkin's disease (HD)-derived cell lines. The counter-receptor for CD30L, ie, CD30, is a type I cytokine receptor that is highly expressed by activated T cells, Hodgkin and Reed-Sternberg (H-RS) cells, and anaplastic large cell lymphoma cells. In the present study, recombinant membrane-bound and soluble human CD30L were instrumental to raise a monoclonal antibody (M80) recognizing membrane-bound CD30L on transfected and native cells. With this reagent, a panel of cultured lymphoma-derived cell lines as well as primary normal, reactive, and HD-involved lymphoid tissues were examined for expression of CD30L by immunostaining and flow cytometry. In reactive lymphnodes and tonsils, CD30L was expressed by a small subset of lymphoid cells, histiocytes, and granulocytes. Higher levels of CD30L expression were noted in HD lesions among bystander cells; ie, T cells and granulocytes that surrounded H-RS cells. Native CD30L displayed at the cell surface was functionally active as shown by the ability of fixed granulocytes to interact with CD30+ cell lines. Moreover, CD30L was detectable, although to a lower staining intensity, in primary H-RS cells of all HD tissues investigated regardless of the histological subtype and the phenotype of H-RS cells (ie, CD30+/CD40+ versus CD30-/CD40+). Co-expression of CD30 and CD30L that was seen on H-RS cells of all, except the CD30- nodular lymphocyte predominant, subtypes of HD may point to the use of this pair of molecules in paracrine and/or autocrine mitogenic cell interactions. Monoclonal antibody M80 may thus represent a useful tool for studying CD30L expression on cultured cell lines and primary cells from normal, reactive, and malignant tissues. PMID- 8701987 TI - Detection of t(2;5)(p23;q35) translocation by reverse transcriptase polymerase chain reaction and in situ hybridization in CD30-positive primary cutaneous lymphoma and lymphomatoid papulosis. AB - The t(2;5) generates a chimeric NPM-ALK transcript encoded by the nucleophosmin NPM gene fused to the anaplastic lymphoma kinase gene ALK. Using a reverse transcriptase nested polymerase chain reaction assay we have detected NPM-ALK transcripts within CD30+ primary cutaneous lymphoma and lymphomatoid papulosis (LP). The t(2;5) was identified in 4 out of 9 CD30+ anaplastic lymphomas and in 1 out of 4 CD30+ pleomorphic lymphomas. Moreover, the t(2;5) was detected in 3 out of 10 LPs. All NPM-ALK-positive lymphomas and 1 NPM-ALK-positive LP exhibited a clonal rearrangement of the T cell receptor gamma-chain gene. The t(2;5) was detected in 2 cases of LP without other evidence for a clonal lymphoid population. To identify cells carrying the t(2;5) translocation, we used immunohistochemistry to detect the ALK-encoded p80 protein and in situ hybridization for the specific detection of NPM-ALK transcripts. Both p80 protein and NPM-ALK transcripts were expressed by anaplastic or large CD30+ lymphoma cells with positive NPM-ALK amplification. The presence of t(2;5) in a subset of CD30+ cutaneous lymphoma and LP may indicate a common pathogenesis with a subset of anaplastic nodal lymphoma. PMID- 8701988 TI - Identification and partial characterization of a novel membrane-associated protein (MAP17) up-regulated in human carcinomas and modulating cell replication and tumor growth. AB - Using the differential display technique, we have recently reported the identification of a novel gene originally designated DD96. As determined by Northern blot and in situ hybridization, DD96 was expressed at significant levels only in a single epithelial cell population, the proximal tubular epithelial cells of the kidney. However, it was diffusely expressed in various carcinomas originating from kidney, colon, lung, and breast. Using a specific polyclonal antibody, we have not determined that the DD96 protein product is a 17-kd membrane-associated protein, which we have therefore redesignated MAP17. In normal tissues, MAP17 is expressed in significant amounts only in the kidney, where it was localized to the brush border of proximal tubular epithelial cells. However, MAP17 is expressed abundantly in carcinomas arising from kidney, colon, lung, and breast, in some cases with a membrane-associated apical glandular distribution. In tissue culture, MAP17 was localized to the cell membrane in areas of cell-cell contact, ie, the distribution of cell-function-associated proteins. Transfection of a full-length wild-type DD96 cDNA clone into a colon carcinoma cell line, HT-29, markedly decreased cell proliferation in vitro and tumor growth in vivo. Although the precise function of MAP17 remains to be determined, our findings suggest that this protein may play an important role in tumor biology. PMID- 8701989 TI - Monocyte chemoattractant protein-1 gene expression in prostatic hyperplasia and prostate adenocarcinoma. AB - Human monocyte chemoattractant protein-1 (MCP-1) has been shown to act as a chemokine in the recruitment of monocyte/macrophages during inflammation states. Furthermore, there is increasing evidence that MCP-1 is involved in the recruitment of tumor-associated macrophages. In vivo, one of the major cellular sources of MCP-1 are the smooth muscle cells. As MCP-1 gene expression and/or protein production in these cells is not necessarily correlated with the accumulation of inflammatory cells, there might possibly be additional functions of this cytokine. In the present study, we investigated by use of 35S-labeled antisense RNA probes whether the MCP-1 gene is expressed in tissue specimens of benign prostatic hyperplasia (n = 13) and specimens of prostate carcinoma (n = 8), both of which are characterized by a prominent fibromuscular stroma and inconspicuous inflammatory infiltrates. MCP-1 transcripts were located in stromal smooth muscle cells and, additionally, in basal cells of benign prostatic glands. In prostate carcinoma, the number of MCP-1 mRNA-expressing cells was significantly less than in benign prostatic hyperplasia. MCP-1 transcripts were located in preserved fibromuscular stroma and in basal cells of entrapped non neoplastic glands but not in carcinomatous cells. Immunohistochemical staining with polyclonal antibodies raised against MCP-1 revealed strong reactivity in the fibromuscular stroma surrounding both benign and malignant glands. MCP-1 gene expression or immunoreactivity for anti-MCP-1 antibodies was not related to the rare, lymphocytic interstitial infiltrates. The results show that 1) in the absence of significant leukocyte accumulation, it is unlikely that MCP-1 exerts chemotactic functions in the prostate and 2) that MCP-1, in contrast to previous findings in a wide variety of other human neoplasms, is not expressed in carcinomatous cells of the prostate. PMID- 8701990 TI - Origins of heterogeneous ovarian carcinomas. A molecular cytogenetic analysis of histologically benign, low malignant potential, and fully malignant components. AB - It is unclear whether ovarian carcinomas develop from malignant transformation of benign precursors or whether they arise de novo. Thus, histologically benign or low malignant potential components found in heterogeneous ovarian carcinomas may be remnants of pre-existing lesions that progressed to malignancy or, alternatively, elements that arose independently (de novo). In a third possible interpretation, they represent areas of malignant epithelium that matured. We evaluated clonal relationships of histological components in 10 heterogeneous ovarian carcinomas using fluorescence in situ hybridization and confocal microscopy. Detailed analysis of aneuploidy for chromosomes 8, 12, and 17 on intact paraffin sections revealed that two tumors were aneuploid in all components, two lacked abnormalities in benign-appearing components, and one lacked aneuploidy in both histologically benign and low malignant potential components. Histological appearance was significantly related to aneuploidy (P < 0.05). The distribution of aneuploidy among tumor components strongly supports the tumor progression theory and demonstrates that the de novo hypothesis is highly unlikely (P < 0.001). Results also indicate that benign-appearing components in heterogeneous ovarian carcinomas do not represent maturation of malignant tissue and suggest that some benign tumors that become cancerous may have genetic aberrations that predispose them to malignant transformation. PMID- 8701991 TI - Keratinocyte growth factor is highly overexpressed in inflammatory bowel disease. AB - Recently we demonstrated an important function of keratinocyte growth factor (KGF) in wound re-epithelialization. As KGF is mitogenic for various epithelial cells, we speculated about a role of KGF in epithelial repair processes of other organs as seen in a variety of inflammatory diseases. Here we demonstrate a strikingly increased expression of KGF in surgical specimens from patients suffering from Crohn's disease and ulcerative colitis. The levels of KGF expression strongly correlated with the degree of inflammation as assessed by histological analysis of adjacent tissue and expression analysis of the pro inflammatory cytokine interleukin-1 beta. The highest levels of KGF mRNA and protein were found in mesenchymal cells of the lamina propria, particularly in highly inflamed areas. As the KGF receptor is expressed in intestinal epithelial cells, KGF seems to act in a paracrine manner to stimulate proliferation of these cells. These data suggest a crucial role of KGF in epithelial repair after injury caused by inflammatory processes. PMID- 8701992 TI - Association of p53 and WAF1 expression with apoptosis in diffuse alveolar damage. AB - Little is known about alterations in cell cycle regulatory proteins such as p53 and WAF1 in diffuse alveolar damage (DAD). We hypothesized that up-regulation of p53 and WAF1 in type II pneumocytes in DAD is associated with underlying DNA damage and apoptosis. Twenty cases of DAD and twenty control specimens of lung adjacent to resected tumors were studied. Immunohistochemical stains with antibodies recognizing p53 and WAF1 were performed, and apoptosis was assessed in sixteen cases by the nick end-labeling method. We identified p53 expression and apoptosis in all cases of DAD but not in any of the control lungs. We detected WAF1 expression in nineteen of twenty cases of DAD and in sixteen of twenty control lungs. In general, the distribution and intensity of WAF1 staining were greater in DAD than in control lungs. Staining for both p53 and WAF1 and labeling of apoptotic cells in DAD were usually focal ( < 10% of cells) and predominantly localized in type II pneumocytes. We conclude that increased p53 and WAF1 expression in DAD reflects normal physiological up-regulation in response to cellular and DNA damage and is associated with apoptosis of type II pneumocytes. p53-dependent apoptosis may contribute to the pathogenesis of this disease. PMID- 8701993 TI - Platelet-derived growth factor causes pulmonary cell proliferation and collagen deposition in vivo. AB - Platelet-derived growth factor (PDGF) is postulated to play a role in the pathophysiology of pulmonary fibrosis. Recombinant human PDGF-BB administered as a single intratracheal injection in rats causes an increase in peribronchial and perivascular stromal cells on days 2 and 3 after injection as evaluated by hematoxylin and eosin histology and 5-bromodeoxyuridine incorporation. Proliferation of bronchial epithelial cells and arterial smooth muscle cells, although not evident by routine histological examination alone, is detected on days 2 and 3 by increased 5-bromodeoxyuridine incorporation. A mild increase in 5 bromodeoxyuridine labeling is observed in peripheral alveolar parenchyma after injection of PDGF. The proliferative peribronchial and perivascular mesenchymal cells appear by light microscopic and ultrastructural criteria to be fibroblasts that are immunoreactive for vimentin but negative for alpha-smooth muscle actin and desmin. Daily intratracheal injection of PDGF-BB for 3 days causes a slightly more pronounced peribronchial and perivascular spindle cell proliferation accompanied by collagen deposition as evaluated by Masson's trichrome stain. PDGF induced increases in cellularity and collagen resolve within 5 days after the last PDGF injection. In conclusion, intratracheal injection of PDGF-BB causes transient proliferation of pulmonary mesenchymal and epithelial cells accompanied by collagen deposition. PMID- 8701994 TI - Healing corneas express embryonic fibronectin isoforms in the epithelium, subepithelial stroma, and endothelium. AB - The cornea is a simple, nonvascularized structure, advantageous for studying the molecular components of epithelial and stromal wound repair. Fibronectin (Fn), of uncertain source and composition, accumulates in healing corneas. We postulated that local synthesis of Fn occurs, as exogenous plasma/tear-derived Fn, which lack the embryonic EIIIA and EIIIB segments, have no consistent beneficial effect on healing. Two contrasting corneal wounds were examined by in situ hybridization: a wound of the anterior stroma, basement membrane, and epithelium (anterior excimer laser keratectomy) and a superficial wound restricted to the epithelium that preserved the basement membrane (mechanical scrape). Both wounds heal without scarring. In normal corneas, only the endothelium had detectable Fn mRNA, containing the V and EIIIB domains, sporadically and at low levels. After anterior keratectomies, extensive expression of Fn mRNA occurred in a specific distribution that changed during the phases of healing. Before re epithelialization (days 1 and 2) V+, EIIIA+, and EIIIB+ isoforms were diffusely found in stromal cells under and adjacent to the wound. After re epithelialization (days 3 to 42) and reconstitution of laminin in the regenerating basement membrane zone, V+, EIIIA+, and EIIIB+ isoform synthesis was largely restricted to subepithelial stromal cells at the epithelial/stromal interface. In addition, the corneal epithelial cells focally expressed Fn mRNA. The endothelium showed increased levels of V+, EIIIA+, and EIIIB+ Fn mRNA in open and recently re-epithelialized wounds. At 12 weeks after keratectomy, Fn mRNA expression returned to control levels. In contrast, scrape wounds had only a modest increase of stromal and endothelial Fn mRNA (EIIIA+, EIIIB+, and V+) during the first 7 days and no evidence of epithelial Fn synthesis. Embryonic Fn isoforms are synthesized transiently by the cornea in response to even the most superficial wounds and are likely to be relevant to corneal healing and restoration of structure without scar formation. PMID- 8701995 TI - Effects of macrophage colony-stimulating factor on macrophages and their related cell populations in the osteopetrosis mouse defective in production of functional macrophage colony-stimulating factor protein. AB - The development of macrophage populations in osteopetrosis (op) mutant mice defective in production of functional macrophage colony-stimulating factor (M CSF) and the response of these cell populations to exogenous M-CSF were used to classify macrophages into four groups: 1) monocytes, monocyte-derived macrophages, and osteoclasts, 2) MOMA-1-positive macrophages, 3) ER-TR9-positive macrophages, and 4) immature tissue macrophages. Monocytes, monocyte-derived macrophages, osteoclasts in bone, microglia in brain, synovial A cells, and MOMA 1- or ER-TR9-positive macrophages were deficient in op/op mice. The former three populations expanded to normal levels in op/op mice after daily M-CSF administration, indicating that they are developed and differentiated due to the effect of M-CSF supplied humorally. In contrast, the other cells did not respond or very slightly responded to M-CSF, and their development seems due to either M CSF produced in situ or expression of receptor for M-CSF. Macrophages present in tissues of the mutant mice were immature and appear to be regulated by either granulocyte/macrophage colony-stimulating factor and/or interleukin-3 produced in situ or receptor expression. Northern blot analysis revealed different expressions of GM-CSF and IL-3 mRNA in various tissues of the op/op mice. However, granulocyte/macrophage colony-stimulating factor and interleukin-3 in serum were not detected by enzyme-linked immunosorbent assay. The immature macrophages differentiated and matured into resident macrophages after M-CSF administration, and some of these cells proliferated in response to M-CSF. PMID- 8701996 TI - Expression and distribution of CD9 in myelin of the central and peripheral nervous systems. AB - CD9 is a member of the newly identified tetra-membrane-spanning protein family. We show here that CD9 is a constituent of myelin in the central and peripheral nervous systems. Expression of CD9 was detected in human cerebral white matter and sciatic nerve by Northern and Western blotting. Myelin in the central and peripheral nervous systems was strongly stained with a monoclonal antibody against human CD9 antigen in paraffin-embedded sections. CD9 was detected in adult nervous tissue but not in developing brain at less than 20 weeks of gestation. Immunohistochemical studies indicated that expression of CD9 is correlated with myelination and is somewhat delayed compared with expression of myelin basic protein, a major component protein of myelin. In the central nervous system, CD9 was detected along the outermost membrane of compact myelin but not inside compact myelin or the periaxonal region. Although the membrane-anchored form of heparin-binding epidermal-growth-factor-like growth factor (proHB-EGF), which is identical to the diphtheria toxin receptor, forms a complex with CD9 in some human and monkey cell lines, proHB-EGF was not detected in myelin immunocytochemically. The distribution of CD9 in the outer surface of myelin and its relatively late developmental appearance suggest that CD9 may interact with the extracellular matrix or cell adhesion molecules and participate in the maintenance of the entire myelin sheath. PMID- 8701997 TI - P3 beta-amyloid peptide has a unique and potentially pathogenic immunohistochemical profile in Alzheimer's disease brain. AB - The presence of beta-amyloid in brain tissue is characteristic of Alzheimer's disease (AD). A naturally occurring derivative of the beta-amyloid peptide, p3, possesses all of the structural determinants required for fibril assembly and neurotoxicity. p3-specific antibodies were used to examine the distribution of this peptide in brain. p3 reactivity was absent or sparse in aged non-AD brains but was prevalent in selected areas of AD brain in diffuse deposits and in a subset of dystrophic neurites. p3-reactive dystrophic neurites were found both independent in the neuropil and associated with plaques. Little or no reactivity was observed to amyloid cores in classical plaques or to amyloid in the cerebral vasculature. The exclusive appearance of p3 reactivity in AD brain plus the selective localization of p3 reactivity to abnormal structures in the temporal lobe limbic system suggests that p3 may be a contributing factor to AD pathology. PMID- 8701998 TI - Identification of differentially expressed genes in rat aortic allograft vasculopathy. AB - Graft vasculopathy is an important complication of long-surviving organ transplants, but its pathogenesis has remained elusive. We investigated rat aortic transplants with vasculopathy, aortic transplants without vasculopathy, and normal aortas for differentially expressed mRNA transcripts to gain further insight into the molecular mechanisms involved. Aortic transplants were performed in allogeneic or syngeneic recipients followed by removal after 1 or 5 months, RNA isolation, and differential display to identify mRNA transcripts the expression of which was modulated in conjunction with the transplant procedure and the development of vasculopathy. Using 80 random primers, 57 differentially displayed polymerase chain reaction products were identified, 18 of which were found in allografts but not in syngeneic grafts or normal vessels, whereas 15 were expressed in normal vessels and syngeneic grafts but not in allografts. Of the differentially displayed amplicons, 13 were successfully reamplified and used as probes for Northern analysis; differential expression was confirmed in 6 instances. DNA sequence analysis of these PCR products revealed identity with the immunoglobulin J chain in 2 instances, the ferritin heavy chain, a sequence related but not identical with Ras, and an established sequence tag recently isolated from a human fetal heart library; 1 sequence was not related to any known gene. To assess whether differential mRNA expression of the J-chain gene, a gene expressed in cells of B lymphocyte lineage, was associated with infiltration of the graft by B lymphocytes, tissue sections were stained with an antibody against the B cell marker CD45RA. Although the number of CD45RA-positive cells was low, there was a significant increase in the number of CD45RA-positive cells in the adventitia and intima of grafts with vasculopathy. Furthermore, immunostaining with anti-ferritin antiserum confirmed the presence of ferritin positive cells within the inner layer of the graft vessel wall and dispersed in the intima, media, and adventitia. The question remains as to which of these genes are critically relevant in the pathogenesis of graft vasculopathy and whether they serve as targets for therapeutic interventions. PMID- 8701999 TI - Microsatellite alteration at chromosome 3p loci in neuroendocrine and non neuroendocrine lung tumors. Histogenetic and clinical relevance. AB - Although chromosome 3p regions are the most frequent site for genetic alterations in small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC), the extent of such abnormality in carcinoid tumors remained to be investigated. Moreover, the histogenetic and biological implications of these findings in non carcinoid lung tumors remain unclear. We studied eight microsatellite loci on chromosome 3p regions by multiplex polymerase chain reaction in paired normal and tumor DNA from 17 carcinoid tumors, 5 SCLCs, and 38 NSCLCs to determine the histogenetic and the clinical significance of their alterations in these neoplasms. Our results revealed a lack of microsatellite abnormalities at all loci tested in both typical and atypical carcinoid tumors. SCLCs and NSCLCs showed loss of heterozygosity in 100% (5/5) and 58.0% (22/38), respectively. Loss of heterozygosity at more than two loci correlated significantly with poor histological differentiation and were preponderantly found in high proliferative index and DNA aneuploid NSCLCs. Microsatellite instability was noted in only one (1.7%) of the lesions. Our study suggests that 1) the difference in chromosome 3p alterations between carcinoid tumors and SCLCs favors a stochastic rather than linear evolution of these tumors, 2) 3p alterations may constitute an initial event in the development of small cell carcinomas, and 3) loss of heterozygosity at 3p loci is associated with aggressive tumor characteristics in non-small-cell carcinomas. PMID- 8702000 TI - Up-regulation of specific NF 1 gene transcripts in sporadic pilocytic astrocytomas. AB - Pilocytic astrocytomas of the optic nerve (optic nerve gliomas) are closely associated with neurofibromatosis 1 (NF1), and allelic losses of the NF1 gene region on chromosome 17q occur in sporadic pilocytic astrocytomas. We therefore hypothesized that the NF1 gene acts as a tumor suppressor gene in pilocytic astrocytomas, and that NF1 gene expression would be reduced or absent in these tumors. To evaluate this possibility, we examined quantitative and qualitative aspects of NF1 gene expression in six sporadic pilocytic astrocytomas. Surprisingly, the NF1 gene was overexpressed up to fourfold in these tumors when compared with normal brain. This up-regulation was accompanied by immunohistochemical positivity using a carboxyl-terminal antibody and by the absence of mutations in one kilobase of the NF1 coding sequence, consistent with the expressed transcript and protein being full length and probably wild type. Pilocytic astrocytomas showed a marked predominance of transcripts containing exon 23a and lacking exon 9br, the same isoforms that are expressed by normal and reactive astrocytes and malignant astrocytomas. These data illustrate that pilocytic astrocytomas overexpress specific NF1 gene transcripts, perhaps as a regulatory response to growth stimuli. The role of the NF1 gene as a tumor suppressor in pilocytic astrocytomas, however, remains to be proven. PMID- 8702001 TI - Prelabeled glycoprotein Ib/IX receptors are not cleared from exposed surfaces of thrombin-activated platelets. AB - The present investigation has re-examined the hypothesis proposing that glycoprotein (GP)Ib/IX receptors for von Willebrand factor are rapidly cleared from exposed surfaces to internal membrane systems after activation of platelets by thrombin in suspension. Platelets were prelabeled with either a polyclonal antibody to GPIb alpha, antiglycocalicin (A-Gl), or a cocktail of two monoclonal antibodies, AP1 and 6D1, exposed to 0.1 or 0.2 U/ml thrombin for 5 or 10 minutes, fixed and stained with Staphylococcus protein A coupled to gold to detect A-Gl or goat anti-mouse IgG bound to gold particles to locate AP1 and 6D1 before or after preparation of frozen thin sections or embedding for plastic thin sections. The frequency and distribution of protein-A-gold markers for GPIb/IX on thrombin activated platelets viewed in thin plastic sections did not differ from the density on resting platelets stained with A-Gl. Cryosections of A-Gl-prelabeled platelets labeled again on cryosections revealed GPIb present on linings of the open canalicular system of resting and activated platelets, but the density of gold in interior channels and frequency of gold particles on exterior surfaces were not altered by thrombin stimulation. Platelets prelabeled with the cocktail of 6D1 and AP1 and studied in cryosections also failed to reveal uptake of GPIb/IX receptors into the open canalicular system after activation by thrombin. The findings do not support the concept that thrombin causes clearance of GPIb/IX receptors from exterior surfaces to interior membranes of activated platelets. PMID- 8702002 TI - Ultrastructural instability of paired helical filaments from corticobasal degeneration as examined by scanning transmission electron microscopy. AB - Paired helical filaments (PHFs) accumulate in the brains of subjects affected with Alzheimer's disease (AD) and certain other neurodegenerative disorders, including corticobasal degeneration (CBD). Electron microscope studies have shown that PHFs from CBD differ from those of AD by being wider and having a longer periodicity of the helical twist. Moreover, PHFs from CBD have been shown to be primarily composed of two rather than three highly phosphorylated polypeptides of tau (PHF-tau), with these polypeptides expressing no exons 3 and 10. To further explore the relationship between the heterogeneity of PHF-tau and the appearance of abnormal filaments, the ultrastructure and physical parameters such as mass per unit length and dimensions were compared in filaments from CBD and AD using high resolution scanning transmission electron microscopy (STEM). Filament enriched fractions were isolated as Sarcosyl-insoluble pellets and for STEM studies, samples were freeze-dried without prior fixation or staining. Ultrastructurally, PHFs from CBD were shown to be a heterogeneous population as double- and single-stranded filaments could be identified based on their width and physical mass per unit length expressed in kilodaltons (kd) per nanometer (nm). Less abundant, double-stranded filaments had a maximal width of 29 nm and a mass per unit length of 133 kd/nm, whereas three times more abundant single stranded filaments were 15 nm wide and bad a mass per unit length of 62 kd/nm. Double-stranded filaments also displayed a distinct axial region of less dense mass, which appeared to divide the PHFs into two protofilament-like strands. Furthermore, these filaments were frequently observed to physically separate along the long axis into two single strands or to break longitudinally. In contrast, PHFs from AD were ultrastructurally stable and uniform both in their width (22 nm) and physical mass per unit length (104 kd/nm). The ultrastructural features indicate that filaments of CBD and AD differ both in stability and packing of tau and that CBD filaments, composed of two distinct protofilaments, are more labile under STEM conditions. As fixed and stained filaments from CBD have been shown to be stable and uniform in size by conventional transmission electron microscopy, STEM studies may be particularly suitable for detecting instability of unstained and unfixed filaments. The results also suggest that molecular heterogeneity and/or post-translational modifications of tau may strongly influence the morphology and stability of abnormal filaments. PMID- 8702003 TI - Immunodetection of histone epitopes correlates with early stages of apoptosis in activated human peripheral T lymphocytes. AB - By coupling intracellular staining with terminal deoxynucleotidyl transferase (TdT)-mediated labeling of internucleosomal DNA strand breaks in a flow cytometric assay, we observed a strong correlation between apoptosis-associated DNA strand breaks and immunoreactivity with the monoclonal antibody (MAb) B-F6 in activated human peripheral blood T lymphocytes (PBTs). Although MAb B-F6 has been reported to be specific for the cytokine interleukin-6, Western blot analysis of activated PBT lysates revealed that the predominant protein band detected by this MAb was 17 kd (p17), distinct from the 23-kd core protein and 26- to 30-kd mature glycosylated forms of interleukin-6. Immunoaffinity isolation and amino-terminal amino acid sequence analysis of p17 revealed identity with the histone H2B, a finding confirmed by Western blot analysis of purified histones and by similar staining of activated PBTs with an unrelated anti-histone MAb. Neither histone staining nor DNA strand breakage was observed in freshly isolated PBTs; however, after T cell activation, histone immunoreactivity appeared to precede the appearance of DNA strand breaks, with both increasing to a maximal level by day 3 after activation. Two-parameter confocal immunofluorescence microscopy of histone and DNA staining confirmed a lack of histone immunoreactivity in viable cells and demonstrated co-localization of histone epitopes with abnormally clumped chromatin in apoptotic cells. These data indicate that alteration of histone epitope accessibility is a marker of early apoptosis and suggest that multiparameter flow cytometric analysis of intracellular epitopes may be a powerful tool in the elucidation of intracellular mechanisms of apoptosis. PMID- 8702004 TI - T cell subsets in normal human epidermis. AB - Freshly isolated human lymphocytes from normal epidermis were characterized with respect to distribution of subsets. The major T cell receptor-alpha beta + compartment was enriched for CD4+, for CD8 alpha alpha +, and for CD4-CD8-T lymphocytes compared with peripheral blood lymphocytes. Furthermore, the majority of epidermal T lymphocytes expressed a CD45RA- CD45ROhigh Fas+ memory/effector phenotype; many also expressed early-intermediate activation markers, suggesting antigenic exposure in vivo. The cutaneous lymphocyte-associated antigen was expressed by almost all epidermal T lymphocytes. A large portion also expressed the mucosal-associated alpha e beta 7-integrin, which may mediate retention to epithelium. These data show that T lymphocytes present in normal human epidermis constitute a distinct T cells compartment with characteristics similar to that of other epithelial-associated T cell compartments. PMID- 8702005 TI - Inhibition of atherosclerosis in CD4 T-cell-ablated and nude (nu/nu) C57BL/6 hyperlipidemic mice. AB - T lymphocytes and monocyte/macrophages are prominent components of atherosclerotic lesions, and many of these cells are activated and secreting cytokines. To determine the role of these cells in the pathogenesis of atherosclerosis, we studied its development in T-cell-deficient mice fed a high fat atherogenic diet. Depleting euthymic mice of their CD4+ lymphocytes by 20 weekly injections of CD4 monoclonal antibodies reduced the mean area of their aortic lesions by approximately 70%. Similarly, the mean lesion area of T-cell deficient nude (nu/nu) mice was 10% of the size of that of their heterozygote (nu/+) litter mates. Flow cytometric studies of splenic T cells and analyses of serum total and HDL cholesterol of these mice indicated that the differences in mean lesion areas among the experimental groups were most closely correlated with differences in splenic T cells content. These studies suggest that in these two models T lymphocytes contribute to the pathogenesis of early atherosclerotic lesions and that a further understanding of this phenomenon may provide future approaches toward the prevention and treatment of the disease. PMID- 8702006 TI - Serum stimulation, cell-cell interactions, and extracellular matrix independently influence smooth muscle cell phenotype in vitro. AB - Vascular injury profoundly alters the vessel wall microenvironment, and smooth muscle cells respond with cell cycle re-entry, loss of contractile elements, extracellular matrix remodeling, and altered signaling by endogenous growth factors and their receptors. Environmental cues include stimulation by exogenous mitogens and both cell-cell and cell-matrix interactions. Modeling this process in smooth muscle cells in vitro, these environmental determinants were varied independently and the phenotypic consequences assessed. Mitogenic stimulation with serum promoted the synthesis of collagen and fibronectin and the expression of fibroblast growth factor receptor-1 and suppressed the content of smooth muscle alpha-actin, myosin heavy chain, and basic fibroblast growth factor. Low cell density (reduced cell-cell contact) was also associated with enhanced extracellular matrix protein production, increased fibroblast growth factor receptor-1 expression, and reduced contractile protein and basic fibroblast growth factor content. The influence of serum stimulation and reduced cell-cell contact were independent and additive. Provision of a type I collagen matrix blunted the influence of serum and cell-cell contact on collagen synthesis but had minor effects on other measures of phenotype. Environmental factors thus independently influence smooth muscle cell phenotype, including endogenous growth factor expression and responsiveness, which can in turn influence the microenvironment of the vessel wall after injury. PMID- 8702007 TI - Expression of perforin in nasal lymphoma. Additional evidence of its natural killer cell derivation. AB - Eight patients with nasal lymphoma in whom fresh-frozen tissues were available were studied to elucidate the nature of the lymphoma cells. Two cases were diagnosed as diffuse, large cell lymphoma, and the remaining six cases as diffuse, mixed cell types. Immunohistochemical studies revealed that all of the cases were positive for perforin, which is a specific marker for cytotoxic T or natural killer (NK) cells. As all of the cases were CD8 negative, the perforin positive finding further confirmed the concept that nasal lymphoma is a distinct neoplastic entity derived from NK or NK-related cells. Light microscopic immunohistochemical studies revealed that these nasal lymphoma cases could be classified into Leu19(CD56)+Leu4(CD3)+ (two cases) and Leu19(CD56)+Leu4(CD3)- (six cases) types according to the phenotypes of the proliferating cells. However, simultaneous staining for perforin and Leu4 (CD3) using immunoelectron microscopy on the Leu19+Leu4+ cases showed that the perforin-positive cells were different from the Leu4-positive cells. This finding suggests that the Leu4 positive cells are not neoplastic NK cells but reactive T cells. Six cases were positive for EBER-1 by in situ hybridization analysis. This finding reconfirms the previous studies that Epstein-Barr virus plays a significant role in the pathogenesis of nasal lymphoma. PMID- 8702008 TI - Expression of peptidyl-glycine alpha-amidating mono-oxygenase (PAM) enzymes in morphological abnormalities adjacent to pulmonary tumors. AB - Carboxyl-terminal amidated peptide hormones are known to be autocrine growth factors for lung tumors and tumor cell lines. Expression of the enzymes necessary for the biosynthesis of active amidated peptide hormones is therefore necessary for autocrine growth stimulation in lung tumors and possibly in the early proliferative stages of lung carcinogenesis. The peptidyl amidating enzymes have previously been identified in cell lines of all histological types of lung cancer and in lung tumors by immunohistochemistry and in situ hybridization. In this study we analyzed the expression of the peptidyl amidating enzymes in histological abnormalities found in the proximity of pulmonary tumors from a series of 59 patients. Most of the lesions in both the proximal airways (basal cell hyperplasia, carcinoma in situ, and some squamous metaplasia) and the alveoli (type II cell hyperplasia, bronchiolization of the alveoli, atypical alveolar hyperplasia, and isolated atypias) had a high proportion of cells strongly positive for the peptidyl amidating enzymes. The intense expression of peptidyl amidating enzymes in type II cell hyperplasia and atypical alveolar cells, together with the high frequency of these abnormalities in the alveoli, which is an area that does not express these enzymes in normal lung, points to the involvement of peptide hormones in the growth biology of pulmonary tumors. These findings suggest that peptide hormone stimulation of mitogenesis is an early event in tumor progression and merits additional investigation as a target for early detection and chemo-intervention of lung carcinogenesis. PMID- 8702010 TI - Non-obese diabetic (NOD) mouse. PMID- 8702009 TI - Clearance kinetics, biodistribution, and organ saturability of phosphorothioate oligodeoxynucleotides in mice. AB - We examined the dynamics of removal from circulation, tissue distribution, and persistence of phosphorothioate oligodeoxynucleotides (S-ODN) anti-tumor-necrosis factor and a control of random sequence (randomer) in mice. After intravenous injection, the majority (96%) of S-ODN cleared rapidly from the circulation in the first two phases. In the first phase, 37.8 +/- 2.3% of the radioactivity had a mean half-life (t1/2) of 2.0 +/- 0.4 minutes. In the second phase, 58.1 +/- 1.5% of the radioactivity cleared with t1/2 of 12.6 +/- 0.2 minutes. The catabolic phase, constituting a minor proportion (4.1 +/- 0.8% of the total radioactivity), had a mean t1/2 of 2.7 +/- 0.5 hours. At a low dose (1 microgram) tissue distribution of both S-ODN anti-tumor-necrosis-factor and randomer were similar. The liver and kidneys were the major organs involved in uptake and removal of S-ODN. Autoradiographic studies showed the liver Kupffer cells to be the major site of uptake and renal urinary space for elimination. The clearance rate from the circulation was increased with the dose of S-ODN. In contrast, the fraction of radioactivity localized in the kidneys, liver, and spleen was decreased with increase in dosage. Furthermore, at a high dose (200 micrograms), the tissue distribution of the S-ODN anti-tumor-necrosis-factor differed significantly from the randomer. These findings have general significance in showing that the liver and kidneys are the major organs for removal of S-ODN and these organs are saturable at high doses. In addition, the results have specific importance in defining different parameters, dose and base composition, that affect utilization of antisense oligonucleotides for controlling gene expression in vivo. PMID- 8702011 TI - Altered neurofilament expression does not contribute to Lewy body formation. PMID- 8702012 TI - Preventing opportunistic infections in human immunodeficiency virus-infected persons: implications for the developing world. AB - More than 18 million persons in the world are estimated to have been infected with human immunodeficiency virus (HIV), the cause of the acquired immunodeficiency syndrome (AIDS). As immunodeficiency progresses, these persons become susceptible to a wide variety of opportunistic infections (OIs) The spectrum of OIs varies among regions of the world. Tuberculosis is the most common serious OI in sub-Saharan Africa and is also more common in Latin America and in Asia than in the United States. Bacterial and parasitic infections are prevalent in Africa; protozoal infections such as toxoplasmosis, cryptosporidiosis, and isosporiasis are also common in Latin America. Fungal infections, including cryptococcosis and Penicillium marneffei infection, appear to be prevalent in Southeast Asia. Despite limited health resources in these regions, some measures that are recommended to prevent OIs in the United States may be useful for prolonging and improving the quality of life of HIV-infected persons. These include trimethoprim-sulfamethoxazole to prevent Pneumocystis carinii pneumonia, toxoplasmosis, and bacterial infections; isoniazid to prevent tuberculosis; and 23-valent pneumococcal vaccine to prevent disease due to Streptococcus pneumoniae. Research is needed to determine the spectrum of OIs and the efficacy of various prevention measures in resource-poor nations, and health officials need to determine a minimum standard of care for HIV-infected persons. An increasing problem in the developing world, HIV/AIDS should receive attention comparable to other tropical diseases. PMID- 8702013 TI - Genetic similarity among Central and South American populations of Leishmania (Viannia) braziliensis. AB - Four populations of Leishmania (Viannia) braziliensis from Central America, Colombia, Peru and Brazil were analyzed and compared for up to 20 enzyme loci. Each of the 180 isolates could be identified as L. braziliensis using combined data from glucose phosphate isomerase and mannose phosphate isomerase. When the most common enzyme band was present at a frequency of < or = 0.95, the populations were polymorphic (more than a single allomorph for an enzyme) for more than 50% of the loci. Included were diagrammatic representations of the enzyme polymorphisms. Comparisons of levels of enzyme polymorphism and of genetic similarity among other Leishmania populations, L. tropica, L. major, L. mexicana, and L. donovani sensu lato, were discussed. The mean +/- SD level of genetic similarity among the four populations was 0.924 +/- 0.036 (range 0.878-0.966), which indicates that L. braziliensis is probably one reproductive population from Mexico in the north to Brazil and Peru in the south. PMID- 8702014 TI - Cellular and molecular biological analyses of nifurtimox resistance in Trypanosoma cruzi. AB - We induced nifurtimox resistance in both epimastigotes and tissue culture-derived trypomastigotes of several Trypanosoma cruzi strains. The magnitude of nifurtimox resistance was strain-dependent. A variety of karyotype changes occurred in the nifurtimox-resistant (NR) strains. Chromosome-specific DNA probes identified karyotype changes common to the NR strains that were moderately resistant to nifurtimox but not the NR strains that were highly resistant to nifurtimox. A marked increase in nifurtimox resistance in one NR strain was accompanied by a 100% increase in nuclear DNA mass and a 50% increase in kinetoplast DNA mass. These data suggest that nifurtimox resistance can be accompanied by a wide spectrum of DNA changes. Both trypanothione reductase and heat-shock proteins may modulate the effects of exposure of T. cruzi to nifurtimox. However, we did not detect qualitative or quantitative differences in these genes or their transcripts between the NR strains and the sensitive strains from which they were derived. An understanding of the spectrum of diversity in nifurtimox resistance at the cellular and molecular levels demonstrated in this report is critical in the development of drug therapies against Chagas' disease. PMID- 8702015 TI - Silent transmission of the dengue virus in southern Taiwan. AB - Immunoglobulin M (IgM) antibody to dengue virus was examined from a total of 3,099 serum samples collected in southern Taiwan. Of 1,232 sera collected from a junior high school and four elementary schools in Liu-Chiu, 35 were IgM-positive, demonstrating that the dengue virus has been circulating on the island, despite the fact that no epidemic has been reported in the past 10 years. Sixteen of 925 sera collected from three elementary schools in Tung-Kang in 1991 were found to be IgM-positive and two of 192 sera from adults in the local community were positive. The IgM-positive subjects tended to be aggregated around a port. Fishing boats that had stopped in neighboring endemic countries were presumed to have introduced the virus periodically, causing a low level of inapparent infections. In the Kaohsiung area, two of 108 suspected clinical cases and four of 642 community-based sera were IgM-positive. Rapid urbanization has provided appropriate circumstances for vector breeding in this area and the high population density has also increased contact frequency between humans and mosquito vectors. This has, in turn, increased the possibility of silent transmission of the dengue virus via either intermittent reintroduction of the virus or continuation of inapparent infections or both. Establishment of a early warning system using the IgM antibody capture-enzyme-linked immunosorbent assay is suggested for effective monitoring of the disease. PMID- 8702016 TI - Prevalence of antibodies to hepatitis A, B, C, and E viruses in a healthy population in Leon, Nicaragua. AB - A cross-sectional survey of the seroprevalence of hepatitis A virus (HAV), B (HBV), C (HCV), and E (HEV) antibodies in a healthy population in Leon, Nicaragua was conducted and associated with demographic data. The overall prevalence of antibodies to HAV was 94.6%, to HBV 6.5% and to HEV between 4.6% and 8.0%, whereas none of 399 tested subjects showed confirmed seropositivity to HCV. A high HAV seropositivity rate (72.7%) was observed even in the lowest age groups tested (2-4 years of age). In contrast, HBV and HEV seropositivity was observed mainly in adults, the seroprevalence in > 40-year-old individuals being 15.4% and 17.6%, respectively. The overall mean hepatitis B surface antigen carrier rate was estimated to be 0.9%, and in individuals more than 20 years of age, 2.0%. The prevalence of anti-HAV as well as anti-HEV was significantly higher in people having their water supply outside rather than inside the house. Furthermore anti HAV seroprevalence correlated with lack of access to a flush toilet. Hepatitis B virus seropositivity was more frequent in people living in a crowded environment than in those living with few household members. These findings indicate that hepatitis A is a childhood infection in Nicaragua and that the spread of the infection is facilitated by poor socioeconomic conditions. In contrast, HBV infection is relatively infrequent in the country and HCV seems to be very uncommon. Hepatitis E virus infection may occur in all age groups and is apparently associated with water-borne transmission. PMID- 8702017 TI - Short report: association between leprosy and hepatitis C infection: a survey in a region of central Brazil. AB - Prevalence of antibodies to hepatitis C virus (HCV) was determined in 216 Brazilian lepromatous patients (83 outpatients and 133 institutionalized). The overall prevalence was 1.8% after confirmatory tests. No difference in the HCV infection was found between outpatients and institutionalized ones. Our results from this region of Central Brazil are lower than those found in leprosy patients in Africa and in Japan. PMID- 8702018 TI - Probability of infection with Trypanosoma cruzi of the vector Triatoma infestans fed on infected humans and dogs in northwest Argentina. AB - The probability that an uninfected Triatoma infestans would become infected with Trypanosoma cruzi after a single feed on people or dogs seropositive for T. cruzi was estimated in Amama, a rural village in northwest Argentina where transmission had resurged four years earlier. The prevalence of seropositivity for T. cruzi was 34.2% among 225 people tested, and 65.1% among 83 dogs tested. Parasitemia was detected by xenodiagnosis in 29.3% of 41 seropositive persons and in 85.3% of 34 seropositive dogs. Parasitemia decreased with age more sharply in seropositive people than in seropositive dogs. Seropositive humans infected 2.6% (95% confidence interval = 1.6%-3.6%) of 963 third or fourth instar nymphs fed once on them, whereas dogs infected 48.7% (44.7%-52.7%) of 610 nymphs. The probability of bug infection increased significantly with instar and was positively related to molting success. The infectivity to bugs of seropositive dogs was 12 times higher than that of seropositive children, and 100 times higher than that of seropositive adults. The weighted probability of infection of an uninfected bug fed randomly on any dog (0.3082) was about 50 times higher than that of bugs fed on any human (0.0062). Such differences in relative infectivity, combined with the relative host-feeding preference of domiciliary Triatoma infestans for dogs, reinforces the important role of domestic dogs as a risk factor for the domestic transmission of T. cruzi. PMID- 8702019 TI - Hypoendemic malaria in Rondonia (Brazil, western Amazon region): seasonal variation and risk groups in an urban locality. AB - A longitudinal epidemiologic survey (1989-1991) plus a cross-sectional parasitologic, clinical, and sociodemographic survey (July-October 1990) were conducted in Candeias do Jamary, a village with approximately 7,000 inhabitants in Rondonia, Brazil. Analysis of the results revealed hypoendemic malaria with a complex epidemiology. Plasmodium vivax predominated over P. falciparum infections while infections with P. malariae were absent. Malaria is present throughout the year but was clearly seasonal with epidemic outbreaks in the dry season from June to August. Malaria prevalence was lower in children less than 10 years of age and significantly higher in young adult males, which represent the high-risk group. The incidence of locally acquired infections (autochthonous cases) was significantly lower in the rainy season as compared with the dry season. This is not true with respect to heterotochthonous (imported) malaria cases, that is, malaria acquired elsewhere by Candeias residents, most of whom are male adults working outside the town. In both cases, however, the age and sex distribution of prevalence and its relationship with occupational activities indicate a predominance of outdoor transmission. The results of the cross-sectional survey are in agreement with those of the longitudinal passive survey and, in addition, disclose the absence of asymptomatic infection. PMID- 8702021 TI - Forty years of chromoblastomycosis in Madagascar: a review. AB - Confirmed cases of chromoblastomycosis in Madagascar from 1955 through 1994 were studied retrospectively. The total number of cases reported was 1,343, of which 98.5% were confirmed by histopathology. Only 30.8% of the cases showed a positive cultivation on mycologic media, and Fonsecaea pedrosoi was identified from 61.8% of the fungal strains. Two distinct areas of endemic chromoblastomycosis, each with a characteristic ecosystem and a single species, are identified. Madagascar represents the most important focus of this fungal disease described to date in the world. PMID- 8702020 TI - A cross-sectional serodiagnostic survey of canine leishmaniasis due to Leishmania chagasi. AB - Jequie, a community of about 144,500 inhabitants located in the State of Bahia, Brazil, is endemic for both visceral and cutaneous leishmaniases. In the present epidemiologic study, the urban and inhabited periurban areas of the town were divided into 140 clusters of 0.25 km2 each. The seroprevalence of canine Leishmania antibodies was investigated using an enzyme-linked immunosorbent assay as a screening test since its sensitivity was significantly higher than that of an indirect immunofluorescence assay. A total of 1,681 dogs was surveyed in 34 randomly sampled clusters. The overall prevalence of Leishmania antibodies in the dog population was 23.5%, with intracluster prevalences ranging from 0% to 67%. There was no correlation of these seroprevalences with the intracluster densities of canine populations, or with the distances from individual clusters to the town center. Moreover, the Leishmania transmission did not seem to follow any clear cut spatial pattern, since large disparities in the seroprevalences of contiguous clusters were found. Curiously, human cases of visceral leishmaniasis have never been observed in some clusters with a relatively high prevalence of canine seroprevalences. Eight parasite isolates from seropositive dogs were found to belong to the same serodeme and zymodeme as Leishmania (L.) chagasi. The implications of these findings with respect to the epidemiology and control of American visceral leishmaniasis are discussed. PMID- 8702022 TI - Effect of cooking fuels on respiratory diseases in preschool children in Lucknow, India. AB - The association between cooking fuels and the risk of respiratory disease in preschool children in Lucknow, India was studied. We interviewed mothers of 650 study children, randomly selected from among 28 urban poor neighborhoods. Children were eligible if they were less than five years of age, free of congenital heart disease, malignancy, and compromised immune status. Respiratory disease (defined as one or more of the following: runny nose, cough, sore throat, breathlessness, and noisy respiration) was assessed by observation. Exposures included the types of cooking fuels and duration of their use in the last week and other potential predictors of respiratory disease. Odds ratios (ORs) for disease were adjusted for covariables using multiple logistic regression. The point prevalence of respiratory disease was 14.5%. Cooking fuels used were wood (56.0%), kerosene (24.2%), coal (19.2%), gas (15.4%), and dung cakes (8.6%). Use of dung cakes, a sun-dried mixture of cow or buffalo dung and straw, as cooking fuel was associated with respiratory disease (adjusted OR = 2.69, 95% confidence interval [CI] = 1.37-5.31, P = 0.004), as was overcrowding in the bedroom (adjusted OR = 1.25 for each additional person, 95% CI = 1.11-1.41, P = 0.001). Age, weight, gender, family income, and household structure were not associated with disease. Use of dung cakes as cooking fuel and overcrowding in the bedroom increased the risk of respiratory disease. Interventions to modify oven design or install chimneys and, where feasible, to reduce the number of people sleeping together should be considered. PMID- 8702023 TI - Dynamic models of schistosomiasis morbidity. AB - Previous attempts to assess the health impact of schistosomiasis control programs on community morbidity have been limited by a lack of a theoretical framework that describes the dynamic relationships between infection and morbidity. In this paper, a model of schistosomal morbidity is developed and parameterized. Morbidity is divided into that due to current heavy infection, and early and late stages of chronic disease. The model was parameterized using data showing resolution of disease after treatment, correlations between prevalence of disease and intensity of infection and using age-morbidity profiles. The fitted parameters suggest that early manifestations of disease such as hepatomegaly in Schistosoma mansoni and S. japonicum infections would resolve relatively quickly following treatment whereas later forms of disease such as liver fibrosis resolve very slowly or not at all. Similar general conclusions were obtained with data on early and late forms of urinary tract morbidity in S. haematobium. PMID- 8702025 TI - Bancroftian filariasis: the patterns of filarial-specific immunoglobulin G1 (IgG1), IgG4, and circulating antigens in an endemic community of northeastern Tanzania. AB - The profile of filarial-specific immunoglobulin G1 (IgG1), IgG4, and Wuchereria bancrofti-specific circulating antigen (Og4C3) was analyzed in individuals one year of age and older in a community with high endemicity for Bancroftian filariasis. The overall microfilarial (mf) prevalence in the examined population was 29%. Fifty-one percent of the population were positive for IgG1 (39% among mf positive individuals and 63% among mf-negative individuals), whereas 90% were positive for IgG4 (97% among mf-positives and 87% among mf-negatives). The levels of IgG1 and IgG4 were clearly related to mf status and age, but they were unrelated to sex, intensity of microfilaremia, or chronic clinical manifestations. The mean level of IgG1 was significantly higher among amicrofilaremic than among microfilaremic individuals, and it was significantly higher in younger than in older persons. The highest mean IgG4 level was seen in young microfilaremic children, where the level was significantly higher than that in amicrofilaremic children of the same age group and that of older individuals irrespective of mf status. For those 10 years of age and older, the difference in mean level of IgG4 between microfilaremic and amicrofilaremic individuals was not significant. The prevalence of positivity for circulating antigens was 28% in the 1-4-year-old age group, and it increased gradually to 84% in the 50-59-year-old age group (average of 55% for all examined). When analyzed in relation to circulating antigen status, the difference in antibody levels between microfilaremic and amicrofilaremic adults decreased for IgG1 but increased for IgG4, indicating that the IgG1 levels were more related to mf status than to infection status, whereas the IgG4 levels were more related to infection status than to mf status. PMID- 8702024 TI - Phase I safety and immunogenicity testing of clinical lots of the synthetic Plasmodium falciparum vaccine SPf66 produced under good manufacturing procedure conditions in the United States. AB - Two clinical lots of alum-adsorbed SPf66 vaccine produced in the United States were evaluated in separate, open-label, Phase I clinical trials involving 15 healthy, malaria-naive, 18-45-year old men and women. Subjects received 2 mg doses subcutaneously in alternate arms at 0, one, and six months. Safety was assessed by monitoring local and systemic reactions and laboratory parameters. The most common side effects were erythema and local tenderness at the site of injection, which increased in frequency with subsequent doses of vaccine. These local reactions were considered mild and resolved within 24-48 hr. Eleven of 14 volunteers who received all three doses of vaccine seroconverted by enzyme-linked immunosorbent assay. The distribution of high, medium, and low nonresponders was comparable with that seen in trials of Colombian-produced vaccine. One high responder developed antibodies reactive with asexual stage parasite antigens by immunofluorescence and immunoblot. The results indicated that at full adult doses, SPf66 of U.S. origin is mildly reactogenic and induces immune responses similar to those reported for SPf66 of Colombian origin. PMID- 8702026 TI - Cytoadherence characteristics of Plasmodium falciparum isolates from Thailand: evidence for chondroitin sulfate a as a cytoadherence receptor. AB - The association between cytoadherence of Plasmodium falciparum-infected erythrocytes and the severity of malaria has been evaluated. In this study, we investigate adherence to C32 melanoma cells, CD36, intracellular adhesion molecule-1 (ICAM-1), thrombospondin (TSP), E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and chondroitin sulfate A (CSA) of 36 P. falciparum isolates from patients suffering from acute falciparum malaria. Adherence to purified adhesion molecules varied greatly among different parasite isolates. All isolates but one adhered to CD36, but none bound to E-selectin and VCAM-1 beyond control levels. Some P. falciparum isolates adhered to ICAM-1 and to CSA, a newly identified receptor for adherence. There was no correlation between in vitro binding to any one receptor and the patients' conditions. In addition, we investigated the characteristics of adherence to CSA and to C32 melanoma cells. Infected erythrocytes continued to adhere after trypsin digestion and soluble CSA inhibited adherence to C32 melanoma cells in a dose-dependent manner. The results imply a role for CSA in the natural infection of P. falciparum. PMID- 8702027 TI - Experimental infection of guinea pigs with Venezuelan hemorrhagic fever virus (Guanarito): a model of human disease. AB - Venezuelan hemorrhagic fever (VHF), a newly described disease caused by an arenavirus (Guanarito), has resulted in multiple human deaths in Venezuela. To develop an animal model of this disease, strain 13 and Hartley strain guinea pigs were inoculated subcutaneously with Guananto strain 95551 of arenavirus in a pilot study to determine susceptibility of the species to the virus. All animals were killed when moribund 12-14 days following inoculation. Animals were necropsied and tissues were fixed and examined by both light and electron microscopy. Viral antigen was demonstrated in the tissues by immunohistochemistry at both the light and electron microscopic levels. Lesions were characterized by single cell necrosis of epithelium of the gastrointestinal tract, interstitial pneumonia, lymphoid and hematopoietic cell necrosis, and the presence of platelet thrombi in occasional blood vessels associated with hemorrhage. Viral antigen was demonstrated in lymphoid tissues and macrophages, endothelial cells of multiple organs, pulmonary epithelium, epithelium of the gastrointestinal tract, and in miscellaneous other tissues and cells. Intact virions and typical arenavirus inclusions were demonstrated by immunoelectron microscopy in these tissues. Based on these findings, the guinea pig appears to be a valid animal model of the human disease. PMID- 8702028 TI - Short report: lack of virus replication in arthropods after intrathoracic inoculation of Ebola Reston virus. AB - To evaluate the potential for arthropods to serve as reservoir hosts of Ebola virus, three mosquito species, Aedes albopictus, Aedes taeniorhynchus, and Culex pipiens, and a soft tick, Ornithodoros sonrai, were inoculated with 1O2.5 plaque forming units of Ebola Reston virus. After incubation at 22 degrees C for 11 days, at least six specimens of each species were triturated and examined for evidence of viral replication by enzyme-linked immunosorbent assay and plaque assay. There was no evidence of viral replication in any of the arthropods tested. Because intrathoracic inoculation bypasses various barriers to viral infection, the lack of replication of Ebola Reston virus in these inoculated arthropods indicates that these mosquito species and soft ticks probably are not involved as natural reservoirs of Ebola virus. PMID- 8702029 TI - Antigenic and genetic analysis of Japanese encephalitis viruses isolated from Korea. AB - The characteristics of the five Korean isolates of Japanese encephalitis (JE) virus were compared with those of the already reported JE virus strains from Japan and China using the hemagglutination test and polymerase chain reaction direct sequencing of the JE virus genomes (capsid/premembrane, envelope region). The hemagglutination patterns of all the isolates were distinctly different from the Nakayama-NIH strain. The optimal pH of hemagglutination of all the Korean isolates was 6.6-7.0 and the reaction range was broader than that of the Nakayama NIH strain. The 198 nucleotide sequences in the capsid/premembrane gene region of the five Korean strains indicated that they were classified into the third genotype group, the JE strains from the countries in the temperate zone including the Nakayama-NIH, JaOArS982, and Beijing-1 strains. Four of the five Korean isolates formed a unique phylogenetic tree within the third genotype group, although the last one was genetically highly related to the Nakayama-NIH strain. The 251 nucleotide sequences in the envelope region of the five isolates were more divergent than the capsid/premembrane region. Four of the five isolates showed a large nucleotide divergency as compared with the JaOArS982 strain (< or = 12.4%), but the last one was similar to the JaOArS982 strain (98% of nucleotide homology). These results suggest the evolutionary divergence of the JE viruses isolated in Korea from the Japanese and Chinese strains and that there may exist at least two antigenically different JE virus strains in Korea. PMID- 8702030 TI - Appraisal of various random amplified polymorphic DNA-polymerase chain reaction primers for Leishmania identification. AB - Pathogenic Leishmania can cause a variety of symptoms ranging from asymptomatic or mild infections to severe mucocutaneous disease, partly according to the species of Leishmania involved. Genomic and kinetoplast-derived DNA probes as well as species complex-specific kinetoplast-derived polymerase chain reaction (PCR) primers have been successful for parasite identification in epidemiologic and taxonomic studies. However, the lack of a species DNA probe or PCR primer set, their relatively poor availability, and unknown comparative sensitivity and specificity have precluded their routine and widespread use as identification tools in many laboratories. This study addresses this problem for 28 different random amplified polymorphic DNA (RAPD)-PCR primers that have been assessed regarding their sensitivity, specificity, and reliability for distinguishing each of four closely related New World Leishmania species. The degree of relatedness between species was quantified and estimates were made of the accuracy and precision of the determinations. The results compared well with standard methods for Leishmania classification. The application of RAPD-PCR for screening isolates for possible interspecific hybrids is also demonstrated. PMID- 8702031 TI - Malaria in the pregnant African woman: epidemiology, practice, research, and policy. PMID- 8702032 TI - Comparability of treatment groups and risk factors for parasitemia at the first antenatal clinic visit in a study of malaria treatment and prevention in pregnancy in rural Malawi. AB - The problems of Plasmodium falciparum infection in pregnant women have been described in numerous sub-Saharan African countries, but the frequency of parasitemia at the first antenatal visit and risk factors for infection have not been fully investigated. During a prospective antimalarial treatment and prophylaxis trial in pregnant women in Malawi (three groups receiving a chloroquine regimen and one group receiving a mefloquine regimen), we examined women at their first antenatal clinic visit to evaluate these issues and to verify that subjects in the study treatment/prevention arms were similar. Among 4,127 women with enrollment blood smear results, 1,836 (44.5%) were parasitemic. The highest infection rates and densities were observed in primigravidas (66% infected, geometric mean parasite density [GMPD] = 1,588 parasites/mm3 of whole blood), followed by second pregnancies (46% infected, GMPD = 615 parasites/mm3) and subsequent pregnancies (29% infected, GMPD = 238 parasites/mm3), (P < 10(-6) for both infection prevalence and density, by chi-square test for trend). Significant risk factors for parasitemia at first antenatal clinic visit in a multivariate model included low gravidity, high transmission season, no use of prophylaxis before first antenatal clinic visit, young age (< 20 years), human immunodeficiency virus (HIV) infection, low hematocrit, short stature, and second trimester (compared with third trimester). Women in the different treatment arms of the study were generally similar in many characteristics; statistically significant differences, where present, were small. Targeting malaria control efforts to women in their first or second pregnancy and during the high transmission season will be an important strategy to reach most parasitemic women and minimize resource expenditure. Women infected with HIV had a 55% increased risk of parasitemia at their first antenatal clinic visit and may represent an additional important risk group whose numbers may be increasing and who may benefit from identification and management for malaria. PMID- 8702033 TI - The problem of malaria and malaria control in pregnancy in sub-Saharan Africa. AB - Plasmodium falciparum infection in pregnant women frequently leads to placental infection and low birth weight (< 2,500 grams) of the infant, particularly in the areas of high malaria transmission found in sub-Saharan Africa. Low birth weight is widely known to be an important risk factor for early infant mortality. To reduce the risk that maternal infection poses to child survival, many antenatal clinic programs recommend and provide antimalarial chemoprophylaxis, often with chloroquine (CQ) as a recommended element for antenatal care. Prior to the 1980s, despite widespread advocacy for this intervention, little was known about the effect of this intervention strategy. As an introduction to the Mangochi Malaria Research Project, which examined the efficacy of several antimalarial regimens using CQ or mefloquine in pregnant women in Malawi, we describe the background of knowledge regarding malaria infection in pregnant African women and the important elements of an intervention and prevention strategy. PMID- 8702034 TI - Malaria parasite infection during pregnancy and at delivery in mother, placenta, and newborn: efficacy of chloroquine and mefloquine in rural Malawi. AB - Despite international recommendations to use malaria treatment and prevention in pregnant women in malaria-endemic areas, few studies have evaluated the efficacy of available antimalarial regimens. This issue is of particular concern in the face of spreading chloroquine (CQ)-resistance of Plasmodium falciparum in malarious areas of sub-Saharan Africa. In a prospective trial in rural Malawian pregnant women, we examined three regimens using CQ (including the existing national policy regimen) and one regimen using mefloquine (MQ). The efficacy of the regimens was determined by comparing rates of clearance of initial parasitemia; prevention of breakthrough infection; and parasitemia at delivery in maternal peripheral blood, placental blood, and in infant umbilical cord blood. Among 1,528 parasitemic women at enrollment, 281 (18.4%) had persistent infections; and among 1,852 initially aparasitemic women, 320 (17.3%) had breakthrough parasitemia on one or more follow-up visits. Compared with women on MQ, women on a CQ regimen were at significantly greater risk of persistent and breakthrough infection (odds ratios [OR] = 30.9 and 11.1, respectively, P < 10( 6)). Other significant risk factors for persistent and breakthrough infections in a multivariate model included first pregnancy; enrollment in the rainy or postrainy season; maternal age < or = 25 years; seropositivity to the human immunodeficiency virus (HIV) (persistent infections only); and no use of antimalarial prophylaxis before enrollment (breakthrough infections only). At delivery, compared with women on MQ, women on a CQ regimen were at significantly greater risk of peripheral, placental, or umbilical cord blood parasitemia (OR = 8.7, 7.4, and 4.1, respectively, P < 10(-6)). Additional risk factors for parasitemia at delivery in multivariate models included first pregnancy; delivery in the rainy or postrainy season; HIV-seropositivity; and maternal age < or = 25 years (risk for peripheral and placental blood parasitemia only). Maternal anemia (hematocrit < 30%) at enrollment or at delivery was not associated with persistent or breakthrough parasitemia or parasitemia at deliver in these multivariate models. While factors leading to increased malaria parasite exposure (high transmission seasons) and lowered or altered host immune response (low pregnancy number, young age, and HIV infection) are important risk factors for malaria in pregnant women, the use of an ineffective intervention (CQ in a setting with CQ-resistant parasites) was the most important determinant of P. falciparum parasitemia in these pregnant women. Strategies to reduce the impact of malaria in pregnant women must use efficacious interventions and may need to consider targeting the intervention to the most susceptible women during the seasons of high malaria exposure. PMID- 8702035 TI - The effect of malaria and malaria prevention in pregnancy on offspring birthweight, prematurity, and intrauterine growth retardation in rural Malawi. AB - While there is broad evidence for the adverse effects of Plasmodium falciparum infection in pregnancy, and the World Health Organization recommends preventive strategies, there is markedly reduced efficacy in sub-Saharan Africa of the most widely available, affordable and used antimalarial drug for chemoprophylaxis chloroquine (CQ). During 1987-1990, we studied pregnant women in an area of high malaria endemicity in rural Malawi to compare the efficacy of CQ (the drug recommended by national policy) with mefloquine (MQ, a relatively new and highly effective antimalarial) in preventing low birth weight (LBW) due to prematurity and intrauterine growth retardation (IUGR). Among 1,766 women monitored during at least their last six weeks of pregnancy with observed ingestion of their regimen and facility delivery of a live born singleton, their babies had a mean +/- SD birth weight of 2,905 +/- 461 gm and 16.8% had LBW. In a multivariate analysis, factors significantly associated with LBW included: first birth (odds ratio [OR] = 4.27), female infant (OR = 2.92), maternal human immunodeficiency virus infection (OR = 2.66), low maternal weight (OR = 1.95), and placental blood P. falciparum infection (OR = 1.71). Factors significantly associated with IUGR-LBW included first birth, female infant, low maternal weight, and placental malaria. Factors significantly associated with preterm-LBW included maternal syphilis infection, umbilical cord blood malaria, first birth, low maternal weight, and female infant. Use of an effective antimalarial (MQ) was protective against LBW through its effect on reducing placental and umbilical cord blood malaria infection. The proportion of LBW babies born to women on MQ (12.5% [parity adjusted for the population of delivering women]) was significantly lower than the proportion born to women on CQ (15.5%; P = 0.05). Effective prevention of malaria in pregnant women in malaria-endemic settings may reduce the likelihood of LBW by 5-14%, and may reduce the amount of preventable LBW by more than 30%. When evaluating antenatal care programs, health policy makers must consider providing an effective preventive drug (either MQ or other drugs identified in additional studies, e.g., sulfa-pyrimethamine compounds) as a means to prevent low birth weight and its consequences. PMID- 8702036 TI - Impairment of a pregnant woman's acquired ability to limit Plasmodium falciparum by infection with human immunodeficiency virus type-1. AB - In Africa, the human immunodeficiency virus (HIV) is the most serious emerging infection and Plasmodium falciparum malaria is one of the most prevalent infectious diseases. Both infections have serious consequences in pregnant women, their fetuses, and infants. We examined the association between HIV and P. falciparum in pregnant women enrolled in a malaria chemoprophylaxis study in rural Malawi. Pregnant women (n = 2,946) were enrolled at their first antenatal clinic visit (mean 5.6 months of pregnancy), placed on one of three chloroquine regimens, and followed through delivery. Plasmodium falciparum parasitemia was measured at enrollment, monthly thereafter, at delivery, and 2-6 months postpartum; placental and newborn (umbilical cord blood) infection was measured for hospital-delivered infants. Serum collected during pregnancy was tested for antibodies to HIV by enzyme-linked immunoassay with Western blot confirmation. Parasitemia was detected in 46% of 2,946 women at enrollment and 19.1% at delivery; HIV seroprevalence was 5.5%. The prevalence and geometric mean density (GMPD) of parasitemia at enrollment and at delivery were higher in HIV seropositive(+) than in HIV-seronegative(-) women (at enrollment: 57% prevalence and a GMPD of 1,558 parasites/mm3 versus 44% and 670/mm3, respectively; P < 0.0001; and at delivery: 35% and 1,589/mm3 versus 18% and 373/mm3; P < 0.0005). Placental infection rates were higher in HIV(+) compared with HIV(-) women, (38% versus 23%; P < 0.0005). This association was strongest in multigravidas. Compared with infants born to HIV(-) women, newborns born to HIV(+) women had higher rates of umbilical cord blood parasitemia. Both HIV(+) and HIV(-) women had similar rates of parasitemia 2-6 months postpartum. The HIV infection diminishes a pregnant woman's capacity to control P. falciparum parasitemia and placental and newborn infection, the major determinants of the impact of P. falciparum on fetal growth and infant survival. PMID- 8702037 TI - Malaria treatment and prevention in pregnancy: indications for use and adverse events associated with use of chloroquine or mefloquine. AB - In sub-Saharan Africa, women frequently report a variety of symptoms during pregnancy, some of which indicate possible illness. Given the adverse impact of malaria in pregnancy, these events may be important for at least two reasons: it may be possible to use reported fever illness as a determinant of which women need an antimalarial intervention, and, it is possible that adverse symptoms following the antimalarial intervention may be important determinants of continued adherence to the prevention regimen. In a cohort of pregnant women enrolled at first antenatal clinic visit in rural Malawi, we evaluated reported fever, determined parasitemia, and placed the women on antimalarial regimens containing chloroquine (CQ) or mefloquine (MQ). We then systematically evaluated reported symptoms following antimalarial drug use after initial therapeutic doses and subsequent prophylactic doses, and monitored women throughout their pregnancy and at delivery. Among 4,187 enrolled women, 1,048 (25%) reported at least one febrile episode during pregnancy before their first antenatal clinic visit. Factors associated with this reported fever included low parity, enrollment in the rainy season, human immunodeficiency virus seropositivity, use of antimalarial prophylaxis before enrollment, high socioeconomic status, normal (compared to low) maternal height and weight, and literacy. Fever before the first antenatal clinic visit was reported by 24.4% of parasitemic women and 25.4% of aparasitemic women; the sensitivity and specificity of fever to identify parasitemic women was 24% and 71%, respectively. In contrast, the sensitivity and specificity of first or second pregnancy to identify parasitemic women was 71% and 57%, respectively. Among women on a CQ or MQ regimen, approximately 60% reported side effects (e.g., itching, dizziness, and gastrointestinal disturbances) after a treatment dose and approximately 25% reported side effects after a prophylactic dose; rates and types of symptoms reported were similar in the CQ and MQ groups. Few serious side effects were observed and rates of fetal loss were low and similar in the groups. Reliance on fever illness will be wholly inadequate to identify parasitemic women; therefore, our findings support existing World Health Organization recommendations that presumptive treatment and prevention regimens should be offered to all pregnant women. When resources are inadequate to offer antimalarial prophylaxis to all pregnant women, women in their first or second pregnancy may be a more appropriate target group than pregnant women with reported fever. Education regarding expected minor side effects may reduce rates of poor compliance and improve the effectiveness of the prevention effort. PMID- 8702038 TI - Transplacental transmission of Plasmodium falciparum in rural Malawi. AB - Malaria during pregnancy may result in fetal exposure to malaria when parasites are transmitted across the placenta. To document the rate of transplacental passage of Plasmodium falciparum and to identify the risk factors for congenitally acquired malaria infection, we examined umbilical cord blood for malaria parasites from 2,080 newborn infants born to mothers enrolled in a study of malaria prophylaxis during pregnancy. Cord blood parasitemia was detected in 140 (6.7%) newborn infants with a geometric mean density of 187 parasites/microliter (range 12-99, 752 parasites/microliter). The likelihood of umbilical cord blood parasitemia was closely linked to the parasite density of placental malaria infection and the density of maternal peripheral blood parasitemia at the time of delivery; all babies born to women with both placental and peripheral blood parasitemia densities > or = 10,000/microliter had cord blood parasitemia. In a multivariate logistic regression model, male sex, premature delivery, and placental and maternal peripheral blood malaria parasitemia were independently associated with a baby being born with umbilical cord blood parasitemia. In this setting, highly endemic for malaria, transplacental transmission of malaria from infected placentae occurs frequently and is directly related to the density of maternal malaria infection. PMID- 8702039 TI - The effect of placental malaria infection on perinatal mortality in rural Malawi. AB - Perinatal deaths (fetal or infant deaths from the 28th week of pregnancy up to the seventh day after birth) occur as a result of adverse conditions during pregnancy, labor, and delivery, or in the first few days of life. Placental malaria infection is known to increase the risk of delivery of a low birth weight infant, thus, potentially increasing the risk of perinatal and infant mortality. To better understand the relationship among the adverse events in pregnancy, including placental malaria infection, adverse conditions in labor, and birth weight to perinatal mortality, we investigated the perinatal mortality among a cohort of infants born to rural Malawian women for whom placental malaria infection status and birth weight were documented. Among the 2,063 mother singleton infant pairs, there were 111 perinatal deaths (53.8 perinatal deaths per 1,000 births). The risk of perinatal death increased as birth weight decreased. Risk factors identified for perinatal mortality among all infants excluding birth weight included abnormal delivery (cesarean section, breech, or vacuum extraction), a history of a late fetal or neonatal death in the most recent previous birth among multiparous women, reactive maternal syphilis serology, nulliparity, and low socioeconomic status. Placental malaria infection was not associated with increased perinatal mortality, but was associated with lower perinatal mortality among normal birth weight (> or = 2,500 g) infants (odds ratio = 0.35, 95% confidence interval = 0.14, 0.92). Interventions to address these risk factors could have a substantial impact on reducing perinatal mortality in this population. PMID- 8702040 TI - Prospective assessment of mortality among a cohort of pregnant women in rural Malawi. AB - Maternal mortality has recently received attention as a neglected public health problem in many developing countries where mortality rates are estimated to be 8 200 times those in developed countries. Most maternal mortality estimates in sub Saharan Africa have used retrospective methods because of the lack of large population-based studies. The Mangochi Malaria Research Project, a trial of antimalarial chemoprophylaxis in pregnant women, provided an opportunity to examine prospectively mortality among the study women. Among 4,053 monitored pregnant women, 27 women were known to have died during pregnancy, labor, delivery and the one-year follow-up period. Three women died during the antenatal period and 12 died within six weeks of delivery for an estimated maternal mortality rate of 370 per 100,000 pregnant women; this rate was consistent with rates reported from retrospective surveys in Malawi. Twelve women died between three and 10 months after delivery, and the mortality rate in this nonmaternal period was estimated to be 341 per 100,000. Mortality rates in the maternal and nonmaternal periods were surprisingly similar. Human immunodeficiency virus type 1 (HIV-1) infection and anemia were strongly associated with death in the nonmaternal period. Mortality among infants of mothers who died was 3.7 times higher than the rate of death among infants born to mothers who survived. This study highlights that for rural Malawian women, pregnancy and delivery are risky periods, that the death of the mother adversely affects the survival of her children, and that HIV and anemia are important contributors to nonmaternal mortality in reproductive-age women. Strategies to reduce mortality among women of child-bearing age in sub-Saharan Africa must focus on decreasing the complications of pregnancy and delivery, and address important preventable causes of death, such as anemia and HIV infection. PMID- 8702041 TI - Malaria infection in infancy in rural Malawi. AB - Malaria infection is thought to be relatively infrequent in infants less than 90 days of age in sub-Saharan Africa. In a rural area of Malawi with intense malaria transmission, we examined the occurrence of malaria infection during infancy and risk factors for parasitemia in the first three months of life in the cohort of infants delivered to women in the Mangochi Malaria Research Project. Among 3,915 liveborn singleton infants, 3,432 (87.7%) were seen at least once during infancy (first 12 months of life); of these, malaria blood smear results were available on 2,649 (77.2%). Overall, in a cross-sectional analysis, 23.3% of infants at three months of age were infected with Plasmodium falciparum; this proportion increased to more than 30% during the high transmission season. By the age of 10 months, 60-80% of the infants were infected, depending on the season. Geometric mean parasite density increased each month after two months of age and plateaued at seven months of age. In a life-table analysis, the median time to acquisition of a positive smear was 199 days. Factors independently associated with smear positivity at < 4 months of age included visit during high transmission season (adjusted odds ratio [AOR] = 4.1), maternal smear positivity at the same visit (AOR = 3.5), history of infant fever in the previous two weeks (AOR = 2.8), birth during the rainy season (AOR = 1.7), low socioeconomic status (AOR = 1.6), and low maternal education (AOR = 1.5). The specificity of a recent fever history for malaria infection in early infancy was high (> 70%). Intervention strategies to reduce the risk of early infant infection need to be targeted toward mothers of infants at high risk. PMID- 8702042 TI - Infant and second-year mortality in rural Malawi: causes and descriptive epidemiology. AB - Community information based on causes and circumstances of death in infants and young children in Malawi was obtained in a prospective cohort of babies delivered to women enrolled in a malaria-prevention-in-pregnancy study. Vital status information was obtained through home visits every two months; for children who died, questions were asked concerning age and date of death, symptoms preceding death, care sought, location of death (home versus facility), and duration of illness. Of 3,274 liveborn singleton infants, 181, 397, and 152 deaths occurred in the neonatal, postneonatal, and second year of life, respectively. For neonates, proportionate mortality was greatest for sepsis/tetanus (16.7%) and fever (8.6%); however, for more than half of neonatal deaths evaluated the cause was not identified. Up to 30% of neonatal deaths may have been related to prematurity. In the postneonatal period, gastrointestinal illness (39.6%), fever (18.3%), and respiratory illness (14.7%) were the leading causes. Most postneonatal illnesses lasted 1 week or less. Two-thirds of postneonatal deaths occurred outside of a health care facility, although 80% were brought to a facility for care during their illness. Infectious disease syndromes continued to be important in the second year of life, with gastrointestinal (31.6%), fever (23.5%), and measles (20.6%) the most commonly reported causes of death. In this area of rural sub-Saharan Africa, neonatal mortality contributes substantially to infant mortality, and prematurity is considered to be an important component of early neonatal deaths; infectious disease syndromes predominate in the postneonatal and second year of life. Strategies to reduce infant deaths in sub Saharan Africa must consider these factors, as well as the observations that most children who died had brief illnesses, were taken to a health care facility before death, yet died at home. PMID- 8702043 TI - Objectives and methodology in a study of malaria treatment and prevention in pregnancy in rural Malawi: The Mangochi Malaria Research Project. AB - Malaria infection due to Plasmodium falciparum has been widely recognized as associated with important adverse consequences in pregnant women, particularly in areas of high transmission. Although strategies using antimalarial drugs for prevention had been recommended, even by the late 1980s, few studies had been carried out to examine the efficacy of these prevention efforts. The objectives of the Mangochi Malaria Research Project investigation were to determine the comparative efficacy of regimens containing chloroquine (CQ) or mefloquine (MQ) antimalarial treatment and chemoprophylaxis in an area of CQ-resistant P. falciparum on the following outcomes: 1) the frequency of placental malaria infection; 2) the frequency of low birth weight; 3) the frequency of prematurity or intrauterine growth retardation; 4) the frequency of maternal fever illness and severe anemia; and 5) the likelihood of infant acquisition of malaria infection. Although the investigation was not designed to evaluate the role of antimalarial chemoprophylaxis and treatment on infant mortality reduction, because babies born to study women were scheduled to be followed for up to two years of life, the study allowed for an examination of mortality and morbidity in this population. The sample size was insufficient to provide more than descriptive analysis of mortality and morbidity in the fetal, perinatal, neonatal, postneonatal, and infant time intervals. The study design allowed for the evaluation of two additional aspects of maternal and infant health: other determinants of the above-listed outcomes in addition to malaria prevention (e.g., maternal age, gravidity, socioeconomic status, infection with human immunodeficiency virus or syphilis) and reported cause-specific mortality in the fetal-to-infant intervals. The study design included 22 months of enrollment of pregnant women at their first antenatal clinic visit from four clinic sites in Mangochi District, Malawi, with assignment to one of four antimalarial regimens and prospective follow-up through pregnancy, at delivery, and during infancy. All drug dosing was performed under supervision by the study team, making this an evaluation of intervention efficacy (excluding the role of patient compliance). PMID- 8702044 TI - Rates and risk factors for mortality during the first two years of life in rural Malawi. AB - Developing nations in sub-Saharan Africa experience childhood mortality rates that are much higher than any other region of the world. In a rural Malawian community we investigated risk factors for deaths occurring during the neonatal (birth-28 days), postneonatal (29-365 days), infant (birth-365 days), and second year (366-730 days) periods among a cohort of 3,724 infants monitored from birth. The neonatal mortality rate in this cohort was 48.6 per 1,000 live births (LB); the postneonatal mortality rate was 108.7/1,000 LB. The overall infant mortality rate was 157.3 deaths/1,000 LB and the mortality rate for the first two years of life was 223.7 deaths/1,000 LB. The predominate risk factors for neonatal deaths identified in multivariate analysis were low (hazard ratio [HR] = 2.3) and very low birth weight (HR = 12.7), first pregnancy (HR = 1.8) and maternal syphilis infection (HR = 2.4). Maternal infection with human immunodeficiency virus (HIV) (HR = 1.5) predominated for postneonatal deaths. Low (HR = 1.4) and very low (HR = 5.0) birth weight, first pregnancy (HR = 1.6), maternal HIV infection (HR = 2.4), and the combination of low education and low socioeconomic status (SES) of the mother (HR = 2.0) were the most important factors during the infant period. Maternal HIV infection (HR = 3.3) and the combination of low education and low SES of the mother (HR = 2.6) were the predominate risk factors for mortality occurring during the second year. Factors that were significant in univariate analysis but not significant in the final multivariate models included prematurity, previous adverse reproductive outcome, dying during high malaria transmission season, and being born at home. Interventions to prevent maternal HIV infection and low birth weight and treatment of syphilis infection would have a great impact on reducing early childhood deaths. Improving the delivery of health care and education to women during their first pregnancy and to the most socially disadvantaged women may also help reduce the burden of early childhood mortality in communities such as the one studied in Malawi. PMID- 8702045 TI - Evaluation of maternal practices, efficacy, and cost-effectiveness of alternative antimalarial regimens for use in pregnancy: chloroquine and sulfadoxine pyrimethamine. AB - With the knowledge that an efficacious antimalarial administered to pregnant women would markedly reduce placental malaria and its associated risk of low birth weight (LBW), investigations were conducted to identify an antimalarial regimen practical for nationwide implementation through the antenatal clinic (ANC) system. Maternal practices, including ANC utilization and malaria treatment and prevention during pregnancy were evaluated as part of a national malaria knowledge, attitudes, and practices survey. A second study was conducted to evaluate the efficacy and cost of selected alternative antimalarial regimens. Women in their first or second pregnancy were placed on chloroquine (CQ) treatment (25 mg/kg) followed by weekly CQ (300 mg) (CQ/CQ); sulfadoxine pyrimethamine (SP) treatment followed by CQ (300 mg weekly) (SP/CQ); or SP treatment during the second trimester and repeated at the beginning of the third trimester (SP/SP). With 87% of women attending ANC two or more times during pregnancy, most pregnant women in Malawi could be reached with an antimalarial intervention. Among 159 women in their first or second pregnancy receiving CQ/CQ, SP/CQ, and SP/SP, placental malaria parasitemia rates were 32%, 26%, and 9%, respectively (P = 0.006, by chi-square test). The SP/SP regimen was also markedly more cost-effective in preventing infant deaths, costing $75 per infant death prevented, compared with $481 for SP/CQ and $542 for CQ/CQ. These investigations suggest that a regimen consisting of two treatment doses of SP during pregnancy is an efficacious and cost-effective intervention to prevent placental malaria, and LBW-associated mortality, that can be delivered to pregnant women through ANCs in settings similar to those found in rural Malawi. PMID- 8702047 TI - [Sepsis, SIRS, MODS--new findings, unanswered questions]. PMID- 8702046 TI - Developing effective strategies for malaria prevention programs for pregnant African women. AB - The control of malaria in pregnant African women, one of several child survival strategies applied through antenatal care, has been particularly challenging. Prevention and control recommendations for typical areas of high Plasmodium falciparum transmission have promoted the use of antimalarial chemoprophylaxis to prevent placental infection. Persistently low program coverage coupled with diminishing intervention effectiveness have forced a re-evaluation of the relative importance of malaria in pregnancy. The Mangochi Malaria Research Project (MMRP), a prospective evaluation of malaria prevention in pregnant women in rural Malawi conducted during 1987-1990, contributed to establishing new criteria for policy and program development for malaria prevention in pregnancy. The principle findings of the MMRP include: 1) populations at risk of the adverse consequences of malaria in pregnancy include women with low parity, women infected with human immunodeficiency virus, pregnancy during the high malaria transmission season, and the use of a malaria drug that is suboptimally efficacious; 2) the estimated maximum benefits of an antimalarial intervention that clears placental and umbilical cord parasitemia are a 5-12% reduction of low birth weight (LBW), an approximately 35% reduction in the risk of LBW for risks that are actually preventable once a woman has become pregnant (e.g., risks such as infectious disease or poor nutrition during gestation), and a 3-5% reduction in the rate of infant mortality; 3) the intervention must be capable of rendering the woman malaria parasite free, including clearance of parasites from the placental vascular space and umbilical cord blood; 4) other diseases adversely affect pregnancy outcome and, while the control of malaria in pregnancy may not warrant independent programming, if coupled with prevention programs to provide a range of antenatal services, the incremental costs of malaria control may prove to be highly cost-effective; and 5) the choice of a regimen must balance intervention efficacy with safety, availability, affordability, and simplicity of delivery, and several antimalarials may meet these criteria. The Malawi Ministry of Health has modified its malaria prevention in pregnancy recommendations and now faces the challenge of effective programming to improve child survival. PMID- 8702048 TI - [The physiopathology of sepsis. Current concepts]. AB - Clinical manifestations of sepsis, such as systemic inflammatory response and multiple organ dysfunction syndrome, are considered to be the results of a decompensated host defense response. If tissue injury is sufficiently severe to overwhelm local defense mechanisms, systemic activation of these essentially protective mechanisms may lead to autodestructive "host defense failure disease." This is not always caused by invading bacteria; sterile inflammation such as results from multiple trauma or pancreatitis can initiate a similar response. Evidence suggests that the activation of the macrophage/monocyte system that underlies the systemic inflammatory response may reflect one facet of a more generalized dysregulation of intercellular communication, as well as a dysfunction of such subcellular processes as signal transduction or stress gene expression. Alterations in signal transduction or stress gene expression can affect the host defense response to subsequent stressful events in either a negative or a positive sense. In particular, the sequential induction of acute phase and heat shock response may initiate programmed cell death, reflecting a potential molecular mechanism for the development of multiple organ dysfunction syndrome. The development of anti-inflammatory treatment strategies seems to be hampered by the discrepancy between locally protective and systemically detrimental properties of the host defense response. PMID- 8702049 TI - [Serum protein binding of fentanyl. The effect of postoperative acute phase reaction with elevated alpha 1-acid glycoprotein and methodologic problems in determination by equilibrium dialysis]. AB - Numerous basic drugs are extensively bound to alpha 1-acid glycoprotein. Fentanyl, with a pKa value of 8.43, is also a basic drug. Protein binding studies have yielded contradictory results concerning binding of fentanyl to alpha 1-acid glycoprotein. In this study we investigated time courses of serum protein concentrations and serum protein binding of fentanyl during postoperative acute phase reaction, assuming that an increase of alpha 1-acid glycoprotein is accompanied by an increase of serum protein binding, if fentanyl is extensively bound to alpha 1-acid glycoprotein. Fentanyl protein binding measurements using equilibrium dialysis can be affected by volume shifts and pH changes. Therefore, volume shifts from buffer to serum and the influence of various phosphate buffers on increasing pH due to loss of CO2 were also evaluated. METHODS. Thirteen patients with no history of renal or hepatic disease undergoing an operation with a significant acute phase reaction were studied. Preoperatively and on the first 3 postoperative days serum concentrations of alpha 1-acid glycoprotein, albumin, total protein and apolipoprotein A and B were determined by rocket immunoeolectrophoresis, biuret method and laser nephelometry, respectively. Corresponding serum protein binding of fentanyl was measured by adding 40 ng of fentanyl to 1 ml serum followed by equilibrium dialysis at 37 degrees C for 4 h. A 0.167 M phosphate buffer (pH 7.27), which gave a final pH of 7.40, was used. Volume shifts from buffer to serum were measured. Fentanyl concentration in serum before dialysis (FS) was determined by gas chromatography, and fentanyl concentration in buffer after dialysis (FB) was determined by radioimmunoassay. Serum protein binding (SPB) was calculated by the formula: SPB = (FS - FB - FB*c)/(FS - FB) where c is a correction factor. Ten randomly selected patient sera were dialyzed against four phosphate buffers of different pH values and molarities, and the serum pH at the end of equilibrium dialysis was measured. RESULTS. Postoperatively, the serum concentration of alpha 1-acid glycoprotein rose to 151% of the control value. In contrast, serum protein binding of fentanyl did not change significantly, with a slight decrease to 96% of control value. There was a significant decrease in serum concentrations of albumin (3rd postoperative day), total protein (2nd postoperative day) and apolipoprotein B (1st-3rd postoperative day) to 85%, 90% and 75% of control values, respectively. Changes in apolipoprotein A concentration were not significant. Protein binding of fentanyl did not correlate with alpha 1-acid glycoprotein and apolipoprotein A, but there was a positive linear relationship between protein binding of fentanyl and albumin, total protein and apolipoprotein B. At the end of equilibrium dialysis the mean volumes of the serum and buffer compartments were 1114 +/- 72 and 834 +/- 68 microliters, respectively. The two phosphate buffers, with pH 7.30 (0.15 M) and pH 7.27 (0.167 M), gave final serum pH of 7.42 and 7.40, respectively. CONCLUSIONS. Present findings suggest that in contrast to other basic drugs, fentanyl binding to alpha 1-acid glycoprotein is of minor importance. In agreement with the findings of former studies, protein binding of fentanyl depended on albumin, total protein and apolipoprotein B concentrations. Due to unspecific binding of fentanyl by hydrophobic interactions, a major role of albumin, which amounts to about 60% of total protein, seems to be evident. Determining fentanyl protein binding by equilibrium dialysis, volume shifts must be taken into account if calculation is based on fentanyl concentrations in plasma (serum) and buffer after dialysis, and an appropriate buffer must be used. PMID- 8702050 TI - [A comparative study of intravenous opioid analgesia. Sufentanil and alfentanil for extracorporeal shock-wave lithotripsy in urologic patients]. AB - Extracorporeal shock-wave lithotripsy (ESWL) is the method of choice for the treatment of solitary stones in the kidney or ureter. Early lithotripters required prolonged immobility of the patient and caused considerable pain, necessitating general or epidural anaesthesia during the procedure. Modern lithotripters are quicker, but still require analgesia. Intravenous opioids are currently the drugs in favour. The opioids most commonly used are fentanyl and its shorter-acting analogue, alfentanil. The latter has a more rapid onset and, because of its reduced lipid solubility, is less cumulative. Sufentanil is a new opioid that is also of the phenylpiperidone group and has been recently licensed and introduced in Germany. Its pharmacokinetic and pharmacodynamic properties suggest an intermediate duration of action, high analgesic potency, and cardiovascular stability with diminished respiratory depression. In this prospective double-blind study, the effects of alfentanil and sufentanil on cardiovascular and respiratory parameters, the quality of analgesia, degree of sedation and the number and type of side-effects were compared. PATIENTS AND METHODS: After giving informed consent and with the approval of the hospital ethics committee, 62 patients (ASA I or II) were investigated. They were randomly allocated to two groups, either receiving sufentanil (n = 32) or alfentanil (n = 30) during ESWL. No premedication was given. Excluded were patients with pain prior to treatment, patients treated with a spasmolytic or analgesic drug and those who had undergone ESWL within the last 6 months. The loading dose was given as a 5-min infusion to each group. The heart rate, systolic and diastolic blood pressure, percutaneous oxygen saturation (SpO2), and the transcutaneous capillary carbon dioxide tension (PicCO2) were recorded prior to the procedure (i.e. before administration of opioid), after 1000 and after 2000 shock waves and then 1 and 2 h after the end of lithotripsy. After 1000 and 2000 shock waves, and 1 an 2 h after the treatment, the patients were asked to express their degree of tiredness and pain on a visual analogue scale (VAS). The occurrence of side-effects such as nausea, vomiting, pruritus or other unpleasant sensations were noted by an anaesthesia nurse. Simultaneously, the anaesthetist recorded his/her impression of the patient's tiredness and degree of pain, both by using the VAS. He was not allowed to question the patient, nor was he aware of the patient's own scores. At the end of the observation period both the patient and the anaesthetist related their overall satisfaction with the anaesthetic procedure, again by using the VAS. Data were analysed with the Mann-Whitney-U for comparisons between groups and with the Wilcoxon test within each group. The side-effects were analysed with the Chi-square test. RESULTS: The systolic and diastolic blood pressure remained stable in both groups during and after treatment. The mean heart rate was different between the two groups at the beginning, and after the end of the treatment it dropped in both groups, but no significant difference was seen between groups. The PicCO2 rose from an initial mean of 36.8 mm Hg to a maximum of 44.6 mm Hg after 1000 shock waves in the sufentanil group, and from 37.8 mm Hg to 46.0 mm Hg after 2000 shock waves in the alfentanil group. The differences were significant within groups until 1 h after the end of the treatment, but there was no significant difference between groups. The oxygen saturation SpO2 dropped slightly in both groups. The differences were not significant between groups. In the alfentanil group, one patient had a maximum carbon dioxide tension of 83 mm Hg after 2000 shock waves, whereas in the sufentanil treated group the oxygen saturation fell to 72% in one case. (ABSTRACT TRUNCATED) PMID- 8702051 TI - [Ventilation-perfusion ratio in patients with acute respiratory insufficiency]. AB - Acute respiratory failure is characterised by mismatch of ventilation with perfusion (VA/Q). The multiple inert gas elimination technique (MIGET) is a complex method which allows the description of a virtually continuous distribution of VA/Q ratios. We investigated VA/Q relationships in patients admitted to the intensive care unit due to acute respiratory failure and thus requiring for mechanical ventilation. METHOD: Eight patients (mean APACHE 11 = 22 +/- 4) who suffered from acute pneumonia (n = 4), traumatic lung contusion (2), toxic lung failure (1) or massive bilateral atelectasis (1) were investigated by MIGET within 3 days after the begin of mechanical ventilation. A mixture of six inert gases, dissolved in isotonic saline, was infused continuously. Arterial and mixed venous blood samples and expired gas samples were obtained and analysed by gas chromatography. Blood-gas partition coefficients were determined, and the ratios of retention and excretion were calculated. The data were transformed in a 50-compartment model of blood flow and ventilation against VA/Q ratio. We assessed the amount of intrapulmonary shunt (VA/Q = 0), low VA/Q regions (VA/Q = 0.005-0.1), normal VA/Q regions (VA/Q = 0.11-10), high VA/Q regions (VA/Q = 11 100) and dead space ventilation (VA/Q > 100). Furthermore, we calculated the logarithmic standard deviation of pulmonary perfusion distribution (logSDQ). RESULTS: In all patients we found moderate to severe intrapulmonary shunt and VA/Q mismatching. The data are expressed as median values and ranges. Inert-gas measured shunt was 21% (3-45.5%), whereas low VA/Q regions were little affected. Normal VA/Q regions ranged from 41.5% to 96.0% (median 76.8%). The amount of alveolar dead space ventilation was 28% (19.7-41.8%). Median logSDQ (normal range 0.3-0.6) was calculated to be 0.855 (0.540-1.490). In patients presenting with moderate lung injury (Murray score < 3), a moderate increase in shunt and a moderate VA/Q mismatch were observed. In contrast, patients with severe lung failure and critically decreased oxygenation (Murray score > 3) were characterised by massive shunting and VA/Q mismatching. Additionally, low VA/Q and high VA/Q compartments and an increase in dead space ventilation was found in these patients. CONCLUSIONS: The impairment of oxygenation in patients with acute respiratory failure is due to several pathophysiological mechanisms: increase in intrapulmonary shunt, VA/Q-mismatching and dead space ventilation, according to the severity of lung failure. We conclude from our results that the prevention and/or reduction of non-ventilated lung areas (atelectasis) is an outstanding therapeutic strategy in the treatment of patients with acute respiratory failure. From this point of view, several techniques of systemic changes in body position should be integrated as supportive therapeutic strategies. PMID- 8702052 TI - [The effect of prophylactically administered n-acetylcysteine on clinical indicators for tissue oxygenation during hyperoxic ventilation in cardiac risk patients]. AB - Hyperoxic ventilation, used to prevent hypoxia during potential periods of hypoventilation, has been reported to paradoxically decrease whole-body oxygen consumption (VO2). Reduction in nutritive blood flow due to oxygen radical production is one possible mechanism. We investigated whether pretreatment with the sulfhydryl group donor and O2 radical scavenger N-acetylcysteine (NAC) would preserve VO2 and other clinical indicators of tissue oxygenation in cardiac risk patients. METHODS: Thirty patients, requiring hemodynamic monitoring (radial and pulmonary artery catheters) because of cardiac risk factors, were included in this randomized investigation. All patients exhibited stable clinical conditions (hemodynamics, body temperature, hemoglobin, F1O2 < 0.5). Cardiac output was determined by thermodilution and VO2 by cardiovascular Fick. After baseline measurements, patients randomly received either 150 mg kg-1 NAC (n = 15) or placebo (n = 15) in 250 ml 5% dextrose i.v. over a period of 30 min. Measurements were repeated 30 min after starting NAC or placebo infusion, 30 min after starting hyperoxia (F1O2 = 1.0), and 30 min after resetting the original F1O2. RESULTS: There were no significant differences between groups in any of the measurements before treatment and after the return to baseline F1O2 at the end of the study, respectively. NAC, but not placebo infusion, caused a slight but not significant increase in cardiac index (CI), left ventricular stroke work index (LVSWI) and a decrease in systemic vascular resistance. Significant differences between groups during hyperoxia were: VO2 (NAC: 108 +/- 38 ml min-1m-2 vs placebo: 79 +/- 22 ml min-1m-2; P < or = 0.05), CI (NAC: 4.6 +/- 1.0 vs placebo: 3.7 +/- 1.11 min-1m-2; P < or = 0.05) and LVSWI (NAC: 47 +/- 12 vs placebo: 38 +/ 9; P < or = 0.05). The mean decrease of VO2 was 22% in the NAC group vs 47% in the placebo group (P < or = 0.05) and the mean difference between groups in venoarterial carbon dioxide gradient (PvaCO2) was 14% (P < or = 0.05). ST segment depression ( > 0.2 mV) was significantly less marked in the NAC group (NAC: -0.02 +/- 0.17 vs placebo: -0.23 +/- 0.15; P < or = 0.05). CONCLUSIONS: NAC helped preserve VO2, oxygen delivery, CI, LVSWI and PvaCO2 during brief hyperoxia in cardiac risk patients. Clinical signs of myocardial ischemia did not occur such as ST-depression if patients were prophylactically treated with NAC. This suggests that pretreatment with NAC could be considered to attenuate impaired tissue oxygenation and to preserve myocardial performance better in cardiac risk patients during hyperoxia. PMID- 8702054 TI - [New airbag-associated injuries in traffic accidents]. AB - Experimental studies have shown that in traffic accidents with frontal impact the new airbag system can significantly reduce the incidence of severe injuries and fatal outcome. The question of whether the airbag itself induces specific patterns of injury needs further investigation. Two cases of traffic accidents with airbag protection are presented here. The first case report clearly shows the life-saving and injury-reducing effect of the airbag system in a traffic accident with frontal impact at 100 km/h. In the second case only minor injuries of the face were diagnosed initially. Hemodynamic instability occurred after 3 h of hospitalization due to rupture of the azygos vein. Analysis of the presented cases shows that, besides the well-known benefits, there are certain injury patterns that seem to be related to the use of airbags. These have not been described before. It is concluded that patients who were involved in traffic accidents with airbag deployment have to be hospitalized and followed up carefully over time, even though they are initially stable, as potentially fatal sequelae of deceleration trauma can occur later. In our opinion it is not possible to estimate the severity of airbag-associated injuries with conventional methods. PMID- 8702053 TI - [Urodilatin (INN: ularitide). A new peptide in the treatment of acute kidney failure following liver transplantation]. AB - Acute renal failure (ARF) is a serious complication following liver transplantation. Many therapeutic regimens have been used so far but with limited success. Urodilatin (URO) is a new member of the atrial natriuretic peptide (ANP) family. When administered intravenously, URO induces strong diuresis and natriuresis with tolerable hemodynamic side effects. Preliminary non-controlled clinical studies demonstrate beneficial effects using URO as a therapeutic agent in patients suffering from ARF following heart and liver transplantation (HTx, LTx). These results prompted us to initiate this first controlled clinical trial to investigate whether URO infusion can improve renal function in patients with emerging ARF following LTx. METHOD: We initiated a randomized, double-blind, placebo-controlled study comparing five patients receiving i.v. URO infusion (20 ng/kg bw/min) with four placebo patients after informed consent was obtained. Optional inclusion criteria were oliguria/anuria ( < 0.5 ml/kg/h), refractory to conventional treatment including administration of furosemide and dopamine, increase of serum creatinine to a least 200% of preoperative values, and BUN levels > or = 25 mmol/l. The primary parameters for efficacy was the frequency of hemodialysis/hemofiltration. RESULTS: The frequency of hemodialysis/hemofiltration during URO or placebo infusion was significantly reduced (P = 0.03) in the URO-treated patients in comparison with placebo. BUN levels did not differ between two groups, but serum creatinine levels were consistently lower in the URO group. Diuresis tended to be stronger in the URO group, maintaining high levels despite a significant reduction in the administration of furosemide in comparison with placebo. CONCLUSION: We conclude that URO seems to be a new approach for the treatment of therapy-resistant postoperative ARF following LTx. PMID- 8702055 TI - [Quality assessment of continuing medical education]. AB - Medical performance is subject to quality control. Continuous advanced training (CAT) and continuous medical education (CME) are essential, and quality must be checked and assured: structure (contents, organizational form, framework, term, demands on teachers), process (term of the CAT, interaction between teachers and participants) and results (satisfaction and acceptance, increased knowledge, influence on medical treatment, improvement of the success rate of medical treatment. In emergency medicine one must differentiate between the necessity for CAT (e.g., certified proof required for working as an emergency physician) and a desire for CME (the individual task of the physician). The diversity of forms of CAT/CME reflects the different individual requirements. Using the new German guidelines to obtain qualification as an emergency physician, "Fachkundenachweises Rettungsdienst" offers measures for quality assessment and assurance can be obtained. STRUCTURE QUALITY: The recommendations for obtaining the "Fachkundenachweis Rettungsdienst" which have been valid until now date from the year 1983 and were set fourth explained very differently in the individual countries medical boards. This led to problems in the comparability of the essential CAT. The quality of the structure has now been improved by establishing new minimum requirements for clinical activity, specification of particular knowledge, number of supervised calls for the emergency car as well as participation in interdisciplinary CAT courses, dealing with general and special aspects of emergency medicine. The aim of these measures is not the (senseless) regimentation of CAT training measures, but the qualified transfer of specific medical knowledge and treatment guidelines. PROCESS QUALITY: On qualifying, hardly any physician has any didactic and/or rhetorical education; the physician must make a personal effort to obtain a qualification of this kind. Conventional and commonly practised forms of learning must therefore be set aside in favour of modern teaching methods (e.g. problem-orientated learning). This will lead to a better acceptance of CAT/CME measures. It is essential for the process quality that the teachers' education meets the following requirements: relevant knowledge of preclinical emergency medicine, rhetorical and didactic abilities, employment of relevant teaching techniques, flexibility in presentation, extensive experience in emergency medicine as well as enthusiasm for high-quality education. RESULT QUALITY: Questionnaires can be used to evaluate the satisfaction and acceptance of the participants, as well as their rating of individual speakers. The results are decisive for planning future CAT/CME measures. The transfer of knowledge can be estimated at the end of advanced training by questionnaire. However, this makes allowance for previous knowledge/skills and how much is forgotten. The influence of advanced training on further medical treatment can be seen in the quality of a given CAT/CME measure, but not in the success rate of medical treatment. The result desired can only be achieved by linking all system components of medical quality control and assurance. Advanced training provides a fundamental contribution to this end. PMID- 8702056 TI - [Difficult intubation in adults]. AB - GOAL OF THIS REVIEW: We review the recent literature and our experience in order to determine how one can recognize and handle patients with difficult endotracheal intubation. DEFINITION AND INCIDENCE: "An intubation is called difficult if a normally trained anesthesiologist needs more than 3 attempts or more than 10 min for a successful endotracheal intubation." The incidence of difficult intubation depends on the degree of difficulty encountered showing a range of 1-18% of all intubations to about 2/10000-1/million for "cannot ventilate-cannot intubate" situations. Three "cannot ventilate-cannot intubate" situations are presented that occurred at our institution in the last 10 years out of about 85000 anaesthesias. PREOPERATIVE RECOGNITION: Intubation will be overtly difficult in patients with a small mouth opening, protruding upper teeth, a stiff neck, engorgement of the tongue, cervical swelling after an operation for a face tumour, or in patients with an unstable cervical spine. In about 50-70%, a difficult intubation can be detected preoperatively in patients with grossly normal cervical anatomy by three indirect signs: if the soft palate cannot be visualized (Mallampati classification), if the inframandibular space is smaller than normal, and if the mobility of the atlanto-occipital joint is reduced to below 15 degrees. It is essential that these indirect parameters be tested preoperatively, especially in patients in whom general anaesthesial is planned for a caesarean section or if an ileus intubation is planned. HANDLING: General handling of difficult intubation, use of special material including a portable unit, and confirmation of the endotracheal position of an endotrachaeal tube are outlined (CO2 et, SaO2, fibreoptic bronchoscopy, direct visualization of the translaryngeal position of the tube). The laryngeal mask airway, transtracheal jet ventilation, and the mini-coniotomy are selectively presented as alternative airways. The American Society of Anesthesiologists' (ASA) difficult airway algorithm is presented. CONCLUSION: With better preoperative evaluation and clear guidelines and training for difficult intubation anaesthetic morbidity and mortality can be reduced. PMID- 8702057 TI - [Remarks on the work of H. Harke et al. Quality comparison of modified neurolept , balanced, and intravenous anesthesia. 1. Study design and patient analysis in the Krefelder study, 1992]. PMID- 8702058 TI - [Remarks on the work of A. Willweber-Strumpf et al. Directions for treatment of chronic pain with opioids. Results from the Serturner workshop "chronic opioid therapy"]. PMID- 8702059 TI - [Praktische medicine--what's new and important? 20th interdisciplinry forum of the Federal Medical Council, Koln, January 1996]. PMID- 8702061 TI - Anteroposterior dysplasia indicator. PMID- 8702062 TI - 1995 Edward H. Angle research prize. PMID- 8702060 TI - [Epidural analgesia in delivery]. PMID- 8702063 TI - Case report MH: treatment of a severe Class II, Division 1 malocclusion in a growing female with Class III skeletal relationship, low mandibular plane angle, and prominent nose and chin. PMID- 8702065 TI - Repair of orthodontically induced root resorption in adolescents. AB - The aim of this investigation was to study the reparative potential of orthodontically induced root resorption. Sixty-four maxillary right and left first premolars in 32 patients (15 boys and 17 girls, mean age 13.7 years) were moved buccally with fixed orthodontic appliances and a continuous force of 50 cN (approximately 50 g), activated weekly for 6 weeks. The patients were divided into 4 groups of 8. Retention periods varied from 1 week to 8 weeks. Histological preparations showed that root resorption affected all the test teeth. The percentage of resorptive areas that had begun to repair ranged from 28% after 1 week of retention to 75% after 8 weeks. The healing cementum was almost exclusively of the cellular type. Partial repair, with the resorption cavity walls only partially covered with cementum, was the most frequent type of repair during the first 4 weeks of retention (17% to 31%). Functional repair, with the total surface of the resorption cavity walls covered with varying thicknesses of cementum, dominated after 5, 6, 7 and 8 weeks of retention (33% to 40%). There were no large differences in the healing potential in the cervical, middle, and apical thirds of the root. After 8 weeks, three out of four resorptive areas showed some degree of repair. Individual variations in healing potential were large. PMID- 8702064 TI - Continuous versus interrupted continuous orthodontic force related to early tooth movement and root resorption. AB - The aim of the present clinical investigation was to assess the effects of continuous and interrupted continuous forces of the same magnitude (50 cN = 50 g) on orthodontic tooth movement and related adverse tissue reactions, i.e., root resorption. Thirty-two maxillary first premolars in 16 patients, 8 boys and 8 girls (mean age 13.9 years), were moved buccally by means of a fixed orthodontic appliance with a sectional arch. The patients were divided into two groups of 8, for experimental periods of 4 and 7 weeks. The continuous force was checked and reactivated weekly to 50 cN. The interrupted continuous force applied to the contralateral premolars was left uncontrolled for 3 weeks, after which the arch was made passive for 1 week for tissue rest and recovery. Tooth movements were studied on dental casts using a coordinate measuring machine (Validator 100, TESA SA, Renens, Switzerland). Horizontal tooth movement with continuous force was more effective than with interrupted continuous force after 7 weeks. Histological sections of the experimental teeth, however, showed no difference in the amount or severity of root resorption between the two forces. Individual variations in both the magnitude of tooth movement and the amount and severity of root resorption for both of the two force systems were great. PMID- 8702066 TI - Self-concept, Class II malocclusion, and early treatment. AB - Increased overjet has been associated with teasing, negative stereotyping, and low self-concept. Early treatment for children with Class II malocclusion is often recommended under the assumption that an improved dental appearance may benefit a child by increasing his or her social acceptance and hence self concept. The self-concept of 208 patients, age 7 to 15 years and with increased overjet, was measured before treatment using the Piers-Harris self-concept scale; a subset of 87 of these children were measured again after 15 months of early growth modification. The mean self-concept score for these children was above the population norm, and there was no association between the child's score and the magnitude of his or her overjet or age. Although some significant associations were found between Class II malocclusion features and self-concept scores, the explained variation in self-concept scores was low (R2 from 5% to 8%). There was no change in the mean self-concept score of these children during early treatment, nor was there any association between reduction of Class II malocclusion features and improved self-concept. These findings suggest that children with Class II malocclusion do not generally present for treatment with low self-concept and, on average, self-concept does not improve during the brief period of early orthodontic treatment. PMID- 8702067 TI - Treatment needs following activator-headgear therapy. AB - The purpose of this study was to analyze the types and prevalence of malocclusions that remain to be corrected after a period of combined activator headgear treatment. Study models of all patients who started treatment with an activator-headgear appliance in the graduate orthodontic clinic at the University of Oslo between 1972 and 1982 were screened. Patients initially judged to need a second phase of treatment and those later judged to have poor cooperation were omitted from the study. The results show that the most frequently remaining problems following activator-headgear treatment were overbite, overjet, and the presence of interdental spaces. Correction of the Class II skeletal and dental relationship was achieved in the majority of the cases. The only predictor for success was age at the time of treatment. PMID- 8702068 TI - Changes in soft tissue profile following treatment with the bionator. AB - The purpose of this study was to determine the changes in the soft tissue profile in patients treated in the mixed dentition with a bionator. Two groups of 30 individuals, between 9 and 12 years old and with Class II, Division 1, malocclusion were matched for age, sex, observation time, and dentofacial characteristics. Patients in the first group were treated with a bionator for an average of 18.7 months, resulting in a Class I molar relationship and reduction of overjet. The second group acted as a control and individuals did not receive any form of orthodontic treatment. Pretreatment and posttreatment cephalograms were analyzed and paired t-tests were used to compare the significance of changes between the two groups. Compared with the control group, the treated group demonstrated 1.97 degrees decrease in ANB, a 3.35 mm increase in anterior facial height, 2.22 degrees decrease in soft tissue profile convexity, and 17.4 degrees increase in mentolabial angle. PMID- 8702069 TI - Incisor stability in patients with anterior rotational mandibular growth. AB - The aim of this study was to investigate stability and patterns of relapse tendency in 42 children in whom mandibular incisors had been proclined as part of orthodontic treatment. All patients were selected on the basis of their predicted anterior rotational mandibular growth pattern. Results were based on study casts and standardized cephalometric profile radiographs, registered before and after active treatment as well as after a postretention period. Results demonstrate the clinical acceptability of the treatment principle employed in that the majority of the treatment changes were maintained well after the cessation of retention. There was, however, a general tendency to slight crowding in the mandibular incisor region in connection with bite deepening and reduction in intercanine distance. The reliability of prediction of mandibular rotation using the morphological criteria method is discussed. PMID- 8702070 TI - Correlation of orthodontic treatment demand with treatment need assessed using two indices. AB - The orthodontic treatment need of 105 first year university students (51 males and 54 females, mean age 19.75 years) at the University of Hong Kong was assessed using the Occlusal Index (OI) and the Index of Orthodontic Treatment Need (IOTN). The results were compared with the subjects' orthodontic treatment demand derived from a questionnaire. The OI assessment correlated better with the individuals' own perceptions of appearance than did the IOTN, and the treatment need indicated by the OI also correlated better with the individuals' actual treatment demands. PMID- 8702071 TI - Nurses denounce proposed cuts, changes in Medicare, Medicaid. PMID- 8702072 TI - Nurses can provide insight into advance directives. PMID- 8702073 TI - Every child by two: a program of the American Nurses Foundation. PMID- 8702074 TI - Nurses combat HIV/AIDS in adolescent community. PMID- 8702075 TI - Home care nursing: bringing the hospital home. PMID- 8702076 TI - CE sessions targeted to APRNs and RN consultants. PMID- 8702078 TI - Nurses advocate for human rights. PMID- 8702077 TI - Pew recommendations: what they mean for nursing. PMID- 8702079 TI - How to maintain your ANCC certification. PMID- 8702080 TI - How to read and understand your professional liability insurance policy. PMID- 8702081 TI - Pew Task Force recommendations. PMID- 8702082 TI - ANA-C: an opportunity to move forward. PMID- 8702083 TI - To die with dignity: should the current system allow for 'automatic' do-not resuscitate orders? As I see it. PMID- 8702084 TI - FLSA amendments threaten nurses. PMID- 8702085 TI - Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. AB - BACKGROUND: Evidence suggests that pathophysiologic processes in bone are important determinants of outcome in osteoarthritis of the knee. Low intake and low serum levels of vitamin D may compromise favorable responses of bone to osteoarthritis, predisposing patients to progression. OBJECTIVE: To determine whether dietary intake and serum levels of vitamin D would predict the incidence and progression of osteoarthritis of the knee in participants of the Framingham Study. DESIGN: Prospective observational study. SETTING: The Framingham Study. PARTICIPANTS: Participants in the Framingham Heart Study who had knee radiography at examinations 18 (done between 1983 and 1985) and 22 (done between 1992 and 1993) and received interim assessments of vitamin D intake and serum levels. MEASUREMENTS: Intake of vitamin D and serum levels of 25-hydroxyvitamin D, calculated on the basis of dietary habits and supplement use as reported on a questionnaire, were evaluated at examination 20 (1988 to 1989). Knee radiographs were given scores for global severity of osteoarthritis, using a modification of the scale of Kellgren and Lawrence (range, 0 to 4), and for the presence of osteophytes and joint-space narrowing (range, 0 to 3). Covariates measured at examinations 18 and 20 were age, sex, body mass index, weight change, injury, physical activity, health status, bone mineral density, and energy intake. RESULTS: 556 participants (mean age at baseline +/- SD, 70.3 +/- 4.5 years) had complete assessments. Incident osteoarthritis occurred in 75 knees; progressive osteoarthritis occurred in 62 knees. Serum levels of vitamin D were modestly correlated with vitamin D intake (r = 0.24). Risk for progression increased threefold in participants in the middle and lower tertiles for both vitamin D intake (odds ratio for the lower compared with the upper tertile, 4.0 [95% Cl, 1.4 to 11.6]) and serum levels of vitamin D (odds ratio for the lower compared with the upper tertile, 2.9[Cl, 1.0 to 8.2]). Low serum levels of vitamin D also predicted loss of cartilage, as assessed by loss of joint space (odds ratio, 2.3 [Cl, 0.9 to 5.5]) and osteophyte growth (odds ratio, 3.1 [Cl, 1.3 to 7.5]). Incident osteoarthritis of the knee occurring after baseline was not consistently related to either intake or serum levels of vitamin D. CONCLUSIONS: Low intake and low serum levels of vitamin D each appear to be associated with an increased risk for progression of osteoarthritis of the knee. PMID- 8702086 TI - Effect of hormone replacement therapy on bone mineral density in postmenopausal women with mild primary hyperparathyroidism. A randomized, controlled trial. AB - BACKGROUND: Most patients with primary hyperparathyroidism are postmenopausal women. The presence of osteopenia in persons with mild primary hyperparathyroidism is considered an indication for parathyroidectomy. No prospective, controlled trials have assessed medical therapies for osteopenia in primary hyperparathyroidism. OBJECTIVE: To examine the effects of estrogen progestin therapy (hormone replacement therapy) on bone mineral density and biochemical indices in postmenopausal women with mild primary hyperparathyroidism. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: University teaching hospital. PATIENTS: 42 postmenopausal women with mild primary hyperparathyroidism. INTERVENTION: Patients were randomly assigned to receive either conjugated estrogens, 0.625 mg/d, and medroxyprogesterone, 5 mg/d, or placebo. MEASUREMENTS: Bone mineral densities of the total body, lumbar spine, proximal femur (femoral neck, Ward triangle, trochanter), and proximal forearm were measured every 6 months using dual-energy x-ray absorptiometry. Biochemical indices of bone turnover and calcium metabolism were measured at baseline, 6 months, and 2 years. RESULTS: In the placebo group, bone mineral densities of the total body and the proximal forearm decreased significantly from baseline (mean +/- SE, -2.3% +/- 0.7% [p = 0.005] and -3.5% +/- 1.2% [p = 0.01], respectively). At the other sites, bone mineral density also tended to decline. In the hormone replacement therapy group, bone mineral density increased from baseline in the total body (1.3% +/- 0.4%; P = 0.004), lumbar spine (5.2% +/- 1.4%; p = 0.002), and femoral neck (3.4% +/- 1.5%; p = 0.05). The between-group differences in bone mineral density at the end of the study ranged from 3.6% to 6.6% and were significant at all sites (P > 0.001 and P < 0.05) except for the Ward triangle (p = 0.06). In the hormone replacement therapy group, serum alkaline phosphatase levels decreased by 22% (p = 0.0004 compared with baseline), urinary hydroxyproline excretion decreased by 42% (p = 0.0004), urinary N telopeptide excretion decreased by 54% (p = 0.001), and urinary calcium excretion decreased by 45% (p = 0.007). Hormone replacement therapy did not change levels of serum ionized calcium or intact parathyroid hormone. CONCLUSIONS: Although hormone replacement therapy has little effect on serum calcium levels, it suppresses bone turnover, reduces urinary calcium excretion, and increase bone mineral density throughout the skeleton in postmenopausal women with mild primary hyperparathyroidism. This therapy is thus an important management option for these patients. PMID- 8702087 TI - A prognostic model for predicting 10-year survival in patients with primary melanoma. The Pigmented Lesion Group. AB - OBJECTIVE: To develop a prognostic model, based on clinical and pathologic data that are routinely available to the clinician, that would estimate the chance for survival of a patient with primary cutaneous melanoma after definitive surgical therapy. DESIGN: Cohort analytical study. SETTING: University medical center. PATIENTS: 488 patients with primary cutaneous melanoma who had no apparent metastatic disease. Patients were followed prospectively for at least 10 years. An independent validation sample of 142 patients was used to assess the stability of the model. MEASUREMENTS: Six clinical and pathologic variables that predict survival and are readily available to the clinician were used to develop a prediction model. The variables were tested for their association with death by using a univariate logistic regression model. Point estimates were generated for the probability of surviving melanoma at 10 years. Variables that were statistically significantly associated with survival were retained for testing in a logistic regression model. RESULTS: 488 patients were followed prospectively for a median of 13.5 years (minimum, 10.0 years; maximum, 20.5 years). The overall 10-year survival of the study group was 78%. Four variables were found to be independent predictors of survival. Presented as adjusted odds ratios, from strongest to weakest relative predictive strength, these variables were tumor thickness (odds ratio, 50.8), site of primary melanoma (odds ratio, 4.4), age of the patient (odds ratio, 3.0), and sex of the patient (odds ratio, 2.0). The four variable model was significantly more accurate than tumor thickness alone, particularly for predicting death. Overall, use of the model reduced the error rate of the prediction of death by 50%. CONCLUSIONS: A prognostic model that uses four readily accessible variables more accurately predicts outcome in patients with primary melanoma than does tumor thickness alone. This four-variable model can identify patients at high risk for the recurrence of disease, an identification that becomes increasingly important as adjuvant therapies are developed for treatment of melanoma. PMID- 8702089 TI - Relation between intake of flavonoids and risk for coronary heart disease in male health professionals. AB - OBJECTIVE: Flavonols and flavones are subgroups of flavonoids and are found in tea, vegetables, fruits, and red wine. Because they have antioxidant properties, we investigated whether intake of these dietary compounds is associated with a lower risk for fatal and nonfatal coronary heart disease. DESIGN: Prospective cohort study. SETTING: United States. PATIENTS: 34,789 male health professionals, 40 to 75 years of age, who responded to a questionnaire in 1986. MEASUREMENTS: In 1986 and 1990, detailed, 131-item questionnaires were used to assess dietary intake of flavonols and flavones. RESULTS: Between 1986 and 1992, 496 patients received a new diagnosis of nonfatal myocardial infarction. The relative risk for nonfatal myocardial infarction was 1.08 (95% Cl, 0.81 to 1.43) for the highest (median, 40.0 mg/d) compared with the lowest (median, 7.1 mg/d) quintiles for intake of flavonols and flavones after adjustment for age, obesity, smoking, intake of vitamin E, intake of alcohol, diabetes, hypertension, hypercholesterolemia, and family history of coronary heart disease. Among the 4814 men who reported that they had previously had coronary heart disease, we found a modest but nonsignificant inverse association between intake of flavonols and flavones and subsequent coronary mortality rates (relative risk, 0.63 [Cl, 0.33 to 1.20] for the highest compared with the lowest quintile for intake of flavonoids). CONCLUSION: The data do not support a strong inverse association between intake of flavonoids and total coronary heart disease, but they do not exclude the possibility that flavonoids have a protective effect in men with established coronary heart disease. PMID- 8702088 TI - Acyclovir with and without prednisone for the treatment of herpes zoster. A randomized, placebo-controlled trial. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. AB - OBJECTIVE: To determine the effect of acyclovir and prednisone treatment of herpes zoster on chronic pain and quality-of-life outcomes. DESIGN: Randomized, double-blind, placebo-controlled study with a 2 x 2 factorial design. SETTING: 15 university hospitals or affilliated clinics. PATIENTS: 208 immunocompetent patients older than 50 years of age who had localized herpes zoster that developed less than 72 hours before study enrollment. INTERVENTION: Acyclovir or a matched placebo was administered orally, 800 mg five times daily, for 21 days. Prednisone or a matched placebo was administered orally at 60 mg/d for the first 7 days, 30 mg/d for days 8 to 14, and 15 mg/d for days 15 to 21. The four treatments regimens given were acyclovir plus prednisone; acyclovir plus prednisone placebo; prednisone plus acyclovir placebo; and placebos for both acyclovir and prednisone. MEASUREMENTS: Patients were monitored daily for the first 28 days for lesion healing, resolution of pain, return to usual activity, and return to uninterrupted sleep. Monitoring was then done monthly for 6 months. Patients documented analgesic requirements each day, and adverse events and laboratory abnormalities were recorded at each clinical visit. An intention-to treat analysis was used. RESULTS: Patients were randomly allocated to receive one of the four regimens. Demographic characteristics were similar for each group. Time to total crusting and healing was accelerated for patients receiving acyclovir plus prednisone compared with patients receiving two placebos; the risk ratios were 2.27 (95% Cl, 1.46 to 3.55) for total crusting and 2.07 (Cl, 1.26 to 3.38) for healing. Similarly, compared with the placebo group, patients receiving acyclovir plus prednisone had accelerated time to cessation of acute neuritis (risk ratio, 3.02 [Cl, 1.42 to 6.41]), time to return to uninterrupted sleep (risk ratio, 2.12 [Cl, 1.25 to 3.58]); time to return to usual daily activity (risk ratio, 3.22 [Cl, 1.92 to 5.40]); and time to cessation of analgesic therapy (risk ratio, 3.15 [Cl, 1.69 to 5.89]). In the acyclovir plus prednisone group, resolution of pain during the 6 months after disease onset did not statistically differ from that in the other groups. No important clinical or laboratory adverse events occurred in any group. CONCLUSIONS: In relatively healthy persons older than 50 years of age who have localized herpes zoster, combined acyclovir and prednisone therapy can improve quality of life. PMID- 8702090 TI - Update in geriatrics. PMID- 8702091 TI - War syndromes and their evaluation: from the U.S. Civil War to the Persian Gulf War. AB - PURPOSE: To better understand the health problems of veterans of the Persian Gulf War by analyzing previous war-related illnesses and identifying possible unifying factors. DATA SOURCE: English-language articles and books on war-related illnesses published since 1863 that were located primarily through a manual search of bibliographies. DATA EXTRACTION: Publications were assessed for information on the clinical characteristics of war-related illnesses and the research methods used to evaluate such illnesses. DATA SYNTHESIS: Poorly understood war syndromes have been associated with armed conflicts at least since the U.S. Civil War. Although these syndromes have been characterized by similar symptoms (fatigue, shortness of breath, headache, sleep disturbance, forgetfulness, and impaired concentration), no single recurring illness that is unrelated to psychological stress is apparent. However, many types of illness were found among evaluated veterans, including well-defined medical and psychiatric conditions, acute combat stress reaction, post-traumatic stress disorder, and possibly the chronic fatigue syndrome. No single disease is apparent, but one unifying factor stands out: A unique population was intensely scrutinized after experiencing an exceptional, life-threatening set of exposures. As a result, research efforts to date have been unable to conclusively show causality, have been subject to reporting bias, and have lacked similar control populations. In addition to research limitations, war syndromes have involved fundamental, unanswered questions about the importance of chronic somatic symptoms and the factors that create a personal sense of ill health. CONCLUSION: Until we can better understand what constitutes health and illness in all adult populations, we risk repeated occurrences of unexplained symptoms among veterans after each war. PMID- 8702092 TI - Predicting clinical states in individual patients. AB - A probability model expresses the relation between the presence of clinical findings (input or independent variables) and the probability that a clinical state will occur (the dependent variable); for example, it expresses the probability that a disease is present or will develop or the probability that an outcome state will be reached. Probability models are developed by using selected study groups. Although these models are most often used to make predictions for groups of patients, they can also predict clinical states for individual patients. The following seven criteria provide a basis for the critical appraisal of probability models. In particular, physicians can use these criteria to decide when a specific probability model should be used to make a prediction in an individual patient. Five of the criteria are concerned with the applicability of a model to a particular patient: 1) the comparability of the patient and the study group used to develop the model; 2) the congruence between the clinical state of interest to patient and physician and the model's outcome; 3) the availability of all input variables where and when the prediction is to be made; 4) the usefulness of a quantitative estimate of the predicted clinical state; and 5) the degree of uncertainty in the probability estimate. The other two criteria are concerned with how well the probability model "works": 6) the fit of probabilities calculated from the model to the outcomes actually observed and 7) the model's ability to discriminate between outcome states relative to chance and to other, more traditional, prediction methods. We illustrate the use of these criteria by applying them, in the form of questions, to a convenient, tabular version of a model that estimates a patient's chances of surviving for 10 years after having definitive surgical therapy for primary cutaneous melanoma. PMID- 8702093 TI - Hormonal influences on bone remodeling and bone loss: application to the management of primary hyperparathyroidism. PMID- 8702094 TI - Atonement. PMID- 8702095 TI - Methionine loading, vitamin B6 status, and premature thromboembolic disease. PMID- 8702096 TI - Aspirin for asymptomatic carotid artery stenosis. PMID- 8702097 TI - Aspirin for asymptomatic carotid artery stenosis. PMID- 8702098 TI - Aspirin for asymptomatic carotid artery stenosis. PMID- 8702099 TI - Theophylline and atrioventricular block. PMID- 8702100 TI - Pressure ulcers. PMID- 8702101 TI - Pressure ulcers. PMID- 8702102 TI - Cortical brain lesions in acute intermittent porphyria. PMID- 8702103 TI - The Raynaud phenomenon and interferon therapy. PMID- 8702104 TI - Apparent interaction between nefazodone and cyclosporine. PMID- 8702105 TI - Vincristine treatment of severe thrombocytopenia in paroxysmal nocturnal hemoglobinuria. PMID- 8702106 TI - Ocular Lyme borreliosis diagnosed by polymerase chain reaction on vitreous fluid. PMID- 8702107 TI - The cardiomyopathy of obstructive sleep apnea. PMID- 8702108 TI - China's eugenics law on maternal and infant health care. PMID- 8702109 TI - Violence in intimate relationships. PMID- 8702110 TI - Violence in intimate relationships. PMID- 8702111 TI - Domestic violence and physician intervention. PMID- 8702112 TI - The potential of critical pathways. PMID- 8702113 TI - Correction: effect of neuroimaging studies on acute ischemic stroke. PMID- 8702114 TI - Retinoid signaling in vertebrate limb development. PMID- 8702115 TI - A new subclass of helix-loop-helix transcription factors expressed in paraxial mesoderm and chondrogenic cell lineages. PMID- 8702116 TI - Role of parathyroid hormone-related protein in skeletal development. PMID- 8702117 TI - Genetic analysis of the retinoid signal. PMID- 8702118 TI - Role of cartilage collagens in formation of the skeleton. PMID- 8702120 TI - Campomelic dysplasia with XY sex reversal: diverse phenotypes resulting from mutations in a single gene. PMID- 8702119 TI - Sulfate transport in chondrodysplasia. PMID- 8702122 TI - Mutations affecting multiple functional domains of FGFR3 cause different skeletal dysplasias: a personal retrospective in honor of John Wasmuth. PMID- 8702121 TI - Progress in human chondrodysplasias: molecular genetics. PMID- 8702123 TI - Fibroblast growth factor receptor-2 mutations in craniosynostosis. PMID- 8702124 TI - The role of Msx genes in mammalian development. PMID- 8702125 TI - Hypochondroplasia: molecular analysis of the fibroblast growth factor receptor 3 gene. PMID- 8702126 TI - Mutations in the cartilage oligomeric matrix protein (COMP) gene in pseudoachondroplasia and multiple epiphyseal dysplasia. PMID- 8702127 TI - A family of chondrodysplasias caused by mutations in the diastrophic dysplasia sulfate transporter gene and associated with impaired sulfation of proteoglycans. PMID- 8702128 TI - A 1.9-Kb 5' fragment from the human COL1A1 gene drives inappropriate expression of the human COL2A1 gene in tissues of transgenic mice that normally express only the COL1A1 gene. PMID- 8702130 TI - Elucidation of homeoprotein Cart-1 function during in vitro chondrogenesis of C3H10T1/2 micromass cultures. PMID- 8702129 TI - Creation of a system for the assembly and expression of DNA constructs encoding novel recombinant human procollagen II. PMID- 8702131 TI - Transcriptional regulation of the human type X collagen gene expression. PMID- 8702132 TI - Modulation of annexin V during chondrocytic differentiation in vitro. PMID- 8702133 TI - Arg519-Cys mutation in COL2A1: evidence for multiple founders. PMID- 8702134 TI - Retinoic acid and interleukin-1 together promote the release of collagen fragments from bovine nasal cartilage in culture. PMID- 8702135 TI - Changes in bone morphogenetic protein sensitivity relative to differentiation in fetal rat bone cell cultures. PMID- 8702136 TI - Sequence elements within intron 1 of the human collagen X gene do not contribute to the regulation of gene expression. PMID- 8702137 TI - Growth factor interactions in limb development. PMID- 8702138 TI - Type X collagen NC1 mutations produced by site-directed mutagenesis prevent in vitro assembly. PMID- 8702139 TI - Recurrent transition at a CG dinucleotide in exon 12 of COL2A1 produces kniest dysplasia with abnormal RNA splicing by chondrocytes and lymphoblasts and interruption of the triple helix of type II collagen. PMID- 8702141 TI - Regulation of chondrocyte differentiation by transforming growth factors beta 1, beta 2, beta 3, and beta 5. PMID- 8702140 TI - Cartilage matrix protein: expression patterns in chicken, mouse, and human. PMID- 8702142 TI - Studies on the G3 domain of aggrecan from human cartilage. PMID- 8702143 TI - Tissue distribution and phenotypic consequences of different type X collagen gene constructs in transgenic mice. PMID- 8702144 TI - Characterization of recombinant human collagen II with Arg519-to-Cys substitution. PMID- 8702145 TI - The effect of overexpression of BMPs and GDF-5 on the development of chick limb skeletal elements. PMID- 8702146 TI - Role of BMP-2a in otic capsule chondrogenesis. PMID- 8702147 TI - Identification of an AP1-like response region for osteogenic protein-1 in type X collagen promoter. PMID- 8702148 TI - Expression of the chicken Sox9 gene marks the onset of cartilage differentiation. PMID- 8702149 TI - Localization of gene expression during endochondral ossification. PMID- 8702150 TI - Beta 1 integrin antibodies inhibit chondrocyte terminal differentiation in whole sterna. PMID- 8702151 TI - Pax genes and skeletal development. PMID- 8702152 TI - Expression of functional link protein domains using an avian-specific retroviral vector. PMID- 8702153 TI - Homeobox gene expression during bone formation induced by BMP. PMID- 8702154 TI - Skeletal and hematopoietic defects in mice transgenic for collagen X. PMID- 8702155 TI - Polarizing activity in early limb cartilaginous condensations. PMID- 8702156 TI - A 47-bp sequence of the first intron of the mouse pro alpha 1(II) collagen gene is sufficient to direct chondrocyte Expression. PMID- 8702157 TI - Role of Krox-20 in endochondral bone formation. PMID- 8702158 TI - In vivo footprinting implicates negative regulators in the expression of the type X collagen gene in chickens. PMID- 8702159 TI - Analysis of cell behavior and gene expression in the developing face of the chick embryo. PMID- 8702160 TI - Expression of Trk receptors during cartilage differentiation. PMID- 8702161 TI - Cleidocranial dysplasia in mice. PMID- 8702162 TI - A mutation in COL9A2 causes multiple epiphyseal dysplasia (EDM2). PMID- 8702163 TI - The c-propeptide of type II procollagen binds to the enhancer region of the type II procollagen gene and regulates its transcription. PMID- 8702164 TI - Analysis of up-regulated genes during chondrocyte hypertrophy. PMID- 8702165 TI - Localization of type IIA procollagen during chondrogenesis. PMID- 8702166 TI - Genetic and molecular analysis of the mouse Ulnaless locus. PMID- 8702167 TI - Characterization of Medea, a gene required for maximal function of the Drosophila BMP homolog Decapentaplegic. PMID- 8702168 TI - Alternative splicing of a chondrocyte-specific gene. PMID- 8702169 TI - mRNA encoding a novel growth regulatory factor is coexpressed with type II procollagen during chondrogenesis. PMID- 8702170 TI - Growth retardation in transgenic mice harboring a type II collagen mutation. PMID- 8702171 TI - Stickler syndrome type 2 and linkage to the COL11A1 gene. PMID- 8702172 TI - CD44 in growing normal and neoplastic rat cartilage. PMID- 8702173 TI - Expression of the ID1 and ID3 genes during chondrocyte differentiation. PMID- 8702174 TI - Function of homeobox genes in skeletal development. PMID- 8702175 TI - Separable regulatory elements from pro-alpha 2 (XI) collagen gene drive distinct patterns of cartilage-specific expression in transgenic mice. PMID- 8702176 TI - Complete structure of the human COL11A2 gene: the exon sizes and other features indicate the gene has not evolved with genes for other fibriller collagens. PMID- 8702177 TI - A splice variant of CD44 expressed in the rat apical ectodermal ridge contributes to limb outgrowth. PMID- 8702178 TI - Aetiology of the skeletal dysmorphology syndrome campomelic dysplasia: expression of the Sox9 gene during chondrogenesis in mouse embryos. PMID- 8702179 TI - Nestin distribution in the developing limb bud in vivo and in vitro. PMID- 8702180 TI - Construction and expression of a functional recombinant gene for proteoglycan. PMID- 8702181 TI - Craniofacial cartilage development in zebrafish. PMID- 8702182 TI - Dlx5 and Dlx6: an evolutionary conserved pair of murine homeobox genes expressed in the embryonic skeleton. PMID- 8702183 TI - Function of the Msx2 gene in the morphogenesis of the skull. PMID- 8702184 TI - Signaling pathways in skeletal formation: a role for BMP receptors. PMID- 8702185 TI - The role of BMPs and GDFs in development of region-specific skeletal structures. PMID- 8702186 TI - BMP signaling in Drosophila embryogenesis. PMID- 8702188 TI - [Hemorrhages during dental surgery: their prevention and treatment. General Session of the National Academy of Pharmacy and Dental Surgery, Wednesday, 28 June 1995]. PMID- 8702187 TI - BMP 7 is required for nephrogenesis, eye development, and skeletal patterning. AB - In summary, the generation of BMP-7-deficient mice has provided additional evidence that this family of growth factors regulate many morphogenetic processes including but not limited to skeletal development. In particular our experiments demonstrate that BMP 7 acts as an early inducer of glomeruli formation, and that it is required for skeletal patterning and lens formation. Our results not only demonstrate that BMP 7 is involved in the differentiation of several organs during development, but also raise the hypothesis that mutations in the Bmp 7 gene itself or in the genetic pathway could be responsible for several human genetic diseases in which glomerulus formation is impaired. PMID- 8702189 TI - [Exploration of hemostasis in current practice]. AB - The exploration of coagulation in biological practice implies simple routine tests. A normal bleeding time associated with a normal platelet count allows to exclude any primary haemostasis abnormality. A prolonged bleeding time is most frequently the result of a thrombocytopenia, the etiology of which remains to be determined. A prolonged bleeding time is also observed in von Willebrand disease and in thrombopathia. Such diagnosis requires appropriate investigation. The exploration of the coagulation cascade includes prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen level. A congenital or acquired deficiency in one or more coagulation factors should be distinguished from a lupus anticoagulant or from the occurrence of an antibody against a coagulation factor. Indeed, a prolonged APTT is not always related to a bleeding risk. Only the identification of the coagulation abnormality can predict the bleeding or thrombotic risk during surgery. In each case, an appropriate preventive therapy should be prescribed. PMID- 8702190 TI - [Problems of hemostasis in odonto-stomatology]. PMID- 8702191 TI - [Trypanocidal structure- activity relationship in 9-thioalkylacridines]. AB - A set of 9-thioalkylacridinones, has been prepared and investigated "in vitro" against T. cruzi. Structure-antiparasitic activity relationships are detailed with a view to identify the major structural parameters for the activity under consideration. PMID- 8702192 TI - [Current knowledge about blood coagulation]. PMID- 8702193 TI - [Study of an anti-serum against phenytoin with two organometallic tracers]. AB - In order to develop a new immunoassay procedure based on the use of organometallic labels, an antiserum is raised against antiepileptic drug: diphenyl-hydantoin (phenytoin). Immunization was performed in rabbits with phenytoin coupled to bovine-serum albumin. The evaluation of the specificity and the affinity constants of the antiserum is studied by radioimmunoassay against different antiepileptic drugs and metallotracers (phenytoin labelled with organometallic fragments derived respectively from cobaltocene and ferrocene). The results of this study indicate that metallotracers cross-react slightly with phenytoin (cross reaction percent about 11 for the two compounds). The affinity constants of the antiserum for phenytoin and for metallohaptens derived from cobaltocene and from ferrocene are respectively 0.03 nM-1, 0.05 nM-1 and 0.06 nM 1. PMID- 8702194 TI - [Topoisomerases: therapeutic value]. AB - Anticancer pharmacology offers rich prospects for future therapeutic design. Knowledge of antitumoral agents pharmacology have widely advanced: understanding of the molecular cytotoxic mechanism of available agents, discovery of new compounds with a different and no-interfering mechanism of action. Since ten years, the identification of a couple of nuclear enzyme, DNA-topoisomerases, has answered to this goal. These enzymes catalyse the topological changes of the double strand DNA, participating to vital processes of cell metabolism. These enzymes are now know to be the intracellular target of widely used cytotoxic agents (such as anthracycline, Etoposide, Teniposide for DNA topoisomerase II) and for two new compounds in clinical trials (irinotecan and topotecan, both analogues of camptothecin, for DNA-topoisomerase I). This two last molecules, currently in phase II development, are promising. They seem to be synergistic in combination with available anticancer agents, but this remains to be demonstrated. Other drugs, inhibiting both DNA-topoisomerases I and II, are yet investigating. Would they provide new answers for the future? PMID- 8702195 TI - [Current and future antithrombotic therapies]. AB - In spite of progress, antithrombotic therapies involve the risk of haemorrhage. Thrombolytic agents have more or less fibrin specificity which is related to the risk of bleeding. These drugs have efficient antidotes which can be administered locally or by systemic route. The usual anticoagulants are vitamin K antagonists and heparin which have propensity to be given at reduced dose. Low molecular weight heparins have demonstrated good efficacy and tolerance in the prevention and treatment of venous thrombosis. New anticoagulants, specific inhibitors of activated factor X or thrombin, are now expected but they lack of specific antidotes. Platelet aggregation inhibitors, mainly aspirin, are widely used in the prevention of arterial thrombosis. New compounds particularly GPII/IIIa fibrinogen receptor antagonists have a broad spectrum but need to be used watchfully. Research underway suggest new molecules which will likely inhibit the procoagulant, phospholipid dependent, platelet activity or block thrombin receptor. Good knowledge of properties and progress in the preparation of improved haemostat agents could significantly reduce, particularly in dental surgery, the risk of haemorrhage. PMID- 8702196 TI - 70 years of furthering Finnish surgeons' professional and scientific interests and development. PMID- 8702197 TI - Surgical treatment of aortic valve disease in the nineties with special emphasis on the use of the pulmonary autograft (Ross-operation). AB - Aortic valve surgery is no longer only a question of immediate survival but as much a question of long term outcome and quality of life. The need for lifelong anticoagulation limits quality of life and carries a significant risk of complications. The new options available to avoid anticoagulation are technically more demanding and our knowledge about the long-term results after these operations is limited. If the patient is willing to accept the prospect of a reoperation to avoid a valve prosthesis he is doing this to get a better quality of life and a lower risk of valve or anticoagulation related complications. We believe that this is a reasonable choice because of the generally improved safety of heart surgery and because we have an increased experience of advanced surgery and reoperations. For patients with advanced endocarditis we are convinced of the superiority of homografts and autografts. In children autograft growth capability and expected superior durability are very important arguments. The final strategy for optimal management of aortic valve disease is yet to be developed. We do not believe in one simple solution for all patients. If the Ross-operation is a step forward, it is in the direction of increased complexity to improve quality of life for the patients. PMID- 8702198 TI - Blunt rupture of the diaphragm. A retrospective analysis of 41 patients. AB - Forty-one patients with multiple injuries together with diaphragmatic rupture due to blunt trauma were reviewed. The rupture was caused by a motor vehicle accident in 29 (71%) and falling from a height in four (10%) patients. A chest X-ray on admission suggested the diagnosis in 70% of the cases. Small bowel herniation did not occur in ruptures smaller than 15 centimetres. All patients had associated injuries and 84% suffered intra-abdominal trauma, most commonly splenic rupture (42% of all patients). 15 out of 18 patients with a concomitant rupture of the spleen were injured in automobile accidents. The occurrence of splenic rupture in patients injured in automobile vs other accidents differed significantly (P = 0.027). The mortality rate was 12%. Mortality and most of the complications were related to associated injuries. We conclude that 1) there is a high occurrence of intra-abdominal injuries, especially splenic ruptures, in patients with rupture of the diaphragm, 2) the occurrence of splenic rupture is higher in patients injured in automobile accidents than in patients injured by some other mechanism, and 3) a chest radiograph on admission is the best diagnostic aid. PMID- 8702199 TI - The long-term outcome after negative appendix operation. AB - We evaluated the long-term outcome of "negative appendix" (NA) by analysing the follow-up results of 76 patients identified from a group of 670 appendectomized patients. Randomly selected and histologically proven cases of true acute appendicitis (TA) matched for age and sex were identified to construct case control pairs. Special interest was focused on gender and age, by analysing the results separately in men and women in two age groups (15-39 years and > or = 40 years). The results showed that NA was most common in women aged 15-39 years (21% of appendectomized cases in this age group). At follow-up examination after a mean follow-up of 2.9 years two-thirds of patients were symptomfree. Women aged 15-39 years had significantly more complaints (P < 0.05) and findings (P < 0.05) than patients with TA. In women aged > or = 40 years no significant differences were detected, nor in either age groups in men. Lactose intolerance was the most common finding in symptomatic patients. In conclusion, patients with NA were mostly young women. At long-term follow-up the great majority of patients were symptomfree and appeared not to have developed any serious disease. Routine follow-up for patients with NA does not thus seem necessary. PMID- 8702200 TI - Video-assisted thoracoscopic pleurectomy in the treatment of recurrent spontaneous pneumothorax. AB - Parietal pleurectomy is the most effective method of preventing a recurrence of spontaneous pneumothorax. Until recently, however, it has required thoracotomy which is associated with significant morbidity. The advent of video-assisted thoracoscopic surgery (VATS) has offered a less traumatizing method of performing parietal pleurectomy, but experience in this operation is limited. In this study we compared the operative results of our first twelve patients treated using VATS (VATS-group) with twelve consecutive patients operated on via thoracotomy (T group) before we started using VATS. The groups were comparable in terms of age, sex ratio and the length of preoperative pleural drainage. In the VATS-group peroperative blood loss was markedly less, but the mean operative time was 16 min longer than in the T-group. There was practically no difference in the number of opioid dosages given postoperatively between the groups, but the hospital stay was approximately three days shorter in the VATS-group than in the T-group. Inability to work lasted two weeks longer in the T-group than in the VATS-group. In the T-group there were no recurrences of pneumothorax, but in the VATS-group pneumothorax recurred in two patients. They were both treated using a Roeder loop to excise bullae. One patient was reoperated via thoracotomy and another was treated by pleural suction. The initial Finnish experience of VATS-pleurectomy shows that parietal pleurectomy can be performed safely with less morbidity in the treatment of recurrent spontaneous pneumothorax. However, recurrences in the VATS-group underlines the proper selection of technical methods when using this method of treatment. PMID- 8702201 TI - Outcome and clinical signs of arthroscopically graded patellar chondromalacia with or without lateral release. AB - In a follow-up study of 67 patients with an arthroscopically diagnosed patellar chondromalacia, we compared the results of plain conservative treatment with those after an open lateral retinacular release. The mean follow-up was 35 months. In Grade I chondromalacia the lateral release did not affect the result, which was in all cases good or excellent. In Grade II to IV chondromalacia the lateral release appeared beneficial, although the difference did not reach statistical significance. We also examined the validity of three clinical signs in arthroscopically verified patellar chondromalacia. Patellar inhibition and tracking tests were clearly more sensitive than the lateral apprehension test, which often gave a false negative result. If the patellar inhibition test is positive and a Grade II to IV chondromalacia of the patella is found at arthroscopy, lateral release should be considered among other procedures, like patellar shaving or patellar resurfacing. PMID- 8702202 TI - Autotransfusion of drained blood after total knee arthroplasty. AB - Osteoarthritic knees were treated by cemented (20 knees) or uncemented (five knees) total knee arthroplasty. The drained blood of the first six postoperative hours was collected, filtered and autotransfused. The blood loss of 20 first postoperative hours averaged 970 ml in the cemented and 1360 ml in the uncemented arthroplasties. An average of 60% of the shed blood was returned to the patients. Transient fever reaction took place during the autotransfusion of three patients, all in the cemented arthroplasty subgroup. No other complications were recorded. The amount of drained blood and transfused blood was compared with a similar series of 16 arthroplasties, treated without autotransfusion. Autotransfusion of filtered blood appears safe and useful in arthroplasty of the knee. Marked reduction of foreign blood transfusion but no direct financial benefit was attained by autotransfusion in these cases. Autotransfusion after uncemented arthroplasty of the knee appears advisable, because of the lack of side-effects, possibly caused by acrylic monomers and because the bleeding (and collection of shed blood) was more extensive than after cemented arthroplasty. PMID- 8702203 TI - Hip fractures in Nordic cities: difference in incidence. AB - All new hip fractures referred to hospital in 1989 were recorded in seven urban populations from Denmark, Finland, Norway and Sweden. The total population at risk (50 years and older) was 588,427, and 4075 fractures were observed (76.5% women). In all cities an age-dependent increase in incidence was found, and the female incidence was highest. When comparing the incidence rates after direct standardization, significant differences in hip fracture incidence were found between the cities for both women and men. The standardized relative rates seemed to decrease when moving south and east with the lowest rates found in Tampere, Finland. This indicates that factors which differ even between urban populations within a restricted geographical region may have an important impact on hip fracture incidence. PMID- 8702204 TI - Mobility, survival and nursing-home requirements after hip fracture. AB - A consecutive series of 117 patients treated for hip fracture were followed up prospectively for three years. The mortality was highest during the first year. The proportion living in nursing-homes was increased by 50% at one year and 25% at three years compared with before injury, but the absolute numbers were reduced because of mortality. Reduced pre-injury mobility greatly increased the risk of becoming institutionalized. The proportion of the survivors who walked without aids was reduced by more than half at one and three years. The proportion of those bedridden increased six fold. Among patients who walked without aids before fracture 31% needed two sticks or more and 7% were bedridden after one year. Among those who before fracture walked with one stick or more, the percentages were 91 and 43. PMID- 8702205 TI - Short term clodronate treatment does not increase trabecular bone in posttraumatic osteopenia. AB - The paper describes the results of two experiments on clodronate treatment on bone metabolism in growing rabbits: 1. the serum and bone concentrations of the drug, and 2. the effects of 18 week clodronate treatment on quantitative histomorphometry of trabecular bone. The results indicated a rapid and high affinity of clodronate to bone after subcutaneous administration. Plate fixation of the tibia without a fracture or any operation on the femur induced a 25% decrease in bone volume per total volume in the femoral condyles. The osteopenic response resulted probably from operative trauma. Clodronate treatment for three months could not inhibit this decrease. The increase in calcium content in bone by the drug treatment (observed in diaphyseal bones in earlier studies) could not be verified on histology of trabecular bone. PMID- 8702206 TI - Clodronate increases bone mineral density in young growing oophorectomized beagles. AB - Nineteen beagles (8.8 +/- 0.1 months, 8.5 +/- 0.2 kg, mean +/- SEM) were oophorectomized (OX) at the beginning of the study. The dogs were randomly allocated into three groups: control group (OX, n = 5), OX+clodronate 20 mg/kg orally group (OX + 20, n = 7) and OX+clodronate 40 mg/kg orally group (OX + 40, n = 7). Clodronate administration began the day following oophorectomy and was continued for eight months. Bone mineral density (BMD) was evaluated by dual energy X-ray absorptiometry (DEXA) at baseline and at four and eight months and by quantitative computed tomography (QCT) at baseline and at eight months. Bone biopsies were taken at the beginning and at the end of the study. The change in BMD (g/cm2) during eight months was +2.0% (NS) in OX, +2.3% (NS) in OX + 20 and +10.0% (P < 0.01) in OX + 40 group when measured by DEXA, QCT revealed the same results but in a lesser extent. There were no differences in static and dynamic histomorphometric parameters between the groups at the end of the study. In conclusion, clodronate at a dose 40 mg/kg/day orally increases BMD in young oophorectomized dogs. PMID- 8702207 TI - Repair of bone defects with absorbable membranes. A study on rabbits. AB - Self-reinforced polyglycolic acid (SR-PGA) devices were developed in the mid eighties, applied for fixation purposes and proved to be biocompatible. In this study SR-PGA membranes (10 x 10 mm) were used to augment defects on the medial aspect of distal femoral metaphysis in 31 New Zealand rabbits. Defects of 3.5 mm were either filled with autografts or left non-grafted. In a control group, no membranes were used. The rabbits were followed up for six, 12 and 24 weeks. Radiography, histology, oxytetracycline (OTC) fluorescence labelling and microradiography were used. Defects where membranes were used, healed by new bone formation. In some cases where polyglycolic acid (PGA) membranes were not used, defects were invaded by fibrous tissue. Membranes sometimes slipped away from their positions opposite to grafted defects. This study proved that the advantage of the use of PGA membranes could be taken in augmentation of cancellous bone defects in rabbits. PMID- 8702208 TI - Multilocular renal cyst. Report of two cases and review of the literature. AB - Multilocular renal cyst (MRC), or cystic nephroma (CN), is a rare tumour of the kidney. Approximately one hundred cases have been reported, half of these in children. Normally these lesions have been confirmed to be benign cystic lesions, but it is possible for them to transform into malignancy. In children this type of tumour may simulate Wilms' tumour. We report two cases of MRC disease with clinical findings, pathology, treatment and survival. PMID- 8702209 TI - Recreational patterns, body composition and socioeconomic status of Western Australian secondary school students. AB - A study of 4672 secondary school students was carried out in order to assess the relationship between body composition, recreational patterns, and socioeconomic status as indicated by parental occupation and the school attended. Results indicated that there were more girls than boys participating in organized sport, and health and fitness activities; and more boys than girls involved in informal recreational activities and home-based passive pursuits. A higher proportion of participants came from the higher socioeconomic status (SES) group. More high-SES students revealed weight appropriate to their height. PMID- 8702210 TI - Menarcheal age in two generations of South African Indians. AB - Intergenerational and socioeconomic effects on menarcheal age were investigated in a sample of 146 mother-daughter pairs of South African Indians living in the urban area of Lenasia, Gauteng Province. Information on menarcheal age, socioeconomic status, and educational attainment of both parents was obtained by questionnaire. Data on menarcheal age of daughters were analysed by probit analysis and descriptive statistics. Mean maternal menarcheal age was 13.20 years (SD = 1.57) and was significantly greater than the menarcheal age of the postmenarcheal daughters at 12.52 years (SD = 1.25) and of mean menarcheal age analysed by probits of 12.40 years (SD = 1.18). Mother-daughter menarcheal ages were significantly correlated (r = 0.23; p < 0.035). This association was confounded by the significant association of maternal menarcheal age to the age at which mothers recalled that event (r = 0.32; p < 0.003). Partial correlations demonstrated that the mother-daughter correlation reduced to a non-significant 0.16 (p < 0.14) after maternal age at recall had been controlled. No significant associations were found between socioeconomic variables and menarcheal age except for family size, in which girls with more than three siblings had significantly later menarcheal ages than girls with three siblings. Secular trends for reduced menarcheal ages were evident in both the intergenerational data (0.24 years/decade) and in comparison to the data of Kark (1953) from four decades ago (0.27 years/decade). PMID- 8702211 TI - mtDNA provides the first known marker distinguishing proto-Indians from the other Caucasoids; it probably predates the diversification between Indians and Orientals. AB - The concomitant presence of the two sites Ddel at 10,394 and Alul at 10,397 has been considered an East-Asian marker of ancient origin (it was also observed in Australians, Melanesians and Native Americans). Unexpectedly, it was found in more than 50% of Indians (133 Hindus and 30 Tribals) who had shown Caucasoid characteristics not only at nuclear DNA but also at mtDNA level. It can therefore no longer be considered an exclusively East-Asian mtDNA feature. The analysis of more than 200 Caucasoids, mainly from the Mediterranean basin, showed that it is only sporadically present in these people. Thus it represents the first known marker which distinguishes Indians from the other Caucasoids. The lack of this marker in Indian mtDNA molecules carrying Caucasoid characteristics suggests that it predates the invasion of India by speakers of an Indo-European language and, if it is valid to extrapolate from Near Eastern data, the arrival in India of the farmers who spread the Dravidian language. If this polymorphism had a common origin in both Orientals and Indians, it should also predate the diversification between ancient Indians and Mongoloids. PMID- 8702212 TI - Prediction of body composition in elderly men over 75 years of age. AB - A comprehensive number of body composition predictions (involving weight, height, skinfold thicknesses, bioelectrical impedance and near-infrared interactance NIRI) were evaluated against total body water (TBW from isotope dilution), in 23 randomly selected men over 75 years old, and dual-energy X-ray absorptiometry (DXA), in 15 volunteers from this group. Comparisons were made between anthropometric and impedance methods for estimating limb muscle mass (obtained using DXA). Bias and 95% limits of agreement between measured TBW and DXA estimates were -2.1 kg and 3.1 kg, respectively (for fat, 5.4% and 6.1% body weight). Agreement between TBW predictions and reference measurements was remarkably variable, irrespective of whether TBW was predicted from TBW-specific equations or indirectly from estimates of fat or fat-free mass: for predictions using anthropometry, bias ranged from -4.7 kg to 1.6 kg and 95% limits of agreement from bias +/- 3.8 kg to +/- 5.0 kg; using impedance, bias was -8.8 kg to 3.2 kg and 95% limits of agreement were bias +/- 3.6 kg to +/- 7.8 kg; corresponding values for NIRI were -5.3 kg and +/- 5.4 kg. Although some non-age specific equations appeared valid, age-specific equations generally predicted TBW better. Limb muscle mass (DXA) was predicted better using the segmental impedance method, from indices of limb muscle area (r = 0.76; SEE = 1.9 kg) and volume (r = 0.86; SEE = 1.6 kg), than by anthropometry alone (r = 0.61 and 0.71; SEE = 2.3 kg and 2.1 kg, respectively). In conclusion, some body composition predictions are unacceptable (at least for TBW) in older men, and care is recommended when selecting from these methods or equations. Also, the segmental impedance method is as good as, if not better than, anthropometry alone in predicting limb muscle mass (DXA) in older men. PMID- 8702213 TI - A portable knemometer: a technique for assessment of short-term growth. AB - Knemometry is the technique of choice for short-term growth studies, as it is the only anthropometric technique available that allows sufficiently accurate measurement of the lower leg (in anatomical terms, the leg) to enable changes in leg length to be detected over as short an interval as a week or less. The portable knemometer, like the Valk knemometer, essentially consists of two main parts: a rigid metal frame holding the footplate, measuring ruler and plateau and a moveable chair that moves on frictionless rollers on a track on the base of the frame. Unlike the Valk knemometer there is a standardized seat position for all subjects, making it easier and quicker to use. Assessment of technical error was done using mean coefficient of variation (CV) of lower leg length measurements done on the portable knemometer. Comparison of measurements made by two different observers was made by using percentage reliability. A small PR implies consistency between the two methods or observers being compared. Measurements from 164 visits were used to calculate the machine precision. Mean CV using all four measurements was 0.13% and using only three, having discarded the first, was 0.11%. Given a mean lower leg length of 246.3 mm for the children studied this translates to a machine precision of 0.32 mm if all four measurements are used and 0.27 mm if the last three measurements in the set are used. The mean difference in lower leg length between observers was 0.11 mm. Percentage reliability between the two observers for the portable knemometer was 0.03%. For comparison, PR for standing height and sitting height are 0.37% and 0.86% respectively. PR between the Valk and the portable knemometer was 0.04%. PMID- 8702214 TI - The relationship between short-term changes in weight and lower leg length in children and young adults. AB - As the knemometer is increasingly being used to study changes in lower leg length in conditions associated with weight changes it is important to clearly delineate the relationship between these two variables. Lower leg length and weight were measured in 26 children and nine adults including one pregnant woman. There was a weak but positive relationship between lower leg length and weight fluctuation in children. Daily fluctuations in weight as well as lower leg length were higher in women than men; median lower leg length fluctuation: women, 0.16 mm (P5-0, P95 0.7); men, 0.1 mm (P5-0, P95-0.48) p approximately 0.02, Wilcoxon signed-rank test. Median weight fluctuation: women 0.15 kg (P5-0, P95-0.54); men, 0.1 kg (P5 0, P95-0.5) p = 0.94 (Wilcoxon signed-rank test). Sustained weight gain in pregnancy led to a reduction in lower leg length followed by an increase which was coincident with the appearance of dependent oedema. Lower leg length changes are likely to be positively related to changes in weight when the latter are only modest in magnitude. However, greater sustained increases in weight are likely to have an opposite effect on lower leg length due to direct compression of the lower leg. Due consideration of weight is essential in longitudinal studies of lower leg length changes, especially in conditions which are associated with significant changes in weight. PMID- 8702215 TI - Autosomal recessive disorders in Saguenay-Lac-Saint-Jean (Quebec, Canada): estimation of inbreeding from isonymy. AB - The total inbreeding coefficient of a group of 574 individuals with autosomal recessive disorders (ARD) from Saguenay-Lac-Saint-Jean, a geographically isolated region of northeastern Quebec, was estimated from isonymy and compared to the mean inbreeding coefficient calculated from the genealogies. Its value was compared to that of 1722 matched controls. The total inbreeding coefficient was similar in both ARD and control groups, but higher than the values calculated from the genealogies. Most of the increase was due to the random component of inbreeding. This isonymy study confirmed that the high frequency of ARD in Saguenay-Lac-Saint-Jean is mainly the result of founder effect and genetic drift. PMID- 8702216 TI - BCR/ABL modulates the cytokine and retinoic acid response of c-Rel in human myeloid cells. AB - A human myeloid cell line, Mo7, and a daughter cell line expressing the bcr/abl oncogene, Mo7-P210, were used in a comparative study analyzing the effects of p210BCR/ABL expression on tyrosine phosphorylation, specific DNA binding and expression of the proto-oncoprotein c-Rel. The steady state expression of c-Rel was indistinguishable in both cell lines. Tyrosine phosphorylation and DNA binding of c-Rel were slightly elevated in Mo7-P210 cells. Further, Mo7 and Mo7 P210 cells showed different responses concerning c-Rel after stimulation with cytokines and retinoic acid. The results presented here demonstrate that c-Rel can be modulated by hematopoietic cytokines and suggest that bcr/abl expression has an impact on these responses and that c-Rel may be a downstream effector for p210BCR/ABL. PMID- 8702217 TI - Molecular analysis of a gene, BB1, overexpressed in bladder and breast carcinoma. AB - The AN43 antigen is a new bladder tumor marker which is present in bladder cancer specimens as well as breast cancer specimens (1). Our objective was to clone the AN43 gene and determine its possible role in bladder and breast tumorigenesis. A bladder tumor cell cDNA expression library was made and screened with a murine monoclonal antibody to the AN43 antigen. A 1897 bp cDNA clone was isolated following expression screening with the AN43 antibody and named BB1. Following DNA sequencing, the BB1 cDNA clone was determined to have no homology to any known gene when screened through GenBank. RNA analysis demonstrated increased expression of BB1 mRNA in metastatic breast and bladder carcinomas relative to normal breast epithelium and urothelium. Treatment with gamma-interferon resulted in decreased mRNA expression. BB1 mRNA expression is increased in malignant cells relative to normal cells and is down-regulated following gamma-interferon treatment and therefore may have a role in tumor progression. Further characterization and functional analysis of this novel gene will be useful in understanding tumor development and metastatic potential. PMID- 8702218 TI - The development of an anchorage-independence assay using human lung tumor cells to screen potential chemopreventive agents. AB - Advances in tumor biology research have led to the possibility of early detection of cancers and rational intervention of cancer development using chemopreventive agents. A significant number of potential chemopreventive agents have been identified from epidemiological surveys, independent research efforts, clinical data or based on structural homology with known chemopreventive agents. We have developed a fast, reliable in vitro model for screening potential chemopreventive agents using inhibition of anchorage-independent growth of a human lung tumor cell line, A427.A427 cells were plated in soft agarose containing a known chemopreventive agent, 13-cis-retinoic acid as the test agent and allowed to develop colonies for 28 days. A cytotoxicity test was used concurrently with anchorage independent assay for measuring the relative survival of cells to ensure that any observed inhibition of anchorage independent growth is due to the biological activity of the chemopreventive agent and not due to cellular toxicity. At the end of 28 days of growth, the stained colonies were enumerated, and the inhibition of spontaneous colony formation was measured. 13-cis-Retinoic acid inhibited the growth of A427 colonies in a concentration dependent manner. Data from 25 successive experiments indicate that a concentration of 33 microM consistently inhibited colony formation by 66.2 +/- 16.5 percent, ranging from 27 to 96.1% inhibition. This assay is a useful tool for screening potential chemopreventive agents, as it uses human cells as substrates rendering the efficacy data feasible for direct extrapolation to humans. PMID- 8702219 TI - In vitro selective modulation of cellular glutathione by a humanized native milk protein isolate in normal cells and rat mammary carcinoma model. AB - We report the in vitro selective inhibitory activity of a humanized whey protein concentrate IMMUNOCAL on growth of mammary carcinoma cells and Jurkat T cells in comparison to normal peripheral blood mononuclear cells. We relate this inhibitory activity to a selective depletion of intracellular glutathione synthesis. The use of humanized whey protein concentrate as a food supplementation may have direct implication in clinical trial with adjuvant chemotherapy. PMID- 8702220 TI - Antiestrogens inhibit endothelial cell growth stimulated by angiogenic growth factors. AB - We have previously reported that the partial estrogen antagonists, tamoxifen, clomiphene and nafoxidine, inhibited angiogenesis in vivo in a dose-related manner in the six-day old chick egg chorioallantoic membrane (CAM) assay. In the present study, we investigated the effect of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) on the growth of porcine pulmonary artery and human dermal microvascular endothelial cells. Both of these growth factors significantly increased the growth of these cells. The antiproliferative activity of the partial antiestrogens, tamoxifen, nafoxidine and clomiphene, and the pure antiestrogen, ICI 182,780, was determined. Tamoxifen, clomiphene, nafoxidine and ICI 182,780 significantly inhibited endothelial cell growth stimulated by bFGF and VEGF. This inhibition of endothelial cells was not altered by the presence of up to 30 microM of estradiol 17 beta. These results indicate that the antiangiogenic action of the antiestrogens does not occur via the estrogen receptor, but by a direct inhibition of growth factor stimulated endothelial cell growth. PMID- 8702221 TI - Cytostatic and cytotoxic action of Z-1, 1-dichloro-2,3-diphenylcyclopropane in three human breast cancer cell lines. AB - Z-1,1-dichloro-2,3-diphenylcyclopropane (a.k.a. Analog II, AII) is known as a potential anti-breast cancer agent and has previously been studied as an antiestrogen (AE). We hypothesized that its activity is independent of estrogen receptor (ER) status. AII and its known and potential metabolites were synthesized and characterized by NMR and MS. ER positive/estrogen and AE sensitive MCF-7, ER positive/estrogen and AE resistant MCF-7/LY2, and ER negative/estrogen and AE resistant MDA-MB231 cells were used in metabolism, cytostasis, cytotoxicity, and serum binding/wash out assays. Bacterial mutation assays were performed with Salmonella typhimurim strain TM677. AII underwent slow solvolysis in culture medium to Z-2-chloro-1,3-diphenyl-2-propen-1-ol and its oxidized form Z-alpha-chlorochalcone (ZCC). ZCC was the major metabolite of AII in all three cell lines. Cytostasis and clonogenic assays showed AII to be cytostatic to each of the lines, and was more potent against MCF-7 and MCF-7/LY2 than MDA-MB231 cells. ZCC was cytotoxic, with IC50 values of 89, 0.5, and 170 nM in MCF-7, MCF-7/LY2, and MDA-MB231 cells, respectively. Cytotoxicity from ZCC was delayed compared to loss in cell viability, suggesting a non-necrotic mechanism. Serum protected against loss of cell viability caused by AII, but had no effect on the action of ZCC. The effects of ZCC could be partially reversed by washing the drug out of cells. The effects of AII persisted after wash out. AII was also shown to be nonmutagenic in forward Salmonella mutation assays both with and without metabolic activation. In conclusion, AII, a chemical with weak antiestrogenicity, anti-breast cancer activity, and low toxicity in whole animals, shows growth inhibitory properties against both ER positive and negative human breast cancer cells in culture. Its direct action appears to be cytostatic and longlived. AII is converted by the cells to a less-retained and -protein bound metabolite, ZCC, that is more cytotoxic. Neither AII nor ZCC appear to have mutagenic activity. Both AII and ZCC thus appear to have potential for use against estrogen-dependent and -independent human breast cancers. PMID- 8702222 TI - Apoptosis and necrosis occurring during different stages of primary and metastatic tumor growth of a rat mammary adenocarcinoma. AB - The pattern of spontaneous apoptosis and necrosis was investigated in an untreated, transplantable rat mammary adenocarcinoma (MTLn3) throughout the natural course of primary and metastatic tumor growth. The occurrence of spontaneous apoptosis was different when comparing primary to metastatic tumor growth. In the primary MTLn3 tumor growing at the mammary fat pad inoculation site we observed an inverse association between tumor growth and apoptosis. As the primary tumor increased in size, the extent of spontaneous apoptosis decreased. In contrast, an increase in apoptosis was associated with tumor growth of MTLn3 metastases in the axillary lymph node and the lung. In regard to necrosis, a similar pattern of increased necrosis was associated with tumor progression in both primary and metastatic tumors. Differences between primary and metastatic tumors in their pattern of spontaneous apoptosis may have important implications for the design of clinical treatment strategies. PMID- 8702223 TI - Evaluation of organoselenium compounds for potential chemopreventive properties in colon cancer. AB - Our previous studies have demonstrated that dietary benzylselenocyanate (BSC) and 1,4-phenylenebis (methylene) selenocyanate (p-XSC); organoselenium compounds, act as potential chemopreventive agents in colon carcinogenesis in F344 rats. As a part of a program aimed to develop less toxic and more effective chemopreventive organoselenium compounds than inorganic selenium and BSC, we evaluated the positional isomers of BSC namely o-, m-, and p-methoxy BSC and dibenzyl diselenide (DDS) for their potential chemopreventive properties using colonic epithelial cell proliferation as an efficacy endpoint. p-XSC and inorganic selenium, which were found to inhibit colon carcinogenesis in earlier preclinical efficacy study, were included as positive controls. Male F344 rats were fed the control diet containing 8 ppm Na2SeO3 or 10 ppm of each o-, m-, and p-methoxy BSC and DDS equivalent to 4.1 ppm Se or 20 ppm p-XSC (10 ppm Se) 2 weeks prior to carcinogen (AOM, 15 mg/kg body wt., once weekly for 2 weeks) administration and during and until 8 weeks after AOM treatment. Vehicle-control animals received an equal volume of normal saline. One hour prior to sacrifice, all animals were injected with bromodeoxyuridine (BrdU, 20 mg/kg body wt.). Administration of o-, m-, and p-methoxy BSC, p-XSC, DDS, and Na2SeO3 resulted in decreased colonic labeling index in animal treated with AOM compared to control diet. Notably, p XSC and Na2SeO3, which showed previously colon tumor inhibitory activity in preclinical efficacy study, were also effective in the present study. The results of our previous and current studies indicate that structurally modified synthetic organoselenium compounds may have great potential as chemopreventive agents. PMID- 8702224 TI - In vitro cytotoxic activity of two potential anticancer drugs isolated from Strychnos: strychnopentamine and usambarensine. AB - The cytotoxicity and the selective antiprotozoal activity of some Strychnos alkaloids, namely strychnopentamine (SP) and usambarensine (US) (7) led us to analyze and compare their effects with emetine (EM) by using mouse B16 melanoma cells cultivated in vitro. We observed by cytological analysis and proliferation rate studies that these substances induce analogous cytotoxic effects in B16 cells, but at different concentrations i.e. formation of lamellar bodies in the cytoplasm, the which contain pre-melanosomes in the case of SP and US, vacuoles and blebs. At concentrations near their respective IC50, SP and US, but not EM, decreased colony formation. We showed by incorporation of labelled precursors that SP and US first inhibit RNA synthesis while EM initially acts on protein synthesis. These alkaloids increased melanin synthesis. Furthermore, only EM and SP caused hemolysis of sheep red blood corpuscles. This could explain why the rate of antiplasmodial activity is higher for SP and EM. PMID- 8702225 TI - The effects of cytokine gene transfer into tumors on host cell infiltration and regression. AB - New strategies are becoming available that promise to revolutionize cancer immunotherapy. Although the task of generating what is in essence a pathogenic autoimmune anti-tumor response in the face of local and systemic immune suppression is likely to remain a formidable one, advances in molecular strategies for enhancing tumor immunity have been made that show considerable promise, in particular those based on gene transfer technology. For example, introduction of certain cytokine genes into murine tumor cells have been shown to enhance tumor immunogenicity and induce regression. Caution is needed in properly interpreting the relevance of observations derived from murine models for human cancer, but clinical trials are underway that will test the utility of cytokine gene therapy for cancer and that will generate data that will be useful for the design of future strategies. Because of the magnitude of the problem of inducing tumor regression, it is argued that, even if genetically engineering can be used to successfully enhance anti-tumor immunity, combination of such strategies with other existing conventional anti-cancer therapies, that increase the effectiveness of both, may be necessary to reliably achieve cure. PMID- 8702226 TI - Immunohistochemical characterisation of immunological changes at the tumour site after chemo-immunotherapy with doxorubicin, interleukin-2 and interferon-gamma. AB - Chemo-immunotherapy for the treatment of cancer, whilst promising from a preclinical and clinical perspective, remains limited by a lack of clear understanding of the in vivo antitumour mechanisms of this multi modality strategy. There is now strong evidence that systemic immunological parameters do not correlate with therapeutic activity. In contrast, information on therapy related immunological change at the tumour site is scarce. Having previously demonstrated that the therapeutic activity of doxorubicin chemotherapy can be significantly augmented by the co-administration of two cytokines, interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), the objective of the present study was to investigate the mechanism of action of this enhanced therapeutic activity by characterising the effect of single, double and triple agent therapy upon local tumour immune parameters. Twenty-four hours after the administration of treatment to WAG rats bearing solid tumour implants of a colonic adenocarcinoma, the extent of tumour infiltration in response to the therapy was assessed in haematoxylin and eosin stained tumour sections. Treatment with doxorubicin/IL-2/IFN-gamma or IL-2/IFN-gamma was associated with a marked augmentation of the size of the tumour infiltrate (P < 0.001), as compared to untreated tumours or to those treated with any other single or double agent combination. Phenotypic evaluation of the tumour infiltrate using immunoperoxidase stained tumour sections revealed that a considerable proportion of the infiltrating cells were T cells and macrophages, whilst B cells were not detected in significant numbers. Although this phenotypic profile was not qualitatively influenced by therapy, marked quantitative differences were observed. Most notably, tumours treated with either doxorubicin/IL-2/IFN-gamma or IL-2/IFN-gamma exhibited a significant increase in the numbers of CD25+ infiltrating cells (P < 0.001). These changes in the tumour immunological response closely paralleled the therapeutic responses described previously. Thus, the enhanced therapeutic activity of the triple agent regimen may result from a profound augmentation of the size of the tumour infiltrate, together with a similar increase in the numbers of activated infiltrating cells. This study supports the concept that the immune response within the tumour is the appropriate site for investigations into the immunological antitumour mechanisms of immunotherapy and chemo-immunotherapy. PMID- 8702227 TI - Antitumor activity of menogaril alone, and in combination against human mammary cancer models in mice and rats. AB - Menogaril is an antitumor agent different from other anthracyclines in being active after oral administration. To predict its clinical effectiveness by this route against human breast cancer, we compared its antitumor activity against breast cancer in experimental animals with that of injected Adriamycin. Menogaril had half the much antitumor activity of Adriamycin against human mammary cancer cell lines. Menogaril given orally also had a antitumor activity against mammary cancer caused by 7,12-dimethyl-benz[a]anthracene in rats comparable with that of Adriamycin. The high concentration of menogaril in tumor tissue seemed to contribute to its effectiveness. Of several combinations of cyclophosphamide, Adriamycin, menogaril, and 5-fluorouracil, the combination of cyclophosphamide, menogaril, and 5-fluorouracil was most effective against mouse leukemia L1210 and human breast cancer xenografts in mice. This combination might have antitumor activity against breast cancer superior to that of the therapy currently of first choice (cyclophosphamide, Adriamycin, and 5-fluorouracil) in the clinic. PMID- 8702228 TI - Vascular cross-sectional area in rat mammary tumours; influence of noradrenaline. AB - A double fluorescent staining technique for visualisation of blood vessels was applied to rat mammary tumours. Rats were exposed to noradrenaline or saline and the stained vascular area was recorded. In tumours exposed to noradrenaline, vascular staining was different from that in those exposed to saline, reflecting the possible closure of part of the vasculature in response to the drug. PMID- 8702229 TI - Cloning of mucosal and cutaneous HPV sequences in a metastatic squamous cell carcinoma from an epidermodysplasia verruciformis patient. AB - Human papillomavirus (HPV) is a DNA tumor virus strongly associated with cervical neoplasias. There are over 80 different types of HPVs which can infect either mucosal or cutaneous tissue. Cutaneous squamous cell carcinomas (SCC) associated with HPV are often seen in patients with epidermodysplasia verruciformis (EV). EV is characterized by cutaneous lesions that progress to SCC upon UV exposure. In characterizing the HPV types associated with an unusually aggressive form of EV, we have cloned an HPV with homology to the moderately oncogenic genital type HPV 34, the oncogenic EV type HPV 5 and from benign oral mucosal type HPV 32. The presence of sequences from these highly divergent types is a novel finding. These three viral types are from different phylogenetic branches of the HPV family believed to have evolved independently from each other. PMID- 8702230 TI - Pharmacokinetics of a new platinum compound, cis-(glycolato-O,O) [(4R,5R)-4,5 bis(aminomethyl)-1,3-dioxolane-2-spiro-1'-cyclohexane]plat inum (II) in dogs. AB - A pharmacokinetic study on cis-(glycolato-O,O)/ (4R,5R)-4,5-bis(aminomethyl)-1,3 dioxolane-2-spiro-1'- cyclohexane]platinum(II) (SKI 2032R) was performed in dogs. A single dose of 2.0 mg/kg of SKI 2032R was administered i.v. bolus to three beagle dogs. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for SKI 2032R declined in a biexponential fashion. The mean area under the concentration-time curve (AUC0 --> infinity) determined for ultrafiltrable platinum derived from SKI 2032R, as an active component, was 2.36 +/- 0.23 micrograms. h/ml (mean +/- S.D.), with an initial half-life of 0.23 +/- 0.20 hour, a terminal half-life of 1.32 +/- 0.49 hour, a total clearance of 14.17 +/- 1.50 ml/min/kg, and a steady-state volume of distribution of 1.21 +/- 0.24 l/kg. PMID- 8702231 TI - Expression of sarcoma-associated antigens p102 and p200 in human sarcoma cell lines. AB - BACKGROUND: Understanding tumor antigen expression and its correlation with the cell cycle may help in designing immunotherapy by monoclonal antibodies. Therefore, we studied the in vitro expression of sarcoma-associated antigens p102 and p200 in the G, S, and G2/M phases of sarcoma cell lines. METHODS: The expression of human cell surface sarcoma-associated antigens p102 and p200 was studied in 13 human sarcoma cell lines, using flow cytometry. RESULTS: p102 was detected by monoclonal antibody 19-24-6 in all 13 sarcoma cell lines, and p200 was detected by monoclonal antibody 29-13-17 in five of 13. p102 antigen expression was 1.4- to 3.4-fold higher (p < 0.001) than p200 expression. Although sarcoma cell lines showed a wide range of p102/p200 antigen expression, over 99% of the entire in vitro and in vivo cell population was found to be p102- and/or p200-positive. In three cell lines, p102 expression was cell cycle-dependent, with relative fluorescence intensity ranging from 13.8% to 23.9% higher at the G1 phase than at the G2/M phase. In three cell lines, the expression of p200 at the GI phase was 22.4% to 40.9% percent higher than at the G2/M phase. CONCLUSIONS: The heterogeneity and cell cycle dependence of p102/p200 antigen expression in sarcoma cells suggest that monoclonal antibodies 19-24-6 and 29-13-17 might be applied to the immunotherapy of sarcoma. PMID- 8702233 TI - IgG generated against benign tumor-associated antigens prevented the effects of 1,2-dimethylhydrazine in rats. AB - We showed the possibility of significant decreasing of the frequency of chemically induced colon cancer in rats by vaccination with polyclonal rabbit IgG generated against purified tumor-associated antigens (TAA). TAA were isolated from benign rat colon tumors by the method developed in our laboratory (Zusman et al 1994) using affinity chromatography columns with gel fiberglass membranes (R. Zusman, 1992) containing anti-tumor IgG. The IgG was isolated from rabbits following their vaccination with TAA. Sprague Dawley rats were vaccinated with anti-TAA IgG (100 micrograms/rat) suspended in Freunds adjuvant by weekly subcutaneous injections for 5 weeks. The induction of colon cancer was caused by weekly injections with 1,2-dimethylhydrazine (DMH) (20 mg/kg) for 7 weeks and was started one week after the end of the vaccination. The results of experiments were evaluated 6 months after the start of cancer induction. IgG protected against the carcinogenic effects of DMH. The number of tumor-bearing rats decreased to 64% as compared with 90% in the control group. In vaccinated rats, the incidence of tumors was almost 3 times less than of control, i.e. 3.6 and 9.3, respectively. The number of malignant tumors was also significantly smaller in vaccinated rats than in controls, being 24% and 58%, respectively. Metastases were found only in controls, 4 of 30 rats. The results of our experiments have shown that anti-TAA IgG not only has anti-tumor effects but also prevents the malignization of benign tumors. As one of the main components of TAA which was isolated from colon cancer rats was soluble p53 antigen (Zusman et al 1994), we suggest that the vaccine which has been generated in our experiments may be regarded as acting mainly against p53 antigen, and its antitumor effects should also be considered as effects of p53 antibodies. The further studies will be performed to clarify this. PMID- 8702232 TI - Biochemical characteristics and differentiating activity of 4-oxo analogs of retinoic acid. AB - 3-Methyl-4-oxoretinoic acid and 3-cinnamyl-4-oxoretinoic acid bind to a cellular retinoic acid-binding protein (CRABP-II) and to a retinoic acid-receptor protein (RARa). These analogs of 4-oxoretinoic acid, as well as the parent compound, have less binding affinity than retinoic acid. Cotransfection assays in CV-1 cells with plasmids containing cDNAs for RAR alpha, RAR beta and RAR gamma (homodimers) and RAR alpha-RXR alpha and RAR beta-RXR alpha (heterodimers), indicate that 3 cinnamyl-4-oxoretinoic acid induces relatively less transcriptional activity than 4-oxoretinoic acid and its 3-methyl analog, both of which are less effective than retinoic acid. In differentiating mouse F9 embryocarcarcinoma cells, the order of effectiveness is retinoic acid > 4-oxoretinoic acid = 3-methyl-4-oxoretinoic acid > 3-cinnamyl-4-oxoretinoic acid. This order of potency is similar to that for inhibition of induction of ornithine decarboxylase (ODC) activity and for prevention of papillomas on the skin of mice. Binding to CRABP-II and activation of RARs appear to be important factors for expression of differentiating activity, inhibition of induction of ODC activity and prevention of papillomas on the skin of mice. PMID- 8702234 TI - Fluorescent in situ hybridization analysis in blood lymphocytes of lung cancer patients. AB - Genetic predisposition to lung cancer was determined by observing nonrandom chromosomal alterations in peripheral blood lymphocytes (PBLs) of lung cancer patients. The histological distribution of the cases showed that chromosomes 7 and 9 were frequently altered in squamous cell lung carcinoma (SCLC) patients. We analyzed PBLs of 26 SCLC patients and 5 controls using fluorescent in situ hybridization (FISH) with whole chromosome painting probes of chromosomes 7 and 9 to further investigate the frequency of rearrangements in these chromosomes. Our results suggested that seeking nonrandom aberrations in larger numbers of cells using FISH strengthened our previous observation of mosaicism and involvement of specific chromosomes in lung cancer patients. On combining our previous data, aberrations in chromosome 7 (16 of 26 patients), chromosome 9 (14 of 26), and the present study, we could actually pinpoint more individuals with abnormalities of chromosome 7 (23 of 26) and chromosome 9 (21 of 26). Thus, analyzing more cells in PBLs and adding FISH analysis serve as useful adjuncts to our studies of nonrandom chromosomal aberrations and genetic mosaicicm. PMID- 8702235 TI - Fluorescent location of cells of cytological interest in cervical smears prestained with thionin. AB - Cervical cells of cytological interest were located in conventional smears, treated with thionin for quantitative DNA staining by subsequent treatment with fluorescent probes for a cell surface protease. Normal mature cervical epithelial cells failed to bind these fluorescent probes whilst metaplastic cells, glandular cells, and dyskaryotic cells were readily located. By this means, the nuclear staining of these fluorescent cells of cyotological interest enabled them to be classified by a cytologist. PMID- 8702236 TI - nm23 expression in advanced and borderline ovarian carcinoma. AB - Twenty-four advanced (surgical stage III and IV) ovarian carcinomas and 15 borderline ovarian tumours were studied for the overexpression of nm23 and HER 2/neu (c-erb-B2) by means of immunohistochemistry on sections from routinely processed, paraffin-embedded, archival tumour blocks, using the NCL-nm23 and the NCL-CB11 monoclonal antibodies and the streptavidin-biotin-peroxidase technique. Significantly more advanced ovarian carcinomas (p = 0.034) expressed high levels of nm23 when compared to borderline tumours. HER-2/neu (c-erb-B2) expression, as could be expected, was also significantly more frequent in advanced ovarian carcinomas (p = 0.006). We were not able to find the previously reported association between nm23 and HER-2/neu overexpression in our tumours. Our results on nm23 overexpression in ovarian cancer are coincident with those previously reported using nm23-mRNA measurements on fresh ovarian tissues. Thus, ovarian carcinoma seems to belong to the group of tumours, like colon carcinoma and neuroblastoma, in which nm23 overexpression is associated with a more malignant phenotype. Immunohistochemistry performed on archival samples from ovarian carcinomas seems adequate for the demonstration of nm23 overexpression in ovarian cancer. This opens the possibility for larger studies on series of patients with a closed follow-up, which could help to establish the role of this gene in this kind of tumour. PMID- 8702237 TI - Transplantable melanomas in gerbils (Meriones unguiculatus). I. Origin, morphology and growth rate. AB - A family of serially transplanted melanomas in gerbils is described. These tumors were derived from the cutaneous melanotic melanoma that arose in 1 of 44 gerbils injected postnatally with N-ethyl-N-nitrosourea. It consists of a slow growing heavily melanotic parental line and two fast growing melanotic (FGM) and amelanotic (A-FGM) lines that appeared abruptly during serial transplantation of the parental tumor. The FGM melanotic line originated after a sudden acceleration of growth of the parental line during the 4th in vivo passage that was accompanied by a decrease in both pigmentation and metastasizing potential. The A FGM derived from the depigmented tissue of the 7th in vivo passage of the FGM line and has been characterized by an amelanotic phenotype, an increased metastasizing potential and similar growth rate to that of the FGM. Once established, both lines expressed considerable phenotypic stability during serial transplantation in gerbils. Thus, the Zeman UJ melanomas represent the first established family of transplantable melanomas in gerbils, which serve as a model for pigmented cell and melanoma research and as a subject for a retrospective analysis of the phenomenon of tumor evolution. PMID- 8702238 TI - Terminal differentiation in a non-small-cell bronchopulmonary carcinoma correlates with increased expression of p53. AB - We studied the pharmacomodulating effects of a marine substance, bistramide D, which is capable of inducing terminal differentiation on the expression of the c erb-B1, ras, src, myc and p53 genes in the NSCLC-N6 cell line established from a non-small cell lung carcinoma. Analysis (subsequent to treatment) demonstrated that among the genes for which it was possible to detect expression, namely c-erb B1, c-myc and p53, only the expression of the p53 gene varied significantly. The increase of the expression rate of the p53 gene underlines its prominent role in the control of cell proliferation and differentiation. PMID- 8702239 TI - Antitumor and antiproliferative effects of a fucan extracted from ascophyllum nodosum against a non-small-cell bronchopulmonary carcinoma line. AB - Fucans, sulfated polysaccharides extracted from brown seaweeds, have been shown to be endowed with inhibitory effects cell growth in various experimental models. We studied both the antiproliferative and antitumor properties of a fucoidan extract (HF) obtained from the brown seaweed Ascophyllum nodosum on a cell line derived from a non-small-cell human bronchopulmonary carcinoma (NSCLC-N6), this type of carcinoma is particularly chemo-resistant. HF exerts in vitro a reversible antiproliferative activity with a block observed in the G1 phase the cell cycle. Studies performed with the NSCLC-bearing nude mice show antitumor activity at subtoxic doses. These preliminary results indicate that HF exhibits inhibitory effect both in vitro and in vivo and is very potent antitumor agent in cancer therapy. PMID- 8702240 TI - In vitro and in vivo interactions of D-penicillamine with tumors. AB - D-penicillamine (PSH) is a copper chelator that generates hydrogen peroxide and inhibits neovascularization. As hydrogen peroxide is toxic to some tumor cells and to blood vessels, we reasoned that PSH plus copper would inhibit tumors in vivo and in vitro. To test this hypothesis, we first incubated murine J558L plasmacytoma cells with varying combinations of drug (PSH and/or copper sulfate) plus modulators (fetal calf serum, dithiothrietol, catalase, eosinophil peroxidase) and then used fluorescence microscopy to measure cell proliferation, necrosis, and apoptosis. We also incubated various types of human tumor cells with PSH plus copper for 24 hours and then measured the number of surviving cells 24 hours later. For the in vivo studies, we measured the effects of 7 daily i.p. injections of 10 mg of PSH on the growth rates of interleukin-5 genetransfected J558L tumors in 20 BALB/c mice. Our experiments demonstrated that PSH plus copper exerted a significant antiproliferative effect on tumor cells in vitro that was neutralized by protein or catalase and enhanced by adherent eosinophil peroxidase. Human acute myelogenous leukemia cells were especially sensitive to PSH plus copper. In vivo, however, PSH had no significant effect on the growth rates of J558L tumors that were infiltrated by eosinophils. We conclude that the interaction of PSH-copper with tumors is primarily antiproliferative, mediated by hydrogen peroxide, and inhibitable by protein. Therefore, for PSH to be an effective antineoplastic drug strategies will need to be developed to prevent its rapid neutralization by protein. PMID- 8702241 TI - Chromatin structure and endonuclease sensitivity in human leukemic cell lines. AB - The relationship between chromatin structure and endonuclease sensitivity was investigated. The cells used in this study were a) human myelogenous leukemic cell lines (HL-60, ML-I, U-937, THP-I) (Group I), which produced internucleosomal DNA cleavage, and b) human T-cell leukemia (MOLT-4), erythroleukemia (K562), glioblastoma (T98G, U87MG) and glioma (KG-1-C) cell lines (Group II), which produced no internucleosomal DNA cleavage, upon treatment with various apoptosis inducing agents. When the nuclei, isolated from these cells were digested with micrococcal nuclease, chromatin DNA was cleaved into oligonucleosomal units. Although sensitivity to micrococcal nuclease considerably differed from cell to cell, Group I cells were generally more sensitive to micrococcal nuclease digestion than Group II cells. Similar sensitivity to DNase I was observed in both groups of cells. Acid-urea polyacrylamide gel electrophoresis of histone fractions from control and apoptosing HL-60 cells (induced either by hydrogen peroxide or UV irradiation) revealed no significant change in the relative composition of five major histones, indicating the absence of selective degradation of histone HI, but rather the nonspecific degradation of many nuclear proteins. These data suggest a difference in a chromatin structure between Group I and II cells, which might result in the selective production of internucleosomal DNA cleavage only in Group I cells. PMID- 8702242 TI - The interaction between two antioxidants, sodium ascorbate and gallic acid: radical intensity and apoptosis induction. AB - ESR spectroscopy revealed that both the radical intensity and degradation rate of sodium ascorbate were increased with increasing pH. Gallic acid significantly reduced the radical intensity of sodium ascorbate, which in turn reduced the radical intensity of gallic acid. Sodium ascorbate inhibited the apoptosis inducing activity of gallic acid, and gallic acid inhibited the intracellular incorporation of ascorbic acid. These data suggest that interaction between sodium ascorbate and gallic acid might modify their biological activity. PMID- 8702243 TI - Characterization of naturally acquired multiple-drug resistance of Yoshida rat ascites hepatoma AH66 cell line. AB - Characteristics of multiple-drug resistance of rat ascites hepatoma AH66, a cell line induced by dimethylaminoazobenzene and established as a transplantable tumor, were compared with those of AH66F, a drug sensitive line obtained from AH66. The AH66 cell line was resistant to vinblastine, adriamycin, SN-38 an active form of camptothesine, etoposide, and clorambucil by 10-fold or more than the AH66F cell line. The resistance of AH66 cells to vinblastine, adriamycin, and SN-38 was closely related to P-glycoprotein overexpression in the plasma membrane, because the resistance was significantly inhibited by verapamil. AH66 cells contained much glutahione and had a high activity of glutathione S transferase P-form (GST-P), compared with AH66F cells, and resistance to clorambucil was decreased by treatment with buthionine sulfoximine, an inhibitor of glutathione synthesis. AH66 cells have a similar topoisomerase I activity, but about 6 times lower topoisomerase II activity than AH66F cells. Therefore, the resistance to etoposide and a part of the resistance to adriamycin of AH66 cells seems to depend upon this low topoisomerase II activity. These results, show that the AH66 cell line has high multiple-drug resistance compared with the AH66F cell line, by several mechanisms. Consequently, the AH66 and AH66F cell lines are useful to study naturally acquired multiple-drug resistance of hepatomas. PMID- 8702244 TI - Effects of antiallergic drugs on the proliferation of estrogen-sensitive mouse Leydig cell line. AB - The proliferation of B-1F cells established from an estrogen-sensitive mouse Leydig cell tumor is negatively regulated by leukotrienes, whose production is suppressed by the addition of estrogen. Disodium cromoglycate, tranilast, repirinast, tazanolast and pemirolast potassium are used as therapeutic agents for allergic diseases. They are known to inhibit the release of chemical mediators such as histamine and leukotrienes from peripheral leukocytes. It is therefore of interest to determine whether these drugs affect the proliferation of B-1 F cells. The drugs in the culture medium stimulated the proliferation of B 1F cells to various extents. The results suggest that chronic administration of these drugs to the patients with allergic diseases may possibly enhance the proliferation of some kinds of tumor cells, resulting in the change from latent to clinical tumors, although there are significant differences between in vitro cultured animal cells and in vivo humans. PMID- 8702245 TI - Immunomodulating activities on cellular cytotoxicity and the blast transformation of human lymphocytes by 10-[n-(phthalimido)alkyl-2-substituted-10H-phenothiazines and 1-(2-chloroethyl)-3-(2-substituted-10 H-phenothiazin-10-yl)alkyl-1-ureas. AB - Phenothiazines, 10-[n-(phthalimido)alkyl-2-substituted-10H- phenothiazines, and 1 (2-chloroethyl)-3-(2-substituted-10H-phenothiazin-10-yl)alkyl-1- ureas were investigated for their effects on antibody-dependent cellular cytotoxicity (ADCC), natural killer (NK) cells and the blast transformation of human peripheral blood mononuclear cells. All of the compounds dose-dependently suppressed mitogen-stimulated T cell proliferation. In contrast, a strong enhancing effect on NK cell activity was detected mostly in the case of 1-(2 choroethyl)-3-(2-substituted-10H-phenothiazin-10-yl)alk yl-1-ureas and their related compounds. The stimulating effect directly influenced the NK cells and was demonstrated at all tested concentrations. PMID- 8702246 TI - Analysis of glial fibrillary acidic protein gene methylation in human malignant gliomas. AB - Glial fibrillary acidic protein (GFAP) is an intermediate filament specifically expressed in glial cells which helps to maintain and stabilize the glial cytoskeleton. Interestingly, with increasing astrocytic anaplasia, there is typically progressive loss of GFAP expression. In in vitro model systems, most permanent glioma cell lines are GFAP-negative. To determine the mechanism by which the transcription of the GFAP gene may be repressed in glioma cell lines, we initially performed a Southern analysis on a panel of human malignant glioma cell lines using a human cDNA probe for GFAP. By this method, no large rearrangements or deletions of the GFAP gene were found. Postulating that a change in methylation status of the GFAP gene could conceivably alter its expression in glioma cell lines, we studied the methylation state of the GFAP gene in the same glioma cell lines using a methyl-sensitive restriction enzyme digest of tumour and control DNA. Our analysis revealed that the GFAP gene was hypermethylated in 2/2 GFAP- negative glioma cell lines but not in 4/4 GFAP positive glioma cell lines. To determine if methylation of CpG islands contained within the GFAP promoter could repress GFAP transcription, we designed deletional constructs from a 6 kb fragment of the mouse GFAP promoter, methylated them using Msp I- and Hpa II-methylases, and tested their activity in a standard CAT assay. Our data suggest that methylation of a 2 kb segment of the mouse GFAP promoter is sufficient to inactivate GFAP transcription. Our results further imply that methylation-mediated repression of GFAP transcription may be one candidate mechanism to account for decreased GFAP expression in certain human malignant glioma cell lines. PMID- 8702247 TI - Benzodiazepine-induced inhibition of human malignant melanoma (M-6) cell growth. AB - Since benzodiazepines (BZs) have been shown to inhibit the growth of some cell lines, the effects of these drugs on human melanoma (M-6) cell growth were examined. Cell growth was measured by the tetrazolium salt (MTT) assay or the Hoechst 33258 DNA assay. Diazepam, a non-selective BZ agonist, and Ro5-4864, a peripheral-type agonist, inhibited M-6 cell proliferation by 36% and 55% with EC50s of 139 microM and 107 microM respectively, after four days of treatment in culture. The central-type agonists, clonazepam and flunitrazepam, were ineffective. The antiproliferative effect of diazepam was partially reversed by treatment with phorbol 12-myristate 13-acetate (PMA). Neither PK 11195, a peripheral-type BZ receptor antagonist, nor flumazenil a central-type antagonist, blocked the effect of diazepam, indicating that these BZ receptors are not involved. The effect of PMA suggests that the antiproliferative effect of the BZs may involve inhibition of a calcium/protein kinase C-related pathway in M-6 cells. PMID- 8702248 TI - Treatment and survival in diffuse malignant pleural mesothelioma; a study of 83 cases from the Massachusetts General Hospital. AB - The influence of treatment on clinical outcome in pleural mesothelioma (PM) is uncertain. We studied 83 patients with PM treated at our institution to evaluate the impact of treatment modality on survival, Methods. Medical records of 83 patients with PM treated between 1978 and 1994 were reviewed. The following data were tabulated for each patient; age, sex, date of diagnosis, history of asbestos exposure, smoking history, method of diagnosis, histologic subtype, type of treatment and survival from diagnosis. Four treatment groups were analyzed; chemotherapy (C), surgery (S), combined modality (CM i.e. S + C with or without radiation therapy) and supportive care alone (SC). Survival curves were calculated and adjustment made for age. Survival curves were compared using Wilcoxon Chi-square analysis. Results. Seventy-one males and 12 females with a mean age of 67 years were analyzed. Seventy-five percent were smokers and 74% reported definite or probable asbestos exposure. Treatment groups did not vary according to smoking or asbestos history. The CM group and SC groups contained similar proportions of patients with epithelial tumors (54% v 56%). Median survival for patients in the CM group was 23.9 months versus 4.5 months among those receiving SC (p < 0.01). Discussion. This analysis suggest prolonged survival among patients with PM receiving CM versus SC or single modality treatment. PMID- 8702249 TI - Prone scintimammography in patients with non-palpable breast lesions. AB - Non-palpable breast lesions are a clinical problem due to the low specificity of mammography and the resulting difficulty in choosing the type and extent of surgery. Twenty-four patients with non-palpable mammographic lesions underwent prone scintimammography after the i.v. injection of 740 MBq of 99m Tc-SestaMIBI (MIBI). For this purpose, we designed a special bed which allows the widest exposure of the breast to the detector and better visualisation of deep mammary tissue without interference from intra-thoracic activity. The day after the scintigraphy, all patients underwent quadrantectomy or a more limited excision. The specimens were X-rayed to check the presence of mammographic microcalcifications or opacities. All surgical specimens were histologically evaluated. The mammographic and scintigraphic findings were compared with the histological ones. Under these conditions, we observed that the MIBI scan has a good specificity (90%) but low sensitivity (50%) for this selected population. When the MIBI scan was positive, the probability of breast cancer was very high (positive predictive value of the test = 88%) as a consequence, a wider excision would be the most accurate surgical choice. On the other hand, if the MIBI scan is normal, the high number of false negative results does not allow any final diagnosis (negative predictive value of the test = 56%). The preliminary results of this work suggest that radionuclide imaging can help the surgeon in surgical planning. PMID- 8702250 TI - A phase I study of 5-day continuous venous infusion of carboplatin at circadian rhythm-modulated rate compared with constant rate. AB - The circadian rhythm-modulated delivery of anticancer drugs has been shown to reduce toxicity and improve anticancer efficacy. The aim of this phase I trial was to compare the feasibility and tolerability of carboplatin (CBDCA) administered at circadian-modulated or flat infusion rate in 24 patients with advanced cancer. Each treatment cycle consisted of a 5-day continuous intravenous infusion of CBDCA, to be repeated at 28-day intervals. Three dose levels were determined, with a CBDCA dose 15%, 40% and 60% over that calculated using Calvert's formula. Two schedules were compared: schedule A (forty-four courses), with a at circadian rhythm-modulated rate (peak at 16.00 hr) and schedule B (fifty courses), at a constant rate. At the first and second dose level neither of the administered cycles were accompanied by hematologic toxicity higher than Grade 3. At the third dose level, two cycles out of 15 for schedule A and two out of 20 for schedule B were accompanied by Grade 4 thrombocytopenia. The repeat cycles were delayed from day 28 to 42 in some patients, with no differences between circadian-modulated and flat infusion. Three partial responses out of 9 evaluable patients were observed in schedule A and 2 out of 10 evaluable patients in schedule B. We showed no potential advantage of the chronomodulated 5-day CBDCA continuous infusion method over the flat rate method. Although antitumor effects were observed in this pilot study, this treatment cannot be assessed for efficacy relative to other schedules. PMID- 8702251 TI - Gender related survival in colorectal cancer. AB - The importance of patient characteristics to long term survival in colorectal carcinoma is the subject of much debate. The importance of female gender as an advantagous factor in prognosis is difficult to determine. A retrospective study based on data from 1050 patients resected for colorectal carcinoma was carried out. A complete follow-up and survival data were available. Categorical variables such as age, sex, tumor stage and location, perioperative blood transfusions, and postoperative complications were used. Standard univariate and multivariate descriptive analysis was applied. In addition to tumor staging patients' sex was a strong significant factor on prognosis. When analysed independently of tumor location, blood transfusions, and severe complications, sex was revealed to be a statistically significant independent prognostic factor in longterm survival. The 5-year survival rate for men was 43.5 % and 54.7 % for women. When the observed survival was compared with sex related life expectancy of a representive population, similar differences of survival were seen for both sexes. PMID- 8702252 TI - Treatment of liver metastases from colorectal cancer. AB - 197 cases of distant metastases from colorectal cancer (Dukes A, B, C) were diagnosed in 664 patients after curative resection of the primary tumor. Extrahepatic progress could be excluded in 98 of 142 patients with liver metastases. These 98 patients were allocated to surgical treatment (n = 17), intraarterial chemotherapy (n = 24), transarterial chemoembolization (n = 20), systemic chemotherapy (n = 10) and syptomatic therapy (n = 27) depending on the extent and localization of the disease within the liver and the patients' general condition. Curative success in 12 of 17 patients with a 5-year survival of 47% was achieved by the careful selection of patients for surgical treatment. Prolonged median survival after systemic chemotherapy (13 months), intraarterial chemotherapy (11 months) and transarterial chemoembolization of hepatic metastases (12 months) compared with the survival of patients with a symptomatic treatment only (median 11 months) could not be demonstrated, in spite o local therapeutic effects (intraarterial chemotherapy response rate 42%, transarterial chemoembolization morphologic response 82%). Effective postoperative diagnostic screening determines the percentage of potential curative surgical treatment; nonsurgical approaches failed to demonstrate prolonged survival. PMID- 8702253 TI - Pulmonary sclerosing hemangioma in a woman with multiple uterine fibromas, cysts to thyroid and kidney. AB - Pulmonary sclerosing hemangioma (PSH) is a relatively rare, homogeneous solitary tumor. Its complex histology may suggest a number of malignancies. We report one case diagnosed in a 62-years-old woman with a tendency to benign tumors (uterine fibromas) and cystes (thyroide, kidney). Bronchoscopy was normal. Pulmonary scintiscan was not done. Chest X-ray showed a 2 x 2 cm solitary, dense, homogeneous, delimited nodule of the LLL. The intraoperatory diagnosis of adenocarcinoma led to lobectomy. The final diagnosis of PSH was done on fixed and stained samples. She is in good condition after 13 months of follow-up. PMID- 8702254 TI - p53 protein expression in human breast carcinoma: lack of prognostic potential for recurrence of the disease. AB - Mutations of the p53 gene are now known to be one of the most commonly detected genetic defects among human cancers. Because of its stability, the mutant p53 protein can be detected by immunohistochemical methods. Overexpression of the mutant p53 protein has been suggested as a prognostic indicator for the recurrence of breast cancer. Using a monoclonal antibody to p53, formalin-fixed, paraffin embedded breast cancer tissues retrieved from up to 10 years storage in the archival files were processed for staining. A total of 125 cases was examined p53 overexpression was identified by brown nuclear staining. Clinical parameters studied included estrogen and progesterone receptors, tumor size, nodal status, obesity, stage, and histopathological grade. The only significant association seen for p53 overexpression was with negative estrogen and progesterone receptors. All other clinical parameters studied were independent of p53 overexpression. Thus, p53 overexpression does not appear to be a useful prognostic indicator for recurrence and survival in human breast cancer. PMID- 8702255 TI - Hemoglobin, horseradish peroxidase, and heme-bovine serum albumin as biocatalyst for the oxidation of dibenzothiophene. AB - Hemoglobin, horseradish peroxidase, and bovine serum albumin incubated heme catalyzed the oxidation of dibenzothiophene into sulfoxide in the presence of hydrogen peroxide. This reaction was carried out in an aqueous buffer containing 25% of water-miscible organic solvents. The observation of this transient state of hemoproteins during sulfoxidation showed heme degradation. None of the compounds usually involved in a classical peroxidative activity mechanism were detected. Furthermore, this activity did not appear to be based on a Fenton-type reaction. The highest degrees of sulfoxidation were obtained with hemoglobin. Under the best conditions of reaction, 100% of dibenzothiophene were converted into dibenzothiophene sulfoxide by hemoglobin. Heat-denatured hemoproteins did keep their sulfoxidation activity. With hemoglobin, a kcat of 0.22 min-1 was determined. Nearly the same values were obtained with heat-denatured hemoglobin and bovine serum albumin-adsorbed heme. With horseradish peroxidase, only 4% of conversion was attained. This percentage could be slightly increased by using a less pure peroxidase or heat-denatured peroxidase. PMID- 8702256 TI - Antigen-antibody diffusion-limited binding kinetics for biosensors. A fractal analysis. AB - A fractal analysis is made for antigen-antibody binding kinetics for different biosensor applications available in the literature. Both types of examples are considered wherein: (1) the antigen is in solution and the antibody is immobilized on the fiberoptic surface, and (2) the antibody is in solution and the antigen is immobilized on the fiberoptic surface. For example, when the antibody is immobilized on the surface, an increase in the antigen Clostridium botulinum toxin A concentration in solution leads to (1) a decrease in the fractal dimension value or state of disorder, and (2) a higher rate constant for binding on the fiberoptic surface. An analysis of the effect of the influence of different parameters on the fractal dimension values for a particular example, such as varying treatments or incubation procedures, helps provide insights into the conformational states and reactions occurring on the fiberoptic surface. The analysis of the different example taken together provides novel physical insights into the state of "disorder" and reactions occurring on the surface. Such types of analysis should help contribute toward manipulating the reactions occurring on the fiberoptic surfaces in desired directions. PMID- 8702257 TI - Continuous ethanol production from nonsterilized carob pod extract by immobilized Saccharomyces cerevisiae on mineral kissiris using a two-reactor system. AB - The continuous production of ethanol from nonsterilized carob pod extract by immobilized Saccharomyces cerevisiae on mineral kissiris using one- and two reactor systems has been investigated. A maximum ethanol productivity of 9.6 g/L/h was obtained at an initial sugar concentration of 200 g/L and D = 0.4 h-1 with 68% of theoretical yield and 34% of sugar utilization using the one-reactor system. At S0 = 200 g/L, D = 0.05 h-1, 83% of theoretical yield, and 64% of sugar utilization, an ethanol productivity of 2.6 g/L/h was achieved. In the two reactor system, a maximum ethanol productivity of 11.4 g/L/h was obtained at S0 = 200 g/L and D = 0.4 h-1 with 68.5% of theoretical yield and 41.5% of sugar utilization. The two-reactor system was operated at a constant dilution rate of 0.3 h-1 for 60 d without loss of the original immobilized yeast activity. In this case, the average ethanol productivity, ethanol yield (% of theoretical), and sugar utilization were 10.7 g/L/h, 71.5%, and 48%, respectively. PMID- 8702258 TI - Cloning of a marine cyanobacterial promoter for foreign gene expression using a promoter probe vector. AB - A marine cyanobacterial promoter was cloned to allow efficient foreign gene expression. This was carried out using chloramphenicol acetyl transferase (CAT) as a marker protein. For rapid and simple measurement of CAT activity, a method based on a fluorescently labeled substrate was improved by utilizing HPLC equipped with a flow-through fluorescent spectrophotometer. This method was used in conjunction with a newly constructed promoter probe vector. Cyanobacterial transformants, harboring plasmid containing a cloned 2-kbp marine cyanobacterial genomic fragment, showed a 10-fold higher CAT activity, compared with that achieved using the kanamycin-resistant gene promoter. From the sequence analysis of the cloned fragment, a putative promoter region was found. PMID- 8702259 TI - Culture variability associated with the U.S. Environmental Protection Agency Tuberculocidal Activity Test Method. AB - Tuberculosis continues to be a major world health threat. The etiologic agent is among the vegetative organisms most resistant to chemical disinfection. Tuberculocidal efficacy testing for regulatory approval of chemical germicides has evolved considerably over the past decade. A method currently in use is the Environmental Protection Agency Tuberculocidal Activity Test Method, a suspension test using a Mycobacterium bovis culture grown under specific conditions and stored frozen until used. Differing tuberculocidal label claims on products with similar formulations have raised questions concerning the equivalence of test suspensions prepared by different laboratories. Five M. bovis suspensions from laboratories currently performing this test were compared against a battery of three disinfectants at a single test site. A significant difference between test cultures was found, with two of the five exhibiting a significant difference from the other three and also from each other. There was a significant culture-by disinfectant interaction, indicating that the five cultures did not respond in a consistent manner across the different disinfectants used. However, these differences were due to cultures that were not prepared in accordance with the standard procedure or otherwise did not meet the test suspension criteria. In addition, a 0.55% sodium hypochlorite solution was found to be a sensitive indicator of culture variability. These data reinforce the need to adhere to published procedures and guidelines when growing and preparing a tuberculocidal test suspension and shed light on the variables associated with this type of testing. PMID- 8702260 TI - Comamonas testosteroni colony phenotype influences exopolysaccharide production and coaggregation with yeast cells. AB - A Comamonas testosteroni strain was isolated from activated sludge on the basis of its ability to coaggregate with yeast cells. On agar plates the following two types of colonies were formed: colonies with a mucoid appearance and colonies with a nonmucoid appearance. On plates this strain alternated between the two forms, making sectored colonies. In liquid medium with constant agitation no such change was observed. In the absence of agitation and in contact with a glass surface a culture with predominantly nonmucoid-colony-forming cells very rapidly shifted to a culture dominated by mucoid-colony-forming cells. In liquid medium the reverse was observed under stress conditions imposed by hydrogen peroxide, sodium dodecyl sulfate, or starvation. Nonmucoid cells formed very rapidly settling flocs with yeast cells, while coaggregation of mucoid cells with yeast cells did not occur. These findings may be relevant to the behavior of activated sludge microbial communities. PMID- 8702261 TI - Purification and characterization of a malic enzyme from the ruminal bacterium Streptococcus bovis ATCC 15352 and cloning and sequencing of its gene. AB - Malic enzyme (EC 1.1.1.39), which catalyzes L-malate oxidative decarboxylation and pyruvate reductive carboxylation, was purified to homogeneity from Streptococcus bovis ATCC 15352, and properties of this enzyme were determined. The 2.9-kb fragment containing the malic enzyme gene was cloned, and the sequence was determined and analyzed. The enzymatic properties of the S. bovis malic enzyme were almost identical to those of other malic enzymes previously reported. However, we found that the S. bovis malic enzyme catalyzed unknown enzymatic reactions, including reduction of 2-oxoisovalerate, reduction of 2 oxoisocaproate, oxidation of D-2-hydroxyisovalerate, and oxidation of D-2 hydroxyisocaproate. The requirement for cations and the optimum pH of these unique activities were different from the requirement for cations and the optimum pH of the L-malate oxidative decarboxylating activity. A sequence analysis of the cloned fragment revealed the presence of two open reading frames that were 1,299 and 1,170 nucleotides long. The 389-amino-acid polypeptide deduced from the 1,170 nucleotide open reading frame was identified as the malic enzyme; this enzyme exhibited high levels of similarity to malic enzymes of Bacillus stearothermophilus and Haemophilus influenzae and was also similar to other malic enzymes and the malolactic enzyme of Lactococcus lactis. PMID- 8702262 TI - Characterization of active recombinant 2,3-dihydro-2,3-dihydroxybiphenyl dehydrogenase from Comamonas testosteroni B-356 and sequence of the encoding gene (bphB). AB - 2,3-Dihydro-2,3-dihydroxybiphenyl-2,3-dehydrogenase (B2,3D) catalyzes the second step in the biphenyl degradation pathway. The nucleotide sequence of Comamonas testosteroni B-356 bphB, which encodes B2,3D, was determined. Structural analysis showed that the dehydrogenases involved in the bacterial degradation of aromatic compounds are related to each other and that their phylogenetic relationships are very similar to the relationships observed for dioxygenases that catalyze the initial reaction in the degradation pathway. The bphB sequence was used to produce recombinant active His-tagged B2,3D, which allowed us to describe for the first time some of the main features of a B2,3D. This enzyme requires NAD+, its optimal pH is 9.5, and its native M(r) was found to be 123,000, which makes it a tetramer. These characteristics are very similar to those reported for the related enzyme cis-toluene dihydrodiol dehydrogenase. The Km value and maximum rate of metabolism for 2,3-dihydro-2,3-dihydroxybiphenyl were 73 +/- 16 microM and 46 +/- 4 nmol min-1 microgram-1, respectively. Compared with the cis-toluene dihydrodiol dehydrogenase, B2,3D appeared to be more substrate specific since it was unable to attack cis-1,2-dihydroxy-cyclohexa-3,5-diene. PMID- 8702263 TI - Chloroform mineralization by toluene-oxidizing bacteria. AB - Seven toluene-oxidizing bacterial strains (Pseudomonas mendocina KR1, Burkholderia cepacia G4, Pseudomonas putida F1, Pseudomonas pickettii PKO1, and Pseudomonas sp. strains ENVPC5, ENVBF1, and ENV113) were tested for their ability to degrade chloroform (CF). The greatest rate of CF oxidation was achieved with strain ENVBF1 (1.9 nmol/min/mg of cell protein). CF also was oxidized by P. mendocina KR1 (0.48 nmol/min/mg of cell protein), strain ENVPC5 (0.49 nmol/min/mg of cell protein), and Escherichia coli DH510B(pRS202), which contained cloned toluene 4-monooxygenase genes from P. mendocina KR1 (0.16 nmol/min/mg of cell protein). Degradation of [14C]CF and ion analysis of culture extracts revealed that CF was mineralized to CO2 (approximately 30 to 57% of the total products), soluble metabolites (approximately 15%), a total carbon fraction irreversibly bound to particulate cellular constituents (approximately 30%), and chloride ions (approximately 75% of the expected yield). CF oxidation by each strain was inhibited in the presence of trichloroethylene, and acetylene significantly inhibited trichloroethylene oxidation by P. mendocina KR1. Differences in the abilities of the CF-oxidizing strains to degrade other halogenated compounds were also identified. CF was not degraded by B. cepacia G4, P. putida F1, P. pickettii PKO1, Pseudomonas sp. strain ENV113, or P. mendocina KRMT, which contains a tmo mutation. PMID- 8702264 TI - Isolation and expression in Escherichia coli of hepB and hepC, genes coding for the glycosaminoglycan-degrading enzymes heparinase II and heparinase III, respectively, from Flavobacterium heparinum. AB - Upon induction with heparin, Flavobacterium heparinum synthesizes and secretes into its periplasmic space heparinase I (EC 4.2.2.7), heparinase II, and heparinase III (heparitinase; EC 4.2.2.8). Heparinase I degrades heparin, and heparinase II degrades both heparin and heparan sulfate, while heparinase III degrades heparan sulfate predominantly. We isolated the genes encoding heparinases II and III (designated hepB and hepC, respectively). These genes are not contiguous with each other or with the heparinase I gene (designated hepA). hepB and hepC were found to contain open reading frames of 2,316 and 1,980 bp, respectively. Enzymatic removal of pyroglutamate groups permitted sequence analysis of the amino termini of both mature proteins. It was determined that the mature forms of heparinases II and III contain 746 and 635 amino acids, respectively, and have calculated molecular weights of 84,545 and 73,135, respectively. The preproteins have signal sequences consisting of 26 and 25 amino acids. Truncated hepB and hepC genes were used to produce active, mature heparinases II and III in the cytoplasm of Escherichia coli. When these enzymes were expressed at 37 degrees C, most of each recombinant enzyme was insoluble, and most of the heparinase III protein was degraded. When the two enzymes were expressed at 25 degrees C, they were both present predominantly in a soluble, active form. PMID- 8702265 TI - Survival of Escherichia coli O157:H7 in broth and processed salami as influenced by pH, water activity, and temperature and suitability of media for its recovery. AB - The survival of unheated and heat-stressed (52 degrees C, 30 min) cells of Escherichia coli O157:H7 inoculated into tryptic soy broth (TSB) adjusted to various pHs (6.0, 5.4, and 4.8) with lactic acid and various water activities (a(w)s) (0.99, 0.95, and 0.90) with NaCl and incubated at 5, 20, 30, and 37 degrees C was studied. The performance of tryptic soy agar (TSA), modified sorbitol MacConkey agar (MSMA), and modified eosin methylene blue agar in supporting colony development of incubated cells was determined. Unheated cells of E. coli O157:H7 grew to population densities of 10(8) to 10(9) CFU ml-1 in TSB (pHs 6.0 and 5.4) at an a(w) of 0.99. Regardless of the pH and a(w) of TSB, survival of E. coli O157:H7 was better at 5 degrees C than at 20 or 30 degrees C. At 30 degrees C, inactivation or inhibition of growth was enhanced by reduction of the a(w) and pH. A decrease in the a(w) (0.99 to 0.90) of TSB in which the cells were heated at 52 degrees C for 30 min resulted in a 1.5-log10 reduction in the number of E. coli O157:H7 cells recovered on TSA; pH did not significantly affect the viability of cells. Recovery was significantly reduced on MSMA when cells were heated in TSB with reduced pH or a(w) for an increased length of time. With the exception of TSB (a(w), 0.90) incubated at 37 degrees C, heat-stressed cells survived for 24 h in recovery broth. TSB (a(w), 0.99) at pH 6.0 or 5.4 supported growth of E. coli O157:H7 cells at 20 or 37 degrees C, but higher numbers of heated cells survived at 5 or 20 degrees C than at 37 degrees C. The ability of unheated and heat-stressed E. coli O157:H7 cells to survive or grow as affected by the a(w) of processed salami was investigated. Decreases of about 1 to 2 log10 CFU g-1 occurred soon after inoculation of salami (pHs 4.86 and 4.63 at a(w)s of 0.95 and 0.90, respectively). Regardless of the physiological condition of the cells before inoculation into processed salami at an a(w) of either 0.95 or 0.90, decreases in populations occurred during storage at 5 or 20 degrees C for 32 days. If present at < or = 100 CFU g-1, E. coli O157:H7 would unlikely survive storage at 5 degrees C for 32 days. However, contamination of salami with E. coli O157:H7 at 10(4) to 10(5) CFU g-1 after processing would pose a health risk to consumers for more than 32 days if storage were at 5 degrees C. Regardless of the treatment conditions, performance of the media tested for the recovery of E. coli O157:H7 cells followed the order TSA > modified eosin methylene blue agar > MSMA. PMID- 8702266 TI - Use of homoduplex ribosomal DNA spacer amplification products and heteroduplex cross-hybridization products in the identification of Salmonella serovars. AB - When the hypervariable 16S-23S intergenic spacer regions found in prokaryotic ribosomal DNA (rDNA) are amplified from conserved adjacent sequences, homoduplex double-stranded DNA structures and heteroduplex structures containing substantial regions of single-stranded DNA are generated. The electrophoretic separation of these structures results in product profile patterns, which may be organized into highly correlated pattern groups of ribosomal spacer and heteroduplex polymorphism (RS/HP) types. In a test panel of 380 Salmonella strains that were analyzed by this procedure, 36 unique RS/HP types were observed. Of the 28 serovars in the test group, 21 showed single characteristic RS/HP types. The remaining seven serovars each contained multiple RS/HP types, which were also unique to individual serovars. Formation of heteroduplex structures with a substantially reduced electrophoretic mobility was observed in 29 of the 36 RS/HP pattern types. Because the mobility of these heteroduplex structures is sensitive to intergenic spacer sequence composition, the presence of these structures adds an additional diagnostic feature that is extremely useful in the differentiation of Salmonella serovars. The RS/HP types show sufficient diversity to be useful in the identification of many commonly observed Salmonella serovars. This analytical procedure is simple to perform and is well suited to rapid and inexpensive screening of large numbers of Salmonella strains. PMID- 8702267 TI - Different domains of Bacillus thuringiensis delta-endotoxins can bind to insect midgut membrane proteins on ligand blots. AB - We investigated the role of the constituent domains of the CryIA(b) and CryIA(c) delta-endotoxins in binding to midgut epithelial cell membrane proteins of Spodoptera exigua and Manduca sexta on ligand blots. A collection of wild-type and CryIC-CryIA hybrid toxins was used for this purpose. As demonstrated elsewhere (R. A. de Maagd, M. S. G. Kwa, H. van der Klei, T. Yamamoto, B. Schipper, J. M. Vlak, W. J. Stiekema, and D. Bosch, Appl. Environ. Microbiol. 62:1537-1543, 1996), CryIA(b) domain III recognized a 205-kDa protein on S. exigua blots, while no specific binding by domain I or II could be detected. In contrast, on ligand blots of M. sexta proteins CryIA(b) domain II recognized a 210-kDa protein and CryIA(b) domain III recognized a 250-kDa protein. Domain III is responsible for the interaction of CryIA(c) with 120-kDa major binding proteins of both S. exigua and M. sexta. In addition, in M. sexta CryIA(c) also reacts with a 210-kDa binding protein through its domain I and/or domain II. These results show that besides domain II, domain III of delta-endotoxins plays a major role in binding to putative receptors on ligand blots. However, for S. exigua there was no clear correlation between binding of toxins on ligand blots and the in vivo toxicity of the toxins. These and previous results suggest that interactions of insect membrane proteins with both domain II and domain III can occur and that detection of these interactions depends on the type of binding assay used. PMID- 8702268 TI - Cloning, sequencing, and expression of genes encoding phosphotransacetylase and acetate kinase from Clostridium acetobutylicum ATCC 824. AB - The enzymes phosphotransacetylase (PTA) and acetate kinase (AK) catalyze the conversion of acetyl coenzyme A to acetate in the fermentation of Clostridium acetobutylicum. The acetate-producing step is an important element in the acidogenic fermentation stage and generates ATP for clostridial cell growth. The genes pta and ack, encoding PTA and AK, respectively, were cloned and sequenced. Enzyme activity assays were performed on cell extracts from Escherichia coli and C. acetobutylicum harboring the subclone, and both AK and PTA activities were shown to be elevated. DNA sequence analysis showed that the pta and ack genes are adjacent in the clostridial chromosome, with pta upstream. The pta gene encodes a protein of 333 amino acid residues with a calculated molecular mass of 36.2 kDa, and ack encodes a polypeptide of 401 residues with a molecular mass of 44.3 kDa. Primer extension analysis identified a single transcriptional start site located 70 bp upstream of the start codon for the pta gene, suggesting an operon arrangement for these tandem genes. The results from overexpression of ack and pta in C. acetobutylicum showed that the final ratios of acetate to other major products were higher and that there was a greater proportion of two- versus four carbon-derived products. PMID- 8702269 TI - Root colonization of maize and lettuce by bioluminescent Rhizobium leguminosarum biovar phaseoli. AB - Two strains of Rhizobium leguminosarum bv. phaseoli and three other plant growth promoting rhizobacteria (PGPR) were examined for the potential of maize and lettuce root colonization. All of these strains were selected in vitro for their phosphate-solubilizing abilities. Maize and lettuce seeds were treated with derivatives of all strains marked with lux genes for bioluminescence and resistance to kanamycin and rifampin prior to planting in nonsterile Promix and natural soil. The introduced bacterial strains were quantified on roots by dilution plating on antibiotic media together with observation of bioluminescence. Rhizobia were superior colonizers compared with other tested bacteria; rhizobial root populations averaged log 4.1 CFU/g (fresh weight) on maize roots 4 weeks after seeding and log 3.7 CFU/g (fresh weight) on lettuce roots 5 weeks after seeding. The average populations of the recovered PGPR strains were log 3.5 and log 3.0 CFU/g (fresh weight) on maize and lettuce roots, respectively. One of the three PGPR was not recovered later than the first week after seeding in Promix. Bioluminescence also permitted visualization of in situ root colonization in rhizoboxes and demonstrated the efficiency of rhizobial strains to colonize and survive on maize and lettuce roots. PMID- 8702270 TI - Purification and characterization of a novel antibacterial protein from the marine bacterium D2. AB - A biofilm-forming marine bacterium, D2, isolated from the surface of the tunicate Ciona intestinalis, was found to produce a novel, 190-kDa protein with antibacterial activity. The protein contained at least two subunits of 60 and 80 kDa, joined together by noncovalent bonds, and was shown to be released by D2 cells into the surrounding medium during stationary phase. N-terminal sequence analysis revealed no close similarity of this protein to any other proteins within the Swiss Prot database. Bacteriocidal activity against a wide variety of marine and medical bacterial isolates was observed, 77% of the strains tested being sensitive to the protein. Bacterial strains varied in their resistance to the D2 protein, with D2 itself being among the most sensitive with an MBC in liquid suspension of 4 micrograms/ml. An apparent increased resistance of D2 to the protein as the cells progressed further into stationary phase was observed and seen as a possible explanation for its survival despite the production of an autoinhibitory factor. The ability of the D2 bacterium to produce an antibacterial factor in addition to its inhibitory effects on marine invertebrates and algae (S. Egan et al., unpublished data) indicates that D2 has the potential to greatly affect the survival of a range of colonizers of the marine surface environment. PMID- 8702271 TI - Prevalence of Giardia cysts and Cryptosporidium oocysts and characterization of Giardia spp. isolated from drinking water in Canada. AB - This study was carried out to estimate the prevalence and potential for human infectivity of Giardia cysts in Canadian drinking water supplies. The presence of Cryptosporidium oocysts was also noted, but isolates were not collected for further study. A total of 1,760 raw water samples, treated water samples, and raw sewage samples were collected from 72 municipalities across Canada for analysis, 58 of which treat their water by chlorination alone. Giardia cysts were found in 73% of raw sewage samples, 21% of raw water samples, and 18.2% of treated water samples. There was a trend to higher concentration and more frequent incidence of Giardia cysts in the spring and fall, but positive samples were found in all seasons. Cryptosporidium oocysts were found in 6.1% of raw sewage samples, 4.5% of raw water samples, and 3.5% of treated water samples. Giardia cyst viability was assessed by infecting Mongolian gerbils (Meriones unguiculatus) and by use of a modified propidium iodide dye exclusion test, and the results were not always in agreement. No Cryptosporidium isolates were recovered from gerbils, but 8 of 276 (3%) water samples and 19 of 113 (17%) sewage samples resulted in positive Giardia infections. Most of the water samples contained a low number of cysts, and 12 Giardia isolates were successfully recovered from gerbils and cultured. Biotyping of these isolates by isoenzyme analysis and karyotyping by pulsed-field gel electrophoresis separated the isolates into the same three discrete groups. Karyotyping revealed four or five chromosomal bands ranging in size from 0.9 to 2 Mb, and four of the isolates had the same banding pattern as that of the WB strain. Analysis of the nucleotide sequences of the 16S DNA coding for rRNA divided the isolates into two distinct groups corresponding to the Polish and Belgian designations found by other investigators. The occurrence of these biotypes and karyotypes appeared to be random and was not related to geographic or other factors (e.g., different types were found in both drinking water and sewage from the same community). Biotyping and karyotyping showed that isolates from this study were genetically and biochemically similar to those found elsewhere, including well-described human source strains such as WB. We conclude that potentially human-infective Giardia cysts are commonly found in raw surface waters and sewage in Canada, although cyst viability is frequently low. Cryptosporidium oocysts are less common in Canada. An action level of three to five Giardia cysts per 100 liters in treated drinking water is proposed on the basis of the monitoring data from outbreak situations. This action level is lower than that proposed by Haas and Rose (C. N. Haas and J. B. Rose, J. Am. Water Works Assoc. 87(9):81-84, 1995) for Cryptosporidium spp. (10 to 30 oocysts per 100 liters). PMID- 8702272 TI - Studies of Giardia spp. and Cryptosporidium spp. in two adjacent watersheds. AB - Two adjacent British Columbia, Canada, watersheds with similar topographical features were studied. Both the Black Mountain Irrigation District (BMID) and the Vernon Irrigation District (VID) serve rural agricultural communities which are active in cattle ranching. The present study was carried out in five phases, during which a total of 249 surface water samples were tested in the study watersheds. The aims of these phases were to determine levels of parasite contamination in raw water samples collected from the intakes as well as from other sites in each watershed and to investigate cattle in the watersheds as potential sources of parasite contamination of surface drinking water supplies. Giardia cysts were not detected in the raw water samples collected from lake sources at the headwaters of both watersheds but were found in 100% (70 or 70) of water samples collected at the BMID intake and 97% (68 of 70) of water samples collected at the VID intake. Significantly higher levels (P < 0.05) of Giardia cysts were found at the BMID intake (phase 1, 7 to 2,215 cysts per 100 liters; phase 3, 4.6 to 1,880 cysts per 100 liters) when compared with that of the VID intake (2 to 114 cysts per 100 liters). The BMID watershed has a more complex system of surface water sources than the VID watershed. Cattle have access to creeks in the BMID watershed, whereas access is restricted in the VID watershed. Collection of raw water samples from a creek upstream and downstream of a cattle ranch in the BMID watershed showed that the downstream location had significantly higher (P < 0.05) levels (0.6 to 42.9 cysts per 100 liters and 1.4 to 300.0 oocysts per 100 liters) of both Giardia cysts and Cryptosporidium oocysts than those of the upstream location (0.5 to 34.4 cysts per 100 liters and 0.5 to 34.4 oocysts per 100 liters). Peak concentrations of both parasites coincided with calving activity. Fecal samples, collected from cattle in both watersheds, showed 10% (3 of 30) in the BMID and 50% (5 of 10) in the VID watersheds to be Giardia positive. No Cryptosporidium-positive fecal samples were found. Giardia cysts isolated from the BMID watershed were repeatedly infective to gerbils in contrast to those from the VID watershed. The 10 BMID drinking water Giardia isolates retrieved into culture and biotyped showed zymodeme and karyotype heterogeneity. The differences in patterns of parasite contamination and cattle management practices contribute to the unique watershed characteristics observed between two areas which are topographically similar and geographically adjacent. PMID- 8702273 TI - Utilization of hemin and hemoglobin by Vibrio vulnificus biotype 2. AB - The eel pathogen Vibrio vulnificus biotype 2 is able to use hemoglobin (Hb) and hemin (Hm) to reverse iron limitation. In this stud, the adjuvant effect of both compounds on eel pathogenicity has been evaluated and confirmed. Further, we have studied the heme-iron acquisition mechanism displayed by this bacterium. Whole cells were capable of binding Hb and Hm, independently of (i) iron levels in growth medium and (ii) the presence of polysaccharide capsules on bacterial surface. The Hb- and Hm-binding capacity was retained by the outer membrane protein (OMP) fraction and was abolished after proteolytic digestion of OMP samples. Western blotting (immunoblotting) of denatured OMPs revealed that two major protein bands of 36 and 32 kDa were involved in both Hm and Hb binding. The expression of these proteins was not affected by iron levels. In addition, V. vulnificus biotype 2 produced extracellular proteases, not regulated by iron, that were active against native Hb. In conclusion, the overall data suggest that the eel pathogen V. vulnificus biotype 2 can obtain iron by means of a mechanism which involves a direct interaction between the heme moiety and constitutive OMPs. PMID- 8702274 TI - Four unnamed species of nonsymbiotic rhizobia isolated from the rhizosphere of Lotus corniculatus. AB - Previously, we found that genetically diverse rhizobia nodulating Lotus corniculatus at a field site devoid of naturalized rhizobia had symbiotic DNA regions identical to those of ICMP3153, the inoculant strain used at the site (J. T. Sullivan, H. N. Patrick, W. L. Lowther, D. B. Scott, and C. W. Ronson, Proc. Natl. Acad. Sci. USA 92:8985-8989, 1995). In this study, we characterized seven nonsymbiotic rhizobial isolates from the rhizosphere of L. corniculatus. These included two from plants at the field site sampled by Sullivan et al. and five from plants at a new field plot adjacent to that site. The isolates did not nodulate Lotus species or hybridize to symbiotic gene probes but did hybridize to genomic DNA probes from Rhizobium loti. Their genetic relationships with symbiotic isolates obtained from the same sites, with inoculant strain ICMP3153, and with R. loti NZP2213T were determined by three methods. Genetic distance estimates based on genomic DNA-DNA hybridization and multilocus enzyme electrophoresis were correlated but were not consistently reflected by 16S rRNA nucleotide sequence divergence. The nonsymbiotic isolates represented four genomic species that were related to R. loti; the diverse symbiotic isolates from the site belonged to one of these species. The inoculant strain ICMP3153 belonged to a fifth genomic species that was more closely related to Rhizobium huakuii. These results support the proposal that nonsymbiotic rhizobia persist in soils in the absence of legumes and acquire symbiotic genes from inoculant strains upon introduction of host legumes. PMID- 8702275 TI - Phosphorus-31 and carbon-13 nuclear magnetic resonance studies of glucose and xylose metabolism in cell suspensions and agarose-immobilized cultures of Pichia stipitis and Saccharomyces cerevisiae. AB - The metabolism of glucose and xylose as a function of oxygenation in Pichia stipitis and Saccharomyces cerevisiae cell suspensions was studied by 31P and 13C nuclear magnetic resonance spectroscopy. The rate of both glucose and xylose metabolism was slightly higher and the production of ethanol was slightly lower in aerobic than in anoxic cell suspensions of P. stipitis. As well, the cytoplasmic pH of oxygenated cells was more alkaline than that of nonoxygenated cells. In contrast, in S. cerevisiae, the intracellular pH and the rate of glucose metabolism and ethanol production were the same under aerobic and anoxic conditions. Agarose-immobilized Pichia stipitis was able to metabolize xylose or glucose for 24 to 60 h at rates and with theoretical yields of ethanol similar to those obtained with anoxic cell suspensions. Cell growth within the beads, however, was severely compromised. The intracellular pH [pH(int)] of the entrapped cells fell to more acidic pH values in the course of the perfusions relative to corresponding cell suspensions. Of importance was the observation that no enhancement in the rate of carbohydrate metabolism occurred in response to changes in the pH(int) value. In contrast to P. stipitis, agarose-immobilized Saccharomyces cerevisiae showed a dramatic twofold increase in its ability to metabolize glucose in the immobilized state relative to cell suspensions. This strain was also able to grow within the beads, although the doubling time for the entrapped cells was longer, by a factor of 2, than the value obtained for log phase batch cultures. Initially, the pH(int) of the immobilized cells was more alkaline than was observed with the corresponding S. cerevisiae cell suspensions; however, over time, the intracellular pH became increasingly acidic. As with immobilized P. stipitis, however, the pH(int) did not play a key role in controlling the rate of glucose metabolism. PMID- 8702276 TI - Cross-resistance of the diamondback moth indicates altered interactions with domain II of Bacillus thuringiensis toxins. AB - We compared responses to six insecticidal crystal proteins from Bacillus thuringiensis by a Cry1A-resistant strain (NO-QA) and a susceptible strain (LAB P) of the diamondback moth, Plutella xylostella. The resistant strain showed > 100-fold cross-resistance to Cry1J and to H04, a hybrid with domains I and II of Cry1Ab and domain III or Cry1C. Cross-resistance was sixfold to Cry1Bb and threefold to Cry1D. The potency of Cry1I did not differ significantly between the resistant and susceptible strains. Cry2B did not kill resistant or susceptible larvae. By combining these new data with previously published results, we classified responses to 14 insecticidal crystal proteins by strains NO-QA and LAB P. NO-QA showed high levels of resistance to Cry1Aa, Cry1Ab, and Cry1Ac and high levels of cross-resistance to Cry1F, Cry1J, and H04. Cross-resistance was low or nil to Cry1Ba, Cry1Bb, Cry1C, Cry1D, Cry1I, and Cry2A. Cry1E and Cry2B showed little or no toxicity to susceptible or resistant larvae. In dendrograms based on levels of amino acid sequence similarity among proteins, Cry1F and Cry1J clustered together with Cry1A proteins for domain II, but not for domain I or III. High levels of cross-resistance to Cry1Ab-Cry1C hybrid H04 show that although Cry1C is toxic to NO-QA, domain III or Cry1C is not sufficient to restore toxicity when it is combined with domains I and II of Cry1Ab. Thus, diamondback moth strain NO-QA cross-resistance extends beyond the Cry1A family of proteins to at least two other families that exhibit high levels of amino sequence similarity with Cry1A in domain II (Cry1F and Cry1J) and to a protein that is identical to Cry1Ab in domain II (H04). The results of this study imply that resistance to Cry1A alters interactions between the insect and domain II. PMID- 8702277 TI - Aminopeptidase N purified from gypsy moth brush border membrane vesicles is a specific receptor for Bacillus thuringiensis CryIAc toxin. AB - We have evaluated the binding of Bacillus thuringiensis Cry toxins to aminopeptidase N (APN) purified from Lymantria dispar (gypsy moth) brush border membrane vesicle (BBMV). CryIAc toxin bound strongly to APN, while either the structurally related CryIAa and CryIAb toxins or CryIC, CryIIA, and CryIIIA toxins showed weak binding to APN. An in vitro competition binding study demonstrated that the binding of CryIAc to L. dispar BBMV was inhibited by APN. Inhibition of short circuit current for CryIAc, measured by voltage clamping of whole L. dispar midgut, was substantially reduced by addition of phosphatidylinositol-specific phospholipase C, which is known to release APN from the midgut membrane. In contrast, addition of phosphatidylinositol-specific phospholipase C had only a marginal effect on the inhibition of short circuit current for CryIAa. These data suggest that APN is the major functional receptor for CryIAc in L. dispar BBMV. A ligand blotting experiment demonstrated that CryIAc recognized a 120-kDa peptide (APN), while CryIAa and CryIAb recognized a 210-kDa molecule in L. dispar BBMV. In contrast, CryIAa and CryIAb bound to both the 120- and 210-kDa molecules in Manduca sexta BBMV, while CryIAc recognized only the 120-kDa peptide. The 120-kDa peptide (APN) in L. dispar BBMV reacted with soybean agglutinin, indicating that N-acetylgalactosamine is a component of this glycoprotein. PMID- 8702278 TI - Glucose-induced secretion of Trichoderma reesei xylanases. AB - To produce two xylanases with Trichoderma reesei grown on glucose, recombinant strains which carry either the xyn1 or the xyn2 (xylanase I and II [XYN I and XYN II]-encoding) structural genes under the expression signals of the homologous pki1 (pyruvate kinase-encoding) gene were constructed. The two types of transformants secreted XYN I or II, respectively, during growth on glucose, as demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunostaining. The corresponding specific xylanase activities of the best transformants on glucose were 76 and 145 U/mg of protein for XYN I and XYN II, respectively, as opposed to that obtained by the parent strain (26 U/mg of protein). When related to the amount of biomass formed, however, they produced only about 4 to 5 U/g, in contrast to much higher activities (10 to 12 U/g) during growth on xylan. The ultrastructural location of XYN II in the transformant strain producing the highest constitutive XYN II formation (ATX2-12) was investigated by immunoelectron microscopy and compared with that in the wild type strain growing on xylan. Cell extracts from both types of transformants grown on glucose exhibited a higher intracellular xylanase activity than did the parent strain grown on xylan. By using electron microscopy and immunogold labelling, XYN II was detected in the endoplasmic reticulum, Golgi-like vesicles, secretory vesicles, vacuoles, and cell walls. The immunolabel in the vacuoles was detected preferentially in subapical cells. When a recombinant strain which expressed xyn2 from the pki1 promoter was compared with the parent strain during growth on xylan, the former exhibited a less proliferated endoplasmic reticulum and a smaller number of secretory vesicles; however, a higher density of labelling was observed. The relationship of these findings to the efficacy of protein secretion during growth on glucose is discussed. PMID- 8702279 TI - Effect of pasteurization on infectivity of Cryptosporidium parvum oocysts in water and milk. AB - Cryptosporidium parvum is a major cause of diarrheal disease in humans and has been identified in 78 other species of mammals. The oocyst stage, excreted in feces of infected humans and animals, has been responsible for recent waterborne outbreaks of human cryptosporidiosis. High temperature and long exposure time have been shown to render oocysts (suspended in water) noninfectious, but for practical purposes, it is important to know if high-temperature--short-time conditions (71.7 degrees C for 15 s) used in commercial pasteurization are sufficient to destroy infectivity of oocysts. In this study, oocysts were suspended in either water or whole milk and heated to 71.7 degrees C for 15, 10, or 5 s in a laboratory-scale pasteurizer. Pasteurized and nonpasteurized (control) oocysts were then tested for the ability to infect infant mice. No mice (0 of 177) given 10(5) oocysts pasteurized for 15, 10, or 5 s in either water or milk were found to be infected with C. parvum on the basis of histologic examination of the terminal ileum. In contrast, all (80 of 80) control mice given nonpasteurized oocysts were heavily infected. These data indicate that high temperature--short-time pasteurization is sufficient to destroy the infectivity of C. parvum oocysts in water and milk. PMID- 8702280 TI - Genetic diversity in marine algal virus communities as revealed by sequence analysis of DNA polymerase genes. AB - Algal-virus-specific PCR primers were used to amplify DNA polymerase gene (pol) fragments (683 to 689 bp) from the virus-sized fraction (0.02 to 0.2 microns) concentrated from inshore and offshore water samples collected from the Gulf of Mexico. Algal-virus-like DNA pol genes were detected in five samples collected from the surface and deep chlorophyll maximum. PCR products from an offshore station were cloned, and the genetic diversity of 33 fragments was examined by restriction fragment length polymorphism and sequence analysis. The five different genotypes or operational taxonomic units (OTUs) that were identified on the basis of restriction fragment length polymorphism banding patterns were present in different relative abundances (9 to 34%). One clone from each OTU was sequenced, and phylogenetic analysis showed that all of the OTUs fell within the family Phycodnaviridae. Four of the OTUs fell within a group of viruses (MpV) which infect the photosynthetic picoplankter Micromonas pusilla. The genetic diversity among these genotypes was as large as that previously found for MpV isolates from different oceans. The remaining genotype formed its own clade between viruses which infect M. pusilla and Chrysochromulina brevifilum. These results imply that marine virus communities contain a diverse assemblage of MpV like viruses, as well as other unknown members of the Phycodnaviridae. PMID- 8702281 TI - Comparative analysis of nitrifying bacteria associated with freshwater and marine aquaria. AB - Three nucleic acid probes, two for autotrophic ammonia-oxidizing bacteria of the beta subdivision of the class Proteobacteria and one for alpha subdivision nitrite-oxidizing bacteria, were developed and used to study nitrifying bacterial phylotypes associated with various freshwater and seawater aquarium biofilters. Nitrosomonas europaea and related species were detected in all nitrifying seawater systems and accounted for as much as 20% of the total eubacterial rRNA. In contrast, nitrifying bacteria belonging to the beta-proteobacterial subdivision were detected in only two samples from freshwater aquaria showing vigorous nitrification rates. rRNA originating from nitrite-oxidizing alpha subdivision proteobacteria was not detected in samples from either aquarium environment. The data obtained indicate that chemolithotrophic ammonia oxidation in the freshwater aquaria was not due to beta-proteobacterial phylotypes related to members of the genus Nitrosomonas and their close relatives, the organisms usually implicated in freshwater nitrification. It is likely that nitrification in natural environments is even more complex than nitrification in these simple systems and is less well characterized with regard to the microorganisms responsible. PMID- 8702282 TI - Characterization of the chemical and antimicrobial properties of piscicolin 126, a bacteriocin produced by Carnobacterium piscicola JG126. AB - A novel peptide bacteriocin produced by the lactic acid bacterium Carnobacterium piscicola JG126 isolated from spoiled ham was purified and characterized. This bacteriocin, designated piscicolin 126, inhibited the growth of several gram positive bacteria, especially the food-borne pathogen Listeria monocytogenes, but had no effect on the growth of a number of yeasts and gram-negative bacteria. Bactericidal activity was not destroyed by exposure to elevated temperatures at low pH values; however, bactericidal activity was lost at high pH values, especially when high pH values were combined with an elevated temperature. Piscicolin 126 activity was not affected by catalase, lipase, or lysozyme but was destroyed by exposure to a range of proteolytic enzymes. Piscicolin 126 was purified to homogeneity and was found to be a peptide having a molecular weight of 4,416.6 +/- 1.9. A sequence analysis revealed that this compound is a cystibiotic (class IIa) bacteriocin containing 44 amino acid residues and one intrapeptide disulfide ring. Piscicolin 126 has regions of homology with some other bacteriocins obtained from lactic acid bacteria and is most closely related to sakacin P and pediocin PA-1 (levels of identity, 75 and 55%, respectively). Addition of piscicolin 126 to a devilled ham paste test food system inhibited the growth of L. monocytogenes for at least 14 days. Piscicolin 126 was more effective than two commercially available bacteriocin preparations tested in the same system. PMID- 8702283 TI - Amplification of 16S rRNA genes from Frankia strains in root nodules of Ceanothus griseus, Coriaria arborea, Coriaria plumosa, Discaria toumatou, and Purshia tridentata. AB - To study the global diversity of plant-symbiotic nitrogen-fixing Frankia strains, a rapid method was used to isolate DNA from these actinomycetes in root nodules. The procedure used involved dissecting the symbiont from nodule lobes; ascorbic acid was used to maintain plant phenolic compounds in the reduced state. Genes for the small-subunit rRNA (16S ribosomal DNA) were amplified by the PCR, and the amplicons were cycle sequenced. Less than 1 mg (fresh weight) of nodule tissue and fewer than 10 vesicle clusters could serve as the starting material for template preparation. Partial sequences were obtained from symbionts residing in nodules from Ceanothus griseus, Coriaria arborea, Coriaria plumosa, Discaria toumatou, and Purshia tridentata. The sequences obtained from Ceonothus griseus and P. tridentata nodules were identical to the sequence previously reported for the endophyte of Dryas drummondii. The sequences from Frankia strains in Coriaria arborea and Coriaria plumosa nodules were identical to one another and indicate a separate lineage for these strains. The Frankia strains in Discaria toumatou nodules yielded a unique sequence that places them in a lineage close to bacteria that infect members of the Elaeagnaceae. PMID- 8702284 TI - Aerobic biodegradation of 4-methylquinoline by a soil bacterium. AB - Methylquinolines and related N-heterocyclic aromatic compounds are common contaminants associated with the use of hydrocarbons in both coal gasification and wood treatment processes. These compounds have been found in groundwater, and many are known mutagens. A stable, five-member bacterial consortium able to degrade 4-methylquinoline was established by selective enrichment using soil collected from an abandoned coal gasification site. The consortium was maintained for 5 years by serial transfer in a medium containing 4-methylquinoline. A gram negative soil bacterium, strain Lep1, was isolated from the consortium and shown to utilize 4-methylquinoline as a source of carbon and energy during growth in liquid medium. A time course experiment demonstrated that both the isolate Lep1 and the consortium containing Lep1 were able to degrade 4-methylquinoline under aerobic conditions. Complete degradation of 4-methylquinoline by either strain Lep1 alone or the consortium was characterized by the production and eventual disappearance of 2-hydroxy-4-methylquinoline, followed by the appearance and persistence of a second metabolite tentatively identified as a hydroxy-4 methylcoumarin. Currently, there is no indication that 4-methylquinoline degradation proceeds differently in the consortium culture compared with Lep1 alone. This is the first report of 4-methylquinoline biodegradation under aerobic conditions. PMID- 8702285 TI - Oxidative modification of a cephalosporin C acylase from Pseudomonas strain N176 and site-directed mutagenesis of the gene. AB - A cephalosporanic acid acylase from Pseudomonas strain N176 catalyzes hydrolysis of both glutarylcephalosporanic acid and cephalosporin C to 7-amino cephalosporanic acid. Chemical modification of the enzyme with acidic hydrogen peroxide was performed to investigate residues which play important roles in enzymatic activity. The activity of the enzyme was reduced to 76% of the original by oxidation. From protein chemical analysis combined with site-directed point mutagenesis, modification of Met-164 was found to correspond to the reduction in activity. To study the effect of Met-164 on the enzymatic character, we prepared mutant acylases in which Met-164 was replaced with several other amino acids and obtained the following data: (i) there existed a trend of mutation to noncharged hydrophilic residues, resulting in an increase of activity against glutarylcephalosporanic acid; (ii) the mutation of Met-164 to Gly and Ala resulted in the lowering of both Km values and the optimal pHs against glutarylcephalosporanic acid; (iii) the mutation to Leu enhanced cephalosporin C acylase activity; and (iv) the mutation to Gln improved the k(cat) value for glutarylcephalosporanic acid. In particular, the mutation to Gln resulted in a high rate of conversion of glutarylcephalosporanic acid to 7-amino cephalosporanic acid under conditions similar to those of a bioreactor system. These results may indicate that Met-164 is located in or near the cephalosporin compound binding pocket on the enzyme. PMID- 8702286 TI - The Bacillus thuringiensis insecticidal toxin binds biotin-containing proteins. AB - Brush border membrane vesicles from larvae of the tobacco hornworm, Manduca sexta, contain protein bands of 85 and 120 kDa which react directly with streptavidin conjugated to alkaline phosphatase. The binding could be prevented either by including 10 microM biotin in the reaction mixture or by prior incubation of the brush border membrane vesicles with an activated 60- to 65-kDa toxin from Bacillus thuringiensis HD-73. The ability of B. thuringiensis toxins to recognize biotin-containing proteins was confirmed by their binding to pyruvate carboxylase, a biotin-containing enzyme, as well as to biotinylated ovalbumin and biotinylated bovine serum albumin but not to their nonbiotinylated counterparts. Activated HD-73 toxin also inhibited the enzymatic activity of pyruvate carboxylase. The biotin binding site is likely contained in domain III of the toxin. Two highly conserved regions within domain III are similar in sequence to the biotin binding sites of avidin, streptavidin, and a biotin specific monoclonal antibody. In particular, block 4 of the B. thuringiensis toxin contains the YAS biotin-specific motif. On the basis of its N-terminal amino acid sequence, the 120-kDa biotin-containing protein is totally distinct from the 120-kDa aminopeptidase N reported to be a receptor for Cry1Ac toxin. PMID- 8702287 TI - Identification of an alternative 2,3-dihydroxybiphenyl 1,2-dioxygenase in Rhodococcus sp. strain RHA1 and cloning of the gene. AB - Gram-positive Rhodococcus sp. strain RHA1 possesses strong polychlorinated biphenyl-degrading capabilities. An RHA1 bphC gene mutant, strain RDC1, had been previously constructed (E. Masai, A. Yamada, J. M. Healy, T. Hatta, K. Kimbara, M. Fukuda, and K. Yano, Appl. Environ. Microbiol. 61:2079-2085, 1995). An alternative 2,3-dihydroxybiphenyl 1,2-dioxygenase (2,3-DHBD), designated EtbC, was identified in RDC1 cells grown on ethylbenzene. EtbC contained the broadest substrate specificity of any meta cleavage dioxygenase identified in a Rhodococcus strain to date, including RHA1 BphC. EtbC was purified to near homogeneity from RDC1 cells grown on ethylbenzene, and a 58-amino-acid NH2 terminal sequence was determined. The NH2-terminal amino acid sequence was used for the identification of the etbC gene from an RDC1 chromosomal DNA 2,3-DHBD expression library. The etbC gene was successfully cloned, and we report here the determination of its nucleotide sequence. The substrate specificity patterns of cell extract and native nondenaturing polyacrylamide gel electrophoresis analysis identified the coexpression of two 2,3-DHBDs (BphC and EtbC) in RHA1 cells grown on either biphenyl or ethylbenzene. The possible implication of coexpressed BphC extradiol dioxygenases in the strong polychlorinated-biphenyl degradation activity of RHA1 was suggested. PMID- 8702288 TI - Single-strand conformation polymorphism analysis of PCR-amplified ribosomal DNA internal transcribed spacers to differentiate species of Aspergillus section Flavi. AB - A novel genetic approach for classifying the species of Aspergillus Section Flavi is described here. This approach consists of PCR amplification of the 5.8S ribosomal DNA-intervening internal transcribed spacer regions (ITS I-5.8S-ITS II) with universal primers and of analysis of the PCR product by the principle of single-strand conformation polymorphism (SSCP). The approximately 570- to 590-bp PCR products were denatured and subjected to electrophoresis on a polyacrylamide gel supplemented with 20% formamide. The SSCP patterns of these species became more distinct by the addition of formamide to the gel and by visualization with ethidium bromide staining. A little interspecific length polymorphism among amplified ribosomal DNAs was enhanced to be detected by PCR-SSCP analysis. This analysis was capable of classifying 67 of the 68 Aspergillus Section Flavi strains tested into the following four groups, regardless of origin: A. flavus/A. oryzae, A. parasiticus/A. sojae, A. tamarii, and A. nomius. The results of restriction fragment length polymorphism analysis with PCR products of the ITS regions were consistent with those of PCR-SSCP analysis, except for A. nomius, which was not clearly differentiated from A. parasiticus/A. sojae. Nonradiolabelled PCR-SSCP analysis is inexpensive and practical to perform without special apparatus or skill and should assist in fungal morphological identification. PMID- 8702289 TI - Distribution of class II transposase and resolvase genes in soil bacteria and their association with mer genes. AB - Southern hybridization was performed on 30 gram-negative, mercury-resistant soil bacteria isolated from three terrestrail sites in Great Britain; two of these sites were mercury polluted (SO and SE), and one was pristine (SB). Most of the isolates (20 of 30) hybridized to probes encoding regions of the transposase (tnpA) and resolvase (tnpR) genes from Tn501 and Tn21. Isolates SE9 and SB3 hybridized to the Tn21 but not the Tn501 tnpA probe; however, they differed in that SB3 hybridized to both Tn501 and Tn21 tnpR probes while SE9 did not hybridize to either tnpR probe. The remaining isolates (7 of 30) did not hybridize to any of the transposon gene probes under the conditions used. tnpA and tnpR regions were PCR amplified from most of the hybridizing isolates and from Tn501 and Tn21, and variation was assessed by restriction fragment length polymorphism analysis. On the basis of these data, tnpA regions were divided into eight restriction fragment length polymorphism classes and tnpR regions were divided into five classes. Similarity coefficients were calculated between classes and used to construct dendrograms showing percent similarity. A compilation of the data from this study on tnpA and tnpR regions and a previous study on merRT delta P regions (A. M. Osborn, K. D. Bruce, P. Strike, and D. A. Ritchie, Appl. Environ. Microbiol. 59:4024-4030, 1993) indicates the presence of hybrid transposons and provides evidence for extensive recombination, both between transposon genes and between transposon and mer genes, within these natural populations of bacteria. PMID- 8702290 TI - Structure-activity relationships in the peptide antibiotic nisin: role of dehydroalanine 5. AB - A mutant of the peptide antibiotic nisin in which the dehydroalanine residue at position 5 has been replaced by an alanine has been produced and structurally characterized. It is shown to have activity very similar to that of wild-type nisin in inhibiting growth of Lactococcus lactis and Micrococcus luteus but is very much less active than nisin as an inhibitor of the outgrowth of spores of Bacillus subtilis. These observations, which parallel those of W. Liu and J. N. Hansen (Appl. Environ. Microbiol. 59:648-651, 1993) on the corresponding mutant of the related antibiotic subtilin, are discussed in terms of the mechanism(s) of action of these antibiotics. PMID- 8702291 TI - Phytoplasma-specific PCR primers based on sequences of the 16S-23S rRNA spacer region. AB - In order to develop a diagnostic tool to identify phytoplasmas and classify them according to their phylogenetic group, we took advantage of the sequence diversity of the 16S-23S intergenic spacer regions (SRs) of phytoplasmas. Ten PCR primers were developed from the SR sequences and were shown to amplify in a group specific fashion. For some groups of phytoplasmas, such as elm yellows, ash yellows, and pear decline, the SR primer was paired with a specific primer from within the 16S rRNA gene. Each of these primer pairs was specific for a specific phytoplasma group, and they did not produce PCR products of the correct size from any other phytoplasma group. One primer was designed to anneal within the conserved tRNA(Ile) and, when paired with a universal primer, amplified all phytoplasmas tested. None of the primers produced PCR amplification products of the correct size from healthy plant DNA. These primers can serve as effective tools for identifying particular phytoplasmas in field samples. PMID- 8702292 TI - Natural transformation in river epilithon. AB - Natural transformation was demonstrated in unenclosed experiments incubated in river epilithon. Strains of Acinetobacter calcoaceticus were transformed to prototrophy by either free DNA (lysates) or live donor cells. The sources of transforming DNA and recipient culture were immobilized on filters, secured to stones, and incubated midstream in the river. The transfer frequency generally increased with temperature. No transfer was detected in the river Taff below 10 degrees C. The age of the recipient culture affected the transformation frequencies in situ but did not significantly affect the transfer frequency on laboratory media. Transformation of recipient cultures which had been incorporated into the natural epilithic biofilm and transformation of the plasmid pQM17 in situ were also demonstrated. This study provides the first direct evidence of natural transformation in situ of bacteria incorporated into an indigenous community. PMID- 8702293 TI - An obligately endosymbiotic mycorrhizal fungus itself harbors obligately intracellular bacteria. AB - Arbuscular-mycorrhizal fungi are obligate endosymbionts that colonize the roots of almost 80% of land plants. This paper describes the employment of a combined morphological and molecular approach to demonstrate that the cytoplasm of the arbuscular-mycorrhizal fungus Gigaspora margarita harbors a further bacterial endosymbiont. Intracytoplasmic bacterium-like organisms (BLOs) were detected ultrastructurally in its spores and germinating and symbiotic mycelia. Morphological observations with a fluorescent stain revealed about 250,000 live bacteria inside each spore. The sequence for the small-subunit rRNA gene obtained for the BLOs from the spores was compared with those for representatives of the eubacterial lineages. Molecular phylogenetic analysis unambiguously showed that the endosymbiont of G. margarita was an rRNA group II pseudomanad (genus Burkholderia). PCR assays with specifically designed oligonucleotides were used to check that the sequence came from the BLOs. Successful amplification was obtained when templates from both the spores and the symbiotic mycelia were used. A band of the expected length was also obtained from spores of a Scutellospora sp. No bands were given by the negative controls. These findings indicate that mycorrhizal systems can include plant, fungal, and bacterial cells. PMID- 8702295 TI - Production of thermostable direct hemolysin by Vibrio parahaemolyticus enhanced by conjugated bile acids. AB - The effects of conjugated bile acids, glycocholic acid, and taurocholic acid (TC) on production of thermostable direct hemolysin (TDH) by Vibrio parahaemolyticus were determined by a reversed passive latex agglutination assay against TDH. The amount of TDH excreted in growth medium containing either glycocholic acid or taurocholic acid (5 mM/liter) was, on a per-cell basis, 4- to 16-fold greater than that excreted in medium without the bile acids. The amounts of TDH released from lysed cells grown with the bile acids (5 mM/liter) were 4- to 32-fold greater than those from lysed cells grown without, suggesting that the bile acids enhanced synthesis of TDH within bacterial cells. These data imply that the conjugated bile acids play a key role in the pathogenicity of V. parahaemolyticus. PMID- 8702294 TI - Development of techniques to genetically manipulate members of the genera Cytophaga, Flavobacterium, Flexibacter, and Sporocytophaga. AB - The Bacteroides-Cytophaga-Flavobacterium branch of the eubacterial phylogenetic tree contains a diverse group of bacterial species. Techniques for the genetic manipulation of Bacteroides spp. are well developed (A. A. Salyers, N. B. Shoemaker, and E. P. Guthrie, Crit. Rev. Microbiol. 14:49-71, 1987). Recently we developed techniques to genetically manipulate the gliding bacterium Cytophaga johnsonae (M. J. McBride and M. J. Kempf, J. Bacteriol. 178:583-590, 1996). We now demonstrate that some of these techniques allow genetic manipulation of a number of environmentally or medically significant bacteria in this group. The Bacteroides transposon Tn4351 was introduced into Cytophaga hutchinsonii, Cytophaga succinicans, Flavobacterium meningosepticum, Flexibacter canadensis, Flexibacter sp. strain FS1, and Sporocytophaga myxococcoides by conjugation. Tn4351 integrated itself into the host chromosomes and conferred erythromycin resistance. We isolated several auxotrophic mutants of Flavobacterium meningosepticum following Tn4351 mutagenesis. The C. johnsonae-Escherichia coli shuttle vector pCP11 functioned in C. succinicans but not in the other bacteria. pLYL03 did not replicate in any of these bacteria and should function as a convenient suicide vector. The identification of a system of gene transfer, a selectable marker, a suicide vector, and a transposon that functions in these diverse bacteria allows genetic manipulations to be performed. PMID- 8702296 TI - PCR-restriction fragment length polymorphism identification and host range of single-spore isolates of the flexible Frankia sp. strain UFI 132715. AB - Twelve single-spore isolates of the flexible Elaeagnus-Frankia strain UFI 132715 fulfilled the third and the fourth of Koch's postulates on both Alnus and Elaeagnus axenic plants. Seminested nifD-nifK PCR-restriction fragment length polymorphisms provided evidence for the genetic uniformity of the single-spore frankiae with the mother strain and its plant reisolates and allowed their molecular identification directly inside Alnus and Elaeagnus nodules. The clonal nature of these single-spore-purified frankiae should allow safe mutagenesis programs, while their flexible phenotype makes them a powerful tool for understanding the molecular interactions between Frankia strains and actinorhizal plants and for identifying Frankia nodulation genes. PMID- 8702298 TI - Polymorphic restriction patterns of ribosomal internal transcribed spacers in the biocontrol fungus Puccinia carduorum correlate with weed host origin. AB - The internal transcribed spacer (ITS) regions of ribosomal DNA were amplified by PCR and used to develop genetic markers for isolates of Puccinia carduorum being evaluated for biological control of Carduus thoermeri (musk thistle). Unique patterns were produced upon restriction of ITS DNA amplified from four separate Puccinia spp. Restriction patterns of ITS DNA of isolates of P. carduorum from Carduus acanthoides and C. thoermeri were distinct from those of P. carduorum from Carduus tenuiflorus and Carduus pycnocephalus. By this technique, isolates of P. carduorum from four different weed hosts can be differentiated from other Puccinia spp. and separated into two host groups. PMID- 8702297 TI - Analysis of partial sequences of genes coding for 16S rRNA of actinomycetes isolated from Casuarina equisetifolia nodules in Mexico. AB - Filamentous bacteria isolated from surface-sterilized nodules of Casuarina equisetifolia trees in Mexico were capable of reducing acetylene, a diagnostic test for nitrogenase, but were unable to nodulate their host. Analysis of partial 16S rRNA gene sequences suggests that the Mexican isolates are not Frankia strains but members of a novel clade. PMID- 8702299 TI - Linear correlation between bacterial overexpression of recombinant peptides and cell light scatter. AB - Fusion of multiple copies of a test peptide leads to insoluble inclusion bodies. Their presence within bacteria increases either forward-angle light scattering or, to a lesser extent, right-angle light scattering. A linear correlation has been established between cell forward-angle scattering and the level of overexpression of atrial natriuretic peptide. The correlation is valid only for unlysed cells and is protein product specific. PMID- 8702300 TI - Isolation of a beta-tubulin gene from Fusarium moniliforme that confers cold sensitive benomyl resistance. AB - A beta-tubulin gene from a UV-irradiated benomyl-resistant mutant of Fusarium moniliforme was isolated, cloned, and sequenced. The gene encodes a 446-amino acid polypeptide with homology to other fungal beta-tubulins. RNA blot analysis showed expression of the gene during vegetative growth and conidial germination but no expression during conidiation. A point mutation, which likely confers benomyl resistance, has been identified in the cloned gene; this mutation results in a single amino acid substitution of asparagine for tyrosine at position 50. Expression of benomyl resistance in the mutant was also cold sensitive. Sexual crosses betweeen the mutant and a wild-type strain indicated cosegregation of benomyl resistance and cold sensitivity. PMID- 8702301 TI - Modified Listeria bacteriophage lysin genes (ply) allow efficient overexpression and one-step purification of biochemically active fusion proteins. AB - Listeria bacteriophage lytic enzymes are useful for in vitro applications such as rapid, gentle cell disruption, and they provide new approaches as selective antimicrobial agents for destruction of Listeria monocytogenes in contaminated foods. We describe here the amino-terminal modification of three cloned Listeria phage lysin genes (ply), resulting in fusion proteins with a 12-amino-acid leader containing six consecutive histidine residues. The recombinant enzymes retain their native specific activity and can be efficiently overproduced in Escherichia coli. By one-step metal chelate affinity chromatography, active lysins could be purified to more than 90% homogeneity. PMID- 8702302 TI - Production of kanosamine by Bacillus cereus UW85. AB - Bacillus cereus UW85 produces two antibiotics that contribute to its ability to suppress certain plant diseases (L. Silo-Suh, B. Lethbridge, S. J. Raffel, H. He, J. Clardy, and J. Handelsman, Appl. Environ. Microbiol. 60:2023-2030, 1994). To enhance the understanding of disease suppression by UW85, we determined the chemical structure, regulation, and the target range of one of the antibiotics. The antibiotic was identified as 3-amino-3-deoxy-D-glucose, also known as kanosamine. Kanosamine was highly inhibitory to growth of plant-pathogenic oomycetes and moderately inhibitory to certain fungi and inhibited few bacterial species tested. Maximum accumulation of kanosamine in B. cereus UW85 culture supernatants coincided with sporulation. Kanosamine accumulation was enhanced by the addition of ferric iron and suppressed by addition of phosphate to rich medium. Kanosamine accumulation was also enhanced more than 300% by the addition of alfalfa seedling exudate to minimal medium. PMID- 8702304 TI - Recent progress in breast cancer research at Osaka Medical Center for Cancer and Cardiovascular Diseases. AB - The Cancer Registry started in Osaka Prefecture in the early Sixties has shown a steady and significant increase in breast cancer incidence. The rate in 1992 was 34 out of 100,000 female population. Breast conserving therapy was applied increasingly in more patients, and 52% received this therapy in 1994. The results (survival and disease-free) for 372 patients were no lower than those for conventional mastectomy. Clonal analysis utilizing RFLP of phosphoglycerokinase gene and PCR revealed that most of so-called multicentric tumors in the breast were intraductally spread lesions (multifocal, not multicentric) and demonstrated that phyllodes tumor is a neoplasm of mesenchymal cells, not of epithelial cells. PMID- 8702303 TI - Growth of and toxin production by nonproteolytic Clostridium botulinum in cooked pureed vegetables at refrigeration temperatures. AB - Seven strains of nonproteolytic Clostridium botulinum (types B, E, and F) were each inoculated into a range of anaerobic cooked pureed vegetables. After incubation at 10 degrees C for 15 to 60 days, all seven strains formed toxin in mushrooms, five did so in broccoli, four did so in cauliflower, three did so in asparagus, and one did so in kale. Growth kinetics of nonproteolytic C. botulinum type B in cooked mushrooms, cauliflower, and potatoes were determined at 16, 10, 8, and 5 degrees C. Growth and toxin production occurred in cooked cauliflower and mushrooms at all temperatures and in potatoes at 16 and 8 degrees C. The C. botulinum neurotoxin was detected within 3 to 5 days at 16 degrees C, 11 to 13 days at 10 degrees C, 10 to 34 days at 8 degrees C, and 17 to 20 days at 5 degrees C. PMID- 8702305 TI - Indications of breast preserving surgery without radiation. AB - Breast preserving surgery has become a standard therapy for early breast cancer. Breast conserving therapy with radiation has been recognized as a standard strategy, because of the low incidence of local failure and minimal postoperative deformity compared with that of quadrantectomy without radiation. Among cases treated with breast preserving surgery, surgical resection alone may be sufficient for local control. We have experienced 11 cases of local failure from 108 cases who were treated with quadrantectomy. The ability of local control with quadrantectomy was analized. Among 11 cases with local failure, 3 cases had an apparently small resection area, and 3 cases had multiple tumors. In the other five cases, intraductal component was observed in primary tumor, 2 out of the five cases had EIC, and 3 of the five cases relapsed around the areola. After close analysis and modification of indication criteria, we could reduce the recurrence rate of late 66 cases to less than 2%. For local failure cases, seven cases were treated with total mastectomy, 4 with partial mastectomy, and no further relapse resulted. Our data indicated that quadrantectomy is effective and safe for local control if its indication is carefully determined. PMID- 8702306 TI - Breast ultrasound. AB - In ultrasound, ultrasonic images are formed by means of echoes among tissues with different acoustic impedance. Acoustic impedance is the product of sound speed and bulk modulus. The bulk modulus expresses the elasticity of an object, and in the human body, the value is increased by conditions such as fibrosis and calcification. The sound speed is usually high in elastic tissues and low in water. In the body, it is lowest in the fatty tissue. Ultrasound echoes are strong on the surface of bones which are hard and have a high sound speed. In organs filled with air such as the lungs, the bulk modulus is low and the sound speed is extremely low at 340 m/s, which produce strong echoes (the sound speed in solid tissues is 1,530 m/s). Human tissue is constructed of units smaller than the ultrasonic beam, and it is necessary to understand back-scattering in order to understand the ultrasonic images of these tissues. When ultrasound passes through tissue, it is absorbed as thermal energy and attenuated. Fiber is a tissue with a high absorption and attenuation rate. When the rate increases, the posterior echoes are attenuated. However, in masses with a high water content such as cysts, the posterior echoes are accentuated. This phenomenon is an important, basic finding for determining the properties of tumors. Breast cancer can be classified into two types: stellate carcinoma and circumscribed carcinoma. Since stellate carcinoma is rich in fiber, the posterior echoes are attenuated or lacking. However, circumscribed carcinoma has a high cellularity and the posterior echoes are accentuated. The same tendency is also seen in benign tumors. In immature fibroadenomas, posterior echoes are accentuated, while in fibroadenomas with hyalinosis, the posterior echoes are attenuated. Therefore, if the fundamentals of this tissue characterization and the histological features are understood, reading of ultrasound becomes easy. Color Doppler has also been developed and has contributed to the diagnosis of breast cancer. Breast cancer is rich in blood vessels. The feeding arteries flow directly into the tumor and are characterized by tortuosity and flexion. Since the intraductal spread of breast cancer can easily be evaluated, ultrasound has come to play an important role in breast conserving treatment. Breast cancer with intraductal spreading causes dilation of the mammary ducts, and the resolution of ultrasound at present has been improved to the degree that this dilation is shown as a tubular hypoechoic area. With the progress made in imaging diagnosis, nonpalpable breast cancer has increased and ultrasonically-guided aspiration cytology and biopsy techniques have been developed to obtain definite diagnoses of these lesions. In cases of micro-calcification detected by mammography, ultrasonically guided biopsy is recommended when identification by ultrasound is possible. Since this is a simple technique, it should be mastered. PMID- 8702307 TI - [Immunohistochemistry in the diagnosis and treatment of breast cancer]. AB - Immunohistochemical staining (immunostaining) has been frequently used with breast cancer in order to give definite histological diagnosis and information for treatment or prognosis. In the histological diagnosis, immunostaining is used for differential diagnoses of tumor origin and malignancy. Immunostainings for hormone receptors and c-erbB-2 are useful for the prediction of the effect of endocrine therapy and prognosis. In the future, more important substances examined by immunohistochemistry are awaited for the diagnosis and treatment of the breast cancer. PMID- 8702308 TI - Rationale of lymph node dissection for breast cancer--from the viewpoint of analysis of axillary lymphatic flow using activated carbon particle CH40. AB - In order to rationalize lymph node dissection for breast cancer, we reviewed regional lymphatic flow from the mesial and outer half of the breast using intra tumoral injection of activated carbon particles (CH40). Seventy patients with breast cancer were included in this study. Cancers were located in the mesial half of the breast in 25 cases and in its outer half in 41 cases. Since regional lymph nodes were blackened by CH40, lymph node dissection was performed easily and small lymph nodes could be readily examined. The average number of resected nodes in each case was 29.4. When CH40 was injected into the mesial half of the breast, the rates of blackened nodes (number of macroscopically blackened lymph nodes/number of total removed lymph nodes) in the stations were 46.6% (No. 1a), 41.4% (No. 1b), 62.1% (No. 1c), 61.8% (No. 2), 69.2.% (No. 2h), and 65.6% (No. 3). When CH40 was injected into outer half of the breast, those were 62.0% (No. 1a), 64.3% (No. 1b), 68.7% (No. 1c), 75.3% (No. 2), and 67.8% (No. 2h). Regardless of tumor location, the rates of blackened nodes were high in each station. In conclusion, regardless of tumor location it is impossible to determine the level of axillary dissection for breast cancer. It should be all or nothing. PMID- 8702309 TI - [The prognostic significance of axillary node metastasis in breast cancer]. AB - Axillary lymph node metastasis information is the most important for estimating prognosis in breast cancer patients. Using the clearing method, we mapped the lymph nodes to observe the way in which axillary metastasis progressed. The results revealed different kinds of progression; rank type, skip type, defense type, diffusely scattered type and so on. Each is correlated with a favorable or poor prognosis. We then attempted to stratify quantitatively the axillary lymph node metastasis condition using the standard 10-year survival rate for each group. The number of lymph node metastases and invasion rate (no. of lymph node metastases/no. of reference lymph nodes) were employed as stratification factors. This information is helpful in selecting post-operative adjuvant therapy for the breast cancer patient. PMID- 8702310 TI - Changes in significance of axillary lymph node dissection for patients with breast cancer. AB - Axillary lymph node dissection has been a routine part of breast cancer treatment for more than 100 years. As so few patients have been shown to have positive nodes, more consideration should be given to eliminating axillary node dissection for duct carcinoma in situ (DCIS) and T1a lesions. And for patients with T1/2N0M0 cancer of the breast, lumpectomy alone without axillary dissection followed by radiation therapy of the intact breast and regional lymph nodes should be a reasonable treatment without any arm morbidity. Between September 1989 and September 1994, we have treated 40 breast cancer patients with this method and no local recurrence nor distant metastasis has been encountered so far. Therefore, it is concluded that axillary dissection should be performed routinely only for N1b lesions and larger. PMID- 8702311 TI - [Detection of breast cancer micrometastases in lymph nodes by amplification of keratin 19 mRNA with reverse-transcriptase polymerase chain reaction]. AB - Keratin 19 mRNA reverse-transcriptase polymerase chain reaction (K 19 RT-PCR) was compared with histological examination in the detection of breast cancer micrometastases in axillary lymph nodes. Sixty-three axillary lymph nodes, which were obtained from 23 breast cancer patients, were bisected. One half was studied by conventional histological analysis of hematoxylin and eosin sections. Total RNA was extracted from the other half and subjected to K 19 RT-PCR. In all the ten lymph nodes, which were histologically metastasis-positive, K 19 mRNA was detected by RT-PCR. Of the 53 histologically negative lymph nodes, five (9%) lymph nodes were found to express K 19 mRNA, indicating the presence of micrometastases which could be detected by RT-PCR but not by a histological examination. These results demonstrate the usefulness of K 19 RT-PCR in the detection of breast cancer micrometastases in lymph nodes. PMID- 8702313 TI - [Molecular analysis of the estrogen receptor (ER) gene in association with ER negativity in breast cancer]. AB - DNA from ninety-eight primary breast cancer biopsies has been examined for loss of heterozygosity (LOH). Thirteen of seventy-two informative cases (18.1%) were positive for LOH, which correlated with age at operation but not with ER status. This result suggests that LOH of the ER gene does not have an important role in the lack of ER function in breast cancer tissues. Thirteen breast cancers with ER negative/progesterone receptor (PgR) positive were screened for mutation analysis of the ER gene using single strand conformational polymorphism (SSCP). We found 2 polymorphisms in codon 10 (C to G) codon 325 (C to T), although neither germline nor somatic mutation was detected. Since the sequence variant of codon 325 tends to be more frequently seen in ER negative/PgR negative breast cancer patients than non-cancer control patients, it is suggested that this polymorphism was related to negativity and function of ER in breast cancer tissues. PMID- 8702312 TI - [Biological functions of cell adhesion molecules in breast cancer]. AB - We investigated the mechanisms of adhesion of breast cancer cells to vascular endothelial cells which is an important step in hematogenous metastasis. The results from the present studies are as follows. The breast cancer cells induce the expression of E-selectin on the endothelial cells chiefly through the release of cytokines, such as IL-beta, from lymphocytes. Following the initial adhesion mediated by E-selectin via sialyl Lewis, breast cancer cells receive stimulation from cytokines, such as HB-EGF, produced by endothelial cells and transmigrate to extravascular tissues through the augmentation of integrins. PMID- 8702314 TI - [Value of cancer-related oncoprotein expression as prognostic factors in breast cancer with one to three axillary lymph nodes positive]. AB - The patient group with breast carcinoma with one to three axillary lymph-node metastases (n1-3) shows a poorer prognosis than the node-negative one but a better prognosis than the group with 4 or more lymph node metastases. Univariate analysis shows that loss of bc1-2 expression, nuclear accumulation of p53, overexpression of c-erbB-2, age at diagnosis, menstrual status, tumor size, histologic grade, number of lymph nodes involved, and estrogen receptor were all significantly associated with the survival rates. Multivariate analysis demonstrated that menstrual status, number of involved lymph nodes, bc1-2, and p53 were significant predictors for overall survival, and that histological grade and number of nodes involved were significant predictors for disease-free survival. Combination of those factors would be useful to select highly aggressive n1-3 breast cancer group. PMID- 8702315 TI - Regulation of endothelial growth factor expressions in breast cancer. AB - Expression of various endothelial growth factors including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), Platelet-derived endothelial cell growth factor (PD-ECGF) and hepatocyte growth factor (HGF) was investigated in human breast carcinoma tissues, and the results were compared to the intratumoral microvessel density evaluated by the immunostaining to anti factor VIII related antigen. VEGF and PD-ECGF were examined by immunostainings, and bFGF and HGF were assessed by enzymatic immunoassays. As a result, VEGF and PD-ECGF were significantly associated with the increment of microvessel density, although no significant correlation was found with bFGF and HGF. In addition, interestingly, a tendency of co-expression between VEGF and PD-ECGF was demonstrated. It was suggested that VEGF and PD-ECGF play important roles in the promotion of angiogenesis in human breast cancer. PMID- 8702316 TI - Mammographic diagnosis of breast cancer. AB - It is very important for exact diagnosis of early breast cancer that both the mammography quality and the film reading ability are on a high level. Not only the radiology technician but doctors must know the mammographic apparatus and quality control to obtain high-quality mammograms. The understanding of the mammographic technique will help systematic reading of the mammograms. Knowledge of the correlation with mammographic findings and pathological findings will also be useful to diagnose the mammograms accurately and rapidly. PMID- 8702317 TI - [Genetic alterations in familial and sporadic breast cancers]. PMID- 8702318 TI - Analysis of local recurrences after breast conserving therapy using postoperative radiotherapy. AB - One hundred and ninety-one breast cancer patients had breast conserving therapy (lumpectomy and postoperative radiotherapy) at the Shikoku Cancer Center Hospital between July 1989 and December 1994. Seven patients developed recurrence, two of them experienced recurrence in the treated breast after a median follow-up of 27 months. One of the two patients with the local recurrence had an inflammatory cancer-like change in the treated breast which consisted of a diffuse induration in the breast and thick overlying skin with redness. It was very difficult to distinguish local recurrence from the local change due to radiation. Her primary tumor showed prominent lymphatic vessel involvement, although the surgical margins were negative histologically. We believe that the possible lymphatic retention after axillary dissection facilitated this type of progression of the residual tumor cells within the lymphatic vessels. Although this type of local recurrence is quite rare, it could cause distant metastases. Reanalysis of surgical treatment and postoperative adjuvant therapy for the patients with breast cancer showing prominent lymphatic vessel involvement is required. PMID- 8702319 TI - Strategy for breast conserving treatment--analysis of recurrence and prognosis after breast cosnserving treatment. AB - Two hundred and four patients with small breast cancer (T < or = 3.0 cm. N0 or N1a) were given breast conserving treatment (radiation group: 101, non-radiation group: 103) during the period from Feb. 1988 to Jan. 1995. Survival analysis of breast conserving treatment radiation group versus non-radiation group revealed the following: 1) Breast conserving treatment had a good prognosis, and a 5-year overall survival rate of 96.2%. 2) There was no significant difference of 5-year overall, disease-free and ipsilateral breast disease-free survival rate between the radiation group and non-radiation group. 3) Surgical margin involvement was the most significant risk factor in local recurrence after breast conserving treatment, and non-radiation was a possible risk factor. 4) Local recurrence was a significant risk factor for distant metastases after breast conserving treatment the same as node positive. These results suggested as follows: 1) Lumpectomy with a clear margin and radiation is the best choice for small breast cancer (T < or = 3.0 cm, N0 or N1a). 2) Adjuvant therapy after surgical treatment is necessary for local recurrence. PMID- 8702320 TI - [Human papillomavirus (HPV) infection in sexual partners of women with condylomatous cervical dysplasia]. AB - OBJECTIVES: Human papillomavirus (HPV) genital infection is a sexually transmitted disease that appears to be involved in the pathogenesis of various tumors of the genitourinary system, especially carcinoma of the uterine cervix. Diagnosis and treatment of sexual partners of female carriers is fundamental in preventing reinfection after treatment. METHODS: A prospective study was conducted on 118 male partners of females diagnosed as having HPV infection by cytology and, in some cases, dysplasia or carcinoma in situ of the cervix. RESULTS: Patient mean age was 38.5 years; 40 had a history of other sexually transmitted diseases. Peneoscopy was performed in all cases, 44 were biopsied and 47 had a urethral cytology. The infection rate was 55%. Peneoscopy and biopsy were the best diagnostic methods. CONCLUSIONS: HPV infection in male partners of female carriers can be diagnosed by peneoscopy and biopsy of the suspected lesions. Treatment and complete eradication of the infection are fundamental since HPV has been implicated in the pathogenesis of carcinoma of the cervix and other urogenital tumors. PMID- 8702321 TI - [Clinical assessment and treatment of spontaneous perirenal hemorrhage]. AB - OBJECTIVES: Four cases of spontaneous perirenal hemorrhage are reviewed, with special reference to the clinical features, diagnosis and treatment. METHODS/RESULTS: Two were due to tumor (sarcomatoid carcinoma and angiomyolipoma) and the rest were secondary to renal lesions. All patients underwent nephrectomy due to hemodynamic instability. CONCLUSIONS: Nephrectomy appears to be the best treatment since this condition may arise from a malignant tumor which, to date, cannot be determined by any diagnostic method. PMID- 8702322 TI - [Clinical and neuro-urodynamic assessment of radical prostatectomy]. AB - OBJECTIVES: To study the clinical and urodynamic parameters after radical prostatectomy in order to standardize the management of these patients in the medium-term. METHODS: 35 cases submitted to radical prostatectomy from February, 1989 to March, 1994 were retrospectively evaluated clinically and urodynamically using a clinical questionnaire, free flowmetry, cystometry, pressure/flow voiding test with simultaneous videocystography and sacral-evoked potentials. The mean age was 65 years and mean follow-up was 14 months. RESULTS: 80% (28) were continent or minimally incontinent on exertion, 9% (3) required the use of some absorbent system and 11% (4) were completely incontinent and required the use of a collecting system. No statistical differences were observed between continence status and tumor stage, patient age or neurovascular preservation. Overall the urodynamic parameters fell within the normal ranges, except for a reduced maximum cystometric capacity. A significant difference (p = 0.05) was found in those patients with significant incontinence vs those who did not for maximum free flow, which disappeared on flowmetry with transducer catheter. Seventy per cent of the incontinent cases were evident on evaluation; 60% had stress incontinence and 40% had instability waves with differential pressure over 80 cm H2O. Six per cent met the criteria for obstruction, whose localization was done during videocystography. Eleven per cent showed non inhibited contractions and 6% showed diminished bladder compliance. The sacral reflex arch was normal in all patients. CONCLUSIONS: The urodynamic study was found to be normal in the majority of patients submitted to radical prostatectomy; therefore performing the study routinely is not justified. However, incontinent patients and those with disturbances on free flowmetry may show incontinence due to instability or obstruction of the urethrovesical junction. We therefore advocate performing a complete study on all patients with significant incontinence and free flowmetry for the rest at least three months after surgery and a complete study should be done if disturbances are found. PMID- 8702323 TI - [Mitomycin C for the treatment of superficial tumors of the bladder (Tis-Ta-T1) with one or more risk factors. Argentinian Cooperative Group of Oncourology (GCAO)]. AB - OBJECTIVES: To determine the efficacy and toxicity of intravesical mitomycin C in superficial bladder tumors (Tis Ta T1) completely resected with one or more risk factors. (Protocol U. 01/90). METHODS: The patients received six instillations weekly of 40 mg mitomycin C within 15 days post-TUR of a superficial bladder tumor with one or more risk factors: histological grade 3, tumor size more than 3 cm and/or multicentric lesion. The patients were evaluated by cystoscopy every three months for the first two years and every six months thereafter. Toxicity was evaluated according to Miller's score. Tumor recurrence, disease-free interval and survival were analyzed. RESULTS: 126 patients were entered into the study; of these, 110 were evaluable. At 18 months mean follow-up (range 6-36 months), 77 patients (70%) remain disease-free; the mean time to recurrence was 13.8 months. There were no differences between patients with one, two or three risk factors or those who received or did not receive previous treatments. The patients tolerated the treatment well; there were no dropouts or systemic toxicity. CONCLUSIONS: 1. At 18 months mean follow-up, 77 of 110 patients (70%) remain disease-free; 2. The mean time to recurrence was 13.8 months; 3. Local toxicity was minimal; 4. There were no dropouts due to toxicity; 5. Systemic toxicity was not observed. PMID- 8702324 TI - [Significance of ploidy in prostatic cancer, quantified by a prospectively applicable procedure]. AB - OBJECTIVES: To determine the ploidy of prostatic adenocarcinoma cells obtained by fine-needle punction-aspiration biopsy using computer-assisted image analysis and its prognostic value. METHODS: The clinical applications of the two most commonly utilized methods, flow cytometry and cytophotometry, is difficult. The ploidy of prostatic adenocarcinoma cells obtained by fine-needle punction-aspiration biopsy in 54 patients was determined by image analysis. Previous cytological preparations from our files were utilized in the present study. Before processing the preparations, the Papanicolau stain used originally was removed. To make the technique simpler, we did not use the Feulgen stain but the progressive hematoxylin stain, which is faster and easier to use. The representative ploidy histograms were classified into four types first and then into two grades of DNA malignancy. The survival curves were plotted using the Kaplan-Meier method and according to the ploidy. RESULTS: Patients with high grade DNA malignancy had a worse survival rate than those with low grade malignancy. Statistical analysis using the log-rank test showed a significant difference, with p < 0.001. CONCLUSIONS: Tumor ploidy in prostate cancer can be determined prospectively using cytological smears with progressive hematoxylin staining and has a prognostic value. PMID- 8702325 TI - [Treatment of complex fistula and urinary stenosis in renal transplantation]. AB - OBJECTIVES: Urological complications in renal transplantation occasionally denote the failure of a technique intended to provide the patient on hemodialysis a significant improvement of quality of life. Our experience in the management of these complicated cases which could not be resolved by conventional measures is described. METHODS: Since the transplantation program began, our department has performed 530 renal transplants. There have been 40 fistulae (7.5%) and 23 stenoses (4.3%) of graft urinary tract. All the foregoing complications had been treated by endourological procedures (nephrostomy or ureteral stent) and/or simple ureteral reinsertion. There were 5 unresolved or recurrent fistulae (0.9%) and 2 stenoses (0.4%) that were repaired using the recipient's ipsilateral urinary tract (6 pyeloureterostomies and 1 pyelopyelostomy). RESULTS: Good results were achieved in all of the cases with adequate urinary tract function. CONCLUSIONS: Urological complications following renal transplantation can be successfully treated by surgical correction (pyeloureterostomy or pyelopyelostomy). PMID- 8702326 TI - [Usefulness of the urodynamic study of the lower urinary tract in renal transplantation]. AB - OBJECTIVES: To analyze the indications, diagnostic cost-effectiveness and therapeutic implications of urodynamic assessment of the lower urinary tract in two groups of patients: 1) those awaiting renal transplantation and those with a functioning renal graft and voiding disturbances. METHODS: The first group comprised 22 patients who were evaluated before renal transplantation for a total of 32 urodynamic studies. The second group comprised 10 patients with a functioning renal graft for a total of 14 post-transplant urodynamic studies. The etiology of the chronic renal failure, indications for urodynamic assessment and videourodynamic findings in both groups were compared. RESULTS: Interstitial nephropathy associated with vesicoureteral reflux was the most common cause of chronic renal failure in the pre-transplant group, whereas glomerular nephropathy was the most common cause of chronic renal failure in the posttransplant group. Vesicoureteral reflux was the most frequent videourodynamic finding and was associated with other urodynamic disturbances in 75% of the cases. Lower urinary tract obstruction was the most common finding in the posttransplant group. CONCLUSIONS: The indications for urodynamic study in patients awaiting renal transplantation are: 1) interstitial nephropathy associated with vesicoureteral reflux, neurogenic bladder and congenital malformations; 2) patients aged 45 or older with a flowmetry suggesting obstruction; 3) those with urinary diversion, and 4) systemic diseases potentially associated with neurological damage. PMID- 8702327 TI - [Usefulness of cystomanometry in the assessment of urinary irritative symptoms]. AB - OBJECTIVES: To analyze the value of cystometry in evaluating patients with irritative voiding symptoms with no remarkable previous medical history. METHODS: 79 patients (24 males, 55 females; mean age 49.6 years) with irritative voiding symptoms and no remarkable previous medical history comprised the study. The patients underwent physical and neurourological examination. The urodynamic assessment included uroflowmetry, filling cystometry, pressure/flow study (and urethral pressure in some cases). Uninhibited detrusor contractions were registered. RESULTS: Cystometry failed to detect involuntary detrusor contractions in 68 of the 79 patients (86.1%) with no relevant medical history. Detrusor instability was not found in 41 of 52 women (78.9%) with irritative voiding symptoms and stress incontinence without neurological disease. Involuntary contractions were not observed in 14 of 16 patients (87.5%) with irritative symptoms with a diagnosis of infravesical obstruction. On the other hand, 33 of 68 patients (48.5%) with irritative complaints and a history of neurologic disease showed no hyperreflexia. A statistically significant difference was found between this latter group of patients and those with no remarkable previous medical history (p < 0.001). CONCLUSIONS: Our results indicate that filling cystometry is of little value in the assessment of patients with irritative voiding symptoms and no remarkable previous medical history, but is more useful in patients with irritative symptoms and neurological disease. Careful history-taking and physical examination should detect the underlying problem in the majority of patients. PMID- 8702328 TI - [Congenital vaginal atresia and simultaneous vesico-vaginal fistula]. AB - OBJECTIVES: To describe an uncommon case of congenital atresia of the vagina associated with vesico-urethro-vaginal fistula caused by violent coitus. METHODS/RESULTS: We report on a patient who was unaware she had the Rokitanski Mayer-Kuster-Hauser syndrome when she had her first sexual intercourse which caused partial destruction of the urethra and bladder neck, resulting in complete incontinence. The different surgical procedures performed to recovery urinary continence and the creation of a viable vaginal tunnel are described. CONCLUSIONS: Congenital atresia of the vagina is uncommon. To our knowledge, this is the first case with associated vesico-urethro-vaginal fistula reported in the literature. PMID- 8702329 TI - [Intradiverticular transitional cell tumor. Report of a case]. AB - OBJECTIVES: To emphasize the diagnostic difficulty in some cases of intradiverticular transitional cell tumor of the bladder. METHODS/RESULTS: A patient with intradiverticular transitional cell tumor is described. The clinical features and diagnostic aspects are discussed. Despite the use of different diagnostic procedures (X-ray, US, CT, retrograde cystography), diagnosis could only be made after surgery. CONCLUSION: In patients suspected as having intradiverticular transitional cell tumor, the definitive diagnosis can only be made following surgery. PMID- 8702330 TI - [Epididymal malacoplakia in a heart transplant recipient: clinico-pathologic study of a case]. AB - OBJECTIVES: An unusual case of malacoplakia is described and the literature reviewed. METHODS/RESULTS: We report on a patient on immunosuppression due to heart transplantation who developed malacoplakia of the epididymis. Patient history and treatment are discussed, with special reference to the differential diagnosis between this condition and tumors. PMID- 8702331 TI - [Intestinal obstruction caused by transitional carcinoma]. AB - OBJECTIVES: To draw attention to the possibility that distant intestinal metastasis can arise from transitional urothelial carcinoma located in the bladder. METHODS: Two female patients developed distant metastasis during treatment of the tumor by transurethral resection of the bladder. RESULTS: Following complicated transurethral resection with perforation of the peritoneal cavity, the patients developed intestinal obstruction from metastatic transitional cell carcinoma. CONCLUSIONS: Direct or distant seeding of tumor cells on previously undamaged peritoneal serosa produced with the resectoscope may not be exceedingly unlikely. PMID- 8702332 TI - [Eosinophilic cystitis and glandular-cystic cystitis as pseudotumor lesions]. AB - OBJECTIVES: To report on two different types of cystitis presenting as pseudotumor. The differential diagnosis between the foregoing lesions and true tumors can only be established by biopsy. METHODS: We report two cases of cystitis (eosinophilic cystitis and glandular-cystic cystitis) with clinical, radiological and endoscopic features of a bladder tumor. The diagnosis, etiopathological aspects, clinical course and treatment of both types of cystitis are reviewed. RESULTS/CONCLUSIONS: Hematuria is the most frequent and most important symptom of these uncommon lesions. They present as space occupying lesions in more than 50% of the cases and have no specific diagnostic features. The diagnosis can only be made by pathological examination following TUR-biopsy. PMID- 8702333 TI - [Adrenal myelolipoma. Report of a case and review of the literature]. AB - OBJECTIVES: Herein we describe an additional case of myelolipoma of the adrenal gland, an uncommon tumor of the adrenal cortex, that had been incidentally discovered during abdominal US evaluation of the biliary tree. The clinical features, diagnosis and treatment of the condition are discussed. METHODS: Surgical treatment of the biliary tree and myelolipoma was performed through a Chevron transversal incision during the same surgical session. RESULTS: Surgery achieved good results and the postoperative course was unremarkable. CONCLUSIONS: Myelolipoma is a benign nonfunctioning tumor of the adrenal cortex comprised of adipose and hematopoietic tissue. It is usually asymptomatic and incidentally discovered during diagnostic evaluation for other pathologies. The diagnosis is made by US, CT and MRI. There is no agreement on whether surgical treatment is warranted. PMID- 8702334 TI - Preliminary reports on morphological and ultrastructural changes in the corpora cavernosa of the rat after chronic arterial obstruction. AB - OBJECTIVES: Various authors have investigated the pathological findings of penile tissue after chronic arterial obstruction, but the significance of these changes in the corpora cavernosa remains unclear. In order to evaluate the possible damages in the erectile tissue after chronic arterial obstruction at different levels, we utilized an experimental model in rats to determine the changes in smooth muscle cells and elastic fibers of the erectile tissue by microscopic immunohistochemical and ultrastructural studies. METHODS: Twelve adult male Wistar rats were employed in this study. Ten were used for the experiments and two as control. The rats were anaesthetized with ether and intraperitoneal 10% chloral hydrate. Microsurgical isolation of the involved vessels was performed with the aid of a Zeiss dissecting microscope. Partial stenosis was achieved with 11/0 nylon and amputation of the penis was performed at previously established time periods. The partial stenosis was carried out at the level of the aortic below the renal vessels (Group A), the common iliac artery on both sides (Group B) and the hypogastric artery on the left side (Group C). Arterial obstruction was maintained in each group for 50, 40 and 25 days, respectively. RESULTS/CONCLUSIONS: In comparison with normal controls, the histological findings revealed discrete and diffuse interstitial hyalinosis with reducted elastic fibers, while dilated vascular lacunae were also present on TEM (Transmission Electron Microscope) and SEM (Scanning Electron Microscope) examination. The greatest ultrastructural damages were observed in the group with obstruction of the common iliac artery on both sides. The foregoing confirms that an eventual chronic obstruction of these arteries does not allow the formation of collateral vessels for the corpora cavernosa. PMID- 8702335 TI - [Experimental study of renal sutures and fibrin adhesive]. AB - OBJECTIVES: An experimental study was conducted in the rat to demonstrate the utility of fibrin adhesive in renal parenchymal lesions and the enhanced anatomopathological results achieved in comparison with suturing. METHODS: 10 Wistar rats were utilized in the study. The animals were anesthetized with Ketolard, diazepam and atropine. A transverse lesion was made in the left kidney and five different treatments were used. Thereafter nephrectomy was performed on day 1, 3, 7, 14 and 21. Anatomopathological studies of the rat kidneys were done and the results were analyzed using Friedman's variance test. RESULTS: Anatomopathological analyses showed a progressive resorption of the fibrin adhesive, which disappeared at two weeks, and a better outcome for the lesions treated by gluing than by suturing. CONCLUSIONS: Fibrin adhesive is effective for hemostasis and can be used safely. It is an excellent watertight sealant that causes minimal inflammatory tissue reaction. It is a valid alternative to renal parenchymal suturing and can be used alone or in combination with conventional suturing to reduce the number of sutures and consequently the degree of renal trauma. PMID- 8702336 TI - [Transurethral thermotherapy with microwaves in symptomatic prostatic benign hypertrophy: comparison between the high-energy (2.5) protocol and the standard protocol (2.0)]. AB - OBJECTIVES: The efficacy of three therapeutic protocols of transurethral microwave thermotherapy (TUMT), was compared in a study comprised of 355 patients that had been treated for benign prostatic hypertrophy (BPH) between March, 1992 and March, 1995. METHODS: TUMT were performed with the Prostatron device with intravenous analgosedation and on an outpatient basis. In the first group (Protocol A), 122 patients received a standard treatment (Prostasoft 2.0/hour); the second group of 81 patients were included into Protocol B (Prostasoft 2.0/2 hours); 152 patients were treated with higher-energy in Protocol C (Prostasoft 2.5/1 hour). The number of sessions (635) performed were based on prostatic length: L < 45 mm - one session (Prostanec catheter); L < 55 mm - two sessions (additional black catheter session); L < 65 mm - three session (additional white catheter session). RESULTS: All groups improved significantly for subjective symptoms (symptom score) and objective parameters (peak flow, residual urine). Comparison of the results between the three groups at 6 and 12 months showed a significantly better clinical outcome in protocol C >> B > A: Morbidity was higher in group C than in group B than in group A. CONCLUSION: Our results indicate that transurethral microwave thermotherapy is a safe and effective procedure which improves objective and subjective parameters. Better outcomes were obtained with long session times (2H) and overall higher energy (2.5) input, which may be explained by the creation by cavities within the prostate, but at the cost of increased morbidity. However, TUMT can still be delivered as an anesthesia-free and outpatient non-surgical alternative treatment for BPH. PMID- 8702337 TI - [Sexual impotence: from unknown to very well-known]. PMID- 8702338 TI - [Physiology of penile erection]. AB - Penile smooth muscle tone (arterial and trabecular) regulates the hemodynamic phenomena of erection. Nitric oxide is perhaps the most important mediator of penile smooth muscle relaxation and, consequently, of erection. Detumescence of the erect penis following contraction of the smooth muscles is mediated by the adrenergic nerves, which release noradrenalin that acts on alpha 1 adrenergic receptors. Other substances such as endothelin and prostanoids appear to be implicated in maintaining penile relaxation. PMID- 8702339 TI - [Anatomophysiology of ejaculation]. AB - OBJECTIVES: The present study reviews the anatomophysiological and neurological aspects of ejaculation and ejaculatory disorders. METHODS/RESULTS: The different phases of the ejaculatory process and the male genitalia are analyzed. CONCLUSIONS: Ejaculation is a complex psychobiological process whose innermost mechanisms have yet to be elucidated. Further studies are warranted to obtain further insight into ejaculatory disorders whose impact on the male population cannot be overemphasized. PMID- 8702340 TI - Nocturnal and real-time Rigiscan monitoring in patients with venous incompetence. AB - OBJECTIVES: In cases of failure of the vascular occlusive system, testing with both nocturnal and real-time monitoring will offer the possibility of making an accurate diagnosis of venous occlusive dysfunction. METHODS/RESULTS: The study was conducted in 124 cases suspected as having venous occlusive dysfunction (VOD). All patients were submitted to cavernometry, which confirmed VOD in 41 cases; however, the existence of a venous disorder could not be established in 83 cases. Nocturnal monitoring with the Rigiscan System was performed in 68 cases; no organic disorder was found in 6 cases. CONCLUSIONS: Although the results of nocturnal monitoring with the Rigiscan is not always consistent, in our experience it has been useful in both nocturnal and real-time monitoring of the erectile responses during many diagnostic tests such as VSS or intracavernosal injection of vasoactive agents. PMID- 8702341 TI - [Digital inflection rigidometry in the study of erectile dysfunction. A new technique]. AB - OBJECTIVES: A device for reliable measurement of penile axial rigidity has been sought for some time. Three years of research have led to the development of the Digital Inflexion Rigidometer. The new technique and the results obtained are described herein. METHOD: The Digital Inflexion Rigidometer was utilized in 150 patients that had consulted for erectile dysfunction of different etiologies. RESULTS: In 60% of the cases, the Rigiscan recorded a circumferential rigidity of 60-70%; However, the Digital Inflexion Rigidometer showed penile axial rigidity to be insufficient for coitus. Fourteen cases with psychogenic erectile dysfunction had an axial rigidity greater than 600 gms, a difference of more than 300 gms in comparison with the recorded clinical postinjection rigidity. Home Digital Inflexion Rigidometry of 14 cases suspected of having venous leakage showed a difference of 300 to 500 gms between the first and second measurement (performed after taking 3 or 4 steps). CONCLUSION: In our view, the Digital Inflexion Rigidometer is a useful diagnostic tool in erectile dysfunction which permits precise and painless measurement of the penile axial rigidity, relative intracavernosal pressure and penile temperature. PMID- 8702342 TI - [Neurologic diagnosis of erectile dysfunction]. AB - OBJECTIVES: To describe a clinical method for the evaluation of neurological disorders in erectile dysfunction. METHODS: A new method for neurological evaluation in erectile dysfunction is presented. CONCLUSIONS: Although the study is complex, the method of evaluation described herein is considered to be indicated basically in erectile dysfunction highly suspected as having an underlying neurogenic cause. PMID- 8702343 TI - [Psycho-therapeutic process of erectile dysfunction]. AB - OBJECTIVES: To underscore the importance of psychological evaluation in erectile dysfunction. METHODS: Different methods of psychological evaluation (questionnaires, tests, directive interview, etc.) are utilized in erectile dysfunction. We use a flexible approach since different patients require different treatments. RESULTS: The curative process is directly related with the psychotherapist's interpretation of the information given by the patient and the analysis of the resistance to the resolution of the underlying conflict that may arise. CONCLUSIONS: Erectile dysfunction may be organic or psychogenic. Although it may arise from organic causes, the physical symptoms cannot be separated from the psychological components. The membrane that separates the conscious from the subconscious becomes permeable through psychotherapy. The success of treatment largely depends on the patient's desire to be cured. Correct diagnosis is essential to treatment by behavioural, psychoanalytical or combined and adaptable therapy. The importance of strict observation of the protocol and a multidisciplinary approach, which includes the intervention of a psychotherapist, is emphasized. PMID- 8702344 TI - [Mechanisms of vacuum erection]. AB - OBJECTIVES: To analyze the vacuum erection devices utilized in the treatment of erectile dysfunction. METHODS: The different devices used for vacuum therapy are described. The indications, contraindications, complications, management and patient acceptance of vacuum erection devices are discussed. RESULTS: The preliminary data from our study show good patient acceptance of and satisfaction with this type of therapy. CONCLUSIONS: Treatment of some forms of erectile dysfunction with vacuum devices has achieved encouraging results. Some cases that require higher pressures may benefit from the new electronic vacuum devices that are currently being developed. PMID- 8702345 TI - [A new vacuum mechanism for the etiologic treatment of erectile dysfunction]. AB - OBJECTIVES: To demonstrate the usefulness of the new, computerized and programmable electronic vacuum erection devices in the etiological treatment and prevention of erectile dysfunction. METHODS: In erectile dysfunction due to incipient fibrosis of the penile vascular system, the programmable vacuum erection devices that achieve passive erection with low negative pressures, act as dilators of the corpus cavernosum arterial vascular system. RESULTS: 20 patients with grades I and II erectile dysfunction were treated with the new Vacuum Plus Tratamiento (VPT) with highly satisfactory results. CONCLUSIONS: The results achieved with the new vacuum erection devices like the VPT show their efficacy in the etiological treatment, as well as prevention, of erectile dysfunction arising from fibrosis of the penile vascular system. PMID- 8702346 TI - [Erectile dysfunction: clinical course with intracavernous PGE1]. AB - OBJECTIVES: The results achieved with PGE1 therapy in 66 patients with erectile dysfunction in our self-injection program are presented. METHODS: Patients with severe conditions (cancer, infectious disease, renal and hepatic failure, etc.), psychological or hormonal disorders were discarded from the study. All patients were tested with PGE1, the dose was adjusted according to individual response, the patient was instructed how to inject the vasoactive drug and included in the self-injection program. Statistical analysis of the data was performed using the chi-square and the Student 't' test. RESULTS: The mean follow-up was 9.8 months (range 1-39). Twenty-five patients (37%) withdrew from the program. Six patients (9%) received another treatment due to pain or poor response. A penile prosthesis was implanted in five patients and one patient was treated with a vacuum erection device. Although not statistically significant, local pain was associated with a shorter follow-up. Prolonged erection was also observed but did not influence the length of follow-up. CONCLUSIONS: Local pain has been associated with a shorter follow-up. A small number of non-responders warranted another therapy. PMID- 8702347 TI - [Long-term results of the treatment with intracavernous injection of vasoactive drugs]. AB - OBJECTIVES: To evaluate the long-term results of treatment of erectile dysfunction with intracavernous self-injection of vasoactive drugs. METHODS: The study comprised 144 patients treated with intracavernous self-injection. The most common etiologies were arterial (27%), corporal-veno-occlusive (22.2%) and diabetic (17.5%). The mean follow up was 15.6 months (range 12-44) and the total number of injections was 7,190. PGE1 was utilized in 135 patients and papaverine + PGE1 in 9 patients. RESULTS: Patients with psychogenic or neurogenic impotence responded to low doses of PGE1 (9.6 microgram and 8.4 microgram, respectively). Adequate rigidity was achieved in 96% for over 30 min in 90%, and coitus was satisfactory in 92%. There were 20 (13.9%) dropouts and 5 (3.5%) recovered erection. The most important local complications were intense pain (4 pts, 0.05%), prolonged erection (3 pts, 0.04%) and secondary fibrosis without penile curvature (3 pts, 2.1%). Systemic complications were observed in only 4 cases: palpitation (1 pt), headache (1 pt) and dizziness (2 pts). CONCLUSIONS: Patients with psychogenic and neurogenic impotence responded to low dose therapy, whereas those with veno-occlusive impotence required the highest doses of PGE1 or papaverine + PGE1. This pharmacological erection program achieved adequate rigidity in 96% and satisfactory coitus in 92%. There were minimal complications: prolonged erection (0.04%), intense pain (0.05%) and fibrosis (2.1%). PMID- 8702348 TI - [New features of pharmacologic treatment of erectile dysfunction]. AB - OBJECTIVES: The present article summarizes the latest advancements in the physiology of erection, with special reference to the role of the adenylate and guanylate cyclase-nitric oxide system. METHODS/RESULTS: New aspects in the pharmacological intracavernous treatment of erectile dysfunction are discussed and new drugs in this field are analyzed, such as nitrovasodilators, calcium channel blocker, potassium channel openers, phosphodiesterase inhibitors and the combination of adenylate cyclase stimulators. CONCLUSIONS: A high percentage of patients with erectile dysfunction depends on intracavernous injection of vasoactive drugs for erection. However, this route of administration is painful and causes anxiety in many cases. Other routes of administration (oral, topical or intraurethral) have yet to be developed, as well as drugs that can diminish penile venous blood outflow in cases with venous leakage, and can enhance arterial blood supply at the same time. The combination of phosphodiesterase inhibitors with adenylate and/or guanylate cyclase stimulators or potassium channel openers may further enhance the results achieved to date. PMID- 8702349 TI - [Priapism induced by vasoactive drugs]. AB - OBJECTIVES: Priapism induced by intracavernous injection of vasoactive drugs is uncommon, easily managed and carries a very low risk of possible sequelae. The pathophysiology, diagnosis and treatment of postinjection priapism is discussed. METHODS/RESULTS: The series of Schramer, Padma-Nathan, Levine and other authors are reviewed. The incidence of postinjection priapism has been found to be less than 0.5% in general, although the incidence has been reported to range from 3 to 12% when papaverine is used alone. CONCLUSIONS: Priapism induced by intracavernous injection of vasoactive drugs is uncommon and easily managed. Treatment, however, should be instituted rapidly. PMID- 8702350 TI - [Morphologic changes in the penis. Impotence coeundi without erectile dysfunction]. AB - Erectile dysfunction is not the only cause of impotence in the male; impotencia coeundi may result from various disorders, although cavernosal erectile function is normal. The present study reviews the congenital and acquired penile disorders, as well as the cutaneous disorders that may cause penile morphological changes. PMID- 8702351 TI - Differential therapies in various stages of penile induration. AB - OBJECTIVES: To evaluate the different therapies for penile induration. The results achieved in our series of 280 patients are described and the literature reviewed. METHODS: The study analyzed 2,752 cases of the literature that had been treated with Potaba, 1420 treated with radiotherapy, 117 cases treated with Orgotein injection and 93 cases that had been treated by surgery (a malleable prosthesis had been implanted 53 patients). RESULTS: In 2,752 cases of the literature that had been treated with Potaba, an improvement was seen in 60% (range 10%-82%) and the median failure rate was 40%. The overall success rate in 117 cases treated with Orgotein was 63%, with a median failure rate of 37%. In 1420 cases that had been treated with radiotherapy, the improvement and failure rates were 60% and 40%, respectively. In 93 patients that had undergone surgery, the improvement rate was 80%. Excellent results were achieved in all but 2 of the 53 patients in whom a malleable prosthesis had been implanted (infection required explantation of the prosthesis in these 2 patients). CONCLUSIONS: The importance of performing a detailed study of the plaque is underscored. A predisposition for abnormal scar tissue formation has to be considered. If surgery is indicated, the correct choice of surgical technique can achieve excellent results. PMID- 8702352 TI - [Penile prosthesis. Indications, classification, technic, complications, and safety]. AB - OBJECTIVES: To review the indications of penile prosthesis in the treatment of erectile dysfunction and describe a new classification based on the design and material of the prosthesis. METHODS: Penile prosthesis are classified. The advantages and disadvantages of the different prosthesis types are given. The surgical technique is described, as well as the pre-, intra- and postoperative complications observed in 300 procedures involving penile prosthesis performed over a 10-year period. RESULTS: 6 of the 300 prosthesis required removal (4 of these 6 prosthesis were reimplanted); 17 prosthesis were changed due to implant failure. CONCLUSIONS: Penile prostheses are the best solution currently available for erectile dysfunction not amenable to any other type of treatment and carry minimal complications if the technique is performed correctly. PMID- 8702353 TI - Prevention and treatment of complications of inflatable penile prosthesis surgery: a review article. AB - Over the last 16 years more than 3,000 procedures involving multi-component inflatable penile prosthesis have been performed. A variety of types of complications have been encountered, including mechanical problems with the prosthesis, intraoperative complications, postoperative complications, problems with infection and patient dissatisfaction. During the course of this experience we have made some observations and developed techniques to minimize and treat the complications seen with both routine and difficult inflatable penile prosthesis implantation surgery. PMID- 8702354 TI - President's message: mentoring and mutual respect in a supportive climate are essential in today's health care environment. PMID- 8702355 TI - Changing to a caring paradigm for teaching and learning. AB - Nephrology nurses have tended to use behavioral strategies to teach people about their diseases and treatments. However, in this article, nurses are encouraged to shift to a caring paradigm for teaching individuals with end stage renal disease. The key concepts in this paradigm include: caring, phenomenology, multiple realities, empowerment, and health promotion. Specific suggestions for planning teaching and learning activities, and evaluating learning in the new paradigm are provided. PMID- 8702356 TI - Family needs of chronic hemodialysis patients: a comparison of perceptions of nurses and families. AB - OBJECTIVE: The objectives of this study were to (a) determine the psychosocial needs of families of ESRD patients receiving hemodialysis as perceived by nurses and family members; and (b) compare the differences of perception of needs between these two groups. DESIGN: The Norris and Grove Questionnaire (1986) was modified for the hemodialysis population to a 33 statement inventory of psychosocial needs. SAMPLE/SETTING: The sample consisted of 10 family members and nine registered nurses. The setting was a Midwestern Veterans Administration Medical Center hemodialysis unit. METHODS: A telephone survey interview was used for 9 family members; one survey was returned by mail. The RNs returned completed questionnaires to the unit. RESULTS: The findings of this study revealed 6 need statements that were statistically significantly different (p < 0.05) between the two groups. All of these need statements were perceived to be more important by the family members than the nurses. CONCLUSIONS: In this study, family members and nurses differed in what they perceived as important family needs. Families identified at least two psychosocial needs--the need for information and the need for comfort as being very important. PMID- 8702357 TI - Losses, maintenance and recruitment of patients in a peritoneal dialysis home training program. AB - The St. Peter Hospital Kidney Dialysis Center began a peritoneal dialysis home training program in 1988, and demonstrated steady growth until the end of its sixth year at which time the census plummeted. Peritoneal dialysis staff sought to determine a cause for the reduction in census by evaluating the reasons for drop-out. They concluded that drop-out rates were not unexpected or unusual and that maintenance and referrals are influenced by: (a) patient predialysis education and (b) continual conversation and collaboration between the nephrologists and peritoneal dialysis home training staff. PMID- 8702358 TI - Continuous venovenous hemofiltration with and without dialysis in pediatric patients. AB - Peritoneal dialysis (PD) is often the preferred modality in dialyzing the pediatric patient in acute renal failure. However, PD may be contraindicated in the presence of the acute surgical abdomen, respiratory compromise, or diaphragmatic disruption. The child's size and cardiovascular instability may also render hemodialysis undesirable. The use of continuous arteriovenous hemofiltration (CAVH) has been an option for the acutely ill child but requires arterial and venous access as well as adequate blood pressure to drive the CAVH circuit. Another option is continuous venovenous hemofiltration (CVVH), which obviates the need for arterial access and provides blood flow via an external pump. This article presents a retrospective of 20 acutely ill pediatric patients who received continuous venovenous hemofiltration with and without dialysis (CVVH/D) during the period covering Fall 1992 through Fall 1993 at Children's Hospital in Seattle. The children ranged in age from 1 day to 12 years (mean age 4 years) and weights ranged from 1.7 kg to 76 kg (mean 15.8 kg). Seventeen of the 20 patients were started on CVVH/D due to hemodynamic instability, 1 for PD complications, and 2 for metabolic disorders. Fluid and solute removal were achieved efficiently and metabolic imbalances were easily corrected. Patients received 1-25 days (mean 7.7 days) of CVVH/D. PMID- 8702359 TI - Family circumstances that influence plans for home peritoneal dialysis. PMID- 8702360 TI - Heparinization schedule for PD catheter not in use. PMID- 8702361 TI - Epoetin alfa--focus on optimal hematocrit. Case study of the anemic patient. AB - Epoetin alfa therapy has dramatically improved therapeutic responses and outcomes for anemic patients with end-stage renal disease. This article examines clinical evidence supporting the correlation between patient outcomes and a higher hematocrit and addresses some of the barriers that may hinder optimal patient outcomes. PMID- 8702362 TI - Calcium acetate: a choice for phosphate management. PMID- 8702363 TI - Risk of community infections in transplant patients. PMID- 8702364 TI - HeartMate device: a bridge to nowhere? PMID- 8702365 TI - Employment after spinal cord injury: relation to selected participant characteristics. AB - OBJECTIVE: To investigate the relation between selected participant characteristics and employment outcomes after spinal cord injury (SCI). Previous studies produced conflicting results with widely varying employment rates due to differences in study participant characteristics. DESIGN: A field study of the employment history of a large stratified sample of people with SCI. Participants were grouped into cohorts and then compared on several employment variables using the chi square statistic and analysis of variance. PARTICIPANTS: Three hundred sixty-two persons with SCI, selected by stratified sampling according to gender, race, and age. Participants were further grouped into cohorts based on time since injury, injury severity, and years of education. MAIN OUTCOME MEASURES: Multidimensional Adjustment Profile, a specially designed measure of multiple outcomes after SCI. RESULTS: The most successful employment outcomes were obtained by Caucasian women, persons up to the age of 29 years at injury, participants with incomplete injuries, and participants who had completed at least 16 years of education. The least successful outcomes were observed in minority men, participants age 50 years or older at injury, persons with complete quadriplegia, and participants with fewer than 12 years of education. CONCLUSIONS: Results point to the need for rehabilitation professionals to make special efforts to maximize employability after SCI among people with biographic characteristics that place them at greatest risk for unemployment. PMID- 8702366 TI - Reported pressure ulcer prevention and management techniques by persons with spinal cord injury. AB - OBJECTIVE: The purpose of this study was to identify factors that resulted in severe pressure ulcers in a community-based sample of 23 persons with spinal cord injury (SCI). DESIGN: A correlational design was used. SUBJECTS: Twenty men and three women, 57% with tetraplegia and 43% with paraplegia, participated. Adult participants with an ulcer of 12 weeks' duration or less were recruited from the plastic surgery clinic of a regional SCI center. MEASURES: A structured survey assessed demographic, SCI and ulcer characteristics; detection method; immediacy and appropriateness of action; time from detection to clinic visit; number of prior ulcers; and knowledge and practice of ulcer prevention techniques. Ulcer characteristics (ie, location, size, and stage) were assessed by examination and compared with participants' descriptions of their ulcers. RESULTS: Severe ulcers and ulcers that progressed in severity after initial detection were less accurately described by participants. Individuals who waited longer to come to the clinic presented with more severe ulcers. Taking immediate or appropriate action when an ulcer was detected was related to reported performance of more preventive behaviors. Contrary to expectation, immediacy and appropriateness of action, and knowledge and practice of preventive behaviors were unrelated to severity, progression of severity, and time from detection to the clinic visit. The findings suggest that educational programs should emphasize more strongly immediate visits to a physician upon detection of an ulcer. Furthermore, such educational models should be assessed for their effectiveness in reducing ulcers and preventing progression in severity once persons with SCI return to the community. PMID- 8702367 TI - Vacuum erection device in spinal cord injured men: patient and partner satisfaction. AB - OBJECTIVE: To assess the efficacy of and patient and partner satisfaction with a vacuum erection device (VED) to treat erectile dysfunction of spinal cord injury. DESIGN: Case series. SETTING: University hospital outpatient clinic. PATIENTS: Twenty spinal cord injured men with erectile dysfunction and their heterosexual partners, recruited from outpatient population and by advertisement. INTERVENTION: Use of a VED to obtain erections for sexual activity. MAIN OUTCOME MEASURES: Efficacy in obtaining adequate penile erection, and patient and partner satisfaction with the device (survey). RESULTS: At 3 months, 93% of the men and 83% of the women reported rigidity sufficient for vaginal penetration, with an average duration of 18 minutes. These numbers decreased somewhat at the 6-month control. At 6 months, 41% of the men and 45% of the women were satisfied with the device, with premature loss of rigidity during intercourse the most commonly reported complaint. Sixty percent of men and 42% of women indicated an improvement of the sexual relationship. Minor side effects, such as petechiae and penile skin edema, occurred frequently, but there were no complications that required treatment. CONCLUSION: The VED is effective in many couples in the treatment of erectile dysfunction associated with spinal cord injury. The devices were not universally accepted, but had a significant impact on sexual activity and sexual satisfaction for nearly half the couples. Vacuum erection devices should be presented to SCI men along with other options for treatment of erectile dysfunction. PMID- 8702368 TI - Predictors of family functioning and change 3 years after traumatic brain injury in children. AB - OBJECTIVES: To examine changes in family functioning from injury to 3 years after pediatric traumatic brain injury; to determine factors most predictive of family outcomes at 3 years and variables that promote positive outcomes and changes over time. DESIGN: Prospective cohort study. SETTING: Two regional tertiary care centers: cases followed for 3 years into community. PARTICIPANTS: Families of 81 children, ages 6 to 15 years, who sustained closed head injury and loss of consciousness (mild = 43, moderate = 20, severe = 18), consecutively enrolled over 15 months. MAIN OUTCOME MEASURES: Family Environment Scale, Family Assessment Device, Family Inventory of Life Events, Health Insurance Survey General Well-Being, NYU Problem Checklist for Significant Others, Family Interview Rating Scale, Family Global Assessment Scale. All were obtained initially and at 3 months, 1 year, and 3 years postinjury. Predictor variables were selected from the instruments above, as well as from the parent and teacher versions of the Child Behavior Checklist, socioeconomic status, and injury severity. RESULTS: Preinjury functioning was the best predictor of 3-year outcomes. Fewer changes in family functioning were reported over 3 years in the mild or moderate groups, whereas more deterioration occurred in the severe group. At 3 years, one third to one half of parents in either the moderate or severe groups reported medium to high strain in 19 of 34 problem areas. Low levels of family control and high levels of expressiveness correlated with better outcomes for severe group. Positive change for the severe group was marked by better preinjury levels of communication, expressiveness, problem solving, use of resources, role flexibility, greater activity orientation, and less conflict, control, and stress. Preinjury variables and severity explained from 26% to 69% of the variation in 3-year outcomes. CONCLUSIONS: Families at risk for poorer outcomes can be prospectively identified and should be supported and encouraged in their efforts to develop new coping resources. PMID- 8702369 TI - Supervision rating scale: a measure of functional outcome from brain injury. AB - OBJECTIVE: To introduce a new outcome rating scale, the Supervision Rating Scale (SRS), which measures the level of supervision that a patient receives from caregivers. The SRS rates level of supervision on a 13-point ordinal scale that can optionally be grouped into five ranked categories (Independent, Overnight Supervision, Part-Time Supervision, Full-Time Indirect Supervision, and Full-Time Direct Supervision). DESIGN: Descriptive correlational study of the scale's interrater reliability and criterion-related validity. SETTING: Brain injury program of a freestanding rehabilitation hospital. PATIENTS: Referred case series of 114 patients with moderate to severe traumatic brain injury (mean time postinjury = 3.8 years) who resided in the community or a nonhospital facility. INTERVENTION: None. MAIN OUTCOME MEASURES: Functional outcome as measured by the Disability Rating Scale (DRS), Glasgow Outcome Scale (GOS), type of living arrangement and independence in selfcare and instrumental activities of daily living (ADL). RESULTS: SRS ratings showed consistent relationships with type of living arrangement and with independence in self-care and instrumental ADL. SRS ratings were also strongly associated with ratings on the DRS and GOS. Interrater reliability of the SRS was evaluated in a subsample of 19 patients and found to be satisfactory (intraclass correlation = .86, weighted kappa = .64). CONCLUSIONS: The results suggest that the SRS should have sufficient reliability and validity to serve as a measure of functional outcome from brain injury. Because SRS ratings are based on observed behaviors, the SRS may have a smaller subjective component as compared to the DRS and GOS. PMID- 8702370 TI - Vulnerability to dysfunction and muscle injury after unloading. AB - OBJECTIVE: To test whether unloading increases vulnerability to eccentric exercise-induced dysfunction and muscle injury. DESIGN: Before-after trial. SETTING: General community. PATIENTS OR OTHER PARTICIPANTS: Two women and 5 men (73 +/- 3kg [mean +/- SE]) who were active college students but were not trained in lower body resistance exercise volunteered. INTERVENTION: Five weeks of unilateral lower limb suspension (ULLS), which has been shown to decrease strength and size of the unloaded, left, but not load-bearing, right quadriceps femoris muscle group (QF) by 20% and 14%, respectively; performance of 10 sets of ten eccentric actions with each QF immediately after the ULLS strength tests with a load equivalent to 65% of the post-ULLS eccentric 1-repetition maximum. MAIN OUTCOME MEASURE(S): Concentric and eccentric 1-repetition maximum for the left, unloaded and the right, load-bearing QF measured immediately after ULLS and 1,4,7,9, and 11 days later; cross-sectional area and spin-spin relaxation time (T2) of each QF as determined by magnetic resonance imaging and measured the last day of ULLS and 3 days later. RESULTS: The mean load used for eccentric exercise was 23 +/- 2 and 30 +/- 3kg for the left, unloaded and right, load-bearing QF, respectively. The concentric and eccentric 1-repetition maximum for the unloaded and already weakened left QF was further decreased by 18% (p = .000) and 27% (p = .000), respectively, 1 day after eccentric exercise. Strength did not return to post-ULLS levels until 7 days of recovery. The right, load-bearing QF showed a 4% decrease (p = .002) in the eccentric 1-repetition maximum 1 day after eccentric exercise. The left, unloaded QF showed an increase in T2 (p = .002) in 18% of its cross-sectional area 3 days after the eccentric exercise, thus indicating muscle injury. The right, load-bearing QF showed no elevation in T2 (p = .280). CONCLUSION: Unloading increases vulnerability to eccentric exercise-induced dysfunction and muscle injury, even at relatively light loads. PMID- 8702371 TI - Air-splint pressure effect on soleus muscle alpha motoneuron reflex excitability in subjects with spinal cord injury. AB - OBJECTIVE: This study investigated circumferential pressure effect on soleus motoneuron reflex excitability in subjects with spinal cord injury (SCI). SETTING: A university neuromuscular research laboratory. SUBJECTS: Six men with SCI, clinical level above L1. OUTCOME MEASURES AND INTERVENTION: Soleus motoneuron reflex excitability was assessed by measuring the average change in the peak-to-peak amplitude of 10 H-reflexes before (baseline), during (1, 3, and 5min) and after (1, 3, and 5min) pressure application. Pressure was applied to the lower leg by manually inflating an air-splint to a maintained range of 36.7 to 40.8mmHg for 5 minutes, after which it was deflated. DESIGN: Repeated measures, planned comparison. Dependent variables compared with baseline values only in post hoc tests. RESULTS: A one-way analysis of variance for repeated measures demonstrated significant difference (F6,30 = 4.03; p = .004) in the H reflex amplitude across test conditions. Post hoc t tests (with Bonferroni's correction for multiple comparisons, p < or = .008) revealed a significant H reflex amplitude reduction at 1, 3, and 5 minutes of pressure application when measurements were compared with the baseline value. Postpressure measurements returned to baseline; however, the third minute measurement was significantly greater than baseline values. CONCLUSIONS: Circumferential pressure applied to the lower leg decreased soleus muscle alpha motoneuron reflex excitability in subjects with SCI. This inhibition lasted only as long as the pressure was applied. Circumferential pressure application may be useful when a temporary decrease in muscle activity is a therapeutic goal in patients with SCI. PMID- 8702372 TI - Physical, psychological, and social outcomes in geriatric rehabilitation patients. AB - OBJECTIVE: Previous research studies that addressed the relationship between age and functional outcome had limited generalizability because of small sample size, lack of an urban population, and limited variables that do not allow for a complete investigation of social, cognitive, psychological, and medical factors in geriatric rehabilitation. The present study attempted to assess the relationship between decade of geriatric life (60s, 70s, 80s, and 90+) and functional outcome. DESIGN: Survey study of geriatric cohorts. SETTING: Inpatient university-affiliated rehabilitation hospital. PATIENTS: 812 urban geriatric rehabilitation patients divided into four groups based on decade of life. MAIN OUTCOME MEASURES: Index of comorbid disease, principal diagnoses, Functional Independence Measure, Mattis Dementia Rating Scale, Geriatric Depression Scale, CAGE alcohol questionnaire, and residential status at admittance and discharge. RESULTS: Although there were no significant demographic differences between groups (apart from age), there were differences in functional outcome suggesting that the younger old (60s and 70s) and the older old (80s and 90+) patients may represent two different rehabilitation groups. CONCLUSIONS: The younger old patients showed significantly higher alcohol abuse and comorbid physical disease, while the older-old patients demonstrated significantly poorer cognitive skills and more dependent social status on discharge from the rehabilitation facility. Despite the younger group's physical problems and alcohol use, they demonstrated better physical recovery. Implications for working with these two groups of urban geriatric patients in a rehabilitation setting are discussed. PMID- 8702373 TI - The reliability, validity, and stability of a measure of physical activity in the elderly. AB - OBJECTIVE: To assess the reliability, validity, and stability of an accelerometer based monitor of physical activity in an elderly population. DESIGN: Six studies were conducted to assess the Tritrac, a newly available accelerometer capable of storing three-dimensional activity data collected in minute epochs. After initial bench testing, the waist-worn devices were assessed for test-retest reliability during sitting and treadmill walking at 1mph and 2mph. Validity testing examined the Tritrac's ability to discriminate between different levels of physical activity and also compared the Tritrac with an established wrist-worn acclerometer, the Actigraph. Stability of the measure was examined over a period of 3 to 7 days, and in a subset of subjects this measurement was performed for a second week. SETTING AND SUBJECTS: Residents of a VA Nursing Home (n = 40; mean age = 76), participants in an in-home nonaerobic exercise program (n = 36; mean age = 77), and community participants in an aerobic exercise program (n = 10; mean age = 71). RESULTS: Intraclass correlation coefficients (ICC) for both the bench testing and test-retest reliability were .97. The device discriminated among subjects independently categorized as sedentary, moderately active, or active (F = 49.4, p = .0001) and between specific activities of varying intensity (F = 114.5, p = .0001). Tritrac and Actigraph measurement comparison showed a correlation of r = .77, p = .0001. Stability of the measure was demonstrated by ICCs = .81 and .78 for mean activity values and proportion of time spent in sedentary activity, respectively. No significant differences were observed when comparing activity measured for two separate weeks. CONCLUSION: The Tritrac is a reliable and valid instrument producing activity measurement that was stable over time in the elderly population we studied. During our longitudinal testing, 20% of the subjects did not comply with wearing the device; this noncompliance issue must be considered in any use of the Tritrac. PMID- 8702374 TI - Personality and stress: an exploratory comparison of rheumatoid arthritis and osteoarthritis. AB - OBJECTIVE: To characterize and investigate the relationship between stress and personality in people with rheumatoid arthritis (RA) compared to those with osteoarthritis (OA). DESIGN: Survey of personality characteristics determined by using Cattell's 16 Personality Factor (16PF) questionnaire and stressful life events at disease onset determined by using the Social Readjustment Rating Scale of Holmes and Rahe. SETTING: Inpatients of an arthritis hospital and outpatients of a clinic, both of which specialize in rheumatic diseases and musculoskeletal problems. PARTICIPANTS: Diagnosed as "definite" or "classical" RA (N = 128) according to the ARA Diagnostic Criteria for Rheumatoid Arthritis (1958 Revision) or as OA (N = 79) according to radiological and clinical evidence; randomly selected, resulting in a close match for gender, age at disease onset, duration of disease, functional classification, and pattern of disease progress. All individuals approached participated. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Twenty personality characteristics, as well as amount of stressful life events at disease onset (Life Change Units). RESULTS: The RA subjects had significantly (p < .001) more stress at disease onset compared to the OA subjects. A subgroup of high-stress-at-onset RA subjects experienced a higher degree of disease severity (p < .01) than did the RA subjects with no stress at onset. Although the mean personality scores for those with RA were not significantly different from those with OA, the RA personality frequency distributions were different. Some of these differences could be explained by the stress-at-onset subgroup personality characteristics. CONCLUSIONS: As a group, subjects with RA exhibited more stress at disease onset than those with OA. Although mean personality scores were not different between RA and OA subjects, they did exhibit different frequency distributions. There appeared to be a high-stress-at-onset subgroup of RA patients who had a worse disease prognosis and who corresponded to a personality frequency subgroup. The interaction between these variables is more complex than implied by the "RA personality" concept. PMID- 8702375 TI - Gait training efficacy using a home-based practice model in chronic hemiplegia. AB - OBJECTIVE: The efficacy of a home practice model for gait training was evaluated in 18 hemiplegic subjects 2.3 years (range, 1 to 5) after stroke. DESIGN: Uncontrolled case series. SETTING: Referral center. SUBJECTS: Patients at least 1 year poststroke referred to an outpatient rehabilitation program. INTERVENTION: Patients were taught home programs in two or more 2- to 5-day blocks averaging 35 physical therapy (PT) contact hours (range, 9.5 to 62.5); training extended over a mean of 22 months (range, 10 to 65). Training emphasized weight bearing, balance, segmental control, stretching, and bracing. MAIN OUTCOME MEASURES: Gait changes were measured using the newly developed Wisconsin Gait Scale (WGS). The patient-rated Falls Efficacy Scale (FES) was administered before and after training to 8 subjects, and the Health Status Questionnaire (HSQ) was retrospectively administered to all subjects to appraise subjective pretraining to posttraining changes and current psychological status. RESULTS: The average WGS score significantly improved (p < .05). Patients perceived that gait training increased the quality of their functional activities (p < .05). In a subset of patients, the FES showed that fear of falling was decreased (p < .05). Perception of well-being was comparable to a normative nonstroke reference population except for physical functioning. Compared to the only other published series (using traditional outpatient programming), the current model was of comparable cost. CONCLUSION: Despite the literature indicating a plateau in mobility function by 6 months after stroke, postacute training of gait in hemiplegic subjects using a home-based training model results in improved gait and the perception of improved function. Additionally, we provide validation for the newly developed Wisconsin Gait Scale, an instrument of gait measurement that may assist in comparing outcomes. PMID- 8702376 TI - Changes in the execution of a complex manual task after ipsilateral ischemic cerebral hemispheric stroke. AB - OBJECTIVE: To analyze behavioral adaptation of hemiplegic patients performing a complex manual task without time constraint. It was postulated that ipsilateral motor disturbance could not be observed after a hemispheric stroke. DESIGN: Two manual tasks were used: (1) a new one, "Pig-Tail," required the patients to run a 3-cm-diameter copper ring in a wooden handle along a wavy copper wire without any time constraint; (2) the second task was the Nine-Hole Peg Test (NHPT). SETTING: A hospital department of rehabilitation. PATIENTS: A consecutive sample of 36 patients, who had all suffered an ischemic stroke in the middle cerebral artery territory, 18 with left hemisphere damage (LHD) and 18 with right (RHD), and who had similar ages (mean 54 +/- 13), stroke severity, time since stroke (mean 60 days), and functional independence according to the FIM. MAIN OUTCOME MEASURE: Main data were number of faults, time in seconds, and difference of time for two trials. Analysis compared the results with the same hand for patients and 86 healthy subjects. RESULTS: Patients scores for NHPT were worse than controls, whatever the side of the lesion (p < .05). For Pig-Tail, the number of faults by patients was greater than by controls (p < .05); time was higher for LHD, but not significantly, and was similar to controls for RHD. All patients and controls speeded up between the two trials. Although the RHD were clumsy, they were always faster than LHD patients. CONCLUSION: There are ipsilateral motor disturbances in a complex manual task after hemispheric stoke, even without a speed constraint, and regardless of the hemisphere damaged. Further studies are needed to examine speed control that seemed impaired by right hemisphere damage and could explain clumsiness in these patients. PMID- 8702377 TI - Motor learning following unilateral stroke. AB - OBJECTIVE: To determine the effect of different motor learning schedules on stroke patients' rate of acquisition and retention of a functional movement sequence using the hemiparetic upper limb. DESIGN: Randomized controlled group study using a retention design with two retention trials. SETTING: Outpatient neurorehabilitation clinic. PATIENTS: Twenty-four patients with chronic hemiparesis secondary to a single unilateral cerebral stroke without evidence of severe cognitive or language impairment. MAIN OUTCOME MEASURE: The primary hypothesis was that hemiparetic motor learning that occurred under conditions of contextual interference (ie, random practice) would be retained better than learning that occurred under conditions of repetitive drill (blocked practice). RESULTS: A significant difference was found among the three groups (ie, random practice, blocked-practice, control) on both the first retention measure (chi 2 = 13.50, p < .01) and the second retention measure (chi 2 = 12.59, p < .01). More importantly, a significant difference was found between the random-practice and blocked-practice groups on both the first retention measure (U = 68.5, p < .01) and the second retention measure (U = 62.0, p = .05). CONCLUSIONS: Findings provide empirical evidence to support the contention that random practice is more effective than blocked practice, with respect to retention over time, when hemiparetic stroke patients attempt to learn functional motor skills. PMID- 8702378 TI - Depression following spinal cord injury. AB - Although depression has been widely studied among persons with spinal cord injury, the ubiquitous and unsophisticated use of the term and presumptions about its manifestations in the rehabilitation setting have needlessly encumbered the understanding and treatment of depression. Major themes and issues in the study, measurement, and treatment of depression among persons with spinal cord injury are reviewed. Greater precision is recommended in distinguishing diagnosable depression from displays of negative affect, anxiety, distress, and dysphoria. Correlates of depressive behavior among persons with SCI are surveyed, and guidelines for research and practice in the SCI setting are explicated. PMID- 8702379 TI - Intrathecal clonidine and baclofen in the management of spasticity and neuropathic pain following spinal cord injury: a case study. AB - Spasticity and pain are common disabling sequelae following spinal cord injury (SCI) and are often difficult to manage. The two problems are also not infrequently related. A variety of pharmacological and other approaches have been described for management of these problems in SCI. This case study reports a 32 year-old woman with an established incomplete C5 tetraplegia (anterior cord syndrome) who developed severe, intractable anal spasm following a hemorrhoidectomy, which persisted despite very good healing. This prevented evacuation of her bowels and resulted in severe rectal pain and episodes of autonomic dysreflexia. Attempts to modify the rate and mode of delivery of intrathecal baclofen through an existing programmable infusion pump failed to reduce anal sphincter spasm or improve symptoms. A right-sided pudendal block with lignocaine provided some relief. Clonidine was added to baclofen in the pump reservoir and both drugs were administered intrathecally in combination. This resulted in an immediate improvement in anal sphincter spasm and pain relief, allowing rapid reestablishment of her normal bowel pattern without need for any supplemental analgesia. It appears that intrathecal clonidine may have an important role in the treatment of spasticity, either as a single or an adjuvant agent, when intrathecal baclofen alone is ineffective or there is increasing tolerance to baclofen. Intrathecal clonidine may also prove useful in the management of intractable neuropathic pain. PMID- 8702380 TI - Gait analysis and motor point block in dynamic varus of the rear foot in a head injured adult. AB - This clinical note describes a typical case of dynamic varus deformity of the hind part of the foot in a head injured adult. Gait analysis objectified, by kinematic data, the perturbed movement of the rear foot in the frontal plane and identified, by dynamic electromyography, the overactive muscle (posterior tibialis) involved in the deformity. The diagnosis was confirmed by a motor point block of the posterior tibialis muscle with functional improvement. Kinematic data also showed improvement after the block. This case report illustrates the usefulness of gait analysis in diagnosis and management of gait disturbances in adult patients. PMID- 8702381 TI - Pregnant teenagers: antenatal education research. AB - Current literature studying pregnant teenagers and their antenatal educational needs has concentrated on subjects such as sex education, nutrition and various teaching methods. What many have neglected to discover are the topics of interest for pregnant teenagers, and if peer discussion groups appeal to them. This article will address these two issues and, furthermore, the preferred time and gestation of a Pregnant Teenagers' Program. A study was conducted, at the Gosford and Wyong Antenatal Clinics of the Central Coast Area Health Service, by voluntary questionnaires to 46 pregnant teenagers attending the clinics, to determine the antenatal educational needs of pregnant teenagers, and if their needs differed from adult pregnant women. PMID- 8702382 TI - National Health and Medical Research Council. Revised statement on the relationship between dietary folic acid and neural tube defects such as spina bifida. PMID- 8702383 TI - Unity in diversity. PMID- 8702384 TI - Carbohydrate-mediated sorting in aggregating embryonal carcinoma cells. AB - The oligosaccharide structure carried by embryoglycan, Lex hapten, as well as E cadherin, has been described to mediate Ca(2+)-dependent cell-cell adhesions in embryonal carcinoma cells. To examine the contribution of these two systems to intercellular adhesion, we analyzed aggregation properties of previously isolated embryoglycan-defective mutants of P19 embryonal carcinoma cells. Our data indicate that the absence of Lex and embryoglycan has no effect on homotypic cell aggregation. Pretreatment of the cells with E-cadherin-specific antibody reduced homotypic aggregation of both parental and mutant cells, suggesting that E cadherin plays a major role in this system. When parental cells were mixed with mutant cells, the aggregates contained either parental or mutant cells; no heterotypic aggregation was observed. The absence of mixed aggregates formed between parental and Lex-or embryoglycan-negative mutant P19 cells suggests that carbohydrates are involved in cadherin-mediated cell sorting. PMID- 8702386 TI - Collagen type X: a component of the surface of normal human, pig, and rat articular cartilage. AB - Collagen type X, a protein generally associated with hypertrophic chondrocytes of avian and mammalian growth plate during endochondral growth of long bones, has been previously shown to be present during disruption of normal metabolic status of articular cartilage during osteoarthritis. We have demonstrated that collagen type X is present as a component of normal articular cartilage in adult human, growing pig and new-born rat. The protein was immunolocalized in these tissues at the surface of the articular cartilage and for human tissue there was some staining of chondrocytes adjacent to the "tidemark' zone. The presence of collagen type X was confirmed by isolating the protein from these tissues and its identification by SDS-PAGE and immunodetection with antibodies specific for collagen type X. PMID- 8702385 TI - Complex formation of JAK2 with PP2A, P13K, and Yes in response to the hematopoietic cytokine interleukin-11. AB - Interleukin-11 is a stromal derived cytokine important in hematopoiesis. IL-11 intracellular signaling travels through cytoplasmic kinases of the Janus family. How JAKs accomplish the multiple functions of IL-11 has not been determined and until recently only a few associated downstream proteins have been identified. We present evidence here for the IL-11 induced association of PP2A, P13K, and Yes to JAK2. Reciprocal immunoprecipitations support the mutual involvement of these signaling components in IL-11 mediated signal transduction. This novel finding of JAK2/PP2A binding and release may have relevance to many serine/threonine regulated mechanisms such as P13K, Stat, and MAPK activation. These associations support a model of JAK2 as a protein kinase docking protein of IL-11 signal transduction that may be applicable to other gp130 and JAK signal transduction systems. PMID- 8702387 TI - Oligopeptides as substrates and inhibitors for a new constitutive nitric oxide synthase from rat cerebellum. AB - A new constitutive nitric oxide synthase (NOS) that utilizes both L-arginine and bradykinin (BK) as substrates has been purified from rat cerebellum. This NOS is calmodulin-dependent with L-arginine, but calmodulin-independent with BK. Peptide products obtained using BK and a related nonapeptide as substrates were isolated and sequenced. Both N- and C-terminal arginines of BK are oxidized to citrullines by this enzyme. With BK as substrate NOS activity is competitively inhibited by NG-methyl-, NG-nitro-L-arginines, and a BK receptor antagonist. Our results suggest that oligopeptide-utilizing NOS may occur in other tissues, and show for the first time that oligopeptides can function as substrates or inhibitors of NOS. PMID- 8702388 TI - Genistein, a tyrosine kinase inhibitor, reduces EGF-induced EGF receptor internalization and degradation in human hepatoma HepG2 cells. AB - In this work, using the ECL Western blotting assay system, it was found that genistein, a specific tyrosine kinase inhibitor, was able to inhibit EGF-induced EGF receptor degradation and tyrosine phosphorylation in human hepatoma HepG2 cells. This inhibition was increased with increasing genistein concentration. With treatment of HepG2 cells with genistein at 37 degrees C for 30 min, the amount of internalized EGF, which was measured by the detection of the sorting of 125I-EGF in the cells, was remarkably decreased. Under the same conditions, in cells untreated with genistein, the degradation of EGF was significantly increased. After preincubation of HepG2 cells with and without genistein for 120 min at 37 degrees C, the ratio between degraded and released EGF was 16 and 24, respectively. These results suggest that EGF-induced internalization and degradation of EGF-EGF receptor complexes in HepG2 cells depend on EGF receptor tyrosine kinase activity. PMID- 8702389 TI - Molecular cloning of the human fertilin beta subunit. AB - Fertilin, a heterodimeric sperm surface protein, first identified in guinea pig, has been shown to play an important role in sperm-egg interactions. We report here the complementary DNA and deduced amino acid sequence of human fertilin beta. The human fertilin beta shares significant sequence homology with mouse, guinea pig and monkey fertilin beta and also exhibits similar structural organization. Of particular interest, the mature guinea pig fertilin beta contains an amino-terminal 90 amino acid disintegrin domain. It has been suggested that the integrin recognition sequence (TDE) of the guinea pig fertilin beta disintegrin domain mediates sperm-egg binding. The amino acid sequence at this position in human fertilin beta differs from the mouse, guinea pig and monkey sequence (mouse-QDE; human-FEE; monkey-FDE). PMID- 8702390 TI - A superactive peptidomimetic analog of a farnesylated dodecapeptide yeast pheromone. AB - The S. cerevisiae a-factor, YIIKGVFWDPAC(s-farnesyl)-OCH3, is one of two peptide mating pheromones which mediate cell-cell communication in S. cerevisiae. We previously reported that replacing Gly5 with D-Ala led to a 4-6 fold increase in activity while the L-Ala5 homolog was 4 to 16-fold less active than the wildtype. To clarify the structural implications of these findings, we conformationally restricted the center of the pheromone by inserting gamma-lactam constraints in place of either the Lys4Gly5 or the Gly5Val6 dipeptide unit. Incorporation of (R) 3-amino-2-oxo-1-pyrrolidineacetic acid in place of Lys4Gly5 led to a super-active agonist which exhibited a 32-fold higher bioactivity than that of the a-factor. In contrast, an analog with (S)-3-amino-2-oxo-1-pyrrolidineacetic acid in place of Gly5Val6 is about 30 to 60-fold less active than the a-factor. These data strongly suggest that the a-factor adopts a reverse turn as its bioactive conformation. PMID- 8702391 TI - Meal-feeding specifically induces obese mRNA expression. AB - Meal-feeding caused a rapid and specific induction of ob mRNA levels in rat adipose tissue. A high-carbohydrate meal caused a mean 5-fold increase in ob mRNA within 3 h after feeding and almost reached the levels of expression seen in rats fed ad lib. After the meal ob mRNA declined with a half-life of less than 2 h. The increase in ob mRNA in response to the meal was prevented by prior injection of actinomycin-D, an inhibitor of transcription. None of the mRNAs for other genes involved in lipid metabolism (lipoprotein lipase, fatty acid synthase, malic enzyme, hormone-sensitive lipase, S14 or adipsin) showed any significant difference between pre-meal and post-meal levels. PMID- 8702392 TI - Antioxidant effects of Ilex paraguariensis: induction of decreased oxidability of human LDL in vivo. AB - We have recently demonstrated that Ilex paraguariensis extracts inhibit LDL oxidation in vitro exhibiting a potency comparable to that of ascorbic acid (Gugliucci, A. and Stahl, A.J.C. 1995; Biochem Mol Biol Int 35, 47-56). In the present work we extend our observations to the in vivo situation. We first examined the oxidability of LDL in whole plasma from healthy fasted human subjects before and after intake of Ilex paraguariensis. Intake of water extracts of Ilex paraguariensis inhibit copper-induced autoxidation of LDL in whole plasma as shown by the end-term production of TBARS, and as a consequence are able to impair the appearance of Schiff base induced fluorescence, higher electrophoretic mobility and fragmentation of apoB. When LDL was isolated from plasma prior to oxidation no significant differences in lag-time, slope or maximum rate of oxidation could be detected. We then conclude that antioxidants in Ilex paraguariensis are absorbed and reach sufficient high levels in plasma to inhibit copper-induced LDL autoxidation by increasing aqueous-phase antioxidant capacity. PMID- 8702393 TI - Independent behavior of rat liver LDL receptor and HMGCoA reductase under estrogen treatment. AB - The main molecules of hepatic cholesterol homeostasis are HMGCoA reductase, the key enzyme of the biosynthetic pathway, and LDL receptor, responsible for the uptake of plasma lipoproteins. Estrogens are reported to cause hypolipidemia in mammalians inducing hepatic LDL receptor. The effect of such hormones on HMGCoA reductase is very ambiguous. The mechanism and the time-dependence of the effects of these hormones on HMGCoA reductase and LDL receptor in rat liver have been investigated at mRNA and protein levels, at different times after estrogen administration. Estrogens cause an early increase of LDLr, at both mRNA and protein level, and an increase of HMGCoA reductase, just at protein level, detectable only after 5 days. The independent behavior of LDLr and HMGCoA reductase under estrogen treatment suggests a not coordinate regulation by these hormones. PMID- 8702394 TI - Chemostat selection of an Escherichia coli mutant containing permease with enhanced lactose affinity. AB - Chemostats supplied with limited lactose were used to ask whether it was possible to generate and isolate any mutant of Escherichia coli lactose permease which allowed cells to grow faster. The permease and beta-galactosidase activities of the chemostat culture initially rose together to reach a plateau. After 30 days, the former underwent a second increase alone. From this culture, a faster-growing mutant was isolated. Its permease gene was cloned, sequenced, and found to have a single base pair changed. Thymine at position 199 was changed to guanine, resulting in serine 67 being substituted by alanine. Cells bearing this mutant in the plasmid could grow faster than parents in 10 microM lactose. The Km of the mutant permease toward lactose was 1.4 mM, about half of the wild-type value. Thus, a mutant with higher affinity for substrate could be selected from the chemostat. PMID- 8702395 TI - Relevance of the biosynthesis of coenzyme Q10 and of the four bases of DNA as a rationale for the molecular causes of cancer and a therapy. AB - In the human, coenzyme Q10 (vitamin Q10) is biosynthesized from tyrosine through a cascade of eight aromatic precursors. These precursors indispensably require eight vitamins, which are tetrahydrobiopterin, vitamins B6, C, B2, B12, folic acid, niacin, and pantothenic acid as their coenzymes. Three of these eight vitamins (the coenzyme B6, and the coenzymes niacin and folic acid) are indispensable in the biosynthesis of the four bases (thymidine, guanine, adenine, and cytosine) of DNA. One or more of the three vitamins required for DNA are known to cause abnormal pairing of the four bases, which can then result in mutations and the diversity of cancer. The coenzyme B6, required for the conversion of tyrosine to p-hydroxybenzoic acid, is the first coenzyme required in the cascade of precursors. A deficiency of the coenzyme B6 can cause dysfunctions, prior to the formation of vitamin Q10, to DNA. Former data on blood levels of Q10 and new data herein on blood levels of B6, measured as EDTA, in cancer patients established deficiencies of Q10 and B6 in cancer. This complete biochemistry relating to biosyntheses of Q10 and the DNA bases is a rationale for the therapy of cancer with Q10 and other entities in this biochemistry. PMID- 8702396 TI - The IGF-I receptor protects tumor cells from apoptosis induced by high concentrations of serum. AB - High concentrations of fetal bovine serum (FBS) induce apoptosis of cells in culture. A decrease in the number of insulin-like growth factor I receptors (IGF IR) sensitizes the cells to serum-induced apoptosis. Autophosphorylation of the IGR-IR is not affected by high serum. These results may explain why the targeting of the IGF-IR renders tumor cells much more sensitive to apoptosis in vivo than in vitro. PMID- 8702397 TI - Glucose-dependent insulinotropic polypeptide stimulates insulin secretion via increased cyclic AMP and [Ca2+]1 and a wortmannin-sensitive signalling pathway. AB - The effect of wortmannin, a fungal metabolite which is known to inhibit phosphatidylinositol 3-kinase (PI3-kinase) at low concentrations, has been examined for its effect on insulin secretion stimulated by glucose-dependent insulinotropic polypeptide (GIP). Using a hamster derived clonal beta-cell line, the HIT-T15 cell, wortmannin inhibited GIP-stimulated insulin secretion under both static incubation and perfusion conditions. In contrast, wortmannin did not inhibit glucose-stimulated or forskolin-stimulated insulin secretion. The inhibitory effect was of large magnitude, although always partial, and occurred within a few minutes of the onset of stimulation by GIP. Thus GIP, like vasoactive intestinal polypeptide (VIP) and pituitary adenylyl cyclase activating polypeptide (PACAP), exerts some of its stimulatory effect on insulin release via a wortmannin-sensitive signal transduction pathway. PMID- 8702398 TI - Plasmid-encoded degradation of p-nitrophenol by Pseudomonas cepacia. AB - A Pseudomonas cepacia strain RKJ 200 capable of utilising p-nitrophenol (PNP+) as the sole source of carbon, nitrogen, and energy was isolated by selective enrichment. The degradation of PNP by this strain proceeds through an oxidative route as indicated by the accumulation of nitrite molecules in the culture medium. Initial studies indicate that the degradation of PNP occurs via hydroquinone as shown by thin layer chromatography and gas chromatography studies; hydroquinone is further degraded via the beta-ketoadipate pathway. A plasmid of approximately 50 kilobase pairs was found to be responsible for carrying genes for PNP degradation in this strain. This was based on the facts that the PNP- mutants lacked the plasmid and that the PNP+ phenotype could conjugally be transferred. In addition, the same plasmid also encoded resistance to inorganic zinc ions. PMID- 8702399 TI - Genomic organization of the hamster phospholipase C-delta 1 gene: differential loss of separate alleles of the phospholipase C-delta 1 gene in two fibroblast mutants lacking phospholipase C-delta 1. AB - In earlier work from this laboratory, mutant Chinese hamster lung fibroblasts D1 6b and D1-9b were shown to lack phosphatidylinositol-specific phospholipase C delta 1 (PLC delta 1). In the current study, Northern analysis of mRNA samples from these mutants fails to detect full-length transcripts for PLC delta 1. Southern analysis of Sac1 digests of wild type and mutant cell genomic DNA hybridized against probe made to full-length rat brain PLC delta 1 cDNA suggested that these mutants differ from one another and wild type controls. This observation is shown to be the result of the differential loss, in both mutants, of one of two alleles for the hamster PLC delta 1 gene normally present in the parental cell line. During the course of these studies, the hamster PLC delta 1 gene was cloned and sequenced. This genomic sequence spans 13 kb of DNA and encoded 98.5% of the predicted coding sequence for the hamster PLC delta 1 cDNA within 15+ exons. PMID- 8702400 TI - Induction of IL-12 gene expression in the brain in septic shock. AB - Mental status changes are usually associated with septic shock. However, the molecular mechanisms underlying physiological changes of the central nervous system (CNS) remain speculative. We have investigated the expression of interleukin (IL)-12, one of the central cytokines in inflammatory and immune responses, in the brain from mice intraperitoneally (i.p.) injected with lipopolysaccharide (LPS). Transcripts of the IL-12 p40 gene are markedly induced in the brain, reaching its maximum level 6 h after LPS injection. Microglia-like cells are the primary producers of the p40 transcripts. In contrast, the IL-12 p35 gene is constitutively expressed in the brain at a very low level. PMID- 8702401 TI - Quantitative analysis of MUC2 synthesis in ulcerative colitis. AB - MUC2 is the predominant mucin in the human colon responsible for the protective mucus layer. We developed methods to quantify MUC2 biosynthesis, which were used to study the regulation of MUC2 expression in the colon of normal individuals and of patients with ulcerative colitis. Colonic biopsies were metabolically labeled, and biosynthesis of MUC2 precursor was quantified using SDS-PAGE. Total MUC2 and MUC2 mRNA were quantified using blotting techniques. MUC2 precursor biosynthesis and total MUC2 levels were significantly decreased in ulcerative colitis patients with active inflammation compared to controls. In contrast, both these parameters returned to control values during remission of the inflammation, demonstrating that colonic biosynthesis and total amounts of MUC2 vary according to the activity of the disease. However, MUC2 mRNA levels were similar in all patients and independent of disease activity, indicating that these variations in MUC2 synthesis are post-transcriptionally regulated. PMID- 8702402 TI - cDNA cloning and expression of the Xenopus laevis vitellogenin receptor. AB - A Xenopus laevis oocyte cDNA library was screened with a PCR-generated X. laevis vitellogenin (VTG) receptor probe and a 3.6 kb cDNA clone containing the entire open reading frame, and 5' and 3' noncoding regions were isolated. The deduced amino acid sequence was 72% homologous to the chicken VLDL/VTG receptor, and the characteristic domains were highly conserved. Ligand binding analysis confirmed that the cloned receptor was Xenopus VTG-specific. Although Northern blotting analysis revealed that this gene was expressed as a major transcript of 3.6 kb in Xenopus ovary, weak but significant expression was observed in other tissues by RT-PCR analysis. The fact that major expression of the gene occurs in the ovary suggests that it has an important function in this organ. PMID- 8702403 TI - Peroxynitrite formation from activated human leukocytes. AB - We showed direct evidence of peroxynitrite formation from polymorphonuclear cells (PMN) with the nitration of 4-hydroxyphenylacetic acid (HPA) to 4-hydroxy-3 nitrophenylacetic acid (NO2HPA). Human PMN from healthy volunteers was stimulated with phorbol-12-myristate-13-acetate (PMA, 10 ng/ml) at 37 degrees C in 2-[4-(2 hydroxyethyl)-1-piperazinyl]ethanesulfonic acid-buffered Hank's balanced salt solution (pH 7.4) with HPA (1 mM). NO2HPA was detected under PMA stimulation only in the presence of myeloperoxidase inhibitor. NO2HPA was eliminated by N monomethyl-L-arginine (100 microM). The inhibition of myeloperoxidase appears to be essential to demonstrate the production of NO2HPA since myeloperoxidase itself or its product, hypochlorite, reacted with peroxynitrite and hampered the formation of NO2HPA. PMID- 8702404 TI - A diabetogenic gene, ODB2, identified on chromosome 14 of the OLETF rat and its synergistic action with ODB1. AB - Genetic analysis of diabetogenic genes involved in developing spontaneous diabetes of NIDDM type in the OLETF rat was performed in (OLETF female X B N male)F2 and (OLETF female X BN male)F1 female X OLETF male backcross male offspring. In the F2 and/or backcross offspring, a high frequency of diabetes was found to be associated with a coat color gene, H (hooded). Since it is know that H gene is located on chromosome 14. an attempt was made to examine the linkage association of the gene responsible for elevating plasma glucose with various microsatellite markers of chromosome 14 in male F2 and/or backcross offspring. The results show that a high linkage exists with a microsatellite marker, D14Mit4 (LOD > 2). The gene was designated Odb2. It was also found that both genes, Odb1 which was previously found on chromosome X, and homozygous Odh2 are required to cause elevated plasma glucose in OGTT. PMID- 8702405 TI - Inducer-specific bidirectional regulation by thalidomide and phenylphthalimides of tumor necrosis factor-alpha production. AB - Regulation by thalidomide [N(alpha)-phthalimidoglutarimide] of tumor necrosis factor (TNF)-alpha production was found to be inducer-specific. Thalidomide enhances TNF-alpha production by human leukemia HL-60 cells induced with 12-O tetradecanoylphorbol 13-acetate (TPA), while it inhibits TNF-alpha production induced with okadaic acid (OA) in the same cell line. Some phthalimide analogs, included PP-33 [2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione] and its 4,5,6,7 tetrafluora derivative FPP-33), also showed such an inducer-specific bidirectional TNF-alpha production-regulating activity. The structure-activity relationships of the compounds tested are similar, but not identical, in the TPA stimulated HL-60 and OA-stimulated HL-60 assay systems. PMID- 8702406 TI - Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors gamma 1 and gamma 2. AB - We describe the molecular cloning and expression of cDNAs encoding human PPAR gamma 1 and PPAR gamma 2. Our sequences are distinct from the published sequence at 3 positions, resulting in nonconservative amino acid substitutions. In humans, PPAR gamma mRNA is expressed in spleen, bone marrow, liver, testis, skeletal muscle and brain, in addition to fat. Three thiazolidinediones were found to 1) displace a radiolabeled thiazolidinedione from both receptors with essentially the same IC50s and 2) to transactivate both PPAR gamma isoforms with similar EC50s in transient cotransfection assays utilizing the adipocyte-specific aP2 promoter. Saturating concentrations of these 3 thiazolidinediones altered the conformation of in vitro synthesized PPAR gamma protein producing a 27 kDa protease-resistant fragment. These results indicate that the antidiabetic effects of thiazolidinediones in humans are likely to be mediated via binding to and transactivation of PPAR gamma 1 and gamma 2. PMID- 8702407 TI - Synthetic peptides derived from the fourth domain of CD4 antagonize off function and inhibit T cell activation. AB - We have developed synthetic peptide analogs to analyze novel surface structures of the human CD4 protein potentially involved in T cell activation. Linear and cyclic peptides derived from the FG and CC' loops of the membrane proximal fourth domain of CD4 displayed inhibitory activities in a CD4-dependent immunological assay. These results suggest that the fourth domain of CD4 plays an important role in T cell activation. In addition, we report the synthesis of a highly stable CD4 peptide analog cyclized by the formation of an amide bond between amino and carboxyl termini. Serum stability studies showed that this main-chain cyclic CD4 peptide was highly resistant to proteolytic degradation while the linear and disulfide cyclic peptides were much less stable. The strategy of main chain cyclization of CD4 peptides may represent a promising approach to generate proteolytically stable, orally active immunoregulatory agents. PMID- 8702408 TI - Determination of the size and degree of acetyl substitution of oligosaccharides from Neisseria meningitidis group A by ionspray mass spectrometry. AB - The capsular polysaccharide produced by Neisseria meningitidis group A has the following structure: [formula: see text] [formula: see text] This polysaccharide was partially hydrolysed with acetic acid, and the oligomers obtained were separated by fast performance liquid chromatography. Six fractions were collected and characterised by ionspray mass spectrometry in the positive ion mode. This soft ionisation technique established the size of the obtained oligosaccharides and the degree of O-acetyl substitution for each fraction. PMID- 8702409 TI - Expression of activin beta subunit genes in Sertoli cells of newt testes. AB - From newt testes we cloned by reverse transcription-polymerase chain reaction (RT PCR) activin beta A and beta B subunit genes, each encoding the mature region of the peptides. A single from for each of the subunit, genes was isolated. Newt beta A and beta B share 80 and 98% protein sequence similarity with the human subunits, respectively. Northern blot analysis showed that beta A subunit mRNA is approximately 7 kilobases in length and is expressed during spermatogenesis in stages from spermatogonial to spermatid, but activin beta B subunit mRNA is barely detectable during these sages. We also isolated a cDNA clone containing the entire coding region of beta A and performed in situ hybridization with its cRNA probe. Newt activin beta A subunit mRNA was detected in Sertoli cells, but not in germ cells or pericystic cells. These findings suggest that activin A plays an important role in newt spermatogenesis. PMID- 8702410 TI - Specific targeting of ISP6 to mitochondria is mediated by sequences other than its amino terminus. AB - Most proteins synthesized in cytoplasm target to mitochondria through sequences at their amino termini. However, a previous study suggests that the native carboxyl terminus of ISP6 might be critical of its specific delivery. Here we investigated the sequence directing ISP6 to yeast mitochondrial outer membrane. Unlike mitochondrial presequences, a region at the amino terminus of ISP6 is dispensable for importing the rest of the protein. The carboxyl-terminal end and the nearby transmembrane region of ISP6 are essential to direct the protein exclusively to its correct membrane destination. ISP6 thus may be directed to mitochondria by an unusual sequence. PMID- 8702411 TI - A microwave-mediated saponification of galactosylceramide and galactosylceramide I3-sulfate and identification of their lyso-compounds by delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry. AB - Small amounts of galactosylceramide (cerebroside) and galactosylceramide I3 sulfate (sulfatide) obtained from porcine spinal cord and equine kidney were deacylated by a rapid method of microwave-mediated saponification to prepare their lyso-compounds. Mass spectra of their protonated or deprotonated molecular ion peaks were detected by recently developed new technology of a delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometer with reflector detector in positive or negative ion mode. Long chain bases of lysocerebroside and lysosulfatide were different between porcine spinal cord and equine kidney, but similar to each other in the same organ, suggesting their common synthetic pathway. It is noted that the new rapid method can be similarly applied to the deacylation of both cerebroside and sulfatide in contrast to our classical method which was able to be applied to cerebroside, but not to sulfatide. PMID- 8702412 TI - Antiproliferative role of 3-O-sulfate glucosamine in heparin on cultured pulmonary artery smooth muscle cells. AB - Heparin macromolecules inhibit vascular remodeling associated with hypoxic pulmonary hypertension. Heparin's antiproliferative effect on smooth muscle cells, based on studies of synthetic pentasaccharide fragments, has been attributed to 3-O-sulfate on the internal glucosamine. To determine the role of 3 O-sulfation in smooth muscle cell growth, we treated three heparins of varying potency with heparitinases I and II, which degrade heparin fragments containing 3 O-sulfate on the glucosamine residue to delta-tetrasaccharides only. Our most antiproliferative heparin gave the least amount of delta-tetrasaccharides. This heparin was then fractionated according to degree of sulfation using ETOH precipitation. Again we found no antiproliferative difference between the highly sulfated fractions and those with a lesser degree of sulfation. These studies suggest that 3-O-sulfate of glucosamine residue is not critical in whole heparins for antiproliferative activity. PMID- 8702413 TI - Cytochrome f encoded by the chloroplast genome is imported into thylakoids via the SecA-dependent pathway. AB - In vitro import of the precursor of tobacco cytochrome f, which is is encoded by the chloroplast genome, into isolated pea thylakoids was analyzed. Upon incubation with thylakoids and a stromal fraction, the precursor of cytochrome f was efficiently imported into thylakoids. The imported cytochrome f was tightly integrated into the thylakoid membrane. Insertion of cytochrome f into the thylakoid membrane was blocked by nigericin, sodium azide, and antibodies against pea chloroplast SecA. These results suggest that cytochrome f utilizes the bacterial-type SecA-dependent pathway to be imported into thylakoids. PMID- 8702414 TI - Upregulation of the APC gene product during neuronal differentiation of rat pheochromocytoma PC12 cells. AB - The adenomatous polyposis coli (APC) gene, the mutation of which is responsible for familial adenomatous polyposis and sporadic colorectal tumors, is highly expressed in the central nervous system. To elucidate the contribution of the APC protein to neuronal differentiation, changes in APC expression were examined during nerve growth factor (NGF)-induced differentiation of rat pheochromocytoma PC12 cells. The expression of APC gradually increased throughout the time course, in particular it increased markedly after 7 days of exposure to NGF. However, forced expression of APC did not induce neuronal differentiation of PC12 cells. These results suggest that the APC protein itself does not have the potential to induce neuronal differentiation, but rather is upregulated secondary to the differentiation of PC12 cells. PMID- 8702415 TI - The apolipoprotein E epsilon 4 allele in Parkinson's disease with Alzheimer lesions. AB - The association between the apolipoprotein E (ApoE) epsilon 4 allele and Parkinson's disease (PD) with coexistent dementia has remained controversial. We determined ApoE allele frequencies in 35 subjects with neuropathologically confirmed Lewy body Parkinsonism with and without concomitant Alzheimer lesions, 27 patients with Alzheimer's disease (AD), and 54 controls without neurodegenerative disease. We hypothesized that if AD lesions in PD evolve by the same pathomechanism as in "pure AD," the ApoE epsilon 4 allele frequency in PD with AD lesions (PD+AD) and pure AD should be similar. The frequency of the ApoE epsilon 4 allele differed significantly between PD+AD (13.3%) and AD cases (35.2%), but not between PD+AD and PD without AD pathology (12.5%) or controls (11.1%). We conclude that the ApoE epsilon 4 allele does not function as a risk factor which influences the development of AD lesions in PD. Our data suggest that Parkinson's disease with Alzheimer lesions and Alzheimer's disease with coexistent Parkinsonian features represent two distinct entities at both the clinicopathological and molecular genetic levels. PMID- 8702416 TI - Telomere reduction and telomerase inactivation during neuronal cell differentiation. AB - Telomerase adds (TTAGGG)n hexanucleotide repeats to the ends of mammalian telomeres. This compensates for telomeric loss with successive rounds of cellular replication. Telomerase activity is detected in many neoplastic cells, but not in most normal somatic cells. To determine whether telomeric length and telomerase activity are associated with cellular differentiation, we measured telomeric lengths and telomerase activity in embryonic NT2 precursor cells prior to and following differentiation into post mitotic hNT neurons. This system allows for studies in a direct neuronal cell lineage and, thus, provides a unique model for studying the role of neuronal telomerase activity. Our results show that telomerase activity was present in precursor cells, but not in neuronal cells. Telomeres were consistently longer in NT2 cells than in hNT cells. These results suggest that changes in telomeric length and loss of telomerase activity play a role in neuronal cellular differentiation. PMID- 8702417 TI - A novel donor splice site mutation in the glycogen debranching enzyme gene is associated with glycogen storage disease type III. AB - Analysis of glycogen debranching enzyme (debrancher) cDNA from a patient with glycogen storage disease type III revealed a deletion of 124 base pairs. A donor splice site mutation (IVS G+1 to T) was identified in the patient's debrancher gene, which caused exon skipping of the upstream exon and resulted in a truncated enzyme due to premature termination. Mutational analysis of the patient's family showed that this point mutation was inherited from the father. Southern blot analysis of the patient's genomic DNA showed an additional, unique EcoRI fragment of 5.8 kb, which was inherited from the mother. These results suggested that the patient was a compound heterozygote for the donor splice site mutation, which is the first identified in the debrancher gene, and had a genetic defect relating to an aberrant 5.8-kb EcoRI fragment. PMID- 8702418 TI - cDNA cloning and functional expression of a novel rat kidney organic cation transporter, OCT2. AB - A cDNA encoding a novel organic cation transporter, designated as OCT2 was isolated from the rat kidney. The rat OCT2 cDNA (2,205 bp) had an open reading frame encoding for a 593-amino acid protein (calculated molecular mass of 66 kDa) which shows 67% identity with the rat OCT1. Northern hybridization and reverse transcription-PCR analyses revealed that the rat OCT2 mRNA transcript was expressed predominantly in the kidney, at higher level in the medulla than in the cortex, but this transcript was not detected in the brain, heart, lung, liver, small intestine or spleen. When expressed in Xenopus oocytes, rat OCT2 stimulated the uptake of tetraethylammonium, and the uptake was markedly inhibited by the presence of cimetidine, procainamide and quinidine. These findings suggest that OCT2 is responsible for the transport of cationic drugs in the kidney. PMID- 8702419 TI - Involvement of rho p21 in cyclic strain-induced tyrosine phosphorylation of focal adhesion kinase (pp125FAK), morphological changes and migration of endothelial cells. AB - The molecular mechanisms by which endothelial cells sense and respond to physical forces remain to be elucidated. Recently we reported that cyclic strain-induced morphological change and migration of EC were regulated by the tyrosine phosphorylation of focal adhesion kinase (pp125FAK) and paxillin. The aim of the present study was to clarify the role of the small GTP-binding protein rho p21 in EC exposed to cyclic strain. Bovine aortic endothelial cells (EC) were subjected to 10% average strain at 60 cycle/min. Clostridium botulinum C3 transferase (C3) was used as a specific inhibitor of rho p21. Preincubation of EC with C3 inhibited ADP-ribosylation of rho (94%) and inhibited the morphological change, reorganization of actin filaments, and migration induced by cyclic strain. Moreover, C3 inhibited the cyclic strain-induced tyrosine phosphorylation of pp125FAK and paxillin. These results demonstrate that rho downregulates the tyrosine phosphorylation of pp125FAK and paxillin and can modulate the morphological changes and migration induced by cyclic strain. PMID- 8702420 TI - Cell polarization as a possible mechanism of response termination. AB - Neutrophils stimulated with a low concentration of chemotactic peptide N-formyl met-leu-phe respond with a brief pulse of actin polymerization and a persistent change in morphology from round to polarized. The recovery of the actin polymerization response is unlikely to be due to usual receptor desensitization mechanisms. We hypothesized that cell polarization and redistribution of signaling components effect the depolymerization phase of the actin response. In this report we show that the overall actin depolymerization is equivalent to the reduction in the volume occupied by F-actin while its concentration at the front of the polarized cell remains undiminished. To test whether the confinement of F actin to a small volume can be caused by receptor redistribution, we observed receptors and F-actin in the same cell and found that their localization was different. To explain our findings, we propose a model based on the affinity of a signaling component, other than the receptor, for the areas of the cell rich in F actin. PMID- 8702421 TI - Leptin receptors expressed on pancreatic beta-cells. AB - Leptin (Ob protein) is a recently isolated hormone produced by adipocytes and is a powerful regulator of satiety centers in the brain. A defect in either leptin production or transmission of the leptin signal in animal models, i.e. ob/ob and db/db mice, respectively, results in a syndrome of obesity and diabetes which closely resembles that which occurs in humans. Leptin release is regulated in part by nutritional status and its expression in adipose tissue is up-regulated by insulin. Since hyperinsulinemia is a primary defect in ob/ob and db/db mice which manifests early in the disease, we postulated that leptin may also regulate insulin release as part of a "adipoinsular' feedback loop. We demonstrate the expression of leptin receptor mRNA in primary rat pancreatic islets and in the insulinoma cell line beta TC-3. Furthermore, we find binding of 125I-leptin to beta TC-3 cells which is significantly displaced by leptin. These findings suggest the possibility that the binding of leptin to its receptor in beta-cells may modulate insulin expression in a negative feedback loop, and thereby may have an anti-obesity effect. PMID- 8702422 TI - Rat p67 GBP is induced by interferon-gamma and isoprenoid-modified in macrophages. AB - The guanylate binding proteins, GBPs, are a family of interferon-induced GTP binding proteins that include the rat p67. We report here that rat p67, for which interferon regulation had not previously been demonstrated, is induced by IFN gamma and also by LPS in both cultured bone marrow-derived macrophages and microglia. The basal level of rat p67 in macrophages is low but increases dramatically between 2 and 4 hours after treating cells with either IFN-gamma or LPS. It then remains elevated over the next 24 hours. Rat p67 is isoprenoid modified. The isoprenoid modification was detected in p67 isolated both from primary IFN-gamma-activated macrophages and when the gene for p67 was transfected into COS cells. This is the first demonstration of in vivo prenylation of a GBP. The interferon regulation and prenylation of rat p67 point toward this protein being significant in the functions of both activated macrophages and microglia. PMID- 8702423 TI - Antisense evidence for two functionally active forms of nitric oxide synthase in brain microvascular endothelium. AB - Other workers have identified two constitutive forms of NOS in endothelial cells: endothelial or eNOS and neuronal or nNOS. The present study tests the functional significance of these NOS in brain surface arterioles of mice. Antisense oligodeoxynucleotides (ODN) were injected into the cerebral ventricles. Anti eNOS and anti nNOS were tested separately and in combination. Each antisense reduced the dilation produced by topical acetylcholine (ACh) or by tetrahydrobiopterin (THBP). These are endothelium dependent, NOS dependent dilators, with the THBP being a cofactor for NOS. The endothelium derived mediator actually causing the dilation is EDRF(ACh). When both antisenses were given together there was an additive effect which approached 100% inhibition. Neither sense nor mismatched (scrambled) ODN inhibited either ACh or THBP. Moreover, anti eNOS did not inhibit dilation by bradykinin (endothelium dependent but not NOS dependent) or by sodium nitroprusside (endothelium independent). The data strongly support the conclusion that both eNOS and nNOS are functionally important in the endothelium of mouse pial arterioles. Each isoform of NOS appears to contribute significantly to the synthesis of basally released (THBP triggered) and agonist (ACh) released EDRFACh. PMID- 8702424 TI - Calcitriol differentially modulates mRNA encoding calcitriol receptors and calcium-binding protein 9 kDa in human fetal jejunum. AB - Human intestinal mucosa consists of highly active epithelial cells in continual renewal and differentiation processes anatomically located at different portions of the villi. Besides its well recognized role in bone cell homeostasis, calcitriol has been attributed a role in cellular differentiation and proliferation in normal and cancerous cells. In this report, we show that in human fetal jejunum, depending upon the stage of gestation, calcitriol either enhances or decreases the levels of mRNA coding for its receptor. However, it up regulates at all times those coding for the Vitamin D-dependent Calcium Binding Protein 9kDa. The present observations open interesting possibilities as to the role of calcitriol in the in utero human gut development and the control of colorectal cancers. PMID- 8702425 TI - Vitamin K-dependent carboxylase: mRNA distribution and effects of vitamin K deficiency and warfarin treatment. AB - A cDNA encoding vitamin K-dependent gamma-glutamyl carboxylase was cloned from a human Hep G2 cDNA library. The RNA transcript of the enzyme was found to be widely distributed in various human and rat tissues with liver showing the highest level. The carboxylase transcription in liver was not affected in rats treated with a single dose of warfarin (10 mg/kg) when measured up to 48 hours after the dose, though, at 12 hours, carboxylase activity measured in liver microsomes was elevated 5.4 fold over controls (p < 0.001). In rats fasted for 72 hours there was no affect on transcription in the liver while hepatic carboxylase activity increased 4.1 fold (p < 0.001). These data suggest that the increase in activity of the liver carboxylase in warfarin treated or fasted rats was not regulated by transcription but more likely was due to a posttranscriptional mechanism. PMID- 8702426 TI - Interferon-gamma-dependent expression of inducible nitric oxide synthase, interleukin-12, and interferon-gamma-inducing factor in macrophages elicited by allografted tumor cells. AB - We have examined the mechanisms of activation of macrophages (Mos) induced by i.p. allografted Meth A tumor cells (Meth A-Mos) during the rejection of the cells by C57BL/6 mice. Inducible nitric oxide (NO) synthase (iNOS), interleukin 12 (IL-12), and interferon-gamma (IFN-gamma)-inducing factor (IGIF) were transiently expressed in Meth A-Mos during the rejection. The expression was impaired in mice in which the gene encoding IFN-gamma had been disrupted (IFN gamma-/-). In vitro studies showed that Meth A-Mos from IFN-gamma +/+ mice induced an apoptotic type of cell death in P815 cells, without cell-to-cell contact, in an NO-dependent manner, whereas Meth A-Mos from IFN-gamma-/- mice could not lyse these cells. The iNOS, IL-12, and IGIF expression was also impaired in bacteria-activated Mos from IFN-gamma-/-mice, indicating that IFN gamma, but not IGIF, would be the initial signal that leads to the activation of Mos in vivo. PMID- 8702427 TI - Cloning and expression of Xenopus HGF-like protein (HLP) and Ron/HLP receptor implicate their involvement in early neural development. AB - HGF-like protein (HLP), also known as macrophage stimulating protein, is a ligand for Ron receptor tyrosine kinase, a member of the c-Met/hepatocyte growth factor receptor family. We cloned a Xenopus homologue of the Ron/HLP receptor (Xron) and HLP (Xhlp) and analyzed temporal and spatial expressions. Both Xron and Xhlp mRNA were detected in Xenopus embryos at the cleavage stage, as maternally pooled RNA. Zygotic expression of Xron mRNA was seen in early embryos during midblastula and neurula (stage 22), while Xhlp was evident during midblastula and early tadpole (stage 40). Xron mRNA was localized in the most frontal region of the neural fold and peripheral regions of the neural plate, while Xhlp mRNA was seen in midline of the neural plate (notoplate) and the most frontal regions of the neural fold in early neurula. Thus, functional coupling between Ron receptor tyrosine kinase and HLP may have an important role in development of embryonic neural tissue in Xenopus laevis. PMID- 8702428 TI - Retinoic acid regulates differentially the expression of IL-1 beta and IL-1 receptor antagonist (IL-1ra) in PMA-activated human monocytes. AB - Retinoic acid (RA) is a well-known immunological modulator. Although it has been shown that RA stimulates IL-1 expression in monocytes, it is of interest for understanding of the regulatory role of RA in inflammation to examine whether RA also modulates the expression of the IL-1 receptor antagonist (IL-1ra), which is reported to reduce IL-1 beta-mediated inflammation. In this study, we examined the effect of RA on expression of IL-1 beta and IL-ra in phorbol-myristate acetate (PMA)-activated human monocytes. RA enhanced gene expression and production of IL-1 beta in PMA-activated monocytes. However, interestingly, gene expression and production of IL-1ra in the cells were markedly inhibited by RA. These results show that RA differentially regulates IL-1 beta and IL-ra expression in PMA-activated human monocytes and suggest that RA may promote IL-1 mediated inflammation. PMID- 8702429 TI - Suppression of inducible nitric oxide synthase mRNA expression by tryptoquinone A. AB - Triptoquinone A (TQA), which is an anti-inflammatory constituent in plants, was studied for its suppressive effect on nitric oxide production by LPS. TQA significantly suppressed smooth muscle relaxation and increase in cyclic GMP levels by nitric oxide (NO) in an L-arginine-induced relaxation experiment. The mechanistic studies showed that TQA did not directly inhibit NO radicals and inducible nitric oxide synthase (iNOS) enzyme but suppressed IL-1 beta and iNOS mRNA expression by LPS. The suppression level of iNOS gene expression by TQA was comparable to that by dexamethasone. TQA may be a useful candidate for the development of a drug as a potent inhibitor of iNOS gene over-expression. PMID- 8702430 TI - Regulation of pituitary growth hormone-releasing factor (GRF) receptor gene expression by GRF. AB - We examined how growth hormone-releasing factor (GRF) regulated pituitary GRF receptor gene expression in the conscious rat. GRF receptor mRNA levels were significantly increased by immunoneutralization of endogenous GRF with its specific antiserum. This effect was dose dependent and the maximum level was 3.8 fold higher than that in control rats. A similar rise in GRF receptor gene expression was obtained by the depletion of noradrenaline, a neurotransmitter thought to stimulate GRF release, and was reversed by 87% by the repeated administration of synthetic GRF. These results indicate that pituitary GRF receptor gene expression was up- or down-regulated in vivo in the absence or presence of GRF, respectively. PMID- 8702431 TI - Effect of Clostridium difficile toxin B on IgE receptor-mediated signal transduction in rat basophilic leukemia cells: inhibition of phospholipase D activation. AB - Antigen (Ag)-stimulated phospholipase D (PLD) activation and secretion were almost abolished by pretreatment of rat basophilic leukemia (RBL)-2H3 cells for 4 h with 5 ng/ml Clostridium difficile Toxin B which is known to inhibit Rho family proteins (Rho, Cdc42, Rac). The concentration-dependent inhibition of PLD activation was well correlated with the level of glucosylation of Rho family proteins. In streptolysin O-permeabilized RBL cells, Toxin B suppressed [3H] phosphatidylbutanol (PBut) formation in response to guanosine 5'-O-(3 thiotriphosphate) (GTP gamma S) and phorbol 12-myristate 13-acetate (PMA) by 67 and 43%, respectively. The synergistic PLD activation by GTP gamma S and PMA was also reduced by Toxin B by 67%. These results suggest that the IgE receptor coupled PLD activation is largely mediated by Rho proteins. PMID- 8702432 TI - Substitution at codon 269 (glutamine --> proline) of the leptin receptor (OB-R) cDNA is the only mutation found in the Zucker fatty (fa/fa) rat. AB - We recently cloned one of spliced variant forms of rat leptin receptor (OB-R), which contains a short intracellular domain, and found obese-phenotype-linked nucleotide alteration in the extracellular domain of the cDNA from the Zucker (fa/fa) rat, which results in a glutamine269 to proline269 amino acid substitution. Reported herein are the cloning and sequencing of another spliced variant forms of rat OB-R cDNA with a long intracellular domain. Both forms of OB R cDNA share the same extracellular domain. In the Zucker (fa/fa) rat, no changes in either the gene structure nor in the nucleotide sequence of the long intracellular domain were observed. However, the expression level of OB-R mRNA in the brain of Zucker (fa/fa) rat was higher than for lean littermates. These facts suggest that the substitution at codon 269 of the OB-R cDNA represents the crucial mutation which results in the obese phenotype of Zucker (fa/fa) rat. PMID- 8702433 TI - Inhibition of Fas antigen-mediated apoptosis of rheumatoid synovial cells in vitro by transforming growth factor beta 1. AB - OBJECTIVE: To investigate the mitogenic and anti-apoptotic effects of transforming growth factor beta 1 (TGF beta 1) on rheumatoid synovial cells in vitro. METHODS: Synovial cells were cultured with or without TGF beta 1. After incubation, the proliferative response of synovial cells and the expression of Fas antigen and bcl-2 on synovial cells were examined. Finally, Fas antigen mediated apoptosis of synovial cells was investigated by the addition of anti-Fas antibody. RESULTS: TGF beta 1 enhanced the proliferation of synovial cells in a dose-dependent manner. In addition, Fas antigen expression on synovial cells was inhibited by the addition of TGF beta 1 with up-regulation of bcl-2 expression. The addition of anti-Fas antibody induced synovial cell apoptosis. However, stimulation of synovial cells with TGF beta 1 became markedly resistant to Fas antigen-mediated apoptosis. The results were not affected by the addition of a neutralizing antibody to platelet-derived growth factor type AA (PDGF-AA), which suggests that the effect of TGF beta 1 on synovial cells was promoted via PDGF-AA independent mechanisms. CONCLUSION: Our results suggest that TGF beta 1 promotes synovial cell proliferation through its mitogenic effect on synovial cells and interference with the apoptotic process mediated by the Fas antigen, resulting in the perpetuation of the synovial hyperplasia in patients with rheumatoid arthritis. PMID- 8702434 TI - The CD69 activation pathway in rheumatoid arthritis synovial fluid T cells. AB - OBJECTIVE: To study the CD69 activation pathway in synovial fluid (SF) T lymphocytes from patients with rheumatoid arthritis (RA). METHODS: Peripheral blood mononuclear cells (PBMC) or SF mononuclear cells (SFMC) were used in proliferation assays with anti-CD69, anti-CD28, anti-CD3, phorbol myristate acetate (PMA), and/or recombinant interleukin-2 (IL-2). CD69+, CD69-, and resting SF T cells were also proliferated. CD25 expression and production of IL-2 after CD69 activation were assessed by flow cytometry and in a bioassay with the IL-2 dependent cell line CTLL-2. RESULTS: RA SFMC did not proliferate either in the presence of anti-CD69 monoclonal antibodies alone or with concomitant PMA activation, when compared with paired or control PBMC. Similar low proliferative responses via the CD3 or CD28 pathway with PMA were observed. This defective proliferation of RA SFMC after stimulation through the CD69 molecule was explained in part by a failure to express CD25 and to produce IL-2. SF CD69- T cells and resting SF T cells had higher rates of proliferation through the alternative costimulatory pathway CD28 than did SF CD69+ T cells or freshly isolated SF T cells. CONCLUSION: Freshly isolated SF T cells present a profound state of hyporesponsiveness through the CD69 and CD28 costimulatory pathways. This state appears to be dependent on the activation status of SF T cells, since CD69- and resting SF T cells showed recovery of the ability to proliferate through the CD28 activation pathway. PMID- 8702435 TI - Expression and function of CD80 and CD86 costimulator molecules on synovial dendritic cells in chronic arthritis. AB - OBJECTIVE: To examine CD86 expression on dendritic cells isolated from the synovial fluid (SFDC) of patients with chronic arthritis, and to determine the importance of both CD80 and CD86 molecules in SFDC-T lymphocyte interactions. METHODS: CD86 messenger RNA (mRNA) and surface expression were analyzed in SFDC using reverse transcriptase-polymerase chain reaction and flow cytometry, respectively. The costimulator activity of the SFDC CD80 and CD86 molecules was determined by allogeneic mixed lymphocyte reaction (MLR). CD80 and CD86 induction on SFDC during in vitro culture was also examined. RESULTS: Fresh SFDC either lacked or showed very weak surface expression of CD86 molecules (as shown previously for CD80), yet contained CD86 mRNA. CD80 antibodies minimally inhibited an allogeneic MLR, whereas CD86 antibodies and CTLA-4 Ig showed significant inhibition. Both CD80 and CD86 molecules were inconsistently induced on SFDC following culture in either media, interferon-gamma, or granulocyte macrophage colony-stimulating factor. CONCLUSION: SFDC may be defective antigen presenting cells in vivo. The ability of CD80 and CD86 molecules to be induced and become functional on SFDC in vitro implies the presence of a negative regulatory compound(s) in the synovial environment. PMID- 8702436 TI - The effects of the phospholipase A2 inhibitor, manoalide, on cartilage degradation, stromelysin expression, and synovial fluid cell count induced by intraarticular injection of human recombinant interleukin-1 alpha in the rabbit. AB - OBJECTIVE: To evaluate the effects of the phospholipase A2 (PLA2) inhibitor manoalide on cartilage degradation, stromelysin expression, and inflammatory cell accumulation in rabbits treated intraarticularly with recombinant human interleukin-1 alpha (rHuIL-1 alpha). METHODS: Rabbits were given an intraarticular injection of rHuIL-1 alpha. At various time points over a 24-hour period, the rabbits were euthanized and the articular space was lavaged with sterile PBS. The proteoglycan content of the lavage fluid was measured using a dimethylmethylene blue assay. PLA2 activity and differential cell counts were also measured. The femur was removed and cartilage proteoglycan content determined. In some experiments, levels of synovial stromelysin messenger RNA (mRNA) were assessed. Manoalide or vehicle was administered 30 minutes before the rHuIL-1 alpha injection. RESULTS: The rHuIL-1 alpha-induced arthritic response is characterized by significant accumulation of inflammatory cells, loss of proteoglycan from the condylar cartilage, and induction of mRNA for stromelysin. PLA2 activity was also elevated in synovial fluids from rHuIL-1 alpha-injected joints. Pretreatment with manoalide (0.3 mg/joint) significantly inhibited PLA2 activity in the synovial fluid, prevented the loss of proteoglycan from the condylar cartilage, and reduced proteoglycan levels in lavage fluids. However, manoalide either had no effect on, or stimulated, cell accumulation. To assess the relationship between the induction of PLA2 and stromelysin, levels of stromelysin mRNA were measured in synovial tissue from manoalide- and vehicle treated joints. Stromelysin message levels were significantly suppressed in a dose-dependent manner. CONCLUSION: These studies demonstrate that manoalide is a potent inhibitor of inflammation and cartilage catabolism, and suggest that PLA2 is involved in the pathophysiology of rHuIL-1 alpha-induced arthritis in rabbits. PMID- 8702437 TI - Significance of anti-nuclear matrix antibodies in patients with in vivo speckled antinuclear antibody staining. AB - OBJECTIVE: Evidence suggests that patients with in vivo speckled antinuclear antibody (ANA) patterns have high titers of circulating ANA, specifically anti-U1 RNP antibody. A small percentage of patients with high titers of anti-U1 RNP antibody have anti-nuclear matrix antibodies, and some also demonstrate in vivo ANA. This study was designed to screen for the presence of anti-nuclear matrix antibodies in patients with in vivo ANA. METHODS: Anti-nuclear matrix antibodies were detected by indirect immunofluorescence on HCI-extracted HEp-2 cell substrate, by enzyme-linked immunosorbent assay, and by immunoblot analysis. RESULTS: All 10 patients with in vivo ANA were found to have anti-nuclear matrix antibody demonstrated using HCI-extracted HEp-2 cell substrate, and all exhibited antibody activity to a 36-kd protein from nuclear matrix antigen. CONCLUSION: These results suggest that anti-nuclear matrix antibodies are a major factor in the development of in vivo ANA. PMID- 8702438 TI - Novel autoantibodies directed against the common tertiary configuration of transfer RNA in a patient with interstitial lung disease. AB - OBJECTIVE: To identify and characterize a novel autoantibody, anti-WS, that binds total transfer RNA (tRNA). METHODS: Serum from patient WS, who had polyarthritis, Sjogren's syndrome, Raynaud's phenomenon, and interstitial pulmonary fibrosis, was used in this study. Characteristics of anti-WS and antibody-reactive determinants of tRNA were investigated by 32P immunoprecipitation using HeLa cell RNA and deletion mutants of tRNA transcribed in vitro. RESULTS: WS serum produced nucleolar and cytoplasmic staining on indirect immunofluorescence. 32P immunoprecipitation assays demonstrated that this serum immunoprecipitated total tRNAs and 5.8S and 5S ribosomal RNAs from 32P-labeled HeLa cell extract. When deproteinized RNA was used as antigen source, total tRNAs were still precipitated by WS serum. An immunoprecipitation study, using various deletion mutants of Escherichia coli tRNA, demonstrated that both D and T psi C loops were needed for antibody binding. Substitution of nucleotide 18G with 18A of E coli tRNA(Trp), which is essential in the formation of the tertiary "L" shape of tRNA, inhibited binding by anti-WS antibodies. CONCLUSION: Anti-WS antibodies are novel autoantibodies directed against tRNAs. The antibody binding site is the common L shaped tertiary structure conformed by the D loop and T psi C loop of tRNA, suggesting that the antibodies are induced by a conserved sequence among all species. Furthermore, these antibodies could be a marker for a newly recognized subset of connective tissue disease. PMID- 8702439 TI - Detection of autoantibodies to nucleolar transcription factor NOR 90/hUBF in sera of patients with rheumatic diseases, by recombinant autoantigen-based assays. AB - OBJECTIVE: We attempted to clarify the clinical characteristics of Japanese patients with autoantibodies to nucleolar transcription factor NOR 90/hUBF (anti NOR 90) and to analyze the autoantigenic epitopes recognized by anti-NOR 90. METHODS: Ninety-one patient sera containing anti-nucleolar antibodies (ANoA) by indirect immunofluorescence were collected. Immunoblottings were performed using recombinant fusion proteins expressed from several cloned complementary DNA (cDNA) encoding the NOR 90/hUBF autoantigen. RESULTS: Anti-NOR 90 were detected in sera from 9 (9.9%) of 91 patients with ANoA. Seven of these patients were diagnosed as having Sjogren's syndrome, 4 had concomitant rheumatoid arthritis, 1 had concomitant systemic sclerosis (SSc), and 2 had SSc alone. All 9 sera were reactive with more than 2 recombinant fusion proteins from cDNA encoding separate regions on the hUBF polypeptide. CONCLUSION: The results suggest that while anti NOR 90 antibodies are rare, they are associated with Sjogren's syndrome in Japanese patients, and that autoimmunity is targeted toward at least 2 separate regions (amino acids 89-310 and 310-633) of the hUBF polypeptide. PMID- 8702440 TI - Variation in the inflammatory properties of basic calcium phosphate crystals according to crystal type. AB - OBJECTIVE: To determine the inflammatory potential of basic calcium phosphate (BCP) crystals, which have been identified in human joints. METHODS: Hydroxyapatite, carbonate apatite, whitlockite, and octacalcium phosphate crystals were injected in rat air pouches. Volume and cellularity of the exudate were measured. Physicochemical properties of the injected BCP crystals were determined, and correlations with the magnitude of induced inflammatory responses were sought. RESULTS: Significant differences were observed among the volumes and white blood cell (WBC) counts of the pouch exudates, based on the various crystal types used to induce inflammation. A strong correlation was demonstrated between the specific surface (SS) area of the injected crystals and the area under the curve for induced WBC count versus time (R2 = 0.88, P = 0.05). This correlation was observed for SS area values below 50 m2/gm, but when SS area increased further, this parameter plateaued. Another parameter of inflammatory response was obtained by dividing the area under the curve figuring WBC counts versus time by the corresponding SS area for each crystal type. This parameter increased linearly with the Ca:P ratio (R2 = 0.97, P = 0.0003). CONCLUSION: The inflammatory potential of BCP crystals appeared to vary according to crystal features. SS area and the Ca:P ratio (which correlates with crystal solubility) influenced inflammatory properties. These results could explain the variable clinical consequences of BCP deposits, and must be taken into account in the choice of apatite ceramics for use as biomaterials. PMID- 8702441 TI - Degenerative joint disease in the guinea pig. Use of magnetic resonance imaging to monitor progression of bone pathology. AB - OBJECTIVE: The suitability of magnetic resonance imaging (MRI) for serial monitoring of bone pathology in the guinea pig stifle joint, an in vivo model of osteoarthritis, was investigated. METHODS: MR images were compared with histologic features and radiographs of 1-mm-thick sections to determine the MR correlates of the bone changes. Ten guinea pigs were then imaged on 7 occasions over the first year of life, enabling serial measurements of subchondral bone thickness, subchondral pseudocysts, and osteophytes. RESULTS: The signal intensity of trabecular bone in MR images accurately reflected the degree of osteopenia and trabecular thinning noted around the cruciate ligament insertions. The extent of subchondral sclerosis and the development of marginal osteophytes were also accurately represented. Serial observations revealed that MRI can detect highly significant progression of lytic bone lesions, subchondral sclerosis, and osteophyte size over periods of 6 weeks. CONCLUSION: MRI is not only a reliable technique for the assessment of bone pathology but is also a useful tool for monitoring the progression of bone damage in osteoarthritis. PMID- 8702442 TI - Heterogeneity of collagen synthesis in normal and systemic sclerosis skin fibroblasts. Increased proportion of high collagen-producing cells in systemic sclerosis fibroblasts. AB - OBJECTIVE: The goal of this study was to quantitatively analyze the distribution of collagen synthesis in normal and systemic sclerosis (SSc) fibroblast populations in order to determine the extent of activation in SSc populations. METHODS: We used quantitative in situ hybridization to assess the population distribution of type I collagen synthesis. Fibroblast cultures were derived from both clinically involved and uninvolved skin regions of patients with SSc, and from healthy adults, and assessed for levels of alpha 1(I) procollagen messenger RNA (mRNA). RESULTS: Dermal fibroblasts from both patients with SSc and normal adults were heterogeneous for distribution of alpha 1(I) procollagen mRNA when assessed by in situ hybridization, with a wide range of grains per cell. In contrast, clones of neonatal fibroblasts showed a relatively homogeneous distribution of grain counts. Involved SSc skin fibroblasts had a larger proportion of cells in the high collagen-producing mRNA subpopulation (mean +/- SEM 28.4 +/- 6.85%), compared with normal fibroblasts (1.75 +/- 1.44%) and uninvolved fibroblasts (9.6 +/- 6.73%). Conversely, within the low collagen producing mRNA subpopulation, involved fibroblasts had a smaller proportion of cells (mean +/- SEM 14.0 +/- 5.63%) than did uninvolved fibroblasts (37.8 +/- 13.69%), while normal fibroblasts had a majority of the cells in this subpopulation (53.5 +/- 8.68%). CONCLUSION: These results suggest that only a specific subset of fibroblasts are activated in SSc, as evidence by an increased proportion of cells with high levels of alpha 1(I) procollagen mRNA. Differences between the SSc and normal fibroblast populations appeared to be quantitative rather than qualitative. This may be a result of either clonal selection or selective activation in the pathogenesis of SSc. PMID- 8702443 TI - Transcriptional activation of the alpha 1(I) procollagen gene in systemic sclerosis dermal fibroblasts. Role of intronic sequences. AB - OBJECTIVE: To investigate the transcriptional regulation of the alpha 1(I) procollagen gene (COL1A1) in cultured dermal fibroblasts from patients with diffuse systemic sclerosis (SSc) of recent onset and to evaluate the role that intronic sequences may play in the upregulated expression of COL1A1 in SSc dermal fibroblasts. METHODS: Dermal fibroblasts from 6 patients with diffuse SSc of recent onset and from 3 healthy individuals were studied. The steady-state levels of alpha 1(I) procollagen messenger RNA were evaluated by Northern hybridization analysis, and the transcriptional regulation of COL1A1 was examined by transient transfection experiments with deletion constructs containing portions of COL1A1 promoter (with 5' end points at -5.3 kb, -2.3 kb, and -804 bp and 3' end point at +42 bp) ligated to the chloramphenicol acetyltransferase (CAT) reporter gene. To examine the role of intronic sequences, constructs containing, in addition to the COL1A1 promoter, a portion of the first intron (+380 bp to +1,440 bp) cloned in front of the CAT gene were transfected. The efficiency of transfections was normalized relative to the net amount of CAT plasmid actually transfected into recipient cells, determined by a modified Southern hybridization procedure. RESULTS: Maximal CAT activity was observed with constructs extending from -804 bp to +42 bp in both normal and SSc fibroblasts. However, the activity driven by this construct was 80-110% higher in SSc fibroblasts. The CAT activity driven by a construct with a 5' end point at -5.3 kb was only 15-20% higher in SSc cells, and the CAT activity driven by a construct with a 5' end point -2.3 kb was 35-45% higher in SSc fibroblasts. The CAT activity driven by the -804-bp promoter construct was increased up to 4-fold in SSc fibroblasts in comparison with normal cells when the intronic segment spanning +380 bp to +1,440 bp was included in the transfected construct. CONCLUSION: The results directly demonstrate the transcriptional activation of COL1A1 in dermal fibroblasts from SSc patients. The data also indicate that first-intron sequences of COL1A1 are required for maximal transcriptional activity of the collagen gene and may play an important role in the up-regulation of its expression in SSc fibroblasts. PMID- 8702444 TI - The centromere kinesin-like protein, CENP-E. An autoantigen in systemic sclerosis. AB - OBJECTIVE: Autoantibodies directed against centromere proteins (CENPs) are a serologic feature in some patients with systemic sclerosis (SSc). Previous studies have focused on autoantibodies to CENPs A, B, and C. CENP-E is a recently described 312-kd protein that also localizes to the centromere. Therefore, we studied the presence of autoantibodies to recombinant CENP-E in patients with SSc. METHODS: Sixty sera from patients with the SSc spectrum of diseases were screened for the presence of autoantibodies against CENP-E, by indirect immunofluorescence and immunoblotting using recombinant CENP-E protein. HLA class II alleles were determined by DNA oligotyping. RESULTS: Among the SSc sera, 15 of 60 (25%) demonstrated antibody reactivity with recombinant CENP-E, and 14 of these 15 sera (93%) had antibodies directed against another CENP. Anti-CENP-E was seen in 13 of 30 sera with anti-CENP (43%). All patients with anti-CENP-E had a limited form of SSc, known as the CREST variant (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias). When patients with anti-CENPs A, B, or C were compared with patients with anti-CENP-E, no unique clinical features in the anti-CENP-E positive group were identified. Ninety-three percent of the patients with anti-CENP-E had HLA-DQB1 alleles that had polar amino acids at position 26 (primarily DQB1*05), similar to patients with other CENP autoantibodies. CONCLUSION: Antibodies to CENP-E are common in patients with SSc, and are seen in higher frequency in sera from patients with a limited form, or CREST variant, of the disease. PMID- 8702445 TI - Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype. AB - OBJECTIVE: To investigate a high prevalence of systemic sclerosis (SSc; scleroderma) in a well-defined population of 21,255 Choctaw Indians residing in 8 southeastern Oklahoma counties who were "users" of Indian Health Services. METHODS: A case-control study of 12 SSc cases and 48 matched non-SSc controls (4 per case) was conducted to investigate potential occupational, residential, and infectious exposures, as well as genetic factors which might predispose to SSc. HLA class II alleles were determined by DNA oligotyping, and class I and III alleles were defined serologically. RESULTS: The prevalence of SSc in full blooded Choctaws was at least 8/1,704, or 469/100,000 (95% confidence interval [95% CI] 203-930) over the 4-year interval 1990-1994 and was significantly higher than that among non-full-blooded Choctaws (6/19,551, or 31/100,000) (P = 0.00001, odds ratio [OR] = 15.4, 95% CI 4.9-49.8). The overall prevalence of SSc in Oklahoma Choctaws (66/100,000) also was significantly higher than that in other Native Americans in Oklahoma (9.5/100,000) (P = 10(-6), OR = 6.95, 95% CI 3.3 13.7), who showed a prevalence similar to that reported for whites (2.1 25.3/100,000). Among the SSc cases, there was striking homogeneity of disease expression with the majority exhibiting diffuse scleroderma, pulmonary fibrosis, and autoantibodies to topoisomerase I. No environmental exposures were found to be in excess among cases versus controls. The strongest risk factor for SSc in cases (100%) versus controls (54%) was an HLA haplotype bearing the alleles B35, Cw4, DRB1*1602 (DR2), DQA1*0501, and DQB1*0301 (DQ7) (P = 0.002, Pcorr = 0.036, OR = 21, 95% CI 2.9-437). Survey of another group of Choctaws residing in another state revealed no cases of SSc despite a high frequency of the same HLA haplotype. CONCLUSION: Full-blooded Choctaw Native Americans living in southeastern Oklahoma have the highest prevalence of SSc yet found in any population. A major risk factor for disease is a uniquely Amerindian HLA haplotype; however, additional genes and/or an as-yet-unidentified environmental exposure seem likely. PMID- 8702446 TI - Use of a radiolabeled monoclonal antibody against E-selectin for imaging of endothelial activation in rheumatoid arthritis. AB - OBJECTIVE: To determine the potential of 111In-labeled anti-E-selectin monoclonal antibody (MAb) to image localized endothelial activation in rheumatoid arthritis (RA). METHODS: Fourteen patients with RA were studied after intravenous administration of 111In-labeled F(ab')2 fragments of MAb against the cytokine inducible endothelial cell activation antigen E-selectin (MAb 1.2B6). To compare uptake of 1.2B6 with that of nonspecific immunoglobulin, 111In-labeled polyclonal human immunoglobulin (HIG) was separately administered to 6 of these patients and the relative uptake of each tracer was determined. RESULTS: Prominent and discrete uptake of the radiolabeled MAb 1.2B6 was clearly visible in inflamed joints of all patients. Compared with 111In-HIG, 111In-1.2B6 provided superior images in terms of sensitivity and image intensity. Furthermore, the distribution of uptake in inflamed joints was different for the 2 tracers, with 1.2B6 showing a more focal localization in synovium. CONCLUSION: This study demonstrates that it is possible to objectively assess E-selectin expression on activated endothelium in vivo in patients with RA, using a radiolabeled MAb. This technique has considerable potential for monitoring disease activity and response to therapy in inflammatory diseases. PMID- 8702447 TI - Cytokine messenger RNA expression in the labial salivary glands of patients with Sjogren's syndrome. AB - OBJECTIVE: To characterize the initiation and progress of localized autoimmune damage in Sjogren's syndrome (SS), an autoimmune disease that is also considered to be a lymphoaggressive disorder, by examining the pattern of cytokine production at the site of autoimmune damage. METHODS: Using a polymerase chain reaction-based method, cytokine messenger RNA (mRNA) expression in the labial salivary glands of 15 patients with SS was investigated. In addition, the infiltrating lymphocytes in the labial salivary glands were examined immunohistochemically. RESULTS: Messenger RNAs of Th1 cytokines, such as interleukin-2 (IL-2) and interferon-gamma, were consistently detected in all patients, while Th2 cytokine mRNAs, such as IL-4 and IL-5, were detected in some cases, in association with strong B cell accumulation in the labial salivary glands. Other cytokine mRNAs produced by a variety of cell types, including IL 10, IL-6, and transforming growth factor beta (TGF beta), were also consistently detected in all patients, while IL-12 mRNA was detected in some of the patients. CONCLUSION: These results suggest that Th1 cytokines, as well as IL-10, IL-6, and TGF beta, are essential in the induction and/or maintenance of SS, while Th2 cytokines are involved in the progression of the disease process, especially local B cell activation. PMID- 8702448 TI - Juvenile rheumatoid arthritis in Rochester, Minnesota 1960-1993. Is the epidemiology changing? AB - OBJECTIVE: To examine trends in the incidence and prevalence of juvenile rheumatoid arthritis (JRA) in Rochester, Minnesota, over 33 years. METHODS: The diagnostic retrieval system of the Rochester Epidemiology Project was utilized to screen medical records of all Rochester residents with any potential diagnoses of JRA from 1978 to 1993 (based on the American College of Rheumatology 1977 revised criteria). In addition, all cases of JRA from our previously identified cohort from 1960-1979 were verified, and the 2 data sets were combined, resulting in an incidence cohort spanning 33 years (1960-1993). RESULTS: Of the 1,240 medical records screened, we identified 65 cases of JRA diagnosed between 1960 and 1993 (48 females, 17 males). The average followup for cases was 12.7 years (range 0-34 years) for a total of 833 person-years of observation. A bimodal distribution of age at diagnosis was observed, with peaks between 0 and 4 years and 9 and 15 years. Seventy-two percent of patients had pauciarticular-onset, 17% had polyarticular-onset, and 11% had systemic-onset disease. Progression of pauciarticular to polyarticular disease occurred in 11% of the cases. The overall age- and sex-adjusted incidence rate was 11.7 per 100,000 population (95% confidence intervals 8.7, 14.8). The incidence rate per 100,000 population was 15.0, 14.1, and 7.8 for the time periods 1960-1969, 1970-1979, and 1980-1993, respectively (P = 0.024). A 3-year, centered, moving average, which was used to display time trends in incidence, suggested a cyclical pattern, with incidence peaks in 1967, 1975, and 1987. CONCLUSION: An overall decrease in the incidence rate over the last decade was observed, most marked in the pauciarticular- and systemic-onset subtypes. This decrease, along with the observed cyclical pattern, suggest that environmental factors may influence disease frequency. PMID- 8702449 TI - Health outcomes of two telephone interventions for patients with rheumatoid arthritis or osteoarthritis. AB - OBJECTIVE: The effects of treatment counseling or symptom monitoring telephone intervention strategies on the health outcomes of patients with rheumatoid arthritis (RA) or osteoarthritis (OA), compared with usual care, were assessed. METHODS: A 3-group, randomized, controlled 9-month trial was conducted incorporating 405 patients with RA or OA and using the Arthritis Impact Measurement Scales (AIMS2) as the outcome measure. RESULTS: Analyses of covariance showed that the AIMS2 total health status of the treatment counseling group (effect size = 33, P < 0.01), but not the symptom monitoring group (effect size = 0.21, P = 0.10), was significantly improved, compared with usual care, for both RA and OA patients. The specific types of benefits differed significantly between RA and OA patients. The mean number of medical visits by OA patients in the treatment counseling group was also significantly reduced (P < 0.01). CONCLUSION: Telephone contact using the treatment counseling strategy produced significant, but different, health status benefits for RA and OA patients. The symptom monitoring strategy produced modest benefits. PMID- 8702450 TI - Which is the active moiety of sulfasalazine in ankylosing spondylitis? A randomized, controlled study. AB - OBJECTIVE: To compare the efficacy of sulfasalazine (SSZ) with its two moieties, 5-aminosalicylic acid (ASA) and sulfapyridine (SP), in patients with active ankylosing spondylitis (AS). METHODS: A 26-week randomized, observer-blinded, 2 center, controlled study of treatment with either SSZ, ASA, or SP was conducted in 90 patients with active AS. Patients were evaluated at baseline and at monthly intervals, using several clinical and laboratory measures of disease activity. A global assessment of treatment efficacy was made by both patients and observers at the end of the study period. RESULTS: There were no significant changes in any of the parameters of disease activity in the ASA treatment group. Levels of serum IgG, IgA, and IgM fell significantly during treatment with SP, but none of the other changes reached statistical significance. Plasma viscosity and IgG and IgA levels fell significantly during treatment with SSZ, as did nocturnal spinal pain and overall spinal pain. Patients and observers reported a favorable outcome after treatment with SSZ or SP significantly more often than with ASA treatment. CONCLUSION: SP appears to be the active moiety in AS, although there was a trend suggesting a better outcome in the SSZ group compared with the SP group, perhaps suggesting the importance of a common sulfonamide structure for efficacy. PMID- 8702451 TI - Computed tomography of the knee joint as an indicator of intraarticular tophi in gout. AB - OBJECTIVE: To evaluate the utility of computed tomography (CT) of the knee joint for detecting intraarticular tophaceous deposits. METHODS: A prospective study of 16 patients with gout affecting the knee was conducted. A condition for inclusion in the study was the presence of needle-shaped crystals with negative birefringence in the knee joint synovial fluid. Conventional radiography and CT were performed in each case. RESULTS: Intraarticular opacities in the capsule and the synovium, consistent with the presence of tophaceous deposits, were found in 5 of the 16 patients (9 knee joints). The mean duration of gout was longer in the patients with intraarticular tophi than in those without tophi, and 2 of the patients with tophi had poor tolerance to antihyperuricemic therapy. CONCLUSION: Intraarticular opacities considered to represent tophi were observed in approximately one-third of the patients. The presence of tophi correlated with a longer duration of the disease and a poor tolerance to medication. We therefore suggest that CT of the knees could be useful in the assessment and followup of certain patients with gout. PMID- 8702452 TI - Human T lymphotropic virus type I in arthropathy and autoimmune disorders. AB - The progressive nature of the disease and the persistent inflammation affecting various organs are common features of idiopathic autoimmune disorders of unknown etiology. Therefore, the HTLV-I-associated disorders described in the present review are outstandingly important models for our understanding of the pathologic mechanisms of organ-specific immune disorders. HTLV-I arthropathy is characterized by chronic inflammatory and proliferative synovitis with lymphoid follicles and pannus formation in the affected joints, indistinguishable from the findings in idiopathic RA. The presence of the tax gene in HTLV-I-negative SS patients suggests that it is responsible for the exocrine gland abnormality, characterized by extensive lymphoproliferative epithelial lesions. Furthermore, the pulmonary lesions of HTLV-I bronchopneumonopathy are similar to those of idiopathic interstitial pneumonitis. Based on these observations, the clinical findings associated with the immunologic abnormalities in HTLV-I-infected patients provide us with valuable information for understanding the pathogenetic mechanisms of chronic inflammatory conditions associated with immune regulatory disorders. Although the clinical and pathologic features of the 2 common HTLV-I associated disorders, ATL and HAM/TSP, have been well characterized and are clearly distinguishable from those of the idiopathic forms of these disorders, other HTLV-I-related autoimmune diseases, e.g., arthropathy, SS, or bronchopneumonopathy, are clinically indistinguishable from the idiopathic forms of the diseases. Such similarity may serve as a clue to the pathogenetic mechanisms of idiopathic autoimmune disorders. PMID- 8702453 TI - A young woman with a photosensitive pruritic rash on her face and upper trunk. PMID- 8702454 TI - All-trans-retinoic acid in POEMS syndrome. Therapeutic effect associated with decreased circulating levels of proinflammatory cytokines. AB - Chronically elevated serum levels of proinflammatory cytokines is a feature of the syndrome known as POEMS (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal [M] protein, skin changes). A patient had a POEMS syndrome with thrombocytosis and biclonal gammopathy and was treated as follows: all-trans-retinoic acid (tretinoin) at 90 mg/day for 50 days, no treatment for 70 days, readministration of tretinoin at 75 mg/day for 180 days. Focal bone lesion irradiation was performed from day 26 to day 50. Serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF alpha), and IL-1 beta normalized within 7 days after the first administration of tretinoin, transiently increased at the time of radiotherapy, increased again after withdrawal of the tretinoin, and decreased again after its reintroduction. The platelet count and gammopathy paralleled the changes in the cytokine levels. This study documents in vivo the ability of all-trans-retinoic acid to down-regulate the release of IL-6, IL-1 beta, and TNF alpha, and illustrates its potential as a therapeutic agent in conditions associated with chronic overproduction of proinflammatory cytokines. PMID- 8702455 TI - Development of complete heart block in an adult patient with Sjogren's syndrome and anti-Ro/SS-A autoantibodies. AB - We describe the occurrence of complete heart block in a patient with Sjogren's syndrome. The patient's serum contained antibodies to both the 60-kd and 52-kd Ro proteins. This case indicates that although the adult atrioventricular node may be relatively resistant to the development of anti-Ro-associated heart block, it can nevertheless be affected. PMID- 8702456 TI - Modulation of human chondrocyte integrins by inflammatory synovial fluid. PMID- 8702457 TI - Monocyte apoptosis in patients with active lupus. PMID- 8702458 TI - Joint and connective tissue ultrasonography in the evaluation of shoulder pain: comment on the article by Manger and Kalden. PMID- 8702459 TI - Toxicity of combination therapies in rheumatoid arthritis: comment on the article by Willkens et al. PMID- 8702460 TI - Results of controlled study of combination therapy with azathioprine and methotrexate in the treatment of rheumatoid arthritis revisited: comment on the article by Willkens et al. PMID- 8702461 TI - The relationship between rheumatoid arthritis and the acquired immunodeficiency syndrome: comment on the article by Ornstein et al. PMID- 8702462 TI - Watermelon stomach and systemic sclerosis: localization of digestive system involvement? PMID- 8702464 TI - Non-equivalent roles for the first and second zinc fingers of protein kinase Cdelta. Effect of their mutation on phorbol ester-induced translocation in NIH 3T3 cells. AB - Classical and novel protein kinase C (PKC) isozymes contain two, so-called cysteine-rich zinc finger domains that represent the binding sites for phorbol esters and the diacylglycerols. X-ray crystallographic, mutational, and modeling studies are providing detailed understanding of the interactions between the phorbol esters and individual PKC zinc fingers. In the present study, we explore the roles of the individual zinc fingers in the context of the intact enzyme. Our approach was to mutate either the first, the second, or both zinc fingers of PKCdelta, to express the mutated enzyme in NIH 3T3 cells, and to monitor the effect of the mutations on the dose-response curve for translocation induced by phorbol 12-myristate 13-acetate. The introduced mutations change into glycine the consensus proline in the phorbol ester binding loop of the zinc finger; in the isolated zinc finger, this mutation causes a 125-fold decrease in phorbol ester binding affinity. We observed that mutation in the first zinc finger caused almost no shift in the dose-response curve for translocation; mutation in the second zinc finger caused a 21-fold shift, whereas mutation in both zinc fingers caused a 138-fold shift. We conclude that the zinc fingers in the intact PKC are not equivalent and that the second zinc finger plays the predominant role in translocation of protein kinase Cdelta in response to phorbol 12-myristate 13 acetate. Our findings have important implications for the understanding and design of PKC inhibitors targeted to the zinc finger domains. PMID- 8702465 TI - Dynamin and beta-arrestin reveal distinct mechanisms for G protein-coupled receptor internalization. AB - The process of agonist-promoted internalization (sequestration) of G protein coupled receptors (GPCRs) is intimately linked to the regulation of GPCR responsiveness. Following agonist-mediated desensitization, sequestration of GPCR is presumably associated with the dephosphorylation and recycling of functional receptors. However, the exact mechanisms responsible for GPCR sequestration, even for the prototypic beta2-adrenergic receptor (beta2AR), have remained controversial. We demonstrate here that dynamin, a GTPase that regulates the formation and internalization of clathrin-coated vesicles, is essential for the agonist-promoted sequestration of the beta2AR, suggesting that the beta2AR internalizes via the clathrin-coated vesicle-mediated endocytic pathway. In contrast, internalization of the angiotensin II type 1A receptor (AT1AR), another typical GPCR, does not require dynamin. In addition, the AT1AR internalizes independent of the function of beta-arrestin, a critical component for beta2AR cellular trafficking, but additional AT1ARs are mobilized to the dynamin dependent pathway upon overexpression of beta-arrestin. These findings demonstrate that GPCRs can utilize distinct endocytic pathways, distinguishable by dynamin and beta-arrestin, and that beta-arrestins function as adaptor proteins specifically targeting GPCRs for dynamin-dependent endocytosis via clathrin-coated vesicles. PMID- 8702466 TI - Protein-tyrosine kinase activation is required for lipopolysaccharide induction of interleukin 1beta and NFkappaB activation, but not NFkappaB nuclear translocation. AB - In human monocytes, interleukin 1beta protein production and steady state mRNA levels are increased in response to lipopolysaccharide, predominantly as a result of increased transcription of the interleukin 1beta gene. Expression of interleukin 1beta and other cytokines, such as interleukin 6 and tumor necrosis factor alpha, has been shown to be dependent on the activation of the transcription factor, NFkappaB. Since recent studies have shown that lipopolysaccharide-induced tyrosine kinase activation is not required for NFkappaB nuclear translocation, we sought to determine whether NFkappaB translocated in the absence of tyrosine kinase activity was active in stimulating transcription. We have found that, in the human pro-monocytic cell line, THP-1, the lipopolysaccharide-induced expression of interleukin 1beta is dependent on tyrosine kinase activation. Tyrosine kinases are not required for lipopolysaccharide-mediated nuclear translocation of NFkappaB. However, in the absence of tyrosine kinase activity, the ability of NFkappaB to stimulate transcription is impaired. This inhibition of transcription is specific for NFkappaB; in the absence of tyrosine kinase activity, AP-1-dependent transcription is enhanced. These results suggest that, while lipopolysaccharide induced expression of inflammatory mediators requires tyrosine kinase activity, tyrosine kinase activity is not obligatory for lipopolysaccharide signal transduction. PMID- 8702467 TI - Synthesis and cleavage- secretion of enzymatically active rabbit angiotensin converting enzyme in Pichia pastoris. AB - Many biologically important ectoproteins that are anchored in the plasma membrane via a hydrophobic domain undergo a proteolytic cleavage process, which releases the ectodomain to the extracellular milieu in a regulated fashion. Angiotensin converting enzyme (ACE) is one such protein that is secreted from human and mouse cells by its cleavage at one of two alternative sites in the ectodomain. Here, we report similar cleavage-secretion of ACE in the yeast Pichia pastoris. The cleavage site used in yeasts was identical to one of the two sites used in mouse cells. Moreover, as in mammalian cells, ACE secretion in yeast was inhibited by compound 3, a potent inhibitor of the metzincin family of metalloproteases. ACE proteins cleavage-secreted from yeast and from mammalian cells had identical enzymatic properties. These results demonstrate the existence of a secretase activity in yeast whose properties closely resemble those of the mammalian ACE secretase. PMID- 8702468 TI - RAD26, the yeast homolog of human Cockayne's syndrome group B gene, encodes a DNA dependent ATPase. AB - Cells from Cockayne's syndrome (CS) patients are sensitive to ultraviolet light and defective in preferential repair of the transcribed DNA strand. CS patients suffer from complex clinical symptoms, including severe growth retardation, neurological degeneration, mental retardation, and cachexia. Two CS complementation groups, CSA and CSB, have been identified so far. RAD26 encodes the yeast counterpart of the CSB gene. Here, we purify Rad26 protein to near homogeneity from yeast cells and show that it is a DNA-dependent ATPase. In contrast to the Mfd protein that functions in transcription-coupled repair in Escherichia coli, and which is a weak and DNA independent ATPase, Rad26 is a much more active ATPase, with a strict dependence on DNA. The possible role of Rad26 ATPase in the displacement of stalled RNA polymerase II from the site of the DNA lesion and in the subsequent recruitment of a DNA repair component is discussed. PMID- 8702469 TI - ORE, a eukaryotic minimal essential osmotic response element. The aldose reductase gene in hyperosmotic stress. AB - Organisms, almost universally, adapt to hyperosmotic stress through increased accumulation of organic osmolytes but the molecular mechanisms have only begun to be addressed. Among mammalian tissues, renal medullary cells are uniquely exposed to extreme hyperosmotic stress. Sorbitol, synthesized through aldose reductase, is a predominant osmolyte induced under hyperosmotic conditions in renal cells. Using a rabbit renal cell line, we originally demonstrated that hyperosmotic stress induces transcription of the aldose reductase gene. Recently, we cloned the rabbit aldose reductase gene, characterized its structure, and found the first evidence of an osmotic response region in a eukaryotic gene. Now, we have progressively subdivided this 3221-base pair (bp) region into discrete fragments in reporter gene constructs. Thereby, we have functionally defined the smallest sequence able to confer hyperosmotic response on a downstream gene independent of other putative cis-elements, that is, a minimal essential osmotic response element (ORE). The sequence of the ORE is CGGAAAATCAC(C) (bp -1105/-1094). A 17 bp fragment (-1108/-1092) containing the ORE used as a probe in electrophoretic mobility shift assays suggests hyperosmotic induction of a slowly migrating band. Isolation of trans-acting factor(s) and characterization of their interaction with the ORE should elucidate the basic mechanisms for regulation of gene expression by hyperosmotic stress. PMID- 8702470 TI - Tyrosine phosphorylation modulates the activity of clostridial neurotoxins. AB - Clostridial neurotoxins' metalloprotease domain selectively cleaves proteins implicated in the process of synaptic vesicle fusion with the plasma membrane and, accordingly, blocks neurotransmitter release into the synaptic cleft. Here we investigate the potential modulation of these neurotoxins by intracellular cascades triggered by environmental signals, which in turn may alter its activity on target substrates. We report that the nonreceptor tyrosine kinase Src phosphorylates botulinum neurotoxins A, B, and E and tetanus neurotoxin. Protein tyrosine phosphorylation of serotypes A and E dramatically increases both their catalytic activity and thermal stability, while dephosphorylation reverses the effect. This suggests that the biologically significant form of the neurotoxins inside neurons is phosphorylated. Indeed, in PC12 cells in which tyrosine kinases such as Src and PYK2 are highly abundant, stimulation by membrane depolarization in presence of extracellular calcium induces rapid and selective tyrosine phosphorylation of internalized light chain, the metalloprotease domain, of botulinum toxin A. These findings provide a conceptual framework to connect intracellular signaling pathways involving tyrosine kinases, G-proteins, phosphoinositides, and calcium with the action of botulinum neurotoxins in abrogating vesicle fusion and neurosecretion. PMID- 8702471 TI - Reengineering the nucleotide cofactor specificity of the RecA protein by mutation of aspartic acid 100. AB - We have recently obtained evidence for a direct linkage between the S0.5 (S0.5 is the substrate concentration required for half-maximal velocity) value of a nucleoside triphosphate and the conformational state of the RecA-ssDNA complex, with an S0.5 value of 125 microM or less required for stabilization of the strand exchange-active conformation. For example, although ATP and ITP are hydrolyzed by the RecA protein with the same turnover number (18 min-1), ATP (S0.5 = 45 microM) functions as a cofactor for the strand exchange reaction, whereas ITP (S0.5 = 500 microM) is inactive as a strand exchange cofactor. The RecA protein crystal structure suggests that cofactor specificity is determined by Asp100, which likely forms a hydrogen bond with the exocyclic 6-amino group of ATP; the higher S0. 5 value for ITP is presumably due to unfavorable interactions between Asp100 and the 6-carbonyl group of the inosine ring. To test this hypothesis, we prepared a mutant RecA protein in which Asp100 was replaced by an asparagine residue. The S0.5(ITP) for the [D100N]RecA protein is 125 microM, indicating favorable interactions between the Asn100 side chain and the 6-carbonyl group of ITP. Correspondingly, ITP functions as a cofactor for the strand exchange activity of the [D100N]RecA protein. This result demonstrates the importance of the residue at position 100 in determining nucleotide cofactor specificity and underscores the importance of the S0.5 value in the RecA protein-promoted strand exchange reaction. PMID- 8702472 TI - Tetrodotoxin reverses brevetoxin allosteric inhibition of scorpion alpha-toxin binding on rat brain sodium channels. AB - Voltage-sensitive sodium channels are responsible for the initiation of action potentials in many excitable cells. Several neurotoxins bind to distinct receptor sites on sodium channels and reveal strong allosteric interactions among them. Scorpion alpha toxins, which inhibit sodium channel inactivation by binding to receptor site 3, have been very important tools to study sodium channel structure and function. Recently, we have shown that brevetoxin induce a strong negative allosteric modulation on scorpion alpha-toxin binding on rat brain sodium channels, in contrast to previously published studies. In this report we have examined the reasons for this discrepancy and found new, unexpected allosteric interactions between the tetrodotoxin and brevetoxin receptor sites, using scorpion alpha-toxin as sensitive probe for subtle conformational changes on sodium channels. Tetrodotoxin reverses the negative modulation induced by brevetoxin on scorpion alpha-toxin binding, revealing new dynamic interactions in sodium channel structure. PMID- 8702473 TI - Constitutively active adenylyl cyclase mutant requires neither G proteins nor cytosolic regulators. AB - Receptor-mediated G protein-linked adenylyl cyclase systems are universal signal transducers. We exploited the essential role of this cascade in Dictyostelium development to screen for random mutations in the catalytic component, ACA. This enzyme is activated by G protein betagamma-subunits acting in concert with a novel cytosolic regulator, CRAC. By suppression of the CRAC-null phenotype, we isolated constitutively active versions of the enzyme that require neither exogenous stimuli nor internal regulators. One mutant displayed a 15-fold increase in its Vmax. It harbors a single amino acid substitution (L394S) affecting a conserved residue located in the first cytoplasmic loop near the N terminal hydrophobic domain of ACA. The screening procedure can be adapted for isolation of constitutive mutations in mammalian adenylyl cyclases. PMID- 8702474 TI - Abrogation of p27Kip1 by cDNA antisense suppresses quiescence (G0 state) in fibroblasts. AB - Progression of eukaryotic cells through the cell cycle is governed by the sequential formation, activation, and subsequent inactivation of a series of cyclin-dependent kinase (Cdk) complexes. p27(Kip1) (p27) is a Cdk inhibitor that blocks, in vitro, the activity of cyclin D-Cdk4, cyclin D-Cdk6, cyclin E-Cdk2 as well as cyclin A-Cdk2, a complex active during S phase. The level of p27 protein expression, usually high in G0/G1 resting cells, declines as cells progress toward S phase and enforced expression of p27 in fibroblasts causes G1 arrest. This situation prevails in CCL39, a Chinese hamster lung fibroblast cell line (this report). However, in addition to p27, several other Cdk inhibitors known to alter G1 progression coexist in most mammalian cells. To investigate the specific contribution of p27 in the control of the mitogen-sensitive G0/G1 arrest, we specifically reduced its synthesis by expressing a full-length p27 antisense cDNA in CCL39 cells. Interestingly, reduction of up to 90% of p27 protein expression increased both basal and serum-stimulated gene transcription of cyclin D1, cyclin A, dihydrofolate reductase, and DNA synthesis reinitiation. Moreover, overexpression of this antisense allows cells to grow for several generations in a serum-free medium supplemented with insulin and transferrin only, thus suggesting that p27-depleted cells cannot exit the cell cycle. These effects were fully reversed by coexpression of a plasmid encoding p27 sense. We conclude that p27, by setting the level of growth factor requirement, plays a pivotal role in controlling cell cycle exit, a fundamental step in growth control. PMID- 8702475 TI - Activation of phospholipase C-gamma by the concerted action of tau proteins and arachidonic acid. AB - Phospholipase C-gamma (PLC-gamma) isozymes are thought to be activated by receptor-induced tyrosine phosphorylation. Proteins that activate PLC-gamma1 have now been purified from bovine brain and identified as members of the tau family of microtubule-associated proteins. Activation of PLC-gamma by tau was enhanced in the presence of unsaturated fatty acids such as arachidonic acid, saturated fatty acids being ineffective. Maximal (15-20-fold) activation was apparent in the presence of 0.15 microM tau and 25 microM arachidonic acid (AA). The effect of tau and AA was specific to PLC-gamma isozymes in the presence of submicromolar concentrations of Ca2+ and was markedly inhibited by phosphatidylcholine. These results suggest that in cells that express tau, receptors coupled to cytosolic phospholipase A2 may activate PLC-gamma isozymes indirectly in the absence of tyrosine phosphorylation through the hydrolysis of phosphatidylcholine to generate AA. PMID- 8702476 TI - Formation of STAT5-containing DNA binding complexes in response to colony stimulating factor-1 and platelet-derived growth factor. AB - Colony-stimulating factor (CSF-1) activates several members belonging to the STAT (signal transducers and activators of transcription) family of transcription factors. We investigated the DNA binding complexes activated by CSF-1 in several cell lines and compared them with complexes activated by platelet-derived growth factor and interleukin 3. Our results indicate that the SIF-A complex activated by CSF-1 and platelet-derived growth factor may contain STAT3/STAT5 heterodimers binding to the high affinity SIF binding site, m67. In addition, both growth factors activate one or several STAT5-containing protein complexes binding to the prolactin-inducible element, PIE. The formation of these complexes was cell type and growth factor specific. Interleukin 3 activated only PIE binding complexes containing STAT5A and STAT5B and did not activate m67 binding complexes. It appears, therefore, that STAT5 cannot bind to m67 as a homodimer, but it can bind if it is dimerized with STAT3, whereas it can bind to the PIE element without being either complexed with STAT3 or any other known STAT protein, possibly as a homodimer or as STAT5A/STAT5B heterodimer. However, in addition, STAT5 may heterodimerize with other proteins and form novel PIE binding complexes. PMID- 8702477 TI - Identification of the major autophosphorylation sites of Nyk/Mer, an NCAM-related receptor tyrosine kinase. AB - Nyk/Mer receptor tyrosine kinase is a new member of the Ufo/Axl tyrosine kinase family and is characterized by its neural cell adhesion molecule-like extracellular domain. By using a vaccinia virus expression system to express a constitutively activated form of Nyk, we identified the major sites of Nyk autophosphorylation in tryptic peptide IY749SGDY753Y754R. Tyr-749, Tyr-753, and Tyr-754 in this peptide lie in the activation loop of the kinase domain. We also studied a series of Nyk mutants in which the three tyrosine residues were replaced individually, in pairs, or all together by phenylalanine. Single mutations of Tyr-749 or Tyr-753 to phenylalanine reduced Nyk kinase activity toward exogenous substrate to 39 or 10% of that of the wild type Nyk, respectively, whereas the Tyr-754 mutant is completely inactive. All of the double and triple Tyr-Phe mutants reduced Nyk kinase activity to a level below the background. Similar results were obtained when Nyk autophosphorylation levels were examined. Our studies suggest that full activity of Nyk/Mer kinase requires phosphorylation of all three tyrosine residues in the kinase domain (Tyr-749, Tyr 753, and Tyr-754) and that Nyk kinase activity is modulated by the level of autophosphorylation in the kinase domain. Given the highly conserved nature of this region among the Ufo/Axl receptor family members, the information presented in this report may provide insight to the biochemical properties of other members of this family. PMID- 8702479 TI - Mutational and DNA binding specificity of the carcinogen 2-amino-3, 8 dimethylimidazo[4,5-f]quinoxaline. AB - The mutagenic specificity of 2-amino-3,8-dimethylimidazo[4, 5-f]quinoxaline (MeIQx), a food-borne mutagen and carcinogen, was studied. Plasmid pK19 was modified by photolysis with the 2-azido form of the carcinogen. High pressure liquid chromatography confirmed that the photoactivated azide formed primarily C8 and N2 guanyl adducts. Transformation of modified pK19 into excision repair competent Escherichia coli resulted in dose-dependent increases in genotoxicity and in mutagenesis within the lacZalpha target sequence. Upon induction of the SOS response, a 20-fold increase in mutation frequency over background was observed. A mutational spectrum for MeIQx, generated by sequencing 125 independent mutants, revealed base substitutions (41%), frameshifts (54%), and complex mutations (5.6%); >90% of the mutations occurred at G-C base pairs. Two hotspots were evident at runs of three or five G-C base pairs; approximately 60% of the mutations occurred at the hotspot sites. The hotspot at position 2532 produced mainly base substitutions, while that at position 2576 gave exclusively frameshift mutations. A polymerase inhibition assay mapped the sites of MeIQx adducts. Arrest sites were primarily at or one base 3' to a guanine residue, which correlated well with the distribution of mutations. No direct correlation was seen, however, between intensity of modification and hotspots for mutation. PMID- 8702478 TI - Molecular cloning of a novel P2 purinoceptor from human erythroleukemia cells. AB - Screening of a human erythroleukemia cell cDNA library with radiolabeled chicken P2Y3 cDNA at low stringency revealed a cDNA clone encoding a novel G protein coupled receptor with homology to P2 purinoceptors. This receptor, designated P2Y7, has 352 amino acids and shares 23-30% amino acid identity with the P2Y1 P2Y6 purinoceptors. The P2Y7 cDNA was transiently expressed in COS-7 cells: binding studies thereon showed a very high affinity for ATP (37 +/- 6 nM), much less for UTP and ADP (approximately 1300 nM), and a novel rank order of affinities in the binding series studied of 8 nucleotides and suramin. The P2Y7 receptor sequence appears to denote a different subfamily from that of all the other known P2Y purinoceptors, with only a few of their characteristic sequence motifs shared. The P2Y7 receptor mRNA is abundantly present in the human heart and the skeletal muscle, moderately in the brain and liver, but not in the other tissues tested. The P2Y7 receptor mRNA was also abundantly present in the rat heart and cultured neonatal rat cardiomyocytes. The P2Y7 receptor is functionally coupled to phospholipase C in COS-7 cells transiently expressing this receptor. The P2Y7 gene was shown to be localized to human chromosome 14. We have thus cloned a unique member of the P2Y purinoceptor family which probably plays a role in the regulation of cardiac muscle contraction. PMID- 8702480 TI - Hydrophobic core but not amino-terminal charged residues are required for translocation of an integral thylakoid membrane protein in vivo. AB - The integral membrane protein cytochrome f contains an amino-terminal signal sequence that is required for translocation into the thylakoid membrane. The signal sequence contains a hydrophobic core neighbored by an amino-terminal charged residue. Mutations that introduce charged amino acids into the hydrophobic core are inhibitory to cytochrome f translocation, and thus render cells non-photosynthetic. We have isolated both nuclear and chloroplast suppressors of these mutations by selecting for restoration of photosynthetic growth of Chlamydomonas. Here we describe the characterization of two chloroplast, second site suppressor mutations. Both suppressors remove the positively charged amino acid that borders the amino terminus of the hydrophobic core, and replace this arginine with either a cysteine or a leucine. The existence of these suppressors suggests that the hydrophobic core can be shifted in position within the signal sequence, and analysis of triple mutants in the signal confirms this hypothesis. Thus this signal that mediates translocation into the thylakoid membrane is characterized by a hydrophobic region whose exact amino acid content is not critical, and that need not be flanked on its amino terminus by a charged residue. PMID- 8702481 TI - Definition of a nucleotide binding site on cytochrome c by photoaffinity labeling. AB - We have used TNP-8N3-AMP (2'(3')-O-(2,4,6-trinitrophenyl)-8-azidoadenosine monophosphate) and TNP-8N3-ATP to probe the ATP binding site(s) of cytochrome c. Irradiation of cytochrome c with close to stoichiometric amounts of TNP-8N3-AMP at low ionic strength derivatized approximately half of the protein, with the mono-derivatized species being associated with four peaks (B, 6%; C, 17%; D, 24%; E, 4%) eluted from a cation exchange column. Irradiation in the presence of ATP suggested that the main peaks C and D resulted from more specific nucleotide binding. Thermolysin digestion and TNP-peptide purification and sequencing revealed that peak C was associated with derivatization of mainly Lys-86 and to a lesser extent Lys-72 and peak D with mainly Lys-87 and less so with Lys-72. Minor peaks B and E could not be identified. TNP-8N3-ATP photolabeling produced similar results, showing favored interaction of the adenyl ring with Lys-86 and Lys-87 and to a lesser extent with Lys-72. The results are compatible with previous findings that suggest that the principal locus of ATP binding is at nearby Arg-91 (Corthesy, B. E., and Wallace, C. J. A.(1986) Biochem. J. 236, 359-364). Molecular modeling with energy-minimized docking of ATP between the 60s helix and the 80s stretch with the gamma-phosphate constrained to interact with Arg-91, places the 8 position close to Lys-86 and Lys-87 in the anti conformation about the glycosidic bond and to Lys-72 in the syn conformation, and the ribose hydroxyls within H-bonding distance of Glu-69. PMID- 8702482 TI - A soluble secretory reporter system in Trypanosoma brucei. Studies on endoplasmic reticulum targeting. AB - A homolog of the endoplasmic reticulum (ER) hsp70 protein, binding protein (BiP), from the parasitic protozoan Trypanosoma brucei (Bangs, J. D., Uyetake, L., Brickman, M. J., Balber, A. E., and Boothroyd, J. C.(1993) J. Cell Sci. 105, 1101 1113) is further characterized. In co-precipitation experiments, BiP transiently associates with newly synthesized secretory proteins, including variant surface glycoprotein (VSG), confirming its role as a molecular chaperone. To study the molecular signals targeting BiP to the ER, we have developed soluble secretory reporters for expression in transformed procyclic trypanosomes. Deletion of the BiP C-terminal tetrapeptide (MDDL) and the glycosylphosphatidylinositol-anchor addition sequence of VSG converts these proteins to secreted forms. Attachment of MDDL to VSG results in intracellular retention confirming that MDDL is a trypanosomal ER localization signal. Secretion of both reporters is inefficient, but further truncation of the BiP C-terminal peptide-binding domain allows quantitative export ( t1/2 approximately 1 h) of the N-terminal ATPase domain (BiPN), consistent with the conserved domain structure of hsp70 proteins. This is the first demonstration of soluble protein secretion in African trypanosomes. Using the BiPN reporter, the sequence specificity of C-terminal tetrapeptide retention signals in trypanosomes is analyzed and found to be similar to higher eukaryotes. These results indicate that the basic signals mediating protein targeting to the ER lumen are conserved throughout the wide range of eukaryotic evolution. PMID- 8702483 TI - Receptor up-regulation, internalization, and interconverting receptor states. Critical components of a quantitative description of N-formyl peptide-receptor dynamics in the neutrophil. AB - High resolution kinetic data of the binding of fluorescent peptide to the N formyl peptide receptor of neutrophils at 37 degrees C has allowed for the development of a ligand binding model that predicts statistically larger binding rate constants than those previously reported for intact neutrophils. The new model accounts for ligand association and dissociation, receptor up-regulation, ligand-receptor complex internalization, a change in receptor affinity, and the quenching of internalized fluorescent ligand. We determined that receptor up regulation is both agonist- and temperature-induced and is inhibited by both phenylarsine oxide and pertussis toxin treatment. Model fits of ligand association to pertussis toxin-treated cells show that while receptor up regulation was inhibited, rate constants for ligand binding, receptor affinity conversion, and internalization of ligand-receptor complexes were unaffected. Results suggest Gi-protein-mediated receptor up-regulation and Gi-protein independent receptor affinity conversion. Simulation of ligand infusion using our model gives insight into the quantitative and dynamic relationship between the low affinity ligand-receptor complex and the actin polymerization response. PMID- 8702484 TI - A negative cofactor containing Dr1/p19 modulates transcription with TFIIA in a promoter-specific fashion. AB - An activity that modulated the relative levels of transcription from the adenovirus major late promoter (MLP), and the immunoglobulin heavy chain mu promoter (mu) was purified as a 90-kDa factor. This factor is suggested to be a heterotetramer of two subunits: a 20-kDa polypeptide identical to the previously described Dr1/p19 and a novel 30-kDa polypeptide. The Dr1/p19 protein has been characterized as a repressor of transcription, and the 30-kDa protein is related to a recently identified yeast gene proposed to encode a repressor of transcription. The 90-kDa factor forms a complex with TATA-binding protein on DNA and at high concentrations of both factors protects over a 150-base pair region around the promoter from DNase I cleavage. The conformation of this complex as assayed by footprinting analysis is altered by the transcription factor TFIIA on the MLP but not on the mu promoter. Similarly, TFIIA reverses the repression of transcription by the 90-kDa factor on the MLP but not on the mu promoter. Thus, the interactions of TATA-binding protein, TFIIA, and the 90-kDa factor are promoter-specific. PMID- 8702485 TI - Isolation and characterization of a gene affecting fatty acid elongation in Saccharomyces cerevisiae. AB - Fatty acid elongation defective mutants were isolated from Saccharomyces cerevisiae by mutagenizing strains that were defective in fatty acid synthase (FAS) activity. Cells of the fatty acid synthase-defective strains can grow when supplemented with tetradecanoic acid (14:0) due to the presence of membrane bound elongation systems that can extend the 14 carbon fatty acid to longer chain species. After mutagenesis and rescue on medium containing a mixture of 14:0, 16:0 and 18:0, cells were screened for their inability to grow on medium containing only 14:0. From 150,000 colonies, four stable isolates were identified, all of which appear to represent the same complementation group. Gas chromatography of lipid extracts from mutant elo1-1 (designated as elongation defective) cells grown with long or medium chain fatty acids indicates that it fails to efficiently elongate (12, 13, or 14) carbon fatty acids. A gene disrupted fas2Delta::LEU2;elo1Delta::HIS3 mutant incorporates 14-18-carbon fatty acids into membrane lipids, indicating that fatty acid transport is not affected by the mutation. Molecular cloning and sequence analysis of the ELO1 gene suggests that the encoded protein is a membrane bound polypeptide that contains at least five potential membrane spanning regions and a presumptive NADPH binding site. Analysis of the ELO1 mRNA levels indicates that the gene is expressed in cells grown on fatty acid deficient medium. It is rapidly induced in wild type cells that are supplemented with 14:0 and is repressed when cells are supplied with 16- and 18-carbon fatty acids. PMID- 8702486 TI - Effects of photo-oxidizing analogs of fluorescein on the sarcoplasmic reticulum Ca2+-ATPase. Functional consequences for substrate hydrolysis and effects on the partial reactions of the hydrolytic cycle. AB - Erythrosin B was used to photo-oxidize the sarcoplasmic reticulum Ca2+-ATPase. The ATPase activity is rapidly and irreversibly inhibited by photo-oxidation with erythrosin. This inhibition is protected by the presence of ATP during the photo oxidation period. After photo-oxidation, the steady-state phosphorylation by ATP remains almost unchanged, whereas phosphorylation by inorganic phosphate is impaired. The pseudo-first order rate constants for phosphorylation by 15 microM ATP at 25 degrees C are strongly inhibited when starting from either a Ca2+-bound or a Ca2+-free enzyme form, decreasing from 145 to 23 s-1 for the Ca2+-bound form and from 50 to 18 s-1 for the Ca2+-free form. Concurrently, the rate constants for dephosphorylation are also severely inhibited, changing from a fast double exponential to a very slow single exponential decay in the reverse direction and from a moderately slow single to a very slow single exponential decay in the forward direction. Ca2+ binding data show that the phosphorylated intermediate formed by the photo-oxidized enzyme contains two occluded Ca2+, and TNP-ATP fluorescence measurements indicate that it accumulates in a E1-P.Ca2-like conformation. Protection by ADP against glutaraldehyde-induced cross-linking indicates that ADP binding to Ca2+-ATPase is not impaired by photo-oxidation nor by free erythrosin. These data support the view that an ADP-insensitive, Ca2+ bound, slowly interconverting phosphoenzyme is formed. Thus, photo-oxidation with erythrosin B leads to impairment of phosphoryl transfer reactions and related conformational changes. PMID- 8702487 TI - Zn2+-stimulated sphingomyelinase is secreted by many cell types and is a product of the acid sphingomyelinase gene. AB - Mammalian sphingomyelinases have been implicated in many important physiological and pathophysiological processes. Although several mammalian sphingomyelinases have been identified and studied, one of these, an acidic Zn2+-stimulated sphingomyelinase (Zn-SMase) originally found in fetal bovine serum, has received little attention since its first and only report 7 years ago. We now show that Zn SMase activity is secreted by human and murine macrophages, human skin fibroblasts, microglial cells, and several other cells in culture and is markedly up-regulated during differentiation of human monocytes to macrophages. Remarkably, peritoneal macrophages from mice in which the acid SMase gene had been disrupted by homologous recombination secreted no Zn-SMase activity, indicating that this enzyme and the intracellular lysosomal SMase, which is Zn independent, arise from the same gene. Furthermore, skin fibroblasts from patients with types A and B Niemann-Pick disease, which are known to lack lysosomal SMase activity, also lack Zn-SMase activity in their conditioned media. Chinese hamster ovary cells stably transfected with a cDNA encoding lysosomal SMase massively overexpress both cellular lysosomal SMase and secreted Zn-SMase activities. Thus, Zn-SMase arises independently of alternative splicing, suggesting a post-translational process. In summary, a wide variety of cell types secrete Zn-SMase activity, which arises from the same gene as lysosomal SMase. This secreted enzyme may play roles in physiological and pathophysiological processes involving extracellular sphingomyelin hydrolysis. PMID- 8702488 TI - Functional Re-expression of laminin-5 in laminin-gamma2-deficient human keratinocytes modifies cell morphology, motility, and adhesion. AB - Herlitz junctional epidermolysis bullosa (H-JEB) is characterized by a reduced adherence of keratinocytes consequent to deficient expression of the extracellular adhesive ligand laminin-5. To complement the genetic defect causing H-JEB, we transferred an eukaryotic cassette expressing the cDNA for the gamma2 chain of laminin-5 into H-JEB keratinocytes in which the expression of the polypeptide is hampered by a homozygous mutation generating a premature termination codon. Transfection using adenovirus-polylysin-transferrin-DNA complexes resulted in a transient synthesis of the recombinant laminin gamma2 chain that associated with the endogenous alpha3 and beta3 chains to form laminin 5 molecules readily deposited on the tissue culture substrate. Furthermore, retroviral-mediated transduction of the gamma2 cDNA yielded persistent expression and polarized secretion of laminin-5. The protein incorporated into the basement membrane produced by the revertant cells inoculated subcutaneously in nude mice. In these transfectants, re-expression of laminin-5 induced changes in cell morphology and reorganization of focal adhesions that assumed the shape and distribution of the counterparts detected in normal keratinocytes. These observations correlated with an enhanced cell-substrate adhesion and a reduced motility of the transfected cells. Our results demonstrate that a restored expression of laminin-5 induces a phenotypic reversion of genetically altered H JEB keratinocytes and open new perspectives to the analysis of the mechanisms regulating adhesion of epithelial cells. PMID- 8702489 TI - Apolipoprotein B sequence requirements for hepatic very low density lipoprotein assembly. Evidence that hydrophobic sequences within apolipoprotein B48 mediate lipid recruitment. AB - We studied the structural requirements of apolipoprotein (apo) B for assembly of very low density lipoproteins (VLDL) using rat hepatoma McA-RH7777 cells expressing human apoB (h-apoB). Recombinant h-apoB48, like endogenous rat apoB48 (r-apoB48), was secreted as VLDL in addition to high density lipoproteins (HDL) by transfected cells, indicating that the N-terminal 48% of apoB contains sequences sufficient for VLDL assembly. Truncation of the C terminus of h-apo-B48 to -B42 or -B37 had little effect on the ability of apoB to assemble VLDL, whereas truncation to -B34 or -B29 markedly diminished or abolished VLDL formation. None of the truncations affected the integration of apoB into HDL. To determine whether the ability to assemble VLDL is governed by apoB length or by sequences beyond apoB29, we created chimeric proteins that contained human apoA-I and a segment derived from between the C-terminal 29 and 34%, 34 and 37%, or 37 and 42% of apoB100. The resulting chimeras, namely AI/B29-34, AI/B34-37, and AI/B37-42, were secreted by the transfected cells as lipoproteins with buoyant density (d < 1.006 g/ml), electrophoretic mobility (pre-beta), and size characteristics of human plasma VLDL. The chimeras could assemble discrete VLDL particles devoid of endogenous r-apoB100, and could actively recruit triglycerides and phospholipids into the lipoproteins. However, these chimeras were secreted inefficiently. Pulse-chase analysis showed that less than 5% of the newly synthesized AI/B proteins were secreted, and more than 70% was degraded intracellularly. Degradation of the chimeras could be blocked by the cysteine protease inhibitor N-acetyl-leucyl-leucyl-norleucinal, but the treatment did not enhance their secretion. Protease protection analysis of microsomes isolated from transfected cells indicated that >65% of AI/B chimeras (compared with <25% of r apoB100) were inaccessible to exogenous trypsin. These data suggest that the recruitment of large quantities of triglycerides during VLDL formation is not governed simply by apoB length, but is mediated by short hydrophobic sequences ranging from 152 to 237 amino acids (3-5%) of apoB. The existence of multiple such hydrophobic sequences within apoB48 may facilitate efficient assembly of hepatic VLDL particles. PMID- 8702490 TI - Undersulfation of proteoglycans synthesized by chondrocytes from a patient with achondrogenesis type 1B homozygous for an L483P substitution in the diastrophic dysplasia sulfate transporter. AB - Achondrogenesis type 1B is an autosomal recessive, lethal chondrodysplasia caused by mutations in the gene encoding a sulfate/chloride antiporter of the cell membrane (Superti-Furga, A., Hastbacka, J., Wilcox, W. R., Cohn, D. H., van der Harten, J. J., Rossi, A., Blau, N., Rimoin, D. L., Steinmann, B., Lander, E. S., and Gitzelmann, R.(1996) Nat. Genet. 12, 100-102). To ascertain the consequences of the sulfate transport defect on proteoglycan synthesis, we studied the structure and sulfation of proteoglycans in cartilage tissue and in fibroblast and chondrocyte cultures from a fetus with achondrogenesis 1B. Proteoglycans extracted from epiphyseal cartilage and separated on agarose gels migrated more slowly than controls and stained poorly with alcian blue. The patient's cultured cells showed reduced incorporation of [35S]sulfate relative to [3H]glucosamine, impaired uptake of sulfate, and higher resistance to chromate toxicity compared to control cells. Epiphyseal chondrocytes cultured in alginate beads synthesized proteoglycans of normal molecular size as judged by gel filtration chromatography, but undersulfated as judged by ion exchange chromatography and by the amount of nonsulfated disaccharide. High performance liquid chromatography analysis of chondroitinase-digested proteoglycans showed that sulfated disaccharides were present, although in reduced amounts, indicating that at least in vitro, other sources of sulfate can partially compensate for sulfate deficiency. A t1475c transition causing a L483P substitution in the eleventh transmembrane domain of the sulfate/chloride antiporter was present on both alleles in the patient who was the product of a consanguineous marriage. The results indicate that the defect of sulfate transport is expressed in both chondrocytes and fibroblasts and results in the synthesis of proteoglycans bearing glycosaminoglycan chains which are poorly sulfated but of normal length. PMID- 8702491 TI - Conversion of thymidylate synthase into an HIV protease substrate. AB - Thymidylate synthase (TS) is an essential enzyme of DNA metabolism. We have carried out an extensive insertional mutagenesis of the Escherichia coli TS gene (thyA) using three different methods. Insertion of exogenous sequences at unique restriction sites or at random positions produced defective mutants, whereas comparison of TS sequences from different species allowed us to identify six zones permissive for insertions of exogenous sequences. The insertion of Human immunodeficiency virus type 1 (HIV-1) protease substrate sequences into the permissive sites converted TS to an HIV-1 protease substrate, and the in vivo cleavage of these insertions by the cloned HIV-1 protease conferred a thymidylate synthase-deficient phenotype in some of our E. coli mutant strains. In agreement with crystallographic data, these results show that the permissive sites are located in regions of the TS protein not essential for enzyme activity and accessible to cleavage by HIV protease. These results also show that it is possible to control a growth phenotype in E. coli through the protease-mediated destruction of an essential metabolic enzyme. Because both wild type and thymidylate synthase-deficient phenotypes are selectable on the appropriate growth medium, these thyA mutants could be used for genetic selections of protease inhibitors and analysis of protease specificities. PMID- 8702492 TI - Effect of nucleotides, peptides, and unfolded proteins on the self-association of the molecular chaperone HSC70. AB - In a previous study, we showed that the molecular chaperone HSC70 self-associates in solution in a reversible and likely unlimited fashion. Here, we examine the influence of nucleotides, nucleotide analogs, peptides, and unfolded proteins on the self-association properties of this protein. Whereas in the presence of ADP, HSC70 exists as a slow, concentration- and temperature-dependent monomer-oligomer equilibrium, in the presence of ATP, the protein is essentially monomeric, indicating that ATP shifts this equilibrium toward the monomer by stabilizing the monomer. Dissociation of oligomers into monomers is also obtained with the slowly hydrolyzable ATP analogs, adenosine 5'-O-(thiotriphosphate) and 5'-adenylyl beta,gamma-imidodiphosphate, or the complex between ADP and the phosphate analog, BeF3, indicating that binding but not hydrolysis of ATP is necessary and sufficient for the stabilization of HSC70 monomer. Furthermore, binding of short peptides or permanently unfolded proteins to the peptide binding site of HSC70 promotes the dissociation of oligomers into monomers, suggesting that protein substrates are able to compete with HSC70 for the same binding site. Because the release of peptides or unfolded proteins from HSC70 has also been shown to require ATP binding, these results indicate that dissociation of oligomers is controlled by a mechanism similar to that of release of protein substrates and suggest that binding of HSC70 to itself occurs via the peptide binding site and mimics binding of HSC70 to protein substrates. PMID- 8702493 TI - The NTF2 gene encodes an essential, highly conserved protein that functions in nuclear transport in vivo. AB - The small protein p10/Ntf2p has been implicated in protein import in vitro (Moore, M. S., and Blobel, G. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 10212 10216; Paschal, B. M., and Gerace, L.(1995) J. Cell Biol. 129, 925-937). Here we present the first evidence that demonstrates an essential in vivo role for the NTF2 gene product in nuclear transport. The NTF2 locus was identified in a screen for temperature-sensitive Saccharomyces cerevisiae mutants defective in the localization of nuclear proteins. Genetic analysis demonstrates that the NTF2 gene is essential for viability in budding yeast. Two temperature-sensitive mutants, ntf2-1 and ntf2-2, that each contain single point mutations in highly conserved amino acid residues show defects in the localization of nuclear proteins but not in the export of poly(A)+ RNA following a shift to the nonpermissive temperature. An epitope-tagged version of Ntf2p was used to show that the protein is concentrated at the nuclear envelope. Finally, the human gene under the control of the yeast promoter fully substitutes for the deleted yeast gene. Taken together, these results demonstrate the exquisite functional conservation of this protein throughout evolution and indicate a critical in vivo role in nuclear transport. PMID- 8702494 TI - Condensation of rat telomere-specific nucleosomal arrays containing unusually short DNA repeats and histone H1. AB - Vertebrate telomeres contain arrays of nucleosomes with unusually short and regular repeat lengths (Makarov, V. L., Lejnine, S., Bedoyan, J., and Langmore, J. P.(1993) Cell 73, 775-787; Lejnine, S., Makarov, V., and Langmore, J. P. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 2393-2397). In order to better define the specific structural features of telomere chromatin, we examined the condensation and H1 content of telomere nucleoproteins from rat liver. Velocity sedimentation analysis shows that telomeric nucleosome arrays condense with increasing ionic strength and molecular weight in a manner comparable with that of bulk chromatin despite the very short repeat length. However, these condensed structures do not exhibit the approximately 100-base pair deoxyribonuclease II repeat characteristic of condensed bulk chromatin. Frictional coefficient calculations suggest that telomere-specific higher order structure is more compact than bulk chromatin. Nucleoprotein gel electrophoresis shows that telomeric dinucleosomes from soluble chromatin contain H1. Finally, direct isolation and analysis of telomere nucleoproteins from formaldehyde-cross-linked nuclei indicate the presence of core histone proteins and H1. These results are consistent with the view that a major fraction of the long telomeres of rat are organized as specialized nucleosome arrays with features similar but not identical to those of bulk chromatin. PMID- 8702495 TI - Directed mutagenesis of chloroplast ribulose-1,5-bisphosphate carboxylase/oxygenase. Loop 6 substitutions complement for structural stability but decrease catalytic efficiency. AB - The structure of active-site loop 6 plays a role in determining the CO2/O2 specificity of chloroplast ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco, EC 4.1.1.39). Rubisco from the green alga Chlamydomonas reinhardtii differs from higher plant Rubisco within the loop 6 region, and the C. reinhardtii enzyme has a CO2/O2 specificity 25% lower than that of higher plant enzymes. To examine whether differences in sequence may account for differences in catalytic efficiency, we focused on a conserved pair of residues that are in van der Waals contact at the base of loop 6. C. reinhardtii Rubisco contains Leu 326 and Met-349, whereas higher plant enzymes contain Ile-326 and Leu-349. By employing in vitro mutagenesis and chloroplast transformation, L326I and M349L substitutions were created within the Rubisco large subunit of C. reinhardtii. M349L had little effect, but L326I destabilized the holoenzyme in vivo and in vitro. When present together, the M349L substitution partially alleviated the instability resulting from the L326I substitution, but caused a 21% decrease in CO2/O2 specificity and a 74% decrease in the Vmax of carboxylation. Interactions between loop 6 and other structural regions are likely to be responsible for both holoenzyme stability and catalytic efficiency in higher plant Rubisco enzymes. PMID- 8702496 TI - Cloning and characterization of PET100, a gene required for the assembly of yeast cytochrome c oxidase. AB - The biogenesis of cytochrome c oxidase in Saccharomyces cerevisiae requires a protein encoded by the nuclear gene, PET100. Cells carrying a recessive mutation (pet100-1) in PET100 are respiratory deficient and have reduced levels of cytochrome c oxidase activity. The PET100 gene has been cloned by complementation of pet100-1, sequenced and disrupted. PET100 is located adjacent to the PDC2 gene on chromosome IV and contains an open reading frame of 333 base pairs. The PET100 protein contains a possible membrane-spanning segment and a putative mitochondrial import sequence at its NH2 terminus. A strain carrying a null mutation in PET100 lacks cytochrome c oxidase activity and assembled cytochromes a and a3, but the other respiratory chain carriers are present. The respiratory deficient phenotype of this strain is not rescued by added hemin or heme A. These findings indicate that the mutation is specific for cytochrome c oxidase and does not affect the biosynthesis of heme A. In addition, mitochondria from the strain carrying a null mutation in PET100 contain each of the subunit polypeptides of cytochrome c oxidase. Together, these findings suggest that PET100p is not required for the synthesis or localization of cytochrome c oxidase subunits to mitochondria, but is required at a later step in their assembly into an active holoenzyme. PMID- 8702497 TI - Activation of the human DNA polymerase beta promoter by a DNA-alkylating agent through induced phosphorylation of cAMP response element-binding protein-1. AB - Treatment of cells with the DNA-alkylating agent N-methyl-N'-nitro-N nitrosoguanidine (MNNG) induces expression of the endogenous mammalian DNA polymerase beta (beta-pol) gene and of the cloned promoter in transient expression studies. The lone cAMP response element (CRE) in the core promoter, along with functional protein kinase A, is critical for the MNNG-induced up regulation. Recently, we described a kinetic mechanism for transcriptional regulation of the beta-pol promoter in vitro and found that CRE-binding protein (CREB) from MNNG-treated cells differentially up-regulates the promoter by stimulating formation of closed preinitiation complex (RPc). Here, using a CRE dependent chimeric beta-pol promoter, we purified the RPc assembled with nuclear extract from MNNG-treated and control HeLa cells. Comparison of proteins in the purified RPc samples revealed that the MNNG induction is associated with a strong increase in the Ser133-phosphorylated form of recombinant CREB (CREB-1). CREB depletion of the nuclear extracts diminished transcriptional activity, and addition of purified Ser133-phosphorylated CREB-1 restored activity, whereas unphosphorylated CREB-1 did not. Addition of phosphorylated CREB-1 to the control cell extract mimicked the MNNG-induced up-regulation of transcriptional activity. These results indicate that phosphorylation of CREB-1 is the probable mechanism of activation of the beta-pol promoter after treatment of cells with the DNA alkylating agent MNNG. PMID- 8702498 TI - Enhanced effectiveness of copper ion buffering by CUP1 metallothionein compared with CRS5 metallothionein in Saccharomyces cerevisiae. AB - The bakers' yeast Saccharomyces cerevisiae contains a metallothionein (MT) gene family comprised of the amplified CUP1 locus and the single copy CRS5 gene. We demonstrate that CUP1 plays the dominant role in copper detoxification. A single copy of CUP1 was far more effective in conferring copper resistance than was CRS5. The CUP1 promoter contributes to this resistance; in a promoter exchange experiment, the Crs5 MT conferred strong copper resistance when its expression was driven by the CUP1 promoter, and conversely, the CRS5 promoter reduced the effectiveness of Cup1 MT. Unlike CUP1, the CRS5 promoter appears to be refractory to high concentrations of copper. The CUP1 coding sequences also contribute to copper tolerance, presumably reflecting the enhanced binding avidity of Cup1 MT for Cu(I) ions. In studies with the bathocuproine Cu(I) chelator, the Cu(I) ions bound to Crs5 were kinetically more labile than the Cu(I) binding to Cup1. Our findings are consistent with the assembly of Crs5 into two metal-binding clusters, similar to mammalian MTs, but unlike Cup1. Overall, the striking differences in gene structure, regulation, and function of CUP1 and CRS5 are remarkably reminiscent of the MTI and MTII genes of the pathogenic yeast Candida glabrata. PMID- 8702499 TI - Gbetagamma transduces [Ca2+]i oscillations and Galphaq a sustained response during stimulation of pancreatic acinar cells with [Ca2+]i-mobilizing agonists. AB - A central unresolved question in agonist-evoked [Ca2+]i signaling is the pathway by which [Ca2+]i oscillations and a sustained response are transduced. We show here that activation of Gbetagamma signal [Ca2+]i oscillations and activation of Galphaq signal a sustained response during stimulation by a number of Ca2+ mobilizing agonists. Thus, infusion of purified Gbetagamma into pancreatic acinar cells through a patch pipette evokes [Ca2+]i oscillations by Ca2+ release from internal stores, which were inhibited by two independent scavengers of Gbetagamma, the beta-adrenergic receptor kinase fragment, and a mutated Galphai1G203A. These proteins, as well as an inhibitory antibody against Galphaq/11, prevent [Ca2+]i oscillations and the sustained response when applied before cell stimulation, possibly by preventing the dissociation of Gq into its subunits. After cell stimulation and dissociation of Gq into Gbetagamma and Galphaq, scavenging Gbetagamma stabilized the sustained response and inhibited reassociation of the subunits on termination of cell stimulation with antagonist, whereas scavenging Galphaq inhibited the sustained response and uncovered the Gbetagamma-dependent oscillations. These findings provide a general mechanism by which Ca2+-mobilizing agonists can control the type of [Ca2+]i signal to be transduced to the cell interior. PMID- 8702500 TI - Immunosuppressant target protein FKBP12 is required for P-glycoprotein function in yeast. AB - The mammalian P-glycoprotein (Pgp) is a approximately 170-kDa membrane protein that mediates multidrug resistance in many chemotherapy-resistant tumors by effluxing toxic compounds from the cell. Pgp homologs are expressed in many organisms, from bacteria to yeast and mammals. Previous studies established a model system to analyze the function of murine, human, and Plasmodium falciparum Pgp by heterologous expression in the yeast Saccharomyces cerevisiae. However, such studies have been hampered by the inherent resistance of yeast cells to chemotherapeutic agents. We find that an erg6 mutation, which blocks the final synthetic step of the membrane sterol ergosterol, renders yeast sensitive to anthracyclines and dactinomycin, clinically relevant Pgp substrates. We demonstrate that expression of the murine mdr3 gene confers dactinomycin resistance in both the erg6 mutant yeast strain and in an erg6 rad52 DNA repair mutant yeast strain. Similarly, murine mdr3 expression confers resistance to the immunosuppressants cyclosporin A (CsA) and FK506 in a CsA-FK506-sensitive vph6 mutant yeast strain. CsA and FK506 are known to partially overcome Pgp-mediated drug resistance, suggesting the targets of these drugs might regulate Pgp function. We find that both murine mdr3 and the yeast Pgp homolog STE6 function in yeast mutants lacking the CsA target proteins cyclophilin A and calcineurin. In contrast, murine mdr3 function was severely compromised in yeast mutants lacking the FK506/rapamycin target protein FKBP12. Both wild-type FKBP12 and an F43Y FKBP12 mutant with reduced prolyl isomerase activity supported mdr3 function. Our results support the model that immunosuppressants reverse multidrug resistance by competing with other Pgp substrates but reveal that inhibition of FKBP12-dependent Pgp function may also contribute to reversal of multidrug resistance by FK506 and rapamycin. PMID- 8702501 TI - Domains of DnaA protein involved in interaction with DnaB protein, and in unwinding the Escherichia coli chromosomal origin. AB - DnaA protein of Escherichia coli is a sequence-specific DNA-binding protein required for the initiation of DNA replication from the chromosomal origin, oriC. It is also required for replication of several plasmids including pSC101, F, P-1, and R6K. A collection of monoclonal antibodies to DnaA protein has been produced and the primary epitopes recognized by them have been determined. These antibodies have also been examined for the ability to inhibit activities of DNA binding, ATP binding, unwinding of oriC, and replication of both an oriC plasmid, and an M13 single-stranded DNA with a proposed hairpin structure containing a DnaA protein-binding site. Replication of the latter DNA is dependent on DnaA protein by a mechanism termed ABC priming. These studies suggest regions of DnaA protein involved in interaction with DnaB protein, and in unwinding of oriC, or low-affinity binding of ATP. PMID- 8702502 TI - Novel covalent chaperone complexes associated with human chorionic gonadotropin beta subunit folding intermediates. AB - Molecular chaperones facilitate the folding of proteins in the endoplasmic reticulum (ER) of mammalian cells. The glycoprotein hormone chorionic gonadotropin beta subunit is a secretory protein whose folding in the ER has been demonstrated (Huth, J. R., Mountjoy, K., Perini, F., and Ruddon, R. W.(1992) J. Biol. Chem. 267, 8870-8879). Because folding of wild type hCG-beta subunit occurs in the ER with a t1/2 = 4-5 min, stable association of ER chaperones with hCG beta have been difficult to detect probably because they have a short half-life. However, beta-chaperone complexes containing the ER chaperones BiP, ERp72, and ERp94 have been detected in slow folding mutants of hCG-beta subunit that lack both of the N-linked oligosaccharides (Feng, W., Matzuk, M. M., Mountjoy, K., Bedows, E., Ruddon, R. W., and Boime, I. (1995) J. Biol. Chem. 270, 11851-11859). The questions addressed here are 1) whether the detection of chaperone-containing complexes is related to the absence of carbohydrate or to the rate of hCG-beta subunit folding, 2) whether such complexes are dead-end or whether they lead to formation of a secreted, mature hCG-beta form, and 3) what the nature of the hCG beta-chaperone binding is. The data obtained indicate that the amount of detectable hCG-beta-chaperone complexes correlates with the rate or extent of folding, that the complexes of hCG-beta with ER chaperones lead to the formation of secretable beta, and that the complexes of hCG-beta with chaperones involve the formation of intermolecular disulfide bonds. PMID- 8702503 TI - Direct identification of naturally processed autoantigen-derived peptides bound to HLA-DR15. AB - Biochemical analysis of HLA class II-associated peptides from antigen-pulsed cells is a potentially useful approach to the analysis of antigen processing and presentation because it examines directly which antigen-derived peptides are presented. This is especially advantageous in the analysis of self-antigen presentation where conventional approaches utilizing antigen-specific T cells may be biased by the presence of self-tolerance. However, successful biochemical analysis has been reported for only one exogenous antigen and no autoantigens. We have used a novel analytical approach coupling biochemical data with the reported properties of class II-associated peptides to characterize the peptides derived from a clinically relevant autoantigen presented on the disease-associated class II type. Incubating the target of autoimmune attack in patients with Goodpasture's disease, the 230-amino acid NC1 domain of the alpha3 chain of type IV collagen (Goodpasture antigen, alpha3(IV)NC1), with human B cells homozygous for HLA-DR15, the allele carried by 80% of patients, we find that alpha3(IV)NC1 is presented as at least two sets of three to five peptides centered on common core sequences (nested sets). Synthetic peptides containing these core sequences bind to HLA-DR15 with intermediate affinity (IC50, 1.1-6 microM). PMID- 8702504 TI - Analysis of the megakaryocyte glycoprotein IX promoter identifies positive and negative regulatory domains and functional GATA and Ets sites. AB - The glycoprotein (GP) Ib-V-IX multisubunit complex binds to von Willebrand factor and mediates the adhesion of platelets to the subendothelium of damaged blood vessels. Expression of the GPIX subunit is required for stability of the complex, and its absence in platelets is associated with the rare bleeding disorder Bernard-Soulier syndrome. Comparative analyses indicate that the four GPIb-V-IX subunits are members of the leucine-rich repeat family and suggest that GPIX resembles a possible primitive progenitor of this group. To characterize GPIX transcriptional regulation, a series of 5' deletion constructs was made linking the GPIX upstream flanking sequence to the luciferase marker gene, and promoter activity was measured in transiently transfected human erythroleukemia cells. This analysis identified two negative regulatory domains between -686 to -423 and -311 to -203 and two positive regulatory domains at -323 to -311 and -151 to -100 relative to the GPIX transcription start site. In addition, site-directed mutagenesis experiments and in vitro gel retardation assays identified Ets and GATA elements at -42 and -65, which positively regulate GPIX promoter activity and specifically bind nuclear factors derived from human erythroleukemia cells. DNase I protection experiments identified a protein-dependent "footprint" and hypersensitive site within the GPIX Ets sequence. These results provide a framework for comparison of the GPIX promoter with others of the GPIb-V-IX system, other megakaryocyte-specific genes, and other members of the leucine-rich repeat family.